PMID- 20159495 TI - The generalizability and specificity of theory. PMID- 20159496 TI - Social and emotional impairment in children and adolescents with ADHD and the impact on quality of life. AB - This review provides an overview as to how the social and emotional impairments involved in Attention-Deficit/Hyperactivity Disorder affect the quality of life of patients and their families. A model of three categories into which the emotional difficulties fall, and how they impair quality of life, is also presented. PMID- 20159497 TI - The impact of parental deployment on child social and emotional functioning: perspectives of school staff. AB - PURPOSE: Since 2001, many military families have experienced multiple and extended deployments. Little is known about the effect of parental deployment on the well-being of children, and few, if any, studies to date have engaged school staff to understand whether and how parental deployments affect the behavioral, social, and emotional outcomes of youth in the school setting. METHODS: Focus groups and semi-structured interviews were conducted with teachers, counselors, and administrative staff at schools serving children from U.S. Army families (N=148 staff). Participants were queried about the academic, behavioral, and emotional issues faced by children of deployed soldiers. Data were analyzed for themes in these areas, with attention to differences by service component (Active Component vs. Army Reserve and National Guard). RESULTS: Although some children seem to be coping well with deployment, school staff felt that children's anxiety related to parental absence, increased responsibilities at home, poor mental health of some nondeployed parents, and difficulty accessing mental health services affected the ability of other students to function well in school. CONCLUSIONS: School staff felt that parental deployment negatively affected social and emotional functioning for some children and youth, although they felt others were coping well. Future research should examine factors related to youth outcomes during parental deployment (e.g., mental health of the non-deployed parent) and assess the effects of deployment on other measures of behavior such as school engagement and academic performance. PMID- 20159498 TI - A longitudinal study of sexual risk behavior among the adolescent children of HIV positive and HIV-negative drug-abusing fathers. AB - PURPOSE: This is a longitudinal study of the precursors of sexual risk behavior among a cohort of adolescent children of HIV-positive and HIV-negative drug abusing or drug-dependent fathers. METHODS: Individual structured interviews were administered to 296 drug-abusing or drug-dependent fathers, 43% of whom were HIV positive, and an adolescent child of each father (mean age = 16.3 years; SD = 2.8). Adolescents were reinterviewed approximately 1 year later, at Time 2. RESULTS: Structural equation modeling showed multiple direct and indirect pathways from psychosocial factors to adolescent sexual risk behavior (sexually active, number of sexual partners, and frequency of condom use). Greater paternal drug addiction and infection with HIV/AIDS, and the youth's perception of environmental hostility (discrimination and victimization), were both related to increased adolescent maladjustment and substance use. Greater paternal drug addiction and infection with HIV/AIDS also were associated with a weaker father child mutual attachment, which was linked with increased adolescent maladjustment and substance use. Greater perceived environmental hostility (discrimination and victimization), a weak father-child relationship, and greater adolescent maladjustment and substance use had direct pathways to adolescent sexual risk behavior. CONCLUSIONS: Findings suggest complex interrelationships among paternal, environmental, social, personal, and substance use factors as longitudinal predictors of sexual risk behavior in children whose fathers abuse or are dependent upon drugs. The importance of perceived environmental hostility, the father-child relationship, and adolescent maladjustment and substance use may have implications for public policy as well as prevention and treatment programs. PMID- 20159499 TI - Factors associated with event level anal sex and condom use during anal sex among adolescent women. AB - PURPOSE: To examine the distribution of and factors associated with event-level heterosexual anal sex and of event-level condom use during anal sex among adolescent women. METHODS: Adolescent women (N=387; age 14-17 years at enrollment) were recruited from primary care clinics for a longitudinal cohort study of sexually transmitted infections and sexual behavior. Data were taken from daily sexual diaries; generalized estimating equation logistic regression assessed the likelihood of anal sex or condom use during anal sex on a given day. RESULTS: Heterosexual anal intercourse is a small but nonrandom event-level component in adolescent women's sexual behavior. About 30% of anal sex events were condom protected. Mood, partner, and situational factors predicted anal sex, but not condom use during anal sex; within-day and recent behavior factors were the strongest influences on both outcomes. CONCLUSIONS: Our findings suggest the importance of providers' screening adolescent women patients during office visits about anal sex and about condom use during anal sex, as well as asking questions about the context of these behaviors to appropriately tailor risk reduction counseling. PMID- 20159500 TI - Update on age at menarche in Italy: toward the leveling off of the secular trend. AB - PURPOSE: To update the information on age at menarche in the Italian population and to verify the influence of genetic, nutritional, and socioeconomic factors on menarcheal age. Recent studies suggest that the magnitude of the secular trend toward an earlier age at menarche is slackening in industrialized countries. METHODS: This multicenter study was conducted on a large, population-based sample of Italian high school girls (n = 3,783), using a self-administered questionnaire. The questionnaire was used to gather information on the girls, including demography, anthropometry, menarcheal date, regularity of menses, behavioral habits, and physical activity. The questionnaire was also used to gather information on parents, including demography and mothers' and sisters' menarcheal ages. The median age at menarche and its 95% confidence interval were estimated by means of Kaplan-Meier survival analysis. To identify the independent predictive factors of age at menarche, multivariate mixed-effects models were applied. RESULTS: The median age at menarche of the subjects was 12.4 years (95% confidence interval: 12.34-12.46). The girls had their first menses approximately one-quarter of a year (median-0.13) earlier than did their mothers (p < .0001). Among all variables, parents' birth area, body mass index, family size, and the mother's menarcheal age were significantly and independently associated with age at menarche. CONCLUSIONS: This study confirmed the reduction in the trend toward earlier menarche in Italy. The results also confirmed that genetic and nutritional factors are strong markers for early menarche. Currently, socioeconomic factors do not seem to play as significant a role as in the past. PMID- 20159501 TI - Body mass index and waist-to-height changes during teen years in girls are influenced by childhood body mass index. AB - PURPOSE: This study examined longitudinal changes in waist-to-height ratio and components of body mass index (BMI) among young and adolescent girls of black and white race/ethnicity. METHODS: Girls were recruited at age 9 years through the National Heart, Lung, and Blood Institute Growth and Health Study (NGHS) and were followed annually over 10 years. Girls were grouped into low (<20(th) percentile), middle, and high (>80(th) percentile) BMI on the basis of race specific BMI percentile rankings at age 9, and low, middle, and high waist-to height ratio, on the basis of waist-to-height ratio at age 11. BMI was partitioned into fat mass index (FM) and fat-free mass index (FMI). RESULTS: Girls accrued fat mass at a greater rate than fat-free mass, and the ratio of fat mass to fat-free mass increased from ages 9 through 18. There was a significant increase in this ratio after age at peak height velocity. Participants with elevated BMI and waist-to-height ratios at age 18 tended to have been elevated at ages 9 and 11, respectively. There were strong correlations between BMI at age 9 with several outcomes at age 18: BMI (.76) and FMI (.72), weaker but significant with FFMI (.37), and ratio of fat mass to fat-free mass (.53). In addition, there was significant tracking of elevated BMI from ages 9 through 18. CONCLUSIONS: In girls, higher BMI levels during childhood lead to greater waist-to-height ratios and greater than expected changes in BMI by age 18, with disproportionate increases in fat mass. These changes are especially evident in adolescent girls of black race/ethnicity and after the pubertal growth spurt. PMID- 20159502 TI - Impact of School-Based Health Center use on academic outcomes. AB - PURPOSE: The purpose of this study was twofold: (1) to examine the effects of School-Based Health Center (SBHC) use on academic outcomes for high school students, using a well-controlled, longitudinal model, and (2) to examine whether SBHC medical and mental health service use differentially impacts academic outcomes. METHODS: Analyses used a latent variable growth curve modeling approach to examine longitudinal outcomes over five school semesters for ninth grade SBHC users and nonusers from Fall 2005 to Fall 2007 (n = 2,306). Propensity score analysis was used to control for self-selection factors in the SBHC user and nonuser groups. RESULTS: Results indicated a significant increase in attendance for SBHC medical users compared to nonusers. Grade point average increases over time were observed for mental health users compared to nonusers. Discipline incidents were not found to be associated with SBHC use. CONCLUSIONS: SBHC use was associated with academic improvements over time for a high-risk group of users. The moderating effect of type of use (medical and mental health) reinforces the importance of looking at subgroups when determining the impact of SBHC use on outcomes. PMID- 20159503 TI - Discrepant trends in mental health complaints among younger and older adolescents in Sweden: an analysis of WHO data 1985-2005. AB - PURPOSE: To elucidate the time trends in self-reported mental health complaints (internalizing problems) among school children in Sweden during a time characterized by economic downturns and upturns, with a focus on possible differences across grades and genders. METHODS: The study uses nationwide and repeated cross-sectional data collected five times during 1985-2005 among students in Sweden in grades 5, 7, and 9. The number of participating students each year varied between 2,933 and 4,421. The attrition rates varied between 10% and 15% in the participating schools. Data were subjected to descriptive analysis and multinomial logistic regression using a composite measure of self-reported mental health complaints. RESULTS: The study results show significantly higher rates of mental health complaints in 2005/2006 compared with 1985/1986 among older adolescents, in particular girls, whereas the rates are almost unchanged among younger boys and girls. Only among girls in grade 9 has there been a successively (linear) increase of mental health complaints across years of investigations. CONCLUSIONS: The increasing rates of mental health complaints among older adolescents, in particular girls, are a cause for concern and a challenge for public health work. By showing discrepant time trends among younger and older adolescents, the results of the study nuance the predominant and unambiguous notions about continuously deteriorating mental health among children and adolescents in Sweden. To address hypotheses concerning the causes of the discrepant time trends, suggestions are made for comparative cross-country analyses based on data from Sweden and other European countries. PMID- 20159504 TI - Adolescents' perceived risk of dying. AB - PURPOSE: Although adolescents' expectations are accurate or moderately optimistic for many significant life events, they greatly overestimate their chances of dying soon. We examine here whether adolescents' mortality judgments are correlated with their perceptions of direct threats to their survival. Such sensitivity would indicate the importance of ensuring that adolescents have accurate information about those threats, as well as the psychological support needed to deal with them. METHODS: Data from two separate studies were used: a national sample of 3,436 14-18-year-old adolescents and a regional sample of 124 seventh graders and 132 ninth graders, 12-16 years old. Participants were asked about their chance of dying in the next year and before age 20, and about the extent of various threats to their physical well-being. RESULTS: Adolescents in both samples greatly overestimated their chance of dying. Those mortality estimates were higher for adolescents who reported direct threats (e.g., an unsafe neighborhood). Thus, adolescents were sensitive to the relative size of threats to their survival, but not to the implications for absolute risk levels. CONCLUSIONS: Contrary to the folk wisdom that adolescents have a unique sense of invulnerability, the individuals studied here reported an exaggerated sense of mortality, which was highest among those reporting greater threats in their lives. Such fears could affect adolescents' short-term well-being and future planning. PMID- 20159505 TI - Point-of-care testing for sexually transmitted infections increases awareness and short-term abstinence in adolescent women. AB - PURPOSE: To evaluate the effect of point-of-care (POC) testing for sexually transmitted infections (STIs) on reported awareness of test results and STI risk reduction behaviors in adolescents. METHODS: Adolescent and young adult women aged 14-21 years were recruited from the Emergency Department or Teen Health Clinic for this longitudinal study and were tested for STIs. Baseline demographics, risk behaviors, treatment, POC tests (wet mount and rapid antigen tests for Trichomonas vaginalis), and other STI test results (available 24-48 hours postvisit) were measured. These were compared to subject's report of test results, abstinence, partner discussion, and partner testing during a postvisit telephone contact. RESULTS: Of 294 subjects, 155 (53%) were contacted: 65 (42%) had a positive STI test result; 28 (43%) were POC positive; and 52 (33.5%) believed their STI results were positive. A positive POC test result increased the proportion of subjects aware of being positive for an STI (89 vs 21%, p < .01). Postvisit, 62% reported abstinence, 82% discussed testing with her partner, and 48% reported partner testing. Predictors of abstinence included a positive POC test result (adjusted odds ratio (AOR) = 4.6, confidence interval (CI) = 1.5 13.6, prior abstinence of >14 days (AOR = 3.9, CI = 1.7-9.0), and black race (AOR = 3.5, CI = 1.2-9.7). Women who believed their STI results were positive were more likely to report partner discussion (odds ratio [OR] = 3.0, CI = 1.0-8.8) and partner testing (OR = 5.1, CI = 2.4-11.2). CONCLUSIONS: Awareness of STI results increases with POC testing. Effective communication of results can increase patient understanding and compliance with risk reduction strategies, which may affect the STI epidemic. PMID- 20159506 TI - Adherence to scheduled appointments among HIV-infected female youth in five U.S. cities. AB - OBJECTIVE: Identify factors associated with appointment-keeping among HIV infected adolescents and young adults. METHODS: HIV-infected adolescent and young adult females in five U.S. cities were followed for a period of 18 months to examine adherence to scheduled clinic visits with their HIV care provider. Psychosocial and behavioral factors that have been shown in other populations to influence appointment adherence were measured at baseline and follow-up visits using an audio computer-assisted self-interview questionnaire. These factors included mood disorder, depressive symptoms, social network support, healthcare satisfaction, disease acceptance, HIV stigma, alcohol use, and marijuana use. CD4 count and prescription of antiretroviral therapy medication were also monitored to understand the influence of health status on appointment- keeping. RESULTS: Participants included 178 youth with a mean age of 20.6 years. Forty-two percent had clinically significant depressive symptoms, 10% had a diagnosable mood disorder, 37% reported marijuana use in the last 90 days, and 47% reported alcohol use. Overall, participants attended 67.3% of their scheduled visits. Controlling for age and health status, marijuana use was the only variable that was associated with appointment-keeping behavior. CONCLUSIONS: Considering the importance of appointment-keeping for maintaining personal health and preventing further transmission, screening HIV-infected adolescents for marijuana use could help alert providers of this specific barrier to visit compliance. PMID- 20159508 TI - The future adolescent medicine workforce: a survey of current adolescent medicine fellows. AB - PURPOSE: To ensure a workforce of board-certified adolescent medicine (AM) specialists, the reasons why physicians choose this specialty must be understood. This study sought to develop a profile of AM fellows and to delineate common experiences that influenced them to seek AM training. METHODS: In April 2008, all AM fellows in Accreditation Council of Graduate Medical Education-accredited fellowships and those committed to begin training in July 2008 or after were electronically surveyed. Survey links were e-mailed to fellowship program directors who forwarded them to current and incoming fellows. The survey included questions regarding demographics, training experiences, career expectations, and attitudes and beliefs about AM. Open-ended questions allowed fellows to describe influential experiences. Means, medians, and percentages were calculated. Three independent reviewers identified themes in open-ended questions. RESULTS: Fifty two respondents completed the survey: 42 of 59 (71%) current fellows, 10 incoming fellows (approximately 35%). Sixty-seven percent reported first exposure to AM before or during medical school and 31% decided to pursue AM before starting residency. Qualitative responses revealed the importance of interactions with those established in the field, the intrinsic appeal of adolescents and their clinical issues, and the inherent personal qualities of the respondents. Many spoke of multiple exposures to AM or adolescents through high school activities, volunteer work, personal experiences, or during medical training. CONCLUSIONS: A variety of experiences with AM and/or adolescents is important in establishing interest in AM as a career. Serving as mentors and capitalizing on brief role modeling opportunities could promote further interest in AM fellowship training. PMID- 20159507 TI - Adolescent offspring of mothers with chronic fatigue syndrome. AB - PURPOSE: The goal of this study was to determine whether adolescent offspring of mothers with chronic fatigue syndrome (CFS) have higher prevalence of CFS and report more fatigue, greater pain sensitivity, more sleep problems, and poorer cardiopulmonary fitness in comparison with offspring with no exposure to maternal CFS. METHODS: A total of 26 adolescent offspring of 20 mothers diagnosed with CFS were compared with 45 adolescent offspring of 30 age-matched healthy control mothers. Study measures included structured interviews and medical and laboratory examinations for CFS; tender point examination; maximum oxygen uptake and perceived exertion; dolorimetry pain ratings; and questionnaires on fatigue severity and sleepiness. RESULTS: In comparison with offspring of healthy mothers, those exposed to mothers with CFS reported higher prevalence of fatigue of at least 1-month duration (23% vs. 4%), fatigue of 6 months or longer (15% vs. 2%), and met criteria for CFS (12% vs. 2%), although these differences only approached statistical significance. CFS and healthy mothers differed on almost all study outcomes, but offspring groups did not differ on measures of current fatigue severity, pain sensitivity, sleep, mean number of tender points, and cardiopulmonary fitness. CONCLUSIONS: The higher prevalence of fatiguing states in offspring of CFS mothers, despite the lack of statistical significance, suggests that familial factors may potentially play a role in developing chronically fatiguing states. Alternately, perturbations in pain sensitivity and cardiopulmonary fitness may be consequences of CFS. Future studies should focus on examining the impact of maternal CFS and associated disability on psychosocial functioning of offspring. PMID- 20159509 TI - Does the "healthy immigrant effect" extend to smoking in immigrant children? AB - The "healthy immigrant effect" may apply to lifestyle-related behaviors in immigrant children. In a cross-sectional study of 1,959 children aged 9-12 years, the number of years lived in Canada was related to an increased risk of smoking among immigrant children. Interventions may be needed for immigrant children to prevent the adoption of unhealthy behaviors prevalent in their new host environments. PMID- 20159510 TI - Using mobile phones for adolescent research in low and middle income countries: preliminary findings from the birth to twenty cohort, South Africa. AB - Mobile phones enable engagement with adolescents through a familiar medium. Survey data are presented from 2,023 South African adolescents who were asked about phone ownership, usage, and their willingness to divulge sensitive information in short message service surveys. Barriers to participation are addressed as are recommendations for follow-up research. PMID- 20159511 TI - Pancreatic cancer: foreword. PMID- 20159512 TI - Pancreatic cancer: preface. PMID- 20159513 TI - PET and PET/CT for pancreatic malignancies. AB - FDG PET imaging is useful for preoperative diagnosis of pancreatic carcinoma in patients with suspected pancreatic cancer in whom CT fails to identify a discrete tumor mass or in whom FNAs are nondiagnostic. FDG PET imaging is useful for M staging and restaging by detecting CT occult metastatic disease, allowing noncurative resection to be avoided in this group of patients. FDG PET can differentiate post-therapy changes from recurrence and holds promise for monitoring neoadjuvant chemoradiation therapy. The technique is less useful in periampullary carcinoma and marginally helpful in staging except for M staging. As with other malignancies, FDG PET is complementary to morphologic imaging with CT, therefore, integrated PET/CT imaging provides optimal images for interpretation and thus more optimal patient care. PMID- 20159514 TI - Endoscopic ultrasound staging and novel therapeutics for pancreatic cancer. AB - Pancreatic cancer remains a challenging disease, being the fourth leading cause of death in both men and women in the United States. Patients with pancreatic cancer present with symptoms including jaundice, pruritus, and weight loss, which often herald advanced disease with little chance for curative resection. Multiple imaging modalities are used to diagnose and stage pancreatic cancer. This article discusses the utility of endoscopic ultrasound (EUS) for diagnosis and staging, and introduces novel EUS-guided therapeutic options for the treatment of pancreatic cancers. EUS-guided fine-needle injection of chemotherapy agents is a promising development in pancreatic tumor treatment. PMID- 20159516 TI - The management of intraductal papillary mucinous neoplasms of the pancreas. AB - Intraductal papillary mucinous neoplasms (IPMN) are mucinous cystic tumors of the pancreas, which were first classified into a unified diagnosis by the World Health Organization in 1996. These lesions originate from the cells of the pancreatic ductal system and may grossly or microscopically involve the pancreatic ducts in a diffuse or multifocal fashion. As experience with IPMN increases, it is becoming more evident that this process presents as a spectrum of neoplasia with significant variation regarding the clinical and radiologic presentation, malignant potential, and disease-specific outcome. IPMN encompasses a spectrum of precursor lesions, from adenoma to intraductal carcinoma to invasive cancer, with molecular data supporting the premise that this dysplastic process has the potential to progress from low-grade dysplasia to invasive carcinoma. Controversy over the management of IPMN exists because of the difficulty in obtaining a preoperative histologic diagnosis, the broad spectrum of neoplasia, the lack of understanding as to the frequency and time to malignant progression. This article describes the radiologic and histopathologic classification system of IPMN; the biologic behavior of these lesions, and the diagnostic testing most commonly used, and discusses the current treatment controversies. PMID- 20159517 TI - Laparoscopic surgery for pancreatic tumors. AB - The rapid growth of minimally invasive technology and experience in recent decades has revolutionized many aspects of oncologic surgery. Adoption of laparoscopic pancreatectomy has been slow due to the inherent anatomic complexity of pancreatic surgery, as well as concerns of perioperative complications and compromised oncologic results. With increasing surgeon experience and growing data, laparoscopic pancreatic resection is generating considerable attention and enthusiasm. This article provides an overview of laparoscopic pancreatic tumor surgery with respect to tumor biology and technical approaches. Current applications of laparoscopic approaches to left pancreatectomy, tumor enucleation, central pancreatectomy, and pancreaticoduodenectomy for treatment of pancreatic tumors are considered in light of available evidence demonstrating feasibility, safety, and oncologic efficacy. Future directions in minimally invasive pancreatic surgery are explored. PMID- 20159518 TI - Current concepts in the surgical management of pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDA) is the most common pancreatic malignancy comprising approximately 85% of cases. Many aspects of surgical resection of pancreatic cancer have been evaluated as to their effects on morbidity and mortality, including evaluation of anastomotic techniques, the role of extended lymphadenectomies, and the use of vascular reconstruction. Progress in the perioperative care of those undergoing pancreatic resection for PDA has resulted in improved outcomes. This review discusses the preoperative evaluation of a patient with pancreatic cancer and addresses the surgical management of these patients, with special attention to recent areas of progress and controversy. PMID- 20159515 TI - Cystic neoplasms of the pancreas. AB - Cystic neoplasms of the pancreas are a heterogeneous group of pancreatic tumors that vary in pathophysiology, malignant potential, clinical course, and outcomes. Their management is heavily predicated on establishing an accurate diagnosis. This can be particularly challenging, but can often be achieved by a thorough history and physical examination combined with high-quality, thin-slice computed tomography, although additional diagnostic tools may be required. Once the diagnosis is established, treatment can range from simple observation to total pancreatectomy. This decision rests on a clear and complete understanding of each disease process in the context of the patient's age and comorbidities. This article reviews the most common cystic neoplasms of the pancreas, focusing on their diagnosis and management. PMID- 20159519 TI - Management of borderline resectable pancreatic cancer. AB - Borderline resectable pancreatic cancer is an emerging stage of disease defined by computed tomogrpahy criteria, patient (Katz type B), or disease characteristics (Katz type C). These patients are particularly well suited to a surgery-last strategy with induction therapy consisting of chemotherapy (gemcitabine alone or in combination) followed by chemoradiation. With appropriate selection and preoperative planning, many patients with borderline resectable disease derive clinical benefit from multimodality therapy. The use of a standardized system for the staging of localized pancreatic cancer avoids indecision and allows for the optimal treatment of all patients guided by the extent of their disease. In this article, 2 case reports are presented, and the term borderline resectable pancreatic cancer is discussed. The advantages of neoadjuvant therapy and surgery are also discussed. PMID- 20159520 TI - Quality improvement for pancreatic cancer care: is regionalization a feasible and effective mechanism? AB - Variability exists in the quality of pancreatic cancer care provided in the United States. High-volume centers have been shown to have improved outcomes for pancreatectomy. Regionalization of pancreatic cancer care to high-volume centers has the potential to improve care and outcomes. Practical limitations such as overloading currently available high-volume centers, extending patient travel times, sharing patients within a multipayer health system, and incorporating patient preferences must be addressed for regionalization to become a reality. The benefits and limitations of regionalization of pancreatic cancer care are discussed in this review. To improve the overall quality of pancreatic cancer care at all hospitals in the United States, a combination of referral of patients with pancreatic cancer to high- and moderate-volume hospitals in conjunction with specific quality-improvement efforts at those institutions is proposed. PMID- 20159521 TI - Update on adjuvant trials for pancreatic cancer. AB - Adjuvant therapy for pancreatic cancer remains a controversial topic, with a paucity of randomized controlled trials in this area and various limitations in the trials that have been conducted to date, leaving many questions as to a true "standard of care" for patients with resectable or potentially resectable disease. Several large and well-conducted phase 3 trials have reported results recently and have helped to solidify the role of chemotherapy, with either 5 fluorouracil or gemcitabine, as an effective intervention in the adjuvant setting. The role of radiotherapy remains unclear, but it does seem to be feasible and safe, and there are trials in development that may shed more light on this question. Many small trials have pointed to the potential utility of neoadjuvant strategies in selecting the patients who are most likely to benefit from surgery and in improving outcomes by providing systemic therapy early on. Larger trials are ongoing in hopes that they will give more definitive answers as to when this strategy should be used. It is hoped that trials using novel agents, either alone or in combination with more traditional therapies, will better define the best strategy for improving outcomes in patients with resectable disease. PMID- 20159522 TI - Status of neoadjuvant therapy for resectable pancreatic cancer. AB - Neoadjuvant treatment in patients with pancreatic cancer has increased the efficiency of surgery and improved patients' response to radiotherapy. It has also been shown to expose previously occult metastatic disease and reduce the incidence of microscopically positive margins and leaks from the pancreatic enteric anastomoses. This article focuses on the effects of the trials and studies conducted on neoadjuvant therapy and also on the hindrances and limitations that must be overcome for this therapy to gain widespread traction. PMID- 20159523 TI - Novel targets for pancreatic cancer therapy. AB - Pancreatic adenocarcinoma (PDA) is one of the cancers that is resistant to most conventional anticancer therapies. PDA-affected patients show a poor prognosis. The 5-year survival rate for PDA is 5% and has changed little over the past few decades. This has prompted extensive research to identify new agents that can be used for anticancer therapy. The only cytotoxic drug that has been approved by the Food and Drug Administration (FDA) is gemcitabine, which offers marginal benefits to patients in terms of symptom control and prolongation of life. Various strategies like targeting the epidermal growth factor receptor pathway and vascular endothelial growth factor receptor pathway have been researched upon. But these strategies have not provided promising results and none of the FDA-approved targeted agents have added any substantial clinical benefit to gemcitabine except for a marginal benefit from erlotinib. This article discusses various possible new targets and new agents for the anticancer therapy for PDA. PMID- 20159524 TI - New frontiers in pancreatic cancer research. AB - Pancreatic adenocarcinoma (PDA) is a highly lethal and aggressive malignancy with high mortality rates. It is critical to evaluate novel therapeutic strategies and targets for the treatment of this disease. In this article, the authors describe the important areas of focus in pancreatic cancer research, recent advances in these areas, and novel approaches that have the potential to bring about positive patient outcomes in this lethal disease. This article also focuses on recent developments in identifying new, more sensitive, and more specific blood biomarkers with potential use in the early detection of PDA. PMID- 20159525 TI - National Priorities Partnership: care coordination. PMID- 20159527 TI - Unintentional hypothermia: implications for perianesthesia nurses. PMID- 20159528 TI - Perioperative rectal administration of nonopioid analgesics. PMID- 20159529 TI - Effect of preoperative rectal indomethacin on postoperative pain reduction after open cholecystectomy. AB - The preoperative administration of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to have a positive impact on postoperative pain, but there is little research regarding the use of rectal NSAIDs given before surgery. The purpose of this study was to evaluate the effects of rectally administered indomethacin on postoperative pain in patients undergoing open cholecystectomy. A randomized controlled design was used to compare rectally administered indomethacin with placebo. Pain intensity, total opioid dose, and postoperative time to first request for analgesic were evaluated. The indomethacin group experienced significantly less postoperative pain and required less total opioid dose compared with the placebo group. Preoperative rectal administration of indomethacin reduces postoperative pain in open cholecystectomy when compared with placebo. PMID- 20159530 TI - Postoperative rewarming: are there alternatives to warm hospital blankets. AB - Mild postoperative hypothermia remains a frequent complication among surgical patients during the immediate postoperative period. Current literature describes a variety of rewarming methods directed toward the treatment of this problem. In 1998, ASPAN developed a Clinical Guideline for the Prevention of Unplanned Perioperative Hypothermia. Eleven studies comparing different methods of postoperative rewarming have been published since the release of that guideline. This article introduces a systematic review of these studies to identify the most effective methods of rewarming surgical patients postoperatively. PMID- 20159531 TI - "I feel your pain": a research study addressing perianesthesia health care providers' knowledge and attitudes toward pain. AB - Patients' feedback about their perianesthesia experience at an acute care 609-bed teaching hospital in Washington, DC, indicated that pain management was an area in need of improvement. A nonexperimental descriptive study related to pain management was conducted in the perianesthesia areas to assess the knowledge and attitudes of health care providers. McCaffrey and Ferrell's 38-item self-report questionnaire was given to anesthesia providers, preoperative nurses, Phase I nurses, and Phase II nurses (N=138). Seventy-two participants responded, yielding a 52% response rate. Results showed a statistically significant difference between the scores of the anesthesia care providers and the preoperative area nurses and between the Phase I nurses and the preoperative nurses. No statistically significant differences were found between the anesthesia providers, and Phase I and Phase II nurses, indicating that at this hospital, nurses who provide postoperative care have similar knowledge and attitudes regarding pain as the anesthesia providers. PMID- 20159532 TI - Vision loss as a complication of nonophthalmologic surgery: implications for care for the perianesthesia nurse. AB - Postoperative vision loss not associated with ophthalmic surgery is a topic that has emerged in recent literature. Although presentation of this complication is rare, perianesthesia nurses should update their knowledge base to include knowledge of these devastating events. A review of common ocular events associated with postoperative vision loss, and the symptoms, assessment, management, and treatment of these events are indicated. The aim of this article is to explore the process of postoperative vision loss and present useful strategies to nurses for optimization of perianesthesia care. PMID- 20159533 TI - Around-the-clock (ATC) dosing of analgesics. PMID- 20159534 TI - The systematic review process: an overview. PMID- 20159536 TI - An interview with the editors: by Daniel D. Moos. PMID- 20159537 TI - Thoughts for the new year. PMID- 20159538 TI - Geriatrics. Preface. PMID- 20159539 TI - Geriatric veterinary care for fish patients. AB - There is little evidence-based research and scientific literature available for providing geriatric care for fish patients. Fish can have tremendous longevity. Although the average life span for most fish species can be only a few days to weeks for the beginning hobbyist, it is becoming more common for clients to have animals for several decades with the advent and continued development of improved life-support systems, husbandry, water quality additives, and fish nutrition. This article discusses fish longevity for several popular species, addresses environmental quality issues for geriatric patients, and provides information on the most common challenges, from a veterinary perspective, to maintain fish over the years. PMID- 20159540 TI - Reptile geriatrics. AB - Although basic notions, such as life expectancy, and thus what constitutes old age, remain to be determined in the vast majority of reptile species, there is a tendency at least for captive reptiles to live longer now than in the past. Clinicians are expected to recognize signs of senescence or old age in reptile patients, to acquire a heightened index of suspicion for diseases likely to affect older individuals of a given species or taxon, and to provide sound advice on geriatric care of such patients. Reptiles are stoic and show few signs of aging, but subtle changes in behavior, mobility, reproduction, weight, or appetite may all signal the onset of senescence to the vigilant caregiver. Serial, for example, yearly or biannual physical examination, blood sampling, and imaging initiated at maturity or earlier are probably the most powerful tools in diagnosing, monitoring, and managing geriatric issues. PMID- 20159541 TI - Geriatric psittacine medicine. AB - This article investigates geriatric psittacine medicine; it identifies how to recognize and treat pain, and describes disease conditions by system, administration of medicine, and examination techniques. PMID- 20159542 TI - The aging raptor. AB - There is little information available in the literature regarding geriatric raptor medicine. Estimating the life span of birds of prey and evaluating factors that influence longevity are continuing to be explored. Identifying disease conditions that arise with advancing age may involve various body systems including the musculoskeletal, cardiovascular, and others. Falconry, exhibit, and wildlife raptors are reviewed with regard to factors that affect their mortality, life expectancy, and age evaluation. In addition, medical conditions that are frequently seen in geriatric raptors are covered in this article. PMID- 20159543 TI - Diseases of geriatric Guinea pigs and chinchillas. AB - Guinea pigs and chinchillas, which have become increasingly popular pets, are today more commonly presented as adult and geriatric animals. Problems of older guinea pigs and chinchillas include those related to diet and management, infections whose symptoms are more common in older animals, and neoplasia. PMID- 20159544 TI - The ancient rat. AB - The past decade has seen an increase in the number of rodents being kept as pets and subsequently in the number of rodent owners seeking veterinary services. The common rat, (Rattus norvegicus) has become increasingly popular, particularly as novel varieties have been introduced to the pet market. The average laboratory or domestic pet rat has a life expectancy of approximately 2.5 to 3 years although 4 years and longer have been reported. As an increasing pet rat population ages, more owners are seeking veterinary consultation on various geriatric rat diseases. This article is an introduction to common rat geriatric diseases. PMID- 20159545 TI - The senior ferret (Mustela putorius furo). AB - Ferrets are an increasingly popular pet in the United States. They are active, gregarious pets that delight their owners with playful antics. One of the issues that ferret owners and veterinarians have had to deal with is their shortened life span. Although literature cites the life span of the ferret as 8 to 10 years, most veterinarians see ferrets as "old" at as early as 3 years of age. Most information on senior ferrets has focused on neoplastic diseases. This article discusses husbandry and nutritional issues of the aging ferret, more commonly seen geriatric diseases, and diagnostic and treatment options. PMID- 20159546 TI - Care of the geriatric rabbit. AB - The average life span reported in laboratory and lay literature for the domestic rabbit is 5 to 10 years. The author and other veterinarians are now regularly seeing rabbits living to 9 or 10 years, the oldest reported in the author's practice being 14 years. Rabbits are herbivorous prey species with continually growing (elodont) teeth. This feature allows the geriatric rabbit to possess teeth that are essentially "new", a distinct advantage over geriatric carnivores. Expanded longevity, while generally desirable, necessarily accompanies an increase in geriatric disorders. This article examines the spectrum of disease that can affect the geriatric rabbit as well as crucial factors concerning the clinical management of the animal up to the end of its life. An improved understanding of geriatric disorders in pet rabbits allows early recognition and the opportunity to improve quality of life. PMID- 20159547 TI - Pathology of aging psittacines. AB - Aging processes leading to specific organ problems are not obvious in aging psittacines. In general, birds live long and age slowly despite their high metabolic rates and very high total lifetime energy expenditures. Most pathologic processes seen in older parrots are generally not specific for aging because they are seen in young birds as well. Pathologic processes that have a tendency to occur more in older psittacines are atherosclerosis and repeated injury processes, such as chronic pulmonary interstitial fibrosis, pneumoconiosis, liver fibrosis, and lens cataracts. Also, some neoplasms are more often seen at an older age. PMID- 20159548 TI - Phosphotyrosine confers client specificity to Hsp90. AB - In this issue of Molecular Cell, Mollapour et al. (2010) report a new tyrosine phosphorylation site in Hsp90, which is essential for Hsp90's interaction with a subset of its client proteins, notably protein kinases. PMID- 20159549 TI - The fast track to multidrug resistance. AB - In this issue of Molecular Cell, Kohanski et al. (2010) demonstrate that even subinhibitory concentrations of bactericidal antibiotics result in the generation of reactive oxygen species, leading to an increase in mutation rate and the emergence of multidrug-resistant bacterial strains. PMID- 20159550 TI - The BCL-2 family reunion. AB - B cell CLL/lymphoma-2 (BCL-2) and its relatives comprise the BCL-2 family of proteins, which were originally characterized with respect to their roles in controlling outer mitochondrial membrane integrity and apoptosis. Current observations expand BCL-2 family function to include numerous cellular pathways. Here we will discuss the mechanisms and functions of the BCL-2 family in the context of these pathways, highlighting the complex integration and regulation of the BCL-2 family in cell fate decisions. PMID- 20159551 TI - Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis. AB - Antibiotic resistance arises through mechanisms such as selection of naturally occurring resistant mutants and horizontal gene transfer. Recently, oxidative stress has been implicated as one of the mechanisms whereby bactericidal antibiotics kill bacteria. Here, we show that sublethal levels of bactericidal antibiotics induce mutagenesis, resulting in heterogeneous increases in the minimum inhibitory concentration for a range of antibiotics, irrespective of the drug target. This increase in mutagenesis correlates with an increase in ROS and is prevented by the ROS scavenger thiourea and by anaerobic conditions, indicating that sublethal concentrations of antibiotics induce mutagenesis by stimulating the production of ROS. We demonstrate that these effects can lead to mutant strains that are sensitive to the applied antibiotic but resistant to other antibiotics. This work establishes a radical-based molecular mechanism whereby sublethal levels of antibiotics can lead to multidrug resistance, which has important implications for the widespread use and misuse of antibiotics. PMID- 20159552 TI - SRC-3Delta4 mediates the interaction of EGFR with FAK to promote cell migration. AB - EGF induces signal transduction between EGFR and FAK, and FAK is required for EGF induced cell migration. It is unknown, however, what factor mediates the interaction between EGFR and FAK and leads to EGF-induced FAK phosphorylation. Here, we identify SRC-3Delta4, a splicing isoform of the SRC-3 oncogene, as a signaling adaptor that links EGFR and FAK and promotes EGF-induced phosphorylations of FAK and c-Src. We identify three PAK1-mediated phosphorylations in SRC-3Delta4 that promote the localization of SRC-3Delta4 to the plasma membrane and mediate the interactions with EGFR and FAK. Importantly, overexpression of SRC-3Delta4 promotes MDA-MB231-induced breast tumor metastasis. Our findings identify phosphorylated SRC-3Delta4 as a missing adaptor between EGFR and its downstream signaling molecule FAK to coordinately regulate EGF induced cell migration. Our study also reveals that a nuclear receptor coactivator can act in the periphery of a cell to directly mediate activation of an enzyme. PMID- 20159554 TI - Asymmetric activation of the hsp90 dimer by its cochaperone aha1. AB - The chaperone Hsp90 is an ATP-dependent, dimeric molecular machine regulated by several cochaperones, including inhibitors and the unique ATPase activator Aha1. Here, we analyzed the mechanism of the Aha1-mediated acceleration of Hsp90 ATPase activity and identified the interaction surfaces of both proteins using multidimensional NMR techniques. For maximum activation of Hsp90, the two domains of Aha1 bind to sites in the middle and N-terminal domains of Hsp90 in a sequential manner. This binding induces the kinetically unfavored N terminally dimerized state of Hsp90, which primes for the hydrolysis-competent conformation. Surprisingly, this activation mechanism is asymmetric. The presence of one Aha1 molecule per Hsp90 dimer is sufficient to bridge the two subunits and to fully stimulate Hsp90 ATPase activity. This seems to functionalize the two subunits of the Hsp90 dimer in different ways, in that one subunit can be used for conformational ATPase regulation and the other for substrate protein processing. PMID- 20159553 TI - Swe1Wee1-dependent tyrosine phosphorylation of Hsp90 regulates distinct facets of chaperone function. AB - Saccharomyces WEE1 (Swe1), the only "true" tyrosine kinase in budding yeast, is an Hsp90 client protein. Here we show that Swe1(Wee1) phosphorylates a conserved tyrosine residue (Y24 in yeast Hsp90 and Y38 in human Hsp90alpha) in the N domain of Hsp90. Phosphorylation is cell-cycle associated and modulates the ability of Hsp90 to chaperone a selected clientele, including v-Src and several other kinases. Nonphosphorylatable mutants have normal ATPase activity, support yeast viability, and productively chaperone the Hsp90 client glucocorticoid receptor. Deletion of SWE1 in yeast increases Hsp90 binding to its inhibitor geldanamycin, and pharmacologic inhibition/silencing of Wee1 sensitizes cancer cells to Hsp90 inhibitor-induced apoptosis. These findings demonstrate that Hsp90 chaperoning of distinct client proteins is differentially regulated by specific posttranslational modification of a unique subcellular pool of the chaperone, and they provide a strategy to increase the cellular potency of Hsp90 inhibitors. PMID- 20159555 TI - A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic protein aggregation. AB - Misfolding and aggregation are associated with cytotoxicity in several protein folding diseases. A large network of molecular chaperones ensures protein quality control. Here, we show that within the Hsp70, Hsp110, and Hsp40 (DNAJ) chaperone families, members of a subclass of the DNAJB family (particularly DNAJB6b and DNAJB8) are superior suppressors of aggregation and toxicity of disease associated polyglutamine proteins. The antiaggregation activity is largely independent of the N-terminal Hsp70-interacting J-domain. Rather, a C-terminal serine-rich (SSF-SST) region and the C-terminal tail are essential. The SSF-SST region is involved in substrate binding, formation of polydisperse oligomeric complexes, and interaction with histone deacetylases (HDAC4, HDAC6, SIRT2). Inhibiting HDAC4 reduced DNAJB8 function. DNAJB8 is (de)acetylated at two conserved C-terminal lysines that are not involved in substrate binding, but do play a role in suppressing protein aggregation. Combined, our data provide a functional link between HDACs and DNAJs in suppressing cytotoxic protein aggregation. PMID- 20159556 TI - The Connecdenn DENN domain: a GEF for Rab35 mediating cargo-specific exit from early endosomes. AB - The DENN domain is an evolutionarily ancient protein module. Mutations in the DENN domain cause developmental defects in plants and human diseases, yet the function of this common module is unknown. We now demonstrate that the connecdenn/DENND1A DENN domain functions as a guanine nucleotide exchange factor (GEF) for Rab35 to regulate endosomal membrane trafficking. Loss of Rab35 activity causes an enlargement of early endosomes and inhibits MHC class I recycling. Moreover, it prevents early endosomal recruitment of EHD1, a common component of tubules involved in endosomal cargo recycling. Our data reveal an enzymatic activity for a DENN domain and demonstrate that distinct Rab GTPases can recruit a common protein machinery to various sites within the endosomal network to establish cargo-selective recycling pathways. PMID- 20159557 TI - Lipid-Induced conformational switch controls fusion activity of longin domain SNARE Ykt6. AB - While most SNAREs are permanently anchored to membranes by their transmembrane domains, the dually lipidated SNARE Ykt6 is found both on intracellular membranes and in the cytosol. The cytosolic Ykt6 is inactive due to the autoinhibition of the SNARE core by its longin domain, although the molecular basis of this inhibition is unknown. Here, we demonstrate that unlipidated Ykt6 adopts multiple conformations, with a small population in the closed state. The structure of Ykt6 in complex with a fatty acid suggests that, upon farnesylation, the Ykt6 SNARE core forms four alpha helices that wrap around the longin domain, forming a dominantly closed conformation. The fatty acid, buried in a hydrophobic groove formed between the longin domain and its SNARE core, is essential for maintaining the autoinhibited conformation of Ykt6. Our study reveals that the posttranslationally attached farnesyl group can actively regulate Ykt6 fusion activity in addition to its anticipated membrane-anchoring role. PMID- 20159558 TI - Regulation of translesion synthesis DNA polymerase eta by monoubiquitination. AB - DNA polymerase eta is a Y family polymerase involved in translesion synthesis (TLS). Its action is initiated by simultaneous interaction between the PIP box in pol eta and PCNA and between the UBZ in pol eta and monoubiquitin attached to PCNA. Whereas monoubiquitination of PCNA is required for its interaction with pol eta during TLS, we now show that monoubiquitination of pol eta inhibits this interaction, preventing its functions in undamaged cells. Identification of monoubiquitination sites within pol eta nuclear localization signal (NLS) led to the discovery that pol eta NLS directly contacts PCNA, forming an extended pol eta-PCNA interaction surface. We name this the PCNA-interacting region (PIR) and show that its monoubiquitination is downregulated by various DNA-damaging agents. We propose that this mechanism ensures optimal availability of nonubiquitinated, TLS-competent pol eta after DNA damage. Our work shows how monoubiquitination can either positively or negatively regulate the assembly of a protein complex, depending on which substrates are targeted by ubiquitin. PMID- 20159559 TI - Unconventional ubiquitin recognition by the ubiquitin-binding motif within the Y family DNA polymerases iota and Rev1. AB - Translesion synthesis is an essential cell survival strategy to promote replication after DNA damage. The accumulation of Y family polymerases (pol) iota and Rev1 at the stalled replication machinery is mediated by the ubiquitin binding motifs (UBMs) of the polymerases and enhanced by PCNA monoubiquitination. We report the solution structures of the C-terminal UBM of human pol iota and its complex with ubiquitin. Distinct from other ubiquitin-binding domains, the UBM binds to the hydrophobic surface of ubiquitin centered at L8. Accordingly, mutation of L8A, but not I44A, of ubiquitin abolishes UBM binding. Human pol iota contains two functional UBMs, both contributing to replication foci formation. In contrast, only the second UBM of Saccharomyces cerevisiae Rev1 binds to ubiquitin and is essential for Rev1-dependent cell survival and mutagenesis. Point mutations disrupting the UBM-ubiquitin interaction also impair the accumulation of pol iota in replication foci and Rev1-mediated DNA damage tolerance in vivo. PMID- 20159560 TI - Noncooperative interactions between transcription factors and clustered DNA binding sites enable graded transcriptional responses to environmental inputs. AB - A paradigm in transcriptional regulation is that graded increases in transcription factor (TF) concentration are translated into on/off transcriptional responses by cooperative TF binding to adjacent sites. Digital transcriptional responses underlie the definition of anatomical boundaries during development. Here we show that NF-kappaB, a TF controlling inflammation and immunity, is conversely an analog transcriptional regulator that uses clustered binding sites noncooperatively. We observed that increasing concentrations of NF kappaB are translated into gradual increments in gene transcription. We provide a thermodynamic interpretation of the experimental observations by combining quantitative measurements and a minimal physical model of an NF-kappaB-dependent promoter. We demonstrate that NF-kappaB binds independently to adjacent sites to promote additive RNA Pol II recruitment and graded transcriptional outputs. These findings reveal an alternative mode of operation of clustered TF binding sites, which might function in biological conditions where the transcriptional output is proportional to the strength of an environmental input. PMID- 20159561 TI - AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. AB - Chromosomal translocations involving the MLL gene are associated with infant acute lymphoblastic and mixed lineage leukemia. There are a large number of translocation partners of MLL that share very little sequence or seemingly functional similarities; however, their translocations into MLL result in the pathogenesis of leukemia. To define the molecular reason why these translocations result in the pathogenesis of leukemia, we purified several of the commonly occurring MLL chimeras. We have identified super elongation complex (SEC) associated with all chimeras purified. SEC includes ELL, P-TEFb, AFF4, and several other factors. AFF4 is required for SEC stability and proper transcription by poised RNA polymerase II in metazoans. Knockdown of AFF4 in leukemic cells shows reduction in MLL chimera target gene expression, suggesting that AFF4/SEC could be a key regulator in the pathogenesis of leukemia through many of the MLL partners. PMID- 20159563 TI - Capitalising on effective treatment strategies for low back pain - How do we bridge the self-management gap? PMID- 20159562 TI - BACH1/FANCJ acts with TopBP1 and participates early in DNA replication checkpoint control. AB - Human TopBP1 plays a critical role in the control of DNA replication checkpoint. In this study, we report a specific interaction between TopBP1 and BACH1/FANCJ, a DNA helicase involved in the repair of DNA crosslinks. The TopBP1/BACH1 interaction is mediated by the very C-terminal tandem BRCT domains of TopBP1 and S phase-specific phosphorylation of BACH1 at Thr 1133 site. Interestingly, we demonstrate that depletion of TopBP1 or BACH1 attenuates the loading of RPA on chromatin. Moreover, both TopBP1 and BACH1 are required for ATR-dependent phosphorylation events in response to replication stress. Taken together, our data suggest that BACH1 has an unexpected early role in replication checkpoint control. A specific interaction between TopBP1 and BACH1 is likely to be required for the extension of single-stranded DNA regions and RPA loading following replication stress, which is a prerequisite for the subsequent activation of replication checkpoint. PMID- 20159564 TI - Identification of a heat shock-responsive cis-acting DNA sequence and its transcriptional regulator: Their roles in the expression of the Spirulina-desD gene in response to heat stress. AB - This study addresses the importance of a heat-shock-responsive cis-acting DNA element and its transcriptional regulator, which play key roles in the regulation of the Spirulina-desD gene on exposure to high temperatures. Temperature response analysis studies showed that the AT-rich region that is located between nt -98 to -80 of the Spirulina-desD gene promoter serves as a binding site for its transcriptional regulator. LC-MS/MS analysis of the DNA-binding protein complex revealed that the amino acid sequences of the bound proteins were homologous to those of several proteins, including a DNA-binding protein, heat shock protein-90 (Hsp90 or HtpG), GroEL and various protein kinases. In addition, western blot analysis indicated that the chaperones GroEL and Hsp90 and a dephosphorylation reaction played a role in the response to elevated temperatures. We conclude that the regulatory DNA segments and the corresponding regulatory binding proteins are distinct for each particular stress condition. This is true, irrespective of whether the regulatory mechanisms that govern the expression of the cold- and heat-regulated desD gene depend on similar phosphorylation- and dephosphorylation dependent conformational changes that modulate the association of the co chaperone. PMID- 20159565 TI - Thermostable Kunitz trypsin inhibitor with cytokine inducing, antitumor and HIV-1 reverse transcriptase inhibitory activities from Korean large black soybeans. AB - A large number of trypsin inhibitors belonging to various types have been purified from different kinds of legumes. In this study, by using liquid chromatography, a Kunitz type trypsin inhibitor (KBTI) with a molecular weight of 20107.645 Da was purified from Korean large black soybeans. KBTI reduced the proteolytic activities of trypsin and alpha-chymotrypsin with the activity of approximately 8520 BAEE units/mg and approximately 24 BTEE units/mg, respectively. It showed high thermal stability (0-100 degrees C) as well as stability over a large range of pH values (pH 3-11). Furthermore, KBTI inhibited HIV-1 reverse transcriptase activity with an IC(50) value of 0.71 microM and induced the release of pro-inflammatory cytokines such as TNF-alpha, IL-1beta, IL 2 and interferon-gamma at the mRNA level. KBTI exerted weak antiproliferative activity toward CNE-2 and HNE-2 nasopharyngeal cancer cells, MCF-7 breast cancer cells, and Hep G2 hepatoma cells. KBTI was destitute of mitogenic, ribonuclease and antifungal activities. PMID- 20159566 TI - Gene cloning and characterization of dihydrolipoamide dehydrogenase from Microbacterium luteolum: A useful enzymatic regeneration system of NAD+ from NADH. AB - Dihydrolipoamide dehydrogenase (LPD), a useful biocatalyst for regenerating NAD(+), was purified from Microbacterium luteolum JCM 9174, and the gene encoding LPD was cloned from the genomic DNA. The gene contained an opening reading frame consisting of 1395 nucleotides encoding 465 amino acid residues with a predicted molecular weight of 49912.1 Da, which displayed 36-78% homology to known LPDs. Moreover, the FAD- and NAD(+)-binding sites and the two catalytic residues in the LPDs were conserved. The enzyme was expressed in recombinant Escherichia coli cells and purified to homogeneity by column chromatography. LPD of M. luteolum (MluLPD) accepted not only lipoamide but also some artificial electron acceptors such as dichlorophenolindophenol (DCIP) and nitrotetrazolium blue (NTB), that is, it functions as a diaphorase. NAD(+) demonstrated a strong activating effect on MluLPD, and the activity was 5.2 times higher than that without NAD(+). The enzyme was suitable for regenerating NAD(+) in biocatalytic reactions because of its high affinity for NADH (6.1 microM). An NAD(+)-regenerating system with MluLPD and laccase using 2,5-dimethoxy-1,4-benzoquinone as a hydrogen acceptor was demonstrated. PMID- 20159567 TI - Production of Xylanase with a transformant of Aspergillus oryzae RIB40 in a Liquid-Surface Immobilization (LSI) System. AB - Xylanase production by a XynF1 (33 kDa)-transformant of Aspergillus oryzae RIB40 was compared between submerged cultivation (SmC) and liquid-surface immobilization (LSI) systems. While the accumulation of xylanase in the SmC decreased by prolonged incubation, LSI system enabled the continuation of xylanase production to afford 4.5-fold xylanase production compared with the SmC system. PMID- 20159568 TI - An extracellular endo-1,4-beta-xylanase from Aspergillus japonicus: Purification, properties, and characterization of the encoding gene. AB - An extracellular endo-1,4-beta-xylanase with specific activity of 566 U/mg was purified from the culture filtrate of a filamentous fungus, Aspergillus japonicus strain MU-2, grown on oat spelt xylan. The purified enzyme showed a single band on SDS-PAGE with an apparent M(r) of 25.1 kDa. Xylanase activity was optimal at pH 5.0 and 60 degrees C. The xylanase gene (xynA) encoded a 42 residue prepropeptide and a 191 residue mature protein. The XynA protein showed the highest sequence identity of 69% to Aspergillus niger XynB (DQ174549), which belongs to the glycoside hydrolase family 11. PMID- 20159569 TI - Reducing the variability of antibiotic production in Streptomyces by cultivation in 24-square deepwell plates. AB - Highly reproducible production values of the aminocoumarin antibiotic novobiocin were achieved by cultivation of a heterologous Streptomyces producer strain in commercially available square deepwell plates consisting of 24 wells of 3 ml culture volume each. Between parallel cultivation batches in the deepwell plates, novobiocin accumulation showed standard deviations of 4-9%, compared to 39% in baffled Erlenmeyer flasks. Mycelia used as inoculum could be frozen in the presence of 20% peptone and stored at -70 degrees C, allowing repeated cultivations from the same batch of inoculum over extended periods of time. Originally, novobiocin titers in the deepwell plate (5-12 mg l(-1)) were lower than in Erlenmeyer flasks (24 mg l(-1)). Optimization of the inoculation procedure as well as addition of a siloxylated ethylene oxide/propylene oxide copolymer, acting as oxygen carrier, to the production medium increased novobiocin production to 54 mg l(-1). The additional overexpression of the pathway-specific positive regulator gene novG increased novobiocin production to 163 mg l(-1). Harvesting the precultures in a defined section of growth phase greatly reduced variability between different batches of inoculum. The use of deepwell plates may considerably reduce the workload and cost of investigations of antibiotic biosynthesis in streptomycetes and other microorganisms due to the high reproducibility and the low requirement for shaker space and culture medium. PMID- 20159570 TI - Heterotrophic growth and nutritional aspects of the diatom Cyclotella cryptica (Bacillariophyceae): Effect of some environmental factors. AB - To investigate the nutritional value of the diatom Cyclotella cryptica (Reimann, Lewin, and Guillard) as an alternative feed for use in the aquaculture industry, the heterotrophic growth characteristics and resultant fatty acid profile of the microalga were studied when cultivated under a variety of controlled salinity and temperature conditions. In addition, the effects of pH on the growth characteristics were also studied. The maximum specific growth rate was affected by initial pH and cultivation temperature, but not by salinity. The optimal pH and temperature ranges for growth were 7.2 to 8.1 and 22.5 to 25.0 degrees C, respectively. Lipid accumulation and the fatty acid composition were also affected by cultivation temperature and salinity. The optimal temperature range and salinity level for lipid accumulation were 18.0 to 25.0 degrees C and 11.2 psu, respectively. In all cases the fatty acid distribution was similar, with the most abundant fatty acids being palmitic acid (16:0), palmitoleic acid (16:1 n 7), stearidonic acid (18:4 n-3, SDA), eicosapentaenoic acid (20:5 n-3, EPA), and decosahexaenoic acid (22:6 n-3, DHA). PMID- 20159571 TI - One-pot conversion of levan prepared from Serratia levanicum NN to difructose anhydride IV by Arthrobacter nicotinovorans levan fructotransferase. AB - The newly established difructose anhydride IV (DFA IV) production system is comprised of the effective production of levan from sucrose by Serratia levanicum NN, the conversion of the levan into DFA IV by levan fructotransferase from Arthrobacter nicotinovorans GS-9, which is highly expressed in an Escherichiacoli transformant, and a practical purification step. The chemical properties of DFA IV were also investigated. PMID- 20159572 TI - Analysis of iron- and sulfur-oxidizing bacteria in a treatment plant of acid rock drainage from a Japanese pyrite mine by use of ribulose-1, 5-bisphosphate carboxylase/oxygenase large-subunit gene. AB - Iron- and sulfur-oxidizing bacteria in a treatment plant of acid rock drainage (ARD) from a pyrite mine in Yanahara, Okayama prefecture, Japan, were analyzed using the gene (cbbL) encoding the large subunit of ribulose-1, 5-bisphosphate carboxylase/oxygenase (RubisCO). Analyses of partial sequences of cbbL genes from Acidithiobacillus ferrooxidans, Acidithiobacillus thiooxidans and Acidithiobacillus caldus strains revealed the diversity in their cbbL gene sequences. In contrast to the presence of two copies of form I cbbL genes (cbbL1 and cbbL2) in A. ferrooxidans genome, A. thiooxidans and A. caldus had a single copy of form I cbbL gene in their genomes. A phylogenetic analysis based on deduced amino acid sequences from cbbL genes detected in the ARD treatment plant and their close relatives revealed that 89% of the total clones were affiliated with A. ferrooxidans. Clones loosely affiliated with the cbbL from A. thiooxidans NB1-3 or Thiobacillus denitrificans was also detected in the treatment plant. cbbL gene sequences of iron- or sulfur-oxidizing bacteria isolated from the ARD and the ARD treatment plant were not detected in the cbbL libraries from the treatment plant, suggesting the low frequencies of isolates in the samples. PMID- 20159573 TI - Removal of polychlorinated dioxins by semi-aerobic fed-batch composting with biostimulation of "Dehalococcoides". AB - A semi-aerobic, mesophilic, fed-batch composting (FBC) reactor loaded with household garbage was used to remove polychlorinated dibenzo-p dioxins/dibenzofurans (PCDD/Fs). The reactor was packed with woodchips as the solid matrix and PCDD/F-contaminated soil or flyash and then operated at a waste loading rate of 0.5 kg (wet wt) day(-1). All congeners of PCDD/Fs (initial concentration, 200-830 pmol g(-1) [dry wt]) were totally reduced during the over period of operation, with a half reduction time of 4 months. Direct cell counting and respiratory quinone profiling showed that the reactors at the fully acclimated stage harbored a high population density of bacteria (10(11) g(-1) [dry wt]) with members of the Actinobacteria predominating. Real-time quantitative PCR showed that the population of "Dehalococcoides" and its phylogenetic relatives of Chloroflexi as the possible dechlorinators varied between at the order of 10(7) to 10(8) g(-1) (dry wt). A "Dehalococcoides" containing dechlorinating culture from the soil-treating reactor was successfully enriched with a model PCDD/F compound, fthalide. 16S rRNA gene-targeted PCR denaturated gradient gel electrophoresis and clone library analyses showed that this culture comprised at least three major phylogenetic groups of bacteria, Acidaminobacter, "Dehalococcoides," and Rhizobium. These results suggest that the semi-aerobic FBC process is applicable for the bioremediation of PCDD/Fs and possibly other haloorganic compounds with the biostimulation of "Dehalococcoides" and its relatives as the potent dechlorinators. PMID- 20159574 TI - Effects of acetic acid and its assimilation in fed-batch cultures of recombinant Escherichia coli containing human-like collagen cDNA. AB - The primary processing problem in recombinant Escherichia coli fermentation is the production of acetic acid, which can inhibit both cell growth and recombinant protein production. The ability of E. coli to assimilate acetate permits it to solve this problem in a rather creative manner. In this study, the effects of acetic acid assimilation through a glucose starvation period at different cell growth phases were investigated in fed-batch cultures of recombinant E. coli. Experimental results showed that the human-like collagen (HLC) production could be improved by introducing glucose starvation at the end of batch culture and pre induction phase, while the glucose starvation at the induction phase resulted in a poor HLC productivity. The acetic acid assimilation was observed during all the glucose starvation periods. In addition, a systematic study for evaluating the effects of acetic acid was carried out by adding acetate into culture media at different cell growth phases and then employing a glucose starvation after several hours. It was found that obvious acetate inhibition on cell growth occurred in the batch culture phases while its inhibitory effect on HLC expression occurred only in the post-induction phase. The longer the elevated acetic acid concentration maintained, the stronger the inhibitory effects were. These results are of significance for optimizing and scaling-up fermentation processes. PMID- 20159575 TI - Differential importance of trehalose accumulation in Saccharomyces cerevisiae in response to various environmental stresses. AB - Trehalose is believed to play an important role in stress tolerance in the yeast Saccharomyces cerevisiae. In this research, the responses to various environmental stresses, such as high ethanol concentration, heat, oxidative, and freezing stresses, were investigated in a strain with deletion of the NTH1, NTH2, and ATH1 genes encoding trehalases that are involved in trehalose degradation and the triple deletion strains overexpressing TPS1 or TPS2, both of which encode trehalose biosynthesis enzymes in S. cerevisiae. The contents of trehalose constitutively accumulated in the TPS1- and TPS2-overexpressing triple deletion strains were higher than that in the original triple deletion strain. High trehalose accumulation and growth activity were observed in the TPS2 overexpressing triple deletion strain after ethanol stress induction. The same was also observed in the triple deletion and the TPS1- and TPS2-overexpressing triple deletion strains after heat stress induction. In case of freezing stress, all the recombinant strains with high constitutive trehalose content showed high tolerance. However, in case of oxidative stress, trehalose accumulation could not make the yeast cells tolerant. Our results indicated that high trehalose accumulation can make yeast cells resistant to multiple stresses, but the importance of this accumulation before or after stress induction is varied depending on the type of stress. PMID- 20159576 TI - Cultivation characteristics and gene expression profiles of Aspergillus oryzae by membrane-surface liquid culture, shaking-flask culture, and agar-plate culture. AB - We cultivated a filamentous fungus, Aspergillus oryzae IAM 2706 by three different cultivation methods, i.e., shaking-flask culture (SFC), agar-plate culture (APC), and membrane-surface liquid culture (MSLC), to elucidate the differences of its behaviors by different cultivation methods under the same media, by measuring the growth, secretion of proteases and alpha-amylase, secreted protein level, and gene transcriptional profile by the DNA microarray analysis. The protease activities detected by MSLC and APC were much higher than that by SFC, using both modified Czapek-Dox (mCD) and dextrin-peptone-yeast extract (DPY) media. The alpha-amylase activity was detected in MSLC and APC in a much larger extent than that in SFC when DPY medium was used. On the basis of SDS PAGE analyses and N-terminal amino acid sequences, 6 proteins were identified in the supernatants of the culture broths using DPY medium, among which oryzin (alkaline protease) and alpha-amylase were detected at a much higher extent for APC and MSLC than those for SFC while only oryzin was detected in mCD medium, in accordance with the activity measurements. A microarray analysis for the fungi cultivated by SFC, APC, and MSLC using mCD medium was carried out to elucidate the differences in the gene transcriptional profile by the cultivation methods. The gene transcriptional profile obtained for the MSLC sample showed a similar tendency to the APC sample while it was quite different from that for the SFC sample. Most of the genes specifically transcribed in the MSLC sample versus those in the SFC sample with a 10-fold up-regulation or higher were unknown or predicted proteins. However, transcription of oryzin gene was only slightly up regulated in the MSLC sample and that of alpha-amylase gene, slightly down regulated. PMID- 20159577 TI - Evaluation of Chinese hamster ovary cell stability during repeated batch culture for large-scale antibody production. AB - Pharmaceutical manufacturing plants can be operated continuously for several months. It is therefore important to use cells with long-term stability for the production of active ingredients. We investigated the reliability and long-term stability of an antibody-producing cell line. A recombinant Chinese hamster ovary (CHO) cell line was cultivated in spinner flasks and reactors, including a practical production-scale reactor (1600 L), for 109 days to produce monoclonal antibodies against the HM1.24 antigen. During cultivation, the cells remained stable and there was an increase in the rate of cell proliferation, yielding viable cells at high density. A decrease in cell-specific productivity was associated with this increase in the rate of cell proliferation. The cells were genetically stable and other measures of cellular function remained consistent throughout the cultivation period. PMID- 20159578 TI - Changes in the quality of antibodies produced by Chinese hamster ovary cells during the death phase of cell culture. AB - Although overproduction of recombinant proteins by mammalian cells is well established, little attention has been paid to analysis of the quality of the products. We focused on the quality of antibodies produced during the death phase of a recombinant Chinese hamster ovary (CHO) cell line. The quality of the monoclonal antibody against HM1.24 antigen and the post-translational characteristics of the subunits during CHO cell culture in a 160-L bioreactor were investigated. The culture supernatant of a stable cell line was collected and purified by affinity chromatography and then analyzed. There were no significant changes in gel-permeation chromatography variables, carbohydrate structure, or antibody-dependent cellular cytotoxicity activity during the death phase of cell culture. However, ion-exchange chromatography analysis revealed that antibody heterogeneity changed, as indicated by a decrease in cell viability. The results presented here provide useful information that will help in determining the time to end each batch culture. PMID- 20159579 TI - Bioconversion of the antihistaminc drug loratadine by tobacco cell suspension cultures expressing human cytochrome P450 3A4. AB - In this study we have expanded the metabolic potential of plant cell suspension cultures by introducing active human cytochrome P450 monooxygenase 3A4 into tobacco cells. Exogenously supplied loratadine was metabolized in a 3A4-specific manner, showing the capacity of this system for the generation of metabolites. PMID- 20159580 TI - Labisia pumila extract protects skin cells from photoaging caused by UVB irradiation. AB - Labisia pumila (Myrsinaceae), known as "Kacip Fatimah," has been used by many generations of Malay women to induce and facilitate child birth as well as a post partum medicine. However, its topical application on skin has not been reported yet. In this study, we have focused on the anti-photoaging effects of L. pumila. Extract of L. pumila was first analyzed for their antioxidant activities using DPPH (2,2-diphenyl-1-picrylhydrazyl) since UV irradiation is a primary cause of reactive oxygen species (ROS) generation in the skin. The 50% free radical scavenging activity (FSC(50)) of L. pumila extract was determined to be 0.006%, which was equal to that produced by 156 microM ascorbic acid. TNF-alpha and cyclooxygenase (COX-2) play a primary role in the inflammation process upon UV irradiation and are known to be stimulated by UVB. Treatment with L. pumila extract markedly inhibited the TNF-alpha production and the expression of COX-2. Decreased collagen synthesis of human fibroblasts by UVB was restored back to normal level after treatment with L. pumila extract. On the other hand, the enhanced MMP-1 expression upon UVB irradiation was down regulated by L. pumila extract in a dose-dependent manner. Furthermore, treatment of normal keratinocytes with L. pumila extract attenuated UVB-induced MMP-9 expression. These results collectively suggest L. pumila extract has tremendous potential as an anti-photoaging cosmetic ingredient. PMID- 20159581 TI - Compressive force inhibits adipogenesis through COX-2-mediated down-regulation of PPARgamma2 and C/EBPalpha. AB - Various mechanical stimuli affect differentiation of mesoderm-derived cells such as osteoblasts or myoblasts, suggesting that adipogenesis may also be influenced by mechanical stimulation. However, effects of mechanical stimuli on adipogenesis are scarcely known. Compressive force was applied to a human preadipocyte cell line, SGBS. Levels of gene expression were estimated by real-time reverse transcription-polymerase chain reaction. The accumulation of lipids was evaluated by Sudan III or Oil Red O staining. In SGBS cells subjected to a compressive force of 226 Pa for 12 h before adipogenic induction, adipogenesis was inhibited. Compressive force immediately after adipogenic induction did not affect the adipogenesis. The expression of peroxisome proliferator-activated receptor (PPAR) gamma2 and CCAAT/enhancer binding protein (C/EBP) alpha mRNA during adipogenesis was inhibited by compressive force, whereas C/EBPbeta and C/EBPdelta mRNA levels were unaffected. In preadipocytes, compressive force increased mRNA levels of Kruppel-like factor 2, preadipocyte factor 1, WNT10b, and cyclooxygenase-2 (COX 2) which are known as negative regulators for the PPARgamma2 and C/EBPalpha genes. Furthermore, a COX-2 inhibitor completely reversed the inhibition of adipogenesis by compressive force. In conclusion, compressive force inhibited adipogenesis by suppressing expression of PPARgamma2 and C/EBPalpha in a COX-2 dependent manner. PMID- 20159582 TI - Heat treatment of electrospun silicate fiber substrates enhances cellular adhesion and proliferation. AB - Synthetic scaffolds support cell attachment in vitro. We prepared ultra-fine silicate fibers using the sol-gel process and electrospinning, heated the fibers to 500 degrees C and investigated their effects on the behavior of human hepatocellular carcinoma (HepG2) cells. Alterations in surface composition following heat treatment improved cell adhesion and influenced cell migration. PMID- 20159583 TI - Fetal calf serum-free suspension culture of Chinese hamster ovary cells employing fish serum. AB - The effects of heat treatment and concentration of fish serum (FS) on cell growth in a suspension culture of recombinant Chinese hamster ovary (CHO) 1-15(500) (ATCC CRL-9606) cells were investigated. An increase in FS concentration from 1% to 4% markedly increased cell density. On the other hand, heat treatment of FS showed nearly no effect on cell density. PMID- 20159584 TI - Growth and differentiation potentials in confluent state of culture of human skeletal muscle myoblasts. AB - The transitional behaviors of myoblasts toward differentiation were investigated in the cultures at the low and high seeding densities (respectively, X(0)=1.0x10(3) and 2.0x10(5) cells/cm(2)). In the culture at the low seeding density, an increase in confluence degree accompanied a decrease in growth potential (R(p)), being R(p)=0.85 and 0.11 at t=48 and 672 h, respectively. Myoblasts seeded at the high density resulted in the immediate cessation of growth with keeping the low range of R(p)=0.02-0.09 throughout the culture. The reduction of R(p) led to the generation of three subpopulations of cells in proliferative, quiescent and differentiated states. Close cell contacts in the confluent state of high seeding culture induced cell quiescence to a higher extent with suppressing differentiation. PMID- 20159585 TI - Disturbed regulatory T cell homeostasis in multiple sclerosis. AB - The pathological features of multiple sclerosis (MS), a chronic inflammatory disorder of the central nervous system, support an autoimmune etiology. Strong evidence has been provided for a potential functional defect of CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs) in patients with relapsing remitting MS. More recently, alterations in homeostatic parameters related to the development and function of naive and memory-like Tregs were discovered in MS patients. In this review, we evaluate the evidence for disturbed Treg homeostasis in MS and discuss the role of potential compensatory mechanisms in the chronic disease phase. Better insights into the processes underlying the compromised immune regulation in MS patients will be important to understand the potential of Treg-based therapies. PMID- 20159586 TI - Telomeric TuRF1 wars. AB - The TRF1 subunit of the shelterin complex controls telomere length by regulating telomerase access to chromosome ends. Work from Zeng et al. (2010) now reveals in atomic detail how a battle between the SCF(FBX4) ubiquitin ligase and the shelterin component TIN2 controls TRF1 abundance and telomere length homeostasis. PMID- 20159588 TI - A PAK-activated linker for EGFR and FAK. AB - Transmembrane growth factor and integrin matrix receptors form multiprotein signaling complexes with FAK, a cytoplasmic cell motility-associated kinase. In a recent issue of Molecular Cell, Long et al. now show that a PAK-phosphorylated alternate-spliced isoform of the steroid receptor coactivator-3 (SRC-3Delta4) bridges EGFR and FAK, enhancing breast carcinoma cell migration and metastasis. PMID- 20159587 TI - Chromatin modifiers, cognitive disorders, and imprinted genes. AB - In this issue of Developmental Cell, Kernohan et al. link the chromatin regulatory proteins ATRX, MeCP2, CTCF, and cohesin with silencing of H19 and other imprinted genes during critical stages of postnatal brain development, perhaps suggesting a common etiology for several human diseases that exhibit defects in brain development and function. PMID- 20159589 TI - Alternative polyadenylation blooms. AB - Alternative polyadenylation generates mRNAs with 3' untranscribed regions of different lengths, often affecting transcript stability. Hornyik et al., in this issue of Developmental Cell, and Liu et al. now demonstrate a role for alternative polyadenylation in gene silencing and the regulation of flowering time in Arabidopsis thaliana. PMID- 20159590 TI - Organogenesis and development of the liver. AB - Embryonic development of the liver has been studied intensely, yielding insights that impact diverse areas of developmental and cell biology. Understanding the fundamental mechanisms that control hepatogenesis has also laid the basis for the rational differentiation of stem cells into cells that display many hepatic functions. Here, we review the basic molecular mechanisms that control the formation of the liver as an organ. PMID- 20159591 TI - ATRX partners with cohesin and MeCP2 and contributes to developmental silencing of imprinted genes in the brain. AB - Human developmental disorders caused by chromatin dysfunction often display overlapping clinical manifestations, such as cognitive deficits, but the underlying molecular links are poorly defined. Here, we show that ATRX, MeCP2, and cohesin, chromatin regulators implicated in ATR-X, RTT, and CdLS syndromes, respectively, interact in the brain and colocalize at the H19 imprinting control region (ICR) with preferential binding on the maternal allele. Importantly, we show that ATRX loss of function alters enrichment of cohesin, CTCF, and histone modifications at the H19 ICR, without affecting DNA methylation on the paternal allele. ATRX also affects cohesin, CTCF, and MeCP2 occupancy within the Gtl2/Dlk1 imprinted domain. Finally, we show that loss of ATRX interferes with the postnatal silencing of the maternal H19 gene along with a larger network of imprinted genes. We propose that ATRX, cohesin, and MeCP2 cooperate to silence a subset of imprinted genes in the postnatal mouse brain. PMID- 20159592 TI - Structural basis of selective ubiquitination of TRF1 by SCFFbx4. AB - TRF1 is a critical regulator of telomere length. As such, TRF1 levels are regulated by ubiquitin-dependent proteolysis via an SCF E3 ligase where Fbx4 contributes to substrate specification. Here, we report the crystal structure of the Fbx4-TRF1 complex at 2.4 A resolution. Fbx4 contains an unusual substrate binding domain that adopts a small GTPase fold. Strikingly, this atypical GTPase domain of Fbx4 binds to a globular domain of TRF1 through an intermolecular beta sheet, instead of recognizing short peptides/degrons as often seen in other F-box protein-substrate complexes. Importantly, mutations in this interface abrogate Fbx4-dependent TRF1 binding and ubiquitination. Furthermore, the data demonstrate that recognition of TRF1 by SCF(Fbx4) is regulated by another telomere protein, TIN2. Our results reveal an atypical small GTPase domain within Fbx4 as a substrate-binding motif for SCF(Fbx4) and uncover a mechanism for selective ubiquitination and degradation of TRF1 in telomere homeostasis control. PMID- 20159593 TI - Differential regulation of protrusion and polarity by PI3K during neutrophil motility in live zebrafish. AB - Cell polarity is crucial for directed migration. Here we show that phosphoinositide 3-kinase (PI(3)K) mediates neutrophil migration in vivo by differentially regulating cell protrusion and polarity. The dynamics of PI(3)K products PI(3,4,5)P(3)-PI(3,4)P(2) during neutrophil migration were visualized in living zebrafish, revealing that PI(3)K activation at the leading edge is critical for neutrophil motility in intact tissues. A genetically encoded photoactivatable Rac was used to demonstrate that localized activation of Rac is sufficient to direct migration with precise temporal and spatial control in vivo. Similar stimulation of PI(3)K-inhibited cells did not direct migration. Localized Rac activation rescued membrane protrusion but not anteroposterior polarization of F-actin dynamics of PI(3)K-inhibited cells. Uncoupling Rac-mediated protrusion and polarization suggests a paradigm of two-tiered PI(3)K-mediated regulation of cell motility. This work provides new insight into how cell signaling at the front and back of the cell is coordinated during polarized cell migration in intact tissues within a multicellular organism. PMID- 20159594 TI - Broad-minded links cell cycle-related kinase to cilia assembly and hedgehog signal transduction. AB - Recent findings indicate that mammalian Sonic hedgehog (Shh) signal transduction occurs within primary cilia, although the cell biological mechanisms underlying both Shh signaling and ciliogenesis have not been fully elucidated. We show that an uncharacterized TBC domain-containing protein, Broad-minded (Bromi), is required for high-level Shh responses in the mouse neural tube. We find that Bromi controls ciliary morphology and proper Gli2 localization within the cilium. By use of a zebrafish model, we further show that Bromi is required for proper association between the ciliary membrane and axoneme. Bromi physically interacts with cell cycle-related kinase (CCRK), whose Chlamydomonas homolog regulates flagellar length. Biochemical and genetic interaction data indicate that Bromi promotes CCRK stability and function. We propose that Bromi and CCRK control the structure of the primary cilium by coordinating assembly of the axoneme and ciliary membrane, allowing Gli proteins to be properly activated in response to Shh signaling. PMID- 20159595 TI - Kinetochores generate microtubules with distal plus ends: their roles and limited lifetime in mitosis. AB - In early mitosis, microtubules can be generated at kinetochores as well as at spindle poles. However, the role and regulation of kinetochore-derived microtubules have been unclear. In general, metaphase spindle microtubules are oriented such that their plus ends bind to kinetochores. However, we now have evidence that, during early mitosis in budding yeast, microtubules are generated at kinetochores with distal plus ends. These kinetochore-derived microtubules interact along their length with microtubules that extend from a spindle pole, facilitating kinetochore loading onto the lateral surface of spindle pole microtubules. Once kinetochores are loaded, microtubules are no longer generated at kinetochores, and those that remain disappear rapidly and do not contribute to the metaphase spindle. Stu2 (the ortholog of vertebrate XMAP215/ch-TOG) localizes to kinetochores and plays a central role in regulating kinetochore-derived microtubules. Our work provides insight into microtubule generation at kinetochores and the mechanisms that facilitate initial kinetochore interaction with spindle pole microtubules. PMID- 20159596 TI - Organism-scale modeling of early Drosophila patterning via bone morphogenetic proteins. AB - Advances in image acquisition and informatics technology have led to organism scale spatiotemporal atlases of gene expression and protein distributions. To maximize the utility of this information for the study of developmental processes, a new generation of mathematical models is needed for discovery and hypothesis testing. Here, we develop a data-driven, geometrically accurate model of early Drosophila embryonic bone morphogenetic protein (BMP)-mediated patterning. We tested nine different mechanisms for signal transduction with feedback, eight combinations of geometry and gene expression prepatterns, and two scale-invariance mechanisms for their ability to reproduce proper BMP signaling output in wild-type and mutant embryos. We found that a model based on positive feedback of a secreted BMP-binding protein, coupled with the experimentally measured embryo geometry, provides the best agreement with population mean image data. Our results demonstrate that using bioimages to build and optimize a three dimensional model provides significant insights into mechanisms that guide tissue patterning. PMID- 20159597 TI - Characterization and in vivo pharmacological rescue of a Wnt2-Gata6 pathway required for cardiac inflow tract development. AB - Little is understood about the molecular mechanisms underlying the morphogenesis of the posterior pole of the heart. Here we show that Wnt2 is expressed specifically in the developing inflow tract mesoderm, which generates portions of the atria and atrio-ventricular canal. Loss of Wnt2 results in defective development of the posterior pole of the heart, resulting in a phenotype resembling the human congenital heart syndrome complete common atrio-ventricular canal. The number and proliferation of posterior second heart field progenitors is reduced in Wnt2(-/-) mutants. Moreover, these defects can be rescued in a temporally restricted manner through pharmacological inhibition of Gsk-3beta. We also show that Wnt2 works in a feedforward transcriptional loop with Gata6 to regulate posterior cardiac development. These data reveal a molecular pathway regulating the posterior cardiac mesoderm and demonstrate that cardiovascular defects caused by loss of Wnt signaling can be rescued pharmacologically in vivo. PMID- 20159598 TI - Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. AB - The Hippo signaling pathway regulates organ size and tissue homeostasis from Drosophila to mammals. Central to this pathway is a kinase cascade wherein Hippo (Hpo), in complex with Salvador (Sav), phosphorylates and activates Warts (Wts), which in turn phosphorylates and inactivates the Yorkie (Yki) oncoprotein, known as the YAP coactivator in mammalian cells. The FERM domain proteins Merlin (Mer) and Expanded (Ex) are upstream components that regulate Hpo activity through unknown mechanisms. Here we identify Kibra as another upstream component of the Hippo signaling pathway. We show that Kibra functions together with Mer and Ex in a protein complex localized to the apical domain of epithelial cells, and that this protein complex regulates the Hippo kinase cascade via direct binding to Hpo and Sav. These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis. PMID- 20159600 TI - The WW domain protein Kibra acts upstream of Hippo in Drosophila. AB - The conserved Hippo kinase pathway plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. Whereas the function of the core kinase cascade, consisting of the serine/threonine kinases Hippo and Warts, in phosphorylating and thereby inactivating the transcriptional coactivator Yorkie is well established, much less is known about the upstream events that regulate Hippo signaling activity. The FERM domain proteins Expanded and Merlin appear to represent two different signaling branches that feed into the Hippo pathway. Signaling by the atypical cadherin Fat may act via Expanded, but how Merlin is regulated has remained elusive. Here, we show that the WW domain protein Kibra is a Hippo signaling component upstream of Hippo and Merlin. Kibra acts synergistically with Expanded, and it physically interacts with Merlin. Thus, Kibra predominantly acts in the Merlin branch upstream of the core kinase cascade to regulate Hippo signaling. PMID- 20159599 TI - Kibra is a regulator of the Salvador/Warts/Hippo signaling network. AB - The Salvador (Sav)/Warts (Wts)/Hippo (Hpo) (SWH) network controls tissue growth by inhibiting cell proliferation and promoting apoptosis. The core of the pathway consists of a MST and LATS family kinase cascade that ultimately phosphorylates and inactivates the YAP/Yorkie (Yki) transcription coactivator. The FERM domain proteins Merlin (Mer) and Expanded (Ex) represent one mode of upstream regulation controlling pathway activity. Here, we identify Kibra as a member of the SWH network. Kibra, which colocalizes and associates with Mer and Ex, also promotes the Mer/Ex association. Furthermore, the Kibra/Mer association is conserved in human cells. Finally, Kibra complexes with Wts and kibra depletion in tissue culture cells induces a marked reduction in Yki phosphorylation without affecting the Yki/Wts interaction. We suggest that Kibra is part of an apical scaffold that promotes SWH pathway activity. PMID- 20159601 TI - The ordered architecture of murine ear epidermis is maintained by progenitor cells with random fate. AB - Typical murine epidermis has a patterned structure, seen clearly in ear skin, with regular columns of differentiated cells overlying the proliferative basal layer. It has been proposed that each column is a clonal epidermal proliferative unit maintained by a central stem cell and its transit amplifying cell progeny. An alternative hypothesis is that proliferating basal cells have random fate, the probability of generating cycling or differentiated cells being balanced so homeostasis is achieved. The stochastic model seems irreconcilable with an ordered tissue. Here we use lineage tracing to reveal that basal cells generate clones with highly irregular shapes that contribute progeny to multiple columns. Basal cell fate and cell cycle time is random. Cell columns form due to the properties of postmitotic cells. We conclude that the ordered architecture of the epidermis is maintained by a stochastic progenitor cell population, providing a simple and robust mechanism of homeostasis. PMID- 20159602 TI - Rapid inactivation of proteins by rapamycin-induced rerouting to mitochondria. AB - We have developed a method for rapidly inactivating proteins with rapamycin induced heterodimerization. Cells were stably transfected with siRNA-resistant, FKBP-tagged subunits of the adaptor protein (AP) complexes of clathrin-coated vesicles (CCVs), together with an FKBP and rapamycin-binding domain-containing construct with a mitochondrial targeting signal. Knocking down the endogenous subunit with siRNA, and then adding rapamycin, caused the APs to be rerouted to mitochondria within seconds. Rerouting AP-2 to mitochondria effectively abolished clathrin-mediated endocytosis of transferrin. In cells with rerouted AP-1, endocytosed cation-independent mannose 6-phosphate receptor (CIMPR) accumulated in a peripheral compartment, and isolated CCVs had reduced levels of CIMPR, but normal levels of the lysosomal hydrolase DNase II. Both observations support a role for AP-1 in retrograde trafficking. This type of approach, which we call a "knocksideways," should be widely applicable as a means of inactivating proteins with a time scale of seconds or minutes rather than days. PMID- 20159603 TI - La mala educacion of tumor-associated macrophages: Diverse pathways and new players. AB - Inflammation is a key component of the tumor microenvironment. Two reports published in this issue of Cancer Cell, Andreu et al. and Erez et al., shed new light on pathways and players involved in the orchestration of cancer-related inflammation. PMID- 20159604 TI - Discovery of novel transcriptional and epigenetic targets in APL by global ChIP analyses: Emerging opportunity and challenge. AB - Identifying transcriptional program(s) deregulated by oncoproteins is key to understanding the molecular basis of the disease. In this issue of Cancer Cell, two studies by Martens et al. and Wang et al. provide global blueprints for transcriptional targets and epigenetic modifications mediated by PML-RARalpha in acute promyelocytic leukemia. PMID- 20159605 TI - Obesity, inflammatory signaling, and hepatocellular carcinoma-an enlarging link. AB - There is growing evidence that obesity increases the risk of hepatocellular carcinoma (HCC). In a recent issue of Cell, Park et al. show that IL-6 and TNF signaling through activation of STAT3 are critical for obesity-promoted HCC development, underscoring the important role of inflammatory pathways in hepatocarcinogenesis. PMID- 20159606 TI - DUB-le Trouble for Cell Survival. AB - Expression of MCL-1 is frequently elevated in cancer and is implicated in the resistance to chemotherapy by the BCL-2 small molecule inhibitor ABT-737. A recent paper in Nature identified USP9X as an antagonist of MCL-1 ubiquitinylation and degradation. Often upregulated in tumor cells, USP9X activity influences the response to ABT-737. PMID- 20159607 TI - MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele. AB - Oncogenic fusion proteins are capable of initiating tumorigenesis, but the role of their wild-type counterparts in this process is poorly understood. The mixed lineage leukemia (MLL) gene undergoes chromosomal translocations, resulting in the formation of oncogenic MLL fusion proteins (MLL-FPs). Here, we show that menin recruits both wild-type MLL and oncogenic MLL-AF9 fusion protein to the loci of HOX genes to activate their transcription. Wild-type MLL not only catalyzes histone methylation at key target genes but also controls distinct MLL AF9-induced histone methylation. Notably, the wild-type Mll allele is required for MLL-AF9-induced leukemogenesis and maintenance of MLL-AF9-transformed cells. These findings suggest an essential cooperation between an oncogene and its wild type counterpart in MLL-AF9-induced leukemogenesis. PMID- 20159608 TI - Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia b cell survival through its hemopexin domain. AB - Matrix metalloproteinase-9 (MMP-9) is the major MMP produced by B-CLL cells and contributes to their tissue infiltration by degrading extracellular and membrane anchored substrates. Here we describe a different function for MMP-9 in B-CLL, which involves the hemopexin domain rather than its catalytic function. Binding of soluble or immobilized (pro)MMP-9, a catalytically inactive proMMP-9 mutant, or the MMP-9 hemopexin domain to its docking receptors alpha4beta1 integrin and CD44v, induces an intracellular signaling pathway that prevents B-CLL apoptosis. This pathway is induced in all B-CLL cases, is active in B-CLL lymphoid tissues, and consists of Lyn activation, STAT3 phosphorylation, and Mcl-1 upregulation. Our results establish that MMP/receptor binding induces intracellular survival signals and highlight the role of (pro)MMP-9 in B-CLL pathogenesis. PMID- 20159609 TI - PML-RARalpha/RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia. AB - Many different molecular mechanisms have been associated with PML-RARalpha dependent transformation of hematopoietic progenitors. Here, we identified high confidence PML-RARalpha binding sites in an acute promyelocytic leukemia (APL) cell line and in two APL primary blasts. We found colocalization of PML-RARalpha with RXR to the vast majority of these binding regions. Genome-wide epigenetic studies revealed that treatment with pharmacological doses of all-trans retinoic acid induces changes in H3 acetylation, but not H3K27me3, H3K9me3, or DNA methylation at the PML-RARalpha/RXR binding sites or at nearby target genes. Our results suggest that PML-RARalpha/RXR functions as a local chromatin modulator and that specific recruitment of histone deacetylase activities to genes important for hematopoietic differentiation, RAR signaling, and epigenetic control is crucial to its transforming potential. PMID- 20159610 TI - PML/RARalpha targets promoter regions containing PU.1 consensus and RARE half sites in acute promyelocytic leukemia. AB - PML/RARalpha is of crucial importance in acute promyelocytic leukemia (APL) both pathologically and therapeutically. Using a genome-wide approach, we identified in vivo PML/RARalpha binding sites in a PML/RARalpha-inducible cell model. Of the 2979 targeted regions, >62% contained canonical PU.1 motifs and >84% of these PU.1 motifs coexisted with one or more RARE half (RAREh) sites in nearby regions. Promoters with such PU.1-RAREh binding sites were transactivated by PU.1. PU.1 mediated transactivation was repressed by PML/RARalpha and restored by the addition of all-trans retinoic acid (ATRA). Genes containing such promoters were significantly represented by genes transcriptionally suppressed in APL and/or reactivated upon treatment with ATRA. Thus, selective targeting of PU.1-regulated genes by PML/RARalpha is a critical mechanism for the pathogenesis of APL. PMID- 20159611 TI - How autophagy saves mice: A cell-autonomous defense system against Sindbis virus infection. AB - Autophagy has diverse roles, including defense against infection. Levine and colleagues (Orvedahl et al., 2010) provide in vivo evidence for the antiviral function of autophagy in vertebrates: autophagy protects mice against lethal Sindbis virus CNS infection by degrading viral proteins whose accumulation would otherwise cause neuronal cell death. PMID- 20159612 TI - Modeling antibody-enhanced dengue virus infection and disease in mice: protection or pathogenesis? AB - While antibodies play an important protective role during dengue virus infection, they have also been linked to more severe clinical outcomes. In this issue of Cell Host & Microbe, Zellweger and colleagues (Zellweger et al., 2010) describe the development of a murine model of antibody-enhanced dengue virus infection that provides a formal link between immune enhancement and severe disease. PMID- 20159613 TI - Small Silencing RNAs: Piecing Together a Viral Genome. AB - Virus-derived small interfering RNAs (siRNAs) are the hallmark of RNAi-based antiviral immunity. Wu and colleagues demonstrate how viral genomes can be assembled from these small RNA sequences. Their results provide an approach for virus discovery as well as important insights into how these siRNAs mediate antiviral defense. PMID- 20159614 TI - Eating at the table of another: metabolomics of host-parasite interactions. AB - The application of metabolomics, the global analysis of metabolite levels, to the study of protozoan parasites has become an important tool for understanding the host-parasite relationship and holds promise for the development of direly needed therapeutics and improved diagnostics. Research advances over the past decade have opened the door for a systems biology approach to protozoan parasites with metabolomics, providing a crucial readout of metabolic activity. In this review, we highlight recent metabolomic approaches to protozoan parasites, including metabolite profiling, integration with genomics, transcription, and proteomic analysis, and the use of metabolic fingerprints for the diagnosis of parasitic infections. PMID- 20159615 TI - Improving development of the molecular signature for diagnosis of acute respiratory viral infections. PMID- 20159617 TI - Influenza virus-induced glucocorticoids compromise innate host defense against a secondary bacterial infection. AB - Multicellular organisms are continuously exposed to many different pathogens. Because different classes of pathogens require different types of immune responses, understanding how an ongoing immune response to one type of infection affects the host's ability to respond to another pathogen is essential for a complete understanding of host-pathogen interactions. Here, we used a mouse model of coinfection to gain insight into the effect of respiratory influenza virus infection on a subsequent systemic bacterial infection. We found that influenza infection triggered a generalized stress response leading to a sustained increase in serum glucocorticoid levels, resulting in a systemic suppression of immune responses. However, virus-induced glucocorticoid production was necessary to control the inflammatory response and prevent lethal immunopathology during coinfection. This study demonstrates that activation of the hypothalamic pituitary-adrenal axis controls the balance between immune defense and immunopathology and is an important component of the host response to coinfection. PMID- 20159618 TI - Autophagy protects against Sindbis virus infection of the central nervous system. AB - Autophagy functions in antiviral immunity. However, the ability of endogenous autophagy genes to protect against viral disease in vertebrates remains to be causally established. Here, we report that the autophagy gene Atg5 function is critical for protection against lethal Sindbis virus (SIN) infection of the mouse central nervous system. Inactivating Atg5 in SIN-infected neurons results in delayed clearance of viral proteins, increased accumulation of the cellular p62 adaptor protein, and increased cell death in neurons, but the levels of viral replication remain unaltered. In vitro, p62 interacts with SIN capsid protein, and genetic knockdown of p62 blocks the targeting of viral capsid to autophagosomes. Moreover, p62 or autophagy gene knockdown increases viral capsid accumulation and accelerates virus-induced cell death without affecting virus replication. These results suggest a function for autophagy in mammalian antiviral defense: a cell-autonomous mechanism in which p62 adaptor-mediated autophagic viral protein clearance promotes cell survival. PMID- 20159619 TI - Microbial colonization drives expansion of IL-1 receptor 1-expressing and IL-17 producing gamma/delta T cells. AB - IL-17 cytokine production by the Th17 T cell subset is regulated by intestinal commmensals. We show that microbial colonization also regulates innate IL-17 production. A population of CD62L(-) gamma/delta T cells, in particular a lineage expressing the IL-1 receptor 1 (IL-1R1), can be quickly activated by microbes to produce IL-17. Antibiotic treatment and monocolonization of mice suggest that specific commensals-but not metronidazole-sensitive anaerobes like Bacteroides species-are required for maintaining IL-1R1(+) gamma/delta T cells. Signaling through the guanine nucleotide exchange factor VAV1, but not through Toll-like receptors or antigen presentation pathways, is essential for inducing IL-1R1(+) gamma/delta T cells. Furthermore, IL-1R1(+) gamma/delta T cells are a potential source of IL-17 that can be activated by IL-23 and IL-1 in both infectious and noninfectious settings in vitro and in vivo. Thus, commensals orchestrate the expansion of phenotypically distinct gammadelta T cells, and innate immunity is a three-way interaction between host, pathogens, and microbiota. PMID- 20159620 TI - GM-CSF-facilitated dendritic cell recruitment and survival govern the intestinal mucosal response to a mouse enteric bacterial pathogen. AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes dendritic cell (DC) differentiation and survival in vitro. However, its role in host defense at the intestinal mucosa is unknown. We report that infection with the mouse enteric pathogen, Citrobacter rodentium, increased colonic GM-CSF production and CD11c(+) DC recruitment. After infection, GM-CSF(-/-) mice had fewer mucosal CD11c(+) DCs, greater bacterial burden, increased mucosal inflammation and systemic spread of infection, decreased antibody responses, and delayed pathogen clearance. This defective mucosal response was rescued by GM-CSF administration to GM-CSF(-/-) mice and mimicked by CD11c(+) DC depletion in wild-type animals. Diminished mucosal DC numbers in infected GM-CSF(-/-) mice reflected decreased DC recruitment and survival, with the recruitment defect being related to a failure to upregulate epithelial cell production of the DC chemoattractant, CCL22. Thus, GM-CSF produced in the intestinal mucosa acts to enhance host protection against an enteric bacterial pathogen through regulating recruitment and survival of DCs. PMID- 20159622 TI - Computed tomography of the pericardium and pericardial disease. AB - The spectrum of pericardial abnormalities includes congenital absence, pericardial cyst, pericarditis, effusion, constriction, tamponade, retained foreign body, and neoplasms. Because of it high spatial and temporal resolutions, multiplanar reconstruction capability, and large field of view, computed tomography (CT) is a very useful tool in the comprehensive anatomical and functional evaluation of the pericardium. Knowledge of normal pericardial anatomy, anatomic variants, and imaging appearances of various pericardial abnormalities is essential for accurate diagnoses and characterization. In this pictorial review, the CT appearances of the normal pericardium and pericardial abnormalities are discussed and illustrated. PMID- 20159621 TI - Pseudomonas syringae effector protein AvrB perturbs Arabidopsis hormone signaling by activating MAP kinase 4. AB - Pathogenic microbes often modulate phytohormone physiology in the host to their advantage. We previously showed that the Pseudomonas syringae effector protein AvrB perturbs hormone signaling, as exemplified by upregulated expression of jasmonic acid response genes, and enhances plant susceptibility. Here we show that these effects of AvrB require the Arabidopsis mitogen-activated protein kinase MAP kinase 4 (MPK4), HSP90 chaperone components, and the AvrB-interacting protein, RIN4. AvrB interacts with MPK4 and the HSP90 chaperone, and AvrB induces MPK4 activation in a manner promoted by HSP90; RIN4 likely acts downstream of MPK4. These findings link Arabidopsis proteins MPK4, HSP90, and RIN4 into a pathway that P. syringae AvrB activates for the benefit of the bacterium, perturbing hormone signaling and enhancing plant susceptibility. PMID- 20159623 TI - Relation of coronary artery plaque location to extent of coronary artery disease studied by computed tomographic angiography. AB - BACKGROUND: Distal coronary artery disease (CAD) is less amenable to surgery or stenting compared with proximal disease. However, little is known about the epidemiology of distal versus proximal CAD. METHODS: We determined the prevalence and factors associated with proximal, mid, and distally located plaque in the left anterior descending, left circumflex, and right coronary arteries in 418 subjects without prior CAD history who underwent coronary computed tomographic angiography for symptoms or stress test results. Clinical characteristics and coronary artery calcium (CAC) scores were also determined. RESULTS: Most subjects (88%) had plaque, but only 18% of plaques were associated with stenosis >50%. In subjects with single-vessel plaque, only 7% had distal plaque, whereas 75% had proximal plaque. With 3-vessel plaque, 70% had distal and 100% had proximal plaques. Of subjects with a single location of plaque along a vessel, most had proximal plaque (69%); isolated distal-vessel plaque was rare (2%). Distal plaque was dominantly found in association with both proximal and mid plaque (88%). After multivariable adjustment for demographics, traditional, and nontraditional risk factors, both increasing number of vessels with plaque and clinically significant CAC scores were independently associated with higher odds of distal plaque, whereas associations of traditional risk factors were weaker. Distal plaque was independently associated with stenosis > 50%. CONCLUSION: These data support the concept that early lesions are most often proximal and that CAC scoring may be a poor screening tool for detecting proximal disease. Furthermore, distal lesions are more associated with advanced disease than with traditional cardiovascular risk factors. PMID- 20159624 TI - Distribution matters: Diagnostic value of coronary plaque in distal segments. PMID- 20159625 TI - Noninvasive quantitative evaluation of coronary artery stent patency using 64-row multidetector computed tomography. AB - BACKGROUND: Many studies have used multidetector computed tomography (MDCT) angiography to evaluate coronary stents qualitatively but not quantitatively. OBJECTIVES: This study sought to validate a method of quantitatively evaluating stent patency by using 64-row compared with invasive coronary angiography (ICA) and to evaluate the stent size threshold of MDCT in detecting stent patency. METHODS: Stented lesions (n=122) in 55 patients (age, 65+/-10 years; 90% men) who underwent both 64-row MDCT and ICA were studied. Density measurements in Hounsfield units (HUs) and stent diameters in millimeters were recorded in the stented segments, with the density of the ascending aorta (AO) taken as a reference. The ratio of the average of stent's proximal, middle, and distal densities to mean AO density was defined as the AS/AO HU. Threshold values for the detection of stent patency were examined by using receiver operator characteristic (ROC) curve analysis. RESULTS: One hundred six of 122 stents were interpretable. By ICA, 24 stents were found to have in-stent restenosis (22 interpretable and 2 noninterpretable with MDCT). The ROC curve showed that the optimal cutoff value of AS/AO HU to predict stent patency on MDCT was 0.81 with sensitivity of 90.9%, specificity of 95.2%, and the optimal stent diameter cutoff value was > or = 2.5 mm with a sensitivity of 91.8% and a specificity of 93.8%. CONCLUSION: With 64-row MDCT, coronary stent patency can be evaluated quantitatively with high sensitivity and specificity and with adequate diagnostic accuracy in stents > or = 2.5 mm in diameter. PMID- 20159626 TI - The challenge of coronary stent imaging. PMID- 20159627 TI - Relationship of aortic valve calcification with coronary artery calcium severity: the Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: Aortic valve calcification (AVC) and atherosclerosis share causative and pathologic features. OBJECTIVE: We evaluated the relationship between AVC and coronary artery calcium (CAC) severity in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: Men and women aged 45-84 years (n=6809; mean age, 62 years) were studied. The presence and burden of AVC and CAC were determined by noncontrast cardiac computed tomography. Relative risk regression was used to model the probability of AVC as a function of CAC > 0 as well as CAC categories (0, 1-99, 100-399, and > or = 400) with the reference group being CAC=0. RESULTS: The prevalence of AVC and CAC was 13% and 50%, respectively. Among those without CAC, the prevalence of AVC was 5% and increased across levels of CAC severity such that 14%, 25%, and 38% had AVC with increasing CAC scores of 1-99, 100-399, and > or = 400, respectively (P for trend<0.0001). After controlling for patient demographic factors and cardiovascular risk factors, the prevalence ratio of AVC among those with mild CAC (1-99) was 1.83 (95% CI, 1.45 2.31) and increased to 3.36 (95% CI, 2.56-4.42) for CAC > or = 400. Similar statistically significant increased risk of AVC was found when CAC was assessed as a continuous variable. CONCLUSION: Our study shows that AVC is independently associated with increasing severity of CAC. PMID- 20159628 TI - Aortic valve calcification and subclinical coronary atherosclerosis. PMID- 20159629 TI - Axial area and anteroposterior diameter as estimates of left atrial size using computed tomography of the chest: comparison with 3-dimensional volume. AB - BACKGROUND: Left atrial (LA) size has incremental value in risk stratification. OBJECTIVES: We aimed to assess feasibility and reproducibility of 2 quick measures of LA size by chest CT (axial LA area and LA anteroposterior [AP] diameter) by using contrast-enhanced and CT scans. METHODS: We measured LA size in 100 contrast-enhanced 64-slice multidetector CT (MDCT) scans (randomly selected from the ROMICAT collective) by (1) axial LA area at the level of the left ventricular outflow tract and the mitral valve leaflets, (2) AP diameter in 3-chamber view, and (3) 3-dimensional (3D) LA volume by Simpson's methods. We assessed interobserver and intraobserver intraclass correlation coefficient (ICC) for axial LA area and AP diameter as well as their correlation to 3D LA volume. For axial area, feasibility and reproducibility were also determined in 100 non contrast MDCT scans, randomly selected from the Framingham Heart Offspring collective. RESULTS: In contrast-enhanced CT, both LA axial area and AP diameter had excellent reproducibility (interobserver: axial area: ICC, 0.96, mean relative difference, 2.4% +/- 7.4%; AP diameter: ICC, 0.91, 3.6% +/- 7.2%; intraobserver: axial area: ICC, 0.99, 0.4% +/- 5.2%; AP diameter: ICC, 0.94, 1.7% +/- 5.5%). Correlations with 3D volume were better for axial area (r=0.88) than for AP diameter (r=0.67). In non-contrast images, axial area could be assessed with excellent reproducibility (interobserver: ICC, 0.96, 0.5% +/- 8.3%; intraobserver: ICC, 0.99, 0.01% +/- 4.4%). CONCLUSION: Both AP diameter and axial LA area permit quick and reproducible estimates of LA volume in contrast-enhanced and non-contrast electrocardiographic-gated chest CT. However, LA area should be used preferably over AP diameter because of its better agreement to 3D LA volume. PMID- 20159630 TI - Left atrial size: when an imperfect measurement may be close enough. PMID- 20159631 TI - Sternal erosion detected by computed tomographic angiography before repeat sternotomy in an adolescent with congenital heart disease. AB - The case of a 17-year-old male with congenital heart disease who was found to have erosion of a pseudoaneurysm into his posterior sternum is presented. The pseudoaneurysm originated from a right ventricle-to-pulmonary artery homograft, which had been placed 11 years before. It had not been appreciated by echocardiography. The pseudoaneurysm and erosion were visualized with computed tomographic angiography before scheduled surgical replacement of the homograft. This unexpected finding was critical for operative planning and was confirmed on direct visualization in the operating room. PMID- 20159632 TI - Images of persistent left superior vena cava draining directly into left atrium and secundum-type atrial septal defect. AB - The images of persistent left superior vena cava with the absence of the right superior vena cava are presented in a patient with the diagnosis of secundum-type atrial septal defect. PMID- 20159633 TI - Consider charity with caution. AB - Cardiac CT offers a non-invasive diagnostic alternative to coronary angiography in the diagnosis of spontaneous coronary dissection. PMID- 20159635 TI - Screening asymptomatic firefighters. PMID- 20159636 TI - President's page: One of 600,000. PMID- 20159637 TI - Assessment of myocardial viability at dobutamine echocardiography by deformation analysis using tissue velocity and speckle-tracking. AB - OBJECTIVES: Comparison of myocardial tissue-velocity imaging (TVI) and speckle tracking echocardiography (STE) for prediction of viability at dobutamine echocardiography (DbE). BACKGROUND: Use of TVI-based strain imaging during DbE may facilitate the prediction of myocardial viability but has technical limitations. STE overcomes these but requires evaluation for prediction of viability. METHODS: We studied 55 patients with ischemic heart disease and left ventricular systolic dysfunction (left ventricular ejection fraction <0.45) who were undergoing DbE for assessment of myocardial viability and who subsequently underwent myocardial revascularization. TVI was used to measure longitudinal end systolic strain (longS) and peak systolic strain rate (SR) at rest and at low dose dobutamine (LDD). Longitudinal, radial, and circumferential strain and strain rate were measured with STE. Segmental functional recovery was defined by improved wall-motion score on side-by-side comparison of echocardiographic images before and 9 months after revascularization and areas under the receiver operator characteristic curves were used to compare methods. RESULTS: Of the 375 segments with abnormal resting function, 154 (41%) showed functional recovery. Only circumferential resting and low-dose STE strain and low-dose longitudinal strain and SR predicted functional recovery independent of wall-motion analysis. Among different strain parameters, only TVI-based longitudinal end-systolic strain and peak systolic SR at LDD had incremental value over wall-motion analysis (areas under the receiver operator characteristic curves of 0.79, 0.79, and 0.74, respectively). STE measurements of strain and SR identified viability only in the anterior circulation, whereas TVI strain and SR accurately identified viability in both anterior and posterior circulations. CONCLUSIONS: Combination of TVI or STE methods with DbE can predict viability, with TVI strain and SR at LDD being the most accurate. TVI measures can predict viability in both anterior and posterior circulations, but STE measurements predict viability only in the anterior circulation. PMID- 20159638 TI - Usefulness of echocardiographic dyssynchrony in patients with borderline QRS duration to assist with selection for cardiac resynchronization therapy. AB - OBJECTIVES: To test the hypothesis that echocardiographic dyssynchrony may assist in the selection of patients with borderline QRS duration for cardiac resynchronization therapy (CRT). BACKGROUND: Although echocardiographic dyssynchrony is currently not recommended to select patients with QRS duration widening for CRT, its utility in patients with borderline QRS widening is unclear. METHODS: Of 221 consecutive heart failure patients with an ejection fraction (EF) < or =35% referred for CRT, 86 had a borderline QRS duration of 100 to 130 ms (115 +/- 8 ms) and 135 patients had wide QRS >130 ms (168 +/- 26 ms). Dyssynchrony was assessed using interventricular mechanical delay, tissue Doppler imaging longitudinal velocity opposing wall delay, and speckle tracking radial strain for septal to posterior wall delay. Response to CRT was defined as > or =15% increase in EF, and reverse remodeling as > or =10% decrease in end-systolic volume. RESULTS: There were 201 patients with baseline quantitative echocardiographic data available, and 187 with follow-up data available 8 +/- 5 months after CRT. A smaller proportion of borderline QRS duration patients (53%) were EF responders compared with 75% with widened QRS (p < 0.05). Interventricular mechanical delay > or =40 ms and opposing wall delay > or =65 ms were predictive of EF response in the wide QRS duration group, but not the borderline QRS duration group. Speckle tracking radial dyssynchrony > or =130 ms, however, was predictive of EF response in both wide QRS interval patients (88% sensitivity, 74% specificity) and borderline QRS interval patients (79% sensitivity, 82% specificity) and associated reverse remodeling with reduction in end-systolic volume (p < 0.0005). CONCLUSIONS: Radial dyssynchrony by speckle tracking strain was associated with EF and reverse remodeling response to CRT in patients with borderline QRS duration and has the potential to assist with patient selection. PMID- 20159639 TI - QRS width and mechanical dyssynchrony for selection of patients for cardiac resynchronization therapy: one can't do without the other. PMID- 20159640 TI - Comparison of magnetic resonance feature tracking for strain calculation with harmonic phase imaging analysis. AB - OBJECTIVES: To compare a steady-state free precession cine sequence-based technique (feature tracking [FT]) to tagged harmonic phase (HARP) analysis for peak average circumferential myocardial strain (epsilon(cc)) analysis in a large and heterogeneous population of boys with Duchenne muscular dystrophy (DMD). BACKGROUND: Current epsilon(cc) assessment techniques require cardiac magnetic resonance-tagged imaging sequences, and their analysis is complex. The FT method can readily be performed on standard cine (steady-state free precession) sequences. METHODS: We compared mid-left ventricular whole-slice epsilon(cc) by the 2 techniques in 191 DMD patients grouped according to age and severity of cardiac dysfunction: group B: DMD patients 10 years and younger with normal ejection fraction (EF); group C: DMD patients older than 10 years with normal EF; group D: DMD patients older than 10 years with reduced EF but negative myocardial delayed enhancement (MDE); group E: DMD patients older than 10 years with reduced EF and positive MDE; and group A: 42 control subjects. Retrospective, offline analysis was performed on matched tagged and steady-state free precession slices. RESULTS: For the entire study population (N = 233), mean FT epsilon(cc) values ( 13.3 +/- 3.8%) were highly correlated with HARP epsilon(cc) values (-13.6 +/- 3.4%), with a Pearson correlation coefficient of 0.899. The mean epsilon(cc) of DMD patients determined by HARP (-12.52 +/- 2.69%) and FT (-12.16 +/- 3.12%) was not significantly different (p = NS). Similarly, the mean epsilon(cc) of the control subjects by determined HARP (-18.85 +/- 1.86) and FT (-18.81 +/- 1.83) was not significantly different (p = NS). Excellent correlation between the 2 methods was found among subgroups A through E, except there was no significant difference in strain between groups B and C with FT analysis. CONCLUSIONS: FT based assessment of epsilon(cc) correlates highly with epsilon(cc) derived from tagged images in a large DMD patient population with a wide range of cardiac dysfunction and can be performed without additional imaging. PMID- 20159641 TI - Straining to justify strain measurement. PMID- 20159642 TI - Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. AB - OBJECTIVES: Our aim was to evaluate the role and mechanism of late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) in identifying cardiac amyloidosis (CA) and to investigate associations between LGE and clinical, morphologic, functional, and biochemical features. BACKGROUND: CA can be challenging to diagnose by echocardiography. Recent studies have demonstrated an emerging role for LGE-CMR. METHODS: LGE-CMR was performed in 120 patients with amyloidosis. Cardiac histology was available in 35 patients. The remaining 85 patients were divided into those with and without echocardiographic evidence of CA. RESULTS: Of the 35 patients with histologically verified CA, abnormal LGE was present in 34 (97%) patients and increased echocardiographic left ventricular wall thickness in 32 (91%) patients. Global transmural or subendocardial LGE (83%) was most common and was associated with greater interstitial amyloid deposition (p = 0.03). Suboptimal myocardial nulling (8%) and patchy focal LGE (6%) were also observed. LGE distribution matched the deposition pattern of interstitial amyloid. Among patients without cardiac histology, LGE was present in 86% of those with evidence of CA by echocardiography and in 47% of those without evidence of CA by echocardiography. In patients without echocardiographic evidence of CA, the presence of LGE was associated with worse clinical, electrocardiographic (ECG), and cardiac biomarker profiles. In all patients, LGE presence and pattern was associated with New York Heart Association functional class, ECG voltage, left ventricular mass index, right ventricular wall thickness, troponin-T, and B-type natriuretic peptide levels. CONCLUSIONS: LGE is common in CA and detects interstitial expansion from amyloid deposition. Global transmural or subendocardial LGE is most common, but suboptimal myocardial nulling and focal patchy LGE are also observed. LGE-CMR may detect early cardiac abnormalities in patients with amyloidosis with normal left ventricular thickness. The presence and pattern of LGE is strongly associated with clinical, morphologic, functional, and biochemical markers of prognosis. PMID- 20159643 TI - MR Imaging and Cardiac Amyloidosis Where to Go From Here? PMID- 20159644 TI - OCT assessment of thin-cap fibroatheroma distribution in native coronary arteries. AB - OBJECTIVES: We evaluated the geographic distribution of thin-cap fibroatheromas (TCFAs) in the coronary arteries using optical coherence tomography (OCT), a high resolution imaging modality. BACKGROUND: Plaque rupture is the most frequent cause of acute myocardial infarction (AMI). It has been recognized that TCFA is the primary plaque type at the site of plaque rupture. METHODS: We performed 3 vessel OCT examinations in 55 patients: 35 AMI and 20 stable angina pectoris patients. The criteria for TCFA in an OCT image was a lipid-rich plaque with fibrotic cap thickness <65 microm. The distance between each TCFA location and the respective coronary artery ostium was measured with motorized OCT imaging pullback. The total length of all 3 coronary arteries imaged by OCT pullbacks was 82 +/- 21 mm in the left anterior descending coronary artery (LAD), 67 +/- 26 mm in the left circumflex coronary artery (LCx), and 104 +/- 32 mm in the right coronary artery (RCA). RESULTS: OCT detected 94 TCFAs in 165 coronary arteries. The minimum fibrous-cap thickness of TCFAs was 57.4 +/- 5.4 microm in AMI patients, and 55.9 +/- 7.3 microm in stable angina pectoris patients (p = 0.4). Of the total of 94 TCFAs, 28 were detected in the LAD, 18 in the LCx, and 48 in the RCA. Most LAD TCFAs were located between 0 and 30 mm from the LAD ostium (76%). Conversely, LCx and RCA TCFAs were evenly distributed throughout the entire coronary length. The clustering of the TCFAs was similar in culprit segments as compared with nonculprit segments. In AMI patients, most LAD TCFAs were distributed near side branches, mainly positioned opposite the side branch bifurcation. CONCLUSIONS: Three-vessel OCT imaging showed that TCFAs tend to cluster in predictable spots within the proximal segment of the LAD, but develop relatively evenly in the LCx and RCA arteries. PMID- 20159645 TI - Myocardial perfusion imaging with contrast ultrasound. AB - This report reviews the development and clinical application of myocardial perfusion imaging with myocardial contrast echocardiography (MCE). This includes the development of microbubble formulations that permit the detection of left ventricular contrast from venous injection and the imaging techniques that have been invented to detect the transit of these microbubbles through the microcirculation. The methods used to quantify myocardial perfusion during a continuous infusion of microbubbles are described. A review of the clinical studies that have examined the clinical utility of myocardial perfusion imaging with MCE during rest and stress echocardiography is then presented. The limitations of MCE are also discussed. PMID- 20159646 TI - Clinical applications of left ventricular opacification. AB - The significant advances made in ultrasound microbubble technology now permits reliable, reproducible left ventricular opacification, and this review reiterates the evidence that has shown contrast echocardiography to be clinically effective, to reduce downstream costs and to spare patients further, potentially hazardous investigations. Despite the evidence and the advances, there remains ambivalence towards the administration of contrast agents in echocardiography laboratories throughout the world, particularly in the performance of rest studies. Therefore, this review also addresses some of the reasons for the suboptimal uptake of contrast agents and encourages physicians, sonographers, and accreditatory bodies to adopt a different approach towards the difficult-to-image patient. PMID- 20159647 TI - Utility contrast echocardiography in the emergency department. AB - The diagnosis and risk stratification of patients presenting with suspected cardiac chest pain to the emergency department (ED) is difficult, inefficient, and costly. Echocardiography can be used to directly detect myocardial ischemia through the identification of a new wall thickening (WT) abnormality. Contrast echocardiography provides further incremental benefit both for assessment of WT, as well as from the evaluation of myocardial perfusion. This review will discuss how echocardiography can be used to diagnose, risk stratify, and potentially reduce costs in patients with suspected acute coronary syndromes in the ED. PMID- 20159648 TI - Molecular imaging of myocardial and vascular disorders with ultrasound. AB - Methods for noninvasive imaging of specific disease-related molecular changes are being developed in order to expand and improve diagnostic capabilities and to enhance therapeutic decision making in the clinical setting. These new techniques have also started to be incorporated into research programs in order to better characterize pathophysiology or evaluate treatment efficacy. Molecular imaging with contrast-enhanced ultrasound relies on the detection of the acoustic signal produced by either microbubbles or other acoustically active particulate agents that are targeted to sites of disease. This review describes the progress that has been made in the development and testing of methods for contrast ultrasound molecular imaging of cardiovascular disease. Specifically, topics that will be addressed include: 1) the bioengineering and detection schemes for targeted probes; 2) specific disease processes (myocardial ischemia, atherosclerosis, and transplant rejection) where molecular imaging may play a role; and 3) the potential role of ultrasound as a molecular imaging technique. PMID- 20159649 TI - Myocardial contrast echocardiography: a wondrous journey! PMID- 20159650 TI - Transesophageal echocardiography to help position and deploy a transcatheter heart valve. PMID- 20159651 TI - Successful transapical transcatheter valve implantation within a dysfunctional mitral bioprosthesis. PMID- 20159652 TI - Contrast echocardiography: over-achievement in research, under-achievement in practice? PMID- 20159653 TI - Is early word-form processing stress-full? How natural variability supports recognition. AB - In a series of studies, we examined how mothers naturally stress words across multiple mentions in speech to their infants and how this marking influences infants' recognition of words in fluent speech. We first collected samples of mothers' infant-directed speech using a technique that induced multiple repetitions of target words. Acoustic analyses revealed that mothers systematically alternated between emphatic and nonemphatic stress when talking to their infants. Using the headturn preference procedure, we then tested 7.5-month old infants on their ability to detect familiarized bisyllabic words in fluent speech. Stress of target words (emphatic and nonemphatic) was systematically varied across familiarization and recognition phases of four experiments. Results indicated that, although infants generally prefer listening to words produced with emphatic stress, recognition was enhanced when the degree of emphatic stress at familiarization matched the degree of emphatic stress at recognition. PMID- 20159654 TI - A cross-sectional evaluation of the first cohort of young adults conceived by in vitro fertilization in the United States. AB - OBJECTIVE: To assess the quality of life and susceptibility for chronic disease development of the oldest generation of young adults conceived by IVF in the U.S. DESIGN: Cross-sectional. SETTING: Single tertiary clinic. PATIENT(S): Young adults conceived by standard IVF between 1981 and 1990. INTERVENTION(S): Self administered questionnaire. MAIN OUTCOME MEASURE(S): Indicators of physical, psychologic, and behavioral health. RESULT(S): A total of 173 (31%) of 560 eligible young adults completed the questionnaire. Mean age was 21.2 years (range 18-26 years) and male-to-female ratio was 3:4. A limited number were conceived through gamete donation but none through oocyte/embryo micromanipulation. Prevalence rates of overweight and obesity were 35% and 10%, respectively. More than 65% were ever diagnosed with a chronic condition; most diagnoses were psychiatric, ocular, respiratory, and cardiometabolic in nature. Almost 40% of respondents were lifetime smokers, 62% reported binge drinking in the previous year, and >90% were physically active in the preceding month. Survey participants were mostly similar to a subsample of the 1999-2004 National Health and Nutrition Examination Survey on selected health indicators. CONCLUSION(S): Young adults conceived by IVF appear to be healthy and well adjusted, although the preponderance of psychologic health problems requires further investigation. PMID- 20159656 TI - Acylated phenylethanoid oligoglycosides with hepatoprotective activity from the desert plant Cistanche tubulosa. AB - The methanolic extract from fresh stems of Cistanche tubulosa (Orobanchaceae) was found to show hepatoprotective effects against D-galactosamine (D GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. From the extract, three new phenylethanoid oligoglycosides, kankanosides H(1) (1), H(2) (2), and I (3), were isolated together with 16 phenylethanoid glycosides (4-19) and two acylated oligosugars (20, 21). The structures of 1-3 were determined on the basis of spectroscopic properties as well as of chemical evidence. Among the isolates, echinacoside (4, IC(50)=10.2 microM), acteoside (5, 4.6 microM), isoacteoside (6, 5.3 microM), 2'-acetylacteoside (8, 4.8 microM), and tubuloside A (10, 8.6 microM) inhibited D-GalN-induced death of hepatocytes. These five isolates, 4 (31.1 microM), 5 (17.8 microM), 6 (22.7 microM), 8 (25.7 microM), and 10 (23.2 microM), and cistantubuloside B(1) (11, 21.4 microM) also reduced TNF-alpha induced cytotoxicity in L929 cells. Moreover, principal constituents (4-6) exhibited in vivo hepatoprotective effects at doses of 25-100mg/kg, po. PMID- 20159655 TI - Stimulating conversation: enhancement of elicited propositional speech in a patient with chronic non-fluent aphasia following transcranial magnetic stimulation. AB - Although evidence suggests that patients with left hemisphere strokes and non fluent aphasia who receive 1Hz repetitive transcranial magnetic stimulation (rTMS) over the intact right inferior frontal gyrus experience persistent benefits in naming, it remains unclear whether the effects of rTMS in these patients generalize to other language abilities. We report a subject with chronic non-fluent aphasia who showed stable deficits of elicited propositional speech over the course of 5 years, and received 1200 pulses of 1Hz rTMS daily for 10 days at a site identified as being optimally responsive to rTMS in this patient. Consistent with prior studies there was improvement in object naming, with a statistically significant improvement in action naming. Improvement was also demonstrated in picture description at 2, 6, and 10 months after rTMS with respect to the number of narrative words and nouns, sentence length, and use of closed class words. Compared to his baseline performance, the patient showed significant improvement on the Western Aphasia Battery (WAB) subscale for spontaneous speech. These findings suggest that manipulation of the intact contralesional cortex in patients with non-fluent aphasia may result in language benefits that generalize beyond naming to include other aspects of language production. PMID- 20159657 TI - Ascorbic acid formation and profiling of genes expressed in its synthesis and recycling in apple leaves of different ages. AB - Ascorbic acid (AsA), as a unique antioxidant and enzyme cofactor, has multiple roles in plants. However, there is very limited information on the mechanism of AsA accumulation and controlling in leaves. In this study, we determined AsA accumulation levels, analyzed expression patterns of the genes involved in synthesizing via l-galactose pathway and recycling as well as enzyme activities in apple (Malus domestica Borkh) leaves with different age. AsA content was found to increase with leaf development, reaching the highest level in 20-day-old leaves. This level was maintained in mature leaves until the dropping in senescent leaves. Comparing with young and senescent leaves, mature leaves had higher capability for AsA synthesis with high expression levels and activity of l galactose dehydrogenase and l-galactono-1,4-lactone dehydrogenase. The mRNA expression of genes involved in AsA synthesis also showed highest abundance in 20 day-old leaves, though GDP-mannose-3',5'-epimerase and l-galactose-1-phosphate phosphatase expression reached the highest levels before 20 days old. These results suggest that AsA accumulation in apple leaves mainly occurs during the transition phase from young to mature leaves with high rates of synthesis and recycling, and that l-galactose-1-phosphate phosphatase could play an important role in regulating AsA biosynthesis via the l-galactose pathway. PMID- 20159658 TI - Characteristics of cellular polyamine transport in prokaryotes and eukaryotes. AB - Polyamine content in cells is regulated by biosynthesis, degradation and transport. In Escherichia coli, there are two polyamine uptake systems, namely spermidine-preferential (PotABCD) and putrescine-specific (PotFGHI), which belong to the family of ATP binding cassette transporters. Putrescine-ornithine and cadaverine-lysine antiporters, PotE and CadB, each consisting of 12 transmembrane segments, are important for cell growth at acidic pH. Spermidine excretion protein (MdtJI) was also recently identified. When putrescine was used as energy source, PuuP functioned as a putrescine transporter. In Saccharomyces cerevisiae, there are four kinds of polyamine uptake proteins (DUR3, SAM3, GAP1 and AGP2), consisting of either 12 or 16 transmembrane segments. Among them, DUR3 and SAM3 mostly contribute to polyamine uptake. There are also five kinds of polyamine excretion proteins (TPO1-5), consisting of 12 transmembrane segments. Among them, TPO1 and TPO5 are the most active proteins. Since a polyamine metabolizing enzyme, spermidine/spermine N(1)-acetyltransferase, is not present in yeast, five kinds of excretion proteins may exist. The current status of polyamine transport in mammalian and plant cells are reviewed. PMID- 20159659 TI - Plasma free metanephrines in healthy cats, cats with non-adrenal disease and a cat with suspected phaeochromocytoma. AB - Phaeochromocytomas are catecholamine-secreting tumours of the adrenal glands and are rare in cats. Plasma metanephrine levels are widely considered the diagnostic test of choice for phaeochromocytoma in people but have not been investigated in cats. In this study plasma free normetanephrine and metanephrine levels were measured using high-pressure liquid chromatography in healthy cats, sick cats with non-adrenal disease and in a cat with a suspected phaeochromocytoma. Plasma normetanephrine was significantly higher in sick cats with non-adrenal disease compared to healthy cats (P<0.05) and markedly higher in the cat with a suspected phaeochromocytoma when compared to either group. Plasma metanephrine was not significantly different in any of the groups. This study establishes a first-line guide reference range for plasma metanephrine and normetanephrine levels in healthy cats and cats with non-adrenal disease. These results provide rationale for further studies to establish the use of plasma normetanephrine levels as a potential diagnostic test for phaeochromocytoma in the cat. PMID- 20159660 TI - The potential role of physical exercise in the treatment of epilepsy. AB - The beneficial effects of exercise for people with epilepsy, including reduction of seizure susceptibility, improvement of quality of life, reduction of anxiety and depression, and better social integration, have increasingly been reported. We present data from human and animal studies supporting the role of exercise as a therapy for epilepsy complementary to standard treatments. PMID- 20159661 TI - Multiple myeloma. AB - Advances in the imaging and treatment of multiple myeloma have occurred over the past decade. This article summarises the current status and highlights how an understanding of both is necessary for optimum management. PMID- 20159662 TI - Free-breathing diffusion-weighted single-shot echo-planar MR imaging using parallel imaging (GRAPPA 2) and high b value for the detection of primary rectal adenocarcinoma. AB - Our objective was to determine the diagnostic accuracy of a free-breathing diffusion-weighted single-shot echo-planar magnetic resonance imaging (FBDW SSEPI) technique with parallel imaging and high diffusion factor value (b = 1000 s/mm2) in the detection of primary rectal adenocarcinomas. Thirty-one patients (14M and 17F; mean age 67 years) with histopathologically proven primary rectal adenocarcinomas and 31 patients without rectal malignancies (14M and 17F; mean age 63.6 years) were examined with FBDW-SSEPI (repetition time (TR/echo time (TE) 3900/91 ms, gradient strength 45 mT/m, acquisition time 2 min) at 1.5 T using generalized autocalibrating partially parallel acquisitions (GRAPPA, acceleration factor 2) and a b value of 1000 s/mm2. Apparent diffusion coefficients (ADCs) of rectal adenocarcinomas and normal rectal wall were measured. FBDW-SSEPI images were evaluated for tumour detection by 2 readers. Sensitivity, specificity, accuracy and Youden score for rectal adenocarcinoma detection were calculated with their 95% confidence intervals (CI) for ADC value measurement and visual image analysis. Rectal adenocarcinomas had significantly lower ADCs (mean 1.036 x 10(-3)+/- 0.107 x 10(-3) mm2/s; median 1.015 x 10(-3) mm2/s; range (0.827-1.239) x 10(-3) mm2/s) compared with the rectal wall of control subjects (mean 1.387 x 10(-3)+/- 0.106 x 10(-3) mm2/s; median 1.385 x 10(-3) mm2/s; range (1.176-1.612) x 10(-3) mm2/s) (p < 0.0001). Using a threshold value < or = 1.240 x 10(-3) mm2/s, all rectal adenocarcinomas were correctly categorized and 100% sensitivity (31/31; 95% CI 95-100%), 94% specificity (31/33; 95% CI 88-100%), 97% accuracy (60/62; 95% CI 92-100%) and Youden index 0.94 were obtained for the diagnosis of rectal adenocarcinoma. FBDW-SSEPI image analysis allowed depiction of all rectal adenocarcinomas but resulted in 2 false-positive findings, yielding 100% sensitivity (31/31; 95% CI 95-100%), 94% specificity (31/33; 95% CI 88-100%), 97% accuracy (60/62; 95% CI 92-100%) and Youden index 0.94 for the diagnosis of primary rectal adenocarcinoma. We can conclude that FBDW-SSEPI using parallel imaging and high b value may be helpful in the detection of primary rectal adenocarcinomas. PMID- 20159663 TI - Molecular imaging in thyroid cancer. AB - Molecular imaging plays an important role in the evaluation and management of thyroid cancer. The routine use of thyroid scanning in all thyroid nodules is no longer recommended by many authorities. In the initial work-up of a thyroid nodule, radioiodine imaging can be particularly helpful when the thyroid stimulating hormone level is low and an autonomously functioning nodule is suspected. Radioiodine imaging can also be helpful in the 10-15% of cases for which fine-needle aspiration biopsy is indeterminate. Therapy of confirmed thyroid cancer frequently involves administration of iodine-131 after surgery to ablate remnant tissue. In the follow-up of thyroid cancer patients, increased thyroglobulin levels will often prompt the empiric administration of 131I followed by whole body radioiodine imaging in the search for recurrent or metastatic disease. 131I imaging of the whole body and blood pharmacokinetics can be used to determine if higher doses of 131I can be given in thyroid cancer. The utility of [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) is steadily increasing. FDG is primarily taken up by dedifferentiated thyroid cancer cells, which are poorly iodine avid. Thus, it is particularly helpful in the patient with an increased thyroglobulin but negative radioiodine scan. FDG PET is also useful in the patient with a neck mass but unknown primary, in patients with aggressive (dedifferentiated) thyroid cancer, and in patients with differentiated cancer where histologic transformation to dedifferentiation is suspected. In rarer types of thyroid cancer, such as medullary thyroid cancer, FDG and other tracers such as 99mTc sestamibi, [11C]methionine, [111In]octreotide, and [68Ga]somatostatin receptor binding reagents have been utilized. 124I is not widely available, but has been used for PET imaging of thyroid cancer and will likely see broader applicability due to the advantages of PET methodology. PMID- 20159664 TI - CT perfusion in oncology: how to do it. AB - Robust technique and accurate data analysis are required for reliable computed tomography perfusion (CTp) imaging. Multislice CT is required for high temporal resolution scanning; 16-slice (or 64-slice) scanners are preferred for adequate volume coverage. After tumour localization, the volume of CTp imaging has to be positioned to include the maximum visible area of the tumour and an adequate arterial vessel. Dynamic scans at high temporal resolution (at least 1-s gantry rotation time) are performed to visualize the first pass of contrast agent within the tumour; repeated scans with low temporal resolution can be planned for late enhancement assessment. A short bolus of conventional iodinated contrast agent, preferably with high iodine concentration, is power injected at a high flow rate (>4 ml/s) in the antecubital vein. The breath-hold technique is required for CTp imaging of the chest and upper abdomen to avoid respiratory motion; free breathing is adequate for CTp imaging of the head, neck and pelvis. Using dedicated software, a region of interest (ROI) has to be placed in an adequate artery (as arterial input) to obtain density-time curves; according to different kinetic models, colour maps of different CTp parameters are generated and generally overlaid on CT images. Additional ROIs can be positioned in the tumour, and in all other parts of the CTp volume, to obtain the values of the CTp parameters within the ROI. PMID- 20159665 TI - HIV-induced immune activation: pathogenesis and clinical relevance - summary of a workshop organized by the German AIDS Society (DAIG e.v.) and the ICH Hamburg, Hamburg, Germany, November 22, 2008. AB - This manuscript is communicated by the German AIDS Society (DAIG) (www.daignet.de). It summarizes a series of presentations and discussions during a workshop on immune activation due to HIV infection. The workshop was held on November 22nd 2008 in Hamburg, Germany. It was organized by the ICH Hamburg under the auspices of the German AIDS Society (DAIG e.V.). PMID- 20159666 TI - Bendamustine in patients with relapsed or refractory multiple myeloma. AB - OBJECTIVE: In patients with multiple myeloma, bendamustine monotherapy is effective as 1st and 2nd line therapy. However, data for patients with advanced multiple myeloma is rare. METHODS: In this retrospective analysis we have identified 39 patients with relapsed or refractory multiple myeloma by means of case research, who have been treated at our institution with bendamustine as salvage therapy. After in median 2 lines of prior therapy (range: 1-5) patients received in median 3 (range: 1-10) cycles of bendamustine. Bendamustine dosage was 80-150 mg on day 1+2 of a monthly cycle. Bendamustine was administered as monotherapy in 39% of patients, whereas 61% received concomitant steroids. RESULTS: Toxicity was mild to moderate. Response rates were as follows: 3% vgPR, 33% PR, 18% MR, 26% SD and 20% PD. The median event-free and overall survival were 7 and 17 months, respectively. CONCLUSIONS: In conclusion, in patients with advanced multiple myeloma bendamustine is effective and associated with mild toxicity. Therefore, the role of bendamustine in patients with multiple myeloma should be investigated in further clinical trials. PMID- 20159667 TI - DNA methylation of the RIZ1 tumor suppressor gene plays an important role in the tumorigenesis of cervical cancer. AB - OBJECTIVE: The retinoblastoma protein-interacting zinc finger gene RIZ1 is a tumor suppressor gene and a member of a nuclear histone/protein methyltransferase superfamily. The purpose of the present study was to examine the expression of RIZ1 and evaluate its carcinogenesis in cervical cancer. The relationship between DNA methylation and transcriptional silencing of RIZ1 was investigated in cervical cancer. METHODS: RIZ1 expression was examined in cervical cancer cell lines and cervical tissues (12 normal and 40 cancerous) by using RT polymerase chain reaction (PCR). Methylation status of the RIZ1 promoter was studied using methylation-specific PCR (MSP). RESULTS: RIZ1 expression is reduced or lost in cervical cancers, compared with normal cervical tissues (P <0.05). The current study results also showed that loss of RIZ1 is mediated by aberrant cytosine methylation of the RIZ1 promoter. 37.5% of carcinomas were methylated, while none of normal tissues were methylated. RIZ1 mRNA expression was significantly higher (P = 0.000) in unmethylated (0.3494 +/- 0.0466, mean +/-SD), compared with methylated tissues (0.1422 +/- 0.1073, mean +/-SD). Treatment with a DNA methyltransferase inhibitor led to reactivation of RIZ1 expression in cell lines that had negligible RIZ1 expression at baseline. CONCLUSIONS: Reduced expression of RIZ1 may play an important role in the pathogenesis and/or development of cervical cancer, and is considered to be caused in part by aberrant DNA methylation. PMID- 20159668 TI - Intensified surveillance after surgery for colorectal cancer significantly improves survival. AB - BACKGROUND: Postoperative surveillance after curative resection for colorectal cancer has been demonstrated to improve survival. It remains unknown however, whether intensified surveillance provides a significant benefit regarding outcome and survival. This study was aimed at comparing different surveillance strategies regarding their effect on long-term outcome. METHODS: Between 1990 and 2006, all curative resections for colorectal cancer were selected from our prospective colorectal cancer database. All patients were offered to follow our institution's surveillance program according to the ASCO guidelines. We defined surveillance as "intensive" in cases where >70% appointments were attended and the program was completed. As "minimal" we defined surveillance with <70% of the appointments attended and an incomplete program. As "none" we defined the group which did not take part in any surveillance. RESULTS: Out of 1469 patients 858 patients underwent "intensive", 297 "minimal" and 314 "none" surveillance. The three groups were well balanced regarding biographical data and tumor characteristics. The 5-year survival rates were 79% (intensive), 76% (minimal) and 54% (none) (OR 1.480, (95% CI 1.135-1.929); p <0.0001), respectively. The 10-year survival rates were 65% (intensive), 50% (minimal) and 31% (none) (p <0.0001), respectively. With a median follow-up of 70 months the median time of survival was 191 months (intensive), 116 months (minimal) and 66 months (none) (p <0.0001). After recurrence, the 5-year survival rates were 32% (intensive, p = 0.034), 13% (minimal, p = 0.001) and 19% (none, p = 0.614). The median time of survival after recurrence was 31 months (intensive, p <0.0001), 21 months (minimal, p <0.0001) and 16 month (none, p <0.0001) respectively. CONCLUSION: Intensive surveillance after curative resection of colorectal cancer improves survival. In cases of recurrent disease, intensive surveillance has a positive impact on patients' prognosis. Large randomized, multicenter trials are needed to substantiate these results. PMID- 20159669 TI - Use of marginal organs in kidney transplantation for marginal recipients: too close to the margins of safety? AB - OBJECTIVE: Due to organ shortage, average waiting time for a kidney in Germany is about 4 years after start of dialysis. Number of kidney grafts recovered can only be maintained by accepting older and expanded criteria donors. The aim of this study was to analyse the impact of donor and recipient risk on kidney long-term function. METHODS: All deceased kidney transplantations were considered. We retrospectively studied 332 patients between 2002 and 2006; divided in 4 groups reflecting donor and recipient risk. RESULTS: Non-marginal recipients were less likely to receive a marginal organ (69 of 207, 33%) as compared to marginal recipients, of whom two-thirds received a marginal organ (p<0.0001). Graft function significantly differed between the groups, but detrimental effect of marginal recipient status on eGFR after 12 months (-6 ml/min/1.73qm, 95% CI -2 to -9) was clearly smaller than the effect of marginal donor status (-10 ml/min/1.73qm, 95% CI -7 to -14). CONCLUSIONS: As we were able to show expanded criteria donor has a far bigger effect on long-term graft function than the "extra risk" recipient. Although there have been attempts to define groups of recipients who should be offered ECD kidneys primarily the discussion is still ongoing. PMID- 20159671 TI - Absolute count of T and B lymphocyte subsets is decreased in systemic sclerosis. AB - BACKGROUND: Previous reports on lymphocyte subpopulations in systemic sclerosis (SSc) are conflicting. Therefore, we aimed to investigate the lymphocyte subsets in SSc patients who were not on immunosuppressive therapy. METHODS: Lymphocyte subsets were assessed in the peripheral blood of SSc patients (n = 29) and healthy controls (n = 29) using the four colour flow cytometry method. Correlation studies were also performed in order to assess the relationship between lymphocyte subsets and clinical parameters. RESULTS: The absolute count of lymphocytes (P = 0.0042), CD3+ (P = 0.0014), CD4+ (P = 0.0070), CD8+ (P = 0.021), and CD19+ cells (P = 0.024) was significantly decreased in SSc patients when compared to healthy controls. CD4+/CD8+ ratio and the absolute count of CD56+ cells observed in SSc patients did not significantly differ from controls (P=0.165; P = 0.632, respectively). There was no substantial relationship between the lymphocyte subset levels and clinical features (i.e., SSc subtype, autoantibody profiles, organ involvement), except for a significant inverse correlation of CD19+ cells and the modified Rodnan skin score (r = -0.43, P = 0.020). CONCLUSION: Our data support previous reports indicating that subsets of T lymphocytes as well as B lymphocytes play a role in the pathogenesis of SSc. PMID- 20159670 TI - Spinning around or stagnation - what do osteoblasts and chondroblasts really like? AB - OBJECTIVE: The influence of cytomechanical forces in cellular migration, proliferation and differentiation of mesenchymal stem cells (MSCs) is still poorly understood in detail. METHODS: Human MSCs were isolated and cultivated onto the surface of a 3 x 3 mm porcine collagen I / III carrier. After incubation, cell cultures were transferred to the different cultures systems: regular static tissue flasks (group I), spinner flasks (group II) and rotating wall vessels (group III). Following standard protocols cells were stimulated lineage specific towards the osteogenic and chondrogenic lines. To evaluate the effects of applied cytomechanical forces towards cellular differentiation distinct parameters were measured (morphology, antigen and antigen expression) after a total cultivation period of 21 days in vitro. RESULTS: Depending on the cultivation technique we found significant differences in both gen and protein expression. CONCLUSION: Cytomechanical forces with rotational components strongly influence the osteogenic and chondrogenic differentiation. PMID- 20159672 TI - Unexpected gamma glutamyltransferase rise increase during levetiracetam monotherapy. AB - Levetiracetam is an antiepileptic drug (AED) with a favourable tolerability profile with little or no effect on liver function. We describe an epileptic patient who developed a significant increase in gamma glutamyltransferase (gammaGT) while on levetiracetam monotherapy. PMID- 20159673 TI - Focal epileptic seizure induced by transient hypoglycaemia in insulin-treated diabetes. AB - Hypoglycaemia, common in diabetic patients treated with insulin, can induce various neurological disturbances. Of these, seizures are the most common acute symptom, mainly of the generalised tonic-clonic type, with focal events only exceptionally being reported and documented. Hypoglycaemia can modify cortical excitability by determining an imbalance between excitation and inhibition; some brain structures, such as the temporal lobe and hippocampus, appear to be particularly susceptible to this insult. We describe a case of a 61-year-old diabetic patient in whom insulin-induced transient hypoglycaemia triggered a focal seizure of temporal origin that was well documented by EEG during 24-hour ambulatory monitoring. This is, to our knowledge, one of the few, well-documented cases of this type of seizure. PMID- 20159674 TI - [Contribution of economic evaluation and budget impact analysis to public decision in health: the example of breast cancer]. AB - The aim of this paper is to draw the reader's attention to the problem of dissemination of costly innovations, particularly in the field of oncology, in a context of scarce resources.Comparison of five economic aggregates related to health and the gross domestic product captures the weight of this sector in the national economy but also its cost to the community. A focus on oncology shows that during the year 2004, the cost of cancer in France, all sites being taken into account, amounted to 10.9 billion euros and the societal cost to 32 billion euros (2% of gross domestic product). The cost of breast cancer (36% of all female cancers) reached 1.5 billion euros for treatment and 3.5 billion euros for societal expenses (0.2% of gross domestic product). Due to the significant, rapid expansion of these costs (+19.2% in 2006 and 18.5% in 2007 for diagnosis-related group outliers) but also to the scarcity of resources, the development of costly innovations remains problematic. This article, based on concrete examples of breast cancer treatment, provides information on the contribution of health technology assessment (particularly cost-utility and budget impact analyses) to public decision. Economic evaluation, in particular, cost-utility assessment, allows comparison of costs and consequences (generic result usually expressed in quality-adjusted life years) in order to prioritize diagnostic and/or therapeutic strategies and to make choices based on social acceptability. Budget impact analysis, without consideration of efficacy, makes it possible to balance the financing needs arising from the adoption of a costly innovation with the paying capabilities of a given institution. PMID- 20159675 TI - [Projection of the incidence of breast cancer in France in 2018]. AB - The objective of this work is to estimate the trends of the incidence of breast cancer until 2018, in the French context on the basis of an age cohort model. The model extrapolates the trend of incidence rate per generation and age, incorporates the effects of demographic changes in the female population in terms of size and age structure and simulates the impact of the withdrawal of the use of hormone therapy for menopause (HTM) under different assumptions. The results suggest a continuous growth in the number of incident cases that would increase from 49,814 to 64,621 between 2005 and 2018. Changes in incidence following the HTM use withdrawal, should be moderate and transient. The most important epidemiological parameters in explaining the future incidence of breast cancer remains the "cohort" effect that continues to have a significant impact until the extinction of cohorts for which the increase was more marked (birth years 1920 to 1945). This factor alone explains 18% of the growth in the number of incident cases in 2018, while the effect of population growth account for 6.6%, the cessation of HTM a 6.4% decrease and aging a 4.6% growth. PMID- 20159676 TI - [UPA/PAI-1: a tool for breast cancer treatment individualization. Biology, clinical implications and quantification assays]. AB - The several options for therapy in breast cancer underline the difficulties to determine the reliable population which can be treated by a specific adjuvant therapy, and the population in which that therapy could generate morbidity, mortality, "medical surcharge" without prognosis improvement. This problem is particularly accurate in node-negative breast cancer patients. Adjuvant therapy has been proved to be more efficient, so a better definition of the prognosis and the response to adjuvant treatments could allow the selection of a sub-group of patients who can be spared chemotherapy. The quantification of the uPA/PAI-1 tumor content is one of the most relevant prognostic factors in this clinical setting. The integration of the uPA/PAI-1 prognostic information gathered in the multidisciplinary medical consensus meetings could be used to select the node negative good/prognosis population in which chemotherapy could be avoided. This review will focus on the uPA/PAI-1 system, its biological role and its clinical implications in breast oncology. The different ways to analyse the uPA and PAI-1 content in tumor cells will be also presented and commented. PMID- 20159677 TI - [Ductal carcinoma in situ of the breast (DCIS). Histopathological features and treatment modalities: analysis of 1,289 cases]. AB - From March 2003 to April 2004, were prospectively collected in France 1,289 ductal carcinoma in situ (DCIS) with data on diagnosis, patient and tumour characteristics, and treatments. Median age was 56 years (range, 30-84). DCIS was diagnosed by mammography in 87.6% of patients. Mastectomy (M), conservative surgery alone (CS) and conservative surgery with radiotherapy (CS + RT) were performed in 30.5, 7.8 and 61.7% of patients, respectively. Sentinel node biopsy (SNB) and axillary dissection (AD) were performed in 21.3 and 10.4% of patients, respectively. Hormone therapy was administered to 13.4% of the patients. Nuclear grade was low in 21% of patients, intermediate in 38.5% and high in 40.5%. Excision was considered complete in 92% (CS) and 88.3% (CS + RT) of patients. Treatment modalities varied widely according to region: mastectomy rate, 20-37%; adjuvant RT, 84-96%; hormone treatment, 6-34%. Our survey on current DCIS management in France has highlighted correlations between pathological features (tumour size, margin, grade) and treatment options, with several similar variations to those observed in recent UK and US studies. PMID- 20159678 TI - [Construction of a recombinant Lactobacillus acidophilus expressing high levels of Helicobacter pylori adhesin Hp0410]. AB - OBJECTIVE: To construct a recombinant Lactobacillus acidophilus that expresses high levels of Helicobacter pylori (Hp) adhesin Hp0410. METHODS: The gene fragment encoding Hp0410 was amplified by PCR from the DNA of H. pylori NCTC11639 strain and cloned into the shuttle plasmid pMG36e to construct pMG36e-Hp0410, which was transformed into Lactobacillus acidophilus by electroporation. The target protein was confirmed with SDS-PAGE and silver nitrate staining and analyzed by Western blotting. The stability of the recombinant plasmid was assessed by drawing the growth curve of the recombinant Lactobacillus acidophilus. RESULTS: A 750-bp fragment was inserted into the pMG36e plasmid and transformed into Lactobacillus lactis. The transformed bacterium expressed the target protein with a relative molecular mass of about 34 kD. Western blotting confirmed that the expressed proteins could be recognized by the serum of patients with Hp infection. The recombinant plasmid pMG36e-Hp0410 exhibited good stability in the presence or absence of erythromycin. CONCLUSIONS: The recombinant Lactobacillus acidophilus with high constitutive expression of Hp0410 has been constructed successfully. PMID- 20159679 TI - [Construction and identification of Rac1-GTPase lentivirus]. AB - OBJECTIVE: To construct lentiviruses carrying dominant negative mutant of Rac1 GTPase (Rac1N17) or the constitutive active mutant of Rac1-GTPase (Rac1L61) and expressing enhanced green fluorescent protein (EGFP) bicistronically. METHODS: The lentiviral expression plasmid Plenti6/v5-Rac1N17 and Plenti6/v5-Rac1L61 were constructed and identified by restriction enzyme digestion and DNA sequence analysis. The two plasmids were packaged using the ViraPowerTM lentiviral expression system to produce replication-incompetent lentiviruses Rac1L61 and Rac1N17, which were used to infect the prefrontal cortex neurons (PFCs) from neonatal SD rats. The transfection efficiency and biological activity of different Rac1 mutants were evaluated and the morphology of the transfected PFCs was observed. RESULTS: The results of DNA sequencing and restriction enzyme analysis demonstrated correct plasmid construction. The packaged lentiviral titer was 1x10(6) TU/ml. Analysis of Rac1 biological activity showed that Rac1N17 lentivirus particles infection significantly inhibited epidermal growth factor stimulated Rac1 activity in the PFCs, while Rac1L61 lentivirus particles enhanced the Rac1 activity. The transfection efficiency of these Rac1 mutant lentivirus particles exceeded 80% in the PFCs. Morphologically, the PFCs exhibited distinct dendritic branches after infection by these lentiviruses. CONCLUSION: The lentiviruses carrying Rac1 dominant negative mutant and constitutive active mutant have been successfully constructed. The lentiviral particles can efficiently infect neonatal rat PFCs and lend important support for the study of Rac1-GTPase. PMID- 20159680 TI - [Construction of cyclin D1 recombinant plasmids and its expression in human nasopharyngeal carcinoma cells]. AB - OBJECTIVE: To construct the eukaryotic expression vectors of human cyclin D1 gene and express them in poorly differentiated nasopharyngeal carcinoma cells (CNE-2Z cells). METHODS: The full-length cyclin D1 was cloned from CNE-2Z cells by RT PCR. The cDNA fragments were inserted into pIRES2-EGFP plasmids and pEGFP-C2 plasmids and confirmed by restriction enzyme digestion, PCR and sequencing. The recombinant vectors were transfected into CNE-2Z cells via Lipofectamine 2000, and the expression of cyclin D1 in the cells was examined by immunofluorescence and Western blotting. RESULTS: Agarose gel electrophoresis showed a 918 bp band of the RT-PCR products, which matched the expected size. Restriction enzyme digestion, PCR and sequencing demonstrated successful construction of the recombinant vectors. CNE-2Z cells transfected with the recombinant vectors expressed cyclin D1 protein or cyclin D1-GFP protein as were verified by immunofluorescence and Western blotting. CONCLUSION: We have cloned cyclin D1 gene and constructed its eukaryotic expression vectors that can be expressed in nasopharyngeal carcinoma cells, which may facilitate the study of the role of cyclin D1 in the development of nasopharyngeal carcinoma. PMID- 20159681 TI - [Cloning and efficient prokaryotic expression of soluble stage-specific antigen cC1 from Cysticercus cellulosae]. AB - OBJECTIVE: To clone the coding gene of the stage-specific antigen cC1 from Cysticercus cellulosae and express high levels of soluble cC1 in E.coli. METHODS: The cC1 gene was amplified from Cysticercus cellulosae by RT-PCR and cloned into pMD18-T vector, followed by subcloning into the prokaryotic expression plasmid pET28a. The recombinant plasmid was transformed into E.coli BL21(DE3) and the expression conditions were optimized. The expressed product was purified by Ni(+) affinity chromatography, analyzed by high-performance liquid chromatography (HPLC), and identified with SDS-PAGE and Western blotting. RESULTS: The fragment length of the amplification product by RT-PCR was 1056 bp. Comparison of the amplified gene sequence with the cC1 gene in Genbank identified a samesense point mutation at 423 position in the gene cloned into the expression plasmids. After a 6-h induction with 0.05 mmol/L IPTG at 37 degrees celsius;, the expression of the 40 kd soluble fusion protein exceeded 60% of the total bacterial protein, and the fusion protein was recognized by Cysticercus-infected human sera. The purity of the fusion protein was about 94% after purification by affinity chromatography. CONCLUSION: The stage-specific antigen cC1 from Cysticercus cellulosae has been successfully cloned and the soluble protein efficiently expressed in E.coli, which provides the basis for its further study and application. PMID- 20159682 TI - [Effect of different doses of recombinant adenovirus mediated hypoxia-inducible factor-1alpha on angiogenesis in ischemic lower hind limb of rabbits]. AB - OBJECTIVE: To investigate the effect of recombinant adenovirus-mediated hypoxia inducible factor-1alpha (Ad-HIF-1alpha) at different doses on angiogenesis in a rabbit model of hind limb ischemia. METHODS: Left hind limb ischemia was induced in 45 Zealand white rabbits by ligation of the left femoral artery. The rabbits were randomly divided into 5 groups (n=9) to receive intramuscular injections of 0.5 ml saline, 2x10(10) PFU empty vector (Ad-null), or different doses of Ad-HIF 1alpha (2x10(9), 2x10(10) or 2x10(11) PFU) immediately after the operation. On the 7th day after the operation, real-time PCR was used to detect the expression of HIF-1alpha mRNA in the skeletal muscles. Immediately and on the 14th and 28th days after the operation, contrast enhanced ultrasound (CEU) was used to observe the blood perfusion of the hind limb. On the 28th day postoperatively, immunohistochemistry for CD31 was performed to evaluate the microvascular density (MVD). RESULTS: Real-time PCR showed that Ad-HIF-1alpha significantly increased the expression of HIF-1alpha mRNA (P<0.01) in a dose-dependent manner as compared with that in the saline and Ad-null groups (P<0.01). CEU revealed greater blood perfusion in the hind limb of rabbits in association with increased dose of Ad HIF-1alpha (P<0.05 or P<0.01); similar changes in the MVD was observed following Ad-HIF-1alpha injections as shown by immunohistochemistry (P<0.05 or P<0.01). No significant differences were found either in the blood perfusion or MVD between saline and Ad-null groups (P>0.05). CONCLUSION: Ad-HIF-1alpha can dose dependently promote the angiogenesis in the ischemic limb of rabbits. PMID- 20159683 TI - [Relationship between accelerated artherosclerosis and Treg/Teff balance in uremic apoE-/- mice]. AB - OBJECTIVE: To establish a uremic apolipoprotein E knockout (apoE-/-) mouse model and explore the relationship between accelerated atherosclerosis and Treg/Teff balance. METHODS: Using apoE-/- mice with C57BL/6J background, uremic apoE-/- mice were created by electrocautery of the right kidney and nephrectomy of the left, and the control apoE-/- mice received a sham-operation. Two weeks after inducing uremia, the renal function of the mice were evaluated to assess the validity of the model. Ten weeks after the operation, blood samples were obtained from the mice to assess the renal function and serum total cholesterol (TCH); the serum concentrations of transforming growth factor-beta(1) (TGF-beta(1)) and interferon-gamma (IFN-gamma) were detected by ELISA, and CD4(+)CD25(+)Foxp3(+)Treg ratio in the spleen was determined by flow cytometry. RT-PCR was used to detect the expression of Foxp3 and IFN-gamma mRNA in the aorta, and oil red O staining used to investigate the relative atherosclerotic area on the frozen sections of the aortic root. The correlation between the renal function parameters and Treg quantity was analyzed. RESULTS: Renal function detection confirmed successful establishment of the uremic apoE-/- mouse model. Ten weeks after the operation, the relative atherosclerotic plaque area in the aortic root plaque increased significantly, the spleen Treg ratio decreased, the serum concentrations of TGF-beta(1) decreased and IFN-gamma and TCH increased, the expression of aortic Foxp3 mRNA decreased and IFN-gamma mRNA increased as compared with those in the control apoE-/- mice. A significant inverse correlation was found between the renal function parameters and Treg quantity in uremic apoE-/- mice. CONCLUSION: In uremic apoE-/- mice, accelerated aortic atherosclerosis is correlated to the T cell subset (Treg/Teff) imbalance shown by decreased quantity and impaired function of Treg and enhanced activity of Teff. PMID- 20159684 TI - [Design and construction of the platform for comparative genomics]. AB - OBJECTIVE: To design a versatile genome comparison and visualization platform based on browser/server mode supported by a local server. METHODS: The server of the platform was Apache HTTP server. Perl was used to integrate such genome alignment package and algorithms as MUMmer, LAGAN, and Mauve for different comparison purposes, and the users could submit data and parameters to the platform via the web page. The results of analysis were also returned via the web page. RESULTS: The platform could handle multiple data input formats, compare complete and draft genome sequence, alignment pair-wise or multi genome of more divergent species, identify regions of high similarity, locate local nucleotide mutations and large-scale recombination, and display the results by visualization interface. Analysis of the homology of 10 new strains of influenza A virus indicated that PB1 gene might evolve from human H3N2 viruses, PB2 and PA genes from avian H3N2 viruses, and HA and NS genes from swine H1N1 viruses. Alignment of Mycobacterium tuberculosis (H37Rv, CDC1551) and Mycobacterium bovis (AF2122/97) genomes revealed that sequence insertion/deletion and duplication were the major source of genomic differences. CONCLUSION: The platform integrate comprehensive resources with a user-friendly interface and intuitive result visualization to facilitate conventional study of comparative genomics. PMID- 20159685 TI - [A double suicide gene system driven by KDR promoter selectively kills human colon adneocarcinoma SW480 cells]. AB - OBJECTIVE: To study the selective killing effect of adenovirus (Ad)-mediated double suicide gene system driven by the KDR promoter (KDR-CDglyTK) on human colon adneocarcinoma SW480 cells. METHODS: KDR-expressing SW480 cells and LS174T cells that did not express KDR were infected by KDR-CDglyTK, and the infection efficiency and the expression of CDglyTK in the cells were detected by RT-PCR. The infected cells were treated with the prodrugs 5-FC and GCV at different concentrations, and the cell-killing effects and bystander effects were evaluated by MTT method. DNA content and the cell cycle changes in SW480 cells were detected by flow cytometry. RESULTS: The expression of green fluorescent protein (GFP) was observed in 95% of the infected SW480 and LS174T cells with a multiplicity of infection (MOI) of 100. RT- PCR demonstrated that the product of CD/TK gene existed in SW480 cells infected by Ad- KDR- CD/TK, but not in infected LS174 cells. The infected SW480 cells exhibited high sensitivity to the prodrugs, but the infected LS174T cells did not (P<0.01). Bystander effects of the double suicide gene system were observed in the coculture of the infected and non infected SW480 cells. At the MOI of 100, treatment of the infected cells with the prodrugs resulted in increased cell percentage in G(0)-G(1) phase and decreased percentage in S phase and the prodrug-treated cells showed an apoptotic peak in flow cytometry. CONCLUSION: CDglyTK fusion gene system driven by the KDR promoter selectively kills and induces the apoptosis of the KDR-CDglyTK SW480 cells. PMID- 20159686 TI - [Hydrogen dioxide increases the expression of vascular endothelial growth factor in human bronchiolar epithelium cell via a PI3K-dependent pathway]. AB - OBJECTIVE: To investigate the effect of hydrogen dioxide (H(2)O(2)) on the expression of vascular endothelial growth factor (VEGF) in human bronchiolar epithelial (HBE) cells. METHODS: MTT assay was used to assess HBE cell viability after exposure to different concentrations of H(2)O(2). VEGF/beta-actin gene fragments were amplified simultaneously by RT-PCR from the total HBE cell RNA, and VEGF protein expression in the cells was detected using ELISA. RESULTS: The exposure to 200 micromol/L H(2)O(2) did not obviously affected the cell viability. Compared with those in the control cell, VEGF165/beta-actin and VEGF189/beta-actin ratios were significantly increased in the cells after treatment with 50, 200, and 600 micromol/L H(2)O(2) (P<0.05). The protein expression of VEGF significantly increased after 50 micromol/L H(2)O(2) treatment (P<0.05), but significantly decreased with pretreatment with the PI3K inhibitor Ly294002 (P>0.05). CONCLUSION: Oxidative stress increases the expression of VEGF via a PI3K-dependent pathway in human bronchiolar epithelial cells, which may play an important role in the onset and maintenance of chronic inflammation in asthma. PMID- 20159687 TI - [Bioinformatics analysis and function prediction of the novel gene AY358935]. AB - OBJECTIVE: To obtain the functional information of AY358935 gene. METHODS: The properties, subcellular location, and structure of AY358935 protein, and the expression profile of AY358935 gene were analyzed by bioinformatics software and the biological functions of the gene were predicted. AY358935 expression was detected by Western blot analysis in early virus infection. RESULTS: AY358935 was evolutionally conserved. The human AY358935 protein had an amino acid similarity of 74%, 60%, 38% and 33% with its counterpart in horses, mice, zebrafish and Xenopus laevis, respectively. Bioinformatics analysis indicated that AY358935 protein was located likely in the mitochondria. There was a N-terminal signal peptide and single transmembrane structure in AY358935 protein, which contained several phosphorylation sites. The secondary structure mainly comprised of alpha helices and random coils. AY358935 was ubiquitously expressed in normal tissues and carcinomas and regulated by the expression of double-stranded RNA-dependent protein kinase. AY358935 protein expression was obviously upregulated in cells 2 h after infection by vesicular stomatitis virus. CONCLUSION: As a predicted secretary protein with a small molecular weight, AY358935 might have important functions in cellular proliferation and anti-viral innate immune regulation. PMID- 20159688 TI - [Analysis of the clinical outcomes of 160 patients undergoing repeated IVF/ICSI ET treatment]. AB - OBJECTIVE: To study the clinical factors affecting the outcomes of repeated assisted reproductive technology (ART) cycles. METHODS: A retrospective analysis of the clinical data and outcomes was conducted among 160 patients undergoing repeated IVF/ICSI-ET treatment between January 2006 and April 2009. RESULTS: The patients with successful clinical pregnancy after two ART cycles (group A) had a younger age and shorter duration of infertility, and had more antral follicles (AFC), more eggs and good-quality embryos with more transferred embryos available and higher good-quality embryo rate (P<0.05) than those who failed to have pregnancy after the cycles (group B). In the second cycle, the patients in group A had higher doses of short-acting GnRHa, r-HCG and HMG and at the same time more good eggs and embryos than in the first cycle. CONCLUSIONS: Female age is one of the most important factors affecting the pregnancy rate after repeated ART cycles. The clinical pregnancy rate can be enhanced by administering short-acting GnRHa, HMG, oral contraceptives and adjusting the dose of Gn as well as changing the culture medium of embryos. PMID- 20159689 TI - [Impact of ultrasound-mediated microbubbles on myocardial vascular permeability in rats]. AB - OBJECTIVE: To investigate the impact of high-dose microbubbles induced by high mechanical index myocardial contrast echocardiography (MCE) on vascular permeability and its recovery time in rats. METHODS: Thirty male Wistar rats were randomized into 4 MCE groups (groups A-D) and a control group. In the MCE groups, Evans blue was injected at 10 s before MCE (A), immediately after the end of MCE (B), and at 5 min (C) and 20 min after the end of MCE (D). In the control group, the microbubbles and Evans blue were injected at the end of a 5-min ultrasound exposure. All the rats were sacrificed 5 min after Evans blue injection, and the content of Evans blue in the myocardium and the percentage of Evans blue leakage area were determined. RESULTS: The percentage of Evans blue leakage area in groups A, B and C were significantly higher than that in the control group (P<0.05), while the percentage was similar between group D and the control group (P>0.05). Evans blue contents in groups A and B were significantly higher than that in the control group (P<0.05), but groups C and D showed comparable contents with the control group E (P>0.05). No significant changes of the heart rates and premature beat number were observed during and after MCE in these groups (P>0.05). CONCLUSION: High mechanical index MCE and a high contrast dose may induce increased microvascular leakage in rats, and the vascular permeability can recover in 20 min after MCE. PMID- 20159690 TI - [High-performance liquid chromatography-based determination of plasma and renal tissue cisplatin levels after subcutaneous cisplatin implantation in mice]. AB - OBJECTIVE: To develop a method for determining plasma and renal tissue concentrations of cisplatin (DDP) after subcutaneous DDP implantation in mice. METHODS: DDP was extracted from the plasma and tissue of mice receiving subcutaneous DDP implantation and reacted with sodium diethyldithiocarbamate (DDTC). The product Pt (DDTC)(2) extracted by diethyl ether was determined using high-performance liquid chromatography (HPLC) with the mobile phase of water and methanol at the ratio of 25:75 and the flow rate of 1.0 ml/min. The derivatives of DDP and nickel chloride were detected at the wavelength of 254 nm. RESULTS: The linear range of DDP was 0.1-10 microg/ml (r=0.9998 for plasma and 0.9993 for kidney). The intra-day and inter-day RSD was below 10%, and the minimum concentration detectable was 50 ng. CONCLUSION: The method is accurate and effective for determining plasma and tissue DDP levels after subcutaneous DDP administration and can be used in pharmacokinetic study of DDP. PMID- 20159691 TI - [Effect of doxapram on the respiratory rhythmical discharge activity in the brainstem slice of neonatal rats]. AB - OBJECTIVE: To investigate the effects of doxapram on the respiratory rhythmical discharge activity (RRDA) in the brainstem slices of neonatal rats. METHODS: Thirty neonatal SD rats (of either sex, 0-3 days old) were randomly divided into 6 equal groups (groups I-VI), and the brainstem slices which contained the medial region of the nucleus retrofacialis (mNRF) were prepared. All the slices were perfused with modified Kreb's solution (MKS), and in group I (control group), the slices were perfused with MKS only; in groups II to IV, the slices were perfused with doxapram in MKS continuously at the concentrations of 2, 5, and 10 micromol/L, respectively; in groups V and VI, the slices were perfused with 20 micromol/L propofol and 20 micromol/L propofol plus 5 micromol/L doxapram, respectively. The RRDA in the hypoglossal nerve was recorded by suction electrode. The discharge time course of the inspiratory (TI), expiratory (TE), respiratory cycle (RC) and integral amplitude of the inspiratory discharge (IA) were recorded at 1, 3, 5, 10, 15, and 30 min after the application of the drugs. RESULTS: The hypoglossal nerve in groups I, II and VI showed no significant changes of RRDA in the entire course of the experiment (P>0.05). In groups III and IV, the TI, IA increased and TE decreased significantly 5 min after doxapram application (P<0.05), and the RC was shortened only at 10 min. In group V, the TI and IA decreased and the RC and TE increased significantly after the drug application (P<0.05). CONCLUSION: Doxapram (>5 micromol/L ) can directly stimulate the RRDA and prevent propofol-induced inhibitory effects in the brainstem slice of neonatal rats, and the effects are mediated by its actions upon the inspiratory neurons in the mNRF. PMID- 20159692 TI - [Effect of FK506 on cytokine secretion in whole blood]. AB - OBJECTIVE: To investigate the effect of FK506 on cytokine secretions in whole blood from healthy individuals. METHODS: Blood samples collected from healthy volunteers were co-cultured with different concentrations of FK506 and stimulated with PMA and IONO. The concentrations of 8 cytokines including IL-2, IL-6, IL-12, IL-17, IFN-gamma, TNF-alpha, GM-CSF and G-CSF were detected by Bio-Plex suspension system. RESULTS: Compared with the control group, high-concentration FK506 (20 ng/ml) significantly inhibited the secretions of IL-2, IL-6, IL-12, IL 17, IFN-gamma, TNF-alpha, GM-CSF and G-CSF. At a moderate concentration (5 ng/ml), FK506 inhibited the secretion of GM-CSF significantly. CONCLUSION: FK506 effectively inhibits the secretion of proinflammatory cytokines including IL-6, IFN-gamma and TNF-alpha and also the secretion of IL-2, IL-12, IL-17, GM-CSF and G-CSF. FK506 might play the role of immunosuppression by inhibiting the production of these cytokines by the immune cells. Monitoring the levels of these cytokines might be a potential method for evaluating the adequacy of FK506 doses administered. PMID- 20159693 TI - [Effect of different dynamic mechanical strain on the proliferation and synthetic function of human periodontal ligament fibroblasts in vitro]. AB - OBJECTIVE: To study the changes in the proliferation and synthetic function of human periodontal ligament fibroblasts (HPDLF) in response to dynamic mechanical strains of different modes, magnitudes and durations. METHODS: Using a 4-point bending system, the effect of dynamic mechanical strains of different modes, magnitudes and durations on the proliferation of HPDLF was investigated by analyzing the cell cycle changes with flow cytometry (FCM), and the total protein level and the activity of alkaline phosphatase (ALP) in HPDLF were assayed by quantitative analysis. RESULTS: The percentage of G(0)/G(1) cell decreased, S phase cells increased, and the proliferation index (PI), total protein level and activity of ALP were augmented significantly in response to dynamic mechanical micro-strains. These changes showed close correlations to the magnitude and duration of the strain. The mode of strain caused significant changes in G(0)/G(1), S, and G(2)/M phase cell percentages as well as the PI, total protein level and ALP activity of the cells. In the gradient strain group, the cell proliferation activity, total protein level and ALP activity were obviously higher than those in 1000 and 4000 microstrain groups. CONCLUSION: The changes in the proliferation and synthetic function of HPDLF are closely correlated to the mode, magnitude and duration of the strains. PMID- 20159694 TI - [Three-dimensional accuracy of plaster casts obtained using three impression materials]. AB - OBJECTIVE: To evaluate the accuracy of 3 impression materials in reproductions of simian dental arches using a 3-dimensional optical digitizer. METHODS: Two simian dental arches were prepared as the master models. Impressions were made for stone casts using three impression materials, including alginate impression materials, C-silicone materials and Impregum-Penta polyether rubber. Five plaster replication models for each master model, as well as for each impression materials were made. The master models and the casts were digitized using a 3 dimensional optical scanner and digitizer. The images of each plaster cast and its original master model were superimposed to obtain the setting cross-section volume of the dental crown. The ratios of the plaster cast volume change and discrepancy distribution patterns were analyzed. RESULTS: Compared with the volume of the master models, the discrepancies of the plaster casts volume were 5.84%, -3.21%, and -0.63% for alginate impression materials, silicone materials and Impregum-Penta polyether rubber, respectively. The discrepancy between the master models and casts from alginate material was statistically significant (P<0.05), but not for silicone materials or Impregum-Penta polyether rubber. Maximal deviation of image fitting was located in the cervix and the gingival areas. CONCLUSION: The volumes of all the plaster casts from the 3 impression material are smaller than that of the master model. Impregum-Penta polyether rubber allows the most precise and silicone material the relatively accurate reproduction of the denture model, while alginate can not. The major error areas are in the dental cervix and gingival region. PMID- 20159695 TI - [Effect of adenovirus-mediated CD/TK double suicide gene system on colorectal cancer growth and cytokines in the tumor microenvironment in mice]. AB - OBJECTIVE: To evaluate the effect of adenovirus-mediated CD/TK double suicide gene system on tumor growth and cytokine levels in the tumor microenvironment in mice bearing transplanted colorectal cancer. METHODS: CT26 cells were implanted subcutaneously into 30 Balb/c mice, which were subsequently randomized into the control (n=15) and experimental group (n=15). After the tumor formation, CD/TK double suicide gene system was administered for tumor treatment, and the changes in the tumor volume, tumor inhibition rate, and levels of cytokines in the tumor microenvironment were investigated. RESULTS: CD/TK double suicide gene system resulted in a significant inhibition of the tumor growth and significantly increased levels of such cytokines as IL-2, IL-10, TNFalpha and IFNgamma in the tumor microenvironment. CONCLUSION: CD/TK double suicide gene system produces significant tumor inhibition effect and causes obvious cytokine changes in the tumor microenvironment in mice bearing transplanted colorectal cancer. PMID- 20159696 TI - [Immunohistochemical study of tumor necrosis factor-alpha expression in the lungs and small intestines in hyperthermia-LPS co-stressed rats]. AB - OBJECTIVE: To investigate the effects of co-exposure to hyperthermia and lipopolysaccharides (LPS) on tumor necrosis factor-alpha (TNF-alpha) expression in the lungs and small intestines of rats. METHODS: Male pathogen-free Wistar rats were randomly assigned into saline-injected normothermic control (C), saline heat exposure (H), LPS normothermic control (L), and LPS plus heat exposure (HL) groups. The rats in H and HL groups were exposed in a chamber at an ambient dry bulb temperature (Tdb) of 35.0-/+0.5 degrees celsius;, and those in C and L groups to 26-/+0.5 degrees celsius;. In L and HL groups, the rats were given an intravenous injection of LPS 10 mg/kg via the tail vein to induce endotoxemia, and those in C and H group received 10 ml/kg injection. The plasma levels of sTNFrI and sTNFrII were detected at different time points using ELISA. The expression of TNF-alpha in the lungs and small intestines was detected by immunohistochemical SABC method, and the damage of the lungs and small intestines evaluated histologically 120 min after the treatment. RESULTS: Co-exposure to hyperthermia and LPS caused significantly enhanced expressions of TNF-alpha and its receptor sTNFrI and sTNFrII in the plasma and tissues and obvious histopathological damage in the lung and small intestines. CONCLUSION: Co-stress of hyperthermia and LPS-induced toxicity is associated with the expression of TNF alpha in the lung and small intestines. PMID- 20159697 TI - [Effects of cyclosporine-impregnated versus freeze-dried bone allografts in repairing radial defects in rabbits: a comparative study]. AB - OBJECTIVE: To compare the effects of cyclosporine-impregnated bone allograft (CAB) and freeze-dried bone allograft (FDAB) in repairing radial defects in rabbits. METHODS: Thirty New Zealand white rabbits were randomized into bone graft donor group, experimental group, and control group (n=10). The bilateral ilia of the donor rabbits were dissected to prepare CAB and FDAB. In the other 20 rabbits, a 10-mm long segmental osteoperiosteal defect was induced in the right radius and repaired with CAB (experimental group) or with FDAB (control group). At postoperative weeks 4 and 12, 5 rabbits from each group were sacrificed to evaluate the bone healing by radiographic, general and histological observations. RESULTS: Four weeks after the operation, the rabbits in the experimental group showed significantly higher X-ray scores (P=0.001) with greater amount of new bone and better incorporation of the allograft and autogenous bone than those in the control group. At 12 weeks, the X-ray scores were still significantly higher in the experimental group (P=0.002), which also showed better bone remodeling than the control group. CONCLUSION: CAB is superior to FDAB for repairing radial defects in rabbits, but the potential involvement of local immunoreaction in this difference awaits further investigation. PMID- 20159698 TI - [Comparison of the pathogenesis of liver fibrosis induced by pig serum exposure and bile duct ligation in rats]. AB - OBJECTIVE: To observe the occurrence and progression of liver fibrosis induced by pig serum exposure and bile duct ligation, and analyze the relationship between hepatic inflammation and liver fibrosis. METHODS: Chronically immune-mediated liver fibrosis was induced in rats by weekly injection of pig serum (IPS) into the peritoneal cavity at 3 ml/kg for 12 weeks. Cholestatic fibrosis was induced by common bile duct ligation (BDL). The Knodell score was used to evaluate the histological changes in the liver, and immunohistochemistry was performed using anti-SMA, anti-ED1, anti-CK7, and anti-CD45 antibodies. Quantitative real time PCR (qPCR) analysis was employed to quantify the mRNA expression of the genes related to inflammation, including interleukin-1beta (IL-1beta), IL-6, monocyte chemotactic protein-1, tumor necrosis factor-alpha, regulated upon activation normal T cell expressed and secreted (RANTES), transforming growth factor-beta, platelet-derived growth factor A, as well as the genes associated with fibrogenesis, namely collagen 1, alphaSMA, MMP-9 and TIMP-1. RESULTS: Knodell scores for periportal necrosis, intralobular degeneration and focal necrosis, and portal inflammation were all significantly higher in the BDL group than in the IPS group (P<0.01), whereas the scores for fibrosis was higher in the IPS group (P<0.05). Immunohistochemistry showed obvious inflammation with numerous alphaSMA positive cells in the liver of the rats in BDL group; the liver of the rats in IPS group showed numerous alphaSMA-positive myofibroblasts with limited inflammatory cell infiltration. qPCR demonstrated a significant up-regulation of the genes related to extracellular matrix remodeling such as collagen 1 (P<0.01), alphaSMA (P<0.01), MMP-9 (P<0.01) and TIMP-1 (P<0.01) in the rat liver in IPS group compared with those in the normal control group, and the mRNA expressions of the inflammation-related cytokines, except for RANTES, were comparable with those in the control. In contrast, the BDL group showed a significant up regulation of all the pro-inflammatory genes examined with also increased expression of the fibrogenesis-related genes (P<0.05). CONCLUSION: Liver fibrosis induced by IPS is characterized by active ECM remodeling in the absence of obvious inflammation, indicating that chronic development of liver fibrosis can be independent of active hepatic inflammation. BDL-induced liver fibrosis highlights obvious inflammation and fibrous proliferation in the liver. PMID- 20159699 TI - [Effects of simvastatin on vasa vasorum and aortic endothelial function in rats]. AB - OBJECTIVE: To investigate the effect of hyperlipidemia on vasa vasorum and vascular endothelial growth factor (VEGF) and study the role of vasa vasorum in arteriosclerosis. METHODS: Thirty SD rats were randomized into normal control, hyperlipidemic and simvastatin treatment groups (n=10). In simvastatin group, hyperlipidemia was induced by a 4-week administration of atherogenic diet followed by a 16-week treatment with simvastatin at the daily dose of 10 mg/kg, and the rats in hyperlipidemic rats received no treatment. The changes in the aorta and vasa vasorum were examined, and serum lipid concentration and VEGF and NO levels were measured. RESULTS: Compared with the control group, the hyperlipidemic rats showed significantly thickened intima and media aorta and increased vasa vasorum density with lowered NO level, but VEGF underwent no significant changes. Simvastatin treatment significantly reduced the thickness of the intima and media aorta and increased vasa vasorum density in comparison with those in hyperlipidemic group. Simvastatin treatment also significantly increased VEGF and NO levels and a positive correlation was noted between their levels. CONCLUSION: Hyperlipidemia can impair the vasa vasorum and aortic endothelial function. Simvastatin increases VEGF and NO and promotes neogenesis of the vasa vasorum for the benefit of the aortic function. PMID- 20159700 TI - [Antitumor effect of calcium phosphate cement incorporating doxorubicin microspheres]. AB - OBJECTIVE: To investigate the antitumor effect of calcium phosphate cement incorporated with doxorubicin microspheres. METHODS: The absorbance at 490 nm of SaoS-2 cells cultured for 5 days in the media containing the extract of the cement incorporating doxorubicin microspheres was measured using Cell Counting Kit-8. SaoS-2 cells were adjusted to the density of 2x10(7) ml(-1) and injected into the left buttock of nude mouse in the volume of 0.2 ml. The cell suspension (0.1 ml) mixed with an equal volume of the cement extract were injected into the right buttock and on the back of the bilateral ears of nude mice. At 12 days after the cell injection, the tumor tissues were obtained and weighed to calculate the tumor inhibition rate, and the pathological samples were observed with HE staining. RESULTS: The extract of the bone cement containing doxorubicin microspheres showed inhibitory effects on the tumor growth in a dose-dependent manner. The tumor inhibition rate reached 61.0% in high-dose group. Tumor necrosis was found in high dose group, but virtually absent in low-dose group. CONCLUSIONS: CPC containing doxorubicin PLGA microspheres can inhibit tumor cell growth both in vitro and in vivo. PMID- 20159701 TI - [Effects of different anesthetic and analgesic protocols on cellular immune function and stress hormone level in patients undergoing lobectomy for esophagus cancer]. AB - OBJECTIVE: To investigate the effects of different anesthetic and analgesic protocols on the cellular immune function and stress hormone in patients undergoing lobectomy for esophagus cancer. METHODS: Sixty ASA I or II patients undergoing lobectomy for esophagus cancer were randomly divided into two groups to receive postoperative general anesthesia and intravenous analgesia (group A, n=30) or intraoperative general anesthesia combined with thoracic epidural anesthesia with postoperative epidural analgesia (group B, n=30). The cervical venous blood samples were obtained from the patients at 30 min before anesthesia induction (T(0)), 2 h after skin incision (T(1)), and at 4 h (T(2)), 24 h (T(3)) and 48 h (T(4)) after the end of operation. The T-lymphocyte subsets (CD4(+) and CD8(+)) were analyzed by flow cytometry, serum concentrations of sIL-2R and IL-2 determined by ELISA, and the levels of growth hormone (GR), prolactin (PRL), IL-8 and cortisol (Cor) measured by radioimmunoassay. Visual analogue scale (VAS) was used for assessment of the postoperative analgesic effects. RESULTS: The VAS scores were significantly lower in group B than in group A at T(2) and T(3) (P<0.05). The percentage of CD4(+) cells and the CD4(+)/CD8(+) ratio in the two groups began to decrease significantly at T(1) (P<0.05), reducing to the lowest level at T(2) in group B and at T(3) in group A. From T(1) to T(4), the percentage of CD4(+) in group B remained significantly higher than those in group A (P<0.05), and from T(3) to T(4), the CD4(+)/CD8(+) ratio in group B were significantly higher than those in group A (P<0.05). The IL-2 level in the two groups began to decrease significantly at T(1) (P<0.05), reaching the lowest level at T(2) in group A and at T(3) in group A. IL-2 level was significantly higher in group B than in group A from T(3) to T(4) (P<0.05). sIL-2R level in group A began to increase at T(1) and peaked at T(3), showing significant differences from the T(0) level, but the level showed no significant variations in group B compared with the T(0) level. From T(2) to T(4), sIL-2R level was significantly higher in group A than in group B (P<0.05). The levels of GH, PRL and Cor increased significantly, while IL-8 decreased in the two groups from T(1) to T(4) (P<0.05), but remained stable in group B. CONCLUSION: General anesthesia combined with thoracic epidural anesthesia may reduce the perioperative stress reaction and adverse effect on cellular immune function in patients undergoing lobectomy for esophagus cancer. PMID- 20159702 TI - [KIR/HLA ligand matching and acute rejection after kidney transplantation]. AB - OBJECTIVE: To explore the effect of KIR/HLA ligand matching which mediates activated or inhibitory signal pathways on acute rejection (AR) after kidney transplantation. METHODS: HLA and KIR genotype assortments were analyzed in 53 donor/recipient pairs of kidney transplantation. The recipients were divided into AR group (GI, n=19) and stable renal function group (GII, n=34) based on the early graft function. The impact of donor HLA, recipient KIR and distinct KIR/HLA class I ligand combinations on acute rejection after kidney transplantation was studied. RESULTS: No significant differences were found in donor HLA-C1/2, HLA A3, HLA-A11, or HLA-Bw4 between GI and GII groups. The frequency for KIR2DL2/2DS2 and KIR genotype assortment (AA) of the recipients in GI group were significantly lower than that in GII group (26.3% vs 55.9%, P=0.038; 31.6% vs 67.6%, P=0.011). The incidence of AR was significantly lower in donor HLA-C1/1 than in non-C1/1 (31.6% vs 46.7%, P>0.05), and lower in recipient KIR genotype assortment (AA) than in non-AA (20.7% vs 52.2%, P=0.011). A significant higher number of matches for the KIR2DL2/ HLA-C1 and KIR2DL3/HLA-C1 were observed in GII group (P=0.030, P=0.028). CONCLUSION: Distinct KIR/HLA class I ligand combinations between the donor and recipient (such as KIR2DL2/ HLA-C1 and KIR2DL3/HLA-C1) may reduce the incidence of AR. A good KIR/HLA class I ligand matching will benefit the survival of the renal allograft. PMID- 20159703 TI - [Immunological influence of iodine-125 implantation in patients with hepatocellular carcinoma resection]. AB - OBJECTIVE: To investigate the effect of iodine-125 implantation on immune cell subsets and cytokine production in patients undergoing hepatocellular carcinoma (HCC) resection. METHODS: Sixty-eight patients with resectable HCC were randomly divided into intrahepatic iodine-125 embedding group and control group. The percentages of T lymphocyte phenotypes (CD3(+), CD4(+), CD8(+)), NK cells, and the plasma concentrations of IL-4, IL-10, IL-12 and IFN-gamma of the patients were determined with flow cytometry and ELISA, respectively. RESULTS: In the control group, the postoperative CD3(+) and CD4(+) immunocytes were (39.38 /+6.98)% and (24.34-/+3.18)%, significantly lower than the preoperative levels [(62.58-/+8.67)% and (30.63-/+4.19)%, respectively, P<0.05)]. The postoperative concentrations of IL-4 and IL-10 were (29.83-/+7.99) and (87.54-/+2.89) ng/L, significantly higher than the preoperative levels (10.35-/+8.76 and 64.25-/+2.54 ng/L, respectively, P<0.05). In the treatment group, the percentages of the immunocytes and cytokine concentrations underwent no significant changes after the operation, but postoperative IL-12 (89.46-/+11.43 ng/L) and IFN-gamma (47.78 /+5.45 ng/L) levels were significantly higher than the preoperative levels (36.13 /+9.16 and 7.14-/+2.17 ng/L, respectively, P<0.05). Significant differences were found between the two groups in the postoperative CD3(+) and CD4(+) immunocytes and IL-4, IL-10, IL-12 and IFN-gamma levels. CONCLUSION: Iodine-125 implantation can strongly stimulates the anti-tumor immune response in HCC patients by increasing CD3(+) and CD4(+) immunocytes and promoting Th2/Th1 deviation. PMID- 20159704 TI - [Effect of skeletal muscle contraction on bone capillary permeability: an experimental study in rabbits]. AB - OBJECTIVE: To assess the effect of muscle contraction on bone capillary permeability. METHODS: Thirty female New Zealand white rabbits were randomly divided into the experimental and control groups (n=15). The bone chambers were implanted medially into the right tibiae of the rabbit, and in the experimental group, the rabbits were stimulated by transcutaneous electrical nerve stimulator (TENS) at 4 Hz (1 h/day, 6 days/week) starting from week 2. From week 3, intravital microscopic observation was carried out weekly till week 10, and the vasculature in the tibiae was observed under fluorescent microscope with FITC and RITC staining. All the images were analyzed by Metamorph program. RESULTS: The bone capillary permeability increased significantly in the experimental group. CONCLUSION: Skeletal muscle contraction can increase the capillary permeability. PMID- 20159705 TI - [Glycyrrhiznatis ameliorates rabbit myocardial ischemia-reperfusion injury through P38MAPK pathway]. AB - OBJECTIVE: To investigate the role of p38MAPK pathway in the protective effect of glycyrrhiznatis against myocardial ischemia-reperfusion in rabbits. METHODS: Thirty rabbits were randomly divided into control group, I/R group, and glycyrrhiznatis group. In the latter two groups, the left anterior descending branch of the coronary artery was ligated for 40 min followed by 120 min of reperfusion, and in glycyrrhiznatis group, glycyrrhiznatis was given intravenously at 2.5 mg/kg before the occlusion. Blood samples were taken to measure the plasma levels of TNF-alpha, IL-6, and IL-8 at 20 min before (T(0)) and 20 min (T(1)) and 40 min (T(2)) after the occlusion, and at 1 h (T(3)) and 2 h (T(4)) after the reperfusion. At the end of the reperfusion, the infarct size and the area at risk were defined by Evams and TTC staining. The heart was harvested and the levels of the p38 MAPK measured by Western blotting. The ultrastructures of the cardiac myocytes were observed under electron microscope. RESULTS: The p38MAPK activity and the plasma levels of the inflammatory factors were significantly lower in gtycyrrhiznatis group than in I/R group (P<0.05). Glycgrrhiznatis significantly reduced the infarct size as compared with that in I/R group. CONCLUSIONS: lycyrrhiznatis can reduce myocardial ischemia-reperfusion injury by inhibiting p38MAPK activity and modulating the cytokine expression. PMID- 20159706 TI - [Study of intra-operative radiotherapy in primary liver cancer]. AB - OBJECTIVE: To study the feasibility of intraoperative radiotherapy (IORT) in primary liver cancer. METHODS: Based on the target of dose curves, the dose volume histogram (DVH) and cost of radiation equipment and radiation therapy, IORT was compared with protonbeam therapy (PBT) and 3DCRT in 16 patients with primary liver cancer using the therapy plan system (TPS). RESULTS: IORT had significantly better performance than 3DCRT to allow a target region surrounded by 90% of the dose lines. IORT was similar to protonbeam therapy in terms of target region surroundings and absorbed dose in the normal organs, but the cost of IORT was significantly lower. CONCLUSION: The TPS of IORT is better than 3DCRT and similar to protonbeam therapy in the treatment of primary liver cancer with similar cost to 3DCRT. IORT can effectively protect the neighboring sensitive organs and improve the absorbed dose in the tumors and the local control rate. PMID- 20159707 TI - [Survivin antisense oligodeoxynucleotides inhibits the proliferation of hepatocellular carcinoma cells and enhances 5-FU sensitivity]. AB - OBJECTIVE: To investigate the inhibitory effect of survivin antisense oligodeoxynuleotides (ASODN) mediated by polyethylenimine (PEI) on hepatocelluar carcinoma SMMC-7721 cell proliferation and its effect on chemosensitivity to 5-FU in tumor-bearing mice. METHODS: The inhibitory effect of PEI-ASODN on SMMC-7721 cell proliferation was assayed by WST-8 test, Trypan blue exclusion test, and cell clone formation assay. In mouse models of transplanted H22 cell hepatocarcinoma and ascites tumor, the effect of 5-FU combined with PEI-ASODN on the weight and volume of the subcutaneous tumors was examined. The tumor inhibition rate in the tumor-bearing mice was calculated and the average survival time recorded. RESULTS: SMMC-7721 cells incubated with different concentrations of PEI-ASODN for 48 h showed significantly reduced cell proliferation in comparison with the control cells, while PEI or ASODN alone produced no such inhibitory effect. Incubation of SMMC-7721 cells with 0.75 micromol/L PEI-ASODN for 24, 48, 72, and 96 h resulted in significantly suppressed cell proliferation, and a 7-day incubation of the cells with PEI-ASODN at different concentrations (0.25-0.75 micromol/L) significantly inhibited the cell clone formation. In the tumor-bearing mice, the tumor weight and volume were obviously reduced with a tumor inhibition rate of 56.91% and volume inhibition rate of 57.83%, significantly different from those in saline-treated mice (P<0.01). In the mice bearing ascites tumor, the average survival time was 22.0 days in saline group and 42.7 days in 5-FU+PEI-ASODN treatment group, showing a a life-prolonging rate of 94.09% in the latter group. A synergetic effect was noted between 5-FU and PEI ASODN. CONCLUSION: PEI-ASODN complex can significantly inhibit the proliferation of hepatocarcinoma SMMC-7721 cells and enhance 5-FU chemosensitivity of the tumor cells in vitro and transplanted H22 tumors in mice. PMID- 20159708 TI - [Retrospective analysis of 125 cases of pregnancies complicated by rheumatic heart disease]. AB - OBJECTIVE: To investigate the impact of rheumatic heart disease on pregnancy. METHODS: A retrospective study was conducted in 125 pregnant women with rheumatic heart disease. These cases were divided into operation (group A) and non operation (group B), and the cardiac function, pregnancy complications, gestational weeks, delivery modes and outcomes of pregnancy were compared. RESULTS: The cardiac function was significantly improved and pregnancy complications reduced after the cardiac operation with extended gestational weeks, showing significant differences between the two groups (P<0.05). One perinatal fetal death without maternal death occurred in group A, as compared with two maternal and two perinatal deaths in group B. Cesarean section was the primary delivery mode in these cases. CONCLUSION: Surgical interventions can improve the cardiac function, reduce the pregnancy complications and improve the pregnancy outcomes in pregnant women with rheumatic heart disease. Cesarean section is the primary choice for pregnant women with prosthetic heart valve replacement. PMID- 20159709 TI - [Correlation between myocardial ischemia and carotid atherosclerosis in hypertensive patients]. AB - OBJECTIVE: To analyze the correlation between myocardial ischemia and carotid atherosclerosis in hypertensive patients. METHODS: The clinical data were collected from 85 hospitalized hypertensive patients admitted between May 2005 and September 2008 without the complication of coronary artery disease as confirmed by cardiac computed tomographic angiography (CTA). According to the results of treadmill exercise test, the patients were divided myocardial ischemia group and ischemia-free group. Univariate and multivariate analyses were used to screen the risk factors of myocardial ischemia. The correlations were analyzed between myocardial ischemia, common carotid artery intima-media thickness (IMT), Crouse score of the carotid plaque, thickness of the intraventricular septum and left artrium. The receiver operating characteristic (ROC) curves were used to evaluate the sensitivity and specificity of IMT and Crouse score in predicting the presence of myocardial ischemia in hypertensive patients. RESULTS: Carotid plaque formation was identified as the major risk factor of myocardial ischemia in hypertensive patients (OR=4.982, P=0.004). The incidence of myocardial ischemia in the hypertensive patients with carotid plaques was significantly higher than that in the patients without the plaque (Chi2=9.317, P=0.002). Myocardial ischemia in hypertensive patients was positively correlated to the thickness of the intraventricular septum (r=0.362, P=0.001) and left artrium (r=0.298, P=0.009), and the IMT of the common carotid artery was positively correlated to the thickness of the intraventricular septum (r=0.231, P=0.045). The area under cure (AUC) of the ROC curve of Crouse score was 0.726-/+0.061 in predicting the presence of myocardial ischemia in the hypertensive patients (P=0.001), and that of IMT was 0.682-/+0.061 (P=0.006). CONCLUSION: Carotid plaque formation is the major risk factor of myocardial ischemia in hypertensive patients and shows a positive correlation to the onset of myocardial ischemia, but both the common carotid artery IMT and the Crouse score of the carotid plaque are not accurate markers for predicting myocardial ischemia in patients with hypertension. PMID- 20159710 TI - [Epidemiological study of the cardiovascular risk factors and clinical medications in patients with cardiovascular diseases in Guangzhou hospitals]. AB - OBJECTIVE: To study the cardiovascular risk factors and clinical medications in patients with cardiovascular disease in Guangzhou hospitals. METHODS: Cluster sampling and non-random sampling methods were used to analyze the cardiovascular risk factors and clinical medications among the 6691 inpatients with cardiovascular diseases in the department of cardiology of 9 large general hospitals in Guangzhou during 1995-2005. RESULTS: Compared with the data in 1995, the incidences of hypertension, type 2 diabetes, and hypertriglyceridemia increased while hypercholesteremia, elevated low-density lipoprotein, and low high-density lipoprotein levels decreased in 2005. The percentage of patients with level 1 (mild) hypertension was lower while that of patients with level 2 (moderate) hypertension higher in 2005 than in 1995. The percentages of use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor antagonist (ARB), beta-blockers, diuretics, and anti-platelet drugs (aspirin, clopidogrel), as well as statins lipid-lowering drugs, increased significantly in 2005 as compared with those in 1995. CONCLUSION: The cardiovascular risk factors and clinical medications underwent significant changes in Guangzhou hospitals in the period from 1995 to 2005, and the blood pressure, blood glucose, hypertriglyceridemia of the patients did not appear to be well controlled. The application rate of ACEI, ARB, beta-blockers, diuretics, aspirin, clopidogrel and statins increased rapidly for treatment of cardiovascular diseases, and these drugs have become the first-line drugs. PMID- 20159711 TI - [Protocols for cloning human bone marrow-derived hepatic stem cells in vitro]. AB - OBJECTIVE: To explore practical protocols for cloning bone marrow-derived hepatic stem cells in vitro. METHODS: The cell fraction rich in CD117(+) cells and CD184(+) cells was separated from fresh bone marrow by density gradient centrifugation and cultured for 0, 7 and 14 days in high-glucose DMEM supplemented with or without 10% autologous serum or in serum-free high-glucose DMEM. All the media were supplemented with different concentrations of hepatocyte growth promoting factors (HGPF), thrombopoietin (TPO) and interleukin-3 (IL-3). The quantitative changes of CD117(+) cells and CD184(+) cells were measured by flow cytometry. RESULTS: The optimal effect for cell cloning was achieved with high-glucose DMEM with 10% autologous serum group supplemented with 40 microg/ml HGPF, 50 ng/ml TPO, and 10 ng/ml IL-3. At day 7 of cell culture in this media, the quantity of CD117(+) cells and CD184(+) cells increased by 6.55 and 6.20 folds, and by 11.62 and 20.57 folds at day 14, respectively. CONCLUSION: It is practical for cloning bone marrow-derived hepatic stem cells in high-glucose DMEM with 10% autologous serum supplemented with 40 microg/ml HGPF, 50 ng/ml TPO, and 10 ng/ml IL-3. PMID- 20159712 TI - [Naringin inhibits monocyte adhesion to high glucose-induced human umbilical vein endothelial cells]. AB - OBJECTIVE: To investigate the inhibitory effect of naringin on monocyte adhesion to high glucose-induced human umbilical vein endothelial cells (HUVECs). METHODS: Cultured HUVECs isolated from human umbilical cords were pretreated with or without naringin and induced with high glucose (33 mmol/L) for 48 h. Human monocyte THP-1 cells, after labeling with BCECF-AM, were co-cultured with the HUVECs for 30 min. The labeled THP-1 cells adhering to HUVECs were observed under fluoroscence microscope, and the inhibitory effect of naringin on the cell adhesion was evaluated by measuring the adhering cell density. Western blot analysis was used to detect the expressions of the adhesion molecules in the HUVECs, and reactive oxygen species (ROS) production in the HUVECs was measured using an oxidation-sensitive fluorescent probe (DCFH-DA). The nuclear extracts of the HUVECs were prepared to examine the expression of nuclear factor-kappa B (NF kappaB) in the cell nuclei by Western blotting. RESULTS: HUVECs in high-glucose culture showed increased adhesion to THP-1 cells and enhanced expressions of the cell adhesion molecules, which were significantly attenuated by pretreatment with naringin (10-50 microg/ml). High glucose induced DCF-sensitive intracellular ROS production in the HUVECs, and this effect was inhibited by naringin pretreatment of the cells. Naringin also suppressed high glucose-induced increment of NF kappaB expression in the cell nuclei of HUVECs. CONCLUSION: Naringin can suppress high glucose-induced vascular inflammation possibly by inhibiting ROS production and NF-kappaB activation in HUVECs. PMID- 20159713 TI - [Expression of HER-2/neu oncogene in hepatocellular carcinoma and the clinical implications]. AB - OBJECTIVE: To investigate the expression of human epidermal growth factor receptor 2 (HER-2/neu) in hepatocellular carcinoma (HCC) patients and its clinical significance. METHODS: The expressions of HER-2/neu were detected by SP immunohistochemistry method in 30 patients with HCC, 10 with portal cirrhosis of the liver and 10 with normal liver. RESULTS: The positivity rate of HER-2/neu was markedly higher in HCC patients than in those with portal cirrhosis and normal liver (Chi(2)=6.482, P=0.032). The expression of HER-2/neu was closely correlated to portal cirrhosis of the liver (P=0.041), tumor invasion (P=0.028) and Edmondson grades (P=0.012). The average survival time was significant shorter in patients with HER-2/neu-positive tumor than in those with HER-2/neu-negative tumor (P=0.036). CONCLUSION: The expression of HER-2/neu may play a role in the invasion, metastasis and progression of HCC. The patients positive for HER-2/neu in the HCC tissues have generally poor prognosis. PMID- 20159714 TI - [Application of 99mTc-DTPA in evaluation of blood-brain barrier permeability in patients receiving whole brain irradiation]. AB - OBJECTIVE: To study the pattern of blood-brain barrier (BBB) permeability changes during whole brain radiotherapy (WBRT) for metastatic brain tumor. METHODS: Twenty patients with metastatic brain tumors receiving WBRT by 6 MV X-ray underwent (99)mTc-DTPA brain SPECT before and during WBRT (20, 40 Gy) and at 2 weeks after the end of irradiation. A frame of transverse (99)mTc-DTPA brain SPECT image that best displayed the brain metastasis was chosen, and the regions of interest (ROI) were defined in the tumor foci (T), the contralateral normal brain tissue (N) and the background outside the soft tissues around the cranium (B). The radioactive counts of every ROI were measured and the ratios of the total counts (T/B and N/B) before and during WBRT (20 Gy, 40 Gy) and at 2 weeks after the irradiation were calculated. RESULTS: The average T/B and N/B in the 20 patients with 30 brain metastases was 142.2-/+51.1 and 82.6-/+42.3 before WBRT, 260.3-/+121.5 and 150.7-/+72.5 during 20 Gy WBRT, 251.6-/+118.3 and 161.8-/+68.4 during 40 Gy WBRT, and 250.3-/+117.2 and 158.6-/+73.5 at 2 weeks after the irradiation, respectively. The measurements during WBRT (20 and 40 Gy) and at 2 weeks after the irradiation group underwent no significant variations (P>0.05), but showed significant differences from those before WBRT (P<0.05). CONCLUSIONS: Irradiation causes direct damage of the BBB function, and the permeability of the BBB increases significantly during and within 2 weeks following 20 and 40 Gy WBRT, which provides the optimal time window for interventions with chemotherapy. PMID- 20159715 TI - [Study of 17 immune cytokines in the peripheral blood of premature infants with chronic lung disease]. AB - OBJECTIVE: To explore the immunomechanism of chronic lung disease (CLD) in premature infants by investigating the changes of 17 cytokines. METHODS: Twenty six preterm neonates who had been in the NICU for over 28 days were divided into CLD group (n=14) and control group consisting of 12 preterm neonates. Seventeen cytokines, namely interleukin 1b (IL-1b), IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL 10, IL-12, IL-13, IL-17, granulocyte-macrophage colony-stimulating factor, interferon-gamma, tumour necrosis factor alpha, granulocyte colony-stimulating factor, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1b were detected in a single sample of peripheral blood by multi-plex technology (Bio-plex). RESULTS: There were no significant differences in the level of the 17 cytokines between the two groups (P>0.05). CONCLUSION: The cytokines examined may not be involved in the later period pathogenesis of CLD. PMID- 20159716 TI - [Effect of epidural anesthesia on hemorheology in patients undergoing gynecological laparoscopy]. AB - OBJECTIVE: To evaluate the effect of epidural anesthesia and patient-controlled epidural analgesia (PCEA) on hemorheology and the incidence of deep venous thrombosis in patients undergoing gynecological laparoscopy. METHODS: One hundred ASA I-II patients undergoing gynecological laparoscopy were randomly allocated into 2 groups to receive general-epidural anesthesia combined with PCEA (GE group) and general anesthesia (G group). Blood samples were taken before anesthesia (T(0)), before operation (T(1)), 30 min after pneumoperitoneum (T(2)), 30 min after pneumoperitoneum cease (T(3)), and 24 and 48 h after the operation (T(4), T(5)) for hemorheological tests. RESULTS: In GE group, the blood viscosity, plasma viscosity and RBC aggregation decreased significantly at T(1) (P<0.05), but no significant variations were detected at the other time points. In G group, blood viscosity and plasma viscosity increased significantly from T(2) to T(5), and were significantly higher than those of GE group. The incidence of deep venous thrombosis of GE group (2%) was significantly lower than that of the G group (8%). CONCLUSION: The blood viscosity, plasma viscosity and RBC aggregation increase during gynecological laparoscopy, and can be reduced by epidural anesthesia and PCEA to lower the incidence of deep venous thrombosis. PMID- 20159717 TI - [Proteomic study of the brain tissues of mice with human cytomegalovirus infection]. AB - OBJECTIVE: To establish the two-dimensional electrophoresis profiles with high resolution and reproducibility from the brain tissues of mice with human cytomegalovirus (HCMV) infection. METHODS: Forty Kunming mice were randomized into HCMV infection group (n=20) with HCMVAD(169) injection and control group (n=20) with saline injection in the brain. Thirty days after the injections, the brain tissue of the mice were taken and the protein fractions were isolated by two-dimensional gel electrophoresis (2-DE). Image Master 2D software was used to identify the differentially expressed proteins, and the peptide mass fingerprint (PMF) data were obtained for identification of the differential protein spots via database searching. Western blotting was performed to verify the expressions of some of the differential proteins. RESULTS AND CONCLUSION: The 2-D maps of the brain tissues with high Well resolution and reproducibility were obtained. Some of the differentially expressed proteins identified by mass spectrometry (MS) matched their counterparts in the SWISS-2DPAGE database. Western blotting analyses verified the differential expression of the individual proteins. These data can be of value for studying the diagnosis, pathogenesis and effective therapeutic targets of the disease. PMID- 20159718 TI - [Clinical analysis of 118 patients with tympanosclerosis]. AB - OBJECTIVE: To study the incidence of tympanosclerosis (TS) and the major risk factors of hearing loss. METHODS: A total of 118 TS patients (137 ears) were compared with 265 patients with chronic otitis media (COM) (311 ears) for gender, age and course of disease. The disease regions and hearing loss of the TS patients were analyzed. RESULTS: TS showed higher prevalence in women of older ages. Sclerosis was seen most frequently in the tympanic membrane, followed by the malleus, incus, incudomalleolar joint, other regions, ariticulus incudostapedius and stapes. The patients with sclerosis or deterioration in the ossicular chain had worse hearing loss than the other patients. Carhart notch occurred in 45 ears (32.85%), an incidence similar to that of inverted "V"-shaped curve of air-conduction audiometry near 2 kHz (47 ears, 34.31%). The factors contributing to the hearing loss, listed in the order of their importance, included pathologies in the incus, malleus, incudomalleolar joint, ariticulus incudostapedius, stapes, other regions, tympanic membrane, and gender. CONCLUSIONS: Female patients may had increased risk of TS. The presence of Carhart notch and inverted "V"-shaped curve in air-conduction audiograph may indicate myringosclerosis or ossicular chain sclerosis. Abnormal ossicular chain is the leading factor contributing to hearing loss. PMID- 20159719 TI - [Clinical study of irinotecan plus cisplatin for advanced non-small cell lung cancer]. AB - OBJECTIVE: To evaluate the efficacy and adverse effects of irinotecan combined with cisplatin in the treatment of advanced non-small cell lung cancer (NSCLC). METHODS: Fifteen patients (10 males and 5 females) aged from 32 to 58 years (median age of 47 years) with KPS>70 and the diagnosis of advanced NSCLC by pathology or cytology were treated with cisplatin 80 mg/m(2) plus irinotecan 60 mg/m(2) by intravenous infusion on 1, 8, 15 days, and the treatment was repeated every 4 weeks. After treatment for at least 2 cycles, the therapeutic effects and adverse drug reactions were evaluated. RESULTS: Of all the cases, PR was achieved in 4 (26.7%), SD in 9 (60%), and PD in 2 (13.3%), with an overall response rate of 26.7%. The median survival time was 11 months and 1-year survival rate was 46.7% (7/15). The main toxicities were delayed diarrhea and granulocytopenia. CONCLUSION: Irinotecan plus cisplatin is an effective and tolerable treatment for advanced NSCLC with low incidence of adverse effects. PMID- 20159720 TI - [Establishment of a cell culture model of corpus cavernosum smooth muscle cells derived from diabetic rats with erectile dysfunction]. AB - OBJECTIVE: To investigate the method for culturing corpus cavernosum smooth muscle cells (CCSMs) derived from diabetic rats with erectile dysfunction (ED) for the study of ED caused by diabetes. METHODS: CCSMs were isolated from the corpus cavernosum of diabetic rats with ED and cultured using a modified method of adherent tissue culture. The cultured cells were identified by immunohistochemistry and the cell morphology and proliferation were observed. RESULTS: The primary culture of CCSM was performed successfully, and the cells were seen to migrate from the small tissue pieces 3 days later, reaching nearly confluence in 16-18 days. A typical "hill-valley" growth pattern was noted in the cell passaging. Immunohistochemical staining for alpha-smooth muscle actin (alpha SM-actin) and desmin yielded positive results in the cells. CONCLUSION: The modified method for adherent tissue culture is convenient and reliable in establishing the in vitro cell culture model of CCSMs from diabetic rats with ED, and the cultured CCSMs display a faster proliferation than normal CCSMs. No obvious differences in the cell morphology can be found between diabetic and normal CCSMs under light microscope. PMID- 20159721 TI - [Study of the three-dimensional structure of the ventricular myocardial fiber in human heart]. AB - OBJECTIVE: To study the three-dimensional structure of ventricular myocardial fiber in human heart. METHODS: Eight human heart were obtained from male donors aged 81.9-/+7.2 years with a heart weight of 455.6-/+65.7 g. Each sample was immersed in water and scanned by diffusion tensor magnetic resonance imaging (DT MRI) using a 3 Tesla Exicte HD by an eight-channel head coils. The duration was 18.6-/+5.2 h from heart arresting to the scanning. The data were obtained using the protocol of single shot echo planar imaging (sshEPI) and sensitivity encoding (SENSE). The SENSE-sshEPI-scans (TE/TRZ86.4/2000 ms) of the whole heart were carried out (b=1000 s/mm(2), voxels 128x128, resolution 1.1 mmx1.1 mmx(3) mm, and FOV 14 cmx14 cm). Fiber tracking and reconstruction were performed using GE Advantage Windows Workstation. The three-dimensional structure of the ventricular myocardial fiber was observed. RESULTS: The left ventricular myocardial fibers showed two layers with different directions of alignment in such regions as the anterior, septum, and posterior walls and the free left ventricular wall. The subendocardial layer ran obliquely from the base to the apex, and the middle layer ran obliquely upward from the base to the apex. The two layers were linked together and aligned in the pattern of helical coils near the apex. CONCLUSIONS: The three-dimensional structure of the myocardial fibers in human heart conforms to Torrent's hypothesis of helical ventricular myocardial band (HVMB). PMID- 20159722 TI - [Lateral mass screws of the atlas combined with vertebra dentata pedicle screws for treatment of upper cervical vertebral instability]. AB - OBJECTIVE: To evaluate the therapeutic effects of fixation and fusion with lateral mass screws of the atlas and vertebra dentata pedicle screws for the treatment of upper vertebral instability. METHODS: Ten patients with atlantoaxial instability, including 3 with old odontoid fracture and 7 with fresh odontoid fracture (Aderson II) received surgeries for fixation and fusion with lateral mass screws of the atlas and vertebra dentata pedicle screws. RESULTS: No spinal cord or vertebral artery injuries occurred in these patients after the surgery. The follow-up duration ranged from 3 to 15 months with an average of 8 months. The postoperative JOA scores were from l3.2 to l6.8, with an average of l4.8. Clinical improvement was achieved in 87.5% of the patients, and the implanted bones all fused successfully without internal fixation rupture or mobilization. CONCLUSION: Lateral mass screws of the atlas combined with vertebra dentata pedicle screws allows three-dimensional fixation for treatment of atlantoaxial instability. PMID- 20159723 TI - [Segmental resection of the liver by Glissonean pedicle transection for primary liver cancer]. AB - OBJECTIVE: To study the clinical effect of segmental resection of the liver using Glissonean pedicle transection for primary liver cancer. METHODS: The clinical data of 55 primary liver cancer patients admitted from January 2006 to October 2008 were analyzed retrospectively. Twenty-five of the patients underwent segmental resection of the liver by Glissonean pedicle transection (group A), and 30 underwent routine hepatectomy (group B). The positivity rate of the resection margin, micrometastasis in the hepatic parenchyma surrounding the lesions and postoperative recurrence rates were investigated. RESULTS: The positivity rate of the resection margin was 4.0% in group A, significantly lower than that of group B. The number of histological micrometastasis was significantly higher in group A than in group B (16 vs 8). The median distance of histological micrometastasis was 6.8 mm (2.7-25.6 mm) in group A and 4.2 mm (2.4-9.0 mm) in group B. The one year recurrence rate was significantly lower in group A than in group B (16% vs 26.7%). CONCLUSION: Glissonean pedicle transection for segmental liver resection is a simpler procedure than routine hepatectomy for primary liver cancer and can reduce the number of histological micrometastasis and recurrence rate. PMID- 20159724 TI - [High-performance liquid chromatography for detecting the concentrations of isoniazid and acetylisoniazid in spinal tuberculosis]. AB - OBJECTIVE: To study the distribution of isoniazid and its metabolite in spinal tuberculosis following chemotherapy. METHODS: Twenty-three patients with spinal tuberculosis received chemotherapy with 2SHRZ/16HRZ (for a total of 18 months). Four weeks after the chemotherapy, all the patients underwent surgery and specimens of the serum, ilium and vertebral tissue including the sclerotic wall, focus inside the sclerotic wall (if present) and destructed foci were obtained. CT was performed in all the cases to test the HU of the foci before operation, and the levels of isoniazid and its metabolite in the specimen were measured with high-performance liquid chromatography (HPLC). RESULTS: The levels of isoniazid and its metabolite were the highest in the serum, followed by normal ilium and non-sclerotic bone, and were extremely low in the sclerotic wall and foci. Their levels in the non-sclerotic bone of the compromised vertebra and normal vertebra showed no significant difference (P>0.05), but in the sclerotic bone, their levels were significantly higher than in the normal vertebra (P<0.05). Isoniazid and its metabolite are hardly detectable in the sclerotic foci in the compromised vertebrae. CONCLUSION: Isoniazid and its metabolite may reach therapeutic concentration in normal vertebra and nonsclerotic bones of the compromised vertebra, but not in the disease foci or the sclerotic bone of the compromised vertebrae. PMID- 20159725 TI - [Microsurgical treatment of intramedullary tumor in the superior cervical spinal cord]. AB - OBJECTIVE: To evaluate the curative effect of microsurgery for intramedullary tumor in the superior cervical spinal cord. METHODS: The clinical manifestations, microsurgical methods and results were reviewed retrospectively in 12 patients with intramedullary tumors in the superior cervical spinal cord. RESULTS: No death occurred in these cases after the operations. The intramedullary tumors were totally resected in 10 patients including 8 with ependymomas and 2 with astrocytomas, and subtotally in 2 patients with astrocytomas. The spinal functions of patients, graded by McCormick scale system 3 months after the operations, were improved in 8 cases and remained unchanged in 4 cases. Nine patients were followed up for 1-3 years after the operations, and no tumor recurrence was found in 8 cases with total tumor resection. CONCLUSION: Radical microneurosurgery is currently the best choice for the treatment of intradullary tumor in the superior cervical spinal cord. PMID- 20159726 TI - [Effect of noninvasive positive pressure ventilation on postoperative pulmonary function in patients undergoing thoracic surgeries]. AB - OBJECTIVE: To evaluate the effects of noninvasive positive pressure ventilation (NPPV) on postoperative pulmonary function recovery in patients receiving thoracic surgeries. METHODS: Fifty thoracic surgical patients were enrolled in this prospective randomized controlled study and divided randomly into conventional treatment group and NPPV group. In the NPPV group, the patients were given NPPV therapy on the basis of conventional treatment. The volume of the residual cavity and the lung function were recorded. RESULTS: At one week after the operation, the changes of lung function parameters were similar between NPPV and control group (P>0.05). CONCLUSIONS: NPPV following thoracic surgeries produces no obvious effects on postoperative pulmonary complications or the lung functions, and bullous resection have less adverse effect than lobectomy on the lung function. PMID- 20159727 TI - [An enzyme-linked immunosorbent assay for determining serum anti-themocyte globulin concentration]. AB - OBJECTIVE: To establish an enzyme-linked immunosorbent assay (ELISA) for determining anti-themocyte globulin (ATG) levels in serum samples. METHODS: The microplate was coated with mouse anti-rabbit IgG monoclonal antibody, and sheep anti-rabbit polyclonal antibody conjugated with HRP was used as the second antibody for detecting the serum ATG levels in patients undergoing allogeneic hematopoietic stem cell transplantation. RESULTS: The optimal concentration of the coating antibody and dilution ratios of the serum samples and IgG-HRP conjugate were 0.2 microg/ml, 1:40 and 1:2500, respectively. The lower sensitivity limit of the assay was 31.25 ng/ml for ATG detection. A linear relationship was established within the concentration range from 40 to 1000 ng/ml, with the coefficients of variation of 7.91 within assay and 5.22 between assays, respectively. Seven patients undergoing stem cell transplantation with ATG pretreatment showed gradually decreased concentration of ATG, and after 90 days ATG could still be detected. CONCLUSION: The sandwich ELISA we established provides a specific and sensitive method for quantitative measurement of ATG in the clinical setting. In patients undergoing stem cell transplantation with ATG pretreatment, the ATG concentration gradually decreases but remains detectable 90 days after the administration. PMID- 20159728 TI - [Glucocorticoid treatment for early postoperative cholangiole cholestasis hyperbilirubinemia after liver transplantation]. AB - OBJECTIVE: To study the therapeutic effect of glucocorticoid on early postoperative cholangiole cholestasis hyperbilirubinemia after liver transplantation. METHODS: Thirteen liver transplantation recipients with serum total bilirubin above 171 micromol/L at two weeks to one month postoperatively were enrolled in this study. After exclusion of liver blood supply anomalies, bile duct complications, and acute rejection and establishment of a pathological diagnosis of cholangiole cholestasis by hepatic biopsy, hydrocortisone sodium succinate was infused. The liver functions of the patients were tested at 1 day before and 1 day and 1 week after the treatment. Hepatic biopsy was performed before and 1 week after the treatment to observe histopathological changes. RESULTS: The serum levels of total bilirubin decreased significantly after the treatment with glucocorticoid. Pathology of the hepatic biopsy demonstrated the resolution of cholangiole cholestasis 1 week after the treatment. CONCLUSION: Glucocorticoid treatment is effective for early postoperative cholangiole cholestasis hyperbilirubinemia after liver transplantation. PMID- 20159729 TI - [Effects of Danqi Huogan Capsule in protecting the liver, promoting circulation and removing clots in patients with chronic hepatitis B]. AB - OBJECTIVE: To assess the effect of Danqi Huogan Capsule in protecting the liver, promoting the circulation and removing blood clots in patients with chronic hepatitis B (CHB). METHODS: A total of 104 CHB patients were randomized into two groups. Routine therapies for liver protection were given in the control group (n=50), and Danqi Huogan Capsule was administered in the therapeutic group (n=54) in addition to the routine therapies. The changes in the clinical symptoms, physical signs, liver functions, and hemorrheology were observed after the 3 month therapies. RESULTS: Danqi Huogan Capsule treatment obvious improved the clinical symptoms, physical signs and liver functions of the patients (P<0.01), and significantly decreased the hematocrit, low-shear blood viscosity, plasma viscosity and index of red blood cell aggregation (P<0.05). CONCLUSION: Danqi Huogan Capsule is effective in protecting the liver, improving hemorrheology, promoting the blood circulation and removing clots in patients with chronic hepatitis B. PMID- 20159730 TI - [A rare vascular malformation of the lung: discussion of the CT findings and nomenclature]. AB - OBJECTIVE: To investigate the characteristic findings of an anomalous systemic arterial supply to the lung without the pulmonary artery on spiral CT and discuss its nomenclature. METHODS: Four cases of anomalous systemic arterial supply to the left basal segment of the lung without the pulmonary artery were retrospectively reviewed with analysis of the characteristic CT findings. RESULTS: On spiral CT scans, the involved left lower lung including the entire left basal segments (n=2), the lateral and posterior basal segment (n=1), and the anterior, medial, and posterior basal segment (n=1) had mild volume loss and areas of ground-glass opacity but with normal bronchial trees. The absence of the entire or part of the basal segments of the normal left lower lobar pulmonary artery, anomalous systemic artery originating from the abdominal aorta, diffuse dilatation of the systemic arterial branches distributed in the basal segments of the left lower lobe, and left lower pulmonary venous drainage into left atrium were found in all these patients. CONCLUSION: This anomaly presents with characteristic findings on chest spiral CT, for which the nomenclature of local absent pulmonary artery better shows the characteristics of the disease. PMID- 20159731 TI - [Chromosome karyotype and Y chromosome microdeletion analysis in 133 idiopathic male infertile patients]. AB - OBJECTIVE: To explore the relationship between chromosomal abnormalities and Y chromosome microdeletions in idiopathic male infertile patients. METHODS: Karyotypic analysis and PCR were carried out in 133 male idiopathic infertile patients for chromosome karyotype and Y chromosome microdeletion analysis. RESULTS: Of the 133 patients, 25 (18.80%) were found to have chromosome abnormalities, and 12 (9.02%) were found to have Y chromosome microdeletions including 2 with varicocele and 2 with cryptorchism. Four patients had both chromosomal abnormalities and Y chromosome microdeletions. CONCLUSION: The chromosomal abnormalities and Y chromosome microdeletions may play an important role in idiopathic male infertility, suggesting the importance of examinations of chromosomal abnormalities and Y chromosome microdeletions in such patients. PMID- 20159732 TI - [Construction and expression of the eukaryotic green fluorescent protein expression vector pEGFP-N1-ZNF217]. AB - OBJECTIVE: To construct the eukaryotic green fluorescent protein expression vector pEGFP-N1-ZNF217 and express the vector in eukaryotic cells. METHODS: ZNF217 gene fragment was amplified by reverse transcriptase-polymerase chain reaction (RT-PCR), and after analysis of the product by electrophoresis and sequencing, the fragment was inserted into pEGFP-N1 fluorescent expression vector. The constructed expression vector was then transfected into eukaryotic cells for its expression. RESULTS AND CONCLUSION: Restriction endonuclease digestion and sequence analysis confirmed correct construction of the recombinant vector pEGFP-N1 and the expression vector pEGFP-N1-ZNF217, which can be stably expressed in eukaryotic cells. PMID- 20159733 TI - [Hysteroscopic treatment of women with previous cesarean scar defect]. AB - OBJECTIVE: To investigate the effects of hysteroscopic treatment of women with previous cesarean scar defect (PCSD). METHODS: From May 2006 to October 2008, 12 patients with PCSD were diagnosed and treated hysteroscopically in our hospital, all of them were successful followed-up for one year postoperatively, and their clinical data were analyzed. RESULTS: All 12 hysteroscopic procedures were completed successfully, and there were no surgical complications. Nine patients with longer periods and 1 patient with intermenstrual spotting preoperatively remained asymptomatic after hysteroscopic surgery, and 1 patient with longer periods and infertility experienced normal periods, while remained infertility, and the remaining 1 patient complaining postcoital bleeding preoperatively had recurrence of the bleeding. CONCLUSION: Hysteroscopic surgery of women with PCSD was minimally invasive and effective. PMID- 20159734 TI - Preventive and therapeutic methods against the toxic effects of mycotoxins - a review. AB - Ingredients used in animal feeds and their contamination with undesirable substances, such as mycotoxins, are fundamentally important both in terms of the quality of animal products and the potential human health impacts associated with the animal-based food production chain. Feed ingredients contaminated with mycotoxins may have a wide range of toxicological effects on animals. Therefore, mycotoxin contamination of feed ingredients constituting complete feed products represents an important potential hazard in farm animal production. This review summarises the potential effects of some preventive methods used during the storage of cereal grains as well as of nutritive (e.g. antioxidants, amino acids, fats) or non-nutritive compounds (e.g. pharmacological substances, carbon- or silica-based polymers) and detoxifying enzymes recommended for use against the toxic effects of different mycotoxins. PMID- 20159735 TI - A pulsed-field gel electrophoresis study of the genetic diversity of Campylobacter jejuni and Campylobacter coli in poultry flocks in Slovenia. AB - Campylobacter jejuni and C. coli have recently become the most frequent cause of bacterial foodborne enteric infection in most industrialised countries. Consumption and handling of undercooked contaminated poultry meat was identified as an important risk factor for human campylobacteriosis. The aim of this study was to ascertain the genetic diversity of C. jejuni and C. coli strains isolated from poultry in Slovenia. A total of 68 isolates (42 C. jejuni , 26 C. coli ) from faeces (n = 48), meat (n = 15) and skin/carcasses (n = 5) of chicken (n = 60) and turkey samples (n = 5) were analysed by pulsed-field gel electrophoresis. Sma I macrorestriction discriminated between C. jejuni and C. coli isolates. C. jejuni isolates exhibited a higher degree of diversity compared to C. coli isolates. In the C. jejuni group, a number of small clusters were apparent, while C. coli strains formed less but larger clusters. Additional Kpn I digestion of selected isolates resulted in poor subtyping. Strains with identical or very similar profiles were found on different farms, either in the same or different regions and time periods. Some of the clones indicated possible cross contamination at slaughterhouses. PMID- 20159736 TI - Phytotherapy of ulcerative dermatitis induced by Aeromonas hydrophila infection in goldfish ( Carassius auratus ). AB - Goldfish ( Carassius auratus ) weighing 13 +/- 2 g were administered intramuscularly a sublethal dose (1.8 x 10 3 cfu/ml) of Aeromonas hydrophila to induce ulcerative dermatitis. On day 3 and day 6 after infection the fish were dip-treated (for 5 min/day) with a tri-herbal concoction of Curcuma longa, Ocimum sanctum and Azadirachta indica (1%). The LD 50 value was recorded at a concentration of 2.3 x 10 4 between 30 and 36 days after infection. In the infected untreated group the cumulative mortality was higher, while in the early treated group (day 3) there was no mortality. In the late-treated group (6th day) the mortality increased to 23.3% on day 36. In the infected group the size of ulcers progressively increased from 43.3% of the body length on day 18 to 86.7% on day 36. In the early-treated fish the size of ulcers was 23.3% of the body length on day 18; by day 36 after treatment the ulcer had completely healed. In contrast, there was only a moderate recovery in the late-treated group. From the results it can be concluded that early tri-herbal treatment ensures successful recovery from ulcerative dermatitis induced by A. hydrophila . PMID- 20159737 TI - Molecular evidence of natural infection with Babesia canis canis in Croatia. AB - The aim of the present study was to detect and characterise the species and subspecies of Babesia spp. that cause canine babesiosis in Croatia. Twenty-eight dogs with typical signs of babesiosis (lethargy, anorexia, fever, dark urine and thrombocytopenia) were included in this study. Their blood smears showed the presence of Babesia canis . The results showed the detection of one subspecies, namely Babesia canis canis using PCR, and subsequent sequence analysis demonstrated portions of the nss rRNA gene in 27 out of 28 samples. Sequence analysis of the isolates showed 100% identity in 11 samples, 99.7% identity (one nucleotide difference) in 11 samples and 99.4% identity (two nucleotides difference) in 5 samples with B. canis canis . The results of this study confirm the presence of B. canis canis in infected dogs in Croatia and demonstrate a slightly new genetic variant of Babesia subspecies. PMID- 20159738 TI - Hepatitis and hydropericardium syndrome associated with adenovirus infection in goslings. AB - Two outbreaks of severe acute disease characterised by hepatitis and hydropericardium were observed in young goslings on large-scale farms in Hungary. Histological examination revealed multifocal necrotic areas and two types of intranuclear inclusion bodies adjacent to necrotic areas in the liver. The most prominent type of inclusion bodies showed strong basophilic staining and completely filled the enlarged nucleus. The other type was eosinophilic and occupied the centre of the nucleus, which had margination of chromatin. In the heart, haemorrhage was associated with multifocal necrosis in the myocardium. The presence of fowl adenovirus DNA in different organs of the naturally infected goslings was detected by polymerase chain reaction (PCR). The virus was isolated, and identified as a goose adenovirus by genomic analysis. This is the first report on the involvement of a goose adenovirus in severe acute disease associated with hepatitis and hydropericardium. PMID- 20159739 TI - Cystatin C analysis in the dog: a comparison of turbidimetric and nephelometric assay results. AB - Cystatin C is a serum protein with low molecular mass, which has been suggested as a marker to assess renal function in the dog. This protein is regularly assessed using particle-enhanced turbidimetric immunoassay (PETIA) and particle enhanced nephelometric immunoassay (PENIA), in which rabbit anti-human cystatin C antibodies are used. The purpose of this work was to compare the results of cystatin C analysis obtained by PETIA and PENIA assays in the dog. Forty dogs of different genders and breeds were classified into four groups of 10 animals each based on serum creatinine concentrations (4 stages of chronic kidney disease). Serum cystatin C concentration was measured using PETIA and PENIA assays, the results were compared, and correlation with serum urea and creatinine concentrations was established. The correlation coefficient for results obtained using PETIA and PENIA assays was r = 0.706. Serum cystatin C concentrations obtained in PETIA had a lower correlation coefficient with creatinine concentrations than those found in PENIA (r = 0.614 and r = 0.904, respectively); similarly, serum cystatin C was less correlated with serum urea concentration in PETIA than in PENIA (r = 0.463 and r = 0.636, respectively). The results obtained in this study suggest that the nephelometric assay is more sensitive and was shown to be more closely correlated with other renal function indicators than the PETIA assay. PMID- 20159740 TI - First description of papillary carcinoma in the thyroid gland of a red-eared slider (Trachemys scripta elegans ). AB - Postmortem examination of the carcass of an approximately 10-year-old male Red eared slider ( Trachemys scripta elegans ) was performed. The thyroid gland was enlarged, showed follicular structure, and shifted the base of the heart caudally. Histology revealed differently shaped and sized follicles in the thyroid gland. Based on the macroscopic appearance and histopathological changes of the thyroid gland, the pathological process was established as a papillary cystic carcinoma. Neoplasia of the endocrine organs, especially of the thyroid gland, is rare in reptiles. The current case seems to be the first report of thyroid carcinoma in a Red-eared slider. PMID- 20159741 TI - Effects of tylosin on serum cytokine levels in healthy and lipopolysaccharide treated mice. AB - The effects of different doses of tylosin on serum cytokine concentrations were investigated in healthy and lipopolysaccharide-treated mice. The mice were divided into seven groups. Lipopolysaccharide (LPS) was injected into the positive control group. The other six groups received three different tylosin doses concurrently without or with LPS: 10 mg/kg, 100 mg/kg, 500 mg/kg, 10 mg/kg + LPS, 100 mg/kg + LPS and 500 mg/kg + LPS. After treatment, serum samples were collected at 0, 1, 2, 3, 6, 12 and 24 hours. Serum tumour necrosis factor alpha (TNFalpha), interleukin 1beta (IL1beta) and IL10 levels were determined by enzyme linked immunosorbent assay (ELISA). Tylosin doses of 10 and 100 mg/kg induced no cytokine production in the healthy mice. Tylosin at 500 mg/kg had no effect on TNFalpha or IL1beta production, but it induced IL10 production in healthy mice. All doses of tylosin reduced the elevated TNFalpha and IL1beta in LPS-treated mice but increased their IL10 levels. In conclusion, these data suggest that tylosin has an immunomodulatory effect at the dose recommended for use against infection. PMID- 20159742 TI - Application of a solid-phase fluorescence immunoassay to determine amoxicillin residues in fish tissue. AB - The present study demonstrates an application of Parallux (a solid-phase fluorescence immunoassay) for amoxicillin analysis in fish tissue. Amoxicillin at the recommended therapeutic dose (400 mg/kg body weight) was orally administered to three groups of 25 olive flounder ( Paralichthys olivaceus ), 25 rockfish ( Sebastes schlegeli ) and 25 red sea bream ( Pagrus major ) for 7 consecutive days. Amoxicillin was detected in the muscle of fish treated by the 3rd day of the withdrawal period. The recovery rates of all spiked muscle samples were > 86% of the spiked values. The present study showed that solid-phase fluorescence immunoassay can be easily adopted in predicting amoxicillin residues in the muscle tissue of farmed fish. PMID- 20159743 TI - Inflammation- and axotomy-induced changes in galanin-like immunoreactive (GAL-LI) nerve structures in the porcine descending colon. AB - This study reports on changes caused by chemically driven inflammation and axotomy in galanin-like immunoreactive (GAL-LI) nerve structures in the porcine descending colon. The distribution pattern of GAL-LI structures was studied using the immunofluorescence technique in the circular muscle layer, the myenteric (MP), outer submucous (OSP) and inner submucous plexuses (ISP), and also in the mucosal layer. Under physiological conditions GAL-LI perikarya were shown to constitute 3.68 +/- 0.32%, 7.02 +/- 0.93% and 10.99 +/- 0.71% in MP, OSP and ISP, respectively. Both colitis and axotomy caused an increase in GAL-like immunoreactivity, which was different in particular parts of the bowel segment studied. The numbers of GAL-LI perikarya increased to 14.16 +/- 0.49%, 16.78 +/- 1.09% and 37.46 +/- 1.18% during colitis and 7.92 +/- 0.72%, 10.44 +/- 0.71% and 16.20 +/- 0.96% after axotomy in MP, OSP and ISP, respectively. Both these processes caused an increase in the number of GAL-LI nerve fibres in the circular muscle and mucosal layers as well as the appearance of a population of GAL-LI cells in the mucosa. PMID- 20159744 TI - Plasma membrane changes during the liquid storage of boar spermatozoa: a comparison of methods. AB - Studies were performed on boar semen routinely used at the local artificial insemination (AI) centre. The semen was stored in a Safe Cell Plus commercial extender at 17 degrees C for nine days. The aim of our research was focused on changes in sperm plasma membrane integrity. The integrity of the sperm plasma membrane and acrosome as well as sperm motility decreased after dilution and during storage of the semen. The highest percentage of live sperm was identified by the eosin-nigrosin method, a lower percentage by the SYBR-14/PI test, and the lowest percentage of live cells was discovered by the hypoosmotic swelling (HOS) test (P < 0.01). There were significant differences between the results of staining methods and sperm motility (P < 0.01). No significant differences were found between the HOS test results and sperm motility. The plasma membrane integrity parameters positively correlated (P < 0.001) with each other and with sperm motility but negatively with aspartate aminotransferase activity. Our findings confirmed that the boar sperm aging changes, which increased during liquid semen preservation, were connected with the loss of function and integrity of the sperm plasma membrane. The employed complementary tests are comprehensive indicators of sperm membrane integrity during long-term semen preservation, and they can help establish the actual number of 'healthy' cells. The assays may be used in AI laboratories and should be incorporated into the routine of semen analysis. PMID- 20159745 TI - Plasma progesterone profiles in Beagle bitches with and without the whelping experience. AB - The aim of this study was to investigate differences between the progesterone profiles of Beagle bitches with (multiparous) and without (nulliparous) the whelping experience and to examine whether the selection of bitches by progesterone analyses before the programmed mating improved the whelping rates. In the first experiment, the progesterone profiles of nulliparous and multiparous bitches were evaluated from Days 1 to 13 (onset of prooestrus = Day 0). The mean duration of the elevation in progesterone levels (> 2 ng/mL) after the onset of prooestrus tended to be approximately 1 day shorter in nulliparous bitches (7.7 days) than in multiparous bitches (8.5 days). In the second experiment, progesterone analyses in the bitches were carried out once on Days 4, 5 or 6. Bitches with progesterone levels of > 10 ng/mL were excluded from mating because it was unclear when the progesterone levels reached > 10 ng/mL considering the optimal date for mating. No significant differences were observed in the percentages of bitches excluded from mating and in the whelping rates of the mated bitches between the groups, irrespective of the day of progesterone analysis and the type of bitch. In conclusion, the initial elevation of progesterone levels was of shorter duration in nulliparous bitches. The selection of bitches by the measurement of progesterone levels once before mating was not effective for the programmed mating. PMID- 20159746 TI - The influence of transfer gun passage time through the uterine cervix on pregnancy rate in recipient heifers. AB - The influence of passage time of the transfer gun through the uterine cervix and body to the embryo insertion site on pregnancy rate was analysed in 248 recipient heifers (mean age: 15-17 months). Embryos (90 fresh and/or 88 and 70 frozen in glycerol and ethylene glycol, respectively, grades 4 and 5, stage 1 or 2) were transferred to the ipsilateral uterine horn on day 7. Two different transfer guns were used in this experiment: a sterilisable steel transfer instrument to be used without sheaths with a removable tip made of gold-plated stainless steel (Worrlein Minitub) or a transfer stylet with sheaths with a metal tip and a side opening (Cassou gun, IMV Technologies). The time of passage of the instruments through the uterine cervix and body to the site of embryo deposition in the uterine horn was measured in the study. In order to randomise the risk of errors, all manipulations were carried out by the same experienced operator. The average time needed for the insertion of embryos into the uterus was 50.6 seconds (s) and it was longer for the transfer gun with sheaths than for the metal-tipped transfer gun (60.1 and 40.8 s, respectively) (P < 0.001). The average conception rate was 45.6%. If the time needed to insert embryos into the uterus was 10-60 s, the conception rate was 53.4% (up to 20, 21-30, 31-40, 41-50 and 51-60 s - 57.7, 52.5, 50, 51.5 and 50%, respectively). In contrast, if the time needed to insert the embryo in the uterine horn was longer than 60 s, the conception rate was 20.4% (61-80, 80.1-120 and > 120 s - 28.0, 6.0 and 24.9%, respectively). Thus, it cannot be excluded that the type of the applied transfer gun may influence pregnancy rate in recipient cows due to its effect on cervical passage time. PMID- 20159747 TI - [Patomechanisms of hepatic steatosis]. AB - Obesity-triggered co-morbidities, such as insulin resistance and the accompanying nonalcoholic fatty liver disease represent major health care burdens worldwide. The first step in the pathogenesis of the disease is the triglyceride deposition in the liver. The resulting hepatic steatosis may lead to steatohepatitis, cryptogenic cirrhosis and eventually, hepatocellular cancer. Steatosis develops when fatty acid uptake and lipogenesis overwhelm fatty acid oxidation and secretion. We highlight these molecular mechanisms in this review to provide further information to understand the background of nonalcoholic fatty liver disease and the cardiometabolic complications that escort obesity and insulin resistance. PMID- 20159748 TI - [Epidemiology of smoking in Hungary--a representative national study]. AB - Our study reviews publications regarding assessment of smoking prevalence rates on Hungarian adult representative samples. Our aim is to report the results on prevalence of smoking of the national representative survey called the National Survey on Addiction Problems in Hungary (NSAPH) carried out in 2007. of the present survey and former studies are compared, as well. METHODS: Target population of the survey was the entire Hungarian population between 18 and 64 years of age. Net size of the sample was 2710 persons. Part of the data collection happened by face-to-face interviews while more sensitive issues were assessed by self-rating questionnaires. RESULTS: 36.1% of the Hungarian adult population smoke cigarettes (29.9% on a daily basis). 40.6% of males while 31.7% of females smoke regularly (rates of daily smokers are 34.6% and 25.3%, respectively). Male gender, lower age, lower education, lower socio-economic status and parental smoking were identified as risk factors for smoking. CONCLUSIONS: Present results support the higher prevalence rates among the heterogeneous results of previous years, while suggest slight increase of smoking at the same time. This tendency is unequivocally due to the increase of smoking among women, while in case of men stagnating prevalence rates can be observed. PMID- 20159749 TI - [Long-term prognostic value of coronary flow reserve in patients without significant left anterior descending coronary artery stenosis: results from the SZEGED Study]. AB - Coronary flow reserve (CFR) measured by pulsed Doppler echocardiography is a useful hemodynamic index to evaluate coronary microcirculatory (dys)function in the left anterior descending coronary artery (LAD), in the absence of macrovascular lesions. AIMS: The present study was designed to evaluate long-term prognostic value of CFR in patients without significant epicardial LAD stenosis. METHODS: A total of 166 patients without significant LAD stenosis were enrolled in this prospective follow-up study. Coronary angiography demonstrated absence of significant LAD disease in all cases. All patients underwent transthoracic and stress transesophageal echocardiography (CFR measurement) and coronary angiography. RESULTS: The success rate of follow-up was 124 out of 166 (75%). During a mean follow-up of 93+/-34 months 27 patients died, including 16 sudden cardiac deaths, 3 acute heart failures, 2 strokes, while 6 patients had pulmonary or gastrointestinal malignancies. Using ROC analysis, the best cut-off value for CFR was 2.13 to predict survival (sensitivity 67%, specificity 60%, area, under the curve 62%, p = 0.046). Patients with CFR < 2.13 had significantly more events (32% vs. 13%, p<0.05). The logistic regression model identified CFR (hazard ratio (HR) 2.43, p = 0.04) and left ventricular end-systolic volume (HR 1.09, p = 0.03) as independent predictors of survival. CONCLUSIONS: Long-term prognostic significance of CFR for prediction of survival has been demonstrated during a long-term follow-up in patients without significant LAD stenosis. PMID- 20159750 TI - [Adjuvant chemotherapy of early stage breast cancer]. AB - Adjuvant systemic therapy reduces the likelihood of both local and distant relapses by eradicating micrometastases. AIM: To survey the adjuvant treatment of early breast cancer. METHODS: Author presents an overview of the systemic therapy of early breast cancer based on relevant literature and own experiences. RESULTS: Three systemic treatment modalities are widely used as adjuvant therapy for early stage breast cancer such as endocrine treatments, chemotherapy, and anti-HER2 therapy with the humanized monoclonal antibody, trastuzumab. As regards endocrine therapy, the most firmly established adjuvant therapy is tamoxifen for both premenopausal and postmenopausal women. Ovarian suppression and/or tamoxifen are accepted therapy for premenopausal patients. The third generation of aromatase inhibitors should be incorporated in the adjuvant endocrine therapy of postmenopausal women. Thus, it is not known whether initial, sequential, or extended use of adjuvant aromatase inhibitors is the optimal strategy. Adjuvant chemotherapy consisting of multiple cycles of polychemotherapy is an important strategy for lowering the risk of breast cancer recurrence and improving survival, not only in women with higher risk, but in node-negative patients, as well. The introduction of taxanes into treatment strategy constitutes an important advance over the traditional therapy with alkylator- and anthracycline based regimens. The biologically-targeted drug, trastuzumab has been incorporated in the adjuvant management of HER2 positive tumors, and its duration of treatment is conventionally 1 year to date. CONCLUSIONS: Adjuvant systemic treatment in breast cancer is a rapidly advancing field of clinical oncology. Taxane-based chemotherapy, aromatase inhibitors in the adjuvant endocrine therapy of postmenopausal women, and the availability of trastuzumab as adjuvant treatment have all led to substantial improvement in the outcome of early breast cancer. PMID- 20159751 TI - [Therapy of erectile dysfunction]. PMID- 20159753 TI - The effect of religiosity and campus alcohol culture on collegiate alcohol consumption. AB - Religiosity and campus culture were examined in relationship to alcohol consumption among college students using reference group theory. PARTICIPANTS AND METHODS: College students (N = 530) at a religious college and at a state university complete questionnaires on alcohol use and religiosity. Statistical tests and logistic regression were utilized to examine alcohol use, religiosity, and campus environment. RESULTS: Alcohol consumption was significantly higher among students at the university (M = 26.9 drinks) versus students at the religious college (M = 11.9 drinks). University students also had lower religiosity scores (M = 23.8) than students at the religious college (M = 26.5). Students who attend a secular university are 4 times more likely to be moderate or heavy drinkers compared to students attending a religiously affiliated college. Students with the least religiosity were 27 times more likely to be a heavy alcohol user and 9 times more likely to be a moderate alcohol user compared to students with greater religiosity. PMID- 20159754 TI - Pregaming: an exploratory study of strategic drinking by college students in Pennsylvania. AB - OBJECTIVES: This exploratory study examined pre-event drinking, or pregaming, by US college students. PARTICIPANTS: 112 undergraduates from 10 Pennsylvania colleges participated. METHOD: A focus group, including a written questionnaire, was conducted at each institution. RESULTS: Only 35.7% of the participants had not pregamed during the last 2 weeks. Pregamers consumed an average of 4.9 (SD = 3.1) drinks during their most recent session. Gender, class year, and other demographic variables did not predict pregaming. Heavier drinkers, and those stating that the average student pregamed 3+ times in the last 2 weeks, were more likely to report pregaming in the last 2 weeks. How much students drink when pregaming is influenced by how much they expect to drink later on. CONCLUSION: Pregaming presents a growing challenge for campus officials. Additional research is needed on the nature of the problem and which combination of prevention strategies might best address this behavior. PMID- 20159755 TI - The virtuous drinker: character virtues as correlates and moderators of college student drinking and consequences. AB - OBJECTIVE: The present study examined the relationship between alcohol use and positive psychology's character virtues1 in a college student sample. Each of the virtues of wisdom, courage, humanity, justice, temperance, and transcendence were examined as protective factors and moderators of drinking consequences. PARTICIPANTS: This sample included 425 undergraduate students at a large Northwest University (69% female; 52% Caucasian, 34% Asian). METHODS: Participants completed paper and pencil questionnaires during October and November 2006 in exchange for extra credit in psychology classes. RESULTS: Higher temperance scores were associated with abstinence, lower risk drinking, and fewer consequences among heavy drinkers; both increased justice and transcendence were independently associated with abstinence only; and wisdom, courage, and humanity were not associated with any outcomes. CONCLUSIONS: The associations between virtues and college student drinking support a collaboration between addictive behaviors and positive psychology to address college student drinking and minimize consequences. PMID- 20159756 TI - Physical activity behaviors of students of a rural historically black college. AB - Physical activity can have a positive impact on health disparities among African Americans. OBJECTIVE: In this study, we assessed physical activity behaviors and correlates of students of a Historically Black College. METHODS: In September 2004, an online survey and pedometers were used to measure physical activity behavior and correlates. PARTICIPANTS: A convenience sample of 106 students completed the survey and received pedometers. Pedometer data were submitted online for 5 weeks. RESULTS: One hundred and six students completed the survey. Twenty-eight percent and 41% of respondents met recommendations for moderate physical activity and vigorous physical activity, respectively. Week 1 daily pedometer step count average was 8,707. Most students reported positive outcome expectations for physical activity. Students submitting pedometer data were less likely to meet MPA recommendations than students only completing the survey. CONCLUSIONS: African American students feel positive about physical activity yet most do not meet recommended levels. PMID- 20159757 TI - The State of the union: sexual health disparities in a national sample of US college students. AB - OBJECTIVE: To examine sexual health disparities between blacks and whites in a national sample of US college students. PARTICIPANTS AND METHOD SUMMARY: Analyses utilized secondary data from 44,165 nonmarried undergraduates (aged 18-24; M = 20.1) responding to the Spring 2007 American College Health Association-National College Health Assessment; 64% were female and 94.7% were white. RESULTS: Whites reported more experience in oral and anal sex, were less likely to use condoms for oral, anal, and vaginal sex, and less likely to have been tested for HIV (human immunodeficiency virus) compared with blacks. However, blacks reported more sex partners, lower use of hormonal contraceptives, and higher rates of adverse sexual health outcomes, such as sexually transmitted infections (STIs) and unintended pregnancy. Sexual behaviors and outcomes also varied across gender. CONCLUSIONS: This study highlights a need to increase access to hormonal contraceptives and early STI screening/treatment among blacks, improve HIV testing among whites, and increase condom use promotion for all students. PMID- 20159758 TI - Efficacy of a web-based, tailored, alcohol prevention/intervention program for college students: initial findings. AB - OBJECTIVE: Reduce college student at-risk drinking (ARD) using a Web-based brief motivational alcohol prevention/intervention called Michigan Prevention and Alcohol Safety for Students (M-PASS). PARTICIPANTS: Participants included 1,137 randomly sampled first-year college students, including 59% female, 80% white, and averaged age 18.1 years. METHODS: Intervention group participants (n = 616) attended 4 online M-PASS sessions, receiving feedback tailored to individual drinking patterns and concepts from 4 behavior change theories. Control group participants (n = 521) completed a mid-phase survey, and both groups were surveyed at baseline and posttest. RESULTS: Evidence of M-PASS's efficacy was found. The intervention was associated with advanced stage of change, lower tolerance of drinking and drink/driving, fewer reasons to drink, and use of more strategies to avoid ARD. Preliminary evidence of behavioral change was also found. Efficacy was greater for women than men. CONCLUSIONS: Web-based programs may be useful in reducing alcohol-related risk among college students. Further evaluation is needed. PMID- 20159759 TI - Brief screening and intervention for alcohol and drug use in a college student health clinic: feasibility, implementation, and outcomes. AB - OBJECTIVE: Evaluation of the Brief Alcohol Screen and Intervention in College Students (BASICS) in a university primary care setting. PARTICIPANTS/METHODS: Undergraduates (N = 449) participated in BASICS and electronic surveys assessing frequency/quantity of alcohol and drug use, psychosocial and mental health outcomes, and demographic information. Data were collected at baseline and 6 month follow-up between August 2006 and August 2008. RESULTS: Drinking and drug use decreased between baseline and 6 months. Participants reported an increase in protective factors and in readiness to change alcohol-related behaviors, and a decrease in alcohol-related consequences and in distress symptoms. Heavy episodic drinking at baseline significantly moderated the changes in number of drinks in a typical week and in a typical weekend, and number of drinks on the occasion drank most on a weekend. CONCLUSIONS: BASICS can be implemented in a primary health care setting and university students may reduce their alcohol and/or drug use. PMID- 20159760 TI - Abstinence and relapse rates following a college campus-based quit & win contest. AB - OBJECTIVE: To conduct and evaluate Quit & Win contests at 2 2-year college and 2 4-year university campuses. PARTICIPANTS: During Spring semester, 2006, undergraduates (N = 588) interested in quitting smoking signed up for a Quit & Win 30-day cessation contest for a chance to win a lottery prize. METHODS: Participants (N = 588) completed a baseline survey, provided a urine sample to verify smoking status before joining the contest, and completed a follow-up survey at contest end to assess abstinence. Participants reporting continuous 30 day abstinence were surveyed again 2 weeks post contest to assess relapse. RESULTS: Participants smoked an average of 9.8 +/- 6.7 cigarettes/day on 26.7 +/- 5.7 days/month. Among participants completing a follow-up survey (74%), 72.1% reported abstinence during the entire contest period (Intent-to-Treat Analysis = 53.2%). 55.3% of those abstinent at the end of contest had resumed smoking 2 weeks post contest. CONCLUSIONS: Campus Quit & Win contests appear feasible, acceptable, and effective at facilitating short-term abstinence. Further research is needed to identify strategies to prevent postcontest relapse. PMID- 20159761 TI - The influence of tobacco countermarketing ads on college students' knowledge, attitudes, and beliefs. AB - OBJECTIVE: To determine which antitobacco messages were perceived effective in changing college students' knowledge, attitudes, and beliefs about tobacco use. PARTICIPANTS: College students (n = 1,020) were surveyed before and after viewing 4 30-second antitobacco advertisements in 1 of 3 theme categories-social norms, health consequences, or tobacco industry manipulation. METHODS: An independent samples t test was used to test for differences in the mean responses to the knowledge, attitude, and belief questions at posttest by smoking status and gender. RESULTS: Health consequences ads significantly increased overall knowledge and negative attitudes and beliefs. CONCLUSION: Findings from this study may help health educators who work in college settings and other young adult settings to include media messages as part of a comprehensive tobacco control program. PMID- 20159762 TI - Trends in alcohol consumption among undergraduate students at a northeastern public university, 2002-2008. AB - OBJECTIVE: This study examined alcohol consumption patterns and trends at a public university in the Northeast from 2002 to 2008. PARTICIPANTS: Stratified random sampling was used to select undergraduate students enrolled in courses during spring semesters in 2002, 2004, 2006, and 2008. METHODS: Data were collected during regularly scheduled classes for 4 measures of alcohol consumption and 5 demographic categories using the Core Alcohol and Drug Survey. RESULTS: Four groups showed significant increases in both frequency and volume of alcohol consumption-students who were female, over 21 years of age or over, living off-campus, or performing well academically. There were no decreasing trends for any demographic group. These results differ from national college health surveys, which have shown alcohol use remaining steady during this period. CONCLUSIONS: Campus-specific trend data can provide unique perspectives and guide programming efforts. These trends suggest a need for new intervention strategies on this campus. PMID- 20159763 TI - Weathering the recession in college health. AB - The current global recession has increased personal stress levels throughout our society. With dwindling resources, institutions of higher learning are especially prone to budgetary cutbacks during such periods. Based on 22 years of experience as a health service director, the author offers some personal insights in the hope that they will help colleagues cope with the current situation. PMID- 20159764 TI - The role of a psychiatric pharmacist in college health. AB - Published evidence indicates there is a growing prevalence of psychiatric illnesses on college campuses, and that approximately one quarter of students may be taking psychotropic medications. But attracting and retaining experienced mental health care professionals to college health settings is a challenging task. The psychiatric pharmacist is one professional resource that can serve as both a clinical and educational consultant for college mental health services. A pilot psychiatric pharmacist service project is described. PMID- 20159765 TI - Alcohol measures and terms: a perfect storm for chronic confusion. AB - Members in the prevention and treatment fields continue to examine how to most effectively assess and label high volume alcohol consumption. Terms such as "binge" drinking have resulted in considerable controversy and debate. Conventionally the criteria for assessing high-risk drinking includes: five or drinks for men and four or more drinks for women during a sitting/event/occasion within the previous two weeks. Several standardized instruments simply use the cut off for high-risk drinking as five or more drinks and do not include the gender variable when defining this behavior. Both of these measures have undergone criticism for not including a more specific time element. Yet asking respondents to recall specific time frames from a night of heavy drinking may also compromise validity. Further the 5+/4+ or 5+ drinking criterion does not adequately assess intoxication levels or more extreme levels of alcohol consumption. A variety of special measures and terms have been created to capture heavy drinking behaviors and ritualistic behavior. Researchers and practitioners may benefit by using different measures and terms based on context and their specific prevention goals. PMID- 20159767 TI - Dr Macdonald Critchley (1900-97). PMID- 20159766 TI - The constitutive activity of epidermal growth factor receptor vIII leads to activation and differential trafficking of wild-type epidermal growth factor receptor and erbB2. AB - A constitutively active epidermal growth factor receptor (EGFR) mutant, EGFR variant III (EGFRvIII), has been detected at high frequencies in certain human cancers. This study evaluated transactivation and trafficking of erbB family members as a result of constitutive EGFR activity in a cancer cell line. Expression of EGFRvIII modulated erbB family members through different mechanisms; the erbB3 mRNA level was reduced, whereas wild-type EGFR (wtEGFR) and erbB2 protein levels were diminished, with no change in their mRNA levels, and there was no change in the erbB4 expression level. Both EGFR and erbB2 were internalized as a result of EGFRvIII's activity and redistributed to the cell surface upon addition of AG1478, an inhibitor of wtEGFR/EGFRvIII catalytic activity. Acute activation of EGFRvIII by removing AG1478 from cells increased phosphorylation of both wtEGFR and erbB2 and caused differential trafficking of EGFRvIII's activation partners; wtEGFR was directed primarily to lysosomal compartments and partially to recycling compartments, whereas erbB2 was directed primarily to recycling compartments and partially to lysosomal compartments. Our data demonstrate that the constitutive activity of EGFRvIII is sufficient to trigger endocytosis and trafficking of wtEGFR and erbB2, which may play a role in activating signaling pathways that are triggered during receptor endocytosis. PMID- 20159768 TI - Integrin activation or alpha 9 expression allows retinal pigmented epithelial cell adhesion on Bruch's membrane in wet age-related macular degeneration. AB - Retinal pigment epithelial cell malfunction is a causative feature of age-related macular degeneration, and transplantation of new retinal pigment epithelial cells is an attractive strategy to prevent further progression and visual loss. However, transplants have shown limited efficacy, mainly because transplanted cells fail to adhere and migrate onto pathological Bruch's membrane. Adhesion to Bruch's membrane is integrin-mediated. Ageing of Bruch's membrane leads to a decline in integrin ligands and, added to this, wet age-related macular degeneration leads to upregulation of anti-adhesive molecules such as tenascin-C. We have therefore investigated whether manipulation of integrin function in retinal pigment epithelial cells can restore their adhesion and migration on wet age-related macular degeneration-damaged Bruch's membrane. Using spontaneously immortalized human retinal pigment epithelial cells (adult retinal pigment epithelium-19), we show that adhesion and migration on the Bruch's membrane components is integrin-dependent and enhanced by integrin-activating agents manganese and TS2/16. These allowed cells to adhere and migrate on low concentrations of ligand, as would be found in aged Bruch's membrane. We next developed a method for stripping cells from Bruch's membrane so that adhesion and migration assays can be performed on its surface. Integrin activation had a moderate effect on enhancing retinal pigmented epithelial cell adhesion and migration on normal human and rat Bruch's membrane. However, on Bruch's membrane prepared from human wet age-related macular degeneration-affected eyes, adhesion was lower and integrin activation had a much greater effect. A candidate molecule for preventing retinal pigmented epithelial interaction with age-related macular degeneration-affected Bruch's membrane is tenascin-C which we confirm is present at high levels in wet age-related macular degeneration membrane. We show that tenascin-C is anti-adhesive for retinal pigmented epithelial cells, but after integrin activation, they can adhere and migrate on it using alphaVbeta3 integrin. Alternatively, we find that transduction of retinal pigmented epithelial cells with alpha9 integrin, a tenascin-C-binding integrin, led to a large increase in alpha9beta1-mediated adhesion and migration on tenascin-C. Both expression of alpha9 integrin and integrin activation greatly enhanced the ability of retinal pigment epithelial cells to adhere to tenascin-rich wet age related macular degeneration-affected Bruch's membranes. Our results suggest that manipulation of retinal pigment epithelial cell integrins through integrin activating strategies, or expression of new integrins such as alpha9, could be effective in improving the efficacy of retinal pigment epithelial cell transplantation in wet age-related macular degeneration-affected eyes. PMID- 20159770 TI - Attenuation of Pseudomonas aeruginosa virulence factors and biofilms by co encapsulation of bismuth-ethanedithiol with tobramycin in liposomes. AB - OBJECTIVES: This study examined the activities of tobramycin and bismuth against quorum sensing, virulence factors and biofilms of Pseudomonas aeruginosa by co encapsulating the agents in liposomes in order to achieve greater delivery of the agents. METHODS: The inhibitory effects of the agents, in either their conventional (free) or vesicle-entrapped (liposomal) formulations, were assessed by measuring the changes in the quorum-sensing signal molecule N-acyl homoserine lactone, pyoverdine, pyocyanin, elastase, protease, chitinase, bacterial attachment and biofilms in vitro. RESULTS: The effectiveness of tobramycin and bismuth was superior when they were co-administered as a liposomal formulation as measured by their ability to attenuate the production of N-acyl homoserine lactone, elastase (P < 0.01), protease (P < 0.05) and chitinase (P < 0.01). In the presence of non-lethal concentrations of free and liposomal tobramycin and bismuth, bacterial attachment was attenuated. Biofilm formation was also attenuated with free tobramycin and bismuth, yet, in the presence of liposomal tobramycin and bismuth, biofilm complexes could form but contained mostly dead bacteria. When established biofilms were treated with higher concentrations, free tobramycin and bismuth killed and detached bacteria, while the liposomal tobramycin and bismuth penetrated and killed bacteria in the cores of the biofilms. CONCLUSIONS: These data suggest that treatment of P. aeruginosa with tobramycin and bismuth, as measured by the changes in quorum sensing, virulence factors and biofilms, is most effective when delivered as a liposomal formulation at a lower concentration compared with the free formulation. PMID- 20159769 TI - Reduced functional connectivity in a right-hemisphere network for volitional ocular motor control in schizophrenia. AB - Patients with schizophrenia consistently show deficient performance on tasks requiring volitional saccades. We previously reported reduced fractional anisotropy in the white matter underlying right dorsal anterior cingulate cortex in schizophrenia, which, along with lower fractional anisotropy in the right frontal eye field and posterior parietal cortex, predicted longer latencies of volitional saccades. This suggests that reduced microstructural integrity of dorsal anterior cingulate cortex white matter disrupts connectivity in the right hemisphere-dominant network for spatial attention and volitional ocular motor control. To test this hypothesis, we examined functional connectivity of the cingulate eye field component of this network, which is located in dorsal anterior cingulate cortex, during a task comprising volitional prosaccades and antisaccades. In patients with schizophrenia, we expected to find reduced functional connectivity, specifically in the right hemisphere, which predicted prolonged saccadic latency. Twenty-seven medicated schizophrenia outpatients and 21 demographically matched healthy controls performed volitional saccades during functional magnetic resonance imaging. Based on task-related activation, seed regions in the right and left cingulate eye field were defined. In both groups, the right and left cingulate eye field showed positive correlations with the ocular motor network and negative correlations with the default network. Patients showed reduced positive functional connectivity of the cingulate eye field, specifically in the right hemisphere. Negative functional connectivity of the right cingulate eye field predicted faster saccades, but these relations differed by group, and were only present in controls. This pattern of relations suggests that the coordination of activity between ocular motor and default networks is important for efficient task performance and is disrupted in schizophrenia. Along with prior observations of reduced white matter microstructural integrity (fractional anisotropy) in schizophrenia, the present finding of reduced functional connectivity suggests that functional and structural abnormalities of the right cingulate eye field disrupt connectivity in the network for spatial attention and volitional ocular motor control. These abnormalities may contribute to deficits in overcoming prepotency in the service of directing eye gaze and attention to the parts of the environment that are the most behaviourally relevant. PMID- 20159771 TI - Inequalities in Croatian pupils' unhealthy behaviours and health outcomes: role of school, peers and family affluence. AB - BACKGROUND: To examine the influence of family affluence (measure of socioeconomic status), school environment (liking school, school pressure, academic achievement and classmates support) and peer group (size of the peer group and frequency of peer contact) on unhealthy behaviours (smoking, drunkenness, physical inactivity, irregular breakfast and soft drink consumption) and health outcomes (self-rated health, multiple health complaints and life satisfaction) in Croatian pupils. METHODS: The Croatian data from Health Behaviour in School-aged Children 2005/06 (HBSC) were used (1666 11-year-olds, and 1630 15-year-olds). Binary logistic regression analysis was conducted (95% confidence intervals, P < 0.05 and P < 0.01). RESULTS: School environment and peer group were connected to more unhealthy behaviours along with greater differences in those behaviours than family affluence. The only exception was physical inactivity at age 11 (compared to high family affluence, low family affluence increased 80% odds for physical inactivity, whereas, compared to favourable school environment, poor school environment increased 50% odds). Compared to favourable school environment, poor school environment was the most consistent and strongest predictor of poor health outcomes (all three measures). No influence of peer group to health outcomes was found. Compared to high affluent families, low-affluent families were associated to higher odds for poor self-rated health and life dissatisfaction, and, for 11-year-olds, medium affluent families to lower odds for multiple health complaints. Gender differences in unhealthy behaviours and health outcomes were also found. CONCLUSIONS: Compared to socioeconomic inequalities, greater inequalities in unhealthy behaviours were connected to school environment and peer group, and in health outcomes to school environment. PMID- 20159772 TI - Promoting tobacco through the international language of dance music: British American Tobacco and the Ministry of Sound. AB - BACKGROUND: Tobacco companies target young adults through marketing strategies that use bars and nightclubs to promote smoking. As restrictions increasingly limit promotions, music marketing has become an important vehicle for tobacco companies to shape brand image, generate brand recognition and promote tobacco. METHODS: Analysis of previously secret tobacco industry documents from British American Tobacco, available at http://legacy.library.ucsf.edu. RESULTS: In 1995, British American Tobacco (BAT) initiated a partnership with London's Ministry of Sound (MOS) nightclub to promote Lucky Strike cigarettes to establish relevance and credibility among young adults in the UK. In 1997, BAT extended their MOS partnership to China and Taiwan to promote State Express 555. BAT sought to transfer values associated with the MOS lifestyle brand to its cigarettes. The BAT/MOS partnership illustrates the broad appeal of international brands across different regions of the world. CONCLUSION: Transnational tobacco companies like BAT are not only striving to stay contemporary with young adults through culturally relevant activities such as those provided by MOS but they are also looking to export their strategies to regions across the world. Partnerships like this BAT/MOS one skirt marketing restrictions recommended by the World Health Organization's Framework Convention on Tobacco Control. The global scope and success of the MOS program emphasizes the challenge for national regulations to restrict such promotions. PMID- 20159773 TI - Reduced elimination of IgG antibodies by engineering the variable region. AB - Fc engineering to increase the binding affinity of IgG antibodies to FcRn has been reported to reduce the elimination of IgG antibodies. Herein, we present a novel non-FcRn-dependent approach to reduce the elimination of IgG antibodies. Pharmacokinetic studies conducted in normal mice of various humanized IgG4 antibodies, which had identical constant regions but different variable region sequences, revealed that an antibody with a lower isoelectric point (pI) has a longer half-life. These antibodies exhibited comparable binding affinity to FcRn, and with the antibodies with lower pIs, a longer half-life was also observed in beta2-microglobulin knockout mice, suggesting that differences in the pharmacokinetics were due to a non-FcRn-dependent mechanism. On the basis of our findings, we attempted to engineer the pharmacokinetic properties of a humanized anti-IL6 receptor IgG1 antibody. Selected substitutions in the variable region, without substitution in the Fc region, lowered the pI but did not reduce the biological activity and showed a significant reduction in the clearance of the antibody in cynomolgus monkey. These results suggest that lowering the pI by engineering the variable region could reduce the elimination of IgG antibodies and could provide an alternative to Fc engineering of IgG antibodies. PMID- 20159774 TI - A DNA damage-activated checkpoint kinase phosphorylates tau and enhances tau induced neurodegeneration. AB - Hyperphosphorylation of the microtubule associated protein tau is detected in the brains of individuals with a range of neurodegenerative diseases including Alzheimer's disease (AD). An imbalance in phosphorylation and/or dephosphorylation of tau at disease-related sites has been suggested to initiate the abnormal metabolism and toxicity of tau in disease pathogenesis. However, the mechanisms underlying abnormal phosphorylation of tau in AD are not fully understood. Here, we show that the DNA damage-activated Checkpoint kinase 2 (Chk2) is a novel tau kinase and enhances tau toxicity in a transgenic Drosophila model. Overexpression of Drosophila Chk2 increases tau phosphorylation at Ser262 and enhances tau-induced neurodegeneration in transgenic flies expressing human tau. The non-phosphorylatable Ser262Ala mutation abolishes Chk2-induced enhancement of tau toxicity, suggesting that the Ser262 phosphorylation site is involved in the enhancement of tau toxicity by Chk2. In vitro kinase assays revealed that human Chk2 and a closely related checkpoint kinase 1 (Chk1) directly phosphorylate human tau at Ser262. We also demonstrate that Drosophila Chk2 does not modulate the activity of the fly homolog of microtubule affinity regulating kinase, which has been shown to be a physiological tau Ser262 kinase. Since accumulation of DNA damage has been detected in the brains of AD patients, our results suggest that the DNA damage-activated kinases Chk1 and Chk2 may be involved in tau phosphorylation and toxicity in the pathogenesis of AD. PMID- 20159775 TI - Allelic expression imbalance at high-density lipoprotein cholesterol locus MMAB MVK. AB - Genome-wide association studies (GWAS) have identified numerous loci associated with various complex traits for which the underlying susceptibility gene(s) remain unknown. In a GWAS for high-density lipoprotein-cholesterol (HDL-C) level, one strongly associated locus contains at least two biologically compelling candidates, methylmalonic aciduria cblB type (MMAB) and mevalonate kinase (MVK). To detect evidence of cis-acting regulation at this locus, we measured relative allelic expression of transcribed SNPs in five genes using human hepatocyte samples heterozygous for the transcribed SNP. If an HDL-C-associated SNP allele differentially regulates mRNA level in cis, samples heterozygous both for a transcribed SNP and an HDL-C-associated SNP should display allelic expression imbalance (AEI) of the transcribed SNP. We designed statistical tests to detect AEI in a comprehensive set of linkage disequilibrium (LD) scenarios between the transcribed SNP and an HDL-C-associated SNP (rs7298565) in phase unknown samples. We observed significant AEI of 22% in MMAB (P = 1.4 x 10(-13), transcribed SNP rs11067231), and the allele associated with lower HDL-C level was associated with greater MMAB transcript level. The same rs7298565 allele was also associated with higher MMAB mRNA level (P = 0.0081) and higher MMAB protein level (P = 0.0020). In contrast, MVK, UBE3B, KCTD10 and ACACB did not show significant AEI (P > or = 0.05). These data suggest MMAB is the most likely gene influencing HDL-C levels at this locus and demonstrate that measuring AEI at loci containing more than one candidate gene can prioritize genes for functional studies. PMID- 20159777 TI - Human neural stem cells: a model system for the study of Lesch-Nyhan disease neurological aspects. AB - The study of Lesch-Nyhan-diseased (LND) human brain is crucial for understanding how mutant hypoxanthine-phosphoribosyltransferase (HPRT) might lead to neuronal dysfunction. Since LND is a rare, inherited disorder caused by a deficiency of the enzyme HPRT, human neural stem cells (hNSCs) that carry this mutation are a precious source for delineating the consequences of HPRT deficiency and for developing new treatments. In our study we have examined the effect of HPRT deficiency on the differentiation of neurons in hNSCs isolated from human LND fetal brain. We have examined the expression of a number of transcription factors essential for neuronal differentiation and marker genes involved in dopamine (DA) biosynthetic pathway. LND hNSCs demonstrate aberrant expression of several transcription factors and DA markers. HPRT-deficient dopaminergic neurons also demonstrate a striking deficit in neurite outgrowth. These results represent direct experimental evidence for aberrant neurogenesis in LND hNSCs and suggest developmental roles for other housekeeping genes in neurodevelopmental disease. Moreover, exposure of the LND hNSCs to retinoic acid medium elicited the generation of dopaminergic neurons. The lack of precise understanding of the neurological dysfunction in LND has precluded development of useful therapies. These results evidence aberrant neurogenesis in LND hNSCs and suggest a role for HPRT gene in neurodevelopment. These cells combine the peculiarity of a neurodevelopmental model and a human, neural origin to provide an important tool to investigate the pathophysiology of HPRT deficiency and more broadly demonstrate the utility of human neural stem cells for studying the disease and identifying potential therapeutics. PMID- 20159776 TI - Thoracic aortic disease in tuberous sclerosis complex: molecular pathogenesis and potential therapies in Tsc2+/- mice. AB - Tuberous sclerosis complex (TSC) is a genetic disorder with pleiotropic manifestations caused by heterozygous mutations in either TSC1 or TSC2. One of the less investigated complications of TSC is the formation of aneurysms of the descending aorta, which are characterized on pathologic examination by smooth muscle cell (SMC) proliferation in the aortic media. SMCs were explanted from Tsc2(+/-) mice to investigate the pathogenesis of aortic aneurysms caused by TSC2 mutations. Tsc2(+/-) SMCs demonstrated increased phosphorylation of mammalian target of rapamycin (mTOR), S6 and p70S6K and increased proliferation rates compared with wild-type (WT) SMCs. Tsc2(+/-) SMCs also had reduced expression of SMC contractile proteins compared with WT SMCs. An inhibitor of mTOR signaling, rapamycin, decreased SMC proliferation and increased contractile protein expression in the Tsc2(+/-) SMCs to levels similar to WT SMCs. Exposure to alpha elastin fragments also decreased proliferation of Tsc2(+/-) SMCs and increased levels of p27(kip1), but failed to increase expression of contractile proteins. In response to artery injury using a carotid artery ligation model, Tsc2(+/-) mice significantly increased neointima formation compared with the control mice, and the neointima formation was inhibited by treatment with rapamycin. These results demonstrate that Tsc2 haploinsufficiency in SMCs increases proliferation and decreases contractile protein expression and suggest that the increased proliferative potential of the mutant cells may be suppressed in vivo by interaction with elastin. These findings provide insights into the molecular pathogenesis of aortic disease in TSC patients and identify a potential therapeutic target for treatment of this complication of the disease. PMID- 20159779 TI - Which types of activities are associated with risk of recurrent falling in older persons? AB - BACKGROUND: This study explored the associations between various types of activities, their underlying physical components, and recurrent falling in community-dwelling older persons. METHODS: This study included 1,329 community dwelling persons (>or=65 years) of the Longitudinal Aging Study Amsterdam (LASA). The time spent in walking, cycling, light and heavy household activities, and two sports was measured using the LASA Physical Activity Questionnaire (LAPAQ). Physical activity components included strength, intensity, mechanical strain, and turning. Time to second fall in a 6-month period was measured during 3 years with fall calendars. Cox proportional hazards models were adjusted for confounders and stratified for physical performance and sex in case of significant (p < .10) interaction. RESULTS: During 3 years, 325 (24.5%) persons became recurrent fallers. In women, doing light (hazard ratios [HRs] = 0.40, 95% confidence intervals [CIs] = 0.20-0.79) or heavy household activities (HR = 0.63, CI = 0.44 0.79) was associated with a decreased risk of recurrent falling. In persons with good physical performance, doing sports (HR = 1.56, CI = 1.07-2.28), high intensity (HR > 1.75, CI = 1.09-3.16), and high mechanical strain (HR = 1.70, CI = 1.01-2.83) activities was associated with an increased risk of recurrent falling. CONCLUSIONS: The results suggest that the relationship between physical activity and recurrent falling differs per type of activity and is modified by physical performance. Doing household activities was associated with a decreased risk of recurrent falling in women. In physically fit older persons, doing sports or activities with high intensity or mechanical strain demands was associated with an increased risk of recurrent falling. PMID- 20159778 TI - Sleep-related factors and mobility in older men and women. AB - BACKGROUND: To examine the association between sleep-related factors and measured and self-reported mobility in a representative sample of older adults. METHODS: This study included 2,825 men and women aged 55 years and older participating in a cross-sectional representative population-based Health 2000 Survey in Finland. Sleep duration, insomnia-related symptoms, and fatigue were inquired. Maximal walking speed was measured, and mobility limitation was defined as self-reported difficulties in walking 500 m or stair climbing. RESULTS: Insomnia-related symptoms and fatigue were prevalent among persons aged 65 years and older in particular. After adjusting for lifestyle factors and diseases, longer sleep (>/=9 hours) was associated with a decreased walking speed in women aged 65 or more years (p = .04) and shorter sleep ( or = 10 years, 95% CI, 1.03 to 2.12; P for trend = .03). There was no association with duration of unopposed estrogen use. Duration of E+P use was associated with an advanced stage at diagnosis (P for trend = .03). CONCLUSION: Use of E+P increased the risk of incident lung cancer in a duration-dependent manner, with an approximate 50% increased risk for use of 10 years or longer. These findings may be helpful for informing women of their risk of developing lung cancer and delineating important pathways involved in hormone metabolism and lung cancer. PMID- 20159814 TI - Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. AB - PURPOSE: Persistence of ligand-mediated androgen receptor signaling has been documented in castration-resistant prostate cancers (CRPCs). Abiraterone acetate (AA) is a potent and selective inhibitor of CYP17, which is required for androgen biosynthesis in the testes, adrenal glands, and prostate tissue. This trial evaluated the efficacy and safety of AA in combination with prednisone to reduce the symptoms of secondary hyperaldosteronism that can occur with AA monotherapy. PATIENTS AND METHODS: Fifty-eight men with progressive metastatic CRPC who experienced treatment failure with docetaxel-based chemotherapy received AA (1,000 mg daily) with prednisone (5 mg twice daily). Twenty-seven (47%) patients had received prior ketoconazole. The primary outcome was > or = 50% prostate specific antigen (PSA) decline, with objective response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and changes in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and circulating tumor cell (CTC) numbers. Safety was also evaluated. RESULTS: A > or = 50% decline in PSA was confirmed in 22 (36%) patients, including 14 (45%) of 31 ketoconazole-naive and seven (26%) of 27 ketoconazole-pretreated patients. Partial responses were seen in four (18%) of 22 patients with RECIST-evaluable target lesions. Improved ECOG PS was seen in 28% of patients. Median time to PSA progression was 169 days (95% CI, 82 to 200 days). CTC conversions with treatment from > or = 5 to < 5 were noted in 10 (34%) of 29 patients. The majority of AA-related adverse events were grade 1 to 2, and no AA-related grade 4 events were seen. CONCLUSION: AA plus prednisone was well tolerated, with encouraging antitumor activity in heavily pretreated CRPC patients. The incidence of mineralocorticoid-related toxicities (hypertension or hypokalemia) was reduced by adding low-dose prednisone. The combination of AA plus prednisone is recommended for phase III investigations. PMID- 20159815 TI - Phase 1b study of dulanermin (recombinant human Apo2L/TRAIL) in combination with paclitaxel, carboplatin, and bevacizumab in patients with advanced non-squamous non-small-cell lung cancer. AB - PURPOSE: To determine the safety, pharmacokinetics (PK), and maximum-tolerated dose (MTD) up to a prespecified target dose of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab (PCB) in patients with previously untreated, nonsquamous, stage IIIb (with pleural effusion)/IV or recurrent non small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this phase 1b study, patients (n = 24) received PCB on day 1 of each 21-day cycle then dulanermin at 4 or 8 mg/kg/d for 5 consecutive days or 15 or 20 mg/kg/d for 2 consecutive days per assigned treatment cohort. Incidence of dose-limiting toxicities (DLTs), adverse events, and antidulanermin antibodies were assessed. PK parameters were recorded for each agent. Tumor response was measured by modified Response Evaluation Criteria in Solid Tumors. RESULTS: Twenty-four patients received at least one dose of dulanermin plus PCB, six in each treatment cohort. There were no DLTs. An MTD was not reached, and the drug combination was well tolerated. Treatment-emergent adverse events were generally as expected for the PCB regimen. Adverse events attributed to dulanermin were grade 1/2; no significant hepatotoxicity occurred. There was minimal impact of PCB on the PK of dulanermin. There was one confirmed complete response and 13 confirmed partial responses. The overall response rate was 58% (95% CI, 37 to 78). Median progression-free survival was 7.2 months (95% CI, 4.7 to 10.3). CONCLUSION: Dulanermin plus PCB was well tolerated with no occurrence of DLTs and demonstrated antitumor activity in this patient population. Dulanermin at 8 mg/kg/d for 5 days and 20 mg/kg/d for 2 days every 3 weeks in combination with PCB is being studied in a phase II trial. PMID- 20159816 TI - Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. AB - PURPOSE: Patients with advanced gastric or gastroesophageal adenocarcinoma need more efficacious and safer treatments than established today. S-1, a contemporary oral fluoropyrimidine, can provide that advantage. PATIENTS AND METHODS: This study was conducted in 24 countries and 146 centers. One thousand fifty-three patients were stratified (center, number of metastatic sites, prior adjuvant therapy, and measurable cancer) and randomly assigned. Patients received either S 1 at 50 mg/m(2) divided in two daily doses for 21 days and cisplatin at 75 mg/m(2) intravenously on day 1, repeated every 28 days (527 patients) or infusional fluorouracil at 1,000 mg/m(2)/24 hours for 120 hours and cisplatin at 100 mg/m(2) intravenously on day 1, repeated every 28 days (526 patients). The primary end point was superiority in overall survival (OS) from cisplatin/S-1 compared with cisplatin/infusional fluorouracil in patients with advanced, untreated gastric, or gastroesophageal adenocarcinoma. The secondary end points were response rate, progression-free survival, time to treatment failure, and safety. RESULTS: The median OS was 8.6 months in the cisplatin/S-1 arm and 7.9 months in the cisplatin/infusional fluorouracil arm (HR, 0.92; 95% CI, 0.80 to 1.05; P = .20). Significant safety advantages were observed in the cisplatin/S-1 arm compared with the cisplatin/infusional fluorouracil arm for the rates of grade 3/4 neutropenia (32.3% v 63.6%), complicated neutropenia (5.0% v 14.4%), stomatitis (1.3% v 13.6%), hypokalemia (3.6% v 10.8%), and treatment-related deaths (2.5% v 4.9%; P < .05). CONCLUSION: Cisplatin/S-1 did not prolong OS of patients with advanced gastric or gastroesophageal adenocarcinoma compared with cisplatin/infusional fluorouracil, but it did result in a significantly improved safety profile. PMID- 20159817 TI - Castration-resistant prostate cancer--hormone therapy redux. PMID- 20159818 TI - Treatment of favorable, limited-stage Hodgkin's lymphoma with chemotherapy without consolidation by radiation therapy. AB - PURPOSE: Limited-stage Hodgkin's lymphoma (HL) has been treated with radiation alone or radiation combined with chemotherapy. Although results in progression free survival and overall survival have been excellent, the long-term, radiation induced, toxic cardiac and secondary oncologic complications occurring in succeeding decades have compromised survival of young patients. This study examines the impact of chemotherapy alone in treatment of limited-stage, nonbulky HL, radiation therapy eliminated from primary treatment. PATIENTS AND METHODS: From 1992 to May 2008, 71 patients with a median age of 29 years (range, 17-44 years) with stages I and II HL without bulky nodes were treated with six cycles of classic combination doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Two patients received six cycles of ABVD-like modification. Two patients received four cycles of ABVD. The ABVD regimen was known to be curative in more advanced disease without radiation therapy. RESULTS: All patients achieved a clinical complete response (CR) or CR unconfirmed. After a median follow-up of at least 60 months (range, at least 12 to at least 204 months), six patients experienced relapse at 6, 10, 11, 16, 20, and 58 months. All relapses occurred at site of presenting disease. No patients have died. Salvage therapy was successful with second-line chemotherapy/radiation and autologous stem-cell transplantation. CONCLUSION: Six cycles of ABVD is an effective and safe treatment for limited stage, nonbulky HL and would spare young patients radiation toxicity. Interim positron emission tomography/computed tomography scans in current and future trials may identify those patients who require less than six cycles of chemotherapy. PMID- 20159819 TI - Effect of complete remission and responses less than complete remission on survival in acute myeloid leukemia: a combined Eastern Cooperative Oncology Group, Southwest Oncology Group, and M. D. Anderson Cancer Center Study. AB - PURPOSE: It is known that complete remission (CR) prolongs survival in acute myeloid leukemia (AML). In 2003, less stringent response categories were introduced, most notably CR with incomplete platelet recovery (CRp). Although the significance of CRp for survival remains unclear, reports of AML trials frequently combine CR with CRp rather than considering CR as a separate entity. PATIENTS AND METHODS: This practice led us to retrospectively examine the effect of CR on outcome in newly diagnosed AML, by using data from 6,283 patients treated on Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group (SWOG) protocols or at M. D. Anderson Cancer Center. This effect was then contrasted with the effect of CRp in the M. D. Anderson Cancer Center cohort. RESULTS: At least 94% of patients receiving cytarabine-based therapy and surviving for more than 3 or 5 years achieved a CR with either initial or salvage therapy; limited data suggest the same for patients receiving initial therapies that did not contain cytarabine. Patients with CR were more likely to live beyond 3 or 5 years than patients with CRp. The likelihood of achieving a CR rather than CRp was greater for patients with AML who had better prognosis. After adjustment for covariates, the relapse-free survival of patients achieving CR was longer than that of patients achieving CRp, whereas patients with CRp survived longer than those with resistant disease. CONCLUSION: Our data indicate that CR is of unique clinical significance and should be reported as separate response in trials of newly diagnosed AML. Nonetheless, our findings validate CRp as a clinically meaningful response. PMID- 20159820 TI - Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women. AB - PURPOSE: We examined how an aerobic exercise intervention influenced circulating estradiol, estrone, sex hormone-binding globulin (SHBG), androstenedione, and testosterone levels, which may be involved in the association between physical activity and breast cancer risk. METHODS: A two-center, two-arm randomized controlled trial of exercise was conducted in 320 postmenopausal, sedentary women age 50 to 74 years. Participants were randomly assigned to a 1-year aerobic exercise intervention of 225 min/wk (n = 160) or to a control group who maintained their usual level of activity (n = 160). Baseline, 6-month, and 12 month assessments of estrone, estradiol, androstenedione, and testosterone were quantified by radioimmunoassay after extraction, and SHBG was quantified by an immunometric assay. Intent-to-treat analyses were performed using linear mixed models. RESULTS: Blood data were available on 309 women (96.6%) at 12 months. Women in the intervention group exercised an average of 3.6 d/wk for 178 min/wk. At 12 months, statistically significant reductions in estradiol (treatment effect ratio [TER] = 0.93; 95% CI, 0.88 to 0.98) and free estradiol (TER = 0.91; 95% CI, 0.87 to 0.96) and increases in SHBG (TER = 1.04; 95% CI, 1.02 to 1.07) were observed in the exercise group compared with the control group. No significant differences in estrone, androstenedione, and testosterone levels were observed between exercisers and controls at 12 months. CONCLUSION: This trial found that previously sedentary postmenopausal women can adhere to a moderate- to vigorous intensity exercise program that results in changes in estradiol and SHBG concentrations that are consistent with a lower risk for postmenopausal breast cancer. PMID- 20159821 TI - Genomic changes in chromosomes 10, 16, and X in malignant peripheral nerve sheath tumors identify a high-risk patient group. AB - PURPOSE: The purpose of this study was to identify genetic aberrations contributing to clinical aggressiveness of malignant peripheral nerve sheath tumors (MPNSTs). PATIENTS AND METHODS: Samples from 48 MPNSTs and 10 neurofibromas were collected from 51 patients with (n = 31) or without (n = 20) neurofibromatosis type 1 (NF1). Genome-wide DNA copy number changes were assessed by chromosomal and array-based comparative genomic hybridization (CGH) and examined for prognostic significance. For a subset of 20 samples, RNA microarray data were integrated with the genome data to identify potential target genes. RESULTS: Forty-four (92%) MPNSTs displayed DNA copy number changes (median, 18 changes per tumor; range, 2 to 35 changes). Known frequent chromosomal gains at chromosome arms 8q (69%), 17q (67%), and 7p (52%) and losses from 9p (50%), 11q (48%), and 17p (44%) were confirmed. Additionally, gains at 16p or losses from 10q or Xq identified a high-risk group with only 11% 10-year disease-specific survival (P = .00005). Multivariate analyses including NF1 status, tumor location, size, grade, sex, complete remission, and initial metastatic status showed that the genomic high-risk group was the most significant predictor of poor survival. Several genes whose expression was affected by the DNA copy number aberrations were identified. CONCLUSION: The presence of specific genetic aberrations was strongly associated with poor survival independent of known clinical risk factors. Conversely, within the total patient cohort with 34% 10 year disease-specific survival, a low-risk group was identified: without changes at chromosomes 10q, 16p, or Xq in their MPNSTs, the patients had 74% 10-year survival. PMID- 20159822 TI - Neoadjuvant clinical trial with sorafenib for patients with stage II or higher renal cell carcinoma. AB - PURPOSE: The multitargeted tyrosine kinase inhibitor sorafenib is used for the treatment of advanced-stage renal cell carcinoma. However, the safety and efficacy of this agent have yet to be evaluated in the preoperative period, where there may be potential advantages including tumor downstaging. This prospective trial evaluates the safety and feasibility of sorafenib in the preoperative setting. PATIENTS AND METHODS: Thirty patients with clinical stage II or higher renal masses, selected based on their candidacy for nephrectomy, underwent preoperative treatment with sorafenib. Toxicities, surgical complications, and tumor responses were monitored. RESULTS: Of the thirty patients enrolled, 17 patients had localized disease and 13 had metastatic disease. After a course of sorafenib therapy (median duration, 33 days), a decrease in primary tumor size (median, 9.6%) and radiographic evidence of loss of intratumoral enhancement, quantified using a methodology similar to Choi criteria (median, 13%), was also observed. According to Response Evaluation Criteria in Solid Tumors, of the 28 patients evaluable for response, two patients had a partial response and 26 had stable disease, with no patients progressing on therapy. Toxicities from sorafenib were similar to that expected with this class of medication. All patients were able to proceed with nephrectomy and no surgical complications related to sorafenib administration were observed. CONCLUSION: The administration of preoperative sorafenib therapy can impact the size and density of the primary tumor and appears safe and feasible. Further studies are required to determine if preoperative systemic therapy improves outcomes in patients undergoing nephrectomy for renal cell carcinoma. PMID- 20159823 TI - Significant and sustained antitumor activity in post-docetaxel, castration resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. AB - PURPOSE: The principal objective of this trial was to evaluate the antitumor activity of abiraterone acetate, an oral, specific, irreversible inhibitor of CYP17 in docetaxel-treated patients with castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: In this multicenter, two-stage, phase II study, abiraterone acetate 1,000 mg was administered once daily continuously. The primary end point was achievement of a prostate-specific antigen (PSA) decline of > or = 50% in at least seven of 35 patients. Per an attained phase II design, more than 35 patients could be enrolled if the primary end point was met. Secondary objectives included: PSA declines of > or = 30% and > or = 90%; rate of RECIST (Response Evaluation Criteria in Solid Tumors) responses and duration on study; time to PSA progression; safety and tolerability; and circulating tumor cell (CTC) enumeration. RESULTS: Docetaxel-treated patients with CRPC (N = 47) were enrolled. PSA declines of > or = 30%, > or = 50% and > or = 90% were seen in 68% (32 of 47), 51% (24 of 47), and 15% (seven of 47) of patients, respectively. Partial responses (by RECIST) were reported in eight (27%) of 30 patients with measurable disease. Median time to PSA progression was 169 days (95% CI, 113 to 281 days). The median number of weeks on study was 24, and 12 (25.5%) of 47 patients remained on study > or = 48 weeks. CTCs were enumerated in 34 patients; 27 (79%) of 34 patients had at least five CTCs at baseline. Eleven (41%) of 27 patients had a decline from at least five to less than 5 CTCs, and 18 (67%) of 27 had a > or = 30% decline in CTCs after starting treatment with abiraterone acetate. Abiraterone acetate was well tolerated. CONCLUSION: Abiraterone acetate has significant antitumor activity in post-docetaxel patients with CRPC. Randomized, phase III trials of abiraterone acetate are underway to define the future role of this agent. PMID- 20159824 TI - Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. AB - PURPOSE: Abiraterone acetate is a prodrug of abiraterone, a selective inhibitor of CYP17, the enzyme catalyst for two essential steps in androgen biosynthesis. In castration-resistant prostate cancers (CRPCs), extragonadal androgen sources may sustain tumor growth despite a castrate environment. This phase I dose escalation study of abiraterone acetate evaluated safety, pharmacokinetics, and effects on steroidogenesis and prostate-specific antigen (PSA) levels in men with CPRC with or without prior ketoconazole therapy. PATIENTS AND METHODS: Thirty three men with chemotherapy-naive progressive CRPC were enrolled. Nineteen patients (58%) had previously received ketoconazole for CRPC. Bone metastases were present in 70% of patients, and visceral involvement was present in 18%. Three patients (9%) had locally advanced disease without distant metastases. Fasted or fed cohorts received abiraterone acetate doses of 250, 500, 750, or 1,000 mg daily. Single-dose pharmacokinetic analyses were performed before continuous daily dosing. RESULTS: Adverse events were predominantly grade 1 or 2. No dose-limiting toxicities were observed. Hypertension (grade 3, 12%) and hypokalemia (grade 3, 6%; grade 4, 3%) were the most frequent serious toxicities and responded to medical management. Confirmed > or = 50% PSA declines at week 12 were seen in 18 (55%) of 33 patients, including nine (47%) of 19 patients with prior ketoconazole therapy and nine (64%) of 14 patients without prior ketoconazole therapy. Substantial declines in circulating androgens and increases in mineralocorticoids were seen with all doses. CONCLUSION: Abiraterone acetate was well tolerated and demonstrated activity in CRPC, including in patients previously treated with ketoconazole. Continued clinical study is warranted. PMID- 20159825 TI - Aspirin intake and survival after breast cancer. AB - PURPOSE: Animal and in vitro studies suggest that aspirin may inhibit breast cancer metastasis. We studied whether aspirin use among women with breast cancer decreased their risk of death from breast cancer. METHODS: This was a prospective observational study based on responses from 4,164 female registered nurses in the Nurses' Health Study who were diagnosed with stages I, II, or III breast cancer between 1976 and 2002 and were observed until death or June 2006, whichever came first. The main outcome was breast cancer mortality risk according to number of days per week of aspirin use (0, 1, 2 to 5, or 6 to 7 days) first assessed at least 12 months after diagnosis and updated. RESULTS: There were 341 breast cancer deaths. Aspirin use was associated with a decreased risk of breast cancer death. The adjusted relative risks (RRs) for 1, 2 to 5, and 6 to 7 days of aspirin use per week compared with no use were 1.07 (95% CI, 0.70 to 1.63), 0.29 (95% CI, 0.16 to 0.52), and 0.36 (95% CI, 0.24 to 0.54), respectively (test for linear trend, P < .001). This association did not differ appreciably by stage, menopausal status, body mass index, or estrogen receptor status. Results were similar for distant recurrence. The adjusted RRs were 0.91 (95% CI, 0.62 to 1.33), 0.40 (95% CI, 0.24 to 0.65), and 0.57 (95% CI, 0.39 to 0.82; test for trend, P = .03) for 1, 2 to 5, and 6 to 7 days of aspirin use, respectively. CONCLUSION: Among women living at least 1 year after a breast cancer diagnosis, aspirin use was associated with a decreased risk of distant recurrence and breast cancer death. PMID- 20159826 TI - Metastasis after radical prostatectomy or external beam radiotherapy for patients with clinically localized prostate cancer: a comparison of clinical cohorts adjusted for case mix. AB - PURPOSE: We assessed the effect of radical prostatectomy (RP) and external beam radiotherapy (EBRT) on distant metastases (DM) rates in patients with localized prostate cancer treated with RP or EBRT at a single specialized cancer center. PATIENTS AND METHODS: Patients with clinical stages T1c-T3b prostate cancer were treated with intensity-modulated EBRT (> or = 81 Gy) or RP. Both cohorts included patients treated with salvage radiotherapy or androgen-deprivation therapy for biochemical failure. Salvage therapy for patients with RP was delivered a median of 13 months after biochemical failure compared with 69 months for EBRT patients. DM was compared controlling for patient age, clinical stage, serum prostate specific antigen level, biopsy Gleason score, and year of treatment. RESULTS: The 8-year probability of freedom from metastatic progression was 97% for RP patients and 93% for EBRT patients. After adjustment for case mix, surgery was associated with a reduced risk of metastasis (hazard ratio, 0.35; 95% CI, 0.19 to 0.65; P < .001). Results were similar for prostate cancer-specific mortality (hazard ratio, 0.32; 95% CI, 0.13 to 0.80; P = .015). Rates of metastatic progression were similar for favorable-risk disease (1.9% difference in 8-year metastasis-free survival), somewhat reduced for intermediate-risk disease (3.3%), and more substantially reduced in unfavorable-risk disease (7.8% in 8-year metastatic progression). CONCLUSION: Metastatic progression is infrequent in men with low risk prostate cancer treated with either RP or EBRT. RP patients with higher-risk disease treated had a lower risk of metastatic progression and prostate cancer specific death than EBRT patients. These results may be confounded by differences in the use and timing of salvage therapy. PMID- 20159827 TI - Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms. AB - PURPOSE: To unravel the regulatory network underlying nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) -mediated lymphomagenesis of anaplastic large-cell lymphoma (ALCL) and to discover diagnostic genomic classifiers for the recognition of patients with ALK-positive and ALK-negative ALCL among T-cell non Hodgkin's lymphoma (T-NHL). PATIENTS AND METHODS: The transcriptome of NPM-ALK positive ALCL cell lines was characterized by silencing the expression of ALK or STAT3, a major effector of ALK oncogenic activity. Gene expression profiling (GEP) was performed in a series of systemic primary T-NHL (n = 70), including a set of ALK-positive and ALK-negative ALCL (n = 36). Genomic classifiers for ALK positive and ALK-negative ALCL were generated by prediction analyses and validated by quantitative reverse-transcriptase polymerase chain reaction and/or immunohistochemistry. RESULTS: In ALCL cell lines, two thirds of ALK-regulated genes were concordantly dependent on STAT3 expression. GEP of systemic primary T NHL significantly clustered ALK-positive ALCL samples in a separate subgroup, underscoring the relevance of in vitro ALK/STAT3 signatures. A set of genomic classifiers for ALK-positive ALCL and for ALCL were identified by prediction analyses. These gene clusters were instrumental for the distinction of ALK negative ALCL from peripheral T-cell lymphomas not otherwise specified (PTCLs NOS) and angioimmunoblastic lymphomas. CONCLUSION: We proved that experimentally controlled GEP in ALCL cell lines represents a powerful tool to identify meaningful signaling networks for the recognition of systemic primary T-NHL. The identification of a molecular signature specific for ALCL suggests that these T NHLs may represent a unique entity discernible from other PTCLs, and that a restricted number of genes can be instrumental for clinical stratification and, possibly, therapy of T-NHL. PMID- 20159828 TI - Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies. AB - BACKGROUND: The ubiquitin proteasome system maintains a dynamic equilibrium of proteins and prevents accumulation of damaged and misfolded proteins, yet its role in human cardiac dysfunction is not well understood. The present study evaluated ubiquitin proteasome system function in human heart failure and hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Proteasome function was studied in human nonfailing donor hearts, explanted failing hearts, and myectomy samples from patients with HCM. Proteasome proteolytic activities were markedly reduced in failing and HCM hearts compared with nonfailing hearts (P<0.01). This activity was partially restored after mechanical unloading in failing hearts (P<0.01) and was significantly lower in HCM hearts with pathogenic sarcomere mutations than in those lacking these mutations (P<0.05). There were no changes in the protein content of ubiquitin proteasome system subunits (ie, 11S, 20S, and 19S) or in active-site labeling of the 20S proteolytic subunit beta-5 among groups to explain decreased ubiquitin proteasome system activity in HCM and failing hearts. Examination of protein oxidation revealed that total protein carbonyls, 4-hydroxynonenylated proteins, and oxidative modification to 19S ATPase subunit Rpt 5 were increased in failing compared with nonfailing hearts. CONCLUSIONS: Proteasome activity in HCM and failing human hearts is impaired in the absence of changes in proteasome protein content or availability of proteolytic active sites. These data provide strong evidence that posttranslational modifications to the proteasome may account for defective protein degradation in human cardiomyopathies. PMID- 20159830 TI - Mechanisms by which adenosine restores conduction in dormant canine pulmonary veins. AB - BACKGROUND: Adenosine acutely reconnects pulmonary veins (PVs) after radiofrequency application, revealing "dormant conduction" and identifying PVs at risk of reconnection, but the underlying mechanisms are unknown. METHODS AND RESULTS: Canine PV and left-atrial (LA) action potentials were recorded with standard microelectrodes and ionic currents with whole-cell patch clamp before and after adenosine perfusion. PVs were isolated with radiofrequency current application in coronary-perfused LA-PV preparations. Adenosine abbreviated action potential duration similarly in PV and LA but significantly hyperpolarized resting potential (by 3.9+/-0.5%; P<0.05) and increased dV/dt(max) (by 34+/-10%) only in PV. Increased dV/dt(max) was not due to direct effects on I(Na), which was reduced similarly by adenosine in LA and PV but correlated with resting potential hyperpolarization (r=0.80). Adenosine induced larger inward rectifier K(+)current (I(KAdo)) in PV (eg, -2.28+/-0.04 pA/pF; -100 mV) versus LA (-1.28+/ 0.16 pA/pF). Radiofrequency ablation isolated PVs by depolarizing resting potential to voltages positive to -60 mV. Adenosine restored conduction in 5 dormant PVs, which had significantly more negative resting potentials (-57+/-6 mV) versus nondormant (-46+/-5 mV, n=6; P<0.001) before adenosine. Adenosine hyperpolarized both, but more negative resting-potential values after adenosine in dormant PVs (-66+/-6 mV versus -56+/-6 mV in nondormant; P<0.001) were sufficient to restore excitability. Adenosine effects on resting potential and conduction reversed on washout. Spontaneous recovery of conduction occurring in dormant PVs after 30 to 60 minutes was predicted by the adenosine response. CONCLUSIONS: Adenosine selectively hyperpolarizes canine PVs by increasing I(KAdo). PVs with dormant conduction show less radiofrequency-induced depolarization than nondormant veins, allowing adenosine-induced hyperpolarization to restore excitability by removing voltage-dependent I(Na) inactivation and explaining the restoration of conduction in dormant PVs. PMID- 20159829 TI - Vascular inflammation in obesity and sleep apnea. AB - BACKGROUND: Unrecognized obstructive sleep apnea (OSA) is highly prevalent in obesity. Both obesity and OSA are associated with vascular endothelial inflammation and increased risk for cardiovascular diseases. We investigated directly whether the endothelial alterations that are attributed commonly to obesity are in fact related to OSA. METHODS AND RESULTS: Seventy-one subjects with a body mass index ranging from normal to obese underwent attended polysomnography. To assess vascular inflammation and oxidative stress directly, we quantified the expression of nuclear factor-kappaB and nitrotyrosine by immunofluorescence in freshly harvested venous endothelial cells. To evaluate basal endothelial nitric oxide (NO) production and activity, we quantified the expression of endothelial NO synthase (eNOS) and phosphorylated eNOS. Vascular reactivity was measured by brachial artery flow-mediated dilation. Expression of eNOS and phosphorylated eNOS and flow-mediated dilation were significantly lower, whereas expression of nitrotyrosine was significantly greater in OSA patients (n=38) than in OSA-free subjects (n=33) regardless of central adiposity. Expression of nuclear factor-kappaB was greater in obese OSA patients than in obese OSA-free subjects (P=0.004). Protein expression and flow-mediated dilation were not significantly affected by increasing body mass index or central obesity in OSA patients and in OSA-free subjects. After 4 weeks of continuous positive airway pressure therapy, flow-mediated dilation and expression of eNOS and phosphorylated eNOS significantly increased whereas expression of nitrotyrosine and nuclear factor-kappaB significantly decreased in OSA patients who adhered to continuous positive airway pressure >/=4 hours daily. CONCLUSIONS: Untreated OSA rather than obesity is a major determinant of vascular endothelial dysfunction, inflammation, and elevated oxidative stress in obese patients. PMID- 20159831 TI - Analysis of the impact of early surgery on in-hospital mortality of native valve endocarditis: use of propensity score and instrumental variable methods to adjust for treatment-selection bias. AB - BACKGROUND: The impact of early surgery on mortality in patients with native valve endocarditis (NVE) is unresolved. This study sought to evaluate valve surgery compared with medical therapy for NVE and to identify characteristics of patients who are most likely to benefit from early surgery. METHODS AND RESULTS: Using a prospective, multinational cohort of patients with definite NVE, the effect of early surgery on in-hospital mortality was assessed by propensity-based matching adjustment for survivor bias and by instrumental variable analysis. Patients were stratified by propensity quintile, paravalvular complications, valve perforation, systemic embolization, stroke, Staphylococcus aureus infection, and congestive heart failure. Of the 1552 patients with NVE, 720 (46%) underwent early surgery and 832 (54%) were treated with medical therapy. Compared with medical therapy, early surgery was associated with a significant reduction in mortality in the overall cohort (12.1% [87/720] versus 20.7% [172/832]) and after propensity-based matching and adjustment for survivor bias (absolute risk reduction [ARR] -5.9%, P<0.001). With a combined instrument, the instrumental variable-adjusted ARR in mortality associated with early surgery was -11.2% (P<0.001). In subgroup analysis, surgery was found to confer a survival benefit compared with medical therapy among patients with a higher propensity for surgery (ARR -10.9% for quintiles 4 and 5, P=0.002) and those with paravalvular complications (ARR -17.3%, P<0.001), systemic embolization (ARR -12.9%, P=0.002), S aureus NVE (ARR -20.1%, P<0.001), and stroke (ARR -13%, P=0.02) but not those with valve perforation or congestive heart failure. CONCLUSIONS: Early surgery for NVE is associated with an in-hospital mortality benefit compared with medical therapy alone. PMID- 20159832 TI - Passive stiffness of myocardium from congenital heart disease and implications for diastole. AB - BACKGROUND: In ventricular dilatation or hypertrophy, an elevated end-diastolic pressure is often assumed to be secondary to increased myocardial stiffness, but stiffness is rarely measured in vivo because of difficulty. We measured in vitro passive stiffness of volume- or pressure-overloaded myocardium mainly from congenital heart disease. METHODS AND RESULTS: Endocardial ventricular biopsies were obtained at open heart surgery (n=61; pressure overload, 36; volume overload, 19; dilated cardiomyopathy, 4; normal donors, 2). In vitro passive force-extension curves and the stiffness modulus were measured in skinned tissue: muscle strips, strips with myofilaments extracted (mainly extracellular matrix), and myocytes. Collagen content (n=38) and titin isoforms (n=16) were determined. End-diastolic pressure was measured at cardiac catheterization (n=14). Pressure overloaded tissue (strips, extracellular matrix, myocytes) had a 2.6- to 7.0-fold greater force and stiffness modulus than volume-overloaded tissue. Myocyte force and stiffness modulus at short stretches (0.05 resting length, L(0)) was pressure overloaded >normal approximately volume-overloaded>dilated cardiomyopathy. Titin N2B:N2BA isoform ratio varied little between conditions. The extracellular matrix contributed more to force at 0.05 L(0) in pressure-overloaded (35.1%) and volume overloaded (17.4%) strips than normal myocardium. Stiffness modulus increased with collagen content in pressure-overloaded but not volume-overloaded strips. In vitro stiffness modulus at 0.05 L(0) was a good predictor of in vivo end diastolic pressure for pressure-overloaded but not volume-overloaded ventricles and estimated normal end-diastolic pressure as 5 to 7 mm Hg. CONCLUSIONS: An elevated end-diastolic pressure in pressure-overloaded, but not volume overloaded, ventricles was related to increased myocardial stiffness. The greater stiffness of pressure-overloaded compared with volume-overloaded myocardium was due to the higher stiffness of both the extracellular matrix and myocytes. The transition from normal to very-low stiffness myocytes may mark irreversible dilatation. PMID- 20159833 TI - Frail patients are at increased risk for mortality and prolonged institutional care after cardiac surgery. AB - BACKGROUND: Frailty is an emerging concept in medicine yet to be explored as a risk factor in cardiac surgery. Where elderly patients are increasingly referred for cardiac surgery, the prevalence of a frail group among these is also on the rise. We assessed frailty as a risk factor for adverse outcomes after cardiac surgery. METHODS AND RESULTS: Functional measures of frailty and clinical data were collected prospectively for all cardiac surgery patients at a single center. Frailty was defined as any impairment in activities of daily living (Katz index), ambulation, or a documented history of dementia. Of 3826 patients, 157 (4.1%) were frail. Frail patients were older, were more likely to be female, and had risk factors for adverse surgical outcomes. By logistic regression, frailty was an independent predictor of in-hospital mortality (odds ratio 1.8, 95% CI 1.1 to 3.0), as well as institutional discharge (odds ratio 6.3, 95% CI 4.2 to 9.4). Frailty was an independent predictor of reduced midterm survival (hazard ratio 1.5, 95% CI 1.1 to 2.2). CONCLUSIONS: Frailty is a risk for postoperative complications and an independent predictor of in-hospital mortality, institutional discharge, and reduced midterm survival. Frailty screening improves risk assessment in cardiac surgery patients and may identify a subgroup of patients who may benefit from innovative processes of care. PMID- 20159834 TI - Hemodynamic support by left ventricular assist devices reduces cardiomyocyte DNA content in the failing human heart. AB - BACKGROUND: Whether adult cardiomyocytes have the capacity to regenerate in response to injury and, if so, to what extent are still issues of intense debate. In human heart failure, cardiomyocytes harbor a polyploid genome. A unique opportunity to study the mechanism of polyploidization is provided through the setting of hemodynamic support by left ventricular assist devices. Hence, the cardiomyocyte DNA content, nuclear morphology, and number of nuclei per cell were assessed before and after left ventricular assist device support. METHODS AND RESULTS: In 23 paired myocardial samples, cardiomyocyte ploidy was investigated by DNA image cytometry, flow cytometry, and in situ hybridization. Nuclear cross sectional area and perimeters were measured morphometrically, and the binucleated cardiomyocytes were counted. The median of the cardiomyocyte DNA content and the number of polyploid cardiomyocytes both declined significantly from 6.79 c to 4.7 c and 40.2% to 23%, whereas a significant increase in diploid cardiomyocytes from 33.4% to 50.3% and in binucleated cardiomyocytes from 4.5% to 10% after unloading was observed. CONCLUSIONS: The decrease in polyploidy and increase in diploidy after left ventricular assist device suggest a numeric increase in diploid cardiomyocytes (eg, through cell cycle progression with completion of mitosis or by increased stem cells). The cardiac regeneration that follows may serve as a morphological correlate of the recovery observed in some patients after unloading. PMID- 20159835 TI - Surgical timing in infectious endocarditis: wrestling with the unrandomized. PMID- 20159836 TI - Taking a load off: nuclear remodeling after mechanically supporting the failing human heart. PMID- 20159837 TI - Inadvertent placement of pacemaker lead into the systemic ventricle in repaired D transposition of the great arteries. PMID- 20159838 TI - Letter by Alfonso et al regarding article, "Paclitaxel-coated balloon catheter versus paclitaxel-coated stent for the treatment of coronary in-stent restenosis". PMID- 20159839 TI - Letter by Messas et al regarding article, "Initial results of posterior leaflet extension for severe type IIIb ischemic mitral regurgitation". PMID- 20159841 TI - Early surgery is recommended for mitral regurgitation. PMID- 20159842 TI - Primum non nocere: the case for watchful waiting in asymptomatic "severe" degenerative mitral regurgitation. PMID- 20159843 TI - Giant mitochondria in the myocardium of a patient with mitochondrial cardiomyopathy: transmission and 3-dimensional scanning electron microscopy. PMID- 20159844 TI - Documenting citizenship in Medicaid: the struggle between ideology and evidence. AB - In 2006 Congress passed, and the Centers for Medicare and Medicaid Services (CMS) rapidly issued, regulations requiring states to obtain proof of citizenship from citizens who had applied for Medicaid. This policy was framed as reducing fraud by illegal aliens to preserve benefits for citizens. In fact, evidence indicates there was no significant problem of fraud by immigrants, and the major effect of the policy was to reduce coverage of eligible citizens. This article addresses the reasons why Congress developed this policy and why CMS acted with uncharacteristic haste to implement these counterproductive policies. We note the importance of the policy's symbolic framing--that is, as establishing sanctions against illegal immigration--in congressional passage during a period of rising nativism in Congress and the nation. The regulatory actions reflected the ideological preferences of political appointees and an increasingly adversarial relationship between CMS and state agencies during this period. These haphazard regulatory actions made the policies more convoluted and likely led more eligible citizens to lose coverage. In 2009, Congress amended the law to modify implementation. These issues have continued to persist in the recent debate on national health care reform. PMID- 20159845 TI - Risky business: effectiveness of state market-based health programs. AB - Since the 1990s, state governments have been leaders of health care reform. Today, approximately 47 million people are without health insurance. As health care costs and uninsurance levels continue to rise, states are pursuing a variety of government- and market-based strategies to address this growing social problem. Health care research has indicated that state-based programs have proven to be successful in extending access to coverage. However, the question remains as to whether the market-based programs have had a positive impact on state health care. Advocates for market-based state health programs argue that the reforms benefit the greater good because they serve an economic development function by improving the economic productivity and overall health of state citizens. Whether market-based policies are accomplishing these goals is a matter of debate. This study examines the effects of the various market-based state policies. The evidence generated by this research sheds light on the societal effectiveness of market-based health care strategies used by state governments. The results of our analysis indicate that programs enacted by states to promote increased access to medical care have developmental effects beyond the client population directly served. PMID- 20159846 TI - Measuring coverage for seniors in Medicare Part A and estimating the cost of making it universal. AB - That Medicare is universal for seniors is widely accepted by leading analysts. But in the context of developing detailed policies that seek to cover as many people as possible, it is inaccurate to make Medicare eligibility sound so simple and inclusive. To estimate the number of seniors without full federal Medicare Part A coverage, we examined data for uninsured seniors, seniors with Medicaid and no Medicare coverage of any kind, seniors with Medicare Part B but without Part A, and seniors bought into Part A by their state Medicaid programs. We found that in 2005, 1.6 million seniors--or 5 percent of the elderly U.S. population- were without a full federal Part A premium subsidy. The share of seniors without this benefit was notably higher in the nation's two largest states--California (12 percent) and New York (8 percent). We estimate that reforming Medicare Part A to make the benefit truly universal and fully federal would cost the federal government $6 billion in new spending in federal fiscal year 2011, an increase in baseline federal Medicare expenditures of 1.1 percent. PMID- 20159847 TI - Medical licensing board characteristics and physician discipline: an empirical analysis. AB - This article investigates the relationship between the characteristics of medical licensing boards and the frequency with which boards discipline physicians. Specifically, we take advantage of variation in the structure of medical licensing boards between 1993 and 2003 to determine the effect of organizational and budgetary independence, public oversight, and resource constraints on rates of physician discipline. We find that larger licensing boards, boards with more staff, and boards that are organizationally independent from state government discipline doctors more frequently. Public oversight and political control over board budgets do not appear to influence the extent to which medical licensing boards discipline doctors. These findings are broadly consistent with theories of regulatory behavior that emphasize the importance of bureaucratic autonomy for effective regulatory enforcement. PMID- 20159848 TI - Inefficiency differences between critical access hospitals and prospectively paid rural hospitals. AB - The Medicare prospective payment system (PPS) contains incentives for hospitals to improve efficiency by placing them at financial risk to earn a positive margin on services rendered to Medicare patients. Concerns about the financial viability of small rural hospitals led to the implementation of the Medicare Rural Hospital Flexibility Program (Flex Program) of 1997, which allows facilities designated as critical access hospitals (CAHs) to be paid on a reasonable cost basis for inpatient and outpatient services. This article compares the cost inefficiency of CAHs with that of nonconverting rural hospitals to contrast the performance of hospitals operating under the different payment systems. Stochastic frontier analysis (SFA) was used to estimate cost inefficiency. Analysis was performed on pooled time-series, cross-sectional data from thirty-four states for the period 1997-2004. Average estimated cost inefficiency was greater in CAHs (15.9 percent) than in nonconverting rural hospitals (10.3 percent). Further, there was a positive association between length of time in the CAH program and estimated cost inefficiency. CAHs exhibited poorer values for a number of proxy measures for efficiency, including expenses per admission and labor productivity (full-time equivalent employees per outpatient-adjusted admission). Non-CAH rural hospitals had a stronger correlation between cost inefficiency and operating margin than CAH facilities did. PMID- 20159849 TI - Jasmonate biochemical pathway. AB - Plants possess a family of potent fatty acid-derived wound-response and developmental regulators: the jasmonates. These compounds are derived from the tri-unsaturated fatty acids alpha-linolenic acid (18:3) and, in plants such as Arabidopsis thaliana and tomato, 7(Z)-, 10(Z)-, and 13(Z)-hexadecatrienoic acid (16:3). The lipoxygenase-catalyzed addition of molecular oxygen to alpha linolenic acid initiates jasmonate synthesis by providing a 13-hydroperoxide substrate for formation of an unstable allene oxide by allene oxide synthase (AOS). This allene oxide then undergoes enzyme-guided cyclization to produce 12 oxophytodienoic acid (OPDA). These first steps take place in plastids, but further OPDA metabolism occurs in peroxisomes. OPDA has several fates, including esterification into plastid lipids and transformation into the 12-carbon prohormone jasmonic acid (JA). JA is itself a substrate for further diverse modifications, including the production of jasmonoyl-isoleucine (JA-Ile), which is a major biologically active jasmonate among a growing number of jasmonate derivatives. Each new jasmonate family member that is discovered provides another key to understanding the fine control of gene expression in immune responses; in the initiation and maintenance of long-distance signal transfer in response to wounding; in the regulation of fertility; and in the turnover, inactivation, and sequestration of jasmonates, among other processes. PMID- 20159850 TI - Arabidopsis jasmonate signaling pathway. AB - Jasmonates control defense gene expression, growth, and fertility throughout the plant kingdom and have been studied extensively in Arabidopsis thaliana. The prohormone jasmonic acid (JA) is conjugated to amino acids such as isoleucine to form the active hormone jasmonoyl-isoleucine (JA-Ile). A series of breakthroughs has identified the SCF [SCF consists of four subunits: a cullin, SKP1 (S-phase kinase-associated protein 1), a RING finger protein (RBX1/HRT1/ROC1), and an F box protein] CORONATINE INSENSITIVE1 (COI1) E3 ubiquitin ligase complex and the JASMONATE ZIM-DOMAIN (JAZ) proteins as central components in the perception of and transcriptional response to JA-Ile. JAZ proteins (most probably as dimers) bind transcription factors such as MYC2 before JA-Ile production. JA-Ile binds to COI1 to facilitate the formation of COI1-JAZ complexes, leading to ubiquitination and subsequent degradation of JAZ proteins. The degradation of JAZ proteins liberates transcription factors that function in the presence of the RNA polymerase II coregulatory complex Mediator to permit the expression of a number of jasmonate-regulated genes. Recent developments include the identification of COI1 as a receptor for jasmonates. Upstream of the signaling events, microRNA319 (miR319) negatively regulates the production of JA and JA-derived signals. PMID- 20159852 TI - Microbial hijacking of complement-toll-like receptor crosstalk. AB - Crosstalk between complement and Toll-like receptors (TLRs) coordinates innate immunity. We report a previously unknown immune subversion mechanism involving microbial exploitation of communication between complement and TLRs. Porphyromonas gingivalis, a major oral and systemic pathogen with complement C5 convertase-like activity, synergizes with C5a (fragment of complement protein C5) to increase cyclic adenosine monophosphate (cAMP) concentrations, resulting in suppression of macrophage immune function and enhanced pathogen survival in vitro and in vivo. This synergy required TLR2 signaling, a pertussis toxin- and thapsigargin-sensitive C5a receptor pathway, with protein kinase A and glycogen synthase kinase-3beta as downstream effectors. Antagonistic blockade of the C5a receptor abrogated this evasive strategy and may thus have important therapeutic implications for periodontitis and atherosclerosis, diseases in which P. gingivalis is implicated. This first demonstration of complement-TLR crosstalk for immunosuppressive cAMP signaling indicates that pathogens may not simply undermine complement or TLRs (or both) as separate entities, but may also exploit their crosstalk pathways. PMID- 20159853 TI - Deciphering protein kinase specificity through large-scale analysis of yeast phosphorylation site motifs. AB - Phosphorylation is a universal mechanism for regulating cell behavior in eukaryotes. Although protein kinases target short linear sequence motifs on their substrates, the rules for kinase substrate recognition are not completely understood. We used a rapid peptide screening approach to determine consensus phosphorylation site motifs targeted by 61 of the 122 kinases in Saccharomyces cerevisiae. By correlating these motifs with kinase primary sequence, we uncovered previously unappreciated rules for determining specificity within the kinase family, including a residue determining P-3 arginine specificity among members of the CMGC [CDK (cyclin-dependent kinase), MAPK (mitogen-activated protein kinase), GSK (glycogen synthase kinase), and CDK-like] group of kinases. Furthermore, computational scanning of the yeast proteome enabled the prediction of thousands of new kinase-substrate relationships. We experimentally verified several candidate substrates of the Prk1 family of kinases in vitro and in vivo and identified a protein substrate of the kinase Vhs1. Together, these results elucidate how kinase catalytic domains recognize their phosphorylation targets and suggest general avenues for the identification of previously unknown kinase substrates across eukaryotes. PMID- 20159854 TI - Effect of 11 beta-hydroxysteroid dehydrogenase-1 inhibition on hepatic glucose metabolism in the conscious dog. AB - Inactive cortisone is converted to active cortisol within the liver by 11 beta hydroxysteroid dehydrogenase-1 (11 beta-HSD1), and impaired regulation of this process may be related to increased hepatic glucose production (HGP) in individuals with type 2 diabetes. The primary aim of this study was to investigate the effect of acute 11 beta-HSD1 inhibition on HGP and fat metabolism during insulin deficiency. Sixteen conscious, 42-h-fasted, lean, healthy dogs were studied. Somatostatin was infused to create insulin deficiency, and the animals were treated with a specific 11 beta-HSD1 inhibitor (compound 531) or placebo for 5 h. 11 beta-HSD1 inhibition completely suppressed hepatic cortisol production, and this attenuated the increase in HGP that occurred during insulin deficiency. PEPCK and glucose-6-phosphatase expression were decreased when 11 beta-HSD1 was inhibited, but gluconeogenic flux was unchanged, implying an effect on glycogenolysis. Since inhibition of hepatic cortisol production reduces HGP during insulin deficiency, 11 beta-HSD1 is a potential therapeutic target for the treatment of excess glucose production that occurs in diabetes. PMID- 20159855 TI - Contraction-related stimuli regulate GLUT4 traffic in C2C12-GLUT4myc skeletal muscle cells. AB - Muscle contraction stimulates glucose uptake acutely to increase energy supply, but suitable cellular models that faithfully reproduce this complex phenomenon are lacking. To this end, we have developed a cellular model of contracting C(2)C(12) myotubes overexpressing GLUT4 with an exofacial myc-epitope tag (GLUT4myc) and explored stimulation of GLUT4 traffic by physiologically relevant agents. Carbachol (an acetylcholine receptor agonist) induced a gain in cell surface GLUT4myc that was mediated by nicotinic acetylcholine receptors. Carbachol also activated AMPK, and this response was sensitive to the contractile myosin ATPase inhibitor N-benzyl-p-toluenesulfonamide. The gain in surface GLUT4myc elicited by carbachol or by the AMPK activator 5-amino-4-carboxamide-1 beta-ribose was sensitive to chemical inhibition of AMPK activity by compound C and partially reduced by siRNA-mediated knockdown of AMPK catalytic subunits or LKB1. In addition, the carbachol-induced gain in cell surface GLUT4myc was partially sensitive to chelation of intracellular calcium with BAPTA-AM. However, the carbachol-induced gain in cell surface GLUT4myc was not sensitive to the CaMKK inhibitor STO-609 despite expression of both isoforms of this enzyme and a rise in cytosolic calcium by carbachol. Therefore, separate AMPK- and calcium dependent signals contribute to mobilizing GLUT4 in response to carbachol, providing an in vitro cell model that recapitulates the two major signals whereby acute contraction regulates glucose uptake in skeletal muscle. This system will be ideal to further analyze the underlying molecular events of contraction regulated GLUT4 traffic. PMID- 20159856 TI - Abnormal in vivo myocardial energy substrate uptake in diet-induced type 2 diabetic cardiomyopathy in rats. AB - The purpose of this study was to determine in vivo myocardial energy metabolism and function in a nutritional model of type 2 diabetes. Wistar rats rendered insulin-resistant and mildly hyperglycemic, hyperinsulinemic, and hypertriglyceridemic with a high-fructose/high-fat diet over a 6-wk period with injection of a small dose of streptozotocin (HFHFS) and control rats were studied using micro-PET (microPET) without or with a euglycemic hyperinsulinemic clamp. During glucose clamp, myocardial metabolic rate of glucose measured with [(18)F]fluorodeoxyglucose ([(18)F]FDG) was reduced by approximately 81% (P < 0.05), whereas myocardial plasma nonesterified fatty acid (NEFA) uptake as determined by [(18)F]fluorothia-6-heptadecanoic acid ([(18)F]FTHA) was not significantly changed in HFHFS vs. control rats. Myocardial oxidative metabolism as assessed by [(11)C]acetate and myocardial perfusion index as assessed by [(13)N]ammonia were similar in both groups, whereas left ventricular ejection fraction as assessed by microPET was reduced by 26% in HFHFS rats (P < 0.05). Without glucose clamp, NEFA uptake was approximately 40% lower in HFHFS rats (P < 0.05). However, myocardial uptake of [(18)F]FTHA administered by gastric gavage was significantly higher in HFHFS rats (P < 0.05). These abnormalities were associated with reduced Glut4 mRNA expression and increased Cd36 mRNA expression and mitochondrial carnitine palmitoyltransferase 1 activity (P < 0.05). HFHFS rats display type 2 diabetes complicated by left ventricular contractile dysfunction with profound reduction in myocardial glucose utilization, activation of fatty acid metabolic pathways, and preserved myocardial oxidative metabolism, suggesting reduced myocardial metabolic efficiency. In this model, increased myocardial fatty acid exposure likely occurs from circulating triglyceride, but not from circulating plasma NEFA. PMID- 20159858 TI - Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death. AB - Prolonged endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) have been linked to apoptosis via several mechanisms, including increased expression of C/EBP homologous protein (Chop). Increased long chain fatty acids, in particular saturated fatty acids, induce ER stress, Chop expression, and apoptosis in liver cells. The first aim of the present study was to determine the role of Chop in lipid-induced hepatocyte cell death and liver injury induced by a methionine-choline-deficient diet. Albumin-bound palmitate increased Chop gene and protein expression in a dose-dependent fashion in H4IIE liver cells. siRNA-mediated silencing of Chop in H4IIE liver cells reduced thapsigargin-mediated cell death by approximately 40% and delayed palmitate mediated cell death, but only at high concentrations of palmitate (400-500 microM). Similar results were observed in primary hepatocytes isolated from Chop knockout mice. Indices of liver injury were also not reduced in Chop-knockout mice provided a methionine-choline-deficient diet. To ascertain whether ER stress was linked to palmitate-induced cell death, primary hepatocytes were incubated in the absence or presence of the chemical chaperones taurine-conjugated ursodeoxycholic acid or 4-phenylbutyric acid. The presence of either of these chemical chaperones protected liver cells from palmitate-mediated ER stress and cell death, in part, via inhibition of JNK activation. These data suggest that ER stress is linked to palmitate-mediated cell death via mechanisms that include JNK activation. PMID- 20159857 TI - Nitration of specific tyrosines in FoF1 ATP synthase and activity loss in aging. AB - It has been reported that C-nitration of proteins occurs under nitrative/oxidative stress; however, its role in pathophysiological situations is not fully understood. In this study, we determined that nitration of Tyr(345) and Tyr(368) in the beta-subunit of the mitochondrial F(o)F(1)-ATPase is a major target for nitrative stress in rat liver under in vivo conditions. The chemical characteristics of these Tyr make them suitable for a facilitated nitration (solvent accessibility, consensus sequence, and pK(a)). Moreover, beta-subunit nitration increased significantly with the age of the rats (from 4 to 80 weeks old) and correlated with decreased ATP hydrolysis and synthesis rates. Although its affinity for ATP binding was unchanged, maximal ATPase activity decreased between young and old rats by a factor of two. These changes directly impacted the available ATP concentration in vivo, and it was expected that they would affect multiple cellular ATP-dependent processes. For instance, at least 50% of available [ATP] in the liver of older rats would have to be committed to sustain maximal Na(+)-K(+)-ATPase activity, whereas only 30% would be required for young rats. If this requirement was not fulfilled, the osmoregulation and Na(+) nutrient cotransport in liver of older rats would be compromised. On the basis of our studies, we propose that targeted nitration of the beta-subunit is an early marker for nitrative stress and aging. PMID- 20159860 TI - A 31-year-old woman with a transformed low-grade glioma. AB - Low-grade gliomas in adults have an incidence of 0.8 to 1.2 per 100,000, and their causes are unknown. Despite their histological classification as low-grade, they cannot be cured by any current treatment mode, and no class I evidence exists to guide initial treatment of these tumors. Median survival ranges between 7.5 years and 10 years, with a 5-year survival probability between 55% and 86%. The prognosis depends on age, World Health Organization (WHO) tumor grade, Karnofsky performance score, cytological type (oligodendroglioma vs astrocytoma), and, potentially, the extent of resection. Oligodendrogliomas with loss of heterozygosity on chromosomes 1p and 19q have a distinctly more favorable prognosis and therapeutic response rate. Low-grade tumors progress to high-grade gliomas with aggressive biological behavior at increasing frequency with advancing age. Ms P is a young woman with a previously treated oligodendroglioma, WHO grade II, with loss of heterozygosity on chromosomes 1p and 19q, which at a third resection had transformed into an oligodendroglioma of WHO grade III. She wants to know her current and future therapeutic options. PMID- 20159861 TI - The cover. Otra Margarita! (Another Marguerite!). PMID- 20159859 TI - A new antidiabetic compound attenuates inflammation and insulin resistance in Zucker diabetic fatty rats. AB - Tissue macrophage inflammatory pathways contribute to obesity-associated insulin resistance. Here, we have examined the efficacy and mechanisms of action of a novel anti-inflammatory compound (HE3286) in vitro and in vivo. In primary murine macrophages, HE3286 attenuates LPS- and TNFalpha-stimulated inflammation. In Zucker diabetic fatty rats, inflammatory cytokine/chemokine expression was downregulated in liver and adipose tissue by HE3286 treatment, as was macrophage infiltration into adipose tissue. In line with reduced inflammation, HE3286 treatment normalized fasting and fed glucose levels, improved glucose tolerance, and enhanced skeletal muscle and liver insulin sensitivity, as assessed by hyperinsulinemic euglycemic clamp studies. In phase 2 clinical trials, HE3286 treatment led to an enhancement in insulin sensitivity in humans. Gluconeogenic capacity was also reduced by HE3286 treatment, as evidenced by a reduced glycemic response during pyruvate tolerance tests and decreased basal hepatic glucose production (HGP) rates. Since serum levels of gluconeogenic substrates were decreased by HE3286, it indicates that the reduction of both intrinsic gluconeogenic capacity and substrate availability contributes to the decrease in HGP. Lipidomic analysis revealed that HE3286 treatment reduced liver cholesterol and triglyceride content, leading to a feedback elevation of LDL receptor and HMG CoA reductase expression. Accordingly, HE3286 treatment markedly decreased total serum cholesterol. In conclusion, HE3286 is a novel anti-inflammatory compound, which displays both glucose-lowering and cholesterol-lowering effects. PMID- 20159862 TI - A piece of my mind. Lonely. PMID- 20159863 TI - Research offers only a limited view of imaging's effect on patient outcomes. PMID- 20159864 TI - Studies probe medication use in pregnancy. PMID- 20159865 TI - Rising autism rates still pose a mystery. PMID- 20159866 TI - Heritable disease and sperm donation. PMID- 20159867 TI - Heritable disease and sperm donation. PMID- 20159868 TI - Minimally invasive vs open radical prostatectomy. PMID- 20159869 TI - Disruptive innovations and health care reform. PMID- 20159870 TI - Dynamics of obesity and chronic health conditions among children and youth. AB - CONTEXT: Rates of obesity and other childhood chronic conditions have increased over recent decades. Patterns of how conditions change over time have not been widely examined. OBJECTIVE: To evaluate change in prevalence of obesity and other chronic conditions in US children, including incidence, remission, and prevalence. DESIGN, SETTING, AND PARTICIPANTS: Prospective study using the National Longitudinal Survey of Youth-Child Cohort (1988-2006) of 3 nationally representative cohorts of children. Children were aged 2 through 8 years at the beginning of each study period, and cohorts were followed up for 6 years, from 1988 to 1994 (cohort 1, n = 2337), 1994 to 2000 (cohort 2, n = 1759), and 2000 to 2006 (n = 905). MAIN OUTCOME MEASURES: Parent report of a child having a health condition that limited activities or schooling or required medicine, special equipment, or specialized health services and that lasted at least 12 months. Obesity was defined as a body mass index at or above the 95th percentile for age. Chronic conditions were grouped into 4 categories: obesity, asthma, other physical conditions, and behavior/learning problems. RESULTS: The end-study prevalence of any chronic health condition was 12.8% (95% confidence interval [CI], 11.2%-14.5%) for cohort 1 in 1994, 25.1% (95% CI, 22.7%-27.6%) for cohort 2 in 2000, and 26.6% (95% CI, 23.5%-29.9%) for cohort 3 in 2006. There was substantial turnover in chronic conditions: 7.4% (95% CI, 6.5%-8.3%) of participants in all cohorts had a chronic condition at the beginning of the study that persisted to the end, 9.3% (95% CI, 8.3%-10.3%) reported conditions at the beginning that resolved within 6 years, and 13.4% (95% CI, 12.3%-14.6%) had new conditions that arose during the 6-year study period. The prevalence of having a chronic condition during any part of the 6-year study period was highest for cohort 3 (51.5%; 95% CI, 47.3%-55.0%), and there were higher rates among male (adjusted odds ratio [AOR], 1.24; 95% CI, 1.07-1.42), Hispanic (AOR, 1.36; 95% CI, 1.11-1.67), and black (AOR, 1.60; 95% CI, 1.35-1.90) youth. CONCLUSIONS: Prevalence of chronic conditions among children and youth increased from 1988 to 2006. However, presence of these conditions was dynamic over each 6-year cohort. PMID- 20159871 TI - Association between a literature-based genetic risk score and cardiovascular events in women. AB - CONTEXT: While multiple genetic markers associated with cardiovascular disease have been identified by genome-wide association studies, their aggregate effect on risk beyond traditional factors is uncertain, particularly among women. OBJECTIVE: To test the predictive ability of a literature-based genetic risk score for cardiovascular disease. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort of 19,313 initially healthy white women in the Women's Genome Health Study followed up over a median of 12.3 years (interquartile range, 11.6-12.8 years). Genetic risk scores were constructed from the National Human Genome Research Institute's catalog of genome-wide association study results published between 2005 and June 2009. MAIN OUTCOME MEASURE: Incident myocardial infarction, stroke, arterial revascularization, and cardiovascular death. RESULTS: A total of 101 single nucleotide polymorphisms reported to be associated with cardiovascular disease or at least 1 intermediate cardiovascular disease phenotype at a published P value of less than 10(-7) were identified and risk alleles were added to create a genetic risk score. During follow-up, 777 cardiovascular disease events occurred (199 myocardial infarctions, 203 strokes, 63 cardiovascular deaths, 312 revascularizations). After adjustment for age, the genetic risk score had a hazard ratio (HR) for cardiovascular disease of 1.02 per risk allele (95% confidence interval [CI], 1.00-1.03/risk allele; P = .006). This corresponds to an absolute cardiovascular disease risk of 3% over 10 years in the lowest tertile of genetic risk (73-99 risk alleles) and 3.7% in the highest tertile (106-125 risk alleles). However, after adjustment for traditional factors, the genetic risk score did not improve discrimination or reclassification (change in c index from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [ATP III] risk score, 0; net reclassification improvement, 0.5%; [P = .24]). The genetic risk score was not associated with cardiovascular disease risk (ATP III-adjusted HR/allele, 1.00; 95% CI, 0.99-1.01). In contrast, self-reported family history remained significantly associated with cardiovascular disease in multivariable models. CONCLUSION: After adjustment for traditional cardiovascular risk factors, a genetic risk score comprising 101 single nucleotide polymorphisms was not significantly associated with the incidence of total cardiovascular disease. PMID- 20159872 TI - Ancestry and pathology in King Tutankhamun's family. AB - CONTEXT: The New Kingdom in ancient Egypt, comprising the 18th, 19th, and 20th dynasties, spanned the mid-16th to the early 11th centuries bc. The late 18th dynasty, which included the reigns of pharaohs Akhenaten and Tutankhamun, was an extraordinary time. The identification of a number of royal mummies from this era, the exact relationships between some members of the royal family, and possible illnesses and causes of death have been matters of debate. OBJECTIVES: To introduce a new approach to molecular and medical Egyptology, to determine familial relationships among 11 royal mummies of the New Kingdom, and to search for pathological features attributable to possible murder, consanguinity, inherited disorders, and infectious diseases. DESIGN: From September 2007 to October 2009, royal mummies underwent detailed anthropological, radiological, and genetic studies as part of the King Tutankhamun Family Project. Mummies distinct from Tutankhamun's immediate lineage served as the genetic and morphological reference. To authenticate DNA results, analytical steps were repeated and independently replicated in a second ancient DNA laboratory staffed by a separate group of personnel. Eleven royal mummies dating from circa 1410-1324 bc and suspected of being kindred of Tutankhamun and 5 royal mummies dating to an earlier period, circa 1550-1479 bc, were examined. MAIN OUTCOME MEASURES: Microsatellite-based haplotypes in the mummies, generational segregation of alleles within possible pedigree variants, and correlation of identified diseases with individual age, archeological evidence, and the written historical record. RESULTS: Genetic fingerprinting allowed the construction of a 5-generation pedigree of Tutankhamun's immediate lineage. The KV55 mummy and KV35YL were identified as the parents of Tutankhamun. No signs of gynecomastia and craniosynostoses (eg, Antley-Bixler syndrome) or Marfan syndrome were found, but an accumulation of malformations in Tutankhamun's family was evident. Several pathologies including Kohler disease II were diagnosed in Tutankhamun; none alone would have caused death. Genetic testing for STEVOR, AMA1, or MSP1 genes specific for Plasmodium falciparum revealed indications of malaria tropica in 4 mummies, including Tutankhamun's. These results suggest avascular bone necrosis in conjunction with the malarial infection as the most likely cause of death in Tutankhamun. Walking impairment and malarial disease sustained by Tutankhamun is supported by the discovery of canes and an afterlife pharmacy in his tomb. CONCLUSION: Using a multidisciplinary scientific approach, we showed the feasibility of gathering data on Pharaonic kinship and diseases and speculated about individual causes of death. PMID- 20159873 TI - Association between 9p21 genomic markers and heart disease: a meta-analysis. AB - CONTEXT: Associations between chromosome 9p21 single-nucleotide polymorphisms (SNPs) and heart disease have been reported and replicated. If testing improves risk assessments using traditional factors, it may provide opportunities to improve public health. OBJECTIVES: To perform a targeted systematic review of published literature for effect size, heterogeneity, publication bias, and strength of evidence and to consider whether testing might provide clinical utility. DATA SOURCES: Electronic search via HuGE Navigator through January 2009 and review of reference lists from included articles. STUDY SELECTION: English language articles that tested for 9p21 SNPs with coronary heart/artery disease or myocardial infarction as primary outcomes. Included articles also provided race, numbers of participants, and data to compute an odds ratio (OR). Articles were excluded if reporting only intermediate outcomes (eg, atherosclerosis) or if all participants had existing disease. Twenty-five articles were initially identified and 16 were included. A follow-up search identified 6 additional articles. DATA EXTRACTION: Independent extraction was performed by 2 reviewers and consensus was reached. Credibility of evidence was assessed using published Venice criteria. DATA SYNTHESIS: Forty-seven distinct data sets from the 22 articles were analyzed, including 35 872 cases and 95 837 controls. The summary OR for heart disease among individuals with 2 vs 1 at-risk alleles was 1.25 (95% confidence interval [CI], 1.21-1.29), with low to moderate heterogeneity. Age at disease diagnosis was a significant covariate, with ORs of 1.35 (95% CI, 1.30-1.40) for age 55 years or younger and 1.21 (95% CI, 1.16-1.25) for age 75 years or younger. For a 65-year-old man, the 10-year heart disease risk for 2 vs 1 at-risk alleles would be 13.2% vs 11%. For a 40-year-old woman, the 10-year heart disease risk for 2 vs 1 at-risk alleles would be 2.4% vs 2.0%. Nearly identical but inverse results were found when comparing 1 vs 0 at-risk alleles. Three studies showed net reclassification indexes ranging from -0.1% to 4.8%. CONCLUSION: We found a statistically significant association between 9p21 SNPs and heart disease that varied by age at disease onset, but the magnitude of the association was small. PMID- 20159874 TI - Potential for revealing individual-level information in genome-wide association studies. PMID- 20159875 TI - Skiers, snowboarders, and safety helmets. PMID- 20159876 TI - Aligning rewards with large-scale improvement. PMID- 20159877 TI - Evolving notions of childhood chronic illness. PMID- 20159878 TI - King Tutankhamun, modern medical science, and the expanding boundaries of historical inquiry. PMID- 20159879 TI - JAMA patient page. Chronic diseases of children. PMID- 20159880 TI - Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. AB - AIMS: microRNA (miRNA) is reported to be present in the blood of humans and has been increasingly suggested as a biomarker for diseases. We aim to determine the potential of cardiac-specific miRNAs in circulation to serve as biomarkers for acute myocardial infarction (AMI). METHODS AND RESULTS: By verifying their tissue expression patterns with real-time polymerase chain reaction (PCR) analysis, muscle-enriched miRNAs (miR-1, miR-133a, and miR-499) and cardiac-specific miR 208a were selected as candidates for this study. With miRNA microarray and real time PCR analyses, miR-1, miR-133a, and miR-499 were present with very low abundance, and miR-208a was absent in the plasma from healthy people. In the AMI rats, the plasma levels of these miRNAs were significantly increased. Especially, miR-208a in plasma was undetected at 0 h, but was significantly increased to a detectable level as early as 1 h after coronary artery occlusion. Further evaluation of the miRNA levels in plasma from AMI patients (n = 33) demonstrated that all four miRNA levels were substantially higher than those from healthy people (n = 30, P < 0.01), patients with non-AMI coronary heart disease (n = 16, P < 0.01), or patients with other cardiovascular diseases (n = 17, P < 0.01). Notably, miR-208a remained undetectable in non-AMI patients, but was easily detected in 90.9% AMI patients and in 100% AMI patients within 4 h of the onset of symptoms. By receiver operating characteristic curve analysis, among the four miRNAs investigated, miR-208a revealed the higher sensitivity and specificity for diagnosing AMI. CONCLUSION: Elevated cardiac-specific miR-208a in plasma may be a novel biomarker for early detection of myocardial injury in humans. PMID- 20159881 TI - Oral anticoagulation with coumarin derivatives and antiplatelet effects of clopidogrel. AB - AIMS: A relevant proportion of patients receiving aspirin and clopidogrel after percutaneous coronary intervention (PCI) also require oral anticoagulation with a coumarin derivative such as phenprocoumon. Both clopidogrel and phenprocoumon are metabolized by the hepatic cytochrome P450 system and a drug-drug interaction may exist at this level. The aim of this study was to investigate the impact of phenprocoumon on the antiplatelet effects of clopidogrel in patients with coronary artery disease. METHODS AND RESULTS: Patients (n = 1223) eligible for this study were under dual maintenance antiplatelet treatment with aspirin and clopidogrel. Adenosine diphosphate-induced platelet aggregation (in AU*min) was measured with multiple electrode platelet aggregometry on a Multiplate analyzer (Dynabyte, Munich, Germany). From the entire study population, 124 (10.1%) patients were under concomitant phenprocoumon treatment at the time point of platelet function testing. Platelet aggregation (median [interquartile range]) was significantly higher in patients with (n = 124) concomitant phenprocoumon treatment compared with patients without (n = 1099) phenprocoumon treatment (308 [190-493] AU*min vs. 224 [145-390] AU*min; P = 0.0001, adjusted P = 0.002). CONCLUSION: Phenprocoumon significantly attenuates the antiplatelet effects of clopidogrel. The impact of this interaction on the risk of thrombotic and bleeding events after PCI requires further investigations. PMID- 20159882 TI - Early complete response during chemotherapy predicts favorable outcome in patients with primary CNS lymphoma. AB - In primary central nervous system lymphoma (PCNSL), 2 international prognostic scores have been developed to estimate the outcome according to certain "prognostic groups". However, these scores do not predict the individual course of a single patient under therapy. In this analysis, we addressed the question of whether early tumor remission in patients still under therapy, according to magnetic resonance imaging (MRI) criteria, helps to predict long-term outcome. Eighty-eight patients treated with 6 polychemotherapy cycles within a pilot/phase II trial underwent MRI scanning within 72 hours prior to initiation of therapy, after the second chemotherapy cycle, and after completion of chemotherapy. Response was assessed by contrast-enhanced MRI of the brain according to the Macdonald criteria. Median follow-up was 42 months (range, 0-124 months). Patients achieving a complete radiographic response after 2 courses of chemotherapy (n = 18) had a significantly longer median overall survival (OS) (not reached) and median time-to-treatment failure (TTF) (not reached) than patients with complete response (CR) after termination of treatment but with only a partial response after the second cycle (n = 24) (OS: 55 months; TTF: 32 months) (P < .01). Early complete tumor response assessed by MRI after the second of sixth scheduled chemotherapy cycles was highly predictive for both OS and TTF in patients with PCNSL treated in this series. PMID- 20159883 TI - Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. AB - BACKGROUND Polycystic ovary syndrome (PCOS) is a common condition in reproductive aged women associated with impaired glucose tolerance (IGT), type 2 diabetes mellitus (DM2) and the metabolic syndrome. METHODS A literature search was conducted (MEDLINE, CINAHL, EMBASE, clinical trial registries and hand-searching) identifying studies reporting prevalence or incidence of IGT, DM2 or metabolic syndrome in women with and without PCOS. Data were presented as odds ratio (OR) [95% confidence interval (CI)] with fixed- and random-effects meta-analysis by Mantel-Haenszel methods. Quality testing was based on Newcastle-Ottawa Scaling and The Cochrane Collaboration's risk of bias assessment tool. Literature searching, data abstraction and quality appraisal were performed by two investigators. RESULTS A total of 2192 studies were reviewed and 35 were selected for final analysis. Women with PCOS had increased prevalence of IGT (OR 2.48, 95% CI 1.63, 3.77; BMI-matched studies OR 2.54, 95% CI 1.44, 4.47), DM2 (OR 4.43, 95% CI 4.06, 4.82; BMI-matched studies OR 4.00, 95% CI 1.97, 8.10) and metabolic syndrome (OR 2.88, 95% CI 2.40, 3.45; BMI-matched studies OR 2.20, 95% CI 1.36, 3.56). One study assessed IGT/DM2 incidence and reported no significant differences in DM2 incidence (OR 2.07, 95% CI 0.68, 6.30). One study assessed conversion from normal glucose tolerance to IGT/DM2 (OR 2.4, 95% CI 0.7, 8.0). No studies reported metabolic syndrome incidence. CONCLUSIONS Women with PCOS had an elevated prevalence of IGT, DM2 and metabolic syndrome in both BMI and non-BMI matched studies. Few studies have determined IGT/DM2 or metabolic syndrome incidence in women with and without PCOS and further research is required. PMID- 20159884 TI - Regulation of actin dynamics by actin-binding proteins in pollen. AB - A dynamic network of polymers, the actin cytoskeleton, co-ordinates numerous fundamental cellular processes. In pollen tubes, organelle movements and cytoplasmic streaming, organization of the tip zone, vesicle trafficking, and tip growth have all been linked to actin-based function. Further, during the self incompatibility response of Papaver rhoeas, destruction of the cytoskeleton is a primary target implicated in the rapid cessation of pollen tube growth and alterations in actin dynamics are associated with the initiation of programmed cell death. Surprisingly, these diverse cellular processes are accomplished with only a small amount of filamentous actin and a huge pool of polymerizable monomers. These observations hint at incredibly fast and complex actin dynamics in pollen. To understand the molecular mechanisms regulating actin dynamics in plant cells, the abundant actin monomer-binding proteins, a major filament nucleator, a family of bundling and severing proteins, and a modulator of growth at the barbed-end of actin filaments have been characterized biochemically. The activities of these proteins are generally consistent with textbook models for actin turnover. For example, the three monomer-binding proteins, profilin, ADF, and CAP, are thought to function synergistically to enhance turnover and the exchange of subunits between monomer and polymer pools. How individual actin filaments behave in living cells, however, remains largely unexplored. Actin dynamics were examined using variable angle epifluorescence microscopy (VAEM) in expanding hypocotyl epidermal cells. Our observations of single filament behaviour are not consistent with filament turnover by treadmilling, but rather represent a novel property called stochastic dynamics. A new model for the dynamic control of actin filament turnover in plant cells is presented. PMID- 20159885 TI - Contribution of carbon fixed by Rubisco and PEPC to phloem export in the Crassulacean acid metabolism plant Kalanchoe daigremontiana. AB - Crassulacean acid metabolism (CAM) plants exhibit a complex interplay between CO(2) fixation by phosphoenolpyruvate carboxylase (PEPC) and ribulose-1,5 bisphosphate carboxylase oxygenase (Rubisco), and carbon demand for CAM maintenance and growth. This study investigated the flux of carbon from PEPC and direct Rubisco fixation to different leaf carbon pools and to phloem sap over the diurnal cycle. Concentrations and carbon isotope compositions of starch, soluble sugars, and organic acids were determined in leaves and phloem exudates of Kalanchoe daigremontiana Hamet et Perr., and related to CO(2) fixation by PEPC and Rubisco. Three types of leaf carbon pools could be distinguished. (i) Starch and malate pools were dominant and showed a pattern of reciprocal mobilization and accumulation (85/54 and 13/48 mg C g(-1) DW, respective, at the beginning/end of phase I). The carbon isotope composition of these pools was compatible with predominant PEPC fixation (delta(13)C values of -13 and -11 per thousand for starch and malate compared to -11 per thousand of PEPC fixed carbon). (ii) Isotopic composition (-17 per thousand and -14 per thousand) and concentration of glucose and fructose (2 and 3 mg C g(-1) DW, respectively) were not affected by diurnal metabolism, suggesting a low turnover. (iii) Sucrose (1-3 mg C g(-1) DW), in contrast, exhibited large diurnal changes in delta(13)C values (from -17 per thousand in the evening to -12 per thousand in the morning), which were not matched by net changes in sucrose concentration. This suggests a high sucrose turnover, fed by nocturnal starch degradation and direct Rubisco fixation during the day. A detailed dissection of the carbon fixation and mobilization pattern in K. daigremontiana revealed that direct fixation of Rubisco during the light accounted for 30% of phloem sucrose, but only 15% of fixed carbon, indicating that carbon from direct Rubisco fixation was preferentially used for leaf export. PMID- 20159887 TI - Doctor could face financial ruin even if he wins libel case. PMID- 20159888 TI - Fatal hepatitis B infection despite immunization in an HIV-infected infant: a possible case of vaccine failure and immune reconstitution inflammatory syndrome. AB - We report a case of hepatitis B immune reconstitution inflammatory syndrome in an 8-month-old girl with Mycobacterium tuberculosis complex and human immunodeficiency virus (HIV) co-infection. In resource-constrained countries, HIV hepatitis B co-infections are often difficult to diagnose and to treat. We highlight on the importance of hepatitis B and HIV screening in pregnant women, to implement efficient preventive measures. PMID- 20159891 TI - How posters promote public health behaviour. PMID- 20159892 TI - Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza. AB - BACKGROUND: Whether the enteric absorption of the neuraminidase inhibitor oseltamivir is impaired in critically ill patients is unknown. We documented the pharmacokinetic profile of oseltamivir in patients admitted to intensive care units (ICUs) with suspected or confirmed pandemic (H1N1) influenza. METHODS: We included 41 patients 18 years of age and older with suspected or confirmed pandemic (H1N1) influenza who were admitted for ventilatory support to nine ICUs in three cities in Canada and Spain. Using tandem mass spectrometry, we assessed plasma levels of oseltamivir free base and its active metabolite carboxylate at baseline (before gastric administration of the drug) and at 2, 4, 6, 9 and 12 hours after the fourth or later dose. RESULTS: Among the 36 patients who did not require dialysis, the median concentration of oseltamivir free base was 10.4 (interquartile range [IQR] 4.8-14.9) microg/L; the median concentration of the carboxylate metabolite was 404 (IQR 257-900) microg/L. The volume of distribution of the carboxylate metabolite did not increase with increasing body weight (R2=0.00, p=0.87). The rate of elimination of oseltamivir carboxylate was modestly correlated with estimations of creatinine clearance (R2=0.27, p<0.001). Drug clearance in the five patients who required continuous renal replacement therapy was about one-sixth that in the 36 patients with relatively normal renal function. INTERPRETATION: Oseltamivir was well absorbed enterically in critically ill patients admitted to the ICU with suspected or confirmed pandemic (H1N1) influenza. The dosage of 75 mg twice daily achieved plasma levels that were comparable to those in ambulatory patients and were far in excess of concentrations required to maximally inhibit neuraminidase activity of the virus. Adjustment of the dosage in patients with renal dysfunction requiring continuous renal replacement therapy is appropriate; adjustment for obesity does not appear to be necessary. PMID- 20159895 TI - Pets in airplane cabins: an unnecessary allergic hazard. PMID- 20159893 TI - Risk of severe outcomes among patients admitted to hospital with pandemic (H1N1) influenza. AB - BACKGROUND: We describe the disease characteristics and outcomes, including risk factors for admission to intensive care unit (ICU) and death, of all patients in Canada admitted to hospital with pandemic (H1N1) influenza during the first five months of the pandemic. METHODS: We obtained data for all patients admitted to hospital with laboratory-confirmed pandemic (H1N1) influenza reported to the Public Health Agency of Canada from Apr. 26 to Sept. 26, 2009. We compared inpatients who had nonsevere disease with those who had severe disease, as indicated by admission to ICU or death. RESULTS: A total of 1479 patients were admitted to hospital with confirmed pandemic (H1N1) influenza during the study period. Of these, 1171 (79.2%) did not have a severe outcome, 236 (16.0%) were admitted to ICU and survived, and 72 (4.9%) died. The median age was 23 years for all of the patients, 18 years for those with a nonsevere outcome, 34 years for those admitted to ICU who survived and 51 years for those who died. The risk of a severe outcome was elevated among those who had an underlying medical condition and those 20 years of age and older. A delay of one day in the median time between the onset of symptoms and admission to hospital increased the risk of death by 5.5%. The risk of a severe outcome remained relatively constant over the five-month period. INTERPRETATION: The population-based incidence of admission to hospital with laboratory-confirmed pandemic (H1N1) influenza was low in the first five months of the pandemic in Canada. The risk of a severe outcome was associated with the presence of one or more underlying medical conditions, age of 20 years or more and a delay in hospital admission. PMID- 20159896 TI - Roadblocks to laws for healthy eating and activity. PMID- 20159897 TI - Acquired reactive perforating collagenosis. PMID- 20159898 TI - Acute urinary tract infection in infants and young children. PMID- 20159900 TI - Erythema ab igne. PMID- 20159899 TI - Prophylaxis of migraine headache. PMID- 20159901 TI - Canada's electronic health records initiative stalled by federal funding freeze. PMID- 20159902 TI - Safety institutes urge better bar-coding of drugs. PMID- 20159903 TI - The future of eye tech. PMID- 20159904 TI - Rosy outlook for people with diabetes. PMID- 20159905 TI - Fund proposed to pay for drugs with greater global impact. PMID- 20159906 TI - Lack of effect of 8 weeks atorvastatin on microvascular endothelial function in patients with systemic sclerosis. AB - OBJECTIVE: The aim of this study was to test the hypothesis that statin therapy confers benefit on the microvasculature, including improving endothelial function, in patients with SSc. METHODS: This was a randomized, parallel group, double-blind study, with assessments at baseline, 4 and 8 weeks. Thirty-six patients were randomly assigned to receive 8 weeks treatment with atorvastatin 20 mg/day or placebo. The primary end-point was endothelial-dependent vasodilation, as assessed by response to iontophoresis with acetylcholine chloride (ACh) as measured by laser Doppler imaging. Secondary end-points included endothelial independent vasodilation, microvascular structure as assessed by videocapillaroscopy, von Willebrand factor, high-sensitivity CRP and plasma cholesterol. RESULTS: Eighteen patients were randomly assigned to atorvastatin and 18 to placebo. Eight weeks treatment resulted in no statistically significant differences in any of the outcome measures (other than cholesterol) between atorvastatin and placebo groups. The median area under the curve for ACh iontophoresis at baseline was 1569 perfusion units (PU).time in the atorvastatin group and 1450 PU.time in the placebo group, and at 8 weeks 2146 and 1822 PU.time, respectively. Mean difference (95% CI) at 8 weeks was 355 (-835, 1544) PU.time. CONCLUSION: Atorvastatin 20 mg/day, given for 8 weeks, was not associated with changes in microvascular function or structure. The large variation in outcome scores means that it is not possible to rule out an effect on the basis of this trial. Future studies should be of longer duration and include patients with early disease who are unlikely to have irreversible structural vascular disease. TRIAL REGISTRATION: EudraCT, https://eudract.emea.europa.eu/, 2005-003775-21. PMID- 20159907 TI - Employment status and socio-economic burden in systemic sclerosis: a cross sectional survey. AB - OBJECTIVE: To assess employment status and socio-economic burden in SSc patients. METHODS: Eighty-seven SSc patients (72 females), fulfilling the ACR or the Leroy and Medsger criteria, or both, were evaluated for employment status, socio economic burden and handicap. Statistical analysis involved Mann-Whitney U-test and Fisher's exact test and backward stepwise regression analysis. RESULTS: In total, 60.9% of the SSc patients were on full-time sick leave and 35.6% were receiving a disability pension. On univariate analysis, myalgia was the only clinical manifestation more frequently encountered in sick-leave patients than others (73.6 vs 47.1%; P = 0.012). Karnofsky performance status (KPS) was lower in SSc patients who were on sick leave or were receiving a disability pension than others [78.5 (10.6) vs 85.8 (9.0); P = 0.004 and 78.1 (8.7) vs 83.1 (11.2); P = 0.016, respectively]. In addition, greater global, hand and mouth handicaps and depression were observed in patients on sick leave [HAQ 0.9 (0.7) vs 0.6 (0.5); P = 0.021; Cochin Hand Function Scale 21.7 (18.9) vs 10.7 (12.1); P = 0.003; mouth handicap scale 20.2 (10.8) vs 14.6 (10.0); P = 0.014; and depression dimension of the hospital anxiety and depression scale 7.1 (3.9) vs 4.8 (3.4); P = 0.003]. On multivariate analysis, factors associated with sick leave were KPS [odds ratio (OR) 0.92; 95%CI 0.88, 0.98] and myalgias (OR 3.19; 95% CI 1.19, 8.58), and the factor associated with receiving a disability pension was decreased income (OR 8.19; 95% CI 2.67, 25.12). CONCLUSIONS: SSc patients commonly have to take full-time sick leave from work. Despite such patients receiving disability pensions, the socio-economic burden is considerable. PMID- 20159908 TI - Liver X receptor agonist prevents the evolution of collagen-induced arthritis in mice. AB - OBJECTIVE: Liver X receptors (LXRs) have been characterized as regulators of macrophage inflammatory pathways. Synthetic LXR agonists inhibit the macrophage response to bacterial pathogens and antagonize the induction of a number of pro inflammatory genes. The aim of this study was to investigate the preventive effects of synthetic LXR agonist, GW3965, treatment on the evolution of arthritis and inflammatory response in a murine CIA model. METHODS: Intradermal injection of bovine type II CIA in DBA/1 mice. Along with the induction of CIA, mice were treated with oral GW3965 (0.1, 0.3 or 1.0 mg/kg/day) or vehicle from Day 1 to Day 40. Clinical assessment for arthritis scores and histopathological assessment of joint sections were performed. The expression of inflammatory mediators was evaluated by immunohistochemical staining. Serum pro-inflammatory cytokine levels were determined using ELISA. RESULTS: The CIA incidence was 100% on Day 27 and the severity progressed until Day 35 with histological features of cartilage erosion in vehicle-treated mice. GW3965 treatment significantly reduced the arthritis incidence and attenuated the clinical and histological severity, compared with vehicle-treated mice. GW3965 treatment also significantly reduced inflammatory mediator production in joint sections and serum pro-inflammatory cytokine levels in a dose-dependent manner. CONCLUSIONS: These results indicate that activation of LXRs suppresses the onset of CIA and reduces inflammation and joint destruction in CIA mice. The data could suggest that LXR treatment is an effective prophylactic approach to suppress the evolution of synovitis and resultant joint destruction observed in RA. PMID- 20159910 TI - Late extrusion of pulmonary plombage outside the thoracic cavity. AB - Plombage, a variant of collapse therapy for patients with pulmonary tuberculosis that uses a variety of foreign materials, was undertaken until the 1950s before the invention of effective antimicrobial therapy. Complications related to previous plombage procedures are not uncommon. Management of these complications can be challenging. We report a patient presenting with extrusion of plombage 59 years later and managed successfully with removal of the plomb and pectoral muscle flap transposition. PMID- 20159909 TI - Up-regulation of the endoplasmic reticulum transmembrane protein UNC93B in the B cells of patients with active systemic lupus erythematosus. AB - OBJECTIVES: The transmembrane endoplasmic reticulum (ER) protein UNC93B plays an essential role in the normal response to signalling through intracellular Toll like receptor (TLR)3, TLR7, TLR8 and TLR9. In the current study, we examined the level of UNC93B expression on peripheral B cells from patients with active SLE, and investigated any correlation with SLE pathogenesis. METHODS: Peripheral blood mononuclear cells (PBMCs) and B cells from 43 active SLE patients were analysed by quantitative RT-PCR to determine the precise levels of UNC93B mRNA. We also analysed UNC93B protein expression on B cells from SLE patients using immunoblotting. RESULTS: The expression of UNC93B mRNA on PBMCs from active SLE patients was significantly higher than that of controls (P < 0.05). The intracellular expression level of UNC93B protein on CD20(+) B cells from active SLE patients was also higher than in the controls. Moreover, the expression of UNC93B on B cells from lupus patients correlated significantly with high titres of anti-dsDNA antibody (P < 0.05). CONCLUSIONS: Up-regulation of the ER membrane protein UNC93B on human lupus B cells suggests that TLR9 and UNC93B play a partial role in the pathogenesis of SLE by inducing defective peripheral B-cell tolerance. PMID- 20159911 TI - Scatter and staff dose levels in paediatric interventional cardiology: a multicentre study. AB - Interventional cardiology procedures usually imply high doses to the staff, as paediatric cardiologists need to stay closer to the patient than during adult procedures. Also, biplane systems are used that imply an additional source of staff doses. The objective of this paper is to measure scatter doses in four X ray systems, using polymethyl methacrylate phantoms with thicknesses ranging from 4 to 16 cm to simulate paediatric patients, for the different acquisition modes. Scatter dose rates measured at the position of cardiologist's eyes ranged from 0.8 to 12 mSv h(-1), and about twice the above values at lower extremities, as a linear function of the surface air kerma at the phantom, keeping the irradiated area constant. Therefore, the respective personal dose equivalent for the lens of the eyes may be around 0.5 and 1 mSv throughout the procedure, if additional protection is not used. Simultaneous cine acquisition in biplane systems yielded scatter doses to cardiologists, increased by factors from 5 to 21, compared with a single C-arm acquisition case and depending on geometry. Knowledge of scatter doses for different operation modes, patient thicknesses and the biplane operation should help paediatric cardiologists to adopt conservative attitudes in respect of their occupational radiation risks. PMID- 20159912 TI - Medium wave exposure characterisation using exposure quotients. AB - One of the aspects considered in the International Commission on Non-Ionizing Radiation Protection guidelines is that, in situations of simultaneous exposure to fields of different frequencies, exposure quotients for thermal and electrical stimulation effects should be examined. The aim of the present work was to analyse the electromagnetic radiation levels and exposure quotients for exposure to multiple-frequency sources in the vicinity of medium wave radio broadcasting antennas. The measurements were made with a spectrum analyser and a monopole antenna. Kriging interpolation was used to prepare contour maps and to estimate the levels in the towns and villages of the zone. The results showed that the exposure quotient criterion based on electrical stimulation effects to be more stringent than those based on thermal effects or power density levels. Improvement of dosimetry evaluations requires the spectral components of the radiation to be quantified, followed by application of the criteria for exposure to multiple-frequency sources. PMID- 20159913 TI - Liquid radiation detectors based on nanosilver surface plasmon resonance phenomena. AB - The rapid development of micro- and nanostructures containing silver nanoparticles is based on their unique physical properties. Despite the new applications of silver nanoparticles in nanomedicine are under heavy discussions, silver nanoparticles could be used in liquid radiation detectors thanks to the irradiation-induced surface plasmon resonance (SPR) phenomena observed in the colloidal solutions. Silver nitrate (1 mM AgNO(3)) and sodium citrate (1 wt% and 5 wt% C(6)H(5)O(7)Na(3)) were used as precursors for the fabrication of colloidal solutions. Prepared solutions were exposed to gamma-rays from a (60)Co gamma therapy unit 'Rokus-M' to varying absorbed doses, from 2 to 250 Gy. A UV/VIS/NIR spectrometer (Avantes-2048) was used for the measurement of the optical properties (absorbance) of the silver solutions. It was found that an initial absorbed dose of 2 Gy induced the formation of spherical silver nanoparticles as it was indicated in the absorbance spectrum of the solution, which had a well pronounced absorption maximum at the wavelength of 410 nm. There is a potential to measure absorbed doses down to around 20 mGy. The SPR peaks at the wavelengths of 500-700 nm were found at the highest investigated doses >100 Gy, indicating the presence of silver nanorods. The colour of colloidal solutions ranged from pale yellow to green and was dependent on the absorbed dose. The investigation has shown that density, size and shape of synthesised silver nanoparticles are dependent on the absorbed dose and that shape transformations of the particles due to irradiation are possible. Application of colloidal solutions containing silver nanoparticles for dosimetric purposes is discussed on the basis of the obtained results. PMID- 20159914 TI - Image rejects/retakes--radiographic challenges. AB - A general held position among radiological personnel prior to digitalisation was that the problem of image rejects/retakes should more or less vanish. However, rejects/retakes still impose several challenges within radiographic imaging; they occupy unnecessary resources, expose patients to unnecessary ionizing radiation and may also indicate suboptimal quality management. The latter is the main objective of this paper, which is based on a survey of international papers published both for screen/film and digital technology. The digital revolution in imaging seems to have reduced the percentage of image rejects/retakes from 10-15 to 3-5 %. The major contribution to the decrease appears to be the dramatic reduction of incorrect exposures. At the same time, rejects/retakes due to lack of operator competence (positioning, etc.) are almost unchanged, or perhaps slightly increased (due to lack of proper technical competence, incorrect organ coding, etc.). However, the causes of rejects/retakes are in many cases defined and reported with reference to radiographers' subjective evaluations. Thus, unless radiographers share common views on image quality and acceptance criteria, objective measurements and assessments of reject/retake rates are challenging tasks. Interestingly, none of the investigated papers employs image quality parameters such as 'too much noise' as categories for rejects/retakes. Surprisingly, no reject/retake analysis seems yet to have been conducted for direct digital radiography departments. An increased percentage of rejects/retakes is related to 'digital skills' of radiographers and therefore points to areas for extended education and training. Furthermore, there is a need to investigate the inter-subjectivity of radiographers' perception of, and attitude towards, both technical and clinical image quality criteria. Finally, there may be a need to validate whether reject/retake rate analysis is such an effective quality indicator as has been asserted. PMID- 20159915 TI - Metabolism of 210Po in rats: volatile 210Po in excreta. AB - Polonium-210 ((210)Po) is one of the most toxic radionuclides and was used as a poison in the Alexander Litvinenko case. In this study of the metabolism of (210)Po in rats, volatile (210)Po in excreta was measured, filling a knowledge gap of the previous studies. Five rats were intravenously administrated with 2 kBq and another five with 10 kBq of (210)Po (citrate form). They were housed in a glass Metabowl system for 4 d following the administration. Volatile (210)Po from the excreta was collected in a trapping system filled with liquid scintillation cocktail and was measured by liquid scintillation counting. Results showed that the daily excretion of volatile (210)Po by the rats is in a very small percentage (0.002-0.009 %) of the administered amounts. However, if the administered amount is large, the excretion of volatile (210)Po can be significant. PMID- 20159916 TI - Analysis of the photoneutron activation effects generated by 9 MeV X-ray in a container cargo inspection facility. AB - The X-ray container cargo inspection facility is extensively implemented with the key objective to counter international terrorism and illicit smuggling of the contraband items via the ports. However, activation products are generated from photoneutron capture reactions in the high-energy X-ray container cargo inspection facility. The activation products release inherent delayed radiations which occupational workers are exposed to. In this study, the activation products are estimated using Monte Carlo method and radiation safety of the facility in terms of occupational dose is reviewed. PMID- 20159917 TI - Consistency of methods for analysing location-specific data. AB - Although the receiver operating characteristic (ROC) method is the acknowledged gold-standard for imaging system assessment, it ignores localisation information and differentiation between multiple abnormalities per case. As the free-response ROC (FROC) method uses localisation information and more closely resembles the clinical reporting process, it is being increasingly used. A number of methods have been proposed to analyse the data that result from an FROC study: jackknife alternative FROC (JAFROC) and a variant termed JAFROC1, initial detection and candidate analysis (IDCA) and ROC analysis via the reduction of the multiple ratings on a case to a single rating. The focus of this paper was to compare JAFROC1, IDCA and the ROC analysis methods using a clinical FROC human data set. All methods agreed on the ordering of the modalities and all yielded statistically significant differences of the figures-of-merit, i.e. p < 0.05. Both IDCA and JAFROC1 yielded much smaller p-values than ROC. The results are consistent with a recent simulation-based validation study comparing these and other methods. In conclusion, IDCA or JAFROC1 analysis of FROC human data may be superior at detecting modality differences than ROC analysis. PMID- 20159918 TI - Mammography radiation dose: initial results from Serbia based on mean glandular dose assessment for phantoms and patients. AB - The primary objective of this study is to investigate the actual mammography dose levels in Serbia and establish a baseline dose database for the future screening programme. The mean glandular dose (MGD) was assessed for standard size breast substituted by 45 mm polymethyl methacrylate (PMMA) phantom and imaged under typical clinical conditions at 30 screen-film mammography facilities. Average MGD was (1.9 +/- 1.0) mGy, with a range of 0.12-5.2 mGy. These results were used for the calculation of the initial diagnostic reference levels in mammography in Serbia, which was set to 2.1 mGy for a standard breast. At some facilities, high doses were observed and the assessed MGD was supplemented by a patient dose survey. MGD was measured for 53 women having a diagnostic mammography in cranio caudal (CC) and mediolateral oblique (MLO) projections at the largest mammography facilities in Serbia. The parameters recorded were: age, compressed breast thickness, tube potential (in kV), tube loading (in mAs) and the MLO projection angle. The average MGD per image was 2.8 mGy for the CC projection and 4.3 mGy for the MLO projection. Dose to breast was compared with dose for PMMA phantoms of various sizes, assessed at the same facilities. The results have indicated that phantom dose values can assist in setting optimisation activities in mammography. Both phantom and patient dose values indicated unnecessary high doses in facilities with an extremely high mammography workload. For these facilities, urgent dose-reduction measures and follow-up actions were recommended. PMID- 20159919 TI - Uranium content and dose assessment for sediment and soil samples from the estuarine system of Santos and Sao Vicente, SP, Brazil. AB - In this work, the uranium (U) content in sediment and soil samples collected near the Santos and Sao Vicente estuaries was determined using the fission track registration technique (SSNTD). The sediment and soil samples after oven-dried and pulverised were prepared in the solution form. About 10 microl of this solution was deposited on a plastic detector and irradiated at the IPEN-IEA-R1 (3.5 MW) nuclear reactor. After the irradiation and chemical etching of the plastic foils, the fission tracks were counted with a system consisting of an optical microscope together with a video camera and a PC. The U content in the analysed samples ranged from 3.12 +/- 0.55 to 18.3 +/- 1.2 ppm for sediments and from 3.21 +/- 0.63 to 11.5 +/- 1.1 ppm for soils or in terms of (238)U equivalent activity from 38.5 +/- 6.8 to 226 +/- 15 and 39.6 +/- 7.8 to 142 +/- 14 Bq kg(-1) for sediments and soils, respectively. These results were compared with other values reported in the literature for sediments and soils collected in environments similar to the ones studied in this work. Most of the values obtained in this work are higher than the world mean and are in reasonable agreement with results found by other authors for sediments and soils from regions considered as polluted or with a high level of radioactivity. PMID- 20159921 TI - Will medical visualisation tools meet medical user requirements in the future? AB - This paper describes state-of-the-art medical visualisation and discusses the need for a research agenda that focuses on the development of the next generation of medical acquisition and visualisation tools, emphasising the fact that these tools must be based on medical user requirement and workflow studies as well as on new technical developments. PMID- 20159920 TI - A clinical audit programme for diagnostic radiology: the approach adopted by the International Atomic Energy Agency. AB - The International Atomic Energy Agency (IAEA) has a mandate to assist member states in areas of human health and particularly in the use of radiation for diagnosis and treatment. Clinical audit is seen as an essential tool to assist in assuring the quality of radiation medicine, particularly in the instance of multidisciplinary audit of diagnostic radiology. Consequently, an external clinical audit programme has been developed by the IAEA to examine the structure and processes existent at a clinical site, with the basic objectives of: (1) improvement in the quality of patient care; (2) promotion of the effective use of resources; (3) enhancement of the provision and organisation of clinical services; (4) further professional education and training. These objectives apply in four general areas of service delivery, namely quality management and infrastructure, patient procedures, technical procedures and education, training and research. In the IAEA approach, the audit process is initiated by a request from the centre seeking the audit. A three-member team, comprising a radiologist, medical physicist and radiographer, subsequently undertakes a 5-d audit visit to the clinical site to perform the audit and write the formal audit report. Preparation for the audit visit is crucial and involves the local clinical centre completing a form, which provides the audit team with information on the clinical centre. While all main aspects of clinical structure and process are examined, particular attention is paid to radiation-related activities as described in the relevant documents such as the IAEA Basic Safety Standards, the Code of Practice for Dosimetry in Diagnostic Radiology and related equipment and quality assurance documentation. It should be stressed, however, that the clinical audit does not have any regulatory function. The main purpose of the IAEA approach to clinical audit is one of promoting quality improvement and learning. This paper describes the background to the clinical audit programme and the IAEA clinical audit protocol. PMID- 20159922 TI - Comparison of KAP values for CAG examinations: the influence of parameter settings. AB - This study shows that changing settings like detector dose, added copper filtration, kV-mA-ms settings and frame rate can substantially reduce the average air kerma-area product value per examination in coronary angiography. The default factory settings of cardiac X-ray systems are often not optimised and therefore the dose settings are mostly too high. The type of modifications that are allowed depends on the X-ray system. With the GE Innovation2000, the freedom of making adjustments is restricted. With the Siemens Coroscop and the Philips Allura Xper FD10, several adjustments can be made. It is possible to lower the dose to patient and staff by not unreservedly accept the default factory settings. However, the point of discussion is 'how low should you go', because the needed clinical image quality is difficult to define objectively using phantom measurements. PMID- 20159923 TI - A study in Europe of patient dosimetry in diagnostic radiology: protocol development and findings. AB - In a multi-centre study more than 600 patient measurements of patients receiving thorax radiography were performed in five European cities. Participating centres were Fulda, Liverpool, Nicosia, Passau and Sofia. The dose quantities measured were the air kerma-area product (AKAP), incident air kerma and entrance surface air kerma (ESAK). In addition, for each patient sex, age, weight, height, focus to-film distance, focus-to-skin distance, patient thickness, kV, mAs, field size and the nominal film speed were registered. Different X-ray machines were used in the participating centres--Thoravision, flat panel detector and film screen combinations in two centres (analogue system). The tube voltages employed varied between 60 and 150 kV and the nominal film speed between 200 and 400/800. All mean dose values (ESAK and AKAP) for the different centres showed a different value for female and male populations. The differences were up to 100 % and always higher for the mean AKAP. For a thorax posteroanterior examination, the mean ESAK varied between 0.06 and 0.46 mGy and the mean AKAP varied between 60 and 690 mGy cm(2). The differences in the results obtained as well as the methodologies for multi-national, multi-centre studies will be discussed. Future perspectives for this type of study within the framework of radiation protection and quality assurance in Europe will also be discussed as well as the role and function of multi-national radiological data sets including patient dose values. PMID- 20159924 TI - Natural background dose measurements in south Cameroon. AB - The natural background doses due to (40)K, (226)Ra and (232)Th have been measured in soil samples collected from various sampling sites in the locality of Lolodorf, Cameroon. For data acquisition and analysis, a high-purity germanium detector and a PC-based MCA were used. The mean activity concentrations of (40)K, (226)Ra and (232)Th were measured to be 2001 +/- 521, 329 +/- 491 and 414 +/- 309 Bq kg(-1), respectively, in rock samples, while in soil samples the activity concentrations were found to be 1482 +/- 280 Bq kg(-1) for (40)K, 134 +/- 64 Bq kg(-1) for (226)Ra and 177 +/- 102 Bq kg(-1) for (232)Th. The average outdoor absorbed dose rates in air, 1 m above the ground surface due to soil samples, were estimated to be 218 +/- 61 and 250 +/- 97 nGy h(-1) in the locations of Ngombas and Bikoue, respectively. The corresponding annual effective dose rates in air were determined to be 0.267 mSv y(-1) in Ngombas and 0.307 mSv y(-1) in Bikoue. The level of radioactivity in the studied area is relatively high. PMID- 20159925 TI - Development of a multi-spectral, multi-geometry computational model for X-ray breast imaging. AB - The introduction of novel applications in X-ray breast imaging warrants new research for image acquisition optimisation. A simulation model was developed to investigate the influence of different imaging techniques and acquisition parameters. It was modelled in Monte Carlo N-Particle Extended and contains an X ray tube with photon production, a breast model and antiscatter grid model. This paper describes the simulation model, compares the results with experimental and literature data and presents the influence of breast and antiscatter grid parameters on scatter radiation. PMID- 20159926 TI - Patterns of thyroid radioiodine uptake: Jordanian experience. AB - This study aimed to determine the reference range of 24-h radioiodine uptake in euthyroid Jordanians, as well as the reference ranges for patients with diffuse and nodular hyperthyroidism. In addition, radioiodine uptake ranges were determined for those patients with Hashimoto's thyroiditis and early-phase subacute thyroiditis. METHODS: The medical records of 285 Jordanian patients referred for (131)I thyroid scintiscans and 24-h radioiodine uptake tests were reviewed. The patients were referred because of a presumed-certain thyroid disorder. The patients included those who were euthyroid or who had Graves' disease, toxic nodules, Hashimoto's thyroiditis, or subacute thyroiditis. Mean radioiodine uptake and the 95% confidence interval were determined in each group. A comparison was made between groups. RESULTS: Mean uptake (+/-SD) for the euthyroid group, toxic-nodule group, and Hashimoto's thyroiditis group was 15% +/ 7%, 19% +/- 9%, and 19% +/- 15%, respectively, and these values were not significantly different from each other (P > 0.05). Mean uptake for the subacute thyroiditis group and Graves' disease group was 3% +/- 4% and 40% +/- 14%, respectively, and both values were significantly different from other groups (P < 0.05). CONCLUSION: The reference range of radioiodine uptake in Jordan is comparable to that reported in North America and Europe because Jordanians likely have a sufficient daily intake of stable iodine. Radioiodine uptake discriminates between euthyroid patients, subacute thyroiditis patients, and Graves' disease patients. Radioiodine uptake in toxic-nodule patients is diagnostic only if combined with image findings. Mean radioiodine uptake in Hashimoto's thyroiditis is higher than the euthyroid mean but has a wide range. PMID- 20159927 TI - Evaluation of zeta-potential and particle size of technetium 99mTc-sulfur colloid subsequent to the addition of lidocaine and sodium bicarbonate. AB - The use of (99m)Tc-sulfur colloid lymphoscintigraphy for the determination of lymph flow patterns from a tumor site and localization of the sentinel node has been widely adopted. However, the effects of multiple injections of the radiopharmaceutical can range from mild discomfort to pain. pH-adjusted lidocaine HCl coadministered with (99m)Tc-sulfur colloid presents a risk of introducing instability of the radiopharmaceutical, which could lead to aggregation, possibly impeding the kinetics of lymphatic drainage from the tumor site. METHODS: In the present study, lidocaine pH-adjusted with 4.2%, 6.3%, or 8.4% sodium bicarbonate was added to the (99m)Tc-sulfur colloid radiopharmaceutical to monitor effects on radiochemical purity, zeta-potential, particle size, and pH. These parameters were then used to evaluate the short-term stability of the preparation. RESULTS: The study revealed that the formulation of lidocaine pH-adjusted with 8.4% sodium bicarbonate added to (99m)Tc-sulfur colloid demonstrated a similar change in zeta potential (-4.09 +/- 2.90 mV) and particle size (10-330 nm) to that of control filtered (99m)Tc-sulfur colloid (-5.09 +/- 1.68 mV and 11-343 nm, respectively). However, the 4.2% preparation showed a zeta-potential of -3.01 +/- 2.24 mV and a particle size range of 10-351 nm. The pH of the 8.4% buffered preparation, at 7.1, was closer to physiologic pH than was the control, at 6.0. The 6.3% pH adjusted lidocaine-(99m)Tc-sulfur colloid preparation failed radiochemical purity; thus, it was not included in the analysis. CONCLUSION: Compared with other (99m)Tc-sulfur colloid test formulations of 4.2% and 6.3% pH-adjusted lidocaine, the 8.4% sodium bicarbonate pH-adjusted lidocaine-(99m)Tc-sulfur colloid preparation, taken as a whole, yielded superior quality-control parameters. This formulation would be an acceptable alternative to the control. PMID- 20159928 TI - A protocol for imaging axillary lymph nodes in patients undergoing breast specific gamma-imaging. AB - The development of small-field-of-view, breast-optimized, gamma-camera designed for breast scintigraphy has resulted in improved breast lesion detection particularly for lesions smaller than 1 cm. However, unlike with the standard gamma-camera, these images do not include the axilla within the field of view. METHODS: Because of the effectiveness of breast scintigraphy using (99m)Tc sestamibi in the detection of axillary lymph node metastases, this article describes the development of an axillary imaging protocol for these small-field of-view systems. RESULTS: In addition, it describes how the improved resolution of these systems affects imaging of the axilla and reports observed, normal variants. CONCLUSION: Last, several example patient cases are discussed, describing both the impact and the limitations of this imaging protocol. PMID- 20159929 TI - Comparison between the values of the hepatic uptake rate obtained by 2 methods, using hepatobiliary scintigraphy in patients with nonalcoholic steatohepatitis. AB - (99m)Tc-mebrofenin hepatobiliary scintigraphy has been introduced for the noninvasive assessment of liver function in the clinical setting and in experimental research. METHODS: During a period of 2 y, 15 patients with fatty livers diagnosed as having nonalcoholic steatohepatitis underwent hepatobiliary scintigraphy using the radiopharmaceutical agent (99m)Tc-labeled mebrofenin. After intravenous administration of 85 MBq of (99m)Tc-mebrofenin, a dynamic image was acquired with the liver and heart in the field of view. In this study, a comparison between the values of hepatic uptake rate obtained by applying 2 methods in patients with nonalcoholic steatohepatitis-multiple-time graphical analysis (Gjedde-Patlak plot) and the differentiation between different regions of interest using hepatobiliary scintigraphy-was made. RESULTS: The values of the uptake rate reveal that uptake obtained by applying the second method are significantly higher than that obtained by applying the first one (P = 0.001). A strong positive association (n = 15; r = 0.92; R(2) = 0.84) was found between these measurements. From a Bland-Altman statistical test that was performed on the results we also found that 87% of the cases (13/15) were within 1.96 SD. CONCLUSION: The Gjedde-Patlak analysis method can be considered as an alternative technique to find and calculate the hepatic uptake rate. PMID- 20159930 TI - Myocardial perfusion imaging with 201Tl. AB - The object of this review is to provide information about (201)Tl-thallous chloride in radionuclide myocardial perfusion imaging. This technique has experienced a recent resurgence because of the shortage of (99m)Tc. After reading this article, the technologist will be able to describe the properties and uptake mechanism of (201)Tl, the procedure for myocardial perfusion imaging with this agent, and the advantages and disadvantages of thallium, compared with the technetium agents. PMID- 20159931 TI - Three-dimensional ordered-subset expectation maximization iterative protocol for evaluation of left ventricular volumes and function by quantitative gated SPECT: a dynamic phantom study. AB - The purposes of this study were to characterize the performance of a 3 dimensional (3D) ordered-subset expectation maximization (OSEM) algorithm in the quantification of left ventricular (LV) function with (99m)Tc-labeled agent gated SPECT (G-SPECT), the QGS program, and a beating-heart phantom and to optimize the reconstruction parameters for clinical applications. METHODS: A G-SPECT image of a dynamic heart phantom simulating the beating left ventricle was acquired. The exact volumes of the phantom were known and were as follows: end-diastolic volume (EDV) of 112 mL, end-systolic volume (ESV) of 37 mL, and stroke volume (SV) of 75 mL; these volumes produced an LV ejection fraction (LVEF) of 67%. Tomographic reconstructions were obtained after 10-20 iterations (I) with 4, 8, and 16 subsets (S) at full width at half maximum (FWHM) gaussian postprocessing filter cutoff values of 8-15 mm. The QGS program was used for quantitative measurements. RESULTS: Measured values ranged from 72 to 92 mL for EDV, from 18 to 32 mL for ESV, and from 54 to 63 mL for SV, and the calculated LVEF ranged from 65% to 76%. Overall, the combination of 10 I, 8 S, and a cutoff filter value of 10 mm produced the most accurate results. The plot of the measures with respect to the expectation maximization-equivalent iterations (I x S product) revealed a bell shaped curve for the LV volumes and a reverse distribution for the LVEF, with the best results in the intermediate range. In particular, FWHM cutoff values exceeding 10 mm affected the estimation of the LV volumes. CONCLUSION: The QGS program is able to correctly calculate the LVEF when used in association with an optimized 3D OSEM algorithm (8 S, 10 I, and FWHM of 10 mm) but underestimates the LV volumes. However, various combinations of technical parameters, including a limited range of I and S (80-160 expectation maximization-equivalent iterations) and low cutoff values (< or =10 mm) for the gaussian postprocessing filter, produced results with similar accuracies and without clinically relevant differences in the LV volumes and the estimated LVEF. PMID- 20159932 TI - A 3-dimensional mathematic cylinder phantom for the evaluation of the fundamental performance of SPECT. AB - Degradation of SPECT images results from various physical factors. The primary aim of this study was the development of a digital phantom for use in the characterization of factors that contribute to image degradation in clinical SPECT studies. METHODS: A 3-dimensional mathematic cylinder (3D-MAC) phantom was devised and developed. The phantom (200 mm in diameter and 200 mm long) comprised 3 imbedded stacks of five 30-mm-long cylinders (diameters, 4, 10, 20, 40, and 60 mm). In simulations, the 3 stacks and the background were assigned radioisotope concentrations and attenuation coefficients. SPECT projection datasets that included Compton scattering effects, photoelectric effects, and gamma-camera models were generated using the electron gamma-shower Monte Carlo simulation program. Collimator parameters, detector resolution, total photons acquired, number of projections acquired, and radius of rotation were varied in simulations. The projection data were formatted in Digital Imaging and Communications in Medicine (DICOM) and imported to and reconstructed using commercial reconstruction software on clinical SPECT workstations. RESULTS: Using the 3D-MAC phantom, we validated that contrast depended on size of region of interest (ROI) and was overestimated when the ROI was small. The low-energy general-purpose collimator caused a greater partial-volume effect than did the low-energy high-resolution collimator, and contrast in the cold region was higher using the filtered backprojection algorithm than using the ordered-subset expectation maximization algorithm in the SPECT images. We used imported DICOM projection data and reconstructed these data using vendor software; in addition, we validated reconstructed images. CONCLUSION: The devised and developed 3D-MAC SPECT phantom is useful for the characterization of various physical factors, contrasts, partial-volume effects, reconstruction algorithms, and such, that contribute to image degradation in clinical SPECT studies. PMID- 20159933 TI - Prevention of brown adipose tissue activation in 18F-FDG PET/CT of breast cancer patients receiving neoadjuvant systemic therapy. AB - (18)F-FDG uptake in brown adipose tissue (BAT) can complicate interpretation and quantification of PET images, especially in regions of possible lymph node metastases such as the axilla and the mediastinum. The aim of this study was to prospectively evaluate the effect of patient preparation using a single oral dose of diazepam and controlled indoor temperature to prevent (18)F-FDG uptake in BAT in breast cancer patients referred for monitoring of therapy response with (18)F FDG PET. METHODS: During the fall and winter months, 53 patients referred for (18)F-FDG PET/CT of breast cancer were included. A cohort of 25 patients was imaged without an intervention, and a second cohort of 28 patients was prepared according to a new protocol that included 10 mg of diazepam and adequate indoor temperature. The generated images were visually assessed for the presence of (18)F-FDG at the location of fat-density tissue on CT images using a 4-point scale. RESULTS: In the cohort without intervention, relevant (18)F-FDG uptake in BAT was identified in 4 patients (16%); in the cohort prepared according to the proposed protocol, in only 1 patient (4%). The mean score of BAT (18)F-FDG uptake evaluated with the 4-point system was 0.04 in the group treated according to the new protocol and 0.16 in the group treated according to the previous protocol. CONCLUSION: In the clinically relevant group of breast cancer patients, (18)F-FDG uptake in BAT can be reduced by a single oral administration of diazepam combined with controlled room temperature in resting rooms. PMID- 20159934 TI - A qualitative study on the needs of caregivers of inpatients with schizophrenia in India. AB - AIM: To explore the needs of caregivers of inpatients with schizophrenia in India. MATERIAL: Thirty caregivers of inpatients with schizophrenia participated in five focus group discussions (FGD), where the needs of the caregivers were discussed. The FGDs were recorded, transcribed and similar needs were grouped and ranked according to their order of importance. DISCUSSION: The main needs that emerged were regarding: managing the behaviour of patients; managing social vocational problems of patients; health issues of caregivers; education about schizophrenia; rehabilitation; and managing sexual and marital problems of patients. CONCLUSION: This study has identified additional needs of caregivers from those found in other studies. PMID- 20159935 TI - The culture and identity schedule a measure of cultural affiliation: acculturation, marginalization and schizophrenia. AB - BACKGROUND: Previous epidemiological studies have shown a high incidence of schizophrenia in African-Caribbeans in the UK, but not in Asians. AIMS: We investigated the hypothesis that cultural adherence might protect the Asians against the stress of living in a majority white culture. METHODS: The Culture and Identity Schedule (CANDID) was given to patients with a diagnosis of schizophrenia making their first contact with psychiatric services, and to a matched group of controls randomly selected from the general population. RESULTS: While the Asian patients displayed no drift away from the traditional values as espoused by their controls, the African-Caribbean patients were less traditional than their controls. CONCLUSIONS: The fact that a movement away from their traditional culture distinguishes African-Caribbean patients with a severe psychiatric illness, schizophrenia, from their mentally healthy controls strongly favours marginalization over biculturalism as an interpretation of this shift. PMID- 20159936 TI - Simple surface sulfonation retards plasticiser migration and impacts upon blood/material contact activation processes. AB - BACKGROUND: The use of Di-2-ethylhexyl phthalate (DEHP) plasticised polyvinyl chloride (DEHPPPVC) in medical devices persists despite evidence suggesting that DEHP migration can be harmful. Researchers have shown that a simple surface sulfonation process can retard the migration of DEHP, which may reduce the associated inflammatory response. The present study is designed to investigate the effects of surface sulfonation on DEHP migration and blood contact activation using in vitro and rodent models. METHODS: The study was carried out in two phases: phase 1, in which the migration rate of DEHP from DEHPPPVC and sulfonated DEHP plasticised PVC (SDEHPPPVC) was measured; phase 2 of the study, in which the materials were incorporated into a rat recirculation biomaterial test model and blood samples taken to assess CD11b expression on neutrophils, IL-6 and Factor XIIa. RESULTS: The initial DEHP concentration washed from the surface after storage was 37.19 +/- 1.17 mg/l in the PPVC group and 5.89 +/- 0.81 mg/l in the SPPVC group (p<0.0001). The post-wash migration rate was 3.07 +/- 0.32 mg/l/hour in the PPVC group compared to 0.46 +/- 0.038 mg/l/hour in the SPPVC group (p<0.0001). In phase 2 of the study, CD11b expression increased by 228.9% +/- 37% over the test period in the PPVC group compared to 118.3% +/- 46% in the SPPVC group (p<0.01). IL-6 levels rose from 3.1 +/- 1.4 pg/ml to 263 +/- 26 pg/ml in the PPVC group and 2.2 +/- 1.6 pg/ml to 161 +/- 29 pg/ml in the SPPVC group (p<0.01). Factor XIIa levels rose from 0.22 +/- 0.13 g/ml to 3.7 +/- 0.32 microg/ml and 0.28 +/- 0.09 to 2.71 +/- 0.21 microg/ml in the PPVC and SPPVC groups, respectively (p<0.05 at 90 minutes). CONCLUSIONS: The simple sulfonation process significantly retards the migration of DEHP and is associated with the moderation of contact activation processes. PMID- 20159937 TI - Simulation in perfusion: where do we go from here? AB - Simulation is a common training modality used in aviation, the nuclear industry and by many medical specialties. The adoption of simulation by introductory perfusion education for beginning students and continuing medical education by cardiovascular perfusion has not kept pace with other fields and this paper explores issues connected with simulation in other professions, including training as it currently exists, access to simulator technology, and what could be achieved by utilizing simulator technology. PMID- 20159938 TI - Genes unlinked to the leptin receptor influence urinary albumin excretion in obese Zucker rats. AB - We have previously shown that 90% of outbred obese Zucker Lepr(fa/fa) rats die prematurely of renal disease. Thus, renal disease in obese Zucker Lepr(fa/fa) rats may be caused by the LEPR mutation on chromosome 5, by the obesity, or it may be influenced by Zucker susceptibility alleles of genes on other chromosomes. We have searched for susceptibility genes on other chromosomes using urinary albumin excretion (UAE) as an early indicator of altered renal function in a backcross of (Brown Norway * inbred Zucker) F1 * inbred Zucker, which we name the BZZ cross. We killed 237 BZZ backcross animals at 15 wk of age. All included animals were homozygous for the fatty mutation of LEPR and were obese. Urinary creatinine measurements were used to calculate the albumin-to-creatinine ratio (ACR). We identified direct effect quantitative trait loci (QTLs) for UAE and ACR on chromosome 1 (LOD scores = 3.6 and 2.86, respectively) in males, and chromosome 4 (LOD score = 2.9) in females. Significant QTLs were identified for left kidney weight for females on chromosomes 3 and 12. We also demonstrated that kidneys from 15 wk old obese inbred Zucker rats already show evidence of kidney pathology: tubular dilation, proteinaceous fluid accumulation, evidence for inflammation, and mild mesangial and tubular membrane basement membrane thickening. Both lean Zucker rats and the Brown Norway rats showed no evidence for these changes. Thus, by removing the influence of the Lepr(fa/fa) mutation from analysis we have identified UAE QTLs unlinked to LEPR. PMID- 20159939 TI - The synthetic cannabinoid WIN 55,212-2 sensitizes hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating p8/CCAAT/enhancer binding protein homologous protein (CHOP)/death receptor 5 (DR5) axis. AB - In this article, we demonstrate that the synthetic cannabinoid R-(+)-(2,3-dihydro 5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)-(1 naphthalenyl) methanone mesylate (WIN 55,212-2) sensitizes human hepatocellular carcinoma (HCC) cells to apoptosis mediated by tumor necrosis-related apoptosis inducing ligand (TRAIL). The apoptotic mechanism induced by treatment with WIN/TRAIL combination involved the loss of the mitochondrial transmembrane potential and led to the activation of caspases. In HCC cells, WIN treatment induced the up-regulation of TRAIL death receptor DR5, an effect that seemed to be related to the increase in the level of p8 and CHOP, two factors implicated in cellular stress response and apoptosis. This relationship was suggested by the observation that the down-regulation of p8 or CHOP by specific small interfering RNAs attenuated both WIN-mediated DR5 up-regulation and the cytotoxicity induced by WIN/TRAIL cotreatment. Moreover, WIN induced a significant decrease in the levels of some survival factors (survivin, c-inhibitor of apoptosis protein 2, and Bcl-2) and in particular in that of the active phosphorylated form of AKT. This event seemed to be dependent on the transcription factor peroxisome proliferator-activated receptor-gamma whose level significantly increased after WIN treatment. Therefore, both the induction of DR5 via p8 and CHOP and the down regulation of survival factors seem to be crucial for the marked synergistic effects induced by the two drugs in HCC cells. Taken together, the results reported in this article indicate that WIN/TRAIL combination could represent a novel important tool for the treatment of HCC. PMID- 20159940 TI - Copper transporters and the cellular pharmacology of the platinum-containing cancer drugs. AB - Multiple lines of evidence indicate that the platinum-containing cancer drugs enter cells, are distributed to various subcellular compartments, and are exported from cells via transporters that evolved to manage copper homeostasis. The cytotoxicity of the platinum drugs is directly related to how much drug enters the cell, and almost all cells that have acquired resistance to the platinum drugs exhibit reduced drug accumulation. The major copper influx transporter, copper transporter 1 (CTR1), has now been shown to control the tumor cell accumulation and cytotoxic effect of cisplatin, carboplatin, and oxaliplatin. There is a good correlation between change in CTR1 expression and acquired cisplatin resistance among ovarian cancer cell lines, and genetic knockout of CTR1 renders cells resistant to cisplatin in vivo. The expression of CTR1 is regulated at the transcriptional level by copper via Sp1 and at the post translational level by the proteosome. Copper and cisplatin both trigger the down regulation of CTR1 via a process that involves ubiquitination and proteosomal degradation and requires the copper chaperone antioxidant protein 1 (ATOX1). The cisplatin-induced degradation of CTR1 can be blocked with the proteosome inhibitor bortezomib, and this increases the cellular uptake and the cytotoxicity of cisplatin in a synergistic manner. Copper and platinum(II) have similar sulfur binding characteristics, and the presence of stacked rings of methionines and cysteines in the CTR1 trimer suggest a mechanism by which CTR1 selectively transports copper and the platinum-containing drugs via sequential transchelation reactions similar to the manner in which copper is passed from ATOX1 to the copper efflux transporters. PMID- 20159941 TI - Functional characterization of vasopressin type 2 receptor substitutions (R137H/C/L) leading to nephrogenic diabetes insipidus and nephrogenic syndrome of inappropriate antidiuresis: implications for treatments. AB - Substitution of arginine-137 of the vasopressin type 2 receptor (V2R) for histidine (R137H-V2R) leads to nephrogenic diabetes insipidus (NDI), whereas substitution of the same residue to cysteine or leucine (R137C/L-V2R) causes the nephrogenic syndrome of inappropriate antidiuresis (NSIAD). These two diseases have opposite clinical outcomes. Still, the three mutant receptors were shown to share constitutive beta-arrestin recruitment and endocytosis, resistance to vasopressin-stimulated cAMP production and mitogen-activated protein kinase activation, and compromised cell surface targeting, raising questions about the contribution of these phenomenons to the diseases and their potential treatments. Blocking endocytosis exacerbated the elevated basal cAMP levels promoted by R137C/L-V2R but not the cAMP production elicited by R137H-V2R, demonstrating that substitution of Arg137 to Cys/Leu, but not His, leads to constitutive V2R stimulated cAMP accumulation that most likely underlies NSIAD. The constitutively elevated endocytosis of R137C/L-V2R attenuates the signaling and most likely reduces the severity of NSIAD, whereas the elevated endocytosis of R137H-V2R probably contributes to NDI. The constitutive signaling of R137C/L-V2R was not inhibited by treatment with the V2R inverse agonist satavaptan (SR121463). In contrast, owing to its pharmacological chaperone property, SR121463 increased the R137C/L-V2R maturation and cell surface targeting, leading to a further increase in basal cAMP production, thus disqualifying it as a potential treatment for patients with R137C/L-V2R-induced NSIAD. However, vasopressin was found to promote beta-arrestin/AP-2-dependent internalization of R137H/C/L-V2R beyond their already elevated endocytosis levels, raising the possibility that vasopressin could have a therapeutic value for patients with R137C/L-V2R-induced NSIAD by reducing steady-state surface receptor levels, thus lowering basal cAMP production. PMID- 20159942 TI - Inhibitor of kappaB kinase beta regulates redox homeostasis by controlling the constitutive levels of glutathione. AB - Cytokine-activated inhibitor of kappaB kinase beta (IKKbeta) is a key mediator of immune and inflammatory responses, but recent studies suggest that IKKbeta is also required for tissue homeostasis in physiopathological processes. Here we report a novel role for IKKbeta in maintenance of constitutive levels of the redox scavenger GSH. Inactivation of IKKbeta by genetic or pharmacological means results in low cellular GSH content and marked reduction of redox potential. Similar to Ikkbeta(-/-) cells, Tnfr1(-/-) and p65(-/-) cells are also GSH deficient. As a consequence, cells deficient in IKKbeta signaling are extremely susceptible to toxicity caused by environmental and pharmacological agents, including oxidants, genotoxic agents, microtubule toxins, and arsenic. GSH biosynthesis depends on the activity of the rate-limiting enzyme glutamate cysteine ligase (GCL), consisting of a catalytic subunit (GCLC) and a modifier subunit (GCLM). We found that loss of IKKbeta signaling significantly reduces basal NF-kappaB activity and decreases binding of NF-kappaB to the promoters of Gclc and Gclm, leading to reduction of GCLC and GCLM expression. Conversely, overexpression of GCLC and GCLM in IKKbeta-null cells partially restores GSH content and prevents stress-induced cytotoxicity. We suggest that maintenance of GSH is a novel physiological role of the IKKbeta-NF-kappaB signaling cascade to prevent oxidative damage and preserve the functional integrity of the cells. PMID- 20159943 TI - H2 relaxin is a biased ligand relative to H3 relaxin at the relaxin family peptide receptor 3 (RXFP3). AB - Relaxin family peptide 3 receptors (RXFP3) are activated by H3-relaxin to inhibit forskolin-stimulated cAMP accumulation and stimulate extracellular signal regulated kinase (ERK) 1/2 phosphorylation. In this study, we sought to identify novel signaling pathways coupled to RXFP3 and to investigate whether other members of the relaxin peptide family activated these pathways. Two patterns of signaling were observed in RXFP3-expressing Chinese hamster ovary (CHO)-K1 and human embryonic kidney (HEK)-293 cells (CHO-RXFP3 and HEK-RXFP3) and murine septal neuron SN56 cell lines: 1) strong inhibition of forskolin-stimulated cAMP accumulation, ERK1/2 activation and nuclear factor (NF)-kappaB reporter gene activation in cells stimulated with H3 relaxin, with weaker activity observed for H2 relaxin, porcine relaxin, or insulin-like peptide (INSL) 3 and 2) strong stimulation of activator protein (AP)-1 reporter genes by H2 relaxin, with weaker activation observed with H3 or porcine relaxin. Two distinct ligand binding sites were identified on RXFP3-expressing cells using two different radioligands. (125)I-INSL5 A-chain/relaxin-3 B-chain chimera bound with high affinity to the RXFP3-expressing cells with competition by H3 relaxin or a H3 relaxin B-chain dimeric peptide, consistent with previous reports. Binding studies with (125)I-H2 relaxin revealed a distinct binding site with potent competition observed with H2 relaxin, H3 relaxin, or INSL3 and weaker competition with porcine relaxin. Thus H3 relaxin potently activates all signaling pathways coupled to RXFP3, whereas H2 relaxin is an AP-1-biased ligand relative to H3 relaxin. PMID- 20159945 TI - Long-Term duloxetine treatment normalizes altered brain-derived neurotrophic factor expression in serotonin transporter knockout rats through the modulation of specific neurotrophin isoforms. AB - Dysfunction of the serotonergic system is implicated in the etiology of many psychiatric disorders, including major depression. Major vulnerability genes for mood disorders are also related to the serotonergic system: one of these genes encodes for the serotonin transporter (SERT), which represent a major target for the action of antidepressant drugs. We have demonstrated recently that SERT knockout (KO) rats, generated by N-ethyl-N-nitrosourea-induced mutagenesis, show reduced expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex, suggesting that depression vulnerability can be associated with impaired neuronal plasticity. In the present study, we demonstrate that chronic treatment with the antidepressant duloxetine (DLX) was able to normalize the expression of BDNF mRNA-coding exon (IX) in the hippocampus and prefrontal cortex of SERT KO rats through the modulation of selected neurotrophin transcripts, whose expression was up-regulated by DLX only in SERT KO rats. On the other hand, the modulation of BDNF protein by DLX in frontal cortex was abolished in mutant rats. These data suggest that animals with a genetic defect of the serotonin transporter maintain the ability to show neuroplastic changes in response to antidepressant drugs. Because these animals show depression-like behavior, the region and isoform-specific increase of BDNF levels may be a mechanism activated by long-term antidepressant treatment to restore normal plasticity that is defective under genetic dysfunction of the serotonin transporter. PMID- 20159944 TI - Arsenic trioxide-dependent activation of thousand-and-one amino acid kinase 2 and transforming growth factor-beta-activated kinase 1. AB - Arsenic trioxide (As(2)O(3)) has potent antileukemic properties in vitro and in vivo, but the mechanisms by which it generates its effects on target leukemic cells are not well understood. Understanding cellular mechanisms and pathways that are activated in leukemic cells to control the generation of As(2)O(3) responses should have important implications in the development of novel approaches using As(2)O(3) for the treatment of leukemias. In this study, we used immunoblotting and immune complex kinase assays to provide evidence that the kinases thousand-and-one amino acid kinase 2 (TAO2) and transforming growth factor-beta-activated kinase 1 (TAK1) are rapidly activated in response to treatment of acute leukemia cells with As(2)O(3). Such activation occurs after the generation of reactive oxygen species and regulates downstream engagement of the p38 mitogen-activated protein kinase. Our studies demonstrate that siRNA mediated knockdown of TAO2 or TAK1 or pharmacological inhibition of TAK1 enhances the suppressive effects of As(2)O(3) on KT-1-derived leukemic progenitor colony formation and on primary leukemic progenitors from patients with acute myelogenous leukemia. These results indicate key negative-feedback regulatory roles for these kinases in the generation of the antileukemic effects of As(2)O(3). Thus, molecular or pharmacological targeting of these kinases may provide a novel approach to enhance the generation of arsenic-dependent antileukemic responses. PMID- 20159946 TI - Identification of stage-specific gene modulation during early thymocyte development by whole-genome profiling analysis after aryl hydrocarbon receptor activation. AB - The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix transcription factor, implicated as an important modulator of the immune system and of early thymocyte development. We have shown previously that AHR activation by the environmental contaminant and potent AHR agonist 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD) leads to a significant decline in the percentage of S-phase cells in the CD3(-)CD4(-)CD8(-) triple-negative stage (TN) 3 and TN4 T-cell committed thymocytes 9 to 12 h after exposure. In the more immature TN1- or TN2-stage cells, no effect on cell cycle was observed. To identify early molecular targets, which could provide insight into how the AHR acts as a modulator of thymocyte development and cell cycle regulation, we performed gene-profiling experiments using RNA isolated from four intrathymic progenitor populations in which the AHR was activated for 6 or 12 h. This microarray analysis of AHR activation identified 108 distinct gene probes that were significantly modulated in the TN1 4 thymocyte progenitor stages. Although most of the genes identified have specific AHR recognition sequences, only seven genes were altered exclusively in the two T-cell committed stages of early thymocyte development (TN3 and TN4) in which the decline of S-phase cells is seen. Moreover, all seven of these genes were reduced in expression, and five of the seven are associated with cell cycle regulatory processes. These seven genes are novel targets for modulation by the TCDD-activated AHR and may be involved in the observed cell-cycle arrest and suppression of early thymocyte development. PMID- 20159947 TI - Increased insertion of glutamate receptor 2-lacking alpha-amino-3-hydroxy-5 methyl-4-isoxazole propionic acid (AMPA) receptors at hippocampal synapses upon repeated morphine administration. AB - Evidence suggests that the long-term adaptations in the hippocampus after repeated drug treatment may parallel its role during memory formation. The neuroplasticity that subserves learning and memory is also believed to underlie addictive processes. We have reported previously that repeated morphine administration alters local distribution of endocytic proteins at hippocampal synapses, which could in turn affect expression of glutamate receptors. Glutamatergic systems, including alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), are believed to be involved in opiate-induced neuronal and behavioral plasticity, although the mechanisms underlying these effects are only beginning to be understood. The present study further examines the effects of repeated morphine administration on the expression and composition of AMPARs and the functional ramifications. Twelve hours after the last morphine injection, we observed an increased expression of AMPARs lacking glutamate receptor (GluR) 2 in hippocampal synaptic fractions. Immunoblotting studies show that 12 h after morphine treatment, GluR1 subunits are increased at the postsynaptic density (PSD) and at extrasynaptic sites, whereas GluR3 subunits are only increased at the PSD, and they show how this alters receptor subunit composition. In addition, we provide electrophysiological evidence that AMPARs are switched to Ca(2+)-permeable (GluR2-lacking) at the synapse 12 h after repeated morphine treatment, affecting the magnitude of long-term depression at hippocampal neurons. We propose that morphine-induced changes in glutamatergic synaptic transmission in the hippocampus may play an important role in the neuroadaptations induced by repeated morphine administration. PMID- 20159948 TI - Effects of corticotropin-releasing factor receptor-1 antagonists on the brain stress system responses to morphine withdrawal. AB - The role of stress in drug addiction is well established. The negative affective states of withdrawal most probably involve recruitment of brain stress neurocircuitry [e.g., induction of hypothalamo-pituitary-adrenocortical (HPA) axis, noradrenergic activity, and corticotropin-releasing factor (CRF) activity]. The present study investigated t$he role of CRF receptor-1 subtype (CRF1R) on the response of brain stress system to morphine withdrawal. The effects of naloxone precipitated morphine withdrawal on noradrenaline (NA) turnover in the paraventricular nucleus (PVN), HPA axis activity, signs of withdrawal, and c-Fos expression were measured in rats pretreated with vehicle, CP-154526 [N-butyl-N ethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine], or antalarmin (selective CRF1R antagonists). Tyrosine hydroxylase-positive neurons expressing CRF1R were seen at the level of the nucleus tractus solitarius-A(2) cell group in both control and morphine-withdrawn rats. CP-154526 and antalarmin attenuated the increases in body weight loss and irritability that were seen during naloxone-induced morphine withdrawal. Pretreatment with CRF1R antagonists resulted in no significant modification of the increased NA turnover at PVN, plasma corticosterone levels, or c-Fos expression that was seen during naloxone induced morphine withdrawal. However, blockade of CRF1R significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropin levels. These results suggest that the CRF1R subtype may be involved in the behavioral and somatic signs and in adrenocorticotropin release (partially) during morphine withdrawal. However, CRF1R activation may not contribute to the functional interaction between NA and CRF systems in mediating morphine withdrawal activation of brain stress neurocircuitry. PMID- 20159949 TI - Modulation of silent and constitutively active nociceptin/orphanin FQ receptors by potent receptor antagonists and Na+ ions in rat sympathetic neurons. AB - The pharmacology of G protein-coupled receptors can be influenced by factors such as constitutive receptor activation and Na(+) ions. In this study, we examined the coupling of natively and heterologously expressed nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors with voltage-dependent Ca(2+) channels after exposure to four high-affinity NOP receptor blockers [[Nphe(1)Arg(14)Lys(15)]N/OFQ-NH(2) (UFP-101), 1-[1-(cyclooctylmethyl)-1,2,3,6 tetrahydro-5-(hydroxymethyl)-4-pyridinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2 one (Trap-101), 1-benzyl-N-{3-[spiroisobenzofuran-1(3H),4'-piperidin-1 yl]propyl}pyrrolidine-2-carboxamide (compound 24), and N-(4-amino-2 methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide hydrochloride (JTC-801)] in sympathetic neurons. The enhanced tonic inhibition of Ca(2+) currents in the absence of agonists, indicative of constitutively active NOP receptors in transfected neurons, was abolished after pretreatment with pertussis toxin. In control neurons, the four antagonists did not exert any effects when applied alone but significantly blocked the N/OFQ-mediated Ca(2+) current inhibition. Exposure of transfected neurons to UFP-101 resulted in partial agonist effects. In contrast, Trap-101, compound 24, and JTC-801 exerted inverse agonism, as measured by the loss of tonic Ca(2+) current inhibition. In experiments designed to measure the N/OFQ concentration-response relationship under varying Na(+) concentrations, a leftward shift of IC(50) values was observed after Na(+) exposure. Although similar N/OFQ efficacies were measured with all solutions, a significant decrease of Hill coefficient values was obtained with increasing Na(+) concentrations. Examination of the allosteric effects of Na(+) on heterologously overexpressed NOP receptors showed that the tonic Ca(2+) current inhibition was abolished in the presence of the monovalent cation. These results demonstrate that constitutively active NOP receptors exhibit differential blocker pharmacology and allosteric regulation by Na(+). Data are also presented demonstrating that heterologously expressed mu opioid receptors in sympathetic neurons are similarly modulated. PMID- 20159950 TI - Ethanol reduces GABAA alpha1 subunit receptor surface expression by a protein kinase Cgamma-dependent mechanism in cultured cerebral cortical neurons. AB - Prolonged ethanol exposure causes central nervous system hyperexcitability that involves a loss of GABAergic inhibition. We previously demonstrated that long term ethanol exposure enhances the internalization of synaptic GABA(A) receptors composed of alpha1beta2/3gamma2 subunits. However, the mechanisms of ethanol mediated internalization are unknown. This study explored the effect of ethanol on surface expression of GABA(A) alpha1 subunit-containing receptors in cultured cerebral cortical neurons and the role of protein kinase C (PKC) beta, gamma, and epsilon isoforms in their trafficking. Cultured neurons were prepared from rat pups on postnatal day 1 and maintained for 18 days. Cells were exposed to ethanol, and surface receptors were isolated by biotinylation and P2 fractionation, whereas functional analysis was conducted by whole-cell patch clamp recording of GABA- and zolpidem-evoked responses. Ethanol exposure for 4 h decreased biotinylated surface expression of GABA(A) receptor alpha1 subunits and reduced zolpidem (100 nM) enhancement of GABA-evoked currents. The PKC activator phorbol-12,13-dibutyrate mimicked the effect of ethanol, and the selective PKC inhibitor calphostin C prevented ethanol-induced internalization of these receptors. Ethanol exposure for 4 h also increased the colocalization and coimmunoprecipitation of PKCgamma with alpha1 subunits, whereas PKCbeta/alpha1 association and PKCepsilon/alpha1 colocalization were not altered by ethanol exposure. Selective PKCgamma inhibition by transfection of selective PKCgamma small interfering RNAs blocked ethanol-induced internalization of GABA(A) receptor alpha1 subunits, whereas PKCbeta inhibition using pseudo-PKCbeta had no effect. These findings suggest that ethanol exposure selectively alters PKCgamma translocation to GABA(A) receptors and PKCgamma regulates GABA(A) alpha1 receptor trafficking after ethanol exposure. PMID- 20159951 TI - Pro-oxidative activities and dose-response relationship of (-)-epigallocatechin-3 gallate in the inhibition of lung cancer cell growth: a comparative study in vivo and in vitro. AB - (-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, has been shown to inhibit tumorigenesis and cancer cell growth in animal models. Nevertheless, the dose-response relationship of the inhibitory activity in vivo has not been systematically characterized. The present studies were conducted to address these issues, as well as the involvement of reactive oxygen species (ROS), in the inhibitory action of EGCG in vivo and in vitro. We characterized the inhibitory actions of EGCG against human lung cancer H1299 cells in culture and in xenograft tumors. The growth of tumors was dose dependently inhibited by EGCG at doses of 0.1, 0.3 and 0.5% in the diet. Tumor cell apoptosis and oxidative DNA damage, assessed by the formation of 8-hydroxy-2'-deoxyguanosine (8 OHdG) and phosphorylated histone 2A variant X (gamma-H2AX), were dose dependently increased by EGCG treatment. However, the levels of 8-OHdG and gamma-H2AX were not changed by the EGCG treatment in host organs. In culture, the growth of viable H1299 cells was dose dependently reduced by EGCG; the estimated concentration that causes 50% inhibition (IC(50)) (20 microM) was much higher than the IC(50) (0.15 microM) observed in vivo. The action of EGCG was mostly abolished by the presence of superoxide dismutase (SOD) and catalase, which decompose the ROS formed in the culture medium. Treatment with EGCG also caused the generation of intracellular ROS and mitochondrial ROS. Although EGCG is generally considered to be an antioxidant, the present study demonstrates the pro oxidative activities of EGCG in vivo and in vitro in the described experimental system. PMID- 20159952 TI - RNA editing of 10 Didymium iridis mitochondrial genes and comparison with the homologous genes in Physarum polycephalum. AB - Regions of the Didymium iridis mitochondrial genome were identified with similarity to typical mitochondrial genes; however, these regions contained numerous stop codons. We used RT-PCR and DNA sequencing to determine whether, through RNA editing, these regions were transcribed into mRNAs that could encode functional proteins. Ten putative gene regions were examined: atp1, atp6, atp8, atp9, cox1, cox2, cytb, nad4L, nad6, and nad7. The cDNA sequences of each gene could encode a functional mitochondrial protein that was highly conserved compared with homologous genes. The type of editing events and editing sequence features were very similar to those observed in the homologous genes of Physarum polycephalum, though the actual editing locations showed a variable degree of conservation. Edited sites were compared with encoded sites in D. iridis and P. polycephalum for all 10 genes. Edited sequence for a portion of the cox1 gene was available for six myxomycetes, which, when compared, showed a high degree of conservation at the protein level. Different types of editing events showed varying degrees of site conservation with C-to-U base changes being the least conserved. Several aspects of single C insertion editing events led to the preferential creation of hydrophobic amino acid codons that may help to minimize adverse effects on the resulting protein structure. PMID- 20159953 TI - Essential role of Tip60-dependent recruitment of ribonucleotide reductase at DNA damage sites in DNA repair during G1 phase. AB - A balanced deoxyribonucleotide (dNTP) supply is essential for DNA repair. Here, we found that ribonucleotide reductase (RNR) subunits RRM1 and RRM2 accumulated very rapidly at damage sites. RRM1 bound physically to Tip60. Chromatin immunoprecipitation analyses of cells with an I-SceI cassette revealed that RRM1 bound to a damage site in a Tip60-dependent manner. Active RRM1 mutants lacking Tip60 binding failed to rescue an impaired DNA repair in RRM1-depleted G1-phase cells. Inhibition of RNR recruitment by an RRM1 C-terminal fragment sensitized cells to DNA damage. We propose that Tip60-dependent recruitment of RNR plays an essential role in dNTP supply for DNA repair. PMID- 20159954 TI - A divalent switch drives H-NS/DNA-binding conformations between stiffening and bridging modes. AB - Heat-stable nucleoid structuring protein (H-NS) is an abundant prokaryotic protein that plays important roles in organizing chromosomal DNA and gene silencing. Two controversial binding modes were identified. H-NS binding stimulating DNA bridging has become the accepted mechanism, whereas H-NS binding causing DNA stiffening has been largely ignored. Here, we report that both modes exist, and that changes in divalent cations drive a switch between them. The stiffening form is present under physiological conditions, and directly responds to pH and temperature in vitro. Our findings have broad implications and require a reinterpretation of the mechanism by which H-NS regulates genes. PMID- 20159955 TI - The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors. AB - Mammalian circadian clocks provide a temporal framework to synchronize biological functions. To obtain robust rhythms with a periodicity of about a day, these clocks use molecular oscillators consisting of two interlocked feedback loops. The core loop generates rhythms by transcriptional repression via the Period (PER) and Cryptochrome (CRY) proteins, whereas the stabilizing loop establishes roughly antiphasic rhythms via nuclear receptors. Nuclear receptors also govern many pathways that affect metabolism and physiology. Here we show that the core loop component PER2 can coordinate circadian output with the circadian oscillator. PER2 interacts with nuclear receptors including PPARalpha and REV ERBalpha and serves as a coregulator of nuclear receptor-mediated transcription. Consequently, PER2 is rhythmically bound at the promoters of nuclear receptor target genes in vivo. In this way, the circadian oscillator can modulate the expression of nuclear receptor target genes like Bmal1, Hnf1alpha, and Glucose-6 phosphatase. The concept that PER2 may propagate clock information to metabolic pathways via nuclear receptors adds an important facet to the clock-dependent regulation of biological networks. PMID- 20159956 TI - Dynamic PER repression mechanisms in the Drosophila circadian clock: from on-DNA to off-DNA. AB - Transcriptional feedback loops are central to the generation and maintenance of circadian rhythms. In animal systems as well as Neurospora, transcriptional repression is believed to occur by catalytic post-translational events. We report here in the Drosophila model two different mechanisms by which the circadian repressor PERIOD (PER) inhibits CLOCK/CYCLE (CLK/CYC)-mediated transcription. First, PER is recruited to circadian promoters, which leads to the nighttime decrease of CLK/CYC activity. This decrease is proportional to PER levels on DNA, and PER recruitment probably occurs via CLK. Then CLK is released from DNA and sequestered in a strong, approximately 1:1 PER-CLK off-DNA complex. The data indicate that the PER levels bound to CLK change dynamically and are important for repression, first on-DNA and then off-DNA. They also suggest that these mechanisms occur upstream of post-translational events, and that elements of this two-step mechanism likely apply to mammals. PMID- 20159957 TI - GPS2-dependent corepressor/SUMO pathways govern anti-inflammatory actions of LRH 1 and LXRbeta in the hepatic acute phase response. AB - The orphan receptor LRH-1 and the oxysterol receptors LXRalpha and LXRbeta are established transcriptional regulators of lipid metabolism that appear to control inflammatory processes. Here, we investigate the anti-inflammatory actions of these nuclear receptors in the hepatic acute phase response (APR). We report that selective synthetic agonists induce SUMOylation-dependent recruitment of either LRH-1 or LXR to hepatic APR promoters and prevent the clearance of the N-CoR corepressor complex upon cytokine stimulation. Investigations of the APR in vivo, using LXR knockout mice, indicate that the anti-inflammatory actions of LXR agonists are triggered selectively by the LXRbeta subtype. We further find that hepatic APR responses in small ubiquitin-like modifier-1 (SUMO-1) knockout mice are increased, which is due in part to diminished LRH-1 action at APR promoters. Finally, we provide evidence that the metabolically important coregulator GPS2 functions as a hitherto unrecognized transrepression mediator of interactions between SUMOylated nuclear receptors and the N-CoR corepressor complex. Our study extends the knowledge of anti-inflammatory mechanisms and pathways directed by metabolic nuclear receptor-corepressor networks to the control of the hepatic APR, and implies alternative pharmacological strategies for the treatment of human metabolic diseases associated with inflammation. PMID- 20159958 TI - A midline switch of receptor processing regulates commissural axon guidance in vertebrates. AB - Commissural axon guidance requires complex modulations of growth cone sensitivity to midline-derived cues, but underlying mechanisms in vertebrates remain largely unknown. By using combinations of ex vivo and in vivo approaches, we uncovered a molecular pathway controlling the gain of response to a midline repellent, Semaphorin3B (Sema3B). First, we provide evidence that Semaphorin3B/Plexin-A1 signaling participates in the guidance of commissural projections at the vertebrate ventral midline. Second, we show that, at the precrossing stage, commissural neurons synthesize the Neuropilin-2 and Plexin-A1 Semaphorin3B receptor subunits, but Plexin-A1 expression is prevented by a calpain1-mediated processing, resulting in silencing commissural responsiveness. Third, we report that, during floor plate (FP) in-growth, calpain1 activity is suppressed by local signals, allowing Plexin-A1 accumulation in the growth cone and sensitization to Sema3B. Finally, we show that the FP cue NrCAM mediates the switch of Plexin-A1 processing underlying growth cone sensitization to Sema3B. This reveals pathway dependent modulation of guidance receptor processing as a novel mechanism for regulating guidance decisions at intermediate targets. PMID- 20159959 TI - A highly coordinated cell wall degradation machine governs spore morphogenesis in Bacillus subtilis. AB - How proteins catalyze morphogenesis is an outstanding question in developmental biology. In bacteria, morphogenesis is intimately linked to remodeling the cell wall exoskeleton. Here, we investigate the mechanisms by which the mother cell engulfs the prospective spore during sporulation in Bacillus subtilis. A membrane anchored protein complex containing two cell wall hydrolases plays a central role in this morphological process. We demonstrate that one of the proteins (SpoIIP) has both amidase and endopeptidase activities, such that it removes the stem peptides from the cell wall and cleaves the cross-links between them. We further show that the other protein (SpoIID) is the founding member of a new family of lytic transglycosylases that degrades the glycan strands of the peptidoglycan into disaccharide units. Importantly, we show that SpoIID binds the cell wall, but will only cleave the glycan strands after the stem peptides have been removed. Finally, we demonstrate that SpoIID also functions as an enhancer of SpoIIP activity. Thus, this membrane-anchored enzyme complex is endowed with complementary, sequential, and stimulatory activities. These activities provide a mechanism for processive cell wall degradation, supporting a model in which circumferentially distributed degradation machines function as motors pulling the mother cell membranes around the forespore. PMID- 20159960 TI - Multistep adhesion of Plasmodium sporozoites. AB - Adhesion of eukaryotic cells is a complex process during which interactions between extracellular ligands and cellular receptors on the plasma membrane modulate the organization of the cytoskeleton. Pathogens particularly rely often on adhesion to tissues or host cells in order to establish an infection. Here, we examined the adhesion of Plasmodium sporozoites, the motile form of the malaria parasite transmitted by the mosquito, to flat surfaces. Experiments using total internal reflection fluorescence microscopy and analysis of sporozoites under flow revealed a stepwise and developmentally regulated adhesion process. The sporozoite-specific transmembrane proteins TRAP and S6 were found to be important for initial adhesion. The structurally related protein TLP appears to play a specific role in adhesion under static conditions, as tlp(-) sporozoites move 4 times less efficiently than wild-type sporozoites. This likely reflects the decreased intradermal sporozoite movement of sporozoites lacking TLP. Further, these three sporozoite surface proteins also act in concert with actin filaments to organize efficient adhesion of the sporozoite prior to initiating motility and host cell invasion. PMID- 20159961 TI - MAPK/Erk-dependent phosphorylation of synapsin mediates formation of functional synapses and short-term homosynaptic plasticity. AB - MAPK/Erk is a protein kinase activated by neurotrophic factors involved in synapse formation and plasticity, which acts at both the nuclear and cytoplasmic level. Synapsin proteins are synaptic-vesicle-associated proteins that are well known to be MAPK/Erk substrates at phylogenetically conserved sites. However, the physiological role of MAPK/Erk-dependent synapsin phosphorylation in regulating synaptic formation and function is poorly understood. Here, we examined whether synapsin acts as a physiological effector of MAPK/Erk in synaptogenesis and plasticity. To this aim, we developed an in vitro model of soma-to-soma paired Helix B2 neurons, that establish bidirectional excitatory synapses. We found that the formation and activity-dependent short-term plasticity of these synapses is dependent on the MAPK/Erk pathway. To address the role of synapsin in this pathway, we generated non-phosphorylatable and pseudo-phosphorylated Helix synapsin mutants at the MAPK/Erk sites. Overexpression experiments revealed that both mutants interfere with presynaptic differentiation, synapsin clustering, and severely impair post-tetanic potentiation, a form of short-term homosynaptic plasticity. Our findings show that MAPK/Erk-dependent synapsin phosphorylation has a dual role both in the establishment of functional synaptic connections and their short-term plasticity, indicating that some of the multiple extranuclear functions of MAPK/Erk in neurons can be mediated by the same multifunctional presynaptic target. PMID- 20159962 TI - Opposing effects of retinoic acid and FGF9 on Nanos2 expression and meiotic entry of mouse germ cells. AB - In the mouse, three genes that are homologous to the Drosophila Nanos (Nos) gene have been identified. Deletion of one of these genes, Nanos2, results in male sterility, owing to loss of germ cells during fetal life. Before apoptosis, Nanos2-null gonocytes enter meiosis, suggesting that Nanos2 functions as a meiotic repressor. Here, we show that Nanos2 is continuously expressed in male germ cells from fetal gonocytes to postnatal spermatogonial stem cells. We observed that the promeiotic factor AtRA, an analog of retinoic acid (RA), downregulates NANOS2 levels, in both fetal and postnatal gonocytes, while promoting meiosis. Interestingly, FGF9, a growth factor crucial for sex differentiation and survival of fetal gonocytes, upregulates levels of NANOS2 in both male and female primordial germ cells (PGCs) and in premeiotic spermatogonia. This effect was paralleled by an impairment of meiotic entry, suggesting that FGF9 acts as an inhibitor of meiosis through the upregulation of Nanos2. We found that NANOS2 interacts with PUM2, and that these two proteins colocalize in the ribonucleoparticle and polysomal fractions on sucrose gradients, supporting the notion that they bind RNA. Finally, we found that recombinant NANOS2 binds to two spermatogonial mRNAs, Gata2 and Taf7l, which are involved in germ-cell differentiation. PMID- 20159963 TI - Dual regulation of a Dictyostelium STAT by cGMP and Ca2+ signalling. AB - When cells are exposed to hyperosmotic stress, the Dictyostelium STAT orthologue STATc is rapidly tyrosine phosphorylated. Previous observations suggest a non paradigmatic mode of STAT activation, whereby stress-induced serine phosphorylation of the PTP3 protein tyrosine phosphatase inhibits its activity towards STATc. We show that two serine residues in PTP3, S448 and S747, are rapidly phosphorylated after osmotic stress. cGMP is a second messenger for hyperosmotic stress response and 8-bromo-cGMP, a membrane-permeable form of cGMP, is a known activator of STATc. GbpC, a cGMP-binding Ras guanine nucleotide exchange factor protein, is a founder member of a protein family that includes LRRK2, the gene commonly mutated in familial Parkinson's disease. Genetic ablation of gbpC prevents STATc activation by 8-bromo-cGMP. However, osmotic stress-induced activation of STATc occurs normally in the gbpC null mutant. Moreover, 8-bromo-cGMP does not stimulate phosphorylation of S448 and S747 of PTP3 in a wild-type strain. These facts imply the occurrence of redundant activation pathways. We present evidence that intracellular Ca(2+) is a parallel second messenger, by showing that agents that elevate intracellular Ca(2+) levels are potent STATc activators that stimulate phosphorylation of S448 and S747. We propose that stress-induced cGMP signalling exerts its stimulatory effect by potentiating the activity of a semi-constitutive tyrosine kinase that phosphorylates STATc, whereas parallel, stress-induced Ca(2+) signalling represses STATc dephosphorylation through its inhibitory effect on PTP3. PMID- 20159964 TI - An exosome-based secretion pathway is responsible for protein export from Leishmania and communication with macrophages. AB - Specialized secretion systems are used by numerous bacterial pathogens to export virulence factors into host target cells. Leishmania and other eukaryotic intracellular pathogens also deliver effector proteins into host cells; however, the mechanisms involved have remained elusive. In this report, we identify exosome-based secretion as a general mechanism for protein secretion by Leishmania, and show that exosomes are involved in the delivery of proteins into host target cells. Comparative quantitative proteomics unambiguously identified 329 proteins in Leishmania exosomes, accounting for >52% of global protein secretion from these organisms. Our findings demonstrate that infection-like stressors (37 degrees C +/- pH 5.5) upregulated exosome release more than twofold and also modified exosome protein composition. Leishmania exosomes and exosomal proteins were detected in the cytosolic compartment of infected macrophages and incubation of macrophages with exosomes selectively induced secretion of IL-8, but not TNF-alpha. We thus provide evidence for an apparently broad-based mechanism of protein export by Leishmania. Moreover, we describe a mechanism for the direct delivery of Leishmania molecules into macrophages. These findings suggest that, like mammalian exosomes, Leishmania exosomes function in long-range communication and immune modulation. PMID- 20159965 TI - Human dermal stem cells differentiate into functional epidermal melanocytes. AB - Melanocytes sustain a lifelong proliferative potential, but a stem cell reservoir in glabrous skin has not yet been found. Here, we show that multipotent dermal stem cells isolated from human foreskins lacking hair follicles are able to home to the epidermis to differentiate into melanocytes. These dermal stem cells, grown as three-dimensional spheres, displayed a capacity for self-renewal and expressed NGFRp75, nestin and OCT4, but not melanocyte markers. In addition, cells derived from single-cell clones were able to differentiate into multiple lineages including melanocytes. In a three-dimensional skin equivalent model, sphere-forming cells differentiated into HMB45-positive melanocytes, which migrated from the dermis to the epidermis and aligned singly among the basal layer keratinocytes in a similar fashion to pigmented melanocytes isolated from the epidermis. The dermal stem cells were negative for E-cadherin and N-cadherin, whereas they acquired E-cadherin expression and lost NGFRp75 expression upon contact with epidermal keratinocytes. These results demonstrate that stem cells in the dermis of human skin with neural-crest-like characteristics can become mature epidermal melanocytes. This finding could significantly change our understanding of the etiological factors in melanocyte transformation and pigmentation disorders; specifically, that early epigenetic or genetic alterations leading to transformation may take place in the dermis rather than in the epidermis. PMID- 20159966 TI - Sirtuin-3 deacetylation of cyclophilin D induces dissociation of hexokinase II from the mitochondria. AB - We demonstrate that the transition from a reliance on glycolysis to oxidative phosphorylation in a transformed cell line is dependent on an increase in the levels and activity of sirtuin-3. Sirtuin-3 deacetylates cyclophilin D, diminishing its peptidyl-prolyl cis-trans isomerase activity and inducing its dissociation from the adenine nucleotide translocator. Moreover, the sirtuin-3 induced inactivation of cyclophilin D causes a detachment of hexokinase II from the mitochondria that is necessary for stimulation of oxidative phosphorylation. These results might have important implications for the role of sirtuin-3 in the metabolism of some cancer cells and their susceptibility to mitochondrial injury and cytotoxicity. PMID- 20159967 TI - GSK-3beta promotes cell survival by modulating Bif-1-dependent autophagy and cell death. AB - Glycogen synthase kinase 3 beta (GSK-3beta) is constantly active in cells and its activity increases after serum deprivation, indicating that GSK-3beta might play a major role in cell survival under serum starvation. In this study, we attempted to determine how GSK-3beta promotes cell survival after serum depletion. Under full culture conditions (10% FBS), GSK-3beta inhibition with chemical inhibitors or siRNAs failed to induce cell death in human prostate cancer cells. By contrast, under conditions of serum starvation, a profound necrotic cell death was observed as evidenced by cellular morphologic features and biochemical markers. Further analysis revealed that GSK-3beta-inhibition-induced cell death was in parallel with an extensive autophagic response. Interestingly, blocking the autophagic response switched GSK-3beta-inhibition-induced necrosis to apoptotic cell death. Finally, GSK-3beta inhibition resulted in a remarkable elevation of Bif-1 protein levels, and silencing Bif-1 expression abrogated GSK 3beta-inhibition-induced autophagic response and cell death. Taken together, our study suggests that GSK-3beta promotes cell survival by modulating Bif-1 dependent autophagic response and cell death. PMID- 20159968 TI - MccE provides resistance to protein synthesis inhibitor microcin C by acetylating the processed form of the antibiotic. AB - The heptapeptide-nucleotide microcin C (McC) is a potent inhibitor of enteric bacteria growth. McC is excreted from producing cells by the MccC transporter. The residual McC that remains in the producing cell can be processed by cellular aminopeptidases with the release of a non-hydrolyzable aspartyl-adenylate, a strong inhibitor of aspartyl-tRNA synthetase. Accumulation of processed McC inside producing cells should therefore lead to translation inhibition and cessation of growth. Here, we show that a product of another gene of the McC biosynthetic cluster, mccE, acetylates processed McC and converts it into a non toxic compound. MccE also makes Escherichia coli resistant to albomycin, a Trojan horse inhibitor unrelated to McC that, upon processing, gives rise to a serine coupled to a thioxylofuranosyl pyrimidine, an inhibitor of seryl-tRNA synthetase. We speculate that MccE and related cellular acetyltransferases of the Rim family may detoxify various aminoacyl-nucleotides, either exogenous or those generated inside the cell. PMID- 20159969 TI - A novel role for protein inhibitor of activated STAT (PIAS) proteins in modulating the activity of Zimp7, a novel PIAS-like protein, in androgen receptor mediated transcription. AB - The PIAS proteins (protein inhibitor of activated STAT) were originally identified as inhibitors of the JAK-STAT pathway. Subsequently, their roles on transcriptional regulation have been identified in modulation of the androgen receptor (AR) and other nuclear hormone receptor-mediated actions. Zimp7, also named Zmiz2, is a novel PIAS-like protein and functions as a transcriptional co activator. In this study, we demonstrate an interaction between Zimp7 and PIAS proteins with higher preference for PIAS3. A modified mammalian one-hybrid assay showed that the NH(2)-terminal proline-rich domain of Zimp7 and the region spanning amino acids 321-486 of PIAS3 were the primary interaction segments. The interaction between Zimp7 and PIAS3 proteins was further confirmed by in vitro protein pull-down and co-immunoprecipitation assays with both exogenous and endogenous proteins. Expression of exogenous PIAS3 further enhances Zimp7 mediated augmentation of AR transcription. Knockdown of the endogenous PIAS3 protein using a specific PIAS3 small hairpin RNA reduced the augmentation of Zimp7 on AR-mediated transcription. Co-localization of Zimp7 and PIAS3 proteins was observed in the nuclei of cells by immunostaining. Exogenous PIAS3 expression enhances the stability of the Zimp7 protein. Using chromatin immunoprecipitation assays, we showed that PIAS3 is involved in the AR- and Zimp7-formed protein complex(es) in the AR downstream target promoter to facilitate androgen-induced transcription. Finally, we further demonstrated that loss of Zimp7 significantly impaired PIAS3-mediated enhancement on AR activity in mouse Zimp7 null (zimp7(-/ )) embryonic fibroblasts. Taken together, these results demonstrate a novel interaction between PIAS and PIAS-like proteins and elucidate a novel regulatory mechanism for PIAS proteins in AR-mediated transcription. PMID- 20159970 TI - MYST family lysine acetyltransferase facilitates ataxia telangiectasia mutated (ATM) kinase-mediated DNA damage response in Toxoplasma gondii. AB - The MYST family of lysine acetyltransferases (KATs) function in a wide variety of cellular operations, including gene regulation and the DNA damage response. Here we report the characterization of the second MYST family KAT in the protozoan parasite Toxoplasma gondii (TgMYST-B). Toxoplasma causes birth defects and is an opportunistic pathogen in the immunocompromised, the latter due to its ability to convert into a latent cyst (bradyzoite). We demonstrate that TgMYST-B can gain access to the parasite nucleus and acetylate histones. Overexpression of recombinant, tagged TgMYST-B reduces growth rate in vitro and confers protection from a DNA-alkylating agent. Expression of mutant TgMYST-B produced no growth defect and failed to protect against DNA damage. We demonstrate that cells overexpressing TgMYST-B have increased levels of ataxia telangiectasia mutated (ATM) kinase and phosphorylated H2AX and that TgMYST-B localizes to the ATM kinase gene. Pharmacological inhibitors of ATM kinase or KATs reverse the slow growth phenotype seen in parasites overexpressing TgMYST-B. These studies are the first to show that a MYST KAT contributes to ATM kinase gene expression, further illuminating the mechanism of how ATM kinase is up-regulated to respond to DNA damage. PMID- 20159971 TI - Protocadherin of the liver, kidney, and colon associates with detergent-resistant membranes during cellular differentiation. AB - Protocadherin LKC (PLKC) is a member of the heterogeneous subgroup of protocadherins that was identified and described as a potential tumor-suppressor gene involved in contact inhibition (Okazaki, N., Takahashi, N., Kojima, S., Masuho, Y., and Koga, H. (2002) Carcinogenesis 23, 1139-1148 and Ose, R., Yanagawa, T., Ikeda, S., Ohara, O., and Koga, H. (2009) Mol. Oncol. 3, 54-66). Several aspects of the structure, posttranslational processing, targeting, and function of this new protocadherin are still not known. Here, we demonstrate that the expression of PLKC at the apical membrane domain and its concentration at regions of cell-cell contacts occur concomitantly with significant elevation of PLKC-mRNA levels. Furthermore, it can be found within the adherens junctions, but it does not colocalize with tight junctions proteins ZO-1 and occludin, respectively. Additionally, unlike E-cadherin, PLKC is not redistributed upon Ca(2+) removal. Biosynthetic labeling revealed N- and O-glycosylation as posttranslational modifications as well as a fast transport to the cell surface and a low turnover rate. During differentiation, PLKC associates with detergent resistant membranes that trigger its redistribution from intracellular membranes to the cell surface. This association occurs concomitant with alterations in the glycosylation pattern. We propose a role for PLKC in the establishment of a proper epithelial cell polarity that requires O-linked glycosylation and association of the protein with detergent-resistant membranes. PMID- 20159972 TI - Functional significance of FRH in regulating the phosphorylation and stability of Neurospora circadian clock protein FRQ. AB - FREQUENCY (FRQ) is the central component of the Neurospora circadian clock. All FRQ proteins form the FFC complex with FRH (FRQ-interacting RNA helicase) that acts as the negative element in the circadian negative feedback loop by repressing frq mRNA levels. To understand the function of the FRQ-FRH interaction, we mapped and identified the minimal FRQ region that is required for FRQ-FRH interaction. We demonstrated that the FRQ-FRH complex formation is required for the interaction between FRQ and the White Collar Complex (WCC) and clock function. On the other hand, in the FRQ-FRH complex, FRQ is also required for the FRH-WCC interaction. Disruption of FRQ-FRH interaction or down-regulation of FRH results in hypophosphorylation, rapid degradation of FRQ, as well as low levels of WHITE COLLAR-1 and WHITE COLLAR-2. Furthermore, we showed that the rapid FRQ degradation in the absence of FRH is independent of FWD-1, the ubiquitin E3 ligase of FRQ under normal conditions, thus uncovering an alternative pathway for FRQ degradation. PMID- 20159973 TI - Sumoylation and the structural maintenance of chromosomes (Smc) 5/6 complex slow senescence through recombination intermediate resolution. AB - Telomeres are repetitive nucleoprotein structures that cap the ends of chromosomes. Without telomerase, telomeres shorten with replication and eventually signal cell cycle arrest (cell senescence). Homologous recombination (HR)-based mechanisms slow senescence, and distinct HR mechanisms support the growth of the rare survivors of senescence. Here, we report novel roles for the post-translational modification of small ubiquitin-like modifier (SUMO) in regulating the rate of senescence in Saccharomyces cerevisiae telomerase mutants. We identify Mms21 as the relevant SUMO E3 ligase and demonstrate that cells lacking Mms21-dependent sumoylation accumulate HR intermediates selectively at telomeres during senescence. One target of Mms21-dependent sumoylation is the cohesin- and condensin-related Smc5-Smc6 complex (Smc5/6). We show that hypomorphic smc5 or smc6 alleles exhibit phenotypes similar to mms21 sumoylation deficient mutants with regard to senescence and the accumulation of unresolved HR intermediates. Further, we provide evidence that Mms21 and Smc5/6 prevent aberrant recombination between sister telomeres and also globally facilitate resolution of sister chromatid HR intermediates. PMID- 20159974 TI - Identification of a linear epitope in sortilin that partakes in pro-neurotrophin binding. AB - Sortilin acts as a cell surface receptor for pro-neurotrophins (pro-NT) that upon complex formation with the p75 neurotrophin receptor (p75(NTR)) is able to signal neuronal cell death. Here we screened a sortilin peptide library comprising 16 mer overlapping sequences for binding of the pro-domains of nerve growth factor and brain-derived neurotrophic factor. We find that a linear surface-exposed sequence, (163)RIFRSSDFAKNF(174), constitutes an important pro-NT binding epitope in sortilin. Systematic mutational analysis revealed residues Arg(163), Phe(165), Arg(166), and Phe(170) to be critical for the interaction. Expression of a sortilin mutant in which these four amino acids were substituted by alanines disrupted pro-NT binding without affecting receptor heterodimerization with p75(NTR) or binding of ligands that selectively engages the centrally located tunnel in the beta-propeller of sortilin. We furthermore demonstrate that a peptide comprising the ligand-binding epitope can prevent pro-NT-induced apoptosis in RN22 schwannoma cells. PMID- 20159975 TI - Rapid modulation of the organic anion transporting polypeptide 2B1 (OATP2B1, SLCO2B1) function by protein kinase C-mediated internalization. AB - Members of the organic anion transporting polypeptide (OATP) family are involved in various pharmacological, pathophysiological, and physiological processes, such as hepatic drug uptake, progress of cancer, or transport of hormones. Although variability in expression and function of OATPs has been investigated in detail, data concerning regulation are rather limited. Here, we report a novel mechanism for rapid regulation of OATP2B1 mediated by protein kinase C (PKC) resulting in significant changes of transport activity. PKC activation by the phorbol ester (phorbol 12-myristate 13-acetate, PMA) resulted in increased phosphorylation of OATP2B1 as well as reduced OATP2B1 transport activity with a decrease in V(max) of E(1)S uptake (288 +/- 21 (control) versus 165 +/- 16 pmol/min/mg of protein (PMA)). This effect was sensitive to the PKC inhibitor bisindolylmaleimide I (BIM I). Confocal microscopy, fluorescence-based internalization assay, and live-cell imaging using green fluorescent protein-tagged OATP2B1 revealed that transport inhibition was due to internalization of the transporter. Furthermore, colocalization with LAMP-2 and chloroquine-sensitive degradation of OATP2B1 suggest that the internalized protein is targeted to a lysosomal degradation pathway. With regard to the underlying mechanism inhibition of caveolin/lipid raft-mediated endocytosis failed to prevent OATP2B1 internalization, whereas inhibition of clathrin-mediated processes blocked OATP2B1 sequestration. However, small interfering RNA-mediated clathrin knock-down affected general trafficking of OATP2B1 and resulted in intracellular accumulation in the absence of PMA. In conclusion, our data demonstrate that OATP2B1 function is regulated by PKC mediated, clathrin-dependent internalization and followed by lysosomal degradation. Furthermore, internalization could be shown in an ex vivo placenta perfusion. Our findings represent a new, rapid mechanism in regulation of human OATPs. PMID- 20159976 TI - Transmembrane domain 6 of the human serotonin transporter contributes to an aqueously accessible binding pocket for serotonin and the psychostimulant 3,4 methylene dioxymethamphetamine. AB - The plasma membrane serotonin (5-HT) transporter (SERT, SLC6A4) clears 5-HT after release at nerve termini and is targeted by both antidepressant medications and psychostimulants (e.g. MDMA, cocaine). Homology modeling of human SERT (hSERT), based on high resolution structures of the microbial SLC6 family member LeuT(Aa), along with biochemical studies of wild type and mutant transporters, predicts transmembrane (TM) domains 1, 3, 6, and 8 comprise the 5-HT-binding pocket. We utilized the substituted cysteine accessibility method along with surface and site-specific biotinylation to probe TM6 for aqueous accessibility and differential interactions with 5-HT and psychostimulants. Our results are consistent with TM6 being composed of an aqueous-accessible, alpha-helical extracellular domain (TM6a) that is separated by a central, unwound section from a cytoplasmically localized domain (TM6b) with limited aqueous accessibility. The substitution G338C appears to lock hSERT in an outward-facing conformation that, although accessible to aminoethylmethanethiosulfonate-biotin, 5-HT, and citalopram, is incapable of inward 5-HT transport. Transport of 5-HT by G338C can be partially restored by the TM1 mutation Y95F. With regard to methanethiosulfonate (MTS) inactivation of uptake, TM6a Cys mutants demonstrate Na(+)-dependent [2-(trimethylammonium)ethyl]-MTS sensitivity. Studies with the centrally located substitution S336C reveal features of a common binding pocket for 5-HT and 3,4-methylenedioxymethamphetamine (MDMA). Interestingly, the substitution I333C reveals an MDMA-induced conformation not observed with 5-HT. In the context of prior studies on TM1, our findings document shared and unique features of TM6 contributing to hSERT aqueous accessibility, ligand recognition, and conformational dynamics. PMID- 20159977 TI - Deciphering the catalytic domain of colicin M, a peptidoglycan lipid II-degrading enzyme. AB - Colicin M inhibits Escherichia coli peptidoglycan synthesis through cleavage of its lipid-linked precursors. It has a compact structure, whereas other related toxins are organized in three independent domains, each devoted to a particular function: translocation through the outer membrane, receptor binding, and toxicity, from the N to the C termini, respectively. To establish whether colicin M displays such an organization despite its structural characteristics, protein dissection experiments were performed, which allowed us to delineate an independent toxicity domain encompassing exactly the C-terminal region conserved among colicin M-like proteins and covering about half of colicin M (residues 124 271). Surprisingly, the in vitro activity of the isolated domain was 45-fold higher than that of the full-length protein, suggesting a mechanism by which the toxicity of this domain is revealed following primary protein maturation. In vivo, the isolated toxicity domain appeared as toxic as the full-length protein under conditions where the reception and translocation steps were by-passed. Contrary to the full-length colicin M, the isolated domain did not require the presence of the periplasmic FkpA protein to be toxic under these conditions, demonstrating that FkpA is involved in the maturation process. Mutational analysis further identified five residues that are essential for cytotoxicity as well as in vitro lipid II-degrading activity: Asp-229, His-235, Asp-226, Tyr-228, and Arg-236. Most of these residues are surface-exposed and located relatively close to each other, hence suggesting they belong to the colicin M active site. PMID- 20159978 TI - Hsp90 directly modulates the spatial distribution of AF9/MLLT3 and affects target gene expression. AB - AF9/MLLT3 contributes to the regulation of the gene encoding the epithelial sodium channel alpha, ENaCalpha, in renal tubular cells. Specifically, increases in AF9 protein lead to a reduction in ENaCalpha expression and changes in AF9 activity appear to be an important component of aldosterone signaling in the kidney. Whereas AF9 is found in the nucleus where it interacts with the histone H3 lysine 79 methyltransferase, Dot1, AF9 is also present in the cytoplasm. Data presented in this report indicate that the heat shock protein Hsp90 directly and specifically interacts with AF9 as part of an Hsp90-Hsp70-p60/Hop chaperone complex. Experimental manipulation of Hsp90 function by the inhibitor novobiocin, but not 17-AAG, results in redistribution of AF9 from a primarily nuclear to cytoplasmic location. Knockdown of Hsp90 with siRNA mimics the effect elicited by novobiocin. As expected, a shift in AF9 from the nucleus to the cytoplasm in response to Hsp90 interference leads to increased ENaCalpha expression. This is accompanied by a decrease in AF9 occupancy at the ENaCalpha promoter. Our data suggest that the interaction of Hsp90, Hsp70, and p60/Hop with AF9 is necessary for the proper subnuclear localization and activity of AF9. AF9 is among a growing number of nuclear proteins recognized to rely on the Hsp90 complex for nuclear targeting. PMID- 20159979 TI - AMSH interacts with ESCRT-0 to regulate the stability and trafficking of CXCR4. AB - Reversible ubiquitination is essential for the endocytic sorting and down regulation of G protein-coupled receptors, such as the chemokine receptor CXCR4. The deubiquitinating enzyme AMSH has been implicated in the endocytic sorting of both G protein-coupled receptors and receptor-tyrosine kinases. Herein, we examine the role of AMSH in the regulation of CXCR4 stability and trafficking and characterize protein-protein interactions critical for this function. Loss of AMSH catalytic activity or depletion by RNAi results in increased steady-state levels of CXCR4 under basal conditions. Analysis of truncation and point mutation of AMSH reveal the importance of an RXXK motif for CXCR4 degradation. The RXXK motif of AMSH interacts with the SH3 domains of the STAM and Grb2 families of adaptor proteins with high affinity. Cells expressing a catalytically inactive mutant of AMSH show basal hyperubiquitination, but not increased degradation, of the ESCRT-0 components STAM1 and Hrs. This is dependent on the RXXK motif of AMSH. Ubiquitination of endocytic machinery modulates their activity, suggesting that AMSH may directly regulate endocytic adaptor protein function. This is reflected in CXCR4 trafficking and provides a mechanism by which AMSH specifies the fate of endocytosed receptors. Taken together, these studies implicate AMSH as a key modulator of receptor fate determination through its action on components of the endocytic machinery. PMID- 20159980 TI - Three homologous subunits form a high affinity peptide-gated ion channel in Hydra. AB - Recently, three ion channel subunits of the degenerin (DEG)/epithelial Na(+) channel (ENaC) gene family have been cloned from the freshwater polyp Hydra magnipapillata, the Hydra Na(+) channels (HyNaCs) 2-4. Two of them, HyNaC2 and HyNaC3, co-assemble to form an ion channel that is gated by the neuropeptides Hydra-RFamides I and II. The HyNaC2/3 channel is so far the only cloned ionotropic receptor from cnidarians and, together with the related ionotropic receptor FMRFamide-activated Na(+) channel (FaNaC) from snails, the only known peptide-gated ionotropic receptor. The HyNaC2/3 channel has pore properties, like a low Na(+) selectivity and a low amiloride affinity, that are different from other channels of the DEG/ENaC gene family, suggesting that a component of the native Hydra channel might still be lacking. Here, we report the cloning of a new ion channel subunit from Hydra, HyNaC5. The new subunit is closely related to HyNaC2 and -3 and co-localizes with HyNaC2 and -3 to the base of the tentacles. Coexpression in Xenopus oocytes of HyNaC5 with HyNaC2 and -3 largely increases current amplitude after peptide stimulation and affinity of the channel to Hydra RFamides I and II. Moreover, the HyNaC2/3/5 channel has altered pore properties and amiloride affinity, more similarly to other DEG/ENaC channels. Collectively, our results suggest that the three homologous subunits HyNaC2, -3, and -5 form a peptide-gated ion channel in Hydra that could contribute to fast synaptic transmission. PMID- 20159981 TI - Mutant ferritin L-chains that cause neurodegeneration act in a dominant-negative manner to reduce ferritin iron incorporation. AB - Nucleotide insertions that modify the C terminus of ferritin light chain (FTL) cause neurodegenerative movement disorders named neuroferritinopathies, which are inherited with dominant transmission. The disorders are characterized by abnormal brain iron accumulation. Here we describe the biochemical and crystallographic characterization of pathogenic FTL mutant p.Phe167SerfsX26 showing that it is a functional ferritin with an altered conformation of the C terminus. Moreover we analyze functional and stability properties of ferritin heteropolymers made of 20 23 H-chains and 1-4 L-chains with representative pathogenic mutations or the last 10-28 residues truncated. All the heteropolymers containing the pathogenic or truncated mutants had a strongly reduced capacity to incorporate iron, both when expressed in Escherichia coli, and in vitro when iron was supplied as Fe(III) in the presence of ascorbate. The mutations also reduced the physical stability of the heteropolymers. The data indicate that even a few mutated L-chains are sufficient to alter the permeability of 1-2 of the 6 hydrophobic channels and modify ferritin capacity to incorporate iron. The dominant-negative action of the mutations explains the dominant transmission of the disorder. The data support the hypothesis that hereditary ferritinopathies are due to alterations of ferritin functionality and provide new input on the mechanism of the function of isoferritins. PMID- 20159982 TI - Protection against cytokine toxicity through endoplasmic reticulum and mitochondrial stress prevention by prostacyclin synthase overexpression in insulin-producing cells. AB - Proinflammatory cytokines play a crucial role in the pathogenesis of type 1 diabetes mellitus. One of the cytokine-regulated pathways mediating inflammation in this autoimmune disease is the arachidonic acid metabolism pathway, comprising both the induction of cyclooxygenases and the production of different prostaglandins. Cytokine toxicity is mediated in many cell types, including pancreatic beta cells through this pathway. Interestingly, some cell types have been shown to be insensitive to such toxicity, and this correlated with a high expression of prostacyclin synthase (PGIS). Using insulin-producing RINm5F cells as a model for pancreatic beta cells, PGIS was overexpressed and exhibited a large protective effect against cytokine toxicity. This protective effect of PGIS against cytokine toxicity correlated with a decreased activation of the transcription factor NFkappaB and the inducible NO synthase promoter as well as a reduced inducible NO synthase protein expression and nitrite production. A reduction in the cytokine-stimulated endoplasmic reticulum and mitochondrial stress was also found in the PGIS-overexpressing cells. Moreover, cytokine induced caspase-3 activation and reduction of glucose oxidation and cell proliferation were suppressed. Thus, PGIS overexpression apparently protects insulin-producing cells against cytokine toxicity via suppression of endoplasmic reticulum and mitochondrial stress-mediated cell death pathways. PMID- 20159983 TI - Structural diversity of triplet repeat RNAs. AB - Tandem repeats of various trinucleotide motifs are present in the human transcriptome, but the functions of these regular sequences, which likely depend on the structures they form, are still poorly understood. To gain new insight into the structural and functional properties of triplet repeats in RNA, we have performed a biochemical structural analysis of the complete set of triplet repeat transcripts, each composed of a single sequence repeated 17 times. We show that these transcripts fall into four structural classes. The repeated CAA, UUG, AAG, CUU, CCU, CCA, and UAA motifs did not form any higher order structure under any analyzed conditions. The CAU, CUA, UUA, AUG, and UAG repeats are ordered according to their increasing tendency to form semistable hairpins. The repeated CGA, CGU, and all CNG motifs form fairly stable hairpins, whereas AGG and UGG repeats fold into stable G-quadruplexes. The triplet repeats that formed the most stable structures were characterized further by biophysical methods. UV-monitored structure melting revealed that CGG and CCG repeats form, respectively, the most and least stable hairpins of all CNG repeats. Circular dichroism spectra showed that the AGG and UGG repeat quadruplexes are formed by parallel RNA strands. Furthermore, we demonstrated that the different susceptibility of various triplet repeat transcripts to serum nucleases can be explained by the sequence and structural features of the tested RNAs. The results of this study provide a comprehensive structural foundation for the functional analysis of triplet repeats in transcripts. PMID- 20159984 TI - Chemotherapeutic drugs inhibit ribosome biogenesis at various levels. AB - Drugs for cancer therapy belong to different categories of chemical substances. The cellular targets for the therapeutic efficacy are often not unambiguously identified. Here, we describe the process of ribosome biogenesis as a target of a large variety of chemotherapeutic drugs. We determined the inhibitory concentration of 36 chemotherapeutic drugs for transcription and processing of ribosomal RNA by in vivo labeling experiments. Inhibitory drug concentrations were correlated to the loss of nucleolar integrity. The synergism of drugs inhibiting ribosomal RNA synthesis at different levels was studied. Drugs inhibited ribosomal RNA synthesis either at the level of (i) rRNA transcription (e.g. oxaliplatin, doxorubicin, mitoxantrone, methotrexate), (ii) early rRNA processing (e.g. camptothecin, flavopiridol, roscovitine), or (iii) late rRNA processing (e.g. 5-fluorouracil, MG-132, homoharringtonine). Blockage of rRNA transcription or early rRNA processing steps caused nucleolar disintegration, whereas blockage of late rRNA processing steps left the nucleolus intact. Flavopiridol and 5-fluorouracil showed a strong synergism for inhibition of rRNA processing. We conclude that inhibition of ribosome biogenesis by chemotherapeutic drugs potentially may contribute to the efficacy of therapeutic regimens. PMID- 20159985 TI - Caspase-7 cleavage of Kaposi sarcoma-associated herpesvirus ORF57 confers a cellular function against viral lytic gene expression. AB - Kaposi sarcoma-associated herpesvirus (KSHV) ORF57 is a viral early protein essential for KSHV multiplication. We found that B cells derived from cavity based B cell lymphoma with lytic KSHV infection display activation of caspase-8 and cleavage of ORF57 in the cytoplasm by caspase-7 at the aspartate residue at position 33 from the N terminus. Caspase-7 cleavage of ORF57 is prevented by pan caspase inhibitor z-VAD, caspase-3 and caspase-7 inhibitor z-DEVD, and caspase-7 small interfering RNAs. The caspase-7 cleavage site (30)DETD(33) in ORF57 is not cleavable by caspase-3, although both enzymes use DEXD as a common cleavage site. B cells with lytic KSHV infection and caspase-7 activation exhibited a greatly reduced level of ORF57. A majority of the cells expressing active caspase-7 appeared to have no detectable ORF57 and vice versa. Upon cleavage with caspase 7, ORF57 was deficient in promoting the expression of viral lytic genes. Inhibiting caspase-7 cleavage of ORF57 in KSHV(+) BCBL-1 cells by z-VAD, z-DEVD, or caspase-7 small interfering RNA led to increased expression of viral lytic genes and production of cell-free virus particles. Collectively, our data provide the first compelling evidence that caspase cleavage of ORF57 may represent a cellular function against lytic KSHV infection. PMID- 20159986 TI - Methylation of ribosomal protein S10 by protein-arginine methyltransferase 5 regulates ribosome biogenesis. AB - Modulation of ribosomal assembly is a fine tuning mechanism for cell number and organ size control. Many ribosomal proteins undergo post-translational modification, but their exact roles remain elusive. Here, we report that ribosomal protein s10 (RPS10) is a novel substrate of an oncoprotein, protein arginine methyltransferase 5 (PRMT5). We show that PRMT5 interacts with RPS10 and catalyzes its methylation at the Arg(158) and Arg(160) residues. The methylation of RPS10 at Arg(158) and Arg(160) plays a role in the proper assembly of ribosomes, protein synthesis, and optimal cell proliferation. The RPS10 R158K/R160K mutant is not efficiently assembled into ribosomes and is unstable and prone to degradation by the proteasomal pathway. In nucleoli, RPS10 interacts with nucleophosmin/B23 and is predominantly concentrated in the granular component region, which is required for ribosome assembly. The RPS10 methylation mutant interacts weakly with nucleophosmin/B23 and fails to concentrate in the granular component region. Our results suggest that PRMT5 is likely to regulate cell proliferation through the methylation of ribosome proteins, and thus reveal a novel mechanism for PRMT5 in tumorigenesis. PMID- 20159987 TI - Ubiquitin chain elongation enzyme Ufd2 regulates a subset of Doa10 substrates. AB - Ufd2 is the founding member of E4 enzymes that are specifically involved in ubiquitin chain elongation but whose roles in proteolysis remain scarce. Here, using a genome-wide screen, we identified one cellular target of yeast Ufd2 as the membrane protein Pex29. The ubiquitin chains assembled on Pex29 in vivo by Ufd2 mainly contain Lys-48 linkages. We found that the ubiquitin-protein E3 ligase for overexpressed Pex29 is Doa10, which is known to be involved in protein quality control. Interestingly, not all Doa10 substrates are regulated by Ufd2, suggesting that E4 involvement is not specific to a particular E3, but may depend on the spatial arrangement of the E3-substrate interaction. Cells lacking UFD2 elicit an unfolded protein response, expanding the physiological function of Ufd2. Our results lead to novel insights into the biological role of Ufd2 and further underscore the significance of Ufd2 in proteolysis. PMID- 20159988 TI - Breast cancer resistance protein (BCRP)-mediated glyburide transport: effect of the C421A/Q141K BCRP single-nucleotide polymorphism. AB - The antidiabetic agent glyburide (glibenclamide) is frequently used for the treatment of type II diabetes and is increasingly being used for the treatment of gestational diabetes. Evidence suggests that breast cancer resistance protein/ATP binding cassette, subfamily G, member 2 (ABCG2) expressed in the placenta protects the fetus against the accumulation of glyburide. A number of studies have investigated the significance of several single-nucleotide polymorphisms (SNPs) in the ABCG2 gene. Associations between the Q141K (C421A) SNP and ABCG2 protein expression, membrane surface translocation, efflux activity, or ATPase activity have been shown. Therefore, alterations in glyburide transport across the placenta, resulting in increased fetal glyburide exposure, may be seen in individuals carrying the C421A allele. The purpose of this study is to investigate whether the Q141K SNP causes alterations in ABCG2-mediated glyburide transport. Glyburide accumulation assays were carried out with stably transfected human embryonic kidney (HEK)-293 cells expressing wild-type ABCG2 (Arg482) and polymorphic ABCG2 (Q141K). Glyburide kinetic parameters were determined for comparison of wild-type and SNP ABCG2 activity by simultaneously fitting data for ABCG2-expressing cells (saturable transport) and empty vector-expressing cells (nonsaturable transport) by nonlinear regression analysis. The apparent K(t) and V(max) values for the transfected HEK-293 cells expressing the polymorphic variant (Q141K) of ABCG2 were significantly higher than those values determined for the wild-type ABCG2-expressing cells (p < 0.05). Our results indicate that the Q141K variant of ABCG2 may have the potential to alter the placental pharmacokinetics of glyburide used in pregnancy. PMID- 20159989 TI - Formation and distribution of NNK metabolites in an isolated perfused rat lung. AB - 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a lung-specific tobacco carcinogen. Metabolism is critical to its elimination given its lipophilic nature. Although NNK can be metabolized through detoxification pathways that safely eliminate it from the body, it can also be bioactivated, resulting in the formation of potentially carcinogenic DNA adducts. The isolated perfused rat lung (IPRL) system was used to determine the effect of NNK perfusate concentration (0.1 and 1.2 microM) on the formation and distribution of metabolites, the level of individual DNA adducts, and total covalent binding in the lung. Coadministration of the chemopreventive agent phenethyl isothiocyanate (PEITC; 20 microM) was also examined to determine its effect on NNK metabolism. NNK was readily metabolized in the IPRL system. In the 0.1 muM perfusions approximately 55% of metabolites formed were through detoxification pathways, whereas roughly 30% were the result of bioactivation pathways. An increase in NNK concentration increased the percentage of unmetabolized NNK and decreased the apparent metabolic clearance in the lung, but the metabolite profiles remained similar between concentrations. The addition of PEITC reduced the formation of oxidative metabolites and increased 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) formation and the percentage of unmetabolized NNK. PEITC also significantly decreased the formation of DNA adducts in the lung tissue. The level of O(2)-[4 (3-pyridyl)-4-oxobut-1-yl]thymidine (O(2)-POB-dThd) and O(6)-[4-(3-pyridyl)-4 oxobut-1-yl]-2'-deoxyguanosine (O(6)-POB-dGuo) decreased by 70 to 75%, and that of O(6)-methylguanine (O(6)-methyl-Gua) and 7-[4-(3-pyridyl)-4-oxobut-1 yl]guanine (7-POB-Gua) decreased by 40 to 45%. Pyridylhydroxybutyl-DNA adducts were not detected in any of the treatment groups. Thus, the IPRL system is useful in determining pulmonary metabolism and DNA adduct formation separate from other metabolizing organs. PMID- 20159990 TI - Reduced argininosuccinate synthetase is a predictive biomarker for the development of pulmonary metastasis in patients with osteosarcoma. AB - Pulmonary metastasis is the most significant prognostic determinant for osteosarcoma, but methods for its prediction and treatment have not been established. Using oligonucleotide microarrays, we compared the global gene expression of biopsy samples between seven osteosarcoma patients who developed pulmonary metastasis within 4 years after neoadjuvant chemotherapy and curative resection, and 12 patients who did not relapse. We identified argininosuccinate synthetase (ASS) as a gene differentially expressed with the highest statistical significance (Welch's t test, P = 2.2 x 10(-5)). Immunohistochemical analysis of an independent cohort of 62 osteosarcoma cases confirmed that reduced expression of ASS protein was significantly correlated with the development of pulmonary metastasis after surgery (log-rank test, P < 0.05). Cox regression analysis revealed that ASS was the sole significant predictive factor (P = 0.039; hazard ratio, 0.319; 95% confidence interval, 0.108-0.945). ASS is one of the enzymes required for the production of a nonessential amino acid, arginine. We showed that osteosarcoma cells lacking ASS expression were auxotrophic for arginine and underwent G(0)-G(1) arrest in arginine-free medium, suggesting that an arginine deprivation therapy could be effective in patients with osteosarcoma. Recently, phase I and II clinical trials in patients with melanoma and hepatocellular carcinoma have shown the safety and efficacy of plasma arginine depletion by stabilized arginine deiminase. Our data indicate that in patients with osteosarcoma, reduced expression of ASS is not only a novel predictive biomarker for the development of metastasis, but also a potential target for pharmacologic intervention. PMID- 20159991 TI - Association of polymorphisms in AKT1 and EGFR with clinical outcome and toxicity in non-small cell lung cancer patients treated with gefitinib. AB - EGFR mutations are strongly predictive of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor activity in non-small cell lung cancer (NSCLC), but resistance mechanisms are not completely understood. The interindividual variability in toxicity also points out to the need of novel pharmacogenetic markers to select patients before therapy. Therefore, we evaluated the associations between EGFR and AKT1 polymorphisms and outcome/toxicity in gefitinib-treated NSCLC patients. Polymorphic loci in EGFR, and AKT1, and EGFR and K-Ras mutations were assessed in DNA isolated from blood samples and/or paraffin-embedded tumor from 96 gefitinib-treated NSCLC patients. Univariate and multivariate analyses compared genetic variants with clinical efficacy and toxicity using Fisher's, log-rank test, and Cox's proportional hazards model. AKT1-SNP4 association with survival was also evaluated in 127 chemotherapy treated/gefitinib-naive patients, whereas its relationship with AKT1 expression and gefitinib cytotoxicity was studied in 15 NSCLC cell lines. AKT1-SNP4 A/A genotype was associated with shorter time-to-progression (P = 0.04) and overall survival (P = 0.007). Multivariate analyses and comparison with the gefitinib nontreated population underlined its predictive significance, whereas the in vitro studies showed the association of lower AKT1 mRNA levels with gefitinib resistance. In contrast, EGFR-activating mutations were significantly correlated with response, longer time-to-progression, and overall survival, whereas EGFR 191C/A (P < 0.001), -216 G/T (P < 0.01), and R497K (P = 0.02) polymorphisms were strongly associated with grade >1 diarrhea. AKT1-SNP4 A/A genotype seems to be a candidate biomarker of primary resistance, whereas EGFR -191C/A, -216G/T, and R497K polymorphisms are associated with diarrhea when using gefitinib in NSCLC patients, thus offering potential new tools for treatment optimization. PMID- 20159992 TI - The FLT3 internal tandem duplication mutation is a secondary target of the aurora B kinase inhibitor AZD1152-HQPA in acute myelogenous leukemia cells. AB - Aurora kinases play an essential role in orchestrating chromosome alignment, segregation, and cytokinesis during mitotic progression and both aurora-A and B are frequently overexpressed in a variety of human malignancies. In this study, we report the effects of AZD1152-HQPA, a highly selective inhibitor of aurora-B kinase, in acute myeloid leukemia (AML) cell lines and primary samples. We show that AZD1152-HQPA inhibits the phosphorylation of Histone H3 (pHH3) on serine 10 resulting in polyploid cells, apoptosis, and loss of viability in a panel of AML cell lines. We also show that AZD1152-HQPA sensitivity in our cell lines is irrespective of p53 status and the FLT3-ITD-expressing MOLM-13 and MV4-11 cell lines are particularly sensitive to AZD1152-HQPA. Internal tandem duplications (ITD) within the FLT3 tyrosine kinase receptor are found in approximately 25% of AML patients and are associated with a poor prognosis. Here, we report that AZD1152-HQPA directly targets phosphorylated FLT3 along with inhibiting its downstream target phospho-signal transducer and activator of transcription 5 (STAT5) in the FLT3-ITD cell lines. We show pHH3 expression in primary AML blasts and its inhibition by AZD1152-HQPA at low doses in all of our primary samples tested. AZD1152-HQPA inhibits the clonogenic potential of primary AML samples, with FLT3-ITD samples being the most sensitive (P = 0.029). FLT3-ITD primary samples are also more sensitive to pHH3 inhibition (P = 0.022) and are particularly sensitive to pSTAT5 downregulation after treatment with AZD1152-HQPA compared with FLT3 wild-type samples (P = 0.007). We conclude that mutant FLT3 is a secondary target of AZD1152-HQPA and that FLT3-ITD primary samples are particularly sensitive to the drug. PMID- 20159993 TI - Promotion of exon 6 inclusion in HuD pre-mRNA by Hu protein family members. AB - The Hu RNA-binding protein family consists of four members: HuR/A, HuB, HuC and HuD. HuR expression is widespread. The other three neuron-specific Hu proteins play an important role in neuronal differentiation through modulating multiple processes of RNA metabolism. In the splicing events examined previously, Hu proteins promote skipping of the alternative exons. Here, we report the first example where Hu proteins promote inclusion of an alternative exon, exon 6 of the HuD pre-mRNA. Sequence alignment analysis indicates the presence of several conserved AU-rich sequences both upstream and downstream to this alternatively spliced exon. We generated a human HuD exon 6 mini-gene reporter construct that includes these conserved sequences. Hu protein over-expression led to significantly increased exon 6 inclusion from this reporter and endogenous HuD. Studies using truncated and mutant HuD exon 6 reporters demonstrate that two AU rich sequences located downstream of exon 6 are important. RNAi knockdown of Hu proteins decreased exon 6 inclusion. An in vitro splicing assay indicates that Hu proteins promote HuD exon 6 inclusion directly at the level of splicing. Our studies demonstrate that Hu proteins can function as splicing enhancers and expand the functional role of Hu proteins as splicing regulators. PMID- 20159994 TI - Post-transcriptional regulation of androgen receptor mRNA by an ErbB3 binding protein 1 in prostate cancer. AB - Androgen receptor (AR)-mediated pathways play a critical role in the development and progression of prostate cancer. However, little is known about the regulation of AR mRNA stability and translation, two central processes that control AR expression. The ErbB3 binding protein 1 (EBP1), an AR corepressor, negatively regulates crosstalk between ErbB3 ligand heregulin (HRG)-triggered signaling and the AR axis, affecting biological properties of prostate cancer cells. EBP1 protein expression is also decreased in clinical prostate cancer. We previously demonstrated that EBP1 overexpression results in decreased AR protein levels by affecting AR promoter activity. However, EBP1 has recently been demonstrated to be an RNA binding protein. We therefore examined the ability of EBP1 to regulate AR post-transcriptionally. Here we show that EBP1 promoted AR mRNA decay through physical interaction with a conserved UC-rich motif within the 3'-UTR of AR. The ability of EBP1 to accelerate AR mRNA decay was further enhanced by HRG treatment. EBP1 also bound to a CAG-formed stem-loop in the 5' coding region of AR mRNA and was able to inhibit AR translation. Thus, decreases of EBP1 in prostate cancer could be important for the post-transcriptional up-regulation of AR contributing to aberrant AR expression and disease progression. PMID- 20159995 TI - A case study in cross-talk: the histone lysine methyltransferases G9a and GLP. AB - The histone code hypothesis predicts that the post-translational modification of histones can bring about distinct chromatin states, and it therefore serves a key regulatory role in chromatin biology. The impact of one mark on another has been termed cross-talk. Some marks are mutually exclusive, while others act in concert. As multiple marks contributing to one outcome are generally brought about by complexes containing multiple catalytic and binding domains, it appears regulation of chromatin involves a web of writers and readers of histone modifications, chromatin remodeling activities and DNA methylation. Here, we focus on the protein lysine methyltransferases G9a and GLP as examples of this extended cross-talk. G9a and GLP can catalyze the formation of and bind to the same methyl mark via distinct domains. We consider the impact of other histone modifications on G9a/GLP activity and the coordination of activities within G9a/GLP containing complexes. We evaluate the potential impact of product binding on product specificity and on maintenance and propagation of the methyl mark. Lastly, we examine the recruitment of other silencing factors by G9a/GLP. Regulated assembly of specific complexes around key marks may reinforce or alter the biological outcome associated with given histone modifications. PMID- 20159996 TI - Establishment of an in vitro trans-splicing system in Trypanosoma brucei that requires endogenous spliced leader RNA. AB - In trypanosomes a 39 nucleotide exon, the spliced leader (SL) is donated to all mRNAs from a small RNA, the SL RNA, by trans-splicing. Since the discovery of trans-splicing in trypanosomes two decades ago, numerous attempts failed to reconstitute the reaction in vitro. In this study, a crude whole-cell extract utilizing the endogenous SL RNA and synthetic tubulin pre-mRNA were used to reconstitute the trans-splicing reaction. An RNase protection assay was used to detect the trans-spliced product. The reaction was optimized and shown to depend on ATP and intact U2 and U6 snRNPs. Mutations introduced at the polypyrimidine tract and the AG splice site reduced the reaction efficiency. To simplify the assay, RT-PCR and quantitative real-time PCR assays were established. The system was used to examine the structural requirements for SL RNA as a substrate in the reaction. Interestingly, synthetic SL RNA assembled poorly to its cognate particle and was not utilized in the reaction. However, SL RNA synthesized in cells lacking Sm proteins, which is defective in cap-4 modification, was active in the reaction. This study is the first step towards further elucidating the mechanism of trans-splicing, an essential reaction which determines the trypanosome transcriptome. PMID- 20159997 TI - Arrangement of 3D structural motifs in ribosomal RNA. AB - Structural 3D motifs in RNA play an important role in the RNA stability and function. Previous studies have focused on the characterization and discovery of 3D motifs in RNA secondary and tertiary structures. However, statistical analyses of the distribution of 3D motifs along the RNA appear to be lacking. Herein, we present a novel strategy for evaluating the distribution of 3D motifs along the RNA chain and those motifs whose distributions are significantly non-random are identified. By applying it to the X-ray structure of the large ribosomal subunit from Haloarcula marismortui, helical motifs were found to cluster together along the chain and in the 3D structure, whereas the known tetraloops tend to be sequentially and spatially dispersed. That the distribution of key structural motifs such as tetraloops differ significantly from a random one suggests that our method could also be used to detect novel 3D motifs of any size in sufficiently long/large RNA structures. The motif distribution type can help in the prediction and design of 3D structures of large RNA molecules. PMID- 20159998 TI - Functional replacement of the endogenous tyrosyl-tRNA synthetase-tRNATyr pair by the archaeal tyrosine pair in Escherichia coli for genetic code expansion. AB - Non-natural amino acids have been genetically encoded in living cells, using aminoacyl-tRNA synthetase-tRNA pairs orthogonal to the host translation system. In the present study, we engineered Escherichia coli cells with a translation system orthogonal to the E. coli tyrosyl-tRNA synthetase (TyrRS)-tRNA(Tyr) pair, to use E. coli TyrRS variants for non-natural amino acids in the cells without interfering with tyrosine incorporation. We showed that the E. coli TyrRS tRNA(Tyr) pair can be functionally replaced by the Methanocaldococcus jannaschii and Saccharomyces cerevisiae tyrosine pairs, which do not cross-react with E. coli TyrRS or tRNA(Tyr). The endogenous TyrRS and tRNA(Tyr) genes were then removed from the chromosome of the E. coli cells expressing the archaeal TyrRS tRNA(Tyr) pair. In this engineered strain, 3-iodo-L-tyrosine and 3-azido-L tyrosine were each successfully encoded with the amber codon, using the E. coli amber suppressor tRNATyr and a TyrRS variant, which was previously developed for 3-iodo-L-tyrosine and was also found to recognize 3-azido-L-tyrosine. The structural basis for the 3-azido-L-tyrosine recognition was revealed by X-ray crystallography. The present engineering allows E. coli TyrRS variants for non natural amino acids to be developed in E. coli, for use in both eukaryotic and bacterial cells for genetic code expansion. PMID- 20159999 TI - Selecting RNA aptamers for synthetic biology: investigating magnesium dependence and predicting binding affinity. AB - The ability to generate RNA aptamers for synthetic biology using in vitro selection depends on the informational complexity (IC) needed to specify functional structures that bind target ligands with desired affinities in physiological concentrations of magnesium. We investigate how selection for high affinity aptamers is constrained by chemical properties of the ligand and the need to bind in low magnesium. We select two sets of RNA aptamers that bind planar ligands with dissociation constants (K(d)s) ranging from 65 nM to 100 microM in physiological buffer conditions. Aptamers selected to bind the non proteinogenic amino acid, p-amino phenylalanine (pAF), are larger and more informationally complex (i.e., rarer in a pool of random sequences) than aptamers selected to bind a larger fluorescent dye, tetramethylrhodamine (TMR). Interestingly, tighter binding aptamers show less dependence on magnesium than weaker-binding aptamers. Thus, selection for high-affinity binding may automatically lead to structures that are functional in physiological conditions (1-2.5 mM Mg(2+)). We hypothesize that selection for high-affinity binding in physiological conditions is primarily constrained by ligand characteristics such as molecular weight (MW) and the number of rotatable bonds. We suggest that it may be possible to estimate aptamer-ligand affinities and predict whether a particular aptamer-based design goal is achievable before performing the selection. PMID- 20160001 TI - Exophytic renal masses: angular interface with renal parenchyma for distinguishing benign from malignant lesions at MR imaging. AB - PURPOSE: To retrospectively determine whether benign exophytic renal masses can be distinguished from renal cell carcinoma (RCC) on the basis of angular interface at single-shot fast spin-echo (SE) T2-weighted magnetic resonance (MR) imaging. MATERIALS AND METHODS: This retrospective study was compliant with HIPAA and was approved by the institutional review board. Patient informed consent was waived. A total of 162 exophytic (2 cm or greater) renal masses in 152 patients (103 men, 49 women; mean age, 58 years; age range, 23-85 years) were included. Two radiologists independently recorded the mass size and angular interface on single-shot fast SE T2-weighted MR images. Surgical pathologic report and MR follow-up were used as reference standards. Logistic regression analysis was used to examine the usefulness of these variables for differentiating benign masses from RCCs. Diagnostic performance was analyzed by comparing values for area under receiver operating characteristic curve (A(z)). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of angular interface for diagnosing benign masses were calculated. Reader agreement was assessed with kappa-weighted statistics and intraclass correlation coefficients (ICCs). RESULTS: Of 162 masses, 65 were benign, and 97 were RCCs. The sensitivity, specificity, PPV, NPV, and A(z) of angular interface for diagnosing benign masses were 78%, 100%, 100%, 87%, and 0.813, respectively. Angular interface (P < .001) was a significant predictor of benign renal mass but mass size (P = .66) was not. There was almost perfect interobserver agreement for mass size (ICC = 0.96) and angular interface (kappa = 0.91). CONCLUSION: The presence of an angular interface with the renal parenchyma at single-shot fast SE T2 weighted MR imaging is a strong predictor of benignity in an exophytic renal mass 2 cm or greater in diameter with high specificity and diagnostic accuracy. PMID- 20160000 TI - Liposomal doxorubicin increases radiofrequency ablation-induced tumor destruction by increasing cellular oxidative and nitrative stress and accelerating apoptotic pathways. AB - PURPOSE: To determine if oxidative and nitrative stress and/or apoptosis contribute to increased coagulation when combining radiofrequency (RF) ablation with liposomal doxorubicin. MATERIALS AND METHODS: Animal care committee approval was obtained. R3230 mammary adenocarcinomas in Fischer rats were treated with either RF ablation (n = 43), 1 mg of intravenously injected liposomal doxorubicin (n = 26), or combined therapy (n = 30) and were compared with control subjects (n = 11). A subset of animals receiving combination therapy (n = 24) were treated in the presence or absence of N-acetylcysteine (NAC) administered 24 hours and 1 hour before RF ablation. Tumors were analyzed 2 minutes to 72 hours after treatment to determine the temporal range of response by using immunohistochemical staining of the apoptosis marker cleaved caspase-3, phosphorylated gammaH2AX, and HSP70 and of markers of oxidative and nitrative stress (8-hydroxydeoxyguanosine [8-OHdG], 4-hydroxynonenal [4-HNE]-modified proteins, and nitrotyrosine [NT]). Statistical analyses, including t tests and analysis of variance for comparisons where appropriate, were performed. RESULTS: By 4 hours after RF ablation alone, a 0.48-mm +/- 0.13 (standard deviation) peripheral band with 57.0% +/- 7.3 cleaved caspase-3 positive cells was noted at the ablation margin, whereas a 0.73-mm +/- 0.18 band with 77.7% +/- 6.3 positivity was seen for combination therapy (P < .03 for both comparisons). Combination therapy caused increased and earlier staining for 4-HNE-modified proteins, 8-OHdG, NT, and gammaH2AX with colocalization to cleaved caspase-3 staining. A rim of increased HSP70 was identified peripheral to the area of cleaved caspase-3. Parameters of oxidative and nitrative stress were significantly inhibited by NAC 1 hour following RF ablation, resulting in decreased cleaved caspase-3 positivity (0.28-mm +/- 0.09 band of 25.9% +/- 7.4 positivity vs 0.59-mm +/- 0.11 band of 62.9% +/- 6.0 positivity, P < .001 for both comparisons). CONCLUSION: Combining RF ablation with liposomal doxorubicin increases cell injury and apoptosis in the zone of increased coagulation by using a mechanism that involves oxidative and nitrative stress that leads to accelerated apoptosis. PMID- 20160002 TI - Kidney and urinary tract imaging: triple-bolus multidetector CT urography as a one-stop shop--protocol design, opacification, and image quality analysis. AB - PURPOSE: To retrospectively evaluate renal, vascular, and urinary tract visualization following a single postcontrast multidetector computed tomographic (CT) urographic sequence performed with three limited-volume bolus injections. MATERIALS AND METHODS: The institutional review board approved this retrospective study. Patient informed consent was waived. Triple-bolus multidetector CT urography was performed in 110 patients. Triple-bolus protocol consisted of 30 mL of contrast material at 2 mL/sec at 0 seconds, 50 mL at 1.5 mL/sec at 435 seconds, 65 mL at 3 mL/sec at 488 seconds, with total abdominal scanning time of 510 seconds. Two independent readers rated urinary tract opacification and qualitatively and quantitatively assessed renal parenchymal and vascular contrast enhancement. Upper urinary tract (UUT) distention was measured by one reader. Interobserver agreement was assessed by using kappa statistics. RESULTS: Complete opacification of the intrarenal collecting system and proximal ureter was achieved in 91% (184 of 202) (kappa = 0.62) and 82% (166 of 202) (kappa = 0.94) of segments, respectively. The distal ureter was not opacified in 21% of the cases (kappa = 0.92), and the bladder was not opacified in 20% of the cases. Mean distention was higher for proximal (3.9 mm) than for distal (3.7 mm) segments. Image quality of renal parenchymal enhancement was excellent in 76% of cases. Arteries showed better contrast enhancement than veins (excellent rating in 89% vs 59% of the cases). Radiation dose calculated for triple-bolus acquisition was 9.8 mSv. CONCLUSION: Triple-bolus multidetector CT urography is a dose-efficient protocol acquiring corticomedullary-nephrographic-excretory and vascular enhancement phases in a single acquisition and provides sufficient opacification and distention of the UUT. Simultaneously, adequate image quality of renal parenchyma and vascular anatomy is achieved. PMID- 20160003 TI - Thoracic aorta: prospective electrocardiographically triggered CT angiography with dual-source CT--feasibility, image quality, and dose reduction. AB - PURPOSE: To prospectively investigate the feasibility, image quality, and radiation dose for prospective electrocardiographically (ECG) triggered sequential dual-source computed tomographic (CT) angiography of the thoracic aorta in comparison to retrospective ECG-gated helical dual-source CT angiography. MATERIALS AND METHODS: This study was approved by the institutional review board; informed consent was obtained. One hundred thirty-nine patients referred for ECG-assisted dual-source CT angiography of the thoracic aorta were prospectively enrolled. Inclusion criteria were stable sinus rhythm and heart rate of 80 beats per minute or less. Tube voltage was adjusted to body mass index (< 25.0 kg/m(2), 100 kV, n = 58; > or = 25.0 kg/m(2), 120 kV, n = 81). In both cohorts, patients were randomly assigned to prospective or retrospective ECG assisted data acquisition. In both groups, tube current (250 mAs per rotation) was centered at 70% of the R-R cycle. The presence of motion or stair-step artifacts of the thoracic aorta was independently assessed by two readers. Effective radiation dose was calculated from the dose-length product. RESULTS: Subjective scoring of motion and stair-step artifacts was equivalent for both techniques. Scan length was not significantly different (23.8 cm +/- 2.4 [standard deviation] vs 23.7 cm +/- 2.5 for prospective and retrospective ECG triggered CT angiography, respectively; P = .54). Scanning time was significantly longer for prospective ECG-triggered CT angiography (18.8 seconds +/- 3.4 vs 16.4 seconds +/- 3.3, P < .001). Mean estimated effective dose was significantly lower for prospective data acquisition (100 kV, 1.9 mSv +/- 0.5 vs 4.1 mSv +/- 0.7, P < .001; 120 kV, 5.3 mSv +/- 1.1 vs 9.5 mSv +/- 3.0, P < .001). CONCLUSION: Prospective ECG-gated sequential dual-source CT angiography of the thoracic aorta is feasible, despite the slightly longer acquisition time. Thus, motion-free imaging of the thoracic aorta is possible at significantly lower radiation exposure than retrospective ECG-gated helical dual-source CT angiography in certain patients with a regular heart rate. PMID- 20160004 TI - State effects of major depression on the assessment of personality and personality disorder. AB - OBJECTIVE: The authors sought to determine whether personality disorders diagnosed during a depressive episode have long-term outcomes more typical of those of other patients with personality disorders or those of patients with noncomorbid major depression. METHOD: The authors used 6-year outcome data collected from the multisite Collaborative Longitudinal Personality Disorders Study (CLPS). Diagnoses and personality measures gathered from the study cohort at the index assessment using interview and self-report methods were associated with symptomatic, functional, and personality measures at 6-year follow-up. Of 668 patients initially recruited to the CLPS, 522 were followed for 6 years. All participants had either a DSM-IV diagnosis of one of four personality disorders (borderline, schizotypal, obsessive-compulsive, or avoidant) or a DSM-IV diagnosis of major depressive disorder with no accompanying personality disorder. RESULTS: Six-year outcomes for patients with comorbid personality disorder and major depressive disorder at the index evaluation were similar to those of patients with pure personality disorder and significantly worse than those of patients with pure major depressive disorder. Stability estimates of personality traits were similar for personality disorder patients with and without major depressive disorder at the index evaluation. CONCLUSIONS: These results suggest that personality disorder diagnoses established during depressive episodes are a valid reflection of personality pathology rather than an artifact of depressive mood. PMID- 20160005 TI - Association of depressed mood and mortality in older adults with and without cognitive impairment in a prospective naturalistic study. AB - OBJECTIVE: The authors examined predictors of mortality in individuals age 50 or older with or without cognitive impairment in a 12-year prospective naturalistic study of subcortical ischemic vascular disease focusing on symptoms of depressed mood, apathy, anhedonia, or anergia. METHOD: A total of 498 participants were recruited from the community and from memory clinics into a multicenter longitudinal study of subcortical ischemic vascular disease. For baseline cognitive status, 36% of participants were assessed as cognitively intact, 31% as cognitively impaired, and 33% as demented. All participants underwent a research protocol MRI, and 41% were classified as having subcortical lacunes. Depressed mood, anhedonia, anergia, and apathy were assessed at baseline using a structured behavioral assessment. Cox regression models were used to investigate the associations between neuropsychiatric symptoms and mortality, controlling for age, gender, race, education level, cognitive status, presence of vascular lacunes, and vascular risk factors. RESULTS: Of 498 participants, 175 (35%) died over the follow-up period, with a median survival time of 5.6 years. In the multivariate analyses, cognitive impairment, age, male gender, depressed mood, and the presence of lacunes predicted higher mortality. Participants with both lacunes and depressed mood had the shortest survival among all cognitive groups. The mortality hazard ratio for participants with depressed mood was 2.2 (95% CI=1.5-3.2) after adjustment for cognitive status, age, gender, education level, race, lacunes, and all vascular conditions. CONCLUSIONS: These findings suggest the importance of detecting depressed mood in individuals with cerebrovascular disease and of developing more aggressive treatment and preventive interventions for this vulnerable population. PMID- 20160006 TI - White matter integrity and cognitive impairment in first-episode psychosis. AB - OBJECTIVE: Impaired cognitive function has been identified as a core feature of schizophrenia. However, a significant proportion of patients do not show any cognitive deficits. The aim of this study was to assess if there were differences in white matter integrity between patients with and without cognitive impairment. METHOD: A diffusion tensor imaging study and neurocognitive assessment were conducted in 49 patients with first-episode psychosis and 41 healthy comparison subjects. Subjects were assessed using the Continuous Performance Test, the Grooved Pegboard Test, the Rey Auditory Verbal Learning Test, and the Trail Making Test Part B. For each test, the patient sample was subdivided according to performance, with those scoring more than one standard deviation below the normative mean categorized as impaired. For each cognitive domain, white matter fractional anisotropy in deficit and nondeficit subgroups was compared using a voxel-based analysis. A nonparametric statistical method, controlling for multiple comparisons, was applied. RESULTS: Impairment on the Trail Making Test Part B was associated with reduced fractional anisotropy in the right/left anterior thalamic radiation and inferior fronto-occipital fasciculus, forceps minor, and left superior and inferior longitudinal fasciculi. Patients exhibiting Grooved Pegboard Test impairment showed reduced fractional anisotropy in the forceps minor, inferior fronto-occipital fasciculus, anterior thalamic radiation, and corticospinal and corticopontine tracts. Impaired performance on the Rey Auditory Verbal Learning Test and Continuous Performance Test was not associated with significant differences in fractional anisotropy. CONCLUSION: Deficits in executive and motor functioning in patients with first-episode psychosis are associated with reductions in white matter integrity in the major fasciculi that connect the frontal and temporal cortices as well as in pathways connecting cortical and subcortical regions. Their presence at the onset of illness, in minimally medicated patients, indicates that these findings are not attributable to effects of chronic illness or its treatment. PMID- 20160008 TI - What propels sexual murderers: a proposed integrated theory of social learning and routine activities theories. AB - Despite the great interest in the study of sexual homicide, little is known about the processes involved in an individual's becoming motivated to sexually kill, deciding to sexually kill, and acting on that desire, intention, and opportunity. To date, no comprehensive model of sexual murdering from the offending perspective has been proposed in the criminological literature. This article incorporates the works of Akers and Cohen and Felson regarding their social learning theory and routine activities theory, respectively, to construct an integrated conceptual offending framework in sexual homicide. This integrated model produces a stronger and more comprehensive explanation of sexual murder than any single theory currently available. PMID- 20160007 TI - The nonpsychoactive cannabinoid cannabidiol inhibits 5-hydroxytryptamine3A receptor-mediated currents in Xenopus laevis oocytes. AB - The effect of the plant-derived nonpsychotropic cannabinoid, cannabidiol (CBD), on the function of hydroxytryptamine (5-HT)3A receptors expressed in Xenopus laevis oocytes was investigated using two-electrode voltage-clamp techniques. CBD reversibly inhibited 5-HT (1 microM)-evoked currents in a concentration-dependent manner (IC50 = 0.6 microM). CBD (1 microM) did not alter specific binding of the 5-HT3A antagonist [3H]3-(5-methyl-1H-imidazol-4-yl)-1-(1-methylindol-3-yl)propan 1-one (GR65630), in oocytes expressing 5-HT3A receptors. In the presence of 1 microM CBD, the maximal 5-HT-induced currents were also inhibited. The EC50 values were 1.2 and 1.4 microM, in the absence and presence of CBD, indicating that CBD acts as a noncompetitive antagonist of 5-HT3 receptors. Neither intracellular BAPTA injection nor pertussis toxin pretreatment (5 microg/ml) altered the CBD-evoked inhibition of 5-HT-induced currents. CBD inhibition was inversely correlated with 5-HT3A expression levels and mean 5-HT3 receptor current density. Pretreatment with actinomycin D, which inhibits protein transcription, decreased the mean 5-HT3 receptor current density and increased the magnitude of CBD inhibition. These data demonstrate that CBD is an allosteric inhibitor of 5-HT3 receptors expressed in X. laevis oocytes. They further suggest that allosteric inhibition of 5-HT3 receptors by CBD may contribute to its physiological roles in the modulation of nociception and emesis. PMID- 20160009 TI - Standard virtual biological parts: a repository of modular modeling components for synthetic biology. AB - MOTIVATION: Fabrication of synthetic biological systems is greatly enhanced by incorporating engineering design principles and techniques such as computer-aided design. To this end, the ongoing standardization of biological parts presents an opportunity to develop libraries of standard virtual parts in the form of mathematical models that can be combined to inform system design. RESULTS: We present an online Repository, populated with a collection of standardized models that can readily be recombined to model different biological systems using the inherent modularity support of the CellML 1.1 model exchange format. The applicability of this approach is demonstrated by modeling gold-medal winning iGEM machines. AVAILABILITY AND IMPLEMENTATION: The Repository is available online as part of http://models.cellml.org. We hope to stimulate the worldwide community to reuse and extend the models therein, and contribute to the Repository of Standard Virtual Parts thus founded. Systems Model architecture information for the Systems Model described here, along with an additional example and a tutorial, is also available as Supplementary information. The example Systems Model from this manuscript can be found at http://models.cellml.org/workspace/bugbuster. The Template models used in the example can be found at http://models.cellml.org/workspace/SVP_Templates200906. PMID- 20160011 TI - Functional interplay between acetylation and methylation of the RelA subunit of NF-kappaB. AB - Posttranslational modifications of the RelA subunit of NF-kappaB, including acetylation and methylation, play a key role in controlling the strength and duration of its nuclear activity. Whether these modifications are functionally linked is largely unknown. Here, we show that the acetylation of lysine 310 of RelA impairs the Set9-mediated methylation of lysines 314 and 315, which is important for the ubiquitination and degradation of chromatin-associated RelA. Abolishing the acetylation of lysine 310 either by the deacetylase SIRT1 or by mutating lysine 310 to arginine enhances methylation. Conversely, enhancing the acetylation of lysine 310 by depleting SIRT1 or by replacing lysine 310 with acetyl-mimetic glutamine inhibits methylation, thereby decreasing ubiquitination, prolonging the stability of chromatin-associated RelA, and enhancing the transcriptional activity of NF-kappaB. The acetylation of lysine 310 of RelA interferes with its interaction with Set9. Based on structural modeling of the SET domain of Set9 with RelA, we propose that the positive charge of lysine 310 is critical for the binding of RelA to a negatively charged "exosite" within the SET domain of Set9. Together, these findings demonstrate for the first time an interplay between RelA acetylation and methylation and also provide a novel mechanism for the regulation of lysine methylation by acetylation. PMID- 20160010 TI - CENP-A reduction induces a p53-dependent cellular senescence response to protect cells from executing defective mitoses. AB - Cellular senescence is an irreversible growth arrest and is presumed to be a natural barrier to tumor development. Like telomere shortening, certain defects in chromosome integrity can trigger senescence; however, the roles of centromere proteins in regulating commitment to the senescent state remains to be established. We examined chromatin structure in senescent human primary fibroblasts and found that CENP-A protein levels are diminished in senescent cells. Senescence-associated reduction of CENP-A is caused by transcriptional and posttranslational control. Surprisingly, forced reduction of CENP-A by short hairpin RNA was found to cause premature senescence in human primary fibroblasts. This premature senescence is dependent on a tumor suppressor, p53, but not on p16(INK4a)-Rb; the depletion of CENP-A in p53-deficient cells results in aberrant mitosis with chromosome missegregation. We propose that p53-dependent senescence that arises from CENP-A reduction acts as a "self-defense mechanism" to prevent centromere-defective cells from undergoing mitotic proliferation that potentially leads to massive generation of aneuploid cells. PMID- 20160012 TI - The RasGAP proteins Ira2 and neurofibromin are negatively regulated by Gpb1 in yeast and ETEA in humans. AB - The neurofibromatosis type 1 (NF1) gene encodes the GTPase-activating protein (GAP) neurofibromin, which negatively regulates Ras activity. The yeast Saccharomyces cerevisiae has two neurofibromin homologs, Ira1 and Ira2. To understand how these proteins are regulated, we utilized an unbiased proteomics approach to identify Ira2 and neurofibromin binding partners. We demonstrate that the Gpb1/Krh2 protein binds and negatively regulates Ira2 by promoting its ubiquitin-dependent proteolysis. We extended our findings to show that in mammalian cells, the ETEA/UBXD8 protein directly interacts with and negatively regulates neurofibromin. ETEA contains both UBA and UBX domains. Overexpression of ETEA downregulates neurofibromin in human cells. Purified ETEA, but not a mutant of ETEA that lacks the UBX domain, ubiquitinates the neurofibromin GAP related domain in vitro. Silencing of ETEA expression increases neurofibromin levels and downregulates Ras activity. These findings provide evidence for conserved ubiquitination pathways regulating the RasGAP proteins Ira2 (in yeast) and neurofibromin (in humans). PMID- 20160013 TI - Upregulated expression of B-cell antigen family tandem repeat proteins by Leishmania amastigotes. AB - Proteins with tandem repeat (TR) domains have been found in various protozoan parasites, and they are often targets of B-cell responses. Through systematic analyses of whole proteomes, we recently demonstrated that two trypanosomatid parasites, Leishmania infantum and Trypanosoma cruzi, are rich in antigenic proteins with large TR domains. However, the reason that these proteins are antigenic was unclear. Here, by performing molecular, immunological, and bioinformatic characterizations of Leishmania TR proteins, we found two possible factors affecting the antigenicity of these proteins; one factor is their fundamental composition as TR proteins, and the other is regulation of their expression by parasites. Enzyme-linked immunosorbent assays (ELISAs) using recombinant proteins revealed that the copy number of the repeat affects the affinity of binding between antigens and antibodies, as expected based on thermodynamic binding kinetics. Other than containing TR domains, the TR proteins do not share characteristics, such as sequence similarity or biased cellular location predicted by the presence of a signal sequence(s) and/or a transmembrane domain(s). However, the TR proteome contained a higher percentage of proteins upregulated in amastigotes than the whole proteome, and upregulated expression of a TR protein seemed to affect its antigenicity. These results indicate that Leishmania parasites actively utilize the TR protein family for parasitism in mammalian hosts. PMID- 20160014 TI - Evaluation of the antigenic diversity of placenta-binding Plasmodium falciparum variants and the antibody repertoire among pregnant women. AB - Pregnant women are infected by specific variants of Plasmodium falciparum that adhere and accumulate in the placenta. Using serological and molecular approaches, we assessed the global antigenic diversity of surface antigens expressed by placenta-binding isolates to better understand immunity to malaria in pregnancy and evolution of polymorphisms and to inform vaccine development. We found that placenta-binding isolates originating from all major regions where malaria occurs were commonly recognized by antibodies in different populations of pregnant women. There was substantial antigenic overlap and sharing of epitopes between isolates, including isolates from distant geographic locations, suggesting that there are limitations to antigenic diversity; however, differences between populations and isolates were also seen. Many women had cross reactive antibodies and/or a broad repertoire of antibodies to different isolates. Studying VAR2CSA as the major antigen expressed by placenta-binding isolates, we identified antibody epitopes encoded by variable sequence blocks in the DBL3 domain. Analysis of global var2csa DBL3 sequences demonstrated that there was extensive sharing of variable blocks between Africa, Asia, Papua New Guinea, and Latin America, which likely contributes to the high level of antigenic overlap between different isolates. However, there was also evidence of geographic clustering of sequences and differences in VAR2CSA sequences between populations. The results indicate that there is limited antigenic diversity in placenta-binding isolates and may explain why immunity to malaria in pregnancy can be achieved after exposure during one pregnancy. Inclusion of a limited number of variants in a candidate vaccine may be sufficient for broad population coverage, but geographic considerations may also have to be included in vaccine design. PMID- 20160015 TI - Sequence analysis and characterization of a transferable hybrid plasmid encoding multidrug resistance and enabling zoonotic potential for extraintestinal Escherichia coli. AB - ColV plasmids of extraintestinal pathogenic Escherichia coli (ExPEC) encode a variety of fitness and virulence factors and have long been associated with septicemia and avian colibacillosis. These plasmids are found significantly more often in ExPEC, including ExPEC associated with human neonatal meningitis and avian colibacillosis, than in commensal E. coli. Here we describe pAPEC-O103 ColBM, a hybrid RepFIIA/FIB plasmid harboring components of the ColV pathogenicity island and a multidrug resistance (MDR)-encoding island. This plasmid is mobilizable and confers the ability to cause septicemia in chickens, the ability to cause bacteremia resulting in meningitis in the rat model of human disease, and the ability to resist the killing effects of multiple antimicrobial agents and human serum. The results of a sequence analysis of this and other ColV plasmids supported previous findings which indicated that these plasmid types arose from a RepFIIA/FIB plasmid backbone on multiple occasions. Comparisons of pAPEC-O103-ColBM with other sequenced ColV and ColBM plasmids indicated that there is a core repertoire of virulence genes that might contribute to the ability of some ExPEC strains to cause high-level bacteremia and meningitis in a rat model. Examination of a neonatal meningitis E. coli (NMEC) population revealed that approximately 58% of the isolates examined harbored ColV-type plasmids and that 26% of these plasmids had genetic contents similar to that of pAPEC-O103-ColBM. The linkage of the ability to confer MDR and the ability contribute to multiple forms of human and animal disease on a single plasmid presents further challenges for preventing and treating ExPEC infections. PMID- 20160016 TI - Leptospiral endostatin-like protein A is a bacterial cell surface receptor for human plasminogen. AB - The spirochete Leptospira interrogans is a highly invasive pathogen of worldwide public health importance. Studies from our laboratories and another have demonstrated that L. interrogans can acquire host plasminogen on its surface. Exogenous plasminogen activators can then convert bound plasminogen into the functionally active protease plasmin. In this study, we extend upon those observations and report that leptospiral endostatin-like protein A (LenA) binds human plasminogen in a dose-dependent manner. LenA-plasminogen interactions were significantly inhibited by the lysine analog xi-aminocaproic acid, suggesting that the lysine-binding sites on the amino-terminal kringle portion of the plasminogen molecule play a role in the binding. Previous studies have shown that LenA also binds complement regulator factor H and the extracellular matrix component laminin. Plasminogen competed with both factor H and laminin for binding to LenA, which suggests overlapping ligand-binding sites on the bacterial receptor. Finally, LenA-bound plasminogen could be converted to plasmin, which in turn degraded fibrinogen, suggesting that acquisition of host-derived plasmin by LenA may aid bacterial dissemination throughout host tissues. PMID- 20160017 TI - Three surface exoglycosidases from Streptococcus pneumoniae, NanA, BgaA, and StrH, promote resistance to opsonophagocytic killing by human neutrophils. AB - Streptococcus pneumoniae (the pneumococcus) is a major human pathogen and a leading cause of inflammatory infections such as pneumonia and otitis media. An important mechanism for host defense against S. pneumoniae is opsonophagocytic killing by neutrophils. To persist in the human host, the pneumococcus has developed strategies to evade opsonization and subsequent neutrophil-mediated killing. Utilizing a genomic approach, we identified NanA, the major pneumococcal neuraminidase, as a factor important for resistance to opsonophagocytic killing in ex vivo killing assays using human neutrophils. The effect of NanA was shown using both type 4 (TIGR4) and type 6A clinical isolates. NanA promotes this resistance by acting in conjunction with two other surface-associated exoglycosidases, BgaA, a beta-galactosidase, and StrH, an N acetylglucosaminidase. Experiments using human serum showed that these exoglycosidases reduced deposition of complement component C3 on the pneumococcal surface, providing a mechanism for this resistance. Additionally, we have shown that antibodies in human serum do not contribute to this phenotype. These results demonstrate that deglycosylation of a human serum glycoconjugate(s) by the combined effects of NanA, BgaA, and StrH, is important for resistance to complement deposition and subsequent phagocytic killing of S. pneumoniae. PMID- 20160018 TI - Interaction of Francisella asiatica with tilapia (Oreochromis niloticus) innate immunity. AB - Members of the genus Francisella are facultative intracellular bacteria that cause important diseases in a wide variety of animals worldwide, including humans and fish. Several genes that are important for intramacrophage survival have been identified, including the iglC gene, which is found in the iglABCD operon in the Francisella sp. pathogenicity island (FPI). In the present study, we examined the interaction of wild-type Francisella asiatica and a Delta iglC mutant strain with fish serum and head kidney-derived macrophages (HKDM). Both the wild-type and the mutant strains were resistant to killing by normal and heat-inactivated sera. The wild-type F. asiatica is able to invade tilapia head kidney-derived macrophages and replicate vigorously within them, causing apoptosis and cytotoxicity in the macrophages at 24 and 36 h postinfection. The Delta iglC mutant, however, is defective for survival, replication, and the ability to cause cytotoxicity in HKDM, but the ability is restored when the mutant is complemented with the iglC gene. Uptake by the HKDM was mediated partially by complement and partially by macrophage mannose receptors, as demonstrated by in vitro assays. Light and electron microscopy analysis of the infected macrophages revealed intracellular bacteria present in a tight vacuole at 2 h postinoculation and the presence of numerous bacteria in spacious vacuoles at 12 h postinfection, with some bacteria free in the cytoplasm. PMID- 20160019 TI - Intracellular invasion by Orientia tsutsugamushi is mediated by integrin signaling and actin cytoskeleton rearrangements. AB - Orientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular pathogen. Previously, we reported that the 56-kDa type-specific antigen (TSA56), a major outer membrane protein of O. tsutsugamushi, binds to fibronectin and facilitates bacterial entry into the host cell, potentially via an interaction with integrins. Here, we demonstrated that O. tsutsugamushi colocalizes with integrin alpha 5 beta 1 and activates integrin signaling effectors, including focal adhesion kinase, Src kinase, and RhoA GTPase, and also recruits signaling adaptors, such as talin and paxillin, to the site of infection. Inhibition of protein tyrosine kinases or RhoA reduced intracellular invasion. We also observed substantial actin reorganization and membrane protrusions at the sites of infection of nonphagocytic host cells. Finally, we identified a region in the extracellular domain of TSA56 that binds to fibronectin. A peptide containing this region was able to significantly reduce bacterial invasion. Taken together, these results clearly indicate that O. tsutsugamushi exploits integrin-mediated signaling and the actin cytoskeleton for invasion of eukaryotic host cells. PMID- 20160021 TI - The use of focus groups to compare tobacco attitudes and behaviors between youth in urban and rural settings. AB - This exploratory study uses focus groups to examine the attitudes and behaviors of male adolescent tobacco users from urban and rural settings. Five focus groups, three urban and two rural, were conducted (n = 28). Results indicate that this is an interesting topic that generated interactions and discussion among participants. Themes that have emerged from the data include the sociability of tobacco initiation and access; tobacco preferences linked to image; social norms against secondhand smoke exposure, especially around children; ambivalence toward daily use as a habit versus an addiction; and avoidance of discussing cessation. The data from this study can help health departments distinguish and target prevention and intervention programs for youth in urban and rural settings. PMID- 20160022 TI - Reaching and retaining high-risk HIV/AIDS clients through the Internet. AB - The Internet is a popular way for people to meet casual sex partners. However, online outreach remains largely unexplored to promote voluntary counseling and testing for HIV. The Student Health Action Coalition's HIV testing program (SHAC HIV) targets high-risk clients through tailored Internet outreach via chat rooms, social networking sites, and online forums. The SHAC-HIV model also demonstrates that nontraditional testing sites can provide low-cost, client-centered, high quality services to support increased demand for HIV-testing services. Within the clinic, SHAC-HIV's testing model includes four major components: (a) reliance on a team of well-trained health sciences student volunteers; (b) rapid oral-fluid HIV tests; (c) universal, consent-based testing with client-centered health education and counseling; and (d) coordinated referrals for follow-up testing, treatment, and care. This approach reaches high-risk clients as well as undiagnosed infections. In 2007, there were nine confirmed positive results out of 389 tests, yielding a 2.3% positivity rate. This positivity percentage is higher than any other nontraditional testing site in North Carolina. This article describes the SHAC-HIV outreach and voluntary counseling and testing program with the aim of encouraging adoption of the model by other nontraditional testing sites. PMID- 20160020 TI - The yersiniabactin transport system is critical for the pathogenesis of bubonic and pneumonic plague. AB - Iron acquisition from the host is an important step in the pathogenic process. While Yersinia pestis has multiple iron transporters, the yersiniabactin (Ybt) siderophore-dependent system plays a major role in iron acquisition in vitro and in vivo. In this study, we determined that the Ybt system is required for the use of iron bound by transferrin and lactoferrin and examined the importance of the Ybt system for virulence in mouse models of bubonic and pneumonic plague. Y. pestis mutants unable to either transport Ybt or synthesize the siderophore were both essentially avirulent via subcutaneous injection (bubonic plague model). Surprisingly, via intranasal instillation (pneumonic plague model), we saw a difference in the virulence of Ybt biosynthetic and transport mutants. Ybt biosynthetic mutants displayed an approximately 24-fold-higher 50% lethal dose (LD(50)) than transport mutants. In contrast, under iron-restricted conditions in vitro, a Ybt transport mutant had a more severe growth defect than the Ybt biosynthetic mutant. Finally, a Delta pgm mutant had a greater loss of virulence than the Ybt biosynthetic mutant, indicating that the 102-kb pgm locus encodes a virulence factor, in addition to Ybt, that plays a role in the pathogenesis of pneumonic plague. PMID- 20160023 TI - The primary care nutrition training program: an approach to communication on behavior change. AB - The New York City Department of Health has designed a Primary Care Nutrition Training program for implementation in high-need neighborhoods that face growing diet-related epidemics of diabetes and obesity and a heavy burden of cardiovascular disease. Seven hundred fifty-six primary care team members complete pretest surveys and 665 complete posttest surveys at 45 training sessions between January and July 2007. Skills-building sessions center on the innovative application of visual aids and manipulatives and the provision of specific language for addressing nutritional issues with patients in busy primary care settings. Program evaluation data indicate that the training was well received by participants of all education levels, including medical assistants, physicians, nurses, and others, with 91% noting that the training content was pitched at about the right comprehension level for them. The Primary Care Nutrition Training Program offers a practical approach to continuing education for health professionals that may help to address the dearth of nutrition services currently in urban primary care. PMID- 20160024 TI - The E2D2 model: a dynamic approach to cancer prevention interventions. AB - The E2D2 model is a systematic, evidence-informed approach to designing comprehensive and strategic interventions focused on cancer prevention, with potential applications to the broader chronic disease community. The model was developed using an omnibus approach to account for multilevel influences and determinants of individual and population health, quality of life, and cancer risk. It is focused on the four pillars of health promotion and intervention practice (evidence, evaluation, development, and delivery) and moves through three fundamental phases: identification of risk factors and sensitizing concepts; mediating mechanisms and modifiable contexts; and program development, delivery, and evaluation. Distinguished from other models in the health promotion field, the E2D2 model is designed to be both sequential and feedback oriented, which allows for the emergence of new evidence, procedural revisions, and knowledge exchange to occur during any of its phases. PMID- 20160025 TI - TRF1 mediates mitotic abnormalities induced by Aurora-A overexpression. AB - Aurora-A, a conserved serine-threonine kinase, plays essential roles in mitosis. Aberrant upregulation of Aurora-A perturbs proper mitotic progression and results in a generation of multinucleated cells with centrosome amplification. The molecular mechanisms for these mitotic defects remain elusive. Here, we show that the overexpressed Aurora-A-induced mitotic defects depend on the telomeric protein TRF1. Live and fixed cell analyses revealed that Aurora-A overexpression in HeLa cells compromises chromosome biorientation, which leads to cytokinetic failure and tetraploidization with increased centrosome numbers. TRF1 depletion by small interfering RNAs or by tankyrase-1 overexpression suppresses Aurora-A induced occurrence of unaligned chromosomes in metaphase, thus preventing the subsequent abnormalities. We found that Aurora-A binds and phosphorylates TRF1. When TRF1 knockdown cells are complemented with wild-type TRF1, Aurora-A-induced mitotic defects recur. By contrast, a TRF1 mutant that is not phosphorylatable by Aurora-A does not restore such Aurora-A-induced phenotype. We propose that TRF1 phosphorylation by excessive Aurora-A may provoke abnormal mitosis and chromosomal instability. PMID- 20160026 TI - Celastrol suppresses angiogenesis-mediated tumor growth through inhibition of AKT/mammalian target of rapamycin pathway. AB - Understanding the molecular basis and target of traditional medicine is critical for drug development. Celastrol, derived from Trypterygium wilfordii Hook F. ("Thunder of God Vine"), a traditional Chinese medicine plant, has been assigned anticancer activities, but its mechanism is not well understood. Here, we investigated whether Celastrol could inhibit angiogenesis-mediated tumor growth and, if so, through what mechanism. When given s.c. to mice bearing human prostate cancer (PC-3 cell) xenografts, Celastrol (2 mg/kg/d) significantly reduced the volume and the weight of solid tumors and decreased tumor angiogenesis. We found that this agent inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, invasion, and capillary-like structure formation by primary cultured human umbilical vascular endothelial cells (HUVEC) in a dose-dependent manner. Furthermore, Celastrol abrogated VEGF induced sprouting of the vessels from aortic rings and inhibited vascular formation in the Matrigel plug assay in vivo. To understand the molecular mechanism of these activities, we next examined the signaling pathways in treated HUVECs and PC-3 tumor cells. Celastrol suppressed the VEGF-induced activation of AKT, mammalian target of rapamycin (mTOR), and ribosomal protein S6 kinase (P70S6K). Additionally, we found that Celastrol inhibited the proliferation of prostate cancer cells and induced apoptosis, and these effects correlated with the extent of inhibition of AKT/mTOR/P70S6K signaling. Taken together, our results suggest that Celastrol targets the AKT/mTOR/P70S6K pathway, which leads to suppression of tumor growth and angiogenesis. PMID- 20160027 TI - Role of secreted frizzled-related protein 3 in human renal cell carcinoma. AB - The secreted frizzled-related protein (sFRP) family plays an important role in the inhibition of the Wnt signaling pathway in various cancers. The functional significance of Wnt antagonist sFRP3 has not been investigated in renal cancer. We performed tissue microarray and found that the level of sFRP3 protein was high in normal kidney, low in primary renal cancer tissues, and high in metastatic renal cancer tissues. Therefore, we hypothesized that sFRP3 may play an important role in metastatic renal cancer. To test this hypothesis, we performed a series of experiments to determine the role of sFRP3 using primary and metastatic renal cancer cell lines. Functional analysis showed increased numbers of viable and invaded cells and tube formation and decreased numbers of apoptotic cells in the sFRP3-transfected renal cancer cell line A498. Promotion of tumor growth was also observed in nude mice injected with sFRP3-transfected A498 cells. In contrast, the number of viable cells and invasive cells was decreased in sFRP3 mRNA knockdown metastatic cells (ACHN and Hs891.T). To investigate the mechanism of sFRP3 function, we performed microarray analysis to see which genes were upregulated or downregulated by sFRP3 expression. Among these genes, MMP-3 and ANGPT1 were significantly upregulated in sFRP3-transfected cells. In conclusion, this is the first report to show that sFRP3 expression promotes cell growth, invasion, and inhibition of apoptosis in renal cancer cells. PMID- 20160028 TI - An oncogenic role for ETV1 in melanoma. AB - Copy gains involving chromosome 7p represent one of the most common genomic alterations found in melanomas, suggesting the presence of "driver" cancer genes. We identified several tumor samples that harbored focal amplifications situated at the peak of common chromosome 7p gains, in which the minimal common overlapping region spanned the ETV1 oncogene. Fluorescence in situ hybridization analysis revealed copy gains spanning the ETV1 locus in >40% of cases, with ETV1 amplification (>6 copies/cell) present in 13% of primary and 18% of metastatic melanomas. Melanoma cell lines, including those with ETV1 amplification, exhibited dependency on ETV1 expression for proliferation and anchorage independent growth. Moreover, overexpression of ETV1 in combination with oncogenic NRAS(G12D) transformed primary melanocytes and promoted tumor formation in mice. ETV1 overexpression elevated microphthalmia-associated transcription factor expression in immortalized melanocytes, which was necessary for ETV1 dependent oncogenicity. These observations implicate deregulated ETV1 in melanoma genesis and suggest a pivotal lineage dependency mediated by oncogenic ETS transcription factors in this malignancy. PMID- 20160029 TI - HER kinase axis receptor dimer partner switching occurs in response to EGFR tyrosine kinase inhibition despite failure to block cellular proliferation. AB - The human epidermal receptor (HER) axis consists of a dynamic, interconnected family of receptors that make critical contributions to a number of malignancies. Therapeutics targeting epidermal growth factor receptor (EGFR) are unable to effectively inhibit tumor growth in a majority of cases. These tumors are assumed to possess primary resistance to anti-EGFR therapies, but the consequence of inhibiting EGFR in these tumors is unclear. We established isogenic cell lines by prolonged gefitinib treatment at concentrations that are in excess of that which is required for complete EGFR kinase inhibition but only minimally affected growth. Subsequently, we monitored the ligand-dependent HER profiles based on receptor expression, phosphorylation, and dimerization in conjunction with measurements of cellular susceptibility to gefitinib. Chronic EGFR kinase inhibition rapidly switched the HER network from dependence on EGFR to HER2. However, both receptors activated the critical signaling proteins AKT and mitogen activated protein kinase, and in both cases, HER3 was the common association partner. Remarkably, the switch in receptor dimers caused diminished susceptibility to EGFR-targeted inhibitors gefitinib and cetuximab but acquired susceptibility to the HER2-targeted inhibitor pertuzumab. Overall, our study indicates that the EGFR pathway is responsive to EGFR inhibiting therapies that are not dependent on EGFR for their growth and survival, thus challenging the current definition of primary therapeutic resistance. Furthermore, EGFR kinase inhibition induces HER kinase receptors to engage in alternative dimerization that can ultimately influence therapeutic selection and responsiveness. PMID- 20160030 TI - An RNA interference screen identifies metabolic regulators NR1D1 and PBP as novel survival factors for breast cancer cells with the ERBB2 signature. AB - Overexpression of the adverse prognostic marker ERBB2 occurs in 30% of breast cancers; however, therapies targeting this gene have not proved to be as effective as was initially hoped. Transcriptional profiling meta-analyses have shown that there are approximately 150 genes co-overexpressed with ERBB2, suggesting that these genes may represent alternative factors influencing ERBB2 positive tumors. Here we describe an RNA interference-based analysis of these genes that identifies transcriptional regulators of fat synthesis and storage as being critical for the survival of these cells. These transcription factors, nuclear receptor subfamily 1, group D, member 1 (NR1D1) and peroxisome proliferator activated receptor gamma binding protein (PBP), both reside on ERBB2 containing 17q12-21 amplicons and are part of the ERBB2 expression signature. We show that NR1D1 and PBP act through a common pathway in upregulating several genes in the de novo fatty acid synthesis network, which is highly active in ERBB2-positive breast cancer cells. Malate dehydrogenase 1 and malic enzyme 1, enzymes that link glycolysis and fatty acid synthesis, are also regulated by NR1D1. The resulting high-level fat production from increased expression of these genes likely contributes to an abnormal cellular energy metabolism based on aerobic glycolysis. Together, these results show that the cells of this aggressive form of breast cancer are genetically preprogrammed to depend on NR1D1 and PBP for the energy production necessary for survival. PMID- 20160031 TI - A Bax-mediated mechanism for obatoclax-induced apoptosis of cholangiocarcinoma cells. AB - Apoptosis induction by BH3 mimetics is a therapeutic strategy for human cancer. These mimetics exert single-agent activity in cells "primed" for cell death. Primed cells are dependent upon antiapoptotic Bcl-2 proteins for survival and are characterized by the ability of the BH3 mimetic to induce cytochrome c release from their isolated mitochondria. Our aim was to examine the single-agent activity of obatoclax, a BH3 mimetic in cholangiocarcinoma cell lines. In clonogenic assays, inhibition of colony formation was observed by obatoclax treatment. Despite single-agent activity by obatoclax, the mitochondria from these cells did not release cytochrome c after incubation with this BH3 mimetic. However, immunofluorescence and cell fractionation studies identified Bax activation and translocation to mitochondria after treatment with obatoclax. shRNA targeted knockdown of Bax doubled the IC50 for obatoclax but did not abrogate its cytotoxicity, whereas knockdown of Bak did not alter the IC50. In a cell-free system, obatoclax induced an activating conformational change of Bax, which was attenuated by a site-directed mutagenesis of a previously identified protein activation site. Finally, the drug also elicited a significant in vivo response in a rodent model of this disease. In conclusion, single-agent obatoclax treatment results in Bax activation, which contributes, in part, to cell death in cholangiocarcinoma cells. These data indicate that BH3 mimetics may also function as direct activators of Bax and induce cytotoxicity in cells not otherwise primed for cell death. PMID- 20160032 TI - Immunotherapeutic suppression of indoleamine 2,3-dioxygenase and tumor growth with ethyl pyruvate. AB - Efforts to improve cancer care in the developing world will benefit from the identification of simple, inexpensive, and broadly applicable medical modalities based on emergent innovations in treatment, such as targeting mechanisms of tumoral immune tolerance. In this report, we offer preclinical evidence that the low-cost, anti-inflammatory agent ethyl pyruvate elicits a potent immune-based antitumor response through inhibition of indoleamine 2,3-dioxygenase (IDO), a key tolerogenic enzyme for many human tumors. Consistent with its reported ability to interfere with NF-kappaB function, ethyl pyruvate blocks IDO induction both in vitro and in vivo. Antitumor activity was achieved in mice with a noncytotoxic dosing regimen of ethyl pyruvate shown previously to protect against lethality from sepsis. Similar outcomes were obtained with the functional ethyl pyruvate analogue 2-acetamidoacrylate. Ethyl pyruvate was ineffective at suppressing tumor outgrowth in both athymic and Ido1-deficient mice, providing in vivo corroboration of the importance of T-cell-dependent immunity and IDO targeting for ethyl pyruvate to achieve antitumor efficacy. Although ethyl pyruvate has undergone early-phase clinical testing, this was done without consideration of its possible applicability to cancer. Our findings that IDO is effectively blocked by ethyl pyruvate treatment deepen emerging links between IDO and inflammatory processes. Further, these findings rationalize oncologic applications for this agent by providing a compelling basis to reposition ethyl pyruvate as a low-cost immunochemotherapy for clinical evaluation in cancer patients. PMID- 20160033 TI - The COXEN principle: translating signatures of in vitro chemosensitivity into tools for clinical outcome prediction and drug discovery in cancer. AB - Substantial effort has been devoted to in vitro testing of candidate chemotherapeutic agents. In particular, the United States National Cancer Institute Developmental Therapeutics Program (NCI-DTP) Human Tumor Cell Line Screen has screened hundreds of thousands of compounds and extracts, for which data on more than 40,000 compounds tested on a panel of 60 cancer cell lines (NCI 60) are publically available. In tandem, gene expression profiling has brought about a sea change in our understanding of cancer biology, allowing discovery of biomarkers or signatures able to characterize, classify, and prognosticate clinical behavior of human tumors. Recent studies have used tumor profiling matched to clinical trial outcome data to derive gene expression models predicting therapeutic outcomes, though such efforts are costly, time-consuming, tumor type-specific, and not amenable to rare diseases. Furthermore, addition of new or established drugs to multidrug combinations in which such models are already available requires the entire model to be re-derived. Can the aforementioned in vitro testing platform, coupled to the universal language of genomics, be used to develop, a priori, gene expression models predictive of clinical outcomes? Recent advances, including the CO-eXpression ExtrapolatioN (COXEN) algorithm, suggest that development of these models may be possible and raise important implications for future trial design and drug discovery. PMID- 20160034 TI - Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. AB - The proteasome was validated as an oncology target following the clinical success of VELCADE (bortezomib) for injection for the treatment of multiple myeloma and recurring mantle cell lymphoma. Consequently, several groups are pursuing the development of additional small-molecule proteasome inhibitors for both hematologic and solid tumor indications. Here, we describe MLN9708, a selective, orally bioavailable, second-generation proteasome inhibitor that is in phase I clinical development. MLN9708 has a shorter proteasome dissociation half-life and improved pharmacokinetics, pharmacodynamics, and antitumor activity compared with bortezomib. MLN9708 has a larger blood volume distribution at steady state, and analysis of 20S proteasome inhibition and markers of the unfolded protein response confirmed that MLN9708 has greater pharmacodynamic effects in tissues than bortezomib. MLN9708 showed activity in both solid tumor and hematologic preclinical xenograft models, and we found a correlation between greater pharmacodynamic responses and improved antitumor activity. Moreover, antitumor activity was shown via multiple dosing routes, including oral gavage. Taken together, these data support the clinical development of MLN9708 for both hematologic and solid tumor indications. PMID- 20160035 TI - Vitamin D deficiency promotes human breast cancer growth in a murine model of bone metastasis. AB - Vitamin D exerts antiproliferative, prodifferentiation, and proapoptotic effects on nonclassic target tissues such as breast. Blood levels of 25-hydroxyvitamin D [25(OH)D], the most sensitive indicator of vitamin D status, are inversely correlated with breast cancer risk; however, a causal relationship between vitamin D deficiency and breast cancer growth in bone has not been assessed. We examined the effect of vitamin D deficiency on the intraskeletal growth of the human breast cancer cell line MDA-MB-231-TxSA in a murine model of malignant bone lesions. Subsets of mice were treated concurrently with osteoprotegerin (OPG) to abrogate bone resorption. Outcomes were assessed by repeated radiographic and end point micro-computed tomography and histologic analyses. Mice weaned onto a vitamin D-free diet developed vitamin D deficiency within 4 weeks [mean +/- SE serum 25(OH)D: 11.5 +/- 0.5 nmol/L], which was sustained throughout the study and was associated with secondary hyperparathyroidism and accelerated bone turnover. Osteolytic lesions appeared earlier and were significantly larger in vitamin D deficient than in vitamin D-sufficient mice after 2 weeks (radiographic osteolysis: +121.5%; histologic tumor area: +314%; P < 0.05). Although OPG treatment reduced the size of radiographic osteolyses and tumor area in both groups, tumors remained larger in OPG-treated vitamin D-deficient compared with OPG-treated vitamin D-sufficient mice (0.53 +/- 0.05 mm(2) versus 0.19 +/- 0.05 mm2; P < 0.05). We conclude that vitamin D deficiency promotes the growth of human breast cancer cells in the bones of nude mice. These effects are partly mediated through secondary changes in the bone microenvironment, along with direct effects of vitamin D on tumor growth. PMID- 20160036 TI - Protein kinase D1 inhibits cell proliferation through matrix metalloproteinase-2 and matrix metalloproteinase-9 secretion in prostate cancer. AB - We and others previously showed that protein kinase D1 (PKD1) is downregulated in several cancers including prostate; interacts with E-cadherin, a major cell adhesion epithelial protein; and causes increased cell aggregation and decreased motility of prostate cancer cells. In this study, we show that PKD1 complexes with beta3-integrin, resulting in activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase-ERK pathway, which causes increased production of matrix metalloproteinase (MMP)-2 and MMP-9, that is associated with shedding of soluble 80 kDa E-cadherin extracellular domain. Interestingly, decreased cell proliferation following PKD1 transfection was rescued by MMP-2 and MMP-9 inhibitors and augmented by recombinant MMP-2 (rMMP-2) and rMMP-9 proteins, suggesting an antiproliferative role for MMPs in prostate cancer. Translational studies by in silico analysis of publicly available DNA microarray data sets show a significant direct correlation between PKD1 and MMP-2 expression in human prostate tissues. The study shows a novel mechanism for antiproliferative effects of PKD1, a protein of emerging translational interest in several human cancers, through increased production of MMP-2 and MMP-9 in cancer cells. PMID- 20160037 TI - Inactivation of junctional adhesion molecule-A enhances antitumoral immune response by promoting dendritic cell and T lymphocyte infiltration. AB - Junctional adhesion molecule-A (JAM-A)-null dendritic cells (DCs) are more motile and effective than their wild-type counterpart in promoting contact hypersensitivity reaction. Here, we show that the growth and aggressiveness of pancreatic islet cell carcinoma induced by SV40 T antigen expression in beta cells (Rip1Tag2 mice) are significantly reduced in JAM-A-null mice. Because these tumor cells do not express JAM-A, we focused on changes in stroma reactivity. In the absence of JAM-A, tumors showed a small but significant reduction in angiogenesis and a marked increase in the immune reaction with enhanced infiltration of DCs (CD11c+ and MHC-II+) and CD4+ and CD8+ lymphocytes. In contrast, phagocyte number was not affected. DC capacity to produce cytokines was not significantly altered, but transmigration through JAM-A-null endothelial cells was increased as compared with JAM-A-positive endothelium. On adoptive transfer, JAM-A(-/-) DCs were recruited to tumors at slightly but significantly higher rate than JAM-A(+/+) DCs. Ablation of CD4+ and CD8+ cells with specific antibodies abrogated the inhibitory effect of JAM-A deletion on tumor growth and angiogenesis. These findings support the idea that, in the Rip1Tag2 tumor model, abrogation of JAM-A reduces cancer development by increasing antitumor immune response. PMID- 20160038 TI - hsa-miR-29c* is linked to the prognosis of malignant pleural mesothelioma. AB - The inability to forecast outcomes for malignant mesothelioma prevents clinicians from providing aggressive multimodality therapy to the most appropriate individuals who may benefit from such an approach. We investigated whether specific microRNAs (miR) could segregate a largely surgically treated group of mesotheliomas into good or bad prognosis categories. A training set of 44 and a test set of 98 mesothelioma tumors were analyzed by a custom miR platform, along with 9 mesothelioma cell lines and 3 normal mesothelial lines. Functional implications as well as downstream targets of potential prognostic miRs were investigated. In both the training and test sets, hsa-miR-29c* was an independent prognostic factor for time to progression as well as survival after surgical cytoreduction. The miR was expressed at higher levels in epithelial mesothelioma, and the level of this miR could segregate patients with this histology into groups with differing prognosis. Increased expression of hsa-miR-29c* predicted a more favorable prognosis, and overexpression of the miR in mesothelioma cell lines resulted in significantly decreased proliferation, migration, invasion, and colony formation. Moreover, major epigenetic regulation of mesothelioma is mediated by hsa-miR-29c* and was shown through downregulation of DNA methyltransferases as well as upregulation of demethylating genes. A single miR has the potential to be a prognostic biomarker in mesothelioma, and validation of these findings as well as investigation of its downstream targets may give insight for potential therapies in the future. PMID- 20160039 TI - Talin1 promotes tumor invasion and metastasis via focal adhesion signaling and anoikis resistance. AB - Talin1 is a focal adhesion complex protein that regulates integrin interactions with ECM. This study investigated the significance of talin1 in prostate cancer progression to metastasis in vitro and in vivo. Talin1 overexpression enhanced prostate cancer cell adhesion, migration, and invasion by activating survival signals and conferring resistance to anoikis. ShRNA-mediated talin1 loss led to a significant suppression of prostate cancer cell migration and transendothelial invasion in vitro and a significant inhibition of prostate cancer metastasis in vivo. Talin1-regulated cell survival signals via phosphorylation of focal adhesion complex proteins, such as focal adhesion kinase and Src, and downstream activation of AKT. Targeting AKT activation led to a significant reduction of talin1-mediated prostate cancer cell invasion. Furthermore, talin1 immunoreactivity directly correlated with prostate tumor progression to metastasis in the transgenic adenocarcinoma mouse prostate mouse model. Talin1 profiling in human prostate specimens revealed a significantly higher expression of cytoplasmic talin1 in metastatic tissue compared with primary prostate tumors (P < 0.0001). These findings suggest (a) a therapeutic significance of disrupting talin1 signaling/focal adhesion interactions in targeting metastatic prostate cancer and (b) a potential value for talin1 as a marker of tumor progression to metastasis. PMID- 20160040 TI - Thioredoxin reductase-1 mediates curcumin-induced radiosensitization of squamous carcinoma cells. AB - Curcumin, a plant polyphenol, is a widely studied chemopreventive agent with demonstrated antitumor activities in preclinical studies and low toxicity profiles in multiple clinical trials against human malignancies. We previously showed that curcumin radiosensitizes cervical tumor cells without increasing the cytotoxic effects of radiation on normal human fibroblasts. Here we report that an inhibitory activity of curcumin on the antioxidant enzyme thioredoxin reductase-1 (TxnRd1) is required for curcumin-mediated radiosensitization of squamous carcinoma cells. Stable knockdown of TxnRd1 in both HeLa and FaDu cells nearly abolished curcumin-mediated radiosensitization. TxnRd1 knockdown cells showed decreased radiation-induced reactive oxygen species and sustained extracellular signal-regulated kinase 1/2 activation, which we previously showed was required for curcumin-mediated radiosensitization. Conversely, overexpressing catalytically active TxnRd1 in HEK293 cells, with low basal levels of TxnRd1, increased their sensitivity to curcumin alone and to the combination of curcumin and ionizing radiation. These results show the critical role of TxnRd1 in curcumin-mediated radiosensitization and suggest that TxnRd1 levels in tumors could have clinical value as a predictor of response to curcumin and radiotherapy. PMID- 20160041 TI - Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer. AB - FOXA1 and FOXA2, members of the forkhead transcription factor family, are critical for epithelial differentiation in many endoderm-derived organs, including the pancreas. However, their role in tumor progression is largely unknown. Here, we identified FOXA1 and FOXA2 as important antagonists of the epithelial-to-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDA) through their positive regulation of E-cadherin and maintenance of the epithelial phenotype. In human PDA samples, FOXA1/2 are expressed in all epithelia from normal to well-differentiated cancer cells, but are lost in undifferentiated cancer cells. In PDA cell lines, FOXA1/2 expression is consistently suppressed in experimental EMT models and RNAi silencing of FOXA1/2 alone is sufficient to induce EMT. Conversely, ectopic FOXA1/2 expression can potently neutralize several EMT-related E-cadherin repressive mechanisms. Finally, ectopic FOXA2 expression could reactivate E-cadherin expression in a PDA cell line with extensive promoter hypermethylation. In fact, demethylation mediated reactivation of E-cadherin expression in these cells required concurrent reactivation of endogenous FOXA2 expression. We conclude that suppression of FOXA1/2 expression is both necessary and sufficient for EMT during PDA malignant progression. PMID- 20160042 TI - Gene therapy for mesothelioma and lung cancer. AB - Both malignant pleural mesothelioma and advanced stage lung cancer are associated with a poor prognosis. Unfortunately, current treatment regimens have had only a modest effect on their progressive course. Gene therapy for thoracic malignancies represents a novel therapeutic approach and has been evaluated in a number of clinical trials over the last two decades. Using viral vectors or anti-sense RNA, strategies have included induction of apoptosis, tumor suppressor gene replacement, suicide gene expression, cytokine-based therapy, various vaccination approaches, and adoptive transfer of modified immune cells. This review will consider the clinical results, limitations, and future directions of gene therapy trials for thoracic malignancies. PMID- 20160043 TI - Cigarette smoke synergizes lipopolysaccharide-induced interleukin-1beta and tumor necrosis factor-alpha secretion from macrophages via substance P-mediated nuclear factor-kappaB activation. AB - A recent study has indicated that alveolar macrophages from smokers incubated with lipopolysaccharide (LPS) secrete much more IL-1beta and TNF-alpha than those from healthy nonsmokers, but the mechanisms underlying this augmented secretion by cigarette smoke (CS) remain unknown. CS and LPS reportedly promote macrophages' secreting substance P (SP) that could up-regulate these cytokines' secretion from macrophages by acting on neurokinin 1 receptor (NK1R). Moreover, NF-kappaB from macrophages participates in NK1R intracellular signaling and synthesis of these cytokines. The present in vitro study was undertaken to examine whether CS is able to synergize these cytokines' response to LPS in macrophages, and if so, whether an amplified SP secretion is responsible for this synergistic cytokines' response via a NK1R-driven NF-kappaB pathway. THP-1 derived and MH-S macrophages were exposed to control medium and CS condensate (CSC) without or with LPS. We found that LPS, CSC, and CSC+LPS significantly increased IL-1beta, TNF-alpha, and SP secretion and that SP secretion markedly preceded cytokines' secretion. CSC+LPS-induced responses were markedly greater than the sum of the responses to CSC and LPS alone, suggesting a synergistic effect. Blocking NK1R reduced the responses of IL-1beta, TNF-alpha, and NF-kappaB activation to CSC+LPS by 41, 40, and 46%, respectively. NF-kappaB inhibitors decreased the CSC+LPS-induced cytokines' responses by 70%. Our findings suggest that CS amplifies the LPS-induced macrophages' secretion of IL-1beta and TNF alpha through synergizing SP secretion, which activates NF-kappaB via binding with NK1R. PMID- 20160044 TI - Involvement of Gax gene in hypoxia-induced pulmonary hypertension, proliferation, and apoptosis of arterial smooth muscle cells. AB - Hypoxia down-regulates the expression of the growth arrest-specific homeobox (Gax) in pulmonary arterial smooth muscle cells (PASMCs), resulting in increased cell proliferation and decreased apoptosis, but the mechanism for this response remains unclear. The present study investigated the role of Gax in the development of hypoxia-induced pulmonary hypertension (PH). We found that hypoxia suppressed the expression of endogenous Gax in rats, but not in those pretreated intratracheally with a Gax construct (Ad-Gax). Hypoxic rats pretreated with Ad Gax were resistant to hypoxia-induced PH, right ventricular hypertrophy, increased wall thickness, and the muscularization of pulmonary arterioles. Hypoxia-induced PASMC proliferation and suppression of Gax expression were blocked by the Mitogen-activated protein kinase (MEK) inhibitor U0126. The PASMCs with Ad-Gax transfection exhibited hyperexpression of the Bcl-2-associated X protein (Bax) and hypoexpression of B-cell lymphoma 2 (Bcl-2), leading to cell apoptosis. Thus, our data indicate that the enhanced expression of Gax inhibits hypoxia-induced PASMC proliferation, probably via the extracellular-signal regulated kinase (ERK) 1/2 pathway, and induces the apoptosis of hypoxic PASMCs via the Bcl-2/Bax pathway. Gax may be a potential new therapeutic target for pulmonary hypertension. PMID- 20160045 TI - Pharmacokinetics and disposition of rilpivirine (TMC278) nanosuspension as a long acting injectable antiretroviral formulation. AB - The next-generation human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitor rilpivirine (TMC278) was administered in rats and dogs as single intramuscular (IM) or subcutaneous (SC) injections, formulated as a 200-nm nanosuspension. The plasma pharmacokinetics, injection site concentrations, disposition to lymphoid tissues, and tolerability were evaluated in support of its potential use as a once-monthly antiretroviral agent in humans. Rilpivirine plasma concentration-time profiles showed sustained and dose proportional release over 2 months in rats and over 6 months in dogs. The absolute bioavailability approached 100%, indicating a complete release from the depot, in spite of rilpivirine concentrations still being high at the injection site(s) 3 months after administration in dogs. For both species, IM administration was associated with higher initial peak plasma concentrations and a more rapid washout than SC administration, which resulted in a stable plasma concentration profile over at least 6 weeks in dogs. The rilpivirine concentrations in the lymph nodes draining the IM injection site exceeded the plasma concentrations by over 100-fold 1 month after administration, while the concentrations in the lymphoid tissues decreased to 3- to 6-fold the plasma concentrations beyond 3 months. These observations suggest uptake of nanoparticles by macrophages, which generates secondary depots in these lymph nodes. Both SC and IM injections were generally well tolerated and safe, with observations of a transient inflammatory response at the injection site. The findings support clinical investigations of rilpivirine nanosuspension as a long acting formulation to improve adherence during antiretroviral therapy and for preexposure prophylaxis. PMID- 20160046 TI - Single-dose pharmacokinetics of famciclovir in infants and population pharmacokinetic analysis in infants and children. AB - A multicenter, open-label study evaluated the single-dose pharmacokinetics and safety of a pediatric oral famciclovir (prodrug of penciclovir) formulation in infants aged 1 to 12 months with suspicion or evidence of herpes simplex virus infection. Individualized single doses of famciclovir based on the infant's body weight ranged from 25 to 175 mg. Eighteen infants were enrolled (1 to <3 months old [n = 8], 3 to <6 months old [n = 5], and 6 to 12 months old [n = 5]). Seventeen infants were included in the pharmacokinetic analysis; one infant experienced immediate emesis and was excluded. Mean C(max) and AUC(0-6) values of penciclovir in infants <6 months of age were approximately 3- to 4-fold lower than those in the 6- to 12-month age group. Specifically, mean AUC(0-6) was 2.2 microg h/ml in infants aged 1 to <3 months, 3.2 microg h/ml in infants aged 3 to <6 months, and 8.8 microg h/ml in infants aged 6 to 12 months. These data suggested that the dose administered to infants <6 months was less than optimal. Eight (44.4%) infants experienced at least one adverse event with gastrointestinal events reported most commonly. An updated pharmacokinetic analysis was conducted, which incorporated the data in infants from the present study and previously published data on children 1 to 12 years of age. An eight step dosing regimen was derived that targeted exposure in infants and children 6 months to 12 years of age to match the penciclovir AUC seen in adults after a 500 mg dose of famciclovir. PMID- 20160047 TI - Lack of a clinically relevant effect of an antacid on the pharmacokinetics of lersivirine. AB - Lersivirine (UK-453,061) is a next-generation nonnucleoside reverse transcriptase inhibitor that displays potent antiviral activity. Lersivirine solubility is pH dependent; therefore, the effect of coadministration of antacid on the pharmacokinetics of lersivirine in healthy subjects was investigated. The ratio of adjusted geometric means (750 mg lersivirine plus 20 ml Maalox Max/750 mg lersivirine alone) for the area under the curve from time zero extrapolated to infinite time (AUC(inf)) was 101.86%, showing that coadministration of an antacid had no effect on lersivirine exposure. Coadministration appeared to be safe and relatively well tolerated. PMID- 20160048 TI - Antistaphylococcal activities of telavancin tested alone and in combination by time-kill assay. AB - Synergy time-kill studies against 40 methicillin-resistant Staphylococcus aureus (MRSA) strains of differing resistance phenotypes were conducted. Subinhibitory concentrations of telavancin were combined with sub-MIC concentrations of other antimicrobial agents that might be used in combination with telavancin to provide Gram-negative coverage. The highest incidence of synergy was found after 24 h with gentamicin (90% of strains), followed by ceftriaxone (88%), rifampin and meropenem (each 65%), cefepime (45%), and ciprofloxacin (38%) for combinations tested at or below the intermediate breakpoint for each agent. PMID- 20160049 TI - Characterization of UDP-glucose dehydrogenase and UDP-glucose pyrophosphorylase mutants of Proteus mirabilis: defectiveness in polymyxin B resistance, swarming, and virulence. AB - Proteus mirabilis is known to be highly resistant to the action of polymyxin B (PB). However, the mechanism underlying PB resistance is not clear. In this study, we used Tn5 transposon mutagenesis to identify genes that may affect PB resistance in P. mirabilis. Two genes, ugd and galU, which may encode UDP-glucose dehydrogenase (Ugd) and UDP-glucose pyrophosphorylase (GalU), respectively, were identified. Knockout mutants of ugd and galU were found to be extremely sensitive to PB, presumably because of alterations in lipopolysaccharide (LPS) structure and cell surface architecture in these mutants. These mutants were defective in swarming, expressed lower levels of virulence factor hemolysin, and had lower cell invasion ability. Complementation of the ugd or galU mutant with the full length ugd or galU gene, respectively, led to the restoration of wild-type phenotypic traits. Interestingly, we found that the expression of Ugd and GalU was induced by PB through RppA, a putative response regulator of the bacterial two-component system that we identified previously. Mutation in either ugd or galU led to activation of RpoE, an extracytoplasmic function sigma factor that has been shown to be activated by protein misfolding and alterations in cell surface structure in other bacteria. Activation of RpoE or RpoE overexpression was found to cause inhibition of FlhDC and hemolysin expression. To our knowledge, this is the first report describing the roles and regulation of Ugd and GalU in P. mirabilis. PMID- 20160050 TI - Empiric combination antibiotic therapy is associated with improved outcome against sepsis due to Gram-negative bacteria: a retrospective analysis. AB - The optimal approach for empirical antibiotic therapy in patients with severe sepsis and septic shock remains controversial. A retrospective cohort study was conducted in the intensive care units of a university hospital. The data from 760 patients with severe sepsis or septic shock associated with Gram-negative bacteremia was analyzed. Among this cohort, 238 (31.3%) patients received inappropriate initial antimicrobial therapy (IIAT). The hospital mortality rate was statistically greater among patients receiving IIAT compared to those initially treated with an appropriate antibiotic regimen (51.7% versus 36.4%; P < 0.001). Patients treated with an empirical combination antibiotic regimen directed against Gram-negative bacteria (i.e., beta-lactam plus aminoglycoside or fluoroquinolone) were less likely to receive IIAT compared to monotherapy (22.2% versus 36.0%; P < 0.001). The addition of an aminoglycoside to a carbapenem would have increased appropriate initial therapy from 89.7 to 94.2%. Similarly, the addition of an aminoglycoside would have increased the appropriate initial therapy for cefepime (83.4 to 89.9%) and piperacillin-tazobactam (79.6 to 91.4%). Logistic regression analysis identified IIAT (adjusted odds ratio [AOR], 2.30; 95% confidence interval [CI] = 1.89 to 2.80) and increasing Apache II scores (1 point increments) (AOR, 1.11; 95% CI = 1.09 to 1.13) as independent predictors for hospital mortality. In conclusion, combination empirical antimicrobial therapy directed against Gram-negative bacteria was associated with greater initial appropriate therapy compared to monotherapy in patients with severe sepsis and septic shock. Our experience suggests that aminoglycosides offer broader coverage than fluoroquinolones as combination agents for patients with this serious infection. PMID- 20160051 TI - Efflux pumps are involved in the defense of Gram-negative bacteria against the natural products isobavachalcone and diospyrone. AB - The activities of two naturally occurring compounds, isobavachalcone and diospyrone, against documented strains and multidrug-resistant (MDR) Gram negative bacterial isolates were evaluated. The results indicated that the two compounds exhibited intrinsic antibacterial activity against several Gram negative bacteria, and their activities were significantly improved in the presence of an efflux pump inhibitor (MIC values decreased to below 10 microg/ml). In addition, the activities of isobavachalcone and diospyrone against various strains exhibiting deletions of the major efflux pump components (AcrAB, TolC) were significantly increased. The overall results indicate that isobavachalcone and diospyrone could be candidates for the development of new drugs against MDR strains and that their use in combination with efflux pump inhibitors reinforces their activity. PMID- 20160052 TI - Kinetic parameters of efflux of penicillins by the multidrug efflux transporter AcrAB-TolC of Escherichia coli. AB - The multidrug efflux transporter AcrAB-TolC is known to pump out a diverse range of antibiotics, including beta-lactams. However, the kinetic constants of the efflux process, needed for the quantitative understanding of resistance, were not available until those accompanying the efflux of some cephalosporins were recently determined by combining efflux with the hydrolysis of drugs by the periplasmic beta-lactamase. In the present study we extended this approach to the study of a wide range of penicillins, from ampicillin and penicillin V to ureidopenicillins and isoxazolylpenicillins, by combining efflux with hydrolysis with the OXA-7 penicillinase. We found that the penicillins had a much stronger apparent affinity to AcrB and higher maximum rates of efflux than the cephalosporins. All penicillins showed strong positive cooperativity kinetics for export. The kinetic constants obtained were validated, as the MICs theoretically predicted on the basis of efflux and hydrolysis kinetics were remarkably similar to the observed MICs (except for the isoxazolylpenicillins). Surprisingly, however, the efflux kinetics of cloxacillin, for example, whose MIC decreased 512 fold in Escherichia coli upon the genetic deletion of the acrB gene, were quite similar to those of ampicillin, whose MIC decreased only 2-fold with the same treatment. Analysis of this phenomenon showed that the extensive decrease in the MIC for the acrB mutant is primarily due to the low permeation of the drug and that comparison of the MICs between the parent and the acrB strains is a very poor measure of the ability of AcrB to pump a drug out. PMID- 20160053 TI - Inhibitors of Leishmania GDP-mannose pyrophosphorylase identified by high throughput screening of small-molecule chemical library. AB - The current treatment for leishmaniasis is based on chemotherapy, which relies on a handful of drugs with serious limitations, such as high cost, toxicity, and a lack of efficacy in regions of endemicity. Therefore, the development of new, effective, and affordable antileishmanial drugs is a global health priority. Leishmania synthesizes a range of mannose-rich glycoconjugates that are essential for parasite virulence and survival. A prerequisite for glycoconjugate biosynthesis is the conversion of monosaccharides to the activated mannose donor, GDP-mannose, the product of a reaction catalyzed by GDP-mannose pyrophosphorylase (GDP-MP). The deletion of the gene encoding GDP-MP in Leishmania led to a total loss of virulence, indicating that the enzyme is an ideal drug target. We developed a phosphate sensor-based high-throughput screening assay to quantify the activity of GDP-MP and screened a library containing approximately 80,000 lead-like compounds for GDP-MP inhibitors. On the basis of their GDP-MP inhibitory properties and chemical structures, the activities of 20 compounds which were not toxic to mammalian cells were tested against ex vivo amastigotes and in macrophage amastigote assays. The most potent compound identified in the primary screen (compound 3), a quinoline derivative, demonstrated dose-dependent activity in both assays (50% inhibitory concentration = 21.9 microM in the macrophage assay) and was shown to be nontoxic to human fibroblasts. In order to elucidate signs of an early structure-activity relationship (SAR) for this class of compounds, we obtained and tested analogues of compound 3 and undertook limited medicinal chemistry optimization, which included the use of a number of SAR probes of the piperazinyl aryl substituent of compound 3. We have identified novel candidate compounds for the design and synthesis of antileishmanial therapeutics. PMID- 20160054 TI - Fast standardized therapeutic-efficacy assay for drug discovery against tuberculosis. AB - Murine models of Mycobacterium tuberculosis infection are essential tools in drug discovery. Here we describe a fast standardized 9-day acute assay intended to measure the efficacy of drugs against M. tuberculosis growing in the lungs of immunocompetent mice. This assay is highly reproducible, allows good throughput, and was validated for drug lead optimization using isoniazid, rifampin, ethambutol, pyrazinamide, linezolid, and moxifloxacin. PMID- 20160055 TI - Evaluation of standard chemotherapy in the guinea pig model of tuberculosis. AB - The purpose of this study was 2-fold. First, we evaluated standard chemotherapy in the guinea pig model of tuberculosis to determine if this animal species could productively be used for this purpose. Second, given the similarities of the pathology of disease in guinea pigs and humans, we wished to evaluate additional parameters, including magnetic resonance imaging, microscopy, and cytokine expression and lymphocyte phenotypes, in response to an infection treated with drug therapy. This study shows that conventional rifampin-isoniazid-pyrazinamide chemotherapy significantly decreased the numbers of the highly virulent Erdman K01 strain of Mycobacterium tuberculosis, with most of the bacilli being eliminated in a month. Despite this result, bacteria could still be detected in the lungs and other tissues for at least another 3 to 4 months. Resolution of the nonnecrotic granulomas in the lungs and lymph nodes could be clearly visualized by magnetic resonance imaging at the macroscopic level. Microscopically, the majority of the pulmonary and extrapulmonary inflammation resolved spontaneously, leaving residual lesions composed of dystrophic calcification and fibrosis marking the site of necrosis of the primary lesion. Residual calcified lesions, which were also associated with pulmonary lymphangitis, contained acid-fast bacilli even following aggressive chemotherapy. The presence of intact extracellular bacilli within these lesions suggests that these could serve as the primary sites of disease reactivation. The chemotherapy reduced the level of T cell influx into infected tissues and was accompanied by a large and sustained increase in TH1 cytokine expression. Chemotherapy also prevented the emergence in lung tissues of high levels of interleukin-10 and Foxp3-positive cells, known markers of regulatory T cells. PMID- 20160056 TI - Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism. AB - Artemisinin (ART)-based combination therapies (ACTs) are the first-line drugs-and often the last treatments-that can effectively cure Plasmodium falciparum infections. Unfortunately, the decreased clinical efficacy of artesunate, one of the major ART derivatives, was recently reported along the Thailand-Cambodia border. Through long-term artemisinin pressure in vitro, we have obtained an ART tolerant strain that can survive extremely high doses of ART. We showed that drug pressure could induce a subpopulation of ring stages into developmental arrest, which can explain the ART tolerance in P. falciparum. We also observed interesting transcriptomic modifications possibly associated with the acquisition of ART tolerance. These modifications include the overexpression of heat shock and erythrocyte surface proteins and the downexpression of a cell cycle regulator and a DNA biosynthesis protein. This study highlights a new phenomenon in the Plasmodium response to ART that may explain the delayed clearance of parasites after artesunate treatment observed on the Thailand-Cambodia border and that provides important information for achieving a better understanding of the mechanisms of antimalarial resistance. PMID- 20160057 TI - Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia/lymphoma. AB - PURPOSE: Adult T-cell leukemia/lymphoma (ATLL) has a very poor prognosis. We have developed the humanized defucosylated anti-CC chemokine receptor 4 (CCR4) monoclonal antibody KW-0761 as a next generation immunotherapeutic agent. The first aim of the present study was to evaluate whether the antitumor activity of KW-0761 would likely be sufficient for therapeutic clinical application against ATLL. The second aim was to fully elucidate the mechanism of antibody-dependent cellular cytotoxicity (ADCC) mediated by this defucosylated monoclonal antibody. EXPERIMENTAL DESIGN: The antitumor activity of KW-0761 against ATLL cell lines was evaluated in vitro using human cells and in mice in vivo. Primary ATLL cells from 23 patients were evaluated for susceptibility to autologous ADCC with KW 0761 by two independent methods. RESULTS: KW-0761 showed potent antitumor activity against ATLL cell lines both in vitro and in the ATLL mouse model in vivo. In addition, KW-0761 showed potent antitumor activity mediated by highly enhanced ADCC against primary ATLL cells both in vitro and ex vivo in an autologous setting. The degree of KW-0761 ADCC against primary ATLL cells in an autologous setting was mainly determined by the amount of effector natural killer cells present, but not the amount of the target molecule CCR4 on the ATLL cell surface. CONCLUSION: KW-0761 should be sufficiently active for therapeutic clinical application for ATLL. In addition, combination treatment strategies that augment natural killer cell activity should be promising for amplifying the effect of KW-0761. In the near future, the actual efficacy of KW-0761 will be established in pivotal clinical trials. PMID- 20160058 TI - Preclinical investigation of PEGylated tumor necrosis factor alpha in dogs with spontaneous tumors: phase I evaluation. AB - PURPOSE: Tumor necrosis factor-alpha (TNF) is a cytokine with potent antitumor activity; however, toxicity and short half-life have limited its utility. Polyethylene glycol (PEG) conjugation of biotherapeutics can decrease immunogenicity while improving bioactivity and half-life. PEGylation of TNF (PEG TNF) significantly improved half-life and toxicity in mice, resulting in enhanced antitumor activity. This study characterized toxicity, biological effect, and antitumor activity of PEG-TNF in pet dogs with spontaneous cancer. EXPERIMENTAL DESIGN: A phase I clinical trial enrolled dogs with measurable tumors in which standard therapy had failed or been declined. Physiologic, hematologic, and biochemical parameters were evaluated and tumor biopsies obtained serially. A subset of patients underwent serial dynamic contrast-enhanced magnetic resonance imaging. RESULTS: Fifteen dogs were enrolled at doses from 20.0 to 30.0 microg/kg. Dose-limiting toxicity at 30.0 microg/kg consisted of vascular leak in one and hypotension/coagulopathy in one, establishing 26.7 microg/kg as the maximum tolerated dose. Mean elimination half-life was 15.3 +/- 4.9 hours. Biological activity (transient fever and leukopenia, increased tumor inflammation, and necrosis) was observed at all dosages. A significant increase in tumor blood flow was observed with dynamic contrast-enhanced magnetic resonance imaging. Minor/transient antitumor responses were observed in dogs with melanoma, squamous cell carcinoma, and mammary carcinoma, and a partial response was observed in a dog with angiosarcoma. CONCLUSIONS: Using a clinically relevant, spontaneous large animal model of neoplasia, we have shown that biologically effective doses of PEG-TNF can be administered safely, and that PEG TNF administration is associated with encouraging biological activity. These results justify the clinical evaluation of PEG-TNF in human cancer. PMID- 20160059 TI - ZIP4 regulates pancreatic cancer cell growth by activating IL-6/STAT3 pathway through zinc finger transcription factor CREB. AB - PURPOSE: Recent studies indicate a strong correlation of zinc transporter ZIP4 and pancreatic cancer progression; however, the underlying mechanisms are unclear. We have recently found that ZIP4 is overexpressed in pancreatic cancer. In this study, we investigated the signaling pathway through which ZIP4 regulates pancreatic cancer growth. EXPERIMENTAL DESIGN: The expression of cyclin D1, interleukin 6 (IL-6), and signal transducer and activator of transcription 3 (STAT3) in pancreatic cancer xenografts and cells were examined by real-time PCR, Bio-Plex cytokine assay, and Western blot, respectively. The activity of cAMP response element-binding protein (CREB) is examined by a promoter activity assay. RESULTS: Cyclin D1 was significantly increased in the ZIP4 overexpressing MIA PaCa-2 cells (MIA-ZIP4)-injected orthotopic xenografts and was downregulated in the ZIP4-silenced ASPC-1 (ASPC-shZIP4) group. The phosphorylation of STAT3, an upstream activator of cyclin D1, was increased in MIA-ZIP4 cells and decreased in ASPC-shZIP4 cells. IL-6, a known upstream activator for STAT3, was also found to be significantly increased in the MIA-ZIP4 cells and xenografts and decreased in the ASPC-shZIP4 group. Overexpression of ZIP4 led to a 75% increase of IL-6 promoter activity and caused increased phosphorylation of CREB. CONCLUSIONS: Our study suggest that ZIP4 overexpression causes increased IL-6 transcription through CREB, which in turn activates STAT3 and leads to increased cyclin D1 expression, resulting in increased cell proliferation and tumor progression in pancreatic cancer. These results elucidated a novel pathway in ZIP4-mediated pancreatic cancer growth and suggest new therapeutic targets, including ZIP4, IL 6, and STAT3, in pancreatic cancer treatment. PMID- 20160060 TI - Diverse patterns of T-cell response against multiple newly identified human Y chromosome-encoded minor histocompatibility epitopes. AB - PURPOSE: Donor T cells respond to minor histocompatibility antigens (mHA), resulting in both graft-versus-host disease and graft versus leukemia after allogeneic hematopoietic stem cell transplantation. Because relatively few mHAs are known, we developed a new approach to predict and subsequently validate candidate mHA. EXPERIMENTAL DESIGN: We developed an algorithm based on genetic disparities between Y chromosome-encoded and X chromosome-encoded proteins and known requirements for binding to HLA class I molecules to predict Y chromosome derived, HLA A*0201-restricted peptides (HY) and ranked peptides based on potential immunogenicity. We evaluated T-cell responses to 41 candidate peptides in 28 male recipients with female donors (FM), 22 male recipients with male donors (MM), and 26 normal individuals. All patients and donors were HLA A*0201 positive. RESULTS: Thirteen peptides derived from five proteins elicited significantly greater T-cell responses in FM patients compared with MM patients and in normal females compared with normal males. Six peptides were more immunogenic than the only previously known HLA A*0201-restricted Y-encoded mHA. Twenty-seven of 28 FM patients responded to at least one HY peptide, but despite a common Y chromosome mismatch and expression of HLA A*0201, each patient responded to a unique set of peptides. CONCLUSIONS: Novel HLA A*0201-restricted HY epitopes can be predicted and validated in patients after allogeneic hematopoietic stem cell transplantation. Highly diverse patterns of T-cell response against these epitopes have been identified. Prospective monitoring of responses to large panels of immunogenic peptides can facilitate the identification of clinically relevant targets of graft-versus-host disease and graft versus leukemia. PMID- 20160062 TI - IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. AB - PURPOSE: Recent studies have shown the prognostic significance of IDH1 mutations in glioma. It is yet unclear if IDH1 mutations are predictive for outcome to chemotherapy. We determined the effect of IDH1 mutations on progression-free survival and overall survival (OS), and its correlation with other clinical and molecular features in the prospective randomized European Organization for Research and Treatment of Cancer study 26951 on adjuvant procarbazine, 1-(2 chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine (PCV) in anaplastic oligodendroglioma. EXPERIMENTAL DESIGN: IDH1 and IDH2 alterations of the mutational hotspot codons R132 and R172 were assessed by the bidirectional cycle sequencing of PCR-amplified fragments. MGMT promoter methylation was assessed using methylation-specific multiplex ligation-dependant probe amplification based on methylation-sensitive restriction analysis. Loss of chromosomes 1p, 19q, 10, and 10q and the gain of 7 and the EGFR gene were assessed with fluorescence in situ hybridization. RESULTS: From 159 patients, sufficient material was available for IDH1 analysis. In 151 and 118 of these patients, respectively, the 1p/19q status and the MGMT promoter methylation status were known. In 73 cases (46%), an IDH1 mutation was found and only one IDH2 mutation was identified. The presence of IDH1 mutations correlated with 1p/19q codeletion and MGMT promoter methylation, and inversely correlated with loss of chromosome 10, EGFR amplification, polysomy of chromosome 7, and the presence of necrosis. IDH1 mutations were found to be prognostic in the radiotherapy- and the radiotherapy/PCV-treated patients, for both progression-free survival and OS. With Cox proportional hazard modeling for OS with stepwise selection, IDH1 mutations and 1p/19q codeletion but not MGMT promoter methylation were independent prognostic factors. CONCLUSION: In this homogeneously treated group of anaplastic oligodendroglioma patients, the presence of IDH1 mutations was found to carry a very strong prognostic significance for OS but without evidence of a predictive significance for outcome to PCV chemotherapy. IDH1 mutations were strongly associated with 1p/19q codeletion and MGMT promoter methylation. PMID- 20160061 TI - Evaluation of treatment-associated inflammatory response on diffusion-weighted magnetic resonance imaging and 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography imaging biomarkers. AB - PURPOSE: Functional imaging biomarkers of cancer treatment response offer the potential for early determination of outcome through the assessment of biochemical, physiologic, and microenvironmental readouts. Cell death may result in an immunologic response, thus complicating the interpretation of biomarker readouts. This study evaluated the temporal effect of treatment-associated inflammatory activity on diffusion magnetic resonance imaging and 2-[(18)F] fluoro-2-deoxy-D-glucose-positron emission tomography imaging (FDG-PET) biomarkers to delineate the effects of the inflammatory response on imaging readouts. EXPERIMENTAL DESIGN: Rats with intracerebral 9L gliosarcomas were separated into four groups consisting of control, an immunosuppressive agent dexamethasone (Dex), 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and BCNU+Dex. Animals were imaged using diffusion-weighted magnetic resonance imaging and FDG PET at 0, 3, and 7 days posttreatment. RESULTS: In the BCNU- and BCNU+Dex-treated animal groups, diffusion values increased progressively over the 7-day study period to approximately 23% over baseline. The FDG percentage change of standard uptake value decreased at day 3 (-30.9%) but increased over baseline levels at day 7 (+20.1%). FDG-PET of BCNU+Dex-treated animals were found to have percentage of standard uptake value reductions of -31.4% and -24.7% at days 3 and 7, respectively, following treatment. Activated macrophages were observed on day 7 in the BCNU treatment group with much fewer found in the BCNU+Dex group. CONCLUSIONS: Results revealed that treatment-associated inflammatory response following tumor therapy resulted in the accentuation of tumor diffusion response along with a corresponding increase in tumor FDG uptake due to the presence of glucose-consuming activated macrophages. The dynamics and magnitude of potential inflammatory response should be considered when interpreting imaging biomarker results. PMID- 20160064 TI - Critical role of G(alpha)12 and G(alpha)13 for human small cell lung cancer cell proliferation in vitro and tumor growth in vivo. AB - PURPOSE: In small cell lung cancer cells (SCLC), various autocrine stimuli lead to the parallel activation of G(q/11) and G(12/13) proteins. Although the contribution of the G(q/11)-phospholipase C-beta cascade to mitogenic effects in SCLC cells is well established, the relevance of G(12/13) signaling is still elusive. In other tumor entities, G(12/13) activation promotes invasiveness without affecting cellular proliferation. Here, we investigate the role of G(12/13)-dependent signaling in SCLC. EXPERIMENTAL DESIGN: We used small hairpin RNA-mediated targeting of G(alpha)(12), G(alpha)(13), or both in H69 and H209 cells and analyzed the effects of G(alpha)(12) and/or G(alpha)(13) knockdown on tumor cells in vitro, tumor growth in vivo, and mitogen-activated protein kinase (MAPK) activation. RESULTS: Lentiviral expression of small hairpin RNAs resulted in robust and specific G(alpha)(12) and G(alpha)(13) knockdown as well as markedly inhibited proliferation, colony formation, and bradykinin-promoted stimulation of cell growth. Analyzing the activation status of all three major MAPK families revealed nonredundant functions of G(alpha)(12) and G(alpha)(13) in SCLC and a marked p42/p44 activation upon G(alpha)(12)/G(alpha)(13) knockdown. In a s.c. tumor xenograft mouse model, G(alpha)(12) or G(alpha)(13) downregulation led to decreased tumor growth due to reduced tumor cell proliferation. More importantly, G(alpha)(12)/G(alpha)(13) double knockdown completely abolished H69 tumorigenicity in mice. CONCLUSIONS: G(alpha)(12) and G(alpha)13) exert a complex pattern of nonredundant effects in SCLC, and in contrast to other tumor types, SCLC cell proliferation in vitro and tumorigenicity in vivo critically depend on G(12/13) signaling. Due to the complete abolishment of tumorgenicity in our study, RNAi-mediated double knockdown may provide a promising new avenue in SCLC treatment. PMID- 20160063 TI - Evaluation of the ETS-related gene mRNA in urine for the detection of prostate cancer. AB - PURPOSE: Prevalent gene fusions in prostate cancer involve androgen-regulated promoters (primarily TMPRSS2) and ETS transcription factors (predominantly ETS regulated gene (ERG)], which result in tumor selective overexpression of ERG in two thirds of patients. Because diverse genomic fusion events lead to ERG overexpression in prostate cancer, we reasoned that it may be more practical to capture such alterations using an assay targeting ERG sequences retained in such gene fusions. This study evaluates the potential of an assay quantitating ERG mRNA in post-digital rectal exam (DRE) urine for improving prostate cancer detection. EXPERIMENTAL DESIGN: Patients scheduled to undergo transrectal ultrasound-guided needle biopsy of the prostate were prospectively enrolled. On the day of biopsy, patients provided a urine sample immediately following a DRE. Urine ERG mRNA was measured and normalized to urine prostate-specific antigen (PSA) mRNA using the DTS 400 system. Demographic traits, clinical characteristics and biopsy results were analyzed for association with urine ERG score. RESULTS: The study was conducted on 237 patients. Prostate cancer was shown on biopsy in 40.9% of study subjects. A higher urine ERG score associated significantly with malignancy on biopsy (P = 0.0145), but not with clinical stage or Gleason score. Urine ERG score performed best in Caucasians and in men with a PSA of r(s) > 0.48) and their perceptions of treatment benefit from hormonal therapy (r(s) = 0.28) and combined therapy (r(s) = 0.27). These relationships were significantly more pronounced for those with higher numeracy, especially for perceived benefit of combined therapy. Results suggest that numeracy influences a patient's ability to interpret numerical estimates of treatment efficacy from decision aids such as Adjuvant!. PMID- 20160072 TI - Retraction for Cannata et al., Triplex-forming oligonucleotide orthophenanthroline conjugates for efficient targeted genome modification. PMID- 20160071 TI - Transcriptional corepressor TLE1 functions with Runx2 in epigenetic repression of ribosomal RNA genes. AB - Epigenetic control of ribosomal RNA (rRNA) gene transcription by cell type specific regulators, such as the osteogenic transcription factor Runx2, conveys cellular memory of growth and differentiation to progeny cells during mitosis. Here, we examined whether coregulatory proteins contribute to epigenetic functions that are mitotically transmitted by Runx2 in osteoblastic cells. We show that the transcriptional corepressor Transducin Like Enhancer-1 (TLE1) associates with rRNA genes during mitosis and interphase through interaction with Runx2. Mechanistically, depletion of TLE1 relieves Runx2-mediated repression of rRNA genes transcription and selectively increases histone modifications linked to active transcription. Biologically, loss of TLE-dependent rRNA gene repression coincides with increased global protein synthesis and enhanced cell proliferation. Our findings reinforce the epigenetic marking target genes by phenotypic transcription factors in mitosis and demonstrate a requirement for retention of coregulatory factors to sustain physiological control of gene expression during proliferation of lineage committed cells. PMID- 20160073 TI - Thyroid hormone exerts negative feedback on hypothalamic type 4 melanocortin receptor expression. AB - The type 4 melanocortin receptor MC4R, a key relay in leptin signaling, links central energy control to peripheral reserve status. MC4R activation in different brain areas reduces food intake and increases energy expenditure. Mice lacking Mc4r are obese. Mc4r is expressed by hypothalamic paraventricular Thyrotropin releasing hormone (TRH) neurons and increases energy usage through activation of Trh and production of the thyroid hormone tri-iodothyronine (T(3)). These facts led us to test the hypothesis that energy homeostasis should require negative feedback by T(3) on Mc4r expression. Quantitative PCR and in situ hybridization showed hyperthyroidism reduces Mc4r mRNA levels in the paraventricular nucleus. Comparative in silico analysis of Mc4r regulatory regions revealed two evolutionarily conserved potential negative thyroid hormone-response elements (nTREs). In vivo ChIP assays on mouse hypothalamus demonstrated association of thyroid hormone receptors (TRs) with a region spanning one nTRE. Further, in vivo gene reporter assays revealed dose-dependent T(3) repression of transcription from the Mc4r promoter in mouse hypothalamus, in parallel with T(3)-dependent Trh repression. Mutagenesis of the nTREs in the Mc4r promoter demonstrated direct regulation by T(3), consolidating the ChIP results. In vivo shRNA knockdown, TR over-expression approaches and use of mutant mice lacking specific TRs showed that both TRalpha and TRbeta contribute to Mc4r regulation. T(3) repression of Mc4r transcription ensures that the energy-saving effects of T(3) feedback on Trh are not overridden by MC4R activation of Trh. Thus parallel repression by T(3) on hypothalamic Mc4r and Trh contributes to energy homeostasis. PMID- 20160074 TI - Membrane curvature controls dynamin polymerization. AB - The generation of membrane curvature in intracellular traffic involves many proteins that can curve lipid bilayers. Among these, dynamin-like proteins were shown to deform membranes into tubules, and thus far are the only proteins known to mechanically drive membrane fission. Because dynamin forms a helical coat circling a membrane tubule, its polymerization is thought to be responsible for this membrane deformation. Here we show that the force generated by dynamin polymerization, 18 pN, is sufficient to deform membranes yet can still be counteracted by high membrane tension. Importantly, we observe that at low dynamin concentration, polymer nucleation strongly depends on membrane curvature. This suggests that dynamin may be precisely recruited to membrane buds' necks because of their high curvature. To understand this curvature dependence, we developed a theory based on the competition between dynamin polymerization and membrane mechanical deformation. This curvature control of dynamin polymerization is predicted for a specific range of concentrations ( approximately 0.1-10 microM), which corresponds to our measurements. More generally, we expect that any protein that binds or self-assembles onto membranes in a curvature-coupled way should behave in a qualitatively similar manner, but with its own specific range of concentration. PMID- 20160075 TI - Macrophage Wnt7b is critical for kidney repair and regeneration. AB - Macrophages are required for tissue homeostasis through their role in regulation of the immune response and the resolution of injury. Here we show, using the kidney as a model, that the Wnt pathway ligand Wnt7b is produced by macrophages to stimulate repair and regeneration. When macrophages are inducibly ablated from the injured kidney, the canonical Wnt pathway response in kidney epithelial cells is reduced. Furthermore, when Wnt7b is somatically deleted in macrophages, repair of injury is greatly diminished. Finally, injection of the Wnt pathway regulator Dkk2 enhances the repair process and suggests a therapeutic option. Because Wnt7b is known to stimulate epithelial responses during kidney development, these findings suggest that macrophages are able to rapidly invade an injured tissue and reestablish a developmental program that is beneficial for repair and regeneration. PMID- 20160076 TI - ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. AB - Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. However, ATM also has been implicated in metabolic regulation, and ATM deficiency is associated with elevated reactive oxygen species (ROS). ROS has a central role in many physiological and pathophysiological processes including inflammation and chronic diseases such as atherosclerosis and cancer, underscoring the importance of cellular pathways involved in redox homeostasis. We have identified a cytoplasmic function for ATM that participates in the cellular damage response to ROS. We show that in response to elevated ROS, ATM activates the TSC2 tumor suppressor via the LKB1/AMPK metabolic pathway in the cytoplasm to repress mTORC1 and induce autophagy. Importantly, elevated ROS and dysregulation of mTORC1 in ATM-deficient cells is inhibited by rapamycin, which also rescues lymphomagenesis in Atm-deficient mice. Our results identify a cytoplasmic pathway for ROS-induced ATM activation of TSC2 to regulate mTORC1 signaling and autophagy, identifying an integration node for the cellular damage response with key pathways involved in metabolism, protein synthesis, and cell survival. PMID- 20160077 TI - Activatable cell penetrating peptides linked to nanoparticles as dual probes for in vivo fluorescence and MR imaging of proteases. AB - High-resolution imaging of molecules intrinsically involved in malignancy and metastasis would be of great value for clinical detection and staging of tumors. We now report in vivo visualization of matrix metalloproteinase activities by MRI and fluorescence of dendrimeric nanoparticles coated with activatable cell penetrating peptides (ACPPs), labeled with Cy5, gadolinium, or both. Uptake of such nanoparticles in tumors is 4- to 15-fold higher than for unconjugated ACPPs. With fluorescent molecules, we are able to detect residual tumor and metastases as small as 200 microm, which can be resected under fluorescence guidance and analyzed histopathologically with fluorescence microscopy. We show that uptake via this mechanism is comparable to that of other near infrared protease sensors, with the added advantage that the approach is translatable to MRI. Once activated, the Gd-labeled nanoparticles deposit high levels (30-50 microM) of Gd in tumor parenchyma with even higher amounts deposited in regions of infiltrative tumor, resulting in useful T(1) contrast lasting several days after injection. These results should improve MRI-guided clinical staging, presurgical planning, and intraoperative fluorescence-guided surgery. The approach may be generalizable to deliver radiation-sensitizing and chemotherapeutic agents. PMID- 20160078 TI - The tolerance-fecundity trade-off and the maintenance of diversity in seed size. AB - Seed size commonly varies by five to six orders of magnitude among coexisting plant species, a pattern ecologists have long sought to explain. Because seed size trades off with seed number, small-seeded species clearly have the advantage in fecundity, but what is the countervailing advantage of large seeds? Higher competitive ability combined with strong competitive asymmetry can in theory allow coexistence through a competition-colonization trade-off, but empirical evidence is inconsistent with this mechanism. Instead, the key advantage of large seeds appears to be their tolerance of stresses such as shade or drought that are present in some but not all regeneration sites. Here I present a simple, analytically tractable model of species coexistence in heterogeneous habitats through a tolerance-fecundity trade-off. Under this mechanism, the more tolerant species win all of the more stressful regeneration sites and some of those that are less stressful, whereas the more fecund species win most but not all of the less stressful sites. The tolerance-fecundity trade-off enables stable coexistence of large numbers of species in models with and without seed limitation. The tolerance-fecundity mechanism provides an excellent explanation for the maintenance of diversity of seed size within plant communities and also suggests new hypotheses for coexistence in animal and microbial communities. PMID- 20160079 TI - TGF-beta regulates T-cell neurokinin-1 receptor internalization and function. AB - Substance P (SP) is a proinflammatory mediator implicated in inflammatory bowel disease (IBD) and other inflammatory states. SP acts by stimulating the neurokinin-1 receptor (NK-1R) on T lymphocytes and other cell types, and regulates these cells in a complex interplay with multiple cytokines. The mechanisms of interaction among these inflammatory mediators are not yet fully understood. Here, we demonstrate that function of the NK-1R, a member of the G protein-coupled receptor (GPCR) superfamily, is modulated by TGF-beta. The latter acts not on a GPCR but via serine-threonine kinase-class receptors. By flow confocal image analysis, we demonstrate that TGF-beta delays SP-induced NK-1R internalization on mucosal T cells isolated from a mouse model of IBD and on granuloma T cells in murine schistosomiasis. Furthermore, luciferase reporter gene assays revealed that NK-1R stimulation activates the nuclear factor of activated T cell- and activator protein-1-dependent signaling pathways, which are known triggers of effector T-cell cytokine production. TGF-beta markedly increases SP-induced activation of these signaling cascades, suggesting that delayed NK-1R internalization results in enhanced signaling. Providing a link to amplified immune function, SP and TGF-beta, when applied in combination, trigger a strong release of the proinflammatory cytokines IFN-gamma and IL17 from intestinal inflammatory T cells, whereas either agonist alone shows no effect. These observations establish precedent that members of two distinct receptor superfamilies can interact via a previously unrecognized mechanism, and reveal a paradigm of GPCR transregulation that is relevant to IBD and possibly other disease processes. PMID- 20160080 TI - Phenotypic plasticity facilitates recurrent rapid adaptation to introduced predators. AB - A central role for phenotypic plasticity in adaptive evolution is often posited yet lacks empirical support. Selection for the stable production of an induced phenotype is hypothesized to modify the regulation of preexisting developmental pathways, producing rapid adaptive change. We examined the role of plasticity in rapid adaptation of the zooplankton Daphnia melanica to novel fish predators. Here we show that plastic up-regulation of the arthropod melanin gene dopa decarboxylase (Ddc) in the absence of UV radiation is associated with reduced pigmentation in D. melanica. Daphnia populations coexisting with recently introduced fish exhibit environmentally invariant up-regulation of Ddc, accompanied by constitutive up-regulation of the interacting arthropod melanin gene ebony. Both changes in regulation are associated with adaptive reduction in the plasticity and mean expression of melanin. Our results provide evidence that the developmental mechanism underlying ancestral plasticity in response to an environmental factor has been repeatedly co-opted to facilitate rapid adaptation to an introduced predator. PMID- 20160081 TI - Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. AB - Social adaptation requires specific cognitive and emotional competences. Individuals with high-functioning autism or with Asperger syndrome cannot understand or engage in social situations despite preserved intellectual abilities. Recently, it has been suggested that oxytocin, a hormone known to promote mother-infant bonds, may be implicated in the social deficit of autism. We investigated the behavioral effects of oxytocin in 13 subjects with autism. In a simulated ball game where participants interacted with fictitious partners, we found that after oxytocin inhalation, patients exhibited stronger interactions with the most socially cooperative partner and reported enhanced feelings of trust and preference. Also, during free viewing of pictures of faces, oxytocin selectively increased patients' gazing time on the socially informative region of the face, namely the eyes. Thus, under oxytocin, patients respond more strongly to others and exhibit more appropriate social behavior and affect, suggesting a therapeutic potential of oxytocin through its action on a core dimension of autism. PMID- 20160082 TI - Regulation of synaptic vesicle recycling by complex formation between intersectin 1 and the clathrin adaptor complex AP2. AB - Clathrin-mediated synaptic vesicle (SV) recycling involves the spatiotemporally controlled assembly of clathrin coat components at phosphatidylinositiol (4, 5) bisphosphate [PI(4,5)P(2)]-enriched membrane sites within the periactive zone. Such spatiotemporal control is needed to coordinate SV cargo sorting with clathrin/AP2 recruitment and to restrain membrane fission and synaptojanin mediated uncoating until membrane deformation and clathrin coat assembly are completed. The molecular events underlying these control mechanisms are unknown. Here we show that the endocytic SH3 domain-containing accessory protein intersectin 1 scaffolds the endocytic process by directly associating with the clathrin adaptor AP2. Acute perturbation of the intersectin 1-AP2 interaction in lamprey synapses in situ inhibits the onset of SV recycling. Structurally, complex formation can be attributed to the direct association of hydrophobic peptides within the intersectin 1 SH3A-B linker region with the "side sites" of the AP2 alpha- and beta-appendage domains. AP2 appendage association of the SH3A B linker region inhibits binding of the inositol phosphatase synaptojanin 1 to intersectin 1. These data identify the intersectin-AP2 complex as an important regulator of clathrin-mediated SV recycling in synapses. PMID- 20160083 TI - Three-dimensional structure of tropism-switching Bordetella bacteriophage. AB - Bacteriophage BPP-1, which infects Bordetella species, can switch its specificity by mutations to the ligand-binding surface of its major tropism-determinant protein, Mtd. This targeted mutagenesis results from the activity of a phage encoded diversity-generating retroelement. Purified Mtd binds its receptor with low affinity, yet BPP-1 binding and infection of Bordettella cells are efficient because of high-avidity binding between phage-associated Mtd and its receptor. Here, using an integrative approach of three-dimensional (3D) structural analyses of the entire phage by cryo-electron tomography and single-prticle cryo-electron microscopy, we provide direct localization of Mtd in the phage and the structural basis of the high-avidity binding of the BPP-1 phage. Our structure shows that each BPP-1 particle has a T = 7 icosahedral head and an unusual tail apparatus consisting of a short central tail "hub," six short tail spikes, and six extended tail fibers. Subtomographic averaging of the tail fiber maps revealed a two-lobed globular structure at the distal end of each long tail fiber. Tomographic reconstructions of immuno-gold-labeled BPP-1 directly localized Mtd to these globular structures. Finally, our icosahedral reconstruction of the BPP-1 head at 7A resolution reveals an HK97-like major capsid protein stabilized by a smaller cementing protein. Our structure represents a unique bacteriophage reconstruction with its tail fibers and ligand-binding domains shown in relation to its tail apparatus. The localization of Mtd at the distal ends of the six tail fibers explains the high avidity binding of Mtd molecules to cell surfaces for initiation of infection. PMID- 20160084 TI - Cortical activity during motor execution, motor imagery, and imagery-based online feedback. AB - Imagery of motor movement plays an important role in learning of complex motor skills, from learning to serve in tennis to perfecting a pirouette in ballet. What and where are the neural substrates that underlie motor imagery-based learning? We measured electrocorticographic cortical surface potentials in eight human subjects during overt action and kinesthetic imagery of the same movement, focusing on power in "high frequency" (76-100 Hz) and "low frequency" (8-32 Hz) ranges. We quantitatively establish that the spatial distribution of local neuronal population activity during motor imagery mimics the spatial distribution of activity during actual motor movement. By comparing responses to electrocortical stimulation with imagery-induced cortical surface activity, we demonstrate the role of primary motor areas in movement imagery. The magnitude of imagery-induced cortical activity change was approximately 25% of that associated with actual movement. However, when subjects learned to use this imagery to control a computer cursor in a simple feedback task, the imagery-induced activity change was significantly augmented, even exceeding that of overt movement. PMID- 20160085 TI - Islet amyloid deposition limits the viability of human islet grafts but not porcine islet grafts. AB - Islet transplantation is a promising treatment for diabetes but long-term success is limited by progressive graft loss. Aggregates of the beta cell peptide islet amyloid polypeptide (IAPP) promote beta cell apoptosis and rapid amyloid formation occurs in transplanted islets. Porcine islets are an attractive alternative islet source as they demonstrate long-term graft survival. We compared the capacity of transplanted human and porcine islets to form amyloid as an explanation for differences in graft survival. Human islets were transplanted into streptozotocin-diabetic immune-deficient mice. Amyloid deposition was detectable at 4 weeks posttransplantation and was associated with islet graft failure. More extensive amyloid deposition was observed after 8 weeks. By contrast, no amyloid was detected in transplanted neonatal or adult porcine islets that had maintained normoglycemia for up to 195 days. To determine whether differences in IAPP sequence between humans and pigs could explain differences in amyloid formation and transplant viability, we sequenced porcine IAPP. Porcine IAPP differs from the human sequence at 10 positions and includes substitutions predicted to reduce its amyloidogenicity. Synthetic porcine IAPP was considerably less amyloidogenic than human IAPP as determined by transmission electron microscopy, circular dichroism, and thioflavin T binding. Viability assays indicated that porcine IAPP is significantly less toxic to INS-1 beta cells than human IAPP. Our findings demonstrate that species differences in IAPP sequence can explain the lack of amyloid formation and improved survival of transplanted porcine islets. These data highlight the potential of porcine islet transplantation as a therapeutic approach for human diabetes. PMID- 20160086 TI - Operation of the voltage sensor of a human voltage- and Ca2+-activated K+ channel. AB - Voltage sensor domains (VSDs) are structurally and functionally conserved protein modules that consist of four transmembrane segments (S1-S4) and confer voltage sensitivity to many ion channels. Depolarization is sensed by VSD-charged residues residing in the membrane field, inducing VSD activation that facilitates channel gating. S4 is typically thought to be the principal functional component of the VSD because it carries, in most channels, a large portion of the VSD gating charge. The VSDs of large-conductance, voltage- and Ca(2+)-activated K(+) channels are peculiar in that more gating charge is carried by transmembrane segments other than S4. Considering its "decentralized" distribution of voltage sensing residues, we probed the BK(Ca) VSD for evidence of cooperativity between charge-carrying segments S2 and S4. We achieved this by optically tracking their activation by using voltage clamp fluorometry, in channels with intact voltage sensors and charge-neutralized mutants. The results from these experiments indicate that S2 and S4 possess distinct voltage dependence, but functionally interact, such that the effective valence of one segment is affected by charge neutralization in the other. Statistical-mechanical modeling of the experimental findings using allosteric interactions demonstrates two mechanisms (mechanical coupling and dynamic focusing of the membrane electric field) that are compatible with the observed cross-segment effects of charge neutralization. PMID- 20160087 TI - Reactogenicity of live-attenuated Vibrio cholerae vaccines is dependent on flagellins. AB - Cholera is a severe diarrheal disease caused by the motile Gram-negative rod Vibrio cholerae. Live-attenuated V. cholerae vaccines harboring deletions of the genes encoding cholera toxin have great promise for reducing the global burden of cholera. However, development of live vaccines has been hampered by the tendency of such strains to induce noncholeric reactogenic diarrhea in human subjects. The molecular bases of reactogenicity are unknown, but it has been speculated that reactogenic diarrhea is a response to V. cholerae's flagellum and/or the motility that it enables. Here, we used an infant rabbit model of reactogenicity to determine what V. cholerae factors trigger this response. We found that V. cholerae ctx mutants that produced flagellins induced diarrhea, regardless of whether the proteins were assembled into a flagellum or whether the flagellum was functional. In contrast, approximately 90% of rabbits infected with V. cholerae lacking all five flagellin-encoding genes did not develop diarrhea. Thus, flagellin production, independent of flagellum assembly or motility, is sufficient for reactogenicity. The intestinal colonization and intraintestinal localization of the nonreactogenic flagellin-deficient strain were indistinguishable from those of a flagellated motile strain; however, the flagellin-deficient strain stimulated fewer mRNA transcripts coding for proinflammatory cytokines in the intestine. Thus, reactogenic diarrhea may be a consequence of an innate host inflammatory response to V. cholerae flagellins. Our results suggest a simple genetic blueprint for engineering defined nonreactogenic live-attenuated V. cholerae vaccine strains. PMID- 20160088 TI - Spatiotemporal compartmentalization of key physiological processes during muscle precursor differentiation. AB - The development of multicellular organisms is controlled by transcriptional networks. Understanding the role of these networks requires a full understanding of transcriptome regulation during embryogenesis. Several microarray studies have characterized the temporal evolution of the transcriptome during development in different organisms [Wang QT, et al. (2004) Dev Cell 6:133-144; Furlong EE, Andersen EC, Null B, White KP, Scott MP (2001) Science 293:1629-1633; Mitiku N, Baker JC (2007) Dev Cell 13:897-907]. In all cases, however, experiments were performed on whole embryos, thus averaging gene expression among many different tissues. Here, we took advantage of the local synchrony of the differentiation process in the paraxial mesoderm. This approach provides a unique opportunity to study the systems-level properties of muscle differentiation. Using high resolution, spatiotemporal profiling of the early stages of muscle development in the zebrafish embryo, we identified a major reorganization of the transcriptome taking place in the presomitic mesoderm. We further show that the differentiation process is associated with a striking modular compartmentalization of the transcription of essential components of cellular physiological programs. Particularly, we identify a tight segregation of cell cycle/DNA metabolic processes and translation/oxidative metabolism at the tissue level, highly reminiscent of the yeast metabolic cycle. These results should expand more investigations into the developmental control of metabolism. PMID- 20160090 TI - Selective loss of polymorphic mating types is associated with rapid phenotypic evolution during morphic speciation. AB - Polymorphism may play an important role in speciation because new species could originate from the distinctive morphs observed in polymorphic populations. However, much remains to be understood about the process by which morphs found new species. To detail the steps of this mode of speciation, we studied the geographic variation and evolutionary history of a throat color polymorphism that distinguishes the "rock-paper-scissors" mating strategies of the side-blotched lizard, Uta stansburiana. We found that the polymorphism is geographically widespread and has been maintained for millions of years. However, there are many populations with reduced numbers of throat color morphs. Phylogenetic reconstruction showed that the polymorphism is ancestral, but it has been independently lost eight times, often giving rise to morphologically distinct subspecies/species. Changes to the polymorphism likely involved selection because the allele for one particular male strategy, the "sneaker" morph, has been lost in all cases. Polymorphism loss was associated with accelerated evolution of male size, female size, and sexual dimorphism, which suggests that polymorphism loss can promote rapid divergence among populations and aid species formation. PMID- 20160089 TI - IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. AB - The peptide substance P (SP) has been implicated in inflammatory conditions, such as psoriasis, where mast cells and VEGF are increased. A relationship between SP and VEGF has not been well studied, nor has any interaction with the proinflammatory cytokines, especially IL-33. Here we report that SP (0.1-10 microM) induces gene expression and secretion of VEGF from human LAD2 mast cells and human umbilical core blood-derived cultured mast cells (hCBMCs). This effect is significantly increased by coadministration of IL-33 (5-100 ng/mL) in both cell types. The effect of SP on VEGF release is inhibited by treatment with the NK-1 receptor antagonist 733,060. SP rapidly increases cytosolic calcium, and so does IL-33 to a smaller extent; the addition of IL-33 augments the calcium increase. SP-induced VEGF production involves calcium-dependent PKC isoforms, as well as the ERK and JNK MAPKs. Gene expression of IL-33 and histidine decarboxylase (HDC), an indicator of mast cell presence/activation, is significantly increased in affected and unaffected (at least 15 cm away from the lesion) psoriatic skin, as compared with normal control skin. Immunohistochemistry indicates that IL-33 is associated with endothelial cells in both the unaffected and affected sites, but is stronger and also associated with immune cells in the affected site. These results imply that functional interactions among SP, IL-33, and mast cells leading to VEGF release contribute to inflammatory conditions, such as the psoriasis, a nonallergic hyperproliferative skin inflammatory disorder with a neurogenic component. PMID- 20160091 TI - Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout mice. AB - Neuronally expressed auxilin and ubiquitously expressed cyclin-G-dependent kinase (GAK) are homologous proteins that act as cochaperones to support the Hsc70 dependent clathrin uncoating of clathrin-coated vesicles. GAK was previously shown to be essential in mouse during embryonic development and in the adult. We have now engineered an auxilin knockout mouse. Mutant mice had a high rate of early postnatal mortality and surviving pups generally had a lower body weight than wild-type pups, although they had a normal life span. GAK was up-regulated as much as 3-fold in the brains of both surviving neonates and adult mutant mice. An increased number of clathrin-coated vesicles and empty cages were present at knockout synapses both in situ and in primary neuronal cultures. Additionally, clathrin-mediated endocytosis of synaptic vesicles in knockout hippocampal neurons was impaired, most likely due to sequestration of coat components in assembled coats and cages. Collectively, our results demonstrate the specialized role of auxilin in the recycling of synaptic vesicles at synapses, but also show that its function can be partially compensated for by up-regulation of GAK. PMID- 20160092 TI - Molecular basis of odor coding in the malaria vector mosquito Anopheles gambiae. AB - A systematic functional analysis across much of the conventional Anopheles gambiae odorant receptor (AgOR) repertoire was carried out in Xenopus oocytes using two-electrode, voltage-clamp electrophysiology. The resulting data indicate that each AgOR manifests a distinct odor-response profile and tuning breadth. The large diversity of tuning responses ranges from AgORs that are responsive to a single or small number of odorants (specialists) to more broadly tuned receptors (generalists). Several AgORs were identified that respond robustly to a range of human volatiles that may play a critical role in anopheline host selection. AgOR responses were analyzed further by constructing a multidimensional odor space representing the relationships between odorants and AgOR responses. Within this space, the distance between odorants is related to both chemical class and concentration and may correlate with olfactory discrimination. This study provides a comprehensive overview of olfactory coding mechanisms of An. gambiae that ultimately may aid in fostering the design and development of olfactory based strategies for reducing the transmission of malaria and other mosquito borne diseases. PMID- 20160093 TI - Diacylglycerol kinase alpha mediates HGF-induced Rac activation and membrane ruffling by regulating atypical PKC and RhoGDI. AB - Diacylglycerol kinases (DGKs) convert diacylglycerol (DAG) into phosphatidic acid (PA), acting as molecular switches between DAG- and PA-mediated signaling. We previously showed that Src-dependent activation and plasma membrane recruitment of DGKalpha are required for growth-factor-induced cell migration and ruffling, through the control of Rac small-GTPase activation and plasma membrane localization. Herein we unveil a signaling pathway through which DGKalpha coordinates the localization of Rac. We show that upon hepatocyte growth-factor stimulation, DGKalpha, by producing PA, provides a key signal to recruit atypical PKCzeta/iota (aPKCzeta/iota) in complex with RhoGDI and Rac at ruffling sites of colony-growing epithelial cells. Then, DGKalpha-dependent activation of aPKCzeta/iota mediates the release of Rac from the inhibitory complex with RhoGDI, allowing its activation and leading to formation of membrane ruffles, which constitute essential requirements for cell migration. These findings highlight DGKalpha as the central element of a lipid signaling pathway linking tyrosine kinase growth-factor receptors to regulation of aPKCs and RhoGDI, and providing a positional signal regulating Rac association to the plasma membrane. PMID- 20160094 TI - N-cadherin ligation, but not Sonic hedgehog binding, initiates Cdo-dependent p38alpha/beta MAPK signaling in skeletal myoblasts. AB - The p38alpha/beta mitogen-activated protein kinase (MAPK) pathway promotes muscle specific gene expression and myoblast differentiation but how pathway activity is initiated during these processes is poorly understood. During myoblast differentiation, the intracellular region of the promyogenic cell surface protein Cdo (also known as Cdon) binds to Bnip-2 and JLP, scaffold proteins for Cdc42 and p38alpha/beta MAPK, respectively. The Bnip-2/Cdc42 and JLP/p38alpha/beta complexes associate in a Cdo-dependent manner, resulting in Bnip-2/Cdc42 dependent p38alpha/beta activation and stimulation of cell differentiation. Although the Cdo ectodomain binds to several different proteins, it is unclear how Cdo-dependent p38alpha/beta activation is initiated. In myoblasts, Cdo interacts with the cell-cell adhesion molecule N-cadherin. Cdo also binds directly to the secreted morphogen Sonic hedgehog (Shh) to promote Shh pathway signaling. We report here that N-cadherin ligation activates p38alpha/beta in myoblasts in a Cdo-, Bnip-2-, and JLP-dependent manner. Furthermore, these proteins and activated Cdc42 cluster at sites of N-cadherin ligation. In contrast, neither JLP nor Bnip-2 is associated with Cdo bound to Shh, and Shh does not activate p38alpha/beta in myoblasts. Taken together, these results link cadherin-based cell-cell adhesion to a defined signaling pathway (Cdo --> p38alpha/beta) that directly regulates a cell-type-specific differentiation program. Furthermore, they are consistent with a model whereby Cdo serves as a multifunctional coreceptor with mechanistically distinct roles in multiple signaling pathways. PMID- 20160095 TI - Innate sensitivity for self-propelled causal agency in newly hatched chicks. AB - The idea that sensitivity to self-produced motion could lie at the foundations of the clear-cut divide that the brain operates between the two basic domains of inanimate and animate objects dates back to Aristotle. Sensitivity to self propelled objects is apparent in human infants from around the fifth month of age, which leaves undetermined whether it is acquired by experience with animate objects or whether it is innately predisposed in the brain. Here, we report that newly hatched, visually naive domestic chicks presented with objects exhibiting motion either self-produced or caused by physical contact prefer to associate with self-propelled objects. This finding supports the idea of an evolutionarily ancient, predisposed neural mechanism in the vertebrate brain for the detection of animacy. PMID- 20160096 TI - Cycles, phase synchronization, and entrainment in single-species phytoplankton populations. AB - Complex dynamics, such as population cycles, can arise when the individual members of a population become synchronized. However, it is an open question how readily and through which mechanisms synchronization-driven cycles can occur in unstructured microbial populations. In experimental chemostats we studied large populations (>10(9) cells) of unicellular phytoplankton that displayed regular, inducible and reproducible population oscillations. Measurements of cell size distributions revealed that progression through the mitotic cycle was synchronized with the population cycles. A mathematical model that accounts for both the cell cycle and population-level processes suggests that cycles occur because individual cells become synchronized by interacting with one another through their common nutrient pool. An external perturbation by direct manipulation of the nutrient availability resulted in phase resetting, unmasking intrinsic oscillations and producing a transient collective cycle as the individuals gradually drift apart. Our study indicates a strong connection between complex within-cell processes and population dynamics, where synchronized cell cycles of unicellular phytoplankton provide sufficient population structure to cause small-amplitude oscillations at the population level. PMID- 20160097 TI - Surgery with molecular fluorescence imaging using activatable cell-penetrating peptides decreases residual cancer and improves survival. AB - The completeness of tumor removal during surgery is dependent on the surgeon's ability to differentiate tumor from normal tissue using subjective criteria that are not easily quantifiable. A way to objectively assess tumor margins during surgery in patients would be of great value. We have developed a method to visualize tumors during surgery using activatable cell-penetrating peptides (ACPPs), in which the fluorescently labeled, polycationic cell-penetrating peptide (CPP) is coupled via a cleavable linker to a neutralizing peptide. Upon exposure to proteases characteristic of tumor tissue, the linker is cleaved, dissociating the inhibitory peptide and allowing the CPP to bind to and enter tumor cells. In mice, xenografts stably transfected with green fluorescent protein show colocalization with the Cy5-labeled ACPPs. In the same mouse models, Cy5-labeled free ACPPs and ACPPs conjugated to dendrimers (ACPPDs) delineate the margin between tumor and adjacent tissue, resulting in improved precision of tumor resection. Surgery guided by ACPPD resulted in fewer residual cancer cells left in the animal after surgery as measured by Alu PCR. A single injection of ACPPD dually labeled with Cy5 and gadolinium chelates enabled preoperative whole body tumor detection by MRI, intraoperative guidance by real-time fluorescence, intraoperative histological analysis of margin status by fluorescence, and postoperative MRI tumor quantification. Animals whose tumors were resected with ACPPD guidance had better long-term tumor-free survival and overall survival than animals whose tumors were resected with traditional bright-field illumination only. PMID- 20160098 TI - Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. AB - For the promise of human induced pluripotent stem cells (iPSCs) to be realized, it is necessary to ask if and how efficiently they may be differentiated to functional cells of various lineages. Here, we have directly compared the neural differentiation capacity of human iPSCs and embryonic stem cells (ESCs). We have shown that human iPSCs use the same transcriptional network to generate neuroepithelia and functionally appropriate neuronal types over the same developmental time course as hESCs in response to the same set of morphogens; however, they do it with significantly reduced efficiency and increased variability. These results were consistent across iPSC lines and independent of the set of reprogramming transgenes used to derive iPSCs as well as the presence or absence of reprogramming transgenes in iPSCs. These findings, which show a need for improving differentiation potency of iPSCs, suggest the possibility of employing human iPSCs in pathological studies, therapeutic screening, and autologous cell transplantation. PMID- 20160099 TI - Dendritic cell targeted HIV gag protein vaccine provides help to a DNA vaccine including mobilization of protective CD8+ T cells. AB - To improve the efficacy of T cell-based vaccination, we pursued the principle that CD4(+) T cells provide help for functional CD8(+) T cell immunity. To do so, we administered HIV gag to mice successively as protein and DNA vaccines. To achieve strong CD4(+) T cell immunity, the protein vaccine was targeted selectively to DEC-205, a receptor for antigen presentation on dendritic cells. This targeting helped CD8(+) T cell immunity develop to a subsequent DNA vaccine and improved protection to intranasal challenge with recombinant vaccinia gag virus, including more rapid accumulation of CD8(+) T cells in the lung. The helper effect of dendritic cell-targeted protein vaccine was mimicked by immunization with specific MHC II binding HIV gag peptides but not peptides from a disparate Yersinia pestis microbe. CD4(+) helper cells upon adoptive transfer allowed wild-type, but not CD40(-/-), recipient mice to respond better to the DNA vaccine. The transfer also enabled recipients to more rapidly accumulate gag specific CD8(+) T cells in the lung following challenge with vaccinia gag virus. Thus, complementary prime boost vaccination, in which prime and boost favor distinct types of T cell immunity, improves plasmid DNA immunization, including mobilization of CD8(+) T cells to sites of infection. PMID- 20160100 TI - Salt bridge integrates GPCR activation with protein trafficking. AB - G protein-coupled receptors (GPCRs) play central roles in almost all physiological functions; mutations in GPCRs are responsible for more than 30 disorders. There is a great deal of information about GPCR structure but little information that directly relates structure to protein trafficking or to activation. The gonadotropin releasing hormone receptor, because of its small size among GPCRs, is amenable to preparation of mutants and was used in this study to establish the relation among a salt bridge, protein trafficking, and receptor activation. This bridge, between residues E(90) [located in transmembrane segment (TM) 2] and K(121) (TM3), is associated with correct trafficking to the plasma membrane. Agonists, but not antagonists, interact with residue K(121), and destabilize the TM2-TM3 association of the receptor in the plasma membrane. The hGnRHR mutant E(90)K has a broken salt bridge, which also destabilizes the TM2-TM3 association and is typically retained in the endoplasmic reticulum. We show that this mutant, if rescued to the plasma membrane by either of two different means, has constitutive activity and shows modified ligand specificity, revealing a role for the salt bridge in receptor activation, ligand specificity, trafficking, and structure. The data indicate that destabilizing the TM2-TM3 relation for receptor activation, while requiring an intact salt bridge for correct trafficking, provides a mechanism that protects the cell from plasma membrane expression of constitutive activity. PMID- 20160101 TI - PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. AB - Vaccination with irradiated B16 melanoma cells expressing either GM-CSF (Gvax) or Flt3-ligand (Fvax) combined with antibody blockade of the negative T-cell costimulatory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) promotes rejection of preimplanted tumors. Despite CTLA-4 blockade, T-cell proliferation and cytokine production can be inhibited by the interaction of programmed death-1 (PD-1) with its ligands PD-L1 and PD-L2 or by the interaction of PD-L1 with B7-1. Here, we show that the combination of CTLA-4 and PD-1 blockade is more than twice as effective as either alone in promoting the rejection of B16 melanomas in conjunction with Fvax. Adding alphaPD-L1 to this regimen results in rejection of 65% of preimplanted tumors vs. 10% with CTLA-4 blockade alone. Combination PD-1 and CTLA-4 blockade increases effector T-cell (Teff) infiltration, resulting in highly advantageous Teff-to-regulatory T-cell ratios with the tumor. The fraction of tumor-infiltrating Teffs expressing CTLA-4 and PD-1 increases, reflecting the proliferation and accumulation of cells that would otherwise be anergized. Combination blockade also synergistically increases Teff-to-myeloid-derived suppressor cell ratios within B16 melanomas. IFN-gamma production increases in both the tumor and vaccine draining lymph nodes, as does the frequency of IFN gamma/TNF-alpha double-producing CD8(+) T cells within the tumor. These results suggest that combination blockade of the PD-1/PD-L1- and CTLA-4-negative costimulatory pathways allows tumor-specific T cells that would otherwise be inactivated to continue to expand and carry out effector functions, thereby shifting the tumor microenvironment from suppressive to inflammatory. PMID- 20160102 TI - Vaccination with partial knowledge of external effectiveness. AB - Economists studying public policy have generally assumed that the relevant planner knows how policy affects population behavior. Planners typically do not possess all of this knowledge, so there is reason to consider policy formation with partial knowledge of policy impacts. Here I consider choice of a vaccination policy when a planner has partial knowledge of the effect of vaccination on illness rates. To begin, I pose a planning problem whose objective is to minimize the utilitarian social cost of illness and vaccination. The consequences of candidate vaccination rates depend on the extent to which vaccination prevents illness. I study the planning problem when the planner has partial knowledge of the external-response function, which expresses how the illness rate of unvaccinated persons varies with the vaccination rate. I suppose that the planner observes the illness rate of a study population whose vaccination rate has been chosen previously. He knows that the illness rate of unvaccinated persons weakly decreases as the vaccination rate increases, but he does not know the magnitude of the preventive effect of vaccination. In this setting, I first show how the planner can eliminate dominated vaccination rates and then how he can use the minimax or minimax-regret criterion to choose an undominated vaccination rate. PMID- 20160103 TI - Cellular in vivo imaging reveals coordinated regulation of pituitary microcirculation and GH cell network function. AB - Growth hormone (GH) exerts its actions via coordinated pulsatile secretion from a GH cell network into the bloodstream. Practically nothing is known about how the network receives its inputs in vivo and releases hormones into pituitary capillaries to shape GH pulses. Here we have developed in vivo approaches to measure local blood flow, oxygen partial pressure, and cell activity at single cell resolution in mouse pituitary glands in situ. When secretagogue (GHRH) distribution was modeled with fluorescent markers injected into either the bloodstream or the nearby intercapillary space, a restricted distribution gradient evolved within the pituitary parenchyma. Injection of GHRH led to stimulation of both GH cell network activities and GH secretion, which was temporally associated with increases in blood flow rates and oxygen supply by capillaries, as well as oxygen consumption. Moreover, we observed a time-limiting step for hormone output at the perivascular level; macromolecules injected into the extracellular parenchyma moved rapidly to the perivascular space, but were then cleared more slowly in a size-dependent manner into capillary blood. Our findings suggest that GH pulse generation is not simply a GH cell network response, but is shaped by a tissue microenvironment context involving a functional association between the GH cell network activity and fluid microcirculation. PMID- 20160104 TI - Caspase 3/caspase-activated DNase promote cell differentiation by inducing DNA strand breaks. AB - Caspase 3 is required for the differentiation of a wide variety of cell types, yet it remains unclear how this apoptotic protein could promote such a cell-fate decision. Caspase signals often result in the activation of the specific nuclease caspase-activated DNase (CAD), suggesting that cell differentiation may be dependent on a CAD-mediated modification in chromatin structure. In this study, we have investigated if caspase 3/CAD plays a role in initiating the DNA strand breaks that are known to occur during the terminal differentiation of skeletal muscle cells. Here, we show that inhibition of caspase 3 or reduction of CAD expression leads to a dramatic loss of strand-break formation and a block in the myogenic program. Caspase-dependent induction of differentiation results in CAD targeting of the p21 promoter, and loss of caspase 3 or CAD leads to a significant down-regulation in p21 expression. These results show that caspase 3/CAD promotes cell differentiation by directly modifying the DNA/nuclear microenvironment, which enhances the expression of critical regulatory genes. PMID- 20160105 TI - RNA looping by PTB: Evidence using FRET and NMR spectroscopy for a role in splicing repression. AB - Alternative splicing plays an important role in generating proteome diversity. The polypyrimidine tract-binding protein (PTB) is a key alternative splicing factor involved in exon repression. It has been proposed that PTB acts by looping out exons flanked by pyrimidine tracts. We present fluorescence, NMR, and in vivo splicing data in support of a role of PTB in inducing RNA loops. We show that the RNA recognition motifs (RRMs) 3 and 4 of PTB can bind two distant pyrimidine tracts and bring their 5' and 3' ends in close proximity, thus looping the RNA. Efficient looping requires an intervening sequence of 15 nucleotides or longer between the pyrimidine tracts. RRM3 and RRM4 bind the 5' and the 3' pyrimidine tracts, respectively, in a specific directionality and work synergistically for efficient splicing repression in vivo. PMID- 20160106 TI - Scaling and shear transformations capture beak shape variation in Darwin's finches. AB - Evolution by natural selection has resulted in a remarkable diversity of organism morphologies that has long fascinated scientists and served to establish the first relations among species. Despite the essential role of morphology as a phenotype of species, there is not yet a formal, mathematical scheme to quantify morphological phenotype and relate it to both the genotype and the underlying developmental genetics. Herein we demonstrate that the morphological diversity in the beaks of Darwin's Finches is quantitatively accounted for by the mathematical group of affine transformations. Specifically, we show that all beak shapes of Ground Finches (genus Geospiza) are related by scaling transformations (a subgroup of the affine group), and the same relationship holds true for all the beak shapes of Tree, Cocos, and Warbler Finches (three distinct genera). This analysis shows that the beak shapes within each of these groups differ only by their scales, such as length and depth, which are genetically controlled by Bmp4 and Calmodulin. By measuring Bmp4 expression in the beak primordia of the species in the genus Geospiza, we provide a quantitative map between beak morphology and the expression levels of Bmp4. The complete morphological variation within the beaks of Darwin's finches can be explained by extending the scaling transformations to the entire affine group, by including shear transformations. Altogether our results suggest that the mathematical theory of groups can help decode morphological variation, and points to a potentially hierarchical structure of morphological diversity and the underlying developmental processes. PMID- 20160107 TI - Learning as a phenomenon occurring in a critical state. AB - Recent physiological measurements have provided clear evidence about scale-free avalanche brain activity and EEG spectra, feeding the classical enigma of how such a chaotic system can ever learn or respond in a controlled and reproducible way. Models for learning, like neural networks or perceptrons, have traditionally avoided strong fluctuations. Conversely, we propose that brain activity having features typical of systems at a critical point represents a crucial ingredient for learning. We present here a study that provides unique insights toward the understanding of the problem. Our model is able to reproduce quantitatively the experimentally observed critical state of the brain and, at the same time, learns and remembers logical rules including the exclusive OR, which has posed difficulties to several previous attempts. We implement the model on a network with topological properties close to the functionality network in real brains. Learning occurs via plastic adaptation of synaptic strengths and exhibits universal features. We find that the learning performance and the average time required to learn are controlled by the strength of plastic adaptation, in a way independent of the specific task assigned to the system. Even complex rules can be learned provided that the plastic adaptation is sufficiently slow. PMID- 20160108 TI - An atomic-level mechanism for activation of the kinesin molecular motors. AB - Kinesin cytoskeletal motors convert the energy of ATP hydrolysis into stepping movement along microtubules. A partial model of this process has been derived from crystal structures, which show that movement of the motor domain relative to its major microtubule binding element, the switch II helix, is coupled to docking of kinesin's neck linker element along the motor domain. This docking would displace the cargo in the direction of travel and so contribute to a step. However, the crystal structures do not reveal how ATP binding and hydrolysis govern this series of events. We used cryoelectron microscopy to derive 8-9 A resolution maps of four nucleotide states encompassing the microtubule-attached kinetic cycle of a kinesin motor. The exceptionally high quality of these maps allowed us to build in crystallographically determined conformations of kinesin's key subcomponents, yielding novel arrangements of kinesin's switch II helix and nucleotide-sensing switch loops. The resulting atomic models reveal a seesaw mechanism in which the switch loops, triggered by ATP binding, propel their side of the motor domain down and thereby elicit docking of the neck linker on the opposite side of the seesaw. Microtubules engage the seesaw mechanism by stabilizing the formation of extra turns at the N terminus of the switch II helix, which then serve as an anchor for the switch loops as they modulate the seesaw angle. These observations explain how microtubules activate kinesin's ATP sensing machinery to promote cargo displacement and inform the mechanism of kinesin's ancestral relative, myosin. PMID- 20160109 TI - Abduction and asylum in the lives of transcription factors. AB - Recent studies suggest that there are many nonfunctional transcription factor binding sites along a genome. Although these "decoy" sites compete with the promoter region for binding of transcription factors, they may also protect these proteins from degradation. We show that in the limit of perfect protection, where bound transcription factors are never degraded, the competitive effect of nonfunctional binding sites is completely canceled out by the stability gained from reduced degradation. We examine the response of an autoregulated gene to the total number of transcription factors to quantify the consequences of competition for transcription factors. We show that intuition about this system can be gained by mathematically constructing a single gene with effective parameters that reproduce the behavior of a gene with added decoy sites. In analogy to dressed particles in many-body systems we term this description a "quasi gene." We find that protective decoys buffer against noise by reducing correlations between transcription factors, specifically in the case of production of transcription factors in bursts. We show that the addition of protective decoy sites causes the level of gene expression to approach that predicted from deterministic mass action models. Finally, we show that protective decoy sites decrease the size of the region of parameter space that exhibits bistability. PMID- 20160110 TI - Pathway of ATP utilization and duplex rRNA unwinding by the DEAD-box helicase, DbpA. AB - DEAD-box RNA helicase proteins use the energy of ATP hydrolysis to drive the unwinding of duplex RNA. However, the mechanism that couples ATP utilization to duplex RNA unwinding is unknown. We measured ATP utilization and duplex RNA unwinding by DbpA, a non-processive bacterial DEAD-box RNA helicase specifically activated by the peptidyl transferase center (PTC) of 23S rRNA. Consumption of a single ATP molecule is sufficient to unwind and displace an 8 base pair rRNA strand annealed to a 32 base pair PTC-RNA "mother strand" fragment. Strand displacement occurs after ATP binding and hydrolysis but before P(i) product release. P(i) release weakens binding to rRNA, thereby facilitating the release of the unwound rRNA mother strand and the recycling of DbpA for additional rounds of unwinding. This work explains how ATPase activity of DEAD-box helicases is linked to RNA unwinding. PMID- 20160111 TI - Yeast Tdp1 regulates the fidelity of nonhomologous end joining. AB - Tyrosyl-DNA-phosphodiesterase 1 (Tdp1) can disjoin peptides covalently bound to DNA. We assessed the role of Tdp1 in nonhomologous end joining (NHEJ) and found that linear DNA molecules with 5' extensions showed a high frequency of misrepair in Deltatdp1 cells. The joining errors in Deltatdp1 cells were predominantly 2-4 nucleotide insertions. Ends with 3' extensions or blunt ends did not show enhanced frequencies of errors, although Deltatdp1 cells repaired blunt DNA ends with greater efficiency than WT cells. We found that insertions required Ku80 and DNA ligase IV, as well as polymerase IV. Our results show that yeast Tdp1 is a component of the NHEJ pathway. We suggest that Tdp1p 3' nucleosidase activity regulates the processing of DNA ends by generating a 3' phosphate, thereby restricting the ability of polymerases and other enzymes from acting at DNA ends. In support of this model, we found that overexpression of Tpp1, a yeast DNA 3' phosphatase, also leads to a higher frequency of insertions, suggesting that the generation of a 3' phosphate is a key step in Tdp1-mediated error prevention during NHEJ. PMID- 20160112 TI - Climatic context and ecological implications of summer fog decline in the coast redwood region. AB - Biogeographical, physiological, and paleoecological evidence suggests that the coast redwood [Sequoia sempervirens (D. Don) Endl.] is closely associated with the presence of summer marine fog along the Pacific coast of California. Here we present a novel record of summer fog frequency in the coast redwood region upon the basis of direct hourly measurements of cloud ceiling heights from 1951 to 2008. Our analysis shows that coastal summer fog frequency is a remarkably integrative measure of United States Pacific coastal climate, with strong statistical connections to the wind-driven upwelling system of the California Current and the broad ocean temperature pattern known as the Pacific Decadal Oscillation. By using a long-term index of daily maximum land temperatures, we infer a 33% reduction in fog frequency since the early 20th century. We present tree physiological data suggesting that coast redwood and other ecosystems along the United States west coast may be increasingly drought stressed under a summer climate of reduced fog frequency and greater evaporative demand. PMID- 20160113 TI - pH (low) insertion peptide (pHLIP) inserts across a lipid bilayer as a helix and exits by a different path. AB - What are the molecular events that occur when a peptide inserts across a membrane or exits from it? Using the pH-triggered insertion of the pH low insertion peptide to enable kinetic analysis, we show that insertion occurs in several steps, with rapid (0.1 sec) interfacial helix formation, followed by a much slower (100 sec) insertion pathway to give a transmembrane helix. The reverse process of unfolding and peptide exit from the bilayer core, which can be induced by a rapid rise of the pH from acidic to basic, proceeds approximately 400 times faster than folding/insertion and through different intermediate states. In the exit pathway, the helix-coil transition is initiated while the polypeptide is still inside the membrane. The peptide starts to exit when about 30% of the helix is unfolded, and continues a rapid exit as it unfolds inside the membrane. These insights may guide understanding of membrane protein folding/unfolding and the design of medically useful peptides for imaging and drug delivery. PMID- 20160114 TI - Severe oxidative stress induces protein mistranslation through impairment of an aminoacyl-tRNA synthetase editing site. AB - Oxidative stress arises from excessive reactive oxygen species (ROS) and affects organisms of all three domains of life. Here we present a previously unknown pathway through which ROS may impact faithful protein synthesis. Aminoacyl-tRNA synthetases are key enzymes in the translation of the genetic code; they attach the correct amino acid to each tRNA species and hydrolyze an incorrectly attached amino acid in a process called editing. We show both in vitro and in vivo in Escherichia coli that ROS reduced the overall translational fidelity by impairing the editing activity of threonyl-tRNA synthetase. Hydrogen peroxide oxidized cysteine182 residue critical for editing, leading to Ser-tRNA(Thr) formation and protein mistranslation that impaired growth of Escherichia coli. The presence of major heat shock proteases was required to allow cell growth in medium containing serine and hydrogen peroxide; this suggests that the mistranslated proteins were misfolded. PMID- 20160115 TI - The Murray Springs Clovis site, Pleistocene extinction, and the question of extraterrestrial impact. AB - Some of the evidence for the recent hypothesis of an extraterrestrial impact that caused late Pleistocene megafaunal extinctions [Firestone et al. (2007) Proc Natl Acad Sci USA 104:16016-16021] was based upon samples collected at Murray Springs, a Clovis archaeological site in southeastern Arizona. Here we describe sampling and analyses of magnetic separates from within, above, and below the lower Younger Dryas boundary (LYDB) black mat at Murray Springs, as well as radiation measurements from the LYDB at Murray Springs and two other well-stratified Clovis sites. The main magnetic fraction at Murray Springs is maghemite. Magnetic microspherules have terrestrial origins but also occur as cosmic dust particles. We failed to find iridium or radiation anomalies. The evidence for massive biomass burning at Murray Springs is addressed and found to be lacking. We could not substantiate some of the claims by Firestone and others, but our findings do not preclude a terminal Pleistocene cosmic event. PMID- 20160116 TI - Field-effect-tuned lateral organic diodes. AB - The operation of organic diodes in solar cells and light-emitting displays strongly depends on the properties of the interfaces between hole- and electron carrying organic semiconductors. Such interfaces are difficult to characterize, as they are usually buried under the surface or exist as an irregular "bulk heterojunction." Using a unique fluorinated barrier layer-based lithographic technique, we fabricated a lateral organic p-n junction, allowing the first observation of the potential at an organic p-n interface simultaneously with the charge transport measurements. We find that the diode characteristics of the device (current output and rectification ratio) are consistent with the changes in the surface potentials near the junction, and the current-voltage curves and junction potentials are strongly and self-consistently modulated by a third, gate electrode. The generality of our technique makes this an attractive method to investigate the physics of organic semiconductor junctions. The lithographic technique is applicable to a wide variety of soft material patterns. The observation of built-in potentials makes an important connection between organic junctions and textbook descriptions of inorganic devices. Finally, these kinds of potentials may prove to be controlling factors in charge separation efficiency in organic photovoltaics. PMID- 20160117 TI - Surface-coupled proton exchange of a membrane-bound proton acceptor. AB - Proton-transfer reactions across and at the surface of biological membranes are central for maintaining the transmembrane proton electrochemical gradients involved in cellular energy conversion. In this study, fluorescence correlation spectroscopy was used to measure the local protonation and deprotonation rates of single pH-sensitive fluorophores conjugated to liposome membranes, and the dependence of these rates on lipid composition and ion concentration. Measurements of proton exchange rates over a wide proton concentration range, using two different pH-sensitive fluorophores with different pK(a)s, revealed two distinct proton exchange regimes. At high pH (> 8), proton association increases rapidly with increasing proton concentrations, presumably because the whole membrane acts as a proton-collecting antenna for the fluorophore. In contrast, at low pH (< 7), the increase in the proton association rate is slower and comparable to that of direct protonation of the fluorophore from the bulk solution. In the latter case, the proton exchange rates of the two fluorophores are indistinguishable, indicating that their protonation rates are determined by the local membrane environment. Measurements on membranes of different surface charge and at different ion concentrations made it possible to determine surface potentials, as well as the distance between the surface and the fluorophore. The results from this study define the conditions under which biological membranes can act as proton-collecting antennae and provide fundamental information on the relation between the membrane surface charge density and the local proton exchange kinetics. PMID- 20160118 TI - Active multilayered capsules for in vivo bone formation. AB - Interest in the development of new sources of transplantable materials for the treatment of injury or disease has led to the convergence of tissue engineering with stem cell technology. Bone and joint disorders are expected to benefit from this new technology because of the low self-regenerating capacity of bone matrix secreting cells. Herein, the differentiation of stem cells to bone cells using active multilayered capsules is presented. The capsules are composed of poly-L glutamic acid and poly-L-lysine with active growth factors embedded into the multilayered film. The bone induction from these active capsules incubated with embryonic stem cells was demonstrated in vitro. Herein, we report the unique demonstration of a multilayered capsule-based delivery system for inducing bone formation in vivo. This strategy is an alternative approach for in vivo bone formation. Strategies using simple chemistry to control complex biological processes would be particularly powerful, as they make production of therapeutic materials simpler and more easily controlled. PMID- 20160119 TI - A role for a bacterial ortholog of the Ro autoantigen in starvation-induced rRNA degradation. AB - Cellular adaptations to stress often involve changes in RNA metabolism. One RNA binding protein that has been implicated in RNA handling during environmental stress in both animal cells and prokaryotes is the Ro autoantigen. However, the function of Ro in stress conditions has been unknown. We report that a Ro protein in the radiation-resistant eubacterium Deinococcus radiodurans participates in ribosomal RNA (rRNA) degradation during growth in stationary phase, a form of starvation. Levels of the Ro ortholog Rsr increase dramatically during growth in stationary phase and the presence of Rsr confers a growth advantage. Examination of rRNA profiles reveals that Rsr, the 3' to 5' exoribonuclease polynucleotide phosphorylase (PNP) and additional nucleases are all involved in the extensive rRNA decay that occurs during starvation of this bacterium. We show that Rsr, PNP, and an Rsr-PNP complex exhibit increased sedimentation with ribosomal subunits during stationary phase. As the fractionation of PNP with ribosomal subunits is strongly enhanced in the presence of Rsr, we propose that Ro proteins function as cofactors to increase the association of exonucleases with certain substrates during stress. PMID- 20160120 TI - Cell-specific differences in the requirements for translation quality control. AB - Protein synthesis has an overall error rate of approximately 10(-4) for each mRNA codon translated. The fidelity of translation is mainly determined by two events: synthesis of cognate amino acid:tRNA pairs by aminoacyl-tRNA synthetases (aaRSs) and accurate selection of aminoacyl-tRNAs (aa-tRNAs) by the ribosome. To ensure faithful aa-tRNA synthesis, many aaRSs employ a proofreading ("editing") activity, such as phenylalanyl-tRNA synthetases (PheRS) that hydrolyze mischarged Tyr-tRNA(Phe). Eukaryotes maintain two distinct PheRS enzymes, a cytoplasmic (ctPheRS) and an organellar form. CtPheRS is similar to bacterial enzymes in that it consists of a heterotetramer in which the alpha-subunits contain the active site and the beta-subunits harbor the editing site. In contrast, mitochondrial PheRS (mtPheRS) is an alpha-subunit monomer that does not edit Tyr-tRNA(Phe), and a comparable transacting activity does not exist in organelles. Although mtPheRS does not edit, it is extremely specific as only one Tyr-tRNA(Phe) is synthesized for every approximately 7,300 Phe-tRNA(Phe), compatible with an error rate in translation of approximately 10(-4). When the error rate of mtPheRS was increased 17-fold, the corresponding strain could not grow on respiratory media and the mitochondrial genome was rapidly lost. In contrast, error-prone mtPheRS, editing deficient ctPheRS, and their wild-type counterparts all supported cytoplasmic protein synthesis and cell growth. These striking differences reveal unexpectedly divergent requirements for quality control in different cell compartments and suggest that the limits of translational accuracy may be largely determined by cellular physiology. PMID- 20160121 TI - Observation of halogen species in the Amundsen Gulf, Arctic, by active long-path differential optical absorption spectroscopy. AB - In the polar tropospheric boundary layer, reactive halogen species (RHS) are responsible for ozone depletion as well as the oxidation of elemental mercury and dimethyl sulphide. After polar sunrise, air masses enriched in reactive bromine cover areas of several million square kilometers. Still, the source and release mechanisms of halogens are not completely understood. We report measurements of halogen oxides performed in the Amundsen Gulf, Arctic, during spring 2008. Active long-path differential optical absorption spectroscopy (LP-DOAS) measurements were set up offshore, several kilometers from the coast, directly on the sea ice, which was never done before. High bromine oxide concentrations were detected frequently during sunlight hours with a characteristic daily cycle showing morning and evening maxima and a minimum at noon. The, so far, highest observed average mixing ratio in the polar boundary layer of 41 pmol/mol (equal to pptv) was detected. Only short sea ice contact is required to release high amounts of bromine. An observed linear decrease of maximum bromine oxide levels with ambient temperature during sunlight, between -24 degrees C and -15 degrees C, provides indications on the conditions required for the emission of RHS. In addition, the data indicate the presence of reactive chlorine in the Arctic boundary layer. In contrast to Antarctica, iodine oxide was not detected above a detection limit of 0.3 pmol/mol. PMID- 20160122 TI - Agonist-induced endocytosis and receptor phosphorylation mediate resensitization of dopamine D(2) receptors. AB - The regulatory mechanisms and functional roles of agonist-induced internalization of G protein-coupled receptors (GPCRs) were analyzed using mutant dopamine D(2) receptors (D(2)Rs) in which all possible GPCR kinase (GRK) phosphorylation sites were mutated or the affinity for beta-arrestins was altered. Agonist-induced internalization of D(2)Rs involved a phosphorylation-dependent component, which was mediated by serine/threonine (S/T) residues in the second loop and T225 in the third loop, and a phosphorylation-independent component. GRK2-mediated enhancement of the internalization and inhibition of D(2)R signaling did not involve receptor phosphorylation, and only the former required the enzymatic activity of GRK2. The phosphorylation-deficient mutant (D(2)R-intracellular loop 2/3) recycled more slowly and showed more agonist-induced desensitization than did the wild-type D(2)R, suggesting that receptor phosphorylation mediates the recycling of the internalized receptors and enhances receptor resensitization. Blockade of the agonist-induced internalization of D(2)R-intracellular loop 2/3 provoked desensitization as in wild-type D(2)R, suggesting that certain cellular processes other than receptor dephosphorylation occurring within the endocytic vesicle are responsible for the resensitization of D(2)R. When dissociation between D(2)R and beta-arrestin was inhibited or when the expression of cellular beta-arrestins was decreased, agonist-induced desensitization of D(2)R did not occur, suggesting that dissociation from beta-arrestin is the main cellular process required for resensitization of D(2)R and is achieved through agonist induced internalization. These results indicate that, in the regulation of some GPCRs, phosphorylation-independent association with beta-arrestin plays a major role in agonist-induced desensitization. PMID- 20160123 TI - Prostaglandin F2alpha represses IGF-I-stimulated IRS1/phosphatidylinositol-3 kinase/AKT signaling in the corpus luteum: role of ERK and P70 ribosomal S6 kinase. AB - Little is known about the early intracellular events that contribute to corpus luteum regression. Experiments were designed to determine the effects of prostaglandin F2alpha (PGF2alpha) on phosphatidylinositol-3-kinase (PI3K)/Akt signaling in the corpus luteum in vivo and in vitro. Treatment of midluteal-phase cows with a luteolytic dose of PGF2alpha resulted in a rapid increase in ERK and mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K1) signaling and a rapid suppression of Akt phosphorylation in luteal tissue. In vitro treatment of primary cultures of luteal cells with PGF2alpha also resulted in an increase in ERK and mTOR/p70S6K1 signaling and a diminished capacity of IGF I to stimulate PI3K, Akt, and protein kinase C zeta activation. Accounting for the reductions in PI3K and Akt activation observed in response to PGF2alpha treatment, we found that PGF2alpha promoted the phosphorylation of serine residues (307, 612, 636) in the insulin receptor substrate 1 (IRS1) peptide sequence in vivo and in vitro. Serine phosphorylation of IRS1 was associated with reduced formation of IGF-I-stimulated IRS1/PI3Kp85 complexes. Furthermore, treatment with inhibitors of the MAPK kinase 1/ERK or mTOR/p70S6K1 signaling pathways prevented PGF2alpha-induced serine phosphorylation of IRS1 and abrogated the inhibitory actions of PGF2alpha on Akt activation. Taken together, these experiments provide compelling evidence that PGF2alpha treatment stimulates IRS1 serine phosphorylation, which may contribute to a diminished capacity to respond to IGF-I. It seems likely that the rapid changes in phosphorylation events are among the early events that mediate PGF2alpha-induced corpus luteum regression. PMID- 20160124 TI - Prenatal exposure to the environmental obesogen tributyltin predisposes multipotent stem cells to become adipocytes. AB - The environmental obesogen hypothesis proposes that pre- and postnatal exposure to environmental chemicals contributes to adipogenesis and the development of obesity. Tributyltin (TBT) is an agonist of both retinoid X receptor (RXR) and peroxisome proliferator-activated receptor gamma (PPARgamma). Activation of these receptors can elevate adipose mass in adult mice exposed to the chemical in utero. Here we show that TBT sensitizes human and mouse multipotent stromal stem cells derived from white adipose tissue [adipose-derived stromal stem cells (ADSCs)] to undergo adipogenesis. In vitro exposure to TBT, or the PPARgamma activator rosiglitazone increases adipogenesis, cellular lipid content, and expression of adipogenic genes. The adipogenic effects of TBT and rosiglitazone were blocked by the addition of PPARgamma antagonists, suggesting that activation of PPARgamma mediates the effect of both compounds on adipogenesis. ADSCs from mice exposed to TBT in utero showed increased adipogenic capacity and reduced osteogenic capacity with enhanced lipid accumulation in response to adipogenic induction. ADSCs retrieved from animals exposed to TBT in utero showed increased expression of PPARgamma target genes such as the early adipogenic differentiation gene marker fatty acid-binding protein 4 and hypomethylation of the promoter/enhancer region of the fatty acid-binding protein 4 locus. Hence, TBT alters the stem cell compartment by sensitizing multipotent stromal stem cells to differentiate into adipocytes, an effect that could likely increase adipose mass over time. PMID- 20160125 TI - Inhibin-A antagonizes TGFbeta2 signaling by down-regulating cell surface expression of the TGFbeta coreceptor betaglycan. AB - Inhibin is an atypical member of the TGFbeta family of signaling ligands and is classically understood to function via competitive antagonism of activin ligand binding. Inhibin-null (Inha-/-) mice develop both gonadal and adrenocortical tumors, the latter of which depend upon gonadectomy for initiation. We have previously shown that gonadectomy initiates adrenal tumorigenesis in Inha-/- mice by elevating production of LH, which drives aberrant proliferation and differentiation of subcapsular adrenocortical progenitor cells. In this study, we demonstrate that LH signaling specifically up-regulates expression of TGFbeta2 in the subcapsular region of the adrenal cortex, which coincides with regions of aberrant Smad3 activation in Inha-/- adrenal glands. Consistent with a functional interaction between inhibin and TGFbeta2, we further demonstrate that recombinant inhibin-A antagonizes signaling by TGFbeta2 in cultured adrenocortical cells. The mechanism of this antagonism depends upon the mutual affinity of inhibin-A and TGFbeta2 for the signaling coreceptor betaglycan. Although inhibin-A cannot physically displace TGFbeta2 from its binding sites on betaglycan, binding of inhibin-A to the cell surface causes endocytic internalization of betaglycan, thereby reducing the number of available binding sites for TGFbeta2 on the cell surface. The mechanism by which inhibin-A induces betaglycan internalization is clathrin independent, making it distinct from the mechanism by which TGFbeta ligands themselves induce betaglycan internalization. These data indicate that inhibin can specifically antagonize TGFbeta2 signaling in cellular contexts where surface expression of betaglycan is limiting and provide a novel mechanism for activin-independent phenotypes in Inha-/- mice. PMID- 20160126 TI - Distinct alterations in chromatin organization of the two IGF-I promoters precede growth hormone-induced activation of IGF-I gene transcription. AB - Many of the physiological actions of GH are mediated by IGF-I, a secreted 70 residue peptide whose gene expression is induced by GH in the liver and other tissues via mechanisms that remain incompletely characterized but depend on the transcription factor Stat5b. Here we investigate the chromatin landscape of the IGF-I gene in the liver of pituitary-deficient young adult male rats and assess the impact of a single systemic GH injection. Despite minimal ongoing transcription in the absence of GH, both IGF-I promoters appear to reside in open chromatin environments, at least as inferred from relatively high levels of acetylation of core histones H3 and H4 when compared with adjacent intergenic DNA and from enhanced trimethylation of histone H3 at lysine 4. This landscape of open chromatin may reflect maturation of the liver. Surprisingly, in the absence of hormone, IGF-I promoter 1 appears poised to be activated, as evidenced by the presence of the transcriptional coactivator p300 and recruitment of RNA polymerase (Pol) II into a preinitiation complex. By contrast, chromatin surrounding IGF-I promoter 2 is devoid of both p300 and RNA Pol II. Systemic GH treatment causes an approximately 15-fold increase in transcription from each IGF I promoter within 60 min of hormone administration, leading to a sustained accumulation of IGF-I mRNA. The coordinated induction of both IGF-I promoters by GH is accompanied by hyperacetylation of histones H3 and H4 in promoter associated chromatin, a decline in monomethylation at lysine 4 of histone H3, and recruitment of RNA Pol II to IGF-I promoter 2. We conclude that GH actions induce rapid and dramatic changes in hepatic chromatin at the IGF-I locus and activate IGF-I gene transcription in the liver by distinct promoter-specific mechanisms: at promoter 1, GH causes RNA Pol II to be released from a previously recruited paused preinitiation complex, whereas at promoter 2, hormone treatment facilitates recruitment and then activation of RNA Pol II to initiate transcription. PMID- 20160127 TI - Glucocorticoid rapidly enhances NMDA-evoked neurotoxicity by attenuating the NR2A containing NMDA receptor-mediated ERK1/2 activation. AB - Glucocorticoid (GC) has been shown to affect the neuronal survival/death through a genomic mechanism, but whether or not it does through a nongenomic mechanism is unknown. Using a previously identified GR-deficient primary hippocampal neuron culture, we show here that a 15-min coexposure of N-methyl-D-aspartate (NMDA) with corticosterone at a stress-induced level significantly enhances neuronal death compared to NMDA alone. This enhancing effect of GC can be mimicked by the BSA-conjugated corticosterone, which is plasma membrane impermeable and cannot be blocked by RU38486 spironolactone. Furthermore, using a calcium-imaging technique, we found that B could increase both the percentage of neurons showing a significant increment of intracellular free calcium ([Ca2+](i)) due to NMDA stimulation and the amplitude of [Ca2+](i) increment in the individual responsive cells. Interestingly, this boosting effect of GC on [Ca2+](i) increment could be blocked by the NMDA receptor subunit 2A (NR2A)-specific antagonist [(R)-[(S)-1-(4 bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl)-methyl] phosphonic acid (NVP-AAM077) but not by the NMDA receptor subunit 2B (NR2B) specific antagonist Ro25-6981. Moreover, we also found that GC can dramatically attenuate the NMDA-induced activation of ERK1/2 without affecting that of p38; and that the NMDA-induced ERK1/2 activation and its attenuation by GC both can be occluded by the NVP-AAM077 but not by Ro25-6981. Consistently, the enhancing effect of GC on NMDA neurotoxicity can also be blocked by NVP-AAM077 and the ERK1/2 inhibitor PD98059 but not by Ro25-6981 and p38 inhibitor SB203580. Indeed, the NMDA neurotoxicity itself can be blocked by Ro25-6981 or SB203580, whereas it is increased by NVP-AAM077 and PD98059. Therefore, it is probable that NMDA triggers a prodeath signaling through the NR2B-p38 MAPK pathway, and a prosurvival signaling through the NR2A-ERK1/2 MAPK pathway, whereas the latter was negatively regulated by rapid GC action. Taken together, the present data suggest a nongenomic action by GC that enhances NMDA neurotoxicity through facilitating [Ca2+](i) increment and attenuating the NR2A-ERK1/2-mediated neuroprotective signaling, implicating a novel pathway underlying the regulatory effect of GC on neuronal survival/death. PMID- 20160128 TI - Profile of Carolyn Bertozzi. Interview by Tinsley Davis. PMID- 20160129 TI - High molecular diversity of extraterrestrial organic matter in Murchison meteorite revealed 40 years after its fall. AB - Numerous descriptions of organic molecules present in the Murchison meteorite have improved our understanding of the early interstellar chemistry that operated at or just before the birth of our solar system. However, all molecular analyses were so far targeted toward selected classes of compounds with a particular emphasis on biologically active components in the context of prebiotic chemistry. Here we demonstrate that a nontargeted ultrahigh-resolution molecular analysis of the solvent-accessible organic fraction of Murchison extracted under mild conditions allows one to extend its indigenous chemical diversity to tens of thousands of different molecular compositions and likely millions of diverse structures. This molecular complexity, which provides hints on heteroatoms chronological assembly, suggests that the extraterrestrial chemodiversity is high compared to terrestrial relevant biological- and biogeochemical-driven chemical space. PMID- 20160130 TI - Characterization of the potent gonadotropin-releasing activity of RF9, a selective antagonist of RF-amide-related peptides and neuropeptide FF receptors: physiological and pharmacological implications. AB - Identification of RF-amide-related peptides (RFRP), as putative mammalian orthologs of the avian gonadotropin-inhibitory hormone, has drawn considerable interest on its potential effects and mechanisms of action in the control of gonadotropin secretion in higher vertebrates. Yet, these analyses have so far relied mostly on indirect approaches, while direct assessment of their physiological roles has been hampered by the lack of suitable antagonists. RF9 was recently reported as a selective and potent antagonist of the receptors for RFRP (RFRPR) and the related neuropeptides, neuropeptide FF (NPFF) and neuropeptide AF (NPFF receptor). We show here that RF9 possesses very strong gonadotropin-releasing activities in vivo. Central administration of RF9 evoked a dose-dependent increase of LH and FSH levels in adult male and female rats. Similarly, male and female mice responded to intracerebroventricular injection of RF9 with robust LH secretory bursts. In rats, administration of RF9 further augmented the gonadotropin-releasing effects of kisspeptin, and its stimulatory effects were detected despite the prevailing suppression of gonadotropin secretion by testosterone or estradiol. In fact, blockade of estrogen receptor alpha partially attenuated gonadotropin responses to RF9. Finally, systemic administration of RF9 modestly stimulated LH secretion in vivo, although no direct effects in terms of gonadotropin secretion were detected at the pituitary in vitro. Altogether, these data are the first to disclose the potent gonadotropin-releasing activity of RF9, a selective antagonist of RFRP (and NPFF) receptors. Our findings support a putative role of the RFRP/gonadotropin inhibitory hormone system in the central control of gonadotropin secretion in mammals and have interesting implications concerning the potential therapeutic indications and pharmacological effects of RF9. PMID- 20160131 TI - Human cytochrome p450c17: single step purification and phosphorylation of serine 258 by protein kinase a. AB - Cytochrome P450c17 (P450c17) is the single microsomal enzyme that catalyzes steroid 17alpha-hydroxylase and 17,20 lyase activities. The ratio of lyase to hydroxylase activity of human P450c17 determines whether steroidogenesis leads to the synthesis of cortisol or sex steroids. This ratio is regulated posttranslationally by factors that influence the efficiency of electron transfer from P450 oxidoreductase to P450c17. One factor favoring more efficient electron transfer and 17,20 lyase activity is cAMP-dependent serine/threonine phosphorylation of P450c17. Identifying the responsible kinase(s) and the P450c17 residues that undergo phosphorylation has been challenging, partly because of difficulties in preparing biochemically useful amounts of pure, catalytically active P450c17. We describe a modified strategy for preparing P450c17 in which the traditional carboxy-terminal 4xHis tag is replaced by 3xGly6xHis. This construct permits more rotational freedom of the protein when bound to the nickel affinity column, reducing steric associations between the protein and the column, and permitting a single-step chromatographic purification to apparent homogeneity. Using this vector, we explored P450c17 phosphorylation by mutagenesis of Ser and/or Thr residues to Asp or Glu to mimic the approximate size and charge of phospho-Ser or phospho-Thr. This strategy did not identify Ser and/or Thr site(s) that increase the ratio of lyase to hydroxylase activity, suggesting that the regulatory phosphorylation strategy of human P450c17 is very complicated. Although previous work has excluded protein kinase A (PKA) as the responsible kinase, the cAMP-inducible nature of the phosphorylation-associated increase in lyase activity suggests that PKA may play a role, possibly as a priming kinase. Using our novel vector and a series of mutations, we identified the P450c17 site phosphorylated by PKA as Ser258. PMID- 20160132 TI - A locus on mouse chromosome 2 is involved in susceptibility to congenital hypothyroidism and contains an essential gene expressed in thyroid. AB - We report here the mapping of a chromosomal region responsible for strain specific development of congenital hypothyroidism in mice heterozygous for null mutations in genes encoding Nkx2-1/Titf1 and Pax8. The two strains showing a differential predisposition to congenital hypothyroidism contain several single nucleotide polymorphisms in this locus, one of which leads to a nonsynonymous amino acid change in a highly conserved region of Dnajc17, a member of the type III heat-shock protein-40 (Hsp40) family. We demonstrate that Dnajc17 is highly expressed in the thyroid bud and had an essential function in development, suggesting an important role of this protein in organogenesis and/or function of the thyroid gland. PMID- 20160134 TI - Maternal dietary fat determines metabolic profile and the magnitude of endocannabinoid inhibition of the stress response in neonatal rat offspring. AB - Endocannabinoids (eCBs) are products of phospholipid (PL)-derived arachidonic acid (AA) that regulate hypothalamus-pituitary-adrenal axis activity. We hypothesized that differences in the quality and quantity of maternal dietary fat would modulate the PL AA content in the neonatal brain affecting stress responsiveness via differences in eCB production and activity in stress-activated brain areas. Pregnant rats were fed a 5% [control (C)] or 30% fat [high fat (HF)] diet rich in either n-6 (HF-n-6) or n-3 (HF-n-3) fat during the last week of gestation and lactation. Postnatal d 10 offspring were tested for metabolic hormones, AA (n-6) and eCB brain content, and hormonal effects of eCB receptor antagonism (AM251, 1 or 3 mg/kg ip) on stress responses. Like maternal diet, milk from HF-n-3 mothers had a reduced n-6/n-3 fat ratio compared with that of C and HF-n-6 mothers. Hypothalamic and hippocampal levels of PL AA were diet specific, reflecting the maternal milk and dietary n-6/n-3 ratio, with HF-n-3 offspring displaying reduced AA content relative to C and HF-n-6 offspring. Plasma corticosterone and insulin were elevated in HF-fed pups, whereas leptin was increased only in HF-n-6 pups. Basal eCB concentrations were also diet and brain region specific. In C pups, eCB receptor antagonist pretreatment increased stress induced ACTH secretion, but not in the HF groups. Stress-induced corticosterone secretion was not sensitive to AM251 treatment in HF-n-3 pups. Thus, the nature of preweaning dietary fat differentially influences neonatal metabolic hormones, brain PL AA levels, and eCB, with functional consequences on hypothalamus pituitary-adrenal axis modulation in developing rat pups. PMID- 20160133 TI - Protein malnutrition during pregnancy in C57BL/6J mice results in offspring with altered circadian physiology before obesity. AB - The mechanisms linking intrauterine growth retardation (IUGR) with adulthood obesity and diabetes are unclear. These studies investigated energy homeostasis in 8- and 20-wk-old male and female mice subjected to protein deficiency in utero. Pregnant C57BL/6J female mice were fed a protein-deficient diet (6% protein). Undernourished offspring (UO) and controls (CO) were cross-fostered to lactating dams fed a 20% control diet. The 24-h profiles of energy expenditure, feeding behavior, physical activity, and whole-body substrate preference was assessed using 8-wk UO and CO weaned onto control diet. Blood chemistries, glucose tolerance, and expression of genes involved in hepatic lipid and glucose metabolism were analyzed in 8- and 20-wk-old CO and UO fed control or a high-fat diet. UO exhibited IUGR with catch-up growth at 8 wk of age and increased severity of diet-induced obesity and insulin resistance by 20 wk of age. Therefore, fetal malnutrition in the C57BL/6J mouse increases sensitivity to diet induced obesity. Abnormal daily rhythms in food intake and metabolism, increased lipogenesis, and inflammation preceded obesity in the UO group. Arrhythmic expression of circadian oscillator genes was evident in brain, liver, and muscle of UO at 8 and 20 wk of age. Expression of the clock-associated nuclear receptor and transcription repressor Rev-erbalpha was reduced in liver and muscle of UO. Altered circadian physiology may be symptomatic of the metabolic dysregulation associated with IUGR, and altered feeding behavior and substrate metabolism may contribute to the obese phenotype. PMID- 20160135 TI - Peroxisome proliferator-activated receptor-(gamma) receptor ligand partially prevents the development of endometrial explants in baboons: a prospective, randomized, placebo-controlled study. AB - A prospective, randomized, placebo-controlled study was conducted in a baboon model to determine if a thiazolidinedione agonist of peroxisome proliferator activated receptor-gamma, pioglitazone, can impede the development of endometriosis. Endometriosis was induced using laparoscopic, intrapelvic injection of eutopic menstrual endometrium, previously incubated with placebo or pioglitazone for 30 min, in 12 female baboons with a normal pelvis that had undergone at least one menstrual cycle since the time of captivity. At this point, the 12 baboons were randomized into two groups and treated from the day of induction. They received either PBS tablets (n = 6, placebo control, placebo tablets once a day by mouth) or pioglitazone (n = 6, test drug, 7.5 mg by mouth each day). A second and final laparoscopy was performed in the baboons to record the extent of endometriotic lesions between 24 and 42 d after induction (no difference in length of treatment between the two groups, P = 0.38). A videolaparoscopy was performed to document the number and surface area of endometriotic lesions. The surface area and volume of endometriotic lesions were significantly lower in pioglitazone treated baboons than the placebo group (surface area, 48.6 vs. 159.0 mm(2), respectively, P = 0.049; vol, 23.7 vs. 131.8 mm(3), respectively, P = 0.041). The surface area (3.5 vs. 17.8 mm(2), P = 0.017, pioglizatone vs. placebo) and overall number (1.5 vs. 9.5, P = 0.007, pioglizatone vs. placebo) of red lesions were lower in the pioglitazone group. A peroxisome proliferator-activated receptor-gamma ligand, pioglitazone, effectively reduced the initiation of endometriotic disease in the baboon endometriosis model. Using this animal model, we have shown that thiazolidinedione is a promising drug for preventive treatment of endometriosis. PMID- 20160136 TI - Selective activation of estrogen receptor-beta target genes by 3,3' diindolylmethane. AB - 3,3'-Diindolylmethane (DIM) is a natural compound found in cruciferous vegetables that has antiproliferative and estrogenic activity. However, it is not clear whether the estrogenic effects are mediated through estrogen receptor (ER)alpha, ERbeta, or both ER subtypes. We investigated whether DIM has ER subtype selectivity on gene transcription. DIM stimulated ERbeta but not ERalpha activation of an estrogen response element upstream of the luciferase reporter gene. DIM also selectively activated multiple endogenous genes through ERbeta. DIM did not bind to ERbeta, indicating that it activates genes by a ligand independent mechanism. DIM causes ERbeta to bind regulatory elements and recruit the steroid receptor coactivator (SRC)-2 coactivator, which leads to the activation of ER target genes. Silencing of SRC-2 inhibited the activation of ER target genes, demonstrating that SRC-2 is required for transcriptional activation by DIM. Our results demonstrate that DIM is a new class of ERbeta-selective compounds, because it does not bind to ERbeta, but instead it selectively recruits ERbeta and coactivators to target genes. PMID- 20160137 TI - Individual differences in reactivity to social stress predict susceptibility and resilience to a depressive phenotype: role of corticotropin-releasing factor. AB - Previous social stress exposure is a common risk factor for affective disorders. However, factors that determine vulnerability or resiliency to social stress induced psychopathologies remain unclear. Using a rodent model of social stress, the present study was designed to identify putative neurobiological substrates that contribute to social stress-induced psychopathology and factors that influence or predict vulnerability. The resident-intruder model of defeat was used as a social stressor in adult male Sprague Dawley rats. The average latency to assume a subordinate posture (signaling defeat) over seven daily defeat exposures was calculated and examined with respect to endpoints of hypothalamic pituitary-adrenal activity, components of the corticotropin-releasing factor (CRF) system, and behaviors that are relevant to human depression. In the present studies, a bimodal distribution emerged in an otherwise homogeneous population of Sprague Dawley rats such that 42% of rats exhibited short defeat latencies (<300 sec), whereas 58% of rats resisted defeat and exhibited longer latencies (>300 sec). These two phenotypes were associated with distinct endocrine and behavioral profiles as well as differences in components of the CRF system. Notably, the short-latency subpopulation exhibited hypothalamic-pituitary-adrenal dysregulation and behavior similar to that observed in melancholic depression. Examination of components of the CRF system suggested that proactive behavior in resisting defeat exhibited by long-latency rats was associated with decreased efficacy of CRF. Together, these data suggest that inherent differences in stress reactivity, perhaps as a result of differences in CRF regulation, may predict long-term consequences of social stress and vulnerability to depressive-like symptoms. PMID- 20160138 TI - Maternal leukemia inhibitory factor (LIF) promotes fetal neurogenesis via a LIF ACTH-LIF signaling relay pathway. AB - Leukemia inhibitory factor (LIF) promotes the proliferation of neuronal progenitor cells in the cerebrum. However, it remains unclear how fetal LIF level is regulated. Here we show evidence that maternal LIF signals drive fetal LIF levels via the placenta, thereby promoting neurogenesis in the fetal brain in rats. Chronological changes showed that LIF concentration in fetal sera (FS) and fetal cerebrospinal fluid peaked at gestational day (GD) 15.5, after the peak of maternal LIF at GD14.5. LIF injection into rat dams at GD15.5 increased the level of ACTH in FS and subsequently increased LIF levels in FS and fetal cerebrospinal fluid. The elevation of fetal LIF after LIF injection into dams was inhibited by in utero injection of anti-ACTH antibody into fetuses. Cultured syncytiotrophoblasts, which express the LIF receptor and glycoprotein 130, were induced to secrete ACTH and up-regulate Pomc expression by the addition of LIF. Nucleated red blood cells from fetuses at GD15.5, but not GD13.5 or GD17.5, displayed LIF secretion in response to ACTH. Moreover, injection of LIF into dams at GD13.5 or GD17.5 did not result in elevation of ACTH or LIF in fetuses. The labeling index of 5-bromo-2'-deoxyuridine-positive cells in the ventricular zone of the cerebral neocortex increased 24 h after injection of LIF into dams at GD15.5 but not GD13.5 or GD17.5. These results suggest that in rats maternal LIF induces ACTH from the placenta, which in turn induces fetal nucleated red blood cells to secrete LIF that finally increases neurogenesis in fetuses around GD15. PMID- 20160139 TI - Maximal exercise electrocardiographic responses and coronary heart disease mortality among men with metabolic syndrome. AB - OBJECTIVE: To examine the association between abnormal exercise electrocardiographic (E-ECG) test results and mortality (all-cause and that resulting from coronary heart disease [CHD] or cardiovascular disease [CVD]) in a large population of asymptomatic men with metabolic syndrome (MetS). PATIENTS AND METHODS: A total of 9191 men (mean age, 46.9 years) met the criteria of having MetS. All completed a maximal E-ECG treadmill test (May 14, 1979, through April 9, 2001) and were without a previous CVD event or diabetes at baseline. Main outcomes were all-cause mortality, mortality due to CHD, and mortality due to CVD. Cox regression analysis was used to quantify the mortality risk according to E-ECG responses. RESULTS: During a follow-up of 14 years, 633 deaths (242 CVD and 150 CHD) were identified. Mortality rates and hazard ratios (HRs) across E-ECG responses were the following: for all-cause mortality: HR, 1.36; 95% confidence interval (CI), 1.09-1.70 for equivocal responses and HR, 1.41; 95% CI, 1.12-1.77 for abnormal responses (P(trend)<.001); for mortality due to CVD: HR, 1.29; 95% CI, 0.88-1.88 for equivocal responses and HR, 2.04; 95% CI, 1.46-2.84 for abnormal responses (P(trend)<.001); and for mortality due to CHD: HR, 1.62; 95% CI, 1.02-2.56 for equivocal responses and HR, 2.45; 95% CI, 1.62-3.69 for abnormal responses (P(trend)<.001). A positive gradient for CHD, CVD, and all cause mortality rates across E-ECG categories within 3, 4, or 5 MetS components was observed (P<.001 for all). CONCLUSION: Among men with MetS, an abnormal E-ECG response was associated with higher risk of all-cause, CVD, and CHD mortality. These findings underscore the importance of E-ECG tests to identify men with MetS who are at risk of dying. PMID- 20160140 TI - Activation of EphA receptors on CD4+CD45RO+ memory cells stimulates migration. AB - We have demonstrated previously that binding of ephrin-A1 to EphA receptors on human CD4(+) and CD8(+) T cells stimulates migration. Two EphA receptors have been reported in T cells: EphA1 at the protein level and EphA4 at the mRNA level. In this study, we wanted to investigate the expression profile of these receptors in T cell subpopulations and to test if expression differences would affect the potential of cells to migrate upon ephrin-A1 binding. We have generated an anti EphA4 mAb for expression analysis. Our data show that functional EphA4 is expressed on the cell surface of CD4(+) and CD8(+) T cells. In addition, EphA4 receptor expression is induced after overnight incubation in serum-free medium, in particular, on CD4(+)CD45RO(+) T cells. Migration of CD4(+) T cells in response to ephrin-A1 is observed for memory cells (CD45RO(+)) and much weaker for naive cells (CD45RA(+)). A signaling complex associated with the EphA4 receptor has also been isolated and includes EphA1, the Src family kinases Fyn and Lck, Slp76, and Vav1. To conclude, T cells express EphA1 and EphA4 receptors. Expression differences of EphA4 are observed in subpopulations of CD4(+) T cells. This is related to the cell migration potential after ephrin-A1 binding. PMID- 20160141 TI - Changes in left and right ventricular mechanics during the Mueller maneuver in healthy adults: a possible mechanism for abnormal cardiac function in patients with obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea is highly prevalent in patients with cardiovascular disease and has detrimental effects on systolic and diastolic function of the ventricles. In this research, the changes in strain (S) and strain rate (SR) during the performance of the Mueller maneuver (MM) in an effort to better understand how negative intrathoracic pressures affect ventricular mechanics. METHODS AND RESULTS: The MM was performed to maintain a target intrathoracic pressure of -40 mm Hg. Echocardiography was used to measure various parameters of cardiac structure and function. Myocardial deformation measurements were performed using tissue speckle tracking. Twenty-four healthy subjects (9 women; mean age, 30+/-6 years) were studied. Global left ventricular longitudinal S in systole and SR in early filling were significantly decreased during the MM (S: baseline, -17.0+/-1.6%; MM, -14.5+/-2.2%; P<0.0001, SR: baseline, 1.09+/-0.20 s(-1); MM, 0.92+/-0.21 s(-1); P=0.01). Global right ventricular longitudinal S was also significantly decreased during the MM (baseline, -22.0+/-3.1%; MM, 17.2+/-2.5%; P<0.0001), as was global right ventricular longitudinal systolic SR (baseline, -1.34+/-0.35 s(-1); MM, -1.02+/-0.21 s(-1); P=0.0006). CONCLUSIONS: Left ventricular and right ventricular longitudinal deformation are significantly reduced during the MM. These results suggest that negative intrathoracic pressure during apnea may contribute to changes in myocardial mechanics. These results could help explain the observed changes in left ventricular and right ventricular mechanics in patients with obstructive sleep apnea. PMID- 20160142 TI - An official American Thoracic Society workshop report: tobacco control initiatives within the American Thoracic Society. AB - Cigarette smoking represents the single most preventable cause of premature morbidity and mortality in the United States and the burden of tobacco use is apparent world-wide. Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease, the third leading cause of death in the United States in 2004. The American Thoracic Society (ATS) and its members have contributed significantly to an understanding of the biological and pathophysiologic mechanisms responsible for the development and management of tobacco-attributable disease and disability. The society's active involvement in tobacco control advocacy and policy-related initiatives are central to its mission. Within the ATS, there is also increased interest in accelerating the society's efforts to understand the mechanisms responsible for the uptake, persistence, and cessation of tobacco use. Scientific, clinical, and educational activities that include an examination of these underlying mechanisms are warranted. This paper describes findings from an ATS initiative that developed a preliminary strategy for enhancing scientific, clinical, educational, and policy related tobacco control efforts that are consistent with the vision of the ATS. The specific aims of this project included the identification of existing mechanisms, as well as the current governance in place within the ATS infrastructure, to address tobacco control issues related to scientific inquiry, policy initiatives, and advocacy for tobacco control. This assessment generated recommendations to inform the ATS leadership with regard to the future development of relevant tobacco control initiatives. PMID- 20160143 TI - The ubiquitin system: historical perspective. PMID- 20160144 TI - Autophagy in the lung. AB - Autophagy is a cellular process for the disposal of damaged organelles or denatured proteins through a lysosomal degradation pathway. By reducing endogenous macromolecules to their basic components (i.e., amino acids, lipids), autophagy serves a homeostatic function by ensuring cell survival during starvation. Increased autophagy can be found in dying cells, although the relationships between autophagy and programmed cell death remain unclear. To date, few studies have examined the regulation and functional significance of autophagy in human lung disease. The lung, a complex organ that functions primarily in gas exchange, consists of diverse cell types (i.e., endothelial, epithelial, mesenchymal, inflammatory). In lung cells, autophagy may represent a general inducible adaptive response to injury resulting from exposure to stress agents, including hypoxia, oxidants, inflammation, ischemia-reperfusion, endoplasmic reticulum stress, pharmaceuticals, or inhaled xenobiotics (i.e., air pollution, cigarette smoke). In recent studies, we have observed increased autophagy in mouse lungs subjected to chronic cigarette smoke exposure, and in pulmonary epithelial cells exposed to cigarette smoke extract. Knockdown of autophagic proteins inhibited apoptosis in response to cigarette smoke exposure in vitro, suggesting that increased autophagy was associated with epithelial cell death. We have also observed increased morphological and biochemical markers of autophagy in human lung specimens from patients with chronic obstructive pulmonary disease (COPD). We hypothesize that increased autophagy contributes to COPD pathogenesis by promoting epithelial cell death. Further research will examine whether autophagy plays a homeostatic or maladaptive role in COPD and other human lung diseases. PMID- 20160145 TI - Autophagy in innate and adaptive immunity. AB - Autophagy (self-eating) is an evolutionary conserved simple process by which cells target their own cellular organelles and long-lived proteins for degradation. Recently, this simple ancient process has proved to be involved in many biological aspects, including host defense, cell survival and death, innate and adaptive immunity, and cancer. The implications of aberrant regulation of autophagy in human diseases are just beginning to unravel. This is a brief review of recent progress in the association of autophagy with innate and adaptive immunity relevant to lung biology and disease. PMID- 20160146 TI - Chaperone-mediated autophagy. AB - Continuous renewal of intracellular components is required to preserve cellular functionality. In fact, failure to timely turnover proteins and organelles leads often to cell death and disease. Different pathways contribute to the degradation of intracellular components in lysosomes or autophagy. In this review, we focus on chaperone-mediated autophagy (CMA), a selective form of autophagy that modulates the turnover of a specific pool of soluble cytosolic proteins. Selectivity in CMA is conferred by the presence of a targeting motif in the cytosolic substrates that, upon recognition by a cytosolic chaperone, determines delivery to the lysosomal surface. Substrate proteins undergo unfolding and translocation across the lysosomal membrane before reaching the lumen, where they are rapidly degraded. Better molecular characterization of the different components of this pathway in recent years, along with the development of transgenic models with modified CMA activity and the identification of CMA dysfunction in different severe human pathologies and in aging, are all behind the recent regained interest in this catabolic pathway. PMID- 20160147 TI - Autophagy in vascular disease. AB - Autophagy, or "self eating," refers to a regulated cellular process for the lysosomal-dependent turnover of organelles and proteins. During starvation or nutrient deficiency, autophagy promotes survival through the replenishment of metabolic precursors derived from the degradation of endogenous cellular components. Autophagy represents a general homeostatic and inducible adaptive response to environmental stress, including endoplasmic reticulum stress, hypoxia, oxidative stress, and exposure to pharmaceuticals and xenobiotics. Whereas elevated autophagy can be observed in dying cells, the functional relationships between autophagy and programmed cell death pathways remain incompletely understood. Preclinical studies have identified autophagy as a process that can be activated during vascular disorders, including ischemia reperfusion injury of the heart and other organs, cardiomyopathy, myocardial injury, and atherosclerosis. The functional significance of autophagy in human cardiovascular disease pathogenesis remains incompletely understood, and potentially involves both adaptive and maladaptive outcomes, depending on model system. Although relatively few studies have been performed in the lung, our recent studies also implicate a role for autophagy in chronic lung disease. Manipulation of the signaling pathways that regulate autophagy could potentially provide a novel therapeutic strategy in the prevention or treatment of human disease. PMID- 20160148 TI - Mammalian target of rapamycin signaling and autophagy: roles in lymphangioleiomyomatosis therapy. AB - The pace of progress in lymphangioleiomyomatosis (LAM) is remarkable. In the year 2000, TSC2 gene mutations were found in LAM cells; in 2001 the tuberous sclerosis complex (TSC) genes were discovered to regulate cell size in Drosophila via the kinase TOR (target of rapamycin); and in 2008 the results were published of a clinical trial of rapamycin, a specific inhibitor of TOR, in patients with TSC and LAM with renal angiomyolipomas. This interval of just 8 years between a genetic discovery for which the relevant signaling pathway was as yet unknown, to the initiation, completion, and publication of a clinical trial, is an almost unparalleled accomplishment in modern biomedical research. This robust foundation of basic, translational, and clinical research in TOR, TSC, and LAM is now poised to optimize and validate effective therapeutic strategies for LAM. An immediate challenge is to deduce the mechanisms underlying the partial response of renal angiomyolipomas to rapamycin, and thereby guide the design of combinatorial approaches. TOR complex 1 (TORC1), which is known to be active in LAM cells, is a key inhibitor of autophagy. One hypothesis, which will be explored here, is that low levels of autophagy in TSC2-null LAM cells limits their survival under conditions of bioenergetic stress. A corollary of this hypothesis is that rapamycin, by inducing autophagy, promotes the survival of LAM cells, while simultaneously arresting their growth. If this hypothesis proves to be correct, then combining TORC1 inhibition with autophagy inhibition may represent an effective clinical strategy for LAM. PMID- 20160149 TI - Regulation of epithelial sodium channel trafficking by ubiquitination. AB - Amiloride-sensitive epithelial sodium (Na(+)) channels (ENaC) play a crucial role in Na(+) transport and fluid reabsorption in the kidney, lung, and colon. The magnitude of ENaC-mediated Na(+) transport in epithelial cells depends on the average open probability of the channels and the number of channels on the apical surface of epithelial cells. The number of channels in the apical membrane, in turn, depends upon a balance between the rate of ENaC insertion and the rate of removal from the apical membrane. ENaC is made up of three homologous subunits, alpha, beta, and gamma. The C-terminal domain of all three subunits is intracellular and contains a proline rich motif (PPxY). Mutations or deletion of this PPxY motif in the beta and gamma subunits prevent the binding of one isoform of a specific ubiquitin ligase, neural precursor cell expressed developmentally down-regulated protein (Nedd4-2) to the channel in vitro and in transfected cell systems, thereby impeding ubiquitin conjugation of the channel subunits. Ubiquitin conjugation would seem to imply that ENaC turnover is determined by the ubiquitin-proteasome system, but when MDCK cells are transfected with ENaC, ubiquitin conjugation apparently leads to lysosomal degradation. However, in untransfected epithelial cells (A6) expressing endogenous ENaC, ENaC appears to be degraded by the ubiquitin-proteasome system. Nonetheless, in both transfected and untransfected cells, the rate of ENaC degradation is apparently controlled by the rate of Nedd4-2-mediated ENaC ubiquitination. Controlling the rate of degradation is apparently important enough to have multiple, redundant pathways to control Nedd4-2 and ENaC ubiquitination. PMID- 20160150 TI - Role of ubiquitination in Na,K-ATPase regulation during lung injury. AB - During acute lung injury edema accumulates in the alveolar space, resulting in hypoxemia due to intrapulmonary shunt. The alveolar Na,K-ATPase, by effecting active Na(+) transport, is essential for removing edema from the alveolar spaces. However, during hypoxia it is endocytosed and degraded, which results in decreased Na,K-ATPase function and impaired lung edema clearance. Na,K-ATPase endocytosis and degradation require the phosphorylation and subsequent ubiquitination of the Na,K-ATPase. These events are the results of cross-talk between post-translational modifications, and how ubiquitination of a specific protein can result from injurious extracellular stimuli. Here, we review current knowledge on the regulation of Na,K-ATPase activity during lung injury, focusing on the role of Na,K-ATPase ubiquitination during hypoxia. A better understanding of these signaling pathways can be of relevance for the design of novel treatments to ameliorate the deleterious effects of acute lung injury. PMID- 20160151 TI - The role of the ubiquitin proteasome pathway in keratin intermediate filament protein degradation. AB - Lung injury, whether caused by hypoxic or mechanical stresses, elicits a variety of responses at the cellular level. Alveolar epithelial cells respond and adapt to such injurious stimuli by reorganizing the cellular cytoskeleton, mainly accomplished through modification of the intermediate filament (IF) network. The structural and mechanical integrity in epithelial cells is maintained through this adaptive reorganization response. Keratin, the predominant IF expressed in epithelial cells, displays highly dynamic properties in response to injury, sometimes in the form of degradation of the keratin IF network. Post translational modification, such as phosphorylation, targets keratin proteins for degradation in these circumstances. As with other structural and regulatory proteins, turnover of keratin is regulated by the ubiquitin (Ub)-proteasome pathway. The degradation process begins with activation of Ub by the Ub activating enzyme (E1), followed by the exchange of Ub to the Ub-conjugating enzyme (E2). E2 shuttles the Ub molecule to the substrate-specific Ub ligase (E3), which then delivers the Ub to the substrate protein, thereby targeting it for degradation. In some cases of injury and IF-related disease, aggresomes form in epithelial cells. The mechanisms that regulate aggresome formation are currently unknown, although proteasome overload may play a role. Therefore, a more complete understanding of keratin degradation--causes, mechanisms, and consequences--will allow for a greater understanding of epithelial cell biology and lung pathology alike. PMID- 20160153 TI - Ubiquitination and proteolysis in limb and respiratory muscles of patients with chronic obstructive pulmonary disease. AB - Peripheral muscle dysfunction associated with chronic diseases is undeniably a growing problem as one of its main causes, chronic obstructive pulmonary disease (COPD), progresses. Among others, muscle atrophy is one component building the concept of muscle dysfunction. Muscle atrophy has a significant impact on patient clinical status, independent of the impairment in lung function. A lot of effort has been devoted lately to increasing our understanding of the relationship between COPD and the initiation and the development of muscle atrophy. A growing body of evidence is showing that the ubiquitin-proteasome system, an ATP dependent proteolytic pathway, is playing a crucial role in the cascade leading to degradation of contractile proteins, thus promoting the development of muscle atrophy. Interestingly, this system is also involved in essential cellular processes such as response to hypoxemia and muscle tissue regeneration. In this review, existing evidence linking the activity of the ubiquitin-proteasome system and the cellular events taking place in respiratory and peripheral muscles of patients with COPD are reported. Based on this information, the reader should be able to understand the essential role of this pathway in the context of muscle homeostasis and to picture the coming research in this area. PMID- 20160152 TI - Proteasomal regulation of pulmonary fibrosis. AB - It is estimated that, combined, 400,000 people are diagnosed with idiopathic pulmonary fibrosis (IPF) or acute lung injury/acute respiratory distress syndrome annually in the United States, and both diseases are associated with an unacceptably high mortality rate. Although these disorders are distinct clinical entities, they share pathogenic mechanisms that may provide overlapping therapeutic targets. One example is fibroblast activation, which occurs concomitant with acute lung injury as well as in the progressive fibrosis of IPF. Both clinical entities are characterized by elevations of the profibrotic cytokine, transforming growth factor (TGF)-beta1. Protein degradation by the ubiquitin-proteasomal system modulates TGF-beta1 expression and signaling. In this review, we highlight the effects of proteasomal inhibition in various animal models of tissue fibrosis and mechanisms by which it may regulate TGF-beta1 expression and signaling. At present, there are no effective therapies for fibroproliferative acute respiratory distress syndrome or IPF, and proteasomal inhibition may provide a novel, attractive target in these devastating diseases. PMID- 20160154 TI - Extracellular alveolar proteasome: possible role in lung injury and repair. AB - The ubiquitin-proteasome system is the major intracellular pathway for protein degradation in eukaryotes, and it also generates oligopeptides for antigen presentation. However, the 20S proteasome is also associated with the cell's outer membrane, and observations indicate its physiologic presence and biological activity in the extracellular alveolar space (i.e., in the epithelial lining fluid). Furthermore, its concentration is increased in the adult respiratory distress syndrome, acute lung injury, and other inflammatory lung disease. While its cellular origin, potential extracellular biological role, and mechanisms for extracellular transport are hitherto unclear, extracellular alveolar proteasomes could have a role in protein clearance, digestion of alveolar debris, modification or activation of secreted precursor proteins, and/or antigen processing, both in health and lung disease. This article summarizes available information on the extracellular alveolar proteasome and its possible role in alveolar maintainance, lung injury, and repair. PMID- 20160155 TI - Influence of CYP3A5 and MDR1 genetic polymorphisms on urinary 6 beta hydroxycortisol/cortisol ratio after grapefruit juice intake in healthy Chinese. AB - Interindividual variability of cytochrome P450 (CYP) 3A inhibition by grapefruit juice was investigated in relation to CYP3A5 and multidrug resistance gene (MDR) 1 genetic polymorphisms in Chinese Han, Uygur, and Kazakh healthy subjects. The measurement of urinary 6 beta-hydroxycortisol/cortisol ratio was used to evaluate CYP3A activity in vivo by high-performance liquid chromatography. CYP3A5*3 and MDR1 C1236T, G2677T/A, and C3435T polymorphisms were analyzed by polymerase chain reaction restriction fragment length polymorphism. After grapefruit juice intake, urinary ratios significantly decreased in 3 Chinese ethnic groups (P < .001). Kazakh had a larger decrease of urinary ratio compared to that of Han (P < .05), and the latter had similar decrease with Uygur. Furthermore, Chinese healthy subjects carrying CYP3A5*3/*3 and MDR1(1236-2677-3435) T-T-T/T-T-T genotypes were found to have the largest reduction of urinary ratio (mean, 61.4%; 95% confidence interval, 53.4%-69.5%), whereas *1/*3 subjects carrying MDR1(1236-2677-3435) C-G C/C-G-C genotypes had the lowest reduction (mean, 25.9%; 95% confidence interval, 3.1%-48.8%; P < .01). In conclusion, both CYP3A5*3 and MDR1 variants influenced the extent of CYP3A inhibition by grapefruit juice in Chinese healthy subjects. The genetic variations influencing the CYP3A inhibitive phenotype might be helpful to explain the individual variability of grapefruit juice-drug interactions. PMID- 20160156 TI - Operating characteristics of a partial-block randomized crossover bioequivalence study for dutasteride, a drug with a long half-life: investigation through simulation and comparison with final results. AB - Studies to establish bioequivalence (BE) of a drug are important elements in support of drug applications. A typical BE study is conducted as a single dose, randomized, 2-period crossover design. For drugs with long half lives (>= 48 hours) and evaluation of multiple BE objectives in 1 trial, this design may not be adequate. A parallel design may then be a more appropriate choice. However, parallel designs require increased sample size, which can become substantial. One option that is a compromise between the complete randomized block design and the parallel design is a partial-block crossover design. This approach came about during the development of a combination of dutasteride and tamsulosin. Previous experience with performing single-dose dutasteride studies suggested that 28 days of washout is needed between treatments because of its half-life of 7-9 days. Simulations were performed to assess the operating characteristics of this design using a previously developed PK model. Four scenarios were developed, and each scenario was simulated 500 times. The results showed that this design demonstrated acceptable consumer and producer risk. Partial-block crossover designs should be considered for studies when the half-life of the drug is long and there are more than 2 periods. PMID- 20160157 TI - Impact of target-mediated drug disposition on Linagliptin pharmacokinetics and DPP-4 inhibition in type 2 diabetic patients. AB - The pharmacokinetics of the novel dipeptidyl-peptidase 4 (DPP-4) inhibitor linagliptin is nonlinear. Based on in vitro experiments, concentration-dependent binding to DPP-4 is the most likely cause for the nonlinearity. Population pharmacokinetic/pharmacodynamic modeling was performed using linagliptin plasma concentrations and plasma DPP-4 activities from 2 phase 2a studies. In these studies, type 2 diabetic patients received either 1, 2.5, 5, or 10 mg of linagliptin once daily over 12 days (study 1) or 2.5, 5, or 10 mg of linagliptin once daily over 28 days (study 2). The modeling results supported the hypothesis that linagliptin exhibits target-mediated drug disposition. The linagliptin plasma concentrations were best described by a 2-compartment model including concentration-dependent protein binding in the central and peripheral compartment. The plasma DPP-4 activity was included in the model in a semi mechanistic way by relating it to the model-calculated plasma DPP-4 occupancy with linagliptin. The target binding has a major impact on linagliptin pharmacokinetics. Although unbound linagliptin is cleared efficiently (CL/F 220 L/h), the concentration-dependent binding is responsible for the long terminal half-life (approximatelly 120 hours) of linagliptin and its nonlinear pharmacokinetics. The model allowed a comprehensive understanding of the impact of target-mediated drug disposition and provides a useful tool to support clinical development. PMID- 20160158 TI - Distribution of lenalidomide into semen of healthy men after multiple oral doses. AB - Lenalidomide is a thalidomide analog and an immunomodulatory drug with demonstrated efficacy in various hematological malignancies. The distribution of lenalidomide into semen was evaluated in healthy subjects. Twenty-four male subjects were randomized into 4 equal groups for semen collection. All subjects received lenalidomide 25 mg once daily for 4 days. After the last dose, a single semen sample was collected from subjects, at approximately 2, 24, 72, and 168 hours for groups 1, 2, 3, and 4, respectively, and serial blood sampling was performed for 24 hours in all groups. The mean lenalidomide concentration in semen was 478 ng/mL at 2 hours and 10.0 ng/mL at 24 hours, which was higher than was the corresponding drug concentration in plasma (219 ng/mL at 2 hours and undetectable at 24 hours) but roughly paralleled the time course in plasma for drug elimination. The mean amount of lenalidomide was 1379 ng/ejaculate at 2 hours and 35 ng/ejaculate at 24 hours. The maximal drug content in a single ejaculate was <2000 ng (<0.01% of the daily 25-mg dose). Lenalidomide was undetectable in semen at 72 and 168 hours. Therefore, lenalidomide is essentially eliminated from seminal reservoirs by 72 hours postdose. PMID- 20160159 TI - Representation of women in randomized clinical trials of cardiovascular disease prevention. AB - BACKGROUND: The 2007 American Heart Association guidelines for cardiovascular disease prevention in women drew heavily on results from randomized clinical trials; however, representation of women in trials of cardiovascular disease prevention has not been systematically assessed. METHODS AND RESULTS: We abstracted 156 randomized clinical trials cited by the 2007 women's prevention guidelines to determine female representation over time and by clinical indication, prevention type, location of trial conduct, and funding source. Both women and men were represented in 135 of 156 (86.5%) trials; 20 trials enrolled only men; 1 enrolled only women. Among all trials, the proportion of women increased significantly over time, from 9% in 1970 to 41% in 2006. Considering only trials that enrolled both women and men, female enrollment was 18% in 1970 and increased to 34% in 2006. Female representation was higher in international versus United States-only trials (32.7% versus 26.7%) and primary versus secondary prevention trials (42.6% versus 26.6%). Female enrollment was comparable in government/foundation-funded versus industry-funded trials (31.9% versus 31.5%). Representation of women was highest among trials in hypertension (44%), diabetes (40%), and stroke (38%) and lowest for heart failure (29%), coronary artery disease (25%), and hyperlipidemia (28%). By contrast, women accounted for 53% of all individuals with hypertension, 50% with diabetes, 51% with heart failure, 49% with hyperlipidemia, and 46% with coronary artery disease. Sex-specific results were discussed in only 31% of primary trial publications. CONCLUSIONS: Enrollment of women in randomized clinical trials has increased over time but remains low relative to their overall representation in disease populations. Efforts are needed to reach a level of representation that is adequate to ensure evidence-based sex-specific recommendations. PMID- 20160160 TI - Evaluation of the American Heart Association cardiovascular disease prevention guideline for women. AB - BACKGROUND: The 2007 update to the American Heart Association (AHA) guidelines for cardiovascular disease prevention in women recommend a simplified approach to risk stratification. We assigned Women's Health Initiative participants to risk categories as described in the guideline and evaluated clinical event rates within and between strata. METHODS AND RESULTS: The Women's Health Initiative enrolled 161 808 women ages 50 to 79 years and followed them prospectively for 7.8 years (mean). Applying the 2007 AHA guideline categories, 11% of women were high risk, 72% at-risk, and 4% at optimal risk; 13% of women did not fall into any category, that is, lacked risk factors but did not adhere to a healthy lifestyle (moderate intensity exercise for 30 minute most days and <7% of calories from saturated fat). Among high risk, at-risk, and optimal risk women, rates of myocardial infarction/coronary death were 12.5%, 3.1%, and 1.1% per 10 years (P for trend <0.0001); the event rate was 1.3% among women who could not be categorized. We observed a graded relationship between risk category and cardiovascular event rates for white, black, Hispanic, and Asian women, although event rates differed among ethnic groups (P for interaction=0.002). The AHA guideline predicted coronary events with accuracy similar to current Framingham risk categories (area under receiver operating characteristic curve for Framingham risk, 0.665; for AHA risk, 0.664; P=0.94) but less well than proposed Framingham 10-year risk categories of <5%, 5% to 20%, and >20% (area under receiver operating characteristic curve for Framingham risk, 0.724; for AHA risk, 0.664; P<0.0001). CONCLUSIONS: Risk stratification as proposed in the 2007 AHA guideline is simple, accessible to patients and providers, and identifies cardiovascular risk with accuracy similar to that of the current Framingham algorithm. Clinical Trial Registration- clinicaltrials.gov. Identifier: NCT00000611. PMID- 20160161 TI - Ischemic heart disease in women: many questions, few facts. PMID- 20160162 TI - The role of social support in health status and depressive symptoms after acute myocardial infarction: evidence for a stronger relationship among women. AB - BACKGROUND: Prior studies have associated low social support (SS) with increased rehospitalization and mortality after acute myocardial infarction. However, relatively little is known about whether similar patterns exist for other outcomes, such as health status and depressive symptoms, and whether these patterns vary by sex. METHODS AND RESULTS: Using data from 2411 English- or Spanish-speaking patients with acute myocardial infarction enrolled in a 19 center prospective study, we examined the association of SS (low, moderate, high) with health status (angina, disease-specific quality of life, general physical and mental functioning) and depressive symptoms over the first year of recovery. Overall and sex-stratified associations were evaluated using mixed-effects Poisson and linear regression, adjusting for site, baseline health status, baseline depressive symptoms, and demographic and clinical factors. Patients with the lowest SS (relative to those with the highest) had increased risk of angina (relative risk, 1.27; 95% confidence interval [CI], 1.10, 1.48); lower disease specific quality of life (mean difference [beta]=-3.33; 95% CI, -5.25, -1.41), lower mental functioning (beta=-1.72; 95% CI, -2.65, -0.79), and more depressive symptoms (beta=0.94; 95% CI, 0.51, 1.38). A nonsignificant trend toward lower physical functioning (beta=-0.87; 95% CI, -1.95, 0.20) was observed. In sex stratified analyses, the relationship between SS and outcomes was stronger for women than for men, with a significant SS-by-sex interaction for disease-specific quality of life, physical functioning, and depressive symptoms (all P<0.02). CONCLUSIONS: Lower SS is associated with worse health status and more depressive symptoms over the first year of acute myocardial infarction recovery, particularly for women. PMID- 20160163 TI - Correlating cellular and molecular signatures of mucosal immunity that distinguish HIV controllers from noncontrollers. AB - HIV "controllers" are persons infected with human immunodeficiency virus, type I (HIV) who maintain long-term control of viremia without antiviral therapy and who usually do not develop the acquired immune deficiency syndrome (AIDS). In this study, we have correlated results from polychromatic flow cytometry and oligonucleotide expression arrays to characterize the mucosal immune responses of these subjects in relation to untreated HIV(+) persons with high viral loads and progressive disease ("noncontrollers"). Paired peripheral blood and rectosigmoid biopsies were analyzed from 9 controllers and 11 noncontrollers. Several cellular immune parameters were found to be concordant between the 2 compartments. Compared with noncontrollers, the mucosal tissues of controllers had similar levels of effector T cells and fewer regulatory T cells (Tregs). Using principal component analysis to correlate immunologic parameters with gene expression profiles, transcripts were identified that accurately distinguished between controllers and noncontrollers. Direct 2-way comparison also revealed genes that are significantly different in their expression between controllers and noncontrollers, all of which had reduced expression in controllers. In addition to providing an approach that integrates flow cytometry datasets with transcriptional profiling analysis, these results underscore the importance of the sustained inflammatory response that attends progressive HIV disease. PMID- 20160164 TI - Wide diversity of PAX5 alterations in B-ALL: a Groupe Francophone de Cytogenetique Hematologique study. AB - PAX5 is the main target of somatic mutations in acute B lymphoblastic leukemia (B ALL). We analyzed 153 adult and child B-ALL harboring karyotypic abnormalities at chromosome 9p, to determine the frequency and the nature of PAX5 alterations. We found PAX5 internal rearrangements in 21% of the cases. To isolate fusion partners, we used classic and innovative techniques (rolling circle amplification rapid amplification of cDNA ends) and single nucleotide polymorphism-comparative genomic hybridization arrays. Recurrent and novel fusion partners were identified, including NCoR1, DACH2, GOLGA6, and TAOK1 genes showing the high variability of the partners. We noted that half the fusion genes can give rise to truncated PAX5 proteins. Furthermore, malignant cells carrying PAX5 fusion genes displayed a simple karyotype. These data strongly suggest that PAX5 fusion genes are early players in leukemogenesis. In addition, PAX5 deletion was observed in 60% of B-ALL with 9p alterations. Contrary to cases with PAX5 fusions, deletions were associated with complex karyotypes and common recurrent translocations. This supports the hypothesis of the secondary nature of the deletion. Our data shed more light on the high variability of PAX5 alterations in B-ALL. Therefore, it is probable that gene fusions occur early, whereas deletions should be regarded as a late/secondary event. PMID- 20160165 TI - Allo-HLA reactivity of virus-specific memory T cells is common. AB - Graft-versus-host disease and graft rejection are major complications of allogeneic HLA-mismatched stem cell transplantation or organ transplantation that are caused by alloreactive T cells. Because a range of acute viral infections have been linked to initiating these complications, we hypothesized that the cross-reactive potential of virus-specific memory T cells to allogeneic (allo) HLA molecules may be able to mediate these complications. To analyze the allo-HLA reactivity, T cells specific for Epstein-Barr virus, cytomegalovirus, varicella zoster virus, and influenza virus were tested against a panel of HLA-typed target cells, and target cells transduced with single HLA molecules. Eighty percent of T cell lines and 45% of virus-specific T-cell clones were shown to cross-react against allo-HLA molecules. The cross-reactivity of the CD8 and CD4 T-cell clones was directed primarily against HLA class I and II, respectively. However, a restricted number of CD8 T cells exhibited cross-reactivity to HLA class II. T cell receptor (TCR) gene transfer confirmed that allo-HLA reactivity and virus specificity were mediated via the same TCR. These results demonstrate that a substantial proportion of virus-specific T cells exert allo-HLA reactivity, which may have important clinical implications in transplantation settings as well as adoptive transfer of third-party virus-specific T cells. PMID- 20160167 TI - Economics and the new generation of targeted therapies for non-small cell lung cancer. PMID- 20160166 TI - Apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells. AB - The activating mutation JAK2 V617F plays a central role in the pathogenesis of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Inhibition of JAK2 activity leads to growth inhibition and apoptosis in cells with mutated JAK2. However, the proapoptotic proteins involved in JAK2 inhibition induced apoptosis remain unclear. In this study, we show that JAK2 inhibition induced apoptosis correlated with up-regulation of the nonphosphorylated form of the BH3-only protein Bim in hematopoietic cell lines bearing JAK2 mutations. Knockdown of Bim dramatically inhibited apoptosis induced by JAK2 inhibition, which was reversed by the BH3 mimetic agent ABT-737. In addition, ABT-737 enhanced the apoptosis induced by JAK2 inhibition in JAK2 V617F(+) HEL and SET-2 cells. The combination of JAK inhibitor I and ABT-737 reduced the number of erythroid colonies derived from CD34(+) cells isolated from JAK2 V617F(+) polycythemia vera patients more efficiently than either drug alone. These data suggest that Bim is a key effector molecule in JAK2 inhibition-induced apoptosis and that targeting this apoptotic pathway could be a novel therapeutic strategy for patients with activating JAK2 mutations. PMID- 20160168 TI - Economic analysis: randomized placebo-controlled clinical trial of erlotinib in advanced non-small cell lung cancer. AB - BACKGROUND: The NCIC Clinical Trials Group conducted the BR.21 trial, a randomized placebo-controlled trial of erlotinib (an epidermal growth factor receptor tyrosine kinase inhibitor) in patients with previously treated advanced non-small cell lung cancer. This trial accrued patients between August 14, 2001, and January 31, 2003, and found that overall survival and quality of life were improved in the erlotinib arm than in the placebo arm. However, funding restrictions limit access to erlotinib in many countries. We undertook an economic analysis of erlotinib treatment in this trial and explored different molecular and clinical predictors of outcome to determine the cost-effectiveness of treating various populations with erlotinib. METHODS: Resource utilization was determined from individual patient data in the BR.21 trial database. The trial recruited 731 patients (488 in the erlotinib arm and 243 in the placebo arm). Costs arising from erlotinib treatment, diagnostic tests, outpatient visits, acute hospitalization, adverse events, lung cancer-related concomitant medications, transfusions, and radiation therapy were captured. The incremental cost-effectiveness ratio was calculated as the ratio of incremental cost (in 2007 Canadian dollars) to incremental effectiveness (life-years gained). In exploratory analyses, we evaluated the benefits of treatment in selected subgroups to determine the impact on the incremental cost-effectiveness ratio. RESULTS: The incremental cost-effectiveness ratio for erlotinib treatment in the BR.21 trial population was $94,638 per life-year gained (95% confidence interval = $52,359 to $429,148). The major drivers of cost-effectiveness included the magnitude of survival benefit and erlotinib cost. Subgroup analyses revealed that erlotinib may be more cost-effective in never-smokers or patients with high EGFR gene copy number. CONCLUSION: With an incremental cost-effectiveness ratio of $94 638 per life-year gained, erlotinib treatment for patients with previously treated advanced non-small cell lung cancer is marginally cost-effective. The use of molecular predictors of benefit for targeted agents may help identify more or less cost-effective subgroups for treatment. PMID- 20160169 TI - Performance of a new leadless implantable cardiac monitor in detecting and quantifying atrial fibrillation: Results of the XPECT trial. AB - BACKGROUND: Current methods for detecting atrial fibrillation (AF) have limited diagnostic yield. Continuous monitoring with automatic arrhythmia detection and classification may improve detection of symptomatic and asymptomatic AF and subsequent patient treatment. The study purpose was to quantify the performance of the first implantable leadless cardiac monitor (ICM) with dedicated AF detection capabilities. METHODS AND RESULTS: Patients (n=247) with an implanted ICM (Reveal XT, Medtronic Inc, Minneapolis, Minn) who were likely to present with paroxysmal AF were selected. A special Holter device stored 46 hours of subcutaneously recorded ECG, ICM markers, and 2 surface ECG leads. The ICM automatic arrhythmia classification was compared with the core laboratory classification of the surface ECG. Of the 206 analyzable Holter recordings collected, 76 (37%) contained at least 1 episode of core laboratory classified AF. The sensitivity, specificity, positive predictive value, and negative predictive value for identifying patients with any AF were 96.1%, 85.4%, 79.3%, and 97.4%, respectively. The AF burden measured with the ICM was very well correlated with the reference value derived from the Holter (Pearson coefficient=0.97). The overall accuracy of the ICM for detecting AF was 98.5%. CONCLUSIONS: In this ICM validation study, the dedicated AF detection algorithm reliably detected the presence or absence of AF and the AF burden was accurately quantified. The ICM is a promising new diagnostic and monitoring tool for the clinician to treat AF patients independently of symptoms. Long-term studies are needed to evaluate the clinical benefits of the technology. PMID- 20160170 TI - Soft drink and juice consumption and risk of physician-diagnosed incident type 2 diabetes: the Singapore Chinese Health Study. AB - Soft drinks and other sweetened beverages may contribute to risk of type 2 diabetes and obesity. However, research has not addressed higher risk and Asian populations. The authors examined the association between soft drinks and juice and the risk of type 2 diabetes among Chinese Singaporeans enrolled in a prospective cohort study of 43,580 participants aged 45-74 years and free of diabetes and other chronic diseases at baseline. The incidence of physician diagnosed type 2 diabetes was assessed by interview and validated; 2,273 participants developed diabetes during follow-up. After adjustment for potential lifestyle and dietary confounders, participants consuming > or =2 soft drinks per week had a relative risk of type 2 diabetes of 1.42 (95% confidence interval (CI): 1.25, 1.62) compared with those who rarely consumed soft drinks. Similarly, consumption of > or =2 juice beverages per week was associated with an increased risk (relative risk (RR) = 1.29, 95% CI: 1.05, 1.58). The association was modified by 5-year weight gain for > or =2 soft drinks per week among those who gained > or =3 kg (RR = 1.70, 95% CI: 1.34, 2.16) compared with those who gained less weight (RR = 1.20, 95% CI: 1.03, 1.41). Relatively frequent intake of soft drinks and juice is associated with an increased risk for development of type 2 diabetes in Chinese men and women. PMID- 20160171 TI - Posttraumatic stress disorder and completed suicide. AB - Most research regarding posttraumatic stress disorder (PTSD) and suicide has focused on suicidal ideation or attempts; no known study of the association between PTSD and completed suicide in a population-based sample has been reported. This study examined the association between PTSD and completed suicide in a population-based sample. Data were obtained from the nationwide Danish health and administrative registries, which include data on all 5.4 million residents of Denmark. All suicides between January 1, 1994, and December 31, 2006, were included, and controls were selected from a sample of all Danish residents. Using this nested case-control design, the authors examined 9,612 suicide cases and 199,306 controls matched to cases on gender, date of birth, and time. Thirty-eight suicide cases (0.40%) and 95 controls (0.05%) were diagnosed with PTSD. The odds ratio associating PTSD with suicide was 9.8 (95% confidence interval: 6.7, 15). The association between PTSD and completed suicide remained after controlling for psychiatric and demographic confounders (odds ratio = 5.3, 95% confidence interval: 3.4, 8.1). Additionally, persons with PTSD and depression had a greater rate of suicide than expected based on their independent effects. In conclusion, a registry-based diagnosis of PTSD based on International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, is a risk factor for completed suicide. PMID- 20160172 TI - Letter by Berenfeld and Jalife regarding article "dominant frequency of atrial fibrillation correlates poorly with atrial fibrillation cycle length". PMID- 20160175 TI - Tachycardia and the AV nodal region: guilt by association? PMID- 20160177 TI - Sudden death in the young: what do we know about it and how to prevent? PMID- 20160176 TI - Arrhythmogenic foci and the mechanisms of atrial fibrillation. PMID- 20160178 TI - Phase mapping of cardiac fibrillation. PMID- 20160183 TI - Adjunctive thrombectomy for primary percutaneous coronary intervention: What would Dr Bayes do? PMID- 20160184 TI - Antiplatelet therapy after percutaneous coronary intervention: Should another regimen be "TAPT?". PMID- 20160185 TI - Incidence and predictors of plaque rupture in the peripheral arteries. AB - BACKGROUND: Plaque rupture may be present in the peripheral arteries of the patients at high risk for cardiovascular events and is possibly associated with vascular vulnerability. METHODS AND RESULTS: One hundred one iliofemoral arteries from 101 patients undergoing angioplasty were studied. Intravascular ultrasound imaging was performed before intervention. Plaque rupture was defined as presence of a cavity that communicated with the lumen with an overlying residual fibrous cap fragment. Incidence, numbers, and location of the plaque rupture were investigated. Plaque rupture was found in 42 of 101 arteries (42%). Patients with plaque rupture had significantly higher prevalence of acute coronary syndrome than did patients without plaque rupture (42% vs 16%, P=0.01). By multivariable logistic regression analysis, acute coronary syndrome (P=0.004) and male sex (P=0.01) were independent clinical correlates of plaque rupture. During follow-up (median, 14.7 months), the incidence of major adverse cardiac or cerebrovascular events (death, myocardial infarction, and ischemic stroke) was similar between the 2 groups. The incidence of major adverse cardiac or cerebrovascular events plus peripheral vascular events (unplanned vascular intervention and amputation) was significantly higher in patients with plaque rupture than in patients without plaque rupture (46% vs 21%, P=0.008). By multivariable Cox regression analysis, plaque rupture (hazard ratio=2.80, 95% CI: 1.23 to 6.37, P=0.01) and Fontaine stage IV (hazard ratio=3.50, 95% CI: 1.58 to 7.71, P=0.002) were independent predictors of major adverse cardiac or cerebrovascular events plus peripheral vascular events. CONCLUSIONS: Ruptured plaque of the iliofemoral arteries is a common finding. Patients with plaque rupture had a higher prevalence of history of acute coronary syndrome and lower major adverse cardiac or cerebrovascular events plus peripheral vascular event-free survival. PMID- 20160186 TI - Anticoagulant therapy for percutaneous coronary intervention. PMID- 20160187 TI - Reduction in myocardial perfusion territory and its effect on the physiological severity of a coronary stenosis. PMID- 20160188 TI - Prediction models that include genetic data. PMID- 20160189 TI - Assessment of improved prediction beyond traditional risk factors: when does a difference make a difference? PMID- 20160190 TI - Morphological analysis of 13 LMNA variants identified in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. AB - BACKGROUND: Mutations in the LMNA gene, encoding lamins A/C, represent a significant cause of dilated cardiomyopathy. We recently identified 18 protein altering LMNA variants in a cohort of 324 unrelated patients with dilated cardiomyopathy. However, at least one family member with dilated cardiomyopathy in each of 6 pedigrees lacked the LMNA mutation (nonsegregation), whereas small sizes of 5 additional families precluded definitive determinations of segregation, raising questions regarding contributions by those variants to disease. METHODS AND RESULTS: We have consequently expressed, in COS7 cells, GFP prelamin A (GFPLaA) fusion constructs incorporating the 6 variants in pedigrees with nonsegregation (R101P, A318T, R388H, R399C, S437Hfsx1, and R654X), the 4 variants in pedigrees with unknown segregation (R89L, R166P [in 2 families], I210S, R471H), and 3 additional missense variants (R190Q, E203K, and L215P) that segregated with disease. Confocal immunofluorescence microscopy was used to characterize GFP-lamin A localization and nuclear morphology. Abnormal phenotypes were observed for 10 of 13 (77%) variants (R89L, R101P, R166P, R190Q, E203K, I210S, L215P, R388H, S437Hfsx1, and R654X), including 4 of 6 showing nonsegregation and 3 of 4 with uncertain segregation. All 7 variants affecting coil 1B and the lamin A-only mutation, R654X, exhibited membrane-bound GFP-lamin A aggregates and nuclear shape abnormalities. Unexpectedly, R388H largely restricted GFP-lamin A to the cytoplasm. Equally unexpected were unique streaked aggregates with S437Hfsx1 and giant aggregates with both S437Hfsx1 and R654X. CONCLUSIONS: This work expands the recognized spectrum of lamin A localization abnormalities in dilated cardiomyopathy. It also provides evidence supporting pathogenicity of 10 of 13 tested LMNA variants, including some with uncertain or nonsegregation. PMID- 20160191 TI - Genetic effects on carotid intima-media thickness: systematic assessment and meta analyses of candidate gene polymorphisms studied in more than 5000 subjects. AB - BACKGROUND: Carotid intima-media thickness (CIMT) is highly heritable and associated with stroke and myocardial infarction, making it a promising quantitative intermediate phenotype for genetic studies of vascular disease. There have been many CIMT candidate gene association studies, but no systematic review to identify consistent, reliable findings. METHODS AND RESULTS: We comprehensively sought all published studies of association between CIMT and any genetic polymorphism. We obtained additional unpublished data and performed meta analyses for the 5 most commonly studied genes (studied in at least 2 studies in a total of >5000 subjects). We used a 3-step meta-analysis method: meta-analysis of variance; genetic model selection; and random effects meta-analysis of the mean CIMT difference between genotypes. We performed subgroup analyses to investigate effects of ethnicity, vascular risk status, and study size. We accounted for potential reporting bias by assessing qualitatively the possible effects of including unavailable data. Polymorphisms in 3 of the 5 genes (apolipoprotein E, angiotensin I converting enzyme, and 5,10 methylenetetrahydrofolate reductase) had an apparent association with CIMT, but for all these, we found evidence of small study bias. Apolipoprotein E epsilon2/epsilon3/epsilon4 was the only polymorphism with a persistent, statistically significant but modest association when we restricted analysis to larger studies (>1000 subjects). CONCLUSIONS: Of the most extensively studied polymorphisms, apolipoprotein E epsilon2/epsilon3/epsilon4 is the only one so far with a convincing association with CIMT. Larger studies than have generally been performed so far may be needed to confirm the associations identified in future genome-wide association studies, and to investigate modification of effect according to characteristics such as ethnicity and vascular risk status. PMID- 20160192 TI - Context-dependent associations between variation in risk of ischemic heart disease and variation in the 5' promoter region of the apolipoprotein E gene in Danish women. AB - OBJECTIVE: Variations in the noncoding single-nucleotide polymorphisms (SNPs) at positions 560 and 832 in the 5' promoter region of the apolipoprotein E gene define genotypes that distinguish between high and low concentrations of plasma total and high-density lipoprotein cholesterol and triglycerides. We addressed whether these genotypes improve the prediction of ischemic heart disease (IHD) in subsamples of individuals defined by traditional risk factors and the genotypes defined by the epsilon(2), epsilon(3), and epsilon(4) alleles in exon 4 of the apolipoprotein E gene. METHODS AND RESULTS: In a sample of 3686 female and 2772 male participants of the Copenhagen City Heart Study who were free of IHD events, 576 individuals (257 women, 7.0% and 319 men, 11.5%) were diagnosed as having developed IHD in 6.5 years of follow-up. Using a stepwise Patient Rule-Induction Method modeling strategy that acknowledges the complex pathobiology of IHD, we identified a subsample of 764 elderly women (> or =65 years) with hypertriglyceridemia who had a history of smoking, a history of hypertension, or a history of both in which the A(560)T(832)/A(560)T(832) and A(560)T(832)/A(560)G(832) 5' 2-SNP genotypes had a higher cumulative incidence of IHD (172/1000) compared to the incidence of 70/1000 in the total sample of women. CONCLUSIONS: Our study validates that 5' apolipoprotein E genotypes improve the prediction of IHD and documents that the improvement is greatest in a subset defined by a particular combination of traditional risk factors in Copenhagen City Heart Study female participants. We discuss the use of these genotypes in medical risk assessment of IHD in the population represented by the Copenhagen City Heart Study. PMID- 20160193 TI - Investigation of variants identified in caucasian genome-wide association studies for plasma high-density lipoprotein cholesterol and triglycerides levels in Mexican dyslipidemic study samples. AB - BACKGROUND: Although epidemiological studies have demonstrated an increased predisposition to low high-density lipoprotein cholesterol and high triglyceride levels in the Mexican population, Mexicans have not been included in any of the previously reported genome-wide association studies for lipids. METHODS AND RESULTS: We investigated 6 single-nucleotide polymorphisms associated with triglycerides, 7 with high-density lipoprotein cholesterol, and 1 with both triglycerides and high-density lipoprotein cholesterol in recent Caucasian genome wide association studies in Mexican familial combined hyperlipidemia families and hypertriglyceridemia case-control study samples. These variants were within or near the genes ABCA1, ANGPTL3, APOA5, APOB, CETP, GALNT2, GCKR, LCAT, LIPC, LPL (2), MMAB-MVK, TRIB1, and XKR6-AMAC1L2. We performed a combined analysis of the family-based and case-control studies (n=2298) using the Z method to combine statistics. Ten of the single-nucleotide polymorphisms were nominally significant and 5 were significant after Bonferroni correction (P=2.20 x 10(-3) to 2.6 x 10( 11)) for the number of tests performed (APOA5, CETP, GCKR, and GALNT2). Interestingly, our strongest signal was obtained for triglycerides with the minor allele of rs964184 (P=2.6 x 10(-11)) in the APOA1/C3/A4/A5 gene cluster region that is significantly more common in Mexicans (27%) than in whites (12%). CONCLUSIONS: It is important to confirm whether known loci have a consistent effect across ethnic groups. We show replication of 5 Caucasian genome-wide association studies lipid associations in Mexicans. The remaining loci will require a comprehensive investigation to exclude or verify their significance in Mexicans. We also demonstrate that rs964184 has a large effect (odds ratio, 1.74) and is more frequent in the Mexican population, and thus it may contribute to the high predisposition to dyslipidemias in Mexicans. PMID- 20160194 TI - Comprehensive analysis of genomic variation in the LPA locus and its relationship to plasma lipoprotein(a) in South Asians, Chinese, and European Caucasians. AB - BACKGROUND: Functional copy number variation in the apolipoprotein(a) gene (LPA) underlies a variable number of protein kringle domains repeated in tandem in the lipoprotein(a) [Lp(a)] particle. Genomic analysis of LPA, including both single nucleotide polymorphisms (SNPs) and kringle IV type 2 (KIV-2) copy number, has yet to be performed. METHODS AND RESULTS: First, we genotyped 49 SNPs within 100 kb of LPA in a multiethnic sample comprising South Asians (n=330), Chinese (n=304), and European Caucasians (n=272). Second, using quantitative polymerase chain reaction, we estimated the KIV-2 copy number in each sample. European Caucasians had the lowest KIV-2 copy number but displayed the strongest correlation between KIV-2 copy number and plasma Lp(a) concentration (r(s)=-0.31, P=4.2 x 10(-7)). SNP rs10455872, only prevalent in European Caucasians, was strongly associated with both plasma Lp(a) concentration (P=4.2 x 10(-29)) and KIV-2 copy number (P=7.2 x 10(-5)). LPA SNP rs6415084, within the same haplotype block as the KIV-2 variation, was significantly associated with both Lp(a) concentration and KIV-2 copy number in the same direction in all 3 ethnicities [Lp(a), P=5.3 x 10(-7); KIV-2, P=2.6 x 10(-4)]. SNPs and KIV-2 copy number together explain a larger proportion of variation in plasma Lp(a) concentrations in European Caucasians (36%) than in Chinese (27%) or South Asians (21%). CONCLUSIONS: LPA SNPs are in linkage disequilibrium with KIV-2 copy number, but KIV-2 copy number explains an increment in plasma Lp(a) variation over SNPs alone. Thus, both SNPs and KIV-2 copy number should be included in future genetic epidemiology studies of Lp(a). PMID- 20160195 TI - Association of scavenger receptor class B type I polymorphisms with subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND: Little is known about the association of scavenger receptor class B type I (SCARB1) single-nucleotide polymorphisms (SNPs) and subclinical atherosclerosis, particularly in subjects of different racial/ethnic backgrounds. We examined this relationship in the Multi-Ethnic Study of Atherosclerosis. METHODS AND RESULTS: Forty-three SCARB1-tagging SNPs were genotyped. Baseline examinations included fasting lipids and subclinical atherosclerosis phenotypes (coronary artery calcification, common carotid intimal-medial artery thickness [CCIMT], and internal carotid intimal-medial artery thickness). Examining SNP associations with different subclinical atherosclerosis phenotypes across multiple racial/ethnic groups with adjustment for multiple covariates, we found that the C allele of SNP rs10846744 was associated with higher CCIMT in African American (P=0.03), Chinese (P=0.02), European American (P=0.05), and Hispanic participants (P=0.03) and was strongly associated in pooled analyses (P=0.0002). The results also showed that the association of this SNP with CCIMT was independent of lipids and other well-established cardiovascular risk factors. Stratifying by sex, there seemed to be a strong association of rs10846744 with CCIMT in women, but no genotype-sex interactions were observed. CONCLUSIONS: Variation in SCARB1 at rs10846744 was significantly associated with CCIMT across racial/ethnic groups in Multi-Ethnic Study of Atherosclerosis. PMID- 20160196 TI - Confirmation that the renin gene distal enhancer polymorphism REN-5312C/T is associated with increased blood pressure. AB - BACKGROUND: Studies of knockout and transgenic mice have demonstrated key roles for genes encoding components of the renin angiotensin system in blood pressure regulation. However, whether polymorphisms in these genes contribute to the cause of essential hypertension in humans is still a matter of debate. METHODS AND RESULTS: We performed an experiment with dense tagging single-nucleotide polymorphism coverage of 4 genes encoding proteins that control the overall activity of the cascade, namely renin, angiotensinogen, angiotensin-converting enzyme, and angiotensin-converting enzyme 2, in 2 Irish populations. Both clinic and 24-hour ambulatory blood pressure measurements were available from population I (n=387), whereas just clinic blood pressure was measured in population II (n=1024). Of the 23 polymorphisms genotyped, only a single renin gene polymorphism, REN-5312C/T, showed consistent statistically significant associations with elevated diastolic pressures. Carriage of one REN-5312T allele was associated with the following age- and sex-adjusted increments in diastolic pressures (mean [95% CI]): population I, clinic, 1.5 mm Hg (0.3 to 2.8); daytime, 1.4 mm Hg (0.4 to 2.4); night-time, 1.3 mm Hg (0.4 to 2.3), and population II, clinic, 1.1 mm Hg (0.1 to 2.1). Haplotypic analyses and multivariate stepwise regression analyses were in concordance with individual single-nucleotide polymorphism analyses. CONCLUSIONS: The REN-5312T allele had been shown previously to result in increased in vitro expression of the renin gene. We have now shown, in 2 independent populations, that carriage of a REN-5312T allele is associated with elevated diastolic blood pressure. These data provide evidence that renin is an important susceptibility gene for arterial hypertension in whites. PMID- 20160197 TI - Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism. AB - BACKGROUND: We previously mapped a quantitative trait locus on chromosome 15 in mice contributing to high-density lipoprotein cholesterol and triglyceride levels and now report the identification of the underlying gene. METHODS AND RESULTS: We first fine-mapped the locus by studying a series of congenic strains derived from the parental strains BALB/cJ and MRL/MpJ. Analysis of gene expression and sequencing followed by transgenic complementation led to the identification of zinc fingers and homeoboxes 2 (Zhx2), a transcription factor previously implicated in the developmental regulation of alpha-fetoprotein. Reduced expression of the protein in BALB/cJ mice resulted in altered hepatic transcript levels for several genes involved in lipoprotein metabolism. Most notably, the Zhx2 mutation resulted in a failure to suppress expression of lipoprotein lipase, a gene normally silenced in the adult liver, and this was normalized in BALB/cJ mice carrying the Zhx2 transgene. CONCLUSIONS: We identified the gene underlying the chromosome 15 quantitative trait locus, and our results show that Zhx2 functions as a novel developmental regulator of key genes influencing lipoprotein metabolism. PMID- 20160198 TI - Altered hepatic gene expression profiles associated with myocardial ischemia. AB - BACKGROUND: Acute coronary syndrome is sometimes accompanied by accelerated coagulability, lipid metabolism, and inflammatory responses, which are not attributable to the cardiac events alone. We hypothesized that the liver plays a pivotal role in the pathophysiology of acute coronary syndrome. We simultaneously analyzed the gene expression profiles of the liver and heart during acute myocardial ischemia in mice. METHODS AND RESULTS: -Mice were divided into 3 treatment groups: sham operation, ischemia/reperfusion, and myocardial infarction. Mice with liver ischemia/reperfusion were included as additional controls. Marked changes in hepatic gene expression were observed after 24 hours, despite the lack of histological changes in the liver. Genes related to tissue remodeling, adhesion molecules, and morphogenesis were significantly upregulated in the livers of mice with myocardial ischemia/reperfusion or infarction but not in those with liver ischemia/reperfusion. Myocardial ischemia, but not changes in the hemodynamic state, was postulated to significantly alter hepatic gene expression. Moreover, detailed analysis of the signaling pathway suggested the presence of humoral factors that intervened between the heart and liver. To address these points, we used isolated primary hepatocytes and showed that osteopontin released from the heart actually altered the signaling pathways of primary hepatocytes to those observed in the livers of mice under myocardial ischemia. Moreover, osteopontin stimulated primary hepatocytes to secrete vascular endothelial growth factor-A, which is important for tissue remodeling. CONCLUSIONS: Hepatic gene expression is potentially regulated by cardiac humoral factors under myocardial ischemia. These results provide new insights into the pathophysiology of acute coronary syndrome. PMID- 20160199 TI - Modulation of mitochondrial proteome and improved mitochondrial function by biventricular pacing of dyssynchronous failing hearts. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) improves chamber mechanoenergetics and morbidity and mortality of patients manifesting heart failure with ventricular dyssynchrony; however, little is known about the molecular changes underlying CRT benefits. We hypothesized that mitochondria may play an important role because of their involvement in energy production. METHODS AND RESULTS: Mitochondria isolated from the left ventricle in a canine model of dyssynchronous or resynchronized (CRT) heart failure were analyzed by a classical, gel-based, proteomic approach. Two-dimensional gel electrophoresis revealed that 31 mitochondrial proteins where changed when controlling the false discovery rate at 30%. Key enzymes in anaplerotic pathways, such as pyruvate carboxylation and branched-chain amino acid oxidation, were increased. These concerted changes, along with others, suggested that CRT may increase the pool of Krebs cycle intermediates and fuel oxidative phosphorylation. Nearly 50% of observed changes pertained to subunits of the respiratory chain. ATP synthase beta subunit of complex V was less degraded, and its phosphorylation modulated by CRT was associated with increased formation (2-fold, P=0.004) and specific activity (+20%, P=0.05) of the mature complex. The importance of these modifications was supported by coordinated changes in mitochondrial chaperones and proteases. CRT increased the mitochondrial respiratory control index with tightened coupling when isolated mitochondria were reexposed to substrates for both complex I (glutamate and malate) and complex II (succinate), an effect likely related to ATP synthase subunit modifications and complex quantity and activity. CONCLUSIONS: CRT potently affects both the mitochondrial proteome and the performance associated with improved cardiac function. PMID- 20160200 TI - Growth-differentiation factor-15 for long-term risk prediction in patients stabilized after an episode of non-ST-segment-elevation acute coronary syndrome. AB - BACKGROUND: Growth-differentiation factor-15 (GDF-15) has emerged as a prognostic biomarker in patients with non-ST-segment-elevation acute coronary syndrome. This study assessed the time course and the long-term prognostic relevance of GDF-15 levels measured repetitively in patients with non-ST-segment-elevation acute coronary syndrome during 6 months after the acute event. METHODS AND RESULTS: GDF 15 and other biomarkers were measured at randomization, after 6 weeks, and after 3 and 6 months in 950 patients with non-ST-segment-elevation acute coronary syndrome included in the FRagmin and Fast Revascularization during InStability in Coronary artery disease II study. Study end points were death, recurrent myocardial infarction, and their composite during 5-year follow-up. Median GDF-15 levels decreased slightly from 1357 ng/L at randomization to 1302 ng/L at 6 months (P<0.001). GDF-15 was consistently related to cardiovascular risk factors and biochemical markers of hemodynamic stress, renal dysfunction, and inflammation. Moreover, GDF-15 was independently related to the 5-year risk of the composite end point when measured at both 3 months (adjusted hazard ratio, 1.8 [1.0 to 3.0]) and 6 months (adjusted hazard ratio, 2.3 [1.3 to 4.1]). Serial measurements of GDF-15 at randomization and 6 months helped to identify patient cohorts at different levels of risk, with patients with persistently elevated GDF 15 levels >1800 ng/L having the highest rate of the composite end point. CONCLUSIONS: GDF-15 is independently related to adverse events in non-ST-segment elevation acute coronary syndrome both in the acute setting and for at least 6 months after clinical stabilization. Therefore, continued research on GDF-15 should be focused on the usefulness of GDF-15 for support of clinical management in acute and chronic ischemic heart disease. PMID- 20160202 TI - Top advances in functional genomics and translational biology for 2009. PMID- 20160201 TI - General Cardiovascular Risk Profile identifies advanced coronary artery calcium and is improved by family history: the multiethnic study of atherosclerosis. AB - BACKGROUND: The General Cardiovascular Risk Profile is a multivariable model that predicts global cardiovascular disease risk. Our goal was to assess the ability of the General Cardiovascular Risk Profile to identify individuals with advanced coronary artery calcification (CAC) and determine whether identification is improved with family history. METHODS AND RESULTS: Using data from the Multiethnic Study of Atherosclerosis, 3 sex-specific models were developed with ordinal logistic regressions to relate risk factors to CAC scores. Model 1 included covariates in the General Cardiovascular Risk Profile. Then family history was added, defined as having at least 1 first-degree relative with premature coronary heart disease (model 2) or as a weak, moderate, or strong family history based on number of relatives with coronary heart disease, age at onset, and the presence of stroke or diabetes in the family (model 3). For each model, we estimated mathematical CAC risk functions, derived CAC score sheets, evaluated the ability to discriminate persons having positive CAC scores, and assessed reclassification of individuals with low, intermediate, or high probability of CAC >300. Model 1 worked well to identify women and men with positive CAC scores; c-statistics were 0.752 and 0.718 and chi(2) values were 821.2 (P<0.0001) and 730.6 (P<0.0001), respectively. Addition of family history improved discrimination and fit of model 1. However, reclassification of participants with advanced CAC was significantly improved with model 3 only. CONCLUSIONS: The General Cardiovascular Risk Profile identifies advanced CAC, an emerging indication for aggressive risk factor modification. Incorporation of family history, especially comprehensive familial risk stratification, provides incremental prognostic value. PMID- 20160203 TI - Mendelian randomization as applied to coronary heart disease, including recent advances incorporating new technology. PMID- 20160204 TI - The brainstem: anatomy, assessment, and clinical syndromes. PMID- 20160205 TI - Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data. AB - This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer's and Parkinson's diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided. PMID- 20160207 TI - Pediatric stroke: plasticity, vulnerability, and age of lesion onset. AB - The authors aim to investigate brain plasticity and vulnerability through the study of the relationship of age at the time of brain injury and neurocognitive and psychiatric outcome. Children with early stroke performed more poorly compared with children with late stroke in a wide variety of domains including intellectual function, language, memory, visuospatial function, academic function, and psychiatric problems. The exception to this pattern was that children with late stroke performed more poorly in two of three executive function tests. These findings suggest that in children with focal brain injury, as in those with more diffuse brain insults, younger age at injury predicts worse neurocognitive outcomes, although this may not apply to selected executive function outcomes. Adverse psychiatric outcome after early stroke is less direct but is evident in terms of severity in affected cases. PMID- 20160206 TI - Frontotemporal dementia and pharmacologic interventions. AB - Frontotemporal lobar degeneration is comprised of three syndromes: frontotemporal dementia (FTD), semantic dementia, and progressive nonfluent aphasia, with FTD being the most prevalent. FTD is characterized predominantly by character change and disordered social conduct. A variety of pathologies may underlie these syndromes, yet it is the location of the pathology rather than the type that dictates the clinical features of the disease. Several medications have been investigated to measure efficacy of treatment in FTD, often with mixed results. The authors review these findings and comment on future directions. PMID- 20160208 TI - Consequences of aggressive behavior in patients with dementia. AB - This study examined aggression as a predictor of nursing-home placement, injuries, use of restraints, and use of health services in community-dwelling patients with newly diagnosed dementia. Participants were identified from 2001 2004 Veterans Administration databases; all had a new diagnosis of dementia and no aggression. Patients and caregivers were evaluated for aggression, using the Cohen-Mansfield Agitation Inventory-aggression subscale, and other outcomes for 2 years, with outcome rates compared between patients who did or did not develop aggression and between pre- and postaggressive periods. Of 215 patients, 88 became aggressive, associated with significantly increased use of psychotropic medication (p< or =0.04), injuries (p< or =0.0001), and nursing-home placement (p< or =0.004). PMID- 20160209 TI - Neuropsychological outcomes of older breast cancer survivors: cognitive features ten or more years after chemotherapy. AB - The authors examined the long-term cognitive implications of cancer treatment among breast cancer survivors over 65 years old who received treatment during midlife. Thirty women survivors were matched with 30 noncancer, healthy older adults in terms of age, education, and IQ. The cancer survivors scored significantly lower in the cognitive domains of executive functioning, working memory, and divided attention, reflecting potential dysfunction in frontal subcortical brain regions. Our findings suggest that among breast cancer survivors who remain disease-free for more than a decade, the previous cancer treatment may further augment cognitive dysfunction associated with age-related brain changes. PMID- 20160210 TI - Hippocampal volumes in adults with bipolar disorder. AB - Functional neuroimaging studies have implicated the hippocampus formation in the pathophysiology of bipolar disorder, but findings from volumetric studies have been less consistent. The authors aim to further investigate the existence of volumetric abnormalities in the hippocampus of individuals with bipolar disorder. In addition to methodological inconsistencies, many previous studies have been lacking clinical robustness with respect to characterizing bipolar patients and comparison subjects. Hence, the present study matched the groups closely across a number of demographic parameters. Using MRI, hippocampal volumes of 24 bipolar patients were compared to 24 sex-, age-, and education-matched comparison subjects, and these findings were further investigated in relation to both illness and treatment factors. A significantly larger (8.5%) right hippocampus was seen in bipolar patients than in comparison subjects, and this difference was not associated with a history of psychosis, familial illness, or lithium treatment, after controlling for potential confounds. Patients reporting fewer affective episodes did however have significantly larger left hippocampus volumes than comparison subjects. The authors found that the left hippocampus was larger in a group of adult bipolar subjects relative to the healthy comparison group. The reason for this is unclear, but in this sample, it was not associated with family history, psychotic features, or medication exposure. A negative association was found between left hippocampal volume and number of episodes or duration of illness, suggesting the hippocampus might be larger in the early phase of bipolar disorder but becomes smaller with time. PMID- 20160211 TI - Mental disorders in Mexican patients with multiple sclerosis. AB - The authors aim to explore psychiatric disorders in Mexican patients with multiple sclerosis. The Structured Clinical Interview for DSM-IV Axis I Disorders, the Montgomery-Asberg Depression Rating Scale, and the Hamilton Anxiety Rating Scale were administered to 37 consecutive multiple sclerosis patients and 37 healthy comparison subjects. The multiple sclerosis group had higher rates of any axis I disorder (OR 1.97; 95% CI=1.78-3.306). The most common comorbid diagnoses were depressive disorders (46% of the multiple sclerosis cases) with higher anxiety scores (p=0.001). No correlations between psychiatric variables, number of relapses, and clinical course of multiple sclerosis were found. PMID- 20160212 TI - Executive dysfunction in remitted late-life depression: Juntendo University Mood Disorder Projects (JUMP). AB - The authors aimed to investigate whether remitted adult and elderly major depressive disorder patients show different patterns of executive dysfunction. Executive functions of 20 euthymic major depressive disorder patients and 29 healthy comparison subjects were evaluated using the Behavioral Assessment of the Dysexecutive Syndrome. Relative to adult patients and healthy comparison subjects, euthymic elderly patients were more impaired in the subtest of Modified Six Elements. Since the regions most implicated in this subtest are the medial prefrontal, the anterior cingulate, and the dorsolateral prefrontal areas, the authors conclude that dysfunctions of such frontal neural networks remain unresolved even in the remission phase of late-life depression. PMID- 20160213 TI - Subgenual cingulate theta activity predicts treatment response of repetitive transcranial magnetic stimulation in participants with vascular depression. AB - Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression. Increased metabolism in the anterior cingulate cortex (ACC) is a known predictor for antidepressant response. The authors assessed whether increased theta power within the ACC predicts rTMS response in participants with vascular depression. Sixty-five participants were randomized to active or sham rTMS. Outcome was assessed using the Hamilton Depression Rating Scale. Electroencephalography was obtained, and comparisons were made among each group with a normative database using low-resolution electromagnetic tomography. Results suggest that vascular depression participants respond well to rTMS and that increased low-theta power in the subgenual ACC predicts response to rTMS. PMID- 20160214 TI - Clock drawing test ratings by dementia specialists: interrater reliability and diagnostic accuracy. AB - The authors conducted a study of clock drawing test scoring by dementia specialists to determine interrater reliability and diagnostic accuracy. The authors randomly assigned 25 clocks from each of six predetermined groups based on consensus diagnosis (cognitive comparison subjects, subjects with a memory complaint but with normal neuropsychological testing, subjects with probable and possible mild cognitive impairment, and subjects with possible and probable Alzheimer's disease) to dementia specialists for blinded scoring using a binary yes/no impairment system and a 0-10 scale as subjectively determined by each individual clinician rater. The authors collapsed the six groups into three (comparison subjects, mild cognitive impairment patients, and Alzheimer's disease patients) and analyzed interrater reliability, sensitivity, and specificity for consensus diagnosis of mild cognitive impairment and Alzheimer's disease. The authors found excellent interrater reliability, sensitivity, and specificity for predicting consensus diagnosis. The 0-10 clock drawing test rating scale was more predictive of consensus diagnosis than the binary impairment scale. Based on rating systems, clock drawing test scoring by dementia clinicians had excellent interrater reliability and sensitivity for differentiating the mild Alzheimer's disease subjects from comparison subjects. PMID- 20160215 TI - Impaired awareness of deficits and neuropsychiatric symptoms in early Alzheimer's disease: the Danish Alzheimer Intervention Study (DAISY). AB - Impaired awareness may be associated with increased neuropsychiatric symptoms in moderate to severe Alzheimer's disease, but relatively little is known about the association in early Alzheimer's disease. The aim of this study was to investigate if impaired awareness was associated with a higher frequency of neuropsychiatric symptoms in early Alzheimer's disease. In a Danish multicenter study, 321 patients with MMSE score > or =20 were evaluated. Patients with poor insight had significantly more neuropsychiatric symptoms than patients with full insight. When patients had increasing neuropsychiatric symptoms, caregivers reported higher levels of distress. PMID- 20160216 TI - Predictors of new-onset depression after mild traumatic brain injury. AB - Mild traumatic brain injury (TBI) is the most common form of TBI. Most people recover after mild TBI, but a small percentage continues to have persistent problems, predominantly depression. There is, however, minimal literature on the risk factors associated with mild TBI depression. In a sample of 43 mild TBI patients, followed longitudinally for 1 year, the prevalence of new-onset depression was found to be 18%. Older age and presence of frontal subdural hemorrhage were the only two significant findings noted in the depressed group compared with the nondepressed group. Identifying risk factors for mild TBI depression can aid in early diagnosis and treatment. PMID- 20160217 TI - Prevalence of Parkinson's disease-induced psychosis in a large U.S. managed care population. AB - Using 10 years' enrollment history, patients with non-drug-induced Parkinson's disease were identified, and the prevalence of Parkinson's disease-induced psychosis (PDP) was estimated using three different claims algorithms based on an expert working group criteria. The estimated prevalence of PDP ranged from 4 to 45/1,000 Parkinson's disease patients. PDP patients were just as likely to be male as female and were significantly older than Parkinson's disease patients without PDP. PDP patients more commonly had evidence of dementia and use of atypical antipsychotics. PDP occurs in up to 45,000 Parkinson's disease patients in the United States but represents a unique neuropsychiatric finding with important treatment implications. PMID- 20160218 TI - The successful treatment of mania due to acquired immunodeficiency syndrome using ziprasidone: a case series. AB - Secondary causes of mania need to be considered when atypical features of mania are manifested. These would include those patients with a later onset and without a prior psychiatric history. This case series investigates the use of ziprasidone for the treatment of mania due to HIV, a complication that could develop in those patients with advanced stages of AIDS. PMID- 20160220 TI - Suggested improvements to the overt aggression scale-modified. PMID- 20160219 TI - Mental rotation of hands in HIV infection: neuropsychological evidence of dysfunction in fronto-striato-parietal networks. AB - Mental rotation, the ability to manipulate three-dimensional objects in space, is a widely studied and neurally complex aspect of spatial cognition that has been largely ignored in the HIV literature. The authors report evidence of a significant interaction between HIV serostatus and performance on mental rotation tasks, whereby individuals with HIV (n=19) committed a greater number of errors than demographically similar seronegative persons (n=15) on Luria's hand rotation task (d=0.74, p<0.05), but not on the corresponding parallelogram rotation task (p>0.10). Hand rotation errors were associated with worse performance on measures of executive functions and working memory, but not with measures of visuoperception. Considered in the context of the preferential frontostriatal neuropathology of HIV-associated neurocognitive disorders, these preliminary findings suggest that the observed deficit in the mental rotation of hands may arise from a disrupted fronto-striato-parietal network. PMID- 20160222 TI - When qEEG gets personal: a reply to Coburn et al. (2006). PMID- 20160224 TI - Brain-derived neurotrophic factor polymorphism as a genetic risk for depression? A short review of the literature. PMID- 20160225 TI - Conversion disorder in a patient with posterior fossa arachnoid cyst. PMID- 20160226 TI - Paroxysmal dyskinesia with deja vu aura. PMID- 20160227 TI - Delusional parasitosis as a presenting feature of dementia. PMID- 20160228 TI - An unusual late presentation of subacute sclerosing panencephalitis with psychotic symptoms. PMID- 20160229 TI - Dissimilar neuropsychiatric presentations of two siblings with juvenile neuronal ceroid lipofuscinosis (Batten disease). PMID- 20160230 TI - A case of severe toluene withdrawal syndrome treated with clonazepam. PMID- 20160231 TI - Paroxysmal ictal phonemes in a patient with angiocentric glioma. PMID- 20160232 TI - An unusual case of neuroleptic malignant syndrome. PMID- 20160233 TI - Retropulsion and back bruises in drug-induced parkinsonism. PMID- 20160234 TI - Cortical linear lesions in Wernicke's encephalopathy: can diffusion-weighted imaging herald prognostic information? PMID- 20160235 TI - Glioblastoma multiforme presenting as treatment-resistant depression. PMID- 20160236 TI - Pathological gambling associated with modafinil. PMID- 20160237 TI - Bupropion-induced status epilepticus and retrograde amnesia. PMID- 20160238 TI - Capgras syndrome and vascular dementia. PMID- 20160239 TI - The Portuguese who could no longer speak French: primary progressive aphasia in a bilingual man. PMID- 20160240 TI - Aripiprazole, hypertension, and confusion. PMID- 20160241 TI - Central pattern generator: the main cause of Huntington's disease. PMID- 20160242 TI - Cellular automaton: a key approach in modeling the outer plexiform layer. PMID- 20160243 TI - Neuropsychological findings in a case of neurosarcoidosis. PMID- 20160244 TI - Resting electromyographic activity of deep thoracic transversospinalis muscles identified as abnormal with palpation. AB - CONTEXT: In the 1940s, osteopathic researchers suggested that paraspinal tissue abnormality was associated with spontaneous muscle activity, but few studies have since re-examined these reports. OBJECTIVE: To determine whether abnormal motor activity plays a role in deep paraspinal tissues that appear abnormal to palpation. METHODS: Using an observational study design, the PVG of participants with thoracic pain were palpated by two examiners for consensus on the most marked level of tissue abnormality. Dual fine-wire, intramuscular electrodes were inserted into the deep transversospinalis (multifidus, rotatores) muscles at the abnormal level and at two normal sites (above and below the abnormal level). Surface electrodes were placed over the erector spinae muscles adjacent to each intramuscular electrode site. Electromyography signals were recorded during initial prone resting, three maximal voluntary isometric contractions (MVIC), and a second prone resting. The area under the curve for a 2-second period was analyzed for each condition, and values were normalized and reported as a percentage of MVIC. Data were analyzed using a 2-factor repeated-measures analysis of variance. RESULTS: Twenty-five participants with mean (SD) thoracic pain of 3.3 (1.9) on a 0 to 10 visual analog pain scale completed the study protocol. There were no statistically significant differences in normalized resting activity between the three intramuscular sites (P=.25) or between the three surface sites (P=.33). Substantial variability in normalized resting activity at each of the three intramuscular sites was evident (mean [SD] percent of MVIC: abnormal 7.83 [8.76]; normal 9.47 [8.45], 6.65 [7.39]). No statistically significant differences existed in the intramuscular EMG values between the two resting baseline periods (P=.10). CONCLUSION: The lack of statistically significant differences between EMG activity at the abnormal and normal paraspinal sites suggests that factors other than muscle activity are responsible for the apparent abnormality of these tissues to palpation. Investigation of these regions for increased tissue fluid and inflammatory mediators is recommended. PMID- 20160245 TI - Empowering patients during insulin initiation: a real-world approach. AB - Glycemic control is suboptimal in many patients with type 2 diabetes mellitus (T2DM). Despite documented benefits of insulin therapy, initiation of insulin is delayed in many cases because of the reluctance of patients and physicians to use this important treatment. A review of the literature revealed that educating patients about the role of insulin in managing T2DM and the advantages of using insulin analogs and insulin delivery devices may help alleviate some patients' concerns regarding insulin therapy. Compared with standard clinic-directed approaches, patient-driven algorithms that empower patients to initiate and titrate basal insulin therapy have been shown to improve glycemic control. Additional research is needed to confirm the importance of patient empowerment programs in T2DM management. PMID- 20160246 TI - Use of osteopathic manipulative treatment to manage compensated trendelenburg gait caused by sacroiliac somatic dysfunction. AB - Gait dysfunctions are commonly encountered in the primary care setting. Compensated Trendelenburg gait is a gait dysfunction that was originally described in patients with weakness of ipsilateral hip abduction. This condition is thought to result from neuronal injury or myopathy. No treatment modalities currently exist for compensated Trendelenburg gait. The authors present a case in which osteopathic manipulative treatment may have improved a Trendelenburg gait dysfunction in a man aged 65 years with multiple sclerosis. Evidence of this improvement was obtained with the GaitMat II system for measuring numerous gait parameters. Based on the results reported in the present case, the authors propose that compensated Trendelenburg gait may arise from somatic dysfunction and may be corrected by osteopathic manipulative treatment. PMID- 20160247 TI - Peripartum heart failure caused by left ventricular diastolic dysfunction. AB - Peripartum cardiomyopathy (PPCM) is a rare but serious cause of heart failure occurring in the last month of pregnancy or the first 5 months postpartum. The current definition of PPCM only includes patients with left ventricular systolic dysfunction. The authors present a case of peripartum heart failure with normal ejection fraction and raise the possibility that the definition of PPCM be expanded to include left ventricular diastolic dysfunction. Because the mortality and morbidity of patients with PPCM are higher in women who experience a subsequent pregnancy after a prior episode of pregnancy-related heart failure, a revised definition of PPCM has important potential implications. PMID- 20160248 TI - Importance of obtaining a detailed medical history in diagnosing emphysematous cystitis. AB - Pneumaturia has long been known to be the characteristic pathognomonic finding in emphysematous cystitis. However, its history is often difficult to elicit. Imaging studies are diagnostic in the majority of emphysematous cystitis cases described in the literature. The authors present a unique case in which the patient did not admit having pneumaturia until detailed questioning about her medical history was completed after diagnostic imaging. Had an earlier and more thorough medical history been conducted, the patient's diagnosis would have been achieved several months earlier, before presentation to the emergency department, as described in the present case. Early diagnosis is vital to decrease the morbidity and mortality associated with emphysematous cystitis. PMID- 20160250 TI - An observational study of the pattern of HIV infection in a specified rural area of India with special reference to migratory laborers. AB - OBJECTIVE: Determination of the pattern of HIV/AIDS in patients attending voluntary confidential counseling and testing center (VCCTC) and prevention of parent-to-child transmission (PPTCT) center of a low-prevalence district of Eastern India. To find out high-risk group and interventional strategy for prevention. METHOD: Cross-sectional exploratory secondary data analysis from the VCCTC and PPTCT register. RESULT: Of the 1348 participants, 160 (11.86%) adults were HIV seropositive. Prevalence in males and females was 9.8% and 20.7%, respectively. Among 22 (1.63%) seropositive children, transmission was vertical in 18 (81.8%). Seventy-one (88.75%) positive adult males were migratory goldsmiths working in Mumbai and other big cities. They were clustered in a particular locality (Daspur). CONCLUSION: Goldsmiths migrated from Daspur to big cities are the bridge populations who are responsible for higher prevalence of HIV in their families and locality. Interventional strategies targeted at this high-risk group are suggested. PMID- 20160249 TI - Evaluation of paradoxical TB-associated IRIS with the use of standardized case definitions for resource-limited settings. AB - OBJECTIVE: Standardized case definitions have recently been proposed by the International Network for the Study of HIV-associated immune reconstitution inflammatory syndrome (INSHI; [IRIS]) for use in resource-limited settings. We evaluated paradoxical tuberculosis (TB)-associated IRIS in a large cohort from a TB endemic setting with the use of these case definitions. DESIGN: A retrospective cohort study. METHOD: We reviewed records from 1250 South African patients who initiated antiretroviral therapy (ART) over a 5-year period. RESULTS: A total of 333 (27%) of the patients in the cohort had prevalent TB at the initiation of ART. Of 54 possible paradoxical TB-associated IRIS cases, 35 fulfilled the INSHI case definitions (11% of TB cases). CONCLUSIONS: INSHI standardized case definitions were used successfully in identifying paradoxical TB-associated IRIS in this cohort and resulted in a similar proportion of TB IRIS cases (11%) as that reported in previous studies from resource-limited settings (8%-13%). This case definition should be evaluated prospectively. PMID- 20160262 TI - Influence of nurses on compliance with breast screening recommendations in an organized breast screening program. AB - BACKGROUND: Evidence from breast screening trials has shown that a significant reduction in breast cancer mortality from screening can be achieved by regular attendance. Few studies have evaluated the influence of nurses on compliance with breast screening recommendations. METHODS: The cohort included 157,788 women ages 50 to 69 years who were screened at 1 of 9 regional cancer centers or 57 affiliated centers with nurses or 26 affiliated centers without nurses between January 1, 2002, and December 31, 2002, within the Ontario Breast Screening Program. These women were followed up prospectively for at least 30 months to compare compliance for annual and biennial screening recommendations among women who attended centers with and without nurses. The associations between type of screening center and the odds of compliance were modeled using mixed-effect logistic regression models. All P values are two-sided. RESULTS: Women attending a regional cancer center [odds ratios (OR), 1.96; 95% confidence interval (95% CI), 1.07-3.58] or affiliated center with nurses (OR, 1.75; 95% CI, 1.38-2.22) were significantly more likely to return within 18 months of their annual screening recommendation than women attending affiliated centers without nurses. In addition, women attending regional cancer centers (OR, 2.28; 95% CI, 1.34 3.89) or affiliated centers with nurses (OR, 2.30; 95% CI, 1.86-2.83) were significantly more likely to make a timely return within the recommended biennial screening interval of between 18 and 30 months. CONCLUSIONS: Breast screening programs should consider methods of integrating educational activities as provided by the nurses to improve compliance with screening. PMID- 20160253 TI - Low to moderate alcohol intake is not associated with increased mortality after breast cancer. AB - BACKGROUND: Both alcohol consumption and obesity have been linked with breast cancer morbidity and mortality. An inverse association between alcohol intake and obesity suggests possible confounding between these variables (and perhaps other factors) with breast cancer outcomes. METHODS: Alcohol intake (beer, wine, spirits, and total) was examined in 3,088 women previously diagnosed and treated for breast cancer within an intervention trial that targeted vegetables, fiber, and fat but not alcohol or weight loss. Factors associated with baseline alcohol intake were included in Cox proportional hazards models for recurrence and mortality. RESULTS: Alcohol intake was significantly associated with higher education and physical activity levels. Neither light alcohol intake nor obesity was significantly associated with breast cancer recurrence, but moderate alcohol intake >300 g/mo was protective against all-cause mortality (hazard ratio, 0.69; 95% confidence intervals, 0.49-0.97) in a proportional hazards model adjusted for obesity. Obese women were 61% more likely to be nondrinkers than drinkers, and 76% more likely to be light drinkers than moderate/heavy drinkers. In nonobese women, alcohol intake >10 g/mo was associated with lower risk of all-cause mortality (hazard ratio, 0.68; 95% confidence intervals, 0.51-0.91). CONCLUSION: Light alcohol intake, regardless of body weight, did not increase the risk of breast cancer recurrence or all-cause mortality in this cohort of middle-aged women previously diagnosed with breast cancer. Alcohol intake was associated with other favorable prognostic indicators, which may explain its apparent protective effect in nonobese women. PMID- 20160264 TI - Breast cancer and urinary biomarkers of polycyclic aromatic hydrocarbon and oxidative stress in the Shanghai Women's Health Study. AB - Polycyclic aromatic hydrocarbon (PAH) exposure and oxidative stress from such and other exposures have been associated with breast cancer in some studies. To further evaluate the role of PAH metabolites and oxidative stress on the development of breast cancer, we conducted a nested case-control study in the Shanghai Women's Health Study. We measured urinary 1-hydroxypyrene and 2-naphthol as PAH metabolites and urinary levels of 8-hydroxy-2'-deoxyguanosine and malondialdehyde as oxidative stress biomarkers in 327 breast cancer cases and 654 controls in the Shanghai Women's Health Study. Information on demographic characteristics, past medical history, lifestyles, history of menstruation, pregnancy history, eating and drinking habit, history of residence, employment history, family history, husband's information, and physical activity were collected by a self-administered questionnaire. The mean age was 52.3 in breast cancer cases (n = 354) and 52.5 in controls (n = 708). Age at menarche (P = 0.04), months of breast-feeding the first baby (P = 0.05), and grade of education (P(trend) < 0.01) were significantly different between cases and controls. No association was observed for PAH metabolites and the oxidative stress biomarkers of urinary malondialdehyde and 8-hydroxy-2'-deoxyguanosine and risk of breast cancer. This nested case-control study provides no evidence of association between PAH exposure and oxidative stress and risk of breast cancer in Shanghai women. PMID- 20160265 TI - Association between statins and prostate tumor inflammatory infiltrate in men undergoing radical prostatectomy. AB - BACKGROUND: Cholesterol-lowering drugs known as statins have been reported to have significant anti-inflammatory properties. Given that inflammation may contribute to prostate cancer progression and that statins may reduce the risk for advanced prostate cancer, we investigated whether statin use was associated with reduced intratumoral inflammation in radical prostatectomy (RP) specimens. METHODS: Inflammation within index tumors of 236 men undergoing RP from 1996 to 2004 was graded by a single pathologist as grade 0 (absent), 1 (mild: < or =10%), and 2 (marked: >10%). Preoperative statin use was analyzed by grouping subjects as statin users or nonusers. Type and dosage of statin was accounted for using dose equivalents with 20 mg simvastatin as reference. Logistic regression was used to determine the association between statin use and intratumoral inflammation controlling for age, race, body mass index, prostate-specific antigen, year of surgery, clinical stage, pathologic Gleason sum, surgical margin status, extracapsular extension, seminal vesicle invasion, prostate weight, time from prostate biopsy to RP, and nonsteroidal anti-inflammatory drug use. RESULTS: Preoperative statin use was significantly associated with lower risk for any (grade > or =1) intratumoral inflammation (odds ratio, 0.31; 95% confidence interval, 0.10-0.98; P = 0.047) on multivariable analysis, with doses > or =20 mg simvastatin equivalents being more strongly associated (relative to nonuse; odds ratio, 0.22; 95% confidence interval, 0.06-0.79; P = 0.02). CONCLUSION: In a cohort of men undergoing RP, statin use was associated with significantly lower risk of any inflammation within prostate tumors. IMPACT: Given previous reports that inflammation is associated with advanced prostate cancer, and statin use is associated with decreased prostate cancer progression risk, our findings suggest that inhibition of inflammation within tumors may be a potential mechanism for purported anti-prostate cancer properties of statins. PMID- 20160267 TI - The potential of genes and other markers to inform about risk. AB - BACKGROUND: Advances in biotechnology have raised expectations that biomarkers, including genetic profiles, will yield information to accurately predict outcomes for individuals. However, results to date have been disappointing. In addition, statistical methods to quantify the predictive information in markers have not been standardized. METHODS: We discuss statistical techniques to summarize predictive information, including risk distribution curves and measures derived from them, that relate to decision making. Attributes of these measures are contrasted with alternatives such as receiver operating characteristic curves, R(2), percent reclassification, and net reclassification index. Data are generated from simple models of risk conferred by genetic profiles for individuals in a population. Statistical techniques are illustrated, and the risk prediction capacities of different risk models are quantified. RESULTS: Risk distribution curves are most informative and relevant to clinical practice. They show proportions of subjects classified into clinically relevant risk categories. In a population in which 10% have the outcome event and subjects are categorized as high risk if their risk exceeds 20%, we identified some settings where more than half of those destined to have an event were classified as high risk by the risk model. Either 150 genes each with odds ratio of 1.5 or 250 genes each with odds ratio of 1.25 were required when the minor allele frequencies are 10%. We show that conclusions based on receiver operating characteristic curves may not be the same as conclusions based on risk distribution curves. CONCLUSIONS: Many highly predictive genes will be required to identify substantial numbers of subjects at high risk. PMID- 20160268 TI - Vitamin D and racial disparities for pancreatic cancer - letter. PMID- 20160270 TI - Marijuana use is not associated with cervical human papillomavirus natural history or cervical neoplasia in HIV-seropositive or HIV-seronegative women. AB - Marijuana use was recently reported to have a positive cross-sectional association with human papillomavirus (HPV)-related head and neck cancer. Laboratory data suggest that marijuana could have an immunomodulatory effect. Little is known, however, regarding the effects of marijuana use on cervical HPV or neoplasia. Therefore, we studied the natural history (i.e., prevalence, incident detection, clearance/persistence) of cervical HPV and cervical neoplasia (i.e., squamous intraepithelial lesions; SIL) in a large prospective cohort of 2,584 HIV-seropositive and 915 HIV-seronegative women. Marijuana use was classified as ever/never, current/not current, and by frequency and duration of use. No positive associations were observed between use of marijuana, and either cervical HPV infection or SIL. The findings were similar among HIV-seropositive and HIV-seronegative women, and in tobacco smokers and nonsmokers. These data suggest that marijuana use does not increase the burden of cervical HPV infection or SIL. PMID- 20160272 TI - Coherence and completeness of population-based family cancer reports. AB - BACKGROUND: Although family history of cancer is widely ascertained in research and clinical care, little is known about assessment methods, accuracy, or other quality measures. Given its widespread use in cancer screening and surveillance, better information is needed about the clarity and accuracy of family history information reported in the general population. METHODS: This telephone survey in Connecticut examined coherence and completeness of reports from 1,019 respondents about 20,504 biological relatives. RESULTS: Of 2,657 cancer reports, 97.7% were judged consistent with malignancy (versus benign or indeterminate conditions); 79% were site specific, 10.1% had unspecified cancer sites, and 8.6% had "ill defined" sites. Only 6.1% of relatives had unknown histories. Unknown histories and ambiguous sites were significantly higher for second-degree relatives. The adjusted percentage of first-degree relative reports with ambiguous sites increased with decreasing education and African-American race of survey respondents, and with deceased vital status of relatives. Ambiguous second-degree relative reports were also associated with deceased vital status and with male gender of respondents. CONCLUSIONS: These findings suggest that family history of cancer reports from the general population are generally complete and coherent. IMPACT: Strategies are needed to improve site specificity and thus maximize the utility of such information in primary care settings. PMID- 20160273 TI - Choline and betaine intake and the risk of colorectal cancer in men. AB - Dietary choline and betaine have been hypothesized to decrease the risk of cancer because of their role as methyl donors in the one-carbon metabolism. However, it remains unknown whether dietary intake of choline and betaine is associated with colorectal cancer risk. We prospectively examined the associations between dietary choline and betaine intake and risk of colorectal cancer in men in the Health Professionals Follow-up Study. We followed 47,302 men and identified a total of 987 incident colorectal cancer cases from 1986 to 2004. We assessed dietary and supplemental choline and betaine intake every 4 years using a validated semiquantitative food frequency questionnaire. The Cox proportional hazards model was used to estimate multivariate relative risks and 95% confidence intervals. All statistical tests were two-sided. We did not find any statistically significant associations between choline intake or betaine intake and risk of colorectal cancer. Comparing the top quintile with bottom quintile, multivariate relative risks (95% confidence interval) were 0.97 (0.79-1.20; P(trend) = 0.87) for choline intake and 0.94 (0.77-1.16; P(trend) = 0.79) for betaine intake. Similarly, we observed no associations between colorectal cancer risk and choline from free choline, glycerophosphocholine, phosphocholine, phosphatidylcholine, or sphingomyelin. Our data do not support the hypothesis that choline and betaine intake is inversely associated with colorectal cancer risk. PMID- 20160274 TI - Accuracy of perceived risk of recurrence among patients with early-stage breast cancer. AB - BACKGROUND: Accurate breast cancer recurrence risk perceptions might motivate health-promoting behaviors and alleviate undue anxiety. Although a few studies have examined early-stage breast cancer survivors' perceived risk of recurrence, none have assessed the accuracy of survivors' perceived risk of recurrence. METHODS: First primary ductal carcinoma in situ and early-invasive breast cancer survivors reported their perceived risk of recurrence during 6- and 12-month postsurgery interviews. We estimated the patients' 10-year risk of recurrence from published clinical trials, and for early-invasive breast cancer patients, risk of distant recurrence was based on their breast cancer-specific mortality calculated using Adjuvant! Online. Patients' perceived risk was compared with their calculated risk and categorized as "Accurate," "Underestimated," "Overestimated," and "Uncertain." Multinomial logit marginal effect models were fitted using Accurate as the reference. RESULTS: Only 17% of 531 patients accurately perceived their risk at 6 months, most of whom inaccurately perceived their risk at 12 months (P = 0.0143). Patients who were nonwhite [odds ratio (OR), 1.70; 95% confidence interval (95% CI), 1.12-2.56] and received radiation therapy (OR, 2.01; 95% CI, 1.07-3.77) were more likely to underestimate their risk. Patients with ductal carcinoma in situ (OR, 1.76; 95% CI, 1.11-2.79), [corrected] lower social support (OR, 0.71; 95% CI, 0.53-0.95), and anxiety (OR, 1.58; 95% CI, 1.01-2.47) were more likely to overestimate their risk. CONCLUSION: Few breast cancer survivors accurately perceived their risk of recurrence. IMPACT: The accuracy of perceived risk may be increased by better physician patient communications about their prognosis, provision of social support, and treatment for coexisting anxiety. PMID- 20160278 TI - Perceived cancer risk: why is it lower among nonwhites than whites? AB - BACKGROUND: We explored racial/ethnic differences in perceived cancer risk and determinants of these differences in a nationally representative sample of whites, blacks, Hispanics, and Asians. METHODS: Multiple regression techniques, including mediational analyses, were used to identify determinants and quantify racial/ethnic differences in the perception of the risk of developing cancer among 5,581 adult respondents to the 2007 Health Information Trends Survey (HINTS). RESULTS: Blacks, Hispanics, and Asians reported lower perceived cancer risk than whites [Bs = -0.40, -0.34, and -0.69, respectively; (Ps < 0.001)]. Contributing factors included relatively lower likelihood of reporting a family history of cancer, lower likelihood of having smoked, and a less strong belief that everything causes cancer among nonwhites than among whites. Racial/ethnic differences in perceived risk were attenuated in older respondents because perceived cancer risk was negatively associated with age for whites but not for nonwhites. CONCLUSIONS: Nonwhites had lower perceptions of cancer risk than whites. Some of the racial/ethnic variability in perceived risk may be due to racial and ethnic differences in awareness of one's family history of cancer and its relevance for cancer risk, experiences with behavioral risk factors, and salience of cancer risk information. PMID- 20160281 TI - Improved stopping rules for the design of efficient small-sample experiments in biomedical and biobehavioral research. AB - Sequential stopping rules (SSRs) should augment traditional hypothesis tests in many planned experiments, because they can provide the same statistical power with up to 30% fewer subjects without additional education or software. This article includes new Monte-Carlo-generated power curves and tables of stopping criteria based on the p values from simulated t tests and one-way ANOVAs. The tables improve existing SSR techniques by holding alpha very close to a target value when 1-10 subjects are added at each iteration. The emphasis is on small sample sizes (3-40 subjects per group) and large standardized effect sizes (0.8 2.0). The generality of the tables for dependent samples and one-tailed tests is discussed. SSR methods should be of interest to ethics bodies governing research when it is desirable to limit the number of subjects tested, such as in studies of pain, experimental disease, or surgery with animal or human subjects. PMID- 20160282 TI - A permutation test for the race model inequality. AB - When participants are asked to respond in the same way to several stimulus identities, responses are often observed to be faster if two stimuli are presented simultaneously as opposed to when a single stimulus is presented (redundant signals effect; Miller, 1982). An important issue of such experiments is whether the observed redundancy gains can be explained by parallel processing of the two stimuli in a race-like fashion. To test the parallel processing model, Miller derived the well-known race model inequality which has become a routine test for behavioral data in experiments with redundant signals. Several statistical procedures have been used for testing the race model inequality. However, the commonly employed procedure does not control the Type I error. In this article a permutation test is described that keeps the Type I error at the desired level. Simulations show that the power of the test is reasonable even for small samples. The scripts discussed in this article may be downloaded as supplemental materials from http://brm.psychonomic journals.org/content/supplemental. PMID- 20160279 TI - Distribution and hepatocellular carcinoma-related viral properties of hepatitis B virus genotypes in Mainland China: a community-based study. AB - INTRODUCTION: Hepatitis B virus (HBV) genotypes, replication status, and mutations have been associated with the risk of hepatocellular carcinoma (HCC). Our aim was to study the distribution and HCC-related viral properties of HBV genotypes/subgenotypes in Mainland China. METHODS: A multistage cluster probability sampling method was applied to select 81,775 participants between 1 and 59 years at 160 national disease surveillance points. We examined hepatitis B surface antigen, HBV genotypes and subgenotypes, hepatitis B e antigen, viral load, and mutations in the PreS and core promoter regions of HBV genome. RESULTS: HBV subgenotypes B2 (27.3%), C1 (10.7%), and C2 (58.0%) were predominant. Genotype D (D1, 80.8%) was frequent in the Uygur. We identified a new subgenotype, C9, mainly in Tibetans. Compositions of subgenotypes B2 and C1 and genotype mixture increased from the North to Central South, which was consistently associated with the increasing prevalence of hepatitis B surface antigen. Hepatitis B e antigen positivity and viral loads were higher in the young with genotype B and declined more rapidly with increasing age than those with genotype C. In contrast to G1896A, PreS deletion, T31C, T1753V, and A1762T/G1764A were more frequent in subgenotype C2 than in subgenotype B2. A1762T/G1764A, T1753V, C1653T, and G1896A, except PreS deletion, consecutively increased with increasing age. CONCLUSION: HBV subgenotypes B2, C1, and C2 are endemic in Mainland China. HBV genotype C exhibits less replication activity in the young and harbors higher frequencies of the HCC-associated mutations than genotype B. IMPACT: These basic data could help evaluate the association of HBV variations with HCC. PMID- 20160283 TI - Two SPSS programs for interpreting multiple regression results. AB - When multiple regression is used in explanation-oriented designs, it is very important to determine both the usefulness of the predictor variables and their relative importance. Standardized regression coefficients are routinely provided by commercial programs. However, they generally function rather poorly as indicators of relative importance, especially in the presence of substantially correlated predictors. We provide two user-friendly SPSS programs that implement currently recommended techniques and recent developments for assessing the relevance of the predictors. The programs also allow the user to take into account the effects of measurement error. The first program, MIMR-Corr.sps, uses a correlation matrix as input, whereas the second program, MIMR-Raw.sps, uses the raw data and computes bootstrap confidence intervals of different statistics. The SPSS syntax, a short manual, and data files related to this article are available as supplemental materials from http://brm.psychonomic journals.org/content/supplemental. PMID- 20160284 TI - Obtaining representative nominal groups. AB - Many researchers studying the effectiveness of working in groups have compared group performance with the scores of individuals combined into nominal groups. Traditionally, methods for forming nominal groups have been shown to be poor, and more recent procedures (Wright, 2007) are difficult to use for complex designs and are inflexible. A new procedure is introduced and tested in which thousands of possible combinations of nominal groups are sampled. Sample characteristics, such as the mean, variance, and distribution, of all these sets are calculated, and the set that is most representative of all of these sets is returned. The user can choose among different ways of conceptualizing the meaning of most representative, but on the basis of simulations and the fact that most subsequent statistical procedures are based on the mean and variance, we argue that finding the set with the mean and variance most similar to the means of the representative statistics for all of the sets is the preferred approach. The algorithm is implemented in a stand-alone C++ executable program and as an R function. Both of these allow anyone to use the procedures freely. PMID- 20160285 TI - multiTree: a computer program for the analysis of multinomial processing tree models. AB - Multinomial processing tree (MPT) models are a family of stochastic models for psychology and related sciences that can be used to model observed categorical frequencies as a function of a sequence of latent states. For the analysis of such models, the present article presents a platform-independent computer program called multiTree, which simplifies the creation and the analysis of MPT models. This makes them more convenient to implement and analyze. Also, multiTree offers advanced modeling features. It provides estimates of the parameters and their variability, goodness-of-fit statistics, hypothesis testing, checks for identifiability, parametric and nonparametric bootstrapping, and power analyses. In this article, the algorithms underlying multiTree are given, and a user guide is provided. The multiTree program can be downloaded from http://psycho3.uni mannheim.de/multitree. PMID- 20160286 TI - CircE: an R implementation of Browne's circular stochastic process model. AB - In confirmatory analysis of whether data have a circumplex structure, Browne's (1992) model has played a major role. However, implementation of this model requires a dedicated program, CIRCUM, because the analysis routine is not integrated in any of the most widely used statistical software packages. Hence, data entry and graphical representation of the results require the use of one or more additional programs. We propose a package for the R statistical environment, termed CircE, that can be used to enter or import data, implement Browne's confirmatory analysis, and graphically represent the results. Using this new software, we put forward a new approach to assess the sustainability of theoretical models when the analysis is carried out at the level of questionnaire items. The CircE package (for either Mac OS X or Windows) and additional files may be downloaded from http://brm.psychonomic-journals.org/content/supplemental. PMID- 20160287 TI - Recognizing emotions in spoken language: a validated set of Portuguese sentences and pseudosentences for research on emotional prosody. AB - A set of semantically neutral sentences and derived pseudosentences was produced by two native European Portuguese speakers varying emotional prosody in order to portray anger, disgust, fear, happiness, sadness, surprise, and neutrality. Accuracy rates and reaction times in a forced-choice identification of these emotions as well as intensity judgments were collected from 80 participants, and a database was constructed with the utterances reaching satisfactory accuracy (190 sentences and 178 pseudosentences). High accuracy (mean correct of 75% for sentences and 71% for pseudosentences), rapid recognition, and high-intensity judgments were obtained for all the portrayed emotional qualities. Sentences and pseudosentences elicited similar accuracy and intensity rates, but participants responded to pseudosentences faster than they did to sentences. This database is a useful tool for research on emotional prosody, including cross-language studies and studies involving Portuguese-speaking participants, and it may be useful for clinical purposes in the assessment of brain-damaged patients. The database is available for download from http://brm.psychonomic journals.org/content/supplemental. PMID- 20160288 TI - Norms for two types of manipulability (graspability and functional usage), familiarity, and age of acquisition for 320 photographs of objects. AB - There is increasing interest in the role that manipulability plays in processing objects. To date, Magnie, Besson, Poncet, and Dolisi's (2003) manipulability ratings, based on the degree to which objects can be uniquely pantomimed, have been the reference point for many studies. However, these ratings do not fully capture some relevant dimensions of manipulability, including whether an object is graspable and the extent to which functional motor associations above and beyond graspability are present. To address this, we collected ratings of these dimensions, in addition to ratings of familiarity and age of acquisition (AoA), for a set of 320 black-and-white photographs of objects. Familiarity and AoA ratings were highly correlated with previously reported ratings of the same dimensions (r = .853, p < .001, and r = .771, p < .001, respectively), validating the present norms. Grasping and functional use ratings, in contrast, were more moderately correlated with Magnie et al.'s pantomime manipulability ratings (r = .507, p < .001). These results were taken as evidence that the new manipulability ratings collected in this research capture distinct aspects of object manipulability. The complete stimuli and norms from this study may be downloaded from http://brm.psychonomic-journals.org/content/supplemental. PMID- 20160289 TI - Feedforward, -backward, and neutral transparency measures for Grade 1 and Grade 2 Greek readers. AB - In the present study, orthographic metrics for Greek children's Grade 1 and Grade 2 reading materials were presented. Data for five transparency metrics--three of which being neither feedforward nor feedbackward--were presented and offered for use in the research of children's reading and spelling acquisition. The analysis demonstrated the complex relationships between metrics and compared the results with those obtained for the English language. The structure of these metrics from a variety of corpus sizes was investigated, and we concluded that large corpus sizes do not necessarily make a substantial contribution to the value of such metrics when compared with smaller samples. PMID- 20160290 TI - Subjective frequency norms for 330 Spanish simple and compound words. AB - Ratings were collected from 102 native speakers of Spanish on the subjective frequency of occurrence of 330 Spanish words, including 120 deverbal compounds and their constituents. These ratings were found to be highly reliable, whether items were analyzed together or separately by type (i.e., compounds, nouns, verbs), as evidenced by indexes of internal consistency and test-retest reliability that were equal to or greater than .98. The validity of the normative ratings was attested to by statistically significant correlations with objective frequency, estimated at .63 for all items together, and .41, .51, and .78 for compounds, nouns, and verbs, respectively. Among the substantive issues addressed was the potential dependency in ratings for compounds and their associated verb noun constituents. No relationship was discerned, supporting the idea that compound and constituent ratings are statistically independent in this experimental task. The theoretical and methodological implications of the findings are discussed. The ratings can be downloaded from http://brm.psychonomic journals.org/content/supplemental. PMID- 20160291 TI - SYLLABARIUM: an online application for deriving complete statistics for Basque and Spanish orthographic syllables. AB - The present article introduces SYLLABARIUM, a new Web tool addressing the needs of linguists, psycholinguists, and cognitive scientists who work with Spanish and/or Basque and are interested in retrieving information about several syllable related parameters. This new online syllabic database allows the user to generate complete lists of Spanish and Basque syllables with information about the syllable frequency. Among other measures, for a given orthographic syllable, SYLLABARIUM provides its number of occurrences (i.e., the type frequency), the summed lexical frequency of the words that contain this syllable (i.e., the token frequency), and the positional distribution of type and token frequencies. The cross-language feature of SYLLABARIUM is of special interest to researchers aiming to explore the influence of the syllable in bilingualism. The Web tool is available at www.bcbl.eu/syllabarium. PMID- 20160292 TI - Objective age of acquisition for 223 Italian words: norms and effects on picture naming speed. AB - The present study provides a set of objective age of acquisition (AoA) norms for 223 Italian words that may be useful for conducting cross-linguistic studies or experiments on Italian language processing. The data were collected by presenting children from the ages of 2 to 11 with a normed picture set (Lotto, Dell'Acqua, & Job, 2001). Following the study of Morrison, Chappell, and Ellis (1997), we report two measures of objective AoA. Both measures strongly correlated with each other, and they also showed a good correlation with the rated AoA provided by adult participants. Furthermore, we assessed the relationship between the AoA measures and other variables used in psycholinguistic experiments. Regression analyses showed that familiarity, typicality, and word frequency were significant predictors of AoA. AoA, but not word frequency, was found to determine naming latencies. Finally, we present a path model in which AoA is a mediator in predicting speed in picture naming. The norms and the picture set can also be downloaded from http://dpss.psy.unipd.it/files/strumenti.php and from http://brm.psychonomic-journals.org/content/supplemental. PMID- 20160293 TI - Affective norms for 210 British English and Finnish nouns. AB - This article presents affective ratings for 210 British English and Finnish nouns, including taboo words. The norms were collected with 135 native British English and 304 native Finnish speakers, who rated the words according to their emotional valence, emotional charge, offensiveness, concreteness, and familiarity. The ratings between the two languages were found to be strongly correlated. The present ratings were also strongly correlated with the American English emotional valence and arousal ratings available in the Affective Norms for English Words database (Bradley & Lang, 1999) and the Janschewitz (2008) database for taboo words. These ratings will help researchers to select stimulus materials for a wide range of experiments involving both monolingual and bilingual processing of British English and Finnish emotional words. Materials associated with this article may be accessed as an online supplement from http://brm.psychonomic-journals.org/content/supplemental. PMID- 20160294 TI - PyParse: a semiautomated system for scoring spoken recall data. AB - Studies of human memory often generate data on the sequence and timing of recalled items, but scoring such data using conventional methods is difficult or impossible. We describe a Python-based semiautomated system that greatly simplifies this task. This software, called PyParse, can easily be used in conjunction with many common experiment authoring systems. Scored data is output in a simple ASCII format and can be accessed with the programming language of choice, allowing for the identification of features such as correct responses, prior-list intrusions, extra-list intrusions, and repetitions. PMID- 20160295 TI - A comparison of blindpulling and blindwalking as measures of perceived absolute distance. AB - Blindwalking has become a common measure of perceived absolute distance and location, but it requires a relatively large testing space and cannot be used with people for whom walking is difficult or impossible. In the present article, we describe an alternative response type that is closely matched to blindwalking in several important respects but is less resource intensive. In the blindpulling technique, participants view a target, then close their eyes and pull a length of tape or rope between the hands to indicate the remembered target distance. As with blindwalking, this response requires integration of cyclical, bilateral limb movements over time. Blind-pulling and blindwalking responses are tightly linked across a range of viewing conditions, and blindpulling is accurate when prior exposure to visually guided pulling is provided. Thus, blindpulling shows promise as a measure of perceived distance that may be used in nonambulatory populations and when the space available for testing is limited. PMID- 20160296 TI - Determining the point of subjective ambiguity of ambiguous biological-motion figures with perspective cues. AB - Orthographic frontal/back projections of biological-motion figures are bistable: The point-light figure in principle can be perceived either as facing toward the viewer or as facing away from the viewer. Some point-light actions--for example, walking--elicit a strong "facing bias": Despite the absence of objective cues to depth, observers tend to interpret the figure as facing toward the viewer in most of the cases. In this article, we present and experimentally validate a technique that affords full experimental control of the perceived in-depth orientation of point-light figures. We demonstrate that by parametrically manipulating the amount of perspective information in the stimulus, it is possible to obtain any desired level of subjective ambiguity. Directions for future research, in which this technique can be fruitfully implemented, are suggested. Program code of a demo is provided that can be modified easily for program code of new experiments. The demo and QuickTime movie files illustrating our perspective manipulation technique may be downloaded from http://brm.psychonomic journals.org/content/supplemental. PMID- 20160297 TI - Inferring intentions from biological motion: a stimulus set of point-light communicative interactions. AB - We present the first database of communicative interactions reproduced through point-light displays (Communicative Interaction Database). The database contains 20 communicative interactions performed by male and by female couples. For each action, we provide movie files from four different viewpoints, as well as text files with the 3-D spatial coordinates of the point lights, allowing researchers to construct customized versions. By including various types of actions performed with different social motives, the database contains a diverse sample of nonconventional communicative gestures. Normative data collected to assess the recognizability of the stimuli suggest that, for most action stimuli, information in point-light displays is sufficient for clear recognition of the action as communicative, as well as for identification of the specific communicative gesture performed by the actor. The full set of stimuli may be downloaded from http://brm.psychonomic-journals.org/content/supplemental and from http://ppw.kuleuven.be/labexppsy/lepSite/resources/CID.rar. PMID- 20160298 TI - DynAOI: a tool for matching eye-movement data with dynamic areas of interest in animations and movies. AB - Analyzing gaze behavior with dynamic stimulus material is of growing importance in experimental psychology; however, there is still a lack of efficient analysis tools that are able to handle dynamically changing areas of interest. In this article, we present DynAOI, an open-source tool that allows for the definition of dynamic areas of interest. It works automatically with animations that are based on virtual three-dimensional models. When one is working with videos of real world scenes, a three-dimensional model of the relevant content needs to be created first. The recorded eye-movement data are matched with the static and dynamic objects in the model underlying the video content, thus creating static and dynamic areas of interest. A validation study asking participants to track particular objects demonstrated that DynAOI is an efficient tool for handling dynamic areas of interest. PMID- 20160299 TI - An adaptive algorithm for fixation, saccade, and glissade detection in eyetracking data. AB - Event detection is used to classify recorded gaze points into periods of fixation, saccade, smooth pursuit, blink, and noise. Although there is an overall consensus that current algorithms for event detection have serious flaws and that a de facto standard for event detection does not exist, surprisingly little work has been done to remedy this problem. We suggest a new velocity-based algorithm that takes several of the previously known limitations into account. Most important, the new algorithm identifies so-called glissades, a wobbling movement at the end of many saccades, as a separate class of eye movements. Part of the solution involves designing an adaptive velocity threshold that makes the event detection less sensitive to variations in noise level and the algorithm settings free for the user. We demonstrate the performance of the new algorithm on eye movements recorded during reading and scene perception and compare it with two of the most commonly used algorithms today. Results show that, unlike the currently used algorithms, fixations, saccades, and glissades are robustly identified by the new algorithm. Using this algorithm, we found that glissades occur in about half of the saccades, during both reading and scene perception, and that they have an average duration close to 24 msec. Due to the high prevalence and long durations of glissades, we argue that researchers must actively choose whether to assign the glissades to saccades or fixations; the choice affects dependent variables such as fixation and saccade duration significantly. Current algorithms do not offer this choice, and their assignments of each glissade are largely arbitrary. PMID- 20160300 TI - Does variability in human performance outweigh imprecision in response devices such as computer keyboards? AB - In chronometric research, it is well-known that many response devices used with personal computers, especially computer keyboards, suffer from measurement inaccuracies due to infrequent polling. In this article, it is investigated whether it is worth being concerned by this added error, given that human performance inherently exhibits a considerable degree of variability. By comparing inaccuracy due to response device imprecision with the level of variability already present in human performance, it is shown that the former is very unlikely to have a negative impact on statistical outcomes. In other words, millisecond resolution of response devices, although desirable, is not a general requirement. PMID- 20160301 TI - RTbox: a device for highly accurate response time measurements. AB - Although computer keyboards and mice are frequently used in measuring response times (RTs), the accuracy of these measurements is quite low. Specialized RT collection devices must be used to obtain more accurate measurements. However, all the existing devices have some shortcomings. We have developed and implemented a new, commercially available device, the RTbox, for highly accurate RT measurements. The RTbox has its own microprocessor and high-resolution clock. It can record the identities and timing of button events with high accuracy, unaffected by potential timing uncertainty or biases during data transmission and processing in the host computer. It stores button events until the host computer chooses to retrieve them. The asynchronous storage greatly simplifies the design of user programs. The RTbox can also receive and record external signals as triggers and can measure RTs with respect to external events. The internal clock of the RTbox can be synchronized with the computer clock, so the device can be used without external triggers. A simple USB connection is sufficient to integrate the RTbox with any standard computer and operating system. PMID- 20160302 TI - MouseTracker: software for studying real-time mental processing using a computer mouse-tracking method. AB - In the present article, we present a software package, MouseTracker, that allows researchers to use a computer mouse-tracking method for assessing real-time processing in psychological tasks. By recording the streaming x-, y-coordinates of the computer mouse while participants move the mouse into one of multiple response alternatives, motor dynamics of the hand can reveal the time course of mental processes. MouseTracker provides researchers with fine-grained information about the real-time evolution of participant responses by sampling 60-75 times/sec the online competition between multiple response alternatives. MouseTracker allows researchers to develop and run experiments and subsequently analyze mouse trajectories in a user-interactive, graphics-based environment. Experiments may incorporate images, letter strings, and sounds. Mouse trajectories can be processed, averaged, visualized, and explored, and measures of spatial attraction/curvature, complexity, velocity, and acceleration can be computed. We describe the software and the method, and we provide details on mouse trajectory analysis. We validate the software by demonstrating the accuracy and reliability of its trajectory and reaction time data. The latest version of MouseTracker is freely available at http://mousetracker.jbfreeman.net. PMID- 20160303 TI - A solution for measuring accurate reaction time to visual stimuli realized with a programmable microcontroller. AB - This article presents a new solution for measuring accurate reaction time (SMART) to visual stimuli. The SMART is a USB device realized with a Cypress Programmable System-on-Chip (PSoC) mixed-signal array programmable microcontroller. A brief overview of the hardware and firmware of the PSoC is provided, together with the results of three experiments. In Experiment 1, we investigated the timing accuracy of the SMART in measuring reaction time (RT) under different conditions of operating systems (OSs; Windows XP or Vista) and monitor displays (a CRT or an LCD). The results indicated that the timing error in measuring RT by the SMART was less than 2 msec, on average, under all combinations of OS and display and that the SMART was tolerant to jitter and noise. In Experiment 2, we tested the SMART with 8 participants. The results indicated that there was no significant difference among RTs obtained with the SMART under the different conditions of OS and display. In Experiment 3, we used Microsoft (MS) PowerPoint to present visual stimuli on the display. We found no significant difference in RTs obtained using MS DirectX technology versus using the PowerPoint file with the SMART. We are certain that the SMART is a simple and practical solution for measuring RTs accurately. Although there are some restrictions in using the SMART with RT paradigms, the SMART is capable of providing both researchers and health professionals working in clinical settings with new ways of using RT paradigms in their work. PMID- 20160304 TI - Eyetracking for two-person tasks with manipulation of a virtual world. AB - Eyetracking facilities are typically restricted to monitoring a single person viewing static images or pre-recorded video. In the present article, we describe a system that makes it possible to study visual attention in coordination with other activity during joint action. The software links two eyetracking systems in parallel and provides an on-screen task. By locating eye movements against dynamic screen regions, it permits automatic tracking of moving on-screen objects. Using existing SR technology, the system can also cross-project each participant's eyetrack and mouse location onto the other's on-screen work space. Keeping a complete record of eyetrack and on-screen events in the same format as subsequent human coding, the system permits the analysis of multiple modalities. The software offers new approaches to spontaneous multimodal communication: joint action and joint attention. These capacities are demonstrated using an experimental paradigm for cooperative on-screen assembly of a two-dimensional model. The software is available under an open source license. PMID- 20160305 TI - Differences in responses to Web and paper surveys among school professionals. AB - This experiment investigated the effects of survey administration mode (Web vs. paper and pencil) and survey length (short or long) on the responses of a large sample of primary and secondary school professionals in the U.S. The 812 participants in this study were part of an initial random sample of 1,000 individuals representing 5.81% of the membership of a national professional organization. The participants were randomly assigned to each of the four treatment conditions. Results indicated (1) substantially lower response rates for Web surveys than for same-length paper surveys; (2) a higher response rate for short surveys than for long surveys with paper, but not Web, questionnaires; and (3) a younger age for Web respondents, as compared with their paper counterparts. In light of prior research, we suggest that paper-and-pencil methods be used for surveying professionals in primary and secondary school settings. PMID- 20160306 TI - A comparison of stimulus ratings made online and in person: gender and method effects. AB - In Experiment 1, separate samples rated nouns on danger, using either an online survey or the same survey in person. In Experiment 2, a single sample rated words on familiarity, using both methods. Women's in-person and online ratings correlated significantly better than men's. In-person ratings correlated significantly better with existing norms in 4 of 8 instances. There were significant effects of condition on mean ratings and completion times. Ratings from participants who withdrew from the experiment correlated significantly less well with existing norms than did ratings from those who completed the whole experiment, in 12 of 16 instances. Analysis of existing data showed that a different statistical conclusion is reached depending on whether in-person or online ratings are used. Furthermore, the categorization of 17.9% (Experiment 1) and 5.3% (Experiment 2) of the items as high or low depends on which ratings are used. Ratings gathered in person and online cannot be freely substituted. PMID- 20160307 TI - The Glasgow Face Matching Test. AB - We describe a new test for unfamiliar face matching, the Glasgow Face Matching Test (GFMT). Viewers are shown pairs of faces, photographed in full-face view but with different cameras, and are asked to make same/different judgments. The full version of the test comprises 168 face pairs, and we also describe a shortened version with 40 pairs. We provide normative data for these tests derived from large subject samples. We also describe associations between the GFMT and other tests of matching and memory. The new test correlates moderately with face memory but more strongly with object matching, a result that is consistent with previous research highlighting a link between object and face matching, specific to unfamiliar faces. The test is available free for scientific use. PMID- 20160308 TI - Video context-dependent recall. AB - In two experiments, we used an effective new method for experimentally manipulating local and global contexts to examine context-dependent recall. The method included video-recorded scenes of real environments, with target words superimposed over the scenes. In Experiment 1, we used a within-subjects manipulation of video contexts and compared the effects of reinstatement of a global context (15 words per context) with effects of less overloaded context cues (1 and 3 words per context) on recall. The size of the reinstatement effects in Experiment 1 show how potently video contexts can cue recall. A strong effect of cue overload was also found; reinstatement effects were smaller, but still quite robust, in the 15 words per context condition. The powerful reinstatement effect was replicated for local contexts in Experiment 2, which included a no contexts-reinstated group, a control condition used to determine whether reinstatement of half of the cues caused biased output interference for uncued targets. The video context method is a potent way to investigate context dependent memory. PMID- 20160309 TI - Ways of probing situated concepts. AB - Two ways of eliciting conceptual content have been to instruct participants to list the intrinsic properties that concept exemplars possess or to report any thoughts that come to mind about the concept. It has been argued that the open, unconstrained probe is better able to elicit the situational information that concepts contain. We evaluated this proposal in two experiments comparing the two probes with regard to the content that they yield for object concepts at the superordinate and basic levels. The results showed that the open probe was better able to elicit situated conceptual knowledge and point out differences in the representations of superordinate and basic concepts. PMID- 20160310 TI - A free software package for a human online-conditioned suppression preparation. AB - MartiansV2 is both a language syntax in which experiments can be written and an implementation of this syntax in a runtime application that, when fed a valid experiment text file, will execute the given experiment. It is based on the original Martians preparation, which has proven a valuable tool for assessing human online-conditioned suppression performance through research on a wide array of learning phenomena. This article can be read as a manual, both for using the Martians paradigm in general and for getting started with MartiansV2. PMID- 20160311 TI - Inducing changes in arousal and valence: comparison of two mood induction procedures. AB - This research examined the relative effectiveness of two mood induction procedures (MIPs) for inducing four specific moods varying along the dimensions of both valence and arousal. Participants were randomly assigned either to an autobiographical recall or to a music and guided imagery MIP and underwent a happiness, serenity, anger, or sadness mood induction. The findings confirmed the effectiveness of the two MIPs in producing changes on both the valence and arousal dimensions of mood. The results also revealed an unexpected greater efficiency of the autobiographical recall than of the combined procedure. PMID- 20160312 TI - Ductus: a software package for the study of handwriting production. AB - Ductus is a software tool designed to analyze and aid understanding of the processes underlying handwriting production. Ductus is a digitizer-based device that provides online information on the handwriting process. It consists of two distinct modules that operate independently. The first module concerns stimulus presentation. It is particularly suited to experiments with children and patients presenting handwriting pathologies. The second module is devoted to data analysis. Apart from the geometrical aspects of handwriting, such as trajectory formation, Ductus provides a wide range of kinematic information, such as velocity, duration, fluency, and pauses, linked to the mastery of the movement itself. Ductus is available free from the authors. It works on a Windows platform with Wacom digitizers. PMID- 20160313 TI - A computer program for testing and analyzing random generation behavior in normal and clinical samples: the Mittenecker Pointing Test. AB - Random sequence generation tests have proved to be a useful diagnostic tool for the identification of clinically relevant impairments of executive functions and for the study of cognitive functioning in healthy individuals. The most prevalent variety, random number generation, involves several limitations, however. In the original Mittenecker Pointing Test (MPT; Mittenecker, 1958), subjects were instructed to point successively and as randomly as possible at nine unlabeled circles irregularly arranged on a cardboard. With the computer program presented here, Mittenecker's classical test has been transferred to a contemporary format. The MPT can be applied using a standard PC keyboard and computes a series of sophisticated measures of deviations from randomness on the basis of information theory analysis. Because of its easy and well-controlled administration and reduced demands on memory and attention, the automatized MPT offers a wide range of application possibilities in normal but also in severely impaired clinical samples. PMID- 20160314 TI - Knowledge space theory, formal concept analysis, and computerized psychological assessment. AB - In the present study, the use of knowledge space theory (KST), jointly with formal concept analysis (FCA), is proposed for developing a formal representation of the relations between the items of a questionnaire and a set of psychodiagnostic criteria. This formal representation can be used to develop an efficient adaptive tool for psychological assessment. Rusch and Wille (1996) have shown some interesting connections between KST and FCA; these connections are applied in the construction of knowledge structures, starting from a formal context representing the relations between items and criteria. The proposed general methodology was applied, as an example, to the Maudsley Obsessional Compulsive Questionnaire. We used a data set provided by a sample of patients with a diagnosis of obsessive-compulsive disorder to validate the obtained structures. The parameters of the basic local independence model (BLIM) were estimated for the obtained knowledge structures. The fit of each model was tested by parametric bootstrap because of the sparseness of the derived data matrix. The results are discussed in light of both psychological and methodological relapses. In particular, we propose a reinterpretation of the BLIM parameters that seems suitable for testing reliability and construct validity; furthermore, it is pointed out how the obtained structures could represent the starting point for the development of a computerized assessment tool. PMID- 20160315 TI - FACES--a database of facial expressions in young, middle-aged, and older women and men: development and validation. AB - Faces are widely used as stimuli in various research fields. Interest in emotion related differences and age-associated changes in the processing of faces is growing. With the aim of systematically varying both expression and age of the face, we created FACES, a database comprising N = 171 naturalistic faces of young, middle-aged, and older women and men. Each face is represented with two sets of six facial expressions (neutrality, sadness, disgust, fear, anger, and happiness), resulting in 2,052 individual images. A total of N = 154 young, middle-aged, and older women and men rated the faces in terms of facial expression and perceived age. With its large age range of faces displaying different expressions, FACES is well suited for investigating developmental and other research questions on emotion, motivation, and cognition, as well as their interactions. Information on using FACES for research purposes can be found at http://faces.mpib-berlin.mpg.de. PMID- 20160316 TI - Comparison of A level and UKCAT performance in students applying to UK medical and dental schools in 2006: cohort study. AB - OBJECTIVES: To determine whether the UK Clinical Aptitude Test (UKCAT) adds value to the selection process for school leaver applicants to medical and dental school, and in particular whether UKCAT can reduce the socioeconomic bias known to affect A levels. DESIGN: Cohort study SETTING: Applicants to 23 UK medical and dental schools in 2006. PARTICIPANTS: 9884 applicants who took the UKCAT in the UK and who achieved at least three passes at A level in their school leaving examinations (53% of all applicants). MAIN OUTCOME MEASURES: Independent predictors of obtaining at least AAB at A level and UKCAT scores at or above the 30th centile for the cohort, for the subsections and the entire test. RESULTS: Independent predictors of obtaining at least AAB at A level were white ethnicity (odds ratio 1.58, 95% confidence interval 1.41 to 1.77), professional or managerial background (1.39, 1.22 to 1.59), and independent or grammar schooling (2.26, 2.02 to 2.52) (all P<0.001). Independent predictors of achieving UKCAT scores at or above the 30th centile for the whole test were male sex (odd ratio 1.48, 1.32 to 1.66), white ethnicity (2.17, 1.94 to 2.43), professional or managerial background (1.34, 1.17 to 1.54), and independent or grammar schooling (1.91, 1.70 to 2.14) (all P<0.001). One major limitation of the study was that socioeconomic status was not volunteered by approximately 30% of the applicants. Those who withheld socioeconomic status data were significantly different from those who provided that information, which may have caused bias in the analysis. CONCLUSIONS: UKCAT was introduced with a high expectation of increasing the diversity and fairness in selection for UK medical and dental schools. This study of a major subgroup of applicants in the first year of operation suggests that it has an inherent favourable bias to men and students from a higher socioeconomic class or independent or grammar schools. However, it does provide a reasonable proxy for A levels in the selection process. PMID- 20160317 TI - Drug firm conflicting interests. If only WHI was done well. PMID- 20160318 TI - Improving the selection of medical students. PMID- 20160319 TI - Fever as nature's engine. Some clinical data. PMID- 20160320 TI - Vitamin D deficiency. New vitamin D preparations needed. PMID- 20160321 TI - Depression in adolescents. Collaboration to overcome barriers in primary care. PMID- 20160322 TI - Venous thromboembolism guidance. Let's not talk about sex ... PMID- 20160323 TI - Venous thromboembolism guidance... or drugs. PMID- 20160324 TI - Vitamin D deficiency. What should we be doing? PMID- 20160325 TI - Vitamin D deficiency. How can we treat it in the UK? PMID- 20160326 TI - Vitamin D deficiency. Systems failure. PMID- 20160327 TI - Vitamin D deficiency. Screen more widely? PMID- 20160328 TI - Vitamin D deficiency. No clear evidence for universal supplementation. PMID- 20160329 TI - Industry influence. Big Pharma's long tentacles. PMID- 20160330 TI - Managing fetal alcohol spectrum disorder in the public school system: a needs assessment pilot. AB - BACKGROUND: Published data and Canadian population reports suggest that approximately 1% of students in Toronto may have learning problems related to Fetal Alcohol Spectrum Disorders (FASDs). It is therefore imperative to understand how the needs of affected students are being met by various practitioners in their school environment. To date no comprehensive follow-up studies on FASD-affected children, families and educators in Toronto public schools are available. Documentation of school experiences associated with FASDs is needed to aid in developing appropriate and efficient intervention models for FASDs. OBJECTIVES: Identify and document needs as related to school capacities and education practitioner capabilities with respect to their abilities to support children diagnosed with FASDs. METHODS: A qualitative approach using semi structured interviews was utilized for this exploratory pilot study. Twelve practitioners from various disciplines, all of whom work for Toronto public schools participated. RESULTS: Participants represented approximately 3500 students enrolled amongst their schools and classrooms. Only one respondent reported having worked with a child diagnosed with an FASD during their career. Education practitioners commonly report a lack of knowledge of FASDs and how to appropriately plan for affected children. CONCLUSIONS: Practitioners need additional supports in order to address FASDs in their schools. As this is the first pilot study on FASDs in the Ontario school system, further study is warranted. PMID- 20160331 TI - Testis T-cell lymphoma. Presentation of 2 cases and review. AB - OBJECTIVE: To present two clinical cases of testicular T cell lymphomas and perform a review of this condition. METHODS/RESULTS: Case 1. Forty-two year old male presenting with painful mass in the right testicle which appeared 2 months earlier. Testicular ultrasound showed diffuse increase in size of the testicle, with alteration in its echogenicity. The patient underwent orchidectomy, and based on histopathological and immunohistochemical tests, a peripheral nonspecific T cell lymphoma was diagnosed. Case 2. Forty-four year old male who presents with a 3 month history of left testicular enlargement without pain associated with reddish-brown macular lesions in the thigh and back and subsequent involvement of the right side of the scrotum. The ultrasonography showed testicles with increased size, with echogenicity altered diffusely. Left orchidectomy was performed and sent for histopathological and Immunophenotypic study which revealed a non-Hodgkin peripheral T cell lymphoma. CONCLUSION: T cell lymphomas involve the testis infrequently, which deserve special attention because of the poor prognosis and the need to make an appropriate diagnosis which could lead to a better therapeutic strategy. PMID- 20160332 TI - Cystoscopy in bladder bilharziasis. PMID- 20160333 TI - Congenital megalourethra associated with massive bilateral reflux. PMID- 20160334 TI - Ground state lasing at 1.30 microm from InAs/GaAs quantum dot lasers grown by metal-organic chemical vapor deposition. AB - We investigated the effects of post-growth annealing on the photoluminescence (PL) characteristics of InAs/GaAs quantum dots (QDs) grown by metal-organic chemical vapor deposition (MOCVD). The onset temperature at which both the peak linewidth and the PL intensity degraded and the blueshift of the ground state emission wavelength occurred was found to depend on both the QD density and the In composition of the capping layer. This behavior is particularly important in view of QD integration in photonic devices. From the knowledge of the dependences of the PL characteristics after annealing on the QD and capping growth conditions, ground state lasing at 1.30 microm could be demonstrated from InAs/GaAs QDs grown by MOCVD. Finally, we compared the laser characteristics of InAs/GaAs QDs with those of InAs/Sb:GaAs QDs, grown according to the antimony mediated growth technique, and showed that InAs/Sb:GaAs QDs are more appropriate for laser fabrication at 1.3 microm by MOCVD. PMID- 20160335 TI - Influence of electrode size and geometry on electrochemical experiments with combined SECM-SFM probes. AB - Gold electrodes integrated into silicon scanning force microscopy (SFM) probes allow the acquisition of spatially correlated data for sample morphology (via SFM) and local electrochemical reactivity via scanning electrochemical microscopy (SECM). The lateral resolution of both techniques is controlled by different properties of the integrated probes. The topographic tracking provided by the SFM mechanism allows the realization of very small working distances for the SECM measurements. Microfabrication technology was used in order to reduce the size of the active electrode area of the tip into the sub-100 nm regime. The functionality of the probes was tested using electrochemical methods. Experiments revealed that the response could be quantitatively compared to numerical simulation. The low working distance, in combination with the small size of the active electrode area, allows for high lateral resolution in the SECM images. This is illustrated with different model substrates that cover a range of different rate constants and illustrate the dependence of the SECM contrast on the local kinetics of the sample in the sub-micrometre size range. PMID- 20160336 TI - Negative capillary-pressure-induced cavitation probability in nanochannels. AB - The capillarity-induced negative pressure of water flow has been investigated in nanochannels of a rectangular cross section by using computational fluid dynamics (CFD) simulation. As a consequent effect of negative pressure, the cavitation probability has been analyzed numerically. The numerical relation between the critical radius of cavitation (R(c)) and geometrical characteristics of channels shows that cavitation does not occur in channels of uniform cross section (UCS), since 2R(c) is larger than the smallest dimension of the channel. However, it may occur in channels of non-uniform cross section (NUCS), except for planar or high aspect ratio channels. The inequality in height and width is favorable for the absence of cavitation. The findings can also be applied to channels of elliptical or circular cross section. The results show the influence of geometrical characteristics of channels on the cavitation probability, which is important to engineer the channel geometrical structure in order to avoid undesirable filling problem 'cavitation' during the flow process. PMID- 20160337 TI - Nonvolatile memory devices based on few-layer graphene films. AB - We report on the electrical characteristics of few-layer graphene (FLG) field effect devices with their various thicknesses. In combination with a ferroelectric polymer layer of poly(vinylidene fluoride/trifluoroethylene) [P(VDF/TrFE)], FLG/ferroelectric devices exhibited nonvolatile resistance changes due to a polarization switching of the P(VDF/TrFE) layer. The bistability and retention properties were highly sensitive to the FLG thickness, which is attributed to a charge screening effect in FLG films. PMID- 20160338 TI - Multisegment CdTe nanowire homojunction photodiode. AB - Electrochemical deposition in nanoporous ion track membranes is used for the preparation of multisegment CdTe--homojunction diode nanowires. Our study is based on the fact that the deposition overpotential strongly influences the composition of the compound semiconductor nanowires. Therefore, the transport behavior of the nanowire devices can be tailored by appropriately choosing a certain sequence of electrodeposition potentials. The wires were characterized using scanning electron microscopy, energy dispersive x-ray analysis, optical spectroscopy and x-ray diffraction. The current-voltage characteristics measured prove that, by appropriately choosing the voltage pulse pattern, one can fabricate nanowires with ohmic or rectifying behavior. The semiconducting nanowires are sensitive to light, their spectral sensitivity being characteristic of CdTe. The preparation of functional nanostructures in such a simple approach provides, as a major advantage, an increase in the process reproducibility and opens a wide field of potential optoelectronic applications. PMID- 20160339 TI - Optical manipulation of plasmonic nanoparticles, bubble formation and patterning of SERS aggregates. AB - We present an optical method for patterning SERS (surface-enhanced Raman spectroscopy)--enhancing aggregates of gold nanoparticles, using a focused laser beam to optically trap the nanoparticles in suspension. At high laser powers, heat generated from the plasmonic excitation causes boiling of the aqueous suspension and the formation of gaseous bubbles of water vapor. By measuring the Raman peak of the hydroxyl bond of water, the temperature in the laser spot during the aggregation can be determined in situ. The hydrophilic nanoparticles are found to aggregate at the liquid-vapor interface. By allowing the suspension to dry, a ring of gold nanoparticles is deposited on the substrate, producing a highly SERS-active region. These aggregates are studied using optical microscopy, scanning electron microscopy and micro-Raman spectroscopy. PMID- 20160340 TI - The fabrication of mono-domain highly ordered nanoporous alumina on a wafer scale by a guided electric field. AB - This paper describes the formation of mono-domain highly ordered nanoporous alumina on the scale of a 2 inch diameter silicon wafer by anodization of aluminium evaporated on a patterned SiO(2) mask on a silicon substrate. The position of the ordered pores correlates with holes in the SiO(2) mask, which guide the electric field during anodization and initiates pore nucleation. The technique is suitable for the production of ordered nanoporous alumina on a wafer scale and overcomes the time, cost and scale limitations of existing processes. PMID- 20160341 TI - Growth and morphology control of carbon nanotubes at the apexes of pyramidal silicon tips. AB - We describe the development of catalysed chemical vapour deposition (cCVD) growth schemes suitable for the production of carbon nanotube atomic force microscopy (CNT-AFM) probes. Growth and sample processing conditions are utilized that both incorporate safety in the process, e.g. the use of ethanol (EtOH) vapour as a carbon feedstock and hydrogen at only 4% (flow proportion), and simplicity, e.g. no catalyst patterning is required. Cobalt is employed as the growth catalyst and thin films of aluminium on silicon as the substrate material. Purpose-fabricated silicon substrates containing large numbers of tip structures are used as models of AFM probes. This enables growth to be carried out on many tips at once, facilitating a thorough investigation of the effect of different growth schemes on yields. cCVD growth schemes are chosen which produce stabilizing high density networks of carbon nanotubes on the sidewalls of the pyramidal tips to aid in anchoring the apex protruding carbon nanotube(s) in place. This results in long lasting AFM imaging tips. We demonstrate that through rational tailoring of cCVD conditions it is possible to tune the growth conditions such that CNTs which protrude straight from tip apexes can be obtained at yields of greater than or equal to 78%. Application of suitable growth schemes to CNT growth on commercially available AFM probes resulted in CNT-AFM probes which were found to be extremely useful for extended lifetime metrological profiling of complex structures. PMID- 20160342 TI - Stereospecific growth of densely populated rutile mesoporous TiO2 nanoplate films: a facile low temperature chemical synthesis approach. AB - We report for the first time, using a simple and environmentally benign chemical method, the low temperature synthesis of densely populated upright-standing rutile TiO(2) nanoplate films onto a glass substrate from a mixture of titanium trichloride, hydrogen peroxide and thiourea in triply distilled water. The rutile TiO(2) nanoplate films (the phase is confirmed from x-ray diffraction analysis, selected area electron diffraction, energy-dispersive x-ray analysis, and Raman shift) are 20-35 nm wide and 100-120 nm long. The chemical reaction kinetics for the growth of these upright-standing TiO(2) nanoplate films is also interpreted. Films of TiO(2) nanoplates are optically transparent in the visible region with a sharp absorption edge close to 350 nm, confirming an indirect band gap energy of 3.12 eV. The Brunauer-Emmet-Teller surface area, Barret-Joyner-Halenda pore volume and pore diameter, obtained from N(2) physisorption studies, are 82 m(2) g(-1), 0.0964 cm(3) g(-1) and 3.5 nm, respectively, confirming the mesoporosity of scratched rutile TiO(2) nanoplate powder that would be ideal for the direct fabrication of nanoscaled devices including upcoming dye-sensitized solar cells and gas sensors. PMID- 20160343 TI - An experimental study on ferromagnetic nickel nanowires functionalized with antibodies for cell separation. AB - In this paper, a cell separation technique has been explored using antibody functionalized Ni nanowires. An antibody (anti-CD31) against mouse endothelial cells (MS1) was conjugated to the Ni nanowire surface through self-assembled monolayers (SAMs) and chemical covalent reactions. The measured cytotoxicity was negligible on the CD-31 antibody-functionalized nanowires by the tetrazolium salt (MTT) assay. The use of functionalized nanowires for magnetically separating MS1 cells revealed that the cell separation yield was closely related to cell concentration and the nanowire/cell ratio. Cell separation yield using functionalized Ni nanowires was compared with that using commercial magnetic beads. Considering the volume difference of the material used between the beads and nanowires, antibody-functionalized nanowires showed an obvious advantage in cell separation. Further study on the effect of Ni nanowires on MS1 cells for extended culture confirmed that cell morphology remained comparable to control cells with a lower proliferation rate. This work demonstrates that antibody functionalized Ni nanowires provide an effective means to separate target cells. PMID- 20160344 TI - On the utility of vacancies and tensile strain-induced quality factor enhancement for mass sensing using graphene monolayers. AB - We have utilized classical molecular dynamics to investigate the mass sensing potential of graphene monolayers, using gold as the model adsorbed atom. In doing so, we report two key findings. First, we find that while perfect graphene monolayers are effective mass sensors at very low (T < 10 K) temperatures, their mass sensing capability is lost at higher temperatures due to diffusion of the adsorbed atom at elevated temperatures. We demonstrate that even if the quality (Q) factors are significantly elevated through the application of tensile mechanical strain, the mass sensing resolution is still lost at elevated temperatures, which demonstrates that high Q-factors alone are insufficient to ensure the mass sensing capability of graphene. Second, we find that while the introduction of single vacancies into the graphene monolayer prevents the diffusion of the adsorbed atom, the mass sensing resolution is still lost at higher temperatures, again due to Q-factor degradation. We finally demonstrate that if the Q-factors of the graphene monolayers with single vacancies are kept acceptably high through the application of tensile strain, then the high Q factors, in conjunction with the single atom vacancies to stop the diffusion of the adsorbed atom, enable graphene to maintain its mass sensing capability across a range of technologically relevant operating temperatures. PMID- 20160345 TI - Elastic behaviour of a nanocomposite thin film undergoing significant strains. AB - For nearly a century, dielectric materials have been used to produce thin film filters capable of precisely modifying electromagnetic wave interactions at material boundaries. Minimizing visible reflections from optical elements is the most mature use of these techniques, but modern applications often require advanced filters that operate in the ultraviolet or infrared regions. Vapour deposition is the dominant coating technology used to produce these filters, but sol-gel processes have also gained a footing. These methods have been used to create organic/inorganic hybrids that can theoretically withstand larger strains than a purely inorganic metal oxide, but demonstrations of thin film filters with strain properties similar to pure polymers have been sorely lacking. A homogeneous composite featuring inorganic nanoparticles in a polymer matrix is capable of very high strains without failure. We demonstrate such a system here with a 38-layer nanocomposite filter that is subjected to 20% strain with simultaneous evaluation of optical performance. The filter's reflectance peak shifts toward the shorter wavelengths as film thickness decreases in response to the strain, but the peak intensity of the reflected light does not substantially change. These results suggest that the nanocomposite layers are behaving as homogeneous materials with consistent optical parameters throughout the test. PMID- 20160346 TI - Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans. AB - Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. NF1 patients display diverse clinical manifestations, including vascular disease, which results from neointima formation and vessel occlusion. However, the pathogenesis of NF1 vascular disease remains unclear. Vessel wall homeostasis is maintained by complex interactions between vascular and bone marrow-derived cells (BMDCs), and neurofibromin regulates the function of each cell type. Therefore, utilizing cre/lox techniques and hematopoietic stem cell transplantation to delete 1 allele of Nf1 in endothelial cells, vascular smooth muscle cells, and BMDCs alone, we determined which cell lineage is critical for neointima formation in vivo in mice. Here we demonstrate that heterozygous inactivation of Nf1 in BMDCs alone was necessary and sufficient for neointima formation after vascular injury and provide evidence of vascular inflammation in Nf1+/- mice. Further, analysis of peripheral blood from NF1 patients without overt vascular disease revealed increased concentrations of inflammatory cells and cytokines previously linked to vascular inflammation and vasoocclusive disease. These data provide genetic and cellular evidence of vascular inflammation in NF1 patients and Nf1+/- mice and provide a framework for understanding the pathogenesis of NF1 vasculopathy and potential therapeutic and diagnostic interventions. PMID- 20160347 TI - Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice. AB - The receptor tyrosine kinase ret protooncogene (RET) is implicated in the pathogenesis of several diseases and in several developmental defects, particularly those in neural crest-derived structures and the genitourinary system. In order to further elucidate RET-mediated mechanisms that contribute to these diseases and decipher the basis for specificity in the pleiotropic effects of RET, we characterized development of the enteric and autonomic nervous systems in mice expressing RET9 or RET51 isoforms harboring mutations in tyrosine residues that act as docking sites for the adaptors Plcgamma, Src, Shc, and Grb2. Using this approach, we found that development of the genitourinary system and the enteric and autonomic nervous systems is dependent on distinct RET-stimulated signaling pathways. Thus, mutation of RET51 at Y1062, a docking site for multiple adaptor proteins including Shc, caused distal colon aganglionosis reminiscent of Hirschsprung disease (HSCR). On the other hand, this mutation in RET9, which encodes an isoform that lacks the Grb2 docking site present in RET51, produced severe abnormalities in multiple organs. Mutations that abrogate RET-Plcgamma binding, previously shown to produce features reminiscent of congenital anomalies of kidneys or urinary tract (CAKUT) syndrome, produced only minor abnormalities in the nervous system. Abrogating RET51-Src binding produced no major defects in these systems. These studies provide insight into the basis of organotypic specificity and redundancy in RET signaling within these unique systems and in diseases such as HSCR and CAKUT. PMID- 20160348 TI - Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis. AB - Tropomyosin-related kinase receptor C (TrkC) is a neurotrophin receptor with tyrosine kinase activity that was expected to be oncogenic. However, it has several characteristics of a tumor suppressor: its expression in tumors has often been associated with good prognosis; and it was recently demonstrated to be a dependence receptor, transducing different positive signals in the presence of ligand but inducing apoptosis in the absence of ligand. Here we show that the TrkC ligand neurotrophin-3 (NT-3) is upregulated in a large fraction of aggressive human neuroblastomas (NBs) and that it blocks TrkC-induced apoptosis of human NB cell lines, consistent with the idea that TrkC is a dependence receptor. Functionally, both siRNA knockdown of NT-3 expression and incubation with a TrkC-specific blocking antibody triggered apoptosis in human NB cell lines. Importantly, disruption of the NT-3 autocrine loop in malignant human neuroblasts triggered in vitro NB cell death and inhibited tumor growth and metastasis in both a chick and a mouse xenograft model. Thus, we believe that our data suggest that NT-3/TrkC disruption is a putative alternative targeted therapeutic strategy for the treatment of NB. PMID- 20160349 TI - Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients. AB - Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis showed that sera from narcolepsy patients with cataplexy had higher Trib2-specific antibody titers compared with either normal controls or patients with idiopathic hypersomnia, multiple sclerosis, or other inflammatory neurological disorders. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2-3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. High Trib2 specific antibody titers correlated with the severity of cataplexy. Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus. Thus, we have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder. PMID- 20160351 TI - Urolithiasis and hepatotoxicity are linked to the anion transporter Sat1 in mice. AB - Urolithiasis, a condition in which stones are present in the urinary system, including the kidneys and bladder, is a poorly understood yet common disorder worldwide that leads to significant health care costs, morbidity, and work loss. Acetaminophen-induced liver damage is a major cause of death in patients with acute liver failure. Kidney and urinary stones and liver toxicity are disturbances linked to alterations in oxalate and sulfate homeostasis, respectively. The sulfate anion transporter-1 (Sat1; also known as Slc26a1) mediates epithelial transport of oxalate and sulfate, and its localization in the kidney, liver, and intestine suggests that it may play a role in oxalate and sulfate homeostasis. To determine the physiological roles of Sat1, we created Sat1-/- mice by gene disruption. These mice exhibited hyperoxaluria with hyperoxalemia, nephrocalcinosis, and calcium oxalate stones in their renal tubules and bladder. Sat1-/- mice also displayed hypersulfaturia, hyposulfatemia, and enhanced acetaminophen-induced liver toxicity. These data suggest that Sat1 regulates both oxalate and sulfate homeostasis and may be critical to the development of calcium oxalate urolithiasis and hepatotoxicity. PMID- 20160353 TI - From 3D to 5D radiotherapy: a blitzkrieg of DTH! PMID- 20160350 TI - PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice. AB - Protein tyrosine phosphatase 1B (PTP1B) and SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) have been shown in mice to regulate metabolism via the central nervous system, but the specific neurons mediating these effects are unknown. Here, we have shown that proopiomelanocortin (POMC) neuron-specific deficiency in PTP1B or SHP2 in mice results in reciprocal effects on weight gain, adiposity, and energy balance induced by high-fat diet. Mice with POMC neuron specific deletion of the gene encoding PTP1B (referred to herein as POMC-Ptp1b-/- mice) had reduced adiposity, improved leptin sensitivity, and increased energy expenditure compared with wild-type mice, whereas mice with POMC neuron-specific deletion of the gene encoding SHP2 (referred to herein as POMC-Shp2-/- mice) had elevated adiposity, decreased leptin sensitivity, and reduced energy expenditure. POMC-Ptp1b-/- mice showed substantially improved glucose homeostasis on a high fat diet, and hyperinsulinemic-euglycemic clamp studies revealed that insulin sensitivity in these mice was improved on a standard chow diet in the absence of any weight difference. In contrast, POMC-Shp2-/- mice displayed impaired glucose tolerance only secondary to their increased weight gain. Interestingly, hypothalamic Pomc mRNA and alpha-melanocyte-stimulating hormone (alphaMSH) peptide levels were markedly reduced in POMC-Shp2-/- mice. These studies implicate PTP1B and SHP2 as important components of POMC neuron regulation of energy balance and point to what we believe to be a novel role for SHP2 in the normal function of the melanocortin system. PMID- 20160352 TI - Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. AB - Wolfram syndrome is an autosomal-recessive disorder characterized by insulin dependent diabetes mellitus, caused by nonautoimmune loss of beta cells, and neurological dysfunctions. We have previously shown that mutations in the Wolfram syndrome 1 (WFS1) gene cause Wolfram syndrome and that WFS1 has a protective function against ER stress. However, it remained to be determined how WFS1 mitigates ER stress. Here we have shown in rodent and human cell lines that WFS1 negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6alpha (ATF6alpha), through the ubiquitin proteasome pathway. WFS1 suppressed expression of ATF6alpha target genes and repressed ATF6alpha-mediated activation of the ER stress response element (ERSE) promoter. Moreover, WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6alpha to the proteasome, and enhanced its ubiquitination and proteasome mediated degradation, leading to suppression of ER stress signaling. Consistent with these data, beta cells from WFS1-deficient mice and lymphocytes from patients with Wolfram syndrome exhibited dysregulated ER stress signaling through upregulation of ATF6alpha and downregulation of HRD1. These results reveal a role for WFS1 in the negative regulation of ER stress signaling and in the pathogenesis of diseases involving chronic, unresolvable ER stress, such as pancreatic beta cell death in diabetes. PMID- 20160354 TI - Surgery for gastric cancer: an evidence-based perspective. AB - Despite a decreasing incidence, stomach cancer is the second leading cause of cancer mortality worldwide. Surgical resection offers the only chance for cure in this aggressive cancer. The surgical management of gastric cancer has witnessed numerous debates in the past decades. These include the extent of lymphadenectomy, extent of surgery, role of laparoscopic gastrectomy, and the impact of high volume of centers, on the outcome of surgery. This review attempts to address these controversies with an evidence-based perspective. A literature search in MEDLINE (www.pubmed.org) has been performed with the relevant key words and corresponding MeSH terms. The search has been limited to English publications on human subjects. A manual search of the bibliographies has also been carried out, to identify the relevant publications for possible inclusion. PMID- 20160355 TI - Is early feeding after major gastrointestinal surgery a fashion or an advance? Evidence-based review of literature. AB - Early enteral nutrition (EN) after major digestive surgery has been receiving increasing attention. Supporting evidence has not been clear. This evidence-based review traces the development of early EN and analyses whether it is indeed an advance. We performed a PubMed search in October 2009 with the key words enteral nutrition, early feeding, and gastrointestinal surgery. Our emphasis was on earliest studies documenting the benefits or adverse effects of EN, comparative studies, documenting the benefits or adverse effects of EN, comparative studies, and randomized controlled trials. Thirty-one results were returned from which 17 were included for evaluation (1979-2009). Fifteen papers concluded that early EN was beneficial. In general, patients put on early EN and immunonutrition postoperatively seemed to have decreased hospital stay, decreased complication rates, decreased treatment and hospital costs, and even decreased morbidity and mortality; however, judicious use has been suggested. One study did not recommend early enteral feeding in well-nourished patients at low risk of nutrition-related complications and another suggested that immunonutrition is not beneficial and should not be used routinely. Early EN has been safely given after major digestive surgery since 1979. It benefits patients undergoing major gastrointestinal (GI) surgeries, with reduction in perioperative infection, better maintainance of nitrogen balance, and shorter hospital stay. Early EN may be superior to total parenteral nutrition (TPN). However, TPN is perhaps better tolerated in the immediate postoperative period. Early enteral immunonutrition should be used only in malnourished and in transfused patients. Early EN after major digestive surgery is an old advance that is now in fashion. PMID- 20160356 TI - Dose optimization of intra-operative high dose rate interstitial brachytherapy implants for soft tissue sarcoma. AB - OBJECTIVE: A three dimensional (3D) image-based dosimetric study to quantitatively compare geometric vs. dose-point optimization in combination with graphical optimization for interstitial brachytherapy of soft tissue sarcoma (STS). MATERIALS AND METHODS: Fifteen consecutive STS patients, treated with intra-operative, interstitial Brachytherapy, were enrolled in this dosimetric study. Treatment plans were generated using dose points situated at the "central plane between the catheters", "between the catheters throughout the implanted volume", at "distances perpendicular to the implant axis" and "on the surface of the target volume" Geometrically optimized plans had dose points defined between the catheters, while dose-point optimized plans had dose points defined at a plane perpendicular to the implant axis and on the target surface. Each plan was graphically optimized and compared using dose volume indices. RESULTS: Target coverage was suboptimal with coverage index (CI = 0.67) when dose points were defined at the central plane while it was superior when the dose points were defined at the target surface (CI=0.93). The coverage of graphically optimized plans (GrO) was similar to non-GrO with dose points defined on surface or perpendicular to the implant axis. A similar pattern was noticed with conformity index (0.61 vs. 0.82). GrO were more conformal and less homogeneous compared to non-GrO. Sum index was superior for dose points defined on the surface of the target and relatively inferior for plans with dose points at other locations (1.35 vs. 1.27). CONCLUSIONS: Optimization with dose points defined away from the implant plane and on target results in superior target coverage with optimal values of other indices. GrO offer better target coverage for implants with non uniform geometry and target volume. PMID- 20160357 TI - Role of nitric oxide and antioxidant enzymes in the pathogenesis of oral cancer. AB - BACKGROUND: Oral cancer is the leading malignancy in India. Nitric oxide and antioxidant enzymes play an important role in etiology of oral cancer. Therefore, the present study evaluates nitric oxide and antioxidant enzyme levels in healthy individual without tobacco habits (NHT, N=30) and healthy individuals with tobacco habits (WHT, n=90), patients with oral precancers (OPC, n=15) and oral cancer patients (n=126). MATERIALS AND METHODS: Blood samples were collected from the subjects. NO2 + NO3 (nitrite+nitrate), superoxide dismutase (SOD) and catalase levels were estimated using highly specific spectrophotometeric methods. Statistical analysis was done by SPSS statistical software version 10. RESULTS: Mean plasma NO2 + NO3 levels were elevated in patients with OPC and oral cancer patients as compared to the controls. Mean activities of erythrocyte SOD and catalase were higher in WHT than NHT. Erythrocyte SOD and catalase levels were higher in WHT and patients with OPC as compared to NHT. The erythrocyte SOD and catalase activities were lower in oral cancer patients than patients with OPC. The erythrocyte SOD activity was higher in advanced oral cancer than the early disease. Erythrocyte catalase activity was lower in poorly differentiated tumors than well and moderately differentiated tumors. Pearson's correlation analysis revealed that alterations in plasma NO2 + NO3 levels were negatively associated with changes in erythrocyte SOD activities. CONCLUSION: The data revealed that the alterations in antioxidant activities were associated with production of nitric oxide in oral cancer, which may have significant role in oral carcinogenesis. PMID- 20160358 TI - Characterization of genetic lesions in apoptosis-regulating and proliferation control genes in diffuse large B-cell non-Hodgkin's lymphoma. AB - BACKGROUND: This study was conducted to analyze the frequency, expression patterns, and the impact of individual proteins BCL2, BCL6, and p53 on overall survival (OS) in adult, diffuse large B-cell lymphoma (DLBCL) patients. BCL2 gene was further investigated for potential alterations at the DNA level and correlated with OS. MATERIALS AND METHODS: A total of 117 adult well characterized DLBCL cases were included. The panel of antibodies comprised CD45, CD20, CD79a, CD3, BCL2, BCL6, and p53. PCR was also employed to correlate the events at the DNA level in BCL2. RESULTS: The mean and median ages were 47.74 and 49 with a M:F ratio of 2.07:1. The incidence of BCL2, BCL6, and p53 expression was observed in 64.10%, 37.60%, and 52.13% of cases, respectively. Amplifiable quality DNA was available from 90 cases. BCL2/IGH translocation was found in 35/90 patients (38.88%) with 24 cases showing BCL2 (MBR)/IGH and 11 cases BCL2 (mcr)/IGH translocation. No association between BCL2 overexpression and BCL2 /IGH translocation was seen. Clinical data were available for 52 patients treated by CHOP therapy. It was found that patients with p53 overexpression had decreased overall survival (P = 0.0004) whereas BCL2, BCL6 expression, and BCL2/IGH translocation had no impact on overall survival. CONCLUSION: Our data suggest that simple p53 protein expression by IHC at the time of diagnosis may help to identify high-risk patients, who may benefit with more aggressive and newer treatments in addition to standard CHOP. PMID- 20160359 TI - Survey of patient dosimetry for head and neck cancer patients undergoing external radiotherapy treatment: a study from northeastern hospitals of India. AB - AIM: To study dosimetry of patients during the external radiotherapy of head and neck cancers from different hospitals of the northeastern region (NER) of India. MATERIALS AND METHODS: 35 confirmed cases of head and neck cancers reporting to three different hospitals in the NER of India who underwent radiation treatment were the materials for the study. Dosimetry was carried out at 8(eight) anatomical points to these patients, namely, target (entrance and exit points), forehead, chest, abdomen, gonad, arm, and leg respectively by thermoluminescence (TL) as well as optically stimulated luminescence (OSL) dosimeters. Unlike conventional appliances, we used common iodized salt as TL/OSL phosphor. RESULTS: Patient dosimetry was found to vary with an average of 1.17 +/- 0.39 Sv at forehead, 1.24 +/- 0.39 Sv at chest, 0.52 +/- 0.13 Sv at gonad to a minimum of 0.26 +/- 0.07 Sv at leg areas when exposed to a cumulative dose of 65 Sv at the target. CONCLUSION: Maximum dose received from a stray radiation is about 1.5 Sv at forehead/chest and dosimetry of patient among the three centers is not significantly different at the 5% level of probability. PMID- 20160360 TI - Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors. AB - AIM: To study the role of neoadjuvant imatinib mesylate in downsizing tumors in patients with locally advanced nonmetastatic gastrointestinal stromal tumors (GISTs), thus improving the possibility of complete resection. MATERIALS AND METHODS: We used neoadjuvant imatinib in six patients with locally advanced GISTs, at a dose of 400 mg daily, given orally in all patients for a median period of 3.5 months (range 1-20 months). All patients had a computerized tomography scan (CT scan) once before starting the treatment and a repeat CT scan 1 month after starting imatinib. Some patients had another CT scan done at 3 months. The tumor volume was calculated using the formula V=4/3 pir3. RESULTS: Following imatinib therapy, the median reduction in the tumor volume was 40% (range 20-50%). Four of the six patients underwent successful complete resection of the tumor following neoadjuvant imatinib for a median period of 2 months, and are disease free after a median follow-up of 10.5 months (range 3-20 months). Two patients in whom the tumors were deemed to be operable after downsizing refused surgery and are continuing imatinib. Imatinib did not produce serious toxicity in any patient. CONCLUSION: Neoadjuvant imatinib can be used successfully in patients with locally advanced nonmetastatic GISTs to improve the rates of complete resection and reduce the chance of tumor spill. The optimal duration of neoadjuvant treatment needs to be tailored based on response assessment at frequent intervals to identify the ideal window period for surgery. PMID- 20160361 TI - Irinotecan associated with cetuximab given every 2 weeks versus cetuximab weekly in metastatic colorectal cancer. AB - AIM: The aim of the present study was to compare the efficacy and safety of weekly versus an every 2-week administration of cetuximab in association with irinotecan in patients with metastatic colorectal cancer (MCRC). METHODS: We reviewed the clinical records of 50 patients with MCRC who began treatment with cetuximab from February 2004 to January 2007. Two different treatment schedules were used. In the first group (N = 32), cetuximab was given at an initial dose of 400 mg/m2, followed by weekly infusions of 250 mg/m2. In the second group (N = 18), cetuximab was administered every 2 weeks at a dose of 500 mg/m2. The two groups were compared for tumor response, time to progression (TTP), overall survival (OS), and toxicity. RESULTS: All patients had received irinotecan and 5 fluorouracil; a majority had previously received oxaliplatin. Disease control (partial response + stable disease) was achieved in 56.3% of patients receiving weekly cetuximab versus 77.8% in the other group (P = 0.21). The median follow-up for all patients was 34.2 months. TTP (Group 1: 28% vs. Group 2: 18%, P = 0.9356) and OS (Group 1: 75% vs. Group 2: 72%, P = 0.6748) rates at 7 months were similar in the two groups. Skin toxicity was the most relevant adverse event: 78.1% of the patients had acne-like rash in the first group and 61% in the second group. However, only one patient in each group had a grade 3 toxic reaction. CONCLUSION: There is no major difference of efficacy and safety between cetuximab given every 2 weeks and a weekly dosing regimen, in association with irinotecan. PMID- 20160362 TI - Dose escalation in image-guided, intensity-modulated radiotherapy of carcinoma prostate: initial experience in India. AB - BACKGROUND: Increasing incidence and significant stage migration from distant metastases to a localized disease, due to screening application of PSA, is taking place in carcinoma prostate. Also, role of radiotherapy is increasing in carcinoma prostate due to rapid strides in technology. AIM: The present retrospective study, evaluates escalating the dose in the treatment of localized carcinoma prostate using integration of multiple advanced techniques. SETTINGS AND DESIGN: The settings designed are: a) use of gold seed internal fiducial markers: b) clinical application of emerging Megavoltage Cone Beam Computed Tomography (MVCBCT) technology for Image Guided Radiotherapy (IGRT); c) Intensity Modulated Radiotherapy (IMRT); d) adopting biochemical method for follow-up. METHODS AND MATERIAL: Twelve consecutive, biopsy proven localized cancer of prostate patients, treated with dose escalation IMRT & IGRT protocol between August 2006 and January 2008, were analyzed. Gold seed markers in prostate were used for daily localization with MVCBCT or Electronic Portal Imaging (EPI). All patients underwent clinical and biochemical follow-up. STATISTICAL ANALYSIS & RESULTS: Planned dose of 7740 cGy was delivered in 10 out of 12 patients (83%). While one patient had migration of maximum of 3 mm, two others had 1 mm migration of one seed during course of treatment. One patient (8%) developed Grade II proctitis at 12th month. During the mean follow-up duration of 12.2 months, 92% (11/12) had biochemical control within 3 months of treatment. CONCLUSIONS: IGRT technique using MVCBCT for implanted fiducial gold seed localization was feasible for IMRT dose escalation in carcinoma prostate with excellent results. PMID- 20160363 TI - Characterization of metal oxide field-effect transistors for first helical tomotherapy Hi-Art II unit in India. AB - PURPOSE: To characterize metal oxide semiconductor field-effect transistors (MOSFETs) for a 6-MV photon beam with a first helical tomotherapy Hi-Art II unit in India. MATERIALS AND METHODS: Standard sensitivity MOSFETs were first calibrated and then characterized for reproducibility, field size dependence, angular dependence, fade effects, and temperature dependence. The detector sensitivity was estimated for static as well as rotational modes for three jaw settings (1.0 cm x 40 cm, 2.5 cm x 40 cm, and 5 cm x 40 cm) at 1.5-cm depth with a source-to-axis distance (SAD) of 85 cm in virtual water slabs. The A1SL ion chamber and thermoluminescence dosimeters (TLDs) were used to compare the results. RESULTS: No significant difference was found in the detector sensitivity for static and rotational procedures. The average detector sensitivity for static procedures was 1.10 mV/cGy (SD 0.02) while it was 1.12 mV/cGy (SD 0.02) for rotational procedures. The average detector sensitivity found was the same within the experimental uncertainty for static and rotational dose deliveries. The MOSFET reading was consistent and its reproducibility was excellent (+0.5%) while there was no significant dependence of field size. The angular dependence of less than 1.0% was observed. There was negligible fading effect of the MOSFET. The MOSFET response was found independent of temperature in the range 18 degrees-30 degrees. The ion chamber readings were assumed to be a reference for the estimation of the MOSFET calibration factor. The ion chamber and the TLD were in good agreement (+2%) with each other. CONCLUSION: This study deals only with the measurements and calibration performed on the surface of the phantom. MOSFET was calibrated and validated for phantom surface measurements for a 6-MV photon beam generated by a tomotherapy machine. The sensitivity of the detector was the same for both modes of treatment delivery with tomotherapy. The performance of the MOSFET was validated for and satisfactory for the helical tomotherapy Hi-Art II unit. However, MOSFET may be used for in vivo surface dosimetry only after it is calibrated under the conditions replicating as much as possible the manner in which the dosimeter will be used clinically. PMID- 20160364 TI - Spinal epidermoid cyst with sudden onset of paraplegia. AB - Spinal epidermoid cysts, whether congenital or iatrogenic, are relatively uncommon in the spinal cord. When they occur, the typical location is in the subdural, extramedullary space of the lumbo-sacral region. We describe an unusual presentation in a 3-year-old male child which mimicked astrocytoma clinicoradiologically. The child developed sudden onset of inability in walking and weakness of both lower limbs after a fall. There was a dramatic reversal of symptoms after surgery. Histopathology revealed an epidermoid cyst of the spine. On the first follow-up visit at 3 months, the child was asymptomatic. PMID- 20160365 TI - Three distinct co-existent primary brain tumors in a patient. AB - A rare case of simultaneous occurrence of three entirely distinct intracranial tumors is described. A 55-year-old male with no evidence of phacomatoses or history of radiation therapy presented with complaints of increased drowsiness, headaches, and dysarthria. Investigations revealed an olfactory groove meningioma, a glioblastoma multiforme in the left medial temporal lobe, and a diffuse glioma in the brain stem. Occurrence of multiple varieties of tumors at the same time is extremely rare. Theories that explain their occurrences including the role of common carcinogens, autocrine growth factors, and tumor suppressor genes are discussed. PMID- 20160366 TI - Pulmonary and nodal multiple myeloma with a pleural effusion mimicking bronchogenic carcinoma. AB - Multiple myeloma (MM) is a hematological malignancy characterized by the occurrence of plasma cell tumor within the bone marrow. Extramedullary plasmacytomas form a small percentage of plasma cell tumors, and although 80-90% of extramedullary lesions occur in the head and neck, pulmonary plasmacytomas are found to be a very uncommon clinical entity. Hereby, we describe a case of a patient with pulmonary plasmacytoma, who developed nodal and pulmonary MM with a pleural effusion, the radiological appearance of which mimicked bronchogenic carcinoma. PMID- 20160367 TI - Lymphoepithelioma-like carcinoma of the uterine cervix. AB - Lymphoepithelioma-like carcinoma (LELC) of the uterine cervix is a rare variant of squamous cell carcinoma (SSC). It differs from the usual SSC of the cervix in its morphology and clinical behavior and shows a better prognosis than the more common SSC of the cervix. We report a case of LELC of the cervix, diagnosed on the basis of histopathology in a 42-year-old female who presented with a history of postcoital bleeding. PMID- 20160368 TI - Acute myelogenous leukemia following treatment of invasive cervix carcinoma: a case report and a review of the literature. AB - Second malignancy is one of the late complications of long-term cancer survivors, treated with radiation or chemotherapy. Here is a case report on acute myelogenous leukemia, which developed after 63 months following the completion of treatment with surgery and platinum-based chemoradiation in a patient of carcinoma cervix IB. The above-mentioned second malignancy is one of the late sequelae of platinum-based chemoradiation. This case is reported here for documentation because of its rarity. PMID- 20160369 TI - Budd-Chiari syndrome and heparin-induced thrombocytopenia in polycythemia vera: successful treatment with repeated TIPS and interferon alpha. AB - Polycythemia vera (PV) is a common cause of Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT). The postpartum period is a precipitating cofactor. An additional heparin-induced thrombocytopenia/thrombosis (HIT/T) leads to a life threatening condition in which transjugular intrahepatic portosystemic shunting (TIPS) seems to be the only life-saving procedure. We describe the case of a subacute BCS and PVT in the late postpartum period. The diagnosis was established using CT scan, MRI, and Doppler ultrasonography of abdominal vessels and the laboratory findings were compatible with PV. After a successful creation of TIPS, a HIT/T worsened the hemorrhagic and thrombotic picture. TIPS procedure was successfully repeated and heparin was replaced with Fondaparinux and then vitamin K antagonist. The treatment with interferon alpha-2A, started after the normalization of liver functions, resulted in a complete remission within 6 months. The JAK2 V617F mutation clone remained undetectable after 2 years' follow up. PMID- 20160370 TI - Chordoma with increased prolactin levels (pseudoprolactinoma) mimicking pituitary adenoma: a case report with review of the literature. AB - The article deals with a rare case of chordoma with increased prolactin levels. It could often result in a diagnostic dilemma and problems in differentiating it from a pituitary adenoma. PMID- 20160371 TI - Late-onset hepatic veno-occlusive disease post autologous peripheral stem cell transplantation successfully treated with oral defibrotide. AB - Hepatic veno-occlusive disease (VOD) remains one of the commonest and most serious complications after myeloablative hematopoietic stem cell transplantation (HSCT). Clinical diagnosis of hepatic VOD is based on the finding of the triad of painful hepatomegaly, hyperbilirubinemia, and unexplained fluid retention occurring within 21 days of the transplant. However, the uncommon clinical entity of late-onset VOD can occur even beyond 20 days and should be considered in the differential diagnosis of any liver disease of more than 3 weeks' duration. While mild cases usually resolve spontaneously, severe VOD is associated with a grim prognosis. Defibrotide, a polydisperse mixture of single-stranded oligonucleotide with antithrombotic and fibrinolytic effects on microvascular endothelium, has emerged as an effective and safe therapy for patients with severe VOD. We describe a patient who presented 55 days post transplant with clinical features suggestive of VOD. Upon treatment with oral defibrotide, he showed complete resolution of the VOD. PMID- 20160372 TI - Pleomorphic liposarcoma of the pectoralis major muscle in an elderly man: report of a case and review of literature. AB - Primary liposarcoma of the pectoral major muscle is extremely rare. We report a case of liposarcoma of the pectoral major muscle which was treated with surgical excision and postoperative radiotherapy. A 70-year-old man admitted with left sided painless progressively growing breast mass. Radiological investigation revealed liposarcoma of the pectoralis major muscle. The patient was treated by surgical removal. Pathological diagnosis was pleomorphic liposarcoma. The patient had postoperative radiotherapy and free of disease for 9 months. Surgical excision and postoperative radiotherapy is the most favored treatment strategy. Careful follow-up is mandatory for detecting recurrences. PMID- 20160373 TI - Giant lumbar paraspinal atypical teratoid/rhabdoid tumor in a child. AB - Atypical teratoid/rhabdoid tumor (AT/RT) is a highly aggressive and uncommon tumor of the central nervous system, primarily affecting young children. AT/RT of the paraspinal region with involvement of the spine and spinal cord is extremely rare, with only few case reports in the literature. We report an unusual case of giant lumbar paraspinal AT/RT with intraspinal extension in a previously healthy 18-month-old female child. To the best of our knowledge, this kind of presentation has not been reported previously in the English literature. PMID- 20160374 TI - Rectal carcinoma metastasizing to the breast: a case report and review of literature. AB - Extramammary breast metastases (from non-breast primaries) are rare, constituting only about 2% of all breast metastases, although autopsy studies show that it may occur in up to 6% of cases. Lymphoma, metastatic melanoma, and bronchial carcinoma are the malignancies that account for the majority of breast metastases. Breast metastases from a colorectal carcinoma have been described in only a small number of cases in the literature. We present a case of a 42-year old woman with an incidental finding of a breast lump. She had a history of Dukes C rectal carcinoma for which she had undergone an anterior resection 11 months earlier. The breast deposit was the first clinical indication of relapse. The patient subsequently developed liver and brain metastases and deteriorated rapidly; she died 2 months after presenting with the breast mass. PMID- 20160375 TI - An unusual case of clear cell meningioma. AB - Clear-cell meningioma (CCM) is an uncommon, aggressive variant of meningioma, usually affecting younger females and having predilection for infratentorial locations. We present a rare case of recurrent supratentorial CCM in a 58-year old male. Ten years back, he had an intra-axial tumor in the left occipital lobe, which was managed by surgical excision and radiotherapy. Currently, the patient presented with sudden severe headache along with speech and vision disturbances. Neuroimaging revealed an extra-axial parietooccipital tumor, with intratumoural bleed. Histopathology of both tumors showed features of CCM, immunopositive for epithelial membrane antigen (EMA) and vimentin. This case illustrates multiple unusual features of a rare variant of meningioma in the form of affection of an adult age group, supratentorial location, recurrence, and intratumoral bleed. It also highlights the importance of incorporating immunohistochemistry in the diagnostic workup, to exclude CCM mimics, each having distinctive biological behavior, and prognostic outcome, and warranting different therapeutic protocols. PMID- 20160376 TI - Primary squamous cell carcinoma of the cecum. AB - Primary squamous cell carcinoma (SSC) of cecum is a very rare malignant neoplasm. The first case was reported by Schmidtman in 1919. Here, a well-differentiated, keratinizing SSC of cecum in a 34-year-old male patient is being reported. The neoplasm originated from surface epithelium, and invaded the bowel wall up to subserosal fat space. No predisposing factor was detected. Clinical features were that of an adenocarcinoma of the colon. Postoperative chemotherapy was given for 6 months to eradicate any micrometastasis. The patient is free of disease 2 years after having had the tumor removed. The case is being presented because of its rare occurrence. PMID- 20160377 TI - Accelerated partial breast irradiation technique for whole-breast radiotherapy: a concern. PMID- 20160378 TI - Primary non-Hodgkin lymphoma of the bone. PMID- 20160379 TI - Pulmonary function in workers exposed to tobacco dust. AB - BACKGROUND: Exposure to vegetable dusts is probable in many industrial and agricultural industries. AIM: The aim of this study was to investigate the relation between exposure to tobacco dusts and lung capacities and airflows. MATERIALS AND METHODS: Two hundred thirty-one individuals who were exposed to tobacco dusts in a cigarette-manufacturing company were included in the study. One hundred individuals who were working in the same area but in other industries and were not exposed to harmful dusts were also selected as controls. Spirometry with American Thoracic Society (ATS) standards was performed for both groups. STATISTICAL ANALYSIS: Spirometry results were compared between the two groups using SPSS software by 't' test. RESULTS: The mean age of the exposed and unexposed groups was 36 +/- 7 and 35 +/- 7 years, respectively. Spirometry results showed that lung capacities and airflows in the exposed group were significantly less than those of controls (P< 0.001). Considering relative variation, the highest reduction was seen in peak expiratory flow (PEF), forced expiratory flow (FEF25%) and peak inspiratory flow (PIF). CONCLUSION: The results of this study show that exposure to tobacco dust would decrease lung capacities and airflows during the years. PMID- 20160380 TI - Extent and determinants of cost of road traffic injuries in an Indian city. AB - BACKGROUND: Studies aimed at estimating losses that are incurred as a result of road traffic injuries (RTIs), especially at the family level, are very limited. AIMS: To ascertain the direct and productivity costs of road traffic injuries and their determinants. SETTINGS AND DESIGN: This study was a cross-sectional survey of all the road traffic crashes recorded by traffic police during 2004 in Chandigarh, a modern planned city of north India. MATERIAL AND METHODS: All road traffic crashes recorded by the traffic police during the year 1st January to 31st December 2004 were included in the study. The houses of all the victims were visited. The direct costs included the immediate medical costs (i.e., emergency and hospital care, follow-up care, medicines and appliances, doctor bills, etc.), and nonmedical costs (transportation, property damage cost, etc.). STATISTICAL ANALYSIS: Work productivity and activity questionnaire (WPAI-SHP), the health and labor questionnaire (HLQ) and Human Capital Method were used for estimating the productivity costs. Percentage, mean, standard deviation of the outcome parameters were calculated. RESULTS: Of the 121 crash victims listed, 95 agreed to participate in the study. The net direct costs incurred were Rs. 8,55,644 ($19,991). The vehicle repair costs constituted more than half of such cost. Surgery, which was conducted in 28 cases, constituted 14.5% of the direct costs. The total productivity cost incurred was Rs. 8,06,24,530 ($1,883,750). Costs incurred due to premature mortality constituted over 99% of these productivity losses suffered by society. Lost wages due to the crash constituted less than 1% [Rs. 1,40,230 ($3276)] of the total productivity loss. CONCLUSIONS: Road traffic injuries are a significant financial drag on the society. The productivity costs far outweigh the direct costs. Premature mortality, vehicle damage and medical costs constituted the major share of the cost of RTIs. PMID- 20160381 TI - A probable association of acute dystonia with gemifloxacin administration. AB - Gemifloxacin is a recently introduced fluoroquinolone antibiotic frequently used for its broad spectrum and once-daily dosing. Fluoroquinolones are associated with various neuropsychiatric side effects, such as seizures, insomnia, confusion, lightheadedness, psychosis, paranoia and hallucinations. We report a case of a 36-year-old woman given gemifloxacin for an upper respiratory tract infection who developed acute dystonia on the third day following therapy initiation. The clinical implications are discussed. PMID- 20160382 TI - Aluminum phosphide poisoning. PMID- 20160383 TI - Ragging: a public health problem. PMID- 20160384 TI - Ethics of placebo use. PMID- 20160385 TI - Abating New York City transit noise: a matter of will, not way. AB - From the latter part of the 19th century, when New York City trains began to operate, until the present time, New York City's Transit Authority has received train noise complaints from riders and residents living near its transit system. The growing body of literature demonstrating the adverse effects of noise on physical and mental health raises the question as to whether transit noise is hazardous to the health of New York City's transit riders and residents living near the transit system. Several studies have examined the impacts of the noise of New York's transit system on hearing, health and learning. Despite the Transit Authority's efforts to remedy transit noise in response to complaints, the noise problem has not yet been satisfactorily ameliorated. This paper will suggest how the Transit Authority could employ techniques that could lower the noise levels of its system and benefit the health and welfare of New Yorkers. The recommendations in this paper could also apply to other cities with major transit systems where noise abatement has not been treated seriously. PMID- 20160386 TI - The associations between noise sensitivity, reported physical and mental health, perceived environmental quality, and noise annoyance. AB - One hundred and ninety residents around Frankfurt Airport (46% female; 17-80 years) were interviewed concerning noise annoyance due to transportation noise (aircraft, road traffic), perceived mental and physical health, perceived environmental quality, and noise sensitivity. The aim of the analyses was to test whether noise sensitivity reflects partly general environmental sensitivity and is associated with an elevated susceptibility for the perception of mental and physical health. In this study, the reported physical and mental health variables were not associated with noise exposure but with noise annoyance, and were interpreted to reflect nonspecific codeterminants of annoyance rather than noise effects. Noise sensitivity was found to influence total noise annoyance and aircraft noise annoyance but to a lesser degree annoyance due to road traffic noise. Noise sensitivity was associated with reported physical health, but not with reported mental health. Noise-sensitive persons reported poorer environmental quality in their residential area than less sensitive persons in particular with regard to air traffic (including the facets noise, pollution, and contaminations) and quietness. Other aspects of the perceived quality of the environment were scarcely associated with noise sensitivity. This indicates that noise sensitivity is more specific and a reliable predictor of responses to noise from the dominant source (in this case air traffic) rather than a predictor of the individual perception of the environmental quality in general. PMID- 20160387 TI - Determining the direction of causality between psychological factors and aircraft noise annoyance. AB - In this paper, an attempt is made to establish the direction of causality between a range of psychological factors and aircraft noise annoyance. For this purpose, a panel model was estimated within a structural equation modeling approach. Data were gathered from two surveys conducted in April 2006 and April 2008, respectively, among the same residents living within the 45 Level day-evening night contour of Amsterdam Airport Schiphol, the largest airport in the Netherlands (n=250). A surprising result is that none of the paths from the psychological factors to aircraft noise annoyance were found to be significant. Yet 2 effects were significant the other way around: (1) from 'aircraft noise annoyance' to 'concern about the negative health effects of noise' and (2) from 'aircraft noise annoyance' to 'belief that noise can be prevented.' Hence aircraft noise annoyance measured at time 1 contained information that can effectively explain changes in these 2 variables at time 2, while controlling for their previous values. Secondary results show that (1) aircraft noise annoyance is very stable through time and (2) that changes in aircraft noise annoyance and the identified psychological factors are correlated. PMID- 20160388 TI - A pilot study of sound levels in an Australian adult general intensive care unit. AB - High technology and activity levels in the intensive care unit (ICU) lead to elevated and disturbing sound levels. As noise has been shown to affect the ability of patients to rest and sleep, continuous sound levels are required during sleep investigations. The aim of this pilot study was to develop a robust protocol to measure continuous sound levels for a larger more substantive future study to improve sleep for the ICU patient. A review of published studies of sound levels in intensive care settings revealed sufficient information to develop a study protocol. The study protocol resulted in 10 usable recordings out of 11 attempts to collect pilot data. The mean recording time was 17.49 +/- 4.5 h. Sound levels exceeded recommendations made by the World Health Organization (WHO) for hospitals. The mean equivalent sound level (LAeq) was 56.22 +/- 1.65 dB and LA90 was 46.8 +/- 2.46 dB. The data reveal the requirement for a noise reduction program within this ICU. PMID- 20160389 TI - Occupational exposure in small and medium scale industry with specific reference to heat and noise. AB - This study was undertaken to assess heat and noise exposure and occupational safety practices in small and medium scale casting and forging units (SMEs) of Northern India. We conducted personal interviews of 350 male workers of these units through a comprehensive questionnaire and collected information on heat and noise exposure, use of protective equipment, sweat loss and water intake, working hour. The ambient wet bulb globe temperature (WBGT index) was measured using quest temp 34/36o area heat stress monitor. A-weighted Leq ambient noise was measured using a quest sound level meter "ANSI SI. 43-1997 (R 2002) type-1 model SOUNDPRO SE/DL". We also incorporated OSHA norms for hearing conservation which include - an exchange rate of 5dB(A), criterion level at 90dB(A), criterion time of eight hours, threshold level is equal to 80dB(A), upper limit is equal to 140dB(A) and with F/S response rate. Results of the study revealed that occupational heat exposure in melting, casting, forging and punching sections is high compared to ACGIH/NIOSH norms. Ambience noise in various sections like casting / molding, drop forging, cutting presses, punching, grinding and barreling process was found to be more than 90dB(A). About 95% of the workers suffered speech interference where as high noise annoyance was reported by only 20%. Overall, 68% workers were not using any personal protective equipment (PPE). The study concluded that the proportion of SME workers exposed to high level heat stress and noise (60 - 72 hrs/week) is high. The workers engaged in forging and grinding sections are more prone to noise induced hearing loss (NIHL) at higher frequencies as compared to workers of other sections. It is recommended that there is a strong need to implement the standard of working hours as well as heat stress and noise control measures. PMID- 20160390 TI - Noise induced hearing loss risk assessment in truck drivers. AB - Hearing sense is one of the key elements which may have impact on the driver's task quality. This cross-sectional study investigates the hearing status of 500 truck drivers by pure tone audiometry (AC) in one of the cities in Fars province, Iran. Hearing threshold levels of the subjects were measured in frequencies of 500Hz-8000Hz. Screening and determination of permanent threshold shift (PTS) was the first aim of this study. Hence tests were done at least 16 hours after any exposure to noticeable sound. The effect of age as a confounding factor was considered using ISO equation and subtracted from whole hearing threshold. The threshold of 25 dB HL and above was considered abnormal but the calculation of hearing was also carried out using 0 dB HL as reference. Subjects were categorized into two groups on the basis of working experience and the hearing threshold of 25 dB was considered a boundary of normal hearing sense. The results of Pearson Chi-Square test showed that working experience as an independent variable has significant contributing effect on hearing thresholds of truck drivers in frequencies of 500, 1000, 2000 and 4000 Hz (p greater than 0.05). Also, it was shown that currently nine and 12.6 % of truck drivers suffer from impaired hearing sense in left and right respectively (hearing threshold level greater than 25 dB) in mid frequencies (500, 1000, 2000 Hz) and 45% in high frequencies of both ears (4000 and 8000 Hz). The results indicated that hearing damage of professional drivers was expected to occur sooner at 4000 and 8000 Hz than lower frequencies. Finally it was deduced that the occupational conditions of truck drivers may have bilateral, symmetrical harmful effect on hearing threshold sense in all frequencies mainly in frequency of 4000 Hz, so health surveillance programs such as education and periodic medical examinations are emphasized for pre-diagnosing and prevention of any possible impairment and an urgent need to take up some interventions such as better maintenance of roads, automobile industry efforts to reduce the noise level emission of vehicles and reducing number of working hours per day of drivers are highlighted to improve the harmful working conditions of truck drivers. PMID- 20160391 TI - Dental practice and perilous auditory effect as occupational hazard. PMID- 20160392 TI - Plasma B-type natriuretic peptide level and cardiovascular events in chronic kidney disease in a community-based population. AB - BACKGROUND: Plasma B-type natriuretic peptide (BNP) levels are confounded by renal dysfunction, so this study examined whether plasma BNP might be a reliable biomarker of the onset of cardiovascular (CV) events in a population-based cohort with impaired renal function. METHODS AND RESULTS: Baseline data, including plasma BNP, serum creatinine, and urinary protein levels, were determined in participants from a community-based population. Estimated glomerular filtration rate (eGFR) was calculated, and chronic kidney disease (CKD) was defined as either: eGFR <60 mlxmin(-1)x1.73 m(-2) and/or proteinuria (CKD definition-1) or GFR <60 mlxmin(-1)x1.73 m(-2) (CKD definition-2). The CV endpoint was surveyed prospectively. The cohorts were followed for 5,275 person-years for CKD definition-1, and for 4,350 person-years for CKD definition-2. The CV event-free survival rate in the highest BNP quartile in either CKD definition was the lowest among the quartile groups (P<0.001). In multivariate Cox regression models adjusted by traditional CV risk factors and atrial fibrillation, relative risk (RR) for CV events was significantly higher in the highest BNP quartile compared with the lowest BNP quartile (CKD definition-1, RR 3.51, P<0.01: CKD definition 2, RR 4.67, both P<0.01). CONCLUSIONS: Plasma BNP level provides strong predictive information about the future onset of CV events in CKD subjects selected from the general population. PMID- 20160393 TI - Risk factor analysis of long-term support with left ventricular assist system. AB - BACKGROUND: This study was designed to elucidate the key factors for successful long-term support with a left ventricular assist system (LVAS) in the situation where heart transplantation is rarely available. METHODS AND RESULTS: From 1992 to 2008, 106 patients underwent 121 LVAS implantations at Osaka University Hospital (Toyobo: 77; Novacor: 18; HeartMate: 14; Jarvik2000: 8; EvaHeart: 2; DuraHeart: 2). Risk factors for infection were early on the former implanted period (odds ratio (OR) 3.30), Toyobo (OR 2.25), mechanical right heart support (OR 2.30) and cardiopulmonary bypass time (OR 1.01). Left atrium as the inflow site was the risk factor for cerebrovascular events (OR 2.84). Older age (OR 1.04) and mechanical right heart support (OR 4.70) were risk factors for mortality. Risk factors for requiring mechanical right heart support were preoperative extracorporeal membranous oxygenation support (OR 5.641), serum total bilirubin (OR 1.11) and serum creatinine (OR 2.46). On the basis of the risk analysis for mortality, patients were divided into 2 subgroups (low and high risk) and the respective cumulative survival at 1 year after LVAS implantation was 75.2% and 25.0%. CONCLUSIONS: Appropriate selection of device, patient and the timing of implantation and less invasive operation are important for successful long-term LVAS support. PMID- 20160394 TI - Relationship between renal dysfunction and severity of coronary artery disease in Japanese patients. AB - BACKGROUND: The relationship between renal dysfunction and the severity of coronary artery disease (CAD) was examined. METHODS AND RESULTS: The severity of CAD in 572 patients was graded according to the number of stenotic coronary arteries, and the estimated glomerular filtration rate (eGFR) was monitored for 3 years. Patients were stratified into 3 eGFR groups: normal (>75 ml x min(-1) x 1.73 m(-2)), mild reduction (60-75) and chronic kidney disease (CKD: <60). There were 161 patients in the CKD group. The average number of stenotic coronary arteries was larger in the CKD group than in the other groups (normal vs mild reduction vs CKD =1.35+/-0.07 (SE) vs 1.22+/-0.08 vs 1.69+/-0.08 vessel disease (VD), P<0.001). During the 3-year follow-up, the renal function of 13.8% of the patients worsened. Those who showed more deterioration of eGFR had more severe CAD than those who did not (1.20+/-0.06 vs 1.61+/-0.06 VD, P<0.001). Multivariate analysis revealed that the severity of CAD was independently and significantly associated with the deterioration of eGFR. CONCLUSIONS: Patients with CKD had more severe CAD, which may explain the high rate of cardiovascular events in these patients. Moreover, the prognosis of renal function was poor in patients with severe CAD, and CAD was found to be an independent risk factor for worsening of renal dysfunction. PMID- 20160395 TI - Risks and benefits of an open irrigation tip catheter in intensive radiofrequency catheter ablation in patients with non-paroxysmal atrial fibrillation. AB - BACKGROUND: Although open irrigation tip catheters (OITC) are effective in producing transmural radiofrequency (RF) lesions, they have the potential for fluid overload or excessive tissue damage. METHODS AND RESULTS: The 203 patients with non-paroxysmal atrial fibrillation (NPAF; 85.2% males, 55.2+/-10.6 years old) who underwent RF catheter ablation (RFCA) were analyzed retrospectively. Clinical outcomes and complications were compared between RFCA using OITC (n=92) and that using conventional catheters (CONC; n=111). Both the total procedure time (P<0.01) and fluoroscopic time (P<0.001) were shorter in the OITC group than in the CONC group. Total fluid loading during RFCA with OITC was 3.2+/-0.9L, and the average body weight increase was 1.8+/-1.2 kg. Symptomatic pulmonary edema and/or pleural effusion occurred in 3.3% of patients who had a bigger left atrium (P=0.005), longer duration of ablation procedure (P=0.002), higher post-RFCA serum pro-ANP level (P<0.001), and longer hospitalization (P<0.01). CONCLUSIONS: RFCA for NPAF using OITC results in a shorter procedure time compared with CONC. However, patients with a large left atrium and a large amount of fluid (>4L) infused via the OITC need to be carefully monitored to prevent pulmonary edema or pleural effusion because of fluid overload. PMID- 20160398 TI - Angiotensin converting enzyme D allele is associated with an increased risk of type 2 diabetes: evidence from a meta-analysis. AB - Associations of angiotensin converting enzyme gene (ACE) insertion/deletion (I/D) polymorphism with type 2 diabetes (T2D) have been inconsistent with both positive, null and negative results. We thereby performed a meta-analysis from all English-published reports to examine ACE I/D polymorphism in association with T2D risk. Case-control studies were identified from MEDLINE, EMBASE and Web of Science as of Dec 10, 2009. A total of 14 studies with 1985 patients with T2D and 4602 controls were finally identified. Random-effects model was applied irrespective of between-study heterogeneity. Study quality was assessed in duplicate. Compared with ACE I allele, presence of D allele conferred a significant increased risk for T2D (OR=1.33; 95% CI, 1.10-1.61; p=0.003). This trend was potentiated after comparing homozygotes of D allele with I allele with a 90% increased risk (p=0.0008). Carriers of D allele had a moderate increased risk for T2D compared with the II genotype carriers (OR=1.34; 95% CI, 1.04-1.72; p=0.02), whereas under recessive model this effect was significantly enhanced (OR=1.73; 95% CI, 1.26-2.38; p=0.0008). Subgroup analyses indicated significant association for population-based study design only, as well as among populations from Africa and Europe ancestries rather than from Asia ancestry. No publication bias was observed using the fail-safe number at the level of 0.05. Our results demonstrated that ACE D allele was significantly associated with an increased risk of T2D, and this effect appeared to be additive. Moreover, this association was more prominent for population-based studies and among Africans and Caucasians. PMID- 20160397 TI - Effect of pioglitazone on various parameters of insulin resistance including lipoprotein subclass according to particle size by a gel-permeation high performance liquid chromatography in newly diagnosed patients with type 2 diabetes. AB - Pioglitazone is an insulin-sensitizing agent that has been reported to have anti arteriosclerotic effects. The aim of this study was to obtain a better understanding of the mechanism involved in the insulin sensitizing effect of pioglitazone. A total of 50 newly diagnosed patients with type 2 diabetes were enrolled in this study and divided into two groups, 25 of who were treated with 15 mg/day pioglitazone and 25 with 500 mg/day metformin for 12 weeks. Changes in various parameters of insulin resistance including lipoprotein subclass according to particle size determined by high performance liquid chromatography, as well as glucose metabolism, were monitored to determine the relationship between lipoprotein subclass and other insulin resistance parameters. Both pioglitazone and metformin treatment were associated with significant reductions in hyperglycemia, HOMA-IR and HbA1c levels. Pioglitazone treatment, but not metformin treatment resulted in significant reductions in serum large very low density lipoprotein (VLDL: 44.5-64.0 nm) and increases in serum adiponectin levels (both <0.001). In the pioglitazone group, the change in large VLDL levels correlated positively with changes in HbA1c (r=0.468, P=0.0174), HOMA-IR (r=0.593, P=0.0014), very small LDL (r=0.714, P<0.0001) and net electronegative charged modified-LDL (r=0.412, P=0.0399), and inversely with changes in adiponectin level (r=-0.526, P=0.0061). The results in this study suggest that the hypoglycemic effect of pioglitazone is achieved mainly through improvement of hepatic insulin resistance, and that pioglitazone may have an antiatherosclerotic effect by decreasing serum atherogenic modified-LDL and by increasing adiponectin. PMID- 20160396 TI - Standard-dose statin therapy provides incremental clinical benefits in normocholesterolemic diabetic patients. AB - BACKGROUND: Randomized trials have established statins as an agent for prevention of coronary heart disease (CHD). The purpose of this study was to assess the hypothesis that standard-dose statin therapy has a beneficial effect in normocholesterolemic diabetic patients with CHD. METHODS AND RESULTS: A prospective, randomized, open, blinded-endpoint trial was conducted from 2002 to 2004 at 55 hospitals in Japan to evaluate the effect of statins on subsequent cardiovascular events. A total number of 1,016 CHD patients (301 patients with type 2 diabetes mellitus [DM] and 715 non-DM patients) with serum total cholesterol levels of 180-240 mg/dl were randomly divided into non-statin and statin treatments. Clinical parameters were comparable between DM and non-DM groups. Serum low-density lipoprotein (LDL)-cholesterol levels were equally decreased after statin treatment in the 2 groups. Statin treatment improved prognosis in both the DM and non-DM groups; however, the number needed to treat (NNT) and relative risk reduction (RRR) were remarkable especially in the DM group (NNT=8, RRR=67%) compared with the non-DM group (NNT=30, RRR=24%). CONCLUSIONS: Standard-dose statin therapy provides incremental clinical benefits in DM patients with normal cholesterol levels compared with non-DM patients. The data suggest that DM patients may enjoy the pleiotropic effects of statins, independent of the LDL-cholesterol lowering effects of these agents. PMID- 20160399 TI - PPARbeta/delta regulates the human SIRT1 gene transcription via Sp1. AB - NAD-dependent deacetylase SIRT1 is known to be activated by caloric restriction and is related to longevity. A natural polyphenolic compound resveratrol is also shown to increases SIRT1 activity and extends lifespan. However, the transcriptional regulation of SIRT1 gene has not completely examined in the context of metabolism. Thus, in this study, we characterized the 5' -flanking region of human SIRT1 gene. We first found that representative metabolic hormones and related factors (glucocorticoid, glucagon/cAMP, and insulin) did not show significant effect on SIRT1 gene transcription. PPARalpha and PPARgamma1 without/with their specific ligands did not have significant effect as well. In contrast, expression of PPARbeta/delta (PPARdelta markedly increased the 5' promoter activity of SIRT1 gene, which was further amplified by the addition of GW501516, a selective PPARdelta agonist. Deletion/mutation mapping analyses failed to identify PPAR binding element but revealed the presence of canonical Sp1 binding site, which was conserved among species. The Sp1 site is functional, because Sp1 overexpresson significantly enhanced SIRT1 promoter activity, and the binding of Sp1 to the element was confirmed by EMSA and ChIP assays. Interestingly, specific Sp1 antagonist mithramycin completely abolished the PPARdelta-mediated induction of SIRT1 gene transcription. Altogether, our data suggest the predominant role of PPARdelta in the transcriptional regulation of SIRT1 gene. Furthermore, the effects of PPARdelta seem to be mediated by Sp1. We assume that, in vivo, starvation increases lipolysis-derived free fatty acid and activates PPARdelta and the resultant increase in SIRT1 expression, in addition to the activation by NAD and AMPK, facilitates the deacetylation of a variety of proteins involved in mitochondrial beta-oxidation pathway and cell survival. PMID- 20160400 TI - High incidence of thyroid cancer in focal thyroid incidentaloma detected by 18F fluorodeoxyglucose [corrected] positron emission tomography in relatively young healthy subjects: results of 3-year follow-up. AB - As 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is becoming a common imaging modality, the number of thyroid incidentalomas identified by FDG PET (PET incidentaloma) is increasing. The purpose of this study was to elucidate the risk of cancer in focal thyroid PET incidentaloma in healthy subjects of relatively younger age as well as the usefulness of repeated FDG-PET. The study was conducted with an observation period of three years. A total of 1,501 healthy volunteers (mean age, 43.5+/-9.7 years) underwent the first FDG-PET from August 2003 to July 2004. When focal thyroid PET incidentaloma was found, further diagnostic examination was conducted. When thyroid cancer was suspected, surgical resection was performed with the patient' s agreement. Patients with PET incidentaloma without surgery were offered annual US and FDG-PET and finally FNAB was performed in the fourth year. Focal thyroid PET incidentaloma was observed in 20 subjects. The final diagnoses in 20 subjects were malignant in 11 (ten papillary thyroid carcinoma (PTC) and one thyroid carcinoma showing thymus-like differentiation), indeterminate in one, and benign in eight subjects. Seven patients not treated surgically at the first examination had annual FDG-PET. One patient with PTC showed increasing SUVmax, but another with a benign nodule exhibited a similar increase. Others (one with PTC, one with an indeterminate nodule, and three with benign nodules) exhibited negligible SUVmax changes. When closely examined, focal thyroid PET incidentaloma in relatively young healthy adults has a high probability of malignancy. Repeated FDG-PET to follow up patients with thyroid nodules is ineffective. PMID- 20160401 TI - Challenges and perspectives of occupational health and safety research in nanotechnologies in Europe. PMID- 20160402 TI - Pulmonary toxicity induced by intratracheal instillation of coarse and fine particles of cerium dioxide in male rats. AB - In order to examine the short-, medium- and long-term effects of cerium dioxide particles of different sizes on the lung, 10-wk-old male Wistar rats were administered a physiological saline solution with a suspension of coarse or fine particles of cerium dioxide at 34 mg/kg body weight by a single intratracheal instillation. Lungs were examined with cellular and biochemical analyses of the bronchoalveolar lavage (BAL) fluid and histopathology on different days after the instillation. Geometric mean and geometric standard deviation of the diameter were 3.90 microm +/- 1.93 for the coarse (Ce-C) particles, and 0.20 microm +/- 1.20 for the fine (Ce-F) particles. There were no lesions in the lung in the Ce-C instilled group at any time point after the instillation. The instillation of Ce F particles primarily induced inflammation, granulomas, mobilization and impairment of alveolar macrophages (AMs), and pulmonary alveolar proteinosis, together with very slight degrees of Type II epithelial cell hyperplasia and of collagen deposition. The pulmonary toxicity of Ce-F-instilled rats was found to be markedly enhanced in sharp contrast to that of Ce-C-instilled rats on the basis of equal mass concentration, suggesting clear dependence of the pulmonary toxicity on numbers and sizes of particles. Causative factors for the pulmonary alveolar proteinosis are discussed with reference to the impaired AMs. PMID- 20160403 TI - Job demand and cardiovascular disease risk factor in white-collar workers. AB - This study was conducted to determine whether job demand played a role as a risk factor of cardiovascular diseases by comparing changes of blood pressure, heart rate and rate pressure product (RPP) showing myocardial oxygen consumption (MVO2) according to levels of job demand. This cross-sectional study divided 177 male white-collar workers without a cardiovascular or metabolic disease according to their job demand and analyzed their body composition and results of graded exercise testing. There was no significant difference in height, body weight, body mass index (BMI), waist to hip ratio (WHR) and body fat percentage according to job demand. Maximal oxygen consumption (VO2max) and anaerobic threshold (AT) also did not show a significant difference. However, systolic blood pressures at the seventh and eighth stages over AT during exercise were significantly different and RPP was found to have a significant difference overall according to the job demand (p<0.05). These results meant that job demand affected systolic pressure in physical activities or at exercise intensity over AT and reduced energy efficiency of myocardium during physical activities. The results suggest that high job demand may be a risk factor of cardiovascular diseases. PMID- 20160404 TI - Risk level based management system: a control banding model for occupational health and safety risk management in a highly regulated environment. AB - The Risk Level Based Management System (RLBMS) is an occupational risk management (ORM) model that focuses occupational safety, hygiene, and health (OSHH) resources on the highest risk procedures at work. This article demonstrates the model's simplicity through an implementation within a heavily regulated research institution. The model utilizes control banding strategies with a stratification of four risk levels (RLs) for many commonly performed maintenance and support activities, characterizing risk consistently for comparable tasks. RLBMS creates an auditable tracking of activities, maximizes OSHH professional field time, and standardizes documentation and control commensurate to a given task's RL. Validation of RLs and their exposure control effectiveness is collected in a traditional quantitative collection regime for regulatory auditing. However, qualitative risk assessment methods are also used within this validation process. Participatory approaches are used throughout the RLBMS process. Workers are involved in all phases of building, maintaining, and improving this model. This worker participation also improves the implementation of established controls. PMID- 20160405 TI - Subjective musculoskeletal symptoms in winter and summer among indoor working construction electricians. AB - To evaluate the effects of cold exposure on the musculoskeletal system, two surveys on the subjective musculoskeletal symptoms among male electricians working in the buildings under construction were performed in winter (N=74) and summer seasons (N=83). A self-administered questionnaire was used to collect information on age, occupational career, working habit, present illness, and subjective musculoskeletal symptoms. Mean age, occupational career and daily smoking of the supervisors were significantly higher than those of the other subjects. In general, prevalence rates of stiffness, numbness, pain and Raynaud's phenomenon in the fingers, finger cold sensation, dull movement of the fingers, pain in the wrist, knee joint pain, pain and numbness in the foot and foot cold sensation in winter were significantly higher than those in summer. These results were marked especially in the workers except supervisors. In winter, there were no significant differences in the prevalence rates of subjective musculoskeletal complaints between the supervisors and the other workers. On the other hand, in summer, prevalence of stiffness and pain in the shoulder, stiffness and pain in the neck, dullness and pain in the arm, finger cold sensation, low back dullness and low back pain in the supervisors were significantly higher than those in the other workers. These results suggest that effects of cold on the musculoskeletal symptoms markedly appeared in the workers except supervisors. PMID- 20160406 TI - Risk assessment of lung cancer and asbestosis in workers exposed to asbestos fibers in brake shoe factory in Iran. AB - Chrysotile asbestos fiber, imported from Russia, is used mainly for manufacturing purposes in Iran and related risks in the form of asbestosis and cancer were studied. Occupational exposure of all male workers (61 persons) to asbestos in a brake shoe factory was monitored. Cumulative exposures were determined through multiplication of typical exposure and work history. Risk assessment of exposed workers was estimated by risk criteria recommended by the American Environmental Protection Agency. Measurement of lung function parameters such as forced expiratory volume in one second (FEV(1)), forced volume capacity (FVC) and FEV(1)/FVC of exposed workers were obtained. Unadjusted correlation and adjusted correlation analysis for support of the association between cumulative exposure (fiber/ml-yr) and lung function parameters were used. Exposure of majority of exposed group was far greater than the occupational exposure limits (0.1 fiber/ml) in the range of 0.06-8.06 fiber/ml. Cumulative exposures in the range of 0.02 to 110.77 fiber/ml-yr were obtained. According to the risk criteria stated by ATSDR, risk assessment of workers in term of fibrotic changes was predicted for at least 24.6 percent of the exposed subjects. Again, according to the lung cancer risk criteria stated by EPA, 59 percent of workers will have excess risk. Negative correlation between lung function parameters (FEV(1), FEV(1)/FVC) and cumulative exposures adjusted for age and BMI were significant (p<0.05). PMID- 20160407 TI - Significance of face velocity fluctuation in relation to laboratory fume hood performance. AB - In order to recognize the problems associated with the transport mechanism of containment during the ventilation process of a laboratory fume hood, a transparent, full scale chemical fume hood is constructed for experimental studies. Distributions of mean velocity and velocity fluctuation in the sash plane are measured using a thermal anemometer. Flow patterns and tracer-gas concentration leakages are respectively diagnosed via the laser-assisted flow visualization method and the EN 14175-3 test protocol. The magnitudes of measured velocity fluctuations exhibit a sharp peak along the perimeter of the sash opening. The results of flow visualization verify that the elevated turbulence fluctuations are induced by the boundary-layer separation when the flow passes over the edges of sash perimeter. The tracer gas experiment shows that the regions where high degree containment leakages detected are located along the perimeter of hood aperture. Eleven commercial hoods which are claimed with fine aerodynamic design are further tested for confirmation of these observations. The results show similar correlations. Conclusions thus are made that large-scale vortex structures occurring around the perimeters of hood aperture due to the boundary-layer separation could induce strong turbulence, and therefore enhance dispersion of the hood containment. PMID- 20160408 TI - Quantitative evaluation of the effect of moisture contents of coconut shell activated carbon used for respirators on adsorption capacity for organic vapors. AB - Activated carbon is an elemental material used for hygienic applications, particularly as an adsorbent for harmful gases and vapors. In Japanese industrial and occupational hygiene, activated carbon produced from coconut shell is a traditional and popular adsorbent material due to its excellent adsorption ability and cost advantage. In this research, in order to clarify the effect of the preliminary content of moisture on the adsorption capacity in detail, we prepared several coconut shell activated carbons which were preconditioned by equilibration with moisture at different relative humidities. We measured their adsorption capacities as breakthrough times for 6 kinds of organic vapor, and attempted to determine the relationships between the relative weight increase of water adsorption and the decrease of adsorption capacities of the activated carbon specimens for the organic vapors. The procedure of the quantitative evaluation of the effect of moisture and the results are useful for practical applications of activated carbon, particularly those used as adsorbents in workplaces. PMID- 20160409 TI - Blood lead level and cardiovascular risk factors among bus drivers in Bangkok, Thailand. AB - This study aimed to clarify the role of blood lead level (Pb-B) as one of the cardiovascular risk factors. To evaluate the cardiovascular risk the second derivative finger photoplethysmogram (SDPTG) was used. The subjects comprised of 420 male bus drivers in Thailand. The subjects' age ranged from 20 to 60 yr. Mean age (+/- standard deviation) were 41.6 (+/- 7.7) yr. Mean working years was 8.8 (+/- 6.8) yr. Pb-B ranged from 2.5 to 16.2 microg/dl with the mean Pb-B of 6.3 (+/- 2.2) microg/dl. The mean of aging index of SDPTG (SDPTG-AI) were -0.50 (+/- 0.30). The SDPTG-AI increases with age, Pb-B, smoking and alcohol consumption. There was significant correlation between Pb-B and SDPTG-AI after controlling for age, body mass index and lifestyle factors. These results suggest that Pb-B is possibly an independent cardiovascular risk factor for bus drivers exposed to lower level of lead. PMID- 20160410 TI - Development and validity of the Japanese version of the organizational justice scale. AB - Organizational justice has recently attracted attention as a predictor of employee mental and physical health. However, the lack of a Japanese translation of the original English-language organizational justice scale (OJS) has precluded its application in Japan. The present study aimed to develop Japanese version of the measure of organizational justice. We translated the original questionnaire, which is comprised of 20 items, from English to Japanese. The OJS is made up of four distinct dimensions: procedural, distributive, interpersonal and information justice. A total of 229 employees responded to the Japanese version of the OJS (OJS-J), the effort-reward imbalance (ERI) model and the Kessler Psychological Distress Scale (K10). To assess construct validity, we recorded job satisfaction using the visual analog scale (VAS). Our exploratory factor analysis supported the four-factor structure model of OJS-J. Correlation coefficients between the OJS-J and ERI, K10 and VAS were statistically significant, indicating a reasonable degree of construct validity. Obtained internal consistency was markedly high (Cronbach's alpha was 0.96), and test-retest reliability as analyzed with an intraclass correlation coefficient was 0.91. These results suggest that the OJS-J is a reliable and valid measure that may be suitable for use as a predictor of employee health in the Japanese work place. PMID- 20160411 TI - Perceived demands and musculoskeletal disorders in operating room nurses of Shiraz city hospitals. AB - Excessive demands on Operation Room (OR) nurses may result in high rates of Musculoskeletal Disorders (MSDs). This study was conducted among Shiraz city hospital OR nurses to determine the prevalence of MSDs and to examine the relationship between perceived demands and reported MSDs. In this cross-sectional study, 375 OR nurses participated (response rate: 80%). The Nordic Musculoskeletal Disorders Questionnaire and the Job Content Questionnaire were used as collecting data tools. Lower back symptoms were found to be the most prevalent problem in the OR nurses studied with a past year prevalence of 60.6%. Perceived physical demands were significantly associated with musculoskeletal symptoms (odds ratio ranged from 2.04 to 7.24). Manual material handling (MMH) activities were most frequently associated with reported symptoms. Association was also found between perceived psychological demands and reported symptoms (odds ratio>1.68). Based on the findings of this study, it could be concluded that operation room was not only a physically but also psychologically demanding environment. Any interventional program for preventing or reducing MSDs among OR nurses had to focus on reducing physical demands, particularly excessive MMH demands as well as considering psychological aspect of working environment. PMID- 20160412 TI - Hospital safety climate, psychosocial risk factors and needlestick injuries in Japan. AB - To investigate the interactions between safety climate, psychosocial issues and Needlestick and Sharps Injuries (NSI), a cross-sectional study was undertaken among nurses at a university teaching hospital in Japan (89% response rate). NSI were correlated with various aspects of hospital safety climate including supporting one another at work, the protection of staff against blood-borne diseases being a high management priority, managers doing their part to protect staff from blood-borne disease, having unsafe work practices corrected by supervisors, having the opportunity to use safety equipment to protect against blood-borne disease exposures, having an uncluttered work area, and having minimal conflict within their department. In conclusion, this study has demonstrated the importance of hospital safety climate in Japanese health care practice, particularly its relationship with NSI. Although the provision of safer devices remains critical in preventing injuries, ensuring a positive safety climate will also be essential in meeting these important challenges for nurses' occupational health. PMID- 20160413 TI - Role of peroxisome proliferator-activated receptor-alpha in hepatobiliary injury induced by ammonium perfluorooctanoate in mouse liver. AB - Peroxisome proliferator-activated receptor-alpha (PPARalpha) has been suggested to protect against chemically induced hepatobiliary injuries in rodents. This function could mask the potential toxicities of perfluorooctanoic acid (PFOA) that is an emerging environmental contaminant and a weak ligand of PPARalpha. However its function has not been clarified. In this study, PFOA was found to elicit hepatocyte and bile duct injuries in Pparalpha-null mice after 4 wk treatment with PFOA ammonium salt (0, 12.5, 25, 50 micromol/kg/d, gavage). In wild-type mice, PFOA caused major hepatocellular damage dose-dependently and minor cholangiopathy observed only at 25 and 50 micromol/kg. In treated Pparalpha null mice, PFOA produced marked fat accumulation, severe cholangiopathy, hepatocellular damage and apoptotic cells especially in bile ducts. Oxidative stress was also increased 4-fold at 50 micromol/kg and TNF-alpha mRNA was upregulated more than 3-fold at 25 micromol/kg in Pparalpha-null mice. Biliary bile acid/phospholipid ratios were higher in Pparalpha-null mice than in wild type mice. Results from these studies suggest that PPARalpha is protective against PFOA and have a critical role in drug induced hepatobiliary injury. PMID- 20160414 TI - Effects of wrist-extension orthosis on shoulder and scapular muscle activities during simulated assembly tasks. AB - The purpose of this study was to observe changes in electromyographic activity appeared in shoulder and scapular muscles when one wears no wrist extension orthosis, short wrist extension orthosis and long wrist extension orthosis when performing two model assembling operations. The study subjects were 16 adults who use right hand and did not have any functional disorder on their wrist or the upper limbs without any orthopedic surgery. The study subjects were asked to do the two model assembling operations without wrist extension orthosis, with a short wrist extension orthosis and with a long wrist extension orthosis. As a result of repetitive assembling operation that requires shoulder movement, electromyographic activity in upper trapezius and serratus anterior increased significantly when the subjects wore the short and long wrist extension orthoses compared to none. When the subjects performed repetitive assembling operation that requires shoulder stability, electromyographic activity in upper trapezius, lower trapezius, serratus anterior, and anterior deltoid showed significant increase when they wore the short and long wrist extension orthoses compared to none. Especially, the upper trapezius showed significantly high electromyographic activity when they wore the long wrist extension orthosis compared to a short one. PMID- 20160415 TI - The effect of hydroxylated polychlorinated biphenyl (OH-PCB) on thyroid hormone receptor (TR)-mediated transcription through native-thyroid hormone response element (TRE). AB - Polychlorinated biphenyls (PCBs) are known as environmental contaminants that may cause abnormal effect in various organs. We have previously reported that low dose of hydroxylated PCBs (OH-PCBs) including 4'-OH-2',3,3',4',5'-pentachloro biphenyl (4'-OH-PCB 106), suppressed thyroid hormone (TH) receptor (TR)-mediated transcription on several artificial TH-response elements (TREs) due to partial dissociation of TR from TRE. In the present study, we examined the effect of OH PCB on TR-mediated transcription on native TRE-containing promoter, using malic enzyme (ME)-TRE. Transcriptional activity was measured by transient transfection based reporter gene assay in CV-1, fibroblast-derived clonal cells. TR-mediated transcription was suppressed by 4'-OH-PCB106 significantly and 4'-OH-PCB187 weakly, but not by 4'-OH-PCB165. To examine TR-TRE bindings under exposure of 4' OH-PCB106, electrophoretic mobility shift assay (EMSA) was performed. In EMSA, TR was dissociated from ME-TRE by 4'-OH-PCB106. These findings suggest that OH-PCB may disrupt TR-mediated transcription on native promoter. PMID- 20160416 TI - Acute expanded perlite exposure with persistent reactive airway dysfunction syndrome. AB - Expanded perlite has been assumed as simple nuisance, however during an accidental spill out in Taiwan, among 24 exposed workers followed for more than 6 months, three developed persisted respiratory symptoms and positive provocation tests were compatible with reactive airway dysfunction syndrome. During simulation experiment expanded perlite is shown to be very dusty and greatly exceed current exposure permission level. Review of literature and evidence, though exposure of expanded perlite below permission level may be generally safe, precautionary protection of short term heavy exposure is warranted. PMID- 20160417 TI - Exposure to human waste from spills while servicing aircraft lavatories: hazards and methods of prevention. AB - Workers service the lavatories of commercial aircraft approximately 11 million times per year in the United States and may have exposure to the spectrum of pathogenic viruses, bacteria and parasites potentially found in human waste. An industrial hygiene walk-through of the workplace was conducted by an interdisciplinary occupational health and safety team, and lavatory waste operators and supervisors and the process was observed. Exposure to untreated waste can occur through dermal, ingestion, and inhalation in quantities ranging from droplets to large spills. Several engineering and administrative measures were advised to minimize worker exposure, including the effective locking of a critical valve, and a mechanism for communicating valve locking problems. PMID- 20160418 TI - Development and characterization of a strain of Babesia gibsoni resistant to diminazene aceturate in vitro. AB - We attempted to develop a strain of Babesia gibsoni resistant to diminazene aceturate (DA), an anti-babesial drug, in vitro. Since the DA-sensitive B. gibsoni strain could survive and proliferate in culture medium containing 1 ng/m l DA, the concentration of DA was gradually increased from 1 to 200 ng/ml. The results showed that the parasites could survive and proliferate in the medium containing 200 ng/m l DA, which was much higher than the 50% inhibitory concentration (IC(50)) of DA for B. gibsoni. Subsequently, these parasites were removed from erythrocytes and exposed directly to 200 ng/ml DA. They were able to survive and invade fresh erythrocytes, though the DA-sensitive B. gibsoni strain did not survive. Based on these results, the parasites cultured within 200 ng/ml DA were determined to be a DA-resistant B. gibsoni strain. In addition, the IC(50) levels of clindamycin, doxycycline and pentamidine for the DA-resistant B. gibsoni strain were determined. The IC(50) levels of clindamycin, doxycycline and pentamidine for the DA-resistant strain were higher than those for the DA sensitive strain. The IC(50) of pentamidine for the resistant strain was much greater than that for the DA-sensitive strain. These results indicated that the DA-resistant B. gibsoni strain could have resistance not only to DA, but also to other anti-babesial drugs. In conclusion, we successfully developed a DA resistant B. gibsoni strain in vitro. PMID- 20160419 TI - Oral administration of paramylon, a beta-1,3-D-glucan isolated from Euglena gracilis Z inhibits development of atopic dermatitis-like skin lesions in NC/Nga mice. AB - Paramylon is a beta-1,3-D-glucan isolated from Euglena gracilis Z. This study was designed to evaluate the suppressive effects of the oral administration of paramylon on the development of atopic dermatitis (AD)-like skin lesions induced by repeated application of 2,4,6-trinitrochlorobenzene (TNCB) in sensitized NC/Nga mice. The effects of paramylon were assessed by measuring macroscopical and histopathological findings of skin, ear swelling, serum levels of total IgE, interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) and IL-18 and IL-12 contents in the skin lesions. Oral administration of paramylon inhibited the development of AD-like skin lesions as exemplified by a significant decrease in dermatitis scores for the back, ear swelling and hypertrophy of the skin, infiltration of inflammatory cells in the skin, and serum IgE levels. Oral administration of paramylon reduced serum levels of both IL-4 and IFN-gamma and IL-18 and IL-12 contents in the skin lesions. Oral administration of paramylon did not cause weight loss, as was observed with prednisolone. These results suggest that paramylon inhibits the development of AD-like skin lesions in NC/Nga mice by suppressing both the T-helper (Th) 1 and Th 2 cell responses. Our results indicate that paramylon treatment could provide an effective alternative therapy for the management of AD. PMID- 20160420 TI - Detection of equine rotavirus by reverse transcription loop-mediated isothermal amplification (RT-LAMP). AB - Reverse transcription loop-mediated isothermal amplification (RT-LAMP) was applied to detection of equine rotavirus. Because equine rotavirus of the single P genotype, P[12], is predominant in the equine population worldwide, an RT-LAMP primer set was designed to target the genotype P[12] sequence and thus detect equine rotavirus. The detection limit of the RT-LAMP assay was 10(3) copies of viral RNA, whereas that of semi-nested RT-PCR for genotype P[12] was 10(5) copies. The RT-LAMP assay specifically amplified genotype P[12] but did not amplify the other P genotype strains. The RT-LAMP assay did not amplify any pathogens related to equine intestinal disorder other than rotavirus. Using 96 diarrheal stools, the RT-LAMP assay detected equine rotavirus in 58 samples, whereas semi-nested RT-PCR only detected equine rotavirus in 25 samples. The RT LAMP assay did not detect equine rotavirus with fecal samples collected from nine healthy foals. These results indicate that the RT-LAMP assay is specific for equine rotavirus and more sensitive than semi-nested RT-PCR. Because it is easy to manipulate without the need for a thermal cycler or gel electrophoresis, the RT-LAMP assay should be applicable to diagnosis of equine rotavirus infections in diagnostic laboratories. PMID- 20160421 TI - Road transportation stress promptly increases bovine peripheral blood absolute NK cell counts and cortisol levels. AB - Livestock transportation effects on the number of circulating leukocytes have been reported. However, data related specifically to the relation between acute stress levels during transport and leukocyte differentiation, including lymphocyte subsets, are lacking. This study was undertaken to evaluate the distribution of peripheral blood leukocyte differential counts, CD25+ lymphocytes and NK cells in calves subjected to truck transportation on different road types. Healthy Japanese Black calves were divided into three treatments: 1) those moved around in a mountainous area (Group M); 2) those moved around on flatland (Group F); and 3) those that were not transported (control). The plasma cortisol levels in Group M increased during transport. The increase was significantly higher at the end of transport than in the controls (P<0.05); a slight increase was noted in Group F. Total leukocytes and the neutrophil to lymphocyte ratio in Group M were elevated with neutrophilia at 2 hr post-transport (P<0.05); the former levels remained higher than those in the controls for 4 hr. The numbers of lymphocytes, monocytes, eosinophils and CD25+ lymphocytes remained unchanged throughout the observations. The number of circulating NK cells in Group M increased during transport and peaked shortly after transport (P<0.05). Subsequent to these time points, the counts in Group F showed a trend toward elevation. The circulating NK cell counts were positively correlated with the plasma cortisol level during transport (M, r=0.755, P<0.0005; F, r=0.653; P<0.005). These results suggest that circulating NK cells might be more rapidly mobilized than other leukocytes. Therefore, they might reflect acute stress levels in calves during road transportation. PMID- 20160422 TI - Ortho-phthalaldehyde exposure levels among endoscope disinfection workers. AB - OBJECTIVES AND METHODS: Recently, the use of ortho-phthalaldehyde (OPA) has been increasing as an alternative to glutaraldehyde for endoscope disinfection. To better understand OPA exposure and its health effects among disinfection workers, we conducted environmental monitoring and administered a questionnaire in 17 endoscope disinfection rooms. There were 9 manual disinfection rooms using immersion vats for scope disinfection and 8 automatic rooms using automatic washers. RESULTS: OPA exposure concentration during the disinfection process of scope was significantly higher in the manual group (median: 1.43ppb, range: not detected (ND-5.37ppb) than in the automatic group (median: 0.35 ppb, range: ND 0.69 ppb). Similarly, during charging and discharging the antiseptic solution, OPA levels were significantly higher in the manual group (median: 2.58 ppb, range: 0.92-10.0 ppb) than in the automatic group (median: 0.46ppb, range: ND 1.35 ppb). Time-weighted averages of OPA exposure concentration during work shifts were 0.33 to 1.15 ppb (median 0.66 ppb) in the manual group and 0.13 to 1.28 ppb (median 0.33 ppb) in the automatic group, which suggests that manual workers are exposed to OPA at higher levels. Among 80 female disinfection workers who used only antiseptic solutions containing OPA, the incidence of disinfection related complaints were 10% skin, 9% eye, and 16% respiratory symptoms. CONCLUSIONS: These findings suggest that it is desirable to introduce automatic washers to decrease OPA exposure levels among disinfection workers. PMID- 20160423 TI - Application of tooth brushing behavior to active rest. AB - OBJECTIVES: We evaluated the usefulness of tooth brushing with toothpaste as active rest using the flicker value as a physiological parameter and a subjective questionnaire as a psychological parameter. METHODS: Seventeen healthy, right handed subjects (12 males and 5 females) aged 22.5 +/- 1.5 yr (mean +/- standard deviation) were randomly divided into tooth brushing with toothpaste (N=9) and non-tooth brushing groups (N=8). The subjects performed a serial calculation task for 20 min using personal computers. Subsequently, the tooth brushing group brushed their teeth, and the flicker value and mood were compared before and after the tooth brushing. RESULTS: The flicker value significantly increased in the tooth brushing group compared with the non-tooth brushing group (p<0.05). Concerning the mood, in the tooth brushing group, the incidence of a "feeling of being refreshed" significantly increased (p<0.05), that of "concentration power" or a "feeling of clear-headedness" tended to increase (p<0.1), and that of "lassitude" or "sleepiness" significantly decreased (p<0.01). CONCLUSIONS: Somatosensory stimulation and intraoral tactile stimulation during tooth brushing activated cerebral activity, producing refreshing effects. These results suggest the applicability of tooth brushing to active rest. PMID- 20160424 TI - Polymorphisms in matrix metalloproteinase-1, -9 and -12 genes and the risk of chronic obstructive pulmonary disease in a Korean population. AB - BACKGROUND: Although a few studies have been conducted to evaluate the association of polymorphisms in matrix metalloproteinase (MMP) genes with chronic obstructive pulmonary disease (COPD), the results have been inconsistent. OBJECTIVES: To investigate the association of 3 polymorphisms of MMP genes (MMP-1 -1607G-->GG, MMP-9 -1562C-->T and MMP-12 N357S), which have been reported to be associated with COPD-related phenotypes, with the risk of COPD in a Korean population. METHODS: The genotypes of the 3 polymorphisms were determined in 301 patients with COPD and 333 healthy controls. RESULTS: Of the 3 polymorphisms studied, only the distribution of the MMP-9 -1562C-->T genotypes was significantly different between the cases and controls (p = 0.01), with the frequency of the variant T allele being significantly lower in the cases than in the controls (10.4 vs. 15.7%; p = 0.006). Individuals with at least 1 variant T allele were at a significantly decreased risk of COPD when compared with those with homozygous wild-type alleles (adjusted odds ratio = 0.69; 95% CI = 0.45 0.98; p = 0.04). CONCLUSIONS: These findings suggest that the MMP-9 -1562C-->T polymorphism could be used as a marker for determining the genetic susceptibility to COPD in a Korean population. PMID- 20160425 TI - Transient abnormal myelopoiesis associated with Down syndrome presenting as severe hydrops fetalis: a case report. AB - We present a case of transient abnormal myelopoiesis (TAM) presenting as non immune fetal hydrops (NIHF). Hydrops fetalis (HF) is a condition associated with very high perinatal mortality, especially when no treatable cause, such as fetal anaemia, exists. In fetuses prior to 24 weeks with NIHF, a chromosomal anomaly is a common association. TAM is a leukaemic condition, almost entirely limited to children with Down syndrome. The presentation of TAM prenatally is unusual but cases may present ultrasonographically with NIHF and associated fetal hepatosplenomegaly. We report a case presenting in this manner with NIHF detected at 29 weeks' gestation and discuss the subsequent diagnosis and management of in utero TAM. PMID- 20160426 TI - Intestinal atresia, encephalocele, and cardiac malformations in infants with 47,XXX: Expansion of the phenotypic spectrum and a review of the literature. AB - Identification of the 47,XXX karyotype often occurs adventitiously during prenatal fetal karyotyping in cases of advanced maternal age. Although most females with 47,XXX appear healthy at birth, various types of congenital malformations have been reported, of which urinary tract anomalies are the most frequent. We report on 2 newborns with 47,XXX and congenital cardiac defects, one of whom had duodenal atresia and the other an occipital encephalocele. This expands the spectrum of malformations reported in association with the triple-X syndrome. We also present a review of the literature on non-urinary tract malformations in females with 47,XXX. We conclude that prenatal identification of the 47,XXX karyotype is an indication for detailed fetal ultrasonography which should include examination of multiple organ systems. Such prenatal screening for possible associated congenital malformations should help to ensure optimal perinatal clinical management of 47,XXX cases. PMID- 20160427 TI - Functional anatomy of incisal biting in Aplodontia rufa and sciuromorph rodents - part 2: sciuromorphy is efficacious for production of force at the incisors. AB - The protrogomorph condition of the rodent masticatory apparatus is thought to be present in only one living species, the mountain beaver Aplodontia rufa. The major anatomical difference between protrogomorphs and sciuromorphs is that the relative size of one part of the masseter muscle, the anterior lateral masseter, is much greater in sciuromorphs than in protrogomorphs. The mechanics of force production at the incisors were compared in A. rufa and six sciuromorph rodents. Is the sciuroid masticatory apparatus more effective for production of forces at the incisors during biting than the primitive, protrogomorph condition? To answer this question, three measures of mechanical ability were employed and three hypotheses were tested: (1) the mechanical advantage of the adductor musculature is greater in sciuromorphs than in A. rufa; (2) the relative force produced at the incisors is greater in sciuromorphs than in A. rufa, and (3) the relative amount of force produced that can be used to drive the incisors into an object, is greater in sciuromorphs than in A. rufa. The results demonstrated that the protrogomorph, A. rufa, is not as efficient at generating bite forces at the incisors as the sciuromorphs. PMID- 20160428 TI - Functional anatomy of incisal biting in Aplodontia rufa and sciuromorph rodents - part 1: masticatory muscles, skull shape and digging. AB - Traditionally, rodents have been grouped into suborders distinguished largely on the basis of characteristics of the jaw adductor muscles and other features of the masticatory apparatus. The three classic suborders are: Sciuromorpha (squirrels), Myomorpha (rats and mice), and Hystricomorpha (porcupines and the South American caviomorph rodents). Protrogomorph rodents are thought to represent the primitive condition of rodent masticatory muscles. Aplodontia rufa, the mountain beaver, is the only living protrogomorphous rodent. The present work is a detailed comparison of the masticatory apparatus in A. rufa and Marmota monax, the woodchuck. But the mandibular region of A. rufa appears remarkable, unlike anything found in other rodents. Is A. rufa a reasonable representative of the primitive, protrogomorphous condition? A.rufa is a member of the aplodontoid sciuroid clade with a wide and flat skull. The large temporalis and mandibular apophyses of A. rufa are features related to its relatively wide skull. Such features are found in less dramatic forms in other sciuromorphous species and the basic arrangement of the masticatory muscles of A. rufa is similar to the arrangement seen in sciuromorphs. PMID- 20160429 TI - Invasion by matrix metalloproteinase-expressing cells is important for primitive streak formation in early chick blastoderm. AB - Epiblast cells in the early chick embryo differentiate to form all three germ layers through ingression of cells at the primitive streak across the basement membrane that underlies the epiblast. We tested the idea that degradation of the extracellular matrix components by matrix metalloproteinase(s) (MMPs) is involved in this process. Epiblast cells and primitive streak cells were dissociated into single cells and seeded onto a reconstituted basement membrane gel in vitro. Following overnight culture, approximately half the cells made holes in the substratum by dissolving the gel matrix. This invasive phenomenon was reproduced in vitro even when the cells were cultured upside down using a hanging culture system. We detected gelatinase activity in the culture supernatants from both prestreak epiblast cells and primitive streak cells. Pro-MMP-2 was detected in the culture media of the prestreak/streak cells as a 72-kDa band by gelatin zymography. In RT-PCR experiments, mRNAs for MMP-2, membrane-type (MT)3-MMP and MMP-11(stromelysin-3) were expressed in the epiblast cells before and during primitive streak formation. Injection of GM 6001 or other MMP inhibitors into the subgerminal cavity of the embryo inhibited the formation of the primitive streak and/or the primitive groove in more than 82% of the injected embryos. On the other hand, injection of a negative control compound instead of GM 6001 did not cause substantial inhibition. These results suggest that MMPs are involved in the enzymatic degradation of the basement membrane underlying the epiblast and are thus important for the ingression of mesendodermal cells along the primitive streak. PMID- 20160430 TI - Curcumin inhibits the growth, induces apoptosis and modulates the function of pituitary folliculostellate cells. AB - The polyphenol curcumin (diferuloylmethane) is the active componenet of the spice plant Curcuma longa and has been shown to exert multiple actions on mammalian cells. We have studied its effect on folliculostellate (FS) TtT/GF mouse pituitary cells, representative of a multifunctional, endocrine inactive cell type of the anterior pituitary. Proliferation of TtT/GF cells was inhibited by curcumin in a monolayer cell culture and in the colony formation assay in soft agar. Fluorescence-activated cell-sorting (FACS) analysis demonstrated curcumin induced cell cycle arrest at G(2)/M accompanied by inhibition of cyclin D(1) protein expression. Curcumin had a small effect on necrosis of TtT/GF cells, but it mainly stimulated apoptosis as demonstrated by FACS analysis (Annexin V fluorescein isothiocyannate/7-aminoactinomycin D staining). Curcumin-induced apoptosis involved suppression of Bcl-2, stimulation of cleaved caspase-3 and induction of DNA fragmentation. Functional studies on FS cell-derived compounds showed that curcumin inhibited mRNA synthesis and release of angiogenic vascular endothelial growth factor-A (VEGF-A). Immune-like functions of FS cells were impaired since curcumin downregulated Toll-like receptor 4, reduced nuclear factor-kappaB expression and suppressed bacterial endotoxin-induced interleukin-6 (IL-6) secretion. The inhibitory action of curcumin on VEGF-A and IL-6 production was also found in primary rat pituitary cell cultures, in which FS cells are the only source of these proteins. The observed effects of curcumin on FS cell growth, apoptosis and functions may have therapeutic consequences for the intrapituitary regulation of hormone production and release as well as for pituitary tumor pathogenesis. PMID- 20160431 TI - While waiting to buy a ferrari, do not leave your current car in the garage! PMID- 20160432 TI - Prospective controlled animal study on biopsy sampling with new flexible cryoprobes versus forceps: evaluation of biopsy size, histological quality and bleeding risk. AB - BACKGROUND: Cryoextraction is a procedure used for the recanalization of obstructed airways caused by visible exophytic endobronchial tumor. Biopsy samples obtained by this technique have been shown to be useful for histological assessment. OBJECTIVES: The aim of the present animal study was to systematically evaluate biopsy size, histological quality and bleeding risk after cryobiopsy with new, flexible cryoprobes in comparison with forceps biopsy, serving as the gold standard. METHODS: Biopsies were obtained from anesthetized pigs with the flexible bronchoscopy technique, and evaluated histologically with respect to their size and quality. Bleeding frequency, bleeding duration and histological changes in the biopsy bed were also recorded. RESULTS: Cryobiopsies were significantly larger than forceps biopsies. The size of cryobiopsies was dependent on the freezing time. The histological quality of the cryobiopsy specimenswas not impaired by the freezing process, whereas forceps biopsies showed typical crush artifacts. Despite the larger defects left in the tracheobronchial system after cryobiopsy, bleeding frequency and duration were not higher compared to forceps biopsy. CONCLUSIONS: Since cryobiopsy sampling is not associated with a higher bleeding risk compared with forceps biopsy, this new biopsy technique offers--in addition to a good specimen quality--a safe and valuable tool with the potential of improving the outcome of diagnostic endoscopy. PMID- 20160433 TI - First-trimester prenatal diagnosis of Okihiro syndrome. AB - A case of Okihiro syndrome (OS) detected by 2- and confirmed by 3-dimensional ultrasound at 13+2 gestational weeks is reported. While the pregnant woman affected by the OS presented with limb anomalies, the fetus showed severe thoracoabdominal and skeletal anomalies. Termination of pregnancy was performed at 14+1 gestational weeks and confirmed the sonographically detected symptoms. The diagnosis was confirmed by autoptic, radiologic and molecular genetic analysis. To our knowledge, this is the first case of prenatal diagnosis of OS. PMID- 20160434 TI - Effects of interleukin-6 on depression risk in dialysis patients. AB - BACKGROUND/AIMS: Depression represents the most frequent psychiatric disorder in nephrology. Cytokines, and especially IL-6, were found to be elevated in depressed patients with normal renal function. The objective of this pilot study was to examine the relationship between depression and cytokines (IL-6, TNF alpha, and IL-10) in patients with end-stage kidney disease (ESKD). METHODS: We studied 44 stable patients with ESKD for 71 +/- 66 months (32 males; 64 +/- 13 years; 27 on hemodialysis and 17 on peritoneal dialysis). The control group included 20 healthy age- and gender-matched individuals (12 males; 60 +/- 12 years). Depression was assessed by the Zung Self-Rating Depression Scale (ZS). Nephelometry for high-sensitivity CRP and ELISA kits for IL-6, IL-10 and TNF alpha were used. RESULTS: Compared to controls, patients with ESKD had higher ZS scores (56.8 +/- 16.8 vs. 44 +/- 12.7, p < 0.01), WBC (7,987 +/- 2,347 vs. 6,413 +/- 870/mm(3), p < 0.01), ESR (36.3 +/- 15.8 vs. 9.4 +/- 3.3 mm, p < 0.001), TNF alpha (52 +/- 18.4 vs. 10.7 +/- 2.8 pg/ml, p < 0.001) and IL-6 (6.3 +/- 4 vs. 1.8 +/- 0.4 pg/ml, p < 0.001). No differences in high-sensitivity CRP and IL-10 were noted between the ESKD and control groups. Serum IL-6 levels were the only parameter positively correlated with the values of the ZS score in ESKD patients (r = 0.34, p < 0.02). CONCLUSIONS: IL-6 may play a role in the pathogenesis of depression in patients with ESKD. PMID- 20160435 TI - Urinary angiotensinogen accurately reflects intrarenal Renin-Angiotensin system activity. AB - BACKGROUND: We recently reported that immunoreactivity of intrarenal angiotensinogen (AGT) is significantly increased in IgA nephropathy patients. Meanwhile, we have developed direct enzyme-linked immunosorbent assays to measure plasma and urinary AGT (UAGT) in humans. This study was performed to test the hypothesis that UAGT levels are increased in chronic glomerulonephritis patients. METHODS: We analyzed 100 urine samples from 70 chronic glomerulonephritis patients (26 from IgA nephropathy, 24 from purpura nephritis, 8 from lupus nephritis, 7 from focal segmental glomerulosclerosis, and 5 from non-IgA mesangial proliferative glomerulonephritis) and 30 normal control subjects. RESULTS: UAGT-creatinine ratio (UAGT/UCre) was correlated positively with diastolic blood pressure (p = 0.0326), urinary albumin-creatinine ratio (p < 0.0001), urinary protein-creatinine ratio (p < 0.0001) and urinary occult blood (p = 0.0094). UAGT/UCre was significantly increased in chronic glomerulonephritis patients not treated with renin-angiotensin system (RAS) blockers compared with control subjects (p < 0.0001). Importantly, glomerulonephritis patients treated with RAS blockers had a marked attenuation of this augmentation (p = 0.0021). CONCLUSION: These data indicate that UAGT are increased in chronic glomerulonephritis patients and treatment with RAS blockers suppressed UAGT. The efficacy of RAS blockade to reduce the intrarenal RAS activity can be confirmed by measurement of UAGT in chronic glomerulonephritis patients. PMID- 20160436 TI - Mesangial cells initiate compensatory tubular cell hypertrophy. AB - Unilateral nephrectomy results in compensatory renal growth, in which both the size and the functional capacity of the remaining kidney are increased. The functional adaptation to the removal of the contralateral kidney consists mostly of an increase in the glomerular filtration rate of the remaining kidney, and hypertrophy of cells comprising the nephron, mainly of the proximal tubular cells. Although the phenomenon of single kidney hypertrophy has been known for the past thousand years and despite intensive research over the past century, the mechanism of this process still remains unclear. The present article reviews the role of mesangial cells in compensatory renal hypertrophy. PMID- 20160437 TI - Curcumin inhibits transforming growth factor-beta activity via inhibition of Smad signaling in HK-2 cells. AB - BACKGROUND: Curcumin, a polyphenolic compound derived from rhizomes of Curcuma spp., has been shown to possess potent anti-fibrotic properties. Here, we investigate the role of curcumin in modulating the profibrotic action of TGF-beta in human proximal tubule cells (HK-2) and its underlying mechanisms. METHODS: HK 2 cells were stimulated with 5 ng/ml TGF-beta(1). The effects of curcumin on TGF beta(1)-regulated gene expression and Smad phosphorylation were analyzed by RT PCR, ELISA and Western blotting. RESULTS: Curcumin inhibited TGF-beta(1)-induced plasminogen activator inhibitor-1 (PAI-1), alpha-smooth muscle actin (alpha-SMA) mRNA and protein expression. Curcumin suppressed not only TGF-beta(1)-induced Smad2 phosphorylation in a dose- and time-dependent manner, but also the nuclear accumulation of receptor-regulated Smads (R-Smad), Smad2 and Smad3. A serine/threonine protein phosphatase inhibitor (microcystin) could partly reverse the inhibitory effect of curcumin on Smad phosphorylation. CONCLUSIONS: Curcumin blocks the profibrotic actions of TGF-beta on HK-2 cells through the down regulation of the Smad signaling pathway, and curcumin may have some similar effect as serine/threonine protein phosphatases. Our findings suggest curcumin as a potential candidate for treatment of tubulointerstitial fibrosis. PMID- 20160438 TI - Preimplantation genetic diagnosis (embryo screening) for enlarged vestibular aqueduct due to SLC26A4 mutation. AB - Preimplantation genetic diagnosis (PGD) is used to analyze embryos genetically before their transfer into the uterus. For families with genetic diseases, PGD offers a chance to have an unaffected child, without facing termination of pregnancy. Although PGD has been performed for many monogenic disorders, such as cystic fibrosis and beta-thalassemia, the application of PGD to hereditary hearing impairment has not been explored. In the present study, we reported the development and application of PGD protocols to address enlarged vestibular aqueduct (EVA), which is a common type of hereditary hearing impairment associated with mutations in the SLC26A4 gene. The family requesting PGD had a history of EVA, segregating the SLC26A4 c.919-2A-->G mutation. In short, the PGD process was composed of two steps: the development of a single-cell testing protocol and clinical PGD cycles (i.e., selection and implantation of unaffected embryos using the single-cell testing protocol). First, protocols for genetic testing in a single cell were established for the c.919-2A-->G mutation using GenomiPhi technology and primer extension mini-sequencing. These protocols were validated on single lymphocytes collected from both parents and their affected child. Two clinical PGD cycles were then performed for the parents, with the second cycle successfully leading to a singleton pregnancy. The baby was homozygous for the wild-type SLC26A4 allele and revealed a normal audiological phenotype after birth. To our knowledge, this is the first report in the literature describing successful PGD in families with genetic hearing impairment. In our opinion, the application of PGD in the field of hereditary hearing impairment involves fewer ethical controversies than other novel applications of PGD and traditional indications for PGD for other monogenic diseases. Therefore, the approach demonstrated in the present study can also be used in a large number of families with other types of hereditary hearing impairment. PMID- 20160439 TI - Rethinking acute dialysis strategies in major disasters: new perspectives and future directions suggested by the haitian earthquake. PMID- 20160440 TI - Oral anticoagulation in nonvalvular atrial fibrillation in clinical practice: impact of CHADS(2) score on outcome. AB - OBJECTIVES: CHADS(2) score predicts embolic risk in patients with nonvalvular atrial fibrillation (NVAF), but also bleeding risk in patients receiving oral anticoagulation (OAC). Our objective is to analyze the effectiveness and safety of OAC in patients with NVAF in daily clinical practice, according to embolic risk evaluated by means of CHADS(2) score. METHODS: All consecutive outpatients with permanent NVAF seen at 2 cardiology clinics were prospectively followed for embolic events (transient ischemic attack, ischemic stroke, peripheral embolism) and severe bleedings. OAC was prescribed according to the recommendations of scientific associations. CHADS(2) score was obtained for each patient. RESULTS: From February 1, 2000 to July 31, 2003, 796 outpatients fulfilled the inclusion criteria. OAC was prescribed to 564 (71%) patients. After 2.4 +/- 1.9 years of follow-up, the embolic event rates (per 100 patient-years) for each stratum of the CHADS(2 )score for patients with/without OAC were: 1/4.1, p = 0.23 (CHADS(2) = 0); 0.6/7.1, p = 0.0018 (CHADS(2) = 1); 0.5/5.1, p = 0.0014 (CHADS(2) = 2); 2.4/12.5, p = 0.0017 (CHADS(2) = 3) and 2.9/20, p = 0.013 (CHADS(2) >or=4). The severe bleeding rates for the same CHADS(2) score strata were 3/0.8, 0.8/0.7, 1.3/0.7, 0.4/0, and 2.9/5 in patients with/without OAC (n.s.). CONCLUSION: OAC is effective and safe in daily clinical practice in patients with NVAF and CHADS(2) score >or=1. PMID- 20160441 TI - The effect of brushing time and dentifrice quantity on fluoride delivery in vivo and enamel surface microhardness in situ. AB - While the clinical anticaries efficacy of fluoride toothpaste is now without question, our understanding of the relation of fluoride efficacy to brushing time and dentifrice quantity is limited. The aim of this in situ study was to determine how differences in brushing time and dentifrice quantity influence (i) fluoride distribution immediately after brushing, (ii) clearance of fluoride in saliva, (iii) enamel fluoride uptake (EFU) and (iv) enamel strengthening, via the increase in surface microhardness. The study compared brushing times of 30, 45, 60, 120 and 180 s with 1.5 g of dentifrice containing 1,100 microg/g fluoride as sodium fluoride. In addition, 60 s of brushing with 0.5 g dentifrice was evaluated. A longer brushing time progressively reduced retention of dentifrice in the brush, thereby increasing the amount delivered into the mouth. A longer brushing time also increased fluoride concentrations in saliva for at least 2 h after the conclusion of brushing, showing that increased contact time promoted fluoride retention in the oral cavity. There was a statistically significant positive linear relationship between brushing time and both enamel strengthening and EFU. Compared to 0.5 g dentifrice, brushing with 1.5 g dentifrice more than doubled the fluoride recovered in saliva after brushing and increased EFU. In conclusion, the results of this preliminary, short-term usage study suggest for the first time that both brushing time and dentifrice quantity may be important determinants both of fluoride retention in the oral cavity and consequent enamel remineralization. PMID- 20160442 TI - Ultrastructural analyses of deciduous teeth affected by hypocalcified amelogenesis imperfecta from a family with a novel Y458X FAM83H nonsense mutation. AB - BACKGROUND: Nonsense mutations in FAM83H are a recently described underlying cause of autosomal dominant (AD) hypocalcified amelogenesis imperfecta (AI). OBJECTIVE: This study aims to report a novel c.1374C>A p.Y458X nonsense mutation and describe the associated ultrastructural phenotype of deciduous teeth. METHODS: A family of European origin from the Iberian Peninsula with AD-inherited AI was ascertained. Family members were assessed through clinical examination and supporting investigations. Naturally exfoliated deciduous teeth from 2 siblings were investigated by scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX) and transverse microradiography (TMR). RESULTS: On clinical and radiographic investigation the appearances of the affected deciduous and permanent teeth were consistent with hypocalcified AI with small focal areas of more normal looking enamel. DNA sequencing identified a novel c.1374C>A p.Y458X FAM83H nonsense mutation in affected, but not in either unaffected family members or unrelated controls. Exfoliated teeth were characterised by substantial post eruptive enamel loss on gross examination. Irregular, poor quality enamel prisms were observed on SEM. These were coated in amorphous material. TMR and EDX confirmed reduced mineral and increased organic content in enamel, respectively. CONCLUSIONS: FAM83H nonsense mutations have recently been recognised as a cause of AD hypocalcified AI. We report a novel nonsense FAM83H mutation and describe the associated preliminary ultrastructural phenotype in deciduous teeth. This is characterised by poorly formed enamel rods with inappropriate retention of amorphous material, which is likely to represent retained organic matrix that contributes to the overall hypomineralised phenotype. PMID- 20160443 TI - Autoimmune hepatitis-primary sclerosing cholangitis overlap syndrome complicated by Crohn's disease. PMID- 20160444 TI - Clinical characteristics of central European and North American samples of pregnant women screened for opioid agonist treatment. AB - BACKGROUND: Little comparable information is available regarding clinical characteristics of opioid-dependent women from different countries. In the present study, women from the USA, Canada and a Central European country, Austria, screened for participation in the Maternal Opioid Treatment Human Experimental Research study, were compared with respect to their demographic and addiction histories. METHODS: Pregnant women (n = 1,074) were screened for study participation using uniformed clinical criteria and instruments. The screening results were compared with regard to exclusion, demographics, drug use, and psychosocial and treatment histories. RESULTS: Compared to the screened US and Canadian women, Austrian women were more likely to be younger (p < 0.001), white (p < 0.001), had significantly lower levels of educational attainment (p < 0.001), were less likely to use opioids daily (p < 0.001) and more likely to have been prescribed buprenorphine (p < 0.001). Compared to both rural and urban US groups, the Austrian group was less likely to have legal issues (p < 0.001) and was younger when first prescribed agonist medication (p < 0.001). CONCLUSION: The differences between North American and European groups may offer unique insights concerning treatment and pregnancy outcomes for opioid-dependent pregnant women. PMID- 20160445 TI - CD8CD11a(high) cells decreased in multiple sclerosis but not in neuromyelitis Optica. AB - In order to clarify the immunological characteristics of multiple sclerosis (MS) and neuromyelitis optica (NMO), we analyzed CD3, CD4, CD8, CD20, CD4(+)CD25(+), CD4(+)CD29(+), and CD8(+)CD11a(high) cells in peripheral blood from patients with MS (16 stable, 6 active) and NMO (15 stable, 7 active), as well as 9 with NMO spectrum, 6 with clinically isolated syndrome (CIS), and 13 with other neurological diseases using flow cytometry. Significant decreases in the numbers of CD8(+) CD11a(high) cells were observed in stable and active MS and CIS. Our findings indicate that CD8(+)CD11a(high) cells play different roles in MS and NMO, and their presence may be related to the pathogenesis of MS from the early stage. PMID- 20160446 TI - Intercellular adhesion molecule-1 and interleukin-6 gene polymorphisms in patients with advanced-stage endometriosis. AB - BACKGROUND/AIMS: The aim of this study was to investigate the possibility that the K469E and G241R polymorphisms in the intercellular adhesion molecule-1 (ICAM 1) gene and the C-634G polymorphism in the interleukin (IL)-6 gene are associated with endometriosis in the Korean population. METHODS: The ICAM-1 gene K469E and G241R polymorphisms and the IL-6 gene C-634G polymorphism were evaluated in 390 patients with endometriosis and 351 controls by polymerase chain reaction restriction fragment length polymorphism analysis. RESULTS: The ICAM-1 gene G241R polymorphism was not observed in all subjects. No differences were observed in the ICAM-1 K469E and IL-6 C-634G genotype distributions and allele frequencies between patients with endometriosis and controls. In subgroup analyses according to the stage of endometriosis or bilaterality of ovarian endometriomas, no significant differences were observed in the ICAM-1 gene K469E or the IL-6 gene C 634G polymorphism frequencies between the subgroups and the controls. The combined analysis of the ICAM-1 gene K469E polymorphism and the IL-6 gene C-634G polymorphism did not show any additional significant findings. CONCLUSIONS: The K469E and G241R polymorphisms in the ICAM-1 gene and the C-634G polymorphism in the IL-6 gene may not be genetic factors related to susceptibility to advanced stage endometriosis in the Korean population. PMID- 20160447 TI - Interrelationship of cytokines, hypothalamic-pituitary-adrenal axis hormones, and psychosocial variables in the prediction of preterm birth. AB - BACKGROUND/AIMS: To examine the relationship of biological mediators (cytokines, stress hormones), psychosocial, obstetric history, and demographic factors in the early prediction of preterm birth (PTB) using a comprehensive logistic regression model incorporating diverse risk factors. METHODS: In this prospective case control study, maternal serum biomarkers were quantified at 9-23 weeks' gestation in 60 women delivering at <37 weeks compared to 123 women delivering at term. Biomarker data were combined with maternal sociodemographic factors and stress data into regression models encompassing 22 preterm risk factors and 1st-order interactions. RESULTS: Among individual biomarkers, we found that macrophage migration inhibitory factor (MIF), interleukin-10, C-reactive protein (CRP), and tumor necrosis factor-alpha were statistically significant predictors of PTB at all cutoff levels tested (75th, 85th, and 90th percentiles). We fit multifactor models for PTB prediction at each biomarker cutoff. Our best models revealed that MIF, CRP, risk-taking behavior, and low educational attainment were consistent predictors of PTB at all biomarker cutoffs. The 75th percentile cutoff yielded the best predicting model with an area under the ROC curve of 0.808 (95% CI 0.743 0.874). CONCLUSION: Our comprehensive models highlight the prominence of behavioral risk factors for PTB and point to MIF as a possible psychobiological mediator. PMID- 20160448 TI - An Escherichia coli-based cell-free system for large-scale production of functional mammalian membrane proteins suitable for X-ray crystallography. AB - A cell-free expression system using an Escherichia coli extract was adapted for large-scale expression and purification of mammalian membrane proteins. The system was tested with a set of human membrane proteins of different sizes, numbers of transmembrane domains, oligomeric arrangements, and native membrane locations. Tens of milligrams of protein were readily expressed and purified from an overnight cell-free reaction. Both reaction 'mode A' (proteins were expressed as precipitant) and 'mode B' (proteins were expressed in the presence of mild detergents to keep them soluble) were investigated. The combination of 'mode B' and the right detergents, used in the subsequent extraction and purification steps, is critical for obtaining properly folded proteins (CX32 and VDAC1) that can be crystallized and diffracted (VDAC1). The E. coli cell-free system is capable of efficient expression of many mammalian membrane proteins. However, fine-tuning of the system, especially to facilitate proper protein folding, will be required for each specific target. PMID- 20160449 TI - History of dementia research in Bohemia and middle Europe. AB - The clinical aspects and histopathology of dementia are best understood when based on knowledge of the historical milestones associated with its development. We studied archive materials and visited some of the psychiatric asylums that were active in Prague during the 19th century. RESULTS: The gradual recognition of dementia and its histological correlates on the territory of the actual Czech Republic from the 1830s are described, together with its links to Austrian, German, and other foreign psychiatry and neurology. A stepwise differentiation between inborn mental incapacity and the acquired forms occurred between 1830 and 1890. This was followed by contributions from Emil Redlich, Arnold Pick, Karel Kuffner, Oskar Fischer and others between 1890 and 1930, elucidating features of senile plaques, and shedding light on behavioral-morphological correlations and on the role of inflammatory tissue changes. These discoveries allowed the distinction between neurodegenerative causes of dementia and other etiological categories. CONCLUSION: One hundred years ago, Prague was one of the cradles from which our modern understanding of neurodegenerative dementia emerged. PMID- 20160450 TI - Dissecting toxicity of tau and beta-amyloid. AB - BACKGROUND: How beta-amyloid (Abeta) and tau exert toxicity in Alzheimer's disease is only partly understood. Major questions include (1) which aggregation state of Abeta confers toxicity, (2) do amyloidogenic proteins have similar mechanisms of toxicity, and (3) does soluble tau interfere with cellular functions? METHODS: To determine Abeta toxicity in P301L mutant tau transgenic mice, mitochondrial function was assessed after insult with monomeric, oligomeric and fibrillar Abeta. Amylin and Abeta toxicity were compared in cortical and hippocampal long-term cultures. To determine tau toxicity, K369I mutant tau mice were established as a model of frontotemporal dementia, analyzed biochemically and compared with human diseased brain. RESULTS: Oligomeric and fibrillar Abeta42 were both toxic, although to different degrees. Human amylin shared toxicity with Abeta42, an effect not observed for nonamyloidogenic rat amylin. Clinical features of K369I tau mice were caused by aberrant interaction of phosphorylated tau with JIP1, a component of the kinesin transport machinery. CONCLUSION: Our data support the notion of a synergistic action of tau and Abeta pathology on mitochondria. A specific conformation of Abeta42 and human amylin determines toxicity. Finally, trapping of JIP1 by phosphorylated tau in the neuronal soma emerges as a fundamental pathomechanism in neurodegeneration. PMID- 20160451 TI - Tau kinase I overexpression induces dentate gyrus degeneration. AB - Familial Alzheimer gene mutations result in a signaling mechanism that converges, downstream, in the activation of GSK3 activity. We have generated a GSK3 transgenic mouse model to study the consequences of GSK3 activation. In this model, dentate gyrus is degenerated in a process in which phosphorylated tau can be involved. PMID- 20160452 TI - Possible role of tau in mediating pathological effects of apoE4 in vivo prior to and following activation of the amyloid cascade. AB - Injection of the neprilysin inhibitor thiorphan into the brain induces the accumulation of Abeta in hippocampal CA1 neurons and septal neurons in apoE4 knock-in mice but not in mice that express the corresponding Alzheimer's disease benign isoform apoE3. We investigated the possible role of tau phosphorylation in mediating this synergistic pathological cross talk between apoE4 and the amyloid cascade. This revealed that in both apoE4 and apoE3 mice, activating the amyloid cascade by inhibiting neprilysin triggers the accumulation of AT100 phosphorylated tau in the perikarya of CA1 neurons. In contrast, in the septum this treatment elevated the level of phosphorylation of the tau AT100 epitope only in the apoE4 mice. This suggests that tau-related processes by themselves do not mediate the synergistic pathological effects of apoE4 and Abeta in CA1 neurons. However, tau and cytoskeletal-related mechanisms may mediate the synergistic pathological effects of apoE4 and Abeta in the septum. The basal levels of tau phosphorylation are also affected by the apoE genotype. This effect, which is associated with hyperphosphorylation of the tau AT8 epitope, is most prominent in hippocampal CA3 neurons. This suggests that the apoE4 mice are already stressed under nonstimulated conditions and that AT8 tau phosphorylation may contribute to their increased susceptibility to brain insults. PMID- 20160453 TI - Transition of tau protein from disordered to misordered in Alzheimer's disease. AB - The neuronal protein tau, a member of the class of intrinsically disordered proteins, is characterized by the absence of any firm 3-D structure and high solubility when free in solution. The tau protein forms insoluble fibrils in the brain of people suffering from Alzheimer's disease (AD) and other tauopathies and plays a key role in the neurodegenerative process. Posttranslational events leading to the transition of tau from a disordered highly soluble protein to the insoluble aggregate seem to be associated with hyperphosphorylation, truncation or a combination of both. These modifications are assumed to change the native disorder of tau into a preaggregation state, which then directly initiates the fibrillization process. Conformation-specific anti-tau antibody DC11 detects pathological truncated tau forms present in AD brains but not in the normal human brain. A truncated tau protein selected from this pool of DC11-positive molecules was sufficient to initiate and drive the complete tau cascade of neurofibrillary pathology in a rat model of tauopathy. Thus, DC11 antibody recognizes the AD specific conformation of tau not found in the normal human brain. We propose the term 'misdisordered' for this distinct conformational state of tau, which is the first step in the transition of tau from a soluble disordered protein to its insoluble, misordered aggregated form. PMID- 20160454 TI - 'Prion-like' propagation of mouse and human tau aggregates in an inducible mouse model of tauopathy. AB - BACKGROUND: Aggregates of the tau protein are a hallmark of Alzheimer's and several other neurodegenerative diseases. Various transgenic mouse models have been generated to study the aggregation process. Since wild-type tau is highly soluble and does not aggregate readily, most models make use of tau mutations that occur in human frontotemporal dementias and are more prone to aggregate. These mouse models show neurofibrillary tangles similar to those of Alzheimer's disease. However, since the mice contain both endogenous wild-type mouse tau and exogenous human mutant tau, the relative contribution of these components to the aggregates has been a matter of debate. OBJECTIVE: Using a new set of regulatable transgenic mouse models, we sought to determine whether mouse tau coaggregates with human tau when it is switched on. Furthermore, we asked what type of tau remains in the aggregates after switching off the expression of exogenous tau. METHODS: We generated doxycycline-inducible transgenic mice expressing either full-length human tau or the tau repeat domain (tau(RD)). In addition, both types of human tau derivatives were expressed in a 'proaggregant' form (with the frontotemporal dementia with parkinsonism linked to chromosome 17 mutation DeltaK280), or in an 'antiaggregant' form (with additional proline mutations to block beta-structure and aggregation). RESULTS: The proaggregant tau(RD) mice develop tangles rapidly after induction, the antiaggregant mice do not. Analysis by biochemistry and immunohistology reveals that the tangles contain both exogenous and endogenous mouse tau. After switching off the proaggregant tau(RD), tangles persist for extended periods. However, they are composed entirely of mouse tau. CONCLUSIONS: Mouse tau and exogenous human tau can coaggregate in transgenic models of tauopathy. The aggregates are in dynamic equilibrium with their subunits, so that exogenous tau disappears when its expression is switched off. Once the seeds of aggregation are generated by the foreign tau species, they propagate in a 'prion-like' fashion within the cell even after the foreign tau has disappeared. PMID- 20160455 TI - Are Abeta and its derivatives causative agents or innocent bystanders in AD? AB - Alzheimer's disease (AD) is characterized by neurodegeneration in neocortical regions of the brain. Currently, Abeta-based theories, including amyloid depositions and soluble Abeta, form the basis of most therapeutic approaches to AD. It remains unclear, however, whether Abeta and its derivatives are the primary causative agents of neuronal loss in AD. Reported studies show no significant correlations between brain amyloid depositions and either degree of dementia or loss of neurons, and brain amyloid loads similar to AD are often found in normal individuals. Furthermore, behavioral abnormalities in animal models overexpressing amyloid precursor protein seem independent of amyloid depositions. Soluble Abeta theories propose toxic Abeta42 or its oligomers as the agents that promote cell death in AD. Abeta peptides, however, are normal components of human serum and CSF, and it is unclear under what conditions these peptides become toxic. Presently, there is little evidence of disease-associated abnormalities in soluble Abeta and no toxic oligomers specific to AD have been found. That familial AD mutations of amyloid precursor protein, PS1 and PS2 promote neurodegeneration suggests the biological functions of these proteins play critical roles in neuronal survival. Evidence shows that the PS/gamma secretase system promotes production of peptides involved in cell surface-to nucleus signaling and gene expression, providing support for the hypothesis that familial AD mutations may contribute to neurodegeneration by inhibiting PS dependent signaling pathways. PMID- 20160456 TI - Neuroinflammation - an early event in both the history and pathogenesis of Alzheimer's disease. AB - BACKGROUND: About hundred years ago, Oskar Fischer proposed that the senile plaques are the consequence of the deposition of a foreign substance that could induce an inflammatory response leading to an abnormal neuritic response of the surrounding neurons. OBJECTIVES: To show that the interest in inflammation in Alzheimer's disease (AD) is not only an early event in the history of AD but that inflammation is also an early event in the pathogenesis of AD. METHODS: Evaluation of the neuropathological, epidemiological and genetic evidence for a role of inflammation early in the pathogenesis of AD. RESULTS: Neuropathological studies show presence of activated microglia and inflammation-related mediators in the cerebral neocortex of autopsied patients with a low Braak stage for AD pathology. Prospective population-based cohort studies indicate that higher serum levels of acute phase proteins predict dementia. On a genetic level, it was found that the production capacity of proinflammatory cytokines after stimulation with lipopolysaccharide (a process that is under strong genetic control) is higher in offspring with a parental history of late-onset AD. CONCLUSION: Neuropathological studies show that a neuroinflammatory response in the cerebral neocortex parallels the early stages of AD pathology and precedes the late stage, tau related pathology. Epidemiological and genetic studies indicate that systemic markers of the innate immunity are risk factors for late-onset AD. PMID- 20160457 TI - Analysis of APL1beta28, a surrogate marker for Alzheimer Abeta42, indicates altered precision of gamma-cleavage in the brains of Alzheimer disease patients. AB - Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Currently, therapeutic intervention after the disease onset is difficult because progressive neuronal death precedes clinical symptoms. Available medicines for AD, such as AchE inhibitors, transiently slow the progression of the dementia symptoms, but they do not inhibit the pathological process. At present, next generation anti-AD drugs are in development in many pharmaceutical companies. Importantly, most of them are to inhibit the progress of the pathological process and, thus, at the same time, the establishment of a highly probable prediction of future AD onset is inseparable. AD is now diagnosed using clinical criteria coupled with brain imaging systems such as SPECT and PET. To diagnose AD cases before the appearance of clinical symptoms, it will be necessary to (a) establish new, more sensitive clinical criteria, (b) develop methods for detecting the pathological accumulation of proteins (e.g. Abeta) in the brain, or (c) develop biomarkers for predicting the accumulation of Abeta/tau in the brain. Our recent discovery of APL1beta28, a possible biomarker of AD, may help in the development of early detection methods for AD. PMID- 20160458 TI - Expression of familial Alzheimer's disease-linked human presenilin 1 variants impair enrichment-induced adult hippocampal neurogenesis. AB - Presenilin 1 (PS1) plays a critical role in neurogenesis both during development and in the adult. We recently reported that ubiquitous expression of familial, early-onset Alzheimer's disease-linked PS1 mutants impairs enrichment-induced proliferation and neurogenesis of hippocampal neural progenitor cells (NPCs) in a non-cell autonomous manner. The impairments in proliferation and neurogenesis are, at least in part, due to alterations in the levels of specific chemokines and growth factors secreted from microglia expressing familial Alzheimer's disease-linked PS1 variants. To test our hypothesis that the fate of hippocampal NPCs in PS1 mutant mice is largely determined by cellular factors produced within the niche itself, we are examining the fate of NPCs from hippocampi of wild-type human PS1 or PS1 mutant mice that are marked with green fluorescent protein and BrdU following transplantation into heterologous hosts. In parallel, we have generated transgenic mice that harbor a transgene encoding the PS1DeltaE9 variant flanked with loxP sites that can be conditionally deleted in a temporal and/or spatial manner using specific cre driver lines. These studies will allow us to assess the contributions of varying cell types within the hippocampal stem cell niche that express mutant PS1 to NPC proliferation and differentiation. PMID- 20160459 TI - p53 is regulated by and regulates members of the gamma-secretase complex. AB - Amyloid beta-peptides is the generic term for a set of hydrophobic peptides that accumulate in Alzheimer's disease (AD)-affected brains. These amyloid-beta peptide fragments are mainly generated by an enzymatic machinery referred to as gamma-secretase complex that is built up by the association of four distinct proteins, namely presenilin 1 (PS1) or PS2, nicastrin, Aph-1 and Pen-2. AD is also characterized by exacerbated cell death that appears linked to the tumor suppressor p53. Interestingly, all members of the gamma-secretase complex control p53-dependent cell death. On the other hand, p53 appears to be able to regulate directly or indirectly the expression and transcription of PS1, PS2 and Pen-2. This review will focus on the functional cross-talk between the members of the gamma-secretase complex and p53 and will discuss the putative implication of this oncogene in AD pathology. PMID- 20160460 TI - Amyloid-beta-derived diffusible ligands cause impaired axonal transport of mitochondria in neurons. AB - BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of dementia predominantly affecting the elderly. It is believed that soluble amyloid-beta (Abeta) oligomers are involved in the pathogenesis of AD, yet the underlying mechanisms remain elusive. OBJECTIVES: Emerging evidence suggests that mitochondrial dysfunction likely plays a critical role in Abeta-induced neuronal degeneration. Previously, we demonstrated that Abeta-derived diffusible ligands (ADDLs) induce reduced mitochondrial density in neurites, and we suspect that an impaired mitochondrial trafficking might be involved, which is tested in this study. METHODS: Using live cell imaging, anterograde and retrograde transport of mitochondria in primary hippocampal neurons treated with sub-lethal doses of ADDLs was measured. RESULTS: We found that ADDLs induced significant impairment in both anterograde and retrograde transport of mitochondria along axons. CONCLUSION: These results suggest that an impaired mitochondrial transport likely contributes to ADDL-induced abnormal mitochondrial distribution and dysfunction and also reinforce the idea that axonal transport is likely involved in AD pathogenesis. PMID- 20160461 TI - The anti-inflammatory agent N-acetyl cysteine exacerbates endotoxin-induced hypoxemia and hypotension and induces polycythemia in the ovine fetus. AB - BACKGROUND: Lipopolysaccharide (LPS) delivered acutely to the ovine fetus induces cerebral white matter injury and brain inflammation. N-acetyl cysteine (NAC) is potentially neuroprotective as it blocks the production of inflammatory cytokines and increases glutathione levels; however, it is unknown whether NAC affects the physiological status of the fetus already exposed to an inflammatory environment. OBJECTIVES: Our objective was to determine whether NAC influences the physiological effects of LPS exposure in the ovine fetus. METHODS: Catheterized fetal sheep underwent one of four treatments (saline, n = 6; LPS, n = 6; LPS + NAC, n = 6; NAC, n = 3) on 5 consecutive days from 95 days of gestation (term approximately 147 days). Fetal arterial pressure and heart rate were recorded and blood samples collected. RESULTS: LPS administration resulted in fetal hypoxemia and hypotension; simultaneous treatment with NAC exacerbated these effects and induced polycythemia. NAC treatment alone had no effect on the fetus. CONCLUSION: In the presence of LPS, NAC compromises fetal physiological status, suggesting that it may not be a suitable antenatal treatment for a fetus with evidence of inflammation. PMID- 20160462 TI - Protective effects of methylxanthines on hypoxia-induced apoptotic neurodegeneration and long-term cognitive functions in the developing rat brain. AB - Aminophylline is widely used in the management of premature apnea. The methylxanthines aminophylline, theophylline and caffeine are nonspecific inhibitors of adenosine receptors. There are no proven effects of methylxanthines on acute brain injury and long-term cognitive functions. This study is aimed at investigating the effects of methylxanthines on brain injury and cognitive functions. Newborn rats were allocated to form four groups, which contained at least 21 pups: two groups were exposed to room air and two groups were exposed to intermittent hypoxia. Intraperitoneal aminophylline was administered to treatment groups during postnatal day 1 through postnatal day 7. All rats were sacrificed on postnatal day 8 via intraperitoneal pentobarbital and the effects of the administered drug on brain injury and adenosine receptor expression were determined. Cognitive functions of rats were evaluated via water maze test. Histopathological evaluation demonstrated that aminophylline significantly diminished the number of 'apoptotic cells' in the hippocampal CA1, CA2, CA3 and gyrus dentatus regions in the brain. Aminophylline treatment immediately after hypoxic insult significantly improved long-term neurobehavioral achievements. In conclusion, aminophylline administration immediately after neonatal hypoxic insult provides benefit over a prolonged period in the developing rat brain. PMID- 20160463 TI - Comparison of intravitreal bevacizumab versus triamcinolone for the treatment of diffuse diabetic macular edema. AB - BACKGROUND: Our purpose was to compare the effect of triamcinolone and bevacizumab (Avastin) on the retinal thickness and functional outcome in patients with diabetic macular edema. METHODS AND MATERIALS: A collective of 32 patients, who had been treated by a single 4.0-mg intravitreal triamcinolone injection (group 1), was matched to 32 patients ('matched pairs'), who had received 3 injections of 1.25 mg of bevacizumab within 3 months in 4-week intervals (group 2). The outcome variables were changes in best corrected visual acuity (VA) and central retinal thickness 3 months after therapy. RESULTS: Both groups did not differ regarding preoperative VA and central retinal thickness measured by optical coherence tomography. The baseline mean VA was 0.72 +/- 0.39 logMAR in group 1 and 0.73 +/- 0.39 logMAR in group 2 (p = 0.709). The mean central retinal thickness measured by optical coherence tomography was 548 +/- 185 mum in group 1 and 507 +/- 192 mum in group 2. While the patients in group 1 experienced a slight increase in VA of on average 0.7 lines following a single triamcinolone injection to a mean of 0.64 +/- 0.40 logMAR (p = 0.066) after 3 months, the patients in group 2 showed almost no effect on VA with an average increase of 0.2 lines to a mean VA of 0.72 +/- 0.30 logMAR (p = 0.948) following 3 intravitreal injections of bevacizumab. Comparing the effect on VA between both groups no statistically significant difference (p = 0.115) was noted. Concerning decrease in central retinal thickness both therapies were highly effective (p < 0.001 each), again, without statistically significant difference between the groups (p < 0.128). CONCLUSION: Our data suggest that a single triamcinolone injection may be as effective as a 3 times repeated intravitreal administration of bevacizumab for the treatment of diabetic macular edema. Further prospective trials should be performed. PMID- 20160464 TI - Physical changes in human meibum with age as measured by infrared spectroscopy. AB - Both lipids and mucins contribute to the stability of the tear film and lipids may inhibit tears from evaporating. Younger people have lower lipid viscosity, higher lipid volume, and a lower rate of tear evaporation. Since age-related changes in human meibum composition and conformation have never been investigated, as a basis for the study of lipid-associated changes with meibomian gland dysfunction, we used the power of infrared spectroscopy to characterize hydrocarbon chain conformation and packing in meibum from humans without dry eye symptoms in relation to age and sex. Meibum from normal human donors ranging in age from 3 to 88 years was studied. Meibum phase transitions were quantified by fitting them to a 4-parameter 2-state sigmoidal equation. Human meibum order and phase transition temperatures decrease with age and this trend may be attributed to lipid compositional changes. If meibum has the same thermodynamic properties on the surface of the tears as it does on the lid margin, a decrease in lipid lipid interaction strength with increasing age could decrease the stability of tears since lipid-lipid interactions on the tear surface must be broken for the tear film to break up. This study also serves as a foundation to examine meibum conformational differences in meibum from people with meibomian gland dysfunction. PMID- 20160465 TI - Polymorphisms of 5,10-methylenetetrahydrofolate reductase and cystathionine beta synthase genes as a risk factor for neural tube defects in Setif, Algeria. AB - BACKGROUND: Neural tube defects (NTD) are severe congenital malformations due to a failure in neural tube formation at the beginning of pregnancy. The etiology of NTD is multifactorial, with environmental and genetic determinants. We suggest a study of gene-gene interactions regarding the possible association of NTD with specific mutations of 5,10-methylenetetrahydrofolate reductase (MTHFR) and cystathionine beta-synthase (CBS) genes. PATIENTS AND METHODS: The genetic analysis of the MTHFR C677T polymorphism was performed by real-time polymerase chain reaction (PCR) on a Light Cycler, the CBS genotype was analyzed by PCR in a thermal cycler. Ninety-two mothers who had conceived NTD children and 48 fathers were investigated. A group of 147 adults, including 82 apparently healthy women, was used as control. RESULTS: Among control mothers, 35 (43%) were heterozygous for the C677T variant and 14 (17%) were TT homozygous. Among the cases, 25 (52%) out of 48 mothers and 22 (46%) out of 48 fathers carried the T allele; 9 mothers (19%) and 5 fathers (10%) had the TT genotype. A homozygous C677T mutation was not an NTD risk factor in this preliminary study in an Algerian population; a possible gene-gene interaction between the MTHFR C677T polymorphism and the CBS 844ins68 has also been examined in relation to NTD, but no such association has been shown. There was a statistically significant difference between the heterozygosity genotype frequency of CBS polymorphisms in mothers with a previous child with NTD compared with the mother controls (odds ratio: 3.72; 95% CI: 1.59 8.73). CONCLUSION: Our results with Algerian NTD mothers did not show a significant association for any group, suggesting that the thermolabile variant C677T in the MTHFR gene is not a risk factor for a mother to have NTD offspring; rather, folic acid supplementation or fortification should become mandatory for all women of reproductive age in Algeria. PMID- 20160466 TI - Giant vertebral artery pseudoaneurysm presenting as neck mass. PMID- 20160467 TI - Multiple 'lumps' and 'bumps' in the head with bilateral proptosis: a unique presentation of systemic non-Hodgkin's lymphoma. PMID- 20160468 TI - The C282Y polymorphism of the hereditary hemochromatosis gene is associated with increased sex hormone-binding globulin and normal testosterone levels in men. AB - BACKGROUND: Hereditary hemochromatosis resulting either from homozygosity for the C282Y polymorphism of the HFE gene, or compound heterozygosity for C282Y and H63D, manifests with liver disease and hypogonadism. However, it is unclear whether men who are heterozygotes for C282Y or H63D exhibit subtle abnormalities of sex hormone status. AIMS: To evaluate whether heterozygosity for either of the HFE gene polymorphisms C282Y or H63D is associated with circulating testosterone and SHBG in men. SUBJECTS AND METHODS: We performed a cross-sectional analysis of 388 community-dwelling men. Men were genotyped for C282Y and H63D. Sera were analysed for testosterone and SHBG, and insulin resistance was estimated using a homeostatic model (HOMA2-IR). RESULTS: Mean age of men in the cohort was 56.9 yr. Men who were heterozygous for the C282Y polymorphism in the HFE gene had higher SHBG levels than men who did not carry this polymorphism (mean +/- SE, 38.2 +/- 1.64 vs 32.8 +/- 0.71 nmol/l, p=0.006). Total and free testosterone levels did not differ in the two groups. In multivariate analysis adjusting for potential confounders including age, waist circumference, testosterone, and HOMA2-IR, C282Y heterozygosity remained associated with SHBG levels (p<0.001). CONCLUSION: The C282Y polymorphism is associated with SHBG levels in men who do not manifest iron overload. Further studies are needed to clarify potential mechanisms and determine the clinical relevance of this finding. PMID- 20160469 TI - Comparison between immunoradiometric and fluorimetric brain natriuretic peptide determination in patients with congestive heart failure. AB - This study compared two different methods, namely the immunoradiometric (IRMA) and fluorimetric (FIA), in order to determine plasma brain natriuretic peptide (BNP) in congestive heart failure (CHF) patients. METHODS: CHF in-patients underwent echocardiography and plasma BNP determination using both two methods. The echocardiograms analysed left ventricular end-systolic (LVESV) and end diastolic (LVEDV) volumes and systolic dysfunction [left ventricular ejection fraction (LVEF) <50%]. RESULTS: Seventy-three (71% males, age 67 +/- 9.6 yr) patients were enrolled, 31.5% affected by valvular heart disease. The mean LVEF was 39.8 +/- 14.1%; in 26 (35%) a hypertensive etiology emerged. The immunoradiometric assay (IRMA) BNP was found to be significantly lower than the FIA determination 116.5 +/- 149 pg/ml vs 267.3 +/- 285.6 pg/ml; p=0.0001) and the two methods were closely correlated (r=0.89; p=0.00001). Logistic regression demonstrated a significant correlation between BNP, LVEF, and LVESV/LVEDV (r= 0.45, p=0.0003; r=-0.48, p=0.00001; r=0.22 p=0.003; r=0.34 p=0.0001; r=0.13 p=0.02; r=0.28 p=0.001 IRMA and FIA, respectively). IRMA BNP and FIA BNP significantly increased according to the worsening functional class [from 34.3 +/ 60.2 pg/ml in NYHA (New York Heart Association) I to 555.5 +/- 273.1 pg/ml in NYHA IV; from 86.1 +/- 162.1 pg/ml in NYHA I to 1070 +/- 42.2 pg/ml in NYHA IV, respectively]. In severe systolic dysfunction (LVEF<30%), receiver operating characteristic analysis revealed a satisfactorily sensitivity and specificity using a cut-off point of 50.6 pg/ml with IRMA and 243 pg/ml with FIA. In mild systolic dysfunction (LVEF<50%), a good sensitivity and specificity using a cut off point of 42 pg/ml with IRMA and 182 pg/ml with FIA emerged. CONCLUSIONS: In CHF patients both BNP methods correlated with NYHA class, LVEF, and ventricular volumes. PMID- 20160470 TI - Impairment of cardiovascular autonomic pattern in obese adolescents with Type 2 diabetes mellitus. AB - The aim of this study was to assess the behaviour of insulin sensitivity and insulin resistance (IR) indexes in a group of obese adolescents with Type 2 diabetes mellitus (T2DM) in comparison to obese adolescents without diabetes and normal controls, moreover to compare these parameters with the cardiac autonomic pattern. Seven T2DM obese (12.7 +/- 0.5 yr), 18 obese without T2DM, and 10 nonobese control adolescents age matched were studied. In all subjects we performed oral glucose tolerance test (OGTT) with insulin and glucose determination, 24-h electrocardiogram Holter, blood pressure monitoring, ecohocardiogram. RESULTS: serum lipids were significantly higher in obese and T2DM. Insulin sensitivity was significantly reduced in T2DM and obese vs controls; T2DM showed a more pronounced oral glucose insulin sensitivity (OGIS) reduction vs obese. Both obese and T2DM presented an higher IR. T2DM showed an impaired beta-cell function, with insulin areas under the curve and disposition index significantly reduced in comparison to controls and obese who showed similar values. A progressive reduction of vagal indexes and an increase of sympathetic indexes were found in obese adolescents and were more pronounced in T2DM. These parameters were correlated with OGIS and beta-cell function parameters in both obese and T2DM adolescents. T2DM showed a significant relative wall thickness increase suggesting a trend toward concentric remodeling. In conclusion, T2DM adolescents are characterized by a more marked IR reduced beta cell function in comparison to non-diabetic obese. These modifications may lead to an early impairment of the autonomic pattern. PMID- 20160471 TI - Body dissatisfaction, abnormal eating behaviours and eating disorder attitude in homo- and heterosexuals. AB - OBJECTIVE: The primary aim of this study was to investigate the relationship between sexual orientation and disordered eating attitudes and behaviours in a sample of homosexuals and heterosexuals subject. METHODS: We screened 110 homosexuals (85 males and 25 females) and 121 heterosexuals (85 males and 36 females) by means of: a) an ad hoc socio-demographic schedule; b) the Eating Disorders Inventory 2 (EDI 2); the Eating Disorders Inventory 2 - Symptom Checklist (EDI-SC); the Body Uneasiness Test (BUT). RESULTS: Male homosexuals obtained much higher scores than male heterosexuals on the EDI 2 Drive for thinness, Bulimia, Ineffectiveness, Interoceptive awareness, Impulse regulation scales and on all the BUT subscales. Similarly, with regard to eating behaviours, a significantly higher frequency in the use of strategies to compensate weight increase was observed. On all these scales the sample of homosexual males did not show any significant differences from the group of hetero- and homosexual women. The male homosexuals who claimed they were not in a stable relationship scored higher in all the variables considered. DISCUSSION: Our findings seem to suggest that homosexual orientation is associated with greater body dissatisfaction and abnormal eating behaviours in males, in particular among those who claimed they were not in a sentimental relationship. PMID- 20160472 TI - Regulation of myogenic stem cell behavior by vessel cells: the "menage a trois" of satellite cells, periendothelial cells and endothelial cells. AB - In skeletal muscle, satellite cells, that are responsible of muscle repair, are localized close to capillaries. Although angiogenesis is known for a long time to be crucial for muscle repair and satellite cell survival, cellular interplays between vessel cells and satellite/myogenic cells have been poorly explored. We analyzed the interrelationships between myogenic cells, endothelial cells, and periendothelial cells that includes smooth muscle cells and endomysial fibroblasts. We found that endothelial cells strongly stimulate myogenic cell growth and, inversely, myogenic cells increase angiogenesis. VEGF plays an essential role in this bidirectional interaction. On the contrary, periendothelial cells promote the return to quiescence of a subset of muscle precursor cells that ensures self-renewal of adult muscle stem cells. We have shown that Angiopoietin-1/Tie-2 signaling controls the entry into quiescence. We propose that during muscle regeneration, i.e., while vessels are not stabilized, endothelial cells and myogenic cells interact with each other to promote both myogenesis and angiogenesis, that have been shown to be concomitant processes in several models. On the other hand, once homeostasis of muscle is reached, the proximity of satellite cells and periendothelial cells allows the responsiveness of satellite cells, that bear Tie-2 receptor, to the secretion of Angiopoietin-1 by periendothelial cells, that, in the same time, stabilize vessels by promoting quiescence of endothelial cells. PMID- 20160473 TI - Tumor initiation via loss of cell contact inhibition versus Ras mutation: do all roads lead to EMT? AB - Many tumors have been found to contain a subset of cells referred to as cancer stem cells. As opposed to the remainder of the tumor, these cells are undifferentiated-they do not express markers of differentiation and they can re express stem cell specification genes. The cells can divide asymmetrically to yield differentiated cells as well as cells comprising the original heterogeneous population of the tumor while maintaining their number. Because cancer stem cells display some properties of stem cells, it has been presumed that the presence of such cells in tumors reflects a stem cell origin for cancer. However, recent studies suggest that cancer can originate with outgrowth of differentiated somatic cells, and that cells with properties of cancer stem cells can be generated as tumors progress. Appearance of such cells may be linked to reprogramming of differentiated somatic cells to a stem cell-like phenotype by overexpression of transcription factors involved in epithelial-mesenchymal transition (EMT). We discuss recent studies from our group and other laboratories linking cell outgrowth in tumors to inhibition of the RB1 pathway, loss of cell contact inhibition and generation of undifferentiated cancer stem-like cells from somatic cells. And, we compare this pathway to that arising with introduction of mutant Ras in cells. PMID- 20160474 TI - Characterization of structural variability sheds light on the specificity determinants of the interaction between effector domains and histone tails. AB - Structural characterization of the interaction between histone tails and effector modules (bromodomains, chromodomains, PHD fingers, etc.) is fundamental to understand the mechanistic aspects of epigenetic regulation of gene expression. In recent years many researchers have applied this approach to specific systems, thus providing a valuable but fragmentary view of the histone-effector interaction. In our work we use this information to characterize the structural features of the two main components of this interaction, histone peptides and the binding site of effector domains (focusing on those which target modified lysines), and increase our knowledge on its specificity determinants. Our results show that the binding sites of effectors are structurally variable, but some clear trends allow their classification in three main groups: flat-groove, narrow groove and cavity-insertion. In addition, we found that even within these classes binding site variability is substantial. These results in context with the work from other researchers indicate that the there are at least two determinants of binding specificity in the binding site of effector modules. Finally, our analysis of the histone peptides sheds light on the structural transition experienced by histone tails upon effector binding, showing that it may vary depending on the local properties of the sequence stretch considered, thus allowing us to identify an additional specificity determinant for this interaction. Overall, the results of our analysis contribute to clarify the origins of specificity: different regions of the binding site and, in particular, differences in the disorder-order transitions experienced by different histone sequence stretches upon binding. PMID- 20160475 TI - Inhibition of focal adhesion kinase decreases tumor growth in human neuroblastoma. AB - Neuroblastoma is the most common extracranial solid tumor of childhood. Focal adhesion kinase (FAK) is an intracellular kinase that regulates both cellular adhesion and apoptosis. FAK is overexpressed in a number of human tumors including neuroblastoma. Previously, we have shown that the MYCN oncogene, the primary adverse prognostic indicator in neuroblastoma, regulates the expression of FAK in neuroblastoma. In this study, we have examined the effects of FAK inhibition upon neuroblastoma using a small molecule [1,2,4,5-benzenetetraamine tetrahydrochloride (Y15)] to inhibit FAK expression and the phosphorylation of FAK at the Y397 site. Utilizing both non-isogenic and isogenic MYCN(+)/MYCN(-) neuroblastoma cell lines, we found that Y15 effectively diminished phosphorylation of the Y397 site of FAK. Treatment with Y15 resulted in increased detachment, decreased cell viability and increased apoptosis in the neuroblastoma cell lines. We also found that the cell lines with higher MYCN are more sensitive to Y15 treatment than their MYCN negative counterparts. In addition, we have shown that treatment with Y15 in vivo leads to less tumor growth in nude mouse xenograft models, again with the greatest effects seen in MYCN(+) tumor xenografts. The results of the current study suggest that FAK and phosphorylation at the Y397 site plays a role in neuroblastoma cell survival, and that the FAK Y397 phosphorylation site is a potential therapeutic target for this childhood tumor. PMID- 20160476 TI - Mutation of the DEAD-box helicase belle downregulates the cyclin-dependent kinase inhibitor Dacapo. AB - The retinoblastoma protein (pRB) negatively regulates cell proliferation by limiting the activity of the family of E2F transcription factors. In Drosophila, mutation of the DEAD-box helicase belle (bel) relieves an E2F/pRB induced G(1) cell cycle arrest; however, the mechanism of this rescue is unknown. Here, we show that the level of the cyclin-dependent kinase inhibitor Dacapo (Dap), homolog of mammalian p21/p27, is strongly reduced both in bel mutant cells in vivo and in tissue culture cells depleted of Bel by RNA interference. Interestingly, the loss of bel also partially alleviates an ectopically induced G(1) cell cycle arrest. Additionally, we show that Bel undergoes nucleocytoplasmic shuttling. Thus, inactivation of bel renders cells less sensitive to several anti-proliferative signals inducing G(1) arrest. PMID- 20160477 TI - Phosphorylation of Ser72 is dispensable for Skp2 assembly into an active SCF ubiquitin ligase and its subcellular localization. AB - F-box proteins are the substrate recognition subunits of SCF (Skp1, Cul1, F-box protein) ubiquitin ligase complexes. Skp2 is a nuclear F-box protein that targets the CDK inhibitor p27 for ubiquitin- and proteasome-dependent degradation. In G(0) and during the G(1) phase of the cell cycle, Skp2 is degraded via the APC/C(Cdh1) ubiquitin ligase to allow stabilization of p27 and inhibition of CDKs, facilitating the maintenance of the G(0)/G(1) state. APC/C(Cdh1) binds Skp2 through an N-terminal domain (amino acids 46-94 in human Skp2). It has been shown that phosphorylation of Ser64 and Ser72 in this domain dissociates Skp2 from APC/C. More recently, it has instead been proposed that phosphorylation of Skp2 on Ser72 by Akt/PKB allows Skp2 binding to Skp1, promoting the assembly of an active SCF(Skp2) ubiquitin ligase, and Skp2 relocalization/retention into the cytoplasm, promoting cell migration via an unknown mechanism. According to these reports, a Skp2 mutant in which Ser72 is substituted with Ala is unable to promote cell proliferation and loses its oncogenic potential. Given the contrasting reports, we revisited these results and conclude that phosphorylation of Skp2 on Ser72 does not control Skp2 binding to Skp1 and Cul1, has no influence on SCF(Skp2) ubiquitin ligase activity, and does not affect the subcellular localization of Skp2. PMID- 20160478 TI - Ubiquitin editing enzyme UCH L1 and microtubule dynamics: implication in mitosis. AB - Microtubules are essential components of the cytoskeleton and are involved in many aspects of cell responses including cell division, migration, and intracellular signal transduction. Among other factors, post-translational modifications play a significant role in the regulation of microtubule dynamics. Here, we demonstrate that the ubiquitin-editing enzyme UCH L1, abundant expression of which is normally restricted to brain tissue, is also a part of the microtubule network in a variety of transformed cells. Moreover, during mitosis, endogenous UCH L1 is expressed and tightly associated with the mitotic spindle through all stages of M phase, suggesting that UCH L1 is involved in regulation of microtubule dynamics. Indeed, addition of recombinant UCH L1 to the reaction of tubulin polymerization in vitro had an inhibitory effect on microtubule formation. Unexpectedly, western blot analysis of tubulin fractions after polymerization revealed the presence of a specific approximately 50 kDa band of UCH L1 (not the normal approximately 25 kDa) in association with microtubules, but not with free tubulin. In addition, we show that along with 25 kDa UCH L1, endogenous high molecular weight UCH L1 complexes exist in cells, and that levels of 50 kDa UCH L1 complexes are increasing in cells during mitosis. Finally, we provide evidence that ubiquitination is involved in tubulin polymerization: the presence of ubiquitin during polymerization in vitro by itself inhibited microtubule formation and enhanced the inhibitory effect of added UCH L1. The inhibitory effects of UCH L1 correlate with an increase in ubiquitination of microtubule components. Since besides being a deubiquitinating enzyme, UCH L1 as a dimer has also been shown to exhibit ubiquitin ligase activity, we discuss the possibility that the approximately 50 kDa UCH L1 observed is a dimer which prevents microtubule formation through ubiquitination of tubulins and/or microtubule-associated proteins. PMID- 20160479 TI - Epstein-Barr virus in Burkitt's lymphoma: a role for latent membrane protein 2A. AB - Burkitt's lymphoma (BL) is characterized by translocation of the MYC gene to an immunoglobulin locus. Transgenic mouse models have been used to study the molecular changes that are necessary to bypass tumor suppression in the presence of translocated MYC. Inactivation of the p53 pathway is a major step to tumor formation in mouse models that is also seen in human disease. Human BL is often highly associated with Epstein-Barr virus (EBV). The EBV latency protein latent membrane protein 2A (LMP2A) is known to promote B cell survival by affecting levels of pro-survival factors. Using LMP2A transgenic mouse models, we have identified a novel mechanism that permits lymphomagenesis in the presence of an intact p53 pathway. This work uncovers a contribution of EBV to molecular events that have documented importance in BL pathogenesis, and may underlie the poorly understood link between EBV and BL. PMID- 20160481 TI - PERpetual motion of the circadian negative feedback loop. PMID- 20160480 TI - New research resources at the Bloomington Drosophila Stock Center. AB - The Bloomington Drosophila Stock Center (BDSC) is a primary source of Drosophila stocks for researchers all over the world. It houses over 27,000 unique fly lines and distributed over 160,000 samples of these stocks this past year. This report provides a brief overview of significant recent events at the BDSC with a focus on new stock sets acquired in the past year, including stocks for phiC31 transformation, RNAi knockdown of gene expression, and SNP and quantitative trait loci discovery. We also describe additions to sets of insertions and molecularly defined chromosomal deficiencies, the creation of a new Deficiency Kit, and planned additions of X chromosome duplication sets. PMID- 20160482 TI - Phosphorylation of Ser72 does not regulate the ubiquitin ligase activity and subcellular localization of Skp2. AB - Skp2 is the substrate binding subunit of the SCF(Skp2) ubiquitin ligase, which plays a key role in the regulation of cell cycle progression. The activity of Skp2 is regulated by the APC(Cdh1), which targets Skp2 for degradation in early G(1) and prevent premature S phase entry. Overexpression of Skp2 leads to dysregulation of the cell cycle and is commonly observed in human cancers. We have previously shown that Skp2 is phosphorylated on Ser64 and Ser72 in vivo, and that these modifications regulate its stability. Recently, two studies have proposed a role for Ser72 phosphorylation in the cytosolic relocalization of Skp2 and in the assembly and activity of SCF(Skp2) ubiquitin ligase complex. We have revisited this question and analyzed the impact of Ser72 phosphorylation site mutations on the biological activity and subcellular localization of Skp2. We show here that phosphorylation of Ser72 does not control Skp2 binding to Skp1 and Cul1, has no influence on SCF(Skp2) ubiquitin ligase activity, and does not affect the subcellular localization of Skp2 in a panel of cell lines. PMID- 20160483 TI - Epigenetic regulation of androgen receptor signaling in prostate cancer. AB - Prostate cancer is the most common cancer in men in the United States, and it is the second leading cause of cancer-related death in American men. The Androgen receptor (AR), a nuclear hormone and transcription factor, is the most therapeutically relevant target in this disease. While most efforts in the clinic are still directed at lowering levels of androgens that activate AR, resistance to androgen deprivation eventually develops, and most prostate cancer deaths are attributable to this castration-resistant form of this disease. Recent work has shed light on the importance of epigenetic events including facilitation of AR signaling by histone-modifying enzymes and also on the role that enzymes such as HDAC6 play in stabilizing AR in prostate cancer cells. Herein, we summarize recent findings on the role of epigenetic enzymes in AR signaling and highlight examples on how interdiction of critical epigenetic enzymes may attenuate AR action in prostate cancer. PMID- 20160484 TI - Targeting the degradation of cyclin D1 will help to eliminate oncogene addiction. PMID- 20160485 TI - The Mdm2 and p53 genes are conserved in the Arachnids. AB - The p53 protein and its negative regulator the ubiquitin E3 ligase Mdm2 have been shown to be conserved from the T. adhaerens to man. In common with D. melanogaster and C. elegans, there is a single copy of the p53 gene in T. adhaerens, while in the vertebrates three p53-like genes can be found: p53, p63 and p73. The Mdm2 gene is not present within the fully sequenced and highly annotated genomes of C. elegans and D. melanogaster. However, it is present in Placazoanand the presence of multiple distinct p53 genes in the Sea anemone N. vectensis led us to examine the genomes of other phyla for p53 and Mdm2-like genes. We report here the discovery of an Mdm2-like gene and two distinct p53 like genes in the Arachnid Ioxodes scapularis (Northern Deer Tick). The two predicted Deer Tick p53 proteins are much more highly related to the human p53 protein in sequence than are the fruit fly and nematode proteins. One of the Deer Tick genes encodes a p53 protein that is initiated within the DNA binding domain of p53 and shows remarkable homology to the newly described N-terminally truncated delta isoforms of human and zebrafish p53. PMID- 20160486 TI - Induction of pluripotency in human endothelial cells resets epigenetic profile on genome scale. AB - Reprogramming of a limited number of human cell types has been achieved through ectopic expression of four transcription factors to yield induced pluripotent stem (iPS) cells that closely resemble human embryonic stem cells (ESCs). Here, we determined functional and epigenetic properties of iPS cells generated from human umbilical vein endothelial cells (HUVEC) by conventional method of direct reprogramming. Retroviral overexpression of four transcription factors resets HUVEC to the pluripotency. Human endothelial cell-derived iPS (endo-iPS) cells were similar to human ESCs in morphology, gene expression, in vitro and in vivo differentiation capacity. Endo-iPS cells were efficiently differentiated in vitro into endothelial cells. Using genome-wide methylation profiling we show that promoter elements of endothelial specific genes were methylated following reprogramming whereas pluripotency-related gene promoters were hypomethylated similar to levels observed in ESCs. Genome-wide methylation analysis of CpG sites located in the functional regions of over than 14,000 genes indicated that human endo-iPS cells were highly similar to human ES cells, although differences in methylation levels of 46 genes were found. Overall CpG methylation of promoter regions in the pluripotent cells was higher than in somatic. We also show that during reprogramming female human endo-iPS cells exhibited reactivation of the somatically silenced X chromosome. Our findings demonstrate that iPS cells can be generated from human endothelial cells and reprogramming resets epigenetic status of endothelial cells to pluripotency. PMID- 20160487 TI - ZEB proteins link cell motility with cell cycle control and cell survival in cancer. AB - Epithelial mesenchymal transitions (EMT), the generation of motile mesenchymal cells from epithelial sheets, are differentiation programs which take place at several critical steps of embryonic development and in metastatic cancer. Recent data have shown that the transcription factors which are master regulators of EMT also regulate cell cycle progression, apoptosis and senescence. In light of these new observations, the role of these factors in human cancer may be broader than previously anticipated. Here we review recent literature on non-EMT functions of EMT-controlling transcription factors. We will mainly focus on transcription factors belonging to the ZEB family, but some important results obtained by investigators studying other key EMT regulators, Snail and Twist are also discussed. PMID- 20160488 TI - Approaching the molecular and physiological function of macroH2A variants. AB - The transition of a cell from one state to another involves large changes in the organization of its chromatin. Indeed, it has become increasingly clear that modifications of the chromatin are the molecular basis of an epigenetic memory that defines cellular identity. Histone variants are likely candidates to contribute to epigenetic regulations. Genome-wide profiling of the unusual macroH2A histone variants and the identification of interacting proteins provided important clues to their molecular and physiological function. PMID- 20160489 TI - Differences underlying EGFR and HER2 oncogene addiction. PMID- 20160490 TI - Negative regulation of CHK2 activity by protein phosphatase 2A is modulated by DNA damage. AB - Checkpoint kinase 2 (CHK2) is a major effector of the DNA damage response pathway and although its mechanism of activation has been well studied, the attenuation of its activity following DNA damage has not been explored. Here, we identify the B'alpha subunit of protein phosphatase 2A (PP 2A) as a CHK2 binding partner and show that their interaction is modulated by DNA damage. B'alpha binds to the SQ/TQ repeat region of CHK2, which is a target of ATM phosphorylation. The induction of DNA double-strand breaks by gamma irradiation as well as treatment with doxorubicin causes dissociation of the B'alpha and CHK2 proteins. This dissociation correlates with an increase in the ATM-dependent phosphorylation of CHK2 at serines 33 and 35 in the SQ/TQ region. Indeed, mutating these sites to mimic phosphorylation increases the dissociation after irradiation. PP 2A negatively regulates CHK2 phosphorylation at multiple sites, as well as its kinase activity. These data reveal a novel mechanism for PP 2A to keep CHK2 inactive under normal conditions while also allowing for a rapid release from this regulation immediately following DNA damage. This is followed by a subsequent reconstitution of the PP 2A/CHK2 complex in later time points after damage, which may help to attenuate the signal. PMID- 20160491 TI - Emerging functions of force-producing kinetochore motors. AB - More than two decades of research has resulted in the identification of some 60 microtubule motor proteins, several of which have been implicated in mitosis. Although some kinesin super-family proteins function as microtubule depolymerases at kinetochores, such as Kinesin-8 and -13, it is now appreciated that there are only two force-producing kinetochore associated motors, the plus end-directed microtubule motor CENP-E and the minus end-directed microtubule motor cytoplasmic dynein. Defining their roles at kinetochores has been hampered by the complexity of mitosis itself, and a multiplicity of mitotic roles, at least for cytoplasmic dynein. Nonetheless, recent advances have served to define the primary roles of the two kinetochore motors in detail. PMID- 20160492 TI - Genomic analysis of pandemic (H1N1) 2009 reveals association of increasing disease severity with emergence of novel hemagglutinin mutations. AB - Experimental studies and epidemiological observations during the first wave of the pandemic (H1N1) 2009 suggest that a novel influenza A (H1N1) virus has significant pandemic potential based on high transmissibility of the virus. Substantial uncertainty remains regarding evolution of the clinical severity of this pandemic during the transition to the second wave which is currently underway in the Northern Hemisphere. We carried-out analysis of large volume of clinical, epidemiological and genomics data for assessment of evolution of the current pandemic in United States, Canada, United Kingdom, Australia and Japan based on official reports of public health agencies of corresponding countries. Analysis of reported sequences of virus strains isolated from postmortem samples indicates that 42.9% of individuals who died from laboratory-confirmed cases of the pandemic (H1N1) were infected with the hemagglutinin (HA) Q310H mutant virus. Overall, six of seven (86%) of virus isolates recovered from the necropsy samples have at least one mutation within the HA 301-316 or HA 219-240 regions. During the second wave of the pandemic (H1N1) 2009, there is an increased number of reported double mutant virus isolates with mutations within both of these HA regions. Mutations within HA 219-240 region at the position D239 (D239E/G/N) are reported with higher frequency. In addition, D239G mutants were detected more frequently in viruses isolated from patients with fatal outcomes and in isolates from lungs. Multiple viral isolates with the novel HA 301-316 mutations (I312V and P314S) have been documented. Statistically significant increase of detection of mutant viruses and H1N1-related death rates is documented in July-September reporting time periods. Our analysis seems to indicate that evolution of current pandemic is associated with notable changes in mortality rate among hospitalized patients and increasing number of reported cases of novel mutations of HA gene. Recently emerged HA mutants are: (1) detected in large proportion of virus isolates recovered from the postmortem samples; (2) documented in multiple independent reports around the world; (3) expanding within global viral population; (4) manifesting spatial and temporal patterns of association with increased mortality rate of hospitalized patients. Identification of candidate virus mutants with potential association to increasing disease severity should facilitate clinical and experimental testing of the validity of both "antigenic drift" and increase virulence hypotheses. The results of these follow-up experiments may have a significant impact on ultimate outcomes of current pandemic. Our analysis indicates the urgent need for international surveillance systems that track disease severity and individual patient influenza sequence data in a representative fashion. Information gained from this type of surveillance will direct experimental work that assesses influenza strainspecific features of virulence and transmissibility through carefully designed and timely executed laboratory studies. Practical implementation of these surveillance systems would facilitate the timely evidence-based resolution of critically important relationships between the antigenic drift of mutant strains and immunogenicity of existing vaccines which should be assessed in the laboratory setting during the course of the ongoing pandemic. PMID- 20160493 TI - Elevation in serum lactate at the time of febrile neutropenia (FN) in hemodynamically-stable patients with hematologic malignancies (HM) is associated with the development of septic shock within 48 hours. AB - BACKGROUND: Hospitalized patients who develop febrile neutropenia (FN) are treated empirically with antibiotics due to a high risk of developing septic shock. Currently, there is no method to predict which patients are at greatest risk. This study was designed to determine whether serum lactate, measured at the time of FN, is associated with the development of septic shock in hospitalized hematologic malignancy (HM) patients. RESULTS: Of the 547 patients enrolled, 46 (8.4%; 95% CI 6.2-10.9) developed septic shock. Baseline characteristics were similar between the groups. In univariate analysis, tachypnea (OR 5.9; 95% CI: 2.0-16.9, p = 0.001) and lactate (OR 18.4; 95% CI: 4.1-81.6, p < 0.001) were significantly associated with the development of septic shock. In multivariate analysis, lactate and tachypnea remained independently associated with the development of septic shock. By ROC analysis, lactate provided incremental prognostic value compared to vital signs alone. METHODS: Vital signs and lactate were measured during episodes of FN. The primary endpoint was the development of septic shock. Using a prospective, nested, case-control design, controls were matched on length of stay at the time of septic shock to achieve 80% power to detect an OR of >or=2.5. Using logistic regression, we evaluated the association of vital signs and lactate with the subsequent development of septic shock. CONCLUSIONS: In FN patients, measurement of lactate during FN adds significant prognostic information about the risk of developing septic shock. Routine measurement of lactate may help identify patients who may benefit from increased monitoring and early intervention strategies. PMID- 20160494 TI - Chk1 inhibition after replicative stress activates a double strand break response mediated by ATM and DNA-dependent protein kinase. AB - Checkpoint kinase 1 (Chk1) regulates cell cycle checkpoints and DNA damage repair in response to genotoxic stress. Inhibition of Chk1 is an emerging strategy for potentiating the cytotoxicity of chemotherapeutic drugs. Here, we demonstrate that AZD7762, an ATP -competitive Chk1/2 inhibitor induces gammaH2AX in gemcitabine-treated cells by altering both dynamics and stability of replication forks, allowing the firing of suppressed replication origins as measured by DNA fiber combing and causing a dramatic increase in DNA breaks as measured by comet assay. Furthermore, we identify ATM and DNA-PK, rather than ATR, as the kinases mediating gammaH2AX induction, suggesting AZD7762 converts stalled forks into double strand breaks (DSBs). Consistent with DSB formation upon fork collapse, cells deficient in DSB repair by lack of BRCA2, XRCC3 or DNA-PK were selectively more sensitive to combined AZD7762 and gemcitabine. Checkpoint abrogation by AZD7762 also caused premature mitosis in gemcitabine-treated cells arrested in G(1)/early S-phase. Prevention of premature mitotic entry via Cdk1 siRNA knockdown suppressed apoptosis. These results demonstrate that chemosensitization of gemcitabine by Chk1 inhibition results from at least three cellular events, namely, activation of origin firing, destabilization of stalled replication forks and entry of cells with damaged DNA into lethal mitosis. Additionally, the current study indicates that the combination of Chk1 inhibitor and gemcitabine may be particularly effective in targeting tumors with specific DNA repair defects. PMID- 20160495 TI - ZD6474 coerces breast cancer for an apoptotic journey. PMID- 20160496 TI - p53-mediated induction of Noxa and p53AIP1 requires NFkappaB. AB - The intricate regulation of cell survival and cell death is critical for the existence of both normal and transformed cells. Two factors central to these processes are p53 and NFkappaB, with both factors having ascribed roles in both promoting and repressing cell death. Not surprisingly, a number of studies have previously reported interplay between p53 and NFkappaB. The mechanistic basis behind these observations, however, is currently incomplete. We report here further insights into this interplay using a system where blockade of NFkappaB inhibits cell death from p53, but at the same time sensitizes cells to death by TNFalpha. We found in agreement with a recent report showing that NFkappaB is required for the efficient activation of the BH3-only protein Noxa by the p53 family member p73, that p53's ability to induce Noxa is also impeded by inhibition of NFkappaB. In contrast to the regulation by p73, however, blockade of NFkappaB downstream of p53 decreases Noxa protein levels without effects on Noxa mRNA. Our further analysis of the effects of NFkappaB inhibition on p53 target gene expression revealed that while most target genes analysed where unaffected by blockade of NFkappaB, the p53-mediated induction of the pro apoptotic gene p53AIP1 was significantly dependent on NFkappaB. These studies therefore add further insight into the complex relationship of p53 and NFkappaB. In addition, since both Noxa and p53AIP1 have been shown to be important components of p53-mediated cell death responses, these findings may also indicate critical points where NFkappaB plays a pro-apoptotic role downstream of p53. PMID- 20160497 TI - Activation of epithelial STAT3 regulates intestinal homeostasis. AB - The intestinal epithelium that lines the mucosal surface along the GI-tract is a key player for the intestinal homeostasis of the healthy individual. In case of a mucosal damage or a barrier defect as seen in patients with inflammatory bowel disease, the balance is disturbed, and translocation of intestinal microbes to the submucosa is facilitated. We recently demonstrated a pivotal role of STAT3 activation in intestinal epithelial cells (IEC) for the restoration of the balance at the mucosal surface of the gut in an experimental colitis model. STAT3 was rapidly induced in intestinal epithelial cells upon challenge of mice in both experimental colitis and intestinal wound healing models. STAT3 activation was found to be dispensable in the steady-state conditions but was important for efficient regeneration of the epithelium in response to injury. Here, we extend our previous findings by showing epithelial STAT3 activation in human patients suffering from IBD and provide additional insights how the activation of epithelial STAT3 by IL-22 regulates intestinal homeostasis and mucosal wound healing. We also demonstrate that antibody-mediated neutralization of IL-22 has little impact on the development of experimental colitis in mice, but significantly delays recovery from colitis. Thus, our data suggest that targeting the STAT3 signaling pathway in IEC is a promising therapeutic approach in situations when the intestinal homeostasis is disturbed, e.g., as seen in Crohn's disease or Ulcerative colitis. PMID- 20160498 TI - The transcriptional regulation of miR-21, its multiple transcripts, and their implication in prostate cancer. AB - MicroRNAs (miRNAs) are a natural part of the most recently discovered and global regulatory pathway known as RNA interference. Functional studies have shown how specific miRNAs can function as tumor suppressors or oncogenes and, correspondingly, deregulated miRNA profiles have been observed in prostate and other cancers. However, the upstream pathways which regulate miRNA expression are only currently being uncovered. The Androgen Receptor (AR) is a nuclear hormone receptor and transcription factor which plays a paramount role in prostate cancer (PCa) pathobiology. We performed high throughput miRNA microarray analysis on two AR-responsive cell lines to identified 16 candidate AR-regulated miRNAs.(1) One of the most androgen-induced candidates was a known oncogenic miRNA, miR-21. In a small study of early grade PCa samples we found that miR-21 levels were frequently elevated in comparison to adjacent normal tissue. This observation was supported in the literature(2,3) and suggests clinical relevance. We found that the activated AR directly interacts with miR-21 regulatory regions, indicating direct transcriptional induction. Furthermore, we provide new reporter studies supporting AR-regulation. Importantly, in functional studies, we found that a modest overexpression of miR-21 enhanced tumor xenograft growth and was sufficient to support androgen-independent proliferation following surgical castration. Thus, our studies suggest a model where miR-21 contributes to androgen-dependent and androgen-independent PCa growth. However, the AR is only one of many reported transcriptional regulators of miR-21. Here we review our recent discoveries and further analyze the reported miR-21 regulatory regions, inhibitory and stimulatory signaling pathways, and primary transcripts. PMID- 20160500 TI - Pathological angiogenesis facilitates tumor cell dissemination and metastasis. AB - Clinically detectable metastases represent an ultimate consequence of the metastatic cascade that consists of distinct processes including tumor cell invasion, dissemination, metastatic niche formation, and re-growth into a detectable metastatic mass. Although angiogenesis is known to promote tumor growth, its role in facilitating early events of the metastatic cascade remains poorly understood. We have recently developed a zebrafish tumor model that enables us to study involvement of pathological angiogenesis in tumor invasion, dissemination and metastasis. This non-invasive in vivo model allows detection of single malignant cell dissemination under both normoxia and hypoxia. Further, hypoxia-induced VEGF significantly facilitates tumor cell invasion and dissemination. These findings demonstrate that VEGF-induced pathological angiogenesis is essential for tumor dissemination and further corroborates potentially beneficial effects of clinically ongoing anti-VEGF drugs for the treatment of various malignancies. PMID- 20160501 TI - GDP366, a novel small molecule dual inhibitor of survivin and Op18, induces cell growth inhibition, cellular senescence and mitotic catastrophe in human cancer cells. AB - Accumulating evidence indicates that survivin plays a pivotal role in not only cell survival but also cell cycle progression. Op18/stathmin is an oncoprotein that regulates microtubule stabilization. Both survivin and Op18 have been proposed as therapeutic targets for cancer. However, few small molecule inhibitors of survivin and Op18 have been reported. In this study, we have identified a novel small molecule compound (GDP366) which potently and selectively inhibited the expression of both survivin and Op18. It decreased both the mRNA and protein levels of survivin and Op18. This inhibitory effect was not dependent on the status of p53 and p21 although GDP366 potently increased p53 and p21 levels. GDP366 significantly inhibited the growth of tumor cells in vitro and in vivo (nude mouse model) without rapid induction of apoptosis. GDP366 induced polyploidy in multiple types of cancer cell lines. GDP366 increased chromosomal instability, and induced cellular senescence by inhibiting telomerase activity. We conclude that GDP366 is a novel dual inhibitor of survivin and Op18. Our results warrant further translational evaluation of this compound. PMID- 20160502 TI - The eye imaginal disc as a model to study the coordination of neuronal and glial development. AB - A complex nervous system comprises two distinct cell types, neurons and glial cells, whose development, differentiation and function is mutually interdependent. Many studies contributed to uncovering the basic mechanisms determining neuronal and glial fate and we are progressing enormously towards an understanding of how neurons interconnect to form intricate neuronal networks. However, the mechanisms used to couple neuronal and glial development remain largely obscure. Here we advocate the usefulness of the developing Drosophila compound eye as a new model to study the complex relationship between glial and neuronal cells. PMID- 20160499 TI - Sex determination in Drosophila: The view from the top. AB - One of the most important decisions in development is whether to be male or female. In Drosophila melanogaster, most cells make this choice independent of their neighbors such that diploid cells with one X chromosome (XY) are male and those with two X chromosomes (XX) are female. X-chromosome number is relayed through regulatory proteins that act together to activate Sex-lethal (Sxl) in XX animals. The resulting SXL female specific RNA binding protein modulates the expression of a set of downstream genes, ultimately leading to sexually dimorphic structures and behaviors. Despite the apparent simplicity of this mechanism, Sxl activity is controlled by a host of transcriptional and posttranscriptional mechanisms that tailor its function to specific developmental scenarios. This review describes recent advances in our understanding of Sxl regulation and function, highlighting work that challenges some of the textbook views about this classical (often cited, yet poorly understood) binary switch gene. PMID- 20160503 TI - Turnover and lineage-specific broadening of the transcription start site in a testis-specific retrogene. AB - Proteasomes are large multisubunit complexes responsible for regulated protein degradation. Made of a core particle (20S) and regulatory caps (19S), proteasomal proteins are encoded by at least 33 genes, of which 12 have been shown to have testis-specific isoforms in Drosophila melanogaster. Pros28.1A (also known as Prosalpha4T1), a young retroduplicate copy of Pros28.1 (also known as Prosalpha4), is one of these isoforms. It is present in the D. melanogaster subgroup and was previously shown to be testis-specific in D. melanogaster. Here, we show its testis-specific transcription in all D. melanogaster subgroup species. Due to this conserved pattern of expression in the species harboring this insertion, we initially expected that a regulatory region common to these species evolved prior to the speciation event. We determined that the region driving testis expression in D. melanogaster is not far from the coding region (within 272 bp upstream of the ATG). However, different Transcription Start Sites (TSSs) are used in D. melanogaster and D. simulans, and a "broad" transcription start site is used in D. yakuba. These results suggest one of the following scenarios: (1) there is a conserved motif in the 5' region of the gene that can be used as an upstream or downstream element or at different distance depending on the species; (2) different species evolved diverse regulatory sequences for the same pattern of expression (i.e., "TSS turnover"); or (3) the transcription start site can be broad or narrow depending on the species. This work reveals the difficulties of studying gene regulation in one species and extrapolating those findings to close relatives. PMID- 20160504 TI - methGraph: a genome visualization tool for PCR-based methylation assays. AB - Abnormalities in DNA methylation of CpG islands that play a role in gene regulation affect gene expression and hence play a role in disease, including cancer. Bisulfite-based DNA methylation analysis methods such as methylation specific PCR (MSP) and bisulfite sequencing (BiSeq) are most commonly used to study gene-specific DNA methylation. Assessing specificity and visualizing the position of PCR primers in their genomic context is a laborious and tedious task, primarily due to the sequence changes induced during the bisulfite conversion. For this purpose, we developed methGraph, a web application for easy, fast and flexible visualization and accurate in silico quality evaluation of PCR-based methylation assays. The visualization process starts by submitting PCR primer sequences for specificity assessment and mapping on the genome using the BiSearch ePCR primer-search algorithm. The next step comprises the selection of relevant UCSC genome annotation tracks for display in the final graph. A custom track showing all individual CpG dinucleotides, representing their distribution in the CpG island is also provided. Finally, methGraph creates a BED file that is automatically uploaded to the UCSC genome browser, after which the resulting image files are extracted and made available for visualization and download. The generated high-quality figures can easily be customized and exported for use in publications or presentations. methGraph is available at http://mellfire.ugent.be/methgraph/. PMID- 20160505 TI - Deregulation of innate immune signaling in myelodysplastic syndromes is associated with deletion of chromosome arm 5q. PMID- 20160507 TI - Methylation destiny: Moira takes account of histones and RNA polymerase II. AB - Aberrant DNA methylation is deeply involved in various human disorders. Contrary to our initial expectation, aberrant methylation is now known to possess several unique characteristics different from mutations, including target gene specificity. Specific cancers have methylation of specific genes and specific inducers of methylation, such as Helicobacter pylori infection, induce methylation of specific genes. Mechanistically, it has been known that low levels of transcription of a gene promote its methylation. multiple studies have shown that high levels of trimethylation of histone H3 lysine27 in normal cells are associated with a risk of becoming methylated during carcinogenesis. We recently demonstrated that genes with high levels of binding of RNA polymerase II, regardless of transcription levels, are resistant to induction of aberrant methylation. Now, epigenetic destiny can be predicted by these factors and interference with these factors might be able to change the destiny. PMID- 20160508 TI - Micro-orchestrating differentiation in cancer. AB - Differentiation involves repression of genes governing proliferation and self renewal, and transcriptional activation of lineage-specific genes. The mechanisms underlying these changes are epigenetic. In cancer cells differentiation genes are locked into a transcriptionally inactive state. Recent results show that in spite of the diversity of the genetic lesions leading to a cancerous phenotype, it may still be possible to release this block and to force differentiation. The key may be microRNAs (miRNAs) which directly or indirectly target epigenetic modifiers. These miRNAs could allow to apply to solid tumors the non-toxic differentiative approach currently adopted in some haematologic malignancies. PMID- 20160509 TI - Going global: novel histone modifications in the globular domain of H3. AB - Post-translational modifications (PTM) of histones are key regulators of chromatin function. New mass spectrometrical technologies have revealed that PTMs are not restricted to the histone tails, but can also be found in the globular domains, especially at the DNA-binding surface of the nucleosomes. Recent work on this new group of epigenetic marks showed that these modifications have not only the potential to alter the physical properties of the nucleosome, but may act as signals that regulate the recruitment of effector proteins to chromatin as well. PMID- 20160506 TI - Tip60: connecting chromatin to DNA damage signaling. AB - Cells are constantly exposed to genotoxic events that can damage DNA. To counter this, cells have evolved a series of highly conserved DNA repair pathways to maintain genomic integrity. The ATM protein kinase is a master regulator of the DNA double-strand break (DSB) repair pathway. DSBs activate ATM's kinase activity, promoting the phosphorylation of proteins involved in both checkpoint activation and DNA repair. Recent work has revealed that two DNA damage response proteins, the Tip60 acetyltransferase and the mre11- rad50-nbs1 (MRN) complex, co operate in the activation of ATM in response to DSBs. MRN functions to target ATM and the Tip60 acetyltransferase to DSBs. Tip60's chromodomain then interacts with histone H3 trimethylated on lysine 9, activating Tip60's acetyltransferase activity and stimulating the subsequent acetylation and activation of ATM's kinase activity. These results underscore the importance of chromatin structure in regulating DNA damage signaling and emphasize how histone modifications co ordinate DNA repair. In addition, human tumors frequently exhibit altered patterns of histone methylation. This rewriting of the histone methylation code in tumor cells may impact the efficiency of DSB repair, increasing genomic instability and contributing to the initiation and progression of cancer. PMID- 20160510 TI - Tuning acetylated chromatin with HAT inhibitors: a novel tool for therapy. AB - Epigenetics, the heritable changes that do not involve DNA sequences, give dynamic propulsion to a static genome and modulate genome accessibility by acting through multiple layers of regulation, ultimately ending with a variable organization of chromatin. The main player in chromatin reprograming is the nucleosome, which modifies its association to DNA depending on a variety of post translational modifications (PTMs) on histone tails. PTMs act directly on higher order chromatin structures and affect the degree of DNA wrap around the histone octamer and the interaction and/or sequential recruitment of chromatin-associated proteins and transcription factors at defined regions. Recently genomic approaches revealed a far more complex epigenome involving key proteins of cell signaling. PMID- 20160511 TI - The p53 response element and transcriptional repression. AB - p53 tumor suppressor has been widely recognized as the "Guardian of the Genome", reflecting its importance in ensuring the proper functioning of the cell. It is well-known for its function as a transcription factor, capable of mediating both transcriptional activation and repression, which brings about many cellular outcomes such as cell cycle arrest, apoptosis, cellular senescence and DNA repair. The canonical p53 response element (p53RE), which contains two repeats of a decamer motif "RRRCWWGYYY" separated by a spacer of 0 to 13 base-pairs, has been characterized as the regulatory region on the target genes that p53 binds for transcriptional activation. It was thought that p53 generally represses genes that lack this canonical p53RE, presumably through the sequestration of basal transcriptional machinery components or transcription activators. However, characterization of individual genes as well as genome-wide studies utilizing gene expression profiling and chromatin immunoprecipitation uncovered a large number of potential p53-repressed targets. Taken together, there appears to be multiple modes of gene repression by p53 with some being mediated through direct binding of p53 to DNA. The aim of this review is to assess the evidence of p53 mediated transcriptional repression and discuss its role in cellular function. PMID- 20160512 TI - A comparison between Skp2 and FOXO1 for their cytoplasmic localization by Akt1. PMID- 20160513 TI - p73 tumor suppressor protein: a close relative of p53 not only in structure but also in anti-cancer approach? AB - The discovery of the p53 tumor suppressor protein in 1979 shed new light on cancer cell biology and introduced a trend in cancer research focusing on p53 like proteins. This in turn led to the discovery of two homologous proteins of p53-p63 in 1998 and p73 in 1997. The p53 family members are mainly involved in apoptosis induction under cellular stress, but also in early embryonic developmental processes. The p63 and p73 proteins activate the transcription of a number of p53 target genes. The precise role of p63 in cancer cells is not fully revealed yet, unlike that of p53 and p73. The p53 tumor suppressor protein is found inactive in approximately 50% of human cancers. However, p73 is not as often inactivated in tumors. Of importance, transcriptionally active forms of p73 induce apoptosis in cancer cells independent of p53 status. Moreover, the regulatory mechanisms governing p73 stability in cells are well described. These features promoted the research concerning p73-targeted anti-cancer treatment. The p73 protein is subject to sophisticated activatory and inhibitory regulatory mechanisms. The up-to-date anti-cancer compounds targeting p73 protein in vitro inhibit its negative regulators, which leads to the activation of p73 pro apoptotic function in cancer cells. In the current review we present the recent scientific findings on p73 regulation in cells and the newest anti-cancer strategies concerning its tumor suppressor function. PMID- 20160514 TI - Shaping the oligodendrocyte identity by epigenetic control. AB - Cell diversity in the central nervous system (CNS) is achieved by a highly regulated process of differentiation from multipotential neural stem cells. The spatial specificity and timing control of neural differentiation is achieved by the interplay between various genetic and epigenetic regulators. Oligodendrocytes, the myelinating cell in the CNS, play an important role in brain development and neuronal function. At present, multiple signaling pathways have been implicated in regulating in oligodendrocyte differentiation, however, the integration of these pathways with transcriptional and posttranscriptional regulatory networks are not fully understood. This review will focus on exploiting epigenetic mechanisms underlying oligodendrocyte development including chromatin remodeling by histone deacetylases and gene silencing by non-coding RNAs (e.g., microRNA), and attempts to summarize the recent advance as to the genetic and epigenetic interaction in controlling oligodendroglial differentiation and myelination. PMID- 20160518 TI - Letter to the editor. Re: a return to diploma-prepared registered nurses, by June F. Kikuchi 22(3). PMID- 20160515 TI - Human iPS cell-based therapy: considerations before clinical applications. AB - Generation of induced pluripotent stem (iPS) cells has revolutionized the field of regenerative medicine. With the exponential increase in iPS cell research in the past three years, human iPS cells have been derived with different technologies and from various cell types. From a translational perspective, however, a number of issues must be addressed before safe and high quality patient-specific iPS cells can be derived for clinical applications. In addition, iPS cell-based therapies also need to be thoroughly evaluated in pre-clinical animal models before they can be applied to human subjects. PMID- 20160519 TI - Leadership profile: Karima Velji, winner 2009 Margret Comack award of excellence in nursing leadership. PMID- 20160520 TI - We are all in this together. PMID- 20160521 TI - Resolving to secure a presence... PMID- 20160522 TI - Rethinking nursing best practices with aboriginal communities: informing dialogue and action. AB - This paper stems from findings of a literature review and consultation with key informants to explore nursing best practices in public health with rural and isolated Aboriginal communities. It summarizes background information on population distribution, the impact of colonization on Aboriginal health and the potential benefits for nurses and communities in adopting a partnership approach, rather than risking cultural imposition while applying best practices and knowledge derived from the dominant culture. The authors provide an alternative working definition for best practices in the context of public health nursing with Aboriginal communities based on findings from the literature review and key informant consultations. Findings include three principles for the development and assessment of nursing best practices with isolated Aboriginal communities: use of indigenous frameworks, capacity building and cultural safety. The discussion highlights examples that demonstrate the feasibility and strengths of these three principles across a selection of isolated, rural and national settings. Implications include a call for nursing leaders, managers and policy makers to take up this challenge and support wider dialogue and action to enable nursing practice that supports the efforts of Aboriginal people to improve health and social conditions. PMID- 20160523 TI - A model for nurse practitioner regulation: principles underpinning a three registration category approach. AB - The issue of professional regulation of advanced nursing practice is one of the most controversial in the area of nursing regulation today. The controversy affects the roles and scope of advanced practice as well as education requirements. Nurse practitioner (NP) practice is one kind of advanced nursing practice receiving attention currently, with a view to developing consistent educational and regulatory approaches. Consistency is needed to enhance the mobility and flexibility of these important healthcare provider resources in time of shortages. This paper describes how the regulatory body in British Columbia decided to register only three categories of NP: family/all ages, adult and pediatrics. It describes the state of NP regulation when the work began, the consultation process used in coming to this decision and the principles underlying the decision. Regulators, educators and administrators may benefit from understanding the issues and reasoning presented. Literature to guide this work was lacking, a gap this paper addresses to help inform decision-making in other settings and contexts. Dialogue about this approach may facilitate movement towards consistent approaches to the regulation, education and deployment of NPs in Canada and elsewhere. PMID- 20160524 TI - Canadian oncology nurse work environments: part I. AB - The global nursing shortage and statistics indicating a steady increase in the cancer patient workload suggest that the recruitment and retention of oncology nurses is and will be a serious problem. The purpose of this research study was to examine oncology nursing work environments in Canada and to determine the presence of workplace and professional practice factors. A total of 615 oncology nurses responded to a national survey in 2004. The majority of nurses indicated that positive nurse-physician relations and autonomy in clinical decision-making were factors that contributed to job satisfaction and the desire to remain in oncology nursing. However, the findings identified that nurse staffing, the lack of nursing leadership and inadequate opportunities to participate in policy decisions were areas of concern. Differences in work environment perceptions were seen most often when responses were compared across provincial regions. While the findings support previous research reports that the key to the nursing shortage is attention to nursing work environments, they also emphasize the need for organizations to act now. A follow-up survey was conducted in 2006; analysis of these data will be presented in a future report on nurses' perceptions of their work environments and job satisfaction over time. PMID- 20160525 TI - "Hit the ground running": perspectives of new nurses and nurse managers on role transition and integration of new graduates. AB - The workplace for new graduates must be a constructive learning environment to facilitate their development. Nurse managers need new graduates who can "hit the ground running." Conflict between the needs of new nurses and the realities of the workplace often creates role confusion and tension in new graduates and threatens employers' ability to retain them. As part of a larger study that examined the effectiveness of a new strategy on new nurse retention and workplace integration, we conducted focus groups with new nurses and nurse managers. This paper discusses the perspectives of new nurses on their role transition from graduates to practising professionals and the perspectives of nurse managers on the workplace integration of new nurses. The thematic findings integrate new nurses' perspectives on their needs during role transition with the perspectives of nurse managers in meeting those needs. The discussion includes strategies to facilitate successful transition and integration of new nurses into the workplace within the context of recruitment and retention. PMID- 20160526 TI - Stakeholders' conceptualizations of the nurse practitioner role in the pediatric emergency department. AB - In Quebec, as in the rest of Canada, the increasing service demands placed on emergency departments (EDs), and the dwindling resources of physicians, nurses and trainees, have obliged those managing EDs to question whether new roles need to be introduced. Increasing acuity and complexity of care, coupled with rising numbers of pediatric patients seeking care for non-urgent health issues, have created a need to address long waiting times for non-urgent patients, as well as more standardized care (using approved and evidence-based protocols) for acutely ill patients during their ED stay. Presently, the nurse practitioner (NP) role may be operationalized in Quebec EDs, as recent legislation has cleared the path for its introduction. Some theorists view the development of a new role such as the NP's as a dynamic process of shared conceptualizations (i.e., expectations and conceptions) that help maintain stable interaction. To succeed in introducing the NP role, and to minimize conflict in the post-implementation phase, it is important to understand the conceptualizations of those most closely involved: the stakeholders. Given the lack of Canadian literature on this subject, a qualitative descriptive design was effected to identify stakeholders' conceptualizations of the paediatric emergency nurse practitioner (ENP) role in the early stages of development. Stakeholders described it as a largely clinical role with other responsibilities, including teaching and mentoring, and minimal research responsibilities to ensure a clinical focus. The stakeholders agreed that they must be involved in the role development process, i.e., implementation must not be a top-down initiative. The results of this study support the view that stakeholders have conceptualizations of the role itself and of the role development process, and that these conceptions guide expectations of both the role and the process. It is imperative for those developing new roles to be well informed about stakeholders' conceptualizations during the early planning phase. PMID- 20160527 TI - Cirrhotics admitted to intensive care unit: the impact of acute renal failure on mortality. AB - BACKGROUND: The exact role of renal dysfunction in critically ill cirrhotics admitted to an intensive care unit (ICU) has not been assessed extensively. AIM: To evaluate the impact of acute renal failure (ARF) on 6 weeks mortality in cirrhotics admitted to ICU. PATIENTS/METHODS: Three hundred and twelve cirrhotics (182 male, mean age 49.6+/-11.5 years) were consecutively admitted during the study period. The patients (n=128, 40%) (group 1) with ARF on admission and/or during ICU were compared with the patients whose ICU stay was not complicated with ARF (n=184, 60%) (group 2). At admission, 40 variables were available, whereas Child-Turcotte-Pugh, Model for End-stage Liver Disease, Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment and Failure Organ System scores on admission, were evaluated and compared by receiver operating characteristic curves. RESULTS: Group 1, compared with group 2 patients, had longer ICU stay (7 vs. 4 days, P=0.04) and required cardiovascular support more frequently with inotropes (90 vs. 75%), (P<0.001). Mortality was significantly higher in group 1, compared with group 2 (91 vs. 47%, P<0.001). At admission, group 1, compared with group 2, had significantly higher Child Turcotte-Pugh (12 vs. 11), Acute Physiology and Chronic Health Evaluation II (22 vs. 17), Model for End-stage Liver Disease (31 vs. 21), Sequential Organ Failure Assessment (13 vs. 9) and Failure Organ System (3 vs. 2) scores (P<0.001). In group 1, factors independently associated with mortality were: higher FiO2 (P=0.044), bilirubin (P=0.021) and creatinine (P=0.002) on admission. Mortality was not significantly different between those with ARF on admission, and those who developed ARF during ICU stay. CONCLUSION: ARF at admission or during ICU stay is strongly predictive of mortality, which is high, despite supportive therapeutic interventions. Preventive measures are needed to prevent ARF, to improve prognosis. PMID- 20160528 TI - Pulmonary vascular diseases 2009: new insights from bench to bedside. PMID- 20160529 TI - Pulmonary arterial hypertension: pathobiology, diagnosis, treatment, and emerging therapies. AB - Pulmonary hypertension is a rare disorder caused by vasoconstriction of the pulmonary arteries that leads to elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. Hypertrophy and proliferation of the pulmonary vascular endothelium leads to remodeling of this vascular system, resulting in a progressive disorder. In the past decade the molecular mechanisms and pathobiology of this disorder has become clearer. In addition, a host of new medical treatments and therapies are now available for what has been previously known to be a devastating disorder. Although much needs to be learned, this review will discuss our current knowledge, results of clinical trials, along with treatment options and emerging therapies available for the treatment of this disorder. PMID- 20160530 TI - Idiopathic pulmonary arterial hypertension in childhood. AB - The introduction of new medicines to treat pulmonary vascular disease has renewed interest in the management of children with idiopathic pulmonary arterial hypertension. We now have a practical classification of pulmonary hypertension, improved diagnostic techniques, and internationally recognized diagnostic and management guidelines. In 2009 the UK Pulmonary Hypertension Service for Children reported survival figures for idiopathic pulmonary arterial hypertension of 85.6% at 1 year, 79.9% at 3 years, and 71.9% at 5 years. A good quality of life can be assured for many years. PMID- 20160531 TI - Inflammation and pulmonary hypertension. AB - Pulmonary hypertension (PH) is a serious disorder with high morbidity and mortality rate. Evidence is accumulating to suggest that inflammation plays a significant role in the pathogenesis of PH. Endothelial cells play an important role in inflammation and immune reactions, and inflammatory cytokines cause endothelial dysfunction. Endothelial dysfunction is a hallmark of PH, consisting of reduced availability of vasodilators and antiproliferative factors and increased production of vasoconstrictors and vascular proliferative factors. Up regulation of inflammatory cytokines and perivascular inflammatory cell infiltration have been detected in the lungs of patients with idiopathic PH. Prevalence of PH in patients with systemic inflammatory diseases is well documented. Interestingly, a significant loss of endothelial caveolin-1, a potent immunomodulator and an inhibitor of cell proliferation, has been reported in human and experimental forms of PH. Reduction in the expression of caveolin-1 is known to result in the removal of antiproliferative activities, thus, leading to deregulated vascular cell proliferation. This article summarizes the roles of inflammation and endothelial caveolin-1 and their possible interrelationship in PH. PMID- 20160532 TI - Management of pulmonary arterial hypertension in the neonatal unit. AB - This review article discusses the pathophysiology and management of pulmonary hypertension (PH) in the newborn unit. The discussion revolves around 2 aspects: persistent pulmonary hypertension in the newborn, which is seen in the first few weeks of life, and PH associated with chronic lung disease in the post neonatal period of infancy. Although the etiopathogenesis as well as prognosis for infantile PH differ from older children and adults, the basic principles of management are similar. Inhaled nitric oxide, intravenous prostacyclin and its analogs, and oral medications like sildenafil and endothelin receptor blockers play a very important role in PH management in the newborn unit, in addition to ventilation strategies and acid-based balance management. PMID- 20160534 TI - Pulmonary arterial hypertension in connective tissue diseases. AB - Pulmonary arterial hypertension (PAH) is an entity that is known to complicate connective tissue diseases (CTD). PAH in CTD is a very important diagnosis which greatly affects treatment and prognosis. The most commonly affected CTD is scleroderma, although lupus, inflammatory myopathies such as poly and dermatomyositis, and mixed CTD are also associated with PAH. The manifestations of PAH have both similarities and differences when occurring in the setting of CTD as compared with idiopathic PAH. These differences are most notable in scleroderma. In this section we will discuss the features of PAH as they appear in CTDs, and in particular, scleroderma. The focus of this article is an approach to the diagnosis and treatment of PAH in CTD, and how this setting might differ from idiopathic and other forms of PAH. PMID- 20160535 TI - Oxidant-redox regulation of pulmonary vascular responses to hypoxia and nitric oxide-cGMP signaling. AB - Most current theories for the mechanism of hypoxic pulmonary vasoconstriction (HPV) include a role for reactive oxygen species and/or changes in redox regulation, but extreme controversy exists regarding which systems and redox changes mediate the HPV response. Nitric oxide (NO) appears to help to maintain low pulmonary arterial pressure, suppress HPV, and prevent the development of pulmonary hypertension. Our studies have found a key role for glucose-6-phosphate dehydrogenase in bovine pulmonary arterial smooth muscle functioning to maintain elevated levels of cytosolic NADPH which fuels the generation of vasodilator levels of hydrogen peroxide. HPV results from hypoxia removing vasodilation by peroxide. Decreased superoxide generation by Nox4 oxidase and its conversion to peroxide by Cu,Zn-SOD appear to be potential factors in sensing hypoxia, and decreased cGMP-associated vasodilation and removal of redox controlled vasodilator mechanisms by increased cytosolic NADPH may be key coordinators of the HPV response. Oxidant generation associated with vascular disease processes, including the removal of NO by superoxide, and attenuation of its ability to stimulate cGMP production by oxidation of the heme and thiols of soluble guanylate cyclase attenuate potential beneficial actions of NO on pulmonary arterial function. While pulmonary hypertension appears to have multiple poorly understood effects on redox-associated processes, potentially influencing responses to hypoxia and NO-cGMP signaling, much remains to be elucidated regarding how these processes may be important factors in the progression, expression and therapeutic treatment of pulmonary hypertension. PMID- 20160533 TI - New approaches to the treatment of pulmonary hypertension: from bench to bedside. AB - Pulmonary hypertension (PH) is a severe, life-threatening disease for which there are no effective curative therapies. A diverse group of agents such as prostacyclins, endothelin antagonists, phosphodiesterase inhibitors, calcium channel blockers, diuretics, inotropic agents, and anticoagulants are used to treat PH; however, none of these agents have a marked effect upon survival. Among the new agents that promise treatment of PH are rho-kinase inhibitors and soluble guanylate cyclase stimulators. Although these new classes of agents have beneficial effects in experimental animal models and clinical studies, they are not selective in their actions on the pulmonary vascular bed. This manuscript reviews the actions of rho-kinase inhibitors and soluble guanylate cyclase stimulators on the pulmonary vascular bed. It is our hypothesis that these new agents may be more effective than current therapies in the treatment of PH. Moreover, new methods in the delivery of these agents to the lung need to be developed so that their main effects will be exerted in the pulmonary vascular bed and their systemic effects can be minimized or avoided. PMID- 20160537 TI - Hypertensive crisis. AB - Hypertension is a common chronic medical condition affecting over 65 million Americans. Uncontrolled hypertension can progress to a hypertensive crisis defined as a systolic blood pressure >180 mm Hg or a diastolic blood pressure >120 mm Hg. Hypertensive crisis can be further classified as a hypertensive urgency or hypertensive emergency depending on end-organ involvement including cardiac, renal, and neurologic injury. The prompt recognition of a hypertensive emergency with the appropriate diagnostic tests and triage will lead to the adequate reduction of blood pressure, ameliorating the incidence of fatal outcomes. Severely hypertensive patients with acute end-organ damage (hypertensive emergencies) warrant admission to an intensive care unit for immediate reduction of blood pressure with a short-acting titratable intravenous antihypertensive medication. Hypertensive urgencies (severe hypertension with no or minimal end-organ damage) may in general be treated with oral antihypertensives as an outpatient. Rapid and short-lived intravenous medications commonly used are labetalol, esmolol, fenoldopam, nicardipine, sodium nitroprusside, and clevidipine. Medications such as hydralazine, immediate release nifedipine, and nitroglycerin should be avoided. Sodium nitroprusside should be used with caution because of its toxicity. The risk factors and prognosticators of a hypertensive crisis are still under recognized. Physicians should perform complete evaluations in patients who present with a hypertensive crisis to effectively reverse, intervene, and correct the underlying trigger, as well as improve long-term outcomes after the episode. PMID- 20160538 TI - Evidence-based nursing: the role of the advanced practice registered nurse in the management of heart failure patients in the outpatient setting. AB - Heart failure (HF) is a chronic debilitating illness that affects millions of Americans each year. Patients with HF are faced with chronic physical symptoms, emotional strain, and significant socioeconomic burden. Goals in the management of HF are to slow the disease progression, decrease symptom acuity, and prevent exacerbations that lead to hospital readmission. Management of HF remains a challenge for healthcare providers. There is a fine balance between optimizing patient functioning and minimizing healthcare expenditures. With the incidence of HF increasing annually, it is important to have effective disease management strategies in place. In any disease management program, it is important to follow those guidelines outlined by evidence-based practice. The purpose of this systematic review was to evaluate current evidence-based practice and determine what benefit exists of having an advanced practice registered nurse assist in the management of patients with HF. PMID- 20160536 TI - History of right heart catheterization: 100 years of experimentation and methodology development. AB - The development of right heart catheterization has provided the clinician the ability to diagnose patients with congenital and acquired right heart disease, and to monitor patients in the intensive care unit with significant cardiovascular illnesses. The development of bedside pulmonary artery catheterization has become a standard of care for the critically ill patient since its introduction into the intensive care unit almost 40 years ago. However, adoption of this procedure into the mainstream of clinical practice occurred without prior evaluation or demonstration of its clinical or cost-effectiveness. Moreover, current randomized, controlled trials provide little evidence in support of the clinical utility of pulmonary artery catheterization in the management of critically ill patients. Nevertheless, the right heart catheter is an important diagnostic tool to assist the clinician in the diagnosis of congenital heart disease and acquired right heart disease, and moreover, when catheter placement is proximal to the right auricle (atria), this catheter provides an important and safe route for administration of fluids, medications, and parenteral nutrition. The purpose of this manuscript is to review the development of right heart catheterization that led to the ability to conduct physiologic studies in cardiovascular dynamics in normal individuals and in patients with cardiovascular diseases, and to review current controversies of the extension of the right heart catheter, the pulmonary artery catheter. PMID- 20160541 TI - Prevention of sepsis after splenectomy. AB - Individuals who do not have a spleen are highly susceptible to severe infections. The purpose of this article was to present vaccination guidelines for prophylactic treatment of sepsis following splenectomy. Nursing considerations for the prevention of sepsis after splenectomy are discussed. PMID- 20160543 TI - NNN language and evidence-based practice guidelines for acute cardiac care: retaining the essence of nursing. AB - Multidisciplinary management of the acute cardiac patient, for decades, has been driven by best practices, treatment algorithms, and research-based protocols. As nurses continue to develop and implement evidence-based care, they must ensure that the essence of nursing is not lost in the process. In this article, strategies for the development of evidence-based practice guidelines for acute cardiac patients using standardized nursing language are provided. PMID- 20160546 TI - Candidly critical: real-life critical care nursing, part 2. AB - This is the second in a series of articles depicting real-life situations in critical care nursing. This discusses one nurse's journey with a friend who developed idiopathic thrombocytopenia purpura. PMID- 20160544 TI - Progress in ethical decision making in the care of the dying. AB - Practitioners in critical care have made a significant progress in caring for dying patients in critical care by taking advantage of the suggestions from their professional groups. Progress has been made in responding to and controlling patients' pain. Major initiatives from the Joint Commission and the American Pain Society have helped direct this improvement. Palliative care consultations as well as ethics consultations have improved symptom control in the critically ill. Issues of consent have been problematic for dying patients in critical care especially in the area of discontinuing therapies. But, better policies related to advance directives have been developed to ensure good care. Spiritual care has received more attention, and now chaplains are recognized by the Society for Critical Care Medicine as integral to the critical care team. The American Association of Critical-Care Nurses has been a leader in improving end-of-life issues and continues to spearhead many projects to improve end-of-life care. PMID- 20160550 TI - Guide to nursing organizations, 2010. PMID- 20160547 TI - A personal reflection: a letter to Grace. AB - This personal reflection chronicles one critical care nurse's experience with a neurological patient and her family. This article covers the care of one patient by one critical care nurses from admission to the intensive care unit, through multiples transfers in and out of the hospital until her eventual death 8 months later. PMID- 20160554 TI - Letter to the editor with author response: commentary on "restarting the clock... again". PMID- 20160552 TI - The intensive care unit: experiences of patients, families, and their nurses. AB - Past studies have examined how nurses can meet the needs of the critically ill patients and their families and the effects of their relatives' critical illness on the families themselves. However, there is a paucity of research studies in the literature conducted on the triad of nurses, patients, and family members looking at the experience of critical illness and their perspective of each from the other. This qualitative phenomenological study was able to elucidate the experiential descriptions, essential relationships, and meaning of structures of the intensive care unit experiences of the 15 participants during critical illness, and strategies to improve nursing practice, research, and education are presented. PMID- 20160557 TI - Chocolate: the health food. PMID- 20160560 TI - Quinacrine sterilization and gynecologic cancers: a case-control study in northern Vietnam. AB - BACKGROUND: Over 100,000 women worldwide have been sterilized by insertion of quinacrine into the uterus to induce tubal scarring. Concern has been expressed about possible carcinogenicity, and specifically the risk of uterine cancer. METHODS: From 2001 through 2006, we conducted a population-based, case-control study of gynecologic cancers in 12 provinces in northern Vietnam, where relatively large numbers of women had received quinacrine. Cases of incident cervical, ovarian, and uterine cancer were identified at provincial hospitals or at referral hospitals in Hanoi. For each case, 3 age- and residence-matched controls were randomly selected from the population registries of the case's home community. RESULTS: The prevalence of quinacrine exposure was 1.2% among cases and 1.1% among controls. For cervical cancer, analysis of 606 cases (9 exposed) and their 1774 matched controls (18 exposed) produced an odds ratio of 1.44 (95% confidence interval = 0.59-3.48) (adjusted for several covariates including human papillomavirus risk score). For ovarian cancer, based on 262 cases (3 exposed) and 755 controls (8 exposed) and adjusted for age and number of years of ovulation, the odds ratio was 1.26 (0.21-5.45). For uterine cancer, none of the cases-including 23 cases of leiomyosarcoma-was exposed to quinacrine. The 95% confidence interval, based on 161 cases (none exposed) and 470 controls (7 exposed) and adjusted only for age, was 0-1.85. CONCLUSION: We found no evidence of a relationship between quinacrine sterilization and gynecologic cancer. PMID- 20160561 TI - Protecting human health from air pollution: shifting from a single-pollutant to a multipollutant approach. AB - To date, the assessment of public health consequences of air pollution has largely focused on a single-pollutant approach aimed at estimating the increased risk of adverse health outcomes associated with the exposure to a single air pollutant, adjusted for the exposure to other air pollutants. However, air masses always contain many pollutants in differing amounts, depending on the types of emission sources and atmospheric conditions. Because humans are simultaneously exposed to a complex mixture of air pollutants, many organizations have encouraged moving towards "a multipollutant approach to air quality." Although there is general agreement that multipollutant approaches are desirable, the challenges of implementing them are vast. PMID- 20160562 TI - First steps toward multipollutant science for air quality decisions. PMID- 20160563 TI - The ghost of public health journalism: past, present, and future. AB - The news industry is undergoing shrinking newspaper circulations, cuts in science and health coverage, and expansion of Internet news sources. We examine the impact of these changes using a case study set in Libby, Montana. In 1999, a Seattle newspaper story focused attention on asbestos exposure and related diseases in this small town. In 2009, that newspaper became an online-only newspaper, just as coverage of a related criminal trial began. Later that year the U.S. Environmental Protection Agency issued a public health emergency. Online newspaper archives and a collaboration between the University of Montana's journalism and law schools contributed to coverage of these developments. Continued efforts to promote interest in and skills needed for high-quality public health and environmental reporting are needed. PMID- 20160564 TI - Journalism: it's the means, not the medium. PMID- 20160565 TI - Vaccine policy and incidence of influenza. PMID- 20160566 TI - Recruiting child controls. PMID- 20160567 TI - Anthropometric characteristics and multiple myeloma risk. PMID- 20160568 TI - Confidence intervals for the interaction contrast ratio. PMID- 20160569 TI - Population interventions for obesity. PMID- 20160570 TI - Birth prevalence of congenital heart disease. PMID- 20160573 TI - But is the platter really silver? PMID- 20160576 TI - American glaucoma society position statement: marijuana and the treatment of glaucoma. PMID- 20160577 TI - Clinical cystoid macular edema after cataract surgery in glaucoma patients. AB - PURPOSE: To determine the prevalence of and risk factors for developing clinical cystoid macular edema (CME) after cataract surgery in patients with glaucoma. PATIENTS AND METHODS: Medical records of patients who had cataract surgery between April 1998 and July 2006 without prior history of CME, a known risk factor to develop CME, or previous nonglaucoma ocular laser procedures or intraocular surgeries were reviewed. Clinical CME was diagnosed by fundus examination within 3 months postoperatively and confirmed with fluorescein angiography or optical coherence tomography. Outcome measures included prevalence of clinical CME by comparing patients with and without glaucoma; and risk factor analysis for clinical CME by comparing patients who did and did not develop CME after cataract surgery. RESULTS: Seven hundred patients (eyes) with glaucoma and 553 patients (eyes) without glaucoma were included. The prevalences of clinical CME in glaucoma and nonglaucoma patients were 5.14% and 5.79%, respectively (P=0.618). Patients who developed clinical CME (68 patients) had statistically higher rates of posterior capsule rupture or required anterior vitrectomy during surgery (P=0.010, odds ratio=3.35, 95% CI 1.33-8.45) compared with patients who did not develop clinical CME (1185 patients). No glaucoma medications used either preoperatively or postoperatively were associated with clinical CME (P>0.05). CONCLUSIONS: Rupture of posterior capsule and anterior vitrectomy during cataract surgery is a potential risk factor for developing clinical CME after cataract surgery. There is no statistically significant difference in the prevalence of clinical CME after small corneal incision phacoemulsification cataract surgery between glaucoma and nonglaucoma patients. PMID- 20160578 TI - More indirect evidence of potential neuroprotective benefits of angiotensin receptor blockers. PMID- 20160579 TI - Does nocturnal blood pressure impair renal function? PMID- 20160580 TI - Renal glutathione S-transferase mu type 1 expression is already reduced in new born spontaneously hypertensive rats. PMID- 20160582 TI - International Society of Hypertension Low and Middle Income Countries Committee: Review of the goals of the Committee and of 5 years of ISH activities in low and middle income countries. PMID- 20160583 TI - Paget-Schroetter syndrome: an uncommon cause of pulmonary embolic disease. AB - Paget-Schroetter syndrome is an uncommon cause of pulmonary thromboembolic disease that should be suspected in young patients in whom effort-related subclavian vein thrombosis should be investigated. Our case illustrates the pivotal role of imaging and the different modalities available to establish such a diagnosis. PMID- 20160584 TI - The role of computed tomography bronchography in the management of bronchopleural fistulas. AB - The management of complex bronchopleural fistulas (BPFs) remains a major diagnostic and therapeutic challenge to all chest physicians. Successful management of a fistula revolves around treatment of the associated empyema cavity first. Definitive repair should be accomplished expeditiously to minimize the number of procedures performed. When treatment is protracted, secondary complications are more likely to develop and survival is adversely affected. Diagnosis and localization of a BPF is therefore paramount; however, it is sometimes difficult and may require multiple imaging studies and bronchoscopies. Herein, we describe our experience with computed tomography bronchography as a new technique for diagnosis and localization of difficult BPF. In addition, other modalities for diagnosis and medical management are discussed along with a relevant review of the literature. PMID- 20160585 TI - MDCT imaging findings of extramedullary granulocytic sarcoma of the heart. AB - Granulocytic sarcoma, also known as chloroma, is an uncommon tumor typically seen in patients with acute myelogenous leukemia (AML). Extramedullary cardiac involvement of granulocytic sarcoma is rare and there is a paucity of information regarding its multidetector computed tomography (MDCT) imaging appearance. We present a case of extramedullary granulocytic sarcoma of the heart detected on MDCT in a young adult male with AML. An understanding of how extramedullary granulocytic sarcoma of the heart appears on MDCT may decrease or prevent delays in diagnosing this uncommon, although important, complication from AML. PMID- 20160586 TI - Isolated left ventricle diverticula: a possible cause of atypical angina? AB - A 49-year-old woman with atypical chest pain was referred for a multidetector computed tomography examination of the coronary arteries after a positive electrocardiography stress test. No coronary atherosclerotic disease was observed on the coronary computed tomography scan. The only findings were 2 side-by-side basal left ventricle diverticula, suggested as a possible etiology for her symptoms and electrocardiographic changes. The entity, congenital left ventricle diverticulum, is reviewed. PMID- 20160588 TI - Large pulmonary artery pseudoaneurysm due to lung carcinoma: pulmonary artery pseudoaneurysm. AB - We present the case of a 54-year-old patient who presented to our institution 4 months after refusing surgical treatment for a right upper lobe cavitary carcinoma. Weight loss, hemoptysis, and worsening pulsatile chest pain were the complaints. Radiologic restaging surprisingly revealed a large pulmonary artery pseudoaneurysm occupying the whole cavity area. A right pneumonectomy with intrapericardial pulmonary artery ligation was performed. Previous cases are extremely rare and differ from ours as patients presented with advanced lung cancer and thus, were not treated with resection, but with coil embolization. PMID- 20160589 TI - Endobronchial lipomatous hamartoma with mediastinal extension. AB - Endobronchial hamartoma is a special form of pulmonary hamartoma. We report a histologically proven case of an endobronchial lipomatous hamartoma with extrabronchial-mediastinal extension in a 64-year-old patient, and we describe the computed tomography and magnetic resonance imaging findings. To our knowledge, this is the first reported case of an endobronchial hamartoma extending into the mediastinum. PMID- 20160590 TI - Celebrating 25 years of the Journal of Thoracic Imaging. PMID- 20160592 TI - The Journal of Thoracic Imaging: the first 25 years. PMID- 20160593 TI - Society of Thoracic Radiology: grown and growing. PMID- 20160594 TI - A history of the Japanese Society of Thoracic Radiology. PMID- 20160595 TI - A history of the Korean Society of Thoracic Radiology. PMID- 20160596 TI - A history of the European Society of Thoracic Imaging. PMID- 20160597 TI - A brief history of the Fleischner Society. PMID- 20160598 TI - Digital radiography: a commentary. PMID- 20160599 TI - High-resolution computed tomography of the pulmonary parenchyma: past, present, and future? PMID- 20160600 TI - Thoracic magnetic resonance imaging 1985 to 2010. PMID- 20160601 TI - Commentary on "Positron Emission Tomography in the Lung" 25 years after publication in the inaugural issue of the Journal of Thoracic Imaging. PMID- 20160602 TI - Dual energy subtraction digital radiography improves performance of a next generation computer-aided detection program. AB - PURPOSE: Computer-aided detection (CAD) has shown potential to assist physicians in the detection of lung nodules on chest radiographs, but widespread acceptance has been stymied by high false-positive rates. Few studies have examined the potential for dual energy subtraction (DES) to improve CAD performance. MATERIALS AND METHODS: Institutional review board approval was obtained, the requirement for informed consent was waived because the study was retrospective, and practices conformed to Health Insurance Portability and Accountability Act regulations. The CAD program was applied retrospectively to dual energy posteroanterior (PA) chest radiographs of 36 patients (17 women, 19 men, mean age 69 y) with 48 pathology proven lung nodules. Results were analyzed to determine the stand-alone CAD program false-positive rates, and sensitivity by nodule subtlety and location. Statistical analysis was performed using the chi(2) or Fisher exact tests for independence of sensitivities between standard PA and DES radiography. Differences in the mean false-positives per image (FPPI) between radiographic modalities were determined using the paired Students t test, and bootstrap confidence intervals were obtained to confirm results. RESULTS: The sensitivity of the CAD program with the standard PA was 46% (22 of 48 nodules) compared with 67% (32 of 48 nodules) using the DES soft tissue or bone-subtracted view (P=0.064). The average number of FPPI identified by CAD was significantly lower using DES (FPPI(soft tissue) = 1.64) when compared with the standard PA chest radiograph (FPPI(PA) = 2.39) (P<0.01). CONCLUSIONS: DES has the potential to improve stand-alone CAD performance by both increasing sensitivity for certain subtle lung cancer lesions and decreasing overall CAD false-positive rates. PMID- 20160603 TI - Nonmassive acute pulmonary embolism: evaluation of the impact of pulmonary arterial wall distensibility on the assessment of the CT obstruction score. AB - PURPOSE: To evaluate the impact of pulmonary arterial wall distensibility on the assessment of a computed tomography (CT) score in patients with nonmassive pulmonary embolism (PE) (ie, Mastora score). MATERIALS AND METHODS: The arterial wall distensibility of five central pulmonary arteries (pulmonary artery trunk, right and left main pulmonary arteries, right and left interlobar pulmonary arteries) was studied on ECG-gated CT angiographic studies of the chest in 15 patients with no pulmonary arterial hypertension (group 1; mean pulmonary artery pressure: 17.2 mm Hg) and 9 patients with nonmassive PE (group 2), using 2D reconstructions at every 10% of the R-R interval. RESULTS: The systolic and diastolic reconstruction time windows of the examined arteries were identical in the 2 groups, obtained at 20% and 80% of the R-R interval, respectively. No statistically significant difference was observed between the mean values of the pulmonary arterial wall distensibility between the 2 groups, varying between 20.5% and 24% in group 1 and between 23.3% and 25.9% in group 2. The coefficients of variation of the average arterial surfaces were found to vary between 4.30% and 6.50% in group 1 and 4.2% and 8.4% in group 2. Except the pulmonary artery trunk in group 2, all the intraclass correlation coefficients were around 0.8 or greater than 0.8, that is the cutoff for good homogeneity of measurements. CONCLUSION: The pulmonary arterial wall systolic-diastolic distensibility does not interfere with the assessment of a CT obstruction score in the setting of nonmassive PE. PMID- 20160604 TI - Evaluation of coronary artery in-stent restenosis by 64-section computed tomography: factors affecting assessment and accurate diagnosis. AB - PURPOSE: To determine factors affecting the ability of 64-multislice computed tomography (MSCT) to detect, assess, and accurately diagnose significant coronary arterial in-stent restenosis (ISR). MATERIALS AND METHODS: The institutional review board approved this study and waived informed consent. Sixty patients underwent CT coronary angiography using 64-MSCT, after implantation of coronary artery stents (n=91). We assessed diagnostic accuracy for ISR with CT in comparison with conventional coronary angiography as the gold standard, visually and with measurement of in-stent coronary lumen density. Possible factors that influenced the diagnostic performance of CT were evaluated, which included image quality (IQ), stent characteristics, and location. RESULTS: Sixty-nine stents (75.8%) were assessable. Low IQ, location in the left circumflex coronary artery, and narrow stent diameter were associated with poor assessment (P<0.05). In stents that could be assessed, sensitivity, specificity, positive predictive value, and negative predictive value of 64-MSCT were 90.0%, 73.5%, 58.1%, and 94.7%, respectively, for significant ISR. The diagnostic accuracy in assessable stents showed a significant increase with better IQ, thinner strut thickness, and nondrug eluting stent. False-positive diagnoses of ISR by CT were explained by coronary lumen density measurements. CONCLUSIONS: Evaluation of stents by 64-MSCT is not recommended in stents with diameters of < or = 2.75 mm or stents located at the left circumflex coronary artery. The diagnostic accuracy of 64-MSCT is affected by IQ and strut thickness in assessable stents. Significant ISR can be excluded with high reliability in selected patients. PMID- 20160605 TI - Thoracolithiasis: 11 cases with a calcified intrapleural loose body. AB - PURPOSE: To describe clinical and imaging characteristics of thoracolithiasis. MATERIALS AND METHODS: Medical records from our center from September 2005 to March 2007 were reviewed. A definitive diagnosis was made by multidetector-row computed tomography studies of the chest, which revealed in each patient an intrapleural calcified nodular opacity, which changed in intrapleural location on serial examinations. Eleven patients fulfilled this criteria. The images were analyzed by experienced radiologists, who focused on the distribution, size, and shape of the thoracolithiasis. RESULTS: The incidence of thoracolithiasis was 0.086% (11 of 12,835 individuals). All the patients were asymptomatic and did not have any history of intrathoracic disease. The nodules ranged in size from 5 to 15 mm (median 8 mm), and were ovoid and smoothly marginated. Each nodule contained homogeneous diffuse calcification. Eight nodules occurred in the left pleural space and 3 in the right. Their locations varied, which included on the diaphragm, along the posterior chest wall of the lower lung, abutting the left cardiac margin, and near the paraspinal space of the lower thoracic spine. Each of the calcified pleural bodies changed in intrapleural location on follow-up computed tomography examination. CONCLUSIONS: The calcified intrapleural nodular opacities of thoracolithiasis tended to be located inferiorly, presumably secondary to the effects of gravity, and they seemed to migrate freely within the pleural cavity. PMID- 20160606 TI - Chest CT features of community-acquired respiratory viral infections in adult inpatients with lower respiratory tract infections. AB - PURPOSE: The appearance of respiratory virus infection on thoracic computed tomography (CT) has been described only to a limited extent in the current literature, and viral pneumonias may be under-recognized by radiologists. Our objective was to describe thoracic CT findings in a broad range of adult inpatients with respiratory virus infections. MATERIALS AND METHODS: A retrospective analysis of chest CTs was performed on symptomatic adult inpatients presenting with positive nucleic acid-based assays for 1 of 4 common community acquired respiratory viruses. Forty-two patients with viral respiratory tract infections who underwent chest CT imaging were evaluated. The reviewer was blinded to virus type and patient information. CT findings were compared with CT reports produced at the time of the original study and correlated with clinical outcome measures. RESULTS: Influenza (n=21), adenovirus (n=9), respiratory syncytial virus (n=8), and parainfluenza (n=4) were represented among the cohort. Three patterns of the disease were seen with viral infection: (1) limited infection with normal imaging (21%), (2) bronchitis/bronchiolitis characterized by bronchial wall thickening and tree-in bud opacities (31%), and (3) pneumonia characterized by multifocal consolidation or ground-glass opacities (36%). Viral infection was suggested in only 4/42 (10%) of the original radiology reports, all of which had evidence of bronchitis/bronchiolitis on chest CT. Viral pneumonia, characterized by multifocal ground-glass opacities or multifocal consolidations, was interpreted as aspiration pneumonia or bacterial pneumonia in 15/16 (94%) of the original CT reports. CONCLUSIONS: CT scans of the inpatients with community acquired viral infections most commonly show 1 of 2 patterns: consolidation and ground-glass opacities or bronchial wall thickening and tree-in-bud opacities. It is important that physicians interpreting CTs with multifocal consolidations and/or multifocal ground-glass opacities consider viral pneumonia when these findings are observed and recommend appropriate diagnostic testing when clinically warranted. PMID- 20160607 TI - Evaluation of the mitral and aortic valves with cardiac CT angiography. AB - Cardiac computed tomographic angiography (CTA) using multidetector computed tomographic scanners has proven to be a reliable technique to image the coronary vessels. CTA also provides excellent visualization of the mitral and aortic valves, and yields useful information regarding valve anatomy and function. Accordingly, an assessment of the valves should be performed whenever possible during CTA interpretation. In this paper, we highlight the imaging features of common functional and structural left-sided valvular disorders that can be seen on CTA examinations. PMID- 20160608 TI - What's new in Shock, March 2010? PMID- 20160610 TI - Increased sarcolemmal permeability as an early event in experimental septic cardiomyopathy: a potential role for oxidative damage to lipids and proteins. AB - This study describes increased sarcolemmal permeability and myofilamentar damage that occur together with lipid peroxidation and protein nitration in the myocardium in severe sepsis induced by cecal ligation and puncture. Male C57BL/6 mice were submitted to moderate and severe septic injury and sham operation. Using light and laser confocal microscopy, diffuse foci of myocytolysis associated with focal disruption of the actin/myosin contractile apparatus could be seen in hearts with severe septic injury. The myocardial expressions of the sarcomeric proteins myosin and actin were downregulated by both severe and moderate injuries. The detection of albumin staining in the cytoplasm of myocytes to evaluate sarcolemmal permeability provided evidence of severe and mild injury of the plasma membrane in hearts with severe and moderate septic injury, respectively. The administration of a superoxide scavenger caused marked reduction of sarcolemmal permeability, indicating the involvement of free radicals in its genesis. On electron microscopy, these changes were seen to correspond to spread blocks of a few myocytes with fragmentation and dissolution of myofibrils, intracellular edema, and, occasionally, rupture of the sarcolemma. In addition, oxidative damage to lipids, using anti-4-hydroxynonenal, an indicator of oxidative stress and disruption of plasma membrane lipids, and to proteins, using antinitrotyrosine, a stable biomarker of peroxynitrite-mediated protein nitration, was demonstrated. These findings make plausible the hypothesis that increased sarcolemmal permeability might be a primary event in myocardial injury in severe sepsis possibly due to oxidative damage to lipids and proteins that could precede phenotypic changes that characterize a septic cardiomyopathy. PMID- 20160611 TI - Increased resistance to LPS-induced myocardial dysfunction in the Brown Norway rats versus Dahl S rats: roles of inflammatory cytokines and nuclear factor kappaB pathway. AB - We previously demonstrated that hearts from Brown Norway (BN) rats were more resistant to ischemic injury than hearts from Dahl S (SS) rats. Here we determined the susceptibility to LPS-induced cardiomyopathy in these rats and examined the involvement of inflammatory signaling. Both strains were treated with LPS (20 mg/kg) via i.p. injection for 6 h. Myocardial function was assessed by the Langendorff system, and proinflammatory cytokines were measured by the enzyme-linked immunosorbent assay. LPS significantly reduced left ventricular developed pressure in both strains. Interestingly, the decrease of left ventricular developed pressure in BN rat hearts was approximately 25% less than that in SS rat hearts. Furthermore, LPS significantly reduced the peak rate of contraction and the peak rate of relaxation in SS hearts but not in BN hearts. No differences in LPS-induced decreases in coronary flow rate were observed between BN and SS rats. In addition, LPS-induced increases in proinflammatory cytokines, TNF-alpha, IL-1beta, and IL-6, were significantly lower in both plasma and hearts of BN rats compared with production in SS rats. LPS notably up-regulated the expression of proinflammatory enzymes, iNOS and cyclooxygenase 2, in SS hearts but not in BN hearts. Interestingly, LPS did not stimulate Toll-like receptor 4 or its adaptor myeloid differentiation factor 88 expression in the hearts of either strain but did increase IkappaB and P65 phosphorylation, less prominently in BN hearts than in SS hearts. These data indicate that reduced production of proinflammatory cytokines and diminished nuclear factor kappaB activation are major mechanisms by which BN hearts are more resistant to LPS-induced myocardial dysfunction than SS hearts. PMID- 20160613 TI - Protease-activated receptor 2 blocking peptide counteracts endotoxin-induced inflammation and coagulation and ameliorates renal fibrin deposition in a rat model of acute renal failure. PMID- 20160609 TI - Fluid resuscitation: past, present, and the future. AB - Hemorrhage remains a major cause of preventable death following both civilian and military trauma. The goals of resuscitation in the face of hemorrhagic shock are restoring end-organ perfusion and maintaining tissue oxygenation while attempting definitive control of bleeding. However, if not performed properly, resuscitation can actually exacerbate cellular injury caused by hemorrhagic shock, and the type of fluid used for resuscitation plays an important role in this injury pattern. This article reviews the historical development and scientific underpinnings of modern resuscitation techniques. We summarized data from a number of studies to illustrate the differential effects of commonly used resuscitation fluids, including isotonic crystalloids, natural and artificial colloids, hypertonic and hyperoncotic solutions, and artificial oxygen carriers, on cellular injury and how these relate to clinical practice. The data reveal that a uniformly safe, effective, and practical resuscitation fluid when blood products are unavailable and direct hemorrhage control is delayed has been elusive. Yet, it is logical to prevent this cellular injury through wiser resuscitation strategies than attempting immunomodulation after the damage has already occurred. Thus, we describe how some novel resuscitation strategies aimed at preventing or ameliorating cellular injury may become clinically available in the future. PMID- 20160615 TI - Atlantoaxial rotatory fixation in the setting of associated congenital malformations: a modified classification system. AB - STUDY DESIGN: A case report. OBJECTIVE: To raise awareness of the development of atlantoaxial rotatory fixation (AARF) in the setting of congenital vertebral anomalies/malformations. SUMMARY OF BACKGROUND DATA: Klippel-Feil Syndrome (KFS) is a complex, heterogeneous condition noted as congenital fusion of 2 or more cervical vertebrae with or without spinal or extraspinal manifestations. Although believed to be a rare occurrence in the population, KFS may be underreported. Proper diagnosis of KFS and other congenital conditions affecting the spine is imperative to devise proper management protocols and avoid potential complications resulting from the altered biomechanics associated with such conditions and their abnormal vertebral morphology. Craniovertebral dislocation and AARF may cause severe cervicomedullary and spinal cord compression and could thereby be potentially fatal, especially in patients with KFS who present with congenitally-associated comorbidities. METHODS: A 13-year-old boy with Chiari type I malformation, craniofacial abnormalities, and other irregularities underwent thoracolumbar spine surgery for his scoliosis curve correction at another institution, which immediately following surgery he became a quadriparetic. The initial preoperative assessment of his cervical spine was limited and the associated KFS was initially undiagnosed. At 14 years of age, he presented to our clinic with an ASIA-C spinal cord injury. Plain radiographs, normal and 3-dimensional reformatted computed tomographs (CT), and magnetic resonance imaging (MRI) noted assimilation of the patient's occiput to the atlas (occipitalization) with congenital fusion of C2-C3, indicative of KFS, and the presence of anterior craniovertebral dislocation with a Fielding and Hawkins type II AARF. Closed reduction of the craniovertebral dislocation was noted, but his atlantoaxial rotatory subluxation was nonresponsive and fixed (AARF). As such, at the age of 14, the patient underwent posterior instrumentation and fusion from the occiput to C4 to maintain reduction of thecraniovertebral dislocation and reduce his AARF. RESULTS: At 9 months postoperative follow-up of his craniovertebral surgery, the instrumentation remained intact, reduction of the atlantoaxial rotatory subluxation was maintained, and posterior bone fusion was noted. Neurologically, he remained an ASIA-C without any substantial return of function. CONCLUSION: This report raises awareness for the need of a thorough evaluation of the cervical spine to determine patients at high risk for craniovertebral dislocation and atlantoaxial rotatory subluxation, primarily in the context of KFS or other congenital conditions. Three-dimensional CT and MR imaging are ideal radiographic methods to determine the presence and extent of craniovertebral dislocation, AARF, and of abnormal vertebral anatomy/malformations. In addition, the authors propose a modification to the Fielding and Hawkins classification of AARF to include variants and subtypes that account for abnormal anatomy and congenital anomalies/malformations. PMID- 20160618 TI - Re: Sangole AP, Aubin CE, Labelle H, et al. Three-dimensional classification of thoracic scoliotic curves. Spine 2009;34:91-9. PMID- 20160619 TI - Re: Coronado-Zarco R, Cruz-Medina E, Arellano-Hernandez A, et al. Effectiveness of calcitonin in intermittent claudication treatment of patients with lumbar spinal stenosis. A systemic review. Spine 2009;34;22:E818-27. PMID- 20160620 TI - Re: Gouveia LO, Castanho P, Ferreira JJ. Safety of chiropractic interventions. A systematic review. Spine 2009;34:E405-13. PMID- 20160623 TI - Anterior cruciate ligament injuries: etiology and prevention. AB - The relatively high risk of noncontact anterior cruciate ligament (ACL) rupture among female athletes has been a major impetus for investigation into the etiology of this injury. A number of risk factors have been identified, both internal and external to the athlete, including neuromuscular, anatomical, hormonal, shoe-surface interaction, and environmental, such as weather. The anatomic and neuromuscular risk factors, often gender related, are the focus of most ACL injury prevention programs. Although studies have shown that biomechanic centered prevention programs can reduce the risk of ACL injury, many questions remain unanswered. More research is needed to increase our understanding of the risk factors for ACL injury; how injury prevention programs work and can the clinical application of such programs be optimized. PMID- 20160624 TI - Posterior mini-incision hamstring harvest. AB - Many orthopedists looking for alternatives to autograft bone-patellar-tendon-bone grafts are uncertain of their ability to harvest a hamstring graft of adequate length. They may use an allograft instead for this reason despite recent reports of high failure rates. This article presents step-by-step instructions for a posterior mini-incision hamstring harvest that offers a safe and simple method of reliably harvesting sufficient hamstring for 4 or 6 strand repair, while using tiny incisions for excellent cosmesis and minimal pain. Access from the posterior mini-incision allows easy identification and differentiation of the semitendinosus and gracilis (Gr) tendons, as well as precise placement of the anterior mini-incision for tibial tunnel drilling and fixation. Most importantly sectioning of the intertendinous cross-connections is performed under easy direct vision posteriorly, instead of at a distance from the typical anterior incision under retractors. This prevents the tendons from being cut too short by the tendon stripper and is particularly useful in large patients. In addition to the surgical procedure, details on the required equipment are presented. PMID- 20160625 TI - Single versus double hamstring tendon harvest for ACL reconstruction. AB - The use of hamstring tendons for anterior cruciate ligament reconstruction has become more accepted in recent years. The use of a doubled semitendinosus tendon graft versus a quadrupled semitendinosus tendon graft is still a matter of contention. We propose a technique of harvesting only the semitendinosus tendon for either single or double bundle anterior cruciate ligament reconstruction. This technique avoids the loss of deep knee flexion and loss of internal rotation strength acquired by sacrificing the gracilis. PMID- 20160626 TI - All-inside ACL: retroconstruction controversies. AB - All-inside anterior cruciate ligament reconstruction is controversial because the technique is new; as a result, evidence-based clinical outcome studies have yet to be published. The purpose of this article is to consider the following controversies (considered alphabetically): anatomy, biomechanics, biology, bioabsorbables, divergence of the femoral interference screw, expansion or widening of tunnels, fixation, future considerations, graft choice, the learning curve, technique, tensioning, and tibia blow-out fracture. The technique should be learned in stages. In the opinion of the author, the history of sports medicine and arthroscopy has been a progression toward less invasive techniques. In the future, all-inside anterior cruciate ligament reconstruction techniques should become more simple and reproducible, and clinical outcomes must be analyzed with long-term follow-up. PMID- 20160628 TI - Anatomic revision ACL reconstruction. AB - Anterior cruciate ligament (ACL) injuries are common in the athletic population. In fact, ACL reconstruction has become one of the most common orthopedic procedures with over 100,000 being performed annually. As the number of primary ACL reconstructions continues to increase, so will the need for revision surgery. The causes of failure are numerous and multifactorial. However, understanding the exact cause of failure before undertaking a revision ACL surgery is paramount in providing the patient with a successful outcome. It is our belief that anatomic restoration of ACL anatomy in the revision setting is best accomplished using the double-bundle technique in the majority of cases. This is a technically demanding procedure that requires proper preoperative preparation. This article outlines our approach to these challenging situations. PMID- 20160627 TI - Anatomic Double-bundle ACL Reconstruction. AB - Rupture of the anterior cruciate ligament (ACL) is one of the most frequent forms of knee trauma. The traditional surgical treatment for ACL rupture is single bundle reconstruction. However, during the past few years there has been a shift in interest toward double-bundle reconstruction to closely restore the native ACL anatomy. This paper evaluates the basis for double-bundle ACL reconstruction including anatomy, biomechanics and kinematics, describes our surgical technique, and discusses why we prefer anatomic double-bundle ACL reconstruction, as well as its outcome, the choices, and the controversies of double-bundle ACL reconstruction. Pitfalls of traditional ACL surgery are also discussed, the recognition of which is the key to performing anatomic ACL reconstruction. PMID- 20160629 TI - Bioresorbable scaffolds for anterior cruciate ligament reconstruction: do we need an off-the-shelf ACL substitute? AB - Currently available anterior cruciate ligament (ACL) graft sources, autograft and allograft, present potential problems that a natural biomaterial ACL graft might be able to solve. Earlier efforts in the development of synthetic ACL grafts were less than optimal, and those devices have largely been abandoned. We can learn from these past failures, and potentially develop a bioresorbable scaffold for ACL reconstruction, which will provide immediate stability, promote and direct tissue in growth, and degrade at an appropriate rate, without harmful wear debris. We have developed a modified silk scaffold, which is currently being evaluated in humans in a pilot study. PMID- 20160630 TI - Current controversies in rehabilitation after anterior cruciate ligament reconstruction. AB - Rehabilitation concepts after anterior cruciate ligament (ACL) reconstruction continue to advance rapidly. A review of the recent literature reveals numerous aspects of the rehabilitation program, the subject of investigation, and validation. Areas discussed in this article include the efficacy of functional bracing after ACL reconstruction and perturbation training programs in nonoperative, preoperative and postoperative rehabilitation programs. Also discussed is the need for criteria-based progression through the late stages (return to sports) of the ACL reconstruction rehabilitation. PMID- 20160631 TI - The future: optimizing the healing environment in anterior cruciate ligament reconstruction. AB - The therapeutic use of autologous platelet-rich plasma constitutes a breakthrough in the stimulation and acceleration of soft-tissue healing and bone regeneration. Platelet-rich technologies seek to facilitate anterior cruciate ligament replacement by mimicking the native tissue and improving the adequacy of tissue function with appropriate cues, ultimately leading to better patient care. There are different technical protocols for preparing platelet-rich plasma, and the resultant products are typically heterogeneous; moreover, protocols for administrating the products in patients vary extensively. Poor standardization in the field makes full evaluation of different plasma products and establishing standards for the most beneficial applications of this technology difficult. This article presents the current data on the use of platelet-rich plasma in the reconstruction of the anterior cruciate ligament. Although the findings are not conclusive, the use of autologous platelet-rich plasma is shown to be safe, reproducible, and effective in mimicking the natural processes of soft tissue and bone healing. Platelet-rich technologies offer new opportunities for research and the application of anterior cruciate ligament tissue engineering. PMID- 20160632 TI - Impact of human leukocyte antigen-B*51-restricted cytotoxic T-lymphocyte pressure on mutation patterns of nonnucleoside reverse transcriptase inhibitor resistance. AB - OBJECTIVE: The objective of this study is to determine the impact of human leukocyte antigen (HLA)-B*51-restricted cytotoxic T-lymphocyte (CTL) pressure on the development of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance. DESIGN: The prevalence of HIV-1 harboring an escape mutation, I135X, in a major epitope of HLA-B*51-restricted CTL located in reverse transcriptase is increasing worldwide. We analyzed the effects of escape mutations on the emerging mutation patterns of NNRTI resistance. METHODS: Monoclonal HIV-1 sequences harboring each of the escape mutations, including I135L (HIV-1I135L), I135V (HIV 1I135V), I135T (HIV-1I135T), and I135R (HIV-1I135R) in reverse transcriptase, and a wild-type monoclonal HIV-1 (HIV-1WT) were cultured in the presence of increasing concentrations of efavirenz. Induced mutations during culture passages of the culture were analyzed. RESULTS: E138K emerged during the cultural passages of HIV-1I135V, HIV-1I135T, and HIV-1I135R, but not during the passages of HIV 1WT. The combination of I135T, the most frequent escape mutation, and E138K (HIV 1I135T/E138K) conferred significant resistance to efavirenz, nevirapine, and etravirine. The HIV-1I135L/E138K and HIV-1I135R/E138K were significantly resistant to nevirapine and etravirine, respectively, though each solo of escape mutations and E138K did not confer significant resistance to NNRTI. Computational analysis indicated that I135T and E138K cooperatively extend the gap between the binding site of reverse transcriptase and NNRTI. CONCLUSION: HLA-B*51-restricted CTL can induce novel mutation patterns of NNRTI resistance by selecting escape mutations. The spread of CTL escape variants may alter the mutation patterns of drug resistance. PMID- 20160633 TI - Etravirine limits the emergence of darunavir and other protease inhibitor resistance-associated mutations in the DUET trials. AB - Etravirine is a recently approved nonnucleoside reverse transcriptase inhibitor. The ability of etravirine to limit the emergence of resistance to protease inhibitors, and specifically to darunavir, was investigated in the subset of treatment-experienced patients with virologic rebound in the phase III DUET trials. Of those experiencing rebound, fewer etravirine-treated than placebo treated patients developed mutations associated with resistance to protease inhibitors in general and to darunavir in particular, and more patients in the etravirine than the placebo-group maintained baseline darunavir susceptibility at endpoint. PMID- 20160634 TI - N348I in reverse transcriptase provides a genetic pathway for HIV-1 to select thymidine analogue mutations and mutations antagonistic to thymidine analogue mutations. AB - OBJECTIVE: Several nonnucleoside (e.g. Y181C) and nucleoside (e.g. L74V and M184V) resistance mutations in HIV-1 reverse transcriptase are antagonistic toward thymidine analogue mutations (TAMs) that confer zidovudine (ZDV) resistance. The N348I mutation in the connection domain of reverse transcriptase also confers ZDV resistance; however, the mechanisms involved are different from TAMs. In this study, we examined whether N348I compensates for the antagonism of the TAM K70R by Y181C, L74V and M184V. DESIGN AND METHODS: The ZDV monophosphate and ribonuclease H activities of recombinant-purified HIV-1 reverse transcriptase containing combinations of K70R, N348I and Y181C, L74V or M184V were assessed using standard biochemical and antiviral assays. RESULTS: As expected, the introduction of the Y181C, L74V or M184V mutations into K70R HIV-1 reverse transcriptase significantly diminished the ATP-mediated ZDV monophosphate excision activity of the enzyme. However, the N348I mutation compensated for this antagonism on RNA/DNA template/primers by significantly decreasing the frequency of secondary ribonuclease H cleavages that reduce the overall efficiency of the excision reaction. CONCLUSION: The acquisition of N348I in HIV-1 reverse transcriptase - which can occur early in therapy, oftentimes before TAMs - may provide a simple genetic pathway that allows the virus to select both TAMs and mutations that are antagonistic toward TAMs. PMID- 20160635 TI - High frequency of integrase Q148R minority variants in HIV-infected patients naive of integrase inhibitors. AB - BACKGROUND: Integrase positions 148 and 155 represent main determinants of resistance to integrase inhibitors. We assessed the prevalence of minority variants harboring such mutations in integrase-naive HIV-infected patients. METHODS: Two groups of patients were studied: 40 heavily antiretroviral experienced patients, initiating a raltegravir-based therapy and 51 antiretroviral-naive patients. Allele-specific real-time PCR (AS-PCR) systems, developed for Q148H, Q148R and N155H mutations, were performed at baseline for antiretroviral-experienced patients. Samples from antiretroviral-naive patients were tested with the Q148R AS-PCR assay. RESULTS: The limits of detection of AS PCR systems were 0.10, 0.10 and 0.05% for Q148H, Q148R and N155H mutations, respectively. AS-PCR systems were successful in 79 of 91 samples. In antiretroviral-experienced patients, Q148R minority variants were frequently detected (26/32 patients, 81%) at low-level frequency (median = 0.40%), whereas no minority variants exhibiting Q148H or N155H mutation were found. Twenty-four of 26 patients exhibiting Q148R variants were virological responders but four of them displayed a delayed virological response occurring between W18 and W36. Two patients exhibited virological failure under raltegravir, both harboring Q148R minority variants at baseline. However, we did not find any association between the presence of Q148R minority variants and an increased risk of virological failure. Q148R minority variants were also found in 86% of antiretroviral-naive patients, a prevalence significantly higher than that of K103N minority variants (26%). CONCLUSION: Q148R variants were frequently detected, always at low-level, in antiretroviral-experienced and naive patients. Although their presence was not consistently associated with virological failure, their impact on long-term viral suppression needs to be further investigated. PMID- 20160636 TI - Sacral nerve stimulation for fecal incontinence: results of a 120-patient prospective multicenter study. AB - BACKGROUND: Sacral nerve stimulation has been approved for use in treating urinary incontinence in the United States since 1997, and in Europe for both urinary and fecal incontinence (FI) since 1994. The purpose of this study was to determine the safety and efficacy of sacral nerve stimulation in a large population under the rigors of Food and Drug Administration-approved investigational protocol. METHODS: Candidates for SNS who provided informed consent were enrolled in this Institutional Review Board-approved multicentered prospective trial. Patients showing > or =50% improvement during test stimulation received chronic implantation of the InterStim Therapy (Medtronic; Minneapolis, MN). The primary efficacy objective was to demonstrate that > or =50% of subjects would achieve therapeutic success, defined as > or =50% reduction of incontinent episodes per week at 12 months compared with baseline. RESULTS: A total of 133 patients underwent test stimulation with a 90% success rate, and 120 (110 females) of a mean age of 60.5 years and a mean duration of FI of 6.8 years received chronic implantation. Mean follow-up was 28 (range, 2.2-69.5) months. At 12 months, 83% of subjects achieved therapeutic success (95% confidence interval: 74%-90%; P < 0.0001), and 41% achieved 100% continence. Therapeutic success was 85% at 24 months. Incontinent episodes decreased from a mean of 9.4 per week at baseline to 1.9 at 12 months and 2.9 at 2 years. There were no reported unanticipated adverse device effects associated with InterStim Therapy. CONCLUSION: Sacral nerve stimulation using InterStim Therapy is a safe and effective treatment for patients with FI. PMID- 20160637 TI - Morbidity and mortality of laparoscopic gastrectomy versus open gastrectomy for gastric cancer: an interim report--a phase III multicenter, prospective, randomized Trial (KLASS Trial). AB - OBJECTIVE: The aim of this study was to evaluate the safety of this trial with respect to morbidity and mortality. SUMMARY BACKGROUND DATA: Laparoscopic assisted distal gastrectomy (LADG) is rapidly gaining popularity. However, there is limited evidence regarding its oncologic safety. We therefore conducted a phase III multicenter, prospective, randomized study comparing LADG with open gastrectomy (ODG). METHODS: Patient eligibility criteria were pathologically proven adenocarcinoma, 20 to 80 years of age, preoperative stage I, no history of other cancer, chemotherapy, or radiotherapy. The primary end point was to determine whether there is a difference in overall survival between 2 groups. The morbidity and mortality were compared to evaluate the safety of this trial. The time was decided on the hypothesis that the morbidity of this trial was not significantly different from that of previous reports on open gastric cancer surgeries (17%-20%). This study is registered at ClinicalTrials.gov and carries the following ID number: NCT00452751. RESULTS: A total of 342 patients were randomized (LADG, 179 patients; ODG, 161 patients) between January 1, 2006 and July 19, 2007. There were no significant differences between the 2 groups in age, gender, and comorbidities. The postoperative complication rates of the LADG and ODG groups were 10.5% (17/179) and 14.7% (24/163), respectively (P = 0.137). Reoperations were required in 3 cases each group. The postoperative mortality was 1.1% (2/179) and 0% (0/163) in the LADG and ODG groups (P = 0.497), respectively. CONCLUSION: There was no significance difference in the morbidity and mortality between the 2 groups. Therefore, we conclude that this trial is safe and is thus ongoing. PMID- 20160638 TI - Predicting high grade lesions of sinusoidal obstruction syndrome related to oxaliplatin-based chemotherapy for colorectal liver metastases: correlation with post-hepatectomy outcome. AB - BACKGROUND/OBJECTIVE: Oxaliplatin-based chemotherapy induces sinusoidal obstruction syndrome (SOS) lesions in the nontumorous liver parenchyma, which may increase the risk of liver resection for colorectal liver metastases. The objective of this study was to evaluate the accuracy of aspartate aminotransferase to platelet ratio index (APRI) and FIB-4 scoring systems to predict chemotherapy-associated liver injury and to correlate the severity of sinusoidal injury with postoperative outcome. METHODS: Between 1998 and 2007, 78 patients were operated for colorectal liver metastases after preoperative oxaliplatin-based chemotherapy. Grading of steatosis and SOS in the nontumorous liver parenchyma was obtained in these patients. Univariate analysis of 18 preoperative factors to predict SOS occurrence was performed as well as multivariate analysis. Relevance of preoperative platelet count level, transaminase levels, and fibrosis scoring systems were evaluated to predict high grade lesions of SOS using a receiving operative curve analysis. Ninety-day mortality and morbidity were studied according to SOS severity in 51 patients who underwent major liver resection. RESULTS: Overall, pathologic examination showed high-grade lesions of SOS (SOS 2/3) in 46 (59%) patients. Univariate analysis showed that a low preoperative platelet count, elevated preoperative aspartate aminotransferase, short interval between chemotherapy and surgery were significant factors associated with high-grade lesions of SOS. Multivariate analysis showed that only the APRI score was an independent predictive factor for severe SOS. Receiving operative curve analysis revealed that the cut-off value predicting high-grade lesions of SOS with the best accuracy was an APRI score of 0.36 (area under the curve, 0.85; sensitivity, 87%; specificity, 69%). After major liver resection (n = 51), SOS 2/3 (n = 38) was associated with postoperative hepatic dysfunction (26/38 in SOS 2/3 vs. 3/13 in SOS 0/1; P = 0.004) and ascites (P = 0.03). CONCLUSION: A low preoperative platelet count and high APRI score seem to be the most reliable indicators to predict SOS severity. PMID- 20160639 TI - Limited resection for the treatment of patients with stage IA lung cancer. AB - OBJECTIVE: Lobectomy is the standard of care for stage IA lung cancer. Some small retrospective studies have suggested similar results after limited resection for tumors < or =2 cm in size. The objective of the study was to compare survival after lobectomy and limited resection among Medicare patients with lung cancer. METHODS: Using the Surveillance, Epidemiology, and End Results registry, linked to Medicare records, we identified 1165 cases of stage I lung cancer < or =2 cm in size that underwent lobectomy or limited resection (segmentectomy or wedge resection). We used logistic regression to determine propensity scores for undergoing limited resection based on the patients' preoperative characteristics. Overall and lung cancer-specific survival of patients treated with lobectomy or limited resection was compared after adjusting for their propensity score. RESULTS: Overall, 196 (17%) patients underwent limited resection. For the entire sample, the adjusted hazard ratio for all cause mortality (1.09; 95% confidence interval: 0.85-1.40) or lung cancer-specific death (hazard ratio: 1.39; 95% confidence interval: 0.97-2.01) for patients undergoing limited resection were not significantly different from those having lobectomy. Similarly, we found no significant differences in overall or lung cancer-specific survival for patients treated with limited resection compared with lobectomy when data was analyzed stratifying and matching patients by their propensity scores. CONCLUSIONS: These results suggest that survival of patients >65 years of age undergoing limited resection or lobectomy for stage IA tumors < or =2 cm appears to be similar. Although these findings should be confirmed in prospective trials, our results suggest that limited resection may be an effective therapeutic alternative for these patients. PMID- 20160640 TI - Enhancement of fibrinolytic activity in vascular endothelial cells by heterologous expression of adenine nucleotide translocase-1. AB - The fibrinolytic activity of blood is regulated by expressing tissue-type plasminogen activator (t-PA) and its specific inhibitor, type-1 plasminogen activator inhibitor (PAI-1), from vascular endothelial cells. Since t-PA is a major plasminogen activator in blood, it is considered that the binding protein for t-PA, which exists on endothelial cell membrane, immobilizes t-PA on the surface of endothelial cells and enhances their antithrombotic property. Recently, we have found a new t-PA binding protein in endothelial cells. Its amino acid sequence has matched that of human adenine nucleotide translocase-1 (ANT1). The aims of this study are to confirm the binding of t-PA to ANT1, and to clarify the effect of ANT1 on fibrinolytic activity around endothelial cells. ANT1 is prepared from recombinant glutathione S-transferase (GST)-ANT1 fusion protein, and reveals t-PA binding activity in a ligand blot assay. In addition, ANT1 is exclusively expressed on endothelial cell membrane by using pDisplay vector. Interaction of t-PA with ANT1, which is expressed on the surface of endothelial cells, is confirmed by IAsys binding analysis and chromogenic assay. The heterologous expression of ANT1 on endothelial cell membrane enhances the t PA binding ability of endothelial cells and the effect of ANT1 expression on fibrinolytic activity is demonstrated by increasing t-PA-catalyzed plasminogen activation. These results suggest that a novel t-PA-binding protein, ANT1, may concentrate t-PA on the surface of cells and enhance fibrinolytic properties around endothelial cells; therefore, ANT1 can be a powerful tool for regulating the plasminogen activation system in the vessel. PMID- 20160641 TI - Establishment of reference intervals for von Willebrand factor antigen and eight coagulation factors in a Korean population following the Clinical and Laboratory Standards Institute guidelines. AB - Establishment of reference intervals for coagulation molecules is important but is costly and sometimes not feasible. Since reference intervals from manufacturers or the literature are mostly out of date or involved Western populations, the authors determined reference intervals for VWF: Ag and eight factors in a Korean population. VWF: Ag, factor VIII (FVIII), FII, FV, FVII, FIX, FX, FXI, and FXII were determined in Korean individuals visiting for routine checkup following the CLSI (Clinical and Laboratory Standards Institute) guidelines. Reagents by Diagnostica Stago were used on the STA Compact Analyzer (Diagnostica Stago). Exclusion criteria were medical history or laboratory findings that could affect the factor levels. Influence of demographic factors was analyzed. Mean +/- 2 x SD or central 95 percentile was used, as appropriate. We obtained data from 266 adults for VWF: Ag, 371 adults for FVIII, and minimum 136 adults for the rest. Reference interval for VWF was 51-176% (52-155% in blood group O and 71-186% for non-O). Reference interval for FVIII was 64-197% (55-150% in O and 77-205% in non-O). Reference interval for FII was 77-121%, FV 81-160%, FVII 68-149%, FIX 67-154%, FX 69-126%, FXI 59-138%, and FXII 48-177%. The medians of VWF: Ag, FVIII, and FIX were significantly higher in the elderly group (> or =60 years). We established local reference intervals for VWF: Ag and eight coagulation factors in a Korean population according to the CLSI guidelines. Significantly, different reference intervals were obtained in blood group O vs. non-O for VWF: Ag and FVIII. The reference intervals obtained in this study could be adopted in other clinical laboratories after appropriate validation. PMID- 20160642 TI - Responses to odors in occupational environments. AB - PURPOSE OF REVIEW: There is mounting evidence that the presence of airborne chemicals that produce odor and irritation can be a significant impediment to a productive and healthy workforce, even among individuals without chemical sensitivity. RECENT FINDINGS: Studies investigating odor and irritant-induced symptoms in occupational environments suggest that poor indoor air quality, coupled with psychosocial factors such as the work environment, personality and stress, can lead to the development of building-related complaints and exacerbate chemical intolerance and symptoms. The practice of introducing pleasant odors in the workplace to improve productivity and mood is not well supported by current research. SUMMARY: Managing the response to odors and irritants in the workplace is critical to maintaining the health and well being of workers. There is a critical need for regulatory organizations in the United States and elsewhere to harmonize guidelines for occupational exposure limits. In addition, management must engage in risk communication and education of workers in order to ensure that misperception of risk from odors does not lead to illness and loss of well being. PMID- 20160643 TI - 13CO2 breath tests, a tool to assess intestinal and liver function in the ICU? AB - PURPOSE OF REVIEW: CO2 breath tests, based on nondispersive infrared (NDIR) measurement technology, offer the chance for a noninvasive online quantitation of physiological processes. With recent extensions of the NDIR measurement technology breath tests could be used in an ICU setting without any restriction. Since online tools to assess feed intolerance with gastric emptying and to quantify gradual changes in liver function are still missing, this review explores the potential of breath tests to fill this gap. RECENT FINDINGS: Gastric emptying may be correctly quantified; however, the corresponding tests fail to capture aberrations in nutrient absorption, which appear to be linked to hyperglycemia and insulin resistance and may contribute to feed intolerance. The progression or ameloriation of liver injury could be assessed with breath tests, which cannot, however, distinguish between functional and macrocirculatory or microcirculatory disorders. SUMMARY: Breath tests for liver function and gastric emptying taken alone may fail in their ability to specifically quantify the clinical disorders. However, invasive test extensions could help to characterize their validity and thus to identify additional, noninvasive measurements to assure and expand this domain. PMID- 20160644 TI - Sedation and analgesia in acute neurologic disease. PMID- 20160645 TI - Imaging brain trauma. AB - PURPOSE OF REVIEW: Traumatic brain injury (TBI) is a leading cause of death and long-term cognitive and behavioral dysfunction in children and young adults, yet effective treatments are lacking, in part because critical aspects of TBI neurobiology and natural history are not understood. We review recent advances in neuroimaging and discuss how they are helping to address these fundamental gaps. RECENT FINDINGS: Novel imaging methods provide detailed information on how TBI affects anatomical integrity (diffusion tensor imaging; voxel-based morphometry; susceptibility-weighted imaging, magnetization transfer imaging), metabolic activity (magnetic resonance spectroscopy), perfusion (positron emission tomography, perfusion computed tomography, perfusion magnetic resonance), and patterns of functional activation (functional magnetic resonance imaging). Individually and collectively, these methods can significantly enhance TBI diagnosis and outcome prediction. SUMMARY: Refinements in neuroimaging offer a window into the complex neuroanatomical and neurophysiological disturbances induced by TBI. Research is needed to understand how these alterations evolve with time and in response to therapeutic interventions. PMID- 20160647 TI - The role of the physician-scientist in bridging basic and clinical research in type 1 diabetes. AB - PURPOSE OF REVIEW: In a relatively short time, advances in both basic science and clinical medicine have revolutionized the way we understand disease processes and suggested novel approaches that may be able to be used to treat or cure some of the most relevant human afflictions. In type 1 diabetes, one unintended consequence of this has been the polarization of the investigational groups (i.e., immunologists and endocrinologists) interested in developing novel therapies for this condition. This review will examine how and why such polarization exists, and why past and current approaches to develop critically needed translational investigators may be falling short. RECENT FINDINGS: Despite significant efforts to increase the number of individuals trained in both basic science and clinical medicine, the number of academic physician-scientists is on the decline. Increased demands from academic institutions coupled with severe difficulty in securing extramural funding are probably playing important roles in this concerning trend. SUMMARY: Type 1 diabetes will continue to be a significant strain on individuals, their families and society until a cure is found. More than ever, there is a critical need to support appropriately trained translational investigators who can best facilitate bringing the promise of basic research to clinical reality. PMID- 20160646 TI - Brown fat as a therapy for obesity and diabetes. AB - PURPOSE OF REVIEW: Human fat consists of white and brown adipose tissue (WAT and BAT). Though most fat is energy-storing WAT, the thermogenic capacity of even small amounts of BAT makes it an attractive therapeutic target for inducing weight loss through energy expenditure. This review evaluates the recent discoveries regarding the identification of functional BAT in adult humans and its potential as a therapy for obesity and diabetes. RECENT FINDINGS: Over the past year, several independent research teams used a combination of positron emission tomography and computed tomography (PET/CT) imaging, immunohistochemistry, and gene and protein expression assays to prove conclusively that adult humans have functional BAT. This has occurred against a backdrop of basic studies defining the origins of BAT, new components of its transcriptional regulation, and the role of hormones in stimulation of BAT growth and differentiation. SUMMARY: Adult humans have functional BAT, a new target for antiobesity and antidiabetes therapies focusing on increasing energy expenditure. Future studies will refine the methodologies used to measure BAT mass and activity, expand our knowledge of critical-control points in BAT regulation, and focus on testing pharmacological agents that increase BAT thermogenesis and help achieve long-lasting weight loss and an improved metabolic profile. PMID- 20160648 TI - New directions in behavioral treatment of autism spectrum disorders. AB - PURPOSE OF REVIEW: The review explores current trends in the behavioral intervention literature for children with an autism spectrum disorder (ASD) during 2008 and 2009. Noteworthy findings and intervention strategies are highlighted. Additionally, the quality of all reviewed studies is systematically evaluated. RECENT FINDINGS: During 2008 and 2009, there was nearly a quarter increase in the number of behavioral intervention studies, as well as more randomized controlled trials and approaches other than applied behavior analysis. Many of the studies investigated commonly used ASD intervention practices or novel treatments. A few were conducted with underserved populations, such as toddlers and adults with ASD. Social impairment was the focus of the largest number of intervention studies. A small percentage of studies were rated as high quality. SUMMARY: Overall, the reviewed studies suggest that ASD-specific deficits can be improved through behavioral intervention. However, whereas progress continues to be made in our understanding of effective treatments for children with ASD, confidence in these findings would be improved with higher quality studies. PMID- 20160649 TI - High-frequency oscillations in epileptic brain. AB - PURPOSE OF REVIEW: It has been 10 years since pathological high-frequency oscillations (pHFOs) were described in the brain of epileptic animals and patients. This review summarizes progress in research on mechanisms of their generation and potential clinical applications over that period. RECENT FINDINGS: Initially, pHFOs were recorded with microelectrodes in the hippocampus of rodents and patients with mesial temporal lobe epilepsy (MTLE), but recently pHFOs have also been recorded with clinical depth and grid electrodes in multiple brain areas including the hippocampus and neocortex of patients with different types of epilepsy. One hypothesis is that pHFOs reflect fields of hypersynchronized action potentials (bursts of population spikes) within small discrete neuronal clusters responsible for seizure generation. Studies suggest that pHFOs can be used as a reliable biomarker for epileptogenesis, epileptogenicity, and the delineation of the epileptogenic region. SUMMARY: Recording of pHFOs with clinical electrodes provides a means for further investigation of their functional role in the epileptic brain and as a potential biomarker of epileptogenesis and epileptogenicity and for presurgical mapping. PMID- 20160650 TI - Neurosteroids and epilepsy. AB - PURPOSE OF REVIEW: Neurosteroids are a family of compounds synthesized directly in the brain by transforming cholesterol into pregnenolone, which is then converted to compounds such as allopregnanolone and allotetrahydrodeoxycorticosterone. In view of their ability to modulate neurotransmission, neurosteroids may influence the clinical course of epileptic disorders. In this review, we highlight two emerging properties of neurosteroids, that is, their anticonvulsant and antiepileptogenic activities. RECENT FINDINGS: It has been shown that fluctuations in neurosteroid synthesis, such as those seen in response to stress or during the ovarian cycle, determine an increase in seizure threshold. Moreover, increased neurosteroid synthesis, presumably occurring in glial cells during epileptogenesis, delays the appearance of recurrent spontaneous seizures in an animal model of temporal lobe epilepsy; such an effect may be due to augmented tonic gamma-aminobutyric acid type A receptor mediated inhibition. Finally, clinical trials with ganaxolone, an allopregnanolone analogue, have demonstrated beneficial effects in pharmacoresistant epileptic patients, whereas finasteride--which interferes with neurosteroid synthesis - facilitates seizures in catamenial epilepsy. SUMMARY: The overall evidence suggests that neurosteroids may represent a novel therapeutic strategy in epileptic disorders and a future perspective to control epileptogenicity. PMID- 20160651 TI - The immune system's role in the biology of autism. AB - PURPOSE OF REVIEW: The following is a review of the most recent research concerning the potential role of immune system dysfunction in autism. This body of literature has expanded dramatically over the past few years as researchers continue to identify immune anomalies in individuals with autism. RECENT FINDINGS: The most exciting of these recent findings is the discovery of autoantibodies targeting brain proteins in both children with autism and their mothers. In particular, circulating maternal autoantibodies directed toward fetal brain proteins are highly specific for autism. This finding has great potential as a biomarker for disease risk and may provide an avenue for future therapeutics and prevention. Additionally, data concerning the cellular immune system in children with autism suggest there may be a defect in signaling pathways that are shared by the immune and central nervous systems. Although studies to explore this hypothesis are ongoing, there is great interest in the commonalities between the neural and immune systems and their extensive interactions. SUMMARY: In summary, the exciting research regarding the role of the immune system in autism spectrum disorders may have profound implications for diagnosis and treatment of this devastating disease. PMID- 20160652 TI - Characterization of Lymphomas in a high prevalence HIV setting. AB - BACKGROUND: HIV infection has been associated with an increased risk of malignancy, both AIDS defining and non-AIDS defining. METHODS: This study presents a detailed pathological description of newly diagnosed lymphomas in Johannesburg, South Africa (January 2004 and December 2006). The review coincides with introduction of combination antiretroviral therapy. RESULTS: One thousand eight hundred and ninety-seven new lymphoproliferative disorders were referred to the Charlotte Maxeke Johannesburg Academic Hospital. B-cell non-Hodgkin lymphoma accounted for 83%, T-cell non-Hodgkin lymphoma 3.5%, and Hodgkin lymphoma 7% of cases. The overall prevalence of HIV infection was 37% (n = 709). Diffuse large B cell lymphoma (21%; n = 401) was the most common lymphoma. HIV prevalence ranged from an absence in follicular or mantle cell lymphoma to a low prevalence in diseases like small lymphocytic lymphoma/chronic lymphocytic leukemia (4%) and pre-B/common ALL (5%) to a high prevalence in diffuse large B-cell lymphoma (80%), Burkitt lymphoma/leukemia (86%), and primary effusion lymphoma (100%). CONCLUSIONS: This study provides a baseline for monitoring the impact of HIV and management thereof on lymphoma trends. The high prevalence of HIV in certain lymphoma categories emphasizes the need for capacity to diagnose and manage dual conditions. This study highlights the need for strengthening of cancer registries within South Africa and the region. PMID- 20160653 TI - The activation of endothelin-1 pathway during methionine-induced homocysteinemia mediates endothelial dysfunction in hypertensive individuals. AB - OBJECTIVES: Endothelin-1 (ET-1) is a key regulator of arterial blood pressure in humans, and homocysteinemia is associated with increased oxidative stress. It is still unclear whether homocysteine-induced oxidative stress is implicated in the regulation of ET-1 expression. We examined the impact of acute homocysteinemia on endothelial function in hypertensive patients and healthy individuals, and the potential role of ET-1. METHODS: In this double-blind, placebo-controlled study, 39 hypertensive and 49 healthy individuals were randomized to receive high-dose vitamins (2 g vitamin C and 800IU vitamin E) or placebo followed by methionine loading 100 mg/kg body weight. Endothelium-dependent dilation (EDD) and endothelium-independent dilation (EID) of the brachial artery were evaluated by plethysmography, at baseline and 4 h postloading (4 h PML). ET-1 was measured by ELISA, whereas total lipid hydroperoxides (per-ox) levels were measured by a commercially available photometric technique. RESULTS: Acute, methionine-induced homocysteinemia decreased EDD in all study groups (P < 0.001 for all), whereas vitamins pretreatment failed to prevent this effect, despite the vitamins-induced reduction of peroxidation in the hypertensives group (P < 0.05). On the contrary, methionine loading significantly increased plasma ET-1 levels only in hypertensives (P < 0.05), an effect which was not prevented by antioxidant vitamins (P < 0.05). EID remained unchanged after methionine loading, in all study groups (P = NS for all groups). CONCLUSION: Experimental homocysteinemia rapidly blunts endothelial function in both hypertensive individuals and healthy individuals. The rapid elevation of ET-1 levels observed only in hypertensives, suggests that ET-1 may be the key mediator of homocysteine-induced endothelial dysfunction, independently of oxidative stress. PMID- 20160655 TI - Psychological predictors of the antihypertensive effects of music-guided slow breathing. AB - BACKGROUND: The possibility that daily sessions of music-guided slow breathing may reduce 24-h ambulatory blood pressure (ABP), and predictors of efficacy were explored in a randomized, placebo-controlled trial with parallel design. METHODS: Age-matched and sex-matched hypertensive patients were randomized to music-guided slow breathing exercises (4-6 breaths/min; 1: 2 ratio of inspiration: expiration duration) (Intervention; n = 29) or to control groups who were thought to relax while either listening to slow music (Control-M; n = 26) or reading a book (Control-R; n = 31). At baseline and at follow-up visits (1 week and 1, 3 and 6 months), ABP monitoring was performed. RESULTS: At mixed model analysis, intervention was associated with a significant reduction of 24-h (P = 0.001) and night-time (0100-0600 h) (P < 0.0001) systolic ABP. The average reduction of systolic 24-h ABP at 6 months was 4.6 mmHg [confidence limits at 95% 1.93-7.35] and 4.1 mmHg (95% confidence limits 1.59-6.67) vs. Control-M and Control-R groups, respectively, (P < 0.001 for both). Antihypertensive treatment was selected as negative predictor of BP reduction at multivariate stepwise analysis. When antihypertensive treatment was inserted as covariate in a generalized linear model, psychological subscales assessed at baseline by the Mental Health Inventory questionnaire were found to affect systolic blood pressure reduction at 6-month follow-up (general positive affect P < 0.001; emotional ties, P < 0.001; loss of behavioral control, P = 0.035). In particular, a level of general positive affect higher than the 75th percentiles was found to be significantly associated with low treatment efficacy (odds ratio 0.09; 95% confidence limits 0.01-0.93). CONCLUSION: Daily sessions of voluntary music-guided slow breathing significantly reduce 24-h systolic ABP, and psychological predictors of efficacy can be identified. PMID- 20160654 TI - Efficacy, safety and pharmacokinetics of candesartan cilexetil in hypertensive children from 1 to less than 6 years of age. AB - BACKGROUND: Few antihypertensive drugs are available in appropriate formulations for infants. METHOD: We investigated candesartan cilexetil liquid suspension in a 4-week, randomized double-blind dose-ranging study followed by a 1-year open label treatment phase (NCT00244621). The drug was administered at 0.05, 0.2 or 0.4 mg/kg per day in 93 hypertensive children aged 1-5 years, of whom 74 had underlying renal disorders. RESULTS: A single-dose pharmacokinetic profile was obtained in 10 patients. At 4 weeks, SBP declined dose dependently by 6, 9 and 12 mmHg in the three dose groups (P = 0.01), and DBP by 5, 8 and 11 mmHg (P = 0.03). During the 1-year follow-up, responder rates (both SBP and DBP < 95th percentile) ranged from 48.2 to 54.1%. Candesartan lowered the blood pressure regardless of age, sex, BMI or cause of hypertension. The pharmacokinetic profile was independent of age, sex and weight, and was similar to that in older children and adults. In participants with proteinuric renal disease (urinary albumin/creatinine ratio >30 mg/g), a 57% median decline in albumin/creatinine ratio was observed at 4 weeks, which was dose related (P = 0.007) and persisted with long-term administration. There were no notable electrocardiographic or laboratory abnormalities. A mild decline in estimated glomerular filtration rate observed at 4 weeks was not progressive with long-term dosing. Candesartan was generally well tolerated; two patients withdrew for adverse events (fatigue and worsening glomerulopathy). One patient died, probably from acute-on-chronic renal failure. CONCLUSION: Candesartan cilexetil dose-dependently decreases blood pressure and albuminuria in hypertensive infants and is generally well tolerated. PMID- 20160657 TI - Applications of adaptive optics scanning laser ophthalmoscopy. AB - Adaptive optics (AO) describes a set of tools to correct or control aberrations in any optical system. In the eye, AO allows for precise control of the ocular aberrations. If used to correct aberrations over a large pupil, for example, cellular level resolution in retinal images can be achieved. AO systems have been demonstrated for advanced ophthalmoscopy as well as for testing and/or improving vision. In fact, AO can be integrated to any ophthalmic instrument where the optics of the eye is involved, with a scope of applications ranging from phoropters to optical coherence tomography systems. In this article, I discuss the applications and advantages of using AO in a specific system, the AO scanning laser ophthalmoscope. Since the Borish award was, in part, awarded to me because of this effort, I felt it appropriate to select this as the topic for this article. Furthermore, users of AO scanning laser ophthalmoscope continue to appreciate the benefits of the technology, some of which were not anticipated at the time of development, and so it is time to revisit this topic and summarize them in a single article. PMID- 20160658 TI - Postvaccination thrombocytopenia in Canada. AB - Active surveillance data from 12 Canadian tertiary-care hospitals on children hospitalized with postvaccination thrombocytopenia were analyzed. Since 1992, there have been 107 cases reported; while 96% of the children were symptomatic, only 2 had severe bleeding. With treatment, 28 children (26%) had normal platelet counts on discharge from hospital and 93% had documented recovery within 3 months. PMID- 20160659 TI - Long-term efficacy and safety of fosamprenavir in human immunodeficiency virus infected pediatric patients. AB - Fosamprenavir (FPV) efficacy in human immunodeficiency virus (HIV)-infected pediatric patients is still being evaluated in ongoing clinical trials. The long term efficacy and safety of FPV boosted with ritonavir (FPV/r) was evaluated in 20 antiretroviral-naive and antiretroviral-experienced HIV-vertically infected pediatric patients. Analyses of CD4(+) T-cells, HIV-ribonucleic acid (RNA), and clinical status were performed during a median of 180 weeks. Initially, median HIV-RNA was 4.6 log(10) in naive and 4.4 log(10) in pretreated patients. Median CD4(+) T-cell was 17% and 31%, respectively. After FPV/r treatment, 18 of 20 patients achieved undetectable HIV-RNA and 4 of 20 experienced adverse events. To date, FPV/r treatment has shown sustained antiviral response and immunologic improvement in our 20 patients. PMID- 20160660 TI - Differential diagnosis of cervical mycobacterial lymphadenitis in children. AB - BACKGROUND AND AIMS: The differential diagnosis between tuberculosis (TB) and lymphadenitis caused by nontuberculous mycobacteria (NTM) in children is often based on epidemiologic and clinical data. The aim of this study was to identify epidemiologic and clinical variables associated with TB lymphadenitis in children attending 2 TB out-patient clinics in northern Italy during a 10-year period. PATIENTS AND METHODS: All children less than 16 years of age attending the study sites suspected of mycobacterial disease from 1999 through 2008 were included in the analysis. Logistic regression was used to evaluate the variables independently associated with TB lymphadenitis. RESULTS: From 299 children diagnosed with mycobacterial disease 121 children (40%) had a clinical diagnosis of cervical mycobacterial lymphadenitis: 38 TB (31%) and 83 NTM lymphadenitis (69%) cases. Increasing age (OR, 1.29; 95% CI, 1.02-1.69; P = 0.04), being foreign born (OR, 11.60; 95% CI, 1.37-114.20; P = 0.02), and having an abnormal chest radiograph (OR, 18.32; 95% CI, 2.37-201.68; P = 0.008) were independently associated with TB lymphadenitis. In the selected model, a 5-year-old foreign born child with cervical lymphadenitis and abnormal findings on chest radiograph has an estimated 0.90 probability of having TB disease. On the other hand, an Italy born child of the same age with cervical lymphadenitis and normal chest radiograph has a 0.04 probability of having TB. CONCLUSION: Epidemiologic and clinical data are useful tools in the differential diagnosis between TB and NTM lymphadenitis when etiologic diagnosis is not available. PMID- 20160661 TI - The proteasome regulates bacterial CpG DNA-induced signaling pathways in murine macrophages. AB - Our previous work has provided strong evidence that the proteasome is central to most of the genes induced in mouse macrophages in response to LPS stimulation. In the studies presented here, we evaluated the role of the macrophage proteasome in response to a second microbial product CpG DNA (unmethylated bacterial DNA). For these studies, we applied Affymetrix microarray analysis of RNA derived from murine macrophages stimulated with CpG DNA in the presence or absence of proteasome inhibitor, lactacystin. The results of these studies revealed that similar to LPS, most of those macrophage genes regulated by CpG DNA are also under the control of the proteasome at 4 h. In contrast to LPS stimulation, however, many of these genes were induced much later than 4 h, at 18 h, in response to CpG DNA. Lactacystin treatment of macrophages completely blocked the CpG DNA-induced gene expression of TNF-alpha and other genes involved in the production of inflammatory mediators. These data strongly support the conclusion that similar to LPS, the macrophage proteasome is a key regulator of CpG DNA induced signaling pathways. PMID- 20160662 TI - Enhanced albumin synthesis in severely burned adults. AB - Albumin plays an important role in maintaining physiological homeostasis. Although decreased albumin concentration has been well described as an acute phase response following injury, it is unclear whether the decrease is due to compromised synthesis of albumin, dilution, or imbalance between synthesis and breakdown rates, particularly after injury. We investigated changes in albumin synthesis in severely burned patients using stable isotope infusion techniques. Five patients (29 +/- 3 years; 80 +/- 7 kg) with burn of 48% +/- 4% total body surface area (TBSA) were enrolled and studied in the ICU at the Burn Unit of the US Army Institute of Surgical Research. Five age- and sex-matched healthy volunteers (33 +/- 5 years; 81 +/- 6 kg) were included as controls. On the study day (13 +/- 3 days after burn), a primed constant infusion (4 h) of stable isotope d5-phenlylalanine and d3-ketoisocaproic acid was given. Hourly arterial blood samples were drawn during the infusion to determine albumin synthesis rates, using gas chromatography-mass spectrometry analysis. Burned patients had higher heart and respiration rates. Plasma total protein in burn patients (4.5 +/ 0.3 g . dL-1) was lower compared with controls (6.8 +/- 0.2 g . dL-1). Plasma albumin concentration in burn patients (1.1 +/- 0.1 g . dL-1) was also lower compared with controls (3.8 +/- 0.1 g . dL-1; both P < 0.05). Albumin synthesis rate in burn patients (4.6 +/- 0.2 mg . kg-1 . h-1) was enhanced compared with controls (2.2 +/- 0.2 mg . kg-1 . h-1; P < 0.05). Despite the decrease in albumin concentration, albumin synthesis was enhanced in severely burned patients during the flow phase. PMID- 20160663 TI - 17beta-estradiol mediated protection against vascular leak after hemorrhagic shock: role of estrogen receptors and apoptotic signaling. AB - Vascular hyperpermeability is a clinical complication associated with hemorrhagic shock (HS) and occurs mainly because of the disruption of the adherens junctional complex. The objective of this study was to understand the role of 17beta estradiol in HS-induced hyperpermeability particularly focusing on estrogen receptors. In male Sprague-Dawley rats, HS was induced by withdrawing blood to reduce the mean arterial pressure to 40 mmHg for 1 hour followed by 1 hour of resuscitation to 90 mmHg. The study groups were 17beta-estradiol, tamoxifen, fulvestrant plus 17beta-estradiol, propyl pyrazole triol plus 17beta-estradiol, and diarylpropionitrile plus 17beta-estradiol. Intravital microscopy was used to study changes in mesenteric postcapillary venules. Mitochondrial reactive oxygen species formation was studied in vivo using dihydrorhodamine 123. The mitochondrial transmembrane potential was studied using the fluorescent cationic probe 5,5',6,6'tetrachloro-1,1',3,3'tetraethylbenzimidazolyl carbocyanine iodide (JC-1). The mesenteric microvasculature was analyzed for cytochrome c levels by enzyme-linked immunosorbent assay and caspase-3 activity by a fluorometric assay. Our results demonstrated that 17beta-estradiol attenuated HS-induced hyperpermeability. Fulvestrant reversed this protective effect (P < 0.05). Tamoxifen 5 mg/kg attenuated HS-induced hyperpermeability, whereas 10 mg/kg induced permeability (P < 0.05). Both alpha and beta estrogen receptor agonists inhibited HS-induced hyperpermeability (P < 0.05). 17beta-Estradiol decreased HS induced reactive oxygen species formation and restored mitochondrial transmembrane potential. 17beta-Estradiol decreased both cytosolic cytochrome c level and activation of caspase-3 (P < 0.05). These findings suggest that 17beta estradiol protects the microvasculature after HS, and that this protection may be mediated through the alpha and beta estrogen receptors. PMID- 20160664 TI - Ablation of TNF-alpha receptors influences mesenchymal stem cell-mediated cardiac protection against ischemia. AB - Mesenchymal stem cell (MSC) infusion may reduce myocardial ischemic injury. TNF alpha is a proinflammatory cytokine produced in large quantities during myocardial ischemia that can exert beneficial or detrimental effects on MSC function by binding to a 55-kd receptor (TNFR1) or a 75-kd receptor (TNFR2) on MSCs. We investigated whether genetic modification with ablation of TNFR1 and/or TNFR2 affects MSC-mediated protection against myocardial ischemic injury. The MSCs were harvested from wild-type mice (WT-MSCs) and knockout mice with ablation of TNFR1 and/or TNFR2 (TNFR1KO, TNFR2KO, and TNFR1/R2KO MSCs). After anesthesia was initiated via inhalation of isoflurane, myocardial ischemia was induced in rats via coronary artery ligation. Hearts were then injected with vehicle or MSCs (1 x 10 cells/mL). Myocardial function was assessed 28 days postsurgery with 2 dimensional echocardiograms and isolated heart perfusion. Myocardial tissue was collected for cytokine analysis and infarct measurements. We found that MSC treatment offered significant protection against myocardial ischemia, namely by decreasing infarct size, improving heart function, and decreasing ventricular remodeling compared with vehicle. Compared with WT-MSCs, TNFR1KO MSCs conferred increased cardiac protection, although TNFR2KO and TNFR1/R2KO MSCs conferred less cardiac protection. In addition, treatment with TNFR1KO MSCs was associated with decreased levels of proinflammatory cytokines and an increased level of vascular endothelial growth factor in the myocardium, whereas treatment with TNFR2KO or TNFR1/R2KO MSCs was associated with increased levels of proinflammatory cytokines and a decreased level of vascular endothelial growth factor compared with treatment with WT-MSCs. We conclude that MSC TNFR1 and TNFR2 play important roles in MSC-mediated cardiac protection after myocardial ischemia. PMID- 20160665 TI - p38 MAP kinase mediates burn serum-induced endothelial barrier dysfunction: involvement of F-actin rearrangement and L-caldesmon phosphorylation. AB - The aim of this study was to test the hypothesis that circulating factors released after a severe burn cause endothelial barrier dysfunction by triggering endothelial cell (EC) contraction through a p38 mitogen-activated protein (MAP) kinase-dependent mechanism. Human umbilical vein ECs (ECV304 cell line) were cultured to create a monolayer of cells that were then cultured with 20% human normal or burn serum. Monolayer permeability was measured by the influx of labeled albumin across the cells. Endothelial cells contraction was determined by alterations of cell surface area and formation of intracellular gaps. P38 MAP kinase activation, F-actin arrangement, and L-caldesmon phosphorylation were assessed by Western blots or immunofluorescence staining. These studies showed that exposure to burn serum resulted in a significant increase in endothelial permeability in a time-dependent manner, which was paralleled by a rapid and persistent activation of p38 MAP kinases. Morphologically, increased intercellular gaps, reduced cell surface area, and a unique rearrangement of F actin cytoskeleton were observed in burn serum-treated ECs. Inhibition of p38 MAP kinase suppressed the rearrangement of F-actin cytoskeleton, reduced the occurrence of burn serum-induced formation of intercellular gaps, and ameliorated endothelial hyperpermeability. Further study showed that phosphorylation of L caldesmon was enhanced in burn serum-treated cells via p38 MAP kinase; overexpression of L-caldesmon by adenovirus transfection, however, attenuated the increase in endothelial permeability by burn serum challenge. Collectively, these results have demonstrated for the first time that p38 MAP kinase is an important participant in mediating burn serum-induced endothelial barrier dysfunction through rearrangement of the F-actin cytoskeleton and phosphorylation of L caldesmon. Inhibition of p38 MAP kinase in vivo, thus, would be a promising therapeutic strategy in ameliorating burn shock development. PMID- 20160666 TI - Effects of a selective iNOS inhibitor versus norepinephrine in the treatment of septic shock. AB - Inhibition of NOS is not beneficial in septic shock; selective inhibition of the inducible form (iNOS) may represent a better option. We compared the effects of the selective iNOS inhibitor BYK191023 with those of norepinephrine (NE) in a sheep model of septic shock. Twenty-four anesthetized, mechanically ventilated ewes received 1.5 g/kg body weight of feces into the abdominal cavity to induce sepsis. Animals were randomized into three groups (each n = 8): NE-only, BYK only, and NE + BYK. The sublingual microcirculation was evaluated with sidestream dark-field videomicroscopy. MAP was higher in the NE + BYK group than in the other groups, but there were no significant differences in cardiac index or systemic vascular resistance. Mean pulmonary arterial pressure was lower in BYK treated animals than in the NE-only group. PaO2/FiO2 was higher and lactate concentration lower in the BYK groups than in the NE-only group. Mesenteric blood flow was higher in BYK groups than in the NE-only group. Renal blood flow was higher in the NE + BYK group than in the other groups. Functional capillary density and proportion of perfused vessels were higher in the BYK groups than in the NE-only group 18 h after induction of peritonitis. Survival times were similar in the three groups. In this model of peritonitis, selective iNOS inhibition had more beneficial effects than NE on pulmonary artery pressures, gas exchange, mesenteric blood flow, microcirculation, and lactate concentration. Combination of this selective iNOS inhibitor with NE allowed a higher arterial pressure and renal blood flow to be maintained. PMID- 20160667 TI - Prediction of nosocomial infection acquisition in ventilated patients by nasal nitric oxide: proof-of-concept study. AB - The development of biomarkers able to predict the occurrence of nosocomial infection could help manage preventive strategies, especially in medical patients whose degree of acquired immunosuppression may be variable. We hypothesized that the NO fraction present in the airways (upper and lower) of critically ill patients under mechanical ventilation could constitute such a biomarker. We conducted an observational proof-of-concept study in a medical intensive care unit of a teaching hospital. Forty-five patients (26 men; 72 [25th-75th percentiles] years [56-82]; Simplified Acute Physiology Score II, 63 [50-81], 14 infected) under mechanical ventilation (>3 days) underwent on day 1 and day 3 of their stay: nasal and exhaled (partitioned in bronchial and alveolar sources) bedside NO measurements, determination of urine NO end products and plasma cytokine (IL-6, IL-10) concentrations, and Sequential Organ Failure Assessment score calculation. Nosocomial infection incidence was recorded during the 15 subsequent days. Fifteen patients (33%) acquired a nosocomial infection (16 infections, 15 ventilator-associated pneumonia and 1 bacteremia). Nasal NO was the only marker significantly different between patients with and without subsequent infection (day 1, 52 ppb [20-142] vs. 134 [84-203], P = 0.038; day 3, 98 ppb [22-140] vs. 225 [89-288], P = 0.006, respectively). Nasal NO fraction 148 ppb or less at day 3 had an 80% sensitivity, a 70% specificity, and an odds ratio of 2.7 (95% confidence interval, 1.9-3.8) to predict acquisition of nosocomial infection. Nonsurvivors had a higher IL-6 concentration on day 3 (P = 0.014), whereas their nasal NO fractions were not significantly different. Nasal NO seems to be a relatively sensitive and specific biomarker of subsequent nosocomial infection acquisition (at least for ventilator-associated pneumonia), which warrants confirmation in a multicenter trial. PMID- 20160669 TI - Differential effects of IL-17 pathway in disseminated candidiasis and zymosan induced multiple organ failure. AB - The role of the IL-17 pathway in antifungal host defense is controversial. Several studies suggested that IL-17 is crucial for the protection against Candida infection, whereas other studies reported that IL-17 may contribute to inflammatory pathology and worsening of fungal disease. To address these discrepancies, we assessed the differential role of IL-17 pathway in two models of fungal sepsis: intravenous infection with live Candida albicans, in which fungal growth is the main cause of mortality, and zymosan-induced multiple organ failure, in which the inflammatory pathology drives the mortality. First, IL-17 receptor-deficient (IL-17RA) mice showed increased mortality and higher fungal loads in the kidneys in the model of disseminated candidiasis, partly caused by lower neutrophil recruitment in the IL-17RA mice. Second, IL-17RA mice were not protected against the multiorgan failure induced by zymosan. These data demonstrate that IL-17 does not have a major contribution to the inflammatory pathology leading to organ failure in fungal sepsis and support the concept that the IL-17 pathway is protective in antifungal host defense. PMID- 20160670 TI - Recombinant thrombomodulin prevents heatstroke by inhibition of high-mobility group box 1 protein in sera of rats. AB - Heatstroke, a severe inflammatory response disease, is a medical emergency characterized by high body temperature. The protein C anticoagulant system inhibits inflammation resulting from various causes. Thrombomodulin (TM), a widely expressed glycoprotein originally identified in vascular endothelium, is an important cofactor in the protein C anticoagulant system. We tested the hypothesis that TM could prevent acute inflammation induced by heat stress in a rodent model. Male Wistar rats received a bolus of 1 mg x kg of body weight of TM or saline injected into the tail vein, followed by heat-stress treatment (exposure to 42 degrees C for 30 min). Serum concentrations of cytokines (IL 1beta, IL-6, and TNF-alpha), NO, and high-mobility group box 1 (HMGB1) protein were measured at various time points after treatment. We observed a decrease in the levels of cytokines and HMGB1 protein in sera of TM-treated animals over time. Inhibition of NO overproduction by recombinant TM was observed during heat stress-induced inflammation. Because of the decline in inflammatory marker levels, TM ameliorated injury to various organs in the rat model of heat stress induced acute inflammation. As TM exhibited a strong anti-inflammatory effect in a rat model of acute inflammation induced by heat stress, TM represents a potential therapeutic for heatstroke prevention or management in patients. PMID- 20160671 TI - Hypoxia-induced alteration of mitochondrial genes in cardiomyocytes: role of Bnip3 and Pdk1. AB - The hypoxic conditions induced by reduced blood flow decreases oxygen availability in target tissues. Cellular hypoxia leads to mitochondrial dysfunction, decreased energy production, and increased production of reactive oxygen species. To determine the alteration in expression of mitochondrial genes after hypoxia in cardiomyocytes, we developed a rodent mitochondrial gene chip (RoMitoChip). The chip had 1088 probe sets including 46 probe sets representing 37 mouse mitochondrial DNA transcripts and the remaining probe sets representing mouse nuclear genes contributing to the mitochondrial structure and function. Mouse cardiomyocytes isolated from neonatal C57BL/6 mice that were subjected to hypoxia (1% oxygen) for different time intervals demonstrated a dichotomy in the expression profile of tRNA and mRNA transcripts. We report a total of 483 signature genes that were altered by hypoxia in the cardiac myocytes and related to mitochondrial structure and function. This includes 23 transcripts on mitochondrial DNA. Pathway analysis demonstrated predominant changes in the expression of genes involved in oxidative phosphorylation, glucose and fatty acid metabolism, and apoptosis. The most upregulated genes after 24 h of hypoxia included hypoxia-inducible factor 1, alpha subunit, inducible genes Bnip3, Pdk1, and Aldoc. Whereas Bnip3 is important in the cardiomyocyte death pathway, Pdk1 enzyme is critical in conserving mitochondrial function by diverting metabolic intermediates to glycolysis. This study identifies the participation of two important pathways, cell death and glycolytic, and two key proteins, Bnip3 and Pdk1, playing critical roles in these pathways in cardiomyocytes after severe hypoxia. PMID- 20160672 TI - Subanesthetic dose of isoflurane protects against zymosan-induced generalized inflammation and its associated acute lung injury in mice. AB - Multiple organ dysfunction syndrome (MODS) is one of the leading causes of death in the intensive care unit. Organ failure especially lung injury is highly associated with the mortality for MODS patients. Volatile anesthetic isoflurane (ISO) is one of the most widely used anesthetic agents, and ISO anesthesia has been reported to improve the survival rate and organ function in sepsis/MODS models. However, the application of anesthetic dose ISO in critically ill patients is limited. Compared with i.v. anesthetic pentobarbital treatment, we showed that twice inhalation of ISO at subanesthetic dose (0.7%, 0.5 minimum alveolar concentration) alleviated lung injury at 24 h after zymosan (ZY) injection and increased the 7-day survival rate from 10% to 45% in mice. We also showed that ISO exerted its protection by significantly improving the activities of superoxide dismutase and catalase in lung and serum when compared with those in pentobarbital-treated mice. The catalase inhibitor 3-amino-1, 2, 4-triazole partially abolished the protective effect of ISO in ZY-challenged mice. We conclude that subanesthetic dose ISO protects against ZY-induced generalized inflammation and its associated lung injury via enhancing the activities of antioxidant enzymes in mice, which may provide a new strategy for the treatment of critically ill patients. PMID- 20160673 TI - Tumor necrosis factor is not associated with intestinal ischemia/reperfusion induced lung inflammation. AB - Intestinal ischemia-reperfusion (I/R) injury may cause acute systemic and lung inflammation. Here, we revisited the role of TNF-alpha in an intestinal I/R model in mice, showing that this cytokine is not required for the local and remote inflammatory response upon intestinal I/R injury using neutralizing TNF-alpha antibodies and TNF ligand-deficient mice. We demonstrate increased neutrophil recruitment in the lung as assessed by myeloperoxidase activity and augmented IL 6, granulocyte colony-stimulating factor, and KC levels, whereas TNF-alpha levels in serum were not increased and only minimally elevated in intestine and lung upon intestinal I/R injury. Importantly, TNF-alpha antibody neutralization neither diminished neutrophil recruitment nor any of the cytokines and chemokines evaluated. In addition, the inflammatory response was not abrogated in TNF and TNF receptors 1 and 2-deficient mice. However, in view of the damage on the intestinal barrier upon intestinal I/R with systemic bacterial translocation, we asked whether Toll-like receptor (TLR) activation is driving the inflammatory response. In fact, the inflammatory lung response is dramatically reduced in TLR2/4-deficient mice, confirming an important role of TLR receptor signaling causing the inflammatory lung response. In conclusion, endogenous TNF-alpha is not or minimally elevated and plays no role as a mediator for the inflammatory response upon ischemic tissue injury. By contrast, TLR2/4 signaling induces an orchestrated cytokine/chemokine response leading to local and remote pulmonary inflammation, and therefore disruption of TLR signaling may represent an alternative therapeutic target. PMID- 20160674 TI - Changes in the mesenteric lymph proteome induced by hemorrhagic shock. AB - Biologically active factors produced by the intestine and transported by the aqueous and protein fraction of mesenteric lymph are now thought to contribute significantly to the development of distant organ failure in hemorrhagic shock. Despite the likely relevance of the protein composition of mesenteric lymph conditioned by hemorrhagic shock, there is no detailed description of its proteome. The aim of this study was to provide the first comprehensive description of the proteome of hemorrhagic shock-conditioned mesenteric lymph. Mesenteric lymph was collected from 16 male Wistar rats randomized to group 1 (n = 8) sham control and group 2 (n = 8) with hemorrhagic shock. The lymph was subjected to proteomic analysis using iTRAQ and liquid chromatography-tandem mass spectrometry. Sixty of the 245 proteins had a significant increase in their relative abundance in the hemorrhagic shock group. A bioinformatics approach highlighted the importance of the key gene ontology pathways relating to response to injury and metabolic responses as changing most significantly in shock. Using an interactome, we identified several highly connected proteins: 14-3-3 Zeta, 14 3-3 epsilon, actin, aldolase A, calmodulin, cofilin 1, cystatin C, fatty acid binding protein 4, profilin 1, prolyl 4-hydrolase, peptidylprolyl isomerase, and transgelin. This study provides the first detailed description of protein changes in hemorrhagic shock-conditioned mesenteric lymph, and using a bioinformatics approach, we identified several targets for possible further research. PMID- 20160676 TI - Toxin induction and protein extraction from Fusarium spp. cultures for proteomic studies. AB - Fusaria are filamentous fungi able to produce different toxins. Fusarium mycotoxins such as deoxynivalenol, nivalenol, T2, zearelenone, fusaric acid, moniliformin, etc... have adverse effects on both human and animal health and some are considered as pathogenicity factors. Proteomic studies showed to be effective for deciphering toxin production mechanisms (Taylor et al., 2008) as well as for identifying potential pathogenic factors (Paper et al., 2007, Houterman et al., 2007) in Fusaria. It becomes therefore fundamental to establish reliable methods for comparing between proteomic studies in order to rely on true differences found in protein expression among experiments, strains and laboratories. The procedure that will be described should contribute to an increased level of standardization of proteomic procedures by two ways. The filmed protocol is used to increase the level of details that can be described precisely. Moreover, the availability of standardized procedures to process biological replicates should guarantee a higher robustness of data, taking into account also the human factor within the technical reproducibility of the extraction procedure. The protocol described requires 16 days for its completion: fourteen days for cultures and two days for protein extraction (figure 1). Briefly, Fusarium strains are grown on solid media for 4 days; they are then manually fragmented and transferred into a modified toxin inducing media (Jiao et al., 2008) for 10 days. Mycelium is collected by filtration through a Miracloth layer. Grinding is performed in a cold chamber. Different operators performed extraction replicates (n=3) in order to take into account the bias due to technical variations (figure 2). Extraction was based on a SDS/DTT buffer as described in Taylor et al. (2008) with slight modifications. Total protein extraction required a precipitation process of the proteins using Aceton/TCA/DTT buffer overnight and Acetone /DTT washing (figure 3a,3b). Proteins were finally resolubilized in the protein-labelling buffer and quantified. Results of the extraction were visualized on a 1D gel (Figure 4, SDS-PAGE), before proceeding to 2D gels (IEF/SDS-PAGE). The same procedure can be applied for proteomic analyses on other growing media and other filamentous fungi (Miles et al., 2007). PMID- 20160675 TI - The protective function of neutrophil elastase inhibitor in liver ischemia/reperfusion injury. AB - BACKGROUND.: A neutrophil elastase (NE) inhibitor, Sivelestat, has been approved for the treatment of acute lung injury associated with systemic inflammation in humans. Some reports have also shown its protective effects in liver inflammatory states. We have recently documented the importance of NE in the pathophysiology of liver ischemia/reperfusion injury, a local Ag-independent inflammation response. This study was designed to explore putative cytoprotective functions of clinically available Sivelestat in liver ischemia/reperfusion injury. METHODS.: Partial warm ischemia was produced in the left and middle hepatic lobes of C57BL/6 mice for 90 min, followed by 6 or 24 hr of reperfusion. The mice were given Sivelestat (100 mg/kg, subcutaneous) at 10 min before ischemia, 10 min before reperfusion, and at 1 and 3 hr of reperfusion thereafter. RESULTS.: Sivelestat treatment significantly reduced serum alanine aminotransferase levels and NE activity, when compared with controls. Histological liver examination has revealed that unlike in controls, Sivelestat ameliorated the hepatocellular damage and decreased local neutrophil activity and infiltration. The expression of proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6), chemokines (CXCL-1, CXCL-2, and CXCL-10), and toll-like receptor 4 was significantly reduced in the treatment group, along with diminished apoptosis through caspase-3 pathway. Moreover, in vitro studies confirmed downregulation of proinflammatory cytokine and chemokine programs in mouse macrophage cell cultures, along with depression of innate toll-like receptor 4 signaling. CONCLUSION.: Sivelestat-mediated NE inhibition may represent an effective therapeutic option in liver transplantation and other inflammation disease states. PMID- 20160677 TI - Dependence of brain DTI maps of fractional anisotropy and mean diffusivity on the number of diffusion weighting directions. AB - The rotational variance dependence of diffusion tensor imaging (DTI) derived parameters on the number of diffusion weighting directions (N) has been investigated by several Monte Carlo simulation studies. However, the dependence of fractional anisotropy (FA) and mean diffusivity (MD) maps on N, in terms of accuracy and contrast between different anatomical structures, has not been assessed in detail. This experimental study further investigated in vivo the effect of the number of diffusion weighting directions on DTI maps of FA and MD. Human brain FA and MD maps of six healthy subjects were acquired at 1.5T with varying N (6, 11, 19, 27, 55). Then, FA and MD mean values in high (FAH, MDH) and low (FAL, MDL) anisotropy segmented brain regions were measured. Moreover, the contrast-to-signal variance ratio (CVRFA, CVRMD) between the main white matter and the surrounding regions was calculated. Analysis of variance showed that FAL, FAH and CVRFA significantly (p < 0.05) depend on N. In particular, FAL decreased (6%-11%) with N, whereas FAH (1.6%-2.5%) and CVRFA (4%-6.5%) increased with N. MDL, MDH and CVRMD did not significantly (p>0.05) depend on N. Unlike MD values, FA values significantly vary with N. It is noteworthy that the observed variation is opposite in low and high anisotropic regions. In clinical studies, the effect of N may represent a confounding variable for anisotropy measurements and the employment of DTI acquisition schemes with high N (> 20) allows an increased CVR and a better visualization of white matter structures in FA maps. PMID- 20160678 TI - Dosimetric effects of air pocket sizes in MammoSite treatment as accelerated partial breast irradiation for early breast cancer. AB - MammoSite Brachytherapy System had been used as one of the Accelerated Partial Breast Irradiation (APBI) techniques since 2002. The clinical results from several clinical institutions had shown comparable treatment efficacy, cosmesis, and toxicity, to other APBI techniques. During MammoSite treatment, air cavities had been one of the primary issues causing treatment cancellation or delay. With the tolerance of the air volume less than 10% of the total Planning Target Volume (PTV) been set, there is still no data available to show the actual dose delivered to the breast tissue with the existence of the air pocket. In this paper, Monte Carlo N-Particle version 5 (MCNP5) was used to model a hypothesis MammoSite phantom with different sizes of air pockets, and compared to the calculation results from the treatment planning system (TPS) without heterogeneous corrections. It was found that without heterogeneous corrections, the difference between the TPS and MCNP5 calculations in the air cavity surface doses and PTV point doses can be up to 2.02% and 3.61%, respectively, with the balloon and air pocket size combinations calculated in this paper. Based on the distance from the point of interest to the balloon surface, an approximate dose can be calculated using the linear relationship found in this study. These equations provide a quick and simple way to predict the actual dose delivered to the breast soft tissue located within the PTV. With the equation applied to the dose from the TPS, the dose error caused by the air pocket during MammoSite treatment can be reduced to the minimum. PMID- 20160679 TI - A grid to facilitate physics staffing justification. AB - Justification of clinical physics staffing levels is difficult due to the lack of direction as how to equate clinical needs with the staffing levels and competency required. When a physicist negotiates staffing requests to administration, she/he often refers to American College of Radiology staffing level suggestions, and resources such as the Abt studies. This approach is often met with questions as to how to fairly derive the time it takes to perform tasks. The result is often insufficient and/or inexperienced staff handling complex and cumbersome tasks. We undertook development of a staffing justification grid to equate the clinical needs to the quantity and quality of staffing required. The first step is using the Abt study, customized to the clinical setting, to derive time per task multiplied by the anticipated number of such tasks. Inclusion of vacation, meeting, and developmental time may be incorporated along with allocated time for education and administration. This is followed by mapping the tasks to the level of competency/experience needed. For example, in an academic setting the faculty appointment levels correlate with experience. Non-staff personnel, such as IMRT QA technicians or clerical staff, should also be part of the equation. By using the staffing justification grid, we derived strong documentation to justify a substantial budget increase. The grid also proved useful when our clinical demands changed. Justification for physics staffing can be significantly strengthened with a properly developed data-based time and work analysis. A staffing grid is presented, along with a development methodology that facilitated our justification. Though our grid is for a large academic facility, the methodology can be extended to a non-academic setting, and to a smaller scale. This grid method not only equates the clinical needs with the quantity of staffing, but can also help generate the personnel budget, based on the type of staff and personnel required. The grid is easily adaptable when changes to the clinical environment change, such as an increase in IMRT or IGRT applications. PMID- 20160680 TI - Evaluation of three APBI techniques under NSABP B-39 guidelines. AB - This work compares two accelerated partial breast irradiation modalities, MammoSite brachytherapy and three dimensional conformal radiotherapy (3D-CRT), to a new method, SAVI brachytherapy, following NSABP B-39 guidelines. A total of 21 patients treated at UC San Diego with the SAVI device were evaluated in this comparison. 9 of the 21 patients were eligible for all three modalities and were dosimetrically compared evaluating V90, V150, V200, total target volume, maximum skin, lung, and chestwall/rib dose. The target volumes (PTV_EVAL) differed with SAVI having the least total volume at 59.9 cc vs. 71.5 cc and 351.6 cc for MammoSite and 3D-CRT, respectively. The median V90, V150 and V200 for the three modalities were 97.7%, 25.0 cc, 10.4 cc (SAVI) vs. 97.6%, 23.9 cc, 5.0 cc (MammoSite) vs. 100% (V90 3D-CRT). The maximum dose for SAVI, MammoSite, and 3D CRT, respectively, relative to the prescribed dose, for the: lung was 80.0%, 150.0%, and 104.9%; for rib 108.8%, 225.0%, and 114.7%: for skin 75.0%, 135.0%, and 108.6%. Comparing modalities, PTV coverage varied between 97.6% - 100.0% with more breast tissue covered by 3D-CRT, as expected, given the differences between external beam and brachytherapy. The maximum lung, skin and rib doses were lowest for the SAVI, highlighting its ability to conform to exclude normal tissues. In offering partial breast radiation, the availability of a variety of techniques allows for maximal patient eligibility, and comparison of individual method pros and cons may guide the most appropriate choice for each patient. PMID- 20160681 TI - Acrylonitrile Butadiene Styrene (ABS) plastic based low cost tissue equivalent phantom for verification dosimetry in IMRT. AB - A novel IMRT phantom was designed and fabricated using Acrylonitrile Butadiene Styrene (ABS) plastic. Physical properties of ABS plastic related to radiation interaction and dosimetry were compared with commonly available phantom materials for dose measurements in radiotherapy. The ABS IMRT phantom has provisions to hold various types of detectors such as ion chambers, radiographic/radiochromic films, TLDs, MOSFETs, and gel dosimeters. The measurements related to pre treatment dose verification in IMRT of carcinoma prostate were carried out using ABS and Scanditronics-Wellhoffer RW3 IMRT phantoms for five different cases. Point dose data were acquired using ionization chamber and TLD discs while Gafchromic EBT and radiographic EDR2 films were used for generating 2-D dose distributions. Treatment planning system (TPS) calculated and measured doses in ABS plastic and RW3 IMRT phantom were in agreement within +/-2%. The dose values at a point in a given patient acquired using ABS and RW3 phantoms were found comparable within 1%. Fluence maps and dose distributions of these patients generated by TPS and measured in ABS IMRT phantom were also found comparable both numerically and spatially. This study indicates that ABS plastic IMRT phantom is a tissue equivalent phantom and dosimetrically it is similar to solid/plastic water IMRT phantoms. Though this material is demonstrated for IMRT dose verification but it can be used as a tissue equivalent phantom material for other dosimetry purposes in radiotherapy. PMID- 20160682 TI - Comparison of a 3-D multi-group SN particle transport code with Monte Carlo for intracavitary brachytherapy of the cervix uteri. AB - A patient dose distribution was calculated by a 3D multi-group S N particle transport code for intracavitary brachytherapy of the cervix uteri and compared to previously published Monte Carlo results. A Cs-137 LDR intracavitary brachytherapy CT data set was chosen from our clinical database. MCNPX version 2.5.c, was used to calculate the dose distribution. A 3D multi-group S N particle transport code, Attila version 6.1.1 was used to simulate the same patient. Each patient applicator was built in SolidWorks, a mechanical design package, and then assembled with a coordinate transformation and rotation for the patient. The SolidWorks exported applicator geometry was imported into Attila for calculation. Dose matrices were overlaid on the patient CT data set. Dose volume histograms and point doses were compared. The MCNPX calculation required 14.8 hours, whereas the Attila calculation required 22.2 minutes on a 1.8 GHz AMD Opteron CPU. Agreement between Attila and MCNPX dose calculations at the ICRU 38 points was within +/- 3%. Calculated doses to the 2 cc and 5 cc volumes of highest dose differed by not more than +/- 1.1% between the two codes. Dose and DVH overlays agreed well qualitatively. Attila can calculate dose accurately and efficiently for this Cs-137 CT-based patient geometry. Our data showed that a three-group cross-section set is adequate for Cs-137 computations. Future work is aimed at implementing an optimized version of Attila for radiotherapy calculations. PMID- 20160683 TI - A simple algorithm to assess patient suitability for Calypso-seed implantation for four-dimensional prostate localization. AB - To retrospectively determine the proportion of prostate cancer patients who are appropriate candidates for prostate localization with Calypso (Calypso Medical, Seattle, WA); to assess the accuracy of surface anatomy in predicting prostate depth; and to describe a simple clinical algorithm predicting patient's appropriateness for Calypso localization. Medical records and archived CT scans of all patients treated for localized prostate cancer at our institution between 2006 and 2007 were reviewed. Association between the feasibility of Calypso use, the depth of the prostate from the anterior torso, and a variety of anatomic factors were assessed (ANOVA, linear regression, and ROC). Patients were appropriate for the Calypso system in 91% of cases (localize and track, 52%; localize only, 39%). Strong correlation between greater trochanter location and the posterior prostate was seen (r 2 = 0.91, mean difference 0.6 cm). The negative predictive value of the greater trochanter measurements was 31%. Thirty one out of forty-five patients (69%) who were deemed inappropriate for Calypso based on greater trochanter to anterior torso measurements were eligible on the basis of CT-based measurements of prostate depth. Weight, BMI, waist circumference, and hip circumference correlated with distance from the prostate to the anterior torso and were predictive of Calypso appropriateness. All patients with weight 1 million deaths yearly. Current therapies prevent new viral genome formation, but do not target pre-existing viral genomic DNA, thus curing only approximately 1/2 of patients. We targeted HBV DNA for cleavage using zinc-finger nucleases (ZFNs), which cleave as dimers. Co-transfection of our ZFN pair with a target plasmid containing the HBV genome resulted in specific cleavage. After 3 days in culture, 26% of the target remained linear, whereas approximately10% was cleaved and misjoined tail-to-tail. Notably, ZFN treatment decreased levels of the hepatitis C virus pregenomic RNA by 29%. A portion of cleaved plasmids are repaired in cells, often with deletions and insertions. To track misrepair, we introduced an XbaI restriction site in the spacer between the ZFN sites. Targeted cleavage and misrepair destroys the XbaI site. After 3 days in culture, approximately 6% of plasmids were XbaI-resistant. Thirteen of 16 clones sequenced contained frameshift mutations that would lead to truncations of the viral core protein. These results demonstrate, for the first time, the possibility of targeting episomal viral DNA genomes using ZFNs. PMID- 20160706 TI - Potent oncolytic activity of raccoonpox virus in the absence of natural pathogenicity. AB - A number of oncolytic virus (OV) candidates currently in clinical trials are human viruses that have been engineered to be safer for patient administration by limiting normal cell targeting and replication. The newest OVs include viruses that cause no disease in humans, yet still have natural tumor tropism. Raccoonpox virus (RCNV) is a member of the Orthopoxvirus genus of Poxviridae and closely related to vaccinia virus, yet has no known pathogenicity in any mammalian species. A screen of cells from the NCI-60 cancer cell panel using growth curves demonstrated greater than a log increase in replication of RCNV in nearly 74% of the cell lines tested, similar to other tested OV poxviruses. In normal cell lines, pretreatment with interferon (IFN)-alpha/beta resulted in significant inhibition of RCNV replication. In both xenograft and syngeneic models of solid tumors, injection of RCNV resulted in significantly slower tumor progression and increased survival of mice. RCNV treatment also prolonged survival in treatment resistant models of brain tumors and decreased tumor burden by systemic administration in models of lung metastasis. PMID- 20160707 TI - Different sets of QTLs influence fitness variation in yeast. AB - Most of the phenotypes in nature are complex and are determined by many quantitative trait loci (QTLs). In this study we identify gene sets that contribute to one important complex trait: the ability of yeast cells to survive under alkali stress. We carried out an in-lab evolution (ILE) experiment, in which we grew yeast populations under increasing alkali stress to enrich for beneficial mutations. The populations acquired different sets of affecting alleles, showing that evolution can provide alternative solutions to the same challenge. We measured the contribution of each allele to the phenotype. The sum of the effects of the QTLs was larger than the difference between the ancestor phenotype and the evolved strains, suggesting epistatic interactions between the QTLs. In parallel, a clinical isolated strain was used to map natural QTLs affecting growth at high pH. In all, 17 candidate regions were found. Using a predictive algorithm based on the distances in protein-interaction networks, candidate genes were defined and validated by gene disruption. Many of the QTLs found by both methods are not directly implied in pH homeostasis but have more general, and often regulatory, roles. PMID- 20160708 TI - Feedback between p21 and reactive oxygen production is necessary for cell senescence. AB - Cellular senescence--the permanent arrest of cycling in normally proliferating cells such as fibroblasts--contributes both to age-related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in-silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of 'deep' cellular senescence. The essential feature of the loop is that long-term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFbeta. These ROS in turn replenish short-lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype. PMID- 20160709 TI - Intracellular transactivation of HIV can account for the decelerating decay of virus load during drug therapy. AB - Basic virus dynamics models have been essential in understanding quantitative issues of HIV replication. However, several parts of the viral life cycle remain elusive. One of the most critical steps is the start of viral transcription, which is governed by the regulatory protein trans-activator of transcription (Tat) that induces a positive feedback loop. It has been shown that this feedback loop can alternate between two states leading to a transient activation of viral transcription. Using Monte Carlo simulations, we integrate the transactivation circuit into a new virus dynamics model having an age-dependent transactivation rate and reversion into latency. The cycling of infected cells between an activated and latent state results in the typical decelerating decay of virus load following therapy. Further, we hypothesize that the activation of latently infected cells is governed by the basal transcription rate of the integrated provirus rather than the intra- or extracellular environment. Finally, our systems approach to modeling virus dynamics offers a promising framework to infer the extracellular dynamics of cell populations from their intracellular reaction networks. PMID- 20160710 TI - Revealing a signaling role of phytosphingosine-1-phosphate in yeast. AB - Sphingolipids including sphingosine-1-phosphate and ceramide participate in numerous cell programs through signaling mechanisms. This class of lipids has important functions in stress responses; however, determining which sphingolipid mediates specific events has remained encumbered by the numerous metabolic interconnections of sphingolipids, such that modulating a specific lipid of interest through manipulating metabolic enzymes causes 'ripple effects', which change levels of many other lipids. Here, we develop a method of integrative analysis for genomic, transcriptomic, and lipidomic data to address this previously intractable problem. This method revealed a specific signaling role for phytosphingosine-1-phosphate, a lipid with no previously defined specific function in yeast, in regulating genes required for mitochondrial respiration through the HAP complex transcription factor. This approach could be applied to extract meaningful biological information from a similar experimental design that produces multiple sets of high-throughput data. PMID- 20160711 TI - Abnormal regional brain activity during rest and (anticipated) gastric distension in functional dyspepsia and the role of anxiety: a H(2)(15)O-PET study. AB - OBJECTIVES: During gastric distension in hypersensitive functional dyspepsia (FD), activation was found in somatosensory cortex (SI/SII) and ventrolateral prefrontal cortex (vlPFC) but, contrary to controls, not in pregenual anterior cingulate (pACC). The aims of this article were to study (i) cortical activations and deactivations during distension and sham compared with baseline in FD, regardless of sensitivity status; (ii) differences in brain activity between health and FD during "no distension" conditions; and (iii) the relationship between anxiety and brain activity in FD. METHODS: Brain H(2)(15)O-PET was performed in 25 FD patients (13 hypersensitive) during three conditions: baseline, distension at discomfort threshold, and sham. Brain activity was compared against healthy controls using SPM2. RESULTS: Discomfort threshold was lower; sensation scores in all conditions were higher in patients than controls. (i) Activations were similar to controls, except for a lack of pACC activation during distension in FD. Patients showed no dorsal pons and amygdala deactivation during distension and sham, respectively. (ii) Comparing baseline or sham activity showed the following differences: higher activity in SII/SI, insula, midcingulate (MCC), dorsolateral and ventrolateral PFC in controls; and higher activity in occipital cortex in FD. Differences in left lateral PFC were specific to sham. (iii) Anxiety correlated negatively with pACC and MCC and positively with dorsal pons activity. CONCLUSIONS: FD patients failed to activate pACC, to deactivate dorsal pons during distension, and to deactivate amygdala during sham; this may represent arousal-anxiety-driven failure of pain modulation. During baseline and sham, differences between patients and controls were found in sensory as well as affective-cognitive areas. PMID- 20160712 TI - The impact of rotating shift work on the prevalence of irritable bowel syndrome in nurses. AB - OBJECTIVES: Shift work has been associated with gastrointestinal symptoms such as abdominal pain, constipation, and diarrhea. These symptoms overlap with those reported by patients with functional bowel disorders. Because shift work will lead to misalignment between the endogenous circadian timing system and the external 24 h environment, we hypothesized that nurses participating in shift work will have a higher prevalence of functional bowel disorders when compared with nurses participating in day shifts. METHODS: Nurses engaged in patient care were invited to complete Rome III, irritable bowel syndrome-quality of life measure (IBS-QOL) and modified Sleep-50 questionnaires. Respondents were classified as working day, night, or rotating shifts. The prevalence of IBS, functional constipation, functional diarrhea, and individual gastrointestinal symptoms was determined. RESULTS: Data were available for 399 nurses (214 day shift, 110 night shift, and 75 rotating shift workers). Rotating shift nurses had a significantly higher prevalence of IBS compared to day shift nurses (48% vs. 31%, P<0.01). Multivariable logistic regression correcting for age, gender, and sleep quality proved this association robust. IBS-QOL scores among groups were similar. Prevalence of functional constipation and functional diarrhea was similar between groups. Rotating shift nurses had a significantly higher prevalence of abdominal pain compared to day shift (81% vs. 54%, P<0.0001) and night shift workers (61%, P=0.003). CONCLUSIONS: Participation in shift work, especially rotating shift work, is associated with the development of IBS and abdominal pain that is independent of sleep quality. Circadian rhythm disturbances may have a function in the pathogenesis of IBS and abdominal pain. PMID- 20160714 TI - Methylation status of genes in non-neoplastic mucosa from patients with ulcerative colitis-associated colorectal cancer. AB - OBJECTIVES: Patients with ulcerative colitis (UC) are at increased risk for developing colorectal cancer (CRC). Surveillance in this at-risk population remains challenging. We assessed the methylation status of genes in the non neoplastic mucosa of UC-CRC patients and controls to identify potential biomarkers of CRC. METHODS: We evaluated the methylation status of 10 genes (p16, p14, runt-related transcript factor-3 (RUNX3), cyclooxygenase-2 (COX-2), E cadherin, methylated-in-tumor-1 (MINT1), MINT31, HPP1, estrogen receptor, SLC5A8) in UC-CRC tumors and non-neoplastic sections from both UC-CRC cases and UC controls (n=114 for each) using methylation-specific PCR. RESULTS: Amplification was successful for 96 UC controls, 83 tumors, and 66 non-adjacent, non-neoplastic samples. The prevalence of methylation was significantly greater in UC-CRC tumors for p16, RUNX3, MINT1, MINT31, and HPP1. Methylation of COX-2 and E-cadherin was greater in UC controls than in tumors. Univariate testing of these genes using non-adjacent, non-neoplastic sections from UC-CRC cases indicated that associations between p16, RUNX3, MINT1, MINT31, E-cadherin, and COX-2 and UC-CRC remained significant. In multivariable analysis of the six genes, only RUNX3, MINT1, and COX-2 remained significantly associated with the UC-CRC cases (odds ratio=12.6, 9.0, and 0.2, respectively). The results remained unaffected by the presence of PSC or severity of inflammation. Logistic regression modeling with the three genes showed interactions that increased the odds ratio for each gene. CONCLUSIONS: RUNX3, MINT1, and COX-2 are potential biomarkers for detecting the presence of CRC in patients with UC. These genes should be evaluated as biomarkers for colorectal dysplasia. PMID- 20160713 TI - Impact of functional gastrointestinal disorders on survival in the community. AB - OBJECTIVES: Functional gastrointestinal disorders (FGIDs) comprise a constellation of symptoms that have no identifiable structural or biochemical abnormality. In view of the lack of data from large-scale population-based studies evaluating the effects of these disorders on survival, we aimed to examine whether FGIDs are associated with impaired survival. METHODS: Between 1988 and 1993, valid self-report questionnaires that recorded gastrointestinal symptoms required for the diagnosis of irritable bowel syndrome (IBS), chronic constipation, chronic diarrhea, dyspepsia, and abdominal pain were mailed to randomly selected cohorts of Olmsted County, Minnesota residents. Minnesota administrative death records were used to identify which of the survey respondents had died over the follow-up period (through April 2008). The association between survival and each FGID was assessed using proportional hazards regression models with univariate and adjusted hazard ratios (HRs, 95% confidence intervals (CIs)), adjusting for age at time of survey, gender, smoking, alcohol, marital status, and Charlson Comorbidity Index (CCI). RESULTS: Of the 5,262 randomly selected eligible subjects who received a questionnaire, a total of 4,176 responded to the surveys (overall response rate 79%). From these respondents, 243 subjects were excluded because of lack of research authorization (or were registered solely at a different medical institution in Olmsted County, MN), resulting in 3,933 eligible subjects for analysis (eligible response rate 75%); 10% reported symptoms of IBS; 16% chronic constipation; 18% chronic diarrhea; 2% dyspepsia; and 15% abdominal pain. At baseline, the mean (s.d.) age was 54 (18) years, and 52% were female. No association with overall survival was detected for IBS (HR=1.06 (95% CI: 0.86-1.32)), chronic diarrhea (HR=1.03 (95% CI: 0.90-1.19)), abdominal pain (HR=1.09 (95% CI: 0.92-1.30)), or dyspepsia (HR=1.08 (95% CI: 0.58-2.02)). Reporting symptoms of chronic constipation was associated with poorer survival (HR=1.23 (95% CI: 1.07-1.42)). This association remained significant after adjusting for the CCI (HR=1.19 (95% CI: 1.03-1.37)). CONCLUSIONS: In this large population-based cohort study with over 30,000 person years of follow-up, no significant association was observed between survival and IBS, chronic diarrhea, dyspepsia, or abdominal pain. Furthermore, no association was found between increasing burden of FGIDs and survival. However, in contrast to these other FGIDs, subjects with symptoms of chronic constipation were found to be at increased risk of poorer survival. Further investigation is required to determine the cause of this observed association. PMID- 20160715 TI - Changes in liver biochemistry during methotrexate use for inflammatory bowel disease. AB - OBJECTIVES: We aimed to characterize the spectrum of liver enzyme test (LET) abnormalities that occur while using methotrexate for inflammatory bowel disease (IBD). METHODS: A retrospective review was undertaken of subjects using methotrexate for IBD at a single center. The clinical and epidemiological parameters, and hepatotoxicity risk factors, were recorded. Subjects were excluded if cumulative methotrexate doses could not be ascertained, if they had a diagnosis of rheumatoid arthritis or psoriasis, or if baseline and follow-up LETs were not available. Also noted were the cumulative methotrexate dose during the peak LET increase, severity of LET increase, and whether normalization occurred. RESULTS: Eighty-seven subjects were included (Crohn's disease, n=67; UC, n=17; indeterminate colitis n=3). The mean therapy duration was 81 weeks (3- to 364 week range), and the cumulative average dose was 1,813 mg (25-8,255-mg range). Thirty-seven (43%) subjects received a cumulative dose >1,500 mg. Sixty-seven (77%) had normal LETs, and in 51 (76%) LETs remained normal throughout methotrexate therapy. In the 16 (24%) who developed LET abnormalities, seven (44%) had underlying risk factor(s) for liver disease. Normalization (without dose reduction) occurred in 14 (88%) while continuing methotrexate. Of 20 subjects with abnormal LETs at baseline, nine (45%) subsequently normalized while continuing methotrexate, whereas nine (45%) worsened. Seventeen liver biopsies were performed in 11 and were classified as Roenigk's grade I in 15 (88%) subjects. Roenigk IIIb or IV was not seen. CONCLUSIONS: Methotrexate is commonly associated with LET abnormalities, but these frequently normalize while still on therapy, and in only 5% will drug discontinuation be necessary. Liver biopsies rarely have substantive abnormalities. PMID- 20160716 TI - Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis. AB - Most cells have the inherent capacity to shift their reliance on glycolysis relative to oxidative metabolism, and studies in model systems have shown that targeting such shifts may be useful in treating or preventing a variety of diseases ranging from cancer to ischemic injury. However, we currently have a limited number of mechanistically distinct classes of drugs that alter the relative activities of these two pathways. We screen for such compounds by scoring the ability of >3,500 small molecules to selectively impair growth and viability of human fibroblasts in media containing either galactose or glucose as the sole sugar source. We identify several clinically used drugs never linked to energy metabolism, including the antiemetic meclizine, which attenuates mitochondrial respiration through a mechanism distinct from that of canonical inhibitors. We further show that meclizine pretreatment confers cardioprotection and neuroprotection against ischemia-reperfusion injury in murine models. Nutrient-sensitized screening may provide a useful framework for understanding gene function and drug action within the context of energy metabolism. PMID- 20160717 TI - Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. AB - Cancer stem cells have been proposed to be important for initiation, maintenance and recurrence of various malignancies, including acute myeloid leukemia (AML). We have previously reported that CD34+CD38- human primary AML stem cells residing in the endosteal region of the bone marrow are relatively chemotherapy resistant. Using a NOD/SCID/IL2rgamma(null) mouse model of human AML, we now show that the AML stem cells in the endosteal region are cell cycle quiescent and that these stem cells can be induced to enter the cell cycle by treatment with granulocyte colony-stimulating factor (G-CSF). In combination with cell cycle-dependent chemotherapy, G-CSF treatment significantly enhances induction of apoptosis and elimination of human primary AML stem cells in vivo. The combination therapy leads to significantly increased survival of secondary recipients after transplantation of leukemia cells compared with chemotherapy alone. PMID- 20160718 TI - Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma. AB - BACKGROUND: Molecularly targeted agents with anti-angiogenic activity, including bevacizumab, have demonstrated clinical activity in patients with advanced/metastatic hepatocellular carcinoma (HCC). This multicentre phase II study involving patients from several Asian countries sought to evaluate the safety and efficacy of bevacizumab plus capecitabine in this population. METHODS: Histologically proven/clinically diagnosed advanced HCC patients received bevacizumab 7.5 mg kg(-1) on day 1 and capecitabine 800 mg m(-2) twice daily on days 1-14 every 3 weeks as first-line therapy. RESULTS: A total of 45 patients were enrolled; 44 (96%) had extrahepatic metastasis and/or major vessel invasion and 30 (67%) had hepatitis B. No grade 3/4 haematological toxicity occurred. Treatment-related grade 3/4 non-haematological toxicities included diarrhoea (n=2, 4%), nausea/vomiting (n=1, 2%), gastrointestinal bleeding (n=4, 9%) and hand-foot syndrome (n=4, 9%). The overall response rate (RECIST) was 9% and the disease control rate was 52%. Overall, median progression-free survival (PFS) and overall survival (OS) were 2.7 and 5.9 months, respectively. Median PFS and OS were 3.6 and 8.2 months, respectively, for Cancer of the Liver Italian Programme (CLIP) score < or =3 patients, and 1.4 and 3.3 months, respectively, for CLIP score 4 patients. CONCLUSION: The bevacizumab-capecitabine combination shows good tolerability and modest anti-tumour activity in patients with advanced HCC. PMID- 20160719 TI - Identification of DBC1 as a transcriptional repressor for BRCA1. AB - BACKGROUND: DBC1/KIAA1967 (deleted in breast cancer 1) is a putative tumour suppressor gene cloned from a heterozygously deleted region in breast cancer specimens. Caspase-dependent processing of DBC1 promotes apoptosis, and depletion of endogenous DBC1 negatively regulates p53-dependent apoptosis through its specific inhibition of SIRT1. Hereditary breast and ovarian cancer susceptibility gene product BRCA1, by binding to the promoter region of SIRT1, is a positive regulator of SIRT1 expression. METHODS: A physical interaction between DBC1 and BRCA1 was investigated both in vivo and in vitro. To determine the pathophysiological significance of DBC1, its role as a transcriptional factor was studied. RESULTS: We found a physical interaction between the amino terminus of DBC1 and the carboxyl terminus of BRCA1, also known as the BRCT domain. Endogenous DBC1 and BRCA1 form a complex in the nucleus of intact cells, which is exported to the cytoplasm during ultraviolet-induced apoptosis. We also showed that the expression of DBC1 represses the transcriptional activation function of BRCT by a transient expression assay. The expression of DBC1 also inhibits the transactivation of the SIRT1 promoter mediated by full-length BRCA1. CONCLUSION: These results revealed that DBC1 may modulate the cellular functions of BRCA1 and have important implications in the understanding of carcinogenesis in breast tissue. PMID- 20160721 TI - KRAS status analysis and anti-EGFR therapies: is comprehensiveness a biologist's fancy or a clinical necessity? PMID- 20160722 TI - Bisphosphonates for osteoporosis treatment are associated with reduced breast cancer risk. AB - BACKGROUND: Bisphosphanates are used primarily for the prevention and treatment of osteoporosis, and are also indicated for osseous complications of malignancy. In addition to their bone resorption properties, the most commonly used nitrogen containing bisphosphonate compounds also inhibit protein prenylation, and thus may exert anti-tumour properties. METHODS: To evaluate whether the use of these drugs may be associated with cancer, specifically breast cancer, we conducted a population-based case-control study in Wisconsin from 2003 to 2006. Participants included 2936 incident invasive breast cancer cases and 2975 population controls aged < 70 years. Bisphosphonate use and potential confounders were assessed by interview. RESULTS: Using multivariable logistic regression, the odds ratio for breast cancer in current bisphosphonate users compared with non-users was 0.67 (95% confidence interval 0.51-0.89). Increasing duration of use was associated with a greater reduction in risk (P-trend=0.01). Risk reduction was observed in women who were not obese (P-interaction=0.005). CONCLUSION: These results are suggestive of an additional benefit of the common use of bisphosphonates, in this instance, the reduction in breast cancer risk. PMID- 20160724 TI - The prognostic value of plasma fibrinogen levels in patients with endometrial cancer: a multi-centre trial. AB - BACKGROUND: To analyse the correlation between pre-treatment plasma fibrinogen levels and clinical-pathological parameters in patients with endometrial cancer and to assess the value of plasma fibrinogen as a prognostic parameter. METHODS: Within a retrospective multi-centre study, the records of 436 patients with endometrial cancer were reviewed and pre-treatment plasma fibrinogen levels were correlated with clinical-pathological parameters and patients' survival. RESULTS: The mean (s.d.) pre-treatment plasma fibrinogen level was 388.9 (102.4) mg per 100 ml. Higher plasma fibrinogen levels were associated with advanced tumour stage (FIGO I vs II vs III and IV, P=0.002), unfavourable histological subtype (endometrioid vs non-endometrioid histology, P=0.03), and higher patients' age (< or =67 years vs >67 years, P=0.04), but not with higher histological grade (G1 vs G2 vs G3, P=0.2). In a multivariate analysis, tumour stage (P<0.001 and P<0.001), histological grade (P=0.009 and P=0.002), patients' age (P=0.001 and P<0.001), and pre-treatment plasma fibrinogen levels (P=0.04 and P=0.02) were associated with disease-free and overall survival, respectively. CONCLUSION: Plasma fibrinogen levels can be used as an independent prognostic parameter for the disease-free and overall survival of patients with endometrial cancer. PMID- 20160723 TI - miR-145 and miR-133a function as tumour suppressors and directly regulate FSCN1 expression in bladder cancer. AB - BACKGROUND: We have recently identified down-regulated microRNAs including miR 145 and miR-133a in bladder cancer (BC). The aim of this study is to determine the genes targeted by miR-145, which is the most down-regulated microRNA in BC. METHODS: We focused on fascin homologue 1 (FSCN1) from the gene expression profile in miR-145 transfectant. The luciferase assay was used to confirm the actual binding sites of FSCN1 mRNA. Cell viability was evaluated by cell growth, wound-healing, and matrigel invasion assays. BC specimens were subjected to immunohistochemistry of FSCN1 and in situ hybridisation of miR-145. RESULTS: The miR-133a as well as miR-145 had the target sequence of FSCN1 mRNA by the database search, and both microRNAs repressed the mRNA and protein expression of FSCN1. The luciferase assay revealed that miR-145 and miR-133a were directly bound to FSCN1 mRNA. Cell viability was significantly inhibited in miR-145, miR-133a, and si-FSCN1 transfectants. In situ hybridisation revealed that miR-145 expression was markedly repressed in the tumour lesion in which FSCN1 was strongly stained. The immunohistochemical score of FSCN1 in invasive BC (n=46) was significantly higher than in non-invasive BC (n=20) (P=0.0055). CONCLUSION: Tumour suppressive miR-145 and miR-133a directly control oncogenic FSCN1 in BC. PMID- 20160725 TI - Prevalence, risk factors and clinical implications of malnutrition in French Comprehensive Cancer Centres. AB - BACKGROUND: This epidemiological observational study aimed at determining the prevalence of malnutrition in non-selected adults with cancer, to identify risk factors of malnutrition and correlate the results with length of stay and 2-month mortality. METHODS: This prospective multicentre 1-day study conducted in 17 French Comprehensive Cancer Centres included 1545 patients. Body mass index (BMI), weight loss (WL) in the past 6 months and age were routinely recorded according to the French national recommendations for hospitalised patients; malnutrition was rated as absent, moderate or severe according to the level of WL and BMI. Age, sex, tumour site, type of hospitalisation and treatment, disease stage, World Health Organisation performance status (PS) and antibiotic therapy were the potential malnutrition risk factors tested. Follow-up at 2 months allowed to determine the correlation with length of stay and mortality. RESULTS: Malnutrition was reported in 30.9% of patients, and was rated as severe in 12.2%. In multivariate analysis, only pre-existing obesity (BMI> or =30), PS > or =2 and head-and-neck or upper digestive cancers were associated with increased risk of malnutrition. Antibiotics use was significantly higher in malnourished patients (35.5 vs 22.8%; P<0.001). Severe malnutrition was independently associated with mortality. The median length of stay was 19.3+/-19.4 days for malnourished patients vs 13.3+/-19.4 days for others (P<0.0001). CONCLUSION: In French Comprehensive Cancer Centres, one out of three cancer patients are malnourished and this was associated with a longer length of stay. Pre-existing obesity could be identified as a new risk factor for malnutrition in our cancer patient population perhaps because of a misidentification or a delay in nutrition support in this category of patients. PMID- 20160726 TI - Combined effects of the bisphosphonate, zoledronic acid and the aromatase inhibitor letrozole on breast cancer cells in vitro: evidence of synergistic interaction. AB - BACKGROUND: Aromatase inhibitors are widely used in the treatment of oestrogen receptor-positive post-menopausal breast cancer. These patients may also be receiving the bisphosphonate, zoledronic acid (ZA) to prevent bone loss or reduce skeletal morbidity in the setting of advanced disease. The potential biological interaction of these two drugs in breast cancer has not been assessed. METHODS: Aromatase-expressing breast cancer cells were treated with letrozole and ZA either simultaneously or in sequence, and the resulting apoptosis was assessed by staining with Hoechst 33342 and propidium iodide and examined using a fluorescent inverted Leica DMIRB microscope and a UV filter. RESULTS: We found that letrozole and ZA induce levels of apoptosis in breast cancer cells in vitro that are significantly greater compared with treatment with each drug alone. However, this potentially, synergistic relationship is drug-sequence dependent, occurring only when cells are treated with letrozole, followed by ZA. The converse sequence, or administering drugs simultaneously, induces levels of apoptosis no greater than each drug alone. CONCLUSION: Owing to the enhanced anti-tumour efficacy of sequential drug administration, our findings may indicate that, for post menopausal women who require treatment with letrozole, ZA should also be considered. PMID- 20160727 TI - The management and outcome of women with post-hydatidiform mole 'low-risk' gestational trophoblastic neoplasia, but hCG levels in excess of 100 000 IU l( 1). AB - BACKGROUND: Gestational trophoblastic neoplasia (GTN) after a hydatidiform mole is either treated with single- or multi-agent chemotherapy determined by a multifactorial scoring system. Women with human chorionic gonadotrophin (hCG) levels >100 000 IU l(-1) can remain within the low-risk/single-agent category and usually choose one drug therapy. Here we compare the success and duration of single- vs multi-agent chemotherapy in this patient group. METHODS: Between 1980 and 2008, 65 women had a pre-treatment hCG >100 000 IU l(-1) and were low risk. The initial hCG level, treatment regimens, changes and duration and overall survival were recorded. RESULTS: Of 37 patients starting low-risk/single-agent treatment, 11 (29.7%) were treated successfully, whereas 26 (70.3%) required additional multi-agent chemotherapy to achieve complete remission (CR). Combination chemotherapy was initially commenced in 28 women, and 2 (7%) required additional drugs for CR. The overall duration of therapy for those commencing and completing single- or multi-agent chemotherapy was 130 and 123 days (P=0.78), respectively. The median-treatment duration for patients commencing single-agent but changing to multi-agent chemotherapy was 13 days more than those receiving high-risk treatment alone (136 vs 123 days; P=0.07). All 3 patients with an initial hCG >400 000 IU l(-1) and treated with single-agent therapy developed drug resistance. Overall survival for all patients was 100%. CONCLUSION: Low-risk post-molar GTN patients with a pre-treatment hCG >100 000 and <400 000 IU l(-1) can be offered low-risk single-agent therapy, as this will cure 30%, is relatively non-toxic and only prolongs treatment by 2 weeks if a change to combination agents is required. Patients whose hCG is >400 000 IU l(-1) should receive multi-agent chemotherapy from the outset. PMID- 20160728 TI - Loss of PTEN expression predicts resistance to EGFR-targeted monoclonal antibodies in patients with metastatic colorectal cancer. PMID- 20160729 TI - NUB1, an interferon-inducible protein, mediates anti-proliferative actions and apoptosis in renal cell carcinoma cells through cell-cycle regulation. AB - BACKGROUND: NEDD8 ultimate buster 1 (NUB1) is an interferon (IFN)-inducible protein that downregulates NEDD8 expression and its conjugation system. Although overexpression of NUB1 induces a growth-inhibitory effect in cells, the mechanisms underlying the anti-mitogenic actions of NUB1 in cancer cells remain uncertain. We investigated the anti-cancer effects of NUB1 in human renal cell carcinoma (RCC) cells. METHODS: Nine human RCC cells were used for this study. The proliferation of RCC cells exposed to IFN-alpha was measured by water-soluble tetrazolium salt assay. The expression level of NUB1 in cells was measured by quantitative reverse transcriptase PCR or western blot analysis. Apoptosis and cell-cycle analysis were performed by flow cytometry. Silencing of NUB1 was performed using a small interfering RNA. RESULTS: Both NUB1 messenger RNA and protein were significantly induced by IFN-alpha in seven out of nine selected RCC cell lines, and the NUB1 expressions induced by IFN-alpha correlated positively with cell growth inhibition. Overexpression of NUB1 remarkably induced S-phase transition during cell cycle and apoptosis in IFN-alpha-resistant A498 cells, in which NUB1 is not induced by IFN-alpha. The expression levels of two cell-cycle regulator proteins, cyclin E and p27, were increased under the aforementioned conditions. The knockdown of NUB1 enhanced cell proliferation of IFN-alpha resistant A498 cells and suppressed IFN-alpha-induced growth inhibition in IFN alpha-sensitive 4TUHR cells. CONCLUSION: NUB1 may be a key factor involved not only in cell growth inhibition by IFN-alpha in RCC cells but also in the anti cancer effect against IFN-alpha-resistant RCC cells. PMID- 20160730 TI - MutSbeta exceeds MutSalpha in dinucleotide loop repair. AB - BACKGROUND: The target substrates of DNA mismatch recognising factors MutSalpha (MSH2+MSH6) and MutSbeta (MSH2+MSH3) have already been widely researched. However, the extent of their functional redundancy and clinical substance remains unclear. Mismatch repair (MMR)-deficient tumours are strongly associated with microsatellite instability (MSI) and the degree and type of MSI seem to be dependent on the MMR gene affected, and is linked to its substrate specificities. Deficiency in MSH2 and MSH6 is associated with both mononucleotide and dinucleotide repeat instability. Although no pathogenic MSH3 mutations have been reported, its deficiency is also suggested to cause low dinucleotide repeat instability. METHODS: To assess the substrate specificities and functionality of MutSalpha and MutSbeta we performed an in vitro MMR assay using three substrate constructs, GT mismatch, 1 and 2 nucleotide insertion/deletion loops (IDLs) in three different cell lines. RESULTS: Our results show that though MutSalpha alone seems to be responsible for GT and IDL1 repair, MutSalpha and MutSbeta indeed have functional redundancy in IDL2 repair and in contrast with earlier studies, MutSbeta seems to exceed MutSalpha. CONCLUSION: The finding is clinically relevant because the strong role of MutSbeta in IDL2 repair indicates MSH3 deficiency in tumours with low dinucleotide and no mononucleotide repeat instability. PMID- 20160731 TI - Population pharmacokinetics of the humanised monoclonal antibody, HuHMFG1 (AS1402), derived from a phase I study on breast cancer. AB - BACKGROUND: HuHMFG1 (AS1402) is a humanised monoclonal antibody that has undergone a phase I trial in metastatic breast cancer. The aim of this study was to characterise the pharmacokinetics (PKs) of HuHMFG1 using a population PK model. METHOD: Data were derived from a phase I study of 26 patients receiving HuHMFG1 at doses ranging from 1 to 16 mg kg(-1). Data were analysed using NONMEM software and covariates were included. A limited sampling strategy (LSS) was developed using training and a validation data set. RESULTS: A linear two compartment model was shown to be adequate to describe data. Covariate analysis indicated that weight was not related to clearance. An LSS was successfully developed on the basis of the model, in which one sample is collected immediately before the start of an infusion and the second is taken at the end of infusion. CONCLUSION: A two-compartment population PK model successfully describes HuHMFG1 behaviour. The model suggests using a fixed dose of HuHMFG1, which would simplify dosing. The model could be used to optimise dose level and dosing schedule if more data on the correlation between exposure and efficacy become available from future studies. The derived LSS could optimise further PK assessment of this antibody. PMID- 20160735 TI - Superfund: is it safe to go home? AB - The Superfund law does not effectively address exposure of the residents surrounding a hazardous waste site before, during, and after cleanup. PMID- 20160732 TI - Study of matrix metalloproteinases and their inhibitors in prostate cancer. AB - BACKGROUND: Extracellular matrix metalloproteases (MMPs) have raised an extraordinary interest in cancer research because of their potential role in basal membrane and extracellular matrix degradation, consequently facilitating tumour invasion and metastases development. METHODS: An immunohistochemical study was performed using tissue arrays and specific antibodies against MMPs 1, 2, 7, 9, 11, 13, 14, and their tissue inhibitors, TIMPs 1, 2 and 3. More than 2600 determinations on cancer specimens from 133 patients with clinically localised prostate carcinoma, 20 patients with prostatic intraepithelial neoplasia and 50 patients with benign prostate hyperplasia and controls, were performed. RESULTS: When compared with benign pathologies, prostate carcinomas had higher expression of all MMPs and TIMPs. Dendogram shows a first-order division of tumours into two distinct MMPs/TIMPs molecular profiles, one of them with high MMPs/TIMs expression profile (n=70; 52.6%). Tumours with high expression of MMP-11 or -13, or cluster thereof, were significantly associated with higher probability of biochemical recurrence. CONCLUSION: The expression of MMPs and TIMPs seems to have an important role in the molecular biology of prostate carcinomas, and their expression by tumours may be of clinical interest to used as indicators of tumour aggressiveness. PMID- 20160736 TI - Out of the frying pan and out of the fire: the indispensable role of exposure science in avoiding risks from replacement chemicals. AB - Exposure science can move us toward a more protective chemicals management policy by preventing human and ecological risks that may occur when existing "bad actors" are replaced with alternative chemicals that may not be as well studied. PMID- 20160737 TI - Targeting the components most responsible for airborne particulate matter health risks. AB - Exposure to ambient air particulate matter (PM) causes more mortality and morbidity than any other regulated environmental pollutant, but PM is ill defined (US Environmental Protection Agency, 2004). Although regulations to protect people from PM have progressively improved, the ultimate goal is to identify the components most responsible for adverse effects so regulations can be more targeted. PMID- 20160738 TI - Interindividual variations of cerebral blood flow, oxygen delivery, and metabolism in relation to hemoglobin concentration measured by positron emission tomography in humans. AB - Regional cerebral blood flow (CBF) and oxygen metabolism can be measured by positron emission tomography (PET) with (15)O-labeled compounds. Hemoglobin (Hb) concentration of blood, a primary determinant of arterial oxygen content (C(a)O(2)), influences cerebral circulation. We investigated interindividual variations of CBF, cerebral blood volume (CBV), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO(2)) in relation to Hb concentration in healthy human volunteers (n=17) and in patients with unilateral steno occlusive disease (n=44). For the patients, data obtained only from the contralateral hemisphere (normal side) were analyzed. The CBF and OEF were inversely correlated with Hb concentration, but CMRO(2) was independent of Hb concentration. Oxygen delivery defined as a product of C(a)O(2) and CBF (C(a)O(2) CBF) increased with a rise of Hb concentration. The analysis with a simple oxygen model showed that oxygen diffusion parameter (L) was constant over the range of Hb concentration, indicating that a homeostatic mechanism controlling CBF is necessary to maintain CMRO(2). The current findings provide important knowledge to understand the control mechanism of cerebral circulation and to interpret the (15)O PET data in clinical practice. PMID- 20160740 TI - The economics of drug development: a grim reality and a role for clinical pharmacology. PMID- 20160743 TI - Biosimilars: evidential standards for health technology assessment. PMID- 20160744 TI - How innovative technology is moving biologics into the 21st century. PMID- 20160745 TI - The (possible) impact of comparative effectiveness research on pharmaceutical industry decision making. AB - Public and private payers in rich and emerging economies are becoming increasingly interested in using evidence to inform health-care resource allocation decisions. The National Institute for Health and Clinical Excellence (NICE) in the United Kingdom has been doing so on behalf of the National Health Service (NHS) for more than 10 years. To some, NICE-type entities are barriers to access and innovation. Increasingly, however, even NICE's critics appreciate that evidence-informed decision making, carried out in a fair, inclusive, and transparent way, is better than arbitrary government-imposed price cuts. For health-care systems in developed and developing countries around the world, faced with limited budgets, there may be no third option. PMID- 20160746 TI - Increasing access to nonprescription medicines: a global public health challenge and opportunity. AB - As escalating health-care costs continue to be a focus of public discourse, the populace has become increasingly attentive to its own health and lifestyle choices. Nonprescription (over-the-counter, OTC) medicines represent an important option in this evolving environment and, through novel "Rx-to-OTC" switch efforts, could expand beyond their traditional role in symptomatic relief of common conditions such as minor pain, coughs, colds, heartburn, and allergy. This is certainly not a new concept. In fact, the self-care movement has roots reaching into the past century. Pharmaceutical companies and their consumer product subsidiaries or partners have long considered and, when feasible, invested in difficult OTC switch development programs. PMID- 20160747 TI - Pediatric dose selection. AB - Selection of a drug dose in pediatrics is generally based on no or incomplete pharmacokinetic data. Traditionally, allometric, or scaling, techniques have been used; however, they have inherent limitations and may not make optimal use of the drug-specific clinical pharmacokinetic information that is available. Modeling is a tool that holds promise. The future challenge is to create a structured approach to determining pediatric doses for new therapeutic agents. PMID- 20160749 TI - Vitamin D replacement in pregnant women in rural north India: a pilot study. PMID- 20160750 TI - Change in the fatty acid pattern of erythrocyte membrane phospholipids after oral supplementation of specific fatty acids in patients with gastrointestinal diseases. AB - BACKGROUND/OBJECTIVES: The fatty acid pattern of membrane phospholipids is suggested to affect membrane fluidity and epithelial barrier function as a result of membrane fatty acid unsaturation. The incorporation of n-3 polyunsaturated fatty acids (PUFAs) into membrane phospholipids may diminish inflammatory potential in patients with gastrointestinal diseases. The aim of this study was to improve the fatty acid profile of erythrocyte membrane phospholipids after oral supplementation of specific fatty acids in patients with maldigestion and/or malabsorption. SUBJECTS/METHODS: We conducted a randomized, double-blind, controlled trial. A total of 48 patients with gastrointestinal diseases received either fat-soluble vitamins A,D,E,K (ADEK) or ADEK plus fatty acids alpha linolenic acid (ALA), docosahexaenoic acid (DHA) and medium-chain triglycerides (FA-ADEK) for 12 weeks. The fatty acid profile of erythrocyte membrane phospholipids, dietary intake, plasma antioxidant vitamins and serum gamma glutamyl transferase (GGT) were evaluated at baseline, 8 and 12 weeks after supplementation. RESULTS: Supplementation with FA-ADEK increased ALA, DHA and eicosapentaenoic acid (EPA) concentrations of erythrocyte membrane phospholipids by 0.040, 1.419 and 0.159%, respectively, compared with ADEK supplementation ( 0.007, 0.151 and 0.002%, respectively) after 12 weeks (all Por=55 years) were included in this study. RESULTS: The average total intake of fluid was 1-1.3 l per day depending on age groups. Water accounted for about one-half of daily fluid intake. The contribution of other types of beverages varied with age (for example, dairy drinks in children and adolescents; alcoholic drinks in adults and seniors). Intake of sodas (including regular and light) was highest in adolescents (169 ml a day). Beverages were mainly consumed at home during meals. CONCLUSIONS: This is the first description of fluid intake in French children, adolescents, adults and seniors, considering amounts, types of beverages, time and place of intake. It shows that water is the main source of fluid in all age groups. Selection of various types of beverages is different according to age. PMID- 20160753 TI - BMI distribution/social stratification in Swiss conscripts from 1875 to present. AB - BACKGROUND/OBJECTIVES: We aimed to extend the actual overweight discussion with new unbiased Swiss conscript data from 2005 to 2006, and to present for the first time Swiss data on body mass index (BMI) before 1950 and for the late-nineteenth century. SUBJECTS/METHODS: For this study, 19-year-old Swiss male conscripts (draft army; Cantons Bern, Zurich, Basel-Stadt and Basel-Land) from the census of 1875-1879, 1933-1939 and 2005-2006 (N=28 033; 2005-2006 census) were included. BMI distribution (World Health Organization (WHO) classification) and social stratification (International Labour Organization classification) were main outcome measures. RESULTS: Mean BMI of 19-year-old men in Switzerland increased in the 50 years between the 1870s and the 1930s by 0.80 kg/m(2) and between the 1930s and 2005 by 1.45 kg/m(2). The modern BMI sample is much more right skewed and s.d. is higher. Obesity prevalence (according to modern WHO classification) has increased by a factor of 105 from 1870s until present. Over 23% of our representative sample of Swiss men in 2005-2006 had a BMI of over 25 kg/m(2). In 2005-2006, contrary to the nineteenth century, unskilled workers had articulately higher BMI values at the 75th, 90th and 95th percentile than students; 12% of unskilled workers were obese against 2% of students. CONCLUSIONS: It thus seems that BMI relations between the upper and the lower end of the socio-economic strata changed inversely from the late-nineteenth century to 2005-2006. We further propose that the phenomenon of massive right-skewing BMI distribution between the 1930s and 2005-2006 affected the lower socio-economic strata to a far greater extent than the higher socio-economic group. PMID- 20160754 TI - FANCM: fork pause, rewind and play. AB - DNA lesions or genomic regions that are difficult to traverse frequently hinder or block DNA replication. In response to replication fork stalling, the cell activates the replication stress response pathway, which acts to protect the fork from collapse, promotes the repair or bypass of the blockage and facilitates the resumption of DNA synthesis. In this issue of the EMBO Journal, two studies conducted by the Constantinou and Niedzwiedz laboratories shed light on how the DNA translocase FANCM acts to regulate the replication stress response (Luke Glaser et al, 2009; Schwab et al, 2009). These studies help to explain how FANCM (mutated in the human cancer predisposition syndrome, Fanconi's anaemia (FA)) co ordinately regulates checkpoint signalling and replication fork progression. PMID- 20160755 TI - Nasonia: a jewel among wasps. PMID- 20160756 TI - Don't forget the ancestral polymorphisms. PMID- 20160757 TI - Gene copy number evolution during tetraploid cotton radiation. AB - After polyploid formation, retention or loss of duplicated genes is not random. Genes with some functional domains are convergently restored to 'singleton' state after many independent genome duplications, and have been referred to as 'duplication-resistant' (DR) genes. To further explore the timeframe for their restoration to the singleton state, 27 cotton homologs of genes found to be 'DR' in Arabidopsis were selected based on diagnostic Pfam domains. Their copy numbers were studied using southern hybridization and sequence analysis in five tetraploid species and their ancestral A and D genome diploids. DR genes had significantly lower copy number than gene families hybridizing to randomly selected cotton ESTs. Three DR genes showed complete loss of D genome-derived homoeologs in some or all tetraploid species. Prior analysis has shown gene loss in polyploid cotton to be rare, and herein only one randomly selected gene showed loss of a homoeolog in only one of the five tetraploid species (Gossypium mustelinum). BAC sequencing confirmed two cases of gene loss in tetraploid cotton. Divergence among 5' sequences of DR genes amplified from G. arboreum, G. raimondii, and Gossypioides kirkii was correlated with gene copy number. These results show that genes containing Pfam domains associated with duplication resistance in Arabidopsis have also been preferentially restored to low copy number after a more recent polyploidization event in cotton. In tetraploid cotton, genes from the progenitor D genome seem to experience more gene copy number divergence than genes from the A genome. Together with D subgenome-biased alterations in gene expression, perhaps gene loss may contribute to the relatively larger portion of quantitative trait variation attributable to D than A subgenome chromosomes of tetraploid cotton. PMID- 20160758 TI - Population structure and historical biogeography of European Arabidopsis lyrata. AB - Understanding the natural history of model organisms is important for the effective use of their genomic resources. Arabidopsis lyrata has emerged as a useful plant for studying ecological and evolutionary genetics, based on its extensive natural variation, sequenced genome and close relationship to A. thaliana. We studied genetic diversity across the entire range of European Arabidopsis lyrata ssp. petraea, in order to explore how population history has influenced population structure. We sampled multiple populations from each region, using nuclear and chloroplast genome markers, and combined population genetic and phylogeographic approaches. Within-population diversity is substantial for nuclear allozyme markers (mean P=0.610, A(e)=1.580, H(e)=0.277) and significantly partitioned among populations (F(ST)=0.271). The Northern populations have modestly increased inbreeding (F(IS)=0.163 verses F(IS)=0.093), but retain comparable diversity to central European populations. Bottlenecks are common among central and northern Europe populations, indicating recent demographic history as a dominant factor in structuring the European diversity. Although the genetic structure was detected at all geographic scales, two clear differentiated units covering northern and central European areas (F(CT) =0.155) were identified by Bayesian analysis and supported by regional pairwise F(CT) calculations. A highly similar geographic pattern was observed from the distribution of chloroplast haplotypes, with the dominant northern haplotypes absent from central Europe. We conclude A. l. petraea's cold-tolerance and preference for disturbed habitats enabled glacial survival between the alpine and Nordic glaciers in central Europe and an additional cryptic refugium. While German populations are probable peri-glacial leftovers, Eastern Austrian populations have diversity patterns possibly compatible with longer-term survival. PMID- 20160759 TI - The B in 'BDM.' William Bateson did not advocate a genic speciation theory. PMID- 20160760 TI - Genetic differentiation of eastern wolves in Algonquin Park despite bridging gene flow between coyotes and grey wolves. AB - Distinguishing genetically differentiated populations within hybrid zones and determining the mechanisms by which introgression occurs are crucial for setting effective conservation policy. Extensive hybridization among grey wolves (Canis lupus), eastern wolves (C. lycaon) and coyotes (C. latrans) in eastern North America has blurred species distinctions, creating a Canis hybrid swarm. Using complementary genetic markers, we tested the hypotheses that eastern wolves have acted as a conduit of sex-biased gene flow between grey wolves and coyotes, and that eastern wolves in Algonquin Provincial Park (APP) have differentiated following a history of introgression. Mitochondrial, Y chromosome and autosomal microsatellite genetic data provided genotypes for 217 canids from three geographic regions in Ontario, Canada: northeastern Ontario, APP and southern Ontario. Coyote mitochondrial DNA (mtDNA) haplotypes were common across regions but coyote-specific Y chromosome haplotypes were absent; grey wolf mtDNA was absent from southern regions, whereas grey wolf Y chromosome haplotypes were present in all three regions. Genetic structuring analyses revealed three distinct clusters within a genetic cline, suggesting some gene flow among species. In APP, however, 78.4% of all breeders and 11 of 15 known breeding pairs had assignment probability of Q?0.8 to the Algonquin cluster, and the proportion of eastern wolf Y chromosome haplotypes in APP breeding males was higher than expected from random mating within the park (P<0.02). The data indicate that Algonquin wolves remain genetically distinct despite providing a sex-biased genetic bridge between coyotes and grey wolves. We speculate that ongoing hybridization within the park is limited by pre-mating reproductive barriers. PMID- 20160762 TI - [Publication ethics--responsibility of all]. PMID- 20160761 TI - Measurement of fine particles and smoking activity in a statewide survey of 36 California Indian casinos. AB - Despite California's 1994 statewide smoking ban, exposure to secondhand smoke (SHS) continues in California's Indian casinos. Few data are available on exposure to airborne fine particles (PM2.5) in casinos, especially on a statewide basis. We sought to measure PM2.5 concentrations in Indian casinos widely distributed across California, exploring differences due to casino size, separation of smoking and non-smoking areas, and area smoker density. A selection of 36 out of the 58 Indian casinos throughout California were each visited for 1 3 h on weekend or holiday evenings, using two or more concealed monitors to measure PM2.5 concentrations every 10 s. For each casino, the physical dimensions and the number of patrons and smokers were estimated. As a preliminary assessment of representativeness, we also measured eight casinos in Reno, NV. The average PM2.5 concentration for the smoking slot machine areas (63 MUg/m3) was nine times as high as outdoors (7 MUg/m3), whereas casino non-smoking restaurants (29 MUg/m3) were four times as high. Levels in non-smoking slot machine areas varied: complete physical separation reduced concentrations almost to outdoor levels, but two other separation types had mean levels that were 13 and 29 MUg/m3, respectively, higher than outdoors. Elevated PM2.5 concentrations in casinos can be attributed primarily to SHS. Average PM2.5 concentrations during 0.5-1 h visits to smoking areas exceeded 35 MUg/m3 for 90% of the casino visits. PMID- 20160763 TI - [Troponin analyses require increased clinical knowledge]. PMID- 20160764 TI - [Vaccine against dengue fever under development]. PMID- 20160765 TI - [Breast cancer mortality versus breast cancer survival]. PMID- 20160767 TI - [Not updated knowledge about hazardous substances]. PMID- 20160768 TI - [The CONOR database--a little piece of Norway]. PMID- 20160769 TI - [Reporting of patient injuries--the supervisory authority's use of sanctions]. AB - BACKGROUND: When health care leads to serious adverse events that result in (or could have resulted in) injuries to patients, hospitals are obliged to report this to The Norwegian Board of Health Supervision in the Counties. The purpose of this study was to quantify how many cases were instigated on the basis of reports sent to the supervisory authority and to what extent health personnel were sanctioned because of them. MATERIAL AND METHODS: Reports received by The Norwegian Board of Health Supervision in the Counties (in the period 1.07.2002- 30.06.2007) and cases instigated by the National Board of Health (on basis of the reports) in the period 1.01.2003-31.12.2007. RESULTS: The supervisory authority received 9268 reports in the period. 443 (4.7 %) of them led to instigation of cases and 19 of these (2 of the reports) resulted in formal sanctioning of health personnel (13 of the sanctions were to physicians; 12 received a warning and one lost her specialist license). The Board of Health Supervision seems to have quite different thresholds for instigating report-based cases in the various counties. INTERPRETATION: Health personnel seem to have little reason to fear that reports on (potential) adverse events will lead to sanctions from the supervisory authority. However, the Board of Health Supervision in the Counties should have a more predictable practice concerning instigation of report-based cases. PMID- 20160770 TI - [Do obstetric complications increase the risk of schizophrenia?]. AB - BACKGROUND: Schizophrenia is a serious mental disease of unknown aetiology. Genetic liability is the most important risk factor. Several studies have demonstrated that pre and perinatal complications/traumas are associated with an increased risk of developing schizophrenia in adult age. The purpose of this article is to provide an overview of research on obstetric complications as risk factors for schizophrenia. MATERIAL AND METHODS: The article is based on literature identified through non-systematic searches in the databases PubMed and Embase. RESULTS: The putative association between obstetric complications and schizophrenia has been investigated for almost 80 years. Numerous controlled studies have found that maternal infection (influenza, rubella, toxoplasmosis), prenatal malnutrition and birth-associated complications (such as low birth weight and asphyxia) are associated with an increased risk of developing schizophrenia. Experiments in animal models suggest that foetal hypoxia and maternal inflammatory responses may affect neuronal development. However, underlying pathophysiological mechanisms and modes of interaction with schizophrenia susceptibility genes are unknown. INTERPRETATION: An association between obstetric complications and an increased risk of schizophrenia is strongly supported by scientific evidence. PMID- 20160771 TI - [Use of TNFalpha antibodies in treatment of inflammatory bowel disease]. AB - BACKGROUND: TNFalpha-antibodies have been used increasingly in treatment of inflammatory bowel disease (IBD) during the last years. This article provides an overview of indications, contraindications, efficacy, and side effects of this so called biological treatment of IBD. MATERIAL AND METHODS: Based on the clinical experience of the authors, literature was selected through a non-systematic search in PubMed. RESULTS: TNFalpha-antibodies have a documented initial effect in 60-70 % of patients with moderate to severe luminal and/or fistulising IBD. Approximately 30 % of patients achieve remission after a relatively short treatment period. However, the effect seems to decrease during long-term treatment. It is still unsettled whether these drugs prevent colectomy in ulcerative colitis. The treatment seems to increase the risk of serious infections and there are also some indications of an increased risk of malignancy. Combination therapy with azathioprin is common and probably increases both the effect and the risk of side effects. INTERPRETATION: TNFalpha-antibodies have become an important part of the treatment for moderate to severe IBD, but the effect decreases during long-term treatment and has to be evaluated in light of potential side effects. Further long-term studies are necessary. PMID- 20160772 TI - [Use of troponin analysis in Norwegian hospitals]. AB - BACKGROUND: A highly sensitive troponin T analysis became available in Norway in 2009. The Norwegian Society of Medical Biochemistry believed that a national strategy for implementation of the analysis would ensure a more coherent practice for diagnosing acute myocardial infarction (AMI). MATERIAL AND METHODS: 70 laboratories were requested to identify (in a questionnaire) the type of assay used, routines for reporting results of analyses, internal quality control programmes (IQA) and local cut-off values for making the diagnosis AMI. RESULTS: 62 laboratories responded and 57 of these analyzed troponins; 60 % used troponin T and 40 % troponin I. 82 % of laboratories were familiar with the decision limit used for diagnosing AMI at their hospital; 43 % of troponin T laboratories used the cut-off recommended by the Norwegian Society of Cardiology (0.03 microg/l) to diagnose AMI. For the two most used troponin I methods (16 laboratories) eight different cut-off values were reported. 24 % (troponin T) and 35 % (troponin I) of laboratories performed IQA at a concentration similar or lower than the local decision limit used when diagnosing AMI. 73 % (troponin T) and 54 % (troponin I) of laboratories used the lower limit of quantification as the lower cut-off value for reportable results. INTERPRETATION: In Norwegian hospitals, users of the same methods for analysis of troponin have different routines for interpreting, IQA and reporting of results. Patient diagnoses may therefore vary according to the hospital used. The Norwegian Society of Medical Biochemistry has developed recommendations for implementation of troponin analyses in Norwegian laboratories. PMID- 20160773 TI - [A fifth plasmodium that can cause malaria]. AB - BACKGROUND: Since 2004, malaria with a "fifth" plasmodium, Plasmodium knowlesi (common in macaque monkeys), has been diagnosed in a number of people in Southeast Asia. This article gives a short overview of the epidemiology, clinical picture, diagnostics and treatment of P. knowlesi infection. MATERIAL AND METHODS: The article is mainly based on articles published in international journals during the last five years. RESULTS: Most cases have been diagnosed in the Malaysian state Sarawak on the island of Borneo. The disease usually presents in the same way as other types of malaria, with the exception that fever spikes comes at 24-hour intervals. Microscopy findings resemble those for P. malariae in the early phase of the disease and many patients have been diagnosed wrongly. Without treatment a serious clinical picture may develop, blood findings may be as serious as for P. falciparum infection and death may occur. Chloroquine tablets are indicated in light infections, while parenteral therapy with artesunate or quinine is necessary in seriously affected patients. P. knowlesi infection has been reported among tourists in Malaysia. INTERPRETATION: The risk of contracting P. knowlesi infection as well as other types of malaria is low in Malaysia and other regions where P knowlesi occurs. PMID- 20160774 TI - [From prison with coma]. AB - A 42-year-old man was found unconscious in his prison cell. Investigations revealed non-recognized diabetes mellitus, possibly secondary to use of prescribed antipsychotic drugs. Second generation antipsychotics are associated with metabolic changes such as weight gain, hyperglycaemia and dyslipidaemia. Severe side effects may also occur; e.g. diabetic ketoacidosis in people without acknowledged diabetes (as presented in this case report). Providing adequate healthcare to people with psychotic disorders may be a demanding task. When these patients develop somatic conditions, a multidisciplinary approach is required. Personnel from many specialities may become involved, and they are not all familiar with drugs commonly used to treat psychiatric disorders or how to deal with their side effects. Several guidelines addressing these problems have been issued during the last years. Norwegian guidelines should aid clinicians in decision-making when confronted with these dilemmas. PMID- 20160775 TI - [Metabolic and cardiovascular health in mental disorders]. PMID- 20160776 TI - [Is social anxiety something to pay attention to?]. PMID- 20160777 TI - [Neonatal screening--more hidden compulsion?]. PMID- 20160778 TI - [Blood group 0--with O as in Ola?]. PMID- 20160780 TI - Optimization of a tabletop high-repetition-rate soft x-ray laser pumped in double pulse single-beam grazing incidence. AB - This Letter reports on the optimization of a tabletop nickel-like molybdenum transient collisionally excited soft x-ray laser (SXRL) at 18.9 nm performed by a double-pulse single-beam grazing incidence pumping (DGRIP). This scheme allows for the first time, to our knowledge, the full control of the pump laser parameters including the pre-pulse duration optimally generating the SXRL amplifier under a grazing incidence. The single-beam geometry of the collinear double-pulse propagation guarantees the ideal overlap of the pre-pulse and main pulse from shot to shot resulting in a more efficient and highly stable SXRL output. SXRL energies up to 2.2 microJ are obtained with a total pump energy less than 1 J for several hours at a 10 Hz repetition rate without realignment under once optimized double pumping pulse parameters including energy ratio, time delay, pre-pulse and main pulse durations, and line focus width. PMID- 20160781 TI - Optical through-turbulence imaging configuration: experimental validation. AB - In this Letter the authors present a field experimental validation of an imaging system that, when combined with a special image-processing algorithm, allows obtaining an improved imaging quality through turbulence perturbation. The system includes simultaneous capturing of three differently focused images and performing an iterative Gerchberg-Saxton based processing for phase retrieval. After the phase is retrieved the intensity of the object is reconstructed by numerical free-space propagation of the extracted complex field to the estimated position of the object. PMID- 20160782 TI - Determination of actual surface azimuthal anchoring strength using a wedge-shaped liquid crystal cell. AB - We present a method that determines the actual surface azimuthal anchoring strength based on the torque balance. It is found by an optical technique of measuring simultaneously the cell thicknesses and twist angles at two regions of a wedge-type liquid crystal cell whose cell thickness varies continuously between different positions in the cell. PMID- 20160783 TI - Hybrid silica-polymer ultra-high-Q microresonators. AB - Ultra-high-quality (UHQ) factor optical cavities have numerous applications throughout engineering and science. Incorporating active elements into these UHQ cavities to create dynamic devices would extend their applicability; however, it is inherently difficult to develop an active UHQ device. Ultra-thin films formed from optically active polymers provide one route to overcome this limitation. In the present work, hybrid devices composed of UHQ planar optical cavities with ultra-thin films are fabricated on a silicon wafer. Using finite element method simulations, the optical field overlap between the cavity and the polymer film is modeled and experimentally verified using two polymers: poly(methyl methacrylate) and polystyrene. These hybrid devices have demonstrated material-limited Q factors above 10(7). PMID- 20160784 TI - Realization of blue, green, and white inverted microcavity top-emitting organic light-emitting devices based on the same emitting layer. AB - High efficiency blue, green, and white inverted microcavity top-emitting organic light-emitting devices based on blue emitter p-bis(p-N,N-diphenyl-amino-styryl) benzene-doped 2-methyl-9,10-di(2-naphthyl) anthracene as the emitting layer are demonstrated. The different colors can be well realized by simply changing the thickness of the hole-transporting layer, thus modifying the cavity length to obtain various resonance wavelengths. The comprehensive analysis on the emission mechanism is presented. PMID- 20160786 TI - Structure fits the purpose: photonic crystal fibers for evanescent-field surface enhanced Raman spectroscopy. AB - We report numerical simulation and hyperspectral Raman imaging of three index guiding solid-core photonic crystal fibers (PCFs) of different air-cladding microstructures to assess their respective potential for evanescent-field Raman spectroscopy, with an emphasis on achieving surface-enhanced Raman scattering (SERS) over the entire fiber length. Suspended-core PCF consisting of a silica core surrounded by three large air channels conjoined by a thin silica web is the most robust of the three SERS-active PCFs, with a demonstrated detection sensitivity of 1x10(-10) M R6G in an aqueous solution of only approximately 7.3 microL sampling volume. PMID- 20160787 TI - Terahertz dual-band resonator on silicon. AB - We have designed and fabricated a dual-band resonator in the terahertz frequency range on high-resistivity silicon. The device is designed to show resonances at 2.6 and 4.3 THz using the finite-difference time-domain modeling method. The characteristics of the fabricated device have been examined by using a Fourier transform IR spectrometer. Measured results are in excellent agreement with the simulated data, showing two polarization-independent resonant peaks observed at 2.60 and 4.37 THz, respectively. The first resonance has a bandwidth of 0.56 THz, while the second one has a bandwidth of 0.70 THz. These dual-band resonant devices can be used for various applications such as dual-band spectral imaging and multiband biosensors. PMID- 20160788 TI - Wavelength scaling of elliptical-polarization dependence of high-order harmonic generation. AB - We report on an experimental study on the wavelength-scaling law of elliptical polarization dependence of high-order harmonic generation. In the elliptical polarization dependence measurements, we keep an identical peak intensity for pump pulses with carrier wavelength ranging from 800 nm to the mid-IR region, and the harmonic emission near the cutoff region is selected for comparison. We find that the experimental measured wavelength scaling of elliptical-polarization dependence could be well fitted with a function (epsilon(1/2) proportional to lambda(-1)) predicted by semiclassical model. PMID- 20160789 TI - Salient target detection based on pseudo-Wigner-Ville distribution and Renyi entropy. AB - We present what we believe to be a novel method based on pseudo-Wigner-Ville distribution (PWVD) and Renyi entropy for salient targets detection. In the foundation of studying the statistical property of Renyi entropy via PWVD, the residual entropy-based saliency map of an input image can be obtained. From the saliency map, target detection is completed by the simple and convenient threshold segmentation. Experimental results demonstrate the proposed method can detect targets effectively in complex ground scenes. PMID- 20160790 TI - Mid-infrared polarization pulse shaping by parametric transfer. AB - We demonstrate the generation of arbitrary amplitude, phase, and polarization controlled pulses in the mid-infrared (MIR) tunable around 3.5 microm. Two temporally separated sets of individually phase and amplitude shaped pulse profiles in the near-infrared are transferred into the MIR via two independent optical parametric amplification processes in two perpendicularly oriented nonlinear crystals in a common-path geometry. The resulting two shaped MIR light fields of orthogonal polarizations are temporally recombined interferometrically in a birefringent material. PMID- 20160791 TI - Tunable single-longitudinal-mode fiber optical parametric oscillator. AB - A tunable single-longitudinal-mode (SLM) fiber optical parametric oscillator (FOPO) is proposed and demonstrated experimentally. A sub-ring cavity with a short cavity length is used to suppress the longitudinal modes and broaden the longitudinal mode spacing. A fiber loop mirror, consisted of an unpumped erbium doped fiber, acts as an autotracking filter for providing fine mode restriction and ensuring the single-frequency operation. The measurement based on a homodyne method shows that the FOPO provides the SLM output. Furthermore the SLM FOPO can be tunable over 14 nm for each of the signal and the idler, which is limited only by the gain bandwidth of the fiber optical parametric amplifier. PMID- 20160792 TI - Thermally tunable lithium-niobate long-period waveguide grating filter fabricated by reactive ion etching. AB - We fabricate a long-period grating band-rejection filter with a lithium niobate (LiNbO(3)) channel waveguide, where the grating is formed on the waveguide surface by plasma reactive ion etching. The filter shows three distinct thermal tuning regimes. Below approximately 55 degrees C, the center wavelength of the rejection band decreases linearly with an increase in the temperature at a high sensitivity (-1.4 nm/ degrees C). The temperature sensitivity drops abruptly to a negligible value at approximately 55 degrees C and stays low up to approximately 70 degrees C, above which it jumps abruptly to a large positive value (1.6 nm/ degrees C). We attribute these peculiar tuning characteristics to the formation of different crystal phases in the core and cladding areas of the LiNbO(3) waveguide and the abrupt transitions of the thermo-optic coefficients of some crystal phases. The grating could be developed into various kinds of integrated optic filters and switches for application in optical signal processing. PMID- 20160793 TI - Applicability of geometrical optics to in-plane liquid-crystal configurations. AB - We study the applicability of geometrical optics to inhomogeneous dielectric nongyrotropic optically anisotropic media typically found in in-plane liquid crystal configurations with refractive indices n(o)=1.5 and n(e)=1.7. To this end, we compare the results of advanced ray- and wave-optics simulations of the propagation of an incident plane wave to a special anisotropic configuration. Based on the results, we conclude that for a good agreement between ray and wave optics, a maximum change in optical properties should occur over a distance of at least 20 wavelengths. PMID- 20160794 TI - All-fiber 10 W holmium lasers pumped at lambda=1.15 microm. AB - Three all-fiber Ho-doped lasers emitting in the range of 2050-2100 nm were fabricated. The lasers were pumped by an Yb-doped fiber laser at 1147 nm with a power up to 35 W. For all the lasers tested, the output power was found to be as high as 10 W, the efficiency slope being 30%. PMID- 20160795 TI - Hybrid multicore photonic-crystal fiber for in-phase supermode selection. AB - We examine a hybrid multicore photonic-crystal fiber, where the cores are separated by high-index solid rods and the microstructure cladding is built on a hexagonal lattice of air holes in silica. Antiresonant reflection from high-index solid rods is shown to assist the field confinement in the cores of such a fiber. When the cores are doped with a laser-active material, the maximum gain is achieved for the in-phase supermode, which translates into a high-quality Gaussian-like beam profile in the far field. PMID- 20160796 TI - Phase shifting grating-slit test with a cross slit. AB - A general graphical convolution method for fringe analysis of testing methods that use a spatially incoherent light source is presented. Results are shown for the grating-slit test using optical narrow and cross slits. The convolution method shows that phase shifting grating-slit test can be done with the cross slit at the expense of a reduced fringe contrast ratio. A phase shifting measurement with a cross-slit modulator yields high measurement precision and validates our fringe contrast theory. PMID- 20160797 TI - Microstructured fiber source of photon pairs at widely separated wavelengths. AB - We demonstrate a source of photon pairs with widely separated wavelengths, 810 and 1548 nm, generated through spontaneous four-wave mixing in a microstructured fiber. The second-order autocorrelation function g((2))(0) was measured to confirm the nonclassical nature of a heralded single-photon source constructed from the fiber. The microstructured fiber presented herein has the interesting property of generating photon pairs with wavelengths suitable for a quantum repeater able to link free-space channels with fiber channels, as well as for a high-quality telecommunication wavelength heralded single photon source. It also has the advantage of potentially low-loss coupling into standard optical fiber. These reasons make this photon pair source particularly interesting for long distance quantum communication. PMID- 20160798 TI - Experimental realization of subwavelength plasmonic slot waveguides on a silicon platform. AB - We report the experimental realization of horizontal plasmonic slot waveguides capable of subdiffraction modal confinement at IR wavelengths. These waveguides have a propagation length of approximately 6 lambda(g) and are monolithically integrated with conventional silicon photonic waveguides on the same silicon-on insulator platform. Direct coupling of light from the silicon waveguides to the plasmonic waveguides was achieved with an efficiency of 30% using taper-funnel couplers to obtain mode matching between the two waveguide systems. PMID- 20160799 TI - Optical parametric amplification of a distributed-feedback quantum-cascade laser in orientation-patterned GaAs. AB - We demonstrate what is to our knowledge the first realization of an optical parametric amplifier in orientation-patterned GaAs amplifying the emission of a quantum-cascade laser (QCL) with a distributed-feedback (DFB) structure. We report a gain as high as 53 dB at 4.5 mum, in good agreement with theoretical calculations. The narrow spectral linewidth and the good beam quality of this source are imposed by the DFB-QCL, while high-peak-power emission is achieved through the parametric amplification. These characteristics are of valuable interest for long-range spectroscopy. PMID- 20160800 TI - Coherent optical computing for T-ray imaging. AB - Single-point imagery of 2D objects is proposed by exploiting the extreme broadband nature of an ultrafast terahertz wave. In the proposed imagery, a collimated terahertz beam is illuminated on an object, and the scattered fields are measured through a hole at the Fourier plane in a conventional terahertz time domain spectroscope. This arrangement allows conversion of radial spatial frequencies of the object to the temporal spectrum of the pulse. Hence, a 2D image can be readily obtained by rotating a hole around the optical axis. Experimental results confirm that a complicated object can be reliably imaged using only 30 waveform measurements. PMID- 20160801 TI - Diode-pumped mode-locked Yb:LuScO(3) single crystal laser with 74 fs pulse duration. AB - The mode locking of the mixed sesquioxide single crystal Yb:LuScO(3) is demonstrated. This crystal is locally disordered and has the broadest emission spectrum of all sesquioxides known so far. Pulse durations as short as 111 and 74 fs were obtained using the semiconductor saturable absorber mirror and Kerr-lens mode locking, respectively. The latter regime was reached using a two-section distributed Bragg-reflector tapered diode laser as a pump source. PMID- 20160802 TI - Self-reference quantitative phase microscopy for microfluidic devices. AB - This Letter describes a quantitative phase microscopy for microfluidic devices using a simple self-referencing interferometry. Compared with the gross dimensions of the microfluidic device, the microchannel occupies only a small area of the device. Hence, the reference field can be generated by inverting the relative position of the specimen and background. Our system is realized using an extended depth-of-field optics in the form of Michelson interferometry, which allows quantitative phase measurement for an increased depth-of-field without moving objective lens or specimen. Furthermore, the system can be readily converted to a higher signal-to-noise ratio Hilbert phase microscopy thanks to the simultaneous acquisition of double interferograms. The performance of our system is verified using polymer beads, micropatterning poly(dimethylsiloxane) (PDMS), and embryo cells in the microchannels. PMID- 20160803 TI - Surface-plasmon-coupled emission microscopy with a spiral phase plate. AB - The surface plasmon-coupled emission microscope provides high sensitivity for surface imaging. However, it suffers from a distorted donut-shape point-spread function (PSF). Here we report an effective yet simple method to correct for the distortion by introducing a spiral phase plate. This modification converts the donut PSF into one that is single lobed, which is preferable for imaging. The optical performance of the system is characterized and compared with previous publications. This technique provides more than twofold lateral resolution enhancement. PMID- 20160805 TI - Fine tuning of conversion/dispersion based optical delays with a 1 pm tunable laser using cascaded acousto-optic mixing. AB - We demonstrate a technique for fine tuning of optical delays using cascaded acousto-optic modulators to improve the delay resolution by 5 orders of magnitude compared to a 1 pm tunable laser. A 256 ns delay with <0.5 ps resolution is shown for 40 Gbits/s return-to-zero on-off keying with no added penalty. PMID- 20160804 TI - High-gain optical amplification in Eu(3+)-doped polymer. AB - Europium (Eu(3+))-doped epoxy-based resin Norland optical adhesive (NOA) polymers have been prepared and characterized optically. Quartz capillary tube encapsulated Eu(3+)-doped NOA polymeric waveguides have been fabricated via a simple withdrawal molding technique. Optical amplification at 612 nm wavelength has been demonstrated in these waveguide devices, and the signal enhancements for different lengths of the devices have been measured. A maximum signal enhancement of ~30 dB has been obtained for a 16 mm long device. PMID- 20160806 TI - Phase locking of two coupled lasers with many longitudinal modes. AB - Detailed experimental and theoretical investigations of two coupled fiber lasers, each with many longitudinal modes, reveal that the behavior of the longitudinal modes depends on both the coupling strength and the detuning between them. For low to moderate coupling strength only longitudinal modes that are common for both lasers phase lock, while those that are not common gradually disappear. For larger coupling strengths, the longitudinal modes that are not common reappear and phase lock. When the coupling strength approaches unity the coupled lasers behave as a single long cavity with correspondingly denser longitudinal modes. Finally, we show that the gradual increase in phase locking as a function of the coupling strength results from competition between phase-locked and non-phase locked longitudinal modes. PMID- 20160807 TI - Surface-plasmon Schottky contact detector based on a symmetric metal stripe in silicon. AB - A Schottky contact detector comprising a symmetric metal stripe buried in Si, capable of detecting surface plasmons at wavelengths below the bandgap of Si, is described. A model for the detector is proposed, and its performance is assessed at lambda(0)=1550 nm assuming a CoSi(2) stripe in p-type Si. End-fire coupled responsivities of about 0.1 A/W and minimum detectable powers of about -20 dBm are predicted at room temperature. PMID- 20160808 TI - Multiphoton coherence domain molecular imaging with pump-probe optical coherence microscopy. AB - We have developed a high-resolution molecular imaging technique, pump-probe optical coherence microscopy (PPOCM), based on the fusion of pump-probe spectroscopy and optical coherence microscopy. We have demonstrated the prototype system on a fixed human skin sample containing a nodular melanoma. The results indicate that the PPOCM can clearly provide a strong contrast between the melanotic and amelanotic regions. Potential applications of the PPOCM imaging of melanin include the early diagnosis of melanoma and the mapping of tumor margins during excision. The technique may in general be applied to any biological chromophore with a known absorption spectrum. PMID- 20160809 TI - Diffractive pulse shaper for arbitrary waveform generation. AB - We propose an all-diffractive pulse shaper for arbitrary waveform generation in the femtosecond regime. This optical device improves in several aspects the performance of our previous quasi-direct pulse shaper reported in Minguez-Vega et al. [Opt. Express16, 16993 (2008)]. In the present implementation, by using grayscale masks we can achieve arbitrary temporal waveforms. Additionally, the holographic reconstruction of the above masks by means of phase holograms allows for a high-efficiency shaping process. The behavior of the pulse shaper is tested by numerical simulations. PMID- 20160810 TI - Multiple-wavelength plasmonic nanoantennas. AB - We propose a type of photonic-plasmonic antennas capable of focusing light into subwavelength focal point(s) at several wavelengths, which are formed by embedding conventional dimer gap or bow-tie nanoantennas into multiple-periodic gratings. Fano-type coupling between localized surface plasmon resonances of dimer antennas and photonic modes in the gratings adds new functionalities, including multiple-wavelength operation and controllable enhancement of the field intensity in the focal point. Multiple-wavelength operation of nanoantennas provides tremendous opportunities for broadband single-molecule fluorescence and Raman sensing, emission enhancement, and near-field imaging. PMID- 20160811 TI - Adiabatic nanofocusing of channel plasmon polaritons. AB - Using the analytical description of channel plasmon polaritons (CPPs) developed recently [Opt. Lett.34, 2039 (2009)], we consider the adiabatic CPP nanofocusing in V grooves with linearly decreasing groove angles, deriving closed-form expressions for local field enhancements. Calculations at telecom wavelengths predict the possibility of reaching the intensity enhancements exceeding approximately 1200 for realistic groove tapers cut into gold. Our conclusions are in good agreement with the results of previous investigations. PMID- 20160812 TI - Ultrahigh-birefringent squeezed lattice photonic crystal fiber with rotated elliptical air holes. AB - We report an experimental realization of a highly birefringent photonic crystal fiber as a result of compressing a regular hexagonal structure. The experimental measurements estimate a group birefringence of approximately 5.5x10(-3) at 1550 nm in good agreement with the numerical results. We study the influence of compressing the regular structure at different directions and magnifications, obtaining a method to realistically enhance the phase birefringence while moderating the group birefringence. PMID- 20160813 TI - Electroluminescence from silicon-based photonic crystal microcavities with PbSe quantum dots. AB - The characteristics of electrically injected silicon-based photonic crystal microcavities with PbSe quantum dots are described. The device includes suitable electron and hole transporting layers and contact layers. The measured electroluminescence at room temperature exhibits an enhanced spontaneous emission. The resonant mode is observed at lambda=1669 nm with a spectral linewidth of 4 nm, corresponding to a cavity Q factor of approximately 420. PMID- 20160814 TI - One-dimensional long-range plasmonic-photonic structures. AB - We have fabricated line gratings from periodically etched fused silica on which a thin silver film is deposited that is in turn covered with a silica index-matched fluid. This dielectrically symmetric geometry supports an independent long-range surface plasmon-polariton (LRSPP) and a short-range surface plasmon polariton, and the associated plasmonic band structure has been probed. Coupling to external light is achieved via the patterned grating, and an ultrasharp LRSPP linewidth of 4 nm is observed. The experimental results are compared with finite-difference time-domain simulations. PMID- 20160815 TI - Bending and coupling losses in terahertz wire waveguides. AB - We present an experimental study of several common perturbations of wire waveguides for terahertz pulses. Sommerfeld waves retain significant signal strength and bandwidth even with large gaps in the wire, exhibiting more efficient recoupling at higher frequencies. We also describe a detailed study of bending losses. For a given turn angle, we observe an optimum radius of curvature that minimizes the overall propagation loss. These results emphasize the impact of the distortion of the spatial mode on the radiative bend loss. PMID- 20160816 TI - Mode-locked picosecond diamond Raman laser. AB - We present a mode-locked diamond Raman laser synchronously pumped by a mode locked laser running at 532 nm and pulse duration 26 ps. The diamond laser generated up to 2.2 W of average power with output pulses of duration 21 ps at a yellow wavelength of 573 nm. The output pulse duration varied notably with small changes in cavity length and decreased to a minimum of 9 ps. The power and pulse duration behavior as a function of cavity length is explained well by a model that includes phonon dephasing and group velocity dispersion of the pump and Stokes fields. PMID- 20160817 TI - Analytic inversion of the Mueller-Jones polarization matrices for homogeneous media. AB - In this Letter we present the equations to calculate the six independent polarization effects of an arbitrary normalized Mueller-Jones matrix corresponding to homogenous media. A comparison between this method and other inversion procedures is discussed, and the application of the analytic inversion to experimental Mueller matrices is illustrated. PMID- 20160818 TI - Electrically switched color with polymer-stabilized blue-phase liquid crystals. AB - We report an electrical-field switched color device using a polymer-stabilized blue-phase (PSBP) liquid crystal in which the Bragg-reflected color of the blue phase (BP) can be switched to reflect a second color. The phase-separated three dimensional polymer network transcribes the cubic structure of a BP liquid crystal and restrains the deformation of cubic lattice by the external electric field. The new wide-range electric-field switched colors with PSBP may be an important step toward ecofriendly color reflective displays. PMID- 20160819 TI - Quasi-phase-matched concurrent nonlinearities in periodically poled KTiOPO(4) for quantum computing over the optical frequency comb. AB - We report the successful design and experimental implementation of three coincident nonlinear interactions, namely ZZZ (type 0), ZYY (type I), and YYZ/YZY (type II) second-harmonic generation of 780 nm light from a 1560 nm pump beam in a single, multigrating, periodically poled KTiOPO(4) crystal. The resulting nonlinear medium is the key component for making a scalable quantum computer over the optical frequency comb of a single optical parametric oscillator. PMID- 20160820 TI - Magneto-optical circulator designed for operation in a uniform external magnetic field. AB - We propose an approach for the design of resonant cavities employed in magnetophotonic crystal (MPC) circulators and isolators. Starting from the analysis of a model circularly symmetric cavity, we show how to obtain a significant splitting of the eigenfrequencies of the two counterrotating cavity modes without introducing subdomains magnetized in opposite directions. Using the multiple-scattering method extended to handle uniaxial gyrotropic materials, we demonstrate numerically an MPC circulator working in a uniform external magnetic field. PMID- 20160821 TI - Embedded optical micro/nano-fibers for stable devices. AB - We present a technique to embed silica micro and nanofibers in low-index material (Teflon) using an inexpensive and straightforward fabrication process based on spin coating. The optical properties of the silica micro/nano-fibers have been investigated when they are bare or completely or partially embedded. Optical degradation occurs in bare fibers with diameters smaller than twice the wavelength of the guided light, thus making protection through embedding necessary. Our results also show that completely embedded fibers do not degrade over a long time, while partially embedded fibers can preserve the large evanescent waves without undergoing considerable degradation, which would be further reduced or even become negligible with functional overlayers. The results represent a step forward toward the development of durable and stable devices based on optical micro/nano fibers. PMID- 20160822 TI - Spectrally encoded confocal scanning laser ophthalmoscopy. AB - We present in vivo human fundus imaging using a fiber-based confocal scanning laser ophthalmoscope (SLO). Spectrally encoded confocal scanning laser ophthalmoscopy (SECSLO) utilizes a spectral encoding technique in one dimension, combined with single-axis lateral scanning, to create video-rate reflectivity maps of the fundus. This implementation of the SLO allows for high-contrast high resolution in vivo human retinal imaging through a single-mode optical fiber. We experimentally quantify the full confocality of SECSLO in both the spectrally encoded and laterally scanned dimensions, and demonstrate 50 Hz frame rate fundus imaging. PMID- 20160823 TI - Laser-induced refractive index changes in nanocrystalline diamond membranes. AB - We have observed what we believe to be a new phenomenon in nanocrystalline diamond membranes. The optical thickness of the membrane is changed under laser irradiation, which leads to a spectral shift of interference fringes in the transmission and photoluminescence spectra of high-quality thin self-supporting nanocrystalline membranes. The direction of the spectral shift (red/blue) can be tuned by the ambient air pressure. The effect is reversible and is accompanied by changes in photoluminescence intensity. We interpret the results in terms of the changes in the index of refraction caused by the photoinduced adsorption/desorption of air molecules that subsequently affect the properties of subgap energy states related to the surface and the grain boundaries of the nanocrystals. PMID- 20160824 TI - Optical probing of electric fields with an electro-acoustic effect toward integrated circuit diagnosis. AB - Electro-optic probing of electric fields has been considered as a promising approach for integrated circuit diagnosis. However, the method is subject to relatively weak voltage sensitivity. In this Letter, we solve the problems with electro-acoustic effect. In contrast to the general electro-optic effect, the light phase modulation induced by the acoustic effect is 2 orders of magnitude stronger at its resonant frequency, as we observed in a GaAs thin film probe. Furthermore, this what we believe to be a novel method shows a highly reproducible linearity between the detected signals and the input voltages, which facilitates the voltage calibration. PMID- 20160825 TI - Excitation mapping of whispering gallery modes in silica microcavities. AB - We report the direct observation of the electromagnetic-field distribution of whispering gallery modes in silica microcavities (spheres and toroids). It is revealed by their excitation efficiency with a tapered fiber coupler swept along the meridian. The originality of this method lies in the use of the coupler itself for the near-field mapping, eliminating the need of additional tools used in previous work. This method is successfully applied to microspheres and microtoroids. PMID- 20160826 TI - Thermal stabilization of Type I fiber Bragg gratings for operation up to 600 degrees C. AB - The thermal stability of Type I gratings is increased by postthermal tuning of the grating. Optimization of the procedure leads to gratings that can withstand temperatures as high as 600 degrees C. Aging tests lead to lifetime predictions as high as 25 years with <3 dB reduction at 400 degrees C. Single exponential relaxation is observed. Above 800 degrees C regeneration is obtained. PMID- 20160827 TI - Role of ocular aberrations in photopic spatial summation in the fovea. AB - An adaptive optics vision simulator was used to measure the role of ocular aberrations in the photopic foveal spatial summation curve for three young subjects. After the correction of the ocular aberrations over a 6 mm pupil, the increment luminance threshold was lowered for small stimuli and the estimated area of complete summation (Ricco's area) was reduced by a factor of 2.6 on average. These results show that the image spread due to natural ocular aberrations partly accounts for the spatial summation observed in the fovea in the photopic light regime. PMID- 20160828 TI - Ultranarrow bandwidth moire reflecting Bragg gratings recorded in photo-thermo refractive glass. AB - An experimental demonstration of a moire reflecting Bragg grating in photo-thermo refractive glass is carried out. This narrowband filter is obtained by the recording of two reflecting Bragg gratings with different periods. Filters with central wavelength at 1550 nm, bandwidth of 50 pm, and transmission higher than 95% are demonstrated. The methods to decrease bandwidth to 1 pm are finally investigated. PMID- 20160829 TI - Polarization properties of scattered light from macrorough surfaces. AB - We have characterized macrorough surfaces by measuring angle-resolved Stokes parameters of scattering. The analysis of the parameters as a function of a virtual scattering angle shows that polarization properties of the scattering in the plane of incidence display a very strong dependence on the surface roughness. The method and results of this analysis have a significant impact on the application of light scattering to the inspection and process-evaluation industry. PMID- 20160830 TI - On-chip waveguide resonator with metallic mirrors. AB - We introduce an optical microresonator consisting of a planar waveguide terminated by metallic mirrors. The resonator was fabricated on a silicon-on insulator platform, and its optical performance was theoretically and experimentally investigated. The demonstrated device had dimensions of 200 mumx40 mum and exhibited a quality factor of about 1000 and a free-spectral range of about 8 nm. Application to high-throughput, label-free biochemical sensing is considered, and optimization with respect to the surface sensitivity is carried out. The optimized sensitivity makes it possible to detect subnanometer layers of molecules adsorbing to the surface of the resonator. PMID- 20160831 TI - Investigations on the UV photorefractivity of LiNbO(3):Hf. AB - The UV photorefractivity of LiNbO(3):Hf was investigated by beam distortion and two-wave coupling experiments. A sharp decrease of beam distortion was found between Hf concentrations of 2 and 2.5 mol.%, indicating a significant increase of photoconductivity there. The energy-transfer direction of the two-wave coupling and the effect of chemical reduction on the UV photorefractivity reveal that electrons are the carriers responsible for the UV photorefraction. Moreover, dissimilar with LiNbO(3) highly doped with Mg, Zn, and In, the grating recorded in LiNbO(3):Hf was found to be nearly stable in the dark but sensitive to red light, which can be attributed to the special location of Fe ions in the crystal lattice. PMID- 20160832 TI - Anisotropy-controlled topological stability of discrete vortex solitons in optically induced photonic lattices. AB - We realize an experimental control over the topological stability of three-lobe discrete vortex solitons by modifying the symmetry of a hexagonal photonic lattice optically induced in a photorefractive crystal. By continuously deforming the lattice wave in one transverse direction, we manipulate the coupling between lattice sites and induce or inhibit the reversal of soliton vorticity. PMID- 20160833 TI - Low-cost cavity-dumped femtosecond Cr:LiSAF laser producing >100 nJ pulses. AB - We report a low-cost cavity-dumped Cr:colquiriite laser for generating enhanced pulse energies. Four single-mode laser diodes were used to pump a Cr:LiSAF laser, which was mode locked with a semiconductor saturable absorber mirror. Cavity dumping at 10 kHz repetition rate, the laser generated approximately 120 fs pulses at approximately 825 nm, with 112 nJ pulse energies and approximately 0.93 MW of peak power, using only approximately 600 mW of incident pump power. At higher dumping rates of up to 1 MHz, reduced pulse energies of 62 nJ could be generated. Two-photon absorption in the saturable absorber mirror limits pulse durations, while Q-switching instabilities limit pulse energy extraction. PMID- 20160834 TI - Well-confined surface plasmon polaritons for sensing applications in the near infrared. AB - The surface plasmon polariton (SPP) dispersion at the interface between a dielectric half-space and a layered metallodielectric metamaterial is investigated. By varying the material constituants, it is shown that the SPP resonance frequency can be readily shifted to the near-IR. Through numerical simulations, the validity domain of homogenization and the effects of the finite number of layers in the metamaterial are studied. It is found that as few as N=2 periods are sufficient for practical operation. These results reveal the potential of employing metallodielectric stacks for sensing applications in the near-IR regime. PMID- 20160835 TI - In-fiber Fabry-Perot refractometer assisted by a long-period grating. AB - We present an optical fiber refractometer based on a Fabry-Perot interferometer defined by two fiber Bragg gratings and an intracavity long-period grating that makes the light confined in the resonator interact with the surrounding medium. The external refractive index is monitored by the resonant frequencies of the Fabry-Perot interferometer, which can be measured either in transmission or in reflection. In this first experiment, wavelength shifts measured with a resolution of 0.1 pm have allowed one to establish a refractive index detection limit of 2.1x10(-5). PMID- 20160836 TI - Risk Factors Linking Maternal Depressed Mood to Growth in Adolescent Substance Use. AB - Maternal depression has been implicated in the development of adolescent substance use. Conceptualizing depression as a continuum, the aims of this study were to (a) understand the relationship between maternal depressed mood and risk factors associated with adolescent substance use; (b) understand the relationship between maternal depressed mood and level and growth in adolescent alcohol, cigarette, and marijuana use assessed at multiple time points during adolescence; and (c) examine the unique and relative contribution of maternal depressed mood after taking into account contextual risk factors related to adolescent substance use. Participants were 792 children and their mothers. Latent growth modeling was used with adolescent alcohol, cigarette, and marijuana use treated as ordinal variables. Child depressive phenomena and child antisocial behavior partially explained the relationship between maternal depressed mood and adolescent alcohol and cigarette use. Mothers' own substance use did not contribute to level or change in adolescent substance use after other risk factors were considered. PMID- 20160837 TI - Bronsted acid-mediated opening of nitroso cycloadducts under anhydrous conditions. AB - An unusual bicyclic hydroxamate resulted from C-O bond cleavage of acylnitroso hetero-Diels-Alder cycloadducts when treated with catalytic Bronsted acids under anhydrous conditions. Similarly, the formation of a nitrone was observed using one equivalent of triflic acid. PMID- 20160838 TI - Inactivation of [Fe-Fe]-Hydrogenase by O(2). Thermodynamics and Frontier Molecular Orbitals Analyses. AB - The oxidation of H-cluster in gas phase, and in aqueous enzyme phase, has been investigated by means of quantum mechanics (QM) and combined quantum mechanics molecular mechanics (QM/MM). Several potential reaction pathways (in the above mentioned chemical environments) have been studied, wherein only the aqueous enzyme phase has been found to lead to an inhibited hydroxylated cluster. Specifically, the inhibitory process occurs at the distal iron (Fe(d)) of the catalytic H-cluster (which is also the atom involved in H(2) synthesis). The processes involved in the H-cluster oxidative pathways are O(2) binding, e(-) transfer, protonation, and H(2)O removal.We found that oxygen binding is non spontaneous in gas phase, and spontaneous for aqueous enzyme phase where both Fe atoms have oxidation state II; however, it is spontaneous for the partially oxidized and reduced clusters in both phases. Hence, in the protein environment the hydroxylated H-cluster is obtained by means of completely exergonic reaction pathway starting with proton transfer.A unifying endeavor has been carried out for the purpose of understanding the thermodynamic results vis-a-vis several other performed electronic structural methods, such as frontier molecular orbitals (FMO), natural bond orbital partial charges (NBO), and H-cluster geometrical analysis. An interesting result of the FMO examination (for gas phase) is that an e(-) is transferred to LUMO(alpha) rather than to SOMO(beta), which is unexpected because SOMO(beta) usually resides in a lower energy rather than LUMO(alpha) for open-shell clusters. PMID- 20160839 TI - Bounding Sample Size Projections for the Area Under a ROC Curve. AB - Studies of diagnostic tests are often designed with the goal of estimating the area under the receiver operating characteristic curve (AUC) because the AUC is a natural summary of a test's overall diagnostic ability. However, sample size projections dealing with AUCs are very sensitive to assumptions about the variance of the empirical AUC estimator, which dependens on two correlation parameters. While these correlation parameters can be estimated from available data, in practice it is hard to find reliable estimates before the study is conducted. Here we derive achievable bounds on the projected sample size that are free of these two correlation parameters. The lower bound is the smallest sample size that would yield the desired level of precision for some model, while the upper bound is the smallest sample size that would yield the desired level of precision for all models. These bounds are important reference points when designing a single or multi-arm study; they are the absolute minimum and maximum sample size that would ever be required. When the study design includes multiple readers or interpreters of the test, we derive bounds pertaining to the average reader AUC and the 'pooled' or overall AUC for the population of readers. These upper bounds for multireader studies are not too conservative when several readers are involved. PMID- 20160840 TI - Efficient Synthesis of the 2-amino-6-chloro-4-cyclopropyl-7-fluoro-5-methoxy pyrido[1,2-c]pyrimidine-1,3-dione core ring system. AB - An optimized total synthesis of the 2-amino-6-chloro-4-cyclopropyl-7-fluoro-5 methoxy-pyrido[1,2-c]pyrimidine-1,3-dione core structure of a new fluoroquinolone like class of antibacterial agents is described. This synthesis is highlighted by a nearly quantitative ring-closing reaction to form the pyrido[1,2-c]pyrimidine core. This bicyclic ring system serves as a scaffold for a family of biologically active compounds. PMID- 20160841 TI - A Robust QTL Mapping Procedure. AB - In quantitative-trait linkage studies using experimental crosses, the conventional normal location-shift model or other parameterizations may be unnecessarily restrictive. We generalize the mapping problem to a genuine nonparametric setup and provide a robust estimation procedure for the situation where the underlying phenotype distributions are completely unspecified. Classical Wilcoxon-Mann-Whitney statistics are employed for point and interval estimation of QTL positions and effects. PMID- 20160842 TI - Reply to the letter to the editor by Bretholz et al. PMID- 20160843 TI - On the Pursuit of Sound Science for the Betterment of the American Indian Community: Reply to Beals et al. AB - We argue that ongoing criticism of existing theories, the development of alternative theories, and empirical theory tests offer the best chance for advancing American Indian research. We, therefore note our appreciation for Beals et al.'s comments. We nevertheless did disagree with many of Beals et al.'s specific claims, noting that (a) our characterization of the existing literature on reservation-dwelling American Indian drinking was accurate; (b) no argument made by Beals et al. undermines their theoretical contention that there is a relative lack of contingency between access to basic life reinforcers and sobriety on many reservations; (c) our theory was developed in a responsible manner: a reservation-tied American Indian developed the theory, which was reviewed by a reservation leadership team, a cultural consultant, and reviewers for this journal, at least one of whom consulted leaders of other reservations; and (d) our theory was based on previous interdisciplinary theory development. We encourage the development and testing of new, alternative theories. PMID- 20160844 TI - Determinants of delayed preconditioning against myocardial stunning in chronically-instrumented pigs. AB - To test the hypothesis that a critical stenosis prevents delayed preconditioning against stunning, studies were conducted in pigs chronically-instrumented with occluders and segment-shortening crystals. In the setting of a critical stenosis, a preconditioning stimulus of repetitive brief occlusions resulted in infarction. Thereafter, a single 10-minute occlusion was used as the preconditioning stimulus. Delayed preconditioning against stunning was documented on subsequent days by the deficit-of-function following brief repetitive occlusions. In contrast to experiments in the naive heart, the deficit-of-function improved on the day after a single 10-minute occlusion (from 60+/-14 to 24+/-6 arbitrary units, p=0.003), and similar improvement occurred when reperfusion was performed through a critical stenosis (32+/-6 units, p=0.02 vs. naive and p=0.34 vs. no stenosis). Delayed preconditioning also reduced the frequency of ventricular fibrillation, and produced a 4-fold increase in both calcium-dependent and calcium-independent NOS activity. Thus, a critical stenosis did not prevent delayed preconditioning against stunning. PMID- 20160845 TI - Novel dimethoxy(aminoalkoxy)borate derived from (S)-diphenylprolinol as highly efficient catalyst for the enantioselective boron-mediated reduction of prochiral ketones. AB - The novel dimethoxyl(aminoalkoxy)borate 1 was isolated as a white crystalline dimer joined by H-bonding as evidenced by X-ray analysis, and demonstrated to be a highly effective catalyst for the asymmetric reduction of representative prochiral ketones with borane-DMS. Optically pure alcohols were obtained using only 1 mol% of catalyst 1 in up to 99% ee. PMID- 20160846 TI - A Scalable Framework For Cluster Ensembles. AB - An ensemble of clustering solutions or partitions may be generated for a number of reasons. If the data set is very large, clustering may be done on tractable size disjoint subsets. The data may be distributed at different sites for which a distributed clustering solution with a final merging of partitions is a natural fit. In this paper, two new approaches to combining partitions, represented by sets of cluster centers, are introduced. The advantage of these approaches is that they provide a final partition of data that is comparable to the best existing approaches, yet scale to extremely large data sets. They can be 100,000 times faster while using much less memory. The new algorithms are compared against the best existing cluster ensemble merging approaches, clustering all the data at once and a clustering algorithm designed for very large data sets. The comparison is done for fuzzy and hard k-means based clustering algorithms. It is shown that the centroid-based ensemble merging algorithms presented here generate partitions of quality comparable to the best label vector approach or clustering all the data at once, while providing very large speedups. PMID- 20160847 TI - A SERS study of the molecular structure of alkanethiol monolayers on Ag nanocubes in the presence of aqueous glucose. AB - We report progress towards the surface-enhanced Raman scattering (SERS) characterization of self-assembled monolayers (SAMs) on uniform Ag nanocubes. This study quantifies changes in the SAMs induced by the presence of aqueous glucose. The SAMs were prepared from dodecanethiol and they were representative of highly ordered monolayers as indicated by SERS analysis. We examined the SAMs response to glucose and observed conformational changes in the alkanethiolate SAMs. Analysis of the trans and gauche bands as well as the C-H stretching modes of the SAMs suggest that the analyte-SAM interactions were superficial and there was no penetration for the glucose molecules into the monolayers. PMID- 20160848 TI - Can a Developmental Psychopathology Perspective Facilitate a Paradigm Shift toward a Mixed Categorical-Dimensional Classification System? AB - Maser et al. (2009) identify several problems with the categorical DSM, and suggest that a shift to a mixed categorical-dimensional system is warranted. Maser et al. support their argument by citing evidence related to mood and anxiety disorders, among other conditions. In this commentary, I consider the applicability of several issues raised by Maser et al. to two disruptive behavior disorders in youth, oppositional defiant disorder (ODD) and conduct disorder (CD). The issues include paradigm shifts concerning (a) the diagnostic threshold, (b) symptoms, and (c) distress/psychosocial impairment. Within each topic, several developmental psychopathology principles that parallel and extend the Maser et al. issues are presented and described. This commentary also provides examples of dimensions that could be useful for conceptualizing ODD and CD within a mixed categorical-dimensional classification system. PMID- 20160849 TI - The power of linkage analysis of a disease-related endophenotype using asymmetrically ascertained sib pairs. AB - A linkage study of a qualitative disease endophenotype in a sample of sib pairs, consisting of one disease affected proband and one sibling is considered. The linkage statistic compares marker allele sharing with the proband in siblings with an abnormal endophenotype to siblings with the normal endophenotype. Expressions for the distribution of this linkage statistic, in terms of the recombination fraction are derived and (1) the genetic parameter values (allele frequency and endophenotype and disease penetrance) and (2) the abnormal endophenotype rates in the population and in classes of relatives of disease affected probands. It is then shown that when either the disease or the abnormal endophenotype has additive penetrance, the expressions simplify to a monotonic function of the difference between abnormal endophenotype rates in siblings and in the population. Thought disorder is considered as a putative schizophrenia endophenotype. Forty sets of genetic parameter values that correspond to the known prevalence values for thought disorder in schizophrenic patients, siblings of schizophrenics and the general population are evaluated. For these genetic parameter values, numerical results show that the test statistic has>70% power (alpha = 0.0001) in general with a sample of 200 or more proband-sibling pairs to detect the linkage between a marker (theta = 0.01), and a locus pleiotropic for schizophrenia and thought disorder. PMID- 20160850 TI - Argument structure effects in action verb naming in static and dynamic conditions. AB - Argument structure, as in the participant roles entailed within the lexical representation of verbs, affects verb processing. Recent neuroimaging studies show that when verbs are heard or read, the posterior temporoparietal region shows increased activation for verbs with greater versus lesser argument structure complexity, usually bilaterally. In addition, patients with agrammatic aphasia show verb production deficits, graded based on argument structure complexity. In the present study, we used fMRI to examine the neural correlates of verb production in overt action naming conditions. In addition, we tested the differential effects of naming when verbs were presented dynamically in video segments versus statically in line drawings. Results showed increased neuronal activity associated with production of transitive as compared to intransitive verbs not only in posterior regions, but also in left inferior frontal cortex. We also found significantly greater activation for transitive versus intransitive action naming for videos compared to pictures in the right inferior and superior parietal cortices, areas associated with object manipulation. These findings indicate that verbs with greater argument structure density engender graded activation of both anterior and posterior portions of the language network and support verb naming deficit patterns reported in lesion studies. In addition, the similar findings derived under video and static picture naming conditions provide validity for using videos in neuroimaging studies, which are more naturalistic and perhaps ecologically valid than using static pictures to investigate action naming. PMID- 20160851 TI - Confidence limits on one-stage model parameters in benchmark risk assessment. AB - In modern environmental risk analysis, inferences are often desired on those low dose levels at which a fixed benchmark risk is achieved. In this paper, we study the use of confidence limits on parameters from a simple one-stage model of risk historically popular in benchmark analysis with quantal data. Based on these confidence bounds, we present methods for deriving upper confidence limits on extra risk and lower bounds on the benchmark dose. The methods are seen to extend automatically to the case where simultaneous inferences are desired at multiple doses. Monte Carlo evaluations explore characteristics of the parameter estimates and the confidence limits under this setting. PMID- 20160852 TI - Bootstrap methods for simultaneous benchmark analysis with quantal response data. AB - A primary objective in quantitative risk assessment is the characterization of risk which is defined to be the likelihood of an adverse effect caused by an environmental toxin or chemcial agent. In modern risk-benchmark analysis, attention centers on the "benchmark dose" at which a fixed benchmark level of risk is achieved, with a lower confidence limits on this dose being of primary interest. In practice, a range of benchmark risks may be under study, so that the individual lower confidence limits on benchmark dose must be corrected for simultaneity in order to maintain a specified overall level of confidence. For the case of quantal data, simultaneous methods have been constructed that appeal to the large sample normality of parameter estimates. The suitability of these methods for use with small sample sizes will be considered. A new bootstrap technique is proposed as an alternative to the large sample methodology. This technique is evaluated via a simulation study and examples from environmental toxicology. PMID- 20160854 TI - Cholesterol Supplementation During Production Increases the Infectivity of Retroviral and Lentiviral Vectors Pseudotyped with the Vesicular Stomatitis Virus Glycoprotein (VSV-G). AB - Cholesterol, a major component of plasma membrane lipid rafts, is important for assembly and budding of enveloped viruses, including influenza and HIV-1. Cholesterol depletion impairs virus assembly and infectivity. This study examined the effects of exogenous cholesterol addition (delivered as a complex with methyl beta cyclodextrin) on the production of Molony murine leukemia virus retroviral vector and HIV-1-based lentiviral vector pseudotyped with the vesicular stomatitis virus glycoprotein (VSV-G). Cholesterol supplementation before and during vector production enhanced the infectivity of retroviral and lentiviral vectors up to 4-fold and 6-fold, respectively. In contrast, the amount of retroviral vector produced was unchanged, and that of lentiviral vector was increased less than two-fold. Both free cholesterol and cholesterol ester content in 293-gag-pol producer cells increased with cholesterol addition. In contrast, the phospholipids headgroup composition was essentially unchanged by cholesterol supplementation in 293-gag-pol packaging cells. Based on these results, it is proposed that cholesterol supplementation increases the infectivity of VSV-G pseudotyped retroviral and lentiviral vectors, possibly by altering the composition of the producer cell membrane where the viral vectors are assembled and bud, and/or by changing the lipid composition of the viral vectors. PMID- 20160853 TI - Platinum(II) Enyne Cycloisomerization Catalysis: Intermediates and Resting States. AB - In situ generated [(PPP)Pt][BF(4)](2) (PPP = triphos) catalyzes the cycloisomerization of 1,6-enyne-ols by initiative pi-activation of the alkyne. This generates an isolable cationic Pt-alkenyl species which subsequently participates in turnover limiting protonolysis with in situ generated acid. This latter reactivity contrasts cationic Pt-alkyls which are more difficult to protonolyze. Mechanistic studies on isolated Pt-alkenyls, and deuterium labeling helped to elucidate the mechanistic details. PMID- 20160855 TI - Formation of six- vs. five-membered cyclic sulfones by C-H insertion. AB - Selectivity of six- vs. five- membered ring formation in C-H insertion on alkylsulfonyl diazoacetates is sensitive to the substrate structure and catalyst used. PMID- 20160856 TI - Reactions of Trimethylsilyl Fluorosulfonyldifluoroacetate with Purine and Pyrimidine Nucleosides. AB - Difluorocarbene, generated from trimethylsilyl fluorosulfonyldifluoroacetate (TFDA), reacts with the uridine and adenosine substrates preferentially at the enolizable amide moiety of the uracil ring and the 6-amino group of the purine ring. 2',3'-Di-O-acetyl-3'-deoxy-3'-methyleneuridine reacts with TFDA to produce 4-O-difluoromethyl product derived from an insertion of difluorocarbene into the 4-hydroxyl group of the enolizable uracil ring. Reaction of the difluorocarbene with the adenosine substrates having the unprotected 6-amino group in the purine ring produced the 6-N-difluoromethyl derivative, while reaction with 6-N-benzoyl protected adenosine analogues gave the difluoromethyl ether product derived from the insertion of difluorocarbene into the enol form of the 6-benzamido group. Treatment of the 6-N-phthaloyl protected adenosine analogues with TFDA resulted in the unexpected one-pot conversion of the imidazole ring of the purine into the corresponding N-difluoromethylthiourea derivatives. Treatment of the suitably protected pyrimidine and purine nucleosides bearing an exomethylene group at carbons 2', 3' or 4' of the sugar rings with TFDA afforded the corresponding spirodifluorocyclopropyl analogues but in low yields. PMID- 20160857 TI - Improved Estimation in Multiple Linear Regression Models with Measurement Error and General Constraint. AB - In this paper, we define two restricted estimators for the regression parameters in a multiple linear regression model with measurement errors when prior information for the parameters is available. We then construct two sets of improved estimators which include the preliminary test estimator, the Stein-type estimator and the positive rule Stein type estimator for both slope and intercept, and examine their statistical properties such as the asymptotic distributional quadratic biases, the asymptotic distributional quadratic risks. We remove the distribution assumption on the error term, which was generally imposed in the literature, but provide a more general investigation of comparison of the quadratic risks for these estimators. Simulation studies illustrate the finite-sample performance of the proposed estimators, which are then used to analyze a dataset from the Nurses Health Study. PMID- 20160858 TI - Introduction: Environment and Child Well-being. AB - In recent years there has been a growing interest in understanding how the particular environment in which children and youth develop affect later outcomes. The articles in this special issue all examine ways in which the larger environment is related to children's well-being. In this introduction, we describe some of the historical research "highlights" showing how the environment affects well-being from several disciplines, discuss current trends in environmentally-based research, provide a short review of the literature on the effects of the environment for children and review, and discuss remaining challenges. PMID- 20160859 TI - Annual variation in vocal performance and its relationship with bill morphology in Lincoln's sparrows. AB - Morphology may affect behavioural performance through a direct, physical link or through indirect, secondary mechanisms. Although some evidence suggests that the bill morphology of songbirds directly constrains vocal performance, bill morphology may influence vocal performance through indirect mechanisms also, such as one in which morphology influences foraging and thus the ability to perform some types of vocal behaviour. This raises the possibility for ecologically induced variation in the relationship between morphology and behaviour. To investigate this, I used an information theoretic approach to examine the relationship between bill morphology and several measures of vocal performance in Lincoln's sparrows (Melospiza lincolnii). I compared this relationship between two breeding seasons that differed markedly in ambient temperatures, phenology of habitat maturation, and food abundance. I found a strong curvilinear relationship between bill shape (height/width) and vocal performance in the seemingly less hospitable season but not in the other, leading to a difference between seasons in the population's mean vocal performance. Currently, I do not know the cause of this annual variation. However, it could be due to the effects of bill shape on foraging and therefore on time budget, energy balance, or some other behavioural or physiological response that manifests mostly under difficult environmental conditions or, alternatively, to associations between male quality and both vocal performance and bill shape. Regardless of the cause, these results suggest the presence of an indirect, ecologically mediated link between morphology and behavioural performance, leading to annual variation in the prevailing environment of acoustic signals. PMID- 20160860 TI - Nanoscale assembly of amine functionalized colloidal iron oxide. AB - We demonstrate a single-step facile approach for highly water stable assembly of amine-functionalized Fe(3)O(4) nanoparticles using thermal decomposition of Fe chloride precursors in ethylene glycol medium in the presence of ethylenediamine. The average size of nanoassemblies is 40+/-1 nm, wherein the individual nanoparticles are about 6 nm. Amine functionalized properties are evident from FTIR, thermal and elemental analysis. The saturation magnetization and spin-echo r(2) of the nanoassemblies were measured to be 64.3 emu/g and 314.6 mM(-1)s(-1), respectively. The higher value of relaxivity ratio (r(2)/r(1)=143) indicates that nanoassemblies are a promising high efficiency T2 contrast agent platform. PMID- 20160861 TI - Flexible Thick-Film Electrochemical Sensors: Impact of Mechanical Bending and Stress on the Electrochemical Behavior. AB - The influence of the mechanical bending, rolling and crimping of flexible screen printed electrodes upon their electrical properties and electrochemical behavior has been elucidated. Three different flexible plastic substrates, Mylar, polyethylene naphthalate (PEN), and Kapton, have been tested in connection to the printing of graphite ink working electrodes. Our data indicate that flexible printed electrodes can be bent to extremely small radii of curvature and still function well, despite a marginal increase the electrical resistance. Below critical radii of curvature of ~8 mm, full recovery of the electrical resistance occurs upon strain release. The electrochemical response is maintained for sub-mm bending radii and a 180 degrees pinch of the electrode does not lead to device failure. The electrodes appear to be resistant to repeated bending. Such capabilities are demonstrated using model compounds, including ferrocyanide, trinitrotoluene (TNT) and nitronaphthalene (NN). These printed electrodes hold great promise for widespread applications requiring flexible, yet robust non planar sensing devices. PMID- 20160862 TI - A mixture model approach for the analysis of small exploratory microarray experiments. AB - The microarray is an important and powerful tool for prescreening of genes for further research. However, alternative solutions are needed to increase power in small microarray experiments. Use of traditional parametric and even non parametric tests for such small experiments lack power and have distributional problems. A mixture model is described that is performed directly on expression differences assuming that genes in alternative treatments are expressed or not in all combinations (i) not expressed in either condition, (ii) expressed only under the first condition, (iii) expressed only under the second condition, and (iv) expressed under both conditions, giving rise to 4 possible clusters with two treatments. The approach is termed a Mean-Difference-Mixture-Model (MD-MM) method. Accuracy and power of the MD-MM was compared to other commonly used methods, using both simulations, microarray data, and quantitative real time PCR (qRT-PCR). The MD-MM was found to be generally superior to other methods in most situations. The advantage was greatest in situations where there were few replicates, poor signal to noise ratios, or non-homogenous variances. PMID- 20160863 TI - HANDLING MISSING DATA BY DELETING COMPLETELY OBSERVED RECORDS. AB - When data are missing, analyzing records that are completely observed may cause bias or inefficiency. Existing approaches in handling missing data include likelihood, imputation and inverse probability weighting. In this paper, we propose three estimators inspired by deleting some completely observed data in the regression setting. First, we generate artificial observation indicators that are independent of outcome given the observed data and draw inferences conditioning on the artificial observation indicators. Second, we propose a closely related weighting method. The proposed weighting method has more stable weights than those of the inverse probability weighting method (Zhao and Lipsitz, 1992). Third, we improve the efficiency of the proposed weighting estimator by subtracting the projection of the estimating function onto the nuisance tangent space. When data are missing completely at random, we show that the proposed estimators have asymptotic variances smaller than or equal to the variance of the estimator obtained from using completely observed records only. Asymptotic relative efficiency computation and simulation studies indicate that the proposed weighting estimators are more efficient than the inverse probability weighting estimators under wide range of practical situations especially when when the missingness proportion is large. PMID- 20160864 TI - Bionectriol A, a polyketide glycoside from the fungus Bionectria sp. associated with the fungus-growing ant, Apterostigma dentigerum. AB - A new polyketide glycoside, bionectriol A (1), was produced by a fungal culture of Bionectria sp., which was isolated from a fungus garden of the fungus-growing ant Apterostigma dentigerum, in Costa Rica. The structure of bionectriol A was determined mainly through NMR and mass spectroscopic data, as well as UV and IR spectra. The relative configurations of the main chain, the pyranohexose, and the pentitol moiety were elucidated by (1)H-(1)H coupling constants and ROESY NMR spectral analysis. PMID- 20160865 TI - Metabolic Depression is Delayed and Mitochondrial Impairment Averted during Prolonged Anoxia in the ghost shrimp, Lepidophthalmus louisianensis (Schmitt, 1935). AB - Lepidophthalmus louisianensis burrows deeply into oxygen-limited estuarine sediments and is subjected to extended anoxia at low tides. Large specimens (>2 g) have a lethal time for 50% mortality (LT(50)) of 64 h under anoxia at 25o C. Small specimens (<1 g) have a significantly higher LT(50) of 113 h, which is the longest ever reported for a crustacean. Whole body lactate levels rise dramatically under anoxia and exceed 120 umol g.f.w.(-1) by 72 h. ATP, ADP, and AMP do not change during 48 h of anoxia, but arginine phosphate declines by over 50%. Thus arginine phosphate may help stabilize the ATP pool. Surprisingly, when compared to the aerobic resting rate, ATP production under anoxia is unchanged during the first 12 h, and drops to only about 50% between 12 and 48 h. Finally, after 48 h of anoxia, a major metabolic depression to less than 5% occurs. Downregulation of metabolism is delayed in L. louisianensis compared to many invertebrates that exhibit facultative anaerobiosis. Bioenergetic constraints as a result of eventual metabolic depression led to ionic disturbances like calcium overload and compromised membrane potential of mitochondria. Because these phenomena trigger apoptosis in mammalian species, we evaluated the susceptibility of ghost shrimp mitochondria to opening of the mitochondrial permeability transition pore (MPTP) and associated damage. Energized mitochondria isolated from hepatopancreas possess a pronounced capacity for calcium uptake. Exogenous calcium does not stimulate opening of the MPTP, which potentially could reduce cell death during prolonged anoxia. PMID- 20160866 TI - Optimization techniques in molecular structure and function elucidation. AB - This paper discusses recent optimization approaches to the protein side-chain prediction problem, protein structural alignment, and molecular structure determination from X-ray diffraction measurements. The machinery employed to solve these problems has included algorithms from linear programming, dynamic programming, combinatorial optimization, and mixed-integer nonlinear programming. Many of these problems are purely continuous in nature. Yet, to this date, they have been approached mostly via combinatorial optimization algorithms that are applied to discrete approximations. The main purpose of the paper is to offer an introduction and motivate further systems approaches to these problems. PMID- 20160868 TI - Wavelength Dependence On The Level Of Post-Source Metastable Ion Decay Observed In Infrared Matrix-Assisted Laser Desorption Ionization. AB - The levels of post-source metastable ion decay (PSD) observed in several peptides and proteins ionized by matrix-assisted laser desorption ionization time-of flight mass spectrometry (MALDI TOF-MS) are measured utilizing both infrared (IR) and ultraviolet (UV) desorption wavelengths. A gridless deceleration ion optic is employed to temporally separate stable analyte ions from analyte metastable neutral and ion fragments. Comparisons of the extent of PSD that is observed in UV-MALDI at 337 nm and IR-MALDI at multiple wavelengths between 2.8 and 3.0 mum are made using the same matrices and analytes. The amount of PSD observed using IR-MALDI was found to be highly dependent on the specific IR wavelength (2.8-3.0 mum) employed for desorption. IR wavelengths shorter than 2.86 mum tended to produce higher levels of PSD, while longer IR wavelengths typically produced significantly less PSD when using a number of common MALDI matrices. Relative PSD levels are quantified by determining the percentage of the neutral fragment signal intensity to the intensity of the stable singly protonated molecular species observed in decelerated MALDI spectra. These studies suggest that an analyte ion activation pathway leading to significant PSD in IR-MALDI may proceed by way of vibrational excitation of the analyte molecules during the desorption event. PMID- 20160867 TI - Molecular biomarkers in stroke diagnosis and prognosis. AB - Serum biomarkers related to the cascade of inflammatory, hemostatic, glial and neuronal perturbations have been identifed to diagnose and characterize intracerebral hemorrhage and cerebral ischemia. Interpretation of most markers is confounded by their latent rise, blood-brain barrier effects, the heterogeneity of etiologies and the wide range of normal values, limiting their application for early diagnosis, lesion size estimation and long-term outcome prediction. Certain hemostatic and inflammatory constituents have been found to predict response to thrombolysis and worsening due to infarct progression and secondary hemorrhage, offering a potential role for improved treatment selection and individualization of therapy. Biomarkers will become increasingly relevant for developing targets for neuroprotective therapies, monitoring response to treatment and as surrogate end points for treatment trials. PMID- 20160869 TI - Rejection sensitivity and disruption of attention by social threat cues. AB - Two studies tested the hypothesis that Rejection Sensitivity (RS) increases vulnerability to disruption of attention by social threat cues, as would be consistent with prior evidence that it motivates individuals to prioritize detecting and managing potential rejection at a cost to other personal and interpersonal goals. In Study 1, RS predicted disruption of ongoing goal-directed attention by social threat but not negative words in an Emotional Stroop task. In Study 2, RS predicted attentional avoidance of threatening but not pleasant faces in a Visual Probe task. Threat-avoidant attention was also associated with features of borderline personality disorder. This research extends understanding of processes by which RS contributes to a self-perpetuating cycle of interpersonal problems and distress. PMID- 20160870 TI - Buffer Standards for the Physiological pH of the Zwitterionic Compound, DIPSO from 5 to 55 degrees C. AB - The values of the second dissociation constant, pK(2), and related thermodynamic quantities of 3-[N,N-bis (2-hydroxyethyl)amino]-2-hydroxypropanesulfonic acid (DIPSO) have already been reported over the temperature range 5 to 55 degrees C including 37 degrees C. This paper reports the pH values of four NaCl-free buffer solutions and four buffer composition containing NaCl salt at I = 0.16 mol.kg( 1). Conventional pa(H) values are reported for all eight buffer solutions. The operational pH values have been calculated for four buffer solutions recommended as pH standards, at 25 and 37 degrees C after correcting the liquid junction potentials with the flowing junction cell. PMID- 20160871 TI - PARENTING AND ADOLESCENTS' SEXUAL INITIATION. AB - This study draws on social control and social learning theories to examine the role of dating-specific attitudes and practices as predictors of adolescents' sexual initiation. We include attention to the adolescent's reaction to control attempts as a further means of assessing family dynamics (i.e., frequency of dating disagreements). The study uses longitudinal data from 697 adolescents who were not sexually active at the first interview as well as separate interviews with parents. In models that include all parenting variables, parental caring, parents' preferences that the child should delay sex, and the frequency of dating disagreements are significant predictors of initiation of teen sexual activity. PMID- 20160872 TI - Application of Ultrasound for Targeted Nanotherapy of Malignant Tumors. AB - The article describes the study of targeted chemotherapeutic intervention on solid tumors by means of ultrasound and doxorubicin- or paclitaxel-loaded perfluoropentane nanoemulsions. Nanodroplets of the emulsions accumulated in a tumor by passive targeting. Under the action of a tumor-directed therapeutic ultrasound, the nanodroplets converted into vapor microbubbles. In vivo, the nanodroplets strongly retained the loaded drugs; yet, under ultrasound-mediated vaporization they released the drugs into the tumor tissue, thereby implementing effective targeting into the tumor. The tumors subjected to this treatment regressed effectively; however, after some time they recurred. The recurring tumors were more resistant to the repeated therapy than the primary ones. At present, the causes of of the resistance development and methods for its elimination are unclear and they are under investigation. PMID- 20160873 TI - Acceleration of Ungapped Extension in Mercury BLAST. AB - The amount of biosequence data being produced each year is growing exponentially. Extracting useful information from this massive amount of data efficiently is becoming an increasingly difficult task. There are many available software tools that molecular biologists use for comparing genomic data. This paper focuses on accelerating the most widely used such tool, BLAST. Mercury BLAST takes a streaming approach to the BLAST computation by off loading the performance critical sections to specialized hardware. This hardware is then used in combination with the processor of the host system to deliver BLAST results in a fraction of the time of the general-purpose processor alone.This paper presents the design of the ungapped extension stage of Mercury BLAST. The architecture of the ungapped extension stage is described along with the context of this stage within the Mercury BLAST system. The design is compact and runs at 100 MHz on available FPGAs, making it an effective and powerful component for accelerating biosequence comparisons. The performance of this stage is 25* that of the standard software distribution, yielding close to 50* performance improvement on the complete BLAST application. The sensitivity is essentially equivalent to that of the standard distribution. PMID- 20160874 TI - Animal models of anorexia and cachexia. AB - BACKGROUND: Cachexia is a devastating syndrome of body wasting that worsens quality of life and survival for patients suffering from diseases such as cancer, chronic kidney disease and chronic heart failure. Successful treatments have been elusive in humans, leaving a clear need for the development of new treatment compounds. Animal models of cachexia are able to recapitulate the clinical findings from human disease and have provided a much-needed means of testing the efficacy of prospective therapies. OBJECTIVE: This review focuses on animal models of cachexia caused by cancer, chronic heart failure and chronic kidney disease, including the features of these models, their implementation, and commonly-followed outcome measures. CONCLUSION: Given a dire clinical need for effective treatments of cachexia, animal models will continue a vital role in assessing the efficacy and safety of potential treatments prior to testing in humans. Also important in the future will be the use of animal models to assess the durability of effect from anti-cachexia treatments and their effect on prognosis of the underlying disease states. PMID- 20160876 TI - Buffer Standards for the Biochemical pH of 3-(N-morpholino)-2 hydroxypropanesulfonic Acid from (278.15 to 328.15) K. AB - The values of the second dissociation constant pK(2) and related thermodynamic quantities of the ampholyte 3-(N-morpholino)-2-hydroxypropanesulfonic acid (MOPSO) have been previously determined at temperatures from (278.15 to 328.15) K. In this study, the pH values of two buffer solutions without NaCl and three buffer solutions with NaCl having ionic strengths (I = 0.16 mol.kg(-1)) similar to those in blood plasma, have been evaluated at 12 temperatures from (278.15 to 328.15) K using an extended form of the Debye-Huckel equation, since the Bates Guggenheim convention is valid up to I = 0.1 mol.kg(-1). The liquid junction potentials (E(j)) between the buffer solutions of MOPSO and saturated KCl solution of the calomel electrode at (298.15 and 310.15) K have been estimated by measurement with a flowing junction cell. These values of E(j) have been used to ascertain the operational pH values at (298.15 and 310.15) K. Three buffer solutions of MOPSO are recommended as useful reference solutions for pH measurements in saline media of ionic strength I = 0.16 mol.kg(-1). PMID- 20160877 TI - DESIGN OF LIPOSOMES CONTAINING PHOTOPOLYMERIZABLE PHOSPHOLIPIDS FOR TRIGGERED RELEASE OF CONTENTS. AB - We describe a novel class of light-triggerable liposomes prepared from a photo polymerizable phospholipid DC(8,9)PC (1,2- bis (tricosa-10,12-diynoyl)-sn-glycero 3-phosphocholine) and DPPC (1,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine). Exposure to UV (254 nm) radiation for 0-45 minutes at 25 degrees C resulted in photo-polymerization of DC(8,9)PC in these liposomes and the release of an encapsulated fluorescent dye (calcein). Kinetics and extents of calcein release correlated with mol% of DC(8,9)PC in the liposomes. Photopolymerization and calcein release occurred only from DPPC/DC(8,9)PC but not from Egg PC/DC(8,9)PC liposomes. Our data indicate that phase separation and packing of polymerizable lipids in the liposome bilayer are major determinants of photo-activation and triggered contents release. PMID- 20160878 TI - NIR-responsive silica-coated NaYbF(4):Er/Tm/Ho upconversion fluorescent nanoparticles with tunable emission colors and their applications in immunolabeling and fluorescent imaging of cancer cells. AB - NaYbF(4): RE upconversion (UC) fluorescent nanoparticles (NPs) were synthesized with variable rare-earth dopants (RE= Er(3+), Tm(3+), or Ho(3+), or a combination of these ions), from rare-earth stearate precursors in a water-ethanol-oleic acid system by using a two-phase solvothermal method. The NPs were shown to emit visible light such as orange, yellow, green, cyan, blue or pink light in response to near infrared (NIR) irradiation, and their emission colors could be simply tuned by changing either the co-dopant concentration or dopant species. The UC NPs were well-dispersed and spherical with an average size of 15~35 nm. They emitted strong UC fluorescence under the 980 nm NIR excitation. The effects of solvothermal reaction time and temperature on nanoparticle size and phase structure as well as UC fluorescence intensity were systematically studied. Water dispersibility was achieved by forming a silica coat on the surface of the UC NPs. After animo-functionalization, the silica-coated UC NPs were chemically conjugated with the rabbit anti-CEA8 antibody and then used as fluorescent biolabels for the immunolabeling and imaging of HeLa cells. The NIR-responsive multicolor visible light emission of these UC NPs will enable potential applications in biolabeling and multiplexed analysis because NIR light can penetrate tissue as deep as several inches and is safe to human body. PMID- 20160879 TI - An Evaluation of Explicit Receptor Flexibility in Molecular Docking Using Molecular Dynamics and Torsion Angle Molecular Dynamics. AB - Incorporating receptor flexibility into molecular docking should improve results for flexible proteins. However, the incorporation of explicit all-atom flexibility with molecular dynamics for the entire protein chain may also introduce significant error and "noise" that could decrease docking accuracy and deteriorate the ability of a scoring function to rank native-like poses. We address this apparent paradox by comparing the success of several flexible receptor models in cross-docking and multiple receptor ensemble docking for p38alpha mitogen-activated protein (MAP) kinase. Explicit all-atom receptor flexibility has been incorporated into a CHARMM-based molecular docking method (CDOCKER) using both molecular dynamics (MD) and torsion angle molecular dynamics (TAMD) for the refinement of predicted protein-ligand binding geometries. These flexible receptor models have been evaluated, and the accuracy and efficiency of TAMD sampling is directly compared to MD sampling. Several flexible receptor models are compared, encompassing flexible side chains, flexible loops, multiple flexible backbone segments, and treatment of the entire chain as flexible. We find that although including side chain and some backbone flexibility is required for improved docking accuracy as expected, docking accuracy also diminishes as additional and unnecessary receptor flexibility is included into the conformational search space. Ensemble docking results demonstrate that including protein flexibility leads to to improved agreement with binding data for 227 active compounds. This comparison also demonstrates that a flexible receptor model enriches high affinity compound identification without significantly increasing the number of false positives from low affinity compounds. PMID- 20160880 TI - Comparison of the Relative Reactivities of the Triisopropylsilyl Group With Two Fluorous Analogs. AB - The relative stabilities of two fluorous analogs, diisopropyl(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl)silyl and diisopropyl-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadeca-fluoroundecyl)silyl [C(8)F(17)(CH(2))(n)Si(i-Pr)(2), where n = 2 or 3], of the standard triisopropylsilyl (TIPS) group are compared in the setting of alcohol protection. The fluorous silyl groups can be installed under standard conditions in comparable yields to the TIPS group, but the derived fluorous silyl ethers are more labile than TIPS ethers towards cleavage by both acids and fluoride. PMID- 20160875 TI - Adenoviral vector-based strategies for cancer therapy. AB - Definitive treatment of cancer has eluded scientists for decades. Current therapeutic modalities like surgery, chemotherapy, radiotherapy and receptor targeted antibodies have varied degree of success and generally have moderate to severe side effects. Gene therapy is one of the novel and promising approaches for therapeutic intervention of cancer. Viral vectors in general and adenoviral (Ad) vectors in particular are efficient natural gene delivery systems and are one of the obvious choices for cancer gene therapy. Clinical and preclinical findings with a wide variety of approaches like tumor suppressor and suicide gene therapy, oncolysis, immunotherapy, anti-angiogenesis and RNA interference using Ad vectors have been quite promising, but there are still many hurdles to overcome. Shortcomings like increased immunogenicity, prevalence of preexisting anti-Ad immunity in human population and lack of specific targeting limit the clinical usefulness of Ad vectors. In recent years, extensive research efforts have been made to overcome these limitations through a variety of approaches including the use of conditionally-replicating Ad and specific targeting of tumor cells. In this review, we discuss the potential strengths and limitations of Ad vectors for cancer therapy. PMID- 20160881 TI - Design and Integration of a Telerobotic System for Minimally Invasive Surgery of the Throat. AB - This paper presents the clinical motivation, design specifications, kinematics, statics, and actuation compensation for a newly constructed telerobotic system for Minimally Invasive Surgery (MIS) of the throat. A hybrid dual-arm telesurgical slave, with twenty joint-space Degrees of Freedom (DoF), is used in this telerobotic system to provide the necessary dexterity in deep surgical fields such as the throat. The telerobotic slave uses novel continuum robots that use multiple super-elastic backbones for actuation and structural integrity. The paper presents the kinematics of the telesurgical slave and methods for actuation compensation to cancel the effects of backlash, friction, and flexibility of the actuation lines. A method for actuation compensation is presented in order to overcome uncertainties of modeling, friction, and backlash. This method uses a tiered hierarchy of two novel approaches of actuation compensation for remotely actuated snake-like robots. The tiered approach for actuation compensation uses compensation in both joint space and configuration space of the continuum robots. These actuation hybrid compensation schemes use intrinsic model information and external data through a recursive linear estimation algorithm and involve compensation using configuration space and joint space variables. Experimental results validate the ability of our integrated telemanipulation system through experiments of suturing and knot tying in confined spaces. PMID- 20160882 TI - Composite block polymer-microfabricated silicon nanoporous membrane. AB - Block polymers offer an attractive route to densely packed, monodisperse nanoscale pores. However, their fragility as thin films complicates their use as membranes. By integrating a block polymer film with a thin (100 microm) silicon substrate, we have developed a composite membrane providing both nanoscale size exclusion and fast transport of small molecules. Here we describe the fabrication of this membrane, evaluate its mechanical integrity, and demonstrate its transport properties for model solutes of large and small molecular weight. The ability to block large molecules without hindering smaller ones, coupled with the potential for surface modification of the polymer and the microelectromechanical system style of support, makes this composite membrane an attractive candidate for interfacing implantable sensing and drug-delivery devices with biological hosts. PMID- 20160883 TI - Synchronized Current Oscillations of Formic Acid Electro-oxidation in a Microchip based Dual-Electrode Flow Cell. AB - We investigate the oscillatory electro-oxidation of formic acid on platinum in a microchip-based dual-electrode cell with microfluidic flow control. The main dynamical features of current oscillations on single Pt electrode that had been observed in macro-cells are reproduced in the microfabricated electrochemical cell. In dual-electrode configuration nearly in-phase synchronized current oscillations occur when the reference/counter electrodes are placed far away from the microelectrodes. The synchronization disappears with close reference/counter electrode placements. We show that the cause for synchronization is weak albeit important, bidirectional electrical coupling between the electrodes; therefore the unidirectional mass transfer interactions are negligible. The experimental design enables the investigation of the dynamical behavior in micro-electrode arrays with well-defined control of flow of the electrolyte in a manner where the size and spacing of the electrodes can be easily varied. PMID- 20160884 TI - New Architectures in Hydrogen Bond Catalysis. AB - New achiral sulfamide, phosphoric triamide, and thiophosphoric triamide compounds have been synthesized. Their activity as hydrogen bond catalysts for the Friedel Crafts and Baylis-Hillman reactions compares favorably with that of a known and active thiourea catalyst. The new compounds were also studied by X-ray crystallography and their solid state structures are described. PMID- 20160885 TI - Context Specific Mental Health Services for Children in Foster Care. AB - Although a high proportion of foster children receive mental health services, existing research suggests limited accessibility and effectiveness of these services. This paper discusses strategies to develop a model to deliver evidence based services using the unique opportunities apparent within publicly funded child welfare systems. An ecologically-focused model providing enhanced services in children's homes and schools could capitalize on these opportunities and radically improve access and effectiveness of mental health services for foster children. We present data from four focus groups conducted with foster parents, caseworkers, and therapists to understand the feasibility of implementing this type of service model. Results support the need for services focused on enhancing interactions in children's foster homes and schools, but also suggest that issues related to priorities and primary roles could limit the extent that caseworkers and agency-based mental health providers would follow through with the proposed service model. PMID- 20160886 TI - Quantitative differentiation of dyes with overlapping one-photon spectra by femtosecond pulse shaping. AB - We demonstrate that DiI and Rhodamine B, which are not easily distinguishable to one-photon measurements, can be differentiated and in fact quantified in mixture via tailored two-photon excitation pulses found by a genetic algorithm (GA). A nearly three-fold difference in the ratio of two-photon fluorescence of the two dyes is achieved, without a drop in signal of the favored fluorophore. Implementing an acousto-optic interferometer, we were able to prove that the mechanism of discrimination is second-harmonic tuning by the phase-shaped pulses to the relative maxima and minima of these cross-sections. PMID- 20160887 TI - The Optimal Linear Combination of Multiple Predictors Under the Generalized Linear Models. AB - Multiple alternative diagnostic tests for one disease are commonly available to clinicians. It's important to use all the good diagnostic predictors simultaneously to establish a new predictor with higher statistical utility. Under the generalized linear model for binary outcomes, the linear combination of multiple predictors in the link function is proved optimal in the sense that the area under the receiver operating characteristic (ROC) curve of this combination is the largest among all possible linear combination. The result was applied to analysis of the data from the Study of Osteoporotic Fractures (SOF) with comparison to Su and Liu's approach. PMID- 20160888 TI - Latest advances in innate antiviral defence. AB - Recent identification of key components in the pattern recognition receptor pathway of retinoic acid-inducible gene-1-like receptors, coupled with characterisation of a new cytoplasmic DNA-sensing molecule, have led to a greater understanding of the role viral nucleic acids play in activating innate immunity. This activation of type I interferon is essential for both limiting viral infection and stimulating activation of the adaptive immune response. PMID- 20160889 TI - Associative Classification of Mammograms using Weighted Rules. AB - In this paper, we present a novel method for the classification of mammograms using a unique weighted association rule based classifier. Images are preprocessed to reveal regions of interest. Texture components are extracted from segmented parts of the image and discretized for rule discovery. Association rules are derived between various texture components extracted from segments of images, and employed for classification based on their intra- and inter-class dependencies. These rules are then employed for the classification of a commonly used mammography dataset, and rigorous experimentation is performed to evaluate the rules' efficacy under different classification scenarios. The experimental results show that this method works well for such datasets, incurring accuracies as high as 89%, which surpasses the accuracy rates of other rule based classification techniques. PMID- 20160890 TI - Non-linear Models for Longitudinal Data. AB - While marginal models, random-effects models, and conditional models are routinely considered to be the three main modeling families for continuous and discrete repeated measures with linear and generalized linear mean structures, respectively, it is less common to consider non-linear models, let alone frame them within the above taxonomy. In the latter situation, indeed, when considered at all, the focus is often exclusively on random-effects models. In this paper, we consider all three families, exemplify their great flexibility and relative ease of use, and apply them to a simple but illustrative set of data on tree circumference growth of orange trees. PMID- 20160891 TI - Localized Ectopic Expression of Dpp Receptors in a Drosophila Embryo. AB - Receptor-mediated BMP degradation has been seen to play an important role in allowing for the formation of relatively stable P Mad patterns. To the extent that receptors act as a "sink" for BMPs, one would predict that the localized over-expression of signaling receptors would cause a net flux of freely diffused BMPs toward the ectopic, i.e., abnormally high concentration, receptor site. One possible consequence would be a depression of BMP signaling in adjacent areas since less BMPs are now available for binding with the same normal concentration of receptors at the adjacent areas. However, recent experiments designed to examine this possible effect were inconclusive. In this paper, we investigate the possibility of depression of Dpp signaling outside the area of elevated tkv in a Drosophila embryo by modeling mathematically the basic biological processes at work in terms of a system of nonlinear reaction diffusion equations with spatially varying (and possibly discontinuous) system properties. The steady state signaling morphogen gradient is investigated by the method of matched asymptotic expansions and by numerical simulations. PMID- 20160892 TI - Inexact Matching of Ontology Graphs Using Expectation-Maximization. AB - We present a new method for mapping ontology schemas that address similar domains. The problem of ontology matching is crucial since we are witnessing a decentralized development and publication of ontological data. We formulate the problem of inferring a match between two ontologies as a maximum likelihood problem, and solve it using the technique of expectation-maximization (EM). Specifically, we adopt directed graphs as our model for ontology schemas and use a generalized version of EM to arrive at a map between the nodes of the graphs. We exploit the structural, lexical and instance similarity between the graphs, and differ from the previous approaches in the way we utilize them to arrive at, a possibly inexact, match. Inexact matching is the process of finding a best possible match between the two graphs when exact matching is not possible or is computationally difficult. In order to scale the method to large ontologies, we identify the computational bottlenecks and adapt the generalized EM by using a memory bounded partitioning scheme. We provide comparative experimental results in support of our method on two well-known ontology alignment benchmarks and discuss their implications. PMID- 20160893 TI - Sham Transcranial Magnetic Stimulation Using Electrical Stimulation of the Scalp. AB - BACKGROUND: Most methods of sham, repetitive transcranial magnetic stimulation (rTMS) fail to replicate the look, sound, and feel of active stimulation in the absence of a significant magnetic field. OBJECTIVE/HYPOTHESIS: To develop and validate a new method of sham rTMS appropriate for a double-blind, placebo controlled study with subject crossover. METHODS: The look and sound of active rTMS was replicated using a matched, air-cooled sham TMS coil. Scalp muscle stimulation associated with rTMS was replicated using large rubber electrodes placed over selected muscles. The intensity and pulse width of electrical stimulation necessary to match 1-Hz rTMS was developed in one sample of normal subjects. The sham technique was validated in back-to-back comparisons with active rTMS in new samples of normal subjects who were either naive or experienced with rTMS. RESULTS: Subjects naive to TMS could not tell which type of stimulation was active or sham or which was electrical or magnetic. Naive subjects incorrectly picked sham stimulation as active, when forced to choose, because electrical stimulation felt more focused than magnetic stimulation. Subjects experienced with TMS could correctly identify sham and active stimulation. Experimenters could detect subtle differences between conditions. CONCLUSIONS: This method of sham rTMS closely mimics the look, sound, and feel of active stimulation at 1Hz without creating a significant magnetic field. It is valid for use with naive subjects and in crossover studies. It can accommodate differences in scalp muscle recruitment at different sites of stimulation, and it could potentially be used with higher frequency stimulation. PMID- 20160894 TI - An Efficient, Microwave-Assisted, One-Pot Synthesis of Indoles Under Sonogashira Conditions. AB - A microwave-assisted, one-pot, three-component coupling reaction for the synthesis of indoles has been developed. The reaction is carried out in two steps under standard Sonogashira coupling conditions from an N-substituted/N,N disubstituted 2-iodoaniline and a terminal alkyne, followed by the addition of acetonitrile and an aryl iodide. A variety of polysubstituted indoles have been prepared in moderate to excellent yields using the present method. PMID- 20160895 TI - Spontaneous onset of atrial fibrillation. AB - Most commonly, atrial fibrillation is triggered by rapid bursts of electrical impulses originating in the myocardial sleeves of pulmonary veins (PVs). However, the nature of such bursts remains poorly understood. Here, we propose a mechanism of bursting consistent with the extensive empirical information about the electrophysiology of the PVs. The mechanism is essentially non-local and involves the spontaneous initiation of non-sustained spiral waves in the distal end of the muscle sleeves of the PVs. It reproduces the experimentally observed dynamics of the bursts, including their frequency, their intermittent character, and the unusual shape of the electrical signals in the pulmonary veins that are reminiscent of so-called early afterdepolarizations (EADs). PMID- 20160897 TI - Studies toward the duocarmycin prodrugs for the antibody prodrug therapy approach. AB - A tricyclic precursor for the synthesis of the prodrugs of pro-1,2,9,9a tetrahydrocyclopropa[c]benz-[e]indole-4-one tetramethoxyindolecarboxamide (CBI TMI) was prepared using the ring-closing metathesis approach. The tricyclic intermediate was converted to an advanced precursor of a CBI-TMI prodrug equipped with a linker presumably suitable for activation using the aldolase catalytic antibody 38C2. An attempted 38C2-catalyzed two-step activation of the hydroxy-pro CBI intermediate involving retro-aldol and the beta-elimination reactions was also examined. PMID- 20160896 TI - Winter Depression: Integrating mood, circadian rhythms, and the sleep/wake and light/dark cycles into a bio-psycho-social-environmental model. AB - The phase shift hypothesis (PSH) states that most patients with SAD become depressed in the winter because of a delay in circadian rhythms with respect to the sleep/wake cycle: According to the PSH, these patients should preferentially respond to the antidepressant effects of bright light exposure when it is scheduled in the morning so as to provide a corrective phase advance and restore optimum alignment between the circadian rhythms tightly coupled to the endogenous circadian pacemaker and those rhythms that are related to the sleep/wake cycle. Recent support for the PSH has come from studies in which symptom severity was shown to correlate with the degree of circadian misalignment: it appears that a subgroup of patients are phase advanced, not phase delayed; however, the phase delayed type is predominant in SAD and perhaps in other disorders as well, such as non-seasonal unipolar depression. It is expected that during the next few years the PSH will be tested in these and other conditions, particularly since healthy subjects appear to have more severe symptoms of sub-clinical dysphoria correlating with phase-delayed circadian misalignment; critically important will be the undertaking of treatment trials to investigate the therapeutic efficacy of morning bright light or afternoon/evening low-dose melatonin in these disorders in which symptoms are more severe as the dim light melatonin onset (DLMO) is delayed with respect to the sleep/wake cycle (non-restorative sleep should also be evaluated, as well as bipolar disorder). The possibility that some individuals (and disorders) will be of the phase-advanced type should be considered, taking into account that the correct timing of phase-resetting agents for them will be bright light scheduled in the evening and/or low-dose melatonin taken in the morning. While sleep researchers and clinicians are accustomed to phase-typing patients with circadian-rhythm sleep disorders according to the timing of sleep, phase typing based on the DLMO with respect to the sleep/wake cycle may lead to quite different recommendations for the optimal scheduling of phase-resetting agents, particularly for the above disorders and conditions. PMID- 20160898 TI - The New Beginnings Program for Divorcing and Separating Families: Moving from Efficacy to Effectiveness. AB - This article describes a program of research on effectively transporting the New Beginnings Program (NBP), a university-tested prevention program for divorced families, to community settings. The status of four steps in this research are described: (1) Selecting a community partner; (2) Developing effective methods of engaging parents; (3) Redesigning the NBP to be easily delivered with high quality and fidelity in community agencies, and (4) Adapting the NBP to meet the needs of the full population of divorcing families. The article concludes with a discussion of plans for an effectiveness trial to evaluate the NBP when delivered in community settings. PMID- 20160899 TI - GENERALIZED PARTIALLY LINEAR MIXED-EFFECTS MODELS INCORPORATING MISMEASURED COVARIATES. AB - In this article we consider a semiparametric generalized mixed-effects model, and propose combining local linear regression, and penalized quasilikelihood and local quasilikelihood techniques to estimate both population and individual parameters and nonparametric curves. The proposed estimators take into account the local correlation structure of the longitudinal data. We establish normality for the estimators of the parameter and asymptotic expansion for the estimators of the nonparametric part. For practical implementation, we propose an appropriate algorithm. We also consider the measurement error problem in covariates in our model, and suggest a strategy for adjusting the effects of measurement errors. We apply the proposed models and methods to study the relation between virologic and immunologic responses in AIDS clinical trials, in which virologic response is classified into binary variables. A dataset from an AIDS clinical study is analyzed. PMID- 20160900 TI - Calcium-independent phospholipase A2 beta is dispensable in inflammasome activation and its inhibition by bromoenol lactone. AB - Calcium-independent phospholipase A2 (iPLA2) has been suggested to play an important role in the activation of caspase-1 induced by lipopolysaccharides (LPS). Here, we used pharmacological and genetic approaches to study the role of iPLA 2 in the activation of caspase-1. Bromoenol lactone (BEL), an inhibitor that was originally used to support a role for iPLA2 in the secretion of IL-1 beta, prevented caspase-1 activation induced by LPS and ATP as described, and also activation triggered by Salmonella infection and cytosolic flagellin, which rely on the Nlrc4 inflammasome. Analysis of BEL enantiomers showed that the S-BEL form was more effective than R-BEL in inhibiting the inflammasome, suggesting a role for iPLA2 . However, caspase-1 activation and IL-1 beta secretion and their inhibition by BEL were unimpaired in macrophages deficient in iPLA2 beta. BEL was originally identified as an inhibitor of serine proteases. Consistent with the latter, the serine proteases inhibitors TPCK, TLCK and AAF-cmk prevented the activation of the Nlrc4 and Nlrp3 inflammasomes while pan-cathepsin inhibitors were ineffective. These results indicate that iPLA2 beta is not critical for caspase-1 activation as currently proposed. Instead, the results suggest that serine protease(s) targeted by BEL may play a critical role in the activation of the inflammasome triggered by microbial stimuli. PMID- 20160901 TI - Tumor targeting and imaging in live animals with functionalized semiconductor quantum rods. AB - In this contribution, we demonstrate that highly luminescent CdSe/CdS/ZnS quantum rods (QRs) coated with PEGylated phospholipids and conjugated with cyclic RGD peptide can be successfully used for tumor targeting and imaging in live animals. The design of these targeted luminescent probes involves encapsulation of hydrophobic CdSe/CdS/ZnS QRs with PEGylated phospholipids, followed by conjugation of these PEGylated phospholipids to ligands that specifically target the tumor vasculature. In vivo optical imaging studies in nude mice bearing pancreatic cancer xenografts, both subcutaneous and orthotopic, indicate that the QR probes accumulate at tumor sites via the cyclic RGD peptides on the QR surface binding to the alpha(V)beta(3) integrins overexpressed in the tumor vasculature, following systemic injection. In vivo tumor detection studies showed no adverse effects even at a dose roughly 6.5 times higher than has been reported for in vivo imaging studies using quantum dots. Cytotoxicity studies indicated the absence of any toxic effect in the cellular and tissue levels arising from functionalized QRs. These results demonstrate the vast potential of QRs as bright, photostable, and biocompatible luminescent probes for the early diagnosis of cancer. PMID- 20160902 TI - Racial/Ethnic Differences in Breastfeeding Initiation and Duration Among Low income, Inner-city Mothers. AB - OBJECTIVES: Despite the promotion of breastfeeding as the "ideal" infant feeding method by health experts, breastfeeding continues to be less common among low income and minority mothers than among other women. This paper investigates how maternal socio-demographic and infant characteristics, household environment, and health behaviors are related to breastfeeding initiation and duration among low income, inner-city mothers, with a specific focus on differences in breastfeeding behavior by race/ethnicity and nativity status. METHODS: Using data from a community-based, longitudinal study of women in Philadelphia, PA (N=1,140), we estimate logistic regression and Cox proportional hazard models to predict breastfeeding initiation and duration. RESULTS: Both foreign-born black mothers and Hispanic mothers (most of whom were foreign-born) were significantly more likely to breastfeed their infants than non-Hispanic white women, findings that were partly explained by foreign-born and Hispanic mothers' prenatal intention to breastfeed. In contrast to previous studies, we also found that native-born black women were more likely to breastfeed than non-Hispanic white women. CONCLUSION: Our findings suggest that when poor whites and African Americans are similarly situated in an inner-city context, the disparity in their behavior with respect to infant feeding is not as distinct as documented in national surveys. Breastfeeding was also more common among low-income immigrant black women than white or native-born black mothers. PMID- 20160903 TI - Quantifying Separate and Unequal: Racial-Ethnic Distributions of Neighborhood Poverty in Metropolitan America. AB - Researchers measuring racial inequality of neighborhood environment across metropolitan areas (MAs) have traditionally employed segregation measures, yet such measures are limited for incorporating a third axis of information, including neighborhood opportunity. Using Census 2000 tract-level data for the largest U.S. MAs, we introduce the interquartile-range overlap statistic to summarize the substantial separation of entire distributions of neighborhood environments between racial groups. We find neighborhood poverty distributions for minorities overlap only 27% with those for whites. Further, the separation of racial groups into neighborhoods of differing poverty rates is strongly correlated with racial residential segregation. The overlap statistic provides a straightforward, policy-relevant metric for monitoring progress towards achieving more equal environments of neighborhood opportunity space. PMID- 20160904 TI - Report of seizure induced by continuous theta burst stimulation. PMID- 20160905 TI - RAPID AND AUTOMATED PROCESSING OF MALDI-FTICR/MS DATA FOR N-METABOLIC LABELING IN A SHOTGUN PROTEOMICS ANALYSIS. AB - Offline high performance liquid chromatography combined with matrix assisted laser desorption and Fourier transform ion cyclotron resonance mass spectrometry (HPLC-MALDI-FTICR/MS) provides the means to rapidly analyze complex mixtures of peptides, such as those produced by proteolytic digestion of a proteome. This method is particularly useful for making quantitative measurements of changes in protein expression by using (15)N-metabolic labeling. Proteolytic digestion of combined labeled and unlabeled proteomes produces complex mixtures that with many mass overlaps when analyzed by HPLC-MALDI-FTICR/MS. A significant challenge to data analysis is the matching of pairs of peaks which represent an unlabeled peptide and its labeled counterpart. We have developed an algorithm and incorporated it into a compute program which significantly accelerates the interpretation of (15)N metabolic labeling data by automating the process of identifying unlabeled/labeled peak pairs. The algorithm takes advantage of the high resolution and mass accuracy of FTICR mass spectrometry. The algorithm is shown to be able to successfully identify the (15)N/(14)N peptide pairs and calculate peptide relative abundance ratios in highly complex mixtures from the proteolytic digest of a whole organism protein extract. PMID- 20160906 TI - Substantial formation of hydrates and hemiacetals from pyridinium ketones. AB - Pyridinium ketones have been found to exist as hydrates and hemiacetals in considerable amount in aqueous and alcoholic solutions, respectively. The relative position of the pyridinium positive charge has a large effect on the equilibrium constants. The polar substituent constants, sigma*, of the pyridinium group substituted at different positions can be estimated from the hydration constants. PMID- 20160907 TI - An Ion Mobility-Mass Spectrometry Investigation of Monocyte Chemoattractant Protein-1. AB - In the present article we describe the gas-phase dissociation behavior of the dimeric form of monocyte chemoattractant protein-1 (MCP-1) using quadrupole traveling wave ion mobility-time of flight mass spectrometry (q-TWIMS-TOF MS) (Waters SynaptTM). Through investigation of the 9(+) charge state of the dimer, we were able to monitor dissociation product ion (monomer) formation as a function of activation energy. Using ion mobility, we were able to observe precursor ion structural changes occurring throughout the activation process. Arrival time distributions (ATDs) for the 5(+) monomeric MCP-1 product ions, derived from the gas-phase dissociation of the 9(+) dimer, were then compared with ATDs obtained for the 5(+) MCP-1 monomer isolated directly from solution. The results show that the dissociated monomer is as compact as the monomer arising from solution, regardless of the trap collision energy (CE) used in the dissociation. The solution-derived monomer, when collisionally activated, also resists significant unfolding within measure. Finally, we compared the collisional activation data for the MCP-1 dimer with an MCP-1 dimer non covalently bound to a single molecule of the semi-synthetic glycosaminoglycan (GAG) analog ArixtraTM; the latter a therapeutic anti-thrombin III-activating pentasaccharide. We observed that while dimeric MCP-1 dissociated at relatively low trap CEs, the Arixtra-bound dimer required much higher energies, which also induced covalent bond cleavage in the bound Arixtra molecule. Both the free and Arixtra-bound dimers became less compact and exhibited longer arrival times with increasing trap CEs, albeit the Arixtra-bound complex at slightly higher energies. That both dimers shifted to longer arrival times with increasing activation energy, while the dissociated MCP-1 monomers remained compact, suggests that the longer arrival times of the Arixtra-free and Arixtra-bound dimers may represent a partial breach of non-covalent interactions between the associated MCP-1 monomers, rather than extensive unfolding of individual subunits. The fact that Arixtra preferentially binds MCP-1 dimers and prevents dimer dissociation at comparable activation energies to the Arixtra-free dimer, may suggest that the drug interacts across the two monomers, thereby inhibiting their dissociation. PMID- 20160908 TI - Constraints on Enhanced Extinction Resulting from Extinction Treatment in the Presence of an Added Excitor. AB - Three Pavlovian fear conditioning experiments with rats as subjects explored the effect of extinction in the presence of a concurrent excitor. Our aim was to explore this particular treatment, documented in previous studies to deepen extinction, with novel control groups to shed light on the processes involved in extinction. Relative to subjects extinguished on the target CS alone, Experiments 1 and 2 found across a range of parameters that any appreciable effect of facilitated extinction due to the concurrent excitor was submerged by generalization decrement going from extinction to testing. In Experiment 3 we used different durations for the target and concurrent stimuli in order to discourage configuring and an ABC renewal design to increase sensitivity, and observed diminished renewal resulting from extinction in the presence of a second excitor. Our findings suggest that there are distinct limits to the observation of extinction in the presence of an excitor and identifies some of the sources of these limitations. PMID- 20160909 TI - Organometallic ruthenium complexes with thiosemicarbazone ligands: Synthesis, structure and cytotoxicity of [(eta-p-cymene)Ru(NS)Cl] (NS = 9-anthraldehyde thiosemicarbazones). AB - A series of half-sandwich arene-ruthenium complexes of the type [(eta(6)-p cymene) Ru(thiosemicarbazone)Cl](+) have been synthesized and their biological activity investigated. The first structurally characterized arene-ruthenium half sandwich complex with a thiosemicarbazone ligand is reported. PMID- 20160910 TI - Does women's greater fear of snakes and spiders originate in infancy? AB - Previous studies with adult humans and non-human animals revealed more rapid fear learning for spiders and snakes than for mushrooms and flowers. The current experiments tested whether 11-month-olds show a similar effect in learning associative pairings between facial emotions and fear-relevant and fear irrelevant stimuli. Consistent with the greater incidence of snake and spider phobias in women, results show that female but not male infants learn rapidly to associate negative facial emotions with fear-relevant stimuli. No difference was found between the sexes for fear-irrelevant stimuli. The results are discussed in relation to fear learning, phobias, and a specialized evolved fear mechanism in humans. PMID- 20160911 TI - Energy transfer dyads based on Nile Red. AB - This project was initiated to develop energy transfer dyads emitting in the 600 - 700 nm region by using Nile Red acceptors. Thus fluorescein- and BODIPY-based donors were linked to these acceptors via alkynes or triazoles. The product dyads (1 - 5) have energy transfer efficiencies of 77 - 97% in organic media. PMID- 20160912 TI - Interaction of E1 and E3 components with the core proteins of the human pyruvate dehydrogenase complex. AB - The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. Both hE2 and hBP consist of three well defined domains, namely the lipoyl domain, the subunit-binding domain and the inner domain, connected with flexible linkers. hE1 (alpha(2)beta(2)) binds to the subunit-binding domain of hE2; whereas hE3 binds to the E3-binding domain of hBP. Among several residues of the C-terminal surface of the hE1beta E1betaD289 was found to interact with hE2K276. The C-terminal residue I329 of the hE1beta did not participate in binding to hE2. This latter finding shows specificity in the interaction between E1beta and E2 in hPDC. The selective binding between hE3 and the E3-binding domain of hBP was investigated using specific mutants. E3R460G and E3340K showed significant reductions in affinity for hBP as determined by surface plasmon resonance. Both residues are involved in the structural organization of the binding site on hE3. Substitution of I157, N137 and R155 of hBP resulted in variable increases in the K(D) for binding with wild-type hE3, suggesting that the binding results from several weak electrostatic bonds and hydrophobic interactions among residues of hBP with residues at the interface of dimeric hE3. These results provide insight in the mono-specificity of binding of E1 to E2 and E3 to BP in hPDC and showed the differences in the binding of peripheral components (E1 and E3) in human and bacterial PDCs. PMID- 20160913 TI - The Curiosity and Exploration Inventory-II: Development, Factor Structure, and Psychometrics. AB - Given curiosity's fundamental role in motivation, learning, and well-being, we sought to refine the measurement of trait curiosity with an improved version of the Curiosity and Exploration Inventory (CEI; Kashdan, Rose, & Fincham, 2004). A preliminary pool of 36 items was administered to 311 undergraduate students, who also completed measures of emotion, emotion regulation, personality, and well being. Factor analyses indicated a two factor model-motivation to seek out knowledge and new experiences (Stretching; 5 items) and a willingness to embrace the novel, uncertain, and unpredictable nature of everyday life (Embracing; 5 items). In two additional samples (ns = 150 and 119), we cross-validated this factor structure and provided initial evidence for construct validity. This includes positive correlations with personal growth, openness to experience, autonomy, purpose in life, self-acceptance, psychological flexibility, positive affect, and positive social relations, among others. Applying item response theory (IRT) to these samples (n = 578), we showed that the items have good discrimination and a desirable breadth of difficulty. The item information functions and test information function were centered near zero, indicating that the scale assesses the mid-range of the latent curiosity trait most reliably. The findings thus far provide good evidence for the psychometric properties of the 10 item CEI-II. PMID- 20160914 TI - Intrarenal Angiotensin ii is associated with inflammation, renal damage and dysfunction in dahl salt-sensitive hypertension. AB - BACKGROUND: The goal of this study was to test the hypothesis that intrarenal Ang II has a proinflammatory effect leading to renal damage and dysfunction in Dahl S rats on high Na intake. METHODS: Forty-six 7-to 8-week old Dahl S or R/Rapp strain rats were maintained for 5 weeks on high sodium (8%) with or without candesartan cilexetil in daily doses of 10-15 mg/kg/day. Arterial catheters were implanted at day 28. RESULTS: By day 35 in the high Na S + candesartan rats, renal tissue Ang II concentration, renal monocytes/macrophages, TNFalpha, and MCP 1 significantly decreased. Plasma Ang II remained at very low levels in all groups. Reduced renal damage in candesartan-treated Dahl S rats was demonstrated by marked decreases in urinary protein excretion and renal glomerular and interstitial damage. After 5 weeks of high Na, compared to high Na Dahl S rats, arterial pressure was unchanged in candesartan S rats, but creatinine clearance was increased. CONCLUSIONS: Therefore, candesartan reduced renal tissue Ang II, renal damage, infiltration of immune cells, cytokines, chemokines, and improved renal hemodynamics. These data suggest that intrarenal Ang II plays an important role in causing renal inflammation which leads to renal cortical damage, proteinuria, and decreases in renal hemodynamics. PMID- 20160915 TI - Sponge-like nanostructured conducting polymers for electrically controlled drug release. AB - An electrically controlled drug release (ECDR) system based on sponge-like nanostructured conducting polymer (CP) polypyrrole (PPy) film was developed. The nanostructured PPy film was composed of template-synthesized nanoporous PPy covered with a thin protective PPy layer. The proposed controlled release system can load drug molecules in the polymer backbones and inside the nanoholes respectively. Electrical stimulation can release drugs from both the polymer backbones and the nanoholes, which significantly improves the drug load and release efficiency. Furthermore, with one drug incorporated in the polymer backbone during electrochemical polymerization, the nanoholes inside the polymer can act as containers to store a different drug, and simultaneous electrically triggered release of different drugs can be realized with this system. PMID- 20160916 TI - Does Watching Smoking in Movies Promote Teenage Smoking? AB - Compared to adolescents with low exposure to smoking in movies, those with high exposure are about three times as likely to try smoking or become smokers. We have observed this effect in nationally representative samples using cross sectional and longitudinal designs. This effect remains statistically significant after controlling for numerous other traditional risk factors, such as personality, parenting style, and sociodemographics. Indeed, the movie-smoking exposure effect on adolescent smoking initiation is greatest among those traditionally considered at lower risk for smoking, such as those low in sensation seeking and those whose parents do not smoke. In this article, we consider possible moderators and mediators of this important media effect as well as health-policy implications. The take-home message is that eliminating smoking in movies may prevent a substantial number of adolescents from smoking. PMID- 20160917 TI - Direct three-dimensional microfabrication of hydrogels via two-photon lithography in aqueous solution. PMID- 20160918 TI - Asymmetric Synthesis of 1,2-dioxanes: Approaches to the Peroxyplakoric Acids. AB - The stereospecific intramolecular alkylation of a hydroperoxyacetal provides the basis for the first asymmetric synthesis of the dioxane propionate core of the peroxyplakorates. Chemoselective hydrometallation of an alkyne in the presence of a peroxide is used to introduce a synthon for the polyunsaturated side chains of the peroxyplakorates. The route suggests a general solution for the 1,2-dioxane unit in many peroxide natural products. PMID- 20160919 TI - Neuroanatomical Correlates of Intelligence. AB - With the advancement of image acquisition and analysis methods in recent decades, unique opportunities have emerged to study the neuroanatomical correlates of intelligence. Traditional approaches examining global measures have been complemented by insights from more regional analyses based on pre-defined areas. Newer state-of-the-art approaches have further enhanced our ability to localize the presence of correlations between cerebral characteristics and intelligence with high anatomic precision. These in vivo assessments have confirmed mainly positive correlations, suggesting that optimally increased brain regions are associated with better cognitive performance. Findings further suggest that the models proposed to explain the anatomical substrates of intelligence should address contributions from not only (pre)frontal regions, but also widely distributed networks throughout the whole brain. PMID- 20160920 TI - The Effects of Fixation and Dehydration on the Histological Quality of Undecalcified Murine Bone Specimens Embedded in Methylmethacrylate. AB - Histological evaluation is a complex, multistep process culminating in tissue staining. All of the steps leading up to the staining affect the final quality, but too often the effects of these preparations are not given enough consideration. Fixatives in particular usually are chosen not for efficacy but for convenience and availability. This study attempts to create guidelines for selecting fixatives for bone tissue histological evaluation. We compared two of the most widely used fixatives, ethanol and formalin, in their use on mouse tibias embedded in methylmethacrylate and subsequently stained with toluidine blue, safranin O, or Von Kossa. Our results show that ethanol fixation (70%) and subsequent processing in methylmethacrylate gives better staining results for bone cell related elements than fixing in 10% neutral buffered formalin with the same processing and embedding techniques. Further we demonstrated than an additional acetone dehydration and clearing step allowed for even better visualization in bone specimens fixed with 70% ethanol. However, the additional acetone step did not enhance visualization in bone specimens fixed with 10% neutral buffered formalin. Finally, marrow elements were more easily visualized when fixed with formalin as opposed to ethanol. PMID- 20160921 TI - Monitoring Simultaneous Distance and Orientation Changes in Discrete Dimers of DNA Linked Gold Nanoparticles. AB - Important optical properties of discrete pairs of DNA tethered gold nanoparticles, including their scattering cross-section and resonance wavelength, depend both on the dimer structure and the refractive index of their immediate environment. We show that far-field polarization microscopy aids the optical identification and interpretation of structural changes including hinge motions and nanoscale distance changes in individual assemblies. Grecco and Martinez have shown in their theoretical work that the interparticle separation dependent polarization anisotropy of discrete nanoparticle dimers enables nanoscale distance measurements (Optics Express 2006, 14, 8716 - 8721). Here we implement this approach experimentally and evaluate measured polarization anisotropies in the framework of a dipolar coupling model. We use polarization sensitive darkfield microscopy to resolve simultaneous distance and orientation changes during the compaction of discrete pairs of DNA tethered gold nanoparticles by fourth generation polyamidoamino (PAMAM) dendrimers. The relative contributions from interparticle separation and refractive index variations to changes in the light polarization and scattering intensity are quantified and compared. PMID- 20160922 TI - Synthesis of pyrrolo[1,3]diazepines by a dipolar cycloaddition - retro-Mannich domino reaction. AB - Microwave irradiation facilitated the synthesis of 4-arylthio-3-oxazolin-5-ones from ethyl cyanoformate, thiophenol, and cyclic ketones. Subsequent decarboxylation and in situ [3+2] cycloaddition provided novel 2,3,4,5-tetrahydro 1H-pyrrolo[1,2-c][1,3]diazepine scaffolds after a spontaneous retro-Mannich domino reaction. PMID- 20160923 TI - A Computational Framework for Fluid-Solid-Growth Modeling in Cardiovascular Simulations. AB - It is now well known that altered hemodynamics can alter the genes that are expressed by diverse vascular cells, which in turn plays a critical role in the ability of a blood vessel to adapt to new biomechanical conditions and governs the natural history of the progression of many types of disease. Fortunately, when taken together, recent advances in molecular and cell biology, in vivo medical imaging, biomechanics, computational mechanics, and computing power provide an unprecedented opportunity to begin to understand such hemodynamic effects on vascular biology, physiology, and pathophysiology. Moreover, with increased understanding will come the promise of improved designs for medical devices and clinical interventions. The goal of this paper, therefore, is to present a new computational framework that brings together recent advances in computational biosolid and biofluid mechanics that can exploit new information on the biology of vascular growth and remodeling as well as in vivo patient-specific medical imaging so as to enable realistic simulations of vascular adaptations, disease progression, and clinical intervention. PMID- 20160924 TI - A combined DFT/Green's function study on electrical conductivity through DNA duplex between Au electrodes. AB - Electrical conducting properties of DNA duplexes sandwiched between Au electrodes have been investigated by use of first-principles molecular simulation based on DFT and Green's function to elucidate the origin of their base sequence dependence. The theoretically simulated effects of DNA base sequence on the electrical conducting properties are in qualitative agreement with experiment. The HOMOs localized on Guanine bases have the major contribution to the electrical conductivity through DNA duplexes. PMID- 20160925 TI - Magnetic Resonance Imaging with Composite (Dual) Gradients. AB - The tradeoff between gradient performance factors, size of the imaging region, and physiological factors such as nerve stimulation typically leads to compromises in gradient design and ultimately suboptimal imaging performance. Local gradient systems can add some performance flexibility, but are cumbersome to set up and remove. In nearly all conventional MRI systems, the use of local gradients precludes the use of the more homogeneous whole body gradients. This paper presents the concept of dynamically selectable composite gradient systems where local gradients and whole body gradients can be selected independently and simultaneously. The relative performance of whole body, insert, and composite gradients is predicted for echoplanar (EPI), turbo spin echo (TSE), and steady state free precession (SSFP). A realization of the concept is presented. PMID- 20160926 TI - A Simple Method for the Conversion of Carboxylic Acids into Thioacids with Lawesson's Reagent. AB - A one-step protocol for the conversion of carboxylic acids to thioesters, using Lawesson's Reagent, has been developed. PMID- 20160927 TI - Modeling and Characterization of Electrostatic Comb-drive Actuators in Conducting Liquid Media. AB - Operation of electrostatic actuators in liquid media has various proposed applications, especially in biological environments. The devices are operated by modulating at a frequency higher than the relaxation rate of the ions in solution. We present circuit models based on electric double layer theories to obtain analytical expression for the frequency-dependent force response of electrostatic actuators in ionic media. The model has been compared with experimental measurements of actuation in media of conductivity spanning five orders of magnitude. Further, impedance spectroscopy is used to measure the values of the circuit models, which are compared with the experiments. These measurements also quantify the parasitic impedances in the devices. A conformal layer of Parylene-C is demonstrated as a passivation scheme for the electrodes in corrosive media. The heating effects due to parasitic impedances are also quantified by temperature measurements of devices in fluids. PMID- 20160928 TI - Estimation of Variance Components in the Mixed-Effects Models: A Comparison Between Analysis of Variance and Spectral Decomposition. AB - The mixed-effects models with two variance components are often used to analyze longitudinal data. For these models, we compare two approaches to estimating the variance components, the analysis of variance approach and the spectral decomposition approach. We establish a necessary and sufficient condition for the two approaches to yield identical estimates, and some sufficient conditions for the superiority of one approach over the other, under the mean squared error criterion. Applications of the methods to circular models and longitudinal data are discussed. Furthermore, simulation results indicate that better estimates of variance components do not necessarily imply higher power of the tests or shorter confidence intervals. PMID- 20160929 TI - Biocatalytic anode for glucose oxidation utilizing carbon nanotubes for direct electron transfer with glucose oxidase. AB - Covalently linked layers of glucose oxidase, single-wall carbon nanotubes and poly-L-lysine on pyrolytic graphite resulted in a stable biofuel cell anode featuring direct electron transfer from the enzyme. Catalytic response observed upon addition of glucose was due to electrochemical oxidation of FADH(2) under aerobic conditions. The electrode potential depended on glucose concentration. This system has essential attributes of an anode in a mediator-free biocatalytic fuel cell. PMID- 20160931 TI - Stress relaxation via addition-fragmentation chain transfer in a thiol-ene photopolymerization. AB - Allyl sulfide addition-fragmentation chain transfer was employed concurrently with the radical-mediated formation of a thiol-ene network to enable network adaptation and mitigation of polymerization-induced shrinkage stress. This result represents the first demonstration of simultaneous polymerization and network adaptation in covalently crosslinked networks with significant implications for the fabrication of low stress polymer networks. For comparison, analogous networks incorporating propyl sulfide moieties, incapable of addition fragmentation, were synthesized and evaluated in parallel. At the highest irradiation intensity, the allyl sulfide-containing material demonstrated a more than 75% reduction in the final stress when compared with the propyl sulfide containing material. Analysis of the conversion evolution revealed that allyl sulfide addition-fragmentation decreased the polymerization rate owing to thiyl radical sequestration. Slow consumption of the allyl sulfide functional group suggests that intramolecular homolytic substitution occurs by a step-wise, rather than concerted, mechanism. Simultaneous stress and conversion measurements demonstrated that the initial stress evolution was identical for both the allyl and propyl sulfide-containing materials but diverged after gelation. While addition-fragmentation chain transfer was found to occur throughout the polymerization, its effect on the stress evolution was concentrated towards the end of polymerization when network rearrangement becomes the dominant mechanism for stress relaxation. Even after the polymerization reaction was completed, the polymerization-induced shrinkage stress in the allyl sulfide-containing material continued to decrease, exhibiting a maximum in the stress evolution and demonstrating the potential for continuing, longer term stress relaxation. PMID- 20160930 TI - An Event-Related Potential Study of Cross-modal Morphological and Phonological Priming. AB - The current work investigated whether differences in phonological overlap between the past- and present-tense forms of regular and irregular verbs can account for the graded neurophysiological effects of verb regularity observed in past-tense priming designs. Event-related potentials were recorded from sixteen healthy participants who performed a lexical-decision task in which past-tense primes immediately preceded present-tense targets. To minimize intra-modal phonological priming effects, cross-modal presentation between auditory primes and visual targets was employed, and results were compared to a companion intra-modal auditory study (Justus, Larsen, de Mornay Davies, & Swick, 2008). For both regular and irregular verbs, faster response times and reduced N400 components were observed for present-tense forms when primed by the corresponding past-tense forms. Although behavioral facilitation was observed with a pseudopast phonological control condition, neither this condition nor an orthographic phonological control produced significant N400 priming effects. Instead, these two types of priming were associated with a post-lexical anterior negativity (PLAN). Results are discussed with regard to dual- and single-system theories of inflectional morphology, as well as intra- and cross-modal prelexical priming. PMID- 20160932 TI - Coiled-Coil Hydrogels. Effect of Grafted Copolymer Composition and Cyclization on Gelation. AB - A mean-field theoretical approach was developed to model gelation of solutions of hydrophilic polymers with grafted peptide motifs capable of forming associates of coiled-coil type. The model addresses the competition between associates engaged in branching and cyclization. It results in relative concentrations of intra- and intermolecular associates in dependence on associate strength and motif concentration. The cyclization probability is derived from the model of equivalent Gaussian chain and takes into account all possible paths connecting the interacting motifs. Examination of the association-dissociation equilibria, controlled by the equilibrium constant for association taken as input information, determines the fractions of inter- and intramolecularly associated motifs. The gelation model is based on the statistical theory of branching processes and in combination with the cyclization model predicts the critical concentration delimiting the regions of gelled and liquid states of the system. A comparison between predictions of the model and experimental data available for aqueous solutions of poly[N-(2-hydroxypropyl)methacrylamide] grafted with oppositely charged pentaheptad peptides, CCE and CCK, indicates that the association constant of grafted motifs by four orders of magnitude lower than that of free motifs. It is predicted that at the critical concentration of each motif of about 6*10(-7) mol/cm(3), about half of motifs in associated state is engaged in intramolecular bonds. PMID- 20160933 TI - Dependence of Photonic Crystal Nanocomposite Elasticity on Crystalline Colloidal Array Particle Size. PMID- 20160934 TI - Electrostatic potential of point charges inside dielectric oblate spheroids. AB - As a sequel to a previous paper on electrostatic potential of point charges inside dielectric prolate spheroids [J. Electrostatics 66 (2008) 549-560], this note further presents the exact solution to the electrostatic problem of finding the electric potential of point charges inside a dielectric oblate spheroid that is embedded in a dissimilar dielectric medium. Numerical experiments have demonstrated the convergence of the proposed series solutions. PMID- 20160935 TI - How Does Facial Feedback Modulate Emotional Experience? AB - Contracting muscles involved in facial expressions (e.g. smiling or frowning) can make emotions more intense, even when unaware one is modifying expression (e.g. Strack, Martin, & Stepper, 1988). However, it is unresolved whether and how inhibiting facial expressions might weaken emotional experience. In the present study, 142 participants watched positive and negative video clips while either inhibiting their facial expressions or not. When hypothesis awareness and effects of distraction were experimentally controlled, inhibiting facial expressions weakened some emotional experiences. These findings provide new insight into ways that inhibition of facial expression can affect emotional experience: the link is not dependent on experimental demand, lay theories about connections between expression and experience, or the distraction involved in inhibiting one's expressions. PMID- 20160936 TI - Trafficking in tobacco farm culture: Tobacco companies use of video imagery to undermine health policy. AB - The cigarette companies and their lobbying organization used tobacco industry produced films and videos about tobacco farming to support their political, public relations, and public policy goals. Critical discourse analysis shows how tobacco companies utilized film and video imagery and narratives of tobacco farmers and tobacco economies for lobbying politicians and influencing consumers, industry-allied groups, and retail shop owners to oppose tobacco control measures and counter publicity on the health hazards, social problems, and environmental effects of tobacco growing. Imagery and narratives of tobacco farmers, tobacco barns, and agricultural landscapes in industry videos constituted a tobacco industry strategy to construct a corporate vision of tobacco farm culture that privileges the economic benefits of tobacco. The positive discursive representations of tobacco farming ignored actual behavior of tobacco companies to promote relationships of dependency and subordination for tobacco farmers and to contribute to tobacco-related poverty, child labor, and deforestation in tobacco growing countries. While showing tobacco farming as a family and a national tradition and a source of jobs, tobacco companies portrayed tobacco as a tradition to be protected instead of an industry to be regulated and denormalized. PMID- 20160938 TI - Scanning Electrochemical Microscopy of One-Dimensional Nanostructure: Effects of Nanostructure Dimensions on the Tip Feedback Current under Unbiased Conditions. AB - Scanning electrochemical microscopy (SECM) is developed as a powerful approach to electrochemical characterization of individual one-dimensional (1D) nanostructures under unbiased conditions. 1D nanostructures comprise high-aspect ratio materials with both nanoscale and macroscale dimensions such as nanowires, nanotubes, nanobelts, and nanobands. Finite element simulations demonstrate that the feedback current at a disk-shaped ultramicroelectrode tip positioned above an unbiased nanoband, as prepared on an insulating substrate, is sensitive to finite dimensions of the band, i.e., micrometer length, nanometer width, and nanometer height from the insulating surface. The electron-transfer rate of a redox mediator at the nanoband surface depends not only on the intrinsic rate but also on the open-circuit potential of the nanoband, which is determined by the dimensions of the nanoband as well as the tip inner and outer radii, and tip substrate distance. The theoretical predictions are confirmed experimentally by employing Au nanobands as fabricated on a SiO(2) surface by electron-beam lithography, thereby yielding well defined dimensions of 100 or 500 nm in width, 47 nm in height, and 50 MUm in length. A 100 nm-wide nanoband can be detected by SECM imaging with ~2 MUm-diameter tips although the tip feedback current is compromised by finite electron-transfer kinetics for Ru(NH(3))(6) (3+) at the nanoband surface. PMID- 20160937 TI - Biodegradable fibrous scaffolds with tunable properties formed from photo-cross linkable poly(glycerol sebacate). AB - It is becoming increasingly apparent that the architecture and mechanical properties of scaffolds, particularly with respect to mimicking features of natural tissues, are important for tissue engineering applications. Acrylated poly(glycerol sebacate) (Acr-PGS) is a material that can be cross-linked upon exposure to ultraviolet light, leading to networks with tunable mechanical and degradation properties through simple changes during Acr-PGS synthesis. For example, the number of acrylate functional groups on the macromer dictates the concentration of cross-links formed in the resulting network. Three macromers were synthesized that form networks that vary dramatically with respect to their tensile modulus ( approximately 30 kPa to 6.6 MPa) and degradation behavior ( approximately 20-100% mass loss at 12 weeks) based on the extent of acrylation ( approximately 1-24%). These macromers were processed into biodegradable fibrous scaffolds using electrospinning, with gelatin as a carrier polymer to facilitate fiber formation and cell adhesion. The resulting scaffolds were also diverse with respect to their mechanics (tensile modulus ranging from approximately 60 kPa to 1 MPa) and degradation ( approximately 45-70% mass loss by 12 weeks). Mesenchymal stem cell adhesion and proliferation on all fibrous scaffolds was indistinguishable from those of controls. The scaffolds showed similar diversity when implanted on the surface of hearts in a rat model of acute myocardial infarction and demonstrated a dependence on the scaffold thickness and chemistry in the host response. In summary, these diverse scaffolds with tailorable chemical, structural, mechanical, and degradation properties are potentially useful for the engineering of a wide range of soft tissues. PMID- 20160939 TI - Coupled Flow-Structure-Biochemistry Simulations of Dynamic Systems of Blood Cells Using an Adaptive Surface Tracking Method. AB - A method for the computation of low Reynolds number dynamic blood cell systems is presented. The specific system of interest here is interaction between cancer cells and white blood cells in an experimental flow system. Fluid dynamics, structural mechanics, six-degree-of freedom motion control and surface biochemistry analysis components are coupled in the context of adaptive octree based grid generation. Analytical and numerical verification of the quasi-steady assumption for the fluid mechanics is presented. The capabilities of the technique are demonstrated by presenting several three-dimensional cell system simulations, including the collision/interaction between a cancer cell and an endothelium adherent polymorphonuclear leukocyte (PMN) cell in a shear flow. PMID- 20160940 TI - Concise Synthesis of the Xenibellols Core. AB - We describe herein a concise synthesis of an intermediate, via 2,3-Wittig rearrangement and Williamson etherification, en route to the natural products, xenibellols A and B. PMID- 20160941 TI - Carbon Fiber/Epoxy Composite Ring-disk Electrode: Fabrication, Characterization and Application to Electrochemical Detection in Capillary High Performance Liquid Chromatography. AB - Carbon fiber/epoxy composite materials, which are manufactured using the pultrusion process, are commercially available in various shapes and sizes at very low cost. Here we demonstrate the application of such a material as an electrochemical detector in a flow system. Cyclic voltammetry shows that the material's electrochemical behavior resembles that of glassy carbon. Using tube and rod composites, we successfully fabricated a ring-disk electrode with a 20 MUm gap between the ring and the disk. The narrow gap is favorable for mass transfer in the generator-collector experiment. This composite ring-disk electrode is assembled in a thin-layer radial-flow cell and used as an electrochemical detector. The disk electrode, placed directly opposite to the flow inlet, is operated as a generator electrode with the ring electrode being a collector. The high collection efficiency on the ring electrode (0.8 for a chemically reversible species) enhances the detection selectivity. PMID- 20160942 TI - Construction of Novel Spiroisoxazolines via Intramolecular Cyclization/Methylation. AB - Improved yields for the syntheses of a variety of spiroisoxazolines were achieved through intramolecular cyclization/methylation reactions of functionalized 5,5 disubstituted isoxazolines in one reaction vessel. Aromatic ring containing nitrile oxides and disubstituted geminal alkenes reacted in a 1,3-dipolar fashion to afford the corresponding 5,5-isoxazoline. A comparison of the relative location of the nucleophile and electrophile on the isoxazoline and two different ester functional groups was performed in order to determine the best isoxazoline system for the intramolecular cyclization/methylation reaction. PMID- 20160943 TI - Selective Detection of Sulfur Derivatives Using Microfabricated Tuning Fork-Based Sensors. AB - The paper describes an integtrated sensor system that can selectively and reversibly detect sulfur derivatives in the presence of interferent molecules. This is accomplished by integrating analyte-specific sensing materials with optimized filter materials. Microfabricated quartz tuning fork arrays are used to provide fast, accurate and low-cost transduction of the analyte binding events into electronic signals. The concept is demonstrated for detection of three sulfur derivatives - dimethyl disulfide, ethanethiol and methylsulfide. PMID- 20160944 TI - Total Synthesis of Isoroquefortine E and Phenylahistin. AB - Isoroquefortine E and phenylahistin were synthesized using the Horner-Wadsworth Emmons reaction as the key step to build the dehydroamino acid moiety. The syntheses provide materials for the biological studies of the roquefortine phenylahistin molecules. PMID- 20160945 TI - Observations in the Synthesis of the Core of the Antitumor Illudins via an Enyne Ring Closing Metathesis Cascade. AB - Observations concerning the synthesis of the core spirocyclic AB-ring system of illudins using an enyne ring closing metathesis (EYRCM) cascade are discussed. Substituent effects, in addition to optimization of the reaction conditions and the olefin tether for the key EYRCM reaction, are examined. PMID- 20160947 TI - Automatic Model Selection for Partially Linear Models. AB - We propose and study a unified procedure for variable selection in partially linear models. A new type of double-penalized least squares is formulated, using the smoothing spline to estimate the nonparametric part and applying a shrinkage penalty on parametric components to achieve model parsimony. Theoretically we show that, with proper choices of the smoothing and regularization parameters, the proposed procedure can be as efficient as the oracle estimator (Fan and Li, 2001). We also study the asymptotic properties of the estimator when the number of parametric effects diverges with the sample size. Frequentist and Bayesian estimates of the covariance and confidence intervals are derived for the estimators. One great advantage of this procedure is its linear mixed model (LMM) representation, which greatly facilitates its implementation by using standard statistical software. Furthermore, the LMM framework enables one to treat the smoothing parameter as a variance component and hence conveniently estimate it together with other regression coefficients. Extensive numerical studies are conducted to demonstrate the effective performance of the proposed procedure. PMID- 20160948 TI - Cyclic Voltammetry at Shallow Recessed Microdisc Electrode: Theoretical and Experimental Study. AB - This study focuses on the cyclic voltammetry behavior at shallow recessed microdisc electrode, particularly on the transition from cottrellian behavior to steady state behavior. Diffusion to the inlaid and recessed microdisc electrode is simulated. From the shape of the CVs, for a given radius and potential scan rate, the transition time from planar diffusion to hemispherical diffusion presents a minimum as the recess increases. Theoretical prediction was confirmed by fitting the simulated CVs with experimental results. Dimensionless transition scan rate has been defined and determined by simulation for inlaid and recessed microdisc electrodes. PMID- 20160946 TI - Characterization of protein secondary structure from NMR chemical shifts. PMID- 20160949 TI - Interaction of Nanoparticles at the DEP Microelectrode Interface under High Conductance Conditions. AB - The separation of nanoparticles from micron size particles in high conductance buffers was achieved using an AC dielectrophoretic (DEP) microarray device with hydrogel over-coated microelectrodes. While nanoparticles could be selectively concentrated into high field regions directly over the platinum microelectrodes, micro-bubbling and electrode darkening was also observed. For similar experiments using un-coated microelectrodes, SEM analysis showed severe erosion of the platinum microelectrodes and fusion of nanoparticles due to the aggressive electrochemistry. PMID- 20160950 TI - Circadian Rhythm Sleep Disorder: Irregular Sleep Wake Rhythm Type. AB - Irregular Sleep Wake Rhythm Disorder (ISWRD) is characterized by the relative absence of a circadian pattern in an individual's sleep-wake cycle. Significant changes in circadian regulation occur with aging and with neurodegenerative diseases, such as Alzheimer's disease prevalent in older adults, which are likely to contribute to the prevalence of ISWRD seen in these populations, although ISWRD is also seen in traumatic brain injury and mental retardation populations. ISWRD is thought to result from some combination of; degeneration or decreased neuronal activity of suprachiasmatic nucleus (SCN) neurons, decreased responsiveness of the circadian clock to entraining agents such as light and activity, and decreased exposure to bright light and structured social and physical activity during the day. Treatment of ISWRD seeks to consolidate sleep during the night and wakefulness during the day; primarily through restoring or enhancing exposure to the various SCN time cues, or "zeitgebers". Studies of the effectiveness of pharmacologic treatments for ISWRD have generally yielded negative or inconsistent results. In general multi-modal non-pharmacological approaches involving increased exposure to light, increased physical and social activities and improved sleep hygiene have been the most successful therapeutic approaches. PMID- 20160952 TI - 2D IR photon echo study of the anharmonic coupling in the OCN region of phenyl cyanate. AB - The vibrations in the OCN stretching region of phenyl cyanate are examined by two dimensional infrared spectroscopy. In water and THF, these spectra display three diagonal peaks having cross peaks characteristic of anharmonically coupled transitions. The pattern of the spectra is reproduced by coupling of two overtones with the OCN fundamental. PMID- 20160951 TI - Perspectives on use of mobility aids in a diverse population of seniors: implications for intervention. AB - BACKGROUND: Many older adults who might benefit from using mobility aids do not or will not use them. Studies show that attitudes and beliefs strongly affect the decision to use mobility aids. Despite the growing diversity of the population, no prior studies have compared attitudes towards and beliefs about mobility aids by race and ethnicity. OBJECTIVE: This study aimed to explore whether and how attitudes towards and beliefs about mobility aid use vary by race and ethnicity. METHODS: We conducted 12 focus groups with 61 community dwelling persons age 65+ years from three groups: White, non-Hispanic Black, and Hispanic. Data were coded and compared across groups. RESULTS: For all groups, perceived benefits of mobility devices in maintaining independence and control produced positive attitudes. However, the association of mobility aid use with aging and physical decline contributed to stigmatizing attitudes. Black and Hispanic participants expressed apprehension about using unsafe or inappropriate secondhand equipment, heightened concerns about mobility aid users becoming subjects of negative biases, and a preference for fashionable aids. Hispanic participants expressed a preference for human assistance. Participants of all groups perceived physicians as influencing their decisions to use aids. CONCLUSIONS: Social pressures and perceived stigma deter mobility aid use, particularly in minority populations. Greater physician involvement, positive peer models and affordable, safe, visually appealing devices would promote greater acceptance of mobility aids. PMID- 20160953 TI - A Mathematical Model for the First-Pass Dynamics of Antibiotics Acting on the Cardiovascular System. AB - We present a preliminary first-pass dynamic model for delivery of drug compounds to the lungs and heart. We use a compartmental mass balance approach to develop a system of nonlinear differential equations for mass accumulated in the heart as a result of intravenous injection. We discuss sensitivity analysis as well as methodology for minimizing mass in the heart while maximizing mass delivered to the lungs on a first circulatory pass. PMID- 20160954 TI - Coupling reactions of hindered isonitriles and hindered alkyl thioacids: Mechanistic studies. AB - The coupling reaction between hindered thioacids and isonitriles is developed and described. The mechanism for the formation of the thiopyruvamide products is explored, and the method is applied to a selection of substrates. PMID- 20160955 TI - Protein Crystal Engineering of YpAC-IV using the Strategy of Excess Charge Reduction. AB - The class IV adenylyl cyclase from Yersinia pestis has been engineered by site specific mutagenesis to facilitate crystallization at neutral pH. The wild-type enzyme crystallized only below pH 5, consistent with the observation of a carboxyl-carboxylate H bond in a crystal contact in the refined structure 2FJT. Based on that unliganded structure at 1.9 A resolution, two different approaches were tested with the goal of producing a higher-pH crystal needed for inhibitor complexation and mechanistic studies. In one approach, Asp 19, which forms the growth-limiting dicarboxyl contact in wild-type triclinic crystals, was modified to Ala and Asn in hopes of relieving the acid-dependence of that crystal form. In the other approach, wild-type residues Met 18, Glu 25, and Asp 55 were (individually) changed to lysine to reduce the protein's excess negative charge in hopes of enabling growth of new, higher-pH forms. These 3 sites were selected based on their high solvent exposure and lack of intraprotein interactions. The D19A and D19N mutants had reduced solubility and did not crystallize. The other 3 mutants all crystallized, producing several new forms at neutral pH. One of these forms, with the D55K mutant, enabled a product complex at 1.6 A resolution, structure 3GHX. This structure shows why the new crystal form required the mutation in order to grow at neutral pH. This approach could be useful in other cases where excess negative charge inhibits the crystallization of low-pI proteins. PMID- 20160956 TI - Multiple roles of mobile active center loops in the E1 component of the Escherichia coli pyruvate dehydrogenase complex - Linkage of protein dynamics to catalysis. AB - The region encompassing residues 401-413 on the E1 component of the pyruvate dehydrogenase multienzyme complex from Escherichia coli comprises a loop (the inner loop) which was not seen in the X-ray structure in the presence of thiamin diphosphate, the required cofactor for the enzyme. This loop is seen in the presence of a stable analogue of the pre-decarboxylation intermediate, the covalent adduct between the substrate analogue methyl acetylphosphonate and thiamin diphosphate, C2alpha-phosphonolactylthiamin diphosphate. It has been shown that the residue H407 and several other residues on this loop are required to reduce the mobility of the loop so electron density corresponding to it can be seen once the pre-decarboxylation intermediate is formed. Concomitantly, the loop encompassing residues 541-557 (the outer loop) appears to work in tandem with the inner loop and there is a hydrogen bond between the two loops ensuring their correlated motion. The inner loop was shown to: a) sequester the active center from carboligase side reactions; b) assist the interaction between the E1 and the E2 components, thereby affecting the overall reaction rate of the entire multienzyme complex; c) control substrate access to the active center. Using viscosity effects on kinetics it was shown that formation of the pre decarboxylation intermediate is specifically affected by loop movement. A cysteine-less variant was created for the E1 component, onto which cysteines were substituted at selected loop positions. Introducing an electron spin resonance spin label and an (19)F NMR label onto these engineered cysteines, the loop mobility was examined: a) both methods suggested that in the absence of ligand, the loop exists in two conformations; b) line-shape analysis of the NMR signal at different temperatures, enabled estimation of the rate constant for loop movement, and this rate constant was found to be of the same order of magnitude as the turnover number for the enzyme under the same conditions. Furthermore, this analysis gave important insights into rate-limiting thermal loop dynamics. Overall, the results suggest that the dynamic properties correlate with catalytic events on the E1 component of the pyruvate dehydrogenase complex. PMID- 20160957 TI - Visual and Multimodal Analysis of Human Spontaneous Behavior: Introduction to the Special Issue of Image & Vision Computing Journal. PMID- 20160958 TI - Charge State Dependent Fragmentation of Gaseous alpha-Synuclein Cations via Ion Trap and Beam-Type Collisional Activation. AB - Ions derived from nano-electrospray ionization (nano-ESI) of alpha-synuclein, a 14.5 kDa, 140 amino acid residue protein that is a major component of the Lewy bodies associated with Parkinson's disease, have been subjected to ion trap and beam-type collisional activation. The former samples products from fragmentation at rates generally lower than 100 s(-1) whereas the latter samples products from fragmentation at rates generally greater than 10(3) s(-1). A wide range of protein charge states spanning from as high as [M+17H](17+) to as low as [M+4H](4+) have been formed either directly from nano-ESI or via ion/ion proton transfer reactions involving the initially formed protein cations and have been subjected to both forms of collision-induced dissociation (CID). The extent of sequence information (i.e., number of distinct amide bond cleavages) available from either CID method was found to be highly sensitive to protein precursor ion charge state. Furthermore, the relative contributions of the various competing dissociation channels were also dependent upon precursor ion charge state. The qualitative trends in the changes in extent of amide bond cleavages and identities of bonds cleaved with precursor ion charge state were similar for two forms of CID. However, for every charge state examined, roughly twice the primary sequence information resulted from beam-type CID relative to ion trap CID. For example, evidence for cleavage of 86% of the protein amide bonds was observed for the [M+9H](9+) precursor ion using beam-type CID whereas 41% of the bonds were cleaved for the same precursor ion using ion trap CID. The higher energies required to drive fragmentation reactions at rates necessary to observe products in the beam experiment access more of the structurally informative fragmentation channels, which has important implications for whole protein tandem mass spectrometry. PMID- 20160959 TI - Interior SPECT- Exact and Stable ROI Reconstruction from Uniformly Attenuated Local Projections. AB - Single photon emission computed tomography (SPECT) is an important biomedical imaging modality. However, since gamma cameras are expensive and bulky, truncated projection data are either preferred or unavoidable. Inspired by the recent results on interior tomography in the x-ray CT field, here we present the interior SPECT approach for exact and stable reconstruction of a region of interest (ROI) from uniformly attenuated local projection data, aided by prior knowledge of a sub-region in the ROI. First, by analytic continuation we prove that interior SPECT is both exact and stable, and by singular value decomposition (SVD) we establish the stability of interior SPECT. Then, given the constant attenuation coefficient and object boundary, our interior SPECT reconstruction is achieved by inverting a generalized truncated Hilbert transform using the SVD technique. Preliminary numerical simulation data demonstrate that our work has practical utilities. The theoretical generalization of our work to the variable attenuation case is underway, and the same numerical approach can be applied. PMID- 20160960 TI - Role of Utility and Inference in the Evolution of Functional Information. AB - Functional information means an encoded network of functions in living organisms from molecular signaling pathways to an organism's behavior. It is represented by two components: code and an interpretation system, which together form a self sustaining semantic closure. Semantic closure allows some freedom between components because small variations of the code are still interpretable. The interpretation system consists of inference rules that control the correspondence between the code and the function (phenotype) and determines the shape of the fitness landscape. The utility factor operates at multiple time scales: short term selection drives evolution towards higher survival and reproduction rate within a given fitness landscape, and long-term selection favors those fitness landscapes that support adaptability and lead to evolutionary expansion of certain lineages. Inference rules make short-term selection possible by shaping the fitness landscape and defining possible directions of evolution, but they are under control of the long-term selection of lineages. Communication normally occurs within a set of agents with compatible interpretation systems, which I call communication system. Functional information cannot be directly transferred between communication systems with incompatible inference rules. Each biological species is a genetic communication system that carries unique functional information together with inference rules that determine evolutionary directions and constraints. This view of the relation between utility and inference can resolve the conflict between realism/positivism and pragmatism. Realism overemphasizes the role of inference in evolution of human knowledge because it assumes that logic is embedded in reality. Pragmatism substitutes usefulness for truth and therefore ignores the advantage of inference. The proposed concept of evolutionary pragmatism rejects the idea that logic is embedded in reality; instead, inference rules are constructed within each communication system to represent reality and they evolve towards higher adaptability on a long time scale. PMID- 20160961 TI - Partnered Decisions? U.S. Couples and Medical Help-seeking for Infertility. AB - We examined male partners' influence on the decision to seek medical help for infertility using from the National Survey of Fertility Barriers. Building upon an existing help-seeking framework, we incorporated characteristics of both partners from 219 heterosexual couples who had ever perceived a fertility problem. In logistic regression analyses, we found an association between couple level attitudes and medical help-seeking even when other predisposing and enabling conditions existed. Overall, the findings highlight that both partners contribute to the infertility help-seeking process, and that different factors may play a role in different stages of help-seeking. Studies of infertility help seeking need to be more inclusive of the context that these decisions are embedded within to better understand service use. PMID- 20160962 TI - Phenanthroindolizidines and Phenanthroquinolizidines: Promising Alkaloids for Anti-Cancer Therapy. AB - The phenanthroindolizidine and phenanthroquinolizidine alkaloids, typified by tylophorine and cryptopleurine, are a family of plant-derived small molecules with significant therapeutic potential. The plant extracts have been used in herbal medicine and the isolated compounds have displayed a range of promising therapeutic activity such as anti-ameobicidal, anti-viral, anti-inflammatory and anti-cancer activity. Despite their therapeutic protential, no compounds in this class have fully passed clinical trials. Drawbacks include low in vivo anti cancer activity, central nervous system toxicity and low natural availability. A number of biological effects of these compounds, such as protein and nucleic acid synthesis suppression, have been identified, but the specific biomolecular targets have not yet been identified. Significant effort has been expended in the synthesis and structure-activity-relationship (SAR) studies of these compounds with the hope that a new drug will emerge. This review will highlight important contributions to the isolation, synthesis, SAR and mechanism of action of the phenanthroindolizidine and pheanthroquinolizidine alkaloids. PMID- 20160963 TI - Evolution of gustatory reflex systems in the brainstems of fishes. AB - The great number of species of teleosts permits highly specialized forms to evolve to occupy particular niches. This diversity allows for extreme variations in brain structure according to particular sensory or motor adaptations. In the case of the taste system, goldfish (Carassius auratus L., 1758) and some carps have evolved a specialized intraoral food-sorting apparatus along with corresponding specializations of gustatory centers in the brainstem. A comparison of circuitry within the complex vagal lobe of goldfish, and of the simpler gustatory lobes in catfish (Ictalurus punctatus Rafinesque, 1818) shows numerous similarities in organization and neurotransmitters. Double labeling studies using horseradish peroxidase and biotinylated dextran amine in catfish shows a direct projection from the vagal lobe to the motoneurons of nucleus ambiguous which innervate oropharyngeal musculature. Therefore, a three neuron reflex arc connects gustatory input to motor output. In the vagal lobe of goldfish, a similar three neuron arc can be identified: from primary gustatory afferent, to vagal lobe interneuron, thence to dendrites of the vagal motoneurons that innervate the pharyngeal muscles. Therefore, despite large differences in the gross appearance of the vagal gustatory systems in the brains of catfish and goldfish, the essential connectivity and circuitry is similar. This suggests that evolutionary change in the central nervous system largely proceeds by rearrangement and elaboration of existing systems, rather than by addition of new structures or circuits. PMID- 20160964 TI - Reading profiles for adults with low-literacy: Cluster analysis with power and speeded measures. AB - The United States' National Institute for Literacy's (NIFL) review of adult literacy instruction research recommended adult education (AE) programs assess underlying reading abilities in order to plan appropriate instruction for low literacy learners. This study developed adult reading ability groups using measures from power tests and speeded tests of phonemic decoding, word recognition, fluency, and comprehension. A multiple cluster analysis of these reading ability scores from 295 low-literacy AE participants yielded seven reading ability groups. These groups are described in terms of instructional needs relevant to an instructor's planning and activities. PMID- 20160965 TI - An Integrated Approach to Treating Non-Offending Parents Affected by Sexual Abuse. AB - Childhood sexual abuse has been associated with a number of serious physical and psychological consequences throughout childhood and into adulthood for both child victims and their families. This paper describes the preliminary outcomes of a pilot group program to treat non-offending parents of sexually abused children. This group program is integrative in its approach combining elements of trauma focused cognitive-behavioral and psychoeducational/supportive interventions to treat non-offending parents of sexually abused children. This study also focuses on outcomes in terms of parental post-traumatic distress and general family functioning.A small group of non-offending parents was recruited from a local child advocacy agency. Parents attended the twelve-week group program and outcomes such as parent post-traumatic stress and family dysfunction were examined. Measures of overall satisfaction and intervention feasibility were also examined at the end of the group intervention.Favorable outcomes included a decrease in parent self-report of post-traumatic stress and select aspects of family dysfunction. Seventy five percent of parents completed the group program. Satisfaction questionnaire responses demonstrated highly favorable perceptions of the group's content, leaders, and helpfulness.This study served as an initial step in the development of larger family-focused interventions involving parallel parent and child groups and focused family sessions. Outcomes may begin to shed some light on the need for more parent- and family-focused interventions in families that have been affected by sexual abuse. PMID- 20160966 TI - Immigration and the American industrial revolution from 1880 to 1920. AB - In this study, we measure the contribution of immigrants and their descendents to the growth and industrial transformation of the American workforce in the age of mass immigration from 1880 to 1920. The size and selectivity of the immigrant community, as well as their disproportionate residence in large cities, meant they were the mainstay of the American industrial workforce. Immigrants and their children comprised over half of manufacturing workers in 1920, and if the third generation (the grandchildren of immigrants) are included, then more than two thirds of workers in the manufacturing sector were of recent immigrant stock. Although higher wages and better working conditions might have encouraged more long-resident native-born workers to the industrial economy, the scale and pace of the American industrial revolution might well have slowed. The closing of the door to mass immigration in the 1920s did lead to increased recruitment of native born workers, particularly from the South, to northern industrial cities in the middle decades of the 20th century. PMID- 20160968 TI - Black-White Disparities in Care in Nursing Homes. AB - Nursing homes serve many severely ill poor people, including large numbers of racial/ethnic minority residents. Previous research indicates that blacks tend to receive care from lower quality nursing homes (Grabowski, 2004). Using the Institute of Medicine (IOM) definition of racial-ethnic disparities, this study decomposes nursing home disparities into within and across facility components. Using detailed person-level nursing home data, we find meaningful black-white disparities for one of the four risk-adjusted quality measures, with both within and across nursing home components of the disparity. The IOM approach, which recognizes mediation through payer status and education, has a small effect on measured disparities in this setting. Although we did not find disparities across the majority of quality measures and alternate disparity definitions, this approach can be applied to other health care services in an effort to disentangle the role of across and within facility variation and the role of potential mediators on racial/ethnic disparities. PMID- 20160969 TI - Naming and Claiming Cancer among African American Women: An Application of Problematic Integration Theory. AB - This study examines how a sample of African American women understands the uncertainties fundamental to cancer risk communication. Utilizing data from four focus groups, Problematic Integration (PI) theory is applied as an interpretive lens for illustrating their felt difficulties of talking openly about cancer and breast cancer in everyday life. The women describe worry about cancer and its prevalence among African American women; ambivalence and uncertainty; belief that what is not uncertain is certain and awful; fear and avoidance; contradictions in "claiming" and "rebuking" cancer; and hopefulness. PMID- 20160967 TI - In vitro models of pancreatic cancer for translational oncology research. AB - BACKGROUND: Pancreatic cancer is a disease of near uniform fatality and the overwhelming majority of patients succumb to their advanced malignancy within a few months of diagnosis. Despite considerable advances in our understanding of molecular mechanisms underlying pancreatic carcinogenesis, this knowledge has not yet been fully translated into clinically available treatment strategies that yield significant improvements in disease free or overall survival. OBJECTIVE: Cell line-based in vitro model systems provide powerful tools to identify potential molecular targets for therapeutic intervention as well as for initial pre-clinical evaluation of novel drug candidates. Here we provide a brief overview of recent literature on cell line-based model systems of pancreatic cancer and their application in the search for novel therapeutics against this vicious disease. CONCLUSION: While in vitro models of pancreatic cancer are of tremendous value for genetic studies and initial functional screenings in drug discovery, they carry several imanent drawbacks and are often poor in predicting therapeutic response in humans. Therefore, in most instances they are successfully exploited to generate hypothesis and identify molecular targets for novel therapeutics, which are subsequently subject to further in-depth characterization using more advanced in vivo model systems and clinical trials. PMID- 20160970 TI - Synthesis of alpha-carboranyl-alpha-acyloxy-amides as potential BNCT agents. AB - Novel alpha-carboranyl-alpha-acyloxy-amides were prepared as potential BNCT agents utilizing three component Passerini reaction. Preliminary cytotoxicity of the representative compounds on two brain tumor cell lines (U-87 and A-172) showed no effect on cell viability; an essential requirement for utility as potential BNCT agents. PMID- 20160971 TI - Synthesis of Fluorenes via the Palladium-Catalyzed 5-Exo-dig Annulation of o Alkynyl Biaryls. AB - The direct Pd-catalyzed intramolecular rapidly with electron-deficient benzene ring, which, in hydroarylation of o-alkynyl biaryls proceeded in highly combination with a substantial isotope effect observed, stereoselective manner producing fluorenes 2, the products of 5-exo-dig cyclization, in excellent yields. The cascade intermolecular arylation, incorporated in this transformation, allowed for efficient synthesis of fully-substituted fluorenes 12. These cyclizations proceed more rapidly with electron-deficient benzene ring, which, in combination with a substantial isotope effect observed, strongly supports a C-H activation mechanism for the key annulation step. PMID- 20160972 TI - Fabrication of Silica Shell Photonic Crystals through Flexible Core Templates. AB - We attached very small silica particles onto flexible monodisperse poly (N isopropylacrylamide, PNIPAm) core particles synthesized by dispersion polymerization. These silica particles were attached to the partially swollen PNIPAm particles by the hydrolysis and condensation of tetraethoxysilane at 24 degrees C. The resulting silica particle-functionalized PNIPAm core particles show reversible swelling and shrinking as the temperature is cycled. These particles form close-packed-array photonic crystals as the solvent evaporates; the cores shrink to form a silica shell around the pure PNIPAm dry core particles as they close pack. The PNIPAm cores were removed by calcination, leaving a PC composed of essentially pure continuous silica shells. These silica shell photonic crystals Bragg diffract UV light at ~310 nm. The close packed particle interstices are continuous and are easily filled by water. In contrast, the silica shells are impervious to water because the process of making them results in a continuous shell of silica without holes. PMID- 20160973 TI - Behavioural biologists don't agree on what constitutes behaviour. AB - Behavioural biology is a major discipline within biology, centred on the key concept of 'behaviour.' But how is 'behaviour' defined, and how should it be defined? We outline what characteristics we believe a scientific definition should have, and why we think it important that a definition have these traits. We then examine the range of available published definitions for the word. Finding no consensus, we present survey responses from 174 members of three behaviour-focused scientific societies as to their understanding of the term. Here again, we find surprisingly widespread disagreement as to what qualifies as behaviour. Respondents contradict themselves, each other, and published definitions, indicating that they are using individually variable intuitive, rather than codified, meanings of 'behaviour.' We offer a new definition, based largely on survey responses: "Behaviour is the internally coordinated responses (actions or inactions) of whole living organisms (individuals or groups) to internal and/or external stimuli, excluding responses more easily understood as developmental changes." Finally, we discuss the usage, meanings and limitations of this definition. PMID- 20160974 TI - The degree of kinship and its association with reciprocity and exchange in the relationships of visually impaired older adults. AB - This study draws on an evolutionary model of exchange in relationships to examine the nature of perceived reciprocity in the context of kin and non-kin relationships among a sample of visually impaired older adults (age 63-99). Further, we examined the direct and moderating impact of functional impairment and adaptation to visual impairment on the nature of perceived reciprocity. Results showed that the greater the degree of genetic relatedness the more imbalanced the exchange. It was also found that degree of adaptation to visual impairment moderated the association between genetic relatedness and perceived exchange, such that the greater the degree of genetic relatedness the more people reported they gave rather than received except at very low levels of adaptation, when people received more than they gave the greater the degree of genetic relatedness. Thus, an evolutionary model was supported such that imbalanced exchange was found more with greater degrees of genetic relatedness, but the direction of exchange was different for high versus low levels of adaptation to vision impairment. PMID- 20160975 TI - Efficient alcoholysis of 5,6-dihydro-1,10-phenanthroline-5,6-epoxide with ytterbium(III) triflate and subsequent enantioselective transesterification with lipases. AB - New 5,6-dihydro-1,10-phenanthroline derivatives were prepared in high yield via ytterbium(III) triflate-catalyzed alcoholysis of the corresponding epoxide. Enzymatic transesterifications of racemic alkoxy alcohols afforded enantioselective separations with up to 99% ee. The lipase derived from Burkholderia cepacia (PSCI) was the most efficient, with E-values of up to 200. The steric effect of substituents in the 6-position on reaction time and enantioselectivities was assessed. PMID- 20160976 TI - Neuroticism, Negative Affect, and Negative Affect Instability: Establishing Convergent and Discriminant Validity Using Ecological Momentary Assessment. AB - Few investigations have examined the role of affective instability within a broad model of general personality functioning. The present study employed self-report and ecological momentary assessments (EMA) to examine the relations between self reported Five-Factor Model Neuroticism, EMA average negative affect, and EMA negative affect instability. Results suggest that Neuroticism and negative affect instability are related yet distinct constructs, and that Neuroticism better represents average negative affect across time. Results also suggest that negative affect instability is related to low Agreeableness and specific externalizing facets of Neuroticism, such as Angry Hostility and Impulsiveness. The implications of these findings and potential areas for future research are discussed. PMID- 20160977 TI - Multivariate concentration determination using principal component regression with residual analysis. AB - Data analysis is an essential tenet of analytical chemistry, extending the possible information obtained from the measurement of chemical phenomena. Chemometric methods have grown considerably in recent years, but their wide use is hindered because some still consider them too complicated. The purpose of this review is to describe a multivariate chemometric method, principal component regression, in a simple manner from the point of view of an analytical chemist, to demonstrate the need for proper quality-control (QC) measures in multivariate analysis and to advocate the use of residuals as a proper QC method. PMID- 20160978 TI - Porous polymer coatings: a versatile approach to superhydrophobic surfaces. AB - We present a facile and inexpensive approach to superhydrophobic polymer coatings. The method involves the in-situ polymerization of common monomers in the presence of a porogenic solvent to afford superhydrophobic surfaces with the desired combination of micro- and nano-scale roughness. The method is applicable to a variety of substrates and is not limited to small areas or flat surfaces. The polymerized material can be ground into a superhydrophobic powder, which, once applied to a surface, renders it superhydrophobic. The morphology of the porous polymer structure can be efficiently controlled by composition of the polymerization mixture, while surface chemistry can be adjusted by photografting. Morphology control is used to reduce the globule size of the porous architecture from micro down to nanoscale thereby affording a transparent material. The influence of both surface chemistry as well as the length scale of surface roughness on the superhydrophobicity is discussed. PMID- 20160980 TI - CHARMM Additive All-Atom Force Field for Acyclic Polyalcohols, Acyclic Carbohydrates and Inositol. AB - Parametrization of the additive all-atom CHARMM force field for acyclic polyalcohols, acyclic carbohydrates and inositol is conducted. Initial parameters were transferred from the alkanes and hexopyranose carbohydrates, with subsequent development and optimization of parameters unique to the molecules considered in this study. Using the model compounds acetone and acetaldehyde, nonbonded parameters for carbonyls were optimized targeting quantum mechanical interaction data for solute-water pairs and pure solvent thermodynamic data. Bond and angle parameters were adjusted by comparing optimized geometries to small molecule crystal survey data and by performing vibrational analyses on acetone, acetaldehyde and glycerol. C-C-C-C, C-C-C-O, C-C-OH and O-C-C-O torsional parameters for polyol chains were fit to quantum mechanical dihedral potential energy scans comprising over 1500 RIMP2/cc-pVTZ//MP2/6-31G(d) conformations using an automated Monte Carlo simulated annealing procedure. Comparison of computed condensed-phase data, including crystal lattice parameters and densities, NMR proton-proton couplings, densities and diffusion coefficients of aqueous solutions, to experimental data validated the optimized parameters. Parameter development for these compounds proved particularly challenging because of the flexibility of the acyclic sugars and polyalcohols as well as the intramolecular hydrogen bonding between vicinal hydroxyls for all of the compounds. The newly optimized additive CHARMM force field parameters are anticipated to be of utility for atomic level of detail simulations of acyclic polyalcohols, acyclic carbohydrates and inositol in solution. PMID- 20160979 TI - Will knowledge of gene-based colorectal cancer disease risk influence quality of life and screening behavior? Findings from a population-based study. AB - BACKGROUND: Several gene variants conveying a modestly increased risk for disease have been described for colorectal cancer. Patient acceptance of gene variant testing in clinical practice is not known. We evaluated the potential impact of hypothetical colorectal-cancer-associated gene variant testing on quality of life, health habits and cancer screening behavior. METHODS: First-degree relatives of colorectal cancer patients and controls from the Seattle Colorectal Cancer Familial Registry were invited to participate in a web-based survey regarding testing for gene variants associated with colorectal cancer risk. RESULTS: 310 relatives and 170 controls completed the questionnaire. Quality of life for the hypothetical carrier state was modestly and nonsignificantly lower than current health after adjustment for sociodemographic and health factors. In the positive test scenario, 30% of respondents expressed willingness to change their diet, 25% to increase exercise, and 43% to start colorectal cancer screening. The proportions willing to modify these habits did not differ between groups. CONCLUSIONS: Testing for gene variants associated with colorectal cancer risk may not influence quality of life, but may impact health habits and screening adherence. Changing behaviors as a result of testing may help to reduce cancer incidence and mortality, particularly among those at higher risk for colorectal cancer. PMID- 20160981 TI - Flexible Chip Scale Package and Interconnect for Implantable MEMS Movable Microelectrodes for the Brain. AB - We report here a novel approach called MEMS microflex interconnect (MMFI) technology for packaging a new generation of Bio-MEMS devices that involve movable microelectrodes implanted in brain tissue. MMFI addresses the need for (i) operating space for movable parts and (ii) flexible interconnects for mechanical isolation. We fabricated a thin polyimide substrate with embedded bond pads, vias, and conducting traces for the interconnect with a backside dry etch, so that the flexible substrate can act as a thin-film cap for the MEMS package. A double gold stud bump rivet bonding mechanism was used to form electrical connections to the chip and also to provide a spacing of approximately 15-20 um for the movable parts. The MMFI approach achieved a chip scale package (CSP) that is lightweight, biocompatible, having flexible interconnects, without an underfill. Reliability tests demonstrated minimal increases of 0.35 mOmega, 0.23 mOmega and 0.15 mOmega in mean contact resistances under high humidity, thermal cycling, and thermal shock conditions respectively. High temperature tests resulted in an increase in resistance of > 90 mOmega when aluminum bond pads were used, but an increase of ~ 4.2 mOmega with gold bond pads. The mean-time-to failure (MTTF) was estimated to be at least one year under physiological conditions. We conclude that MMFI technology is a feasible and reliable approach for packaging and interconnecting Bio-MEMS devices. PMID- 20160983 TI - Confidence Estimation via the Parametric Bootstrap in Logistic Joinpoint Regression. AB - We consider asymptotic properties of the maximum likelihood and related estimators in a clustered logistic joinpoint model with an unknown joinpoint. Sufficient conditions are given for the consistency of confidence bounds produced by the parametric bootstrap; one of the conditions required is that the true location of the joinpoint is not at one of the observation times. A simulation study is presented to illustrate the lack of consistency of the bootstrap confidence bounds when the joinpoint is an observation time. A removal algorithm is presented which corrects this problem, but at the price of an increased mean square error. Finally, the methods are applied to data on yearly cancer mortality in the United States for individuals age 65 and over. PMID- 20160982 TI - An optoelectronic nose for the detection of toxic gases. AB - We have developed a simple colorimetric sensor array that detects a wide range of volatile analytes and then applied it to the detection of toxic gases. The sensor consists of a disposable array of cross-responsive nanoporous pigments with colours that are changed by diverse chemical interactions with analytes. Although no single chemically responsive pigment is specific for any one analyte, the pattern of colour change for the array is a unique molecular fingerprint. Clear differentiation among 19 different toxic industrial chemicals (TICs) within two minutes of exposure at concentrations immediately dangerous to life or health were demonstrated. Based on the colour change of the array, quantification of each analyte was accomplished easily, and excellent detection limits were achieved, generally below the permissible exposure limits. Different TICs were identified readily using a standard chemometric approach (hierarchical clustering analysis), with no misclassifications over 140 trials. PMID- 20160984 TI - Automated Assessment of Prosody Production. AB - Assessment of prosody is important for diagnosis and remediation of speech and language disorders, for diagnosis of neurological conditions, and for foreign language instruction. Current assessment is largely auditory-perceptual, which has obvious drawbacks; however, automation of assessment faces numerous obstacles. We propose methods for automatically assessing production of lexical stress, focus, phrasing, pragmatic style, and vocal affect. Speech was analyzed from children in six tasks designed to elicit specific prosodic contrasts. The methods involve dynamic and global features, using spectral, fundamental frequency, and temporal information. The automatically computed scores were validated against mean scores from judges who, in all but one task, listened to "prosodic minimal pairs" of recordings, each pair containing two utterances from the same child with approximately the same phonemic material but differing on a specific prosodic dimension, such as stress. The judges identified the prosodic categories of the two utterances and rated the strength of their contrast. For almost all tasks, we found that the automated scores correlated with the mean scores approximately as well as the judges' individual scores. Real-time scores assigned during examination - as is fairly typical in speech assessment - correlated substantially less than the automated scores with the mean scores. PMID- 20160985 TI - Functional Neuroimaging of Language Using Magnetoencephalography. AB - Magnetoencephalography (MEG) is a novel functional brain mapping technique capable of non-invasively measuring neurophysiological activity based on direct measures of the magnetic flux at the head surface associated with the synchronized electrical activity of neuronal populations. Among the most actively sought applications of MEG has been localization of language-specific cortex. This is in part due to its practical application for pre-surgical evaluation of patients with epilepsy or brain tumors. Until recently, comprehensive language mapping during surgical planning has relied on the application of invasive diagnostic methods, namely the Wada procedure and direct electrocortical stimulation mapping, often considered as the "gold standard" techniques for identifying language-specific cortex. In this review, we evaluate the utility of MEG as a tool for functional mapping of language in both clinical and normal populations. In particular, we provide a general description of MEG, with emphasis on facets of the technique related to language mapping. Additionally, we discuss the application of appropriate MEG language-mapping protocols developed to reliably generate spatiotemporal profiles of language activity, and address the validity of the technique against the "gold standards" of the Wada and electrocortical mapping procedures. PMID- 20160986 TI - Perceptual learning of co-articulation in speech. AB - Four experiments investigated the novel issue of learning to accommodate the coarticulated nature of speech. Experiment 1 established a co-articulatory mismatch effect for a set of vowel-consonant (VC) syllables (reaction times were faster for co-articulation matching than for mismatching stimuli). A rhyme judgment training task on words (Experiment 2) or VC stimuli (Experiment 3) with mismatching information was followed by a phoneme monitoring task on a set of VC stimuli; training and test stimuli contained physically identical (same condition) or new (different condition) mismatching coarticulatory information (along with a set containing matching coarticulatory information). A third group received no training. A coarticulatory mismatch effect was found without training but not when the same mismatching tokens were used at training and test. Both word (Experiment 2) and syllable (Experiment 3) training stimuli eliminated the mismatch effect; overall reaction times were somewhat slower when the training stimuli were words. Perceptual learning generalized to new tokens only when the acoustic manifestation of the critical co-articulatory information in the training stimuli was sufficiently large (Experiments 3 and 4). The results are discussed in terms of speech processing and perceptual learning in speech perception. PMID- 20160987 TI - The Inner Healer: Mind-body Strategies for Health. PMID- 20160988 TI - Developmental Changes in Judgments of Authentic Objects. AB - This study examined the development of an understanding of authenticity among 112 children (preschoolers, kindergarten, 1(st)-graders, and 4(th)-graders) and 119 college students. Participants were presented with pairs of photographs depicting authentic and non-authentic objects and asked to pick which one belongs in a museum and which one they would want to have. Results suggest that both children and adults recognize the special nature of authentic objects by reporting that they belong in a museum. However, this belief broadens with age, at first just for famous associations (preschool), then also for original creations (kindergarten), and finally for personal associations as well (4(th) grade). At all ages, an object's authentic nature is distinct from its desirability. Thus, from an early age, children appear to understand that the historical path of an authentic object affects its nature. This work demonstrates the importance of non obvious properties in children's concepts. For preschool as well as older children, history (a non-visible property) adds meaning beyond the material or functional worth of an object. PMID- 20160989 TI - Perceived Social Standing among Asian Immigrants in the U.S.: Do Reasons for Immigration Matter? AB - We investigate the association between a subjective measure of social status and the reasons for immigration among Asian immigrants in the U.S. We use data from the National Latino and Asian American Study to test several hypotheses about this association. Our analyses show the positive effect on perceived social standing of migrating for better education, the negative effect of migrating to seek employment, and the negative impact of refugee status. Migrating for family reunification can be associated with various circumstances, which lead to differing outcomes. The results suggest that the notion that immigrants arrive in the U.S. with limited resources and few skills and move slowly up the socioeconomic ladder must be reassessed in light of the complex social context and factors such as ethnicity, gender, divergent immigration paths, and a range of associated circumstances. PMID- 20160990 TI - Let's Talk about Complementary and Alternative Therapies. PMID- 20160992 TI - Parents' Beliefs about Emotions and Children's Recognition of Parents' Emotions. AB - This study investigated parents' emotion-related beliefs, experience, and expression, and children's recognition of their parents' emotions with 40 parent child dyads. Parents reported beliefs about danger and guidance of children's emotions. While viewing emotion-eliciting film clips, parents self-reported their emotional experience and masking of emotion. Children and observers rated videos of parents watching emotion-eliciting film clips. Fathers reported more masking than mothers and their emotional expressions were more difficult for both observers and children to recognize compared with mothers' emotional expressions. For fathers, but not mothers, showing clearer expressions was related to children's general skill at recognizing emotional expressions. Parents who believe emotions are dangerous reported greater masking of emotional expression. Contrary to hypothesis, when parents strongly believe in guiding their child's emotion socialization, children showed less accurate recognition of their parents' emotions. PMID- 20160993 TI - Synthesis and in vitro Efficacy Studies of Silver Carbene Complexes on Biosafety Level 3 Bacteria. AB - A series of N-heterocyclic carbene silver complexes have been synthesized and tested against the select group of bio-safety level 3 bacteria Burkholderia pseudomallei, Burkholderia mallei, Bacillus anthracis, methicillin-resistant Staphylococcus aureus and Yersinia pestis. Minimal inhibitory concentrations, minimal bactericidal and killing assays demonstrated the exceptional efficacy of the complexes against these potentially weaponizable pathogens. PMID- 20160991 TI - Automated NMR Assignment and Protein Structure Determination using Sparse Dipolar Coupling Constraints. PMID- 20160994 TI - Figure-Ground Segmentation Using Factor Graphs. AB - Foreground-background segmentation has recently been applied [26,12] to the detection and segmentation of specific objects or structures of interest from the background as an efficient alternative to techniques such as deformable templates [27]. We introduce a graphical model (i.e. Markov random field)-based formulation of structure-specific figure-ground segmentation based on simple geometric features extracted from an image, such as local configurations of linear features, that are characteristic of the desired figure structure. Our formulation is novel in that it is based on factor graphs, which are graphical models that encode interactions among arbitrary numbers of random variables. The ability of factor graphs to express interactions higher than pairwise order (the highest order encountered in most graphical models used in computer vision) is useful for modeling a variety of pattern recognition problems. In particular, we show how this property makes factor graphs a natural framework for performing grouping and segmentation, and demonstrate that the factor graph framework emerges naturally from a simple maximum entropy model of figure-ground segmentation.We cast our approach in a learning framework, in which the contributions of multiple grouping cues are learned from training data, and apply our framework to the problem of finding printed text in natural scenes. Experimental results are described, including a performance analysis that demonstrates the feasibility of the approach. PMID- 20160995 TI - PEI-PEG-Chitosan Copolymer Coated Iron Oxide Nanoparticles for Safe Gene Delivery: synthesis, complexation, and transfection. AB - Gene therapy offers the potential of mediating disease through modification of specific cellular functions of target cells. However, effective transport of nucleic acids to target cells with minimal side effects remains a challenge despite the use of unique viral and non-viral delivery approaches. Here we present a non-viral nanoparticle gene carrier that demonstrates effective gene delivery and transfection both in vitro and in vivo. The nanoparticle system (NP CP-PEI) is made of a superparamagnetic iron oxide nanoparticle (NP), which enables magnetic resonance imaging, coated with a novel copolymer (CP-PEI) comprised of short chain polyethylenimine (PEI) and poly(ethylene glycol) (PEG) grafted to the natural polysaccharide, chitosan (CP), which allows efficient loading and protection of the nucleic acids. The function of each component material in this nanoparticle system is illustrated by comparative studies of three nanoparticle systems of different surface chemistries, through material property characterization, DNA loading and transfection analyses, and toxicity assessment. Significantly, NP-CP-PEI demonstrates an innocuous toxic profile and a high level of expression of the delivered plasmid DNA in a C6 xenograft mouse model, making it a potential candidate for safe in vivo delivery of DNA for gene therapy. PMID- 20160996 TI - "God Made me Gay for a Reason": Young Men who have Sex with Men's Resiliency in Resolving Internalized Homophobia from Religious Sources. AB - Research investigating the role of religion in the lives of young men who have sex with men (YMSM) is limited. Given the unique developmental stage of emerging adults and the fact that most religions have restrictions on homosexual behavior, it is important to understand how YMSM integrate their sexual and religious/spiritual identities. Drawing upon a longitudinal, mixed methods study, we explore the role of religion and spirituality in the lives of a sample of YMSM. Presented are descriptions of messages about homosexuality from religious contexts and how these messages are internalized. The process used to resolve the conflict between these messages and their sexual identity is then described. Findings discuss how to help YMSM retain the more supportive and nurturing aspects of religion to integrate their sexual and religious identities for a functional support system. PMID- 20160997 TI - Making simple sentences hard: Verb bias effects in simple direct object sentences. AB - Constraint-based lexical models of language processing assume that readers resolve temporary ambiguities by relying on a variety of cues, including particular knowledge of how verbs combine with nouns. Previous experiments have demonstrated verb bias effects only in structurally complex sentences, and have been criticized on the grounds that such effects could be due to a rapid reanalysis stage in a two-stage modular processing system. In a self-paced reading experiment and an eyetracking experiment, we demonstrate verb bias effects in sentences with simple structures that should require no reanalyis, and thus provide evidence that the combinatorial properties of individual words influence the earliest stages of sentence comprehension. PMID- 20160998 TI - Estimating smooth distribution function in the presence of heteroscedastic measurement errors. AB - Measurement error occurs in many biomedical fields. The challenges arise when errors are heteroscedastic since we literally have only one observation for each error distribution. This paper concerns the estimation of smooth distribution function when data are contaminated with heteroscedastic errors. We study two types of methods to recover the unknown distribution function: a Fourier-type deconvolution method and a simulation extrapolation (SIMEX) method. The asymptotics of the two estimators are explored and the asymptotic pointwise confidence bands of the SIMEX estimator are obtained. The finite sample performances of the two estimators are evaluated through a simulation study. Finally, we illustrate the methods with medical rehabilitation data from a neuro muscular electrical stimulation experiment. PMID- 20160999 TI - Use of nuclear magnetic resonance-based metabolomics in detecting drug resistance in cancer. AB - Cancer cells possess a highly unique metabolic phenotype, which is characterized by high glucose uptake, increased glycolytic activity, decreased mitochondrial activity, low bioenergetic and increased phospholipid turnover. These metabolic hallmarks can be readily assessed by metabolic technologies - either in vitro or in vivo - to monitor responsiveness and resistance to novel targeted drugs, where specific inhibition of cell proliferation (cytostatic effect) occurs rather than direct induction of cell death (cytotoxicity). Using modern analytical technologies in combination with statistical approaches, 'metabolomics', a global metabolic profile on patient samples can be established and validated for responders and nonresponders, providing additional metabolic end points. Discovered metabolic end points should be translated into noninvasive metabolic imaging protocols. PMID- 20161001 TI - Formation and properties of magnetic chains for 100 nm nanoparticles used in separations of molecules and cells. AB - Optical observations of 100 nm metallic magnetic nanoparticles are used to study their magnetic field induced self assembly. Chains with lengths of tens of microns are observed to form within minutes at nanoparticle concentrations of 10(10) per mL. Chain rotation and magnetophoresis are readily observed, and SEM reveals that long chains are not simple single particle filaments. Similar chains are detected for several 100 nm commercial bio-separation nanoparticles. We demonstrate the staged magnetic condensation of different types of nanoparticles into composite structures and show that magnetic chains bind to immunomagnetically labeled cells, serving as temporary handles which allow novel magnetic cell manipulations. PMID- 20161002 TI - Theory for nanoparticle retention time in the helical channel of quadrupole magnetic field-flow fractionation. AB - Quadrupole magnetic field-flow fractionation (QMgFFF) is a separation and characterization technique for magnetic nanoparticles such as those used for cell labeling and for targeted drug therapy. A helical separation channel is used to efficiently exploit the quadrupole magnetic field. The fluid and sample components therefore have angular and longitudinal components to their motion in the thin annular space occupied by the helical channel. The retention ratio is defined as the ratio of the times for non retained and a retained material to pass through the channel. Equations are derived for the respective angular and longitudinal components to retention ratio. PMID- 20161000 TI - Noninvasive methods to assess the risk of kidney transplant rejection. AB - In current clinical practice, immune reactivity of kidney transplant recipients is estimated by monitoring the levels of immunosuppressive drugs, and by functional and/or histological evaluation of the allograft. The availability of assays that could directly quantify the extent of the recipient's immune response towards the allograft would help clinicians to customize the prescription of immunosuppressive drugs to individual patients. Importantly, these assays might provide a more in-depth understanding of the complex mechanisms of acute rejection, chronic injury, and tolerance in organ transplantation, allowing the design of new and potentially more effective strategies for the minimization of immunosuppression, or even for the induction of immunological tolerance. The purpose of this review is to summarize results from recent studies in this field. PMID- 20161003 TI - Modelling and Recognition of the Linguistic Components in American Sign Language. AB - The manual signs in sign languages are generated and interpreted using three basic building blocks: handshape, motion, and place of articulation. When combined, these three components (together with palm orientation) uniquely determine the meaning of the manual sign. This means that the use of pattern recognition techniques that only employ a subset of these components is inappropriate for interpreting the sign or to build automatic recognizers of the language. In this paper, we define an algorithm to model these three basic components form a single video sequence of two-dimensional pictures of a sign. Recognition of these three components are then combined to determine the class of the signs in the videos. Experiments are performed on a database of (isolated) American Sign Language (ASL) signs. The results demonstrate that, using semi automatic detection, all three components can be reliably recovered from two dimensional video sequences, allowing for an accurate representation and recognition of the signs. PMID- 20161005 TI - CHARMM Additive All-Atom Force Field for Glycosidic Linkages between Hexopyranoses. AB - We present an extension of the CHARMM hexopyranose monosaccharide additive all atom force field to enable modeling of glycosidic-linked hexopyranose polysaccharides. The new force field parameters encompass 1->1, 1->2, 1->3, 1->4, and 1->6 hexopyranose glycosidic linkages, as well as O-methylation at the C(1) anomeric carbon, and are developed to be consistent with the CHARMM all-atom biomolecular force fields for proteins, nucleic acids, and lipids. The parameters are developed in a hierarchical fashion using model compounds containing the key atoms in the full carbohydrates, in particular O-methyl-tetrahydropyran and glycosidic-linked dimers consisting of two molecules of tetrahyropyran or one of tetrahydropyran and one of cyclohexane. Target data for parameter optimization include full two-dimensional energy surfaces defined by the Phi/Psi glycosidic dihedral angles in the disaccharide analogs as determined by quantum mechanical MP2/cc-pVTZ single point energies on MP2/6-31G(d) optimized structures (MP2/cc pVTZ//MP2/6-31G(d)). In order to achieve balanced, transferable dihedral parameters for the Phi/Psi glycosidic dihedral angles, surfaces for all possible chiralities at the ring carbon atoms involved in the glycosidic linkages are considered, resulting in over 5000 MP2/cc-pVTZ//MP2/6-31G(d) conformational energies. Also included as target data are vibrational frequencies, pair interaction energies and distances with water molecules, and intramolecular geometries including distortion of the glycosidic valence angle as a function of the glycosidic dihedral angles. The model-compound optimized force field parameters are validated on full disaccharides through comparison of molecular dynamics results to available experimental data. Good agreement is achieved with experiment for a variety of properties including crystal cell parameters and intramolecular geometries, aqueous densities, and aqueous NMR coupling constants associated with the glycosidic linkage. The newly-developed parameters allow for the modeling of linear, branched, and cyclic hexopyranose glycosides both alone and in heterogenous systems including proteins, nucleic acids and/or lipids when combined with existing CHARMM biomolecular force fields. PMID- 20161004 TI - Multifunctional Quantum Dots for Personalized Medicine. AB - Successes in biomedical research and state-of-the-art medicine have undoubtedly improved the quality of life. However, a number of diseases, such as cancer, immunodeficiencies, and neurological disorders, still evade conventional diagnostic and therapeutic approaches. A transformation towards personalized medicine may help to combat these diseases. For this, identification of disease molecular fingerprints and their association with prognosis and targeted therapy must become available. Quantum dots (QDs), semiconductor nanocrystals with unique photo-physical properties, represent a novel class of fluorescence probes to address many of the needs of personalized medicine. This review outlines the properties of QDs that make them a suitable platform for advancing personalized medicine, examines several proof-of-concept studies showing utility of QDs for clinically relevant applications, and discusses current challenges in introducing QDs into clinical practice. PMID- 20161006 TI - The processing and comprehension of wh-questions among L2 German speakers. AB - Using the self-paced-reading paradigm, the present study examines whether highly proficient second language (L2) speakers of German (English L1) use case-marking information during the on-line comprehension of unambiguous wh-extractions, even when task demands do not draw explicit attention to this morphosyntactic feature in German. Results support previous findings, in that both the native and the L2 German speakers exhibited an immediate subject-preference in the matrix clause, suggesting they were sensitive to case-marking information. However, only among the native speakers did this subject-preference carry over to reading times in the complement clause. The results from the present study are discussed in light of current debates regarding the ability of L2 speakers to attain native-like processing strategies in their L2. PMID- 20161007 TI - Stable isotope-labeled tracers for the investigation of fatty acid and triglyceride metabolism in humans in vivo. AB - Understanding lipid metabolism and its regulation requires information on the rates at which lipids are produced within the body, absorbed (dietary lipids) into the body, transported within the body, and utilized by various tissues. This article focuses on the use of stable isotope-labeled tracers for the quantitative evaluation of major pathways of fatty acid and triglyceride metabolism in humans in vivo. Adipose tissue lipolysis and free fatty acid appearance in plasma, fatty acid tissue uptake and oxidation, and hepatic very low-density lipoprotein triglyceride secretion are among the metabolic pathways that can be studied by using stable isotope labeled tracers, and will be discussed in detail. The methodology has been in use for many years and is constantly being refined. A variety of tracers and analytical approaches are available and can be used; knowing the advantages, assumptions, and limitations of each is essential for the planning of studies and the interpretation of data, which can provide unique insights into human lipid metabolism. PMID- 20161009 TI - Using a similarity measure for credible classification. AB - This paper concerns classification by Boolean functions. We investigate the classification accuracy obtained by standard classification techniques on unseen points (elements of the domain, {0, 1}(n), for some n) that are similar, in particular senses, to the points that have been observed as training observations. Explicitly, we use a new measure of how similar a point x in {0, 1}(n) is to a set of such points to restrict the domain of points on which we offer a classification. For points sufficiently dissimilar, no classification is given. We report on experimental results which indicate that the classification accuracies obtained on the resulting restricted domains are better than those obtained without restriction. These experiments involve a number of standard data sets and classification techniques. We also compare the classification accuracies with those obtained by restricting the domain on which classification is given by using the Hamming distance. PMID- 20161008 TI - Longitudinal Predictors of Bipolar Spectrum Disorders: A Behavioral Approach System (BAS) Perspective. AB - We review longitudinal predictors, primarily psychosocial, of the onset, course, and expression of bipolar spectrum disorders. We organize our review along a proximal - distal continuum, discussing the most proximal (i.e., prodromes) predictors of bipolar episodes first, then recent environmental (i.e., life events) predictors of bipolar symptoms and episodes next, followed by more distal psychological (i.e., cognitive styles) predictors, and ending with the most distal temperament (i.e., Behavioral Approach System sensitivity) predictors. We then present a theoretical model, the Behavioral Approach System (BAS) dysregulation model, for understanding and integrating the role of these predictors of bipolar spectrum disorders. Finally, we consider the implications of the reviewed longitudinal predictors for future research and psychosocial treatments of bipolar disorders. PMID- 20161010 TI - Current Directions in Videoconferencing Tele-Mental Health Research. AB - The provision of mental health services via videoconferencing tele-mental health has become an increasingly routine component of mental health service delivery throughout the world. Emphasizing the research literature since 2003, we examine: 1) the extent to which the field of tele-mental health has advanced the research agenda previously suggested; and 2) implications for tele-mental health care delivery for special clinical populations. Previous findings have demonstrated that tele-mental health services are satisfactory to patients, improve outcomes, and are probably cost effective. In the very small number of randomized controlled studies that have been conducted to date, tele-mental health has demonstrated equivalent efficacy compared to face-to-face care in a variety of clinical settings and with specific patient populations. However, methodologically flawed or limited research studies are the norm, and thus the research agenda for tele-mental health has not been fully maximized. Implications for future research and practice are discussed. PMID- 20161011 TI - New Approach to 4-Phenyl-beta-aminotetralin from 4-(3-Halophenyl)tetralen-2-ol Phenylacetate. AB - Mixed trifluoroacetyl phenylacetyl anhydride and 3-halostyrenes (fluoro, chloro, and bromo) or vinylcycloalkanes (cyclohexyl, cyclooctyl), undergo cascade Friedel Crafts cycli-acylalkylation, enolization, and O-acylation to give 4-substituted tetralen-2-ol phenylacetates, without additional solvent in good yields. Base alcoholysis of 4-phenyltetralen-2-ol phenylacetate reveals the tetral-2-one for asymmetric transfer hydrogenation. Bromophenyltetralen-2-ol phenylacetate undergoes Suzuki coupling, and provides a short route to trans-4-phenyl-beta aminotetralin. PMID- 20161013 TI - An improved bound on the Maximum Agreement Subtree problem. AB - We improve the lower bound on the extremal version of the Maximum Agreement Subtree problem. Namely we prove that two binary trees on the same n leaves have subtrees with the same >= c log log n leaves which are homeomorphic, such that homeomorphism is identity on the leaves. PMID- 20161012 TI - When less is more and when more is more: The mediating roles of capacity and speed in brain-behavior efficiency. AB - An enduring enterprise of experimental psychology has been to account for individual differences in human performance. Recent advances in neuroimaging have permitted testing of hypotheses regarding the neural bases of individual differences but this burgeoning literature has been characterized by inconsistent results. We argue that careful design and analysis of neuroimaging studies is required to separate individual differences in processing capacity from individual differences in processing speed to account for these differences in the literature. We utilized task designs which permitted separation of processing capacity influences on brain-behavior relationships from those related to processing speed. In one set of studies, participants performed verbal delayed recognition tasks during blocked and event-related fMRI scanning. The results indicated that those participants with greater working memory (WM) capacity showed greater prefrontal cortical activity, strategically capitalized on the additional processing time available in the delay period, and evinced faster WM retrieval rates than low-capacity participants. In another study, participants performed a digit-symbol substitution task (DSST) designed to minimize WM storage capacity requirements and maximize processing speed requirements during fMRI scanning. In some prefrontal cortical (PFC) brain regions, participants with faster processing speed showed less PFC activity than slower performers while in other PFC and parietal regions they showed greater activity. Regional-causality analysis indicated that PFC exerted more influence over other brain regions for slower than for faster individuals. These results support a model of neural efficiency in which individuals differ in the extent of direct processing links between neural nodes. One benefit of direct processing links may be a surplus of resources that maximize available capacity permitting fast and accurate performance. PMID- 20161014 TI - Automatic processing of wh- and NP-movement in agrammatic aphasia: Evidence from eyetracking. AB - Individuals with agrammatic Broca's aphasia show deficits in comprehension of non canonical wh-movement and NP-movement sentences. Previous work using eyetracking has found that agrammatic and unimpaired listeners show very similar patterns of automatic processing for wh-movement sentences. The current study attempts to replicate this finding for sentences with wh-movement (in object relatives in the current study) and to extend it to sentences with NP movement (passives). For wh movement sentences, aphasic and control participants' eye-movements differed most dramatically in late regions of the sentence and post-offset, with aphasic participants exhibiting lingering attention to a salient but grammatically impermissible competitor. The eye-movement differences between correct and incorrect trials for wh-movement sentences were similar, with incorrect trials also exhibiting competition from an impermissible interpretation late in the sentence. Furthermore, the two groups exhibited similar eye-movement patterns in response to passive NP-movement sentences, but showed little evidence of gap filling for passives. The results suggest that aphasic and unimpaired individuals may generate similar representations during comprehension, but that aphasics are highly vulnerable to interference from alternative interpretations (Ferreira, 2003). PMID- 20161016 TI - An Examination of Content Overlap and Disorder-Specific Predictions in the Associations of Neuroticism with Anxiety and Depression. AB - This study examines whether content overlap artificially inflates estimates of the associations of emotional disorders with neuroticism and whether disorder specificity of prediction exists. We demonstrated a statistical approach for testing the validity of hypothesized facets of neuroticism. In a sample of 627 adolescents, we indentified six facets of neuroticism, one intermediate facet, and a general neuroticism factor (GNF). Only the GNF and the depression facet were significantly associated with depressive symptomatology. The GNF and all facets significantly predicted anxiety symptomatology. This study offers a new statistical approach for addressing content overlap, testing for disorder specific prediction and identifying facets of a broad personality trait, while indicating that content overlap does not largely explain the associations of neuroticism with psychopathology. PMID- 20161015 TI - A bonding model for gold(I) carbene complexes. AB - The last decade has witnessed dramatic growth in the number of reactions catalyzed by electrophilic gold complexes. While proposed mechanisms often invoke the intermediacy of gold-stabilized cationic species, the nature of bonding in these intermediates remains unclear. Herein, we propose that the carbon-gold bond in these intermediates is comprised of varying degrees of both sigma and pi bonding; however, the overall bond order is generally less than or equal to unity. The bonding in a given gold-stabilized intermediate, and the position of this intermediate on a continuum ranging from gold-stabilized singlet carbene to gold-coordinated carbocation, is dictated by the carbene substituents and the ancillary ligand. Experiments show that the correlation between bonding and reactivity is reflected in the yield of gold-catalyzed cyclopropanation reactions. PMID- 20161017 TI - Letter-transposition effects are not universal: The impact of transposing letters in Hebrew. AB - We examined the effects of letter transposition in Hebrew in three masked-priming experiments. Hebrew, like English has an alphabetic orthography where sequential and contiguous letter strings represent phonemes. However, being a Semitic language it has a non-concatenated morphology that is based on root derivations. Experiment 1 showed that transposed-letter (TL) root primes inhibited responses to targets derived from the non-transposed root letters, and that this inhibition was unrelated to relative root frequency. Experiment 2 replicated this result and showed that if the transposed letters of the root created a nonsense-root that had no lexical representation, then no inhibition and no facilitation were obtained. Finally, Experiment 3 demonstrated that in contrast to English, French, or Spanish, TL nonword primes did not facilitate recognition of targets, and when the root letters embedded in them consisted of a legal root morpheme, they produced inhibition. These results suggest that lexical space in alphabetic orthographies may be structured very differently in different languages if their morphological structure diverges qualitatively. In Hebrew, lexical space is organized according to root families rather than simple orthographic structure, so that all words derived from the same root are interconnected or clustered together, independent of overall orthographic similarity. PMID- 20161018 TI - Modeling Covariance Matrices via Partial Autocorrelations. AB - We study the role of partial autocorrelations in the reparameterization and parsimonious modeling of a covariance matrix. The work is motivated by and tries to mimic the phenomenal success of the partial autocorrelations function (PACF) in model formulation, removing the positive-definiteness constraint on the autocorrelation function of a stationary time series and in reparameterizing the stationarity-invertibility domain of ARMA models. It turns out that once an order is fixed among the variables of a general random vector, then the above properties continue to hold and follows from establishing a one-to-one correspondence between a correlation matrix and its associated matrix of partial autocorrelations. Connections between the latter and the parameters of the modified Cholesky decomposition of a covariance matrix are discussed. Graphical tools similar to partial correlograms for model formulation and various priors based on the partial autocorrelations are proposed. We develop frequentist/Bayesian procedures for modelling correlation matrices, illustrate them using a real dataset, and explore their properties via simulations. PMID- 20161019 TI - Optimization of ceramic strength using elastic gradients. AB - We present a new concept for strengthening ceamics by utilizing a graded structure with a low elastic modulus at both top and bottom surfaces sandwiching a high-modulus interior. Closed-form equations have been developed for stress analysis of simply supported graded sandwich beams subject to transverse center loads. Theory predicts that suitable modulus gradients at the ceramic surface can effectively reduce and spread the maximum bending stress from the surface into the interior. The magnitude of such stress dissipation is governed by the thickness ratio of the beam to the graded layers. We test our concept by infiltrating both top and bottom surfaces of a strong class of zirconia ceramic with an in-house prepared glass of similar coefficient of thermal expansion and Poisson's ratio to zirconia, producing a controlled modulus gradient at the surface without significant long-range residual stresses. The resultant graded glass/zirconia/glass composite exhibits significantly higher load-bearing capacity than homogeneous zirconia. PMID- 20161020 TI - Approaches to biomarkers in human colorectal cancer: looking back, to go forward. AB - Like all human cancers, colorectal cancer is a complicated disease. While a mature body of research involving colorectal cancer has implicated the putative sequence of genetic alterations that trigger the disease and sustain its progression, there is a surprising paucity of well-validated, clinically useful diagnostic markers of this disease. For prognosis or guiding therapy, single gene based markers of colorectal cancer often have limited specificity and sensitivity. Genome-wide analyses (microarrays) have been used to propose candidate patterns of gene expression that are prognostic of outcome or predict the tumor's response to a therapy regimen; however, these patterns frequently do not overlap, and this has raised questions concerning their use as biomarkers. The limitation of gene-expression approaches to marker discovery occurs because the change in mRNA expression across tumors is highly variable and, alone, accounts for a limited variability of the phenotype, such as with cancer. More robust and accurate markers of cancer will result from integrating all the information we have about the cell: genomics, proteomics and interactomics. This article will discuss traditional markers in colorectal cancer, both genomic and proteomic, including their respective approaches and limitations, then conclude with examples of systems biology-based approaches for candidate marker discovery, and discuss how this approach is reshaping our view of a biomarker. PMID- 20161021 TI - Optimizing Data Intensive GPGPU Computations for DNA Sequence Alignment. AB - MUMmerGPU uses highly-parallel commodity graphics processing units (GPU) to accelerate the data-intensive computation of aligning next generation DNA sequence data to a reference sequence for use in diverse applications such as disease genotyping and personal genomics. MUMmerGPU 2.0 features a new stackless depth-first-search print kernel and is 13* faster than the serial CPU version of the alignment code and nearly 4* faster in total computation time than MUMmerGPU 1.0. We exhaustively examined 128 GPU data layout configurations to improve register footprint and running time and conclude higher occupancy has greater impact than reduced latency. MUMmerGPU is available open-source at http://mummergpu.sourceforge.net. PMID- 20161022 TI - Coordination of Mastication, Swallowing and Breathing. AB - The pathways for air and food cross in the pharynx. In breathing, air may flow through either the nose or the mouth, it always flows through the pharynx. During swallowing, the pharynx changes from an airway to a food channel. The pharynx is isolated from the nasal cavity and lower airway by velopharyngeal and laryngeal closure during the pharyngeal swallow. During mastication, the food bolus accumulates in the pharynx prior to swallow initiation. The structures in the oral cavity, pharynx and larynx serve multiple functions in breathing, speaking, mastication and swallowing. Thus, the fine temporal coordination of feeding among breathing, mastication and swallowing is essential to provide proper food nutrition and to prevent pulmonary aspiration. This review paper will review the temporo-spatial coordination of the movements of oral, pharyngeal, and laryngeal structures during mastication and swallowing, and temporal coordination between breathing, mastication, and swallowing. PMID- 20161023 TI - Spatial distortion correction and crystal identification for MRI-compatible position-sensitive avalanche photodiode-based PET scanners. AB - Position-sensitive avalanche photodiodes (PSAPDs) are gaining widespread acceptance in modern PET scanner designs, and owing to their relative insensitivity to magnetic fields, especially in those that are MRI-compatible. Flood histograms in PET scanners are used to determine the crystal of annihilation photon interaction and hence, for detector characterization and routine quality control. For PET detectors that use PSAPDs, flood histograms show a characteristic pincushion distortion when Anger logic is used for event positioning. A small rotation in the flood histogram is also observed when the detectors are placed in a magnetic field. We first present a general purpose automatic method for spatial distortion correction for flood histograms of PSAPD based PET detectors when placed both inside and outside a MRI scanner. Analytical formulae derived for this scheme are based on a hybrid approach that combines desirable properties from two existing event positioning schemes. The rotation of the flood histogram due to the magnetic field is determined iteratively and is accounted for in the scheme. We then provide implementation details of a method for crystal identification we have previously proposed and evaluate it for cases when the PET detectors are both outside and in a magnetic field. In this scheme, Fourier analysis is used to generate a lower-order spatial approximation of the distortion-corrected PSAPD flood histogram, which we call the 'template'. The template is then registered to the flood histogram using a diffeomorphic iterative intensity-based warping scheme. The calculated deformation field is then applied to the segmentation of the template to obtain a segmentation of the flood histogram. A manual correction tool is also developed for exceptional cases. We present a quantitative assessment of the proposed distortion correction scheme and crystal identification method against conventional methods. Our results indicate that our proposed methods lead to a large reduction in manual labor and indeed can routinely be used for calibration and characterization studies in MRI-compatible PET scanners based on PSAPDs. PMID- 20161024 TI - Hijacking transferrin bound iron: protein-receptor interactions involved in iron transport in N. gonorrhoeae. AB - Neisseria gonorrhoeae has the capacity to acquire iron from its human host by removing this essential nutrient from serum transferrin. The transferrin binding proteins, TbpA and TbpB constitute the outer membrane receptor complex responsible for binding transferrin, extracting the tightly bound iron from the host-derived molecule, and transporting iron into the periplasmic space of this Gram-negative bacterium. Once iron is transported across the outer membrane, ferric binding protein A (FbpA) moves the iron across the periplasmic space and initiates the process of transport into the bacterial cytosol. The results of the studies reported here define the multiple steps in the iron transport process in which TbpA and TbpB participate. Using the SUPREX technique for assessing the thermodynamic stability of protein-ligand complexes, we report herein the first direct measurement of periplasmic FbpA binding to the outer membrane protein TbpA. We also show that TbpA discriminates between apo- and holo-FbpA; i.e. the TbpA interaction with apo-FbpA is higher affinity than the TbpA interaction with holo-FbpA. Further, we demonstrate that both TbpA and TbpB individually can deferrate transferrin and ferrate FbpA without energy supplied from TonB resulting in sequestration by apo-FbpA. PMID- 20161025 TI - Effects of Aging on Associative Memory for Related and Unrelated Pictures. AB - Associative memory deficits are pervasive with age. Memory for complex pictures, however, also seems to require the association of several scene elements into one representation, but picture memory is often age-invariant. We speculated that the natural relationships contained in pictures may explain this distinction and that memory for scenes with unusual novel relationships would be affected with aging. In three experiments, we found that, counter to our predictions, the relatedness of scene elements exerted little influence on picture memory and did not differentially affect older compared to younger adults. These data suggest that the semantically rich associations contained in pictures need not rely on prior knowledge and experiences in order to support age-invariant picture memory. Our results indicate that associative memory for complex pictures may differ from memory for inter-item associations, which may be more affected by aging. PMID- 20161026 TI - Two-Mode Models of Self-Regulation as a Tool for Conceptualizing Effects of the Serotonin System in Normal Behavior and Diverse Disorders. AB - The serotonin system is a collection of neural pathways whose overall level of functioning (from low to high) relates to diverse kinds of psychological and behavioral variability. Individual differences in serotonergic function are important both in personality and in vulnerability to psychological disorders. These disorders range widely-from impulsive aggression to depression. One way to understand such diverse reflections of differences in serotonergic function is by viewing serotonergic function through the lens of two-mode (or dual-process) models of self-regulation. Such theories posit a lower-order system that responds quickly to associative cues of the moment and a higher-order system that responds reflectively and planfully. Low serotonergic function appears to enhance influence of the lower-order system. This often yields impulsive reactivity. Why, then, does low serotonergic function also relate to depression, which is characterized by lethargy and unresponsiveness? The answer must be that ascendance of the lower system interacts with other factors. One hypothesis is that low serotonergic function plus high sensitivity to incentives yields vulnerability to impulsive approach, whereas low serotonergic function plus low incentive sensitivity yields vulnerability to depression. Conceptualizing serotonergic function this way helps integrate information pertaining to very different disorders into a coherent picture. PMID- 20161027 TI - Isolation of Specific Cranberry Flavonoids for Biological Activity Assessment. PMID- 20161028 TI - An Examination of the Role of Perceptions in Neighborhood Research. AB - Accumulating research demonstrates that both archival indicators and residents' self-reports of neighborhood conditions are useful predictors of a variety of physical health, mental health, substance use, criminal, and educational outcomes. Although studies have shown these two types of measures are often related, no research has systematically examined their relationship. With a sample of Mexican Americans, this study examined this relationship and demographic factors that might account for variations of residents' perceptions of their neighborhoods. Results showed that country of birth, social class, family structure, and gender moderated relations between archival variables and adults' perceptions of danger. Thus using information from both archival data and self-reports should improve the ability of neighborhood researchers to understand individual differences in responses to neighborhood conditions. PMID- 20161029 TI - The inverse problem for certain tree parameters. AB - Let p be a graph parameter that assigns a positive integer value to every graph. The inverse problem for p asks for a graph within a prescribed class (here, we will only be concerned with trees), given the value of p. In this context, it is of interest to know whether such a graph can be found for all or at least almost all integer values of p. We will provide a very general setting for this type of problem over the set of all trees, describe some simple examples and finally consider the interesting parameter "number of subtrees", where the problem can be reduced to some number-theoretic considerations. Specifically, we will prove that every positive integer, with only 34 exceptions, is the number of subtrees of some tree. PMID- 20161030 TI - Trajectories of Conflict over Raising Adolescent Children and Marital Satisfaction. AB - The present study examined trajectories of marital satisfaction among couples with adolescent children and evaluated how changes in parents' conflict over raising adolescent children were associated with changes in marital satisfaction over four years. Using a prospective, longitudinal research design and controlling for family socioeconomic status, dyadic growth curve analysis from a sample of 431 couples with adolescent children indicated that marital satisfaction decreased over time for parents with adolescent children, and that the trajectories for mothers and fathers were substantially linked. More importantly, the study demonstrated that increases or decreases in parents' marital conflict over raising adolescent children were associated with corresponding decreases or increases in marital satisfaction for both mothers and fathers. PMID- 20161031 TI - Context Awareness in a Handheld Exercise Agent. AB - Work towards the development of a handheld health counseling agent designed to promote physical activity is described. Previous work on automated health counselors is discussed, along with the affordances of mobility and context awareness for health behavior interventions. We present a general-purpose software architecture for the rapid design and deployment of mobile health counseling agents. We also describe the results of an initial field trial in which such a mobile agent plays the role of an exercise coach designed to motivate users to walk more. Results were mixed. We found that the context awareness mechanism that was implemented for detecting walking led to greater user-agent social bonding, but less walking in study participants. PMID- 20161032 TI - Retro iminonitroso Diels-Alder reactions: interconversion of nitroso cycloadducts. AB - Retro iminonitroso Diels-Alder reactions were investigated in both solution and solid phase. In thermal or Cu(I)-mediated reactions, interconversion of various nitroso cycloadducts occurred in the presence of separate dienes. Up to 99% of conversion was observed. Use of chiral ligands in the Cu(I)-medicated reactions gave new cycloadducts enantioselectively. PMID- 20161033 TI - Personalized pharmacotherapy for Type 2 diabetes mellitus. AB - Genome-wide linkage and association studies have been applied to Type 2 diabetes in order to discover common genetic variation that contributes to disease risk. While there has been progress in understanding how genetic variation predisposes to diabetes, there is less of an understanding of how genetics can alter drug response. The hope is that in the future, pharmacogenetics can help guide the treatment of diabetes, thereby improving control while minimizing side effects in a large group of patients. PMID- 20161034 TI - THE EFFICACY OF HYPNOTIC ANALGESIA IN ADULTS: A REVIEW OF THE LITERATURE. AB - This article both summarizes the previous reviews of randomized, controlled trials of hypnotic analgesia for the treatment of chronic and acute pain in adults, and reviews similar trials which have recently been published in the scientific literature. The results indicate that for both chronic and acute pain conditions: (1) hypnotic analgesia consistently results in greater decreases in a variety of pain outcomes compared to no treatment/standard care; (2) hypnosis frequently out-performs non-hypnotic interventions (e.g. education, supportive therapy) in terms of reductions in pain-related outcomes; and (3) hypnosis performs similarly to treatments that contain hypnotic elements (such as progressive muscle relaxation), but is not surpassed in efficacy by these alternative treatments. Factors that may influence the efficacy of hypnotic analgesia interventions are discussed, including, but not limited to, the patient's level of suggestibility, treatment outcome expectancy, and provider expertise. Based upon this body of literature, suggestions are offered for practitioners who are using, or would like to use, hypnosis for the amelioration of pain problems in their patients or clients. PMID- 20161035 TI - Laplace-Beltrami Eigenvalues and Topological Features of Eigenfunctions for Statistical Shape Analysis. AB - This paper proposes the use of the surface based Laplace-Beltrami and the volumetric Laplace eigenvalues and -functions as shape descriptors for the comparison and analysis of shapes. These spectral measures are isometry invariant and therefore allow for shape comparisons with minimal shape pre-processing. In particular, no registration, mapping, or remeshing is necessary. The discriminatory power of the 2D surface and 3D solid methods is demonstrated on a population of female caudate nuclei (a subcortical gray matter structure of the brain, involved in memory function, emotion processing, and learning) of normal control subjects and of subjects with schizotypal personality disorder. The behavior and properties of the Laplace-Beltrami eigenvalues and -functions are discussed extensively for both the Dirichlet and Neumann boundary condition showing advantages of the Neumann vs. the Dirichlet spectra in 3D. Furthermore, topological analyses employing the Morse-Smale complex (on the surfaces) and the Reeb graph (in the solids) are performed on selected eigenfunctions, yielding shape descriptors, that are capable of localizing geometric properties and detecting shape differences by indirectly registering topological features such as critical points, level sets and integral lines of the gradient field across subjects. The use of these topological features of the Laplace-Beltrami eigenfunctions in 2D and 3D for statistical shape analysis is novel. PMID- 20161036 TI - Functional brain imaging of development-related risk and vulnerability for substance use in adolescents. AB - The adolescent period is characterized by substantial behavioral changes, including increases in novelty-seeking and risk-taking, which may facilitate substance use and experimentation. These behavioral changes co-occur with widespread structural and functional neural developments. Ontogenic changes affecting the neural circuitry subserving inhibitory control and reward-related processes are particularly relevant to adolescent risk-taking behavior. Impairment or immaturity of these processes are shown to contribute to enhanced risk for substance abuse. Additionally, the direct neural action of drugs of abuse in adolescents may have more severe consequences than in adults because of the additional potential effects on development. Functional neuroimaging research is beginning to examine the neural correlates of reward and inhibitory processes in adolescents. However, the study of the consequences of exposure to drugs of abuse on brain function in adolescents is lagging. This review summarizes the functional neuroimaging literature that can inform conceptualizations of risk and consequences of substance use in adolescence. PMID- 20161037 TI - Family sources of educational gender inequality in rural china: A critical assessment. AB - In this paper, we investigate the gender gap in education in rural northwest China. We first discuss parental perceptions of abilities and appropriate roles for girls and boys; parental concerns about old-age support; and parental perceptions of different labor market outcomes for girls' and boys' education. We then investigate gender disparities in investments in children, children's performance at school, and children's subsequent attainment. We analyze a survey of 9-12-year-old children and their families conducted in rural Gansu Province in the year 2000, along with follow-up information about subsequent educational attainment collected 7 years later. We complement our main analysis with two illustrative case studies of rural families drawn from 11 months of fieldwork conducted in rural Gansu between 2003 and 2005 by the second author.In 2000, most mothers expressed egalitarian views about girls' and boys' rights and abilities, in the abstract. However, the vast majority of mothers still expected to rely on sons for old-age support, and nearly one in five mothers interviewed agreed with the traditional saying, "Sending girls to school is useless since they will get married and leave home." Compared to boys, girls faced somewhat lower (though still very high) maternal educational expectations and a greater likelihood of being called on for household chores than boys. However, there was little evidence of a gender gap in economic investments in education. Girls rivaled or outperformed boys in academic performance and engagement. Seven years later, boys had attained just about a third of a year more schooling than girls-a quite modest advantage that could not be fully explained by early parental attitudes and investments, or student performance or engagement. Fieldwork confirmed that parents of sons and daughters tended to have high aspirations for their children. Parents sometimes viewed boys as having greater aptitude, but tended to view girls as having more dedication-an attribute parents perceived as being critical for educational success. Findings suggest that at least in Gansu, rural parental educational attitudes and practices toward boys and girls are more complicated and less uniformly negative for girls than commonly portrayed. PMID- 20161039 TI - Applying capacity analyses to psychophysical evaluation of multisensory interactions. AB - Determining when, if, and how information from separate sensory channels has been combined is a fundamental goal of research on multisensory processing in the brain. This can be a particular challenge in psychophysical data, as there is no direct recording of neural output. The most common way to characterize multisensory interactions in behavioral data is to compare responses to multisensory stimulation with the race model, a model of parallel, independent processing constructed from the probability of responses to the two unisensory stimuli which make up the multisensory stimulus. If observed multisensory reaction times are faster than those predicted by the model, it is inferred that information from the two channels is being combined rather than processed independently. Recently, behavioral research has been published employing capacity analyses where comparisons between two conditions are carried out at the level of the integrated hazard function. Capacity analyses seem to be particularly appealing technique for evaluating multisensory functioning, as they describe relationships between conditions across the entire distribution curve, are relatively easy and intuitive to interpret. The current paper presents capacity analysis of a behavioral data set previously analyzed using the race model. While applications of capacity analyses are still somewhat limited due to their novelty, it is hoped that this exploration of capacity and race model analyses will encourage the use of this promising new technique both in multisensory research and other applicable fields. PMID- 20161038 TI - Molecular imaging and therapy of cancer with radiolabeled nanoparticles. AB - This review summarizes the current state-of-the-art of radiolabeled nanoparticles for molecular imaging and internal radiotherapy applications targeting cancer. With the capacity to provide enormous flexibility, radiolabeled nanoparticles have the potential to profoundly impact disease diagnosis and patient management in the near future. Currently, the major challenges facing the research on radiolabeled nanoparticles are desirable (tumor) targeting efficacy, robust chemistry for both radionuclide encapsulation/incorporation and targeting ligand conjugation, favorable safety profile, as well as certain commercial and regulatory hurdles. PMID- 20161040 TI - A resolution measure for three-dimensional microscopy. AB - A three-dimensional (3D) resolution measure for the conventional optical microscope is introduced which overcomes the drawbacks of the classical 3D (axial) resolution limit. Formulated within the context of a parameter estimation problem and based on the Cramer-Rao lower bound, this 3D resolution measure indicates the accuracy with which a given distance between two objects in 3D space can be determined from the acquired image. It predicts that, given enough photons from the objects of interest, arbitrarily small distances of separation can be estimated with prespecified accuracy. Using simulated images of point source pairs, we show that the maximum likelihood estimator is capable of attaining the accuracy predicted by the resolution measure. We also demonstrate how different factors, such as extraneous noise sources and the spatial orientation of the imaged object pair, can affect the accuracy with which a given distance of separation can be determined. PMID- 20161042 TI - A Vapor Based Microfluidic Flow Regulator. AB - We introduce a flow regulating technology that uses trapped air bubbles in a hydrophobic microfluidic channel. We present basic designs for flow regulators and flow valves using trapped air. Experiments have successfully demonstrated the capability of this technique for delivering constant and varying flow rate, and for on-off valving. This approach to valving provides a simple, yet effective way to monolithically integrate flow and valve control on polymer Lab-on-Chip devices. PMID- 20161041 TI - A new class of mammalian carboxylesterase CES6. AB - Mammalian carboxylesterases (CES) exhibit broad substrate specificities, catalyse hydrolytic and transesterification reactions with a wide range of drugs and xenobiotics and are widely distributed in the body. Four CES classes have been previously described, namely CES1 (major liver form); CES2 (major intestinal form); CES3 (highest activity in the colon); and CES5, a secreted enzyme found in mammalian kidney and male reproductive fluids. In silico methods were used to predict the amino acid sequences, structures and gene locations for a new class of CES genes and proteins, designated as CES6. Mammalian CES6 amino acid sequence alignments and predicted secondary and tertiary structures enabled the identification of key CES sequences previously reported for human CES1, but with CES6 specific sequences and properties: high isoelectric points (pI values of 8.8 - 9.4 compared with 5.4 - 6.2 for human CES1, CES2, CES3 and CES5); being predicted for secretion into body fluids compared with human CES1, human CES2 and CES3, which are membrane bound; and having Asn or Glu residues at the predicted CES1 Z-site for which a Gly residue plays a major role in cholesterol binding. Mammalian CES6 genes are located in tandem with CES2 and CES3 genes, are transcribed on the positive DNA strand and contain 14 exons. Human and mouse CES6 like transcripts have been previously reported to be widely distributed in the body but are localized in specific regions of the brain, including the cerebellum. CES6 may play a role in the detoxification of drugs and xenobiotics in neural and other tissues of the body and in the cerebrospinal fluid. PMID- 20161043 TI - Stereotype Strength and Attentional Bias: Preference for Confirming versus Disconfirming Information Depends on Processing Capacity. AB - In two experiments, we investigated the relationships among stereotype strength, processing capacity, and the allocation of attention to stereotype-consistent versus stereotype-inconsistent information describing a target person. The results of both experiments showed that, with full capacity, greater stereotype strength was associated with increased attention toward stereotype-consistent versus stereotype-inconsistent information. However, when capacity was diminished, greater stereotype strength was associated with increased attention toward inconsistent versus consistent information. Thus, strong stereotypes may act as self-confirming filters when processing capacity is plentiful, but as efficient information gathering devices that maximize the acquisition of novel (disconfirming) information when capacity is depleted. Implications for models of stereotyping and stereotype change are discussed. PMID- 20161044 TI - Nanostructured Biomimetic Catalysts for Asymmetric Hydrogenation of Enamides using Molecular Imprinting Technology. AB - A new class of heterogeneous catalysts for asymmetric hydrogenation of enamides was synthesized using molecular imprinting technology. These new catalysts are molecularly imprinted polymers (MIPs) made from rhodium (I) and copper (II) complexes with the bis(oxazoline) chiral ligands. One of the Rh-MIPs showed 87% ee toward L-enantiomeric product while the Cu-MIP showed 82% ee toward D enantiomeric product. Both MIPs are easy to separate and reusable. PMID- 20161045 TI - Identity-Based Motivation: Constraints and Opportunities in Consumer Research. AB - This commentary underscores the integrative nature of the identity-based motivation model (Oyserman, 2009). We situate the model within existing literatures in psychology and consumer behavior, and illustrate its novel elements with research examples. Special attention is devoted to, 1) how product- and brand-based affordances constrain identity-based motivation processes and, 2) the mindsets and action tendencies that can be triggered by specific cultural identities in pursuit of consumer goals. Future opportunities are suggested for researching the antecedents of product meanings and relevant identities. PMID- 20161046 TI - MEMS Electrostatic Actuation in Conducting Biological Media. AB - We present design and experimental implementation of electrostatic comb-drive actuators in solutions of high conductivity relevant for biological cells. The actuators are operated in the frequency range 1-10 MHz in ionic and biological cell culture media, with ionic strengths up to 150 mMoles/L. Typical displacement is 3.5 MUm at an applied peak-to-peak signal of 5V. Two different actuation schemes are presented and tested for performance at high frequency. A differential drive design is demonstrated to overcome the attenuation due to losses in parasitic impedances. The frequency dependence of the electrostatic force has been characterized in media of different ionic strengths. Circuit models for the electric double layer phenomena are used to understand and predict the actuator behavior. The actuator is integrated into a planar force sensing system to measure the stiffness of cells cultured on suspended structures. PMID- 20161047 TI - Role of Imaging in Prostate Cancer. PMID- 20161048 TI - Simultaneous Non-invasive Analysis of DNA Condensation and Stability by Two-step QD-FRET. AB - Nanoscale vectors comprised of cationic polymers that condense DNA to form nanocomplexes are promising options for gene transfer. The rational design of more efficient nonviral gene carriers will be possible only with better mechanistic understanding of the critical rate-limiting steps, such as nanocomplex unpacking to release DNA and degradation by nucleases. We present a two-step quantum dot fluorescence resonance energy transfer (two-step QD-FRET) approach to simultaneously and non-invasively analyze DNA condensation and stability. Plasmid DNA, double-labeled with QD (525 nm emission) and nucleic acid dyes, were complexed with Cy5-labeled cationic gene carriers. The QD donor drives energy transfer stepwise through the intermediate nucleic acid dye to the final acceptor Cy5. At least three distinct states of DNA condensation and integrity were distinguished in single particle manner and within cells by quantitative ratiometric analysis of energy transfer efficiencies. This novel two-step QD-FRET method allows for more detailed assessment of the onset of DNA release and degradation simultaneously. PMID- 20161050 TI - Biodiversity conservation and drug discovery: Can they be combined? The Suriname and Madagascar experiences. AB - The approach to new drugs through natural products has proved to be the single most successful strategy for the discovery of new drugs, but in recent years its use has been deemphasized by many pharmaceutical companies in favor of approaches based on combinatorial chemistry and genomics, among others.Drug discovery from natural sources requires continued access to plant, marine, and microbial biomass, and so the preservation of tropical rainforests is an important part of our drug discovery program. Sadly, many of the tropical forests of the world are under severe environmental pressure, and deforestation is a serious problem in most tropical countries. One way to combat this loss is to demonstrate their value as potential sources of new pharmaceutical or agrochemical products.As part of an effort to integrate biodiversity conservation and drug discovery with economic development, we initiated an International Cooperative biodiversity Group (ICBG) to discover potential pharmaceuticals from the plant biodiversity of Suriname and Madagascar. The Group, established with funding from agencies of the United States government, involved participants from the USA, Suriname, and Madagascar. The basic approach was to search for bioactive plants in the Suriname and Malagasy flora, and to isolate their bioactive constituents by the best available methods, but the work included capacity building as well as research. Progress on this project will be reported, drawing on results obtained from the isolation of bioactive natural products from Suriname and Madagascar. The benefits of this general approach to biodiversity and drug discovery will also be discussed. PMID- 20161051 TI - FDG PET in Prostate Cancer. PMID- 20161052 TI - Synthesis and Characterization of the Chromium(III) complexes of Ethylene Cross Bridged Cyclam and Cyclen Ligands. AB - Dichloro(4,10-dimethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane)chromium(III) chloride, Dichloro(4,10-dibenzyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane) chromium(III) chloride, and Dichloro(4,11-dimethyl-1,4,8,11 tetraazabicyclo[6.6.2] hexadecane)chromium)(III) chloride have been prepared by the reaction of anhydrous chromium(III) chloride with the appropriate cross bridged tetraazamacrocycle. Aquation of these complexes proved difficult, but Chlorohydroxo(4,11-dimethyl-1,4,8,11 tetraazabicyclo[6.6.2]hexadecane)chromium)(III) chloride was synthesized directly from chromium(II) chloride complexation followed by exposure or the reaction to air in the presence of water. The four complexes were characterized by X-ray crystal structure determination. All contain the chromium(III) ion in a distorted octahedral geometry and the macrocycle in the cis-V configuration, as dictated by the ethylene cross-bridge. Further characterization of the hydroxo complex reveals a magnetic moment of mu(eff) = 3.95 B.M. and electronic absorbtions in acetonitrile at lambda(max) = 583nm (epsilon = 65.8 L/cm.mol), 431nm (epsilon = 34.8 L/cm.mol) and 369nm (epsilon = 17 L/cm.mol). PMID- 20161049 TI - Transglutaminase activation in neurodegenerative diseases. AB - The following review examines the role of calcium in promoting the in vitro and in vivo activation of transglutaminases in neurodegenerative disorders. Diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease exhibit increased transglutaminase activity and rises in intracellular calcium concentrations, which may be related. The aberrant activation of transglutaminase by calcium is thought to give rise to a variety of pathological moieties in these diseases, and the inhibition has been shown to have therapeutic benefit in animal and cellular models of neurodegeneration. Given the potential clinical relevance of transglutaminase inhibitors, we have also reviewed the recent development of such compounds. PMID- 20161053 TI - Joint Models for the Association of Longitudinal Binary and Continuous Processes With Application to a Smoking Cessation Trial. AB - Joint models for the association of a longitudinal binary and a longitudinal continuous process are proposed for situations in which their association is of direct interest. The models are parameterized such that the dependence between the two processes is characterized by unconstrained regression coefficients. Bayesian variable selection techniques are used to parsimoniously model these coefficients. A Markov chain Monte Carlo (MCMC) sampling algorithm is developed for sampling from the posterior distribution, using data augmentation steps to handle missing data. Several technical issues are addressed to implement the MCMC algorithm efficiently. The models are motivated by, and are used for, the analysis of a smoking cessation clinical trial in which an important question of interest was the effect of the (exercise) treatment on the relationship between smoking cessation and weight gain. PMID- 20161055 TI - Boundary conditions and buffering effects: Does depressive symptomology moderate the effectiveness of distanced-analysis for facilitating adaptive self reflection? AB - Recent findings indicate that a critical factor determining whether people's attempts to adaptively analyze negative experiences succeed or fail is the type of self-perspective (self-immersed vs. self-distanced) they adopt while analyzing negative feelings. The present research examined whether these findings generalize to individuals displaying high levels of depression symptoms who are particularly vulnerable to rumination. Findings revealed that the effectiveness of self-distancing for attenuating emotional reactivity increased linearly with depression symptoms. Moreover, mediation analyses revealed that participants tendency to recount vs reconstrue their experience accounted for the regulatory effects of self-distancing on emotional reactivity regardless of depression symptoms. PMID- 20161056 TI - Psychosocial Interventions for School Refusal Behavior in Children and Adolescents. AB - This article reviews empirical evidence for the efficacy of psychosocial interventions for school refusal behavior. Data corresponding to eight experimental single-case and seven group-design studies are presented. Across studies, behavioral and cognitive-behavioral treatments emerged as promising lines of intervention. These interventions produced improvements in school attendance and youths'symptom levels (e.g., anxiety, fear, depression, anger) based on this study's examination of effect sizes. The article concludes with suggestions for interventionists, researchers, and policymakers attempting to deal with the problem of school refusal. PMID- 20161054 TI - The functional neuroanatomy of language. AB - There has been substantial progress over the last several years in understanding aspects of the functional neuroanatomy of language. These advances are summarized in this review. It will be argued that recognizing speech sounds is carried out in the superior temporal lobe bilaterally, that the superior temporal sulcus bilaterally is involved in phonological-level aspects of this process, that the frontal/motor system is not central to speech recognition although it may modulate auditory perception of speech, that conceptual access mechanisms are likely located in the lateral posterior temporal lobe (middle and inferior temporal gyri), that speech production involves sensory-related systems in the posterior superior temporal lobe in the left hemisphere, that the interface between perceptual and motor systems is supported by a sensory-motor circuit for vocal tract actions (not dedicated to speech) that is very similar to sensory motor circuits found in primate parietal lobe, that verbal short-term memory can be understand as an emergent property of this sensory-motor circuit. These observations are understood within the context of a dual stream model of speech processing in which one pathway supports speech comprehension and the other supports sensory-motor integration. Additional topics of discussion include the functional organization of the planum temporale for spatial hearing and speech related sensory-motor processes, the anatomical and functional basis of a form of acquired language disorder, conduction aphasia, the neural basis of vocabulary development, and sentence-level/grammatical processing. PMID- 20161057 TI - 5-Cyanotryptophan as an Infrared Probe of Local Hydration Status of Proteins. AB - The nitrile (C=N) stretching vibration is sensitive to environment, making nitrile-derivatized amino acids an increasingly utilized tool to study various biological processes. Herein, we show that the bandwidth of the C=N stretching vibration of 5-cyanotryptophan is particularly sensitive to water, rendering it an attractive infrared probe of local hydration status. We confirm the utility of this probe in biological applications by using it to examine how the hydration status of individual tryptophan sidechains of an antimicrobial peptide, indolicidin, changes upon peptide binding to model membranes. Furthermore, we show that p-cyanophenylalanine and 5-cyanotryptophan constitute a useful fluorescence energy transfer pair. PMID- 20161058 TI - Visual feedback and self-monitoring of sign language. AB - The perceptual loop theory of self-monitoring posits that auditory speech output is parsed by the comprehension system. For sign language, however, visual input from one's own signing is distinct from visual input received from another's signing. Two experiments investigated the role of visual feedback in the production of American Sign Language (ASL). Experiment 1 revealed that signers were poor at recognizing ASL signs when viewed as they would appear during self produced signing. Experiment 2 showed that the absence or blurring of visual feedback did not affect production performance when deaf signers learned to reproduce signs from Russian Sign Language, and production performance of hearing non-signers was slightly worse with visual feedback. Signers may rely primarily on somatosensory feedback when monitoring language output, and if the perceptual loop theory is to be maintained, the comprehension system must be able to parse a somatosensory signal as well as an external perceptual signal for both sign and speech. PMID- 20161059 TI - Computation of intra-operative brain shift using dynamic relaxation. AB - Many researchers have proposed the use of biomechanical models for high accuracy soft organ non-rigid image registration, but one main problem in using comprehensive models is the long computation time required to obtain the solution. In this paper we propose to use the Total Lagrangian formulation of the Finite Element method together with Dynamic Relaxation for computing intra operative organ deformations. We study the best ways of estimating the parameters involved and we propose a termination criteria that can be used in order to obtain fast results with prescribed accuracy. The simulation results prove the accuracy and computational efficiency of the method, even in cases involving large deformations, nonlinear materials and contacts. PMID- 20161060 TI - Age-Related Changes in the Anatomy of Language Regions in Autism Spectrum Disorder. AB - Impairments in language and communication are core features of autism spectrum disorder (ASD). The anatomy of critical language areas has been studied in ASD with inconsistent findings. We used MRI to measure gray matter volume and asymmetry of Heschl's gyrus, planum temporale, pars triangularis, and pars opercularis in 40 children and adolescents with ASD and 40 typically developing individuals, each divided into younger (7-11 years) and older (12-19 years) cohorts. The older group had larger left planum temporale volume and stronger leftward asymmetry than the younger group, regardless of diagnosis. The pars triangularis and opercularis together were larger in ASD than controls. Correlations between frontal language areas with language and symptom severity scores were significant in younger ASD children. Results suggest similar developmental changes in planum temporale anatomy in both groups, but group differences in pars triangularis and opercularis that may be related to language abilities and autism symptom severity. PMID- 20161061 TI - Tracing the Effects of Hurricane Katrina on the Population of New Orleans: The Displaced New Orleans Residents Pilot Study. AB - The Displaced New Orleans Residents Pilot Study was designed to examine the current location, well-being, and plans of people who lived in the City of New Orleans when Hurricane Katrina struck on 29 August 2005. The study is based on a representative sample of pre-Katrina dwellings in the city. Respondents were administered a short paper-and-pencil interview by mail, by telephone, or in person. The pilot study was fielded in the fall of 2006, approximately one year after Hurricane Katrina. In this paper, we describe the motivation for the pilot study, outline its design, and describe the fieldwork results using a set of fieldwork outcome rates and multivariate logistic models. We end with a discussion of the lessons learned from the pilot study for future studies of the effects of Hurricane Katrina on the population of New Orleans. The results point to the challenges and opportunities of studying this unique population. PMID- 20161062 TI - Cyclic Hydraulic Pressure and Fluid Flow Differentially Modulate Cytoskeleton Re Organization in MC3T3 Osteoblasts. AB - Mechanical loads are essential towards maintaining bone mass and skeletal integrity. Such loads generate various stimuli at the cellular level, including cyclic hydraulic pressure (CHP) and fluid shear stress (FSS). To gain insight into the anabolic responses of osteoblasts to CHP and FSS, we subjected MC3T3-E1 preosteoblasts to either FSS (12 dynes/cm(2)) or CHP varying from 0 to 68 kPa at 0.5 Hz. As with FSS, CHP produced a significant increase in ATP release over static controls within 5 min of onset. Cell stiffness examined by atomic force microscopy increased after 15 min of either CHP or FSS stimulation, which was attenuated when extracellular ATP was hydrolyzed with apyrase. As previously shown FSS induced polymerization of actins into stress fibers. However, the microtubule network was completely disrupted under FSS. In contrast, CHP appeared to maintain strong microtubule and f-actin networks. The purinergic signaling was found to be involved in the remodeling of f-actin, but not microtubule. Both CHP and FSS applied for 1 hour increased expression of COX-2. These data indicate that, while CHP and FSS produce similar anabolic responses, these stimuli have very different effects on the cytoskeleton remodeling and could contribute to loss of mechanosensitivity with extended loading. PMID- 20161063 TI - Intensive Treatment of Specific Phobias in Children and Adolescents. AB - One-session treatment (OST), a variant of cognitive-behavioral therapy, combines graduated in vivo exposure, participant modeling, reinforcement, psychoeducation, cognitive challenges, and skills training in an intensive treatment model. Treatment is maximized to one 3-hour session. In this paper, we review the application of OST for specific phobia in youth and highlight practical matters related to OST and its use in a clinical setting. We also briefly review results of treatment outcome studies and suggest future directions for clinical research and practice. We conclude that OST is an efficient and efficacious treatment. PMID- 20161064 TI - A Beautiful Day in the Neighborhood: An Event-Related Potential Study of Lexical Relationships and Prediction in Context. AB - Two related questions critical to understanding the predictive processes that come online during sentence comprehension are 1) what information is included in the representation created through prediction and 2) at what functional stage does top-down, predicted information begin to affect bottom-up word processing? We investigated these questions by recording event-related potentials (ERPs) as participants read sentences that ended with expected words or with unexpected items (words, pseudowords, or illegal strings) that were either orthographically unrelated to the expected word or were one of its orthographic neighbors. The data show that, regardless of lexical status, attempts at semantic access (N400) for orthographic neighbors of expected words is facilitated relative to the processing of orthographically unrelated items. Our findings support a view of sentence processing wherein orthographically organized information is brought online by prediction and interacts with input prior to any filter on lexical status. PMID- 20161065 TI - The effect of daily prefrontal repetitive transcranial magnetic stimulation over several weeks on resting motor threshold. AB - BACKGROUND: The resting motor threshold (rMT) is an important factor in the selection of treatment intensity for patients receiving repetitive transcranial magnetic stimulation (rTMS). In many clinical studies to date, due to concerns about potential drift, the rMT has been routinely re-measured weekly or every fifth session. OBJECTIVE: Our aim is to investigate whether ongoing treatment with rTMS affects the rMT, the degree of change, and whether frequent remeasurement is needed. METHODS: Clinical data were drawn from 50 medication free patients receiving treatment for major depression with rTMS in a large U.S. NIH-sponsored multisite study. Four measurements of rMT were obtained including before and after the double blind phase, followed by weekly measurements during the open phase. Active treatment consisted of 75 four second trains of 10Hz stimulation applied over 37.5 minutes with the coil over the left DLPFC at 120% rMT. RESULTS: For the group as a whole, there was no significant change in the rMT during a minimum of 2 weeks of treatment with prefrontal rTMS (p=0.911, one way ANOVA). The average within-subject coefficient of variation was 6.58%. On average the last rMT was 2.45% less than the baseline rMT (range 32.3% increase, 40.6% decrease). CONCLUSION: Daily left prefrontal rTMS over several weeks as delivered in this trial does not cause systematic changes in rMT. While most subjects had <10% variance in rMT over time, 5 subjects had changes of approximately 20% from baseline, raising dosing and safety issues if undetected. We recommend that clinical trials of rTMS have periodic retesting of rMT, especially if the dose is at or near the edge of the TMS safety tables. PMID- 20161066 TI - A Fast Implementation of a Scan Statistic for Identifying Chromosomal Patterns of Genome Wide Association Studies. AB - In order to take into account the complex genomic distribution of SNP variations when identifying chromosomal regions with significant SNP effects, a single nucleotide polymorphism (SNP) association scan statistic was developed. To address the computational needs of genome wide association (GWA) studies, a fast Java application, which combines single-locus SNP tests and a scan statistic for identifying chromosomal regions with significant clusters of significant SNP effects, was developed and implemented. To illustrate this application, SNP associations were analyzed in a pharmacogenomic study of the blood pressure lowering effect of thiazide-diuretics (N=195) using the Affymetrix Human Mapping 100K Set. 55,335 tagSNPs (pair-wise linkage disequilibrium R(2)<0.5) were selected to reduce the frequency correlation between SNPs. A typical workstation can complete the whole genome scan including 10,000 permutation tests within 3 hours. The most significant regions locate on chromosome 3, 6, 13 and 16, two of which contain candidate genes that may be involved in the underlying drug response mechanism. The computational performance of ChromoScan-GWA and its scalability were tested with up to 1,000,000 SNPs and up to 4,000 subjects. Using 10,000 permutations, the computation time grew linearly in these datasets. This scan statistic application provides a robust statistical and computational foundation for identifying genomic regions associated with disease and provides a method to compare GWA results even across different platforms. PMID- 20161067 TI - The Buffering Effect of Hope on Clinicians' Behavior: A Test in Pediatric Primary Care. AB - Although trait hope is thought to motivate goal directed actions in the face of impediments, few studies have examined directly hope's role in overcoming obstacles, and none have done so while accounting for related goal constructs. We describe a study of 127 pediatric primary care providers who over the course of a year were asked to identify new cases of asthma and confirm previously diagnosed active disease by completing for each of their patients a brief survey validated for this purpose. These clinicians also completed measures of hope, self efficacy, conscientiousness, and perceived obstacles to implementing a pediatric asthma management program. As predicted by hope theory, the agency component of hope buffered clinicians from perceived obstacles by facilitating the identification of asthma cases among high hope clinicians in the face of obstacles. This buffering effect remained after controlling for self-efficacy and conscientiousness. We discuss the study findings in terms of current theories of goal directed behavior and implications for delivering hope-related interventions, and we offer a testable hypothesis regarding when agency and pathways thinking facilitate goal-related behavior. PMID- 20161068 TI - Radical-mediated thiodesulfonylation of the vinyl sulfones: Access to (alpha fluoro)vinyl sulfides. AB - Radical-mediated thiodesulfonylation of the vinyl and (alpha-fluoro)vinyl sulfones, derived from aldehydes and ketones, with aryl thiols in organic or aqueous medium provided access to vinyl and (alpha-fluoro)vinyl sulfides. The vinyl sulfides were formed predominantly with E stereochemistry independent of the stereochemistry of the starting vinyl sulfones. PMID- 20161069 TI - Creating alternatives in science. AB - Traditional scientist training at the PhD level does not prepare students to be competitive in biotechnology or other non-academic science careers. Some universities have developed biotechnology-relevant doctoral programmes, but most have not. Forming a life science career club makes a statement to university administrators that it is time to rework the curriculum to include biotechnology relevant training. A career club can supplement traditional PhD training by introducing students to available career choices, help them develop a personal network and teach the business skills that they will need to be competitive in science outside of academia. This paper is an instructional guide designed to help students create a science career club at their own university. These suggestions are based on the experience gained in establishing such a club for the Graduate School at the University of Colorado Denver. We describe the activities that can be offered, the job descriptions for the offices required and potential challenges. With determination, a creative spirit, and the guidance of this paper, students should be able to greatly increase awareness of science career options, and begin building the skills necessary to become competitive in non-academic science. PMID- 20161070 TI - Intracellular Flow Cytometric Measurement of Extracellular Matrix Components in Porcine Intervertebral Disc Cells. AB - The objective of this study was to develop and demonstrate the utility of a novel method of evaluating intracellular levels of extracellular matrix (ECM) components in intervertebral disc (IVD) cells using flow cytometry. By using this method, this study discriminated between cell populations in porcine IVD and examined the response of IVD cells to monolayer cultures, a traditional method of cell expansion, by measuring phenotypic attributes of ECM component production. It was found that monolayer cultures affected collagen production of IVD cells while there were differences in collagen type II production between the cells isolated from the annulus fibrosus (AF) and nucleus pulposus (NP) regions of IVD. Size distributions of fresh and cultured cells were also presented while the relationships between cell size and intracellular collagen level revealed heterogeneous cell populations in AF and NP regions. Furthermore, this study showed that the intracellular collagen signals of IVD cells were significantly enhanced by the treatments of Brefeldin-A and ascorbic acid. This suggests that Brefeldin-A and ascorbic acid could be used to increase the sensitivity of flow cytometric analysis on intracellular collagen levels by maximizing collagen accumulation inside cells. Since a unique feature of the flow cytometric screening tool is the ability to discriminate between various cell populations in a single sample, the flow cytometric method developed in this study may have the potential to identify specific collagen-producing cell populations from tissues or cell cultures. PMID- 20161071 TI - Influence of vocal fold stiffness and acoustic loading on flow-induced vibration of a single-layer vocal fold model. AB - The flow-induced vibrations of a single-layer vocal fold model were investigated as a function of vocal fold stiffness, and subglottal and supraglottal acoustic loading. Previously, it was reported that the single-layer vocal fold model failed to vibrate when short, clinically-relevant tracheal tubes were used. Moreover, it was reported that the model had a propensity to be acoustically driven, and aerodynamically driven vibration was observed only when a vertical restraint was applied superiorly to the vocal folds. However, in this study involving a wider range of source/tract conditions, the previous conclusions were shown to apply only for the special case of a stiff vocal fold model, for which self-oscillation occurred only when the vocal fold vibration synchronized to either a subglottal or supraglottal resonance. For a more general case, when vocal fold stiffness was decreased, the model did exhibit self-oscillation at short tracheal tubes, and no vertical restraint was needed to induce aerodynamically driven phonation. Nevertheless, the vocal fold vibration transitioned from aerodynamically-driven to acoustically-driven vibration when one of the subglottal resonance frequencies approximated one of the natural frequencies of the vocal folds. In this region, strong superior-inferior vibrations were observed, the phonation threshold pressure was significantly reduced, and the phonation onset frequency was heavily influenced by the dominant acoustic resonance. For acoustically-driven phonation, a compliant subglottal system always lowered phonation threshold. However, an inertive vocal tract could either increase or decrease phonation threshold pressure, depending on the phonation frequency. PMID- 20161072 TI - Isolation and Characterization of Aromatase Inhibitors from Brassaiopsis glomerulata (Araliaceae). AB - The hexane- and ethyl acetate-soluble extracts of the leaves of Brassaiopsis glomerulata (Blume) Regel (Araliaceae), collected in Indonesia, were found to inhibit aromatase, the rate-limiting enzyme in the production of estrogens from androgens, in both enzyme- and cell-based aromatase inhibition (AI) assays. Bioassay-guided fractionation led to the isolation of six known compounds of the steroid and triterpenoid classes (1-6) from the hexane extract, of which 6beta hydroxystimasta-4-en-3-one (5), was moderately active in the cell-based AI assay. Fractionation of the ethyl acetate extract afforded seven pure isolates (7-13) of the modified peptide, fatty acid, monoterpenoid, and benzenoid types, including six known compounds and the new natural product, N-benzoyl-L-phenylalanine methyl ester (9). The absolute stereochemistry of 9 and the other two peptides, 7 and 8, was determined by Marfey's analysis. Linoleic acid (10) was found to be active in the enzyme-based AI assay, while 9 and (-)-dehydrololiolide (12) showed activity in the cell-based AI assay. PMID- 20161073 TI - Toward a physical basis of attention and self regulation. AB - The concept of self-regulation is central to the understanding of human development. Self-regulation allows effective socialization and predicts both psychological pathologies and levels of achievement in schools. What has been missing are neural mechanisms to provide understanding of the cellular and molecular basis for self-regulation. We show that self-regulation can be measured during childhood by parental reports and by self-reports of adolescents and adults. These reports are summarized by a higher order factor called effortful control, which reflects perceptions about the ability of a given person to regulate their behavior in accord with cultural norms. Throughout childhood effortful control is related to children's performance in computerized conflict related tasks. Conflict tasks have been shown in neuroimaging studies to activate specific brain networks of executive attention. Several brain areas work together at rest and during cognitive tasks to regulate competing brain activity and thus control resulting behavior. The cellular structure of the anterior cingulate and insula contain cells, unique to humans and higher primates that provide strong links to remote brain areas. During conflict tasks, anterior cingulate activity is correlated with activity in remote sensory and emotional systems, depending upon the information selected for the task. During adolescence the structure and activity of the anterior cingulate has been found to be correlated with self reports of effortful control.Studies have provided a perspective on how genes and environment act to shape the executive attention network, providing a physical basis for self-regulation. The anterior cingulate is regulated by dopamine. Genes that influence dopamine levels in the CNS have been shown to influence the efficiency of self-regulation. For example, alleles of the COMT gene that influence the efficiency of dopamine transmission are related to the ability to resolve conflict. Humans with disorders involving deletion of this gene exhibit large deficits in self-regulation. Alleles of other genes influencing dopamine and serotonin transmission have also been found to influence ability to resolve conflict in cognitive tasks. However, as is the case for many genes, the effectiveness of COMT alleles in shaping self-regulation depends upon cultural influences such as parenting. Studies find that aspects of parenting quality and parent training can influence child behavior and the efficiency of self regulation.During development, the network that relates to self-regulation undergoes important changes in connectivity. Infants can use parts of the self regulatory network to detect errors in sensory information, but the network does not yet have sufficient connectivity to organize brain activity in a coherent way. During middle childhood, along with increased projection cells involved in remote connections of dorsal anterior cingulate and prefrontal and parietal cortex, executive network connectivity increases and shifts from predominantly short to longer range connections. During this period specific exercises can influence network development and improve self-regulation. Understanding the physical basis of self-regulation has already cast light on individual differences in normal and pathological states and gives promise of allowing the design of methods to improve aspects of human development. PMID- 20161074 TI - The Life-Long Mortality Risks Of World War II Experiences. AB - OBJECTIVE: This longitudinal study of American veterans investigated the mortality risks of five World War II military experiences (i.e., combat exposure) and their variation among veterans in the post-war years. METHODS: The male subjects (N=854) are members of the Stanford-Terman study, and 38 percent served in World War II. Cox models (proportional hazards regressions) compared the relative mortality risk associated with each military experience. RESULTS: Overseas duty, service in the Pacific and exposure to combat significantly increased the mortality risks of veterans in the study. Individual differences in education, mental health in 1950, and age at entry into the military, as well as personality factors made no difference in these results. CONCLUSIONS: A gradient is observable such that active duty on the home front, followed by overseas duty, service in the Pacific, and combat exposure markedly increased the risk of relatively early mortality. Potential linking mechanisms include heavy drinking. PMID- 20161075 TI - Survival in 19th Century Cities: The Larger the City, the Smaller Your Chances. AB - Using Union Army veterans' lifetime socioeconomic and health records, this essay finds a consistent and persistent hierarchy in survival rates and hazard ratios by urban size at and across three stages of life: birth, late adolescence, and death. This urban mortality penalty remains after controlling for variables associated with each individual veteran. The results of our geographical mobility analyses suggest that, with respect to these veterans, the search for an explanation should focus on late adolescence and adulthood as much as on early life. A complete explanation of the penalty requires a project of greater scope. PMID- 20161076 TI - Novel approaches to imaging epilepsy by MRI. AB - As the concept of a network of injury has emerged in the treatment of epilepsy, the importance of evaluating that network noninvasively has also grown. Recently, studies utilizing magnetic resonance spectroscopic imaging, manganese-enhanced MRI and functional (f)MRI measures of resting state connectivity have demonstrated their ability to detect injury and dysfunction in cerebral networks involved in the propagation of seizures. The ability to noninvasively detect neuronal injury and dysfunction throughout cerebral networks should improve surgical planning, provide guidance for placement of devices that target network propagation and provide insights into the mechanisms of recurrence following resective surgery. PMID- 20161078 TI - Partner Status Influences Women's Interest in the Opposite Sex. AB - Previous research has demonstrated that hormones, relationship goals, and social context influence interest in the opposite sex. It has not been previously reported, however, whether having a current sexual partner also influences interest in members of the opposite sex. To test this, we obtained explicit and implicit measures of interest by measuring men's and women's subjective ratings and response times while they evaluated photos of opposite-sex faces. Fifty-nine men and 56 women rated 510 photos of opposite-sex faces for realism, masculinity, attractiveness, or affect. We found that these subjective ratings were not influenced by partner status in either men or women. However, women who did not report having a current sexual partner spent more time evaluating the photos than women who did have partners, demonstrating greater interest in the photos. Sexual partner status did not predict men's response times. These findings may reveal that relationship commitment in women suppresses interest in alternative partners. PMID- 20161077 TI - Girls' Disruptive Behavior and its Relationship to Family Functioning: A Review. AB - Although a number of reviews of gender differences in disruptive behavior and parental socialization exist, we extend this literature by addressing the question of differential development among girls and by placing both disruptive behavior and parenting behavior in a developmental framework. Clarifying the heterogeneity of development in girls is important for developing and optimizing gender-specific prevention and treatment programs. In the current review, we describe the unique aspects of the development of disruptive behavior in girls and explore how the gender-specific development of disruptive behavior can be explained by family linked risk and protective processes. Based on this review, we formulate a gender-specific reciprocal model of the influence of social factors on the development of disruptive behavior in girls in order to steer further research and better inform prevention and treatment programs. PMID- 20161079 TI - Empirical Likelihood based Inference for Additive Partial Linear Measurement Error Models. AB - This paper considers statistical inference for additive partial linear models when the linear covariate is measured with error. To improve the accuracy of the normal approximation based confidence intervals, we develop an empirical likelihood based statistic, which is shown to be asymptotically chi-square distributed. We emphasize the finite-sample performance of the proposed method by conducting simulation experiments. The method is used to analyze the relationship between semen quality and phthalate exposure from an environment study. PMID- 20161080 TI - Mapping Gray's BIS and BAS Constructs onto Factor 1 and Factor 2 of Hare's Psychopathy Checklist - Revised. AB - Reinforcement Sensitivity Theory (RST; Gray, 1987; Gray & McNaughton, 2000) has proven to be a valuable tool for understanding psychopathy (e.g., Fowles, 1980, 1988; Newman & Malterer, 2009; Poythress, Edens, Landfield, Lilienfeld, Skeem, & Douglas, 2008). Recent research has linked two RST constructs, the Behavioral Inhibition System (BIS) and the Behavioral Activation System (BAS), to individuals with primary psychopathy and secondary psychopathy (Lykken, 1995; Newman, MacCoon, Vaughn, & Sadeh, 2005): Primary psychopaths manifest low BIS reactivity and secondary psychopaths manifest high BAS reactivity. In the present study, we examine the relationships between the BIS/BAS constructs and Factors 1 and 2 of the Psychopathy Checklist - Revised (PCL-R) in a sample of 472 incarcerated male offenders. Paralleling their relationships with primary and secondary psychopathy, the BIS/BAS constructs were differentially related to the two PCL-R factors. Specifically, the influence of the BIS was found to be more prominent than the influence of the BAS for Factor 1, and the influence of the BAS was more prominent than that of the BIS for Factor 2. PMID- 20161081 TI - Disparities in Health Services for HIV/AIDS, Hepatitis C Virus, and Sexually Transmitted Infections: Role of Substance Abuse Treatment Programs. AB - OBJECTIVES: This report focused upon the availability of infection-related health services in substance abuse treatment programs with and without addiction services tailored for special populations (women and non-white populations). METHODS: In a cross-sectional, descriptive design, treatment program administrators across the United States within the National Drug Abuse Treatment Clinical Trials Network provided information on program characteristics, the availability of infection-related services (four medical services and three non medical services for HIV, HCV, and STI), and barriers to providing infection related services. RESULTS: Of 319 programs, 269 submitted surveys (84% response rate). Of these, 80% provided addiction services for special populations. Programs providing addiction services designed for at least one special population, were more likely to provide infection-related health services, especially HIV-related education (94% versus 85%, p = 0.05) and patient counseling (76% versus 60%, p = 0.03) and were more likely to include outpatient addiction services (86% versus 57%, p<0.001) and outreach and support services (92% versus 70%, p=0.01). Barriers to providing infection-related services included funding (cited by 48.3% to 74.7% of programs), health insurance (cited by 28.9% to 60.8% of programs), and patient acceptance (cited by 23.2% to 54.3% of programs). CONCLUSIONS: Despite many barriers, infection-related healthcare is available in programs with addiction treatment services tailored for special populations, especially for African Americans and Latino Americans. Tailoring substance abuse treatment along with reducing barriers to infection-related care represent public health interventions with potential to reduce the burdens and disparities associated with these infections. PMID- 20161082 TI - Early Child Maltreatment, Runaway Youths, and Risk of Delinquency and Victimization in Adolescence: A Mediational Model. AB - This article examines whether running away from home mediates the link between child maltreatment and later delinquency and victimization in adolescence. Specifically, the authors tested the hypothesis that childhood physical and psychological abuse increase the risk of a child's running away from home by the time of adolescence. Running away from home is, in turn, hypothesized to increase the risk of delinquency and victimization. Childhood sexual abuse, modeled independently of physical and psychological abuse, is hypothesized to have a similar effect on the intervening factor of running away, as well as the two adolescent outcomes: delinquency and victimization. The sample of 416 adolescents was drawn from the Lehigh Longitudinal Study conducted in a two-county area of Pennsylvania. Findings show that physical and psychological abuse predict a child's running away from home. Running away predicts later delinquency and victimization and partially mediates the effect of earlier abuse. Both child abuse and running away from home are adverse events that can be addressed through systematic prevention and intervention efforts tailored to those who have been victimized. Findings can support social workers in their efforts to advocate on behalf of child abuse victims in developing interventions and support services. PMID- 20161083 TI - Life Course Perspectives on the Links Between Poverty and Obesity During the Transition to Young Adulthood. AB - Increasing obesity among Americans is a serious issue in the U.S., especially in the pediatric and young adult population. We use a longitudinal design to examine the relationship between childhood poverty/welfare receipt and obesity onset and continuity from adolescence into young adulthood using three waves of the National Longitudinal Study of Adolescent Health. We include multiple measures of disadvantage that co-occur with poverty and model potential mediating mechanisms within a life course framework. We find a significant effect of poverty/welfare receipt in childhood on obesity outcomes for females, but not for males. However, other measures of socioeconomic disadvantage such as neighborhood poverty, and low parental education are related to obesity in both males and females. Poverty may impact female obesity through the mediating effects of physical activity, inadequate sleep, skipping breakfast and certain forms of parental monitoring, while race is an important confounder of poverty's influence. This paper highlights the important influence of poverty and other aspects of social disadvantage on obesity outcomes during this critical transition to adulthood. Implications of this research include physical activity and parenting interventions for low-income youth. In addition, governmental efforts should be made to increase physical activity opportunities in poor neighborhoods. PMID- 20161084 TI - 2-Nitrophenyl Aryl Sulfides Undergo Both Intramolecular and Electrospray-Induced Intermolecular Oxidation of Sulfur: An Experimental and Theoretical Case Study. AB - Aromatic sulfides bearing a nitro group undergo sulfur oxidation upon electrospray ionization in the positive-ion mode. For example, 2-nitrophenyl phenyl sulfide, its para nitro isomer, and its chloro and methyl substituted analogs pick up an oxygen atom to afford [M + H + O](+) and [M + Na + O](+) ions upon ESI. Elemental-composition determination and tandem mass spectrometry confirm the reactions. Another oxidation of the sulfur, by the ortho nitro group of the [M + H](+) ions, occurs as intramolecular oxygen-transfer processes, evidenced by characteristic losses of SO, SO(2) and SO(2)H(*), the latter yielding the carbazole radical cation, and the generation of the aryl-SO(+) product ion. The intramolecular oxidation via oxygen transfer from the nitro group to the sulfur was corroborated by molecular modeling. The results substantiate both inter- and intramolecular oxidation and provide more evidence that care must be taken when analyzing not only methionine-containing peptides but also small sulfides. PMID- 20161085 TI - Population Pharmacokinetic/Pharmacodyanamic Mixture Models via Maximum a Posteriori Estimation. AB - Pharmacokinetic/pharmacodynamic phenotypes are identified using nonlinear random effects models with finite mixture structures. A maximum a posteriori probability estimation approach is presented using an EM algorithm with importance sampling. Parameters for the conjugate prior densities can be based on prior studies or set to represent vague knowledge about the model parameters. A detailed simulation study illustrates the feasibility of the approach and evaluates its performance, including selecting the number of mixture components and proper subject classification. PMID- 20161086 TI - Miniaturizing sample spots for matrix-assisted laser desorption/ionization mass spectrometry. AB - The trend of miniaturization in bioanalytical chemistry is shifting from technical development to practical application. In matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), progress in miniaturizing sample spots has been driven by the needs to increase sensitivity and speed, to interface with other analytical microtechnologies, and to develop miniaturized instrumentation.We review recent developments in miniaturizing sample spots for MALDI-MS. We cover both target modification and microdispensing technologies, and we emphasize the benefits with respect to sensitivity, throughput and automation.We hope that this review will encourage further method development and application of miniaturized sample spots for MALDI-MS, so as to expand applications in analytical chemistry, protein science and molecular biology. PMID- 20161087 TI - Can We Improve Our Physical Health by Altering Our Social Networks? AB - Persons with more types of social relationships live longer and have less cognitive decline with aging, greater resistance to infectious disease, and better prognoses when facing chronic life-threatening illnesses. We have known about the importance of social integration (engaging in diverse types of relationships) for health and longevity for 30 years. Yet, we still do not know why having a more diverse social network would have a positive influence on our health, and we have yet to design effective interventions that influence key components of the network and in turn physical health. Better understanding of the role of social integration in health will require research on how integrated social networks influence health relevant behaviors, regulate emotions and biological responses, and contribute to our expectations and worldviews. PMID- 20161088 TI - Longitudinal Associations between Maternal Work Stress, Negative Work-Family Spillover, and Depressive Symptoms. AB - The current study examined associations over an 18-month period between maternal work stressors, negative work-family spillover, and depressive symptoms in a sample of 414 employed mothers with young children living in six predominantly nonmetropolitan counties in the Eastern United States. Results from a one-group mediation model revealed that a less flexible work environment and greater work pressure predicted higher levels of depressive symptoms, and further, that these associations were mediated by perceptions of negative work-family spillover. Additionally, results from a two-group mediation model suggested that work pressure predicted greater perceptions of spillover only for mothers employed full-time. Findings suggest the need for policies that reduce levels of work stress and help mothers manage their work and family responsibilities. PMID- 20161089 TI - An Improved Algorithm and Its Parallel Implementation for Solving a General Blood Tissue Transport and Metabolism Model. AB - Fast algorithms for simulating mathematical models of coupled blood-tissue transport and metabolism are critical for the analysis of data on transport and reaction in tissues. Here, by combining the method of characteristics with the standard grid discretization technique, a novel algorithm is introduced for solving a general blood-tissue transport and metabolism model governed by a large system of one-dimensional semilinear first order partial differential equations. The key part of the algorithm is to approximate the model as a group of independent ordinary differential equation (ODE) systems such that each ODE system has the same size as the model and can be integrated independently. Thus the method can be easily implemented in parallel on a large scale multiprocessor computer. The accuracy of the algorithm is demonstrated for solving a simple blood-tissue exchange model introduced by Sangren and Sheppard (Bull. Math. Biophys. 15:387-394, 1953), which has an analytical solution. Numerical experiments made on a distributed-memory parallel computer (an HP Linux cluster) and a shared-memory parallel computer (a SGI Origin 2000) demonstrate the parallel efficiency of the algorithm. PMID- 20161090 TI - Discovery of 8-methoxypyrazino[1,2-a]indole as a New Potent Antiproliferative Agent Against Human Leukemia K562 Cells. A Structure-Activity Relationship Study. AB - Identification of novel and selective anticancer agents remains an important and challenging goal in pharmacological research. The indole nucleus, frequently encountered as a molecular fragment in natural products and pharmaceutically active compounds, was employed as the initial building block for the synthesis of a series of pyrazino[1,2-a]indoles 1a-k, variably substituted at the 6, 7, 8 and 9-positions. Compound 1e, bearing the methoxy group at the 8-position of the pyrazino[1,2-a]indole nucleus was identified as a novel potent antiproliferative agent against the human chronic myelogenous leukemia K562 cell line, but it was much less active against several other cancer cell lines. Comparison of positional isomers indicated that moving the methoxy group from the 8- to the 7- or 6-position, to furnish compounds 1f and 1g, respectively, yielded inactive compounds. The analysis of structure-activity relationships observed in the series of investigated compounds may represent the basis for the design of more active molecules. PMID- 20161091 TI - Housing insecurity and lack of public assistance are risk factors for tuberculin skin test conversion among persons who use illicit drugs in New York City. AB - BACKGROUND: Persons who use illicit drugs are at increased risk of new tuberculosis (TB) infection. We conducted a prospective cohort study to assess rates and risk factors for tuberculin skin test (TST) conversion among persons with a history of illicit drug use, who were enrolled in a methadone program and had a negative baseline 2-step TST (eligible participants). METHODS: TST and standardized interviews were administered to 401 eligible participants from 1995 through 1999, every 6 months for a 2-year follow-up time. Analyses were conducted in 2006. RESULTS: A total of 1,447 repeat TSTs were performed during 843 person years of follow-up (median: 2.0 years). The TST conversion rate was 3.7 per 100 person-years. In multivariate analysis, participants who converted were more likely to report ever having been homeless (HR, 2.4; 95% CI, 1.2-5.0) or ever having lived in a homeless shelter (HR, 2.4; 95% CI, 1.2-4.9) at the baseline interview, and less likely to have reported receiving public assistance since the last study visit (RR, 0.15; 95% CI, 0.07-0.32). CONCLUSIONS: This is the first study utilizing 2-step TST at baseline to measure the incidence of TST conversion among persons who use illicit drugs. Controlling for homelessness, persons with a lack of current public assistance was identified as a risk factor for TST conversion. These individuals may most benefit from annual tuberculin skin testing. PMID- 20161092 TI - Why do People Hurt Themselves? New Insights Into the Nature and Functions of Self Injury. AB - Nonsuicidal self-injury (NSSI) is a prevalent but perplexing behavior problem in which people deliberately harm themselves without lethal intent. Research reveals that NSSI typically has its onset during early adolescence; most often involves cutting or carving the skin; and appears equally prevalent across sexes, ethnicities, and socioeconomic statuses. Less is known about why people engage in NSSI. This article presents a theoretical model of the development and maintenance of NSSI. Rather than a symptom of mental disorder, NSSI is conceptualized as a harmful behavior that can serve several intrapersonal (e.g., affect regulation) and interpersonal (e.g., help-seeking) functions. Risk of NSSI is increased by general factors that contribute to problems with affect regulation or interpersonal communication (e.g., childhood abuse) and by specific factors that influence the decision to use NSSI rather than some other behavior to serve these functions (e.g., social modeling). This model synthesizes research from several different areas of the literature and points toward several lines of research needed to further advance the understanding of why people hurt themselves. PMID- 20161093 TI - A Class of Transformed Mean Residual Life Models With Censored Survival Data. AB - The mean residual life function is an attractive alternative to the survival function or the hazard function of a survival time in practice. It provides the remaining life expectancy of a subject surviving up to time t. In this study, we propose a class of transformed mean residual life models for fitting survival data under right censoring. To estimate the model parameters, we make use of the inverse probability of censoring weighting approach and develop a system of estimating equations. Efficiency and robustness of the estimators are also studied. Both asymptotic and finite sample properties of the proposed estimators are established and the approach is applied to two real-life datasets collected from clinical trials. PMID- 20161094 TI - Pathological Gambling: Biological and Clinical Considerations. AB - Pathological gambling (PG) is categorized as an impulse control disorder (ICD). Phenomenological, neurobiological and pharmacological data suggest similarities in the pathophysiologies of substance use disorders (SUDs) and PG. Both behavioral and pharmacological approaches, including those that have been empirically validated for SUDs, have shown promise in the treatment of PG. Findings from biological studies of PG are reviewed, and treatment approaches based on controlled studies are summarized. PMID- 20161096 TI - Suppression of quantum dot blinking in DTT-doped polymer films. AB - In this report we evaluate the emission properties of single quantum dots embedded in a thin, thiol containing polymer film. We report the suppression of quantum dot blinking leading to a continuous photon flux from both organic and water soluble quantum dots and demonstrate their application as robust fluorescent point sources for ultrahigh resolution localization. In addition, we apply the polymer coating to cell samples immunostained with antibody conjugated QDs and show that fluorescence intensity from the polymer embedded cells shows no sign of degradation after 67 hours of continuous excitation. The reported thin polymer film coating may prove advantageous for immuno-cyto/histo-chemistry as well as for the fabrication of quantum dot containing devices requiring a reliable and stable photon source (including a single photon source) or stable charge characteristics while maintaining intimate contact between the quantum dot and the surrounding matrix. PMID- 20161095 TI - Induced pluripotent reprogramming from promiscuous human stemness related factors. AB - Ectopic expression of pluripotency gene sets provokes nuclear reprogramming in permissive somatic tissue environments generating induced pluripotent stem (iPS) cells. The evolutionary conserved function of stemness orthologs was here tested through interspecies transduction. A spectrum of HIV-based lentiviral vectors was designed, and point mutations in the HIV-1 capsid region identified for efficient infectivity and expanded trans-species tropism. Human pluripotent gene sequences, OCT3/4, SOX2, KLF4 and c-MYC, packaged into engineered lentiviral expression vectors achieved consistent expression in non-human fibroblasts. Despite variation in primary amino-acid sequence between species, introduction of human pluripotent genes produced cell lines with embryonic stem cell-like morphology. Transduced fibroblasts differentiated in vitro into all three germ layers according to gastrulation gene expression profiles, and formed in vivo teratoma with multi-lineage potential. Reprogrammed progeny incorporated into non-human morula to produce blastomeres capable of developing into chimeric embryos with competent organogenesis. This model system establishes a prototypic approach to examine consequences of human stemness factors induced reprogramming in the context of normal embryonic development, exploiting non-human early stage embryos. Thus, ectopic xeno-transduction across species unmasks the promiscuous nature of stemness induction, suggesting evolutionary selection of core processes for somatic tissue reprogramming. PMID- 20161097 TI - ADOLESCENT IDENTITIES AND SEXUAL BEHAVIOR: AN EXAMINATION OF ANDERSON'S 'PLAYER' HYPOTHESIS. AB - We investigate the social and behavioral characteristics of male adolescents who self-identify as players, focusing particularly on Anderson's claim that this social role is inextricably linked with poverty and minority status. Results indicate that African American respondents, those affiliated with liberal peers and young men who initially report a relatively high number of sexual partners are more likely to resonate with this identity label. Nevertheless, analyses reveal that a number of players within the sample are not disadvantaged African American youth, and there is considerable variability in their attitude and behavior profiles. Findings based on longitudinal analyses indicate that the player identity is a significant predictor of later variations in self-reported sexual behavior, net of traditional predictors, including prior behavior. Yet results of in-depth interviews conducted with a subset of the respondents complicate these quantitative findings, highlighting that young men's perceptions of this identity are not as uniformly positive as Anderson's depiction might lead us to expect. PMID- 20161098 TI - Polycrystalline Mercuric Iodide Films on CMOS Readout Arrays. AB - We have created high-resolution x-ray imaging devices using polycrystalline mercuric iodide (HgI(2)) films grown directly onto CMOS readout chips using a thermal vapor transport process. Images from prototype 400x400 pixel HgI(2) coated CMOS readout chips are presented, where the pixel grid is 30 mum x 30 mum. The devices exhibited sensitivity of 6.2 muC/Rcm(2) with corresponding dark current of approximately 2.7 nA/cm(2), and a 80 mum FWHM planar image response to a 50 mum slit aperture. X-ray CT images demonstrate a point spread function sufficient to obtain a 50 mum spatial resolution in reconstructed CT images at a substantially reduced dose compared to phosphor-coated readouts. The use of CMOS technology allows for small pixels (30 mum), fast readout speeds (8 fps for a 3200x3200 pixel array), and future design flexibility due to the use of well developed fabrication processes. PMID- 20161099 TI - Analysis of association constant for ground state dye-electron acceptor complex of photoinitiator systems and the association constant effect on the kinetics of visible-light-induced polymerizations. AB - We investigated the formation of ground state donor/acceptor complexes between xanthene dyes (rose Bengal (RB) and fluorescein (FL)) and a diphenyl iodonium salt (DPI) which is dissolved in 2-hydroxyethyl methacrylate (HEMA) monomer. To characterize the association constant of the complex, we have suggested a new analysis model based upon the Benesi-Hildebrand model. Because the assumption of the original Benesi-Hildebrand model is that the absorption bands are due only to the presence of the complex and that the absorption by the free component is negligible; the model cannot be applied to our systems, which is a dye-based initiator system. For each dye, the molar absorptivity of the ground state complex was evaluated as a function of wavelength and this analysis confirmed the validity of the modified Benesi-Hildebrand model. In addition, we observed the RB/DPI photoinitiator system failed to produce a perceptible polymerization rate but the FL/DPI photoinitiator system provided very high rates of polymerization. Based upon the association constant for these complexes, we concluded that the observed kinetic differences arise from the different association constant values of the ground state dye-acceptor complex, resulting in back electron transfer reaction. PMID- 20161100 TI - Thermally Stable Improved First-Generation Glucose Biosensors based on Nafion/Glucose-Oxidase Modified Heated Electrodes. AB - We illustrate how the use of heated electrodes enhances the performance of glucose biosensors based on amperometric detection of the glucose-oxidase generated hydrogen peroxide. Nafion is shown to be an excellent matrix to protect glucose oxidase from thermal inactivation during the heating pulses. The influence of the electrode temperature upon the amperometric response is examined. Temperature pulse amperometry (TPA) has been used to obtain convenient peak-shaped analytical signals. Surprisingly, up to 67.5 degrees C, the activity of Nafion-entrapped glucose oxidase is greatly enhanced (24 -fold) by accelerated kinetics rather than decreased by thermal inactivation. Amperometric signals even at elevated temperatures are stable upon prolonged operation involving repetitive measurements. The linear calibration range is significantly extended. PMID- 20161101 TI - WEAR BEHAVIOR OF CARBON NANOTUBE/HIGH DENSITY POLYETHYLENE COMPOSITES. AB - Carbon Nanotube/High Density Polyethylene (CNT/HDPE) composites were manufactured and tested to determine their wear behavior. The nanocomposites were made from untreated multi-walled carbon nanotubes and HDPE pellets. Thin films of the precursor materials were created with varying weight percentages of nanotubes (1%, 3%, and 5%), through a process of mixing and extruding. The precursor composites were then molded and machined to create test specimens for mechanical and wear tests. These included small punch testing to compare stiffness, maximum load and work-to-failure and block-on-ring testing to determine wear behavior. Each of the tests was conducted for the different weight percentages of composite as well as pure HDPE as the baseline. The measured mechanical properties and wear resistance of the composite materials increased with increasing nanotube content in the range studied. PMID- 20161102 TI - Variational Generation of Prismatic Boundary-Layer Meshes for Biomedical Computing. AB - Boundary-layer meshes are important for numerical simulations in computational fluid dynamics, including computational biofluid dynamics of air flow in lungs and blood flow in hearts. Generating boundary-layer meshes is challenging for complex biological geometries. In this paper, we propose a novel technique for generating prismatic boundary-layer meshes for such complex geometries. Our method computes a feature size of the geometry, adapts the surface mesh based on the feature size, and then generates the prismatic layers by propagating the triangulated surface using the face-offsetting method. We derive a new variational method to optimize the prismatic layers to improve the triangle shapes and edge orthogonality of the prismatic elements and also introduce simple and effective measures to guarantee the validity of the mesh. Coupled with a high quality tetrahedral mesh generator for the interior of the domain, our method generates high-quality hybrid meshes for accurate and efficient numerical simulations. We present comparative study to demonstrate the robustness and quality of our method for complex biomedical geometries. PMID- 20161104 TI - Vacuuming with my mouth?: Children's ability to comprehend novel extensions of familiar verbs. AB - Can 6- and 8-year-olds (and adults) comprehend common instrument verbs when extended to novel situations? Participants heard eight unusual extensions of common verbs and were asked to paraphrase the verbs' meanings. Half of the verbs used were specified instrument verbs that include the name of the instrument used to perform the action (e.g., a vacuum is used to vacuum); the other half were open instrument verbs (e.g., write) whose function can be performed with a range of objects. Results suggest that children's ability to interpret verb extensions increases with age, that open instrument verb extensions were more difficult to comprehend than specified instrument verb extensions and that performance on verb extension correlates with scores on a standardized test of language acquisition. Verb knowledge continues to develop well beyond the preschool years. PMID- 20161105 TI - Emotional Self-Regulation, Peer Rejection, and Antisocial Behavior: Developmental Associations from Early Childhood to Early Adolescence. AB - This study examined relations among emotional self-regulation, peer rejection, and antisocial behavior in a sample of 122 boys from low-income families who participated in a summer camp and were followed longitudinally from early childhood to early adolescence. Emotional self- regulation strategies were coded in early childhood from a waiting task, measures of peer rejection were collected during middle childhood at the summer camp, and reports of antisocial behavior were obtained during early adolescence. Structural equation modeling was utilized to examine longitudinal relations among these constructs, with results supporting a negative association between use of active distraction and peer rejection and a positive association between peer rejection and antisocial behavior. Furthermore, an indirect effect of active distraction on antisocial behavior was found through peer rejection. Thus, adaptive self-regulation strategy use in early childhood demonstrated direct longitudinal relations with peer rejection and an indirect association with antisocial behavior in early adolescence. Results have implications for early prevention and intervention efforts to foster adaptive self-regulation of emotion and reduce risk for later social problems and delinquency. PMID- 20161103 TI - Targeting the immunoregulatory indoleamine 2,3 dioxygenase pathway in immunotherapy. AB - Natural immune tolerance is a formidable barrier to successful immunotherapy to treat established cancers and chronic infections. Conversely, creating robust immune tolerance via immunotherapy is the major goal in treating autoimmune and allergic diseases, and enhancing survival of transplanted organs and tissues. In this review, we focus on a natural mechanism that creates local T-cell tolerance in many clinically relevant settings of chronic inflammation involving expression of the cytosolic enzyme indoleamine 2,3-dioxygenase (IDO) by specialized subsets of dendritic cells. IDO-expressing dendritic cells suppress antigen-specific T cell responses directly, and induce bystander suppression by activating regulatory T cells. Thus, manipulating IDO is a promising strategy to treat a range of chronic inflammatory diseases. PMID- 20161106 TI - Analytic Bounds on Causal Risk Differences in Directed Acyclic Graphs Involving Three Observed Binary Variables. AB - We apply a linear programming approach which uses the causal risk difference (RD(C)) as the objective function and provides minimum and maximum values that RD(C) can achieve under any set of linear constraints on the potential response type distribution. We consider two scenarios involving binary exposure X, covariate Z and outcome Y. In the first, Z is not affected by X, and is a potential confounder of the causal effect of X on Y. In the second, Z is affected by X and intermediate in the causal pathway between X and Y. For each scenario we consider various linear constraints corresponding to the presence or absence of arcs in the associated directed acyclic graph (DAG), monotonicity assumptions, and presence or absence of additive-scale interactions. We also estimate Z stratum-specific bounds when Z is a potential effect measure modifier and bounds for both controlled and natural direct effects when Z is affected by X. In the absence of any additional constraints deriving from background knowledge, the well-known bounds on RDc are duplicated: -Pr(Y not equalX) 65% from a 750 ul sample volume in 1 minute. PMID- 20161149 TI - Influence of the Circadian System on Disease Severity. AB - The severity of many diseases varies across the day and night. For example, adverse cardiovascular incidents peak in the morning, asthma is often worse at night and temporal lobe epileptic seizures are most prevalent in the afternoon. These patterns may be due to the day/night rhythm in environment and behavior, and/or endogenous circadian rhythms in physiology. Furthermore, chronic misalignment between the endogenous circadian timing system and the behavioral cycles could be a cause of increased risk of diabetes, obesity, cardiovascular disease and certain cancers in shift workers. Here we describe the magnitude, relevance and potential biological basis of such daily changes in disease severity and of circadian/behavioral misalignment, and present how these insights may help in the development of appropriate chronotherapy. PMID- 20161155 TI - Characterization of a novel ultra low refractive index material for biosensor application. AB - Nanoporous materials can provide significant benefits to the field of biosensors. Their size and porous structure makes them an ideal tool for improving sensor performance. This study characterized a novel ultra low index of refraction nanoporous organosilicate (NPO) material for use as an optical platform for fluorescence-based optical biosensors. While serving as the low index cladding material, the novel coating based on organosilicate nanoparticles also provides an opportunity for a high surface area coating that can be utilized for immobilizing biological probes. Biological molecules were immobilized onto NPO, which was spin-coated on silicon and glass substrates. The biological molecule was composed of Protein A conjugated to AlexaFluor 546 fluorophore and then immobilized onto the NPO substrate via silanization. Sample analysis consisted of spectrofluorometry, FT-IR spectroscopy, scanning electron microscopy, contact angle measurement and ellipsometry. The results showed the presence of emission peaks at 574 nm, indicating that the immobilization of Protein A to the NPO material is possible. When compared to Si and glass substrates not coated with NPO, the results showed a 100X and 10X increase in packing density with the NPO coated films respectively. Ellipsometric analysis, FT-IR, contact angle, and SEM imaging of the surface immobilized NPO films suggested that while the surface modifications did induce some damage, it did not incur significant changes to its unique characteristics, i.e., pore structure, wettability and index of refraction. It was concluded that NPO films would be a viable sensor substrate to enhance sensitivity and improve sensor performance. PMID- 20161154 TI - Single-Molecule Fluorescence Studies of RNA: A Decade's Progress. AB - Over the past decade, single-molecule fluorescence studies have elucidated the structure-function relationship of RNA molecules. The real-time observation of individual RNAs by single-molecule fluorescence has unveiled the dynamic behavior of complex RNA systems in unprecedented detail, revealing the presence of transient intermediate states and their kinetic pathways. This review provides an overview of how single-molecule fluorescence has been used to explore the dynamics of RNA folding and catalysis. PMID- 20161157 TI - Thio-mediated synthesis of derivatized N-linked glycopeptides using isonitrile chemistry. AB - The reaction of oligosaccharide isonitriles with peptide thioacids in the presence of bulky thiophenol as activator to provide N-linked glycopeptides at room temperature is described. PMID- 20161156 TI - Reliability and validity of measures of hammer toe deformity angle and tibial torsion. AB - BACKGROUND: Measures of second-fourth metatarsophalangeal joint (MTPJ) angle (indicator of hammer toe deformity) and clinical measures of tibial torsion have limited evidence for validity and reliability. The purposes of this study are to determine: (1) reliability of using a 3D digitizer (Metrecom) and computed tomography (CT) to measure MTPJ angle for toes 2-4; (2) reliability of goniometer, 3D digitizer, and CT to measure tibial torsion; (3) validity of MTPJ angle measures for toes 2-4 using goniometry and 3D digitizer compared to CT (gold standard) and (4) validity of tibial torsion measures using goniometry and 3D digitizer (Metrecom) compared to CT (gold standard). METHODS: Twenty-nine subjects participated in this study. 27 feet with hammer toe deformity and 31 feet without hammer toe deformity were tested using standardized gonimetric, 3D digitizer and CT methods. ICCs (3,1), standard error of the measurement (SEM) values, and difference measures were used to characterize intrarater reliability. Pearson correlation coefficients and an analysis of variance were used to determine associations and differences between the measurement techniques. FINDINGS: 3D digitizer and CT measures of MTPJ angle had high test-retest reliability (ICC = 0.95-0.96 and 0.98-0.99, respectively; SEM = 2.64-3.35 degrees and 1.42-1.47 degrees, respectively). Goniometry, 3D digitizer, and CT measures of tibial torsion had good test-retest reliability (ICC = 0.75, 0.85, and 0.98, respectively; SEM = 2.15 degrees, 1.74 degrees, and 0.72 degree, respectively). Both goniometric and 3D digitizer measures of MTPJ angle were highly correlated with CT measures of MTPJ angle (r = 0.84-0.90, r = 0.84-0.88, respectively) and tibial torsion (r = 0.72, r = 0.83). Goniometry, 3D digitizer, and CT measures were all different from each other for measures of hammer toe deformity (p < 0.001). Goniometry measures were different from CT measures and 3D digitizer measures of tibial torsion (p < 0.002). CT measures and 3D digitizer measures of tibial torsion were similar (p = 0.112). INTERPRETATIONS: These results suggest that 3D digitizer and CT scan measures of MTPJ angle and goniometric, 3D digitizer, and CT scan measures of tibial torsion are reliable. Goniometer and 3D digitizer measures of MTPJ angle and tibial torsion measures are highly correlated with the gold standard CT method indicating good validity of measures, but the measures are not interchangeable. PMID- 20161158 TI - A microfluidic electrochemical device for high sensitivity biosensing: detection of nanomolar hydrogen peroxide. AB - We report herein a simple device for rapid biosensing consisting of a single microfluidic channel made from poly(dimethylsiloxane) (PDMS) coupled to an injector, and incorporating a biocatalytic sensing electrode, reference and counter electrodes. The sensing electrode was a gold wire coated with 5 nm glutathione-decorated gold nanoparticles (AuNPs). Sensitive detection of H(2)O(2) based on direct bioelectrocatalysis by horseradish peroxidase (HRP) was used for evaluation. HRP was covalently linked the glutathione-AuNPs. This electrode presented quasi-reversible cyclic voltammetry peaks at -0.01 V vs Ag/AgCl at pH 6.5 for the HRP heme Fe(III)/Fe(II) couple. Direct electrochemical activity of HRP was used to detect H(2)O(2) at high sensitivity with a detection limit of 5 nM in an unmediated system. PMID- 20161159 TI - Associations among False-belief Understanding, Executive Function, and Social Competence: A Longitudinal Analysis. AB - A growing number of studies demonstrate associations among false-belief understanding (FBU), executive function (EF), and social competence. This study extends previous studies by exploring longitudinal associations among FBU and its correlates within a low-income sample of preschoolers attending Head Start. Sixty eight children (time 1 mean age = 5 years 2 months) were assessed over their preschool and kindergarten years. Results indicated bidirectional relations between FBU and social competence; FBU in preschool was positively associated with social competence in kindergarten and social competence in preschool was positively associated with FBU in kindergarten. Preschool EF was positively associated with social competence both in preschool and kindergarten and with FBU in preschool. Mediation analyses suggest that the bidirectional longitudinal link between FBU and social competence was independent of EF. These findings extend the FBU literature by examining its development and correlates in early childhood. Implications for future research and practice are discussed. PMID- 20161160 TI - The Path Taken: Consequences of Attaining Intrinsic and Extrinsic Aspirations in Post-College Life. AB - Life goals, or aspirations, organize and direct behavior over extended periods of time. The present study, guided by self-determination theory, examined the consequences of pursuing and attaining aspirations over a one-year period in a post-college sample. Results indicated that placing importance on either intrinsic or extrinsic aspirations related positively to attainment of those goals. Yet, whereas attainment of intrinsic aspirations related positively to psychological health, attainment of extrinsic aspirations did not; indeed, attainment of extrinsic aspirations related positively to indicators of ill being. Also as predicted, the association between change in attainment of intrinsic aspirations and change in psychological health was mediated by change in the satisfaction of the basic psychological needs for autonomy, competence, and relatedness. Discussion focuses on the idea that not all goal attainment is beneficial; rather, attainment of aspirations with different contents relates differentially to psychological health. PMID- 20161161 TI - Degradation of Trichloroethylene and Dichlorobiphenyls by Iron-Based Bimetallic Nanoparticles. AB - Bimetallic nanoparticles of Ni/Fe and Pd/Fe were used to study the degradation of trichloroethylene (TCE) at room temperature. The activity for different iron based nanoparticles with nickel as the catalytic dopant was analyzed using iron mass-normalized hydrogen generation rate. Degradation kinetics in terms of surface area-normalized rate constant was observed to have a strong correlation with the hydrogen generated by iron oxidation. A sorption study was conducted, and a mathematical model was derived that incorporates the reaction and Langmuirian-type sorption terms to estimate the intrinsic rate constant and rate limiting step in the degradation process, assuming negligible mass transfer resistance of TCE to the solid particles phase. A longevity study through repeated cycle experiments was conducted to analyze the effect of activity loss on the reaction mechanistic pathway, and the results showed that the attenuation in the nanoparticles activity did not adversely affect the reaction mechanisms in generating gaseous products such as ethylene and ethane. PMID- 20161162 TI - Green Nanotechnology from Tea: Phytochemicals in Tea as Building Blocks for Production of Biocompatible Gold Nanoparticles. AB - Phytochemicals occluded in tea have been extensively used as dietary supplements and as natural pharmaceuticals in the treatment of various diseases including human cancer. Results on the reduction capabilities of phytochemicals present in tea to reduce gold salts to the corresponding gold nanoparticles are presented in this paper. The phytochemicals present in tea serve the dual roles as effective reducing agents to reduce gold and also as stabilizers to provide robust coating on the gold nanoparticles in a single step. The Tea-generated gold nanoparticles (T-AuNPs), have demonstrated remarkable in vitro stability in various buffers including saline, histidine, HSA, and cysteine solutions. T-AuNPs with phytochemical coatings have shown significant affinity toward prostate (PC-3) and breast (MCF-7) cancer cells. Results on the cellular internalization of T-AuNPs through endocytosis into the PC-3 and MCF-7 cells are presented. The generation of T-AuNPs follows all principles of green chemistry and have been found to be non toxic as assessed through MTT assays. No 'man made' chemicals, other than gold salts, are used in this true biogenic green nanotechnological process thus paving excellent opportunities for their applications in molecular imaging and therapy. PMID- 20161164 TI - Review of the results from the International C. elegans first experiment (ICE FIRST). AB - In an effort to speed the rate of discovery in space biology and medicine NASA introduced the now defunct model specimen program. Four nations applied this approach with C. elegans in the ICE-FIRST experiment. Here we review the standardized culturing as well as the investigation of muscle adaptation, space biology radiation, and gene expression in response to spaceflight. Muscle studies demonstrated that decreased expression of myogenic transcription factors underlie the decreased expression of myosin seen in flight, a response that would appear to be evolutionarily conserved. Radiation studies demonstrated that radiation damaged cells should be able to be removed via apoptosis in flight, and that C. elegans can be employed as a biological accumulating dosimeter. Lastly, ICE-FIRST gave us our first glimpse at the genomic response to spaceflight, suggesting that altered Insulin and/or TGF-beta signaling in-flight may underlie many of the biological changes seen in response to spaceflight. The fact that the results obtained with C. elegans appear to have strong similarities in human beings suggests that not only will C. elegans prove an invaluable model for understanding the fundamental biological changes seen during spaceflight but that it may also be invaluable for understanding those changes associated with human health concerns in space. PMID- 20161163 TI - C-reactive Protein among Community-Dwelling Hypertensives on Single-agent Antihypertensive Treatment. AB - BACKGROUND: C-reactive protein is a predictor of adverse cardiovascular outcomes. The effect of antihypertensive therapy on C-reactive protein levels is largely unknown. METHOD: We undertook a cross-sectional study of CRP levels among participants with primary hypertension on single-agent anti-hypertensive therapy in the community-based biracial Genetic Epidemiology Network of Arteriopathy cohort. Linear regression models were used to assess the association of anti hypertensive medication class with log-transformed C-reactive protein after adjustment for age, gender, ethnicity, body mass index, smoking, diabetes, HMG-Co A reductase inhibitor use, achieved blood pressure control (<140/90 mmHg), serum creatinine and urine albumin-to-creatinine ratios. RESULTS: There were 662 participants in the cohort taking single-agent therapy for hypertension. Median C reactive protein levels differed across participants: 0.40 mg/dL for those on diuretics, 0.34 mg/dL on calcium channel blockers, 0.25 mg/dL on beta blockers and 0.27 mg/dL on renin-angiotensin-aldosterone system inhibitors (p<0.001). With multivariable adjustment, the group on renin-angiotensin-aldosterone system inhibitors had a 20% lower mean CRP on average than the group on diuretics (p=0.044), differences between other medication classes were not apparent. Heart rate had a strong association with C-reactive protein (p < 0.001). CONCLUSIONS: Antihypertensive medication class may influence inflammation, particularly in patients on RAAS inhibitors. PMID- 20161165 TI - Preparation of the Major Urinary Metabolite of (-)-Prostaglandin E(2). AB - The best way to measure whole body production of the locally acting hormone prostaglandin E(2) (PGE(2)) is to assess the accumulation of the major urinary metabolite, PGE(2) U (M). A practical preparation of this delicate diacid is described. This synthetic PGE(2)U(M) will enable production of the antibodies that will be used to quantify this key metabolite. PMID- 20161166 TI - Incorporating Quality into Data Envelopment Analysis of Nursing Home Performance: A Case Study. AB - When using data envelopment analysis (DEA) as a benchmarking technique for nursing homes, it is essential to include measures of the quality of care. We survey applications where quality has been incorporated into DEA models and consider the concerns that arise when the results show that quality measures have been effectively ignored. Three modeling techniques are identified that address these concerns. Each of these techniques requires some input from management as to the proper emphasis to be placed on the quality aspect of performance. We report the results of a case study in which we apply these techniques to a DEA model of nursing home performance. We examine in depth not only the resulting efficiency scores, but also the benchmark sets and the weights given to the input and output measures. We find that two of the techniques are effective in insuring that DEA results discriminate between high and low quality performance. PMID- 20161167 TI - Comparing measures of model selection for penalized splines in Cox models. AB - This article presents an application and a simulation study of model fit criteria for selecting the optimal degree of smoothness for penalized splines in Cox models. The criteria considered were the Akaike information criterion, the corrected AIC, two formulations of the Bayesian information criterion, and a generalized cross-validation method. The estimated curves selected by the five methods were compared to each other in a study of rectal cancer mortality in autoworkers. In the stimulation study, we estimated the fit of the penalized spline models in six exposure-response scenarios, using the five model fit criteria. The methods were compared based on a mean squared-error score and the power and size of hypothesis tests for any effect and for detecting nonlinearity. All comparisons were made across a range in the total sample size and number of cases. PMID- 20161168 TI - Are girls really becoming more delinquent? Testing the gender convergence hypothesis by race and ethnicity, 1976-2005. AB - Historically, girls have been less delinquent than boys. However, increased justice system involvement among girls and current portrayals of girls in the popular media and press suggest that girls' delinquency, particularly their violence and drug use, is becoming more similar to that of boys. Are girls really becoming more delinquent? To date, this question remains unresolved. Girls' increased system involvement might reflect actual changes in their behavior or changes in justice system policies and practices. Given that girls of color are overrepresented in the justice system, efforts to rigorously examine the gender convergence hypothesis must consider the role of race/ethnicity in girls' delinquency. This study uses self-report data from a large, nationally representative sample of youth to investigate the extent to which the magnitude of gender differences in violence and substance use varies across racial/ethnic groups and explore whether these differences have decreased over time. We find little support for the gender convergence hypothesis, because, with a few exceptions, the data do not show increases in girls' violence or drug use. Furthermore, even when girls' violent behavior or drug use has increased, the magnitude of the increase is not substantial enough to account for the dramatic increases in girls' arrests for violence and drug abuse violations. PMID- 20161169 TI - Microfluidic Generation of Lipidic Mesophases for Membrane Protein Crystallization. AB - We report on a microfluidic method for the formation of aqueous/lipid mesophases to enable screening of suitable crystallization conditions of membrane proteins from a membrane-like phase in sub-20 nanoliter volumes. This integrated microfluidic chip and the employed mixing strategy address the specific challenges associated with the mixing of fluids of highly different viscosities (here a factor of 30) as well as the non-Newtonian character of the resulting mesophases. The chip requires less than 20 nL of material per condition screened whereas typically on the order of 10 MUL or more is needed for a batch preparation in the present screening methods. We validated our approach with the successful crystallization of the membrane protein bacteriorhodopsin. PMID- 20161171 TI - Synthesis of the northern sector (C8-C19) of rapamycin via Chan rearrangement and oxidation of an alpha-acyloxyacetate. AB - Two routes to the masked tricarbonyl segment of the immunosuppressant rapamycin comprising C8-C19 were explored beginning from D-xylose. The first approach employed a protected form of 2,4,5-trihydroxypentanol to obtain dithiane 43, which failed to react with dimethyl oxalate to give a 1,2,3-tricarbonyl unit corresponding to the northern sector of rapamycin. A second approach employing carboxylic acid 61 derived from 43 utilized base-mediated (Chan) rearrangement of alpha-acyloxyacetate 62 with trapping of the resultant enediolate as bis silyl ether 63. Epoxidation of this diene afforded masked tri-keto ester 65 which underwent acid-catalyzed methanolysis to produce cyclic ketal 67. PMID- 20161172 TI - A Two-Factor Model of Temperament. AB - The higher order structure of temperament was examined in two studies using the Adult Temperament Questionnaire. Because previous research showed robust levels of convergence between Rothbart's constructs of temperament and the Big Five factors, we hypothesized a higher order two-factor model of temperament based on Digman's higher order two-factor model of personality traits derived from factor analysis of the Big Five factors. Study 1 included 258 undergraduates. Digman's model did not fit the data well, so we conducted an exploratory two-factor solution. One factor included extraversion/positive emotionality, orienting sensitivity, and affiliativeness, and the other, negative affect versus effortful control content. This two-factor model of temperament model diverged from the Digman model only on the agreeableness-affiliativeness loadings. Study 2 involved a community sample of 700 participants. Confirmatory factor analysis supported the alternative model found in Study 1. Findings are discussed in relation to research on attention and emotion. PMID- 20161173 TI - Clinical Issues in the Pediatric Hypertrophic Cardiomyopathies. PMID- 20161170 TI - Pathophysiology, management and treatment of smoke inhalation injury. AB - Smoke inhalation injury continues to increase morbidity and mortality in burn patients in both the third world and industrialized countries. The lack of uniform criteria for the diagnosis and definition of smoke inhalation injury contributes to the fact that, despite extensive research, mortality rates have changed little in recent decades. The formation of reactive oxygen and nitrogen species, as well as the procoagulant and antifibrinolytic imbalance of alveolar homeostasis, all play a central role in the pathogenesis of smoke inhalation injury. Further hallmarks include massive airway obstruction owing to cast formation, bronchospasm, the increase in bronchial circulation and transvascular fluid flux. Therefore, anticoagulants, antioxidants and bronchodilators, especially when administered as an aerosol, represent the most promising treatment strategies. The purpose of this review article is to provide an overview of the pathophysiological changes, management and treatment options of smoke inhalation injury based on the current literature. PMID- 20161174 TI - An Ultrahigh Resolution SPECT System for I-125 Mouse Brain Imaging Studies. AB - This paper presents some initial experimental results obtained with a dual-head prototype single photon emission microscope system (SPEM) that is dedicated to mouse brain studies using I-125 labeled radiotracers. In particular, this system will be used for in vivo tacking of radiolabeled T cells in mouse brain. This system is based on the use of the intensified electron multiplying charge-coupled device (I-EMCCD) camera that offers the combination of an excellent intrinsic spatial resolution, a good signal-to-noise ratio, a large active area and a reasonable detection efficiency over an energy range between 27-140keV. In this study, the dual-head SPEM system was evaluated using both resolution phantoms and a mouse with locally injected T cells labelled with I-125. It was demonstrated that for a relatively concentrated source object, the current dual-head SPEM system is capable of visualizing the tiny amount of radioactivity (~12 nCi) carried by a very small number (<1000) of T cells. The current SPEM system design allows four or six camera heads to be installed in a stationary system configuration that offers a doubled or tripled sensitivity at a spatial resolution similar to that obtained with the dualhead system. This development would provide a powerful tool for in vivo and non-invasive tracking of radiolabeled T cells in mouse brain and potentially for other rodent brain imaging studies. PMID- 20161175 TI - Detection and Identification of Bioanalytes with High Resolution LSPR Spectroscopy and MALDI Mass Spectrometry. AB - High resolution localized surface plasmon resonance (HR-LSPR) sensors were combined with matrix assisted laser desorption ionization mass spectrometry (MALDI-MS) for the first time. LSPR sensors provide real-time label-free detection of molecular adsorption. Subsequent MALDI-MS analysis enables identification of the adsorbed molecules. This synergistic LSPR-MS approach was applied to the detection and identification of amyloid beta oligomers which play an important role in the molecular pathogenesis of Alzheimer's Disease. PMID- 20161176 TI - Genetic and Environmental Influences on Aspects of Literacy and Language in Early Childhood: Continuity and Change from Preschool to Grade 2. AB - Early literacy and language skills of twin children in the USA, Australia, and Scandinavia were explored in a genetically sensitive design (maximum N = 615 pairs). For this article, we report aspects of preschool and Grade 2 data. In Grade 2, there were strong genetic influences on word reading, reading comprehension, and spelling. Vocabulary was about equally affected by genes and shared environment. Multivariate analyses indicated substantial genetic overlap among the Grade 2 literacy variables. Longitudinal analyses showed that genetic factors evident at the preschool stage continued to affect literacy and vocabulary three years later in Grade 2, but there was also evidence of new genetic factors coming into play over the time interval, at least for literacy. Suggestions are made about the search for underlying biological and cognitive processes, and educational implications are explored. PMID- 20161178 TI - New synthetic strategies for the stereocontrolled synthesis of substituted "skipped" diepoxides. AB - This report describes a number of new synthetic approaches towards methyl substituted mono- and diepoxy alcohols that serve as substrates for endo selective epoxide-opening cascades. The key transformations involve the manipulation of alkynes. Highlighted are the directed methylmetalation of bishomopropargylic alcohols, the bromoallylation of alkynes, and Pd-catalyzed cross-coupling between an alkenyl boronate ester and allylic bromides. PMID- 20161177 TI - A Rhodium(I)-Xylyl-BINAP Catalyzed Asymmetric Ynamide-[2 + 2 + 2] Cycloaddition in the Synthesis of Optically Enriched N,O-Biaryls. AB - A rhodium(I)-xylyl-BINAP catalyzed asymmetric [2 + 2 + 2] cycloaddition of achiral conjugated aryl ynamides with various diynes is described here. This asymmetric cycloaddition provides a series of structurally interesting chiral N,O biaryls with excellent enantioselectivity along with a modest diastereoselectivity with respect to both C-C and C-N axial chirality. PMID- 20161179 TI - A Transferable Coarse Grain Non-bonded Interaction Model For Amino Acids. AB - The large quantity of protein sequences being generated from genomic data has greatly outpaced the throughput of experimental protein structure determining methods and consequently brought urgency to the need for accurate protein structure prediction tools. Reduced resolution, or coarse grained (CG) models, have become a mainstay in computational protein structure prediction perfoming among the best tools available. The quest for high quality generalized CG models presents an extremely challenging yet popular endeavor. To this point, a CG based interaction potential is presented here for the naturally occurring amino acids. In the present approach, three to four heavy atoms and associated hydrogens are condensed into a single CG site. The parameterization of the site-site interaction potential relies on experimental data thus providing a novel approach that is neither based on all-atom (AA) simulations nor experimental protein structural data. Specifically, intermolecular potentials, which are based on Lennard-Jones (LJ) style functional forms, are parameterized using thermodynamic data including surface tension and density. Using this approach, an amino acid potential dataset has been developed for use in modeling peptides and proteins. The potential is evaluated here by comparing the solvent accessible surface area (SASA) to AA representations and ranking of protein decoy data sets provided by Decoys 'R' Us. The model is shown to perform very well compared to other existing prediction models for these properties. PMID- 20161180 TI - EPIDEMIOLOGY OF AGE-DEPENDENCE IN SLEEP DISORDERED BREATHING (SDB) IN OLD AGE: THE BAY AREA SLEEP COHORT (BASC). AB - Sleep Disordered Breathing (SDB) is highly prevalent in elderly populations and is thought to reflect, at least in part, age-dependence. Several studies suggest that SDB in elderly populations may hold different functional outcomes relative to SDB in middle-aged populations. Risk factors for SDB specific for the elderly remain uncertain. In this report, we examined changes in SDB, body weight and pulmonary function in 103 individuals over an average interval of 7 years to determine whether changes in these measures covaried. In-lab polysomnography was performed on members of an elderly cohort (Bay Area Sleep Cohort) on two separate occasions (Time 1, Time 2) with multiple nights of measurement typically made on each occasion. Results indicated that: a) SDB progressed over time in both men and women; b) changes in body weight were unrelated to the progression in SDB; c) relative declines in lung volumes (Forced Vital Capacity, Forced Expiratory Volume in 1.0 second) were associated with relative increases in SDB, with the effects slightly stronger in men. These data suggest that age-dependence in one commonly ascribed aging biomarker (lung function) were coupled to increments in SDB. Maintenance of healthy lung function into old age may confer some protective benefits in the development of age-dependent SDB. PMID- 20161181 TI - Microwave Assisted Synthesis of Iron(III) Oxyhydroxides/Oxides Characterized Using Transmission Electron Microscopy, X-ray Diffraction, and X-ray Absorption Spectroscopy. AB - Microwave assisted synthesis of iron oxide/oxyhydroxide nanophases was conducted using iron(III) chloride titrated with sodium hydroxide at seven different temperatures from 100 degrees C to 250 degrees C with pulsed microwaves. From the XRD results, it was determined that there were two different phases synthesized during the reactions which were temperature dependent. At the lower temperatures, 100 degrees C and 125 degrees C, it was determined that an iron oxyhydroxide chloride was synthesized. Whereas, at higher temperatures, at 150 degrees C and above, iron(III) oxide was synthesized. From the XRD, we also determined the FWHM and the average size of the nanoparticles using the Scherrer equation. The average size of the nanoparticles synthesized using the experimental conditions were 17, 21, 12, 22, 26, 33, 28 nm, respectively for the reactions from 100 degrees C to 250 degrees C. The particles also had low anisotropy indicating spherical nanoparticles, which was later confirmed using TEM. Finally, XAS studies show that the iron present in the nanophase was present as iron(III) coordinated to six oxygen atoms in the first coordination shell. The higher coordination shells also conform very closely to the ideal or bulk crystal structures. PMID- 20161182 TI - Enhanced Fluorescence Emission of Me-ADOTA by Self-Assembled Silver Nanoparticles on a Gold Film. AB - We report a multi-fold enhancement of the fluorescence of methyl azadioxatriangulenium chloride (Me-ADOTA*Cl) in PVA deposited on a 50 nm thick gold mirror carrying an evaporation induced self-assembly of colloidal silver nanoparticles (Ag-SACs). The average measured increase in fluorescence emission of about 50-fold is accompanied by hot spots with a local enhancement in brigthness close to 200. The long lifetime of the dye allows for the first direct determination of the correlation between the enhancement of emission intensity and the decrease in fluorescence lifetime. The Ag-SACs surface preparation and observed enhancements are highly reproducible. We believe that these robust plasmonic surfaces will find use in sensing platforms for ultrasensitive detection. PMID- 20161183 TI - Relevance of Iron Deposition in Deep Gray Matter Brain Structures to Cognitive and Motor Performance in Healthy Elderly Men and Women: Exploratory Findings. AB - Iron deposition increases in normal aging, has its greatest presence in structures of the extrapyramidal system, and may contribute to functional decline. MR imaging provides a method for indexing iron deposition in brain structures because of iron's ferromagnetic properties, which interact with the MRI environment to cause signal intensity attenuation that is quantifiable by comparing images collected at 1.5 and 3.0 T. We tested functional correlates of an MR-based iron index in 10 healthy, elderly individuals previously reported to have a higher iron burden in the putamen and lower in the thalamus than young individuals. Lower scores on the Dementia Rating Scale and longer reaction times on a two-choice attention test correlated with higher iron estimates in the caudate nucleus and putamen; poorer Mini-Mental State Examination and Digit Symbol scores correlated with lower iron estimates in the thalamus. Further analyses based on multiple regression, which considered regional FDRI estimates and volume measures as predictors of performance, identified iron but not the sampled volume as the unique predictor in each case. These exploratory correlations suggest a substrate of performance degradation in aging and have implications for regional signal darkening in an array of MR-based imaging protocols. PMID- 20161184 TI - Use of Larger Species such as Dog and Pig as Model Systems to Study Cardiac Disease. PMID- 20161185 TI - Synthesis of Sulfur-Containing Aryl and Heteroaryl Vinyls via Suzuki-Miyaura Cross-Coupling for the Preparation of SERS-Active Polymers. AB - The preparation of sulfur-containing aryl and heteroaryl vinyl co-monomers via Suzuki-Miyaura cross-coupling between the corresponding mercaptomethyl arylboronates and in situ-generated vinyl bromides is described. Surface enhanced Raman scattering (SERS) studies of the target compounds on gold nanoparticles confirmed their potential as spectroscopic tags in the fabrication of SERS encoded polymers for combinatorial screening and biomedical diagnostics. PMID- 20161186 TI - Determination, mechanism and monitoring of knockdown resistance in permethrin resistant human head lice, Pediculus humanus capitis. AB - Permethrin resistance has been reported worldwide and clinical failures to commercial pediculicides containing permethrin have likewise occurred. Permethrin resistance in head lice populations from the U.S. is widespread but is not yet uniform and the level of resistance is relatively low (~4-8 fold). Permethrin resistant lice are cross-resistant to pyrethrins, PBO-synergized pyrethrins and to DDT. Nix((R)), when applied to human hair tufts following manufacture's instructions, did not provide 100% control when assessed by the hair tuft bioassay in conjunction with the in vitro rearing system. Resistance to permethrin is due to knockdown resistance (kdr), which is the result of three point mutations within the alpha-subunit gene of the voltage-gated sodium channel that causes amino acid substitutions, leading to nerve insensitivity.A three tiered resistance monitoring system has been established based on molecular resistance detection techniques. Quantitative sequencing (QS) has been developed to predict the kdr allele frequency in head lice at a population level. The speed, simplicity and accuracy of QS made it an ideal candidate for a routine primary resistance monitoring tool to screen a large number of louse populations as an alternative to conventional bioassay. As a secondary monitoring method, real-time PASA (rtPASA) has been devised for a more precise determination of low resistance allele frequencies. To obtain more detailed information on resistance allele zygosity, as well as allele frequency, serial invasive signal amplification reaction (SISAR) has been developed as an individual genotyping method. Our approach of using three tiers of molecular resistance detection should facilitate large-scale routine resistance monitoring of permethrin resistance in head lice using field-collected samples. PMID- 20161187 TI - Individual versus Household Migration Decision Rules: Gender and Marital Status Differences in Intentions to Migrate in South Africa. AB - This research tests the thesis that the neoclassical micro-economic and the new household economic theoretical assumptions on migration decision-making rules are segmented by gender, marital status, and time frame of intention to migrate. Comparative tests of both theories within the same study design are relatively rare. Utilizing data from the Causes of Migration in South Africa national migration survey, we analyze how individually held "own-future" versus alternative "household well-being" migration decision rules effect the intentions to migrate of male and female adults in South Africa. Results from the gender and marital status specific logistic regressions models show consistent support for the different gender-marital status decision rule thesis. Specifically, the "maximizing one's own future" neoclassical microeconomic theory proposition is more applicable for never married men and women, the "maximizing household income" proposition for married men with short-term migration intentions, and the "reduce household risk" proposition for longer time horizon migration intentions of married men and women. Results provide new evidence on the way household strategies and individual goals jointly affect intentions to move or stay. PMID- 20161188 TI - IMAGE ENHANCEMENT FOR IMPAIRED VISION: THE CHALLENGE OF EVALUATION. AB - With the aging of the population, the prevalence of eye diseases and thus of vision impairment is increasing. The TV watching habits of people with vision impairments are comparable to normally sighted people1, however their vision loss prevents them from fully benefiting from this medium. For over 20 years we have been developing video image-enhancement techniques designed to assist people with visual impairments, particularly those due to central retinal vision loss. A major difficulty in this endeavor is the lack of evaluation techniques to assess and compare the effectiveness of various enhancement methods. This paper reviews our approaches to image enhancement and the results we have obtained, with special emphasis on the difficulties encountered in the evaluation of the benefits of enhancement and the solutions we have developed to date. PMID- 20161189 TI - Simulating Language-specific and Language-general Effects in a Statistical Learning Model of Chinese Reading. AB - Many theoretical models of reading assume that different writing systems require different processing assumptions. For example, it is often claimed that print-to sound mappings in Chinese are not represented or processed sub-lexically. We present a connectionist model that learns the print to sound mappings of Chinese characters using the same functional architecture and learning rules that have been applied to English. The model predicts an interaction between item frequency and print-to-sound consistency analogous to what has been found for English, as well as a language-specific regularity effect particular to Chinese. Behavioral naming experiments using the same test items as the model confirmed these predictions. Corpus properties and the analyses of internal representations that evolved over training revealed that the model was able to capitalize on information in "phonetic components" - sub-lexical structures of variable size that convey probabilistic information about pronunciation. The results suggest that adult reading performance across very different writing systems may be explained as the result of applying the same learning mechanisms to the particular input statistics of writing systems shaped by both culture and the exigencies of communicating spoken language in a visual medium. PMID- 20161190 TI - The genomes of the South American opossum (Monodelphis domestica) and platypus (Ornithorhynchus anatinus) encode a more complete purine catabolic pathway than placental mammals. AB - The end product of purine catabolism varies amongst vertebrates and is a consequence of independent gene inactivation events that have truncated the purine catabolic pathway. Mammals have traditionally been grouped into two classes based on their end product of purine catabolism: most mammals, whose end product is allantoin due to an ancient loss of allantoinase (ALLN), and the hominoids, whose end product is uric acid due to recent inactivations of urate oxidase (UOX). However little is known about purine catabolism in marsupials and monotremes. Here we report the results of a comparative genomics study designed to characterize the purine catabolic pathway in a marsupial, the South American opossum (Monodelphis domestica), and a monotreme, the platypus (Ornithorhynchus anatinus). We found that both genomes encode a more complete set of genes for purine catabolism than do eutherians and conclude that a near complete purine catabolic pathway was present in the common ancestor of all mammals, and that the loss of ALLN is specific to placental mammals. Our results therefore provide a revised history for gene loss in the purine catabolic pathway and suggest that marsupials and monotremes represent a third class of mammals with respect to their end products of purine catabolism. PMID- 20161191 TI - Total synthesis of haouamine A: the indeno-tetrahydropyridine core. AB - A full account of synthetic efforts towards the indeno-tetrahydropyridine core of haouamine A is presented. Initial failed strategies led to the unexpected discovery of a mild abnormal Chichibabin pyridine synthesis and provided knowledge and inspiration for the development of a cascade annulation that has enabled rapid and scalable access to the core in either racemic or enantiopure form. PMID- 20161192 TI - Current-polarized ion-selective membranes: The influence of plasticizer and lipophilic background electrolyte on concentration profiles, resistance, and voltage transients. AB - Lipophilic background electrolytes consisting of a lipophilic cation and a lipophilic anion, such as tetradodecylammonium tetrakis(4-chlorophenyl) borate (ETH 500), or bis(triphenylphosphoranylidene) ammonium tetrakis[3,5bis(trifluoromethyl) phenyl] borate (BTPPATFPB) are incorporated into the membranes of ion-selective electrodes (ISEs) to improve the detection limit and selectivity of the electrodes and decrease the resistance of the sensing membrane. In this work, spectroelectrochemical microscopy (SpECM) is used in conjunction with chronopotentiometry to quantify the effects of a lipophilic background electrolyte on the concentration profiles induced inside current polarized membranes and on the measured voltage transients in chronopotentiometric experiments. In agreement with the theoretical model, the lipophilic background electrolyte incorporated into o-NPOE or DOS plasticized membranes decreases the membrane resistance and thus the contribution of migration in the overall transport across ion-selective membranes. Consequently, it has a significant influence on the changing concentration profiles of the ion ionophore complex during chronopotentiometric experiments. PMID- 20161193 TI - Maternal Control and Sensitivity, Child Gender, and Maternal Education in Relation to Children's Behavioral Outcomes in African American Families. AB - This study examined relationships between mother-child interactions and children's behaviors in 119 urban African American mothers and their 6 - 7 year old children. Interactions during a cooking task and a follow-up child clean-up task were videotaped. Principal components analyses of behaviors during the cooking task yielded two factors in mothers (Sensitivity and Control), and three in children (Task Involvement, Responsiveness, and Communicative). Children's negativity during a clean up task was coded and mothers were interviewed about their children's problem behaviors. Parenting sensitivity was associated with positive child behaviors and parenting control was associated with negative child behaviors. Maternal education was associated with greater maternal sensitivity and less control. Child gender predicted their task involvement, responsiveness, communicativeness, negativity during clean-up, and behavior problems; maternal control and sensitivity mediated some of these relations. Findings underscore heterogeneity of African American parenting and factors that promote positive parenting and children's behavioral adjustment in early childhood. PMID- 20161194 TI - Back to the Future: Personality and Assessment and Personality Development. AB - In this essay I consider the future of personality development in light of the past effects of Personality and Assessment on the field of personality in general and personality development in particular. The essay is organized around 1) the effect of Mischel's book on the foundational theories informing personality development; 2) definitions of personality traits; 3) an alternative model of personality traits, described as the sociogenomic model of personality traits, that can bridge the divide that still characterizes the field of personality development; 4) the application of the sociogenomic model of personality traits to issues of personality trait development, and 5) a "Newtonian" vision for the future of personality psychology. PMID- 20161195 TI - Stereoselective Synthesis of Cyclometalated Iridium (III) Complexes: Characterization and Photophysical Properties. AB - The stereoselective synthesis of a highly luminescent neutral Ir(III) complex comprising two bidentate chiral, cyclometalating phenylpyridine derivatives, and one acetylacetonate as ligands is described. The final complex and some intermediates were characterized by X-ray structural analysis, NMR-, CD-, and CPL spectroscopy. PMID- 20161196 TI - Spongipyran Synthetic Studies. Total Synthesis of (+)-Spongistatin 2. AB - Evolution of a convergent synthetic strategy to access (+)-spongistatin 2 (2), a potent cytotoxic marine macrolide, is described. Highlights of the synthesis include: development of a multicomponent dithiane-mediated linchpin union tactic, devised and implemented specifically for construction of the spongistatin AB and CD spiro ring systems; application of a Ca(II) ion controlled acid promoted equilibration to set the thermodynamically less stable axial-equitorial stereogenicity in the CD spiroketal; use of sulfone addition/Julia methylenation sequences to unite the AB and CD fragments and introduce the C(44)-C(51) side chain; and fragment union and final elaboration to (+)-spongistatin 2 (2) exploiting Wittig olefination to unite the advanced ABCD and EF fragments, followed by regioselective Yamaguchi macrolactonization and global deprotection. Correction of the CD spiro ring stereogenicity was subsequently achieved via acid equilibration in the presence of Ca(II) ion to furnish (+)-spongistatin 2 (2). The synthesis proceeded with a longest linear sequence of 41 steps. PMID- 20161197 TI - New Routes to Low-Coordinate Iron Hydride Complexes: The Binuclear Oxidative Addition of H(2). AB - The oxidative addition and reductive elimination reactions of H(2) on unsaturated transition-metal complexes are crucial in utilizing this important molecule. Both biological and man-made iron catalysts use iron to perform H(2) transformations, and highly unsaturated iron complexes in unusual geometries (tetrahedral and trigonal planar) are anticipated to give unusual or novel reactions. In this paper, two new synthetic routes to the low-coordinate iron hydride complex [L(tBu)Fe(MU-H)](2) are reported. Et(3)SiH was used as the hydride source in one route by taking advantage of the silaphilicity of the fluoride ligand in three coordinate L(tBu)FeF. The other synthetic method proceeded through the binuclear oxidative addition of H(2) or D(2) to a putative Fe(I) intermediate. Deuteration was verified through reduction of an alkyne and release of the deuterated alkene product. Mossbauer spectra of [L(tBu)Fe(MU-H)](2) indicate that the samples are pure, and that the iron(II) centers are high-spin. PMID- 20161198 TI - Leaf species identity and combination affect performance and oviposition choice of two container mosquito species. AB - 1. Resource diversity can be an important determinant of individual and population performance in insects. Fallen parts of plants form the nutritive base for many aquatic systems, including mosquito habitats, but the effect of plant diversity on mosquito production is poorly understood.2. To determine the effects of diverse plant inputs on larval mosquitoes, experiments were conducted that examined how leaves of Vitis aestivalis, Quercus virginiana, Psychotria nervosa, and Nephrolepis exalta affected the container species Aedes triseriatus and Aedes albopictus.3. The hypothesis that leaf species have different effects on larval survival, growth, population performance, and oviposition choice of the two mosquito species was tested. The hypothesis that larval performance of A. albopictus responds additively to combinations of the four plant species was also tested.4. Larval survival and growth differed among the four leaf species, and oviposition preference differed among the two leaf species examined. Measurements of population performance demonstrated significant variation between leaf treatments. Larval outcomes for A. albopictus were significantly affected by leaf combination, and the hypothesis of additivity could be rejected.5. These results indicate that individual leaf species are important in determining the performance of container dwelling mosquitoes, which grow larger and survive better on mixed-species resource than expected based on an additive model of resource utilisation. PMID- 20161199 TI - Cross-Validation of a Screener to Predict Opioid Misuse in Chronic Pain Patients (SOAPP-R). AB - OBJECTIVES: The Screener and Opioid Assessment for Patients with Pain - Revised (SOAPP-R) is a self-report questionnaire designed to predict aberrant medication related behaviors among persons with chronic pain. This measure was developed to complement current risk assessment practices and to improve a clinician's ability to assess a patient's risk for opioid misuse. The aim of this study was to cross validate the SOAPP-R with a new sample of chronic, non-cancer pain patients. METHODS: Three hundred and two participants (N=302) prescribed opioids for pain were recruited from five pain management centers in the U.S. Subjects completed a series of self-report measures and were followed for five months. Patients were rated by their treating physician, had a urine toxicology screen, and were classified on the Aberrant Drug Behavior index. RESULTS: Seventy-three percent (73.2%) of the subjects (N= 221) were followed and 66 participants repeated the SOAPP-R after one week for test-retest reliability. The reliability and predictive validity, as measured by the area under the curve (AUC), were found to be highly significant (test-retest reliability = .91; coefficient alpha = .86; AUC = .74) and were sufficiently similar to values found with the initial sample. A cut-off score of 18 revealed a sensitivity of .80 and specificity of .52. CONCLUSIONS: Results of this cross-validation study suggest that the psychometric parameters of the SOAPP-R are not based solely on the unique characteristics of the initial validation sample. The SOAPP-R is found to be a reliable and valid screening tool for risk of aberrant drug-related behavior among chronic pain patients. PMID- 20161200 TI - Family, Neighborhood, and Peer Characteristics as Predictors of Child Adjustment: A Longitudinal Analysis of Additive and Mediation Models. AB - The purpose of this study was to test direct, additive, and mediation models involving family, neighborhood, and peer factors in relation to emerging antisocial behavior and social skills. Neighborhood danger, maternal depressive symptoms, and supportive parenting were assessed in early childhood. Peer group acceptance was measured in middle childhood, and data on antisocial behavior and social skills were collected when boys were 11 and 12 years old. Results were consistent with an additive effects model of child antisocial behavior. In contrast, peer relationships were stronger predictors of social skills than were family factors. Support for mediation was found in models involving neighborhood danger and supportive parenting. However, only peer group acceptance predicted change in antisocial and prosocial behavior. Implications for family and peer relations as socialization contexts are discussed. PMID- 20161201 TI - Approximating the risk score for disease diagnosis using MARS. AB - In disease screening and diagnosis, often multiple markers are measured and they are combined in order to improve the accuracy of diagnosis. McIntosh and Pepe (2002, Biometrics58, 657-644) showed that the risk score, defined as the probability of disease conditional on multiple markers, is the optimal function for classification based on the Neyman-Pearson Lemma. They proposed a two-step procedure to approximate the risk score. However, the resulted ROC curve is only defined in a subrange (L, h) of the false-positive rates in (0,1) and determination of the lower limit L needs extra prior information. In practice, most diagnostic tests are not perfect and it is usually rare that a single marker is uniformly better than the other tests. Using simulation, I show that multivariate adaptive regression spline (MARS) is a useful tool to approximate the risk score when combining multiple markers, especially when the ROC curves from multiple tests cross. The resulted ROC is defined in the whole range of (0,1) and it is easy to implement and has intuitive interpretation. The sample code of the application is shown in the appendix. PMID- 20161202 TI - Marital Conflict in the Context of Parental Depressive Symptoms: Implications for the Development of Children's Adjustment Problems. AB - Relations among parental depressive symptoms, overt and covert marital conflict, and child internalizing and externalizing symptoms were examined in a community sample of 235 couples and their children. Families were assessed once yearly for three years, starting when children were in kindergarten. Parents completed measures of depressive symptoms and children's internalizing and externalizing symptoms. Behavioral observations of marital conflict behaviors (insult, threat, pursuit, and defensiveness) and self-report of covert negativity (feeling worry, sorry, worthless, and helpless) were assessed based on problem solving interactions. Results indicated that fathers' greater covert negativity and mothers' overt destructive conflict behaviors served as intervening variables in the link between fathers' depressive symptoms and child internalizing symptoms, with modest support for the pathway through fathers' covert negativity found even after controlling for earlier levels of constructs. These findings support the role of marital conflict in the impact of fathers' depressive symptoms on child internalizing symptoms. PMID- 20161203 TI - Behavioral Profile Predicts Dominance Status in Mountain Chickadees. AB - Individual variation in stable behavioral traits may explain variation in ecologically-relevant behaviors such as foraging, dispersal, anti-predator behavior, and dominance. We investigated behavioral variation in mountain chickadees (Poecile gambeli), a North American parid that lives in dominance structured winter flocks, using two common measures of behavioral profile: exploration of a novel room and novel object exploration. We related those behavioral traits to dominance status in male chickadees following brief, pair wise encounters. Low-exploring birds (birds that visited less than four locations in the novel room) were significantly more likely to become dominant in brief, pairwise encounters with high-exploring birds (i.e., birds that visited all perching locations within a novel room). On the other hand, there was no relationship between novel object exploration and dominance. Interestingly, novel room exploration was also not correlated with novel object exploration. These results suggest that behavioral profile may predict the social status of group living individuals. Moreover, our results contradict the idea that novel object exploration and novel room exploration are always interchangeable measures of individuals' sensitivity to environmental novelty. PMID- 20161204 TI - Synthesis and Preliminary Evaluation of Duocarmycin Analogues Incorporating the 1,2,11,11a-Tetrahydrocyclopropa[c]naphtho[2,3-e]indol-4-one (CNI) and 1,2,11,11a Tetrahydrocyclopropa[c]naphtho[1,2-e]indol-4-one (iso-CNI) Alkylation Subunits. AB - Efficient syntheses and a preliminary evaluation of 1,2,11,11a tetrahydrocyclopropa[c]-naphtho[2,3-e]indole (CNI) and 1,2,11,11a tetrahydrocyclopropa[c]naphtho[1,2-e]indole (iso-CNI), and their derivatives containing an anthracene and phenanthrene variant of the CC-1065 or duocarmycin alkylation subunit are detailed. PMID- 20161205 TI - Design, fabrication and demonstration of a magnetophoresis chamber with 25 output fractions. AB - Our goal is to develop an instrument for parallel and multiplexed bioassay using magnetic labels. Toward this end we are developing a multi-outlet magnetophoresis instrument incorporating a fluidic flow chamber placed inside a magnetic field gradient. Magnetic microparticles are sorted by their magnetic moment for eventual use as biological labels based on magnetic signature.In this paper we concentrate on developments in our flow chamber fabrication methods that have allowed us to scale the number of sorting channels from 8 to 25. We present data for instrument performance and reproducibility of sorting. PMID- 20161206 TI - Regional Health and Function in the hippocampus: Evolutionary compromises for a critical brain region. AB - The hippocampus is especially vulnerable to damage caused by metabolic dysregulation. However distinct sub-regions within the hippocampus differ by their relative susceptibility to such damage. Region CA1 pyramidal neurons are most sensitive to metabolic perturbations while region CA3 pyramidal neurons show more resistance, and these unique profiles of susceptibility are but one example that differentiates CA1/CA3 neurons. We present here a hypothesis that inextricably links the unique biochemistries of learning and memory in region CA1, to that of cell survival signaling, and in so doing, suggest an explanation for region CA1 susceptibility to metabolic dysfunction. Further, we propose a signaling mechanism to explain how both pathways can be simultaneously regulated. Critical to this process is the protein phosphatase PHLPP1. Finally we discuss the implications of this hypothesis and the inherent challenges it poses for treatment of neurological disorders resulting in reduced hippocampal function by increased neuron death. PMID- 20161207 TI - Measuring the nucleation rate of Lysozyme using microfluidics. AB - We employ the PhaseChip, a (poly)dimethylsiloxane (PDMS) microfluidic device, for statistical studies of protein crystal nucleation. The PhaseChip is designed to decouple nucleation and growth of protein crystals and so improve their yield and quality. Two layers of fluidic channels containing salt reservoirs and nanoliter sized wells for protein drops in oil are separated by a thin PDMS membrane, which is permeable to water, but not to salt or macromolecules such as protein. We reversibly vary the supersaturation of protein inside the stored droplets by controlling the chemical potential of the reservoir. Lysozyme in the presence of sodium chloride is used as a model system. We determine the crystal nucleation rate as a function of protein supersaturation by counting the number of crystal nuclei per droplet, as demonstrated by Galkin and Vekilov.1. PMID- 20161208 TI - PHOSPHINE-CATALYZED [4+2] ANNULATION: SYNTHESIS OF ETHYL 6-PHENYL-1-TOSYL-1,2,5,6 TETRAHYDROPYRIDINE-3-CARBOXYLATE. PMID- 20161209 TI - Helicase inhibitors as specifically targeted antiviral therapy for hepatitis C. AB - The hepatitis C virus (HCV) leads to chronic liver disease and affects more than 2% of the world's population. Complications of the disease include fibrosis, cirrhosis and hepatocellular carcinoma. Current therapy for chronic HCV infection, a combination of ribavirin and pegylated IFN-alpha, is expensive, causes profound side effects and is only moderately effective against several common HCV strains. Specifically targeted antiviral therapy for hepatitis C (STAT C) will probably supplement or replace present therapies. Leading compounds for STAT-C target the HCV nonstructural (NS)5B polymerase and NS3 protease, however, owing to the constant threat of viral resistance, other targets must be continually developed. One such underdeveloped target is the helicase domain of the HCV NS3 protein. The HCV helicase uses energy derived from ATP hydrolysis to separate based-paired RNA or DNA. This article discusses unique features of the HCV helicase, recently discovered compounds that inhibit HCV helicase catalyzed reactions and HCV cellular replication, and new methods to monitor helicase action in a high-throughput format. PMID- 20161210 TI - Reactive and proactive control in incarcerated and community adolescents and young adults. AB - This study compared the cognitive control skills of male incarcerated adolescents (n=44), male control adolescents (n=33), male incarcerated young adults (n=41), and male control young adults (n=35) using the AX-Continuous Performance Task. This task measures proactive control (the ability to maintain a mental representation of goal-related information in preparation for a behavioral response) and reactive control (the ability to activate goal-related information in response to an external trigger). Incarcerated individuals had more difficulty implementing proactive control, whereas control individuals had more difficulty implementing reactive control. Adolescents had more difficulty with both reactive and proactive control compared to young adults, suggesting that both skills improve with age. Additional analyses indicated that the effect of age on proactive control was due to the presence of attention-deficit/hyperactivity disorder, whereas the effect of age on reactive control appeared to be a natural developmental trend that could not be explained by other variables. These findings are considered in relation to the dual mechanisms of control theory (Braver, Gray, & Burgess, 2007). PMID- 20161211 TI - Review: Thermal preference in Drosophila. AB - Environmental temperature strongly affects physiology of ectotherms. Small ectotherms, like Drosophila, cannot endogenously regulate body temperature so must rely on behavior to maintain body temperature within a physiologically permissive range. Here we review what is known about Drosophila thermal preference. Work on thermal behavior in this group is particularly exciting because it provides the opportunity to connect genes to neuromolecular mechanisms to behavior to fitness in the wild. PMID- 20161212 TI - New feature: pathways and important genes from PharmGKB. PMID- 20161213 TI - Strategic use of nickel(0)-catalyzed enyne-epoxide reductive coupling towards the synthesis of (-)-cyatha-3,12-diene. AB - Various situations are explored in which the nickel(0)-catalyzed enyne-epoxide reductive coupling was utilized to access key intermediates towards the total synthesis of (-)-cyatha-3,12-diene (1). Enantioenriched 3,5-dien-1-ols with a variety of functionality were obtained in a straightforward manner from easily accessible 1,3-enynes and terminal epoxides. PMID- 20161215 TI - Microfluidic Reactor Array Device for Massively Parallel In-situ Synthesis of Oligonucleotides. AB - We have designed and fabricated a microfluidic reactor array device for massively parallel in-situ synthesis of oligonucleotides (oDNA). The device is made of glass anodically bonded to silicon consisting of three level features: microreactors, microchannels and through inlet/outlet holes. Main challenges in the design of this device include preventing diffusion of photogenerated reagents upon activation and achieving uniform reagent flow through thousands of parallel reactors. The device embodies a simple and effective dynamic isolation mechanism which prevents the intermixing of active reagents between discrete microreactors. Depending on the design parameters, it is possible to achieve uniform flow and synthesis reaction in all of the reactors by proper design of the microreactors and the microchannels. We demonstrated the use of this device on a solution based, light-directed parallel in-situ oDNA synthesis. We were able to synthesize long oDNA, up to 120 mers at stepwise yield of 98 %. The quality of our microfluidic oDNA microarray including sensitivity, signal noise, specificity, spot variation and accuracy was characterized. Our microfluidic reactor array devices show a great potential for genomics and proteomics researches. PMID- 20161216 TI - Miniaturized implantable pressure and oxygen sensors based on polydimethylsiloxane thin films. AB - We demonstrate the application of polydimethylsiloxane (PDMS) thin films in highly sensitive pressure and oxygen sensors, designed for pressure and oxygen content measurements within the heart and blood vessels. PDMS thin film displacement as a result of pressure changes was transduced by a capacitive detection technique to produce quantitative measurement of absolute pressures. Oxygen measurements were obtained by transducing the current change between a Pt and an Ag/AgCl electrode on a glass substrate, with KCl soaked filter paper as the electrolytic media that is separated from the oxygen carrying fluid by a thin PDMS membrane. The best sensitivity for the pressure sensor was ~0.1 nA/KPa, with a noise limited resolution of ~0.09 KPa. For the oxygen sensor, the best sensitivity was ~2.75 MUA for 1% change in oxygen content of the surrounding media, with a noise limited resolution of ~6.18 ppm oxygen. These experimental results agree with theoretical modeling predictions, and suggest that the semi permeable and biocompatible PDMS can be successfully adopted as the contacting membrane in an integrated sensor design to quantify pressure and oxygen content in blood. PMID- 20161217 TI - Tracking Control of Hysteretic Piezoelectric Actuator using Adaptive Rate Dependent Controller. AB - With the increasing popularity of actuators involving smart materials like piezoelectric, control of such materials becomes important. The existence of the inherent hysteretic behavior hinders the tracking accuracy of the actuators. To make matters worse, the hysteretic behavior changes with rate. One of the suggested ways is to have a feedforward controller to linearize the relationship between the input and output. Thus, the hysteretic behavior of the actuator must first be modeled by sensing the relationship between the input voltage and output displacement. Unfortunately, the hysteretic behavior is dependent on individual actuator and also environmental conditions like temperature. It is troublesome and costly to model the hysteresis regularly. In addition, the hysteretic behavior of the actuators also changes with age. Most literature model the actuator using a cascade of rate-independent hysteresis operators and a dynamical system. However, the inertial dynamics of the structure is not the only contributing factor. A complete model will be complex. Thus, based on the studies done on the phenomenological hysteretic behavior with rate, this paper proposes an adaptive rate-dependent feedforward controller with Prandtl-Ishlinskii (PI) hysteresis operators for piezoelectric actuators. This adaptive controller is achieved by adapting the coefficients to manipulate the weights of the play operators. Actual experiments are conducted to demonstrate the effectiveness of the adaptive controller. The main contribution of this paper is its ability to perform tracking control of non-periodic motion and is illustrated with the tracking control ability of a couple of different non-periodic waveforms which were created by passing random numbers through a low pass filter with a cutoff frequency of 20Hz. PMID- 20161214 TI - Developmental hearing loss disrupts synaptic inhibition: implications for auditory processing. AB - Hearing loss during development leads to central deficits that persist even after the restoration of peripheral function. One key class of deficits is due to changes in central inhibitory synapses, which play a fundamental role in all aspects of auditory processing. This review focuses on the anatomical and physiological alterations of inhibitory connections at several regions within the central auditory pathway following hearing loss. Such aberrant inhibitory synaptic function may be linked to deficits in encoding binaural and spectral cues. Understanding the cellular changes that occur at inhibitory synapses following hearing loss may provide specific loci that can be targeted to improve function. PMID- 20161218 TI - Alone and Without Purpose: Life Loses Meaning Following Social Exclusion. AB - Four studies (N = 643) supported the hypothesis that social exclusion would reduce the global perception of life as meaningful. Social exclusion was manipulated experimentally by having a confederate refuse to meet participants after seeing their videotaped introduction (Study 1) and by ostracizing participants in a computerized ball-tossing game (Study 2). Compared to control condition and acceptance conditions, social exclusion led to perceiving life as less meaningful. Exclusion was also operationalized as self-reported loneliness, which was a better predictor of low meaning than other potent variables (Study 3). Study 4 found support for Baumeister's model of meaning (1991), by demonstrating that the effect of exclusion on meaning was mediated by purpose, value, and positive self-worth. PMID- 20161219 TI - A Diary Study of Implicit Self-esteem, Interpersonal Interactions and Alcohol Consumption in College Students. AB - A 30-day daily diary study examined the relations among implicit self-esteem, interpersonal interactions, and alcohol consumption in college students. Multilevel analyses revealed that students with low implicit self-esteem drank more on days when they experienced more negative interpersonal interactions. In contrast, students with high implicit self-esteem drank more on days when they experienced more positive interpersonal interactions. Spending time with people who were drinking mediated both the low implicit self-esteem by negative interpersonal events interaction and the high implicit self-esteem by positive interpersonal events interaction. These findings suggest that people with low implicit self-esteem may unintentionally drink as a way to regulate unfulfilled needs for acceptance. On the other hand, people with high implicit self-esteem may drink as a way to enhance positive interpersonal experiences. PMID- 20161221 TI - Counterfactual Thinking Facilitates Behavioral Intentions. AB - People often ponder what might have been, and these counterfactual inferences have been linked to behavior regulation. Counterfactuals may enhance performance by either a content-specific pathway (via shift in behavioral intentions) and/or a content-neutral pathway (via mindsets or motivation). Three experiments provided new specification of the content-specific pathway. A sequential priming paradigm revealed that counterfactual judgments facilitated RTs to complete behavioral intention judgments relative to control judgments and to a no-judgment baseline (Experiment 1). This facilitation effect was found only for intention judgments that matched the information content of the counterfactual (Experiment 2) and only for intention judgments as opposed to a different judgment that nevertheless focused on the same information content (Experiment 3). These findings clarify the content-specific pathway by which counterfactuals influence behavior. PMID- 20161220 TI - Effect of Light on Human Circadian Physiology. AB - The circadian system in animals and humans, being near but not exactly 24-hours in cycle length, must be reset on a daily basis in order to remain in synchrony with external environmental time. This process of entrainment is achieved in most mammals through regular exposure to light and darkness. In this chapter, we review the results of studies conducted in our laboratory and others over the past 25 years in which the effects of light on the human circadian timing system were investigated. These studies have revealed, how the timing, intensity, duration, and wavelength of light affect the human biological clock. Our most recent studies also demonstrate that there is much yet to learn about the effects of light on the human circadian timing system. PMID- 20161222 TI - Resource Dependent Effects During Sex Categorization. AB - The limited capacity of face perception resources in the left cerebral hemisphere was examined using a sex categorization task. One study tested the hypothesis that sex categorization is impeded whenever feature extraction resources in the left hemisphere are simultaneously being utilized by another task. This hypothesis was tested by presenting prime faces for either 32 ms or 320 ms to either the left or right visual-field just before centrally presented target faces were categorized by sex. Results showed that sex categorization was slower after prime faces were presented for 32 ms in the right visual-field compared to the left visual-field. This difference was not found after the 320 ms prime length. The results are interpreted in the context of a neurocognitive model of social perception and suggest that efficient sex categorization depends, in part, on the availability of facial feature extraction resources in the left hemisphere. PMID- 20161223 TI - The Effects of Strain on STM Lithography on HS-ssDNA/Au (111) Surface. AB - Scanning tunneling microscopy (STM) lithography was utilized to investigate a 12 mer HS-ssDNA self-assembled Au (111) surface. Under low sample bias and high tunneling current, the repeated scanning resulted in the growth of nanostripes. The stripe orientation, the stripe width, and the spacer width between adjacent nanostripes were found to be dependent on their relative locations from dislocation points where two adjacent gold terraces overlap. The stripe and the spacer width also vary with the distance from these points. The results indicate that such stripes may reflect the strain distributions and the release pathway along the Au surfaces. The results also suggest that the presence of HS-ssDNA molecules enhances the lithography processes on the gold surface by acting as force transmitters. PMID- 20161224 TI - The Choice of the Number of Bins for the M Statistic. AB - Methods to monitor spatial patterns of disease in populations are of interest in public health practice. The M statistic uses interpoint distances between cases to detect abnormalities in the spatial patterns of diseases. This statistic compares the observed distribution of interpoint distances with that which is expected when no unusual spatial patterns exist. We show the relationship of M to Pearson's Chi Square statistic, xn2. Both statistics require the discretization of continuous data into bins and then are formed by creating a quadratic form, scaled by an appropriate variance covariance matrix. We seek to choose the number and type of these bins for the M statistic so as to maximize the power to detect spatial anomalies. By showing the relationship between M to xn2, we argue for the extension of the theory that has been developed for the selection of the number and type of bins for xn2 to M. We further show that spatial data provides a unique insight into the problem through examples with simulated data and spatial data from a health care provider. In the spatial setting, these indicate that the optimal number of bins depends on the size of the cluster. For large clusters, a smaller number of bins appears to be preferrable, however for small clusters having many bins increases the power. Further, results indicate that the number of bins does not appear to vary with m, the number of spatial locations. We discuss the implications of this result for further work. PMID- 20161225 TI - The Interaction of Masculinity and Control and its Impact on the Experience of Suffering for an Older Man. AB - Previous work suggests that control and suffering are related to one another. Although it would be expected that within cultures which emphasize the importance of masculinity, as well as personal control, there would be greater suffering among individuals who lose their sense of masculinity or control, how these constructs relate to each other and are individually negotiated has been largely understudied. This paper takes a case study approach to further exploring how the constructs of control, masculinity, and suffering are related in the lived experience of an older European American man, Mr. Gregor. Analysis of this case shows that masculinity is related to control and that these constructs act as themes which interact over Mr. Gregor's lifetime in a variety of ways. The level of control maintained by Mr. Gregor in different aspects of his life affects his sense of suffering. In some instances his sense of masculinity helps to protect Mr. Gregor against suffering; in others, it contributes to his suffering. These findings support the notion that there are culturally dependent possibilities for how control and masculinity are related. PMID- 20161226 TI - Do adult eastern bluebird Sialia sialis males recognize juvenile-specific traits? AB - Juveniles of many avian species possess spotted or mottled plumage that is distinct from the plumage of adults. Such plumage has typically been assumed to aid in camouflaging vulnerable immature birds. Here, we propose that spotty plumage signals juvenile status, thereby decreasing aggression from territorial adults. We tested this hypothesis by measuring the aggressive responses of adult eastern bluebird males to different combinations of simultaneously presented taxidermic mounts. We found that territorial males attacked adult models significantly more than juvenile models, and that they attacked adult models with orange breasts (typical of adults) more frequently than they attacked adult models with spotty breasts (typical of juveniles). We found no difference in attack rates when models with white breasts (a novel trait) were presented with models possessing spotty breasts. These observations indicate that breast colour is a cue used by territorial adults when identifying conspecific intruders, but that adults do not recognize juvenile-specific plumage as such. Adults respond aggressively only to orange-breasted intruders. PMID- 20161227 TI - Natural Choice in Chimpanzees (Pan troglodytes): Perceptual and Temporal Effects on Selective Value. AB - In three experiments, four chimpanzees made choices between two visible food options to assess the validity of the selective value effect (the assignment of value to only the most preferred type of food presented in a comparison). In Experiment 1, we established that all chimpanzees preferred single banana pieces to single apple pieces before presenting the critical test. In this test two chimpanzees preferred a mix of one banana piece and one apple piece to a single banana piece when both banana piece were approximately the same size, but two chimpanzees were indifferent between the two options, exhibiting the selective value effect. In Experiment 2, when the banana pieces in both options were more closely equated in size the chimpanzees then were biased to choose the single banana piece over the mixed array even though this was the smaller total amount of food. However, in Experiment 3, when we introduced longer intervals between each trial, the chimpanzees preferred the mixed set and thus the larger total amount of food. The results demonstrate that only some chimpanzees exhibit the choice pattern indicative of the selective value effect, and they do so only when item size is not carefully controlled and trials are presented quickly in succession. Thus, the behavior pattern originally labeled the selective value effect may actually be explained by a combination of chimpanzees' sensitivity to small differences in preferred food amount and chimpanzees tendency to avoid less preferred foods that would delay the acquisition of further preferred food items. PMID- 20161228 TI - A Torquoselective Extrusion of Isoxazoline N-Oxides. Application to the Synthesis of Aryl Vinyl and Divinyl Ketones for Nazarov Cyclization. AB - A mild, convenient reaction sequence for the synthesis of Nazarov cyclization substrates is described. The [3+2] dipolar cycloaddition of a nitrone and an electron-deficient alkyne gives an isolable isoxazoline intermediate, which upon oxidation undergoes stereoselective extrusion of nitrosomethane to give aryl vinyl or divinyl ketones. PMID- 20161230 TI - N-Heterocyclic Carbene-Catalyzed Oxidations. AB - N-Heterocyclic carbenes catalyze the oxidation of allylic and benzylic alcohols as well as saturated aldehydes to esters with manganese(IV) oxide in excellent yields. A variety of esters can be synthesized, including protected carboxylates. The oxidation proceeds under mild conditions, with low loadings of a simple triazolium salt pre-catalyst in the presence of base. Substrates containing potentially epimerizable centers are oxidized while preserving stereochemical integrity. The acyl triazolium intermediate generated under catalytic conditions can be employed as a chiral acylating agent in the desymmetrization of meso diols. PMID- 20161229 TI - Vascular Smooth Muscle Cell Signaling Mechanisms for Contraction to Angiotensin II and Endothelin-1. AB - Vasoactive peptides, such as endothelin-1 and angiotensin II are recognized by specific receptor proteins located in the cell membrane of target cells. Following receptor recognition, the specificity of the cellular response is achieved by G-protein coupling of ligand binding to the regulation of intracellular effectors. These intracellular effectors will be the subject of this brief review on contractile activity initiated by endothelin-1 and angiotensin II.Activation of receptors by endothelin-1 and angiotensin II in smooth muscle cells results in phopholipase C (PLC) activation leading to the generation of the second messengers insitol trisphosphate (IP(3)) and diacylglycerol (DAG). IP(3) stimulates intracellular Ca(2+) release from the sarcoplasmic reticulum and DAG causes protein kinase C (PKC) activation. Additionally, different Ca(2+) entry channels, such as voltage-operated (VOC), receptor-operated (ROC), and store-operated (SOC) Ca(2+) channels, as well as Ca(2+)-permeable nonselective cation channels (NSCC), are involved in the elevation of intracellular Ca(2+) concentration. The elevation in intracellular Ca(2+) is transient and initiates contractile activity by a Ca(2+)-calmodulin interaction, stimulating myosin light chain (MLC) phosphorylation. When the Ca(2+) concentration begins to decline, Ca(2+)-sensitization of the contractile proteins is signaled by the RhoA/Rho-kinase pathway to inhibit the dephosphorylation of MLC phosphatase (MLCP) thereby maintaining force generation. Removal of Ca(2+) from the cytosol and stimulation of MLCP initiates the process of smooth muscle relaxation. In pathological conditions such as hypertension, alterations in these cellular signaling components can lead to an over stimulated state causing maintained vasoconstriction and blood pressure elevation. PMID- 20161231 TI - Microwave-Assisted Direct Biaryl Coupling: First Application to the Synthesis of Aporphines. AB - We have investigated the use of microwaves in a direct biaryl coupling reaction for the synthesis of analogs of the aporphine alkaloid nantenine. Our study shows that the aporphine core may be rapidly accessed from benzyl tetrahydroisoquinoline substrates with this method. This is the first report of a microwave-assisted direct biaryl coupling reaction in the synthesis of aporphine molecules. PMID- 20161232 TI - Synthesis of ultrasmall magnetic iron oxide nanoparticles and study of their colloid and surface chemistry. AB - Colloidal nanoparticles of Fe(3)O(4) (4 nm) were synthesized by high-temperature hydrolysis of chelated iron (II) and (III) diethylene glycol alkoxide complexes in a solution of the parent alcohol (H(2)DEG) without using capping ligands or surfactants: [Fe(DEG)Cl(2)](2-) + 2[Fe(DEG)Cl(3)](2-) + 2H(2)O + 2OH(-) -> Fe(3)O(4) + 3H(2)DEG + 8Cl(-) The obtained particles were reacted with different small-molecule polydentate ligands, and the resulting adducts were tested for aqueous colloid formation. Both the carboxyl and alpha-hydroxyl groups of the hydroxyacids are involved in coordination to the nanoparticles' surface. This coordination provides the major contribution to the stability of the ligand coated nanoparticles against hydrolysis. PMID- 20161233 TI - An improved synthesis of a fluorescent gabapentin-choline conjugate for single molecule detection. AB - Voltage-gated calcium ion channels are comprised of pore-forming alpha(1) and auxiliary alpha(2)delta, beta and gamma subunits. They are important molecular devices involved in a variety of cell functions. Fluorescently labeled acylcholine analogues are important in studies such as ion channel regulation. Cy3-3-acetylcholine has recently been synthesized for single molecule detection studies; albeit in an extremely low overall yield (0.06 %). In this work, an alternative route to that used in the previous Cy3-3-acetylcholine synthesis was developed with a 90 % yield at a significantly lower material cost. PMID- 20161234 TI - A comparison of iterative algorithms and a mixed approach for in-line x-ray phase retrieval. AB - Previous studies have shown that iterative in-line x-ray phase retrieval algorithms may have higher precision than direct retrieval algorithms. This communication compares three iterative phase retrieval algorithms in terms of accuracy and efficiency using computer simulations. We found the Fourier transformation based algorithm (FT) is of the fastest convergence, while the Poisson-solver based algorithm (PS) has higher precision. The traditional Gerchberg-Saxton algorithm (GS) is very slow and sometimes does not converge in our tests. Then a mixed FT-PS algorithm is presented to achieve both high efficiency and high accuracy. The mixed algorithm is tested using simulated images with different noise level and experimentally obtained images of a piece of chicken breast muscle. PMID- 20161235 TI - Spatial Latent Class Analysis Model for Spatially Distributed Multivariate Binary Data. AB - A spatial latent class analysis model that extends the classic latent class analysis model by adding spatial structure to the latent class distribution through the use of the multinomial probit model is introduced. Linear combinations of independent Gaussian spatial processes are used to develop multivariate spatial processes that are underlying the categorical latent classes. This allows the latent class membership to be correlated across spatially distributed sites and it allows correlation between the probabilities of particular types of classes at any one site. The number of latent classes is assumed fixed but is chosen by model comparison via cross-validation. An application of the spatial latent class analysis model is shown using soil pollution samples where 8 heavy metals were measured to be above or below government pollution limits across a 25 square kilometer region. Estimation is performed within a Bayesian framework using MCMC and is implemented using the OpenBUGS software. PMID- 20161236 TI - Spatiotemporal and Spatial Threshold Models for Relating UV Exposures and Skin Cancer in the Central United States. AB - The exact mechanisms relating exposure to ultraviolet (UV) radiation and elevated risk of skin cancer remain the subject of debate. For example, there is disagreement on whether the main risk factor is duration of the exposure, its intensity, or some combination of both. There is also uncertainty regarding the form of the dose-response curve, with many authors believing only exposures exceeding a given (but unknown) threshold are important. In this paper we explore methods to estimate such thresholds using hierarchical spatial logistic models based on a sample of a cohort of x-ray technologists for whom we have self reports of time spent in the sun and numbers of blistering sunburns in childhood. A preliminary goal is to explore the temporal pattern of UV exposure and its gradient. Changes here would imply that identical exposure self-reports from different calendar years may correspond to differing cancer risks. PMID- 20161237 TI - Unexpected Formation of Highly Functionalized Dihydropyrans via Addition Cyclization Reactions Between Dimethyl Oxoglutaconate and alpha,beta-Unsaturated Hydrazones. AB - The condensation between dienophiles and alpha,beta-unsaturated hydrazone azadienes was previously reported to afford piperidines. During an attempt to adapt this reaction to the preparation of piperidine-based conformationally restricted analogs of glutamate, it was discovered that the electrophile, dimethyl oxoglutaconate (DOG) led to highly substituted dihydropyrans in 20-50% yield. The unexpected pyran product likely results from an initial 1,4-addition of the hydrazone to the oxoglutaconate followed by intramolecular cyclization of the resultant enolate oxygen to the alpha,beta-unsaturated iminium ion. Further manipulations afford substituted tetrahydropyran 6-methamino-2,4-dicarboxylic acids. PMID- 20161238 TI - Iron and Cobalt Complexes of 2,6-Diacetylpyridine-bis(R-thiosemicarbazone) (R=H, phenyl) Showing Unprecedented Ligand Deviation from Planarity. AB - The syntheses, characterization, and single-crystal X-ray crystal structures are reported for four complexes of iron and cobalt with the pentadentate ligands, 2,6 diacetylpyridinebis(thiosemicarbazone) (H(2)L(1)) and 2,6-diacetylpyridinebis (phenylthiosemicarbazone) (H(2)L(2)), including a cobalt dimer displaying a deviation from planarity which is unprecedented for this class of ligands and allows the ligand to occupy five positions of a pseudo-octahedral coordination sphere. This dimer reacts with KCN to produce a mononuclear complex of relevance to the active site of cobalt nitrile hydratase. PMID- 20161239 TI - Personality Moderates the Interaction between Positive and Negative Daily Events Predicting Negative Affect and Stress. AB - A 30-day diary study examined personality moderators (neuroticism and extraversion) of the interaction between positive and negative daily events predicting daily negative affect and night-time stress. Multilevel analyses revealed positive daily events buffered the effect of negative daily events on negative affect for individuals low in neuroticism and individuals high in extraversion, but not for individuals high in neuroticism or individuals low in extraversion. Positive daily events also buffered the effect of negative daily events on that night's stress, but only for participants low in neuroticism. As such, this research linked today's events to tonight's stressfulness. This study advances our understanding of how neuroticism and extraversion influence within person associations between positive and negative events predicting negative affect and stress. PMID- 20161240 TI - Do Health Behaviors Explain the Effect of Neuroticism on Mortality? Longitudinal Findings from the VA Normative Aging Study. AB - Studies have shown that higher levels of neuroticism are associated with greater risk of mortality. Yet what accounts for this association? One major theoretical position holds that persons higher in neuroticism engage in poorer health behaviors, such as smoking and excessive drinking, thus leading to earlier death. We tested this hypothesis using 30-year mortality in 1,788 men from the VA Normative Aging Study. Using proportional hazards (Cox) models we found that one health behavior, smoking, attenuated the effect of neuroticism on mortality by 40%. However, 60% remained unexplained, suggesting that the effects of other pathways (e.g., biological) also influence the relationship between neuroticism and mortality. PMID- 20161241 TI - Arterial Stiffness and Wave Reflection: Biomarkers of Cardiovascular Risk. AB - Arterial stiffness and excessive pressure pulsatility have emerged as important risk factors for cardiovascular disease. Arterial stiffness increases with age and in the presence of traditional cardiovascular disease risk factors, such as hypertension, diabetes and lipid disorders. Pathologic stiffening of large arteries with advancing age and risk factor exposure predominantly involves the elastic aorta and carotid arteries, whereas stiffness changes are relatively limited in muscular arteries. Aortic stiffening is associated with increased pulse wave velocity and pulse pressure, which are related but distinct measures of the pulsatile energy content of the pressure waveform. A dramatic increase in pulsatile energy content of pressure and flow waves in the arterial system places considerable pulsatile stress on the heart, large arteries and distal circulation. Large artery stiffening is associated with abnormalities in microvascular structure and function that may contribute to tissue damage, particularly in susceptible high flow organs such as the brain and kidneys. This brief review summarizes results of recent research on risk factors for and adverse effects of large artery stiffening. PMID- 20161242 TI - Quantitative Measurement of Protease-Activity with Correction of Probe Delivery and Tissue Absorption Effects. AB - Proteases play important roles in a variety of pathologies from heart disease to cancer. Quantitative measurement of protease activity is possible using a novel spectrally matched dual fluorophore probe and a small animal lifetime imager. The recorded fluorescence from an activatable fluorophore, one that changes its fluorescent amplitude after biological target interaction, is also influenced by other factors including imaging probe delivery and optical tissue absorption of excitation and emission light.Fluorescence from a second spectrally matched constant (non-activatable) fluorophore on each nanoparticle platform can be used to correct for both probe delivery and tissue absorption. The fluorescence from each fluorophore is separated using fluorescence lifetime methods. PMID- 20161243 TI - How are pronunciation variants of spoken words recognized? A test of generalization to newly learned words. AB - One account of how pronunciation variants of spoken words (center-> "senner" or "sennah") are recognized is that sublexical processes use information about variation in the same phonological environments to recover the intended segments (Gaskell & Marslen-Wilson, 1998). The present study tests the limits of this phonological inference account by examining how listeners process for the first time a pronunciation variant of a newly learned word. Recognition of such a variant should occur as long as it possesses the phonological structure that legitimizes the variation. Experiments 1 and 2 identify a phonological environment that satisfies the conditions necessary for a phonological inference mechanism to be operational. Using a word-learning paradigm, Experiments 3 through 5 show that inference alone is not sufficient for generalization but could facilitate it, and that one condition that leads to generalization is meaningful exposure to the variant in an overheard conversation, demonstrating that lexical processing is necessary for variant recognition. PMID- 20161245 TI - Online Phenotype Discovery based on Minimum Classification Error Model. AB - Identifying and validating novel phenotypes from images inputting online is a major challenge against high-content RNA interference (RNAi) screening. Newly discovered phenotypes should be visually distinct from existing ones and make biological sense. An online phenotype discovery method featuring adaptive phenotype modeling and iterative cluster merging using improved gap statistics is proposed. Clustering results based on compactness criteria and Gaussian mixture models (GMM) for existing phenotypes iteratively modify each other by multiple hypothesis test and model optimization based on minimum classification error (MCE). The method works well on discovering new phenotypes adaptively when applied to both of synthetic datasets and RNAi high content screen (HCS) images with ground truth labels. PMID- 20161244 TI - Information Processing in Toddlers: Continuity from Infancy and Persistence of Preterm Deficits. AB - The present report assesses information processing in the toddler years (24 and 36 months), using a cohort of preterms (<1750 g) and full-terms initially seen in infancy. The children received a battery of tasks tapping 11 specific abilities from four domains - memory, processing speed, attention, and representational competence. The same battery had been used earlier - at 7 and 12 months. There were four main findings. (1) Preterms showed no 'catch-up,' but rather persistent deficits in immediate recognition, recall, encoding speed, and attention. (2) There was significant continuity from infancy through the toddler years for most aspects of information processing. (3) These specific abilities combined additively to account for global cognitive ability, consistent with the componential theory of intelligence. (4) Toddler information processing abilities completely mediated the relative deficits of preterms in general cognitive ability. Thus, although the toddler years have often been characterized as a period of discontinuity and transformation, these results indicate that continuity prevails for information processing abilities over the first three years of life. PMID- 20161246 TI - Catalytic enantioselective conjugate additions with alpha,beta-unsaturated sulfones. AB - We describe the development of a highly efficient catalytic asymmetric conjugate addition to alpha,beta-unsaturated sulfones. Utilizing practical bifunctional organic catalysts and involving air- and moisture-tolerant conditions, conjugate additions of a wide range of Michael donors to alpha,beta-unsaturated sulfones proceeded in excellent enantioselectivity/diastereoselectivity and high yield. This efficient and operationally simple new catalytic asymmetric reaction should provide a versatile approach for the asymmetric synthesis of chiral sulfones bearing all-carbon quaternary stereocenters. PMID- 20161247 TI - Conceptual plural information is used to guide early parsing decisions: Evidence from garden-path sentences with reciprocal verbs. AB - In three eyetracking studies, we investigated the role of conceptual plurality in initial parsing decisions in temporarily ambiguous sentences with reciprocal verbs (e.g., While the lovers kissed the baby played alone). We varied the subject of the first clause using three types of plural noun phrases: conjoined noun phrases (the bride and the groom), plural definite descriptions (the lovers), and numerically quantified noun phrases (the two lovers). We found no evidence for garden-path effects when the subject was conjoined (Ferreira & McClure, 1997), but traditional garden-path effects were found with the other plural noun phrases. In addition, we tested plural anaphors that had a plural antecedent present in the discourse. We found that when the antecedent was conjoined, garden-path effects were absent compared to cases in which the antecedent was a plural definite description. Our results indicate that the parser is sensitive to the conceptual representation of a plural constituent. In particular, it appears that a Complex Reference Object (Moxey et al., 2004) automatically activates a reciprocal reading of a reciprocal verb. PMID- 20161248 TI - Microfabricated magnetic sifter for high-throughput and high-gradient magnetic separation. AB - A microfabricated magnetic sifter has been designed and fabricated for applications in biological sample preparation. The device enables high throughput, high-gradient magnetic separation of magnetic nanoparticles by utilizing columnar fluid flow through a dense array (~5000/mm(2)) of micropatterned slots in a magnetically soft membrane. The potential of the sifter for separation of magnetic nanoparticles conjugated with capture antibodies is demonstrated through quantitative separation experiments with CD138-labelled MACS nanoparticles. Capture efficiencies ranging from 28-37% and elution efficiencies greater than 73% were measured for a single pass through the sifter. PMID- 20161249 TI - Beyond the Patch: Disturbance Affects Species Abundances in the surrounding Community. AB - The role of disturbance in community ecology has been studied extensively and is thought to free resources and reset successional sequences at the local scale and create heterogeneity at the regional scale. Most studies have investigated effects on either the disturbed patch or on the entire community, but have generally ignored any effect of or on the community surrounding disturbed patches. We used marine fouling communities to examine the effect of a surrounding community on species abundance within a disturbed patch and the effect of a disturbance on species abudance in the surrounding community. We varied both the magnitude and pattern of disturbance on experimental settlement plates. Settlement plates were dominated by a non-native bryozoan, which may have established because of the large amount of initial space available on plates. Percent cover of each species within the patch were affected by the surrounding community, confirming previous studies' predictions about edge effects from the surrounding community on dynamics within a patch. Disturbance resulted in lower percent cover in the surrounding community, but there were no differences between magnitudes or spatial patterns of disturbance. Disturbance lowered population growth rates in the surrounding community, potentially by altering the abiotic environment or species interactions. Following disturbance, the recovery of species within a patch may be affected by species in the surrounding community, but the effects of a disturbance can extend beyond the patch and alter abundances in the surrounding community. The dependence of patch dynamics on the surrounding community and the extended effects of disturbance on the surrounding community, suggest an important feedback of disturbance on patch dynamics indirectly via the surrounding community. PMID- 20161250 TI - Portable ladder assessment tool development and validation-quantifying best practices in the field. AB - Many causes for falls from ladders in construction are related to the user's activities; however, the extent to which users comply with ladder use best practices is unknown and has not been well quantified before. We developed and tested an audit tool that assesses compliance with best practices guidelines for portable ladder use designed for applications in the construction industry. Implemented on a hand-held computer, the assessment tool consisted of a series of checklists categorized in four groups; ladder condition, setup, moving on a ladder, and completing tasks from a ladder. For these four observational categories, the resulting tool contained 31 and 33 questions for step and extension ladders, respectively. Three individuals trained to use the tool scored a set of photographs and videos depicting 25 ladder conditions, 20 ladder setups, 10 users moving on ladders, and 13 users completing tasks from a ladder for a total of 78 observations. The assessment tool had good agreement across and within raters. For the three raters, agreement ranged from 79% to 97% across the questions. Within one subject, kappa coefficients for the intrarater reliability ranged from 0.67 to 0.91. The tool offers a practical method to quantify best practices associated with ladder use that can ultimately inform targeted intervention efforts. PMID- 20161251 TI - Robust principal axes determination for point-based shapes using least median of squares. AB - A robust technique for determining the principal axes of a 3D shape represented by a point set, possibly with noise, is presented. We use techniques from robust statistics to guide the classical principal component analysis (PCA) computation. Our algorithm is based on a robust statistics method: least median of squares (LMS), for outlier detection. Using this method, an outlier-free major region of the shape is extracted, which ignores the effect on other minor regions regarded as the outliers of the shape.In order to effectively approximate the LMS optimization, the forward search technique is utilized. We start from a small outlier-free subset robustly chosen as the major region, where an octree is used for accelerating computation. Then the region is iteratively increased by adding samples at a time. Finally, by treating the points on minor regions as outliers, we are able to define the principal axes of the shape as one of the major region. One of the advantages of our algorithm is that it automatically disregards outliers and distinguishes the shape as the major and minor regions during the principal axes determination without any extra segmentation procedure. The presented algorithm is simple and effective and gives good results for point based shapes. The application on shape alignment is considered for demonstration purpose. PMID- 20161252 TI - Switching the selectivity of a polyglycerol dendrimer monomolecularly imprinted with D-(-)-fructose. AB - A polyglycerol dendrimer unimolecularly imprinted with D-(-)-fructose (Fru) was synthesized. The dendrimer formed adducts with several monosaccharides, Fru, D (+)-galactose, D-(+)-glucose, D-(+)-mannose, and methyl-alpha-D-mannopyranoside (MMan), by removal of four water molecules. The dendrimer preferred Fru in the absence of N,N,N',N'-tetramethylmethylenediamine (TMDAM), whereas it preferred MMan in the presence of TMDAM. PMID- 20161253 TI - Enhanced Detection Resonance Frequency Shift of a Piezoelectric Microcantilever Sensor by a DC Bias Electric Field in Humidity Detection. AB - We have examined the relative longitudinal flexural resonance frequency shift of a PMN-PT/tin PEMS with a DC bias electric field, E, in humidity detection. We showed that the relative resonance frequency shift could be enhanced by applying an E to the PMN-PT layer during detection. A maximum enhancement of more than three times in resonance frequency shift was observed at E = -6 kV/cm as compared to the resonance frequency shift without a bias field. The maximal relative resonance frequency shift at E = -6 kV/cm was about 1000 times larger than could be accounted for by mass loading alone. PMID- 20161254 TI - Molecular Solids from Symmetrical Bis(piperazine-2,5-diones) with Open and Closed Monomer Conformations. AB - The design, synthesis and solid state structures of a new class of xylylene linked bis(1,4- piperazine-2,5-diones) are reported in an effort to extend the molecular framework of piperazine-2,5-diones. These compounds were derived from piperazine-2,5-dione as the core structure, synthesized via a new efficient route, and their crystal structures were determined. We examined the effects of side chain substitution on conformations of the linked bis-DKPs. Crystallization of 3,3'-[1,4-phenylenebis(methylene)]-bis[6-(hydroxymethyl)-1,4 dimethylpiperazine-2,5-dione] yielded molecular solids with an unusual network of "C"-shaped monomers held together by four intermolecular hydrogen bonds per asymmetric unit. Similarly, intermolecular interactions between the iodomethyl groups in 3,3'-[1,4-phenylenebis(methylene)]-bis[6-(iodomethyl)-1,4-dimethyl piperazine-2,5-dione] result in the monomers adopting a "C"-shape in the solid state. Assembly of the monomers with side chains converted to methyl groups or tert-butyldimethylsilyl ethers, thereby lacking these stabilizing intermolecular interactions, results in an infinite array of "S"-shaped conformations. These results suggest that the interplay between the attractive intermolecular interactions and repulsive steric interactions of the substituents at the C6 and C6' positions of the diketopiperazine rings is important in determining the solid state conformations of xylylene-linked bis(piperazine-2,5-diones). PMID- 20161255 TI - Synthesis of Pd Complexes Bearing an Enantiomerically-Resolved Seven-Membered N Heterocyclic Carbene Ligands and Initial Studies of their Use in Asymmetric Wacker-Type Oxidative Cyclization Reactions. AB - The development of enantiomerically-resolved, axially-chiral seven-membered N heterocyclic carbene ((7)NHC) ligands for palladium is described. These (7)NHC ligands are derived from enatiomerically pure 2,2'-diamino-6,6'-dimethylbiphenyl, which is transformed via a synthetic sequence consisting of ortho-arylation, N alkylation, and cyclization to afford seven-membered-ring amidinium salts. Synthesis of the 7-membered amidinium salts benefits from microwave irradiation, and in-situ metalation of the amidinium salts yields (7)NHC-Pd(II) complexes. The chiral (7)NHC-Pd complexes were examined as chiral catalysts under aerobic conditions in two intramolecular oxidative amination reactions of alkenes. In one case, enantioselectivities up to 63% e.e. were obtained, while the other substrate underwent cyclization to afford essentially racemic products. The catalytic data compare favorably to results obtained with a Pd(II) catalyst bearing a chiral five-membered-ring NHC ligand and, thereby, highlight the potential significance of this new class of chiral NHC ligands. PMID- 20161256 TI - Effects of stimulus duration and choice delay on visual categorization in pigeons. AB - We (Lazareva, Freiburger, & Wasserman, 2004) previously trained four pigeons to classify color photographs into their basic-level categories (cars, chairs, flowers, or people) or into their superordinate-level categories (natural or artificial). Here, we found that brief stimulus durations had the most detrimental effect on the basic-level discrimination of natural stimuli by the same pigeons. Increasing the delay between stimulus presentation and choice responding had greater detrimental effect on the basic-level discrimination than the superordinate-level discrimination. These results suggest that basic-level discriminations required longer stimulus durations and were more subject to forgetting than were superordinate-level discriminations. Additionally, categorization of natural stimuli required longer stimulus durations than categorization of artificial stimuli, but only at the basic level. Together, these findings suggest that basic-level categorization may not always be superior to superordinate-level categorization and provide additional evidence of a dissociation between natural and artificial stimuli in pigeons' categorization. PMID- 20161257 TI - 1,3-Dipolar cycloaddition of arynes with azomethine imines: synthesis of 1,2 dihydropyrazolo[1,2-a]indazol-3(9H)-ones. AB - A [3+2] 1,3-dipolar cycloaddition reaction of arynes with stable azomethine imines has been developed. The reaction rapidly assembles tricyclic pyrazoloindazolone derivatives in moderate yields under mild reaction conditions. PMID- 20161258 TI - Craving Predicts Within Session Drinking Behavior Following Placebo. AB - Tiffany's (1990) cognitive processing model postulates that craving will only occur when access to alcohol is blocked. To test a hypothesis based on this model, we analyzed data from a naturalistic laboratory alcohol challenge study involving moderate-to-heavy drinking young adults (N = 174) with a focus on the placebo beverage condition of this study. Our hypothesis was that self-reports of "wanting more alcohol" (i.e., craving) in the lab, following placebo, would predict subsequent ad libitum consumption because placebo administration would constitute partial blocking of access to alcohol. We also tested the possibility that craving might mediate associations between personality traits and ad libitum consumption. Both trait disinhibition and reports of craving following the placebo beverage significantly predicted ad libitum consumption. Further, craving partially mediated the association between trait disinhibition and ad libitum consumption. Potential implications of these findings are discussed. PMID- 20161259 TI - Facile synthesis of 1-(acetic acid)-4,7,10-tris(tert-butoxycarbonylmethyl) 1,4,7,10-tetraaza-cyclododecane: a reactive precursor chelating agent. AB - 1-(acetic acid)-4,7,10-tris(tert-butoxycarbonylmethyl)-1,4,7,10 tetraazacyclododecane (DOTA-Tris(t)Bu ester or 1) is a precursor chelating agent for lanthanide ions and can be efficiently labeled with various functional moieties or macromolecules to improve the targeting specificity, intracellular delivery, bio-compatibility, and pharmacokinetics of resulting contrast media used in molecular imaging. This compound is commercially available but the extremely high cost seriously limits its wide utilization. Thus, we sought a convenient and inexpensive synthesis of DOTA-Tris-(t)Bu ester that is readily adapted for use in any laboratory. The synthetic approach described here is straightforward and has an overall yield of 92%. Significantly, the product can be purified conveniently without using of a time- and labor-intensive column chromatography. Other advantages of this method, such as operational convenience, starting material availability, and atom efficiency make it very attractive to prepare DOTA-Tris-(t)Bu ester in large quantity with a reduced cost. PMID- 20161260 TI - Permutation test for non-inferiority of the linear to the optimal combination of multiple tests. AB - We proposed a permutation test for non-inferiority of the linear discriminant function to the optimal combination of multiple tests based on Mann-Whitney statistic estimate of the area under the receiver operating characteristic curve. Monte Carlo simulations showed its good performance. PMID- 20161261 TI - Trends in Child Welfare's Focus on Children's Mental Health and Services from 1980-2004. AB - This study examined how one of the oldest and most widely distributed child welfare practice journals addressed children's mental health issues over a 25 year period. The content of 478 articles was coded. Logistic regression findings indicate that mental health issues were discussed less frequently over the first half of the period examined, and then more frequently over the last decade. Residential treatment was discussed less frequently over time, but other community-based alternatives to residential treatment were rarely discussed at any point, so that overall the content related to treatment of mental health issues decreased as discussion of residential treatment decreased. These findings suggest that although the child welfare literature has recently focused more on children's mental health, dissemination of specific concepts from the mental health to the child welfare literature does not naturally occur over time. Efforts targeted at dissemination of effective community-based mental health interventions for foster children may be needed to support this process. PMID- 20161262 TI - Computational Studies on the Pt(II)-Catalyzed Cycloisomerization of 1,6-dienes into Bicyclopropanes: A Mechanistic Quandary Evaluated by DFT. AB - The mechanism of the (bis(phosphanylethyl)phosphane)Pt(2+) catalyzed cyclo isomerization reaction of 7-methyl-octa-1,6-diene to form 1 isopropylbicyclo[3.1.0]hexane was studied using computational methods. The cyclopropanation step was found to be the turnover-limiting step. The overall reaction proceeds via both a 5-exo and a 6-endo route. W conformations were shown to facilitate cyclopropanation, but do not have any influence on the rate of the 1,2-hydride shifts. PMID- 20161263 TI - An exceptionally simple and efficient synthesis of 6-methyl-6-vinylfulvene, and its oxidative transformations. AB - A new efficient synthesis of 6-methyl-6-vinylfulvene was developed, starting from the 6-(2-hydroxyethyl)-6-methylfulvene. With larger quantities of the title compound in hand, its photooxygenation with singlet oxygen was studied. Cyclization of the cyclopropanone intermediate to both vinyl moieties in the unsaturated system was observed, whereas the saturated endoperoxide gave mostly the cyclopentenone derivative. m-CPBA attacks exclusively the endocyclic double bonds and gives the 3-cyclopentenones via the unstable epoxides. PMID- 20161264 TI - Risk-Taking Propensity Changes Throughout the Course of Residential Substance Abuse Treatment. AB - High rates of relapse following treatment have compelled researchers to elucidate the individual difference factors that change among those who receive substance abuse treatment. Previous research has suggested that trait-disinhibition variables may be of particular relevance. Given that these variables are primarily considered to be trait-level factors, the extent to which they are malleable by treatment is an important consideration. Thus, the purpose of this study was to examine the effect of a residential substance abuse treatment program on specific trait-disinhibition variables (e.g., risk-taking, impulsivity). A sample of 81 inner-city substance users were assessed on self report and behavioral indicators of trait-disinhibition over a 30-day course of treatment. Risk-taking propensity was found to significantly decrease from pre- to post-treatment. Results are discussed with respect to implications for better understanding the factors that may operate as mechanisms of change during treatment, thereby having the potential to inform substance abuse prevention and treatment programs. PMID- 20161265 TI - A Robust Unified Approach to Analyzing Methylation and Gene Expression Data. AB - Microarray technology has made it possible to investigate expression levels, and more recently methylation signatures, of thousands of genes simultaneously, in a biological sample. Since more and more data from different biological systems or technological platforms are being generated at an incredible rate, there is an increasing need to develop statistical methods that are applicable to multiple data types and platforms. Motivated by such a need, a flexible finite mixture model that is applicable to methylation, gene expression, and potentially data from other biological systems, is proposed. Two major thrusts of this approach are to allow for a variable number of components in the mixture to capture non biological variation and small biases, and to use a robust procedure for parameter estimation and probe classification. The method was applied to the analysis of methylation signatures of three breast cancer cell lines. It was also tested on three sets of expression microarray data to study its power and type I error rates. Comparison with a number of existing methods in the literature yielded very encouraging results; lower type I error rates and comparable/better power were achieved based on the limited study. Furthermore, the method also leads to more biologically interpretable results for the three breast cancer cell lines. PMID- 20161267 TI - Optimization of Spin-Unrestricted Density Functional Theory for Redox Properties of Rubredoxin Redox Site Analogues. AB - Quantum chemical calculations of metal clusters in proteins for redox studies require both computational feasibility as well as accuracies of at least ~50 mV for redox energies but only ~0.05 A for bond lengths. Thus, optimization of spin unrestricted density functional theory (DFT) methods, especially the hybrid generalized gradient approximation functionals, for energies while maintaining good geometries is essential. Here, different DFT functionals with effective core potential (ECP) and full core basis sets for [Fe(SCH(3))(4)](2-/1-) and [Fe(SCH(3))(3)](1-/0), which are analogs of the iron-sulfur protein rubredoxin, are investigated in comparison to experiment as well as other more computationally intensive electron correlation methods. In particular, redox energies are calibrated against gas-phase photoelectron spectroscopy data so no approximations for the environment are needed. B3LYP gives the best balance of accuracy in energy and geometry compared B97gga1 and BHandH and is better for energies than Moller-Plesset perturbation theory series (MP2, MP3, MP4SDQ) and comparable to coupled cluster [CCSD, CCSD(T)] methods. Of the full core basis sets tested, the 6-31G** basis sets give good geometries, and addition of diffuse functions to only the sulfur significantly improves the energies. Moreover, a basis set with an ECP on only the iron gives a less accurate but still reasonable geometries and energies. PMID- 20161266 TI - Exploring feature-based approaches in PET images for predicting cancer treatment outcomes. AB - Accumulating evidence suggests that characteristics of pre-treatment FDG-PET could be used as prognostic factors to predict outcomes in different cancer sites. Current risk analyses are limited to visual assessment or direct uptake value measurements. We are investigating intensity-volume histogram metrics and shape and texture features extracted from PET images to predict patient's response to treatment. These approaches were demonstrated using datasets from cervix and head and neck cancers, where AUC of 0.76 and 1.0 were achieved, respectively. The preliminary results suggest that the proposed approaches could potentially provide better tools and discriminant power for utilizing functional imaging in clinical prognosis. PMID- 20161268 TI - Suffering and Generativity: Repairing Threats to Self in Old Age. AB - Suffering is a powerful experience that can be difficult to articulate. Suffering differs from pain alone and includes an individual's awareness of a threat to self through death, loss of identity, or uncertaintly of the meaningfulness of one's life. In response to this threat, generative acts, especially creative expressions imbued with the self, may act as a means to repair the self in crisis. The case of Mr. A., an 85-year old man in good health, illustrates how various artistic pieces he created - a wooden dog and several poems -- helps him to restore a "fading" self. For Mr. A, the idea of "fading away" or becoming weaker and less useful until eventually disappearing is a major source of personal suffering. Through his art, he creates unique, interactive and tangible entities that can outlive his physical body and help him reclaim or repair threats to selfhood. PMID- 20161269 TI - One Carbon Homologation of Halides to Benzyl Ethers. AB - The preparation of one carbon homologated benzyl ethers from alkyl and aromatic halides is reported. The coupling reaction is rapid and efficient at room temperature. PMID- 20161270 TI - Synthesis of 2H-chromenes and 1,2-dihydroquinolines from aryl aldehydes, amines, and alkenylboron compounds. AB - The one-step reaction of salicylaldehydes with amines and alkenyl boronic acids or alkenyl trifluoroborates to form 2H-chromenes (2H-1-benzopyrans) has been investigated in more detail and new suitable conditions have been identified, including the use of tertiary amines and protic solvents including water. This process was applied to a concise synthesis of a tocopherol analog. The analogous condensation reaction between 2-sulfamidobenzaldehydes and alkenyl trifluoroborates provides an efficient synthesis of 1,2-dihydroquinoline derivatives. PMID- 20161271 TI - Dorsal cortex volume in male side-blotched lizards (Uta stansburiana) is associated with different space use strategies. AB - Spatial abilities have been associated with many ecologically-relevant behaviors such as territoriality, mate choice, navigation and acquisition of food resources. Differential demands on spatial abilities in birds and mammals have been shown to affect the hippocampus, the region of the brain responsible for spatial processing. In some bird and mammal species, higher demands on spatial abilities are associated with larger hippocampal volumes. The medial and dorsal cortices are the putative reptilian homologues of the mammalian hippocampus, yet few studies have examined the relationship between these brain areas and differential spatial use strategies in reptiles. Further, many studies in birds and mammals compare hippocampal attributes between species that utilize space differently, potentially confounding species-specific effects with effects due to differential behaviors in spatial use. Here, we investigated the relationship between spatial use strategies and medial and dorsal cortical volumes in males of the side-blotched lizard (Uta stansburiana). In this species, males occur in three different morphs, each morph using different spatial niches: large territory holders, small territory holders and non-territory holders with home ranges smaller than the territories of small territory holders. We found that large territory holders had larger dorsal cortical volumes relative to the remainder of the telencephalon compared with non-territorial males, and small territory holders were intermediate. These results suggest that some aspect of holding a large territory may place demands on spatial abilities, which is reflected in a brain region thought partially responsible for spatial processing. PMID- 20161272 TI - An amine-derivatized, DOTA-loaded polymeric support for Fmoc Solid Phase Peptide Synthesis. AB - An amine-derivatized DOTA has been used to modify the surface of a polymeric support for conventional Solid Phase Peptide Synthesis (SPPS) following standard Fmoc chemistry methods. This methodology was used to synthesize a peptide-DOTA conjugate that was demonstrated to be a PARACEST MRI contrast agent. Therefore, this synthesis methodology can facilitate Fmoc SPPS of molecular imaging contrast agents. PMID- 20161273 TI - Effects of dispersion and interfacial modification on the macroscale properties of TiO(2) polymer matrix nanocomposites. AB - This paper quantifies how the quality of dispersion and the quality of the interfacial interaction between TiO(2) nanoparticles and host polymer independently affect benchmark properties such as glass transition temperature (Tg), elastic modulus and loss modulus. By examining these composites with differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA) and scanning electron microscopy (SEM), we were able to demonstrate changes in properties depending on the adhesive/wetting or repulsive/dewetting interactions the nanoparticles have with the bulk polymer. We further quantified the dispersion of TiO(2) nanoparticles in polymethylmethacrylate (PMMA) matrices by a digital-optical method and correlated those values to the degree of Tg depression compared to neat PMMA. Samples with the same weight percent of nanoparticles but better dispersion showed larger shifts in Tg. PMID- 20161274 TI - Modelling and spatial discrimination of small mammal assemblages: an example from western Sichuan (China). AB - We investigate the relationship between landscape heterogeneity and the spatial distribution of small mammals in two areas of Western Sichuan, China. Given a large diversity of species trapped within a large number of habitats, we first classified small mammal assemblages and then modelled the habitat of each in the space of quantitative environmental descriptors. Our original two step "classify then model" procedure is appropriate for the frequently encountered study scenario: trapping data collected in remote areas with sampling guided by expert field knowledge.In the classification step, we defined assemblages by grouping sites of similar species composition and relative densities using an expert-class merging procedure which reduced redundancy in the habitat factor used within a multinomial logistic regression predicting species trapping probabilities. Assemblages were thus defined as mixtures of small mammal frequency distributions in discrete groups of sampled sites.In the modelling step, assemblages' habitats and environments of the two sampled areas were discriminated in the space of remotely sensed environmental descriptors. First, we compared the discrimination of assemblage/study areas by linear and non-linear forms of Discriminant Analysis (Linear Discriminant Analysis versus Mixture Discriminant Analysis) and of Multiple Regression (Generalized Linear Models versus Multiple Adaptive Regression Splines). The "best" predictive modelling technique was then used to quantify the contribution of each environmental variable in discriminations of assemblages and areas.Mixtures of Gaussians provided a more efficient model of assemblage coverage in environmental space than a single Gaussian cluster model. However, non-linearity in assemblage response to environmental gradients was consistently predicted with lower deviance and misclassification error by Multiple Adaptive Regression Splines. The two study areas were mainly discriminated along vegetation indices. However, although the Normalized Difference Vegetation Index (NDVI) could discriminate forested from non-forested habitats, its power to discriminate assemblages in Maerkang, where a greater diversity of forest habitat was observed, was seen to be limited, and in this case NDVI was outperformed by the Enhanced Vegetation Index (EVI). Our analyses highlight previously unobserved differences between the environments and small mammal communities of two fringe areas of the Tibetan plateau and suggests that a biogeograph-ical approach is required to elucidate ecological processes in small mammal communities and to reduce extrapolation uncertainty in distribution mapping. PMID- 20161275 TI - Ecosystem Modeling of College Drinking: Parameter Estimation and Comparing Models to Data. AB - Recently we developed a model composed of five impulsive differential equations that describes the changes in drinking patterns (that persist at epidemic level) amongst college students. Many of the model parameters cannot be measured directly from data; thus, an inverse problem approach, which chooses the set of parameters that results in the "best" model to data fit, is crucial for using this model as a predictive tool. The purpose of this paper is to present the procedure and results of an unconventional approach to parameter estimation that we developed after more common approaches were unsuccessful for our specific problem. The results show that our model provides a good fit to survey data for 32 campuses. Using these parameter estimates, we examined the effect of two hypothetical intervention policies: 1) reducing environmental wetness, and 2) penalizing students who are caught drinking. The results suggest that reducing campus wetness may be a very effective way of reducing heavy episodic (binge) drinking on a college campus, while a policy that penalizes students who drink is not nearly as effective. PMID- 20161278 TI - Synthetic Studies Towards the Mitomycins: Construction of the Tetracyclic Core via a Reductive Aminocyclization Reaction. AB - The tetracyclic core of the mitomycin family of natural products has been formed in one step from an acyclic precursor via a reductive aminocyclization reaction. Additionally, the 8-membered benzazocine can be prepared without the need for prior activation of the aniline. Construction of a mitomycin K analogue lacking the C9a methoxy moiety is also reported herein. PMID- 20161276 TI - alpha-Haloarylsulfonamides: Multiple Cyclization Pathways to Skeletally Diverse Benzofused Sultams. AB - The development of new methods to skeletally diverse sultams based on a central alpha-halo benzene sulfonamide building block is reported. Several salient features of this building block are utilized in multiple reaction pathways, including the Heck reaction, C- and O-arylation, Sonogashira-Pauson-Khand, Sonogashira-intramolecular hydroamination, lithiative cyclization and domino aza Michael Heck for the generation of 5-, 6- and 7-membered benzofused bicyclic and tricyclic sultams. PMID- 20161277 TI - Metathesis Cascade Strategies (ROM-RCM-CM): A DOS approach to Skeletally Diverse Sultams. AB - The development of a ring-opening metathesis/ring-closing metathesis/cross metathesis (ROM-RCM-CM) cascade strategy to the synthesis of a diverse collection of bi- and tricyclic sultams is reported. In this study, functionalized sultam scaffolds derived from intramolecular Diels-Alder (IMDA) reactions undergo metathesis cascades to yield a collection tricyclic sultams. Additional appendage based diversity was achieved by utilizing a variety of CM partners. PMID- 20161279 TI - Caught in the Act: How Extraverted and Introverted Friends Communally Cope with Being Recorded. AB - This study explored how close friends who were similar or opposite on extraversion communally coped with being put on the spot to produce a recorded conversation. Participants were 50 pairs of same-sex college-age friends (54% female) who explicitly discussed the fact that their conversation was being recorded. The initial 'on-stage' episode emerged consistently earliest for extraverted dyads, and the majority of their episodes quickly diverted the on stage moment. Dyads that included at least one introvert engaged in more extensive assortments of on-stage maneuvers, including research talk, soothing, and joking. In introvert-extravert dyads the extravert usually initiated and ended these episodes. Implications are discussed for understanding how personality is reciprocally implicated in managing shared everyday problems. PMID- 20161280 TI - Is perceptual space inherently non-Euclidean? AB - It is often assumed that the space we perceive is Euclidean, although this idea has been challenged by many authors. Here we show that, if spatial cues are combined as described by Maximum Likelihood Estimation, Bayesian, or equivalent models, as appears to be the case, then Euclidean geometry cannot describe our perceptual experience. Rather, our perceptual spatial structure would be better described as belonging to an arbitrarily curved Riemannian space. PMID- 20161281 TI - How to Compare Apples and Oranges: Infants' Object Identification Tested With Equally Salient Shape, Luminance and Color Changes. AB - What kind of featural information do infants rely on when they are trying to recognize a previously seen object? The question of whether infants use certain features (e.g. shape or color) more than others (e. g. luminance), can only be studied legitimately if visual salience is controlled, since the magnitude of feature values - how noticeable and interesting they are - will affect results. We employed a novel methodology, 'Interdimensional Salience Mapping', that allowed us to quantify and calibrate salience changes along shape, luminance and color feature dimensions. We then compared 9-month-old infants' identification of objects, employing feature changes that were equally salient. These results show that infants more readily identify objects on the basis of color and shape than luminance. Additionally, we show that relative salience changes rapidly in infancy - in particular, we found significantly higher salience thresholds for color in younger (6.5-month-old) infants - but that individual differences within an age group are remarkably modest. PMID- 20161282 TI - Effects of ignoring baseline on modeling transitions from intact cognition to dementia. AB - This paper evaluates the effect of ignoring baseline when modeling transitions from intact cognition to dementia with mild cognitive impairment (MCI) and global impairment (GI) as intervening cognitive states. Transitions among states are modeled by a discrete-time Markov chain having three transient (intact cognition, MCI, and GI) and two competing absorbing states (death and dementia). Transition probabilities depend on two covariates, age and the presence/absence of an apolipoprotein E-epsilon4 allele, through a multinomial logistic model with shared random effects. Results are illustrated with an application to the Nun Study, a cohort of 678 participants 75+ years of age at baseline and followed longitudinally with up to ten cognitive assessments per nun. PMID- 20161283 TI - In vivo wireless ethanol vapor detection in the Wistar rat. AB - Traditional alcohol studies measure blood alcohol concentration to elucidate the biomedical factors that contribute to alcohol abuse and alcoholism. These measurements require large and expensive equipment, are labor intensive, and are disruptive to the subject. To alleviate these problems, we have developed an implantable, wireless biosensor that is capable of measuring alcohol levels for up to six weeks. Ethanol levels were measured in vivo in the interstitial fluid of a Wistar rat after administering 1 g/kg and 2 g/kg ethanol by intraperitoneal (IP) injection. The data were transmitted wirelessly using a biosensor selective for alcohol detection. A low-power piezoresistive microcantilever sensor array was used with a polymer coating suitable for measuring ethanol concentrations at 100% humidity over several hours. A hydrophobic, vapor permeable nanopore membrane was used to screen liquid and ions while allowing vapor to pass to the sensor from the subcutaneous interstitial fluid. PMID- 20161284 TI - Design, fabrication and test of a microfluidic nebulizer chip for desorption electrospray ionization mass spectrometry. AB - This paper presents design, microfabrication, and test of a microfluidic nebulizer chip for desorption electrospray ionization mass spectrometry (DESI-MS) in proteomic analysis. The microfluidic chip is fabricated using cyclic olefin copolymer (COC) substrates. The fluidic channels are thermally embossed onto a base substrate using a nickel master and then a top substrate is thermally bonded to seal the channels. Carbon ink embossed into the top COC substrate is used to established electrical connection between the external power supply and the liquid in the channel. The microfluidic chip to external capillary connection is fabricated using Nanoport() interconnection system. Preliminary leakage test was performed to demonstrate the interconnection system is leak-free and pressure test was performed to evaluate the burst pressure. Finally, the nebulizer chip was used to perform DESI-MS for analyzing peptides (BSA and bradykinin) and reserpine on the nanoporous alumina surface. DESI-MS performance of the microfluidic nebulizer chip is compared with that obtained using a conventional DESI nebulizer. PMID- 20161285 TI - Characteristics of a cobalt-based phosphate microelectrode for in situ monitoring of phosphate and its biological application. AB - The in situ monitoring of phosphate has been of great importance in many environmental applications, particularly those involving biological treatment processes and eutrophication monitoring. A microelectrode with small tip size (~10 mum) was fabricated with cobalt wire, characterized and evaluated for in situ and in vivo environmental analysis of phosphate in biological applications. The electrochemical performance of this cobalt-based microelectrode was fully examined for its characteristics, including detection limit, response time, selectivity, reproducibility, life time, interference with pH, ions and dissolved oxygen (DO), and the stirring effect. The microelectrode showed excellent selectivity for the orthophosphate ions (HPO(4) (2-), H(2)PO(4) (-)) in various environmental conditions. Alkalinity and DO were found to interfere with electrode response to phosphate. The phosphate microelectrode was also evaluated with Scanning Electron Microscopy (SEM) and Cyclic Voltammetry (CV). The developed microelectrode was used for in situ monitoring of phosphate in microbial flocs. Well-defined phosphate profiles across the flocs were observed under anaerobic (phosphorus release) conditions. This full characterization and successful application showed that the cobalt-based phosphate microelectrodes can be a very useful tool for in situ measurement of phosphate in various environmental conditions, including within microbial flocs. PMID- 20161286 TI - Deviance Information Criterion (DIC) in Bayesian Multiple QTL Mapping. AB - Mapping multiple quantitative trait loci (QTL) is commonly viewed as a problem of model selection. Various model selection criteria have been proposed, primarily in the non-Bayesian framework. The deviance information criterion (DIC) is the most popular criterion for Bayesian model selection and model comparison but has not been applied to Bayesian multiple QTL mapping. A derivation of the DIC is presented for multiple interacting QTL models and calculation of the DIC is demonstrated using posterior samples generated by Markov chain Monte Carlo (MCMC) algorithms. The DIC measures posterior predictive error by penalizing the fit of a model (deviance) by its complexity, determined by the effective number of parameters. The effective number of parameters simultaneously accounts for the sample size, the cross design, the number and lengths of chromosomes, covariates, the number of QTL, the type of QTL effects, and QTL effect sizes. The DIC provides a computationally efficient way to perform sensitivity analysis and can be used to quantitatively evaluate if including environmental effects, gene-gene interactions, and/or gene-environment interactions in the prior specification is worth the extra parameterization. The DIC has been implemented in the freely available package R/qtlbim, which greatly facilitates the general usage of Bayesian methodology for genome-wide interacting QTL analysis. PMID- 20161287 TI - Total Synthesis of Tovophyllin B. AB - The first total synthesis of tovophyllin B (2), an antimicrobial xanthone derived from mangosteen, has been accomplished through a convergent strategy from building blocks 6 and 7 involving lithium-mediated coupling, dehydrative cyclization, and 6pi electrocyclization as key steps. PMID- 20161288 TI - Electron Transfer Dissociation of Oligonucleotide Cations. AB - Electron transfer dissociation (ETD) of multi-protonated 6 - 20-mer oligonucleotides and 12- and 14-mer duplexes is compared to collision activated dissociation (CAD). ETD causes efficient charge reduction of the multi-protonated oligonucleotides in addition to limited backbone cleavages to yield sequence ions of low abundance. Subsequent CAD of the charge-reduced oligonucleotides formed upon electron transfer, in a net process termed electron transfer collision activated dissociation (ETcaD), results in rich fragmentation in terms of w, a, z, and d products, with a marked decrease in the abundance of base loss ions and internal fragments. Complete sequencing was possible for nearly all oligonucleotides studied. ETcaD of an oligonucleotide duplex resulted in specific backbone cleavages, with conservation of weaker non-covalent bonds. PMID- 20161289 TI - Central Limit Theorems and Uniform Laws of Large Numbers for Arrays of Random Fields. AB - Over the last decades, spatial-interaction models have been increasingly used in economics. However, the development of a sufficiently general asymptotic theory for nonlinear spatial models has been hampered by a lack of relevant central limit theorems (CLTs), uniform laws of large numbers (ULLNs) and pointwise laws of large numbers (LLNs). These limit theorems form the essential building blocks towards developing the asymptotic theory of M-estimators, including maximum likelihood and generalized method of moments estimators. The paper establishes a CLT, ULLN, and LLN for spatial processes or random fields that should be applicable to a broad range of data processes. PMID- 20161291 TI - Preparation and reactions of N-thioformyl peptides from amino thioacids and isonitriles. AB - The preparation of N-thioformyl peptides from amino thioacids and isonitriles at room temperature is described. PMID- 20161290 TI - Inhibition by methylated organo-arsenicals of the respiratory 2-oxo-acid dehydrogenases. AB - Inorganic arsenic that is ingested through drinking water or inhalation is metabolized by biological methylation pathways into organoarsenical metabolites. It is now becoming understood that this metabolism that was formerly considered to be detoxification may contribute as much or more to increasing the toxicity of arsenic. One proposed mode of the toxic action of arsenic and its organoarsenic metabolites is through its binding to proteins and inactivating their enzymatic activity. The classic case has been considered the affinity of the proximal 1,3 sulfhydryl groups of the lipoic acid cofactor of the pyruvate dehydrogenase complex for arsenic. A 2:1 stoichiometry of sulfhydryl to arsenic groups has been measured in proteins and arsenical complexes can be synthesized using free D,L lipoic acid. The relative importance of this site for arsenic binding has come in to question through the use of methylating bifunctional arsenic complexes that suggested the methylation of an active site histidine may also be important, and the suggestion that arsenic inhibits the pyruvate dehydrogenase complex indirectly by elevating mitochondrial hydrogen peroxide generation. In order to separate the effects of direct trivalent arsenite toxicity from that of hydrogen peroxide and activated oxygen, we studied the inhibition of the PDH complex under conditions that did not generate hydrogen peroxide but did expose the lipoic acid group in its reduced state to arsenicals. We also studied the effects of arsenicals in the inhibition of the alpha-ketoglutarate dehydrogenase complex. We found that only trivalent arsenical compounds inhibited the activity of both dehydrogenase complexes and only when the lipoic acid was in its reduced form. Arsenite inhibited both enzyme complexes approximately equivalently while monomethylarsenite inhibited the PDH complex to a greater extent than the KGDH complex - although both complexes were very sensitive to inhibition by this complex. Dimethylarsenite inhibition of both complexes was only observed with longer pre-incubation periods. Cumulative inhibition by the reduced arsenical was observed for all complexes indicating a binding mode of inhibition that is dependent upon lipoic acid being in its reduced state. PMID- 20161292 TI - Synthesis and redox-enzyme modulation by amino-1,4-dihydro-benzo[d][1,2]dithiine derivatives. AB - A convenient method to prepare a series of benzodithiine derivatives was developed, via the synthesis of cyclic disulfide building blocks containing an amino-group linker. Some of the novel cyclic disulfide compounds are shown to modulate the activity of the redox-enzyme glutathione reductase. PMID- 20161293 TI - Evaluation of Chlorofusin, its Seven Chromophore Diastereomers, and Key Analogues. AB - Chlorofusin, its seven chromophore diastereomers, and key analogues were comparatively examined for inhibition of MDM2-p53 binding revealing that the chromophore, but not simple replacements, contributes significantly to the natural products properties, and that this contribution is independent of its relative and absolute stereochemistry. PMID- 20161294 TI - A Review of Services and Interventions for Runaway and Homeless Youth: Moving Forward. AB - Research focused on the impact of community-based services and treatment interventions designed to intervene in the lives of runaway and homeless youth has increased in the last two decades in the U.S. and internationally. In light of the tremendous need for identifying effective strategies to end homelessness and its associated problems among youth, this paper summarizes and critiques the findings of the extant literature including U.S., international, and qualitative studies. Thirty-two papers met criteria for inclusion in the review. Among the conclusions are that comprehensive interventions which target the varied and interconnected needs of these youth and families may be worthy of more study than studies that isolate the intervention focus on one problem. Also, more research incorporating design strategies that increase the reliability and validity of study findings is needed. Other preliminary conclusions and future directions are offered. PMID- 20161295 TI - OBSERVATION OF THE NATURAL EVOLUTION OF INSOMNIA IN THE AMERICAN GENERAL POPULATION COHORT. PMID- 20161296 TI - Experience affects the outcome of agonistic contests without affecting the selective advantage of size. AB - In the field, phenotypic determinants of competitive success are not always absolute. For example, contest experience may alter future competitive performance. As future contests are not determined solely on phenotypic attributes, prior experience could also potentially alter phenotype-fitness associations. In this study, we examined the influence of single and multiple experiences on contest outcomes in the jumping spider Phidippus clarus. We also examined whether phenotype-fitness associations altered as individuals gained more experience. Using both size-matched contests and a tournament design, we found that both winning and losing experience affected future contest success; males with prior winning experience were more likely to win subsequent contests. Although experience was a significant determinant of success in future contests, male weight was approximately 1.3 times more important than experience in predicting contest outcomes. Despite the importance of experience in determining contest outcomes, patterns of selection did not change between rounds. Overall, our results show that experience can be an important determinant in contest outcomes, even in short-lived invertebrates, and that experience alone is unlikely to alter phenotype-fitness associations. PMID- 20161297 TI - De Novo Asymmetric Syntheses of (+)-Goniothalamin, (+)-Goniothalamin oxide and 7,8-Bis-epi-Goniothalamin using Asymmetric Allylations. AB - A highly enantio- and diastereoselective approach to either enantiomer of (+) goniothalamin, (+)-goniothalamin oxide and 7,8-bis-epi-goniothalamin oxide has been developed from achiral cinnamyl alcohol or cinnamaldehyde. The asymmetry of the synthesis was installed by means of a Krische or Leighton allylation. The remaining stereochemistry was installed by a diastereoselective epoxidation. PMID- 20161298 TI - Studies on Paraherquamide Biosynthesis: Synthesis of Deuterium-Labeled 7-Hydroxy Pre-Paraherquamide, a Putative Precursor of Paraherquamides A, E & F. AB - The stereocontrolled, asymmetric synthesis of triply deuterium-labeled 7-hydroxy pre-paraherquamide (27) was accomplished, employing a diastereoselective intramolecular S(N)2' cyclization strategy. The deuterium-labeled substrate was interrogated in a precursor incorporation experiment in the paraherquamide producing organism Penicillium fellutanum. The isolated sample of paraherquamide A revealed incorporation of one of the two geminal deuterons of the CD(2)-group at C-12 exclusively. The lack of signals for the second deuteron of the CD(2) group at C-12 and for the CH(2)D-group (C-22/C-23) suggests that this substrate suffered an unexpectedly selective catabolic degradation and metabolic re incorporation of deuterium thus casting doubt on the proposed biosynthetic intermediacy of 27. Consideration of alternative biosynthetic pathways, including oxidation of the indole C-6 position prior to hydroxylation at C-7 or oxidative spiro-contraction of pre-paraherquamide prior to construction of the dioxepin is discussed. The synthesis of 27 also provides for a concise, asymmetric stereocontrolled synthesis of an advanced intermediate that will be potentially useful in the synthesis of paraherquamide E & F. PMID- 20161299 TI - Explicit disassociation of a conditioned stimulus and unconditioned stimulus during extinction training reduces both time to asymptotic extinction and spontaneous recovery of a conditioned taste aversion. AB - Conditioned taste aversions (CTAs) may be acquired when an animal consumes a novel taste (CS) and then experiences the symptoms of poisoning (US). This aversion may be extinguished by repeated exposure to the CS alone. However, following a latency period in which the CS is not presented, the CTA will spontaneously recover (SR). In the current study we employed an explicitly unpaired extinction procedure (EU-EXT) to determine if it could thwart SR of a CTA. Sprague-Dawley rats acquired a strong CTA after 3 pairings of saccharin (SAC the CS) and Lithium Chloride (LiCl the US). CTA acquisition was followed by extinction (EXT) training consisting of either (a) CS-only exposure (CSO) or, (b) exposure to saccharin and Lithium Chloride on alternate days (i.e., explicitly unpaired: EU). Both extinction procedures resulted in >/= 90% reacceptance of SAC, although the EU extinction procedure (EU-EXT) significantly decreased the time necessary for rats to reach this criterion (compared to CSO controls). Rats were subsequently tested for SR of the CTA upon re-exposure to SAC following a 30 day latency period of water drinking. Rats that acquired a CTA and then underwent the CSO extinction procedure exhibited a significant suppression of SAC drinking during the SR test (as compared to their SAC drinking at the end of extinction). However, animals in the EU-EXT group did not show such suppression in drinking compared to CSO controls. These data suggest that the EU-EXT procedure may be useful in reducing both time to extinction and the spontaneous recovery of fears. PMID- 20161300 TI - Rationale, design and findings from the Wisconsin Sleep Cohort Study: Toward understanding the total societal burden of sleep disordered breathing. PMID- 20161302 TI - Using Multilevel Systems Theory to Integrate Dynamic Person-in-Context Systems. PMID- 20161301 TI - CFD Simulation and Experimental Validation of Fluid Flow and Particle Transport in a Model of Alveolated Airways. AB - Accurate modeling of air flow and aerosol transport in the alveolated airways is essential for quantitative predictions of pulmonary aerosol deposition. However, experimental validation of such modeling studies has been scarce. The objective of this study is to validate CFD predictions of flow field and particle trajectory with experiments within a scaled-up model of alveolated airways. Steady flow (Re = 0.13) of silicone oil was captured by particle image velocimetry (PIV), and the trajectories of 0.5 mm and 1.2 mm spherical iron beads (representing 0.7 to 14.6 mum aerosol in vivo) were obtained by particle tracking velocimetry (PTV). At twelve selected cross sections, the velocity profiles obtained by CFD matched well with those by PIV (within 1.7% on average). The CFD predicted trajectories also matched well with PTV experiments. These results showed that air flow and aerosol transport in models of human alveolated airways can be simulated by CFD techniques with reasonable accuracy. PMID- 20161303 TI - Balancing Type One and Two Errors in Multiple Testing for Differential Expression of Genes. AB - A new procedure is proposed to balance type I and II errors in significance testing for differential expression of individual genes. Suppose that a collection, F(k), of k lists of selected genes is available, each of them approximating by their content the true set of differentially expressed genes. For example, such sets can be generated by a subsampling counterpart of the delete-d-jackknife method controlling the per-comparison error rate for each subsample. A final list of candidate genes, denoted by S(*), is composed in such a way that its contents be closest in some sense to all the sets thus generated. To measure "closeness" of gene lists, we introduce an asymmetric distance between sets with its asymmetry arising from a generally unequal assignment of the relative costs of type I and type II errors committed in the course of gene selection. The optimal set S(*) is defined as a minimizer of the average asymmetric distance from an arbitrary set S to all sets in the collection F(k). The minimization problem can be solved explicitly, leading to a frequency criterion for the inclusion of each gene in the final set. The proposed method is tested by resampling from real microarray gene expression data with artificially introduced shifts in expression levels of pre-defined genes, thereby mimicking their differential expression. PMID- 20161304 TI - Lipid Compositions in Escherichia coli and Bacillus subtilis During Growth as Determined by MALDI-TOF and TOF/TOF Mass Spectrometry. AB - Lipids in Escherichia coli and Bacillus subtilis were analyzed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry and TOF/TOF tandem mass spectrometry. Lipids were extracted from bacterial cells using an equal volume mixture of dichloromethane, ethanol, and water, which formed a biphasic system with the lipids in the organic layer. The resulting mass spectra of the extracts from both bacteria showed a series of peaks corresponding to sodiated phospholipids - primarily phosphatidylethanolamines (PE) and phosphatidylglycerols (PG). The relative amounts of the phospholipids and the fatty acid compositions inferred from the spectra were in good agreement with previously reported values from GC/MS and thin-layer chromatography studies. E. coli and B. subtilis were easily differentiated by dissimilarities in the composition and relative amounts of the phospholipids present as well as by the presence of lysyl-phosphatidylglycerol and diglucosyl diglycerides solely in the B. subtilis mass spectra. Changes in lipid content in the bacteria during their growth phases were also monitored. In E. coli, the spectra indicated an increase in the amount of the unique C(cy-17) fatty acid (in which the fatty acid chain contains a cyclopropane ring) formed during exponential growth. During stationary growth, the spectra indicated an increase in the amount of saturated fatty acids. In B. subtilis, the phospholipid composition remained relatively unchanged during exponential growth, but the amount of PG slightly decreased while the amount of PE slightly increased during stationary growth. No significant changes were observed for the lysyl-phosphatidylglycerols or glycolipids during the exponential or stationary growth phases. PMID- 20161305 TI - Decarboxylative Cyclizations and Cycloadditions of Palladium-polarized Aza-ortho Xylylenes. PMID- 20161306 TI - A new approach to carbon-carbon bond formation: Development of aerobic Pd catalyzed reductive coupling reactions of organometallic reagents and styrenes. AB - Alkenes are attractive starting materials for organic synthesis and the development of new selective functionalization reactions are desired. Previously, our laboratory discovered a unique Pd-catalyzed hydroalkoxylation reaction of styrenes containing a phenol. Based upon deuterium labeling experiments, a mechanism involving an aerobic alcohol oxidation coupled to alkene functionalization was proposed. These results inspired the development of a new Pd-catalyzed reductive coupling reaction of alkenes and organometallic reagents that generates a new carbon-carbon bond. Optimization of the conditions for the coupling of both organostannanes and organoboronic esters is described and the initial scope of the transformation is presented. Additionally, several mechanistic experiments are outlined and support the rationale for the development of the reaction based upon coupling alcohol oxidation to alkene functionalization. PMID- 20161307 TI - A Model for HCMV Infection in Immunosuppressed Patients. AB - We propose a model for HCMV infection in healthy and immunosuppressed patients. First, we present the biological model and formulate a system of ordinary differential equations to describe the pathogenesis of primary HCMV infection in immunocompetent and immunosuppressed individuals. We then investigate how clinical data can be applied to this model. Approximate parameter values for the model are derived from data available in the literature and from mathematical and physiological considerations. Simulations with the approximated parameter values demonstrates that the model is capable of describing primary, latent, and secondary (reactivated) HCMV infection. Reactivation simulations with this model provide a window into the dynamics of HCMV infection in (D-R+) transplant situations, where latently-infected recipients (R+) receive transplant tissue from HCMV-naive donors (D-). PMID- 20161308 TI - Hydrophobic Effects in the Critical Destabilization and Release Dynamics of Degradable Multilayer Films. AB - Recent research has highlighted the ability of hydrolytically degradable electrostatic layer-by-layer films to act as versatile drug delivery systems capable of multi-agent release. A key element of these films is the potential to gain precise control of release by evoking a surface-erosion mechanism. Here we sought to determine the extent to which manipulation of chemical structure could be used to control release from hydrolytically degradable layer-by-layer films through modification of the degradable polycation. Toward this goal, films composed of poly(beta-amino ester)s, varying only in the choice of diacrylate monomer, and the model biological drug, dextran sulfate, were used to ascertain the role of alkyl chain length, steric hindrance, and hydrophobicity on release dynamics. Above a critical polycation hydrophobicity, as determined using octanol:water coefficients, the film becomes rapidly destabilized and quickly released its contents. These findings indicate that in these unique electrostatic assemblies, hydrolytic susceptibility is dependent not only on hydrophobicity, but a complex balance between hydrophobic composition, charge density, and stability of electrostatic ion pairs. Computational determination of octanol:water coefficients allowed for the reliable prediction of release dynamics. The determination of a correlation between octanol:water coefficient and release duration will enables advanced engineering to produce custom drug delivery systems. PMID- 20161309 TI - Synthesis of beta-Heteroaryl Propionates via Trapping of Carbocations with pi Nucleophiles. AB - A variety of heterocyclic alcohols and acetates were coupled with silyl ketene acetals and other pi-nucleophiles in the presence of trimethylsilyl trifluoromethanesulfonate to provide an array of substituted beta-heteroaryl propionates, including those with contiguous quaternary centers, as well as vinylogs thereof. This reaction also proceeds with high diastereoselectivity when the pi-nucleophile bears a chiral auxiliary. PMID- 20161311 TI - Efficient Organocatalytic alpha-Sulfenylation of Substituted Piperazine-2,5 diones. AB - Organocatalytic alpha-sulfenylation of substituted piperazine-2,5-diones is reported through the use of cinchona alkaloids as Lewis bases and electrophilic sulfur transfer reagents. 1-Phenylsulfanyl[1,2,4]triazole, a novel sulfur transfer reagent, gave excellent product yields with a number of substituted piperazine-2,5-diones under mild conditions. Catalyst loading, stoichiometry of sulfur electrophile, temperature and solvent were optimized to achieve high product yields. PMID- 20161310 TI - Decreasing procedural pain over time of left prefrontal rTMS for depression: initial results from the open-label phase of a multi-site trial (OPT-TMS). AB - BACKGROUND: There is much interest in whether daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) over several weeks may become a clinically useful antidepressant treatment. Although rTMS appears largely safe, many patients report that this procedure is somewhat painful, which may restrict its ultimate appeal and utility. We analyzed interim results from the open-label phase of a multi-site randomized trial of rTMS as a treatment for depression to investigate whether the procedural pain of left prefrontal rTMS changes over time. METHODS: Patients with unipolar depression who had failed to respond during at least three weeks of the sham-controlled double-masked rTMS were then offered three more weeks (15 sessions) of open-label rTMS. Retrospective pain ratings and state emotional factors from 20 subjects were assessed using visual analog scales (VAS) recorded on computers before and after each treatment (289 sessions). RESULTS: Over the 15 treatment sessions, subjective reports of the painfulness of rTMS decreased 48% from baseline. This reduction, although greatest in the first few days, continued steadily (average 2.11 points per session) over the 3 weeks of treatment. The analysis found a significant effect for rTMS-session (p<0.0001) on rTMS-procedural pain over and above changes in subjective emotional states. CONCLUSION: The procedural pain of left, prefrontal rTMS decreases over time, apparently independently of other emotional changes. Since rTMS scalp pain may decline over time, physicians and patients may decide to continue treatment despite initial discomfort. These observational data can be better tested once the data from the blinded phase of the trial becomes available. PMID- 20161312 TI - Synthesis of an enantiopure isoxazolidine monomer for beta-aspartic acid in chemoselective beta-oligopeptide synthesis. AB - The synthesis of an enantiopure isoxazolidine monomer for the incorporation of beta(3)-apartic acid residues into beta(3)-oligopeptides via chemoselective alpha ketoacid-hydroxylamine amide formation. This route involves nitrone cycloaddition of 3-thiophenylpropanal and circumvents limitations of other potential starting materials. PMID- 20161313 TI - Estimation of graphical models whose conditional independence graphs are interval graphs and its application to modeling linkage disequilibrium. AB - Estimation of graphical models whose conditional independence graph comes from the general class of decomposable graphs is compared with estimation under the more restrictive assumption that the graphs are interval graphs. This restriction is shown to improve the mixing of the Markov chain Monte Carlo search to find an optimal model with little effect on the haplotype frequencies implied by the estimates. A further restriction requiring intervals to cover specified points is also considered and shown to be appropriate for modeling associations between alleles at genetic loci. As well as usefully describing the patterns of associations, these estimates can also be used to model population haplotype frequencies in statistical gene mapping methods such as linkage analysis and association studies. PMID- 20161314 TI - On Being Liked on the Web and in the "Real World": Consistency in First Impressions across Personal Webpages and Spontaneous Behavior. AB - With recent growth in the use of personal webpages and online social networking, people are changing the way that they meet and form impressions of each other. The current research examines the correspondence in impressions formed from face to-face interaction and personal webpages. As expected, people liked by interaction partners were also liked on the basis of their Facebook((R)) pages. Across the two social mediums, social perceivers utilized analogous criteria in forming impressions: interaction partners and webpage viewers liked people who were socially expressive in face-to-face interaction and personal webpages, respectively. Finally, webpage expressivity and webpage self-disclosure were independent constructs, predictive of face-to-face counterparts: nonverbal expressivity and verbal self-disclosure. Implications for the changing landscape of social perception are discussed. PMID- 20161315 TI - CHILDREN'S MENTAL HEALTH SERVICE USE AND MATERNAL MENTAL HEALTH: A PATH ANALYTIC MODEL. AB - OBJECTIVE: This observational study explores pathways towards any past year use of child mental health services. METHODS: Data from the 2002 National Survey of American Families were used to explore the relationship between past month maternal mental health and past year child mental health services use. Observations were limited to the 8072 most knowledgeable adults who were the mothers of target children aged 6-11. Logistic regressions were performed to determine the odds of any child mental health service use followed by path analyses using Maximum Likelihood estimation with robust standard errors. RESULTS: Multiple factors were associated with odds of any child mental health service use. In the path analytic model poor past month maternal mental health was associated with increased aggravation which in turn was associated with increased use of mental health visits. Negative child behaviors as reported by the mother were also associated with increased maternal aggravation and increased service use. CONCLUSIONS: Parental perception of child behaviors influences treatment seeking, both directly and indirectly through parental aggravation. Parental mental health influences tolerance for child behaviors. Findings are consistent with other studies. Interventions should address the entire family and their psychosocial circumstances through collaboration between multiple service sectors. PMID- 20161316 TI - Analysis of single molecule folding studies with replica correlation functions. AB - Single molecule experiments that can track individual trajectories of biomolecular processes provide a challenge for understanding how these stochastic trajectories relate to the global energy landscape. Using trajectories from a native structure based simulation, we use order parameters that accurately distinguish between protein folding mechanisms that involve a simple, single set of pathways versus a complex one with multiple sets of competing pathways. We show how the folding dynamics can be analyzed with replica correlation functions in a way compatible with single molecule experiments. PMID- 20161317 TI - Making sense of the labor market height premium: Evidence from the British Household Panel Survey. AB - We use data from the British Household Panel Survey to examine the labor market premium in height. Most of the premium is explained by higher average educational attainment and sorting into higher-status occupations and industries by those who are taller. PMID- 20161318 TI - PM(2.5) Characterization for Time Series Studies: Organic Molecular Marker Speciation Methods and Observations from Daily Measurements in Denver. AB - Particulate matter less than 2.5 microns in diameter (PM(2.5)) has been shown to have a wide range of adverse health effects and consequently is regulated in accordance with the US-EPA's National Ambient Air Quality Standards. PM(2.5) originates from multiple primary sources and is also formed through secondary processes in the atmosphere. It is plausible that some sources form PM(2.5) that is more toxic than PM(2.5) from other sources. Identifying the responsible sources could provide insight into the biological mechanisms causing the observed health effects and provide a more efficient approach to regulation. This is the goal of the Denver Aerosol Sources and Health (DASH) study, a multi-year PM(2.5) source apportionment and health study.The first step in apportioning the PM(2.5) to different sources is to determine the chemical make-up of the PM(2.5). This paper presents the methodology used during the DASH study for organic speciation of PM(2.5). Specifically, methods are covered for solvent extraction of non-polar and semi-polar organic molecular markers using gas chromatography-mass spectrometry (GC-MS). Vast reductions in detection limits were obtained through the use of a programmable temperature vaporization (PTV) inlet along with other method improvements. Results are presented for the first 1.5 years of the DASH study revealing seasonal and source-related patterns in the molecular markers and their long-term correlation structure. Preliminary analysis suggests that point sources are not a significant contributor to the organic molecular markers measured at our receptor site. Several motor vehicle emission markers help identify a gasoline/diesel split in the ambient data. Findings show both similarities and differences when compared with other cities where similar measurements and assessments have been made. PMID- 20161319 TI - Mixture modeling with applications in schizophrenia research. AB - Finite mixture modeling, together with the EM algorithm, have been widely used in clustering analysis. Under such methods, the unknown group membership is usually treated as missing data. When the "complete data" (log-)likelihood function does not have an explicit solution, the simplicity of the EM algorithm breaks down. Authors, including Rai and Matthews (1993), Lange (1995a) and Titterington (1984), developed modified algorithms therefore. As motivated by research in a large neurobiological project, we propose in this paper a new variant of such modifications and show that it is self-consistent. Moreover, simulations are conducted to demonstrate that the new variant converges faster than its predecessors. PMID- 20161320 TI - ERP Effects of Short Interval Masked Associative and Repetition Priming. AB - In a previous study we used event-related potentials to dissociate semantic (associative) and repetition priming when prime words were masked below (40 ms primes) and above (80 and 120 ms primes) levels of awareness (Holcomb et al., 2005). While robust priming effects were present on the N400 component regardless of the prime duration in the repetition priming experiment, in the semantic priming experiment significant priming effects were only obtained when primes were consciously detected. In the current study we again compared associative and repetition priming, but this time within a single experiment and using a short interval priming paradigm. As in several recent studies we again found robust repetition priming effects on both the N400 and an earlier index of priming, the N250. However, there was no evidence of any priming effect in the semantic/associative condition. The findings are discussed in the context of the functional significance of masked priming effects. PMID- 20161321 TI - The use of plasmodes as a supplement to simulations: A simple example evaluating individual admixture estimation methodologies. AB - With the advent of powerful computers, simulation studies are becoming an important tool in statistical methodology research. However, computer simulations of a specific process are only as good as our understanding of the underlying mechanisms. An attractive supplement to simulations is the use of plasmode datasets. Plasmodes are data sets that are generated by natural biologic processes, under experimental conditions that allow some aspect of the truth to be known. The benefit of the plasmode approach is that the data are generated through completely natural processes, thus circumventing the common concern of the realism and accuracy of computer simulated data. The estimation of admixture, or the proportion of an individual's genome that originates from different founding populations, is a particularly difficult research endeavor that is well suited to the use of plasmodes. Current methods have been tested with simulations of complex populations where the underlying mechanisms such as the rate and distribution of recombination are not well understood. To demonstrate the utility of this method data derived from mouse crosses is used to evaluate the effectiveness of several admixture estimation methodologies. Each cross shares a common founding population so that the ancestry proportion for each individual is known, allowing for the comparison of true and estimated individual admixture values. Analysis shows that the different estimation methodologies (Structure, AdmixMap and FRAPPE) examined all perform well with simple datasets. However, the performance of the estimation methodologies varied greatly when applied to a plasmode consisting of three founding populations. The results of these examples illustrate the utility of plasmodes in the evaluation of statistical genetics methodologies. PMID- 20161322 TI - An approach to the synthesis of dimeric resveratrol natural products via a palladium-catalyzed domino reaction. AB - A route for the rapid assembly of the carbon framework of several resveratrol natural products is presented. A palladium-catalyzed domino reaction of bromostilbene derivative 6 and tolane 7, involving two sequential Heck coupling reactions, provides access to the benzofulvene-based core of various resveratrol derived natural products. The carbon skeleton of pallidol and its congeners is achieved by a Lewis acid-induced Nazarov-type oxidative cyclization of 9. PMID- 20161323 TI - Depressed Mood and Maternal Report of Child Behavior Problems: Another Look at the Depression-Distortion Hypothesis. AB - Caregiver depression has been described as leading to overreport of child behavior problems. This study examines this "depression-distortion" hypothesis in terms of high-risk families of young adolescents. Questionnaire and diagnostic interview data were collected from mothers, teachers, and fathers, and self report information was obtained from youth between ages 10 and 14 years. First, convergent and discriminant validity were demonstrated for internalizing and externalizing multiagent constructs. Second, the depression-distortion hypothesis was examined, revealing a modest effect of maternal depression, leading to the inflation of reported son externalizing and daughter internalizing problems. The data suggest the need to consider multiple influences on parental perceptions of child behavior and psychopathology in research and clinical settings. PMID- 20161324 TI - Computer-aided Prognosis of Neuroblastoma on Whole-slide Images: Classification of Stromal Development. AB - We are developing a computer-aided prognosis system for neuroblastoma (NB), a cancer of the nervous system and one of the most malignant tumors affecting children. Histopathological examination is an important stage for further treatment planning in routine clinical diagnosis of NB. According to the International Neuroblastoma Pathology Classification (the Shimada system), NB patients are classified into favorable and unfavorable histology based on the tissue morphology. In this study, we propose an image analysis system that operates on digitized H&E stained whole-slide NB tissue samples and classifies each slide as either stroma-rich or stroma-poor based on the degree of Schwannian stromal development. Our statistical framework performs the classification based on texture features extracted using co-occurrence statistics and local binary patterns. Due to the high resolution of digitized whole-slide images, we propose a multi-resolution approach that mimics the evaluation of a pathologist such that the image analysis starts from the lowest resolution and switches to higher resolutions when necessary. We employ an offine feature selection step, which determines the most discriminative features at each resolution level during the training step. A modified k-nearest neighbor classifier is used to determine the confidence level of the classification to make the decision at a particular resolution level. The proposed approach was independently tested on 43 whole slide samples and provided an overall classification accuracy of 88.4%. PMID- 20161325 TI - Positive association between cognitive ability and cortical thickness in a representative US sample of healthy 6 to 18 year-olds. AB - Neuroimaging studies, using various modalities, have evidenced a link between the general intelligence factor (g) and regional brain function and structure in several multimodal association areas. While in the last few years, developments in computational neuroanatomy have made possible the in vivo quantification of cortical thickness, the relationship between cortical thickness and psychometric intelligence has been little studied. Recently, cortical thickness estimations have been improved by the use of an iterative hemisphere-specific template registration algorithm which provides a better between-subject alignment of brain surfaces. Using this improvement, we aimed to further characterize brain regions where cortical thickness was associated with cognitive ability differences and to test the hypothesis that these regions are mostly located in multimodal association areas. We report associations between a general cognitive ability factor (as an estimate of g) derived from the four subtests of the Wechsler Abbreviated Scale of Intelligence and cortical thickness adjusted for age, gender, and scanner in a large sample of healthy children and adolescents (ages 6 18, N=216) representative of the US population. Significant positive associations were evidenced between the cognitive ability factor and cortical thickness in most multimodal association areas. Results are consistent with a distributed model of intelligence. PMID- 20161326 TI - Microcalcification classification assisted by content-based image retrieval for breast cancer diagnosis. AB - In this paper we propose a microcalcification classification scheme, assisted by content-based mammogram retrieval, for breast cancer diagnosis. We recently developed a machine learning approach for mammogram retrieval where the similarity measure between two lesion mammograms was modeled after expert observers. In this work we investigate how to use retrieved similar cases as references to improve the performance of a numerical classifier. Our rationale is that by adaptively incorporating local proximity information into a classifier, it can help to improve its classification accuracy, thereby leading to an improved "second opinion" to radiologists. Our experimental results on a mammogram database demonstrate that the proposed retrieval-driven approach with an adaptive support vector machine (SVM) could improve the classification performance from 0.78 to 0.82 in terms of the area under the ROC curve. PMID- 20161327 TI - Assumption Adequacy Averaging as a Concept to Develop More Robust Methods for Differential Gene Expression Analysis. AB - The concept of assumption adequacy averaging is introduced as a technique to develop more robust methods that incorporate assessments of assumption adequacy into the analysis. The concept is illustrated by using it to develop a method that averages results from the t-test and nonparametric rank-sum test with weights obtained from using the Shapiro-Wilk test to test the assumption of normality. Through this averaging process, the proposed method is able to rely more heavily on the statistical test that the data suggests is superior for each individual gene. Subsequently, this method developed by assumption adequacy averaging outperforms its two component methods (the t-test and rank-sum test) in a series of traditional and bootstrap-based simulation studies. The proposed method showed greater concordance in gene selection across two studies of gene expression in acute myeloid leukemia than did the t-test or rank-sum test. An R routine to implement the method is available upon request. PMID- 20161328 TI - Learning in Noise: Dynamic Decision-Making in a Variable Environment. AB - In engineering systems, noise is a curse, obscuring important signals and increasing the uncertainty associated with measurement. However, the negative effects of noise and uncertainty are not universal. In this paper, we examine how people learn sequential control strategies given different sources and amounts of feedback variability. In particular, we consider people's behavior in a task where short- and long-term rewards are placed in conflict (i.e., the best option in the short-term is worst in the long-term). Consistent with a model based on reinforcement learning principles (Gureckis & Love, in press), we find that learners differentially weight information predictive of the current task state. In particular, when cues that signal state are noisy and uncertain, we find that participants' ability to identify an optimal strategy is strongly impaired relative to equivalent amounts of uncertainty that obscure the rewards/valuations of those states. In other situations, we find that noise and uncertainty in reward signals may paradoxically improve performance by encouraging exploration. Our results demonstrate how experimentally-manipulated task variability can be used to test predictions about the mechanisms that learners engage in dynamic decision making tasks. PMID- 20161329 TI - Thio-mediated two-component coupling reaction of carboxylic acids and isonitriles under mild conditions. AB - The coupling reaction between carboxylic acids and isonitriles in the presence of thio phenol as activator under mild conditions is described. PMID- 20161330 TI - Extraction methods determine the antioxidant capacity and induction of quinone reductase by soy products in vitro. AB - Gastrointestinal (GI) mimic and organic solvent extracts of whole soybean powder (WSP), soy protein concentrate (SPC), and soy protein isolate (SPI) as well as soy isoflavone concentrate (SIC) were analyzed for total phenols; quinone reductase (QR) induction in hepa1c1c7 cells; antioxidant scavenging of DPPH, HOCl, ONOO(-), and O(2) (-.); and total antioxidant capacity via FRAP and ORAC assays. GI extracts of all the soy products had higher concentrations of total phenols than from acidified methanol (MeOH) but lower antioxidant potency. The MeOH extract of SPC was most potent in quenching HOCl and ONOO(-) and increasing FRAP and ORAC, but did not induce QR. Despite weak antioxidant activity, hexane (HX) extracts induced QR more than GI and MeOH extracts with WSP > SPC > SPI > IC. Soy extracts were ineffective scavengers of DPPH and O(2) (-.). Thus, extraction methods markedly affect the antioxidant profile and QR induction capacity of soy products. PMID- 20161331 TI - Alcohol Outlet Density, Parental Monitoring, and Adolescent Deviance: A Multilevel Analysis. AB - Lower levels of parental monitoring are associated with youth problem behaviors, including substance use and delinquency. Recent studies employing routine activities theory have hypothesized that greater densities of alcohol outlets, particularly bars, may provide parents more opportunities to socialize outside the home. This, in turn, may decrease a parent's ability to effectively monitor the activities of his or her child, resulting in more deviant behaviors by the adolescent. Using hierarchical linear modeling (HLM), the current study assesses whether or not greater densities of alcohol outlets in zip code areas (n = 50) interact with levels of parental monitoring to affect levels of deviance among adolescents aged 14 to 16 (n = 1,541). The study finds that adolescents who have higher grade point averages and have not used alcohol report the lowest levels of deviant behaviors. Furthermore, the density of bars interacts with reports of parental monitoring such that adolescents in areas with more bars per roadway mile report lower levels of parental monitoring behaviors, which is associated with higher levels of deviance. These findings suggest that in those areas with greater densities of bars parents may be spending more time away from home, making monitoring of their adolescents more difficult, or parents may be drinking more frequently, thus impairing their ability to adequately monitor their children. Policies and practices that limit the number of bars in neighborhood areas with large populations of adolescents may reduce deviant behaviors. PMID- 20161333 TI - Synthesis and Characterization of a Tetramethyl Furanone Functionalized Diiminedioxime, A Potential Ligand for Cu Radiopharmaceuticals, and its Copper(II) and Nickel(II) Complexes. AB - As part of our on-going effort to develop (64)Cu-based radiopharmaceuticals for PET (positron emission tomography) imaging of multidrug resistance in cancer, we prepared a tetramethylfuranone-functionalized diiminedioxime ligand, TMFPreH (TMFPreH = 4-[3-(4-Hydroxyimino-2,2,5,5-dimethyl-dihydro-furan-3-ylideneamino) propylimino]-2,2,5,5-tetramethyl-dihydro-furan-3-one oxime) and its Cu(II) and Ni(II) complexes. When the copper(II) complex was prepared from Cu(ClO(4))(2) in ethanol, it was isolated as a Cu(II)-bridged dimer, but when it was prepared from Cu(OAc)(2) and heated in acetone, an unusual example of an acetone adduct of the ligand is formed by reduction of one of the imine double bonds by the solvent. The Ni(II) complex is square pyramidal with the perchlorate counterion at the apex. PMID- 20161332 TI - Structural model and excitonic properties of the dimeric RC-LH1-PufX complex from Rhodobacter sphaeroides. AB - The light-harvesting apparatus of the purple bacterial photosynthetic unit consists of a pool of peripheral light-harvesting complexes that transfer excitation energy to a reaction center (RC) via the surrounding pigment-protein complex LH1. Recent electron microscopy and atomic force microscopy studies have revealed that RC-LH1 units of Rhodobacter sphaeroides form membrane-bending dimeric complexes together with the polypeptide PufX. We present a structural model for these RC-LH1-PufX dimeric complexes constructed using the molecular dynamics flexible fitting method based on an EM density map. The arrangement of the LH1 BChls displays a distortion near the proposed location of the PufX polypeptide. The resulting atomic model for BChl arrays is used to compute the excitonic properties of the dimeric RC-LH1 complex. A comparison is presented between the structural and excitonic features of the S-shaped dimeric BChl array of Rhodobacter sphaeroides and the circular BChl arrangement found in other purple bacteria. PMID- 20161334 TI - The application of vinylogous iminium salt derivatives to efficient formal syntheses of the marine akaloids lamellarin G trimethyl ether and ningalin B. AB - Studies directed at the synthesis of lamellarin G trimethyl ether and ningalin B via vinylogous iminium salt derivatives are described. The successful strategy relies on the formation of a 2,4-disubstituted pyrrole or a 1,2,3,4 tetrasubstituted pyrrole from a vinylogous iminium salt or vinylogous iminium salt derivative. Subsequent transformations of these highly substituted pyrroles lead to efficient and regiocontrolled formal syntheses of the respective pyrrole containing natural products. PMID- 20161335 TI - AUTO-IK: a 2D indicator kriging program for the automated non-parametric modeling of local uncertainty in earth sciences. AB - Indicator kriging provides a flexible interpolation approach that is well suited for datasets where: 1) many observations are below the detection limit, 2) the histogram is strongly skewed, or 3) specific classes of attribute values are better connected in space than others (e.g. low pollutant concentrations). To apply indicator kriging at its full potential requires, however, the tedious inference and modeling of multiple indicator semivariograms, as well as the post processing of the results to retrieve attribute estimates and associated measures of uncertainty. This paper presents a computer code that performs automatically the following tasks: selection of thresholds for binary coding of continuous data, computation and modeling of indicator semivariograms, modeling of probability distributions at unmonitored locations (regular or irregular grids), and estimation of the mean and variance of these distributions. The program also offers tools for quantifying the goodness of the model of uncertainty within a cross-validation and jack-knife frameworks. The different functionalities are illustrated using heavy metal concentrations from the well-known soil Jura dataset. A sensitivity analysis demonstrates the benefit of using more thresholds when indicator kriging is implemented with a linear interpolation model, in particular for variables with positively skewed histograms. PMID- 20161336 TI - Non-iterative sampling-based Bayesian methods for identifying changepoints in the sequence of cases of haemolytic uraemic syndrome. AB - Diarrhoea-associated Haemolytic uraemic syndrome (HUS) is a disease that affects the kidneys and other organs. Motivated by the annual number of cases of HUS collected in Birmingham and Newcastle of England, respectively, from 1970 to 1989, we consider Bayesian changepoint analysis with specific attention to Poisson changepoint models. For changepoint models with unknown number of changepoints, we propose a new non-iterative Bayesian sampling approach (called exact IBF sampling), which completely avoids the problem of convergence and slow convergence associated with iterative Markov chain Monte Carlo (MCMC) methods. The idea is to first utilize the sampling inverse Bayes formula (IBF) to derive the conditional distribution of the latent data given the observed data, and then to draw iid samples from the complete-data posterior distribution. For the purpose of selecting the appropriate model (or determining the number of changepoints), we develop two alternative formulae to exactly calculate marginal likelihood (or Bayes factor) by using the exact IBF output and the point-wise IBF, respectively. The HUS data are re-analyzed using the proposed methods. Simulations are implemented to validate the performance of the proposed methods. PMID- 20161337 TI - Problems with the BIS/BAS scales or Lykken's model of primary psychopathy? A reply to. AB - Citing a dearth of research on the Carver and White (1994) BIS scale in offender samples, its limited coverage of the psychological functions attributed to the BIS construct, and the fact that the BIS scale has a stronger association with measures of negative emotionality than with fear sensitivity, Poythress, Edens, Landfield, Lilienfeld, Skeem, and Douglas (2008) "recommend a moratorium on the use of the BIS scale to test Lykken's theory of primary psychopathy" (p. 269). In this response, we: 1) present evidence that supports the reliability and validity of the BIS scale in a large offender sample involving multiple prison sites, 2) challenge unfounded assertions regarding the inadequate coverage of the BIS, 3) propose that the problems cited by Poythress et al. are as much a function of Lykken's model as Carver and White's measure, and 4) conclude that further research is needed to clarify the distinction between primary and secondary psychopathy and that the BIS/BAS scales may play a valuable role in this regard. PMID- 20161338 TI - Synthesis of (R)-3,4-dihydro-2H-pyran-2-carboxaldehyde: application to the synthesis of potent adenosine A(2A) and A(3) receptor agonist. AB - Synthesis of potent adenosine A(2A) and A(3) receptor agonist from the modification of adenosine-5'-N-ethylcarboxamide (NECA) has been reported. Diastereoisomer possessing an (R) 3,4-dihydro-2H-pyranyl (DHP) moiety exhibited the highest affinity at the A(2A) and A(3) receptors. The key steps involve the synthesis of (R)-3,4-dihydro-2H-pyran-2-carboxaldehyde (7), which was obtained through the enzyme catalyzed kinetic resolution of (+/-)-2-acetoxymethyl-3,4 dihydro-2H-pyran (5). PMID- 20161339 TI - Adoption of Moringa oleifera to combat under-nutrition viewed through the lens of the "Diffusion of innovations" theory. AB - Moringa oleifera, an edible tree found worldwide in the dry tropics, is increasingly being used for nutritional supplementation. Its nutrient-dense leaves are high in protein quality, leading to its widespread use by doctors, healers, nutritionists and community leaders, to treat under-nutrition and a variety of illnesses. Despite the fact that no rigorous clinical trial has tested its efficacy for treating under-nutrition, the adoption of M. oleifera continues to increase. The "Diffusion of innovations theory" describes well, the evidence for growth and adoption of dietary M. oleifera leaves, and it highlights the need for a scientific consensus on the nutritional benefits. PMID- 20161340 TI - Outcomes from the Tucson Children's Assessment of Sleep Apnea Study (TuCASA). PMID- 20161342 TI - Speaker-Independent Phoneme Alignment Using Transition-Dependent States. AB - Determining the location of phonemes is important to a number of speech applications, including training of automatic speech recognition systems, building text-to-speech systems, and research on human speech processing. Agreement of humans on the location of phonemes is, on average, 93.78% within 20 msec on a variety of corpora, and 93.49% within 20 msec on the TIMIT corpus. We describe a baseline forced-alignment system and a proposed system with several modifications to this baseline. Modifications include the addition of energy based features to the standard cepstral feature set, the use of probabilities of a state transition given an observation, and the computation of probabilities of distinctive phonetic features instead of phoneme-level probabilities. Performance of the baseline system on the test partition of the TIMIT corpus is 91.48% within 20 msec, and performance of the proposed system on this corpus is 93.36% within 20 msec. The results of the proposed system are a 22% relative reduction in error over the baseline system, and a 14% reduction in error over results from a non HMM alignment system. This result of 93.36% agreement is the best known reported result on the TIMIT corpus. PMID- 20161341 TI - Bovine Carboxylesterases: Evidence for Two CES1 and Five Families of CES Genes on Chromosome 18. AB - Predicted bovine carboxylesterase (CES) protein and gene sequences were derived from bovine (Bos taurus) genomic sequence data. Two bovine CES1 genes (CES1.1 and CES1.2) were located on chromosome 18 encoding amino acid sequences that were 81% identical. Two forms of CES1.2 were also observed apparently caused by an indel polymorphism encoded at the C-terminus end. Two CES gene clusters were observed on chromosome 18: CES5-CES1.1-CES1.2 and CES2-CES3-CES6. Bovine CES1, CES2, CES3, CES5 and CES6 shared 39-45% identity with each other, but showed 71-76% identity with each of the five corresponding human CES family members. Phylogeny studies indicated that bovine CES genes originated from five ancestral gene duplication events which predated the eutherian mammalian common ancestor. In addition, a subsequent CES1 gene duplication event is proposed during mammalian evolution prior to the appearance of the Bovidae common ancestor ~ 20 MY ago. PMID- 20161343 TI - Estimation and Comparison of Receiver Operating Characteristic Curves. AB - The receiver operating characteristic (ROC) curve displays the capacity of a marker or diagnostic test to discriminate between two groups of subjects, cases versus controls. We present a comprehensive suite of Stata commands for performing ROC analysis. Non-parametric, semiparametric and parametric estimators are calculated. Comparisons between curves are based on the area or partial area under the ROC curve. Alternatively pointwise comparisons between ROC curves or inverse ROC curves can be made. Options to adjust these analyses for covariates, and to perform ROC regression are described in a companion article. We use a unified framework by representing the ROC curve as the distribution of the marker in cases after standardizing it to the control reference distribution. PMID- 20161345 TI - Mapping of Sample Collection Data: GIS Tools for the Natural Product Researcher. AB - Scientists engaged in the research of natural products often either conduct field collections themselves or collaborate with partners who do, such as botanists, mycologists, or SCUBA divers. The information gleaned from such collecting trips (e.g. longitude/latitude coordinates, geography, elevation, and a multitude of other field observations) have provided valuable data to the scientific community (e.g., biodiversity), even if it is tangential to the direct aims of the natural products research, which are often focused on drug discovery and/or chemical ecology. Geographic Information Systems (GIS) have been used to display, manage, and analyze geographic data, including collection sites for natural products. However, to the uninitiated, these tools are often beyond the financial and/or computational means of the natural product scientist. With new, free, and easy-to use geospatial visualization tools, such as Google Earth, mapping and geographic imaging of sampling data are now within the reach of natural products scientists. The goals of the present study were to develop simple tools that are tailored for the natural products setting, thereby presenting a means to map such information, particularly via open source software like Google Earth. PMID- 20161346 TI - Rearing Environmental Influences on Religiousness: An Investigation of Adolescent Adoptees. AB - Religiousness is widely considered to be a culturally transmitted trait. However, twin studies suggest that religiousness is genetically influenced in adulthood, although largely environmentally influenced in childhood/adolescence. We examined genetic and environmental influences on a self-report measure of religiousness in a sample consisting of 284 adoptive families (two adopted adolescent siblings and their rearing parents); 208 biological families (two full biological adolescent siblings and their parents); and 124 mixed families (one adopted and one biological adolescent sibling and their parents). A sibling-family model was fit to the data to estimate genetic, shared environmental, and nonshared environmental effects on religiousness, as well as cultural transmission and assortative mating effects. Religiousness showed little evidence of heritability and large environmental effects, which did not vary significantly by gender. This finding is consistent with the results of twin studies of religiousness in adolescent and preadolescent samples. PMID- 20161348 TI - Facile syntheses of cylindrical molecular brushes by a sequential RAFT and ROMP "grafting-through" methodology. PMID- 20161349 TI - FOCUSING OF HIGH POWER ULTRASOUND BEAMS AND LIMITING VALUES OF SHOCK WAVE PARAMETERS. AB - In this work, the influence of nonlinear and diffraction effects on amplification factors of focused ultrasound systems is investigated. The limiting values of acoustic field parameters obtained by focusing of high power ultrasound are studied. The Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation was used for the numerical modeling. Solutions for the nonlinear acoustic field were obtained at output levels corresponding to both pre- and post- shock formation conditions in the focal area of the beam in a weakly dissipative medium. Numerical solutions were compared with experimental data as well as with known analytic predictions. PMID- 20161344 TI - Adult combination antiretroviral therapy in sub-Saharan Africa: lessons from Botswana and future challenges. AB - Numerous national public initiatives offering first-line combination antiretroviral therapy (cART) for HIV infection have commenced in sub-Saharan Africa since 2002. Presently, 2.1 million of an estimated seven million Africans in need of cART are receiving treatment. Analyses from the region report favorable clinical/treatment outcomes and impressive declines in AIDS-related mortality among HIV-1-infected adults and children receiving cART. While immunologic recovery, virologic suppression and cART adherence rates are on par with resource-rich settings, loss to follow-up and high mortality rates, especially within the first 6 months of treatment, remain a significant problem. Over the next decade, cART coverage rates are expected to improve across the region, with attendant increases in healthcare utilization for HIV- and non-HIV related complications and the need for expanded laboratory and clinical services. Planned and in-progress trials will evaluate the use of cART to prevent primary HIV-1 infection with so-called 'test and treat' expansions of coverage and treatment. Education and training programs as well as patient-retention strategies will need to be strengthened as national cART programs are expanded and more people require lifelong monitoring and care. PMID- 20161350 TI - Violence, Older Peers, and the Socialization of Adolescent Boys in Disadvantaged Neighborhoods. AB - Most theoretical perspectives on neighborhood effects on youth assume that neighborhood context serves as a source of socialization, but the exact sources and processes underlying adolescent socialization in disadvantaged neighborhoods are largely unspecified and unelaborated. This paper proposes that cross-cohort socialization by older neighborhood peers is one source of socialization for adolescent boys in such neighborhoods. Data from the National Educational Longitudinal Survey suggest that adolescents in disadvantaged neighborhoods are more likely to spend time with older individuals. Qualitative interview data from 60 adolescent boys in three neighborhoods in Boston are analyzed to understand the causes and consequences of these interactions and relationships. I find that some of the strategies these adolescents employ to cope with violence in disadvantaged neighborhoods promote interaction with older peers, particularly those who are most disadvantaged, and that such interactions can expose adolescents to local, "unconventional," or "alternative" cultural models. PMID- 20161351 TI - Poly-N-Isopropylacrylamide/acrylic Acid Copolymers for the Generation of Nanostructures at Mica Surfaces and as Hydrophobic Host Systems for the Porin MspA from Mycobacterium smegmatis. AB - The work presented here aims at utilizing poly-N-isopropyl-acrylamide/acrylic acid copolymers to create nanostructured layers on mica surfaces by a simple spin casting procedure. The average composition of the copolymers determined by elemental analysis correlates excellently with the feed composition indicating that the radical polymerization process is statistical. The resulting surfaces were characterized by Atomic Force Microscopy (magnetic AC-mode) at the copolymer/air interface. Postpolymerization modification of the acrylic acid functions with perfluoro-octyl-iodide decreased the tendency towards spontaneous formation of nanopores. Crosslinking of individual polymer chains permitted the generation of ultraflat layers, which hosted the mycobacterial channel protein MspA, without compromising its channel function. The comparison of copolymers of very similar chemical composition that have been prepared by living radical polymerization and classic radical polymerization indicated that differences in polydispersity played only a minor role when poly-N-isopropyl-acrylamide/acrylic acid copolymers were spincast, but a major role when copolymers featuring the strongly hydrophobic perfluoro-octyl-labels were used. The mean pore diameters were 23.8+/-4.4 nm for P[(NIPAM)(95.5)-co-(AA)(4.5)] (PDI (polydispersity index)=1.55) and 21.8+/-4.2 nm for P[(NIPAM)(95.3)-co-(AA)(4.7)] (PDI=1.25). The depth of the nanopores was approx. 4 nm. When depositing P[(NIPAM)(95)-co (AA)(2.8)-AAC(8)F(17 2.2)] (PDI=1.29) on Mica, the resulting mean pore diameter was 35.8+/-7.1 nm, with a depth of only 2 nm. PMID- 20161352 TI - Asymmetric [4+2] cycloadditions employing 1,3-dienes derived from (R)-4-t butyldimethyl-silyloxy-2-cyclohexen-1-one. AB - 1.3-Dienes derived from (R)-4-t-butyldimethylsilyloxy-2-cyclohexen-1-one react with activated dienophiles to form predominately (or sometimes exclusively) syn/endo products. These controlled [4+2] cycloadditions increase the asymmetric complexity from one asymmetric center in the starting material to five asymmetric centers in the products in a single step, and provide a powerful approach for the asymmetric synthesis of compounds containing the bicyclo[2.2.2]octanone carbon skeleton. PMID- 20161353 TI - Amine Terminated SAMs: Investigating Why Oxygen is Present in these Films. AB - Self-assembled monolayers (SAMs) on gold prepared from amine-terminated alkanethiols have long been employed as model positively charged surfaces. Yet in previous studies significant amounts of unexpected oxygen containing species are always detected in amine terminated SAMs. Thus, the goal of this investigation was to determine the source of these oxygen species and minimize their presence in the SAM. The surface composition, structure, and order of amine-terminated SAMs on Au were characterized by X-ray photoelectron spectroscopy (XPS), time-of flight secondary ion mass spectroscopy (ToF-SIMS), sum frequency generation (SFG) and near edge X-ray absorption fine structure (NEXAFS) spectroscopy. XPS determined compositions of amine-terminated SAMs in the current study exhibited oxygen concentrations of 2.4 +/- 0.4 atomic %, a substantially lower amount of oxygen than reported in previously published studies. High-resolution XPS results from the S(2p), C(1s) and N(1s) regions did not detect any oxidized species. Angle-resolved XPS indicated that the small amount of oxygen detected was located at or near the amine head group. Small amounts of oxidized nitrogen, carbon and sulfur secondary ions, as well as ions attributed to water, were detected in the ToF-SIMS data due to the higher sensitivity of ToF-SIMS. The lack of N-O, S-O, and C-O stretches in the SFG spectra are consistent with the XPS and ToF-SIMS results and together show that oxidation of the amine-terminated thiols alone can only account for, at most, a small fraction of the oxygen detected by XPS. Both the SFG and angle-dependent NEXAFS indicated the presence of gauche defects in the amine SAMs. However, the SFG spectral features near 2865 cm(-1), assigned to the stretch of the methylene group next to the terminal amine unit, demonstrate the SAM is reasonably ordered. The SFG results also show another broad feature near 3200 cm(-1) related to hydrogen-bonded water. From this multi-technique investigation it is clear that the majority of the oxygen detected within these amine-terminated SAMs arises from the presence of oxygen containing adsorbates such as tightly bound water. PMID- 20161354 TI - Sleep Disturbances and their Relationship to Cardiovascular Disease. AB - Sleep disturbances are a common problem with chronic insomnia occurring in 10% of the general adult population and obstructive sleep apnea present in 4% and 2% of middle-aged men and women respectively. In addition, Americans are sleeping fewer hours per night than they did 20 years ago. There is now increasing evidence that reductions and increases in sleep duration, and various sleep disorders including obstructive sleep apnea and insomnia may be causal factors in the development of cardiovascular disease. Some of the evidence linking disturbances of sleep with cardiovascular disease is described in this review. PMID- 20161355 TI - Evidence for singlet-oxygen generation and biocidal activity in photoresponsive metallic nitride fullerene-polymer adhesive films. AB - The adhesive properties, as measured by bulk tack analysis, are found to decrease in blends of isomerically pure Sc3N@I(h)-C80 metallic nitride fullerene (MNF) and polystyrene-block-polyisoprene-block-polystyrene (SIS) copolymer pressure sensitive adhesive under white light irradiation in air. The reduction of tack is attributed to the in situ generation of 1O2 and subsequent photooxidative cross linking of the adhesive film. Comparisons are drawn to classical fullerenes C60 and C70 for this process. This work represents the first demonstration of 1O2 generating ability in the general class of MNFs (M3N@C80). Additional support is provided for the sensitizing ability of Sc3N@I(h)-C80 through the successful photooxygenation of 2-methyl-2-butene to its allylic hydroperoxides in benzene d(6) under irradiation at 420 nm, a process that occurs at a rate comparable to that of C(60). Photooxygenation of 2-methyl-2-butene is found to be influenced by the fullerene sensitizer concentration and O2 flow rate. Molar extinction coefficients are reported for Sc3N@I(h)-C80 at 420 and 536 nm. Evaluation of the potential antimicrobial activity of films prepared in this study stemming from the in situ generation of 1O2 led to an observed 1 log kill for select Gram positive and Gram-negative bacteria. PMID- 20161356 TI - The Effectiveness of Lifestyle Physical Activity Interventions to Reduce Cardiovascular Disease. AB - Lifestyle interventions have evolved from proof of concept pilot studies to efficacy and effectiveness studies and have now moved toward translation and dissemination studies because of their demonstrated ability to improve cardiovascular diseases (CVD) outcomes including blood pressure. When combined with diet, they also have demonstrated the ability to normalize blood glucose and help to regulate weight. This review highlights the converging lines of evidence that led to lifestyle physical activity interventions beginning with early epidemiology studies and provides evidence for the efficacy and effectiveness of lifestyle interventions. However, if lifestyle interventions are to play a role in preventing CVD and improving CVD outcomes, their use must be more widespread. This will require translational and dissemination research in order to understand how to move into real world settings. Successful examples of translational studies will be highlighted and issues related to theoretical and practical issues as well as capacity building will be discussed. Building bridges between research and practice must be done if lifestyle interventions are to deliver on their public health promise. PMID- 20161357 TI - 2-Mercapto-1-t-butylimidazolyl as a Bridging Ligand: Synthesis and Structural Characterization of Nickel and Palladium Paddlewheel Complexes. AB - Nickel and palladium paddlewheel complexes that feature 2-mercapto-1-t butylimidazolyl (mim(Bu(t) )) bridging ligands, namely Ni(2)[mim (Bu(t) )](4) and Pd(2)[mim (Bu(t) )](4), have been synthesized and structurally characterized by X ray diffraction. Since the mim (Bu(t) ) ligand bridges in an asymmetric manner via a sulfur and nitrogen donor, paddlewheel compounds of the type M(2)[mim (Bu(t) )](4) may exist as isomers that are distinguished by the relative orientations of the ligands. In this regard, the (4,0)-Ni(2)[mim (Bu(t) )](4) and trans-(2,2)-Ni(2)[mim (Bu(t) )](4) isomers have been isolated for the nickel system, while the (4,0)-Pd(2)[mim (Bu(t) )](4) and (3,1)-Pd(2)[mim (Bu(t) )](4) isomers have been isolated for the palladium system. PMID- 20161358 TI - Resonance Energy Transfer Between Luminescent Quantum Dots and Diverse Fluorescent Protein Acceptors. AB - We characterized the resonance energy transfer interactions for conjugates consisting of QD donors self-assembled with three distinct fluorescent protein acceptors: two monomeric fluorescent proteins, the dsRed derivative mCherry or yellow fluorescent protein and the multi-chromophore b-phycoerythrin light harvesting complex. Using steady-state and time-resolved fluorescence, we showed that nonradiative transfer of excitation energy in these conjugates can be described within the Forster dipole-dipole formalism, with transfer efficiencies that vary with the degree of spectral overlap, donor-acceptor separation distance and the number of acceptors per QD. Comparison between the quenching data and simulation of the conjugate structures indicated that while energy transfer to monomeric proteins was identical to what was measured for QD-dye pairs, interactions with b-phycoerythrin were more complex. For the latter, the overall transfer efficiency results from the cumulative contribution of individual channels between the central QD and the chromophores distributed throughout the protein structure. Due to the biocompatible nature of fluorescent proteins, these QD-assemblies may have great potential for use in intracellular imaging and sensing. PMID- 20161359 TI - Physical Activity Transitions and Chronic Disease. AB - The 20(th) century in the United States (U.S.) has experienced a dramatic increase in life expectancy among adult men and women, an increase unprecedented in the history of this country. As a result, the pattern of disease and conditions most responsible for death in the U.S. shifted during the past century from infectious diseases and unintentional injuries to the current array of the leading causes of mortality dominated by the chronic diseases. During this same period, daily lifestyle dramatically shifted from a life full of active living to one of inactivity. The argument has been made that in the case of human beings, there has been little or no change in our genotype within the past 50 years. However, there have been major changes documented in the living environment among economically developed societies during this same time period. Through the collection of epidemiologic, clinical, and experimental findings, evidence exists to suggest that physical inactivity is associated with the onset of chronic diseases of our day. Trends in physical inactivity evident through the monitoring of transport, recreational, sport, and purposeful activity have demonstrated that the current lifestyle of the 21(st) century has contributed substantially to the chronic disease burden in the U.S. and elsewhere. By addressing the domains that influence physical activity behaviors including the environment (both physical and social/cultural), health systems access, and behavioral correlates of physical activity and inactivity, the current chronic disease crisis can potentially be addressed. PMID- 20161360 TI - Intensity Standardization Simplifies Brain MR Image Segmentation. AB - Typically, brain MR images present significant intensity variation across patients and scanners. Consequently, training a classifier on a set of images and using it subsequently for brain segmentation may yield poor results. Adaptive iterative methods usually need to be employed to account for the variations of the particular scan. These methods are complicated, difficult to implement and often involve significant computational costs. In this paper, a simple, non iterative method is proposed for brain MR image segmentation. Two preprocessing techniques, namely intensity inhomogeneity correction, and more importantly MR image intensity standardization, used prior to segmentation, play a vital role in making the MR image intensities have a tissue-specific numeric meaning, which leads us to a very simple brain tissue segmentation strategy.Vectorial scale based fuzzy connectedness and certain morphological operations are utilized first to generate the brain intracranial mask. The fuzzy membership value of each voxel within the intracranial mask for each brain tissue is then estimated. Finally, a maximum likelihood criterion with spatial constraints taken into account is utilized in classifying all voxels in the intracranial mask into different brain tissue groups. A set of inhomogeneity corrected and intensity standardized images is utilized as a training data set. We introduce two methods to estimate fuzzy membership values. In the first method, called SMG (for simple membership based on a gaussian model), the fuzzy membership value is estimated by fitting a multivariate Gaussian model to the intensity distribution of each brain tissue whose mean intensity vector and covariance matrix are estimated and fixed from the training data sets. The second method, called SMH (for simple membership based on a histogram), estimates fuzzy membership value directly via the intensity distribution of each brain tissue obtained from the training data sets. We present several studies to evaluate the performance of these two methods based on 10 clinical MR images of normal subjects and 10 clinical MR images of Multiple Sclerosis (MS) patients. A quantitative comparison indicates that both methods have overall better accuracy than the k-nearest neighbors (kNN) method, and have much better efficiency than the Finite Mixture (FM) model based Expectation Maximization (EM) method. Accuracy is similar for our methods and EM method for the normal subject data sets, but much better for our methods for the patient data sets. PMID- 20161361 TI - Wave-ering: An ERP study of syntactic and semantic context effects on ambiguity resolution for noun/verb homographs. AB - Two event-related potential experiments investigated the effects of syntactic and semantic context information on the processing of noun/verb (NV) homographs (e.g., park). Experiment 1 embedded NV-homographs and matched unambiguous words in contexts that provided only syntactic cues or both syntactic and semantic constraints. Replicating prior work, when only syntactic information was available NV-homographs elicited sustained frontal negativity relative to unambiguous words. Semantic constraints eliminated this frontal ambiguity effect. Semantic constraints also reduced N400 amplitudes, but less so for homographs than unambiguous words. Experiment 2 showed that this reduced N400 facilitation was limited to cases in which the semantic context picks out a nondominant meaning, likely reflecting the semantic mismatch between the context and residual, automatic activation of the contextually-inappropriate dominant sense. Overall, the findings suggest that ambiguity resolution in context involves the interplay between multiple neural networks, some involving more automatic semantic processing mechanisms and others involving top-down control mechanisms. PMID- 20161362 TI - A commentary on 'Exercise and Depression' (): And the Verdict Is... PMID- 20161363 TI - REAL-TIME PROBING OF THE GROWTH DYNAMICS OF NANOPARTICLES USING POTENTIOMETRIC ION-SELECTIVE ELECTRODES. AB - This Communication demonstrates the ability of potentiometric ion-selective electrodes (ISE) to probe the growth dynamics of metal nanoparticles in real time. The new monitoring capability is illustrated using a solid-contact silver ISE for monitoring the hydroquinone-induced precipitation of silver on gold nanoparticle seeds. Potential-time recordings obtained under different conditions are used to monitor the depletion of the silver ion during the nanoparticle formation and shed useful insights into the growth dynamics of the nanoparticles. Such potentiometric profiles correlate well with the analogous optical measurements. The new real-time electrochemical probing of the particle growth process reflects the direct, rapid and sensitive response of modern ISE to changes in the level of the precipitated metal ion from the bulk solution and holds considerable promise for probing the preparation of different nanoscale materials. PMID- 20161364 TI - Synthesis of 2,6-disubstituted dihydropyrans via an efficient BiBr(3)-initiated three component, one-pot cascade. AB - The rapid synthesis of cis-2,6-disubstituted dihydropyrans is achieved in a three component, one-pot cascade reaction. BiBr(3)-ediated addition of ketene silyl acetals or silyl enol ethers to beta,gamma-unsaturated cis-4-trimethylsilyl-3 butenal provides a Mukaiyama aldol adduct containing a vinylsilane moiety tethered to a silyl ether. Addition of a second aldehyde initiates a domino sequence involving intermolecular addition followed by an intramolecular silyl modified Sakurai (ISMS) reaction. Isolated yields of this one-pot reaction vary from 44 to 80% and all compounds were isolated as the cis-diastereomers (10 examples). PMID- 20161365 TI - The Columbia University Sub-micron Charged Particle Beam. AB - A lens system consisting of two electrostatic quadrupole triplets has been designed and constructed at the Radiological Research Accelerator Facility (RARAF) of Columbia University. The lens system has been used to focus 6-MeV (4)He ions to a beam spot in air with a diameter of 0.8 um. The quadrupole electrodes can withstand voltages high enough to focus (4)He ions up to 10 MeV and protons up to 5 MeV. The quadrupole triplet design is novel in that alignment is made through precise construction and the relative strengths of the quadrupoles are accomplished by the lengths of the elements, so that the magnitudes of the voltages required for focusing are nearly identical. The insulating sections between electrodes have had ion implantation to improve the voltage stability of the lens. The lens design employs Russian symmetry for the quadrupole elements. PMID- 20161366 TI - Pharmacological modulators of the circadian clock as potential therapeutic drugs. AB - Circadian clocks are molecular time-keeping systems that underlie daily fluctuations in multiple physiological and biochemical processes. It is well recognized now that dysfunctions of the circadian system (both genetically and environmentally induced) are associated with the development of various pathological conditions. Here we describe the application of high throughput screening approach designed to search for small molecules capable of pharmacological modulation of the molecular clock. We provide evidence for the feasibility and value of this approach for both scientific and therapeutic purposes. PMID- 20161367 TI - WHITE FLIGHT REVISITED: A MULTIETHNIC PERSPECTIVE ON NEIGHBORHOOD OUT-MIGRATION. AB - Using geo-linked data from the Panel Study of Income Dynamics and the decennial census, we compare probabilities of neighborhood out-migration for Anglos, blacks, Mexicans, Puerto Ricans, and Cubans by varying ethno-racial neighborhood compositions. Analyses for Latinos are disaggregated by nativity status. The results indicate that Anglos have a higher likelihood of moving when they have many minority neighbors and there is little difference whether minority neighbors are black or Latino. Among minorities there is some evidence of "minority flight" from whiter neighborhoods. Cubans, especially foreign-born Cubans, demonstrate the strongest propensity to flee neighborhoods with large black populations, whereas the probability of moving out decreases for Mexicans and Puerto Ricans when their neighbors are more likely to be black. Ethno-racial neighborhood composition has little effect on blacks' decision to leave their neighborhood. PMID- 20161368 TI - Differences in African American and White Women's Attitudes Toward Lesbians and Gay Men. AB - The aim of the present study was to examine racial differences in women's attitudes toward lesbians and gay men and to offer an understanding of these differences. Participants were 224 18-30 year old heterosexual African American (64%) and White (36%) female undergraduates from a large urban university in the southeastern United States. Participants completed measures of social demographics, sexual orientation, and sexual prejudice. Results showed that African American, relative to White, women endorsed more negative attitudes toward lesbians and gay men. Also, unlike White women, African American women reported more negative attitudes toward gay men than lesbians. Implications are discussed regarding differences in cultural contexts that exist between African American and White women. PMID- 20161369 TI - Arsenic species interactions with a porous carbon electrode as determined with an electrochemical quartz crystal microbalance. AB - The interactions of arsenic species with platinum and porous carbon electrodes were investigated with an electrochemical quartz crystal microbalance (EQCM) and cyclic voltammetry in alkaline solutions. It is shown that the redox reactions in arsenic-containing solutions, due to arsenic reduction/deposition, oxidation/desorption, and electrocatalyzed oxidation by Pt can be readily distinguished with the EQCM. This approach was used to show that the arsenic redox reactions on the carbon electrode are mechanistically similar to that on the bare Pt electrode. This could not be concluded with just classical cyclic voltammetry alone due to the obfuscation of the faradaic features by the large capacitative effects of the carbon double layer.For the porous carbon electrode, a continual mass loss was always observed during potential cycling, with or without arsenic in the solution. This was attributed to electrogasification of the carbon. The apparent mass loss per cycle was observed to decrease with increasing arsenic concentration due to a net mass increase in adsorbed arsenic per cycle that increased with arsenic concentration, offsetting the carbon mass loss. Additional carbon adsorption sites involved in arsenic species interactions are created during electrogasification, thereby augmenting the net uptake of arsenic per cycle.It is demonstrated that EQCM, and in particular the information given by the behavior of the time derivative of the mass vs. potential, or massogram, is very useful for distinguishing arsenic species interactions with carbon electrodes. It may also prove to be effective for investigating redox/adsorption/desorption behavior of other species in solution with carbon materials as well. PMID- 20161370 TI - pH- and mol-ratio dependent formation of zinc(II) coordination polymers with iminodiacetic acid: synthesis, spectroscpic, crystal structure and thermal studies. AB - Three novel zinc coordination polymers (NH(4))(n)[Zn(Hida)Cl(2)](n) (1), [Zn(ida)(H(2)O)(2)](n) (2), [Zn(Hida)(2)](n).4nH(2)O (3) (H(2)ida = iminodiacetic acid) and a monomeric complex [Zn(ida)(phen)(H(2)O)].2H(2)O (4) (phen=1,10 phenanthroline) have been synthesized and characterized by X-ray diffraction methods. 1 and 2 form one-dimensional (1-D) chain structures, whereas 3 exhibits a three-dimensional (3-D) diamondoid framework with an open channel. The mononuclear complex 4 is extended into a 3-D supramolecular architecture through hydrogen bonds and pi-pi stacking. Interestingly, cyclic nonplanar tetrameric water clusters are observed that encapsulated in the 3-D lattice of 4. Based on (1)H and (13)C NMR observations, there is obvious coordination of complex 2 in solution, while 1 and 3 decompose into free iminodiacetate ligand. Monomer [Zn(ida)(H(2)O)(3)] (5) is considered as a possible discrete species from 2. These coordination polymers can serve as good molecular precursors for zinc oxide. PMID- 20161371 TI - Transcranial magnetic stimulation studies of visuospatial attentional control. AB - Transcranial magnetic stimulation (TMS) is an established technique in cognitive neuroscience which is used to interrupt processing in the brain, creating a brief 'virtual lesion'. Here, we review recent studies that have employed TMS to gain insight into the roles of frontal and parietal cortex in visuospatial attention control. PMID- 20161372 TI - Promoting Lifestyle Physical Activity: Experiences with the First Step Program. AB - The purpose of this article is to describe a pedometer-based physical activity intervention (and the research that has been conducted on this program) to provide insight into workable strategies focused on promoting lifestyle physical activity. The First Step Program (FSP) is facilitated theory-based behavior modification program, originally developed for individuals with Type 2 diabetes, which capitalizes on the unique properties of a pedometer to serve as a stimulus for walking and an instrument for individual goal-setting, self-monitoring, and feedback. Formative evaluation revealed that participants were highly enthusiastic about the program and pilot testing demonstrated an immediate and dramatic increase in walking behavior (by approximately 3,700 steps/day or 34 minutes of walking a day). A randomized and controlled evaluation produced similar results, as have head-to-head comparisons of participant outcomes produced by professional vs. peer delivery, and adaptations of the program to worksite and community-based delivery. The effectiveness of the FSP can be explained by a thoughtful consideration of pedometer characteristics, program features, and the people who participate. Sustained delivery is contingent on funding sources and administrative structures that support formalized implementation. PMID- 20161373 TI - Endosomal Toll-like receptors in autoimmunity: mechanisms for clinical diversity. AB - The endosomal Toll-like receptors (TLR3, TLR7 and TLR9) have been implicated in the pathogenesis of autoimmune diseases. Their signaling pathways show remarkable similarities and yet the outcomes following activation of each of these TLRs lead to clinically distinct autoimmune disease phenotypes. This review discusses how differences may arise at a molecular and cellular level to account for this diversity of responses. Understanding the roles of individual TLR pathways and the relationships between them and non-TLR innate immune pathways in the pathogenesis of diseases such as systemic lupus erythematosis highlights potential treatment targets for this spectrum of autoimmune diseases. PMID- 20161374 TI - Local Linear Regression for Data with AR Errors. AB - In many statistical applications, data are collected over time, and they are likely correlated. In this paper, we investigate how to incorporate the correlation information into the local linear regression. Under the assumption that the error process is an auto-regressive process, a new estimation procedure is proposed for the nonparametric regression by using local linear regression method and the profile least squares techniques. We further propose the SCAD penalized profile least squares method to determine the order of auto-regressive process. Extensive Monte Carlo simulation studies are conducted to examine the finite sample performance of the proposed procedure, and to compare the performance of the proposed procedures with the existing one. From our empirical studies, the newly proposed procedures can dramatically improve the accuracy of naive local linear regression with working-independent error structure. We illustrate the proposed methodology by an analysis of real data set. PMID- 20161375 TI - More than words: Adults learn probabilities over categories and relationships between them. AB - This study examines whether human learners can acquire statistics over abstract categories and their relationships to each other. Adult learners were exposed to miniature artificial languages containing variation in the ordering of the Subject, Object, and Verb constituents. Different orders (e.g. SOV, VSO) occurred in the input with different frequencies, but the occurrence of one order versus another was not predictable. Importantly, the language was constructed such that participants could only match the overall input probabilities if they were tracking statistics over abstract categories, not over individual words. At test, participants reproduced the probabilities present in the input with a high degree of accuracy. Closer examination revealed that learner's were matching the probabilities associated with individual verbs rather than the category as a whole. However, individual nouns had no impact on word orders produced. Thus, participants learned the probabilities of a particular ordering of the abstract grammatical categories Subject and Object associated with each verb. Results suggest that statistical learning mechanisms are capable of tracking relationships between abstract linguistic categories in addition to individual items. PMID- 20161376 TI - The Concept of Development in Developmental Psychopathology. AB - So important is the perspective of development for understanding psychopathology that it spawned a new discipline-"developmental psychopathology"-which has seen remarkable advances since its introduction,, but has yet to completely fulfill its promise. To do this requires maintaining a thoroughgoing developmental perspective. When we take development seriously, there are implications for how we understand psychopathology, describe and conceptualize the origins and course of disorder, and interpret research findings. From this perspective, disorders are complex products of development; for example, we can view neurophysiological associates of disorder not as causes but as markers, the development of which we need to understand. Research on developmental psychopathology requires an examination of the history of problem behavior from early in life, and it unites multiple features of adaptation and maladaptation (contextual, experiential, physiological, and genetic). PMID- 20161377 TI - Recent Departures in the Synthesis of Peptides and Glycopeptides. AB - In this account, we describe the results of a research program directed to the proposition that chemical synthesis can play a valuable role in identifying biologic level molecules worthy of pharma level development. We recount our journey towards the chemical synthesis of homogeneous erythropoietin, the challenges we encountered, and our efforts to address deficiencies in the current "state of the art" of glycopeptide synthesis. Here we describe new methods for the synthesis of glycopeptides that have emerged from the erythropoietin adventure, including the development of unique C-terminal acyl donors, novel amide bond forming methods, and new ligation and coupling strategies. PMID- 20161378 TI - Recent progress in protein drug design and discovery with a focus on novel approaches to the development of anti-cocaine medications. AB - Cocaine is highly addictive and no anti-cocaine medication is currently available. Accelerating cocaine metabolism, producing biologically inactive metabolites, is recognized as an ideal anti-cocaine medication strategy, especially for the treatment of acute cocaine toxicity. However, currently known wild-type enzymes have either too low a catalytic efficiency against the abused cocaine, in other words (-)-cocaine, or the in vivo half-life is too short. Novel computational strategies and design approaches have been developed recently to design and discover thermostable or high-activity mutants of enzymes based on detailed structures and catalytic/inactivation mechanisms. The structure- and mechanism-based computational design efforts have led to the discovery of high activity mutants of butyrylcholinesterase and thermostable mutants of cocaine esterase as promising anti-cocaine therapeutics. The structure- and mechanism based computational strategies and design approaches may be used to design high activity and/or thermostable mutants of many other proteins that have clear therapeutic potentials and to design completely new therapeutic enzymes. PMID- 20161379 TI - Scope and Mechanistic Investigations on the Solvent-Controlled Regio- and Stereoselective Formation of Enol Esters from the Ruthenium-Catalyzed Coupling Reaction of Terminal Alkynes and Carboxylic Acids. AB - The ruthenium-hydride complex (PCy(3))(2)(CO)RuHCl was found to be a highly effective catalyst for the alkyne-to-carboxylic acid coupling reaction to give synthetically useful enol ester products. Strong solvent effect was observed for the ruthenium catalyst in modulating the activity and selectivity; the coupling reaction in CH(2)Cl(2) led to the regioselective formation of gem-enol ester products, while the stereoselective formation of (Z)-enol esters was obtained in THF. The coupling reaction was found to be strongly inhibited by PCy(3). The coupling reaction of both PhCO(2)H/PhC identical withCD and PhCO(2)D/PhC identical withCH led to the extensive deuterium incorporation on the vinyl positions of the enol ester products. An opposite Hammett value was observed when the correlation of a series of para-substituted p-X-C(6)H(4)CO(2)H (X = OMe, CH(3), H, CF(3), CN) with phenylacetylene was examined in CDCl(3) (rho = +0.30) and THF (rho = -0.68). Catalytically relevant Ru-carboxylate and -vinylidene carboxylate complexes, (PCy(3))(2)(CO)(Cl)Ru(kappa(2)-O(2)CC(6)H(4)-p-OMe) and (PCy(3))(2)(CO)(Cl)RuC(=CHPh)O(2)CC(6)H(4)-p-OMe, were isolated, and the structure of both complexes was completely established by X-ray crystallography. A detailed mechanism of the coupling reaction involving a rate-limiting C-O bond formation step was proposed on the basis of these kinetic and structural studies. The regioselective formation of the gem-enol ester products in CH(2)Cl(2) was rationalized by a direct migratory insertion of the terminal alkyne via a Ru carboxylate species, whereas the stereoselective formation of (Z)-enol ester products in THF was explained by invoking a Ru-vinylidene species. PMID- 20161380 TI - Sensing of proteins in human serum using conjugates of nanoparticles and green fluorescent protein. AB - There is a direct correlation between protein levels and disease states in human serum, which makes it an attractive target for sensors and diagnostics. However, this is challenging because serum features more than 20,000 proteins, with an overall protein content greater than 1 mM. Here we report a sensor based on a hybrid synthetic-biomolecule that uses arrays of green fluorescent protein and nanoparticles to detect proteins at biorelevant concentrations in both buffer and human serum. Distinct and reproducible fluorescence-response patterns were obtained from five serum proteins (human serum albumin, immunoglobulin G, transferrin, fibrinogen and a-antitrypsin), both in buffer and when spiked into human serum. Using linear discriminant analysis we identified these proteins with an identification accuracy of 100% in buffer and 97% in human serum. The arrays were also able to discriminate between different concentrations of the same protein, as well as a mixture of different proteins in human serum. PMID- 20161381 TI - Automated Freehand Sketch Segmentation Using Radial Basis Functions. AB - Freehand sketching is widely regarded as an efficient and natural way for interaction between computers and humans. We present a robust computerized scheme to automatically segment freehand sketches into a series of components with specific geometric meaning regardless of whether these are generated online or offline. This task is a necessary first step toward sketch understanding. By exploiting the interpolation / extrapolation characteristic of Radial Basis Functions (RBFs), a greedy algorithm consisting of forward and backward operations is proposed for finding the minimum set of segmentation points that can be used to reconstruct with high fitting accuracy freehand sketches in the form of implicit functions. To obtain segmentation points, a simple angle based rule is used to remove "bridging" points that provide a smooth transition between consecutive sketch components. Feasibility of the proposed algorithm is demonstrated by a preliminary performance assessment study using ten computer generated drawings. These experiments show that in this dataset sensitivity of the segmentation was higher than 97.5% with a false positive (FP) rate of approximately 25%. The majority of false positive identifications are located on arc regions where a larger number of segmentation points are needed for reconstruction purposes. The primary contribution of this algorithm is that it transforms an ambiguous problem namely, freehand sketch segmentation, into an implicit function fitting operation. Therefore, this proposed approach has several advantages including independence of the actual sketching activity, and the ability for a satisfactory detection of the transition point between a line and an arc or between two arcs. PMID- 20161382 TI - Synthesis of novel 2H,5H-Dihydrofuran-3-yl Ketones via ISNC reactions. AB - Unique 1-[2H,5H-dihydrofur-3-yl]ketones have been synthesized from propargylic nitroethers via intramolecular cycloadditions involving silyl nitronates. Various substituent groups were placed on the 2 and 5 positions of the dihydrofuran rings. We examined the scope of the long-range coupling in proton NMR of the oxo dihydrofuran products. The identities of the diastereomers resulting from the Michael Addition/cycloaddition reactions were tentatively assigned for the first time. CAChe MNDO PM5 and CONFLEX programs were engaged to assist with the identification of these stereoisomers. The reaction times and conditions for these oxo-dihydrofurans were found to be different than that of the published dihydrofuranals, which led us to propose a different mechanism. PMID- 20161383 TI - Genomic approaches in the identification of hypoxia biomarkers in model fish species. AB - Eutrophication leading to hypoxic water conditions has become a major problem in aquatic systems worldwide. Monitoring the levels and biological effects of lowered oxygen levels in aquatic systems may provide data useful in management of natural aquatic environments. Fishes represent an economically important resource that is subject to hypoxia exposure effects. Due to the extreme diversity of fish species and their habitats, fishes in general have evolved unique capabilities to modulate gene expression patterns in response to hypoxic stress. Recent studies have attempted to document quantitative changes in gene expression patterns induced in various fish species in response to reduced dissolved oxygen levels. From a management perspective, the goal of these studies is to provide a more complete characterization of hypoxia responsive genes in fish, as molecular indicators (biomarkers) of ecosystem hypoxic stress.The molecular genetic response to hypoxia is highly complex and overlaps with other stress responses making it difficult to identify hypoxia specific responses using traditional single gene or low throughput approaches. Therefore, recent approaches have been aimed at developing functional genomic (e.g. high density microarray and real time PCR) and proteomic (two-dimensional fluorescence difference in gel electrophoresis coupled with mass spectrometry based peptide identification) technologies that employ fish species. Many of the fish species utilized in these studies do not have the advantages of underlying genome resources (i.e., genome or transcriptome sequences). Efforts have attempted to establish correlations between discreet molecular responses elicited by fish in response to hypoxia and changes in the genetic profiles of stressed organs or tissues. Notable progress in these areas has been made using several different versions of either cDNA or oligonucleotide based microarrays to profile changes in gene expression patterns in response to hypoxic stress.Due to these efforts, hundreds of hypoxia responsive genes have been identified both from laboratory reared aquaria fish and from feral fish derived from both fresh and saltwater habitats. Herein, we review these reports and the emergence of hypoxia biomarker development in aquatic species. We also include some of our own recent results using the medaka (Oryzias latipes) as a model to define genetic profiles of hypoxia exposure. PMID- 20161385 TI - Affective response to exercise as a component of exercise motivation: Attitudes, norms, self-efficacy, and temporal stability of intentions. AB - PROBLEM: A positive affective response is associated with increased participation in voluntary exercise, but the mechanisms by which this occurs are not well known. Consistent with a Theory of Planned Behaviour perspective, we tested whether affective response to exercise leads to greater motivation in terms of attitudes, subjective norms, self-efficacy and intentions to exercise. We were also specifically interested in whether a positive affective response leads to more temporally stable intentions. METHOD: Participants (N = 127) self-reported Theory of Planned Behaviour constructs and exercise behavior at baseline and three months later, and provided reports of exercise-related affect during a 30 minute bout of moderate intensity treadmill exercise at baseline. RESULTS: We show that participants who experience greater improvements in positive affect, negative affect and fatigue during exercise tended to report more positive attitudes, exercise self-efficacy and intentions to exercise three months later. Affective response was not predictive of subjective norms. As hypothesized, positive affective response was associated with more stable intentions over time. CONCLUSIONS: We conclude that a positive affective response to acute bouts of exercise can aid in building and sustaining exercise motivation over time. PMID- 20161386 TI - Asymmetric synthesis of (2S,3R)-(-)-epi-CP-99,994 using sulfinimine-derived anti 2,3-diamino esters. AB - A differentially protected C-3 N-sulfinyl, C-2 N,N-(diphenylmethylene) 2,3 diamino ester was employed in the synthesis of the amino piperidine (2S,3R)-(-) epi-CP-99,994. Key steps in the synthesis included the chemoselective hydrolysis of the C-2 N,N-(diphenylmethylene) group and its reprotection as a dibenzylamino group. PMID- 20161384 TI - Impact of Absorption and Transport on Intelligent Therapeutics and Nano-scale Delivery of Protein Therapeutic Agents. AB - The combination of materials design and advances in nanotechnology has led to the development of new therapeutic protein delivery systems. The pulmonary, nasal, buccal and other routes have been investigated as delivery options for protein therapy, but none result in improved patient compliances and patient quality of life as the oral route. For the oral administration of these new systems, an understanding of protein transport is essential because of the dynamic nature of the gastrointestinal tract and the barriers to transport that exist.Models have been developed to describe the transport between the gastrointestinal lumen and the bloodstream, and laboratory techniques like cell culture provide a means to investigate the absorption and transport of many therapeutic agents. Biomaterials, including stimuli-sensitive complexation hydrogels, have been investigated as promising carriers for oral delivery. However, the need to develop models that accurately predict protein blood concentration as a function of the material structure and properties still exists. PMID- 20161387 TI - Perspectives on utilizing unique features of microfluidics technology for particle and cell sorting. AB - Sample preparation is often the most tedious and demanding step in an assay, but it also plays an essential role in determining the quality of results. As biological questions and analytical methods become increasingly sophisticated, there is a rapidly growing need for systems that can reliably and reproducibly separate cells and particles with high purity, throughput and recovery. Microfluidics technology represents a compelling approach in this regard, allowing precise control of separation forces for high performance separation in inexpensive, or even disposable, devices. In addition, microfluidics technology enables the fabrication of arrayed and integrated systems that operate either in parallel or in tandem, in a capacity that would be difficult to achieve in macro scale systems. In this report, we use recent examples from our work to illustrate the potential of microfluidic cell- and particle-sorting devices. We demonstrate the potential of chip-based high-gradient magnetophoresis that enable high-purity separation through reversible trapping of target particles paired with high stringency washing with minimal loss. We also describe our work in the development of devices that perform simultaneous multi-target sorting, either through precise control of magnetic and fluidic forces or through the integration of multiple actuation forces into a single monolithic device. We believe that such devices may serve as a powerful "front-end" module of highly integrated analytical platforms capable of providing actionable diagnostic information directly from crude, unprocessed samples - the success of such systems may hold the key to advancing point-of-care diagnostics and personalized medicine. PMID- 20161388 TI - Impact of Relative Residence Times in Highly Distinct Environments on the Distribution of Heavy Drinkers. AB - Alcohol consumption is a function of social dynamics, environmental contexts, individuals' preferences and family history. Empirical surveys have focused primarily on identification of risk factors for high-level drinking but have done little to clarify the underlying mechanisms at work. Also, there have been few attempts to apply nonlinear dynamics to the study of these mechanisms and processes at the population level. A simple framework where drinking is modeled as a socially contagious process in low- and high-risk connected environments is introduced. Individuals are classified as light, moderate (assumed mobile), and heavy drinkers. Moderate drinkers provide the link between both environments, that is, they are assumed to be the only individuals drinking in both settings. The focus here is on the effect of moderate drinkers, measured by the proportion of their time spent in "low-" versus "high-" risk drinking environments, on the distribution of drinkers.A simple model within our contact framework predicts that if the relative residence times of moderate drinkers is distributed randomly between low- and high-risk environments then the proportion of heavy drinkers is likely to be higher than expected. However, the full story even in a highly simplified setting is not so simple because "strong" local social mixing tends to increase high-risk drinking on its own. High levels of social interaction between light and moderate drinkers in low-risk environments can diminish the importance of the distribution of relative drinking times on the prevalence of heavy drinking. PMID- 20161389 TI - Marital Aspirations, Sexual Behaviors, and HIV/AIDS in Rural Malawi. AB - We explore how marital aspirations are related to the sexual behaviors of adolescents and young adults in Malawi, where HIV/AIDS prevalence among adults exceeds 10%. We also consider whether the specter of AIDS is shaping ideals about marriage. By combining survey data (N = 1,087) and in-depth interviews (N = 133) with young Malawians from the Malawi Diffusion and Ideational Change Project, we show that looking for and finding a suitable spouse are linked to sexual behaviors and, thus, HIV risks. Moreover, concerns about contracting HIV are closely tied to the ideal characteristics of a future spouse. Our findings draw long-overdue attention to the importance of marital aspirations in understanding adolescent sexual behaviors and risks in the era of AIDS. PMID- 20161390 TI - Memory Issues Pertaining to Social Marketing Messages about Behavior Enactment versus Non-enactment. PMID- 20161391 TI - Racial/Ethnic Composition, Social Disorganization, and Offsite Alcohol Availability in San Diego County, California* AB - We draw upon social disorganization theory to examine the effects of community characteristics on the distribution of offsite alcohol outlets in San Diego County, California. Of particular interest is whether alcohol availability varies according to neighborhood racial/ethnic composition once measures of social disorganization (socioeconomic disadvantage, residential instability, and racial/ethnic heterogeneity) are controlled. Using data from the 1990 Census and 1993 alcohol license reports, we estimate a series of negative binomial regression models with corrections for spatial autocorrelation. The results show that percent Asian is associated with lower offsite alcohol outlet density. Once socioeconomic disadvantage is controlled, percent Latino is related to lower alcohol availability. Although similar suppressor patterns are observed, percent Black is generally unrelated to outlet density. Consistent with social disorganization theory, socioeconomic disadvantage and residential instability predict increased alcohol availability. Neighborhood racial/ethnic composition is either unrelated or inversely related to outlet density once social disorganization and other neighborhood characteristics are taken into account. PMID- 20161392 TI - Biomimetic Control of Calcite Morphology with Homopolyanions. AB - Biomineralization is an intricate process that relies on precise physiological control of solution and interface properties. Despite much research of the process, mechanistic details of biomineralization are only beginning to be understood, and studies of additives seldom investigate a wide space of chemical conditions in mineralizing solutions. We present a ternary diagram-based method that globally identifies the changing roles and effects of polymer additives in mineralization. Simple polyanions were demonstrated to induce a great variety of morphologies, each of which can be selectively and reproducibly fabricated. This chemical and physical analysis also aided in identifying conditions that selectively promote heterogeneous nucleation and controlled cooperative assembly, manifested here in the form of highly organized cones. Similar complex shapes of CaCO(3) have previously been synthesized using double hydrophilic block copolymers. We have found the biomimetic mineralization process to occur interfacially and by the assembly of precursor modules, which generate large mesocrystals with high dependence on pH and substrate surface. PMID- 20161393 TI - Glycoprofiling of the Human Salivary Proteome. AB - Glycosylation is important for a number of biological processes and is perhaps the most abundant and complicated of the known post-translational modifications found on proteins. This work combines two-dimensional polyacrylamide gel electrophoresis (2-DE) and lectin blotting to map the salivary glycome, and mass spectrometry to identity the proteins that are associated with the glycome map. A panel of 15 lectins that recognize six sugar-specific categories was used to visualize the type and extent of glycosylation in saliva from two healthy male individuals. Lectin blots were compared to 2-D gels stained either with Sypro Ruby (protein stain) or Pro-Q Emerald 488 (glycoprotein stain). Each lectin shows a distinct pattern, even those belonging to the same sugar-specific category. In addition, the glycosylation profiles generated from the lectin blots show that most of the salivary proteins are glycosylated and that the pattern is more widespread than is demonstrated by the glycoprotein stained gel. Finally, the co reactivity between two lectins was measured to determine the glycan structures that are most and least often associated with one another along with the population variation of the lectin reactivity for 66 individuals. PMID- 20161394 TI - The "Humpty Dumpty Problem" in the Study of Early Cognitive Development: Putting the Infant Back Together Again. AB - In this article, I propose that the big question for the field of infant cognitive development is best characterized as the "Humpty Dumpty problem": Now that we have studied cognitive abilities in isolation, how do we put the developing cognitive system (and the infant) back together again? This problem is significant because cognitive abilities do not occur in isolation. Infants remember the items they have attended to and perceived, and their emotional state will influence their perception and representation of the events they encounter. Moreover, by examining the development of the whole cognitive system, or the whole child, we gain a deeper understanding of mechanisms developmental change. Thus, the big question for the study of infant cognition is like the question confronting all the king's horses and all the king's men: How do we put the infant's cognitive system back together again? PMID- 20161396 TI - Insights into the Nature of Mo(V) Species in Solution: Modeling Catalytic Cycles for Molybdenum Enzymes. AB - The tris(pyrazolyl)borate and related tripodal N-donor ligands originally developed by Trofimenko stabilize mononuclear compounds containing Mo(VI)O(2), Mo(VI)O, Mo(V)O, and Mo(IV)O units and effectively inhibit their polynucleation in organic solvents. Dioxo-Mo(VI) complexes of the type LMoO(2)(SPh), where L = hydrotris(3,5-dimethylpyrazol-1-yl)borate (Tp*), hydrotris(3-isopropylpyrazol-1 yl)borate (Tp(i) (Pr)), and hydrotris(3,5-dimethyl-1,2,4-triazol-1-yl)borate (Tz) and related derivatives are the only model systems that mimic the complete reaction sequence of sulfite oxidase, in which oxygen from water is ultimately incorporated into product. The quasi-reversible, one-electron reduction of Tp*MoO(2)(SPh) in acetonitrile exhibits a positive potential shift upon addition of a hydroxylic proton donor, and the magnitude of the shift correlates with the acidity of the proton donor. These reductions produce two Mo(V) species, [Tp*Mo(V)O(2)(SPh)](-) and Tp*Mo(V)O(OH)(SPh), that are related by protonation. Measurement of the relative amounts of these two Mo(V) species by EPR spectroscopy enabled the pK(a) of the Mo(V)(OH) unit in acetonitrile to be determined and showed it to be several pK(a) units smaller than that for water in acetonitrile. Similar electrochemical-EPR experiments for Tp(i) (Pr)MoO(2)(SPh) indicated that the pK(a) for its Mo(V)(OH) unit was ~1.7 units smaller than that for Tp*Mo(V)O(OH)(SPh). Density functional theory calculations also predict a smaller pK(a) for (iPr)Mo(V)O(OH)(SPh) compared to Tp*Mo(V)O(OH)(SPh). Analysis of these results indicates that coupled electron-proton transfer (CEPT) is thermodynamically favored over the indirect process of metal reduction followed by protonation. The crystal structure of Tp(i) (Pr)MoO(2)(SPh) is also presented. PMID- 20161397 TI - Gas-Phase Hydrogen/Deuterium Exchange of Dinucleotides and 5'-Monophosphate Dinucleotides in a Quadrupole Ion Trap. AB - Gas-phase hydrogen/deuterium (H/D) exchange reactions of four deprotonated dinucleotides (dAA, dAG, dGA, dGG) and their 5'-monophosphate analogs (5'-dAA, 5' dAG, 5'-dGA, 5'-dGG) with D(2)O were performed in a quadrupole ion trap mass spectrometer. Significant differences in the rates and extents of exchange were found when the 5'-hydroxyl group of the dinucleotides was replaced by a phosphate functionality. Extensive and nucleobase-dependent exchange occurred for the deprotonated 5'-monophosphate dinucleotides, whereas the dinucleotides all exhibited essentially the same limited exchange. Results for the isomeric 5' monophosphates, 5'-dAG and 5'-dGA, were remarkably different, indicating that the H/D exchange reaction was sequence dependent. An elaborate array of computations was performed to investigate the gas-phase structures of the ions individually and also as participants in ion-molecule complexes with D(2)O. Integration of the experimental and theoretical results supports a relay exchange mechanism and suggests that the exchange behavior depends highly on the identity and sequence of the nucleobases as well as their ability to interact with the deprotonation site. Finally, a shuttling mechanism is proposed to possibly account for the bimodal H/D exchange behavior observed for deprotonated 5'P-dGA. In this case, hydrogen bonding between the nucleobases in concert with interaction from the deuterating agent creates an ion-molecule complex in which hydrogen and deuterium atoms may be shuttled amongst the hydrogen bonded participants. PMID- 20161398 TI - The Synthesis and X-ray Structural Characterization of mer and fac isomers of the Technetium(I) Nitrosyl Complex [TcCl(2)(NO)(PNPpr)]. AB - The nitrosyl complex H[TcNOCl(4)] reacts with the tridentate ligand bis[(2 diphenylphosphino)propyl]amine (PNPpr) to yield a mixture of the mer or fac isomers of [TcCl(2)(NO)(PNPpr)]. In acetonitrile, where the ligand is freely soluble, reaction occurs at room temperature to yield mostly the mer isomer with the linear nitrosyl ligand cis to the amine ligand; and the phosphine ligands arranged in a mutually trans orientation. The reaction in methanol requires reflux to dissolve the lipophilic ligand and generates the fac isomer of [TcCl2(NO)(PNPpr)] as the major product, with the tridentate ligand in a facial arrangement, leaving the chlorides and nitrosyl ligand in the remaining facial sites. The steric bulk of the tridentate ligand's diphenylphophino- moieties results in a significant distortion from octahedral geometry, with the P-Tc-P bond angle expanded to 99.48(4) degrees . The infrared spectra display absorptions from these nitrosyl ligands in the 1700 and 1800 cm(-1) regions for the fac and mer isomers respectively. The ESI(+) mass spectra each display the parent ion at 647 m/z. PMID- 20161399 TI - Psychiatry of Intellectual and Developmental Disability in the US: Time for a New Beginning. AB - Although psychiatry in the United States owes its origins to the treatment of persons with intellectual disabilities (ID), over the past 50 years, clinical services, education of professionals and research in psychiatry of ID have consistently lagged behind other fields in psychiatry. The historical and contemporary reasons for this development are discussed with recommendations for establishment of a fully credentialed subspecialty of Psychiatry of Intellectual and Developmental Disabilities in the United States. PMID- 20161400 TI - Free classification of American English dialects by native and non-native listeners. AB - Most second language acquisition research focuses on linguistic structures, and less research has examined the acquisition of sociolinguistic patterns. The current study explored the perceptual classification of regional dialects of American English by native and non-native listeners using a free classification task. Results revealed similar classification strategies for the native and non native listeners. However, the native listeners were more accurate overall than the non-native listeners. In addition, the non-native listeners were less able to make use of constellations of cues to accurately classify the talkers by dialect. However, the non-native listeners were able to attend to cues that were either phonologically or sociolinguistically relevant in their native language. These results suggest that non-native listeners can use information in the speech signal to classify talkers by regional dialect, but that their lack of signal independent cultural knowledge about variation in the second language leads to less accurate classification performance. PMID- 20161401 TI - Becoming Irreplaceable: How Comparisons to the Partner's Alternatives Differentially Affect Low and High Self-Esteem People. AB - It is proposed that people are motivated to feel hard to replace in romantic relationships because feeling irreplaceable fosters trust in a partner's continued responsiveness. By contrast, feeling replaceable motivates compensatory behavior aimed at strengthening the partner's commitment to the relationship. A correlational study of dating couples and 2 experiments examined how satiating/thwarting the goal of feeling irreplaceable differentially affects relationship perception and behavior for low and high self-esteem people. The results revealed that satiating the goal of feeling irreplaceable increases trust for people low in self-esteem. In contrast, thwarting the goal of feeling irreplaceable increases compensatory behaviors meant to prove one's indispensability for people high in self-esteem. PMID- 20161402 TI - Self-Protective Changes in Athletic Identity Following Anterior Cruciate Ligament Reconstruction. AB - OBJECTIVES: This study was designed to examine the possibility of self-protective changes in athletic identity (AI) being initiated after the occurrence of a severe injury. METHOD: People (72 men and 36 women) undergoing anterior cruciate ligament (ACL) surgery and rehabilitation were asked to complete a measure of AI prior to surgery and measures of AI and rehabilitation progress at approximately 6, 12, and 24 months after surgery. RESULTS: A repeated-measures ANCOVA controlling for age and gender indicated that AI decreased significantly across the 24-month period following surgery, with the most substantial decline occurring between 6 and 12 months postsurgery. Significantly greater decreases in AI were observed among participants whose rehabilitation progress was slowest from 6 to 12 months postsurgery. CONCLUSIONS: The findings suggest that some participants reduced their identification with the athlete role in response to the threat to a positive self-image posed by their ACL injuries and the difficulties they encountered in postoperative rehabilitation. PMID- 20161403 TI - Photodetectors for Nuclear Medical Imaging. AB - There have been a number of recent advances in photodetector technology, notably in photomultiplier tubes with high quantum efficiency (up to ~50%), hybrid photodetectors, and silicon-based Geiger-mode photodetectors. This paper looks at the potential benefits that these technologies can bring to nuclear medicine, notably SPECT and PET. We find that while the potential benefits to SPECT are relatively small, they can bring performance improvements in many areas for PET. PMID- 20161395 TI - Recent Advances in the Application of Solution NMR Spectroscopy to Multi-Span Integral Membrane Proteins. PMID- 20161404 TI - Syntheses of protoporphyrin-IX derivatives bearing extended propionate side chains. AB - In order to investigate the relationship between depth within membranes of singlet oxygen generation and effectiveness of photodynamic therapy of tumors, analogs of protoporphyrin-IX 1 bearing five 4 and seven 5 carbon atoms (in place of the 3-carbon atom chain in 1) were synthesized from monopyrrole precursors. PMID- 20161405 TI - Future directions in the treatment of HIV-HBV coinfection. AB - Liver disease is a major cause of mortality in individuals with HIV-HBV coinfection. The pathogenesis of liver disease in this setting is unknown, but is likely to involve drug toxicity, infection of hepatic cells with both HIV and HBV, and an altered immune response to HBV. The availability of therapeutic agents that target both HIV and HBV replication enable dual viral suppression, and assessment of chronic hepatitis B is important prior to commencement of antiretroviral therapy. Greater importance is now placed on HBV DNA levels and staging of liver fibrosis, either by liver biopsy or noninvasive measurement, such as transient elastography, since significant liver fibrosis may exist in the presence of normal liver function tests. Earlier treatment of both HIV and HBV is now generally advocated and treatment is usually lifelong. PMID- 20161406 TI - ROMP from ROMP: A New Approach to Graft Copolymer Synthesis. AB - A new strategy is presented for the synthesis of graft copolymers using only the ring-opening metathesis polymerization (ROMP). From a ROMP-derived main chain, pendant maleimide functional groups are converted into norbornene moieties via a Diels-Alder reaction with cyclopentadiene. The norbornene groups serve as sites of initiation, and subsequent ROMP from the main chain yields graft copolymers with both main and side chains derived from ROMP. This strategy offers ready access to defined graft copolymers. PMID- 20161408 TI - Synthesis and characterization of noscapine loaded magnetic polymeric nanoparticles. AB - The delivery of noscapine therapies directly to the site of the tumor would ultimately allow higher concentrations of the drug to be delivered, and prolong circulation time in vivo to enhance the therapeutic outcome of this drug. Therefore, we sought to design magnetic based polymeric nanoparticles for the site directed delivery of noscapine to invasive tumors. We synthesized Fe(3)O(4) nanoparticles with an average size of 10 +/- 2.5 nm. These Fe(3)O(4) NPs were used to prepare noscapine loaded magnetic polymeric nanoparticles (NMNP) with an average size of 252 +/- 6.3 nm. Fourier transform infrared (FT-IR) spectroscopy showed the encapsulation of noscapine on the surface of the polymer matrix. The encapsulation of the Fe(3)O(4) NPs on the surface of the polymer was confirmed by elemental analysis. We studied the drug loading efficiency of polylactide acid (PLLA) and poly (L-lactide acid-co-gylocolide) (PLGA) polymeric systems of various molecular weights. Our findings revealed that the molecular weight of the polymer plays a crucial role in the capacity of the drug loading on the polymer surface. Using a constant amount of polymer and Fe(3)O(4) NPs, both PLLA and PLGA at lower molecule weights showed higher loading efficiencies for the drug on their surfaces. PMID- 20161409 TI - ENZYMATIC POLYMERIZATION OF PHENOLS IN ROOM TEMPERATURE IONIC LIQUIDS. AB - Soybean peroxidase (SBP) was used to catalyze the polymerization of phenols in room-temperature ionic liquids (RTILs). Phenolic polymers with number average molecular weights ranging from 1200 to 4100 D were obtained depending on the composition of the reaction medium and the nature of the phenol. Specifically, SBP was highly active in methylimidazolium-containing RTILs, including 1-butyl-3 methylimidazolium tetrafluoroborate (BMIM(BF(4))), and 1-butyl-3-methylpyridinium tetrafluoroborate (BMPy(BF(4))) with the ionic liquid content as high as 90% (v/v); the balance being aqueous buffer. Gel permeation chromatography and MALDI TOF analysis indicated that higher molecular weight polymers can be synthesized in the presence of higher RTIL concentrations, with selective control over polymer size achieved by varying the RTIL concentration. The resulting polyphenols exhibited high thermostability and possessed thermosetting properties. PMID- 20161410 TI - Synthesis of a quinolone library from ynones. AB - A library of 72 quinolones was synthesized from substituted anthranilic acids, using ynone intermediates. These masked beta-dicarbonyl synthons allowed cyclization under milder conditions than previously reported quinolone syntheses. PMID- 20161407 TI - To fold or not to fold: modulation and consequences of Hsp90 inhibition. AB - BACKGROUND: The 90-kDa heat-shock proteins (Hsp90) have rapidly evolved into promising therapeutic targets for the treatment of several diseases, including cancer and neurodegenerative diseases. Hsp90 is a molecular chaperone that aids in the conformational maturation of nascent polypeptides, as well as the rematuration of denatured proteins. DISCUSSION: Many of the Hsp90-dependent client proteins are associated with cellular growth and survival and, consequently, inhibition of Hsp90 represents a promising approach for the treatment of cancer. Conversely, stimulation of heat-shock protein levels has potential therapeutic applications for the treatment of neurodegenerative diseases that result from misfolded and aggregated proteins. CONCLUSION: Hsp90 modulation exhibits the potential to treat unrelated disease states, from cancer to neurodegenerative diseases, and, thus, to fold or not to fold, becomes a question of great value. PMID- 20161411 TI - High Fidelity Nano-Hole Enhanced Raman Spectroscopy. AB - Surface Enhanced Raman Spectroscopy (SERS) is a sensitive technique that can even detect single molecules. However, in many SERS applications, the strongly inhomogeneous distribution of intense local fields makes it very difficult for a quantitive assessment of the fidelity, or reproducibility of the signal, which limits the application of SERS. Herein we report the development of exceptionally high fidelity Hole-Enhanced Raman Spectroscopy (HERS) from ordered, two dimensional hexagonal nanohole arrays. We take the fidelity f to be a measure of the percent deviation of the Raman peaks from measurement to measurement. Overall, area averaged fidelities for 12 gold array samples ranged from f ~ 2% - 15% for HERS using aqueous R6G molecules. Furthermore, intensity modulations of the enhanced Raman spectra were measured for the first time as a function of polarization angle. The best of these measurements, which focus on static laser spots on the sample, could be consistent with even higher fidelities than the area-averaged results. Nanohole arrays in silver provided supporting polarization measurements and a more complete enhanced Raman fingerprint for phenylalanine molecules. We also carried out finite-difference time-domain calculations to assist in the interpretation of the experiments, identifying the polarization dependence as possibly arising from hole-hole interactions. Our results represent a step towards making quantitative and reproducible enhanced Raman measurements possible and also open new avenues for a large scale source of highly uniform hot spots. PMID- 20161412 TI - Chemical measurements in Drosophila. AB - The fruit fly, Drosophila melanogaster, has been extensively used as a model organism in genetics research and has significantly contributed to understanding molecular, cellular and evolutionary aspects of human behavior. Recently, research has focused on developing analytical methods to obtain highly sensitive chemical quantification along with spatiotemporal information from Drosophila melanogaster. We review a number of these advances in capillary electrophoresis, high-performance liquid chromatography, mass spectrometry and technologies involving intact organisms, including in vivo electrochemistry. PMID- 20161413 TI - A conditional expectation approach for associating ambient air pollutant exposures with health outcomes. AB - Our research focuses on the association between exposure to an airborne pollutant and counts of emergency department visits attributed to a specific chronic illness. The motivating example for this analysis of measurement error in time series studies of air pollution and acute health outcomes was a study of emergency department visits from a 20-county Atlanta metropolitan statistical area from 1993-1999. The research presented illustrates the impact of using various surrogates for unobserved measurements of ambient concentrations at the zip code level. Simulation results indicate that the impact of measurement error on the association between pollutant exposure and a health outcome can be substantial. The proposed conditional expectation approach provided reliable estimates of the association and exhibited good confidence interval coverage for a variety of magnitudes of association. Use of a single-centrally located monitor, the arithmetic average, the nearest-neighbor monitor, and the inverse distance weighted average surrogates resulted in biased estimates and poor coverage rates, especially for larger magnitudes of the association. A focus on obtaining reasonable exposure measurements within clearly defined subregions is important when the pollutant exposure of interest exhibits strong spatial variability. PMID- 20161414 TI - Investigation of Key Factors for Accident Severity at Railroad Grade Crossings by Using a Logit Model. AB - Although several studies have used logit or probit models and their variants to fit data of accident severity on roadway segments, few have investigated accident severity at a railroad grade crossing (RGC). Compared to accident risk analysis in terms of accident frequency and severity of a highway system, investigation of the factors contributing to traffic accidents at an RGC may be more complicated because of additional highway-railway interactions. Because the proportional odds assumption was violated while fitting cumulative logit modeled by the proportional odds models with stepwise variable selection to ordinal accident severity data collected at 592 RGCs in Taiwan, as suggested by Strokes et al. (2000, p. 249) a generalized logit model with stepwise variable selection was used instead to identify explanatory variables (factors or covariates) that were significantly associated with the severity of collisions. Hence, the fitted model was used to predict the level of accident severity, given a set of values in the explanatory variables. Number of daily trains, highway separation, number of daily trucks, obstacle detection device, and approaching crossing markings significantly affected levels of accident severity at an RGC (p-value = 0.0009, 0.0008, 0.0112, 0.0017, and 0.0003, respectively). Finally, marginal effect analysis on the number of daily trains and law enforcement camera was conducted to evaluate the effect of the number of daily trains and presence of a law enforcement camera on the potential accident severity. PMID- 20161415 TI - Separation and Purification of Phenolic Acids and Myricetin from Black Currant by High Speed Countercurrent Chromatography. AB - Black currant is an important material for food industry, but little research has been reported on the isolation of phenolic acids because of their low content. In present study, high-speed countercurrent chromatography (HSCCC) has been successfully used for the preparative isolation of the minor phenolic compounds from the ethyl acetate extracts of black currant fruit. The HSCCC separation was performed with a two-phase solvent system composed of n-hexane/EtOAc/MeOH/H(2)O (5:15:4:7 v/v) at a flow rate of 1.5 mL/min. From 500 mg crude sample 0.8 mg of protocatechuic acid, 1.0 mg of caffeic acid, 0.5 mg of 4-hydroxybenzoic acid and 2.5 mg of myricetin were purified by one-step HSCCC operation,. Their chemical structures were confirmed by MS and NMR. PMID- 20161416 TI - Construction of an N-nitroso database for assessing dietary intake. AB - Dietary N-nitroso compounds are carcinogens synthesized during food processing from two main classes of precursors, oxides of nitrogen and amines or amides. Quantification of the dietary intake of N-nitroso compounds is significant to human cancers, including those of the stomach and upper gastro-intestinal tract, colon, and brain. Previous studies investigating these cancers primarily used proxy estimates of N-nitroso intake and not a full and complete database. In this report, we describe the development of a database to be used in conjunction with a food frequency questionnaire (FFQ) or twenty-four hour dietary records. Published analytical data for N-nitroso compounds were compiled and evaluated for inclusion in the database. The final database consisted of 23 different N-nitroso compounds for 500 foods from 39 different food subgroups. Next, database foods were matched to foods in a standard FFQ by imputation, or calculated value, or assumed zero. Using the FFQ modified with N-nitroso values, we evaluated the ability to compute N-nitroso intakes for a sample of healthy control subjects of cancer epidemiological studies. N-nitroso content of food items ranged from <0.01MUg/100 g. to 142 MUg/100 g and the richest sources were sausage, smoked meats, bacon, and luncheon meats. The database is useful to quantify N-nitroso intake for observational and epidemiological studies. PMID- 20161417 TI - The risk of assimilating? Alcohol use among immigrant and U.S.-born Mexican youth. AB - Rising rates of substance use among Hispanic youth, coupled with substantial growth of this minority group, merit grounds for concern. The process of assimilation is frequently examined in studies of Hispanic substance use and has been cited as a reason for higher rates of substance use by U.S.-born Hispanics, compared to their foreign-born peers. However, many previous studies use individual or unidimensional measures of assimilation, when this term is multifaceted, representing different concepts. The current study addresses this gap by testing the longitudinal effect of different assimilation processes (acculturation as well as structural, spatial, and straight-line assimilation), while simultaneously controlling for important familial and social risk and protective factors on the likelihood of alcohol use among U.S.-born Mexican and Mexican immigrant youth. Results indicate that, although alcohol use is higher among immigrant youth, assimilation measures do not predict alcohol use for immigrants or U.S.-born youth. We conclude that the effects of assimilation may vary by person and place, particularly in ethnic enclaves, and suggest the use of measures that incorporate cultural, personal, social, and environmental factors. PMID- 20161418 TI - Challenges in converting an interviewer-administered food probe database to self administration in the National Cancer Institute Automated Self-administered 24 Hour Recall (ASA24). AB - The National Cancer Institute (NCI) is developing an automated, self-administered 24-hour dietary recall (ASA24) application to collect and code dietary intake data. The goal of the ASA24 development is to create a web-based dietary interview based on the US Department of Agriculture (USDA) Automated Multiple Pass Method (AMPM) instrument currently used in the National Health and Nutrition Examination Survey (NHANES). The ASA24 food list, detail probes, and portion probes were drawn from the AMPM instrument; portion-size pictures from Baylor College of Medicine's Food Intake Recording Software System (FIRSSt) were added; and the food code/portion code assignments were linked to the USDA Food and Nutrient Database for Dietary Studies (FNDDS). The requirements that the interview be self-administered and fully auto-coded presented several challenges as the AMPM probes and responses were linked with the FNDDS food codes and portion pictures. This linking was accomplished through a "food pathway," or the sequence of steps that leads from a respondent's initial food selection, through the AMPM probes and portion pictures, to the point at which a food code and gram weight portion size are assigned. The ASA24 interview database that accomplishes this contains more than 1,100 food probes and more than 2 million food pathways and will include about 10,000 pictures of individual foods depicting up to 8 portion sizes per food. The ASA24 will make the administration of multiple days of recalls in large-scale studies economical and feasible. PMID- 20161419 TI - A New Paradigm for Protein Design and Biological Self-Assembly. AB - Very few molecules with biological origins contain the element fluorine. Nature's inability to incorporate fluorine into biomolecules is related to the low concentration of free fluoride in sea and surface water. However, judicious introduction of fluorine into proteins, nucleic acids, lipids and carbohydrates has allowed mechanistic scrutiny of enzyme catalysis, control of protein oligomerization in membranes, clustered display of ligands on surfaces of living cells, and in increasing the protease stability of protein and peptide therapeutics. PMID- 20161420 TI - Analysis of Retina and Erythrocyte Glycerophospholipid Alterations in a Rat Model of Type 1 Diabetes. AB - An automated tandem mass spectrometry based analysis employing precursor ion and neutral loss scans in a triple quadrupole mass spectrometer has been employed to identify and quantify changes in the abundances of glycerophospholipids extracted from retina and erythrocytes in a rat streptozotocin model of type 1 diabetes, 6 weeks and 36 weeks following induction of diabetes, compared to age matched nondiabetic controls. The utility of an 'internal standard' method compared to an 'internal standard free' method for quantification of differences in the abundances of specific lipid ions was evaluated in both retina and erythrocyte lipid extracts. In retina, equivalent results were obtained by using the internal standard and 'internal standard free' methods for quantification. In erythrocytes, the two methods of analysis yielded significantly different results, suggesting that factors intrinsic to particular sample types may influence the outcome of label-free lipidome quantification approaches.Overall increases (~25% to ~35%) in the abundances of major retina glycerophospholipid classes were demonstrated in rats at 6 weeks of diabetes, relative to control animals. However, at 36 weeks of diabetes, subsequent overall decreases in retina glycerophosphocholine and glycerophosphoethanolamine abundances of 16% and 33%, respectively, were observed. Additionally, retina and erythrocyte glycerophosphocholine lipids at both 6 week and 36 weeks of diabetes exhibited increased incorporation of linoleic acid((18:2n6)) and a decrease in docosahexaenoic acid (DHA((22:6n3))) content. Finally, an approximately 5-fold increase in the abundances of specific glycated glycerophosphoethanolamine (Amadori-GPEtn) lipids were observed in the retina of 36 week diabetic rats, with a corresponding 1.6 fold increase of Amadori-GPEtn lipids in diabetic erythrocytes. PMID- 20161421 TI - Child Effortful Control, Teacher-student Relationships, and Achievement in Academically At-risk Children: Additive and Interactive Effects. AB - The joint contributions of child effortful control (using inhibitory control and task accuracy as behavioral indices) and positive teacher-student relationships at first grade on reading and mathematics achievement at second grade were examined in 761 children who were predominantly from low-income and ethnic minority backgrounds and assessed to be academically at-risk at entry to first grade. Analyses accounted for clustering effects, covariates, baselines of effortful control measures, and prior levels of achievement. Even with such conservative statistical controls, interactive effects were found for task accuracy and positive teacher-student relationships on future achievement. Results suggest that task accuracy served as a protective factor so that children with high task accuracy performed well academically despite not having positive teacher-student relationships. Further, positive teacher-student relationships served as a compensatory factor so that children with low task accuracy performed just as well as those with high task accuracy if they were paired with a positive and supportive teacher. Importantly, results indicate that the influence of positive teacher-student relationships on future achievement was most pronounced for students with low effortful control on tasks that require fine motor skills, accuracy, and attention-related skills. Study results have implications for narrowing achievement disparities for academically at-risk children. PMID- 20161422 TI - Low School Engagement and Sexual Behaviors among African American Youth: Examining the Influences of Gender, Peer Norms, and Gang Involvement. AB - This research examined whether negative peer influences (i.e., norms favoring risky sex and drug use and gang involvement) mediated the relationship between school engagement (i.e., grade point averages [GPAs] obtained from school records and student-teacher connectedness) and sexual behaviors (i.e., sexual debut, sex without condoms, group sex, and sex while using drugs) among African American high school adolescents, and whether these relationships varied by gender. Five hundred sixty-three high school adolescents (ages 13 to 19) completed self administered questionnaires that assessed school engagement markers (GPAs obtained from student records, and student-teacher connectedness), peer influences, sexual debut, and risky sex (sex without condoms, group sex, and sex while using drugs). Major findings for boys indicate that GPA was negatively associated with both sexual debut and risky sex. Additionally, the relationship between student-teacher connectedness and risky sex was mediated by gang involvement. For girls, higher GPAs were associated with fewer norms favoring risky sex and drug use and such norms were associated with sexual debut. Moreover, the relationship between GPA, sexual debut and risky sex was mediated by risky peer norms. Intervention programs to delay sexual debut and reduce risky sex among youths should attend to the gendered ways through which such behaviors occur. PMID- 20161423 TI - Calculation of Double-Quantum-Coherence Two-dimensional Spectra: Distance Measurements and Orientational Correlations. AB - The double quantum coherence (DQC) echo signal for two coupled nitroxides separated by distances ?10 A, is calculated rigorously for the six-pulse sequence. Successive application of six pulses on the initial density matrix, with appropriate inter-pulse time evolution and coherence pathway selection leaves only the coherent pathways of interest. The amplitude of the echo signal following the last pi pulse can be used to obtain a one-dimensional dipolar spectrum (Pake doublet), and the echo envelope can be used to construct the two dimensional DQC spectrum. The calculations are carried out using the product space spanned by the two electron-spin magnetic quantum numbers m(1), m(2) and the two nuclear-spin magnetic quantum numbers M(1), M(2), describing e.g. two coupled nitroxides in bilabeled proteins. The density matrix is subjected to a cascade of unitary transformations taking into account dipolar and electron exchange interactions during each pulse and during the evolution in the absence of a pulse. The unitary transformations use the eigensystem of the effective spin Hamiltonians obtained by numerical matrix diagonalization. Simulations are carried out for a range of dipolar interactions, D, and microwave magnetic field strength B for both fixed and random orientations of the two (14)N (and (15)N) nitroxides. Relaxation effects were not included. Several examples of one- and two-dimensional Fourier transforms of the time domain signals vs. dipolar evolution and spin-echo envelope time variables are shown for illustration. Comparisons are made between 1D rigorous simulations and analytical approximations. The rigorous simulations presented here provide insights into DQC ESR spectroscopy, they serve as a standard to evaluate the results of approximate theories, and they can be employed to plan future DQC experiments. PMID- 20161424 TI - Substance Use and Substance Use Disorders as Foster Youth Transition to Adulthood. PMID- 20161425 TI - Gastrointestinal Emergency Room Admissions and Florida Red Tide Blooms. AB - Human exposure to brevetoxins during Florida red tide blooms formed by Karenia brevis has been documented to cause acute gastrointestinal, neurologic, and respiratory health effects.. Traditionally, the routes of brevetoxin exposure have been through the consumption of contaminated bivalve shellfish and the inhalation of contaminated aerosols. However, recent studies using more sensitive methods have demonstrated the presence of brevetoxins in many components of the aquatic food web which may indicate potential alternative routes for human exposure.This study examined whether the presence of a Florida red tide bloom affected the rates of admission for a gastrointestinal diagnosis to a hospital emergency room in Sarasota, FL. The rates of gastrointestinal diagnoses admissions were compared for a 3-month time period in 2001 when Florida red tide bloom was present onshore to the same 3-month period in 2002 when no Florida red tide bloom occurred. A significant 40% increase in the total number of gastrointestinal emergency room admissions for the Florida red tide bloom period was found compared to the non red tide period.These results suggest that the healthcare community may experience a significant and unrecognized impact from patients needing emergency medical care for gastrointestinal illnesses during Florida red tide blooms. Thus, additional studies characterizing the potential sources of exposure to the toxins, as well as the dose/effect relationship of brevetoxin exposure, should be undertaken. PMID- 20161426 TI - The Relationship of Place to Substance use and Perceptions of Risk and Safety in Urban Adolescents. PMID- 20161427 TI - Enantioselective synthesis of Bakuchiol using diazosulfonate C-H insertion to install the quaternary center. AB - Bakuchiol was prepared from commercial (-)-citronellol using the diazosulfonate C H insertion to control the regioselectivity and install the quaternary center. PMID- 20161428 TI - A Note on the Existence of the Posteriors for One-way Random Effect Probit Models. AB - The existence of the posterior distribution for one-way random effect probit models has been investigated when the uniform prior is applied to the overall mean and a class of noninformative priors are applied to the variance parameter. The sufficient conditions to ensure the propriety of the posterior are given for the cases with replicates at some factor levels. It is shown that the posterior distribution is never proper if there is only one observation at each factor level. For this case, however, a class of proper priors for the variance parameter can provide the necessary and sufficient conditions for the propriety of the posterior. PMID- 20161429 TI - Stepfamily Formation: Implications for Adolescent Ties to Mothers, Nonresident Fathers, and Stepfathers. AB - This study examines how the entrance of a stepfather influences adolescent ties to mothers and nonresident fathers, and how prior ties to each biological parent influences the development of stepfather-stepchild ties. Data come from 1753 adolescents in the National Longitudinal Study of Adolescent Health who lived with a single mother in Wave 1 that remained single, cohabited, or married by Wave 2, approximately one year later. Stepfamily formation had little consequence for adolescent-nonresident father ties. Adolescent-mother closeness, however, declined when cohabiting, but not married, stepfathers entered the household. Close ties to married stepfathers were more likely to develop when adolescents were closer to their mothers before stepfather entry. Prior ties to nonresident fathers were unrelated to stepfather-stepchild ties. PMID- 20161430 TI - Alpha, Dimension-Free, and Model-Based Internal Consistency Reliability. AB - As pointed out by Sijtsma (in press), coefficient alpha is inappropriate as a single summary of the internal consistency of a composite score. Better estimators of internal consistency are available. In addition to those mentioned by Sijtsma, an old dimension-free coefficient and structural equation model based coefficients are proposed to improve the routine reporting of psychometric internal consistency. The various ways to measure internal consistency are also shown to be appropriate to binary and polytomous items. PMID- 20161431 TI - THE MECHANISM OF LESION FORMATION BY FOCUSED ULTRASOUND ABLATION CATHETER FOR TREATMENT OF ATRIAL FIBRILLATION. AB - The application of therapeutic ultrasound for the treatment of atrial fibrillation (AF) is investigated. The results of theoretical and experimental investigation of ultrasound ablation catheter are presented. The major components of the catheter are the high power cylindrical piezoelectric element and parabolic balloon reflector. Thermal elevation in the ostia of pulmonary veins is achieved by focusing the ultrasound beam in shape of a torus that transverses the myocardial tissue. High intensity ultrasound heating in the focal zone results in a lesion surrounding the pulmonary veins that creates an electrical conduction blocks and relief from AF symptoms. The success of the ablation procedure largely depends on the correct choice of reflector geometry and ultrasonic power. We present a theoretical model of the catheter's acoustic field and bioheat transfer modeling of cardiac lesions. The application of an empirically derived relation between lesion formation and acoustic power is shown to correlate with the experimental data. Developed control methods combine the knowledge of theoretical acoustics and the thermal lesion formation simulations with experiment and thereby establish rigorous dosimetry that contributes to a safe and effective ultrasound ablation procedure. PMID- 20161432 TI - Bifunctional Asymmetric Catalysis with Hydrogen Chloride: Enantioselective Ring Opening of Aziridines Catalyzed by a Phosphinothiourea. AB - Ring-opening of aziridines with hydrogen chloride to form beta-chloroamine derivatives is catalyzed by a chiral phosphinothiourea derivative in high yields and with high enantioselectivities. On the basis of (31)P NMR studies, activation of HCl appears to proceed via quantitative protonation of the catalyst to afford a phosphonium chloride complex. PMID- 20161433 TI - "Stains" on their self-discipline: Public health, hygiene, and the disciplining of undocumented immigrant parents in the nation's internal borderlands. AB - Histories of the role of public health in nation building have revealed the centrality of hygiene to eugenic mechanisms of racial exclusion in the turn-of the-20th-century United States, yet little scholarship has examined its role in the present day. Through ethnography in a Mexican migrant farmworking community in California's Central Valley, we explore the role of oral-hygiene campaigns in racializing Mexican immigrant parents and shaping the substance of their citizenship. Public health officials perceive migrant farmworkers' children's oral disease as a "stain of backwardness," amplifying Mexican immigrants' status as "aliens." We suggest, however, that the recent concern with Mexican immigrant children's oral health blends classic eugenic concerns in public health with neoliberal concerns regarding different immigrant groups' capacity for self governance. PMID- 20161435 TI - Electrochemical reduction of silver vanadium phosphorous oxide, Ag(2)VO(2)PO(4): the formation of electrically conductive metallic silver nanoparticles. AB - As a cathode material, silver vanadium phosphorous oxide (Ag(2)VO(2)PO(4)) displays several notable electrochemical properties: large capacity, high current capability, and an effective delivery of high current pulses. These cell performance characteristics can be attributed to the presence of silver nanoparticles formed in-situ during the electrochemical reduction of Ag(2)VO(2)PO(4). Specifically, changes in the composition and structure of Ag(2)VO(2)PO(4) with reduction, especially the formation of silver nanoparticles, are detailed to rationalize a 15,000 fold increase in conductivity with initial discharge, which can be related to the power characteristics associated with Ag(2)VO(2)PO(4) cathodes in primary lithium batteries. PMID- 20161434 TI - Lessening Homelessness Among Persons with Mental Illness: A Comparison of Five Randomized Treatment Trials. AB - We evaluate the influence of housing, services, and individual characteristics on housing loss among formerly homeless mentally ill persons who participated in a five-site (4-city) study in the U.S. Housing and service availability were manipulated within randomized experimental designs and substance abuse and other covariates were measured with a common protocol. Findings indicate that housing availability was the primary predictor of subsequent ability to avoid homelessness, while enhanced services reduced the risk of homelessness if housing was also available. Substance abuse increased the risk of housing loss in some conditions in some projects, but specific findings differed between projects and with respect to time spent in shelters and on the streets. We identify implications for research on homeless persons with mental illness that spans different national and local contexts and involves diverse ethnic groups. PMID- 20161436 TI - An old dog learns new tricks: novel functions of the exocyst complex in polarized epithelia in animals. AB - The role of the exocyst complex has been studied mainly in the context of basolateral sorting of cargos in polarized cells. Recent developments indicate an extended yet specific function of the exocyst in the outgrowth of the primary cilium from the apical membrane, thereby highlighting a role for the exocyst in ensuring membrane trafficking to important signaling stations in the cell, the tight junctions, and the cilia. PMID- 20161437 TI - Estimation of Transitional Probabilities of Discrete Event Systems from Cross Sectional Survey and its Application in Tobacco Control. AB - In order to find better strategies for tobacco control, it is often critical to know the transitional probabilities among various stages of tobacco use. Traditionally, such probabilities are estimated by analyzing data from longitudinal surveys that are often time-consuming and expensive to conduct. Since cross-sectional surveys are much easier to conduct, it will be much more practical and useful to estimate transitional probabilities from cross-sectional survey data if possible. However, no previous research has attempted to do this. In this paper, we propose a method to estimate transitional probabilities from cross-sectional survey data. The method is novel and is based on a discrete event system framework. In particular, we introduce state probabilities and transitional probabilities to conventional discrete event system models. We derive various equations that can be used to estimate the transitional probabilities. We test the method using cross-sectional data of the National Survey on Drug Use and Health. The estimated transitional probabilities can be used in predicting the future smoking behavior for decision-making, planning and evaluation of various tobacco control programs. The method also allows a sensitivity analysis that can be used to find the most effective way of tobacco control. Since there are much more cross-sectional survey data in existence than longitudinal ones, the impact of this new method is expected to be significant. PMID- 20161438 TI - Synthesis of labeled meropenem for the analysis of M. tuberculosis transpeptidases. AB - A concise synthesis of (14)C labeled meropenem prepared from (14)C dimethylamine hydrochloride is described. Using a similar reaction sequence, the meropenem nucleus was also attached to biotin providing a probe for protein interaction studies. PMID- 20161439 TI - Biomedical applications of chemically-modified silk fibroin. AB - Silk proteins belong to a class of unique, high molecular weight, block copolymer like proteins that have found widespread use in biomaterials and regenerative medicine. The useful features of these proteins, including self-assembly, robust mechanical properties, biocompatibility and biodegradability can be enhanced through a variety of chemical modifications. These modifications provide chemical handles for the attachment of growth factors, cell binding domains and other polymers to silk, expanding the range of cell and tissue engineering applications attainable. This review focuses on the chemical reactions that have been used to modify the amino acids in silk proteins, and describes their utility in biomedical applications. PMID- 20161440 TI - Genetic Basis of Antifungal Drug Resistance. AB - Antifungal resistance caused by mutations of the drug target, overexpression of the drug target, and drug efflux by the upregulation of transporters is increasingly common. Recently our understanding of fungal drug resistance has been advanced by the identification of three key transcriptional regulators of resistance: Tac1p, Upc2p, and Mrr1p. The discovery of hyperactive variants of these regulators in resistant clinical isolates confirms the importance of transcriptional regulation in the development of antifungal resistance. Alternative mechanisms of drug resistance including aneuploidy and biofilm formation have recently been documented in fungi; as well as the phenomenon of drug tolerance. Characterization of the transcriptional regulation of fungal drug resistance and the identification of novel mechanisms of resistance has implications for current therapy and for the development of future antifungal drugs. PMID- 20161442 TI - Reply. PMID- 20161441 TI - Anxiety disorders in children with williams syndrome, their mothers, and their siblings: implications for the etiology of anxiety disorders. AB - PURPOSE: To determine the prevalence of anxiety disorders in children with Williams syndrome (WS), their sibling closest in age, and their mothers and to examine the predictors of anxiety in these groups. METHODS: The prevalence of anxiety disorders was assessed and compared to that in the general population. RESULTS: Children with WS had a significantly higher prevalence of specific phobia, generalized anxiety disorder (GAD), and separation anxiety in comparison to children in the general population. While mothers had a higher prevalence of GAD than population controls, the excess was accounted for by mothers who had onset after the birth of their WS child. The siblings had rates similar to the general population. CONCLUSIONS: This pattern of findings suggests the presence of a gene in the WS region whose deletion predisposes to anxiety disorders. It is also worthwhile to investigate relations between genes deleted in WS and genes previously implicated in anxiety disorders. PMID- 20161443 TI - mGluR4-positive allosteric modulation as potential treatment for Parkinson's disease. AB - Although Parkinson's disease was first diagnosed nearly 200 years ago, its effective treatment still remains elusive for most of those diagnosed. The gold standard of treatment for most patients is 3,4-dihydroxy-L-phenylalanine. This drug works for most individuals early in the disease; however, resistant symptoms start to emerge after several years of treatment. There has been increased interest in finding novel therapies to help Parkinson's disease patients. Such strategies may have the benefit of not only treating the symptomatic issues of the disorder, but might also offer promise in protecting dopaminergic neurons from further degeneration. One such target that is now receiving much attention from the scientific community is the metabotropic glutamate receptor mGluR4. In this article, we briefly review Parkinson's disease and then recent work in the mGluR area, with a focus on the efforts being made toward finding and optimizing novel mGluR4 positive allosteric modulators (PAMs). Preclinically in rodent models, mGluR4 activation has offered much promise as a novel treatment of Parkinson's disease. Additionally, the specific use of PAMs, rather than direct acting agonists at the orthosteric glutamate site, continues to be validated as a viable treatment option for this target. It is anticipated that continued progress in this area will further our understanding of the potential of mGluR4 modulation as a novel symptomatic and potentially disease-modifying treatment for Parkinson's disease. PMID- 20161445 TI - Articulation rate across dialect, age, and gender. AB - The understanding of sociolinguistic variation is growing rapidly, but basic gaps still remain. Whether some languages or dialects are spoken faster or slower than others constitutes such a gap. Speech tempo is interconnected with social, physical and psychological markings of speech. This study examines regional variation in articulation rate and its manifestations across speaker age, gender and speaking situations (reading vs. free conversation). The results of an experimental investigation show that articulation rate differs significantly between two regional varieties of American English examined here. A group of Northern speakers (from Wisconsin) spoke significantly faster than a group of Southern speakers (from North Carolina). With regard to age and gender, young adults read faster than older adults in both regions; in free speech, only Northern young adults spoke faster than older adults. Effects of gender were smaller and less consistent; men generally spoke slightly faster than women. As the body of work on the sociophonetics of American English continues to grow in scope and depth, we argue that it is important to include fundamental phonetic information as part of our catalog of regional differences and patterns of change in American English. PMID- 20161444 TI - Lymphocyte-bound complement activation products as biomarkers for diagnosis of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is frequently misdiagnosed due to the lack of definitive diagnostic tests. The purpose of this study was to determine specifically whether complement activation products (CAP) are deposited on lymphocytes of SLE patients and whether lymphocyte-bound CAP (LB-CAP) may serve as novel biomarkers for the diagnosis of SLE. We conducted a cross-sectional study of 224 patients with SLE, 179 patients with other diseases, and 114 healthy controls. LB-CAP on peripheral blood lymphocytes was measured by flow cytometry. Diagnostic utility of LB-CAP was determined by receiver operating characteristic (ROC) analysis. Significantly elevated levels of C4d and C3d were detected specifically on T and B lymphocytes (designated T-C4d, T-C3d, B-C4d, and B-C3d) of SLE patients. As diagnostic tools, T-C4d and B-C4d, respectively, were 56% sensitive/80% specific and 60% sensitive/82% specific in differentiating SLE from other diseases. Moreover, compared with measurement of anti-dsDNA, serum C3, or serum C4, measurement of T-C4d/B-C4d was significantly more sensitive in identifying SLE patients during a single clinic visit. This is the first investigation of lymphocytes bearing complement activation products in human disease. T-C4d and B-C4d have high diagnostic sensitivity and specificity for SLE and may have added value to current laboratory tests for SLE diagnosis. PMID- 20161447 TI - Toward Kuleana (Responsibility): A Case Study of a Contextually Grounded Intervention for Native Hawaiian Youth and Young Adults. AB - As a minority ethnic group, Native Hawaiian youth and young adults face an array of issues associated with colonization, such as persistent structural discrimination and the loss of land and indigenous ways of knowing. They are also at risk for a wide range of negative behaviors, including interpersonal violence, suicide, substance use, and juvenile delinquency. This article explores how community youth development, critical pedagogies, and Hawaiian epistemology can help Native Hawaiian young adults cope with such issues. It begins with a brief discussion of critiques on conventional youth violence prevention programs. To address these critiques, three bodies of literature are introduced: 1) community youth development, 2) critical pedagogy, and 3) community epistemology. Data were derived from a single case study of a community-based youth program. The program, located in an impoverished, rural community in Hawai'i, entailed running an organic farm. Seventeen participants were involved in the study. Semi-structured interviews were used to collect data. Utilizing critical indigenous qualitative research, a content analysis of the interviews was conducted to build a working conceptual model. Preliminary findings suggest that a program with key processes of community youth development, critical pedagogies, and Hawaiian epistemology may serve as a vehicle for health and wellness, thus preventing a host of negative behaviors, such as violence. Based on the findings, a critical contextually based approach to violence prevention that focuses on providing opportunities for Native Hawaiian young adults to take an active participatory role in promoting health is proposed. PMID- 20161446 TI - Chemical and Biochemical Basis of Cell-Bone Matrix Interaction in Health and Disease. AB - Bone, a calcified tissue composed of 60% inorganic component (hydroxyapatite), 10% water and 30% organic component (proteins), has three functions: providing mechanical support for locomotion, protecting vital organs, and regulating mineral homeostasis. A lifelong execution of these functions depends on a healthy skeleton, which is maintained by constant bone remodeling in which old bone is removed by the bone-resorbing cell, osteoclasts, and then replaced by new bone formed by the bone-forming cell, osteoblasts. This remodeling process requires a physical interaction of bone with these bone cells. Moreover, numerous cancers including breast and prostate have a high tendency to metastasize to bone, which is in part attributable to the capacity of the tumor cells to attach to bone. The intensive investigation in the past two decades has led to the notion that the cell-bone interaction involves integrins on cell surface and bone matrix proteins. However, the biochemical composition of bone and emerging evidence are inconsistent with this belief. In this review, I will discuss the current understanding of the molecular mechanism underlying the cell-bone interaction. I will also highlight the facts and new findings supporting that the inorganic, rather than the organic, component of bone is likely responsible for cellular attachment. PMID- 20161448 TI - Adolescents with Nonresident Fathers: Are Daughters more Disadvantaged than Sons? AB - This study examined sons' and daughters' involvement with nonresident fathers and associated outcomes (N=4,663). Results indicate that sons and daughters report equal involvement with nonresident fathers on most measures of father investment, although sons report more overnight visits, sports, and movies, and feeling closer to their fathers compared to daughters. Sons and daughters generally benefit from nonresident father involvement in the same way in internalizing and externalizing problems and grades. However, feeling close to one's nonresident father is associated with lower internalizing problems for daughters than sons. These findings suggest that nonresident fathers should be encouraged to be equally involved with their sons and daughters, as such involvement is associated with higher levels of well-being for both sons and daughters. PMID- 20161449 TI - DEVELOPMENT AND EVALUATION OF VISION MULTIPLEXING DEVICES FOR VISION IMPAIRMENTS. AB - We have proposed a novel concept of vision multiplexing for the visually impaired - superimposing contour images over their natural view of a scene or over original images presented on a TV screen. We have implemented the concept using an optical see-through head mounted display to provide either visual field expansion to patients with peripheral field loss or vision enhancement to patients with central vision loss. We have also implemented the concept in a video player with dynamic magnification for patients with central vision loss. Results of initial testing in the lab and on the street are promising. PMID- 20161450 TI - ANALYSIS OF FLOW-STRUCTURE COUPLING IN A MECHANICAL MODEL OF THE VOCAL FOLDS AND THE SUBGLOTTAL SYSTEM. AB - An analysis is made of the nonlinear interactions between flow in the subglottal vocal tract and glottis, sound waves in the subglottal system and a mechanical model of the vocal folds. The mean flow through the system is produced by a nominally steady contraction of the lungs, and mechanical experiments frequently involve a 'lung cavity' coupled to an experimental subglottal tube of arbitrary or ill-defined effective length L, on the basis that the actual value of L has little or no influence on excitation of the vocal folds. A simple, self-exciting single mass mathematical model of the vocal folds is used to investigate the sound generated within the subglottal domain and the unsteady volume flux from the glottis for experiments where it is required to suppress feedback of sound from the supraglottal vocal tract. In experiments where the assumed absorption of sound within the sponge-like interior of the lungs is small, the influence of changes in L can be very significant: when the subglottal tube behaves as an open ended resonator (when L is as large as half the acoustic wavelength) there is predicted to be a mild increase in volume flux magnitude and a small change in waveform. However, the strong appearance of second harmonics of the acoustic field is predicted at intermediate lengths, when L is roughly one quarter of the acoustic wavelength. In cases of large lung damping, however, only modest changes in the volume flux are predicted to occur with variations in L. PMID- 20161451 TI - Quantifying Correlations Between Allosteric Sites in Thermodynamic Ensembles. AB - Allostery describes altered protein function at one site due to a perturbation at another site. One mechanism of allostery involves correlated motions, which can occur even in the absence of substantial conformational change. We present a novel method, "MutInf", to identify statistically significant correlated motions from equilibrium molecular dynamics simulations. Our approach analyzes both backbone and sidechain motions using internal coordinates to account for the gear like twists that can take place even in the absence of the large conformational changes typical of traditional allosteric proteins. We quantify correlated motions using a mutual information metric, which we extend to incorporate data from multiple short simulations and to filter out correlations that are not statistically significant. Applying our approach to uncover mechanisms of cooperative small molecule binding in human interleukin-2, we identify clusters of correlated residues from 50 ns of molecular dynamics simulations. Interestingly, two of the clusters with the strongest correlations highlight known cooperative small-molecule binding sites and show substantial correlations between these sites. These cooperative binding sites on interleukin-2 are correlated not only through the hydrophobic core of the protein but also through a dynamic polar network of hydrogen bonding and electrostatic interactions. Since this approach identifies correlated conformations in an unbiased, statistically robust manner, it should be a useful tool for finding novel or "orphan" allosteric sites in proteins of biological and therapeutic importance. PMID- 20161452 TI - Application of Multiplexed Replica Exchange Molecular Dynamics to the UNRES Force Field: Tests with alpha and alpha+beta Proteins. AB - The replica exchange (RE) method is increasingly used to improve sampling in molecular dynamics (MD) simulations of biomolecular systems. Recently, we implemented the united-residue UNRES force field for mesoscopic MD. Initial results from UNRES MD simulations show that we are able to simulate folding events that take place in a microsecond or even a millisecond time scale. To speed up the search further, we applied the multiplexing replica exchange molecular dynamics (MREMD) method. The multiplexed variant (MREMD) of the RE method, developed by Rhee and Pande, differs from the original RE method in that several trajectories are run at a given temperature. Each set of trajectories run at a different temperature constitutes a layer. Exchanges are attempted not only within a single layer but also between layers. The code has been parallelized and scales up to 4000 processors. We present a comparison of canonical MD, REMD, and MREMD simulations of protein folding with the UNRES force-field. We demonstrate that the multiplexed procedure increases the power of replica exchange MD considerably and convergence of the thermodynamic quantities is achieved much faster. PMID- 20161453 TI - A New Analytic Framework for Moderation Analysis --- Moving Beyond Analytic Interactions. AB - Conceptually, a moderator is a variable that modifies the effect of a predictor on a response. Analytically, a common approach as used in most moderation analyses is to add analytic interactions involving the predictor and moderator in the form of cross-variable products and test the significance of such terms. The narrow scope of such a procedure is inconsistent with the broader conceptual definition of moderation, leading to confusion in interpretation of study findings. In this paper, we develop a new approach to the analytic procedure that is consistent with the concept of moderation. The proposed framework defines moderation as a process that modifies an existing relationship between the predictor and the outcome, rather than simply a test of a predictor by moderator interaction. The approach is illustrated with data from a real study. PMID- 20161454 TI - Turning the knots in your stomach into bows: Reappraising arousal improves performance on the GRE. AB - This research examined the benefits of interpreting physiological arousal as a challenge response on practice and actual Graduate Record Examination (GRE) scores. Participants who were preparing to take the GRE reported to the laboratory for a practice GRE study. Participants assigned to a reappraisal condition were told arousal improves performance, whereas control participants were not given this information. We collected saliva samples at baseline and after the appraisal manipulation, which were then assayed for salivary alpha amylase (sAA), a measure of sympathetic nervous system activation. Reappraisal participants exhibited a significant increase in sAA and outperformed controls on the GRE-math section. One to three months later, participants returned to the lab and provided their score reports from their actual GRE. Again, reappraisal participants scored higher than controls on the GRE-math section. These findings illuminate the powerful influence appraisal has on physiology and performance both in and out of the laboratory. PMID- 20161457 TI - Hearsay Ethnography: Conversational Journals as a Method for Studying Culture in Action. AB - Social scientists have long struggled to develop methods adequate to their theoretical understanding of meaning as collective and dynamic. While culture is widely understood as an emergent property of collectivities, the methods we use keep pulling us back towards interview-situated accounts and an image of culture as located in individual experience. Scholars who seek to access supra-individual semiotic structures by studying public rituals and other collectively-produced texts then have difficulty capturing the dynamic processes through which such meanings are created and changed in situ. To try to capture more effectively the way meaning is produced and re-produced in everyday life, we focus here on conversational interactions-the voices and actions that constitute the relational space among actors. Conversational journals provide us with a method: the analysis of texts produced by cultural insiders who keep journals of who-said what-to-whom in conversations they overhear or events they participate in during the course of their daily lives. We describe the method, distinguishing it from other approaches and noting its drawbacks. We then illustrate the methodological advantages of conversational journals with examples from our texts. We end with a discussion of the method's potential in our setting as well as in other places and times. PMID- 20161456 TI - Psychosocial Interventions for Bipolar Disorder: Perspective from the Behavioral Approach System (BAS) Dysregulation Theory. AB - Research has emerged providing consistent support for the behavioral approach system (BAS) dysregulation theory of bipolar disorder. The objective of the current article is to examine the extent to which findings from the BAS dysregulation theory can inform psychosocial interventions for bipolar disorder. Towards this end, we first provide an overview of the BAS dysregulation theory. Second, we review extant research on psychosocial interventions for bipolar disorder. And, third, we discuss means by which research and theory in line with the BAS dysregulation model can inform psychosocial interventions for bipolar disorder. Particular attention is given to the clinical implications of research suggesting that bipolar disorder is characterized by high drive/incentive motivation, ambitious goal-setting, and perfectionism in the achievement domain. PMID- 20161458 TI - 'Teach a Man to Fish': The Doctrine of Sustainability and Its Effects on Three Strata of Malawian Society. AB - This paper analyzes the social impacts of the commitment to "sustainability" in donor-funded AIDS programs. Using survey, interview, and ethnographic data from rural Malawi, we examine how efforts to mobilize and empower local communities affect three strata of Malawian society: the villagers these programs are meant to help, the insecure local elites whose efforts directly link programs to their intended beneficiaries, and, more briefly, national elites who implement AIDS policies and programs. We describe indirect effects of sustainability on the experiences, identities, and aspirations of Malawians-effects that are much broader and deeper than the direct impacts of funding. PMID- 20161459 TI - Naturopathic Treatment of Obesity. PMID- 20161460 TI - An examination of Bayesian statistical approaches to modeling change in cognitive decline in an Alzheimer's disease population. AB - The mini mental state examination (MMSE) is a common tool for measuring cognitive decline in Alzhiemer's Disease (AD) subjects. Subjects are usually observed for a specified period of time or until death to determine the trajectory of the decline which for the most part appears to be linear. However, it may be noted that the decline may not be modeled by a single linear model over a specified period of time. There may be a point called a change point where the rate or gradient of the decline may change depending on the length of time of observation. A Bayesian approach is used to model the trajectory and determine an appropriate posterior estimate of the change point as well as the predicted model of decline before and after the change point. Estimates of the appropriate parameters as well as their posterior credible regions or regions of interest are established. Coherent prior to posterior analysis using mainly non informative priors for the parameters of interest is provided. This approach is applied to an existing AD database. PMID- 20161461 TI - Spatial and Temporal Variations in Traffic-related Particulate Matter at New York City High Schools. AB - Relatively little is known about exposures to traffic-related particulate matter at schools located in dense urban areas. The purpose of this study was to examine the influences of diesel traffic proximity and intensity on ambient concentrations of fine particulate matter (PM(2.5)) and black carbon (BC), an indicator of diesel exhaust particles, at New York City (NYC) high schools. Outdoor PM(2.5) and BC were monitored continuously for 4-6 weeks at each of 3 NYC schools and 1 suburban school located 20 kilometers upwind of the city. Traffic count data were obtained using an automated traffic counter or video camera. BC concentrations were 2-3 fold higher at urban schools compared with the suburban school, and among the 3 urban schools, BC concentrations were higher at schools located adjacent to highways. PM(2.5) concentrations were significantly higher at urban schools than at the suburban school, but concentrations did not vary significantly among urban schools. Both hourly average counts of trucks and buses and meteorological factors such as wind direction, wind speed, and humidity were significantly associated with hourly average ambient BC and PM(2.5) concentrations in multivariate regression models. An increase of 443 trucks/buses per hour was associated with a 0.62 mug/m(3) increase in hourly average BC at a NYC school located adjacent to a major interstate highway. Car traffic counts were not associated with BC. The results suggest that local diesel vehicle traffic may be important sources of airborne fine particles in dense urban areas and consequently may contribute to local variations in PM(2.5) concentrations. In urban areas with higher levels of diesel traffic, local, neighborhood-scale monitoring of pollutants such as BC, which compared to PM(2.5), is a more specific indicator of diesel exhaust particles, may more accurately represent population exposures. PMID- 20161462 TI - Accuracy and run-time comparison for different potential approaches and iterative solvers in finite element method based EEG source analysis. AB - Accuracy and run-time play an important role in medical diagnostics and research as well as in the field of neuroscience. In Electroencephalography (EEG) source reconstruction, a current distribution in the human brain is reconstructed noninvasively from measured potentials at the head surface (the EEG inverse problem). Numerical modeling techniques are used to simulate head surface potentials for dipolar current sources in the human cortex, the so-called EEG forward problem.In this paper, the efficiency of algebraic multigrid (AMG), incomplete Cholesky (IC) and Jacobi preconditioners for the conjugate gradient (CG) method are compared for iteratively solving the finite element (FE) method based EEG forward problem. The interplay of the three solvers with a full subtraction approach and two direct potential approaches, the Venant and the partial integration method for the treatment of the dipole singularity is examined. The examination is performed in a four-compartment sphere model with anisotropic skull layer, where quasi-analytical solutions allow for an exact quantification of computational speed versus numerical error. Specifically-tuned constrained Delaunay tetrahedralization (CDT) FE meshes lead to high accuracies for both the full subtraction and the direct potential approaches. Best accuracies are achieved by the full subtraction approach if the homogeneity condition is fulfilled. It is shown that the AMG-CG achieves an order of magnitude higher computational speed than the CG with the standard preconditioners with an increasing gain factor when decreasing mesh size. Our results should broaden the application of accurate and fast high-resolution FE volume conductor modeling in source analysis routine. PMID- 20161463 TI - Electron transfer-induced blinking in Ag nanodot fluorescence. AB - Various single-standed DNA-encapsulated Ag nanoclusters (nanodots) exhibit strong, discrete fluorescence with solvent polarity-dependent absorption and emission throughout the visible and near-IR. All species examined, regardless of their excitation and emission energies, show similar us single-molecule blinking dynamics and near IR transient absorptions. The polarity dependence, usec blinking, and indistinguishable usec-decaying transient absorption spectra for multiple nanodots suggest a common charge transfer-based mechanism that gives rise to nanodot fluorescence intermittency. Photoinduced charge transfer that is common to all nanodot emitters is proposed to occur from the Ag cluster into the nearby DNA bases to yield a long-lived charge-separated trap state that results in blinking on the single molecule level. PMID- 20161464 TI - Efficient Semiparametric Marginal Estimation for the Partially Linear Additive Model for Longitudinal/Clustered Data. AB - We consider the efficient estimation of a regression parameter in a partially linear additive nonparametric regression model from repeated measures data when the covariates are multivariate. To date, while there is some literature in the scalar covariate case, the problem has not been addressed in the multivariate additive model case. Ours represents a first contribution in this direction. As part of this work, we first describe the behavior of nonparametric estimators for additive models with repeated measures when the underlying model is not additive. These results are critical when one considers variants of the basic additive model. We apply them to the partially linear additive repeated-measures model, deriving an explicit consistent estimator of the parametric component; if the errors are in addition Gaussian, the estimator is semiparametric efficient. We also apply our basic methods to a unique testing problem that arises in genetic epidemiology; in combination with a projection argument we develop an efficient and easily computed testing scheme. Simulations and an empirical example from nutritional epidemiology illustrate our methods. PMID- 20161465 TI - An Implicit Measure of Anti-Gay Attitudes: Prospective Associations with Emotion Regulation Strategies and Psychological Distress. AB - Members of stigmatized groups are at increased risk for mental health problems, and recent research has suggested that emotion dysregulation may be one mechanism explaining the stigma-distress association. However, little is known regarding characteristics that predict vulnerabilities to emotion dysregulation and subsequent distress. We examined whether anti-gay attitudes would predict poorer emotion regulation and greater psychological distress in 31 lesbian, gay, and bisexual (LGB) respondents. Respondents completed implicit and explicit attitude measures at baseline, and participated in an experience sampling study examining stigma-related stressors, emotion regulation strategies, and mood over the course of ten days. Implicit and explicit attitude measures were not correlated. LGB respondents with greater implicit anti-gay attitudes engaged in significantly more rumination and suppression and reported more psychological distress. Rumination fully mediated the prospective association between implicit prejudicial attitudes and psychological distress, and suppression was a marginally significant mediator. PMID- 20161466 TI - Sequence-dependent gelation kinetics of beta-hairpin peptide hydrogels. AB - The gelation kinetics of four beta-hairpin oligopeptides that have been designed to exhibit responsive behavior to changes in environmental conditions, such as pH, ionic strength and temperature, are characterized using multiple particle tracking microrheology and circular dichroism (CD) spectroscopy. The peptides, predominantly an alternating sequence of valine and lysine residues, differ by a point substitution of a single amino acid near a type II'beta-turn sequence. The rate of gelation becomes faster for point substitutions which reduce the total charge of the peptide. Similarly, increasing the ionic strength reduces or screens intra- and inter-molecular electrostatic repulsions, again leading to faster gelation kinetics. CD measurements show that the concentration of folded peptide at the gel point decreases as the gelation kinetics become slower, possibly indicating a relationship between the assembly rate and the resulting gel microstructure. Finally, a model is developed based on the electrostatic barrier to peptide folding and association which agrees semi-quantitatively with the microrheology results. This represents a first step towards understanding the role of peptide charge and physico-chemical conditions in the self-assembly of these peptide hydrogelators. PMID- 20161468 TI - Modeling Hofmeister Effects. AB - A two dimensional model of water, so-called Mercedes-Benz model, was used to study effects of the size of hydrophobic solute on the insertion thermodynamics in electrolyte solutions. The model was examined by the constant pressure Monte Carlo computer simulation. The results were compared with the experimental data for noble gasses and methane in water and electrolyte solution. The influence of different ions at infinite dilution on the free energy of transfer was explored. Qualitative agreement with the experimental results was obtained. The mechanism of Hofmeister effects was proposed. PMID- 20161469 TI - Social-Contextual Influences on Adolescent Romantic Involvement: The Constraints of Being a Numerical Minority. AB - This research explores white-black differences in adolescent heterosexual romantic involvement and how these differences are shaped by social context. We find that, parallel to patterns of marriage in adulthood, Non-Hispanic white girls are more likely to be in a romantic relationship than African American girls. This is particularly true when we focus on heterosexual romantic relationships formed with schoolmates. Among boys, African Americans are more likely to be romantically involved than Non-Hispanic whites. We investigate the contribution of two broad types of social-demographic factors to these race ethnic differences, population composition and normative climate. We develop theory about why being a numerical minority should lead to lower levels of relationship formation, especially when interracial relationships are rare. Results support the population composition hypotheses but not the idea that race ethnic differences arise because of differences in normative climate. PMID- 20161467 TI - Executive Functions after Age 5: Changes and Correlates. AB - Research and theorizing on executive function (EF) in childhood has been disproportionately focused on preschool age children. This review paper outlines the importance of examining EF throughout childhood, and even across the lifespan. First, examining EF in older children can address the question of whether EF is a unitary construct. The relations among the EF components, particularly as they are recruited for complex tasks, appear to change over the course of development. Second, much of the development of EF, especially working memory, shifting, and planning, occurs after age 5. Third, important applications of EF research concern the role of school-age children's EF in various aspects of school performance, as well as social functioning and emotional control. Future research needs to examine a more complete developmental span, from early childhood through late adulthood, in order to address developmental issues adequately. PMID- 20161470 TI - Trying to keep children out of trouble: Child characteristics, neighborhood quality, and within-household resource allocation. AB - Prior ethnographic evidence suggests that parents combat neighborhood dangers through spending time with and money on children perceived to be at risk. This paper summarizes a secondary data investigation of whether interactions between neighborhood quality and child characteristics predict patterns of intra household resource allocation. Using a sample of N=1879 12- and 13-year-olds from the National Longitudinal Survey of Youth, I find that in neighborhoods with greater numbers of problems, parents spend more time and money with firstborn children and who are particularly short or impulsive relative to how parents treat such children in lower problem neighborhoods. Comparisons of cross sectional and sibling fixed-effect models suggest the shortness and firstborn effects are not due to unobserved family characteristics. These results lend modest support to the assertion that parents systematically try to use within family resources to protect certain children from threats posed by neighborhoods with high levels of crime or low levels of social cohesiveness. PMID- 20161471 TI - Estimation and Efficiency with Recurrent Event Data under Informative Monitoring. AB - This article deals with studies that monitor occurrences of a recurrent event for n subjects or experimental units. It is assumed that the i(th) unit is monitored over a random period [0,tau(i)]. The successive inter-event times T(i1), T(i2), ..., are assumed independent of tau(i). The random number of event occurrences over the monitoring period is K(i) = max{k in {0, 1, 2, ...} : T(i1) + T(i2) + ... + T(ik) 0, a generalized Koziol-Green (cf., Koziol and Green (1976); Chen, Hollander, and Langberg (1982)) model. Asymptotic properties of estimators of theta, beta, and F are presented. Efficiencies of estimators of theta and F are ascertained relative to estimators which ignores the informative monitoring aspect. These comparisons reveal the gain in efficiency when the informative structure of the model is exploited. Concrete demonstrations were performed for F exponential and a two-parameter Weibull. PMID- 20161472 TI - Unpacking racial socialization: Considering female African American primary caregivers' racial identity. AB - The relationship between female African American primary caregivers' racial identity and their racial socialization emphases was examined. Three components of racial identity were evaluated: (1) the importance of race to the self-concept (centrality); (2) affective feelings towards group membership (private regard); and, (3) perceptions of how group members are perceived by nonmembers (public regard). Latent class cluster analysis was used to identify racial identity profiles, or dominant combinations of racial centrality, private regard, and public regard among a sample of 208 female African American primary caregivers. Mean differences in the content of caregivers' socialization emphases by profile group were then assessed. Findings indicated that caregivers' with different identity profiles emphasized different messages. These findings and their implications are discussed. PMID- 20161473 TI - Tensions in Independent Living Facilities for Elders: A Model of Connected Disconnections. AB - OBJECTIVE: To gain an increased understanding about the geriatric health and safety concerns related to vulnerable elders residing alone in independent living facilities (ILFs). METHODS: Qualitative focus group methodology was used to elicit the perceptions of elderly residents representing three ILFs, their family members, housing staff, and Nurse Practitioner consultants. RESULTS: Staff comprised 3 focus groups, residents 4 groups, and families 1 group for a total of 26 participants across eight focus groups. Content analyses of transcripts revealed that falls, forgetfulness/confusion, medication management and unexpected critical health events were concerns shared across the groups. Subgroups differed greatly in other concerns and service expectations. DISCUSSION: Findings resulted in a thematic model of Connected Disconnections with shared concerns, differences in beliefs and tension points. Problems arise when the wrong residents are living in the wrong type of housing. More attention to pre-admission resident evaluation and clarifying service expectations with families before acceptance and during periods of elder functional decline are recommended. PMID- 20161475 TI - Aqueous - Phase Synthesis of PAA in PVDF Membrane Pores for Nanoparticle Synthesis and Dichlorobiphenyl Degradation. AB - This paper deals with bimetallic (Fe/Pd) nanoparticle synthesis inside the membrane pores and application for catalytic dechlorination of toxic organic compounds form aqueous streams. Membranes have been used as platforms for nanoparticle synthesis in order to reduce the agglomeration, encountered in solution phase synthesis which leads to a dramatic loss of reactivity. The membrane support, polyvinylidene fluoride (PVDF) was modified by in situ polymerization of acrylic acid in aqueous phase. Subsequent steps included ion exchange with Fe(2+), reduction to Fe(0) with sodium borohydride and Pd deposition. Various techniques, such as STEM, EDX, FTIR and permeability measurements, were used for membrane characterization and showed that bimetallic (Fe/Pd) nanoparticles with an average size of 20-30 nm have been incorporated inside of the PAA-coated membrane pores. The Fe/Pd-modified membranes showed a high reactivity toward a model compound, 2, 2'-dichlorobyphenyl and a strong dependence of degradation on Pd (hydrogenation catalyst) content. The use of convective flow substantially reduces the degradation time: 43% conversion of dichlorobiphenyl to biphenyl can be achieved in less than 40 s residence time. Another important aspect is the ability to regenerate and reuse the Fe/Pd bimetallic systems by washing with a solution of sodium borohydride, because the iron becomes inactivated (corroded) as the dechlorination reaction proceeds. PMID- 20161474 TI - Opportunities and challenges in synthetic oligosaccharide and glycoconjugate research. AB - Synthetic oligosaccharides and glycoconjugates are increasingly used as probes for biological research and as lead compounds for drug and vaccine discovery. These endeavors are, however, complicated by a lack of general methods for the routine preparation of this important class of compounds. Recent development such as one-pot multi-step protecting group manipulations, the use of unified monosaccharide building blocks, the introduction of stereoselective glycosylation protocols, and convergent strategies for oligosaccharide assembly, are beginning to address these problems. Furthermore, oligosaccharide synthesis can be facilitated by chemo-enzymatic methods, which employ a range of glycosyl transferases to modify a synthetic oligosaccharide precursor. Glycosynthases, which are mutant glycosidases, that can readily form glycosidic linkages are addressing a lack of a wide range glycosyltransferases. The power of carbohydrate chemistry is highlighted by an ability to synthesize glycoproteins. PMID- 20161476 TI - A [Cyclentetrakis(methylene)]tetrakis[2-hydroxybenzamide] Ligand That Complexes and Sensitizes Lanthanide(III) Ions. AB - The synthesis of the cyclen derivative H(4)L(1).2 HBr containing four 2 hydroxybenzamide groups is described. The spectroscopic properties of the Ln(III) conplexes of L(1) (Ln=Gd, Tb, Yb, and Eu) reveal changes of the UV/VIS absorption, circular-dichroism-absorption, luminescence, and circularly polarized luminescence spectra. It is shown that at least two metal-complex species are present in solution, whose relative amounts are pH dependent. At pH > 8.0, an intense long-lived emission is observed (for [TbL(1)] and [YbL(1)]), while at pH < 8.0, a weaker, shorter-lived species predominates. Unconventional Ln(III) emitters (Pr, Nd, Sm, Dy, and Tm) were sensitized in basic solution, both in the VIS and in the near-IR, to measure the emission of these ions. PMID- 20161477 TI - The impact of AIDS on intergenerational support in South Africa: Evidence from the Cape Area Panel Study. AB - This study uses panel data from Cape Town to document the role played by aging parents in caring for grandchildren who lose parents due to illnesses such as AIDS. We quantify the probabilities that older adults and their adult children provide financial support to orphaned grandchildren. We find significant transfers of public and private funds to older adults caring for orphans. Perhaps because of these transfers we find no differences in expenditure patterns between households with orphans and other older adult households. We also find no impact of either the death of a child or taking in orphaned grandchildren on adult well being as measured by ability to work, depression, or self reported health. Our findings suggest that the combined public and private safety net in South Africa mitigates many of the consequences older adults could suffer when an adult child dies and leaves behind grandchildren needing care. PMID- 20161479 TI - The Making of Evidence-based Practice: The Case of Project ALERT. AB - Evidence-based practice has been enthusiastically embraced within the field of drug prevention during the past decade. Project ALERT, a school-based universal prevention program, is among the most widely advocated evidence-based interventions. We examined the results of three large-scale evaluations of Project ALERT, and concluded that assessment of data from the total samples shows that the program has little effect on drug use. Despite this, Project ALERT is included on evidence-based drug prevention lists because the criteria for inclusion are extremely weak. We discuss the implications of this for drug prevention evaluation research and the creation of evidence-based practice lists. PMID- 20161480 TI - Simulating suppression effects in Pulsed ENDOR, and the 'hole in the middle' of Mims and Davies ENDOR Spectra. AB - All pulsed ENDOR techniques, and in particular the Mims and Davies sequences, suffer from detectability biases ('blindspots') that are directly correlated to the size of the hyperfine interactions of coupled nuclei. Our efforts at ENDOR 'crystallography' and 'mechanism determination' with these techniques has led our group to refine our simulations of pulsed ENDOR spectra to take into account these biases, and we here describe the process and illustrate it with several examples. We first focus on an issue whose major significance is not widely appreciated, the 'hole in the middle' of pulsed ENDOR spectra caused by the n = 0 suppression hole in Mims ENDOR and by the analogous A->0 suppression in Davies ENDOR (Section I). This section discusses the issue for nuclei with I = 1/2 and also for (2)H (I = 1), using the treatment of Section II. In Section II we discuss the general treatment of suppression effects for I = 1, illustrating it with a treatment of Mims suppression for (14)N (I = 1) (Section II). PMID- 20161478 TI - Biochemical insights into the role of matrix metalloproteinases in regeneration: challenges and recent developments. AB - Matrix metalloproteinases (MMPs) are a group of proteases that belong to the metazincin family. These proteins consist of similar structures featuring a signaling peptide, a propeptide domain, a catalytic domain where the notable zinc ion binding site is found and a hinge region that binds to the C-terminal hemoplexin domain. MMPs can be produced by numerous cell types through secretion or localization to the cell membrane. While certain chemical compounds have been known to generally inhibit MMPs, naturally occurring proteins known as tissue inhibitors of metalloproteinases (TIMPs) effectively interact with MMPs to modify their biological roles. MMPs are very important enzymes that actively participate in remodeling the extracellular matrix by degrading certain constituents, along with promoting cell proliferation, migration, differentiation, apoptosis and angiogenesis. In normal adult tissue, they are almost undetectable; however, when perturbed through injury, disease or pregnancy, they have elevated expression. The goal of this review is to identify new experimental findings that have provided further insight into the role of MMPs in skeletal muscle, nerve and dermal tissue, as well as in the liver, heart and kidneys. Increased expression of MMPs can improve the regeneration potential of wounds; however, an imbalance between MMP and TIMP expression can prove to be destructive for afflicted tissues. PMID- 20161481 TI - Disease Restaging and Diagnosis of Recurrent and Metastatic Disease Following Primary Therapy with FDG-PET Imaging. PMID- 20161482 TI - Buffer Standards for the Physiological pH of the Zwitterionic Compound, ACES from 5 to 55 degrees C. AB - The values of the second dissociation constant pK2 and related thermodynamic quantities of [N-(2-acetamido)-2-aminoethanesulfonic acid] (ACES) have already been reported over the temperature range 5 to 55 degrees C including 37 degrees C. This paper reports the paH values of four chloride ion free buffer solutions and eight buffer solutions with I = 0.16 mol.kg -1, matching closely to that of the physiological sample. Conventional paH values for all twelve buffer solutions from 5 to 55 degrees C, are reported. The residual liquid junction potential correction for two widely used temperatures, 25 and 37 degrees C, has been made. The flowing-junction calomel cell method has been utilized to measure Ej , the liquid junction potential. The operational pH values for four buffer solutions at 25 and 37 degrees C are calculated using the physiological phosphate buffer standard based on NBS/NIST convention. These solutions are recommended as pH standards in the pH range of 6.8 to 7.2 for physiological fluids. PMID- 20161483 TI - Fluorous-based Peptide Microarrays for Protease Screening. AB - As ever more protease sequences are uncovered through genome sequencing projects, efficient parallel methods to discover the potential substrates of these proteases becomes crucial. Herein we describe the first use of fluorous-based microarrays to probe peptide sequences and begin to define the scope and limitations of fluorous microarray technologies for the screening of proteases. Comparison of a series of serine proteases showed that their ability to cleave peptide substrates in solution was maintained upon immobilization of these substrates onto fluorous-coated glass slides. The fluorous surface did not serve to significantly inactivate the enzymes. However, addition of hydrophilic components to the peptide sequences could induce lower rates of substrate cleavage with enzymes such as chymotrypsin with affinities to hydrophobic moieties. This work represents the first step to creating robust protease screening platforms using noncovalent microarray interface that can easily incorporate a range of compounds on the same slide. PMID- 20161484 TI - Self-regulated learning and self-directed study in a pre-college sample. AB - Self-regulated learning (SRL) is a multi-dimensional construct that has been difficult to operationalize using traditional, variable-centered methodologies. The current paper takes a person-centered approach to the study of SRL in a sample of 205 high-school students. Using latent profile analysis on self-reports of seven aspects of SRL, three groups were identified: high SRL, low SRL, and average SRL. Student self-reports of goal orientation were used as validation for the profile solution, with the high academic self- regulation group reporting the highest levels of mastery orientation while the low self-regulation group reported highest levels of avoidant orientation. Profiles were also compared on independently collected, behavioral measures of study behaviors, with the highly self-regulated group tending to study more material and for a longer time than less self-regulated individuals. PMID- 20161485 TI - Buffer Standards for pH Measurement of N-(2-Hydroxyethyl)piperazine-N'-2 ethanesulfonic Acid (HEPES) for I = 0.16 mol.kg from 5 to 55 degrees C. AB - The values of the second dissociation constant, pK(2) of N-(2-hydroxyethyl) piperazine-N'-2-ethanesulfonic acid (HEPES) have been reported at 12 temperatures over the temperature range 5 to 55 degrees C, including 37 degrees C. This paper reports the results for the pa(H) of eight isotonic saline buffer solutions with an I = 0.16 mol*kg(-1) including compositions: (a) HEPES (0.01 mol*kg(-1)) + NaHEPES (0.01 mol*kg(-1)) + NaCl (0.15 mol*kg(-1)); (b) HEPES (0.02 mol*kg(-1)) + NaHEPES (0.02 mol*kg(-1)) + NaCl (0.14 mol*kg(-1)); (c) HEPES (0.03 mol*kg(-1)) + NaHEPES (0.03 mol*kg(-1)) + NaCl (0.13 mol*kg(-1)); (d) HEPES (0.04 mol*kg(-1)) + NaHEPES (0.04 mol*kg(-1)) + NaCl (0.12 mol*kg(-1)); (e) HEPES (0.05 mol*kg(-1)) + NaHEPES (0.05 mol*kg(-1)) + NaCl (0.11 mol*kg(-1)); (f) HEPES (0.06 mol*kg(-1)) + NaHEPES (0.06 mol*kg(-1)) + NaCl (0.10 mol*kg(-1)); (g) HEPES (0.07 mol*kg(-1)) + NaHEPES (0.07 mol*kg(-1)) + NaCl (0.09 mol*kg(-1)); and (h) HEPES (0.08 mol*kg( 1)) + NaHEPES (0.08 mol*kg(-1)) + NaCl (0.08 mol*kg(-1)). Conventional pa(H) values, for all eight buffer solutions from 5 to 55 degrees C have been calculated. The operational pH values with liquid junction corrections, at 25 and 37 degrees C have been determined based on the NBS/NIST standard between the physiological phosphate standard and four buffer solutions. These are recommended as pH standards for physiological fluids in the range of pH 7.3 to 7.5 at I = 0.16 mol*kg(-1). PMID- 20161486 TI - The effect of computer-mediated administration on self-disclosure of problems on the addiction severity index. AB - OBJECTIVES: People tend to disclose more personal information when communication is mediated through the use of a computer. This study was conducted to examine the impact of this phenomenon on the way respondents answer questions during computer-mediated, self-administration of the Addiction Severity Index (ASI) called the Addiction Severity Index-Multimedia Version((R)) (ASI-MV((R))). METHODS: A sample of 142 clients in substance abuse treatment was administered the ASI via an interviewer and the computerized ASI-MV((R)), three to five days apart in a counterbalanced order. Seven composite scores were compared between the two test administrations using paired t-tests. Post hoc analyses examined interviewer effects. RESULTS: Comparisons of composite scores for each of the domains between the face-to-face administered and computer-mediated, self administered ASI revealed that significantly greater problem severity was reported by clients in five of the seven domains during administration of the computer-mediated, self-administered version compared to the trained interviewer version. Item analyses identified certain items as responsible for significant differences, especially those asking clients to rate need for treatment. All items that were significantly different between the two modes of administration revealed greater problem severity reported on the ASI-MV((R)) as compared to the interview administered assessment. Post hoc analyses yielded significant interviewer effects on four of the five domains where differences were observed. CONCLUSIONS: These data support a growing literature documenting a tendency for respondents to be more self-disclosing in a computer-mediated format over a face to-face interview. Differences in interviewer skill in establishing rapport may account for these observations. PMID- 20161487 TI - Cytokines and matrix metalloproteinases as potential biomarkers in chronic heart failure. AB - Heart failure (HF) is accompanied by the upregulation of bioactive signaling molecules, known as cytokines, and a family of downstream proteases, matrix metalloproteinases (MMPs). It is now apparent that these molecules contribute to adverse myocardial remodeling during HF. Elevated levels of cytokines and MMPs exist in the myocardium and can subsequently spill over into the systemic circulation. The purpose of this article is to examine clinical studies of HF that have quantified levels of different types of cytokines, MMPs and endogenous tissue inhibitors of MMPs in relation to this disease process. HF is a complex syndrome that can develop from various etiologies and can be characterized into two distinct phenotypes: systolic and diastolic. This article will present recent clinical studies that have identified significant differences between the cytokine and MMP circulating profile of systolic and diastolic HF patients. In general, elevated levels of cytokines and MMPs exist in systolic HF patients when compared with diastolic HF patients, whereas diastolic HF patients have elevated levels of cytokines and MMPs when compared with controls. Therefore, future studies distinguishing between HF phenotypes may provide more consistent results in determining possible analytes to be used as biomarkers. Furthermore, this article will emphasize why standardization of analytical techniques and establishment of referent cytokine and MMP levels are necessary if these analytes are to be used as biomarkers for the diagnosis, prognosis and evaluation of treatment in the context of HF. PMID- 20161488 TI - Internal Consistency and Test-Retest Stability of the Geriatric Depression Scale Short Form in African American Older Adults. AB - The Geriatric Depression Scale (GDS) is one of the most widely used self-rated mood questionnaires for older adults. It is highly correlated with clinical diagnoses of depression and has demonstrated validity across different patient populations. However, the reliability of the GDS among African American older adults remains to be firmly established. In a baseline sample of 401 African American adults age 51 and over, the GDS-15 item short form demonstrates good internal consistency (KR20=.71). Stability over a 15-month interval in a retest sample of 51 adults is deemed adequate (r=.68). These findings support the use of the GDS-15 item short form as a reliable mood questionnaire among African American older adults. PMID- 20161489 TI - Brdm2 - an aberrant hypomorphic p63 allele. PMID- 20161490 TI - Parents' and Children's Religiosity and Child Behavioral Adjustment among Maltreated and Nonmaltreated Children. AB - We investigated the role of parents' and children's religiosity in behavioral adjustment among maltreated and nonmaltreated children. Data were collected on 170 maltreated and 159 nonmaltreated children from low-income families (mean age = 10 years). We performed dyadic data analyses to examine unique contributions of parents' and children's religiosity and their interaction to predicting child internalizing and externalizing symptomatology. A four group structural equation modeling was used to test whether the structural relations among religiosity predictors and child outcomes differed by child maltreatment status and child gender. We found evidence of parent-child religiosity interaction suggesting that (1) parents' frequent church attendance was related to lower levels of internalizing symptomatology among nonmaltreated children with low church attendance and (2) parents' importance of faith was associated with lower levels of internalizing and externalizing symptomatology among nonmaltreated children with low faith. The results suggest that independent effects of parents' religiosity varied depending on children's religiosity and parent-child relationship. PMID- 20161491 TI - Iminonitroso ene reactions: experimental studies on reactivity, regioselectivity and enantioselectivity. AB - Ene reactions of iminonitroso agents with olefins were investigated in both solution and solid phase. Reactions afforded allyl hydroxylamine products in up to 99% yield and with high regioselectivity. A Cu(I)-mediated enantioselective nitroso ene reaction gave an ene product with up to 40% ee. PMID- 20161492 TI - Changes in lead and zinc lability during weathering-induced acidification of desert mine tailings: Coupling chemical and micro-scale analyses. AB - Desert mine tailings may accumulate toxic metals in the near surface centimeters because of low water through-flux rates. Along with other constraints, metal toxicity precludes natural plant colonization even over decadal time scales. Since unconsolidated particles can be subjected to transport by wind and water erosion, potentially resulting in direct human and ecosystem exposure, there is a need to know how the lability and form of metals change in the tailings weathering environment. A combination of chemical extractions, X-ray diffraction, micro-X-ray fluorescence spectroscopy, and micro-Raman spectroscopy were employed to study Pb and Zn contamination in surficial arid mine tailings from the Arizona Klondyke State Superfund Site. Initial site characterization indicated a wide range in pH (2.5 to 8.0) in the surficial tailings pile. Ligand-promoted (DTPA) extractions, used to assess plant-available metal pools, showed decreasing available Zn and Mn with progressive tailings acidification. Aluminum shows the inverse trend, and Pb and Fe show more complex pH dependence. Since the tailings derive from a common source and parent mineralogy, it is presumed that variations in pH and "bioavailable" metal concentrations result from associated variation in particle-scale geochemistry. Four sub-samples, ranging in pH from 2.6 to 5.4, were subjected to further characterization to elucidate micro-scale controls on metal mobility. With acidification, total Pb (ranging from 5 - 13 g kg(-1)) was increasingly associated with Fe and S in plumbojarosite aggregates. For Zn, both total (0.4 - 6 g kg(-1)) and labile fractions decreased with decreasing pH. Zinc was found to be primarily associated with the secondary Mn phases manjiroite and chalcophanite. The results suggest that progressive tailings acidification diminishes the overall lability of the total Pb and Zn pools. PMID- 20161494 TI - On the role of entailment patterns and scalar implicatures in the processing of numerals. AB - There has been much debate, in both the linguistics and the psycholinguistics literature, concerning numbers and the interpretation of number denoting determiners ('numerals'). Such debate concerns, in particular, the nature and distribution of upper-bounded ('at-least') interpretations vs. lower-bounded ('exact') construals. In the present paper we show that the interpretation and processing of numerals are affected by the entailment properties of the context in which they occur. Experiment 1 established off-line preferences using a questionnaire. Experiment 2 investigated the processing issue through an eye tracking experiment using a silent reading task. Our results show that the upper bounded interpretation of numerals occurs more often in an upward entailing context than in a downward entailing context. Reading times of the numeral itself were longer when it was embedded in an upward entailing context than when it was not, indicating that processing resources were required when the context triggered an upper-bounded interpretation. However, reading of a following context that required an upper-bounded interpretation triggered more regressions towards the numeral when it had occurred in a downward entailing context than in an upward entailing one. Such findings show that speakers' interpretation and processing of numerals is systematically affected by the polarity of the sentence in which they occur, and support the hypothesis that the upper-bounded interpretation of numerals is due to a scalar implicature. PMID- 20161493 TI - Intervention strategies for an influenza pandemic taking into account secondary bacterial infections. AB - Influenza infections often predispose individuals to consecutive bacterial infections. Both during seasonal and pandemic influenza outbreaks, morbidity and mortality due to secondary bacterial infections can be substantial. With the help of a mathematical model, we investigate the potential impact of such bacterial infections during an influenza pandemic, and we analyze how antiviral and antibacterial treatment or prophylaxis affect morbidity and mortality. We consider different scenarios for the spread of bacteria, the emergence of antiviral resistance, and different levels of severity for influenza infections (1918-like and 2009-like). We find that while antibacterial intervention strategies are unlikely to play an important role in reducing the overall number of cases, such interventions can lead to a significant reduction in mortality and in the number of bacterial infections. Antibacterial interventions become even more important if one considers the--very likely--scenario that during a pandemic outbreak, influenza strains resistant to antivirals emerge. Overall, our study suggests that pandemic preparedness plans should consider intervention strategies based on antibacterial treatment or prophylaxis through drugs or vaccines as part of the overall control strategy. A major caveat for our results is the lack of data that would allow precise estimation of many of the model parameters. As our results show, this leads to very large uncertainty in model outcomes. As we discuss, precise assessment of the impact of antibacterial strategies during an influenza pandemic will require the collection of further data to better estimate key parameters, especially those related to the bacterial infections and the impact of antibacterial intervention strategies. PMID- 20161495 TI - NETWORKS, BIOLOGY AND SYSTEMS ENGINEERING: A CASE STUDY IN INFLAMMATION. AB - Biological systems can be modeled as networks of interacting components across multiple scales. A central problem in computational systems biology is to identify those critical components and the rules that define their interactions and give rise to the emergent behavior of a host response. In this paper we will discuss two fundamental problems related to the construction of transcription factor networks and the identification of networks of functional modules describing disease progression. We focus on inflammation as a key physiological response of clinical and translational importance. PMID- 20161497 TI - Pathways and Predictors of Antisocial Behaviors in African American Adolescents from Poor Neighborhoods. AB - Antisocial behavior among youth remains a serious personal and social problem in the United States. The purposes of this study were to (1) identify the shape and number of developmental trajectories of antisocial behavior in a sample of poor, inner-city African American youth, and (2) test predictors of group membership and the developmental course of antisocial behaviors. Using growth mixture modeling, we examined predictors of antisocial behavior pathways and the likelihood of arrest in a sample of 566 poor, urban African American adolescents (ages 11 to 16). Three distinct trajectory classes of antisocial behavior were identified over a period of six years: one low-risk group (low steady) and two high-risk groups (incremental and high starter). The conditional probabilities for being arrested during ages 14-16 were 0.18 for the low steady class, 0.68 for the incremental class, and 0.31 for high starter class. Prevention strategies for adolescents at high risk are discussed. PMID- 20161498 TI - Expeditious Enyne Construction from Alkynes via Oxidative Pd(II) Catalyzed Heck Type Coupling. AB - The enyne, ubiquitous in natural products, can be a challenge to generate since these moieties require many synthetic transformations to assemble them. We developed a simpler protocol to construct enynes while we found that this oxidative reaction was tolerant in substrate scope. In addition, the utility of this reaction was demonstrated through the attempt in synthesizing antifungal agent Lamisi. PMID- 20161496 TI - Studying Enzymes by In Vivo C Magnetic Resonance Spectroscopy. PMID- 20161499 TI - The Impact of Bacterial Strain on the Products of Dissimilatory Iron Reduction. AB - Three bacterial strains from the genus Shewanella were used to examine the influence of specific bacteria on the products of dissimilatory iron reduction. Strains CN32, MR-4 and W3-18-1 were incubated with HFO (hydrous ferric oxide) as the terminal electron acceptor and lactate as the organic carbon and energy source. Mineral products of iron reduction were analyzed using X-ray powder diffraction, electron microscopy, coulometry and susceptometry. Under identical nutrient loadings, iron reduction rates for strains CN32 and W3-18-1 were similar, and about twice as fast as MR-4. Qualitative and quantitative assessment of mineralized end products (secondary minerals) indicated that different products were formed during experiments with similar reduction rates but different strains (CN32 and W3-18-1), and similar products were formed during experiments with different iron reduction rates and different strains (CN32 and MR-4). The major product of iron reduction by strains CN32 and MR-4 was magnetite, while for W3-18-1 it was a mixture of magnetite and iron carbonate hydroxide hydrate (green rust), a precursor to fougerite. Another notable difference was that strains CN32 and MR-4 converted all of the starting ferric iron material into magnetite, while W3-18-1 did not convert most of the Fe(3+) into a recognizable crystalline material. Biofilm formation is more robust in W3 18-1 than in the other two strains used in this study. The differences in mineralization may be an indicator that EPS (or another cellular product from W3 18-1) may interfere with the crystallization of magnetite or facilitate formation of green rust. These results suggest that the relative abundance of mineral end products and the relative distribution of these products are strongly dependent on the bacterial species or strain catalyzing iron reduction. PMID- 20161500 TI - Synthesis of the 6'-iso analogues of neplanocin A and 5'-homoneplanocin A. AB - An efficient synthesis of 6'-isoneplanocin A and 6-isohomoneplanocin A is reported. The key steps in the synthesis include an enyne metathesis and a regioselective oxidation. PMID- 20161501 TI - Research highlights from the UIC/NIH Center for Botanical Dietary Supplements Research for Women's Health: Black cohosh from the field to the clinic. AB - In 1999, the Department of Medicinal Chemistry and Pharmacognosy at the College of Pharmacy, University of Illinois (UIC) at Chicago was funded to establish a Botanical Dietary Supplements Research Center from the National Institutes of Health (NIH). The emphasis of the UIC/NIH Center for Botanical Dietary Supplements Research (CBDSR) is botanical dietary supplements (BDS) for women's health. Center's research has focused on BDS that may improve women's health and quality of life, specifically in the areas of menopause, premenstrual syndrome, and persistent urinary tract infections. Center investigators have overcome many challenges associated with botanical dietary supplements research, including acquiring and identifying plant species for investigation, isolating and identifying active constituents, elucidating the mechanisms of action of these botanicals, and conducting phase I and phase II clinical studies. Black cohosh [Actaea racemosa L. (Ranunculaceae)] has been used as a model to illustrate the steps involved in taking a botanical dietary supplement from the field, all the way to clinical trials. Bioassays are described that were necessary to elucidate the pertinent biological studies of plant extracts and their mechanisms of action. The Center has used an innovative multidisciplinary approach to this type of research, and thus has been very successful in fulfilling its specific aims. PMID- 20161502 TI - Adult Coping with Childhood Sexual Abuse: A Theoretical and Empirical Review. AB - Coping has been suggested as an important element in understanding the long-term functioning of individuals with a history of child sexual abuse (CSA). The present review synthesizes the literature on coping with CSA, first by examining theories of coping with trauma, and, second by examining how these theories have been applied to studies of coping in samples of CSA victims. Thirty-nine studies were reviewed, including eleven descriptive studies of the coping strategies employed by individuals with a history of CSA, eighteen correlational studies of the relationship between coping strategies and long-term functioning of CSA victims, and ten investigations in which coping was examined as a mediational factor in relation to long-term outcomes. These studies provide initial information regarding early sexual abuse and subsequent coping processes. However, this literature is limited by several theoretical and methodological issues, including a failure to specify the process of coping as it occurs, a disparity between theory and research, and limited applicability to clinical practice. Future directions of research are discussed and include the need to understand coping as a process, identification of coping in relation to adaptive outcomes, and considerations of more complex mediational and moderational processes in the study of coping with CSA. PMID- 20161503 TI - Local Impacts of Religious Discourses on Rights to Express Same-Sex Sexual Desires in Peri-Urban Rio de Janeiro. AB - This article reports on a study that examined how religious discourses of inclusion and exclusion-in Roman Catholic, evangelical Protestant, and Afro Brazilian religious traditions-affected people's rights to express same-sex sexual desires, behaviors, and identities in the socioeconomically marginalized urban periphery of Rio de Janeiro, Brazil. Using extended ethnographic observation of institutions and religious events over a period of 2 years, the authors identified how sexual rights were constructed within religious discourses and conducted ethnographic interviews with 45 religious leaders. In the low income and violent urban periphery of Rio de Janeiro, religious leaders and institutions play key roles in molding community inclusion and exclusion. A comparison of the 3 major religious denominations shows a diversity of discourses about same-sex sexual desires and their impacts on community formation. PMID- 20161504 TI - Inland Transport of Aerosolized Florida Red Tide Toxins. AB - Florida red tides, an annual event off the west coast of Florida, are caused by the toxic dinoflagellate, Karenia brevis. K. brevis produces a suite of potent neurotoxins, brevetoxins, which kill fish, sea birds, and marine mammals, as well as sickening humans who consume contaminated shellfish. These toxins become part of the marine aerosol, and can also be inhaled by humans and other animals. Recent studies have demonstrated a significant increase in symptoms and decrease lung function in asthmatics after only one hour of beach exposure during an onshore Florida red tide bloom.This study constructed a transect line placing high volume air samplers to measure brevetoxins at sites beginning at the beach, moving approximately 6.4 km inland. One non-exposure and 2 exposure studies, each of 5 days duration, were conducted. No toxins were measured in the air during the non-exposure period. During the 2 exposure periods, the amount of brevetoxins varied considerably by site and by date. Nevertheless, brevetoxins were measured at least 4.2 kilometers from the beach and/or 1.6 km from the coastal shoreline. Therefore, populations sensitive to brevetoxins (such as asthmatics) need to know that leaving the beach may not discontinue their environmental exposure to brevetoxin aerosols. PMID- 20161505 TI - The Case for Examining and Treating the Combined Effects of Parental Drug Use and Interparental Violence on Children in their Homes. AB - This review examines what have been, to this point, generally two divergent lines of research: (a) effects of parental drug abuse on children, and (b) effects of children's exposure to interparental violence. A small, but growing body of literature has documented the robust relationship between drug use and intimate partner violence. Despite awareness of the interrelationship, little attention has been paid to the combined effect of these deleterious parent behaviors on children in these homes. Thus, we argue for the need to examine the developmental impact of these behaviors (both individually and combined) on children in these homes and for treatment development to reflect how each of these parent behaviors may affect children of substance abusers. PMID- 20161506 TI - First-Principles Determination of Molecular Conformations of Indolizidine (-) 235B' in Solution. AB - Indolizidine (-)-235B' is a particularly interesting natural product, as it is the currently known, most potent and subtype-selective open-channel blocker of the alpha4beta2 nicotinic acetylcholine receptor (nAChR). In the current study, extensive first-principles electronic structure calculations have been carried out in order to determine the stable molecular conformations and their relative free energies of the protonated and deprotonated states of (-)-235B' in the gas phase, in chloroform, and in aqueous solution. The (1)H and (13)C NMR chemical shifts calculated using the computationally determined dominant molecular conformation of the deprotonated state are all consistent with available experimental NMR spectra of (-)-235B' in chloroform, which suggests that the computationally determined molecular conformations are reasonable. Our computational results reveal for the first time that two geminal H atoms on carbon-3 (C3) of (-)-235B' have remarkably different chemical shifts (i.e. 3.24 and 2.03 ppm). The computational results help one to better understand and analyze the experimental (1)H NMR spectra of (-)-235B'. The finding of remarkably different chemical shifts of two C3 geminal H atoms in a certain molecular conformation of (-)-235B' may also be valuable in analysis of NMR spectra of other related ring-containing compounds. In addition, the pK(a) of (-)-235B' in aqueous solution is predicted to be ~9.7. All of the computational results provide a solid basis for future studies of the microscopic and phenomenological binding of various receptor proteins with the protonated and deprotonated structures of this unique open-channel blocker of alpha4beta2 nAChRs. This computational study also demonstrates how one can appropriately use computational modeling and spectroscopic analysis to address the structural and spectroscopic problems that cannot be addressed by experiments alone. PMID- 20161508 TI - Electron tunneling through sensitizer wires bound to proteins. AB - We report a quantitative theoretical analysis of long-range electron transfer through sensitizer wires bound in the active-site channel of cytochrome P450cam. Each sensitizer wire consists of a substrate group with high binding affinity for the enzyme active site connected to a ruthenium-diimine through a bridging aliphatic or aromatic chain. Experiments have revealed a dramatic dependence of electron transfer rates on the chemical composition of both the bridging group and the substrate. Using combined molecular dynamics simulations and electronic coupling calculations, we show that electron tunneling through perfluorinated aromatic bridges is promoted by enhanced superexchange coupling through virtual reduced states. In contrast, electron flow through aliphatic bridges occurs by hole-mediated superexchange. We have found that a small number of wire conformations with strong donor-acceptor couplings can account for the observed electron tunneling rates for sensitizer wires terminated with either ethylbenzene or adamantane. In these instances, the rate is dependent not only on electronic coupling of the donor and acceptor but also on the nuclear motion of the sensitizer wire, necessitating the calculation of average rates over the course of a molecular dynamics simulation. These calculations along with related recent findings have made it possible to analyze the results of many other sensitizer wire experiments that in turn point to new directions in our attempts to observe reactive intermediates in the catalytic cycles of P450 and other heme enzymes. PMID- 20161507 TI - Role of cortical cell type and morphology in subthreshold and suprathreshold uniform electric field stimulation in vitro. AB - BACKGROUND: The neocortex is the most common target of subdural electrotherapy and noninvasive brain stimulation modalities, including transcranial magnetic stimulation (TMS) and transcranial current simulation (TCS). Specific neuronal elements targeted by cortical stimulation are considered to underlie therapeutic effects, but the exact cell type(s) affected by these methods remains poorly understood. OBJECTIVE: We determined whether neuronal morphology or cell type predicted responses to subthreshold and suprathreshold uniform electric fields. METHODS: We characterized the effects of subthreshold and suprathreshold electrical stimulation on identified cortical neurons in vitro. Uniform electric fields were applied to rat motor cortex brain slices, while recording from interneurons and pyramidal cells across cortical layers, using a whole-cell patch clamp. Neuron morphology was reconstructed after intracellular dialysis of biocytin. Based solely on volume-weighted morphology, we developed a parsimonious model of neuronal soma polarization by subthreshold electric fields. RESULTS: We found that neuronal morphology correlated with somatic subthreshold polarization. Based on neuronal morphology, we predict layer V pyramidal neuronal soma to be individually the most sensitive to polarization by optimally oriented subthreshold fields. Suprathreshold electric field action potential threshold was shown to reflect both direct cell polarization and synaptic (network) activation. Layer V/VI neuron absolute electric field action potential thresholds were lower than layer II/III pyramidal neurons and interneurons. Compared with somatic current injection, electric fields promoted burst firing and modulated action potential firing times. CONCLUSIONS: We present experimental data indicating that cortical neuron morphology relative to electric fields and cortical cell type are factors in determining sensitivity to sub- and supra-threshold brain stimulation. PMID- 20161509 TI - Lipoprotein Particle Profiles by Nuclear Magnetic Resonance Spectroscopy in Medically-Underserved HIV-Infected Persons. AB - BACKGROUND: HIV infection is associated with dyslipidemia and increased risk for cardiovascular events. Few studies have described lipid status in medically underserved, HIV-infected ethnic minorities, a group that is characterized by health disparities. OBJECTIVE: The objective was to characterize the lipid profile of a medically-underserved, largely ethnic minority sample of HIV infected persons using standard lipid panels and nuclear magnetic resonance (NMR) -derived lipoprotein particle profiles. METHODS: Participants were recruited from a randomized controlled trial of a dietary supplement to manage HIV-related dyslipidemia (N=132). At the initial screening visit, sociodemographic, clinical, and behavioral data were collected, and fasting peripheral venous blood specimens were obtained and lipid status was analyzed using the standard lipid panel and the NMR-derived lipoprotein particle profile. RESULTS: Using NMR-derived LDL particle cutoffs, a higher percentage of participants was outside the target range (50%) than when standard LDL cholesterol NCEP cutoffs were used (24%). Antiretroviral therapy, especially protease inhibitor-containing regimens, was associated with higher LDL particle concentration. CONCLUSION: Substantial numbers of medically-underserved, asymptomatic HIV-infected minorities may be at increased risk for CHD based on NMR-derived lipoprotein values. PMID- 20161510 TI - Robust Satisficing Linear Regression: performance/robustness trade-off and consistency criterion. AB - Linear regression quantifies the linear relationship between paired sets of input and output observations. The well known least-squares regression optimizes the performance criterion defined by the residual error, but is highly sensitive to uncertainties or perturbations in the observations. Robust least-squares algorithms have been developed to optimize the worst case performance for a given limit on the level of uncertainty, but they are applicable only when that limit is known. Herein, we present a robust-satisficing approach that maximizes the robustness to uncertainties in the observations, while satisficing a critical sub optimal level of performance. The method emphasizes the trade-off between performance and robustness, which are inversely correlated. To resolve the resulting trade-off we introduce a new criterion, which assesses the consistency between the observations and the linear model. The proposed criterion determines a unique robust-satisficing regression and reveals the underlying level of uncertainty in the observations with only weak assumptions. These algorithms are demonstrated for the challenging application of linear regression to neural decoding for brain-machine interfaces. The model-consistent robust-satisfying regression provides superior performance for new observations under both similar and different conditions. PMID- 20161511 TI - Improving efficiency and robustness of the doubly robust estimator for a population mean with incomplete data. AB - Considerable recent interest has focused on doubly robust estimators for a population mean response in the presence of incomplete data, which involve models for both the propensity score and the regression of outcome on covariates. The usual doubly robust estimator may yield severely biased inferences if neither of these models is correctly specified and can exhibit nonnegligible bias if the estimated propensity score is close to zero for some observations. We propose alternative doubly robust estimators that achieve comparable or improved performance relative to existing methods, even with some estimated propensity scores close to zero. PMID- 20161512 TI - Statistical Approaches to Modeling Multiple Outcomes In Psychiatric Studies. AB - Increasingly, multiple outcomes are collected in order to characterize treatment effectiveness or to evaluate risk factors. These outcomes tend to be correlated because they are measuring related quantities in the same individuals. While the analysis of outcomes measured in the same scale (commensurate outcomes) can be undertaken with standard statistical methods, outcomes measured in different scales (non-commensurate outcomes), such as mixed binary and continuous outcomes, present more difficult challenges.In this paper we contrast some statistical approaches to analyze non-commensurate multiple outcomes. We discuss the advantages of a multivariate method for the analysis of non-commensurate outcomes including situations of missing data. A real data example from a clinical trial, comparing different treatments for depression in low-income women, is used to illustrate the differences between the statistical approaches. PMID- 20161513 TI - Impact of individual differences upon emotion-induced memory trade-offs. AB - After seeing a scene containing an emotional component (e.g., a snake in a forest) people often demonstrate a "trade-off" in memory, where memory for the emotional component (e.g., the snake) is good, but memory for the nonemotional elements (e.g., the forest) is poor. The result is an incomplete memory retaining central emotional information at the expense of neutral background information. Though almost everyone demonstrates the trade-off, there may be individual differences in the magnitude of the effect. We investigated whether differences in the strength of the trade-off would correlate with anxiety levels, working memory capacity, and executive functioning abilities. Sixty-four participants studied scenes comprised of a negative or neutral item placed on a neutral background, and memory was later tested for items and backgrounds separately. The magnitude of the trade-off correlated positively with anxiety and negatively with visuospatial working memory and executive function. These results suggest that greater anxiety, poor visuospatial working memory, and poor executive function may inhibit formation of complete mental representations of these complex emotional scenes. PMID- 20161514 TI - Adolescents with Two Nonresident Biological Parents: Living Arrangements, Parental Involvement, and Well-Being. AB - We know little about children who have two living nonresident biological parents. Using data from the National Longitudinal Study of Adolescent Health, this study examines the diverse living arrangements of U.S. adolescents in this situation, the kinds of relationships they have with each of their nonresident parents, and how these living arrangements are associated with adolescent well-being. Differences between these adolescents (N = 502) and those who have one nonresident biological parent (N = 4746) are also examined. Results point to certain groups of adolescents with two nonresident parents who are at particular risk of exhibiting higher levels of behavior problems (those living alone or with an aunt and uncle) or who, alternatively, are faring comparatively better (those living with biological relative caregivers or two nonbiological parent figures). PMID- 20161515 TI - How Intelligence and Education Contribute to Substance Use: Hints from the Minnesota Twin Family Study. AB - In old and even middle age, there are associations between physical health and both intelligence and education. This may occur because intelligence and/or education exert effects on lifestyle choices that, in turn, affect later health. Substance use is one aspect of lifestyle choice in young adulthood that could play such a role. The effects of intelligence and/or education on substance use could be direct and environmental, or indirect due to the presence of confounding genetic and shared family influences. We used the Minnesota Twin Family Study to distinguish these effects in males and females at age 24. In contrast to prevailing expectations, there were moderately negative direct nonshared environmental effects of both IQ and education on both smoking and drinking in both males and females. That is, controlling for positive family background effects in the form of both genetic and shared environmental influences, both higher IQ and greater education were associated with greater alcohol and nicotine use. These effects were accounted for by alcohol and nicotine use at age 17. Our results suggest that genetic and family-culture variables confound the associations between intelligence and education and substance use in young adults, rendering them indirect. Further research is needed to understand the roles of IQ and education in alcohol and nicotine use and their relative impacts on physical health throughout the lifespan. PMID- 20161516 TI - Intergenerational Experiences of Discrimination in Chinese American Families: Influences of Socialization and Stress. AB - In this longitudinal study, we investigated the mechanisms by which Chinese American parents' experiences of discrimination influenced their adolescents' ethnicity-related stressors (i.e., cultural misfit, discrimination, attitudes toward education). We focused on whether parents' ethnic-racial socialization practices and perpetual foreigner stress moderated or mediated this relationship. Participants were 444 Chinese American families. Results indicated no evidence of moderation, but we observed support for mediation. Parental experiences of discrimination were associated with more ethnic-racial socialization practices and greater parental perpetual foreigner stress. More ethnic-racial socialization was related to greater cultural misfit in adolescents, whereas more perpetual foreigner stress was related to adolescents' poorer attitudes toward education and more reported discrimination. Relationships between mediators and outcomes were stronger for fathers than for mothers. PMID- 20161517 TI - Stretch and Shear Interactions Affect Intercellular Junction Protein Expression and Turnover in Endothelial Cells. AB - Complex hemodynamics play a role in the localization and development of atherosclerosis. Endothelial cells (ECs) lining blood vessel walls are directly influenced by various hemodynamic forces: simultaneous wall shear stress (WSS), normal stress, and circumferential stress/strain (CS) due to pulsatile flow, pressure, and diameter changes. ECs sense and transduce these forces into biomolecular responses that may affect intercellular junctions. In this study, a hemodynamic simulator was used to investigate the combined effects of WSS and CS on EC junctions with emphasis on the stress phase angle (SPA), the temporal phase difference between WSS and CS. Regions of the circulation with highly negative SPA, such as the coronary arteries and carotid bifurcation, are more susceptible to the development of atherosclerosis. At 5 h, expression of the tight junction protein zonula occludens-1 was significantly higher for the atheroprotective SPA = 0 degrees compared to the atherogenic SPA = -180 degrees while the apoptosis rate was significantly higher for SPA = -180 degrees than SPA = 0 degrees . This decrease in tight junction protein and increase in apoptosis and associated leaky junctions suggest a decreased junctional stability and a higher paracellular permeability for atherogenic macromolecules for the atherogenic SPA = -180 degrees compared to SPA = 0 degrees . PMID- 20161518 TI - MALDI-induced Fragmentation of Leucine enkephalin, Nitro-Tyr Leucine Enkaphalin, and d(5)-Phe-Nitro-Tyr Leucine Enkephalin. AB - The long-term objective of this study is to use MALDI MS and MS/MS to study the fragmentation pattern of in vitro nitrotyrosine-containing peptides in order to assist the interpretation of MS-identification of endogenous nitroproteins in human tissues and fluids. The short-term objective is to study synthetic leucine enkephalin, nitro-Tyr-leucine enkephalin, and d(5)-Phe-nitro-Tyr-leucine enkephalin with a vacuum matrix-assisted laser desorption/ionization linear ion trap mass spectrometer (vMALDI-LTQ). The results demonstrated the UV laser induced photochemical decomposition of the nitro group. Although photochemical decomposition decreased the ion intensity and complicated the MS spectrum, the recognition of that unique decomposition pattern unambiguously identified a nitrotyrosine. The a(4)- and b(4)-ions were the most-intense fragment ions found in the MS/MS spectra for those three synthetic peptides. Compared to the unmodified peptides, more collision energy optimized the fragmentation of the nitropeptide, increased the intensity of the a(4)-ion, and decreased the intensity of the b(4)-ion. Optimized laser fluence maximized the fragmentation of the nitropeptide. MS(3) analysis confirmed the MS(2)-derived amino acid sequence, but required much more sample. To detect a nitropeptide, the sensitivity of vMALDI-LTQ is 1 fmol for MS detection and 10 fmol for MS(2) detection; the S/N ratio was ca. 50:1 in those studies. Those data are important for an analysis of low-abundance endogenous nitroproteins, where preferential enrichment of nitroproteins and optimized mass spectrometry parameters are used. PMID- 20161519 TI - Synthesis and biochemical evaluation of des-vinyl secologanin aglycones with alternate stereochemistry. AB - Based on the X-ray structure of the enzyme strictosidine synthase, the glucose moiety of the seco-iridoid glucoside, secologanin, appears to be the key for orienting the substrate. We hypothesized that removing the glucose moiety would allow alternate stereoisomers of secologanin to be turned over. A convenient synthesis to prepare stereoisomers of des-vinyl secologanin is presented. The choice of protective group was the key to access this series of compounds. The analogs were assayed with strictosidine synthase and, interestingly, both the natural 2,4-trans diastereomer and the unnatural 2,4-cis diastereomer are turned over. The trans/cis selectivity increases with increased acetal substituent size. The results add to our understanding of how strictosidine synthase discriminates among stereoisomers. PMID- 20161520 TI - Biocompatible polysiloxane-containing diblock copolymer PEO-b-PgammaMPS for coating magnetic nanoparticles. AB - We report a biocompatible polysiloxane containing amphiphilic diblock copolymer, poly(ethylene oxide)-block-poly(gamma-methacryloxypropyltrimethoxysilane) (PEO-b PgammaMPS), for coating and stabilizing nanoparticles for biomedical applications. Such an amphiphilic diblock copolymer that comprises both a hydrophobic segment with "surface anchoring moiety" (silane group) and a hydrophilic segment with PEO (M(n) = 5000 g/mol) was obtained by the reversible addition-fragmentation chain transfer (RAFT) polymerization using the PEO macromolecular chain transfer agent. When used for coating paramagnetic iron oxide nanoparticles (IONPs), copolymers were mixed with hydrophobic oleic acid coated core size uniformed IONPs (D = 13 nm) in cosolvent tetrahydrofuran. After being aged over a period of time, resulting monodispersed IONPs can be transferred into aqueous medium. With proper PgammaMPS block length (M(n) = 10 000 g/mol), polysiloxane containing diblock copolymers formed a thin layer of coating (approximately 3 nm) around monocrystalline nanoparticles as measured by transmission electron microscopy (TEM). Magnetic resonance imaging (MRI) experiments showed excellent T(2) weighted contrast effect from coated IONPs with a transverse relaxivity r(2) = 98.6 mM(-1) s(-1) (at 1.5 T). Such thin coating layer has little effect on the relaxivity when compared to that of IONPs coated with conventional amphiphilic copolymer. Polysiloxane containing diblock copolymer coated IONPs are stable without aggregation or binding to proteins in serum when incubated for 24 h in culture medium containing 10% serum. Furthermore, a much lower level of intracellular uptake by macrophage cells was observed with polysiloxane containing diblock copolymers coated IONPs, suggesting the reduction of nonspecific cell uptakes and antibiofouling effect. PMID- 20161521 TI - Detecting Genes and Gene-gene Interactions for Age-related Macular Degeneration with a Forest-based Approach. AB - Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly. Genetic mechanisms underlying AMD are complex. Understanding the etiology of AMD is important because of the significant health and social concerns. In this paper, we describe a forest-based approach to systematically identifying multiple genes, gene-gene interactions and gene-environment interactions underlying complex diseases in genomewide case-control studies and the application of this approach to a published data set on AMD. Our analysis not only confirmed two known haplotypes, ACTCCG (on chromosome 1 with a p-value of 1.98e-6) and TCTGGACGACA (on chromosome 7 with a p-value of 9.81e-3), but also revealed two novel haplotypes, GATAGT (on chromosome 5 with a p-value of 3.46e-3) and TCTTACGTAGA (on chromosome 12 with a p-value of 3.16e-2). Thus, the significance of this work is twofold. First, we propose a powerful and robust method to identify high-risk haplotypes and their interactions; second, we reveal potential genetic variants associated with AMD. PMID- 20161522 TI - Electron Flow through Proteins. AB - Electron transfers in photosynthesis and respiration commonly occur between metal containing cofactors that are separated by large molecular distances. Employing laser flash-quench triggering methods, we have shown that 20-A, coupling-limited Fe(II) to Ru(III) and Cu(I) to Ru(III) electron tunneling in Ru-modified cytochromes and blue copper proteins can occur on the microsecond timescale both in solutions and crystals. Redox equivalents can be transferred even longer distances by multistep tunneling, often called hopping, through intervening amino acid side chains. Our work has established that 20-A hole hopping through an intervening tryptophan is two orders of magnitude faster than single-step electron tunneling in a Re-modified blue copper protein. PMID- 20161524 TI - An indicator displacement assay with independent dual wavelength emission. AB - A multifunctional metallo-receptor was designed with both metal and boronic acid binding groups. A sensor ensemble was prepared using the metallo-receptor and the fluorescent dye ARS. The dye produced two distinct fluorescent bands from interaction with the boronic acid and the metal respectively. Partial displacement of the dye by simple analytes led to different fluorescent signatures than full displacement. This differential response provided easy discrimination of the individual analytes. PMID- 20161525 TI - Comparison of carcinogen, carbon monoxide, and ultrafine particle emissions from narghile waterpipe and cigarette smoking: Sidestream smoke measurements and assessment of second-hand smoke emission factors. AB - The lack of scientific evidence on the constituents, properties, and health effects of second-hand waterpipe smoke has fueled controversy over whether public smoking bans should include the waterpipe. The purpose of this study was to investigate and compare emissions of ultrafine particles (UFP, <100 nm), carcinogenic polyaromatic hydrocarbons (PAH), volatile aldehydes, and carbon monoxide (CO) for cigarettes and narghile (shisha, hookah) waterpipes. These smoke constituents are associated with a variety of cancers, and heart and pulmonary diseases, and span the volatility range found in tobacco smoke.Sidestream cigarette and waterpipe smoke was captured and aged in a 1 m(3) Teflon-coated chamber operating at 1.5 air changes per hour (ACH). The chamber was characterized for particle mass and number surface deposition rates. UFP and CO concentrations were measured online using a fast particle spectrometer (TSI 3090 Engine Exhaust Particle Sizer), and an indoor air quality monitor. Particulate PAH and gaseous volatile aldehydes were captured on glass fiber filters and DNPH-coated SPE cartridges, respectively, and analyzed off-line using GC-MS and HPLC-MS. PAH compounds quantified were the 5- and 6-ring compounds of the EPA priority list. Measured aldehydes consisted of formaldehyde, acetaldehyde, acrolein, methacrolein, and propionaldehyde.We found that a single waterpipe use session emits in the sidestream smoke approximately four times the carcinogenic PAH, four times the volatile aldehydes, and 30 times the CO of a single cigarette. Accounting for exhaled mainstream smoke, and given a habitual smoker smoking rate of 2 cigarettes per hour, during a typical one-hour waterpipe use session a waterpipe smoker likely generates ambient carcinogens and toxicants equivalent to 2-10 cigarette smokers, depending on the compound in question. There is therefore good reason to include waterpipe tobacco smoking in public smoking bans. PMID- 20161526 TI - Schools, Schooling, and Children's Support of Their Aging Parents. AB - Intergenerational transfers play an important role in individuals' lives across the life course. In this paper I pull together theories on intergenerational transfers and social change to inform our understanding of how changes in the educational context influence children's support of their parents. By examining multiple aspects of a couple's educational context, including husbands' and wives' education and exposure to schools, this paper provides new information on the mechanisms through which changes in social context influence children's support of their parents. Using data from a rural Nepalese area I use multilevel logistic regression to estimate the relationship between schooling, exposure to schools, and the likelihood of couples giving to their parents. I find that both schooling and exposure to schools itself have separate, opposite effects on support of aging parents. Higher levels of schooling for husbands was associated with a higher likelihood of having given support to husbands' parents. On the other hand, increased exposure to schools for husbands and wives was associated with a lower likelihood of having given to wives' parents. Findings constitute evidence that multiple motivations for intergenerational support exist simultaneously and are related to social context through different mechanisms. PMID- 20161523 TI - Transmitted drug resistance in nonsubtype B HIV-1 infection. AB - HIV-1 nonsubtype B variants account for the majority of HIV infections worldwide. Drug resistance in individuals who have never undergone antiretroviral therapy can lead to early failure and limited treatment options and, therefore, is an important concern. Evaluation of reported transmitted drug resistance (TDR) is challenging owing to varying definitions and study designs, and is further complicated by HIV-1 subtype diversity. In this article, we discuss the importance of various mutation lists for TDR definition, summarize TDR in nonsubtype B HIV-1 and highlight TDR reporting and interpreting challenges in the context of HIV-1 diversity. When examined carefully, TDR in HIV-1 non-B protease and reverse transcriptase is still relatively low in most regions. Whether it will increase with time and therapy access, as observed in subtype-B-predominant regions, remains to be determined. PMID- 20161527 TI - Stem Cells: It's Good To Have Choices. AB - Three types of stem cells, embryonic, adult, and induced pluripotent stem cells, are currently studied by scientists. Barack Obama's presidency has opened the door for stem cell research by revoking statements and orders made during the former President Bush's administration. This provisional period will allow the National Institute of Health to rewrite policies governing how federal funds are distributed for stem cell research. These new regulations will grant more freedom to researchers wishing to use stem cells in their research and challenge them to determine the most appropriate stem cell treatment for a given disorder. PMID- 20161528 TI - Ask, advise and refer: hypothesis generation to promote a brief tobacco-cessation intervention in community pharmacies. AB - OBJECTIVES: A preliminary qualitative study was conducted to identify key facilitators and barriers for pharmacists' adoption of a brief tobacco-cessation protocol, Ask-Advise-Refer (AAR). METHODS: Ten community pharmacists were interviewed using semi-structured, face-to-face interviews with open-ended questions. Purposive and saturation sampling techniques were applied to identify participants and determine sample size respectively. Interviews were audio recorded and transcribed. Using thematic analysis, two reviewers independently coded all transcripts to identify prominent themes. Appropriate measures were taken to ensure study rigor and validity. KEY FINDINGS: All facilitators and barriers identified were grouped into nine distinct themes. Pharmacists' fear of negative patient reaction was the most prominent barrier to initiating tobacco cessation discussions with patients. Other themes identified in decreasing order of prevalence were pharmacists perceiving a rationale for initiating tobacco cessation, pharmacy environment, pharmacists' perception of/prior knowledge of patients' willingness to discuss tobacco cessation/to quit, patient initiation of tobacco-cessation or worsening-health discussion, pharmacists' perceptions of AAR characteristics, length of pharmacist-patient relationship/rapport with patients, low expectations of pharmacy patrons and pharmacists' communication ability. CONCLUSIONS: This study highlights the potential fear among pharmacists about negative reactions from patients in response to initiating tobacco cessation discussions. Based on the results of this study it is hypothesized that the following strategies would facilitate adoption of AAR: (1) train pharmacists to initiate cessation discussions; (2) initially target discussions with patients who have a disease or medication adversely affected by tobacco use; (3) encourage patient enquiry about pharmacy cessation services through visual cues; and (4) help pharmacists set up a workflow system compatible with the AAR protocol. PMID- 20161529 TI - Original biological and ecological data on the endemic Chinese jumping mouse Eozapus setchuanus (Pousargues, 1896). PMID- 20161530 TI - Formulation with ascorbic acid and sucrose modulates catechin bioavailability from green tea. AB - In order to investigate the impact of common food ingredients on catechin absorption, green tea (GT) extract (50 mg) was formulated plain, with sucrose (GT+S), with ascorbic acid (GT+AA) and with sucrose and ascorbic acid (GT+S+AA). Bioavailability and bioaccessibility were assessed in Sprague Dawley rats and an in vitro digestion/Caco-2 cell model respectively. Absorption of epigallocatechin (EGC) and epigallocatechin gallate (EGCG) was significantly (P<0.05) enhanced in GT+S+AA formulations (AUC(0-6h)= 3237.0 and 181.8 pmol*h/L plasma respectively) relative to GT control (AUC(0-6h) = 1304.1 and 61.0 pmol*h/L plasma respectively). In vitro digestive recovery was higher for EGC and epicatechin (EC) (~51-53%) relative to EGCG and epicatechin gallate (ECG) (< 20%) and was modestly enhanced in GT+S and GT+S+AA formulations. Accumulation of EGC, EGCG and ECG by Caco-2 cells was significantly (P<0.05) higher from GT+S+AA compared to other formulations while retention of catechins was enhanced in presence of ascorbic acid. These data suggest that formulation with sucrose and ascorbic acid may improve catechin bioavailability by enhancing bioaccessibility and intestinal uptake from tea. PMID- 20161532 TI - Who Gentrifies Low-Income Neighborhoods? AB - This paper uses confidential Census data, specifically the 1990 and 2000 Census Long Form data, to study demographic processes in neighborhoods that gentrified during the 1990's. In contrast to previous studies, the analysis is conducted at the more refined census-tract level, with a narrower definition of gentrification and more closely matched comparison neighborhoods. Furthermore, our access to individual-level data with census tract identifiers allows us to separately identify recent in-migrants and long-term residents. Our results indicate that, on average, the demographic flows associated with the gentrification of urban neighborhoods during the 1990's are not consistent with displacement and harm to minority households. In fact, taken as a whole, our results suggest that gentrification of predominantly black neighborhoods creates neighborhoods that are attractive to middle-class black households. PMID- 20161531 TI - Smoking intensity and lipoprotein abnormalities in active smokers. AB - BACKGROUND: Smoking is associated with decreased high-density lipoprotein cholesterol (HDL-C) and elevated triglycerides. OBJECTIVE: To evaluate the effects of five markers of smoking intensity on lipoprotein concentrations and particle sizes in a large, modern cohort of current smokers. METHODS: Fasting nuclear magnetic resonance spectroscopy lipoprotein profiles were obtained in a large cohort of current smokers enrolled in a smoking cessation trial. Multivariate linear regression models were constructed to determine predictors of lipoprotein fractions. Models included age, sex, race, waist circumference, level of physical activity and alcohol consumption. Smoking intensity parameters included: current cigarettes smoked/day, pack-years, the Fagerstrom Test of Nicotine Dependence (FTND) score, and carbon monoxide (CO) levels. RESULTS: The 1,504 subjects (58% women, 84% white) had a mean (standard deviation) age of 45 (11.0) years. They smoked 21.4 (8.9) cigarettes/day (29.4 [20.4] pack-years). HDL C (42.0 [13.5] mg/dL) and total HDL particles (30.3 [5.9] MUmol/L) were low. Cigarettes smoked/day independently predicted higher total cholesterol (p=0.009), low-density lipoprotein cholesterol (p=0.023), and triglycerides (p=0.002). CO levels predicted lower HDL-C (p=0.027) and total HDL particles (p=0.009). However, the incremental R(2) for each marker of smoking intensity on each lipoprotein was small. Relationships between the FTND score and lipoproteins were weak and inconsistent. Participants in the lowest quintiles of current smoking, pack-years, and CO had more favorable lipoproteins (all p<0.04). CONCLUSIONS: Among current smokers, increased smoking burden is associated with small increases in total cholesterol, LDL-C, and triglycerides. Increased recent smoke exposure is associated with small decreases in HDL-C and HDL particles. PMID- 20161533 TI - Chemically Polymerized Polypyrrole for On-Chip Concentration of Volatile Breath Metabolites. AB - A wide range of metabolites are measured in the gas phase of exhaled human breath, and some of these biomarkers are frequently observed to be up- or down regulated in certain disease states. Portable breath analysis systems have the potential for a wide range of applications in health diagnostics. However, this is currently limited by the lack of concentration mechanisms to enhance trace metabolites found in the breath to levels that can be adequately recorded using miniaturized gas-phase sensors. In this study we have created chip-based polymeric pre-concentration devices capable of absorbing and desorbing breath volatiles for subsequent chemical analysis. These devices appear to concentrate chemicals from both environmental air samples as well as directly from exhaled human breath, and these devices may have applications in lab-on-a-chip-based environmental and health monitoring systems. PMID- 20161534 TI - Utilizing transmembrane convection to enhance solute sampling and delivery by microdialysis: theory and in vitro validation. AB - Microdialysis is a well-developed membrane-based tool relying on diffusion to sample diffusible constituents of complex media, such as biological tissue. The objective of this research is to expand the utility of microdialysis by combining transmembrane convection with diffusion to enhance solute exchange between microdialysis probes and the surrounding medium. We have developed a mathematical model to describe probe performance and performed validation experiments utilizing tracer solutes and commercially available probes with 100-kDa molecular weight cutoff membranes. Diffusive and fluid permeabilities of the probe membranes are evaluated for probes immersed in well-stirred bathing media in vitro. Transmembrane convection alters the solute extraction fraction, i.e., the fractional loss of a solute from the probe perfusate during delivery and the fractional gain by the perfusate during sampling. The extraction fraction change depends upon the magnitude and direction (inward or outward) of fluid movement across the membrane. However, for solutes with zero reflection coefficients, equality is maintained between these delivery and sampling extraction fractions. This equality is a prerequisite for probe calibration approaches that rely on analyte delivery from the perfusate. Thus, we have provided the theoretical and experimental basis for exploiting convection in a quantitative manner to enhance solute delivery and sampling in microdialysis applications. PMID- 20161535 TI - Multiscale photoacoustic microscopy and computed tomography. AB - Photoacoustic tomography (PAT) is probably the fastest growing biomedical imaging technology owing to its capability of high-resolution sensing of rich optical contrast in vivo at depths beyond the optical transport mean free path (~1 mm in the skin). Existing high-resolution optical imaging technologies, such as confocal microscopy and two-photon microscopy, have fundamentally impacted biomedicine but cannot reach such depths. Taking advantage of low ultrasonic scattering, PAT indirectly improves tissue transparency by 100 to 1000 fold and consequently enables deeply penetrating functional and molecular imaging at high spatial resolution. Further, PAT holds the promise of in vivo imaging at multiple length scales ranging from subcellular organelles to organs with the same contrast origin, an important application in multiscale systems biology research. PMID- 20161536 TI - Fourier method for large scale surface modeling and registration. AB - Spherical harmonic (SPHARM) description is a powerful Fourier shape modeling method for processing arbitrarily shaped but simply connected 3D objects. As a highly promising method, SPHARM has been widely used in several domains including medical imaging. However, its primary use has been focused on modeling small or moderately-sized surfaces that are relatively smooth, due to challenges related to its applicability, robustness and scalability. This paper presents an enhanced SPHARM framework that addresses these issues and show that the use of SPHARM can expand into broader areas. In particular, we present a simple and efficient Fourier expansion method on the sphere that enables large scale modeling, and propose a new SPHARM registration method that aims to preserve the important homological properties between 3D models. Although SPHARM is a global descriptor, our experimental results show that the proposed SPHARM framework can accurately describe complicated graphics models and highly convoluted 3D surfaces and the proposed registration method allows for effective alignment and registration of these 3D models for further processing or analysis. These methods greatly enable the potential of applying SPHARM to broader areas such as computer graphics, medical imaging, CAD/CAM, bioinformatics, and other related geometric modeling and processing fields. PMID- 20161537 TI - Acculturation gaps in Vietnamese immigrant families: Impact on family relationships. AB - Vietnamese immigrants in the United States face acculturation challenges involving the individual, family, and community. Experts suggest that immigrant family members acculturate at different rates resulting in an acculturation gap, which negatively influences family adjustment. In this study we examined the degree and patterns of acculturation differences between 104 first generation immigrant Vietnamese adolescents and their parents, and whether acculturation gap affected family relationships. Operationalizing the "gap" as both absolute value of differences in acculturation and interactions of parent and adolescent acculturation levels, we examined the impact of such gaps in Vietnamese and American language, identity, and behavioral acculturation on family relationships. Results revealed that family cohesion and satisfaction were predicted by gaps in Vietnamese identity acculturation, but not by gaps in other acculturation domains. PMID- 20161538 TI - Association of epilepsy and comorbid conditions. AB - Comorbid health conditions are common among people with epilepsy. Proposed explanations for this association include the possibility that first, epilepsy (including its treatment) causes the comorbid condition; second, the comorbid condition (including its treatment) causes epilepsy; or third, a common pathogenic mechanism mediates the co-occurrence of epilepsy and the comorbid condition. It is unlikely that a single explanation will suffice for all of the epilepsy comorbid conditions. Determining the basis of the association between epilepsy and its comorbid conditions has important implications for diagnosis and management. In this paper, we discuss this issue in the context of five common epilepsy comorbid conditions: bone health and fractures, stroke, depression, migraine and attention-deficit hyperactivity disorder. Current findings, research limitations and future directions of research efforts are discussed. PMID- 20161539 TI - Cognition and incident coronary heart disease in late midlife: The Whitehall II study. AB - The purpose of this study was to investigate whether cognitive function in midlife predicts incident coronary heart disease (CHD), followed up over 6 years. Data on 5292 (28% women, mean age 55) individuals free from CHD at baseline were drawn from the British Whitehall II study. We used Cox regression to model the association between cognition and CHD in analyses adjusted for socio-demographic variables, cardiovascular risk factors and health behaviors. The results show a one standard deviation lower score on the "general" cognitive measure and measures of reasoning and vocabulary to be associated with elevated CHD risk. There was some evidence that these effects differed between high and low socioeconomic status (SES) groups with associations only seen in the low SES group. These results were not explained by threshold effects or by the different SES groups representing different parts of the cognitive test score distribution. Three other possible explanations of these results are discussed: sub clinical vascular disease drives the observed association but no effect is observed in the high SES group due to compensation provided by greater cognitive reserve, cognition is a marker of overall bodily integrity particularly in low-SES groups, and SES is a moderator of the association between cognition and CHD, because it marks a range of other risk factors. PMID- 20161541 TI - Python Environment for Bayesian Learning: Inferring the Structure of Bayesian Networks from Knowledge and Data. AB - In this paper, we introduce pebl, a Python library and application for learning Bayesian network structure from data and prior knowledge that provides features unmatched by alternative software packages: the ability to use interventional data, flexible specification of structural priors, modeling with hidden variables and exploitation of parallel processing. PMID- 20161542 TI - Why Do White Americans Oppose Race-Targeted Policies? Clarifying the Impact of Symbolic Racism. AB - Measures of symbolic racism (SR) have often been used to tap racial prejudice toward Blacks. However, given the wording of questions used for this purpose, some of the apparent effects on attitudes toward policies to help Blacks may instead be due to political conservatism, attitudes toward government, and/or attitudes toward redistributive government policies in general. Using data from national probability sample surveys and an experiment, we explored whether SR has effects even when controlling for these potential confounds and whether its effects are specific to policies involving Blacks. Holding constant conservatism and attitudes toward limited government, SR predicted Whites' opposition to policies designed to help Blacks and more weakly predicted attitudes toward social programs whose beneficiaries were racially ambiguous. An experimental manipulation of policy beneficiaries revealed that SR predicted policy attitudes when Blacks were the beneficiary but not when women were. These findings are consistent with the claim that SR's association with racial policy preferences is not due to these confounds. PMID- 20161540 TI - Networks and pathways in pigmentation, health, and disease. AB - Extensive studies of the biology of the pigment-producing cell (melanocyte) have resulted in a wealth of knowledge regarding the genetics and developmental mechanisms governing skin and hair pigmentation. The ease of identification of altered pigment phenotypes, particularly in mouse coat color mutants, facilitated early use of the pigmentary system in mammalian genetics and development. In addition to the large collection of developmental genetics data, melanocytes are of interest because their malignancy results in melanoma, a highly aggressive and frequently fatal cancer that is increasing in Caucasian populations worldwide. The genetic programs regulating melanocyte development, function, and malignancy are highly complex and only partially understood. Current research in melanocyte development and pigmentation is revealing new genes important in these processes and additional functions for previously known individual components. A detailed understanding of all the components involved in melanocyte development and function, including interactions with neighboring cells and response to environmental stimuli, will be necessary to fully comprehend this complex system. The inherent characteristics of pigmentation biology as well as the resources available to researchers in the pigment cell community make melanocytes an ideal cell type for analysis using systems biology approaches. In this review, the study of melanocyte development and pigmentation is considered as a candidate for systems biology-based analyses. PMID- 20161544 TI - Permeate from cheese whey ultrafiltration is a source of milk oligosaccharides. AB - Previously undescribed oligosaccharides in bovine cheese whey permeate were characterized by a combination of nanoelectrospray Fourier Transform Ion Cyclotron Resonance (nESI-FTICR) mass spectrometry and matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance (MALDI-FTICR) mass spectrometry. Oligosaccharide composition was elucidated by collision induced dissociation within the ICR cell. In addition to sialyllactose (the most abundant oligosaccharide in bovine colostrum), we identified 14 other oligosaccharides, half of which have the same composition of human milk oligosaccharides. These oligosaccharides could potentially be used as additives in infant formula and products for the pharmaceutical industry. Because whey permeate is a by-product from the production of whey protein concentrate (WPC) and is readily available, it is an attractive source of oligosaccharides for potential application in human nutrition. PMID- 20161543 TI - Acculturation stress, anxiety disorders, and alcohol dependence in a select population of young adult Mexican Americans. AB - OBJECTIVES: Mexican Americans comprise one of the most rapidly growing populations in the U.S. and within this population the process of acculturation has been suggested to be associated with some mental health problems. This study sought to ascertain quantitative information indexing acculturation stress and its association with mental health disorders in a select community sample of Mexican Americans. METHODS: Demographic information, DSM-III-R diagnoses, and information on cultural identity and acculturation stress were obtained from 240 Mexican American young adults that were recruited by fliers and were residing in selected areas of San Diego. RESULTS: No associations were found between measures of cultural identification and lifetime diagnoses of drug or alcohol dependence, major depressive disorder, anxiety disorders or antisocial personality disorder/conduct disorder in this sample of Mexican American young adults. However, lifetime diagnoses of alcohol dependence, substance dependence, and anxiety disorders were associated with elevations in acculturation stress. CONCLUSION: Quantitative measures of acculturation stress, but not cultural identity per se, were found to be significantly associated with substance dependence and anxiety disorders in this select population of Mexican American young adults. These data may be helpful in designing prevention and intervention programs for this high risk population. PMID- 20161545 TI - Impact on Image Noise of Incorporating Detector Blurring into Image Reconstruction for a Small Animal PET Scanner. AB - We study the noise characteristics of an image reconstruction algorithm that incorporates a model of the non-stationary detector blurring (DB) for a mouse imaging positron emission tomography (PET) scanner. The algorithm uses ordered subsets expectation maximization (OSEM) image reconstruction, which is used to suppress statistical noise. Including the non-stationary detector blurring in the reconstruction process (OSEM(DB)) has been shown to increase contrast in images reconstructed from measured data acquired on the fully-3D MiCES PET scanner developed at the University of Washington. As an extension, this study uses simulation studies with a fully-3D acquisition mode and our proposed FORE+OSEM(DB) reconstruction process to evaluate the volumetric contrast versus noise trade-offs of this approach. Multiple realizations were simulated to estimate the true noise properties of the algorithm. The results show that incorporation of detector blurring (FORE+OSEM(DB)) into the reconstruction process improves the contrast/noise trade-offs compared to FORE+OSEM in a radially dependent manner. Adding post reconstruction 3D Gaussian smoothing to FORE+OSEM and FORE+OSEM(DB) reduces the contrast versus noise advantages of FORE+OSEM(DB). PMID- 20161546 TI - Truancy Intervention Programs: Challenges and Innovations to Implementation. AB - School truancy, particularly in primary and secondary schools, represents a serious issue deserving attention in communities across the nation. Most often treated as a management and disciplinary problem, serious attention to the underlying causes of truancy is usually given after the youth's absence from school becomes frequent or chronic. Truant youths are at considerable risk of continuing their troubled behavior in school, experiencing psychosocial difficulties, and entering the juvenile justice system. Unfortunately, with few exceptions, truancy has not received significant attention by criminologists. This paper addresses three questions: (1) What kinds of truancy programs exist in the U.S? (2) What evidence do we have regarding their effectiveness? (3) What system and programmatic issues present obstacles to implementing successful truancy programs, and need to be considered in establishing effective programs? Finally, we discuss efforts that are underway in Hillsborough County, Florida in implementing an effective continuum of service for truant youths and their families. PMID- 20161547 TI - A 236-GHz Fe EPR STUDY OF NANO-PARTICLES OF THE FERRO-MAGNETIC ROOM-TEMPERATURE SEMICONDUCTOR Sn(1-x)Fe(x)O(2)(x=0.005). AB - High frequency (236 GHz) electron paramagnetic resonance (EPR) studies of Fe(3+) ions at 255 K are reported in a Sn(1-x)Fe(x)O(2) powder with x = 0.005 which is a ferromagnetic semiconductor at room temperature. The observed EPR spectrum can be simulated reasonably well as overlap of spectra due to four magnetically inequivalent high-spin (HS) Fe(3+) ions (S = 5/2). The spectrum intensity is calculated, using the overlap I(BL) + (I(HS1)+I(HS2)+I(HS3)+I(HS4))*e( 0.00001*B), where B is the magnetic field intensity in Gauss, I represents the intensity of an EPR line (HS1, HS2, HS3, HS4), and BL stands for the base line. (The exponential factor, as found by fitting to the experimental spectrum, is related to the Boltzmann population distribution of energy levels at 255 K, which is the temperature of the sample in the spectrometer.) These high-frequency EPR results are significantly different from those at X-band. The large values of the zero-field splitting parameter (D) observed here for the four centers at the high frequency of 236 GHz are beyond the capability of X-band, which can only record spectra of ions only with much smaller D values than those reported here. PMID- 20161548 TI - Regioselective Intermolecular Coupling Reaction of Arylketones and Alkenes Involving C-H Bond Activation Catalyzed by an In-Situ Formed Cationic Ruthenium Hydride Complex. AB - The cationic ruthenium-hydride complex, formed in-situ from the treatment of the tetranuclear ruthenium-hydride complex {[(PCy(3))(CO)RuH](4)(mu(4)-O)(mu(3) OH)(mu(2)-OH)} with HBF(4).OEt(2), was found to be a highly effective catalyst for the intermolecular coupling reaction of arylketones and 1-alkenes to give the substituted indene and ortho-C-H insertion products. The formation of the indene products was resulted from the initial alkene isomerization followed by regioselective ortho-C-H insertion of 2-alkene and the dehydrative cyclization. The preliminary mechanistic studies revealed a rapid and reversible ortho-C-H bond activation followed by the rate-limiting C-C bond formation step for the coupling reaction. PMID- 20161550 TI - A Reusable, Low-profile, Cryogenic Wire Seal. AB - We describe the design of a reusable Indium wire seal which has a small profile and is leak tight to better than 1x10(-10) std. cc/sec. from room temperature down to approximately mK. The pressure necessary to deform the Indium wire o-ring is provided by a screw-cap mating to threads on the outside of the cylindrical volume to be sealed. PMID- 20161549 TI - Stereotype Activation, Inhibition, and Aging. AB - This research explored age-related changes in drawing stereotypic inferences during the comprehension of narrative texts. Previous research suggests that declines in inhibitory function can lead older adults to rely more on stereotypes and be more prejudiced than younger adults, even in the face of a desire to be non-prejudiced. In two experiments reported here, younger and older adults read stories that allowed for stereotypic inferences. Older adults were less likely to inhibit stereotypic inferences as measured by recognition measures and lexical decision times. A third control experiment verified that the results of the lexical decision task were not due to a priori response biases for the specific target words. Overall, older adults were more likely to make and maintain stereotypic inferences than younger adults, potentially causing them to be more prejudiced than younger adults. PMID- 20161551 TI - Direct organocatalytic coupling of carboxylated piperazine-2,5-diones with indoles through conjugate addition of carbon nucleophiles to indolenine intermediates. AB - The indole-diketopiperazine bridge is an important structural feature of many bispyrrolidinoindoline and epipolythiodiketopiperazine fungal metabolites. Organocatalytic conjugate addition of diketopiperazines to indoles was achieved in good to excellent yields through electrophilic indolenine intermediates generated under mild conditions. Screening of catalysts and solvents at different temperatures was performed in order to achieve high product yields. PMID- 20161552 TI - Total Syntheses of Naamidine G and 14-Methoxynaamidine G. AB - Simple total syntheses of two Leucetta-derived marine alkaloids have been developed using position specific halogen-metal exchange of polyhaloimidazoles to introduce the benzyl substituted sidechains. Introduction of the C2 amine group by lithiation and trapping with tosyl azide provides amines on catalytic hydrogenation, which can be converted to naamidine G and 14-methoxynaamidine G using a procedure described in the literature. PMID- 20161553 TI - Behavioral Sleep Medicine Interventions for Restless Legs Syndrome and Periodic Limb Movement Disorder. AB - Restless Legs Syndrome (RLS) and Periodic Limb Movement Disorder (PLMD) are sleep disorders that are commonly seen in clinical practice. The standard treatment recommendations for these disorders are pharmacologic; most recently both conditions are most typically managed with pramipexole or ropinerole, which are FDA approved for the treatment of RLS. A mix of behavioral suggestions is included in treatment algorithms for providers as well as in patient education materials. While these suggestions have considerable merit, they are typically not delivered as an intervention, but instead provided as a series of helpful tips. There is emerging evidence for providing such suggestions as a more active and comprehensive intervention as part of a cognitive-behavioral package as well as for exercise therapy and cognitive behavioral therapy for insomnia to be delivered as active treatments for RLS and/or PLMD. PMID- 20161554 TI - Fast Image Registration by Hierarchical Soft Correspondence Detection. AB - A new approach, based on the hierarchical soft correspondence detection, has been presented for significantly improving the speed of our previous HAMMER image registration algorithm. Currently, HAMMER takes a relative long time, e.g., up to 80 minutes, to register two regular sized images using Linux machine (with 2.40GHz CPU and 2-Gbyte memory). This is because the results of correspondence detection, used to guide the image warping, can be ambiguous in complex structures and thus the image warping has to be conservative and accordingly takes long time to complete. In this paper, a hierarchical soft correspondence detection technique has been employed to detect correspondences more robustly, thereby allowing the image warping to be completed straightforwardly and fast. By incorporating this hierarchical soft correspondence detection technique into the HAMMER registration framework, the robustness and the accuracy of registration (in terms of low average registration error) can be both achieved. Experimental results on real and simulated data show that the new registration algorithm, based the hierarchical soft correspondence detection, can run nine times faster than HAMMER while keeping the similar registration accuracy. PMID- 20161555 TI - An Automatic 3D Mesh Generation Method for Domains with Multiple Materials. AB - This paper describes an automatic and efficient approach to construct unstructured tetrahedral and hexahedral meshes for a composite domain made up of heterogeneous materials. The boundaries of these material regions form non manifold surfaces. In earlier papers, we developed an octree-based isocontouring method to construct unstructured 3D meshes for a single-material (homogeneous) domain with manifold boundary. In this paper, we introduce the notion of a material change edge and use it to identify the interface between two or several different materials. A novel method to calculate the minimizer point for a cell shared by more than two materials is provided, which forms a non-manifold node on the boundary. We then mesh all the material regions simultaneously and automatically while conforming to their boundaries directly from volumetric data. Both material change edges and interior edges are analyzed to construct tetrahedral meshes, and interior grid points are analyzed for proper hexahedral mesh construction. Finally, edge-contraction and smoothing methods are used to improve the quality of tetrahedral meshes, and a combination of pillowing, geometric flow and optimization techniques is used for hexahedral mesh quality improvement. The shrink set of pillowing schemes is defined automatically as the boundary of each material region. Several application results of our multi material mesh generation method are also provided. PMID- 20161556 TI - Multi-scale, multi-resolution brain cancer modeling. AB - In advancing discrete-based computational cancer models towards clinical applications, one faces the dilemma of how to deal with an ever growing amount of biomedical data that ought to be incorporated eventually in one form or another. Model scalability becomes of paramount interest. In an effort to start addressing this critical issue, here, we present a novel multi-scale and multi-resolution agent-based in silico glioma model. While 'multi-scale' refers to employing an epidermal growth factor receptor (EGFR)-driven molecular network to process cellular phenotypic decisions within the micro-macroscopic environment, 'multi resolution' is achieved through algorithms that classify cells to either active or inactive spatial clusters, which determine the resolution they are simulated at. The aim is to assign computational resources where and when they matter most for maintaining or improving the predictive power of the algorithm, onto specific tumor areas and at particular times. Using a previously described 2D brain tumor model, we have developed four different computational methods for achieving the multi-resolution scheme, three of which are designed to dynamically train on the high-resolution simulation that serves as control. To quantify the algorithms' performance, we rank them by weighing the distinct computational time savings of the simulation runs versus the methods' ability to accurately reproduce the high resolution results of the control. Finally, to demonstrate the flexibility of the underlying concept, we show the added value of combining the two highest-ranked methods. The main finding of this work is that by pursuing a multi-resolution approach, one can reduce the computation time of a discrete-based model substantially while still maintaining a comparably high predictive power. This hints at even more computational savings in the more realistic 3D setting over time, and thus appears to outline a possible path to achieve scalability for the all-important clinical translation. PMID- 20161558 TI - Syllable Type Consistency is Related to Age, Social Status, and Reproductive Success in the Tropical Mockingbird. AB - Many animals repeat standardized displays multiple times while attracting a mate or deterring a rival. In such contexts it is possible that the ability to perform each display or signal type in a consistent fashion is under direct selection. Studies on sexual selection on song learning in birds have focused on differences in repertoire size with less attention to the potential importance of being able to perform each song/syllable type with high consistency. We present evidence that tropical mockingbirds decrease the variation between renditions of each syllable type as they grow older (i.e., become more consistent) and that more consistent males in this species tend to have higher dominance status and reproductive success. These findings stress the importance of consistency in the performance of sexual displays and suggest that this parameter may be very relevant even in species that are selected for high vocal diversity (i.e., large repertoires). In addition to signalling dominance status and age, we hypothesize that syllable type consistency may also be an indicator of the integrity of brain function in birds analogous to the tests used for neuropsychological assessment in humans. PMID- 20161557 TI - Effectiveness of Early Phonological Awareness Interventions for Students with Speech or Language Impairments. AB - This article reviews research examining the efficacy of early phonological interventions for young students identified with Speech or Language impairments. Eighteen studies are included, providing results for nearly 500 students in preschool through third grade. Although findings were generally positive, there were large individual differences in response to intervention. Further, there was little evidence that interventions enabled students to catch up in phonological or reading skills to typically developing peers. Methodological issues are described and implications for practice and future research are discussed. PMID- 20161559 TI - CHALLENGES TO IMPLEMENTING AND ENFORCING CALIFORNIA'S SMOKE-FREE WORKPLACE ACT IN BARS. AB - California's 1995 Smoke-Free Workplace Act-Assembly Bill 13 (AB 13)-was extended to bars in 1998. This paper examines the challenges faced by officials responsible for implementing and enforcing the law. As part of a series of studies evaluating AB 13 in bars, researchers conducted confidential in-depth interviews with 35 state, county and municipal authorities and representatives of non-governmental agencies. The interviews were recorded, transcribed, coded and analyzed by themes and respondent categories. Data from structured observations in sampled bars and interviews with bar staff and patrons offer contextual information. Analyses indicated the following challenges: 1) an ineffective administrative structure, 2) problems associated with the complaint-driven system used to enforce the law, 3) lack of funding for enforcement, 4) low prioritization of enforcement, and 5) the minimal deterrence effect of the sanctioning penalties. The findings indicate why indoor smoking may continue in some bars despite the state law prohibiting smoking in workplaces. Many municipalities, states and countries may be considering restricting smoking in workplaces including bars, and our findings show that clear delineation of procedures and enforcement criteria, as well as funding and substantive penalties, should be considered in drafting these laws. PMID- 20161560 TI - Young Adult Migration from a Northern Plains Indian Reservation: Who Stays and Who Leaves. AB - We evaluated how ambitions, community ties, monetary sufficiency, employment, and alcohol consumption related to whether young American Indian adults had moved from their Northern Plains reservation. Of 518 Northern Plains reservation residents in 1993, we located 472 in 2003-2005 and found that 89 lived more than a four-hour drive from the reservation. Coding the 472 as to whether they had stayed on/near the reservation or moved away, we ran logistic regressions on data they reported in 1996 to determine which demographic and attitudinal variables were associated with having moved. We found ambitions and goals were more associated with moving away than were ties to the community, which in turn were more related than monetary and personal characteristics that promote independence and prosperity. The more importance they placed on getting a good education or carrying on the tribe's traditions, the more likely they were to have moved away. We found too that the odds of moving away decreased with greater alcohol consumption. Tribal council members and college administrators therefore may wish to promote policies that increase opportunities for young adults to achieve higher education goals while remaining on reservation to carry on tribal traditions. Benefits may also come from encouraging and assisting reservation members studying off-reservation to return after completing their education. These findings would argue too for greater investment in alcohol services for reservation-dwelling populations. PMID- 20161561 TI - The effects of tone language experience on pitch processing in the brainstem. AB - Neural encoding of pitch in the auditory brainstem is shaped by long-term experience with language. The aim herein was to determine to what extent this experience-dependent effect is specific to a particular language. Analysis of variance of brainstem responses to Mandarin and Thai tones revealed that regardless of language identity, pitch-tracking accuracy of whole tones was higher in the two tone language groups (Chinese, Thai) compared to the non-tone language group (English), and that pitch strength of 40-ms tonal sections was generally more robust in tone relative to non-tone languages. Discriminant analysis of tonal sections, as defined by variation in direction and degree of slope, showed that moderate rising pitch was the most important variable for classifying English, Chinese, and Thai participants into their respective groups. We conclude that language-dependent enhancement of pitch representation transfers to other languages with similar phonological systems. From a neurobiological perspective, these findings suggest that neural mechanisms local to the brainstem are tuned for processing pitch dimensions that are perceptually salient depending upon the melodic patterns of a language. PMID- 20161562 TI - The reality of phonological forms: a reply to Port. AB - I suggest four grounds on which an argument can be made that phonological language forms are not merely emergent properties of the public language use of members of a language community. They are: 1) the existence of spontaneous errors of speech production in which whole consonants or vowels misorder or are replaced; 2) the necessary existence of language "particles" used by individual language users in order for words to be able to be coined; 3) the remarkable effectiveness of alphabetic writing systems and the tight coupling among skilled readers of orthographic and phonological language forms; 4) the finding that, by late infancy, children have discovered phonological constancies despite phonetic variation. PMID- 20161563 TI - Enantioselective sulfonylation reactions mediated by a tetrapeptide catalyst. AB - While Nature excels at performing selective modifications of complex polyfunctional molecules through the use of tailoring enzymes, synthetic chemistry has lagged behind in this regard. In prior work, we have applied a biomimetic approach to this problem, developing small peptides to achieve various group transfer reactions on polyol substrates with high enantio- or regioselectivity. The utility of sulfonates as synthetic building blocks and the scarcity of direct, selective methods for their preparation prompted our investigation into this area. In this article we report the development of a pi methyl histidine-based tetrameric peptide that effects the desymmetrization of meso-1,3-diols through enantioselective (mono)sulfonylation. The catalyst exhibits structural similarities to another catalyst found to be effective in orthogonal group transfers, but results in modification of the enantiotopic alcohol. The practical and mechanistic implications of this discovery may extend beyond synthetic considerations and provide analogies to the diverse roles of histidine in enzyme active sites. PMID- 20161564 TI - Effective Conservative Treatment for Chronic Low Back Pain. AB - Evidence suggests that effective conservative treatment is available for chronic low back pain. The effectiveness of conservative treatment has recently received attention following publication of several randomized controlled trials (RCTs) that reported similar improvements in outcomes from cognitive intervention with exercise as from spinal fusion surgery. This paper will explore the conservative treatment arms of these RCTs with the goal of educating the reader about the principles of cognitive intervention with exercise. These principles can be incorporated into the care of chronic low back pain patients both as primary treatment and as a means of augmenting surgical outcomes. PMID- 20161565 TI - Driving Retirement in Older Adults with Dementia. AB - In order to characterize the driving and mobility status of older adults with dementia, a questionnaire was mailed to 527 informants; 119 were returned. The majority of patients were diagnosed with Dementia of the Alzheimer's Type. Only 28% were actively driving at the time of survey. Informants rated 53% of current or recently retired drivers as potentially unsafe. Few informants reported using community/educational resources. Individuals with progressive dementia retire from driving for differing reasons, many subsequent to family recognition of impaired driving performance. Opportunities for education and supportive assistance exist but are underutilized. PMID- 20161566 TI - The Epidemiologic Transition: Changing Patterns of Mortality and Population Dynamics. AB - The epidemiologic transition describes changing patterns of population age distributions, mortality, fertility, life expectancy, and causes of death. A number of critiques of the theory have revealed limitations, including an insufficient account of the role of poverty in determining disease risk and mortality, a failure to distinguish adequately the risk of dying from a given cause or set of causes from the relative contributions of various causes of death to overall mortality, and oversimplification of the transition patterns, which do not fit neatly into either historical periods or geographic locations. Recent developments in epidemiologic methods reveal other limitations. A life course perspective prompts examination of changes in causal pathways across the life span when considering shifts in the age distribution of a population as described by the epidemiologic transition theory. The ecological model assumes multiple levels of determinants acting in complex and interrelated ways, with higher level determinants exhibiting emergent properties. Development, testing, and implementation of innovative approaches to reduce the risks associated with the sedentary lifestyle and hyper nutrition in developed countries should not overshadow the continuing threat from infectious diseases, especially resistant strains or newly encountered agents. Interventions must fit populations and the threats to health they experience, while anticipating changes that will emerge with success in some areas. This will require new ways of thinking that go beyond the epidemiologic transition theory. PMID- 20161567 TI - Myth and Reality of the Word Caller: The Relation Between Teacher Nominations and Prevalence Among Elementary School Children. AB - The purpose of the study was to investigate (a) the prevalence of word callers in elementary school, (b) the accuracy of teachers' word caller nominations, and (c) teachers' conceptualization of reading fluency and reading comprehension. To this end, 2 cross-sectional studies of second- and third- (N = 868) and of third- and fifth-grade (N = 202) children were conducted. Our findings suggest that word callers occur infrequently in the primary grades but that they are more prevalent in late elementary school. Regardless of grade level, teachers often overnominated children as word callers. Furthermore, a great deal of ambiguity and inconsistency seems to exist regarding teachers' understanding and use of the term. These findings suggest that the term should be used relatively rarely and that reading educators should be cautious about their identification of word callers in early elementary school. PMID- 20161568 TI - PREVENTION OF ATHEROSCLEROSIS WITH LDL-C LOWERING - LIPOPROTEIN CHANGES AND INTERACTIONS: THE SANDS STUDY. AB - BACKGROUND: Lowering low-density lipoprotein cholesterol (LDL-C) with statins reduces atherosclerosis. LDL and high-density lipoprotein (HDL) are commonly measured by their cholesterol content, but non-HDL cholesterol, LDL particle number (LDL-P), or total apolipoprotein B (apoB) may better predict cardiovascular risk. Few studies have examined relations among lipoprotein levels and composition before and after interventions to lower LDL-C and non-HDL-C. OBJECTIVE: To measure changes in carotid artery intimal media thickness (CIMT) and lipid concentration and composition during 36 months of statin therapy. METHODS: Analyses were conducted on 418 diabetic individuals, with complete data and no prior cardiovascular events, who were randomized to aggressive (AG) versus standard (STD) treatment for LDL-C, non-HDL-C, and systolic blood pressure (SBP) as part of the Stop Atherosclerosis in Native Diabetics Study (SANDS). RESULTS: The AG group achieved average LDL-C and non-HDL-C of 71mg/dL and 100mg/dL and a decrease in CIMT. No significant interactions were observed between treatment effect and initial levels of LDL-C, non-HDL-C, HDL-C, triglycerides, apoB, or LDL P. Decreases in LDL-C (p<.005) and non-HDL-C (p<.001) were independently correlated with CIMT regression in the AG group. Changes in apoB and LDL-P showed borderline correlations with CIMT regression (p=.07 and p=.09). CONCLUSIONS: In diabetic adults with no prior cardiovascular events, treatment to current targets for lipids and SBP reduces atherosclerosis progression and when more aggressive targets are met, atherosclerosis regresses. The aggressive targets for LDL-C and non-HDL-C appeared to be the main determinants of CIMT regression and were more predictive of this outcome than changes in LDL-P or apoB. PMID- 20161570 TI - Family Income at the Bottom and at the Top: Income Sources and Family Characteristics. AB - Attention has recently been focused on wealth as a source of long-term economic security and on wealth ownership as a crucial aspect of the racial economic divisions in the United States. This literature, however has been concerned primarily with the wealth gap between poor and middle-class families, and between the white and black middle class. In this paper, we investigate the incomes of families at the top and bottom of the family income distribution. We examine the sources of income and the demographic characteristics of these high-income and low-income families using family level data from the 1988-2003 Current Population Surveys.We find that, at the bottom of the distribution, transfer income is the major income source; in particular, income from social security, supplemental security, and public assistance. At the top, employment income is the largest component of family income. Non-white, female, and non-married householders are disproportionately located at the bottom of the family income distribution. These families consist of both young and old adults, with high-school educations or less, in low-level service occupations. Many are disabled, many are retired. Householders at the top of the income distribution are typically male, white, and married. Householders and spouses at the top are typically middle-age, with college educations, employed in professional service and managerial occupations.We find that wealth is not an important source of income for families at the highest percentiles. The highest income families during this period in the U.S. were not a "property elite": their income is mostly from employment. We speculate, however, that they will join the "property elite" later in the life course as they retire and receive income from their investments. PMID- 20161569 TI - A Bioecological Analysis of Risk and Protective Factors Associated With Early Sexual Intercourse of Young Adolescents. AB - Microsystem risk and protective factors associated with early sexual intercourse among low-income adolescents were assessed using bioecological theory and a risk and resiliency framework. Waves 1 and 2 of Welfare, Children and Families: A Three-City Study were used (N=984, 10-14 years). Findings showed age, gender, race, two-parent households, separated households, households where the mother formed a union between waves, transitioning onto welfare between waves, and delinquency increased the odds that adolescents were sexually active. Protective factors for early sexual activity included maternal education and father involvement. Risk factors for early sexual debut were age, gender, race, two parent households, separated households, and delinquency. A protective factor for early sexual debut was maternal education. Findings differed by gender, race, and race*gender. Policy implications include increasing social and human capital among low-income mothers to promote family stability and providing diversified sexual education programs due to gender differences. PMID- 20161571 TI - Predicting dementia: role of dementia risk indices. AB - There are currently more than 5 million people in the USA living with Alzheimer's disease and other forms of dementia, and prevalence is expected to triple over the next 40 years. As new strategies for prevention and treatment are developed, it will be critically important to be able to identify older adults who do not currently have dementia but have a high risk of developing symptoms within a few years so that they can be targeted for monitoring, prevention and early treatment. In other fields, prognostic models and risk indices are often used to identify high-risk individuals (e.g., Framingham Heart Index and Breast Cancer Risk Assessment Tool). The objective of this paper is to describe the development of Dementia Risk Indices and to discuss the potential for these tools to be incorporated into clinical and research settings for the identification of individuals with a high risk of dementia. PMID- 20161573 TI - Through-Space Effects of Substituents Dominate Molecular Electrostatic Potentials of Substituted Arenes. AB - Model systems have been studied using density functional theory to assess the contributions of pi-resonance and through-space effects on electrostatic potentials of substituted arenes. The results contradict the widespread assumption that changes in molecular ESPs reflect only local changes in the electron density. Substituent effects on the ESP above the molecular plane are commonly attributed to changes in the aryl pi-system. We show that ESP changes for a collection of substituted benzenes and more complex aromatic systems can be accounted for mostly by through-space effects, with no change in the aryl pi electron density. Only when pi-resonance effects are substantial do they influence changes in the ESP above the aromatic ring to any extent. Examples of substituted arenes studied here are taken from the fields of drug design, host guest chemistry, and crystal engineering. These findings emphasize the potential pitfalls of assuming ESP changes reflect changes in the local electron density. Since ESP changes are frequently used to rationalize and predict intermolecular interactions, these findings have profound implications for our understanding of substituent effects in countless areas of chemistry and molecular biology. Specifically, in many non-covalent interactions there are significant, often neglected, through-space interactions with the substituents. Finally, the present results explain the perhaps unexpectedly good performance of many molecular mechanics force-fields applied to supramolecular assembly phenomena and pi-pi interactions in biological systems despite the neglect of the polarization of the aryl pi-system by substituents. PMID- 20161572 TI - Clinical Case Discussion: Pathological Gambling and Nicotine Dependence. PMID- 20161574 TI - Prospective associations between alcohol and drug consumption and risky sex among female college students. AB - Females who ever had vaginal sex were interviewed annually in their first two years of college (n=386, ages 17 to 20 at study outset) and asked about risky sex behaviors and substance use. In year one, 60.2%(wt) had intoxicated sex, 31.4%(wt) had multiple sex partners, and 48.9%(wt) had unprotected sex (i.e., without a condom). At follow-up, high rates of persistence (86.0%, 52.7%, 78.8% respectively) and initiation (36.0%, 23.9%, 41.8%) were observed. In multiple logistic regression analyses, drug use and drinking were independently associated with having multiple sex partners. Intoxicated sex independently predicted condom non-use and multiple sex partners, and appeared to mediate the relationship between substance use and multiple sex partners. Implications for prevention and future research are discussed. PMID- 20161575 TI - Body Size and Social Self-Image among Adolescent African American Girls: The Moderating Influence of Family Racial Socialization. AB - Social psychologists have amassed a large body of work demonstrating that overweight African American adolescent girls have generally positive self-images, particularly when compared with overweight females from other racial and ethnic groups. Some scholars have proposed that elements of African American social experience may contribute to the maintenance of these positive self-views. In this paper, we evaluate these arguments using data drawn from a panel study of socio-economically diverse African American adolescent girls living in Iowa and Georgia. We analyze the relationship between body size and social self-image over three waves of data, starting when the girls were 10 years of age and concluding when they were approximately 14. We find that heavier respondents hold less positive social self-images but also find that being raised in a family that practices racial socialization moderates this relationship. PMID- 20161577 TI - Adolescent Family Context and Adult Identity Formation. AB - This study examines the links between adolescent family context and coming to see oneself as an adult. Using data from the National Longitudinal Study of Adolescent Health, we investigate how adolescent family structure, resources, and processes together influence adult identity and whether they do so similarly for men and women. We find that youth in single- or step-parent families, but not in two parent adoptive families, are more likely to identify as adults compared to those in two biological parent families. These relationships, however, are mediated by both family resources and processes. We also find that one of these processes, parental control, is especially influential for youth in single-father and "other" family structures, and that parent-adolescent relationship quality and living in "other" structure families are more consequential for young women than men. PMID- 20161576 TI - Correlates and Treatments of Nightmares in Adults. AB - Nightmares, distressing dreams that primarily arise from REM sleep, are prevalent among the general population and even more so among clinical populations. The frequency of nightmares and related nightmare distress are linked to both sleep disturbance and waking psychopathology. Based on the extant evidence, nightmares appear to be particularly relevant to posttraumatic stress disorder, and may even be implicated in its pathophysiology. Significant advances in treatment have occurred in recent years, with effective pharmacological and psychosocial interventions now available. Despite the progress that has been made, however, more consistent assessment methods and more rigorous study designs are needed to fully understand the causes and consequences of nightmares. PMID- 20161578 TI - Growth of hydroxyapatite coatings on biodegradable polymer microspheres. AB - Mineral-coated microspheres were prepared via a bioinspired, heterogeneous nucleation process at physiological temperature. Poly(d,l-lactide-co-glycolide) (PLG) microspheres were fabricated via a water-in-oil-in-water emulsion method and were mineral-coated via incubation in a modified simulated body fluid (mSBF). X-ray diffraction, Fourier transform infrared spectroscopy, and scanning electron microscopy with associated energy-dispersive X-ray spectroscopy confirmed the presence of a continuous mineral coating on the microspheres. The mineral grown on the PLG microsphere surface has characteristics analogous to those of bone mineral (termed "bonelike" mineral), with a carbonate-containing hydroxyapatite phase and a porous structure of platelike crystals at the nanometer scale. The assembly of mineral-coated microspheres into aggregates was observed when microsphere concentrations above 0.50 mg/mL were incubated in mSBF for 7 days, and the size of the aggregates was dependent on the microsphere concentration in solution. In vitro mineral dissolution studies performed in Tris-buffered saline confirmed that the mineral formed was resorbable. A surfactant additive (Tween 20) was incorporated into mSBF to gain insight into the mineral growth process, and Tween 20 not only prevented aggregation but also significantly inhibited mineral formation and influenced the characteristics of the mineral formed on the surface of PLG microspheres. Taken together, these findings indicate that mineral coated PLG microspheres or mineral-coated microsphere aggregates can be synthesized in a controllable manner using a bioinspired process. These materials may be useful in a range of applications, including controlled drug delivery and biomolecule purification. PMID- 20161579 TI - Chiral spiroaminoborate ester as a highly enantioselective and efficient catalyst for the borane reduction of furyl, thiophene, chroman and thiochroman containing ketones. AB - Prochiral heteroaryl ketones containing furan, thiophene, chroman and thiochroman moieties were successfully reduced in the presence of 1 - 10 mol % of spiroaminoborate ester 1 with different borane sources to afford non-racemic alcohols in up to 99% ee. In addition, modest enantioselectivity, around 80% ee, was achieved in the reduction of linear alpha,beta-unsaturated heteroaryl ketones. PMID- 20161580 TI - An Efficient Boric Acid Mediated Preparation of alpha-Hydroxyamides. AB - An efficient methodology for the preparation of alpha-hydroxyamides via boric acid mediated addition of isonitriles on to aldehydes has been developed. The reaction of isonitriles with alpha-boronobenzaldehyde takes place under intramolecular catalysis conditions to provide functionalized benzoxaboroles. PMID- 20161581 TI - Biochemical indices as correlates of recent growth in juvenile green turtles (Chelonia mydas). AB - Nucleic acid and protein concentrations and their ratios are increasingly used as correlates of nutritional condition and growth in marine species. However, their application in studies of reptile growth has not yet been validated. The green turtle (Chelonia mydas) is an endangered marine reptile for which assessing population health requires knowledge of demographic parameters such as individual growth rates. The purpose of this study was to evaluate a number of biochemical indices ([DNA], [RNA], RNA:DNA ratio, [protein], protein:DNA ratio, and RNA:protein ratio) in liver, heart, and blood as potential predictors of recent growth rate in juvenile green turtles under controlled feeding conditions. Intake of juvenile green turtles was manipulated over twelve weeks to obtain a range of growth rates. With the exception of [RNA](blood), [DNA](heart), and [protein]:[DNA](liver), all biochemical indices demonstrated significant linear relationships with growth rate during the last 1.5 weeks of the study. The best single predictors of recent growth were hepatic [RNA] and [RNA]:[protein], which explained 66% and 49%, respectively, of the variance in growth. Contrary to expectations, these two indices were negatively correlated with growth rate. To investigate the possibility that hepatic [RNA] was higher in slow-growing turtles because of elevated expression of antioxidant genes, we quantified glutathione peroxidase activity and total antioxidant potential. Both measures of antioxidant function were affected by intake and growth histories, but these effects did not explain our results for hepatic RNA and protein concentrations. We developed a model that predicted 68% of the variance in specific growth rate (SGR) with the equation SGR = -0.913(ln[RNA](liver)) + 17.689(Condition Index) + 4.316. In addition, our findings that [DNA] and [RNA]:[DNA] for blood were significantly correlated with SGR demonstrate the potential utility of minimally invasive tissue sampling that could facilitate instantaneous population monitoring. PMID- 20161582 TI - Evidence-Based Reading Instruction for Individuals with Autism Spectrum Disorders. AB - Legislation mandates that all children, including children with autism spectrum disorders (ASD) be taught to read in ways that are consistent with reading research, and target the five components of evidence-based reading instruction: phonemic awareness, phonics, reading fluency, vocabulary and comprehension strategies. The purpose of this review is to synthesize the literature on reading instruction for children with ASD that encompasses one or more of the five components of reading. The review yielded 11 studies with 61 participants ages 4 to 17. Results indicate that children with ASD can benefit from reading instruction consistent with reading research. Research in this area is still preliminary, and more research is needed to guide practice. Possible directions for future research are provided. PMID- 20161583 TI - Localized orbital corrections for the calculation of barrier heights in density functional theory. AB - This work describes the extension of a previously reported empirical localized orbital correction model for density functional theory (DFT-LOC) for atomization energies, ionization potentials, electron affinities, and reaction enthalpies to the correction of barrier heights for chemical reactions of various types including cycloadditions, cycloreversions, dipolar cycloadditions, S(N)2's, carbon radical reactions, hydrogen radical reactions, sigmatropic shifts, and electrocyclizations. The B3LYP localized orbital correction version of the model (B3LYP-LOC) reduces the number of outliers and overall mean unsigned error (MUE) vs. experiment or ab initio values from 3.2 to 1.3 kcal/mole for barrier heights and from 5.1 to 1.1 kcal/mole for reaction enthalpies versus B3LYP. Furthermore, the new model has essentially zero additional computational cost beyond standard DFT calculations. Although the model is heuristic and is based on multiple linear regression to experimental or ab initio data, each of the parameters is justified on chemical grounds and provides insight into the fundamental limitations of DFT, most importantly the failure of current DFT methods to accurately account for nondynamical electron correlation. PMID- 20161584 TI - A Microfluidic Cartridge System for Multiplexed Clinical Analysis. AB - Cartridge-based microfluidics is a promising technology for clinical diagnostics. By miniaturizing the fluid-handling processes required for genomic and proteomic analyses, reagent and specimen volume is minimized along with the size of the system. We demonstrate an automated microfluidic system capable of performing six multiplexed genomic and proteomic analyses simultaneously, by means of an integrated electrochemical sensor and embedded controls. PMID- 20161585 TI - The first chemical synthesis of novel MeO-3-GlcUA derivative of hyaluronan-based disaccharide to elucidate the catalytic mechanism of hyaluronic acid synthases (HASs). AB - The first chemical synthesis of MeO-3-GlcUAbeta(1->3)GlcNAc-UDP to elucidate the catalytic mechanism of hyaluronic acid synthases (HASs) is described. Construction of the desired beta(1->3)-linked disaccharide 10 was achieved very efficiently by coupling MeO-3-GlcUA donor 3 with the suitable protected GlcNTroc acceptor 4 using BF(3(.) )Et(2)O as Lewis acid. Chemoselective removal of anomeric NAP, phosphorylation, hydrogenation, coupling with UMP-morpholidate and finally complete deprotection gave the target compound 1 in good yield. PMID- 20161586 TI - An Empirical Likelihood-Based Method for Comparison of Treatment Effects-Test of Equality of Coefficients in Linear Models. AB - To compare two treatment effects, which can be described as the difference of the parameters in two linear models, we propose an empirical likelihood-based method to make inference for the difference. Our method is free of the assumptions of normally distributed and homogeneous errors, and equal sample sizes. The empirical likelihood ratio for the difference of the parameters of interest is shown to be asymptotically chi-squared. Simulation experiments illustrate that our method outperforms the published ones. Our method is used to analyze a data set from a drug study. PMID- 20161587 TI - Enantioselective Host-Guest Complexation of Ru(II) trisdiimine complexes using neutral and anionic derivatized cyclodextrins. AB - Enantioselective host-guest complexation between five racemic Ru(II) trisdiimine complexes and eight derivatized cyclodextrins (CDs) has been examined by NMR techniques. The appearance of non-equivalent complexation-induced shifts of between the Delta and Lambda-enantionomers of the Ru(II) trisdiimine complexes and derivatized CDs is readily observed by NMR. In particular, sulfobutyl ether beta-cyclodextrin sodium salt (SBE-beta-CD), R-naphtylethyl carbamate beta cyclodextrin (RN-beta-CD), and S-naphtylethyl carbamate beta-cyclodextrin (SN beta-CD) showed good enantiodiscrimination for all five Ru complexes examined, which indicates that aromatic and anionic derivatizing groups are beneficial for chiral recognition. The complexation stoichiometry between SBE-beta-CD and [Ru(phen)(3)](2+) was found to be 1: 1 and binding constants reveal that Lambda [Ru(phen)(3)](2+) binds more strongly to SBE-beta-CD than the Delta-enantiomer. Correlations between this NMR method and separative techniques based on CDs as chiral discriminating agents (i.e., selectors) are discussed in detail. PMID- 20161588 TI - Do personality problems improve during psychodynamic supportive-expressive psychotherapy? Secondary outcome results from a randomized controlled trial for psychiatric outpatients with personality disorders. AB - Studies involving patients with personality disorders (PDs) have not focused on improvement of core aspects of the PD. The authors examined changes in quality of object relations, interpersonal problems, psychological mindedness, and personality traits in a sample of 156 patients with Diagnostic and Statistical Manual of Mental Disorders (4th ed.) PD diagnoses being randomized to either manualized or nonmanualized dynamic psychotherapy. Effect sizes adjusted for symptomatic change and reliable change indices were calculated. The authors found that both treatments were equally effective at reducing personality pathology. Only in neuroticism did the nonmanualized group do better during the follow-up period. The largest improvement was found in quality of object relations. For the remaining variables, only small and clinically insignificant magnitudes of change were found. (PsycINFO Database Record PMID- 20161590 TI - Graph-theoretic criteria for injectivity and unique equilibria in general chemical reaction systems. AB - In this paper we discuss the question of how to decide when a general chemical reaction system is incapable of admitting multiple equilibria, regardless of parameter values such as reaction rate constants, and regardless of the type of chemical kinetics, such as mass-action kinetics, Michaelis-Menten kinetics, etc. Our results relate previously described linear algebraic and graph-theoretic conditions for injectivity of chemical reaction systems. After developing a translation between the two formalisms, we show that a graph-theoretic test developed earlier in the context of systems with mass action kinetics, can be applied to reaction systems with arbitrary kinetics. The test, which is easy to implement algorithmically, and can often be decided without the need for any computation, rules out the possibility of multiple equilibria for the systems in question. PMID- 20161589 TI - Sources of Urinary Proteins and their Analysis by Urinary Proteomics for the Detection of Biomarkers of Disease. AB - Renal disorders account for a substantial fraction of the budget for health care in many countries. Proteinuria is a frequent manifestation in afflicted patients, but the origin of the proteins varies based on the nature of the disorder. The emerging field of urinary proteomics has the potential to replace kidney biopsy as the diagnostic procedure of choice for patients with some glomerular forms of renal disease. To fully realize this potential, it is vital to understand the basis for the urinary excretion of protein in physiological and pathological conditions. In this review, we discuss the structure of the nephron, the functional unit of the kidney, and the process by which proteins/peptides enter the urine. We discuss several aspects of proteinuria that impact the proteomic analysis of urine of patients with renal diseases. PMID- 20161592 TI - Multidisciplinary Evaluation of Patients With Suspected Lung Cancer. AB - Lung cancer diagnosis and treatment has evolved to require the input and expertise of multiple diverse medical and surgical specialties. The approach to lung cancer patients requires the adherence to a few principles that include thorough use of staging modalities to assure the proper treatment for each patient, and an understanding of the limitations and advantages of each of these modalities. Evidence is continuing to emerge that supports the notion that diagnostic workup and treatment of lung cancer patients is best done within the context of a multidisciplinary team devoted to this purpose. PMID- 20161593 TI - BAYESIAN ANALYSIS OF REPEATED EVENTS USING EVENT-DEPENDENT FRAILTY MODELS: AN APPLICATION TO BEHAVIORAL OBSERVATION DATA. AB - In social interaction studies, one commonly encounters repeated displays of behaviors along with their duration data. Statistical methods for the analysis of such data use either parametric (e.g., Weibull) or semi-nonparametric (e.g., Cox) proportional hazard models, modified to include random effects (frailty) which account for the correlation of repeated occurrences of behaviors within a unit (dyad). However, dyad-specific random effects by themselves are not able to account for the ordering of event occurrences within dyads. The occurrence of an event (behavior) can make further occurrences of the same behavior to be more or less likely during an interaction. This paper develops event-dependent random effects models for analyzing repeated behaviors data using a Bayesian approach. The models are illustrated by a dataset relating to emotion regulation in families with children who have behavioral or emotional problems. PMID- 20161591 TI - Mrs. Malaprop's Neighborhood: Using Word Errors to Reveal Neighborhood Structure. AB - Many theories of language production and perception assume that in the normal course of processing a word, additional non-target words (lexical neighbors) become active. The properties of these neighbors can provide insight into the structure of representations and processing mechanisms in the language processing system. To infer the properties of neighbors, we examined the non-semantic errors produced in both spoken and written word production by four individuals who suffered neurological injury. Using converging evidence from multiple language tasks, we first demonstrate that the errors originate in disruption to the processes involved in the retrieval of word form representations from long-term memory. The targets and errors produced were then examined for their similarity along a number of dimensions. A novel statistical simulation procedure was developed to determine the significance of the observed similarities between targets and errors relative to multiple chance baselines. The results reveal that in addition to position-specific form overlap (the only consistent claim of traditional definitions of neighborhood structure) the dimensions of lexical frequency, grammatical category, target length and initial segment independently contribute to the activation of non-target words in both spoken and written production. Additional analyses confirm the relevance of these dimensions for word production showing that, in both written and spoken modalities, the retrieval of a target word is facilitated by increasing neighborhood density, as defined by the results of the target-error analyses. PMID- 20161594 TI - Automatic morphological classification of galaxy images. AB - We describe an image analysis supervised learning algorithm that can automatically classify galaxy images. The algorithm is first trained using a manually classified images of elliptical, spiral, and edge-on galaxies. A large set of image features is extracted from each image, and the most informative features are selected using Fisher scores. Test images can then be classified using a simple Weighted Nearest Neighbor rule such that the Fisher scores are used as the feature weights. Experimental results show that galaxy images from Galaxy Zoo can be classified automatically to spiral, elliptical and edge-on galaxies with accuracy of ~90% compared to classifications carried out by the author. Full compilable source code of the algorithm is available for free download, and its general-purpose nature makes it suitable for other uses that involve automatic image analysis of celestial objects. PMID- 20161595 TI - Indentation of an elastic half space with material properties varying with depth. AB - We consider the effect of an elastic modulus that decreases with depth on the load-displacement relation for indentation of a graded half space by a rigid indenter. A closed-form approximation incorporating features of the plate on an elastic substrate and the Hertzian contact theory is compared with finite element results for the case of a uniform stiff layer on a homogeneous substrate. Some general results are presented for the case where the grading has inverse power law form and the effects of truncation to a finite surface value are investigated numerically. Finally, a more practical error-function grading is considered. In all cases, the load-displacement relation is closer to linear than in the homogeneous case. We conclude that the experimental data can be used to determine parameters in a predetermined form of grading, but that comparative insensitivity to the exact form of the grading would make it difficult to distincguish experimentally between different models based on indentation experiments alone. PMID- 20161596 TI - Analyzing Quadratic Unconstrained Binary Optimization Problems Via Multicommodity Flows. AB - Quadratic Unconstrained Binary Optimization (QUBO) problems concern the minimization of quadratic polynomials in n {0, 1}-valued variables. These problems are NP-complete, but prior work has identified a sequence of polynomial time computable lower bounds on the minimum value, denoted by C(2), C(3), C(4),.... It is known that C(2) can be computed by solving a maximum-flow problem, whereas the only previously known algorithms for computing C(k) (k > 2) require solving a linear program. In this paper we prove that C(3) can be computed by solving a maximum multicommodity flow problem in a graph constructed from the quadratic function. In addition to providing a lower bound on the minimum value of the quadratic function on {0, 1}(n), this multicommodity flow problem also provides some information about the coordinates of the point where this minimum is achieved. By looking at the edges that are never saturated in any maximum multicommodity flow, we can identify relational persistencies: pairs of variables that must have the same or different values in any minimizing assignment. We furthermore show that all of these persistencies can be detected by solving single-commodity flow problems in the same network. PMID- 20161597 TI - Biochemically responsive smart surface. AB - A design of smart surfaces responsive to biochemical analytes is demonstrated in the example of mixed monolayers of biotin/fluorocarbon. The contact angle of aqueous solutions on such surfaces decreases upon streptavidin binding and can be used in detecting this protein. The specificity of the effect is confirmed by the lack of a contact angle change by streptavidin blocked with biotin and by bovine serum albumin. PMID- 20161598 TI - IMPACT OF CLIMATE CHANGE ON RICE PRODUCTION IN THAILAND. PMID- 20161599 TI - Giving to the Good and the Needy: Parental Support of Grown Children. AB - Parents may provide many types of support to their grown children. Parents aged 40 to 60 (N = 633) reported the support they exchange with each child over age 18 (n = 1,384). Mothers and fathers differentiated among children within families, but provided emotional, financial, and practical help on average every few weeks to each child. Offspring received most assistance when they: (a) had greater needs (due to problems or younger age) or (b) were perceived as more successful. Parents received more from high achieving offspring. Findings support contingency theory; parents give more material and financial support to children in need. Motivation to enhance the self or to assure support later in life may explain support to high achieving offspring. PMID- 20161600 TI - Abstract syntax in sentence production: Evidence from stem-exchange errors. AB - Three experiments tested theories of syntactic representation by assessing stem exchange errors ("hates the record" -> "records the hate"). Previous research has shown that in stem exchanges, speakers pronounce intended nouns ("REcord") as verbs ("reCORD"), yielding syntactically well-formed utterances. By lexically based theories, resulting utterances are well-formed because speakers originally selected verbal forms ("reCORD"). By frame-based theories, resulting utterances are well-formed because independent syntactic frames compel conversion of intended nouns into verbs. Lexically based theories predict stem exchange errors should occur independently of syntactic context. Experiment 1 showed that speakers pronounced nouns as verbs only in utterances that required verbs; when utterances allowed nouns or verbs ("record and hate"), speakers pronounced nouns as nouns. Experiment 2 showed this was not an artifact of requiring specific utterance types. Experiment 3 ruled out a phonological influence over syntactic production. Consistent with frame-based theories, this evidence suggests that syntactic frames are abstract and independent. PMID- 20161601 TI - Phonological Knowledge Guides Two-year-olds' and Adults' Interpretation of Salient Pitch Contours in Word Learning. AB - Phonology provides a system by which a limited number of types of phonetic variation can signal communicative intentions at multiple levels of linguistic analysis. Because phonologies vary from language to language, acquiring the phonology of a language demands learning to attribute phonetic variation appropriately. Here, we studied the case of pitch-contour variation. In English, pitch contour does not differentiate words, but serves other functions, like marking yes/no questions and conveying emotions. We show that, in accordance with their phonology, English-speaking adults and two-year-olds do not interpret salient pitch contours as inherent to novel words. We taught participants a new word with consistent segmental and pitch characteristics, and then tested word recognition for trained and deviant pronunciations using an eyegaze-based procedure. Vowel-quality mispronunciations impaired recognition, but large changes in pitch contour did not. By age two, children already apply their knowledge of English phonology to interpret phonetic consistencies in their experience with words. PMID- 20161602 TI - Interpretation of chronopotentiometric transients of ion-selective membranes with two transition times. AB - Passing currents through ion-selective membranes has contributed to the development of a variety of novel methods. In this work, chronopotentiometric (CP) transients with two transition times (breakpoints) are presented for the first time, with the theoretical interpretation of such voltage transients. The validity of our theory has been confirmed in experiments utilizing ETH 5294 chromoionophore-based pH sensitive membranes with and without lipophilic background electrolyte and ETH 5234 ionophore-based calcium selective membranes in which the ionophore forms 3:1 complexes with Ca(2+) ions. The conditions under which two breakpoints can be identified in the chronopotentiometric voltage transients are discussed.Spectroelectrochemical microscopy (SpECM) is used to show that the two breakpoints in the CP curves emerge approximately when the free ionophore and ion-ionophore complex concentrations approach zero at the opposite membrane-solution interfaces. The two breakpoint times can be utilized to follow simultaneously the concentration changes of the free ionophore, the ion-ionophore complex, and the mobile anionic sites in cation-selective membranes. In membranes with known composition, the time instances where breakpoints occur can be used to estimate the free ionophore and the ion-ionophore complex diffusion coefficients. PMID- 20161603 TI - Halogenated catechols from cycloaddition reactions of eta-(2 ethoxyvinylketene)iron(0) complexes with 1-haloalkynes. AB - 1-chloroalkynes and 1-bromohexyne undergo cycloaddition reactions with ethoxyvinylketeneiron(0) complexes to form chloro and bromocatechols. With most substituents, the halogen is incorporated ortho to the phenolic hydroxyl group regioselectively. With chloroethyne, chlorohexyne, and methyl chloropropiolate, the reverse regioselection is observed. Ab initio calculations reveal that the products are, in most cases, nearly isoenergetic, which indicates that the intermediate ketene-alkyne adduct geometry must be important in determining the product distribution. PMID- 20161604 TI - ETHICAL CONSIDERATIONS FOR COGNITIVE-BEHAVIORAL THERAPISTS IN PSYCHOTHERAPY RESEARCH TRIALS. AB - Psychotherapy research studies can place particular demands on clinicians, patients, and research staff due to the need to balance the pursuit of knowledge with the offer of treatment. However, the literature with regard to ethical considerations in psychotherapy trials is minimal. The current paper aims to depict CBT community standards of practice in the context of two NIMH-funded treatment trials of major depression, both involving CBT and medication. We describe issues that arose; discuss the ethical considerations involved; and describe our course of action, along with our rationale. PMID- 20161605 TI - The Association between Membership in the Sandwich Generation and Health Behaviors: A Longitudinal Study. AB - The current study examined the association between membership in the sandwich generation, defined as providing care to both children and parents or in-laws, and five health behaviors: checking the food label for health value when buying foods, using a seat belt, choosing foods based on health value, exercising regularly, and cigarette smoking. Participants (N=4943) were from a longitudinal study of a midwestern community-based sample. Regression analyses tested the unique effect of sandwich generation membership on health behaviors above and beyond demographic factors and prior levels of the same behavior. Compared to other caregivers and noncaregivers, multigenerational caregivers were less likely to check food labels and to choose foods based on health values. Multigenerational caregivers were less likely than noncaregivers and those who cared for children only to use seat belts, and they smoked marginally more cigarettes per day than those groups. Multigenerational caregivers were less likely than noncaregivers and those who cared for parents/in-laws only to exercise regularly. Thus, in general, healthy behaviors were diminished for multigenerational caregivers. PMID- 20161606 TI - Fundamental Principles of Network Formation among Preschool Children. AB - The goal of this research was to investigate the origins of social networks by examining the formation of children's peer relationships in 11 preschool classes throughout the school year. We investigated whether several fundamental processes of relationship formation were evident at this age, including reciprocity, popularity, and triadic closure effects. We expected these mechanisms to change in importance over time as the network crystallizes, allowing more complex structures to evolve from simpler ones in a process we refer to as structural cascading. We analyzed intensive longitudinal observational data of children's interactions using the SIENA actor-based model. We found evidence that reciprocity, popularity, and triadic closure all shaped the formation of preschool children's networks. The influence of reciprocity remained consistent, whereas popularity and triadic closure became increasingly important over the course of the school year. Interactions between age and endogenous network effects were nonsignificant, suggesting that these network formation processes were not moderated by age in this sample of young children. We discuss the implications of our longitudinal network approach and findings for the study of early network developmental processes. PMID- 20161608 TI - Heating in the MRI environment due to superparamagnetic fluid suspensions in a rotating magnetic field. AB - In the presence of alternating-sinusoidal or rotating magnetic fields, magnetic nanoparticles will act to realign their magnetic moment with the applied magnetic field. The realignment is characterized by the nanoparticle's time constant, tau. As the magnetic field frequency is increased, the nanoparticle's magnetic moment lags the applied magnetic field at a constant angle for a given frequency, Omega, in rad/s. Associated with this misalignment is a power dissipation that increases the bulk magnetic fluid's temperature which has been utilized as a method of magnetic nanoparticle hyperthermia, particularly suited for cancer in low perfusion tissue (e.g., breast) where temperature increases of between 4 degrees C and 7 degrees C above the ambient in vivo temperature cause tumor hyperthermia. This work examines the rise in the magnetic fluid's temperature in the MRI environment which is characterized by a large DC field, B(0). Theoretical analysis and simulation is used to predict the effect of both alternating sinusoidal and rotating magnetic fields transverse to B(0). Results are presented for the expected temperature increase in small tumors (~1 cm radius) over an appropriate range of magnetic fluid concentrations (0.002 to 0.01 solid volume fraction) and nanoparticle radii (1 to 10 nm). The results indicate that significant heating can take place, even in low-field MRI systems where magnetic fluid saturation is not significant, with careful selection of the rotating or sinusoidal field parameters (field frequency and amplitude). The work indicates that it may be feasible to combine low-field MRI with a magnetic hyperthermia system using superparamagnetic iron oxide nanoparticles. PMID- 20161607 TI - Contribution of Regional White Matter Integrity to Visuospatial Construction Accuracy, Organizational Strategy, and Memory for a Complex Figure in Abstinent Alcoholics. AB - Visuospatial construction ability as used in drawing complex figures is commonly impaired in chronic alcoholics, but memory for such information can be enhanced by use of a holistic drawing strategy during encoding. We administered the Rey Osterrieth Complex Figure Test (ROCFT) to 41 alcoholic and 38 control men and women and assessed the contribution of diffusion tensor imaging (DTI) measures of integrity of selected white matter tracts to ROCFT copy accuracy, copy strategy, and recall accuracy. Although alcoholics copied the figure less accurately than controls, a more holistic strategy at copy was associated with better recall in both groups. Greater radial diffusivity, reflecting compromised myelin integrity, in occipital forceps and external capsule was associated with poorer copy accuracy in both groups. Lower FA, reflecting compromised fiber microstructure in the inferior cingulate bundle, which links frontal and medial temporal episodic memory systems, was associated with piecemeal copy strategy and poorer immediate recall in the alcoholics. The correlations were generally modest and should be considered exploratory. To the extent that the inferior cingulate was relatively spared in alcoholics, it may have provided an alternative pathway to the compromised frontal system for successful copy strategy and, by extension, aided recall. PMID- 20161609 TI - Estimation and inference based on Neumann series approximation to locally efficient score in missing data problems. AB - Theory on semiparametric efficient estimation in missing data problems has been systematically developed by Robins and his coauthors. Except in relatively simple problems, semiparametric efficient scores cannot be expressed in closed forms. Instead, the efficient scores are often expressed as solutions to integral equations. Neumann series was proposed in the form of successive approximation to the efficient scores in those situations. Statistical properties of the estimator based on the Neumann series approximation are difficult to obtain and as a result, have not been clearly studied. In this paper, we reformulate the successive approximation in a simple iterative form and study the statistical properties of the estimator based on the reformulation. We show that a doubly robust locally-efficient estimator can be obtained following the algorithm in robustifying the likelihood score. The results can be applied to, among others, the parametric regression, the marginal regression, and the Cox regression when data are subject to missing values and the missing data are missing at random. A simulation study is conducted to evaluate the performance of the approach and a real data example is analyzed to demonstrate the use of the approach. PMID- 20161610 TI - Cultural Differences in Emotional Responses to Success and Failure. AB - The emotional responses to achievement contexts of 149 preschool children from three cultural groups were observed. The children were Japanese (N=32), African American (N=63) and White American of mixed European ancestry (N=54). The results showed that Japanese children differed from American children in expressing less shame, pride, and sadness, but more of both exposure and evaluative embarrassment. African American and White American children did not differ from one another. American children however showed more evaluative as opposed to exposure embarrassment. This finding supports the idea that success and failure are interpreted differently by Japanese children during the preschool years. The low amount of sadness and shame expression, and the limited range of number of different expressions observed in the Japanese children agree with the general finding that East Asian infants and young children differ from Western infants and children primarily in the display of negative expressions. These results demonstrate that cultural differences, whether due to temperament or direct socialization of cultural values, influence how children respond to achievement situations. PMID- 20161612 TI - A New and Efficient Approach to the Synthesis of Nicotine and Anabasine Analogues. AB - A straightforward and practical approach was established for the synthesis of nicotine and anabasine analogues by the cyclization of mesylated 1-(3-pyridinyl) 1,4, and 1,5-diol derivatives to form the pyrrolidino or piperidino fragments. Nicotine analogue (S)-15 was prepared with good enantioselectivity using the developed azacyclization procedure of nonracemic (R)-1-pyridin-3-yl-butane-1,4 diol, which was obtained by the borane-mediated reduction of ketone 12 in the presence of the spiroborate ester derived from diphenyl prolinol and ethylene glycol. PMID- 20161611 TI - Advances and Perspectives in the Molecular Diagnosis of Head and Neck Cancer. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a debilitating and lethal disease. Despite significant advances in radiotherapy and surgical management, the 5-year survival rate for head and neck cancer has remained a dismal 50%. Advances in early detection have been made, but to improve patient outcomes better biomarkers and targeted therapeutic agents are needed. Novel biomarkers can improve early detection and provide data to optimize therapeutic strategy and patient survival, and could lead to potentially effective targeted therapies. OBJECTIVE: Report the advances in the discovery of novel biomarkers for HNSCC, and review the potential utility of biomarkers in the molecular diagnosis of HNSCC. METHODS: A review of the English literature (PubMed) from 1980 to 2009. RESULTS/CONCLUSION: Currently the most widely accepted biomarker for HNSCC is high risk HPV status. EGFR is another promising biomarker, however, further research is necessary to determine its prognostic benefit. A large number of promising biomarker candidates are currently being evaluated including epigenetic, expression, and genomic based markers. Studies to validate the sensitivity and specificity of these biomarkers in clinical samples from adequately powered prospective cohorts are needed for successful translation of these findings into potential molecular diagnostic, prognostic, and therapeutic biomarkers for HNSCC. PMID- 20161613 TI - Radioprotection in normal tissue and delayed tumor growth by blockade of CD47 signaling. AB - Radiation-induced damage of normal tissues restricts the therapeutic doses of ionizing radiation that can be delivered to tumors and thereby limits the effectiveness of radiotherapy. Thrombospondin-1 signaling through its cell surface receptor CD47 limits recovery from several types of stress, and mice lacking either gene are profoundly resistant to radiation injury. We describe strategies to protect normal tissues from radiation damage using CD47 or thrombospondin-1 antibodies, a CD47-binding peptide, or antisense suppression of CD47. A morpholino oligonucleotide targeting CD47 confers radioresistance to human endothelial cells in vitro and protects soft tissue, bone marrow, and tumor associated leukocytes in irradiated mice. In contrast, CD47 suppression in mice bearing melanoma or squamous lung tumors prior to irradiation result in 89% and 71% smaller tumors, respectively. Thus, inhibiting CD47 signaling maintains the viability of normal tissues following irradiation while increasing the radiosensitivity of tumors. PMID- 20161615 TI - Enantioselective organocatalytic alpha-sulfenylation of substituted diketopiperazines. AB - The asymmetric organocatalytic alpha-sulfenylation of substituted piperazine-2,5 diones is reported, with cinchona alkaloids as chiral Lewis bases and electrophilic sulfur transfer reagents. Catalyst loadings, the type of sulfur transfer reagent, temperature and solvent were investigated in order to optimize the reaction conditions. The effects of ring substitution and the type of catalyst on the yield and enantioselectivity of the reaction are reported. PMID- 20161614 TI - Preschool Personality Antecedents of Narcissism in Adolescence and Emergent Adulthood: A 20-Year Longitudinal Study. AB - This prospective study examined relations between preschool personality attributes and narcissism during adolescence and emerging adulthood. We created five a priori preschool scales anticipated to foretell future narcissism. Independent assessors evaluated the participants' personality at ages 14, 18, and 23. Based upon these evaluations, we generated observer-based narcissism scales for each of these three ages. All preschool scales predicted subsequent narcissism, except Interpersonal Antagonism at age 23. According to mean scale and item scores analyses, narcissism increased significantly from age 14 to 18, followed by a slight but non-significant decline from age 18 to 23. The discussion focused on a developmental view of narcissism, the need for research on automatic processing and psychological defenses, and links between narcissism and attachment. PMID- 20161616 TI - Pronouns in Catalan: Games of Partial Information and the Use of Linguistic Resources. AB - This paper investigates the variation between null and overt subject pronouns in Catalan, a null subject language. We account for this variation in game theoretical terms: that is, we analyze the distribution of both overt and null pronouns as a result of the strategic interaction between participants in a communicative exchange.First, we examine the Position of Antecedent Hypothesis (PAH), as put forward by Carminati (2002). This hypothesis proposes that null and overt pronouns have different biases: null pronouns prefer antecedents in subject positions, while overt pronouns prefer antecedents in non-subject positions. Carminati (2002) tested the PAH for Italian in a variety of intrasentential contexts. In this paper, we show experimentally that the PAH also holds for Catalan even in across-sentence contexts. In the second place, we also show how the PAH can be naturally redefined as a game of partial information, in which speaker and hearer are trying to communicate. This redefinition does not just translate the PAH into a different notation, but it extends the PAH into a model that makes more accurate predictions, since it can account also for the cases in which the biases predicted by the PAH are not obeyed. PMID- 20161617 TI - Property Taxes and Elderly Mobility. AB - The 2000-05 housing market boom in the U.S. has caused sharp increases in residential property taxes. Housing-rich but income-poor elderly homeowners often complain about rising tax burdens, and anecdotal evidence suggests that some move to reduce their tax burden. There has been little systematic analysis, however, of the link between property tax levels and the mobility rate of elderly homeowners. This paper investigates this link using household-level panel data from the Health and Retirement Study (HRS) and a newly collected data set on state-provided property tax relief programs. These relief programs generate variation in effective property tax burdens that is not due solely to arguably endogenous local community choices about taxes and expenditure programs. The findings provide evidence suggesting that higher property taxes raise mobility among elderly homeowners. The point estimates from instrumental variable estimation using relief programs to generate instruments suggest that a $100 increase in annual property taxes is associated with a 0.73 percentage point increase in the two-year mobility rate for homeowners over the age of 50. This is an eight percent increase from the baseline two-year mobility rate of nine percent. These results are robust to alternative specifications. PMID- 20161618 TI - Detectability of Discrete Event Systems with Dynamic Event Observation. AB - Our previous work considers detectability of discrete event systems which is to determine the current state and subsequent states of a system based on event observation. We assume that event observation is static, that is, if an event is observable, then all its occurrences are observable. However, in practical systems such as sensor networks, event observation often needs to be dynamic, that is, the occurrences of same events may or may not be observable, depending on the state of the system. In this paper, we generalize static event observation into dynamic event observation and consider the detectability problem under dynamic event observation. We define four types of detectabilities. To check detectabilities, we construct the observer with exponential complexity. To reduce computational complexity, we can also construct a detector with polynomial complexity to check strong detectabilities. Dynamic event observation can be implemented in two possible ways: a passive observation and an active observation. For the active observation, we discuss how to find minimal event observation policies that preserve four types of detectabilities respectively. PMID- 20161619 TI - Passive Microfluidic device for Sub Millisecond Mixing. AB - We report the investigation of a novel microfluidic mixing device to achieve submillisecond mixing. The micromixer combines two fluid streams of several microliters per second into a mixing compartment integrated with two T- type premixers and 4 butterfly-shaped in-channel mixing elements. We have employed three dimensional fluidic simulations to evaluate the mixing efficiency, and have constructed physical devices utilizing conventional microfabrication techniques. The simulation indicated thorough mixing at flow rate as low as 6 uL/s. The corresponding mean residence time is 0.44 ms for 90% of the particles simulated, or 0.49 ms for 95% of the particles simulated, respectively. The mixing efficiency of the physical device was also evaluated using fluorescein dye solutions and FluoSphere-red nanoparticles suspensions. The constructed micromixers achieved thorough mixing at the same flow rate of 6 uL/s, with the mixing indices of 96% +/- 1%, and 98% +/- 1% for the dye and the nanoparticle, respectively. The experimental results are consistent with the simulation data. The device demonstrated promising capabilities for time resolved studies for macromolecular dynamics of biological macromolecules. PMID- 20161620 TI - A Portable Stereo Vision System for Whole Body Surface Imaging. AB - This paper presents a whole body surface imaging system based on stereo vision technology. We have adopted a compact and economical configuration which involves only four stereo units to image the frontal and rear sides of the body. The success of the system depends on a stereo matching process that can effectively segment the body from the background in addition to recovering sufficient geometric details. For this purpose, we have developed a novel sub-pixel, dense stereo matching algorithm which includes two major phases. In the first phase, the foreground is accurately segmented with the help of a predefined virtual interface in the disparity space image, and a coarse disparity map is generated with block matching. In the second phase, local least squares matching is performed in combination with global optimization within a regularization framework, so as to ensure both accuracy and reliability. Our experimental results show that the system can realistically capture smooth and natural whole body shapes with high accuracy. PMID- 20161621 TI - Advances in Systemic siRNA Delivery. AB - Sequence-specific gene silencing with small interfering RNA (siRNA) has transformed basic science research, and the efficacy of siRNA therapeutics toward a variety of diseases is now being evaluated in pre-clinical and clinical trials. Despite its potential value, the highly negatively charged siRNA has the classic delivery problem of requiring transport across cell membranes to the cytosol. Consequently, carrier development for siRNA delivery is one of the most important problems to solve before siRNA can achieve widespread clinical use. An assortment of non-viral carriers including liposomes, peptides, polymers, and aptamers are being evaluated for their ability to shepherd siRNA to the target tissue and cross the plasma membrane barrier into the cell. Several promising carriers with low toxicity and increased specificity for disease targets have emerged for siRNA based therapeutics. This review will discuss non-viral approaches for siRNA therapeutics, with particular focus on synthetic carriers for in vivo systemic delivery of siRNA. PMID- 20161622 TI - Vitamin D, the immune system and asthma. AB - The effects of vitamin D on bone metabolism and calcium homeostasis have long been recognized. Emerging evidence has implicated vitamin D as a critical regulator of immunity, playing a role in both the innate and cell-mediated immune systems. Vitamin D deficiency has been found to be associated with several immune mediated diseases, susceptibility to infection and cancer. Recently, there has been increasing interest in the possible link between vitamin D and asthma. Further elucidation of the role of vitamin D in lung development and immune system function may hold profound implications for the prevention and treatment of asthma. PMID- 20161624 TI - Flexibility of Catalytic Zinc Coordination in Thermolysin and HDAC8: A Born Oppenheimer ab initio QM/MM Molecular Dynamics Study. AB - The different coordination modes and fast ligand exchange of zinc coordination has been suggested to be one key catalytic feature of the zinc ion which makes it an invaluable metal in biological catalysis. However, partly due to the well known difficulties for zinc to be characterized by spectroscopy methods, evidence for dynamic nature of the catalytic zinc coordination has so far mainly been indirect. In this work, Born-Oppenheimer ab initio QM/MM molecular dynamics simulation has been employed, which allows for a first-principle description of the dynamics of the metal active site while properly including effects of the heterogeneous and fluctuating protein environment. Our simulations have provided direct evidence regarding inherent flexibility of the catalytic zinc coordination shell in Thermolysin (TLN) and Histone Deacetylase 8 (HDAC8). We have observed different coordination modes and fast ligand exchange during the picosecond's time-scale. For TLN, the coordination of the carboxylate group of Glu166 to Zinc is found to continuously change between monodentate and bidentate manner dynamically; while for HDAC8, the flexibility mainly comes from the coordination to a non-amino-acid ligand. Such distinct dynamics in the zinc coordination shell between two enzymes suggests that the catalytic role of Zinc in TLN and HDAC8 is likely to be different in spite of the fact that both catalyze the hydrolysis of amide bond. Meanwhile, considering that such Born-Oppenheimer ab initio QM/MM MD simulations are very much desired but are widely considered to be too computationally expensive to be feasible, our current study demonstrates the viability and powerfulness of this state-of-the-art approach in simulating metalloenzymes. PMID- 20161623 TI - Mechanisms of brain iron transport: insight into neurodegeneration and CNS disorders. AB - Trace metals such as iron, copper, zinc, manganese, and cobalt are essential cofactors for many cellular enzymes. Extensive research on iron, the most abundant transition metal in biology, has contributed to an increased understanding of the molecular machinery involved in maintaining its homeostasis in mammalian peripheral tissues. However, the cellular and intercellular iron transport mechanisms in the central nervous system (CNS) are still poorly understood. Accumulating evidence suggests that impaired iron metabolism is an initial cause of neurodegeneration, and several common genetic and sporadic neurodegenerative disorders have been proposed to be associated with dysregulated CNS iron homeostasis. This review aims to provide a summary of the molecular mechanisms of brain iron transport. Our discussion is focused on iron transport across endothelial cells of the blood-brain barrier and within the neuro- and glial-vascular units of the brain, with the aim of revealing novel therapeutic targets for neurodegenerative and CNS disorders. PMID- 20161625 TI - THE LEFT TEMPORAL POLE IS IMPORTANT FOR RETRIEVING WORDS FOR UNIQUE CONCRETE ENTITIES. AB - BACKGROUND: The neuroanatomical basis of lexical retrieval has been studied intensively. The current review focuses on the special case of proper nouns. AIMS: This article reviews a program of research that has used both lesion deficit and functional imaging (PET) approaches to investigate the neuroanatomical basis for lexical retrieval of proper nouns. In lesion-deficit studies, we found that damage to the left temporal polar (TP) region leads to reliable and specific impairments in naming famous persons (e.g., "George Clooney") and famous landmarks (e.g., "Golden Gate Bridge"). In functional imaging studies, we found that when participants name famous persons and landmarks, they produce specific activation (increases in regional cerebral blood flow) in the left TP region. MAIN CONTRIBUTION: These findings converge with lesion and functional imaging data from other laboratories to support the idea that the left TP region is important for the retrieval of names for unique concrete entities, persons and landmarks being typical examples of such categories of entities. CONCLUSIONS: We have interpreted these results within a theoretical framework that suggests that left TP contains convergence regions that operate as intermediaries between conceptual knowledge retrieval and lexical retrieval for classes of unique concrete entities. PMID- 20161626 TI - Empirical Model for Predicting Concentrations of Refractory Hydrophobic Organic Compounds in Digested Sludge from Municipal Wastewater Treatment Plants. AB - An empirical model is presented allowing for the prediction of concentrations of hydrophobic organic compounds (HOCs) prone to accumulate and persist in digested sludge (biosolids) generated during conventional municipal wastewater treatment. The sole input requirements of the model are the concentrations of the individual HOCs entering the wastewater treatment plant in raw sewage, the compound's respective pH-dependent octanol-water partitioning coefficient (D(OW)), and an empirically determined fitting parameter (p(fit)) that reflects persistence of compounds in biosolids after accounting for all potential removal mechanisms during wastewater treatment. The accuracy of the model was successfully confirmed at the 99% confidence level in a paired t test that compared predicted concentrations in biosolids to empirical measurements reported in the literature. After successful validation, the resultant model was applied to predict levels of various HOCs for which occurrence data in biosolids thus far are lacking. PMID- 20161627 TI - Wanting and Liking: Observations from the Neuroscience and Psychology Laboratory. AB - Different brain mechanisms seem to mediate wanting and liking for the same reward. This may have implications for the modular nature of mental processes, and for understanding addictions, compulsions, free will and other aspects of desire. A few wanting and liking phenomena are presented here, together with discussion of some of these implications. PMID- 20161628 TI - Commentary on Grolnick and Pomerantz, "Issues and Challenges in Studying Parental Control: Toward a New Conceptualization" AB - Grolnick and Pomerantz (this issue) take on the difficult challenge of rethinking how investigators might use the concept of parental control in the study of child and adolescent development. They note that previous conceptual and empirical work has employed a wide variety of definitions of parental control and argue that this broad range of approaches has created problems for the field. For example, they cite Rollins and Thomas (1979), who identified more than 15 different labels for the construct. This multiplicity of definitions, the authors suggest, has led to ambiguity in the interpretation of research findings. In particular, Grolnick and Pomerantz propose that the multiple-forms approach to defining parental control is so fraught with problems that scholars should replace it with another strategy for describing and measuring control and related constructs. They then suggest a new approach that they believe will solve the problem and also increase the theoretical value of research on these types of parenting behaviors. In this commentary, I first discuss their critique of the multiple-forms approach and then analyze their proposed solution to the conceptual difficulties they describe. PMID- 20161629 TI - Accelerated Recurrence Time Models. AB - For the analysis with recurrent events, we propose a generalization of the accelerated failure time model to allow for evolving covariate effects. These so called accelerated recurrence time models postulate that time to expected recurrence frequency, upon transformation, is a linear function of covariates with frequency-dependent coefficients. This modeling strategy shares the same spirit as quantile regression. An estimation and inference procedure is developed by generalizing the celebrated Powell's (1984, 1986) estimator for censored quantile regression. Consistency and asymptotic normality of the proposed estimator are established. An algorithm is devised to attain good computational efficiency. Simulations demonstrate that this proposal performs well under practical settings. This methodology is illustrated in an application to the well known bladder cancer study. PMID- 20161630 TI - Community Reaction to Older-age Parental AIDS Caregivers and their Families: Evidence from Cambodia. AB - Accounts of community reaction to persons with HIV/AIDS and their families typically focus only on negative reactions stemming from stigmatization with little acknowledgement of variation over time and across settings. To usefully guide local interventions, a broader view is needed that also encompasses attitudes and actions stemming from sympathy and friendship. We examine community reaction in Cambodia to families from the perspective of parents of adults who died of AIDS or currently receive antiretroviral therapy. Survey evidence and open-ended interviews reveal a mixture of reactions with respect to social relations, interactions with local officials, gossip, business patronage, funeral participation, and orphaned grandchildren. Positive support is often dominant and reactions typically improve substantially over time. Misplaced fears of contagion through casual contact underlie most negative reactions. Moral condemnation or blame is not evident as a source of negative reactions. Overall a sufficiently supportive atmosphere likely exists in many localities to facilitate community based efforts to mitigate the epidemic's impact on affected families. PMID- 20161631 TI - Self-focused Cognitive Styles and Bipolar Spectrum Disorders: Concurrent and Prospective Associations. AB - We examined concurrent and prospective associations of self-focused cognitive styles with bipolar spectrum disorders. Controlling for depressive and hypomanic/manic symptoms, 125 individuals with bipolar spectrum disorders scored higher than 149 demographically similar normal controls on the rumination scale of the Response Styles Questionnaire (RSQ) and the private self-consciousness subscale of the Self-Consciousness Scale (SCS). The two groups did not differ on the distraction scale of the RSQ or the public self-consciousness and social anxiety subscales of the SCS. In addition, among the bipolar individuals, controlling for initial depressive and hypomanic/manic symptoms, rumination predicted the number, but not the likelihood of onset, of depressive episodes, whereas private self-consciousness predicted the likelihood of onset, but not the number, of hypomanic/manic episodes over a 3.5-year follow-up. PMID- 20161632 TI - Natural Products as a Foundation for Drug Discovery. AB - Natural products have contributed to the development of many drugs for diverse indications. While most U.S. pharmaceutical companies have reduced or eliminated their in-house natural product groups, new paradigms and new enterprises have evolved to carry on a role for natural products in the pharmaceutical industry. Many of the reasons for the decline in popularity of natural products are being addressed by the development of new techniques for screening and production. This overview aims to inform pharmacologists of current strategies and techniques that make natural products a viable strategic choice for inclusion in drug discovery programs. PMID- 20161633 TI - Synthesis of Substituted Quinolines by the Electrophilic Cyclization of N-(2 Alkynyl)anilines. AB - A wide variety of substituted quinolines are readily synthesized under mild reaction conditions by the 6-endo-dig electrophilic cyclization of N-(2 alkynyl)anilines by ICl, I(2), Br(2), PhSeBr and p-O(2)NC(6)H(4)SCl. The reaction affords 3-halogen-, selenium- and sulfur-containing quinolines in moderate to good yields in the presence of various functional groups. Analogous quinolines bearing a hydrogen in the 3-position have been synthesized by the Hg(OTf)(2) catalyzed ring closure of these same alkynylanilines. PMID- 20161634 TI - Synthesis of Novel Pyrazoles via [2+3]-Dipolar Cycloaddition Using Alkyne Surrogates. AB - The syntheses of an important class of hitherto unreported novel pyrazoles are described. The regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles was achieved by the Huisgen cyclization of nitrile imines with a trisubstituted bromoalkene. The substituted bromoalkene functions as an alkyne synthon which was used to construct 5,5-disubstituted bromopyrazoline intermediates that undergo aromatization to the analogous pyrazoles through the loss of HBr. The cycloaddition regioselectivity was confirmed through single X-ray crystal data of one of the pyrazoles. PMID- 20161635 TI - First Multi-gram Preparation SCP-123, A Novel Water Soluble Analgesic. AB - A short multi-gram process for the preparation of the analgesic compound SCP-123 (4) and its sodium salt has been developed. PMID- 20161636 TI - Physically Based Modeling and Simulation with Dynamic Spherical Volumetric Simplex Splines. AB - In this paper, we present a novel computational modeling and simulation framework based on dynamic spherical volumetric simplex splines. The framework can handle the modeling and simulation of genus-zero objects with real physical properties. In this framework, we first develop an accurate and efficient algorithm to reconstruct the high-fidelity digital model of a real-world object with spherical volumetric simplex splines which can represent with accuracy geometric, material, and other properties of the object simultaneously. With the tight coupling of Lagrangian mechanics, the dynamic volumetric simplex splines representing the object can accurately simulate its physical behavior because it can unify the geometric and material properties in the simulation. The visualization can be directly computed from the object's geometric or physical representation based on the dynamic spherical volumetric simplex splines during simulation without interpolation or resampling. We have applied the framework for biomechanic simulation of brain deformations, such as brain shifting during the surgery and brain injury under blunt impact. We have compared our simulation results with the ground truth obtained through intra-operative magnetic resonance imaging and the real biomechanic experiments. The evaluations demonstrate the excellent performance of our new technique. PMID- 20161637 TI - Synthesis of (+/-)-Oleocanthal via a Tandem Intramolecular Michael Cyclization HWE Olefination. AB - A synthesis of racemic oleocanthal has been accomplished in eleven steps from 1,3 propanediol by a key tandem intramolecular Michael cyclization-Horner Wadsworth Emmons olefination. PMID- 20161638 TI - Design and Synthesis of Fast-Degrading Poly(anhydride-esters). AB - Fast-degrading, salicylate-based poly(anhydride-esters) were designed to degrade and release the active component, salicylic acid (SA), within 1 week. The polymer degradation was enhanced by using shorter or oxygen-containing aliphatic chains. A copolymer of diglycolic acid was also made with a salicylate-based diacid for comparison of polymer properties, including SA release. Both methods resulted in polyanhydrides with molecular weights ranging from 14 500 to 27 800 Da and displayed glass transition temperatures near physiological conditions, namely 33 40 degrees C. the homo- and copolymers completely degraded within one week releasing the chemically incorporated SA. PMID- 20161639 TI - Focal and bi-directional modulation of lower limb motor cortex using anodal transcranial direct current stimulation. AB - BACKGROUND: Because we are interested in non-invasive transcranial brain stimulation as an adjuvant to post-stroke walking therapy, we applied direct current stimulation (tDCS) preferentially to either the left or right lower limb motor cortex (M1) in two separate sessions and assessed the resulting modulation in both cortices. OBJECTIVE/HYPOTHESIS: We hypothesized that tDCS applied preferentially to one lower limb M1 of healthy subjects would induce between hemisphere opposite sign modulation. METHODS: Transcranial magnetic stimulation (TMS) with the coil offset 2 cm either side of vertex was used to assess the percent change in rectified motor evoked potential (MEP) area recorded bilaterally from vastus lateralis (VL) and tibialis anterior (TA) of 10 subjects during weak tonic contraction. RESULTS: ANOVA revealed an up-regulation of the target cortex and a down-regulation of the non-target cortex (p = 0.001) and no effects of hemisphere (left, right) or muscle (TA, VL). Significant modulation was evident in 78% of VL and TA muscles (all p < 0.05). Excitability increased in 60%, but decreased in 18%. For 43% when excitability increased, a simultaneous decrease in excitability was evident in homologous muscle responses providing support for our hypothesis. CONCLUSIONS: The results indicate a modest effectiveness and focality of anodal tDCS when applied to lower limb M1, suggesting in a human model that the strength and depth of polarizing cortical currents induced by tDCS likely depend on inter-individual differences in the electrical properties of superficial brain structures. PMID- 20161640 TI - Adult Suicide Mortality in the United States: Marital Status, Family Size, Socioeconomic Status, and Differences by Sex. AB - OBJECTIVE: This paper addresses the relationship between suicide mortality and family structure and socioeconomic status for U.S. adult men and women. METHODS: We use Cox proportional hazard models and individual level, prospective data from the National Health Interview Survey Linked Mortality File (1986-2002) to examine adult suicide mortality. RESULTS: Larger families and employment are associated with lower risks of suicide for both men and women. Low levels of education or being divorced or separated, widowed, or never married are associated with increased risks of suicide among men, but not among women. CONCLUSIONS: We find important sex differences in the relationship between suicide mortality and marital status and education. Future suicide research should use both aggregate and individual level data and recognize important sex differences in the relationship between risk factors and suicide mortality-a central cause of preventable death in the United States. PMID- 20161641 TI - Quantile map: simultaneous visualization of patterns in many distributions with application to tandem mass spectrometry. AB - High-throughput experiments have become more and more prevalent in biomedical research. The high-dimensional data have brought new challenges. Effective data reduction, summarization and visualization are important keys to initial exploration in the data mining. In this paper, we introduce a visualization tool, namely quantile map, to present information contained in a probabilistic distribution. We demonstrate its use as an effective visual analysis tool through the application of a tandem mass spectrometry data set. Information of quantiles of a distribution is presented in gradient colors by concentric doughnuts. The width of the doughnuts is proportional to the Fisher information of the distribution to present unbiased visualization effect. A parametric empirical Bayes (PEB) approach is shown to improve the simple maximum likelihood estimate (MLE) approach when estimating the Fisher information. In the motivating example from tandem mass spectrometry data, multiple probabilistic distributions are to be displayed in two-dimensional grids. A hierarchical clustering to reorder rows and columns and a gradient color selection from a Hue-Chroma-Luminance model, similar to that commonly applied in heatmaps of microarray analysis, are adopted to improve the visualization. Both simulations and the motivating example show superior performance of quantile map in summarization and visualization of such high-throughput data sets. PMID- 20161642 TI - Assessing a child's experience of multiple maltreatment types: Some unfinished business. PMID- 20161643 TI - Influence of salt and pyrophosphate on bovine fast and slow myosin S1 dissociation from actin. AB - The kinetics of myosin dissociation from actin was investigated and also the impact of salt, MgPPi, and myosin heavy chain isoform on myosin subfragment 1 (S1) dissociation from actin using purified proteins and fluorescence spectroscopy. Both NaCl and MgPPi increased myosin S1 dissociation rate. When salt concentrations increased from 0.1 to 1.0 M, the dissociation rate of S1 from bovine masseter (slow) and cutaneous trunci (fast) muscle increased 38 and 78 fold, respectively. MgPPi had an even greater effect on S1 dissociation from actin. With the addition of MgPPi to the mixture of pyrene actin and S1, the fluorescence increased about 85% within the dead time of the mixing approach.. Unlike salt, MgPPi had no apparent difference in its ability to dissociate slow or fast S1 isoforms from actin. The results reveal that salt and MgPPi increase myosin extraction and functionality in meat by weakening the actomyosin interaction and that some of the difference in the functionality of red and white muscle may be related to actomyosin dissociation. PMID- 20161644 TI - Chronic disaster syndrome: Displacement, disaster capitalism, and the eviction of the poor from New Orleans. AB - Many New Orleans residents who were displaced in 2005 by Hurricanes Katrina and Rita and the subsequent levee failures and floods are still displaced. Living with long-term stress related to loss of family, community, jobs, and social security as well as the continuous struggle for a decent life in unsettled life circumstances, they manifest what we are calling "chronic disaster syndrome." The term refers not only to the physiological and psychological effects generated at the individual level by ongoing social disruption but also to the nexus of socioeconomic and political conditions that produce this situation as a long-term and intractable problem. Chronic disaster syndrome emerges from the convergence of three phenomena that create a nexus of displacement: long-term effects of personal trauma (including near loss of life and loss of family members, homes, jobs, community, financial security, and well-being); the social arrangements that enable the smooth functioning of what Naomi Klein calls "disaster capitalism," in which "disaster" is prolonged as a way of life; and the permanent displacement of the most vulnerable populations from the social landscape as a perceived remedy that actually exacerbates the syndrome. PMID- 20161645 TI - Assessing Body Fat Changes during Moderate Weight Loss with Anthropometry and Bioelectrical Impedance. AB - BACKGROUND/OBJECTIVES: Monitoring changes in total fat mass and abdominal adiposity are important in understanding the impact of different types of weight loss interventions on health risks. Our objective was to assess the usefulness of anthropometry and bioelectrical impedance analysis (BIA) in predicting fat mass changes during moderate weight loss. SUBJECTS/METHODS: Fat mass changes were assessed in 34 overweight adults (24 females, 10 males) after a 12-week supervised weight loss induced by caloric restriction (-30% of requirement) using BIA and DXA. Agreement between BIA and DXA measurements were assessed by Bland Altman plots. Linear regression modeling was used to predict body and truncal fat mass from anthropometric measures. RESULTS: Diet intervention resulted in a significant decrease in body weight (- 7.86 +/- 2.87 kg), body mass index (BMI - 2.69 +/- 0.98 kg/m(2)), total body fat (- 5.22 +/- 2.32 kg), truncal fat (- 2.80 +/- 1.94 kg) and waist circumference (- 5.52 +/- 3.57 cm). BMI and body weight were highly correlated with body fat (0.83 and 0.92 in females and 0.94 and 0.92 in males respectively) and truncal fat (0.75 and 0.87 in females; 0.90 and 0.84 in males respectively) during weight loss. Waist circumference was more correlated with truncal fat in males than females (0.94 vs. 0.85 in females). Compared to DXA, BIA underestimated total body fat changes in males (- 8.8 kg, p<0.001) and overestimated total body fat changes in females (+ 2.1 kg, p< 0.001). CONCLUSIONS: Body mass index, body weight, and waist circumference provide simple and more accurate than BIA estimates of relative changes in total and truncal fat during moderate weight loss in adults. PMID- 20161646 TI - The hormonal correlates of implicit power motivation. AB - Attempts to link testosterone to dominance dispositions using self-report measures of dominance have yielded inconsistent findings. Similarly, attempts to link testosterone changes to a situational outcome like winning or losing a dominance contest have yielded inconsistent findings. However, research has consistently shown that an indirect measure of an individual's dominance disposition, implicit power motivation, is positively related to baseline testosterone levels and, in interaction with situational outcomes, predicts testosterone changes. We propose a hormonal model of implicit power motivation that describes how testosterone levels change as an interactive function of individuals' implicit power motivation and dominance situations. We also propose that estradiol, and not testosterone, plays a key role in dominance motivation in women. PMID- 20161647 TI - A Comparison of Laboratory and Clinical Working Memory Tests and Their Prediction of Fluid Intelligence. AB - The working memory (WM) construct is conceptualized similarly across domains of psychology, yet the methods used to measure WM function vary widely. The present study examined the relationship between WM measures used in the laboratory and those used in applied settings. A large sample of undergraduates completed three laboratory-based WM measures (operation span, listening span, and n-back), as well as the WM subtests from the Wechsler Adult Intelligence Scale-III and the Wechsler Memory Scale-III. Performance on all of the WM subtests of the clinical batteries shared positive correlations with the lab measures; however, the Arithmetic and Spatial Span subtests shared lower correlations than the other WM tests. Factor analyses revealed that a factor comprising scores from the three lab WM measures and the clinical subtest, Letter-Number Sequencing (LNS), provided the best measurement of WM. Additionally, a latent variable approach was taken using fluid intelligence as a criterion construct to further discriminate between the WM tests. The results revealed that the lab measures, along with the LNS task, were the best predictors of fluid abilities. PMID- 20161648 TI - Revised Charge Equilibration Parameters for More Accurate Hydration Free Energies of Alkanes. AB - We present a refined alkane charge equilibration (CHEQ) force field, improving our previously reported CHEQ alkane force field[1] to better reproduce experimental hydration free energies. Experimental hydration free energies of ethane, propane, butane, pentane, hexane, and heptane are reproduced to within 3.6% on average. We demonstrate that explicit polarization results in a shift in molecular dipole moment for water molecules associated with the alkane molecule. We also show that our new parameters do not have a significant effect on the alkane-water interactions as measured by the radial distribution function (RDF). PMID- 20161649 TI - Public library computer training for older adults to access high-quality Internet health information. AB - An innovative experiment to develop and evaluate a public library computer training program to teach older adults to access and use high-quality Internet health information involved a productive collaboration among public libraries, the National Institute on Aging and the National Library of Medicine of the National Institutes of Health (NIH), and a Library and Information Science (LIS) academic program at a state university. One hundred and thirty-one older adults aged 54-89 participated in the study between September 2007 and July 2008. Key findings include: a) participants had overwhelmingly positive perceptions of the training program; b) after learning about two NIH websites (http://nihseniorhealth.gov and http://medlineplus.gov) from the training, many participants started using these online resources to find high quality health and medical information and, further, to guide their decision-making regarding a health- or medically-related matter; and c) computer anxiety significantly decreased (p < .001) while computer interest and efficacy significantly increased (p = .001 and p < .001, respectively) from pre- to post-training, suggesting statistically significant improvements in computer attitudes between pre- and post-training. The findings have implications for public libraries, LIS academic programs, and other organizations interested in providing similar programs in their communities. PMID- 20161650 TI - Approaches to monitoring, control and management of harmful algal blooms (HABs). AB - Virtually every coastal country in the world is affected by harmful algal blooms (HABs, commonly called "red tides"). These phenomena are caused by blooms of microscopic algae. Some of these algae are toxic, and can lead to illness and death in humans, fish, seabirds, marine mammals, and other oceanic life, typically as a result of the transfer of toxins through the food web. Sometimes the direct release of toxic compounds can be lethal to marine animals. Non-toxic HABs cause damage to ecosystems, fisheries resources, and recreational facilities, often due to the sheer biomass of the accumulated algae. The term "HAB" also applies to non-toxic blooms of macroalgae (seaweeds), which can cause major ecological impacts such as the displacement of indigenous species, habitat alteration and oxygen depletion in bottom waters.Globally, the nature of the HAB problem has changed considerably over the last several decades. The number of toxic blooms, the resulting economic losses, the types of resources affected, and the number of toxins and toxic species have all increased dramatically. Some of this expansion has been attributed to storms, currents and other natural phenomena, but human activities are also frequently implicated. Humans have contributed by transporting toxic species in ballast water, and by adding massive and increasing quantities of industrial, agricultural and sewage effluents to coastal waters. In many urbanized coastal regions, these inputs have altered the size and composition of the nutrient pool which has, in turn, created a more favorable nutrient environment for certain HAB species. The steady expansion in the use of fertilizers for agricultural production represents a large and worrisome source of nutrients in coastal waters that promote some HABs.The diversity in HAB species and their impacts presents a significant challenge to those responsible for the management of coastal resources. Furthermore, HABs are complex oceanographic phenomena that require multidisciplinary study ranging from molecular and cell biology to large-scale field surveys, numerical modelling, and remote sensing from space. Our understanding of these phenomena is increasing dramatically, and with this understanding come technologies and management tools that can reduce HAB incidence and impact. Here I summarize the global HAB problem, its trends and causes, and new technologies and approaches to monitoring, control and management, highlighting molecular probes for cell detection, rapid and sensitive toxin assays, remote sensing detection and tracking of blooms, bloom control and mitigation strategies, and the use of large scale physical/biological models to analyze past blooms and forecast future ones. PMID- 20161652 TI - Adjusted Maximum Likelihood Method in Small Area Estimation Problems. AB - For the well-known Fay-Herriot small area model, standard variance component estimation methods frequently produce zero estimates of the strictly positive model variance. As a consequence, an empirical best linear unbiased predictor of a small area mean, commonly used in the small area estimation, could reduce to a simple regression estimator, which typically has an overshrinking problem. We propose an adjusted maximum likelihood estimator of the model variance that maximizes an adjusted likelihood defined as a product of the model variance and a standard likelihood (e.g., profile or residual likelihood) function. The adjustment factor was suggested earlier by Carl Morris in the context of approximating a hierarchical Bayes solution where the hyperparameters, including the model variance, are assumed to follow a prior distribution. Interestingly, the proposed adjustment does not affect the mean squared error property of the model variance estimator or the corresponding empirical best linear unbiased predictors of the small area means in a higher order asymptotic sense. However, as demonstrated in our simulation study, the proposed adjustment has a considerable advantage in the small sample inference, especially in estimating the shrinkage parameters and in constructing the parametric bootstrap prediction intervals of the small area means, which require the use of a strictly positive consistent model variance estimate. PMID- 20161651 TI - Frontal Atrophy and Attention Deficits in Older Adults with a History of Elevated Depressive Symptoms. AB - Studies of older adults with depressive disorders indicate greater cognitive deficits and brain alterations than would be expected for their age. There is some evidence that these findings are present after a single episode of depression, but this work has been cross-sectional in nature. We investigated both cross-sectional and longitudinal associations between a history of elevated depressive symptoms (HDS), frontal lobe volumes, and cognitive performance within the context of normal age-related changes over time in the Baltimore Longitudinal Study of Aging. After controlling for age, HDS was associated with smaller total frontal gray matter volumes and with smaller regional volumes in the cingulate gyrus and orbitofrontal cortex. Men, but not women, with HDS showed deficits in auditory attention span at older ages. Results confirm previous reports that even a single episode of depression is associated with adverse outcomes in older adults but suggest that HDS does not affect longitudinal trajectories of cognitive and brain volume change. PMID- 20161653 TI - Individual differences in the joint effects of semantic priming and word frequency: The role of lexical integrity. AB - Word frequency and semantic priming effects are among the most robust effects in visual word recognition, and it has been generally assumed that these two variables produce interactive effects in lexical decision performance, with larger priming effects for low-frequency targets. The results from four lexical decision experiments indicate that the joint effects of semantic priming and word frequency are critically dependent upon differences in the vocabulary knowledge of the participants. Specifically, across two Universities, additive effects of the two variables were observed in participants with more vocabulary knowledge, while interactive effects were observed in participants with less vocabulary knowledge. These results are discussed with reference to Borowsky and Besner's (1993) multistage account and Plaut and Booth's (2000) single-mechanism model. In general, the findings are also consistent with a flexible lexical processing system that optimizes performance based on processing fluency and task demands. PMID- 20161654 TI - Fundamental Causes of Housing Loss among Persons Diagnosed with Serious and Persistent Mental Illness: A Theoretically Guided Test. AB - Previous research on housing loss among severely mentally ill persons who have been placed in housing after being homeless has been largely atheoretical and has yielded inconsistent results. We develop a theory of housing loss based on identifying fundamental causes-problems in motives, means and social situation and test these influences in a longitudinal, randomized comparison of housing alternatives. As hypothesized, individuals were more likely to lose housing if they had a history of alcohol or drug abuse, desired strongly to live independently contrary to clinician recommendations, or were African Americans placed in independent housing. Deficits in daily functioning did not explain these influences, but contributed to risk of housing loss. Our results demonstrate the importance of substance abuse, the value of distinguishing support preferences from support needs, and the necessity of explaining effects of race within a social context and thus should help to improve comparative research. PMID- 20161655 TI - Frequent release of low amounts of herpes simplex virus from neurons: results of a mathematical model. AB - Herpes simplex virus-2 (HSV-2) is a sexually transmitted infection that is the leading cause of genital ulcers worldwide. Infection is life long and is characterized by repeated asymptomatic and symptomatic shedding episodes of virus that are initiated when virus is released from neurons into the genital tract. The pattern of HSV-2 release from neurons into the genital tract is poorly understood. We fit a mathematical model of HSV-2 pathogenesis to curves generated from daily quantification of HSV in mucosal swabs performed from patients with herpetic genital ulcers. We used virologic parameters derived from model fitting for stochastic model simulations. These simulations reproduced previously documented estimates for shedding frequency, and herpetic lesion diameter and frequency. The most realistic model output occurred when we assumed minimal amounts of daily neuronal virus introduction. In our simulations, small changes in average total quantity of HSV-2 released from neurons influenced detectable shedding frequency, while changes in frequency of neuronal HSV-2 release had little effect. Frequent HSV-2 shedding episodes in humans are explained by nearly constant release of small numbers of viruses from neurons that terminate in the genital tract. PMID- 20161657 TI - Social cognition of indirect speech: Evidence from Parkinson's Disease. AB - We examined potential neurocognitive mechanisms of indirect speech in support of face management in 28 patients with Parkinson's disease (PD) and 32 elderly controls with chronic disease. In experiment 1, we demonstrated automatic activation of indirect meanings of particularized implicatures in controls but not in PD patients. Failure to automatically engage comprehension of indirect meanings of indirect speech acts in PD patients was correlated with a measure of prefrontal dysfunction. In experiment 2, we showed that while PD patients and controls offered similar interpretations of indirect speech acts, PD participants were overly confident in their interpretations and unaware of errors of interpretation. Efficient reputational adjustment mechanisms apparently require intact striatal-prefrontal networks. PMID- 20161656 TI - Cascades of Emotion: The Emergence of Borderline Personality Disorder from Emotional and Behavioral Dysregulation. AB - Theories of borderline personality disorder (BPD) have often considered it a disorder involving both emotional and behavioral dysregulation (Linehan, 1993), yet the connection between these phenomena has been elusive. The following paper proposes the Emotional Cascade Model, a model that attempts to establish a clear relationship between emotional dysregulation and the wide array of dysregulated behaviors found in BPD. In this model, subsequent to an emotional stimulus, ruminative processes result in a positive feedback loop that increases emotional intensity, and this emotional intensity leads to ensuing behavioral dysregulation. These behaviors then provide negative feedback, in the form of distraction, which induces temporary reduction of negative emotion and thus relief. The model is presented in a framework in which BPD is considered an emergent phenomenon (Lewin, 1992), where the disorder arises from the total interactions of a network containing emotional cascades and other important factors. The model is then evaluated in light of various theories and therapeutic traditions, including both cognitive-behavioral and psychodynamic, indicating that it is a model that may transcend traditional theoretical and therapeutic doctrines. PMID- 20161658 TI - Bis-amidopyrrolyl Receptors Based on Anthracene and Carbazole. AB - A new set of diamide receptors containing anthracene and carbazole bridging subunits and either pyrrole or phenyl substituents were synthesized. The four systems produced in this way were shown to bind representative anions in DMSO d(6) solution and in the solid state. A higher relative affinity for two test oxoanions, namely dihydrogen phosphate and benzoate, over chloride anion was seen in solution, with the anions in question being studied in the form of their respective tetrabutylammonium salts. However, the specifics of the anion recognition process were seen to depend on structure, with the pyrrole-containing systems displaying higher relative affinities than their corresponding phenyl containing congeners, and the carbazole receptors proving more effective than the anthracene analogues. Such observations provide support for the notion that both the carbazole NH and the pyrrolic NH protons play an important role in stabilizing the receptor-bound anions in solution. Structural analyses of several anion complexes of the diamidopyrrole carbazole receptor reveal that this is not necessarily the case in the solid state; specifically, the pyrrole NH protons are seen to interact with the amide oxygen of another molecule. The net result is an extended a one-dimensional coordinaton polymer. PMID- 20161660 TI - Control of colloid surface chemistry through matrix confinement: facile preparation of stable antibody functionalized silver nanoparticles. AB - Here we describe a simple yet efficient gel-matrix-assisted preparation method that improves synthetic control over the interface between inorganic nanomaterials and biopolymers and yields stable biofunctionalized silver nanoparticles. Covalent functionalization of the noble metal surface is aided by the confinement of polyethylene glycol acetic acid functionalized silver nanoparticles in thin slabs of a 1% agarose gel. The gel-confined nanoparticles can be transferred between reaction and washing media simply by immersing the gel slab in the solution of interest. The agarose matrix retains nanoparticles but is swiftly penetrated by the antibodies of interest. The antibodies are covalently anchored to the nanoparticles using conventional cross-linking strategies, and the resulting antibody functionalized nanoparticles are recovered from the gel through electroelution. We demonstrate the efficacy of this nanoparticle functionalization approach by labeling specific receptors on cellular surfaces with functionalized silver nanoparticles that are stable under physiological conditions. PMID- 20161659 TI - Tetracyclines that promote SMN2 exon 7 splicing as therapeutics for spinal muscular atrophy. AB - There is at present no cure or effective therapy for spinal muscular atrophy (SMA), a neurodegenerative disease that is the leading genetic cause of infant mortality. SMA usually results from loss of the SMN1 (survival of motor neuron 1) gene, which leads to selective motor neuron degeneration. SMN2 is nearly identical to SMN1 but has a nucleotide replacement that causes exon 7 skipping, resulting in a truncated, unstable version of the SMA protein. SMN2 is present in all SMA patients, and correcting SMN2 splicing is a promising approach for SMA therapy. We identified a tetracycline-like compound, PTK-SMA1, which stimulates exon 7 splicing and increases SMN protein levels in vitro and in vivo in mice. Unlike previously identified molecules that stimulate SMN production via SMN2 promoter activation or undefined mechanisms, PTK-SMA1 is a unique therapeutic candidate in that it acts by directly stimulating splicing of exon 7. Synthetic small-molecule compounds such as PTK-SMA1 offer an alternative to antisense oligonucleotide therapies that are being developed as therapeutics for a number of disease-associated splicing defects. PMID- 20161661 TI - A two step synthesis of BzR/GABAergic active flavones via a Wacker-related oxidation. AB - A general route for the synthesis of biologically important flavones is reported via a two step sequence employing a catalytic Wacker-Cook oxidation4b as the key step. PMID- 20161662 TI - Human TSH receptor ligands as pharmacological probes with potential clinical application. AB - The biologic role of thyroid-stimulating hormone (TSH; thyrotropin) as an activator (agonist) of the TSH receptor (TSHR) in the hypothalamic-pituitary thyroid axis is well known and activation of TSHR by recombinant human TSH is used clinically in patients with thyroid cancer. TSHR ligands other than TSH could be used to probe TSHR biology in thyroidal and extrathyroidal tissues, and potentially be employed in patients. A number of different TSHR ligands have been reported, including TSH analogs, antibodies and small-molecule, drug-like compounds. In this review, we will provide an update on all these classes of TSHR agonists and antagonists but place emphasis on small-molecule ligands. PMID- 20161664 TI - Measurement and clinical monitoring of human lymphocyte clonality by massively parallel VDJ pyrosequencing. AB - The complex repertoire of immune receptors generated by B and T cells enables recognition of diverse threats to the host organism. In this work, we show that massively parallel DNA sequencing of rearranged immune receptor loci can provide direct detection and tracking of immune diversity and expanded clonal lymphocyte populations in physiological and pathological contexts. DNA was isolated from blood and tissue samples, a series of redundant primers was used to amplify diverse DNA rearrangements, and the resulting mixtures of barcoded amplicons were sequenced using long-read ultra deep sequencing. Individual DNA molecules were then characterized on the basis of DNA segments that had been joined to make a functional (or nonfunctional) immune effector. Current experimental designs can accommodate up to 150 samples in a single sequence run, with the depth of sequencing sufficient to identify stable and dynamic aspects of the immune repertoire in both normal and diseased circumstances. These data provide a high resolution picture of immune spectra in normal individuals and in patients with hematological malignancies, illuminating, in the latter case, both the initial behavior of clonal tumor populations and the later suppression or re-emergence of such populations after treatment. PMID- 20161663 TI - B-cell tolerance in transplantation: is repertoire remodeling the answer? AB - T lymphocytes are the primary targets of immunotherapy in clinical transplantation; however, B lymphocytes and their secreted alloantibodies are also highly detrimental to the allograft. Therefore, the achievement of sustained organ transplant survival will likely require the induction of B-lymphocyte tolerance. During development, acquisition of B-cell tolerance to self-antigens relies on clonal deletion in the early stages of B-cell compartment ontogeny. We contend that this mechanism should be recapitulated in the setting of alloantigens and organ transplantation to eliminate the alloreactive B-cell subset from the recipient. Clinically feasible targets of B-cell-directed immunotherapy, such as CD20 and B-lymphocyte stimulator (BLyS), should drive upcoming clinical trials aimed at remodeling the recipient B-cell repertoire. PMID- 20161665 TI - Directional transneuronal spread of alpha-herpesvirus infection. AB - Most alpha-herpesviruses are pantropic, neuroinvasive pathogens that establish a reactivateable, latent infection in the PNS of their natural hosts. Various manifestations of herpes disease rely on extent and direction of the spread of infection between the surface epithelia and the nervous system components that innervate that surface. One aspect of such controlled spread of infection is the capacity for synaptically defined, transneuronal spread, a property that makes alpha-herpesviruses useful tools for determining the connectivity of neural circuits. The current understanding of intra-axonal transport and transneuronal spread of alpha-herpesviruses is reviewed, focusing on work with herpes simplex virus and pseudorabies virus, the available in vitro technology used to study viral transport and spread is evaluated and how certain viral mutants can be used to examine neural circuit architecture is described in this article. PMID- 20161668 TI - Behavioral Stability Across Time and Situations: Nonverbal Versus Verbal Consistency. AB - Behavioral consistency has been at the center of debates regarding the stability of personality. We argue that people are consistent but that such consistency is best observed in nonverbal behavior. In Study 1, participants' verbal and nonverbal behaviors were observed in a mock interview and then in an informal interaction. In Study 2, medical students' verbal and nonverbal behaviors were observed during first- and third-year clinical skills evaluation. Nonverbal behavior exhibited consistency across context and time (a duration of 2 years) whereas verbal behavior did not. Discussion focuses on implications for theories of personality and nonverbal behavior. PMID- 20161666 TI - Personalized dendritic cell-based tumor immunotherapy. AB - Advances in the understanding of the immunoregulatory functions of dendritic cells (DCs) in animal models and humans have led to their exploitation as anticancer vaccines. Although DC-based immunotherapy has proven clinically safe and efficient to induce tumor-specific immune responses, only a limited number of objective clinical responses have been reported in cancer patients. These relatively disappointing results have prompted the evaluation of multiple approaches to improve the efficacy of DC vaccines. The topic of this review focuses on personalized DC-based anticancer vaccines, which in theory have the potential to present to the host immune system the entire repertoire of antigens harbored by autologous tumor cells. We also discuss the implementation of these vaccines in cancer therapeutic strategies, their limitations and the future challenges for effective immunotherapy against cancer. PMID- 20161669 TI - Newspaper Coverage of Cancer Prevention: Multilevel Evidence for Knowledge Gap Effects. AB - Prior research on knowledge gap effects, in health as well as in other domains, has focused largely on assessing individual-level differences in exposure to news based on self-report of media use. Inherent inferential limitations of this approach are addressed by testing the hypothesis that the relationship between education and cancer prevention knowledge will be moderated by regional differences in U.S. news coverage of cancer prevention. The study also tests, using these methods, findings by Kwak (1999) suggesting that the importance of attention to relevant news in predicting knowledge decreases as information available in the news increases. Using a representative national sample of newspaper coverage to assess regional differences in cancer prevention coverage, a representative national probability sample to assess respondent education and cancer prevention knowledge, and multilevel analyses of the relationship between regional coverage differences and knowledge of persons in those regions, support is found for both of these propositions. PMID- 20161667 TI - Type 2 scavenger receptor CD36 in platelet activation: the role of hyperlipemia and oxidative stress. AB - Platelet hyper-reactivity and a systemic prothrombotic state are associated with atherosclerosis and other inflammatory conditions. CD36, a member of the Type 2 scavenger receptor family, is a multiligand pattern recognition receptor that recognizes specific oxidized phospholipids, molecules expressed on microbial pathogens, apoptotic cells, and cell-derived microparticles. Recent studies have demonstrated that CD36 binding to oxidized LDL or microparticles activates a specific signaling pathway that induces platelet activation. This pathway is activated in vivo in the setting of hyperlipidemia and oxidant stress. Genetic deletion of CD36 protects mice from pathological thrombosis associated with hyperlipidemia without any apparent effect on normal hemostasis. Targeting CD36 or its signaling pathway could potentially lead to the development of novel antithrombotic therapies for patients with atheroinflammatory disorders. PMID- 20161670 TI - Development in Children and Adolescents Whose Mothers Have Borderline Personality Disorder. AB - A mother's mental illness may have a profound effect on her child's development, including an increased risk of the child developing the same disorder. From a developmental psychopathology perspective, offspring provide an opportunity to examine pathways to disorder versus resilience. Borderline personality disorder (BPD) is a severe disorder diagnosed in early adulthood involving stormy relationships, an unstable sense of identity, and self-destructive behavior. Interestingly, the domains of dysfunction are conceptually similar to developmental tasks in early childhood reworked in adolescence: attachment, self development, and self-regulation. Early deviation may increase the risk for later disorder. There are five empirical studies of children whose mothers have BPD, two conducted from a developmental perspective. This article proposes a theoretical framework and an innovative methodology with which to extend this research, and suggests an intervention to bring development back on track if necessary. PMID- 20161671 TI - Response to Intervention: Prevention and Remediation, Perhaps. Diagnosis, No. AB - Fletcher and Vaughn (this issue) describe recent changes to federal laws governing special education eligibility for specific learning disabilities focusing on what is commonly known as response to intervention (RTI). We are concerned about what appears to us as a selective review of empirical support for RTI and a consequently overly optimistic view of many practical issues surrounding the implementation of RTI models that neglects the potential negative long-term impact on the range of students with and without a learning disability. These include (1) the lack of a firm evidence base reflected in vagaries and ambiguity of the critical details of the model in practice; (2) the worrisome shortcomings of the RTI process as a means of diagnosis or determination of a disability; (3) the contextual, situation-dependent nature of who is identified; (4) the seeming lack of consideration of bright struggling readers in the RTI process; and (5) the apparent lack of student-based data to guide the most effective choice of approaches to, and specific components of, intervention. PMID- 20161672 TI - On the Importance of a Unified Model of Responsiveness-To-Intervention. AB - In this commentary, we take issue with only one idea in Fletcher and Vaughn's overall balanced description of the potential advantages and disadvantages of RTI: the assertion that RTI models are best conceptualized as a set of processes, not as a single model of service delivery. We argue that RTI's major goal, to prevent long-term and debilitating academic failure, is better served by a unified model that encourages shared understanding among all school-based practitioners about intervention intensity, roles and responsibilities, and constructive and effective relationships between general and special education. We briefly describe a unified model, explain how it eases some of the challenges associated with RTI implementation, and consider implications for learning disabilities. PMID- 20161673 TI - Urine-based assays for the detection of bladder cancer. AB - Bladder cancer is one of the most prevalent cancers worldwide. Furthermore, nonmuscle invasive bladder cancer has a 70% rate of recurrence, making it a considerable strain to the healthcare system. Patients with bladder cancer require repeat cystoscopic examinations of the bladder to monitor for tumor recurrence. The reason these patients have to undergo these costly, painful, invasive procedures is owing to the absence of accurate urine-based assays to detect the presence of bladder cancer noninvasively. Consequently, the development of a urine-based test to detect bladder cancer would be of tremendous benefit to both patients and healthcare systems. This article reports some of the more prominent urine markers in use today. In addition, the article will highlight some new technologies that are used to investigate novel urinary markers. PMID- 20161674 TI - Assessment of the roles of antioxidant enzymes and glutathione in 3,3',4,4',5 Pentachlorobiphenyl (PCB 126)-induced oxidative stress in the brain tissues of rats after subchronic exposure. AB - The abilities of various doses of 3,3',4,4',5-pentachlorobiphenyl (PCB126) to induce changes in antioxidant enzyme activities and glutathione levels in the brain tissues of rats were examined in rats after subchronic exposure. Groups of rats were administered 10,30, 100, 300, 550 or 1000 ng PCB 126/kg/day, p.o., for 13 weeks and the activities of supeoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), as well as (GSH) levels were determined in the brain tissue homogenates. Treatment resulted in significant and dose-dependent increases in the activities of the three tested enzymes. While maximal increase GSH-Px activity was achieved with a dose of 100-175 mg/kg/day, CAT and SOD activities continued to increase in response to maximal dose used for this study. GSH levels on the other hand, were suppressed significantly in a dose-dependent fashion. Data suggest that previously observed increase in oxidative stress production by PCB-126 in the brain tissues of rats is associated with dose dependent rise in antioxidant enzyme activities and GSH depletion. However, the increases in the antioxidant enzyme activities can not provide full protection against oxidative damage induced by the same doses. In addition, GSH depletion plays a critical role in the previously observed oxidative stress in response to this compound. PMID- 20161675 TI - Education and personalized genomics: deciphering the public's genetic health report. AB - Where do members of the public turn to understand what genetic tests mean in terms of their own health? Now that genome-wide association studies and complete genome sequencing are widely available, the importance of education in personalized genomics cannot be overstated. Although some media have introduced the concept of genetic testing to better understand health and disease, the public's understanding of the scope and impact of genetic variation has not kept up with the pace of the science or technology. Unfortunately, the likely sources to which the public turn to for guidance - their physician and the media - are often no better prepared. We examine several venues for information, including print and online guides for both lay and health-oriented audiences, and summarize selected resources in multiple formats. We also note on the roadblocks to progress and discuss ways to remove them, as urgent action is needed to connect people with their genomes in a meaningful way. PMID- 20161676 TI - Evidence for RNA-mediated toxicity in the fragile X-associated tremor/ataxia syndrome. AB - Fragile X premutation carriers are at risk for developing a late-onset, progressive neurodegenerative disorder termed fragile X-associated tremor/ataxia syndrome (FXTAS). A growing body of evidence suggests the characteristic excess CGG repeat containing FMR1 mRNA observed in premutation carriers is pathogenic and leads to clinical features of FXTAS. The current model suggests premutation mRNA transcripts can induce the formation of intranuclear inclusions by the sequestration of RNA-binding proteins and other proteins. The sequestered proteins are prevented from performing their normal functions, which is thought to lead to the neuropathology-observed FXTAS. This paper discusses the existing evidence that microsatellite expansions at the level of RNA play a role in the disease pathogenesis of FXTAS and some of the approaches that may uncover downstream effects of expanded riboCGG expression. PMID- 20161677 TI - The link between allergies and eosinophilic esophagitis: implications for management strategies. AB - Eosinophilic esophagitis (EE) has an increased incidence of diagnosis similar to other atopic diseases. We present a recent literature review of the common features between atopic diseases (i.e., asthma, allergic rhinitis and atopic dermatitis) and EE. All of the disorders have allergen triggers and evidence of a possible Th2 inflammation at the site of disease. Murine models have also shown similar features with the importance of T cells and Th2 cytokines for the development of disease. The diseases share underlying inflammation with the potential for remodeling with an increase in TGF-beta expression in asthma and EE. However, differences do exist between the diseases in treatment and pathogenesis. For EE, there are two basic treatment options: avoidance of the food triggers or treatment of the eosinophilic inflammation with corticosteroids. PMID- 20161678 TI - Next-generation sequencing of cancer genomes: back to the future. AB - The systematic karyotyping of bone marrow cells was the first genomic approach used to personalize therapy for patients with leukemia. The paradigm established by cytogenetic studies in leukemia (from gene discovery to therapeutic intervention) now has the potential to be rapidly extended with the use of whole genome sequencing approaches for cancer, which are now possible. We are now entering a period of exponential growth in cancer gene discovery that will provide many novel therapeutic targets for a large number of cancer types. Establishing the pathogenetic relevance of individual mutations is a major challenge that must be solved. However, after thousands of cancer genomes have been sequenced, the genetic rules of cancer will become known and new approaches for diagnosis, risk stratification and individualized treatment of cancer patients will surely follow. PMID- 20161679 TI - Dengue virus markers of virulence and pathogenicity. AB - The increased spread of dengue fever and its more severe form, dengue hemorrhagic fever, have made the study of the mosquito-borne dengue viruses that cause these diseases a public health priority. Little is known about how or why the four different (serotypes 1-4) dengue viruses cause pathology in humans only, and there have been no animal models of disease to date. Therefore, there are no vaccines or antivirals to prevent or treat infection and mortality rates of dengue hemorrhagic fever patients can reach up to 20%. Cases occur mainly in tropical zones within developing countries worldwide, and control measures have been limited to the elimination of the mosquito vectors. Thus, it is imperative that we develop new methods of studying dengue virus pathogenicity. This article presents new approaches that may help us to understand dengue virus virulence and the specific mechanisms that lead to dengue fever and severe disease. PMID- 20161680 TI - A factorial analysis of timed and untimed measures of mathematics and reading abilities in school aged twins. AB - The present study examined the phenotypic and genetic relationship between fluency and non-fluency-based measures of reading and mathematics performance. Participants were drawn from the Western Reserve Reading and Math Project, an ongoing longitudinal twin project of same-sex MZ and DZ twins from Ohio. The present analyses are based on tester-administered measures available from 228 twin pairs (age M=9.86 years). Measurement models suggested that four factors represent the data, namely Decoding, Fluency, Comprehension, and Math. Subsequent quantitative genetic analyses of these latent factors suggested that a single genetic factor accounted for the covariance among these four latent factors. However, there were also unique genetic effects on Fluency and Math, independent from the common genetic factor. Thus, although there is a significant genetic overlap among different reading and math skills, there may be independent genetic sources of variation related to measures of decoding fluency and mathematics. PMID- 20161681 TI - Mathematical Disabilities: Reflections on Cognitive, Neuropsychological, and Genetic Components. AB - The collection of articles in this special issue and related studies over the past decade provides a fine example of the substantial progress that has been made in our understanding and remediation of mathematical learning disabilities and difficulties since 1993 (Geary, 1993). The originally proposed procedural and retrieval deficits have been supported and a number sense deficit has been identified. There is evidence for visuospatial contributions to some aspects of mathematical learning, but identification of a core visuospatial deficit underlying some forms of mathematics learning disabilities and difficulties has been elusive. The contributions of working memory to the development and expression of these deficits is more nuanced than I originally proposed as are the brain systems supporting mathematical learning. Although much has been learned about children's difficulties in learning mathematics, but there is just as much and likely more than remains to be discovered. PMID- 20161682 TI - POLYMER TRACK MEMBRANES FOR ATMOSPHERIC PRESSURE FIELD EXTRACTION OF IONS FROM LIQUID SOLUTIONS. AB - An approach to the generation of gas phase ions by field extraction from liquid solutions has been investigated. The method uses a polymer membrane with nano size channels as an interface between the liquid and the atmospheric pressure gas. Ions are produced by dissociation in the polar solvent and secondary ion molecular reactions in the solution, which fills the channels of the membrane. Field extraction of the ions from the channels is stimulated by pulses of the electric discharge between the membrane and an adjacent electrode in the gas. The gas-phase ions are removed from the extraction zone by air flow and are detected by mass spectrometry. Possibilities of the membrane interface for generation of gas phase ions have been demonstrated from mass spectral investigation curried out for angiotensin II, gramicidin S and cytochrome C solutions. The current kinetics of the membrane ion source has been investigated to elucidate the mechanism of the ion extraction. PMID- 20161683 TI - Emerging role of astroglia in pain hypersensitivity. AB - Recent studies suggest that astroglia, a major non-neuronal cell type in the central nervous system, actively participate in synaptic activity and potentially contribute to neurological disorders including chronic pain. Astroglia exhibit a hyperactive phenotype, also referred to as reactive astrocytosis, in response to peripheral injury. This process is often referred to as astroglial activation. By immunostaining against glial fibrillary acidic proteins, an intermediate cytoskeleton filament protein selectively localized to matured astrocytes, hypertrophy of astrocytes are clearly visible in the spinal cord dorsal horn and spinal trigeminal nucleus following a variety of injuries. Injury-related astroglial activation correlates with behavioral hyperalgesia and conversely, astroglial inhibition attenuates pain hypersensitivity. Astrocytes have a close anatomical relationship with neurons. Interactions between astrocytes and neurons contribute to the mechanisms of chronic pain. Astroglial activation is accompanied by initiation of cellular signal transduction pathways that lead to transcriptional gene regulation and release of a variety of chemical mediators or gliotransmitters, down-regulation of glutamate transporter activity that directly affects synaptic transmission, changes in gap junction proteins by which calcium waves spread, and alterations of the blood brain barrier. These coordinated changes in astroglial functions in turn modulate neuronal activity and facilitate pain transmission. PMID- 20161684 TI - Organocatalyzed synthesis of 2-amino-8-oxo-5,6,7,8-tetrahydro-4H-chromene-3 carbonitriles. AB - 2-Amino-8-oxo-tetrahydro-4H-chromene-3-carbonitriles were synthesized for the first time from a tandem Michael addition - cyclization reaction between cyclohexane-1,2-dione and benzylidenemalononitriles. An enantioselective synthesis of these compounds was achieved in moderate ee values (up to 63% ee) by using a cinchona alkaloid-derived thiouea catalyst. PMID- 20161685 TI - The normalization of deviance in healthcare delivery. AB - Many serious medical errors result from violations of recognized standards of practice. Over time, even egregious violations of standards of practice may become "normalized" in healthcare delivery systems. This article describes what leads to this normalization and explains why flagrant practice deviations can persist for years, despite the importance of the standards at issue. This article also provides recommendations to aid healthcare organizations in identifying and managing unsafe practice deviations before they become normalized and pose genuine risks to patient safety, quality care, and employee morale. PMID- 20161687 TI - Abnormal N400 Responses But Intact Differential Hemispheric Processing of Ambiguity in Schizophrenia. AB - Disordered thinking in schizophrenia may be a consequence of the selection of conceptual associates of dominant meanings of ambiguous words despite contextual information suggesting subordinate meanings are more appropriate. Previous work using short sentences showed a large N400 event-related potential to subordinate meaning associates and a behavioral semantic bias, but results were variable. The current experiment used word pairs to simplify the procedure and to less tax memory maintenance. Furthermore, hemispheric responses were compared, as evidence suggests the left hemisphere may select dominant meanings, while the right hemisphere may keep all possible meanings active. Subjects indicated whether two words (CUE, TARGET) were related. The CUE, presented for 1 second, could be an ambiguous or an unambiguous noun, and the TARGET, presented 1.25 seconds after the onset of the CUE, was a dominant or subordinate associate, or a related or an unrelated word, respectively. The N400-effect was calculated from difference waveforms over 400-600 msec. Groups (23 schizophrenia, 25 matched controls) showed significantly different N400-effects to the words (group x word, p =.04). Controls showed a graded response, with dominant < subordinate < unrelated. Schizophrenia patients showed the largest N400-effect to subordinate associates, with less activity to dominant meaning associates and unrelated words. Both groups showed a right hemisphere distribution to unrelated words and substantial left hemisphere activation to subordinate associates (word x hemisphere, p <.001). These data support a semantic bias in schizophrenia. They also demonstrate a special role of the right hemisphere in maintaining broad homograph meaning hierarchies. This hemispheric specialization appears to be intact in schizophrenia. PMID- 20161686 TI - Development of Scalable Culture Systems for Human Embryonic Stem Cells. AB - The use of human pluripotent stem cells, including embryonic and induced pluripotent stem cells, in therapeutic applications will require the development of robust, scalable culture technologies for undifferentiated cells. Advances made in large-scale cultures of other mammalian cells will facilitate expansion of undifferentiated human embryonic stem cells (hESCs), but challenges specific to hESCs will also have to be addressed, including development of defined, humanized culture media and substrates, monitoring spontaneous differentiation and heterogeneity in the cultures, and maintaining karyotypic integrity in the cells. This review will describe our current understanding of environmental factors that regulate hESC self-renewal and efforts to provide these cues in various scalable bioreactor culture systems. PMID- 20161688 TI - Towards Antitumor Active trans-Platinum Compounds. AB - Substitution of NH(3) by a range of amines in trans-[PtCl(2)(NH(3))(2)] produces compounds with cytotoxicity significantly improved over the parent transplatin and in many cases equivalent to that of cisplatin. This microreview summarizes the chemistry and biology of trans-platinum compounds containing principally planar amines and succinctly reviews the current status of anticancer relevance of the trans-platinum geometry. The nature of bifunctional DNA adducts (intrastrand, interstrand) is remarkably dependent on the nature of the amine. Further, the stability of monofunctional adducts allows for competitive production of DNA-protein crosslinks and overall the results suggest that the trans-platinum chemotype may offer significant potential for design of selective DNA-protein crosslinking agents. A subset of proteins known to bind to DNA modified by trans-platinum is that comprised of zinc fingers - model studies show the potential for formation of heteronuclear thiolate-bridged species as precedent for zinc displacement from the biomolecule. PMID- 20161690 TI - Osmotic Swelling Pressure Response of Smart Hydrogels Suitable for Chronically Implantable Glucose Sensors. AB - In the last few years, a new type of glucose-sensitive hydrogel (GSH) has been developed that shrinks with increasing glucose concentration due to the formation of reversible crosslinks The first osmotic swelling pressure results measured for any member of this new class of GSH are reported, so that their suitability for use in sensors combining pressure transducers and smart gels can be evaluated. Comparison is also made with results obtained for an older type of GSH that expands with increasing glucose concentration due to an increase in the concentration of counterions within the gel. The newer type of GSH exhibits both faster kinetics and weaker fructose interference, and therefore is more suitable for in vivo glucose sensing. PMID- 20161691 TI - Permeability - Selectivity Analysis for Ultrafiltration: Effect of Pore Geometry. AB - The effects of pore size on the performance of ultrafiltration membranes are fairly well understood, but there is currently no information on the impact of pore geometry on the trade-off between the selectivity and permeability for membranes with pore size below 100 nm. Experimental data are presented for both commercial ultrafiltration membranes and for novel silicon membranes having slit shaped nanopores of uniform size fabricated by photolithography using a sacrificial oxide technique. Data are compared with theoretical calculations based on available hydrodynamic models for solute and solvent transport through membranes composed of a parallel array of either cylindrical or slit-shaped pores. The results clearly demonstrate that membranes with slit-shaped pores have higher performance, i.e., greater selectivity at a given value of the permeability, than membranes with cylindrical pores. Theoretical calculations indicate that this improved performance becomes much less pronounced as the breadth of the pore size distribution increases. These results provide new insights into the effects of pore geometry on the performance of ultrafiltration membranes. PMID- 20161689 TI - The Genetic Basis of Thought Disorder and Language and Communication Disturbances in Schizophrenia. AB - Thought disorder as well as language and communication disturbances are associated with schizophrenia and are over-represented in clinically unaffected relatives of schizophrenics. All three kinds of dysfunction involve some element of deviant verbalizations, most notably, semantic anomalies. Of particular importance, thought disorder characterized primarily by deviant verbalizations has a higher recurrence in relatives of schizophrenic patients than schizophrenia itself. These findings suggest that deviant verbalizations may be more penetrant expressions of schizophrenia susceptibility genes than schizophrenia. This paper reviews the evidence documenting the presence of thought, language and communication disorders in schizophrenic patients and in their first-degree relatives. This familial aggregation potentially implicates genetic factors in the etiology of thought disorder, language anomalies, and communication disturbances in schizophrenia families. We also present two examples of ways in which thought, language and communication disorders can enrich genetic studies, including those involving schizophrenia. PMID- 20161692 TI - Developing Force Fields from the Microscopic Structure of Solutions. AB - We have been developing force fields designed for the eventual simulation of peptides and proteins using the Kirkwood-Buff (KB) theory of solutions as a guide. KB theory provides exact information on the relative distributions for each species present in solution. This information can also be obtained from computer simulations. Hence, one can use KB theory to help test and modify the parameters commonly used in biomolecular studies. A series of small molecule force fields representative of the fragments found in peptides and proteins have been developed. Since this approach is guided by the KB theory, our results provide a reasonable balance in the interactions between self-association of solutes and solute solvation. Here, we present our progress to date. In addition, our investigations have provided a wealth of data concerning the properties of solution mixtures, which is also summarized. Specific examples of the properties of aromatic (benzene, phenol, p-cresol) and sulfur compounds (methanethiol, dimethylsulfide, dimethyldisulfide) and their mixtures with methanol or toluene are provided as an illustration of this kind of approach. PMID- 20161693 TI - A robust numerical method for self-polarization energy of spherical quantum dots with finite confinement barriers. AB - By utilizing a novel three-layer dielectric model for the interface between a spherical quantum dot and the surrounding matrix, a robust numerical method for calculating the self-polarization energy of a spherical quantum dot with a finite confinement barrier is presented in this paper. The proposed numerical method can not only overcome the inherent mathematical divergence in the self-polarization energy which arises for the simplest and most widely used step-like model of the dielectric interface, but also completely eliminate the potential numerical divergence which may occur in the Bolcatto-Proetto's formula [J. Phys.: Condens. Matter 13, 319-334 (2001)], an approximation method commonly employed for more realistic three-layer dielectric models such as the linear and the cosine-like models frequently mentioned in the literature. Numerical experiments have demonstrated the convergence of the proposed numerical method as the number of the steps used to discretize the translation layer in a three-layer model goes to infinity, an important property that the Bolcatto-Proetto's formula appears not necessarily to possess. PMID- 20161694 TI - 'Hot' macromolecular crystals. AB - Transcriptional regulator protein TM1030 from the hyperthermophile Thermotoga maritima, as well as its complex with DNA, was crystallized at a wide range of temperatures. Crystallization plates were incubated at 4, 20, 37 and 50 degrees C over 3 weeks. The best crystals of TM1030 in complex with DNA were obtained at 4, 20 and 37 degrees C, while TM1030 alone crystallized almost equally well in all temperatures. The crystals grown at different temperatures were used for X ray diffraction experiments and their structures were compared. Surprisingly, the models of TM1030 obtained from crystals grown at different temperatures are similar in quality. While there are some examples of structures of proteins grown at elevated temperatures in the PDB, these temperatures appear to be underrepresented. Our studies show that crystals of some proteins may be grown and are stable at broad range of temperatures. We suggest that crystallization experiments at elevated temperatures could be used as a standard part of the crystallization protocol. PMID- 20161695 TI - Gold(I)-catalyzed synthesis of (1E,3E)-dienes from propargylic esters. AB - A mild and stereoselective gold(I)-catalyzed domino transformation of propargylic esters leading to substituted (1E,3E)-dienes has been developed. This cascade process proceeds via a sequence of 1,3-acyloxy- or 1,3-phosphatyloxy migrations to form allenic intermediate followed by a proton transfer. PMID- 20161696 TI - Enumerating the decomposable neighbours of a decomposable graph under a simple perturbation scheme. AB - Given a decomposable graph, we characterize and enumerate the set of pairs of vertices whose connection or disconnection results in a new graph that is also decomposable. We discuss the relevance of this results to Markov chain Monte Carlo methods that sample or optimize over the space of decomposable graphical models according to probabilities determined by a posterior distribution given observed multivariate data. PMID- 20161697 TI - Neurophysiological correlates of executive function: a comparison of European canadian and chinese-canadian 5-year-old children. AB - This study explored the neurophysiological correlates of executive function (EF) in young children from two different cultural backgrounds. Twenty European Canadian and 17 Chinese-Canadian 5-year-olds participated in a go/no-go task, during which high-density electroencephalographic (EEG) data were recorded. No cultural group differences were observed in children's behavioral performance on the task, but marked differences were revealed by ERP analyses, which focused on the amplitude and latency of the N2 waveform. Chinese-Canadian children showed larger (i.e., more negative) N2 amplitudes than European-Canadian children on the right side of the scalp on no-go trials, as well as on the left side of the scalp on go trials, and for all children, larger N2 amplitudes were associated with faster median reaction times. Source analyses of the N2 were consistent with the hypothesis that compared to European-Canadian children, Chinese-Canadian children showed more activation in dorsomedial, ventromedial, and (bilateral) ventrolateral prefrontal cortex. These findings reveal that EEG can provide a measure of cultural differences in neurocognitive function that is more sensitive than behavioral data alone; that Chinese-Canadian children show a pattern of hemispheric differentiation in the context of this task than that is more pronounced than that of age-matched European-Canadian children; that the asymmetrically lateralized N2 may be a reliable marker of both effortful inhibition (on the right) and effortful approach (on the left); and that the neural correlates of EF may vary across samples of healthy participants, even in children. PMID- 20161698 TI - GLT-1 Promoter Activity in Astrocytes and Neurons of Mouse Hippocampus and Somatic Sensory Cortex. AB - GLT-1 eGFP BAC reporter transgenic adult mice were used to detect GLT-1 gene expression in individual cells of CA1, CA3 and SI, and eGFP fluorescence was measured to analyze quantitatively GLT-1 promoter activity in different cells of neocortex and hippocampus. Virtually all GFAP+ astrocytes were eGFP+; we also found that about 80% of neurons in CA3 pyramidal layer, 10-70% of neurons in I-VI layers of SI and rare neurons in all strata of CA1 and in strata oriens and radiatum of CA3 were eGFP+. Analysis of eGFP intensity showed that astrocytes had a higher GLT-1 promoter activity in SI than in CA1 and CA3, and that neurons had the highest levels of GLT-1 promoter activity in CA3 stratum pyramidale and in layer VI of SI. Finally, we observed that the intensity of GLT-1 promoter activity in neurons is 1-20% of that measured in astrocytes. These results showed that in the hippocampus and neocortex GLT-1 promoter activity is observed in astrocytes and neurons, detailed the distribution of GLT-1 expressing neurons, and indicated that GLT-1 promoter activity in both astrocytes and neurons varies in different brain regions. PMID- 20161701 TI - Spontaneous recovery of the injured higher olfactory center in the terrestrial slug limax. AB - BACKGROUND: Of all organs and tissues in adult mammals, the brain shows the most limited regeneration and recovery after injury. This is one reason why treating neurological damage such as ischemic injury after stroke presents such a challenge. Here we report a novel mode of regeneration which the slug's cognitive center, the procerebrum, shows after surgical lesioning in the adult. It is well known that the land slug Limax possesses the capacity to demonstrate conditioned food aversion. This learning ability critically depends on the procerebrum, which is the higher olfactory center in the brain of the terrestrial mollusk. PRINCIPAL FINDINGS: In the present study, after a 1-month recovery period post-surgical lesioning of the procerebrum we investigated whether the brain of the slug shows recovery from damage. We found that learning ability, local field potential oscillation, and the number of cells in the procerebrum (PC) all recovered spontaneously within 1 month of bilateral lesioning of the PC. Moreover, neurogenesis was enhanced in the lesioned PC. However, memory acquired before the surgery could not be retrieved 1 month after surgery although the procerebrum had recovered from injury by this time, consistent with the notion that the procerebrum is the storage site of odor-aversion memory, or deeply involved in the memory recall process. SIGNIFICANCE: Our findings are the first to demonstrate that a brain region responsible for the associative memory of an adult organism can spontaneously reconstitute itself, and can recover its function following injury. PMID- 20161700 TI - A review of adversity, the amygdala and the hippocampus: a consideration of developmental timing. AB - A review of the human developmental neuroimaging literature that investigates outcomes following exposure to psychosocial adversity is presented with a focus on two subcortical structures - the hippocampus and the amygdala. Throughout this review, we discuss how a consideration of developmental timing of adverse experiences and age at measurement might provide insight into the seemingly discrepant findings across studies. We use findings from animal studies to suggest some mechanisms through which timing of experiences may result in differences across time and studies. The literature suggests that early life may be a time of heightened susceptibility to environmental stressors, but that expression of these effects will vary by age at measurement. PMID- 20161699 TI - Defective glycinergic synaptic transmission in zebrafish motility mutants. AB - Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Recently, in vivo analysis of glycinergic synaptic transmission has been pursued in zebrafish using molecular genetics. An ENU mutagenesis screen identified two behavioral mutants that are defective in glycinergic synaptic transmission. Zebrafish bandoneon (beo) mutants have a defect in glrbb, one of the duplicated glycine receptor (GlyR) beta subunit genes. These mutants exhibit a loss of glycinergic synaptic transmission due to a lack of synaptic aggregation of GlyRs. Due to the consequent loss of reciprocal inhibition of motor circuits between the two sides of the spinal cord, motor neurons activate simultaneously on both sides resulting in bilateral contraction of axial muscles of beo mutants, eliciting the so-called 'accordion' phenotype. Similar defects in GlyR subunit genes have been observed in several mammals and are the basis for human hyperekplexia/startle disease. By contrast, zebrafish shocked (sho) mutants have a defect in slc6a9, encoding GlyT1, a glycine transporter that is expressed by astroglial cells surrounding the glycinergic synapse in the hindbrain and spinal cord. GlyT1 mediates rapid uptake of glycine from the synaptic cleft, terminating synaptic transmission. In zebrafish sho mutants, there appears to be elevated extracellular glycine resulting in persistent inhibition of postsynaptic neurons and subsequent reduced motility, causing the 'twitch-once' phenotype. We review current knowledge regarding zebrafish 'accordion' and 'twitch-once' mutants, including beo and sho, and report the identification of a new alpha2 subunit that revises the phylogeny of zebrafish GlyRs. PMID- 20161702 TI - BAC-HAPPY mapping (BAP mapping): a new and efficient protocol for physical mapping. AB - Physical and linkage mapping underpin efforts to sequence and characterize the genomes of eukaryotic organisms by providing a skeleton framework for whole genome assembly. Hitherto, linkage and physical "contig" maps were generated independently prior to merging. Here, we develop a new and easy method, BAC HAPPY MAPPING (BAP mapping), that utilizes BAC library pools as a HAPPY mapping panel together with an Mbp-sized DNA panel to integrate the linkage and physical mapping efforts into one pipeline. Using Arabidopsis thaliana as an exemplar, a set of 40 Sequence Tagged Site (STS) markers spanning approximately 10% of chromosome 4 were simultaneously assembled onto a BAP map compiled using both a series of BAC pools each comprising 0.7x genome coverage and dilute (0.7x genome) samples of sheared genomic DNA. The resultant BAP map overcomes the need for polymorphic loci to separate genetic loci by recombination and allows physical mapping in segments of suppressed recombination that are difficult to analyze using traditional mapping techniques. Even virtual "BAC-HAPPY-mapping" to convert BAC landing data into BAC linkage contigs is possible. PMID- 20161703 TI - Extracellular BCL2 proteins are danger-associated molecular patterns that reduce tissue damage in murine models of ischemia-reperfusion injury. AB - BACKGROUND: Ischemia-reperfusion (I/R) injury contributes to organ dysfunction in a variety of clinical disorders, including myocardial infarction, stroke, organ transplantation, and hemorrhagic shock. Recent investigations have demonstrated that apoptosis as an important mechanism of cell death leading to organ dysfunction following I/R. Intracellular danger-associated molecular patterns (DAMPs) released during cell death can activate cytoprotective responses by engaging receptors of the innate immune system. METHODOLOGY/PRINCIPAL FINDINGS: Ischemia was induced in the mouse hind limb by tourniquet or in the heart by coronary artery ligation. Reperfusion injury of skeletal or cardiac muscle was markedly reduced by intraperitoneal or subcutaneous injection of recombinant human (rh)BCL2 protein or rhBCL2-related protein A1 (BCL2A1) (50 ng/g) given prior to ischemia or at the time of reperfusion. The cytoprotective activity of extracellular rhBCL2 or rhBCL2A1 protein was mapped to the BH4 domain, as treatment with a mutant BCL2 protein lacking the BH4 domain was not protective, whereas peptides derived from the BH4 domain of BCL2 or the BH4-like domain of BCL2A1 were. Protection by extracellular rhBCL2 or rhBCL2A1 was associated with a reduction in apoptosis in skeletal and cardiac muscle following I/R, concomitant with increased expression of endogenous mouse BCL2 (mBCL2) protein. Notably, treatment with rhBCL2A1 protein did not protect mice deficient in toll-like receptor-2 (TLR2) or the adaptor protein, myeloid differentiation factor-88 (MyD88). CONCLUSIONS/SIGNIFICANCE: Treatment with cytokine-like doses of rhBCL2 or rhBCL2A1 protein or BH4-domain peptides reduces apoptosis and tissue injury following I/R by a TLR2-MyD88-dependent mechanism. These findings establish a novel extracellular cytoprotective activity of BCL2 BH4-domain proteins as potent cytoprotective DAMPs. PMID- 20161704 TI - Osteoblasts and bone marrow mesenchymal stromal cells control hematopoietic stem cell migration and proliferation in 3D in vitro model. AB - BACKGROUND: Migration, proliferation, and differentiation of hematopoietic stem cells (HSCs) are dependent upon a complex three-dimensional (3D) bone marrow microenvironment. Although osteoblasts control the HSC pool, the subendosteal niche is complex and its cellular composition and the role of each cell population in HSC fate have not been established. In vivo models are complex and involve subtle species-specific differences, while bidimensional cultures do not reflect the 3D tissue organization. The aim of this study was to investigate in vitro the role of human bone marrow-derived mesenchymal stromal cells (BMSC) and active osteoblasts in control of migration, lodgment, and proliferation of HSCs. METHODOLOGY/PRINCIPAL FINDINGS: A complex mixed multicellular spheroid in vitro model was developed with human BMSC, undifferentiated or induced for one week into osteoblasts. A clear limit between the two stromal cells was established, and deposition of extracellular matrix proteins fibronectin, collagens I and IV, laminin, and osteopontin was similar to the observed in vivo. Noninduced BMSC cultured as spheroid expressed higher levels of mRNA for the chemokine CXCL12, and the growth factors Wnt5a and Kit ligand. Cord blood and bone marrow CD34(+) cells moved in and out the spheroids, and some lodged at the interface of the two stromal cells. Myeloid colony-forming cells were maintained after seven days of coculture with mixed spheroids, and the frequency of cycling CD34(+) cells was decreased. CONCLUSIONS/SIGNIFICANCE: Undifferentiated and one-week osteo-induced BMSC self-assembled in a 3D spheroid and formed a microenvironment that is informative for hematopoietic progenitor cells, allowing their lodgment and controlling their proliferation. PMID- 20161705 TI - G protein coupled receptors in embryonic stem cells: a role for Gs-alpha signaling. AB - BACKGROUND: Identification of receptor mediated signaling pathways in embryonic stem (ES) cells is needed to facilitate strategies for cell replacement using ES cells. One large receptor family, largely uninvestigated in ES cells, is G protein coupled receptors (GPCRs). An important role for these receptors in embryonic development has been described, but little is known about GPCR expression in ES cells. METHODOLOGY/PRINCIPAL FINDINGS: We have examined the expression profile of 343 different GPCRs in mouse ES cells demonstrating for the first time that a large number of GPCRs are expressed in undifferentiated and differentiating ES cells, and in many cases at high levels. To begin to define a role for GPCR signaling in ES cells, the impact of activating Gs-alpha, one of the major alpha subunits that couples to GPCRs, was investigated. Gs-alpha activation resulted in larger embryoid bodies (EBs), due, in part, to increased cell proliferation and prevented the time-related decline in expression of transcription factors important for maintaining ES cell pluripotency. SIGNIFICANCE/CONCLUSIONS: These studies suggest that Gs-alpha signaling contributes to ES cell proliferation and pluripotency and provide a framework for further investigation of GPCRs in ES cells. PMID- 20161706 TI - New class of monoclonal antibodies against severe influenza: prophylactic and therapeutic efficacy in ferrets. AB - BACKGROUND: The urgent medical need for innovative approaches to control influenza is emphasized by the widespread resistance of circulating subtype H1N1 viruses to the leading antiviral drug oseltamivir, the pandemic threat posed by the occurrences of human infections with highly pathogenic avian H5N1 viruses, and indeed the evolving swine-origin H1N1 influenza pandemic. A recently discovered class of human monoclonal antibodies with the ability to neutralize a broad spectrum of influenza viruses (including H1, H2, H5, H6 and H9 subtypes) has the potential to prevent and treat influenza in humans. Here we report the latest efficacy data for a representative antibody of this novel class. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the prophylactic and therapeutic efficacy of the human monoclonal antibody CR6261 against lethal challenge with the highly pathogenic avian H5N1 virus in ferrets, the optimal model of human influenza infection. Survival rates, clinically relevant disease signs such as changes in body weight and temperature, virus replication in lungs and upper respiratory tract, as well as macro- and microscopic pathology were investigated. Prophylactic administration of 30 and 10 mg/kg CR6261 prior to viral challenge completely prevented mortality, weight loss and reduced the amount of infectious virus in the lungs by more than 99.9%, abolished shedding of virus in pharyngeal secretions and largely prevented H5N1-induced lung pathology. When administered therapeutically 1 day after challenge, 30 mg/kg CR6261 prevented death in all animals and blunted disease, as evidenced by decreased weight loss and temperature rise, reduced lung viral loads and shedding, and less lung damage. CONCLUSIONS/SIGNIFICANCE: These data demonstrate the prophylactic and therapeutic efficacy of this new class of human monoclonal antibodies in a highly stringent and clinically relevant animal model of influenza and justify clinical development of this approach as intervention for both seasonal and pandemic influenza. PMID- 20161708 TI - SRRM2, a potential blood biomarker revealing high alternative splicing in Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects about five million people worldwide. Diagnosis remains clinical, based on phenotypic patterns. The discovery of laboratory markers that will enhance diagnostic accuracy, allow pre-clinical detection and tracking of disease progression is critically needed. These biomarkers may include transcripts with different isoforms. METHODOLOGY/PRINCIPAL FINDINGS: We performed extensive analysis on 3 PD microarray experiments available through GEO and found that the RNA splicing gene SRRM2 (or SRm300), sereine/arginine repetitive matrix 2, was the only gene differentially upregulated among all the three PD experiments. SRRM2 expression was not changed in the blood of other neurological diseased patients versus the healthy controls. Using real-time PCR, we report that the shorter transcript of SRRM2 was 1.7 fold (p = 0.008) upregulated in the substantia nigra of PDs vs controls while the longer transcript was 0.4 downregulated in both the substantia nigra (p = 0.03) and amygdala (p = 0.003). To validate our results and test for the possibility of alternative splicing in PD, we performed independent microarray scans, using Affymetrix Exon_ST1 arrays, from peripheral blood of 28 individuals (17 PDs and 11 Ctrls) and found a significant upregulation of the upstream (5') exons of SRRM2 and a downregulation of the downstream exons, causing a total of 0.7 fold down regulation (p = 0.04) of the long isoform. In addition, we report novel information about hundreds of genes with significant alternative splicing (differential exonic expression) in PD blood versus controls. CONCLUSIONS/SIGNIFICANCE: The consistent dysregulation of the RNA splicing factor SRRM2 in two different PD neuronal sources and in PD blood but not in blood of other neurologically diseased patients makes SRRM2 a strong candidate gene for PD and draws attention to the role of RNA splicing in the disease. PMID- 20161707 TI - Lymphoid hyperplasia and lymphoma in transgenic mice expressing the small non coding RNA, EBER1 of Epstein-Barr virus. AB - BACKGROUND: Non-coding RNAs have critical functions in diverse biological processes, particularly in gene regulation. Viruses, like their host cells, employ such functional RNAs and the human cancer associated Epstein-Barr virus (EBV) is no exception. Nearly all EBV associated tumours express the EBV small, non-coding RNAs (EBERs) 1 and 2, however their role in viral pathogenesis remains largely obscure. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the action of EBER1 in vivo, we produced ten transgenic mouse lines expressing EBER1 in the lymphoid compartment using the mouse immunoglobulin heavy chain intronic enhancer Emicro. Mice of several of these EmicroEBER1 lines developed lymphoid hyperplasia which in some cases proceeded to B cell malignancy. The hallmark of the transgenic phenotype is enlargement of the spleen and mesenteric lymph nodes and in some cases enlargement of the thymus, liver and peripheral lymph nodes. The tumours were found to be of B cell origin and showed clonal IgH rearrangements. In order to explore if EBER1 would cooperate with c-Myc (deregulated in Burkitt's lymphoma) to accelerate lymphomagenesis, a cross-breeding study was undertaken with EmicroEBER1 and EmicroMyc mice. While no significant reduction in latency to lymphoma onset was observed in bi-transgenic mice, c-Myc induction was detected in some EmuEBER1 single transgenic tumours, indicative of a functional cooperation. CONCLUSIONS/SIGNIFICANCE: This study is the first to describe the in vivo expression of a polymerase III, non-coding viral gene and demonstrate its oncogenic potential. The data suggest that EBER1 plays an oncogenic role in EBV associated malignant disease. PMID- 20161709 TI - Community-acquired bacterial meningitis in alcoholic patients. AB - BACKGROUND: Alcoholism is associated with susceptibility to infectious disease, particularly bacterial pneumonia. In the present study we described characteristics in alcoholic patients with bacterial meningitis and delineate the differences with findings in non-alcoholic adults with bacterial meningitis. METHODS/PRINCIPAL FINDINGS: This was a prospective nationwide observational cohort study including patients aged >16 years who had bacterial meningitis confirmed by culture of cerebrospinal fluid (696 episodes of bacterial meningitis occurring in 671 patients). Alcoholism was present in 27 of 686 recorded episodes of bacterial meningitis (4%) and alcoholics were more often male than non alcoholics (82% vs 48%, P = 0.001). A higher proportion of alcoholics had underlying pneumonia (41% vs 11% P<0.001). Alcoholics were more likely to have meningitis due to infection with Streptococcus pneumoniae (70% vs 50%, P = 0.01) and Listeria monocytogenes (19% vs 4%, P = 0.005), whereas Neisseria meningitidis was more common in non-alcoholic patients (39% vs 4%, P = 0.01). A large proportion of alcoholics developed complications during clinical course (82% vs 62%, as compared with non-alcoholics; P = 0.04), often cardiorespiratory failure (52% vs 28%, as compared with non-alcoholics; P = 0.01). Alcoholic patients were at risk for unfavourable outcome (67% vs 33%, as compared with non-alcoholics; P<0.001). CONCLUSIONS/SIGNIFICANCE: Alcoholic patients are at high risk for complications resulting in high morbidity and mortality. They are especially at risk for cardiorespiratory failure due to underlying pneumonia, and therefore, aggressive supportive care may be crucial in the treatment of these patients. PMID- 20161710 TI - Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors. AB - BACKGROUND: Notch receptors normally play a key role in guiding a variety of cell fate decisions during development and differentiation of metazoan organisms. On the other hand, dysregulation of Notch1 signaling is associated with many different types of cancer as well as tumor angiogenesis, making Notch1 a potential therapeutic target. PRINCIPAL FINDINGS: Here we report the in vitro activities of inhibitory Notch1 monoclonal antibodies derived from cell-based and solid-phase screening of a phage display library. Two classes of antibodies were found, one directed against the EGF-repeat region that encompasses the ligand binding domain (LBD), and the second directed against the activation switch of the receptor, the Notch negative regulatory region (NRR). The antibodies are selective for Notch1, inhibiting Jag2-dependent signaling by Notch1 but not by Notch 2 and 3 in reporter gene assays, with EC(50) values as low as 5+/-3 nM and 0.13+/-0.09 nM for the LBD and NRR antibodies, respectively, and fail to recognize Notch4. While more potent, NRR antibodies are incomplete antagonists of Notch1 signaling. The antagonistic activity of LBD, but not NRR, antibodies is strongly dependent on the activating ligand. Both LBD and NRR antibodies bind to Notch1 on human tumor cell lines and inhibit the expression of sentinel Notch target genes, including HES1, HES5, and DTX1. NRR antibodies also strongly inhibit ligand-independent signaling in heterologous cells transiently expressing Notch1 receptors with diverse NRR "class I" point mutations, the most common type of mutation found in human T-cell acute lymphoblastic leukemia (T-ALL). In contrast, NRR antibodies failed to antagonize Notch1 receptors bearing rare "class II" or "class III" mutations, in which amino acid insertions generate a duplicated or constitutively sensitive metalloprotease cleavage site. Signaling in T-ALL cell lines bearing class I mutations is partially refractory to inhibitory antibodies as compared to cell-penetrating gamma-secretase inhibitors. CONCLUSIONS/SIGNIFICANCE: Antibodies that compete with Notch1 ligand binding or that bind to the negative regulatory region can act as potent inhibitors of Notch1 signaling. These antibodies may have clinical utility for conditions in which inhibition of signaling by wild-type Notch1 is desired, but are likely to be of limited value for treatment of T-ALLs associated with aberrant Notch1 activation. PMID- 20161711 TI - DKK1 mediated inhibition of Wnt signaling in postnatal mice leads to loss of TEC progenitors and thymic degeneration. AB - BACKGROUND: Thymic epithelial cell (TEC) microenvironments are essential for the recruitment of T cell precursors from the bone marrow, as well as the subsequent expansion and selection of thymocytes resulting in a mature self-tolerant T cell repertoire. The molecular mechanisms, which control both the initial development and subsequent maintenance of these critical microenvironments, are poorly defined. Wnt signaling has been shown to be important to the development of several epithelial tissues and organs. Regulation of Wnt signaling has also been shown to impact both early thymocyte and thymic epithelial development. However, early blocks in thymic organogenesis or death of the mice have prevented analysis of a role of canonical Wnt signaling in the maintenance of TECs in the postnatal thymus. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate that tetracycline regulated expression of the canonical Wnt inhibitor DKK1 in TECs localized in both the cortex and medulla of adult mice, results in rapid thymic degeneration characterized by a loss of DeltaNP63(+) Foxn1(+) and Aire(+) TECs, loss of K5K8DP TECs thought to represent or contain an immature TEC progenitor, decreased TEC proliferation and the development of cystic structures, similar to an aged thymus. Removal of DKK1 from DKK1-involuted mice results in full recovery, suggesting that canonical Wnt signaling is required for the differentiation or proliferation of TEC populations needed for maintenance of properly organized adult thymic epithelial microenvironments. CONCLUSIONS/SIGNIFICANCE: Taken together, the results of this study demonstrate that canonical Wnt signaling within TECs is required for the maintenance of epithelial microenvironments in the postnatal thymus, possibly through effects on TEC progenitor/stem cell populations. Downstream targets of Wnt signaling, which are responsible for maintenance of these TEC progenitors may provide useful targets for therapies aimed at counteracting age associated thymic involution or the premature thymic degeneration associated with cancer therapy and bone marrow transplants. PMID- 20161712 TI - Unexpected tolerance of alpha-cleavage of the prion protein to sequence variations. AB - The cellular form of the prion protein, PrP(C), undergoes extensive proteolysis at the alpha site (109K [see text]H110). Expression of non-cleavable PrP(C) mutants in transgenic mice correlates with neurotoxicity, suggesting that alpha cleavage is important for PrP(C) physiology. To gain insights into the mechanisms of alpha-cleavage, we generated a library of PrP(C) mutants with mutations in the region neighbouring the alpha-cleavage site. The prevalence of C1, the carboxy adduct of alpha-cleavage, was determined for each mutant. In cell lines of disparate origin, C1 prevalence was unaffected by variations in charge and hydrophobicity of the region neighbouring the alpha-cleavage site, and by substitutions of the residues in the palindrome that flanks this site. Instead, alpha-cleavage was size-dependently impaired by deletions within the domain 106 119. Almost no cleavage was observed upon full deletion of this domain. These results suggest that alpha-cleavage is executed by an alpha-PrPase whose activity, despite surprisingly limited sequence specificity, is dependent on the size of the central region of PrP(C). PMID- 20161713 TI - Ambient air pollution and the progression of atherosclerosis in adults. AB - BACKGROUND: Cross-sectional studies suggest an association between exposure to ambient air pollution and atherosclerosis. We investigated the association between outdoor air quality and progression of subclinical atherosclerosis (common carotid artery intima-media thickness, CIMT). METHODOLOGY/PRINCIPAL FINDINGS: We examined data from five double-blind randomized trials that assessed effects of various treatments on the change in CIMT. The trials were conducted in the Los Angeles area. Spatial models and land-use data were used to estimate the home outdoor mean concentration of particulate matter up to 2.5 micrometer in diameter (PM2.5), and to classify residence by proximity to traffic-related pollution (within 100 m of highways). PM2.5 and traffic proximity were positively associated with CIMT progression. Adjusted coefficients were larger than crude associations, not sensitive to modelling specifications, and statistically significant for highway proximity while of borderline significance for PM2.5 (P = 0.08). Annual CIMT progression among those living within 100 m of a highway was accelerated (5.5 micrometers/yr [95%CI: 0.13-10.79; p = 0.04]) or more than twice the population mean progression. For PM2.5, coefficients were positive as well, reaching statistical significance in the socially disadvantaged; in subjects reporting lipid lowering treatment at baseline; among participants receiving on trial treatments; and among the pool of four out of the five trials. CONCLUSION: Consistent with cross-sectional findings and animal studies, this is the first study to report an association between exposure to air pollution and the progression of atherosclerosis--indicated with CIMT change--in humans. Ostensibly, our results suggest that air pollution may contribute to the acceleration of cardiovascular disease development--the main causes of morbidity and mortality in many countries. However, the heterogeneity of the volunteering populations across the five trials, the limited sample size within trials and other relevant subgroups, and the fact that some key findings reached statistical significance in subgroups rather than the sample precludes generalizations to the general population. PMID- 20161714 TI - Honeybees learn odour mixtures via a selection of key odorants. AB - BACKGROUND: The honeybee has to detect, process and learn numerous complex odours from her natural environment on a daily basis. Most of these odours are floral scents, which are mixtures of dozens of different odorants. To date, it is still unclear how the bee brain unravels the complex information contained in scent mixtures. METHODOLOGY/PRINCIPAL FINDINGS: This study investigates learning of complex odour mixtures in honeybees using a simple olfactory conditioning procedure, the Proboscis-Extension-Reflex (PER) paradigm. Restrained honeybees were trained to three scent mixtures composed of 14 floral odorants each, and then tested with the individual odorants of each mixture. Bees did not respond to all odorants of a mixture equally: They responded well to a selection of key odorants, which were unique for each of the three scent mixtures. Bees showed less or very little response to the other odorants of the mixtures. The bees' response to mixtures composed of only the key odorants was as good as to the original mixtures of 14 odorants. A mixture composed of the other, non-key odorants elicited a significantly lower response. Neither an odorant's volatility or molecular structure, nor learning efficiencies for individual odorants affected whether an odorant became a key odorant for a particular mixture. Odorant concentration had a positive effect, with odorants at high concentration likely to become key odorants. CONCLUSIONS/SIGNIFICANCE: Our study suggests that the brain processes complex scent mixtures by predominantly learning information from selected key odorants. Our observations on key odorant learning lend significant support to previous work on olfactory learning and mixture processing in honeybees. PMID- 20161715 TI - Eukaryotic DING proteins are endogenous: an immunohistological study in mouse tissues. AB - BACKGROUND: DING proteins encompass an intriguing protein family first characterized by their conserved N-terminal sequences. Some of these proteins seem to have key roles in various human diseases, e.g., rheumatoid arthritis, atherosclerosis, HIV suppression. Although this protein family seems to be ubiquitous in eukaryotes, their genes are consistently lacking from genomic databases. Such a lack has considerably hampered functional studies and has fostered therefore the hypothesis that DING proteins isolated from eukaryotes were in fact prokaryotic contaminants. PRINCIPAL FINDINGS: In the framework of our study, we have performed a comprehensive immunological detection of DING proteins in mice. We demonstrate that DING proteins are present in all tissues tested as isoforms of various molecular weights (MWs). Their intracellular localization is tissue-dependant, being exclusively nuclear in neurons, but cytoplasmic and nuclear in other tissues. We also provide evidence that germ-free mouse plasma contains as much DING protein as wild-type. SIGNIFICANCE: Hence, data herein provide a valuable basis for future investigations aimed at eukaryotic DING proteins, revealing that these proteins seem ubiquitous in mouse tissue. Our results strongly suggest that mouse DING proteins are endogenous. Moreover, the determination in this study of the precise cellular localization of DING proteins constitute a precious evidence to understand their molecular involvements in their related human diseases. PMID- 20161716 TI - mRNA secondary structures fold sequentially but exchange rapidly in vivo. AB - RNAs adopt defined structures to perform biological activities, and conformational transitions among alternative structures are critical to virtually all RNA-mediated processes ranging from metabolite-activation of bacterial riboswitches to pre-mRNA splicing and viral replication in eukaryotes. Mechanistic analysis of an RNA folding reaction in a biological context is challenging because many steps usually intervene between assembly of a functional RNA structure and execution of a biological function. We developed a system to probe mechanisms of secondary structure folding and exchange directly in vivo using self-cleavage to monitor competition between mutually exclusive structures that promote or inhibit ribozyme assembly. In previous work, upstream structures were more effective than downstream structures in blocking ribozyme assembly during transcription in vitro, consistent with a sequential folding mechanism. However, upstream and downstream structures blocked ribozyme assembly equally well in vivo, suggesting that intracellular folding outcomes reflect thermodynamic equilibration or that annealing of contiguous sequences is favored kinetically. We have extended these studies to learn when, if ever, thermodynamic stability becomes an impediment to rapid equilibration among alternative RNA structures in vivo. We find that a narrow thermodynamic threshold determines whether kinetics or thermodynamics govern RNA folding outcomes in vivo. mRNA secondary structures fold sequentially in vivo, but exchange between adjacent secondary structures is much faster in vivo than it is in vitro. Previous work showed that simple base-paired RNA helices dissociate at similar rates in vivo and in vitro so exchange between adjacent structures must occur through a different mechanism, one that likely involves facilitation of branch migration by proteins associated with nascent transcripts. PMID- 20161717 TI - A novel high-affinity sucrose transporter is required for virulence of the plant pathogen Ustilago maydis. AB - Plant pathogenic fungi cause massive yield losses and affect both quality and safety of food and feed produced from infected plants. The main objective of plant pathogenic fungi is to get access to the organic carbon sources of their carbon-autotrophic hosts. However, the chemical nature of the carbon source(s) and the mode of uptake are largely unknown. Here, we present a novel, plasma membrane-localized sucrose transporter (Srt1) from the corn smut fungus Ustilago maydis and its characterization as a fungal virulence factor. Srt1 has an unusually high substrate affinity, is absolutely sucrose specific, and allows the direct utilization of sucrose at the plant/fungal interface without extracellular hydrolysis and, thus, without the production of extracellular monosaccharides known to elicit plant immune responses. srt1 is expressed exclusively during infection, and its deletion strongly reduces fungal virulence. This emphasizes the central role of this protein both for efficient carbon supply and for avoidance of apoplastic signals potentially recognized by the host. PMID- 20161718 TI - Developing global maps of the dominant anopheles vectors of human malaria. PMID- 20161719 TI - Paleovirology--modern consequences of ancient viruses. PMID- 20161720 TI - Using structural information to change the phosphotransfer specificity of a two component chemotaxis signalling complex. AB - Two-component signal transduction pathways comprising histidine protein kinases (HPKs) and their response regulators (RRs) are widely used to control bacterial responses to environmental challenges. Some bacteria have over 150 different two component pathways, and the specificity of the phosphotransfer reactions within these systems is tightly controlled to prevent unwanted crosstalk. One of the best understood two-component signalling pathways is the chemotaxis pathway. Here, we present the 1.40 A crystal structure of the histidine-containing phosphotransfer domain of the chemotaxis HPK, CheA(3), in complex with its cognate RR, CheY(6). A methionine finger on CheY(6) that nestles in a hydrophobic pocket in CheA(3) was shown to be important for the interaction and was found to only occur in the cognate RRs of CheA(3), CheY(6), and CheB(2). Site-directed mutagenesis of this methionine in combination with two adjacent residues abolished binding, as shown by surface plasmon resonance studies, and phosphotransfer from CheA(3)-P to CheY(6). Introduction of this methionine and an adjacent alanine residue into a range of noncognate CheYs, dramatically changed their specificity, allowing protein interaction and rapid phosphotransfer from CheA(3)-P. The structure presented here has allowed us to identify specificity determinants for the CheA-CheY interaction and subsequently to successfully reengineer phosphotransfer signalling. In summary, our results provide valuable insight into how cells mediate specificity in one of the most abundant signalling pathways in biology, two-component signal transduction. PMID- 20161721 TI - Living the sweet life: how does a plant pathogenic fungus acquire sugar from plants? PMID- 20161722 TI - The global research neglect of unassisted smoking cessation: causes and consequences. PMID- 20161723 TI - Impact of antiretroviral therapy on incidence of pregnancy among HIV-infected women in Sub-Saharan Africa: a cohort study. AB - BACKGROUND: With the rapid expansion of antiretroviral therapy (ART) services in sub-Saharan Africa there is growing recognition of the importance of fertility and childbearing among HIV-infected women. However there are few data on whether ART initiation influences pregnancy rates. METHODS AND FINDINGS: We analyzed data from the Mother-to-Child Transmission-Plus (MTCT-Plus) Initiative, a multicountry HIV care and treatment program for women, children, and families. From 11 programs in seven African countries, women were enrolled into care regardless of HIV disease stage and followed at regular intervals; ART was initiated according to national guidelines on the basis of immunological and/or clinical criteria. Standardized forms were used to collect sociodemographic and clinical data, including incident pregnancies. Overall 589 incident pregnancies were observed among the 4,531 women included in this analysis (pregnancy incidence, 7.8/100 person-years [PY]). The rate of new pregnancies was significantly higher among women receiving ART (9.0/100 PY) compared to women not on ART (6.5/100 PY) (adjusted hazard ratio, 1.74; 95% confidence interval, 1.19-2.54). Other factors independently associated with increased risk of incident pregnancy included younger age, lower educational attainment, being married or cohabiting, having a male partner enrolled into the program, failure to use nonbarrier contraception, and higher CD4 cell counts. CONCLUSIONS: ART use is associated with significantly higher pregnancy rates among HIV-infected women in sub-Saharan Africa. While the possible behavioral or biomedical mechanisms that may underlie this association require further investigation, these data highlight the importance of pregnancy planning and management as a critical but neglected component of HIV care and treatment services. Please see later in the article for the Editors' Summary. PMID- 20161724 TI - An "in-depth" description of the small non-coding RNA population of Schistosoma japonicum schistosomulum. AB - Parasitic flatworms of the genus Schistosoma are the causative agents of schistosomiasis, which afflicts more than 200 million people yearly in tropical regions of South America, Asia and Africa. A promising approach to the control of this and many other diseases involves the application of our understanding of small non-coding RNA function to the design of safe and effective means of treatment. In a previous study, we identified five conserved miRNAs from the adult stage of Schistosoma japonicum. Here, we applied Illumina Solexa high throughput sequencing methods (deep sequencing) to investigate the small RNAs expressed in S. japonicum schistosomulum (3 weeks post-infection). This has allowed us to examine over four million sequence reads including both frequently and infrequently represented members of the RNA population. Thus we have identified 20 conserved miRNA families that have orthologs in well-studied model organisms and 16 miRNA that appear to be specific to Schistosoma. We have also observed minor amounts of heterogeneity in both 3' and 5' terminal positions of some miRNA as well as RNA fragments resulting from the processing of miRNA precursor. An investigation of the genomic arrangement of the 36 identified miRNA revealed that seven were tightly linked in two clusters. We also identified members of the small RNA population whose structure indicates that they are part of an endogenously derived RNA silencing pathway, as evidenced by their extensive complementarities with retrotransposon and retrovirus-related Pol polyprotein from transposon. PMID- 20161725 TI - Schistosoma mansoni Stomatin like protein-2 is located in the tegument and induces partial protection against challenge infection. AB - BACKGROUND: Schistosomiasis affects more than 200 million individuals worldwide, with a further 650 million living at risk of infection, constituting a severe health problem in developing countries. Even though an effective treatment exists, it does not prevent re-infection, and the development of an effective vaccine still remains the most desirable means of control for this disease. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we report the cloning and characterization of a S. mansoni Stomatin-like protein 2 (SmStoLP-2). In silico analysis predicts three putative sites for palmitoylation (Cys11, Cys61 and Cys330), which could contribute to protein membrane association; and a putative mitochondrial targeting sequence, similar to that described for human Stomatin like protein 2 (HuSLP-2). The protein was detected by Western blot with comparable levels in all stages across the parasite life cycle. Fractionation by differential centrifugation of schistosome tegument suggested that SmStoLP-2 displays a dual targeting to the tegument membranes and mitochondria; additionally, immunolocalization experiments confirm its localization in the tegument of the adult worms and, more importantly, in 7-day-old schistosomula. Analysis of the antibody isotype profile to rSmStoLP-2 in the sera of patients living in endemic areas for schistosomiasis revealed that IgG1, IgG2, IgG3 and IgA antibodies were predominant in sera of individuals resistant to reinfection as compared to those susceptible. Next, immunization of mice with rSmStoLP-2 engendered a 30%-32% reduction in adult worm burden. Protective immunity in mice was associated with specific anti-rSmStoLP-2 IgG1 and IgG2a antibodies and elevated production of IFN-gamma and TNF-alpha, while no IL-4 production was detected, suggesting a Th1-predominant immune response. CONCLUSIONS/SIGNIFICANCE: Data presented here demonstrate that SmStoLP-2 is a novel tegument protein located in the host-parasite interface. It is recognized by different subclasses of antibodies in patients resistant and susceptible to reinfection and, based on the data from murine studies, shows protective potential against schistosomiasis. These results indicate that SmStoLP-2 could be useful in a combination vaccine. PMID- 20161726 TI - Temporal expression of chemokines dictates the hepatic inflammatory infiltrate in a murine model of schistosomiasis. AB - Schistosomiasis continues to be an important cause of parasitic morbidity and mortality world-wide. Determining the molecular mechanisms regulating the development of granulomas and fibrosis will be essential for understanding how schistosome antigens interact with the host environment. We report here the first whole genome microarray analysis of the murine liver during the progression of Schistosoma japonicum egg-induced granuloma formation and hepatic fibrosis. Our results reveal a distinct temporal relationship between the expression of chemokine subsets and the recruitment of cells to the infected liver. Genes up regulated earlier in the response included T- and B-cell chemoattractants, reflecting the early recruitment of these cells illustrated by flow cytometry. The later phases of the response corresponded with peak recruitment of eosinophils, neutrophils, macrophages and myofibroblasts/hepatic stellate cells (HSCs) and the expression of chemokines with activity for these cells including CCL11 (eotaxin 1), members of the Monocyte-chemoattractant protein family (CCL7, CCL8, CCL12) and the Hepatic Stellate Cell/Fibrocyte chemoattractant CXCL1. Peak expression of macrophage chemoattractants (CCL6, CXCL14) and markers of alternatively activated macrophages (e.g. Retnla) during this later phase provides further evidence of a role for these cells in schistosome-induced pathology. Additionally, we demonstrate that CCL7 immunolocalises to the fibrotic zone of granulomas. Furthermore, striking up-regulation of neutrophil markers and the localisation of neutrophils and the neutrophil chemokine S100A8 to fibrotic areas suggest the involvement of neutrophils in S. japonicum-induced hepatic fibrosis. These results further our understanding of the immunopathogenic and, especially, chemokine signalling pathways that regulate the development of S. japonicum-induced granulomas and fibrosis and may provide correlative insight into the pathogenesis of other chronic inflammatory diseases of the liver where fibrosis is a common feature. PMID- 20161727 TI - Of cattle, sand flies and men: a systematic review of risk factor analyses for South Asian visceral leishmaniasis and implications for elimination. AB - BACKGROUND: Studies performed over the past decade have identified fairly consistent epidemiological patterns of risk factors for visceral leishmaniasis (VL) in the Indian subcontinent. METHODS AND PRINCIPAL FINDINGS: To inform the current regional VL elimination effort and identify key gaps in knowledge, we performed a systematic review of the literature, with a special emphasis on data regarding the role of cattle because primary risk factor studies have yielded apparently contradictory results. Because humans form the sole infection reservoir, clustering of kala-azar cases is a prominent epidemiological feature, both at the household level and on a larger scale. Subclinical infection also tends to show clustering around kala-azar cases. Within villages, areas become saturated over a period of several years; kala-azar incidence then decreases while neighboring areas see increases. More recently, post kala-azar dermal leishmaniasis (PKDL) cases have followed kala-azar peaks. Mud walls, palpable dampness in houses, and peri-domestic vegetation may increase infection risk through enhanced density and prolonged survival of the sand fly vector. Bed net use, sleeping on a cot and indoor residual spraying are generally associated with decreased risk. Poor micronutrient status increases the risk of progression to kala-azar. The presence of cattle is associated with increased risk in some studies and decreased risk in others, reflecting the complexity of the effect of bovines on sand fly abundance, aggregation, feeding behavior and leishmanial infection rates. Poverty is an overarching theme, interacting with individual risk factors on multiple levels. CONCLUSIONS: Carefully designed demonstration projects, taking into account the complex web of interconnected risk factors, are needed to provide direct proof of principle for elimination and to identify the most effective maintenance activities to prevent a rapid resurgence when interventions are scaled back. More effective, short-course treatment regimens for PKDL are urgently needed to enable the elimination initiative to succeed. PMID- 20161728 TI - Transcriptional changes in Schistosoma mansoni during early schistosomula development and in the presence of erythrocytes. AB - BACKGROUND: Schistosomes cause more mortality and morbidity than any other human helminth, but control primarily relies on a single drug that kills adult worms. The newly transformed schistosomulum stage is susceptible to the immune response and is a target for vaccine development and rational drug design. METHODOLOGY/PRINCIPAL FINDINGS: To identify genes which are up-regulated during the maturation of Schistosoma mansoni schistosomula in vitro, we cultured newly transformed parasites for 3 h or 5 days with and without erythrocytes and compared their transcriptional profiles using cDNA microarrays. The most apparent changes were in the up-regulation of genes between 3 h and 5 day schistosomula involved in blood feeding, tegument and cytoskeletal development, cell adhesion, and stress responses. The most highly up-regulated genes included a tegument tetraspanin Sm-tsp-3 (1,600-fold up-regulation), a protein kinase, a novel serine protease and serine protease inhibitor, and intestinal proteases belonging to distinct mechanistic classes. The inclusion of erythrocytes in the culture medium resulted in a general but less pronounced increase in transcriptional activity, with the highest up-regulation of genes involved in iron metabolism, proteolysis, and transport of fatty acids and sugars. CONCLUSIONS: We have identified the genes that are up-regulated during the first 5 days of schistosomula development in vitro. Using a combination of gene silencing techniques and murine protection studies, some of these highly up-regulated transcripts can be targeted for future development of new vaccines and drugs. PMID- 20161730 TI - Engineering clostridium strain to accept unmethylated DNA. AB - It is difficult to genetically manipulate the medically and biotechnologically important genus Clostridium due to the existence of the restriction and modification (RM) systems. We identified and engineered the RM system of a model clostridial species, C. acetobutylicum, with the aim to allow the host to accept the unmethylated DNA efficiently. A gene CAC1502 putatively encoding the type II restriction endonuclease Cac824I was identified from the genome of C. acetobutylicum DSM1731, and disrupted using the ClosTron system based on group II intron insertion. The resulting strain SMB009 lost the type II restriction endonuclease activity, and can be transformed with unmethylated DNA as efficiently as with methylated DNA. The strategy reported here makes it easy to genetically modify the clostridial species using unmethylated DNA, which will help to advance the understanding of the clostridial physiology from the molecular level. PMID- 20161729 TI - Berberine inhibits HIV protease inhibitor-induced inflammatory response by modulating ER stress signaling pathways in murine macrophages. AB - BACKGROUND: HIV protease inhibitor (PI)-induced inflammatory response plays an important role in HIV PI-associated dyslipidemia and cardiovascular complications. This study examined the effect of berberine, a traditional herb medicine, on HIV PI-induced inflammatory response and further investigated the underlying cellular/molecular mechanisms in macrophages. METHODOLOGY AND PRINCIPAL FINDINGS: Cultured mouse J774A.1 macrophages and primary mouse macrophages were used in this study. The expression of TNF-alpha and IL-6 were detected by real-time RT-PCR and ELISA. Activations of ER stress and ERK signaling pathways were determined by Western blot analysis. Immunofluorescent staining was used to determine the intracellular localization of RNA binding protein HuR. RNA-pull down assay was used to determine the association of HuR with endogenous TNF-alpha and IL-6. Berberine significantly inhibited HIV PI induced TNF-alpha and IL-6 expression by modulating ER stress signaling pathways and subsequent ERK activation, in turn preventing the accumulation of the RNA binding protein HuR in cytosol and inhibiting the binding of HuR to the 3'-UTRs of TNF-alpha and IL-6 in macrophages. CONCLUSIONS AND SIGNIFICANCE: Inhibition of ER stress represents a key mechanism by which berberine prevents HIV PI-induced inflammatory response. Our findings provide a new insight into the molecular mechanisms of berberine and show the potential application of berberine as a complimentary therapeutic agent for HIV infection. PMID- 20161731 TI - The manual habituation and discrimination of shapes in preterm human infants from 33 to 34+6 post-conceptional age. AB - BACKGROUND: Grasping at birth is well-known as a reflex in response to a stimulation of the palm of the hand. Recent studies revealed that this grasping was not only a pure reflex because human newborns are able to detect and to remember differences in shape features. The manual perception of shapes has not been investigated in preterm human infants. The aim of the present study was to investigate manual perception by preterm infants. METHODOLOGY/PRINCIPAL FINDINGS: We used a habituation/reaction to novelty procedure in twenty-four human preterm infants from 33 to 34+6 post-conceptional age. After habituation to an object (prism or cylinder) in one hand (left or right) in a habituation phase, babies were given either the same object or the other (novel) object in the same hand in a test phase. We observed that after successive presentations of the same object, a decrease of the holding time is observed for each preterm infant. Moreover, a significant increase of the holding time is obtained with the presentation of the novel object. Finally, the comparison between the current performance of preterm infants and those of full-term newborns showed that preterm babies only had a faster tactile habituation to a shape. CONCLUSION/SIGNIFICANCE: For the first time, the results reveal that preterm infants from 33 to 34+6 GW can detect the specific features that differentiate prism and cylinder shapes by touch, and remember them. The results suggest that there is no qualitative, but only quantitative, difference between the perceptual abilities of preterm babies and those of full-term babies in perceiving shape manually. PMID- 20161732 TI - PLUNC is a novel airway surfactant protein with anti-biofilm activity. AB - BACKGROUND: The PLUNC ("Palate, lung, nasal epithelium clone") protein is an abundant secretory product of epithelia present throughout the conducting airways of humans and other mammals, which is evolutionarily related to the lipid transfer/lipopolysaccharide binding protein (LT/LBP) family. Two members of this family--the bactericidal/permeability increasing protein (BPI) and the lipopolysaccharide binding protein (LBP)--are innate immune molecules with recognized roles in sensing and responding to Gram negative bacteria, leading many to propose that PLUNC may play a host defense role in the human airways. METHODOLOGY/PRINCIPAL FINDINGS: Based on its marked hydrophobicity, we hypothesized that PLUNC may be an airway surfactant. We found that purified recombinant human PLUNC greatly enhanced the ability of aqueous solutions to spread on a hydrophobic surface. Furthermore, we discovered that PLUNC significantly reduced surface tension at the air-liquid interface in aqueous solutions, indicating novel and biologically relevant surfactant properties. Of note, surface tensions achieved by adding PLUNC to solutions are very similar to measurements of the surface tension in tracheobronchial secretions from humans and animal models. Because surfactants of microbial origin can disperse matrix encased bacterial clusters known as biofilms [1], we hypothesized that PLUNC may also have anti-biofilm activity. We found that, at a physiologically relevant concentration, PLUNC inhibited biofilm formation by the airway pathogen Pseudomonas aeruginosa in an in vitro model. CONCLUSIONS/SIGNIFICANCE: Our data suggest that the PLUNC protein contributes to the surfactant properties of airway secretions, and that this activity may interfere with biofilm formation by an airway pathogen. PMID- 20161733 TI - Insertion of tetracysteine motifs into dopamine transporter extracellular domains. AB - The neuronal dopamine transporter (DAT) is a major determinant of extracellular dopamine (DA) levels and is the primary target for a variety of addictive and therapeutic psychoactive drugs. DAT is acutely regulated by protein kinase C (PKC) activation and amphetamine exposure, both of which modulate DAT surface expression by endocytic trafficking. In order to use live imaging approaches to study DAT endocytosis, methods are needed to exclusively label the DAT surface pool. The use of membrane impermeant, sulfonated biarsenic dyes holds potential as one such approach, and requires introduction of an extracellular tetracysteine motif (tetraCys; CCPGCC) to facilitate dye binding. In the current study, we took advantage of intrinsic proline-glycine (Pro-Gly) dipeptides encoded in predicted DAT extracellular domains to introduce tetraCys motifs into DAT extracellular loops 2, 3, and 4. [(3)H]DA uptake studies, surface biotinylation and fluorescence microscopy in PC12 cells indicate that tetraCys insertion into the DAT second extracellular loop results in a functional transporter that maintains PKC-mediated downregulation. Introduction of tetraCys into extracellular loops 3 and 4 yielded DATs with severely compromised function that failed to mature and traffic to the cell surface. This is the first demonstration of successful introduction of a tetracysteine motif into a DAT extracellular domain, and may hold promise for use of biarsenic dyes in live DAT imaging studies. PMID- 20161734 TI - Causal relationship of susceptibility genes to ischemic stroke: comparison to ischemic heart disease and biochemical determinants. AB - Interrelationships between genetic and biochemical factors underlying ischemic stroke and ischemic heart disease are poorly understood. We: 1) undertook the most comprehensive meta-analysis of genetic polymorphisms in ischemic stroke to date; 2) compared genetic determinants of ischemic stroke with those of ischemic heart disease, and 3) compared effect sizes of gene-stroke associations with those predicted from independent biochemical data using a mendelian randomization strategy. Electronic databases were searched up to January 2009. We identified: 1) 187 ischemic stroke studies (37,481 cases; 95,322 controls) interrogating 43 polymorphisms in 29 genes; 2) 13 meta-analyses testing equivalent polymorphisms in ischemic heart disease; and 3) for the top five gene-stroke associations, 146 studies (65,703 subjects) describing equivalent gene-biochemical relationships, and 28 studies (46,928 subjects) describing biochemical-stroke relationships. Meta-analyses demonstrated positive associations with ischemic stroke for factor V Leiden Gln506, ACE I/D, MTHFR C677T, prothrombin G20210A, PAI-1 5G allele and glycoprotein IIIa Leu33Pro polymorphisms (ORs: 1.11 - 1.60). Most genetic associations show congruent levels of risk comparing ischemic stroke with ischemic heart disease, but three genes--glycoprotein IIIa, PAI-1 and angiotensinogen--show significant dissociations. The magnitudes of stroke risk observed for factor V Leiden, ACE, MTHFR and prothrombin, but not PAI-1, polymorphisms, are consistent with risks associated with equivalent changes in activated protein C resistance, ACE activity, homocysteine, prothrombin, and PAI 1 levels, respectively. Our results demonstrate causal relationships for four of the most robust genes associated with stroke while also showing that PAI-1 4G/5G polymorphism influences cardiovascular risk via a mechanism not simply related to plasma levels of PAI-1 (or tPA) alone. PMID- 20161735 TI - DHP-derivative and low oxygen tension effectively induces human adipose stromal cell reprogramming. AB - BACKGROUND AND METHODS: In this study, we utilized a combination of low oxygen tension and a novel anti-oxidant, 4-(3,4-dihydroxy-phenyl)-derivative (DHP-d) to directly induce adipose tissue stromal cells (ATSC) to de-differentiate into more primitive stem cells. De-differentiated ATSCs was overexpress stemness genes, Rex 1, Oct-4, Sox-2, and Nanog. Additionally, demethylation of the regulatory regions of Rex-1, stemnesses, and HIF1alpha and scavenging of reactive oxygen species were finally resulted in an improved stem cell behavior of de-differentiate ATSC (de-ATSC). Proliferation activity of ATSCs after dedifferentiation was induced by REX1, Oct4, and JAK/STAT3 directly or indirectly. De-ATSCs showed increased migration activity that mediated by P38/JUNK and ERK phosphorylation. Moreover, regenerative efficacy of de-ATSC engrafted spinal cord-injured rats and chemical induced diabetes animals were significantly restored their functions. CONCLUSIONS/SIGNIFICANCE: Our stem cell remodeling system may provide a good model which would provide insight into the molecular mechanisms underlying ATSC proliferation and transdifferentiation. Also, these multipotent stem cells can be harvested may provide us with a valuable reservoir of primitive and autologous stem cells for use in a broad spectrum of regenerative cell-based disease therapy. PMID- 20161736 TI - The induction of colitis and ileitis in mice is associated with marked increases in intestinal concentrations of stimulants of TLRs 2, 4, and 5. AB - BACKGROUND: Inflammatory bowel diseases (IBDs) appear to be modulated by the interaction of pathogen-associated molecular patterns (PAMPs) derived from intestinal bacteria with their respective innate immune receptors, including Toll like receptors (TLRs). We aimed to establish if intestinal concentrations of proinflammatory bacterial ligands of TLR2, TLR4, or TLR5 may be altered in murine IBD models, and to characterize which of the major bacterial groups may contribute to each signal. METHODOLOGY/PRINCIPAL FINDINGS: PAMPs specific for TLR2 (lipopeptide equivalents), TLR4 (lipopolysaccharide equivalents), and TLR5 (flagellin equivalents) in human and murine fecal and intestinal samples were quantified using HEK-293 cells transfected with respective TLRs and calibrated with defined standard PAMPs. The induction of colitis in mice by dextran-sodium sulphate treatment significantly increased colonic lipopeptide (fourfold) and LPS equivalent (550-fold) concentrations, while flagellin equivalent concentrations remained similar. The induction of ileitis by oral infection with Toxoplasma gondii dramatically increased ileal concentrations of lipopeptide (370-fold), LPS (3,300-fold), and flagellin equivalents (38-fold), all P<0.01. Analysis of representative strains of the major bacterial groups of the human intestine revealed that enterobacterial species are likely to be more significant contributors of soluble TLR2 and TLR4 stimulants to the intestinal milieu than Bacteroides species or Gram-positive Firmicutes. CONCLUSIONS/SIGNIFICANCE: We conclude that the induction of colitis or ileitis in mice is associated with significant disease-specific alterations to the PAMP profile of the gut microbiota. PMID- 20161737 TI - Microsatellite typing of clinical and environmental Cryptococcus neoformans var. grubii isolates from Cuba shows multiple genetic lineages. AB - BACKGROUND: Human cryptococcal infections have been associated with bird droppings as a likely source of infection. Studies toward the local and global epidemiology of Cryptococcus spp. have been hampered by the lack of rapid, discriminatory, and exchangeable molecular typing methods. METHODOLOGY/PRINCIPAL FINDINGS: We selected nine microsatellite markers for high-resolution fingerprinting from the genome of C. neoformans var. grubii. This panel of markers was applied to a collection of clinical (n = 122) and environmental (n = 68; from pigeon guano) C. neoformans var. grubii isolates from Cuba. All markers proved to be polymorphic. The average number of alleles per marker was 9 (range 5 51). A total of 104 genotypes could be distinguished. The discriminatory power of this panel of markers was 0.993. Multiple clusters of related genotypes could be discriminated that differed in only one or two microsatellite markers. These clusters were assigned as microsatellite complexes. The majority of environmental isolates (>70%) fell into 1 microsatellite complex containing only few clinical isolates (49 environmental versus 2 clinical). Clinical isolates were segregated over multiple microsatellite complexes. CONCLUSIONS/SIGNIFICANCE: A large genotypic variation exists in C. neoformans var. grubii. The genotypic segregation between clinical and environmental isolates from pigeon guano suggests additional source(s) of human cryptococcal infections. The selected panel of microsatellite markers is an excellent tool to study the epidemiology of C. neoformans var. grubii. PMID- 20161738 TI - Work-related pain in extrinsic finger extensor musculature of instrumentalists is associated with intracellular pH compartmentation during exercise. AB - BACKGROUND: Although non-specific pain in the upper limb muscles of workers engaged in mild repetitive tasks is a common occupational health problem, much is unknown about the associated structural and biochemical changes. In this study, we compared the muscle energy metabolism of the extrinsic finger extensor musculature in instrumentalists suffering from work-related pain with that of healthy control instrumentalists using non-invasive phosphorus magnetic resonance spectroscopy ((31)P-MRS). We hypothesize that the affected muscles will show alterations related with an impaired energy metabolism. METHODOLOGY/PRINCIPAL FINDINGS: We studied 19 volunteer instrumentalists (11 subjects with work-related pain affecting the extrinsic finger extensor musculature and 8 healthy controls). We used (31)P-MRS to find deviations from the expected metabolic response to exercise in phosphocreatine (PCr), inorganic phosphate (Pi), Pi/PCr ratio and intracellular pH kinetics. We observed a reduced finger extensor exercise tolerance in instrumentalists with myalgia, an intracellular pH compartmentation in the form of neutral and acid compartments, as detected by Pi peak splitting in (31)P-MRS spectra, predominantly in myalgic muscles, and a strong association of this pattern with the condition. CONCLUSIONS/SIGNIFICANCE: Work-related pain in the finger extrinsic extensor muscles is associated with intracellular pH compartmentation during exercise, non-invasively detectable by (31)P-MRS and consistent with the simultaneous energy production by oxidative metabolism and glycolysis. We speculate that a deficit in energy production by oxidative pathways may exist in the affected muscles. Two possible explanations for this would be the partial and/or local reduction of blood supply and the reduction of the muscle oxidative capacity itself. PMID- 20161739 TI - Same-sex gaze attraction influences mate-choice copying in humans. AB - Mate-choice copying occurs when animals rely on the mating choices of others to inform their own mating decisions. The proximate mechanisms underlying mate choice copying remain unknown. To address this question, we tracked the gaze of men and women as they viewed a series of photographs in which a potential mate was pictured beside an opposite-sex partner; the participants then indicated their willingness to engage in a long-term relationship with each potential mate. We found that both men and women expressed more interest in engaging in a relationship with a potential mate if that mate was paired with an attractive partner. Men and women's attention to partners varied with partner attractiveness and this gaze attraction influenced their subsequent mate choices. These results highlight the prevalence of non-independent mate choice in humans and implicate social attention and reward circuitry in these decisions. PMID- 20161740 TI - High prevalence of both humoral and cellular immunity to Zaire ebolavirus among rural populations in Gabon. AB - To better understand Zaire ebolavirus (ZEBOV) circulation and transmission to humans, we conducted a large serological survey of rural populations in Gabon, a country characterized by both epidemic and non epidemic regions. The survey lasted three years and covered 4,349 individuals from 220 randomly selected villages, representing 10.7% of all villages in Gabon. Using a sensitive and specific ELISA method, we found a ZEBOV-specific IgG seroprevalence of 15.3% overall, the highest ever reported. The seroprevalence rate was significantly higher in forested areas (19.4%) than in other ecosystems, namely grassland (12.4%), savannah (10.5%), and lakeland (2.7%). No other risk factors for seropositivity were found. The specificity of anti-ZEBOV IgG was confirmed by Western blot in 138 individuals, and CD8 T cells from seven IgG+ individuals were shown to produce IFN-gamma after ZEBOV stimulation. Together, these findings show that a large fraction of the human population living in forested areas of Gabon has both humoral and cellular immunity to ZEBOV. In the absence of identified risk factors, the high prevalence of "immune" persons suggests a common source of human exposure such as fruits contaminated by bat saliva. These findings provide significant new insights into ZEBOV circulation and human exposure, and raise important questions as to the human pathogenicity of ZEBOV and the existence of natural protective immunization. PMID- 20161742 TI - Individual variation in pheromone response correlates with reproductive traits and brain gene expression in worker honey bees. AB - BACKGROUND: Variation in individual behavior within social groups can affect the fitness of the group as well as the individual, and can be caused by a combination of genetic and environmental factors. However, the molecular factors associated with individual variation in social behavior remain relatively unexplored. We used honey bees (Apis mellifera) as a model to examine differences in socially-regulated behavior among individual workers, and used transcriptional profiling to determine if specific gene expression patterns are associated with these individual differences. In honey bees, the reproductive queen produces a pheromonal signal that regulates many aspects of worker behavior and physiology and maintains colony organization. METHODOLOGY/PRINCIPAL FINDINGS: Here, we demonstrate that there is substantial natural variation in individual worker attraction to queen pheromone (QMP). Furthermore, worker attraction is negatively correlated with ovariole number-a trait associated with reproductive potential in workers. We identified transcriptional differences in the adult brain associated with individual worker attraction to QMP, and identified hundreds of transcripts that are organized into statistically-correlated gene networks and associated with this response. CONCLUSIONS/SIGNIFICANCE: Our studies demonstrate that there is substantial variation in worker attraction to QMP among individuals, and that this variation is linked with specific differences in physiology and brain gene expression patterns. This variation in individual response thresholds may reveal underlying variation in queen-worker reproductive conflict, and may mediate colony function and productivity by creating variation in individual task performance. PMID- 20161741 TI - Functional overlap between eIF4G isoforms in Saccharomyces cerevisiae. AB - Initiation factor eIF4G is a key regulator of eukaryotic protein synthesis, recognizing proteins bound at both ends of an mRNA to help recruit messages to the small (40S) ribosomal subunit. Notably, the genomes of a wide variety of eukaryotes encode multiple distinct variants of eIF4G. We found that deletion of eIF4G1, but not eIF4G2, impairs growth and global translation initiation rates in budding yeast under standard laboratory conditions. Not all mRNAs are equally sensitive to loss of eIF4G1; genes that encode messages with longer poly(A) tails are preferentially affected. However, eIF4G1-deletion strains contain significantly lower levels of total eIF4G, relative to eIF4G2-delete or wild type strains. Homogenic strains, which encode two copies of either eIF4G1 or eIF4G2 under native promoter control, express a single isoform at levels similar to the total amount of eIF4G in a wild type cell and have a similar capacity to support normal translation initiation rates. Polysome microarray analysis of these strains and the wild type parent showed that translationally active mRNAs are similar. These results suggest that total eIF4G levels, but not isoform-specific functions, determine mRNA-specific translational efficiency. PMID- 20161743 TI - An empirical method for establishing positional confidence intervals tailored for composite interval mapping of QTL. AB - BACKGROUND: Improved genetic resolution and availability of sequenced genomes have made positional cloning of moderate-effect QTL realistic in several systems, emphasizing the need for precise and accurate derivation of positional confidence intervals (CIs) for QTL. Support interval (SI) methods based on the shape of the QTL likelihood curve have proven adequate for standard interval mapping, but have not been shown to be appropriate for use with composite interval mapping (CIM), which is one of the most commonly used QTL mapping methods. RESULTS: Based on a non-parametric confidence interval (NPCI) method designed for use with the Haley Knott regression method for mapping QTL, a CIM-specific method (CIM-NPCI) was developed to appropriately account for the selection of background markers during analysis of bootstrap-resampled data sets. Coverage probabilities and interval widths resulting from use of the NPCI, SI, and CIM-NPCI methods were compared in a series of simulations analyzed via CIM, wherein four genetic effects were simulated in chromosomal regions with distinct marker densities while heritability was fixed at 0.6 for a population of 200 isolines. CIM-NPCIs consistently capture the simulated QTL across these conditions while slightly narrower SIs and NPCIs fail at unacceptably high rates, especially in genomic regions where marker density is high, which is increasingly common for real studies. The effects of a known CIM bias toward locating QTL peaks at markers were also investigated for each marker density case. Evaluation of sub simulations that varied according to the positions of simulated effects relative to the nearest markers showed that the CIM-NPCI method overcomes this bias, offering an explanation for the improved coverage probabilities when marker densities are high. CONCLUSIONS: Extensive simulation studies herein demonstrate that the QTL confidence interval methods typically used to positionally evaluate CIM results can be dramatically improved by accounting for the procedural complexity of CIM via an empirical approach, CIM-NPCI. Confidence intervals are a critical measure of QTL utility, but have received inadequate treatment due to a perception that QTL mapping is not sufficiently precise for procedural improvements to matter. Technological advances will continue to challenge this assumption, creating even more need for the current improvement to be refined. PMID- 20161744 TI - Role of the gerP operon in germination and outgrowth of Bacillus anthracis spores. AB - Germination of Bacillus anthracis spores occurs when nutrients such as amino acids or purine nucleosides stimulate specific germinant receptors located in the spore inner membrane. The gerP(ABCDEF) operon has been suggested to play a role in facilitating the interaction between germinants and their receptors in spores of Bacillus subtilis and Bacillus cereus. B. anthracis mutants containing deletions in each of the six genes belonging to the orthologue of the gerP(ABCDEF) operon, or deletion of the entire operon, were tested for their ability to germinate. Deletion of the entire gerP operon resulted in a significant delay in germination in response to nutrient germinants. These spores eventually germinated to levels equivalent to wild-type, suggesting that an additional entry point for nutrient germinants may exist. Deletions of each individual gene resulted in a similar phenotype, with the exception of DeltagerPF, which showed no obvious defect. The removal of two additional gerPF like orthologues was necessary to achieve the germination defect observed for the other mutants. Upon physical removal of the spore coat, the mutant lacking the full gerP operon no longer exhibited a germination defect, suggesting that the GerP proteins play a role in spore coat permeability. Additionally, each of the gerP mutants exhibited a severe defect in calcium-dipicolinic acid (Ca-DPA) dependent germination, suggesting a role for the GerP proteins in this process. Collectively, these data implicate all GerP proteins in the early stages of spore germination. PMID- 20161745 TI - Maternal investment influences expression of resource polymorphism in amphibians: implications for the evolution of novel resource-use phenotypes. AB - Maternal effects--where an individual's phenotype is influenced by the phenotype or environment of its mother--are taxonomically and ecologically widespread. Yet, their role in the origin of novel, complex traits remains unclear. Here we investigate the role of maternal effects in influencing the induction of a novel resource-use phenotype. Spadefoot toad tadpoles, Spea multiplicata, often deviate from their normal development and produce a morphologically distinctive carnivore morph phenotype, which specializes on anostracan fairy shrimp. We evaluated whether maternal investment influences expression of this novel phenotype. We found that larger females invested in larger eggs, which, in turn, produced larger tadpoles. Such larger tadpoles are better able to capture the shrimp that induce carnivores. By influencing the expression of novel resource-use phenotypes, maternal effects may play a largely underappreciated role in the origins of novelty. PMID- 20161746 TI - High nucleosome occupancy is encoded at human regulatory sequences. AB - Active eukaryotic regulatory sites are characterized by open chromatin, and yeast promoters and transcription factor binding sites (TFBSs) typically have low intrinsic nucleosome occupancy. Here, we show that in contrast to yeast, DNA at human promoters, enhancers, and TFBSs generally encodes high intrinsic nucleosome occupancy. In most cases we examined, these elements also have high experimentally measured nucleosome occupancy in vivo. These regions typically have high G+C content, which correlates positively with intrinsic nucleosome occupancy, and are depleted for nucleosome-excluding poly-A sequences. We propose that high nucleosome preference is directly encoded at regulatory sequences in the human genome to restrict access to regulatory information that will ultimately be utilized in only a subset of differentiated cells. PMID- 20161747 TI - Negative feedback regulation of Wnt4 signaling by EAF1 and EAF2/U19. AB - Previous studies indicated that EAF (ELL-associated factor) family members, EAF1 and EAF2/U19, play a role in cancer and embryogenesis. For example, EAF2/U19 may serve as a tumor suppressor in prostate cancer. At the same time, EAF2/U19 is a downstream factor in the non-canonical Wnt 4 signaling pathway required for eye development in Xenopus laevis, and along with EAF1, contributes to convergence and extension movements in zebrafish embryos through Wnt maintenance. Here, we used zebrafish embryos and mammalian cells to show that both EAF1 and EAF2/U19 were up-regulated by Wnt4 (Wnt4a). Furthermore, we found that EAF1 and EAF2/U19 suppressed Wnt4 expression by directly binding to the Wnt4 promoter as seen in chromatin immunoprecipitation assays. These findings indicate that an auto regulatory negative feedback loop occurs between Wnt4 and the EAF family, which is conserved between zebrafish and mammalian. The rescue experiments in zebrafish embryos showed that early embryonic development required the maintenance of the appropriate levels of Wnt4a through the feedback loop. Others have demonstrated that the tumor suppressors p63, p73 and WT1 positively regulate Wnt4 expression while p21 has the opposite effect, suggesting that maintenance of appropriate Wnt4 expression may also be critical for adult tissue homeostasis and prevention against tumor initiation. Thus, the auto-regulatory negative feedback loop that controls expression of Wnt4 and EAF proteins may play an important role in both embryonic development and tumor suppression. Our findings provide the first convincing line of evidence that EAF and Wnt4 form an auto-regulatory negative feedback loop in vivo. PMID- 20161748 TI - Membrane protein biogenesis in Ffh- or FtsY-depleted Escherichia coli. AB - BACKGROUND: The Escherichia coli version of the mammalian signal recognition particle (SRP) system is required for biogenesis of membrane proteins and contains two essential proteins: the SRP subunit Ffh and the SRP-receptor FtsY. Scattered in vivo studies have raised the possibility that expression of membrane proteins is inhibited in cells depleted of FtsY, whereas Ffh-depletion only affects their assembly. These differential results are surprising in light of the proposed model that FtsY and Ffh play a role in the same pathway of ribosome targeting to the membrane. Therefore, we decided to evaluate these unexpected results systematically. METHODOLOGY/PRINCIPAL FINDINGS: We characterized the following aspects of membrane protein biogenesis under conditions of either FtsY- or Ffh-depletion: (i) Protein expression, stability and localization; (ii) mRNA levels; (iii) folding and activity. With FtsY, we show that it is specifically required for expression of membrane proteins. Since no changes in mRNA levels or membrane protein stability were detected in cells depleted of FtsY, we propose that its depletion may lead to specific inhibition of translation of membrane proteins. Surprisingly, although FtsY and Ffh function in the same pathway, depletion of Ffh did not affect membrane protein expression or localization. CONCLUSIONS: Our results suggest that indeed, while FtsY-depletion affects earlier steps in the pathway (possibly translation), Ffh-depletion disrupts membrane protein biogenesis later during the targeting pathway by preventing their functional assembly in the membrane. PMID- 20161750 TI - Visual search for human gaze direction by a Chimpanzee (Pan troglodytes). AB - BACKGROUND: Humans detect faces with direct gazes among those with averted gazes more efficiently than they detect faces with averted gazes among those with direct gazes. We examined whether this "stare-in-the-crowd" effect occurs in chimpanzees (Pan troglodytes), whose eye morphology differs from that of humans (i.e., low-contrast eyes, dark sclera). METHODOLOGY/PRINCIPAL FINDINGS: An adult female chimpanzee was trained to search for an odd-item target (front view of a human face) among distractors that differed from the target only with respect to the direction of the eye gaze. During visual-search testing, she performed more efficiently when the target was a direct-gaze face than when it was an averted gaze face. This direct-gaze superiority was maintained when the faces were inverted and when parts of the face were scrambled. Subsequent tests revealed that gaze perception in the chimpanzee was controlled by the contrast between iris and sclera, as in humans, but that the chimpanzee attended only to the position of the iris in the eye, irrespective of head direction. CONCLUSION/SIGNIFICANCE: These results suggest that the chimpanzee can discriminate among human gaze directions and are more sensitive to direct gazes. However, limitations in the perception of human gaze by the chimpanzee are suggested by her inability to completely transfer her performance to faces showing a three-quarter view. PMID- 20161749 TI - Intravaginal practices, vaginal infections and HIV acquisition: systematic review and meta-analysis. AB - BACKGROUND: Intravaginal practices are commonly used by women to manage their vaginal health and sexual life. These practices could, however, affect intravaginal mucosal integrity. The objectives of this study were to examine evidence for associations between: intravaginal practices and acquisition of HIV infection; intravaginal practices and vaginal infections; and vaginal infections and HIV acquisition. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a systematic review of prospective longitudinal studies, searching 15 electronic databases of journals and abstracts from two international conferences to 31(st) January 2008. Relevant articles were selected and data extracted in duplicate. Results were examined visually in forest plots and combined using random effects meta-analysis where appropriate. Of 2120 unique references we included 22 publications from 15 different studies in sub-Saharan Africa and the USA. Seven publications from five studies examined a range of intravaginal practices and HIV infection. No specific vaginal practices showed a protective effect against HIV or vaginal infections. Insertion of products for sex was associated with HIV in unadjusted analyses; only one study gave an adjusted estimate, which showed no association (hazard ratio 1.09, 95% confidence interval, CI 0.71, 1.67). HIV incidence was higher in women reporting intravaginal cleansing but confidence intervals were wide and heterogeneity high (adjusted hazard ratio 1.88, 95%CI 0.53, 6.69, I(2) 83.2%). HIV incidence was higher in women with bacterial vaginosis (adjusted effect 1.57, 95%CI 1.26, 1.94, I(2) 19.0%) and Trichomonas vaginalis (adjusted effect 1.64, 95%CI 1.28, 2.09, I(2) 0.0%). CONCLUSIONS/SIGNIFICANCE: A pathway linking intravaginal cleaning practices with vaginal infections that increase susceptibility to HIV infection is plausible but conclusive evidence is lacking. Intravaginal practices do not appear to protect women from vaginal infections or HIV and some might be harmful. PMID- 20161751 TI - Is the relationship between body size and trophic niche position time-invariant in a predatory fish? First stable isotope evidence. AB - Characterizing relationships between individual body size and trophic niche position is essential for understanding how population and food-web dynamics are mediated by size-dependent trophic interactions. However, whether (and how) intraspecific size-trophic relationships (i.e., trophic ontogeny pattern at the population level) vary with time remains poorly understood. Using archival specimens of a freshwater predatory fish Gymnogobius isaza (Tanaka 1916) from Lake Biwa, Japan, we assembled a long-term (>40 years) time-series of the size dependence of trophic niche position by examining nitrogen stable isotope ratios (delta(15)N) of the fish specimens. The size-dependence of trophic niche position was defined as the slope of the relationship between delta(15)N and log body size. Our analyses showed that the slope was significantly positive in about 60% of years and null in other years, changing through time. This is the first quantitative (i.e., stable isotope) evidence of long-term variability in the size trophic relationship in a predatory fish. This finding had implications for the fish trophic dynamics, despite that about 60% of the yearly values were not statistically different from the long-term average. We proposed hypotheses for the underlying mechanism of the time-varying size-trophic relationship. PMID- 20161753 TI - Identification of differentially expressed proteins in murine embryonic and postnatal cortical neural progenitors. AB - BACKGROUND: The central nervous system (CNS) develops from a heterogeneous pool of neural stem and progenitor cells (NSPC), the underlying differences among which are poorly understood. The study of NSPC would be greatly facilitated by the identification of additional proteins that mediate their function and that would distinguish amongst different progenitor populations. METHODOLOGY/PRINCIPAL FINDINGS: To identify membrane and membrane-associated proteins expressed by NSPC, we used a proteomics approach to profile NSPC cultured as neurospheres (NS) isolated from the murine cortex during a period of neurogenesis (embryonic day 11.5, E11.5), as compared to NSPC isolated at a peak of gliogenesis (postnatal day 1, P0) and to differentiated E11.5 NS. 54 proteins were identified with high expression in E11.5 NS, including the TrkC receptor, several heterotrimeric G proteins, and the Neogenin receptor. 24 proteins were identified with similar expression in E11.5 and P0 NS over differentiated E11.5 NS, and 13 proteins were identified with high expression specifically in P0 NS compared to E11.5 NS. To illustrate the potential relevance of these identified proteins to neural stem cell biology, the function of Neogenin was further studied. Using Fluorescence Activated Cell Sorting (FACS) analysis, expression of Neogenin was associated with a self-renewing population present in both E11.5 and adult subventricular zone (SVZ) NS but not in P0 NS. E11.5 NS expressed a putative Neogenin ligand, RGMa, and underwent apoptosis when exposed to a ligand-blocking antibody. CONCLUSIONS/SIGNIFICANCE: There are fundamental differences between the continuously self-renewing and more limited progenitors of the developing cortex. We identified a subset of differentially expressed proteins that serve not only as a set of functionally important proteins, but as a useful set of markers for the subsequent analysis of NSPC. Neogenin is associated with the continuously self-renewing and neurogenic cells present in E11.5 cortical and adult SVZ NS, and the Neogenin/RGMa receptor/ligand pair may regulate cell survival during development. PMID- 20161752 TI - Telomere shortening sensitizes cancer cells to selected cytotoxic agents: in vitro and in vivo studies and putative mechanisms. AB - BACKGROUND: Telomere/telomerase system has been recently recognized as an attractive target for anticancer therapy. Telomerase inhibition results in tumor regression and increased sensitivity to various cytotoxic drugs. However, it has not been fully established yet whether the mediator of these effects is telomerase inhibition per se or telomere shortening resulting from inhibition of telomerase activity. In addition, the characteristics and mechanisms of sensitization to cytotoxic drugs caused by telomerase inhibition has not been elucidated in a systematic manner. METHODOLOGY/PRINCIPAL FINDINGS: In this study we characterized the relative importance of telomerase inhibition versus telomere shortening in cancer cells. Sensitization of cancer cells to cytotoxic drugs was achieved by telomere shortening in a length dependent manner and not by telomerase inhibition per se. In our system this sensitization was related to the mechanism of action of the cytotoxic drug. In addition, telomere shortening affected also other cancer cell functions such as migration. Telomere shortening induced DNA damage whose repair was impaired after administration of cisplatinum while doxorubicin or vincristine did not affect the DNA repair. These findings were verified also in in vivo mouse model. The putative explanation underlying the phenotype induced by telomere shortening may be related to changes in expression of various microRNAs triggered by telomere shortening. CONCLUSIONS/SIGNIFICANCE: To our best knowledge this is the first study characterizing the relative impact of telomerase inhibition and telomere shortening on several aspects of cancer cell phenotype, especially related to sensitivity to cytotoxic drugs and its putative mechanisms. The microRNA changes in cancer cells upon telomere shortening are novel information. These findings may facilitate the development of telomere based approaches in treatment of cancer. PMID- 20161754 TI - Sensory regulation of neuroligins and neurexin I in the honeybee brain. AB - BACKGROUND: Neurexins and neuroligins, which have recently been associated with neurological disorders such as autism in humans, are highly conserved adhesive proteins found on synaptic membranes of neurons. These binding partners produce a trans-synaptic bridge that facilitates maturation and specification of synapses. It is believed that there exists an optimal spatio-temporal code of neurexin and neuroligin interactions that guide synapse formation in the postnatal developing brain. Therefore, we investigated whether neuroligins and neurexin are differentially regulated by sensory input using a behavioural model system with an advanced capacity for sensory processing, learning and memory, the honeybee. METHODOLOGY/PRINCIPAL FINDINGS: Whole brain expression levels of neuroligin 1-5 (NLG1-5) and neurexin I (NrxI) were estimated by qRT-PCR analysis in three different behavioural paradigms: sensory deprivation, associative scent learning, and lateralised sensory input. Sensory deprived bees had a lower level of NLG1 expression, but a generally increased level of NLG2-5 and NrxI expression compared to hive bees. Bees that had undergone associative scent training had significantly increased levels of NrxI, NLG1 and NLG3 expression compared to untrained control bees. Bees that had lateralised sensory input after antennal amputation showed a specific increase in NLG1 expression compared to control bees, which only happened over time. CONCLUSIONS/SIGNIFICANCE: Our results suggest that (1) there is a lack of synaptic pruning during sensory deprivation; (2) NLG1 expression increases with sensory stimulation; (3) concomitant changes in gene expression suggests NrxI interacts with all neuroligins; (4) there is evidence for synaptic compensation after lateralised injury. PMID- 20161755 TI - Comparison of breast cancer to healthy control tissue discovers novel markers with potential for prognosis and early detection. AB - This study was initiated to identify biomarkers with potential value for the early detection of poor-outcome breast cancer. Two sets of well-characterized tissues were utilized: one from breast cancer patients with favorable vs. poor outcome and the other from healthy women undergoing reduction mammaplasty. Over 46 differentially expressed genes were identified from a large list of potential targets by a) mining publicly available expression data (identifying 134 genes for quantitative PCR) and b) utilizing a commercial PCR array. Three genes show elevated expression in cancers with poor outcome and low expression in all other tissues, warranting further investigation as potential blood markers for early detection of cancers with poor outcome. Twelve genes showed lower expression in cancers with poor outcome than in cancers with favorable outcome but no differential expression between aggressive cancers and most healthy controls. These genes are more likely to be useful as prognostic tissue markers than as serum markers for early detection of aggressive disease. As a secondary finding was that, when histologically normal breast tissue was removed from a distant site in a breast with cancer, 7 of 38 specimens displayed a cancer-like expression profile, while the remaining 31 were genetically similar to the reduction mammaplasty control group. This finding suggests that some regions of ipsilateral histologically 'normal' breast tissue are predisposed to becoming malignant and that normal-appearing tissue with malignant signature might warrant treatment to prevent new primary tumors. PMID- 20161757 TI - Step process for selecting and testing surrogates and indicators of afrotemperate forest invertebrate diversity. AB - BACKGROUND: The diversity and complexity of invertebrate communities usually result in their exclusion from conservation activities. Here we provide a step process for assessing predominantly ground-dwelling Afrotemperate forest invertebrates' (earthworms, centipedes, millipedes, ants, molluscs) potential as surrogates for conservation and indicators for monitoring. We also evaluated sampling methods (soil and litter samples, pitfall traps, active searching quadrats and tree beating) and temporal (seasonal) effects. METHODOLOGY/PRINCIPAL FINDINGS: Lack of congruence of species richness across taxa indicated poor surrogacy potential for any of the focus taxa. Based on abundance and richness, seasonal stability, and ease of sampling, molluscs were the most appropriate taxon for use in monitoring of disturbance impacts. Mollusc richness was highest in March (Antipodal late summer wet season). The most effective and efficient methods were active searching quadrats and searching litter samples. We tested the effectiveness of molluscs as indicators for monitoring by contrasting species richness and community structure in burned relative to unburned forests. Both species richness and community structure changed significantly with burning. Some mollusc species (e.g. Macroptychia africana) showed marked negative responses to burning, and these species have potential for use as indicators. CONCLUSIONS/SIGNIFICANCE: Despite habitat type (i.e., Afrotemperate forest) being constant, species richness and community structure varied across forest patches. Therefore, in conservation planning, setting targets for coarse filter features (e.g., habitat type) requires fine filter features (e.g., localities for individual species). This is especially true for limited mobility taxa such as those studied here. Molluscs have high potential for indicators for monitoring, and this requires broader study. PMID- 20161756 TI - Different thymosin Beta 4 immunoreactivity in foetal and adult gastrointestinal tract. AB - BACKGROUND: Thymosin beta 4 (Tbeta(4)) is a member of beta-thymosins, a family of peptides that play essential roles in many cellular functions. A recent study from our group suggested a role for Tbeta(4) in the development of human salivary glands. The aim of this study was to analyze the expression of Tbeta(4) in the human gut during development, and in the adult. METHODOLOGY/PRINCIPAL FINDINGS: Immunolocalization of Tbeta(4) was studied in autoptic samples of tongue, oesophagus, stomach, ileum, colon, liver and pancreas obtained from two human foetuses and two adults. Tbeta(4) appeared unevenly distributed, with marked differences between foetuses and adults. In the stomach, superficial epithelium was positive in foetuses and negative in adults. Ileal enterocytes were strongly positive in the adult and weakly positive in the foetuses. An increase in reactivity for Tbeta(4) was observed in superficial colon epithelium of adults as compared with the foetuses. Striking differences were found between foetal and adult liver: the former showed a very low reactivity for Tbeta(4) while in the adult we observed a strong reactivity in the vast majority of the hepatocytes. A peculiar pattern was found in the pancreas, with the strongest reactivity observed in foetal and adult islet cells. SIGNIFICANCE: Our data show a strong expression of Tbeta(4) in the human gut and in endocrine pancreas during development. The observed differential expression of Tbeta(4) suggests specific roles of the peptide in the gut of foetuses and adults. The observed heterogeneity of Tbeta(4) expression in the foetal life, ranging from a very rare detection in liver cells up to a diffuse reactivity in endocrine pancreas, should be taken into account when the role of Tbeta(4) in the development of human embryo is assessed. Future studies are needed to shed light on the link between Tbeta(4) and organogenesis. PMID- 20161758 TI - Frontal white matter volume is associated with brain enlargement and higher structural connectivity in anthropoid primates. AB - Previous research has indicated the importance of the frontal lobe and its 'executive' connections to other brain structures as crucial in explaining primate neocortical adaptations. However, a representative sample of volumetric measurements of frontal connective tissue (white matter) has not been available. In this study, we present new volumetric measurements of white and grey matter in the frontal and non-frontal neocortical lobes from 18 anthropoid species. We analyze this data in the context of existing theories of neocortex, frontal lobe and white versus grey matter hyperscaling. Results indicate that the 'universal scaling law' of neocortical white to grey matter applies separately for frontal and non-frontal lobes; that hyperscaling of both neocortex and frontal lobe to rest of brain is mainly due to frontal white matter; and that changes in frontal (but not non-frontal) white matter volume are associated with changes in rest of brain and basal ganglia, a group of subcortical nuclei functionally linked to 'executive control'. Results suggest a central role for frontal white matter in explaining neocortex and frontal lobe hyperscaling, brain size variation and higher neural structural connectivity in anthropoids. PMID- 20161759 TI - Sex determining region Y-Box 2 (SOX2) is a potential cell-lineage gene highly expressed in the pathogenesis of squamous cell carcinomas of the lung. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) represents the majority (85%) of lung cancers and is comprised mainly of adenocarcinomas and squamous cell carcinomas (SCCs). The sequential pathogenesis of lung adenocarcinomas and SCCs occurs through dissimilar phases as the former tumors typically arise in the lung periphery whereas the latter normally arise near the central airway. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the expression of SOX2, an embryonic stem cell transcriptional factor that also plays important roles in the proliferation of basal tracheal cells and whose expression is restricted to the main and central airways and bronchioles of the developing and adult mouse lung, in NSCLC by various methodologies. Here, we found that SOX2 mRNA levels, from various published datasets, were significantly elevated in lung SCCs compared to adenocarcinomas (all p<0.001). Moreover, a previously characterized OCT4/SOX2/NANOG signature effectively separated lung SCCs from adenocarcinomas in two independent publicly available datasets which correlated with increased SOX2 mRNA in SCCs. Immunohistochemical analysis of various histological lung tissue specimens demonstrated marked nuclear SOX2 protein expression in all normal bronchial epithelia, alveolar bronchiolization structures and premalignant lesions in SCC development (hyperplasia, dysplasia and carcinoma in situ) and absence of expression in all normal alveoli and atypical adenomatous hyperplasias. Moreover, SOX2 protein expression was greatly higher in lung SCCs compared to adenocarcinomas following analyses in two independent large TMA sets (TMA set I, n = 287; TMA set II, n = 511 both p<0.001). Furthermore, amplification of SOX2 DNA was detected in 20% of lung SCCs tested (n = 40) and in none of the adenocarcinomas (n = 17). CONCLUSIONS/SIGNIFICANCE: Our findings highlight a cell-lineage gene expression pattern for the stem cell transcriptional factor SOX2 in the pathogenesis of lung SCCs and suggest a differential activation of stem cell-related pathways between squamous cell carcinomas and adenocarcinomas of the lung. PMID- 20161762 TI - Pooling ARV Drug Patents: A Pro-Access Fitting Strategy? PMID- 20161761 TI - ENU mutagenesis reveals a novel phenotype of reduced limb strength in mice lacking fibrillin 2. AB - BACKGROUND: Fibrillins 1 (FBN1) and 2 (FBN2) are components of microfibrils, microfilaments that are present in many connective tissues, either alone or in association with elastin. Marfan's syndrome and congenital contractural arachnodactyly (CCA) result from dominant mutations in the genes FBN1 and FBN2 respectively. Patients with both conditions often present with specific muscle atrophy or weakness, yet this has not been reported in the mouse models. In the case of Fbn1, this is due to perinatal lethality of the homozygous null mice making measurements of strength difficult. In the case of Fbn2, four different mutant alleles have been described in the mouse and in all cases syndactyly was reported as the defining phenotypic feature of homozygotes. METHODOLOGY/PRINCIPAL FINDINGS: As part of a large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis screen, we identified a mouse mutant, Mariusz, which exhibited muscle weakness along with hindlimb syndactyly. We identified an amber nonsense mutation in Fbn2 in this mouse mutant. Examination of a previously characterised Fbn2-null mutant, Fbn2(fp), identified a similar muscle weakness phenotype. The two Fbn2 mutant alleles complement each other confirming that the weakness is the result of a lack of Fbn2 activity. Skeletal muscle from mutants proved to be abnormal with higher than average numbers of fibres with centrally placed nuclei, an indicator that there are some regenerating muscle fibres. Physiological tests indicated that the mutant muscle produces significantly less maximal force, possibly as a result of the muscles being relatively smaller in Mariusz mice. CONCLUSIONS: These findings indicate that Fbn2 is involved in integrity of structures required for strength in limb movement. As human patients with mutations in the fibrillin genes FBN1 and FBN2 often present with muscle weakness and atrophy as a symptom, Fbn2-null mice will be a useful model for examining this aspect of the disease process further. PMID- 20161760 TI - Phenylbutyric acid rescues endoplasmic reticulum stress-induced suppression of APP proteolysis and prevents apoptosis in neuronal cells. AB - BACKGROUND: The familial and sporadic forms of Alzheimer's disease (AD) have an identical pathology with a severe disparity in the time of onset [1]. The pathological similarity suggests that epigenetic processes may phenocopy the Familial Alzheimer's disease (FAD) mutations within sporadic AD. Numerous groups have demonstrated that FAD mutations in presenilin result in 'loss of function' of gamma-secretase mediated APP cleavage [2], [3], [4], [5]. Accordingly, ER stress is prominent within the pathologically impacted brain regions in AD patients [6] and is reported to inhibit APP trafficking through the secretory pathway [7], [8]. As the maturation of APP and the cleaving secretases requires trafficking through the secretory pathway [9], [10], [11], we hypothesized that ER stress may block trafficking requisite for normal levels of APP cleavage and that the small molecular chaperone 4-phenylbutyrate (PBA) may rescue the proteolytic deficit. METHODOLOGY/PRINCIPAL FINDINGS: The APP-Gal4VP16/Gal4 reporter screen was stably incorporated into neuroblastoma cells in order to assay gamma-secretase mediated APP proteolysis under normal and pharmacologically induced ER stress conditions. Three unrelated pharmacological agents (tunicamycin, thapsigargin and brefeldin A) all repressed APP proteolysis in parallel with activation of unfolded protein response (UPR) signaling-a biochemical marker of ER stress. Co-treatment of the gamma-secretase reporter cells with PBA blocked the repressive effects of tunicamycin and thapsigargin upon APP proteolysis, UPR activation, and apoptosis. In unstressed cells, PBA stimulated gamma-secretase mediated cleavage of APP by 8-10 fold, in the absence of any significant effects upon amyloid production, by promoting APP trafficking through the secretory pathway and the stimulation of the non-pathogenic alpha/gamma-cleavage. CONCLUSIONS/SIGNIFICANCE: ER stress represses gamma secretase mediated APP proteolysis, which replicates some of the proteolytic deficits associated with the FAD mutations. The small molecular chaperone PBA can reverse ER stress induced effects upon APP proteolysis, trafficking and cellular viability. Pharmaceutical agents, such as PBA, that stimulate alpha/gamma cleavage of APP by modifying intracellular trafficking should be explored as AD therapeutics. PMID- 20161763 TI - The Locust Standard Brain: A 3D Standard of the Central Complex as a Platform for Neural Network Analysis. AB - Many insects use the pattern of polarized light in the sky for spatial orientation and navigation. We have investigated the polarization vision system in the desert locust. To create a common platform for anatomical studies on polarization vision pathways, Kurylas et al. (2008) have generated a three dimensional (3D) standard brain from confocal microscopy image stacks of 10 male brains, using two different standardization methods, the Iterative Shape Averaging (ISA) procedure and the Virtual Insect Brain (VIB) protocol. Comparison of both standardization methods showed that the VIB standard is ideal for comparative volume analysis of neuropils, whereas the ISA standard is the method of choice to analyze the morphology and connectivity of neurons. The central complex is a key processing stage for polarization information in the locust brain. To investigate neuronal connections between diverse central-complex neurons, we generated a higher-resolution standard atlas of the central complex and surrounding areas, using the ISA method based on brain sections from 20 individual central complexes. To explore the usefulness of this atlas, two central-complex neurons, a polarization-sensitive columnar neuron (type CPU1a) and a tangential neuron that is activated during flight, the giant fan-shaped (GFS) neuron, were reconstructed 3D from brain sections. To examine whether the GFS neuron is a candidate to contribute to synaptic input to the CPU1a neuron, we registered both neurons into the standardized central complex. Visualization of both neurons revealed a potential connection of the CPU1a and GFS neurons in layer II of the upper division of the central body. PMID- 20161764 TI - Mathematical modeling of the effectiveness of facemasks in reducing the spread of novel influenza A (H1N1). AB - On June 11, 2009, the World Health Organization declared the outbreak of novel influenza A (H1N1) a pandemic. With limited supplies of antivirals and vaccines, countries and individuals are looking at other ways to reduce the spread of pandemic (H1N1) 2009, particularly options that are cost effective and relatively easy to implement. Recent experiences with the 2003 SARS and 2009 H1N1 epidemics have shown that people are willing to wear facemasks to protect themselves against infection; however, little research has been done to quantify the impact of using facemasks in reducing the spread of disease. We construct and analyze a mathematical model for a population in which some people wear facemasks during the pandemic and quantify impact of these masks on the spread of influenza. To estimate the parameter values used for the effectiveness of facemasks, we used available data from studies on N95 respirators and surgical facemasks. The results show that if N95 respirators are only 20% effective in reducing susceptibility and infectivity, only 10% of the population would have to wear them to reduce the number of influenza A (H1N1) cases by 20%. We can conclude from our model that, if worn properly, facemasks are an effective intervention strategy in reducing the spread of pandemic (H1N1) 2009. PMID- 20161765 TI - A safe vaccine (DV-STM-07) against Salmonella infection prevents abortion and confers protective immunity to the pregnant and new born mice. AB - Pregnancy is a transient immuno-compromised condition which has evolved to avoid the immune rejection of the fetus by the maternal immune system. The altered immune response of the pregnant female leads to increased susceptibility to invading pathogens, resulting in abortion and congenital defects of the fetus and a subnormal response to vaccination. Active vaccination during pregnancy may lead to abortion induced by heightened cell mediated immune response. In this study, we have administered the highly attenuated vaccine strain DeltapmrG-HM-D (DV-STM 07) in female mice before the onset of pregnancy and followed the immune reaction against challenge with virulent S. Typhimurium in pregnant mice. Here we demonstrate that DV-STM-07 vaccine gives protection against Salmonella in pregnant mice and also prevents Salmonella induced abortion. This protection is conferred by directing the immune response towards Th2 activation and Th1 suppression. The low Th1 response prevents abortion. The use of live attenuated vaccine just before pregnancy carries the risk of transmission to the fetus. We have shown that this vaccine is safe as the vaccine strain is quickly eliminated from the mother and is not transmitted to the fetus. This vaccine also confers immunity to the new born mice of vaccinated mothers. Since there is no evidence of the vaccine candidate reaching the new born mice, we hypothesize that it may be due to trans-colostral transfer of protective anti-Salmonella antibodies. These results suggest that our vaccine DV-STM-07 can be very useful in preventing abortion in the pregnant individuals and confer immunity to the new born. Since there are no such vaccine candidates which can be given to the new born and to the pregnant women, this vaccine holds a very bright future to combat Salmonella induced pregnancy loss. PMID- 20161766 TI - Using imputation to provide location information for nongeocoded addresses. AB - BACKGROUND: The importance of geography as a source of variation in health research continues to receive sustained attention in the literature. The inclusion of geographic information in such research often begins by adding data to a map which is predicated by some knowledge of location. A precise level of spatial information is conventionally achieved through geocoding, the geographic information system (GIS) process of translating mailing address information to coordinates on a map. The geocoding process is not without its limitations, though, since there is always a percentage of addresses which cannot be converted successfully (nongeocodable). This raises concerns regarding bias since traditionally the practice has been to exclude nongeocoded data records from analysis. METHODOLOGY/PRINCIPAL FINDINGS: In this manuscript we develop and evaluate a set of imputation strategies for dealing with missing spatial information from nongeocoded addresses. The strategies are developed assuming a known zip code with increasing use of collateral information, namely the spatial distribution of the population at risk. Strategies are evaluated using prostate cancer data obtained from the Maryland Cancer Registry. We consider total case enumerations at the Census county, tract, and block group level as the outcome of interest when applying and evaluating the methods. Multiple imputation is used to provide estimated total case counts based on complete data (geocodes plus imputed nongeocodes) with a measure of uncertainty. Results indicate that the imputation strategy based on using available population-based age, gender, and race information performed the best overall at the county, tract, and block group levels. CONCLUSIONS/SIGNIFICANCE: The procedure allows for the potentially biased and likely under reported outcome, case enumerations based on only the geocoded records, to be presented with a statistically adjusted count (imputed count) with a measure of uncertainty that are based on all the case data, the geocodes and imputed nongeocodes. Similar strategies can be applied in other analysis settings. PMID- 20161767 TI - Corazonin neurons function in sexually dimorphic circuitry that shape behavioral responses to stress in Drosophila. AB - All organisms are confronted with dynamic environmental changes that challenge homeostasis, which is the operational definition of stress. Stress produces adaptive behavioral and physiological responses, which, in the Metazoa, are mediated through the actions of various hormones. Based on its associated phenotypes and its expression profiles, a candidate stress hormone in Drosophila is the corazonin neuropeptide. We evaluated the potential roles of corazonin in mediating stress-related changes in target behaviors and physiologies through genetic alteration of corazonin neuronal excitability. Ablation of corazonin neurons confers resistance to metabolic, osmotic, and oxidative stress, as measured by survival. Silencing and activation of corazonin neurons lead to differential lifespan under stress, and these effects showed a strong dependence on sex. Additionally, altered corazonin neuron physiology leads to fundamental differences in locomotor activity, and these effects were also sex-dependent. The dynamics of altered locomotor behavior accompanying stress was likewise altered in flies with altered corazonin neuronal function. We report that corazonin transcript expression is altered under starvation and osmotic stress, and that triglyceride and dopamine levels are equally impacted in corazonin neuronal alterations and these phenotypes similarly show significant sexual dimorphisms. Notably, these sexual dimorphisms map to corazonin neurons. These results underscore the importance of central peptidergic processing within the context of stress and place corazonin signaling as a critical feature of neuroendocrine events that shape stress responses and may underlie the inherent sexual dimorphic differences in stress responses. PMID- 20161768 TI - Factors affecting daughter cells' arrangement during the early bacterial divisions. AB - On agar plates, daughter cells of Escherichia coli mutually slide and align side by-side in parallel during the first round of binary fission. This phenomenon has been previously attributed to an elastic material that restricts apparently separated bacteria from being in string. We hypothesize that the interaction between bacteria and the underneath substratum may affect the arrangement of the daughter bacteria. To test this hypothesis, bacterial division on hyaluronic acid (HA) gel, as an alternative substratum, was examined. Consistent with our proposition, the HA gel differs from agar by suppressing the typical side-by-side alignments to a rare population. Examination of bacterial surface molecules that may contribute to the daughter cells' arrangement yielded an observation that, with disrupted lpp, the E. coli daughter cells increasingly formed non-typical patterns, i.e. neither sliding side-by-side in parallel nor forming elongated strings. Therefore, our results suggest strongly that the early cell patterning is affected by multiple interaction factors. With oscillatory optical tweezers, we further demonstrated that the interaction force decreased in bacteria without Lpp, a result substantiating our notion that the side-by-side sliding phenomenon directly reflects the strength of in-situ interaction between bacteria and substratum. PMID- 20161769 TI - The duration of the effects of repeated widespread badger culling on cattle tuberculosis following the cessation of culling. AB - BACKGROUND: In the British Isles, control of cattle tuberculosis (TB) is hindered by persistent infection of wild badger (Meles meles) populations. A large-scale field trial--the Randomised Badger Culling Trial (RBCT)--previously showed that widespread badger culling produced modest reductions in cattle TB incidence during culling, which were offset by elevated TB risks for cattle on adjoining lands. Once culling was halted, beneficial effects inside culling areas increased, while detrimental effects on adjoining lands disappeared. However, a full assessment of the utility of badger culling requires information on the duration of culling effects. METHODOLOGY/PRINCIPAL FINDINGS: We monitored cattle TB incidence in and around RBCT areas after culling ended. We found that benefits inside culled areas declined over time, and were no longer detectable by three years post-culling. On adjoining lands, a trend suggesting beneficial effects immediately after the end of culling was insignificant, and disappeared after 18 months post-culling. From completion of the first cull to the loss of detectable effects (an average five-year culling period plus 2.5 years post-culling), cattle TB incidence was 28.7% lower (95% confidence interval [CI] 20.7 to 35.8% lower) inside ten 100 km(2) culled areas than inside ten matched no-culling areas, and comparable (11.7% higher, 95% CI: 13.0% lower to 43.4% higher, p = 0.39) on lands or=10%, and five of the antibiotic group developed obesity. The treatment by vancomycin-plus-gentamycin was an independent predictor of BMI increase of >or=10% (adjusted OR, 6.7; 95% CI, 1.37-33.0; p = 0.02), but not treatment with other antibiotics. Weight gain was particularly high in male patients older than 65 who did not undergo cardiac surgery. Indeed, all three vancomycin-treated patients with these characteristics developed obesity. CONCLUSIONS/SIGNIFICANCE: A major and significant weight gain can occur after a six-week intravenous treatment by vancomycin plus gentamycin for IE with a risk of obesity, especially in males older than 65 who have not undergone surgery. We speculate on the role of the gut colonization by Lactobacillus sp, a microorganism intrinsically resistant to vancomycin, used as a growth promoter in animals, and found at a high concentration in the feces of obese patients. Thus, nutritional programs and weight follow-up should be utilized in patients under such treatment. PMID- 20161777 TI - A second actin-like MamK protein in Magnetospirillum magneticum AMB-1 encoded outside the genomic magnetosome island. AB - Magnetotactic bacteria are able to swim navigating along geomagnetic field lines. They synthesize ferromagnetic nanocrystals that are embedded in cytoplasmic membrane invaginations forming magnetosomes. Regularly aligned in the cytoplasm along cytoskeleton filaments, the magnetosome chain effectively forms a compass needle bestowing on bacteria their magnetotactic behaviour. A large genomic island, conserved among magnetotactic bacteria, contains the genes potentially involved in magnetosome formation. One of the genes, mamK has been described as encoding a prokaryotic actin-like protein which when it polymerizes forms in the cytoplasm filamentous structures that provide the scaffold for magnetosome alignment. Here, we have identified a series of genes highly similar to the mam genes in the genome of Magnetospirillum magneticum AMB-1. The newly annotated genes are clustered in a genomic islet distinct and distant from the known magnetosome genomic island and most probably acquired by lateral gene transfer rather than duplication. We focused on a mamK-like gene whose product shares 54.5% identity with the actin-like MamK. Filament bundles of polymerized MamK like protein were observed in vitro with electron microscopy and in vivo in E. coli cells expressing MamK-like-Venus fusions by fluorescence microscopy. In addition, we demonstrate that mamK-like is transcribed in AMB-1 wild-type and DeltamamK mutant cells and that the actin-like filamentous structures observed in the DeltamamK strain are probably MamK-like polymers. Thus MamK-like is a new member of the prokaryotic actin-like family. This is the first evidence of a functional mam gene encoded outside the magnetosome genomic island. PMID- 20161776 TI - Structural determination of functional units of the nucleotide binding domain (NBD94) of the reticulocyte binding protein Py235 of Plasmodium yoelii. AB - BACKGROUND: Invasion of the red blood cells (RBC) by the merozoite of malaria parasites involves a large number of receptor ligand interactions. The reticulocyte binding protein homologue family (RH) plays an important role in erythrocyte recognition as well as virulence. Recently, it has been shown that members of RH in addition to receptor binding may also have a role as ATP/ADP sensor. A 94 kDa region named Nucleotide-Binding Domain 94 (NBD94) of Plasmodium yoelii YM, representative of the putative nucleotide binding region of RH, has been demonstrated to bind ATP and ADP selectively. Binding of ATP or ADP induced nucleotide-dependent structural changes in the C-terminal hinge-region of NBD94, and directly impacted on the RBC binding ability of RH. METHODOLOGY/PRINCIPAL FINDINGS: In order to find the smallest structural unit, able to bind nucleotides, and its coupling module, the hinge region, three truncated domains of NBD94 have been generated, termed NBD94(444-547), NBD94(566-663) and NBD94(674 793), respectively. Using fluorescence correlation spectroscopy NBD94(444-547) has been identified to form the smallest nucleotide binding segment, sensitive for ATP and ADP, which became inhibited by 4-Chloro-7-nitrobenzofurazan. The shape of NBD94(444-547) in solution was calculated from small-angle X-ray scattering data, revealing an elongated molecule, comprised of two globular domains, connected by a spiral segment of about 73.1 A in length. The high quality of the constructs, forming the hinge-region, NBD94(566-663) and NBD94(674 793) enabled to determine the first crystallographic and solution structure, respectively. The crystal structure of NBD94(566-663) consists of two helices with 97.8 A and 48.6 A in length, linked by a loop. By comparison, the low resolution structure of NBD94(674-793) in solution represents a chair-like shape with three architectural segments. CONCLUSIONS: These structures give the first insight into how nucleotide binding impacts on the overall structure of RH and demonstrates the potential use of this region as a novel drug target. PMID- 20161778 TI - Gab2 promotes hematopoietic stem cell maintenance and self-renewal synergistically with STAT5. AB - BACKGROUND: Grb2-associated binding (Gab) adapter proteins play major roles in coordinating signaling downstream of hematopoietic cytokine receptors. In hematopoietic cells, Gab2 can modulate phosphatidylinositol-3 kinase and mitogen associated protein kinase activities and regulate the long-term multilineage competitive repopulating activity of hematopoietic stem cells (HSCs). Gab2 may also act in a linear pathway upstream or downstream of signal transducer and activator of transcription-5 (STAT5), a major positive regulator of HSC function. Therefore, we aimed to determine whether Gab2 and STAT5 function in hematopoiesis in a redundant or non-redundant manner. METHODOLOGY/PRINCIPAL FINDINGS: To do this we generated Gab2 mutant mice with heterozygous and homozygous deletions of STAT5. In heterozygous STAT5 mutant mice, deficiencies in HSC/multipotent progenitors were reflected by decreased long-term repopulating activity. This reduction in repopulation function was mirrored in the reduced growth response to early-acting cytokines from sorted double mutant c-Kit(+)Lin(-)Sca-1(+) (KLS) cells. Importantly, in non-ablated newborn mice, the host steady-state engraftment ability was impaired by loss of Gab2 in heterozygous STAT5 mutant background. Fetal liver cells isolated from homozygous STAT5 mutant mice lacking Gab2 showed significant reduction in HSC number (KLS CD150(+)CD48(-)), reduced HSC survival, and dramatic loss of self-renewal potential as measured by serial transplantation. CONCLUSIONS/SIGNIFICANCE: These data demonstrate new functions for Gab2 in hematopoiesis in a manner that is non-redundant with STAT5. Furthermore, important synergy between STAT5 and Gab2 was observed in HSC self renewal, which might be exploited to optimize stem cell-based therapeutics. PMID- 20161779 TI - Investigation of type 2 diabetes risk alleles support CDKN2A/B, CDKAL1, and TCF7L2 as susceptibility genes in a Han Chinese cohort. AB - BACKGROUND: Recent genome-wide association studies (GWASs) have reported several genetic variants to be reproducibly associated with type 2 diabetes. Additional variants have also been detected from a metaanalysis of three GWASs, performed in populations of European ancestry. In the present study, we evaluated the influence of 17 genetic variants from 15 candidate loci, identified in type 2 diabetes GWASs and the metaanalysis, in a Han Chinese cohort. METHODOLOGY/PRINCIPAL FINDINGS: Selected type 2 diabetes-associated genetic variants were genotyped in 1,165 type 2 diabetic patients and 1,136 normoglycemic control individuals of Southern Han Chinese ancestry. The OR for risk of developing type 2 diabetes was calculated using a logistic regression model adjusted for age, sex, and BMI. Genotype-phenotype associations were tested using a multivariate linear regression model. Genetic variants in CDKN2A/B, CDKAL1, TCF7L2, TCF2, MC4R, and PPARG showed a nominal association with type 2 diabetes (P/= 50%). Compared with older subjects (mean age 56+/-8 years), younger subjects had a lower prevalence of MDCT findings of CAD 55.5% vs. 12.5%, respectively (P<0.001), regardless of risk factors. Males had more CAD (mostly non-significant) compared with females (109 [72.7%] vs. 19 [50.3%], respectively; P= 0.007). Subjects with >/= 2 risk factors had a higher prevalence of CAD in general and significant CAD in particular (P<0.001). CONCLUSION: CAD in asymptomatic population seems to be not uncommon. Using MDCT a high prevalence of non-significant and low prevalence of significant CAD was discovered in middle age asymptomatic population. PMID- 20161815 TI - SERPING1 polymorphisms in polypoidal choroidal vasculopathy. AB - PURPOSE: To investigate whether common genetic variants in the complement component 1 inhibitor gene (serpin peptidase inhibitor, clade G, member 1, SERPING1) are associated with polypoidal choroidal vasculopathy (PCV) in a Chinese Han population. METHODS: DNA samples were obtained from 118 PCV patients and 115 healthy subjects. Data derived from the HapMap project were used to select tag single nucleotide polymorphisms (SNPs) across the extended SERPING1 region. A previously reported age-related macular degeneration-related risk factor (rs2511989) was forcibly included. Genotyping of each tag SNP was performed by PCR restriction fragment length polymorphism and direct DNA sequencing techniques. RESULTS: Four SNPs for SERPING1, rs2509897, rs1005510, rs11603020, and rs2511989, were chosen as tag SNPs. None of these tag SNPs were associated with PCV, according to the single-SNP association test (p=0.41-0.83). Evaluation of common haplotypes across SERPING1 did not reveal any association with PCV (p=0.49-0.82). CONCLUSIONS: We found no evidence to support the role of any common SERPING1 variants, including the rs2511989 variant, in the susceptibility to PCV in a Chinese Han population. PMID- 20161816 TI - A new locus for autosomal recessive congenital cataract identified in a Pakistani family. AB - PURPOSE: To identify the disease locus for autosomal recessive congenital cataract in a consanguineous Pakistani family. METHODS: All affected individuals underwent detailed ophthalmologic and medical examination. Blood samples were collected and DNA was extracted. A genome-wide scan was performed with polymorphic microsatellite markers on genomic DNA from affected and unaffected family members, and logarithm of odds (LOD) scores were calculated. RESULTS: The clinical records and ophthalmological examinations suggested that all affected individuals have nuclear cataracts. Maximum LOD scores of 5.01, 4.38, and 4.17 at theta=0 were obtained with markers D7630, D7S657, and D7S515, respectively. Fine mapping refined the critical interval and suggested that markers in a 27.78 cM (27.96 Mb) interval are flanked by markers D7S660 and D7S799, which co-segregate with the disease phenotype in family PKCC108. CONCLUSIONS: We have identified a new locus for autosomal recessive congenital cataract, localized to chromosome 7q21.11-q31.1 in a consanguineous Pakistani family. PMID- 20161817 TI - Brimonidine is neuroprotective against glutamate-induced neurotoxicity, oxidative stress, and hypoxia in purified rat retinal ganglion cells. AB - PURPOSE: To investigate the neuroprotective effect of alpha2-adrenergic agonist brimonidine in the presence of glutamate-induced neurotoxicity, oxidative stress, and hypoxia on in vitro cultures of purified rat retinal ganglion cells (RGCs). METHODS: Purified RGC cultures were obtained from retinas of 6-8-day old Wistar rats, following a two-step immunopanning procedure. After 72 h of cultivation, the neuroprotective effect of brimonidine (0.01 microM, 0.1 microM, and 1 microM) was investigated by culturing the RGCs under glutamate, oxidative, and hypoxic stress for a further 72 h, 24 h, and 12 h, respectively. Glutamate neurotoxicity was induced by adding glutamate (25 microM), while oxidative stress was induced by substituting the culture medium with B27 supplement without antioxidants, and hypoxia was induced by cultivation in a controlled-atmosphere incubator with oxygen levels 5% of the normal partial pressure. The RGC viability under each stress condition normalized to that under normal condition was evaluated as live cell percentage based on a total of 7-8 full repeated experiments. RESULTS: The cell survival percentages of cultures exposed to glutamate, oxidative, and hypoxic stress were 58.2%, 59.3%, and 53.2%, respectively. Brimonidine dose dependently increased RGC survival in the presence of glutamate (80.6% at 1 microM), oxidative (79.8% at 1 microM), and hypoxic (72.3 and 77.4% at 0.1 and 1 microM, respectively) stress. In the presence of alpha2-adrenergic antagonist yohimbine (10 microM), brimonidine (1 microM) showed no protective effects on RGC viability. CONCLUSIONS: At a concentration of 0.1 microM or higher, brimonidine increased survival of purified rat RGCs in the presence of glutamate neurotoxicity, oxidative stress, and hypoxia. The neuroprotective effect of brimonidine is mediated via alpha2-adrenergic receptors at the RGC level. PMID- 20161818 TI - Temporal ChIP-on-Chip of RNA-Polymerase-II to detect novel gene activation events during photoreceptor maturation. AB - PURPOSE: During retinal development, post-mitotic neural progenitor cells must activate thousands of genes to complete synaptogenesis and terminal maturation. While many of these genes are known, others remain beyond the sensitivity of expression microarray analysis. Some of these elusive gene activation events can be detected by mapping changes in RNA polymerase-II (Pol-II) association around transcription start sites. METHODS: High-resolution (35 bp) chromatin immunoprecipitation (ChIP)-on-chip was used to map changes in Pol-II binding surrounding 26,000 gene transcription start sites during photoreceptor maturation of the mouse neural retina, comparing postnatal age 25 (P25) to P2. Coverage was 10-12 kb per transcription start site, including 2.5 kb downstream. Pol-II-active regions were mapped to the mouse genomic DNA sequence by using computational methods (Tiling Analysis Software-TAS program), and the ratio of maximum Pol-II binding (P25/P2) was calculated for each gene. A validation set of 36 genes (3%), representing a full range of Pol-II signal ratios (P25/P2), were examined with quantitative ChIP assays for transcriptionally active Pol-II. Gene expression assays were also performed for 19 genes of the validation set, again on independent samples. FLT-3 Interacting Zinc-finger-1 (FIZ1), a zinc-finger protein that associates with active promoter complexes of photoreceptor-specific genes, provided an additional ChIP marker to highlight genes activated in the mature neural retina. To demonstrate the use of ChIP-on-chip predictions to find novel gene activation events, four additional genes were selected for quantitative PCR analysis (qRT-PCR analysis); these four genes have human homologs located in unidentified retinal disease regions: Solute carrier family 25 member 33 (Slc25a33), Lysophosphatidylcholine acyltransferase 1 (Lpcat1), Coiled-coil domain-containing 126 (Ccdc126), and ADP-ribosylation factor-like 4D (Arl4d). RESULTS: ChIP-on-chip Pol-II peak signal ratios >1.8 predicted increased amounts of transcribing Pol-II and increased expression with an estimated 97% accuracy, based on analysis of the validation gene set. Using this threshold ratio, 1,101 genes were predicted to experience increased binding of Pol-II in their promoter regions during terminal maturation of the neural retina. Over 800 of these gene activations were additional to those previously reported by microarray analysis. Slc25a33, Lpcat1, Ccdc126, and Arl4d increased expression significantly (p<0.001) during photoreceptor maturation. Expression of all four genes was diminished in adult retinas lacking rod photoreceptors (Rd1 mice) compared to normal retinas (90% loss for Ccdc126 and Arl4d). For rhodopsin (Rho), a marker of photoreceptor maturation, two regions of maximum Pol-II signal corresponded to the upstream rhodopsin enhancer region and the rhodopsin proximal promoter region. CONCLUSIONS: High-resolution maps of Pol-II binding around transcription start sites were generated for the postnatal mouse retina; which can predict activation increases for a specific gene of interest. Novel gene activation predictions are enriched for biologic functions relevant to vision, neural function, and chromatin regulation. Use of the data set to detect novel activation increases was demonstrated by expression analysis for several genes that have human homologs located within unidentified retinal disease regions: Slc25a33, Lpcat1, Ccdc126, and Arl4d. Analysis of photoreceptor-deficient retinas indicated that all four genes are expressed in photoreceptors. Genome-wide maps of Pol-II binding were developed for visual access in the University of California, Santa Cruz (UCSC) Genome Browser and its eye-centric version EyeBrowse (National Eye Institute-NEI). Single promoter resolution of Pol-II distribution patterns suggest the Rho enhancer region and the Rho proximal promoter region become closely associated with the activated gene's promoter complex. PMID- 20161819 TI - Protein expression in human trabecular meshwork: downregulation of RhoGDI by dexamethasone in vitro. AB - PURPOSE: The characterization of the human trabecular meshwork (TM) proteome is a valuable step toward understanding its role under normal and glaucomatous conditions. This study uses proteomic techniques to investigate the set of proteins expressed in normal human TM and to identify those differentially expressed in response to dexamethasone (DEX) treatment of TM cells (TMCs) in vitro. METHODS: TM tissue (TMT) was isolated from human donor eyes and pooled. Immortalized human TMCs were cultured with or without DEX. Protein extracts from each were separated by two-dimensional electrophoresis (2-DE). Protein spots in TMT gel were excised, destained, and subjected to in-gel tryptic digestion and identification with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). To determine those proteins whose expression patterns were affected by glucocorticoids, TMCs were treated with DEX and assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) dye and 2 DE. A differentially expressed protein, RhoGDI, was validated by both western blotting and immunocytological staining. RESULTS: The comprehensive protein set included more than 850 protein spots from both the TMT and TMCs, as visualized on 2-DE gel. Two-hundred-and-thirty-five spots were successfully identified in the TMT gel. The functional categories of the identified proteins were mainly comprised of metabolic process, cell adhesion, anti-apoptosis, cell motility, carbohydrate metabolic process, signal transduction, and regulation of transcription. During three days of DEX treatment, TMCs' proliferation was inhibited in a time- and dose-dependent manner, as evidenced by MTT assay. In the 48 h cultured cell group, RhoGDI expression was reduced, as detected by 2-DE, western blotting, and immunocytological staining. In contrast, the expression of RhoA, a target of RhoGDI, increased in response to DEX treatment. CONCLUSIONS: Using the classic proteomic workflow, the main protein complement of normal human TMT was detected, identified, and categorized. The DEX inhibition of RhoGDI expression in TMCs was evidenced. PMID- 20161820 TI - Novel and known mutations of TGFBI, their genotype-phenotype correlation and structural modeling in 3 Chinese families with lattice corneal dystrophy. AB - PURPOSE: To report novel transforming growth factor beta-induced (TGFBI) mutations responsible for lattice corneal dystrophy (LCD), the associated genotype-phenotype correlation, and structural changes in the mutant proteins in three Chinese families. METHODS: Three unrelated Chinese families were diagnosed as Type I LCD. Mutations in TGFBI were detected by sequencing all of the 17 exons and splice sites of the gene. Phenotype, including corneal erosions, and opacification in the families were compared. Structural changes of the mutant proteins were modeled. One hundred healthy volunteers were recruited as controls for sequence analysis of TGFBI. RESULTS: Two novel mutations, c.(1702G>C and 1706T>A; p.Arg514Pro and Phe515Leu) in TGFBI were identified in Family 1. Two known hotspot mutations, c. 531C>T (p. Arg124Cys) and c.1876A>G (p.His572Arg), were revealed in Family 2 and Family 3, respectively. Sequence analysis in the 100 healthy control subjects, the unaffected members in Family 1, and evolutionary alignment showed that the novel mutations occurred in the conserved amino acids. Structural modeling revealed changes in the 2nd structure of the mutant proteins, but did not detect gross structural changes. Mutations c.(1702G>C and 1706T>A; p.Arg514Pro and Phe515Leu) and the c. 531C>T (p. Arg124Cys) were present in the corneas with sever opacification. CONCLUSIONS: The novel mutations c.(1702G>C and 1706T>A; p.Arg514Pro and Phe515Leu), c. 531C>T (p. Arg124Cys), c.1876A>G (p.His572Arg) in TGFBI were responsible for LCD in the 3 families. Mutations c.(1702G>C and 1706T>A) (p.Arg514Pro and Phe515Leu) and the c. 531C>T (p. Arg124Cys) were associated with more severe LCD phenotypes in the families. These results provide more data for molecular diagnosis and prognosis of the disease. PMID- 20161821 TI - Editorial. PMID- 20161822 TI - The use of AlphaScreen technology in HTS: current status. AB - AlphaScreen (Amplified Luminescent Proximity Homogeneous Assay Screen) is versatile assay technology developed to measuring analytes using a homogenous protocol. This technology is an example of a bead-based proximity assay and was developed from a diagnostic assay technology known as LOCI (Luminescent Oxygen Channeling Assay). Here, singlet oxygen molecules, generated by high energy irradiation of Donor beads, travel over a constrained distance (approx. 200 nm) to Acceptor beads. This results in excitation of a cascading series of chemical reactions, ultimately causing generation of a chemiluminescent signal.In the past decade, a wide variety of applications has been reported, ranging from detection of analytes involved in cell signaling, including protein:protein, protein:peptide, protein:small molecule or peptide:peptide interactions. Numerous homogeneous HTS-optimized assays have been reported using the approach, including generation of second messengers (such as accumulation of cyclic AMP, cyclic GMP, inositol [1, 4, 5] trisphosphate or phosphorylated ERK) from liganded GPCRs or tyrosine kinase receptors, post-translational modification of proteins (such as proteolytic cleavage, phosphorylation, ubiquination and sumoylation) as well as protein-protein and protein-nucleic acid interactions.Recently, the basic AlphaScreen technology was extended in that the chemistry of the Acceptor bead was modified such that emitted light is more intense and spectrally defined, thereby markedly reducing interference from biological fluid matrices (such as trace hemolysis in serum and plasma). In this format, referred to as AlphaLISA, it provides an alternative technology to classical ELISA assays and is suitable for high throughput automated fluid dispensing and detection systems.Collectively, AlphaScreen and AlphaLISA technologies provide a facile assay platform with which one can quantitate complex cellular processes using simple no-wash microtiter plate based assays. They provide the means by which large compound libraries can be screened in a high throughput fashion at a diverse range of therapeutically important targets, often not readily undertaken using other homogeneous assay technologies. This review assesses the current status of the technology in drug discovery, in general, and high throughput screening (HTS), in particular. PMID- 20161823 TI - Multiplexing bioluminescent and fluorescent reporters to monitor live cells. AB - Reporter proteins are valuable tools to monitor promoter activities and characterize signal transduction pathways. Many of the currently available promoter reporters have drawbacks that compromise their performance. Enzyme-based reporter systems using cytosolic luciferases are highly sensitive, but require a cell lysis step that prevents their use in long-term monitoring. By contrast, secreted bioluminescent reporters like Metridia luciferase and Secreted Alkaline Phosphatase can be assayed repeatedly, using supernatant from the same live cell population to produce many sets of data over time. This is crucial for studies with limited amounts of cells, as in the case of stem cells. The use of secreted bioluminescent reporters also enables broader applications to provide more detailed information using live cells; for example, multiplexing with fluorescent proteins. Here, data is presented describing the characteristics of secreted Metridia luciferase and its use in multiplexing applications with either Secreted Alkaline Phosphatase or a fluorescent protein. PMID- 20161824 TI - Development of a HTRF kinase assay for determination of Syk activity. AB - Regulation of protein phosphorylation is a primary cellular signaling mechanism. Many cellular responses to internal and external events are mitigated by protein kinase signaling cascades. Dysfunction of protein kinase activity has been linked to a variety of human pathologies, in the areas of cancer, inflammation, metabolism, cell cycle, apoptosis, as well as cardiovascular, neurodegenerative and autoimmune diseases. As such, there is an important need for protein kinase activity detection methodologies for researchers engaged in Drug Discovery. A number of different technologies have been employed for the measurement of protein kinase activity, including radioactive methods, luminescent methods, and fluorescent methods. More recently, Homogeneous Time Resolved Fluorescence technology (HTRF), based on the principle of time-resolved fluorescent resonance energy transfer (TR-FRET), has been developed and applied for the measurement of protein kinase activity in vitro. This technology note describes the development of an HTRF assay for detection of Syk enzyme activity in a format consistent with the requirements of High-Throughput Screening (HTS) campaigns currently used in drug discovery. PMID- 20161825 TI - Cellular assays for high-throughput screening for modulators of Trk receptor tyrosine kinases. AB - Trk receptor tyrosine kinases are required for signal transduction initiated by neurotrophins leading to cell proliferation, differentiation, survival and death. Alterations in Trk kinase activity have been linked to various diseases. To address the need for cell-based assays for screening and studying the selectivity of Trk kinase modulators, we developed high-throughput cell-based assays for Trk receptor kinases using nuclear factor of activated T-cells (NFAT) beta-lactamase reporter lines stably expressing full length human Trk kinases. These assays were functionally validated with cognate neurotrophin(s), inhibitors and TRK RNAi oligos and demonstrated for their utility in identifying potent and selective modulators of Trk receptor kinases. PMID- 20161826 TI - Homogenous fluorescent assays for characterizing small-molecule activators of AMP activated protein kinase (AMPK). AB - AMP activated protein kinase (AMPK) is a key regulator of cellular metabolism. AMPK activity is modulated in part by binding of AMP to the gamma-subunit of the kinase, which increases the activity of the catalytic alpha-subunit. Because increased AMPK activity in the liver and in skeletal muscle leads to increased fatty acid oxidation and decreased cholesterol and fatty acid biosynthesis, activators of AMPK are being sought for treatment of type-2 diabetes and other metabolic disorders. The unique mechanism of AMPK activation offers an opportunity to develop small molecules that directly upregulate AMPK activity, and there exists a need for simplified methods to identify and characterize small molecules that show isoform-specific effects on AMPK. We have developed a suite of fluorescence-based assays to identify and characterize such compounds, and have used these to characterize and compare activity of recombinant AMPK alpha(1)beta(1)gamma(1) and alpha(2)beta(1)gamma(1) isoforms in response to small molecule activators and inhibitors. PMID- 20161827 TI - Fluorescent cascade and direct assays for characterization of RAF signaling pathway inhibitors. AB - RAF kinases are part of a conserved signaling pathway that impacts cell growth, differentiation, and survival, and RAF pathway dysregulation is an attractive target for therapeutic intervention. We describe two homogeneous fluorescent formats that distinguish RAF pathway inhibitors from direct RAF kinase inhibitors, using B-RAF, B-RAF V599E, and C-RAF. A Forster-resonance energy transfer (FRET) based method was used to develop RAF and MEK cascade assays as well as a direct ERK kinase assay. This method uses a peptide substrate, that is terminally labeled with a FRET-pair of fluorophores, and that is more sensitive to proteolysis relative to the phosphorylated peptide. A second time-resolved FRET-based assay using fluorescently labeled MEK substrate was used to detect direct inhibitors of RAF kinase activity. The cascade assays detect compounds that interact with activated and unactivated kinases within the recapitulated RAF pathway, and the direct assays isolate the point of action for an inhibitor. PMID- 20161828 TI - Cellular Ser/Thr-kinase assays using generic peptide substrates. AB - High-throughput cellular profiling has successfully stimulated early drug discovery pipelines by facilitating targeted as well as opportunistic lead finding, hit annotation and SAR analysis. While automation-friendly universal assay formats exist to address most established drug target classes like GPCRs, NHRs, ion channels or Tyr-kinases, no such cellular assay technology is currently enabling an equally broad and rapid interrogation of the Ser/Thr-kinase space. Here we present the foundation of an emerging cellular Ser/Thr-kinase platform that involves a) coexpression of targeted kinases with promiscuous peptide substrates and b) quantification of intracellular substrate phosphorylation by homogeneous TR-FRET. Proof-of-concept data is provided for cellular AKT, B-RAF and CamK2delta assays. Importantly, comparable activity profiles were found for well characterized B-Raf inhibitors in TR-FRET assays relying on either promiscuous peptide substrates or a MEK1(WT) protein substrate respectively. Moreover, IC(50)-values correlated strongly between cellular TR-FRET assays and a gold standard Ba/F3 proliferation assay for B-Raf activity. Finally, we expanded our initial assay panel by screening a kinase-focused cDNA library and identified starting points for >20 cellular Ser/Thr-kinase assays. PMID- 20161829 TI - The imaging probe development center and the production of molecular imaging probes. AB - The Imaging Probe Development Center (IPDC), part of the NIH Roadmap for Medical Research Initiative (http://nihroadmap.nih.gov/) recently became fully operational at its newly refurbished laboratories in Rockville, MD. The IPDC (http://nihroadmap.nih.gov/molecularlibraries/ipdc/) is dedicated to the production of known and novel molecular imaging probes, with its services currently being used by the NIH intramural community, although in the future it is intended that the extramural community will also benefit from the IPDC's resources. The Center has been set up with the belief that molecular imaging, and the probe chemistry that underpins it, will constitute key technologies going forward. As part of the larger molecular libraries and imaging initiative, it is planned that the IPDC will work closely with scientists from the molecular libraries effort. Probes produced at the IPDC include optical, radionuclide and magnetic resonance agents and may encompass any type of contrast agent. As IPDC is a trans-NIH resource it can serve each of the 27 Institutes and Centers that comprise NIH so its influence can be expected to impact widely different subjects and disease conditions spanning biological research. IPDC is expected to play a key part in interdisciplinary collaborative imaging projects and to support translational R&D from basic research through clinical development, for all of the imaging modalities. Examples of probes already prepared or under preparation are outlined to illustrate the breadth of the chemistries undertaken together with a reference outline of the diverse biological applications for which the various probes are intended. PMID- 20161830 TI - Comparison on functional assays for Gq-coupled GPCRs by measuring inositol monophospate-1 and intracellular calcium in 1536-well plate format. AB - Cell-based functional assays used for compound screening and lead optimization play an important role in drug discovery for G-protein coupled receptors (GPCRs). Cell-based assays can define the role of a compound as an agonist, antagonist or inverse agonist and can provide detailed information about the potency and efficacy of a compound. In addition, cell-based screens can be used to identify allosteric modulators that interact with sites other than the binding site of the endogenous ligand. Intracellular calcium assays which use a fluorescent calcium binding dye (such as Fluo-3, Fluo-4 or Fura-2) have been used in compound screening campaigns to measure the activity of Gq-coupled GPCRs. However, such screening methodologies require a special instrumentation to record the rapid change in intracellular free calcium concentration over time. The radioactive inositol 1,4,5- triphosphate (IP(3)) assay measures (3)H-inositol incorporation and is another traditional assay for the assessment of Gq-coupled GPCR activity, but it is not suitable for screening of large size compound collections because it requires a cell wash step and generates radioactive waste. To avoid these limitations, we have optimized and miniaturized a TR-FRET based IP-One assay that measures inositol monophosphate in a 1536-well plate format. This assay is homogenous, non-radioactive and does not require a kinetic readout. It has been tested with the cell lines expressing M(1) acetylcholine, FFAR1, vasopressin V1b, or Neuropeptide S receptors. The activities of antagonists determined in the IP One assay correlated well with these measured in the intracellular calcium assay while the correlation of agonist activities might vary from cell line to cell line. This IP-One assay offers an alternative method for high throughput screening of Gq-coupled GPCRs without using costly kinetic plate readers. PMID- 20161831 TI - HTS-compatible beta-lactamase transcriptional reporter gene assay for interrogating the heat shock response pathway. AB - Moderate environmental and physiological stressors are known to initiate protective heat shock response (HSR) leading to cell survival. HSR is largely mediated by the activation of heat shock factor (HSF), resulting in increased heat shock protein expression. Dysregulation of the HSR signaling has been associated with various diseases including cancer, inflammation and neurodegenerative disorders. Compounds that can modulate HSR have been pursued for the treatment of these diseases. To facilitate the discovery of HSR modulators, we developed a high-throughput amenable betalactamase transcriptional reporter gene assay for monitoring the function of HSF. HeLa cells were engineered to express the beta-lactamase reporter under the control of HSF response elements (HSE) present in the HSP70 gene promoter. The HSE-beta lactamase (HSE-bla) reporter gene assay was validated by using HSF-specific siRNAs and known small molecule modulators. Taking the advantage of fluorescence resonance energy transfer (FRET)-based cell permeable betalactamase substrate, this assay can be miniaturized into 1536-well format. Our results demonstrate that the assay is robust and can be applied to high-throughput screening (HTS) for modulators of HSR. PMID- 20161832 TI - Phenotypic fingerprinting of small molecule cell cycle kinase inhibitors for drug discovery. AB - Phenotypic drug discovery, primarily abandoned in the 1980's in favor of targeted approaches to drug development, is once again demonstrating its value when used in conjunction with new technologies. Phenotypic discovery has been brought back to the fore mainly due to recent advances in the field of high content imaging (HCI). HCI elucidates cellular responses using a combination of immunofluorescent assays and computer analysis which increase both the sensitivity and throughput of phenotypic assays. Although HCI data characterize cellular responses in individual cells, these data are usually analyzed as an aggregate of the treated population and are unable to discern differentially responsive subpopulations. A collection of 44 kinase inhibitors affecting cell cycle and apoptosis were characterized with a number of univariate, bivariate, and multivariate subpopulation analyses demonstrating that each level of complexity adds additional information about the treated populations and often distinguishes between compounds with seemingly similar mechanisms of action. Finally, these subpopulation data were used to characterize compounds as they relate in chemical space. PMID- 20161833 TI - HTRF: A technology tailored for drug discovery - a review of theoretical aspects and recent applications. AB - HTRF (Homogeneous Time Resolved Fluorescence) is the most frequently used generic assay technology to measure analytes in a homogenous format, which is the ideal platform used for drug target studies in high-throughput screening (HTS). This technology combines fluorescence resonance energy transfer technology (FRET) with time-resolved measurement (TR). In TR-FRET assays, a signal is generated through fluorescent resonance energy transfer between a donor and an acceptor molecule when in close proximity to each other. Buffer and media interference is dramatically reduced by dual-wavelength detection, and the final signal is proportional to the extent of product formation. The HTRF assay is usually sensitive and robust that can be miniaturized into the 384 and 1536-well plate formats. This assay technology has been applied to many antibody-based assays including GPCR signaling (cAMP and IP-One), kinases, cytokines and biomarkers, bioprocess (antibody and protein production), as well as the assays for protein protein, proteinpeptide, and protein-DNA/RNA interactions.Since its introduction to the drug-screening world over ten years ago, researchers have used HTRF to expedite the study of GPCRs, kinases, new biomarkers, protein-protein interactions, and other targets of interest. HTRF has also been utilized as an alternative method for bioprocess monitoring. The first-generation HTRF technology, which uses Europium cryptate as a fluorescence donor to monitor reactions between biomolecules, was extended in 2008 through the introduction of a second-generation donor, Terbium cryptate (Tb), enhancing screening performance. Terbium cryptate possesses different photophysical properties compared to Europium, including increased quantum yield and a higher molar extinction coefficient. In addition to being compatible with the same acceptor fluorophors used with Europium, it can serve as a donor fluorophore to green emitting fluors because it has multiple emission peaks including one at 490 nm. Moreover, all Terbium HTRF assays can be read on the same HTRF-compatible instruments as Europium HTRF assays.Overall, HTRF is a highly sensitive, robust technology for the detection of molecular interactions in vitro and is widely used for primary and secondary screening phases of drug development. This review addresses the general principles of HTRF and its current applications in drug discovery. PMID- 20161834 TI - In vitro viability and cytotoxicity testing and same-well multi-parametric combinations for high throughput screening. AB - In vitro cytotoxicity testing has become an integral aspect of drug discovery because it is a convenient, costeffective, and predictive means of characterizing the toxic potential of new chemical entities. The early and routine implementation of this testing is testament to its prognostic importance for humans. Although a plethora of assay chemistries and methods exist for 96-well formats, few are practical and sufficiently sensitive enough for application in high throughput screening (HTS). Here we briefly describe a handful of the currently most robust and validated HTS assays for accurate and efficient assessment of cytotoxic risk. We also provide guidance for successful HTS implementation and discuss unique merits and detractions inherent in each method. Lastly, we discuss the advantages of combining specific HTS compatible assays into multi-parametric, same-well formats. PMID- 20161835 TI - A high throughput assay to identify small molecule modulators of prostatic acid phosphatase. AB - Prostatic acid phosphatase (PAP) is expressed in nociceptive neurons and functions as an ectonucleotidase. Injection of the secretory isoform of PAP has potent antinociceptive effects in mouse models of chronic pain. These data suggested that a small molecule activator of PAP may have utility as a novel therapeutic for chronic pain, while inhibitors could be used to acutely inhibit PAP in vitro and in vivo. To identify small molecule modulators of PAP activity, we validated a high throughput, fluorescence-based biochemical assay and then used this assay to screen a compound library. We decreased the frequency of false positive activators by subtracting compound fluorescence from the final assay fluorescence. This approach significantly reduced the number of false positive activators found in the screen. While no activators were confirmed, seven novel inhibitors of PAP were identified. Our results suggest this high throughput assay could be used to identify small molecule modulators of PAP activity. PMID- 20161836 TI - An agarose-gel based method for transporting cell lines. AB - Cryopreserved cells stored in dry ice or liquid nitrogen is the classical method for transporting cells between research laboratories in different cities around the world in order to maintain cell viability. An alternative method is to ship the live cells in flasks filled with cell culture medium. Both methods have limitations of either a requirement on special shipping container or short times for the cells to survive on the shipping process. We have recently developed an agarose gel based method for directly transporting the live adherent cells in cell culture plates or dishes in ambient temperature. This convenient method simplifies the transportation of live cells in long distance that can maintain cells in good viability for several days. PMID- 20161837 TI - Development of improved models for phosphodiesterase-4 inhibitors with a multi conformational structure-based QSAR method. AB - Phosphodiesterase-4 (PDE-4) is an important drug target for several diseases, including COPD (chronic obstructive pulmonary disorder) and neurodegenerative diseases. In this paper, we describe the development of improved QSAR (quantitative structure-activity relationship) models using a novel multi conformational structure-based pharmacophore key (MC-SBPPK) method. Similar to our previous work, this method calculates molecular descriptors based on the matching of a molecule's pharmacophore features with those of the target binding pocket. Therefore, these descriptors are PDE4-specific, and most relevant to the problem under study. Furthermore, this work expands our previous SBPPK QSAR method by explicitly including multiple conformations of the PDE-4 inhibitors in the regression analysis, and thus addresses the issue of molecular flexibility. The nonlinear regression problem resulted from including multiple conformations has been transformed into a linear equation and solved by an iterative partial least square (iPLS) procedure, according to the Lukacova-Balaz scheme. 35 PDE-4 inhibitors have been analyzed with this new method, and predictive models have been developed. Based on the prediction statistics for both the training set and the test set, these new models are more robust and predictive than those obtained by traditional ligand-based QSAR techniques as well as that obtained with the SBPPK method reported in our previous work. As a result, multiple predictive models have been added to the collection of QSAR models for PDE4 inhibitors. Collectively, these models will be useful for the discovery of new drug candidates targeting the PDE-4 enzyme. PMID- 20161838 TI - Inhibition of inducible nitric oxide synthase expression by a novel small molecule activator of the unfolded protein response. AB - The transcription of inducible nitric oxide synthase (iNOS) is activated by a network of proinflammatory signaling pathways. Here we describe the identification of a small molecule that downregulates the expression of iNOS mRNA and protein in cytokine-activated cells and suppresses nitric oxide production in vivo. Mechanistic analysis suggests that this small molecule, erstressin, also activates the unfolded protein response (UPR), a signaling pathway triggered by endoplasmic reticulum stress. Erstressin induces rapid phosphorylation of eIF2alpha and the alternative splicing of XBP-1, hallmark initiating events of the UPR. Further, erstressin activates the transcription of multiple genes involved in the UPR. These data suggest an inverse relationship between UPR activation and iNOS mRNA and protein expression under proinflammatory conditions. PMID- 20161839 TI - Improvements in live cell analysis of G protein coupled receptors using second generation BD calcium assay kits. AB - BD Calcium Assay Kits are designed for cell-based calcium mobilization high throughput screening assays. The kits use a proprietary formulation including a non-fluorescent calcium indicator that becomes activated inside the cell and shows increased fluorescence upon calcium binding. The formulation includes a signal-enhancing reagent to maximize the signal over background in a homogeneous, no-wash assay format, based on a technology developed at BD. We have compared the next generation BD calcium assay kit product family to previous versions of the formulation, and to other commercially available homogeneous calcium assay kits. The improvements have enabled better performance on the cell lines and receptors that we have tested in all plate formats including 1536. PMID- 20161840 TI - A novel bioluminescent protease assay using engineered firefly luciferase. AB - Proteases play important roles in a variety of disease processes. Understanding their biological functions underpins the efforts of drug discovery. We have developed a bioluminescent protease assay using a circularly permuted form of firefly luciferase, wherein the native enzyme termini were joined by a peptide containing a protease site of interest. Protease cleavage of these mutant luciferases greatly activates the enzyme, typically over 100 fold. The mutant luciferase substrates are easily generated by molecular cloning and cell-free translation reactions and thus the protease substrates do not need to be chemically synthesized or purchased. The assay has broad applicability using a variety of proteases and their cognate sites and can sensitively detect protease activity. In this report we further demonstrate its utility for the evaluation of protease recognition sequence specificity and subsequent establishment of an optimized assay for the identification and characterization of protease inhibitors using high throughput screening. PMID- 20161841 TI - A new structure-based QSAR method affords both descriptive and predictive models for phosphodiesterase-4 inhibitors. AB - We describe the application of a new QSAR (quantitative structure-activity relationship) formalism to the analysis and modeling of PDE-4 inhibitors. This new method takes advantage of the X-ray structural information of the PDE-4 enzyme to characterize the small molecule inhibitors. It calculates molecular descriptors based on the matching of their pharmacophore feature pairs with those (the reference) of the target binding pocket. Since the reference is derived from the X-ray crystal structures of the target under study, these descriptors are target-specific and easy to interpret. We have analyzed 35 indole derivative based PDE-4 inhibitors where Partial Least Square (PLS) analysis has been employed to obtain the predictive models. Compared to traditional QSAR methods such as CoMFA and CoMSIA, our models are more robust and predictive measured by statistics for both the training and test sets of molecules. Our method can also identify critical pharmacophore features that are responsible for the inhibitory potency of the small molecules. Thus, this structure-based QSAR method affords both descriptive and predictive models for phosphodiesterase-4 inhibitors. The success of this study has also laid a solid foundation for systematic QSAR modeling of the PDE family of enzymes, which will ultimately contribute to chemical genomics research and drug discovery targeting the PDE enzymes. PMID- 20161842 TI - A homogenous luminescent proximity assay for 14-3-3 interactions with both phosphorylated and nonphosphorylated client peptides. AB - The 14-3-3 proteins are a family of dimeric eukaryotic proteins that mediate both phosphorylation-dependent and -independent protein-protein interactions. Through these interactions, 14-3-3 proteins participate in the regulation of a wide range of cellular processes, including cell proliferation, cell cycle progression, and apoptosis. Because of their fundamental importance, 14-3-3 proteins have also been implicated in a variety of diseases, including cancer and neurodegenerative disorders. In order to monitor 14-3-3/client protein interactions for the discovery of small molecule 14-3-3 modulators, we have designed and optimized 14 3-3 protein binding assays based on the amplified luminescent proximity homogeneous assay (AlphaScreen) technology. Using the interaction of 14-3-3 with a phosphorylated Raf-1 peptide and a nonphosphorylated R18 peptide as model systems, we have established homogenous "add-and-measure" high-throughput screening assays. Both assays achieved robust performance with S/B ratios above 7 and Z' factors above 0.7. Application of the known antagonistic peptides in our studies further validated the assay for screening of chemical compound libraries to identify small molecules that can modulate 14-3-3 protein-protein interactions. PMID- 20161843 TI - A novel fluorogenic coumarin substrate for monitoring acid phosphatase activity at low pH environment. AB - This article described the synthesis and application of 6-chloro-8-fluoro-4 methylumbelliferone phosphate (CF-MUP) in analyzing acid phosphatase activity. Compared to the existing MUP, the new coumarin phosphate, CF-MUP, demonstrateed much higher sensitivity and was more robust for detecting the activity of acid phosphatase than the classic substrate 4-methylumbelliferone phosphate (MUP). The product of enzyme reaction, 6-chloro-8-fluoro-4-methylumbelliferone (CF-MU) possesses strong fluorescence at approximately 450 nm with low pKa (4.7), high fluorescence quantum yield and pH independence in the physiological pH range. This new fluorescence dye, CF-MU, is a convenient tool for assays with buffer pH between 4.5 and 8. PMID- 20161844 TI - A high throughput serum paraoxonase assay for discovery of small molecule modulators of PON1 activity. AB - PON1 has been demonstrated to be the serum enzyme responsible for detoxifying organophosphate chemical weapons and plays a protective role against atherosclerosis. In order to identify small molecules that modulate PON1 activity in serum, we developed a high throughput kinetic absorbance assay using mouse serum and the organophosphate paraoxon. The IC(50) value obtained for the known PON1 inhibitor, 2-hydroxyquinoline, matched the value reported for purified PON1. A compound library was screened resulting in no confirmed activators, but 12 confirmed inhibitors. Seven of these hits also inhibited purified human PON1. One compound was only two-fold less potent than 2-hydroxyquinoline in the serum assay, but 10-fold more potent against purified PON1. This compound (IC(50) = 420 nM) may be useful towards a chemical probe for PON1. Therefore, this assay has utility as a high throughput assay for discovery of small molecule modulators of PON1 activity that maintain activity in serum. PMID- 20161845 TI - Comparative docking assessment of glucokinase interactions with its allosteric activators. AB - Glucokinase (GK) is expressed in multiple organs and plays a key role in hepatic glucose metabolism and pancreatic insulin secretion. GK could indeed serve as pacemaker of glycolysis and could be an attractive target for type 2 diabetes (T2D). The recent preclinical data of first GK activator RO-28-1675 has opened up a new field of GK activation as a powerful tool in T2D therapies. The GK allosteric site is located ~20A away from glucose binding site. Chemical structure of Glucokinase activators (GKA) includes three chemical arms; all consisting of cyclic moiety and joined in a shape resembling the letter Y. In this study, comparative docking assessment using Autodock4 revealed that the three arms bind to three aromatic/hydrophobic subpockets at the allosteric site. Our dockings have overall consistency with experimental data in both docking modes and simulated binding free energies, and offer insights on understanding GK/GKA interactions and further GKA design. Specifically, for the first pocket, involvement of Arg63 as key residue in two specific hydrogen-bond formations with all allosteric activators defines the binding feature; for the second pocket, it has the most diverse binding interactions, mostly aromatic, hydrophobic and multiple hydrogen bonds. The site has the best potential for further GKA optimization by utilizing aromatic heterocycles and hydrogen bond forming linkers to build the GKA 2(nd) arm. PMID- 20161846 TI - Development of fluorescence polarization assays for the molecular chaperone Hsp70 family members: Hsp72 and DnaK. AB - The heat shock protein 70 (Hsp70) family of chaperones play crucial roles in protein folding and have been linked to numerous diseases. We were interested in developing a generally applicable assay format for the Hsp70 family and have developed fluorescence polarization based assays for both the mammalian Hsp72 and its bacterial counterpart, DnaK. These assays are comparable in assay set-up, incubation conditions and buffer components. Both unfolded polypeptides and synthetic peptides can be utilized as tracers to detect binding although peptides meeting the minimum seven residue length for Hsp70 binders have weaken binding when modified with fluorescein presumably due to steric effects. Although we did not identify a suitable general substrate for all Hsp70 proteins, fluorescein tagged peptide substrates that gave high affinity binding were identified for both DnaK and hsp72. We would predict that these assays will be suitable for identifying both selective chemical probes of Hsp70 family members and "pan" Hsp70 inhibitors. PMID- 20161847 TI - Cutaneous remodeling and photorejuvenation using radiofrequency devices. AB - Radio frequency (RF) is electromagnetic radiation in the frequency range of 3 300GHz. The primary effects of RF energy on living tissue are considered to be thermal. The goal of the new devices based on these frequency ranges is to heat specific layers of the skin. The directed use of RF can induce dermal heating and cause collagen degeneration. Wound healing mechanisms promote the remodeling of collagen and wound contraction, which ultimately clinically enhances the appearance of mild to moderate skin laxity. Preliminary studies have reported efficacy in the treatment of laxity that involves the periorbital area and jowls. Because RF energy is not dependent on specific chromophore interaction, epidermal melanin is not at risk of destruction and treatment of all skin types is possible. As such, radiofrequency-based systems have been used successfully for nonablative skin rejuvenation, atrophic scar revision and treatment of unwanted hair, vascular lesions and inflammatory acne. The use of RF is becoming more popular, although a misunderstanding exists regarding the mechanisms and limitations of its actions. This concise review serves as an introduction and guide to many aspects of RF in the non ablative rejuvenation of skin. PMID- 20161848 TI - Immune zones in leprosy. AB - Leprosy affects mainly those areas of skin which have a relatively lower temperature and are more exposed to trauma. Certain zones like scalp, palms and soles, genitalia, groins, axillae, eyelids, transverse band of skin over lumboscaral area, midline of back and perineum have been described to be immune to the development of lesions in leprosy. But clinical, histological and bacteriological evidence of involvement of these so called immune zones though infrequent have been documented. Hence, these immune zones should be termed as relatively immune, rather than absolutely immune zones of leprosy. PMID- 20161849 TI - Biologics in dermatologic therapy - an update. AB - Biologics are protein molecules which are used in various diseases to target the specific points in the immunopathogenesis of the diseases. The molecules are produced by recombinant DNA technology. The molecules bind to the specific targets without interfering wtih rest of the pathogenetic pathways. Therefore the so called 'immunosuppressives' have, although, a broader broader spectrum of action on immune system, their side-effects are also equally more. The biologics, because of their spefic action on the immune system, have very little side effects. The biologics which have revolutionized the treatment of various dermatologic diseases have been discussed here. PMID- 20161850 TI - Oxidative stress in experimental vitiligo C57BL/6 mice. AB - AIM: To evaluate whether oxidative stress is implicated in melanocyte damage in vitiligo. BACKGROUND: Vitiligo is a complex disorder characterized by gradually enlarging areas of depigmentation. A new unifying hypothesis for the etiology of this pigment disorder is proposed, in which we postulate that the final destruction of melanocytes in vitiligo results from a cascade of reactions initiated by a disregulation of melanogenesis, as the result of a breakdown in free radical defense. METHODS: We evaluated 18 vitiligo mice and 12 controls that were age matched. Parameters of oxidative stress such as catalase (CAT), superoxide dismutase (SOD), and plasma malondialdehyde (MDA) were measured by spectrophotometry. RESULTS: MDA levels in vitiligo mice were significantly higher than in controls (P < 0.001). CAT, SOD, and glutathione peroxidase (GPx) activities in mice were significantly lower than controls (P < 0.05 and P < 0.001, respectively). CONCLUSION: Our results confirmed that oxidative stress plays an important role in the pathogenesis of vitiligo. Melanocyte damage in vitiligo might be linked to generalized oxidative stress. This study is the first report on antioxidant parameters in experimental vitiligo mice. PMID- 20161851 TI - Determination of the relationship between Basal cell carcinoma and human papilloma virus, based on immunohistochemistry staining method. AB - BACKGROUND: Basal cell carcinoma (BCC) is the most common skin cancer among Caucasians, and in most cases, occurs in the sun-exposed areas. In recent years, in addition to many other etiologies such as exposure to UV radiation, and occasionally xeroderma pigmentosa, burns, tattoos, and pox scars, human papillomavirus (HPV) is also considered to have an etiologic role. Different studies were conducted with varied results in this regard. AIMS: We evaluate this plausible relationship between HPV and BCC by means of immunohistochemistry (IHC) staining method. METHODS: This is an analytic cross-sectional study in which 160 samples were selected randomly consisting of 80 BCC lesions and 80 safe margins. Sampling was done among paraffin-embedded blocks in pathology ward of Kashani and Alzahra hospitals, Isfahan-Iran, from 2004-2007. A section of each block was IHC stained for HPV immunoreactivity (DAKO, Denmark). This was followed by microscopic evaluation in terms of being positive or negative. RESULTS: Fifty seven point five percent of the samples belonged to men and the others to women. In 10%, HPV marker was positive, both in lesion and margin. In 83.8% neither the lesions nor the margins were immunoreactive for HPV. Only in 5 cases (6.3%) the lesion was positive and the margin was negative for this marker. There was no case of immunoreactivity for HPV marker in margins, while it was negative in lesions. Our study results followed by McNemar analysis did not show a significant relationship between BCC incidence and HPV existence. This was consistent in both genders (P > 0.05, power > 90%). CONCLUSION: In this study we did not find a significant relationship between BCC and HPV, but based on review of articles it appears that large multicentric studies are to be conducted in this regard. PMID- 20161852 TI - Serum mucosa-associated epithelial chemokine in atopic dermatitis: a specific marker for severity. AB - BACKGROUND: Mucosa-associated epithelial chemokine (MEC; CCL28) is considered pivotal in mediating migration of CCR3 and CCR10-expressing skin-homing memory CLA(+) T cells. CCL28 is selectively and continuously expressed by epidermal keratinocytes, but highly upregulated in inflammatory skin diseases such as atopic dermatitis (AD). AIMS: This controlled longitudinal study was designed to evaluate the expression of CCL28 serum levels in childhood AD and bronchial asthma (BA) and its possible relations to disease severity and activity. METHODS: Serum CCL28 levels were measured in 36 children with AD, 23 children with BA, and 14 children who had both conditions as well as in 21 healthy age and gender matched subjects serving as controls. Sixteen patients in the AD group were followed-up and re-sampled for serum CCL28 after clinical remission. Serum CCL28 levels were correlated with some AD disease activity and severity variables. RESULTS: Serum CCL28 levels in patients with AD whether during flare (median = 1530; mean +/- SD = 1590.4 +/- 724.3 pg/ml) or quiescence (median = 1477; mean +/ SD = 1575.2 +/- 522.1 pg/ml) were significantly higher than the values in healthy children (median = 301; mean +/- SD = 189.6 +/- 92.8 pg/ml). However, the levels during flare and quiescence were statistically comparable. The serum levels in BA (median = 340; mean +/- SD = 201.6 +/- 109.5 pg/ml) were significantly lower than the AD group and comparable with the healthy control values. Serum CCL28 levels in severe AD were significantly higher as compared with mild and moderate cases and correlated positively to the calculated severity scores (LSS and SCORAD). CCL28 levels during exacerbation of AD could be positively correlated to the corresponding values during remission, the peripheral absolute eosinophil counts, and the serum lactate dehydrogenase levels. Serum CCL28 did not vary with the serum total IgE values in AD. CONCLUSION: Our data reinforce the concept that CCL28 might share in the pathogenesis of AD probably through selective migration and infiltration of effector/memory Th2 cells into the skin. It may also represent an objective prognostic marker for disease severity. Further studies may pave the way for CCL28 antagonism among the adjuvant therapeutic strategies. PMID- 20161853 TI - CELL PROLIFERATION AND CYTOKINE INDUCTION BY TNF-alpha OF PSORIATIC KERATINOCYTES ARE NOT DIFFERENT FROM NORMAL KERATINOCYTES IN VITRO. AB - BACKGROUND: Recent studies indicate that various cytokines including tumor necrosis factor-alpha (TNF-alpha) play an essential role in the induction and maintenance of psoriatic lesion. AIMS: To compare the cell proliferation of keratinocytes by various cytokines and TNF-alpha-induced cytokine secretion among normal keratinocytes, uninvolved, and involved keratinocytes. METHODS: The keratinocytes from normal skin, uninvolved, and involved psoriasis were cultured in the presence of IL-6, IL-8, epidermal growth factor (EGF), hepatocyte growth factor (HGF), transforming growth factor-alpha (TGF-alpha) epiregulin, amphiregulin, and TNF-alpha and then MTT assay for keratinocytes proliferation was performed. Furthermore, TNF-alpha-induced secretion of IL-6, IL-8, EGF, HGF, TGF-alpha, epiregulin, and amphiregulin were compared among these keratinocytes. RESULTS: IL-6, IL-8, EFG, TGF-alpha, epiregulin, and amphiregulin, but not TNF alpha increased keratinocyte proliferation of normal, psoriatic uninvolved, and involved skin. The increased cell proliferation by these cytokines and growth factors were not different among the keratinocytes derived from normal skin, uninvolved, and involved psoriasis. The significant induction of TNF-alpha increased IL-6, IL-8, EGF, HGF, TGF-alpha, epiregulin, and amphiregulin, but the increase in these cytokines and growth factors were not different among normal skin, uninvolved, and involved psoriasis. CONCLUSION: Cell proliferation by various cytokines and growth factors and TNF-alpha-induced cytokine secretion are not different between normal and psoriatic keratinocytes. PMID- 20161854 TI - The 'holi' dermatoses: annual spate of skin diseases following the spring festival in India. AB - BACKGROUND: 'Holi' is an annual spring festival celebrated all over India. The central ritual of Holi involves throwing of colors on one another. Playing with toxic industrial dyes often results in various dermatological complaints in a significant number of people immediately following the celebration. AIMS: To describe patterns of various skin manifestations directly or indirectly related to the use of different colors in the celebration of Holi. METHODS: Observational clinical study on consecutive patients presenting to a teaching hospital in Kolkata, India. RESULTS: Forty-two patients with a mean age of 24.2 years were studied. Itching was the commonest symptom (25, 59.5%), followed by burning sensation, pain, oozing, and scaling. Eleven patients' symptoms were attributed to activities related to preparation of colors and the removal of colors from the skin surface. Eczematous lesions were the most common pattern (24, 57.1%) followed by erosions, xerosis and scaling, erythema, urticaria, acute nail-fold inflammation, and abrasions. Thirteen (30.9%) patients reported aggravation of preexisting dermatoses (acne, eczema, and paronychia). Secondary pyoderma occurred in 3 (7.1%). Face was the commonest site affected (24, 57.1%), followed by dorsum of the hands, scalp, forearm, palms, arms, and trunk. Ocular complaints in the form of redness, watering, and grittiness occurred in 7 (16.7%) patients. CONCLUSION: Various forms of cutaneous manifestations, often associated with ocular complaints, occur commonly due to Holi colors. Public awareness and regulatory actions are needed to avoid these preventable conditions. PMID- 20161855 TI - Patch testing with dermatophagoides and its correlation with chronic eczema and atopic dermatitis. AB - BACKGROUND: Chronic eczema is commonly encountered in the Indian set up. So also is atopic dermatitis. House dust mites (Dermatophagoides) are implicated in various diseases like atopic dermatitis, asthma, and perennial rhinitis. It has also been proven that patch testing with Dermatophagoides pteronyssinus (DP) is important for detection of contact sensitization in chronic dermatitis. AIMS: To study clinical characteristics of DP mix positive patients with regards to chronic dermatitis and atopic dermatitis. METHODS: Dermatology outpatients presenting to the department of Skin and STD of Kasturba Medical College (KMC), with clinically diagnosed atopic dermatitis and chronic eczema were chosen for the study. Inclusion and exclusion criteria were well demarked. Eighty six randomly selected patients of dermatitis were subjected to patch testing with standard series and DP mix. RESULTS: Of the 86, 50 (58%) showed positive reaction to DP mix. Among these positive patients, chronic dermatitis was seen in 42 (84%) with involvement of exposed parts in 37 (74%). Atopic dermatitis was seen in 19 patients (38%) from DP positive group whereas it was observed in 4 patients (17%) from the other group. CONCLUSION: Dermatophagoides mix positivity was statistically significant in chronic eczema as well as atopic dermatitis. Patch testing is an important tool to detect delayed type allergy to house dust mite. PMID- 20161856 TI - Benign and malignant skin lesions in renal transplant recipients. AB - BACKGROUND: Skin lesions - benign and malignant - occur frequently in organ transplant recipients receiving long-term immunosuppressive therapy. These patients are at greater risk of skin cancers. AIMS: To study dermatologic problems in renal transplant recipients (RTRs). METHODS: One hundred patients (53 men and 47 women) were consecutively examined for benign and malignant skin complications since transplantation in Razi Hospital in Tehran Medical University. The main immunosuppressive therapy regimen in these patients was a combination of prednisolone, azathioprine, and cyclosporine. RESULTS: The early and most common complication was cosmetic side effects that occurred in 98% patients. Skin infections occurred in 83% of the patients and most of them were viral infections (65%), especially of human papilloma viruses (HPVs) in 40% of the patients. We found six cases of malignancy in these patients in that four cases were skin cancers, including one case of SCC, one BCC, and two cases of Kaposi's sarcoma. Dermatologic problems occur most frequently in RTRs, especially skin cancers which have higher frequency in these patients than general population, particularly, Kaposi sarcoma. Sun exposure has an important role in developing epithelial skin cancers following transplantation. The age of developing skin cancer in these patients was early than normal population. CONCLUSION: Our results emphasize the importance of dermatologic examinations and monitoring RTRs to obtain an early diagnosis and treatment of cutaneous manifestations. PMID- 20161857 TI - Lupus anticoagulant and leg ulcers in sickle cell anemia. AB - BACKGROUND: The cause of chronic leg ulcer (CLU) in patients with sickle cell anemia (SCA) is unknown; it has been attributed to hypercoagulability associated with the disease. Recently, it has been suggested that a subset of SCA patients may be prone to developing CLU and that hemolysis may be an underlying factor in the development of CLU. The lupus anticoagulant (LA) is an antiphospholipid antibody (aPLa), these antibodies have been described in patients with SCA. AIMS: This study was designed to determine the frequency of LA in SCA patients with CLU compared with those without CLU. MATERIALS AND METHODS: Study design is a descriptive, cross-sectional one. Thirty-three SCA patients with CLU and 33 patients without CLU were screened for the presence of LA using the Kaolin clotting time (KCT), which is an important assay, and Kaolin clotting time index was calculated. Means were compared using the students' t test, proportions were compared using the chi-square test, level of significance was set at 0.05, odds ratio was calculated. RESULTS: About 18.18% of patients with CLU had LA, compared with 6.06% among controls (P < 0.05); odds ratio was 3.44 (95% CI 0.64 - 18.51). CONCLUSIONS: We conclude that SCA patients with CLU may be more likely to develop LA, and this may be related to the degree of hemolysis. Further studies are required to find out if CLU and LA are a result of hemolysis or if LA is responsible for the higher incidence of hemolysis and CLU found among these patients. PMID- 20161858 TI - Mucocutaneous changes in tuberous sclerosis complex: a clinical profile of 27 Indian patients. AB - BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disease resulting in a wide array of clinical manifestations, primarily affecting the skin and central nervous system. Mucocutaneous features play a very important role in the recognition of this syndrome. AIMS: To review the prevalence and patterns of cutaneous manifestations in tuberous sclerosis, in a group of patients from eastern India. METHODS: Observational clinical study on twenty-seven consecutive patients of tuberous sclerosis collected during a period of four years. RESULTS: Most were between 10-20 years of age; the male to female ratio was 2:1. Family history was found in two-thirds. The classical triad of tuberous sclerosis was present in only nine (33.3%) patients. Adenoma sebaceum was the most common cutaneous feature (100%), followed by hypomelanotic macules (92.6%), connective tissue nevi (66.6%), and Koenen's tumors (33.3%). Oral mucosal fibromas were seen in six (22.22%) patients. Fibromatous plaque over forehead and scalp was seen in three patients. Limitation of the study was small size of study sample. CONCLUSION: Prominent mucocutaneous changes are extremely common manifestation of TSC, which may provide crucial diagnostic clues for primary care physicians. PMID- 20161859 TI - Anti-idiotype antibodies in immune regulation of anca associated vasculitis. AB - BACKGROUND: Anti-idiotype antibodies (anti-ids) have a potential role in the immunomodulation of various autoimmune disorders. The immunoregulatory role of anti-idiotypic antibodies in ANCA-associated vasculitis needs to be studied. This study was conducted in clinically and histopathologically diagnosed ANCA associated vasculitis (AAV) patients. METHODS: Anti-ids were tested in 100 AAV patients of which 80 had anti-MPO and 20 had anti-PR3 antibodies at various stages of disease over a period of 2-3 years. The disease activity was estimated by the Birmingham vasculitis activity score (BVAS). The affinity-purified ANCA F(ab')2 fragments were prepared using three each of anti-MPO and anti-PR3 high titer sera and were used as idiotype coats for anti-idiotype antibody detection by ELISA. Positivity was confirmed by fluid phase inhibition ELISA. RESULTS: Patients who went into remission showed 53.8% anti-ids to anti-MPO and 52.9% to anti-PR3 with low BVAS values (0-8), whereas in patients with active disease, only 12.5% had anti-ids to anti-MPO and 10% had anti-ids to anti-PR3 with comparatively high BVAS (18-32), while five cases who had relapse (BVAS 18-20) did not have anti-ids to anti-MPO or anti-PR3. An inverse correlation was noted between ANCA and anti-ids (r = -0.901). CONCLUSIONS: High prevalence of anti-ids in remission cases and low prevalence in active cases with absence of anti-ids in relapse cases as well as an inverse correlation of ANCA and anti-ids indicate its beneficial effect on the disease process, thus suggesting the dynamic role of anti-idiotype networks in the immunoregulation of AAV. PMID- 20161860 TI - Urticaria. PMID- 20161861 TI - Contact urticaria: present scenario. AB - Immunological contact urticaria is a hypersensitivity reaction that appears on the skin following contact with an eliciting substance. Recent advances in our understanding of the molecular mechanism and pathogenesis of this reaction have altered its classification, diagnosis, and treatment. We discuss classification, epidemiology, diagnosis, testing, and treatment options that are available to patients with contact urticaria. PMID- 20161862 TI - Chronic autoimmune urticaria: where we stand? AB - It is well-recognized that 30-40% of chronic idiopathic urticaria is autoimmune in nature. Chronic autoimmune urticaria is caused by anti-FcepsilonRI and less frequently, by anti-IgE autoantibodies that lead to mast cell and basophil activation, thereby giving rise to the release of histamine and other proinflammatory mediators. Activation of the classical complement pathway and formation of C5a are important in dermal mast cell activation. C5a is also a neutrophil and eosinophil chemoattractant. Chronic autoimmune urticaria has been found to be associated with autoimmune thyroid disease. The autologous serum skin test is used as a screening test for chronic autoimmune urticaria and has a sensitivity and specificity of about 70 and 80%, respectively. The current gold standard diagnostic test is the basophil histamine release assay. The treatment of chronic autoimmune urticaria, as in chronic idiopathic urticaria, is with H1 antihistamines. Oral corticosteroids may be used during acute flares. Refractory cases have been shown to respond to cyclosporine and other immunomodulators. The prevalence of chronic autoimmune urticaria in Singapore is similar to that reported in Western countries at about 42%. The presence of thyroid autoimmunity appears to be higher than reported, with 22.5% of patients with chronic idiopathic urticaria here, exhibiting presence of thyroid autoantibodies. PMID- 20161863 TI - Management of difficult urticaria. AB - Chronic urticaria, a major health problem causing patient's distress, induces often physicians' dilemma while dealing with its etiology, investigations and management. Clinical approach of such cases should include apart from clinical history and physical examination laboratory investigations like routine blood test, thyroid profile, etc. as well as sometimes special test like autologous serum skin test. Management includes reassurance, avoidance of precipitating factors, treatment of underlying disorders, and non-pharmacological approach along with pharmacotherapy. First line drug therapy comprises non-sedative and sedative antihistamines, second line doxepin, nifedipine, leukotriene-inhibitors, sulfasalazine, etc. and third line cyclosporine, dapsone, colchicin, etc. PMID- 20161864 TI - What'S new in urticaria? AB - Urticaria, a perplexing disease of ever-changing explanations, is being renovated almost everyday by newer facts and findings accumulated from different parts of the globe. Cost of the urticaria treatment gradually grows higher and higher whereas the ailment disturbs the quality of life very adversely. Disorder of coagulation cascade has recently thrown some new light into its mechanism. Non allergic angioedema induced by bradykinin caused by genetic defects and ACE inhibitors has also been noted. Role of H. pylori in the pathogenesis of urticaria has also been re-reviewed. Urticaria could sometimes mimic erythema multiforme and is termed urticaria multiforme. Skin biopsy showed features of vasculitis in good number of urticaria irrespective of clinical features. Contact sensitization showed positive results in certain cases thus proving contact urticaria. Topical clobetasol, systemic omalizumab and NB UVB have shown promising results in certain forms of urticaria. PMID- 20161865 TI - Bowenoid papulosis of the genitalia successfully treated with topical tazarotene: a report of two cases. AB - Bowenoid papulosis is a rare condition of the genital area caused by human papilloma virus. Clinically, it resembles viral wart and histopathologically Bowen's disease. We herein report two male patients presenting with multiple flat papules on the penis and scrotum. The second patient was HIV-positive. Histopathology showed features of bowenoid papulosis. Both the patients were treated with topical tazarotene gel 0.05%. Lesions cleared within 2 weeks in both the patients.Second patient had recurrences that cleared after retreatment with tazarotene. PMID- 20161866 TI - Hypertrophic lupus vulgaris: an unusual presentation. AB - Lupus vulgaris is the most common form of cutaneous tuberculosis occurring in previously sensitized individuals with a high degree of tuberculin sensitivity. Various forms including plaque, ulcerative, hypertrophic, vegetative, papular, and nodular forms have been described. A 30-year-old male patient presented with a very large hypertrophic lupus vulgaris lesion over left side of chest since 22 years. Histopathological examination showed granulomatous infiltration without caseation necrosis. The Mantoux reaction was strongly positive. Hypertrophic lupus vulgaris of such a giant size and that too at an unusual site is extremely rare and hence is being reported. PMID- 20161867 TI - Hematohidrosis - a rare clinical phenomenon. AB - Hematohidrosis is a very rare condition of sweating blood. A case of hematohidrosis is reported. There are only few reports in the literature. PMID- 20161868 TI - Low chromate diet in dermatology. AB - Chromium is an essential trace element found in soil, water, air, and in the biosphere. It is the fourth most common element in the earth's crust, mostly used to manufacture stainless steel and other alloys. Chromate allergy is not uncommon and its prevalence rate is reported to be 6%. Once developed, it tends to persist for a long time. Chromate is present in most of the dietary items. Chromate content in food often varies considerably from place to place. However, certain foods are routinely high in chromate content. Chromate in the diet of a chromate sensitive person can provoke dermatitis. Careful selection of food with relatively low chromate concentration can bring a reduction in the total dietary intake of chromate per day. This can influence outcome of the disease, especially chronic vesicular hand eczema due to chromate sensitivity, and can benefit a chromate-sensitive patient. PMID- 20161869 TI - Acrokeratosis verruciformis of hopf associated with dilated cardiomyopathy. PMID- 20161870 TI - "Interaction between bcl2 and jun B in primary cutaneous lymphoma: a gene ontology approach": a comment on the new approach in dermatology. PMID- 20161871 TI - Congenital bathing trunk nevus with ambiguous genitalia: a rare coincidence. PMID- 20161872 TI - Alkaptonuria associated with degenerative collagenous palmar plaques. PMID- 20161873 TI - Hand-foot syndrome due to capecitabine. PMID- 20161874 TI - A review of the scientific basis and practical application of a new test of utricular function--ocular vestibular-evoked myogenic potentials to bone conducted vibration. AB - This is a review of recently published papers showing that bone-conducted vibration of the head causes linear acceleration stimulation of both inner ears and this linear acceleration is an effective way of selectively activating otolithic afferent neurons. This simple stimulus is used in a new test to evaluate clinically the function of the otoliths of the human inner ear. Single neuron studies in animals have shown that semicircular canal neurons are rarely activated by levels of bone-conducted vibration at 500 Hz which generate vigorous firing in otolithic irregular neurons and which result in a variety of vestibulo spinal and vestibulo-ocular responses, and the latter is the focus of this review. In humans, 500 Hz bone-conducted vibration, delivered at the midline of the forehead, at the hairline (Fz), causes simultaneous and approximately equal amplitude linear acceleration stimulation at both mastoids and results in ocular evoked myogenic potentials (oVEMPs) beneath both eyes. The first component of this myogenic potential, at a latency to peak of about 10 ms is a negative potential and is called n10 and, in healthy subjects, is equal in amplitude beneath both eyes, but after unilateral vestibular loss, the n10 potential beneath the eye opposite to the lesioned ear is greatly reduced or totally absent. n10 is a myogenic potential due to a crossed otolith-ocular pathway. In patients with total unilateral superior vestibular neuritis, in whom saccular function is largely intact (as shown by the presence of cervical vestibular evoked myogenic potentials (cVEMPs), but utricular function is probably compromised, there is a reduced n10 response beneath the contralesional eye, strongly indicating that n10 is due to utricular otolithic function. PMID- 20161875 TI - The usefulness of toluidine staining as a diagnostic tool for precancerous and cancerous oropharyngeal and oral cavity lesions. AB - Toluidine blue stain is used as a marker to differentiate lesions at high risk of progression in order to improve early diagnosis of oropharyngeal carcinomas. This study focused on 45 oral mucosal lesions in 32 patients (13 female, 19 male). In 9 cases, multiple biopsies were collected. Of the 45 lesions examined, 26 (57.0%) were defined clinically benign, while 19 (42.3%) were defined as suspected lesions (premalignant or malignant). According to the clinical examination, the sensitivity was 53% (16/30) and for toluidine blue staining 96.2% (26/27) (p = 0.0007). The specificity was 80% (12/15) for clinical examination and 77.7% (14/15) for toluidine blue staining (p = 0.79). In conclusion toluidine blue stain has been shown to be a reliable aid when clinical examination is unable to differentiate lesions at high risk of progression and then it improves early diagnosis for oral cavity and oropharyngeal cancer. PMID- 20161876 TI - Transnasal endoscopic treatment of cerebrospinal fluid leak: 17 years' experience. AB - Aim of this report is to describe the long-term results of endoscopic endonasal repair of cerebrospinal fluid leak using a septal mucoperichondrial graft. A case series of 52 patients operated for cerebrospinal fluid rhinorrhea between 1990 and 2006 is presented. All patients underwent surgical treatment for endoscopic endonasal closure of a cerebrospinal fluid leak using a septal mucoperichondrial graft. No lumbar drain and fluorescein tests were used. The intra-operative localization of the fistula was aided by Valsalva's manoeuvre by the anaesthetist. The success rate, after the first attempt, was 88.5% (46/52 patients); for the remaining 11.5% (6/52 patients), a second attempt was necessary which proved successful in 5 cases, raising the overall success rate to 98.1% (51/52 patients). Relapse occurred in only one case (1.9%), after the second attempt. In conclusion, a free mucoperichondrial graft offered good results for cerebrospinal fluid leak repair. In the Authors' experience, a high success rate can be achieved without the use of intrathecal fluorescein and lumbar drain. PMID- 20161877 TI - Notes on the microbiology of cholesteatoma: clinical findings and treatment. AB - Anomalous proliferation of the cholesteatoma epithelium is caused by extrinsic factors such as toxins or bacterial antigens combined with lytic enzymes, lymphokines and cytokines released from the inflammatory infiltrate. This could explain the close relationship between the aggressiveness of cholesteatoma and repeated bacterial superinfection, therefore it is very important to know the bacteria involved in order to control the regrowth of skin following surgery, reduce the aggressive potential of the cholesteatoma and limit the incidence of complications. This study focused on 70 females and 80 males aged between 15 and 65 years, affected by cholesteatomatous otitis media; all underwent bacteriological examination of the auricular secretion. The floral bacteria which proved to play the most important role (60.3%) were the aerobic type and the highest levels were those of Pseudomonas aeruginosa (31.1%) followed by Staphylococcus aureus (19.1%), Proteus mirabilis (7.7%), Escherichia coli (1.4%) and Klebsiella pneumoniae (1%). Anaerobic floral bacteria were found in a fairly high percentage of cases (38.2%); in particular, anaerobic gram-positive cocci (Peptococcus 12.4% and Peptostreptococcus in 4.8% of cases), Bacteroides (12.4%), Clostridium (3.8%), Fusobacterium (2.9%) and Propionobacterium (1.9%) were isolated. In 3 cases of mycetes (1.4%) only Aspergillus, in association with Pseudomonas and Staphylococcus, was identified. The study showed, then, how effective second generation fluoroquinolones and third generation cephalosporins are (the latter being used in pre-adolescent children), the reason being that these antibiotics work not only on Pseudomonas and Staphylococcus, but also on the anaerobic bacteria. PMID- 20161878 TI - The McGurk phenomenon in Italian listeners. AB - In the classic example of the McGurk effect, when subjects see a speaker say /ga/ and hear a simultaneous /ba/, they typically perceive /da/, a syllable that was not presented either acoustically, or visually. This phenomenon, although non natural and recreated in laboratory investigations, has been studied in order to better understand how, where and when the central nervous system processes and integrates visual and auditory signals. Till now, it has been demonstrated for English, Spanish and German languages, while in Japanese and Chinese it seems weaker. Aim of this study was to evaluate the entity of the McGurk effect for the Italian language. Results obtained demonstrate a robust McGurk effect for the Italian language, which has never been described before. The phenomenon is highly significant when an auditory bilabial Consonant-Vowel is dubbed with a visual apico-dental or velar Consonant-Vowel. Results are discussed on the basis of the recent hypothesis regarding the bimodal perception. PMID- 20161879 TI - A new dynamic endonasal stent for bilateral congenital choanal atresia. AB - The Authors describe a new dynamic endonasal Teflon stent, nick-named "little gun", used after the surgical transnasal endoscopic treatment of bilateral choanal atresia in a 4-day-old male. This Teflon stent, conceived to perfectly fit the new naso-choanal openings and to achieve an "orthopaedic" tutorial function, is made of three portions: "A", the barrel, "B", the breech, "C" the butt. The butt is the active part of the splint and must be rolled up around itself, in order to create a spiral tube, fitting to the new choanal openings, able to expand laterally on account of its intrinsic elastic resilience. PMID- 20161880 TI - Lingual thyroid causing dysphagia and dyspnoea. Case reports and review of the literature. AB - Lingual thyroid is a rare embryological anomaly and originates from failure of the thyroid gland to descend from the foramen caecum to its normal eutopic pre laryngeal site. The ectopic gland located at the base of the tongue is often asymptomatic but may cause local symptoms such as dysphagia, dysphonia with stomatolalia, upper airway obstruction and haemorrhage, often with hypothyroidism. Two cases are presented, one in a 62-year-old female and the other in a 42-year-old female, both of whom complained of sensation of a foreign body and progressive dysphagia and dyspnoea caused by ectopic lingual thyroid. Treatment was performed with a partial endoscopic removal and an external cervical approach, followed by substitutive hormone treatment, respectively. Diagnostic procedures and therapeutic options are discussed and a review has been made of reports of lingual thyroid appearing in the literature. PMID- 20161881 TI - Central nervous system tissue heterotopia of the nose: case report and review of the literature. AB - The authors present a case of heterotopic central nervous system tissue observed in an 81-year-old male in the form of an ethmoidal polyp. A review of the literature indicates that this is a rare condition characterised by a connective tissue lesion with astrocytic and oligodendrocytic glial cells, which may be located outside the nasal pyramid in some cases and inside the nasal cavity in others. The most important diagnostic aspect involves differentiating these from meningoencephalocele, which maintains an anatomical connection with central nervous system tissue. Contrast-enhanced imaging is essential for diagnosis, as in cases of heterotopic central nervous system tissue, it will demonstrate that there are no connections with intra-cranial tissue. Endoscopic excision is the treatment of choice. PMID- 20161882 TI - Multiple mucosal involvement in cicatricial pemphigoid. AB - Mucous membrane pemphigoid includes chronic autoimmune sub-epithelial blistering diseases that predominantly affect mucous membranes, with varying combinations of oral, ocular, cutaneous, genital, nasopharyngeal, oesophageal and laryngeal lesions. The case is reported of a man with multiple manifestations of mucous membrane pemphigoid. A 53-year-old male presented at our Department with a 4-year clinical history of diagnosed cicatricial pemphigoid. The patient was affected by ocular and urinary symptoms and presented with nasal obstruction and dysphonia. Nasal endoscopy revealed crusting and synechiae with pale and atrophic mucosa. Computed tomography examination showed hypodense-hyperdense material occupying all paranasal sinuses and nasal fossae. Laryngoscopy showed anterior para commessural and inter-arytenoidal synechiae. The patient underwent functional endoscopic sinus surgery for incision of synechiae and removal of scars and inflammatory material from all sinuses. Nasal splints were then inserted. A wait and-see policy was adopted for the laryngeal lesion. One year later, the splints were removed; the upper airways were still free and there were no signs of nasal obstruction. An endoscopic approach appears to be efficacious in the surgical treatment of nasal cicatricial pemphigoid, and long-term stenting may be necessary to avoid recurrence. Although surgery has not a curative role in long term therapeutic strategies, it may, nonetheless, improve the quality of life and ensure good nasal respiration. PMID- 20161883 TI - Some remarks on the revival of rhinoplasty in Europe in the early nineteenth century. PMID- 20161885 TI - Zizyphus spina-christi extract protects against aflatoxin B1-initiated hepatic carcinogenicity. AB - Aflatoxins (AF), a group of closely related, extremely toxic mycotoxins, produced by Aspergillus flavus and A. parasiticus can occur as natural contaminants of foods and feeds. Aflatoxins have been shown to be hepatotoxic, carcinogenic, mutagenic, and teratogenic to different animal species. Zizyphus spina-christi L. extract was investigated for its antifungal and antimicrobial activities. The aim of the present work was to evaluate the antioxidant activity of the methanol extract of Z. spina-christi L. leaves against the oxidative stress of aflatoxin in rats. Fourty male Sprague-Dawley male rats were divided into four groups including the control group, the group fed aflatoxin-contaminated diet (3 mg/kg diet) and the groups treated with Zizyphus extract (5 mg/kg b.w) alone or in combination with AF for 15 days. Biochemical analysis revealed that treatment with AF resulted in a significant increase in ALT, AST, cholesterol, triglycerides, uric acid, TNFa, LPO, NO and CEA, whereas it decrease significantly GPX and SOD. The histopathological examination of the liver, kidney and testis showed sever histological changes typical to those reported for aflatoxicosis. Animals treated with Zizyphus extract alone or plus AF showed a significant improvement in all biochemical parameters and histological picture of liver, kidney and testis. It could be concluded that Zizyphus extract have a power protective role against aflatoxicosis. PMID- 20161886 TI - Flavonoid glycosides from Byrsocarpus coccineus leaves. Schum and Thonn (Connaraceae). AB - The bioactive ethyl acetate and N-butanol soluble parts of an ethanolic extract of Byrsocarpus coccineus leaves was subjected to column chromatography over silica gel G (60-120 microns) and repeated purification of the flavonoid rich fraction over sephadex LH-20 eluted with methanol led to the isolation of three flavonoid glycosides identified as quercetin 3-O-alpha-arabinoside (I), quercetin (II) and quercetin 3-beta-D-glucoside. Their structures were elucidated by (1)H and (13)C-NMR data and are reported here for the first time in this plant. PMID- 20161887 TI - Spasmogenic effect of the aqueous extract of Tamarindus indica L. (Caesalpiniaceae) on the contractile activity of guinea-pig taenia coli. AB - The effect of aqueous extract of Tamarindus indica (AETI) was studied on the guinea pig taenia coli, due to its use for treatment of constipation in traditional medicines. AETI, at concentrations ranging from 10(-8) mg/ml to 10( 2) mg/ml, increased the spontaneous contractile activity of guinea pig taenia coli in a dose-dependent manner (EC50 = 4x10(-6) mg/ml). This activity was unaffected by atropine. In high K(+), Ca(2+)-free solution containing EDTA, AETI as well as acetylcholine, used as a control, induced tonic contraction. These results suggest that the plant extract exert a spasmogenic effect that would not involve cholinergic mechanism of action. However, these active principles could mobilize both extra cellular calcium and intracellular calcium from internal stores. PMID- 20161888 TI - Comparative chemical and analgesic properties of essential oils of Cymbopogon nardus (L) Rendle of Benin and Congo. AB - The chemical and analgesic comparison of essential oils of Cymbopogon nardus (L) Rendle of Benin and Congo was investigated. The chemical analysis wa carried out by using GS/MS for identification of components of the two essential oils while acetic acid-induced writhings, hot plate and tail flick test models were used for analgesic activity. The results showed that the two essential oils exhibited comparable activity on acetic acid-induced writhings, however, the essential oil of Benin induced more significant effect on hot plate model while the Congolese specie showed more effect in the tail flick test. These observations could be explained by some qualitative and/or quantitative differences observed between the constituents of the two essential oils studied. PMID- 20161889 TI - Self-reported use of traditional, complementary and over-the-counter medicines by HIV-infected patients on antiretroviral therapy in Pretoria, South Africa. AB - Current management of HIV involves the use of conventional prescription medicines, called 'antiretroviral drugs' (ARV), over-the-counter (OTC), complementary and alternative medicines (CAM), as well as African traditional medicine (ATM). The aim of this study was to determine the prevalence of use of traditional, complementary and over-the-counter medicines. A cross-sectional survey of HIV-infected patients who started ART between July 2004 and August 2005 at Dr George Mukhari Hospital (Pretoria), who consented to be interviewed, was conducted. Using a pre-tested structured questionnaire, data were collected by two trained interviewers on sociodemographic characteristics, and on non prescribed medicines used of three sources: African traditional medicine (ATM), complementary and alternative medicine (CAM), and over-the-counter (OTC) medicines. The 180 patients who consented to be interviewed had a mean age of 36.7 (+/-8.1) years old; 68.8% were female, 86.7% unemployed, 73.9% with high school level of education, 77.8% single. Some 8.9% of respondents used at least one non-prescribed medicine. In descending order, 4.4% of respondents used ATM, 3.3% CAM, and 1.7% OTC medicines. The ATM products used included unspecified traditional mixtures, and those made of the African potato (Hypoxis hemerocallidea), and coconut (Cocos nucifera); OTC products used were paracetamol and sennosides (Senokot) tablets as well as a soap containing triclosan 1.5%; CAM products used were "sex booster" capsules of unknown composition, mercury containing soaps (Mekako), and the Zion Church of Christ special tea, a mixture of Rooibos tea (Aspalathus linearis) plus sunflower oil (Helianthus annuus) and prayed for. In conclusion, only 8.9% of HIV-infected patients on ART in this study used a limited range of over-the-counter products as well as those from traditional, complementary and alternative medicine practices. PMID- 20161890 TI - Hypolipidemic activities of Ficus racemosa Linn. bark in alloxan induced diabetic rats. AB - Ficus racemosa (Moraceae family) is used in traditional system of medicine for the treatment of several disorders including diabetes mellitus. The aim of the study was to investigate the antihyperglycemic and hypolipidemic activities of ethanolic extract of Ficus racemosa bark (FrEBet) in alloxan-induced diabetic rats. A total number of 30 animals were divided into 5 groups of six each. Diabetes mellitus was induced by single intraperitoneal injection of freshly prepared solution of alloxan monohydrate (150 mg/kg bw) dissolved in physiological saline in overnight fasted wistar rats. Dose dependent studies for FrEBet (100-500 mg/kg bw) was carried out to find out the effective pharmacological dose (antidiabetic and hypolipidemic) to alloxan-induced diabetic rats. Blood glucose, plasma insulin, total cholesterol, phospholipids, triglycerides, free fatty acids, HDL cholesterol and LDL cholesterol levels in plasma, erythrocyte membranes, liver and kidney were determined by specific colorimetric methods. An increase in blood glucose was accompanied by an increase in total cholesterol, phospholipids, triglycerides, FFA and decrease in HDL cholesterol in diabetic rats. Oral administration of FrEBet (300 mg/kg bw) to diabetic rats restored the status of blood glucose, lipids and lipoproteins to near normal range. Our investigation thus shows that FrEBet has potent antidiabetic and hypolipidemic effects in alloxan-induced diabetic rats and these effects were much comparable to that of the standard reference drug, glibenclamide. PMID- 20161891 TI - Lipid fraction constituents and evaluation of anti-anaphylactic activity of Prunus mahaleb L. kernels. AB - The lipid fraction constituents as well as evaluation of anti-anaphylactic activity of Prunus mahaleb L. kernels were studied. Prunus mahaleb L. kernels were obtained from the local market in Cairo, Egypt. Investigation of the fatty acids revealed that oleic and linoleic acids are the major constituents. 12 compounds were identified from the hydrocarbon fraction. The sterol fraction comprises of cholesterol, stigmasterol, beta-sitosterol and campesterol. The pharmacotoxicity studies were carried out on total and defatted ethanolic extracts as well as the oil fraction. The oil fraction proved to be extremely safe and free from any acute lethal toxicity in intraperitoneal (i.p.) and oral doses up to 100 ml/kg. In vivo assessment of prophylactic efficacy was afforded by 7 days course of daily medication schedule of sensitized adult male guinea pigs against ovalbumin bronchospasm. The prophylactic anti-inflammatory activity of the total ethanolic extract was higher than that of the defatted ethanolic extract. In addition, the lipid fraction of Prunus mahaleb L. kernels evoked complete anti-inflammatory efficacy among the survival animals receiving low and medium doses. PMID- 20161892 TI - Piptaderol from Piptadenia africana. AB - A new glyceryl derivative (Glyceryl-1-hexacosanoate) and a flavone derivative (methyletherapigenin) were isolated from the stem bark extract of Piptadenia africana, a western Cameroonian plant species. Common terpenes like sitosterol, beta-amyrin and eicosane were also isolated. These compounds were identified using physical and spectroscopic methods including mp, IR, (1)H and (13)C-NMR, DEPT, COSY, HMQC, HMBC, EI MS, HREI MS as well as some chemical transformations. The antibacterial activity of the extract, the fractions and the pure compounds is also discussed. PMID- 20161894 TI - Phenolic compounds and bioactivity of leaves of Mayodendron igneum Kurz. AB - Four apigenin glycosides were isolated from the ethyl acetate extract of the leaves of Mayodendron igneum Fam.Bignoniaceae. They were identified as apigenin 7 O-glucoside; 6-methoxy apigenin-7-O-glucoside; 6-methoxy apigenin-7-O rhamnoglucoside and 6-hydroxy apigenin-7-O-rhamnoglucoside. In addition an isoflavone glycoside was isolated, and identified as genistin 5,4'-methyl ether. Ethanol (80%) extract of Mayodendron igneum leaves exhibited significant anti inflammatory and analgesic activities. LD(50) determination of the extract indicated the safety of the leaves of the plant. PMID- 20161893 TI - Effect of walnut leaf, coriander and pomegranate on blood glucose and histopathology of pancreas of alloxan induced diabetic rats. AB - Mechanism of most of herbal used for diabetes mellitus treatment has not been well defined. This study was performed to investigate hypoglycemic effect of walnut leaf (Juglans regia L.), coriander leaf (Coriandrum sativum L.) or pomegranate seed (Punica granatum L.), and their possible role on pancreatic tissue. Diabetes mellitus was induced in 20 adult male Sprague Dawley rats and the animals were divided into four groups; three of them fed a diet supplemented with about 15 gram (60 g/ kg body weight /day) of mentioned plants for 15 days. The fourth diabetic untreated group (positive control) and a non-diabetic group (negative control) received standard diet. Blood glucose was measured every day and on the last day pancreases were isolated and stained with hematoxylin & eosin (H&E) and Gomeri aldehyde fuchsin (GAF). Histomorphology and following morphometric factors were studied; Volume density of beta cells, volume density of islets, percent of beta cells, number of islets per square centimeter and average area of islets. The results of this study indicate that only walnut leaf was able to reduce blood glucose significantly compared with diabetic untreated group (9.029 vs. 14.358 mmol/l) (P<0.05). Hypercellularity of islets tissue, increased hyperchromic nucleus in pancreatic islets of this group was obvious. Density of islets in pancreatic tissue, percent of beta cells and islets size increased significantly in this group in comparison with diabetic untreated group which may signify regeneration of islets or beta cells in group received walnut leaf (P<0.05). PMID- 20161895 TI - Antimicrobial activity of some Indian medicinal plants. AB - The antimicrobial potential of seventy-seven extracts from twenty-four plants was screened against eight bacteria and four pathogenic fungi, using microbroth dilution assay. Lowest concentration of the extract, which inhibits any visual microbial growth after treatment with p-iodonitrotetrazolium violet, was considered to be minimum inhibitory concentration (MIC). Water extracts of Acacia nilotica, Justicia zelanica, Lantana camara and Saraca asoca exhibited good activity against all the bacteria tested and the MIC was recorded in range of 9.375-37.5 microg/ml and 75.0-300.0 microg/ml against the bacterial and fungal pathogens, respectively. The other extracts of Phyllanthus urinaria, Thevetia nerifolia, Jatropha gossypifolia Saraca asoca, Tamarindus indica, Aegle marmelos, Acacia nilotica, Chlorophytum borivilianum, Mangifera indica, Woodfordia fruticosa and Phyllanthus emblica showed antimicrobial activity in a range of 75 1200 microg/ml. PMID- 20161896 TI - Indian systems of medicine: a brief profile. AB - Medicinal plants based traditional systems of medicines are playing important role in providing health care to large section of population, especially in developing countries. Interest in them and utilization of herbal products produced based on them is increasing in developed countries also. To obtain optimum benefit and to understand the way these systems function, it is necessary to have minimum basic level information on their different aspects. Indian Systems of Medicine are among the well known global traditional systems of medicine. In this review, an attempt has been made to provide general information pertaining to different aspects of these systems. This is being done to enable the readers to appreciate the importance of the conceptual basis of these system in evolving the material medica. The aspects covered include information about historical background, conceptual basis, different disciplines studied in the systems, Research and Development aspects, Drug manufacturing aspects and impact of globalization on Ayurveda. In addition, basic information on Siddha and Unani systems has also been provided. PMID- 20161897 TI - In vitro antimicrobial activity of crude extracts from plants Bryophyllum pinnatum and Kalanchoe crenata. AB - Extracts from the leaves of Bryophyllum pinnatum and Kalanchoe crenata were screened for their antimicrobial activities. Solvents used included water, methanol, and local solvents such as palmwine, local gin (Seaman's Schnapps 40% alcoholic drink,) and "omi ekan-ogi" (Sour water from 3 days fermented milled maize). Leaves were dried and powdered before being soaked in solvents for 3 days. Another traditional method of extraction by squeezing raw juice from the leaves was also employed. All extracts were lyophilized. These extracts were tested against some gram-negative organisms (Escherichia coli ATCC 25922, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Shigella flexneri, Salmonella paratyphi, Citrobacter spp); gram-positive organisms Staphylococcus aureus ATCC 25213, Staphylococcus aureus, Enterococcus faecalis, Bacillus subtilis) and a fungus (Candida albicans). Agar well diffusion and broth dilution methods were used to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) at concentrations of 512 mg/ml to 4 mg/ml. All the organisms except Candida albicans were susceptible to the extracts obtained from the traditional method. The squeezed-leaf juice of Kalanchoe crenata was the most active one with MIC of 8 mg/ml against Pseudomonas aeruginosa, Klebsiella pneumoniae and Bacillus subtilis, 32 mg/ml against Shigella flexneri, 64 mg/ml against Escherichia coli and 128 mg/ml against the control strain Staphylococcus aureus while its MBC is 256 mg/ml against these organisms except Bacillus subtilis and Klebsiella pneumoniae. The gram-positive organisms were more sensitive to the methanol and local gin-extract of Bryophyllum pinnatum. Extracts from other solvents showed moderate to weak activity. PMID- 20161898 TI - Apoptosis inducing effect of andrographolide on TD-47 human breast cancer cell line. AB - Andrographolide isolated from Andrographis paniculata Ness (Acanthaceae) at 0.35 mM, 0.70 mM and 1.40 mM induced DNA fragmentation and increased the percentage of apoptotic cells when TD-47 human breast cancer cell line was treated for 24, 48 and 72 h. The results demonstrated that andrographolide can induce apoptosis in TD-47 human breast cancer cell line in a time and concentration-dependent manner by increase expression of p53, bax, caspase-3 and decrease expression of bcl-2 determined by immunohistochemical analysis. PMID- 20161899 TI - Antibacterial activities of the extracts and conessine from Holarrhena floribunda G. Don. (Apocynaceae). AB - The methanolic extract and conessine isolated from the stem bark of Holarrhena floribunda (Hf) were tested for their antibacterial activities on Bacillus: Bacillus cereus, Bacillus subtilis, Bacillus megaterium and Bacillus stearothermophilus using the disc diffusion method. Phytochemical analysis of the crude extract and fractions was also conducted. The inhibition parameters of the crude methanol extract and the total alkaloid fraction were determined using the macrodilution method. The results showed that the crude extract, the total alkaloid fraction and conessine exhibited a significant antibacterial effect against all the strains studied. The antibacterial effect of conessine is almost similar to that of chloramphenicol used as reference. The ratio of the minimal bactericidal concentration (MBC) over the minimal inhibitive concentration (MIC) indicates the bactericidal effect of the plant. These results support common use of stem bark of Hf and conessine isolated from Hf in the treatment of some infectious diseases. PMID- 20161900 TI - Hints on writing for publication. PMID- 20161901 TI - Antihyperglycemic effects of separate and composite extract of root of Musa paradisiaca and leaf of Coccinia indica in streptozotocin-induced diabetic male albino rat. AB - We evaluated the antihyperglycaemic properties of aqueous-methanolic (40:60) extract of root of Musa paradisiaca and leaf of Coccinia indica in separate as well as in composite manner by conducting experiment on streptozotocin-induced diabetic rats. We measured food and water intake ability, the fasting blood glucose level, glucose tolerance, activities of important carbohydrate metabolic enzymes like glucose-6-phosphatase, glucose-6-phosphate dehydrogenase, hexokinase in liver along with quantification of glycogen in liver and in skeletal muscle and serum insulin level. We noted that after treatment of aqueous methanolic extract of above plant parts in separate as well as in composite manner at a concentration of 80 mg/100 g body weight/day to streptozotocin-induced diabetic rat resulted in a significant remedial effect on blood glucose level as well as carbohydrate metabolic enzymes and the quantity of liver and skeletal muscle glycogen. Serum insulin level that was diminished in streptozotocin-induced diabetic rat recovered significantly after the co-administration of extract of above plant parts. All the above parameters showed a more potent remedial effect after composite extract treatment with respect to separate treatment and none of the extract has any general metabolic toxicity induction. PMID- 20161902 TI - Anti-inflammatory and antimicrobial activities of Hippocratea indica root bark and Poga oleosa fruits. AB - The methanolic extracts of Hippocratea indica root bark and Poga oleosa fruits were investigated for anti-inflammatory and antimicrobial activities. Both extracts inhibited carrageenan-induced paw oedema significantly in rats in a dose dependent manner in 4 h. H. indica inhibited oedema significantly at the minimal dose (125 mg/ml, p< 0.05) from 2 h onward, and gave 100% inhibition in 4 h. at 250 mg/kg. It was shown to be a more potent anti-inflammatory agent than P. oleosa. Also, H. indica extract exhibited greater antimicrobial activity against tested bacteria, with Staphylococcus aureus being the most susceptible bacterium (MIC, 16 mg/ml). Both plants were inactive against Candida albicans. These results confirm the anti-inflammatory and antibacterial activities of the two plants. PMID- 20161903 TI - Professional responsibilities to custodians of traditional knowledge. PMID- 20161904 TI - Poverty and development in Africa: more action is required from stakeholders. PMID- 20161905 TI - Isolation of a stilbene glycoside and other constituents of Terminalia sericeae. AB - The ethanol extract of the root bark of Terminalia sericea yielded an unreported stilbene glycoside, 3'5'-dihydroxy-4-(2-hydroxy-ethoxy) resveratrol-3-O-beta rutinoside (1) together with known compounds resveratrol-3-beta-rutinoside glycoside (2), 3',4,5'-Trihydroxystilbene (resveratrol) (3), triterpenoic acid arjungenin and a mixture of beta-sitosterol and stigmasterol. Structure determination of the isolated compounds was achieved on the basis of spectroscopic measurements. PMID- 20161906 TI - Hypoglycemic effect of Treculia africana Decne root bark in normal and alloxan induced diabetic rats. AB - The solvent partitioned purified fractions of the hydro-acetone root bark extract of the African breadfruit (Treculia africana Decne) were evaluated for hypoglycemic activities in normal and diabetic albino rats. Fasting blood glucose levels were estimated by the use of a glucometer at pre-determined intervals after oral administration of the test extracts/fractions. Results revealed that the test fractions have only a slight effect on blood sugar level of normal rats. On short term and chronic administration in diabetic rats however, diethyl ether soluble (DEF) and the water-soluble (WSF) fractions significantly reduced the fasting blood sugar levels (p<0.05) at differing rates when compared with the control group of animals. The diethyl ether soluble fraction (10 mg kg(-1) dose level) was found to exhibit the highest activity giving 69.4% reduction in blood sugar level (at 240 hours) which was in comparable range with the reference standard glibenclamide (0.5 mg kg(-1)) which reduced blood sugar levels by 65.8% below the initial baseline values. PMID- 20161907 TI - Antimicrobial effects of the stem bark extracts of Parkia biglobosa (Jacq.) Benth. on Shigellae. AB - Total and hydroalcoholic extracts of the stem barks of Parkia biglobosa (Jacq) Benth. (Mimosaceae) were tested on strains belonging to three species of Shigellae: S. dysenteriae, S. flexneri and S. boydii collected from hospitals in Ouagadougou, Burkina Faso. The results showed that both extracts were active against Shigellae. The hydroalcoholic extract was more active than the decoction (aqueous one) prescribed by the traditional healer. Both extracts were particularly effective against S. dysenteriae, the most virulent of the three pathogenic species. The effects of the extracts have been compared to that of gentamicin. The phytochemical screening on the extracts revealed the presence of sterols, triterpenes, polyphenolic compounds including tannins, flavonoids, coumarins, anthocyanidins. Other components are saponosides and reducing sugars. PMID- 20161908 TI - Artocarpus communis Forst. root-bark aqueous extract- and streptozotocin-induced ultrastructural and metabolic changes in hepatic tissues of Wistar rats. AB - Decoctions and infusions of Artocarpus communis (Forst.) (family: Moraceae) root bark are commonly used traditionally among the Yoruba-speaking people of Western Nigeria as folk remedies for the management, control and/or treatment of an array of human diseases, including type 2, adult-onset diabetes mellitus. Although numerous bioactive flavonoids have been isolated from the roots, stem-bark and leaves of A. communis, to the best of our knowledge, the effects of the plant's root-bark extract on animal model of diabetes mellitus and on liver tissues have hitherto, not been reported in the biomedical literature. In view of this, the present study was undertaken to investigate the glycaemic effect of, and hepatic tissue ultrastructural, morphological and metabolic changes induced by A. communis root-bark aqueous extract (ACE) in Wistar rats. The ultrastructural, morphological and metabolic effects of ACE have been compared with those induced by streptozotocin (STZ) in rat experimental paradigms. Four groups (A, B, C and D) of Wistar rats, each group containing 10 rats, were used. Diabetes mellitus was induced in the diabetic groups B and C animals by intraperitoneal injections of STZ (75 mg/kg body weight), while group A rats received A. communis root-bark aqueous extract (ACE, 100 mg/kg body weight, i.p.) alone. Control group D rats received distilled water in quantities equivalent to the volume of ACE administered intraperitoneally. The rats in group C were additionally treated with ACE (100 mg/kg body weight i. p.) daily from day 3 to day 10 after STZ treatment. Hepatic glucokinase, hexokinase, glutamate dehydrogenase, succinate dehydrogenase, beta-hydroxybutyrate dehydrogenase, serum insulin and blood glucose levels of the animals were measured and recorded before and after ACE, STZ and STZ+ACE treatments. Hepatic tissues were also processed for transmission electron microscopy. Electron microscopic examinations showed toxic, deleterious alterations in the ultrastructures of groups A, B and C hepatic cells, the most prominent deleterious effects being on the hepatocytes. Ultrastructural changes observed within the hepatocytes of groups A, B and C rats include disrupted mitochondria with increase in lipid droplets, extensive hepatocellular vacuolation, scanty rough endoplasmic reticulum (RER) and ribosomes. Large glycogen clusters were also noticed displacing the mitochondria and RER in group A rats. Group A rats also developed significant hyperglycemia (p<0.05) immediately after ACE administration, while groups B and C rats developed hyperglycemia 24 hours after STZ treatment. When compared with the control group D rats, the activities of all the three subsystems were disrupted, leading to overall inhibition of oxidative phosphorylation of the liver mitochondria in groups A, B and C rats, but remain normal in the untreated group D control rats. The findings of the present study indicate that A. communis root-bark aqueous extract induces hyperglycaemia in the experimental animal model used, and that the plant's extract disrupts the ultrastructural characteristics and architecture of hepatocytes as well as oxidative energy metabolism. PMID- 20161909 TI - Anti-inflammatory and anti-nociceptive activities of methanolic extract of the leaves of Fraxinus floribunda Wallich. AB - Fraxinus floribunda Wallich (Family-Oleaceae) is a wide green tree in the sub alpine region of Sikkim, India. The methanolic extract of the leaves of Fraxinus floribunda (MEFF) at 100, 200 and 400 mg/kg/p.o was screened in rats for anti inflammatory activity by acute-carrageenan induced paw edema, sub-acute cotton pellet induced granuloma and chronic Freund's adjuvant induced arthritis models. In all the three models of anti- inflammatory studies 200 and 400 mg/kg/p.o doses of the extract showed significant effect (P<0.001). Antinociceptive evaluation was performed by writhing and tail-immersion tests in mice. Anti-nociceptive evaluation revealed that MEFF at the dose of 400 mg/kg/p.o had significant activity against the control. The relieving effect was through the peripheral and central mechanism of action of the extract. This study rationalized the ethno medicinal use of the plant for relieving pain in inflammatory pathological conditions like fracture and dislocation. PMID- 20161910 TI - Chemical composition, cytotoxic activity and antimicrobial activity of essential oils of leaves and berries of Juniperus phoenicea L. grown in Egypt. AB - Hydrodistillation of berries and leaves of Juniperus phoenicea grown in Sinai yielded volatile oils in the yield of 0.36 and 1.96%, respectively. Using gas chromatography/mass spectrometry technique, fifty eight compounds were identified in berry oil representing 99.2% of the oil composition. alpha-Pinene was the major compound in berry oil (39.30%) followed by sabinene (24.29%). Berry oil composed mainly of monoterpenoids which amounted to 90.53%, of which 72.85% was monoterpene hydrocarbons. The sesquiterpenoids accounted for about 8% of the total oil composition. Leaf oil was composed of about 66 compounds representing 99.16% of the total composition of the oil. alpha-Pinene was the major constituent of leaf oil at concentration of 38.22%, followed by alpha-cedrol (31.23%). The monoterpene hydrocarbon was the predominant chemical group (41.29%) followed by the oxygenated sesquiterpenes (32.21%). Both oils showed very high cytotoxic activities against all cell line tested. They showed equal activities against brain (0.6 microg/ml) and cervix (5.0 microg/ml) human cell lines, while berry oil was slightly more active than leaf oil against lung (0.6 and 0.7 micro/ml, respectively), liver (0.7 and 0.9 microg/ml, respectively) and breast human cell lines (0.8 and 1. microg/ml, respectively).The antimicrobial activity and minimum inhibitory concentration (MIC) of leaf and berry oils were also determined. The oils showed high activity against most of the tested strains. PMID- 20161911 TI - Synergistic antimicrobial activities of phytoestrogens in crude extracts of two sesame species against some common pathogenic microorganisms. AB - Intensive studies on extracts and biologically active compounds isolated from medicinal plants have doubled in the last decade worldwide. However, as a result of paucity of knowledge and folkloric claim on the effectiveness of sesame leaves in infectious disease treatments, we aimed to determine the synergistic antimicrobial activity of essential oils and lignans present in the crude leaves extracts of Sesame radiatum and Sesame indicum. Ethanolic, methanolic and aqueous extracts of both leaves were studied for their in-vitro synergistic antimicrobial activity against both gram positive and gram negative micro-organisms, and Yeast using Agar diffusion method. The GC-MS phytochemical screening of methanolic extract showed that the major compounds in essential oils are of carboxylic acids and phenolic groups especially, the most potent antioxidants known to man like sesamol, sesamolin and sesamin among others. Methanolic and ethanolic extracts have broad spectrum antimicrobial effect against all the tested pathogenic micro organisms except Streptococcus pneumoniae and Staphylococcus aureus respectively, while the aqueous extract exhibited inhibitory activity on Staphylococcus aureus, Streptococcus pneumoniae and Candida albicans. The result confirmed the folkloric claims of the antimicrobial effectiveness of locally consumed sesame leaves extracts especially against bacterial and common skin infection in many areas of Nigeria. PMID- 20161912 TI - Ethno-veterinary practices amongst small-holder farmers in Ekiti state, Nigeria. AB - This paper aimed at identifying factors influencing the use of ethno-veterinary practices amongst goat and poultry farmers in Ekiti state, Nigeria. It specifically described the socio-economic characteristics of the farmers; identified some diseases of goats and poultry with their corresponding indigenous cures; presented the procedures used in developing some of the ethno-veterinary medicine amongst farmers; identified the reasons for using ethnoveterinary practices; analysed the ecological factors influencing ethno-veterinary practices; identified the roles played by institutions in the utilisation of ethno-veterinary practices; and examined the benefits and problems associated with ethno-veterinary practices in Ekiti State, Nigeria. A multi-stage sampling procedure was used to select 100 respondents from ten communities, namely: Otun Ekiti, Igogo-Ekiti, Osin-Ekiti, Omuo-Ekiti, Ilasa-Ekiti, Araromi-Ekiti, Efon Alaaye, Oba-Ayetoro, Ise-Ekiti, and Orun-Ekiti. Pre-tested structured and unstructured interview schedules were used to collect quantitative data, while Focused Group Discussions (FGDs) were used to elicit qualitative data from the respondents. Frequency distribution, percentages, means and standard deviation were used to describe the data. Inferential statistics such as correlation and Chi-Square analyses were used to make deductions. The correlation result showed that at p < or = 0.05 level of significance, age (r = 0.368), family size (r = 0.114) and association membership (r = 0.231) were positively and significantly correlated with the utilisation of ethno-veterinary practices while education level (r = 0.342), farming scope (r = -0.261,) and cosmopoliteness (-0.135) had negative but significant correlation with the utilisation of ethno-veterinary practices. Some of the problems (associated with the use of indigenous knowledge) identified by the farmers were lack of institutional support and the seasonal nature of some medicinal plants. It is, thus, suggested that all identified constraints need be removed by government to enhance the use of low-external inputs for sustainable agricultural development. PMID- 20161913 TI - Evolving concepts related to achieving benefit sharing for custodians of traditional knowledge. AB - In the context of evolving intellectual property law, defining ownership of traditional knowledge can be challenging when claims of origin are conflicting and requires accepting parameters of how uniqueness is defined and patent law is applied to protect this information. For purposes of this paper, the complexities of evolving benefit sharing for custodians of traditional knowledge are discussed in relationship to the use of medicinal plants. Parameters of ownership can vary not only by the perception of individuals that lay claim to the information but also by international, regional and national laws that govern how benefits should be fairly appropriated. Examples are provided to exemplify the wide variation that presently exists in this evolving process with illustrations of how this information, novel or otherwise, can be utilized to optimize its commercial worth. PMID- 20161914 TI - Traditional leafy vegetables in Senegal: diversity and medicinal uses. AB - Six administrative regions of Senegal were investigated. Forty species of vegetable leaves which are traditionally consumed in Senegal have been inventoried. All species are members of twenty-one families the most numerous of which are Amaranthaceae Juss., Malvaceae Juss., Moraceae Link., the Papilionaceae Giseke and Tiliaceae Juss. The species are subdivided into three groups: cultivated leafy vegetables, plants gathered annually, perennial sub-ligneous and ligneous species. The gathered species represent 67.5% of the inventory, 40.7% of which is ligneous. Cultivated species account for 32.5% of the inventory. The species are consumed for their medicinal properties, nutritive value and eating habits linked to specific ethnic traditions. During the drought years, with the scarcity of main food (millet, mays) consumption of leafy vegetables is high. All species reported except Sesuvium portulacastrum L. are consumed like vegetable herbs. The species of Hibiscus are eaten in spinach and condiment form while Sesuvium portulacastrum L is cooked in salad. Of the forty species examined, eleven are widely consumed. Within the entire study area, Hibiscus sabdariffa predominates among species consumed, followed by Moringa oleifera Lam. and Senna obtusifolia Link. A high consumption level of some species like amarante, Corchorus tridens L., Corchorus aestuans L., Leptadenia hastata Decne. and Vigna unguiculata (L.) Walp is confined to certain areas. In addition to their consumption as vegetables, the medicinal uses of 57.5% of these is of primary importance. The most commonly exploited parts are, respectively, leaf (40%), roots (20%), and bark (13.3%). Among the numerous pathologies treated, abscess, constipation, and rheumatism are predominant followed by aphrodisiac uses. The Amaranthus spp. L., Leptadenia hastata Decne., Senna obtusifolia Link., Adansonia digitata L. and Tamarindus indica L. are species with multiple medicinal uses. PMID- 20161915 TI - Phytochemical and in vitro antimicrobial assay of the leaf extract of Newbouldia laevis. AB - The methanolic leaf extract of Newbouldia laevis was subjected to preliminary phytochemical screening and in-vitro antimicrobial tests. The extract revealed the presence of flavonoids, tannins, terpenes, steroidal and cardiac glycosides. The antimicrobial activity of the plant extract was assayed by the agar plate disc diffusion and nutrient broth dilution techniques. Test microorganisms were Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Salmonella typhi, Klebsiella spp. and Candida albicans; all the organisms were laboratory isolates. The extract inhibited the growth of all the test organisms especially against Klebsiella spp. and S. aureus which had mean inhibition zone of 42.3+/ 1.5 and 32.3+/-1.5 mm respectively. The results showed minimum inhibitory concentration (MIC) of 1.563 mg/ml against Escherichia coli and Klebsiella spp. and 3.125 mg/ml against Pseudomonas aeruginosa, Staphylococcus aureus and Salmonella typhi. The minimal bactericidal concentration (MBC) against Escherichia coli and Staphylococcus aureus was 0.39 mg/ml. This study has justified the traditional use of this plant for the treatment of stomach discomfort, diarrhea, dysentery and as a remedy for wound healing whose causative agents are some of the organisms used in this study. PMID- 20161916 TI - Antimicrobial, wound healing and antioxidant activities of Anthocephalus cadamba. AB - Anthocephalus cadamba (Roxb.) Miq. Syn A. chinensis (Lamk) A. Rich (Rubiaceae) is ethnomedicinally widely used in the form of paste by tribe in western Ghats for treating skin diseases. In this context, antimicrobial potential of A. cadamba against a wide range of microorganisms was studied. To validate the ethnotherapeutic claims of the plant in skin diseases, wound healing activity was studied, besides antioxidant activity to understand the mechanism of wound healing. The alchoholic and aqueous extract of this plant showed significant antibacterial and antifungal activity against almost all the organisms: Micrococcus luteus, Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and four fungi Candida albicans, Trichophyton rubrum--dermatophyte fungi, Aspergillus niger, Aspergillus flavus and Aspergillus nidulans--systemic fungi, with especially good activity against the dermatophyte (Trichophyton rubrum) and some infectious bacteria (Escherichia coli, Proteus mirabilis and Staphylococcus aureus) with an MIC of 2.5 microg/disc. The results show that A. cadamba extract has potent wound healing capacity as shown from the wound contraction and increased tensile strength. The results also indicated that A. cadamba extract possesses potent antioxidant activity by inhibiting lipid peroxidation and increase in the superoxide dismutase (SOD) and catalase activity. PMID- 20161917 TI - Phytochemical and antimicrobial effects of Chrozophora senegalensis. AB - The in vitro antimicrobial activities of the whole plant extract (ethanolic-CEE) of Chrozophora senegalensis and its fractions (ethyl acetate-EAA, n-butanol-NBE, aqueous-AQE) were assayed using the agar plate diffusion and nutrient broth dilution methods. Test microorganisms were Bacillus subtilis (NCTC 8326 B76), Escherichia coli (ATCC 11775), Pseudomonas aeruginosa (ATCC 10145), Staphylococcus aureus (ATCC 021001). Aspergillus flavus, Aspergillus niger, Candida albicans and Salmonella typhi--laboratory isolates. CEE, EAA and NBE inhibited all the test bacterial organisms and a fungus--Aspergillus flavus. AQE inhibited only Salmonella typhi and Bacillus subtilis. None of the extracts had activity on other 3 fungal organisms tested. CEE and EAA showed minimum inhibition concentration (MIC) of 0.390 and 3.125 mg/ml against S. typhi and E. coli, while NBE and AQE had MIC of 3.125 and 1.563 mg/ml against S. typhi respectively. NBE had an MIC of 12.500 mg/ml against E. coli. The minimum bactericidal concentration (MBC) of CEE and EAA was found to be <0.098 against S. typhi. The MBC of AQE was 12.5 mg/ml against E. coli and S. aureus, and 6.25 mg/ml towards P. aeruginosa. CEE and EAA exhibited similar antibacterial activities, followed by AQE. The extracts revealed the presence of carbohydrates, tannins, saponins, sterols determined by utilizing standard methods of analysis. This study has justified the traditional use of the plant for treating diarrhea, boils and syphilis. PMID- 20161919 TI - Karanga traditional medicine and healing. AB - In this paper we present the Karanga traditional system of therapy of illness and disease manifest in the treatments administered by the medical practitioners. In order to establish the traditional system of therapy of illness and disease, numerous interviews were carried out with healers, herbalists and elders in the field area. This enabled a systematic compilation of cases. There was also the pressing need to be present at rituals and instances where healing was effected and to observe therapeutic processes. PMID- 20161918 TI - Phytochemical studies and antioxidant properties of four medicinal plants used in Cameroon. AB - Four plants (Amphimas pterocaroides, Harungana madagascariensis, Myrianthus arboreus, and Cussonia barteri) that are commonly used in Cameroon for the management or reversal of anaemia were screened for their phytochemical content and antioxidant potential. Four extracts (methanolic, hydro-ethanolic, aqueous, and hydrolysed) from each of the plants were prepared and analysed. Qualitative phytochemical tests were used to detect the presence of alkaloids, tannins, saponins, flavonoids, glycosides and phenols, while three quantitative methods; Folin, Ferric Reducing Antioxidant Power (FRAP) and diphenyl-1, 2-picryl hydrazyl (DPPH) were used to determine the antioxidant potential of these extracts. With the exception of the extracts of Cussonia barteri (negative for triterpenes and phenols) and the aqueous extract of Harungana madagascariensis (negative result for cardiac glycosides and glycosides), all other extracts contained the phytochemicals tested. The highest antioxidant activities were observed in the hydrolysed extracts of each plant, while the aqueous extract showed the least activity irrespective of the method used. The presence of active phytochemical substances with antioxidant activities may provide substantial basis for the use of these plants in ethnomedicine. PMID- 20161920 TI - In vitro antimicrobial assay of plants used in traditional medicine in Bukoba Rural district, Tanzania. AB - Plants used in traditional medicine in Bukoba Rural district in Tanzania were evaluated for their in vitro antimicrobial activities. Plant materials from eight plant species (Harungana madagascariensis (Lam) Poir., Jatropha curcas L., Lantana trifolia L., Plectranthus barbatus Andr., Pseudospondias microcarpa Engl., Psorospermum febrifugum Spach, Teclea nobilis Del. and Vernonia adoensis [Warp.] SL) were collected based on ethnomedical information provided by traditional herbal practitioners. Results of the study indicate that extracts from the eight plant species were active against at least one or more of the test organisms (Bacillus subtilis, Staphylococcus aureus [gram positive], Escherichia coli, Pseudomonas aeruginosa [gram negative] and Candida albicans [Yeast]). A profile of secondary metabolites (alkaloids, terpenoids, triterpenes, phenolics, tannins, flavonoids, anthraquinones, flavonols/flavones and /or chalcones, sterols and saponins) was obtained for three plant species (Jatropha curcas L., Plectranthus barbatus Andr., and Pseudospondias microcarpa Engl.). The paper discusses the probable therapeutic basis of these traditional plants based on their secondary metabolite profiles and for the first time draws research attention to Bukoba Rural district as a source for plants with potential pharmaceutical applications. PMID- 20161921 TI - Anti-diarrheal activity of the leaf extracts of Daniellia oliveri Hutch and Dalz (Fabaceae) and Ficus sycomorus Miq (Moraceae). AB - The leaves of the plants Daniellia oliveri (Fabaceae) and Ficus sycomorus (Moraceae) used in diarrhea treatment in Hausa ethnomedicine of Northern Nigeria were investigated. The study was carried out on perfused isolated rabbit jejunum and castor oil-induced diarrhea in mice. The n-butanol extracts: NBD and NBF (0.16-3.2 mg/ml) caused a dose-dependent relaxation of isolated rabbit jejunum. The acute toxicity test for NBD and NBT in mice established an i.p LD(50) of > 4000 mg/kg for D. oliveri and 1131.4 mg/kg for F. sycomorus. In castor oil induced diarrhea, 80% protection was observed for D. oliveri at doses of 200 mg/kg and 60% protection was observed at 100 mg/kg and 50 mg/kg respectively. For F. sycomorus 100% protection was observed at doses of 120 mg/kg and 60 mg/kg, for the n-butanol extract. The antidiarrheal activity was comparable to loperamide 5 mg/kg. The result revealed that the extracts have pharmacological activity against diarrhea. PMID- 20161922 TI - Screening of traditionally used endemic Soqotraen plants for cytotoxic activity. AB - Thirty extracts obtained from 10 endemic plant species belonging to 8 plant families used in the traditional medicine in Socotra have been tested for cytotoxic activity against FL-cells. Extracts of Eureiandra balfourii and Commiphora ornifolia showed the strongest activity against FL-cells with IC(50) < 10 microg/ml and 39.3 microg/ml respectively. PMID- 20161923 TI - Biodiversity, globalisation and poverty. AB - The erosion of the stock of biodiversity on earth developed historically with the so-called voyages of discovery (and their antecedents), colonial conquests and the accompanying movements of natural products and peoples, i.e. movements of populations and genetic materials. These events happened with the development of technology and the so-called conquest, by man, of his environment and the appertaining development of specialization not only in industry but also in agriculture and environmental management. The development of specialization resulted in the homogenization of processes, products, inputs and input industries; this increased homogenization had the corollary of arrested heterogeneity across the board; what they call globalization is part of this process. The efficiency of homogenization, however, engendered new problems of fragility of human environment and of production and social relations and processes. The effects of this complex situation, in general terms and in terms of biodiversity in particular, have been more devastating for the more vulnerable regions, classes of people, and peoples of the world. A continuous rethinking of the epistemology and the social and political bases of existing policies on environment in general, and of biodiversity conservation in particular, has become imperative. PMID- 20161924 TI - Promoting sustainable economic growth and industrialisation: solution to mass unemployment and poverty. AB - This paper analysed the twin-problems of unemployment and poverty. The methodology adopted in the analyses was a combination of the historical and logico-mathematical research perspectives. The results showed that the technologically advanced nations (TANs) experienced mass unemployment, low productivity, high inflation and prevalent poverty problems for many centuries before they achieved industrial revolution (IR). When they achieved the modern IR, not only did the mass unemployment problem disappear, but also, there were not enough adults persons to fill the employment openings created by the industrialisation. Consequently, industrialists resorted to employing children who worked in factories for many hours everyday, and prevented them from receiving education. Unemployment and poverty, therefore are symptoms of stagnation and lack of industrialisation (the disease). The long-term solution to mass unemployment and poverty therefore is industrialisation, for there is no industrialised nation that is poor. The short-term solution is promoting sustainable economic growth and competence-building. However, because achieving sustainable economic growth, competence-building and industrialisation are learning processes, Nigeria and other developing nations need to develop good educational systems. They should also establish suitable frameworks for training university graduates, scientists and engineers in particular in a curriculum based scheme to acquire complementary practical skills in the economy outside campuses. This is how the poor nations can achieve sustainable growth, build-up individual and national competence, promote industrialisation and eliminate unemployment and poverty problems, speedily. PMID- 20161925 TI - Development and poverty: a symbiotic relationship and its implication in Africa. AB - Poverty is present everywhere but the kind in Africa is of great magnitude both in its spread and destitutive dimension. In other places any manifestation of poverty is a challenge to move forward but in Africa, the reverse is the case. Therefore the continent and international community are not happy about it, hence various programmes and strategies were put in place. Ironically there is little to show for it. For instance, about ten years before the end of millennium, the common slogan in Africa was 'water for all, food for all, education for all, health for all and so on by the year 2000'. The 'miracle' year 2000 has come and gone and water, food, education and health are not enjoyed by many citizens of the continent. Development is still illusive. In this paper I examine the issues of poverty and development in the context of deforestation/biodiversity a consequent effect of global warming being one of the major threats to humanity. Some questions are raised with a view to proffer recommendations that may move the continent forward. These are: What are the roots of poverty in Africa? Why should there be a symbiotic relationship between poverty and development in Africa? Can Africa really develop? PMID- 20161926 TI - Effectiveness and safety assessment of Mist Tonica, a herbal haematinic. AB - Anaemia is a widespread public health problem, and in Ghana it is the fourth leading cause of hospital admissions and the second factor contributing to death. Mist Tonica, an herbal haematinic produced by the Centre for Scientific Research into Plant Medicine (CSRPM), Ghana, was assessed for its effectiveness and safety in humans after Ethics Committee approval. Clinically established anaemic patients aged, 13 years and above, with haemoglobin levels less than 11.5 g/dl and 13.5 g/dl for females and males respectively were treated with Mist Tonica, 8.96 g/40 mls three times daily for two weeks. The mean haemoglobin rise per week caused by Mist Tonica was 1.92 (0.76) g/dl, range (1.66-2.55) g/dl/week and over 88% of the patients on Mist Tonica had their appetite for food improved. Haematological profile, liver and kidney functions were not adversely affected by Mist Tonica. Results of the study suggest that Mist Tonica is an effective and safe herbal haematinic. PMID- 20161927 TI - The need for enhancement of research, development, and commercialization of natural medicinal products in Nigeria: lessons from the Malaysian experience. AB - The use of natural medicinal products in modern medicine as complementary and alternative therapies is of the increase globally. More so in developing and third world countries where the cost of research and development of synthetic drugs is prohibitive and technological facilities as well as expertise are lacking. These, coupled with the crumbling health care management systems in many of such countries make herbal medicines attractive alternatives. The potential medicinal values of these plant products are not being properly harnessed and research and development (R&D) in this area are lagging behind. R&D and consultancy services span from phytochemical analysis, standardization and quality control of herbs, and dosage forms design to preclinical and clinical trials. This paper tries to highlight all the necessary steps needed to conduct research and development in this area and proposes the nitty-gritty needed to impose statutory regulations on ensuring the quality, safety, efficacy, and commercial distribution of such products. The paper examines these important issues and highlights by way of examples, some of the steps taken and the positive achievements of the people and government of Malaysia towards self reliance in the area of natural medicinal plant research. It is primarily intended to map out strategies on how Nigeria in conjunction with research and academic institutions can be actively involved in natural products R&D, taking the Malaysian experience as a prototype. It is also aimed at urging government's efforts to encourage research in this area and impose regulations for commercial production and distribution of such products. PMID- 20161928 TI - Standardization of a Siddha formulation Amukkara curanam by HPTLC. AB - Amukkara curanam, a Siddha formulation, currently used in all types of gastric disorders, rheumatic pain, insomnia and sexual insufficiency, was investigated for the estimation of the marker compounds, withaferine A and piperine contents in a prepared standard formulation and a commercial formulation by using HPTLC method of analysis. The two formulations were subjected to methanol, ethyl acetate and chloroform extractions by using Soxhhlet apparatus The chromatogram was developed using chloroform: methanol (8.5:1.5 v/v) and toluene: ethyl acetate (7:3 v/v) as mobile phases for the estimation of withferine A and piperine respectively. The detection and quantification were performed at a wavelength of 220 nm for withaferine A and 254 nm for piperine. The linear regression analysis of calibration plots of withferine A and piperine exhibited linear relationship in the range of 5-15 microg and 50-150 ng respectively, while the % recovery was found to be 94.52% w/w of withaferine A and 98.73% w/w of piperine, thus proving the accuracy and precision of the analysis. Methanol and ethyl acetate were found to be the suitable solvents for the extraction of withaferin A and piperine respectively. The withaferine A content in standard formulation was found to be much higher in all the three extracts than that of the commercial sample. However, the piperine content in all the three extracts of standard formulation was slightly lower than the respective extracts of commercial formulation. The proposed HPTLC method was found to be rapid, simple and accurate for quantitative estimation of withferine A and piperine in different formulation extracts. PMID- 20161929 TI - Anti-nociceptive and anti-inflammatory activities of aqueous leaves extract of Ocimum gratissimum (Labiate) in rodents. AB - The aqueous leaves extract of Ocimum gratissimum was investigated for anti nociceptive and anti-inflammatory effects in mice and rats. The models used to study the effect on nociception are the acetic acid-induced abdominal constriction test, hot-plate method in mice. The anti-inflammatory effect was investigated employing the formalin-induced hind-paw oedema in rats. The extract caused a significant (p<0.05), dose-dependent inhibition of acetic acid-induced writhing and hot-plate method. The extract also exhibited anti-inflammatory effect which was significant (P<0.001) at all the three doses. The intraperitoneal LD(50) value of the extract was 1264.9 mg/kg body weight in mice. Preliminary phytochemical screening revealed the presence of alkaloids, saponins, tannins and flavonoids. The results suggest the extract contained pharmacologically active principles, and supports the local application of the plant in painful and inflammatory conditions. PMID- 20161930 TI - Behavioural effects of the methanolic root bark extract of Securinega virosa in rodents. AB - Securinega virosa is used traditionally as sedative in children and in mental illnesses. In this study, the behavioral effects of methanolic root bark extract of S. virosa were investigated in mice. The results revealed that the extract significantly (P<0.05) and dose-dependently reduced the onset and prolonged the duration of sleep. The extract significantly (P<0.05) decreased exploratory activity and reduced the rate of apomorphine-induced stereotyped climbing at the doses tested (6.25-25 mg/kg). It also produced a significant and dose-dependent motor coordination deficit in mice at the doses tested (P<0.01). The intraperitoneal median lethal dose in mice was 774.6 mg/kg while the preliminary phytochemical screening revealed the presence of alkaloids, tannins, saponins and flavonoids. These results suggest that methanolic root bark extract of S. virosa contains biologically active principles that are sedative in nature and lend pharmacological credence to the ethnomedical use of the plant. PMID- 20161931 TI - Antidiabetic activity of Gladiolus psittascinus in alloxan induced diabetic rats. AB - The methanol extract of Gladiolus psittascinus bulb was evaluated for its antidiabetic activities in alloxan-induced diabetic rats. Blood glucose levels of the glucose loaded and alloxan-induced diabetic rats were estimated over 180 minutes using the O-toluidine and glucose-oxidase methods. The methanol extract at 1 g/kg dose exhibited 16.2% decrease in blood glucose level in the glucose loaded rats and a peak effect of 78.9% in the alloxan-induced diabetic rats. The extract exhibited significant blood glucose lowering effects in the oral glucose tolerance test and type 2 diabetic rats. This study shows a possible beneficial effect of Gladiolus psittascinus in the management of non-insulin dependent diabetes (NIDDM). PMID- 20161933 TI - Multi-plant or single-plant extracts, which is the most effective for local healing in Tanzania? AB - Use of multi-plant extracts against infectious diseases is increasing in rural Tanzania. The study evaluated this ethnomedicinal practice by using mixed root extracts of Carisa edulis, Ximenia caffra, Harrisonia abyssinica and Euclea natalensis against single extracts of the same plants. Disc diffusion assay and Tube dilution techniques were used to compare bioactivity of plant extracts in vitro. The ANOVA test indicated significant difference (P < 0.05) between these extracts types. Multi-plant extracts had inhibition zones of up to 26 mm as compared to 14 mm for single extracts. Minimum Inhibitory Concentration for multi plant extract was 8.3 microg/ml against 69 microg/ml for single extracts. Multi plant extracts inhibited all the five test bacterial species while single extracts inhibited three species. Eight out of ten multi-plant extracts (80%) were bactericidal while only two out of four single extracts (50%) were bactericidal. Generally, multi-plant extracts were more superior over single plant extracts and could be developed into more potent antibiotics against resistant pathogens. PMID- 20161932 TI - Hepatoprotective and antioxidant effects of Argyreia speciosa in rats. AB - The present study has been designed to evaluate the liver protective and in-vivo antioxidant role of Ethanolic extract (EtAS) and Ethyl acetate extract (EAAS) of roots of Argyreia speciosa, an important 'rasayana' herb in Indian System of medicine, in CCl(4)-induced hepatotoxicity and oxidative stress in rats. Animals were treated with EtAS and EAAS at doses of 200 mg and 400 mg/kg body weight p.o. along with CCl(4) (0.7 ml/kg in olive oil, 1:1 v/v i.p. on every alternate days) for seven days. Serum biochemical parameters such as SGOT, SGPT, ALP, cholesterol, total and direct bilirubin were determined. Antioxidant status in liver was determined by measuring the activities of Super oxide dismutase (SOD), catalase and peroxidase. Histopathological study of isolated liver specimens was also carried out to know the protection offered by the extracts. There was a significant rise in the levels of serum GOT, GPT, and ALP and other biochemical parameters, decrease in the levels of SOD, catalase and peroxidase after administration of CCl(4). Suspensions of EtAS and EAAS (200 and 400 mg/kg) successfully prevented the alterations of these effects in rats (p< 0.001). Histopathological examination demonstrated that CCl(4) treated group induces ballooning degeneration and centrilobular necrosis. Groups treated with EtAS and EAAS showed recovery on ballooning degeneration and centrolobular bridging necrosis was occasionally present. Data also showed that these extracts possessed strong antioxidant activity, and were comparable to Silymarin, a well known liver protecting herbal formulation. PMID- 20161934 TI - Phyto-constituents and anti-oxidant activity of the pulp of snake tomato (Trichosanthes cucumerina L.). AB - The phyto-constituents and antioxidant activity of the fruit pulp of Trichosanthes cucumerina L. have not been reported in literature and were therefore studied. Two identified morphotypes of this plant (Morphotype I [V1] having long fruit with deep green background and white stripes; and Morphotype II [V2] having light green coloured long fruit) were used for the studies. The dry matter contents of the pulp of the V1 and V2 were 10.9 and 9.6 g/100 g fresh weight (FW), while the ascorbic acid contents were 25.7 and 24.8 mg/100 g fresh weight (FW), and lycopene contents were 18.0 and 16.1 mg/100 g FW, respectively. The total phenolics, total flavonoids and total ferric reducing antioxidant power (FRAP) of V2 were significantly higher (P< 0.05) than that of V1 by 46.8%, 78.0% and 26.2%, respectively. Bulk of the carotenoids is made up of lutein in the concentration of 15.6 and 18.4 mg/100 g FW, for V1 and V2, respectively. The alpha-carotene contents were 10.3 and 10.7 mg/100 g FW while the beta-carotene contents were 2.4 and 2.8 mg/100 g FW for V1 and V2, respectively. It is concluded from the results of this study that the two morphotypes of T. cucumerina possess valuable nutraceutical properties that can qualify them as viable substitute to the Solanaceous tomato. PMID- 20161936 TI - Antimicrobial activity of essential oils of Ocimum gratissimum L. From different populations of Kenya. AB - Hydro-distilled volatile oils from the leaves of Ocimum gratissimum L. (Lamiaceae) of 13 populations of different silvicultural zones were evaluated for antimicrobial activity against gram positive (Staphylococcus aereus, Bacillus spp.) and gram negative (Escherichia coli, Pseudomonas aeruginosa, Samonella typhi, Klebisiella pneumoniae, Proteus mirabilis) bacteria and a pathogenic fungus, Candida albicans. All the essential oils are active to the tested microbiles with different strength. The highest antimicrobial activity against gram positive bacteria (Staphylococcus aureus) and gram negative bacteria (Pseudomonas aeruginosae and Proteus mirabilis) was observed from the eastern Kenya (Meru) oil. Meru oil was the best and its effectiveness was consistent on nearly all the microbes tested. The oil from the plant growing in the coastal region of Kenya (Mombasa) showed the best effect only on gram negative bacteria (Escherichia coli and Proteus mirabilis). Both oils (Meru and Mombasa) were dominated by monoterpenes accounting for 92.48% and 81.37% respectively. The monoterpene fraction was characterized by a high percentage of eugenol (68.8%) for Meru oil and 74.10% for Mombasa oil. The other major monoterpene was methyl eugenol (13.21%). Camphor (0.95%) was observed only in the Meru oil. (Cis) Ocimene, (trans)-ocimene and beta-pinene were present in both Meru and Mombasa oils. The sesquiterpenes present in fairly good amounts in both oils were germacrene D and (trans)-caryophyllene. The minor sesquiterpenes were alpha farnesene (0.85%) and beta-bisabolene (0.74%) which were present in the Meru oil only. PMID- 20161935 TI - Protective effect of Garcinia kola (kolaviron) extract on predisposition of rats to cardiovascular diseases following separate administration of amodiaquine and artesunate. AB - This study was carried out to investigate the cardiovascular effect of administration of antimalarial drugs amodiaquine and artesunate and the efficacy of Garcinia kola extract (kolaviron) in protecting against such possible effect. Thirty (30) adult male albino rats divided into six (6) groups were used in this study. Groups D, E and F were treated with 100 mg/Kg b. w. of the extract twice daily for the first one week and 200 mg/Kg b. w./day for the subsequent three (3) weeks. Amodiaquine (10 mg/Kg b. w./day) was administered orally for four (4) days into rats in groups A and E while rats in groups B and F were treated with artesunate (5 mg/Kg b. w./day) for four (4) days. Group C rats (normal control) were treated with normal saline. All the rats were sacrificed after four (4) weeks treatment period. Blood was withdrawn by cardiac puncture while the liver, kidney, stomach and heart were removed, cleansed and weighed. Total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were measured in the serum, while total fibrinogen, platelet count, red blood cell and white blood cell count were measured in the whole blood. The artherogenic and coronary risk index were also determined. Results indicate that both amodiaquine and artesunate predispose to cardiovascular disease, however the effect was more pronounced with artesunate than amodiaquine. The result also suggests that both drugs could increase the risk of coronary and artherogenic diseases and that Garcinia kola do not prevent the cardiotoxicity and coronary risk effect. PMID- 20161937 TI - Evaluation of the chemical composition of Dacryodes edulis and Raphia hookeri Mann and Wendl exudates used in herbal medicine in south eastern Nigeria. AB - The phytochemical contents and medicinal values of Dacroydes edulis and Raphia hookeri exudates were investigated. Phytochemical screening of the plant showed that they contain the presence of bioactive compounds comprising saponins (2.08 3.98 mg 100 g(-1)), alkaloids (0.28-0.49 mg 100 g(-1)), tannins (0.47-0.72 mg 100 g(-1)), flavonoids (0.26-0.39 mg 100 g(-1)), and phenolic compounds (0.01-0.05 mg 100 g(-1)). The carbohydrates, lipids and protein content were 77.42-78.90%, 2.02 4.185% and 16.63-18.38% respectively. The exudates are a good source of water soluble vitamins; ascorbic acid (7.04-26.40 mg 100 g(-1)), niacin (3.12-4.00 mg 100 g(-1)), riboflavin (0.14-0.54 mg 100 g(-1)) and thiamine (0.15-0.22 mg 100 g( 1)). Both plants exudates are good sources of minerals such as Ca, Mg, P, Fe, Zn, Cu and Mn while Cr and Co were trace. These results indicate that exudates can be potential sources of feedstock for the pharmaceutical industry. PMID- 20161938 TI - Hypoglycaemic activity of Nauclea latifolia Sm. (Rubiaceae) in experimental animals. AB - Aqueous, ethanolic and hexane extracts of the leaves of Nauclea latifolia (Rubiaceae) were assessed for their fasting blood glucose lowering effect in normoglycaemic and streptozotocin-diabetic rats. Wistar strain albino rats were given different doses of the extracts after 18 hrs fast and their blood glucose measured at 0, 1, 2, 4 and 6 hours after treatment. The aqueous and ethanolic extracts significantly lowered the fasting blood glucose levels of the STZ diabetic rats in a dose-dependent manner. The highest dose administered (400 mg/kg) lowered the fasting blood glucose of the diabetic rats by 31.7% (aqueous) and 36.1% (ethanolic) extracts. The aqueous extract did not significantly lower the glucose levels of normoglycaemic rats (maximum 6.6%), nor was any significant decrease seen in the rats administered with the hexane (maximum of 4.0% for normoglycaemic and 2.4% for diabetics) extract. The hypoglycaemic and antihyperglycaemic potentials of the aqueous and ethanolic extracts were comparable to that of glibenclamide (1 mg/kg).These results further support the traditional use of the plant in the treatment of diabetes mellitus. PMID- 20161939 TI - Anti-nociceptive and anti-inflammatory activities of ethanol extract of syzygium aromaticum flower bud in Wistar rats and mice. AB - The ethanol extracts of Syzygium aromaticum flower bud were tested for anti nociceptive and anti-inflammatory effects in mice and Wistar rats which were carried out using acetic acid-induced abdominal contractions in mice and formalin induced hind paw edema in Wistar rats. Three doses of the ethanol extract (50, 100, and 200 mg/kg body weight i.p.) were used for both studies. The extract had an LD(50) of 565.7 mg/kg body weight intraperitoneally in mice. The extracts produced significant effect (P<0.05) at all the three doses. Similarly, the anti nociceptive activity produced significant effects (P<0.05) at all the three doses of the extract. The result supports the local use of the plant in painful and inflammatory conditions. PMID- 20161941 TI - Antimicrobial effects of three tropical plant extracts on Staphylococcus aureus, Escherichia coli and Candida albicans. AB - Antimicrobial activities of the leaf extracts of Cymbopogon citatrus (lemongrass) and Vernonia amygdalina (bitter leaf) and the seed extracts of Garcinia kola (bitter kola) were carried out. G. kola had effect only on Staphylococcus aureus and Escherichia coli with no inhibition on Candida albicans. Ethanol, cold water and hot water extracts of Vernonia amygdalina and Cymbopogon citratus showed inhibition on the three organism but G. kola ethanol, cold water and hot water extracts only inhibited S. aureus and E. coli with no inhibition on Candida albicans. The organism's susceptibility varied with more inhibition to S. aureus and least to Candida albicans. PMID- 20161940 TI - Clerodendron inerme protects cellular integrity during 7,12-dimethylbenz[A] anthracene induced hamster buccal pouch carcinogenesis. AB - Aim of the present study was to investigate the protective effect of Clerodendron inerme on cellular integrity by measuring the status of glycoconjugates, lipids, osmotic fragility, and membrane bound enzyme activity in 7,12-dimethylbenz (a) anthracene (DMBA)-induced oral carcinogenesis. Oral squamous cell carcinoma was induced in the buccal pouch of Syrian golden hamsters by painting with 0.5% DMBA in liquid paraffin thrice a week for 14 weeks. The levels of glycoconjugates, lipids, osmotic fragility and membrane bound enzyme activity were analyzed by using specific colorimetric methods. We observed 100% tumor formation in DMBA painted hamsters. Altered glycoconjugates and lipid pattern were observed in DMBA painted hamsters as compared to control hamsters. Erythrocytes from DMBA painted hamsters were more fragile than those from control hamsters. The activity of membrane bound enzyme (Na(+) K(+) ATPase) decreased in DMBA painted hamsters as compared to control hamsters. Oral administration of aqueous leaf extract of Clerodendron inerme (CiALet) at a dose of 500 mg/kg body weight significantly prevented the tumor formation and histopathological abnormalities as well as normalized the above said biochemical variables in DMBA painted hamsters. Our results thus demonstrate the protective effect of Clerodendron inerme on cellular integrity during DMBA induced oral carcinogenesis. PMID- 20161942 TI - Biological activities of Asparagus racemosus. AB - Cytotoxic, antioxidant, tyrosinase inhibitory, antimicrobial activities of the crude ethanol extract of dry powdered roots of Asparagus racemosus (Liliaceae) were investigated. The LC(50) to brine shrimp was 2189.49 microg/ml; the EC(50) for DPPH radical scavenging was 381.91 microg/ml; the IC(50) for tyrosinase inhibition was 7.98 mg/ml. The extract was active at 5-20 mg/ml against various pathogenic microbial (16 species, 18 strains) using the agar dilution assay, with the minimum inhibitory concentration (MIC) between 10-20 mg/ml for enteropathogens, the MIC between 5-20 mg/ml for dermatopathogens, and MIC = 10 mg/ml for a pneumonia causing bacteria Klebsiella pneumoniae. TLC and HPLC finger printing showed the presence of steroids-terpenes, alkaloids and flavonoids. PMID- 20161943 TI - Comparative study of leaf and stem bark extracts of Parkia biglobosa against enterobacteria. AB - Hydroethanolic and aqueous extracts of leaf and stem bark of Parkia biglobosa (Jacq) Benth. (Mimosaceae) were tested against clinical isolates Escherichia coli, Salmonella typhi, Shigella dysenteriae and Enterococcus faecalis, and corresponding collection strains E. coli CIP 105 182, Salmonella enterica CIP 105 150, Shigella dysenteriae CIP 54-51 and Enterococcus faecalis CIP 103 907. Discs of Gentamicin, a broad spectrum antibiotic were used as positive controls. The results showed that all the extracts possess antimicrobial activities. A comparative study of the antibacterial activity of the leaves and that of the bark showed that for all the tested microorganisms, the hydroalcoholic extract of the bark is more active than the aqueous extract of the leaf. The hydroethanolic extract of the leaves is as effective as the aqueous extract of the stem bark prescribed by the traditional healer, suggesting it is possible to use leaves other than the roots and bark. The phytochemical screening showed that sterols and triterpenes, saponosides, tannins, reducing compounds, coumarins, anthocyanosides, flavonosides are present in both bark and leaf but in different concentrations. PMID- 20161944 TI - Larvicidal effects of Aframomum danieli seed extracts against gastrointestinal nematode of sheep: in vitro studies. PMID- 20161945 TI - Anti-nociceptive and anti-inflammatory effects of a Nigerian polyherbal tonic tea (PHT) extract in rodents. AB - The study investigated the anti-nociceptive and anti-inflammatory properties of a Nigerian Polyherbal Health Tonic tea aqueous extract (PHT) in rodents of both sexes. 100-500 mg kg(-1) of the aqueous extract was administered via the intra peritoneal (i.p.) and oral (p.o.) routes to 5 groups of mice using tail immersion, tail clip, formalin and acetic acid-induced writhing tests of experimental nociceptive models. Each of the models showed that PHT possesses a significant (p<0.05) anti-nociceptive effects which were peripherally and centrally mediated as both the early and late phases of pain significantly (p<0.05) were inhibited. However, the peripherally mediated analgesic effect of PHT, although similar to that of aspirin but was found to be more potent than aspirin. In assessing its anti-inflammatory potentials, 300-1340 mg kg(-1) PHT was also administered via oral and intraperitoneal routes, which, significantly (p<0.05) reduced the volume of carrageenan-induced oedema. Although, PHT administered via i.p. route was more effective than the oral but there was barely any difference between the percentage inhibition of oedema volume at both 600 and 1340 mg kg(-1) given orally. PHT anti-inflammatory effect was elucidated to be significantly (p<0.05) mediated via histaminergic, serotonergic, bradykinin and prostaglandin inhibition. PHT was also shown to be more protective than acetylsalicylic acid (ASA) in the castor oil-induced diarrhea model, which suggests the involvement of other mechanisms. Thus, lending supports to its folkloric use in pain and swelling management. PMID- 20161946 TI - Studies on effect of piperine on oral bioavailability of ampicillin and norfloxacin. AB - Ampicillin and Norfloxacin are used to treat variety of bacterial infections. These two drugs have low oral bioavailability. Co-administration of Piperine (20 mg/kg), an alkaloid from Piper nigrum L. enhanced oral bioavailability of Ampicillin and Norfloxacin in animal model. This is reflected in various pharmacokinetic measurements like Cmax, Tmax, AUC and t(1/2) of the above antibiotics in animal model. PMID- 20161947 TI - Role of wormwood (Artemisia absinthium) extract on oxidative stress in ameliorating lead induced haematotoxicity. AB - Effects of ROS generation have been postulated to be major contributors to lead exposure related disease. The aim of the study was to investigate the effect of aqueous extract of wormwood (Artemisia absinthium) on oxidative stress in rats protractedly exposed to lead. Aqueous extract of wormwood plant was administered orally (200 mg x kg(-1) body weight). Plasma vitamin C, E and non-protein thiol concentrations, red blood cells (RBC) thiobarbituric acid reactive substances, reduced glutathione levels and haemolysis test were evaluated. In addition, RBC antioxidant enzymes activities such as superoxide dismutases, catalase, glutathione peroxidase, glutathione reductase were also estimated. After 11 weeks, significant decreases of plasma vitamin C, E, non protein-thiol (NP-SH) and RBC-reduced glutathione levels were observed in Pb compared to control group (-32.9%, -57.1%, -53.1%, -33.9%, respectively); superoxide dismutase, glutathione peroxidase, uric aminolevulinic acid and haemolysis test significantly increased in Pb compared to control group (+64.3%, +40.3%, +145%, +44.3%, respectively). In our investigation, after 4-weeks of treatment all treated groups did not show any difference compared to the control group, except for glutathione peroxidase and RBC-superoxide dismutase activity (-15.7% and +16.4%, respectively). The findings of this study suggest that wormwood (Artemisia absinthium) extract restored the enzymes activities perturbed by exposure to lead, and had a protective role against lipid peroxidation. PMID- 20161948 TI - A pilot study on the effect of Catha edulis Frosk., (Celastraceae) on metabolic syndrome in WOKW rats. AB - This study investigated the effect of Catha edulis (khat) on some important parameters of the metabolic syndrome in Wistar Ottawa Karlsburg W (WOKW) rat. The animals were fed with the standard chow containing 5% air dried pulverized khat leaves for 14 days; followed by the standard chow for 16 days. The khat leaves were sorted into green (khat light; KL) and crimson (khat dark; KD) leaves. The control rats were fed on standard chow. Blood glucose (G), serum insulin, serum leptin and serum lipids (triglycerides, total cholesterol, HDL-, LDL-, and VLDL cholesterol) were determined. Feeding with khat leaves reduced the body weight and the triglyceride level of the animals. The effect of KD on these parameters was stronger than that of KL. KD lowered the blood glucose concentration and the leptin content whereas KL was inactive. The khat intake had no significant influence on serum insulin, total serum cholesterol, HDL-, LDL- and VLDL cholesterol. PMID- 20161949 TI - Inhibition of microsomal lipid peroxidation and protein oxidation by extracts from plants used in Bamun folk medicine (Cameroon) against hepatitis. AB - The antioxidant activities of 53 medicinal plants used in Bamun folk medicine for the management of jaundice and hepatitis were investigated. The studies were done using rat hepatic microsomes for lipid peroxidation and bovine serum albumin (BSA) for carbonyl group formation. Silymarine was used as reference compound. Fifteen different extracts were effective at a dose of 200 microg/ml in both experiments. Specifically, 25 extracts inhibited lipid peroxidation initiated non enzymatically by ascorbic acid while 18 inhibited peroxidation as determined by reduced Nicotinamide Adenine Dinucleotide Phosphate (NADPH). The inhibitory concentration 50 (IC(50)) of 23 different plant extracts was lower than 200 microg/ml in the microsomal lipid peroxidation inhibition study. Fifteen of the 23 extracts were active in preventing protein oxidation by inhibiting the formation of the carbonyl group on BSA with an IC(50) value less than 200 microg/ml. The results suggest that the antioxidant activity of the extracts, may be due to their ability to scavenge free radicals involved in microsomal lipid peroxidation or in protein oxidation. These biochemical processes are involved in the aetiology of toxic hepatitis. PMID- 20161950 TI - Evaluation of phytochemical and antibacterial potential of Helicteres isora L. fruits against enteric bacterial pathogens. AB - Antibacterial activities of aqueous, acetone, ethanol and methanol extracts of fruits of Helicteres isora (Mororphali) were studied. The fruit aqueous extracts of H. isora showed prominent antibacterial activities against E. coli, Staphylococcus epidermidis, Salmonella typhimurium and Proteus vulgaris; moderate activity against Enterobacter aerogenes, Staphylococcus aureus, Salmonella typhi and least activity against Pseudomonas aeruginosa. The aqueous extract showed maximal, the ethanol and methanol extract moderate and acetone extracts least antibacterial activities. Phytochemical screening revealed the presence of carbohydrates, anthraquinon glycosides, proteins, tannin and phenolic compounds and steroids These antibacterial properties supports its traditional use of fruits of H. isora in the treatment of enteric or diarrhoeal infections. PMID- 20161951 TI - Influence of Mitragyna ciliata (MYTA) on the microsomal activity of ATPase Na+/K+ dependent extract on a rabbit heart. AB - Mitragyna ciliata (MYTA) (Rubiaceae) inhibits plasmodia activity. MYTA induces a cardiotonicity of the digitalic type on rat's isolated heart. In this work we studied the effect of MYTA on microsomal Na(+)/K(+) dependant ATPase (Na(+), K(+) ATPase) extracted from the heart of a rabbit since digitalics inhibit Na(+), K(+) ATPase. Our results revealed that the Na(+)/K(+) ATPase has an optimum pH of 7.4 and temperature of 37 degrees C respectively. There is a linear relationship between the organic phosphate formed and the incubation time over 25 mins incubation period. The ATP hydrolysis rate in the presence of MYTA was 0.775 microM/min. LINEWEAVER and BURK plots showed that MYTA did not alter K(M) (1.31 mM) but decreased V(MAX). This study shows that MYTA exerts a non-competitive inhibition on the microsomal Na(+)/K(+) ATPase extracted from rabbit heart with a Ci(50) of 48 microg/ml. We conclude that the mechanism of action of MYTA is linked to the inhibition of the Na(+)/K(+) ATPase like cardiotonics of the digitalic type. PMID- 20161952 TI - The antimalarial potential of medicinal plants used for the treatment of malaria in Cameroonian folk medicine. AB - Malaria remains one of the leading public health problems in Cameroon as in other parts of Sub-Saharan Africa. In the past decades, this situation has been aggravated by the increasing spread of drug-resistant Plasmodium falciparum strains. New antimalarial drug leads are therefore urgently needed. Traditional healers have long used plants to prevent or cure infections. This article reviews the current status of botanical screening efforts in Cameroon as well as experimental studies done on antimalarial plants. Data collected from 54 references from various research groups in the literature up to June 2007 shows that 217 different species have been cited for their use as antimalarials in folk medicine in Cameroon. About a hundred phytochemicals have been isolated from 26 species some among which are potential leads for development of new antiamalarials. Crude extracts and or essential oils prepared from 54 other species showed a wide range of activity on Plasmodium spp. Moreover, some 137 plants from 48 families that are employed by traditional healers remain uninvestigated for their presumed antimalarial properties. The present study shows that Cameroonian flora represents a high potential for new antimalarial compounds. Further ethnobotanical surveys and laboratory investigations are needed to fully exploit the potential of the identified species in the control of malaria. PMID- 20161953 TI - Induced differentiation of hepatocellular carcinoma by natural products. AB - Hepatocellular carcinoma is one of the most common malignant tumors worldwide. For the difficulty of the giving sufficient dose because of the poor liver function and the low sensitivity of hepatoma cells for the chemotherapeutic agents, chemotherapy adds little to overall survival of hepatocellular carcinoma patients. The induction of terminal differentiation in tumor cells represents a possible therapeutic strategy with less toxicity. Gekko sulfated polysaccharides, isoverbascoside, Ginsenoside-Rh2, Camptothecin, 9-nitro-camptothecin, tachyplesin, Matrine, tylophorine, 7-OH-4-CH(3)-coumarin and arsenic trioxide are known to have a differentiation-inducing capability on hepatocellular carcinoma in vitro and/or in vivo. Although the therapeutic effect of the differentiation inducing agents may not be potent when compared with that of conventional chemotherapeutic agents, they have multiple therapeutic targets, low toxicity and less probability of drug resistance. More data are required on the molecular mechanisms of therapeutic effects, dose response and potential toxicities. PMID- 20161954 TI - Effect of cycloart-24-en-3beta-ol from Euphorbia royleana latex on neuroenzyme AChE and oxidative metabolism of freshwater fish, Channa punctatus. AB - Cycloart-24-en-3beta-ol isolated from Euphorbia royleana latex possesses potent piscicidal activity against freshwater predatory fish Channa punctatus. Their short as well as long-term exposure causes significant (P<0.05) time and dose dependent reversible alteration in the oxidative metabolism of the fish Channa punctatus Cycloart-24-en-3beta-ol also shifts fish respiratory pathway, inhibits energy production and AChE activity reversibly may be advantageous for their use as environmentally safe piscicide for controlling the predatory fish C. punctatus population from carp culture ponds. PMID- 20161955 TI - Ethnobotanical survey of anti-asthmatic plants in South Western Nigeria. AB - The paper presents the results of an ethnobotanical survey of plants used in the treatment of asthma in Ogun, Osun and Oyo states. Twenty markets were visited and forty-six plants belonging to thirty-three different families were collected. The plants' families represented in the collection include, Amaryllidaceae, Apocynaceae, Combretaceae, Euphorbiaceae, Moraceae, Solanaceae, Zingiberaceae and others. Most of the herbs were prescribed along with other recipes, mono prescription was rare. Modes of administration of the phytomedicines were concoction, decoctions and powdered ash residue. PMID- 20161956 TI - Evaluation of a safer male circumcision training programme for traditional surgeons and nurses in the Eastern Cape, South Africa. AB - Training designed to improve circumcision knowledge, attitude and practice was delivered over 5 days to 34 traditional surgeons and 49 traditional nurses in the Eastern Cape, South Africa. Training included the following topics: initiation rites; statutory regulation of traditional male circumcision and initiation into Manhood (TCIM); structure and function of the male sex organs; procedure of safe circumcision, infection control; sexually transmitted infections (STIs); HIV/AIDS; infection control measures; aftercare of the initiate including after care of the circumcision wound and initiate as a whole; detection and early management of common complications of circumcision; nutrition and fluid management; code of conduct and ethics; and sexual health education. The evaluation of the training consisted of a prospective assessment of knowledge and attitude immediately prior to and after training. Significant improvement in knowledge and/or attitudes was observed in legal aspects, STI, HIV and environmental aspects, attitudes in terms of improved collaboration with biomedical health care providers, normal and abnormal anatomy and physiology, sexually transmitted infections and including HIV, circumcision practice and aftercare of initiates. We concluded that safer circumcision training can be successfully delivered to traditional surgeons and nurses. PMID- 20161957 TI - Antinociceptive and antiinflammatory effects of essential oil of Dennettia tripetala G.Baker (Annonaceae) in rodents. AB - In this study we evaluated the analgesic and anti-inflammatory activities of the essential oil (EO) of the fruits of Dennettia tripetala in rodents. The plant is a tropical African plant and the fruits are commonly eaten as spices and consumed as a stimulant, and its various parts are used in the treatment of fever, cough and as anti-emetics.The analgesic effects of the oil was assessed in mice using the hot plate, acetic acid-induced writhings and formalin test, while carrageenan induced paw oedema was used to study the antiinflammatory effects in rats. The EO at 25-50 mg/kg exhibited significant (p<0.05) antinociceptive effects comparable to a potent opioid agonist, morphine (10 mg/kg) and non-steroidal anti inflammatory drugs such as, aspirin (100 mg/kg) and indomethacin (80 mg/kg). The antinociceptive effect of the EO was also blocked by naloxone (2 mg/kg) in all the models used. The EO demonstrated significant (p<0.05) anti-inflammatory effect in the carrageenan-induced paw oedema model of inflammation that is also comparable to dexamethasone (1 mg/kg) The results showed that the essential oil of D. tripetala possesses significant antinociceptive and antiinflammatory effects in the animal models used. The results also suggest that the analgesic effects may be mediated both centrally as well as peripherally, while the antiinflammatory activity may be effective in both early and late phases of inflammation. The results obtained may therefore be used to rationalize the use of the plant in the treatment of pain and fever in traditional medicine. PMID- 20161958 TI - Antimicrobial activity of various extracts of Ocimum basilicum L. and observation of the inhibition effect on bacterial cells by use of scanning electron microscopy. AB - The antimicrobial activities of chloroform, acetone and two different concentrations of methanol extracts of Ocimum basilicum L. were studied. These extracts were tested in vitro against 10 bacteria and 4 yeasts strains by the disc diffusion method. The results indicated that the methanol extracts of O. basilucum exhibited the antimicrobial activity against tested microorganisms. While the chloroform and acetone extracts had no effect, the methanol extracts showed inhibition zones against strains of Pseudomonas aeruginosa, Shigella sp., Listeria monocytogenes, Staphylococcus aureus and two different strains of Escherichia coli. The cells of microorganisms, which were treated and untreated with plant extracts, were observed by using the scanning electron microscope. It was observed that the treated cells were damaged. PMID- 20161959 TI - Patients consulting traditional health practioners in the context of HIV/AIDS in urban areas in KwaZulu-Natal, South Africa. AB - The purpose of this study is to assess patients consulting full-time traditional health practitioners (THPs) and the practice of THPs after they had been trained on Human Immunodeficiency Virus (HIV)/ Sexually Transmitted Infections (STI) prevention and care. The sample included 222 patients interviewed when exiting a THP's practice (n=17) in purposefully chosen two urban sites in KwaZulu-Natal. Results indicate that at post training evaluation the majority of the THPs were involved in HIV/STI management and most had low levels of HIV risk practices at the workplace. Major self-reported reasons for consulting the THP included a complex of supernatural or psychosocial problems, chronic conditions, acute conditions, generalized pain, HIV and other STIs. Overall, patients including HIV positive (n=18) patients had moderate knowledge of Antiretroviral Therapy (ART). A number of HIV positive patients were using traditional medicine and ART concurrently, dropped out of ART because of side effects and were using traditional medicine for HIV. PMID- 20161960 TI - Traditional healers and nurses: a qualitative study on their role on sexually transmitted infections including HIV and AIDS in KwaZulu-Natal, South Africa. AB - The aim of this study was to investigate the role of traditional healers in sexually transmitted infections including HIV/AIDS and collaboration between the traditional and biomedical health care systems as seen by nurses and traditional healers. A convenient sample of 15 professional nurses and 15 traditional healers were interviewed using a semi-structured questionnaire. Qualitative analyses identified the following themes: (1) attitude and respect, (2) collaboration between traditional healers and nurses, (3) control/regulation of (traditional) health practices, (4) training needs of healers and nurses. The main results indicated that the professional nurses had mixed attitudes towards traditional healers, mostly negative (e.g. lacked training, used expired medicines, gave improper dosages, and kept poor or no records), but, also positive, such as contributing to the management of opportunistic infections (STIs). The traditional healers also had mixed attitudes towards nurses. The traditional healers believed that nurses undermined their work (did not accept their efficacy in treatment and consequently did not refer patients). Notably, most of the traditional healers were willing to learn and refer patients to clinics and hospitals, while this was not true for the nurses. PMID- 20161961 TI - A review of traditional plants used in the treatment of epilepsy amongst the Hausa/Fulani tribes of northern Nigeria. AB - Five prescriptions used in the treatment of epilepsy amongst the Hausa/Fulani tribe of Northern Nigeria were collected from traditional healers. The five prescriptions containing eight plants were reviewed as in literature to ascertain scientific basis of their use in treatment of epilepsy. Securidaca longipedunculata (family Polygalaceace) was reported to have such property; Mitragyna inermis (family Rubiaceae) has alkaloids structurally similar to clinically useful anticonvulsant. Celtis integrefolia (family Ulmaceae) was reported to contain gamma amino butyric acid (GABA) that its deficiency may lead to convulsions. The remaining plants were basically helpful in alleviation of associated symptoms of epilepsy except Centaurea praecox (family Asteraceae) which was reported to have neurotoxic substances that may worsen the disease. PMID- 20161962 TI - Antimicrobial activity of essential oils of Xylopia aethiopica. AB - Xylopia aethiopica is a medicinal plant of great repute in West Africa which produces a variety of complex chemical compounds. The fresh and dried fruits, leaf, stem bark and root bark essential oils showed various degrees of activity against the gram positive bacteria, Bacillus subtilis and Staphylococcus aureus, the gram negative bacteria Pseudomonas aeruginosa and the yeast-like fungus Candida albicans, using the cup plate method. However, none of the oils showed activity against Escherichia coli. PMID- 20161963 TI - Toxicity and immunomodulatory activity of fractions of Hibiscus sabdariffa Linn (family Malvaceae) in animal models. AB - This study evaluated immunomodulatory properties and the sub-acute toxicity profile of two fractions of the aqueous alcoholic extract of the dried calyx of Hibiscus sabdariffa in experimental animals. Immunomodulatory activity was evaluated using red blood cell-induced immunostimulation. The fractions were not found to be toxic after 7-day administration, though there was severe weight loss with the residual water-soluble fraction (RWSF) and weight gain with the ethyl acetate soluble fraction (EAC). The EAC exhibited a significant dose-dependent immunostimulation (p<0.05) higher than that observed for levamisole (positive control). The residual water-soluble fraction exhibited immunostimulatory activity at 100 mg/kg body weight. The two fractions caused a significant reduction in production of tissue necrosis factor-alpha and an increase in interleukin 10 (IL-10). PMID- 20161964 TI - Market survey of Mondia whytei (mulondo) roots in Kampala City, Uganda. AB - This study explored the consumers' and vendors' perceptions about Mondia whitei roots, in Kampala city, Uganda; determined the marketing margins and the market flow of the roots in the city; documented demand and supply opportunities as well as challenges to marketing of the roots by the vendors. Seventy vendors and 70 consumers of the roots were administered with semi-structured questionnaires. Results showed that M. whytei roots are largely perceived as sexual stimulant, appetiser, flavours for food and drinks, and stimulant for milk production in lactating mothers. Majority of the vendors (74%) and consumers (85%) perceived the trade in the roots as worthwhile. Men and adolescent boys were reported to be the main consumers. Retailers who buy the roots directly from collectors and later sell to consumers dominate the trade. The average price charged per piece and a kilogram of roots increases from collectors, middlemen and to the retailers. The average retail price was US $0.12 per piece of the root and US $1.50 per kg of the roots. Collectors charged the lowest price (US $0.06 and US $0.60 per piece and a kilogram of the roots respectively) though their profit margins remained the highest (50%). Several demand and supply opportunities exist for M. whytei roots and these included few sexual stimulant accepted alternatives to M. whytei roots in Kampala city; consumers' willingness to pay high prices when the roots are scarce, and a large number of M. whytei roots gatherers that could promote the cultivation of this plant for the market. Challenges, such as seasonal low supply of the roots, and unorganised market structure, hamper the trade in M. whytei roots. There is a need for experimental research on efficacies of the perceived uses of the roots reported in this study. The possibility of value addition to the roots sold should be investigated. PMID- 20161966 TI - Phytochemical and laxative studies of Globimetula braunii (Engle) Van Tiegh growing on Cola acuminata (Schott & Endl). PMID- 20161965 TI - Anti-tumor activity of four Ayurvedic herbs in Dalton lymphoma ascites bearing mice and their short-term in vitro cytotoxicity on DLA-cell-line. AB - The anti-tumor activity and chemopreventive potential of four Ayurvedic herbs viz. Curcuma longa L., Ocimum sanctum L., Tinospora cordifolia (Wild) Miers ex Hook.f & Thomas and Zizyphus mauritiana Lam. were evaluated using Dalton Lymphoma ascites (DLA) tumor model in Swiss Albino mice. The outcome was assessed using survival time, peritoneal ascitic fluid (Tumor volume) and hematological indices as parameters. Animals were divided into five groups (n = 6) viz. one DLA control and four Herb + DLA treated groups. All the four herb + DLA groups were pre treated with respective herbs for 7 days and hematological indices were measured for entire five groups. On day-8 animals were inoculated with 1x10(6) DLA cells i.p., and Herb + DLA groups were continued with oral herbal treatment for 21 days. Hematological parameters and tumor volume were assessed to find the effects of herbs. Short term in vitro cytotoxicity was determined by Trypan Blue exclusion method and LDH leakage assay using different concentrations of herbal extracts and 5-FU as a positive control and IC(50) for each herbal extract and 5 FU were determined. Oral administration of crude herb increased the survival time and decreased the peritoneal ascitic fluid content significantly. Hb, RBCs and total WBC which were altered by DLA inoculation were restored significantly by all the herbs except O. sanctum. All the four herbs showed in vitro cytotoxic activity against DLA cell-line. Moreover inter group comparison of all the four herbs for anti-tumor activity showed efficacy in the following order--T. cordifolia > Z. mauritiana > or = C. longa > O. sanctum respectively. PMID- 20161967 TI - Antibacterial activity of some folklore medicinal plants from South India. AB - Antibacterial activity and phytochemical tests of eight whole plant methanol extracts belonging to family Euphorbiaceae were evaluated. In agar well diffusion assay the diameter of inhibition zones ranged from 3-13 mm. Phyllanthus emblica showed maximum activity of 13 mm. The MIC and MBC observed were 30-140 mcg/ml and 40-160 mcg/ml, respectively. P. piscatorum and P. emblica showed the lowest MIC (30 mcg/ml), P. emblica the lowest MBC (40 mcg/ml) and thus an effective inhibitor of the tested bacteria. Alkaloids, saponins and tannins were detected in 7 out of 8 tested plants. PMID- 20161968 TI - Iron complexation to oxygen rich marine natural products: a computational study. AB - The natural products kahalalide F, halichondrin B, and discodermolide are relatively large structures that were originally harvested from marine organisms. They are oxygen rich structures that, to varying degrees, should have the ability to bind iron (II or III) by Fe-O and/or Fe-N bonds. In this semi empirical study, the binding of these natural products to iron (II) is studied and the aqueous stability factor (ASF) is used to determine which bonding configuration is most stable. The energy, the complex charge (+1), the average Fe-O (or Fe-N) bond distances and the dipole moments are used to calculate the ASF. The ASF provides insight to which complex will be the most stable and water soluble, important for a medicinal application. The ability of a molecule with a more than six oxygen and/or nitrogen atoms to bind iron (hexavalent, octahedral) by shifting which six atoms (O/N) are bound to the iron qualifies it as a polarity adaptive molecule. PMID- 20161970 TI - Inhibitory activity of marine sponge-derived natural products against parasitic protozoa. AB - In this study, thirteen sponge-derived terpenoids, including five linear furanoterpenes: furospinulosin-1 (1), furospinulosin-2 (2), furospongin-1 (3), furospongin-4 (4), and demethylfurospongin-4 (5); four linear meroterpenes: 2 (hexaprenylmethyl)-2-methylchromenol (6), 4-hydroxy-3-octaprenylbenzoic acid (7), 4-hydroxy-3-tetraprenyl-phenylacetic acid (8), and heptaprenyl-p-quinol (9); a linear triterpene, squalene (10); two spongian-type diterpenes dorisenone D (11) and 11 beta-acetoxyspongi-12-en-16-one (12); a scalarane-type sesterterpene; 12 epi-deoxoscalarin (13), as well as an indole alkaloid, tryptophol (14) were screened for their in vitro activity against four parasitic protozoa; Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani and Plasmodium falciparum. Cytotoxic potential of the compounds on mammalian cells was also assessed. All compounds were active against T. brucei rhodesiense, with compound 8 being the most potent (IC(50) 0.60 microg/mL), whereas 9 and 12 were the most active compounds against T. cruzi, with IC(50) values around 4 microg/mL. Compound 12 showed the strongest leishmanicidal activity (IC(50) 0.75 microg/mL), which was comparable to that of miltefosine (IC(50) 0.20 microg/mL). The best antiplasmodial effect was exerted by compound 11 (IC(50) 0.43 microg/mL), followed by compounds 7, 10, and 12 with IC(50) values around 1 microg/mL. Compounds 9, 11 and 12 exhibited, besides their antiprotozoal activity, also some cytotoxicity, whereas all other compounds had low or no cytotoxicity towards the mammalian cell line. This is the first report of antiprotozoal activity of marine metabolites 1-14, and points out the potential of marine sponges in discovery of new antiprotozoal lead compounds. PMID- 20161969 TI - Chitin deacetylases: properties and applications. AB - Chitin deacetylases, occurring in marine bacteria, several fungi and a few insects, catalyze the deacetylation of chitin, a structural biopolymer found in countless forms of marine life, fungal cell and spore walls as well as insect cuticle and peritrophic matrices. The deacetylases recognize a sequence of four GlcNAc units in the substrate, one of which undergoes deacetylation: the resulting chitosan has a more regular deacetylation pattern than a chitosan treated with hot NaOH. Nevertheless plain chitin is a poor substrate, but glycolated, reprecipitated or depolymerized chitins are good ones. The marine Vibrio sp. colonize the chitin particles and decompose the chitin thanks to the concerted action of chitinases and deacetylases, otherwise they could not tolerate chitosan, a recognized antibacterial biopolymer. In fact, chitosan is used to prevent infections in fishes and crustaceans. Considering that chitin deacetylases play very important roles in the biological attack and defense systems, they may find applications for the biological control of fungal plant pathogens or insect pests in agriculture and for the biocontrol of opportunistic fungal human pathogens. PMID- 20161971 TI - Effects of marine toxins on the reproduction and early stages development of aquatic organisms. AB - Marine organisms, and specially phytoplankton species, are able to produce a diverse array of toxic compounds that are not yet fully understood in terms of their main targets and biological function. Toxins such as saxitoxins, tetrodotoxin, palytoxin, nodularin, okadaic acid, domoic acid, may be produced in large amounts by dinoflagellates, cyanobacteria, bacteria and diatoms and accumulate in vectors that transfer the toxin along food chains. These may affect top predator organisms, including human populations, leading in some cases to death. Nevertheless, these toxins may also affect the reproduction of aquatic organisms that may be in contact with the toxins, either by decreasing the amount or quality of gametes or by affecting embryonic development. Adults of some species may be insensitive to toxins but early stages are more prone to intoxication because they lack effective enzymatic systems to detoxify the toxins and are more exposed to the toxins due to a higher metabolic growth rate. In this paper we review the current knowledge on the effects of some of the most common marine toxins on the reproduction and development of early stages of some organisms. PMID- 20161972 TI - Geoditin A induces oxidative stress and apoptosis on human colon HT29 cells. AB - Geoditin A, an isomalabaricane triterpene isolated from the marine sponge Geodia japonica, has been demonstrated to dissipate mitochondrial membrane potential, activate caspase 3, decrease cytoplasmic proliferating cell nuclear antigen (PCNA), and induce apoptosis of leukemia cells, but the underlying mechanism remains unclear [1]. In this study, we found fragmentation of Golgi structure, suppression of transferrin receptor expression, production of oxidants, and DNA fragmentation in human colon cancer HT29 cells after treatment with geoditin A for 24 h. This apoptosis was not abrogated by chelation of intracellular iron with salicylaldehyde isonicotinoyl hydrazone (SIH), but suppressed by N acetylcysteine (NAC), a thiol antioxidant and GSH precursor, indicating that the cytotoxic effect of geoditin A is likely mediated by a NAC-inhibitable oxidative stress. Our results provide a better understanding of the apoptotic properties and chemotherapeutical potential of this marine triterpene. PMID- 20161973 TI - Antimicrobial photodynamic therapy: study of bacterial recovery viability and potential development of resistance after treatment. AB - Antimicrobial photodynamic therapy (aPDT) has emerged in the clinical field as a potential alternative to antibiotics to treat microbial infections. No cases of microbial viability recovery or any resistance mechanisms against it are yet known. 5,10,15-tris(1-Methylpyridinium-4-yl)-20-(pentafluorophenyl)-porphyrin triiodide (Tri-Py(+)-Me-PF) was used as photosensitizer. Vibrio fischeri and recombinant Escherichia coli were the studied bacteria. To determine the bacterial recovery after treatment, Tri-Py(+)-Me-PF (5.0 microM) was added to bacterial suspensions and the samples were irradiated with white light (40 W m( 2)) for 270 minutes. Then, the samples were protected from light, aliquots collected at different intervals and the bioluminescence measured. To assess the development of resistance after treatment, bacterial suspensions were exposed to white light (25 minutes), in presence of 5.0 microM of Tri-Py(+)-Me-PF (99.99% of inactivation) and plated. After the first irradiation period, surviving colonies were collected from the plate and resuspended in PBS. Then, an identical protocol was used and repeated ten times for each bacterium. The results suggest that aPDT using Tri-Py(+)-Me-PF represents a promising approach to efficiently destroy bacteria since after a single treatment these microorganisms do not recover their viability and after ten generations of partially photosensitized cells neither of the bacteria develop resistance to the photodynamic process. PMID- 20161974 TI - Complementary UV-absorption of mycosporine-like amino acids and scytonemin is responsible for the UV-insensitivity of photosynthesis in Nostoc flagelliforme. AB - Mycosporine-like amino acids (MAAs) and scytonemin are UV-screening compounds that have presumably appeared early in the history of life and are widespread in cyanobacteria. Natural colonies of the UV-insensitive Nostoc flagelliforme were found to be especially rich in MAAs (32.1 mg g DW(-1)), concentrated in the glycan sheath together with scytonemin. MAAs are present in the form of oligosaccharide-linked molecules. Photosystem II activity, measured using PAM fluorescence and oxygen evolution, was used as a most sensitive physiological parameter to analyse the effectiveness of UV-protection. Laboratory experiments were performed under controlled conditions with a simulated solar radiation specifically deprived of UV-wavebands with cut-off filters (295, 305, 320, 345 and 395 nm). The UV-insensitivity of N. flagelliforme was found to cover the whole UV-A (315-400 nm) and UV-B (280-320 nm) range and is almost certainly due to the complementary UV-absorption of MAAs and scytonemin. The experimental approach used is proposed to be suitable for the comparison of the UV-protection ability in organisms that differ in their complement of UV-sunscreen compounds. Furthermore, this study performed with a genuinely terrestrial organism points to the relevance of marine photoprotective compounds for life on Earth, especially for the colonization of terrestrial environments. PMID- 20161975 TI - Calyculins and related marine natural products as serine-threonine protein phosphatase PP1 and PP2A inhibitors and total syntheses of calyculin A, B, and C. AB - Calyculins, highly cytotoxic polyketides, originally isolated from the marine sponge Discodermia calyx by Fusetani and co-workers, belong to the lithistid sponges group. These molecules have become interesting targets for cell biologists and synthetic organic chemists. The serine/threonine protein phosphatases play an essential role in the cellular signalling, metabolism, and cell cycle control. Calyculins express potent protein phosphatase 1 and 2A inhibitory activity, and have therefore become valuable tools for cellular biologists studying intracellular processes and their control by reversible phosphorylation. Calyculins might also play an important role in the development of several diseases such as cancer, neurodegenerative diseases, and type 2 diabetes mellitus. The fascinating structures of calyculins have inspired various groups of synthetic organic chemists to develop total syntheses of the most abundant calyculins A and C. However, with fifteen chiral centres, a cyano-capped tetraene unit, a phosphate-bearing spiroketal, an anti, anti, anti dipropionate segment, an alpha-chiral oxazole, and a trihydroxylated gamma-amino acid, calyculins reach versatility that only few natural products can surpass, and truly challenge modern chemists' asymmetric synthesis skills. PMID- 20161976 TI - Qualitative and quantitative saponin contents in five sea cucumbers from the Indian ocean. AB - To avoid predation, holothuroids produce feeding-deterrent molecules in their body wall and viscera, the so-called saponins. Five tropical sea cucumber species of the family Holothuriidae were investigated in order to study their saponin content in two different organs, the body wall and the Cuvierian tubules. Mass spectrometry techniques (MALDI- and ESI-MS) were used to detect and analyze saponins. The smallest number of saponins was observed in Holothuria atra, which contained a total of four congeners, followed by Holothuria leucospilota, Pearsonothuria graeffei and Actinopyga echinites with six, eight and ten congeners, respectively. Bohadschia subrubra revealed the highest saponin diversity (19 congeners). Saponin mixtures also varied between the two body compartments within a given animal. A semi-quantitative approach completed these results and showed that a high diversity of saponins is not particularly correlated to a high saponin concentration. Although the complexity of the saponin mixtures described makes the elucidation of their respective biological roles difficult, the comparisons between species and between body compartments give some clues about how these molecules may act as predator repellents. PMID- 20161977 TI - ESI FTICR-MS analysis of larvae from the marine sponge Luffariella variabilis. AB - The viviparous Great Barrier Reef sponge Luffariella variabilis (Polejaeff 1884) contains a range of secondary metabolites, including manoalide (1) and manoalide monoacetate (3). ESI (+) FTICR-MS accurate mass determination has, for the first time, been used to detected the presence of 3 only in an organic extract of a single L. variabilis larva showing that the parentally produced 3 is sequestered in the larva. As 3 has previously been shown to have antibacterial and quorum sensing inhibition activity, and readily converts to 1, which also exhibits similar activity, it may provide a chemical defence against predation and microbial attack. PMID- 20161979 TI - Hippocampal Conceptual Representations and their Reward Value. PMID- 20161978 TI - Agarase: review of major sources, categories, purification method, enzyme characteristics and applications. AB - Agarases are the enzymes which catalyze the hydrolysis of agar. They are classified into alpha-agarase (E.C. 3.2.1.158) and beta-agarase (E.C. 3.2.1.81) according to the cleavage pattern. Several agarases have been isolated from different genera of bacteria found in seawater and marine sediments, as well as engineered microorganisms. Agarases have wide applications in food industry, cosmetics, and medical fields because they produce oligosaccharides with remarkable activities. They are also used as a tool enzyme for biological, physiological, and cytological studies. The paper reviews the category, source, purification method, major characteristics, and application fields of these native and gene cloned agarases in the past, present, and future. PMID- 20161980 TI - Safety of etanercept in elderly subjects with rheumatoid arthritis. AB - OBJECTIVE: To report side effects seen in a clinical cohort of patients aged >65 years with rheumatoid arthritis (RA) treated with the tumor necrosis factor-alpha TNF-alpha blocker etanercept and to compare the side effects rate with patients aged 65 years and 62 (40 females, 22 males) aged <65 years. In the patients aged >65 years, the safety profile (defined as rate of side effects) of etanercept was similar to that in patients aged 0.05) and the survival curves between the groups were similar (P > 0.05). CONCLUSIONS: In our three-year experience, the anti-TNFalpha agent etanercept has been well tolerated and safe in elderly patients. The risk of side effects in these patients was no greater than in subjects aged 5x10(7) cfu/g was found in 89 (59.33%) of the preparations, while average plate count of < or = 5x10(7) cfu/g was found in 42 (28%) and no bacterial count was obtained in 19 (12.67%) of the preparations. Correlation was positive (P = 0.01; r = +0.109) between the physical parameters tested and the bacterial load. Antibacterial activities result of some common antibiotics showed that all the antibiotics had activities on the test bacterial isolates at various minimum inhibitory concentrations. Most traditionally prepared herbal medications in Kaduna state are likely to be contaminated with a wide variety of potentially pathogenic bacteria. The quality assurance of these products should be thoroughly enforced and monitored in the production and distribution of herbal preparations. PMID- 20162045 TI - Effects of Tephrosia purpurea aqueous seed extract on blood glucose and antioxidant enzyme activities in streptozotocin induced diabetic rats. AB - The aim of the present study was to evaluate the effects of aqueous seed extract of Tephrosia purpurea (TpASet) on blood glucose and antioxidant status in streptozotocin induced diabetic rats. Hyperglycemia associated with an altered hexokinase and glucose-6-phosphatase activities, elevated lipid peroxidation, disturbed enzymatic [Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)] and non enzymatic [Glutathione, vitamin C and vitamin E] antioxidant status were observed in streptozotocin induced diabetic rats. Oral administration of "TpASet" at a dose of 600 mg/kg body weight showed significant improvement in above mentioned parameters. Our results clearly indicate that "TpASet" has potent antihyperglycemic and antioxidant effects in streptozotocin induced diabetic rats and therefore further studies are warranted to isolate and characterize the bioactive principles from "TpASet". PMID- 20162046 TI - Chemopreventive efficacy of ginger (Zingiber officinale) in ethionine induced rat hepatocarcinogenesis. AB - Ginger (Zingiber officinale Rosco) is widely used in foods as a spice all around the world. It has been reported to have antioxidant and anticarcinogenic properties. We investigated the effect of ginger in ethionine induced rat hepatocarcinogenesis. Male Wistar rats were divided into 5 groups: group 1 and 2 served as controls and they received normal rat chow and olive oil respectively. Group 3 was fed with ginger oleoresin dissolved in olive oil at 100 mg/kg body wt. Group 4 was fed with choline deficient diet and 0.1% ethionine in drinking water (CDE diet), and group 5 received ginger with CDE diet. Blood samples were taken from the orbital sinus at 0 and 8 weeks of experiment for the determination of antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase and lipid peroxidation end product, malondialdehyde (MDA). Rats were also killed at 8 weeks for the observation of liver tumor formation. CDE diet induced the formation of liver nodules in rats and increased SOD activity. However, it had no effect on catalase, GPx and MDA levels when compared to both controls at 8 weeks of experiment. When CDE rats were treated with ginger, the formation of liver tumour, SOD activity and MDA level reduced, catalase activity was increased but no change was observed for GPx activity when compared to CDE group. In conclusion, ginger supplementation suppressed liver carcinogenesis by scavenging the free radical formation, and by reducing lipid peroxidation. PMID- 20162047 TI - Protective role of Withaferin-A on red blood cell integrity during 7,12 dimethylbenz[a]anthracene induced oral carcinogenesis. AB - The aim of the present study was to investigate the protective effect of Withaferin-A on red blood cell integrity during 7,12-dimethylbenz[a]anthracene (DMBA) induced oral carcinogenesis. The protective effect of Withaferin-A was assessed by measuring the status of glycoconjugates, membrane bound enzyme activity and red blood cell osmotic fragility. Oral squamous cell carcinoma was induced in the buccal pouch of Syrian golden hamsters by painting with 0.5% DMBA in liquid paraffin thrice a week for 14 weeks. The levels of glycoconjugates, membrane bound enzyme activity, osmotic fragility and thiobarbituric acid reactive substances (TBARS) were analyzed by using specific colorimetric methods. We observed 100% tumor formation in DMBA painted hamsters. Increase in plasma glycoconjugates at the expense of red blood cell membrane glycoconjugates levels were observed in DMBA painted hamsters as compared to control hamsters. Erythrocytes from DMBA painted hamsters were more fragile than those from control hamsters. The activity of membrane bound enzyme (Na(+) K(+) ATPase) decreased whereas TBARS level was increased in DMBA painted hamsters as compared to control hamsters. Oral administration of Withaferin-A at a dose of 20 mg kg(-1) bw significantly prevented the tumor formation as well as normalized the biochemical variables in DMBA painted hamsters. Our results thus demonstrate the protective effect of Withaferin-A on red blood cell integrity during DMBA induced oral carcinogenesis. PMID- 20162048 TI - Whether co-administration of garlic has negative influence on Scutellaria baicalensis Georgi in treating models rats with pelvic inflammation? AB - The research was to explore whether co-administration of garlic has negative influence on Scutellaria baicalensis Georgi (Scutellaria baicalensis) in treating models rats with pelvic inflammation. Twelve model rats were randomized into a Scutellaria baicalensis group and a Scutellaria baicalensis+garlic group with six in each group for pharmacokinetic analysis. Twenty-four rats were randomized into a Scutellaria baicalensis group, a Scutellaria baicalensis+garlic group, a model control group and a normal control group with six rats in each group for detecting the serum levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) with enzyme-linked immunosorbent assay (ELISA). The results showed that in the Scutellaria baicalensis group, the maximum concentration (C(max)) of baicalin, area under the plasma concentration-time curve (AUC) and the time to C(max) (T(max)) were significantly higher and apparent clearance (CL/F) were significantly lower than those of Scutellaria baicalensis+garlic group. The serum levels of TNF-alpha and IL-6 in the Scutellaria baicalensis group were both significantly lower than Scutellaria baicalensis+garlic group. It was then concluded that garlic not only had negative influence on the absorption of active compounds in Scutellaria baicalensis, but decreased the curative effects of Scutellaria baicalensis in treating model rats with pelvic inflammation. Garlic should not be co-administered with Scutellaria baicalensis. PMID- 20162050 TI - Flavonoids, anti-inflammatory activity and cytotoxicity of Macfadyena unguis-cati L. AB - Ethyl acetate and ethanol extracts of unflowering aerial part of Macfadyena unguis-cati L. (Fam. Bignoniaceae) were found to be rich in phenolic compounds. From ethyl acetate extract, six flavonoids were identified, 8, methoxy, acacetin, 7-O glucoside; 6, methoxy apigenin 7-O glucoside; 4'-O methyl scutellarin, 6-O apiosyl galactoside; acacetin, 7-O glucosyl, 8-C rhamnosyl, 3-O-alpha arabinofuranoside; 4'-methyl, 6- methoxy kaempferol, 7-O, 8-C diglucoside and vicenin II were isolated, while 6, methoxy, acacetin 7-O glucoside; and quercitrin were isolated from ethanol extract. These compounds were characterized and identified by their physicochemical and spectral data. The crude ethanol extract exhibited significant anti-inflammatory activity (80.47%) and moderate cytotoxic activity against lung cell line. PMID- 20162051 TI - Analgesic and anti-inflammatory activities of Asparagus africanus root extract. AB - The methanolic extract of the roots of Asparagus africanus Lam (Liliaceae) which contains mainly saponins and carbohydrate showed significant analgesic and anti inflammatory activities (P<0.05) in the tail-flick/hot-plate test and egg albumen induced rat paw oedema tests that were comparable to the test drugs (morphine 20 mg/kg and indomethacin 50 mg/kg respectively). These results indicate that the extract possesses analgesic and anti-inflammatory properties. PMID- 20162049 TI - An overview of Indian novel traditional medicinal plants with anti-diabetic potentials. AB - Diabetes mellitus is a global metabolic epidemic affecting essential biochemical activities in almost every age group. Indian literatures like Ayurveda have already mentioned herbal remediation for a number of human ailments. Among Indian traditional medicinal plants several potential anti-diabetic plants and herbs are being used as part of our diet since prehistoric time. India has a long list of native medicinal plants with confirmed blood sugar lowering property. Some of these have proved remarkable for cure of diabetes and its complications. The current paper is aimed at providing a review on clinical and experimental studies carried out on the most effective and commonly used hypoglycemic plants and herbs species from traditional Indian flora. This write-up includes hypoglycemic and anti-hyperglycemic activities of plants, active hypoglycemic compounds and constituents along with their available toxicity status. PMID- 20162052 TI - Antigenotoxic effect of ferulic acid in 7,12-dimethyl benz(a)-anthracene (DMBA) induced genotoxicity. AB - The antigenotoxic effect of ferulic acid was carried out by evaluating the cytogenetic markers, the micronuclei frequency and chromosomal aberrations, in the bone marrow of hamsters in 7,12-dimethylbenz(a)anthracene (DMBA) induced genotoxicity. Genotoxicity was induced in experimental hamsters by single intraperitoneal injection of DMBA (30 mg kg(-1) b.w.). Pretreatment of ferulic acid orally at a dose of 40 mg kg(-1) b.w. for five days significantly reduced the frequency of micronucleated polychromatic erythrocytes (MnPCEs) and the percentage of chromosomal aberrations in hamster's bone marrow. Our results thus suggest that ferulic acid has potent antigenotoxic effect in DMBA induced genotoxicity in golden Syrian hamsters. PMID- 20162053 TI - Evaluation of the antioxidant effects of Ziziphus mauritiana Lam. Leaf extracts against chronic ethanol-induced hepatotoxicity in rat liver. AB - Chronic alcohol ingestion is known to increase the generation of reactive oxygen species (ROS), thereby leading to liver damage. Antioxidant enzymes act individually or in combination to reduce or counter the effect of these ROS. Chronic administration of alcohol at (40% v/v, 1 ml/100 g), for 6 weeks showed a significant (p<0.05) elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TB). There was also a significant (p<0.05) decreased levels of catalase, glutathione peroxidase, glutathione reductase and superoxide dismutase compared to control rats. Pre-treatment of rats with 200, 400 mg/kg body weight of aqueous leaf extract of Ziziphus mauritiana or 100 mg/kg silymarin resulted in a significant (p<0.05) decreased levels of ALT, AST, ALP, and TB with levels of catalase, glutathione peroxidase, glutathione reductase and superoxide dismutase showing a significant (p<0.05) increase compared to group administered alcohol only. Histopathology of rat liver administered with alcohol only resulted in severe necrosis, mononuclear cell aggregation and fatty degeneration in the central and mid zonal areas which was a characteristic of a damaged liver. Pre-treatment with the aqueous extract of Ziziphus mauritiana or silymarin reduced the morphological changes that are associated with chronic alcohol administration. The presence of tannins, saponins and phenolic compounds observed in the plant extract could be responsible for the observed effects of decreasing the levels of injured tissue marker and lipid peroxidation. PMID- 20162054 TI - In vivo screening of antimalarial activity of Acacia mellifera (Benth) (Leguminosae) on Plasmodium berghei in mice. AB - The activities of total extracts and lupane triterpenes, isolated from the stem bark of Acacia mellifera, were evaluated against Plasmodium berghei strain ANKA in a female Swiss mouse model. Five isolated compounds and the crude extracts were evaluated for antimalarial activity and Quinine hydrochloride was used as a positive control. Only betulin and the methanolic extract produced considerable antimalarial activity in mice infected with P. berghei parasites. This study demonstrated the presence of bioactive agents in Acacia mellifera. PMID- 20162055 TI - Antimicrobial activity of some medicinal plants used by herbalists in Eastern province, Kenya. AB - The aqueous extracts from medicinal plants commonly used by herbalists in Mbeere, and Embu districts of Eastern province, Kenya, were tested for their inhibitory activity against three selected strains of bacteria. All the selected plant extracts (infusions: 1.0 g sample in 100 ml water) investigated showed activity against Escherichia coli with inhibition zone diameters ranging from 5.8-18.0 mm. Terminalia brownii gave the largest inhibition zones against E. coli and Staphylococcus aureus. Vernonia lasiopus and Tithonia diversifolia were inactive to S. aureus and Bacillus subtilis, respectively. Eighteen and sixteen plants showed sensitivity of greater than 10 mm against S. aureus and B. subtilis, respectively. All control discs gave zones of inhibition of 12-24 mm, which were larger than those of the extracts. The present study validated the use of the selected medicinal plants by the herbalists in the treatment of bacterial ailments caused by the strains of bacteria investigated. Medicinal plants used for non-bacterial diseases also exhibited sensitivity towards bacterial strains tested. This implied they could be used as multi-purpose medicinal plants. PMID- 20162056 TI - Direct detection of triterpenoid saponins in medicinal plants. AB - Direct detection of saponins in medicinal plants using Fourier Transform Infrared (FTIR) spectroscopy is reported in this paper. Crude dry plant powders were mixed with potassium bromide (KBr) powder and compressed to a thin pellet for infrared examination. FTIR spectra of the test samples showed -OH, -C=O, C-H, and C=C absorptions characteristic of oleanane triterpenoid saponins. The C-O-C absorptions indicated glycoside linkages to the sapogenins. Phytochemical analysis confirmed the presence of saponins in the tested specimens. Entada leptostachya was used as a reference sample. Dry plant powder was extracted sequentially with hexane, dichloromethane, ethyl acetate and methanol. FTIR spectra of the reference sample powder and its organic solvent extracts showed characteristic saponin absorption peaks. These results indicated that direct detection of saponins in medicinal plants was possible by infrared analysis. Lengthy exhaustive chemical analyses necessary for detection of saponins could be avoided. PMID- 20162057 TI - In vitro antioxidant activities of the fractions of Coccinia grandis L. leaf extract. AB - The present study was aimed at investigating the antioxidant activities of the various fractions of the hydromethanolic extract of the leaves of Coccinia grandis L. Voigt. (Cucurbitaceae). The antioxidant activities of the fractions have been evaluated by using nine in vitro assays and were compared to standard antioxidants such as ascorbic acid, alpha-tocopherol, curcumin and butylated hydroxyl toluene (BHT). All the fractions showed effective H-donor activity, reducing power, free radical scavenging activity, metal chelating ability and inhibition of beta-carotene bleaching. None of the fractions exerted an obvious pro-oxidant activity. The antioxidant property depends upon concentration and increased with increasing amount of the fractions. The free radical scavenging and antioxidant activities may be attributed to the presence of phenolic and flavonoid compounds present in the fractions. The results obtained in the present study indicate that the leaves of C. grandis are a potential source of natural antioxidant. PMID- 20162058 TI - Microbial load and antimicrobial property of two Nigerian herbal remedies. AB - The use of herbal remedies had increased significantly in the last one decade in Nigeria. This has led to the production of herbal products with bogus claims. The microbial quality and antibacterial properties of two Nigerian herbal remedies with such claimed efficacy of curing all manners of microbial diseases were assessed. The herbal remedies were discovered to be contaminated with the following microorganisms: Bacillus subtilis, Bacillus coagulans, Bacillus cereus, Basidiobotrytis sp, Oedocephalum sp, Varicosporium sp and Articulospora inflata. Antibacterial analysis using the killing rate revealed that the herbal remedies had bacteriostatic and not bacteriocidal effect. Qualitative phytochemical screening of the herbal remedies revealed the presence of saponin, tannins, alkaloids, anthraquinone and cardiac glycosides which suggest possible antimicrobial effect. However, the presence of microbial contaminants in the herbal remedies suggests that they may serve as source of infection to end users. PMID- 20162059 TI - In vivo and in vitro effects of Bidens pilosa L. (Asteraceae) leaf aqueous and ethanol extracts on primed-oestrogenized rat uterine muscle. AB - Bidens pilosa L. is an Asteraceae growing in tropical zones, and traditionally utilized worldwide in herbal medicine. The present work is based on its traditional use during child birth as a labour facilitator. In vivo tests of acute toxicity showed a weak toxic effect for both extracts but the toxicity of the ethanol extract (LD(50)=6.15 g/kg) was upper than that of the aqueous extract (LD(50)=12.30 g/kg). The three-days uterotrophic assay on immature mice showed body weight gain followed by a concentration-dependent decrease up to 4 mg/g and a concentration dependent uterine wet weight increase. The ethanol extract exhibited the higher body weight gain representing 22.8+/-0.7%, (P < or = 0.001), at the concentration of 500 microg/g/day, while the aqueous extract was significantly more efficient on the uterine wet weight gain of 0.24+/-0.001% (P < or = 0.05), at the concentration of 1000 microg/g/day. In vitro isometric contraction measurement of oestrogen-primed rat uterine strips showed a significant high aqueous extract-induced contractile effect from 0.03-1.97 mg/ml: on the amplitude of contraction (EC(50) = 0.44+/-0.10 mg/ml, P < or = 0.05), and on the rate (1.21+/-0.25 mg/ml, P > 0.05). Inspite of the higher effect of the aqueous extract on the tonus (57.23+/-23%), the ethanol extract showed a high effect (EC(50)=0.34+/-0.09 mg/ml, P < or = 0.05). The weak toxicity, the estrogenic-like and the oxytocic-like activities observed could explain the empirical use of Bidens pilosa leaf aqueous extract as an uterotonic preparation to enhance labour, probably due to the presence of biologically active compound(s) which act directly on the uterine muscle. PMID- 20162060 TI - Phytochemical, analgesic and anti-inflammatory effects of the ethylacetate extract of the leaves of Pseudocedrella kotschyii. AB - Phytochemical screening was carried out on the ethylacetate portion of the ethanolic extract of the leaves of Pseudocedrella kotschyii and then evaluated for its analgesic (acetic acid-induced writhing) and anti-inflammatory (raw egg albumin-induced oedema) activities in mice and rats respectively. Phytochemical screening of the ethylacetate partition portion of ethanolic extract revealed the presence of flavonoids, glycosides and tannins as major chemical constituents. Alkaloids saponins, cardiac glycosides, steroids were not dictated in the extract. The ethylacetate extract (50 and 100 mg/kg i.p) exhibited significant activity (p<0.05) against acetic acid-induced writhing in a dose dependent manner. In the anti-inflammatory activity the ethylacetate extract (50 and 100 mg/kg i.p.) caused a slight effect against the raw egg albumin-induced oedema. The effect was however observed not to be dose dependent. All these effects were compared with standard drug piroxicam (20 mg/kg i.p.). PMID- 20162061 TI - In vivo evaluation of antidiarrhoeal activity of Rhus semialata fruit extract in rats. AB - Rhus semialata Murr. (Anacardiaceae) is a deciduous tree of north eastern India. The fruit of this plant is traditionally used to control diarrhoea and dysentery. The Present study was undertaken to evaluate anti-diarrhoeal potency of methanol extract of fruits of R. semialata using Wister albino rats to substantiate folklore claims. The extract at graded doses (100, 200, 400 and 600 mg/kg body weight) was investigated for anti-diarrhoeal activity in term of reduction in the rate of defecation in castor oil induced diarrhoea. To understand the mechanism of its antidiarrhoeal activity, the gastrointestinal transit and PGE(2)-induced intestinal fluid accumulation (enteropooling) were further evaluated. At graded doses, the extract showed a remarkable anti-diarrhoeal activity evidenced by the reduction in the rate of defecation up to 80.70% of control diarrhoeal animals at the dose of 600 mg/kg body weight. Results are comparable to that of standard drug diphenoxylate (50 mg/kg body weight). Extract produced profound decrease in intestinal transit (8.02-47.05%) at selected doses comparable to that of single intraperitoneal injection of standard drug atropine sulphate at doses of 0.1 mg/kg body weight. It significantly inhibited PGE(2)-induced enteropooling (21.98 56.03%). The results indicated that the methanol extract of the fruits of R. semialata possesses significant anti-diarrhoeal effect and substantiated the use of this herbal remedy as a non-specific treatment for diarrhoea in folk medicine. PMID- 20162062 TI - Herbal treatments in Aldai and Kaptumo divisions in Nandi district, Rift valley province, Kenya. PMID- 20162063 TI - Western Africa Network Natural Products Research Scientists (Wannpres), 2nd scientific meeting the Elmina Beach Resort, Elmina, Ghana. August 1-4, 2006, Elmina, Ghana. PMID- 20162065 TI - The effect of a local mineral kadosero towards the antimicrobial activity of medicinal plant's extract: case of Lake Victoria Basin, Tarime Tanzania. AB - The effect of kadosero, a crude mineral used by traditional healers as a supplement to plant extracts against microbial infections was evaluated. A sample of kadosero from a local market was both analyzed for its basic composition and its role on bioactivity of plant extract. Titrimetric, Gravimetric and Atomic Absorption Spectrometric analyses were used to determine contents of the mineral kadosero. Disc Diffusion Assay was used for bioactivity screening in-vitro. Chemical analysis of kadosero revealed the presence of SO4-2 (0.0038 mg/g), Fe(2) (0.0027 mg/g), Cl(-) (232.683 mg/g) and Na(+) (151.25 mg/g). In-vitro tests revealed that supplementing extract of Balanites aegyptiaca with a mineral kadosero by using untreated well water reduced number of bacterial from 100 colony forming units to nil at a mass of a mineral between 60-100 mg. On the other hand, a mineral kadosero did not increase bioactivity of the extract of B. aegyptiaca against the test microbes in agar disc diffusion assay. This was attributed by interaction between the mineral kadosero and nutrient agar medium. The crude mineral kadosero can be supplemented to other plant extracts used locally for treatment of general bacterial infections for increased bioactivity. Further study is recommended to determine mechanisms for bacterial vulnerability to this mineral supplement. PMID- 20162066 TI - Estrogenic and pregnancy interceptory effects of Achyranthes aspera Linn. root. AB - Achyranthes aspera Linn. (Amaranthaceae) is an abundant indigenous herb in India. It is traditionally being used as an abortifacient. Four successive solvent extracts of the root were screened for antifertility activity in female albino rats. The chloroform and ethanol extracts exhibited 100% anti-implantation activity when given orally at 200 mg/kg body weight. Both the extracts at the dose of 200 mg/kg body weight also exhibited estrogenic activity. Histological studies of the uterus were carried out to confirm this estrogenic activity. PMID- 20162067 TI - Chemopreventive effect of Cousinia shulabadensis Attar & Ghahraman ethanol extract. AB - Matrix metalloproteinases (MMPs) play an important role in several pathologic processes such as malignancy in which they facilitate invasion and metastasis and can be targets for anticancer therapies. Here, in this study, we investigated the cytotoxicity effect of Cousinia shulabadensis Attar & Ghahraman extract as well as its impact on MMPs activity using a model of cell line (Fibrosarcoma-Wehi164). To assess anti-invasiveness potentials, a modified zymoanalysis method was used to measure MMP-2 and MMP-9 activities in the conditioned-media. The concentration necessary to produce 50% cell death was >80 microg/ml for ethanol extract of Cousinia shulabadensis, while a 23 microg/ml concentration of the diclofenac sodium produced the same effect. The invasion of WEHI 164 cells was considerably inhibited at concentrations > 20 microg/ml by total plant extract. The total extract of the plant did not show high toxicity at all tested concentrations, but demonstrated significant inhibition of MMP activity in dose-response fashion. PMID- 20162068 TI - Evaluation of 17 medicinal plants from Northern Cote d'Ivoire for their in vitro activity against Streptococcus pneumoniae. AB - Twenty crude extracts from 17 species out of 11 families were assessed for their antibacterial activity against Streptococcus pneumoniae (Pneumococcus). The selected plants are used in Northern Cote d'Ivoire to treat various infections including respiratory track diseases. From all the tested extracts, only 7 from 6 plants showed a promising in vitro bactericidal activity against Pneumococcus, including strains resistant to penicillin. The most active extracts were from Erythrina senegalensis (Fabaceae), Piliostigma thonningii (Caesalpiniaceae), Waltheria indica (Sterculiaceae), Andira inermis (Fabaceae), Uapaca togoensis (Euphorbiaceae), Keetia hispida (Rubiaceae) and Combretum molle (Combretaceae). This is the first time that the antipneumococcal activity of the tested plants is reported. The results of this preliminary investigation support the traditional use of these plants in the treatment of pneumococcal infections. The most active of them could be candidates for isolation of compounds which could serve as lead structures for the development of new drugs against Streptococcus pneumoniae. PMID- 20162069 TI - Tetrapleura tetraptera: molluscicidal activity and chemical constituents. AB - Tetrapleura tetraptera (Schumach. And Thonn) Taub, Mimosaceae, commonly known as Aridan (fruit), A single stemmed, robust, perennial tree of about 30 m. It has a grey/brown, smooth/rough bark with glabrous yound branchlets. The flower is yellow/pink and racemes white the fruit has dark brown, four winged pods 12-25 x 3.5-6.5 cm. It is generally found in the lowland forest of tropical Africa. The fruit consists of a fleshy pulp with small, brownish-black seeds. The fruit possesses a fragrant, characteristically pungent aromatic odour, which is attributed to its insect repellent property. It is used as spices and aroma (exotic tropical scents) and fish poisoning. It is one of the molluscicidal medicinal plants of Nigeria, also useful in the management of convulsions, leprosy, inflammation and/or rheumatoid pains. The documented biological and-or pharmacological activities are found to be molluscicidal, cardio-vascular, neuromuscular, hypotensive, anti-convulsant, trypanocidal, hirudinicidal, schistosomiasis control, anti-ulcerative, ectoxicity, anti-inflammatory, hypoglycaemic, anti-microbial, emulsifying property, birth control, food value and the control of intestinal parasites. Activity-guided fractionation of the methanol extract of the fruits of T. tetraptera led to the isolation of a saponin glycoside with an oleanolic acid aglycone, a monodesmosidic diglycoside of the rare sapogenin 27-hydroxyolean-12 (13)-en-28-oic acid; echinocystic acid-3-0 sodium sulfate from the stembark, umbelliferone and ferulic acid from the leaves and branches respectively. Also isolated from the fruits were aridanin and three of its olean-12-en-28-oic acid derivatives. All the compounds isolated either from the fruits or other parts were found to exhibit strong molluscicidal properties against the schistosomiasis-transmitting snails Biomphalaria glabrata. PMID- 20162070 TI - Effects of the aqueous and hexane extracts of Mondia whitei on the sexual behaviour and some fertility parameters of sexually inexperienced male rats. AB - The effects of Mondia whitei Hook (Skeels) were studied on the sexual behaviour and some fertility parameters of sexually inexperienced male rats. Animals were orally administered 100 mg/kg and 500 mg/kg of body weight (b.w) of either the aqueous or the hexane extracts of Mondia whitei whilst the control group received 10 mL/kg b.w of 0.3% Tween 80 once/day for 14 days. Their sexual behaviour was monitored on days 0, 1, 7 and 14 days of treatment and 14 days post-treatment. Some fertility parameters (index libido, quantal pregnancy, fertility index) of the treated rat were evaluated on day 13 of treatment by pairing it overnight with two proestrus females. Results showed that Mondia whitei extracts significantly (p<0.001) reduced the mount latency and the hexane extract was found to be more efficient than the aqueous extract. The treatment had no significant effect (p>0.05) on intromission, ejaculation and erection. The fertility of the animals remained unaffected. It's concluded that Mondia whitei had sexual enhancement of the sexually inexperienced male rats. PMID- 20162071 TI - Antidiabetic effect of Ceiba pentandra extract on streptozotocin-induced non insulin-dependent diabetic (NIDDM) rats. AB - The aim of this work was to investigate the effect of daily oral administration of root bark methylene chloride/methanol extract of Ceiba pentandra (Linn) in streptozotocin-induced type-2 diabetic rats, and the effect of this treatment on the physiological and metabolic parameters that are related in diabetic animals. The diabetic rats were separated into four groups and each given the following samples by gavage, daily for 28 days: vehicle (diabetic control), Ceiba pentandra extract at the dose of 40 mg/kg, Ceiba pentandra extract at the dose of 75 mg/kg and glibenclamide (5 mg/kg). All the parameters were also determined in healthy (non diabetic) rats for comparison. The methylene chloride/methanol extract of Ceiba pentandra treatment significantly reduced the intake of both food and water as well as the levels of blood glucose, serum cholesterol, triglyceride, creatinine and urea, in comparison with diabetic controls. The treatment also improves impaired glucose tolerance but no effect was observed in the level of hepatic glycogen. The effect of Ceiba pentandra (40 mg/kg) was more prominent when compared to glibenclamide in lowering blood glucose, with the added benefit of considerably reducing serum cholesterol and triglyceride concentrations. The results of this experimental animal study indicated that Ceiba pentandra possesses antidiabetic activity; and thus is capable of ameliorating hyperglycaemia in streptozotocin-induced type-2 diabetic rats and is a potential source for isolation of new orally active agent(s) for anti-diabetic therapy. PMID- 20162072 TI - Naphthaquinones of Alkanna orientalis (L.) Boiss. AB - The roots of Alkanna orientalis (L.) Boiss yielded alpha-methyl-n-butyl alkannin (compound 1) and alkannin acetate (compound 2). The compounds were identified by UV, MS, (1)H NMR and (13)C NMR. Quantitative determination of alpha-methyl-n butyl alkannin and alkannin acetate in Alkanna orientalis (L) Boiss roots was established by TLC densitometry. PMID- 20162073 TI - Antimicrobial activities and toxicity of crude extract of the Psophocarpus tetragonolobus pods. AB - The extract of the Psophocarpus tetragonolobus pods has been tested for antimicrobial activity in a disk diffusion assay on eight human pathogenic bacteria and two human pathogenic yeasts. The extracts of P. tetragonolobus possessed antimicrobial activity against all tested strains. The ethanolic extract of P. tetragonolobus pods was further tested for in vivo brine shrimp lethality test and in vitro sheep erythrocyte cytotoxic assay. The brine shrimp lethality test exhibited no significant toxicity (LC(50)=1.88 mg/ml) against Artemia salina, whereas sheep erythrocyte test showed significant toxicity. The reason for haemolysis of erythrocyte was discussed. The P. tetragonolobus extract with high LC(50) value signified that this plant is not toxic to human. This result also suggested that the ethanolic extract of P. tetragonolobus pods is potential source for novel antimicrobial compounds. PMID- 20162075 TI - Traditional medicines among the Embu and Mbeere peoples of Kenya. AB - Ethnobotanical information and traditional medicines were investigated and documented in Embu and Mbeere districts, Eastern Province of Kenya. Oral interviews were obtained from over 100 herbalists, both men and women aged between 40 and 80 years. All the herbalists interviewed were Christians and had little formal education. Non-Christian herbalists were purported to combine herbal medicines with witchcraft and were not interviewed. Of the 40 commonly used herbal plants 25 were used as multi-purpose medicinal plants (mpmp), while 15 were used to treat one disease type. There was a correlation between the outpatient morbidity data at the local District hospital, and the common incident diseases treated by the herbalists. Generally a decoction or infusion of the herb was recommended for the treatment of internal or external condition of the patients. Malaria and typhoid were treatable with a total of 15 and 12 plants respectively and were among the first two commonest diseases found in the study area. Terminalia brownii was found to be the most used medicinal plant either alone or in combination with other herbs. The second and third most utilized medicinal plants were Ovariodendron anisatum and Wurbugia ugadensis respectively. PMID- 20162074 TI - Protective effect of quercetin on the morphology of pancreatic beta-cells of streptozotocin-treated diabetic rats. AB - This study was undertaken to investigate the protective effects of quercetin (QCT) on the morphology of pancreatic beta-cells against diabetes mellitus and oxidative stress experimentally-induced by streptozotocin (STZ) treatment in Wistar rats. Fifty male and female Wistar rats (200-250 g) were randomly divided into three experimental groups (i. e., control, STZ-treated, and STZ + Quercetin treated groups). Diabetes was induced in the diabetic groups (B and C) of animals, by a single intraperitoneal injection of STZ (75 mg/kg), while each of the rats in the 'control' group received equal volume of citrate buffer (pH 6.3) solution intraperitoneally. In group C rats, quercetin (QCT, 25 mg/kg/day i.p.) was injected daily for 3 days prior to STZ treatment, and QCT administration continued until the end of the study period (30 days). Diabetes mellitus was confirmed by using Bayer's Glucometer Elite and compatible blood glucose test strips. The rats were sacrificed serially until the end of the study period (after 30 days). The pancreases of the sacrificed rats were excised and randomly processed for histological staining and biochemical assays for antioxidant enzymes [such as glutathione peroxidase (GSHPx), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) and serum nitric oxide (NO)]. In the diabetic state, pancreatic beta-cells of STZ-treated group B rats histologically demonstrated an early chromatin aggregation, cytoplasmic vesiculation in the central beta-cells, nuclear shrinkage, and lysis of beta-cells with distortion of granules. The morphology of QCT-treated rats' pancreases showed viable cellularity with distinct beta-cell mass. STZ treatment significantly decreased (p<0.05) GSHPx, SOD, CAT and pancreatic insulin content. However, STZ treatment increased blood glucose concentrations, MDA and serum NO. The QCT-treated group of animals showed a significant decrease (p<0.05) in elevated blood glucose, MDA and NO. Furthermore, QCT treatment significantly increased (p<0.05) antioxidant enzymes' activities, as well as pancreatic insulin contents. Quercetin (QCT) treatment protected and preserved pancreatic beta-cell architecture and integrity. In conclusion, the findings of the present experimental animal study indicate that QCT treatment has beneficial effects on pancreatic tissues subjected to STZ-induced oxidative stress by directly quenching lipid peroxides and indirectly enhancing production of endogenous antioxidants. PMID- 20162076 TI - Evaluation of antimicrobial activity of the stem bark of Cylicodiscus gabunensis (Mimosaceae). AB - Ethyl acetate (EA) extract of the stem bark of Cylicodiscus gabunensis (CG) was analysed phytochemically and evaluated for its antimicrobial activity against 17 pathogenic species isolated from patient: Escherichia coli, Klebsiella pneumoniae, Shigella dysenteriae, Shigella flexneri, Morganella morganii, Proteus vulgaris, Proteus mirabilis, Salmonella typhi, Citrobacter freundii, Enterobacter cloacae, Enterobacter agglomerans, Staphylococcus aureus, Streptococcus feacalis, Pseudomonas aeruginosa, Bacillus cereus T, Candida albicans and Candida glabrata. Flavonoids, saponins, tannins, polyphenols, coumarins, triterpenes and/or sterols and reducing sugars were detected in the (EA) extract of CG. The best MIC and MBC values for the microorganisms sensitive to the extract were 0.00078 and 0.00315 mg/ml respectively. The greater and remarkable antimicrobial activity of the (EA) extract of CG was recorded with Staphylococcus aureus, Proteus vulgaris and Bacillus cereus T. These results provide a rationalization for the traditional use of this plant for the treatment of infectious diseases. PMID- 20162077 TI - Anticonvulsant activity of extracts of Diospyros fischeri stem bark. AB - Evaluation of extracts of Diospyros fischeri Gurke (Ebenaceae), which is used traditionally for the treatment of epilepsy shows that the aqueous extract of the tem bark has no effect against picrotoxin induced convulsions in mice. However, an 80% ethanol extract of the bark caused dose-dependent suppression of convulsions induced by 10 mg/kg body wt picrotoxin, at doses between 100-3200 mg/kg body wt. Petroleum ether, 1:1 dichloromethane:methanol, and methanol extracts also suppressed picrotoxin-induced convulsions, but had a slightly lower inhibitory effect. The petroleum ether extract was the most active, but all were less active than the ethanol extract. Unlike phenobarbitone, which at 50 mg/kg body wt completely suppressed convulsions induced by 10 mg/kg body wt picrotoxin, none of the plant extracts completely suppressed convulsions in the mice. These results support the traditional uses of D.fischeri for the treatment of epilepsy. Given the seemingly innocuous nature of the extracts more work is suggested to ascertain their clinical application. PMID- 20162078 TI - Potential of neuroprotective antioxidant-based therapeutics from Peltophorum africanum Sond. (Fabaceae). AB - There is ample scientific and empirical evidence supporting the use of plant derived antioxidants for the control of neurodegenerative disorders. Antioxidants may have neuroprotective (preventing apoptosis) and neuroregenerative roles, by reducing or reversing cellular damage and by slowing progression of neuronal cell loss. Although demand for phytotherapeutic agents is growing, there is need for their scientific validation before plant-derived extracts gain wider acceptance and use. We have evaluated antioxidant potential of Peltophorum africanum (weeping wattle), a plant widespread in the tropics and traditionally used, inter alia, for the relief of acute and chronic pain, anxiety and depression. The dried leaves, bark and root of P. africanum were extracted with acetone. Thin layer chromatograms were sprayed with 0.2% 2,2-diphenyl-1-picryl hydrazyl (DPPH) in methanol for screening for antioxidants. Quantification of antioxidant activity was assessed against 6-hydroxy-2, 5,7,8-tetramethylchromane-2-carboxylic acid (Trolox) and L-ascorbic acid (both standard antioxidants), using two free radicals, 2,2'-azinobis (3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS) and DPPH, respectively. Results of our study show that the bark and root extracts had higher antioxidant activity than L-ascorbic acid and Trolox, a synthetic vitamin E analogue. The respective TEAC (Trolox Equivalent Antioxidant Capacity) values for the bark and root extracts, and Trolox were 1.08, 1.28 and 1.0. EC(50) values for L-ascorbic acid (5.04 microg/mL) was more active than the leaf 6.54 (microg/mL), but much less active than the bark (4.37 microg/mL) and root (3.82 microg/mL) extracts. Continued work on P. africanum, and other plants rich in antioxidants, may avail neuroscientists with potent neuroprotective antioxidant therapeutics. PMID- 20162079 TI - Antimalarial activity in crude extracts of some Cameroonian medicinal plants. AB - Fifteen crude extracts from the stem bark and seeds of four medicinal plants, viz: Entandrophragma angolense, Picralima nitida, Schumanniophyton magnificum and Thomandersia hensii were tested in vitro for their antimalarial activity against the chloroquine-resistant Plasmodium falciparum W2 strain. The results showed that the extracts of these plants possessed some antimalarial activity, the methanol extract of Picralima nitida demonstrating the highest activity in vitro. Further isolation and identification of some active compounds from these plants will justify their common use in traditional medicine for the treatment of malaria or fever in Cameroon. PMID- 20162080 TI - Treatment of common ailments by plant-based remedies among the people of District Attock (Punjab) of northern Pakistan. AB - District Attock is one of the resource-based areas of medicinal plants in the north of Punjab province of Pakistan. The local people of the area have always used medicinal plants for their common ailments by traditional methods. Indigenous knowledge of local people about medicinal plants is directly linked to their culture and history. It is therefore felt worthwhile to record the indigenous knowledge about the plant-based remedies. The present communication deals with the common diseases treated by plant based remedies such as abdominal pain and worms, asthma, cough and bronchitis, cold, flu, influenza, diabetes, diarrheoa, dysentery, digestive disorders, ear infections and eye complaints. 25 species belonging to 25 genera were used for common ailments. It was found that plant based remedies were used in effective prescriptions, which are simple, inexpensive, and acceptable among the local inhabitants of the area. PMID- 20162081 TI - Artemisia annua as a herbal tea for malaria. PMID- 20162083 TI - Acute and subacute toxicity of Aspilia africana leaves. AB - This study was designed to evaluate the toxicity of the aqueous extract of Aspilia africana leaves. Oral doses of 500 mg/kg and 1000 mg/kg were administered for 28 days to rats after every 2 days for sub-acute toxicity. For acute toxicity, 5 doses of 2, 4, 8, 12 and 16 g/Kg body weight were investigated in mice. The control groups consisted of mice or rats administered with distilled water. The signs of toxicity fluctuated lightly from one mammal to another throughout the experiment. The liver, kidneys and heart weight of rats revealed no significant differences between the test groups and the control. The results indicated that the medium lethal dose (LD(50)) was found to be greater in females than males with an average of 6.6 g/Kg body weight for both sexes. Regardless of the significant differences observed at certain points in some biochemical parameters (ALT, AST, ALP, Creatinine and Glutathione); none showed any linear dose responsiveness. On the other hand, most of the parameters investigated were found to be gender dependent. These results suggested that A Africana can be classified among substances with low toxicity. PMID- 20162084 TI - The antiplasmodial agents of the stem bark of Entandrophragma angolense (Meliaceae). AB - In the search of active principles from the stem bark of Entandrophragma angolense, we submitted the compounds isolated from the dichloromethane-methanol (1:1) extract of the stem bark to antimalarial test against chloroquine resistant strain W2 of Plasmodium falciparum malaria parasite. Only 7alpha-obacunyl acetate and a cycloartane derivative exhibited a good activity, with IC(50)s of 2 and 5.4 microg/ml respectively. Other compounds were moderately active. PMID- 20162085 TI - Acute and subchronic toxicity of Anacardium occidentale Linn (Anacardiaceae) leaves hexane extract in mice. AB - These studies focus on the toxicity leaf hexane extract of A. occidentale L (Anacardiaceae) used in Cameroon traditional medicine for the treatment of diabetes and hypertension. Previous findings on antidiabetic and anti inflammatory have given support to the ethnopharmacological applications of the plant. After acute oral administration, it was found that doses of the extract less than 6 g/kg are not toxic. Signs of toxicity at high doses were asthenia, anorexia, diarrhoea, and syncope. The LD(50) of the extract, determined in mice of both sexes after oral administration was 16 g/kg. In the subchronic study, mice received A. occidentale at doses of 6, 10 and 14 g/kg (by oral route) for 56 days. At doses of 2, 6 and 10 g/kg of extract, repeated oral administration to mice produced a reduction in food intake, weight gain, and behavioural effects. Liver or the kidney function tests were assessed by determining serum parameters like, creatinine, transaminases, and urea. All these parameters were significantly (p<0.01) abnormal. Histopathological studies revealed evidence of microscopic lesions either in the liver or in the kidney which may be correlated with biochemical disturbances. We conclude that toxic effects of A. occidentale L hexane leaf extract occurred at higher doses than those used in Cameroon folk medicine. PMID- 20162086 TI - Anthelmintic efficacy of Nauclea latifolia extract against gastrointestinal nematodes of sheep: in vitro and in vivo studies. AB - Direct effects of Nauclea latifolia extracts on different gastrointestinal nematodes of sheep is described. In vivo and in vitro studies were conducted to determine possible anthelmintic effect of leaf extracts of Nauclea latifolia toward different ovine gastro intestinal nematodes. A larval development assay was used to investigate in vitro, the effect of aqueous and ethanolic extracts of N. latifolia towards strongyles larvae. The development and survival of infective larvae (L(3)) was assessed and best-fit LC(50) values were computed by global model of non-linear regression analysis curve-fitting (95% CI). Twenty sheep harbouring naturally acquired gastrointestinal nematodes were treated with oral administration of ethanolic extracts at a dose rate of 125 mg/kg, 250 mg/kg and 500 mg/kg to evaluate therapeutic efficacy, in vivo.The presence of the extracts in the cultures decreased the survival of larvae. The LC(50) of aqueous and ethanolic extract were 0.704 and 0.650 mg/ml respectively and differ significantly (P<0.05, paired t test). Faecal egg counts (FEC) on day 12 after treatment showed that the extract is effective, relative to control (1-way ANOVA, Dunnett's multiple comparison test), at 500 mg/kg against Haemonchus spp, Trichostrongylus spp (p<0.05), Strongyloides spp (P < 0.01); at 250 mg/kg against Trichuris spp (P < 0.01) and ineffective against Oesophagostomum spp (p>0.05). The effect of doses is extremely significant; the day after treatment is sometimes significant while interaction between dose and day after treatment is insignificant (2-way ANOVA). N. latifolia extract could therefore find application in the control of helminth in livestock, by the ethnoveterinary medicine approach. PMID- 20162087 TI - Biological activities of Schefflera leucantha. AB - This study investigated various biological activities of the ethanolic extract of dried ground leaves of Schefflera leucantha Viguier (Araliaceae). The extract possessed very low cytotoxicity to brine-shrimp with the LC(50) of 4,111.15 microg/ml; the significant antioxidant activity on DPPH with the EC(50) of 71.90 microg/ml; the inhibitory activity on mushroom tyrosinase with the IC(50) of 10.53 mg/ml using the dopachrome microplate-assay. The extract of 5-20 mg/ml range in the agar dilution assay were active against various pathogenic microbial (11 species, 11 strains), with the minimum inhibitory concentration (MIC) of 5 mg/ml against Clostridium spp.; MIC=10 mg/ml against enteropathogens as Bacteroides spp., Enterococcus faecalis ATCC 29212, Lactobacillus spp., Peptococcus spp. and Streptococcus mutans; MIC=10 mg/ml against a pneumonia causing bacteria Klebsiella pneumoniae and a dermatopathogen as Propionibacterium acnes; MIC=20 mg/ml against dermatopathogens as Staphylococcus aureus ATCC 6538, Streptococcus spp. and Candida albicans ATCC 90028. TLC fingerprints of the specific extracts from the leaf powder exhibited zones of steroids-terpenes and flavonoids. HPLC fingerprint of the flavonoid extract was performed. PMID- 20162088 TI - Prevention of radiation induced hematological alterations by medicinal plant Rosmarinus officinalis, in mice. AB - The modulatory influence of Rosmarinus officinalis (rosemary) leaves extract was investigated in Swiss albino mice at a dose of 3 Gy gamma radiation. For this purpose, adult Swiss albino mice were irradiated with 3 Gy gamma rays in the presence (experimental) or absence (control) of rosemary (1000 mg/kg body wt.). These animals were necropsied and their blood was collected at days 1, 3, 5, 10, 20 and 30 post-irradiation. A decrease in the number of erythrocyte and leucocyte counts, hemoglobin content and hematocrit percentage was scored in the control group; whereas a recovery pattern was recorded in experimental animals and a normal value of hematological parameters were regained by day 30 post-treatment. In irradiated group, glutathione level was registered low in the blood, whereas a significant elevation was estimated in rosemary pre-treated animals. An increase in lipid peroxidation level above normal was evident in serum of irradiated mice, while a significant decrease in such values was noted in rosemary pretreated group. The present study suggests the possible radioprotective ability of rosemary extract. PMID- 20162089 TI - Antimicrobial and antioxidant activities of some Nigerian medicinal plants. AB - Ten Nigerian plants suggested from their ethnomedical uses to possess antimicrobial and antioxidant activities were studied for their anti-microbial and anti-oxidant properties. Antimicrobial activity was tested against Escherichia coli NCTC 10418, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, Candida albicans, Candida pseudotropicalis and Trichophyton rubrum (clinical isolate). Trichilia heudelotti leaf extract showed both antibacterial and antifungal activities and was the most active against all the strains of bacteria tested. Boerhavia diffusa, Markhamia tomentosa and T. heudelotti leaf extracts inhibited the gram negative bacteria E. coli and P. aeruginosa strains whereas those of M. tomentosa, T. heudelotti and Sphenoceutrum jollyamum root inhibited at least one of the fungi tested. At a concentration of 312 microg/ml, hexane and chloroform fractions of T. heudelotti extract inhibited 6 and 14% of the fifty multi-drug resistant bacteria isolates from clinical infections, respectively. At < or = 5 mg/ml, the CHCl(3) (64%) and aqueous (22%) fractions of T. heudelotti and those of CHCl(3) (34%) and EtOAC (48%) of M. tomentosa gave the highest inhibition that was stronger than their corresponding methanol extracts. The corresponding EC(50) of the extracts on M. acuminata, T. heudelotti, E. senegalensis and M. tomentosa were 4.00, 6.50, 13.33, and 16.50 ig/ml using the TLC staining and 1,1-dipheyl-2-picry-hydrazyl (DPPH) free radical scavenging assay. Therefore, leaf extracts of M. tomentosa and T. heudelotti, especially the latter, possess strong antimicrobial and antioxidant activities and should be further investigated. These activities justified the ethnomedical uses of these plants. PMID- 20162090 TI - Evaluation of the antimicrobial properties of different parts of Citrus aurantifolia (lime fruit) as used locally. AB - We investigated the potency of Citrus aurantifolia (Lime fruit), against pathogens, in the different forms in which this fruit plant is used locally (juice of the fruit, burnt rind of the fruit commonly known as "epa-ijebu" in the Yoruba dialect) and the oil obtained from steam distillation of the fruit. The antimicrobial activity of "epa-ijebu" in different solvents was also compared. The solvents include palm-wine (a local alcoholic drink tapped from palm trees), Seaman's Schnapps 40% alcoholic drink, water, ethanol and fermented water from 3 days soaked milled maize known as "ekan-ogi" or "omidun" in the Yoruba dialect. Antimicrobial activity was carried out by the agar well diffusion. The clinical isolates used included Anaerobic facultative bacteria, namely: Staphylococcus aureus ATCC 25213, Staphylococcus aureus, Salmonella paratyphi, Shigella flexnerii, Streptococcus faecalis, Citrobacter spp, Serratia spp, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli ATCC 25922, and Escherichia coli; Fungi such as Aspergillus niger and Candida albicans; and Anaerobes which includes Bacteroides spp, Porphyromonas spp, and Clostridium spp. Crude extracts of all solvents used varied in zones of inhibition. The anaerobes and the gram positive bacteria were susceptible to all the extracts with minimum inhibitory concentration (MIC) ranging from 32 mg/ml-128 g/ml. The activity against the fungi showed only the oil extract potent for A. niger, while Candida albicans was susceptible to all the extracts with MIC ranging from 256 mg/ml-512 mg/ml. The gram-negatives have MIC ranging from 64 mg/ml-512 mg/ml. Minimum bactericidal concentration (MBC) ranged between 32 mg/ml to 512 mg/ml depending on isolates and extracting solvent. The oil and palm-wine extract of "epa-ijebu" showed greater activity than the other extracts. The killing rate of the schnapps extract on S. aureus and E. coli was 1 and 3.5 hours respectively. PMID- 20162091 TI - Medicinal plants useful for malaria therapy in Okeigbo, Ondo State, Southwest Nigeria. AB - There is increasing resistance of malaria parasites to chloroquine, the cheapest and commonly used drug for malaria in Nigeria. Artemisin, a product from medicinal plant indigenous to China, based on active principle of Artemisia annua, has been introduced into the Nigerian market. However not much has been done to project antimalaria properties of indigenous medicinal plants. This study thus, has the main objective of presenting medicinal plants used for malaria therapy in Okeigbo, Ondo State, South west Nigeria. Focus group discussions and interview were held about plants often found useful for malaria therapy in the community. Fifty species (local names) including for example: Morinda lucida (Oruwo), Enantia chlorantha (Awopa), Alstonia boonei (Ahun), Azadirachta indica (Dongoyaro) and Khaya grandifoliola (Oganwo) plants were found to be in use for malaria therapy at Okeigbo, Southwest, Nigeria . The parts of plants used could either be the barks, roots, leaves or whole plants. The recipes also, could be a combination of various species of plants or plant parts. This study highlights potential sources for the development of new antimalarial drugs from indigenous medicinal plants found in Okeigbo, Nigeria. PMID- 20162092 TI - Antibacterial screening of Aegle marmelos, Lawsonia inermis and Albizzia libbeck. AB - Three medicinal plant Aegle marmelos, Lawsonia inermis, Albizzia libbeck were extracted by soxhlet apparatus using petroleum ether, ethanol, chloroform and aqueous as solvent. Among those extract, the petroleum ether was considered as effective one. The extracts were subjected to preliminary phytochemical screening and the three plants with four extracts were tested against three gram positive bacteria (B. cereus, B. subtilis, S. aureus) and three gram negative bacteria (E. coli, P. vulgaris, and P. aeruginosa) by disc diffusion method. Maximum inhibition (3.8 cm) was recorded in Lawsonia inermis. It also showed inhibitory action against all the six pathogen tested. The zone of inhibition of the extracts was compared with the standard antibiotics Streptomycin and Spectinomycin. The study suggests that the plant is promising the development of phytomedicine for antimicrobial properties. PMID- 20162093 TI - Identifying hearing loss by means of iridology. AB - Isolated reports of hearing loss presenting as markings on the iris exist, but to date the effectiveness of iridology to identify hearing loss has not been investigated. This study therefore aimed to determine the efficacy of iridological analysis in the identification of moderate to profound sensorineural hearing loss in adolescents. A controlled trial was conducted with an iridologist, blind to the actual hearing status of participants, analyzing the irises of participants with and without hearing loss. Fifty hearing impaired and fifty normal hearing subjects, between the ages of 15 and 19 years, controlled for gender, participated in the study. An experienced iridologist analyzed the randomised set of participants' irises. A 70% correct identification of hearing status was obtained by iridological analyses with a false negative rate of 41% compared to a 19% false positive rate. The respective sensitivity and specificity rates therefore came to 59% and 81%. Iridological analysis of hearing status indicated a statistically significant relationship to actual hearing status (P < 0.05). Although statistically significant sensitivity and specificity rates for identifying hearing loss by iridology were not comparable to those of traditional audiological screening procedures. PMID- 20162094 TI - Ethno-medicinal plants and methods used by Gwandara tribe of Sabo Wuse in Niger State, Nigeria, to treat mental illness. AB - The Gwandara people of Sabo Wuse in Niger State, Nigeria are the original inhabitants of Wuse in Abuja Municipal Area Council. They were resettled at this present location of Sabo Wuse from Wuse in the Federal Capital Territory Abuja when the seat of government moved from Lagos to Abuja 30 years ago. Sabo Wuse still remains relatively a remote settlement and their lifestyle unchanged. They still depend to a large extent on their traditional knowledge of medicinal plants to treat ailments. Ethnobotanical survey was conducted to identify and document methods traditionally utilized for treatment of mental illness and to expand the quality and quantity of information for research and development especially in the area of new drug discovery and development. About sixty seven (67) Traditional Medicine Practitioners were interviewed orally with use of questionnaire. From our survey, various methods were found to be used by the traditional medicine practitioners to treat mental illness and associated disorders. These include music, incantations and medicinal plants in various formulations--decoction, powder, infusion--which are administered in various ways like fumigation, inhalation, bathing, steaming and drinking. Eighteen plant species belonging to twelve different families were documented to be included in these therapies. In conclusion, there is an array of plants used locally to treat mental illness and it is recommended that such surveys should be funded and leads for drugs to treat mental illness obtained from such, at the same time documenting our indigenous knowledge. PMID- 20162095 TI - Brine shrimp toxicity evaluation of some Tanzanian plants used traditionally for the treatment of fungal infections. AB - Plants which are used by traditional healers in Tanzania have been evaluated to obtain preliminary data of their toxicity using the brine shrimps test. The results indicate that 9 out of 44 plant species whose extracts were tested exhibited high toxicity with LC(50) values below 20 microg/ml. These include Aloe lateritia Engl. (Aloaceae) [19.1 microg/ml], Cassia abbreviata Oliv. (Caesalpiniaceae) [12.7 microg/ml], Croton scheffleri Pax (Euphorbiaceae) [13.7 microg/ml], Hymenodactyon parvifolium Brig (Rubiaceae) [13.4 microg/ml], Kigelia Africana L. (Bignoniaceae) [7.2 microg/ml], and Ocimum suave Oliv. (Labiatae) [16.7 microg/ml]. Twelve plants gave LC(50) values between 21 and 50 microg/ml, 11 plants gave LC(50) values between 50 and 100 microg/ml, and 18 plants gave LC(50) values greater than 100 microg/ml. PMID- 20162096 TI - Anticonvulsant activity of Diospyros fischeri root extracts. AB - Diospyros fischeri Gurke (Ebenaceae) is used in traditional medicine for the treatment of epilepsy. Dichloromethane, ethylacetate, and ethanol extracts of the roots, at doses between 100 and 1600 mg/kg BW, inhibited convulsions induced by the gamma-aminobutyric acid type A (GABAa) receptor antagonist, pentylenetetrazole (PTZ), in a dose dependent manner. The extracts also exhibited low toxicity against brine shrimps giving LC(50) values between 45.4 and 95.4 microg/ml. These results provide evidence for the potential of D. fischeri extracts to treat absence seizures, especially given their seemingly innocuous nature. PMID- 20162097 TI - Screening of twenty-four South African Combretum and six Terminalia species (Combretaceae) for antioxidant activities. AB - The dried leaves of Combretum and Terminalia species (Combretaceae) were extracted with acetone, hexane, dichloromethane and methanol. Thin layer chromatography (TLC) plates were developed under saturated conditions and sprayed with 0.2% 2,2-diphenyl-1-picryl hydrazyl (DPPH) in methanol for antioxidant screening. Visualization of separated bands exhibiting antioxidant activities enabled the localization and the subsequent identification of the potential active compounds. The acetone and methanol extracts displayed the presence of antioxidant activity after spraying the chromatogram with DPPH. Hexane and dichloromethane extracts did not have any antioxidant activity. C. hereroense had the highest number of active compounds, followed by C. collinum ssp. taborense, which were 16 and 10, respectively. Acetone extracts of all tested Combretum species had 53 active bands and methanol had 55. All Terminalia species extracted with acetone and methanol had antioxidant activity. T. gazensis and T. mollis methanol extracts had 11 and 14 active compounds respectively in one of the solvent systems used. The qualitative DPPH assay on TLC was successfully used in this study to systematically assess the total antioxidant activity of the Combretum and Terminalia species extracts. PMID- 20162098 TI - Analgesic and anti-inflammatory properties of aqueous extract from leaves of Solanum torvum (Solanaceae). AB - Solanum torvum is used in Cameroonian traditional medicine for the management of pain and inflammation. The present work assesses the pain-killing and anti inflammatory properties of the aqueous extracts of Solanum torvum leaves. Acetic acid- and pressure- induced pains were reduced by this extract while carrageenan induced inflammation was inhibited at various doses of the extract. The extract therefore has both analgesic and anti-inflammatory properties. PMID- 20162101 TI - Material world. PMID- 20162100 TI - Persistent mitochondrial damage by nitric oxide and its derivatives: neuropathological implications. AB - Approximately 15 years ago we reported that cytochrome c oxidase (CcO) was persistently inhibited as a consequence of endogenous induction and activation of nitric oxide ((*)NO) synthase-2 (NOS2) in astrocytes. Furthermore, the reactive nitrogen species implicated was peroxynitrite. In contrast to the reversible inhibition by (*)NO, which occurs rapidly, in competition with O(2), and has signaling regulatory implications, the irreversible CcO damage by peroxynitrite is progressive in nature and follows and/or is accompanied by damage to other key mitochondrial bioenergetic targets. In purified CcO it has been reported that the irreversible inhibition occurs through a mechanism involving damage of the heme a(3)-Cu(B) binuclear center leading to an increase in the K(m) for oxygen. Astrocyte survival, as a consequence of peroxynitrite exposure, is preserved due to their robust bioenergetic and antioxidant defense mechanisms. However, by releasing peroxynitrite to the neighboring neurons, whose antioxidant defense can, under certain conditions, be fragile, activated astrocytes trigger bioenergetic stress leading to neuronal cell death. Thus, such irreversible inhibition of CcO by peroxynitrite may be a plausible mechanism for the neuronal death associated with neurodegenerative diseases, in which the activation of astrocytes plays a crucial role. PMID- 20162102 TI - Adult stem cells derived from human maxillary sinus membrane and their osteogenic differentiation. AB - PURPOSE: To investigate the method and conditions of isolation and proliferation of multipotent mesenchymal stem cells (MSCs) from human maxillary sinus membrane in vitro and to induce osteogenic differentiation directly for identification. MATERIALS AND METHODS: A human maxillary sinus membrane specimen was collected in aseptic conditions from an orthognathic surgery patient and cultured. The cells at passage three were sorted by flow cytometry and treated with osteogenic differentiation media. To determine the osteogenic potential of these cells, the authors analyzed alkaline phosphatase (ALP) expression, mineralization of extracellular matrix, and osteocalcin expression; staining with alizarin red and von Kossa and reverse-transcriptase polymerase chain reaction were also performed. RESULTS: Maxillary sinus membrane-derived cells were positive for STRO 1 and CD105 and negative for CD34. After 7 days, ALP began to be expressed. After 21 and 28 days, most cells showed expression of ALP. Mineralization of the extracellular matrix was observed and, after 21 and 28 days, most of the cells showed mineralization. After 7 days, the osteocalcin gene was expressed; this expression was strongest on the 28th day. CONCLUSIONS: The results suggest that there are MSCs in human maxillary sinus membrane tissue, which can be differentiated into osteoblasts under osteogenic induction. This indicates that maxillary sinus membrane may be a useful source of MSCs for cell therapy. PMID- 20162103 TI - Biomechanical evaluation of implant placement in the reconstructed mandible. AB - PURPOSE: Following resection of malignant tumors from the mandible, immediate reconstruction of the discontinuous jaw is commonly performed. The present study aims to define the risks associated with dynamic loading of the reconstructed mandible. MATERIALS AND METHODS: Computer-aided design simulations of eight mandibles were produced and termed normal models. The normal models were then modified by removing part of the right body and restoring the defects with bone from the rib or fibula. These modified models were termed reconstructed models. Thereafter, an implant was embedded in the first molar region of the left side for all models. Using finite element analysis, the stresses occurring at the implant-bone interface with simulated mastication were calculated. The Wilcoxon signed rank test was applied to compare the magnitudes of stresses in both models. RESULTS: In terms of the stress exerted at the implant-bone interface during mastication, the normal models and the reconstructed models showed no significant differences (P > .05). CONCLUSION: Placement of an implant on the nonreconstructed side following partial resection and mandibular reconstruction presents no significant risk. PMID- 20162104 TI - Quantifying the influence of bone density and thickness on resonance frequency analysis: an in vitro study of biomechanical test materials. AB - PURPOSE: Resonance frequency analysis (RFA) offers the opportunity to monitor the osseointegration of an implant in a simple, noninvasive way. A better comprehension of the relationship between RFA and parameters related to bone quality would therefore help clinicians improve diagnoses. In this study, a bone analog made from polyurethane foam was used to isolate the influences of bone density and cortical thickness in RFA. MATERIALS AND METHODS: Straumann standard implants were inserted in polyurethane foam blocks, and primary implant stability was measured with RFA. The blocks were composed of two superimposed layers with different densities. The top layer was dense to mimic cortical bone, whereas the bottom layer had a lower density to represent trabecular bone. Different densities for both layers and different thicknesses for the simulated cortical layer were tested, resulting in eight different block combinations. RFA was compared with two other mechanical evaluations of primary stability: removal torque and axial loading response. RESULTS: The primary stability measured with RFA did not correlate with the two other methods, but there was a significant correlation between removal torque and the axial loading response (P < .005). Statistical analysis revealed that each method was sensitive to different aspects of bone quality. RFA was the only method able to detect changes in both bone density and cortical thickness. However, changes in trabecular bone density were easier to distinguish with removal torque and axial loading than with RFA. CONCLUSIONS: This study shows that RFA, removal torque, and axial loading are sensitive to different aspects of the bone-implant interface. This explains the absence of correlation among the methods and proves that no standard procedure exists for the evaluation of primary stability. PMID- 20162105 TI - Meta-analysis of methods used to assess implant stability. AB - PURPOSE: To evaluate correlations between Periotest, cutting torque or insertion torque, and/or the reverse torque test with resonance frequency analysis measurements. MATERIALS AND METHODS: The combined search terms dental implant, primary stability, resonance frequency analysis, removal torque, vibration analysis, torque, Periotest, cutting torque, and insertion torque and specific inclusion and exclusion criteria were used to retrieve eligible articles published between 1998 and 2008 (up to April 1) from PubMed, EMBASE, OVID, The Cochrane Library databases, and 10 journals by hand-searching. The pooled P value was calculated with the Fisher method. The correlation coefficients (r) were combined using fixed and random effect models. Heterogeneity of the studies was tested by performing the homogeneity test. RESULTS: Fifty articles were identified, but 3 studies were excluded because of limitations in study design. Studies that fulfilled the inclusion criteria fell into a variety of categories (11 human cadaver, 16 clinical, 15 animal, and 5 in vitro studies). Assessment of P values revealed that correlation between cutting torque or insertion torque and resonance frequency analysis was significant (6 studies; P = .0022). Correlation between Periotest and cutting torque or insertion torque was significant (1 study; P = .015), and correlations between resonance frequency analysis and reverse torque test values (1 study; P = .319; r = 0.405) and Periotest and resonance frequency analysis (P = .28) were insignificant. Nine articles provided r values, and cutting torque or insertion torque and resonance frequency analysis showed a statistically significant and direct relationship of 55.4% (P = .000). One study provided an r value of -0.149. A statistically significant and direct relationship of 87.6% was found between cutting torque or insertion torque and reverse torque (2 studies; P = .000). CONCLUSION: This meta-analysis of 47 studies showed a statistically significant correlation between cutting torque or insertion torque and resonance frequency analysis. PMID- 20162106 TI - Divergence correction associated with implant placement: a radiographic study. AB - PURPOSE: To evaluate implant angulations and alignments with neighboring teeth/implants and compare them to angulations and alignments measured with preinsertion surgical gauges. MATERIALS AND METHODS: Two hundred implants placed freehand were included. For each site, two panoramic radio?graphs were obtained, one with a gauge and one with an implant. The mesiodistal angular relationships between gauge and subsequently placed implant, gauge and gauge (for neighboring implants), gauge and neighboring teeth, implant and neighboring teeth, and gauge and the inferior border of the mandible were measured. RESULTS: The mean gauge implant discrepancy was -0.72 degrees. The gauge to teeth angulation was -3.95 degrees, the implant-teeth angulation was -4.67 degrees, the gauge-gauge angulation was 0.49 degrees, and the angulation between the gauge and the inferior border of the mandible was 86.86 degrees. Maxillary implants were more divergent than mandibular implants (-9.89 degrees versus -2.14 degrees). Likewise, implants placed away from (opposite) the clinician's side had smaller gauge-implant discrepancies than those placed in the ipsilateral side (-0.94 degrees versus -1.66 degrees). Implant location (incisor, premolar, molar) also affected this angular relationship; implants placed in the anterior region diverged more (-3.96 degrees) than implants placed in premolar (-1.02 degrees) and molar regions (0.06 degrees). Implants that were placed adjacent to teeth had greater divergence than implants placed in an edentulous region (-1.66 degrees versus 0.09 degrees). Likewise, gauges placed in conjunction with shorter implants (10 mm or shorter) were more divergent than those placed in conjunction with longer implants (-8.29 degrees versus -3.259 degrees, respectively). CONCLUSION: Placement of dental implants, even without the use of a surgical guide, can result in adequate dental implant angular relationships. An implant's location (arch, side, or site) and the presence of adjacent teeth might affect these relationships. PMID- 20162107 TI - Stress analysis in simulation models with or without implant threads representation. AB - PURPOSE: This study aimed to evaluate the influence of implants with or without threads representation on the outcome of a two-dimensional finite element (FE) analysis. MATERIALS AND METHODS: Two-dimensional FE models that reproduced a frontal section of edentulous mandibular posterior bone were constructed using a standard crown/implant/screw system representation. To evaluate the effect of implant threads, two models were created: a model in which the implant threads were accurately simulated (precise model) and a model in which implants with a smooth surface (press-fit implant) were used (simplified model). An evaluation was performed on ANSYS software, in which a load of 133 N was applied at a 30 degree angulation and 2 mm off-axis from the long axis of the implant on the models. The Von Mises stresses were measured. RESULTS: The precise model (1.45 MPa) showed higher maximum stress values than the simplified model (1.2 MPa). Whereas in the cortical bone, the stress values differed by about 36% (292.95 MPa for the precise model and 401.14 MPa for the simplified model), in trabecular bone (19.35 MPa and 20.35 MPa, respectively), the stress distribution and stress values were similar. Stress concentrations occurred around the implant neck and the implant apex. CONCLUSIONS: Considering implant and cortical bone analysis, remarkable differences in stress values were found between the models. Although the models showed different absolute stress values, the stress distribution was similar. PMID- 20162108 TI - The effect of different screw-tightening techniques on the stress generated on an internal-connection implant superstructure. AB - PURPOSE: This study evaluated the effect of different screw-tightening sequences, forces, and methods on the stresses generated on a well-fitting internal connection implant (Astra Tech) superstructure. MATERIALS AND METHODS: A metal framework directly connected to four parallel implants was fabricated on a fully edentulous mandibular resin model. Six stone casts with four implant replicas were made from a pickup impression of the superstructure to represent a "well fitting" situation. Stresses generated by four screw-tightening sequences (1-2-3 4, 4-3-2-1, 2-4-3-1, and 2-3-1-4), two forces (10 and 20 Ncm), and two methods (one-step and two-step) were evaluated. In the two-step method, screws were tightened to the initial torque (10 Ncm) in a predetermined screw-tightening sequence and then to the final torque (20 Ncm) in the same sequence. Stresses were recorded twice by three strain gauges attached to the framework (superior face midway between abutments). Deformation data were analyzed using multiple analysis of variance at a .05 level of statistical significance. RESULTS: In all stone casts, stresses were produced by the superstructure connection, regardless of screw-tightening sequence, force, and method. No statistically significant differences for superstructure preload stresses were found based on screw tightening sequences (-180.0 to -181.6 microm/m) or forces (-163.4 and -169.2 microm/m) (P > .05). However, different screw-tightening methods induced different stresses on the superstructure. The two-step screw-tightening method ( 180.1 microm/m) produced significantly higher stress than the one-step method ( 169.2 microm/m) (P = .0457). CONCLUSIONS: Within the limitations of this in vitro study, screw-tightening sequence and force were not critical factors in the stress generated on a well-fitting internal-connection implant superstructure. The stress caused by the two-step method was greater than that produced using the one-step method. Further studies are needed to evaluate the effect of screw tightening techniques on preload stress in various different clinical situations. PMID- 20162109 TI - Evaluation of the osteogenic potential in experimental defects, with and without bone marrow, in the rabbit tibia: a pilot study. AB - PURPOSE: The influence of bone marrow in the osteogenic potential of bone has not been evaluated in the rabbit tibia model. Previous studies employed this model extensively to test the osteogenic capabilities of bone grafts. The primary aim of the present study was to assess the role of bone marrow in the healing of experimental defects in the rabbit tibia model. MATERIALS AND METHODS: Ten New Zealand rabbits were divided into two groups of five each. In the first experimental test group (PoP), the marrow cavity was emptied completely under a 6 mm defect in the rabbit tibia metaphysis; the marrow was replaced by plaster of Paris, and a round piece of lyophilized collagen membrane was placed in contact with the endosteum and rested on the plaster. In the second experimental group (control), similar artificial defects were made, but the marrow was left intact. After 8 weeks, the animals were sacrificed and prepared for histologic and histomorphometric analysis. RESULTS: There was a statistically significant difference (P = .016) in newly formed bone area between the control group (mean, 68.08% +/- 12.09%) and the PoP group (mean, 54.02% +/- 13.93%). Similarly, there was a statistically significant difference in new bone density (P < .001) between the control group (mean, 95.99% +/- 1.74%) and the PoP group (mean, 75.37% +/- 13.27%). CONCLUSIONS: The current study confirms the significant effect that bone marrow has in bone regeneration and also the true regenerative capabilities of the osseous walls of the defects. The proposed experimental model may be a more reliable method of investigating and comparing the potential of different graft materials and methods. PMID- 20162110 TI - In vitro evaluation of reverse torque value of abutment screw and marginal opening in a screw- and cement-retained implant fixed partial denture design. AB - PURPOSE: The purpose of this study was to evaluate the clinical efficacy of implant prostheses retained by screws and cement (SCPs) by examining the reverse torque values (RTVs) of the abutment screws and the marginal openings of the implant prostheses. MATERIALS AND METHODS: Two implants (3.8 x 13 mm; Camlog Biotechnologies) were embedded in an acrylic resin block 5 mm apart. Eighteen copies of this resin specimen were fabricated and randomly divided into two groups. Two-unit implant prostheses with two different designs-purely cement retained implant prostheses (group 1) and SCPs (group 2)-were made out of type IV gold alloy and placed on the implants. After tightening to about 30 Ncm, the preloading RTVs of the abutment screws were measured. After retightening the abutment screws or cementing the prostheses, followed by cyclic loading, the postloading RTVs of the abutment screws were examined. Also, the marginal openings of the prostheses in the two groups were measured under a stereomicroscope. These measurements were compared statistically. RESULTS: The postloading RTVs and their differences from the preloading RTVs of the abutment screws demonstrated no significant differences between groups (P > .05). Group 2 prostheses showed significantly smaller marginal openings than group 1 prostheses (P < .05). CONCLUSION: The forces generated when torquing the abutment screw of the SCP did not cause more loosening of the abutment screws than the purely cement-retained implant prosthesis. The SCP showed better marginal adaptation of the cement-retained part than the purely cement-retained implant prosthesis, possibly as a result of the screw-retained abutment seating the restoration. Within the limitations of this in vitro test, the SCP showed no significant difference in RTV of the abutment screw and a smaller marginal gap compared to a purely cement-retained implant prosthesis. PMID- 20162111 TI - The effects of growth hormone on the initial bone formation around implants. AB - PURPOSE: The aim of this study was to evaluate the effect of the topical application of growth hormone on the osseointegration of dental implants in beagle dogs 14 days after placement. MATERIALS AND METHODS: Maxillary and mandibular premolars and molars were extracted from 12 beagle dogs. Two months later, each mandible received cylindric screw-type implants of 3.25 mm in diameter and 10 mm in length. The implants were randomly assigned to the mesial and distal sites on each side of the mandible. Prior to implantation, lyophilized powdered growth hormone was applied to one osteotomy on each side of the mandible. No growth hormone was applied at the control sites. Eight histologic sections per implant were obtained for histomorphometric analysis. RESULTS: After a 2-week treatment period, the growth hormone-treated sites showed significant (P < .0001) increases in the perimeter of bone that was in direct contact with the treated implants (40.19% +/- 2.51%), total peri-implant area (P < .001) (69.57% +/- 3.53%), and new bone formation (P < .0001) (35.18% +/- 0.31%), in comparison to control implants (25.05% +/- 2.43%, 53.40% +/- 4.58%, and 28.65% +/- 1.92%, respectively). There was no significant increase in interthread bone in growth hormone-treated implants (27.92% +/- 3.31%) in comparison to control implants (25.08% +/- 3.47%) (P > .05). CONCLUSION: Topical application of growth hormone may act as a bone stimulant in the placement of endosseous dental implants. PMID- 20162112 TI - Influence of osteopenia in autogenous bone graft healing with or without expanded polytetrafluoroethylene membranes: histologic and histomorphometric study in rats. AB - PURPOSE: The aim of this study was to quantitatively evaluate and qualitatively describe autogenous bone graft healing with or without an expanded polytetrafluoroethylene (e-PTFE) membrane in ovariectomized rats. MATERIALS AND METHODS: Eighty Wistar rats, weighing approximately 300 g each, were used. A graft was obtained from the parietal bone and fixed to the sidewall of each animal's left mandibular ramus. The animals were randomly divided into four experimental groups (n = 20 in each group): group 1, sham operated and autogenous bone graft only; group 2, sham operated and autogenous bone graft covered by e PTFE membrane; group 3, ovariectomized (OVX) and autogenous bone graft only; group 4, OVX and autogenous bone graft covered by e-PTFE membrane. The animals were sacrificed at five different time points: immediately after grafting or at 7, 21, 45, or 60 days after grafting. Histologic examination and morphometric measurement of the sections were performed, and values were submitted to statistical analyses. RESULTS: Both groups (sham and OVX) experienced loss of the original graft volume when it was not covered by the membrane, whereas use of the membrane resulted in additional bone formation beyond the edges of the graft and under the membrane. Histologic analysis showed integration of the grafts in all animals, although a larger number of marrow spaces was found in OVX groups. CONCLUSIONS: Association of bone graft with an e-PTFE membrane resulted in maintenance of its original volume as well as formation of new bone that filled the space under the membrane. Osteopenia did not influence bone graft repair, regardless of whether or not it was associated with e-PTFE membrane, but descriptive histologic analysis showed larger numbers of marrow spaces in the bone graft and receptor bed and formation of new bone in the OVX animals. PMID- 20162113 TI - Mechanical stability of immediately loaded implants with various surfaces and designs: a pilot study in dogs. AB - PURPOSE: Immediate loading is among the most innovative techniques in implant therapy today. This pilot study investigates the biomechanical outcome of various designs and surfaces that claim to shorten implant treatment. MATERIALS AND METHODS: In each quadrant of two mongrel dogs, four different implants were used for immediate loading. The following implants were placed 3 months after tooth extraction: screw with low thread profile and anodic oxidized surface (LPAOS), solid screw with wide thread profile and titanium plasma spray coating (WPTPS), screw with low profile and hybrid design of double-etched and machined surface (LPHES), and screw with two thread profiles and a sandblasted and acid-etched surface (DTSAE). The insertion torque of each implant was above 35 Ncm. Resonance frequency analysis was performed after implant placement and again after sacrifice. Additionally, the removal torque and the amount of embedded titanium particles in the peri-implant bone were measured. RESULTS: All 16 prostheses were functional after a 5-month loading period. The highest mean removal torque values were recorded with WPTPS implants (24.4 Ncm/mm), followed by DTSAE implants (22.3 Ncm/mm) and LPAOS implants (18.7 Ncm/mm); the lowest score was obtained by LPHES (12.0 Ncm/mm). The ISQ values increased between the time of surgery and recall for all systems on average, but a significant positive correlation was found for DTSAE only. Significantly higher amounts of titanium were found in the surrounding bone with WPTPS (0.76%) and LPAOS (0.41%) in comparison with DTSAE (0.10%) and LPHES (0.03%). CONCLUSION: Immediate loading is possible with various designs and surfaces if high primary stability can be achieved during implant placement. PMID- 20162114 TI - Clinical histology of microimplants placed in two different biomaterials. AB - PURPOSE: This randomized, controlled study was designed to compare bone formation around microimplants with a sandblasted, acid-etched surface placed at the time of maxillary sinus floor augmentation with a synthetic biphasic calcium phosphate (BCP) or deproteinized bovine bone (DBB). MATERIALS AND METHODS: Nine completely edentulous patients and two partially edentulous patients (six women, five men) with a mean age of 67 years (range, 50 to 79 years) requiring bilateral sinus augmentation were included in the study. The patients were randomized for augmentation with BCP (test) in one side and DBB (control) in the contralateral side. At the time of augmentation, one microimplant on each side was placed vertically from the top of the alveolar crest, penetrating the residual bone and the grafting material. After 8 months of graft healing, at the time of ordinary implant placement, all 22 microimplants were retrieved with a surrounding bone core for histologic analyses. RESULTS: The bone-to-implant contact in the BCP group was 64.6% +/- 9.0%, versus 55.0% +/- 16.0% for the DBB group. The difference was not significant. The corresponding values for the area of newly formed bone in the biopsies were 41.1% +/- 9.8% and 41.6% +/- 14.0% for BCP and DBB, respectively. There were significantly more DBB particles in contact with newly formed bone than BCP particles (87.9 +/- 18.2% versus 53.9 +/- 26.1%; Wilcoxon rank sum test; P = .007). CONCLUSION: In this randomized, controlled clinical trial, new bone formation and bone-to-implant contact around microimplants with a sandblasted, acid-etched surface was found to be equivalent between sinuses augmented with BCP or DBB. Significantly more DBB particles than BCP particles were in contact with newly formed bone, but the clinical relevance of this has yet to be established. PMID- 20162115 TI - Evaluation of the effect of tumor necrosis factor-alpha gene polymorphism on the risk of peri-implantitis: a case-control study. AB - PURPOSE: Tumor necrosis factor-alpha (TNFalpha) is a proinflammatory cytokine, which promotes bone resorption and mediates the inflammatory response to infection. Because implant failures appear to cluster in subsets of individuals, this phenomenon may be related to gene polymorphisms. Therefore, the aim of this study was to investigate the relationship between a specific polymorphism in the TNFalpha gene (allele 2 of TNFalpha(-308)) and peri-implantitis. MATERIALS AND METHODS: This case-control study included Caucasian nonsmoking Brazilian patients with implant-supported restorations. Oral epithelial cells were taken from patients with and without peri-implantitis to evaluate the frequencies of different alleles of the TNFalpha(-308) gene by polymerase chain reaction. RESULTS: Ninety patients (49 with peri-implantitis and 41 with healthy implants) were enrolled in this study. Polymorphism in allele 2 of TNFalpha(-308) was not associated with an increased risk for peri-implantitis (P = .8171), although 14.63% of the subjects in the control group carried allele 2 and 19.39% in the peri-implantitis group carried allele 2 (chi-squared = 0.708; P = .5202). CONCLUSION: Polymorphism of the TNFalpha(-308) gene was not associated with an increased risk of peri-implantitis in the population evaluated in this study. PMID- 20162116 TI - Immediate functional loading in the maxilla using implants with platform switching: five-year results. AB - PURPOSE: Immediate loading in the maxilla is not a routinely recommended treatment concept; however, some clinical series have shown a high survival rate for nonfunctionally loaded implants. The purpose of this study was to demonstrate the prognosis for immediately loaded implants with a progressive thread design and platform switching placed in the maxilla with or without simultaneous augmentations using autogenous bone. MATERIALS AND METHODS: Ninety implants were placed (six in each maxillary arch) in 15 patients. Immediately after surgery, the implants were loaded with a provisional acrylic resin prosthesis (immediate occlusal loading). Splinting of the implants with the provisional remained for 6 to 8 weeks of healing. In patients with augmented sites, a 3-month period of provisionalization was necessary to ensure implant stability; a soft/liquid diet was recommended for this intermediate transitional period. Definitive fixed restorations were then fabricated and delivered. Clinical and radiologic examinations of the implants were performed at various times. RESULTS: After a mean loading period of 42.4 (+/- 19.15) months, only three failures were reported. This represented a survival rate of 96.66%. No complications, including inflammation or bone loss, were reported during the study period. CONCLUSIONS: Based on these results, the immediate loading protocol in the maxilla can be used successfully when implant primary stability, cross-arch stabilization, and a soft diet for the initial stages of healing are considered. PMID- 20162117 TI - A retrospective study of the survival of smooth- and rough-surface dental implants. AB - PURPOSE: To compare the time-dependent cumulative survival rates of smooth- and rough-surface dental implants. MATERIALS AND METHODS: A retrospective chart review was conducted for two time periods: January 1, 1991, through December 31, 1996, during which smooth-surface implants were used, and January 1, 2001, through December 31, 2005, during which rough-surface implants were used. This study included all implants placed and restored in one institution during the two time frames. Data were collected relative to patient age, gender, implant diameter, implant length, and anatomic location of implants. To facilitate the comparison, implants from the first and second time periods were followed through mid-1998 and mid-2007, respectively. Associations of patient/implant characteristics with implant survival were evaluated using marginal Cox proportional hazards models (adjusted for age and gender) and summarized with hazard ratios and corresponding 95% confidence intervals. RESULTS: A total of 593 patients (322 women and 271 men; mean age, 51.3 +/- 18.5 years) received 2,182 smooth-surface implants between 1991 and 1996, while 905 patients (539 women and 366 men; mean age, 48.2 +/- 17.8 years) received 2,425 rough-surface implants between 2001 and 2005. At 5 years after implant placement, survival rates were 94.0% and 94.5%, respectively, for smooth- and rough-surface implants (difference not significant). Among the smooth implants, implant length Cr(IV) --> Cr(II) and Cr(VI) --> Cr(IV) --> Cr(III). The mechanism is supported by the observation of free radicals, CrO(2)(2+) (superoxoCr(III) ion) and Cr(V) as reaction intermediates. The EPR spectra show that five-co-ordinate oxo-Cr(V) bischelates are formed at pH < or = 4 with the uronic acid bound to Cr(V) through the carboxylate and the alpha-OH group of the furanose form. Five-co-ordinated oxo-Cr(V) monochelates are observed as minor species in addition to the major five-co-ordinated oxo-Cr(V) bischelates. At pH 7.5 the EPR spectra show the formation of a Cr(V) complex where the cis-diol groups of Glucur participate in the bonding to Cr(V). In vitro, our studies on the chemistry of Cr(V) complexes can provide information on the nature of the species that are likely to be stabilized in vivo. In particular, the EPR pattern of Glucur-Cr(V) species can be used as a finger print to identify Cr(V) complexes formed in biological systems. PMID- 20162194 TI - The useful properties of H2O as a ligand of a hydrogenase mimic. AB - This paper investigates the required properties of Ru-coordinated ligands of a Ni Ru based hydrogenase mimic. A series of ligands, including MeCN, pyridine, H(2)O and OH(-) were coordinated to Ru, with H(2)O being the only ligand to promote H(2)-activation. In addition, a tethered pyridyl moiety was synthesised and found to completely inhibit H(2)-activation. We conclude, therefore, that H(2)O is the ideal ligand for this mimic as a result of both its mild basicity and the availability of two lone pairs for simultaneous binding to Ru and H(2). PMID- 20162195 TI - Controllable synthesis and luminescent properties of novel erythrocyte-like CaMoO4 hierarchical nanostructures via a simple surfactant-free hydrothermal route. AB - Synthesis of metal molybdates (XMoO(4), X = Ca, Sr, Ba) have received much attention recently because of their interesting structural and luminescent properties. Here novel erythrocyte-like CaMoO(4) hierarchical nanostructures are synthesized via a simple surfactant-free hydrothermal route. The formation of the calcium molybdate erythrocytes is controllable through adjusting the fundamental experimental parameters including reaction time, temperature and DMAc to H(2)O ratio. The as-synthesized products are characterized using X-ray powder diffraction, scanning electron microscopy, Brunauer-Emmett-Teller and transmission electron microscopy. The results show that the nucleation and growth of the novel erythrocyte-like CaMoO(4) hierarchical nanostructures are governed by an oriented attachment growth mechanism. The luminescent properties of the CaMoO(4) erythrocytes are then studied using a spectrophotometer and the erythrocyte-like CaMoO(4) nanostructures display a strong blue emission. This study provides an easy surfactant-free synthetic route for the controllable construction of inorganic materials with high hierarchy in the absence of any surfactants. PMID- 20162196 TI - Chromium containing zinc oxide materials from organobimetallic precursors. AB - Zinc oxide has become one of the most important semiconductor materials and it possesses a multitude of properties and applications. An even wider spectrum of properties can be envisioned if an additional element is introduced. On the cation side there is large interest in the combination of ZnO with paramagnetic metal centres like Cr(III). Two new single source precursors containing "ZnO" and chromium in the ratios 1 : 1 and 1 : 2 are presented. Advantages and disadvantages of using these precursors are reported. One of the advantages is that the geometric organization of the magnetic centres in the ZnO matrix can be preorganized on the molecular scale. PMID- 20162197 TI - Synthesis, characterisation and biological properties of gold(III) compounds with modified bipyridine and bipyridylamine ligands. AB - Square planar gold(III) complexes that contain functionalised bipyridine ligands of general formula [Au(N--N)Cl(2)][PF(6)] [where N--N = 2,2'-bipyridine, 4,4' dimethyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine and 4,4'-diamino-2,2' bipyridine] have been prepared and characterised by NMR spectroscopy and mass spectrometry. Two of the complexes have also been characterised in the solid state by X-ray crystallography. In addition, a gold(iii) compound bearing a dipyridin-2-ylamine ligand was also prepared and characterised. The complexes were found to undergo hydrolysis under pseudo-physiological conditions. Moreover, the complexes showed moderate to good cytotoxicity in vitro towards the A2780 human ovarian carcinoma cell line and the cisplatin resistant variant A2780cisR. Reactivity studies with biomolecules, such as reducing agents, plasmid DNA and a model protein (ubiquitin) were also performed to provide tentative insights into the mode of action of the complexes. PMID- 20162198 TI - Synthesis and in situ transformation of PST-1: a potassium gallosilicate natrolite with a high Ga content. AB - The synthetic details of a novel potassium gallosilicate natrolite with Si/Ga = 1.28, denoted PST-1, are described. The presence of K(+) and Ga with well-defined levels of concentration in the synthesis mixture is essential for directing its crystallisation. PST-1 transforms rapidly into TNU-6 under hydrothermal conditions, behaviour that contrasts sharply with its very high thermal and hydrothermal stability, which is unusual for a material of such a high Ga content. These stability issues are discussed and rationalized based on chemical composition, likely violations of Loewenstein's rule and the temperature of dehydration of as-made K-PST-1. The crystal structure of TNU-6 has been resolved through the combined use of synchrotron X-ray and electron diffraction data; it has the BaFeGaO(4) structure type with an additional radical 3a x radical 3a "GeAlO(4)" superstructure that arises from tilting of some of the tetrahedral units in all of the 6-rings. PMID- 20162199 TI - Synthesis of zirconia sol stabilized by trivalent cations (yttrium and neodymium or americium): a precursor for Am-bearing cubic stabilized zirconia. AB - Recent concepts for nuclear fuel and targets for transmuting long-lived radionuclides (minor actinides) and for the development of innovative Gen-IV nuclear fuel cycles imply fabricating host phases for actinide or mixed actinide compounds. Cubic stabilized zirconia (Zr, Y, Am)O(2-x) is one of the mixed phases tested in transmutation experiments. Wet chemical routes as an alternative to the powder metallurgy are being investigated to obtain the required phases while minimizing the handling of contaminating radioactive powder. Hydrolysis of zirconium, neodymium (a typical surrogate for americium) and yttrium in aqueous media in the presence of acetylacetone was firstly investigated. Progressive hydrolysis of zirconium acetylacetonate and sorption of trivalent cations and acacH on the zirconia particles led to a stable dispersion of nanoparticles (5-7 nm) in the 6-7 pH range. This sol gels with time or with temperature. The application to americium-containing solutions was then successfully tested: a stable sol was synthesized, characterized and used to prepare cubic stabilized zirconia (Zr, Y, Am)O(2-x). PMID- 20162200 TI - Synthesis, structure, transformation studies and catalytic properties of open framework cadmium thiosulfate compounds. AB - Five new thiosulfate based inorganic-organic hybrid open-framework compounds have been synthesized employing mild reaction conditions. Of the five compounds, [Na(2)(H(2)O)(8)][Cd(C(10)H(8)N(2))(S(2)O(3))(2)].2H(2)O, I and [Cd(2)(C(10)H(8)N(2))(2)(HS(2)O(3))(2)(S(2)O(3))(2)][(C(10)H(9)N(2))(2)(C(10)H(8) (2))(2)].8H(2)O, II have one-dimensional (1D) structures and [Cd(C(10)H(8)N(2))(H(2)O)(2)(S(2)O(3))].2H(2)O, III, [Cd(2)(C(10)H(8)N(2))(3)(S(2)O(3))(2)], IV and [Cd(2)(C(10)H(8)N(2))(2.5)(S(2)O(3))(2)], V have three-dimensional (3D) structures. The 1D structures are somewhat related, formed by the bonding between tetrahedral Cd centers (CdN(2)S(2)) and 4,4'-bipyridine (bpy) units. The inter chain spaces are occupied by the hanging thiosulfate units in both the cases along with Na(H(2)O)(6) chains in I and free bpy units in II. The three 3D structures have one-dimensional cadmium thiosulfate chains linked by bpy units. Interpenetration has been observed in all the 3D structures. The 3D structures appear to be related and can be derived from fgs net. Transformation studies on the 1D compound, [Na(2)(H(2)O)(8)][Cd(C(10)H(8)N(2))(S(2)O(3))(2)].2H(2)O, I, indicated a facile formation of [Cd(C(10)H(8)N(2))(H(2)O)(2)(S(2)O(3))].2H(2)O, III. Prolonged heating of I gave rise to a 3D cadmium sulfate phase, [Cd(2)(C(10)H(8)N(2))(2)(H(2)O)(3)(SO(4))(2)].2H(2)O, VI. Compound VI has one dimensional cadmium sulfate chains formed by six-membered rings connected by bpy units to form a 3D structure, which appears to resemble the topological arrangement of III. Transformation studies of III indicates the formation of IV and V, and at a higher temperature a new 3D cadmium sulfate, [Cd(C(10)H(8)N(2))(SO(4))], VII. Compound VII has a 4 x 4 grid cadmium sulfate layers pillared by bpy units. All the compounds were characterized by PXRD, TGA, IR and UV-visible studies. Preliminary studies on the possible use of the 3D compounds (III-VII) in heterogeneous cyanosilylation of imines appear to be promising. PMID- 20162201 TI - Dynamic combinatorial chemistry in a solvothermal process of Cu(I,II) and organosulfur ligands. AB - An unprecedented microwave C(sp(2))-S and S-S bond activation of 2,2' dipyridyldisulfide (2-dpds) and the formation of a new architecture of coordination networks obtained by reaction of Cu(HCO(2))(2).xH(2)O with 2-dpds under solvothermal microwave conditions are reported. This unusual reaction proceeds with the partial oxidation of 2,2'-dipyridyldisulfide to sulfate. The process generates: a Cu(I) dimetallic complex [Cu(2)(mu Hpyt)(2)(Hpyt)(4)](SO(4)).approximately 5EtOH (1), a Cu(I,II) polycationic coordination polymer [Cu(H(2)O)(6)][Cu(6)(mu-Hpyt)(12)](SO(4))(4).4H(2)O (2) and a dimetallic Cu(II) complex [Cu(2-dps)(mu-SO(4))(H(2)O)](2).3H(2)O (3). It is worth mentioning the strong red luminescence shown by compounds 1 and 2. PMID- 20162202 TI - An iron(II) incomplete spin-crossover compound: pressure effects and Mossbauer spectroscopy study. AB - A one-dimensional iron(II) spin-crossover compound [Fe(3py-im)(2)(NCS)(2)].7H(2)O (1) (3py-im = 2,4,5-tris(4-pyridly)-imidazole) has been solvothermally synthesized and structurally characterized. Compound 1 crystallizes in the monoclinic space group P2/c with a = 11.9078(2), b = 9.9474(1), c = 17.7290(3) and beta = 102.361(2) degrees at 105 K. Studies on the variable-temperature magnetic susceptibilities and Mossbauer spectra suggest that compound undergoes incomplete spin transition behaviour. Pressure effects on the transition behaviour have also been investigated, the thermal-induced spin transition becomes more gradual and the critical temperature shifts towards slightly higher temperature range when external pressure increases. However, the spin transition can not be completed by applying external pressure even as high as 0.79 GPa. PMID- 20162203 TI - Structural, electronic and magnetic properties of Cu(II) complexes of 2 substituted tropones bearing a ferrocenyl group at 5-position. AB - Heterotrinuclear Fe(II)-Cu(II)-Fe(II) complexes [Cu(FcTropOMe)(2)(H(2)O)(2)](OTf)(2) (FcTropOMe = 5-ferrocenyl-2-methoxytropone) (1), [Cu(FcTropNEt(2))(2)](OTf)(2) (FcTropNEt(2) = 2-(N,N-diethylamino)-5 ferrocenyltropone) (2) and [Cu(FcTropNEt)(2)] (FcTropNEt = 2-(N-ethylamino)-5 ferrocenyltroponate) (3) were synthesized. In addition, a hexafluorophosphate salt of heterotrinuclear Fe(III)-Cu(II)-Fe(III) complex [Cu(FcTropNEt)(2)](2+) (3(2+)) was successfully obtained as single crystals by electrochemical oxidation of 3. By comparing the X-ray structures and absorption spectra of dicationic complexes 1 and 2, the 2-(diethylamino)tropone ligand was found to induce a greater intramolecular charge transfer (CT) from ferrocenyl to tropone-Cu(II) moieties than the 2-methoxytropone ligand. On the other hand, 3(2+) showed a broad CT band in the near-infrared (NIR) region similar to 2, which can be assigned to a transition from troponato-Cu(II) to ferrocenium moieties. As for the magnetic properties of 3(2+)(PF(6)(-))(2), measurements of temperature dependence of magnetic susceptibility and ESR on the solid state and in solution revealed the presence of a strong ferromagnetic interaction (J(Fe-Cu) = +12.0 cm( 1)) between the low spin Fe(III) ion with S = 1/2 and Cu(II) ion with S = 1/2 despite a long distance pathway via the aminotroponato and cyclopentadienyl moieties. DFT calculations supported this intramolecular ferromagnetism, which is induced by a spin polarization mechanism through the pi-spacers. PMID- 20162204 TI - Copper(II) 5-methoxyisophthalate coordination polymers incorporating dipyridyl co ligands: syntheses, crystal structures, and magnetic properties. AB - Hydrothermal reactions of mixed ligands 5-methoxyisophthalate (CH(3)O-H(2)ip) and dipyridyl with Cu(OAc)(2).2H(2)O afford five new coordination polymers, including {[Cu(CH(3)O-ip)(bpa)].H(2)O}(n) (1), [Cu(2)(CH(3)O-ip)(2)(bpa)(0.5)(H(2)O)](n) (2), [Cu(2)(CH(3)O-ip)(2)(bpp)(H(2)O)](n) (3), {[Cu(3)(CH(3)O ip)(3)(bpp)(2)(H(2)O)].3H(2)O}(n) (4) and [Cu(4)(CH(3)O-ip)(3)(bpe)(OH)(2)](n) (5) (bpp = 1,3-di(4-pyridyl)propane, bpa = 1,2-bi(4-pyridyl)ethane, and bpe = 1,2 di(4-pyridyl)ethylene). Compound 1 consists of CH(3)O-ip anion-bridged 1D Cu(II) chains that are linked by trans-bpa into a 2D layer. Compound 2 is a 2D (4,4) layer that is connected by CH(3)O-ip anions. The gauche bpa in 2 lies in the cavity and meets the coordination requirement of the paddle-wheel dimeric copper unit. Compound 3 is an extended 3D polythreading network consisting of 2D (4,4) motifs with dangling bpp lateral arms. Compound 4 exhibits a 3D (4,6)-connected self-penetrating (6(5).8)(6(14).8) network that is composed of binuclear and mononuclear metal nodes. Compound 5 exhibits a 3D network with the tetranuclear [Cu(4)(mu(3)-OH)(2)](6+) cluster acting as nodes, which is constructed by the interconnection of 2D helical layers via bpe pillars. The results of magnetic determination show that the syn-anti carboxylato bridges in our cases induce a weak antiferromagnetic interaction in 1, and the syn-syn carboxylato bridge in 3 and 4 mediates a strong antiferromagnetic interaction. PMID- 20162206 TI - Tripodal polyphosphine ligands as inductors of chelate ring-opening processes in mononuclear palladium(II) and platinum(II) compounds. The X-ray crystal structure of two derivatives containing dangling phosphorus. AB - The reaction of NP(3) (tris[2-(diphenylphosphino)ethyl]amine and PP(3) (tris[2 (diphenylphosphino)ethyl]phosphine) with the five-coordinate complexes [PdCl(NP(3))]Cl (1) and [MX(PP(3))]X [M = Pd: X = Cl(2), Br(3), I(4); M = Pt: X = Cl(5), Br(6), I(7)], respectively, followed by (31)P{(1)H}NMR when X = Cl, led to the formation of unprecedented four-coordinate halides in a 1 : 2 metal to ligand ratio, [M(AP(3))(2)]X(2) [A = N, M = Pd: X = Cl(8); A = P, M = Pd: X = Cl(9), Br(10), I(11); A = P, M = Pt: X = Cl(12), Br(13), I (14)], containing reactive dangling phosphorus. Given the non characterised precursors [M(ONO(2))(PP(3))](NO(3))], the interaction between the heteronuclear species [MAg(NO(3))(3)(PP(3))] [M = Pd(15), Pt(16)] and PP(3) was explored. It was found that the addition of 1 equivalent of phosphine afforded [MAg(NO(3))(PP(3))(2)](NO(3))(2) [M = Pd(15*), Pt(16*)] containing Ag(I) bound to two dangling phosphorus while the reaction with 2 equivalents led to the complexes [M(PP(3))(2)](NO(3))(2) [M = Pd (17), Pt (18)] in coexistence with [Ag(2)(mu-PP(3))(2)](NO(3))(2). The fate of Ag(I) on the reaction of the mixed metal compounds with excess PP(3) consisted of preventing dissociation, observed in solution for halides, and acting as an assistant for crystallization. Colourless single crystals of 18 and 10, studied by X-ray diffraction, were afforded by reaction of 16 with 4 equivalents of PP(3) and from solutions of 10 in chloroform coexisting with red crystals of 3, respectively. The structures revealed the presence of dications [M(PP(3))(2)](2+) that show two five-membered chelate rings to M(II) in a square-planar arrangement and four uncoordinated phosphine arms with the counter anions being symmetrically placed at 4.431 (Br( )) and 13.823 (NO(3)(-)) A from M(II) above and below its coordination, MP(4), plane. Complexes 9 and 12 were shown to undergo an interesting reactivity in solution versus group 11 monocations. The reactions consisted of conversions of the two five-membered chelate rings to M into three (structure I) or two (structure II) fused five-membered chelate rings, formation of species where Pt(II) retained its square-planar environment with the two dangling phosphine arms of each PP(3) bound to Cu(I) or Ag(I) (structure III) and complexes bearing distorted square-planar (P(2)MCl(2)) and presumably tetrahedral (AuP(4)+ P(2)AuCl(2)) arrangements (structure IV). The processes with Ag(I) salts also gave mixtures of I+III (chloride and nitrate) or II+III (nitrate). PMID- 20162205 TI - Chirality and diastereoselection in the mu-oxo diiron complexes L(2)Fe-O-FeL(2) (L = bidentate salicylaldiminato). AB - A number of bis(salicylaldiminato) (Schiff base) complexes of Fe(II) i.e. L(2)Fe with a variety of ligand substituents and functionality are synthesised, usually by salt metathesis but on one occasion via the (sal)(2)Fe complex, and characterised by standard methods. Two molecular structure determinations indicate the expected tetrahedral geometry. Treatment with dry oxygen yielded the Fe(III) complexes [(FeL(2))(2)-mu-O], generally in high yield and in the absence of hydroxylated impurities; one bulky complex L(2)Fe gave no oxidation product for steric reasons, and one hydroxyl-substituted compound gave an insoluble product. Five molecular structures of these [(FeL(2))(2)-mu-O] compounds were determined. All were homochiral in the sense that the absolute configuration at Fe was the same for both atoms. Three of the structures - those based on optically pure salicylaldimine ligands - were diastereomeric. For two, the diastereomers observed are those predicted on the basis of steric considerations, while a third highly distorted and congested structure represents the unexpected diastereomer. Powder X-ray diffraction confirms high phase purity of the bulk samples (i.e. they are diastereomerically pure to the level detectable). These investigations, coupled with molecular structure and NMR studies on model gallium complexes, indicate that the diastereoselection arises from cooperative interactions across the oxo bridge. PMID- 20162207 TI - Half a grid is better than no grid: competition between 2,2':6',2''-terpyridine and 3,6-di(pyrid-2-yl)pyridazine for copper(II). AB - The reaction between Cu(NO(3))(2).3H(2)O, 2,2':6',2''-terpyridine (tpy) and 3,6 di(pyrid-2-yl)pyridazine (1) in a 2 : 2 : 1 molar equivalent ratio in aqueous MeCN in the presence of excess NH(4)PF(6) leads to competition between the assembly of the dinuclear half-grid [Cu(2)(1)(tpy)(2)][PF(6)](4).2H(2)O and the mononuclear complex [Cu(1)(2)(OH(2))][PF(6)](2). The yield of [Cu(2)(1)(tpy)(2)][PF(6)](4).2H(2)O has been optimized using microwave conditions. [Cu(1)(2)(OH(2))][PF(6)](2) can be selectively produced by treating Cu(NO(3))(2).3H(2)O with 1 (1 : 2 molar equivalents) in aqueous MeCN in the presence of NH(4)PF(6). The single crystal structures of [Cu(2)(1)(tpy)(2)][PF(6)](4).4MeNO(2) and [Cu(1)(2)(OH(2))][PF(6)](2) are presented. In the [Cu(2)(1)(tpy)(2)](4+) cation, ligand 1 bridges the two copper(II) centres, each of which is further coordinated by a tpy ligand. The copper(II) coordination geometry is closely associated with the arrangement of the two tpy ligands which engage in efficient face-to-face pi-stacking. Magnetic data for crystalline [Cu(2)(1)(tpy)(2)][PF(6)](4).4MeNO(2) are consistent with a weak antiferromagnetic interaction between the two copper(II) centres. EPR spectroscopic data for a powder sample of [Cu(2)(1)(tpy)(2)][PF(6)](4).2H(2)O are consistent with the dinuclear structure, but in frozen DMF and DMSO solutions, the data indicate that the dinuclear structure of [Cu(2)(1)(tpy)(2)](4+) is not preserved. PMID- 20162208 TI - Direct synthesis of an heterometallic {Mn(II)3Cr(III)4} wheel by decomposition of Reineckes salt. AB - A new heterometallic Mn/Cr molecular wheel complex has been synthesized using zerovalent manganese, Reineckes salt, ammonium thiocyanate and triethanolamine (H(3)tea) as starting materials. The compound [Mn(3)Cr(4)(NCS)(6)(Htea)(6)] (1) has been characterized in terms of its electrochemical, IR and EPR spectroscopic as well as its magnetic properties. The magnetic susceptibility and magnetization data were treated simultaneously during the optimization routine and resulted in J(Mn-Cr) = +0.43 cm(-1), J(Cr-Cr) = -4.75 cm(-1), J(Mn-Mn) = +1.78 cm(-1), g(eff) = 1.878 with the ground state S = 15/2. PMID- 20162209 TI - Ferromagnetic coupling and magnetic anisotropy in oxalato-bridged trinuclear chromium(III)-cobalt(II) complexes with aromatic diimine ligands. AB - Two novel heterotrinuclear chromium(III)-cobalt(II) complexes of formula {[Cr(III)(bpy)(ox)(2)](2)Co(II)(Me(2)bpy)}.2H(2)O (1) and {[Cr(III)(phen)(ox)(2)](2)Co(II)(Me(2)bpy)}.1.5H(2)O (2) [ox = oxalato, bpy = 2,2'-bipyridine, Me(2)bpy = 6,6'-dimethyl-2,2'-bipyridine, and phen = 1,10 phenanthroline] have been synthesized using the "complex-as-ligand/complex-as metal" strategy. The X-ray crystal structure of 2 consists of neutral oxalato bridged Cr(III)(2)Co(II) bent entities formed by the coordination of two anionic [Cr(III)(phen)(ox)(2)](-) complexes through one of their oxalato groups toward a cationic cis-[Co(II)(Me(2)bpy)](2+) complex. The three tris(chelated), six coordinated metal atoms possess alternating propeller chiralities leading thus to a racemic mixture of heterochiral (Lambda,Delta,Lambda)- and (Delta,Lambda,Delta) Cr(III)Co(II)Cr(III) triads, whereby the two peripheral chromium(III) ions adopt a trigonal distorted trapezoidal bipyramidal geometry and the central high-spin cobalt(II) ion exhibits a compressed rectangular bipyramidal one. The intermolecular pi-pi stacking interactions between the enantiomeric pairs of heterochiral Cr(III)(2)Co(II) entities through the aromatic diimine terminal ligands lead to a unique two-dimensional supramolecular network. Variable temperature (2.0-300 K) magnetic susceptibility and variable-field (0-5.0 T) magnetization measurements for 1 and 2 reveal the presence of weak but non negligible intermolecular antiferromagnetic interactions [zj = -0.012 (2a) and 0.08 cm(-1) (2b)] between the Cr(III)(2)Co(II) molecules possessing a moderately anisotropic S = 9/2 ground state. This results from the moderately weak intramolecular ferromagnetic coupling [J = +2.43 (1) and +2.34 cm(-1) (2)] between the two peripheral Cr(III) (S(Cr) = 3/2) and the central high-spin Co(II) (S(Co) = 3/2) ions across the oxalato bridge as well as the appreciable single ion axial magnetic anisotropy of the central high-spin Co(II) (S(Co) = 3/2) ion [D(Co) = -2.29 (1) and -2.15 cm(-1) (2)]. A simple molecular orbital analysis of the exchange interaction in 1 and 2 identifies the sigma- and pi-type pathways involving the d(x(2)-y(2))(Cr)/d(xy)(Co) and d(xz)(Cr)/d(yz)(Co) pairs of orthogonal magnetic orbitals, respectively, as the two main individual contributions responsible for the overall ferromagnetic coupling observed. PMID- 20162210 TI - Synthesis and characterization of regioselective substituted tetrapyridophenazine ligands and their Ru(II) complexes. AB - A series of novel regioselective substituted tpphz ligands and two novel mononuclear ruthenium complexes of the type [(tbbpy)(2)Ru(tpphzR(n))](PF(6))(2) (where tbbpy = 4,4'-di-tert.-butyl-2,2'-bipyridine, tpphz = tetrapyrido[3,2 a:2',3'-c:3'',2''-h:2''',3'''-j]phenazine, with n = 2 and R represents the bromine substituents at different positions) have been synthesized. All compounds were completely characterized by NMR and MS spectroscopy, absorption and steady state emission spectroscopy as well as emission lifetime and electrochemical measurements. Additionally the solid-state structures of the two isomers [(tbbpy)(2)Ru(Br(2)tpphz)](PF(6))(2) 6 and [(tbbpy)(2)Ru(tpphzBr(2))](PF(6))(2) 7 are presented and compared with the results of density-functional theory calculations (DFT). Furthermore calculated Raman spectra were obtained by means of DFT calculations and used to assign the vibrational modes of the measured off resonance Raman spectra. A clear influence caused by the electronic effects of the different type and position of the substituents of tpphz on the photophysical behavior was observed. PMID- 20162211 TI - Self-assembly of silver(I) metallomacrocycles using unsupported 1,4-substituted 1,2,3-triazole "click" ligands. AB - Readily synthesised mono- and di- 1,4-substituted-1,2,3-triazole "click" ligands are shown to self-assemble into discrete metallocyclic architectures with Ag(I) ions. The silver metallomacrocycles are stable in solution and the solid state and have been fully characterised by elemental analysis, HR-ESMS, IR, (1)H and (13)C NMR and in three cases the structures were confirmed by X-ray crystallography. PMID- 20162212 TI - Oxidation reactions of a phosphine-borane-stabilised dialkylstannylene. AB - The acyclic dialkylstannylene [(Me(3)Si){Me(2)P(BH(3))}CH](2)Sn (7) reacts with any of methyl iodide, neopentyl iodide or benzyl bromide to yield the corresponding oxidative addition products [(Me(3)Si){Me(2)P(BH(3))}CH](2)Sn(Me)(I) (8), [(Me(3)Si){Me(2)P(BH(3))}CH](2)Sn(CH(2)CMe(3))(I) (9), and [(Me(3)Si){Me(2)P(BH(3))}CH](2)Sn(CH(2)Ph)(Br) (10), respectively. The crystal structures of 8, 9, and 10 reveal that there are no close B-H...Sn contacts. In addition, 7 reacts with benzil or elemental sulfur to yield [{Me(2)P(BH(3))}(Me(3)Si)CH](2)Sn(OCPh=CPhO) (11) and [{Me(2)P(BH(3))}(Me(3)Si)CH](2)Sn(S) (12), respectively, as confirmed by multinuclear NMR spectroscopy and elemental analysis. PMID- 20162213 TI - Molecular metallocycles, acyclic metallodimers and 2D coordination polymers containing the twisted ligand bis(pyrimidin-2-ylthio)methane. AB - The versatile coordination chemistry of bis(pyrimidin-2-ylthio)methane (bptm) allows the synthesis of a series of different metal complexes with diverse structures. We describe here the synthesis and structural characterization of three kinds of compounds: four cyclic dimers, [Co(2)Cl(4)(bptm)(2)] (1), [Zn(2)I(4)(bptm)(2)] (2), [Cd(2)I(4)(bptm)(2)] (3), [Cu(2)(NO(3))(4)(bptm)(2)] (4); two acyclic dimers, [Cu(2)Br(4)(bptm)(3)] (5), [Cu(2)(AcO)(4)(bptm)(2)] (6); and two 2D coordination polymers, [CuBr(bptm)] (7) and [CuI(bptm)] (8). Different structural models are obtained on making small changes in the building units under different synthetic conditions. The effects of the weak interactions in the crystal packing were also analyzed. PMID- 20162214 TI - Synthesis, photophysical and theoretical studies of luminescent silver(I) copper(I) alkynyl-diphosphine complexes. AB - The novel heterometallic aggregates [Ag(8)Cu(2)(C(2)C(6)H(4)X)(6)(PPh(2)C(6)H(4)PPh(2))(6)][PF(6)](4) (X = H, 1; OMe, 2; NMe(2), 3) were prepared by the self-assembly reactions starting from simple precursors. These compounds consist of the central [Ag(6)Cu(2)(C(2)C(6)H(4)X)(6)](2+) clusters capped by two tripodal fragments [Ag(diphosphine)(3)](+). The solid state structures of complexes 1 and 3 have been determined by X-ray crystallographic studies, and NMR spectroscopy confirmed that the compounds remain intact in solution. In solution such as CH(3)CN, complexes 1-3 show a weak to moderate room-temperature phosphorescence in the blue region with a maximum quantum yield of 0.038 (2), while strong phosphorescence was recorded in the solid film of with a quantum yield of 0.26. Photophysical experiments revealed a relatively small effect of luminescence quenching by O(2) for 1, but more prominent quenching for 2 and 3 in solution. Computational approaches are in good agreement with the experimental data, supporting the proposed structural motif, and provide an additional insight into the electronic properties of these compounds to rationalize the different behavior of 1 compared to 2 and 3. PMID- 20162215 TI - Exploring the redox reactivity of magnesium porphine. Insight into the origins of electropolymerisation. AB - Magnesium(II) porphine, MgP (1), was synthesised according to the Lindsey procedure allowing to isolate and crystallise 1-formyldipyrromethane (2) as a synthetic intermediate. Unprecedented X-ray diffraction studies revealed multiple intermolecular associations in the crystal between neighbouring units of 2, namely hydrogen bonds and CH...pi. The electrochemical behaviour of 1 was examined by means of cyclic voltammetry. In oxidation, two well-defined and distinct steps are assigned to macrocycle concerned electron transfers yielding initially the pi-cation radical and pi-dication, respectively. The highly reactive dication condenses neutral magnesium porphine to form a diprotonated di isoporphine species, which is assumed to be a key intermediate at the origin of the electropolymerisation. Electrolyses were performed at the potential of the pi cation radical generation. Investigation of the electrolysed solution by UV-vis spectroscopy and MALDI-TOF spectrometry revealed the presence of several oligoporphyrins, with diporphine as an important product. In all the oligomers series, extensive demetallation is evidenced, due to the increasing acidity of the medium as oligomerisation progresses. This demetallation could be prevented by addition of 2,6-lutidine as a base prior to electrolysis. In the oligomer series, the porphine units seem to be connected through meso-meso bonds, an argument supported by certain features of the UV-vis spectrum. Finally, the mechanism of oxidative oligomerisation is discussed, from the point of view of the initial steps of the electropolymerisation. PMID- 20162216 TI - Synthetic, structural and computational studies on adducts of the 4,1,2-SnC2B10 supraicosahedral stannacarborane. AB - The stannacarborane 1,2-mu-(CH(2))(3)-4,1,2-closo-SnC(2)B(10)H(10) (1) and its adducts with 2,2'-bipyridine (bipy), 1,10-phenanthroline (o-phen) and 4,4' diphenyl-2,2'-bipyridine (Ph(2)bipy), 1,2-mu-(CH(2))(3)-4-(bipy)-4,1,2-closo SnC(2)B(10)H(10) (2), 1,2-mu-(CH(2))(3)-4-(o-phen)-4,1,2-closo-SnC(2)B(10)H(10) (3) and 1,2-mu-(CH(2))(3)-4-(Ph(2)bipy)-4,1,2-closo-SnC(2)B(10)H(10) (4), respectively, together with the analogous compound 1,2-mu-{C(6)H(4)(CH(2))(2)}-4 (bipy)-4,1,2-closo-SnC(2)B(10)H(10) (5) have been prepared and characterised. In solution at ambient temperature, compounds 1-5 all display NMR spectra which are interpreted in terms of (time-averaged) C(s) molecular symmetry, but whilst (effectively) C(s) symmetry is retained in the structures of 2-5 in the crystal (i.e. henicosahedral cage structures are observed), 1 has a (C(1)-symmetric) docosahedral structure. A method for quantifying the "percentage docosahedral character" of 13-vertex 1,2-C(2) heteroboranes is described, based on the angles around the C1C2B9B5 quadrilateral. The structures of "carbons adjacent" 1-5 all reveal less slipping of the Sn atom (or {SnL(2)} fragment) across the C(2)B(4) carborane face than has previously been observed in analogous "carbons apart" 4,1,6-closo-SnC(2)B(10) species, a surprising result in the context of previous studies of slipping in icosahedral platinacarboranes. A computational study of "carbons adjacent" and "carbons apart" icosahedral and supraicosahedral platinacarboranes has revealed that the origin of this observation is steric control of the slipping distortion in both "carbons apart" species and in the "carbons adjacent" 13-vertex species, with orbital interactions proving dominant only in the case of the "carbons adjacent" icosahedral compound. PMID- 20162218 TI - Controlled oxidation of organic sulfides to sulfoxides under ambient conditions by a series of titanium isopropoxide complexes using environmentally benign H2O2 as an oxidant. AB - Controlled oxidation of organic sulfides to sulfoxides under ambient conditions has been achieved by a series of titanium isopropoxide complexes that use environmentally benign H(2)O(2) as a primary oxidant. Specifically, the [N,N' bis(2-oxo-3-R(1)-5-R(2)-phenylmethyl)-N,N'-bis(methylene-R(3)) ethylenediamine]Ti(O(i)Pr)(2) [R(1) = t-Bu, R(2) = Me, R(3) = C(7)H(5)O(2) (1b); R(1) = R(2) = t-Bu, R(3) = C(7)H(5)O(2) (2b); R(1) = R(2) = Cl, R(3) = C(7)H(5)O(2) (3b) and R(1) = R(2) = Cl, R(3) = C(6)H(5) (4b)] complexes efficiently catalyzed the sulfoxidation reactions of organic sulfides to sulfoxides at room temperature within 30 min of the reaction time using aqueous H(2)O(2) as an oxidant. A mechanistic pathway, modeled using density functional theory for a representative thioanisole substrate catalyzed by 4b, suggested that the reaction proceeds via a titanium peroxo intermediate 4c', which displays an activation barrier of 22.5 kcal mol(-1) (DeltaG(++)) for the overall catalytic cycle in undergoing an attack by the S atom of the thioanisole substrate at its sigma*-orbital of the peroxo moiety. The formation of the titanium peroxo intermediate was experimentally corroborated by a mild ionization atmospheric pressure chemical ionization (APCI) mass spectrometric technique. PMID- 20162217 TI - Dichlorostannylene complexes of group 10 metals, a unique bonding mode stabilized by bridging 2-pyridyldiphenylphosphine ligands. AB - The reaction of tin dichloride with catalytically-relevant group 10 metal precursors [M(Cl)(X)(2-PyPPh(2))(2)] (M = Ni, Pd, Pt; 2-PyPPh(2) = 2 pyridyldiphenylphosphine; X = Cl, Me) provides easy access to unprecedented cationic dichlorostannylene complexes [M(X)(2-PyPPh(2))(2)(SnCl(2))](+) where the M-Sn bond is bridged by two head-to-head coordinated 2-PyPPh(2) ligands. The formation of such species instead of the classical neutral trichlorostannyl derivatives [M(X)(SnCl(3))(2-PyPPh(2))(2)] offers a new insight on the specific effect of the SnCl(2) cocatalyst in group 10 metal catalyzed transformations. PMID- 20162219 TI - [Pt2(mu-SAz)(mu-S)]2+ (SAz = azolium thiolate) dication as an unusual source for quadruply bridging sulfide in [Ag2Pt2(mu-SAz)(mu4-S)]3+. AB - Functionalisation of the {Pt(2)(mu-S)(2)} core of [Pt(2)(mu-S)(2)(PPh(3))(4)] by imidazolium, benzimidazolium and thiazolium salts results in a series of cationic complexes with mixed-bridging ligands of azolium thiolate and sulfide. The complex [Pt(2)(mu-S)(mu-SCH(2)CH(2)C(3)H(3)N(2)CH(3))(PPh(3))(4)][PF(6)](2) reacts readily with Ag(OTf) (OTf = triflate) to give [Pt(2)(mu SAg(2)CF(3)SO(4)H(2))(mu-SCH(2)CH(2)C(3)H(3)N(2)CH(3))(PPh(3))(4)][PF(6)](3). X ray crystallographic analysis was carried out on [Pt(2)(mu-S)(mu SCH(2)CH(2)C(3)H(3)N(2)CH(3))(PPh(3))(4)][PF(6)](2), [Pt(2)(mu-S)(mu S(CH(2))(3)C(7)H(5)NS)(PPh(3))(4)][PF(6)](2), [Pt(2)(mu-S)(mu SCH(2)CH(2)C(3)H(3)N(2)CH(3))(dppy)(4)][PF(6)](2), [Pt(2)(mu-S)(mu SCH(2)CH(2)C(3)H(3)N(2)CH(3))(dppf)(4)][PF(6)](2), [Pt(2)(mu SAg(2)CF(3)SO(4)H(2))(mu-SCH(2)CH(2)C(3)H(3)N(2)CH(3))(PPh(3))(4)][PF(6)](3) and [Pt(2)(mu-SCH(3))(mu-SCH(2)CH(2)C(3)H(3)N(2)CH(3))(PPh(3))(4)][PF(6)](3). The complex [Pt(2)(mu-SAg(2)CF(3)SO(4)H(2))(mu SCH(2)CH(2)C(3)H(3)N(2)CH(3))(PPh(3))(4)][PF(6)](3) reveals an unusual quadruply bridging sulfide, whose presence demonstrates an unexpected ability for the unsubstituted sulfide in the [Pt(2)(SR)(S)] core to capture silver moieties. PMID- 20162220 TI - An analysis of the role of Na+ in the construction of metal organic frameworks possessing the chiral (10,3)-a (srs) topology. PMID- 20162226 TI - Microfluidics for the upstream pipeline of DNA sequencing--a worthy application? AB - Technological advances and economic investment into DNA sequencing during this decade has provided the industry of genome sequencing with a suite of dedicated sequencing machines capable of rapidly generating vast quantities of sequence data. This next generation of equipment for DNA sequencing is freely available and is utilised more commonly; this has lead to the traditional bottle-neck in the sequencing pipeline transferring from the sequencing process, i.e. reading the bases on the older capillary based machines, to the upstream processes of sample preparation, i.e. creating the DNA libraries that are to be read. Essentially, advancement in sequencing technology is running faster than the equivalent for sample preparation technology and, without a remedy, we will no longer be able to provide samples quick enough to keep the sequencing machines running at full capacity. PMID- 20162228 TI - Distinguishing the viability of a single yeast cell with an ultra-sensitive radio frequency sensor. AB - We propose and demonstrate a simple, ultra sensitive radio frequency (RF) sensor to detect a single yeast cell and distinguish its viability in a microfluidic channel. On-chip interference is used to cancel background probing signals to improve sensor sensitivity. Individual viable and nonviable yeast cells (approximately 5.83 +/- 0.85 microm in diameter) are measured with clear sensing and identification of these cells. PMID- 20162227 TI - Irreversible, direct bonding of nanoporous polymer membranes to PDMS or glass microdevices. AB - A method for integrating porous polymer membranes such as polycarbonate, polyethersulfone and polyethylene terephthalate to microfluidic devices is described. The use of 3-aminopropyltriethoxysilane as a chemical crosslinking agent was extended to integrate membranes with PDMS and glass microfluidic channels. A strong, irreversible bond between the membranes and microfluidic structure was achieved. The bonding strength in the APTES treated devices was significantly greater than in devices fabricated using either a PDMS "glue" or two-part epoxy bonding method. Evaluation of a filtering microdevice and the pore structure via SEM indicates the APTES conjugation does not significantly alter the membrane transport function and pore morphology. PMID- 20162229 TI - Observation of enhanced cell adhesion and transfection efficiency on superhydrophobic surfaces. AB - It was found that cells attached preferentially on the roughened area of patterned superhydrophobic surfaces allowing the formation of cell microarrays with the advantages of improved cell adhesion, natural separation of colonies and enhanced transfection efficiency. PMID- 20162230 TI - On-demand droplet release for droplet-based microfluidic system. AB - On-demand droplet release from microwell was successfully implemented and well combined with droplet trapping/fusion functions to make an ideal and integrated droplet based microfluidic system. PMID- 20162231 TI - Measuring the local pressure amplitude in microchannel acoustophoresis. AB - A new method is reported on how to measure the local pressure amplitude and the Q factor of ultrasound resonances in microfluidic chips designed for acoustophoresis of particle suspensions. The method relies on tracking individual polystyrene tracer microbeads in straight water-filled silicon/glass microchannels. The system is actuated by a PZT piezo transducer attached beneath the chip and driven by an applied ac voltage near its eigenfrequency of 2 MHz. For a given frequency a number of particle tracks are recorded by a CCD camera and fitted to a theoretical expression for the acoustophoretic motion of the microbeads. From the curve fits we obtain the acoustic energy density, and hence the pressure amplitude as well as the acoustophoretic force. By plotting the obtained energy densities as a function of applied frequency, we obtain Lorentzian line shapes, from which the resonance frequency and the Q factor for each resonance peak are derived. Typical measurements yield acoustic energy densities of the order of 10 J/m(3), pressure amplitudes of 0.2 MPa, and Q factors around 500. The observed half wavelength of the transverse acoustic pressure wave is equal within 2% to the measured width w = 377 microm of the channel. PMID- 20162232 TI - Continuously perfused, non-cross-contaminating microfluidic chamber array for studying cellular responses to orthogonal combinations of matrix and soluble signals. AB - We present a microfluidic cell culture array with unique versatility and parallelization for experimental trials requiring perfusion cultures. Specifically, we realize a rectangular chamber array in a PDMS device with three attributes: (i) continuous perfusion; (ii) flow paths that forbid cross-chamber contamination; and (iii) chamber shielding from direct perfusion to minimize shear-induced cell behaviour. These attributes are made possible by a bridge-and underpass architecture, where flow streams travel vertically to pass over (or under) channels and on-chip valves. The array is also designed for considerable versatility, providing subarray, row, column, or single chamber addressing. It allows for incubation with adsorbed molecules, perfusion of differing media, seeding or extraction of cells, and assay staining. We use the device to characterize different phenotypes of alveolar epithelial type II (ATII) cells, particularly the extent of epithelial-to-mesenchymal transition (EMT), a highly suspected pathway in tissue regeneration and fibrosis. Cells are cultured on combinations of matrix proteins (fibronectin or laminin by row) and soluble signals (with or without transforming growth factor-beta1 by column) with two repeats per chip. Fluorescent assays are performed in the array to assess viability, cytoskeletal organization, and cell-cell junction formation. Assay and morphological data are used to tease-out effects of cues driving each phenotype, confirming this as an effective and versatile combinatorial screening platform. PMID- 20162233 TI - Parallel microfluidic surface plasmon resonance imaging arrays. AB - Surface plasmon resonance imaging (SPRi) is a label-free technique used for the quantitation of binding affinities and concentrations for a wide variety of target molecules. Although SPRi is capable of determining binding constants for multiple ligands in parallel, current commercial instruments are limited to a single analyte stream on multiple ligand spots. Measurement of binding kinetics requires the serial introduction of different analyte concentrations; such repeated experiments are conducted manually and are therefore time-intensive. To address these challenges, we have developed an integrated microfluidic array using soft lithography techniques for high-throughput SPRi-based detection and determination of binding affinities of antibodies against protein targets. The device consists of 264 element-addressable chambers isolated by microvalves. The resulting 700 pL chamber volumes, combined with a serial dilution network for simultaneous interrogation of up to six different analyte concentrations, allow for further speeding detection times. To test for device performance, human alpha thrombin was immobilized on the sensor surface and anti-human alpha-thrombin IgG was injected across the surface at different concentrations. The equilibrium dissociation constant was determined to be 5.0 +/- 1.9 nM, which agrees well with values reported in the literature. The interrogation of multiple ligands to multiple analytes in a single device was also investigated and samples were recovered with no cross-contamination. Since each chamber can be addressed independently, this array is capable of interrogating binding events from up to 264 different immobilized ligands against multiple analytes in a single experiment. The development of high-throughput protein analytic measurements is a critical technology for systems approaches to biology and medicine. PMID- 20162234 TI - Lifespan-on-a-chip: microfluidic chambers for performing lifelong observation of C. elegans. AB - This article describes the fabrication of a microfluidic device for the liquid culture of many individual nematode worms (Caenorhabditis elegans) in separate chambers. Each chamber houses a single worm from the fourth larval stage until death, and enables examination of a population of individual worms for their entire adult lifespans. Adjacent to the chambers, the device includes microfluidic worm clamps, which enable periodic, temporary immobilization of each worm. The device made it possible to track changes in body size and locomotion in individual worms throughout their lifespans. This ability to perform longitudinal measurements within the device enabled the identification of age-related phenotypic changes that correlate with lifespan in C. elegans. PMID- 20162235 TI - Ultrafast microfluidic mixer with three-dimensional flow focusing for studies of biochemical kinetics. AB - Studies of the kinetics of biochemical reactions, especially of folding of proteins and RNA, are important for understanding the function of biomolecules and processes in live cells. Many biochemical reactions occur rapidly and thus need to be triggered on very short time scales for their kinetics to be studied, which is often accomplished by mixing in a turbulent flow. More rapid and sample efficient mixing is achieved in laminar flow in a microfluidic device, in which the sample is two-dimensionally (2D) focused to a thin sheet. Here we describe the design and operation of an ultrafast microfluidic mixer with three dimensional (3D) flow focusing. The confinement of a 3D-focused sample to a narrow stream near the middle of a microchannel renders its velocity nearly uniform and makes it possible to monitor the reaction kinetics without exclusion of any parts of the sample. Hence, the sample consumption is substantially reduced and the fluorescence of the sample can be monitored without a confocal setup. Moreover, the 3D-focusing allows facile measurements of velocity of the sample with a high spatial resolution using a specially developed technique based on epi-fluorescence imaging. The data on the velocity vs. position are used to precisely calibrate the conversion between position and the reaction time, which is essential for accurate kinetic measurements. The device performs mixing on a 10 micros scale, which is comparable to that of the laminar mixers with 2D focusing. Unlike previous ultrafast laminar mixers, which were machined in hard materials, the present microfluidic device is made of a single cast of poly(dimethylsiloxane), PDMS, and is thus simpler and less expensive to manufacture. PMID- 20162236 TI - A microfluidic approach for high efficiency extraction of low molecular weight RNA. AB - The lack of sample pre-treatment concepts that are easily automatable, miniaturized and highly efficient for both small volumes and low target concentrations, is one of the key issues that block the road towards effective miniaturized diagnostic instruments. This paper presents a novel, highly efficient and simple method for low-molecular weight RNA extraction using electricity only. Cells are lysed by thermo-electric lysis and RNA is purified using a gel-electrophoretic purification step. The combination of the two steps in one integrated cartridge reduces the time frame between the two steps, thus protecting RNA from enzymatic degradation. A disposable chip solution is proposed using a novel dry film resist laminate technology that allows cheap, large-scale fabrication. The chip contains crucial microfluidic innovations that allow for a simple user interface, reproducible functioning and precise quantification. Phaseguides are invented that allow controlled spatial injection of gel, injection of sample and recovery of extracted RNA. A precise sample volume can be defined by integrating electrophoretic actuation electrodes in the microfluidic chamber. Electrolytic gas bubbles that are the result of constant-current actuation are driven out from the chip by the novel introduction of capillary bubble-expulsion techniques. The extraction approach and the functionality of the chip are demonstrated for Escherichia coli and Streptococcus thermophilus bacteria. Linear extraction behavior is obtained for transfer-messenger RNA down to one colony-forming unit per microlitre, or five colony-forming units per chip. The latter is an increase in extraction efficiency of a factor of 1000 with respect to the commercial extraction kit Ambion Ribopure. The chip shows particularly good performance for extraction of low-molecular weight RNA, thereby eliminating the need for large ribosomal RNA and DNA removal. RNA can be extracted in less than 11 min, being a speed-up of more than a factor of 20 with respect to commercial extraction kits. The presented solution may find broad acceptance and application in drug discovery and clinical diagnostics. PMID- 20162237 TI - A microfluidic device for reversible environmental changes around single cells using optical tweezers for cell selection and positioning. AB - Cells naturally exist in a dynamic chemical environment, and therefore it is necessary to study cell behaviour under dynamic stimulation conditions in order to understand the signalling transduction pathways regulating the cellular response. However, until recently, experiments looking at the cellular response to chemical stimuli have mainly been performed by adding a stress substance to a population of cells and thus only varying the magnitude of the stress. In this paper we demonstrate an experimental method enabling acquisition of data on the behaviour of single cells upon reversible environmental perturbations, where microfluidics is combined with optical tweezers and fluorescence microscopy. The cells are individually selected and positioned in the measurement region on the bottom surface of the microfluidic device using optical tweezers. The optical tweezers thus enable precise control of the cell density as well as the total number of cells within the measurement region. Consequently, the number of cells in each experiment can be optimized while clusters of cells, that render subsequent image analysis more difficult, can be avoided. The microfluidic device is modelled and demonstrated to enable reliable changes between two different media in less than 2 s. The experimental method is tested by following the cycling of GFP-tagged proteins (Mig1 and Msn2, respectively) between the cytosol and the nucleus in Saccharomyces cerevisiae upon changes in glucose availability. PMID- 20162238 TI - Electrochemical cell lysis device for DNA extraction. AB - We present a novel electrochemical cell lysis device to prepare DNA samples for lab-on-a-chip (LOC) applications. It utilizes the electrolysis of saline solution to generate hydroxide ions (OH(-)) at the cathode as alkaline lytic agents. Cathode and anode chambers are separated by a negatively-charged ion exchangeable polymer diaphragm to maintain the high pH level for efficient cell lysis in the cathode chamber, to prevent inflow of PCR-amplification inhibitors from the anode chamber, and to minimize binding of DNA molecules. Electric current flow and pH maintenance, which depended on the device design, were two important parameters of the device performance. After optimizing the design and visually confirming cell lysis of Chinese hamster ovary (CHO) cells in a very short amount of time, we directly electrolyzed four bacterial cell types suspended in saline solution. Real-time PCR (qPCR) analysis showed that our device could lyse both gram positive and gram-negative bacterial cells with higher efficiency than other common methods and could detect DNA on the microlitre scale. Our data demonstrate several advantages of the proposed device: absence of cell lysis chemicals and heating; no adverse effects on PCR amplification; low DNA loss; low voltage and power consumption; and rapid processing. The device could potentially be applied as an on-chip DNA extraction component. PMID- 20162239 TI - Femtomolar detection of 2,4-dichlorophenoxyacetic acid herbicides via competitive immunoassays using microfluidic based carbon nanotube liquid gated transistor. AB - Monitoring of environmental pollutants has become increasingly important due to concern over potential health and environmental impact inflicted by these chemicals. In this contribution, we focus on the development of an all-plastic biosensor comprising laminated single-walled carbon nanotubes as the active element and its conductance modulation in a liquid-gated field effect transistor, as the principle of transduction, for the detection of 2,4-dicholorophenoxy acetic acid (2,4-D) herbicide. The reported biosensor is capable of performing real-time label-free detection of analytes in liquid environment. This biosensor which relies on immunoassay principle for specificity is able to detect down to 500 fM levels of 2,4-D in soil samples. PMID- 20162240 TI - Study on the kinetics of homogeneous enzyme reactions in a micro/nanofluidics device. AB - In this paper, a micro/nanofluidic preconcentration device integrated with an electrochemical detector has been used to study the enrichment of enzymes and homogeneous enzyme reaction kinetics. The enzymes are first concentrated in front of a nanochannel via an exclusion-enrichment effect (EEE) mechanism of the nanochannel integrated in a microfluidics device. If a substrate is electrokinetically transported to the concentrated enzymes, homogeneous enzymatic reaction occurs. The enzymatic reaction product can penetrate through the nanochannel to be detected electrochemically. In this device, the enriched enzymes can be well retained and repeatedly used, thus, the enzymatic reaction occurs in a continuous-flow mode. For demonstration, Glucose oxidase (GOx) was chosen as the model enzyme to study the influence of enzyme concentration on its reaction kinetics. The different concentration of GOx in front of the nanochannel was simply achieved by using different enrichment time. When substrate glucose was introduced electrokinetically, a rapid electrochemical steady-state response could be obtained. It was found that the electrochemical response to a constant glucose concentration increased with the increase of enzyme enrichment time, which is expected for homogeneous enzymatic reactions. Under proper conditions, the electrochemical responds linearly to the glucose concentration ranging from 0 to 15 mM, and the Michaelis constants (K(m)) are relatively low, which indicates a more efficient complex formation between enzyme and substrate. These results suggest that the present micro/nanofluidics device is promising for the study of enzymatic reaction kinetics and other bioassays such as cell assays, drug discovery, and clinical diagnosis. PMID- 20162241 TI - A lab-on-a-chip platform for studying the subcellular functional proteome of neuronal axons. AB - Axons are long, slender processes extending from the cell bodies of neurons and play diverse and crucial roles in the development and function of nervous systems. Here, we describe the development of a chip device that can be used to produce large quantities of axons for proteomic and RNA analyses. On the chip surface, bundles of axons of rat hippocampal neurons in culture are guided to grow in areas distinct and distant from where their cell bodies reside. Fluorescence immunocytochemical studies have confirmed that the areas where these axons are guided to grow are occupied exclusively by axons and not by neuronal somatodendrites or astroglial cells. These axon-occupied parts are easily separated from the remainder of the chip and collected by breaking the chip along the well-positioned linear grooves made on the backside. One- and two-dimensional gel electrophoresis and Western blotting analyses reveal that the axons and whole cells differ in their protein compositions. RT-PCR analyses also indicate that the axons contain only a subset of neuronal RNAs. Furthermore, the chip device could be easily modified to address other issues concerning neuronal axons, such as the molecular composition of the axon substructure, the growth cone and shaft, the degeneration and regeneration processes associated with injured axons and the effects of extrinsic molecules, such as axon guidance cues and cell adhesion molecules, on the axon. With these diverse applications, the chip device described here will serve as a powerful platform for studying the functional proteome of neuronal axons. PMID- 20162242 TI - A magnetic microchip for controlled transport of attomole levels of proteins. AB - A novel method of controlled transport of proteins immobilized on micrometre sized magnetic beads in a lab-on-a-chip environment is presented. Bead motion is controlled by lithographically made magnetic elements forming transportation lines in combination with an applied in-plane rotating magnetic field. In this way, transport of attomole amounts of proteins is controlled with micrometre precision. Also, the activity of proteins immobilized on the beads is demonstrated by injecting antibodies into the system. A critical step in developing the method was to reduce sticking forces between beads and substrate during transportation of proteins. Charge interaction was found to be of minor importance compared to hydrophobic forces. To achieve a reliable transport of biologically active proteins, both substrate and beads were coated with polyethylene glycol (PEG) and the protein covered beads were suspended in buffer with surfactants. The described system fulfils all the important unit operations of a microfluidic platform and, as a further advantage, presents less need for microchannels and electric wiring. PMID- 20162245 TI - Initial and delayed stress phase imaging in a single-injection double-acquisition SPECT. The potential value of early 99mTc-MIBI redistribution in assessment of myocardial perfusion reversibility in patients with coronary artery disease. AB - Some studies reported that 99mTc-MIBI may redistribute in ischaemic myocardium and this phenomenon may have potential role for better assessment of viability by delayed 99mTc-MIBI imaging. Some studies also suggested that infusion of low dose dobutamine during delayed imaging may enhance the value of 99mTc-MIBI imaging for evaluation of viability. The aim of this study is to determine whether the observed changes of perfusion defects on delayed images are caused by early radiotracer redistribution or as a result of reversal partial volume effect secondary to inotropic stimulation. PATIENTS, METHODS: 89 patients with angiographically proven coronary artery disease (CAD) were enrolled in this randomized clinical trial study. In all cases, gated-SPECT images were obtained 60 minutes after stress with dipyridamole injection. Subsequently the patients were randomly allocated in two groups and the second imaging was performed at 120th minute during low dose dobutamine (dobutamine group; 45 cases) or placebo infusion (placebo group; 44 cases). Difference between summed stress score of the first (SSS1) and second (SSS2) stress images (DeltaSSS) was considered as a marker of reversibility in single-injection double-acquisition (SIDA) protocol. Also summed difference score (SDS) was recorded as a marker of reversibility in standard stress/rest, double-injection double-acquisition (DIDA) protocol. DeltaSSS of the two studied groups were compared. Also the correlation and agreement between DeltaSSS and SDS were analyzed. RESULTS: A significant difference was found between SSS1 (median 15, range 0-48) and SSS2 (median 11, range 0-42) in total patients (p < 0.0001). A significant correlation was noted between DeltaSSS and SDS in dobutamine group (r = 0.58, p = 0.002) as well as in placebo group (r = 0.57, p < 0.0001). Considering DIDA protocol as a standard reference method, the influence of dobutamine infusion was not shown to be significantly different from the placebo effect on the magnitude of fixed or reversible perfusion defects in SIDA protocol. CONCLUSION: The changes in the magnitude of the perfusion defects may occur in the first hours of 99mTc-MIBI injection in the stress phase imaging. These changes correlate well and are in agreement with perfusion improvement on the rest images. This phenomenon may be independent of improvement in myocardial function, in more delayed imaging or following inotropic augmentation, and thus is likely due to 99mTc-MIBI redistribution. This may open new technical and clinical aspects and potentials for 99mTc-MIBI imaging. PMID- 20162246 TI - Impact of FDG PET on the management of TBC treatment. A pilot study. AB - The aim of this study is to assess the potential impact of double-phase FDG PET versus routine staging in HIV-negative patients suffering from tuberculosis. PATIENTS, METHODS: 16 consecutive patients suffering from tuberculosis underwent contrast-enhanced CT and double-phase FDG PET imaging (45 min, 120 min). Early (E) and delayed (D) SUVmax values were determined for all identified lesions and % change in SUV calculated (DeltaSUV). RESULTS: Seven patients presented with lung lesions on PET as well as CT (mean SUVmaxE 8.2, mean SUVmaxD 11.1, (p = 0.002), DeltaSUV 35%. In two patients, lesions were judged as non-active on CT. In nine patients, 18 sites of LN involvement were identified on both early and delayed FDG PET images (mean SUVmaxE 6.3, mean SUVmaxD 7.9, (p = 0.0001), DeltaSUV: 25%). 9 out of 18 sites of LN involvement, occurring in five patients, were missed on CT. In four of these five patients, sites of LN involvement were the only sites of extra-pulmonary involvement identified. In 6 out of 16 patients, pleural involvement was identified, respectively in 5 on FDG PET and in 6 on CT imaging (mean SUVmaxE 1.3, mean SUVmaxD 1.7, (p = 0.06), DeltaSUV 21%). In 4 patients, osseous involvement was identified by both FDG PET and CT (mean SUVmaxE 7.2, mean SUVmaxD 10.7, (p = 0,06), DeltaSUV 45%). Finally, in 3 patients, joint involvement was identified on both FDG PET as well as on CT imaging (mean SUVmaxE 4.7, mean SUVmaxD 5.2, DeltaSUV 23%). FDG PET did not identify CT-additional sites of involvement that would have resulted in a prolonged treatment. CONCLUSION: In HIV-negative patients suffering from tuberculosis, FDG PET images suggested a more extensive involvement by Mycobacterium tuberculosis when compared to contrast enhanced CT. PMID- 20162247 TI - The coagulant response in sepsis and inflammation. AB - Critically ill patients often have systemic activation of both inflammation and coagulation. Increasing evidence points to an extensive cross-talk between these two systems, whereby inflammation not only leads to activation of coagulation, but coagulation also considerably affects inflammatory activity. The intricate relationship between inflammation and coagulation may have major consequences for the pathogenesis of microvascular failure and subsequent multiple organ failure, as a result of severe infection and the associated systemic inflammatory response. Molecular pathways that contribute to inflammation-induced activation of coagulation have been precisely identified. Activation of the coagulation system and ensuing thrombin generation is dependent on an interleukin-6-induced expression of tissue factor on activated mononuclear cells and endothelial cells and is insufficiently counteracted by tissue factor pathway inhibitor. Simultaneously, endothelial-bound anticoagulant mechanisms, in particular the protein C system and the antithrombin system, are shut-off by pro-inflammatory cytokines. Modulation of inflammatory activity by activation of coagulation also occurs by various mechanisms. Activated coagulation proteases, such as the tissue factor-factor VIIa complex, factor Xa and thrombin can bind to protease-activated receptors on various cells and the ensuing intracellular signaling leads to increased production of pro-inflammatory cytokines and chemokines. Physiological anticoagulants can modulate inflammatory activity as well. Increasing knowledge on the various mechanisms underlying activation of inflammation and coagulation may lead to better (adjunctive) management strategies in critically ill patients. PMID- 20162248 TI - Inflammation, innate immunity and blood coagulation. AB - Inflammation drives arterial, venous and microvascular thrombosis. Chronic inflammation contributes to arterial thrombotic complications, whereas acute inflammation drives venous thrombosis and microvascular thrombosis. Mechanistically, inflammation modulates thrombotic responses by upregulating procoagulants, downregulating anticoagulants and suppressing fibrinolysis. The inflammatory response can also result in cell apoptosis or necrosis. Products released from the dead cells, particularly histones, propagate further inflammation, tissue death and organ failure. Inhibition of histone mediated cytotoxicity appears to be a new mechanism for protecting against this deadly cascade. PMID- 20162249 TI - Heparin-induced thrombocytopenia. AB - Heparin-induced thrombocytopenia (HIT), typically occurring in the second week of heparin therapy, is an antibody-mediated adverse drug reaction associated with increased thrombotic risk. The most important antigens are located on platelet factor 4 (PF4)/heparin complexes. HIT is always caused by platelet-activating antibodies, but not all PF4/heparin-reactive antibodies cause HIT. Thus, tests have a high negative, but only a moderate, positive predictive value. Clinical suspicion of HIT requires cessation of heparin and substitution with an alternative anticoagulant. As these drugs have an increased bleeding risk, they should be used in therapeutic doses only if HIT is considered very likely. Avoiding/postponing coumarin is crucial in minimizing microthrombotic complications. Recent studies of HIT immunobiology suggest that HIT mimics immunity against repetitive antigens, as are relevant in microbial defense. Thus, understanding HIT may help unravel why host defenses can trigger autoimmunity. PMID- 20162250 TI - Phenotypic approaches to gene mapping in platelet function disorders - identification of new variant of P2Y12, TxA2 and GPVI receptors. AB - Platelet number or function disorders cause a range of bleeding symptoms from mild to severe. Patients with platelet dysfunction but normal platelet number are the most prevalent and typically have mild bleeding symptoms. The study of this group of patients is particularly difficult because of the lack of a gold standard test of platelet function and the variable penetrance of the bleeding phenotype among affected individuals. The purpose of this short review is to discuss the way in which this group of patients can be investigated through platelet phenotyping in combination with targeted gene sequencing. This approach has been used recently to identify patients with mutations in key platelet activation receptors, namely those for ADP, collagen and thromboxane A2 (TxA2). One interesting finding from this work is that for some patients, mild bleeding is associated with heterozygous mutations in platelet proteins that are co inherited with other genetic disorders of haemostasis such as type 1 von Willebrand's disease. Thus, the phenotype of mild bleeding may be multifactorial in some patients and may be considered to be a complex trait. PMID- 20162251 TI - [Diagnostics in venous thrombosis and pulmonary embolism]. AB - Deep vein thrombosis and pulmonary embolism (venous thromboembolism) have a prevalence as high as 1-2/1000/year. Timely diagnosis and therapy prevent or reduce the acute life threatening and the long term disabling complications. Due to the variability in its signs and symptoms, venous thromboembolism should frequently be considered as a differential diagnosis. When doing so, only one in five or six suspected cases actually will have the disease. A low estimate of the clinical probability in conjunction with a negative D-Dimer test may rule out the diagnosis in 40-50% of cases. All other patients need imaging procedures. Current standard of care for deep vein thrombosis is venous ultrasound of the leg, for pulmonary embolism it is CT pulmonary angiography. Sensitivity and specificity of both methods are high enough to allow for a definitive diagnosis. Diagnostic challenges remain the suspicion of relapsing disease and venous thromboembolism in pregnancy. PMID- 20162252 TI - Pneumococcal pathogenesis: "innate invasion" yet organ-specific damage. AB - Streptococcus pneumoniae encounters a variety of unique cellular situations during colonization of the nasopharynx or invasion into the lungs, the bloodstream, or the central nervous system. The ligand/receptor pairings that enable this progression of disease appear to be shared by many respiratory pathogens suggesting that a primitive "innate invasion" mechanism may underlie the well-known species-specific mechanisms of pathogenesis. That the acute phase of the innate immune response includes elements to interrupt this path supports this concept. However, it also appears that each cell type or organ responds differently to activation of this innate invasion pathway leaving some organs, such as the lung, intact post-infection but others, such as the brain, largely destroyed. This review posits a concept of innate invasion but cautions that organ-specific responses complicate opportunities for a simple approach to protect from organ damage. PMID- 20162253 TI - [Radiological diagnosis of the paranasal sinuses]. AB - Although diseases of the paranasal sinuses have a relatively homogeneous clinical presentation, their causes can vary considerably. Radiological imaging only became relevant in paranasal sinus diagnostics following the introduction of cross-sectional imaging. In addition to technical details on imaging procedures and the individual criteria of the different modalities, anatomic details and congenital variations are presented. Particularly in acute inflammatory diseases as well as traumatic lesions, imaging is essential in preoperative planning and postoperative control. The article gives a detailed description of options in radiologic imaging of the paranasal sinuses. PMID- 20162255 TI - Genome-wide identification of intron fragment insertion mutations and their potential use as SCAR molecular markers in the soybean. AB - Introns often have a high probability of mutation as a result of DNA insertions and deletions (indels). In this study, 503 introns with exon-derived insertions were identified using a comprehensive search of the soybean genome. Of the 375 pairs of PCR primer sets designed for the loci in question, 161 primer sets amplified length polymorphism among nine soybean varieties and were identified as soybean gene-intron-driven functional sequence characterized amplified region (SCAR) markers. These SCAR markers are distributed among all 20 of the soybean chromosomes, and they developed from numerous genes involved in various physiological and biochemical processes that influence important agronomic traits of the soybean. The development of these novel gene-driven functional SCAR markers was fast and cost effective, and their use will facilitate molecular assisted breeding of the soybean. PMID- 20162256 TI - Brassica GLABRA2 genes: analysis of function related to seed oil content and development of functional markers. AB - Regulation of seed oil accumulation in oilseed rape (Brassica napus) has important economic significance. However, few genes have been characterized that affect final seed oil content. Through a mutant identification, the class IV homeodomain-ZIP transcription factor GLABRA2 (GL2) has been found to regulate seed oil accumulation in Arabidopsis, in addition to its role in trichome development. In this study, we isolated four distinct orthologues of GL2 from B. napus (AC-genome), B. rapa (A) and B. oleracea (C), using an overlapping-PCR strategy. The four GL2 orthologues were very similar, with 96.10-99.69% identity in exon regions, 75.45-93.84% in intron regions, 97.34-99.87% in amino acid sequences. Alignments of the four genes revealed that the A-genome sequences of BnaA.GL2.a from B. napus and BraA.GL2.a from B. rapa are more similar than the others, and likewise the C-genome sequences of BnaC.GL2.b from B. napus and BolC.GL2.a from B. oleracea are more similar. BnaA.GL2.a and BraA.GL2.a from the A-genome are highly expressed in roots, whilst BnaC.GL2.b and BolC.GL2.a from the C-genome are preferentially expressed in seeds. Transgenic ectopic overexpression and suppression of BnaC.GL2.b in Arabidopsis allowed further investigation of the effect on seed oil content. Overexpression generated two phenotypes: the wild type-like and the gl2-mutant-like (an Arabidopsis glabrous mutant of gl2-2), with increases in seed oil content of 3.5-5.0% in the gl2-mutant-like transgenic plants. Suppression resulted in increases of 2.5-6.1% in seed oil content, and reduced trichome number at the leaf margins. These results suggest that BnaC.GL2.b can negatively regulate oil accumulation in Arabidopsis seeds. As a result of comparing the four GL2 genes, three A/C-genome-specific primer sets were developed and a C-genome-specific EcoRV cleavage site was identified, which can be used as functional markers to distinguish these orthologues within Brassica species. The genes identified and their molecular markers developed in this study will be valuable both for oilseed rape breeding focusing on improvement of seed oil content, and for detecting gene flow between populations. PMID- 20162258 TI - Can Patellar Tendon Angle reveal sagittal kinematics in total knee arthroplasty? AB - The Patellar Tendon Angle is strongly correlated with both patello-femoral and tibio-femoral joint kinematics. Thus, the Patellar Tendon Angle might be regarded as a concise indicator of the antero-posterior translation of the femur with respect to the tibia. Twelve subjects, who had undergone total knee arthroplasty, were investigated by video-fluoroscopy during step-up/down. The kinematics at the replaced knee was reconstructed by means of 3D fluoroscopy. The Patellar Tendon Angle and the knee-flexion angle were measured on sagittal fluoroscopic images with software designed for the purpose. The slope of the linear trend of the Patellar Tendon Angle versus knee-flexion angle relationship correlated significantly with the mean (p = 0.001), most anterior (p = 0.001), and most posterior (p = 0.016) position reached by the femur over the tibia. The Patellar Tendon Angle versus knee-flexion angle relationship provides relevant information about the anterior or posterior positioning of the femur over the tibia, but it cannot be interpreted as quantification of the actual antero-posterior translation of the femur over the tibia. PMID- 20162260 TI - Perchlorate in tap water, groundwater, surface waters, and bottled water from China and its association with other inorganic anions and with disinfection byproducts. AB - Perchlorate is a potent thyroid hormone-disrupting compound. Drinking water is one of the major sources of human exposure to perchlorate. Little is known about the occurrence of perchlorate in waters from China. In this study, water samples (n = 300) collected from 15 locations in 13 provinces and municipalities were analyzed for the presence of perchlorate. In addition, other inorganic anions that commonly occur in water--iodide, bromide, and nitrate--and the disinfection byproducts, bromate, chlorate, and chlorite were determined by high-performance liquid chromatography interfaced with tandem mass spectrometry. Perchlorate was detected in 86% of the samples analyzed, at concentrations ranging from <0.02 to 54.4 microg l(-1) (mean +/- SD 2.20 +/- 6.39 microg l(-1); median 0.62 microg l( 1)). Mean concentrations of perchlorate in tap water, groundwater, surface waters, and bottled water were 2.46, 3.04, 2.82, and 0.22 microg l(-1), respectively. Significant positive correlations were found between the concentrations of perchlorate and nitrate, perchlorate and chlorate, bromide and iodide, and nitrate and iodide. PMID- 20162259 TI - Risk of subsequent fracture and mortality within 5 years after a non-vertebral fracture. AB - SUMMARY: The absolute 5-year risk of subsequent non-vertebral fractures (NVFs) in 1,921 patients presenting with a NVF was 17.6% and of mortality was 32.3%. These risks were highest within the first year, indicating the need to study which reversible factors can be targeted to immediately minimise subsequent fracture risk and mortality. INTRODUCTION: NVFs are the most frequent clinical fractures in patients presenting at the emergency unit because of a clinical fracture. The aim of the study was to determine the 5-year absolute risk (AR) of subsequent NVF and mortality in patients at the time they present with a NVF. METHODS: Between 1999 and 2001, 1,921 consecutive patients 50+ years from a level 1 trauma centre were included. All NVFs were confirmed on radiograph reports, and mortality was checked in the national obituary database. Available potential risk factors for a subsequent NVF and mortality (age, sex and baseline fracture location: major-hip, pelvis, multiple ribs, proximal tibia/humerus and distal femur; minor-all others) were expressed as hazard ratios (HR) with 95% confidence intervals (CI) using multivariable Cox regression analysis. RESULTS: The AR for a subsequent NVF was 17.6% and was related to age (HR per decade, 1.44; 95%CI, 1.29-1.60). The AR for mortality was 32.3% and was related to age (HR per decade, 2.59; 95%CI, 2.37 2.84), male sex (HR, 1.74; 95%CI, 1.44-2.10), major fracture at baseline (HR, 5.56; 95%CI, 3.48-8.88; not constant over time) and subsequent fracture (HR, 1.65; 95%CI, 1.33-2.05). The highest risks were found within the first year (NVFs, 6.4%; mortality, 12.2%) and were related to age and, in addition, to baseline fracture location for mortality. CONCLUSIONS: Within 5 years after an initial NVF, nearly one in five patients sustained a subsequent NVF and one in three died. One third of subsequent NVFs and mortality occurred within 1 year, indicating the need to study which reversible factors can be targeted to immediately prevent subsequent fractures and mortality. PMID- 20162261 TI - Assessment of metallothioneins in tissues of the clam Megapitaria squalida as biomarkers for environmental cadmium pollution from areas enriched in phosphorite. AB - The aim of this study was to evaluate the use of metallothionein (MT) concentrations in tissues of the clam Megapitaria squalida as biomarkers of environmental cadmium (Cd) pollution from phosphorite enrichments in the marine environment, which resulted from mining activities in La Paz Bay, Baja California Sur, Mexico. Cd and MT were quantified in gills, digestive gland, and kidney of clams exposed to 0.2 or 0.5 mg Cd l(-1) for 10, 20, or 30 days. In addition, clams from four strategically selected natural sites of La Paz Bay were collected for analysis. In tissues of bioassayed and untreated clams, the gradient of Cd concentrations was digestive gland>>gills>kidney, whereas that of MT was digestive gland>gills>kidney. Digestive gland of the clams exposed to 0.5 mg Cd l(-1) for 30 days showed the highest concentrations of Cd (16.3+/-3.9 microg Cd g(-1)). The highest statistically significant MT concentrations were found in digestive gland at 10 days of exposure to Cd. In the untreated clams, one of the highest Cd concentrations, but not MT levels, was found in digestive glands of the organisms collected from the area close to phosphorite mining activities. For environmental monitoring, MT levels in digestive gland can be used as a first approximation of the presence of high levels of divalent metals in the environment. However, in this study, MT levels did not correlate with high Cd levels in clams that had been collected from areas associated with phosphorite enrichment. PMID- 20162262 TI - Heavy metal accumulation in lake sediments, fish (Oreochromis niloticus and Serranochromis thumbergi), and crayfish (Cherax quadricarinatus) in Lake Itezhi tezhi and Lake Kariba, Zambia. AB - We measured the level of heavy metal accumulation in lake sediments, herbivorous (Oreochromis niloticus) and carnivorous (Serranochromis thumbergi) fish, and crayfish (Cherax quadricarinatus) from Lake Itezhi-tezhi (ITT) and Lake Kariba. We used atomic absorption spectrophotometry to quantify the levels of seven heavy metals (Cr, Co, Cu, Zn, Cd, Pb, and Ni). The sediment and the herbivorous fish O. niloticus accumulated a very high concentration of Cu in Lake ITT, most likely due to the discharge of Cu waste from a mining area 450 km upstream. The aquatic species we sampled in Lake Kariba had higher concentrations of Cr, Ni, and Pb relative to those in Lake ITT. This is most likely due to anthropogenic activities, such as the use of leaded petrol and antifouling agents in marine paints. Interestingly, we observed a negative correlation between the coefficient of condition (K) and Ni concentration in the crayfish hepatopancreas. Both O. niloticus and the crayfish had much higher biota-sediment accumulation factors (BSAF) for Cu, Zn, and Cd relative to Cr, Co, Pb, and Ni. The rank of BSAF values for O. niloticus (Cu>Cd>Zn) and C. quadricarinatus (Zn>Cd>Cu) differed from the expected ranks based on the general order of affinity of metals (Cd>>Zn>Cu). PMID- 20162264 TI - Multipesticide residue assessment of agricultural soil and water in major farming areas in Benguet, Philippines. AB - This study investigated the concentration and presence of pesticide residues in water and soil in Benguet, which is a vegetable producing region in the Philippines. Seventy-eight samples and 49 water samples were taken from different farms covering three municipalities in the province of Benguet and were analyzed using gas chromatography. Meteorological conditions of temperature and humidity were also taken. Thirty-four of the soil samples were found to be positive for pesticide residues. The most significant pesticide type with the highest concentration was technical endosulfan, with a mean concentration of 0.025 mg/kg, followed by endosulfan sulfate (0.015 mg/kg), chlorpyrifos (0.01 mg/kg), profenofos (0.003 mg/kg), chlorothanil, cypermethrin, and cylohathrin (all at 0.002 mg/kg). One water sample was found to be positive for pesticide residue of chlorpyrifos in municipality 2 at a concentration of 0.07 mg/L. The data also showed that endosulfan, which is restricted in the Philippines and banned in other countries, was found to be the most prevalent pesticide used (17.7%) and the second highest in concentration (0.015 mg/kg) in soil samples. The study also showed a relationship between temperature and pesticide concentration in soil. In conclusion, pesticide residues were found in soil and water samples in the farming areas of Benguet. PMID- 20162263 TI - Distribution of trace metals and methylmercury in soft tissues of the freshwater eel Anguilla marmorata in Vietnam. AB - This study investigated trace metals in water, sediment, and various organs of the mature eel Anguilla marmorata in the Ba River, Vietnam. The metal concentrations in water and sediment did not exceed the Vietnam water criteria and sediment background concentration, except for Mn and Pb in sediment. The results of metal analysis in eel specimens indicated that the liver and kidney were the dominant organs for almost all trace metals, whereas muscle tended to accumulate high levels of Hg and approximately 87.4-100% of Hg was methylmercury. A strong positive correlation between mercury levels in muscle and age were found, but there was no correlation between mercury and body size. Interestingly, a high concentration of Zn was found in the gonad and liver; this indicated that high levels of Zn in the liver might play a physiologically important role in the eel's biological mechanisms during gonadal maturation. Though almost none of the metal concentrations in the muscle exceeded the reference doses of the U.S. EPA, approximately 80% of eels from the river contained mercury exceeding the recommended levels (0.30 microg/g) of the U.S. EPA and might present a risk for human consumption. PMID- 20162265 TI - Impact of urban wastewater discharges on the sediments of a small Mediterranean river and associated coastal environment: assessment of estrogenic and dioxin like activities. AB - The Mediterranean region includes many small coastal rivers about which little is known concerning organic contaminant loads in their sediment. This study was designed to assess organic contamination in one of these small coastal rivers (Lez River) and associated coastal sediments. Levels of alkylphenols (APs), polycylic aromatic hydrocarbons (PAHs), and polychlorinated biphenyls (PCBs) were measured in sediments of the Lez River and two coastal lagoons impacted by wastewater discharges. In parallel, sediment surrounding a recently built submarine outfall that discharges treated wastewater, from an area encompassing some 450,000 inhabitants, into the sea was monitored a year after the beginning of emission via the outfall. Finally, these sediments were characterized by screening estrogenic, PAH-like and dioxin-like activities using in vitro bioassays. Both chemical analyses and bioassays revealed that wastewater inputs were a source of organic contamination of sediments from the Lez and lagoons, which still persisted 2 years after the discharges were stopped. APs could explain a small proportion of the overall estrogenic activities (up to 31%), suggesting that other estrogenic compounds were also present in the sediments. PAHs explained a great share (83% on average) of the EROD induction potency of the extracts. This survey should be the first step in the long-term monitoring of these sites. PMID- 20162266 TI - Intraspecific and interspecific tolerance to copper sulphate in five Iberian amphibian species at two developmental stages. AB - Intraspecific and interspecific variations have been observed across many taxa with respect to resistance to natural environmental stressors. It has already been well documented that amphibians are sensitive to habitat degradation and are regarded as bioindicators of aquatic and agricultural ecosystems. In southern Spain, different toxic substances, including copper sulphate, which is used to control Cycloconium oleaginum (Fungi, Ascomycota, Venturiaceae) during spring and autumn, are used in intensive olive tree agriculture. In this context, many wetlands are affected by a diffuse pollution process. Thus, toxicological studies using different species living in wetlands surrounded by agricultural activity are needed to understand the alterations suffered by these ecosystems. To achieve this understanding, individuals of five amphibian species (Bufo bufo, Epidalea calamita, Discoglossus jeanneae, Pelobates cultripes, and Pelophylax perezi) at Gosner developmental stages 19 and 25 were exposed to different copper sulphate concentrations in 96 h acute toxicity tests. Exposure to copper sulphate had a negative effect on total larval length reached at the end of the experimental period and generated approximately 30% of growth reduction respect to control treatments. P. perezi was the most tolerant species studied and showed no mortality at the maximum concentration tested (0.20 mg Cu L(-1)), whereas the most sensitive species (B. bufo, E. calamita, and D. jeanneae) showed approximately 90% mortality at the same concentration. These results indicates that the sole presence in wetlands of P. perezi, the most abundant species in southeast of Iberian Peninsula, might be correlated with its high tolerance to agrochemicals. PMID- 20162267 TI - Variable vitellogenin response of Japanese medaka (Oryzias latipes) to weekly estrogen exposure. AB - Japanese medaka (Oryzias latipes) is a valuable model organism in reproductive and developmental toxicity testing. The purpose of this experiment is to assess the response of medaka to aquatic estrogen exposure over the course of 1 year. Each week, three pairs of adult male medaka were exposed separately for 4 days (100% static renewal daily) to 17beta-estradiol at a nominal level of 25 microg/l, with a fourth pair of fish exposed separately to an ethanol control. Vitellogenin (VTG) induction was observed each week, with hepatic and plasma VTG levels significantly higher (P < 0.001) than reported for ethanol control specimens. A significant (P < 0.001) increasing trend was observed for plasma VTG results over the duration of the study, whereas a decreasing trend (P = 0.030) of hepatic VTG was evident. A Durbin-Watson test, however, did not demonstrate any serial autocorrelation of hepatic (d = 1.180) or plasma (d = 1.311) VTG levels over the duration of the study. Time-series transformations of the hepatic and plasma VTG data did not reveal any significant seasonal or behavioral patterns. However, significant intermittent peaks in VTG production were observed in both tissue types during the study. These data indicate that some consideration must be taken to time long-term medaka exposures (>20 weeks) in order to eliminate any influence of cyclic changes on plasma VTG response. Alternatively, hepatic cytosolic measurement of VTG appears to show a more sensitive response to aquatic estrogen exposure. PMID- 20162268 TI - Shock following administration of contrast medium in a patient with Kawasaki disease. PMID- 20162269 TI - Comparison of aggregation enhancement and inhibition as strategies for reducing the cytotoxicity of the aortic amyloid polypeptide medin. AB - Aortic medial amyloid (AMA) occurs as localised non-atheromatous plaques in virtually all individuals over the age of 50. The major protein component of AMA is the 50-residue polypeptide medin. Here we propose two methods of manipulating medin aggregation to reduce the cytotoxic species of medin: either by promoting formation of larger benign species or retaining small non-cytotoxic species. Medin co-localises with a variety of factors including glycosaminoglycans (GAGs). The first approach shows that the GAG heparin enhances the rate of medin aggregation and alters the morphology of the amyloid fibrils. Cellular viability measurements suggest that heparin eliminates small cytotoxic species of medin, promoting formation of benign fibrils. The second approach applies a previously successful approach of designing small peptide moieties that are complementary to the key amyloidogenic sequence but which contain modified amino acids known to disrupt hydrogen bonding and therefore prevent aggregation of the target protein. This approach also reduces cellular toxicity of medin at all stages of the aggregation process examined exhibiting a different mode of action to heparin. These results raise the question of whether enhancement of medin aggregation by GAGs is beneficial, by eliminating toxic oligomers, or has deleterious effects by reducing arterial plasticity associated with increased fibril load and whether small peptide inhibitors can be applied as drug candidates for amyloid diseases. PMID- 20162270 TI - The antiviral protein cyanovirin-N: the current state of its production and applications. AB - Human immunodeficiency virus (HIV)/AIDS continues to spread worldwide, and most of the HIV-infected people living in developing countries have little or no access to highly active antiretroviral therapy. The development of efficient and low-cost microbicides to prevent sexual transmission of HIV should be given high priority because there is no vaccine available yet. Cyanovirin-N (CVN) is an entry inhibitor of HIV and many other viruses, and it represents a new generation of microbicide that has specific and potent activity, a different mechanism of action, and unusual chemicophysical stability. In vitro and in vivo antiviral tests suggested that the anti-HIV effect of CVN is stronger than a well-known gp120-targeted antibody (2G12) and another microbicide candidate, PRO2000. CVN is a cyanobacteria-derived protein that has special structural features, making the artificial production of this protein very difficult. In order to develop an efficient and relatively low-cost approach for large-scale production of recombinant CVN to satisfy medical use, this protein has been expressed in many systems by trial and error. Here, to summarize the potential and remaining challenges for the development of this protein into an HIV prevention agent, the progress in the structural mechanism determination, heterologous production and pharmacological evaluation of CVN is reviewed. PMID- 20162271 TI - Efficient treatment of garbage slurry in methanogenic bioreactor packed by fibrous sponge with high porosity. AB - Adding a supporting material to a methanogenic bioreactor treating garbage slurry can improve efficiency of methane production. However, little is known on how characteristics (e.g., porosity and hydrophobicity) of the supporting material affect the bioreactor degrading garbage slurry. We describe the reactor performances and microbial communities in bioreactors containing hydrophilic or hydrophobic sheets, or fibrous hydrophilic or hydrophobic sponges. The porosity affected the efficiency of methane production and solid waste removal more than the hydrophilic or hydrophobic nature of the supporting material. When the terminal restriction fragment length polymorphism technique was used at a lower organic loading rate (OLR), microbial diversities in the suspended fraction were retained on the hydrophobic, but not the hydrophilic, sheets. Moreover, real-time quantitative polymerase chain reaction (PCR) performed at a higher OLR revealed that the excellent performance of reactors containing fibrous sponges with high porosity (98%) was supported by a clear increase in the numbers of methanogens on these sponges, resulting in larger total numbers of methanogens in the reactors. In addition, the bacterial communities in fractions retained on both the hydrophobic and hydrophilic fibrous sponges differed from those in the suspended fraction, thus increasing bacterial diversity in the reactor. Thus, higher porosity of the supporting material improves the bioreactor performance by increasing the amount of methanogens and bacterial diversity; surface hydrophobicity contributes to maintaining the suspended microbial community. PMID- 20162272 TI - Hepatocellular carcinoma of the iliac bone with unknown primary. AB - We report a case of hepatocellular carcinoma of the iliac bone in which the primary tumor was not detected. No malignant primary lesions such as hepatocellular carcinoma or hepatoid carcinoma were detected at the time or during 10 years' follow-up. In this case, transcatheter arterial chemo embolization and radiation therapy resulted in complete regression of the iliac bone tumor and in long-term survival. We focus in particular on the clinical, histological, and therapeutic aspects of the presented case, as well as the imaging and diagnostic aspects. PMID- 20162273 TI - Recombinant human bone morphogenetic protein 2-induced heterotopic ossification of the retroperitoneum, psoas muscle, pelvis and abdominal wall following lumbar spinal fusion. AB - A 45-year-old man presented with vertebral collapse at L5 as an initial manifestation of multiple myeloma and underwent spinal fusion surgery using recombinant human bone morphogenetic protein-2 (rhBMP-2). Subsequent computed tomography (CT) scans and X-rays revealed heterotopic ossification of the left psoas muscle, pelvis, and anterior abdominal wall. While the occurrence of heterotopic ossification has previously been reported when rhBMP-2 has been used for spinal fusion surgery, this case demonstrates that it can occur to a much greater degree than previously seen. PMID- 20162274 TI - Mind the costs: rescaling and multi-level environmental governance in Venice lagoon. AB - Competences over environmental matters are distributed across agencies at different scales on a national-to-local continuum. This article adopts a transaction costs economics perspective in order to explore the question whether, in the light of a particular problem, the scale at which a certain competence is attributed can be reconsidered. Specifically, it tests whether a presumption of least-cost operation concerning an agency at a given scale can hold. By doing so, it investigates whether the rescaling of certain tasks, aiming at solving a scale related problem, is likely to produce an increase in costs for day-to-day agency operations as compared to the status quo. The article explores such a perspective for the case of Venice Lagoon. The negative aspects of the present arrangement concerning fishery management and morphological remediation are directly linked to the scale of the agencies involved. The analysis suggests that scales have been chosen correctly, at least from the point of view of the costs incurred to the agencies involved. Consequently, a rescaling of those agencies does not represent a viable option. PMID- 20162275 TI - Major energy plants and their potential for bioenergy development in China. AB - China is rich in energy plant resources. In this article, 64 plant species are identified as potential energy plants in China. The energy plant species include 38 oilseed crops, 5 starch-producing crops, 3 sugar-producing crops and 18 species for lignocellulosic biomass. The species were evaluated on the basis of their production capacity and their resistance to salt, drought, and/or low temperature stress. Ten plant species have high production and/or stress resistance and can be potentially developed as the candidate energy plants. Of these, four species could be the primary energy plants in China: Barbados nut (Jatropha curcas L.), Jerusalem artichoke (Helianthus tuberosus L.), sweet sorghum (Sorghum bicolor L.) and Chinese silvergrass (Miscanthus sinensis Anderss.). We discuss the use of biotechnological techniques such as genome sequencing, molecular markers, and genetic transformation to improve energy plants. These techniques are being used to develop new cultivars and to analyze and manipulate genetic variation to improve attributes of energy plants in China. PMID- 20162276 TI - Regulatory T cells in peripheral blood, lymph node, and thyroid tissue in patients with medullary thyroid carcinoma. AB - BACKGROUND: Immunological response of the human body is controlled by the suppressive characteristics of regulatory T cells (Tregs). In various diseases a change in the number of Tregs is evident. For example, whereas Tregs are reduced in auto-immunological processes, an increase of Tregs is found with various malignant tumors. Regarding medullary thyroid carcinoma (MTC) no such studies have been performed to date. METHODS: Expression of CD4 and CD25 in CD45+ leukocytes from blood and lymph nodes was studied by flow cytometry in patients with MTC and patients with benign goiter. We also examined the marker forkhead box P3 (FoxP3), an intracellular transcription factor, which is supposed to be the most specific marker for Tregs. Immunohistochemical staining for FoxP3 was performed on lymph node and thyroid tissue. RESULTS: The number of FoxP3+ lymphocytes in peripheral blood was significantly higher in patients with MTC than in controls (p = 0.02). This result was confirmed immunohistochemically in lymph node and thyroid tissue, as well as in carcinoma tissue. No difference in CD4+CD25+ lymphocytes was observed between the two groups. After clinical staging (International Union against Cancer-UICC-stages) of MTC patients, triplication of FoxP3+ lymphocytes could be observed from MTC < UICC II to MTC > UICC II. CONCLUSIONS: An increase of FoxP3+ lymphocytes could be shown in peripheral blood of patients with MTC but not in patients with benign goiter; this increase also correlates with findings in lymph nodes and thyroid gland. The number of FoxP3+ cells correlated with the patients' prognosis. Therefore, FoxP3+ lymphocytes are a good diagnostic criterion for malignancy in patients with medullary thyroid carcinoma, and their presence at staging may influence therapeutic decisions. PMID- 20162277 TI - An international perspective on ultrasound training and use for thyroid and parathyroid disease. AB - BACKGROUND: Use of ultrasound (USN) by endocrine surgeons has dramatically increased. Presently, optimal training and certification requirements have not been standardized at any level (resident/fellow/attending). We sought to define the types of USN training endocrine surgeons receive and how USN is employed in practice. We hypothesized that in more recent years fellowship-trained endocrine surgeons were more likely to receive formal training in the use of USN during their endocrine surgery fellowship. METHODS: A survey link was sent via email to a large group of endocrine surgeons around the world asking about the settings in which they received USN training, the type of instruction received, current use of USN, and other various questions. chi(2) analysis was performed and P < 0.05 was considered significant. RESULTS: One hundred twenty-one surveys were collected from respondents in 27 countries. Median time from completion of residency to the present was 17 years (range = 2-49). Fifty-nine percent of both fellowship- and nonfellowship-trained endocrine surgeons currently use USN in their practice. Of those currently performing USN, 38% reported no USN training of any kind (47% international vs. 23% United States). USN experience among international and U.S. residents was not different (P = 0.27). Fifty-nine percent of respondents reported completing an endocrine surgery fellowship; of those, 85% reported no formal USN training. Forty-one percent reported not being comfortable performing USN at the completion of their endocrine surgery fellowships, requiring the presence of someone else to assist with the exam. CONCLUSIONS: USN training among endocrine surgeons varies widely around the world. Despite an increase in the number of formal endocrine surgery fellowships offered, it does not appear that the number with formal USN training and certification has increased. Formal USN certification is achieved in only a minority of cases among practicing endocrine surgeons. It is currently unknown whether there is a difference in competency between endocrine surgeons with formal versus informal USN training. PMID- 20162279 TI - Sacral neuromodulation: does it affect the rectoanal angle in patients with fecal incontinence? AB - BACKGROUND: In the past decade numerous studies have been published on the successful treatment of fecal incontinence with sacral neuromodulation (SNM). The underlying mechanism of action for lower bowel motility disorders has been unclear. In the present study, the effect of SNM on the rectoanal angle in patients with fecal incontinence was investigated. PATIENTS AND METHODS: In 12 consecutive patients who qualified for SNM an X-defecography study was performed before SNM and at 6 months after permanent implant. Three single lateral rectal views were taken: one during rest, one during squeeze, and one during Valsalva's maneuver, after which the patient was asked to evacuate as rapidly and completely as possible during lateral fluoroscopy. At 6 months two further defecography studies were performed, one during stimulation with the pacemaker on and one with the pacemaker off. RESULTS: The defecography studies showed that the rectoanal angle decreased during rest, squeeze, and Valsalva's maneuver. A slight increase in rectoanal angle was seen during defecation. However, the differences did not reach statistical significance. Sacral neuromodulation improved fecal continence significantly in all patients at 6 months. Median incontinence episodes per week decreased from 6.2 to 1.0 (P = 0.001), and incontinent days per week decreased from 3.7 to 1.0 (P = 0.001) with SNM. There were no significant changes in the median resting and squeeze anal canal pressures, 46.5 versus 49.7 mmHg and 67.1 versus 72.3 mmHg, respectively. Median stimulation amplitude at follow-up was 2.7 V (range: 0.9-5.3 V). CONCLUSIONS: Rectoanal angle did not decrease significantly in patients with fecal incontinence during SNM. PMID- 20162281 TI - Managing patients with a preoperative diagnosis of AJCC/UICC stage I (T1N0M0) papillary thyroid carcinoma: East versus West, whose policy is best? PMID- 20162280 TI - Retroperitoneal soft tissue sarcomas: experience at a single institution in Mexico. AB - BACKGROUND: Retroperitoneal soft tissue sarcomas (RSTS) are a rare and uncommon entity with a poor 5-year overall survival (OS) of approximately 50%, even though they rarely metastasize. The aim of the present study was to analyze the survival of patients with RSTS treated at our institution. PATIENTS AND METHODS: Patients with RSTS treated between 1990 and 2008 were included. Variables analyzed were age, sex, histological type, TNM stage, tumor size, grade of differentiation, and treatment (surgery, chemotherapy only, radiotherapy only, adjuvant radiotherapy, and best supportive care). R0, R1, and R2 resection were analyzed. Overall survival, recurrence-free survival (RFS), cancer-specific survival (CSS), and survival comparison by stage, grade, and type of resection were analyzed. RESULTS: Data for 46 patients were analyzed, 20 men and 26 women. Median age was 51.1 years. Surgery with a curative intent was performed in 32 patients, and R0 resection was feasible in 19 (59.4%). The 5- and 10-year OS rates were 47 and 30%, respectively, for the entire group. The median CSS for resected patients was 102 months; the 5-year OS for stages I, III, and IV was 83, 37, and 0%, respectively; the 5-year OS for low histological grade disease and high histological grade disease was 82 and 35%, respectively; and for R0, R1, and R2 resection, the 5-year OS was 81, 56, and 14%, respectively. Median RFS was 79 months. CONCLUSIONS: Incomplete surgical resection, unresectable disease, high histological grade, and advanced TNM stage are associated with a poor survival in patients with RSTS. Complete resection is still the treatment of choice. PMID- 20162282 TI - Hemodynamic effects of combined therapy using partial splenic embolization and transjugular retrograde obliteration for gastric varices with gastrorenal shunt. AB - BACKGROUND: The purpose of the present study was to investigate the short-term effects of combined therapy using partial splenic embolization (PSE) and transjugular retrograde obliteration (TJO) on the portal hemodynamics of gastric varices with a gastrorenal shunt. PATIENTS AND METHODS: Sixteen patients with gastric varices and a gastrorenal shunt were included in this study. Partial splenic embolization was applied 2 weeks before TJO. The portal blood flow was measured by an ultrasonic duplex Doppler system, and the wedged hepatic venous pressure (WHVP) was measured by hepatic venous catheterization, before and after the combined therapy. RESULTS: The complete obliteration of the gastrorenal shunt and gastric varices was revealed by retrograde shuntography and computed tomography after TJO in all cases. The WHVP before and just after PSE was 23 +/- 7 and 19 +/- 7 mmHg, respectively, showing a significant change (P < 0.01). The WHVP before and the day after TJO was 20 +/- 5 mmHg and 22 +/- 6 mmHg, respectively, showing a significant change (P < 0.01). There was no significant difference between the WHVP before and after the combined therapy. The portal venous flow volume before and after the combined therapy were 514 +/- 146 and 512 +/- 161 ml/min, respectively, showing no significant change. However, the splenic venous flow volume before and after the combined therapy was 319 +/- 131 and 179 +/- 113 ml/min, respectively, showing a significant change (P < 0.05). CONCLUSIONS: The WHVP did not change after the combined therapy of PSE and TJO. Partial splenic embolization contributed to protecting portal congestion after TJO. We conclude that the combined therapy using PSE and TJO is an effective treatment for gastric varices from the portal hemodynamic point of view. PMID- 20162283 TI - High-intensity focused ultrasound effect in breast cancer nodal metastasis. PMID- 20162284 TI - Endovascular treatment of complications of femoral arterial access. AB - Endovascular repair of femoral arterial access complications is nowadays the treatment of choice in a group of patients who cannot tolerate vascular reconstruction and bleeding due to advanced cardiovascular disease. Endovascular procedures can be performed under local anesthesia, are well tolerated by the patient, and are associated with a short hospitalization time. Ninitinol stent technology allows for safe stent and stent-graft extension at the common femoral artery (CFA) level, due to increased resistance to external compression and bending stress. Active pelvic bleeding can be insidious, and prompt placement of a stent-graft at the site of leakage is a lifesaving procedure. Percutaneous thrombin injection under US guidance is the treatment of choice for femoral pseudoaneurysms (PAs); this can theoretically be safer with simultaneous balloon occlusion across the entry site of a PA without a neck or with a short and wide neck. In a few cases with thrombin failure due to a large arterial defect or accompanying arteriovenous fistula (AVF), a stent-graft can be deployed. The vast majority of catheter-induced AVFs can be treated effectively with stent-graft implantation even if they are located very close to the femoral bifurcation. Obstructive dissection flaps localized in the CFA are usually treated with prolonged balloon inflation; however, in more extensive dissections involving iliac arteries, self-expanding stents should be deployed. Iliofemoral thrombosis can be treated effectively with catheter-directed thrombolysis (CDT) followed by prolonged balloon inflation or stent placement. Balloon angioplasty and CDT can occasionally be used to treat stenoses and occlusions complicating the use of percutaneous closure devices. PMID- 20162285 TI - Lung volumes, ventricular function and pulmonary arterial flow in children operated on for left-sided congenital diaphragmatic hernia: long-term results. AB - OBJECTIVES: To compare MRI-based functional pulmonary and cardiac measurements in the long-term follow-up of children operated on for left-sided congenital diaphragmatic hernia (CDH) with age- and body size-matched healthy controls. METHODS: Twelve children who received immediate postnatal surgery for closure of isolated left-sided CDH were included and received basic medical examinations, pulmonary function testing and echocardiography. MRI included measurement of lung volume, ventricular function assessment and velocity-encoded imaging of the pulmonary arteries and was compared with the data for 12 healthy children matched for age and body size. RESULTS: While patients' clinical test results were not suspicious, comparison between the MRI data for patients and those for healthy controls revealed significant differences. In patients, the volumes of the left lungs were increased and the tidal volume was larger on the right side. While the stroke volumes of both ventricles were reduced, heart rate and ejection fraction were increased. Flow, acceleration time and cross-sectional area of the left pulmonary artery were reduced. CONCLUSION: Functional MRI detected pulmonary and cardiac findings in the late follow-up of CDH children which may be missed by standard clinical methods and might be relevant for decisions regarding late outcome and treatment. PMID- 20162286 TI - Spinal dermal sinus tract. PMID- 20162288 TI - No change in adolescents' neglect on contraceptive use over two decades. AB - PURPOSE: The sexual activity and contraceptive use is evaluated over 21 years amongst Danish adolescents in ninth grade. METHODS: A repeated, cross-sectional questionnaire study in the municipality of Viborg, comparing the results of four consecutive surveys between 1986 and 2007. RESULTS: In 2007, 40% of the pupils had sexual debut at an average age of 15.3 +/- 1.5 years. At sexual debut condoms were used in 77% of the adolescents and the contraceptive pill in 15%. At their latest coitus 34% used any contraceptive pill as 27% of pupils changed from use of condom to the pill. Practical experience with condoms was found in 90% of both sexes at sexual debut. Fourteen percent of the adolescents used no contraception at all at debut in 2007, which is similar to 1986, 1993, and 2000. Eighteen percent of the pupils used no contraception at all at their last intercourse in 2007 and 2000. CONCLUSION: Knowledge about and use of condoms is substantial amongst adolescents already at sexual debut. A shift is confirmed from condoms at first coitus to more frequent use of the pill later on. A considerable number of pupils (10-20%) are neither protected against sexually transmitted infections nor pregnancy at first or later intercourse. PMID- 20162289 TI - Levels of dihydrotestosterone, testosterone, androstenedione, and estradiol in canalicular, saccular, and alveolar mouse lungs. AB - Androgens and estrogens are known regulators of fetal and postnatal lung development, but their levels in the developing lung have never been determined. We present here, for the first time, a gas chromatography-mass spectrometry (GC/MS) quantification of dihydrotestosterone, testosterone, androstenedione, and estradiol in canalicular, saccular, and alveolar stage lungs of both sexes. Testosterone, androstenedione, and estradiol were observed in all the analyzed lung samples from gestation day (GD) 16.5 to postnatal day (PN) 30, totalizing 383 individual mice. Levels of these three steroids decreased between birth and PN 5. In contrast, dihydrotestosterone was detected only in male samples on GD 19.5, PN 0, and PN 30. A significant sex difference was observed for testosterone and androstenedione but not for estradiol. Steroid levels were also determined in skinned hind legs for comparison. Three-way analysis of variance revealed that tissue (lung or leg) had a significant effect on testosterone levels for both sexes, but not on androstenedione and estradiol levels. Low but significant testosterone and androstenedione levels were observed in all the females and in prepubertal male samples. These levels must be sufficient to induce androgen receptor activation, as suggested by our recent report showing the presence of androgen receptor in the nucleus of several lung cells in corresponding developmental ages and sexes. PMID- 20162290 TI - Re-evaluating the role of Tao1 in the spindle checkpoint. AB - The spindle checkpoint restrains anaphase onset and mitotic exit until all chromosomes are stably attached to the mitotic spindle via their kinetochores. The Tao1 protein kinase was recently reported as a novel spindle checkpoint component. When an siRNA was used to repress Tao1, the essential spindle checkpoint component Mad2 failed to localise to kinetochores, and cells rapidly exited mitosis. Tao1 was also shown to interact with BubR1, another essential checkpoint component, and be rapidly degraded after mitosis, a feature typical of many mitotic regulators. Here, we identify four different siRNAs that repress Tao1 protein levels as efficiently as the previously reported siRNA. However, these siRNAs do not override the spindle checkpoint. We also present data indicating that Tao1 does not interact with BubR1 and that it is not rapidly degraded after mitosis. We show that the previously reported siRNA not only represses Tao1 but also dramatically reduces Mad2 protein levels. Crucially, expression of exogenous Mad2, but not Tao1, rescued the spindle checkpoint phenotype induced by this siRNA. Thus, the key functional data implicating Tao1 in the spindle checkpoint can be explained by an off-target siRNA phenomenon that results in Mad2 inhibition. Taken together, our data do not support the notion that Tao1 is a component of the spindle checkpoint. PMID- 20162291 TI - Meiotic silencing and fragmentation of the male germline restricted chromosome in zebra finch. AB - During male meiotic prophase in mammals, X and Y are in a largely unsynapsed configuration, which is thought to trigger meiotic sex chromosome inactivation (MSCI). In avian species, females are ZW, and males ZZ. Although Z and W in chicken oocytes show complete, largely heterologous synapsis, they too undergo MSCI, albeit only transiently. The W chromosome is already inactive in early meiotic prophase, and inactive chromatin marks may spread on to the Z upon synapsis. Mammalian MSCI is considered as a specialised form of the general meiotic silencing mechanism, named meiotic silencing of unsynapsed chromatin (MSUC). Herein, we studied the avian form of MSUC, by analysing the behaviour of the peculiar germline restricted chromosome (GRC) that is present as a single copy in zebra finch spermatocytes. In the female germline, this chromosome is present in two copies, which normally synapse and recombine. In contrast, during male meiosis, the single GRC is always eliminated. We found that the GRC in the male germline is silenced from early leptotene onwards, similar to the W chromosome in avian oocytes. The GRC remains largely unsynapsed throughout meiotic prophase I, although patches of SYCP1 staining indicate that part of the GRC may self-synapse. In addition, the GRC is largely devoid of meiotic double strand breaks. We observed a lack of the inner centromere protein INCENP on the GRC and elimination of the GRC following metaphase I. Subsequently, the GRC forms a micronucleus in which the DNA is fragmented. We conclude that in contrast to MSUC in mammals, meiotic silencing of this single chromosome in the avian germline occurs prior to, and independent of DNA double strand breaks and chromosome pairing, hence we have named this phenomenon meiotic silencing prior to synapsis (MSPS). PMID- 20162292 TI - Using oral microbial DNA analysis to identify expirated bloodspatter. AB - Distinguishing expirated bloodstains (blood forced by airflow out of the nose, mouth or a chest wound) from impact spatter (blood from gunshots, explosives, blunt force trauma and/or machinery accidents) is an important challenge in forensic science. Streptococcal bacteria are only found in the human mouth and saliva. This study developed a polymerase chain reaction (PCR) method that detects DNA from these bacteria as a sensitive tool to detect the presence of saliva. The PCR method was very specific to human oral streptococci, with no PCR product being made from human DNA or DNA from other microbes that were tested. It was also very sensitive, detecting as little as 60 fg of target DNA. The PCR amplification gave product with 99 out of 100 saliva samples tested. PCR was not inhibited by the presence of blood and could detect target DNA in expirated bloodstains in a range of materials and for up to 92 days after deposit on cardboard or cotton fabric. In a blind trial, the PCR method was able to distinguish three mock forensic samples that contained expirated blood from four that did not. Our data show that bacteria present in the oral cavity can be detected in bloodstains that contain saliva and therefore can potentially be used as a marker in forensic work to distinguish mouth-expirated bloodstains from other types of bloodstains. PMID- 20162293 TI - Separation of positional CPP isomers by chiral HPLC-DAD of seized tablets. AB - Meta-chlorophenylpiperazine, one of the synthetic piperazine-derived designer drugs, is to date controlled as an illicit substance in five European member states. Depending on the position of the chlorine atom, different positional isomers of CPP (ortho-, meta- and para-) are possible. Therefore, there is a need to develop an analytical method for the separation and identification of the three 1-chlorophenylpiperazines in tablets containing CPP. In this work, the position isomers o-, m- and p-CPP were separated by liquid chromatography (HPLC) on a reversed-phase chiral column. Different mobile phase compositions and pH ranges were systematically studied to find optimum chromatographic conditions. Best results were achieved with isocratic mobile phase of triethyl amine buffer and methanol (V/V = 70/30) at pH 9 with a flow rate of 0.8 ml/min. The method was validated in terms of selectivity, linearity, limit of detection and quantification and precision. At last, the developed method was successfully applied on seized ecstasy tablets. PMID- 20162294 TI - A survey on the use of general anesthesia for cataract surgery. PMID- 20162295 TI - Lens epithelial cell apoptosis initiates diabetic cataractogenesis in the Zucker diabetic fatty rat. AB - BACKGROUND: It has been suggested that damage of lens epithelial cell (LEC) may play an important role in cataract formation. Nitric oxide is involved in cataract development. Here, we investigated the relationship between LEC damage and iNOS expression in the Zucker diabetic fatty (ZDF) rat. METHODS: At 21 weeks of age, the eyes were enucleated and the lens opacity was then examined. Apoptosis were detected by TUNEL assay, and the expression of iNOS and NF-kappaB activation were studied by immunohistochemistry and southwestern histochemistry respectively. RESULTS: In 21-week-old male ZDF rats, cataract was developed, TUNEL-positive LECs were markedly increased, and the expression levels of iNOS mRNA and protein were significantly upregulated. The expression pattern of iNOS was closely correlated with apoptotic change of LECs. In addition, advanced glycation end products (AGEs) were accumulated in cytoplasm of LECs. Activated NF kappaB was mainly detected in nucleus of LECs. CONCLUSIONS: The higher expressions of AGEs, NF-kappaB and iNOS in LECs of diabetic rats suggest that these factors are involved in apoptosis of LEC alterations related to diabetic cataract. PMID- 20162296 TI - Visual results and complications of primary intraocular lens implantation in infants aged 6 to 12 months. AB - BACKGROUND: To present the visual results and the complications of primary intraocular lens (IOL) implantation in infants aged 6 to 12 months between January 2002 and July 2007. METHODS: A total of 26 consecutive eyes, of 16 infants with cataract aged 6 to 12 months, were reviewed in the study. All patients had cataract extraction with anterior and posterior capsulorrhexis combined with anterior vitrectomy and primary hydrophobic acrylic IOL implantation. Six infants (six eyes) had unilateral congenital cataract and ten (20 eyes), bilateral cataract. Visual acuity and complications were recorded throughout the 46.4-month mean follow-up (range 22 to 79 months). RESULTS: All eyes had primary IOL implantation. The mean best-corrected visual acuity (logMAR) was 0.98 +/- 0.18,0.50 +/- 0.14 and 0.61 +/- 0.25 for unilateral, bilateral and all eyes respectively at the last follow-up. IOLs were implanted in the capsular bag of 25 eyes (96.2%) and in the sulcus of the remaining one eye (3.8%). Seven eyes (26.9%) developed visual axis opacification (VAO), and four eyes required secondary pars plana vitrectomy (PPV). IOL opacification occurred in one eye 54 months after implantation. Late onset open-angle glaucoma developed in one eye, and required trabeculectomy surgery. The predictors of good best-corrected visual acuity (BCVA) included partial cataract, bilateral cataract, absence of strabismus or nystagmus, and good amblyopic treatment. The greatest annual myopic change (5.15 +/- 2.08 D) was observed during the first 12 months after surgery. In unilateral cases, there was no significant difference in the axial length between the cataractous eye and the fellow normal eye both at the time of surgery (P = 0.891) and final follow-up (P = 0.693). CONCLUSIONS: Primary IOL implantation was safe and effective for infantile cataract surgery. Total or unilateral cataract, nystagmus or strabismus, and inadequate amblyopic therapy were predictors of poor BCVA. Significant myopic shifts occurred especially in infants in the first year of surgery. The pseudophakic eye had a similar growth rate, as measured by axial length, to that of the fellow normal eye, in unilateral cases. PMID- 20162297 TI - Thrombophilic risk factors in the pathogenesis of non-arteritic anterior ischemic optic neuropathy patients. AB - BACKGROUND: Non-arteritic anterior ischemic optic neuropathy (N-AION) is caused by acute ischemic infarction of the optic nerve head, supplied by the posterior ciliary arteries. Thrombophilia is the tendency/predisposition to vascular thromboses of arteries and veins, and the existence of thrombophilic risk factors leads to blood hypercoagulability and potentially increased risk for thromboses. OBJECTIVES: To investigate whether there is an association between N-AION and a wide spectrum of thrombophilic risk factors. PATIENTS AND METHODS: Seventy-seven consecutive cases of confirmed N-AION and 60 age- and sex-matched consecutive controls constituted the study group. Fibrinogen levels, deficiency of proteins C, S, ATIII, lupus anticoagulant, activated protein C resistance, factor V Leiden, factor V H1299R, factor II G20210A, MTHFR C677T, MTHFR A1298C, GPIIIa A1/A2, and ACE I/D polymorphisms were analysed. RESULTS: Statistical analysis of the plasma proteins in our study demonstrated that the only significant difference was the one concerning protein S levels. In particular, the mean value for N-AION patients was 78.8% +/- 21.2, and for the control group the mean value was 88% +/- 21.2 (p = 0.013). Despite the above-mentioned result, there was not any statistical difference between the two subgroups regarding actual protein S deficiency, as 9/77 (11.7%) patients and 4/60 (6.7%) controls had protein S levels below 60% (p = 0.32). In our study sample, homozygosity for MTHFR C677T polymorphism in the study group as a whole, and the presence of at least one A2 allele of GPIIIa in the subgroup of male patients as compared to healthy male controls, proved to be the most significant thrombophilic risk factors, with odds ratios of 16.78 (95% C.I 0.96-294.42, p = 0.054) and 4.6 (95% C.I 1.52-13.88, p = 0.007) respectively. CONCLUSION: Screening for these polymorphisms would probably constitute a valuable procedure in N-AION patients, as they may have an important contribution to the pathogenesis of the disease. PMID- 20162299 TI - Ultrasonic Doppler measurements of blood flow velocity of rabbit retinal vessels using a 45-MHz needle transducer. AB - BACKGROUND: The purpose of this study is to measure blood flow velocity of rabbit retinal vessels using a 45-MHz ultrasonic Doppler system with a needle transducer. METHODS: A high-frequency pulsed Doppler system that utilizes a 45 MHz PMN-PT needle transducer was developed to measure retinal blood flow velocity in situ. The pulsed Doppler allowed the differentiation of retinal from choroidal blood flow velocity. The needle transducer was inserted into the vitreous cavity through a 20-gauge incision port to access the retinal vessels. The first phase of the experiment evaluated the reproducibility of the measurements. The second phase measured velocities at four positions from the optic disc edge to the distal part of each vessel in nine eyes for the temporal and six eyes for the nasal portions. The angle between the transducer and the retinal vessel at each site was measured in enucleated rabbit eyes to estimate and compensate for measurement errors. RESULTS: In the first phase, the average measurement error was 5.97 +/- 1.34%. There was no significant difference comparing all eyes. In the second phase, the velocities gradually slowed from the disc edge to the distal part, and temporal velocities were faster than nasal velocities at all measurement sites. CONCLUSION: This study demonstrated the feasibility of reliably measuring retinal blood flow velocity using a 45-MHz ultrasonic Doppler system with a needle transducer. PMID- 20162298 TI - Verteporfin PDT for non-standard indications--a review of current literature. AB - BACKGROUND: Verteporfin photodynamic therapy (PDT) is approved for the treatment of predominantly classic subfoveal choroidal neovascularization (CNV) due to age related macular degeneration (AMD), as well as for subfoveal CNV due to pathologic myopia and ocular histoplasmosis syndrome. Verteporfin PDT addresses the underlying pathology of ocular vascular disorders through its angio-occlusive mechanism of action, which reduces both visual acuity loss and the underlying leakage associated with lesions. Verteporfin PDT has also been associated with encouraging treatment outcomes in case studies involving patients with choroidal vascular disorders such as polypoidal choroidal vasculopathy, central serous chorioretinopathy, choroidal haemangioma, angioid streaks, and inflammatory CNV, i.e. conditions currently considered as non-standard indications of verteporfin PDT. In many studies, outcomes were better than expected based on the natural courses of each of these conditions. Although the anti-vascular endothelial growth factor (VEGF) therapies, ranibizumab and pegaptanib, have been approved for CNV due to AMD, their role in these other choroidal vascular disorders remains to be established. We summarize current literature that has documented the use of verteporfin PDT in these conditions. CONCLUSIONS: The complex pathogenesis of CNV provides a rationale for investigating combination approaches comprising verteporfin PDT and anti-VEGF therapies. Randomized controlled studies are warranted to confirm the preliminary results of verteporfin PDT as a monotherapy or in combination with anti-VEGF therapies in the treatment of a variety of choroidal vascular conditions. PMID- 20162300 TI - The effect of different dynamic stretch velocities on jump performance. AB - Dynamic stretching has gained popularity, due to a number of studies showing an increase in high intensity performance compared to static stretch modalities. Twenty-four males (age mean 21 +/- 0.3 years) performed a standardised 10 min jogging warm-up followed by either; no stretching (NS), slow dynamic stretching at 50 b/min (SDS) or fast dynamic stretching at 100 b/min (FDS). Post-warm-up, squat, countermovement and depth jumps were performed. Heart rate, tympanic temperature, electromyography (EMG) and kinematic data (100 Hz) were collected during each jump. Results indicated that the FDS condition showed significantly greater jump height in all tests compared to the SDS and NS conditions. Further, the SDS trial resulted in significantly greater performance in the drop and squat jump compared to the NS condition. The reasons behind these performance changes are multi-faceted, but appear to be related to increases in heart rate and core temperature with slow dynamic stretches, while the greater increase in performance for the fast dynamic stretch intervention is linked to greater nervous system activation, shown by significant increases in EMG. In conclusion, a faster dynamic stretch component appears to prepare an athlete for a more optimum performance. PMID- 20162301 TI - Effect of cold water immersion on 100-m sprint performance in well-trained swimmers. AB - The aim of the present study was to examine the effect of cold water immersion (CWI) on sprint swimming performance in simulated competition conditions. Ten well-trained swimmers (5 males, 5 females; 19.0 +/- 3.9 years) performed two 100 m swimming sprints (S1 and S2) interspersed with a 30-min passive recovery period, during which athletes were randomly assigned to 5 min of CWI (14 degrees C) or an out-of-water control condition (CON 28 degrees C). During tests, sprint times, heart rate (HR), pre- and post-race parasympathetic activity via HR variability (natural logarithm of the square root of the mean of the sum of the squares of differences between adjacent normal R-R intervals; Ln rMSSD) and blood lactate accumulation ([La](ac)) and clearance ([La](cle)) were recorded. Rates of perceived recovery (RPR) and exertion (RPE) were evaluated before and after each sprint. CWI was associated with a 'likely' decrease in swimming performance [1.8% (90% CI 0.2, 3.5)], as well as 'likely' lower peak HR [-1.9% (-3.6, -0.2)]. CWI was also associated with a 'likely' smaller decrease in Ln rMSSD after the first sprint [-16.7% (-30.9, -4.1)]. RPR was 'likely' better [+27.2% (-3.7, 68.0)] following CWI. 'unclear' effects were observed for [La](ac) [+24.7% (-13.4, 79.5)], [La](cle) [-7.6% (-24.2, 12.7)] or RPE [+2.0% (-12.3, 18.5)]. Following CWI, changes in sprint times were 'largely' correlated with changes in peak HR (r = 0.80). Despite a subjective perception of improved recovery following CWI, this recovery intervention resulted in slower swimming times in well-trained athletes swimming in simulated competition conditions. PMID- 20162303 TI - Transgenic zebrafish models of neurodegenerative diseases. AB - Since the introduction of the zebrafish as a model for the study of vertebrate developmental biology, an extensive array of techniques for its experimental manipulation and analysis has been developed. Recently it has become apparent that these powerful methodologies might be deployed in order to elucidate the pathogenesis of human neurodegenerative diseases and to identify candidate therapeutic approaches. In this article, we consider evidence that the zebrafish central nervous system provides an appropriate setting in which to model human neurological disease and we review techniques and resources available for generating transgenic models. We then examine recent publications showing that appropriate phenotypes can be provoked in the zebrafish through transgenic manipulations analogous to genetic abnormalities known to cause human tauopathies, polyglutamine diseases or motor neuron degenerations. These studies show proof of concept that findings in zebrafish models can be applicable to the pathogenic mechanisms underlying human diseases. Consequently, the prospects for providing novel insights into neurodegenerative diseases by exploiting transgenic zebrafish models and discovery-driven approaches seem favorable. PMID- 20162304 TI - Determination of serum antibodies against swine-origin influenza A virus H1N1/09 by immunofluorescence, haemagglutination inhibition, and by neutralization tests: how is the prevalence rate of protecting antibodies in humans? AB - In April 2009, a new variant of influenza A virus, subtype H1N1v emerged in Mexico and spread all over the world producing the H1N1 pandemic in mankind after 1918-1920 and 1978/1979. Obviously there was no herd immunity against this new virus variant. Mainly young people, but less elderly were affected and presented severe and even lethal courses of disease. Since virus-specific antibodies are commonly regarded as markers of partial or complete immunoprotection, we performed antibody determinations in serum samples obtained from people before and after the pandemic has arrived in our region (Frankfurt/M., Germany). The assays were done by indirect immunofluorescence, by neutralization test, and by a haemagglutination inhibition test (HI), which was established in a practical modification for general and easy use. Among 145 individuals, of whom serum specimens had been drawn before the onset of pandemic, 19 revealed humoral immunity, i.e. titres of H1N1v neutralizing antibodies (at least 1:64). Eleven were older than 60 years, one belonged to the age group 40-59 years, three to the age group 20-39 years, and two to the age group 15-19 years. After the onset of pandemic in Frankfurt, serum specimens drawn from n = 225 randomly selected patients of our local university hospital were investigated for antibodies against H1N1v by HI, which is generally recommended for routine check of immunity. Twenty-eight individuals revealed the protecting antibody titre of at least 1:40. The age distribution had moved to mean age groups. The results fit to the incidence of influenza A/H1N1(09) disease, as confirmed by RT-PCR in patients admitted to our hospital, peaking in the younger age groups up to 30 years (second affected group: 30-40 years). While commonly used solid-phase antibody tests (like immunofluorescence) are not suitable to diagnose passed H1N1(09) infection and acquired immunity, this can be easily done by HI. Expecting the next waves of influenza A/H1N1v infections, HI testing may avoid vaccinations under special risk of severe or hidden adverse reactions. PMID- 20162302 TI - Understanding inflammatory pain: ion channels contributing to acute and chronic nociception. AB - Inflammatory pain results from the increased excitability of peripheral nociceptive sensory fibres produced by the action of inflammatory mediators. This excitatory effect, in turn, is a result of the altered activity of ion channels within affected sensory fibres. This review will consider the molecular consequences of inflammation within the peripheral nerves with particular focus on the effects of different inflammatory mediators on the ion channels in sensory neurons. We will discuss the main signalling pathways triggered in neurons by inflammatory mediators; the ionic mechanisms underlying inflammatory hyperalgesia and spontaneous inflammatory pain and finally will briefly consider ion channels underlying pain in chronic inflammation. PMID- 20162305 TI - Early germination of Arabidopsis pollen in a double null mutant for the arabinogalactan protein genes AGP6 and AGP11. AB - The pollen specificity of the Arabidopsis arabinogalactan protein (AGP) genes AGP6 and AGP11 suggests that they are integral to pollen biogenesis, and their high percent of sequence similarity may indicate a potential for overlapping function. Arabidopsis agp6 agp11 double null mutants have been studied in our laboratory, and in the present work, we characterize the germination and growth of its pollen. When compared to wild type, mutant agp6 agp11 pollen displayed reduced germination and elongation, both in vivo and in vitro, and precocious germination inside the anthers, provided that sufficient moisture was available. This characteristic was not observed in wild type plants, even in water content conditions which for the mutant were sufficient for pollen germination. Therefore, an additional distinctive phenotypic trait of arabinogalactan proteins AGP6 and AGP11 may be to avert untimely germination of pollen. Such AGPs may control germination through water uptake, suggesting an important biological function of this gene family in pollen. PMID- 20162306 TI - Do mitochondria in Dendrobium petal mesophyll cells form vacuole-like vesicles? AB - Using transmission electron microscopy, we investigated the ultrastructure of mitochondria in petal mesophyll cells of the orchid Dendrobium cv. Lucky Duan, from the time of floral opening to visible petal senescence. Cells close to the vascular bundle contained many mitochondria, some of which showed internal degeneration. This inner mitochondrial breakdown was accompanied by an eightfold increase in mitochondrial volume. Small electron-dense granules (approximately 0.04 mum in diameter) at the periphery of the mitochondrial matrix remained. These granules were used as an indicator of still later stages of mitochondrial development in these cells. The apparent final stage of mitochondrial degeneration was a single-membrane-bound vesicle, resembling a vacuole. No evidence was found for the idea that mitochondria became transferred (intact or degenerated) into a lytic vacuole. Taken together, the data suggest the hypotheses that (a) mitochondria in cells close to the vascular bundle in petals of open Dendrobium cv. Lucky Duan flowers undergo large-scale internal degeneration and that (b) such degenerating mitochondria form vacuole-like vesicles. PMID- 20162307 TI - Nutrition and health relevant regulation of intestinal sulfur amino acid metabolism. AB - Sulfur amino acids (SAA), particularly methionine and cysteine, are critical for the gut to maintain its functions including the digestion, absorption and metabolism of nutrients, the immune surveillance of the intestinal epithelial layer and regulation of the mucosal response to foreign antigens. However, the metabolism of SAA in the gut, specifically the transmethylation of methionine, will result in a net release of homocysteine, which is shown to be associated with cardiovascular disease and stroke. Furthermore, the extensive catabolism of dietary methionine by the intestine or by luminal microbes may result in a decrease in nutritional efficiency. Therefore, the regulation of SAA metabolism in the gut is not only nutritionally relevant, but also relevant to the overall health and well-being. The superiority of DL-2-hydroxy-4-methylthiobutyrate to DL methionine in decreasing homocysteine production, alleviating stress responses, and reducing the first-pass intestinal metabolism of dietary methionine may provide a promising implication for nutritional strategies to manipulate SAA metabolism and thus to improve the nutrition and health status of animals and perhaps humans. PMID- 20162308 TI - Do 5-fluorouracil therapies alter CYP2C19 metaboliser status? AB - PURPOSE: To report a case of altered CYP2C19 metaboliser status following 5 fluorouracil treatment. METHODS: A 78-year-old male with stage III colorectal adenocarcinoma was prescribed with weekly iv 5-fluorouracil and folinic acid (FU/FA). Fourteen weeks after starting FU/FA, the patient was enrolled in a clinical study to investigate the role of tumour burden on drug metabolising enzyme activity. CYP2C19 genotype was determined and the activity of CYP2C19 was measured using proguanil (PG) as a probe substrate. A metabolic ratio (PG/CG) for CYP2C19 activity was determined on three separate occasions, 7 days apart. RESULTS: The patient was homozygous wild type (CYP2C19*1/*1), and on the first test, the metabolic ratio was concordant with the extensive metaboliser genotype. However, at day 14 and day 21, the metabolic capacity of this enzyme had decreased, and the subject had become a poor metaboliser (PG/CG > 30). The patient developed grade III hand and foot syndrome at day 10 of the study during the period of null CYP2C19 activity. CONCLUSIONS: Although 5FU is not a substrate for hepatic drug metabolising CYP enzymes, it may interfere with the synthesis of CYP2C19. Decreased activity of a related enzyme, CYP2C9, following 5FU has been reported previously. Down regulation of CYP2C9 and CYP2C19 synthesis by 5FU therapies may explain the adverse effect of 5FU on the clinical disposition of warfarin and phenytoin. PMID- 20162309 TI - Theoretical calculation of partition coefficients of dimethoxypyrimidinylsalicylic acids. AB - Despite their importance as herbicides, dimethoxypyrimidinylsalicylic acids has been poorly characterized from a physical-chemical point of view. This lack of information has prevented the assessment of their impact in the environment once they are released. In this study, environmentally important properties (free energy of solvation, Henry's law constant, octanol/air, and octanol/water partition coefficients) of 39 dimethoxypyrimidinylsalicylic derived compounds are calculated by density functional theory (DFT) methods at B3LYP/6-31G(d,p) level of theory using the Poisson-Boltzmann solvation model. These properties have not been reported previously for this family of compounds, neither experimentally or theoretically. PMID- 20162310 TI - A density functional study towards substituent effects on anion sensing with urea receptors. AB - Effects of substituents on anion binding in different urea based receptors have been examined using density functional (B3LYP/6-311+G**) level of theory. The complexes formed by a variety of substituted urea with a halide anion (fluoride) and an oxy-anion (acetate) have been calculated. The stronger complexes were predicted for receptors with fluoride ion than that of acetate ion, however, in water the preference was found to be reversed. The pK ( a ) calculations showed the preferred sites of deprotonation for positional isomers, while interacting with anions. The position of the substituent in the receptor, however, could change the preferred sites of deprotonation compared to the site predicted with pK ( a ) values. Figure The substituent effects on anion binding towards different urea receptors have been examined by DFT with B3LYP/6-311+G** level of theory. PMID- 20162311 TI - Analysis of anisotropic effects in trinuclear metal carbonyl compounds by visualization of through-space NMR shielding. AB - Through-space NMR shieldings were calculated for trinuclear metal-carbonyl compounds [M(3)(CO)(12)] (M = Fe, Ru, Os), employing the nucleus-independent chemical shift approach. The through-space shieldings were visualized as a contour plot of iso-chemical shielding surfaces, and were applied to quantify the overall anisotropic effect of the carbonyl groups, as well as to identify the influence of the transition metal on the scopes of the corresponding anisotropy cones. The shielding surfaces show that the anisotropic effect of the carbonyl groups at equatorial positions changes depending on the metal. This effect was associated with pi-backdonation from the metal to the carbonyl groups in that position, in agreement with geometric data as well as calculated NMR parameters. Therefore, visualization of the through-space NMR shieldings of trinuclear metal carbonyl compounds of group 8 is able to reflect the distinct arrangements of the carbonyl groups in these organometallic compounds. PMID- 20162312 TI - An improved generalized AMBER force field (GAFF) for urea. AB - We describe an improved force field parameter set for the generalized AMBER force field (GAFF) for urea. Quantum chemical computations were used to obtain geometrical and energetic parameters of urea dimers and larger oligomers using AM1 semiempirical MO theory, density functional theory at the B3LYP/6-31G(d,p) level, MP2 and CCSD ab initio calculations with the 6-311++G(d,p), aug-cc-pVDZ, aug-cc-pVTZ, and aug-cc-pVQZ basis sets, and with the CBS-QB3 and CBS-APNO complete basis set methods. Seven different urea dimer structures were optimized at the MP2/aug-cc-pVDZ level to obtain accurate interaction energies. Atomic partial charges were calculated at the MP2/aug-cc-pVDZ level with the restrained electrostatic potential (RESP) fitting approach. The interaction energies computed with these new RESP charges in the force field are consistent with those obtained from CCSD and MP2 calculations. The linear dimer structure calculated using the force field with modified geometrical parameters and the new RESP charge set agrees well with available experimental data. PMID- 20162313 TI - Brachial-brachial autogenous arteriovenous fistula in a dialysis patient with Staphylococcus aureus bacteremia. AB - As the number of patients on hemodialysis increases, there will also be an increase in the number of patients with inadequate superficial veins for the creation of an autogenous arteriovenous fistula (AVF). In those patients, medical devices such as vascular prostheses or tunneled-cuffed catheters are necessary to maintain dialysis access. However, these devices are frequently associated with bacterial infection. We recently encountered a dialysis patient who underwent tunneled-cuffed catheter insertion because of the lack of usable superficial veins for autogenous access, and this patient subsequently developed catheter related Staphylococcus aureus bacteremia with multiple metastatic infections. Despite immediate removal of the catheter, the infection persisted over an extended period, which was a condition precluding the further use of catheters or other prosthetic materials. To handle this situation, we utilized the deep brachial vein to construct an autogenous AVF. After ligating numerous branches, the vein was anastomosed to the brachial artery and then transposed to the subcutaneous space. The newly constructed autogenous AVF, which successfully kept the patient free from foreign materials, greatly contributed to the relief of persistent infection. Although the brachial vein is rarely used for AVF creation, we suggest that it can serve as an option to create an alternative AVF in a patient with inadequate superficial veins. PMID- 20162314 TI - A case of Carpentier-Edwards pericardial bioprosthesis in mitral position explanted 22 years after implantation. AB - A case of Carpentier-Edwards PERIMOUNT (CEP) mitral pericardial bioprosthesis explanted 22 years after the valve replacement is reported. This patient underwent the previous replacement at the age of 50. The extracted bioprosthesis showed three rigid leaflets, one of which had a tear causing severe mitral regurgitation. The X-ray demonstrated calcification of varied extent among these leaflets, ranging from none to severe. When leaflet calcification is suppressed, perhaps the lifespan of a CEP valve can be prolonged more than previously expected. When a literature search was conducted, this case was found to represent the longest reported interval from the implantation of a CEP valve in the mitral position to the explantation as a result of severe mitral regurgitation caused by structural valve deterioration (SVD). PMID- 20162315 TI - Augmentation index in patients with rheumatoid arthritis and ankylosing spondylitis treated with infliximab. AB - Premature atherosclerosis is linked to inflammation. Arterial stiffness is a marker of vascular dysfunction. We tested the hypothesis that treatment with infliximab, which is effective in reducing inflammation in rheumatoid arthritis (RA) and ankylosing spondylitis (AS), also lowers the augmentation index (AIx) in patients with active disease. We also analyzed the subendocardial viability ratio (SEVR), which is a measure of myocardial perfusion relative to cardiac workload. Included in the study were 30 patients (17 RA, 13 AS). Conventional treatment failed in all patients. The AIx and SEVR were determined by radial applanation tonometry before and after treatment with infliximab, at baseline and at week 7. After treatment with infliximab, Disease Activity Score for 28 joints (RA patients), Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index (AS patients), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) improved significantly (p < 0.001). The AIx for all patients increased from 22.0 +/- 14.0% to 24.6 +/- 13.0% (p = 0.03). The increase in the RA sub-group (p = 0.01) was also significant. The SEVR decreased from 148.6 +/- 23.7% to 141.2 +/- 23.7% (p = 0.04). Infliximab did not reduce the AIx in patients with RA and AS, although there were clinical improvements and CRP and ESR decreased. Instead, the AIx increased. This could negatively influence cardiac workload. PMID- 20162316 TI - Effects of KTP laser on oral soft tissues. An in vitro study. AB - A biopsy is a surgical procedure performed to establish a clear diagnosis of a lesion in order to clarify a clinical diagnostic suspicion. During a biopsy procedure it is fundamental to maintain safe and readable cut margins in order to permit histological visualization of possible marginal infiltrations or malignant transformation of a lesion. The aim of this study was to evaluate the histological peripheral damage caused by application of a KTP (potassium titanium phosphate) laser during oral soft tissue biopsy procedures. A KTP laser (lambda 532 nm) at different power settings and fluences was used to obtain 45 samples from pig cadaver tongues. The samples were then subdivided into five groups of nine samples each. A final specimen was taken by scalpel as a control. All samples were put into test tubes containing 10% buffered formalin solution, and were examined separately under an optical microscope by two pathologists to evaluate the peripheral thermal damage induced by the laser. In all specimens the cut edges of the incision were free from histological artefacts, especially when lower settings were applied. Statistical analysis showed no differences among the groups. The KTP laser demonstrated surgical effectiveness and caused little peripheral damage to the cut edges, and therefore would always allow a safe histological diagnosis to be obtained. PMID- 20162317 TI - Microleakage of repaired class V silorane and nano-hybrid composite restorations after preparation with erbium:yttrium-aluminum-garnet laser and diamond bur. AB - The aim of this in vitro study was to compare the microleakage of repaired class V resin composite restorations prepared either by Er:YAG laser or a diamond bur. Ninety-six intact human molar teeth were randomly distributed into eight groups. In the first four groups, class V cavities (3 * 3 * 3 mm) prepared on the buccal and lingual surfaces of the teeth using an erbium:yttrium-aluminum-garnet laser (VersaWave, HOYA ConBio, Japan). Similar class V cavities were prepared in the second four groups using a diamond bur (S-Class, Komet, UK). Teeth in groups 1, 2, and 5, 6 were restored with a nano-ceramic composite (Ceram.X duo, DENTSPLY), whereas a silorane material (Filtek Silorane, 3M ESPE) was used to restore cavities in groups 3, 4, and 7, 8. Two different adhesive systems (XP Bond, DENTSPLY, and Silorane System Adhesive, 3M ESPE) were also used. All specimens were aged for 7 days. New cavities (3 * 3 * 3 mm) were prepared adjacent to the old restorations with Er:YAG laser (groups I-IV) or diamond bur (groups V-VIII). Different repair materials were then applied to the new cavities using the previous two restorative materials and two adhesive systems. All teeth were subjected to thermocycling (5,000 cycles between 5 and 55 degrees C) and axial loadcycling (30 N, 1 Hz, 2,000 cycles). Specimens were immersed in 50% w/w silver nitrate solution. Teeth were sectioned longitudinally in buccolingual direction. Stereomicroscope (Nikon SMZ 800) and SEM (JEOL JSM 5600) were used to evaluate the microleakage that existed at the interface between the old restorations and the repair materials. Data were analyzed statistically with one-way ANOVA and Tukey tests (p < 0.05). Even though no statistically significant differences were found between any of the groups, the cavities repaired with different restoratives showed slight microleakage, especially those prepared by Er:YAG laser (p > 0.05). No microleakage scores were obtained in the groups repaired with Filtek Silorane/Filtek Silorane and Ceram.X/Ceram.X. All the substances tested can be used as repair materials for immediate repair after Er:YAG laser and diamond bur. All substances tested in this study can be used as immediate repair materials after cavity preparations with Er:YAG laser or diamond bur. PMID- 20162318 TI - Activation of the extracellular signal-regulated kinase signal pathway by light emitting diode irradiation. AB - Irradiation by light emitting diode (LED) promotes fibroblast proliferation and wound healing. However, its mechanism is still unknown. The purpose of this study was to clarify the mechanism of fibroblast proliferation by LED irradiation. Cultured NIH3T3 fibroblasts from normal mice were irradiated by LED with a center wavelength of 627 nm. LED irradiation was performed with an energy density of 4 J/cm(2), at subculture and 24 h later. The expression of several growth factors and their receptors was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR): platelet-derived growth factor (PDGF)-A, PDGF-B, and PDGF-C, transforming growth factor-beta (TGF-beta), basic fibroblast growth factor (bFGF), PDGF-alpha receptor, and TGF-beta receptor. Then, the activation of the extracellular signal-regulated kinase (ERK) pathway was examined by Western blotting with and without the PDGF receptor inhibitor. LED irradiation induced cell growth of NIH3T3 fibroblasts. The expression of PDGF-C had significantly increased in the irradiated group (P < 0.01). Although strong activation of the ERK pathway was observed in the irradiated group, its activation was completely suppressed by the PDGF receptor inhibitor. We concluded that LED irradiation promotes fibroblast proliferation by increasing autocrine production of PDGF-C and activating the ERK pathway through phosphorylation of the PDGF receptor. PMID- 20162319 TI - Antenatal diagnosis of Lowe syndrome. PMID- 20162320 TI - A method for evaluating dynamic functional network connectivity and task modulation: application to schizophrenia. AB - OBJECTIVE: In this paper, we develop a dynamic functional network connectivity (FNC) analysis approach using correlations between windowed time-courses of different brain networks (components) estimated via spatial independent component analysis (sICA). We apply the developed method to fMRI data to evaluate it and to study task-modulation of functional connections. MATERIALS AND METHODS: We study the theoretical basis of the approach, perform a simulation analysis and apply it to fMRI data from schizophrenia patients (SP) and healthy controls (HC). Analyses on the fMRI data include: (a) group sICA to determine regions of significant task related activity, (b) static and dynamic FNC analysis among these networks by using maximal lagged-correlation and time-frequency analysis, and (c) HC-SP group differences in functional network connections and in task-modulation of these connections. RESULTS: This new approach enables an assessment of task-modulation of connectivity and identifies meaningful inter-component linkages and differences between the two study groups during performance of an auditory oddball task (AOT). The static FNC results revealed that connectivities involving medial visual-frontal, medial temporal-medial visual, parietal-medial temporal, parietal-medial visual and medial temporal-anterior temporal were significantly greater in HC, whereas only the right lateral fronto-parietal (RLFP) orbitofrontal connection was significantly greater in SP. The dynamic FNC revealed that task-modulation of motor-frontal, RLFP-medial temporal and posterior default mode (pDM)-parietal connections were significantly greater in SP, and task modulation of orbitofrontal-pDM and medial temporal-frontal connections were significantly greater in HC (all P < 0.05). CONCLUSION: The task modulation of dynamic FNC provided findings and differences between the two groups that are consistent with the existing hypothesis that schizophrenia patients show less segregated motor, sensory, cognitive functions and less segregated default mode network activity when engaged with a task. Dynamic FNC, based on sICA, provided additional results which are different than, but complementary to, those of static FNC. For example, it revealed dynamic changes in default mode network connectivities with other regions which were significantly different in schizophrenia in terms of task-modulation, findings which were not possible to discover by static FNC. PMID- 20162321 TI - Anticancer activity and mode of action of titanocene C. AB - Titanocenes constitute a class of metal-based anticancer agents that seem to display a mode of action distinct from that of platinum complexes and to be more tolerable with a differing spectrum of activity. In the present study, titanocene C (bis-(N,N-dimethylamino-2(N-methylpyrrolyl)-methyl-cyclopentadienyl) titanium(IV) dichloride) was shown to exhibit antiproliferative activity against human tumor cell lines with a mean IC50 value of 48.3 +/- 32.5 uM. In particular, high activity was found against small cell lung cancer (SCLC) cell lines with a profile different from cisplatin. Titanocene C induced cell cycle arrest at the G1/0-S interphase. Cross-resistance to either cisplatin or oxoplatin, respectively, was low for titanocene C and absent for titanocene Y in variant HL 60 cell lines. Alterations in gene expression of NCI-H526 SCLC cells induced by titanocene C were investigated using genome-wide expression arrays. Downregulation was found for genes coding for topoisomerases I and IIalpha, histones of the HIST1H4 cluster, enzymes involved in glycolysis, components of the cytoskeleton and vesicular transport, among others. In contrast, expression of genes involved in apoptosis, stress response, particularly members of the metallothionein gene cluster 1, DNA damage and growth factors was upregulated following exposure to titanocene C. Approximately 50% of those genes downregulated by titanocene C and cisplatin were concordant, including the previously identified markers of cisplatin-sensitivity, tubulin and stathmin, indicating partial overlap of the pathways affected by these metal complexes. The present findings point helicases/topoisomerases and HIST1H4 core histones out as targets of titanocene C and metallothioneins as putative main effectors of drug resistance. PMID- 20162322 TI - Slanted orientations of dentine tubules on remineralized dentine surfaces. AB - Dentine carious lesions can be remineralized under optimal conditions, while the surface characteristics of the caries-attacked area may play an important role in the remineralization process. To understand such a surface mechanism, we examined the microstructures of the remineralized area pretreated with different methods. It was found that dentinal tubules on the remineralized surface orientated differently from intrinsic dentine tubules, with the specific alignment angle determined by different surface treatments. Various surface treatments included in this study were 37% phosphoric acid treatment (the etched group), 37% phosphoric acid etching followed by the application of 10% sodium hypochlorite treatment (the deproteinized group), and untreatment (the control group). These findings are helpful for understanding the non-restorative repair of dentine lesions and the remineralization process of the caries-affected dentin surface. PMID- 20162323 TI - Preparation and properties of gold nanoparticle-electrodeposited titanium substrates with Arg-Gly-Asp-Cys peptides. AB - Titanium metal has good biocompatibility, superior mechanical properties and excellent corrosion resistance. Like most metals, however, it exhibits poor bioactive properties and fails to bond to bone tissue. To improve its bioactivity, bioactive molecules, such as peptides, can be grafted onto titanium surfaces. In order to do this, the first step may be to establish a stable and compatible linking layer on the titanium surface. In this study, we used electrochemical methods to deposit gold (Au) nanoparticles onto titanium substrates, to which we then grafted arginine-glycine-asparagine-cysteine (RGDC) peptides by thiolate covalent coupling. Properties of electrodeposited Au nanoparticles were evaluated using a variety of techniques, including microstructural, chemical and electrochemical measurements. The biological responses of the RGDC-grafted Ti substrates were evaluated using MG3 human osteoblast-like cells. The results of thin-film X-ray diffraction (TFXRD) and scanning electron microscopy (SEM) indicated the polycrystalline orientation of Au nanoparticles deposited on the titanium surfaces with high density and controllable particle size. The RGDC peptide could be covalently bonded to Au deposited Ti substrates via Au-thiolate species, as expected. Cell morphology showed that, on RGDC-immobilized titanium with Au particles, MG63 cells attached and spread more rapidly than on Ti substrates either without peptide or with direct loading of the peptide. Immunostaining for focal adhesion kinase (FAK) demonstrated that RGDC enhanced cell attachment. The present method for the formation of Au nanoparticles may serve as an alternative route for bioactive molecule immobilization on Ti implants. PMID- 20162324 TI - Effect of MgO contents on the mechanical properties and biological performances of bioceramics in the MgO-CaO-SiO2 system. AB - The aim of this research was to investigate the effect of the chemical composition on the mechanical properties, bioactivity, and cytocompatibility in vitro of bioceramics in the MgO-CaO-SiO(2) system. Three single-phase ceramics (merwinite, akermanite and monticellite ceramics) with different MgO contents were fabricated. The mechanical properties were tested by an electronic universal machine, while the bioactivity in vitro of the ceramics was detected by investigating the bone-like apatite-formation ability in simulated body fluid (SBF), and the cytocompatibility was evaluated through osteoblast proliferation and adhesion assay. The results showed that their mechanical properties were improved from merwinite to akermanite and monticellite ceramics with the increase of MgO contents, whereas the apatite-formation ability in SBF and cell proliferation decreased. Furthermore, osteoblasts could adhere, spread and proliferate on these ceramic wafers. Finally, the elongated appearance and minor filopodia of cells on merwinite ceramic were more obvious than the other two ceramics. PMID- 20162325 TI - Characterization of commercial rigid polyurethane foams used as bone analogs for implant testing. AB - Mechanical properties and microstructure characterization of a series of graded commercial rigid polyurethane foams commonly used to mimic trabecular bone in testing orthopaedic devices is reported. Compressive testing conducted according to ASTM standard F1839-08, which requires large specimens (50.8 mm x 50.8 mm x 25.4 mm blocks) gave elastic modulus and compressive strength values ranging from 115 to 794 MPa and 4.7 to 24.7 MPa, respectively, for foams having densities of 0.240-0.641 g/cm(3). All these results were within the requirements of the specification for the corresponding grades. Compression testing using smaller specimens (7.5 mm diameter x 15 mm) typical of testing bone, gave results in good agreement with those obtained in the standard tests. Microstructural measurements showed the average pore size ranged from 125 to 234 microm for densities ranging from 0.641 to 0.159 g/cm(3), respectively. The relative modulus as a function of relative density of the foams fit well to the model of Gibson and Ashby. Cyclic testing revealed hysteresis in the lower density foams with a loading modulus statistically equivalent to that measured in monotonic testing. Shore DO durometry (hardness) measurements show good correlations to elastic modulus and compressive strength. The results suggest additional parameters to consider for the evaluation of polyurethane foams for bone analog applications. PMID- 20162326 TI - Zirconia-MWCNT nanocomposites for biomedical applications obtained by colloidal processing. AB - Zirconia ceramics are widely used as femoral heads, but case studies show that delayed failure can occur in vivo due to crack propagation. The addition of carbon nanotubes (CNT) is aimed to avoid the slow crack propagation and to enhance the toughness of the ceramic material used for prostheses. However, to really enhance the mechanical properties of the material it is necessary to achieve a uniform distribution of the CNT in the zirconia matrix. Colloidal processing has demonstrated to be suitable for obtaining ceramic-based composites with homogeneous distribution of the phases and high green density. This work compares the colloidal behavior of the as-received multi wall carbon nanotubes (ar-MWCNT) and the partially coated MWCNT (pc-MWCNT) when immersed in a nanozirconia matrix. With pc-MWCNT an improvement in the dispersion is proved. Moreover, the sintered samples that contain pc-MWCNT show higher density, lower grain size, improved toughness and enhanced hardness under the same sintering cycle when compared to the samples with ar-MWCNT. PMID- 20162327 TI - A novel method for local administration of strontium from implant surfaces. AB - This study proves that a film of Strontianite (SrCO(3)) successfully can be formed on a bioactive surface of sodium titanate when exposed to a strontium acetate solution. This Strontianite film is believed to enable local release of strontium ions from implant surfaces and thus stimulate bone formation in vivo. Depending on the method, different types of films were achieved with different release rates of strontium ions, and the results points at the possibility to tailor the rate and amount of strontium that is to be released from the surface. Strontium has earlier been shown to be highly involved in the formation of new bone as it stimulates the replication of osteoblasts and decreases the activity of osteoclasts. The benefit of strontium has for example been proved in studies where the number of vertebral compression fractures in osteoporotic persons was drastically reduced in patients receiving therapeutical doses of strontium. Therefore, it is here suggested that the bone healing process around an implant may be improved if strontium is administered locally at the site of the implant. The films described in this paper were produced by a simple immersion process where alkali treated titanium was exposed to an aqueous solution containing strontium acetate. By heating the samples at different times during the process, different release rates of strontium ions were achieved when the samples were exposed to simulated body fluid. The strontium containing films also promoted precipitation of bone like apatite when exposed to a simulated body fluid. PMID- 20162328 TI - Influence of unsaturated carbonic acids on hemocompatibility and cytotoxicity of poly-vinylacetate based co-polymers. AB - The aim of this study was to investigate hemocompatibility and cytotoxicity properties of synthetic polymer coatings containing various unsaturated carbonic acids with vinylacetate. Co-polymers of vinylacetate and crotonic acid (CA), maleic acid (MA), and itaconic acid (IA) were made. The materials were characterized in terms of their adhesion to metal supports (titanium and stainless steel) as well as hemocompatibility (% hemolysis, wettability, erythrocyte aggregation, hemoglobin content, thrombocyte count and lipid peroxidation levels) and cytotoxicity (human endothelial cell activity in vitro and chromosome aberrations, bone marrow proliferation and cell ploidy in rats). Co-polymers of unsaturated carbonic acids with vinylacetate exhibited good hemocompatibility properties, as opposed to vinylacetate homopolymer for which substantial levels of hemolysis were observed. By coating the metal supports with co-polymers the cytotoxic effects associated with the bare metal samples were markedly reduced. MA samples showed excellent hemocompatibility and no cytotoxicity, yet they lacked good adhesion properties to metal substrate, probably due to high water content. CA samples, having the highest density of carboxylic groups among the samples under investigation, showed increased bone marrow proliferation activity and cell ploidy in rats, as compared to controls. The most promising results in the present study were obtained for the samples with IA, which showed good adhesion to metal substrates, good hemocompatibility and low cytotoxicity. Thus, co-polymers of vinylacetate and IA rich in carboxylic groups are promising materials for the design of novel drug-eluting stents. PMID- 20162329 TI - The inhibition of collagenase induced degradation of collagen by the galloyl containing polyphenols tannic acid, epigallocatechin gallate and epicatechin gallate. AB - Collagen based cosmetic fillers require repeat treatments due to collagenase derived degradation of the filler in the intradermal injection site. The objective of this study was to investigate the inhibition of this degradation by the galloyl-containing compounds tannic acid, epigallocatechin gallate (EGCG), epicatechin gallate (ECG) and gallic acid (GA). A gel permeation chromatography assay was developed to quantitate the collagenase induced reductions in collagen molecular weight. The binding of the compounds to collagen was measured using HPLC. The stabilization of collagen was measured using Differential Scanning Calorimetry (DSC). Tannic acid, EGCG and ECG (but not GA) were found to strongly inhibit collagen degradation at concentrations in the low micromolar range. The compounds bound strongly to collagen and stabilized collagen. It is concluded that tannic acid, EGCG and ECG bind to collagen via extensive hydrogen bonding augmented by some hydrophobic interactions and prevent the free access of collagenase to active sites on the collagen chains. PMID- 20162330 TI - Osteoblast response to polymethyl methacrylate bioactive glass composite. AB - Polymethylmethacrylate (PMMA) has been used in many orthopedic and dental applications since the 1960s. Biocompatibility of newly developed surface porous fiber reinforced (SPFR) PMMA based composite has not been previously proven in cell culture environment. Analysis of rat bone marrow stromal cells grown on the different test materials showed only little difference in normalized cell activity or bone sialoprotein (BSP) production between the test materials, but the osteocalcin (OC) levels remained higher (P < 0.015-0.005) through out the test with SPFR-material when compared to tissue culture poly styrene (TCPS). The cells grown on SP-FRC material also showed highest calcium depletion from the culture medium (P < 0.026-0.001) when compared to all other test substrates. SEM images of the cultured samples confirmed that all the materials enabled cell spreading and growth on their surface, but the roughened surface remarkably enhanced this process of cell attachment, division and calcified nodule formation. This study shows that the SP-FRC composite material does not elicit harmful/toxic reactions in cell cultures more than neutral TCPS and can be considered biocompatible. The material possesses good capabilities to form new mineralized tissue onto its surface, and through that a possibility to bond directly to bone. Rough surface seems to enhance osteoblast proliferation and formation of mineralized extracellular matrix. PMID- 20162331 TI - Bioglass as a carrier for reindeer bone protein extract in the healing of rat femur defect. AB - Bioactive glasses have been developed as scaffolds for bone tissue engineering but combination with reindeer bone protein extract has not been evaluated. We investigated the effects of bone protein extract implants (5-40 mg dosages) with bioglass (BG) carrier on the healing of rat femur defects. Bioglass implants and untreated defects served as controls. All doses of extract increased bone formation compared with the control groups, and bone union was enhanced with doses of 10 mg or more. In comparison with untreated defect, mean cross-sectional bone area at the defect site was greater when implants with BG + 15 mg of extract or bioglass alone were used, bone density at the defect site was higher in all bioglass groups with and without bone extract, and the BG + 15 mg extract dosage marginally increased bone torsional stiffness in mechanical testing. Bioglass performed well as a carrier candidate for reindeer bone protein extract. PMID- 20162332 TI - In vitro evaluation of human osteoblast adhesion to a thermally oxidized gamma TiAl intermetallic alloy of composition Ti-48Al-2Cr-2Nb (at.%). AB - Ti-48Al-2Cr-2Nb (at.%) (gamma-TiAl), a gamma titanium aluminide alloy originally designed for aerospace applications, appears to have excellent potential as implant material. Thermal treatment of gamma-TiAl renders this alloy extremely corrosion resistant in vitro, which could improve its biocompatibility. In this study, the surface oxides produced by thermal oxidation (at 500 degrees C, and at 800 degrees C for 1 h in air) on gamma-TiAl were characterized by X-ray photoelectron spectroscopy (XPS). hFOB 1.19 cell adhesion on thermally oxidized gamma-TiAl was examined in vitro by a hexosaminidase assay, scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) after 1, 7 and 14 days. Ti-6Al-4V surfaces were used for comparison. Hexosaminidase assay data and CLSM analysis of focal contacts and cytoskeleton organization showed no differences in cell attachment on autoclaved and both heat-treated gamma-TiAl surfaces at the different time points. SEM images showed well organized multi layers of differentiated cells adhered on thermally oxidized gamma-TiAl surfaces at day 14. Unexpectedly, thermally oxidized Ti-6Al-4V surfaces oxidized at 800 degrees C exhibited cytotoxic effects on hFOB 1.19 cells. Our results indicate that thermal oxidation of gamma-TiAl seems to be a promising method to generate highly corrosion resistant and biocompatible surfaces for implant applications. PMID- 20162333 TI - Role of immune cells and inflammatory cytokines in regulation of fibrosis around silicone expander implants. AB - This study aimed to investigate the progress of wound healing around silicone expander with particular emphasis on fibroblasts, myofibroblasts and collagen in the repair phase. Semi-quantitative evaluation of inflammatory cells and their cytokines, fibroblasts and myofibroblasts at the tissue-material interface was carried out. Commercially available silicone expander was implanted in gluteus muscle of young female Wistar rats for 3, 7, 14, 30, 90 and 180 days. Ultra high molecular weight polyethylene served as control. The cellular response was studied by immunohistochemistry and Transmission Electron Microscopy. A thick collagenous fibrous capsule was observed around the silicone expander at 180 days, with persistent myofibroblasts, lymphocytes and macrophages as compared to the thin fibrous encapsulation around the UHMWPE implants. The regulatory role of cytokines and immune cells in myofibroblast persistence in tissue-implant interface around silicone expander has been extensively studied. Results of this study indicate the need to elucidate the signaling molecules in the transition of fibroblast to myofibroblast around silicone expander implants. PMID- 20162334 TI - Influence of Fe(II) and Fe(III) on the expression of genes related to cholesterol and fatty acid metabolism in human vascular smooth muscle cells. AB - Iron is the major alloy component for a large variety of cardiovascular devices such as stents. In recent studies it has been shown that biodegradable iron or iron based stents exhibit good mechanical features with no pronounced neointimal proliferation. Whole genome gene profiling using DNA chip technology revealed that genes involved in cholesterol and fatty acid metabolism (low-density lipoprotein receptor, LDL-R; 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 (HMGCS1) and fatty acid desaturase 1 (FADS1) are up-regulated after exposure of vascular smooth muscle cells with soluble ferrous iron. To analyze the effects of iron on these genes in detail we co-incubated human vascular smooth muscle cells for 12 and 24 h with different concentrations of ferrous (soluble iron(II) gluconate) and ferric iron (soluble iron(III)-chloride), Ferrlecit, a commercially available drug (ferric iron-gluconate complex) and solid iron coils. The expression of LDL-R, HMGCS1 and FADS1 was analyzed using TaqMan Real-time PCR. After 24 h, all forms of iron led to a significant up-regulation of the examined genes. At high concentrations the expression rates declined, probably as a result of reduced metabolic activity. The most prominent effects were observed after co-incubation with Ferrlecit, probably caused by an increased bioavailability of the iron gluconate complex. We postulate that both, bi- and trivalent forms of iron induce the expression of LDL-R, HMGCS1 and FADS1 by generation of highly reactive oxygen species. Further animal experiments using tissues from iron-stented vessels may lead to a more profound insight into iron induced expression of cholesterol- and fatty acid metabolism related genes. PMID- 20162335 TI - Maintaining cell depth viability: on the efficacy of a trimodal scaffold pore architecture and dynamic rotational culturing. AB - Tissue-engineering scaffold-based strategies have suffered from limited cell depth viability when cultured in vitro with viable cells typically existing at the fluid-scaffold interface. This is primarily believed to be due to the lack of nutrient delivery into and waste removal from the inner regions of the scaffold construct. This work focused on the assessment of a hydroxyapatite multi-domain porous scaffold architecture (i.e. a scaffold providing a discrete domain for cell occupancy and a separate domain for nutrient delivery). It has been demonstrated that incorporating unidirectional channels into a porous scaffold material significantly enhanced initial cell seeding distribution, while maintaining relatively high seeding efficiencies. In vitro static culturing showed that providing a discrete domain for nutrient diffusion and metabolic waste removal is insufficient to enhance or maintain homogeneous cell viability throughout the entire scaffold depth during a 7-day culture period. In contrast, scaffolds subjected to dynamic rotational culturing maintained uniform cell viability throughout the scaffold depth with increasing culturing time and enhanced the extent of cell proliferation (approximately 2-2.4-fold increase) compared to static culturing. PMID- 20162336 TI - Effects of HA released calcium ion on osteoblast differentiation. AB - Hydroxyapatite (HA) is a widely used calcium phosphate implant substitute and has dissolution property. Although HA has been shown a beneficial effect on osteoblast differentiation, the exact mechanism is still unclear. In the present study, we proposed that Ca(2+) released from HA activated the expression bone associated proteins, OPN and BSP, mediated by L-type calcium channel and calcium/calmodulin-dependent protein kinase (CaMK) 2 which resulted into improved osteoblast differentiation. Results showed that HA elevated ALP expression as well as OPN and BSP expression in MC3T3-E1 cells. The result from western blot of CaMK2alpha indicated that HA released Ca(2+) activated CaMK2 through L-type calcium channel. Furthermore, upregulation of OPN and BSP mRNA expression was significantly inhibited when blocking both the L-type calcium channel and CaMK2. These findings suggested that HA accelerated the osteoblast differentiation by releasing Ca(2+). PMID- 20162337 TI - Doxorubicin and irinotecan drug-eluting beads for treatment of glioma: a pilot study in a rat model. AB - Despite some progress in therapy, the prognosis of patients with malignant gliomas remains poor. Local delivery of cytostatics to the tumour has been proven to be an efficacious therapeutic approach but which nevertheless needs further improvements. Drug Eluting Beads (DEB), have been developed as drug delivery embolisation systems for use in trans-arterial chemoembolisation. We tested in a rat model of malignant glioma, whether DEB, loaded with doxorubicin or irinotecan, may be used for local treatment of brain tumours. Unloaded and drug loaded DEB were implanted into the brains of healthy and tumour bearing BD IX rats followed by histological investigations and survival assessment. Intracerebral implantation of unloaded DEB caused no significant local tissue damage, whilst both doxorubicin and irinotecan DEB improved survival time significantly. However, a significant local toxicity was found after the implantation of doxorubicin DEB but not with irinotecan DEB. We concluded that irinotecan appears to be superior in terms of the risk-benefit ratio and that DEB may be used for local treatment of brain tumours. PMID- 20162338 TI - Dendrimeric alkylated polyethylenimine nano-carriers with acid-cleavable outer cationic shells mediate improved transfection efficiency without increasing toxicity. AB - PURPOSE: Improved polycation-based non-viral DNA vectors were sought by preparing dendrimers with polyethylenimine cores surrounded by various shells incorporating structural features intended to facilitate steps in transfection mechanisms. Dendrimeric vectors were designed with (a) an outer oligocation shell, intended to facilitate DNA release inside cells, (b) a hydrophobic C-16 alkyl shell, and (c) a polycationic core, the latter two intended to combine lipid-depletion and osmotic burst endosome escape mechanisms, respectively, and were (d) attached through an a acid-cleavable linker reported to hydrolyze at endosomal pH values. METHODS: Vectors and DNA complexes were characterized by dynamic and static light scattering. Flow cytometry was used to quantitate transfection activity and cytotoxicity in CHO-K1 cells. RESULTS: About 5-fold increased transfection activity was obtained for a vector constructed with an outer shell of oligocations attached through acid-cleavable linkers, relative to a control dendrimer with an acid-stable linker. The most effective oligocation component of outer shells tested was spermine. Neither modification was associated with increased cytotoxicity. This vector design did not permit an evaluation of the benefit of combining endosome release mechanisms. CONCLUSION: Using acid cleavable linkers to attach an outer shell of short, highly-charged oligocations to a PEI-based dendrimeric vector substantially increased transfection efficiency without increasing cytotoxicity. PMID- 20162339 TI - Identification of peptide ligands for targeting to the blood-brain barrier. AB - PURPOSE: Transport of drugs to the brain is limited by the blood-brain barrier. New, specific brain endothelium ligands can facilitate brain-specific delivery of drugs. METHODS: We used phage display in an in situ brain perfusion model to screen for new brain endothelium peptide ligands. RESULTS: Two phage clones, displaying 15 amino acid-peptides (GLA and GYR) that were selected for brain binding in the mouse model, showed significant binding to human brain endothelium (hCMEC/D3), compared to a random control phage. This binding was not seen for other human endothelial cells (HUVEC). Binding to hCMEC/D3 cells was dose dependent. When phage GLA and GYR were individually perfused through the murine brain, their ability to bind to the brain was 6-fold (GLA) and 5-fold (GYR) higher than the control phage. When compared to lung perfusion, phage showed an 8.5-fold (GYR) and 48-fold (GLA) preference for brain over lung compared to the control. CONCLUSIONS: These results indicate that two new peptide ligands have been identified that may be used for specific targeting of drugs to the blood brain barrier. PMID- 20162340 TI - Influence of gallate esterification on the activity of procyanidin B2 in androgen dependent human prostate carcinoma LNCaP cells. AB - PURPOSE: Present study assessed the influence of gallate esterification on the anti-cancer activity of procyanidin B2 (B2) in androgen-dependent human prostate carcinoma LNCaP cells employing B2-3,3'-di-O-gallate (B2-G(2)), two mono-gallate esters B2-3-O-gallate (B2-3G) and B2-3'-O-gallate (B2-3'G) and the parent compound B2, all isolated from grape seed extract (GSE). MATERIALS AND METHODS: Study compounds were isolated from GSE by several chromatographic steps and structures determined by a combination of enzymatic hydrolysis, mass spectrometry and comparisons with standards. Cells, treated with these compounds, were assessed for viability and apoptosis and examined by western blotting. RESULTS: Gallate esters B2-G(2), B2-3G and B2-3'G significantly decreased LNCaP cell viability; however, B2 and gallic acid were ineffective. Furthermore, only B2 G(2) also significantly decreased cell growth. Decreases in cell viability were largely due to apoptosis induction with B2-G(2) and B2-3'G exhibiting comparable effects, whereas B2-3G was less effective. In mechanistic studies, B2-G(2) and B2 3'G treatments caused caspases-9 and -3 and PARP cleavage, and down-regulated Bcl 2, Bcl-Xl and androgen receptor levels. CONCLUSION: Together, our findings demonstrate anti-PCA efficacy of B2-G(2) and suggest that a gallate ester moiety at 3' position of procyanidin B2 contributes more extensively toward the biological activity of the di-gallate ester than esterification of position 3. PMID- 20162341 TI - Physician identification and management of psychosocial problems in primary care. AB - Often the burden of identifying children with behavioral or developmental problems is left up to the primary care physician (PCP). However, previous literature shows that PCPs consistently underidentify children with developmental/behavioral problems in pediatric primary care. For the current study, questionnaires containing three vignettes followed by questions addressing common psychosocial problems, general questions about their practice and training, and the Physician Belief Scale were distributed to physicians. Results indicated that physicians were better at identifying severe problems, had more difficulty identifying psychosocial problems with mild symptomatology, and tended to refer to a medical specialist or mental health professional more often for severe problems, depression or a developmental problem. Physicians tended to view treating psychosocial problems favorably. PMID- 20162342 TI - I spy with my little eye: jurors' detection of internal validity threats in expert evidence. AB - This experiment examined whether jury-eligible community members (N = 223) were able to detect internally invalid psychological science presented at trial. Participants read a simulated child sexual abuse case in which the defense expert described a study he had conducted on witness memory and suggestibility. We varied the study's internal validity (valid, missing control group, confound, and experimenter bias) and publication status (published, unpublished). Expert evidence quality ratings were higher for the valid versus missing control group version only. Publication increased ratings of defendant guilt when the study was missing a control group. Variations in internal validity did not influence perceptions of child victim credibility or police interview quality. Participants' limited detection of internal validity threats underscores the need to examine the effectiveness of traditional legal safeguards against junk science in court and improve the scientific reasoning ability of lay people and legal professionals. PMID- 20162343 TI - Modulation of programmed forms of cell death by intracoronary levosimendan during regional myocardial ischemia in anesthetized pigs. AB - PURPOSE: Powerful mediators of programmed cell death, such as apoptosis and autophagy, can contribute to myocyte cell loss during pathological cardiac conditions. Levosimendan has been shown to exert beneficial hemodynamic effects in presence of global myocardial ischemia and heart failure through vasodilatation and increase of cardiac contractility. Recently, the intracoronary administration of a bolus levosimendan was found to exert favourable cardiac anti stunning effects without lowering arterial pressure, which limits the use of levosimendan mainly in coronary artery disease. Here we tested whether the intracoronary administration of levosimendan can beneficially modulate programmed cell death in acute regional myocardial ischemia. METHODS: Acute regional myocardial ischemia was induced in 20 anaesthetized pigs and intracoronary levosimendan 15 min bolus administration was started 4 h afterwards. The effects of levosimendan on coronary blood flow and cardiac function were evaluated and myocardial biopsies were examined for criteria of autophagy and apoptosis. RESULTS: The administration of levosimendan caused a significant increase of coronary blood flow (p < 0.05) in absence of changes in cardiac function. Moreover, levosimendan prevented the down-regulation of the anti-apoptotic gene, Bcl-2, and the up-regulation of the apoptotic markers Bax and cytochrome c, which resulted in a reduced expression of TUNEL fragmented nuclei (p < 0.05). Furthermore, levosimendan maintained Beclin 1 at 4 h and potentiated LC3 II expression, these results being consistent with autophagy activation. CONCLUSIONS: Such effects of intracoronary levosimendan bolus administration during regional myocardial ischemia indicate the occurrence of cardio-protection by modulation of programmed form of cell death. PMID- 20162344 TI - Social competence intervention for youth with Asperger Syndrome and high functioning autism: an initial investigation. AB - Individuals with high functioning autism (HFA) or Asperger Syndrome (AS) exhibit difficulties in the knowledge or correct performance of social skills. This subgroup's social difficulties appear to be associated with deficits in three social cognition processes: theory of mind, emotion recognition and executive functioning. The current study outlines the development and initial administration of the group-based Social Competence Intervention (SCI), which targeted these deficits using cognitive behavioral principles. Across 27 students age 11-14 with a HFA/AS diagnosis, results indicated significant improvement on parent reports of social skills and executive functioning. Participants evidenced significant growth on direct assessments measuring facial expression recognition, theory of mind and problem solving. SCI appears promising, however, larger samples and application in naturalistic settings are warranted. PMID- 20162345 TI - Task engagement and escape maintained challenging behavior: differential effects of general and explicit cues when implementing a signaled delay in the delivery of reinforcement. AB - This study was designed to evaluate the effects of explicit and general delay cues when implementing a tolerance for a delay in the delivery of a reinforcement procedure to increase task engagement and decrease escape maintained challenging behavior. Two preschool children with autism participated in an alternating treatments design with changing criterions for task engagement. For both children, descriptive and experimental analyses verified that the challenging behavior functioned to escape instructional task demands. Subsequently, two types of tasks were identified for each participant with assignment to either the explicit or general cue procedures. Both participants demonstrated increased task engagement with concurrent decreases in challenging behavior with both types of delay cues, though rate of successful work unit completion advanced more quickly with explicit delay cues. PMID- 20162346 TI - Men's beliefs about HPV-related disease. AB - While human papillomavirus (HPV) infection is associated with genital warts, anal cancer, and oral cancer, limited research has examined what men think causes these diseases. We sought to examine knowledge and beliefs about HPV-related disease among gay and bisexual men, who are at high risk for HPV infection and HPV-related cancers, and compare them to heterosexual men. We conducted an online survey in January 2009 with a national sample of men aged 18-59 who self identified as either gay or bisexual (n = 312) or heterosexual (n = 296). The response rate was 70%. Fewer than half of men knew that HPV can cause genital warts (41%), anal cancer (24%), and oral cancers (23%). However, gay and bisexual men typically knew more than heterosexual men about these topics. Overall, most men believed that sexual behavior causes genital warts (70%) and anal cancer (54%), and tobacco use causes oral cancer (89%). Perceived causal factors differed substantially among the three diseases, while differences by sexual orientation were fewer and smaller in magnitude. Many men were unaware that HPV infection can cause genital warts, oral cancer, and anal cancer. PMID- 20162347 TI - On optimal channel configurations for SMR-based brain-computer interfaces. AB - One crucial question in the design of electroencephalogram (EEG)-based brain computer interface (BCI) experiments is the selection of EEG channels. While a setup with few channels is more convenient and requires less preparation time, a dense placement of electrodes provides more detailed information and henceforth could lead to a better classification performance. Here, we investigate this question for a specific setting: a BCI that uses the popular CSP algorithm in order to classify voluntary modulations of sensorimotor rhythms (SMR). In a first approach 13 different fixed channel configurations are compared to the full one consisting of 119 channels. The configuration with 48 channels results to be the best one, while configurations with less channels, from 32 to 8, performed not significantly worse than the best configuration in cases where only few training trials are available. In a second approach an optimal channel configuration is obtained by an iterative procedure in the spirit of stepwise variable selection with nonparametric multiple comparisons. As a surprising result, in the second approach a setting with 22 channels centered over the motor areas was selected. Thanks to the acquisition of a large data set recorded from 80 novice participants using 119 EEG channels, the results of this study can be expected to have a high degree of generalizability. PMID- 20162348 TI - The genetic and environmental etiology of sympathetic and parasympathetic activity in children. AB - The present study examines the genetic and environmental etiology of the associations among respiratory sinus arrhythmia (RSA), heart rate (HR), skin conductance level (SCL), and non-specific skin conductance responses (NS-SCR) measures that purportedly index the parasympathetic and sympathetic branches of the autonomic nervous system. The sample was drawn from a cohort of 1,219 preadolescent twins (aged 9-10). Multivariate analyses of the data were conducted using structural equation modeling. Almost all genetic and environmental influences on the measures acted through two latent factors. The first latent factor was largely responsible for the variance in heart rate, SCL and NS-SCR, reflecting sympathetic activity, and its proportions of variance due to genetic and shared environmental influences were 27 and 28% in males, and 31 and 41% in females, respectively. The second latent factor accounted for the variance in RSA and heart rate, reflecting parasympathetic activity; genetic and shared environmental factors explained 27 and 23% of the variance in males, respectively, and 35 and 18% of the variance in females. Measurement-specific genetic effects accounted for 14-27% of the total variance in RSA and SCL, and measurement-specific shared environmental effects accounted for 10-12% in SCL. In general, the validity of separate sympathetic and parasympathetic constructs was supported. PMID- 20162349 TI - Expression of brain-derived neurotrophic factor and TrkB in the lateral line system of zebrafish during development. AB - The neuromasts of the lateral line system are regarded as a model to study the mechanisms of hearing, deafness, and ototoxicity. The neurotrophins (NTs), especially brain-derived neurotrophic factor (BDNF), and its signaling receptor TrkB are involved in the development and maintenance of neuromasts. To know the period in which the BDNF/TrkB complex has more effects in the neuromast biology, the age-related changes were studied. Normal zebrafish from 10 to 180 days post fertilization (dpf), as well as transgenic ET4 zebrafish 10 and 20 dpf, was analyzed using qRT-PCR, western blot, and immunohistochemistry. BDNF and TrkB mRNAs followed a parallel course, peaking at 20 dpf, and thereafter progressively decreased. Specific immunoreactivity for BDNF and TrkB was found co-localized in all hairy cells of neuromasts in 20 and 30 dpf; then, the number of immunoreactive cells decreased, and by 180 dpf BDNF remains restricted to a subpopulation of hairy cells, and TrkB to a few number of sensory and non-sensory cells. At all ages examined, TrkB immunoreactivity was detected in sensory ganglia innervating the neuromasts. The present results demonstrate that there is a parallel time-related decline in the expression of BDNF and TrkB in zebrafish. Also, the patterns of cell expression suggest that autocrine/paracrine mechanisms for this NT system might occur within the neuromasts. Because TrkB in lateral line ganglia did not vary with age, their neurons are potentially capable to respond to BDNF during the entire lifespan of zebrafish. PMID- 20162350 TI - Transcriptional regulation of the vascular endothelial glycome by angiogenic and inflammatory signalling. AB - Vascular endothelial cells undergo many molecular changes during pathological processes such as inflammation and tumour development. Tumours such as malignant lymphomas affecting bone marrow are dependent on interactions with endothelial cells for (1) site-specific homing and (2) tumour-induced angiogenesis. Modifications in glycosylation are responsible for fine-tuning of distinct endothelial surface receptors. In order to gain a comprehensive insight into the regulation of the endothelial glycome, comprising genes encoding for sugar transporters (sugar s/t), glycosyltransferases (GT), glycan-degrading enzymes (GD) and lectins (GBP), we performed gene profiling analysis of the human bone marrow-derived microvascular endothelial cell line HBMEC-60 that resembles closely in its biological behaviour primary bone marrow endothelial cells. HBMEC were activated by either angiogenic VEGF or the inflammatory cytokine TNF. Approximately 48% (207 genes) of the 432 glycome genes tested were found to be expressed in HBMEC-60 cells. Inflammatory and angiogenic signals produce different profiles of up- or down-regulated glycome genes, most prominent changes were seen under TNF stimulation in terms of signal intensity and number of alterations. Stimulation by VEGF and TNF affected primarily genes encoding for glycosyltransferases and in particular those important for terminal modulation. For instance, an enhanced alpha2,6 sialylation was observed after TNF stimulation at the transcriptional and glycan expression level whereas transcription of ST3Gal1 sialylating in alpha2,3 position was enhanced after VEGF stimulation. Transcriptional analysis of the glycome gives insights into the differential regulation of glycosylation pathways and may help to understand the functional impact of endothelial glycosylation. PMID- 20162351 TI - Leucine-rich glioma inactivated 3 induces neurite outgrowth through Akt and focal adhesion kinase. AB - Leucine-rich glioma inactivated 3 (LGI3) is a secreted protein that belongs to LGI/epitempin family. LGI3 is highly expressed in brain in a transcriptionally and developmentally regulated manner. Here we found that LGI3 induced neurite outgrowth in Neuro-2a cells and dorsal root ganglia explants. LGI3 treatment or overexpression increased neurite outgrowth and knockdown of LGI3 by siRNA had opposite effect. LGI3 treatment increased phosphorylation of Akt and a 125-kDa protein. Immunoprecipitation identified the 125-kDa protein as focal adhesion kinase (FAK). LGI3 overexpression increased phospho-Akt, phospho-FAK and FAK protein. Inhibition of Akt activation by PI3 kinase inhibitor attenuated LGI3 induced FAK phosphorylation and neurite outgrowth. Taken together, we propose that LGI3 is a neuritogenic factor whose signaling pathway involves Akt-mediated FAK activation. PMID- 20162352 TI - Inhibitory effect of luteolin on osteoclast differentiation and function. AB - Osteoclasts are multinucleated cells that play a crucial role in bone resorption, and are formed by the fusion of mononuclear osteoclasts derived from osteoclast precursors of the macrophage lineage. Compounds that specifically target functional osteoclasts would be ideal candidates for anti-resorptive agents for clinical applications. In the present study, we investigated the effects of luteolin, a flavonoid, on the regulation of receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclastogenesis, functions and signaling pathway. Addition of luteolin to a coculture system of mouse bone marrow cells and ST2 cells in the presence of 10(-8) M 1alpha,25(OH)(2)D(3) caused significant inhibition of osteoclastogenesis. Luteolin had no effects on the 1alpha,25(OH)(2)D(3)-induced expressions of RANKL, osteoprotegerin and macrophage colony-stimulating factor mRNAs. Next, we examined the direct effects of luteolin on osteoclast precursors using bone marrow macrophages and RAW264.7 cells. Luteolin completely inhibited RANKL-induced osteoclast formation. Moreover, luteolin inhibited the bone resorption by mature osteoclasts accompanied by the disruption of their actin rings, and these effects were reversely induced by the disruption of the actin rings in mature osteoclasts. Finally, we found that luteolin inhibited RANKL-induced osteoclastogenesis through the suppression of ATF2, downstream of p38 MAPK and nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) expression, respectively. Taken together, the present results indicate that naturally occurring luteolin has inhibitory activities toward both osteoclast differentiation and functions through inhibition of RANKL-induced signaling pathway as well as actin ring disruption, respectively. PMID- 20162353 TI - Registration of micro-computed tomography and histological images of the guinea pig cochlea to construct an ear model using an iterative closest point algorithm. AB - We present a practical and systematic method to reconstruct accurate physical models of the guinea pig ear (n = 1). The method uses a semi-automatic technique to create three-dimensional (3-D) models of the guinea pig cochlea by registration of micro-computed tomography (CT) and histological images. An iterative closest point algorithm was employed to minimize the sum of square errors with respect to the closest histological model and corresponding micro-CT model. This allowed creation of an accurate geometric ear model including external ear canal, tympanic membrane, middle ear cavity, auditory ossicles, and the cochlea. The characteristic cross-sectional areas of scala tympani, scala vestibuli, and scala media were measured. The length, thickness, and apex width of the guinea pig's basilar membrane were compared to the data found in literature. Some shape parameters were also compared among different species. The results confirmed that the geometric model created by this method was accurate. This method provides an effective way to visualize the 3-D structure and the detailed information about ear geometry required for finite element and multibody dynamic analysis. PMID- 20162354 TI - Impedance in isolated mouse lungs for the determination of site of action of vasoactive agents and disease. AB - Hypoxic pulmonary hypertension is a disease of the lung vasculature that is usually quantified by pulmonary vascular resistance (PVR). However, a more complete description of lung vascular function and right ventricular afterload is provided by pulmonary vascular impedance (PVZ) from spectral analysis of pulsatile pressure-flow relationships. We studied pulsatile pressure-flow relationships in isolated, perfused lungs of mice in normoxia, after induction of hypoxic pulmonary hypertension by 10 days of hypoxic exposure, and after the administration of the vasoactive agents sodium nitroprusside and serotonin in order to gain insight into the effects of disease and vasoactive agents on afterload. Chronic hypoxia exposure increased 0 Hz impedance (Z(0)) from 2.0 +/- 0.2 to 3.3 +/- 0.2 mmHg min/mL but decreased characteristic impedance (Z(C)) from 0.21 +/- 0.02 to 0.18 +/- 0.01 mmHg min/mL (both p < 0.05). Sodium nitroprusside only slightly decreased Z(0) but increased Z(C) in normal lungs (p < 0.05) and did not affect Z(C) and decreased Z(0) in hypertensive lungs (p < 0.05). Serotonin increased Z(C) in normal and hypertensive lungs but decreased Z(0) in hypertensive lungs (p < 0.05). There was an inverse correlation between mean pulmonary artery pressure and Z(C) in all circumstances. These findings demonstrate that vasoactive interventions can have different sites of action (i.e., proximal vs. distal segments) in the normal and chronically hypoxic pulmonary vasculature, and the pressure-dependency of Z(C) and R(W). The measurement of PVZ in isolated lungs allows for an improved understanding of the modes of action of drugs and hypoxia on the pulmonary circulation. PMID- 20162355 TI - HUVEC ICAM-1 and VCAM-1 synthesis in response to potentially athero-prone and athero-protective mechanical and nicotine chemical stimuli. AB - Previous mechano-transduction studies have investigated the endothelial cell (EC) morphological response to mechanical stimuli; generally consisting of a wall shear stress (WSS) and a cyclic tensile hoop strain (THS). More recent studies have investigated the EC biochemical response (intercellular adhesion molecule, ICAM-1, and vascular cellular adhesion molecule, VCAM-1, expression) to idealized mechanical stimuli. However, current literature is lacking in the area of EC biochemical response to combinations of physiological WSS and THS mechanical stimuli. The objective of this study is to investigate the EC response to physiological WSS and THS stimuli and to compare this response to that of ECs exposed to idealized steady WSS and cyclic THS of the same magnitudes. This study also investigated the EC response to a nicotine chemical stimulus combined with a suspected athero-prone physiological mechanical stimulus. A bioreactor was designed to apply a range of combinations of physiological WSS and THS waveforms. The bioreactor was calibrated and validated using computational fluid dynamics and video extensometry techniques. The bioreactor was used to investigated the biochemical response exhibited by human umbilical vein endothelial cells (HUVECs) exposed to physiological athero-protective (first bioreactor test case, pulsatile WSS combined with pulsatile THS) and athero-prone (second bioreactor test case, oscillating WSS combined with pulsatile THS) mechanical environments. The final testing environment (third bioreactor test case) combined a nicotine chemical stimulus with the mechanical stimuli of the second bioreactor test case. In first and second bioreactor test cases, the addition of a pulsatile THS to the WSS resulted in opposite trends of ICAM-1 down-regulation and up-regulation, respectively. This outcome suggests that the effect of the additional pulsatile THS depends on the state of the applied WSS waveform. Similarly, in first and second bioreactor test cases, the addition of a pulsatile THS to the WSS resulted in a VCAM-1 up-regulation. However, it has been previously shown that the addition of a cyclic THS to a high- or low-steady WSS resulted in a VCAM-1 down regulation, indicating that the EC response to idealized mechanical stimuli (steady WSS and cyclic THS) is not comparable to physiological mechanical stimuli (unsteady WSS and pulsatile THS), even though in both situations the average magnitude of WSS and THS applied were similar. In third bioreactor test case, a nicotine chemical stimulus induced a substantial VCAM-1 up-regulation and a moderate ICAM-1 up-regulation. The addition of the mechanical stimuli of the second bioreactors test case resulted in a greater VCAM-1 up-regulation than what was expected, considering the observations of the previous second bioreactor test case alone. This study found that the EC biochemical response to physiological mechanical stimuli is not comparable to the previously observed EC response to idealized mechanical stimuli, even though in both environments the mechanical stimuli were of a similar magnitude. Also, the level of VCAM-1 expressed by the nicotine stimulated ECs showed an elevated level of sensitivity to the athero prone mechanical stimuli. PMID- 20162356 TI - The pipeline still leaks and more than you think: a status report on gender diversity in biomedical engineering. AB - While the percentage of women in biomedical engineering is higher than in many other technical fields, it is far from being in proportion to the US population. The decrease in the proportion of women and underrepresented minorities in biomedical engineering from the bachelors to the masters to the doctoral levels is evidence of a still leaky pipeline in our discipline. In addition, the percentage of women faculty members at the assistant, associate and full professor levels remain disappointingly low even after years of improved recruitment of women into biomedical engineering at the undergraduate level. Worse, the percentage of women graduating with undergraduate degrees in biomedical engineering has been decreasing nationwide for the most recent three year span for which national data are available. Increasing diversity in biomedical engineering is predicted to have significant research and educational benefits. The barriers to women's success in biomedical engineering and strategies for overcoming these obstacles-and fixing the leaks in the pipeline are reviewed. PMID- 20162357 TI - Airway wall stiffening increases peak wall shear stress: a fluid-structure interaction study in rigid and compliant airways. AB - The airflow characteristics in a computed tomography (CT) based human airway bifurcation model with rigid and compliant walls are investigated numerically. An in-house three-dimensional (3D) fluid-structure interaction (FSI) method is applied to simulate the flow at different Reynolds numbers and airway wall stiffness. As the Reynolds number increases, the airway wall deformation increases and the secondary flow becomes more prominent. It is found that the peak wall shear stress on the rigid airway wall can be five times stronger than that on the compliant airway wall. When adding tethering forces to the model, we find that these forces, which produce larger airway deformation than without tethering, lead to more skewed velocity profiles in the lower branches and further reduced wall shear stresses via a larger airway lumen. This implies that pathologic changes in the lung such as fibrosis or remodeling of the airway wall both of which can serve to restrain airway wall motion-have the potential to increase wall shear stress and thus can form a positive feed-back loop for the development of altered flow profiles and airway remodeling. These observations are particularly interesting as we try to understand flow and structural changes seen in, for instance, asthma, emphysema, cystic fibrosis, and interstitial lung disease. PMID- 20162358 TI - Computer modeling of controlled microsphere release and targeting in a representative hepatic artery system. AB - Combating liver tumors via yttrium-90 ((90)Y) radioembolization is a viable treatment option of nonresectable liver tumors. Employing clinical (90)Y microparticles (i.e., SIR-Spheres and TheraSpheres) in a computational model of a representative hepatic artery system, laminar transient 3D particle-hemodynamics were simulated. Specifically, optimal particle release positions in the right hepatic (parent) artery as well as the best temporal release window were determined for the microspheres to exit specific outlet daughter vessels, potentially connected to liver tumors. The results illustrate the influence of a curved geometry on the velocity field and the particle trajectory dependence on the spatial and temporal particle injection conditions. The differing physical particle characteristics of the SIR-Spheres and the TheraSpheres had a subtle impact on particle trajectories in the decelerating portion of the arterial pulse, i.e., when the inertial forces on the particles are weaker. Conversely, particle characteristics and inelastic wall collisions had little effect on particles released during the accelerating phase of the arterial pulse, i.e., both types of microspheres followed organized paths to predetermined outlets. Such results begin paving the way towards directing 100% of the released microspheres to specific daughter vessels (e.g., those connected to tumors) under transient flow conditions in realistic geometries via a novel drug-particle targeting methodology. PMID- 20162359 TI - AAA stent-grafts: past problems and future prospects. AB - Endovascular aneurysm repair (EVAR) has quickly gained popularity for infrarenal abdominal aortic aneurysm repair during the last two decades. The improvement of available EVAR devices is critical for the advancement of patient care in vascular surgery. Problems are still associated with the grafts, many of which can necessitate the conversion of the patient to open repair, or even result in rupture of the aneurysm. This review attempts to address these problems, by highlighting why they occur and what the failings of the currently available stent grafts are, respectively. In addition, the review gives critical appraisal as to the novel methods required for dealing with these problems and identifies the new generation of stent grafts that are being or need to be designed and constructed in order to overcome the issues that are associated with the existing first- and second-generation devices. PMID- 20162360 TI - How crouch gait can dynamically induce stiff-knee gait. AB - Children with cerebral palsy frequently experience foot dragging and tripping during walking due to a lack of adequate knee flexion in swing (stiff-knee gait). Stiff-knee gait is often accompanied by an overly flexed knee during stance (crouch gait). Studies on stiff-knee gait have mostly focused on excessive knee muscle activity during (pre)swing, but the passive dynamics of the limbs may also have an important effect. To examine the effects of a crouched posture on swing knee flexion, we developed a forward-dynamic model of human walking with a passive swing knee, capable of stable cyclic walking for a range of stance knee crouch angles. As crouch angle during stance was increased, the knee naturally flexed much less during swing, resulting in a 'stiff-knee' gait pattern and reduced foot clearance. Reduced swing knee flexion was primarily due to altered gravitational moments around the joints during initial swing. We also considered the effects of increased push-off strength and swing hip flexion torque, which both increased swing knee flexion, but the effect of crouch angle was dominant. These findings demonstrate that decreased knee flexion during swing can occur purely as the dynamical result of crouch, rather than from altered muscle function or pathoneurological control alone. PMID- 20162361 TI - Erratum to: Blood HbO2 and HbCO2 dissociation curves at varied O2, CO2, pH, 2,3 DPG and temperature levels. AB - New mathematical model equations for O(2) and CO(2) saturations of hemoglobin (S(HbO)(2) and S(HbCO)(2) are developed here from the equilibrium binding of O(2) and CO(2) with hemoglobin inside RBCs. They are in the form of an invertible Hill type equation with the apparent Hill coefficients KHbO(2) and KHbCO(2) in the expressions for SHbO(2) and SHbCO(2) dependent on the levels of O(2) and CO(2) partial pressures (P(O)(2) and P(CO)(2)), pH, 2,3-DPG concentration, and temperature in blood. The invertibility of these new equations allows PO(2) and PCO(2) to be computed efficiently from S(HbO)(2) and S(HbCO)(2) and vice versa. The oxyhemoglobin (HbO(2)) and carbamino-hemoglobin (HbCO(2)) dissociation curves computed from these equations are in good agreement with the published experimental and theoretical curves in the literature. The model solutions describe that, at standard physiological conditions, the hemoglobin is about 97.2% saturated by O(2) and the amino group of hemoglobin is about 13.1% saturated by CO(2). The O(2) and CO(2) content in whole blood are also calculated here from the gas solubilities, hematocrits, and the new formulas for S(HbO)(2) and S(HbCO)(2). Because of the mathematical simplicity and invertibility, these new formulas can be conveniently used in the modeling of simultaneous transport and exchange of O(2) and CO(2) in the alveoli-blood and blood-tissue exchange systems. PMID- 20162362 TI - Defining life: synthesis and conclusions. AB - The first part of the paper offers philosophical landmarks on the general issue of defining life. Section 1 defends that the recognition of "life" has always been and remains primarily an intuitive process, for the scientist as for the layperson. However we should not expect, then, to be able to draw a definition from this original experience, because our cognitive apparatus has not been primarily designed for this. Section 2 is about definitions in general. Two kinds of definition should be carefully distinguished: lexical definitions (based upon current uses of a word), and stipulative or legislative definitions, which deliberately assign a meaning to a word, for the purpose of clarifying scientific or philosophical arguments. The present volume provides examples of these two kinds of definitions. Section 3 examines three traditional philosophical definitions of life, all of which have been elaborated prior to the emergence of biology as a specific scientific discipline: life as animation (Aristotle), life as mechanism, and life as organization (Kant). All three concepts constitute a common heritage that structures in depth a good deal of our cultural intuitions and vocabulary any time we try to think about "life". The present volume offers examples of these three concepts in contemporary scientific discourse. The second part of the paper proposes a synthesis of the major debates developed in this volume. Three major questions have been discussed. A first issue (Section 4) is whether we should define life or not, and why. Most authors are skeptical about the possibility of defining life in a strong way, although all admit that criteria are useful in contexts such as exobiology, artificial life and the origins of life. Section 5 examines the possible kinds of definitions of life presented in the volume. Those authors who have explicitly defended that a definition of life is needed, can be classified into two categories. The first category (or standard view) refers to two conditions: individual self-maintenance and the open-ended evolution of a collection of similar entities. The other category refuse to include reproduction and evolution, and take a sort of psychic view of the living. Section 6 examines the relationship between the question of the definition of life and that of the origins of life. There is a close parallel between the general conceptions of the origins of life and the definitions of life. PMID- 20162364 TI - The biochemical basis of hereditary fructose intolerance. AB - Hereditary fructose intolerance is a rare, but potentially lethal, inherited disorder of fructose metabolism, caused by mutation of the aldolase B gene. Treatment currently relies solely on dietary restriction of problematic sugars. Biochemical study of defective aldolase B enzymes is key to revealing the molecular basis of the disease and providing a stronger basis for improved treatment and diagnosis. Such studies have revealed changes in enzyme activity, stability and oligomerisation. However, linking these changes to disease phenotypes has not always been straightforward. This review gives a general overview of the features of hereditary fructose intolerance, then concentrates on the biochemistry of the AP variant (Ala149Pro variant of aldolase B) and molecular pathological consequences of mutation of the aldolase B gene. PMID- 20162365 TI - Serum MIP-1 alpha level: a biomarker for the follow-up of lentiviral therapy in mucopolysaccharidosis IIIB mice. AB - Mucopolysaccharidosis (MPS) IIIB is an inherited lysosomal storage disorder caused by deficiency of alpha-N-acetylglucosaminidase (NAGLU). The disease is characterized by mild somatic features and severe neurological involvement, with high mortality rates. Although some therapeutic approaches have been applied to the murine model of the disease, no effective therapy is available. Moreover, assessing therapeutic efficacy is challenged by the lack of markers to for progression and severity. In this study, we examined the effect of brain-directed lentiviral (LV) gene therapy on serum levels of macrophage inflammatory protein 1 alpha (MIP-1alpha) and brain-derived neurotrophic factor (BDNF) proteins in the murine model of MPS IIIB to identify novel serum biomarkers. The cytokine MIP 1alpha was elevated in MPS IIIB mouse serum, and following gene therapy, it was reduced to normal levels. For neurotrophin BDNF, the difference in serum levels between MPS IIIB and normal mice was not statistically significant; after LV gene therapy, an increase in protein was found in treated mice, although the values were not statistically significant. Our studies suggest MIP-1alpha as the first serum biomarker that could be used to monitor disease progression and treatment for MPS IIIB disease. PMID- 20162366 TI - Therapeutic approaches for neuronopathic lysosomal storage disorders. AB - Therapy of the central nervous system (CNS) manifestations of lysosomal storage diseases (LSDs) has remained a major challenge because of its inability to deliver therapeutic agents efficiently across the intact blood-brain barrier. Non specific therapies such as hematopoietic stem cell transplantation have been useful in globoid cell leukodystrophy (Krabbe disease) and in some mucopolysaccharidoses. Anti-inflammatory agents also show promise as adjuvant therapy. High doses of replacement therapy with native or modified enzyme show renewed promise for correction of CNS cells. Alternatively, small molecules can enter the brain relatively easily and promote reduction of accumulated substrate or function as pharmacological chaperones to enhance the level of the deficient enzyme. Gene therapy is still being developed and tested in patients. It is therefore likely that, thanks to a better understanding of disease mechanism, a variety of therapeutic approaches, used alone or in combination, will be useful to treat the devastating neurological complications of LSDs. PMID- 20162369 TI - A phenomenological analysis of bodily self-awareness in the experience of pain and pleasure: on dys-appearance and eu-appearance. AB - The aim of this article is to explore nuances within the field of bodily self awareness. My starting-point is phenomenological. I focus on how the subject experiences her or his body, i.e. how the body stands forth to the subject. I build on the phenomenologist Drew Leder's distinction between bodily dis appearance and dys-appearance. In bodily dis-appearance, I am only prereflectively aware of my body. My body is not a thematic object of my experience. Bodily dys-appearance takes place when the body appears to me as "ill" or "bad." This is often the case when I experience pain or illness. Here, I will examine three versions of bodily dys-appearance. Whereas many phenomenological studies have explored cases of bodily dys-appearance, few studies have focused on the opposite of bodily dys-appearance, i.e. on bodily modes of being where the body appears to the subject as something good, easy or well. This is done in this article. When the body stands forth as good, easy or well to the subject, I suggest that the body eu-appears to this person. The analysis of eu-appearance shows that the subject can attend to her or his body as something positive and that this attention need not result in discomfort or alienation. Eu-appearance can take place in physical exercise, in sexual pleasure and in some cases of wanted pregnancies. I also discuss, briefly, the case of masochism. PMID- 20162367 TI - Dermatan sulfate and heparan sulfate as a biomarker for mucopolysaccharidosis I. AB - Mucopolysaccharidosis I (MPS I) is an autosomal recessive disorder caused by deficiency of alpha-L-iduronidase leading to accumulation of its catabolic substrates, dermatan sulfate (DS) and heparan sulfate (HS), in lysosomes. This results in progressive multiorgan dysfunction and death in early childhood. The recent success of enzyme replacement therapy (ERT) for MPS I highlights the need for biomarkers that reflect response to such therapy. To determine which biochemical markers are better, we determined serum and urine DS and HS levels by liquid chromatography tandem mass spectrometry in ERT-treated MPS I patients. The group included one Hurler, 11 Hurler/Scheie, and two Scheie patients. Seven patients were treated from week 1, whereas the other seven were treated from week 26. Serum and urine DS (DeltaDi-4S/6S) and HS (DeltaDiHS-0S, DeltaDiHS-NS) were measured at baseline, week 26, and week 72. Serum DeltaDi-4S/6S, DeltaDiHS-0S, and DeltaDiHS-NS levels decreased by 72%, 56%, and 56%, respectively, from baseline at week 72. Urinary glycosaminoglycan level decreased by 61.2%, whereas urine DeltaDi-4S/6S, DeltaDiHS-0S, and DeltaDiHS-NS decreased by 66.8%, 71.8%, and 71%, respectively. Regardless of age and clinical severity, all patients showed marked decrease of DS and HS in blood and urine samples. We also evaluated serum DS and HS from dried blood-spot samples of three MPS I newborn patients, showing marked elevation of DS and HS levels compared with those in control newborns. In conclusion, blood and urine levels of DS and HS provide an intrinsic monitoring and screening tool for MPS I patients. PMID- 20162368 TI - Dealing with methionine/homocysteine sulfur: cysteine metabolism to taurine and inorganic sulfur. AB - Synthesis of cysteine as a product of the transsulfuration pathway can be viewed as part of methionine or homocysteine degradation, with cysteine being the vehicle for sulfur conversion to end products (sulfate, taurine) that can be excreted in the urine. Transsulfuration is regulated by stimulation of cystathionine beta-synthase and inhibition of methylene tetrahydrofolate reductase in response to changes in the level of S-adenosylmethionine, and this promotes homocysteine degradation when methionine availability is high. Cysteine is catabolized by several desulfuration reactions that release sulfur in a reduced oxidation state, generating sulfane sulfur or hydrogen sulfide (H2S), which can be further oxidized to sulfate. Cysteine desulfuration is accomplished by alternate reactions catalyzed by cystathionine beta-synthase and cystathionine gamma-lyase. Cysteine is also catabolized by pathways that require the initial oxidation of the cysteine thiol by cysteine dioxygenase to form cysteinesulfinate. The oxidative pathway leads to production of taurine and sulfate in a ratio of approximately 2:1. Relative metabolism of cysteine by desulfuration versus oxidative pathways is influenced by cysteine dioxygenase activity, which is low in animals fed low-protein diets and high in animals fed excess sulfur amino acids. Thus, desulfuration reactions dominate when cysteine is deficient, whereas oxidative catabolism dominates when cysteine is in excess. In rats consuming a diet with an adequate level of sulfur amino acids, about two thirds of cysteine catabolism occurs by oxidative pathways and one third by desulfuration pathways. Cysteine dioxygenase is robustly regulated in response to cysteine availability and may function to provide a pathway to siphon cysteine to less toxic metabolites than those produced by cysteine desulfuration reactions. PMID- 20162370 TI - Anemia of aging and obstructive sleep apnea. AB - INTRODUCTION: World Health Organization defined anemia of aging (AOA) when men and women greater than 65 years, respectively, have unexplained hemoglobin (Hgb) less than 13 and 12 g/dl. Recent evidence suggests that this is likely a chronic inflammatory process involving interleukins (IL) 6, 12, and C-reactive protein. Among elderly with obstructive sleep apnea (OSA), hypoxic stimulation of erythropoiesis may obscure AOA. Treatment of OSA may paradoxically restore AOA. We sought to identify OSA and AOA coexistence and OSA treatment AOA interaction. METHODS: Records of 101 successive patients older than 65 years and with OSA who were treated with continuous positive airway pressure were analyzed retrospectively. Differences among pre/post-treatment of OSA hemograms were assessed using paired two-tailed Student's t test. Hemogram changes were compared to apnea-hypopnea index (AHI), respiratory effort related arousals (RERA), and duration patients slept with oxyhemoglobin saturation <89% (hypoxic time (HT)) and were assessed for correlative significance using Pearson coefficient correlation. RESULTS: Eighty-two of one hundred one patients (27 men, 55 women; average age 71 years) had charted all the study data variables cited above. Mean pre-treatment and mean 1-year post-treatment of OSA Hgb/hematocrit (Hct) for men and women, respectively, were 13 g/dl/40.7% to 12.7 g/dl/39.1% and 12.1 g/dl/38.1% to 11.9 g/dl/37.6%. Hct changed significantly among both men and women (p < 0.05). Among 56% and 30% of the 82 patient study cohort, 1-year post treatment of OSA, Hct declined (mean 4.8%) and increased (mean 3.7%), respectively; both changes were statistically significant (p < 0.01). These changes did not correlate significantly with AHI, RERA, or HT. DISCUSSION: Among the entire cohort for both men and women, we did not see AOA before OSA treatment and we did see AOA 1 year after OSA treatment. However, post-treatment of OSA Hct distributed bimodally, with significant increases and declines of Hct. While these Hct changes did not correlate significantly with selected sleep-breathing variables, we remain intrigued by a possible AOA-OSA interaction. AOA and OSA share common inflammatory processes. We believe OSA inflammatory processes interact with OSA hypoxia-induced erythropoiesis. The balance of these sets of processes determines the effect of OSA and OSA treatment on AOA. PMID- 20162371 TI - The state of indoor air quality in Pakistan--a review. AB - BACKGROUND AND PURPOSE: In Pakistan, almost 70% of the population lives in rural areas. Ninety-four percent of households in rural areas and 58% in urban areas depend on biomass fuels (wood, dung, and agricultural waste). These solid fuels have poor combustion efficiency. Due to incomplete combustion of the biomass fuels, the resulting smoke contains a range of health-deteriorating substances that, at varying concentrations, can pose a serious threat to human health. Indoor air pollution accounts for 28,000 deaths a year and 40 million cases of acute respiratory illness. It places a significant economic burden on Pakistan with an annual cost of 1% of GDP. Despite the mounting evidence of an association between indoor air pollution and ill health, policy makers have paid little attention to it. This review analyzes the existing information on levels of indoor air pollution in Pakistan and suggests suitable intervention methods. METHODS: This review is focused on studies of indoor air pollution, due to biomass fuels, in Pakistan published in both scientific journals and by the Government and international organizations. In addition, the importance of environmental tobacco smoke as an indoor pollutant is highlighted. RESULTS: Unlike many other developing countries, there are no long-term studies on the levels of indoor air pollution. The limited studies that have been undertaken indicate that indoor air pollution should be a public health concern. High levels of particulate matter and carbon monoxide have been reported, and generally, women and children are subject to the maximum exposure. There have been a few interventions, with improved stoves, in some areas since 1990. However, the effectiveness of these interventions has not been fully evaluated. CONCLUSION: Indoor air pollution has a significant impact on the health of the population in Pakistan. The use of biomass fuel as an energy source is the biggest contributor to poor indoor air quality followed by smoking. In order to arrest the increasing levels of indoor pollution, there is a dire need to recognize it as a major health hazard and formulate a national policy to combat it. An integrated effort, with involvement of all stakeholders, could yield promising results. A countrywide public awareness campaign, on the association of indoor air pollution with ill health, followed by practical intervention would be an appropriate approach. Due to the current socioeconomic conditions in the country, development and adoption of improved cooking stoves for the population at large would be the most suitable choice. However, the potential of biogas as a fuel should be explored further, and modern fuels (natural gas and LPG) need to be accessible and economical. Smoking in closed public spaces should be banned, and knowledge of the effect of smoking on indoor air quality needs to be quantified. PMID- 20162372 TI - Seasonal variation of pollution biomarkers to assess the impact on the health status of juvenile Pacific oysters Crassostrea gigas exposed in situ. AB - BACKGROUND, AIM, AND SCOPE: In this study, a suite of sublethal stress biomarkers were analyzed in juveniles of the sentinel species, the Pacific oyster Crassostrea gigas, with a view to using them as pollution monitoring tools. The aim of this work was (1) to study baseline seasonal variations of biomarkers in different body compartments of C. gigas in the reference site and, after selecting biomarkers presenting no seasonal variations, (2) to compare responses of these biomarkers between contaminated and reference sites. MATERIALS AND METHODS: Juvenile oysters were transplanted from Bouin (France), a reference site, to three different sites in Marennes-Oleron Bay (France), located in another water body and next to different contamination sources. Animals were exposed in situ for 3 months in summer, autumn, and winter. The following biomarkers were measured: superoxide dismutase (SOD) and glutathione peroxidase (GPx) in gills and digestive gland and lysozyme and phenoloxidase (PO) in plasma. RESULTS: No significant seasonal variations for SOD in gills and digestive gland, GPx in gills, and PO in plasma were observed in the reference site. Significant differences in enzyme activity were observed between contaminated and reference sites for SOD in gills and digestive gland and PO in plasma, depending on the body compartment, the season, and/or the site. CONCLUSIONS: In conclusion, these data suggest the potential application of these biomarkers in C. gigas to provide ecologically relevant information and, therefore, to be used as biomarkers in coastal pollution monitoring. PMID- 20162374 TI - From the Editor's desk: legislating change. PMID- 20162373 TI - Feasibility of dissemination of cognitive behavioral therapy to Texas community mental health centers. AB - State mental health systems are actively seeking to disseminate empirically supported treatment approaches to improve the outcomes of adults with serious mental illnesses. However, many of these interventions have not been studied within public mental health settings. Cognitive behavioral therapy (CBT) has been shown to be effective for major depression in well-controlled trials, but its effectiveness in public mental health settings is less known. The present study examines the feasibility of dissemination of CBT in the Texas public mental health system. Seven clinicians were trained by a CBT expert and supervised for 5 months, during which time their skills approached competency levels of therapists in randomized controlled trials. Forty clients were treated during the therapists' training phase, attending an average of ten sessions and experiencing a significant reduction in depressive symptoms. Study results are compared with previously published studies of CBT. PMID- 20162375 TI - Introduction: esophagus, dysplasia, and early esophageal adenocarcinoma: managing the transition. PMID- 20162376 TI - Quantification and comparison of soil elements in the Tibetan Plateau Kaschin Beck disease area : a case study in Zamtang County, Sichuan Province, China. AB - The prevalence rate of Kaschin-Beck disease (KBD) in most parts of China is currently decreasing, but the disease is still active and severe on the Tibetan Plateau. Soil samples including the surface layer (0-20 cm) and the subsurface layer (20-40 cm) in the cultivated and natural soil profiles were collected, and the mechanical composite and total concentration of arsenic, cobalt, copper, iron, mercury, manganese, molybdenum, selenium, and zinc were determined. Concentrations of arsenic, iron, manganese, copper, and selenium in the surface soil were lower than those in the subsurface soil. The same was true of physical clay in the soil profiles. However, there were no significant differences between the different soil layers. The concentrations of selenium, molybdenum, and mercury were somewhat lower compared with the average concentrations of soils in China. Deficiencies of molybdenum and selenium both play a critical role in occurrence of KBD, but whether or not soil mercury at a low level contributes to KBD is still unclear. A correlation analysis of soil elements showed that there is a positive correlation between iron, cobalt, and manganese due to their similar chemical characteristics. Selenium concentrations in soil as well as the physical clay and iron descend with the deterioration of KBD, but mercury concentrations in soil ascend with the aggravation of the disease. The results show that selenium deficiencies greatly influence the disease, and a deficiency of molybdenum is likely another important factor in inducing KBD. Moreover, determining whether low levels of soil mercury contribute to KBD should be investigated in the future. PMID- 20162377 TI - Interactions between cadmium and zinc in the biological samples of Pakistani smokers and nonsmokers cardiovascular disease patients. AB - The pathogenesis of some cardiovascular diseases (CVDs) has been altered with changes in the balance of certain trace and toxic elements. The aim of the present study was to assess the role of zinc (Zn) and cadmium (Cd) in smoker and nonsmoker male CVD patients (n = 457) of two age groups (31-45) and (46-60). The both elements were determined in biological samples (scalp hair, blood, and urine) of CVD patients and healthy referents for comparison purpose. The concentrations of Zn and Cd were measured by atomic absorption spectrophotometer prior to microwave-assisted acid digestion. It was observed that the mean values of Cd were significantly higher in the biological samples of smokers CVD as compared to nonsmoker CVD patients, while the level of Zn was lower in both smoker and nonsmoker patients. The concentrations of Zn in whole blood and scalp hair samples were lower in CVD patients as compared to referents (p > 0.001). Results showed significant changes of levels of Cd and Zn in blood and scalp hair samples of CVD patients when compared with healthy referents, while reverse in the case of urine samples. It was observed that low Zn levels were associated with both smoker and nonsmoker CVD patients, while increased cadmium accumulation was observed in smoker patients as compared to nonsmoker patients (p > 0.025). PMID- 20162378 TI - Generation of a novel high-affinity monoclonal antibody with conformational recognition epitope on human IgM. AB - As IgM is the first isotype of antibody which appears in blood after initial exposure to a foreign antigen in the pattern of primary response, detection, and quantification of this molecule in blood seems invaluable. To approach these goals, generation, and characterization of a highly specific mAb (monoclonal antibody) against human IgM were investigated. Human IgM immunoglobulins were used to immunize Balb/c mice. Spleen cells taken from the immunized animals were fused with SP2/O myeloma cells using PEG (polyethylene glycol, MW 1450) as fusogen. The hybridomas were cultured in HAT containing medium and supernatants from the growing hybrids were screened by enzyme-linked immunosorbent assay (ELISA) using plates coated with pure human IgM and the positive wells were then cloned at limiting dilutions. The best clone designated as MAN-1, was injected intraperitoneally to some Pristane-injected mice. Anti-IgM mAb was purified from the animals' ascitic fluid by protein-G sepharose followed by DEAE-cellulose ion exchange chromatography. MAN-1 interacted with human IgM with a very high specificity and affinity. The purity of the sample was tested by SDS-PAGE and the affinity constant was measured (K(a) = 3.5 x 10(9)M(-1). Immunoblotting and competitive ELISA were done and the results showed that the harvested antibody recognizes a conformational epitope on the mu chain of human IgM and there was no cross-reactivity with other subclasses of immunoglobulins. Furthermore, isotyping test was done and the results showed the subclass of the obtained mAb which was IgG(1)kappa. PMID- 20162379 TI - Putting the "community" back into "mental health": the challenge of a great crisis in the health and well-being of children and families. AB - For more than a generation, the levels of anxiety, depression, and misconduct among young people in the United States have been steadily increasing. So too have isolation, alienation, mistrust, and boredom, with the result that ongoing social support has been diminishing, particularly for young people. These trends constitute a national public health crisis affecting young people in general, those already defined as having mental health problems, and their families. To respond adequately, the child mental health system must change dramatically--away from the provision of units of service defined by protocols, time, and professionals' presence and toward the engagement of primary community institutions in the creation and maintenance of new norms of giving and receiving help. Initial evidence suggests that such a shift requires massive effort but that it is feasible and potentially effective. PMID- 20162380 TI - Personal breast: customizing agents and biomarkers for optimal adjuvant endocrine therapy. PMID- 20162381 TI - Medicolegal evaluation of suicidal deaths exemplified by the situation in Germany. AB - Suicide is a significant form of unnatural death and must be differentiated as such from other violent manners of death (homicide, accident), but also from unexpected deaths due to natural causes. The distinction is made on the basis of a careful collection and correct interpretation of post-mortem forensic findings on the one hand, the general background of the case and the criminal investigation at the scene on the other. For competent assessment by the post mortem medical examiner and/or forensic pathologist, a thorough knowledge of the numerous methods of committing suicide and their pathomorphological correlates is indispensable. This not only includes the constellation of findings and injury patterns typical of suicide, but also unusual manifestations. Highly conspicuous are complex suicides, in which several methods are applied simultaneously, or one after the other, as well as joint suicides and homicide-suicides involving several persons. Certain settings also deserve special attention. Moreover, simulated or dissimulated suicide is a possibility that must always be borne in mind in forensic practice. PMID- 20162382 TI - Time for paradigmatic substitution in psychology. What are the alternatives? AB - This article focuses on the "machine paradigm" in psychology and its consequences for (mis)understanding of human beings. It discusses causes of the mainstream epistemology in Western societies, referring to philosophical traditions, the prestige of some natural sciences and mathematical statistics. It emphasizes how the higher psychological functions develop dialectically from a biological basis and how the brain due to its plasticity changes with mental and physical activity. This makes a causal machine paradigm unfit to describe and explain human psychology and human development. Some concepts for an alternative paradigm are suggested. PMID- 20162383 TI - Feelings in literature. AB - In this article it is argued that feelings are all important to the function of literature. In contradiction to music that is concerned with the inwardness of humankind, literature has, because of language, the capacity to create fictional worlds that in many respects are similar to and related to the life world within which we live. One of the most important reasons for our emotional engagement in literature is our empathy with others and our constant imagining and hypothesizing on possible developments in our interactions with them. Hence, we understand and engage ourselves in fictional worlds. It is further claimed and exemplified, how poetic texts are very good at rhetorically engage and manipulate our feelings. Finally, with reference to the important work of Ellen Dissanayake, it is pointed out that the first kind of communication in which we engage, that between mother and infant, is a kind of speech that positively engages the infant in a dialogue with the mother by means of poetic devices. PMID- 20162384 TI - Strength of antimicrobial bone cement decreases with increased poragen fraction. AB - BACKGROUND: Adding soluble particulate poragens to antimicrobial-loaded bone cement increases the permeability of the bone cement and increases the antimicrobial release, but the mechanical effect of adding poragens is not well known. QUESTIONS/PURPOSES: We therefore asked the following questions: (1) Does the poragen fraction in antimicrobial-loaded bone cement affect its antimicrobial release? (2) Does poragen fraction in antimicrobial-loaded bone cement affect its compressive strength; and (3) Does the effect on compressive strength change over time in elution? METHODS: Antimicrobial-loaded bone cement made in the proportions of 40 g polymer powder, 20 mL monomer liquid, 1 g tobramycin powder and one of six different doses of poragen powder (0, 1, 2, 4, 8, or 16 g of particulate xylitol per batch) was formed into standardized test cylinders and eluted for 30 days. We determined the cumulative recovered tobramycin and the change in compressive strength over 30 days of elution. RESULTS: Antimicrobial release progressively increased with increasing poragen fraction. Compressive strength progressively decreased with increasing poragen fraction and with increasing time in elution. Poragen fractions greater than 2 g per batch caused the compressive strength to decrease below 70 MPa over 30 days of elution. CLINICAL RELEVANCE: The use of poragens can increase elution of antimicrobials from antimicrobial-loaded bone cement. However, for implant fixation, to avoid deleterious reduction of compressive strength, the amount of poragen that can be added in addition to 1 g of antimicrobial powder may be limited to 2 g per batch. PMID- 20162385 TI - Fractures in brief: scaphoid fractures. PMID- 20162386 TI - Blood culture flasks for culturing synovial fluid in prosthetic joint infections. AB - BACKGROUND: Identifying the etiologic microorganism is essential to guide antimicrobial therapy in prosthetic joint infection. QUESTIONS/PURPOSE: We (1) compared the frequency of positive cultures with synovial fluid inoculated in blood culture flasks (SF) with those of periprosthetic tissues or swabs in traditional cultures from patients with acute and chronic prosthetic joint infections (PJI) and (2) determined the sensitivity, specificity, and predictive values of the three methods. PATIENTS AND METHODS: We retrospectively reviewed 87 patients with PJIs (54 knees, 33 hips) and 63 patients with aseptic loosening (34 knees, 29 hips). Two SF, periprosthetic tissue, and swab samples were taken for culture in all 150 patients except for 14 in whom only one SF fluid sample was obtained. Synovial fluid was inoculated in blood culture flasks and periprosthetic tissue and swab samples in standard media. Positive cultures were identified with standard biochemical procedures. RESULTS: SF samples were positive in 78 of 87 infected cases (90%), periprosthetic tissue samples were positive in 71 (82%), and swab samples were positive in 59 (68%). SF, periprosthetic tissue, and swab samples were positive more frequently in acute than in chronic infections (96% versus 82% for SF, 87% versus 74% for periprosthetic tissue, and 87% versus 44% for swabs). The sensitivity, specificity, and positive and negative predictive values of SF were 91, 100, 100, and 93 for acute infections and 79, 100, 100, and 88 for chronic infections, respectively. CONCLUSIONS: SF samples cultured in flasks had higher sensitivity, specificity, and positive and negative predictive values for diagnosis of PJI when compared with standard tissue and swab samples. The usefulness of all samples was less in chronic than in acute infections. LEVEL OF EVIDENCE: Level II, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20162387 TI - The classic: on the inner architecture of bones and its importance for bone growth. 1870. PMID- 20162388 TI - Compliance with appropriate use criteria for cardiac radionuclide imaging. PMID- 20162390 TI - This month in APR. PMID- 20162389 TI - Wallerian-like degeneration of central neurons after synchronized and geometrically registered mass axotomy in a three-compartmental microfluidic chip. AB - Degeneration of central axons may occur following injury or due to various diseases and it involves complex molecular mechanisms that need to be elucidated. Existing in vitro axotomy models are difficult to perform, and they provide limited information on the localization of events along the axon. We present here a novel experimental model system, based on microfluidic isolation, which consists of three distinct compartments, interconnected by parallel microchannels allowing axon outgrowth. Neurons cultured in one compartment successfully elongated their axons to cross a short central compartment and invade the outermost compartment. This design provides an interesting model system for studying axonal degeneration and death mechanisms, with a previously impossible spatial and temporal control on specific molecular pathways. We provide a proof of-concept of the system by reporting its application to a well-characterized experimental paradigm, axotomy-induced Wallerian degeneration in primary central neurons. Using this model, we applied localized central axotomy by a brief, isolated flux of detergent. We report that mouse embryonic cortical neurons exhibit rapid Wallerian-like distal degeneration but no somatic death following central axotomy. Distal axons show progressive degeneration leading to axonal beading and cytoskeletal fragmentation within a few hours after axotomy. Degeneration is asynchronous, reminiscent of in vivo Wallerian degeneration. Axonal cytoskeletal fragmentation is significantly delayed with nicotinamide adenine dinucleotide pretreatment, but it does not change when distal calpain or caspase activity is inhibited. These findings, consistent with previous experiments in vivo, confirm the power and biological relevance of this microfluidic architecture. PMID- 20162391 TI - Wnt/beta-catenin signaling: a novel target for therapeutic intervention of fibrotic kidney disease. AB - Fibrosis of epithelial parenchymal organs and end-stage organ failure, the final common pathway of many progressive chronic diseases including chronic kidney disease, continue to increase worldwide and are a major determinant of morbidity and mortality. Fibrosis is an active biosynthetic healing response initiated to protect the tissue from injury through the timed release of proteins but leads to serious tissue damage when it becomes independent from the initiating stimulus. Massive deposition of extracellular matrix by accumulation of myofibroblasts and disruption of the normal tissue architecture are characteristic of tissue fibrosis. The highly conserved Wnt/beta-catenin signaling pathway is essential to embryonic development in general and kidney morphogenesis in particular by regulating the expression of target genes, most often through the transcription factor T cell factor (TCF) and/or lymphoid enhancer factor (LEF). Emerging evidence from studies of renal fibrosis suggests that altered Wnt/beta-catenin signaling is linked to the pathogenesis of renal fibrosis. The renoprotective properties of some currently available drugs might be attributable in part to inhibition of Wnt signaling. The development of orally active Wnt modulators will provide a potentially important pharmacological tool for further investigating the role of Wnt/beta-catenin signaling and might offer a novel therapeutic strategy in renal fibrosis. PMID- 20162392 TI - N-methyl amine-substituted fluoxetine derivatives: new dopamine transporter inhibitors. AB - Transport of dopamine (DA) by the dopamine transporter from the synaptic cleft into the presynaptic terminals plays a key role in terminating dopaminergic neurotransmission. The binding of psychostimulants to their recognition sites on the DA transporter leads to an inhibition of DA transport and a subsequent rising of the dopamine contents in the synaptic cleft is ascribed to a mode of psychostimulation. Discovery of dopamine transporter inhibitors would be useful with regard to substituting for cocaine and minimizing its abuse. Recently, a number of fluoxetine analogues were synthesized, especially focusing on the substitution of N-methyl amine group through modifying the structure of the fluoxetine, N-methyl-3-[p-trifluoromethylphenoxy]-3-phenylpropylamine, widely used as an antidepressant. Among them, the pharmacological properties of FD-2, (R)-N-ethanol-3-(4-trifluorophenoxy)-3-phenyl propaneamine and FD-4, N-(R)-3 trifluorophenoxy-3-phenylpropane-imidazole with a higher affinity for the DA transporter were characterized in terms of dopamine transporter inhibition expecting for useful cocaine substitutes. Effects of the compounds on [H(3)]dopamine uptake, [I(125)]RTI-55 binding, and DA transporter-associated currents were examined with the ligand binding assays and voltage clamping technique in human embryonic kidney (HEK)-293 cells where the recombinant human DA transporter (hDAT) was stably expressed. Our results showed that (i) fluoxetine was potent in inhibiting both the uptake of [H(3)]DA (IC(50) = 0.21 +/ 0.032 mM, n = 3) and the [I(125)]RTI-55 binding (IC(50) = 0.23 +/- 0.012 mM, n = 10); (ii) N-methyl amine substituted fluoxetine analogues, FD-2 and FD-4 were equally or more potent than fluoxetine itself in terms of inhibition of [H(3)]DA uptake (IC50 FD-2: 0.077 +/- 0.0032 mM (n = 3); FD-4: 0.26 +/- 0.13 mM (n = 3), inhibition of [I(125)]RTI-55 binding, and reduction in DA transporter-associated currents, suggesting that these analogues could be a new class of dopamine transporter inhibitors. PMID- 20162393 TI - Facile synthesis of hydroxy wilfordic acid, a esterifying unit of anti-HIV sesquiterpene pyridine alkaloids. AB - Sesquiterpene pyridine alkaloids were isolated mainly from plants of the genus Tripterygium (Celastraceae) which have been used traditionally in Chinese medicine. These compounds have polyhydroxy dihydro-beta-agarofuran core and esterifying substituent with dilactone bridges, and recently demonstrated promising anti-HIV activity. We have achieved the synthesis of hydroxy wilfordic acid and its ester via asymmetric cyanosilylation. With a NMR study of (S)- and (R)-PGME (phenylglycine methyl ester) amide, the tertiary alcohol stereochemistry of synthetic hydroxyl wilfordic acids was determined. Our synthetic approach will provide a contribution to the synthesis of sesquiterpene pyridine alkaloids and the development of their analogs for anti-HIV activity. PMID- 20162394 TI - Cytotoxic phenolic compounds from Chionanthus retusus. AB - Cytotoxicity-guided fractionation and purification of MeOH extract from Chionanthus retusus Lindl. et Paxton resulted in the isolation of compounds. Fourteen phenolic compounds were isolated from the EtOAc soluble fraction, and their structures were determined by spectroscopic analysis. Isolated compounds were identified as phillygenin (1), scopoletin (2), pinoresinol (3), kaempferol (4), aromadendrin (5), 2-(4-hydroxyphenyl)ethanol (6), 3,3',5,5',7 pentahydroxyflavanone (7), luteolin (8), quercetin (9), apigenin (10), chrysoeriol (11), phillyrin (12), oleuropein (13), (7R,8R)-guaiacylglycerol (14). All compounds except for 12 and 13 were isolated for the first time from this plant and genus Chionanthus. Anti-proliferative effect of isolated compounds were evaluated by the sulforhodamin B assay against four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT15). Compounds 4 and 8-10 were significantly active with ED50 values of 1.84-6.35 microg/mL. Also, compounds 1, 3, 5 and 7 revealed cytotoxic effects at concentrations below 30 microg/mL. PMID- 20162395 TI - Rapid identification and characterization of antioxidants from Ligularia fischeri. AB - The objectives of this study were to investigate the radical-scavenging activity of Ligularia fischeri on oxidative damage by the radical 1,1-diphenyl-2 picrylhydrazyl (DPPH) and to rapidly identify the active components using the bioassay-linked fractionation method. The MeOH extract and fractions of CH(2)Cl(2), BuOH, and H(2)O from L. fischeri showed DPPH radical-scavenging effects in a dose-dependent manner (p < 0.01). In particular, the BuOH fraction had the most effective (p < 0.05) antioxidative capacity. The active constituents from the BuOH fraction of L. fischeri were rapidly isolated by bioassay-linked HPLC method and identified as hyperoside and 2''-acetylhyperoside with potent antioxidant effects against the DPPH radical, with IC(50) values of 1.31 and 7.09 microg/mL, respectively. They have not been reported from L. fischeri yet. PMID- 20162396 TI - A new C29-sterol with a cyclopropane ring at C-25 and 26 from the Vietnamese marine sponge lanthella sp. AB - One new C(29) sterol with a cyclopropane ring at C-25 and C-26, aragusteroketal B (1), and aragusterol B (2) were isolated from the Vietnamese marine sponge Ianthella sp. Their structures were elucidated by extensive spectroscopic analyses. Both 1 and 2 showed moderate cytotoxic activity against MCF-7, SK-Hep 1, and HeLa cell lines with IC(50) in the range of 12.8-27.8 microM. PMID- 20162397 TI - A new abietic acid-type diterpene glucoside from the needles of Pinus densiflora. AB - From the ethyl acetate fraction of the methanol extract of the needles of Pinus densiflora (Pinaceae), a new diterpenoid glucoside [9alpha,13alpha-epoxy 8beta,14beta-dihydroxy-abietic acid-18-O-beta-D: -glucopyranoside] (1), two flavonoid glucosides [kaempferol 3-O-beta-D: -glucoside (2) and 6-C-methyl kaempferol 3-O-beta-D: -glucoside (3)], and two monoterpenoid glucosides [bornyl 6-O-alpha-Larabinofuranosyl (1-->6)-beta-D: -glucopyranoside (4) and bornyl 6-O beta-D: -apiofuranosyl (1-->6)-beta-D: -glucopyranoside (5)] were isolated and characterized on the basis of spectral analysis. Of all the compounds, 2 and 3 showed peroxynitrite scavenging activity. PMID- 20162398 TI - Purunusides A-C, alpha-glucosidase inhibitory homoisoflavone glucosides from Prunus domestica. AB - Purunusides A-C (1-3), new homoisoflavone glucosides together with the known compounds beta-sitosterol (4) and 6,7-methylenedioxy-8-methoxycoumarin (5) have been isolated from n-butanol and ethyl acetate soluble fractions of Prunus domestica. Their structures were assigned on the basis of spectral studies. The compounds 1-3 showed potent inhibitory activity against the enzyme alpha glucosidase. PMID- 20162399 TI - Antibacterial effects of vulgarone B from Artemisia iwayomogi alone and in combination with oxacillin. AB - The antibacterial activities of vulgarone B, a component of Artemisia iwayomogi essential oil, were evaluated against some antibiotic-susceptible and -resistant human pathogens. Moreover, the effects of combining antibiotics, such as oxacillin, with vulgarone B were determined in this study. Significant inhibitory activities of Artemisia oils against antibiotic-susceptible and -resistant bacteria were confirmed by broth microdilution methods. The effects of vulgarone B on bacterial morphology and DNA were observed by scanning electron microscope and electrophoresis, respectively. In checkerboard microtiter tests, vulgarone B and A. iwayomogi oil combined with oxacillin resulted in synergism, or additive effects. Moreover, the safety of Artemisia oil and vulgarone B were confirmed in vivo. Both vulgarone B and the essential oil fraction of A. iwayomogi showed significant inhibitory activities against strains of antibioticsusceptible and resistant bacteria. The oils showed synergism or additive effects when combined with oxacillin against two strains of Staphylococcus aureus. The antibiotic mechanism involved might be related to DNA cleavage. Thus, vulgarone B and the essential oil fraction of A. iwayomogi may be promising candidates for a safe, effective, natural agent active against antibiotic-resistant S. aureus, especially when combined with oxacillin. PMID- 20162400 TI - Effects of oral epigallocatechin gallate on the pharmacokinetics of nicardipine in rats. AB - Epigallocatechin gallate (EGCG), irreversibly inhibits cytochrome P450 (CYP) 3A subfamily and P-glycoprotein (P-gp) in vitro. This study investigated the effect of oral EGCG on the pharmacokinetics of intravenous and oral nicardipine in rats. Nicardipine was administered orally (12 mg/kg) or intravenously (4 mg/kg) with or without oral EGCG (0.5, 3 or 10 mg/kg) to rats. Compared to controls (without EGCG), the total areas under the plasma concentration-time curve (AUCs) of intravenous nicardipine were greater with oral EGCG. Compared to controls (without EGCG), the AUCs of oral nicardipine and the extent of absolute oral bioavailability (F) were also greater with oral EGCG. The above data suggest that oral EGCG inhibited both the hepatic CYP3A subfamily and intestinal P-gp. PMID- 20162401 TI - Apoptosis of human Burkitt's lymphoma cells induced by 2-N,N diethylaminocarbonyloxymethyl-1-diphenylmethyl-4-(3,4,5-trimethoxybenzoyl) piperazine hydrochloride (PMS-1077). AB - Piperazine is one of the heterocycles which are associated with diverse pharmacological activities. 2-N,N-Diethylaminocarbonyloxymethyl-1-diphenylmethyl 4-(3,4,5-trimethoxybenzoyl) piperazine hydrochloride (PMS-1077) is a trisubstituted piperazine which contains a trimethoxybenzene ring and a benzhydrylpiperazine fragment, both of which can induce cell proliferation regression by different mechanisms. We have therefore examined the effects of PMS 1077 on Human Burkitt's lymphoma cells (Raji). The viability of Raji cells was determined by MTT assay and also assessed by trypan blue dye exclusion method. The results demonstrate that PMS-1077 can suppress the proliferation of Raji cells in a dose- and timedependent manner, while inhibit colony formation ability of Raji cells merely in a dose-dependent manner in vitro. Meanwhile, morphological changes were observed using fluorescence microscope. Flow cytometric analysis through PI stains showed that PMS-1077 blocked the growth of Raji cells in the G(0)/G(1) period, and induced apoptosis of Raji cells after 48 h of incubation. Cell apoptosis induced by PMS-1077 was further confirmed by staining with Annexin-V FITC and PI. Preliminary study by molecular docking suggests that PMS-1077 may inhibit tubulin polymerization. More experiments are in progress in our laboratory to reveal the mode of action of PMS-1077 in the induction of apoptosis of Raji cells. PMID- 20162402 TI - In vitro chemosensitivity in breast cancer using ATP-tumor chemosensitivity assay. AB - Chemotherapy for breast cancer is given on the basis of empirical information from clinical trials, an approach which falls to take into account the known heterogeneity of chemosensitivity between patients. This study aimed to demonstrate the degree of heterogeneity of chemosensitivity in breast cancers. In this study, we examined the heterogeneity of chemosensitivity in breast cancer specimens (n = 50) using an ex vivo ATP-tumor chemosensitivity assay (ATP-TCA). Assay evaluability was 92% in surgical biopsies or pleural aspirates. A variety of chemosensitivity agents were tested. We found that the most active single agent tested was paclitaxel, to which 65.9% of samples were sensitive. Combinations of agents also showed more strong sensitivity cases. The Adriamycin+5-FU demonstrated a strong sensitivity in 23 of 43 (52.3%) of samples. Adriamycin+paclitaxel was more effective, with strong sensitivity in 37 of 43 cases tested (86.0%). There was a marked heterogeneity of chemosensitivity in breast cancer. Chemosensitivity testing may provide a practical method of testing new regimens before clinical trials in breast cancer patients. PMID- 20162403 TI - Liquid chromatography-tandem mass spectrometry of a new PPARalpha/gamma dual agonist PAR-5359 in rat plasma. AB - PAR-5359, 3-(4-{2-[4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethoxy} phenyl)-2-ethoxypropionic acid, is a well-balanced PPARalpha/gamma dual agonist with the excellent antihyperglycemic and hypolipidemic activities. A reliable, selective and sensitive high-performance liquid chromatography with electrospray ionization tandem mass spectrometry was developed for the determination of PAR 5359 in rat plasma. PAR-5359 was twice extracted from rat plasma using methyl tert-butyl ether at neutral pH. The analytes were separated on an Allure Biphenyl column with the mobile phase of 78% methanol in 10 mM ammonium formate (pH 3.0) and detected by tandem mass spectrometry in the selective reaction monitoring mode. The calibration curve was linear (r = 0.9993) over the concentration range of 2.00-1000.0 ng/mL and the lower limit of quantification was 2.00 ng/mL using 50 microL plasma sample. The coefficient of variation and relative error at four QC levels were 1.2 to 12.3% and -2.5 to 6.3%, respectively. The present method was successfully applied to the pharmacokinetic study of PAR-5359 after oral dose of PAR-5359 at a dose of 1 mg/kg to male SD rats. PMID- 20162404 TI - Antibiotic resistance and assessment of food-borne pathogenic bacteria in frozen foods. AB - One hundred ninety-three frozen food samples collected in Korea various public bazaars from October 2006 to September 2007. Staphylococci were detected in 21.8% of frozen food samples. Staphylococcus aureus was isolated from 17 (8.8%) samples. Other staphylococci isolates were identified as S. warneri (7.8%), S. epidermidis (2.1%), S. xylosus (1.6%), S. eguorum (1%), and S. vitulinus (0.5%). Additionally, the antimicrobial susceptibility of 42 staphylococcal isolates to ten different antimicrobial agents was determined. The staphylococcal isolates demonstrated antimicrobial resistance to mupirocin (31%) oxacillin (14.3%), gentamicin (9.5%), teicoplanin (7.1%) and ciprofloxacin (7.1%). Most of the staphylococcal isolates showed high-level resistance to mupirocin (MIC(90), >128 microg/mL). Fortunately, most of the isolates were susceptible to vancomycin. The total bacteria and Escherichia coli count were tested to investigate the microbiological quality of frozen foods. From 193 frozen food samples, 43 (22.3%), 34 (17.6%) and 19 (9.8%) samples were shown to be of unacceptable quality due to total bacteria, coliform and E. coli counts, respectively. PMID- 20162405 TI - A method for removing contaminating protein during purification of human papillomavirus type 18 L1 protein from Saccharomyces cerevisiae. AB - Human papillomavirus (HPV) types 16 and 18 are the main targets in the field of prophylactic vaccines for preventing cervical cancer. L1 protein, the major capsid protein of HPV, selfassembles into virus-like particles (VLP), which are the major component of prophylactic vaccines. To obtain highly purified L1 protein, contaminants must be removed by several chromatography steps. However, this requires a great deal of time and labor, and results in loss of large amounts of the target protein. Therefore, we have sought to develop an efficient method for removing contaminants prior to chromatography during the purification of HPV18 L1 protein from Saccharomyces cerevisiae. For this purpose the contaminating proteins were removed by an ammonium sulfate precipitation step and further removed by a removal of precipitated contaminants step. Purification of the L1 protein by chromatography was significantly improved by the removal of precipitated contaminants step. In the present work we developed two one-step chromatography methods (heparin and cation-exchange chromatography), and HPV18 L1 proteins purified by both methods self-assembled into VLP. The two chromatographic purification methods are simpler and more convenient than previous methods and are widely applicable to work with VLPs. PMID- 20162406 TI - Application of mixture experimental design in the formulation and optimization of matrix tablets containing carbomer and hydroxy-propylmethylcellulose. AB - Using mixture experimental design, the effect of carbomer (Carbopol((R)) 971P NF) and hydroxypropylmethylcellulose (Methocel((R)) K100M or Methocel((R)) K4M) combination on the release profile and on the mechanism of drug liberation from matrix tablet was investigated. The numerical optimization procedure was also applied to establish and obtain formulation with desired drug release. The amount of TP released, release rate and mechanism varied with carbomer ratio in total matrix and HPMC viscosity. Increasing carbomer fractions led to a decrease in drug release. Anomalous diffusion was found in all matrices containing carbomer, while Case - II transport was predominant for tablet based on HPMC only. The predicted and obtained profiles for optimized formulations showed similarity. Those results indicate that Simplex Lattice Mixture experimental design and numerical optimization procedure can be applied during development to obtain sustained release matrix formulation with desired release profile. PMID- 20162407 TI - Characterization of a calcitonin gene-related peptide release assay in rat isolated distal colon. AB - The release of calcitonin gene-related peptide (CGRP) plays a key role gastrointestinal tract homeostasis. We aimed to investigate mechanisms that mediate CGRP release from the rat colon in vitro. Colon segments were stimulated and the amount of CGRP released was measured using an enzyme immunoassay. Capsaicin and low pH induced significant increases in CGRP release which was shown to be mediated by TRPV1 activation as demonstrated with the TRPV1 antagonists CTPC and capsazepine. The mast cell degranulator, compound 48/80 significantly increased CGRP release an effect that was blocked in the presence of the mast cell stabilizer, ketotifen and the selective Gi inhibitor benzalkonium chloride. The addition of a mixture of inflammatory mediators containing pro-inflammatory cytokines, 5HT, bradykinin and PGE2 showed no effect at neutral pH but at low pH a significant additive effect was observed. We conclude that CGRP release in the rat distal colon occurs in response to mast cell degranulation, inflammatory mediators, low pH and capsaicin and describe a role for TRPV1 receptors in mediating the response. PMID- 20162408 TI - Inhibitory effects of curcuminoids on passive cutaneous anaphylaxis reaction and scratching behavior in mice. AB - To understand anti-allergic effect of Curcuma aromatica (family Zingerberaceae), which inhibited passive cutenous anaphylaxis (PCA) reaction in preliminary study, we isolated its main constituents, curcumin, demethoxycurcumin and bisdemethoxycurcumin, and investigated their inhibitory effects against PCA reaction and scratching behavior. These curcuminoids inhibited the PCA reaction induced by the IgE-antigen complex (IAC) and the scratching behavior induced by compound 48/80. These curcuminoids also inhibited degranulation, protein expression of TNF-alpha and IL-4, and transcription factor NF-kappaB activation in IAC-induced RBL-2H3 cells. Of these curcuminoids, curcumin exhibited the most potent inhibition, followed by demethoxycurcumin and bisdemethoxycurcumin. These findings suggest that curcuminoids, particularly curcumin, can improve the symptoms of allergic diseases, such as anaphylaxis and itching. PMID- 20162409 TI - Magnolol induces apoptosis via activation of both mitochondrial and death receptor pathways in A375-S2 cells. AB - Magnolol inhibited proliferation of human malignant melanoma A375-S2 cells. The drug induced oligonucleosomal fragmentation of DNA in A375-S2 cells and increased caspase-3, 8, 9 activities followed by the degradation of caspase-3 substrates, inhibitor of caspase dependent DNase (ICAD) and poly-(ADP-ribose) polymerase (PARP). Pan-caspase inhibitor (z-VADfmk), caspase-3 inhibitor (z-DEVD-fmk), capase-8 inhibitor (z-IETD-fmk), caspase-9 inhibitor (z-LEHD-fmk) and caspase-10 inhibitor (z-AEVD-fmk) inhibited magnolol-induced A375-S2 cell apoptosis. The level of anti-apoptotic mitochondrial protein Bcl-2 was up-regulated while the level of pro-apoptotic protein Bax was down-regulated. Taken together, our results indicate that magnolol induces apoptosis by activation of both mitochondrial and death receptor pathways in A375-S2 cells. PMID- 20162410 TI - Simultaneous HPLC analysis of ceramide and dihydroceramide in human hairs. AB - Ceramide, a major class of hair lipid, can help determine the physicochemical properties of human hairs such as the chemical diffusion barrier and water retention. In this study, we developed a quantitation method for ceramide and dihydroceramide, a saturated form of ceramide, in human hairs. Lipids were extracted with ethanol from human hairs spiked with N-oleoyl-D-erythro-C(17) sphingosine, an internal standard. Ceramide and dihydroceramide were resolved by TLC and deacylated by sphingolipid-ceramide deacylase to release sphingosine and dihydrosphingosine, respectively. The hair content of ceramide was measured by HPLC following derivatization with o-phthalaldehyde. The limits of detection and quantification for ceramide extracted from hair fibers were 0.1 and 1 pmol, respectively. The linear range of hair weight for determining ceramide and dihydroceramide contents was 1 to 50 mg, with R(2) values of 0.9695 and 0.9898, respectively. The recoveries of ceramide and dihydroceramide from intra-day and interday assays were 99.55% to 98.53%, respectively. Concentrations of dihydroceramide from the hair roots to distal tip ends ranged from 10.42 +/- 2.19 to 1.20 +/- 0.11 nmol/g hair, while those of ceramide ranged from 2.27 +/- 0.22 to 1.47 +/- 0.15 nmol/g hair. The present analytical method provides a simultaneous and reproducible quantification of ceramide and dihydroceramide, and may be used as a potential biomarker for lipid abnormality-related diseases. PMID- 20162411 TI - [Lie detection and mind reading: is there a use for fMRI?: A critical survey and reflection]. AB - Great efforts have been made in recent years to use functional magnetic resonance imaging (fMRI) in the context of lie detection. In the present paper the pros and cons of such an approach are analyzed and critically discussed.Both epistemological and methodical considerations have shown that all attempts to derive mental states from fMRI findings ("reverse inference") are not valid. Consequently, fMRI scans cannot reveal a person's thoughts and whether (s)he is lying or telling the truth. PMID- 20162412 TI - Neurodegenerative influence of oxidative stress in the retina of a murine model of diabetes. AB - AIMS/HYPOTHESIS: Diabetic retinopathy is a progressive neurodegenerative disease, but the underlying mechanism is still obscure. Here, we focused on oxidative stress in the retina, and analysed its influence on retinal neurodegeneration, using an antioxidant, lutein. METHODS: C57BL/6 mice with streptozotocin-induced diabetes were constantly fed either a lutein-supplemented diet or a control diet from the onset of diabetes, and their metabolic data were recorded. In 1-month diabetic mice, reactive oxygen species (ROS) in the retina were measured using dihydroethidium and visual function was evaluated by electroretinograms. Levels of activated extracellular signal-regulated kinase (ERK), synaptophysin and brain derived neurotrophic factor (BDNF) were also measured by immunoblotting in the retina of 1-month-diabetic mice. In the retinal sections of 4-month-diabetic mice, histological changes, cleaved caspase-3 and TUNEL staining were analysed. RESULTS: Lutein did not affect the metabolic status of the diabetic mice, but it prevented ROS generation in the retina and the visual impairment induced by diabetes. ERK activation, the subsequent synaptophysin reduction, and the BDNF depletion in the diabetic retina were all prevented by lutein. Later, in 4-month diabetic mice, a decrease in the thickness of the inner plexiform and nuclear layers, and ganglion cell number, together with increase in cleaved caspase-3- and TUNEL-positive cells, were avoided in the retina of lutein-fed mice. CONCLUSIONS/INTERPRETATION: The results indicated that local oxidative stress that has a neurodegenerative influence in the diabetic retina is prevented by constant intake of a lutein-supplemented diet. The antioxidant, lutein may be a potential therapeutic approach to protect visual function in diabetes. PMID- 20162413 TI - Unbalanced reporting of benefits and harms in abstracts on rofecoxib. AB - PURPOSE: It was predicted from the mechanism of action that, compared to older non-steroidal anti-inflammatory drugs, rofecoxib (Vioxx) would reduce gastrointestinal bleeding, but also that it would increase the occurrence of cardiovascular thrombosis. From the patient's point of view, both effects are important and should be investigated and reported similarly. We studied how they have been reported over time. METHODS: We searched PubMed for abstracts on rofecoxib that commented on gastrointestinal bleeding or cardiovascular thrombosis or both. Two researchers, blinded to date of publication and authors, assessed the abstracts independently. We judged the authors' view on rofecoxib and comments on gastrointestinal bleeding and thrombosis as being favourable, neutral or unfavourable towards rofecoxib. RESULTS: We included 393 abstracts commenting on gastrointestinal bleeding (72%) and cardiovascular thrombosis (54%) or both. Before October 2000, all abstracts (n = 27) mentioned only gastrointestinal bleeding and 89% were positive towards rofecoxib. The year before the withdrawal of rofecoxib (October 2003 to September 2004) (n = 46), 59% of abstracts commented on gastrointestinal bleeding only, 17% on thrombosis only, 24% on both and 67% were still positive. From October 2006 to September 2007 (n = 54), 13% mentioned gastrointestinal bleeding, 54% thrombosis, 33% mentioned both and only 11% were positive. CONCLUSIONS: The reporting of benefits and harms was not balanced and changed markedly over time. Knowledge of increased risk of thrombosis existed early on, but the harms came into focus too late, when the drug was already withdrawn, and when tens of thousands of patients had been harmed unnecessarily. PMID- 20162414 TI - Immunoglobulin heavy chain diversity in Pteropid bats: evidence for a diverse and highly specific antigen binding repertoire. AB - Bats are the natural host reservoir for range of emerging and re-emerging viruses, many of which cause significant morbidity and mortality in other mammals, yet appear to result in no clinical consequences for bats. The ability of bats to coexist with a variety of viruses presents an interesting immunological problem that has not been examined in any detail but which could provide significant insights into the evolution of antiviral mechanisms in mammals. Towards a better understanding of the bat immune system, we analysed the expressed heavy chain variable (VH) regions of antibodies from the black flying fox, Pteropus alecto. The germline repertoire of the closely related Pteropid bat, Pteropus vampyrus, whose genome has been sequenced was also examined for comparative purposes. Representative VH genes were found in all three mammalian VH clans (I, II and III) in both the expressed P. alecto VH repertoire and the germline P. vampyrus VH repertoire. Evidence for the use of multiple heavy chain diversity (DH) and joining (JH) segments for the generation of diverse VDJ rearrangements was also present in the expressed antibody repertoire of P. alecto. The long period of co-evolutionary history of bats with viruses may have resulted in a variety of highly specific VH segments being hardwired into the genomes of bats and may have implications for their ability to successfully cope with a diversity of viral antigens. PMID- 20162415 TI - Clinical application of locked plating system in children. An orthopaedic view. AB - In recent years, the locked plating system has gained favour in the treatment of certain fractures in adults; however, there is not much information regarding its use in children. We think there could be some advantages and applications such as: an alternative to external fixation, the bridge plating technique, unicortical screws, removal of hardware, metadiaphyseal fractures, periarticular fractures, poor quality bone, and allograft fixation. However, there are some disadvantages to keep in mind and the final decision for using it should be based on the osteosynthesis method principle the surgeon would like to apply. In this review article we discuss the up-to-date possible clinical applications and issues of this system. PMID- 20162416 TI - Treatment of articular cartilage lesions of the knee. AB - Treatment of articular cartilage lesions in the knee remains a challenge for the practising orthopaedic surgeon. A wide range of options are currently practised, ranging from conservative measures through various types of operations and, recently, use of growth factors and emerging gene therapy techniques. The end result of these methods is usually a fibrous repair tissue (fibrocartilage), which lacks the biomechanical characteristics of hyaline cartilage that are necessary to withstand the compressive forces distributed across the knee. The fibrocartilage generally deteriorates over time, resulting in a return of the original symptoms and occasionally reported progression to osteoarthritis. Our purpose in this study was to review the aetiology, pathogenesis and treatment options for articular cartilage lesions of the knee. At present, autologous cell therapies, growth factor techniques and biomaterials offer more promising avenues of research to find clinical answers. PMID- 20162417 TI - Variation in the position, relation and vasculature of left suprarenal gland: a case report. AB - A malposition of the left suprarenal gland with varied relations and vasculature was observed in a 50-year-old male cadaver during the routine dissection of the abdominal region. The gland was partly situated over the hilum of the left kidney. Its posterior surface was related to the left crus of the diaphragm and to the hilum of the left kidney extending some distance above on the medial margin of the kidney. Its anterior surface was totally covered by the body of the pancreas and the splenic artery and vein. There were only two suprarenal arteries. A left lateral branch of the aorta divided into three branches of which the middle and inferior branches entered the gland as seperate suprarenal arteries. There were the two suprarenal veins of the gland which were draining into the left renal vein. Such a malposition with varied relations and vasculature is of utmost importance from the surgical point of view because it can affect the orientation of the surgeon in laparoscopic adrenalectomy. PMID- 20162418 TI - Classical and resource-based competition: a unifying graphical approach. AB - A graphical technique is given for determining the outcome of two species competition for two resources. This method is unifying in the sense that the graphical criterion leading to the various outcomes of competition are consistent across most of the spectrum of resource types (from those that fulfill the same growth needs to those that fulfill different needs) regardless of the classification method used, and the resulting graphs bear a striking resemblance to the well-known phase portraits for two species Lotka-Volterra competition. Our graphical method complements that of Tilman. Both include zero net growth isoclines. However, instead of using the consumption vectors at potential coexistence equilibria to determine input resource concentrations leading to specific competitive outcomes, we introduce curves bounding the feasible set (the set where the resource concentrations of any equilibrium solution must be located). The washout equilibrium (corresponding to the supply point) occurs at an intersection of curves defining the feasible set boundary. The resource concentrations of all other equilibria are found where zero net growth isoclines either intersect each other inside the feasible set or they intersect the feasible set boundary. A species has positive biomass at such an equilibrium only if its zero net growth isocline is involved in such an intersection. The competitive outcomes are then determined from the position of the single species equilibria, just as in the phase portrait analysis for classical competition (rather than from information at potential coexistence equilibria as in Tilman's method). PMID- 20162419 TI - Prevalance of latex sensitization and associated risk factors in Turkish children with spina bifida. AB - PURPOSE: Among children with spina bifida there is a high prevalence of latex allergy in reports from Europe and USA. The aim of this study was to investigate the incidence of latex sensitization and associated risk factors in children with spina bifida in Middle-Eastern region (Istanbul, Turkey). MATERIALS AND METHODS: Eighty consecutive children affected with spina bifida were included in the study. Data were collected about age, sex, family and personal history of atopy, and the number and type of operations classified as neurosurgical, urological, and orthopedic. All patients underwent skin prick test using latex solutions and cross-reacting foods. Total and latex-specific IgE levels were also measured. RESULTS: Latex sensitization was shown in 16% (13/80) of the patients with specific IgE > 0.7 kU/L. The number of operation, using intermittent bladder catheterization and ventricular-peritoneal shunt were significantly associated with latex sensitization. CONCLUSION: The incidence of latex sensitization in this study was lower than reported in the literature. Environmental factors such as the type and number of operations and geographical location may play a role in the development of latex sensitization. PMID- 20162420 TI - Effects of bioflavonoids in the management of subclinical varicocele. AB - BACKGROUND: Subclinical varicocele is a relative rare condition. The aim of this study is to identify the role of bioflavonoids in the management of subclinical varicocele. MATERIALS AND METHODS: We analyzed the medical charts of patients treated for subclinical varicocele with bioflavonoids between 1999 and 2004; inclusion criteria were created before treatment. Short and long-term results after treatment were studied and compared with untreated patients. RESULTS: One hundred and sixty-eight patients with left subclinical varicocele were included in the study. Long-term results showed a possible correlation between use of bioflavonoids and lesser rate of clinical progression to palpable varicocele (11 vs. 31%), higher rate of stable vein reflux (47 vs. 38%) and higher resolution rate (41 vs. 31%) (p > 0.05). Bioflavonoids did not show any protective factor against testicular growth arrest. CONCLUSIONS: Subclinical varicocele should be considered as the starting point of varicocele, and although the use of bioflavonoids in patients with subclinical varicocele could reduce the development of palpable varicocele, it cannot prevent the onset of testicular growth arrest. PMID- 20162421 TI - Contribution of laparoscopy in the abdominal tuberculosis diagnosis: retrospective study of about 11 cases. AB - OBJECTIVE: Abdominal tuberculosis is one of the most frequent extra-pulmonary localizations. Its diagnosis is difficult and may lead to a delayed prescription of specific treatment. This study is aimed at stressing the role of laparoscopy associated with a biopsy in the diagnostic confirmation of abdominal tuberculosis particularly in doubtful cases. METHODS: The diagnostic features of 11 cases hospitalized for abdominal tuberculosis in the Paediatric Surgery Department of Fattouma Bourguiba Hospital in Monastir for a 6-year period (2001-2006), were evaluated retrospectively. The diagnosis of abdominal tuberculosis was substantiated histopathologically by laparoscopy in all cases. The epidemiological and clinical characteristics along with the laboratory, radiological and histological data were studied. RESULTS: Eleven cases of abdominal tuberculosis with a mean age of 5.6 years were diagnosed. It was peritoneal tuberculosis in all cases and associated with intestinal localization in one case. A conversion to laparotomy was practiced in three patients: appendicular plastron in one case, pseudo-tumor aspect of an intestinal loop in another case and because of their pathological aspect appendicectomy and caecum biopsy in the third. The diagnosis was confirmed histologically by biopsies in nine cases and on excision pieces in the other two cases. All patients had an uneventful course with an antituberculosis treatment. CONCLUSION: Abdominal tuberculosis is still frequent in Tunisia. Because of its non-specific clinical presentation and the limited means of investigation, a laparoscopy with biopsy should be practiced as first line diagnostic tool in case of doubtful abdominal tuberculosis. The earlier the diagnosis is established and an adapted antituberculosis treatment is started, the better the prognosis is. PMID- 20162422 TI - Differential expression of the chemokines GRO-2, GRO-3, and interleukin-8 in colon cancer and their impact on metastatic disease and survival. AB - BACKGROUND AND AIM: Chemotactic cytokines play a role in angiogenesis and attraction of immune cells. However, their contribution to tumor formation remains incompletely understood. In a previous transcriptome study, we identified a family of structurally related chemokines of the CXC-family to be specifically up-regulated in colorectal cancer. The aim of the present study was to investigate the regulation of their expression in colon cancer cells and to test the hypothesis that altered CXC-chemokine expression is related to critical clinical parameters, such as survival or metastasis formation. MATERIALS AND METHODS: Expression levels of interleukin-8 (CXCL-8) and growth-related oncogenes 2 and 3 (GRO-2/CXCL-2 and GRO-3/CXCL-3) were quantified using qRT-PCR in 97 patients with completely resected colon carcinoma and correlated with clinical parameters. Moreover, 16 samples of normal mucosa, nine samples of benign adenoma, and 11 samples of liver metastasis were analyzed. Next, the regulation of chemokine expression in response to various stimuli was tested in colon cancer cell lines (HT29, HCT116, CaCO2). RESULTS: Expression of GRO-2, GRO-3, and IL-8 was significantly increased in colon cancer as compared to normal colon tissue. Expression of GRO-2 and GRO-3 was already enhanced in premalignant adenomas, and GRO-3 was significantly down-regulated in liver metastasis as compared to the primary tumor. Importantly, expression of GRO-3 was significantly higher in patients with local versus systemic disease. Moreover, IL-8 expression was significantly associated to overall post-operative survival. Finally, all chemokines were strongly induced by IL-1alpha in the colon cancer cell lines tested, indicating a potential link to inflammatory processes. CONCLUSION: In accordance with earlier findings, we report here a significantly increased expression of GRO-2, GRO-3, and IL-8 in colon carcinoma as compared to normal tissue. Furthermore, GRO-3 was related to metastasis formation, and IL-8 was associated with survival, suggesting a potential predictive power of these markers. PMID- 20162424 TI - Sacral nerve stimulation for constipation: do we still miss something? Role of psychological evaluation. AB - INTRODUCTION: The aim of this study was to try to understand if psychological evaluation of patients candidate to sacral nerve stimulation (SNS) could be a potential selection criterion to identify those patients who could successfully respond to this treatment. MATERIALS AND METHODS: From 2005 to 2007, 68 patients with slow transit constipation were identified, and all of them fulfill the selection criteria for the SNS treatment. The MMPI-2 test was purposed to all the patients. Wexner score, bowel movements, and SF36 were recorded in all the patients. RESULTS: Twenty-three patients (33.8%) refused the psychological evaluation. Forty-five patients completed the test: only 13 patients (19.1%) had a score in the normal range of the scales of the MMPI-2 and were implanted with the temporary test for SNS. After the screening period, 11 patients (84.6%) reported more than 50% improvement of bowel movements per week and no need of laxatives, so they were definitively implanted. The mean follow-up period was 22 months (range 12-36). The mean number of bowel movements per week and Wexner score were significantly improved after 1 year (p < 0.001). CONCLUSIONS: A complete and accurate psychological evaluation could be very important in the selection of the patients with STC that could benefit from SNS. PMID- 20162423 TI - The role of laparoscopic surgery for ulcerative colitis: systematic review with meta-analysis. AB - PURPOSE: Crohn's disease is established in laparoscopic surgery due to partial bowel dissection and low postoperative complication rate. However, laparoscopic surgery for ulcerative colitis remains further discussed even if the trend of minimally invasive technique exists. This study is to figure out how laparoscopic surgery works for ulcerative colitis. METHODS: Sixteen controlled trials were identified through the search strategy mentioned below. There was only one prospective randomized study among the studies selected. A meta-analysis pooled the outcome effects of laparoscopic surgery and open surgery was performed. Fixed effect model or random effect model was respectively used depending on the heterogeneity test of trials. RESULTS: Postoperative fasting time and postoperative hospital stay were shorter in laparoscopic surgery for ulcerative colitis (-1.37 [-2.15, -0.58], -3.22 [-4.20, -2.24], respectively, P < 0.05). Overall complication rate was higher in open surgery, compared with laparoscopic surgery (54.8% versus 39.3%, P = 0.004). However, duration of laparoscopic surgery for ulcerative colitis was extended compared with open surgery (weighted mean difference 69.29 min, P = 0.04). As to recovery of bowel function, peritoneal abscess, anastomotic leakage, postoperative bowel obstruction, wound infection, blood loss, and mortality, laparoscopic surgery did not show any superiority over open surgery. Re-operation rate was almost even (5.2% versus 7.3%). The whole conversion to open surgery was 4.2%. CONCLUSIONS: Laparoscopic surgery for ulcerative colitis was at least as safe as open surgery, even better in postoperative fasting time, postoperative hospital stay, and overall complication rate. However, clinical value of laparoscopic surgery for ulcerative colitis needed further evaluation with more well-designed and long-term follow-up studies. PMID- 20162425 TI - Lead time of carcinoembryonic antigen elevation in the postoperative follow-up of colorectal cancer did not affect the survival rate after recurrence. AB - BACKGROUND AND AIMS: The role of carcinoembryonic antigen (CEA) in the early detection of recurrence during the postoperative follow-up of colorectal cancer remains unclear. We hypothesize that the tumor with longer lead time of CEA elevation to the definite recurrence may have a better prognosis because of its slower growth rate and closer observation. MATERIALS AND METHODS: From 1995 to 2003, 4,841 consecutive patients who received curative resection of localized colorectal adenocarcinoma were enrolled from a prospective database. The patients with persisting CEA elevation after operation had been already excluded. Postoperative follow-up, including physical examination, imaging, and CEA test, were performed according to a surveillance program. A CEA >/=5 ng/mL was defined as elevated. The definition of the CEA lead time was the period between CEA elevation and detection of recurrence. All statistical analyses were performed by SPSS package for Windows (Microsoft, Redmond, WA, USA). RESULTS: The postoperative median follow-up time for the 4,841 patients was 68 months. A total of 999 patients (20.6%) had CEA elevation and recurrence. Among these patients, recurrence was confirmed in 727 patients (72.8%)before, at the same time, or within 3 months of CEA elevation and thus had a short lead time of CEA elevation (SLT group). In 272 patients (27.2%), recurrence was confirmed after more than 3 months of CEA elevation and thus had a longer lead time of CEA elevation (LLT group). The recurrence pattern showed similarities in these two groups. A total of 193 patients (193/999, 19.3%) received a second radical operation, and 806 patients (80.7%) were inoperable. The re-resection rate between the SLT group (146 patients, 20.1%) and the LLT group (47 patients, 17.3%) was not significantly different. The overall survival rate after recurrence showed no difference between these two groups (P = 0.123). CONCLUSION: Most cases of recurrence were detected at nearly the same time when the CEA level was elevated. Therefore, a more sensitive test is needed for early detection. The relationship between the lead time of CEA and the clinical outcome was not statistically significant. A more aggressive approach to the patient who has CEA elevation and is highly suspect of recurrence may be needed. PMID- 20162426 TI - What was new, interesting and frequently cited in 2009? PMID- 20162427 TI - Claude Francois Lallemand (1790-1854). PMID- 20162429 TI - A competitive integration model of exogenous and endogenous eye movements. AB - We present a model of the eye movement system in which the programming of an eye movement is the result of the competitive integration of information in the superior colliculi (SC). This brain area receives input from occipital cortex, the frontal eye fields, and the dorsolateral prefrontal cortex, on the basis of which it computes the location of the next saccadic target. Two critical assumptions in the model are that cortical inputs are not only excitatory, but can also inhibit saccades to specific locations, and that the SC continue to influence the trajectory of a saccade while it is being executed. With these assumptions, we account for many neurophysiological and behavioral findings from eye movement research. Interactions within the saccade map are shown to account for effects of distractors on saccadic reaction time (SRT) and saccade trajectory, including the global effect and oculomotor capture. In addition, the model accounts for express saccades, the gap effect, saccadic reaction times for antisaccades, and recorded responses from neurons in the SC and frontal eye fields in these tasks. PMID- 20162428 TI - Visual short-term memory binding in Alzheimer's disease and depression. AB - The differential diagnosis between Alzheimer's disease (AD) and major depression (MD) in the elderly can be problematic because the cognitive profile of the two conditions overlaps. Associative learning tasks seem to separate AD from MD. However, they are sensitive to the effects of normal ageing. Short-term memory binding tasks have proved insensitive to the effects of normal ageing and highly sensitive to AD. However, they have not been used to differentiate AD from MD. The present study was aimed at investigating visual short-term memory binding in AD and MD. Fourteen AD patients, 14 patients with MD, and 14 healthy older adults were asked to perform a visual short-term memory binding task that investigated the retention of shapes, colors, or combinations of shapes and colors. Participants were to recognize changes occurring between two consecutive displays either in a single dimension (i.e., shape or color only) or in two dimensions (i.e., shape-color binding). Short-term memory performance for shape or color only was equivalent across groups. The only significant effect found was in short term memory for shape-color binding and this was due to AD patients performing poorly in this condition only. The results extend previous findings in AD to visual short-term memory and suggest that the specific impairment in binding information in memory differentiates between the performance of AD and patients with MD. PMID- 20162430 TI - The role of dogs in transmission of Ascaris lumbricoides for humans. AB - The dog's role as a definitive host for a number of zoonotic parasites has been widely studied and recognized as being a significant public health problem worldwide. This study aimed to report, for the first time, our investigation into the role of dogs as a biological transmitter for Ascaris lumbricoides, via necropsy of a sample of rural stray dogs in a developing community in Giza governorate, Egypt, where promiscuous defecation by human was common, and examination for A. lumbricoides worms as well as other ascaridiod nematodes of dogs. The recovered worms were identified in the laboratory after observing cephalic alae and egg morphology under a microscope, as well as scanning electron microscopy of their anterior ends. Of the 25 dogs examined, 14 were infected with Toxocara canis (56.0%), two with Toxascaris leonina (8.0%), and two with A. lumbricoides (8.0%). One dog was co-infected with T. canis and T. leonina. A. lumbricoides eggs were shown to be viable and 75-80% of eggs embryonated following 3 weeks of incubation at 28 degrees C. The present study suggested that dogs could act as reservoir hosts of A. lumbricoides and environmental contaminators that increase risk of infection in humans. PMID- 20162431 TI - Molecular characterizations of an inhibitor of apoptosis from Schistosoma japonicum. AB - Apoptosis is a normal process for regulating cellular death of many organisms. Here, we molecularly characterized an inhibitor of apoptosis from Schistosoma japonicum (SjIAP). The transcription of the SjIAP predominantly occurred at the developmental stages in a final host. Functional assay indicated that the SjIAP could inhibit caspase activity either in 293T cell or in schistosome lysates. Additionally, there were differently expressed profiles of the SjIAP in S. japonicum living in different hosts. Our preliminary results suggest that the SjIAP may play important roles in parasitic living and development as well as in the host-parasite interactions, and drug target of SjIAP might be a potential for controlling schistosomiasis. PMID- 20162432 TI - Insecticidal, acaricidal and repellent effects of DEET- and IR3535-impregnated bed nets using a novel long-lasting polymer-coating technique. AB - A novel long-lasting repellent-treated net (LLRTN) has been designed by binding the skin repellents N,N-diethyl-m-toluamide (DEET), or IR3535, onto the fibres of bed net fabric using a new polymer-coating technique. The repellent toxicological effectiveness and residual activity of a factory-based repellent-impregnated fabric has been evaluated by laboratory testing against adult Aedes aegypti mosquitoes and nymphal Ixodes ricinus ticks. By using this repellent-embedding impregnation technique, concentrations exceeding 10 g/m(2) could be achieved with one single polymer layer. Both DEET- and IR3535-impregnated fabrics revealed a dose-dependent insecticidal as well as acaricidal activity. One hundred percent knockdown times of DEET-treated bed nets ranged from 187.5 +/- 31.8 to 27.5 +/- 3.5 min against A. aegypti, and between 214 +/- 47 and 22.6 +/- 5 min against nymphal I. ricinus, linked to a DEET concentration of 1.08 and 10.58 g/m(2), respectively. With IR3535, A. aegypti produced dose-dependent 100% knockdown times varying from 87.5 +/- 10.6 to 57.5 +/- 3.5 min and between 131.4 +/- 6.5 and 33.8 +/- 5 min against nymphal I. ricinus, respectively, linked to concentrations between 1.59 and 10.02 g/m(2). One hundred percent repellency measured by complete landing and biting protection of impregnated fabric by using the arm-in-cage test could be achieved at DEET concentrations exceeding 3.7 to 3.9 g/m(2), and for IR3535 concentrations over 10 g/m(2). One hundred percent landing and biting protection could be preserved with DEET-treated fabrics for 29 weeks at an initial concentration of 4.66 g/m(2), 54 weeks at 8.8 g/m(2), 58 weeks at 9.96 g/m(2) and 61 weeks at 10.48 g/m(2) for DEET, and 23 weeks for IR3535-treated fabric at a concentration of 10.02 g/m(2). Unlike repellent treated fabric, a brand of a commercially available long-lasting insecticide treated net tested containing 500 mg permethrin/m(2) did not protect from mosquito bites. First results on bioactivity and long-lasting efficacy show that the new LLRTN technique is highly promising as a potential candidate for future malaria control strategies, especially in areas where pyrethroid resistance occurs. PMID- 20162433 TI - Schizonts of Theileria annulata interact with the microtubuli network of their host cell via the membrane protein TaSP. AB - Intracellular leukoproliferative Theileria are unique as eukaryotic organisms that transform the immune cells of their ruminant host. Theileria utilize the uncontrolled proliferation for rapid multiplication and distribution into host daughter cells. The parasite distribution into the daughter cells is accompanied by a tight association with the host cell mitotic apparatus. Since the molecular basis for this interaction is largely unknown, we investigated the possible involvement of the immunodominant Theileria annulata surface protein, TaSP, in the attachment of the parasite to host cell microtubule network. Confocal microscopic analyses showed co-localization of the TaSP protein with alpha tubulin and reciprocal immuno-co-precipitation experiments demonstrated an association of TaSP with alpha-tubulin in vivo. In addition, the partially expressed predicted extracellular domain of TaSP co-localized with the mitotic spindle of dividing cells and was co-immunoprecipitated with alpha-tubulin in transiently transfected Cos-7 cells devoid of other T. annulata expressed proteins. Pull-down studies showed that there is a direct interaction between TaSP and polymerized microtubules. Analysis of the interaction of TaSP and host microtubulin during host cell mitosis indicated that TaSP co-localizes and interacts with the spindle poles, the mitotic spindle apparatus and the mid-body. Moreover, TaSP was demonstrated to be localized to the microtubule organizing center and to physically interact with gamma-tubulin. These data support the notion that the TaSP-microtubule interaction may be playing a potential role in parasite distribution into daughter host cells and give rise to the speculation that TaSP may be involved in regulation of microtubule assembly in the host cell. PMID- 20162434 TI - FY polymorphisms and vivax malaria in inhabitants of Amazonas State, Brazil. AB - Although the importance of glycoprotein Duffy in the human red cells invasion process by Plasmodium vivax merozoites has been demonstrated, little is known about the associations of FY polymorphisms with malaria vivax parasitic density. In this study, we investigated the associations of the SNPs 125 G>A, 265 C>T, and 298 G>A on FY gene and the SNP -33T>C on GATA box with the vivax malaria parasitic density in inhabitants of Amazon State, Brazil. Verifications of P. vivax, as well as the definition of parasitism, were determined by standard screening tests in 497 patients. FY phenotyping was performed in all samples by hemagglutination using gel cards. Molecular analysis for FY/GATA polymorphisms were performed by polymerase chain reaction-restriction fragment length polymorphism. Our data showed that in this population, FY*A/FY*B-33 and FY*B/FY*B 33 genotypes may be a selective advantage, reducing the frequency of P. vivax infection in the studied area. FY*A/FY*B and FY*A/FY*A genotypes showed to be associated with the rise of the frequency of P. vivax infection, and FY*B/FY*X and FY*A/FY*X showed to be associated with the low levels of parasitism. These results suggest that natural adaptations, in malaria-endemic regions, could be leading to the arising of partial defense mechanisms against P. vivax, which is different from the previously described in African descents, as well as adaptations that could be increasing the susceptibility of human to this kind of malaria. PMID- 20162435 TI - Low-dose but not high-dose prostaglandin E(1) improves the histological outcome of severe forebrain ischemia in rats. AB - PURPOSE: Prostaglandin E(1) (PGE(1)) has been shown to provide short-term neuroprotection against various types of brain ischemia in a dose-dependent manner in mice. However, these findings were obtained from experiments performed without any control over physiological parameters. We performed an outcome study where physiological parameters were controlled in an attempt to confirm the dose dependant neuroprotective effects of PGE(1). METHODS: A rat model of severe forebrain ischemia was used. Two doses of PGE(1) were administered during the pre ischemic period, a low dose (LowPG group) and a high dose (HighPG group). Normotension was maintained in the LowPG group, while hypotension was induced in the HighPG group. In separate groups, normal saline (Control) or sodium nitroprusside (SNP) were infused to compare outcomes under similar blood pressure conditions. Histological outcomes in the hippocampal CA1 and entorhinal cortex were evaluated 5 days post-ischemia. RESULTS: HighPG resulted in hyperglycemia. The percentage of dead neurons in the hippocampal CA1 and entorhinal cortex were similar in the Control, SNP, and HighPG groups, the percentage being significantly attenuated in the LowPG group (CA1: Control = 92.8 +/- 2.4%, LowPG = 85.0 +/- 8.5%, HighPG = 95.3 +/- 2.4%, and SNP = 96.4 +/- 0.7%, P < 0.01; entorhinal cortex: Control = 73.8 +/- 4.0%, LowPG = 53.2 +/- 12.3%, HighPG = 72.1 +/- 12.6%, and SNP = 76.5 +/- 4.1%, P < 0.01). CONCLUSION: Pre-ischemic administration of low-dose PGE(1) in rats provided neuroprotection against severe forebrain ischemia. A dose dependency was not observed with PGE(1) dose and outcome. PMID- 20162436 TI - Urinary levels of cross-linked N-terminal telopeptide of type I collagen and nutritional status in Japanese professional baseball players. AB - The objective of the present study was to investigate the nutritional status from the aspect of bone metabolism in Japanese elite male athletes with increased bone resorption. Urinary levels of a bone resorption marker, cross-linked N-terminal telopeptide of type 1 collagen (NTX), were measured in 71 professional baseball players (age, 18-39 years); the mean urinary NTX level was 65.6 (range, 17.5 269.0) nM BCE/mM Cr. Of 71 athletes, 9 with high levels of urinary NTX (greater than mean + 1 SD) were examined by measuring serum biochemical markers and nutritional assessment (simple food frequency questionnaire). Serum biochemical marker analysis showed that 7 of these 9 athletes had vitamin D insufficiency, as indicated by low serum levels of 25-hydroxyvitamin D, and that all 9 athletes showed vitamin K insufficiency as indicated by low levels of vitamins K(1) and K(2). Nutritional assessment revealed high intakes of protein and low intakes of calcium and vitamin D based on adequate intake (AI). However, daily vitamin K intake achieved the AI. These results suggest that there exist elite male athletes who show increased bone resorption and calcium and vitamin D insufficiency. However, there was a discrepancy between vitamin K intake and serum levels of vitamins K(1) and K(2). The present study raised an issue regarding the nutritional status from the point of view of bone metabolism in elite male athletes such as professional baseball players. PMID- 20162437 TI - Atypical, perhaps under-recognized? An unusual phenotype of Friedreich ataxia. AB - Friedreich ataxia (FRDA) is typically characterized by slowly progressive ataxia, depressed tendon reflexes, dysarthria, pyramidal signs, and loss of position and vibration sense with onset before 25 years. While several atypical forms of FRDA are recognized, profound vision deficit is rare. We describe here a 41-year-old man with profound vision deficit and episodic complete blindness associated with marked optic atrophy, spastic paraparesis, and sensory neuropathy without ataxia whose diagnostic evaluation revealed compound heterozygosity for two frataxin mutations, a 994 GAA repeat intronic expansion and c.389G > T (p.G130V) missense mutation. This case emphasizes that FRDA should be considered for individuals with significant vision deficit with optic atrophy and sensory neuropathy, even in the absence of ataxia. This case also raises the additional, related concern that prior studies may underestimate the frequency and varieties of variant forms of FRDA. PMID- 20162438 TI - Uncovering and improving upon the inherent deficiencies of radiology reporting through data mining. AB - Uncertainty has been the perceived Achilles heel of the radiology report since the inception of the free-text report. As a measure of diagnostic confidence (or lack thereof), uncertainty in reporting has the potential to lead to diagnostic errors, delayed clinical decision making, increased cost of healthcare delivery, and adverse outcomes. Recent developments in data mining technologies, such as natural language processing (NLP), have provided the medical informatics community with an opportunity to quantify report concepts, such as uncertainty. The challenge ahead lies in taking the next step from quantification to understanding, which requires combining standardized report content, data mining, and artificial intelligence; thereby creating Knowledge Discovery Databases (KDD). The development of this database technology will expand our ability to record, track, and analyze report data, along with the potential to create data driven and automated decision support technologies at the point of care. For the radiologist community, this could improve report content through an objective and thorough understanding of uncertainty, identifying its causative factors, and providing data-driven analysis for enhanced diagnosis and clinical outcomes. PMID- 20162439 TI - Perceived sufficiency of full-field digital mammograms with and without irreversible image data compression for comparison with next-year mammograms. AB - Problems associated with the large file sizes of digital mammograms have impeded the integration of digital mammography with picture archiving and communications systems. Digital mammograms irreversibly compressed by the novel wavelet Access Over Network (AON) compression algorithm were compared with lossless-compressed digital mammograms in a blinded reader study to evaluate the perceived sufficiency of irreversibly compressed images for comparison with next-year mammograms. Fifteen radiologists compared the same 100 digital mammograms in three different comparison modes: lossless-compressed vs 20:1 irreversibly compressed images (mode 1), lossless-compressed vs 40:1 irreversibly compressed images (mode 2), and 20:1 irreversibly compressed images vs 40:1 irreversibly compressed images (mode 3). Compression levels were randomly assigned between monitors. For each mode, the less compressed of the two images was correctly identified no more frequently than would occur by chance if all images were identical in compression. Perceived sufficiency for comparison with next-year mammograms was achieved by 97.37% of the lossless-compressed images and 97.37% of the 20:1 irreversibly compressed images in mode 1, 97.67% of the lossless compressed images and 97.67% of the 40:1 irreversibly compressed images in mode 2, and 99.33% of the 20:1 irreversibly compressed images and 99.19% of the 40:1 irreversibly compressed images in mode 3. In a random-effect analysis, the irreversibly compressed images were found to be noninferior to the lossless compressed images. Digital mammograms irreversibly compressed by the wavelet AON compression algorithm were as frequently judged sufficient for comparison with next-year mammograms as lossless-compressed digital mammograms. PMID- 20162440 TI - Programming in the small. AB - Academic medical centers, in general, and radiation oncology research, in particular, rely heavily on custom software tools and applications. The code development is typically the responsibility of a single individual or at most a small team. Often these individuals are not professional programmers but physicists, students, and physicians. While they possess domain expertise and algorithm knowledge, they often are not fully aware of general "safe coding" practices--nor do they need the full complexity familiar in large commercial software projects to succeed. Rather, some simple guidelines we refer to as "programming in the small" can be used. PMID- 20162441 TI - Isolation and characterization of a novel zinc finger gene, ZNFD, activating AP1(PMA) transcriptional activities. AB - ZFPs (Zinc Finger Proteins) play important roles in various cellular functions, including transcriptional activation, transcriptional repression, cell proliferation, and development. C(2)H(2) (Cys-Cys-His-His motif) ZFPs are the most abundant proteins among the founding members of the ZFP super family in eukaryotes. In this study, we isolate a novel C(2)H(2) ZNF (Zinc Finger) gene ZNFD. It contains an ORF (Open Reading Frame) with a length of 990 bp, encoding 329 amino acids. The predicted protein contains a C(2)H(2) zinc finger. RT-PCR analysis in 18 human adult tissues indicated that it was expressed in five human adult tissues. Green fluorescence protein localization analysis showed that human ZNFD was located in the nucleus of Hela cells. Overexpression of ZNFD in the COS7 cells activates the transcriptional activities of AP1(PMA) (Activator of protein 1, that responds specifically to phorbol ester). Together the data indicate that ZNFD is probably a new type of C(2)H(2) ZFP and the ZNFD protein may act as a transcriptional activator in PKC (protein kinase C) signal pathway to mediate cellular functions. PMID- 20162442 TI - Treatment utilization of pathological gamblers with and without PTSD. AB - This paper represents the first study of treatment utilization among pathological gamblers with and without PTSD. Comorbidity of PG and PTSD is increasingly recognized as an important association, both in its rate and clinical severity. The sample comprised 106 adults from the community (35 with current PG; 36 with current PTSD, and 35 with BOTH). Four areas were addressed: current treatment utilization, lifetime treatment utilization, specific treatments utilized, and satisfaction with treatments. Results indicated that the presence of PTSD was associated with higher treatment utilization (for current utilization, PTSD was higher than PG; and for lifetime, PTSD and PTSD/PG were both higher than PG). Indeed, only a minority of the PG group had ever attended current or lifetime treatment, whereas the majority of PTSD and PTSD/PG had. Yet notably, those with PG who utilized current treatment had no less satisfaction, number of treatment types, nor number of days in treatment than the other two groups. For all three groups, the most common current treatments were individual therapy and psychiatric medications. Study strengths include a rigorously diagnosed sample; an extensive interview-based assessment of treatment utilization, and identification of both current and lifetime utilization. Limitations include the inability to explore change over time or test-retest reliability of responses. PMID- 20162443 TI - A truly new view from the summit: from translational science to outcomes research in clinical arrhythmology. PMID- 20162444 TI - Fatty acid percentage in erythrocyte membranes of atrial flutter/fibrillation patients and controls. AB - PURPOSE: Several epidemiological published data support the protective role of omega-3 consumption in coronary artery disease, sudden cardiac death and ventricular arrhythmias, but interestingly, this is not the case for atrial arrhythmias. The purpose of this study is to evaluate different fatty acid profile between AF/AFL subjects and healthy controls. METHODS: Gas chromatography was employed to determine fatty acid percentage of erythrocyte membranes from 40 idiopathic AFL/AF patients and 53 healthy control subjects. RESULTS: AFL/AF erythrocyte membranes had significantly lower percentage of saturated fatty acid (43.1 +/- SD2.2 versus 47.8 +/- SD9.6, p < 0.001), monounsaturated fatty acid (18.2 +/- SD2.5 versus 22.6 +/- SD5.2, p < 0.001) and total trans fatty acid (0.2 +/- SD0.1 vs 1.3 +/- SD1.1, p < 0.001) than controls. Furthermore, fatty acid (FA) profiles of arrhythmic individuals showed an increased percent of total polyunsaturated fatty acid (PUFA) (36.7 +/- SD2.4 versus 26.4 +/- SD10.4, p < 0.001), PUFA n-3 (5.3 +/- SD1.1 versus 2.8 +/- SD1.8, p < 0.001) and n-6 (31.4 +/ SD2.2 versus 23.5 +/- SD9.9, p < 0.001). CONCLUSION: This study shows that the erythrocyte membranes FA composition of AF/AFL subjects differs from that of healthy controls. PMID- 20162445 TI - HC-Pro, a potyvirus RNA silencing suppressor, cancels cycling of Cucumber mosaic virus in Nicotiana benthamiana plants. AB - The mixed infection of Cucumber mosaic virus (CMV) and a potyvirus has been known to increase CMV titer in Nicotiana benthamiana plants, resulting in synergistic viral symptoms. We found that among three potyviruses--Potato virus Y (PVY), Turnip mosaic virus (TuMV), and Clover yellow vein virus (C1YVV)--synergistic effects on CMV (or a recombinant CMV vector) titers were most efficiently induced by a co-infection with PVY in N. benthamiana plants. In addition, the helper component-proteinase (HC-Pro) gene of PVY expressed by transgenic plants, which is a viral RNA silencing suppressor, was sufficient to cancel the cycling pattern of CMV titer, resulting in increased levels of overall CMV accumulation. Surprisingly, we found that the levels of CMV and the foreign protein expressed from the CMV vector were much higher in the HC-Pro-transgenic plants than the levels detected in the plants mixed-infected with CMV and PVY. The mechanism for canceling the cyclic infection of CMV by the HC-Pro protein alone is discussed in view of the interaction between RNA silencing and HC-Pro, as well as the possible involvement of the 3a protein. PMID- 20162446 TI - Complete nucleotide sequence and taxonomy of Sugarcane streak mosaic virus, member of a novel genus in the family Potyviridae. AB - The complete genomic sequence of a Pakistani isolate of Sugarcane streak mosaic virus (SCSMV-PAK) is determined to be 9782 nucleotides in length, excluding the 3' poly(A) tail, and it comprises a large open reading frame encoding a polyprotein of 3130 amino acid residues. The deduced polyprotein is likely to be cleaved at nine putative protease sites by three viral proteases to ten mature proteins. Conserved motifs of orthologous proteins of other potyviruses are identified in corresponding positions of SCSMV-PAK. The genomic organization is virtually identical to the genera Ipomovirus, Potyvirus, Rymovirus, and Tritimovirus in the family Potyviridae. Sequence analyses indicate that the SCSMV PAK genomic sequence is different from those of Sugarcane mosaic virus and Sorghum mosaic virus, two viruses with very similar symptoms and host range to SCSMV-PAK. SCSMV-PAK shares 52.7% identity with Triticum mosaic virus (TriMV) and 26.4-31.5% identities with species of the existing genera and unassigned viruses in the Potyviridae at the polyprotein sequence level. Phylogenetic analyses of the polyprotein and deduced mature protein amino acid sequences reveal that SCSMV, together with TriMV, forms a distinct group in the family at the genus level. Therefore, SCSMV should represent a new genus, Susmovirus, in the Potyviridae. PMID- 20162448 TI - Evaluation of environmental impacts of Integrated Industrial Estate-Pantnagar through application of air and water quality indices. AB - Large-scale industrialization, population inflow, and rapid urbanization coupled with unfavorable meteorological conditions often induce significant degradation of urban environment. In order to assess the extent of environmental impacts due to establishment of the Integrated Industrial Estate-Pantnagar (IIE-Pantnagar), ambient air and groundwater were monitored from June 2007 to May 2008. Collected baseline information was normalized and interpreted with the application of air (AQI) and water quality indices (WQI). Among the pre-identified air pollutants, suspended particulate matter was found to be the principal culprit to deteriorate ambient air quality, with a maximum annual concentration of 418.5 MUg/m(3). Monthly average concentrations of respirable particulate matter (aerodynamic diameter < 10 MUm) also persist at a critical level with an annual maximum of 207.3 MUg/m(3). A segmented linear function with maximum operator concept was used to compute AQI, and the developed index was found well suitable to demonstrate temporal variations of ambient air quality. The computed AQI value for the selected study region varied from moderate (97.0) to very poor pollution level (309.2) in respect to developed air quality standards. Furthermore, an integrated WQI was developed comprising 9 parameters, and among all the 10 pre identified locations, the average groundwater quality was found acceptable in terms of Indian drinking water standards. The maximum WQI (70.6) was found at the Kichha Railway Station during summer months, revealing moderate pollution load. Industrial discharge from IIE-Pantnagar coupled with other industrial setup may hold responsible for such kind of degradation of water quality. In contrast, WQI computed at Rudrapur City demonstrate minimum (15.0-22.1) pollution load. For 95% of the monitoring period, the computed WQI was found acceptable for all selected locations with few exceptions. The application of WQI to assess temporal variations in groundwater quality was therefore found satisfactory. PMID- 20162447 TI - Characteristics of Epstein-Barr virus envelope protein gp42. AB - Epstein-Barr virus (EBV) glycoprotein 42 (gp42) is a membrane protein essential for fusion and entry of EBV into host B-lymphocytes. Gp42 is a member of the protein-fold family C-type lectin or lectin-like domains (CLECT or CTLD) and specifically is classified as a natural-killer receptor (NKR)-like CLECT. Literature review and phylogenetic comparison show that EBV gp42 shares a common structure with other NKR-like CLECTs and possibly with many viral CTLDs, but does not appear to exhibit some common binding characteristics of many CTLDs, such as features required for calcium binding. The flexible N-terminal region adjacent to the CTLD fold is important for binding to other EBV glycoproteins and for a cleavage site that is necessary for infection of host cells. From structural studies of gp42 unbound and bound to receptor and extensive mutational analysis, a general model of how gp42 triggers membrane fusion utilizing both the flexible N-terminal region and the CTLD domain has emerged. PMID- 20162449 TI - Nitrogen and phosphorus budgets for the Yucatan littoral: An approach for groundwater management. AB - Human activities have altered the balance of ecosystems to the detriment of natural environments. Eutrophication is a serious risk in Yucatan, a state in the eastern peninsula of Mexico where groundwater supplies the only freshwater to a karst shelf environment. While economic development in Yucatan is increasing, environmental awareness is lagging, and efficient waste treatment systems are lacking. To assess potential nitrogen and phosphorus inputs into the coastal zone of Yucatan, we analyzed government reports and the chemical composition of groundwater and aquaculture wastewater. Swine, poultry, and tourism are revealed as the main continental nutrient sources, while groundwater with high nitrate concentrations is the principal coastal nutrient source, a pattern similar to other river discharges around the world. This study demonstrates that environmental risk management practices must be implemented in the Yucatan region to protect groundwater quality. PMID- 20162450 TI - 17beta-estradiol combined with testosterone promotes chicken osteoblast proliferation and differentiation by accelerating the cell cycle and inhibiting apoptosis in vitro. AB - Medullary bone is a unique tissue in the long bones cavities of lay hens, and plays an important role as a calcium reservoir for egg-shell formation. Medullary bone formation requires the synergistic action of estrogen and androgen on osteoblasts during the early stage of sexual maturity. The objective of the current study was to investigate the effects of 17beta-estradiol, testosterone, and the combination on the proliferation, alkaline phosphatase (ALP) activity, apoptosis, the cell cycle of chicken osteoblasts in vitro. The proliferation of osteoblasts was examined with the MTT assay. Apoptosis and the cell cycle were assessed with flow cytometry. Either 17beta-estradiol (200 pg ml(-1)) or testosterone (100 pg ml(-1)) or the combination (100 pg ml(-1) each) significantly enhanced osteoblast proliferation and ALP activity, accelerated the osteoblast cell cycle, and stimulated osteoblast DNA synthesis in a period of 24 h. 17beta-estradiol, used alone or with testosterone, inhibited chicken osteoblast apoptosis; However, testosterone alone induced cell apoptosis. In conclusion, 17beta-estradiol combined with testosterone promoted osteoblast proliferation and ALP activity, accelerated the osteoblast cell cycle, inhibited osteoblast apoptosis. PMID- 20162451 TI - Determining relationships between physical health and spiritual experience, religious practices, and congregational support in a heterogeneous medical sample. AB - Previous research indicates that increased religiosity/spirituality is related to better health, but the specific nature of these relationships is unclear. The purpose of this study was to determine the relationships between physical health and spiritual belief, religious practices, and congregational support using the Brief Multidimensional Measure of Religiousness/Spirituality and the Medical Outcomes Scale Shortform-36. A total of 168 participants were surveyed with the following medical disorders: Cancer, Spinal Cord Injury, Traumatic Brain Injury, and Stroke, plus a healthy sample from a primary care setting. The results show that individuals with chronic medical conditions do not automatically turn to religious and spiritual resources following onset of their disorder. Physical health is positively related to frequency of attendance at religious services, which may be related to better health leading to increased ability to attend services. In addition, spiritual belief in a loving, higher power, and a positive worldview are associated with better health, consistent with psychoneuroimmunological models of health. Practical implications for health care providers are discussed. PMID- 20162452 TI - The impact of behaviors upon burnout among parish-based clergy. AB - Burnout has an important impact upon the professional satisfaction of clergy. Identifying protective behaviors that may prevent against burnout is important for the long-term emotional health of individual clergy as well as the wider church. This research reports findings among 358 parish-based clergy that identifies the prevalence of burnout and correlates this data with demographic risk factors and protective behaviors. Clergy who met criteria for burnout were younger, identified themselves as being depressed and unsatisfied with their spiritual life, and have endured a traumatic church placement. This research also suggests that having a variety of interests and activities outside of one's vocation may protect against burnout. In particular, behaviors that enhance relationships-such as seeking mentors and attending retreats-as well as pursuing outside activities-such as regular exercise and scholarly reading-protect against burnout. Further implications for the wider church are discussed. PMID- 20162453 TI - Phosphorylation of eIF2 alpha in Sf9 cells: a stress, survival and suicidal signal. AB - An analysis of the stress-induced phosphorylation of the alpha-subunit of eukaryotic initiation factor (eIF2alpha) involved in translation regulation, in the ovarian cells of Spodoptera frugiperda (Sf9) for its role in cell survival and death reveals that it stimulates casapase activation and cell death in the absence of BiP, a chaperone and stress marker of the endoplasmic reticulum (ER). While Phospho-JNK and GADD-153 levels are elevated in non-ER stress-induced eIF2alpha phosphorylation-mediated cell death, ATF4 levels are elevated both in response to ER and non-ER stress-induced eIF2alpha phosphorylation. Infection of Sf9 cells by wt and a mutant Deltapk2 baculovirus that harbor the anti-apoptotic p35 gene induces BiP expression. However, UV-induced eIF2alpha phosphorylation and caspase activation are mitigated more efficiently by wt, but not by Deltapk2 baculovirus that lacks pk2, an inhibitor of eIF2alpha kinase. z-VAD-fmk, a caspase inhibitor reduces the late stages, but not the initial stages of non-ER stress-induced eIF2alpha phosphorylation, thereby suggesting that eIF2alpha phosphorylation is a cause and consequence of caspase activation. The importance of BiP affecting the delicate balance between eIF2alpha phosphorylation-mediated cell survival and death is further supported by the findings that tunicamycin treated cells expressing BiP resist eIF2alpha phosphorylation-mediated cell death and addition of a purified recombinant mutant phosphomimetic form, but not wt eIF2alpha, stimulates caspase activation in cell extracts devoid of BiP. These findings therefore suggest that eIF2alpha phosphorylation is primarily a stress signal and evokes adaptive or apoptotic responses depending on its cellular location, changes in gene expression, coincident signaling activities, and inter protein interactions. PMID- 20162454 TI - Loss of SFRP1 expression is associated with aberrant beta-catenin distribution and tumor progression in mucoepidermoid carcinoma of salivary glands. AB - BACKGROUND: Cytoplasmic and nuclear accumulation of beta-catenin in mucoepidermoid carcinoma (MEC) is frequently noted, but the mechanism is unknown. METHODS: The methylation status of adenomatous polyposis coli (APC) and secreted frizzled-related proteins (SFRPs) was examined by methylation-specific polymerase chain reaction (MSP) assay. The association of SFRP1, beta-catenin, and cyclin D1 expression in MEC was evaluated by immunohistochemical staining. RESULTS: A high percentage of methylation in APC and the SFRP genes was found in MEC compared with adjacent normal tissues, in which SFRP1 (58.6%) was the most frequent methylated gene. Moreover, abundant expression of SFRP1 was noted in normal tissues, whereas reduced SFRP1 expression was detected in 71.7% (33/46) of MECs. There was significant association between methylation and reduced expression of SFRP1. Cytoplasmic/nuclear (C/N) beta-catenin and high cyclin D1 expression were found in 13/55 (23.6%) and 36/55 (65.5%) of cases, respectively. There was significant correlation between C/N beta-catenin expression and reduced SFRP1 expression (P = 0.009). In addition, SFRP1 and beta-catenin expression correlated with tumor malignancy index such as tumor grade and stage. Overall patient survival was significantly worse in patients with reduced SFRP1 and C/N beta catenin expression (P = 0.009 and P = 0.002, respectively). CONCLUSIONS: Methylation of the SFRP1 gene was the major cause of reduced SFRP1 expression. Reduced SFRP1 led to C/N accumulation of beta-catenin and was associated with tumor malignancy. Therefore, examination of SFRP1 expression and beta-catenin location could be useful predictors of tumor progression and prognosis in patients with MEC. PMID- 20162455 TI - Biobanking of human pancreas cancer tissue: impact of ex-vivo procurement times on RNA quality. AB - BACKGROUND: Tissue banking has become a major initiative at many oncology centers. The influence of warm ex-vivo ischemia times, storage times, and biobanking protocols on RNA integrity and subsequent microarray data is not well documented. METHODS: A prospective institutional review board-approved protocol for the banking of abdominal neoplasms was initiated at Memorial Sloan-Kettering Cancer Center in 2001. Sixty-four representative pancreas cancer specimens snap frozen at various ex-vivo procurement times (< or =10 min, 11-30 min, 31-60 min, >1 h) and banked during three time periods (2001-2004, 2004-2006, 2006-2008) were processed. RNA integrity was determined by microcapillary electrophoresis using the RNA integrity number (RIN) algorithm and by results of laser-capture microdissection (LCM). RESULTS: Overall, 42% of human pancreas cancer specimens banked under a dedicated protocol yielded RNA with a RIN of > or =7. Limited warm ex-vivo ischemia times did not negatively impact RNA quality (percentage of tissue with total RNA with RIN of > or =7 for < or =10 min, 42%; 11-30 min, 58%; 31-60 min, 33%; >60 min, 42%), and long-term storage of banked pancreas cancer biospecimens did not negatively influence RNA quality (total RNA with RIN of > or =7 banked 2001-2004, 44%; 2004-2006, 38%; 2006-2008, 50%). RNA retrieved from pancreatic cancer samples with RIN of > or =7 subject to LCM yielded RNA suitable for further downstream applications. CONCLUSIONS: Fresh-frozen pancreas tissue banked within a standardized research protocol yields high-quality RNA in approximately 50% of specimens and can be used for enrichment by LCM. Quality of tissues of the biobank were not adversely impacted by limited variations of warm ischemia times or different storage periods. This study shows the challenges and investments required to initiate and maintain high-quality tissue repositories. PMID- 20162456 TI - Positive expression of L1-CAM is associated with perineural invasion and poor outcome in pancreatic ductal adenocarcinoma. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) frequently invades and migrates along neural tissue, which results in local tumor recurrences, distant metastases, and poor prognosis. We evaluated whether L1 cell adhesion molecule (L1-CAM) and glial cell line-derived neurotrophic factor (GDNF) expression in PDAC correlated with neural invasion and overall survival on a large cohort of previously untreated patients. METHODS: L1-CAM and GDNF were examined by immunohistochemistry in pancreatic cancer tissue samples of 94 cases with PDAC on a tissue microarray. The molecular findings were correlated with pain, clinicopathologic characteristics, and overall survival in these patients. RESULTS: L1-CAM and GDNF were overexpressed in pancreatic cancer tissues compared with the adjacent normal tissues of pancreas. Positive L1-CAM expression was associated with node involvement (P = 0.007), vascular invasion (P = 0.012), perineural invasion (P = 0.001), and higher degree of pain (P = 0.005). In univariate analysis, tissue expression of L1-CAM was associated with poor survival (hazard ratio, 2.508; 95% confidence interval, 1.551-4.053; P < 0.001), and this was also significant in multivariate analysis (hazard ratio, 2.046; 95% confidence interval, 1.200-3.488; P = 0.009). Positive staining of GDNF, neural invasion, and vascular invasion were all statistically significantly related to unfavorable prognosis. CONCLUSIONS: Enhanced expression of L1-CAM may contribute to the pain syndrome and perineural invasion and may correlate with poor overall survival in human pancreatic cancer. PMID- 20162457 TI - Invasive lobular vs. ductal breast cancer: a stage-matched comparison of outcomes. AB - BACKGROUND: Invasive lobular breast cancer (ILC) is less common than invasive ductal breast cancer (IDC), more difficult to detect mammographically, and usually diagnosed at a later stage. Does delayed diagnosis of ILC affect survival? We used a national registry to compare outcomes of patients with stage matched ILC and IDC. METHODS: Query of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) tumor registry identified 263,408 women diagnosed with IDC or ILC between 1993 and 2003. Survival of patients matched by T and N stage was compared using Kaplan-Meier curves and log rank analysis. RESULTS: When compared with IDC, ILC was more likely to be >2 cm (43.1 vs. 32.6%; P < 0.001), lymph node positive (36.8 vs. 34.4%; P < 0.001), and ER positive (93.1 vs. 75.6%; P < 0.001). The 5-year disease-specific survival (DSS) was significantly better for patients with ILC than for those with IDC, before (90 vs. 88%; P < 0.001) and after matching for stage T1N0 (98 vs. 96%; P < 0.001), T2N0 (94 vs. 88%; P < 0.001), and T3N0 (92 vs. 83%, P < 0.001). The 5 year DSS for patients with nodal metastasis of ILC vs. IDC was 89% vs. 88% (P = NS) for stage T1N1, 81 vs. 73% (P < 0.001) for T2N1, and 72 vs. 56% (P < 0.001) for T3N1. Multivariate analysis identified a 14% survival benefit for ILC (hazard ratio 0.86, 95% confidence interval 0.80-0.92). CONCLUSIONS: Stage-matched prognosis is better for patients with ILC than for those with IDC. Our findings support a different biology for ILC and are important for counseling and risk stratification. PMID- 20162458 TI - Impact of omission of axillary lymph node dissection after negative sentinel lymph node biopsy: 70-month follow-up. AB - BACKGROUND: The objective of this study is to assess the oncologic safety of sentinel lymph node biopsy (SLNB), especially with regard to the axillary recurrence (AR) rate, and to determine the risk factors for AR and disease-free survival (DFS) and overall survival (OS) after negative SLNB. MATERIALS AND METHODS: Between 2003 and 2006, a total of 1626 patients with invasive breast cancer and clinically axillary node-negative tumors underwent SLNB using a radioisotope at the Asan Medical Center. Of these patients, 1196 were negative on SLNB. Among these, 709 underwent SLNB only, and 487 underwent SLNB and axillary lymph node dissection (ALND). We included patients with any size tumors, except for those with inflammatory breast cancer, if patients had clinically negative lymph nodes. RESULTS: Mean follow-up was 70.2 months for the SLNB-only group and 71.5 months for the SLNB and ALND group. The 5-year axillary-free survival rates were 98.91% (95% confidence interval [95% CI] 70.2-71.0) and 99.36% (95% CI 71.3 72.0), respectively; the 5-year DFS rates were 95.17% and 95.18%, respectively (log rank P = .543); and the 5-year OS rates were 98.36% and 98.75%, respectively (log rank P = .380). Univariate analysis showed that negative hormone receptor status (P = .002) and high tumor grade (P = .032) were significant prognostic factors for AR in the SLNB only group. Multifocality and tumor size did not affect the rate of AR. CONCLUSION: SLNB alone is an oncologically safe procedure in clinically node negative patients abrogating the need for further ALND. Negative hormone receptor status and high tumor grade might be risk factors for AR. PMID- 20162459 TI - Incidental breast lesions identified by 18F-fluorodeoxyglucose-positron emission tomography. AB - BACKGROUND: Positron emission tomography (PET) scanning is now part of the standard evaluation for patients with a variety of different malignancies. We describe our experience with breast incidentalomas in a large series of PET scans performed for patients without a known history of breast cancer. MATERIALS AND METHODS: From March 2000 through June 2007, approximately 45,000 PET scans were performed; 163 had breast findings unrelated to the primary malignancy. In 103 of 163 (63%), findings included physiologic variation, lactation, implants, or benign calcifications. Chart review was conducted in the remaining 60 of 163 patients (37%). RESULTS: In 20 of 60 patients (33%), no additional evaluation was performed due to advanced stage of the primary malignancy; 40 of 60 (67%) underwent additional imaging and evaluation. In 16 of 40 patients (40%), the lesion resolved on repeat PET; the lesion persisted in 10 of 40 (25%). Additional breast imaging was performed in 14 of 40 (35%). In total, 12 of 40 (30%) underwent biopsy; 7 of 40 (18%) were positive for malignancy. CONCLUSIONS: In our experience, 29% of breast incidentalomas (7 of 24) with persistent imaging findings were malignant. Further evaluation of these lesions should be based on overall clinical status. In patients where results would not change overall management, biopsy may not be warranted. PMID- 20162460 TI - Parenchyma-preserving resections for small nonfunctioning pancreatic endocrine tumors. AB - BACKGROUND: Parenchyma-preserving resections (PPRs), including enucleation and middle pancreatectomy (MP), are accepted procedures for insulinomas, but their role in the treatment of nonfunctioning pancreatic endocrine tumors (NF-PETs) is debated. The aim of this study was to evaluate perioperative and long-term outcomes after PPRs for NF-PETs. METHODS: All patients who underwent PPRs for NF PETs between 1990 and 2005 were included. Patients with multiple endocrine neoplasia type 1 were excluded. RESULTS: Overall, 50 patients (23 men, 27 women, median age 59 years) underwent 26 enucleations and 24 MP. A total of 58% of NF PETs were incidentally discovered. Median size of the tumors was 13.5 mm with no preoperative suspicion of malignancy in all patients. Overall morbidity and pancreatic fistula rates were 58 and 50%, respectively. Reoperation rate was 4%, with no mortality. Postoperative complications were higher in the MP group. At pathology, there were 34 (68%) benign lesions, 13 (26%) neoplasms of uncertain behavior, and 3 (6%) well-differentiated carcinomas. Forty-one patients (82%) had tumors < or =2 cm in size. Only eight patients (16%) had at least one lymph node removed. After a median follow-up of 58 months, no patient died of disease. Overall, four patients (8%) experienced tumor recurrence after a mean of 68 months. The incidence of exocrine/endocrine insufficiency was 8%. CONCLUSIONS: PPRs are generally safe and effective procedures for treating small NF-PETs. However, better selection criteria must be identified, and lymph node sampling should be performed routinely to avoid understaging. Long-term follow-up evaluation (>5 years) is of paramount importance given the possible risk of late recurrence. PMID- 20162461 TI - Variations in surgeon treatment recommendations for lobectomy in early-stage non small-cell lung cancer by patient age and comorbidity. AB - BACKGROUND: Prior research suggests that older patients are less likely to undergo resection of early-stage non-small-cell lung carcinomas (NSCLCs). We surveyed surgeons to understand how their recommendations for lobectomy were influenced by age, the presence and severity of smoking-related lung disease, or by characteristics of the surgeons and their practices. METHODS: We surveyed surgeons caring for NSCLC patients regarding whether they would recommend lobectomy for hypothetical patients with early-stage NSCLC who varied by age (55 vs. 80 years) and comorbid illness (none, moderate, severe chronic obstructive pulmonary disease [COPD]). Ordinal logistic regression was used to identify the importance of patient, surgeon, and practice characteristics on surgery recommendations. RESULTS: Surgeons recommended lobectomy for nearly all patients who were 55 years old with no comorbidity (adjusted proportion 98.6%), 55 years old with moderate COPD (adjusted proportion 97.8%), or 80 years old with no comorbidity (adjusted proportion 98.1%). Fewer recommended lobectomy for 80-year old patients with moderate COPD (adjusted proportion 82.3%), and far fewer recommended lobectomy for severe COPD, irrespective of age (adjusted rate 18.7% for the 55-year-old patient and 6.1% for the 80-year-old patient) (P < 0.002). Surgeons who enroll patients onto clinical trials (P = 0.03) were more likely than others to recommend lobectomy, but no other surgeon characteristic predicted recommendations. CONCLUSIONS: Lower rates of lobectomy among older patients do not seem to be explained by age-related biases among surgeons for otherwise healthy patients. PMID- 20162462 TI - Sentinel node mapping guided by indocyanine green fluorescence imaging during laparoscopic surgery in gastric cancer. AB - BACKGROUND: Indocyanine green (ICG) fluorescence imaging has recently been reported as a new method for sentinel node (SN) mapping in several types of cancers. In this study, we determined the possible usefulness of SN mapping guided by ICG fluorescence imaging during laparoscopy-assisted gastrectomy (LAG) for gastric cancer. METHODS: Our series consisted of 77 patients with cT1- or cT2 stage gastric cancer who had undergone LAG (LAG group; 38 patients) or conventional open gastrectomy (OG group; 39 patients). Intraoperative SN mapping guided by ICG fluorescence imaging was conducted with a charge-coupled device camera with a light-emitting diode as the light source and a cut filter as the detector. RESULTS: The detection rate and mean number of fluorescent nodes (FNs) were 94.7% and 7.9, respectively, in the LAG group, and 94.9% and 7.2, respectively, in the OG group. The accuracy and false-negative rates were 97.2% (35 of 36 cases) and 25% (1 of 4), respectively, in the LAG group, and 91.9% (34 of 37) and 23.1% (3 of 13), respectively, in the OG group. Among 33 LAG group patients and 27 OG group patients without FN metastasis, lymph node metastasis was found only in non-SNs located in the same lymphatic basin as the detected FNs. CONCLUSIONS: SN mapping guidance by ICG fluorescence imaging could be useful for predicting the lymph node metastasis in gastric cancer, even during LAG. Our data suggest that dissection of the lymphatic basin containing FNs with laparoscopic surgery may be a promising approach as a new type of minimally invasive surgery for patients with cT1- or cT2-stage gastric cancer having no metastasis in FNs. PMID- 20162463 TI - Serum CA 19-9 as a marker of resectability and survival in patients with potentially resectable pancreatic cancer treated with neoadjuvant chemoradiation. AB - PURPOSE: The role of carbohydrate antigen (CA) 19-9 in the evaluation of patients with resectable pancreatic cancer treated with neoadjuvant therapy prior to planned surgical resection is unknown. We evaluated CA 19-9 as a marker of therapeutic response, completion of therapy, and survival in patients enrolled on two recently reported clinical trials. PATIENTS AND METHODS: We analyzed patients with radiographically resectable adenocarcinoma of the head/uncinate process treated on two phase II trials of neoadjuvant chemoradiation. Patients without evidence of disease progression following chemoradiation underwent pancreaticoduodenectomy (PD). CA 19-9 was evaluated in patients with a normal bilirubin level. RESULTS: We enrolled 174 patients, and 119 (68%) completed all therapy including PD. Pretreatment CA 19-9 <37 U/ml had a positive predictive value (PPV) for completing PD of 86% but a negative predictive value (NPV) of 33%. Among patients without evidence of disease at last follow-up, the highest pretreatment CA 19-9 was 1,125 U/ml. Restaging CA 19-9 <61 U/ml had a PPV of 93% and a NPV of 28% for completing PD among resectable patients. The area under the receiver-operating characteristics curve of pretreatment and restaging CA 19-9 levels for completing PD was 0.59 and 0.74, respectively. We identified no association between change in CA 19-9 and histopathologic response (P = 0.74). CONCLUSIONS: Although the PPV of CA 19-9 for completing neoadjuvant therapy and undergoing PD was high, its clinical utility was compromised by a low NPV. Decision-making for patients with resectable PC should remain based on clinical assessment and radiographic staging. PMID- 20162464 TI - Epithelial-mesenchymal transition induced by hepatitis C virus core protein in cholangiocarcinoma. AB - BACKGROUND: Cholangiocarcinoma (CC) is associated with chronic hepatitis C virus (HCV) infection. We investigated the effect of hepatitis C virus core protein (HCVc) on epithelial-mesenchymal transition (EMT) in CC and tried to identify its target trigger. METHODS: First, we examined expression of HCVc and epithelial and mesenchymal markers in CC tissues. Then we transient-transfected HCVc gene into a CC cell line and examined expression of lysyl oxidase-like 2 (LOXL2) and epithelial and mesenchymal markers by quantitative real-time polymerase chain reaction (PCR) and Western blotting. Finally, LOXL2 gene silencing was shown in QBC939/HCVc cells by RNA interference (RNAi), and we further examined expression of epithelial and mesenchymal markers by quantitative real-time PCR and Western blotting. RESULTS: Through immunohistochemical staining, the present study showed that HCVc is significantly associated with CC invasion and metastasis. In vitro study showed that HCVc expression induces EMT in CC cell line QBC939, and a mechanism through LOXL2 pathway is suggested. Expression of HCVc was significantly correlated with greater migratory and invasive potential of CC cells. CONCLUSIONS: These observations indicate that HCVc plays a critical role in promoting invasion and metastasis of CC cells. PMID- 20162465 TI - Simulation of the complex countermovement jumping by means of a simple four degrees-of-freedom model. AB - By means of a four-degrees-of-freedom model the vertical movements of an athlete and the time course of the ground reaction force were simulated during a countermovement jump on a concrete and a wooden surface. The model masses were connected to each other and to the surface by springs and dampers. At first the stiffness of the springs decreased in order to initiate the countermovement. Afterwards the stiffness increased like the muscle activity so that the flexion of the model 'legs' were decelerated before the extension starts. The best result was attained when the stiffness of the spring between the model masses 'thighs' and 'trunk' increased before the other three springs. Compared with the muscle activity this means that for a successful jump the upper body segments have to be accelerated before the segments near to the ground are accelerated. The model 'athlete' was connected to a model of the surface. It could be shown that the jump on a concrete surface results in a better jump height than the jump on an elastic wooden surface if the muscle activation is not adapted to the surface properties. PMID- 20162466 TI - Patient-specific computational fluid dynamics: structured mesh generation from coronary angiography. AB - Patient-specific simulations are widely used to investigate the local hemodynamics within realistic morphologies. However, pre-processing and mesh generation are time consuming, operator dependent, and the quality of the resulting mesh is often suboptimal. Therefore, a semi-automatic methodology for patient-specific reconstruction and structured meshing of a left coronary tree from biplane angiography is presented. Seven hexahedral grids have been generated with the new method (50,000-3,200,000 cells) and compared to nine unstructured tetrahedral grids with prismatic boundary layer (150,000-3,100,000 cells). Steady state blood flow simulation using Computational Fluid Dynamics (CFD) has been used to calculate the Wall Shear Stress (WSS). Our results (99 percentile, area weighted and local WSS values along a line) demonstrate that hexahedral meshes with respect to tetrahedral/prismatic meshes converge better, and for the same accuracy of the result, six times less cells and 14 times less computational time are required. Hexahedral meshes are superior to tetrahedral/prismatic meshes and should be preferred for the calculation of the WSS. PMID- 20162467 TI - The analysis of the factors affecting lumbar spinal stenosis in adult patients. AB - BACKGROUND: In this study 67 lumbar spinal stenosis in adult patients operated in our clinic in 3 years are aimed to be analysed in terms of clinical and surgical techniques. METHODS: Diagnoses were made on the basis of patients' histories and their clinical examinations. RESULTS: Average age was 52.16 +/- 8.9 (33-64). 70.1% (47) of patients were females and 29.9% (20) were males. The most frequent neurological symptoms were 71.1% lasque (+) and 56.7% sensory loss. The anterior posterior diameter was below 11.5 mm in 56.7% of the cases. Partial recovery was observed in the early term of 71.6% the cases. 56.7% of the cases were applied total laminectomy. CONCLUSION: Decompressive laminectomy can be performed safely and effectively in patients of with lumbar stenosis. PMID- 20162469 TI - Progressive osteosclerosis and visceral calcification after cord blood transplantation. AB - A 26-year-old woman, who successfully underwent umbilical cord blood transplantation for aplastic anemia 4 years previously, had suffered from hepatosplenic microabscesses caused by unidentifiable grocott stain-positive spores from immediately after the transplantation. At 51 months post-transplant, we attempted bone marrow biopsy from her posterior iliac crest, but failed to penetrate the cortical bone. X-ray of her spine and pelvis showed marked and diffuse osteosclerosis. Retrospective analysis of computed tomography revealed the gradual replacement of sternal, vertebral, and pelvic bone marrow with calcified tissues in addition to the dispersed calcification of the liver, spleen, and kidneys over the last 2 years. The bone mineral density of the lumbar spine had increased but not that of the femoral neck. Biomedical parameters for bone remodeling demonstrated enhanced bone formation as well as bone resorption and secondary hyperparathyroidism. Based on the past reports, we suggest that chronic fungal infection, which caused visceral calcification, induced the production of humoral factors for osteoblastic activation. PMID- 20162468 TI - Progenitor cells for regenerative medicine and consequences of ART and cloning associated epimutations. AB - The "holy grail" of regenerative medicine is the identification of an undifferentiated progenitor cell that is pluripotent, patient specific, and ethically unambiguous. Such a progenitor cell must also be able to differentiate into functional, transplantable tissue, while avoiding the risks of immune rejection. With reports detailing aberrant genomic imprinting associated with assisted reproductive technologies (ART) and reproductive cloning, the idea that human embryonic stem cells (hESCs) derived from surplus in vitro fertilized embryos or nuclear transfer ESCs (ntESCs) harvested from cloned embryos may harbor dangerous epigenetic errors has gained attention. Various progenitor cell sources have been proposed for human therapy, from hESCs to ntESCs, and from adult stem cells to induced pluripotent stem cells (iPS and piPS cells). This review highlights the advantages and disadvantages of each of these technologies, with particular emphasis on epigenetic stability. PMID- 20162470 TI - Interactive decision support for risk management: a qualitative evaluation in cancer genetic counselling sessions. AB - Genetic counselling for inherited susceptibility to cancer involves communication of a significant amount of information about possible consequences of different interventions. This study explores counsellors' attitudes to computer software designed to aid this process. Eight genetic counsellors used the software with actors playing patients. Clinicians' rating of expected patient satisfaction, content, accuracy, timeliness, format, overall value, ease of use, effect on the patient-provider relationship and effect on clinician's performance were evaluated via qualitative and quantitative analysis of interviews, training tasks and questionnaires. Most counsellors found the software effective. Concerns related to possible impact on consultation dynamics and content. Participants suggested countering these through appropriate new counselling skills and selective use of the computer. The REACT software could provide effective support for genetic risk management counselling. PMID- 20162471 TI - "Living by the hoe" in the age of treatment: perceptions of household well-being after antiretroviral treatment among family members of persons with AIDS. AB - This paper considers the effects of antiretroviral treatment on the households of person with AIDS in western Uganda. Interviews were carried out with 110 co resident "treatment partners" of people receiving treatment. We discuss these family members' accounts of the impact of sickness, followed by treatment, on their household's livelihood, defined as the activities needed to obtain and process the resources required to sustain the households. The household's ability to muster labour for subsistence agriculture was of paramount concern when family members considered what treatment meant for the households. While they were very happy with the treatment, they said that households have not yet recovered from the shock of AIDS sicknesses. PMID- 20162472 TI - Monohalogenated maleimides as potential agents for the inhibition of Pseudomonas aeruginosa biofilm. AB - New monohalogenated maleimide derivatives (with bromine, chlorine or iodine) were synthesized to test the effect of halogen atoms in inhibiting the formation of Pseudomonas aeruginosa biofilm. The evaluation of their biological activities clearly defines a structure-activity relationship. In this study, the bactericidal action of the three compounds was observed at the concentration range 0.3-5.0 mM on Luria-Bertani agar plates. The halogen atom of these molecules was critical in modulating the antibacterial activity, with a slightly higher effectiveness for chlorine. Confocal laser scanning microscopy was used to examine P. aeruginosa biofilms cultivated in flow cells. At concentration as low as 40 microM, the bromine and iodine compounds displayed a total inhibition towards the formation of bacterial biofilm. At this concentration, the bacterial attachment to glass surfaces was strongly affected by the presence of bromine and iodine whereas the chlorine derivative behaved as a bactericidal compound. A bioluminescent reporter strain was then used to detect the effect of the chemically synthesized maleimides on quorum sensing (QS) in P. aeruginosa. At the concentration range 10-100 microM, bioluminescence assays reveal that halogenated maleimides were able to interfere with the QS of the bacterium. Although the relationship between the weak inhibition of cell-to-cell communication (15-55% of the signal) and the high inhibition of biofilm formation has not been elucidated clearly, the results demonstrate that bromo- and iodo-N-substituted maleimides bromine and iodine may be used as new potent inhibitors that control bacterial biofilms. PMID- 20162473 TI - A multi-platform comparison of efficient probabilistic methods in the prediction of total knee replacement mechanics. AB - Explicit finite element (FE) and multi-body dynamics (MBD) models have been developed to evaluate total knee replacement (TKR) mechanics as a complement to experimental methods. In conjunction with these models, probabilistic methods have been implemented to predict performance bounds and identify important parameters, subject to uncertainty in component alignment and experimental conditions. Probabilistic methods, such as advanced mean value (AMV) and response surface method (RSM), provide an efficient alternative to the gold standard Monte Carlo simulation technique(MCST). The objective of the current study was to benchmark models from three platforms (two FE and one MBD) using various probabilistic methods by predicting the influence of alignment variability and experimental parameters on TKR mechanics in simulated gait. Predicted kinematics envelopes were on average about 2.6mm for tibial anterior-posterior translation, 2.98 for tibial internal-external rotation and 1.9 MPa for tibial peak contact pressure for the various platforms and methods. Based on this good agreement with the MCST, the efficient probabilistic techniques may prove useful in the fast evaluation of new implant designs, including considerations of uncertainty, e.g. misalignment. PMID- 20162474 TI - A critical examination of the maximum velocity of shortening used in simulation models of human movement. AB - The maximum velocity of shortening of a muscle is an important parameter in musculoskeletal models. The most commonly used values are derived from animal studies; however, these values are well above the values that have been reported for human muscle. The purpose of this study was to examine the sensitivity of simulations of maximum vertical jumping performance to the parameters describing the force-velocity properties of muscle. Simulations performed with parameters derived from animal studies were similar to measured jump heights from previous experimental studies. While simulations performed with parameters derived from human muscle were much lower than previously measured jump heights. If current measurements of maximum shortening velocity in human muscle are correct, a compensating error must exist. Of the possible compensating errors that could produce this discrepancy, it was concluded that reduced muscle fibre excursion is the most likely candidate. PMID- 20162475 TI - Biomechanical response of impacted bony pelvis: influence of the morphometry and bone density. AB - Mechanical properties of human pelvic bone tissue according morphological parameters were few studied in anterior-posterior compression tests and few data are available to correctly validate finite element pelvis models. In order to reduce this gap, 12 pelvic bones were removed from male and female embalmed cadavers and compressed. Anatomic angles were measured and bone's density was calculated after each test. Fractures observed during those tests were coherent with those observed in real life. Bone's density and percentage of mineralisation were not significantly different between the male and female groups. The retropubic angle was significantly larger in the female group (p < 0.05). Mean load necessary to obtain the collapse was significantly higher in the male group (p < 0.05). PMID- 20162476 TI - Understanding teenage pregnancy in a post-apartheid South African township. AB - Although South Africa's total fertility rate is one of the lowest in sub-Saharan Africa, high rates of early childbearing remain a concern. Most teenage pregnancies occur among poor black and coloured South Africans. The majority of these pregnancies are said to be unwanted and unplanned and the teenager's relationships, unstable. Becoming a mother during one's teenage years is perceived to be socially, economically and physically deleterious for the teenager and her baby. This paper presents ethnographic data collected over a five-year period in the South African township of Nyanga East in the Western Cape. It draws attention to the circumstances that surround teenage pregnancy and discusses reactions to teenage pregnancies in this community. Findings highlight that despite the negative perception of teenage pregnancy within the township, particular social and cultural circumstances provided fertile ground for its occurrence. Furthermore, the paper argues that in this particular community the management of a teenage pregnancy played a functional and critical role in maintaining and reproducing social norms and ideals regarding intergenerational relationships, which ultimately ensured that the rates of early childbearing remained high. PMID- 20162477 TI - The silent treatment: parents' narratives of sexuality education with young people. AB - This paper is based on research undertaken in Ireland that sought to understand how parents communicate with their children about sexuality. Forty-three parents were interviewed and data were analysed using analytical induction. Data indicated that while parents tended to pride themselves on the culture of openness to sexuality that prevailed in their home, they often described situations where very little dialogue on the subject actually transpired. However, unlike previous research on the topic that identified parent-related factors (such as ignorance or embarrassment) as the main impediments to parent young person communication about sex, participants in our study identified the central obstacle to be a reticence on the part of the young person to engage in such dialogue. Participants described various blocking techniques apparently used by the young people, including claims to have full prior knowledge on the issue, physically absenting themselves from the situation, becoming irritated or annoyed, or ridiculing parents' educational efforts. In our analysis, we consider our findings in light of the shifting power of children historically and the new cultural aspiration of maintaining harmonious and democratic relations with one's offspring. PMID- 20162480 TI - Magic Johnson doesn't worry about how to pay for medicine: experiences of black men who have sex with men living with HIV. AB - Despite high and rapidly growing incidence of HIV, little is known about the everyday lived experiences of HIV-positive black men who have sex with men. Lack of empirical knowledge about members of this group is especially problematic as HIV-positive individuals continue to live in a world of hope, fear, waiting and wondering, which can heavily influence their everyday lives. In this exploratory study, we examine the everyday lives of HIV-positive black gay, bisexual and other men who have sex with men, particularly how being a racial minority may influence the ways that they manage living with the illness. Our goal was to provide a forum from which black men could share their personal experiences regarding the various aspects of living with HIV. In doing so, we identified five themes that may be unique to black men or experienced differently by black men due, in the USA, to their racial minority status. PMID- 20162481 TI - Negotiating homosexual identities: the experiences of men who have sex with men in Guangzhou. AB - This paper reports on an ethnographic study of male homosexuality in contemporary Chinese society. The study focused on how men negotiated with the mainstream Chinese heterosexual society and in so doing constructed their sexual identities. The factors found to inform sexual identity were: the cultural imperative of heterosexual marriage, normative family obligations, desired gender roles, emotional experiences and a need for social belonging. The four types of sexual identities constructed included: establishing a deliberate non-homosexual identity, accumulating an individual homosexual identity, forming a collective homosexual identity and adopting a flexible sexual identity. For the men interviewed, sexual identity was both fluid and fragmented, derived from highly personalised negotiations between individualised needs and social and cultural constructs. The analysis is set against the background of China's rapid and recent economic development, shifting national and international social environments and improved access to the Internet. PMID- 20162482 TI - Evidence-based dialogue with communities for district health systems' performance improvement. AB - Despite focused health policies and a reform agenda Kenya has not made a breakthrough in improving the situations of households entrapped in the vicious cycle of poverty and ill health. Consequently, Great Lakes University of Kisumu developed and tested a model for facilitating improvement in the performance of the District Health System (DHS) and, hence, the health status of poor households served. The model consisted of evidence-based dialogue between the communities and service providers, working with service consumers as partners in improving service delivery and outcomes. The study was undertaken in partnership with the Ministry of Health (MOH) and the Communities. The model was tested by introducing it in selected sites and carrying out health facility and household sample surveys at the beginning of the intervention and two years later in both intervention and control sites. Among the key improvements noted were: governance and management of the health system; service delivery and health outcomes in terms of immunisation coverage; usage of insecticide treated nets; and utilisation of skilled attendance at childbirth. Based on the results, the Kenyan MOH adopted the model as a strategy for the implementation of the Kenya Essential Package for Health countrywide. The University developed the implementation guidelines and training materials for rolling out the strategy countrywide. PMID- 20162483 TI - Developing policy options for SARS and SARS-like diseases - a Delphi study. AB - The objective of the SARSControl Delphi study was to develop options for national and international emerging infectious diseases policies. The aim of this paper is to present the results of the study, which gathered expert opinions on gaps and inconsistencies concerning preparedness and response planning for Severe Acute Respiratory Syndrome (SARS) and SARS-like diseases. The Delphi technique was employed, which comprised a pilot round, two written rounds and a face-to-face meeting. The Delphi panel consisted of 38 experts from 22 countries, who highlighted the necessity to test plans and stressed the importance of surveillance measures for the swift containment of communicable disease outbreaks and the inclusion of detailed triage plans in national pandemic plans. The experts also suggested a need to define criteria for testing pandemic preparedness plans at different regional levels. New policy alternatives were identified, such as the need for generic plans on pandemics and universal access to healthcare during an outbreak. The usefulness of some non-medical interventions, such as bans on travel, could not be established and need further research. Dissemination of the findings will help to bridge gaps and rectify inconsistencies in current pandemic planning and response strategies for SARS and SARS-like diseases, as well as add valuable knowledge towards the development of national and international emerging infectious disease policies. PMID- 20162484 TI - Assessment of human exposure to environmental heavy metals in soils and bryophytes of the central region of Portugal. AB - This study intends to identify the spatial patterns of variation for some metals and metalloids, in soils and mosses, in the central region of Portugal. The purposes were: (i) to identify relationships amongst five elements (Cu, Pb, Zn, Cr and As) in three different media (topsoil, bottom soil and bryophytes) and with some site-specific characteristics, using Multiple Correspondence Analysis; (ii) to define spatial patterns of variation for the associations identified by Multiple Correspondence Analysis using Variography and Ordinary Kriging; and (iii) to assess atmospheric deposition as a source of heavy metals to the topsoil by crossing results with the biomonitors. The results indicated relatively low metal concentrations in soils and mosses. Some metal associations and dissociations were identified. The spatial patterns of variation of bottom and topsoil are distinct. There is some evidence that different site-specific characteristics control the spatial distribution of different elements. The areas within the central region of Portugal with a higher vulnerability to metal contamination were identified. PMID- 20162485 TI - Study of the health effects of long-term exposure to cadmium and lead in a region of Poland. AB - A region in Poland with a high concentration of lead (Pb) and cadmium (Cd) was used as a case study to look for the potential health consequences of chronic cadmium and lead exposure. The analysis of the incidence of cardiovascular diseases and neoplasms mortality were carried out and the mortality using SDR (standardized death rate) were compared with Cd and Pb pollution in each of 13 cities. To estimate the association between health effect and the pollutant concentration, the linear regression method was used. On the basis of calculated regression, the magnitude of changes in the health state has been estimated assuming that the ambient air pollution decrease is 10%. The reduction of the concentrations of both heavy metals in the air will lower SDR, by 24.4 and 31.6 people for cadmium and lead, respectively. PMID- 20162486 TI - Effect of production variables on microbiological removal in locally-produced ceramic filters for household water treatment. AB - Diarrhoeal diseases cause an estimated 1.87 million child deaths per year. Point of-use filtration using locally made ceramic filters improves microbiological quality of stored drinking water and prevents diarrhoeal disease. Scaling-up ceramic filtration is inhibited by lack of universal quality control standards. We investigated filter production variables to determine their affect on microbiological removal during 5-6 weeks of simulated normal use. Decreases in the clay:sawdust ratio and changes in the burnable decreased effectiveness of the filter. Method of silver application and shape of filter did not impact filter effectiveness. A maximum flow rate of 1.7 l(-hr) was established as a potential quality control measure for one particular filter to ensure 99% (2- log(10)) removal of total coliforms. Further research is indicated to determine additional production variables associated with filter effectiveness and develop standardized filter production procedures prior to scaling-up. PMID- 20162487 TI - Household and community variations and nested risk factors for diarrhoea prevalence in southern Malawi: a binary logistic multi-level analysis. AB - This paper examines household and community-level influences on diarrhoeal prevalence in southern Malawi. A Bayesian multi-level modelling technique is used in the estimation of hierarchically built data from a survey of individuals nested within households nested within communities. Households have strong unobserved influence on diarrhoeal illness (sigma(2)(u) = 4.476; 95% CI: 2.081, 6.871). A joint Wald test of significance shows that an individual's age [chi(2)(4) = 55.921, p = 0.000] and school [chi(2)(2) = 18.203, p = 0.000] have strong influence on an individual's diarrhoeal prevalence. An individual's history of malarial-like illness also has a strong positive relationship with diarrhoeal prevalence [beta = 0.606, p = 0.000]. Household factors that influence diarrhoea include employment status of head of household [beta = -0.619, p < 0.021], maternal age [beta = -0.013, p < 0.003], and size of household [beta = 0.669, p = 0.000]. The positive relationship between diarrhoea and malaria-like episodes highlights common risk factors hence the need for common approaches to combat the diseases. Significant household effects underline the importance of household considerations in policy issues. PMID- 20162488 TI - Analysis of polycyclic aromatic hydrocarbons extracted from air particulate matter using a temperature programmable injector coupled to GC-C-IRMS. AB - Compound specific isotopic analysis (CSIA) can provide information about the origin of analysed compounds - in this case, polycyclic aromatic hydrocarbons (PAHs). In the study, PAHs were extracted from three dust samples: winter and summer filter dust and tunnel dust. The measurement was performed using the method validated in our laboratory using pure, solid compounds and EPA 610 reference assortment. CSIA required an appropriate clean-up method to avoid an unresolved complex in the gas chromatographic analysis usually found in the chromatography of PAHs. Extensive sample clean-up for this particular matrix was found to be necessary to obtain good gas chromatography-combustion-isotope ratio mass spectrometry analysis results. The sample purification method included two steps in which the sample is cleaned up and the aliphatic and aromatic hydrocarbons are separated. The concentration of PAHs in the measured samples was low; so a large volume injection technique (100 microl) was applied. The delta(VPDB)(13)C was measured with a final uncertainty smaller than 1 per thousand. Comparison of the delta(VPDB)(13)C signatures of PAHs extracted from different dust samples was feasible with this method and, doing so, significant differences were observed. PMID- 20162490 TI - Who is to blame? Neural correlates of causal attribution in social situations. AB - In everyday life causal attribution is important in order to structure the complex world, provide explanations for events and to understand why our environment interacts with us in a particular way. This study used functional magnetic resonance imaging (fMRI) in 30 healthy subjects to separate the neural correlates of self vs. external responsibility for social events and explore the neural basis of self-serving attributions (internal attributions of positive events and external attributions of negative events). We presented short sentences describing positive and negative social events and asked participants to imagine the event, to decide the main cause and assign it to one of the categories (internal vs. external). FMRI data were analyzed using a 2 x 2 factorial design with the factors emotional valence and attribution. Internal compared to external attribution revealed activations along the right temporoparietal junction (TPJ). The reverse contrast showed a left lateralized network mainly involving the TPJ, the precuneus and the superior/medial frontal gyrus. These results confirmed the involvement of a fronto-temporoparietal network in differentiating self and external responsibility. Analysis of the self serving bias yielded activation in the dorsal anterior cingulate and in the dorsal striatum, suggesting a rewarding value of these attributions. PMID- 20162491 TI - The development and neural basis of pointing comprehension. AB - The neurological correlates of pointing comprehension in adults and 8-month-old infants are explored. Both age groups demonstrate differential activation to congruent and incongruent pointing gestures over posterior temporal areas. The functional similarity of the adult N200 and the infant P400 component suggests that they might have a common source. PMID- 20162492 TI - Social cognition in individuals with agenesis of the corpus callosum. AB - Past research has revealed that individuals with agenesis of the corpus callosum (ACC) have deficits in interhemispheric transfer, complex novel problem-solving, and the comprehension of paralinguistic aspects of language. Case studies and family reports also suggest problems in social cognition. The performance of 11 individuals with complete ACC and with normal intelligence was compared to that of 13 IQ- and age-matched controls on three measures of social cognition. Individuals with ACC were indistinguishable from controls on the Happe Theory of Mind Stories and the Adult Faux Pas Test, but performed significantly worse on various portions of the Thames Awareness of Social Inference Test (TASIT) involving interpretations of videotaped social vignettes. Further analysis of the TASIT indicated that individuals with ACC showed deficiency in the recognition of emotion, weakness in understanding paradoxical sarcasm, and particular difficulty interpreting textual versus visual social cues. These results suggest that the tendency for deficient social cognition in individuals with ACC stems from a combination of difficulty integrating information from multiple sources, using paralinguistic cues for emotion, and understanding nonliteral speech. Together, these deficits would contribute to a less robust theory of mind. PMID- 20162493 TI - Neural activity associated with attention orienting triggered by gaze cues: A study of lateralized ERPs. AB - This study investigated the electrophysiological (event-related potential, ERP) and behavioral (reaction time, RT) correlates of gaze-cued shifts of visuospatial attention. Participants viewed centrally presented faces with neutral expressions in which eyes looked straight ahead and then shifted to the left or right. Upon movement of the eyes, the facial expression either stayed the same (neutral) or changed to a fearful or happy expression. Participants' task was to identify a probe letter (T or L), which appeared in either the same or the opposite location to the direction of the eye gaze. There was behavioral evidence of a gaze congruency effect, as RTs were faster when the eyes looked toward rather than away from the location of the target. The ERP data indicated the presence of a significant gaze-congruent anterior directing attention negativity (ADAN) at anterior locations (300-500 ms after the onset of the gaze cue). ERP data did not show evidence of initial orienting of attention triggered by gaze cues in the early directing attention negativity (EDAN) at posterior locations (200-300 ms post-cue onset). The gaze cueing effects in the RT and ERP data were not significantly influenced by the emotional expression of the faces. The presence of the ADAN may reflect neural mechanisms that underlie the holding of attention on gazed-at locations. PMID- 20162494 TI - Assessing mental flexibility: neuroanatomical and neuropsychological correlates of the Trail Making Test in elderly people. AB - The Trail Making Test part B (TMT-B) is highly sensitive to age-related changes in the brain and cognitive function. However, the precise contribution of periventricular hyperintensities (PVH), deep white matter hyperintensities (DWMH), and medial temporal lobe atrophy (MTA) to task performance remains unspecified. Similarly, diminished performance may be due to deficient flexibility functions, but also to other age-related cognitive decline (e.g., mental slowing). The aim of the present study was to determine neuroanatomical (PVH, DWMH, MTA) and neuropsychological (working memory, executive function, speed and attention, episodic memory) predictors of TMT-B performance in elderly people. Results showed that MTA was the strongest predictor of TMT-B performance. The predictive value of the neuropsychological scores differed among the various TMT-B variables. For example, all neuropsychological domains predicted the TMT-B total completion time, whereas only executive function predicted the ratio score (TMT-B/A). We conclude that MTA is a very important predictor of TMT-B performance in elderly people. Furthermore, multiple cognitive functions are involved in TMT-B performance and a mild decline in any of these functions may result in diminished TMT-B performance. Therefore it is crucial to use the ratio score when one wishes to examine executive function ability. PMID- 20162496 TI - MMPI-2 validity scores in defense- versus plaintiff-selected examinations: a repeated measures study of examiner effects. AB - The effects of forensic examiner role on validity scores have rarely been studied empirically. We used a repeated measures design to examine the association between examiner role (plaintiff- and defense-selected neuropsychologists) and scores on eight Minnesota Multiphasic Inventory-2 validity scores (MMPI-2-VRIN, TRIN, -L, -K, -F, -Fb, -Fp, and -FBS) of the same 80 individuals. All 80 were involved in litigation following mostly minor neurological injuries. We found no significant within-group differences on any of the MMPI-2 validity scales. Concordance of pass/fail rates between examinations was above 80%, except for MMPI-2-Fb. For example, the Symptom Validity Scale (MMPI-2-FBS) showed equivalently high failure rates (70%) during both examinations. This study does not support the view that examiner role affects symptom validity scores in forensic settings. PMID- 20162495 TI - Neurocognitive functioning in HIV-1 infection: effects of cerebrovascular risk factors and age. AB - This study examined the interactive effects of cerebrovascular risks, advancing age, and HIV infection on neurocognition, and explored whether pharmacological treatment of cerebrovascular risk factors attenuated neurocognitive dysfunction. Participants included 98 HIV-seropositive adults (cerebrovascular risk: 23.5%; age > 50: 27.6%). Cerebrovascular risk was associated with slower processing speed even after controlling for age effects (b = -2.071; p =.04), and the interaction of age and cerebrovascular risk was associated with poorer verbal fluency (b = 1.276, p =.002). Participants with pharmacologically untreated cerebrovascular risk demonstrated reduced processing speed, learning/memory, and executive functioning relative to those on medication. Poor cerebrovascular health confers significant risk for HIV+ individuals, and this effect may be of greater consequence than advancing age. The cognitive impact of risk appears to be more pronounced in the absence of adequate pharmacological treatment. PMID- 20162498 TI - [Quality management--certification: curse or blessing?]. PMID- 20162499 TI - [BGH VI ZR 157/08--when can inadequate therapy and prognosis education be a major treatment error?]. PMID- 20162500 TI - [Quality and quality assurance of teaching in surgery - recommendations from a workshop of the surgical cooperative for quality assurance]. AB - The shortage of surgeons in the operative disciplines field has in recent years further increased. The training of a surgeon and the required lifestyle combined with the work-life balance of the surgeons are perceived as being less attractive, so that young doctors after finishing medical school rarely decide for surgical careers. Changes in the social environment outside of our clinics has resulted in a decline of the social prestige. The modified structural preconditions require a rethinking of the training processes for studying and working conditions in surgery. The quality of surgical education is therefore a cornerstone for the future development of our subject and is directly linked to the training and junior development. The CAQ meeting in Greifswald in February 2009, has focused on the teaching in surgery and developed together with medical students of different faculties solutions for the three major problem factors: teaching, training and junior development. The students are demanding clear guidelines regarding the required theoretical and practical knowledge in the form of catalogues or learning logs. The absence of intrinsic commitment to an excellent teaching and role model is due to the ongoing conflict between patient care and teaching. Because in teaching usually neither the quantity nor the quality will be systematically registered and no sanctions promote the lesson, so that the training is always considered as a last resort. One approach could be a scoring system for teaching that reflect the quantity and quality of teaching in points. The practical year needs to be reformed, since over 25% of the students spend their surgery part abroad, because they are afraid to be considered as cheap labour. Especially at this point, the lecturer is asked to reform the education of students during the practical year and to strengthen the role model for young academic teachers. PMID- 20162501 TI - [Patient assignment to a surgical intensive care unit - plea for a preoperative risk stratification]. AB - BACKGROUND: Surgical intensive care units (ICUs) have to meet the demands of caring for elective surgical patients, for surgical emergencies, and for trauma patients. To achieve this a high flexibility and a high rate of admissions and discharges are needed. ICU beds are scant and expensive, so who is to be admitted? PATIENTS AND METHODS: All admissions and dis-charges of a 20-bed surgical ICU in a university hospital within one year have been analysed. RESULTS: During the analysed year 2524 patients were admitted to the surgical ICU (6.9 + or - 3.1 per day). Of 1886 planned admissions (elective surgery) only 1234 were eventually admitted, but there were 1290 additional patients admitted as emergencies. Of all realised admissions only 49 % were planned. In 653 requested but refused elective admissions, the surgery was performed with-out intensive care admission in 432 patients (64.9 %). CONCLUSIONS: Half of the patients of the surgical ICU are electively surgical, half of them are emergencies. The limited number of ICU beds requires strict indications for admission. It turns out to be useful to create a category of patients in whom postoperative intensive care is desirable but not mandatory. PMID- 20162502 TI - [Timing and concepts of surgical treatment of upper gastrointestinal haemorrhage]. AB - BACKGROUND: Upper gastrointestinal bleeding is a frequently occurring clinical scenario with a potentially serious prognosis. In spite of excellent endoscopic results, the mortality rate after an insufficient endoscopic treatment is exception-ally high (12.5-36 %). It is crucial to recognise factors in which endoscopy reaches its limitations. Until now, no uniform guidelines and concepts concerning diagnosis and treatment as well as timing of surgical interventions, in particular, have been defined. The main goal of this study is to lower the morbidity and mortality rates after upper gastrointestinal bleeding, with potential risk stratification according to the literature and our own data. PATIENTS / MATERIAL AND METHODS: In a retrospectively designed study 220 patients were evaluated with upper gastrointestinal haemorrhage, who were hospitalised as emergencies from 1999 to 2002. Only those patients were accepted in the study who were examined within 48 hours endoscopically by oesophagogastroduodenoscopy. In order to exclude bleeding complications of a preceding endoscopic therapy, those patients were excluded who had been investigated by endoscopy in the past than 8 days. RESULTS: After endoscopic evaluation of the bleed-ing activity of 33 Forrest I a / I b bleedings 5 patients and of 52 Forrest II a / II b / II c bleedings 6 patients had to undergo surgery. The haemoglobin content of conventionally treated patients was on average 10.3 mg / dL as compared to 8.4 mg / dL for the operated patients. The conventionally treated patients received an average of 3 red cell concentrates whereas the operated patients had 11 blood transfusions. The source of haemorrhage in the operated patients was located in bulbus duodeni (n = 7), cardia and fundus (n = 2) and the corpus (n = 2). CONCLUSION: The evaluation of our own patient data including the experiences of other authors shows that a risk stratification is possible and meaningful. The indication for surgery thereby -depends on different factors: the comorbidity of the patient, the haemodynamic in- / stability, the number of necessary blood transfusions and the localisation of the bleeding source. PMID- 20162503 TI - [Second-look operation in pancreatic carcinoma previously assessed as unresectable]. AB - BACKGROUND: The only curative therapy for patients with pancreatic carcinoma consists of -complete surgical tumour removal. Preoperative diagnostic investigations may help, however, the definite decision on tumour resectability can only be made intraoperatively during explorative laparotomy. PATIENTS AND METHODS: We report herein on 17 patients who were judged during exploratory laparotomy elsewhere to suffer from non-resectable pancreatic cancer and who underwent a second-look operation after referral to our hospital. RESULTS: During the second-look operation 13 patients (76.5 %) underwent tumour resection, where as in 4 patients (23.5 %) the tumour remained non-resectable. An R0 resection was achieved in 9 of 13 (69 %) and an R1 resection in 4 of 13 (31 %) patients, respectively. The classic Kausch-Whipple operation was performed in 4, pylorus preserving pancreaticoduodenectomy in 5, and left pancreatic -resection in another 4 patients. Mean survival in patients after tumour resection was increased, reach-ing 17.6 months compared to 6.5 months in patients with non resectable pancreatic cancer. CONCLUSIONS: Our results suggest that the prediction of resectability depends highly on the experience of the surgical team. Although considered as non-resectable during prior laparotomy else-where, the majority of patients (76.5 %) suffered from a resectable tumour disease. Moreover, most of them (69 %) underwent complete (R0) -tumour removal. Thus, complex visceral operations like pancreatic carcinoma resection should preferably be performed in high-volume centres exclusively. PMID- 20162505 TI - Ectopic Cushing's syndrome caused by a well differentiated ACTH-secreting neuroendocrine carcinoma of the ileum. AB - Cushing's syndrome can be caused by adrenocorticotropic hormone-secreting solid tumors. We report a rare case of an ileal endocrine carcinoma that produced ACTH and induced hypercortisolism. A now 47-year-old man presented at age 41 with weight gain, tremor, perspiration, and general fatigue. Laboratory testing showed hypercortisolism and diabetes mellitus. Further examinations revealed ectopic Cushing's syndrome. The search for the primary tumor was difficult. The patient underwent subtotal thyroidectomy and surgical removal of a pituitary lesion. After resection of an ACTH-producing metastasis of the mesentery, temporary remission of Cushing's syndrome ensued. At the age 45 the primary tumor was detected in the ileum by Ga-68 DOTATOC-PET scan and explorative laparotomy. After surgical removal of this well differentiated neuroendocrine carcinoma the patient significantly improved clinically. He experienced better blood pressure and remission of his diabetes mellitus in addition to increased muscular strength. Endocrine laboratory testing at follow-up examinations confirmed remission of hypercortisolism and diabetes mellitus. A Ga-68 DOTATOC PET scan and a 1 mg dexamethasone suppression test 5 months after surgery showed normal results. Ectopic ACTH secretion within the small bowel is very rare. This case underscores the difficulty in locating the source of ectopic ACTH secretion and suggests using small bowel barium study, tubus endoscopy or video endoscopy for preoperative localization if the small bowel is suspected as tumor source. PMID- 20162504 TI - 10-day hyperlipidemic clamp in cats: effects on insulin sensitivity, inflammation, and glucose metabolism-related genes. AB - Obesity and hyperlipidemia are associated with impaired insulin sensitivity in human type 2 diabetes mellitus, possibly due to activation of a mild inflammatory response. Because obesity-induced insulin resistance predisposes cats to diabetes and because hyperlipidemia is a frequent concurrent finding, excess lipids may also impair insulin sensitivity in cats. Healthy cats (n=6) were infused with lipids (Lipovenoes 10%) for 10 days to clamp blood triglycerides at the approximate concentration of untreated feline diabetes (3-7 mmol/l). Controls received saline (n=5). On day 10, plasma adiponectin and proinflammatory markers were measured. Whole-body insulin sensitivity was calculated following an intravenous glucose tolerance test. Tissue mRNAs of glucose metabolism-related genes were quantified in subcutaneous and visceral fat, liver, and skeletal muscles. Accumulation of lipids was assessed in liver. At the termination of infusion, whole-body insulin sensitivity did not differ between groups. Compared to saline, cats infused with lipids had 50% higher plasma adiponectin and 2-3 times higher alpha(1)-acid glycoprotein and monocyte chemoattractant protein-1. Unexpectedly, lipid-infused cats had increased glucose transporter-4 (GLUT4) mRNA in the visceral fat, and increased peroxisome proliferative activated receptor gamma2 (PPARgamma2) in subcutaneous fat; adiponectin expression was not affected in any tissue. Lipid-infused cats developed hepatic steatosis. Although hyperlipidemia induced systemic inflammation, whole-body insulin sensitivity was not impaired after 10 day infusion. Increased circulating adiponectin may have contributed to prevent insulin resistance, possibly by increasing GLUT4 and PPARgamma2 transcripts in fat depots. PMID- 20162506 TI - Sarcoidosis following Cushing's syndrome: A report of two cases and review of the literature. AB - Cushing's syndrome is characterized by excessive elevation of glucocorticoid concentrations. In rare cases, the treatment of Cushing's syndrome may result in unmasking or aggravation of diseases responsive to glucocorticoid medication. We report two cases of sarcoidosis following Cushing's syndrome. A 43 year-old male developed cutaneous sarcoidosis and mediastinal lymphadenopathy after resection of an ACTH-secreting pituitary microadenoma. A 32 year-old female showed cutaneous sarcoidosis, arthralgia, mediastinal lymphadenopathy and elevation of angiotensin-converting enzyme and interleukin 2-receptor concentrations after traumatic adrenal bleeding, which ceased formerly undiagnosed hypercortisolism caused by an adrenal adenoma. Sarcoidosis seems to be a rare sequel following the treatment of hypercortisolism. Skin affections were present and suggestive for the diagnosis in all reported cases. As some cases are probably missed when skin affections are lacking, a more frequent evaluation of patients after Cushing's syndrome for the possible diagnosis of sarcoidosis might be necessary. PMID- 20162507 TI - Role of electrolytes and glucose in the insulin-induced electrochemical effect in sheep pleura. AB - AIM: Insulin induces electrochemical alterations in sheep visceral and parietal pleura, an effect abolished by the Na (+)-channel blocker amiloride and the Na (+)-K (+) pump inhibitor ouabain. The aim of this study was to further investigate the role of different electrolytes and glucose in these electrochemical changes. MATERIALS AND METHODS: Sheep pleural specimens were mounted in Ussing chambers. Insulin (10 (-7)M) was added mesothelially in Na (+), K (+), Ca (2+)-free, low H (+) and glucose solutions. In other experiments, specimens were pretreated with K (+) and Ca (2+)-free Krebs solutions. Trans mesothelial Resistance was determined. RESULTS: Insulin did not increase Trans mesothelial Resistance of visceral and parietal pleura in K (+)-free (p=0.008 and p=0.028 respectively), Ca (2+)-free (p=0.006 and p=0.012 respectively) and low glucose (p=0.009 and p=0.03 respectively) solutions. This effect was totally inhibited in Na (+)-free solutions or in specimens pretreated with Ca (2+) -free Krebs solution and partially inhibited, when low H (+) solutions were used (p=0.042 for visceral and p=0.045 for parietal). CONCLUSION: Insulin-induced electrochemical changes in sheep pleura are mainly associated with alterations in Na (+) and Ca (2+) concentrations. Since amiloride and ouabain abolish these electrochemical changes, it may be suggested that insulin could influence the pleural fluid recycling, mainly via the Na (+) transportation system, irrespective of the glucose content. PMID- 20162508 TI - Fasting plasma glucose is not sufficient to detect ongoing glucose intolerance after pregnancy complicated by gestational diabetes. AB - AIMS: Women who develop diabetes during pregnancy are at significant risk of developing Type 2 diabetes later in life, and "should be offered blood glucose testing ... to exclude persisting hyperglycaemia" after delivery. New UK guidelines now recommend that this is done by measurement of fasting blood glucose, rather than an oral glucose tolerance test (OGTT). Our study aims to establish whether assessment by fasting blood glucose gives equivalent results to an OGTT. METHODS: Retrospective data were obtained from four centres in the West Midlands, UK, who performed a postnatal OGTT on 470 women during a 12-month period. All centres used a 75 g, 2-h protocol. RESULTS: 28 of 470 (6.0%) women had diabetes mellitus after testing of fasting plasma glucose. After OGTT, 70 women (14.9%) were found to have impaired glucose tolerance (IGT), and 10 further cases of diabetes were detected (overall prevalence of DM 8.1%). Of the 400 women with normal fasting plasma glucose. After OGTT, 70 women (14.9%) were found to have impaired glucose tolerance (IGT), and 10 further cases of diabetes were detected (overall prevalence of DM 8.1%). Of the 400 women with normal fasting plasma glucose (< or = 6.0 mmol/l), 55 were found to have impaired glucose tolerance and 4 had overt diabetes. In all, 26% of women with diabetes were missed by FPG. CONCLUSION: Fasting plasma glucose alone does not allow detection of IGT, and misses a substantial proportion of women with Type 2 diabetes. Recognition of ongoing IGT or DM is important in identifying women who may benefit from lifestyle modification, and who may need early intervention in subsequent pregnancies. Our results suggest that OGTT should be the investigation of choice in the postnatal assessment of women who have had GDM. PMID- 20162509 TI - Alpha-lipoic acid improves endothelial dysfunction in patients with subclinical hypothyroidism. AB - OBJECTIVE: Many studies showed that impairment of flow-mediated endothelium dependent arterial dilation (FMD) exists in patients with subclinical hypothyroidism (sHT). The crucial mechanism of this endothelial dysfunction remain unclear. We hypothesized that oxidative stress may be partially responsible for the impairment in FMD in patients with sHT. Thus, the present study was designed to assess whether the antioxidant alpha-lipoic acid can improve endothelial dysfunction in patients with sHT. PATIENTS AND METHODS: Forty women with newly diagnosed sHT and 18 healthy women with euthyroid status were enrolled. Patients were randomized into 2 groups to receive no treatment (n = 20), alpha-lipoic acid (n = 20) for 3 weeks. We measured the FMD at baseline and after 3 weeks. RESULTS: FMD in alpha-lipoic acid and no-treatment group were 3.92% and 4.02%, respectively, which were significantly lower than that in controls (5.64%) (p<0.001). After 3 weeks treatment, compared with before treatment in sHT patients, plasma thiobarbituric acid reactive substances (TBARS) levels decreased significantly in alpha-lipoic acid group (p<0.001), and remain unchanged in no-treatment group (p>0.05). FMD improved markedly (4.82%) in alpha lipoic acid group (p<0.01), and remain unchanged in no-treatment group (p>0.05). The absolute changes in FMD showed significant negative correlation with the changes in TBARS (r = -0.773, p<0.001). CONCLUSION: Our data showed that sHT patients exists impaired endothelial function, and antioxidant alpha-lipoic acid can improve endothelial function, through decrease of oxygen- derived free radicals. PMID- 20162512 TI - [May the Force be with antileukotriene drugs]. PMID- 20162513 TI - [The impact of socioeconomic status on the quality of life in patients with chronic obstructive pulmonary disease]. AB - INTRODUCTION: In addition to the traditional biomedical parameters, quality of life (QoL) evaluation has found its well-deserved place in the overall assessment of patients with chronic obstructive pulmonary disease (COPD). The impact of socioeconomic status (SES) was rarely evaluated in QoL studies in such patients with no such studies having been conducted in Poland. The aim of our study was to compare QoL between COPD patients and the control group and to evaluate the impact of SES, selected demographic characteristics, smoking and bronchial tree obstruction on the QoL in COPD patients. MATERIAL AND METHODS: We enrolled 120 patients with COPD (98 men and 22 women; mean age: 62.3 years) with no comorbidities and 85 healthy individuals (39 men and 46 women; mean age: 56.0 years). All the COPD patients underwent spirometry. QoL was assessed with the SF 36 Health Survey and the St George's Respiratory Questionnaire. To assess SES, demographic variables and smoking we used a questionnaire of our own authorship. RESULTS: COPD patients showed a significantly lower QoL compared to controls. Univariate analysis demonstrated effects of educational background, income, occupation, employment status and bronchial obstruction on the individual QoL domains. Multivariate regression analysis revealed that the sociodemographic factors significantly affecting the overall QoL included: present occupation, employment status, monthly income, educational background and total exposure to cigarette smoke. No effects of age, sex or smoking status on the QoL in COPD were shown. CONCLUSIONS: The QoL in patients with COPD is affected by many factors. In addition to spirometric abnormalities the significant factors that modify QoL are: educational background, monthly income, present occupation and employment status, while sex, age and smoking status do not significantly affect QoL. PMID- 20162514 TI - [Elevated serum NSE level in locally advanced and metastatic NSCLC predispose to better response to chemotherapy but worse survival]. AB - The aim of the study was to evaluate the predictive and prognostic values of elevated serum levels of selected cancer markers (NSE, Cyfra 21-1, CEA, ferritin, free beta-hCG, LDH) in patients with inoperable non-small-cell lung cancer (NSCLC). We investigated a group of 79 patients (49 men and 30 women) with NSCLC. Multivariate regression analysis showed response in patients with NSE > 12.5 ng/ml (p = 0.002), good performance status (p = 0.007) and elderly patients (p = 0.005). However, elevated NSE adversely affected the prognosis. Median survival in patients with NSE < 12.5 ng/ml, 12.5-20.0 ng/ml and > 20.0 ng/ml was 13.3, 11.3 and 6.7 months, respectively (p = 0.004). The negative effect of elevated NSE was independent of the response category. Univariate regression analysis showed that the following factors had a significantly negative effect on the prognosis: performance status, stage IIIB or IV, weight loss of > 10%, NSE > 20 ng/ml, Cyfra 21-1 > 10 ng/ml, CEA > 3 ng/ml, ferritin ratio > 1 and LDH > 480 IU/l. Multivariate analysis showed an independent adverse prognostic effect of stage IIIB or IV and elevated ferritin. PMID- 20162515 TI - [The underdiagnosis and undertreatment of asthma in general population of the Lodz Province (Poland)]. AB - INTRODUCTION: Hundreds of studies investigating the epidemiology of asthma in various populations have been conducted in the past 30 years, yielding a large body of interesting data, including data on prevalence and risk factors. Less information is, however, available on the accurate diagnosis of asthma and its correct treatment. Epidemiological studies of the prevalence of asthma in the general population was conducted between 1998 and 2000 in the Lodz Province in Poland. The present analysis is an evaluation of the detectability and treatment of this disease. MATERIAL AND METHODS: The study group consisted of 1522 randomly selected residents of the Lodz Province aged 3 to 80 years. The demographics and medical history were collected using standardised questionnaires. All the respondents underwent skin prick tests and screening spirometry. Additional diagnostic tests were performed in doubtful cases. RESULTS: Complete data collected from 1340 subjects (1057 adults and 283 children) were included in the analysis. The prevalence of asthma was calculated at 7.3% in adults and 8.5% in children. The accurate diagnosis of asthma had not been made in 71% of symptomatic children and 49% of the adults. Forty-eight percent of adult asthmatics had not used any antiasthmatic medication in the previous 12 months. Subjects suffering from asthma had most commonly used the following drugs in the previous 12 months: beta(2)-agonists (46.8%), anticholinergics (13%), inhalation glucocorticoids (36.4%), oral glucocorticoids (16.9%), parenteral glucocorticoids (3.9%), xanthine derivatives (33.8%) and cromones (11.7%). CONCLUSIONS: The results of this study reveal shortcomings in the healthcare system which require appropriate actions aimed at early diagnosis and improvement of allergy treatment before the patient's health deteriorates irreversibly. PMID- 20162516 TI - [Chronic obstructive pulmonary disease and cardiovascular diseases]. AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Patients with COPD are at increased risk of cardiovascular diseases, osteoporosis and lung cancer. Although some of the associations between COPD and atherosclerosis may be the result of common risk factors such as smoking, epidemiological evidence suggest that impaired lung function is a risk factor for increased cardiovascular death, independent of tobacco use. This phenomenon may be related to common genetic predisposition for atherosclerosis and emphysema. Chronic obstructive pulmonary disease, like atherosclerosis, is a disease of systemic inflammation and may hasten the progression of atherosclerosis and contribute to the higher rate of death in COPD. This article reviews close relationship between COPD and cardiovascular diseases, mainly atherosclerosis. The authors also present some preliminary data suggesting a possible influence of statin therapy on the clinical course of COPD. PMID- 20162517 TI - [Pulmonary neuroendocrine tumors. The spectrum of histologic subtypes and current concept on diagnosis and treatment]. AB - Neuroendocrine tumors of the lung represent a broad spectrum of morphologic types that share specific morphologic, immunohistochemical, ultrastructural, and molecular characteristics. The classification of neuroendocrine lung tumors has changed over the last decades and currently four categories are distinguished: typical carcinoid tumor, atypical carcinoid tumor, large cell neuroendocrine carcinoma and small cell carcinoma. Neuroendocrine tumors of the lung comprise approximately 20% of all primary lung cancers. Among them, the most frequent is small cell carcinoma (13-17%). Because of differences in clinical behavior, therapy, and prognosis, a reliable histological diagnosis, as well as clinical and pathological staging system are essential for an appropriate medical proceedings. The most effective treatment of bronchial carcinoids and large cell neuroendocrine carcinoma in an early stage is complete surgical resection, whereas chemotherapy remains the primary treatment for small cell carcinoma. All carcinoids are malignant tumors with the potential to metastasize. The majority of patients with pulmonary carcinoid have an excellent survival, even if they present with lymph node metastases. Large cell neuroendocrine and small cell carcinoma progress rapidly and are generally widespread at the moment of diagnosis. Their overall prognosis is poor. Increased knowledge about pulmonary neuroendocrine tumors biology and the genetic characteristics, imply that carcinoid tumors appear to have a different etiology and pathogenesis than large cell neuroendocrine and small cell carcinoma. In practice, it could be easiest to conceptualize this group of pulmonary tumors as a spectrum of malignancy ranging from the low grade typical carcinoid to the highly malignant large cell neuroendocrine and small cell carcinoma. Typical carcinoid tumors associated with a fairly benign behavior should be classified as low-grade neuroendocrine tumor/carcinoma (G1) and atypical carcinoid tumors as intermediate-grade tumor/carcinoma (G2). Whereas, large cell neuroendocrine and small cell carcinoma should be grouped together under the designation of high-grade neuroendocrine tumor/carcinoma (G3). PMID- 20162518 TI - [Diagnostics of selected respiratory virus infections]. AB - Viral infections are the most common infectious diseases of the respiratory tract characterized by the considerable mortality (especially among children and elderly people) and considered as the significant economic burden. It has been demonstrated that implementation of rapid diagnostic methods enabled more appropriate treatment of respiratory viral infections, reduced mean hospitalization time and cost, as well as resulted in the significantly decreased mortality. Modern diagnostic methods effectively identify respiratory virus, its antigen or nucleic acids in biological samples by means of the immunological and molecular techniques. This article presents critical overview of those methods with particular emphasis on their clinical usefulness and clinical reliability. PMID- 20162519 TI - [Microbiological diagnosis of respiratory infections caused by Legionella pneumophila]. AB - Legionella pneumophila is an important causative agent of pneumonia in humans which is difficult to diagnose because the signs and symptoms are nonspecific and do not distinguish Legionella infection from other common causes of pneumonia. Currently, the diagnosis of Legionnaires' disease is based on phenotyping (culture, antibody detection in human sera, antigen detection in urine) and genotyping methods such as PCR (polymerase chain reaction). This review focuses on current diagnostic tests for surveillance of Legionella pneumophila infections in Poland. PMID- 20162520 TI - [Antileukotrienes in asthma - critical view]. AB - This article discusses the role of cysteinyl leukotrienes in asthma and addresses the problem of the use of leukotriene receptor antagonists (LTRA) in the treatment of asthma. The author points out that these drugs are inferior to inhaled corticosteroids and long acting beta agonists and should be used as "add on" drugs being a third choice in the management of asthma. Lack of response to LTRA has a genetic background. Side effects of LTRA therapy is discussed, particularly Churg-Strauss syndrome. According to the recent literature, LTRA monotherapy should not be applied. In general, the author suggests that there is a risk of LTRA overtreatment particularly in children. PMID- 20162521 TI - [Status of leukotrienes in the pathophysiology of asthma. Necessity for antileukotrienes treatment]. AB - Asthma is a chronic inflammatory airway disease in which many inflammatory cells and mediators participate. Inhaled corticosteroids (ICs) are recommended as the most effective anti-inflammatory medications currently available for the treatment of asthma. However, some patients don't achieve asthma control even when these agents are used in high doses in monotherapy or in combination with long-acting beta2-mimetics. During asthmatic inflammation various cellular pathways are activated. Among them, leukotriene synthesis pathway is of great importance. Leukotrienes, such as leukotriene C4, D4, E4 (named "cysteinyl leukotrienes") are known as both strong bronchoconstrictors and inflammation stimulators. They increase vascular permeability, mucus production in bronchi and may contribute to airway remodeling. Their chemotactic effect on various inflammatory cells (eosinophils, mast cells, neutrophils) contributes to the maintenance of chronic inflammation in the airways. These biological activities suggest a prominent role of leukotrienes in the pathogenesis of asthma. Although ICs suppress many of the components of asthmatic inflammation, they don't affect the leukotriene synthesis. Thus, additional therapy with leukotriene antagonists, may be beneficial for this group of asthmatics. It is well documented that antileukotrienes have anti-inflammatory and bronchoprotective effects. They are particularly effective in patients with aspirin-sensitive asthma and those with concomitant allergic rhinitis. Antileukotrienes are also used in the prevention of exercise- and cold-air-induced bronchoconstriction. Less effective in monotherapy, as add-on therapy to ICs, antileukotrienes improve asthma control resulting in the reduction of the frequency of asthma exacerbations and the use of short-acting beta2-mimetics as well as the improvement in lung function. This review summarizes current knowledge on the role of leukotrienes in the pathogenesis of asthma and clinical aspects of therapy with antileukotrienes. PMID- 20162522 TI - [Antileukotriene drugs in the treatment of obstructive lung diseases and rhinitis]. AB - Recently published international recommendations including Global INitiative for Asthma, PRACTicing ALLergology and Allergic Rhinitis and its Impact on Asthma offer antileukotriene drugs for adult and childhood asthma and allergic rhinitis. In this article we discuss the arguments for and against antileukotriene drugs therapy in the treatment of obstructive lung diseases and rhinitis. PMID- 20162523 TI - [Pleural sarcoidosis - a report of three cases]. AB - Three patients with pleural sarcoidosis are reported. Pleural effusion in two patients and a massive pleural thickening that mimicked a tumour were observed. Histological examination of pleural biopsies revealed sarcoidosis. None of the patients received treatment. No recurrence of the pleural effusion was observed after a year of follow-up and the massive pleural thickening remained stable. PMID- 20162525 TI - [Common variable immunodeficiency mimicking granulomatous diseases needs to fulfill diagnostic criteria. Commentary to the article of Modrzewska K. et al. "Common variable immunodeficiency in a patient with suspected sarcoidosis"]. PMID- 20162527 TI - Thunder Road--the beginning of a new era. PMID- 20162528 TI - Improvement of immune dysfunction in patients with severe acute pancreatitis by high-volume hemofiltration: a preliminary report. AB - OBJECTIVE: The aim of this study was to investigate the effect of high-volume hemofiltration (HVHF) on ameliorating immune dysfunction in patients with severe acute pancreatitis (SAP). METHODS: Twelve patients diagnosed with SAP admitted to the intensive care unit of general surgery, Jinling Hospital, from January 2004 to December 2006 were included in this study. They were assigned to the standard medical therapy group (SMT group, n=4) or HVHF group (n=8) immediately after enrollment, in a 1:2 ratio. The SMT group were given standard treatment for SAP, while the HVHF group were given standard as well as 72-hour HVHF treatment initiated within 2 hours after enrollment. Patients in the 2 groups were comparable for the baseline clinical parameters. All patients were monitored over a 72-hour observation period for continuous clinical status, blood cell counts including monocytes, CD4+ and CD8+ T cells, and HLA-DR expression on monocytes. Blood samples were collected from those patients at 0, 6, 12, 24, 48, and 72 hour after enrollment for measurement of plasma Th1-type cytokines (interleukin-1 [IL 1], IL-2, interferon-gamma [IFN-gamma], and tumor necrosis factor-alpha [TNF alpha]) and Th2-type cytokines (IL-4, IL-5, IL-6, IL-IO, and IL-13) using ELISA. RESULTS: Within 72 hours, all measured cytokines except IL-4 were maintained at high levels, accompanied with a low level of peripheral monocytes, CD4+ and CD8+ T cell counts, and HLA-DR expression. Seventy-two hours later, plasma cytokines IFN-gamma, IL-1, IL-2, IL-5, IL-10, and IL-13 (p<0.05), but not TNF-alpha and IL 6, in patients in the HVHF group were significantly reduced, while there was no change for these parameters in the SMT group. Plasma levels of IFN-gamma, TNF alpha, IL-1, IL-2, IL-5, and IL-13 in the HVHF group were significantly lower than those in the SMT group. Peripheral CD4+ and CD8+ T cells, monocyte count, and HLA-DR expression were increased significantly (p<0.05) only in the HVHF group, not in the SMT group. HLA-DR expression in the HVHF group was significant higher than that in the SMT group (p<0.05). CONCLUSIONS: HVHF significantly reduced plasma inflammatory cytokine concentrations including those of IFN-gamma, TNF-alpha, IL-1, IL-2, IL-5, and IL-13, while it increased monocyte HLA-DR expression in patients with SAP. The association of plasma cytokine reduction and cellular immune function recovery and clinical outcome needs further investigation. PMID- 20162529 TI - Population study about the attitude toward organ xenotransplantation in the population from Eastern Europe resident in southeast Spain. AB - BACKGROUND: The objective of this paper is to analyze the attitude toward xenotransplantation and to determine the variables that influence this attitude in the population of southeast Spain who were born in Eastern European countries. METHODS: A random sample was taken of natives from Eastern Europe residing in southeast Spain (n=320). The sample was obtained randomly between November 2005 and April 2006 and stratified according to the respondents' nationality. Attitude was evaluated using a validated questionnaire which was self-administered and completed anonymously. The control group was a random sample of the native Spanish population (n=250). The statistical analysis used included Student's t test, the chi-square test, Fisher's exact test, and a logistic regression analysis. RESULTS: The questionnaire completion rate was 83% (n=267). Regarding the use of animal organs for transplantation in humans, if the outcome were similar to that achieved when using human organs, 43% (n=114) would be in favor, 32% (n=86) undecided, and the remaining 25% (n=67) would be against it. This attitude is less favorable than in the control group (43% versus 74%, p<0.001). The attitude was related to the following factors: 1) the country of origin (p<0.001); 2) participation in social help activities (p<0.001); 3) discussion on organ donation and transplantation within the family (p=0.005); 4) previous experience of organ donation and transplantation (p=0.002); 5) the respondent's religion (p=0.002); 6) knowing that one's partner had a favorable attitude toward transplantation (p<0.001); 7) the respondent's belief that he or she might need a transplant in the future (p<0.001); 8) the attitude toward human donation, both from cadaver (p<0.001) and living (p<0.001) donors. The following were also independent variables in the subsequent multivariate analysis: 1) favorable attitude toward cadaver organ donation (OR=4.998); 2) previous experience of donation (0R=2.857); 3) partner's attitude against transplantation (OR=0.079); and 4) attitude toward living donation (OR=12. 703). CONCLUSIONS: The attitude toward xenotransplantation is less positive among Eastern Europeans living in Spain than in the native Spanish population and is influenced by many psychosocial factors that are mainly related to human organ donation. PMID- 20162530 TI - Functional characterization of the unconventional splicing of Yarrowia lipolytica HAC1 mRNA induced by unfolded protein response. AB - In the yeast Saccharomyces cerevisiae, the unfolded protein response (UPR) involves the unconventional splicing of HAC1 mRNA, which is mediated by the activated Ire1p transmembrane kinase/endonuclease. In this study, we isolated and characterized a Yarrowia lipolytica HAC1 (YlHAC1) encoding a basic-leucine zipper transcription factor. The null mutant strain of YlHAC1 (DeltaYlhac1) displayed a significantly increased sensitivity to dithiothreitol (DTT) and tunicamycin (TM), along with a defect in hyphal growth, suggesting the essential function of YlHAC1 in UPR. The unconventional splicing of YlHAC1 mRNA occurred under the UPR conditions induced by DTT or TM treatment. Unlike S. cerevisiae HAC1 mRNA with an intron of 252 nt, YlHAC1 mRNA was shown to harbour a short intron of length 29 nt. The YlHAC1 mRNA harboured the nucleotides CAG, conserved at the intron borders in the filamentous fungi hac1/hacA and mammalian XBP1, as well as a conserved bipartite element within the 3' untranslated region. The expression of the spliced form of YlHAC1 mRNA in the wild-type andDeltaYlhac1 strains resulted in an increased resistance to DTT, thereby indicating that the spliced form is translated into a functional YlHac1p. PMID- 20162531 TI - Multiple bHLH proteins regulate CIT2 expression in Saccharomyces cerevisiae. AB - The basic helix-loop-helix (bHLH) proteins comprise a eukaryotic transcription factor family involved in multiple biological processes. They have the ability to form multiple dimer combinations and most of them also bind a 6 bp site (E-box) with limited specificity. These properties make them ideal for combinatorial regulation of gene expression. The Saccharomyces cerevisiae CIT2 gene, which encodes citrate synthase, was previously known to be induced by the bHLH proteins Rtg1p and Rtg3p in response to mitochondrial damage. Rtg1p-Rtg3p dimers bind two R-boxes (modified E-boxes) in the CIT2 promoter. The current study tested the ability of all nine S. cerevisiae bHLH proteins to regulate the CIT2 gene. The results showed that expression of CIT2-lacZ reporter was induced in a rho(0) strain by the presence of inositol via the Ino2p and Ino4p bHLH proteins, which are known regulators of phospholipid synthesis. Promoter mutations revealed that inositol induction required a distal E-box in the CIT2 promoter. Interestingly, deleting the INO2, INO4 genes or the cognate E-box revealed phosphate induction of CIT2 expression. This layer of expression required the two R-boxes and the Pho4p bHLH protein, which is known to be required for phosphate-specific regulation. Lastly, the data show that the Hms1p and Sgc1p bHLH proteins also play important roles in repression of CIT2-lacZ expression. Collectively, these results support the model that yeast bHLH proteins coordinate different biological pathways. PMID- 20162532 TI - Chemical inhibition of CaaX protease activity disrupts yeast Ras localization. AB - Proteins possessing a C-terminal CaaX motif, such as the Ras GTPases, undergo extensive post-translational modification that includes attachment of an isoprenoid lipid, proteolytic processing and carboxylmethylation. Inhibition of the enzymes involved in these processes is considered a cancer-therapeutic strategy. We previously identified nine in vitro inhibitors of the yeast CaaX protease Rce1p in a chemical library screen (Manandhar et al., 2007). Here, we demonstrate that these agents disrupt the normal plasma membrane distribution of yeast GFP-Ras reporters in a manner that pharmacologically phenocopies effects observed upon genetic loss of CaaX protease function. Consistent with Rce1p being the in vivo target of the inhibitors, we observe that compound-induced delocalization is suppressed by increasing the gene dosage of RCE1. Moreover, we observe that Rce1p biochemical activity associated with inhibitor-treated cells is inversely correlated with compound dose. Genetic loss of CaaX proteolysis results in mistargeting of GFP-Ras2p to subcellular foci that are positive for the endoplasmic reticulum marker Sec63p. Pharmacological inhibition of CaaX protease activity also delocalizes GFP-Ras2p to foci, but these foci are not as strongly positive for Sec63p. Lastly, we demonstrate that heterologously expressed human Rce1p can mediate proper targeting of yeast Ras and that its activity can also be perturbed by some of the above inhibitors. Together, these results indicate that disrupting the proteolytic modification of Ras GTPases impacts their in vivo trafficking. PMID- 20162533 TI - Association of two clones allows for optimal detection of human FOXP3. AB - FOXP3 is a key transcription factor expressed by regulatory T cells (Treg cells). However, differences in staining and analysis protocols have led to conflicting results. Moreover, the transient upregulation of FOXP3 that follows activation in non-Treg cells renders the interpretation of FOXP3 data more difficult in humans than in mice. Human peripheral blood mononuclear cells (PBMCs), isolated CD25(-) or CD25(+)CD4(+) T cells were stained with three different anti-FOXP3 clones (PCH101, 206D, and 259D) alone or in combination, and using different permeabilization methods. FOXP3 expression was evaluated following T cell activation by several pathways. Gating based on a population that did not express FOXP3 (such as CD3(-)CD4(-) T cells) allowed for the optimal characterization of Treg cells. The 206D clone detected a lower percentage of cells than PCH101 or 259D. In contrast, 259D stained a population of activated T cells that PCH101 did not. Staining with two clones together consistently increased the proportion of FOXP3(+) cells. However, it is likely that only the double positive cells are Treg cells, as they expressed the highest CD25 and lowest CD127 levels. Our results emphasize that the choice of staining protocol leads to very different results concerning the frequency of Treg cells in humans. A more consistent identification of these cells will improve the knowledge of their biology, particularly during disease processes. PMID- 20162534 TI - DeadEasy neurons: automatic counting of HB9 neuronal nuclei in Drosophila. AB - Research into the genetic basis of nervous system development and neurodegenerative diseases requires counting neurons to find out the extent of neurogenesis or neuronal loss. Drosophila is a widely used model organism for in vivo studies. However, counting neurons throughout the nervous system of the intact animal is humanly unfeasible. Automatic methods for cell counting in intact Drosophila are desirable. Here, we show a method called DeadEasy Neurons to count the number of neurons stained with anti-HB9 antibodies in Drosophila embryos. DeadEasy Neurons employs image filtering and mathematical morphology techniques in 2D and 3D, followed by identification of nuclei in 3D based on minimum volume, to count automatically the number of HB9 neurons in vivo. The resultant method has been validated for Drosophila embryos and we show here how it can be used to address biological questions. Counting neurons with DeadEasy is very fast, extremely accurate, and objective, and it enables analyses otherwise humanly unmanageable. DeadEasy Neurons can be modified by the user for other applications, and it will be freely available as an ImageJ plug-in. DeadEasy Neurons will be of interest to the microscopy, image processing, Drosophila, neurobiology, and biomedical communities. PMID- 20162535 TI - Society of Urodynamics and Female Urology 2010 Winter Meeting, February 23-27, 2010, St. Petersburg, Florida. Abstracts. PMID- 20162536 TI - Reagents for investigating MAPK signalling in model yeast species. AB - Here we present a set of resources (bacterial expression plasmids and antibodies) for the interrogation of proteins involved in yeast MAPK signalling. We constructed bacterial protein expression plasmids for 25 proteins involved in MAPK signalling in budding yeast. From these constructs we expressed and purified proteins and generated rabbit polyclonal antibodies against 13 proteins in the pheromone MAPK pathway. We verified the specificity of the antibodies and employed them to follow pathway proteins in cells stimulated with pheromone. We show that these reagents can be used to detect pheromone-induced post translational modifications and changes in the oligomeric state of pathway proteins. In addition to recognizing their target proteins in Saccharomyces cerevisiae, these antibodies allow the detection of predicted orthologues in the distant evolutionary relatives Kluyveromyces lactis and Schizosaccharomyces pombe. These antibodies are new tools for investigating MAPK signalling in model yeast species and may be useful for studying MAPK signalling in higher eukaryotes. PMID- 20162537 TI - Development of a fast liquid chromatography/mass spectrometry screening method for angiotensin-converting enzyme (ACE) inhibitors in complex natural mixtures like snake venom. AB - A new robust high-performance liquid chromatography/electrospray ionization mass spectrometry (HPLC/ESI-MS)-based screening method for angiotensin-converting enzyme (ACE)-inhibiting substances in crude samples is described. The ACE assay is carried out in a typical offline setup by incubation of the samples with ACE and angiotensin I (AI), followed by stopping the reaction with acetonitrile containing val(5)-AI serving as internal standard (I.S.). AI and the product angiotensin II (AII) are extracted from the incubation mixture by turbulent-flow chromatography (TFC) applied in backflush mode as online solid-phase extraction and are directly quantified by ESI(+)-MS. The presence of ACE inhibitors (ACEi) is detected by an increase in AI signal intensity and a corresponding decrease of AII signal, as compared to the blank assay. The overall time of analysis of the TFC/ESI-MS method was 5 min, thus making the described setup suitable for a rapid screening method. The assay was validated using a known ACE inhibitor and the IC(50) values found were in good accordance with a common HPLC/UV method and literature data. The method was successfully applied for the screening of size exclusion chromatography fractions of the venom of the pitviper Bothrops moojeni. Three of 18 analyzed fractions inhibited ACE, due to peptides present as components of this snake venom. These compounds were extracted from the two most active fractions by means of TFC and isolated by means of HPLC. Three peptides with ACE inhibitory activity were characterized and their structures were elucidated with ESI-MS/MS-based de novo sequencing to be ZKWPPGKVPP, ZKWPRPGPEIPP and ZNWPRPGPEIPP, respectively (Z = pyroglutamic acid). PMID- 20162539 TI - Gastrointestinal involvement and manifestations in systemic mastocytosis. AB - Mastocytosis is a rare and heterogeneous disease characterized by various biological and clinical features with different prognosis and treatments. The disease is usually divided into 2 categories: a pure cutaneous and a systemic disease. Clinical features can be related to mast cells' mediators release or to pathological mast cells infiltration. The diagnosis of mastocytosis is based on clinical, biological, histological, and molecular international criteria. Among all manifestations of the disease, gastrointestinal (GI) symptoms are common and can significantly impair the quality of life. The aim of this article is to review the data regarding GI involvement in mastocytosis. Articles dealing with clinical, pathophysiological, and therapeutic aspects of mastocytosis GI tract involvement were searched for using PubMed. GI manifestations in mastocytosis are reviewed. Pathogenesis of GI symptoms in systemic mastocytosis and their treatment are critically discussed. The most frequent GI symptoms are abdominal pain, diarrhea, nausea, and vomiting. GI lesions may involve all the digestive tract, from the esophagus to the rectum. The histological diagnosis of GI involvement is difficult. The treatment of GI symptoms aims to prevent and limit mast cells degranulation and/or its consequences and more rarely to control tumoral mast cells infiltration. The high prevalence of GI symptoms in mastocytosis and their important functional impact deserves better characterization and treatment in order to improve patients' quality of life. Diagnosis of mastocytosis GI manifestations should be evoked in the case of unexplained severe GI disorders. PMID- 20162538 TI - Genetic characterization of specific pathogen-free rhesus macaque (Macaca mulatta) populations at the California National Primate Research Center (CNPRC). AB - A study based on 14 STRs was conducted to understand intergenerational genetic changes that have occurred within the California National Primate Research Center's (CNPRC) regular specific pathogen-free (SPF) and super-SPF captive rhesus macaque populations relative to their conventional founders. Intergenerational genetic drift has caused age cohorts of each study population, especially within the conventional population, to become increasingly differentiated from each other and from their founders. Although there is still only minimal stratification between the conventional population and either of the two SPF populations, separate derivation of the regular and super-SPF animals from their conventional founders has caused the two SPF populations to remain marginally different from each other. The regular SPF and, especially, the super SPF populations have been influenced by the effects of differential ancestry, sampling, and lost rare alleles, causing a substantial degree of genetic divergence between these subpopulations. The country of origin of founders is the principal determinant of the MHC haplotype composition of the SPF stocks at the CNPRC. Selection of SPF colony breeders bearing desired genotypes of Mamu-A*01 or -B*01 has not affected the overall genetic heterogeneity of the conventional and the SPF research stocks.Because misclassifying the ancestry of research stocks can undermine experimental outcomes by excluding animals with regional-specific genotypes or phenotypes of importance, understanding founder/descendent genetic relationships is crucial for investigating candidate genes with distinct geographic origins. Together with demographic management, population genetic assessments of SPF colonies can curtail excessive phenotypic variation among the study stocks and facilitate successful production goals. PMID- 20162540 TI - Reduced intensity conditioning regimen with fludarabine, busulfan, and low-dose TBI (Flu-BU2-TBI): clinical efficacy in high-risk patients. AB - Reduced intensity conditioning (RIC) regimens are widely used in allogeneic stem cell transplantation (SCT). In this study, we retrospectively investigated the clinical outcomes of RIC with fludarabine (Flu; 180 mg/m(2)), intravenous busulfan (BU; 6.4 mg/kg) or oral BU (8 mg/kg), and low-dose total body irradiation (TBI; 4 Gy) (Flu-BU2-TBI) in 66 patients (median age: 54.5 years) with various hematological malignancies. Thirty-eight patients (58%) were high risk patients (median age: 56 years). The overall survival rate at 2 years of the high-risk patients was 64.5%, which was comparable to the survival rate of 70.9% in standard-risk patients (P = 0.68). The relapse rates at 2 years in the standard-risk and high-risk patients were 16 and 28%, respectively, and day 100 treatment-related mortality rates were 0 and 6%, respectively. The Flu-BU2-TBI regimen for high-risk patients showed therapeutic effects equivalent to those for standard-risk patients and favorable outcomes compared with those of other previous RIC regimens. PMID- 20162542 TI - All that glitters is gold? PMID- 20162541 TI - Non-myeloablative conditioning and allogeneic transplantation for multiple myeloma. AB - In multiple myeloma (MM), allogeneic stem cell transplantation (alloHCT) carries a lower relapse risk than autologous transplantation but a greater transplant related mortality. Nonmyeloablative conditioning for allogeneic transplantation (NST) reduces transplant-related toxicity. Results are encouraging when used during first remission in low-risk patients, but less-so in relapsed or refractory disease. This is a single-center retrospective analysis of 20 previously treated MM patients who underwent NST from matched-related or matched unrelated donors from 2000-2006. Median age was 52.7 years (37.2-68.0). Twenty five percent had advanced or high-risk disease. Eleven still had active disease prior to NST. Conditioning was total body irradiation 200 cGy on a single fraction on day -5, followed by antithymocyte globulin (ATG) 1.5 mg/kg/day and fludarabine 30 mg/m(2)/day on days -4 to -2. All received immunosuppression, most commonly with oral mycofenylate mofetil and cyclosporine beginning on day -5. At day 100, 50% had achieved complete remission. Transplant-related mortality was 25%. Median overall survival (OS) was 21.2 months (0.6-90+) and progression-free survival (PFS) 6.6 months (0.6-90+). Both OS and PFS were 24% at 3 years. OS was significantly greater for patients with age <52 years (median 27 months vs. 7.9 months, P = 0.031), and there was a trend toward greater OS for those with beta2 microglobulin <2.5 mg/l (median 27 months vs. 7.7 months, P = 0.08). Donor characteristics and Ig type had no significant effect on survival. These data suggest a benefit of NST in relapsed/refractory MM. Randomized trials must be performed to confirm and further qualify this benefit. PMID- 20162543 TI - Liver function tests and absolute lymphocyte count at day +100 are predictive factors for extensive and severe chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplant. PMID- 20162544 TI - Analytic validity of genetic tests to identify factor V Leiden and prothrombin G20210A. AB - The objective of this study is to systematically review methods for detecting Factor V Leiden or prothrombin G20210A. English-language literature from MEDLINE, EMBASE, The Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature, PsycInfo(c), 2000-December 2008. Studies assessed methods for detection of these mutations in at least 10 human blood samples and reported concordance, discordance, or reproducibility. Two investigators abstracted data on the sample selection criteria, test operators, DNA extraction, experimental test, reference standard, commercial instruments, concordance rates, explanation of any discordance, and whether discordance resolved after repetition. We assessed strength of the evidence using the GRADE criteria. We reviewed 7,777 titles and included 66 articles. The majority of the reviewed studies used PCR RFLP or AS-PCR as the reference standard. The studies demonstrated that commercially available and precommercial tests have high analytic validity with all having greater than 99% concordance with the reference standard. With a few exceptions, discordance resolved with repetition of the test, suggesting operator or administrative errors were responsible for the discordant results. In the quality assurance studies, greater than 98% of laboratories demonstrated high, even perfect, accuracy when asked to diagnose a sample with a known mutation. The majority of errors came from a limited number of laboratories. Although not all methods may be accurate, there is high-grade evidence that genetic tests for the detection of FVL and prothrombin G20210A have excellent analytic validity. There is high-grade evidence that most, but not all, clinical laboratories test for FVL and prothrombin G20210A accurately. PMID- 20162545 TI - Vitamin D status may effect the skeletal complications of multiple myeloma. PMID- 20162546 TI - Is the JAK2(V617F) mutation detectable in healthy volunteers? PMID- 20162548 TI - Mixed-mode chromatography/isotope ratio mass spectrometry. AB - Liquid chromatography coupled to molecular mass spectrometry (LC/MS) has been a standard technique since the early 1970s but liquid chromatography coupled to high-precision isotope ratio mass spectrometry (LC/IRMS) has only been available commercially since 2004. This development has, for the first time, enabled natural abundance and low enrichment delta(13)C measurements to be applied to individual analytes in aqueous mixtures creating new opportunities for IRMS applications, particularly for the isotopic study of biological molecules. A growing number of applications have been published in a range of areas including amino acid metabolism, carbohydrates studies, quantification of cellular and plasma metabolites, dietary tracer and nucleic acid studies. There is strong potential to extend these to new compounds and complex matrices but several challenges face the development of LC/IRMS methods. To achieve accurate isotopic measurements, HPLC separations must provide baseline-resolution between analyte peaks; however, the design of current liquid interfaces places severe restrictions on compatible flow rates and in particular mobile phase compositions. These create a significant challenge on which reports associated with LC/IRMS have not previously focused. Accordingly, this paper will address aspects of chromatography in the context of LC/IRMS, in particular focusing on mixed-mode separations and their benefits in light of these restrictions. It aims to provide an overview of mixed-mode stationary phases and of ways to improve high aqueous separations through manipulation of parameters such as column length, temperature and mobile phase pH. The results of several practical experiments are given using proteogenic amino acids and nucleosides both of which are of noted importance in the LC/IRMS literature. This communication aims to demonstrate that mixed-mode stationary phases provide a flexible approach given the constraints of LC/IRMS interface design and acts as a practical guide for the development of new chromatographic methods compatible with LC/IRMS applications. PMID- 20162547 TI - Lactational programming? Mother's milk energy predicts infant behavior and temperament in rhesus macaques (Macaca mulatta). AB - There are many aspects of "mothering" that may provide information to the mammalian infant about environmental conditions during critical periods of development. One essential element of mothering involves the quantity and quality of milk that mothers provide for their infants, but little is known about the consequences of variation in milk production. Mother's milk may affect infant behavior by contributing to brain development and to the development of behavioral dispositions. Here we present the first evidence for any mammal that natural variation in available milk energy (AME) from the mother is associated with later variation in infant behavior and temperament in rhesus macaques (Macaca mulatta, N=59). In the early postnatal period, heavier mothers with more reproductive experience produced greater AME, which is the product of milk energy density (kcal/g) and milk yield (g). Moreover, infants whose mothers produced greater AME in the early postnatal period showed higher activity levels and greater confidence in a stressful setting later in infancy. Our results suggest that the milk energy available soon after birth may be a nutritional cue that calibrates the infant's behavior to environmental or maternal conditions. These data provide new insight into potential mechanisms for the development of behavior and temperament and illuminate new directions for investigating maternal effects, nutritional programming, and developmental plasticity. PMID- 20162549 TI - Inhibition of HIV replication by a CD4-reactive Fab of an IgM clone isolated from a healthy HIV-seronegative individual. AB - HIV replication is restricted by some anti-CD4 mouse mAb in vitro and in vivo. However, a human monoclonal anti-CD4 Ab has not been isolated. We screened EBV transformed peripheral B cells from 12 adult donors for CD4-reactive Ab production followed by functional reconstitution of Fab genes. Three independent IgM Fab clones reactive specifically to CD4 were isolated from a healthy HIV seronegative adult (approximately 0.0013% of the peripheral B cells). The germ line combinations for the VH and VL genes were VH3-33/L6, VH3-33/L12, and VH4 4/L12, respectively, accompanied by somatic hypermutations. Genetic analysis revealed a preference for V-gene usage to develop CD4-reactive Ab. Notably, one of the CD4-reactive clones, HO538-213, with an 1 x 10(-8) M dissociation constant (Kd) to recombinant human CD4, limited the replication of R5-tropic and X4-tropic HIV-1 strains at 1-2.5 microg/mL in primary mononuclear cells. This is the first clonal genetic analysis of human monoclonal CD4-reactive Ab. A mAb against CD4 isolated from a healthy individual could be useful in the intervention of HIV/AIDS. PMID- 20162550 TI - Alpha-GalCer ameliorates listeriosis by accelerating infiltration of Gr-1+ cells into the liver. AB - Alpha-galactosylceramide (alpha-GalCer) activates invariant (i)NKT cells, which in turn stimulate immunocompetent cells. Although activation of iNKT cells appears critical for regulation of immune responses, it remains elusive whether protection against intracellular bacteria can be induced by alpha-GalCer. Here, we show that alpha-GalCer treatment ameliorates murine listeriosis, and inhibits inflammation following Listeria monocytogenes infection. Liver infiltration of Gr 1+ cells and gamma/delta T cells was accelerated by alpha-GalCer treatment. Gr-1+ cell and gamma/delta T-cell depletion exacerbated listeriosis in alpha-GalCer treated mice, and this effect was more pronounced after depletion of Gr-1+ cells than that of gamma/delta T cells. Although GM-CSF and IL-17 were secreted by NKT cells after alpha-GalCer treatment, liver infiltration of Gr-1+ cells was not prevented by neutralizing mAb. In parallel to the numerical increase of CD11b+Gr 1+ cells in the liver following alpha-GalCer treatment, CD11b-Gr-1+ cells were numerically reduced in the bone marrow. In addition, respiratory burst in Gr-1+ cells was enhanced by alpha-GalCer treatment. Our results indicate that alpha GalCer-induced antibacterial immunity is caused, in part, by accelerated infiltration of Gr-1+ cells and to a lesser degree of gamma/delta T cells into the liver. We also suggest that the infiltration of Gr-1+ cells is caused by an accelerated supply from the bone marrow. PMID- 20162551 TI - A regulatory role for macrophage class A scavenger receptors in TLR4-mediated LPS responses. AB - Recognition of microbial components by TLR, key sensors of infection, leads to induction of inflammatory responses. We found that, in vivo, TLR4 engagement by LPS induces up-regulation of the class A scavenger receptors (SR) macrophage receptor with a collagenous structure (MARCO) and SR-A, which occurs, at least in the case of MARCO, via both MyD88-dependent and -independent pathways. When challenging mice with a low dose of LPS followed by a high dose, class A SR deficient mice showed a higher survival rate than WT mice. This was paired with increased production of IL-10 and anti-LPS Ab, as well as increased activation status of marginal zone B cells. However, the receptors were not crucial for survival when challenging mice i.p. with Neisseria meningitidis or Listeria monocytogenes, but they were found to contribute to microbial capture and clearance. This indicates physiological significance for the up-regulation of class A SR during early stages of bacterial infection. Thus, we believe that we have revealed a mechanism where SR regulate the activation status of the immune system and are involved in balancing a proper immune response to infection. This regulation could also be important in maintaining tolerance since these receptors have been shown to be involved in regulation of self-reactivity. PMID- 20162552 TI - H2-M3-restricted CD8+ T cells augment CD4+ T-cell responses by promoting DC maturation. AB - Infection with Listeria monocytogenes triggers the activation and expansion of nonconventional CD8+ T cells restricted by the MHC class Ib molecule, H2-M3. H2 M3-restricted CD8+ T cells exhibit a memory phenotype, rapidly produce cytokines, and reach peak frequencies sooner than conventional MHC class Ia-restricted CD8+ T cells. In this study, we found that simultaneous in vivo priming of H2-M3 restricted T cells and adoptively transferred OT-II CD4+ T cells on the same DC enhances the survival of OT-II cells. Stimulation of H2-M3-restricted T cells were found to induce DC maturation resulting in costimulatory molecule upregulation and production of TH1-type cytokines, which was dependent on both cell-to-cell contact and soluble factors, particularly TNF-alpha, produced by activated H2-M3-restricted T cells. Interestingly, H2-M3-restricted T cells were more efficient than activated NK cells in inducing DC maturation. Furthermore, we found that OVA(323-339)-coated DC matured by coculturing with peptide-stimulated H2-M3-restricted T cells were more efficient in stimulating the proliferation of Ag-activated OT-II cells. This study indicates that H2-M3-restricted T cells promote immune responses by CD4+ T cells by inducing DC maturation and suggests novel mechanisms for vaccine development. PMID- 20162553 TI - Regulation of the autophagic machinery in human neutrophils. AB - The induction of the autophagy machinery, a process for the catabolism of cytosolic proteins and organelles, constitutes a crucial mechanism in innate immunity. However, the involvement of autophagy in human neutrophils and the possible inducers of this process have not been completely elucidated. In this study, the induction of autophagy was examined in human neutrophils treated with various activators and detected by the formation of acidified autophagosomes through monodansylcadaverine staining and via LC-3B conversion screened by immunoblotting and immunofluorescence confocal microscopy. In addition, the expression of the ATG genes was assessed by real-time RT-PCR. We provide evidence that autophagy is implicated in human neutrophils in both a phagocytosis independent (rapamycin, TLR agonists, PMA) and phagocytosis (Escherichia coli) dependent initiation manner. ROS activation is a positive mechanism for autophagy induction in the case of PMA, TLR activation and phagocytosis. Furthermore, LC3B gene expression was uniformly upregulated, indicating a transcriptional level of regulation for the autophagic machinery. This study provides a stepping stone toward further investigation of autophagy in neutrophil-driven inflammatory disorders. PMID- 20162554 TI - Antigenic strength controls the generation of antigen-specific IL-10-secreting T regulatory cells. AB - Administration of peptides i.n. induces peripheral tolerance in Tg4 myelin basic protein-specific TCR-Tg mice. This is characterized by the generation of anergic, IL-10-secreting CD4+ T cells with regulatory function (IL-10 Treg). Myelin basic protein Ac1-9 peptide analogs, displaying a hierarchy of affinities for H-2 A(u) (Ac1-9[4K]<<[4A]<[4Y]), were used to investigate the mechanisms of tolerance induction, focusing on IL-10 Treg generation. Repeated i.n. administration of the highest affinity peptide, Ac1-9[4Y], provided complete protection against EAE, while i.n. Ac1-9[4A] and Ac1-9[4K] treatment resulted in only partial protection. Ac1-9[4Y] was also the most potent stimulus for IL-10 Treg generation. Although i.n. treatment with Ac1-9[4A] gave rise to IL-10-secreting CD4+ T cells, the population as a whole was also capable of secreting IFN-gamma after an in vitro recall response to Ac1-9[4A] or [4Y]. In addition to IL-10 production, other facets of tolerance, namely, anergy and suppression (both in vitro and in vivo), were affinity dependent, with i.n. Ac1-9[4Y]-, [4A]- or [4K]-treated CD4+ T cells being the most, intermediate and least anergic/suppressive, respectively. These findings demonstrate that the generation of IL-10 Treg in vivo is driven by high signal strength. PMID- 20162555 TI - c-Rel: a pioneer in directing regulatory T-cell lineage commitment? AB - The transcription factor Foxp3 controls the differentiation and function of Treg, but the molecular mechanisms that regulate Foxp3 transcription remain elusive. In particular, signals and factors that open and remodel the Foxp3 locus and imprint developing Treg with a stable Foxp3 phenotype are largely unknown. Two reports in this issue of the European Journal of Immunology, together with recent reports published elsewhere, demonstrate that a member of the NF-kappaB family transcription factors, c-Rel, is required for thymic differentiation of Foxp3(+) Treg. Moreover, c-Rel is shown to regulate Foxp3 transcription directly by binding to cis-regulatory elements at the Foxp3 locus upon TCR/CD28 stimulation, including the promoter and the newly identified conserved non-coding DNA sequence harboring a "permissive" chromatin status in Treg precursors. These findings collectively suggest that c-Rel may act as a pioneer transcription factor in initiating Foxp3 transcription in Treg precursors in the thymus. PMID- 20162556 TI - A simple and efficient frit preparation method for one-end tapered-fused silica packed capillary columns in nano-LC-ESI MS. AB - A novel frit preparation method for one-end tapered-fused silica-packed capillary columns in nano-LC-ESI MS was developed. A hollow-fused silica capillary column with a tapered tip as nano-spray emitter was filled with 5 microm C(18) beads, and then a sintered frit about 0.25 mm in length was prepared at the tip by butane flame. A stainless steel protection tube with 0.5 mm id was used to control the length of the frit and to protect the packed C(18) beads behind the sintered frit during the sintering. C(18) sintered frits were evaluated by BSA tryptic digests with nano-LC-LTQ. The sintered frits did not produce post-column band broadening due to very small volume (about 0.2 nL) and did not produce adsorption to sample. The sintered frit columns had good separation reproducibility and separation performance compared with self-assembled particles frit columns and commercial columns. PMID- 20162557 TI - Use of SELDI MS to discover and identify potential biomarkers of toxicity in InnoMed PredTox: a multi-site, multi-compound study. AB - A serious bottleneck in the drug development pipeline is the inability of current pre-clinical toxicology evaluation methods to predict early on, and with good accuracy, that a drug candidate will have to be removed from development due to toxicology/safety issues. The InnoMed PredTox consortium attempted to address this issue by assessing the value of using molecular profiling techniques (proteomics, transcriptomics, and metabonomics), in combination with conventional toxicology measurements, on decision making earlier in pre-clinical safety evaluation. In this study, we report on the SELDI-TOF-MS proteomics component of the InnoMed PredTox project. In this large scale, multi-site, multi-compound study, tissue and plasma samples from 14-day in vivo rat experiments conducted for 16 hepato- and nephro-toxicants with known toxicology endpoints (including 14 proprietary compounds and 2 reference compounds) were analyzed by SELDI-TOF-MS. We have identified seven plasma proteins and four liver proteins which were shown to be modulated by treatment, and correlated with histopathological evaluations and can be considered potential biomarker candidates for the given toxicology endpoints. In addition, we report on the intra- and inter-site variations observed based on measurements from a reference sample, and steps that can be taken to minimize this variation. PMID- 20162558 TI - Identification of Neospora caninum proteins regulated during the differentiation process from tachyzoite to bradyzoite stage by DIGE. AB - Identification of differentially expressed proteins during Neospora caninum tachyzoite-bradyzoite conversion processes may lead to a better knowledge of the pathogenic mechanisms developed by this important parasite of cattle. In the present work, a differential expression proteomic study of tachyzoite and bradyzoite stages was accomplished for the first time by applying DIGE technology coupled with MS analysis. Up to 72 differentially expressed spots were visualized (1.5-fold in relative abundance, p<0.05, t-test). A total of 53 spots were more abundant in bradyzoites and 19 spots in tachyzoites. MS analysis identified 26 proteins; 20 of them overexpressed in the bradyzoite stage and 6 in the tachyzoite stage. Among the novel proteins, enolase and glyceraldehyde-3 phosphate dehydrogenase (involved in glycolysis), HSP70 and HSP90 (related to stress response) as well as the dense granule protein GRA9, which showed higher abundance in the bradyzoite stage, might be highlighted. On the other hand, isocitrate dehydrogenase 2, involved in the Krebs cycle, was found to be more abundant in tachyzoites extract. Biological functions from most novel proteins were correlated with previously reported processes during the differentiation process in Toxoplasma gondii. Thus, DIGE technology arises as a suitable tool to study mechanisms involved in the N. caninum tachyzoite to bradyzoite conversion. PMID- 20162559 TI - Identification of kaempferol-regulated proteins in rat calvarial osteoblasts during mineralization by proteomics. AB - Kaempferol, a flavonoid, promotes osteoblast mineralization in vitro and bone formation in vivo; however, its mechanism of action is yet unknown. We adopted proteomic approach to identify the differential effect of kaempferol on rat primary calvarial osteoblasts during mineralization. The primary rat calvarial osteoblasts were treated with kaempferol (5.0 microM) for 9 days under mineralizing condition that resulted in significant increase in alkaline phosphatase activity and mineralization of the cells. Further, 2-D analysis of the kaempferol-treated osteoblast lysates revealed 18 differentially expressed proteins (nine upregulated and nine downregulated) on the basis of >/<2.0-fold as cut-off (p<0.01) that were then identified by MALDI-TOF MS. These included cytoskeletal proteins, intracellular signaling protein, chaperone, extracellular matrix protein, and proteins involved in glycolysis and cell-matrix interactions. Proteomics data were confirmed by Western blotting and quantitative real-time PCR by randomly selecting two upregulated and two downregulated proteins. Western blot analysis confirmed upregulation of HSP-70 and cytokeratin-14 levels, and downregulation of aldose reductase and caldesmon expression. We further demonstrated that kaempferol treatment inhibits aldose reductase activity in osteoblasts indicating an altered cellular metabolism by decelerating polyol pathway that was associated with the kaempferol-induced osteoblast mineralization. In conclusion, this is a first comprehensive study on the differential regulation of proteins by kaempferol in primary osteoblast, which would further help to elucidate the role of the identified proteins in the process of osteoblast mineralization. PMID- 20162560 TI - Comprehensive proteome profiling of the Fe(III)-reducing myxobacterium Anaeromyxobacter dehalogenans 2CP-C during growth with fumarate and ferric citrate. AB - Anaeromyxobacter dehalogenans is a microaerophilic member of the delta proteobacteria which is able to utilize a wide range of electron acceptors, including halogenated phenols, U(VI), Fe(III), nitrate, nitrite, oxygen and fumarate. To date, the knowledge regarding general metabolic activities of this ecologically relevant bacterium is limited. Here, we present a first systematic 2 D reference map of the soluble A. dehalogenans proteome in order to provide a sound basis for further proteomic studies as well as to gain first global insights into the metabolic activities of this bacterium. Using a combination of 2-DE and MALDI-TOF-MS, a total of 720 proteins spots were identified, representing 559 unique protein species. Using the proteome data, altogether 50 metabolic pathways were found to be expressed during growth with fumarate as primary electron acceptor. An analysis of the pathways revealed an extensive display of enzymes involved in the catabolism and anabolism of a variety of amino acids, including the unexpected fermentation of lysine to butyrate. Moreover, using the reference gel as basis, a semi-quantitative analysis of protein expression changes of A. dehalogenans during growth with ferric citrate as electron acceptor was conducted. The adaptation to Fe(III) reducing conditions involved the expression changes of a total of 239 proteins. The results suggest that the adaptation to Fe(III) reductive conditions involves an increase in metabolic flux through the tricarboxylic acid cycle, which is fueled by an increased catabolism of amino acids. PMID- 20162561 TI - Matrigel: a complex protein mixture required for optimal growth of cell culture. AB - Numerous cell types require a surface for attachment to grow and proliferate. Certain cells, particularly primary and stem cells, necessitate the use of specialized growth matrices along with specific culture media conditions to maintain the cells in an undifferentiated state. A gelatinous protein mixture derived from mouse tumor cells and commercialized as Matrigel is commonly used as a basement membrane matrix for stem cells because it retains the stem cells in an undifferentiated state. However, Matrigel is not a well-defined matrix, and therefore can produce a source of variability in experimental results. In this study, we present an in-depth proteomic analysis of Matrigel using a dynamic iterative exclusion method coupled with fractionation protocols that involve ammonium sulfate precipitation, size exclusion chromatography, and one dimensional SDS-PAGE. The ability to identify the low mass and abundance components of Matrigel illustrates the utility of this method for the analysis of the extracellular matrix, as well as the complexity of the matrix itself. PMID- 20162562 TI - Changing the phospholipid composition of Staphylococcus aureus causes distinct changes in membrane proteome and membrane-sensory regulators. AB - The dynamic lipid composition of bacterial cytoplasmic membranes has a profound impact on vital bacterial fitness and susceptibility to membrane-damaging agents, temperature, or osmotic stress. However, it has remained largely unknown how changes in lipid patterns affect the abundance and expression of membrane proteins. Using recently developed gel-free proteomics technology, we explored the membrane proteome of the important human pathogen Staphylococcus aureus in the presence or absence of the cationic phospholipid lysyl-phosphatidylglycerol (Lys-PG). We were able to detect almost half of all theoretical integral membrane proteins and could reliably quantify more than 35% of them. It is worth noting that the deletion of the Lys-PG synthase MprF did not lead to a massive alteration but a very distinct up- or down-regulation of only 1.5 or 3.5% of the quantified proteins. Lys-PG deficiency had no major impact on the abundance of lipid-biosynthetic enzymes but significantly affected the amounts of the cell envelope stress-sensing regulatory proteins such as SaeS and MsrR, and of the SaeS-regulated proteins Sbi, Efb, and SaeP. These data indicate very critical interactions of membrane-sensory proteins with phospholipids and they demonstrate the power of membrane proteomics for the characterization of bacterial physiology and pathogenicity. PMID- 20162563 TI - Site-specific opening of the blood-brain barrier. AB - The blood-brain barrier (BBB) poses a significant impediment for the delivery of therapeutic drugs into the brain. This is particularly problematic for the treatment of malignant gliomas which are characterized by diffuse infiltration of tumor cells into normal brain where they are protected by a patent BBB. Selective disruption of the BBB, followed by administration of anti-cancer agents, represents a promising approach for the elimination of infiltrating glioma cells. A summary of the techniques (focused ultrasound, photodynamic therapy and photochemical internalization) for site-specific opening of the BBB will be discussed in this review. Each approach is capable of causing localized and transient opening of the BBB with minimal damage to surrounding normal brain as evidenced from magnetic resonance images and histology. PMID- 20162564 TI - Characterization of a stretch-activated potassium channel in chondrocytes. AB - Chondrocytes possess the capacity to transduce load-induced mechanical stimuli into electrochemical signals. The aim of this study was to functionally characterize an ion channel activated in response to membrane stretch in isolated primary equine chondrocytes. We used patch-clamp electrophysiology to functionally characterize this channel and immunohistochemistry to examine its distribution in articular cartilage. In cell-attached patch experiments, the application of negative pressures to the patch pipette (in the range of 20-200 mmHg) activated ion channel currents in six of seven patches. The mean activated current was 45.9 +/- 1.1 pA (n = 4) at a membrane potential of 33 mV (cell surface area approximately 240 microm(2)). The mean slope conductance of the principal single channels resolved within the total stretch-activated current was 118 +/- 19 pS (n = 6), and reversed near the theoretical potassium equilibrium potential, E(K+), suggesting it was a high-conductance potassium channel. Activation of these high-conductance potassium channels was inhibited by extracellular TEA (K(d) approx. 900 microM) and iberiotoxin (K(d) approx. 40 nM). This suggests that the current was largely carried by BK-like potassium (MaxiK) channels. To further characterize these BK-like channels, we used inside-out patches of chondrocyte membrane: we found these channels to be activated by elevation in bath calcium concentration. Immunohistochemical staining of equine cartilage samples with polyclonal antibodies to the alpha1- and beta1-subunits of the BK channel revealed positive immunoreactivity for both subunits in superficial zone chondrocytes. These experiments support the hypothesis that functional BK channels are present in chondrocytes and may be involved in mechanotransduction and chemotransduction. PMID- 20162565 TI - Enrichment for STRO-1 expression enhances the cardiovascular paracrine activity of human bone marrow-derived mesenchymal cell populations. AB - The cardiovascular therapeutic potential of bone marrow mesenchymal stromal/stem cells (MSC) is largely mediated by paracrine effects. Traditional preparation of MSC has involved plastic adherence-isolation. In contrast, prospective immunoselection aims to improve cell isolation by enriching for mesenchymal precursor cells (MPC) at higher purity. This study compared the biological characteristics and cardiovascular trophic activity of plastic adherence-isolated MSC (PA-MSC) and MPC prepared from the same human donors by immunoselection for stromal precursor antigen-1 (STRO-1). Compared to PA-MSC, STRO-1-MPC displayed greater (1) clonogenicity, (2) proliferative capacity, (3) multilineage differentiation potential, and (4) mRNA expression of mesenchymal stem cell related transcripts. In vitro assays demonstrated that conditioned medium from STRO-1-MPC had greater paracrine activity than PA-MSC, with respect to cardiac cell proliferation and migration and endothelial cell migration and tube formation. In keeping with this, STRO-1-MPC exhibited higher gene and protein expression of CXCL12 and HGF. Inhibition of these cytokines attenuated endothelial tube formation and cardiac cell proliferation, respectively. Paracrine responses were enhanced by using supernatant from STRO-1(Bright) MPC and diminished with STRO-1(Dim) conditioned medium. Together, these findings indicate that prospective isolation gives rise to mesenchymal progeny that maintain a higher proportion of immature precursor cells compared to traditional plastic adherence-isolation. Enrichment for STRO-1 is also accompanied by increased expression of cardiovascular-relevant cytokines and enhanced trophic activity. Immunoselection thus provides a strategy for improving the cardiovascular reparative potential of mesenchymal cells. PMID- 20162566 TI - Cleavage of galectin-3 by matrix metalloproteases induces angiogenesis in breast cancer. AB - Galectin-3 cleavage is related to progression of human breast and prostate cancer and is partly responsible for tumor growth, angiogenesis and apoptosis resistance in mouse models. A functional polymorphism in galectin-3 gene, determining its susceptibility to cleavage by matrix metalloproteinases (MMPs)-2/-9 is related to racial disparity in breast cancer incidence in Asian and Caucasian women. The purpose of our study is to evaluate (i) if cleavage of galectin-3 could be related to angiogenesis during the progression of human breast cancer, (ii) the role of cleaved galectin-3 in induction of angiogenesis and (iii) determination of the galectin-3 domain responsible for induction of angiogenic response. Galectin-3 null breast cancer cells BT-459 were transfected with either cleavable full-length galectin-3 or its fragmented peptides. Chemotaxis, chemoinvasion, heterotypic aggregation, epithelial-endothelial cell interactions and angiogenesis were compared to noncleavable galectin-3. BT-549-H(64) cells harboring cleavable galectin-3 exhibited increased chemotaxis, invasion and interactions with endothelial cells resulting in angiogenesis and 3D morphogenesis compared to BT-549-P(64) cells harboring noncleavable galectin-3. BT-549-H(64) cells induced increased migration and phosphorylation of focal adhesion kinase in migrating endothelial cells. Endothelial cells cocultured with BT-549 cells transfected with galectin-3 peptides indicate that amino acids 1-62 and 33-250 stimulate migration and morphogenesis of endothelial cells. Immunohistochemical analysis of blood vessel density and galectin-3 cleavage in a breast cancer progression tissue array support the in vitro findings. We conclude that the cleavage of the N terminus of galectin-3 followed by its release in the tumor microenvironment in part leads to breast cancer angiogenesis and progression. PMID- 20162567 TI - Deguelin--an inhibitor to tumor lymphangiogenesis and lymphatic metastasis by downregulation of vascular endothelial cell growth factor-D in lung tumor model. AB - Deguelin, a rotenoid of the flavonoid family, has been reported to possess antiproliferative and anticarcinogenic activities in several cell lines and tumor models. However, it is still unclear whether deguelin effectively inhibits tumor associated lymphangiogenesis and lymphatic metastasis. Since tumor production of vascular endothelial cell growth factor (VEGF)-D was associated with tumor lymphangiogenesis and lymphatic metastasis, we established the mouse lymphatic metastasis model by transfecting high expression VEGF-D into LL/2 Lewis lung cells (VEGF-D-LL/2) and explored the effects of deguelin on lymphatic metastasis in the immunocompetent C57BL/6 mice. Our results indicated that deguelin inhibited proliferation, migration of VEGF-D-LL/2 cells via downregulating AKT and mitogen-activated protein kinase pathway and interfered tube formation of lymphatic vascular endothelial cells on matrigel at nanomolar concentrations. Deguelin significantly downregulated the expression of VEGF-D both at mRNA and protein levels in VEGF-D-LL/2 cells in a dose-dependent manner. In the in vivo study, intraperitoneal administration of deguelin (4 mg/kg) remarkably inhibited the tumor-associated lymphangiogenesis and lymphatic metastasis. The rates of lymph node and lung metastasis in deguelin-treated mice were 0 and 16.7% compared with 58.3 and 83.3% in control group mice, respectively. Deguelin also resulted in a remarkable delay of tumor growth and prolongation of life span. Immunohistochemical staining with antibodies against VEGF-D, LYVE-1 and VEGFR-3 revealed fewer positive vessel-like structures in deguelin-treated mice compared with control group mice. Taken together, we demonstrate for the first time that deguelin suppresses tumor-associated lymphangiogenesis and lymphatic metastasis by downregulation of VEGF-D both in vitro and in vivo. PMID- 20162568 TI - Cigar and pipe smoking and cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). AB - The carcinogenicity of cigar and pipe smoking is established but the effect of detailed smoking characteristics is less well defined. We examined the effects on cancer incidence of exclusive cigar and pipe smoking, and in combination with cigarettes, among 102,395 men from Denmark, Germany, Spain, Sweden and the United Kingdom in the EPIC cohort. Hazard ratios (HR) and their 95% confidence intervals (CI) for cancer during a median 9-year follow-up from ages 35 to 70 years were estimated using proportional hazards models. Compared to never smokers, HR of cancers of lung, upper aerodigestive tract and bladder combined was 2.2 (95% CI: 1.3, 3.8) for exclusive cigar smokers (16 cases), 3.0 (2.1, 4.5) for exclusive pipe smokers (33 cases) and 5.3 (4.4, 6.4) for exclusive cigarette smokers (1,069 cases). For each smoking type, effects were stronger in current smokers than in ex-smokers and in inhalers than in non-inhalers. Ever smokers of both cigarettes and cigars [HR 5.7 (4.4, 7.3), 120 cases] and cigarettes and pipes [5.1 (4.1, 6.4), 247 cases] had as high a raised risk as had exclusive cigarette smokers. In these smokers, the magnitude of the raised risk was smaller if they had switched to cigars or pipes only (i.e., quit cigarettes) and had not compensated with greater smoking intensity. Cigar and pipe smoking is not a safe alternative to cigarette smoking. The lower cancer risk of cigar and pipe smokers as compared to cigarette smokers is explained by lesser degree of inhalation and lower smoking intensity. PMID- 20162569 TI - Endothelial-like cells derived directly from human tumor xenografts. AB - Tumor-associated endothelial cells (TAECs) harboring various genomic abnormalities have been described in human cancers although their origins remain obscure. We generated 4 human cancer cell lines tagged with multiple markers, grew them as xenografts, and characterized their TAECs. Depending on their tumor of origin, 5-40% of TAECs reproducibly expressed all tags. Tagged TAECs (tTAECS) were morphologically, immunologically and functionally similar, although not identical, to normal endothelial cells (ECs) and contained only human chromosomes. tTAECs underwent a senescent-like proliferative arrest after several in vitro passages, but could be immortalized by telomerase, thus allowing us to show that the retention of the EC phenotype was of long-term duration. In contrast, nonimmortalized tTAECs could be propagated in vivo where they incorporated into the tumor neo-vasculature. Although consistent with previous reports that some tumor cells may undergo "vasculogenic mimicry" (VM), the tumor derived endothelial-like cells described here appear distinctly different. Moreover, their properties and behaviors are more durable than expected for cells undergoing VM, are not the result of fusions between ECs and tumor cells, and are cell autonomous. These findings could have significant implications for therapies that target tumor angiogenesis. PMID- 20162570 TI - Prognostic relevance of global histone H3 lysine 4 (H3K4) methylation in renal cell carcinoma. AB - Epigenetic alterations play an important role in carcinogenesis. Recent studies suggested that global histone modifications are predictors of cancer recurrence in various tumor entities. Our study was performed to evaluate histone H3 lysine 4 mono-methyl (H3K4me1), -di-methyl (H3K4me2) and -trimethyl (H3K4me3) patterns in renal cell carcinoma (RCC) using a tissue microarray with 193 RCC (including 142 clear cell, 31 papillary, 10 chromophobe and 10 sarcomatoid RCC) and 10 oncocytoma specimens: H3K4me3 staining was more intense in papillary RCC, whereas H3K4me1 and H3K4me2 were similar in the diverse RCC subtypes. H3K4me2 and H3K4me3 levels were increased in oncocytoma. H3K4me1-3 levels were inversely correlated with Fuhrman grading, pT stage, lymph node involvement and distant metastasis. Progression-free survival and cancer-specific survival were shorter in patients with low levels of H3K4me1-3 in the univariate analysis, but we did not observe a significant correlation of a single modification in a multivariate model, which also included the established prognostic parameters TNM-stage and Fuhrman grade. In comparison, the H3K4me score, which combined staining levels of the H3K4 modifications, was an independent predictor of RCC progression-free survival. Our study on H3K4 methylation supports the concept of global histone modifications as potential cancer prognosis markers. PMID- 20162571 TI - Glioblastoma cells incorporate into tumor vasculature and contribute to vascular radioresistance. AB - Glioblastoma multiforme (GBM) remains the most devastating neoplasm of the central nervous system and has a dismal prognosis. Ionizing radiation represents an effective therapy for GBM, but radiotherapy remains only palliative because of radioresistance. In this study, we demonstrate that glioma cells participate in tumor vascularization and contribute to vascular radioresistance. Using a 3 dimensional coculture system, we observed an intimate interaction of glioma cells with endothelial cells whereby endothelial cells form vascular structures, followed by the recruitment and vascular patterning of glioma cells. In addition, tumor cells stabilize the vascular structures and render them radioresistant. Blocking initial endothelial vascular formation with endothelial-specific inhibitors prevented tumor cells from forming any structures. However, these inhibitors exhibited minimum effects on vascular structures formed by tumor cells, due to the absence of the targeted receptors on tumor cells. Consistent with the in vitro findings, we show that glioma cells form perfused blood vessels in xenograft tumor models. Together, these data suggest that glioma cells mimic endothelial cells and incorporate into tumor vasculature, which may contribute to radioresistance observed in GBM. Therefore, interventions aimed at the glioma vasculature should take into consideration the chimeric nature of the tumor vasculature. PMID- 20162572 TI - KIF1A and EDNRB are differentially methylated in primary HNSCC and salivary rinses. AB - Silencing of tumor suppressor genes plays a vital role in head and neck carcinogenesis. In this study, we aimed to evaluate to the utility of aberrant promoter hypermethylation for detection in a panel of 10 genes (KIF1A, EDNRB, CDH4, TERT, CD44, NISCH, PAK3, VGF, MAL and FKBP4) in head and neck squamous cell carcinoma (HNSCC) via a candidate gene approach. We investigated methylation of the gene promoters by bisulfite modification and quantitative methylation specific PCR (Q-MSP) in a preliminary study of a limited cohort of salivary rinses from healthy subjects (n = 61) and patients with HNSCC (n = 33). The methylation status of 2 selected genes (EDNRB and KIF1A) were then analyzed in 15 normal mucosa samples from a healthy population, 101 HNSCC tumors and the corresponding salivary rinses from 71 out of the 101 HNSCC patients were collected before treatment. The promoter regions of CDH4, TERT, VGF, MAL, FKBP4, NISCH and PAK3 were methylated in normal salivary rinses while no methylation of CD44 was observed in either normal salivary rinses or tumor samples. However, KIF1A and EDNRB were methylated in 98 and 97% of primary HNSCC tissues respectively and were only methylated in 2 and 6.6% of normal salivary rinses. In addition, KIF1A and EDNRB were methylated in 38 and 67.6% of salivary rinses from HNSCC patients, respectively. Promoter hypermethylation of KIF1A and EDNRB is a frequent event in primary HNSCC, and these genes are preferentially methylated in salivary rinses from HNSCC patients. KIF1A and EDNRB are potential biomarkers for HNSCC detection. PMID- 20162573 TI - Strong expression of IGF1R in pediatric gastrointestinal stromal tumors without IGF1R genomic amplification. AB - Wildtype (WT) gastrointestinal stromal tumors (GISTs), lacking mutations in KIT or PDGFRA, represent 85% of GISTs in pediatric patients. Treatment options for pediatric WT GIST are limited. Recently, expression profiling of a limited number of pediatric and adult WT GISTs and more in depth study of a single pediatric WT GIST implicated the insulin-like growth factor 1 receptor (IGF1R) as a potential therapeutic target in pediatric WT GIST. We performed immunoblotting, SNP and FISH studies to determine the extent of expression, biochemical activation and genomic amplification of IGF1R in a larger number of pediatric WT GISTs. Pediatric WT GISTs expressed IGF1R strongly, whereas typical adult KIT mutant GISTs did not. IGF1R gene amplification was not detected in pediatric WT GISTs, and some KIT-mutant GISTs had IGF1R gene deletion due to monosomy 15. Despite the absence of apparent genomic activation mechanisms accounting for overexpression, clinical study of IGF1R-directed therapies in pediatric WT GIST is warranted. PMID- 20162574 TI - miR-181b modulates multidrug resistance by targeting BCL2 in human cancer cell lines. AB - MicroRNAs (miRNAs) are short noncoding RNA molecules, which posttranscriptionally regulate genes expression and play crucial roles in diverse biological processes, such as development, differentiation, apoptosis and proliferation. Here, we investigated the possible role of miRNAs in the development of multidrug resistance (MDR) in human gastric and lung cancer cell lines. We found that miR 181b was downregulated in both multidrug-resistant human gastric cancer cell line SGC7901/vincristine (VCR) and multidrug-resistant human lung cancer cell line A549/cisplatin (CDDP), and the downregulation of miR-181b in SGC7901/VCR and A549/CDDP cells was concurrent with the upregulation of BCL2 protein, compared with the parental SGC7901 and A549 cell lines, respectively. In vitro drug sensitivity assay demonstrated that overexpression of miR-181b sensitized SGC7901/VCR and A549/CDDP cells to anticancer drugs, respectively. The luciferase activity of a BCL2 3'-untranslated region-based reporter construct in SGC7901/VCR and A549/CDDP cells suggests that a new target site in the 3'UTR of BCL2 of the mature miR-181s (miR-181a, miR-181b, miR-181c and miR-181d) was found. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively. Taken together, our findings suggest that miR-181b could play a role in the development of MDR in both gastric and lung cancer cell lines, at least in part, by modulation of apoptosis via targeting BCL2. PMID- 20162575 TI - The effect of GHRH antagonists on human glioblastomas and their mechanism of action. AB - The effects of new growth hormone-releasing hormone (GHRH) antagonists JMR-132 and MIA-602 and their mechanism of action were investigated on 2 human glioblastoma cell lines, DBTRG-05 and U-87MG, in vitro and in vivo. GHRH receptors and their main splice variant, SV1 were found on both cell lines. After treatment with JMR-132 or MIA-602, the cell viability decreased significantly. A major decrease in the levels of phospho-Akt, phospho-GSK3beta and phosho-ERK 1/2 was detected at 5 and 10 min following treatment with the GHRH antagonists, whereas elevated levels of phospho-p38 were observed at 24 hr. The expression of caspase-3 and poly(ADP-ribose) (PARP), as the downstream executioners of apoptosis were found to be significantly elevated after treatment. Following treatment of the glioblastoma cells with GHRH antagonists, nuclear translocation of apoptosis inducing factor (AIF) and Endonuclease G (Endo G) and the mitochondrial release of cytochrome c (cyt c) were detected, indicating that the cells were undergoing apoptosis. In cells treated with GHRH antagonists, the collapse of the mitochondrial membrane potential was shown with fluorescence microscopy and JC-1 membrane potential sensitive dye. There were no significant differences between results obtained in DBTRG-05 or U-87MG cell lines. After treatment with MIA-602 and JMR-132, the reduction rate in the growth of DBTRG-05 glioblastoma, xenografted into nude mice, was significant and tumor doubling time was also significantly extended when compared with controls. Our study demonstrates that GHRH antagonists induce apoptosis through key proapoptotic pathways and shows the efficacy of MIA-602 for experimental treatment of glioblastoma. PMID- 20162576 TI - Colon cancer in Iceland--a nationwide comparative study on various pathology parameters with respect to right and left tumor location and patients age. AB - Increasing evidence suggests genetic, biological and demographical difference between right and left colon cancer. Studies have also indicated age differences in the pathology of colon cancer. There is a scarcity of large-scale studies that closely examine the pathological differences regarding age and tumor location. The aim of our study was to do an extensive comparison of right- and left- sided colon cancers as well as comparing patients <50 years with older patients. A retrospective, population-based study was carried out on all patients with colon cancer in Iceland between 1955 and 2004. A total of 2293 cases were analyzed (1148 men, 1145 women). All histopathology material was re-evaluated. Differences in tumor characteristics between right and left location and younger (<50) and older (>=50) patients was evaluated in particular. Higher TNM-stage, larger tumors, vessel invasion, mucinous type, high grade and expanding tumor border occurred more frequently in right- versus left-sided lesions while annular and polypoid tumors were more common in left-sided tumors (p < 0.05). Young patients had more frequent lymph node metastases, vessel invasion, nonpolypoid lesions and infiltrating tumor border (p < 0.05). Right-sided lesions show more aggressive features, reflected in morphology and stage. Younger patients present more frequently with adverse features than do older patients. Frequency of right- and left-sided colon cancer differs by age with pronounced age-location differences in females. This supports the assumption of differences in etiology and carcinogenesis of right- and left-sided colon cancer, and between young and old patients. PMID- 20162577 TI - MUC12 mRNA expression is an independent marker of prognosis in stage II and stage III colorectal cancer. AB - Distant metastasis is the major cause of death in colorectal cancer (CRC) patients. To identify genes influencing the prognosis of patients with CRC, we compared gene expression in primary tumors with and without distant metastasis using an oligonucleotide microarray. We also examined the expression of the candidate gene in 100 CRC patients by quantitative real-time reverse transcription PCR and studied the relationship between its expression and the prognosis of patients with CRC. As a result, we identified MUC12 as a candidate gene involved in metastasis processes by microarray analysis. Quantitative real time reverse transcription PCR showed that MUC12 expression was significantly lower in cancer tissues than in adjacent normal tissues (p < 0.001). In Stages II and III CRC, patients with low expression showed worse disease-free survival (p = 0.020). Multivariate analysis disclosed that MUC12 expression status was an independent prognostic factor in Stages II and III CRC (relative risk, 8.236; 95% confidence interval, 1.702-39.849 p = 0.009). Our study revealed the prognostic value of MUC12 expression in CRC patients. Moreover, our result suggests MUC12 expression is a possible candidate gene for assessing postoperative adjuvant therapy for CRC patients. PMID- 20162578 TI - Tubulin tyrosine ligase like 12 links to prostate cancer through tubulin posttranslational modification and chromosome ploidy. AB - Prostate cancer is a common cause of death, and an important goal is to establish the pathways and functions of causative genes. We isolated RNAs that are differentially expressed in macrodissected prostate cancer samples. This study focused on 1 identified gene, TTLL12, which was predicted to modify tubulins, an established target for tumor therapy. TTLL12 is the most poorly characterized member of a recently discovered 14-member family of proteins that catalyze posttranslational modification of tubulins. We show that human TTLL12 is expressed in the proliferating layer of benign prostate. Expression increases during cancer progression to metastasis. It is highly expressed in many metastatic prostate cancer cell lines. It partially colocalizes with vimentin intermediate filaments and cellular structures containing tubulin, including midbodies, centrosomes, intercellular bridges and the mitotic spindle. Downregulation of TTLL12 affects several posttranslational modifications of tubulin (detyrosination and subsequent deglutamylation and polyglutamylation). Overexpression alters chromosomal ploidy. These results raise the possibility that TTLL12 could contribute to tumorigenesis through effects on the cytoskeleton, tubulin modification and chromosome number stability. This study contributes a step toward developing more selective agents targeting microtubules, an already successful target for tumor therapy. PMID- 20162580 TI - Thalamocortical sensorimotor circuit in multiple sclerosis: an integrated structural and electrophysiological assessment. AB - Demyelination and axonal damage are pathologic hallmarks of multiple sclerosis (MS), leading to loss of neuronal synchronization, functional disconnection amongst brain relays, and clinical sequelae. To investigate these properties, the primary component of the sensorimotor network was analyzed in mildly disabled Relapsing-Remitting MS patients without sensory symptoms at the time of the investigation. By magnetoencephalography (MEG), the recruitment pattern within the primary sensory (S1) and motor (M1) areas was estimated through the morphology of the early components of somatosensory evoked magnetic fields (SEFs), after evaluating the S1 responsiveness to sensory inputs from the contralateral arm. In each hemisphere, network recruitment properties were correlated with ispilateral thalamus volume, estimated by morphometric techniques upon high-resolution 3D structural magnetic resonance images (MRI). S1 activation was preserved, whereas SEF morphology was strikingly distorted in MS patients, marking a disruption of primary somatosensory network patterning. An unbalance of S1-M1 dynamic recruitment was documented and correlated with the thalamic volume reduction in the left hemisphere. These findings support the model of MS as a disconnection syndrome, with major susceptibility to damage experienced by nodes belonging to more frequently recruited and highly specialized networks. PMID- 20162583 TI - A novel polyacrylamide gel system for proteomic use offering controllable pore expansion by crosslinker cleavage. AB - SDS-PAGE is still one of the most widespread separation techniques in proteomic research and usually coupled to subsequent MS measurement for protein identification. The proteins are digested while embedded in the gel matrix. The resultant peptides are eluted out of the gel and finally analyzed. The in-gel digestion process suffers from several drawbacks which influence the experimental outcome with respect to protein sequence coverage and detection sensitivity. Limited accessibility of the protease to the substrate protein and insufficient peptide extraction represent the two major problems. To specifically target these issues, we established a novel partly reversible gel system, in which the gel matrix can be conditionally cleaved to increase the pore diameters. By using a crosslinker mixture consisting of Bis and ethylene-glycol-diacrylate the acrylamide filament interconnections can be partly hydrolyzed in alkaline solution. The new hybrid gels have been tested to be compatible with a variety of acidic staining techniques. They exhibit similar electrophoretic performance compared with regular solely Bis-based gels, but yield significantly better MS results. Thus, the Bis/ethylene-glycol-diacrylate SDS-PAGE gel system is a promising alternative for MS-based in-gel workflows and might be transferred to other gel-electrophoretic applications. PMID- 20162579 TI - Connective tissue growth factor associated with oncogenic activities and drug resistance in glioblastoma multiforme. AB - Connective tissue growth factor (CTGF or CCN2) is a secreted protein that belongs to the CCN [cysteine-rich CYR61/CTGF/nephroblastoma-overexpressed gene] family. These proteins have been implicated in various biological processes, including stimulation of cell proliferation, migration, angiogenesis and tumorigenesis. In a previous study, we found that CTGF mRNA was elevated in primary gliomas, and a significant correlation existed between CTGF mRNA levels versus tumor grade, histology and patient survival. In this study, the role of CTGF in glioma tumorigenesis was explored. Forced expression of CTGF in glioblastoma multiforme (GBM) cells accelerated their growth in liquid culture and soft agar, stimulated cells migration in Boyden chamber assays and significantly increased their ability to form large, vascularized tumors in nude mice. CTGF induced the expression of the antiapoptotic proteins, Bcl-xl, Survivin and Flip. Overexpression of CTGF caused the U343 GBM cells to survive for longer than 40 days in serum-free medium and resist antitumor drugs including tumor necrosis factor (TNF), TNF-related apoptosis-inducing ligand, VELCADE (bortezomib, proteasome inhibitor) and temozolomide. Our data suggest that CTGF plays an important role in glioma progression, by supporting tumor cells survival and drug resistance. PMID- 20162584 TI - CBB staining protocol with higher sensitivity and mass spectrometric compatibility. AB - Various CBB-based methods for staining proteins separated by 2-D gel electrophoresis were compared with regard to sensitivity and resolution. A modified Kang's CBB staining protocol, which we have modified, includes phosphoric acid in a concentration of 8% instead of the original 2%. This proved to be the best approach. Protein amounts as low as 2 ng and approximately 2300 spots in the gel can be detected by employing this protocol. The modified procedure takes less time to carry out. Moreover, this practice is more sensitive and resolves more protein spots than most protocols reported to date and is compatible with subsequent mass spectrometric analysis. PMID- 20162585 TI - Identification of candidate biomarkers in ovarian cancer serum by depletion of highly abundant proteins and differential in-gel electrophoresis. AB - Ovarian cancer is the fifth leading cause of cancer death for women in the US, yet survival rates are over 90% when it is diagnosed at an early stage, highlighting the need for biomarkers for early detection. To enhance the discovery of tumor-specific proteins that could represent novel serum biomarkers for ovarian cancer, we depleted serum of highly abundant proteins which can mask the detection of proteins present in serum at low concentrations. Three commercial immunoaffinity columns were used in parallel to deplete the highly abundant proteins in serum from 60 patients with serous ovarian carcinoma and 60 non-cancer controls. Medium and low abundance serum proteins from each serum pool were then evaluated by the quantitative proteomic technique of differential in gel electrophoresis. The number of protein spots that were elevated in ovarian cancer sera by at least twofold ranged from 36 to 248, depending upon the depletion and separation methods. From the 33 spots picked for MS analysis, nine different proteins were identified, including the novel candidate ovarian cancer biomarkers leucine-rich alpha2 glycoprotein-1 and ficolin 3. Western blotting validated the relative increases in serum protein levels for three of the proteins identified, demonstrating the utility of this approach for the identification of novel serum biomarkers for ovarian cancer. PMID- 20162586 TI - A fluorescent derivatization method of proteins for the detection of low-level impurities by microchip capillary gel electrophoresis. AB - A novel pre-chip fluorescent derivatization method is presented for protein sizing and quantification by microchip CGE. The derivatization reaction employed a water-soluble and stable fluorescent dye and was performed under conditions that favored the formation of homogeneous reaction products. The method delivered in terms of protein sizing similar results as microchip CGE with on-chip staining but showed an extended linear dynamic range for protein quantification encompassing four orders of magnitude. The sensitivity of the method was similar to standard silver-stained planar gels. The characterization of derivatization reaction products by MS and preparative isoelectric focusing indicated that a constant degree of dye molecule tagging was obtained over a broad range of protein/dye ratios. The method allowed detecting and quantifying an impurity spiked into an antibody preparation down to a level of 0.05%. Advantages of this method compared with CGE approaches with pre-column derivatization include a shorter analysis time and an increased robustness and ease of use. PMID- 20162587 TI - Capillary modified with covalently attached coating for enhanced CE separation of biopolymers. AB - delta-Gluconolactone was covalently coupled with aminopropyl-derivatized capillary, creating hydrophilic brushes on the inner wall of the capillary. The hydrophilic coating provided suppression of EOF and minimized protein adsorption, resulting in the separation of basic proteins and DNA with efficiencies up to 450 000 plates/m. The intra- and inter-day repeatabilities of the coating referring to the migration times of the four tested proteins were satisfactory with RSD of no more than 1.1 and 1.8% (n=5), respectively. Two hundred consecutive runs were performed with negligible change in migration times and efficiency. PMID- 20162588 TI - A CE-based assay for human protein kinase CK2 activity measurement and inhibitor screening. AB - A new assay for protein kinase CK2 activity determination based on the quantification of a phosphorylated substrate was developed. The common CK2 substrate peptide RRRDDDSDDD, conjugated with the fluorophore 5-[(2 aminoethyl)amino]naphthalene-1-sulfonic acid at the C-terminus served as the analyte. By means of CZE using 2 mol/L acetic acid as electrolyte and UV detection at 214 nm, the non-phosphorylated and the phosphorylated peptide variants could be resolved within 6 min from a complex assay mixture. By this means, activity of human CK2 could be monitored by a kinetic, as well as an endpoint, method. Inhibition of human recombinant CK2 holoenzyme by 6-methyl 1,3,8-trihydroxyanthraquinone and 4,5,6,7-tetrabromobenzotriazole resulted in IC(50) values of 1.33 and 0.27 microM, respectively, which were similar to those obtained with the standard radiometric assay. These results suggest that the CE/UV strategy described here is a straightforward assay for CK2 inhibitor testing. PMID- 20162589 TI - Optimized DNA hybridization detection on nanocolloidal particles by dielectrophoresis. AB - Oligonucleotides of varying surface coverage are functionalized onto the surface of 100 nm silica particles and the corresponding hybridization reaction with target ssDNA is studied using dielectrophoresis (DEP). The measured DEP cross over frequency (cof) is found to be sensitive to the oligonucleotide surface conformation. Zeta potential and particle size measurements suggest that at low oligo surface concentrations, non-specific binding of oligo to the particle surface prevents efficient hybridization. At high surface coverage, steric hindrance due to the fully stretched, tightly packed oligo conformation prevents diffusion of DNA molecules to the particle surface. The optimum surface coverage exists at intermediate coverage where the particle is found to be the least electrically conductive, and hence exhibits the lowest measured cof. A simple DEP cof measurement hence allows one to determine the optimal oligo surface coverage for increased hybridization efficiency and detection sensitivity. PMID- 20162590 TI - CE coupled to MALDI with novel covalently coated capillaries. AB - CE offers the advantage of flexibility and method development options. It excels in the area of separation of ions, chiral, polar and biological compounds (especially proteins and peptides). Masking the active sites on the inner surface of a bare fused silica capillary wall is often necessary for CE separations of basic compounds, proteins and peptides. The use of capillary surface coating is one of the approaches to prevent the adsorption phenomena and improve the repeatability of migration times and peak areas of these analytes. In this study, new capillary coatings consisting of (i) derivatized polystyrene nanoparticles and (ii) derivatized fullerenes were investigated for the analysis of peptides and protein digest by CE. The coated capillaries showed excellent run-to-run and batch-to-batch reproducibility (RSD of migration time < or = 0.5% for run-to-run and < or = 9.5% for batch-to-batch experiments). Furthermore, the capillaries offer high stability from pH 2.0 to 10.0. The actual potential of the coated capillaries was tested by combining CE with MALDI-MS for analysing complex samples, such as peptides, whereas the overall performance of the CE-MALDI-MS system was investigated by analysing a five-protein digest mixture. Subsequently, the peak list (peptide mass fingerprint) generated from the mass spectra of each fraction was entered into the Swiss-Prot database in order to search for matching tryptic fragments using the MASCOT software. The sequence coverage of analysed proteins was between 36 and 68%. The established technology benefits from the synergism of high separation efficiency and the structure selective identification via MS. PMID- 20162591 TI - Microstructure of microemulsion in MEEKC. AB - The influences of the composition of microemulsion on the microstructure including dimensions and zeta potentials of microdroplets were measured in details. The average dynamic dimension of microdroplets was measured by dynamic laser light scattering, and zeta potential was determined to characterize average surface charge density of microdroplets. The experiment results showed that increase of the amount of surfactant resulted in decrease of microdroplet size but almost invariant zeta potential, which would enlarge migration time of the microdroplet in MEEKC. With increment of cosurfactant concentration, the microdroplet size had an increasing trend, whereas the zeta potential decreased. Thus, observed migration velocity of microdroplets increased, which made the separation window in MEEKC shortened. Neither dimension nor zeta potential of microdroplets changed by varying both the type and the amount of the oil phase. Adding organic solvent as modifier to microemulsion did not change the microdroplet size, but lowered zeta potential. The migration time of microdroplet still became larger, since EOF slowed down owing to organic solvent in capillary. So, besides increment of surfactant concentration, organic additive could also enlarge the separation window. Increase of cosurfactant concentration was beneficial for separation efficiency thanks to the looser structure of swollen microdroplet, and the peak sharpening might compensate for the resolution and peak capacity owing to a narrow separation window. Except the oil phase, tuning the composition of microemulsion would change the microstructure, eventually could be exploited to optimize the resolution and save analysis time in MEEKC. PMID- 20162592 TI - Comparison and prediction of the retention in micellar electrokinetic chromatography and microemulsion electrokinetic chromatography for disubstituted benzenes. AB - Retention index (I), rather than retention factor (k), was found to be a more reasonable parameter for comparison of the relative affinity of disubstituted benzenes in MEEKC and MEKC, due to independent of I with the SDS surfactant concentration. MEKC and MEEKC may give similar or different I values, depending on types of moieties. With known I and K(ow) for alkylbenzenes as references in MEKC and MEEKC, the values of K(ow) for disubstituted benzenes can be estimated from the observed I values, where K(ow) is the octanol-water distribution constant. In addition, a group additive approach can be used to predict I for disubstituted benzenes with different moieties from the average observed I for the disubstituted benzenes with same moieties. However, electronic effects and/or intramolecular interaction may result in the different observed I from prediction. PMID- 20162593 TI - Combining poly (methacrylic acid-co-ethylene glycol dimethacrylate) monolith microextraction and octadecyl phosphonic acid-modified zirconia-coated CEC with field-enhanced sample injection for analysis of antidepressants in human plasma and urine. AB - A method based on poly (methacrylic acid-co-ethylene glycol dimethacrylate) monolith microextraction and octadecylphosphonic acid-modified zirconia-coated CEC followed by field-enhanced sample injection preconcentration technique was proposed for sensitive CE-UV analysis of six antidepressants (doxepin, clozapine, imipramine, paroxetine, fluoxetine and chlorimipramine) in human plasma and urine. A poly(methacrylic acid-co-ethylene glycol dimethacrylate) monolithic capillary column was introduced for the extraction of antidepressants from urine and plasma samples. The hydrophobic main chains and acidic pendant groups of the monolithic column make it a superior material for extraction of basic analytes from aqueous matrix. After extraction, the desorption solvent, which normally provided an excellent medium to ensure direct compatibility for field-enhanced sample injection in CE, was analyzed by CE directly. By the use of alkylphosphonate-modified zirconia-coated CEC for separation of the basic compounds of antidepressants, high separation efficiency and resolution were achieved because that both hydrophobic interaction between analytes and alkylphosphonate-modified zirconia coat and electrophoretic effect work on the separation of antidepressants. The best separation was achieved using a buffer composed of 0.3 M ammonium acetate (adjusted to pH 4.5 with 1 M acetic acid) and 35% ACN v/v, with a temperature and voltage of 20 degrees C and 20 kV, respectively. By applying both preconcentration procedures, LODs of 11.4-51.5 and 3.7-17.0 microg/L were achieved for the six antidepressants in human plasma and urine, respectively. Excellent method of reproducibility was found over a linear range of 50-5000 microg/L in plasma and urine sample. PMID- 20162594 TI - Intellectual abilities and white matter microstructure in development: a diffusion tensor imaging study. AB - Higher-order cognitive functions are supported by distributed networks of multiple interconnected cortical and subcortical regions. Efficient cognitive processing depends on fast communication between these regions, so the integrity of the connections between them is of great importance. It is known that white matter (WM) development is a slow process, continuing into adulthood. While the significance of cortical maturation for intellectual development is described, less is known about the relationships between cognitive functions and maturation of WM connectivity. In this cross-sectional study, we investigated the associations between intellectual abilities and development of diffusion tensor imaging (DTI) derived measures of WM microstructure in 168 right-handed participants aged 8-30 years. Independently of age and sex, both verbal and performance abilities were positively related to fractional anisotropy (FA) and negatively related to mean diffusivity (MD) and radial diffusivity (RD), predominantly in the left hemisphere. Further, verbal, but not performance abilities, were associated with developmental differences in DTI indices in widespread regions in both hemispheres. Regional analyses showed relations with both FA and RD bilaterally in the anterior thalamic radiation and the cortico spinal tract and in the right superior longitudinal fasciculus. In these regions, our results suggest that participants with high verbal abilities may show accelerated WM development in late childhood and a subsequent earlier developmental plateau, in contrast to a steadier and prolonged development in participants with average verbal abilities. Longitudinal data are needed to validate these interpretations. The results provide insight into the neurobiological underpinnings of intellectual development. PMID- 20162596 TI - Dynamic EEG-informed fMRI modeling of the pain matrix using 20-ms root mean square segments. AB - Previous studies on the spatio-temporal dynamics of cortical pain processing using electroencephalography (EEG), magnetoencephalography (MEG), or intracranial recordings point towards a high degree of parallelism, e.g. parallel instead of sequential activation of primary and secondary somatosensory areas or simultaneous activation of somatosensory areas and the mid-cingulate cortex. However, because of the inverse problem, EEG and MEG provide only limited spatial resolution and certainty about the generators of cortical pain-induced electromagnetic activity, especially when multiple sources are simultaneously active. On the other hand, intracranial recordings are invasive and do not provide whole-brain coverage. In this study, we thought to investigate the spatio temporal dynamics of cortical pain processing in 10 healthy subjects using simultaneous EEG/functional magnetic resonance imaging (fMRI). Voltages of 20 ms segments of the EEG root mean square (a global, largely reference-free measure of event-related EEG activity) in a time window 0-400 ms poststimulus were used to model trial-to-trial fluctuations in the fMRI blood oxygen level dependent (BOLD) signal. EEG-derived regressors explained additional variance in the BOLD signal from 140 ms poststimulus onward. According to this analysis, the contralateral parietal operculum was the first cortical area to become activated upon painful laser stimulation. The activation pattern in BOLD analyses informed by subsequent EEG-time windows suggests largely parallel signal processing in the bilateral operculo-insular and mid-cingulate cortices. In that regard, our data are in line with previous reports. However, the approach presented here is noninvasive and bypasses the inverse problem using only temporal information from the EEG. PMID- 20162595 TI - Working memory for vibrotactile frequencies: comparison of cortical activity in blind and sighted individuals. AB - In blind, occipital cortex showed robust activation to nonvisual stimuli in many prior functional neuroimaging studies. The cognitive processes represented by these activations are not fully determined, although a verbal recognition memory role has been demonstrated. In congenitally blind and sighted (10 per group), we contrasted responses to a vibrotactile one-back frequency retention task with 5-s delays and a vibrotactile amplitude-change task; both tasks involved the same vibration parameters. The one-back paradigm required continuous updating for working memory (WM). Findings in both groups confirmed roles in WM for right hemisphere dorsolateral prefrontal (DLPFC) and dorsal/ventral attention components of posterior parietal cortex. Negative findings in bilateral ventrolateral prefrontal cortex suggested task performance without subvocalization. In bilateral occipital cortex, blind showed comparable positive responses to both tasks, whereas WM evoked large negative responses in sighted. Greater utilization of attention resources in blind were suggested as causing larger responses in dorsal and ventral attention systems, right DLPFC, and persistent responses across delays between trials in somatosensory and premotor cortex. In sighted, responses in somatosensory and premotor areas showed iterated peaks matched to stimulation trial intervals. The findings in occipital cortex of blind suggest that tactile activations do not represent cognitive operations for nonverbal WM task. However, these data suggest a role in sensory processing for tactile information in blind that parallels a similar contribution for visual stimuli in occipital cortex of sighted. PMID- 20162597 TI - Abnormal water diffusivity in corticostriatal projections in children with Tourette syndrome. AB - The fronto-striato-thalamic circuit has been implicated in the pathomechanism of Tourette Syndrome (TS). To study white and gray matter comprehensively, we used a novel technique called Tract-Based Spatial Statistics (TBSS) combined with voxel based analysis (VBA) of diffusion tensor MR images in children with TS as compared to typically developing controls. These automated and unbiased methods allow analysis of cerebral white matter and gray matter regions. We compared 15 right-handed children with TS (mean age: 11.6 +/- 2.5 years, 12 males) to 14 age matched right-handed healthy controls (NC; mean age: 12.29 +/- 3.2 years, 6 males). Tic severity and neurobehavioral scores were correlated with FA and ADC values in regions found abnormal by these methods. For white matter, TBSS analysis showed regions of increased ADC in the corticostriatal projection pathways including left external capsule and left and right subcallosal fasciculus pathway in TS group compared to NC group. Within the TS group, ADC for the left external capsule was negatively associated with tic severity (r= -0.586, P = 0.02). For gray matter, VBA revealed increased ADC for bilateral orbitofrontal cortex, left putamen, and left insular cortex. ADC for the right and left orbitofrontal cortex was highly correlated with internalizing problems (r = 0.665; P = 0.009, r = 0.545; P = 0.04, respectively). Altogether, this analysis revealed focal diffusion abnormalities in the corticostriatal pathway and in gray matter structures involved in the fronto-striatal circuit in TS. These diffusion abnormalities could serve as a neuroimaging marker related to tic severity and neurobehavioral abnormalities in TS subjects. PMID- 20162598 TI - Optimal transcranial magnetic stimulation coil placement for targeting the dorsolateral prefrontal cortex using novel magnetic resonance image-guided neuronavigation. AB - The dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathophysiology of several psychiatric illnesses including major depressive disorder and schizophrenia. In this regard, the DLPFC has been targeted in repetitive transcranial magnetic stimulation (rTMS) studies as a form of treatment to those patients who are resistant to medications. The '5-cm method' and the '10-20 method' for positioning the transcranial magnetic stimulation (TMS) coil over DLPFC have been scrutinised due to poor targeting accuracies attributed to inter-subject variability. We evaluated the accuracy of such methods to localise the DLPFC on the scalp in 15 healthy subjects and compared them with our novel neuronavigational method, which first estimates the DLPFC position in the cortex based on a standard template and then determines the most appropriate position on the scalp in which to place the TMS coil. Our neuronavigational method yielded a scalp position for the left DLPFC between electrodes F3 and F5 in standard space and was closest to electrode F5 in individual space. Further, we found that there was significantly less inter subject variability using our neuronavigational method for localising the DLPFC on the scalp compared with the '5-cm method' and the '10-20 method'. Our findings also suggest that the '10-20 method' is superior to the '5-cm method' in reducing inter-subject variability and that electrode F5 should be the stimulation location of choice when MRI co-registration is not available. PMID- 20162599 TI - Differential effects of semantic processing on memory encoding. AB - Deeper semantic processing of words leads to enhanced memory encoding (depth of processing effect). The left inferior prefrontal cortex (LIPC) and the left hippocampus are known to be involved in this effect. We tested the hypothesis that different semantic encoding processes contribute qualitatively differently to memory encoding. In a memory experiment using functional magnetic resonance imaging, we compared three different encoding tasks: a nonsemantic alphabetical, an animacy decision, and a size comparison tasks. Recognition memory was tested subsequently. We hypothesized that the size comparison task would activate brain areas involved in the processing of object features and that this would be associated with successful memory encoding. Results showed that the size comparison task led to significantly better memory encoding than the two other tasks. As with the animacy decision task, it led to stronger activation of the LIPC and left hippocampus than the nonsemantic task. Both regions also had stronger activations for later remembered than for nonremembered words. The size comparison task additionally led to stronger activation in the left anterior fusiform gyrus, which was also associated with successful memory encoding. We conclude that different types of semantic processing affect memory encoding based on distinguishable brain processes. PMID- 20162600 TI - The volatility of the amygdala response to masked fearful eyes. AB - Recently, it has been suggested that backwardly masked, and thus subliminally presented, fearful eyes are processed by the amygdala. Here, we investigated in four functional magnetic resonance imaging experiments whether the amygdala responds to subliminally presented fearful eyes per se or whether an interaction of masked eyes with the masks or with parts of the masks used for backward masking might be responsible for the amygdala activation. In these experiments, we varied the mask as well as the position of the target eyes. The results show that the amygdala does not respond to masked fearful eyes per se but to an interaction between masked fearful eyes and the eyes of neutral faces used for masking. This finding questions the hypothesis that the amygdala processes context-free parts of the human face without awareness. PMID- 20162601 TI - Assessment of white matter tract damage in mild cognitive impairment and Alzheimer's disease. AB - Diffusion tensor MRI-based tractography was used to investigate white matter (WM) changes in the major limbic (i.e., fornix and cingulum) and cortico-cortical association pathways [i.e., the uncinate fasciculus, the inferior fronto occipital fasciculus, the inferior longitudinal fasciculus (ILF), the superior longitudinal fasciculus, and the corpus callosum] in 25 Alzheimer's disease (AD) patients, 19 amnestic mild cognitive impairment (aMCI) patients, and 15 healthy controls (HC). Mean diffusivity (MD), fractional anisotropy (FA), as well as axial (DA) and radial (DR) diffusivities were measured for each tract, using an atlas-based tractography approach. The association of WM tract integrity with hippocampal volume was also assessed. MD values were significantly different among groups in all WM tracts (P values ranging from 0.002 to 0.03), except in the fornix (P = 0.06) and the inferior fronto-occipital fasciculus (P = 0.09). Conversely, FA was significantly different among groups in the fornix only (P = 0.02). DA values were significantly different among groups in all WM tracts (P values ranging from 0.001 to 0.01), except in the fornix (P = 0.13) and the cingulum (P = 0.29). Significantly different DR values among groups were found in the fornix (P = 0.02) and the ILF (P = 0.01). In the fornix and cingulum, DR was significantly more increased than DA in both patient groups compared to HC. No difference in DA versus DR was found in cortico-cortical WM tracts. DA values in the fornix were significantly correlated with the hippocampal volume. This study demonstrates a different pattern of WM involvement in the limbic and cortico cortical association pathways in aMCI and AD patients. PMID- 20162602 TI - Scan-rescan reliability of subcortical brain volumes derived from automated segmentation. AB - Large-scale longitudinal studies of regional brain volume require reliable quantification using automated segmentation and labeling. However, repeated MR scanning of the same subject, even if using the same scanner and acquisition parameters, does not result in identical images due to small changes in image orientation, changes in prescan parameters, and magnetic field instability. These differences may lead to appreciable changes in estimates of volume for different structures. This study examined scan-rescan reliability of automated segmentation algorithms for measuring several subcortical regions, using both within-day and across-day comparison sessions in a group of 23 normal participants. We found that the reliability of volume measures including percent volume difference, percent volume overlap (Dice's coefficient), and intraclass correlation coefficient (ICC), varied substantially across brain regions. Low reliability was observed in some structures such as the amygdala (ICC = 0.6), with higher reliability (ICC = 0.9) for other structures such as the thalamus and caudate. Patterns of reliability across regions were similar for automated segmentation with FSL/FIRST and FreeSurfer (longitudinal stream). Reliability was associated with the volume of the structure, the ratio of volume to surface area for the structure, the magnitude of the interscan interval, and the method of segmentation. Sample size estimates for detecting changes in brain volume for a range of likely effect sizes also differed by region. Thus, longitudinal research requires a careful analysis of sample size and choice of segmentation method combined with a consideration of the brain structure(s) of interest and the magnitude of the anticipated effects. PMID- 20162603 TI - Interest in politics modulates neural activity in the amygdala and ventral striatum. AB - Studies on political participation have found that a person's interest in politics contributes to the likelihood that he or she will be involved in the political process. Here, we looked at whether or not interest in politics affects patterns of brain activity when individuals think about political matters. Using functional magnetic resonance imaging (fMRI), we scanned individuals (either interested or uninterested in politics based on a self-report questionnaire) while they were expressing their agreement or disagreement with political opinions. After scanning, participants were asked to rate each political opinion presented in the scanner for emotional valence and emotional intensity. Behavioral results showed that those political opinions participants agreed with were perceived as more emotionally intense and more positive by individuals interested in politics relative to individuals uninterested in politics. In addition, individuals interested in politics showed greater activation in the amygdala and the ventral striatum (ventral putamen) relative to individuals uninterested in politics when reading political opinions in accordance with their own views. This study shows that having an interest in politics elicits activations in emotion- and reward-related brain areas even when simply agreeing with written political opinions. PMID- 20162605 TI - Fronto-cingulate effective connectivity in obsessive compulsive disorder: a study with fMRI and dynamic causal modeling. AB - Evidence suggests that obsessive compulsive disorder (OCD) is associated with an overactive error control system. A key role in error detection and control has been ascribed to the fronto-cingulate system. However, the exact functional interplay between the single components of this network in OCD is largely unknown. Therefore, the present study combined a univariate data analysis and effective connectivity analysis using dynamic causal modeling (DCM) to examine error control in 21 patients with OCD and 21 matched healthy controls. All subjects performed an adapted version of the Stroop color-word task while undergoing fMRI scans. Enhanced activation in the fronto-cingulate system could be detected in OCD patients during the incongruent task condition. Additionally, task-related modulation of effective connectivity from the dorsal ACC to left DLPFC was significantly stronger in OCD patients. These findings are consistent with an overactive error control system in OCD subserving suppression of prepotent responses during decision-making. PMID- 20162604 TI - Parkinson's disease and healthy aging: independent and interacting effects on action selection. AB - Functional reorganization of the motor system occurs in response to both aging and Parkinson's disease (PD). Since PD typically develops in older adults, disease progression and the effects of treatment may interact with normal aging. Using event-related functional magnetic resonance imaging, we studied patients "on" and "off" their normal dopaminergic medication, age-matched controls and younger adults on tasks of action and action selection. For manual movements, aging increased activity in bilateral motor, premotor and cingulate cortex. Activation in the premotor regions of "on" patients was higher relative to age matched controls. However, in contrast to controls and "off" patients, the activations for patients when "on" decreased with age. Voluntary selection of actions was associated with activation in a bilateral network of fronto-parietal cortex. Within this network, advancing severity of PD was associated with decreased activity particularly in premotor and ventrolateral prefrontal cortex. Together, these results reveal very different patterns of age-related changes in health and PD. Younger patients are able to exert greater compensatory activity in premotor cortex than older patients, even after correction for disease severity. This effect is dopamine dependant, and may in part explain the clinical observation of reduced dopamine responsiveness in older patients with PD. PMID- 20162606 TI - Decreased neuronal activity in reward circuitry of pathological gamblers during processing of personal relevant stimuli. AB - Pathological gamblers impress by an increasing preoccupation with gambling, which leads to the neglect of stimuli, interests, and behaviors that were once of high personal relevance. Neurobiologically dysfunctions in reward circuitry underlay pathological gambling. To explore the association of both findings, we investigated 16 unmedicated pathological gamblers using an fMRI paradigm that included two different tasks: the evaluation of personal relevance and a reward task that served as a functional localizer. Pathological gamblers revealed diminished deactivation during monetary loss events in some of our core reward regions, the left nucleus accumbens and the left putamen. Moreover, while pathological gamblers viewed stimuli of high personal relevance, we found decreased neuronal activity in all of our core reward regions, including the bilateral nucleus accumbens and the left ventral putamen cortex as compared to healthy controls. We demonstrated for the first time altered neuronal activity in reward circuitry during personal relevance in pathological gamblers. Our findings may provide new insights into the neurobiological basis of pathological gamblers' preoccupation by gambling. PMID- 20162607 TI - Tactile shape discrimination recruits human lateral occipital complex during early perceptual processing. AB - Neuroimaging studies investigating somatosensory-based object recognition in humans have revealed activity in the lateral occipital complex, a cluster of regions primarily associated with visual object recognition. To date, determining whether this activity occurs during or subsequent to recognition per se, has been difficult to assess due to the low temporal resolution of the hemodynamic response. To more finely measure the timing of somatosensory object recognition processes we employed high density EEG using a modified version of a paradigm previously applied to neuroimaging experiments. Simple geometric shapes were presented to the right index finger of 10 participants while the ongoing EEG was measured time locked to the stimulus. In the condition of primary interest participants discriminated the shape of the stimulus. In the alternate condition they judged stimulus duration. Using traditional event-related potential analysis techniques we found significantly greater amplitudes in the evoked potentials of the shape discrimination condition between 140 and 160 ms, a timeframe in which LOC mediated perceptual processes are believed to occur during visual object recognition. Scalp voltage topography and source analysis procedures indicated the lateral occipital complex as the likely source behind this effect. This finding supports a multisensory role for the lateral occipital complex during object recognition. PMID- 20162609 TI - Population-based breast (female) and cervix cancer rates in the Gambia: evidence of ethnicity-related variations. AB - Since 1987, the Gambia National Cancer Registry has provided nationwide cancer registration for the Gambia. We used data from 1998 to 2006 to assess age standardized incidence rates (ASRs) of 2 common cancers in women, breast and cervix. With an ASR of 15.42 (95% CI [14.18-16.66]) for cervix and 5.86 (95% CI [5.12-6.59]) for breast per 10(5) person-years, these cancers ranked first and third, respectively, among Gambian women (the second most common being liver, ASR 14.90). Incidence of both cancers, breast and cervix, increased rapidly at young ages to reach a peak at ages 40-44 years. Significant differences were observed in relation to ethnicity. Using the Mandinka (42% of the population) as a reference, breast cancer incidence rates were 2.16-fold higher (95% CI [1.33 3.52]) in Jola (10% of the population), specially at early-onset ages (before 40 years). For cervix cancer, highest rates were observed in Fula (18% of the population; risk ratio (RR): 1.84 (95% CI [1.44-2.36])). In contrast, a significantly lower risk was observed in the Serrahuleh (9% of the population; RR: 0.54 (95% CI [0.31-0.96]). This study revealed a preponderance of early-onset breast cancer among Gambian women similar to that seen in African women in more developed countries but also demonstrates large ethnic variations. It points to the need for further studies on cancer determinants to improve prevention, early detection and therapeutic management of these diseases in a low-resource setting in West Africa. PMID- 20162608 TI - Overlapping and distinct role of CXCR7-SDF-1/ITAC and CXCR4-SDF-1 axes in regulating metastatic behavior of human rhabdomyosarcomas. AB - We have demonstrated that the alpha-chemokine stromal-derived factor (SDF)-1 CXCR4 axis plays an important role in rhabdomyosarcoma (RMS) metastasis. With the recent description of CXCR7, a new receptor for SDF-1 that also binds the interferon-inducible T-cell alpha chemoattractant (ITAC) chemokine, we became interested in the role of the CXCR7-SDF-1/ITAC axis in RMS progression. To address this issue, we evaluated 6 highly metastatic alveolar (A)RMS and 3 less metastatic embryonal (E)RMS cell lines and found that all these cell lines express CXCR7. Although CXCR4 was expressed at a much higher level by highly metastatic ARMS lines, CXCR7 was present at a high level on ERMS lines. We also noticed that CXCR7 expression on RMS cells was downregulated in hypoxic conditions. More importantly, the CXCR7 receptor on RMS cell lines was functional after stimulation with ITAC and SDF-1 as evidenced by mitogen-activated protein kinase (MAPK)p42/44 and AKT phosphorylation as well as CXCR7 internalization, chemotaxis, cell motility and adhesion assays. Similarly to CXCR4, signaling from activated CXCR7 was not associated with increased RMS proliferation or cell survival. Moreover, CXCR7(+) RMS cells responded to SDF-1 and I-TAC in the presence of CXCR4 antagonists (T140, AMD3100). Furthermore, while intravenous injection of RMS cells with overexpressed CXCR7 resulted in increased seeding efficiency of tumor cells to bone marrow, CXCR7 downregulation showed the opposite effect. In conclusion, the CXCR7-SDF-1/ITAC axis is involved in the progression of RMS; targeting of the CXCR4-SDF-1 axis alone without simultaneous blockage of CXCR7 will be an inefficient strategy for inhibiting SDF-1-mediated prometastatic responses of RMS cells. PMID- 20162610 TI - Cancer incidence in a rural population of South Africa, 1998-2002. AB - Cancer incidence rates and patterns are reported for a rural population, living in the Eastern Cape Province of South Africa for the period 1998-2002. The population-based cancer registry has operated for 20 years, using both active and passive methods for case finding, through collaborations with 19 health facilities: 11 district hospitals, 7 referral hospitals and 1 regional laboratory. The age standardized incidence rates for all cancers were 73.1 per 100,000 in males and 64.1 per 100,000 in females. The leading top 5 cancers for males were oesophagus (32.7 per 100,000), lung (5.8 per 100,000), prostate (4.4 per 100,000), liver (4.4 per 100,000) and larynx (2.5 per 100,000) whereas for females they were cervix (21.7 per 100,000), oesophagus (20.2 per 100,000), breast (7.5 per 100,000), ovary (0.9 per 100,000) and liver (0.9 per 100,000). The incidence of Kaposi sarcoma was low, and higher for males (1.6 per 100,000) than females (0.3 per 100,000). Lung cancer in both males and females was relatively low compared to the high incidence of oesophagus cancer. PMID- 20162611 TI - Noncollagenous region of the streptococcal collagen-like protein is a trimerization domain that supports refolding of adjacent homologous and heterologous collagenous domains. AB - Proper folding of the (Gly-Xaa-Yaa)(n) sequence of animal collagens requires adjacent N- or C-terminal noncollagenous trimerization domains which often contain coiled-coil or beta sheet structure. Collagen-like proteins have been found recently in a number of bacteria, but little is known about their folding mechanism. The Scl2 collagen-like protein from Streptococcus pyogenes has an N terminal globular domain, designated V(sp), adjacent to its triple-helix domain. The V(sp) domain is required for proper refolding of the Scl2 protein in vitro. Here, recombinant V(sp) domain alone is shown to form trimers with a significant alpha-helix content and to have a thermal stability of T(m) = 45 degrees C. Examination of a new construct shows that the V(sp) domain facilitates efficient in vitro refolding only when it is located N-terminal to the triple-helix domain but not when C-terminal to the triple-helix domain. Fusion of the V(sp) domain N terminal to a heterologous (Gly-Xaa-Yaa)(n) sequence from Clostridium perfringens led to correct folding and refolding of this triple-helix, which was unable to fold into a triple-helical, soluble protein on its own. These results suggest that placement of a functional trimerization module adjacent to a heterologous Gly-Xaa-Yaa repeating sequence can lead to proper folding in some cases but also shows specificity in the relative location of the trimerization and triple-helix domains. This information about their modular nature can be used in the production of novel types of bacterial collagen for biomaterial applications. PMID- 20162612 TI - Structural insights into the molecular mechanism of H-NOX activation. AB - Nitric oxide (NO) signaling in mammals controls important processes such as smooth muscle relaxation and neurotransmission by the activation of soluble guanylate cyclase (sGC). NO binding to the heme domain of sGC leads to dissociation of the iron-histidine (Fe-His) bond, which is required for enzyme activity. The heme domain of sGC belongs to a larger class of proteins called H NOX (Heme-Nitric oxide/OXygen) binding domains. Previous crystallographic studies on H-NOX domains demonstrate a correlation between heme bending and protein conformation. It was unclear, however, whether these structural changes were important for signal transduction. Subsequent NMR solution structures of H-NOX proteins show a conformational change upon disconnection of the heme and proximal helix, similar to those observed in the crystallographic studies. The atomic details of these conformational changes, however, are lacking in the NMR structures especially at the heme pocket. Here, a high-resolution crystal structure of an H-NOX mutant mimicking a broken Fe-His bond is reported. This mutant exhibits specific changes in heme conformation and major N-terminal displacements relative to the wild-type H-NOX protein. Fe-His ligation is ubiquitous in all H-NOX domains, and therefore, the heme and protein conformational changes observed in this study are likely to occur throughout the H-NOX family when NO binding leads to rupture of the Fe-His bond. PMID- 20162613 TI - Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. AB - 25-Hydroxyvitamin D (25[OH]D) can potentially interfere with inflammatory response and fibrogenesis. Its role in disease progression in chronic hepatitis C (CHC) and its relation with histological and sustained virological response (SVR) to therapy are unknown. One hundred ninety-seven patients with biopsy-proven genotype 1 (G1) CHC and 49 healthy subjects matched by age and sex were consecutively evaluated. One hundred sixty-seven patients underwent antiviral therapy with pegylated interferon plus ribavirin. The 25(OH)D serum levels were measured by high-pressure liquid chromatography. Tissue expression of cytochrome (CY) P27A1 and CYP2R1, liver 25-hydroxylating enzymes, were assessed by immunochemistry in 34 patients with CHC, and in eight controls. The 25(OH)D serum levels were significantly lower in CHC than in controls (25.07 +/- 9.92 microg/L versus 43.06 +/- 10.19; P < 0.001). Lower levels of 25(OH)D were independently linked to female sex (P = 0.007) and necroinflammation (P = 0.04) by linear regression analysis. CYP27A1, but not CYP2R1, was directly related to 25(OH)D levels (P = 0.01), and inversely to necroinflammation (P = 0.01). Low 25(OH)D (odds ratio [OR], 0.942; 95% confidence interval [CI], 0.893-0.994) and cholesterol (OR, 0.981; 95%CI, 0.969-0.992) levels, older age (OR, 1.043; 95%CI, 1.002-1.085), high ferritin (OR, 1.003; 95%CI, 1.001-1.005), and necroinflammation (OR, 2.235; 95%CI, 1.014-4.929) were independently associated with severe fibrosis (F3-F4) by multivariate logistic analysis. Seventy patients (41%) achieved SVR. By multivariate analysis, hepatic steatosis (OR, 0.971; 95%CI, 0.944-0.999), lower cholesterol (OR, 1.009; 95% CI, 1.000-1.018), and 25(OH)D levels (OR, 1.039; 95%CI, 1.002-1.077) were independently associated with no SVR. CONCLUSION: G1 CHC patients had low 25(OH)D serum levels, possibly because of reduced CYP27A1 expression. Low vitamin D is linked to severe fibrosis and low SVR on interferon (IFN)-based therapy. PMID- 20162614 TI - Comparative characterization of random-sequence proteins consisting of 5, 12, and 20 kinds of amino acids. AB - Screening of functional proteins from a random-sequence library has been used to evolve novel proteins in the field of evolutionary protein engineering. However, random-sequence proteins consisting of the 20 natural amino acids tend to aggregate, and the occurrence rate of functional proteins in a random-sequence library is low. From the viewpoint of the origin of life, it has been proposed that primordial proteins consisted of a limited set of amino acids that could have been abundantly formed early during chemical evolution. We have previously found that members of a random-sequence protein library constructed with five primitive amino acids show high solubility (Doi et al., Protein Eng Des Sel 2005;18:279-284). Although such a library is expected to be appropriate for finding functional proteins, the functionality may be limited, because they have no positively charged amino acid. Here, we constructed three libraries of 120 amino acid, random-sequence proteins using alphabets of 5, 12, and 20 amino acids by preselection using mRNA display (to eliminate sequences containing stop codons and frameshifts) and characterized and compared the structural properties of random-sequence proteins arbitrarily chosen from these libraries. We found that random-sequence proteins constructed with the 12-member alphabet (including five primitive amino acids and positively charged amino acids) have higher solubility than those constructed with the 20-member alphabet, though other biophysical properties are very similar in the two libraries. Thus, a library of moderate complexity constructed from 12 amino acids may be a more appropriate resource for functional screening than one constructed from 20 amino acids. PMID- 20162615 TI - Computational model of hepatitis B virus DNA polymerase: molecular dynamics and docking to understand resistant mutations. AB - Hepatitis B virus (HBV) DNA polymerase (HDP) is a pharmacological target of intense interest. Of the seven agents approved in USA for the treatment of HBV infections, five are HDP inhibitors. However, resistance development against HDP inhibitors, such as lamivudine and adefovir, has severely hurt their efficacy to treat HBV. As a step toward understanding the mechanism of resistance development and for gaining detailed insights about the active site of the enzyme, we have built a homology model of HDP which is an advance over previously reported ones. Validation using various techniques, including PROSTAT, PROCHECK, and Verify-3D profile, proved the model to be stereochemically significant. The stability of the model was studied using a 5 ns molecular dynamics simulation. The model was found to be sufficiently stable after the initial 2.5 ns with overall root mean squared deviation (RMSD) of 4.13 A. The homology model matched the results of experimental mutation studies of HDP reported in the literature, including those of antiviral-resistant mutations. Our model suggests the significant role of conserved residues, such as rtLys32, in binding of the inhibitors, contrary to previous studies. The model provides an explanation for the inactivity of some anti-HIV molecules which are inactive against HDP. Conformational changes which occurred in certain binding pocket amino acids helped to explain the better binding of some of the inhibitors in comparison to the substrates. PMID- 20162616 TI - A reported archaeal mechanosensitive channel is a structural homolog of MarR-like transcriptional regulators. AB - Several archaeal mechanosensitive (MS) channels have been reported, including one from Thermoplasma volcanium designated MscTV. Here, we report the crystal structure of MscTV at 1.6-A resolution. Unexpectedly, MscTV was found to be a water-soluble protein exhibiting a winged helix-turn-helix (wHTH) motif, which is the signature of the MarR (multiple antibiotic resistance regulator) family of transcriptional regulators. A cell-based osmotic downshock functional assay demonstrated that MscTV was unable to protect a knockout strain of Escherichia coli from hypoosmotic shock, further indicating that it does not function as a MS channel. We propose this protein be renamed MLPTv for MarR-like protein from T. volcanium. PMID- 20162617 TI - Cells of extraembryonic mesodermal origin confer human dystrophin in the mdx model of Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy is an X-linked recessive genetic disease characterized by severe skeletal muscular degeneration. The placenta is considered to be a promising candidate cell source for cellular therapeutics because it contains a large number of cells and heterogenous cell populations with myogenic potentials. We analyzed the myogenic potential of cells obtained from six parts of the placenta, that is, umbilical cord, amniotic epithelium, amniotic mesoderm, chorionic plate, villous chorion, and decidua basalis. In vitro cells derived from amniotic mesoderm, chorionic plate, and villous chorion efficiently transdifferentiate into myotubes. In addition, in vivo implantation of placenta-derived cells into dystrophic muscles of immunodeficient mdx mice restored sarcolemmal expression of human dystrophin. Differential contribution to myogenesis in this study may be attributed to placental portion-dependent default cell state. Molecular taxonomic characterization of placenta-derived maternal and fetal cells in vitro will help determine the feasibility of cell-based therapy. PMID- 20162618 TI - Differential expression and cellular distribution of gamma-tubulin and betaIII tubulin in medulloblastomas and human medulloblastoma cell lines. AB - In previous studies, we have shown overexpression and ectopic subcellular distribution of gamma-tubulin and betaIII-tubulin in human glioblastomas and glioblastoma cell lines (Katsetos et al., 2006, J Neuropathol Exp Neurol 65:455 467; Katsetos et al., 2007, Neurochem Res 32:1387-1398). Here we determined the expression of gamma-tubulin in surgically excised medulloblastomas (n = 20) and in the human medulloblastoma cell lines D283 Med and DAOY. In clinical tissue samples, the immunohistochemical distribution of gamma-tubulin labeling was pervasive and inversely related to neuritogenesis. Overexpression of gamma tubulin was widespread in poorly differentiated, proliferating tumor cells but was significantly diminished in quiescent differentiating tumor cells undergoing neuritogenesis, highlighted by betaIII-tubulin immunolabeling. By quantitative real-time PCR, gamma-tubulin transcripts for TUBG1, TUBG2, and TUBB3 genes were detected in both cell lines but expression was less prominent when compared with the human glioblastoma cell lines. Immunoblotting revealed comparable amounts of gamma-tubulin and betaIII-tubulin in different phases of cell cycle; however, a larger amount of gamma-tubulin was detected in D283 Med when compared with DAOY cells. Interphase D283 Med cells exhibited predominantly diffuse cytoplasmic gamma-tubulin localization, in addition to the expected centrosome-associated distribution. Robust betaIII-tubulin immunoreactivity was detected in mitotic spindles of DAOY cells. Our data indicate that overexpression of gamma-tubulin may be linked to phenotypic dedifferentiation (anaplasia) and tumor progression in medulloblastomas and may potentially serve as a promising tumor marker. PMID- 20162620 TI - Should antiviral treatment be extended to patients with chronic hepatitis B and mildly elevated alanine aminotransferase? PMID- 20162619 TI - Adeno-associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo. AB - Adeno-associated virus (AAV) vectors are ideal for performing gene repair due to their ability to target multiple different genomic loci, low immunogenicity, capability to achieve targeted and stable expression through integration, and low mutagenic and oncogenic potential. However, many handicaps to gene repair therapy remain. Most notable is the low frequency of correction in vivo. To date, this frequency is too low to be of therapeutic value for any disease. To address this, a point-mutation-based mouse model of the metabolic disease hereditary tyrosinemia type I was used to test whether targeted AAV integration by homologous recombination could achieve high-level stable gene repair in vivo. Both neonatal and adult mice were treated with AAV serotypes 2 and 8 carrying a wild-type genomic sequence for repairing the mutated Fah (fumarylacetoacetate hydrolase) gene. Hepatic gene repair was quantified by immunohistochemistry and supported with reverse transcription polymerase chain reaction and serology for functional correction parameters. Successful gene repair was observed with both serotypes but was more efficient with AAV8. Correction frequencies of up to 10( 3) were achieved and highly reproducible within typical dose ranges. In this model, repaired hepatocytes have a selective growth advantage and are thus able to proliferate to efficiently repopulate mutant livers and cure the underlying metabolic disease. CONCLUSION: AAV-mediated gene repair is feasible in vivo and can functionally correct an appropriate selection-based metabolic liver disease in both adults and neonates. PMID- 20162621 TI - Functional proteomic analysis of nonalcoholic fatty liver disease in rat models: enoyl-coenzyme a hydratase down-regulation exacerbates hepatic steatosis. AB - Nonalcoholic fatty liver disease (NAFLD) has emerged as a common public health problem that can progress to end-stage liver disease. A high-fat diet (HFD) may promote the development of NAFLD through a mechanism that is poorly understood. We adopted a proteomic approach to examine the effect of HFD on the liver proteome during the progression of NAFLD. Male Sprague-Dawley rats fed an HFD for 4, 12, and 24 weeks replicated the progression of human NAFLD: steatosis, nonspecific inflammation, and steatohepatitis. Using two-dimensional difference gel electrophoresis (DIGE) combined with matrix-assisted laser desorption ionization time of flight/time of flight analysis, 95 proteins exhibiting significant changes (ratio > or = 1.5 or < or =-1.5, P < 0.05) during the development of NAFLD were identified. Biological functions for these proteins reflected phase-specific characteristics during the progression of the disease. The potential role of enoyl-coenzyme A hydratase (ECHS1), an enzyme that catalyzes the second step of mitochondrial fatty acid beta-oxidation, received further investigation. First, the reduced protein level of ECHS1 was validated both in rat models and in patients with biopsy-proven hepatic simple steatosis via immunoblotting or immunohistochemical analysis. Then the small interfering RNA (siRNA)-mediated knockdown of ECHS1 in the murine hepatocyte cell line alpha mouse liver 12 (AML12) demonstrated increased cellular lipid accumulation induced by free fatty acid (FFA) overload. Furthermore, using a hydradynamic transfection method, the in vivo silencing effect of siRNA duplexes targeting ECHS1 was further investigated in mice. Administering ECHS1 siRNA specifically reduced the expression of ECHS1 protein in mice liver, which significantly exacerbated the hepatic steatosis induced by an HFD. CONCLUSION: Our results revealed that ECHS1 down-regulation contributed to HFD-induced hepatic steatosis, which may help clarify the pathogenesis of NAFLD and point to potential targets for therapeutic interventions. PMID- 20162622 TI - Madelung's disease and alcoholic liver disorder. PMID- 20162623 TI - Activin A induction of erythroid differentiation through MKK6-p38alpha/p38beta pathway is inhibited by follistatin. AB - Activin A is a member of the transforming growth factor (TGF)-beta superfamily that regulates cell proliferation and differentiation. Using the p38 inhibitor SB203580, our previous studies demonstrated that p38 was involved in activin A mediated hemoglobin (Hb) synthesis in K562 cells. SB203580 is an inhibitor of p38alpha and p38beta isoforms. In this study, we show that p38alpha and p38beta mRNA were expressed in K562 cells and that activin A activated the kinase activities of these isoforms. To investigate the roles of p38alpha and p38beta isoforms in activin A-mediated erythroid differentiation, we generated stable clones that over-expressed the dominant negative p38 isoforms p38alpha(AF) and p38beta(AF) in K562 cells. The expressions of either p38alpha(AF) or p38beta(AF) reduced activin A-induced p38 activation, Hb synthesis, and zeta-globin promoter activity. Similarly, down-regulation of either p38alpha or p38beta by isoform specific siRNAs also reduced activin A-induced zeta-globin promoter activity. Co expressions of p38alpha(AF) and p38beta(AF), together, greatly inhibited the transcription activity of the zeta-globin promoter. Conversely, expression of mitogen-activated protein kinase kinase (MKK) 6b(E), a constitutive activator of p38, significantly activated zeta-globin promoter. Co-expressions of either p38alpha or p38beta with MKK6b had a similar activation of zeta-globin promoter. Activin A induction of erythroid differentiation was inhibited by follistatin. Activin A-induced phosphorylation of MKK6 and p38 was also inhibited by follistatin. Moreover, over-expression of MKK6b(E) reverted follistatin inhibition of activin A-induced zeta-globin promoter activity. These results demonstrate that activin A induces erythroid differentiation of K562 cells through activation of MKK6-p38alpha/p38beta pathway and follistatin inhibits those effects. PMID- 20162624 TI - Computational delineation of the catalytic step of a high-fidelity DNA polymerase. AB - The Bacillus fragment, belonging to a class of high-fidelity polymerases, demonstrates high processivity (adding approximately 115 bases per DNA binding event) and exceptional accuracy (1 error in 10(6) nucleotide incorporations) during DNA replication. We present analysis of structural rearrangements and energetics just before and during the chemical step (phosphodiester bond formation) using a combination of classical molecular dynamics, mixed quantum mechanics molecular mechanics simulations, and free energy computations. We find that the reaction is associative, proceeding via the two-metal-ion mechanism, and requiring the proton on the terminal primer O3' to transfer to the pyrophosphate tail of the incoming nucleotide before the formation of the pentacovalent transition state. Different protonation states for key active site residues direct the system to alternative pathways of catalysis and we estimate a free energy barrier of approximately 12 kcal/mol for the chemical step. We propose that the protonation of a highly conserved catalytic aspartic acid residue is essential for the high processivity demonstrated by the enzyme and suggest that global motions could be part of the reaction free energy landscape. PMID- 20162625 TI - Discovery and characterization of a mammalian amyloid disaggregation activity. AB - The formation of amyloid, a cross-beta-sheet fibrillar aggregate, is associated with a variety of aging-associated degenerative diseases. Herein, we report the existence of a mammalian amyloid disaggregase activity that is present in all tissues and cell types tested. Homogenates from mammalian tissues and cell lines are able to disaggregate amyloid fibrils composed of amyloid beta (A beta)(1-40) or the 8 kDa plasma gelsolin fragment. The mammalian disaggregase activity is sensitive to proteinase K digestion and can be uncoupled from proteolysis activity using a protease inhibitor cocktail. Amyloid disaggregation and proteolysis activities are remarkably resistant to changes in temperature and pH. Identification and manipulation of the proteins responsible for the amyloid disaggregation/degradation activities offers the possibility of ameliorating aggregation-associated diseases. PMID- 20162626 TI - Conformational changes in oxidatively stressed monoclonal antibodies studied by hydrogen exchange mass spectrometry. AB - Oxidation of methionine residues in biopharmaceuticals is a common and often unwanted modification that frequently occurs during their manufacture and storage. It often results in a lack of stability and biological function of the product, necessitating continuous testing for the modification throughout the product shelf life. A major class of biopharmaceutical products are monoclonal antibodies (mAbs), however, techniques for their detailed structural analysis have until recently been limited. Hydrogen/deuterium exchange mass spectrometry (HXMS) has recently been successfully applied to the analysis of mAbs. Here we used HXMS to identify and localise the structural changes that occurred in a mAb (IgG1) after accelerated oxidative stress. Structural alterations in a number of segments of the Fc region were observed and these related to oxidation of methionine residues. These included a large change in the hydrogen exchange profile of residues 247-253 of the heavy chain, while smaller changes in hydrogen exchange profile were identified for peptides that contained residues in the interface of the C(H)2 and C(H)3 domains. PMID- 20162627 TI - Fast and automated functional classification with MED-SuMo: an application on purine-binding proteins. AB - Ligand-protein interactions are essential for biological processes, and precise characterization of protein binding sites is crucial to understand protein functions. MED-SuMo is a powerful technology to localize similar local regions on protein surfaces. Its heuristic is based on a 3D representation of macromolecules using specific surface chemical features associating chemical characteristics with geometrical properties. MED-SMA is an automated and fast method to classify binding sites. It is based on MED-SuMo technology, which builds a similarity graph, and it uses the Markov Clustering algorithm. Purine binding sites are well studied as drug targets. Here, purine binding sites of the Protein DataBank (PDB) are classified. Proteins potentially inhibited or activated through the same mechanism are gathered. Results are analyzed according to PROSITE annotations and to carefully refined functional annotations extracted from the PDB. As expected, binding sites associated with related mechanisms are gathered, for example, the Small GTPases. Nevertheless, protein kinases from different Kinome families are also found together, for example, Aurora-A and CDK2 proteins which are inhibited by the same drugs. Representative examples of different clusters are presented. The effectiveness of the MED-SMA approach is demonstrated as it gathers binding sites of proteins with similar structure-activity relationships. Moreover, an efficient new protocol associates structures absent of cocrystallized ligands to the purine clusters enabling those structures to be associated with a specific binding mechanism. Applications of this classification by binding mode similarity include target-based drug design and prediction of cross-reactivity and therefore potential toxic side effects. PMID- 20162628 TI - Limited genetic covariance between autistic traits and intelligence: findings from a longitudinal twin study. AB - Intellectual disability is common in individuals with autism spectrum conditions. However, the strength of the association between both conditions and its relevance to finding the underlying (genetic) causes of autism is unclear. This study aimed to investigate the longitudinal association between autistic traits and intelligence in a general population twin sample and to examine the etiology of this association. Parental ratings of autistic traits and performance on intelligence tests were collected in a sample of 8,848 twin pairs when the children were 7/8, 9, and 12 years old. Phenotypic and longitudinal correlations in the sample as a whole were compared to the associations in the most extreme scoring 5% of the population. The genetic and environmental influences on the overlap between autistic traits and IQ and on the stability of this relationship over time were estimated using structural equation modeling. Autistic traits were modestly negatively correlated to intellectual ability, both in the extreme scoring groups and among the full-range scores. The correlation was stable over time and was mainly explained by autistic trait items assessing communication difficulties. Genetic model fitting showed that autistic traits and IQ were influenced by a common set of genes and a common set of environmental influences that continuously affect these traits throughout childhood. The genetic correlation between autistic traits and IQ was only modest. These findings suggest that individual differences in autistic traits are substantially genetically independent of intellectual functioning. The relevance of these findings to future studies is discussed. PMID- 20162630 TI - Determination of thermodynamic parameters in reversed phase chromatography for polyethylene glycols and their methyl ethers in different mobile phases. AB - The thermodynamic parameters (entropy and enthalpy change) and their increment per repeat unit have been determined in RP chromatography of PEG and its mono- and dimethyl ethers in different mobile phases. The different approaches for their determination and the problems related to the characteristic volumes (void volume, interstitial volume, pore volume) of the column are discussed. Very different dependences or the thermodynamic parameters were observed in aqueous mobile phases containing ACN, acetone, or methanol as organic modifier. In the first two mobile phases a linear dependence on the number of repeat units n is found, and the additional entropy and enthalpy changes per repeat unit are positive. In methanol-water, the enthalpy change is negative with a non-linear dependence on n, and the entropy change is independent on n and close to zero. The contribution of the end groups is almost the same in the first two mobile phases, but much smaller in methanol-water. PMID- 20162629 TI - Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay. AB - NRXN1 is highly expressed in brain and has been shown recently to be associated with ASD, schizophrenia, cognitive and behavioral abnormalities, and alcohol and nicotine dependence. We present three families, in whom we identified intragenic rearrangements within NRXN1 using a clinical targeted oligonucleotide array CGH. An approximately 380 kb deletion was identified in a woman with Asperger syndrome, anxiety, and depression and in all four of her children affected with autism, anxiety, developmental delay, and speech delay but not in an unaffected child. An approximately 180 kb tandem duplication was found in a patient with autistic disorder and cognitive delays, and in his mother and younger brother who have speech delay. An approximately 330 kb tandem duplication was identified in a patient with autistic features. As predicted by conceptual translation, all three genomic rearrangements led to the premature truncation of NRXN1. Our data support previous observations that NRXN1 may be pathogenic in a wide variety of psychiatric diseases, including autism spectrum disorder, global developmental delay, anxiety, and depression. PMID- 20162631 TI - Application of Hadamard transform to gas chromatography/nonresonant multiphoton ionization/time-of-flight mass spectrometry. AB - The technique of Hadamard transform was successfully coupled with GC/nonresonant multiphoton ionization/TOFMS, for the first time. 1,4-Dichlorobenzene and the fourth harmonic generation (266 nm) of a Nd:YAG laser were employed as a model sample and an ionization laser, respectively. A Hadamard-injector coupled with a capillary-based supersonic jet nozzle (capillary-injector) was also developed in this study. The Hadamard-injector was used to obtain the chromatogram, which was encoded by successive sample introduction based on Hadamard codes, and the capillary-injector was used for injection of GC-elutes into TOFMS. Compared with a conventional single injection method, the S/N ratios were substantially improved after inverse Hadamard transformation of the encoded chromatogram. Under optimized conditions, when Hadamard matrices of 103 and 255 were used, the S/N ratios of the signals for 1,4-dichlorobenzene (concentration level, 4 microg/1 mL ACN) were substantially improved to 4.1- and 6.6-fold, respectively, and those improvements are in good agreement with those obtained by theory (5.1- and 8.0 fold). PMID- 20162633 TI - Characterization of novel astragaloside malonates from Radix Astragali by HPLC with ESI quadrupole TOF MS. AB - A structurally identified new compound named malonylastragaloside I was isolated and obtained from Radix Astragali. This novel compound was found to be unstable especially under high temperature and pH value. Using sonication extraction, addition of formic acid, and an efficient medium pressure ODS C(18) column chromatography method, a high yield of 40 mg of this compound was obtained from 150 g of powdered crude herbal medicine. Malonylastragaloside I was structurally characterized by NMR and ESI quadrupole TOF MS. With the strategy of target precursor ions scan, a total of 22 astragalosides including 8 astragaloside malonates were screened and characterized from the methanolic extract of Radix Astragali by HPLC-Q-TOF/MS. The eight astragaloside malonates were found in both Astragalus membranaceus var. mongholicus and A. membranaceus. The results provided a real profile of various triterpene saponins in Radix Astragali. It is a first report regarding isolation and characterization of astragaloside malonates in Astragalus species. PMID- 20162632 TI - Multivariate-adjusted pharmacoepidemiologic analyses of confidential information pooled from multiple health care utilization databases. AB - PURPOSE: Mandated post-marketing drug safety studies require vast databases pooled from multiple administrative data sources which can contain private and proprietary information. We sought to create a method to conduct pooled analyses while keeping information private and allowing for full confounder adjustment. METHODS: We propose a method based on propensity score (PS) techniques. A set of propensity scores are computed in each data-contributing center and a PS-adjusted analysis is then carried out on a pooled basis. The method is demonstrated in a study of the potentially negative effects of concurrent initiation of clopidogrel and proton pump inhibitors (PPIs) in four cohorts of patients assembled from North American claims data sources. Clinical outcomes were myocardial infarction (MI) hospitalization and hospitalization for revascularization procedure. Success of the method was indicated by equivalent performance of our PS-based method and traditional confounder adjustment. We also implemented and evaluated high dimensional propensity scores and meta-analytic techniques. RESULTS: On both a pooled and individual cohort basis, we saw substantially similar point estimates and confidence intervals for studies adjusted by covariates and from privacy maintaining propensity scores. The pooled, adjusted OR for MI hospitalization was 1.20 (95% confidence interval 1.03, 1.41) with individual variable adjustment and 1.16 (1.00, 1.36) with PS adjustment. The revascularization OR estimates differed by < 1%. Meta-analysis and pooling yielded substantially similar results. CONCLUSIONS: We observed little difference in point estimates when we employed standard techniques or the proposed privacy-maintaining pooling method. We would recommend the technique in instances where multi-center studies require both privacy and multivariate adjustment. PMID- 20162634 TI - Luminescent determination of flavonoids in orange juices by LC with post-column derivatization with aluminum and terbium. AB - A new post-column derivatization system is described and applied to the determination of flavonoids in citric beverages after their separation by LC using a monolithic column. The derivatization involves the formation of the chelates of the analytes with aluminum (III) and terbium (III) in the presence of the surfactant SDS and the measurement of the terbium sensitized luminescence at lambda(ex) 360 and lambda(em) 545 nm. Naringin, hesperidin, quercetin, naringenin, and kaempferol have been chosen as analyte models. The large Stokes shift and the relatively long wavelength emission of terbium(III) can minimize interferences from background sample matrix, which usually emit at shorter wavelengths. Calibration graphs were constructed in the intervals 6.0-1700 ng/mL naringin, 9.8-1700 ng/mL hesperidin, 2.1-2000 ng/mL quercetin, 5.2-1500 ng/mL naringenin and 2.5-2000 ng/mL kaempferol, with regression coefficients higher than 0.9935 in all instances. The precision of the method, expressed as RSD%, was established at two concentration levels, with values of 1.3 and 4.7%, which corresponded to the minimal and maximal error zones of the calibration graphs. The practical usefulness of the method is demonstrated by the analysis of orange juices, which were diluted and directly injected into the chromatographic system, obtaining recoveries between 86.9 and 108.2%. PMID- 20162635 TI - Post-translational regulation of Crmp in developing and regenerating chick spinal cord. AB - It is becoming apparent that regulation at the protein level plays crucial roles in developmental and pathological processes. Therefore, we performed a proteomics screen to identify proteins that are differently expressed or modified at stages of development permissive (E11) and nonpermissive for regeneration (E15) of the chick spinal cord. Proteins regulated either developmentally or in response to spinal-cord injury included collapsin-response-mediator proteins (Crmps), known to modulate microtubule dynamic and axonal growth. No significant changes in Crmp transcripts following injury were observed, indicating regulation mainly at the protein level. Analysis of Crmp-2 protein and its phosphorylated forms, pS522 and pT514, showed that Crmp-2 is developmentally regulated and also expressed in neural progenitors in vivo and in neurospheres. Its cellular localization changed both with development and following spinal-cord injury. In addition, although overall levels of Crmp-2 expression were not affected by injury, abundance of certain phosphorylated forms was altered. pT514 Crmp-2 appeared to be associated with dividing neural progenitors and was greatly reduced at nonpermissive stages for regeneration, whereas it did not seem affected by injury. In contrast, phosphorylation of Crmp-2 at S522 was upregulated early after injury in regenerating spinal cords and the ratio between phosphorylated to total Crmp-2 increased, as indicated by 2D Western blots. Altogether, this study shows highly dynamic regulation of Crmp-2 forms during development and identifies post translational changes in Crmp-2 as putative contributors to the maintenance of spinal-cord regenerative ability, possibly via a transient stabilization of the neuronal cytoskeleton. PMID- 20162636 TI - Induction of cellular growth by the axon guidance regulators netrin A and semaphorin-1a. AB - Although neurite outgrowth has been linked to axon guidance regulators, the effects of guidance molecules on cellular growth are not well understood. Use of the Drosophila wing imaginal disc, an epithelial tissue and a well-characterized system for analysis of cellular growth regulation, permits analysis of the impacts of guidance molecules on cellular growth in a setting in which axon guidance is not a confounding factor. In this investigation, the impacts of Netrin A (NetA) and Semaphorin-1a (Sema1a) signaling on cellular growth are examined during wing development. Levels of these genes were modulated in somatic clones in the developing wing disc, and clone areas, as well as individual sizes of clonal cells were assessed. NetA and Sema1a signaling were found to induce cellular growth in these assays. Furthermore, immunohistochemical analyses indicated that NetA and Sema1a signaling induce expression of several growth regulators, including myc, cycD, cdk4, PCNA, and MapK in the wing disc. These data illustrate that NetA and Sema1a can specifically promote growth through induction of key cellular growth regulators. The abilities of NetA and Sema1a to regulate cellular growth are likely critical to their functions in both nervous system development and oncogenesis. PMID- 20162637 TI - Convenient electrophilic fluorination of functionalized aryl and heteroaryl magnesium reagents. PMID- 20162638 TI - Two-component gel formation by pseudoenantiomeric ethynylhelicene oligomers. PMID- 20162639 TI - Pd-PEPPSI-IPent: low-temperature negishi cross-coupling for the preparation of highly functionalized, tetra-ortho-substituted biaryls. PMID- 20162640 TI - Synthesis and molecular structure of beta-phosphinoyl carboxamides: an unexpected case of chiral discrimination of hydrogen-bonded dimers in the solid state. AB - A series of N,P,P-trisubstituted aminophosphanes react with diphenylcyclopropenone to afford an easily separable mixture of two diastereomeric alpha,beta-diphenyl-beta-phosphinoyl carboxamides in good yields. X-ray crystal structures reveal that these compounds associate into dimers, formed from two enantiomeric units linked by two bifurcated hydrogen bonds, whereby the oxygen atom of the phosphoryl group acts as a dual acceptor for the vicinal NH and CH of a carbonyl group of a neighbouring molecule. Studies on the interconversion between diastereomeric phosphinoyl carboxamides in basic solution show that the thermodynamically most stable isomer depends on the nature of the substituent at the nitrogen atom. Simple computational calculations explain this phenomenon. PMID- 20162641 TI - Iron-catalyzed direct arylation of unactivated arenes with aryl halides. PMID- 20162642 TI - Soft-X-ray-induced redox isomerism in a cobalt dioxolene complex. PMID- 20162644 TI - Two-photon absorption circular dichroism: a new twist in nonlinear spectroscopy. AB - Herein we report on the full experimental measurement of the two-photon absorption circular dichroism spectra of (S)-(-)-1,1'-bi(2-naphthol) and (R)-(+) 1,1'-bi(2-naphthol), their analysis, and theoretical support. The finding of new nonlinear optical fingerprints in chiral molecules offers new opportunities in the recognition and understanding of optically active systems in regions where CD could present strong limitations. PMID- 20162645 TI - Octakis(3-azidopropyl)octasilsesquioxane: a versatile nanobuilding block for the efficient preparation of highly functionalized cube-octameric polyhedral oligosilsesquioxane frameworks through click assembly. AB - A one-step synthesis of octakis(3-azidopropyl)octasilsesquioxane from commercially available octakis(3-aminopropyl)octasilsesquioxane has been developed through a highly efficient diazo-transfer reaction under very mild conditions. Nonaflyl azide is shown to be a safer, cheaper, and more efficient reagent for this transformation than the better known and generally used diazo transfer reagent triflyl azide. Octakis(3-azidopropyl)octasilsesquioxane is an excellent nanobuilding block that can be readily octafunctionalized with a range of terminal alkynes by copper(I)-catalyzed 1,3-dipolar azide-alkyne cycloaddition to provide new functional nanocages, maintaining a perfect 3D cubic symmetry. The mildness, simplicity, and efficiency of this approach have been demonstrated in the preparation of a glyco-polyhedral oligosilsesquioxane (POSS) conjugate and a BODIPY-POSS cluster (BODIPY = boron dipyrromethene). PMID- 20162643 TI - DNA-based micelles: synthesis, micellar properties and size-dependent cell permeability. AB - Functional nanomaterials based on molecular self-assembly hold great promise for applications in biomedicine and biotechnology. However, their efficacy could be a problem and can be improved by precisely controlling the size, structure, and functions. This would require a molecular engineering design capable of producing monodispersed functional materials characterized by beneficial changes in size, shape, and chemical structure. To address this challenge, we have designed and constructed a series of amphiphilic oligonucleotide molecules. In aqueous solutions, the amphiphilic oligonucleotide molecules, consisting of a hydrophilic oligonucleotide covalently linked to hydrophobic diacyllipid tails, spontaneously self-assemble into monodispersed, three-dimensional micellar nanostructures with a lipid core and a DNA corona. These hierarchical architectures are results of intermolecular hydrophobic interactions. Experimental testing further showed that these types of micelles have excellent thermal stability and their size can be fine-tuned by changing the length of the DNA sequence. Moreover, in the micelle system, the molecular recognition properties of DNA are intact, thus, our DNA micelles can hybridize with complimentary sequences while retaining their structural integrity. Importantly, when interacting with cell membranes, the highly charged DNA micelles are able to disintegrate themselves and insert into the cell membrane, completing the process of internalization by endocytosis. Interestingly, the fluorescence was found accumulated in confined regions of cytosole. Finally, we show that the kinetics of this internalization process is size-dependent. Therefore, cell permeability, combined with small sizes and natural nontoxicity are all excellent features that make our DNA-micelles highly suitable for a variety of applications in nanobiotechnology, cell biology, and drug delivery systems. PMID- 20162646 TI - Photoisomerization of a maleonitrile-type salen Schiff base and its application in fine-tuning infinite coordination polymers. AB - Strategically designed salen ligand 2,3-bis[4-(di-p-tolylamino)-2 hydroxybenzylideneamino]maleonitrile (1), which has pronounced excited-state charge-transfer properties, shows a previously unrecognized form of photoisomerization. On electronic excitation (denoted by an asterisk), 1Z*-->1E isomerization takes place by rotation about the C2--C3 bond, which takes on single-bond character due to the charge-transfer reaction. The isomerization takes place nonadiabatically from the excited-state (1Z) to the ground-state (1E) potential-energy surface in the singlet manifold; 1Z and 1E are neither thermally inconvertible at ambient temperature (25-30 degrees C), nor does photoinduced reverse 1E*-->1Z (or 1Z*) isomerization occur. Isomers 1Z and 1E show very different coordination chemistry towards a Zn(II) precursor. More prominent coordination chemistry is evidenced by a derivative of 1 bearing a carboxyl group, namely, N,N'-dicyanoethenebis(salicylideneimine)dicarboxylic acid (2). Applying 2Z and its photoinduced isomer 2E as building blocks, we then demonstrate remarkable differences in morphology (sphere- and needlelike nanostructure, respectively) of their infinite coordination polymers with Zn(II). PMID- 20162647 TI - Stable anticancer gold(III)-porphyrin complexes: effects of porphyrin structure. AB - In the design of physiologically stable anticancer gold(III) complexes, we have employed strongly chelating porphyrinato ligands to stabilize a gold(III) ion [Chem. Commun. 2003, 1718; Coord. Chem. Rev. 2009, 253, 1682]. In this work, a family of gold(III) tetraarylporphyrins with porphyrinato ligands containing different peripheral substituents on the meso-aryl rings were prepared, and these complexes were used to study the structure-bioactivity relationship. The cytotoxic IC(50) values of [Au(Por)](+) (Por=porphyrinato ligand), which range from 0.033 to >100 microM, correlate with their lipophilicity and cellular uptake. Some of them induce apoptosis and display preferential cytotoxicity toward cancer cells than to normal noncancerous cells. A new gold(III)-porphyrin with saccharide conjugation [Au(4-glucosyl-TPP)]Cl (2a; H(2)(4-glucosyl-TPP)=meso tetrakis(4-beta-D-glucosylphenyl)porphyrin) exhibits significant cytostatic activity to cancer cells (IC(50)=1.2-9.0 microM) without causing cell death and is much less toxic to lung fibroblast cells (IC(50)>100 microM). The gold(III) porphyrin complexes induce S-phase cell-cycle arrest of cancer cells as indicated by flow cytometric analysis, suggesting that the anticancer activity may be, in part, due to termination of DNA replication. The gold(III)-porphyrin complexes can bind to DNA in vitro with binding constants in the range of 4.9 x 10(5) to 4.1 x 10(6) dm(3) mol(-1) as determined by absorption titration. Complexes 2a and [Au(TMPyP)]Cl(5) (4a; [H(2)TMPyP](4+)=meso-tetrakis(N-methylpyridinium-4 yl)porphyrin) interact with DNA in a manner similar to the DNA intercalator ethidium bromide as revealed by gel mobility shift assays and viscosity measurements. Both of them also inhibited the topoisomerase I induced relaxation of supercoiled DNA. Complex 4a, a gold(III) derivative of the known G-quadruplex interactive porphyrin [H(2)TMPyP](4+), can similarly inhibit the amplification of a DNA substrate containing G-quadruplex structures in a polymerase chain reaction stop assay. In contrast to these reported complexes, complex 2a and the parental gold(III)-porphyrin 1a do not display a significant inhibitory effect (<10%) on telomerase. Based on the results of protein expression analysis and computational docking experiments, the anti-apoptotic bcl-2 protein is a potential target for those gold(III)-porphyrin complexes with apoptosis-inducing properties. Complex 2a also displays prominent anti-angiogenic properties in vitro. Taken together, the enhanced stabilization of the gold(III) ion and the ease of structural modification render porphyrins an attractive ligand system in the development of physiologically stable gold(III) complexes with anticancer and anti-angiogenic activities. PMID- 20162648 TI - Noncovalent assembly of picket-fence porphyrins on nitrogen-doped carbon nanotubes for highly efficient catalysis and biosensing. AB - A water-insoluble picket-fence porphyrin was first assembled on nitrogen-doped multiwalled carbon nanotubes (CN(x) MWNTs) through Fe--N coordination for highly efficient catalysis and biosensing. Scanning electron micrographs, Raman spectra, X-ray photoelectron spectra, UV/Vis absorption spectra, and electrochemical impedance spectra were employed to characterize this novel nanocomposite. By using electrochemical methods on the porphyrin at low potential in neutral aqueous solution, the presence of CN(x) MWNTs led to the direct formation of a high-valent iron(IV)-porphyrin unit, which produced excellent catalytic activity toward the oxidation of sulfite ions. By using sulfite ions, a widely used versatile additive and preservative in the food and beverage industries, as a model, a highly sensitive amperometric biosensor was proposed. The biosensor showed a linear range of four orders of magnitude from 8.0x10(-7) to 4.9x10(-3) mol L(-1) and a detection limit of 3.5x10(-7) mol L(-1) due to the highly efficient catalysis of the nanocomposite. The designed platform and method had good analytical performance and could be successfully applied in the determination of sulfite ions in beverages. The direct noncovalent assembly of porphyrin on CN(x) MWNTs provided a facile way to design novel biofunctional materials for biosensing and photovoltaic devices. PMID- 20162649 TI - 3-Mercapto-2,6-pyridinedicarboxylic acid: a small lanthanide-binding tag for protein studies by NMR spectroscopy. AB - Paramagnetic effects from lanthanide ions present powerful tools for protein studies by nuclear magnetic resonance (NMR) spectroscopy provided that the lanthanide can be site-specifically and rigidly attached to the protein. A new, particularly small and rigid lanthanide-binding tag, 3-mercapto-2,6 pyridinedicarboxylic acid (3MDPA), was synthesized and attached to two different proteins via a disulfide bond. The complexes of the N-terminal domain of the E. coli arginine repressor (ArgN) with seven different paramagnetic lanthanide ions and Co(2+) were analyzed in detail by NMR spectroscopy. The magnetic susceptibility anisotropy (Delta chi) tensors and metal position were determined from pseudocontact shifts. The 3MDPA tag generated very different Delta chi tensor orientations compared to the previously studied 4-mercaptomethyl-DPA tag, making it a highly complementary and useful tool for protein NMR studies. PMID- 20162650 TI - Photocontrolled living anionic polymerization of phosphorus-bridged [1]ferrocenophanes: a route to well-defined polyferrocenylphosphine (PFP) homopolymers and block copolymers. AB - Phosphorus-bridged strained [1]ferrocenophanes [Fe{(eta C(5)H(4))(2)P(CH(2)CMe(3))}] (2) and [Fe{(eta-C(5)H(4))(2)P(CH(2)SiMe(3))}] (3) with neopentyl and (trimethylsilyl)methyl substituents on phosphorus, respectively, have been synthesized and characterized. Photocontrolled living anionic ring-opening polymerization (ROP) of the known phosphorus-bridged [1]ferrocenophane [Fe{(eta-C(5)H(4))(2)P(CMe(3))}] (1) and the new monomers 2 and 3, initiated by Na[C(5)H(5)] in THF at 5 degrees C, yielded well-defined polyferrocenylphosphines (PFPs), [Fe{(eta-C(5)H(4))(2)PR}](n) (R=CMe(3) (4), CH(2)CMe(3) (5), and CH(2)SiMe(3) (6)), with controlled molecular weights (up to ca. 60 x 10(3) Da) and narrow molecular weight distributions. The PFPs 4-6 were characterized by multinuclear NMR spectroscopy, DSC, and by GPC analysis of the corresponding poly(ferrocenylphosphine sulfides) obtained by sulfurization of the phosphorus(III) centers. The living nature of the photocontrolled anionic ROP allowed the synthesis of well-defined all-organometallic PFP-b-PFS(F) (7a and 7b) (PFS(F)=polyferrocenylmethyl(3,3,3,-trifluoropropyl)silane) diblock copolymers through sequential monomer addition. TEM studies of the thin films of the diblock copolymer 7b showed microphase separation to form cylindrical PFS(F) domains in a PFP matrix. PMID- 20162651 TI - Structure-based design of highly crowded ribostamycin/kanamycin hybrids as a new family of antibiotics. PMID- 20162652 TI - Synthesis and photovoltaic properties of cyclopentadithiophene-based low-bandgap copolymers that contain electron-withdrawing thiazole derivatives. AB - We have synthesized four types of cyclopentadithiophene (CDT)-based low-bandgap copolymers, poly[{4,4-bis(2-ethylhexyl)-4H-cyclopenta[2,1-b:3,4-b']dithiophene 2,6-diyl}-alt-(2,2'-bithiazole-5,5'-diyl)] (PehCDT-BT), poly[(4,4-dioctyl-4H cyclopenta[2,1-b:3,4-b']dithiophene-2,6-diyl)-alt-(2,2'-bithiazole-5,5'-diyl)] (PocCDT-BT), poly[{4,4-bis(2-ethylhexyl)-4H-cyclopenta[2,1-b:3,4-b']dithiophene 2,6-diyl}-alt-{2,5-di(thiophen-2-yl)thiazolo[5,4-d]thiazole-5,5'-diyl}] (PehCDT TZ), and poly[(4,4-dioctyl-4H-cyclopenta[2,1-b:3,4-b']dithiophene-2,6-diyl)-alt {2,5-di(thiophen-2-yl)thiazolo[5,4-d]thiazole-5,5'-diyl}] (PocCDT-TZ), for use in photovoltaic applications. The intramolecular charge-transfer interaction between the electron-sufficient CDT unit and electron-deficient bithiazole (BT) or thiazolothiazole (TZ) units in the polymeric backbone induced a low bandgap and broad absorption that covered 300 nm to 700-800 nm. The optical bandgap was measured to be around 1.9 eV for PehCDT-BT and PocCDT-BT, and around 1.8 eV for PehCDT-TZ and PocCDT-TZ. Gel permeation chromatography showed that number-average molecular weights ranged from 8000 to 14,000 g mol(-1). Field-effect mobility measurements showed hole mobility of 10(-6)-10(-4) cm(2) V(-1) s(-1) for the copolymers. The film morphology of the bulk heterojunction mixtures with [6,6]phenyl-C(61)-butyric acid methyl ester (PCBM) was also examined by atomic force microscopy before and after heat treatment. When the polymers were blended with PCBM, PehCDT-TZ exhibited the best performance with an open circuit voltage of 0.69 V, short-circuit current of 7.14 mA cm(-2), and power conversion efficiency of 2.23 % under air mass (AM) 1.5 global (1.5 G) illumination conditions (100 mW cm(-2)). PMID- 20162654 TI - Efficient microwave-assisted synthesis of secondary alkylpropargylamines by using A3-coupling with primary aliphatic amines. PMID- 20162653 TI - A highly selective FRET-based fluorescent probe for detection of cysteine and homocysteine. PMID- 20162655 TI - Structure determination of a flexible cyclic peptide based on NMR and MD simulation 3J-coupling. AB - Molecular dynamics (MD) simulations, in which experimental values such as nuclear Overhauser effects (NOEs), dipolar couplings, (3)J-coupling constants or crystallographic structure factors are used to bias the values of specific molecular properties towards experimental ones, are often carried out to study the structure refinement of peptides and proteins. However, (3)J-coupling constants are usually not employed because of the multiplicity of torsional angle values (phi) corresponding to each (3)J-coupling constant value. Here, we apply the method of adaptively enforced restraining using a local-elevation (LE) biasing potential energy function in which a memory function penalizes conformations in case both the average <(3)J> and the current (3)J-values deviate from the experimental target value. Then, the molecule is forced to sample other parts of the conformational space, thereby being able to cross high energy barriers and to bring the simulated average <(3)J> close to the measured <(3)J> value. Herein, we show the applicability of this method in structure refinement of a cyclo-beta-tetrapeptide by enforcing the (3)J-value restraining with LE on twelve backbone torsional angles. The resulting structural ensemble satisfies the experimental (3)J-coupling data better than the NMR model structure derived using conventional single-structure refinement based on these data. Thus, application of local-elevation search MD simulation in combination with biasing towards (3)J coupling makes it possible to use (3)J-couplings quantitatively in structure determination of peptides. PMID- 20162657 TI - Two versatile and parallel approaches to highly symmetrical open and closed natural product-based structures. AB - Two parallel approaches for preparing diverse and highly symmetrical homohybrids derived from a series of mono- and diterpenes, steroids, and alkaloids are reported. Both procedures are based on the mono-addition of bis(alkynyl) dilithium reagents to natural products having a carbonyl group to produce the corresponding alkynyl derivatives. The Glaser-Hay Cu-promoted homocoupling of these alkynyl natural product mono-adducts as well as the Huisgen Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction resulted in the synthesis of steroid , terpene-, and alkaloid-based homohybrid derivatives incorporating diverse spacers to join the natural product scaffolds. Straightforward entries to novel closed highly symmetrical and complex estrone-based macrocyclic and cage architectures by means of the Glaser-Eglinton homocoupling and the CuAAC reaction have been devised. PMID- 20162656 TI - Tailored porous silicon microparticles: fabrication and properties. AB - The use of mesoporous silicon particles for drug delivery has been widely explored thanks to their biodegradability and biocompatibility. The ability to tailor the physicochemical properties of porous silicon at the micro- and nanoscale confers versatility to this material. A method for the fabrication of highly reproducible, monodisperse, mesoporous silicon particles with controlled physical characteristics through electrochemical etching of patterned silicon trenches is presented. The particle size is tailored in the micrometer range and pore size in the nanometer range, the shape from tubular to discoidal to hemispherical, and the porosity from 46 to over 80%. In addition, the properties of the porous matrix are correlated with the loading of model nanoparticles (quantum dots) and their three-dimensional arrangement within the matrix is observed by transmission electron microscopy tomography. The methods developed in this study provide effective means to fabricate mesoporous silicon particles according to the principles of rational design for therapeutic vectors and to characterize the distribution of nanoparticles within the porous matrix. PMID- 20162658 TI - Turning riboswitches loose. PMID- 20162661 TI - What's in a title? A two-step approach to optimisation for man and machine: writing good titles is a crucial part of optimising articles' chances of being peer reviewed, and later found in the literature via Google: here are some tips... PMID- 20162662 TI - PI3K inhibition in inflammation: Toward tailored therapies for specific diseases. AB - In the past decade, the availability of genetically modified animals has enabled the discovery of interesting roles for phosphatidylinositol 3-kinase-gamma (PI3Kgamma) and -delta (PI3Kdelta) in different cell types orchestrating innate and adaptive immune responses. Therefore, these PI3K isoforms appear to be attractive drug targets for the treatment of diseases caused by unrestrained immune reactions. Currently, pharmacological targeting of PI3Kgamma and/or PI3Kdelta represents one of the most promising challenges for companies interested in the development of novel safe treatments for inflammatory diseases. In this review we provide a general outline of PI3Kgamma- and PI3Kdelta-specific functions in distinct subsets of inflammatory cells. We also discuss the therapeutic impact of novel compounds targeting PI3Kgamma, PI3Kdelta or both, in mouse models of autoimmune disorders (systemic lupus erythematosus (SLE) and rheumatoid arthritis), respiratory diseases (allergic asthma and chronic obstructive pulmonary disease) and cardiovascular dysfunctions (atherosclerosis and myocardial infarction). PMID- 20162666 TI - Spindle cells from acquired immune deficiency syndrome-associated Kaposi's sarcoma lesions express telomerase activity directly relating to the RNA levels of fibroblast growth factor-2. PMID- 20162667 TI - Endometrial cancer incidence trends in Norway during 1953-2007 and predictions for 2008-2027. AB - Endometrial cancer is the most common cancer of the female genital tract in Western countries. Monitoring the incidence is important for health care planning and the identification of risk factors. We present an age-period-cohort analysis of incidence trends of endometrial cancer in Norway from 1953 to 2007 and compare the incidence trends with those in 3 other Nordic countries. Based on the observed trends, we have predicted endometrial cancer rates in Norway in 2015 and 2025. In women at postmenopausal age (>=55 years), the annual incidence increase was 2.1% (95% CI: 0.9%, 3.4%) from 1988 to 1997 and 1.7% (95% CI: 0.6%, 2.8%) from 1998 to 2007. In younger women, there was an annual reduction of 0.6% (95% CI: -2.3%, 2.2%) from 1988 to 1997, followed by an annual increase of 1.7% (95% CI: -0.4%, 3.9%) from 1998 to 2007. The secular changes are likely to reflect both cohort and period effects. Our prediction estimates by 2025 suggest an incidence increase in the range of 50 to 100%, relative to the observed incidence in 2005. There has been a strong and consistent incidence increase in endometrial cancer in the Nordic countries over the last 50 years. The increase has been most pronounced in postmenopausal women, but in the last decade, rates have increased also in women younger than 55 years. The prediction for the next 20 years suggests that endometrial cancer rates will dramatically increase unless effective preventive strategies are implemented. PMID- 20162668 TI - Combined analysis of specific KRAS mutation, BRAF and microsatellite instability identifies prognostic subgroups of sporadic and hereditary colorectal cancer. AB - Confounding effects of specific KRAS gene alterations on colorectal cancer (CRC) prognosis stratified by microsatellite instability (MSI) and BRAF(V600E) have not yet been investigated. The aim of our study was to evaluate the combined effects of MSI, BRAF(V600E) and specific KRAS mutation (Gly -> Asp; G12D, Gly -> Asp, G13D; Gly -> Val; G12V) on prognosis in 404 sporadic and 94 hereditary CRC patients. MSI status was determined according to the Bethesda guidelines. Mutational status of KRAS and BRAF(V600E) was assessed by direct DNA sequencing. In sporadic CRC, KRAS G12D mutations had a negative prognostic effect compared to G13D and wild-type cancers (p = 0.038). With MSI, specific KRAS and BRAF(V600E) mutations, 3 distinct prognostic subgroups were observed in univariate (p = 0.006) and multivariable (p = 0.051) analysis: patients with (i) KRAS mutation G12D, G12V or BRAF(V600E) mutation, (ii) KRAS/BRAF(V600E) wild-type or KRAS G13D mutations in MSS/MSI-L and (iii) MSI-H and KRAS G13D mutations. Moreover, none of the sporadic MSI-H or hereditary patients with KRAS G13 mutations had a fatal outcome. Specific KRAS mutation is an informative prognostic factor in both sporadic and hereditary CRC and applied in an algorithm with BRAF(V600E) and MSI may identify sporadic CRC patients with poor clinical outcome. PMID- 20162669 TI - Breast cancer survival in England, Norway and Sweden: a population-based comparison. AB - Several international studies have found that survival from breast cancer is lower in the United Kingdom than in some other European countries. We have compared breast cancer survival between the national populations of England, Norway and Sweden, with a view to identifying subsets of patients with particularly good or adverse survival outcomes. We extracted cases of breast cancer in women diagnosed 1996-2004 from the national cancer registries of the 3 countries. The study comprised 303,657 English cases, 24,919 Norwegian cases and 57,512 cases from Sweden. Follow-up was in 2001-2004. The main outcome measures were 5-year cumulative relative survival and excess death rates, stratified by age and period of follow-up. In comparison with Norway and Sweden, the excess mortality in England was particularly pronounced in the first month and in the first year after diagnosis, and generally more marked in the oldest age groups. Compared with Norwegian patients, 81% of the excess deaths in the English patients occurred in the first 2 years after diagnosis. Our findings emphasise the importance of awareness of symptoms and early detection as the main strategy to improve breast cancer survival in the United Kingdom. PMID- 20162670 TI - Use in current clinical practice of 70-gene signature in early breast cancer. PMID- 20162672 TI - Involvement of MMP-9 in peribiliary fibrosis and cholangiocarcinogenesis via Rac1 dependent DNA damage in a hamster model. AB - Peribiliary fibrosis caused by chronic infection with Opisthorchis viverrini (OV) is a risk factor of cholangiocarcinoma (CCA) in northeastern Thailand. Matrix metalloproteinases (MMPs) are enzymes capable of degrading and remodeling the extracellular matrix in the process of fibrosis and carcinogenesis. We examined MMPs expression and their role in fibrogenesis and cholangiocarcinogenesis in hamsters treated with OV and N-nitrosodimethylamine (NDMA). We assessed the time profiles of MMPs, inducible nitric oxide synthase (iNOS), Rac1, alpha-smooth muscle actin (alpha-SMA) and DNA lesions (8-nitroguanine and 8-oxo-7,8-dihydro-2' deoxyguanosine, 8-oxodG) in relation to fibrosis and CCA development. Histopathology revealed OV and NDMA synergistically induced peribiliary fibrosis time-dependently, and CCA occurred at 3 months, whereas OV or NDMA alone induced less fibrosis. Hydroxyproline levels in the liver and plasma were positively associated with the expression of collagen I and alpha-SMA. MMP-9 expression was significantly increased and correlated with the accumulation of myofibroblast, fibrosis levels and cholangiocarcinogenesis. MMP-9 activity was correlated with iNOS, and immunocolocalization was observed in inflammed tissues, early and invasive CCA. OV and NDMA synergistically induced MMP-9 expression in association to Rac1. In addition, Rac1 was colocalized with iNOS, and 8-nitroguanine, in inflammed tissues and CCA. Formation of 8-nitroguanine and 8-oxodG increased with tumor progression. The results suggest that MMP-9 expression is associated with the accumulation of peribiliary fibrosis in conjunction to the induction of iNOS and Rac1 that may potentiate DNA damage and cholangiocarcinogenesis. PMID- 20162673 TI - Deregulation of the cell cycle by breast tumor kinase (Brk). AB - Brk is a cytoplasmic nonreceptor tyrosine kinase that is overexpressed in breast tumors but undetectable in normal or benign mammary tissues. Brk promotes proliferation of human mammary epithelial cells and tumor growth in a mouse model, but the role of Brk in cell cycle regulation is not known. In this study, we describe the mechanism of Brk-induced deregulation of the cell cycle. We provide evidence that Brk antagonizes the transcriptional activity of the transcription factor FoxO family of proteins by inhibiting its nuclear localization. As a result, the cell cycle inhibitor p27, a FoxO target gene, is down-regulated. This event is accompanied by G1/S cell cycle progression of quiescent cells. As p27 is a key regulator of the G1/S cell cycle checkpoint, these data suggest that perturbation of p27 expression induced by Brk causes S phase entrance. Deregulation of the cell cycle is a key event in neoplasia, and thus, the mechanism presented here likely contributes to breast cancer development. PMID- 20162674 TI - A unique expression pattern of Tbx10 in the hindbrain as revealed by Tbx10(LacZ) allele. AB - To study the expression/function of Tbx10, a T-box gene, Tbx10(LacZ/+) mice were established by replacing the T-box coding region with a LacZ gene. X-gal staining showed that LacZ(+) cells were localized to two-cell populations in rhombomere 4 and rhombomere 6. No significant differences in the locations of LacZ(+) cells were found between Tbx10(LacZ/+) and Tbx10(LacZ/LacZ) mice, and the Tbx10(LacZ/LacZ) mice were viable and fertile. We found that the LacZ(+) cells are present in both embryonic and adult mice. Histological studies suggest that the rhombomere 4-derived LacZ(+) cells are a subpopulation of the ventral interneurons in the pons. PMID- 20162675 TI - Three inhibitors of FGF receptor, ERK, and GSK3 establishes germline-competent embryonic stem cells of C57BL/6N mouse strain with high efficiency and stability. AB - C57BL/6 mouse is the most standard strain in mouse genetics. The strain does, however, have several disadvantages; one being the difficulty in establishing embryonic stem (ES) cells. No reliable C57BL/6 ES cell line is widely available for creating mutant mice through gene targeting. It also greatly favors mouse genetics if one can routinely make multiple mutations by stably culturing germline-competent C57BL/6 ES cells or if one can routinely establish ES cells from C57BL/6-derived mutant mice to make multiple mutations. Recently, an ES culture method with three inhibitors (3i: SU5402 for FGFR, PD184352 for ERK, and CHIR99021 for GSK3) has been reported. Here we show that this 3i method is extremely instrumental in establishing and culturing germline-competent ES cells in the C57BL/6N strain. PMID- 20162677 TI - Measuring sensory nerve action potential electrical power. AB - Sensory nerve action potential (SNAP) amplitudes are frequently examined for evidence of axonal loss. Because digital nerves have parallel fibers, and parallel voltages do not add, SNAP amplitude may not accurately reflect axonal loss. In contrast, electrical power can be measured for digital nerves, and is additive. In this study we explore the ability of SNAP electrical power (SELP) to discriminate the increased number of axons in fingers with two median digital nerves versus fingers with only one median digital nerve. Antidromic SNAP amplitudes and SELPs were obtained for 15 fingers. Seventeen external resistors, R(ext), were sequentially connected from electrode to ground for SELP determination. The resulting bell-shaped power vs. R(ext) plot was regressed to the power transfer equation, which has a peak that defines SELP. SELPs of two digital-nerve (median) fingers were 360-670 femtowatts (mean 525 fW). For one digital-nerve fingers, SELP was 90-230 fW (mean 190 fW). Evaluation of one- vs. two-median-digital-nerve statistics showed the SNAP amplitude difference-of-means to be insignificant, whereas the SELP difference-of-means was 3.3 SD (P < 0.01). Using a criterion of 2 SDs, SNAP amplitude did not discriminate any one-median digital-nerve fingers, whereas SELP discriminated all with no false positives. Because parallel voltages do not add, SNAP amplitudes may not reflect axonal loss. In contrast, electrical power is additive. We describe the SELP technique and demonstrate its ability to discriminate different numbers of axons as reflected by one digital nerve vs. two digital nerves. PMID- 20162678 TI - Perioral skin biopsy to study skeletal muscle protein expression. AB - Clinical trials for muscular dystrophy molecular treatment require multiple sampling of skeletal muscle to monitor protein rescue. This practice is invasive and could raise ethical problems. A less invasive tool to obtain sequential muscle sampling is necessary. Using indirect immunofluorescence, we evaluated muscle protein expression in myofiber bundles included in 2-2.5-mm punch skin biopsies from the perioral region from 6 healthy subjects and 6 patients with genetically defined forms of muscular dystrophy. Large intradermal bundles of orbicularis oris muscle were constantly present in skin biopsies. They showed a typical muscular antigenic pattern in controls and the expected protein defect in muscular dystrophy patients. These results demonstrate the feasibility of muscular protein expression analysis using skin biopsy. We propose this minimally invasive technique to follow-up the response to genetic or conventional therapies in muscular dystrophies and to confirm the diagnosis in some special clinical conditions. PMID- 20162679 TI - Reversal of the proposed concept in ALS: are the cortical changes secondary? PMID- 20162683 TI - Accessory spleen: differential diagnosis for lymphoma in autoimmune lymphoproliferative syndrome. AB - Mutations of Fas or, less frequently, Fas ligand genes result in a rare inherited lymphoid disorder called autoimmune lymphoproliferative syndrome (ALPS) in which lymphoma frequency is increased. We report on a patient with ALPS who had been splenectomized for giant splenomegaly and progressively developed a voluminous abdominal tumor. The histology of the removed tumor revealed that it was an accessory spleen exhibiting typical features of ALPS involvement, as shown by the presence of a large excess of CD3+CD4-CD8- T cells and plasma cells without a detectable monoclonal population. This observation highlights the lymphoma's differential diagnosis in this context. PMID- 20162684 TI - Immunisation practices of paediatric oncology and shared care oncology consultants: a United Kingdom survey. AB - BACKGROUND: In March 2002, the Royal College of Paediatrics and Child Health (RCPCH) introduced guidelines for re-immunisation of children after completion of standard-dose chemotherapy and after haematopoietic stem cell transplant (HSCT). AIMS: To ascertain whether these guidelines form standard unit policy by undertaking a survey of UK paediatric principal treatment centre (PTC) consultants and shared care (SC) consultants. PROCEDURES: In October 2008, a link to an on-line anonymised survey was sent by e-mail to all UK PTC consultants in Children's Cancer and Leukaemia Group (CCLG) centres and to SC consultants linked to eight of these centres. RESULTS: Responses were received from 55 PTC consultants (representing all 21 CCLG centres) and 54 SC consultants. In accordance with the RCPCH guidelines, most PTC and SC consultants recommend initiating re-immunisation at 6 months after completion of standard-dose chemotherapy (99/105, 94.3%). Re-immunisation at the recommended time after HSCT for each transplant type was reported by 93-100% of respondents. Pneumococcal conjugate vaccine (PCV) was recommended after chemotherapy by 58.3% (35/60) of respondents and by 51.7% (30/58) after HSCT. There were distinct differences between PTC and SC consultants in their choice of varicella (VZV) post-exposure prophylaxis. CONCLUSIONS: There is a high level of stated compliance with RCPCH guidelines. Recommendations for PCV after chemotherapy and HSCT were lower than expected. This may reflect the absence of specific guidelines after chemotherapy but not in HSCT patients where guidelines do exist. Variation in VZV post exposure prophylaxis suggests further studies are required. PMID- 20162685 TI - Groshong catheter-related complications in children with cancer. AB - BACKGROUND: Children with cancer undergo intensive treatments requiring reliable vascular access. Central venous catheters (CVCs) reduce discomfort due to venipuncture and the risks of extravasations from chemotherapy administration. The aim of our retrospective study was to assess safety and complications of Groshong devices in children with cancer. PATIENTS AND METHODS: One hundred ninety Groshong CVCs were placed in 166 children over a 5-year period. Early complications, and infectious and mechanical events were collected. RESULTS: The mean period of permanence of the CVCs was 330 days per patient (range 7-1,037). Of the febrile episodes, 36 (34.6%) were CVC-related, with an incidence rate of 0.56 per 1,000 CVC days. Severe neutropenia conditions most of all complicated CVC-related infectious events (94.4%) and Gram-negative bacteria were those most often isolated (55%). Twenty CVCs were affected by mechanical or thrombotic complications, with an incidence of 0.33 episodes per 1,000 CVC days. Mechanical complications led to CVC removal in 6 (3.1%) cases, while CVC-related infective episodes were responsible for 10 (5.2%) CVC removals. CONCLUSIONS: The long in situ duration of this device allowed it to be safely employed from the beginning to the end of the treatment period in most children. PMID- 20162686 TI - Orbital sarcoma with metastases at diagnosis: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. AB - We reviewed clinicopathologic features and treatment outcomes in seven patients diagnosed with Stage 4/Group IV orbital sarcoma and treated on IRSG protocols I III. Three patients had embryonal rhabdomyosarcoma (RMS), and two patients each had alveolar RMS or unclassified sarcoma. Median age at diagnosis was 1.8 years (range 0.2-6.9 years). All patients had bone marrow involvement, including six with normal complete blood count at diagnosis. Cerebrospinal fluid was normal in six patients. Three patients survived >5 years, including one with local recurrence. In conclusion, further study is needed to determine necessity of bone marrow and CSF examination in orbital sarcoma patients. PMID- 20162687 TI - Abdominal undifferentiated small round cell tumor with unique translocation (X;19)(q13;q13.3). AB - We describe a male with a large abdominal mass, most likely originating from the liver, with capsule rupture and tumor dissemination into the abdominal cavity. Adherence of the tumor to the diaphragm and lower right colon also were noted. A comprehensive evaluation of the mass revealed no tumor-defining histopathologic, immunocytochemical, ultrastructural, cytogenetic, or translocation features. The malignant tumor was found to have a novel translocation (X;19)(q13;13.3), which has not been reported in small round cell tumors of childhood or adults. The final diagnosis rendered was an undifferentiated small round cell tumor of uncertain cell of origin. PMID- 20162688 TI - A composite pheochromocytoma/ganglioneuroblastoma of the adrenal gland. AB - A 9-year-old female presented with a large abdominal mass. At surgery, the mass was noted to arise from the right adrenal gland. As the mass was manipulated, the patient developed severe hypertension. The final diagnosis was a cystic composite pheochromocytoma/ganglioneuroblastoma. This compound adrenal tumor is only the fourth case reported in a child. Because composite pheochromocytomas are rare in the pediatric population, the management, optimal surveillance schedule and outcomes have not been characterized. PMID- 20162690 TI - Nanoparticulate devices for brain drug delivery. AB - The blood-brain barrier (BBB) limits the transport of therapeutic molecules from the blood compartment into the brain, thus greatly reducing the species of therapeutic compounds that can be efficiently accumulated in the central nervous system (CNS). Various strategies have been proposed for improving the delivery of drugs to this tissue, and numerous invasive and noninvasive methods have been proposed by different scientists in an attempt to circumvent the BBB and to increase the delivery of drug compounds into the brain. An interesting alternative, in the solution of this problem and also that of reaching a suitable target in the CNS, has recently been provided through the use of nanoparticulate colloidal devices as a noninvasive technique for brain drug delivery. These systems offer diverse advantages over invasive strategies, because (1) they are designed using biocompatible and biodegradable materials; (2) they avoid the disruption and/or modification of the BBB; and (3) they modulate the biopharmaceutical properties of the entrapped drugs. Moreover, the possibility of targeting specific brain tissue, thanks to ligands linked to the surface of the nanoparticulate colloidal devices, confers the necessary characteristics for the treatment of CNS pathologies to these drug carriers. The aim of this review is to focus on describing the main strategies in use for designing nanoparticulate colloidal devices for CNS delivery, their potentiality as noninvasive strategies in the delivery of drugs to the cerebral tissues, and their biological and clinical applications in cerebral drug delivery. PMID- 20162694 TI - Influence of bone density on the cement fixation of femoral hip resurfacing components. AB - In clinical outcome studies, small component sizes, female gender, femoral shape, focal bone defects, bad bone quality, and biomechanics have been associated with failures of resurfacing arthroplasties. We used a well-established experimental setup and human bone specimens to analyze the effects of bone density on cement fixation of femoral hip resurfacing components. Thirty-one fresh frozen femora were prepared for resurfacing using the original instruments. ASR resurfacing prostheses were implanted after dual-energy X-ray densitometer scans. Real-time measurements of pressure and temperature during implantation, analyses of cement penetration, and measurements of micro motions under torque application were performed. The associations of bone density and measurement data were examined calculating regression lines and multiple correlation coefficients; acceptability was tested with ANOVA. We found significant relations between bone density and micro motion, cement penetration, cement mantle thickness, cement pressure, and interface temperature. Mean bone density of the femora was 0.82 +/- 0.13 g/cm(2), t-score was -0.7 +/- 1.0, and mean micro motion between bone and femoral resurfacing component was 17.5 +/- 9.1 microm/Nm. The regression line between bone density and micro motion was equal to -56.7 x bone density + 63.8, R = 0.815 (p < 0.001). Bone density scans are most helpful for patient selection in hip resurfacing, and a better bone quality leads to higher initial component stability. A sophisticated cementing technique is recommended to avoid vigorous impaction and incomplete seating, since increasing bone density also results in higher cement pressures, lower cement penetration, lower interface temperatures, and thicker cement mantles. PMID- 20162695 TI - Kissing versus crushing stents! Don't let the words deceive you! PMID- 20162696 TI - Carboxy terminus of secreted phosphoprotein-24 kDa (spp24) is essential for full inhibition of BMP-2 activity. AB - Secreted phosphoprotein-24 kDa (spp24) is a bone morphogenetic protein (BMP) binding protein isolated from bone. It exists in a number of size forms and is hypothesized to function as a BMP latency protein and/or a "slow release" mechanism for BMPs involved in bone turnover and repair. We have examined the hypothesis that proteolytic modification of the C-terminus of spp24 affects its BMP-2-binding properties and bioactivity in the BMP-2-stimulated ectopic bone forming bioassay. Three different size forms of recombinant spp24 that correspond to predicted 18.1 kDa, 16.0 kDa, and 14.5 kDa proteolytic products were compared to full-length (fl) spp24. One of these forms (spp18.1) we hypothesize to be the protein which Urist initially, but apparently inaccurately, called "BMP." Only full-length spp24 completely inhibited BMP-2-induced bone formation. The 18.1 kDa truncated isoform of spp24 which we hypothesize to be Urist's protein did not. The inhibitory capacity of the proteins was correlated with their kinetic constants, assessed by surface plasmon resonance. At the highest, inhibitory, dose of spp24 and its derivatives, k(d) ("stability") best predicted the extent of ectopic bone formation whereas at the lowest dose, which was not inhibitory, k(a) ("recognition") best predicted the extent of ectopic bone formation. We conclude that proteolytic processing of spp24 affects the interaction of this protein with BMP-2 and this affects the function of the protein. PMID- 20162697 TI - Systemic rapamycin to prevent restenosis: a glimpse to the past? PMID- 20162698 TI - Is diabetes a leveler of efficacy of DES types? PMID- 20162699 TI - Limitations of stints: a good, albeit imperfect, therapy; for a less than perfect world. PMID- 20162700 TI - Defining adverse events. PMID- 20162702 TI - The short but not the long of it; how well does the artery heal after vascular closure? PMID- 20162701 TI - Antineoplastic therapy use in patients with advanced cancer admitted to an acute palliative care unit at a comprehensive cancer center: a simultaneous care model. AB - BACKGROUND: Cancer patients admitted to a palliative care unit generally have a poor prognosis. The role of antineoplastic therapy (ANT) in these patients remains controversial. In the current study, the authors examined the frequency and predictors associated with ANT use in hospitalized patients who required admission to an acute palliative care unit (APCU). METHODS: Included in the study were all 2604 patients admitted over a 5-year period to a 12-bed APCU located within a National Cancer Institute comprehensive cancer center, in which patients had access to both palliative care and ANT. Institutional databases were used to retrospectively retrieve data regarding patient demographics, cancer diagnosis, ANT use, length of hospital stay, and survival from time of admission. RESULTS: The median hospital stay was 11 days, and the median survival was 22 days. During hospitalization, 435 patients (17%) received ANT, including chemotherapy (N = 297; 11%), hormonal agents (N = 54; 2%), and targeted therapy (N = 155; 6%). No significant change in the frequency of ANT use was detected over the 5-year period. Multivariate logistic regression analysis revealed that younger age, specific cancer diagnoses, and longer admissions were independently associated with ANT use. CONCLUSIONS: The use of ANT during hospitalization that included an APCU stay was limited to a small percentage of patients and did not increase over time. ANT use was associated with younger age, specific cancer diagnoses, and longer admissions. The APCU facilitates simultaneous care for patients receiving ANT. PMID- 20162703 TI - Approach-avoidance of side-branch wire entrapment. PMID- 20162704 TI - Acute forearm muscle swelling post transradial catheterization and compartment syndrome: prevention is better than treatment! PMID- 20162705 TI - Blood loss following invasive cardiac procedures: Going beyond the CBC. PMID- 20162706 TI - Gemcitabine versus bacille Calmette-Guerin after initial bacille Calmette-Guerin failure in non-muscle-invasive bladder cancer: a multicenter prospective randomized trial. AB - BACKGROUND: The efficacy of intravesical gemcitabine was evaluated compared with repeated administration of bacille Calmette-Guerin (BCG) after BCG failure in high-risk, non-muscle-invasive bladder cancer (BC). METHODS: In this multicenter, prospective, randomized, phase 2 trial, eligible patients were those with high risk non-muscle-invasive BC, failing 1 course of BCG therapy. All patients were randomly allocated to Group A, receiving intravesical gemcitabine (at a dose of 2000 mg/50 mL) twice weekly for 6 consecutive weeks and then weekly for 3 consecutive weeks at 3, 6, and 12 months, or Group B, receiving intravesical BCG (Connaught strain, 81 mg/50 mL) over a 6-week induction course and each week for 3 weeks at 3, 6, and 12 months. Outcome measures were recurrence rate, time to first recurrence, and progression rate. Treatment-related complications were also evaluated. RESULTS: Eighty participants were enrolled, 40 for each group 52.5% in Group A developed disease recurrence versus 87.5% of those in Group B (P = .002). There was no statistically significant difference in mean time to the first recurrence (Group A, 3.9 months; Group B, 3.1 months; P = .09). Kaplan-Meier analysis of 2-year recurrence-free survival showed significant differences between Group A and B (19% and 3%, respectively, P < .008). Seven of 21 (33%) patients in Group A and 13 of 35 (37.5%) patients in Group B had disease progression and underwent radical cystectomy (P = .12). Both intravesical administrations were generally well tolerated. CONCLUSIONS: Gemcitabine might represent a second-line treatment option after BCG failure in high-risk non muscle-invasive BC patients. PMID- 20162707 TI - Radiation monotherapy as regional treatment for lymph node-positive Merkel cell carcinoma. AB - BACKGROUND: : Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy with a high risk of lymph node involvement. To the authors' knowledge, few data have been published to date regarding the optimal regional therapy for lymph node positive patients. This cohort study was performed to analyze the outcomes of patients with lymph node-positive MCC treated with lymph node irradiation as definitive therapy compared with completion lymphadenectomy (CLND). METHODS: : Fifty patients with lymph node involvement of MCC at presentation and adequate follow-up data were included in this analysis. Forty-three of these patients were enrolled and followed prospectively. Twenty-six patients presented with microscopic lymph node disease, and 24 patients presented with palpable lymph node involvement. RESULTS: : Regional control for patients with microscopically involved lymph nodes was 100% regardless of treatment modality-definitive lymph node irradiation (n = 19) or CLND +/- radiotherapy (n = 7) with median follow-up of 18 months. Patients with clinically positive lymph nodes had 2-year regional recurrence-free survival rate of 78% and 73% in the definitive lymph node irradiation (n = 9) and CLND +/- radiotherapy (n = 15) groups, respectively (P = .8) with a median follow-up of 16 months. CONCLUSIONS: : To the best of the authors' knowledge, the current study is the largest series published to date of radiation monotherapy as regional treatment for lymph node-positive MCC. Lymph node irradiation alone to positive regional lymph nodes was found to confer an excellent regional control rate that was comparable to CLND for both microscopic and palpable lymph node disease. There was no difference noted with regard to overall survival. Given their similar efficacy, the choice between these lymph node therapies may be based on the clinical scenario and anticipated side effect profiles. Cancer 2010. (c) 2010 American Cancer Society. PMID- 20162708 TI - Angiosarcoma after breast-conserving therapy: long-term outcomes with hyperfractionated radiotherapy. AB - BACKGROUND: With breast-conserving therapy (BCT) as the standard of care for patients with noninvasive and early stage invasive breast cancer, a small incidence of post-BCT angiosarcoma has emerged. The majority of therapeutic interventions have been unsuccessful. To the authors' knowledge, there is no consensus in the medical literature to date regarding the treatment of this malignancy. The current study was conducted to report the long-term outcomes of a novel approach using hyperfractionated and accelerated radiotherapy (HART) for angiosarcoma developing after BCT. METHODS: The authors retrospectively reviewed the outcomes of 14 patients treated with HART with or without surgery at the University of Florida between November 1997 and March 2006 for angiosarcoma that developed after BCT. RESULTS: At the time of last follow-up, 9 patients had remained continuously without evidence of disease for a median of 61 months after HART (range, 36-127 months). Five patients had further manifestations of angiosarcoma after HART at a median of 1 month (range, 1-28 months): 3 with progressive pulmonary and/or mediastinal disease that was likely present before HART and 2 with local or regional disease extension. Progression-free survival rates for the 14 patients at 2 years and 5 years were 71% and 64%, respectively. The overall and cause-specific survival rates were both 86% at 2 years and 5 years. CONCLUSIONS: To the best of the authors' knowledge, HART with or without subsequent surgery, as documented in the current series, is the first approach to provide a high rate of local control, disease-free survival, and overall survival after the development of post-BCT angiosarcoma. The authors believe the success noted with this approach is related to both the hyperfractionation and acceleration of the RT. PMID- 20162709 TI - Cause of death in patients with lower-risk myelodysplastic syndrome. AB - BACKGROUND: The authors have recently shown that a majority of patients with myelodysplastic syndrome (MDS) classified by the International Prognostic Scoring System as lower risk die without transformation to acute myelogenous leukemia (AML). The cause of death (COD) of these patients is not well understood. Identifying the COD could help to guide early therapy decisions. METHODS: The authors retrospectively analyzed the COD in a cohort of 273 deceased patients with lower-risk MDS according to the International Prognostic Scoring System at presentation to The University of Texas M. D. Anderson Cancer Center from 1980 to 2004. MDS-related death was defined as infection, bleeding, transformation to AML, or disease progression. Remaining CODs were classified as non-MDS-related. RESULTS: Median age at presentation was 66 years (range, 19-88 years). Overall median survival was 59 weeks (range, 1-831 weeks). All French-American-British leukemia classification subgroups were represented. The percentage of International Prognostic Scoring System low and intermediate-1 groups were 21% and 79%, respectively. The most common cytogenetic abnormality (9%) was del(5q). Patients received supportive care only. The COD was identified as MDS-related in 230 of 273 (84%) patients. The most common disease-related CODs were infection (38%), transformation to AML (15%), and hemorrhage (13%). The most frequent non disease-related COD was cardiovascular events (19 of 43 patients). CONCLUSIONS: The majority of patients with low- or intermediate-1 risk MDS will die because of causes related to their underlying disease. Although these results need to be validated in different populations, early therapeutic intervention could be considered in the management of these patients to improve survival. PMID- 20162710 TI - Impact of postoperative prostate-specific antigen disease recurrence and the use of salvage therapy on the risk of death. AB - BACKGROUND: This report evaluated whether biochemical recurrence (BCR) as a time dependent covariate (t) after radical prostatectomy (RP) for prostate cancer was associated with the risk of death and whether salvage therapy with radiotherapy (RT) and/or hormonal therapy (HT) can lessen this risk METHODS: This was a retrospective cohort study of 3071 men who underwent RP at Duke University between 1988 and 2008 and had complete follow-up data. A Cox regression multivariable analysis was used to determine whether BCR (t) was associated with the risk of death in men after adjusting for age, prostatectomy findings, and the use of salvage RT and/or HT. RESULTS: After a median follow-up of 7.4 years, 546 (17.8%) men experienced BCR and 454 (14.8%) died. The median follow-up after prostate-specific antigen (PSA) failure was 11.2 years (interquartile range, 5.8 16.0 years). BCR (t) was associated with an increased risk of death (adjusted hazards ratio [AHR], 1.03; 95% confidence interval [95% CI], 1.004-1.06 [P = .025]). In men who experienced BCR, a PSA doubling time <6 months was associated with an increased risk of death (AHR, 1.55; 95% CI, 1.15-2.1 [P = .004]); whereas a decrease in the risk of death was observed in men who received RT (AHR, 0.58; 95% CI, 0.40-0.58 [P = .002]) or HT (AHR, 0.56; 95% CI, 0.37-0.84 [P = .005]) after BCR. CONCLUSIONS: The occurrence of BCR was found to increase the risk of death in men undergoing RP for prostate cancer, and this risk appeared to increase as the time to BCR shortened. However, the addition of RT and/or HT in men with BCR significantly lowered this risk. PMID- 20162711 TI - Optimizing technique and outcomes in structural heart disease interventions: Rapid pacing during aortic valvuloplasty? PMID- 20162712 TI - Large diameter covered stent treatment of aortic coarctation. PMID- 20162713 TI - Wear, delamination, and fatigue resistance of melt-annealed highly crosslinked UHMWPE cruciate-retaining knee inserts under activities of daily living. AB - The wear, delamination, and fatigue resistance of artificially aged gamma irradiation-sterilized conventional polyethylene (CPE) and gas-plasma-sterilized melt-annealed highly crosslinked polyethylene tibial inserts (HXPE) were compared. Six CPE and 12 HXPE (six irradiated at 58 kGy and six at 72 kGy) left knee inserts were wear tested for 5.5 million cycles (Mc) under loads and motions that mimic activities of daily living, such as walking, chair rise, stair ascent, and deep squatting. Another six HXPE (72 kGy) and six CPE inserts were also tested under conditions that could produce severe delamination for 8 Mc. Ten other knees (five 72 kGy HXPE and five CPE) were subjected to posterior edge loading fatigue testing for 5 Mc. The HXPE inserts had an average wear rate reduction of about 80% relative to their CPE counterparts during all activities. All of the CPE inserts delaminated and fractured during high cycle deep squat (152 degrees flexion) motions, while all the HXPE remained intact. None of the HXPE inserts delaminated after 8 Mc, while all of the CPE inserts developed delamination damage within 1.5-5.8 Mc of delamination testing. All CPE inserts developed subsurface cracks and delamination within 2.8 Mc during posterior edge loading fatigue studies, while none of the HXPE inserts showed cracking or delamination after 5 Mc. These results show that aged HXPE has higher wear and fatigue resistance than aged CPE, and offers potential long-term advantages for young active patients with sustained activities of daily living. PMID- 20162714 TI - Augmentation of surgical angiogenesis in vascularized bone allotransplants with host-derived a/v bundle implantation, fibroblast growth factor-2, and vascular endothelial growth factor administration. AB - We have previously shown experimental transplantation of living allogeneic bone to be feasible without long-term immunosuppression by development of a recipient derived neoangiogenic circulation within bone. In this study, we examine the role of angiogenic cytokine delivery with biodegradable microspheres to enhance this process. Microsurgical femoral allotransplantation was performed from Dark Agouti to Piebald Virol Glaxo rats. Poly(D,L-lactide-co-glycolide) microspheres loaded with buffer, basic fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), or both, were inserted intramedullarly along with a recipient derived arteriovenous (a/v) bundle. FK-506 was administered daily for 14 days, then discontinued. At 28 days, bone blood flow was measured using hydrogen washout. Microangiography, histologic, and histomorphometric analyses were performed. Capillary density was greater in the FGF+VEGF group (35.1%) than control (13.9%) (p < 0.05), and a linear trend was found from control, FGF, VEGF, to FGF+VEGF (p < 0.005). Bone formation rates were greater with VEGF (p < 0.01) and FGF+VEGF (p < 0.05). VEGF or FGF alone increased blood flow more than when combined. Histology rejection grading was low in all grafts. Local administration of vascular and fibroblast growth factors augments angiogenesis, bone formation, and bone blood flow from implanted blood vessels of donor origin in vascularized bone allografts after removal of immunosuppression. PMID- 20162715 TI - Cefazolin embedded biodegradable polypeptide nanofilms promising for infection prevention: a preliminary study on cell responses. AB - Implant-associated infection is a serious complication in orthopedic surgery, and endowing implant surfaces with antibacterial properties could be one of the most promising approaches for preventing such infection. In this study, we developed cefazolin loaded biodegradable polypeptide multilayer nanofilms on orthopedic implants. We found that the amount of cefazolin released could be tuned. A high local concentration of cefazolin was achieved within the first a few hours and therefore may inhibit bacterial colonization in the critical postimplantation period. The developed cefazolin loaded nanofilms showed their in vitro efficacy against Staphylococcus aureus; the more antibiotics loaded, the longer the nanocoated implant had antibacterial properties. More interestingly, antibiotic loaded polypeptide multilayer nanofilms also improved osteoblast bioactivity including cell viability and proliferation. These findings suggested that biodegradable polypeptide multilayer nanofilms as antibiotic carriers at the implant/tissue interface are compatible with human cells such as osteoblasts and bactericidal to bacteria such as S. aureus. These characteristics could be promising for preventing implant-associated infection and potentially improving bone healing. PMID- 20162716 TI - Sex or survival: short-term versus long-term androgen deprivation in patients with locally advanced prostate cancer treated with radiotherapy. AB - BACKGROUND: Combined long-term androgen deprivation (LTAD) and radiation conveys a prostate cancer-specific survival advantage over combined short-term androgen deprivation (STAD) and radiation. The seminal question is whether or not the gains are worth the adverse effects of LTAD with respect to patient preferences. METHODS: Preferences for LTAD compared with STAD were elicited by direct patient interview using the probability trade-off method. "Time trade-off utilities" (TTOu) for erectile dysfunction and osteoporosis were elicited using the time trade-off method. Participants' current prostate cancer-specific health state was assessed using the Patient-Oriented Prostate Utility Scale-Psychometric. Participants' current sexual function was assessed using the International Index of Erectile Function (IIEF). RESULTS: All participants were willing to trade survival rather than undergo LTAD compared with STAD. The mean minimally required increment in prostate cancer-specific survival (MRIS) was 8.2%. The mean TTOu for impotence was 0.78, and the mean TTOu for osteoporosis was 0.71. The MRIS was correlated with the Sexual Desire domain score of the IIEF (Spearman rank correlation coefficient, r = 0.50; P<.0001). CONCLUSIONS: Patients desired more prostate cancer-specific survival than what was afforded by LTAD and radiotherapy compared with STAD and radiotherapy. PMID- 20162717 TI - Circadian variation in radiation-induced intestinal mucositis in patients with cervical carcinoma. AB - BACKGROUND: Mucositis, a radiotherapy-associated toxicity, is an important factor determining morbidity and treatment compliance. Gastrointestinal mucositis in patients undergoing radiotherapy may also depend on time of administration of radiation in addition to several other factors. The presence of any correlation between the severity of acute gastrointestinal mucositis in cervical carcinoma patients and the time of irradiation was prospectively evaluated. METHODS: A total of 229 patients with cervical carcinoma were randomized to morning (8:00 10:00 AM) and evening (6:00-8:00 PM) arms. The incidence of mucositis in the 2 arms was assessed and reported in terms of various grades of diarrhea. RESULTS: Overall (grade I-IV) as well as higher grade (III and IV) diarrhea was found to be significantly increased in the morning arm as compared with the evening arm (overall: 87.39 % vs 68.18 %, P < .01; higher grade: 14.29% vs 5.45%, P < .05). Other radiation-induced toxicity was also higher in the morning arm, but its occurrence in the 2 arms did not differ significantly (13.45% vs 12.73%, P > .05). After completion of treatment, patients' response to radiation in the 2 arms was similar (P > .05). CONCLUSIONS: The significant difference in the incidence of higher grade diarrhea between the morning and evening arms is indirect evidence of the influence of circadian rhythm on the intestinal mucosa of the human intestine. This knowledge may facilitate treating patients with decreased toxicity to the intestinal mucosa. PMID- 20162718 TI - Matrix metalloproteinase (MMP)-3 gene up-regulation in a rat tail compression loading-induced disc degeneration model. AB - The rodent static compression loading-induced disc degeneration model still has important gaps among the radiographic, magnetic resonance imaging (MRI), and histological schemes and the acute and chronic expression of catabolic genes such as matrix metalloproteinase (MMP)-3. Our objectives were to assess the validity of a rat tail two-disc static compression model and to elucidate a representative catabolic marker, MMP-3 gene alterations, throughout the degenerative process. Static compression at 1.3 MPa for up to 56 days produced progressive disc height loss in radiographs, lower nucleus intensity on T2-weighted MRIs, and histomorphological degeneration. Real-time RT-PCR mRNA quantification showed significant MMP-3 up-regulation in nucleus pulposus cells from 7 days and a significantly progressive increase as the loading duration lengthened, with high correlations to radiological degenerative scores. Immunohistochemistry demonstrated progressively increased positive staining for MMP-3. These results validate this animal model for disc degeneration research. Progressive mRNA and protein-distributional up-regulations indicate the significant role of MMP-3 and its feasibility as a disc degenerative marker. This model should prove useful for investigating the pathomechanism and for evaluating molecular therapies for degenerative disc disease. PMID- 20162719 TI - Cell-free assay breakthrough for MLH1 variants. PMID- 20162720 TI - Mutation clusters offer insight into predicting pathogenicity. PMID- 20162721 TI - Stimulation of glucocorticoid-induced tumor necrosis factor receptor family related protein ligand (GITRL) induces inflammatory activation of microglia in culture. AB - Glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL) is a member of the tumor necrosis factor superfamily (TNFSF) and is known to act as a costimulator in the immune system by binding to GITR. GITRL is expressed in endothelial cells, dendritic cells, macrophages, and B cells, but it is not known whether GITRL is expressed in brain microglia cells. Here, we investigated the expression of GITR and GITRL and their potential role in microglia cells. Using BV-2 mouse microglia cells and mouse primary microglia cultures, we have demonstrated that 1) both GITR and GITRL are expressed in microglia cells; 2) stimulation of GITRL induces inflammatory activation of microglia on the basis of production of nitric oxide (NO) and expression of inducible nitric oxide synthase, cyclooxygenase-2, CD40, and matrix metalloproteinase-9; 3) GITRL-mediated microglial NO production partially depends on p38 MAPK, JNK, and nuclear factor-kappaB pathways; and 4) GITRL stimulation also induces microglia cell death. These results indicate that GITR and GITRL are functionally expressed on brain microglia and that the stimulation of GITRL can induce inflammatory activation of microglia. The GITR/GITRL system may play an important role in neuroinflammation. PMID- 20162722 TI - Higher order structure of short collagen model peptides attached to dendrimers and linear polymers. AB - Collagen, which is used as a biomaterial, is the most abundant protein in mammals. We have previously reported that a dendrimer modified with collagen model peptides, (Gly-Pro-Pro)(5), formed a collagen-like triple-helical structure, showing thermal reversibility. In this study, various collagen-mimic dendrimers of different generations and at different binding ratios were synthesized, to investigate the relationship between the peptide clustering effect and the higher order structure formation. The formation of the higher order structure was influenced by the binding ratios of the peptide to the dendrimer, but was not influenced by the dendrimer generation. A spacer, placed between the dendrimer terminal group and the peptide, negatively contributed to the formation of the higher order structure. The collagen model peptides were also attached to poly(allylamine) (PAA) and poly-L-lysine (poly(Lys)) to compare them with the collagen-mimic dendrimers. The PAA-based collagen-mimic compound, bearing more collagen model peptides than the dendrimer, exhibited a thermally stable higher order structure. In contrast, this was not observed for the collagen-mimic polymers based on poly(Lys). Therefore, dendrimers and vinyl polymers act as a scaffold for collagen model peptides and subsequently induce higher order structures. PMID- 20162723 TI - Abrasion resistance of oxidized zirconium in comparison with CoCrMo and titanium nitride coatings for artificial knee joints. AB - Most total knee replacement joints consist of a metal femoral component made from a cobalt-chromium- molybdenum (CoCrMo)-alloy and a tibial component with an ultrahigh molecular weight polyethylene (UHMWPE) bearing surface. Wear of the UHMWPE remains the primary disadvantage of these implants. The allergic potential ascribed to CoCrMo-alloys is a further concern. Other metallic alloys with and without ceramic coatings are clinically used to avoid these problems. This study compared the mechanical surface properties of an oxidized zirconium alloy with those of cast and wrought CoCrMo and TiAlV6-4. Additionally, the influence of a titanium nitride (TiN)-plasma coating on the surface properties was investigated. The composition of the oxidized zirconium layer was analyzed. Micro- and macrohardness tests as well as adhesion tests were used to reveal material differences in terms of their abrasive wear potential in artificial joints. PMID- 20162724 TI - A de novo designed 11 kDa polypeptide: model for amyloidogenic intrinsically disordered proteins. AB - A de novo polypeptide GH(6)[(GA)(3)GY(GA)(3)GE](8)GAH(6) (YE8) has a significant number of identical weakly interacting beta-strands with the turns and termini functionalized by charged amino acids to control polypeptide folding and aggregation. YE8 exists in a soluble, disordered form at neutral pH but is responsive to changes in pH and ionic strength. The evolution of YE8 secondary structure has been successfully quantified during all stages of polypeptide fibrillation by deep UV resonance Raman (DUVRR) spectroscopy combined with other morphological, structural, spectral, and tinctorial characterization. The YE8 folding kinetics at pH 3.5 are strongly dependent on polypeptide concentration with a lag phase that can be eliminated by seeding with a solution of folded fibrillar YE8. The lag phase of polypeptide folding is concentration dependent leading to the conclusion that beta-sheet folding of the 11-kDa amyloidogenic polypeptide is completely aggregation driven. PMID- 20162725 TI - Histone deacetylase inhibitors (HDACIs). Structure--activity relationships: history and new QSAR perspectives. AB - Histone deacetylase (HDAC) inhibition is a recent, clinically validated therapeutic strategy for cancer treatment. HDAC inhibitors (HDACIs) block angiogenesis, arrest cell growth, and lead to differentiation and apoptosis in tumor cells. In this article, a survey of published quantitative structure activity relationships (QSARs) studies are presented and discussed in the hope of identifying the structural determinants for anticancer activity. Secondly a two dimensional QSAR study was carried out on biological results derived from various types of HDACIs and from different assays using the C-QSAR program of Biobyte. The QSAR analysis presented here is an attempt to organize the knowledge on the HDACIs with the purpose of designing new chemical entities with enhanced inhibitory potencies and to study the mechanism of action of the compounds. This study revealed that lipophilicity is one of the most important determinants of activity. Additionally, steric factors such as the overall molar refractivity (CMR), molar volume (MgVol), the substituent's molar refractivity (MR) (linear or parabola), or the sterimol parameters B(1) and L are important. Electronic parameters indicated as sigma(p), are found to be present only in one case. PMID- 20162726 TI - Solid freeform fabrication and characterization of porous calcium polyphosphate structures for tissue engineering purposes. AB - Solid freeform fabrication (SFF) enables the fabrication of anatomically shaped porous components required for formation of tissue engineered implants. This article reports on the characterization of a three-dimensional-printing method, as a powder-based SFF technique, to create reproducible porous structures composed of calcium polyphosphate (CPP). CPP powder of 75-150 microm was mixed with 10 wt % polyvinyl alcohol (PVA) polymeric binder, and used in the SFF machine with appropriate settings for powder mesh size. The PVA binder was eliminated during the annealing procedure used to sinter the CPP particles. The porous SFF fabricated components were characterized using scanning electron microscopy, micro-CT scanning, X-ray diffraction, and mercury intrusion porosimetry. In addition, mechanical testing was conducted to determine the compressive strength of the CPP cylinders. The 35 vol % porous structures displayed compressive strength on average of 33.86 MPa, a value 57% higher than CPP of equivalent volume percent porosity made through conventional gravity sintering. Dimensional deviation and shrinkage analysis was conducted to identify anisotropic factors required for dimensional compensation during SFF sample formation and subsequent sintering. Cell culture studies showed that the substrate supported cartilage formation in vitro, which was integrated with the top surface of the porous CPP similar to that observed when chondrocytes were grown on CPP formed by conventional gravity sintering methods as determined histologically and biochemically. PMID- 20162727 TI - CXC chemokine ligand 4 (Cxcl4) is a platelet-derived mediator of experimental liver fibrosis. AB - Liver fibrosis is a major cause of morbidity and mortality worldwide. Platelets are involved in liver damage, but the underlying molecular mechanisms remain elusive. Here, we investigate the platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) as a molecular mediator of fibrotic liver damage. Serum concentrations and intrahepatic messenger RNA of CXCL4 were measured in patients with chronic liver diseases and mice after toxic liver injury. Platelet aggregation in early fibrosis was determined by electron microscopy in patients and by immunohistochemistry in mice. Cxcl4(-/-) and wild-type mice were subjected to two models of chronic liver injury (CCl(4) and thioacetamide). The fibrotic phenotype was analyzed by histological, biochemical, and molecular analyses. Intrahepatic infiltration of immune cells was investigated by fluorescence-activated cell sorting, and stellate cells were stimulated with recombinant Cxcl4 in vitro. The results showed that patients with advanced hepatitis C virus-induced fibrosis or nonalcoholic steatohepatitis had increased serum levels and intrahepatic CXCL4 messenger RNA concentrations. Platelets were found directly adjacent to collagen fibrils. The CCl(4) and thioacetamide treatment led to an increase of hepatic Cxcl4 levels, platelet activation, and aggregation in early fibrosis in mice. Accordingly, genetic deletion of Cxcl4 in mice significantly reduced histological and biochemical liver damage in vivo, which was accompanied by changes in the expression of fibrosis-related genes (Timp-1 [tissue inhibitor of matrix metalloproteinase 1], Mmp9 [matrix metalloproteinase 9], Tgf-beta [transforming growth factor beta], IL10 [interleukin 10]). Functionally, Cxcl4(-/-) mice showed a strongly decreased infiltration of neutrophils (Ly6G) and CD8(+) T cells into the liver. In vitro, recombinant murine Cxcl4 stimulated the proliferation, chemotaxis, and chemokine expression of hepatic stellate cells. CONCLUSION: The results underscore an important role of platelets in chronic liver damage and imply a new target for antifibrotic therapies. PMID- 20162728 TI - Disruption of the growth hormone--signal transducer and activator of transcription 5--insulinlike growth factor 1 axis severely aggravates liver fibrosis in a mouse model of cholestasis. AB - Growth hormone (GH) resistance and low serum levels of insulinlike growth factor 1 (IGF-1) are common features in human liver fibrosis and cirrhosis. Signal transducer and activator of transcription 5 (STAT5) controls several vital functions in the liver, including GH-mediated transcription of IGF-1. To investigate the role of STAT5 in liver fibrogenesis, we specifically deleted the Stat5a/b locus both in hepatocytes and cholangiocytes in the multidrug resistance gene 2 knockout (Mdr2(-/-)) mouse model of cholestasis. Double knockout mice develop an early and severe liver fibrosis phenotype, accompanied by perturbed expression of key regulators of bile acid homeostasis. Deletion of Stat5 resulted in GH resistance, and IGF-1 levels in serum were undetectable. We could observe reduced expression of important hepatoprotective genes, such as epidermal growth factor receptor (Egfr), hepatocyte nuclear factor 6 (Hnf6), prolactin receptor (Prlr), and leukemia inhibitory factor receptor (Lifr) as well as increased numbers of apoptotic hepatocytes. CONCLUSION: Our data suggest that loss of STAT5 sensitizes hepatocytes to bile acid-induced damage and apoptosis caused by disruption of GH-induced transcription of Igf-1 and down-regulation of hepatoprotective genes. These findings could contribute to the understanding of liver fibrosis and future treatment strategies for liver fibrosis. PMID- 20162729 TI - Cancer caused by too much apoptosis--an intriguing contradiction? PMID- 20162730 TI - Estimation of the healthy upper limits for serum alanine aminotransferase in Asian populations with normal liver histology. AB - A recent study in young Italian subjects suggested that the healthy thresholds for serum alanine aminotransferase (ALT) levels should be adjusted to 30 IU/L for men and 19 IU/L for women when assessing risk factors for nonalcoholic fatty liver disease. Our aim was to assess serum ALT concentrations in healthy Korean individuals and to determine the factors affecting ALT levels in these populations. We included 1,105 potential liver donors (643 men and 462 women) with biopsy-proven normal livers. Median ages were 25 years in men and 30 years in women, with a median body mass index (BMI) of 22.3 kg/m(2) in men and 21.4 kg/m(2) in women. The calculated thresholds for ALT values in these subjects were 35 IU/L for men and 26 IU/L for women. Age and BMI were independently correlated with ALT levels in both sexes, whereas serum total cholesterol concentration was significant only in men and blood glucose level only in women (P < 0.05). When we chose a subgroup of 665 individuals (346 men and 319 women) using Prati criteria, modified by the BMI cutoff points for Asians (<23 kg/m(2)), we found that the healthy ALT values were 33 IU/L for men and 25 IU/L for women. The mean ALT concentrations for subjects within the Prati criteria were significantly lower than for those outside the criteria (16.7 versus 19.5 IU/L for men, 12.8 versus 14.9 IU/L for women; P < 0.001). CONCLUSION: The healthy ALT thresholds in biopsy proven normal Asians were clearly lower than the previously accepted thresholds, as has also been noted in Europeans. Age, BMI, and/or other metabolic parameters significantly affect ALT levels, even in subjects with normal livers. PMID- 20162731 TI - Hepatitis C virus core protein interacts with fibrinogen-beta and attenuates cytokine stimulated acute-phase response. AB - Fibrinogen-beta (FBG-beta), an important acute-phase protein (APP), is generated by the liver as a target for inflammatory mediators. Here we identified FBG-beta as a hepatitis C virus (HCV) core interacting protein by screening a human liver complementary DNA (cDNA) library using mammalian two-hybrid analysis. An association between FBG-beta and HCV core protein was verified by confocal microscopy and coimmunoprecipitation from the transfected human hepatocyte (Huh 7) cell line. HCV core or genomic RNA transfected Huh-7 cells modestly increased FBG-beta protein expression when compared to the basal level in control hepatocytes. Transfection of HCV core or full-length (FL) gene into Huh-7 cells up-regulated basal FBG-beta promoter activity. Exogenous addition of IL-6 stimulates FBG-beta promoter activity in hepatocytes. However, ectopic expression of HCV core or FL in hepatocytes inhibited IL-6-stimulated FBG-beta promoter activation. Inhibition of endogenous FBG-beta expression following introduction of small interfering RNA (siRNA) into cells displayed a gain of function of promoter regulation by HCV core protein. Further studies suggested that HCV core gene expression in stable transfectants of Huh-7 cells resulted in a basal up regulation of FBG-beta and other APPs. However, treatment with cytokines, interleukin-6 (IL-6), or tumor necrosis factor-alpha repressed FBG-beta and other acute-phase response (APR) genes. CONCLUSION: Our results reveal that the core/FBG-beta interaction may act as a regulatory feedback, allowing repression of IL-6-stimulated APR genes. Together, these data suggested a network of interactions between HCV core and the hepatic APR genes, and may contribute to impaired innate immunity for viral persistence. PMID- 20162732 TI - Vitamin C deficiency attenuates liver fibrosis by way of up-regulated peroxisome proliferator-activated receptor-gamma expression in senescence marker protein 30 knockout mice. AB - Senescence marker protein 30 (SMP30), an important aging marker molecule that is highly expressed in the liver, has been known to protect hepatocytes from apoptosis by the synthesis of vitamin C. To explore the function of SMP30 in liver fibrosis, the effect of SMP30 deficiency on liver fibrosis was investigated in SMP30 knockout (KO) mice. Moreover, the in vivo results were further confirmed by way of hepatic stellate cell (HSC) isolation. We demonstrated that carbon tetrachloride (CCl(4))-induced liver fibrosis and the nuclear translocation of p Smad2/3, the immediate downstream of transforming growth factor beta (TGF-beta), were significantly inhibited in the liver of SMP30 KO mice compared with wildtype (WT) mice. We also confirmed that both WT and SMP30 KO HSCs did not express SMP30. Finally, we further confirmed that up-regulation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) caused by a lack of vitamin C was the pivotal factor in the mechanisms for attenuated liver fibrosis of SMP30 KO mice, and feeding with vitamin C restored CCl(4)-induced liver fibrosis in SMP30 KO mice. CONCLUSION: Vitamin C deficiency by SMP30 depletion attenuated liver fibrosis by way of up-regulated PPAR-gamma expression in SMP30 KO mice. Our results provide, for the first time, the possible mechanisms underlying inhibition of HSC activation associated with vitamin C and PPAR-gamma up regulation in liver fibrosis of SMP30 KO mice. PMID- 20162733 TI - Single coronary artery: right coronary artery originated from middle of left anterior descending artery in a patient with severe mitral regurgitation. AB - The single coronary artery is a benign and very rare coronary artery abnormality. Anomalous origin of the right coronary artery originating from the left anterior descending artery has been reported previously in just a few cases. In this article, we presented a patient with an anomalous origin of the right coronary artery from the midportion of the left anterior descending artery. The anomalous coronary artery was discovered incidentally during a coronary angiography performed prior to mitral valve surgery. PMID- 20162734 TI - Ischemic left ventricular systolic dysfunction as first manifestation of primary antiphospholipid syndrome in a young patient. PMID- 20162735 TI - Right-sided chest leads in exercise testing for detection of coronary restenosis. AB - BACKGROUND: The incorporation of right-sided chest leads (V(3)R through V(5)R) into standard exercise testing has been reported to improve its diagnostic utility. HYPOTHESIS: The purpose of this study was to evaluate any improvement in the ability of exercise testing in detecting restenosis, using additional V(3)R through V(5)R leads, in asymptomatic patients undergoing percutaneous coronary intervention (PCI) in the right coronary artery (RCA) or/and left circumflex (LCX). METHODS: We studied 172 consecutive patients (54 +/- 7 years old, 106 males) undergoing PCI in RCA or/and LCX. A treadmill test had been performed before PCI. Six months later, all patients underwent a second treadmill test and arteriography in order to detect silent ischemia due to restenosis. Recordings during exercise were obtained with the standard 12-leads plus V(3)R through V(5)R. RESULTS: Out of 172 patients, 106 had stenosis in RCA, 35 in LCX, and 31 in both vessels while 6 months later, restenosis was detected in 8 (for RCA), 3 (for LCX), and 3 (for both vessels) patients respectively. Sensitivity, specificity, positive prognostic value, negative prognostic value, and accuracy of exercise testing performed post PCI were ameliorated using V(3)R through V(5)R (79% vs 57%, 97% vs 80%, 69% vs 21%, 98% vs 95%, and 95% vs 78% respectively, P < .05 for all except negative prognostic value). Maximal exercise-induced ST segment deviation (in mm) was not changed post PCI in 12 leads (1.4 +/- 0.2 vs 1.5 +/- 0.2, P = NS) while it was decreased in V(3)R through V(5)R (0.2 +/- 0.2 vs 1.2 +/- 0.3, P < .01). CONCLUSIONS: The addition of V(3)R through V(5)R improves the diagnostic ability of standard exercise testing in detecting silent ischemia due to restenosis in patients undergoing PCI in RCA or/and LCX. PMID- 20162736 TI - Nebivolol efficacy and safety in patients with stage I-II hypertension. AB - BACKGROUND: Nebivolol is a novel, beta(1)-adrenergic receptor blocker with vasodilatory properties mediated through activation of the L-arginine/nitric oxide pathway. HYPOTHESIS: This multicenter, double-blind, parallel-group, placebo-controlled study investigated the antihypertensive efficacy and safety of nebivolol in patients with stage I through stage II hypertension (sitting diastolic blood pressure [SiDBP] > or = 95 mm Hg and < or = 109 mm Hg). METHODS: A total of 811 patients were randomized to placebo or nebivolol 5 mg, 10 mg, or 20 mg once daily for 12 weeks. The primary efficacy endpoint was the reduction in mean trough SiDBP from baseline. RESULTS: At study end, the least squares mean reductions in trough SiDBP from baseline with nebivolol 5 mg, 10 mg, and 20 mg were - 7.8 mm Hg, - 8.5 mm Hg, and - 9.1 mm Hg, respectively, compared with - 4.6 mm Hg for placebo (P = .002 for nebivolol 5 mg, P<.001 for nebivolol 10 mg and 20 mg, vs placebo). Nebivolol treatment also produced reductions in trough sitting systolic blood pressure; however, only the 20 mg dose was statistically significant compared with placebo (-6.7 mm Hg vs - 0.4 mm Hg; P<.001). Response rates (defined as an average trough SiDBP < 90 mm Hg or a decrease by > or = 10 mm Hg from baseline at the end of the study) ranged from 66.0% to 68.9% with nebivolol 5-20 mg, compared with 49.3% with placebo (P< or =.009). Nebivolol 5 mg and 10 mg doses were well tolerated, with an overall adverse event incidence comparable to placebo. CONCLUSIONS: Once-daily nebivolol is an effective antihypertensive agent in patients with stage I-II hypertension. PMID- 20162737 TI - Profiles in cardiology. Jonathan Campbell Meakins. PMID- 20162738 TI - Influence of heart rate on quality of life in patients with chronic atrial fibrillation. AB - BACKGROUND: Current criteria for rate control in atrial fibrillation (AF) treatment are empirical and based on a small amount of scientific data. HYPOTHESIS: This study was designed to analyze the influence of heart rate (HR, measured by the 6-minute walk test [6MWT] and 24-hour Holter monitoring) on quality of life (QoL). METHODS: A total of 89 male patients with chronic atrial fibrillation (AF) and resting HR < 90 bpm were included. QoL (assessed by the Short Form-36 Health Survey [SF-36] questionnaire) was compared among 3 groups of patients classified by HR testing results: group 1 had HR < or = 110 bpm on 6MWT and < or = 80 bpm on Holter monitor; group 2 had HR in the target area by 1 but not both tests; and group 3 had HR > 110 bpm on 6MWT and > 80 bpm on Holter monitor. RESULTS: There were significant differences among the 3 groups in physical and mental component summary scores (285.9 +/- 73.9; 276.6 +/- 80.8; 230.3 +/- 91.0, P = .035; and 319.8 +/- 70.2; 294.7 +/- 76.0; 255.0 +/- 107.1, P = .026, respectively).When the methods were analyzed separately, there was a significant difference on QoL in physical and mental summary scores in patients with maximal HR < or = 110 bpm on 6MWT in comparison with HR > 110 bpm (P = .04 and P = .01, respectively) and in the physical summary score in patients with average HR < or = 80 bpm on Holter monitor in comparison with HR > 80 bpm (P = .02). CONCLUSIONS: Holter monitoring and 6MWT should be performed as complementary methods to better predict QoL. PMID- 20162739 TI - Uric acid: the past decade. PMID- 20162740 TI - Conflict of interest in science communication: more than a financial issue. Report from Esteve Foundation Discussion Group, April 2009. PMID- 20162741 TI - Uric acid and antioxidant effects of wine. AB - The aim of this article is to review the role of uric acid in the context of antioxidant effects of wine and its potential implication to human health. We described and discussed the mechanisms of increase in plasma antioxidant capacity after consumption of moderate amounts of wine. Because this effect is largely contributed by acute elevation in plasma uric acid, we paid special attention to wine constituents and metabolic processes that are likely to be involved in uric acid elevation. PMID- 20162742 TI - Predictive value of 8 genetic loci for serum uric acid concentration. AB - AIM: To investigate the value of genomic information in prediction of individual serum uric acid concentrations. METHODS: Three population samples were investigated: from isolated Adriatic island communities of Vis (n=980) and Korcula (n=944), and from general population of the city of Split (n=507). Serum uric acid concentration was correlated with the genetic risk score based on 8 previously described genes: PDZK1, GCKR, SLC2A9, ABCG2, LRRC16A, SLC17A1, SLC16A9, and SLC22A12, represented by a total of 16 single-nucleotide polymorphisms (SNP). The data were analyzed using classification and regression tree (CART) and general linear modeling. RESULTS: The most important variables for uric acid prediction with CART were genetic risk score in men and age in women. The percent of variance for any single SNP in predicting serum uric acid concentration varied from 0.0%-2.0%. The use of genetic risk score explained 0.1% 2.5% of uric acid variance in men and 3.9%-4.9% in women. The highest percent of variance was obtained when age, sex, and genetic risk score were used as predictors, with a total of 30.9% of variance in pooled analysis. CONCLUSION: Despite overall low percent of explained variance, uric acid seems to be among the most predictive human quantitative traits based on the currently available SNP information. The use of genetic risk scores is a valuable approach in genetic epidemiology and increases the predictability of human quantitative traits based on genomic information compared with single SNP approach. PMID- 20162744 TI - Interactions between genetic variants in glucose transporter type 9 (SLC2A9) and dietary habits in serum uric acid regulation. AB - AIM: To investigate possible interactions between genetic variants in glucose transporter type 9 (SLC2A9) gene and dietary habits in serum uric acid regulation. METHODS: Participants for this study were recruited from two isolated Croatian island communities of Vis (n=918) and Korcula (n=898). Three single nucleotide polymorphisms (SNP) from the SLC2A9 gene (rs1014290, rs6449213, rs737267) were correlated with dietary habits and uric acid. RESULTS: A significant decrease in uric acid levels was recorded with increasing consumption of milk, sour cream, duck and turkey, and eggs. The only significant interaction was found between potato consumption and rs737267 and a near-significant interaction was found between soft drinks and rs1014290 (interaction P=0.068). Increased consumption of soft drinks interacting with the TT genotype at rs1014290 increased serum uric acid. No significant interactions were observed between food products consumption and rs6449213. CONCLUSION: There is a certain extent of interaction between SLC2A9 and dietary patterns in serum uric acid determination. The metabolic effect of soft drinks seems to be determined by the underlying genotype of rs1014290. PMID- 20162743 TI - Common variants in SLC17A3 gene affect intra-personal variation in serum uric acid levels in longitudinal time series. AB - AIM: To investigate whether intra-personal variation in serum uric acid concentration is influenced by genes that were described to be associated with serum uric acid levels in cross-sectional studies. METHODS: The study included 92 participants from the isolated community of the Croatian island of Vis. For each participant, two uric acid concentration measurements were available, one from 2002 and one from 2003. Changes in uric acid concentration were correlated with a set of 8 genes known to affect it: PDZK1, GCKR, SLC2A9, ABCG2, LRRC16A, SLC17A3, SLC16A9, and SLC22A12. RESULTS: Thirteen participants (14%) had uric acid concentration change greater than 130 micromol/L. Greater variability of uric acid concentration was recorded in women (coefficient of variation 49% vs 12% in men). Two SNPs belonging to SLC17A3 gene (rs9393672 and rs942379) yielded significant association with serum uric acid concentration changes in women. These two single-nucleotide polymorphisms (SNP) explained 0.2%-1.3% of variance for 2002 or 2003 uric acid measurement and 1.1%-1.8% of variance for the average value of these two measurements. CONCLUSIONS: Repeated measurements offer a possibility to enrich the percent of explained variance and contribute to the understanding of the "missing heritability" concept. Although a number of genes have been shown to affect serum uric acid concentration, SLC17A3 seems to have a major role in determination of serum uric acid repeated measurements variation. PMID- 20162745 TI - Association of nephrolithiasis and gene for glucose transporter type 9 (SLC2A9): study of 145 patients. AB - AIM: To investigate the association of nephrolithiasis and solute carrier family 2, facilitated glucose transporter, member 9 (SLC2A9), also known as glucose transporter type 9, Glut9. METHODS: A total of 145 participants were recruited in the period April-October 2008 from the Department of Mineral Research of the Medical School Osijek, Osijek, Croatia; 58 (40%) had confirmed nephrolithiasis and 87 (60%) were asymptomatic. Four single nucleotide polymorphisms (SNP) from the SLC2A9 gene were genotyped in both groups (rs733175, rs6449213, rs1014290, and rs737267). RESULTS: There was a weak but significant association of all 4 SNPs and nephrolithiasis (P=0.029 for rs733175; P=0.006 for rs6449213; P=0.020 for rs1014290, and P=0.011 for rs737267). Logistic regression in an age- and sex adjusted model suggested that genotype C/T for rs6449213 had odds ratio for nephrolithiasis of 2.89 (95% confidence interval 1.13-7.40). This SNP explained a total of 4.4% of nephrolithiasis variance. CONCLUSION: Development of nephrolithiasis may be associated with SLC2A9 gene. Further studies are needed to clarify the role of SLC2A9 gene as a link between uric acid and nephrolithiasis. PMID- 20162746 TI - Evaluation of 14 Y-chromosomal short tandem repeat haplotype with focus on DYS449, DYS456, and DYS458: Czech population sample. AB - AIM: To evaluate the novel triplex polymerase chain reaction (PCR) assay for the analysis of polymorphic Y-chromosomal short tandem repeat loci (Y-STR). METHODS: A total of 14 Y-STR loci was analyzed. Allele frequencies for 3 tetrameric Y-STR loci (DYS449, DYS456, and DYS458) and extended haplotype loci typed by Y-PLEXTM 12 system were investigated in a sample of 50 unrelated healthy Czech male donors. We computed the relevant intra-population statistic parameters for our data (gene diversity, average gene diversity over loci, and mean number of pairwise differences) and compared our sample set with other Central European populations using RST pairwise genetic distance. RESULTS: We focused on the comparison of genetic diversity between the Y-STR extended haplotype loci and that of the 3 additional loci, and on the benefit of using DYS449, DYS456, and DYS458 in forensic and population genetics applications. Total gene diversity in our sample set was 0.998367 when using all 14 loci. Our data analysis revealed very high genetic diversity at DYS449 locus (0.876735), which surpasses even the diversity at DYS385a/b (0.819592). Population comparison showed no difference between Czech, Bavarian, Austrian, and Saxon sample set. A minor difference was found between Czech and Polish sample set. CONCLUSION: Typing of 3 Y-chromosomal microsatellite polymorphisms may provide a useful complement to already established sets of Y-STRs. PMID- 20162747 TI - Is escitalopram really relevantly superior to citalopram in treatment of major depressive disorder? A meta-analysis of head-to-head randomized trials. AB - AIM: To evaluate clinical relevance of differences between escitalopram and citalopram (equimolar) for major depressive disorder. METHODS: Review and meta analysis of comparative randomized controlled trials (RCT). Comparisons were in relation to Montgomery-Asberg depression rating scale (MADRS) score reduction at weeks 1 (5 RCTs), 4 (5 RCTs), 6 (4 RCTs), 8 (5 RCTs), and 24 (1 RCT); proportion of responders at weeks 2, 4, 6 (2 RCTs for each time point), 8 (5 RCTs), and 24 (1 RCT); clinical global impression-severity (CGI-S) reduction at weeks 6 (1 RCT), 8 (5 RCTs), and 24 (1 RCT), and discontinuation due to adverse events or inefficacy during short-term (up to 8 weeks) and medium-term (24 weeks) treatment. RESULTS: MADRS reduction was greater with escitalopram, but 95% confidence intervals (CI) around the mean difference were entirely or largely below 2 scale points (minimally important difference) and CI around the effect size (ES) was below 0.32 ("small") at all time points. Risk of response was higher with escitalopram at week 8 (relative risk, 1.14; 95% CI, 1.04 to 1.26) but number needed to treat was 14 (95% CI, 7 to 111). All 95% CIs around the mean difference and ES of CGI-S reduction at week 8 were below 0.32 points and the limit of "small," respectively. Data for severe patients (MADRS> or =30) are scarce (only 1 RCT), indicating somewhat greater efficacy (response rate and MADRS reduction at week 8, but not CGI-S reduction) of escitalopram, but without compelling evidence of clinically relevant differences. Discontinuations due to adverse events or inefficacy up to 8 weeks of treatment were comparable. Data for the period up to 24 weeks are scarce and inconclusive. CONCLUSION: Presently, the claims about clinically relevant superiority of escitalopram over citalopram in short-to-medium term treatment of major depressive disorder are not supported by evidence. PMID- 20162748 TI - Systematic review of interventions to prevent the spread of sexually transmitted infections, including HIV, among young people in Europe. AB - AIM: To examine the effectiveness of interventions seeking to prevent the spread of sexually transmitted infections (STIs), including HIV, among young people in the European Union. METHODS: For this systematic review, we examined interventions that aimed at STI risk reduction and health promotion conducted in schools, clinics, and in the community for reported effectiveness (in changing sexual behavior and/or knowledge) between 1995 and 2005. We also reviewed study design and intervention methodology to discover how these factors affected the results, and we compiled a list of characteristics associated with successful and unsuccessful programs. Studies were eligible if they employed a randomized control design or intervention-only design that examined change over time and measured behavioral, biologic, or certain psychosocial outcomes. RESULTS: Of the 19 studies that satisfied our review criteria, 11 reported improvements in the sexual health knowledge and/or attitudes of young people. Ten of the 19 studies aimed to change sexual risk behavior and 3 studies reported a significant reduction in a specific aspect of sexual risk behavior. Two of the interventions that led to behavioral change were peer-led and the other was teacher-led. Only 1 of the 8 randomized controlled trials reported any statistically significant change in sexual behavior, and then only for young females. CONCLUSION: The young people studied were more accepting of peer-led than teacher-led interventions. Peer-led interventions were also more successful in improving sexual knowledge, though there was no clear difference in their effectiveness in changing behavior. The improvement in sexual health knowledge does not necessarily lead to behavioral change. While knowledge may help improve health-seeking behavior, additional interventions are needed to reduce STIs among young people. PMID- 20162749 TI - Health services management in Qatar. AB - AIM: To assess health care delivery system in the State of Qatar and audit it according to the Joint Commission International (JCI) standard. METHODS: The data for this retrospective descriptive study were taken from the Annual Health Report of the National Health Authority and Hamad Medical Corporation and various additional sources like World Health Organization reports, Annual Report of Saudi Arabia, and Compendium of Health Statistics, UK. Population per physician, per general practitioner, and per hospital bed, and nurses per physician ratio were calculated. RESULTS: In 2008, the population per physician in Qatar was 444; the population per general practitioner (GP) was 949; the population per hospital bed was 716; and nurses per physician ratio was 2.6. During the last decade, the population of Qatar has more than doubled, which has resulted in a similar increase in the number of health care providers; moreover, many initiatives launched in cooperation with internationally recognized institutions have greatly improved the quality of the health service. The weighted mean number of visits for 100 population was calculated for the UK and Qatar, taking into consideration the difference in age and sex structure. After comparison with the UK data, population/GP ratio for Qatar should be 1193. CONCLUSION: The Qatar health system has improved in the last decade, but there is still the need for more medical workers in primary health care. PMID- 20162750 TI - What can Mchinji and Ntcheu districts in Malawi tell maternal health pundits globally? PMID- 20162751 TI - The "authorized" oncologist. PMID- 20162752 TI - Invited commentary. PMID- 20162764 TI - Intensity of continuous renal-replacement therapy. PMID- 20162765 TI - Intensity of continuous renal-replacement therapy. PMID- 20162766 TI - Functional status of elderly adults receiving dialysis. PMID- 20162767 TI - Ankle-brachial index and peripheral arterial disease. PMID- 20162834 TI - Thyrotoxic periodic paralysis in the Chinese population: clinical features in 45 cases. AB - OBJECTIVE: Thyrotoxic periodic paralysis (TPP) occurs predominantly in Asian males, but there are few reports about TPP in the mainland of the People's Republic of China. The purpose of this study was to report the clinical features of cases of TPP in mainland China. METHODS: Forty-five cases of TPP, admitted to Zhongnan Hospital of Wuhan University during a 5-year period, were retrospectively reviewed. RESULTS: Patients typically presented with acute paralysis of the limbs, almost half (48.6%) initiated with legs, while the rest (51.4%) with both arms and legs. Twenty of 45 patients (44.4%) who had been diagnosed with hyperthyroidism suffered sudden attacks, while the remaining 25 patients were newly diagnosed with TPP. 16 patients had low potassium serum concentrations (1.44-3.00 mmol/L). There was a correlation between the lowest muscle strengths of the proximal and distal legs and serum potassium concentrations (Spearman correlation, r=0.556, P=0.049). CONCLUSIONS: TPP is not an uncommon disease in mainland China. Thyrotoxic patients need to improve medication compliance and follow-up. At the time of the TPP attack, a detailed interview and inquiry with a thorough physical examination usually provide clues to the diagnosis. Leg muscle strength evaluation may be useful to assess the severity of hypokalemia. PMID- 20162835 TI - Bile leak from the duct of Luschka. AB - A 64-year-old diabetic man underwent an open cholecystectomy for acute necrotizing cholecystitis. Post-operatively he developed a biloma which was drained percutaneously. A bile leak was suspected and he underwent an ERCP. Initial cholangiography was normal, but upon continued injection of contrast agent, a bile leak originating from a branch of the right hepatic duct or duct of Luschka became evident. A sphincterotomy was performed and a plastic stent was placed into the common bile duct. The leak resolved and the plastic stent was removed 6 weeks later. PMID- 20162836 TI - Project set to map marks on genome. PMID- 20162837 TI - The future of psychiatry in low- and middle-income countries. AB - The great shortage, and inequitable distribution, of psychiatrists in low- and middle-income countries is one of the key reasons for the large treatment gap for people with mental disorders. Psychiatrists need to play a public mental health leadership role in increasing the coverage of mental health care through task shifting of effective interventions to non-specialist health workers. Psychiatrists' new roles should include designing and managing such programmes, building clinical capacity, supervision and quality assurance, providing referral pathways and research. PMID- 20162839 TI - Effect of host gender on blood digestion in fleas: mediating role of environment. AB - We investigated mechanisms of male-biased parasitism by studying the rate of digestion and survival time after a single blood meal in fleas Xenopsylla ramesis parasitizing males and females of the rodent Meriones crassus. Assuming that male hosts represent better patches for fleas than female hosts, we predicted that fleas (1) will digest blood of a male host faster than blood of a female host and (2) will survive longer after a single blood meal taken from a male host. To understand the possible role of environmental factors in mediation of the relationship between flea performance and host gender, we tested our predictions in male and female fleas under low (75%) and high (95%) relative humidity (RH). Host gender affected duration of digestion only at the middle and late stages of digestion and only interacting with either flea gender or RH or both. At the early stage of digestion, fleas of the same gender at the same RH digested blood at similar rates, independent of host gender. The rate of digestion did not differ between male and female fleas at 75% RH, but the duration of early stage was significantly shorter in female than in male fleas at 95% RH. At the middle stage of digestion, male fleas at both RH digested blood of male and female hosts at similar rates, but at lower RH, female fleas digested blood from male hosts at a significantly faster rate than blood from female hosts. At the late stage of digestion, both male and female fleas digested blood faster from male hosts than from female hosts at 75% RH, but the opposite was true at 95% RH. Survival time of fleas after completion of digestion was affected by RH, being longer at 95%, and flea gender, being longer in females. Fleas fed on female hosts died faster than fleas fed on male hosts, but this was found only at 95% humidity. We concluded that the relationship between flea performance and host gender was mediated by external conditions. PMID- 20162840 TI - Abnormalities on cephalic hooklets of advanced third-stage larvae from Gnathostoma Owen, 1836 (Nematoda: Gnathostomidae) collected from Mexican rivulus Millerichthys robustus Costa, 1995 (Ciprinodontiformes: Rivulidae) in Tlacotalpan, Veracruz, Mexico. AB - Morphological abnormalities were observed on the cephalic bulb hooklets of advanced third-stage larvae (AdvL(3)) of genus Gnathostoma. The larvae were obtained from the fish "Mexican rivulus" Millerichthys robustus collected from a seasonal pond near Tlacotalpan, Veracruz, Mexico. The abnormalities involved (1) extra rudimentary hooklets, located between the four rows and after the fourth row, (2) branched or lobulated hooklets, and (3) fragmented hooklets not uniformly disposed in rows. The alterations observed on the cephalic bulb hooklets do not represent intraspecific variations, and they may be considered as a potential tool for assessing the presence of pollutants or stressors located within the ecosystem. PMID- 20162841 TI - Does rain reduce the efficacy of Butox 7.5 pour on (deltamethrin) against biting midges (Culicoides specimens)? AB - Previous studies have shown that cattle and sheep that are treated topically with Butox 7.5 (deltamethrin) on the neck or along the back are protected from biting Culicoides spp. for up to 4 weeks. During these studies, the animals were provided with adequate shelter against the rain. The efficacy of deltamethrin on wet animals was, therefore, not tested. The present experiment was done to determine if thoroughly wetting the test subjects twice a week would affect the efficacy of deltamethrin. Cattle and sheep were treated with Butox 7.5 along the neck or dorsal midline. Test animals were wet thoroughly with tap water twice weekly. Control animals remained dry. Hair was clipped off the legs, near the claws, at day 7, 14, 21, and 28 after treatment of test and control animals. Recently caught C. obsoletus midges were then exposed to the hair for 15, 30, 60, and 120 s. Time taken for the midges to die after exposure was recorded. The product remained effective for at least up to 28 days, although, differences in the time taken to kill the midges were noted. Differences in time taken for the midges to die were also seen between those exposed to treated cattle hair and those exposed to treated sheep hair. PMID- 20162842 TI - Morphological adaptation of the tarso-metatarsal joints onto load transmission in the foot. AB - PURPOSE: Undefined middle foot pain among older individuals is an increasingly problem. Thereby the tarso-metatarsal joints (Lisfranc's joint, TMT joints) are particularly important for foot structure. The aim of this study was to obtain into force transmission in TMT joints by analysing degenerative morphological changes (DMC) of the articular cartilage and subchondral density patterns. MATERIALS AND METHODS: We used seven formalin-fixed foot preparations (average age 80.8) from the undergraduate dissection course. Applying the Collins schema, localisation of cartilaginous surface DMC was examined. For showing subchondral density patterns, the well-established method of CT-osteoabsorptiometry (CT-OAM) was used. RESULTS: The cartilaginous surface DMCs were frequently located at the medial edges. Maximum density areas were found at the medial and dorsal edges. There was a clear correlation of topical cartilage degeneration and subchondral density. CONCLUSION: In healthy feet, force transmission in the TMT joints appears to occur via the dorsal and medial edges. Considering the correlation of topical cartilaginous surface DMC and subchondral density patterns, clinical application of CT-OAM seems to be recommendable in the case of undefined middle foot pain. PMID- 20162844 TI - Health and nutritional promotion program for patients with dementia (Nutrialz Study): design and baseline data. PMID- 20162845 TI - AAA proteins: movers and shakers. PMID- 20162846 TI - [The Physiocratic Society in Bohemia and the activity of its Entomology Section]. PMID- 20162847 TI - [The first course in forestry and the anniversary celebration at the Department of Forestry at the University of Agriculture in Brno, founded 1929]. PMID- 20162849 TI - [Negotiations of remembrance: collective memory and literature fifty years after the annihilation of European Jewry]. PMID- 20162850 TI - Female demographic disadvantage in India 1981-1991: sex selective abortions and female infanticide. PMID- 20162851 TI - [Good news and bad news regarding obesity]. PMID- 20162852 TI - Highlights from the 60th Annual Meeting of the AASLD. PMID- 20162853 TI - New WHO guidelines on antiretrovirals welcomed worldwide. PMID- 20162854 TI - The risk of malignancy index (RMI) in diagnosis of ovarian malignancy. AB - OBJECTIVE: To evaluate the ability of two risk of malignancy indices (RMI) based on serum levels of CA 125, ultrasonographic score, and menopausal status to discriminate between benign and borderline or malignant ovarian tumor. MATERIALS AND METHODS: A retrospective study was conducted in 209 women with pelvic masses admitted for laparotomy at Srinagarind Hospital, between January 2002 and December 2007. The sensitivity, specificity and positive predictive (PPV) and negative predictive (NPV) values of two RMI were calculated. RESULTS: Using a cut off level of 200 to indicate malignancy, the RMI 1 gave sensitivity of 70.6%, specificity of 83.9%, PPV of 75%, and NPV of 80.6%. The RMI 2 gave sensitivity of 80%, specificity of 78.2%, PPV of 71.6%, and NPV of 85.1%. The RMI 2 was significantly better in predicting malignancy than RMI 1. CONCLUSION: The RMI is able to discriminate between benign and borderline or malignant ovarian tumor. PMID- 20162855 TI - Pesticides, fresh water fish, liver flukes and nitrosamines: A story of cholangiocarcinoma development in Thailand. AB - Cholangiocarcinoma is a common hepatobiliary carcinoma in Thailand. It is believed that both chronic exposure to liver fluke infestation and nitrosamine exposure are the two main underlying factors leading to the carcinogenesis. Here, the author further extrapolates and proposes a new hypothesis based on the environmental ecological data that the stimulation of fresh water fish by contaminated pesticide in water reservoirs might be a possible background of the high prevalence of cholangiocarcinoma in Thailand. PMID- 20162856 TI - [Management of highly calcified annular ring during mitral valve surgery]. PMID- 20162857 TI - [Mechanism of chromosome protection by telomere and telomerase]. PMID- 20162858 TI - [Patch repair of complications of acute myocardial infarction (perforation of the ventricular septum and rupture of left ventricular free wall)]. PMID- 20162859 TI - [Imaging diagnosis Q & A: Corrected transposition of great vessels and stenosis of the left ventricular flow tract]. PMID- 20162860 TI - NG2 positive cells of rat spinal cord activated during experimental autoimmune encephalomyelitis are spatially associated with radially oriented astroglia and express p75 receptor: a role for nerve growth factor in oligodendrocyte progenitor migration? AB - Data have been provided from several studies that support the proposal that the adult oligodendrocyte progenitors migrate into the lesioned areas under conditions of experimental autoimmune encephalomyelitis (EAE). However, the routes of migration of these cells and the governing mechanisms are not clear. In the present studies, we have examined the effect of EAE upon activation of endogenous oligodendroglia progenitors and their spatial distribution in the spinal cord of Lewis rats using immunocytochemical procedures. Antibodies against the marker chondroitin sulfate proteoglycan NG2, are used for identification of oligodendroglia progenitors. We find that the activated elongated subpopulation of NG2 positive oligodendroglia progenitors of white matter is spatially associated with the radially-oriented astroglia during the acute phase of EAE. The latter re-expressed the phenotypic embryonic marker nestin while still expressing the mature astroglial marker GFAP. The elongated oligodendroglia progenitors express p75 receptor. In addition, colocalization of NG2 and p75 is observed also in ependymal neural cells of the central canal and the subventricular zone. This raises the possibility that the activated NG2+/p75+ parenchymal cell pool may also be recruited from multipotent neural cells of the germination areas. Our data suggest that, under EAE conditions, the radially oriented astroglia of juvenile phenotype may serve as scaffolding for migrating activated endogenous oligodendroglia progenitors just like radial glia provide a path for neuronal and oligodendroglia progenitor cells in embryonic stage. The expression of p75 receptor in oligodendroglia progenitors associated with radially oriented astroglia during EAE may implicate a role for NGF in the regulation of migration of oligodendroglia progenitors. PMID- 20162861 TI - A biphasic daily pattern of slow wave activity during a two-day 90-minute sleep wake schedule. AB - Twenty-four hour sleep patterns were measured in six healthy male volunteers during a 90-minute short sleep-wake (SW 30:60) cycle protocol for 48 hours. Sleep pressure estimates (amount of Slow Wave Sleep [SWS], SWA, and Rate of Synchronization [RoS: the rate of SWA build-up at the beginning of the NREM period]) were compared with the 24-hour patterns of body temperature (Tb24) and sleep propensity. A moderate sleep debt was incurred over the 48 hour study as indicated by decreased levels of 24 hour sleep. On day 1, ultradian patterns of REM and SWS sleep were prominent; on day 2, more prominent were circadian patterns of REM sleep, SWS, Sleep Latency, TST and Tb24. Also on Day 2, biphasic patterns of SWA and RoS were expressed, with peaks occurring during the falling and rising limbs of Tb24. The biphasic peaks in SWA and RoS may be associated with phase-specific interactions of the circadian pacemaker with the sleep homeostat during conditions of moderate sleep pressure. Further research is needed to replicate the finding and to identify biological factors that may underlie the twelve hour pattern in SWA. PMID- 20162862 TI - RACK1, a potential target to decrease morphine reward in mice. AB - Morphine reexposure induces the decrease of receptor for activated C-kinase 1 protein (RACK1) levels in frontal cortex, and the increase of p-ERK (extracellular signal-regulated kinase) levels in mouse frontal cortex, striatum, hippocampus and nucleus accumbens (NAcc). Moreover, RACK1 is associated with the core kinases of the ERK pathway, Raf, MEK, and ERK. The purpose of this study is to investigate the effect of overexpression of RACK1 on the conditioned place preference (CPP) and the level of p-ERK in morphine reexposure mice. Mice were subcutaneously injected with morphine on the 2nd, 4th, 6th, and the 8th day, saline was delivered the next day. After mice showed place preference, RACK1 was administered by intraventricular injection 20 minutes after injection of morphine on the 11th, 13th, 15th, and 17th day. CPP was measured on the 18th day. It was found that morphine reexposured mice showed a decreased RACK1 level in the frontal cortex, striatum and an increased RACK1 level in hippocampus and NAcc, but this effect was reversed after administration of RACK1. In this study we demonstrated that RACK1 decreased p-ERK and erased CPP during reexposure of morphine and there was no an effect in reexposure saline mice. It strongly suggests that RACK1 may play a crucial role in morphine reexposured mice and the RACK1 has the potential to be a remedy to the morphine reward. PMID- 20162863 TI - Methylated tin toxicity a reappraisal using rodents models. AB - Trimethyltin-induced intoxication has a great impact on human health due to the widespread occurrence of methyltin compounds. Acute TMT intoxication in humans leads to a variety of neurological symptoms which involve primarily the limbic system. In the present review we summarized the neuromorphological correlates of this neurological syndrome extending the analysis to various extra-limbic regions and detailing the fine ultrastructure of TMT-induced neuronal alterations. In order to comprehend the pathophysiology of TMT-induced neuronal damage we analysed the various experimental models of TMT-induced neurotoxicity. When comparing various animal species, it seems that the variety of neuropathological correlates are not related to species difference in the sensitivity to TMT toxicity but to a different susceptibility to secondary effects produced by TMT. In fact, apart from a primary neurotoxic damage induced by TMT at neuronal level, this compound promotes the onset of limbic and generalized seizures, which in turn add a secondary damage to that induced immediately by TMT. Thus, the different neuropathology observed in different animal species is produced mainly by a different sensitivity to epilepsy-induced brain damage. PMID- 20162864 TI - BRCA1/2 predictive testing and gender: uptake, motivation and psychological characteristics. AB - BRCA1/2 predictive testing and gender: Uptake, motivation and psychological characteristics: Data on male uptake of BRCA1/2 predictive testing and psychological characteristics of males in comparison to females are scarce. We investigated gender differences in the cohort tested at the Center for Human Genetics in Leuven during a 10-year period (1998-2007). Males were significantly older than females. Breast cancer related distress (IES) was significantly lower in men and was not associated with BRCA1 or BRCA2. The groups of both males and females were psychologically stronger than average (SCL-90, UCL) and self selected. Men were unanimously motivated (personal relevance of 12 motives rated on a Likert scale) by concern for their daughters, and significantly more so than women. One third of them (versus 12% women) referred to child-bearing decisions. Considering all unaffected siblings in the family of origin, uptake of predictive testing was significantly higher in females. Moreover, uptake was significantly higher in women belonging to a BRCA2 than to a BRCA1 family. In the descendants of identified carriers, uptake was predicted by gender and age, but not by the parent's gender or by BRCA1 or BRCA2 status. PMID- 20162865 TI - The velo-cardio-facial syndrome: the spectrum of psychiatric problems and cognitive deterioration at adult age. AB - The velo-cardio-facial syndrome: the spectrum of psychiatric problems and cognitive deterioration at adult age: Deletion 22q11.2 syndrome, or the velo cardio-facial syndrome (VCFS), is a syndrome with a known but varied clinical and behavioral phenotype. We report 7 patients with 22q11.2 deletion syndrome and an intellectual disability. Aside from the described behavioral phenotype in literature, a moderate, severe or profound intellectual disability may be present. Special attention should be given to cognitive deterioration. PMID- 20162866 TI - Genetic testing offered directly after the diagnosis of colorectal cancer: a pilot study on the reactions of patients. AB - Genetic testing offered directly after the diagnosis of colorectal cancer: a pilot study on the reactions of patients: INTRODUCTION: When colorectal cancer is diagnosed before the age of 50 years, then consideration should be given to a hereditary cause. Indications of heredity can be found in tumour tissue with the aid of microsatellite instability (MSI) testing. A positive MSI test means an increased risk of hereditary colorectal cancer, the so-called Lynch syndrome. Until recently, the usual approach was to postpone genetic testing for colorectal cancer until the family history had been studied extensively and information had been made available by a clinical geneticist about the possible consequences. However, it is now possible for MSI testing to be performed on the initiative of the pathologist when the newly diagnosed patient with colorectal cancer is younger than 50 years. This speeds up the procedure considerably. The psychological effects of discussing genetic testing and referring patients during treatment for colorectal cancer are currently unknown. This paper describes an exploratory study on the experience of eight colorectal cancer patients with the new Lynch syndrome detection strategy. METHODS: The patients were interviewed at home using a semistructured questionnaire based on the multicausal model of problem analysis and adapted with items for colorectal cancer and genetic testing. RESULTS: Three coordinating themes were found: (1) 'a changed life after the diagnosis of colorectal cancer', (2) 'warning for the future' and (3) 'communication with family'. It was a considerable challenge for these patients to cope with the physical and psychosocial consequences of colorectal cancer. The majority regarded possible carriership of a hereditary disposition for the Lynch syndrome as useful medico-preventive knowledge for their children. The timing of the confrontation with genetic testing was considered to save time in receiving follow-up advice for their children. However, these patients were apprehensive about having to discuss a hereditary disposition for cancer with their family. CONCLUSION: In this early phase, coping with the diagnosis of colorectal cancer and the consequences of treatment mainly determined the reactions of these patients and their physical well-being. This small group of patients was of the opinion that the advantages of genetic testing will weigh-up against the disadvantages. PMID- 20162867 TI - Prenatal diagnosis of a de novo supernumerary marker chromosome originating from chromosome 16. AB - Prenatal diagnosis of a de novo supernumerary marker chromosome originating from chromosome 16: A 37 year old pregnant woman was referred for amniocentesis at 18 weeks of gestation due to advanced maternal age and abnormal serum biochemistry. A nonsatellited, monocentric marker chromosome was observed with a frequency of 57% in cultured amniocytes. Parental karyotypes were normal. The marker chromosome was found to be derived from chromosome 16 by FISH using CEP16 and WCP16 probes. Marker chromosomes were not painted with M-FISH probe mixture, indicating an exclusively heterochromatin nature. CGH analysis using genomic DNA isolated from uncultured amniocytes also supported the M-FISH results. Genetic counseling was given to parents and the family decided to continue the pregnancy to term. The baby was born at 36 weeks of gestation without any dysmorphic features. Follow-up at 7 months of age revealed no developmental abnormalities. PMID- 20162868 TI - Fluorescence in situ hybridization and single nucleotide polymorphism of a new case with inv dup del(8p). AB - Fluorescence In Situ Hybridization and single nucleotide polymorphism of a new case with inv dup del(8p): Inverted duplication deletion of 8p [inv dup del(8p)] is a complex chromosome rearrangement leading among others to deletion of the chromosome region distal to the duplication in 8p. A new case with an inverted duplication deletion of 8p and the results of SNP-array analysis and fluorescence in situ hybridization (FISH) are reported here. Our results are in concordance with earlier reported inv dup del(8p) cases. PMID- 20162869 TI - Two cases of 9p deletion syndrome and a case of partial trisomy 8 and partial monosomy 9p. AB - Two cases of 9p deletion syndrome anda case of partial trisomy 8 and partial monosomy 9p: We report 3 girls with mental retardation (MR), distinctive malformations of the skull and facial region, including trigonocephaly, small palpebral fissures, and unusually midface hypoplasia, congenital heart defects which are characteristics of monosomy 9p. We performed GTG banding and fluorescence in situ hybridization (FISH) method in all cases. By using cytogenetic methods, three terminal deletions of the short arm of the chromosome 9 were identified and in 2 patients the deletion was de novo, and one patient inherited deletion. FISH analysis showed 46,XX,del(9)(pter-p22).ish del(9)(pter- >p22) in two patients and 46,XX,-9,+der(9)t(8;9)(q24.3;p22)pat.ish der(9)t(8;9)(q24.3;p22)pat (305J7-T7x1,wcp8+,wcp9+) in the third patient. This report compares the symptoms and features of our patients with previously reported patients with a 9p deletion syndrome. PMID- 20162870 TI - Werdnig-Hoffmann disease: report of the first case clinically identified and genetically confirmed in central Africa (Kinshasa-Congo). AB - Werdnig-Hoffmann Disease: Report of the first case clinically identified and genetically confirmed in Central Africa (Kinshasa-Congo): Type 1 spinal muscular atrophy (SMA1) or Werdnig-Hoffman disease is rarely described in black populations. We report on one black patient diagnosed in Kinshasa. This patient was referred to Paediatric consultation at the age of 5 months 1/2 with extreme hypotonia progressing since birth, severe muscular weakness in his trunk and proximal parts of the extremities, ASD type II, and repeated episodes of pulmonary infections. He died of severe respiratory failure at the age of 10 months. EMG analysis revealed motor neuron a defect without nerve conduction anomaly, suggesting the diagnosis of spinal muscular atrophy disease. The diagnosis of SMA1 was definitely confirmed by a quantitative PCR-based testing that demonstrated homozygous deletion of SMN1, the primary disease-causing gene for spinal muscular atrophy, while two normal SMN2 alleles were present. There was a history of similar clinical symptomatology in a patient's older brother, suggesting a familial involvement. To the best of our knowledge, this is the first documented Werdnig-Hoffman case ever reported from Central Africa people. PMID- 20162871 TI - A provisionally unique syndrome with features including "molar tooth" sign and "femoral hypoplasia". AB - A provisionally unique syndrome with features including "molar tooth" sign and "femoral hypoplasia": The femoral-facial syndrome (FH-UFS) is a rare syndrome of uncertain inheritance comprising hypoplastic femora, microretrognathia, and peculiar facies. We describe a new case with facial dysmorphism, broad chest and widely spaced nipples, shorter right lower limb with femoral hypoplasia and unilateral fibular hemimelia, bilateral absence of 5th metatarsal and toe, and bilateral talipes equinovarus. In addition, a complete agenesis of corpus callosum, cerebellar vermis hypoplasia with molar tooth sign and Dandy-Walker malformation were present. Posterior fossa abnormalities in FH-UFS have not been described in the literature until now, thus extending the clinical spectrum of this entity. Other syndromes characterized by femoral hypoplasia and/or molar tooth sign are also discussed. PMID- 20162872 TI - The Wiedemann-Rautenstrauch or neonatal progeroid syndrome: report of a patient with hypospadias. AB - The Wiedemann-Rautenstrauch or neonatal progeroid syndrome: report of a patient with hypospadias: Wiedemann-Rautenstrauch syndrome is known as a neonatal progeroid syndrome, with only few published case reports. The syndrome is characterized by progeroid appearance (triangular old-looking face with relatively large skull, prominent veins especially of the scalp, sparse scalp hair, and large anterior fontanelle), decreased subcutaneous fat (giving the clinical appearance of prominent veins and muscles), hypotrichosis, macrocephaly, and natal teeth. We report a new additional patient with a new feature of the hypospadias, not previously described, to our knowledge. PMID- 20162873 TI - A prenatally sonographically diagnosed conotruncal anomaly with mosaic type trisomy 21 and 22q11.2 microdeletion/DiGeorge syndrome. AB - A prenatally sonographically diagnosed conotruncal anomaly with mosaic type trisomy 21 and 22q11.2 microdeletion/DiGeorge syndrome: We report a prenatally sonographically diagnosed conotruncal and urogenital anomaly. Postnatally, the patient presented with seizures, hypocalcemia, hypoparathyroidism and thymic aplasia and diagnosed as DiGeorge syndrome. Echocardiography showed malalignment VSD, supravalvular pulmonary stenosis and overriding aorta. Chromosome and FISH studies showed the association of mosaic type trisomy 21 and 22q11.2 microdeletion. The present patient is the second case of mosaic type of Down syndrome associated with 22q11.2 microdeletion. In addition the patient also had clinical and laboratory features of DiGeorge syndrome. PMID- 20162874 TI - Report of a girl with vacterl syndrome and right pulmonary agenesis. AB - Report of a girl with VACTERL syndrome and right pulmonary agenesis: VACTERL syndrome is a combination of vertebral anomalies (V), anal atresia (A), congenital heart defects (C), tracheo-esophageal fistula (T), esophageal atresia (E), abnormalities of kidneys (renal anomalies, R) and limbs (L). In the present patient right pulmonary agenesis is co-occurring with VACTERL syndrome. We report on this case because the association of right pulmonary agenesis and VACTERL syndrome is rare. PMID- 20162875 TI - Unreported "de novo" rearrangement of chromosomes 4 and 7. AB - Unreported "de novo" rearrangement of chromosomes 4 and 7: Unbalanced rearrangements of the chromosomes are extremely rare and associated with an abnormal phenotype and usually result in an abortion in early pregnancy. The current literature includes reports on the conditions related with rearrangements of chromosome 4 and 7. Herein, we describe a rearrangement between these two chromosomes, which is the first presentation ofa specific translocation t(4;7)(q31;p15) and its consequent phenotype following de novo rearrangement of the chromosomes. It brought into light phenotypic similarities with other aberrations following breakage from adjacent band loci. We hope these features will help further genetic investigations on these chromosome regions. PMID- 20162876 TI - Hyperextension of the fetal head with sinus bradycardia in 22q11 deletion. PMID- 20162877 TI - Mitral valve prolapse in two siblings with pyknodysostosis. PMID- 20162878 TI - Albany: the way to practise midwifery. PMID- 20162879 TI - 'Choices are not choices if you are not allowed to make them for yourself'. PMID- 20162880 TI - Albany midwifery practice loses King's contract. PMID- 20162881 TI - In fear of difference, in fear of excellence. PMID- 20162882 TI - With woman, at the heart of the community. PMID- 20162883 TI - My Albany. PMID- 20162884 TI - Women with disabilities: the midwife's role and responsibilities. PMID- 20162885 TI - Midwives and mental health: the need for postnatal clarity. Part 1: Predisposing factors. PMID- 20162886 TI - Maternal mental health: a Cinderella service? PMID- 20162887 TI - Baby Bumps--addressing social inequalities. PMID- 20162888 TI - Building on the success of Change 4 Life. PMID- 20162889 TI - Inspiration from the past (5). Martha Mears, nature worshipper. PMID- 20162890 TI - Profile. Ishbel Kargar. PMID- 20162891 TI - Midwifery basics: understanding research (3). Sampling. PMID- 20162892 TI - Remember what it's all about! PMID- 20162893 TI - Students! Our future. PMID- 20162894 TI - Gerontology education initiatives in the health sciences: seeking advice from students in focus group conversations. PMID- 20162895 TI - The fragile balance: single elderly women and the Canadian economy. PMID- 20162896 TI - Geriatric emergency management in Ontario: a model for senior's care. PMID- 20162900 TI - A force for good. Interview by Catharine Sadler. AB - Nurse Richard Harwin uses his experience as a mental health intervention police officer. PMID- 20162901 TI - Great act to follow. Interviews by Richard Staines and Adele Waters. AB - The two finalists in the Nurse of the Year category recognising excellence in ward management talk about their work and its challenges. PMID- 20162903 TI - The real skills. PMID- 20162902 TI - In Florence's footsteps. AB - The charity Teams4U recently arranged for a small team of nurses and doctors to carry out an education and training programme in Crimea. PMID- 20162904 TI - Nursing by degrees. PMID- 20162905 TI - Professional development for registered nurses. AB - There is increasing recognition that health professionals should engage in continuing professional development and lifelong learning. In addition, planned changes to pre-registration nurse education mean that many registered nurses are considering, or will consider, further academic study. This article aims to demystify academic terminology and provide practical guidance on preparing for and accessing higher education. PMID- 20162906 TI - The nurse-patient relationship in the post-anaesthetic care unit. AB - AIM: To explore how post-anaesthetic care (PAC) nurses perceive their role, acknowledging the activities that they undertake routinely in their practice. METHOD: A generic qualitative research approach was used; eight PAC nurses were interviewed, with each interview lasting between 30 minutes and one hour. FINDINGS: A salient finding related to the psychosocial dimension of nursing, with much of the data referring to the nurse-patient relationship pre and post operatively. Three themes were identified: communication, being an advocate and being remembered. CONCLUSION: The findings suggest that PAC nurses have the opportunity to develop relationships with patients both pre-operatively when the patients arrive in the operating department and post-operatively. The findings may help to challenge existing beliefs that when patients are in the care of PAC nurses, they are unconscious and therefore unable to engage in dialogue with the nurse. While the findings reflect the views of PAC nurses only, operating department practitioners might hold similar views. This study highlighted that there may be potential for development of the role of the PAC nurse, and as there is little documented about this role, further research is warranted. PMID- 20162907 TI - Nursing management of patients with severe ulcerative colitis. AB - Ulcerative colitis is a relapsing chronic disease that has an unpredictable course. A relapse in the condition requires timely intervention and expert monitoring. A severe flare-up will often necessitate admission to hospital. This article provides an overview of the medical management of severe ulcerative colitis and the nursing interventions required. PMID- 20162908 TI - Community nursing. PMID- 20162909 TI - Life saving students. PMID- 20162910 TI - Witness an expert at work. PMID- 20162911 TI - Pressure point. PMID- 20162913 TI - Training is a 'lottery' for HCAs. PMID- 20162914 TI - Where do patients get a choice? PMID- 20162915 TI - Relighting the lamp. AB - Florence Nightingale transformed the public's perception of nursing and laid the foundation for nursing schools and community nursing. PMID- 20162916 TI - Sister's champion. Interview by Adele Waters. AB - Pioneering research undertaken by Susan Pembrey in the 1970s has been affirmed by a recent report into the ward sister's role. PMID- 20162917 TI - The 'sick day rules'. AB - 'Sick day rules' is an indicator of when people should change their hydrocortisone dose. PMID- 20162918 TI - Walk the patch. PMID- 20162919 TI - "We were not expecting you". PMID- 20162920 TI - Breast cancer risk in women: the protective role of pregnancy. AB - Many countries have experienced a pronounced shift towards later childbearing in recent years. Having children later in life has become a characteristic of contemporary fertility in affluent societies. Childbearing, particularly at a younger age, has been shown consistently to reduce the risk of breast cancer in the long term. Breast cancer constitutes the most common cancer in women and is an important public health concern worldwide. Early age at full-term pregnancy lowers the risk of breast cancer in women, whereas in older women first full-term pregnancy appears to increase the risk. Lactation seems to be relatively important in reducing the risk and abortion is associated neither with increased nor reduced risk. Several hypotheses have been proposed to account for the protective effects of parity. These include an altered systemic hormonal environment and an altered mammary cell fate. PMID- 20162921 TI - Supporting people with learning disabilities in acute care. AB - It is recognised that people with learning disabilities fail to access health screening and that in the past, hospital services failed to meet the needs of this group of patients. This article explains how, through a partnership between the health facilitation and acute liaison team at Coventry and Warwickshire NHS Partnership Trust and staff at University Hospitals Coventry and Warwickshire NHS Trust, these issues have been addressed. The article discusses the protocols, systems and training that have been introduced to raise awareness of the needs of people with learning disabilities, and focuses on the working partnership between the community and hospital settings. PMID- 20162922 TI - Assessment and treatment of patients with haemorrhoids. AB - This article examines the care of patients with haemorrhoids, and explores the aetiology, epidemiology and assessment of the condition. Information is provided on the different forms of treatment, and the importance of lifestyle interventions is reinforced. The post-operative nursing care of patients undergoing surgical procedures, including haemorrhoidectomy, is discussed, emphasising pain relief, hygiene and prevention of constipation. PMID- 20162923 TI - Basic life support. PMID- 20162924 TI - Turn failure into success. PMID- 20162925 TI - Where the eyes have it. PMID- 20162926 TI - Glad to be in the thick of it. Interview by Lynne Wallis. PMID- 20162927 TI - Water quality in water lines of dental units in the public dental health service in Goteborg, Sweden. AB - Presence of bacteria in high levels in the water lines of dental units is well known. The extent of this problem is however less well studied.This study was conducted to evaluate the water quality of all dental units within the Public Dental Health Service (Folktandvarden, FTV) of the city of Goteborg, Sweden. 405 dental units in 35 clinics were tested.The evaluation included both "fast growing" (2 days incubation) and "slow growing" (7 days incubation) bacteria in 50 ml water sample from the units. The presence of potential pathogens, e.g., coliforms, Pseudomonas spp and Legionella pneumophila were also examined. Of the 405 dental units, 303 (75%) did not have acceptable (<100 CFU/ml fast growing and <5000 CFU/ml of slow growing bacteria) water quality. From 61 (15%) dental units in 13 clinics L. pneumophila were present but usually as few cells only. Immediate measures were introduced in Legionella positive units. No coliforms or Pseudomonas spp were detected. It can be concluded that the water in the dental units is generally not acceptable and does not fulfill drinking water standard. Many units have extremely high bacterial levels, which must be regarded as a risk for certain patient groups, e.g., immune-compromised and older patients. A general program for desinfection of all units of the Public Dental Health Service is needed. PMID- 20162928 TI - Management of root resorption in a large orthodontic clinic. AB - The aim of this study was to investigate, describe and analyse how the problem of root resorption is handled in a large orthodontic clinic and if these approaches were in accordance with the recommendations and guidelines described in the literature, and to estimate the prevalence of root resorption found in the radiographic material. All records of patients who terminated active treatment with fixed or removable appliances during the year 2004 at the Department of Orthodontics, University Clinics of Odontology, Goteborg, Sweden were examined (902 patients). In 837 records adequate information was obtained. The factors studied included: the presence of journal recordings of predisposing factors, the presence of radiographic examinations before, during and after treatment, the frequency of radiographic examinations and the prevalence of moderate or severe root resorption reported. The most frequent registrations were for trauma, and nail biting. Before treatment 81.5% of the patients were examined with periapical radiographs. After 6 months of treatment the percentage was 54.5%, while 15.8% of the patients were examined twelve months after treatment. At the end of treatment 52.5% of the patients were examined. When moderate root resorption was diagnosed during treatment the use of lower forces, resting periods and decrease of the treatment duration were the most common preventive measures. The prevalence of light root resorption was 1.9%, 3.2%, 4.9% and 8.6% at the beginning, after 6 and 12 months and at the end of treatment, respectively. Severe root resorption was found in 1.9% at the end of treatment. In conclusion before treatment periapical radiographs were taken in most cases. The percentage of the radiographs dropped significantly at 6 and 12 months. At the end of treatment half of the patients were examined with periapical radiographs.When moderate root resorption was diagnosed the use of lower forces, resting periods and decrease of treatment time were common preventive measures. Light root resorption was found in less than 10% while severe root resorption was noted in 2% after active treatment. PMID- 20162929 TI - Inter- and intra-individual variations in saliva secretion rates--a comparison of unsupervised and supervised sample collection. AB - The aim of this study was to investigate if unsupervised measurement of saliva secretion could be used instead of supervised measurement at the dental clinic. One hundred patients attending a dental clinic for regular dental care were asked to participate (group A). A control group of 40 subjects was recruited (group B). Saliva samples were collected and stimulated saliva secretion rates were determined. After instruction, subjects in both groups collected the first sample at day 1 at the dental clinic. Subjects in group A continued to collect 2 more samples at day 1 and 3 samples at each of day 3 and day 5 outside the clinic. Subjects in group B did 3 saliva samplings at day 1, day 3, and day 5 under supervision at the dental clinic. In total 9 samples from each subject were collected. Median secretion rates in group A were, in day 1, 2.1 ml/min (range: 0.1-5.1); day 3, 1.9 ml/min (range: 0.1-5.3); and day 5, 1.9 ml/min (range: 0.1 5.5). Corresponding rates in group B were, in day 1, 2.1 ml/min (range: 0.6-4.4); day 3, 2.0 ml/min (range: 0.7-4.6); and day 5, 2.0 ml/min (range: 0.9-4.1). No significant difference in secretion rates appeared between groups A and B at day 1, 3, and 5 or during the 5 days of observations. Analysis of intra-individual differences in secretion rates showed that in group Athere was a significant difference between measurements, while in group B measurements did not differ significantly. The intra-individual variation expressed as mean coefficient of variation during the 5-day period was 20.4% in group A and 17.3% in group B. In conclusion, measurement of saliva secretion capacity under unsupervised conditions may be a feasible method to judge saliva secretion capacity in clinical practice. PMID- 20162930 TI - One year clinical performance and post-operative sensitivity of a bioactive dental luting cement--a prospective clinical study. AB - A one-year clinical study was performed on the efficacy of a bioactive dental cement (Ceramir C&B) with calcium aluminate and glass ionomer components. The study was performed on 38 crown and bridge abutments in 17 patients. Preparation parameters were recorded, as well as working-times, setting-times, and other handling characteristics. Baseline data were also recorded for gingival inflammation (GI) and pre-cementation sensitivity. Post-cementation parameters included sensitivity, gingival tissue reactions, marginal integrity and discolorations. All patients were seen for recall examinations at 30 days, and 6 months. For sixteen patients one-year recall data were collected on retention and subjective sensitivity. Fifteen subjects were available for one year clinical examinations. Three independent examiners found the working and setting time of the cement to be well within expected limits and that cement removal was easy. Four patients reported low-grades of immediate post-cementation sensitivity, however, this disappeared after an occlusal adjustment or without intervention within one month. At 12 months no retentive failures were recorded and no subjective sensitivity reported. All crowns were rated in the "Excellent" quality category for marginal integrity. Both GI-scores and scores for tooth sensitivity decreased during the course of the study. One year recall data yielded no incidence of secondary caries and no visible marginal discoloration. The new cement was thus found to perform favorably as a luting agent for permanent cementation. PMID- 20162931 TI - Setting goals for healthy living. PMID- 20162932 TI - Frugal cooking. Using canned goods. PMID- 20162933 TI - Home blood pressure monitoring. Should you be doing it? PMID- 20162934 TI - Prepare whole foods fast! Using a pressure cooker. PMID- 20162935 TI - Diabetes quiz. How much do you know about diabetes and alcohol? PMID- 20162936 TI - Diabetes nutrition bars and shakes. What can they do for you? PMID- 20162937 TI - What your doctor is reading. PMID- 20162938 TI - Supermarket smarts. Hot and cold breakfast cereals. PMID- 20162939 TI - Is your office prepared for an accidental needlestick or other unexpected exposure incident? AB - Recommendations and mandatory guidelines for preventing and managing needlestick incidents and other accidental exposures to bloodborne pathogens in healthcare facilities have been published by the Occupational Safety and Health Administration (OSHA) and the Centers for Disease Control and Prevention (CDC) for more than 2 decades. Over the years, the incidence of official enforcement actions has declined and a complacency about the standards may have evolved in some dental offices. Some practitioners may not have written an occupational exposure incident protocol or made appropriate arrangements for medical laboratory testing and postexposure medical evaluation following an unexpected needlestick or other exposure incident in the office. When an unexpected event occurs, practitioners may become confused regarding the steps to be taken, and may turn to their local dental society or fellow practitioners for guidance. The provided information may or may not be complete, accurate and/or current. Implementation of periodic personnel training to prevent exposure incidents is extremely important and could ultimately save a dental practice thousands of dollars in expenses related to the occurrence of even one exposure incident, as well as save the life and/or career of a dental healthcare provider. This article does not comprehensively detail all infection control and bloodborne pathogen transmission prevention requirements for dental offices. Rather, the article provides suggestions for dental practitioners regarding the step by step management of exposure incidents, and provides resource information for additional steps that can be taken towards prevention, improved office compliance, and improved litigation protection. PMID- 20162940 TI - Following your moral compass. PMID- 20162941 TI - Power in the "present". How you are represented at the American Dental Association. PMID- 20162942 TI - Reviewing the gold standard. PMID- 20162944 TI - "Motivate" patients and increase retention. PMID- 20162943 TI - A secret new source of money for your office. PMID- 20162945 TI - Oral and maxillofacial pathology case of the month. Verruciform xanthoma. PMID- 20162946 TI - The use of MTA in the modern management of teeth affected by dens invaginatus. AB - Dens invaginatus is a dental anomaly that can result in loss of tooth vitality and the need for root canal treatment. The pulpal morphology of these teeth can be complex which makes successful root canal treatment difficult to achieve. To maintain vitality attempts have been made to prophylactically treat these teeth by sealing the invagination with a variety of materials. This paper describes the use of mineral trioxide aggregate (MTA) in both the prophylactic treatment of teeth with minor invaginations and the incorporation of MTA in the final obturation of non-vital teeth with invaginations with grossly atypical morphology. PMID- 20162947 TI - Inequality in dental care utilisation among Thai children: evidence from Thailand where universal coverage has been achieved. AB - AIMS: To quantify the extent of the socioeconomic-related inequality in dental care utilisation among Thai children and to examine the characteristics of dental care utilisation, after the country achieved universal coverage. DESIGN: The data to perform analyses were taken from the nationally representative Health and Welfare Survey (HWS) and Socioeconomic Survey (SES) 2007 in Thailand. PARTICIPANTS: Data of 15,736 representative Thai children (aged below 15 years) were selected. METHODS: Descriptive analyses were performed to reveal the features of dental care utilisation among Thai children, in addition to use the concentration index (CI) to measure socioeconomic-related inequality in dental care utilisation. Logistic regression was employed to determine inequality in dental care across socioeconomic strata. RESULTS: The unequivocal gradient in dental care utilisation persistence among Thai children and the socioeconomic related inequality in dental care utilisation is more concentrated among the better-off as the positive CI value (equals 0.069) emerged. Poor children, however, are more likely to utilise dental care at public facilities, particularly primary care facilities. CONCLUSION: The evidence from Thailand, where universal coverage has been virtually achieved, provides some lesson for other countries particularly developing countries. Although the socioeconomic related inequality in dental care utilisation among Thai children still exists, the pro-poor dental care utilisation at public facilities, particularly primary care facilities substantiate the impressive stride towards the concerted effort to reducing inequitable dental care delivery for Thai children. PMID- 20162948 TI - The erosive potential of lollipops. AB - AIM: To determine the erosive potential of several commercially available lollipops and the protective effect of saliva. METHODS: The erosive potential of lollipops was determined in vitro by measuring the pH and neutralisable acidity. Subsequently, 10 healthy volunteers tested different types of lollipops. Whole saliva was collected 5 minutes before, 15 minutes during and 10 minutes after consumption. Salivary flow rate and pH were determined. RESULTS: Fruit flavoured and cola flavoured lollipops have a very low pH (2.3 - 2.4). Yogurt-containing and salmiak (salty liquorice) flavoured lollipops have much higher pH values (3.8 4.7). The neutralisable acidity of 1g of lollipop showed a large variation from < 200 microl to > 1700 microl 0.1 M NaOH. In vivo, lollipops induced 2.5 to 4.7 fold increase in salivary flow rate with a concomitant drop in salivary pH. For fruit flavoured and cola flavoured lollipops the salivary pH dropped below pH 5.5. For strawberry yogurt and salmiak lollipops, the salivary pH remained above this critical value. The volunteers did not report significant differences in preferences for the lollipops. CONCLUSIONS: Lollipops differ considerable in erosive potential, with fruit flavoured and cola flavoured lollipops having the highest risk for inducing dental erosion. This information is of use for clinicians counselling juvenile patients with dental erosion. PMID- 20162949 TI - Dental caries in children in South Africa and Swaziland: a systematic review 1919 2007. AB - OBJECTIVE: To determine caries rate trends in children in South Africa and Swaziland since the first published epidemiological study in 1910. METHOD: Cochrane Collaboration methods were used to do a systematic review of reported caries rates from 1919 to 2007 in 5-6y, 11-13y and 14-17y children. RESULTS: There are variations in caries rates among racial groups and between rural and urban areas but secular trends show decreasing prevalence and dmft or DMFT over time. CONCLUSION: This systematic review shows decreasing caries rates in children in a developing region of Africa. PMID- 20162950 TI - Relationships between oral conditions and physical performance in a rural elderly population in Japan. AB - OBJECTIVES: To show relationships between oral conditions and physical performance in the elderly living independently. METHODS: A total of 821 persons participated. Data on background factors and self-assessed masticatory ability were collected by means of questionnaires. An intraoral examination was performed to examine the pattern of occluding pairs of natural teeth. Handgrip strength and one-leg standing time with eyes open were measured. Step-wise linear regression models were conducted with muscle strength or one-leg standing time as the dependent variables; the pattern of occluding pairs and self-assessed masticatory ability as the principal independent variables. RESULTS: The self-assessed masticatory ability was retained in the final model of the step-wise regression for the handgrip strength, and significant relationships were established in the participants aged 65-74, but the pattern of occluding pairs was not retained. The pattern of occluding pairs, and the self-assessed masticatory ability were retained in the final models for the one-leg standing time, and significant relationships were shown here. CONCLUSION: The self-assessed masticatory ability may be significantly related to muscle strength and static balance function, and the pattern of occluding pairs may be significantly related to the static balance function, particularly in the elderly aged 65-74. PMID- 20162951 TI - A cross-sectional study of dentine hypersensitivity in China. AB - OBJECTIVE: To carry out a cross-sectional study of the prevalence of dentine hypersensitivity and related risk factors in Chengdu City, China. METHODS: A total of 1,320 subjects were distributed equally in six communities in Chengdu City and of all age groups (10 years for an age group) including the same number of male and female subjects in each community. Each subject completed a structured interview and the subjects who reported hypersensitivity were examined further using a triple syringe to administer a blast of cold air to confirm the diagnosis of dentine hypersensitivity. Periodontal attachment loss and gingival recession of all sensitive teeth were measured. RESULTS: The prevalence of dentine hypersensitivity was 25.5% in the oral test. Only 16.6% of subjects who reported hypersensitivity symptoms had received desensitising treatment. 50-59 year age group was the cohort with the greatest number of subjects with DH and the premolar was the most commonly affected tooth. Low education level, gingival recession, and attachment loss were related to dentine hypersensitivity. CONCLUSIONS: The prevalence of dentine hypersensitivity in an urban adult population in Chengdu City was 25.5%. PMID- 20162961 TI - [Body, nutrition and psychiatry]. PMID- 20162952 TI - Using an oral health-related quality of life measure in three cultural settings. AB - AIM: To assess the application of the Oral Impacts on Daily Performances (OIDP) index for use in three different language and cultural settings; OBJECTIVES: To develop a Spanish and Afrikaans version of the OIDP for use in the USA and South Africa and to assess its reliability and validity in three counties: UK, USA and South Africa. DESIGN: Co-ordinated pilot studies using the OIDP questionnaire and clinical examination using WHO criteria in the three countries using cross sectional convenience samples of children. SETTINGS: Two populations in each country: relatively well-off and more socially disadvantaged in three age groups 40 years+, 15-16 and 11-12 year-olds. RESULTS: 525 volunteers participated in the study; 154 in Texas, 177 in Bristol and 194 in Cape Town, the majority being females. The prevalence of oral impacts on daily performances varied between the three sites, with the sample in Bristol showing lower prevalence of 28.8% reporting at least one oral impact in the past six months. Difficulty eating was a common impact in all three sites, reported by 22.7% of the Texas sample, 18.6% of the Bristol sample and 33.0% of the Cape Town sample. Criterion and construct validity: the OIDP performed consistently well in all three sites. The combined dental caries status of the two lower age groups (12- and 16-year-olds) varied by site: Texas had the highest overall mean DMFT of 4.31, then Bristol with 3.07 and Cape Town the lowest at 2.89. CONCLUSIONS: The OIDP index had excellent psychometric properties in the Cape Town and Texas samples and had an overall good performance in the Bristol sample. Potentially the index can be used for oral health needs assessment and planning services. Further studies using larger samples might provide information relevant to the revision of existing oral health care systems. PMID- 20162962 TI - [Sociocultural influences, body image dissatisfaction and eating disorders]. PMID- 20162963 TI - [Eating disorders in adolescence]. PMID- 20162964 TI - [Monitoring of patients using atypical psychotics and screening for metabolic syndrome]. PMID- 20162965 TI - [Care using "little onions"]. PMID- 20162966 TI - [Weight gain and getting back in shape]. PMID- 20162967 TI - [Criteria for evaluation and surveillance in managing a suicidal crisis]. PMID- 20162968 TI - [A study of the representations of psychiatric disorders]. PMID- 20162969 TI - Scrutinize your readmissions and take steps to avoid them. PMID- 20162970 TI - Look beyond hospital walls to avoid readmissions. PMID- 20162972 TI - CM redesign reduces LOS, increases case mix index. PMID- 20162971 TI - Home care nurses help patients avoid readmission. PMID- 20162973 TI - Triad model of CM improves patient flow. PMID- 20162974 TI - Innovative thinking helps CMs prepare for RACs. PMID- 20162975 TI - These strategies can pave the way to a clean claim. PMID- 20162976 TI - Kaiser/VA/DoD partnership piloting a nationwide EHR network. AB - Sharing of relevant medical data can help prevent potentially deadly drug interactions. Storing all information in a single EHR network can be a big time saver for providers. Using an outside vendor can help ensure objective measurement of outcomes. PMID- 20162977 TI - Nurses improve medication administration accuracy. AB - Frontline nurses often have good ideas, but are not empowered to express or implement them. QI solutions do not have to "break the bank" of your hospital. Ongoing monitoring is critical if you want to sustain the gains you achieve. PMID- 20162978 TI - First the RACs, now wait o for what's coming next. AB - Auditors could look at quality issues as part of the continuum of care, such as readmissions. Pilot program provides information about RACs but not much information about MICs, which could vary by state. Largest providers in largest population centers likely to be first MIC targets. PMID- 20162979 TI - Hospital reimbursement from all payers is at risk. AB - Develop a committee to deal with MICs and commercial insurance auditors. Define the record request by type and track deadlines, which may vary. Make sure letters from auditors are looked at directly by the appropriate area. PMID- 20162980 TI - Follow-up calls help avoid readmissions. AB - Nurse care coordinators, who follow up with patients after discharge, are assigned by service line and follow the patient throughout the hospital stay. Patients who are discharged home with post-acute services, those who will be home alone after a hospital discharge, first-time mothers discharged to home with their babies, families of babies who are discharged from the NICU, and any patient the care coordinator is concerned about after discharge are called. Coordinators use a template to gather specified info from discharge patients. PMID- 20162981 TI - [Termination of the treatment initiated by the dentist]. PMID- 20162983 TI - [Dental voluntarism in Israel]. PMID- 20162982 TI - Prosthetic care for a mentally ill patient. AB - A manic-depressive 64 old female arrived to the clinic for prosthetic treatment. She was fully edentulous and wore an old poor set of complete dentures. Her general attitude was apathy, nonattached and almost indifferent to the general environment as well as to the proposed oral care. This behavior can change for the worse at any stage during treatment, especially after the delivery stage, with the possibility of a change from an indifferent to a hostile, non cooperative attitude. The intended care was explained in detail to the patient and her accompanying daughter. After their approval, we were able to perform successfully a new set of complete dentures with improved esthetics and functional capabilities. Flat bony ridges with shallow mucosal coverage precluded vertical mandibular denture extension at the lingual surface. Consequently the resulting prosthesis had reduced lateral lingual flanges with limited support and retation. PMID- 20162984 TI - [Electronic Apex Locator as a dental instrument]. AB - Electronic Apex Locators (EAL) have become widely used in the last decade. The first apex locator was introduced in 1962, based on a constant electrical resistance (6.5 K.) between the oral mucosa and periodontal ligament. The first and second generations of EAL were inaccurate and could not detect the apex in the presence of conducting fluids. The third generation solved this problem by using two alternating frequencies and calculating the impedance between them. This provided reliable and accurate results in dry canals, or in the presence of blood, electrolytes or other fluid in the root canals, when the pulp was necrotic or when there was a perforation along the root. The Root ZX and Apit (Endex) are the most documented devices. The new fourth generation of apex locators is a diverse group: some use multifrequency currents, others use a "lookup matrix" rather than calculate the readings. Several of the newer EALs are smaller, and others connect to computers. PMID- 20162985 TI - [Endodontal and periodontal aspects of root perforations]. AB - Root perforation is an artificial communication between the root canal system to supporting tooth tissues or to the oral cavity. The etiology of the perforation can be mechanical errors during dental procedures or pathological processes. Infection of the perforation site affects the prognosis of the treated root perforation, which is influenced by time between occurrence of the perforation and appropriate treatment, size, and location of the perforation. Careful treatment planning and operative techniques are imperative to prevent root perforations. PMID- 20162986 TI - Darwin and his theory. PMID- 20162987 TI - Suggested guidelines for basic dental education in Europe. AB - With the enlargement of the European Community, a great effort was done. In order to abolish the inequalities that exists in the provision of oral health education and Oral healthcare delivery between Eastern and Western Europe. On the other hand, each day more emphasis is placed on the basic competencies and abilities gained during basic dental education due to internal and external driving forces. The differences between the systems are often very important prominent and seem to depend mainly on the national institutions or the government policy. Therefore there is a major responsibility for the profession in helping to integrate the dental practitioners in an updated approach. As a similar basic dental education will progressively been developed, the Continuing Education could become more complex. For this purpose, following a basic dental education complying with the current needs and demands, a more adapted Continuing Education program must be elaborated and promoted. PMID- 20162988 TI - The importance of correct diagnosis in complete dentures treatment. AB - A 68 years edentulous female, wearing unsuccessful complete dentures, was treated by making a new set of dentures. The main initial complains were unaesthetic teeth, excessive gums display, speech impairment and severe difficulties in mastication. With the patient's full collaboration and following sound established prosthodontics principles, a successful set of full dentures was provided. The main changes performed with the new set of dentures were: A. Provision of three millimeters interocclusal rest space between the vertical dimension while in occlusion and the vertical dimension of rest. B. The full anterior and premolars maxillary teeth and the incisal's third of the mandibular anterior teeth were displayed when patient was speaking, smiling and laughing. No artificial gums were displayed during any normal facial or oral activities. C. The occlusal plane was established after the selection of the anterior teeth. The plane was made parallel to the ala tragus (Camper's) line. PMID- 20162989 TI - [The new IADT guidelines for dental trauma management: an introduction for the Israeli dentist]. AB - Dental trauma is, unfortunately, not uncommon in the Israeli population. High risk populations include children, sport participants, military personnel and patients with oral (tongue) and/or lip piercing. In 2007, the International Association of Dental Trauma (IADT) updated the guidelines for the management of traumatic dental injuries. This paper is aimed to discuss and present the new guidelines for the management of traumatic dental injuries and to offer some highlights to the Israeli dental population. Good prognosis of injured teeth largely depends on prompt and appropriate management. Thus, it is important for healthcare-givers, especially dental practitioners, to maintain an adequate level of updated knowledge. PMID- 20162990 TI - [Early childhood caries]. AB - ECC was defined by the American Academy of pediatric dentistry at 2003 as the presence of 1 or more decayed (noncavitated or cavitated lesions), missing (due to caries), or filled tooth surfaces in any primary tooth in a child 71 months of age or younger. This is a virulent type of dental caries that start soon after the tooth erupts and progress rapidly. The prevalence is 1-12% in developed countries and 70% in developing countries, and changes in different cultures, communities, socioeconomic status, etc. The etiology of the disease is multifactorial like in any dental caries. The risk factors include high levels of SM and LB, enamel defects, oral habits, complication at pregnancy and birth, social and demographic factors and the child's age. The disease implications are: high risk of new caries defects in both permanent and deciduous dentitions, insufficient physical development, hospitalization and emergency room visits, loss of school days and increased days with restricted activity, increased treatment costs and time, diminished ability to learn, and diminished oral health related quality of life. Due to the aggressive pattern of the disease, treatment should be specific for each individual patient, and should be given by an expert dentist with experience who could manage the young child and the process of the disease. Treatment options are: 1. Conservative approach which includes recalls and topical fluoride, 2. Aggressive restorative approach. In both we should first stop the carious habit and encourage prevention. Before choosing the type of treatment, we should consider the severity of the lesions, child's age, caries risk, child's behavior, and parents' cooperation. Prevention at home includes: 1. decreasing the mother's/primary caregiver's mutans streptococci levels, 2. avoid sharing the same utensils in the family, 3. implementing oral hygiene measures as the first primary tooth erupts, 4. dental home, 5. avoid inappropriate feeding practices of infants and toddlers. Prevention at clinic includes: 1. topical fluoride application, 2. proximal slices in appropriate cases. PMID- 20162991 TI - [Endodontal and periodontal aspects of root perforations]. AB - The purpose of treatment of perforations is to achieve a tight and permanent seal that will prevent bacteria and their by-products in the root canal from entering into the surrounding periodontal tissues. It is important to consider the type of perforation according to the classification for selection of the proper material and technique for each case. Modern techniques for treatment of perforations by orthograde and surgical approach result in prolonged survival of the tooth. PMID- 20162992 TI - Computerized tomography in dentistry--new advances. PMID- 20162993 TI - ED managers must dig beneath the surface to uncover all potential sources of liability. AB - Studying your data on issues such as radiological miss rates and identifying common complaints that have led to lawsuits will identify areas where your ED might be legally vulnerable. However, dig deeper to uncover all areas of potential legal trouble. Perform chart audits to examine issues such as aggressive use of midlevel practitioners for acute care. Review operational risks, as they could lead to legal problems down the road. Measure how well you are listening to your patients and their families. PMID- 20162994 TI - Get at root causes to reduce risk. AB - To address and eliminate areas of liability concern, the first step is to identify the root causes of those problems. Conduct follow-up calls with as many "treat-and-release" patients as possible to get their input. Use patient satisfaction surveys to uncover areas of concern in terms of quality and professionalism. Let your staff know that lawsuits are not inevitable and that there are positive steps they can take to address areas of weakness. PMID- 20162995 TI - Patient satisfaction is a best practice. AB - There are several best practices ED physicians and nurses can adopt to minimize the likelihood of a lawsuit, but perhaps none is more important than ensuring high patient satisfaction scores. Research shows a definite correlation between increasing patient satisfaction and decreasing the medical malpractice frequency. Bad outcomes are more likely to lead to lawsuits if the patient doesn't like their doctor or nurse. Being attuned to patients and their perspective is one of the best ways to prevent complaints, which eventually can lead to lawsuits. PMID- 20162996 TI - Admit mistakes, show your concern. AB - Complaint management strategies and service recovery in particular, can be extremely effective in reducing the likelihood that a dissatisfied patient or family member will sue. Acknowledge your mistakes, and take concrete steps designed to ensure they will not be repeated. If possible, involve the patient or family member in the solution. Make sure the complaining individual realizes that you are listening to him or her and that what he or she says is important to you. Be proactive. If a patient appears unhappy, engage him or her in conversation and ask what's wrong. PMID- 20162997 TI - Scribes, EMR please docs, save $600,000. AB - The leaders of the ED at Tri-City Medical Center have come up with an initiative that has saved them $600,000, generated a billing increase of 10% per provider per hour, and won over physicians: using physician scribes in concert with their electronic medical record (EMR). It eliminates the concern that EMRs will slow them down. They have seen a 6.45% increase in productivity based on patients seen per hour. The physicians can focus on the bedside and look at the patient at the same time the scribe enters information into the electronic chart. Scribes prepare the discharge forms, including medication reconciliation, so they are ready for the doctor to sign. PMID- 20162998 TI - Include oral health in your ongoing health curriculum--February is National Children's Dental Health Month. PMID- 20162999 TI - When there is no school nurse--are teachers prepared for students with peanut allergies? AB - Peanut allergies account for the majority of severe food-related allergic reactions and affect 1% of Americans today. Therefore, food allergies among students are one of the most common healthcare conditions that must be addressed in the school setting. With the lack of full-time school nurses, teachers feel overwhelmed when the responsibility is placed upon them to care for these students. This article will discuss the prevalence of peanut allergies in schools and acknowledge the difficulties faced by teachers when dealing with a student with a peanut allergy. It is imperative that teachers receive a comprehensive educational program on peanut allergies when no school nurse is available. Ultimately, we want teachers and school staff responsible for student supervision to recognize quickly what symptoms might indicate anaphylaxis and know how and when to get help. This knowledge would increase their awareness of their own role in preventing allergy-related deaths. PMID- 20163000 TI - What content is still missing from health class? PMID- 20163001 TI - Year-round school and the school nurse. PMID- 20163002 TI - Usher syndrome. PMID- 20163003 TI - The role of physical activity in diabetes management and risk factor reduction for type 2 diabetes in youth. PMID- 20163004 TI - Nurses say patients at risk under working time rules. PMID- 20163005 TI - It is the education system that leads students to reject basic care. PMID- 20163006 TI - What is the evidence base for the assessment and evaluation of body temperature? AB - Measurement and management of body temperature is often based on traditionand personal ideas and beliefs rather than evidence based knowledge. This article summarises the literature to provide a guide to evidence based assessment and evaluation of body temperature in clinical practice. PMID- 20163007 TI - Interfering with the body's natural defence response to infection? PMID- 20163008 TI - How to ensure patient observations lead to effective management of patients with pyrexia. AB - Pyrexia is defined by the National Institute for Health and Clinical Excellence as an elevation of body temperature above the normal daily variation. A sudden rise in temperature usually indicates infection, although there are many other noninfectious causes. This article outlines the causes of pyrexia and discusses management options. PMID- 20163009 TI - Implementing online tools and resources to help nurses apply evidence based care. AB - While nurses maybe aware of tools and resources for quality improvement, this does not necessarily mean they are used in practice. An alliance between NHS Quality Improvement Scotland and The Joanna Briggs Institute in Australia has been set up to promote and facilitate the use of online tools and resources to support the development of practice and, ultimately, to enhance care. This article summarises the tools available and discusses the implementation and evaluation of this project. PMID- 20163010 TI - Tuberculosis 1: exploring the challenges facing its control and how to reduce its spread. AB - The first in this two part unit on tuberculosis discusses global and UK rates, and explains strategies to control it in the UK. Certain challenges are discussed, such as HIV co-infection and drug resistance. PMID- 20163011 TI - The NHS must not pay for the failures of bankers. PMID- 20163012 TI - Mental health opportunities go independent. PMID- 20163013 TI - [A half-century of respirology--past accomplishments and aspirations for the future]. PMID- 20163014 TI - [A questionnaire study on the necessity of approval for revaccination of the pneumococcal polysaccharide vaccine]. AB - To clarify the current situation of revaccination with pneumococcal polysaccharide vaccine (PPV) and the adverse effects caused by revaccination with PPV in the elderly in Japan, a questionnaire study was carried out among the 989 members of the directors and councillors of the Japanese Respirology Society and the Japanese Association for Infectious Diseases. Of 385 evaluable respondents, 290 who had had experience giving PPV immunization were regarded as the study subjects. Of whom 46 subjects (15.9%) had had experience of PPV revaccination. However, 252 subjects (86.9%) recognized that PPV revaccination is necessary. In addition, of the 290 subjects, 114 subjects (49.7%) had experienced a patient refusing the first vaccination with PPV because of contraindications for PPV revaccination. Of 46 subjects with experience of PPV vaccination, 4 subjects found adverse effects in the recipients of PPV revaccination. The adverse effects found were not serious. The present study demonstrated that most of the study subjects recognized the necessity of PPV revaccination, and in part, those subjects implementing PPV revaccination were responding to requests by patients or their family. It was also suggested that the contraindication for PPV revaccination could prevent the increase of the coverage rate of PPV. PMID- 20163015 TI - [Seven cases of diffuse alveolar hemorrhage with acute respiratory failure treated by plasma exchange]. AB - We conducted a retrospective analysis of 7 cases of diffuse alveolar hemorrhage at our hospital, diagnosis of which was made on the presence of bloody bronchoalveolar lavage fluid. There were 3 men and 4 women, with a mean age of 68 years. A rapidly progressiving diffuse infiltrative shadow on chest X-ray film and failing to respond to antibiotic therapy were the major signs of the condition in these cases. Respiratory failure was seen in all cases. In addition to high-dose steroid therapy and mechanical ventilation, we immediately performed plasma exchange. All of the 3 MPO-ANCA-positive patients survived, but 3 of the 4 MPO-ANCA-negative patients died. Diffuse alveolar hemorrhage secondary to ANCA associated vasculitis usually advances rapidly and its prognosis tends to be poor. However, early initiation of plasma exchange can be expected to improve the survival rate of patients with this disease. PMID- 20163016 TI - [Differences of fractional exhaled nitric oxide (FeNO) levels performed using two different analyzers]. AB - The measurement of fractional exhaled nitric oxide (FeNO) is going to become more wide-spread as a noninvasive marker for diagnosing and controlling bronchial asthma. In Japan, both stationary and portable FeNO analyzers are now available. However, the difference between these analyzers has not been fully examined. Therefore, the aim of this study is to determine whether there is a difference between a stationary FeNO analyzer (NA623NP, CHEST inc. Tokyo, Japan) and a portable analyzer (NIOX MINO, Aerocrine, Solna, Sweden). One hundred subjects (17 non-treated asthma cases, 45 asthma cases treated with inhaled corticosteroids, 21 with other respiratory disorders, 17 healthy subjects) were enrolled in the study. All the subjects were non- or ex-smokers. There was a strong positive correlation between FeNO (CHEST) and FeNO (MINO) (r = 0.970, p < 0.001). However, when FeNO levels between FeNO (CHEST) and FeNO (MINO) were compared in all subjects and each subject group, the levels of FeNO (MINO) were significantly lower than those of FeNO (CHEST) (p < 0.05). Finally, the following conversion equation was calculated: FeNO (CHEST) = FeNO (MINO) x 1.278 + 3.065. From these results, the following conclusion was drawn: when FeNO is measured by different analyzers, there might be differences between devices. Therefore, the conversion equation could help clinicians and researchers to compare data obtainable by these two analyzers. PMID- 20163017 TI - [Bronchoscopic follow-up of secondary racemose hemangioma of the bronchial artery]. AB - A 63-year-old woman with cystic bronchiectasis who had been treated in our institute was admitted for recurrent prolonged hemoptysis. Bronchoscopic examination showed bloody discharges in the left basal bronchus and a bulging polypoid lesion covered with intact bronchial mucosa in the left B8. In comparison with the bronchoscopic examination 6 years ago, the lesion was larger and the mucosal color changed more injected. A bronchial arteriogram revealed a convoluted and dilated left bronchial artery. Because bronchial artery embolization failed, a left lower lobectomy was performed. The diagnosis of secondary racemose hemangioma of the bronchial artery was pathologically established. A racemose hemangioma of the bronchial artery is characterized by an enlarged and convoluted bronchial artery. The bronchoscopic findings of this disorder have been rarely reported. This case may provide valuable information about serial bronchoscopic findings and the progression of secondary racemose hemangioma in the bronchial artery. PMID- 20163018 TI - [A case of refractory pulmonary peripheral T cell lymphoma successfully treated with Cisplatin Plus Gemcitabine Plus Solumedrol]. AB - A 56-year-old man had an endoscopic examination for dysphagia in March 2007 which revealed tumors in the esophagus and stomach. Pathological examination of the esophagus biopsy specimens showed an unspecified peripheral T cell lymphoma. The esophagus tumor was tolerant to CHOP and EPOCH therapy. After an autologous peripheral blood stem cell transplantation, a complete response was observed in the patient. However, a lymphoma relapse was diagnosed in the lung in September 2008. The relapsed lung lymphoma was tolerant to EPOCH therapy. The refractory pulmonary peripheral T cell lymphoma was remarkably reduced by PEGS therapy. PEGS therapy is useful for relapsed peripheral T cell lymphoma cases that tolerated standard chemotherapy. An allogenic hematopoietic stem cell transplantation or new molecular target therapy might be finally selected for refractory peripheral T cell lymphoma. However, an allogenic transplantation has some severe complications. Furthermore we could not easily try phase I or II new molecular target drug treatment. We think that PEGS therapy is a useful treatment for refractory peripheral T cell lymphoma before allogenic transplantation or new molecular target drug treatment. PMID- 20163019 TI - [Two cases of pulmonary sarcomatoid carcinoma mimicking malignant mesothelioma]. AB - We report 2 cases of pulmonary sarcomatoid carcinoma mimicking malignant mesothelioma. Case 1: A 69 year-old man presented, complaining of right chest pain. The chest X ray film and CT showed tumors in the right chest wall and pleura. Histological findings of specimens obtained from a percutaneous biopsy revealed spindle tumor cells, and the immunohistochemistry showed that the tumor cells were positive for CK-7, AE1/AE3, and vimentin and negative for calretinin, D2-40, and WT-1. We diagnosed pulmonary sarcomatoid carcinoma and started chemotherapy with carboplatin and paclitaxel, but it was ineffective. Case 2: A 68 year-old man was admitted complaining of general malaise. The chest X ray film and CT revealed tumors in the right chest wall. Histological findings showed necrosis and spindle tumor cells which were positive for AE1/AE3 and vimentin, and negative for calretinin, D2-40, and WT-1. We diagnosed pulmonary sarcomatoid carcinoma and started chemotherapy with carboplatin and paclitaxel. However the disease continued to progress and he died 2 months after admission. The pulmonary sarcomatoid carcinoma was reported to have spred to the pleural and chest wall. The present two cases showed prominent chest wall and pleural tumors with obscure primary lung tumors. Therefore, we needed to differentiate sarcomatoid carcinoma from malignant pleural mesothelioma. PMID- 20163020 TI - [Two cases of anomalous systemic arterial supply to the basal segments of bilateral lungs]. AB - We encountered two cases of systemic arterial supply to the basal segments of bilateral lung with elevated serum CEA levels. The patients were a 36-year-old man and a 30-year-old man with the abnormal chest shadows, discovered during physical checkups. A chest computed tomogram (CT) of the 36-year-old patient showed reticulonodular shadows in the bilateral lower lobe with anomalous vessels arising from the descending aorta and running into the lower lobe on each side, and his abdominal CT revealed a duplicated vena cava inferior. His aortogram confirmed an anomalous systemic arterial supply to the basal segments of bilateral lungs. The chest CT of the 30-year-old patient revealed a cystic lesion in the right lower lobe and no abnormality in the left lung field. His aortograms showed aberrant systemic arterial supplies to the bilateral lower lobe. Because the cystic lesion had increased in size, it was resected and an anomalous systemic artery was seen. Intralobar sequestration in the right lung and anomalous systemic arterial supply in the left lung was diagnosed. Serum CEA was high at the initial visit in each patient but it decreased spontaneously in the first patient, and after the resection of the cystic lesion in the second patient. We report two cases of anomalous systemic arterial supply to the basal segments of bilateral lung, which is extremely rare. Our literature search revealed that only 13 cases have been reported to date. PMID- 20163021 TI - [A case of cellular NSIP with anti-OJ (anti-isoleucyl tRNA synthetase) antibodies]. AB - A 54-year-old woman, complaining of a dry cough in the beginning of December 2004, was admitted to our hospital because of its exacerbation in January 2005. Interstitial pneumonia was suspected according to a chest Xray and chest CT. The pathological diagnosis of cellular nonspecific interstitial pneumonia (NSIP) was made after video assisted thoracic surgery. She did not have muscle weakness or arthralgia but she had a skin lesion ("mechanic's hand") which is often seen in patients with antisynthetase syndrome. Anti-Jo-1 antibody was negative but anti OJ antibody was positive. Therefore, anti-aminoacyl tRNA synthetase syndrome with cellular NSIP was diagnosed. She had a favorable response to the initial treatment of methylprednisolone pulse therapy followed by prednisolone 1 mg/kg/day. Her symptoms, pulmonary function test and chest imaging findings have showed improvement after therapy. PMID- 20163022 TI - [A case of lymphomatoid granulomatosis which initially demonstrated a diffuse ground glass appearance]. AB - Lymphomatoid granulomatosis is defined as an Epstein-Barr virus-associated B-cell lymphoma which possibly progresses to malignant lymphoma. The pulmonary lesions associated with this disease typically reveal multiple poorly defined nodules. A 71-year-old man with acute respiratory failure consulted a local doctor. A chest CT scan demonstrated a bilateral lower ground glass appearance. The shadow improved after pulse steroid therapy but it showed multiple nodules after the corticosteroid treatment was tapered. We finally diagnosed lymphomatoid granulomatosis (grade 2) based on the findings of a thoracoscopic lung biopsy. Pathologically, an angiocentric proliferation of large atypical lymphoid cells were observed which were positive for EBER (EBV-encoded small RNA). We herein report the details of this case because of its rare radiographic findings. PMID- 20163023 TI - [A case of multiple and metachronous pleural tuberculomas during the course of anti-tuberculous chemotherapy and follow-up of a caseous pneumonia]. AB - A 21-year-old woman was admitted to our hospital because of high fever, a productive cough and general fatigue. Her chest radiography scan revealed dense consolidation with air-bronchograms in the left lower lobe. Bacterial pneumonia was diagnosed and she was treated with antibiotics, although the specific cause could not be identified. After one month, a bronchoscopy was performed due to lack of improvement of consolidation in chest radiography. A smear examination of the bronchial washing specimen was positive for acid-fast bacilli (AFB) and Mycobacterium tuberculosis (MTB) was confirmed by PCR. After anti-tuberculous drugs (INH, RFP, EB, and PZA) were prescribed for 6 months, chest X-ray findings improved markedly. Two pleural tuberculomas were found in the left upper and lower lung fields 3 months after beginning therapy, and a new pleural tuberculoma appeared in the left upper lung fields 6 months after finishing therapy. Histopathological findings (HE stain) of a CT-guided needle lung biopsy showed epithelioid cell granulomas without caseous necrosis with multinuclear giant cells which were negative for acid-fast bacterium. All of the pleural tuberculomas improved without any additional therapy 18 months after finishing therapy. It was thought that such cases of multiple and metachronous pleural tuberculomas during the course of anti-tuberculous chemotherapy and follow-up of caseous pneumonia are rare. We suggest the possibility that the pleural tuberculomas were due to a paradoxical or hypersensitive reaction to the anti tuberculous chemotherapy in this case. PMID- 20163024 TI - [Two cases of tuberculosis after treatment of rheumatoid arthritis with infliximab]. AB - We report two cases of tuberculosis (TB) after treatment with infliximab (IFX) for rheumatoid arthritis (RA). The first case, a 69-year-old woman with RA, developed miliary TB with acute respiratory distress syndrome 21 months after initiation of IFX therapy. Sputum samples revealed smears and cultures positive for Mycobacterium tuberculosis and also positive polymerase chain reaction for TB (PCR-TB); in addition urine samples were smear-negative and culture-positive for TB. She was treated with corticosteroid pulse therapy and anti-tuberculosis drugs, and recovered. The second case, a 51-year-old man with RA, had had contact with a tuberculosis patient four years after initiation of IFX therapy. One year later, he developed pulmonary and pleural tuberculosis. Mycobacterium tuberculosis was detected in the bronchial lavage fluid and pleural effusion (smear-negative and culture- and PCR-TB positive). He clinically improved by treatment with anti-tuberculosis drugs. In both cases, the enzyme-linked immunosorbent spot (ELISPOT) tests revealed positive responses although the QuantiFERON TB-2G tests were not positive. We suggest that the ELISPOT test may be useful as a supportive diagnostic tool for tuberculosis in immunocompromised conditions including RA treated with a tumor necrosis factor-alpha (TNF-alpha) inhibitor. PMID- 20163025 TI - [A case of lung adenocarcinoma exhibiting Garcin syndrome]. AB - We report a rare case of lung adenocarcinoma exhibiting Garcin syndrome due to skull base metastasis. A diagnosis of lung adenocarcinoma and intraperitoneal lymph node metastases was given to a 50-year-old man after pathological examination of a superclavicular lymph node biopsy. After systemic chemotherapy with cisplatin plus docetaxel, he had left hearing loss and vertigo. Since auditory nerve damage might occur due to cisplatin, the chemotherapy regimen was changed. However, facial paralysis occurred and his auditory nerve disorder progressed to deafness. He was diagnosed with Garcin syndrome due to the skull base and spinal cord metastases by brain and spine MRI, and cytological examination of the spinal fluid. After intrathecal administration of methotrexate and cranial irradiation, the progression of facial paralysis and auditory nerve disorder were halted. It is important to consider Garcin syndrome as a possible complication in lung cancer patients who have central nervous system symptoms. PMID- 20163026 TI - [Rheumatoid arthritis diagnosis based on the detection of a pulmonary rheumatoid nodule in a patient with Hansen's disease]. AB - A 77-year-old man with Hansen's disease was referred to our hospital because of a small nodular lesion detected adjacent to the pleura in the right lower lobe (S10) on chest CT. He had lost all ten fingers due to Hansen's disease and was using a prosthetic limb after amputation of the right lower leg. Although the patient had an 11-year history of shoulder and back pain and was suspected of having interstitial pneumonia 6 years previously, no detailed examination had been conducted. Bronchoscopy did not yield a definitive diagnosis, and a lung biopsy was performed under thoracoscopic guidance. Histological examination of the resected nodule with colliquative necrosis revealed palisading granulomas with multinucleated giant cells and plasma cell infiltration with formation of lymphoid follicles. Since serum levels of both anti-MMP3 and anti CCP antibodies were elevated, rheumatoid arthritis (RA) with rheumatoid lung was diagnosed. Therefore, the nodule was considered a rheumatoid nodule. Since diagnosis of rheumatoid arthritis is difficult when lacking characteristic joint manifestations, it is important to include rheumatoid nodules as a differential diagnosis and to measure RA specific autoantibodies, to make a comprehensive diagnosis for non-specific necrotizing granulomas. PMID- 20163027 TI - [A case of intravascular lymphoma with diffuse centrilobular opacities]. AB - A 54-year-old woman was admitted with general fatigue and dyspnea on exertion. Her serum LDH level was markedly elevated to 2145 IU/L, and chest CT revealed diffuse centrilobular opacities. Total cell counts in bronchoalveolar lavage fluid were elevated, and lymphocytes accounted for 98% of the cells. A transbronchial lung biopsy demonstrated numerous CD20-positive atypical cells in the alveolar capillaries, so intravascular lymphoma (IVL) was diagnosed as having. Lymphoma cells were also present in the bone marrow sinusoids, while there was no sign of hemophagocytosis. Combined chemotherapy (CHOP with rituximab) successfully induced complete remission, and she has been free of recurrence for 40 months. In cases with diffuse centrilobular opacities on chest CT, accompanied by elevated serum LDH, it is important to rule out IVL by performing TBLB. PMID- 20163028 TI - [Henoch-schonlein purpura induced by erlotinib (Tarceva): a case report]. AB - Erlotinib is a newly developed molecular-targeting or molecular-targeted drug with selective inhibitory activity for tyrosine kinase of the epidermal growth factor receptor. A adverse drug reactions including diarrhea, skin eruptions are considered mild. We report a case of recurrent adenocarcinoma of the lung in a 68 year-old woman who suffered from Henoch-Schonlein purpura induced by erlotinib. She received daily administration of erlotinib 150 mg as second-line chemotherapy. Her tumors decreased in size and pleural effusion disappeared, so we considered erlotinib effective. However after 3 months of treatment with erlotinib, the patient presented palpable purpuric lesions mostly located on her lower legs. We diagnosed Henoch-Schonlein purpura based on skin histological findings. Erlotinib was reduced but continued, with improvement of the eruptions. Henoch-Schonlein purpura is often accompanied by systemic manifestations, such as renal disease and arthritis, so more careful follow-up is warranted. PMID- 20163029 TI - [Assessment of airway lesions using "virtual bronchoscopy" in a patient with relapsing polychondritis]. AB - A 44-year-old woman was referred to our department complaining of a persistent cough and dyspnea which were resistant to inhaled corticosteroids or a bronchodilator. In addition, she suffered tenderness on the sternum, costicartilage, and bilateral fingers of both hands as well as sensorineural deafness. Virtual bronchoscopy images, re-constituted from three dimensional computed tomography, revealed the thickness of the pan-tracheal wall ranging from the vocal cord towards the bilateral bronchi. These lesions showed an increased uptake in gallium-67 scintigraphy. Enhanced levels of an anti-type II collagen antibody were detected. These findings and symptoms satisfied Damiani's criteria of diagnosis and thus relapsing polychondritis was diagnosed. Treatment with oral prednisolone (40 mg/day) was started. Her cough improved immediately, and two months later virtual bronchoscopy showed improvement in the tracheal wall thickness. The level of the anti-type II collagen antibody was also attenuated, along with a decreased uptake of gallium-67 scintigraphy. However, the virtual bronchoscopy demonstrated that the cartilage ring surrounding the trachea and bronchi remained absent, suggesting the cartilage was already destroyed. Our case demonstrated that virtual bronchoscopy plays a key role in the assessment of airway lesions in relapsing polychondritis. PMID- 20163030 TI - [A case of interstitial pneumonia with anti-signal recognition particle (SRP) antibody without myopathy]. AB - Interstitial pneumonia in a 54-year-old woman was diagnosed in April 2007, without symptoms. She was admitted to our hospital in February 2009 because chest radiography showed gradual worsening. On physical examination, she had fine crackles on chest auscultation and "mechanic's hands", without arthritis, myopathy, or Reynaud disease. On laboratory tests, antinuclear antibody (speckled and cytoplasmic pattern) and anti SS-A antibody were positive. Chest CT showed ground-glass opacities in both lower lobes with volume loss and she had a restrictive disorder on a pulmonary function test. Bronchoalveolar lavage was within almost normal limits. For a definitive diagnosis, video associated thracoscopic surgery was performed. The histopathological findings showed a fibrotic nonspecific interstitial (f-NSIP) pattern. Corticosteroid therapy (prednisolone, initially 40 mg/day) was started, and the chest radiography improved. Later, an RNA immunoprecipitation test was positive for anti-signal recognition particle (SRP) antibody. This is a rare case of interstitial pneumonia with anti-SRP antibody without myopathy. PMID- 20163031 TI - Treatment of chronic hepatitis C in patients with human immunodeficiency virus (HIV) with weekly peginterferon alpha-2b plus ribavirin: a multi-centred Belgian study. AB - BACKGROUND AND STUDY AIMS: In Belgium, 10-15% of patients infected with the human immunodeficiency virus (HIV) are coinfected with hepatitis C virus (HCV). Because of increased incidence of antiretroviral drug-related hepatotoxicity and more rapid clinical evolution towards end-stage liver disease, treatment of chronic hepatitis C becomes a priority. We report the results of a multi-centred Belgian study evaluating efficacy and safety of peginterferon alpha-2b plus ribavirin in HIV-HCV co-infected patients without AIDS and without decompensated liver disease. PATIENTS AND METHODS: Forty-one patients, all genotypes, were screened to participate. Eventually 37 received treatment with peginterferon alpha-2b (1.5 microg/kg/week) plus daily weight-based ribavirin for 52 weeks. About one third of the patients were genotypes 1, 2/3, and genotype 4, most of the latter being of Central African origin. About 56% of the patients had severe fibrosis (Metavir score > or = F3). RESULTS: Sustained viral response (SVR) at 24 weeks of follow up was observed in 10/37 (27%) of patients. SVR was higher in genotype 2/3 compared to genotype 1/4 (46.7% versus 13.6%; p = 0.06) and in low (F0-F1) versus high (F2-F4) grade fibrosis (p = 0.06). Treatment was withdrawn for side effects in 11/37 patients (30%). One Child A cirrhosis patient at the start of therapy died 7 months after treatment withdrawal as a result of severe haemolytic anaemia. CONCLUSIONS: It can be concluded that weight-based peginterferon alpha 2b plus ribavirin can be successful in selected HIV-HCV co-infected patients. Caution should be applied in patients with advanced liver disease. PMID- 20163032 TI - Microalbuminuria in inflammatory bowel diseases using immunoturbidimetry and high performance liquid chromatography. AB - BACKGROUND AND STUDY AIMS: To measure urinary albumin excretion using immunoturbidimetry (IT) and high-performance liquid chromatography (HPLC) in inflammatory bowel diseases. PATIENTS AND METHODS: A cross-sectional study was carried out on 60 selected patients with Crohn's disease (CD), 57 with ulcerative colitis (UC) and 22 healthy volunteers, as controls. Urinary albumin excretion was measured by IT and HPLC, and albumin-creatinine ratio was calculated. This ratio was compared in patients with active and inactive CD and UC and in healthy volunteers. RESULTS: Patients with CD and UC had higher albumin-creatinine ratio compared to controls using both IT and HPLC (p < 0.05). We measured higher albumin-creatinine ratio in patients with active compared to inactive CD (p < 0.05). Albuminuria did not correlate with disease duration of CD or UC, but patients with more extended CD according to the Montreal classification had higher HPLC-albumin-creatinine ratio. In CD, we found a significant correlation between HPLC-albumin-creatinine ratio and some inflammatory markers i.e. white blood cells (p < 0.05) and erythrocyte sedimentation rate (p < 0.05). In UC, there was no significant correlation between HPLC-albumin-creatinine ratio and the above markers of systemic inflammation or activity of UC. Albumin-creatinine ratio measured by HPLC was higher in both active and inactive CD and UC groups than albumin-creatinine ratio measured by IT. Using a receiver operating characteristics curve analysis, in case of HPLC-albumin-creatinine ratio cut-off values of the activity of CD were 2.46 mg/mmol for men, 5.30 mg/mmol for women. CONCLUSIONS: HPLC-urinary albumin-creatinine ratio is associated with the clinical and laboratory disease activity indices in CD, but not in UC. Using HPLC we found a more sensitive method compared to IT to measure albuminuria that would be a sensitive activity marker in CD. PMID- 20163033 TI - Incidence of adult form of autoimmune hepatitis in Valencia (Spain). AB - BACKGROUND AND STUDY AIMS: There is little information on the incidence of autoimmune hepatitis (AIH) because on many occasions the disease can progress asymptomatically, different diagnostic criteria have been proposed during the last 20 years, and many epidemiological studies are based on retrospective clinical series. The aim of this study was to determine the incidence of AIH in the province of Valencia, Spain, during the year 2003. PATIENTS AND METHODS: The Services of Gastroenterology of eight acute-care reference hospitals in the province of Valencia, Spain, covering 1,774,736 inhabitants over 14 years of age, participated in a prospective study. All newly diagnosed patients with AIH between January 1, 2003 and December 31, 2003 were eligible. The diagnosis was based on criteria of the International Autoimmune Hepatitis Group revised in 1999. RESULTS: There were 19 new cases of AIH, 18 females and 1 male [mean (SD) age of 54.3 (11.2) years, range 23-73]. Incidence peaked in the 45-54 year age group. Eighteen cases were classified as AIH type 1 and one case as AIH type 2. The incidence rate of AIH for the year 2003 in people older than 14 years of age was 1.07 new cases per 100,000 inhabitants, with 1.96 cases per 100,000 inhabitants in females and 0.12 cases per 100,000 inhabitants in males. CONCLUSIONS: The 2003 annual incidence of AIH in Valencia, Spain, was similar to that reported in other European countries. AIH occurred more frequently in women and in the 45-54 year age group, type 1 being the most common. PMID- 20163034 TI - Expression of claudin-4 and beta-catenin in gastric premalignant lesions. AB - BACKGROUND AND STUDY AIMS: Abnormal expression of claudin-4 and beta-catenin play a role in carcinogenesis. The purpose of the present study was to examine claudin 4 and beta-catenin expression in normal and precancerous gastric mucosa. PATIENTS AND METHODS: Endoscopic biopsy specimens [normal gastric mucosa (n = 22), intestinal metaplasia (n = 24), dysplasia (n = 18), Helicobacter pylori (H. pylori)-associated chronic gastritis (n = 32) and remnant gastric mucosa (n = 18)] obtained from different 114 patients were examined by immunohistochemistry. RESULTS: Claudin-4 expression was present in 94.4% of dysplasia, 87.5% of intestinal metaplasia, 62.5% H. pylori-associated chronic gastritis, and 88.9% remnant gastric mucosa but only 18.2% of normal gastric mucosa biopsies. Decreased expression of beta-catenin was present in 27.8% of dysplasia, 8.3% of intestinal metaplasia, 15.6% of H. pylori-associated chronic gastritis, and 22.2% of remnant gastric mucosa biopsies, but was not present in normal gastric mucosa. When compared with normal gastric mucosa, there was a significant difference in claudin-4 expression in all groups (P < 0.05), but a significant difference was detected in dysplasia and remnant gastric mucosa for beta-catenin (P < 0.05). CONCLUSIONS: Our results suggest that claudin-4 expression is upregulated in premalignant gastric alterations. PMID- 20163035 TI - Sexually transmitted diseases and anorectum. AB - Sexually transmitted diseases (STD) are a major public health problem because their incidence is increasing worldwide despite prevention campaigns and because they raise the risk of HIV infection. Anorectal localisations of STD are common among men who have sex with men (MSM) but can also be seen among heterosexuals (men or women). Transmission of such infections is due to anal sex or to other sexual behaviours like "fisting". Although some pathogens (like Human Papillomavirus-HPV) are common in gastroenterologist/proctologist consultations, others are not so well-known. Furthermore during the last years, sexual risky behaviours have led to resurgence of old affections (like syphilis) or to emergence of unknown diseases (like lymphogranuloma venereum) in our countries. This presentation tends to focus on clinical manifestation, diagnosis and treatment of different STD: HPV, Herpes Simplex Virus, Neisseria gonorrhoeae, Chlamydia trachomatis (in particularly lymphogranuloma venereum) and Treponema pallidum. PMID- 20163036 TI - Virological tools for optimal management of chronic hepatitis C. AB - Serological and virological tests are useful in management of HCV patients, and include anti-HCV antibody assays, measurement of HCV RNA and HCV genotyping. They are used to diagnose infection, initiate treatment and assess the virological response to antiviral therapy. Monitoring of viral kinetics during the early phases of antiviral treatment is crucial in making treatment decisions concerning arrest of treatment and optimization of its duration. A 2-log drop in viral load at week 12 (early virological response) has good negative predictive value when assessing the sustained virological response (SVR), as most patients without a 2 log drop in viral load at week 12 will not attain a SVR. In contrast, undetectable HCV RNA at week 4 (rapid virological response) has good positive predictive value, as patients with undetectable HCV RNA at week 4 have high probability of reaching a SVR. Recent data suggest that some rapid responders can be treated for shorter periods than usually recommended without compromising their chance of a sustained response. On the other hand, slow virological responders infected with genotype 1 should be treated longer to increase the probability of viral eradication. Future studies should focus on identification of the earliest criterion which is both highly sensitive and highly specific in order to predict early SVR and nonresponse, as well as to avoid useless treatment prolongation. PMID- 20163037 TI - Usefulness of histopathological markers in diagnosing Barrett's intraepithelial neoplasia (dysplasia). AB - The incidence of oesophageal adenocarcinoma has significantly increased in Europe over the last 30 years. The progression from normal mucosa to adenocarcinoma has been associated with genetic and morphological traits regrouped under the term "intraepithelial neoplasia" (IEN) according to the Vienna classification. The early detection of such lesions represents the first step in the identification of high-risk patients. The morphological criteria of IEN are the gold standard to identify such patients. Firstly described by Riddell et al in 1983, IEN is based on morphological criteria including both cytological and architectural alterations and is classified into different stages of severity. However, large studies have clearly demonstrated the lack of reproducibility, with large inter individual discrepancies for both discrete and severe lesions. Discrepancies between high grade IEN and adenocarcinoma can be minimized by using the Vienna classification, which groups both of these lesions under the "stage IV". Discrepancies between low-grade IEN and uncertain lesions remain too important. Erroneous and overstated diagnosis of low grade IEN induces an unnecessary follow up of patients with obvious psychological and economic consequences. Recent studies have demonstrated that the reading of the slides by 2 to 3 gastrointestinal (GI) pathologists significantly decreases interpretation mistakes. Because of these interpretation problems, scientists have looked for non-morphological criteria to confirm the pre-cancerous state. The current PubMed literature proposes many putative biomarkers. However, none of these has been correctly validated in large prospective case-control studies, which hampers their use in clinical routine. DNA quantification by flux cytometry and morphometry represent alternative methods of documenting IEN but these techniques are complex and expensive. The use of the proliferation marker Ki67 needs deep sampling with correct orientation and standardized cell counting. P504 S has been studied in Barrett's disease and might be a novel tool. The only promising tool thus far is the overexpression of p53 as shown in prospective studies demonstrating a nice correlation with clinical evolution and is easy to use in clinical routine. PMID- 20163038 TI - Hemostasis in patients with liver disease. AB - In patients with liver disease alterations in the hemostatic system frequently occur. Although it was generally believed that these changes result in a bleeding tendency, laboratory models and clinical data have shown evidence for a rebalanced hemostasis in liver disease, as a result of a concomitant decrease in both pro- and antihemostatic systems. The rebalanced system presumably has much narrower margins as compared to healthy individuals and therefore can more easily turn to either a hypo- or hypercoagulable state. Bleeding does occur in patients with liver disease but this is frequently related to non-hematological factors, for example bleeding from ruptured esophageal varices. Further clinical data supporting the concept of rebalanced hemostasis include the lack of major blood loss in a great proportion of patients during liver transplantation and the fact that patients with liver disease are not fully protected from thromboembolic complications including venous thrombosis and thrombosis of the hepatic vessels. It is still common practice to prophylactically treat patients with liver disease prior to invasive procedures to prevent bleeding. Because of a lack of data supporting the effectiveness of this management and the proven side-effects of transfusion of blood products, we believe transfusion of blood products can and should be restricted. The most important thrombotic problem after liver transplantation is hepatic artery thrombosis, a potentially devastating complication. Since the bleeding tendency in patients with liver disease may not be primarily caused by a deranged hemostatic system, the restricted use of anticoagulant drugs in the post-transplant setting should be reconsidered. PMID- 20163039 TI - Anal transitional zone adenocarcinoma following restorative proctocolectomy for ulcerative colitis: case report and review of literature. AB - Conservative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become the intervention of choice for severe ulcerative colitis (UC) requiring surgery. Sporadically, the occurrence of carcinoma arising in or near the ileo-anal pouch after IPAA for UC has been reported. This issue is of utmost importance as an endoscopic follow-up is mandatory also after the operation. The present paper reports a case of cancer which developed four years after proctocolectomy with IPAA in a young man suffering from UC. Moreover, the authors provide update (PubMed research) by literature review on this issue. PMID- 20163040 TI - Lemierre's syndrome secondary to Fusobacterium necrophorum infection, a rare cause of hepatic abscess. AB - An 18-year-old male was admitted to the Accident & Emergency department with complaints of abdominal pain, vomiting and diarrhoea. He was clinically jaundiced and further CT scan suggested liver abscess. Later on blood cultures showed gram negative bacilli and a further liver aspirate culture confirmed the presence of the rare Fusobacterium necrophorum. A diagnosis of hepatic abscess secondary to Lemierre's syndrome was made and patient was treated with appropriate antibiotics. Lemierre's syndrome, although a rare condition, may be associated with serious life-threatening complications. Early recognition and treatment is essential in successfully treating this rare condition. A review of Lemierre's syndrome is presented. We recommend clinicians to be aware of this condition (Lemierre's Syndrome) especially when dealing with young patients with sore throat and jaundice. It is important for primary care physicians to be aware of this condition as they are discouraged from prescribing antibiotics for young patients with sore throat. Although it is a rare condition, it is associated with severe life threatening complication like liver abscesses. PMID- 20163041 TI - Diagnosis and surgical management of abdominal cocoon: results from 12 cases. AB - This study was designed to describe the characteristics, diagnostic and therapeutic methods of abdominal cocoon. Twelve patients with abdominal cocoon were surgically treated. The clinical findings from these patients were analyzed. All patients presented with acute complete intestinal obstruction, and 10 had a previous history of abdominal mass. In nine patients, the whole or part of the small intestines were covered by an ash gray, dense and tough fibrous membrane. The capsule was surgically excised, and the adhesion was released. Partial resection of the small intestines was performed. In the other three patients, the small intestines were only partially covered by a membrane, and there was an extensive adhesion of intestinal tract, forming a large mass which could not be relieved by surgical lysis. Intestinal tube was put in, and fistulation procedures were performed. All patients recovered fully after the surgery. CONCLUSIONS: There are four types of surgical findings in abdominal cocoon. The most common type is that the small intestines are fully covered by a thick white membrane, causing intestinal obstruction. Surgical excision of the membrane and the release of adhesion is the treatment of choice. PMID- 20163042 TI - Tubulovillous adenoma in the common bile duct causing obstructive jaundice. AB - Villous adenomas are benign epithelial lesions with a malignant potential which can occur at any site in the gastrointestinal tract, usually in the rectum and colon, less frequently in the small bowel and very rarely in the biliary tract. Villous adenomas of the extrahepatic bile ducts are exceptional and only a few cases have been reported. Common bile duct (CBD) adenomas often present in a fashion similar to their malignant counterparts, and adenocarcinoma arising from a villous adenoma of the ampullary biliary epithelium is also extremely rare. We present here a tubulovillous adenoma, arising in the common bile duct, as a cause of obstructive jaundice, and discuss the characteristics of these lesions. PMID- 20163043 TI - Acute abdomen due to intestinal angioedema induced by ACE inhibitors: not so rare? AB - During the last 5 years we identified 7 patients with a history of episodic acute abdominal pain and subobstruction due to intestinal angioedema secondary to the use of Angiotensin Converting Enzyme (ACE) inhibitors. These cases were all diagnosed in one gastroenterology department. This is thereby the largest single centre case series of ACE inhibitor-induced angioedema that has been published until now. Our findings suggest that this syndrome is far more frequent than international literature would let us believe. We also describe one of the first male cases diagnosed with this entity for which there is a significant female predominance. In the presence of an appropriate history and suggestive findings on CT scan, this diagnosis can relatively easily be made if one is sufficiently intent on it. An appropriate diagnosis can save these patients a lot of unnecessary diagnostic procedures and discomfort. PMID- 20163044 TI - Giant small intestine gastrointestinal stromal tumor with gastrointestinal bleeding. AB - Small intestine stromal tumors are relatively rare and cause subtle clinical signs and symptoms. Their diagnosis is often delayed until complications develop. Even if complications occur, an exact preoperative diagnosis may be very difficult. Surgery remains the mainstay of treatment, and other treatment modalities are limited. We present herein a patient with a giant gastrointestinal tumor who presented with gastrointestinal bleeding. Complete resection was performed despite the large tumor size (23 x 20 x 8 cm) and the patient was free of signs and symptoms during the 4-month follow-up. PMID- 20163045 TI - Papillary serous cystadenocarcinoma of the stomach, peritoneum and ovary. PMID- 20163046 TI - Outcome of septorhinoplasty: a comparison of patient and surgeon views. AB - OBJECTIVE: The aim of septo-rhinoplasty and the outcome were evaluated by the patient and the surgeon. The assessment focused on six well-defined characteristics of the nose: profile, width of the osteocartilaginous dorsum, symmetry, nasal tip, nostrils and nasal patency. Patient and surgeon assessments were compared. MATERIALS AND METHODS: Both patient and surgeon opinions were obtained using a self-designed questionnaire covering the aim of the surgery, the most important positive and negative post-operative results, a general rating of the postoperative result and a rating of the pre-operative information given by the surgeon. We compared patient and surgeon views about the late (between 6 and 18 months) post-operative result of septorhinoplasty using Kappa statistics. RESULTS: Sixty-nine patients were studied; 44 responded. The match between patient and surgeon views was closest in respect of the pre-operative aims and negative post-operative results. Patient and surgeon opinions differed most in terms of why a result was positive: nasal width was a more important issue for patients, and nasal symmetry was more important to the surgeon. Nasal patency and profile were equally important to both. The general rating on a visual analogue scale was a mean of 7.05 out of 10. The quality of the pre-operative information was found to be good by most patients. CONCLUSIONS: Using a self-designed questionnaire for septorhinoplasty, we mainly found significant differences between patient and surgeon opinions in the post-operative evaluation of why results of the surgery are positively appreciated. PMID- 20163047 TI - Diagnosis of isolated sphenoid lesions. AB - Isolated lesions of the sphenoid sinus are rare, and diagnosis is difficult because of the non-specific symptoms and clinical signs. The pathology of these lesions can be divided into three groups: inflammatory lesions, tumoural lesions, and a small group of so-called miscellaneous lesions. In a retrospective study, we evaluated the diagnosis and underlying pathology of 49 consecutive isolated sphenoid lesions all subjected to diagnostic and/or therapeutic endoscopic sinus surgery. The diagnosis of isolated sphenoid lesions based on clinical history and clinical examination, including nasal endoscopy, was not reliable because of the non-specific symptoms and clinical signs. A definitive diagnosis could be made only by radiological imaging and/or surgical exploration. The largest group of patients suffered from inflammatory lesions (29 patients), followed by tumoural lesions in 17 patients. Two patients had a sphenoidal cerebrospinal fluid leak, and one patient had a cholesterol granuloma. The outcome for patients who underwent a therapeutic endoscopic surgical procedure was favorable in 22% and perfect in 67%. There were no complications during or after endoscopic surgery. PMID- 20163048 TI - Is planned surgery important in sinonasal inverted papilloma? AB - OBJECTIVE: To evaluate which clinical characteristics of inverted papilloma (IP) can result easily in misdiagnosis by clinicians and to determine the recurrence rate of inverted papilloma depending on diagnosis confirmation pre-operatively, intra-operatively or post-operatively. PATIENTS AND METHODS: Fifty-one patients were treated for IP and 47 patients attended regular post-operative follow-up appointments for at least one year (mean: 54 months). RESULTS: The patients were assigned to 3 groups: group Ia, in which IP was not confirmed until the post operative pathology findings; group Ib, in which IP was confirmed during the operation; and group II, in which IP was confirmed before the operation. There were nineteen (37%) patients in group Ia, nine patients (18%) in group Ib and twenty-three patients (45%) in group II. The recurrence rates for groups Ia, Ib and II were 33%, 11% and 5% respectively. CONCLUSIONS: The initial presentation of bilateral sinonasal disease can easily lead the doctor into the misdiagnosis of IP. Bony erosion, remodelling, and a widening of the natural orifice of the sinuses on a CT scan are useful signs indicating IP. The correct diagnosis prior to surgery is a determinant of outcome. The use of frozen sections should, however, improve outcome as well. In this study we highlight the high prevalence and relatively low control rate of misdiagnosed IP (pathology undetermined pre operatively) and hope to remind clinicians that early recognition of the tumour is most beneficial to patients. PMID- 20163049 TI - Magnetic resonance imaging of cholesteatoma: an update. AB - OBJECTIVE: To report on the value and limitations of new MRI techniques in pre- and post-operative MRI of cholesteatoma. The current value of magnetic resonance imaging (MRI) in diagnosing congenital, acquired, and post-operative recurrent or residual cholesteatoma is described. METHODOLOGY AND RESULTS: High resolution computed tomography (HRCT) is still considered the imaging modality of choice for detecting acquired or congenital middle ear cholesteatoma. However, MRI may provide additional information on the delineation and extension of cholesteatoma and on potential complications. Detecting post-operative residual or recurrent cholesteatoma with HRCT was shown to be inaccurate due to the technique's low sensitivity and specificity. CONCLUSIONS: Recently, improvements in MRI techniques have led to a more accurate diagnoses of cholesteatoma using delayed contrast enhanced T1-weighted imaging and diffusion-weighted imaging. PMID- 20163050 TI - Tinnitus and otosclerosis. AB - OBJECTIVE: To establish the origin of tinnitus in patients with otosclerosis. METHODOLOGY: We performed a literature review to identify the characteristics of tinnitus in the general population and among patients with otosclerosis. RESULTS: Characteristics of tinnitus among patients with otosclerosis differ from those among the general population, suggesting mechanisms other than those implicated in presbycusis. Considerable improvements in the prevalence of tinnitus following corrective surgery demonstrate the limited contribution of diffuse labyrinth lesions. Middle ear and possibly secondary inner ear dysfunction produced by stapes blockage appear to be major etiopathogenic factors in the development of tinnitus in patients with otosclerosis. CONCLUSION: The conductive hearing deprivation produced by otosclerosis is associated with limited and reversible modifications in the central auditory pathway that are linked to tinnitus. PMID- 20163051 TI - Uvulopalatopharyngoplasty with tonsillectomy in the treatment of severe OSAS. AB - OBJECTIVE: To establish the efficacy of uvulopalatopharyngoplasty with tonsillectomy for treating selected patients with severe obstructive sleep apnea syndrome. METHODOLOGY: Retrospective study of patients who underwent clinical/instrumental evaluation and surgical treatment. SETTING: University ENT division with a tertiary snoring referral center. PARTICIPANTS: Twenty-two patients with normal body mass index affected by severe obstructive sleep apnea syndrome. MAIN OUTCOME MEASURES: Pre- and post-operative cardiopulmonary monitoring during sleep, daytime sleepiness evaluation, post-treatment complication recording. RESULTS: Complete response to therapy was obtained in 78% of patients. Four patients had relief of symptoms but retained apnea/hypopnea index scores greater than 5. CONCLUSIONS: Uvulopalatopharyngoplasty associated with tonsillectomy can beemployed safely to treat patients with normal body mass index who suffer from severe obstructive sleep apnea. PMID- 20163052 TI - Sleep apnoea/hypopnoea syndrome: combination therapy with the Pillar palatal implant technique and continuous positive airway pressure (CPAP). A preliminary report. AB - A preliminary report. The objective of this study was to evaluate the possibility of reducing CPAP pressure levels and improving patient adherence to CPAP therapy by stiffening the soft palate tissue with a Pillar palatal implant. Many patients have difficulty complying with CPAP therapy if high levels of airway pressure are necessary for their therapy to be successful. Twenty-one patients (16 males and 5 females) with moderate to severe OSAHS treated with CPAP therapy underwent Pillar palatal treatment in an office-based procedure. The mean age was 49.6 +/- 11.2 years, mean baseline body mass index (BMI) was 31.4 +/- 3.2 Kg/m2. At 3 months follow-up a significant reduction of CPAP pressure levels was found. Mean CPAP pressure levels before and after Pillar application were 11.2 +/- 1.69 cm H2O vs. 9.3 +/- 2.5 cm H2O respectively (p < 0.001). The Pillar system is intended for use in stiffening the soft palate tissue, so this minimally invasive procedure, which was introduced to clinical practice as a treatment for the palatal component of OSAHS, could make it possible to reduce CPAP pressures and improve patient adherence to CPAP therapy. The preliminary results of this combined therapeutic approach indicate the safety and efficacy of the treatment of OSAHS. Further studies are needed to evaluate the long-term results. PMID- 20163053 TI - Head and neck reconstruction with dorsoradial forearm free flap: a preliminary clinical study. AB - Head and neck reconstruction with dorsoradial forearm free flap: a preliminary clinical study. PROBLEMS/OBJECTIVES: The most common criticism of the radial forearm free flap (RFFF) is donor site morbidity. Delayed or defected integration of split thickness skin graft (STSG) is the most commonly encountered complication. Defective healing or excessively thin skin coverage of important forearm structures, such as the median nerve and ulnar artery-nerve bundle, places these structures at increased risk of injury. The current study aims to modify the RFFF to utilize a dorsoradial skin island in order to protect the volar tissue aspect of these structures. METHODOLOGY: Seven patients were included in the study between 2005 and 2008. All patients had oncologic resections in the oral cavity necessitating free tissue transfer. The main variation from the standard RFFF technique is that the medial incision was placed 1 cm lateral to the palmaris longus tendon. The dissection was extended laterally and dorsally, depending on the necessary flap size. The donor side defect was covered with a thigh STSG. RESULTS: None of the patients had partial or complete flap necrosis. This surgical modification provided tissue coverage along the course of the median nerve and ulnar neurovascular bundle. CONCLUSIONS: Dorsoradial forearm free flap is a feasible technique that allows preservation of tissue coverage on the volar surface of the forearm. PMID- 20163054 TI - Unusual presentation of adenoid cystic carcinoma of the maxillary antrum. AB - Unusual presentation of adenoid cystic carcinoma of the maxillary antrum. Adenoid cystic carcinoma (ACC) is a rare tumour which affects mainly the major and accessory salivary glands. It is an aggressive neoplasm characterized by early neural invasion and a high incidence of local recurrence and distant metastases, which may develop years after the initial resection. Surgery followed by radiotherapy seems to be the best treatment. Based on a well-illustrated case of extensive maxillary ACC involving the palate, orbit floor, and pterygo-palatine fossa, we discuss the prognosis and the importance of an early diagnosis of ACC. PMID- 20163055 TI - An unusual tumour of the cerebellopontine angle. AB - An unusual tumour of the cerebellopontine angle. OBJECTIVE: To report an extremely rare case of lipoma of the cerebellopontine angle (CPA). CASE REPORT: A 33-year-old woman presented with vertigo and tinnitus in the left ear. Her physical examination was unremarkable. Audiometric evaluation was normal in both ears. T1-weighted magnetic resonance imaging (MRI) without fat signal suppression revealed a hyperintense lesion of the left CPA. Based on the neuroimaging findings, the diagnosis was left CPA lipoma. The patient was managed conservatively. After 48 months, follow-up MRI revealed no further growth of the lesion and the patient was symptom free. CONCLUSION: Lipomas of the CPA should be considered in the differential diagnosis of vertigo and tinnitus. Accurate diagnosis by MRI is critical. PMID- 20163056 TI - Myofibroma of the external auditory canal: report of an adult case. AB - Myofibroma of the external auditory canal: report of an adult case. OBJECTIVE: Myofibroma is a benign fibrous proliferative disease generally reported to occur in neonates and children. Similar lesions have been reported in adults, but solitary tumours affecting the external auditory canal are extremely rare. Only one such case has been reported in the literature. CASE REPORT: The case of solitary myofibroma occurring in the external auditory canal of a 42-year-old woman is presented. The diagnosis of myofibromatosis was made on the basis of its histological appearance and corroborated by immunohistochemical staining. CONCLUSIONS: Clinicians and pathologists must be aware that myofibromatosis may occur in adults at extremely rare locations. Myofibroma should be included in the differential diagnosis of fibrous lesions in the external auditory canal. PMID- 20163057 TI - Traumatic nasal abscess concomitant with sinusitis: a case report. AB - PROBLEMS/OBJECTIVES: Nasal septal abscesses are usually formed following nasal trauma or haematoma. A nasal septal abscess is defined as a collection of purulent material (pus) between the cartilage or bony septum and the mucoperichondrium or mucoperiosteum. Sinusitis and periorbital cellulites have been reported among the etiological factors and the complications. METHODOLOGY: A case of posttraumatic nasal septal abscess is reported in a 35-year-old male patient. RESULTS: Frontal, ethmoid, and sphenoid sinusitis, as well as periorbital cellulites were seen to accompany the septal abscess. The abscess was surgically drained and intravenous antibiotherapy was instituted. CONCLUSION: Nasal trauma patients should be carefully assessed for posttraumatic haematoma and abscess formation, so that possible complications can be avoided by taking appropriate therapeutic measures. PMID- 20163058 TI - A historical vignette (16). Following in the footsteps of Vesalius around Brussels. AB - Following in the footsteps of Vesalius around Brussels. Every physician is indebted to Vesalius! Andreas Vesalius (1514-1564) lived in Brussels for about thirty years in all. First from birth until the age of sixteen years (1514-1530), and later as an adult (1544-1559). These two periods of time in Brussels can be described by walking around some areas of the city. PMID- 20163059 TI - Gene expression profile of human skeletal muscle and adipose tissue of Chinese Han patients with type 2 diabetes mellitus. AB - OBJECTIVE: To study the differential patterns of gene expression in skeletal muscle and adipose tissue between type 2 diabetes mellitus (T2DM) patients and healthy subjects using DNA microarray analysis. METHODS: T2DM patiens were divided into female group, young male group and old male group. DNA microarray analysis and quantitative real-time PCR were carried out to analyze the relation between gene expressions and T2DM. RESULTS: The mRNA expression of 298, 578, and 350 genes was changed in the skeletal muscle of diabetes mellitus patients compared with control subjects. The 1320, 1143, and 2847 genes were modified in adipose tissue of the three groups. Among the genes surveyed, the change of 25 and 39 gene transcripts in skeletal muscle and adipose tissue was > or = 2 folds. These differentially expressed genes were classified into 15 categories according to their functions. CONCLUSION: New genes are found and T2DM can be prevented or cured. PMID- 20163060 TI - Correlation of serum leptin level with bone mineral density and bone turnover markers in Chinese adolescent dancers. AB - OBJECTIVE: To investigate plasma leptin concentrations in adolescent female dancers and to determine whether leptin has some effects on their bone mineral density (BMD) and bone turnover markers. METHODS: Sixty dancers aged 15-17 years and 77 healthy controls were enrolled in the study. Bone mineral density (BMD) and body composition were detected by dual energy X-ray absorptiometry. Serum leptin concentrations were measured by radioimmunoassay (RIA). Two bone turnover markers, bone-specific alkaline phosphatase (BAP) and tartrate-resistant acid phosphatase(TRACP), were determined by ELISA. RESULTS: The dancers had a lower fat mass and a lower leptin level than the controls, while they had a relatively higher BMD of the total body and legs after adjustment for BMI and age. The levels of bone resorption and formation of markers were higher in the dancers than in the controls. Leptin was positively correlated with BMI, body weight, fat mass, and percentage of body fat. In dancers, Leptin was positively correlated with the BMD of the total body and the left leg. However, after adjustment for BMI, no correlation of serum leptin concentrations with BMD values was found in either dancers or controls. Nor correlation was found between leptin and bone turnover markers after adjustment for BMI. CONCLUSION: The leptin profile is different between the controls and the dancers with a lower BMI and a lower fat mass. Circulating plasma leptin level depends on BMI and is not a direct determinant of BMD in Chinese adolescent dancers. PMID- 20163061 TI - Comparison of Hsps expression after radio-frequency field exposure in three human glioma cell lines. AB - OBJECTIVE: To investigate and compare the effect of radio-frequency (RF) field exposure on expression of heat shock proteins (Hsps) in three human glioma cell lines (MO54, A172, and T98). METHODS: Cells were exposed to sham or 1950 MHz continuous-wave for 1 h. Specific absorption rates (SARs) were 1 and 10 W/kg. Localization and expression of Hsp27 and phosphorylated Hsp27 ((78) Ser) (p Hsp27) were examined by immunocytochemistry. Expression levels of Hsp27, p-Hs27, and Hsp70 were determined by Western blotting. RESULTS: The Hsp27 was primarily located within the cytoplasm, p-Hsp27 in both cytoplasm and nuclei of MO54, A172, and T98 cells. RF field exposure did not affect the distribution or expression of Hsp27. In addition, Western blotting showed no significant differences in protein expression of Hsp27 or Hsp70 between sham- and RF field-exposed cells at a SAR of 1 W/kg and 10 W/kg for 1 h in three cells lines. Exposure to RF field at a SAR of 10 W/kg for 1 h slightly decreased the protein level of phosphorylated Hsp27 in MO54 cells. CONCLUSION: The 1950 MHz RF field has only little or no apparent effect on Hsp70 and Hsp27 expression in MO54, A172, and T98 cells. PMID- 20163062 TI - Inhibitory effect of estrogens, phytoestrogens, and caloric restriction on oxidative stress and hepato-toxicity in aged rats. AB - OBJECTIVE: To investigate the protective effect of 17beta-estradiol (E2), peganum harmala extract (PHE) administration and calorie restriction (CR) treatment (60%) on oxidative stress and hepato-toxicity in aged rats. METHODS: Eighteen months old animals that were treated at the age of 12 months were divided into 4 groups: normal control group with free access to food, E2 treatment group, PHE treatment group and CR treatment group of the food given to control group. Six male rats at the age of 4 months were used as a reference group. RESULTS: Aging significantly decreased superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), and increased lactate deshydrogenase (LDH), gamma-glytamyl transferase (GGT), phosphatase alkalines (PAL), aspartate and lactate transaminase (AST and ALT) activities in the liver. Aging also induced an increased lipid peroxidation level, histological changes and a decreased E2 level. However, treatment with E2, PHE, and CR increased 17beta-estradiol, and decreased hepatic dysfunction parameters and lipid peroxidation as well as histological changes in the liver of aged rats. CONCLUSION: The antioxidant and hepatoprotective activity of PHE and CR is possibly attributed to its ability to increase E2 level, which as an antioxidant, acts as a scavenger of ROS. Further studies on the pharmaceutical functions of E2 in males may contribute to its clinical application. PMID- 20163063 TI - Immunological effect of subunit influenza vaccine entrapped by liposomes. AB - OBJECTIVE: To elevate the immunological effect of subunit influenza vaccine in infants and aged people (over 60) using liposomal adjuvant in the context of its relatively low immunity and to investigate the relation between vaccine antigens and liposomal characteristics. METHODS: Several formulations of liposomal subunit influenza vaccine were prepared. Their relevant characteristics were investigated to optimize the preparation method. Antisera obtained from immunizinged mice were used to evaluate the antibody titers of various samples by HI and ELISA. RESULTS: Liposomal trivalent influenza vaccine prepared by film evaporation in combinedation with freeze-drying significantly increased its immunological effect in SPF Balb/c mice. Liposomal vaccine stimulated the antibody titer of H3N2, H1N1, and B much stronger than conventional influenza vaccine. As a result, liposomal vaccine (mean size: 4.5-5.5 microm, entrapment efficiency: 30%-40%) significantly increased the immunological effect of subunit influenza vaccine. CONCLUSION: The immune effect of liposomal vaccine depends on different antigens, and enhanced immunity is not positively correlated with the mean size of liposome or its entrapped efficiency. PMID- 20163064 TI - Analysis of translocation of the CagA protein and induction of a scattering phenotype in AGS cells infected with Helicobacter pylori. AB - OBJECTIVE: To investigate whether the presence of structured CagA proteins in Western- and Eastern-type Helicobacter pylori (H. pylori) induces different incidences of gastric diseases. METHODS: CagA and phosphorylated CagA were expressed in AGS gastric epithelial cells infected with wild type and mutant strains. The ability of individual CagA was determined by immunoprecipitation and Western blot assay. Morphological changes of these cells were observed under microscope to evaluate the appearance of elongation hummingbird phenotype. RESULTS: The sizes of CagA proteins in different strains were different, and no phosphorylated CagA proteins were detected in wild-type strains. Meanwhile, the kinetics of CagA status in AGS infected with H. pylori was detected. The molecular weight of phosphorylated CagA with the same size of CagA proteins in H. pylori was different in infections with different wild-type strains. CagA and phosphorylated CagA increased in a time-dependent manner after the infection. The hummingbird phenotype with H. pylori for time-course was observed under microscope. Instead of HPK5 strain, the wild-type 26695 strain induced hummingbird phenotype in a time-dependent manner. CONCLUSION: Translocation and phosphorylation of CagA are necessary, but not sufficient, for the induction of hummingbird phenotype in AGS cells. PMID- 20163065 TI - Antibiotic resistance of probiotic strains of lactic acid bacteria isolated from marketed foods and drugs. AB - OBJECTIVE: To identify the antimicrobial resistance of commercial lactic acid bacteria present in microbial foods and drug additives by analyzing their isolated strains used for fermentation and probiotics. METHODS: Antimicrobial susceptibility of 41 screened isolates was tested with disc diffusion and E-test methods after species-level identification. Resistant strains were selected and examined for the presence of resistance genes by PCR. RESULTS: Distribution of resistance was found in different species. All isolates were susceptible to chloramphenicol, tetracycline, ampicillin, amoxicillin/clavulanic acid, cephalothin, and imipenem. In addition, isolates resistant to vancomycin, rifampicin, streptomycin, bacitracin, and erythromycin were detected, although the incidence of resistance to these antibiotics was relatively low. In contrast, most strains were resistant to ciprofloxacin, amikacin, trimethoprim/sulphamethoxazole, and gentamycin. The genes msrC, vanX, and dfrA were detected in strains of Enterococcus faecium, Lactobacillus plantarum, Streptococcus thermophilus, and Lactococcus lactis. CONCLUSION: Antibiotic resistance is present in different species of probiotic strains, which poses a threat to food safety. Evaluation of the safety of lactic acid bacteria for human consumption should be guided by established criteria, guidelines and regulations. PMID- 20163066 TI - Comparison of changes in body composition during puberty development of obese and normal-weight children in China. AB - OBJECTIVE: To compare the changes in body composition, including fat mass index (FMI) and fat free mass index (FFMI) during puberty development of obese and normal-weight children in China, and to explore the effect of age and gender on body composition. METHODS: A total of 356 children at the age of 7-15 years were enrolled in this study. Body composition of 10 normal-weight and obese children in each age group was measured by dual-energy x-ray absorptiometry (DEXA). FFMI and FMI were calculated according to the following formula: FFMI (kg x m(-2)) = FFM(kg) / height2 (m2) and FMI (kg x m(-2)) = FM (kg) / height2 (m2). RESULTS: The fat mass and fat free mass of obese children were significantly higher than those of normal-weight children (P < 0.05). The FMI and FFMI of obese children increased significantly with age and were higher than those of the same sex, gender, and age normal-weight children (P < 0.05). CONCLUSION: The levels of fat mass, fat free mass, FMI, and FFMI are different in obese and normal-weight children, and gender effects are significant in boys having higher levels of these indicators than in girls. FFMI and FMI can be used as monitoring indexes in weight control of obese children. PMID- 20163067 TI - Reporter gene assay for detection of shellfish toxins. AB - OBJECTIVE: To explore the potential reporter gene assay for the detection of sodium channel-specific toxins in shellfish as an alternative for screening harmful algal bloom (HAB) toxins, considering the fact that the existing methods including HPLC and bioassay are inappropriate for identifying HAB toxins which poses a serious problem on human health and shellfish industry. METHODS: A reporter plasmid pEGFP-c-fos containing c-fos promoter and EGFP was constructed and transfected into T24 cells using LipofectAMINE 2000. Positive transfectants were screened by G418 to produce a pEGFP-c-fos-T24 cell line. After addition of increasing neurotoxic shellfish poison (NSP) or GTX2,3, primary components of paralytic shellfish poison (PSP), changes in expression of EGFP in the cell line were observed under a laser scanning confocal microscope and quantified with Image-pro Plus software. RESULTS: Dose-dependent changes in the intensity of green fluorescence were observed for NSP in a range from 0 to 10 ng/mL and for GTX2,3 from 0 to 16 ng/mL. CONCLUSION: pEGFP-c-fos-T24 can be applied in detecting HAB toxins, and cell-based assay can be used as an alternative for screening sodium channel-specific HAB toxins. PMID- 20163068 TI - Lipid peroxidation and ultrastructural modifications in brain after perinatal exposure to lead and/or cadmium in rat pups. AB - OBJECTIVE: To assess lipid peroxidation and ultrastructural modifications in rat brains following perinatal exposure to lead (Pb) and/or cadmium (Cd). METHODS: Female rats were divided into four groups: control group, Pb (300 mg/L) group, Cd group (10 mg/L) and Pb+Cd (300 mg/L, 10 mg/L) group. The compounds were delivered in the drinking water throughout pregnancy and lactation. RESULTS: The levels of compounds in blood and brain of the Pb+Cd group were similar to those of other groups, but the effects of Pb+Cd on pups' body and brain weights were higher than on other compounds. Electron microscopy revealed that Pb and Cd had effects on mitochondrial swelling, disruption and cristae loss, Nissl body dissolution, degenerated organelles and vacuoles, cytomembrane disappearance, and nuclear chromoplasm concentration. The activity of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), acetylcholinesterase (AChE) was decreased, whereas the activity of maleic dialdehyde (MDA) was increased. CONCLUSION: Perinatal exposure to low doses of Pb and Cd can produce alterations in lipid peroxidation and ultrastructural modifications in rat brains, and exposure to both metals can result in greater damages. PMID- 20163069 TI - Evaluation of impact of major causes of death on life expectancy changes in China, 1990-2005. AB - OBJECTIVE: To evaluate the impact of major causes of death on changes of life expectancy in China. METHODS: Life expectancy was calculated by standard life table techniques using mortality data from the national censuses in 1990 and 2000 and the 1% National Population Sampling Surveys in 1995 and 2005. Mortality data about the major causes of death from VR-MOH were used as reference values to estimate their death proportions of the specific age groups by sex and regions, as well as all-cause mortality and age-specific mortality rates of major causes of death. Decomposition method was used to quantitatively evaluate the impact. RESULTS: Three key findings were identified in our study. First, China's health challenge was shifted from diseases related to living conditions to those related to behavior and lifestyle, with rural areas relatively lagged behind urban areas. Second, the impacts of cardiovascular diseases and neoplasm on the middle aged and elderly population were stressed. Third, compared to the urban population, the rural population tended to have increasing mortality of neoplasm and cardiovascular diseases, especially in adults at the age of 15-39 years. CONCLUSION: Further efforts should be made to reduce the incidence of neoplasm and cardiovascular diseases, especially in rural areas, by promoting healthy behavior and lifestyle and providing appropriate therapies for all patients in need. PMID- 20163070 TI - Perilipin gene 1237 T > C polymorphism is not associated with obesity risk in northern Chinese Han adults. AB - OBJECTIVE: To identify the association between PLIN 1237 polymorphism and obesity in Chinese Han adults. METHODS: A total of 994 adults (157 obese subjects, 322 overweight subjects, and 515 normal controls) were recruited from two rural communities. PLIN 1237 polymorphism was genotyped by polymerase chain reaction restriction-fragment-length-polymorphism (PCR-RFLP). Association between PLIN polymorphisms and obesity status was estimated by ordinal logistic regression. RESULTS: The three genotypes of PLIN 1237 were detected with a percentage of 54.3%, 37.1%, and 8.6% in TT, TC, and CC genotypes, respectively. For the PLIN 1237 polymorphism locus, the frequency of alleles T and C was 0.73 and 0.27, respectively. The PLIN 1237 polymorphisms were in Hardy-Weinberg equilibrium. PLIN 1237 polymorphism was not associated with obesity. The odds ratio for overweight or obesity for the CC+TC genotype was 0.8 (0.4, 1.4) in women (P = 0.4) and 0.6 (0.3, 1.3) in men (P = 0.2) after adjustment for age, education, household income and alcohol consumption, smoking, and physical activity. CONCLUSION: Chinese Han adults have a lower frequency of variant-allele C in PLIN 1237. PLIN 1237 T > C polymorphism is not significantly associated with obesity in northern Chinese adults. PMID- 20163071 TI - Percentage thickness increase and absolute difference from thinnest to describe thickness profile. PMID- 20163072 TI - Artisan phakic IOL for the correction of ametropia after deep anterior lamellar keratoplasty. PMID- 20163073 TI - LASIK for myopia and astigmatism using the SCHWIND AMARIS excimer laser: an international multicenter trial. AB - PURPOSE: To assess the efficacy, predictability, and safety of LASIK for the surgical correction of low to moderate myopia with astigmatism using the SCHWIND AMARIS excimer laser. METHODS: Six international study sites enrolled 358 eyes with a manifest refraction spherical equivalent (MRSE) from -0.50 to -7.38 diopters (D) (mean sphere: -3.13+/-1.58 D) with up to -5.00 D of astigmatism (mean: -0.69+/-0.67 D). All eyes underwent treatment with the nonwavefront-guided aspheric algorithm of the SCHWIND AMARIS excimer laser. All eyes were targeted for emmetropia. Refractive outcomes and corneal higher order aberrations were analyzed pre- and postoperatively. Visual quality was assessed using photopic and mesopic contrast sensitivity. Six-month postoperative outcomes are reported. RESULTS: At 6 months postoperative, the MRSE for all eyes was -0.21+/-0.20 D, and 96% (343/358) of eyes had MRSE within +/-0.50 D. Uncorrected visual acuity was 20/20 or better in 98% (351/358) of eyes, and no eyes lost 2 or more lines of best spectacle-corrected visual acuity. The total corneal higher order aberrations root-mean-square increased by 0.09 microm, spherical aberration increased by 0.08 microm, and coma increased by 0.04 microm postoperatively. Photopic and mesopic contrast sensitivity did not change 6 months postoperatively. CONCLUSIONS: Treatment of myopia with astigmatism using the SCHWIND AMARIS excimer laser is safe, efficacious, predictable, and maintains visual quality. PMID- 20163074 TI - Safety and effectiveness of thin-flap LASIK using a femtosecond laser and microkeratome in the correction of high myopia in Chinese patients. AB - PURPOSE: To establish safety and effectiveness of thin-flap LASIK using a femtosecond laser and microkeratome in correcting high myopia in Chinese patients. METHODS: Two hundred seventy-four eyes of 148 Chinese patients with high myopia whose spherical equivalent refraction (SE) ranged from -6.12 to 15.75 diopters (D) received thin-flap LASIK with the VISX S4 IR excimer laser system. Corneal flaps were created with a femtosecond laser (15-kHz IntraLase, 134 eyes of 76 patients, target flap thickness 100 microm) and Moria M2 microkeratome (90-microm head, 140 eyes of 72 patients, target flap thickness 110 microm). Clinical outcomes were assessed with uncorrected (UCVA) and best spectacle-corrected visual acuity (BSCVA), manifest refraction, wavefront aberrometry, Schirmer tests, and tear break-up time (TBUT) at 1 day, 1 week, and 1 and 3 months postoperatively. RESULTS: At 3 months, both groups showed comparable clinical outcomes in most parameters assessed, including the percent of postoperative UCVA better than or equal to preoperative BSCVA (P=.642), mean residual spherical equivalent refraction (P=.448), mean Schirmer test (P=.950), and mean TBUT (P=.867). Postoperative coma, trefoil, and spherical aberration were similar in both groups (P=.202, P=.898, and P=.890, respectively). Both groups had a similar percent of eyes with a change of SE of <1.00 D (P=.284). CONCLUSIONS: Thin-flap LASIK with a femtosecond laser and microkeratome are both safe and effective for the correction of high myopia in Chinese patients. Femtosecond laser shows similar predictability, stability, and induction of higher order aberrations to the microkeratome. PMID- 20163075 TI - Accuracy and reproducibility of artemis central flap thickness and visual outcomes of LASIK with the Carl Zeiss Meditec VisuMax femtosecond laser and MEL 80 excimer laser platforms. AB - PURPOSE: To quantify the accuracy and reproducibility of central flap thickness for flaps created with the VisuMax femtosecond laser system. METHODS: This was a prospective study of 24 eyes of 12 myopic LASIK patients. The VisuMax femtosecond laser was used to create flaps with an intended central flap thickness of 110 microm. Artemis 1 very high-frequency digital ultrasound scans were performed preoperatively and 3 months postoperatively. Central flap thickness was calculated as the addition of the preoperative epithelial thickness and the postoperative stromal component of the flap. Descriptive statistics (mean, standard deviation, minimum, maximum, and range) of central Reinstein Flap Thickness were calculated for all flaps. Central flap thickness accuracy was calculated as the difference between the mean and intended flap thickness. Reproducibility was evaluated as the flap thickness standard deviation between eyes. RESULTS: At 3 months, mean central Reinstein Flap Thickness was 112.3+/-7.9 microm (range: 102.6 to 132.9 microm). The accuracy was +2.3 microm and reproducibility was 7.9 microm. On average, the flap diameter was 0.47+/-0.21 mm greater than the intended flap diameter. CONCLUSIONS: The VisuMax femtosecond laser system was found to create flaps accurate to the intended thickness in the center with a low standard deviation, which will help reduce the risk of obtaining an excessively thick flap. PMID- 20163076 TI - Comparison of internal anterior chamber diameter imaging modalities: 35-MHz ultrasound biomicroscopy, Visante optical coherence tomography, and Pentacam. AB - PURPOSE: To compare the internal diameter of the anterior chamber among three different imaging modalities: 35-MHz ultrasound biomicroscopy (UBM), Visante optical coherence tomography (OCT), and Pentacam, and to compare the internal diameters with white-to-white (WTW) distance measured by Orbscan. METHODS: The internal horizontal anterior chamber diameter was measured in 20 normal eyes using 35-MHz UBM (Optikon), Visante OCT (Carl Zeiss Meditec), and Pentacam (Oculus Inc). The mean horizontal anterior chamber diameters were compared, and the correlations between each pair of two different methods were evaluated. Horizontal WTW distance was measured by Orbscan IIz (Bausch & Lomb-Orbtek Inc) and then correlated with the measurements of internal anterior chamber diameter. RESULTS: The mean horizontal anterior chamber diameter was 10.99+/-0.47 mm with UBM, 11.70+/-0.47 mm with OCT, and 11.86+/-0.45 mm with Pentacam. Ultrasound biomicroscopy measurements were significantly different than those of OCT and Pentacam (P<.001 for both). However, no significant difference was found between OCT and Pentacam (P=.19). Regarding the correlations between each pair of two different methods, UBM and OCT showed significant correlation (r=0.848, P<.001), but there was no significant correlation between OCT and Pentacam (r=0.403, P=.078), even though the mean values were similar. In the Bland-Altman plots, the range of agreement was 0.51 mm between OCT and UBM, and 0.99 mm between Pentacam and OCT. CONCLUSIONS: Although the internal anterior chamber diameters measured by 35-MHz UBM were significantly smaller than those measured by Visante OCT and Pentacam, the measurements of UBM and Visante OCT showed significant correlation and good agreement with each other. Pentacam showed poor correlation with other measurements. PMID- 20163077 TI - Central corneal thickness, anterior chamber depth, and pupil diameter measurements using Visante OCT, Orbscan, and Pentacam. AB - PURPOSE: To evaluate the agreement among three different optical methods in measuring anterior chamber depth (ACD), central corneal thickness (CCT), and pupil diameter. METHODS: One hundred eyes of 50 healthy patients (25 men, 25 women) were enrolled in the study. Mean patient age was 25 years (range: 21 to 32 years). Exclusion criteria were history of any intraocular or corneal surgery, contact lens wear, corneal anomalies, and spherical refraction >5.00 diopters (D) or cylindrical refraction >2.00 D. All measurements were done by the same operator under mesopic light conditions and repeated using three different optical methods: Visante optical coherence tomography (OCT) (Carl Zeiss Meditec), Orbscan (Bausch & Lomb), and Pentacam (Oculus Optikgerate GmbH). RESULTS: Mean CCT as measured by Visante OCT, Orbscan, and Pentacam was 529+/-30.5 microm, 554+/-32.7 microm, and 552+/-29.3 microm, respectively. Mean ACD values were 2.94+/-0.34 mm, 2.84+/-0.33 mm, and 2.98+/-0.33 mm, respectively. Mean pupil diameter measurements were 4.87+/-1.09 mm, 4.0+/-0.67 mm, and 3.05+/-0.59 mm, respectively. The Visante OCT measured CCT thinner and Orbscan measured ACD shallower than the other two methods. All three methods measured pupil diameters significantly different. CONCLUSIONS: This study found some statistically significant but clinically insignificant differences among the optical methods assessed. The differences are small and do not influence decisions for refractive surgery in clinical practice. PMID- 20163078 TI - Comparison of the Colvard, Procyon, and Neuroptics pupillometers for measuring pupil diameter under low ambient illumination. AB - PURPOSE: To compare three different pupillometers (Colvard, Procyon, and Neuroptics) for determining pupil diameter at 0.04 and 0.4 lux ambient illumination. METHODS: In 92 eyes of 46 healthy volunteers, pupil diameter was measured at 0.04 and 0.4 lux. After dark adaptation for 2 minutes, measurements were performed with each device by two examiners. Interobserver agreement, instrument agreement, and repeatability were analyzed. RESULTS: Mean pupil diameter was 6.63+/-0.68 mm, 6.24+/-1.01 mm, and 6.99+/-0.67 mm at 0.04 lux and 6.22+/-0.74, 4.64+/-1.04, and 6.73+/-0.72 mm at 0.4 lux with the Colvard, Procyon, and Neuroptics pupillometers, respectively. The interobserver disagreement ranged within narrower limits for the Colvard (0.04 lux: -1.0 to 0.5 mm; 0.4 lux: -0.75 to 1.0 mm) and Neuroptics (0.04 lux: -1.0 to 0.5 mm; 0.4 lux: 1.7 to 0.7 mm) than for the Procyon (0.04 lux: -0.74 to 1.14 mm; 0.4 lux -1.82 to 2.4 mm) under both light conditions. Instrument agreement ranged within narrower limits for the Colvard versus Neuroptics (0.04 lux: -1.3 to 0.75 mm; 0.4 lux: 1.55 to 1.40 mm) than for the Neuroptics versus Procyon (0.04 lux: -1.06 to 2.69 mm; 0.4 lux: 0.18 to 3.69 mm) or Colvard versus Procyon (0.04 lux: -0.63 to 2.60 mm; 0.4 lux: -0.32 to 3.13 mm) at both light levels. At 0.04 lux, repeatability showed no measurement difference outside +/-0.5 mm for the Colvard and Neuroptics; for the Procyon, 25% of consecutive measurements showed a difference >+/-0.5 mm. At 0.4 lux, 2.5% of consecutive measurements for the Colvard and 5% for the Neuroptics differed by >+/-0.5 mm; for the Procyon, 13% of measurements differed by more than this amount. CONCLUSIONS: Pupil diameters under both light conditions were largest with the Neuroptics pupillometer and smallest with the Procyon. The most "examiner independent" Procyon pupillometer performed poorly. The underestimation of the pupil diameter might have severe consequences for refractive surgery patients. The Neuroptics pupillometer showed a high interobserver agreement and repeatability and therefore high safety. PMID- 20163080 TI - Electrolyte-added one-pot synthesis for producing monodisperse, micrometer-sized silica particles up to 7 microm. AB - A facile one-pot synthesis to produce micrometer-sized silica particles with low polydispersity was examined in a semibatch process where an ethanol solution of tetraethyl orthosilicate (TEOS) was continuously supplied to another ethanol solution of water and ammonia containing an electrolyte of LiCl, NaCl, or KCl. Supply rates of the TEOS solution was ranged with the water and electrolyte concentrations, which indicated that the addition of KCl at a low water concentration was effective to increase size of silica particles in a micrometer range. Highly monodisperse silica particles with an average size of 6.6 microm were successfully produced at 3 mol/m(3) KCl and 5 kmol/m(3) water. The efficiency of KCl addition for producing the large particles is interpreted by the previously proposed nucleation and growth mechanism that expects rapid particle coagulation in early reaction stage for particles which have reduced surface potential by the adsorption of cations with a large ionic radius. It is confirmed from competitive growth reactions that the silica particle growth follows the reaction-limited mechanism even in the semibatch process. PMID- 20163079 TI - Topography-guided transepithelial surface ablation followed by corneal collagen cross-linking performed in a single combined procedure for the treatment of keratoconus and pellucid marginal degeneration. AB - PURPOSE: To evaluate a combination of topography-guided custom ablation and corneal collagen cross-linking (CXL) in a single procedure for the treatment of keratectasia. METHODS: Twelve eyes of 12 patients with keratectasia were treated with topography-guided custom ablation and CXL. Topography-guided custom ablation was performed using a transepithelial technique with the iVIS Suite 1 kHz flying spot excimer laser. Collagen cross-linking was performed immediately after topography-guided custom ablation, according to standard protocol. Postoperative follow-up examinations were performed at 1, 3, 6, and 12 months. Uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), refractive change, corneal topography, and pachymetry were analyzed pre- and postoperatively. RESULTS: Mean UCVA increased from 20/1000 preoperatively to 20/125 12 months postoperatively. Mean BSCVA increased from 20/57 to 20/35, with no loss of lines of visual acuity. Mean astigmatism was reduced from 5.40+/-2.13 diopters (D) to 2.70+/-1.44 D, and keratometric asymmetry decreased from 6.38+/ 1.02 D to 2.76+/-0.73 D. Only minor changes in posterior corneal surface elevation and stability of refraction were found, confirming that no progression of ectasia occurred during the observation time. CONCLUSIONS: A combination of topography-guided custom ablation and CXL improved patients' visual, refractive, and topography outcomes and halted the progression of keratectasia within the observation period of 12 months. This method may postpone or eliminate the need for corneal transplantation in suitable cases with keratectasia. PMID- 20163081 TI - Interaction of a charged polymer with zwitterionic lipid vesicles. AB - The interaction between polyethylenimine (PEI) and phospholipid bilayers plays an important role in several biophysical applications such as DNA transfection of target cells. Despite considerable investigation into the nature of the interaction between PEI and phospholipid bilayers, the physical process remains poorly understood. In this paper, we study the impact of PEI on 1,2-dimyristoyl sn-glycero-3-phosphocholine (DMPC) vesicles as a function of salt concentration using several techniques including dynamic (DLS) and static (SLS) light scattering, differential scanning calorimetry (DSC), and nuclear magnetic resonance (NMR). At low salt concentration, vesicles aggregate, leading to the formation of stable clusters whose final size depends on the PEI concentration. At high salt concentration the system does not aggregate; DSC and NMR data reveal that the PEI penetrates into the bilayer, and SLS measurements are consistent with PEI crossing the bilayer. The transfectional ability of PEI is discussed in terms of these results. PMID- 20163082 TI - EQCM study of the [Au(III)Cl4](-)-[Au(I)Cl2](-)-Au(0) redox system in 1-ethyl-3 methylimidazolium tetrafluoroborate room-temperature ionic liquid. AB - The electrochemical behavior of the [Au(III)Cl(4)](-)-[Au(I)Cl(2)](-)-Au(0) redox system in room temperature ionic liquid (RTIL) of 1-ethyl-3-methylimidazolium tetrafluoroborate (EMIBF(4)) has been investigated quantitatively using an in situ electrochemical quartz crystal microbalance (EQCM) technique based on a Pt film-coated quartz crystal electrode (Pt-QCE). A series of two-electron (2e) and one-electron (1e) reductions of the [Au(III)Cl(4)](-) to [Au(I)Cl(2)](-) and [Au(I)Cl(2)](-) to Au metal were recognized at the Pt surface. Besides, the disproportionation reaction of [Au(I)Cl(2)](-) (i.e., the 2e-reduction product of [Au(III)Cl(4)](-)) to [Au(III)Cl(4)](-) and Au metal was also observed. Electro dissolution of the Au deposited on the Pt electrode through a 1e-oxidation reaction in the presence of chloride ions was also confirmed using the Pt-QCE based EQCM technique. A 2e-oxidation reaction of [Au(I)Cl(2)](-) (i.e., the dissolved product) to [Au(III)Cl(4)](-) along with the oxidation of Cl(-) ion on the Pt surface was also realized at high anodic potential. The results demonstrate that in situ EQCM technique is applicable and powerful in elucidating electrochemical surface phenomena accompanying a mass change in RTIL. PMID- 20163083 TI - Adsorption of a water treatment protein from Moringa oleifera seeds to a silicon oxide surface studied by neutron reflection. AB - An extract from the seeds of the Moringa oleifera tree that is principally a low molecular mass protein is known to be efficient as a coagulating agent for water treatment. The present paper investigates the adsorption of the purified protein to silica interfaces in order to elucidate the mechanism of its function as a flocculent. Neutron reflection permits the determination of the structure and composition of interfacial layers at the solid/solution interface. Dense layers of protein with about 5.5 mg m(-2) were found at concentrations above 0.025% wt. The overall thickness with a dense layer in excess of 60 A at 0.05 wt % suggests strong co-operative binding rather than single isolated molecules. An ionic surfactant, sodium dodecyl sulfate, was also seen to coadsorb. This strong adsorption of protein in combination with the tendency for the protein to associate suggests a mechanism for destabilizing particulate dispersions to provide filterable water. This can occur even for the protein that has previously been identified as being of low mass (about 7 kDaltons) and thus is unlikely to be efficient in bridging or depletion flocculation. PMID- 20163084 TI - Dye diffusion at surfaces: charge matters. AB - Fluorescence correlation spectroscopy and single molecule burst analysis were used to measure the effects of glass surface interactions on the diffusion of two common fluorescent dyes, one cationic and one anionic. The effects of dye-surface interactions on measured diffusion rates as a function of distance from the surface were investigated. Use of a three-axis piezo stage, combined with reference calibration measurements, enabled the accurate acquisition of surface distance-dependent transport data. This analysis reveals attractive interactions between the cationic dye and the surface, which significantly alter the extracted diffusion values and persist in the measurements up to 1.0 microm from the surface. The Coulomb attraction between the cationic dye and the surface also results in rare, long-lived association events that lead to irreproducibility in extracted diffusion values. In addition to an assignment of the association lifetime for these events, this paper demonstrates that, if experiments must be performed with cationic probes near a glass surface, the use of solution electrolytes can eliminate deleterious dye-surface interactions, as the dyes were tested in a variety of environments. Finally, our data demonstrate that a better dye choice is an anionic probe, which exhibits no depth dependence of diffusion characteristics above a glass surface. PMID- 20163085 TI - Formation of protein-rich coatings around lipid droplets using the electrostatic deposition method. AB - The purpose of this study was to determine whether protein-rich coatings could be formed around lipid droplets using an electrostatic deposition method. These coatings were assembled using two methods: (i) beta-lactoglobulin was adsorbed to beta-lactoglobulin-pectin-coated lipid droplets; (ii) beta-lactoglobulin-pectin complexes were adsorbed to beta-lactoglobulin-coated lipid droplets. Composite particles, consisting of lipid droplets with protein-rich biopolymer coatings, could be formed using both approaches (e.g., at pH 4, the protein surface load could be increased from 3 to 59 mg m(-2)). These composite particles could be made small (d < 500 nm) and relatively stable to gravitational separation at certain protein concentrations. Nevertheless, aggregation and sedimentation occurred at sufficiently high protein concentrations because of charge neutralization. The composite particles remained stable after they were heated above the thermal denaturation temperature of the globular proteins at pH 4. When the heated composite particles were adjusted to pH 7, where beta-lactoglobulin and pectin are both negatively charged, some of the pectin and beta-lactoglobulin became detached from the droplet surfaces but the protein surface load was still higher than in a nontreated sample. These composite particles may be useful for increasing the protein concentration in biopolymer coatings surrounding lipid droplets, which potentially has practical applications in the food industry (e.g., in protecting omega-3 oils from oxidation or in developing natural weighting agents). PMID- 20163086 TI - A general and convenient preparation of [bis(trifluoroacetoxy)iodo]perfluoroalkanes and [bis(trifluoroacetoxy)iodo]arenes by oxidation of organic iodides using oxone and trifluoroacetic acid. AB - [Bis(trifluoroacetoxy)iodo]perfluoroalkanes C(n)F(2n+1)I(OCOCF(3))(2) (n = 4, 6, 8, 10, 12) can be conveniently prepared by the oxidation of the corresponding perfluoroalkyl iodides with Oxone in trifluoroacetic acid at room temperature and subsequently converted to the stable [hydroxy(tosyloxy)iodo]perfluoroalkanes, C(n)F(2n+1)I(OH)OTs, by treatment with p-toluenesulfonic acid. This general and convenient procedure has been further extended to the synthesis of various [bis(trifluoroacetoxy)iodo]arenes, ArI(OCOCF(3))(2). PMID- 20163087 TI - Water chemistry alters gene expression and physiological end points of chronic waterborne copper exposure in zebrafish, Danio rerio. AB - This is the first study to implement a genomic approach to ascertain both transcriptional and functional end points of chronic Cu toxicity in fish associated with experimentally manipulated water chemistries. Over 21 d, zebrafish acclimated to softwater (Na(+) = 0.06 mM, Ca(2+) = 0.08 mM, Mg(2+) = 0.03 mM) were exposed to the following: soft-water (Ctrl); 12 microg L(-1) Cu (Cu); 3.3 mM Na(+) (Na); 3.3 mM Na(+) + 12 microg L(-1) Cu (Na + Cu); 3.3 mM Ca(2+) (Ca); or 3.3 mM Ca(2+) + 12 microg L(-1) Cu (Ca + Cu). Although effective at reducing Cu load in all tissues, Na(+) in the presence of Cu did not decrease the degree of oxidative damage, particularly in the gill and gut. In contrast, Ca + Cu treatment decreased Cu accumulation in gill, but not liver or gut, with no reduction in oxidative damage. Transcriptional analysis of candidate genes (atp7a, ctr1, ECaC, esr1) showed principally a down regulation of transcripts with the Cu only treatment, while Ca + Cu treatment restored some of the genes to control levels. Conversely, the Na + Cu treatment had a strong, opposing affect when compared to that of Cu alone. Zebrafish Affymetrix GeneChips revealed significantly clustered patterns of expression. Changes in expression induced by Cu appeared to be opposite to the majority of the other treatments. Our data on the preventative or enhancing effects of Na(+) and Ca(2+) both alone and in the presence of Cu, may, in the future, facilitate the incorporation of gene expression end points into a biotic ligand model predicting chronic Cu toxicity in this tropical model species of genomic importance. PMID- 20163088 TI - Fuel-mix, fuel efficiency, and transport demand affect prospects for biofuels in northern Europe. AB - Rising greenhouse gas (GHG) emissions in the road transport sector represents a difficult mitigation challenge due to a multitude of intricate factors, namely the dependency on liquid energy carriers and infrastructure lock-in. For this reason, low-carbon renewable energy carriers, particularly second generation biofuels, are often seen as a prominent candidate for realizing reduced emissions and lowered oil dependency over the medium- and long-term horizons. However, the overarching question is whether advanced biofuels can be an environmentally effective mitigation strategy in the face of increasing consumption and resource constraints. Here we develop both biofuel production and road transport consumption scenarios for northern Europe-a region with a vast surplus of forest bioenergy resources-to assess the potential role that forest-based biofuels may play over the medium- and long-term time horizons using an environmentally extended, multiregion input-output model. Through scenarios, we explore how evolving vehicle technologies and consumption patterns will affect the mitigation opportunities afforded by any future supply of forest biofuels. We find that in a scenario involving ambitious biofuel targets, the size of the GHG mitigation wedge attributed to the market supply of biofuels is severely reduced under business-as-usual growth in consumption in the road transport sector. Our results indicate that climate policies targeting the road transport sector which give high emphases to reducing demand (volume), accelerating the deployment of more fuel-efficient vehicles, and promoting altered consumption patterns (structure) can be significantly more effective than those with single emphasis on expanded biofuel supply. PMID- 20163090 TI - Gas-phase synthesis and characterization of CH4-loaded hydroquinone clathrates. AB - A CH(4)-loaded hydroquinone (HQ) clathrate was synthesized via a gas-phase reaction using the alpha-form of crystalline HQ and CH(4) gas at 12 MPa and room temperature. Solid-state (13)C cross-polarization/magic angle spinning (CP/MAS) NMR and Raman spectroscopic measurements confirm the incorporation of CH(4) molecules into the cages of the HQ clathrate framework. The chemical analysis indicates that about 69% of the cages are filled by CH(4) molecules, that is, 0.69 CH(4) per three HQ molecules. Rietveld refinement using synchrotron X-ray powder diffraction (XRD) data shows that the CH(4)-loaded HQ clathrate adopts the beta-form of HQ clathrate in a hexagonal space group R3 with lattice parameters of a = 16.6191 A and c = 5.5038 A. Time-resolved synchrotron XRD and quadrupole mass spectroscopic measurements show that the CH(4)-loaded HQ clathrate is stable up to 368 K and gradually transforms to the alpha-form by releasing the confined CH(4) gases between 368-378 K. Using solid-state (13)C CP/MAS NMR, the reaction kinetics between the alpha-form HQ and CH(4) gas is qualitatively described in terms of the particle size of the crystalline HQ. PMID- 20163089 TI - Interactions of alamethicin with model cell membranes investigated using sum frequency generation vibrational spectroscopy in real time in situ. AB - Structures of membrane-associated peptides and molecular interactions between peptides and cell membrane bilayers govern biological functions of these peptides. Sum frequency generation (SFG) vibrational spectroscopy has been demonstrated to be a powerful technique to study such structures and interactions at the molecular level. In this research, SFG has been applied, supplemented by attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), to characterize the interactions between alamethicin (a model for larger channel proteins) and different lipid bilayers in the absence of membrane potential. The orientation of alamethicin in lipid bilayers has been determined using SFG amide I spectra detected with different polarization combinations. It was found that alamethicin adopts a mixed alpha-helical and 3(10)-helical structure in fluid phase lipid bilayers. The helix (mainly alpha-helix) at the N-terminus tilts at about 63 degrees versus the surface normal in a fluid-phase 1,2-dimyristoyl-d54 sn-glycero-3-phosphocholine-1,1,2,2-d4-N,N,N-trimethyl-d9 (d-DMPC)/1,2 dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayer. The 3(10)-helix at the C terminus (beyond the Pro14 residue) tilts at about 43 degrees versus the surface normal. This is the first time to apply SFG to study a 3(10)-helix experimentally. When interacting with a gel-phase lipid bilayer, alamethicin lies down on the gel-phase bilayer surface or aggregates or both, which does not have significant insertion into the lipid bilayer. PMID- 20163091 TI - On the rate of decline of persistent organic contaminants in lake trout (Salvelinus namaycush) from the Great Lakes, 1970-2003. AB - Thirty-four years of data from the Great Lakes Fish Monitoring Program (GLFMP) show significant changes in the behavior of most contaminants in lake trout over time consistent with changes in contaminant inputs following regulation and remediation. Polybrominated diphenyl ethers (PBDEs) show positive apparent first order rate constants falling to near zero. Dieldrin shows relatively unchanging half-lives of around 10 years except in Lake Superior (approximately 25 years). Mirex, consistently detected only in Lake Ontario fish, shows a slow decrease until the 1990s, when remediation of a source site occurred, after which half lives are 2-3 years. Half-lives of oxychlordane, polychlorinated biphenyls (PCBs), and dichloro-diphenyl-trichlorethane (DDT) and its metabolites were typically 3-6 years until the mid 1980s; since then, the newest data confirm half lives are usually around 15-30 years. For PCBs, an increasing half-life is found in other media as well. Changes in food web structure, fishery dynamics, and climate undoubtedly affect concentrations but cannot explain observed long-term trends across several media. Concentrations of legacy contaminants in the Great Lakes are likely to continue to decline only slowly and pose a health concern for decades without identifying and containing remaining sources. PMID- 20163092 TI - Reassessing the strategies for trapping catalytic intermediates during nitrate reductase turnover. AB - We examined the kinetics of nitrate reduction by periplasmic nitrate reductase (Nap) by using protein film voltammetry and solution assays. We demonstrate that, under turnover conditions, the enzyme exists as a mixture of active and inactive forms which interconvert on a time scale that is much slower than turnover. The dead-end species accumulates under mildly reducing conditions and at high nitrate concentration, resulting in substrate inhibition and in an uncommon hysteresis in the voltammetric signature. Solution assays with two electron donors having different reduction potentials fully support the electrochemical results. This illustrates the consequences of the high flexibility of the active site molybdenum coordination sphere and questions the conclusions from earlier studies in which attempts were made to trap catalytic intermediates of Nap in experiments carried out under turnover conditions at very high substrate concentration. PMID- 20163093 TI - Synthesis and immobilization of Ag(0) nanoparticles on diazonium modified electrodes: SECM and cyclic voltammetry studies of the modified interfaces. AB - A versatile method was used to prepare modified surfaces on which metallic silver nanoparticles are immobilized on an organic layer. The preparation method takes advantage, on one hand, of the activated reactivity of some alkyl halides with Ag Pd alloys to produce metallic silver nanoparticles and, on the other hand, of the facile production of an anchoring polyphenyl acetate layer by the electrografting of substituted diazonium salts on carbon surfaces. Transport properties inside such modified layers were investigated by cyclic voltammetry, scanning electrochemical microscopy (SECM) in feedback mode, and conducting AFM imaging for characterizing the presence and nature of the conducting pathways. The modification of the blocking properties of the surface (or its conductivity) was found to vary to a large extent on the solvents used for surface examination (H(2)O, CH(2)Cl(2), and DMF). PMID- 20163094 TI - Rapid formation of coordination multilayers using accelerated self-assembly procedure (ASAP). AB - Layer-by-layer (LbL) assembly of multilayers on surfaces using metal-organic coordination between consecutive layers is a well-established method for multilayer construction. The basic scheme includes self-assembly of a ligand (anchor) monolayer on the surface, followed by alternate binding of metal ions and multifunctional ligand layers to form a coordination multilayer. Binding of the ligand repeat unit to form a new layer is commonly a slow process, taking typically overnight to complete. This renders the process of multilayer preparation exceedingly slow and, in many cases, impractical. Here we describe a method for LbL synthesis of self-assembled coordination multilayers denoted accelerated self-assembly procedure (ASAP), where binding of a full organic ligand layer occurs in ca. 1 min. In the new protocol a small volume of a dilute ligand solution is spread on the substrate surface and evaporated under natural convection conditions, leaving the surface covered with excess ligand. Extensive rinsing in pure solvent results in complete removal of unbound molecules from the surface, leaving only the new coordinated layer. ASAP is demonstrated here by the construction of two kinds of coordination multilayers, comprising mercaptoundecanoic acid-Cu(II) and bishydroxamate-Zr(IV). Multilayers prepared by ASAP and by the standard (overnight adsorption) procedure are compared using ellipsometry, contact-angle, and FTIR data, showing regular multilayer growth in both cases. However, the rapid binding associated with ASAP may lead to a different structure than the one reached after prolonged assembly. Study of the ASAP mechanism suggests that the fast ligand binding kinetics are attributed to a large increase of the local ligand concentration at the moving liquid front when the solvent evaporates on the surface. PMID- 20163095 TI - pH-switchable bioelectrocatalysis of hydrogen peroxide on layer-by-layer films assembled by concanavalin A and horseradish peroxidase with electroactive mediator in solution. AB - The lectin protein concanavalin A (Con A) and the glycoenzyme horseradish peroxidase (HRP) were assembled into {Con A/HRP}(n) layer-by-layer films on electrodes mainly by biospecific affinity between them. The cyclic voltammetric (CV) response of ferricyanide (Fe(CN)(6)(3-)) at {Con A/HRP}(n) film electrodes was very sensitive to the environmental pH. The peak currents of Fe(CN)(6)(3-) were quite large at pH 4.0 but greatly suppressed at pH 9.0, demonstrating reversible pH-sensitive "on-off" behavior. This property could be used to realize pH-controlled electrochemical reduction of H(2)O(2) catalyzed by HRP immobilized in {Con A/HRP}(n) films and mediated by Fe(CN)(6)(3-) in solution. The modulation of the solution pH was also realized by in situ biochemical reactions with various enzymes in solution and was used to tune the pH-switchable bioelectrocatalysis. The possible mechanism of the pH-responsive on-off behavior of the films toward the probe was explored, and the electrostatic interaction between the films and the probe is believed to play a key role in deciding the pH sensitive behavior of the films. This "smart" interface may be used to establish a foundation for fabricating novel pH-controllable electrochemical biosensors based on bioelectrocatalysis with immobilized enzymes. PMID- 20163096 TI - Mechanism of the hydride transfer between Anabaena Tyr303Ser FNR(rd)/FNR(ox) and NADP+/H. A combined pre-steady-state kinetic/ensemble-averaged transition-state theory with multidimensional tunneling study. AB - The flavoenzyme ferredoxin-NADP(+) reductase (FNR) catalyzes the production of NADPH during photosynthesis. The hydride-transfer reactions between the Anabaena mutant Tyr303Ser FNR(rd)/FNR(ox) and NADP(+)/H have been studied both experimentally and theoretically. Stopped-flow pre-steady-state kinetic measurements have shown that, in contrast to that observed for WT FNR, the physiological hydride transfer from Tyr303Ser FNR(rd) to NADP(+) does not occur. Conversely, the reverse reaction does take place with a rate constant just slightly slower than for WT FNR. This latter process shows temperature-dependent rates, but essentially temperature independent kinetic isotope effects, suggesting the reaction takes place following the vibration-driven tunneling model. In turn, ensemble-averaged variational transition-state theory with multidimensional tunneling calculations provide reaction rate constant values and kinetic isotope effects that agree with the experimental results, the experimental and the theoretical values for the reverse process being noticeably similar. The reaction mechanism behind these hydride transfers has been analyzed. The formation of a close contact ionic pair FADH(-):NADP(+) surrounded by the polar environment of the enzyme in the reactant complex of the mutant might be the cause of the huge difference between the direct and the reverse reaction. PMID- 20163097 TI - Simultaneous control of emission localization and two-photon absorption efficiency in dissymmetrical chromophores. AB - The aim of the present work is to demonstrate that combined spatial tuning of fluorescence and two-photon absorption (TPA) properties of multipolar chromophores can be achieved by introduction of slight electronic chemical dissymmetry. In that perspective, two model series of structurally related chromophores have been designed and investigated. One is based on rod-like quadrupolar chromophores bearing either two identical or different electron donating (D) end groups and the other on three-branched octupolar chromophores built from a trigonal donating moiety bearing identical or different acceptor (A) peripheral groups. The influence of the electronic dissymmetry is investigated by combined experimental and theoretical studies of the linear and nonlinear optical properties of dissymmetrical chromophores compared to their symmetrical counterparts. In both types of systems (i.e., quadrupoles and octupoles), experiments and theory reveal that excitation is essentially delocalized and that excitation involves synchronized charge redistribution (i.e., concerted intramolecular charge transfer) between the different D and A moieties within the multipolar structure. In contrast, the emission stems only from a particular dipolar subunit bearing the strongest D or A moiety due to fast excitation localization after excitation, prior to emission. Hence, control of emission characteristics (polarization and emission spectrum), can be achieved, in addition to localization, by controlled introduction of electronic dissymmetry (i.e., replacement of one of the D or A end-groups by a slightly stronger D' or A' unit). Interestingly, slight dissymmetrical functionalization of both quadrupolar and octupolar compounds does not lead to significant loss in TPA responses and can even be beneficial due to the spectral broadening and peak position tuning that it allows. This study thus reveals an original molecular engineering route allowing TPA enhancement in multipolar structures, due to concerted core-to-periphery or periphery-to-core intramolecular charge redistribution upon excitation, while providing for control of emission localization. Such a route could be extended to more intricate (dendritic) and multipolar (3D) systems. PMID- 20163098 TI - Influence of ethylene glycol and propylene glycol on polymer diffusion in poly(butyl acrylate-co-methyl methacrylate) latex films. AB - We describe fluorescence resonance energy transfer (FRET) experiments carried out to examine the effect of ethylene glycol and propylene glycol on the early stages of polymer diffusion in poly(butyl acrylate-co-methyl methacrylate) latex films. In our approach, we temporarily arrest the drying process of a wet latex film by sealing the film in a previously cooled airtight sample chamber. This arrests propagation of the drying front and suppresses polymer diffusion during the measurements. We then measure donor fluorescence decays from 0.5 mm diameter spots at various locations on the film. From our analysis, we obtain information about the earliest stages of polymer diffusion as the film is still drying. We also investigate the effect of these glycols on polymer diffusion at longer aging times on predried latex films. Ethylene glycol and propylene glycol retard polymer diffusion at early times immediately after the passing of the drying front but enhance the rate of polymer diffusion at later aging times. This behavior is described quantitatively in terms of free-volume theory and the partitioning of the glycols between the aqueous and polymer phases in the film. PMID- 20163100 TI - Quality of graphite target for biological/biomedical/environmental applications of 14C-accelerator mass spectrometry. AB - Catalytic graphitization for (14)C-accelerator mass spectrometry ((14)C-AMS) produced various forms of elemental carbon. Our high-throughput Zn reduction method (C/Fe = 1:5, 500 degrees C, 3 h) produced the AMS target of graphite coated iron powder (GCIP), a mix of nongraphitic carbon and Fe(3)C. Crystallinity of the AMS targets of GCIP (nongraphitic carbon) was increased to turbostratic carbon by raising the C/Fe ratio from 1:5 to 1:1 and the graphitization temperature from 500 to 585 degrees C. The AMS target of GCIP containing turbostratic carbon had a large isotopic fractionation and a low AMS ion current. The AMS target of GCIP containing turbostratic carbon also yielded less accurate/precise (14)C-AMS measurements because of the lower graphitization yield and lower thermal conductivity that were caused by the higher C/Fe ratio of 1:1. On the other hand, the AMS target of GCIP containing nongraphitic carbon had higher graphitization yield and better thermal conductivity over the AMS target of GCIP containing turbostratic carbon due to optimal surface area provided by the iron powder. Finally, graphitization yield and thermal conductivity were stronger determinants (over graphite crystallinity) for accurate/precise/high throughput biological, biomedical, and environmental (14)C-AMS applications such as absorption, distribution, metabolism, elimination (ADME), and physiologically based pharmacokinetics (PBPK) of nutrients, drugs, phytochemicals, and environmental chemicals. PMID- 20163101 TI - DFT study of H adsorption on magnesium-doped aluminum clusters. AB - In this study we use density functional theory (DFT) to investigate the properties and H adsorption characteristics of structural isomers of the magnesium-doped aluminum cluster, Al(12)Mg. Our results show that the exohedral structure (exo-MgAl(12)) is significantly lower in energy (1.59 eV) than the endohedral structure (endo-Al(12)Mg); however, the exohedral structure shows significant structural distortion. Our calculations demonstrate that H binds favorably to both exohedral and endohedral structures. Generally, binding energies for H to both clusters range from approximately 2.3 to 2.5 eV with atop positions slightly favored, except for addition directly to the exohedral Mg atom, where the binding energy drops to 1.92 eV. We include a DFT molecular dynamics study of the endo-Al(12)Mg and endo-Al(12)MgH clusters which revealed the isomerization to the respective exostructures at finite temperatures (100-600 K). Interestingly, hydrogen adsorption appears to enhance the isomerization. PMID- 20163102 TI - Aerosol synthesis of porous particles using simple salts as a pore template. AB - Ultrasonic spray pyrolysis has been used as a facile aerosol route to macroporous SiO(2) particles using simple inorganic salts as a pore template and colloidal SiO(2) as building blocks to the larger porous particles. As we found, the use of template salts with low melting points was vital to macroporous particle synthesis, as a dynamic droplet phase can be maintained throughout product formation. Otherwise, relatively compact particles are produced. Significantly, this approach avoids the need for post-isolation elimination of the template, instead permitting aqueous removal during product collection. Produced particles were characterized by SEM, TEM, and surface area and pore size measurements, while the influence of the selected salts on the reactivity between the building block SiO(2) colloids is discussed. PMID- 20163103 TI - Geographical distribution of perfluorinated compounds in fish from Minnesota lakes and rivers. AB - In response to growing interest in human exposure to perfluorinated compounds (PFCs), the state of Minnesota measured and reported PFC concentrations in fish collected from the Minneapolis-St. Paul area. To better determine the geographical distribution of PFC contamination throughout Minnesota, fish were collected from 59 lakes throughout the state and several areas along the Mississippi River. Composite fish samples were analyzed for 10 PFC analytes by solid-phase extraction (SPE) and liquid chromatography-tandem mass spectrometry (LC/MS/MS). PFOS (perfluorooctanesulfonate) was the most commonly detected PFC, occurring in 73% of fish from the Mississippi River but only 22% of fish from lakes. Fish from Mississippi River Pool 2 near the Minneapolis-St. Paul area had the highest levels of PFOS, whereas locations upstream had PFOS concentrations below 40 ng/g, the concentration at which Minnesota issues "one meal per week" fish consumption advice. Fish from most Minnesota lakes tested (88%) had PFOS concentrations below 3 ng/g. Two lakes, McCarrons and Zumbro, contained fish with PFOS levels above 40 ng/g. The results reported here will help researchers to better understand the extent of PFC contamination in Minnesota fish and evaluate potential sources of contamination and will provide a basis for comprehensive fish consumption advice. PMID- 20163104 TI - Biofunctional titania nanotubes for visible-light-activated photoelectrochemical biosensing. AB - The photoelectrochemical detection method is a newly developed and promising analytical method for biosensing. In this work, photoactive TiO(2) nanotubes (TNs) immobilized with horseradish peroxidase (HRP) were prepared and used for visible-light-activated photoelectrochemical detection of H(2)O(2). TNs were fabricated by anodic oxidation of titanium substrate and possessed large surface areas, good uniformity and conformability, and high porosity, which were favorable for enzyme immobilization. Electrochemical and UV-vis spectroscopic measurements demonstrated that TNs provided excellent matrixes for the adsorption of HRP and the adsorbed HRP effectively retained its bioactivities. The photocurrent spectra of HRP/TNs showed an obvious photocurrent response under visible-light irradiation (lambda > or = 400 nm), suggesting the possibility of photoelectrochemical detection of H(2)O(2) upon visible-light irradiation. It was found that the generated photocurrent of HRP/TNs at 400 nm was significantly enhanced after the addition of H(2)O(2) in solution and the photocurrent intensity increased with the increase of the H(2)O(2) concentration. The HRP/TNs electrode displayed a linear range of 5.0 x 10(-7)-3.5 x 10(-5) M and a low detection limit of 1.8 x 10(-7) M for H(2)O(2) determination. Thus, the protein immobilized TNs would be expected to be a novel photoactive material for photoelectrochemical biosensing. This proposed strategy may open a new avenue for the applications of nanotubular TiO(2) in visible-light-activated photoelectrochemical biosensing, which could largely reduce the destructive effect of UV light and the photoholes generated by illuminated TiO(2) to biomolecules. PMID- 20163105 TI - Electronic structure analysis of the dinuclear metal center in the bioremediator glycerophosphodiesterase (GpdQ) from Enterobacter aerogenes. AB - The glycerophosphodiesterase (GpdQ) from Enterobacter aerogenes is a promiscuous, dinuclear metallohydrolase that has potential application in the remediation of organophosphate nerve agents and pesticides. GpdQ employs an unusual reaction mechanism in which the enzyme is predominantly mononuclear in the resting state, and substrate binding induces the formation of the catalytically competent dinuclear center (Hadler et al. J. Am. Chem. Soc. 2008, 130, 14129). Reactivity is further modulated by the coordination flexibility of Asn80, a ligand that binds to the second, loosely bound metal ion (Hadler et al. J. Am. Chem. Soc. 2009, 131, 11900). It is proposed that hydrolysis is initiated by a terminal, metal-bound hydroxide molecule which is activated at unusually low pH by electrostatic/hydrogen bonding interactions with a bridging hydroxide species. In this study, electronic structure analysis of the dinuclear center is employed to study the coordination environment of the dinuclear center at the resting and product-bound stage of catalysis. This is achieved through the use of variable temperature, variable field magnetic circular dichroism experiments involving the Co(II)-substituted wild type enzyme and its Asn80Asp variant. The data support the above model for the catalytic mechanism whereby the metal ion-bridging hydroxide molecule activates a terminally bound hydroxide nucleophile. Replacement of Asn80 by an aspartate residue does prevent coordination flexibility but also leads to cleavage of the mu-hydroxide bridge and reduced reactivity. This is the first study to investigate the electronic structure of an enzyme with a mu-1,1-carboxylate bridged dicobalt(II) center. PMID- 20163106 TI - Functionalized O-alkyldithiocarbonates: a new class of ligands designed for luminescent heterometallic materials. AB - The new ligand 4-PyCH(2)OCS(2)Na, that combines two different donor groups in one molecule (a soft -CS(2)(-) group and a hard pyridine moiety), has been synthesized. The ligand coordinates to a [(bipy)Re(CO)(3)](+) center in a monodentate fashion through one of its soft sulfur atoms, leaving the hard pyridine terminus free for further coordination chemistry. Using a Ni(II) dithiophosphonate linker, the heterometallic {[CH(3)OCH(2)CH(2)OP(An)S(2)](2)Ni}[4-PyCH(2)OCS(2)Re(bipy)(CO)(3)](2) complex is obtained, through the coordination of two pyridine groups to the Ni(II) center. This simple, high-yield stepwise strategy toward heterometallic complexes could be easily transferable to other 1,1-dithiolate ligands and used in combination with a large variety of luminescent metallic systems. PMID- 20163107 TI - New chelating ligands based on S-organosulfurdiimides: synthesis and single crystal X-ray structures of their lithium complexes. AB - Three new diimidosulfinates, [TMSCH(2)S(N(t)Bu)(2)Li](2) (1), [2 PyCH(2)S(N(t)Bu)(2)Li](2) (2), and [{PhCH(2)S(N(t)Bu)(2)Li}(2) x THF] (3) (TMS = trimethylsilyl; Py = 2-pyridyl), have been synthesized by the reaction of functionalized alpha-CH(2)-organolithium compounds with bis-tert butylsulfurdiimide. These new organolithium chelates are characterized by NMR ((1)H, (13)C, (7)Li, and (29)Si) spectroscopy and single-crystal X-ray diffraction analyses. Compounds 1 and 2 crystallize as dimers without donor molecules, whereas one of the lithium atoms in 3 is coordinated by a single THF molecule. The crystal structure of 1 shows significant intramolecular proximity between one methyl group of the trimethylsilyl (TMS) and one lithium atom, which could be described as an electrostatic Li...C interaction. The coordination sphere of each lithium atom in 2 is completed by donation from the nitrogen atom of the pyridyl ring; however, one of the lithium atoms in 3 is coordinated by a THF molecule. In addition, the first mixed sulfurdiimide species containing a diimidosulfinate and a diimidosulfite fragment, [{PhCHS(N(t)Bu)(2)Li(2)(THF)(2)}{MeS(N(t)Bu)(2)Li(THF)}] (4), was isolated by deprotonation of the alpha-CH(2) group in 3. The single-crystal X-ray structure of 4 revealed two different S-bound substituents coexisting in one dimer and two asymmetrically coordinated lithium atoms. PMID- 20163108 TI - Heterodinuclear Fe(III)Zn(II)-bioinspired complex supported on 3-aminopropyl silica. Efficient hydrolysis of phosphate diester bonds. AB - Presented herein is the synthesis and characterization of a new Fe(III)Zn(II) complex containing a Fe(III)-bound phenolate with a carbonyl functional group, which was anchored to 3-aminopropyl-functionalized silica as the solid support. The catalytic efficiency of the immobilized catalyst in the hydrolysis of 2,4 bis(dinitrophenyl)phosphate is comparable to the homogeneous reaction, and the supported catalyst can be reused for subsequent diester hydrolysis reactions. PMID- 20163109 TI - Quantum tunneling of hydrogen atom in dissociation of photoexcited methylamine. AB - The probability of hydrogen atom release, following photoexcitation of methylamine, CH(3)NH(2), is found to increase extensively as higher vibrational states on the first excited electronic state are accessed. This behavior is consistent with theoretical calculations, based on the probability of H atom tunneling through an energy barrier on the excited potential energy surface, implying that N-H bond breaking is dominated by quantum tunneling. PMID- 20163110 TI - Influence of simultaneous variations in temperature and relative humidity on chemical stability of two vitamin C forms and implications for shelf life models. AB - Vitamin C powder ingredients are popular food fortificants and are among the most commonly added nutrients. While information on degradation kinetics and shelf life of vitamin C exists, current models are limited in their applicability to systems where relative humidity (RH) and temperature are varied simultaneously, and where phase transformations occur. This study monitored stability of two forms of vitamin C (sodium ascorbate and ascorbic acid) under various RH and temperature conditions. Vitamin C was measured colorimetrically, and stability data were used to improve understanding of vitamin C shelf life when deliquescence occurs during storage. RH and temperature both significantly impacted vitamin stability, though RH had a larger effect. Vitamin dissolution preceded extensive degradation and was found to be a good predictor of vitamin C loss. This research highlights the importance of considering phase transformations when constructing shelf life models and maintaining vitamin C in the solid state for enhanced stability. PMID- 20163111 TI - Comparative study of the phenolic composition of seeds and skins from Carmenere and Cabernet Sauvignon grape varieties (Vitis vinifera L.) during ripening. AB - The phenolic composition of skins and seeds from Vitis vinifera L. cv. Carmenere and Cabernet Sauvignon grapes during ripening was evaluated by high-performance liquid chromatography-diode array detection and spectrophotometric analysis. As compared to Cabernet Sauvignon grape skins, Carmenere grape skins presented higher contents of total anthocyanins, monomeric flavan-3-ols, and total flavonoids, a higher mean degree of polymerization, a higher percentage of galloylation, a higher average molecular weight of the flavanol fraction, and a higher color intensity. As compared to Cabernet Sauvignon grape seeds, Carmenere grape seeds presented a lower content of monomeric flavan-3-ols, a higher mean degree of polymerization, a higher percentage of galloylation, a higher average molecular weight of the flavanol fraction, a lower content of (+)-catechin, and higher contents of (-)-epicatechin, epicatechin-3-O-gallate, gallic acid, and dimeric procyanidins esterified with gallic acid. Altogether, we conclude that Carmenere grapes present a differential composition and evolution of phenolic compounds when compared to Cabernet Sauvignon grapes. PMID- 20163112 TI - Spectral alteration and degradation of cyanidin-3-glucoside exposed to pulsed electric field. AB - Anthocyanins are polyphenol antioxidants that have been shown to prevent many chronic diseases. The compounds are not stable, so they tend to be decolorized or degraded during processing and storage. In this study, the spectral characteristics alteration and degradation products of cyanidin-3-glucoside (Cyd 3-glc) exposed to pulsed electric field (PEF) were investigated, and the reaction kinetics was discussed. The intensity of the UV-vis spectra decreased noticeably upon PEF treatment without modification of the spectral pattern. Protocatechuic acid and 2,4,6-trihydroxybenzoic acid were identified as degradation products of both PEF and thermally treated Cyd-3-glc, but cyanidin present in thermally treated Cyd-3-glc was absent in PEF-treated Cyd-3-glc, indicating that the first step of Cyd-3-glc degradation induced by PEF was not the hydrolysis of glycosidic bonds, which was different from that of thermal degradation. With increased electric field intensity or treatment time, the degradation of Cyd-3-glc and the formation of protocatechuic acid were enhanced; their kinetics (except 7 kV/cm for protocatechuic acid formation) were well fitted to a first-order reaction. Meanwhile, a good correlation was present between Cyd-3-glc degradation and protocatechuic acid formation. PMID- 20163113 TI - Glucosinolate profile variation of growth stages of wild radish (Raphanus raphanistrum). AB - Wild radish (Raphanus raphanistrum L.) produces glucosinolates (GSL), which are important for its use as a biofumigation or allelopathic plant for weed management. Total GSL concentrations and individual GSLs were quantified in different plant parts at different developmental stages. Eight GSLs were found in various plant tissues but glucoerucin, glucoraphenin, and glucotropaeolin comprised >90% of the total GSLs. All three are degraded to isothiocyanates, which are associated with weed suppression. Maximum GSL concentration (1942.2 micromol/plant) occurred at 50% flowering stage prior to the time of maximum biomass production, when GSL concentration was 1246.65 mumol/plant. Roots contributed <15% of the total GSL. The highest concentration of GSLs was in flowers at flowering stage, but due to the low biomass they contributed only 11.83% to the total GSL. On the basis of these results, wild radish should be incorporated into soil at 50% flowering to provide the most GSLs for weed suppression. PMID- 20163114 TI - Refined methodology for the determination of neonicotinoid pesticides and their metabolites in honey bees and bee products by liquid chromatography-tandem mass spectrometry (LC-MS/MS). AB - An analytical method was refined for the extraction and determination of neonicotinoid pesticide residues and their metabolites in honey bees and bee products. Samples were extracted with 2% triethylamine (TEA) in acetonitrile (ACN) followed by salting out, solid phase extraction (SPE) cleanup, and detection using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method was validated in triplicate at three fortification concentrations in each matrix. Good recoveries were observed for most analytes and ranged between 70 and 120% with relative standard deviations between replicates of <20% in most cases. The method limits of detection were 0.2 ng/g for the parent neonicotinoid pesticides and ranged between 0.2 and 15 ng/g for the neonicotinoid metabolites. This refined method provides lower detection limits and improved recovery of neonicotinoids and their metabolites, which will help researchers evaluate subchronic effects of these pesticides, address data gaps related to colony collapse disorder (CCD), and determine the role of pesticides in pollinator decline. PMID- 20163115 TI - Piracetam defines a new binding site for allosteric modulators of alpha-amino-3 hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors. AB - Glutamate receptors are the most prevalent excitatory neurotransmitter receptors in the vertebrate central nervous system and are important potential drug targets for cognitive enhancement and the treatment of schizophrenia. Allosteric modulators of AMPA receptors promote dimerization by binding to a dimer interface and reducing desensitization and deactivation. The pyrrolidine allosteric modulators, piracetam and aniracetam, were among the first of this class of drugs to be discovered. We have determined the structure of the ligand binding domain of the AMPA receptor subtypes GluA2 and GluA3 with piracetam and a corresponding structure of GluA3 with aniracetam. Both drugs bind to GluA2 and GluA3 in a very similar manner, suggesting little subunit specificity. However, the binding sites for piracetam and aniracetam differ considerably. Aniracetam binds to a symmetrical site at the center of the dimer interface. Piracetam binds to multiple sites along the dimer interface with low occupation, one of which is a unique binding site for potential allosteric modulators. This new site may be of importance in the design of new allosteric regulators. PMID- 20163116 TI - The discovery of 4-{1-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3 thienyl}carbonyl)amino]cyclopropyl}benzoic acid (MK-2894), a potent and selective prostaglandin E2 subtype 4 receptor antagonist. AB - The discovery of highly potent and selective second generation EP(4) antagonist MK-2894 (34d) is discussed. This compound exhibits favorable pharmacokinetic profile in a number of preclinical species and potent anti-inflammatory activity in several animal models of pain/inflammation. It also shows favorable GI tolerability profile in rats when compared to traditional NSAID indomethacin. PMID- 20163118 TI - Enantioselective ring opening of epoxides by fluoride anion promoted by a cooperative dual-catalyst system. AB - An enantioselective method for the synthesis of beta-fluoroalcohols by catalytic nucleophilic fluorination of epoxides is described. Mild reaction conditions and high selectivity are made possible by the use of benzoyl fluoride as a soluble, latent source of fluoride anion. A chiral amine and chiral Lewis acid serve as cooperative catalysts for desymmetrizations of five- through eight-membered cyclic epoxides, affording products in up to 95% ee. The cocatalytic protocol is also effective for kinetic resolutions of racemic terminal epoxides, which proceed with k(rel) values as high as 300. PMID- 20163117 TI - Chiral silver amide-catalyzed enantioselective [3 + 2] cycloaddition of alpha aminophosphonates with olefins. AB - The first catalytic asymmetric [3 + 2] cycloadditions of Schiff bases of alpha aminophosphonates with olefins have been developed. Chiral silver amide complexes bearing (R)-DTBM-SEGPHOS worked well as catalysts for the first time, and proline phosphonic analogues were obtained in high yields with excellent exo- and enantioselectivities. PMID- 20163119 TI - Diastereoisomerically pure fulleropyrrolidines as chiral platforms for the design of optically active liquid crystals. AB - Incorporation of [60]fullerene (C(60)) within self-organizing systems is conceptually challenging but allows us to obtain materials which combine the characteristics (anisotropy, organization) of condensed mesophases with the properties of C(60) (photo- and electrochemical activity). Here, we report on the synthesis, characterization, and liquid-crystalline properties of four optically active fullerodendrimers, which are chiral at the point of conjunction between the fullerene scaffold and the mesogenic moieties. Thus, the novelty of this study is to take advantage of the asymmetric carbon atom created during the 1,3 dipolar cycloaddition reaction on C(60) in order to induce mesoscopic chirality in the materials. Four diastereoisomeric fulleropyrrolidines ((R,S)-1, (R,R)-1, (S,R)-1, and (S,S)-1) were synthesized and associated with a second-generation nematic (N) dendron to give fullerodendrimers ((R,S)-2, (R,R)-2, (S,R)-2, and (S,S)-2) which display chiral nematic (N*) phases. The absolute configurations of the stereogenic centers were determined by X-ray crystallography, 1D and 2D NMR experiments, and circular dichroism (CD) spectroscopy. The liquid-crystalline properties of the fullerodendrimers were studied by polarized optical microscopy (POM) and differential scanning calorimetry (DSC). The fulleropyrrolidine derivatives 2 exhibit supramolecular helicoidal organizations with a right-handed helix for the (R,S)-2 and (R,R)-2 diastereoisomers and a left-handed helix for the (S,R)-2 and (S,S)-2 diastereoisomers. This result suggests that the self organization of such supermolecular materials can be controlled at the molecular level by the introduction of only one chiral center. PMID- 20163120 TI - Asymmetric hydrovinylation of unactivated linear 1,3-dienes. AB - Monosubstituted acyclic (E)-1,3-dienes undergo efficient hydrovinylation giving (Z)-3-alkylhexa-1,4-dienes upon treatment with catalytic amounts of bidentate phosphine-CoCl(2) complexes {[P~P](CoCl(2))} and Me(3)Al in an atmosphere of ethylene. The regioselectivity of the reaction (i.e., 1,4- or 1,2-addition) depends on the nature of the ligand and temperature at which the reaction is carried out. Complexes derived from (RR)-DIOP and (SS)-BDDP at -45 degrees C give very high enantioselectivities for several prototypical 1,3-dienes. In sharp contrast to the corresponding Ni(II)-catalyzed hydrovinylation, 1-aryl substituted 1,3-dienes give almost exclusively achiral linear 1,4-addition products, unless the 2-position is also substituted. Solid-state structures of the precatalysts are presented. PMID- 20163121 TI - Octafluorocalix[4]pyrrole: a chloride/bicarbonate antiport agent. AB - meso-Octamethyloctafluorocalixpyrrole, a simple tetrapyrrolic macrocycle, has been shown to function as both a chloride/nitrate and a chloride/bicarbonate antiport agent for lipid bilayer transmembrane anion transport. This is the first example of a synthetic macrocyclic pyrrole-based receptor capable of transmembrane bicarbonate transport. PMID- 20163122 TI - Demonstration of prominent Cu(II)-promoted leaving group stabilization of the cleavage of a homologous set of phosphate mono-, di-, and triesters in methanol. AB - A series of phosphate mono-, di-, and triesters with a common leaving group (LG) (2'-(2-phenoxy)-1,10-phenanthroline) was prepared, and the kinetics of decomposition of their Cu(II) complexes was studied in methanol at 25 degrees C under (s)(s)pH-controlled conditions. The Cu(II) complexes of 2-[2' phenanthrolyl]phenyl phosphate (Cu(II):6), 2-[2'-phenanthrolyl]phenyl methyl phosphate (Cu(II):7), and 2-[2'-phenanthrolyl]phenyl dimethyl phosphate (Cu(II):8) are tightly bound, having dissociation constants Kd < or = 3 x 10(-7) M, with the Cu(II) being in contact with the departing phenoxide. The (s)(s)pH/rate profile for cleavage of Cu(II):6 has a low (s)(s)pH plateau (k(o) = 6.3 x 10(-3) s(-1)), followed by a bell-shaped maximum (kcat(max) = 14.7 +/- 0.4 s(-1)) dependent on two ionizations with (s)(s)pKa(2) and (s)(s)pKa(3) = 7.8 +/- 0.1 and 11.8 +/- 0.2. The (s)(s)pH/rate profile for cleavage of Cu(II):7 has a broad plateau from (s)(s)pH 3 to (s)(s)pH 10 followed by a descending wing at higher (s)(s)pH with a gradient of -2. The (s)(s)pH/rate profile for cleavage of Cu(II):8 is sigmoidal with two plateaus (k1 = (2.0 +/- 0.2) x 10(-5) s(-1), k2 = (1.2 +/- 0.2) x 10(-6) s(-1)), connected by an ionization with a (s)(s)pKa of 6.03. Activation parameters are given for the reactions in the plateau regions: all three species show similar DeltaH(double dagger) terms of 21.4-21.6 kcal/mol, with major differences in the DeltaS(double dagger) terms, which vary from 18 to 2.3 to -7.4 cal/(mol x K) passing from the mono- to di- to triester. Detailed analyses of the kinetics indicate that the reactions involve spontaneous solvent mediated cleavage of the Cu(II)-coordinated phosphate dianion [Cu(II):6b]0 and phosphate diester monoanion [Cu(II):7b]+ and, for the triester, complexes containing Cu(II) and Cu(II):(-)OCH3 designated as [Cu(II):8a]2+ and [Cu(II):8b]+. Reactions where methoxide is the active nucleophile are not observed. Comparisons of the rates of the decomposition of these species at their (s)(s)pH maxima in the neutral (s)(s)pH region with the estimated rates of the background reactions indicate that leaving group assistance provided by the coordinated Cu(II) accelerates the cleavage of the phosphate mono-, di-, and triesters by 10(14) to 10(15), 10(14), and 10(5). Detailed Hyperquad 2000 analysis of titration data indicates that phenoxide 9- is bound 23 kcal/mol stronger than the phosphate triester 8. It is the realization of part of this energy in the emerging products resulting from P-O(LG) cleavage that provides the driving force for the catalyzed reactions. PMID- 20163123 TI - Metal-controlled assembly of near-infrared-emitting pentanuclear lanthanide beta diketone clusters. AB - Metal-controlled assembly results in a series of lanthanide clusters with the formula of Ln(5)(DBM)(10)(OH)(5) x n(solvent) (DBM = dibenzoylmethanido; Ln = Nd (1), Gd (2), Er (3), and Yb (4); solvent = CH(3)CN or toluene). These pentanuclear clusters with square-pyramidal core structures have been characterized by X-ray diffraction analysis. Clusters 1, 3, and 4 show typical near-infrared (NIR) luminescence upon excitation at 350 nm, which represents the first examples of pentanuclear lanthanide clusters with sensitized NIR emission. PMID- 20163124 TI - Temperature dependence of the thermal conductivity of thin silicon nanowires. AB - We compute the lattice thermal conductivity (kappa) of silicon nanowires as a function of temperature by molecular dynamics simulations. In wires with amorphous surfaces kappa may reach values close to that of amorphous silicon and is nearly constant between 200 and 600 K; this behavior is determined by the presence of a majority of nonpropagating vibrational modes. We develop a parameter-free model that accounts for the temperature dependence observed in our simulations and provides a qualitative explanation of recent experiments. PMID- 20163125 TI - High-performance single nanowire tunnel diodes. AB - We demonstrate single nanowire tunnel diodes with room temperature peak current densities of up to 329 A/cm(2). Despite the large surface to volume ratio of the type-II InP-GaAs axial heterostructure nanowires, we measure peak to valley current ratios (PVCR) of up to 8.2 at room temperature and 27.6 at liquid helium temperature. These sub-100-nm-diameter structures are promising components for solar cells as well as electronic applications. PMID- 20163126 TI - Diastereoselective allylstannane additions to (S)-5,6-dihydro-2H-5-phenyloxazin-2 one. A concise synthesis of (S)-beta-methylisoleucine. AB - The addition of allyl stannanes to (S)-4,5-dihydro-5-phenyl-2H-oxazinone (3) was achieved under Bronsted acid catalysis to give 2-allylmorpholinones with high diastereoselectivity (up to dr 14.2:1). The product of dimethylallyltributylstannane addition to 3 was converted to l-beta methylisoleucine, an alpha-amino acid residue found in the complex, biologically active marine-derived peptides polytheonamides A and B, and polydiscamides A-C. PMID- 20163127 TI - Reaction discovery using microfluidic-based multidimensional screening of polycyclic iminium ethers. AB - Polycyclic iminium ethers are ambident electrophilic intermediates that react with a range of nucleophiles in a highly condition-dependent manner to afford densely functionalized lactams. In an effort to expand the scope of reactivity and assist in the generation of new chemotypes from these intermediates, several iminium ethers were subjected to reaction screening using an automated microfluidics reaction platform. Application of this approach led to the discovery of several interesting reaction pathways involving the iminium ether intermediates that will be described. PMID- 20163128 TI - Quantitative online analysis of liquid-phase products of methanol oxidation in aqueous sulfuric acid solutions using electrospray ionization mass spectrometry. AB - We describe a novel method and setup for quantitative online analysis of the liquid-phase methanol oxidation products in acidic aqueous solutions by electrospray ionization mass spectrometry (ESI-MS). This includes a specially designed flow system, which allows continuous online mixing, derivatization, extraction, separation, and quantitative detection within ca. 3 min. For electrospray ionization of formaldehyde, it is first online-derivatized by 2,4 dinitrophenyl hydrazine to form the easily ionizable 2,4-dinitrophenyl hydrazone. Then, both formic acid and derivatized formaldehyde are online extracted into an immiscible organic phase, which, after separation from the aqueous phase, is piped to the ESI-MS for analysis. This strategy ensures complete removal of the highly corrosive sulfuric acid from the analyte and allows the liquid-phase methanol oxidation reaction (MOR) products (formaldehyde and formic acid) to be quantitatively detected by ESI-MS. Finally, the potential of this method for online analysis in electroanalysis and electrocatalysis is discussed. PMID- 20163129 TI - Temperature-dependent subsurface growth during atomic layer deposition on polypropylene and cellulose fibers. AB - Nucleation and subsequent growth of aluminum oxide by atomic layer deposition (ALD) on polypropylene fiber substrates is strongly dependent on processing temperature and polymer backbone structure. Deposition on cellulose cotton, which contains ample hydroxyl sites for ALD nucleation and growth on the polymer backbone, readily produces a uniform and conformal coating. However, similar ALD processing on polypropylene, which contains no readily available active sites for growth initiation, results in a graded and intermixed polymer/inorganic interface layer. The structure of the polymer/inorganic layer depends strongly on the process temperature, where lower temperature (60 degrees C) produced a more abrupt transition. Cross-sectional transmission electron microscopy images of polypropylene fibers coated at higher temperature (90 degrees C) show that non coalesced particles form in the near-surface region of the polymer, and the particles grow in size and coalesce into a film as the number of ALD cycles increases. Quartz crystal microbalance analysis on polypropylene films confirms enhanced mass uptake at higher processing temperatures, and X-ray photoelectron spectroscopy data also confirm heterogeneous mixing between the aluminum oxide and the polypropylene during deposition at higher temperatures. The strong temperature dependence of film nucleation and subsurface growth is ascribed to a relatively large increase in bulk species diffusivity that occurs upon the temperature-driven free volume expansion of the polypropylene. These results provide helpful insight into mechanisms for controlled organic/inorganic thin film and fiber materials integration. PMID- 20163130 TI - Aggregation-induced emission enhancement in organic ion pairs. AB - We present here a new example of aggregation-induced emission enhancement (AIEE), which involves an original mechanism based on the formation of organic ion pairs. The phenol 4-hydroxy-7-nitrobenzoxadiazole (NBDOH) is dissociated in water at pH 5.0 to give the corresponding phenolate, which is poorly fluorescent in this medium. We bring evidence that fluorescence quenching is due to an interaction with water molecules. In the presence of a relatively bulky ammonium salt, specifically tetrabutylammonium bromide (TBAB), NBDOH forms a hydrophobic salt, TBA(+)NBDO(-). This has no influence on the fluorescence of the anion as long as the salt is dissolved. However, the salt readily crystallizes in the medium and transition to the solid state is accompanied by a strong increase in fluorescence intensity. This effect can be explained by two reasons. The anions are protected from water molecules, and above all, the presence of the bulky cations prevents parallel-stacking of the anions, thus leading to an original molecular arrangement that is favorable to fluorescence. As the nature of the organic cation may be easily changed, the versatility of the system is very interesting for the design of new organic micro- and nanoparticles that must be fluorescent in the solid state, possibly in an aqueous environment. PMID- 20163131 TI - Parallel fabrication of electrode arrays on single-walled carbon nanotubes using dip-pen-nanolithography-patterned etch masks. AB - This article presents a novel application of using dip-pen nanolithography (DPN) to fabricate Au electrodes concurrently in a high-throughput fashion through an etch resist. We have fabricated 26 pairs of electrodes, where cleanly etched electrode architectures, along with a high degree of feature-size controllability and tip-to-tip uniformity, were observed. Moreover, electrode gaps in the sub-100 nm regime have been successfully fabricated. Conductivity measurements of multiple electrodes in the array were all comparable to that of bulk Au, confirming the reliability and the low-resistance property of the electrodes. Finally, as a demonstration of electrode functionality, SWNT devices were fabricated and the electrical properties of an SWNT device were measured. Hence, our experimental results validate DPN as an effective tool in generating high quality electrodes in a parallel manner with mild, simple processing steps at a relatively low cost. PMID- 20163132 TI - Sub-10 ohm resistance gold films prepared by removal of ligands from thiol stabilized 6 nm gold nanoparticles. AB - The optical and electrical properties of dodecanethiol-stabilized nanoparticles (6 nm diameter gold core) have been investigated over a range of film thicknesses and temperatures. The surface plasmon resonance absorbance is found to be dependent on temperature. Heating of the nanoparticle film causes desorption of the thiol from the surface of the gold nanoparticle, resulting in irreversible changes to the absorption spectra of the nanoparticle film. Atomic force microscopy images of the samples before and after heating for different film thicknesses reveal structural changes and increased domain connectivity for thicker films leading to sub-10 ohm resistances measured for the 15-layer film. PMID- 20163133 TI - Microwave makes carbon nanotubes less defective. AB - An ultrafast microwave annealing process has been developed to reduce the defect density in vertically aligned carbon nanotubes (CNTs). Raman and thermogravimetric analyses have shown a distinct defect reduction in the CNTs annealed in microwave for 3 min. Fibers spun from the as-annealed CNTs, in comparison with those from the pristine CNTs, show increases of approximately 35% and approximately 65%, respectively, in tensile strength ( approximately 0.8 GPa) and modulus (approximately 90 GPa) during tensile testing; an approximately 20% improvement in electrical conductivity (approximately 80000 S m(-1)) was also reported. The mechanism of the microwave response of CNTs was discussed. PMID- 20163134 TI - Two-dimensional quasistatic stationary short range surface plasmons in flat nanoprisms. AB - We report on the nanometer scale spectral imaging of surface plasmons within individual silver triangular nanoprisms by electron energy loss spectroscopy and on related discrete dipole approximation simulations. A dependence of the energy and intensity of the three detected modes as function of the edge length is clearly identified both experimentally and with simulations. We show that for experimentally available prisms (edge lengths ca. 70 to 300 nm) the energies and intensities of the different modes show a monotonic dependence as function of the aspect ratio of the prisms. For shorter or longer prisms, deviations to this behavior are identified thanks to simulations. These modes have symmetric charge distribution and result from the strong coupling of the upper and lower triangular surfaces. They also form a standing wave in the in-plane direction and are identified as quasistatic short range surface plasmons of different orders as emphasized within a continuum dielectric model. This model explains in simple terms the measured and simulated energy and intensity changes as function of geometric parameters. By providing a unified vision of surface plasmons in platelets, such a model should be useful for engineering of the optical properties of metallic nanoplatelets. PMID- 20163135 TI - Rheology and microstructure of polymer nanocomposite melts: variation of polymer segment-surface interaction. AB - We have studied the effects of particle packing fraction, polymer molecular weight (MW), and polymer-segment-particle-surface affinity on the phase behavior of 44 nm silica dispersions in unentangled, low MW polyethylene oxide (PEO), polyethylene oxide dimethyl ether (PEODME), and polytetrahydrofuran (PTHF) through rheological measurement and small-angle X-ray scattering. Particles are shown to be stable in PEO nanocomposites up to high volume fractions due to an adsorbed layer of polymer segments that stabilizes particles in the melt. Comparison of the PEO nanocomposite to PEODME and PTHF nanocomposites reveals little evidence of an adsorbed layer in the spirit of the PEO nanocomposite. Measurement of the PTHF nanocomposite viscosity reveals evidence of segment slip at the particle surface by the particle intrinsic viscosity being less than Einstein's value. At higher particle volume fractions, the viscosity diverges, yielding an elastic response. The elastic response of the PEO nanocomposite has the signatures of a colloidal glass, while the PEODME and PTHF nanocomposites resemble a gel. Measurement of the particle structure factor reveals a change from overall repulsive particles in PEO to attractive particles in PTHF as the segment-surface interaction is changed. PMID- 20163136 TI - Highlighting cavities in proteins by NMR using sulfur hexafluoride as a spy molecule. AB - Cavities in proteins can be studied experimentally by using some detectable atoms, such as xenon, or molecules which act as reporter, such as a spy. The interest of sulfur hexafluoride (SF(6)) for probing hydrophobic cavities by solution-state NMR is investigated. The wheat nonspecific lipid transfer protein (LTP) was selected as a model system for this purpose. The binding of SF(6) is straightforwardly detected by the (19)F chemical shift, line width, or longitudinal relaxation time measurements, which can be carried out at low SF(6) concentration without interference from resonances of the protein. Most interestingly, the binding of SF(6) gives rise to selective intermolecular (1)H{(19)F} heteronuclear Overhauser effects (HOEs). Molecular dynamics simulation and NMR spectrum modeling show that the experimental HOESY spectra are consistent with (1)H{(19)F} HOEs arising from SF(6) in the cavity of LTP. SF(6) is found to be an advantageous alternative to hyperpolarized (129)Xe and small organic compounds for probing cavities in proteins by solution-state NMR. PMID- 20163137 TI - Optimizing the performance of bias-exchange metadynamics: folding a 48-residue LysM domain using a coarse-grained model. AB - Computer simulation of complex conformational transitions in biomolecules, such as protein folding, is considered one of the main goals of computational chemistry. A recently developed methodology, bias-exchange metadynamics, was successfully used to reversibly fold some small globular proteins. The objective of this work is to further improve this promising technique. This is accomplished by searching for the optimal set of parameters that enable folding a 48 amino acid protein, 1E0G , in the shortest possible time, using a coarse-grained force field UNRES. It is shown that bias-exchange metadynamics, if appropriately optimized, allows finding the folded state of 1E0G significantly faster than normal replica exchange. PMID- 20163139 TI - Gold nanoparticle self-similar chain structure organized by DNA origami. AB - Here we demonstrate Au nanoparticle self-similar chain structure organized by triangle DNA origami with well-controlled orientation and <10 nm spacing. We show for the first time that a large DNA complex (origami) and multiple AuNP conjugates can be well-assembled and purified with reliable yields. The assembled structure could be used to generate high local-field enhancement. The same method can be used to precisely localize multiple components on a DNA template for potential applications in nanophotonic, nanomagnetic, and nanoelectronic devices. PMID- 20163138 TI - Constitutive NADPH-dependent electron transferase activity of the Nox4 dehydrogenase domain. AB - NADPH oxidase 4 (Nox4) is constitutively active, while Nox2 requires the cytosolic regulatory subunits p47(phox) and p67(phox) and activated Rac with activation by phorbol 12-myristate 13-acetate (PMA). This study was undertaken to identify the domain on Nox4 that confers constitutive activity. Lysates from Nox4 expressing cells exhibited constitutive NADPH- but not NADH-dependent hydrogen peroxide production with a K(m) for NADPH of 55 +/- 10 microM. The concentration of Nox4 in cell lysates was estimated using Western blotting and allowed calculation of a turnover of approximately 200 mol of H(2)O(2) min(-1) (mol of Nox4)(-1). A chimeric protein (Nox2/4) consisting of the Nox2 transmembrane (TM) domain and the Nox4 dehydrogenase (DH) domain showed H(2)O(2) production in the absence of cytosolic regulatory subunits. In contrast, chimera Nox4/2, consisting of the Nox4 TM and Nox2 DH domains, exhibited PMA-dependent activation that required coexpression of regulatory subunits. Nox DH domains from several Nox isoforms were purified and evaluated for their electron transferase activities. Nox1 DH, Nox2 DH, and Nox5 DH domains exhibited barely detectable activities toward artificial electron acceptors, while the Nox4 DH domain exhibited significant rates of reduction of cytochrome c (160 min(-1), largely superoxide dismutase-independent), ferricyanide (470 min(-1)), and other electron acceptors (artificial dyes and cytochrome b(5)). Rates were similar to those observed for H(2)O(2) production by the Nox4 holoenzyme in cell lysates. The activity required added FAD and was seen with NADPH but not NADH. These results indicate that the Nox4 DH domain exists in an intrinsically activated state and that electron transfer from NADPH to FAD is likely to be rate-limiting in the NADPH-dependent reduction of oxygen by holo-Nox4. PMID- 20163140 TI - Molecular mechanism of long-range diffusion in phospholipid membranes studied by quasielastic neutron scattering. AB - The motion of phospholipids has previously been studied on many time scales due to the significance for living cells and technological applications. The motions on a pico- to nanosecond time scale were determined by quasielastic neutron scattering (QENS) to be much faster than the ones on the microsecond scale covered by fluorescence recovery after photobleaching (FRAP). This was explained by assuming that the molecules rattle fast in a cage of neighbors (observed with QENS) from which they escape once in a while; this escape was then the primary step of the slower diffusion measured by FRAP. However, nanosecond MD simulation studies could not observe any escape events; recent findings even suggested that the long-range motion in phospholipid membranes on short time scales is not diffusive but has flow-like characteristics. To check this novel view, we have repeated the QENS experiments with today's significantly improved instrumentation. By using the advantage of QENS that allows tuning of the observation time in the pico- to nanosecond range, it was possible to study the evolution of motions in this time frame. Localized motions, e.g., of the head and tail groups, appear separated from the long-range motion and do not obfuscate the analysis as they do in a mean squared displacement plot. The results for the long range motion are indeed compatible with flow patterns, whereas the localized motions can account for the fast motions interpreted as motions in a cage before. Hereby, we give experimental evidence for a completely different mechanism of long-range motion on short time scales in phospholipid membranes. PMID- 20163141 TI - Synthesis and colloidal polymerization of ferromagnetic Au-Co nanoparticles into Au-Co3O4 nanowires. AB - The preparation of cobalt oxide nanowires with gold nanoparticle (AuNP) inclusions (Au-Co(3)O(4) nanowires) via colloidal polymerization of dipolar core shell NPs is reported. Polystyrene-coated ferromagnetic NPs composed of a dipolar metallic cobalt shell and a gold NP core (PS-AuCoNPs) were synthesized by thermolysis of octacarbonyldicobalt [Co(2)(CO)(8)] in the presence of AuNP seeds and polymeric ligands. The colloidal polymerization process of these dipolar PS AuCoNPs comprises dipolar nanoparticle assembly and solution oxidation of preorganized NPs to form interconnected cobalt oxide nanowires via the nanoscale Kirkendall effect, with AuNP inclusions in every repeating unit of the one dimensional mesostructure. Calcination of the polymer-coated nanowires afforded polycrystalline Au-Co(3)O(4) nanowires that were determined to be electroactive. Nanocomposite materials were characterized by transmission electron microscopy, field-emission scanning electron microscopy, X-ray diffraction, vibrating sample magnetometry, and cyclic voltammetry. We demonstrate that the optical and electrochemical properties of Au-Co(3)O(4) nanowires are significantly enhanced in comparison with hollow Co(3)O(4) nanowires prepared via colloidal polymerization. PMID- 20163142 TI - In situ transformation of TON silica zeolite into the less dense ITW: structure direction overcoming framework instability in the synthesis of SiO2 zeolites. AB - Under specific synthesis conditions the crystallization of a dense silica zeolite (TON) is followed by its in situ transformation into a less dense and, in the absence of occluded species, less stable zeolite (ITW). Periodic ab initio calculations including energy corrections for van der Waals interactions as well as zero-point and thermal effects are used first to assess the relative stability of both SiO(2) (calcined) phases and then to investigate host-guest interactions in the as-made zeolites, as well as their relative stability. The less dense SiO(2)-ITW is less stable than SiO(2)-TON, with an energy difference that is significantly larger than expected from their difference in molar volume. This extra destabilization is ascribed to the strained double 4-ring units of silica tetrahedra (D4R). Regarding the as-made materials, the organic cation fills in more efficiently the zeolitic voids in ITW than in TON, bringing about a larger stabilization in the former owing to the extension of the long-range addition of dispersion force contributions. On the other hand, fluoride induces a polarization of the silica framework that is highly localized in TON (showing pentacoordinated [SiO(4/2)F](-) units) but has a large global character in ITW (where fluoride is encapsulated into D4R units). We argue that the structure directing role toward D4R materials that has been proposed for fluoride consists fundamentally in the ability to induce a global polarization of the silica framework that allows relaxation of the strain associated with these units. In this sense, fluoride stabilizes the otherwise strained D4R-SiO(2) frameworks making them reachable for crystallization. This work documents a case in which the structure directing agents "choose" a structure not kinetically but through stabilization. PMID- 20163143 TI - Solving the alpha-conotoxin folding problem: efficient selenium-directed on-resin generation of more potent and stable nicotinic acetylcholine receptor antagonists. AB - Alpha-conotoxins are tightly folded miniproteins that antagonize nicotinic acetylcholine receptors (nAChR) with high specificity for diverse subtypes. Here we report the use of selenocysteine in a supported phase method to direct native folding and produce alpha-conotoxins efficiently with improved biophysical properties. By replacing complementary cysteine pairs with selenocysteine pairs on an amphiphilic resin, we were able to chemically direct all five structural subclasses of alpha-conotoxins exclusively into their native folds. X-ray analysis at 1.4 A resolution of alpha-selenoconotoxin PnIA confirmed the isosteric character of the diselenide bond and the integrity of the alpha conotoxin fold. The alpha-selenoconotoxins exhibited similar or improved potency at rat diaphragm muscle and alpha3beta4, alpha7, and alpha1beta1 deltagamma nAChRs expressed in Xenopus oocytes plus improved disulfide bond scrambling stability in plasma. Together, these results underpin the development of more stable and potent nicotinic antagonists suitable for new drug therapies, and highlight the application of selenocysteine technology more broadly to disulfide bonded peptides and proteins. PMID- 20163144 TI - Anisotropic strain-induced curvature in type-II CdSe/CdTe nanorod heterostructures. AB - Type-II band-offset CdSe/CdTe nanorod heterostructures with curved and linear shapes have been synthesized and examined with atomic-resolution transmission electron microscopy techniques. Strain from growth of larger-lattice CdTe partly on the sides of CdSe nanorod seeds is shown to lead to an overall curvature in the rods. Lattice expansion from the inner to the outer portion of the curved region exceeds the expected lattice mismatch between the two materials because of the buildup of an unusual compressive strain in the CdSe. In contrast, exclusive tip growth results in linear barbell-shaped heterostructures that do not exhibit strain-induced curvature. The ability to vary the anisotropic lattice strain should allow control over the underlying electronic structure, providing new approaches to directing photogenerated carriers that may facilitate incorporation of nanorod heterostructures in various energy applications. PMID- 20163146 TI - Free-flow zone electrophoresis of peptides and proteins in PDMS microchip for narrow pI range sample prefractionation coupled with mass spectrometry. AB - In this paper, we are evaluating the strategy of sorting peptides/proteins based on the charge to mass without resorting to ampholytes and/or isoelectric focusing, using a single- and two-step free-flow zone electrophoresis. We developed a simple fabrication method to create a salt bridge for free-flow zone electrophoresis in PDMS chips by surface printing a hydrophobic layer on a glass substrate. Since the surface-printed hydrophobic layer prevents plasma bonding between the PDMS chip and the substrate, an electrical junction gap can be created for free-flow zone electrophoresis. With this device, we demonstrated a separation of positive and negative peptides and proteins at a given pH in standard buffer systems and validated the sorting result with LC/MS. Furthermore, we coupled two sorting steps via off-chip titration and isolated peptides within specific pI ranges from sample mixtures, where the pI range was simply set by the pH values of the buffer solutions. This free-flow zone electrophoresis sorting device, with its simplicity of fabrication, and a sorting resolution of 0.5 pH unit, can potentially be a high-throughput sample fractionation tool for targeted proteomics using LC/MS. PMID- 20163148 TI - 1-Ethyl-3-methylimidazolium ethylsulfate/copper catalyst for the enhancement of glucose chemiluminescent detection: effects on light emission and enzyme activity. AB - The effect of the ionic liquid 1-ethyl-3-methylimidazolium ethylsulfate ([Emim][EtSO(4)]) on the copper-catalyzed luminol chemiluminescence (CL) is reported. A drastic light emission enhancement is observed, related to a strong interaction between Cu(2+) and the imidazolium ring. In these conditions, the CL reaction was able to produce light efficiently at pH as low as 6.5 (amplification factor: Intensity(+IL)/Intensity(-IL) = 2900). Interesting effects of [Emim][EtSO(4)] on the enzyme glucose oxidase activity were also evidenced, and advantages were taken from this enhancement to perform sensitive chemiluminescent glucose detection (LOD = 4 microM) at pH 8.0. PMID- 20163147 TI - Recombinant isotope labeled and selenium quantified proteins for absolute protein quantification. AB - A novel, widely applicable method for the production of absolutely quantified proteins is described, which can be used as internal standards for quantitative proteomic studies based on mass spectrometry. These standards are recombinant proteins containing an isotope label and selenomethionine. For recombinant protein expression, assembly of expression vectors fitted to cell-free protein synthesis was conducted using the gateway technology which offers fast access to a variety of genes via open reading frame libraries and an easy shuttling of genes between vectors. The proteins are generated by cell-free expression in a medium in which methionine is exchanged against selenomethionine and at least one amino acid is exchanged by a highly stable isotope labeled analogue. After protein synthesis and purification, selenium is used for absolute quantification by element mass spectrometry, while the heavy amino acids in the protein serve as reference in subsequent analyses by LC-ESI-MS or MALDI-MS. Accordingly, these standards are denominated RISQ (for recombinant isotope labeled and selenium quantified) proteins. In this study, a protein was generated containing Lys+6 ([(13)C(6)]-lysine) and Arg+10 ([(13)C(6),(15)N(4)]-arginine) so that each standard tryptic peptide contains a labeled amino acid. Apolipoprotein A1 was synthesized as RISQ protein, and its use as internal standard led to quantification of a reference material within the specified value. Owing to their cell-free expression, RISQ proteins do not contain posttranslational modifications. Thus, correct quantitative data by ESI- or MALDI-MS are restricted to quantifications based on peptides derived from unmodified regions of the analyte protein. Therefore, besides serving as internal standards, RISQ proteins stand out as new tools for quantitative analysis of covalent protein modifications. PMID- 20163145 TI - Single-molecule spectroscopy and imaging of biomolecules in living cells. AB - The number of reports per year on single-molecule imaging experiments has grown roughly exponentially since the first successful efforts to optically detect a single molecule were completed over two decades ago. Single-molecule spectroscopy has developed into a field that includes a wealth of experiments at room temperature and inside living cells. The fast growth of single-molecule biophysics has resulted from its benefits in probing heterogeneous populations, one molecule at a time, as well as from advances in microscopes and detectors. This Perspective summarizes the field of live-cell imaging of single biomolecules. PMID- 20163149 TI - MLi2Ti6O14 (M = Sr, Ba, 2Na) lithium insertion titanate materials: a comparative study. AB - MLi(2)Ti(6)O(14) (M = Sr, Ba, 2Na) titanates have been investigated as lithium insertion materials for lithium-ion batteries. A comparative study has been undertaken based on the structure, morphology, and electrochemical properties of the titanate materials, which were prepared by sol-gel synthesis. Their lithium insertion behavior was analyzed by crystallographic considerations. While Na(2)Li(2)Ti(6)O(14) can reversibly host two Li(+) ions, SrLi(2)Ti(6)O(14) and BaLi(2)Ti(6)O(14) can reversibly insert almost four lithium ions per unit formula. Among the three materials, SrLi(2)Ti(6)O(14) showed superior capacity and rate capability. It was concluded that this class of materials could be of practical use in high-power lithium batteries for transportation applications. PMID- 20163150 TI - Proteomics and disease revisited: the challenge of providing proteomic tools into clinical practice. PMID- 20163151 TI - Atomic force spectroscopy of thermoresponsive photo-cross-linked hydrogel films. AB - Responsive hydrogel thin films are interesting materials as responsive adhesives or as an active matrix in actuators and sensing applications, and thus, knowledge about their structural and micromechanical properties is of high relevance. Using atomic force spectroscopy, temperature-induced structural and adhesive changes of thermoresponsive hydrogel layers with micrometer thickness based on photo-cross linked N-isopropylacrylamide (NiPAAm) were investigated in the temperature range of 18-50 degrees C. Grafted onto flat surfaces, these hydrogel layers are restricted to a highly anisotropic swelling and deswelling predominantly perpendicular to the substrate surface, which was monitored and evaluated by force spectroscopy during vertical tip approach and retraction. Analyses of the tip penetration depth yielded quantitative information about the degree of swelling. As a second feature, the critical temperature was found to decrease with increasing cross-linking density. Temperature-dependent measurements with hydrophobic and hydrophilic atomic force microscopy (AFM) tips revealed a strong adhesion to the hydrogel layer in the swollen state, which was reduced upon the layer volume collapse. These observations on the micrometer-thick gel network layers are in contrast to previous reports on ultrathin pNiPAAm brushes and monolayers, which show no adhesion in the swollen state but only in the collapsed state. Furthermore, it was found that the hydrophobicity of the hydrogel probed with a hydrophobic tip continuously increases with temperature over a broad range of at least 30 K. PMID- 20163152 TI - Correlation between fractal dimension and surface characterization by small angle X-ray scattering in marble. AB - Among several analysis techniques applied to the study of surface passivation using dicarboxylic acids, small angle X-ray scattering (SAXS) has proved to be relevant in the physicochemical interpretation of the surface association resulting between calcium carbonate and the molecular structure of malonic acid. It is possible to establish chemical affinity principles through bidimensional geometric analysis in terms of the fractal dimension obtained experimentally by SAXS. In this Article, we present results about the adsorption of malonic acid on calcite, using theoretical and mathematical principles of the fractal dimension. PMID- 20163153 TI - Synthesis and characterization of stereocontrolled poly(N-isopropylacrylamide) hydrogel prepared in the presence of Y(OTf)3 Lewis acid. AB - Macroporous poly(N-isopropylacrylamide) (PNIPAM) hydrogels have been prepared in methanol-water (1:1, v/v) mixture in the presence of 0, 0.05, 0.1, 0.15, and 0.2 M Y(OTf)(3) Lewis acid concentrations. Synthesis of the corresponding linear PNIPAM homopolymers in the absence of a cross-linker keeping all other conditions the same shows that the isotacticity (meso dyad, %) and the cloud point temperature of the resulted in polymers increases and decreases, respectively, with the increase in the concentration of the Lewis acid. SEM micrographs reveal that the resulted hydrogels are highly porous. Swelling ratios of all the hydrogels in water decrease with the increase in the temperature. Moreover, swelling ratios of all the hydrogels in different methanol-water mixtures pass through a minimum in the co-nonsolvency zone, and the co-nonsolvency zone shifts toward the lower methanol-content solvent mixture with gradual increase in the Lewis acid concentration. Deswelling rate of the hydrogel prepared in methanol water (1:1, v/v) mixture is much faster than that of the conventional hydrogel prepared in water. Moreover, the deswelling rate slightly increases with the hydrogels prepared with the increasing concentrations of Lewis acid. But, the reswelling rate of the hydrogels follows almost the reverse order. All these results have been explained on the basis of the formation of highly porous hydrogels with higher isotactic PNIPAM chain segment owing to the faster polymerization rate in the methanol-water mixture in the presence of Lewis acid and the co-nonsolvency behavior of the methanol-water (1:1, v/v) mixture toward PNIPAM chain segment in the PNIPAM hydrogel. PMID- 20163155 TI - Role of asparagine 510 in the relative timing of substrate bond cleavages in the reaction catalyzed by choline oxidase. AB - The flavoprotein choline oxidase catalyzes the oxidation of choline to glycine betaine with transient formation of an aldehyde intermediate and molecular oxygen as final electron acceptor. The enzyme has been grouped in the glucose-methanol choline oxidoreductase enzyme superfamily, which shares a highly conserved His Asn catalytic pair in the active site. In this study, the conserved asparagine residue at position 510 in choline oxidase was replaced with alanine, aspartate, histidine, or leucine by site-directed mutagenesis, and the resulting mutant enzymes were purified and characterized in their biochemical and mechanistic properties. All of the substitutions resulted in low incorporation of FAD into the protein. The Asn510Asp enzyme was not catalytically active with choline and had 75% of the flavin associated noncovalently. The most notable changes in the catalytic parameters with respect to wild-type choline oxidase were seen in the Asn510Ala enzyme, with decreases of 4300-fold in the k(cat)/K(choline), 600-fold in the k(red), 660-fold in the k(cat), and 50-fold in the k(cat)/K(oxygen) values. Smaller, but nonetheless similar, changes were seen also in the Asn510His enzyme. Both the K(d) and K(m) values for choline changed < or = 7-fold. These data are consistent with Asn510 participating in both the reductive and oxidative half-reactions but having a minimal role in substrate binding. Substrate, solvent, and multiple kinetic isotope effects on the k(red) values indicated that the substitution of Asn510 with alanine, but not with histidine, resulted in a change from stepwise to concerted mechanisms for the cleavages of the OH and CH bonds of choline catalyzed by the enzyme. PMID- 20163154 TI - Neuropeptidomics of the mosquito Aedes aegypti. AB - Neuropeptidomic data were collected on the mosquito Ae. aegypti, which is considered the most tractable mosquito species for physiological and endocrine studies. The data were solely obtained by direct mass spectrometric profiling, including tandem fragmentation, of selected tissues from single specimens, which yielded a largely complete accounting of the putative bioactive neuropeptides; truncated neuropeptides with low abundance were not counted as mature peptides. Differential processing within the CNS was detected for the CAPA-precursor, and differential post-translational processing (pyroglutamate formation) was detected for AST-C and CAPA-PVK-2. For the first time in insects, we succeeded in the direct mass spectrometric profiling of midgut tissue which yielded a comprehensive and immediate overview of the peptides involved in the endocrine system of the gut. Head peptides which were earlier identified as the most abundant RFamides of Ae. aegypti, were not detected in any part of the CNS or midgut. This study provides a framework for future investigations on mosquito endocrinology and neurobiology. Given the high sequence similarity of neuropeptide precursors identified in other medically important mosquitoes, conclusions regarding the peptidome of Ae. aegypti likely are applicable to these mosquitoes. PMID- 20163157 TI - Increased sensitivity in antigen detection with fluorescent latex nanosphere-IgG antibody conjugates. AB - IgG antibodies were conjugated to Kodak X-Sight nanospheres to develop fluorescent-labeled antibodies using two different synthetic routes: one involving the DTT reduction method, and the other involving Traut's Reagent modification method. These two methods result in different conjugation efficiencies and different performances in antigen detection. Western blotting shows that the nanosphere-IgG antibody conjugates synthesized using the DTT reduction method are more immunospecific than the conjugates synthesized using Traut's Reagent modification method. In addition, the conjugates synthesized using DTT reduction also show higher antigen detection sensitivity than other commercially available fluorescent-IgG antibody conjugates, including Alexa Fluor, Qdot, and CyDye conjugates. PMID- 20163156 TI - Low-potential detection of endogenous and physiological uric acid at uricase thionine-single-walled carbon nanotube modified electrodes. AB - This work develops and validates an electrochemical approach for uric acid (UA) determinations in both endogenous (cell lysate) and physiological (serum) samples. This approach is based on the electrocatalytic reduction of enzymatically generated H(2)O(2) at the biosensor of uricase-thionine-single walled carbon nanotube/glassy carbon (UOx-Th-SWNTs/GC) with the use of Th-SWNTs nanostructure as a mediator and an enzyme immobilization matrix. The biosensor, which was fabricated by immobilizing UOx on the surface of Th-SWNTs, exhibited a rapid response (ca. 2 s), a low detection limit (0.5 +/- 0.05 microM), a wide linear range (2 microM to 2 mM), high sensitivity (approximately 90 microA mM(-1) cm(-2)), as well as good stability and repeatability. In addition, the common interfering species, such as ascorbic acid, 3,4-dihydroxyphenylacetic acid, 4 acetamidophenol, etc., did not cause any interference due to the use of a low operating potential (-400 mV vs saturated calomel electrode). Therefore, this work has demonstrated a simple and effective sensing platform for selective detection of UA in the physiological levels. In particular, the developed approach could be very important and useful to determine the relative role of endogenous and physiological UA in various conditions such as hypertension and cardiovascular disease. PMID- 20163158 TI - Studies on the mechanism of action of dextrin-phospholipase A2 and its suitability for use in combination therapy. AB - The bioresponsive conjugate dextrin-phospholipase A2 (PLA2) is a novel anticancer polymer therapeutic. Dextrin conjugation decreases PLA2 bioactivity, but this can be restored following triggered degradation by alpha-amylase. The conjugate displays reduced hemolytic activity but retains, or shows enhanced, cytotoxicity in vitro that partially correlates with epidermal growth factor receptor (EGFR) expression. Here, we investigate further the mechanism of action of dextrin-PLA2 with the aim of judging its potential for combination with tyrosine kinase inhibitors (TKI) and/or chemotherapy and selecting the first models for in vivo evaluation. The endocytic fate of Oregon Green (OG)-labeled probes was assessed in MCF-7 cells. Whereas PLA2-OG showed greatest membrane binding, the dextrin PLA2-OG conjugate displayed higher internalization. Moreover, cells incubated with PLA(2)-OG and dextrin-PLA2-OG showed an altered pattern of intracellular vesicle distribution compared to dextrin-OG. When cell lines known to express different levels of EGFR were used to assess cytotoxicity, free PLA2 activity was enhanced by addition of EGF whereas the conjugate was less cytotoxic, perhaps due to differences in their PK/PD profile. Co-incubation of cells with the TKI inhibitor, gefitinib, led to reduced cytotoxicity of both PLA2 and dextrin-PLA2 suggesting a TK-mediated PLA2 mechanism of action. However, the enhanced cytotoxicity seen in the presence of doxorubicin suggested potential for development of a dextrin-PLA2/doxorubicin combination therapy. PMID- 20163159 TI - Autocatalytic nature of permanganate oxidations exploited for highly sensitive chemiluminescence detection. AB - Manganese(II) salts catalyze the chemiluminescent oxidation of organic compounds with acidic potassium permanganate. The formation of insoluble manganese(IV) species from the reaction between manganese(II) and permanganate can be prevented with sodium polyphosphate, and therefore, relatively high concentrations of the catalyst can be added to the reagent before the light-producing reaction is initiated. The rapid and intense emissions from these manganese(II) catalyzed chemiluminescence reactions provide highly sensitive detection and greater compatibility with liquid chromatography. PMID- 20163161 TI - Effects of experimental setup on the apparent concentration dependency of active efflux transport in in vitro cell permeation experiments. AB - P-Glycoprotein mediated efflux is one of the barriers limiting drug absorption from the intestine. Predictions of the intestinal P-glycoprotein function need to take into account the concentration dependency because high intestinal drug concentrations may saturate P-glycoprotein. However, the substrate binding site of P-glycoprotein lies inside the cells and the drug concentration at the binding site cannot be measured directly. Therefore, rigorous determination of concentration dependent P-glycoprotein kinetics is challenging. In this study, the effects of the aqueous boundary layers, extracellular pH and cellular retention on the apparent saturation kinetics of P-glycoprotein mediated transport of quinidine in an in vitro cell permeation setting were explored. The changes in the experimental conditions caused 1 order of magnitude variation in the apparent affinity to P-glycoprotein (K(m,app)) and a 5-fold difference in the maximum effective P-glycoprotein mediated transport rate of quinidine (V(max,app)). However, fitting the concentration data into a compartmental model which accounted for the aqueous boundary layers, cell membranes and cellular retention suggested that the P-glycoprotein function per se was not altered, it was the differences in the passive transfer of quinidine which changed the apparent transport kinetics. These results provide further insight into the dynamics of the P-glycoprotein mediated transport and on the roles of several confounding factors involved in in vitro experimental setting. Further, the results confirm the applicability of compartmental model based data analysis approach in the determination of active transporter kinetics. PMID- 20163160 TI - Effect of HEPES buffer on the uptake and transport of P-glycoprotein substrates and large neutral amino acids. AB - HEPES has been widely employed as an organic buffer agent in cell culture medium as well as uptake and transport experiments in vitro. However, concentrations of HEPES used in such studies vary from one laboratory to another. In this study, we investigated the effect of HEPES on the uptake and bidirectional transport of P gp substrates employing both Caco-2 and MDCK-MDR1 cells. ATP-dependent uptake of glutamic acid was also examined. ATP production was further quantified applying ATP Determination Kit. An addition of HEPES to the growth and incubation media significantly altered the uptake and transport of P-gp substrates in both Caco-2 and MDCK-MDR1 cells. Uptake of P-gp substrates substantially diminished as the HEPES concentration was raised to 25 mM. Bidirectional (A-B and B-A) transport studies revealed that permeability ratio of P(appB-A) to P(appA-B) in the presence of 25 mM HEPES was significantly higher than control. The uptake of phenylalanine is an ATP-independent process, whereas the accumulation of glutamic acid is ATP-dependent. While phenylalanine uptake remained unchanged, glutamic acid uptake was elevated with the addition of HEPES. Verapamil is an inhibitor of P-gp mediated uptake; elevation of cyclosporine uptake in the presence of 5 muM verapamil was compromised by the presence of 25 mM HEPES. The results of ATP assay indicated that HEPES stimulated the production of ATP. This study suggests that the addition of HEPES in the medium modulated the energy dependent efflux and uptake processes. The effect of HEPES on P-gp mediated drug efflux and transport may provide some mechanistic insight into possible reasons for inconsistencies in the results reported from various laboratories. PMID- 20163162 TI - Modeling the electrostatic signature of single enzyme activity. AB - Charge sensors based on nanoscale field-effect transistors are a promising new tool to probe the dynamics of individual enzymes. However, it is currently unknown whether the electrostatic signals associated with biological activity exceed detection limits. We report calculations of electrostatic signatures of two representative enzymes, deoxyribonuclease I and T4 lysozyme. Our simulations reveal that substrate binding to deoxyribonuclease and internal dynamics of lysozyme are detectable at the single-molecule level using existing point functionalized carbon nanotube sensors. PMID- 20163163 TI - Terahertz (far-infrared) characterization of tris(hydroxymethyl)aminomethane using high-resolution waveguide THz-TDS. AB - Waveguide THz-TDS using metal parallel plate waveguides is employed to obtain a high-resolution terahertz vibrational spectrum of tris(hydroxymethyl)aminomethane, commonly known as Tris or THAM, an important biological buffer component, a neuroinhibitor and an organic thermal energy storing molecule. Dropcast and sublimated thin films are used to characterize the sample. The development (with cooling) of 3 broad resonances seen at room temperature into 12 highly resolved spectral features for the dropcast sample and 11 features for a sublimated sample at 13.6 K is tracked by measuring the temperature dependence of the transmission spectrum. Resonances with fwhm linewidths as narrow as 12 GHz are obtained. These results provide strong constraints on theoretical modeling. PMID- 20163164 TI - Ab initio study of nonadditivity effects: spin-spin coupling constants for tetrafluoroethene in ternary pi complexes. AB - C(2)F(4) coupling constants have been evaluated at EOM-CCSD/(qzp,qz2p) in binary complexes with electron donors X (X = HLi, Cl(-), CN(-)) and with the electron acceptor FH, and in ternary complexes FH:C(2)F(4):X in which X and FH are located on opposite faces of the C(2)F(4) pi cloud. The electron donors X and the electron acceptor FH have opposite effects on (1)J(C-C), (1)J(C-F), (2)J(C-F), and (3)J(F-F) in binary complexes. Effects of X and FH on a particular coupling constant in a ternary complex are additive if the change in the coupling constant in this complex relative to C(2)F(4) is within 1 Hz of the sum of the changes in the corresponding binary complexes. This is the case for (1)J(C-F). Both positive and negative nonadditivities are computed for the remaining coupling constants. Although the values of most coupling constants lie between the values for FH:C(2)F(4) and C(2)F(4):X, that is not the case for (2)J(C-F), and the effect of FH is enhanced by the presence of X. Moreover, values of (3)J(F-F) trans and cis for FH:C(2)F(4):X when X is Cl(-) or CN(-) bonded through C are within 1 Hz of the values for the corresponding binary complex C(2)F(4):X. Significant differences can be found between the relative contributions of the PSO, FC, and SD terms to total J and to the nonadditivities of J in ternary complexes FH:C(2)F(4):X. PMID- 20163165 TI - Structural influence on radical formation and sensitizing capacity of alkylic limonene hydroperoxide analogues in allergic contact dermatitis. AB - Hydroperoxides are known to be strong contact allergens and a common cause of contact allergy. They are easily formed by the autoxidation of, for example, fragrance terpenes, compounds that are common in perfumes, cosmetics, and household products. A requirement of the immunological mechanisms of contact allergy is the formation of an immunogenic hapten-protein complex. For hydroperoxides, a radical mechanism is postulated for this formation. In our previous investigations of allylic limonene hydroperoxides, we found that the formation of carbon- and oxygen-centered radicals, as well as the sensitizing capacity, is influenced by the structure of the hydroperoxides. The aim of the present work was to further investigate the connection between structure, radical formation, and sensitizing capacity by studying alkylic analogues of the previously investigated allylic limonene hydroperoxides. The radical formation was studied in radical-trapping experiments employing 5,10,15,20-tetraphenyl 21H,23H-porphine iron(III) chloride as an initiator and 1,1,3,3 tetramethylisoindolin-2-yloxyl as a radical trapper. We found that the investigated hydroperoxides initially form carbon- and oxygen-centered radicals that subsequently form alcohols and ketones. Trapped carbon-centered radicals and nonradical products were isolated and identified. Small changes in structure, like the omission of the endocyclic double bond or the addition of a methyl group, resulted in large differences in radical formation. The results indicate that alkoxyl radicals seem to be more important than carbon-centered radicals in the immunogenic complex formation. The sensitizing capacities were studied in the murine local lymph node assay (LLNA), and all hydroperoxides tested were found to be potent sensitizers. For two of the hydroperoxides investigated, the recently suggested thiol-ene reaction is a possible mechanism for the formation of immunogenic complexes. For the third investigated, fully saturated, hydroperoxide, the thiol-ene mechanism is not possible for immunogenic complex formation. This strongly indicates that several radical reaction pathways for immunogenic complex formation of limonene hydroperoxides are active in parallel. PMID- 20163166 TI - Fluorescent coordination polymeric gel from tartaric acid-assisted self-assembly. AB - A fluorescent organogel is obtained from the reaction of Zn(OAc)(2) x 2 H(2)O, 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene (bpd), and tartaric acid (H(4)tar) in methanol. The gel is proposed to have formed by the cross-linking of linear 1D coordination polymers [Zn(bpd)](n) with tartarate coligand in a highly random fashion which entrapped the solvent molecules through hydrogen-bonding interactions between the tar coligand and solvent molecules. Higher dimensional coordination polymeric structure is proposed for this gel based on the corresponding complexes formed by oxalic and succinic acids. The presence of three components is essential for the gelation. Interestingly, organogelation of the coordination polymer has induced remarkable fluorescence properties in the weakly emissive bpd. Such fluorescence enhancement is attributed to the reduction in nonradiative decay in the aggregated state. The organogel exhibits viscoelastic behavior as evidenced from the rheological studies. PMID- 20163167 TI - Mucoadhesive nanoparticles as carrier systems for prolonged ocular delivery of gatifloxacin/prednisolone bitherapy. AB - A fluoroquinolone/glucocorticoid combination for the treatment of bacterial keratitis in the form of mucoadhesive nanoparticle suspensions was developed to prolong the release and improve patient compliance. Gatifloxacin/prednisolone loaded nanoparticles were prepared using Eudragit RS 100 and RL 100 and coated with the bioadhesive polymer, hyaluronic acid. FT-IR and DSC studies revealed no interaction between gatifloxacin and prednisolone. The effects of the drug:polymer ratio (D:P) and the RS/RL ratio were studied. The obtained nanoparticles were distinct and spherical with a solid dense structure. They have average particle size range of 315.2 to 973.65 nm. Increasing the D:P ratio significantly lowered the entrapment efficiency for both drugs (p < 0.05). The nanoparticle suspensions revealed significantly prolonged drug release comparing to the free drugs (p < 0.05) with no burst effect. Increasing the polymer concentration and the Eudragit RS ratio significantly decreased the release efficiency values. Gatifloxacin showed anomalous release (n = 0.4943) from 1:1 D:P ratio nanoparticle suspension and Fickian diffusion mechanism (n < 0.45) from formulas prepared at higher D:P ratios. Gatifloxacin showed better bioavailability and sustained action in aqueous humor and corneal tissue from the nanoparticles compared to the commercial eye drops. The resulting nanoparticle suspension is promising in reducing dose frequency and improving patient compliance. PMID- 20163168 TI - Binding of adenosine-based ligands to the MjDim1 rRNA methyltransferase: implications for reaction mechanism and drug design. AB - The KsgA/Dim1 family of proteins is intimately involved in ribosome biogenesis in all organisms. These enzymes share the common function of dimethylating two adenosine residues near the 3'-OH end of the small subunit rRNA; orthologs in the three kingdoms, along with eukaryotic organelles, have evolved additional functions in rRNA processing, ribosome assembly, and, surprisingly, transcription in mitochondria. The methyltransferase reaction is intriguingly elaborate. The enzymes can bind to naked small subunit rRNA but cannot methylate their target bases until a subset of ribosomal proteins have bound and the nascent subunit has reached a certain level of maturity. Once this threshold is reached, the enzyme must stabilize two adenosines into the active site at separate times and two methyl groups must be transferred to each adenosine, with concomitant exchanges of the product S-adenosyl-l-homocysteine and the methyl donor substrate S adenosyl-l-methionine. A detailed molecular understanding of this mechanism is currently lacking. Structural analysis of the interactions between the enzyme and substrate will aid in this understanding. Here we present the structure of KsgA from Methanocaldococcus jannaschii in complex with several ligands, including the first structure of S-adenosyl-l-methionine bound to a KsgA/Dim1 enzyme in a catalytically productive way. We also discuss the inability thus far to determine a structure of a target adenosine bound in its active site. PMID- 20163169 TI - Structures of alkali metal ion-adenine complexes and hydrated complexes by IRMPD spectroscopy and electronic structure calculations. AB - Complexes between adenine and the alkali metal ions Li(+), Na(+), K(+), and Cs(+) have been investigated by infrared multiple photon dissociation (IRMPD) spectroscopy between 2800 and 3900 cm(-1), as have some singly hydrated complexes. The IRMPD spectra clearly show the N-H stretching and the NH(2) symmetric and asymmetric stretching vibrations of adenine; and for the solvated ions, the O-H stretching vibrations are observed. These experimental spectra were compared with those for a variety of possible structures, including both A9 (A9 refers to the tautomer where hydrogen is on the nitrogen in position 9 of adenine, see Scheme 1) and A7 adenine tautomers, computed using B3-LYP/6 31+G(d,p). By comparing the experimental and the simulated spectra it is possible to rule out various structures and to further assign structures to the species probed in these experiments. Single-point calculations on the B3-LYP/6-31+G(d,p) geometries have been performed at MP2/6-311++G(2d, p) to obtain good estimates of the relative thermochemistries for the different structures. In all cases the computed IR spectrum for the lowest energy structure is consistent with the experimental IRMPD spectrum, but in some cases structural assignment cannot be confirmed based solely upon comparison with the experimental spectra so computed thermochemistries can be used to rule out high-energy structures. On the basis of the IRMPD spectra and the energy calculations, all adenine-M(+) and adenine-M(+) H(2)O are concluded to be composed of the A7 tautomer of adenine, which is bound to the cations in a bidentate fashion through N3 and N9 (see Scheme 1 for numbering convention). For the hydrated ions water binds directly to the metal ion through oxygen, as would be expected since the metal contains most positive charge density. For the hydrated lithium cation-bound adenine dimer, the water molecule is concluded to be hydrogen bonded to a free basic site of one of the adenine monomers, which is also bound to the lithium cation. Experimental and theoretical results on adenine-Li(+)-H(2)O suggest that the electrosprayed adenine-Li(+) resembles the lowest-energy solution phase ion rather than the lowest-energy gas-phase ion, which is the imine form. PMID- 20163170 TI - Tumor-targeting, pH-responsive, and stable unimolecular micelles as drug nanocarriers for targeted cancer therapy. AB - A new type of multifunctional unimolecular micelle drug nanocarrier based on amphiphilic hyperbranched block copolymer for targeted cancer therapy was developed. The core of the unimolecular micelle was a hyperbranched aliphatic polyester, Boltorn H40. The inner hydrophobic layer was composed of random copolymer of poly(epsilon-caprolactone) and poly(malic acid) (PMA-co-PCL) segments, while the outer hydrophilic shell was composed of poly(ethylene glycol) (PEG) segments. Active tumor-targeting ligands, i.e., folate (FA), were selectively conjugated to the distal ends of the PEG segments. An anticancer drug, i.e., doxorubicin (DOX) molecules, was conjugated onto the PMA segments with pH-sensitive drug binding linkers for pH-triggered drug release. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis showed that the unimolecular micelles were uniform with a mean hydrodynamic diameter around 25 nm. The drug loading content was determined to be 14.2%. The drug release profile, cell uptake and distribution, and cytotoxicity of the unimolecular micelles were evaluated in vitro. The folate-conjugated micelles can be internalized by the cancer cells via folate-receptor-mediated endocytosis; thus, they exhibited enhanced cell uptake and cytotoxicity. At pH 7.4, the physiological condition of bloodstream, DOX conjugated onto the unimolecular micelles exhibited excellent stability; however, once the micelles were internalized by the cancer cells, the pH-sensitive hydrazone linkages were cleavable by the intracellular acidic environment, which initially caused a rapid release of DOX. These findings indicate that these unique unimolecular micelles may offer a very promising approach for targeted cancer therapy. PMID- 20163171 TI - On the role of the cis Hoogsteen:sugar-edge family of base pairs in platforms and triplets-quantum chemical insights into RNA structural biology. AB - Base pairs belonging to the cis Hoogsteen:sugar-edge (H:S) family play important structural roles in folded RNA molecules. Several of these are present in internal loops, where they are involved in interactions leading to planar dinucleotide platforms which stabilize higher order structures such as base triplets and quartets. We report results of analysis of 30 representative examples spanning 16 possible base pair combinations, with several of them showing multimodality of base pairing geometry. The geometries of 23 of these base pairs were modeled directly from coordinates extracted from RNA crystal structures. The other seven were predicted structures which were modeled on the basis of observed isosteric analogues. After appropriate satisfaction of residual valencies, these structures were relaxed using the B3LYP/6-31G(d,p) method and interaction energies were derived at the RIMP2/aug-cc-pVDZ level of theory. The geometries for each of the studied base pairs have been characterized in terms of the number and nature of H-bonds, rmsd values observed on optimization, base pair geometrical parameters, and sugar pucker analysis. In addition to its evaluation, the nature of intermolecular interaction in these complexes was also analyzed using Morokuma decomposition. The gas phase interaction energies range between 5.2 and -20.6 kcal/mol and, in contrast to the H:S trans base pairs, show enhanced relative importance of the electron correlation component, indicative of the greater role of dispersion energy in stabilization of these base pairs. The rich variety of hydrogen bonding pattern, involving the flexible sugar edge, appears to hold the key to several features of structural motifs, such as planarity and propensity to participate in triplets, observed in this family of base pairs. This work explores these aspects by integrating database analysis, and detailed base pairing geometry analysis at the atomistic level, with ab initio computation of interaction energies. The study, involving alternative classification of base pairs and triplets, provides insights into intrinsic properties of these base pairs and their possible structural and functional roles. PMID- 20163174 TI - Inhibition of a protein tyrosine phosphatase using mesoporous oxides. AB - The feasibility of utilizing mesoporous matrices of alumina and silica for the inhibition of enzymatic activity is presented here. These studies were performed on a protein tyrosine phosphatase by the name chick retinal tyrosine phosphotase 2 (CRYP-2), a protein that is identical in sequence to the human glomerular epithelial protein-1 and involved in hepatic carcinoma. The inhibition of CRYP-2 is of tremendous therapeutic importance. Inhibition of catalytic activity was examined using the sustained delivery of p-nitrocatechol sulfate (pNCS) from bare and amine functionalized mesoporous silica (MCM-48) and mesoporous alumina (Al(2)O(3)). Among the various mesoporous matrices employed, amine functionalized MCM-48 exhibited the best release of pNCS and also inhibition of CRYP-2. The maximum speed of reaction v(max) (=160 +/- 10 micromol/mnt/mg) and inhibition constant K(i) (=85.0 +/- 5.0 micromol) estimated using a competitive inhibition model were found to be very similar to inhibition activities of protein tyrosine phosphatases using other methods. PMID- 20163175 TI - Effects of lability of metal complex on free ion measurement using DMT. AB - Very low concentrations of free metal ion in natural samples can be measured using the Donnan membrane technique (DMT) based on ion transport kinetics. In this paper, the possible effects of slow dissociation of metal complexes on the interpretation of kinetic DMT are investigated both theoretically and experimentally. The expressions of the lability parameter, Lgrangian , were derived for DMT. Analysis of new experimental studies using synthetic solution containing NTA as the ligand and Cu(2+) ions shows that when the ionic strength is low (or=18 years) with type 2 diabetes and were receiving pharmacological anti-diabetes treatment(s). Data were collected electronically and results were analysed using a standard statistical model designed for choice games (conditional logit). Six characteristics relating to treatment of diabetes were examined: weight (gain or loss), mean glycated haemoglobin level (HbA(1c)), hypoglycaemic events, nausea, need for injections (with or independently of meals), and blood glucose testing. RESULTS: A total of 461 people with type 2 diabetes (291 males; 170 females) completed an internet questionnaire and were eligible for inclusion. Participants placed high value on weight loss and nausea avoidance; they would pay 176 Swedish Krona (SEK)/euro15.61 per month to lose 1 kg, and would pay SEK 560 (euro49.67) per month to avoid nausea completely. Patients wanting to reduce the number of hypoglycaemic events from three per month to none were willing to pay SEK 419 (euro37.17) per month. Patients valued a 1 percentage point reduction in HbA(1c) at SEK 414 (euro36.72) per month. Participants preferred taking tablets to injections and required a compensation of SEK 376 (euro33.35) to accept one injection/day. Injections independent of meals were preferred to injections with meals (WTP: SEK 140/euro12.42 per month). Potential limitations of this study are that the preferences expressed may not match preferences in real-life situations, and bias through the use of electronic questionnaire, which restricted participation to those with access to, and experience with, the internet. CONCLUSION: People with type 2 diabetes were willing to pay a considerable amount of money each month to lose weight, reduce or avoid hypoglycaemic events and reduce HbA(1C). PMID- 20163196 TI - Helicobacter pylori seroprevalence in patients with chronic prostatitis: a pilot study. AB - OBJECTIVE: This study investigated the possible relationship between Helicobacter pylori infection and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). The rate of seropositivity for antibodies against H. pylori was determined in a cohort of subjects with CP/CPPS and prostatitis-free control subjects. MATERIAL AND METHODS: Sixty-four consecutive patients with CP/CPPS and 55 randomly selected asymptomatic men were recruited to the study. Blood samples from enrolled patients and control subjects were analysed using an enzyme-linked Immulite analyser immunoglobulin G serological test for H. pylori diagnosis. Prostate volume, prostate-specific antigen level, maximum urinary flow rate, and International Prostate Symptom Score (IPSS) and National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score of the subjects were also determined. The results were analysed with chi-squared and Student's t test and statistical analysis was carried out using SPSS software. RESULTS: There were no significant differences in age and social status between the CP/CPPS and control groups (p > 0.05). Total NIH-CPSI score was significantly higher in the CP/CPPS group. Seropositivity for antibody against H. pylori was higher in the CP/CPPS than the control group (p < 0.05). CONCLUSIONS: This pilot study supports the hypothesis that H. pylori may play a role in CP/CPPS. The infection may be related to the immune response and increased cytokines in seminal plasma and/or expressed prostatic secretion. However, no study has investigated the relationship between CP/CPPS and H. pylori stool antigen positivity. This study showed that H. pylori seropositivity is high in CP/CPPS patients, but this needs to be confirmed by other studies. PMID- 20163197 TI - Effects of extended release niacin/laropiprant, laropiprant, extended release niacin and placebo on platelet aggregation and bleeding time in healthy subjects. AB - Laropiprant (LRPT) has been shown to reduce flushing symptoms induced by niacin and has been combined with niacin for treatment of dyslipidemia. LRPT, a potent PGD(2) receptor (DP1) antagonist that also has modest activity at the thromboxane receptor (TP), may have the potential to alter platelet function either by enhancing platelet reactivity through DP1 antagonism or by inhibiting platelet aggregation through TP antagonism. Studies of platelet aggregation ex vivo and bleeding time have shown that LRPT, at therapeutic doses, does not produce clinically meaningful alterations in platelet function. The present study was conducted to assess platelet reactivity to LRPT using methods that increase the sensitivity to detect changes in platelet responsiveness to collagen and ADP. The responsiveness of platelets was quantified by determining the EC(50) of collagen to induce platelet aggregation ex vivo. At 24 hours post-dose on Day 7, the responsiveness of platelets to collagen-induced aggregation was similar following daily treatment with extended-release niacin (ERN) 2 g/LRPT 40 mg or ERN 2 g. At 2 hours post-dose on Day 7, the EC(50) for collagen-induced platelet aggregation was approximately two-fold higher in the presence of LRPT, consistent with a small, transient inhibition of platelet responsiveness to collagen. There was no clinical difference between treatments for bleeding time, suggesting that this small effect on collagen EC(50) does not result in a clinically meaningful alteration of platelet function in vivo. The results of this highly sensitive method demonstrate that LRPT does not enhance platelet reactivity when given alone or with ERN. PMID- 20163198 TI - The relationship between cisplatin-induced reactive oxygen species, glutathione, and BCL-2 and resistance to cisplatin. AB - Cisplatin (cDDP) is an anticancer agent that is widely used in the treatment of many solid tumors. A major obstacle to successful cDDP-based chemotherapy, however, is the intrinsic and acquired resistance of tumor cells to this drug. Greater insight into the molecular mechanisms underlying the modulation of cellular responses to cDDP will aid in the development and optimization of new therapeutic strategies. Apart from induction of DNA damage, recent data have suggested that cDDP also induces the formation of reactive oxygen species that can trigger cell death. Cell death occurs as the result of several simultaneously activated signaling pathways. The specific pathway responsible for cell death depends on the cell type and the treatment conditions. This review focuses on the relationship between glutathione and BCL-2 and their protective role in cDDP induced reactive oxygen species formation and cDDP resistance. PMID- 20163199 TI - Evaluation of solid free-form fabrication-based scaffolds seeded with osteoblasts and human umbilical vein endothelial cells for use in vivo osteogenesis. AB - We investigated the feasibility of using solid free-form fabrication (SFF)-based scaffolds seeded with osteoblasts, derived from human adipose-derived stem cells, and human umbilical vein endothelial cells (HUVECs) to enhance osteogenesis. To accomplish this goal, SFF-based polycaprolactone/poly-lactic-co-glycolic acid/tricalcium phosphate scaffolds were fabricated using a multihead deposition system, which is one SFF technique. The blended polycaprolactone/poly-lactic-co glycolic acid/TCP scaffolds were seeded with human osteoblasts and HUVECs and implanted into calvaria defects in rats. At 8 and 12 weeks after implantation, microcomputed tomography, real-time polymerase chain reaction, and histological assays (hematoxylin and eosin staining and Alizarin red staining) were conducted to determine the effects of SFF-based scaffolds on osteogenic potential. In vivo experiments indicated that the osteoblast-only and osteoblast-HUVEC group produced bone formation. Additionally, scaffolds in the osteoblast-HUVEC group had the largest area of new bone tissue. Therefore, we demonstrated through microcomputed tomography and histological assays that scaffolds seeded with both human osteoblasts and HUVECs were superior to other groups for effective bone formation. PMID- 20163200 TI - Valproate-induced hyperammonemic encephalopathy, rapidly improved by i.v. carnitine and glucose/thiamine. PMID- 20163201 TI - Fatal esophageal perforation caused by oral iron. PMID- 20163202 TI - An association between functional FceRIalpha polymorphisms and total serum IgE levels in patients with inflammatory bowel disease. PMID- 20163203 TI - Prediction of 6-thioguanine nucleotides levels in Japanese patients with inflammatory bowel diseases during long-term thiopurine administration. AB - BACKGROUND: The monitoring of 6-thioguanine nucleotides (6-TGN) levels is warranted during thiopurine therapy for patients with inflammatory bowel diseases. AIMS: The aim of this study was to elucidate the parameters that can predict the 6-TGN levels among Japanese patients with inflammatory bowel diseases undergoing thiopurine therapy. MATERIAL AND METHODS: The 6-TGN levels were measured in 54 patients with inflammatory bowel diseases (32 with ulcerative colitis and 22 with Crohn's disease), who had been administered azathioprine or 6 mercaptopurine for more than 90 days. Possible correlations between the hematologic parameters and 6-TGN levels were investigated. The clinical and hematologic variables were evaluated to determine the 6-TGN levels of less than or over 235 pmol/8 x 10(8) RBCs. RESULTS: The 6-TGN levels correlated significantly with changes in the mean corpuscular volume (R = 0.423, p = 0.001) and the lymphocyte counts (R = -0.280, p = 0.04). A multivariate analysis revealed changes in the mean corpuscular volume (OR: 1.22, 95% CI: 1.07-1.40) and hemoglobin levels (OR: 0.59, 95% CI: 0.35-0.99) to be factors predictive of the 6 TGN levels. An increase in the mean corpuscular volume of 3.5 fl was determined to be the most preferable cut-off value to distinguish patients with 6-TGN >or= 235 pmol/8 x 10(8) RBCs from those with a lower concentration. CONCLUSIONS: Changes in the mean corpuscular volume are considered to be predictive of the 6 TGN levels in patients with inflammatory bowel diseases receiving thiopurine therapy. PMID- 20163204 TI - Encapsulation of pancreatic islets within nano-thin functional polyethylene glycol coatings for enhanced insulin secretion. AB - Covalent attachment of polymers to cells and tissues could be used to solve a variety of problems associated with cellular therapies. Insulin-dependent diabetes mellitus is a disease resulting from the autoimmune destruction of the beta cells of the islets of Langerhans in the pancreas. Transplantation of islets into diabetic patients is an attractive form of treatment, provided that the islets could be protected from the host's immune system to prevent graft rejection, and smaller numbers of islets transplanted in smaller volumes could be sufficient to reverse diabetes. Therefore, a need exists to develop islet encapsulation strategies that minimize transplant volume. In this study, we demonstrate the formation of nano-thin, poly(ethylene glycol) (PEG)-rich functional conformal coatings on individual islets via layer-by-layer assembly technique. The surface of the islets is modified with biotin-PEG-N hydroxysuccinimide (NHS), and the islets are further covered by streptavidin (SA) and biotin-PEG-peptide conjugates using the layer-by-layer method. An insulinotropic ligand, glucagon-like peptide-1 (GLP-1), is conjugated to biotin PEG-NHS. The insulinotropic effect of GLP-1 is investigated through layer-by layer encapsulation of islets using the biotin-PEG-GLP-1 conjugate. The effect of islet surface modification using the biotin-PEG-GLP-1 conjugate on insulin secretion in response to glucose challenge is compared via static incubation and dynamic perifusion assays. The results show that islets coated with the functional PEG conjugate are capable of secreting more insulin in response to high glucose levels compared to control islets. Finally, the presence of SA is confirmed by indirect fluorescent staining with SA-Cy3, and the presence of PEG peptide on the surface of the islets after treatment with biotin-PEG-GLP-1 is confirmed by indirect fluorescent staining with biotin-PEG-fluorescein isothiocyanate (FITC) and separately with an anti-GLP-1 antibody. This work demonstrates the feasibility of treating pancreatic islets with reactive polymeric segments and provides the foundation for a novel means of potential immunoisolation. With this technique, it may be possible to encapsulate and/or modify islets before portal vein transplantation and reduce transplantation volume significantly, and promote islet viability and insulin secretion due to the presence of insulinotropic peptides on the islet surface. Layer-by-layer self assembly of PEG-GLP-1 offers a unique approach to islet encapsulation to stimulate insulin secretion in response to high glucose levels. PMID- 20163205 TI - Human trypsinogens in the pancreas and in cancer. AB - This study led to the development of monoclonal antibodies and time-resolved immunofluorometric methods recognizing human trypsinogen-1 and -2, respectively. Using these methods in normal sera the concentration of trypsinogen-1 was found to be higher than that of trypsinogen-2. However, in acute pancreatitis the concentration of serum trypsinogen-2 was 50-fold higher than in controls, whereas the difference in trypsinogen-1 concentration was only 15-fold. Serum samples from patients who had undergone pancreatoduodenectomy contained trypsinogen-2, while trypsinogen-1 was detected in only one of nine samples. Furthermore, in human ovarian cyst fluids tumor-associated trypsinogen-2 (TAT-2) is the predominant isoenzyme and in mucinous cyst fluids the levels of TAT-2 were associated with malignancy. These results suggest that (i) trypsinogen-2 could be used as a diagnostic marker for acute pancreatitis, (ii) its expression is not restricted to the pancreas, and (iii) TAT could be involved in ovarian tumor dissemination and breakage of tissue barriers. In ion exchange chromatography, isoelectric variants of the trypsinogen isoenzymes were seen. Mass spectrometric analysis of these revealed that pancreatic trypsinogens are sulfated at tyrosine 154 (Tyr154), whereas TAT-2 from a colon carcinoma cell line is not. Tyr154 is located within the primary substrate binding pocket of trypsin. Thus, Tyr154 sulfation is likely to influence substrate binding. The previously known differences in charge and substrate binding between pancreatic and tumor associated trypsinogens are suggested to be caused by sulfation of Tyr154 in pancreatic trypsinogens. PMID- 20163206 TI - Mesenchymal stem cells, osteoblasts and extracellular matrix proteins: enhancing cell adhesion and differentiation for bone tissue engineering. AB - Cell adhesion to scaffolds has remained one of the challenges in tissue engineering. Although protein surface modification has been proven to enhance cell adhesion and retention, its specificity depending on cell and biomaterial types means that the best protein and concentration must be established for each specific application. This review focuses on the improvement of cell adhesion for human mesenchymal stem cells with an osteogenesis approach. A brief outline of the cell adhesion process and extracellular matrix proteins precedes an overview of works focused on the adhesion of mesenchymal stem cells and osteoblasts to biomaterials and this effect in their differentiation into osteoblasts. PMID- 20163208 TI - Ethical aspects of soft tissue engineering for congenital birth defects in children--what do experts in the field say? AB - This article is part of the EuroSTEC project, which aims at developing tissue engineering-based treatments for structural disorders present at birth. EuroSTEC is positioned at the intersection of three areas with their own ethical issues: (1) regenerative medicine, (2) research with pregnant women and fetuses, and (3) research with neonates. Because of the overlap of these three areas in this project, we can expect to be confronted with new ethical challenges. To be able to respond adequately and timely to current and possible future ethical issues, a prospective and anticipatory ethical analysis is essential. To obtain a first survey of ethical issues that might arise during the different phases of the project, the Delphi method was used. The professionals directly involved in the EuroSTEC project were questioned about their views on possible ethical issues. The first round yielded 27 ethical issues, which the respondents were asked to prioritize in the second round. For the fundamental research phase, issues deemed most important were privacy and informed consent of the tissue donor. For the animal experimentation phase, three issues were mentioned (in order of decreasing priority): the suffering of animals, the use of animals as means to an end, and the limited adequacy of the animal models. Issues that were deemed most important during the clinical (trial) phase pertained to the problem of weighing risks and benefits for the fetus/child and the pregnant woman. PMID- 20163207 TI - Chemical induction of cardiac differentiation in p19 embryonal carcinoma stem cells. AB - P19 cells, a pluripotent cell line derived from a teratocarcinoma induced in C3H/HeHa mice, have been widely used as a model system to study cardiac differentiation. We have used these cells to evaluate the extent to which exposure to DMSO and/or cardiogenol C for 4 days in suspension culture enhanced their differentiation into cardiomyocytes. Cardiac differentiation was assessed by observing beating clusters and further confirmed using immunocytochemical, biochemical, and pharmacological approaches. The presence of functional gap junctions in differentiated P19 cells was identified through calcium wave analyses. Proliferation rate and cell death were analyzed by BrdU incorporation and activated caspase-3 immunodetection, respectively. Beating clusters of differentiated P19 cells were only found in cultures treated with DMSO. In addition, groups treated with DMSO up-regulated cardiac troponin-T expression. However, when DMSO was used together with cardiogenol C the up-regulation was less than that with DMSO alone, approximately 1.5 times. Moreover, P19 cells cultured in DMSO or DMSO plus 0.25 microM cardiogenol C had lower proliferation rates and higher numbers of activated caspase-3-positive cells. In summary, using several methodological approaches we have demonstrated that DMSO can induce cardiac differentiation of P19 cells but that cardiogenol C does not. PMID- 20163211 TI - Comparison of potentials between stem cells isolated from human anterior cruciate ligament and bone marrow for ligament tissue engineering. AB - We have previously isolated and identified stem cells from human anterior cruciate ligament (ACL). The purpose of this study was to evaluate the differences in proliferation, differentiation, and extracellular matrix (ECM) formation abilities between bone marrow stem cells (BMSCs) and ACL-derived stem cells (LSCs) from the same donors when cultured with different growth factors, including basic fibroblast growth factor (bFGF), epidermal growth factor, and transforming growth factor-beta 1 (TGF-beta1). Ligament tissues and bone marrow aspirate were obtained from patients undergoing total knee arthroplasty and ACL reconstruction surgeries. Proliferation, colony formation, and population doubling capacity as well as multilineage differentiation potentials of LSCs and BMSCs were compared. Gene expression and ECM production for ligament engineering were also evaluated. It was found that BMSCs possessed better osteogenic differentiation potential than LSCs, while similar adipogenic and chondrogenic differentiation abilities were observed. Proliferation rates of both LSCs and BMSCs were enhanced by bFGF and TGF-beta1. TGF-beta1 treatment significantly increased the expression of type I collagen, type III collagen, fibronectin, and alpha-smooth muscle actin in LSCs, but TGF-beta1 only upregulated type I collagen and tenascin-c in BMSCs. Protein quantification further confirmed the results of differential gene expression and suggested that LSCs and BMSCs increase ECM production upon TGF-beta1 treatment. In summary, in comparison with BMSCs, LSCs proliferate faster and maintain an undifferentiated state with bFGF treatment, whereas under TGF-beta1 treatment, LSCs upregulate major tendinous gene expression and produce a robust amount of ligament ECM protein, making LSCs a potential cell source in future applications of ACL tissue engineering. PMID- 20163215 TI - Student attitudes to peer physical examination: a qualitative study of changes in expressed willingness to participate. AB - BACKGROUND: A number of studies have explored student attitudes to examining each other (peer physical examination: PPE). Differences have emerged in whether students prefer to be examined by friends or strangers. Changes have been reported in how students feel about PPE if asked before or after the PPE programme commences. RESEARCH INTENTION: Since a Grounded Theory paradigm was employed, there was no formal research hypothesis: the research intention was to explore factors which might underlie changes in student willingness to undertake PPE following familiarity with the process. METHODS: Students who had completed an Examining Fellow Students Questionnaire at the beginning and end of the academic year, and who had indicated a change in willingness to participate, were invited to attend focus groups. Four focus groups were convened and transcripts were analysed for common themes. RESULTS: Surprisingly, students downplayed the significance of changes. Also unexpectedly, dichotomous views emerged on familiarity, with some students preferring friends for examination and others preferring strangers. Staff embarrassment also emerged as a factor inhibiting student participation. CONCLUSIONS: The significance of reported changes in attitudes to PPE may have been exaggerated. Proposals for increasing the willingness of students to participate in PPE are developed from the emergent themes. PMID- 20163216 TI - Improving residents' teaching skills: a program evaluation of residents as teachers course. AB - BACKGROUND: The role of residents as teachers is recognized as an important part of medical education. However, residents may not possess the practical skills needed to teach medical students effectively. AIM: In response to a Liaison Committee on Medical Education citation concerning surgery residents' teaching skills, the University of Louisville School of Medicine instituted a campus-wide residents as teachers program based on the bringing education and service together curriculum. METHODS: This evaluation plan is grounded on Kirkpatrick's four levels model. Levels 1 and 2 data included post-session learner questionnaires (2007 and 2008) and open-ended facilitator questionnaires (2008). Levels 3 and 4 data included third year medical students' responses to CourseEval questions on residents as teachers (2005-2006 and 2007-2008) and data from third year medical student focus groups (2008). RESULTS: Levels 1 and 2 data analysis showed statistically significant improvements from session to session in Year I and significant improvements between Years I and II. Levels 3 and 4 data analysis showed third year students' perceptions of most residents as teachers remained high and improved significantly in the surgery clerkship. CONCLUSION: Short-term and long-term measures show this curriculum to be successful for an interdisciplinary group of residents. PMID- 20163217 TI - A model of quality assurance and quality improvement for post-graduate medical education in Europe. AB - BACKGROUND: The issue of quality assurance (QA) and quality improvement (QI), being the quality of medical education intimately related to the quality of the health care, is becoming of paramount importance worldwide. AIM: To describe a model of implementing a system for internal QA and QI within a post-graduate paediatric training programme based on the ISO 9001:2000 standard. METHODS: For the ISO 9001:2000 standard, the curriculum was managed as a series of interrelated processes and their level of function was monitored by ad hoc elaborated objective indicators. RESULTS: The training programme was fragmented in 19 interlinked processes, 15 related procedures and 24 working instructions. All these materials, along with the quality policy, the mission, the strategies and the values were made publicly available. Based on the measurable indicators developed to monitor some of the processes, areas of weakness of the system were objectively identified and consequently QI actions implemented. The appropriateness of all this allowed the programme to finally achieve an official ISO 9000:2001 certification. CONCLUSIONS: The application of the ISO 9001:2000 standard served to develop an internal QA and QI system and to meet most of the standards developed for QA in higher and medical education. PMID- 20163218 TI - A novel assessment of an evidence-based practice course using an authentic assignment. AB - BACKGROUND: Evidence-based practice (EBP) is now a component of most medical curricula. Summative assessment instruments are often of debatable quality, do not cover the full spectrum of EBP or lack authenticity. AIM: To develop and evaluate the quality of an authentic assessment instrument for use in summative assessment of general practice trainees. METHODS: An assignment was designed based on the ask, acquire, appraise and apply steps of EBP. Content validity was evaluated by external EBP experts. Concurrent validity was tested with the Fresno test. Inter-rater agreement and internal consistency were measured. Acceptability and feasibility were also assessed. RESULTS: EBP experts agreed that the instrument had good content validity. Concurrent validity was good (disattenuated intraclass correlation coefficient 0.75). Inter-rater agreement varied from 0.70 to 0.83. Internal consistency was high (Cronbach's alpha 0.70-0.86). The procedure was feasible but only moderately acceptable to students. CONCLUSION: Our authentic assignment provided a valid, reliable and feasible procedure to assess our students. Acceptability was moderate, probably due to teething problems in instructions given and unfamiliarity with the format. Consequential validity data are lacking and would be of value. Our instrument could be an interesting alternative to other validated tests that may be less authentic. PMID- 20163219 TI - New fitness-to-practice requirements for pharmacists in Ireland: implications for undergraduate pharmacy education. AB - Internationally, there is tighter monitoring and enforcement of fitness-to practice requirements in healthcare, which are being specified within legislation and guidelines. In Ireland, the Pharmacy Act 2007, that was recently published and is being gradually implemented, includes a provision for monitoring fitness to-practice of pharmacists practicing here. This will mean that upon initial and continued registration by the Council of the Pharmaceutical Society of Ireland, pharmacists must satisfy a fitness-to-practice committee. Two routes by which a pharmacist can be deemed unfit to practice are specified within the Act - on the basis of ill health and through technical incompetence/malice. However, the exact nature of professional, cultural, and technical competencies required to satisfy these new fitness-to-practice requirements remain undecided and a further consultation with all stakeholders is required. Importantly, this consultative process must consider current practice standards and raise awareness of these issues among pharmacists while also considering the current and future undergraduate pharmacy students, i.e. the future pharmacists of Ireland. Radical cultural shifts in monitoring fitness-to-practice, with full professional accountability, must inform changes in the undergraduate curriculum and in assessing students, such that when they graduate, they are thoroughly prepared for ongoing fitness-to-practice scrutiny. Here, different approaches to international pharmacy education that may help pharmacy educators in Ireland prepare their students for the new fitness-to-practice requirements are reviewed and discussed. PMID- 20163220 TI - Policy and attitude-related reasons for gender disparity in post allocation for graduate medical education in Austria. AB - OBJECTIVE: A previous study found that in Austria 50.3% physicians (m: 43.2%, f: 58.6%) have not attained their chosen specialty. We aimed to explore the policy - and attitude-related reasons for gender disparity in training post allocation. METHODS: This cross-sectional study used a quantitative and a qualitative method. A self-administered 12-item questionnaire was sent twice to all 8127 licensed Viennese physicians. Physicians' opinions regarding why the chosen medical specialty was not attained were analyzed. To estimate the responder bias respondents from the first and second mailing were compared. RESULTS: A total of 2736 questionnaires (34%) were returned. When a specialty is favored by men, the chance for women to achieve that specialty decreases. According to the qualitative results, men were more often ready to accept training in a specialty different from the one originally desired. Female physicians were put at a disadvantage by consultants due to organizational considerations and sex stereotyping. CONCLUSIONS: According to physicians' self-reported opinions, consultants do not place female candidates at disadvantage as a result of an unconscious process but mainly based on reasoning about organizational aspects and sex-stereotyping. Several explanations for the phenomenon that men are more often ready to accept training in a specialty different from the one originally desired were identified. PMID- 20163221 TI - Developing self-assessment skills amongst doctors in Nepal. AB - BACKGROUND: Accurate self-assessment is essential to direct life-long learning. Most research on self-assessment is from the West. This study takes place in Kathmandu, Nepal. AIM: To develop tools to aid the development of self-assessment skills in Nepali doctors. METHODS: Fifteen doctors were asked to complete three self-assessment tasks per month over a 6-month period; one mini-clinical evaluation exercise, one clinical case review and one significant event analysis. Self-assessment was compared with mentor assessment for each task. Changes over time for each individual were noted. Results were analyzed using SPSS 10.0. Self and tutor scores were compared using Pearson's correlation coefficient. Reliability of the tools was assessed using Cronbach's Alpha. Participants completed a qualitative questionnaire regarding each tool. RESULTS: All three tools had high content and face validity, as well as reliability. The use of the "intra individual" approach, with multiple assessments over time demonstrated that most doctors were able to accurately self-assess in some areas. Feedback from a senior tutor was vital. Doctors appreciated feedback that was immediate, specific and delivered in a safe environment. Even where self-assessment was less accurate, the process itself helped to develop awareness of key learning issues. CONCLUSIONS: These self-assessment tools are feasible, reliable and valid for the hospital setting in Nepal. PMID- 20163222 TI - A teaching encounter card to evaluate clinical supervisors across clerkship rotations. AB - BACKGROUND: Evaluation of faculty teaching is critical to improving the educational experience for both students and faculty. AIM: Our objectives were to implement an evaluation system, using the teaching encounter card, across multiple rotations in the clerkship and determine the feasibility, reliability and validity of this evaluation tool in this expanded setting. METHODS: Students were asked to rate clinical supervisors on nine teaching behaviours using a 6 point rating scale and asked whether they would like to nominate the teacher for a clinical teaching award. RESULTS: A total of 3971 cards for 587 clinical supervisors across seven clerkship rotations were analyzed. There was an average of 7.3 cards per supervisor (median = 5, range 2-66). There was high internal consistency between items on the card (Cronbach's alpha 0.965). The reliability was fair at 0.63. Seventeen cards per supervisor would be required to achieve a reliability >0.8 (G study). Ratings were higher for encounters that occurred in the operating room and within the anaesthesia rotation. The teachers who had a positive recommendation for teaching award nomination received higher scores than their colleagues. CONCLUSION: We successfully implemented a faculty evaluation card across clerkship rotations that was flexible enough to use in multiple learning environments and allowed the identification of outstanding clinical teachers. PMID- 20163223 TI - Team-based learning: moving forward in curriculum innovation: a commentary. PMID- 20163224 TI - The AMEE Fringe, the antidote for PowerPoint poisoning. PMID- 20163225 TI - Reform of medical education in Korea. AB - There are 41 medical schools in South Korea with over 3500 students graduating from the medical schools annually with the appropriate qualifications to practice medicine. Korean medical educators have made significant efforts to enhance the effectiveness of medical education by preparing students for the rapidly changing global environment of medicine and healthcare. This article outlines the reform efforts made by Korean medical schools to meet such demands, which includes the adoption of student-centered and competency-based education, e-learning, and authentic assessment of clinical performance. It also discusses the recent reform of the medical education system, driven by the Government's policy to prepare Korean higher education for an increasingly knowledge-based society. PMID- 20163226 TI - Twelve tips for doing effective Team-Based Learning (TBL). AB - Team-based learning (TBL) in medical education has emerged over the past few years as an instructional strategy to enhance active learning and critical thinking - even in large, basic science courses. Although TBL consistently improves academic outcomes by shifting the instructional focus from knowledge transmission to knowledge application, it also addresses several professional competencies that cannot be achieved or evaluated through lecture-based instruction. These 12 tips provide the reader with a set of specific recommendations which, if followed, will ensure the successful design and implementation of TBL for a unit of study. PMID- 20163227 TI - Using team-based learning to prepare medical students for future problem-based learning. AB - BACKGROUND: The original concept of problem-based learning (PBL) was built upon an acceptance that its participants would be of a more mature age, and with personal and potential qualities that would equip them for problem solving as part of their learning process. However, despite global acceptance for the use of PBL in medical and health sciences education, and knowledge of the diverse background of students about to embark upon PBL, structured programs preparing medical students for such an educational activity are not common. AIM: The primary aim of this study is to describe the experience in adopting and adapting an educational approach analogous to PBL, team-based learning (TBL), in preparing medical students to later study in a PBL environment and secondarily, to measure the students' reaction to this experience. METHODS: At the University of Sharjah, 363 students were enrolled over four semesters in the 'Introduction to Medical Sciences Education (IMSE)' course. They were divided into groups of 25-27 students per class, where their learning was facilitated through a TBL approach. The course was evaluated both quantitatively and qualitatively and appropriate statistical analysis was applied to their responses. RESULTS: Out of 363 students, 304 (84%) responded to a 28-item closed-ended questionnaire. Their mean scores and consensus measurements indicated a high degree of students' satisfaction. Eighty-two students (65%) responded to the open-ended questions providing 139 comments. Content analysis of the responses supported the quantitative results. CONCLUSION: This study demonstrated a high degree of students' satisfaction from the course in acquiring skills preparing them for future PBL. Although this represents an evaluation of the TBL effects upon the early exposures to PBL, TBL was considered to be a feasible, efficient and cost effective educational approach in preparing the students for their new educational experience. PMID- 20163228 TI - Using team-based learning to teach pharmacology to second year medical students improves student performance. AB - BACKGROUND: Team-based learning (TBL) is an innovative instructional method that fosters active learning. It has been shown to improve student performance in some health care education courses. AIM: To examine the effect of teaching pharmacology using a TBL approach on second year medical students' satisfaction and performance. METHODS: A modified TBL method was used in two case-based discussion sessions of the second year pharmacology course: a relatively easy drug metabolism/pharmacogenetics session and a more challenging pharmacokinetics/pharmacodynamics (PK/PD) session. Individual and group answers to all questions were recorded, and an evaluation form was collected for each session. Class performance on a summative quiz was compared to previous years. RESULTS: Students provided positive feedback. Group performance was better than individual performance during the TBL exercises. TBL was less successful when the questions were very difficult, with a difficulty range of 30-70% being the most appropriate. Performance of the class on the pharmacology summative quiz showed significant improvement over that in previous years in the PK/PD part, but was unchanged in other topics taught traditionally. CONCLUSION: The results suggest that TBL provides a better outcome for students, and provide insight into appropriate design of TBL exercises. PMID- 20163229 TI - Identifying professional characteristics of the ideal medical doctor: the laddering technique. AB - OBJECTIVE: The aim was to examine the utility of the laddering interview technique to investigate complex issues in medical education, such as professionalism. METHOD: The laddering technique was used to identify examples of professional behaviour associated with the ideal medical doctor, and to explain why participants thought these behaviours were important. Three groups were interviewed: doctors (n = 30), first-year medical students (n = 31) and patients (n = 33). RESULTS: All groups identified characteristics associated with a 'communication and interpersonal skills' theme. Data suggested the essence of the doctor-patient interaction was shared by the groups, with varying later emphases due to their different perspectives. Additionally, Doctors and Students generated characteristics associated with 'team-working' and 'competence' themes; Doctors' conceptualization of each theme was more detailed. Positive and negative impacts of Doctor's professional behaviour on the patient, doctor and the wider medical arena were also identified. CONCLUSION: Use of laddering resulted in data-rich results for each of the three stakeholder groups, illustrating shared and divergent preferences as to the preferred characteristics of a medical doctor and effects of successful and less-successful doctor-patient interactions. The identified characteristics are relevant to the area under investigation and salient to these key stakeholders. PMID- 20163230 TI - Three methods of multi-source feedback compared: a plea for narrative comments and coworkers' perspectives. AB - BACKGROUND: Doctor performance assessments based on multi-source feedback (MSF) are increasingly central in professional self-regulation. Research has shown that simple MSF is often unproductive. It has been suggested that MSF should be delivered by a facilitator and combined with a portfolio. AIMS: To compare three methods of MSF for consultants in the Netherlands and evaluate the feasibility, topics addressed and perceived impact upon clinical practice. METHOD: In 2007, 38 facilitators and 109 consultants participated in the study. The performance assessment system was composed of (i) one of the three MSF methods, namely, Violato's Physician Achievement Review (PAR), the method developed by Ramsey et al. for the American Board of Internal Medicine (ABIM), or the Dutch Appraisal and Assessment Instrument (AAI), (ii) portfolio, (iii) assessment interview with a facilitator and (iv) personal development plan. The evaluation consisted of a postal survey for facilitators and consultants. Generalized estimating equations were used to assess the association between MSF method used and perceived impact. RESULTS: It takes on average 8 hours to conduct one assessment. The CanMEDS roles 'collaborator', 'communicator' and 'manager' were discussed in, respectively, 79, 74 and 71% of the assessment interviews. The 'health advocate role' was the subject of conversation in 35% of the interviews. Consultants are more satisfied with feedback that contains narrative comments. The perceived impact of MSF that includes coworkers' perspectives significantly exceeds the perceived impact of methods not including this perspective. CONCLUSIONS: Performance assessments based on MSF combined with a portfolio and a facilitator-led interview seem to be feasible in hospital settings. The perceived impact of MSF increases when it contains coworkers' perspectives. PMID- 20163231 TI - Being a mentor for undergraduate medical students enhances personal and professional development. AB - BACKGROUND: There is increasing evidence of the positive effects of mentoring in medical undergraduate programmes, but as far as we know, no studies on the effects for the mentors have yet been described in the field of medicine. AIM: This study aims to evaluate an undergraduate mentor programme from the mentors' perspective, focusing particularly on the effect of mentorship, the relationships between mentoring and teaching and the mentors' perceived professional and personal development. METHODS: Data was gathered through a questionnaire to all 83 mentors (response rate 75%) and semi-structured interviews with a representative sample of 10 mentors. RESULTS: Findings show, for example, that a majority of respondents developed their teaching as a result of their mentorship and improved their relations with students. Most respondents also claimed that being a mentor led to an increased interest in teaching and increased reflections regarding their own values and work practices. CONCLUSION: Being a mentor was perceived as rewarding and may lead to both personal and professional development. PMID- 20163232 TI - A standard setting method with the best performing students as point of reference: practical and affordable. AB - BACKGROUND: Teachers involved in test development usually prefer criterion referenced standard setting methods using panels. Since expert panels are costly, standards are often set by a pre-fixed percentage of questions answered correctly or norm-referenced methods aimed at ranking examinees. AIM: To discuss the (dis)advantages of commonly used criterion and norm-referenced methods and present a new compromise method: standards based on a fixed cut-off score using the best scoring students as reference point. METHODS: Historical data from 54 Maastricht (norm-referenced) and 52 Groningen (criterion-referenced) tests were used to demonstrate huge discrepancies and variability in cut-off scores and failure rates. Subsequently, the compromise model - known as Cohen's method - was applied to the Groningen tests. RESULTS: The Maastricht norm-referenced method led to a large variation in required cut-off scores (15-46%), but a stable failure rate (about 17%). The Groningen method with a conventional, pre-fixed standard of 60% led to a large variation in failure rates (17-97%). The compromise method reduced variation in required cut-off scores as well as failure rates. CONCLUSION: Both the criterion and norm-referenced standards, used in practice, have disadvantages. The proposed compromise model reduces the disadvantages of both methods and is considered more acceptable. Last but not least, compared to standard setting methods using panels, this method is affordable. PMID- 20163233 TI - PHEEM 'downunder'. AB - BACKGROUND: The use of the Postgraduate Hospital Education Environment Measure (PHEEM) has been previously described in this journal. AIMS: We established a nine-hospital project to test the acceptability of the PHEEM in Australia. METHOD: We adapted the language of some items in the PHEEM in order to localize the terminology (such as 'beeped'/'paged') and adjusted the demographics section to facilitate tracking of individual hospitals in the project. RESULTS: Over two years, more than 400 PHEEMs were returned. Eight of the nine hospitals have an educational environment that is 'more positive than negative but with room for improvement'. One has an 'excellent' environment. None are in the two lowest scoring categories. The lowest scoring items in the collaborative project related to 'feedback', 'information and support', 'infrastructure' and 'interruptions'. The highest scoring items related to 'teachers', 'personal security' and 'working together'. CONCLUSION: The PHEEM is valuable for systematically collecting information about the educational environment of hospitals. It has brought particular attention to problems associated with protected training time for first year trainees, inappropriate paging and lack of feedback. PMID- 20163234 TI - Medical students seeking medical help: a qualitative study. AB - BACKGROUND: This study explores the factors influencing students to seek medical help, and student perceptions in relation to student-doctor interactions with implications for health help-seeking behaviours. METHOD: Students were interviewed across year groups. The interviews were audiotaped, transcribed and qualitatively analysed. RESULTS: We interviewed 22 students and identified common themes. CONCLUSION: Medical students reflect on issues related to seeking medical help, their choice of GP and the decision whether to divulge they are medical students. PMID- 20163235 TI - Teaching in the clinical environment: guide supplement 34.3--practical application. PMID- 20163236 TI - Continuing medical education: guide supplement 35.1--Viewpoint. PMID- 20163237 TI - Continuing medical education: guide supplement 35.2--Viewpoint. PMID- 20163238 TI - Setting and maintaining standards in multiple choice examinations: guide supplement 37.1--Viewpoint. PMID- 20163239 TI - An innovative model for the structured on-ward supervision of final year students. PMID- 20163240 TI - eMedical Teacher. Thermodynamics of learning. PMID- 20163242 TI - Quantitative monitoring of lipid accumulation over time in cultured adipocytes as function of culture conditions: toward controlled adipose tissue engineering. AB - Adipose tissue engineering is investigated for native fat substitutes and wound healing model systems. Research and clinical applications of bioartificial fat require a quantitative and objective method to continuously measure adipogenesis in living cultures as opposed to currently used culture-destructive techniques that stain lipid droplet (LD) accumulation. To allow standardization, automatic quantification of LD size is further needed, but currently LD size is measured mostly manually. We developed an image processing-based method that does not require staining to monitor adipose cell maturation in vitro nondestructively using optical micrographs taken consecutively during culturing. We employed our method to monitor LD accumulation in 3T3-L1 and mesenchymal stem cells over 37 days. For each cell type, percentage of lipid area, number of droplets per cell, and droplet diameter were obtained every 2-3 days. In 3T3-L1 cultures, high insulin concentration (10 microg/mL) yielded a significantly different (p < 0.01) time course of all three outcome measures. In mesenchymal stem cell cultures, high fetal bovine serum concentration (12.5%) produced significantly more lipid area (p < 0.01). Our method was able to successfully characterize time courses and extents of adipogenesis and is useful for a wide range of applications testing the effects of biochemical, mechanical, and thermal stimulations in tissue engineering of bioartificial fat constructs. PMID- 20163243 TI - Evaluation of maxillary alveolar reconstruction using a resorbable collagen sponge with recombinant human bone morphogenetic protein-2 in cleft lip and palate patients. AB - INTRODUCTION: A resorbable collagen matrix with recombinant human bone morphogenetic protein (rhBMP-2) was compared with traditional iliac crest bone graft for the closure of alveolar defects during secondary dental eruption. METHODS: Sixteen patients with unilateral cleft lip and palate, aged 8 to 12 years, were selected and randomly assigned to group 1 (rhBMP-2) or group 2 (iliac crest bone graft). Computed tomography was performed to assess both groups preoperatively and at months 6 and 12 postoperatively. Bone height and defect volume were calculated through Osirix Dicom Viewer (Pixmeo, Apple Inc.). Overall morbidity was recorded. RESULTS: Preoperative and follow-up examinations revealed progressive alveolar bone union in all patients. For group 1, final completion of the defect with a 65.0% mean bone height was detected 12 months postoperatively. For group 2, final completion of the defect with an 83.8% mean bone height was detected 6 months postoperatively. Dental eruption routinely occurred in both groups. Clinical complications included significant swelling in three group 1 patients (37.5%) and significant donor-site pain in seven group 2 patients (87.5%). CONCLUSIONS: For this select group of patients with immature skeleton, rhBMP-2 therapy resulted in satisfactory bone healing and reduced morbidity compared with traditional iliac crest bone grafting. PMID- 20163244 TI - A stochastic model for annual reproductive success. AB - Demographic stochasticity can have large effects on the dynamics of small populations as well as on the persistence of rare genotypes and lineages. Survival is sensibly modeled as a binomial process, but annual reproductive success (ARS) is more complex and general models for demographic stochasticity do not exist. Here we introduce a stochastic model framework for ARS and illustrate some of its properties. We model a sequence of stochastic events: nest completion, the number of eggs or neonates produced, nest predation, and the survival of individual offspring to independence. We also allow multiple nesting attempts within a breeding season. Most of these components can be described by Bernoulli or binomial processes; the exception is the distribution of offspring number. Using clutch and litter size distributions from 53 vertebrate species, we demonstrate that among-individual variability in offspring number can usually be described by the generalized Poisson distribution. Our model framework allows the demographic variance to be calculated from underlying biological processes and can easily be linked to models of environmental stochasticity or selection because of its parametric structure. In addition, it reveals that the distributions of ARS are often multimodal and skewed, with implications for extinction risk and evolution in small populations. PMID- 20163245 TI - Adeno-associated virus-mediated correction of a canine model of glycogen storage disease type Ia. AB - Glycogen storage disease type Ia (GSDIa; von Gierke disease; MIM 232200) is caused by a deficiency in glucose-6-phosphatase-alpha. Patients with GSDIa are unable to maintain glucose homeostasis and suffer from severe hypoglycemia, hepatomegaly, hyperlipidemia, hyperuricemia, and lactic acidosis. The canine model of GSDIa is naturally occurring and recapitulates almost all aspects of the human form of disease. We investigated the potential of recombinant adeno associated virus (rAAV) vector-based therapy to treat the canine model of GSDIa. After delivery of a therapeutic rAAV2/8 vector to a 1-day-old GSDIa dog, improvement was noted as early as 2 weeks posttreatment. Correction was transient, however, and by 2 months posttreatment the rAAV2/8-treated dog could no longer sustain normal blood glucose levels after 1 hr of fasting. The same animal was then dosed with a therapeutic rAAV2/1 vector delivered via the portal vein. Two months after rAAV2/1 dosing, both blood glucose and lactate levels were normal at 4 hr postfasting. With more prolonged fasting, the dog still maintained near-normal glucose concentrations, but lactate levels were elevated by 9 hr, indicating that partial correction was achieved. Dietary glucose supplementation was discontinued starting 1 month after rAAV2/1 delivery and the dog continues to thrive with minimal laboratory abnormalities at 23 months of age (18 months after rAAV2/1 treatment). These results demonstrate that delivery of rAAV vectors can mediate significant correction of the GSDIa phenotype and that gene transfer may be a promising alternative therapy for this disease and other genetic diseases of the liver. PMID- 20163246 TI - Future prospects and challenges of antiangiogenic cancer gene therapy. AB - In 1971 Judah Folkman proposed the concept of antiangiogenesis as a therapeutic target for cancer. More than 30 years later, concept became reality with the approval of the antivascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab as a first-line treatment for metastatic colorectal cancer. Monoclonal antibodies and small molecular drugs are the most widely applied methods for inhibition of angiogenesis. The efficacy of these antiangiogenic modalities has been proven, in both preclinical and clinical settings. Although angiogenesis plays a major role in wound healing, hypoxia, and in the female reproductive cycle, inhibition of angiogenesis seems to be a relatively safe therapeutic option against cancers, and has therefore become a logical arena for a wide range of experimentation. The twentieth century has shown the boom of gene therapy and thus it has been applied also in the antiangiogenic setting. This review summarizes methods to induce antiangiogenic responses with gene therapy and discusses the obstacles and future prospects of antiangiogenic cancer gene therapy. PMID- 20163247 TI - Induction of human blood group a antigen expression on mouse cells, using lentiviral gene transduction. AB - The ABO histo-blood group system is the most important antigen system in transplantation medicine, yet no small animal model of the ABO system exists. To determine the feasibility of developing a murine model, we previously subcloned the human alpha-1,2-fucosyltransferase (H-transferase, EC 2.4.1.69) cDNA and the human alpha-1,3-N-acetylgalactosaminyltransferase (A-transferase, EC 2.4.1.40) cDNA into lentiviral vectors to study their ability to induce human histo-blood group A antigen expression on mouse cells. Herein we investigated the optimal conditions for human A and H antigen expression in murine cells. We determined that transduction of a bicistronic lentiviral vector (LvEF1-AH-trs) resulted in the expression of A antigen in a mouse endothelial cell line. We also studied the in vivo utility of this vector to induce human A antigen expression in mouse liver. After intrahepatic injection of LvEF1-AH-trs, A antigen expression was observed on hepatocytes as detected by immunohistochemistry and real-time RT-PCR. In human group A erythrocyte-sensitized mice, A antigen expression in the liver was associated with tissue damage, and deposition of antibody and complement. These results suggest that this gene transfer strategy can be used to simulate the human ABO blood group system in a murine model. This model will facilitate progress in the development of interventions for ABO-incompatible transplantation and transfusion scenarios, which are difficult to develop in clinical or large animal settings. PMID- 20163248 TI - Evaluation of hydrodynamic limb vein injections in nonhuman primates. AB - The administration route is emerging as a critical aspect of nonviral and viral vector delivery to muscle, so as to enable gene therapy for disorders such as muscular dystrophy. Although direct intramuscular routes were used initially, intravascular routes are garnering interest because of their ability to target multiple muscles at once and to increase the efficiency of delivery and expression. For the delivery of naked plasmid DNA, our group has developed a hydrodynamic, limb vein procedure that entails placing a tourniquet over the proximal part of the target limb to block all blood flow and injecting the gene vector rapidly in a large volume so as to enable the gene vector to be extravasated and to access the myofibers. The present study was conducted in part to optimize the procedure in preparation for a human clinical study. Various injection parameters such as the effect of papaverine preinjection, tourniquet inflation pressure and duration, and rate of injection were evaluated in rats and nonhuman primates. In addition, the safety of the procedure was further established by determining the effect of the procedure on the neuromuscular and vascular systems. The results from these studies provide additional evidence that the procedure is well tolerated and they provide a foundation on which to formulate the procedure for a human clinical study. PMID- 20163249 TI - Double-regulated oncolytic adenovirus-mediated interleukin-24 overexpression exhibits potent antitumor activity on gastric adenocarcinoma. AB - Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), identified by subtraction hybridization in the mid-1990s, is a potent gene therapeutic for cancer. Using a replication-deficient adenovirus as vector, it provokes apoptosis in diverse cancer cells without harming normal cells or tissues. To exploit the anticancer capability of IL-24 to the best, in this study, we generated a novel gene-virotherapy agent MUD55-IL-24, utilizing a replication-competent oncolytic adenovirus MUD55 as the gene delivery vector. It was documented that MUD55-IL-24 exhibited much stronger antitumor activity on gastric carcinoma both in vitro and in vivo, and its safety was comparable to the replication-deficient adenovirus Ad-IL-24. The unique properties of IL-24, including apoptosis induction, antiangiogenesis, and antimigration, were all significantly enhanced in MUD55-IL-24. After looking into the underlying mechanism, we found that intracellular ROS (Reactive Oxygen Species) generation may have caused the induction of apoptosis, mitochondrial dysfunction, and the activation of caspases in MUD55-IL-24-infected SG-7901 cells. Taken together, these results suggest that MUD55-IL-24 may be able to provide a potential strategy for future treatment of human gastric carcinoma. PMID- 20163251 TI - Mesenchymal stem cells inhibit complement activation by secreting factor H. AB - Mesenchymal stem cells (MSCs) possess potent and broad immunosuppressive capabilities, and have shown promise in clinical trials treating many inflammatory diseases. Previous studies have found that MSCs inhibit dendritic cell, T-cell, and B-cell activities in the adaptive immunity; however, whether MSCs inhibit complement in the innate immunity, and if so, by which mechanism, have not been established. In this report, we found that MSCs constitutively secrete factor H, which potently inhibits complement activation. Depletion of factor H in the MSC-conditioned serum-free media abolishes their complement inhibitory activities. In addition, production of factor H by MSCs is augmented by inflammatory cytokines TNF-alpha and interferon-gamma (IFN-gamma) in dose- and time-dependent manners, while IL-6 does not have a significant effect. Furthermore, the factor H production from MSCs is significantly suppressed by the prostaglandin E2 (PGE2) synthesis inhibitor indomethacin and the indoleamine 2,3 dioxygenase (IDO) inhibitor 1-methyl-d-tryptophan (1-MT), both of which inhibitors are known to efficiently dampen MSCs immunosuppressive activity. These results indicate that MSCs inhibit complement activation by producing factor H, which could be another mechanism underlying MSCs broad immunosuppressive capabilities. PMID- 20163250 TI - Cytotoxicity associated with artemis overexpression after lentiviral vector mediated gene transfer. AB - Artemis is a hairpin-opening endonuclease involved in nonhomologous end-joining and V(D)J recombination. Deficiency of Artemis results in radiation-sensitive severe combined immunodeficiency (SCID) characterized by complete absence of T and B cells due to an arrest at the receptor recombination stage. We have generated several lentiviral vectors for transduction of the Artemis sequence, intending to complement the deficient phenotype. We found that transduction by a lentiviral vector in which Artemis is regulated by a strong EF-1alpha promoter resulted in a dose-dependent loss of cell viability due to perturbed cell cycle distribution, increased DNA damage, and increased apoptotic cell frequency. This toxic response was not observed in cultures exposed to identical amounts of control vector. Loss of cell viability was also observed in cells transfected with an Artemis expression construct, indicating that toxicity is independent of lentiviral transduction. Reduced toxicity was observed when cells were transduced with a moderate-strength phosphoglycerate kinase promoter to regulate Artemis expression. These results present a novel challenge in the establishment of conditions that support Artemis expression at levels that are nontoxic yet sufficient to correct the T(-)B(-) phenotype, crucial for preclinical studies and clinical application of Artemis gene transfer in the treatment of human SCID-A. PMID- 20163252 TI - Contraceptive options for women with preexisting medical conditions. AB - Most healthy women have normal pregnancies; however, even healthy women may experience serious morbidity during pregnancy. Women with chronic medical problems face increased pregnancy-related risks compared with their healthy peers. Planning pregnancy improves maternal and fetal outcomes; medical conditions can be stabilized, teratogens can be avoided, and early antenatal intervention and surveillance can be instituted. The safest and most effective forms of contraception should be offered to women with medical conditions. Overestimatation of risk associated with the use of contraception among clinicians and women limits access to effective contraception. Contraception decision making should include consideration of the risks and benefits of a given method vs. the consequences of an unintended pregnancy. Published guidelines can inform contraceptive management of women with chronic medical conditions. Patient counseling should focus on helping women understand the need for contraception while optimizing their health for pregnancy. PMID- 20163253 TI - Searching for genes for cleft lip and/or palate based on breakpoint analysis of a balanced translocation t(9;17)(q32;q12). Letter. PMID- 20163254 TI - Survey of management of children with cleft lip and palate in teaching and specialist hospitals in Nigeria. AB - OBJECTIVE: A national survey was conducted to obtain an overall view of the current management of children with cleft lip and/or palate in Nigeria. METHOD: Questionnaires were sent to 44 identified cleft surgeons in all teaching and specialist hospitals in Nigeria. RESULTS: A total of 38 respondents returned completed questionnaires. The findings are as follows: (1) a majority of the surgeons (68.4%) are "low-volume operators," undertaking 10 or fewer new cleft repairs annually; (2) 86.8% of the surgeons repair cleft lip at 3 to 4 months of age, and the most common (71%) unilateral cleft lip repair method is the rotation advancement technique; (3) 50% of the surgeons use straight line repair for bilateral cleft lip; (4) a majority (79%) of the respondents close the soft and hard palates as a single procedure; 47.3% of respondents use the von Langenbeck technique, 21.1% use the double-opposing Z-plasty and 21.1%, the palatal pushback; (5) in the management of protruding premaxilla, 52.6% of the respondents choose adhesive tape; (6) procedures such as alveolar bone grafting, rhinoplasty, and surgical treatment for velopharyngeal incompetence are rarely done as part of cleft management; and (7) the interdisciplinary team approach is practiced by 21% of respondents. CONCLUSIONS: Issues are raised regarding the current organization of cleft services. We hope the findings of this study will provide preliminary information needed for the eventual establishment of standard cleft management for children with cleft lip and palate deformity in Nigeria. PMID- 20163255 TI - MRI and 3D Computer Modeling of the Levator Veli Palatini Muscle Before and After Primary Palatoplasty. AB - Abstract Objective: This study was designed for two purposes: (a) to obtain qualitative and quantitative information of the velopharyngeal mechanism in infants born with cleft palate before and after primary palatoplasty using MRI and 3D computer technology and (b) to demonstrate the potential of using computer technology and MRI for presurgical planning. Methods: Clinical MRI data were obtained from the medical charts of four infants (two with cleft lip and palate and two without) between 8 - 15 months of age. Computer technology was used to obtain quantitative measures of the levator veli palatini (levator) muscle and to create 3D computer models. Results: There was little difference in angles of origin between individuals with normal velopharyngeal anatomy (ranging from 41 masculine-45 masculine). Subjects with cleft palate displayed smaller angles of origins (average of 40 masculine) prior to surgery compared to that of the subjects without cleft palate (average of 43 masculine). Following surgery, the levator muscle increased in length (ranging from 32mm-40.4mm) and formed larger angles of origin (average of 39 masculine) becoming more similar to the angles of origin observed in the subjects without cleft palate. Conclusions: Although the subjects with normal anatomy displayed levator muscle lengths, thickness, and distance between origins that were dissimilar, nevertheless the angles of origin measures were similar. Subjects with cleft palate had greater variations in the angle of origin. It is possible that the angle of the muscle as it descends from the base of the skull might be a critical feature to produce velopharyngeal closure. PMID- 20163257 TI - Surgical site infections as a health care quality issue. PMID- 20163256 TI - Chromosomal abnormalities in Finnish orofacial cleft patients: excess of submucous cleft patients? AB - OBJECTIVE: The aim was to identify chromosomal regions possibly involved in the development of orofacial clefts and to compare syndromic cleft phenotypes with previous reports. DESIGN: We have retrospectively gathered and analyzed chromosomal aberrations and phenotypes of Finnish cleft patients treated at the Cleft and Craniofacial Centre, Helsinki University Central Hospital. SETTING: The study was carried out at the Cleft and Craniofacial Centre, Helsinki University Central Hospital. PATIENTS: The cleft register contains information on about 7600 Finnish cleft patients. MAIN OUTCOME MEASURES: Identification of patients for further molecular analyses and identification of chromosomal regions associated with orofacial clefting. RESULTS: We identified 37 cleft patients with chromosomal aberrations of putative research interest. CONCLUSIONS: We were able to efficiently select patients for further molecular analyses and identify chromosomal regions that might be associated with orofacial clefting. The percentage of submucous cleft patients among cleft patients with chromosomal aberrations was unexpectedly high. PMID- 20163258 TI - The pathogen of ventilator-associated pneumonia does not influence the mortality rate of surgical intensive care unit patients treated with a rotational antibiotic system. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is one of the leading causes of morbidity in critically ill surgical patients. Certain pathogens (e.g., methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa) have been associated with an excess mortality rate from sepsis in several studies, but not in the surgical setting specifically or when protocol-driven antibiotic therapy is administered. PURPOSE: We sought to determine which factors and, in particular, whether the individual pathogen affected the mortality rate in our surgical intensive care unit (ICU), where a rotational antibiotic system has been employed continuously since 1997. We hypothesized that the type of pathogen and illness severity were the primary influences on the mortality rate of patients with VAP. METHODS: A total of 198 consecutive patients from a university surgical ICU, with clinical signs of VAP confirmed by quantified isolation of significant numbers of a pathogen (> or =10(4) colony-forming units [cfu]/mL) from bronchoalveolar (BAL) fluid obtained by fiberoptic bronchoscopy, were identified prospectively from January 2001 to November 2004. The data collected were age, sex, Acute Physiology and Chronic Health Evaluation (APACHE) III score, multiple organ dysfunction score, unit day of diagnosis, time (h) to antibiotic administration (TTA), appropriateness of initial therapy (AIT), unit and hospital length of stay, and mortality rate. Pathogens were classified as non-lactose fermenting gram-negative bacilli (NGNB), lactose-fermenting gram-negative bacilli (LGNB), methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus, yeast, community-acquired pneumonia (e.g., Streptococcus pneumoniae), or other pathogens. Patients with a polymicrobial isolate were placed in the "other" category. RESULTS: The overall mortality rate was 32.3% vs. 55% as predicted by APACHE III normative data. The overall AIT was 92%. The mortality rate for NGNB infections was 35.6% vs. 29.4% for LGNB infections (p = NS). By logistic regression, neither TTA, AIT, nor pathogen influenced the mortality rate. CONCLUSIONS: The type of pathogen does not influence death in surgical ICU patients with VAP diagnosed rigorously and treated by a rotational antibiotic system. The high proportion of AIT as a result of the rotational antibiotic administration system optimizes bacterial killing and negates the impact of bacterial resistance, contributing to better outcomes. PMID- 20163259 TI - Nanofiber micro-dispersed oxidized cellulose as a carrier for topical antimicrobials: first experience. AB - BACKGROUND: Micro-dispersed oxidized cellulose, already used for hemostasis, might be helpful for introduction of an antimicrobial drug. AIM: To examine the effect of topically applied gentamicin attached to a new biodegradable carrier formed by micro-dispersed oxidized cellulose in microfiber and nanofiber form for treatment of acute wound infection and to assess the influence of this carrier on healing. MATERIALS AND METHODS: A model of a full-thickness infected dermal wound was created in 12 female domestic pigs. The effectiveness of topical gentamicin delivered with micro-dispersed oxidized cellulose carrier was tested in acute wound infections caused by Staphylococcus aureus, Pseudomonas aeruginosa, or Escherichia coli. RESULTS: The effectiveness of nanofiber micro-dispersed oxidized cellulose with gentamicin was proved according to culture findings. When assessed macroscopically, 100% of wounds treated by the nanofiber product had no signs of local infection. When microfiber micro-dispersed oxidized cellulose was used, cultures demonstrated residual bacteria in 94.4% of treated incisions despite the absence of clinically recognized infection. CONCLUSIONS: Micro dispersed oxidized cellulose carrier with a sufficient concentration of an attached antibiotic appears to be effective for the treatment of full-thickness skin infections. The positive influence of the product on the healing of a dermal incision was shown, and a good hemostatic effect was confirmed. PMID- 20163260 TI - Effects of human immunodeficiency virus status on trauma outcomes: a review of the national trauma database. AB - BACKGROUND: The prevalence of human immunodeficiency virus (HIV) is disproportionately elevated in trauma patients. Although HIV traditionally has been associated with poorer outcomes among the critically ill, recent evidence suggests that the outcomes of surgical patients have improved with the greater use of antiretroviral regimens. The purpose of this study was to utilize the National Trauma Data Bank (NTDB) to examine the impact of HIV on surgical outcomes in a large group of trauma patients. METHODS: We identified all patients for whom HIV status at time of admission was recorded. Results were stratified by age and Injury Severity Score. Our primary outcome was death. Secondary outcomes were length of hospital stay (LOS), length of intensive care unit (ICU) stay, duration of mechanical ventilation, and complications. Data were analyzed using Student t-tests or chi-square analysis, as appropriate. RESULTS: The overall mortality rates were not significantly different in the HIV-positive and HIV negative groups. Mortality rates remained similar in the two groups even when stratifying by ISS and age, with the exception of those patients who were 65 years or older. The HIV-positive patients had significantly longer LOS (7.6 vs. 5.6 days), shorter duration of mechanical ventilation (6.3 vs. 8.3 days), and no difference in length of ICU stay. The HIV-positive patients were significantly more likely to develop pneumonia, bacteremia, or wound infection. CONCLUSIONS: These findings are consistent with those of recent smaller studies that demonstrated no significant difference in the mortality rate for patients with HIV. Although mortality rates are similar, HIV-positive patients are more likely to develop certain infectious complications and to require a longer LOS. Infection with HIV remains a major public health issue in the U.S. and internationally, and further research is necessary to explore the relation between HIV status and trauma outcomes, particularly with regard to the possible effects of antiretroviral treatment and individual immune status. PMID- 20163261 TI - Severe pneumoperitoneum caused by infected pelvic hematoma: report of a case and review of the literature. AB - BACKGROUND: Pneumoperitoneum usually is caused by hollow viscus perforation with associated peritonitis. Severe pneumoperitoneum secondary to infection of a hematoma with gas-forming organisms is exceedingly rare. METHODS: Case report and literature review. RESULTS: A 43-year-old man with a history of abdominoperineal resection for rectal cancer developed abdominal distention, fever, and elevated white blood cell count after lysis of adhesions with bowel resection for recurrent small bowel obstruction. Abdominal radiography and a computed tomography scan demonstrated a large amount of free air in the peritoneal cavity. Contrary to expectations, reexploration revealed no signs of viscus perforation or anastomotic leak, but instead a large pelvic hematoma with an odor was identified and evacuated. Cultures from the hematoma yielded anaerobic gram negative bacilli (not Bacteroides fragilis). The patient recovered uneventfully. CONCLUSION: Infected hematoma should be recognized as a cause of pneumoperitoneum after surgery. Awareness of this rare condition may prevent unnecessary surgical explorations in doubtful situations. PMID- 20163262 TI - Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. AB - Evidence-based guidelines for managing patients with intra-abdominal infection were prepared by an Expert Panel of the Surgical Infection Society and the Infectious Diseases Society of America. These updated guidelines replace those previously published in 2002 and 2003. The guidelines are intended for treating patients who either have these infections or may be at risk for them. New information, based on publications from the period 2003-2008, is incorporated into this guideline document. The panel has also added recommendations for managing intra-abdominal infection in children, particularly where such management differs from that of adults; for appendicitis in patients of all ages; and for necrotizing enterocolitis in neonates. PMID- 20163263 TI - Extent and time course of pain intensity upon treatment with a topical diclofenac sodium patch versus placebo in acute traumatic injury based on a validated end point: post hoc analysis of a randomized placebo-controlled trial. AB - OBJECTIVE: To investigate the extent and time course of pain intensity upon treatment with a topical diclofenac patch compared with placebo in acute traumatic sport injury based on a validated and established end point. METHODS: Post hoc analysis of a randomized, placebo-controlled, double-blind, multicentre, 1-week study in 120 patients with traumatic blunt soft tissue injury. Visual analogue scale (VAS) scores (in millimetres) for pain on movement were analysed. The mean absolute VAS changes in pain intensity from baseline over the study course were calculated for the diclofenac patch formulation (active) and placebo; mean differences between active and placebo were assessed twice daily during the first 3 days after enrolment and then once daily up to day 7. RESULTS: The diclofenac patch was consistently superior to placebo in relieving pain. The mean differences compared with placebo were greatest on day 2 (23.6 - 30.6 mm, p < 0.0001) and day 3 (24.5 - 24.6 mm, p < 0.0001). Diminishing differences were observed over the study course. CONCLUSION: The investigated diclofenac sodium patch provides clinically relevant pain relief in patients with acute traumatic injuries. Maximum effects versus placebo are detected at 2 - 3 days post-injury. This analysis may serve as useful information for the planning of clinical trials in acute traumatic injury. PMID- 20163264 TI - Monitoring adherence rates in glaucoma patients using the Travatan Dosing Aid. A 6-month study comparing patients on travoprost 0.004% and patients on travoprost 0.004%/timolol 0.5% fixed combination. AB - OBJECTIVE: To assess adherence in glaucoma patients using the Travatan Dosing Aid (TDA); to record differences in adherence by age, sex, therapy, systemic therapies, years from diagnosis, type of therapy and intraocular pressure (IOP). RESEARCH DESIGN AND METHODS: Sixth-month cohort study; fifty-six Caucasian, primary open-angle glaucoma patients on travoprost (T) or travoprost/timolol fixed combination (TTFC) monotherapy were submitted to four visits: at baseline and months 1, 3 and 6 (M1, M3, M6). Adherence was recorded with TDA and classified as 'high' if greater than 90%. Self-reported and physician-presumed adherence data were collected. Kruskall-Wallis and Fisher's exact tests were applied. RESULTS: Thirty-two patients (54.2%) were treated with T. Age, sex, level of schooling, presence of systemic comorbidities, duration of current therapy and IOP were similar between T and TTFC. Seventeen subjects (30.3%) recorded high adherence at every visit, 13 (23.2%) at two visits, 26 (46.4%) otherwise. Adherence was maintained over time with a slight decrease from month 1 to month 6 without statistical differences within and between groups. Adherence was statistically influenced by age (p = 0.007) and duration of therapy (p = 0.004). CONCLUSION: The typical nonadherent patient is elderly. TDA records indicate that only a minority of patients are really adherent: predictive models to screen for poor adherence are needed. PMID- 20163265 TI - Treatment of multiple sclerosis in children and adolescents. AB - IMPORTANCE OF THE FIELD: Pediatric multiple sclerosis is an acquired inflammatory, demyelinating CNS disorder associated with recurrent episodes of neurologic dysfunction. Precise diagnosis is increasingly important as disease modifying therapies have been developed in adults and introduced into pediatric practice. AREAS COVERED IN THIS REVIEW: Literature published over the past two decades relating to pharmacologic treatment of multiple sclerosis (MS) in adults and children is reviewed, with emphasis on current publications. WHAT THE READER WILL GAIN: This article reviews available research and clinical experience regarding treatment of acute episodes of CNS demyelination in children and adolescents, strategies for introduction and modification of disease-modifying therapies depending on disease course, and use of medication for symptomatic improvement in quality of life. TAKE HOME MESSAGE: Pharmacotherapy for MS has been studied in adults but to a significantly lesser extent in children or adolescents. However, children and adolescents have different biology than adults in terms of drug metabolism, immune mechanisms and incomplete maturity of CNS myelin. Effectiveness as well as long-term safety needs to be studied in children and adolescents. PMID- 20163266 TI - Pharmacological strategies against cold ischemia reperfusion injury. AB - IMPORTANCE OF THE FIELD: Good organ preservation is a determinant of graft outcome after revascularization. The necessity of increasing the quality of organ preservation, as well as of extending cold storage time, has made it necessary to consider the use of pharmacological additives. AREAS COVERED IN THIS REVIEW: The complex physiopathology of cold-ischemia-reperfusion (I/R) injury--and in particular cell death, mitochondrial injury and endoplasmic reticulum stress--are reviewed. Basic principles of the formulation of the different preservation solutions are discussed. WHAT THE READER WILL GAIN: Current strategies and new trends in static organ preservation using additives such as trimetazidine, polyethylene glycols, melatonin, trophic factors and endothelin antagonists in solution are presented and discussed. The benefits and mechanisms responsible for enhancing organ protection against I/R injury are also discussed. Graft preservation was substantially improved when additives were added to the preservation solutions. TAKE HOME MESSAGE: Enrichment of preservation solutions by additives is clinically useful only for short periods. For longer periods of cold ischemia, the use of such additives becomes insufficient because graft function deteriorates as a result of ischemia. In such conditions, the preservation strategy should be changed by the use of machine perfusion in normothermic conditions. PMID- 20163267 TI - Cutaneous and mucocutaneous leishmaniasis: emerging therapies and progress in disease management. AB - IMPORTANCE OF THE FIELD: Cutaneous leishmaniasis (CL) is a major tropical skin disease. Its incidence continues to increase, and disease control and management are challenging. Available therapies remain inadequate and are associated with low efficacy, toxicity, difficulties with administration, or are expensive. AREAS COVERED IN THIS REVIEW: This article describes progress in the therapeutics of CL since 2006. Clinical trials have provided further evidence for the use of alternative systemic agents to first-line antimonials, an enhanced topical paromomycin preparation, the efficacy of thermotherapy, photodynamic therapy as an emerging physical therapy, and the role of immunotherapy and immunomodulators as adjuncts to chemotherapy. In addition, in vitro studies have demonstrated the anti-leishmanial effects of several drugs, which might represent potential future therapeutic agents for CL. WHAT THE READER WILL GAIN: An overview of the magnitude and complexity of this heterogenous disease, and an update on recent advances in therapeutics and future directions for new drug development. TAKE HOME MESSAGE: Drug therapy for CL must be tailored according to infective species, endemic region, and host responses; a range of different therapies and modalities is therefore required. The impetus for new drug development must continue, combination therapies need to be evaluated, and robust and comparative trials of existing agents are required to adequately assess their efficacy and tolerability. PMID- 20163268 TI - Treatment of chronic hepatitis C in elderly patients. AB - IMPORTANCE OF THE FIELD: The issue of age in cases of chronic hepatitis C (HCV) in the West is a major problem; the average age of patients with HCV is increasing and its prevalence increases with advancing age. AREAS COVERED IN THIS REVIEW: This review is devoted to the analysis of the limited number of clinical studies performed to treat HCV in elderly patients. WHAT THE READER WILL GAIN: The importance of the age factor is outlined in nearly all the studies done in the field. Advanced age is associated with a lower sustained virologic response (SVR) rate. Moreover, in elderly patients, these studies also tend to suggest that, before initiating an antiviral treatment, the physician should not only take into account the classical parameters associated with SVR but also the presence of co-morbidities and life expectancy. TAKE-HOME MESSAGES: Antiviral therapy should be used in selected elderly HCV patients with advanced fibrosis and more studies are required in this population to better define the parameters associated with SVR. As age is an important factor in the success of antiviral therapy, starting antiviral treatment at a young age should be favored. PMID- 20163269 TI - State of the art: radiolabeled microspheres treatment for liver malignancies. AB - IMPORTANCE OF THE FIELD: Metastatic tumours of the liver are responsible for significant morbidity and mortality, and only a small percentage is resectable with curative intent. Hepatic artery radioembolization (RE) with yttrium-90 ((90)Y)-loaded microspheres is an alternative treatment for patients with unresectable primary or secondary liver tumours, especially in cases of metastatic colorectal cancer (mCRC) and hepatocellular carcinoma (HCC). AREAS COVERED IN THIS REVIEW: Data from recent relevant clinical trials with (90)Y-RE are discussed, focusing on response rate assessments and treatment outcome. WHAT THE READER WILL GAIN: Current data show that (90)Y-RE combined with radiosensitizing chemotherapy is a safe and efficient modality that extends the time to progression in liver mCRC and unresectable HCC, although no survival benefits have been demonstrated. The treatment response after (90)Y-RE seems to be better assessed using metabolic response assessments with serial fluorodeoxyglucose positron emission tomography (FDG-PET) in cases of FDG-avid tumours than with morphological criteria measured on computed tomography or magnetic resonance imaging (RECIST or WHO trials). Predictive models using multimodality imaging approaches (PET-SPECT-CT image fusion algorithms) have been proposed to better select patients for (90)Y-RE. The optimal routine role of radioembolization remains to be defined; the complexity and wide availability of available therapeutic alternatives confuses the role of a locoregional treatment in a generalized disease. TAKE HOME MESSAGE: (90)Y-RE is a safe and efficient treatment modality in salvage therapy of colorectal cancer metastatic to the liver and in unresectable HCC. However, it has still to find its place as a first or second-line treatment of mCRC in combination with or as an alternative to available biological agents. The role of (90)Y-RE in other solid tumour types metastatic to the liver is much more uncertain and investigations in clinical situations in which disease is strictly limited to the liver are required. Pretherapeutic work-up, initially developed to explore hepatic vasculature and to assess lung shunting, might be able to predict treatment outcome, allowing a better patient selection. PMID- 20163270 TI - Acute promyelocytic leukemia: what are the treatment options? AB - IMPORTANCE OF THE FIELD: Acute promyelocytic leukemia (APL) represents a paradigm of therapeutic success in clinical hematology. Since the introduction of all trans-retinoic-acid in the early 1980s, complete remission rates exceed 90% and the cure rate is > 70%. Notwithstanding, various questions concerning the management of APL remain unanswered. AREAS COVERED IN THIS REVIEW: The aim of this article is to focus on still controversial issues in the management of APL, such as the role of arsenic trioxide as front-line therapy, the management of older unfit patients, the potential utility of gemtuzumab-ozogamycin and the effectiveness (if any) of maintenance therapy for patients in molecular remission. In addition, the possibility of reducing the intensity of post remission therapy, which is associated with substantial morbidity in potentially cured patients, is discussed. WHAT THE READER WILL GAIN: Current and future therapeutic options for the treatment of newly diagnosed and relapsed APL. TAKE HOME MESSAGE: To date, the therapy of APL is the most successful example of differentiation therapy and its scientific history can serve as a model for subsequent development of similar treatments in other leukemias and cancers. However, treatment strategies continue to evolve rapidly, with particular focus on minimizing the early and late effects of cytotoxic chemotherapy. PMID- 20163271 TI - Pharmacotherapy of end-stage renal disease. AB - IMPORTANCE OF THE FIELD: The incidence and prevalence of end-stage renal disease (ESRD) requiring renal replacement therapy (RRT) continues to grow worldwide. ESRD causes significant morbidity and mortality and has enormous financial and personal costs. AREAS COVERED IN THIS REVIEW: Major electronic databases (including the Cochrane Library, MEDLINE and EMBASE) were searched from 1989 to September 2009 to summarize current pharmacotherapy of ESRD-associated complications in adults receiving maintenance dialysis (hemodialysis or continuous ambulatory peritoneal dialysis). Current guidelines for the treatment of ESRD (e.g., NKF-K/DOQI, KDIGO, and the ERA-EDTA's European Renal Best Practice Guidelines) were included. WHAT THE READER WILL GAIN: Commonly used pharmacological treatment strategies for chronic arterial hypertension, anemia, iron management, dyslipidemia, hyperglycemia, and for disturbances of bone and mineral metabolism, including hyperphosphatemia and secondary hyperparathyroidism in ESRD, are presented. In addition, the reader will learn that nonadherence to oral medication in ESRD can contribute significantly to excess morbidity and mortality of the dialysis population. TAKE HOME MESSAGE: Improvements in pharmacotherapy of ESRD may be at least in part counteracted by continuously increasing age and comorbid disease of the dialysis population. Individualized and tailor-made pharmacological management of the ESRD patient remains a challenge for the future. PMID- 20163272 TI - Daptomycin: pharmacology and clinical use. AB - IMPORTANCE OF THE FIELD: Infections caused by Gram-positive organisms have increased in frequency and severity. Daptomycin offers a therapeutic option in an era of increasing resistance. AREAS COVERED IN THIS REVIEW: Literature from 1986 to present was reviewed for pharmacological, preclinical and clinical studies on daptomycin. WHAT THE READER WILL GAIN: The pharmacological properties, resistance mechanisms and clinical applications of daptomycin are discussed. Recommendations are offered on the use of this agent for the treatment of resistant Gram-positive infections. TAKE HOME MESSAGE: Daptomycin is a reliable agent for the treatment of Gram-positive infections. It has been shown to be effective in bacteremia and endocarditis, as well as in soft-tissue infections caused by Gram-positive organisms. Its role in the treatment of bone and joint infections is not well defined. Resistance is currently uncommon in clinical isolates. However, emergence of resistance during therapy is a concern. This may be prevented by use of higher doses. PMID- 20163273 TI - Levodopa in Parkinson's disease: from the past to the future. AB - IMPORTANCE OF THE FIELD: Levodopa is the mainstay of symptomatic treatment for Parkinson's disease (PD). Although other treatments have been developed in the last 30 years, most patients use levodopa in view of its superior efficacy in controlling PD symptoms. Unfortunately, levodopa is associated with long-term motor complications (motor fluctuations and dyskinesias). The main causes of these undesirable effects are the narrowing of the therapeutic window with the natural progression of the disease, pulsatile dopaminergic stimulation due to the short half-life of the drug and erratic absorption. Several studies suggest that PD control could be enhanced by changing the mode of levodopa delivery so as to ensure continuous and stable supply of the drug to the brain. The objective of this text is to review the ascertained strengths and limitations of levodopa in PD, starting from its history, and propose novel modes of usage designed to cover currently unmet medical needs. AREAS COVERED IN THIS REVIEW: Medline literature search (from 1973 to date). WHAT THE READER WILL GAIN: A perspective on the evolution of PD pharmacological treatment. TAKE HOME MESSAGE: Levodopa still is the best treatment for PD. Truly stable and controlled formulations that ensure clinical response should be developed to reduce the undesirable effects that restrict its efficacy. PMID- 20163274 TI - Tolvaptan: a new tool for the effective treatment of hyponatremia in psychotic disorders. AB - IMPORTANCE OF THE FIELD: Hyponatremia (serum sodium concentration < 136 mEq/liter) is a common and potentially life-threatening medical comorbidity seen in patients with psychotic disorders. Tolvaptan, a selective antagonist of the V(2)-receptor, is FDA-approved for the treatment of clinically significant hypervolemic and euvolemic hyponatremia. This represents a major development in the care of psychotic individuals with hyponatremia. AREAS COVERED IN THE REVIEW: This review provides an overview of the existing literature on prevalence rates and risk factors associated with hyponatremia in psychotic patients (1923 - present). Tolvaptan is discussed as a potential advance in the treatment of hyponatremia in patients with psychotic disorders, and preliminary data are reviewed. WHAT THE READER WILL GAIN: The reader will gain an appreciation of the prevalence of hyponatremia among psychotic individuals, an understanding of the distinctions between acute and chronic hyponatremia in this population, and awareness that effective treatments are becoming available. TAKE HOME MESSAGE: A modest literature exists regarding prevalence rates and risk factors associated with hyponatremia in psychotic populations. Hyponatremia is common and serious enough to merit clinical concern. Perhaps, now that tolvaptan has been FDA approved, progress will accelerate and new insights will develop that begin to bring relief from this medical comorbidity among psychotic patients. PMID- 20163275 TI - Rotigotine transdermal delivery for the treatment of restless legs syndrome. AB - IMPORTANCE OF THE FIELD: Rotigotine is a non-ergot dopamine agonist devised to be applied transdermally as a patch. It is currently licensed for treatment of early (USA and Europe) and advanced (Europe) Parkinson's disease, as well as for the treatment of moderate to severe restless legs syndrome (RLS) (Europe). Constant drug delivery and ease of use due to the application of an adhesive patch once daily are the potential advantages of the rotigotine patch for the treatment of RLS. AREAS COVERED IN THIS REVIEW: The evidence on the efficacy, tolerability and safety of rotigotine in the treatment of RLS is reviewed. Source material was identified using a PubMed search using the key words 'rotigotine' (up to September 2009) and using data from rotigotine trials being submitted or published in abstract form. This review focuses only on publications related to rotigotine for the treatment of RLS. WHAT THE READER WILL GAIN: In the drug trials summarized here, rotigotine transdermal patch is efficacious for the treatment of RLS, using dosages between 1 and 3 mg/24 h, up to 30% of severely affected patients reached freedom of symptoms with an IRLS (International Restless Legs Syndrome Severity Scale) of zero. Safety and tolerability are similar to other non-ergot dopamine agonists, except for application site reactions, which may limit practicability. Retrospective analysis of augmentation were 1.5% in placebo-controlled 6-month trials and 2.9% in a 1-year open trial. TAKE HOME MESSAGE: The rotigotine transdermal patch can provide 'around the clock' treatment for moderate to severe RLS. Further comparative studies need to clarify whether continuous low-dose dopamine-agonist therapy will have any influence on augmentation rates. PMID- 20163276 TI - Laromustine (cloretazine). AB - IMPORTANCE OF THE FIELD: In spite of the recent progress, the prognosis of acute myelogenous leukemia (AML) remains poor, particularly in patients with relapsed disease and in the elderly. In these situations, there is at present no standard of care, and new drugs are urgently needed. AREAS COVERED IN THIS REVIEW: Preclinical and clinical studies of Laromustine (formerly cloretazine, VNP 40101M), a new sulfonylhydrazine alkylator, in AML published between 2000 and September 2009 are presented and discussed. WHAT THE READER WILL GAIN: Mechanisms of action of Laromustine and preclincal data that support the rationale for its use in patients with AML are summarized. Laromustine has limited extramedullary toxicity. In Phase II studies, it produced 32% complete responses in elderly patients with previously untreated AML. In a Phase III comparative study of its combination with cytarabine in relapsed AML, increased response rate was offset by excessive toxicity. TAKE HOME MESSAGE: Laromustine has significant activity in AML. As a single agent, laromustine may represent an alternative to conventional treatments for elderly patients. Although significant activity was seen, safety and optimal dosing in combination regimen remain to be established and are now being investigated. PMID- 20163277 TI - Ertapenem. AB - IMPORTANCE OF THE FIELD: Given their broad-spectrum and safety, carbapenems are a widely used class of antibiotics, especially in the treatment of hospital acquired infections including infections due to multidrug-resistant organisms. Ertapenem is a unique member of this class, with a narrower spectrum that lacks reliable activity against Pseudomonas and Enterococcus. Given its spectrum and half-life of 4 h it is better suited to use in community-acquired infections and it is particularly well positioned for use in the outpatient setting. AREAS COVERED IN THIS REVIEW: Chemistry, mechanism of action, pharmacokinetics/pharmacodynamics, safety and indications for use will be covered in this review. Similar to other beta-lactams, the carbapenems inhibit cell wall synthesis by binding to and inhibiting penicillin-binding proteins. Their resistance to beta-lactamases including AmpC and extended-spectrum beta lactamases enhances their usefulness. Similar to other beta-lactams, ertapenem exhibits time-dependent killing. Given this profile, ertapenem has been found to be useful in intra-abdominal infections, acute pelvic infections, complicated skin and skin structure infections, community-acquired pneumonia and complicated urinary tract infections. WHAT THE READER WILL GAIN: This review will enable the reader to understand differences between the different carbapenems, especially with regard to ertapenem. Once an understanding is gained with regard to pharmacology and microbiology, the reader will be positioned to understand better those circumstances in which use of ertapenem should be considered. TAKE HOME MESSAGE: Substantial differences between the carbapenems exist. Ertapenem has unique characteristics that may make it useful in specific clinical circumstances that are detailed in this review. PMID- 20163278 TI - Role of ribavirin in HCV treatment response: now and in the future. AB - IMPORTANCE OF THE FIELD: Ribavirin is a broad spectrum antiviral agent that is used with pegylated IFN (Peg-IFN) for HCV treatment. Ribavirin does not significantly reduce HCV viral load when used alone but increases rates of sustained virologic response (SVR) when combined with Peg-IFN. HCV genotype 1 infected patients require higher doses of ribavirin administered for a longer duration of time versus HCV genotypes 2 and 3 patients who respond effectively to Peg-IFN with lower doses of ribavirin and shorter duration of therapy. Higher serum concentrations of ribavirin are associated with higher response rates but also higher rates of hemolytic anemia which is a dose limiting side effect. Alternatives to current therapy are under clinical evaluation. AREAS COVERED IN THIS REVIEW: Systematic literature review of ribavirin use in HCV patients from 1995 to 2009 was conducted. WHAT THE READER WILL GAIN: To review the efficacy and safety of ribavirin in current HCV treatment and in new therapies in Phase III clinical trials. TAKE HOME MESSAGE: Ribavirin is a drug which is essential to produce higher SVR rates both with Peg-IFN and HCV protease inhibitors currently in Phase III clinical trials. Thus, ribavirin is and will remain an important drug to achieving higher SVR rates in HCV infected persons. PMID- 20163279 TI - Sertindole and fluoxetine overdose with benign outcome. PMID- 20163280 TI - Observation of dynamic samples using simple coverslip fluidics. AB - The ability to observe samples undergoing controlled fluid flow under the microscope is important for studying biochemical processes and motion dynamics. We describe here a simple method to achieve this using coverslips shaped using a fiber scribe. Testing showed good directional flow control within the test range of 0-1 ml/min flow rate and an ability to sustain a flow rate up to approximately 1 ml/min. Testing with a sealed T-channel coverslip demonstrated the ability to construct fluid network branches with this scheme. We also demonstrated the usefulness of this procedure in motion dynamic studies of Dunaliella algae swimming under fluid flow. PMID- 20163281 TI - Five-year evaluation of bloodstream yeast infections in a tertiary hospital: the predominance of non-C. albicans Candida species. AB - This is a retrospective observational study of clinical and epidemiologic data from bloodstream yeast infections over 5 years (2004-2008) in a tertiary-care hospital. During this period, there were 52 such infections, at a rate of 2.4 per 1,000 hospital admissions. Non-C. albicans Candida species and other genera were responsible for 82% of infections, with C. tropicalis and C. parapsilosis being the most common. In 2008 no C. albicans infections occurred. Several uncommon fungal pathogens were observed, including Trichosporon asahii, Rhodotorula spp. and Candida zeylanoides. Of 16 isolates tested, 3 (19%) were resistant to fluconazole, including one C. zeylanoides (MIC 8 microg/ml) and one C. tropicalis (MIC 16 microg/ml) isolate, as well as intrinsically resistant C. krusei. All isolates tested were susceptible to itraconazole (n = 7) and amphotericin B (n = 8). Yeast infections were associated with severe underlying diseases, mainly hematological/solid cancers (71%), hospitalization in the ICU (41%), central venous catheters (80%), and use of antimicrobials (94%). The overall mortality rate was 50%. Our finding of a predominance of non-C. albicans Candida species infection with uncommon yeasts, and fluconazole resistance, suggests the need for continuous surveillance of fungemia and of antibiotic susceptibility trends, in order to adopt treatment strategies applicable to particular healthcare institutions. PMID- 20163282 TI - Expression of activation and cytotoxic molecules by peripheral blood lymphocytes of patients with paracoccidioidomycosis. AB - In a previous study, we reported an increased number of T CD8(+) cells in the bronchoalveolar lavage (BAL) of patients with pulmonary paracoccidioidomycosis, suggesting a role for these cells in the local immune response. The aims of this study were to verify, by flow cytometry, the activation state, as well as the production of cytotoxic molecules by peripheral blood lymphocytes (CD8(+) and CD4(+)). Specimens were obtained from patients with paracoccidioidomycosis (PCM), individuals with PCM-infection, i.e., healthy individuals with demonstrated strong cellular response against the fungus (PI) and controls, with studies conducted both ex-vivo and in vitro, after stimulation with Paracoccidioides brasiliensis yeast cells. The ex-vivo analysis demonstrated that PCM patients presented a lower frequency of granzyme A, B and perforin-positive cells, as compared to individuals with PCM infection (PI). P. brasiliensis stimulation led to a discrete increase in CD69(+) cells and a reduction in cytotoxic granule expression in all groups. The addition of IL-15 induced an increase in the frequency of CD69(+) cells only in PI individuals and controls. The effect of IL 15 on granzyme A and B expression was low, but a higher frequency of CD8(+) perforin(+) was detected in PI individuals than in patients with active PCM. IL 15Ralpha expression was lower in CD4(+) T cells from patients, in relation to the PI group. Furthermore, low levels of granulysin were detected in sera from PCM patients, but a tendency for an increase in these levels was observed after antifungal therapy. Taken together, these results indicate that lymphocytes from PCM patients are poorly activated, express low levels of IL-15Ralpha and produce basal levels of cytotoxic granules. These findings may account for the defective cytotoxic activity in patients and, consequently, a low capacity to kill the fungus. PMID- 20163283 TI - Relation of CYP2C19 loss-of-function polymorphism to the occurrence of stent thrombosis. AB - IMPORTANCE OF THE FIELD: Major adverse cardiovascular events including stent thrombosis associated with residual platelet reactivity on antiplatelet treatment in high risk vascular patients is a hot issue that needs a strong effort to be solved. Dual antiplatelet therapy with clopidogrel and aspirin prevents ischemic events and improves outcomes following acute coronary syndromes and percutaneous coronary intervention. However, adverse cardiovascular events occur in these patients, and several studies have shown that patients who suffer cardiovascular complications have high post-treatment platelet reactivity despite antiplatelet treatment. Clopidogrel requires conversion to active metabolite by CYP isoenzymes. Recently, CYP2C19*2 polymorphism (G681A nucleotide substitution) has been shown to be associated with decreased metabolisation of clopidogrel, poor antiaggregant effect and increased adverse cardiovascular events. AREAS COVERED IN THIS REVIEW: This review summarises the principal studies contributing to establish the relationship between CYP2C19*2 polymorphism and adverse outcomes in high risk patients on clopidogrel treatment. TAKE HOME MESSAGE: Prospective studies are urgently needed to determine the clinical impact of a score that takes into account individual characteristics of patients - CYP2C19*2 genotypes, residual platelet reactivity, drug-drug interaction, as well as traditional and procedural risk factors - for the identification of the therapeutic strategy that provides the best benefit for the single subject. PMID- 20163284 TI - Coated whey protein/alginate microparticles as oral controlled delivery systems for probiotic yeast. AB - Viable Saccharomyces boulardii, used as a biotherapeutic agent, was encapsulated in food-grade whey protein isolate (WP) and alginate (ALG) microparticles, in order to protect and vehicle them in gastrointestinal environment. Yeast-loaded microparticles with a WP/ALG ratio of 62/38 were produced with high encapsulation efficiency (95%) using an extrusion/cold gelation method and coated with ALG or WP by a simple immersion method. Swelling, yeast survival, WP loss and yeast release in simulated gastric and intestinal fluids (SGF and SIF, pH 1.2 and 7.5) with and without their respective digestive enzymes (pepsin and pancreatin) were investigated. In SGF, ALG network shrinkage limited enzyme diffusion into the WP/ALG matrix. Coated and uncoated WP/ALG microparticles were resistant in SGF even with pepsin. Survival of yeast cells in microparticles was 40% compared to 10% for free yeast cells and was improved to 60% by coating. In SIF, yeast cell release followed coated microparticle swelling with a desirable delay. Coated WP/ALG microparticles appear to have potential as oral delivery systems for Saccharomyces boulardii or as encapsulation means for probiotic cells in pharmaceutical or food processing applications. PMID- 20163285 TI - Interpenetrating network hydrogel beads of carboxymethylcellulose and egg albumin for controlled release of lipid lowering drug. AB - Novel interpenetrating network hydrogel beads of sodium carboxymethylcellulose and egg albumin loaded with a lipid lowering drug, simvastatin, were prepared by ionotropic gelation and covalent cross-linking method. The IPN beads were characterized by differential scanning colorimetric analysis, X-ray diffractometry to understand the crystalline nature of the drug after entrapment into IPN matrix. Fourier transform infrared spectroscopy was used to find the chemical stability of drug in the polymer matrix and scanning electron microscopy was performed to study the surface morphology. The ionically cross-linked beads were capable of releasing drug up to 7 h, whereas the drug release was extended up to 12 h in case of dual cross-linked beads. The beads which were prepared with higher concentration of glutaraldehyde released the drug more slowly. The release data were fitted to an empirical equation to determine the transport mechanism, which indicated the non-Fickian trend for drug transport. PMID- 20163286 TI - Comparisons of simple and complex coacervations for preparation of sprayable insect sex pheromone microcapsules and release control of the encapsulated pheromone molecule. AB - With dodecanol (C12OH) as a model molecule of insect sex pheromone as core material, natural polymers gelatin (GE) and acacia gum (AG) as wall materials, microcapsules aiming to be a sprayable environment-friendly pesticide were prepared via GE simple coacervation and complex coacervation of GE and AG. C12OH encapsulation in complex coacervation was higher than those in simple coacervation. Its encapsulation was enhanced with increase in wall material cross linking. C12OH release revealed that samples from simple coacervation reached their end in 7 days, whereas those from complex coacervation manifested a quick release followed by a constant release. With increase in wall material cross linking, the release was slowed down. SEM observation confirmed that core-shell morphology existed in the capsules. PMID- 20163287 TI - YKL-40 and hyaluronic acid (HA) as noninvasive markers of liver fibrosis in kidney transplant patients with HCV chronic infection. AB - OBJECTIVE: Hepatitis C is highly prevalent among kidney transplant (KT) recipients. In this population, the natural history of hepatitis C virus (HCV) infection and its proper management remains controversial. The invasiveness of the procedure and the interpretation variability of liver biopsy limit its use in these patients. We sought to evaluate the performance of YKL-40 and HA as markers of liver fibrosis in KT patients with HCV infection. MATERIAL AND METHODS: This cross-sectional study included HCV infected KT individuals. Univariate analysis was used to identify variables associated with significant fibrosis (METAVIR >or= F2). The diagnostic values of the YKL-40 and HA were compared using receiver operating characteristic (ROC) curves. RESULTS: Eighty-five patients were included (60% males, mean age 44.9 +/- 9.4 years). Significant fibrosis was observed in 14 patients (17%). When compared to F0/F1 individuals, patients with significant fibrosis were older, showed a higher time since transplantation, and higher prevalence of diabetes. No difference was observed in YKL-40 levels between the groups. Significantly higher levels of HA were noted in METAVIR >or= F2 subjects (108 vs. 37 ng/ml, p = 0.002). The AUROCs of YKL-40 and HA for predicting significant fibrosis were 0.615 and 0.765, respectively (p = 0.144). Levels of YKL-40 or= 418 ng/ml and HA >or= 120 ng/ml exhibited a PPV of 31% and 39%, respectively. CONCLUSIONS: Increased serum levels of HA but not of YKL-40 were associated with more advanced stages of liver fibrosis in KT HCV infected patients. PMID- 20163288 TI - The study on the role of inflammatory cells and mediators in post-infectious functional dyspepsia. AB - OBJECTIVE: Functional dyspepsia is a common gastrointestinal disorder. The pathogenesis of functional dyspepsia remains unclear. Functional dyspepsia may begin after a bout of gastroenteritis (post-infectious functional dyspepsia) or de novo (nonspecific functional dyspepsia). The aim of this study was to investigate the prevalence and probable mechanisms of post-infectious functional dyspepsia. MATERIAL AND METHODS: Functional dyspepsia patients with a history of unsanitary food intake and acute gastroenteritis 6-12 months ago were enrolled. (13)C-UBT confirmed absence of H. pylori infection. Controls consisted of healthy nondyspeptic volunteers and patients with nonspecific functional dyspepsia. Gastric biopsies were used for routine histology, immunohistochemistry, electron microscopy, ELISA, HPLC assays and Western blot examination. RESULTS: Eighty-five subjects were entered including 35 with post-infectious functional dyspepsia, 30 with nonspecific functional dyspepsia, and 20 healthy controls. The number of mast cells in post-infectious functional dyspepsia and nonspecific functional dyspepsia were significantly greater than that in healthy controls. The number of enterochromaffin cells (ECs) in post-infectious functional dyspepsia was significantly higher than those in nonspecific functional dyspepsia or in healthy controls. The number of mast cells and ECs increased with the density of chronic inflammatory cells. The release of histamine and 5-hydroxytryptamine from gastric mucosa of post-infectious functional dyspepsia patients was significantly greater than those from nonspecific functional dyspepsia or healthy controls. Tryptase protein expression was higher in post-infectious functional dyspepsia and nonspecific functional dyspepsia than in healthy controls. The histological score of chronic gastric inflammation was greater in post-infectious functional dyspepsia versus patients with nonspecific functional dyspepsia or healthy controls. Electron microscopy showed secreting granules in the cytoplasm of both mast cells and ECs. The number of activated mast cells and Ecs at a distance of < 5 microm of nerve fibers were significantly greater in post-infectious functional dyspepsia versus nonspecific functional dyspepsia or controls. CONCLUSIONS: Dyspepsia may occur after an acute onset of gastroenteritis in a part of patients. Potent chemicals derived from mast cells and ECs, including histamine, tryptase and 5-hydroxytryptamine may be involved in the pathogenesis of post infectious functional dyspepsia. PMID- 20163289 TI - Histopathological and gene expression analysis of mice exposed to diethylstilbestrol. AB - The estrogenic compound diethylstilbestrol (DES) has been widely studied to understand its potential involvement in endocrine function and carcinogenesis. This study examined the influence of DES on adult mice by histopathological analysis and studied the gene expression changes using mRNA differential display. Pathological changes in the mice following DES exposure included testicular atrophy, ovarian and hepatic fibrosis, and reduced numbers of mature oocytes and spermatogenic cells. Other pathological changes, such as cirrhosis of the liver, were also found. To elucidate the molecular mechanism underlying these effects, we used mRNA differential display to analyze changes in gene expression following DES exposure. In total, 20 genes were differentially expressed in liver, kidney, ovary, uterus, and testis. All putative target genes were validated by QRT-PCR. The study provides evidence that DES has an acute effect on gene expression. The results may facilitate the discovery of the genotoxic mechanism of DES and allow one to discover new DES-responsive genes. PMID- 20163290 TI - Effects of dopamine antagonists on methamphetamine-induced dopamine release in high and low alcohol preference rats. AB - The authors have previously shown that high alcohol preference rats (HAP) have a significantly higher sensitivity than low alcohol preference rats (LAP) for methamphetamine (MAP). In this study, changes in dopamine and serotonin release induced by MAP (1 mg/kg, intraperitoneally) after pre-treatment with D1 and D2 receptor antagonists were examined in the striatum of rats with different alcohol preferences to elucidate differences in receptor levels between the two rat strains. D1 receptor antagonist SCH23390 or D2 receptor antagonist haloperidol were administrated intracerebroventricularly 10 min before MAP stimulation. This study investigated the effect of methamphetamine-induced dopamine and serotonin release in striatum using microdialysis of freely moving rats coupled to ECD HPLC. With haloperidol treatment both strains of rats showed a significantly greater maximum increase on MAP-induced dopamine release compared with respective control rats. However, after SCH23390 treatment only HAP rats showed a significantly greater increase in dopamine release compared with controls. SCH23390 blocks mainly D1 receptors only in the post-synaptic membrane, whereas haloperidol blocks D2 receptors in both the pre-synaptic and post-synaptic membranes. The MAP-induced increase in dopamine release following haloperidol pre treatment was greater than SCH23390 pre-treatment in both strains. This result indicates that D2 receptors (autoreceptors) in the pre-synaptic membrane were blocked, leading to the elimination of the feedback function that regulates dopamine release. These data suggested that alcohol preference is associated with the action of MAP, and the dopaminergic mechanism, specifically the D1 system in the striatum, might have a different pathway dependent on alcohol preference. PMID- 20163291 TI - Excretion of bisphenol A into rat milk. AB - Bisphenol A (BPA), an endocrine-disrupting chemical, is widely used in the production of polycarbonate plastic and epoxy resins. This study analyzed the BPA concentration in rat milk, in order to assess the risk of BPA transfer to the offspring via milk. The rats ingested BPA by oral administration or by drinking the water in a polycarbonate bottle, and the milk samples were collected using an automated experimental milker. The BPA concentration in the samples of milk, drinking water, and food was analyzed by LC/MS. In the case of milk samples obtained from rats injected with BPA at 2, 4, 8, and 24 h prior to milking, the BPA concentrations were 0.462 +/- 0.182 ppm, 0.138 +/- 0.0185 ppm, 0.080 +/- 0.0197 ppm, and 0.0232 +/- 0.0051 ppm, respectively. Also, in the cases of the water sample left in polycarbonate bottle and the milk sample obtained from rats provided it as drinking water, the concentrations of BPA were 0.000332 +/- 0.00015 ppm and 0.0184 +/- 0.0050 ppm, respectively. The results indicate that the BPA administered to the dams was transferred to their milk, and that BPA concentration in milk was higher at the early period after the single bolus dose. Additionally, these results reveal that sequential elution of BPA from polycarbonate containers in a much diluted form would undergo bioaccumulation in dams and likely be transferred to pups via milk in a much concentrated form. PMID- 20163292 TI - Changes in extracellular striatal acetylcholine and brain seizure activity following acute exposure to nerve agents in freely moving guinea pigs. AB - Organophosphorus nerve agents irreversibly inhibit acetylcholinesterase (AChE) in the peripheral and central nervous systems, causing an increase in the concentration of acetylcholine (ACh) in the synapse or neuromuscular junction and subsequent adverse effects. In this study, in vivo microdialysis was utilized to collect samples from the striatum for monitoring changes in extracellular ACh levels along with cortical electroencephalographic (EEG) recordings for identifying seizure activity after acute subcutaneous (s.c.) exposure to 1.0 x LD(50) of the nerve agents sarin, soman, or one of two V-type agents (VX, or a Russian V-agent, designated VR) in unanesthetized freely moving guinea pigs. Based on EEG recordings, these animals were subsequently divided into groups that developed seizures (S) and those that did not develop seizures (NS). Maximum ACh levels in the striatum were observed at 60-70 min for sarin and soman S groups and 105 min for VX and VR S groups. In all NS groups the greatest increase in extracellular ACh occurred within 30 min after exposure, although in the sarin NS group a few sporadic increases of ACh from control occurred. Animals that developed seizures, regardless of the nerve agent, had significantly higher extracellular striatal ACh levels compared to the controls or those animals that did not develop seizures, yet both S and NS groups displayed similar levels of blood AChE inhibition. Regardless of the agent, all animals in the non-seizure groups survived 24 h, while lethality (25-42%) was observed only in animals that experienced seizure activity. PMID- 20163293 TI - Gynostemma pentaphyllum protects mouse male germ cells against apoptosis caused by zearalenone via Bax and Bcl-2 regulation. AB - The objective of this study was to explore the effects of Gynostemma pentaphyllum on Zearalenone-induced apoptosis in mouse male germ cells. Fifty Kunming male mice at 25-days-old were classified into five groups: group A was the control (10% ethanol, 0.5 ml/day); group B with 10 microg Zearalenone/day; group C with 10 microg Zearalenone and 50 mg/kg/day Gynostemma pentaphyllum; group D with 10 microg Zearalenone and 100 mg/kg/day Gynostemma pentaphyllum; and group E with 10 microg Zearalenone and 200 mg/kg/day Gynostemma pentaphyllum. It was found that Gynostemma pentaphyllum has a marked effect on protecting male germ cells against Zearalenone-induced apoptosis, as evidenced by a reduced apoptosis rate of male germ cells and Bax expression as well as an enhancement of Bcl-2 expression in Gynostemma pentaphyllum-treated groups compared to the control. In addition, Gynostemma pentaphyllum remarkably improved pathologic changes of testicular tissue, reduced the content of malondialdehyde (MDA), and increased the activity of superoxide dismutase (SOD) caused by Zearalenone. Taken together, these results suggest that Gynostemma pentaphyllum protects against toxicity caused by Zearalenone through anti-oxidation and anti-apoptosis via the regulation of Bax and Bcl-2 expression. PMID- 20163295 TI - Burden of schizophrenia in recently diagnosed patients: healthcare utilisation and cost perspective. AB - BACKGROUND: Inpatient care to manage relapse of patients with schizophrenia contributes greatly to the overall financial burden of treatment. The present study explores to what extent this is influenced by duration of illness. METHODS: Medical and pharmaceutical claims data for patients diagnosed with schizophrenia (ICD-9 295.xx) were obtained from the PharMetrics Integrated Database, a large, regionally representative US insurance claims database, for the period 1998-2007. Recently diagnosed (n = 970) and chronic patients (n = 2996) were distinguished based on ICD-9 295.xx classification, age and claims history relative to the first year (recently diagnosed) and the third year onwards (chronic) after the first index schizophrenia event. RESULTS: The medical resource use and costs during the year following the index schizophrenia event differed significantly between cohorts. A higher proportion of recently diagnosed patients were hospitalised compared with chronic patients (22.3% vs 12.4%; p < 0.0001), spending a greater mean number of days in hospital (5.1 days vs 3.0 days; p = 0.0065) as well as making more frequent use of emergency room (ER) resources during this time. The mean annual healthcare costs of recently diagnosed patients were also greater ($20,654 vs $15,489; p < 0.0001) with inpatient costs making up a higher proportion of total costs (62.9%) compared with chronic patients (38.5%). CONCLUSIONS: There is a considerably higher overall economic burden in the year following their first schizophrenia event in the treatment of recently diagnosed schizophrenia patients compared with chronic patients. Since hospitalisations and ER visits are the most significant components contributing to this finding, efforts that focus on measures to reduce the risk of relapse, particularly amongst recently diagnosed patients, such as improved adherence programs, may lead to better clinical and economic outcomes in the management of schizophrenia. LIMITATIONS: Only commercially insured patients and direct medical costs were included, therefore, results may underestimate the economic burden of schizophrenia. PMID- 20163296 TI - Physicians' treatment decisions, patient persistence, and interruptions in the continuous use of prostaglandin therapy in glaucoma. AB - BACKGROUND: Uninterrupted use of ocular hypotensive medication by glaucoma patients is important to prevent vision loss, but medication persistence is poor. Efficacy and tolerability influence physicians' decisions and patient persistence, and differences between medications may impact persistence. OBJECTIVE: To examine differences in physician's decisions to continue, switch, or discontinue therapy across three prostaglandin analogs (PGAs) latanoprost, bimatoprost, and travoprost using claims data supplemented by evaluation of physicians' charted therapeutic decisions. METHODS: A year of pharmacy claims data for 6271 patients with a first (index) fill between 5/1/2001 and 11/30/2004 for PGA monotherapy were classified as 'persistent', 'switched', 'restarted', or 'discontinued' with initial PGA use. An analysis of index therapy continuation during the first 2 years reflected chart reviews for 223 patients with PGA monotherapy as the index prescription. RESULTS: Ten percent of patients had uninterrupted use of the initial PGA alone or in combination for a year. More than half (56%) stopped and then restarted, 16% switched, and 19% discontinued the initial PGA. Patients using latanoprost were more likely to be persistent (11%) compared to bimatoprost (9%) or travoprost (5%; p < 0.0001 overall comparison). Overall, 68% of patients on latanoprost persisted or restarted after a gap compared to 61% for bimatoprost and 58% for travoprost (p < 0.0001). Patient charts demonstrated a parallel pattern in physicians' decisions to continue latanoprost (56%), bimatoprost (45%), and travoprost (40%). Study limitations included the inability to establish causal links between variables, to account for sample use, or to document reasons for patient-driven changes in therapy. The study should be replicated in a more recent database including a larger population. CONCLUSIONS: Uninterrupted use of ocular hypotensive therapy for a full year is relatively rare. Differences in physicians' decisions to continue, switch, or discontinue PGAs were observed in claims data, and parallel trends were observed in patient medical records. PMID- 20163297 TI - Sublingual immunotherapy in daily medical practice: effectiveness of different treatment schedules - IPD meta-analysis. AB - OBJECTIVE: To compare the effectiveness of perennial and co-seasonal high-dose sublingual immunotherapy (SLIT) treatments as well as ultra-rush and classical titrations in a real-world setting for pollen allergens. METHODS: An individual patient data (IPD) meta-analysis was performed of three open, prospective observational studies on high-dose SLIT using IR-standardised allergen extracts in patients with allergic rhinitis with and without asthma. RESULTS: In total, 1052 patients aged 24.9 years (mean) were treated with SLIT and included in this IPD meta-analysis. Individual studies and total data pool analyses revealed consistent improvements in rhinoconjunctivitis symptom scores. Stratified analyses revealed consistent improvements in symptomatic score and medication score regardless of the type of sensitisation and type of treatment. Ultra-rush titration resulted in considerably more pronounced improvement in symptom scores than classical titration, possibly due to better compliance of patients receiving that supervised titration. Adverse events occurred in 24% of patients during titration and in 18% of patients during maintenance treatment. The vast majority of events (89% and 87%) were mild-to-moderate, predominantly local symptoms in the oral cavity. There were no differences detected between the study titration or treatment schedules. No serious adverse reactions were reported. Nearly all patients (88%) decided to continue SLIT after completion of the studies. CONCLUSION: High-dose SLIT with seasonal allergens given as co-seasonal or perennial treatment appears to be effective and well-tolerated in daily medical practice. Improved compliance under ultra-rush titration and seasonal SLIT treatment may further enhance effectiveness. Randomised controlled trials are requested for the further evaluation of these findings. PMID- 20163298 TI - Association between HDL-C concentration and risk for a major cardiovascular event. AB - OBJECTIVE: To determine the association between baseline HDL-C concentrations and risk of a major cardiovascular event (within 5 years) in a large US claims database. METHODS: A retrospective longitudinal analysis using claims data from the i3 Ingenix LabRx database was conducted. Patients were included if they had complete lipid panel lab results, were continuously enrolled for >or=6 months prior to and >or=12 months following the lab test (index date), and were >or=50 years of age. Cox proportional hazards analysis assessed the association between HDL-C concentrations and risk of a major cardiovascular event within 5 years of the index date, after adjusting for covariates. RESULTS: There was a statistically significant association between HDL-C and risk of a major cardiovascular event. A 0.026 mmol/L (1 mg/dL) increase in HDL-C from baseline was associated with a 1.3% decreased risk of a major cardiovascular event (e.g., a 0.13 mmol/L [5 mg/dL] increase in HDL-C above baseline concentrations was associated with a 6.5% decrease). This association became evident within 1 year of follow-up. CONCLUSIONS: HDL-C concentrations were inversely associated with the occurrence of cardiovascular events within 5 years. Women who were >or=0.26 mmol/L (10 mg/dL) below their target concentrations had cardiovascular risk similar to that of women with baseline ischemic heart disease and hypertension, and men who were >or=0.26 mmol/L (10 mg/dL) below their target concentrations had cardiovascular risk similar to that of men with baseline cardiovascular disease, diabetes, or cerebrovascular disease. Limitations inherent to claims-based analyses must be considered when interpreting these findings, such as the potential for miscoding or incomplete data, and the fact that the presence of a diagnosis code on a medical claim is not positive presence of disease. Furthermore, patients who suffered a fatal cardiovascular event at home during the study period, and therefore did not receive treatment, were not captured in this analysis. PMID- 20163319 TI - Mechanisms of ketamine-involved regulation of cytochrome P450 gene expression. AB - IMPORTANCE OF THE FIELD: Ketamine, a widely used intravenous anesthetic agent, is biotransformed by cytochrome P450s (CYPs). Considerable attention is devoted to the ketamine-involved regulation of CYP gene expression. Assessing how ketamine regulates CYP gene expression is significant in recognizing the pharmacology of this anesthetic agent and its clinical application. AREAS COVERED IN THIS REVIEW: In this review, the authors discuss the effects of ketamine on the regulation of CYP gene expression and its possible mechanisms from the aspects of cytoskeletal remodeling, mitochondrial dysfunction, and alterations of intracellular ATP levels and calcium homeostasis. WHAT THE READER WILL GAIN: This review may provide readers with more clues for recognizing and avoiding possible ketamine drug interactions. TAKE HOME MESSAGE: Ketamine may inhibit CYP3A4 expression possibly through reducing calcium mobilization and mitochondrial ATP synthesis and consequently disturbing cytoskeleton remodeling. PMID- 20163318 TI - Nuclear receptor-mediated regulation of carboxylesterase expression and activity. AB - IMPORTANCE OF THE FIELD: Emerging evidence demonstrates that several nuclear receptor (NR) family members regulate drug-inducible expression and activity of several important carboxylesterase (CES) enzymes in mammalian liver and intestine. Numerous clinically prescribed anticancer prodrugs, carbamate and pyrethroid insecticides, environmental toxicants and procarcinogens are substrates for CES enzymes. Moreover, a key strategy used in rational drug design frequently utilizes an ester linkage methodology to selectively target a prodrug, or to improve the water solubility of a novel compound. AREAS COVERED IN THIS REVIEW: This review summarizes the current state of knowledge regarding NR mediated regulation of CES enzymes in mammals and highlights their importance in drug metabolism, drug-drug interactions and toxicology. WHAT THE READER WILL GAIN: New knowledge regarding the transcriptional regulation of CES enzymes by NR proteins pregnane x receptor (NR1I2) and constitutive androstane receptor (NR1I3) has recently come to light through the use of knockout and transgenic mouse models. Novel insights regarding the species-specific cross-regulation of glucocorticoid receptor (NR3C1) and PPAR-alpha (NR1C1) signaling and CES gene expression are discussed. TAKE HOME MESSAGE: Elucidation of the role of NR mediated regulation of CES enzymes in liver and intestine will have a significant impact on rational drug design and the development of novel prodrugs, especially for patients on combination therapy. PMID- 20163320 TI - Clinical implications of chemotherapy-induced tumor gene expression in human breast cancers. AB - IMPORTANCE OF THE FIELD: There has been much interest in generating gene signatures to predict treatment response in breast cancer. AREAS COVERED IN THIS REVIEW: There are at least 15 published studies that describe baseline tumor gene signatures predicting chemotherapy sensitivity. As an extension of these baseline studies, there have been at least 8 published studies evaluating chemotherapy induced tumor genomic changes over time in human breast cancers. WHAT THE READER WILL GAIN: Studies on chemotherapy-induced gene expression changes were reviewed in detail. Drug-induced biological changes within the tumor shed light on mechanisms of drug resistance and provided valuable insights regarding genes and pathways that were regulated by different drugs, including therapeutic targets that could be exploited to overcome resistance. One study also suggested post chemotherapy gene signatures to be more predictive of response and survival than the unchallenged baseline signatures. TAKE HOME MESSAGE: Studies on chemotherapy induced changes, although informative, are logistically demanding to execute, often with significant attrition of collected samples resulting in small datasets. They are further limited by heterogeneity of study population, chemotherapy regimens used, timing of the post-therapy sample and definition of response endpoint, making cross-comparisons of studies and data interpretation difficult. Future studies should address these limitations, and should involve larger sample sets and prospective studies for validation. PMID- 20163321 TI - Recent development in high-throughput bioanalytical support for in vitro ADMET profiling. AB - IMPORTANCE OF THE FIELD: High-throughput in vitro ADMET (absorption, distribution, metabolism, excretion and toxicity) profiling has become an important common practice in the pharmaceutical industry to assess compound liability early in the drug discovery process. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the bioanalytical method of choice for ADMET profiling assays that require compound-specific detection. However, the in vitro ADMET profiling environment, with its unique bioanalytical requirements of analyzing many samples generated from many discrete compounds in a high-throughput fashion, poses significant challenges for the traditional LC-MS/MS technology and process workflow, which were originally designed and optimized for single-compound bioanalysis. AREAS COVERED IN THIS REVIEW: This article reviews advances made during the last several years in both conventional high-throughput LC-MS/MS approaches and a number of promising novel MS-based technologies specifically developed to address the unique challenges in an ADMET environment. The advantages and limitations of each technology are also discussed. In addition, software solutions to enable and integrate these hardware improvements into the high-throughput ADMET workflow are reviewed. WHAT THE READER WILL GAIN: The reader will gain an updated knowledge of the state-of-the-art technologies and practices, as well as promising novel MS-based methodologies in the field of ADMET bioanalysis. TAKE HOME MESSAGE: Recent advances such as automated MS/MS optimization, high-speed and multiplexed LC separation, and integrated software support have significantly increased the speed and quality of ADMET bioanalysis using LC-MS/MS. Emerging novel technologies in front-end sample introduction, ionization and mass analysis are expected to further push the current throughput limit and potentially transform the existing bioanalytical paradigm in the future. PMID- 20163322 TI - Alefacept: where it stands today. AB - IMPORTANCE OF THE FIELD: The use of biologics that target a subset of immune cells in the treatment of immune-mediated ailments is an emerging field. Alefacept is one of the first biologics in the treatment of psoriasis. It selectively reduces CD45RO(+) memory T cells and inhibits T-cell activation. Clinical data support its safety and efficacy in a substantial subset of patients with psoriasis. AREAS COVERED IN THIS REVIEW: This article reviews the mechanism of action and the pharmacokinetic and pharmacodynamic properties of alefacept. It also presents the available data about its effectiveness, modes of treatment as well as safety and efficacy in the treatment of psoriasis and other immune-based dermatologic disorders. WHAT THE READER WILL GAIN: An overview of the published data about the clinical and adverse effects of alefacept in the treatment of psoriasis and a myriad of immunologically-based disorders. TAKE HOME MESSAGE: Ongoing literature supports that alefacept is a safe alternative for the treatment of psoriasis. However, it remains the least prescribed medication in this group of drugs, mainly because it is only effective in a small proportion of patients. Nonetheless, its long-lasting effects and tolerability make it an excellent choice for those who do respond. PMID- 20163323 TI - Acamprosate. AB - IMPORTANCE OF THE FIELD: Alcohol abuse and dependence are major causes of morbidity and mortality and come with a high societal cost. The illness is notoriously difficult to treat and relapse is a common occurrence. Acamprosate represents an effective addition to the treatment options available for alcohol dependence with a novel mechanism of action. AREAS COVERED IN THIS REVIEW: We review the published acamprosate literature focusing on major and recent comparative clinical trials and meta-analyses. We included all studies found in National Library of Medicine's PubMed database searching on Mesh term: acamprosate excluded animal studies excluding non-English publications, and focusing on efficacy/effectiveness studies. Additionally, we discuss background information on alcohol dependence and acamprosate's putative mechanism of action. Safety and tolerability data are also presented. WHAT THE READER WILL GAIN: The reader will gain a better understanding of the role of acamprosate in the treatment of alcohol dependence and find a useful synopsis of the more recently published literature evaluating acamprosate's effectiveness based on what are not always identically defined primary study outcomes. TAKE HOME MESSAGE: Acamprosate is safe and effective in the maintenance of abstinence from alcohol use/abuse and is most commonly used in combination with nonpharmacologic therapeutic modalities. The effect size ranged from 1.3 to 2 for most of the studies included in this review. PMID- 20163324 TI - Inhaled albuterol/salbutamol and ipratropium bromide and their combination in the treatment of chronic obstructive pulmonary disease. AB - IMPORTANCE OF THE FIELD: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality throughout the world. Combination therapy with albuterol and ipratropium bromide was approved > 15 years ago for the treatment of COPD. We review the mechanism of action, clinical efficacy, and safety of albuterol, ipratropium and combined albuterol-ipratropium therapy. AREAS COVERED IN THIS REVIEW: We conducted a PubMed literature search using the keywords COPD, albuterol, ipratropium bromide and Combivent (Boehringer Ingelheim Corp., Ridgefield, CT, USA); pertinent references within the identified citations are included in the review. Data from the manufacturers are also evaluated. WHAT THE READER WILL GAIN: At the time of its approval, albuterol/ipratropium bromide was an innovative combination of existing medications for the treatment of COPD. The combined formulation provides better improvement in airflow than either component alone and, by reducing the number of separate inhalers, simplifies therapy and improves compliance compared with the individual components. TAKE HOME MESSAGE: The recent development and approval of longer acting and more potent beta agonists, anticholinergics and newer combination treatments have surpassed many of the advantages of combined albuterol-ipratropium for the treatment of patients with stable COPD. PMID- 20163325 TI - QbD approach of rapid disintegrating tablets incorporating indomethacin solid dispersion. AB - The development of rapid disintegrating tablets (RDT) requires the use of highly soluble components to support the intended use of these products. In an attempt to prepare RDT of indomethacin, its solid dispersion with polyvinyl pyrrolidone K25 (PVP) was incorporated in a fast disintegrating matrix. Drug polymer interactions were investigated using X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). Indomethacin 1:1 solid dispersion with PVP was used to prepare its RDT. Two factors at 3 levels full factorial design were employed as a statistical approach to optimize the amount of superdisintegrant (Ac-di-sol) and hardness value regarding the desired disintegration and release characteristics. Drug to carrier ratio was the controlling factor for dissolution improvement. XRD and FTIR data revealed a remarkable interaction between the drug and the carrier that might be responsible for the dissolution enhancement. Multiple regression analysis revealed a significant effect of the polynomial terms for obtaining rapid disintegrating tablets. It was inferred that the hardness value is the most important factor controlling the disintegration time and the release characteristics. In conclusion, this study demonstrated that quality by design (QbD) is a potential paradigm for understanding the quality and optimizing the formulation of RDT containing indomethacin solid dispersion. PMID- 20163326 TI - Maternal plasma retinol binding protein 4 in acute pyelonephritis during pregnancy. AB - OBJECTIVE: Adipokines have been implicated in metabolic regulation and the immune response thus providing a molecular mechanism for the interaction between these two systems. Retinol binding protein 4 (RBP4) is a novel adipokine that plays a role in the pathophysiology of obesity-induced insulin resistance, as well as in the modulation of inflammation. The aim of this study was to determine whether there are changes in maternal plasma concentrations of RBP4 in pregnant women with acute pyelonephritis. STUDY DESIGN: This cross-sectional study included pregnant women in the following groups: 1) normal pregnancy (n=80); 2) pyelonephritis (n=39). Maternal plasma RBP4 concentrations were determined by enzyme-linked immunoassays. Non-parametric statistics were used for analyses. RESULTS: 1) The median maternal plasma RBP4 concentration was lower in patients with acute pyelonephritis than in those with a normal pregnancy (3709.6 ng/mL, interquartile range (IQR) 2917.7-5484.2 vs. 9167.6 ng/mL, IQR 7496.1- 10,384.1, P<0.001; 2) the median maternal plasma RBP4 concentration did not differ significantly between patients with acute pyelonephritis who had a positive blood culture and those with a negative culture (3285.3 ng/mL, IQR 2274.1-4741.1 vs. 3922.6 ng/mL, IQR 3126.8-5547.1, respectively, P=0.2); and 3) lower maternal plasma RBP4 concentrations were independently associated with pyelonephritis after adjustment for confounding factors. CONCLUSIONS: In contrast to what has been reported in preeclampsia, acute pyelonephritis during pregnancy is associated with lower maternal plasma RBP4 concentrations than in normal pregnancy. This finding suggests that the acute maternal inflammatory process associated with pyelonephritis is fundamentally different from that of the chronic systemic inflammatory process suggested in preeclampsia, in which RBP4 concentrations were found to be elevated. PMID- 20163328 TI - Identification and characterization of glucocorticoid receptor-binding sites in the human genome. AB - Glucocorticoids regulate gene expression via binding of the ligand-activated glucocorticoid receptor (GR) to glucocorticoid-responsive elements (GRE). To identify GR-binding sites, we developed a modified yeast one-hybrid system which enables rapid and efficient identification of genomic targets for DNA-binding proteins. The human GR expression vector was transformed into yeast cells containing a library of human genomic fragments cloned upstream of the reporter gene URA3. The genomic fragments with GR-binding sites were identified by growth of yeast clones in media lacking uracil but containing dexamethasone. DNA fragments were recovered by colony-direct PCR and GRE sequences were predicted by in silico analysis. Using electrophoretic mobility shift assay and fluorescence correlation spectroscopy, we demonstrated that 314 predicted GREs could directly interact with recombinant human GR proteins. In addition, when the genomic fragments were inserted in front of the heterologous SV40 promoter, at least 150 fragments could function as GREs in HEK293 cells. Furthermore, we identified four functional regulatory polymorphisms which may influence individual variation in sensitivity to glucocorticoids. These results provide insights into the molecular mechanisms underlying the physiological and pathological actions of glucocorticoid. PMID- 20163327 TI - Curcumin inhibits TNFalpha-induced lectin-like oxidised LDL receptor-1 (LOX-1) expression and suppresses the inflammatory response in human umbilical vein endothelial cells (HUVECs) by an antioxidant mechanism. AB - In this study, the anti-oxidative activities of 70% ethanol extract from Curcuma aromatica Salisb. (CAS) and curcumin (CUR) were studied. The CAS extracts and CUR were both found to have a potent scavenging activity against the reactive species tested, as well as an inhibitory effect on LDL oxidation. Cultured human umbilical vein endothelial cells (HUVECs) were stimulated with tumour necrosis factor alpha (TNFalpha), expression of intracellular reactive oxygen species (ROS), nitric oxide (NO), endothelial nitric oxide synthase (eNOS), lectin-like oxidised LDL receptor-1 (LOX-1), adhesion molecules, inhibitory kappa Balpha (IkappaBalpha) and nuclear factor kappa B (NFkappaB) were measured. In HUVECs stimulated with TNFalpha, CUR significantly suppressed expression of the intracellular ROS, LOX-1 and adhesion molecules, degradation of IkappaBalpha and translocation of NFkappaB, while inducing production of NO by phosphorylation of eNOS (p <0.05). In conclusion, CAS and CUR may modulate lipoprotein composition and attenuate oxidative stress by elevated antioxidant processes. PMID- 20163329 TI - Development and characterization of effective topical liposomal system for localized treatment of cutaneous candidiasis. AB - The localized delivery of fluconazole (FLZ) by conventional therapy is a major impediment in achieving its therapeutic efficacy against skin infections, such as cutaneous candidiasis. Therefore, the present study was aimed to develop FLZ loaded vesicular construct(s), such as liposomes and niosomes, incorporated into carbopol gel (1%; w/w) for sustained, localized application. The liposomes and niosomes were prepared by the lipid/nonionic surfactant-based dry-film hydration method and were characterized for different parameters. In addition, antifungal activity was carried out on experimentally induced cutaneous candidiasis in immunosuppressed albino rats. The results showed that the size of liposomes and niosomes was found to be 0.348 +/- 0.054 and 0.326 +/- 0.033 MUm with encapsulation efficiency of 31.8 +/- 1.36 and 27.6 +/- 1.08%, respectively. The skin-retention studies of FLZ from in vitro and in vivo experiments showed significantly higher accumulation of drug in the case of liposomal gel. The in vivo localization studies in viable skin showed that liposomal gel could produce 14.2-fold higher drug accumulation, compared with plain gel, while it was 3.3 fold more in the case of an equivalent-dose application in the form of niosomal gel. The antifungal study also confirmed the maximum therapeutic efficacy of liposomal gel, as the lowest number of cfu/mL was recorded following liposomal FLZ application. The studies signify the potential of liposomal gel for topical delivery of FLZ with increased accumulation of drug in various strata of skin vis a-vis through sustained release of drug could maintain the localized effect, resulting in an effective treatment of a life-threatening cutaneous fungal infection. PMID- 20163330 TI - [Efficacy of clinical examination and computed tomography at T-staging of laryngeal carcinoma]. AB - OBJECTIVES: The purpose of this study is to investigate the accuracy rates of tumor T-staging and the efficacy of methods used at T-staging. PATIENTS AND METHODS: Forty-seven laryngeal carcinoma patients (6 females, 41 males; mean age 57.9+/-9.8 years; range 38 to 81 years) who underwent surgery at Haydarpasa Numune Education and Research Hospital 2nd Ear Nose Throat Clinic between March 2003 and June 2008 were included in the study. T-staging of the tumors were separately determined according to their clinical examination, computed tomography (CT) findings, and their correlation between these methods. Staging according to histopathological examination was accepted as real accurate staging. Rates of accurate staging according to postoperative histopathological examination results were evaluated under guidance of the literature. RESULTS: When their accuracy rates in determining histopathological T-stages of tumors were compared, there were no significant differences between the methods. The rates of accuracy in determining histopathologic T-stage of tumors were 40% by clinical examination; 66% by CT; and 76% when both methods were used together. The most successful results were obtained at the tumors of glottic region. Among the patients whose tumors had been staged inaccurately by clinical examination, 71% were underestimated while 29% were overestimated. Underestimation and overestimation of stagings were found to be 37% and 63%, respectively, with CT examination. CONCLUSION: Success of staging increases when clinical examination is used in together with CT. While there is a tendency towards underestimation of T-stage when staging is done only by means of clinical examination, this tendency is towards overestimation when CT is used alone. Thus, combination of clinical examination findings with CT is necessary for an accurate T-staging of a laryngeal cancer. PMID- 20163331 TI - Cartilage tympanoplasty with island technique for reconstruction of tympanic membrane perforation: anatomic and audiologic results. AB - OBJECTIVES: The aim of this study was to evaluate anatomic/audiologic outcomes of cartilage tympanoplasty with island technique and compare the results with the results of temporalis fascia tympanoplasty. PATIENTS AND METHODS: The charts of 40 patients who underwent surgery for primary type 1 tympanoplasty either with perichondrium-cartilage (12 males, 11 females; mean age 29.7 years; range 12 to 58 years) or fascia graft (9 males, 8 females; mean age 32.4 years; range 13 to 61 years) between January 2006 and January 2008 were retrospectively reviewed. Patients in whom the only pathology was subtotal tympanic membrane perforation with intact ossicular chain were included in the study. Pre- and postoperative audiograms, postoperative otoscopy findings and follow-up time were obtained from the patient's chart in both groups. Reviewed parameters were the complete closure rates of the tympanic membrane perforation and the change in air bone gap at each of four frequencies (0.5, 1, 2, 4 kHz). Audiologic evaluation was made among the patients in whom complete ear drum closure was achieved in both groups. RESULTS: Anatomic closure rates of the tympanic membrane perforation for perichondrium cartilage and fascia group were 91.3% and 88.2%, respectively. Pre- and postoperative pure tone average air bone gap obtained at four frequencies for the perichondrium-cartilage and fascia group were 21.3+/-6.7 dB, 9.0+/-3.9 dB, and 21.2+/-6.9 dB, 8.5+/-4.4 dB, respectively. These findings revealed the overall gains of 12.3 dB for the cartilage-perichondrium group and 12.7 dB for the fascia group (p>0.05). CONCLUSION: The anatomic and audiologic results after cartilage tympanoplasty with island technique are comparable to those after temporalis fascia tympanoplasty. Furthermore, the cartilage is more resistant than the fascia to the anatomic deformation and necrosis. Therefore, we advise its use as a routine tympanic membrane reconstruction material without concern about effecting audiometric resuls. PMID- 20163332 TI - [Frontal sinus obliteration with pericranial-subgaleal flap]. AB - OBJECTIVES: We evaluated the results of patients who underwent frontal sinus obliteration with vascularized pericranial-subgaleal flap. PATIENTS AND METHODS: Charts of patients (7 males 1 female; mean age 40.5+/-17.1 years; range 9 to 61 years) who underwent frontal sinus obliteration with pericranial-subgaleal flap between June 2001 and January 2008 were retrospectively reviewed. Demographics, indications for frontal sinus obliteration, immediate and late postoperative complications were recorded. All patients were invited to the clinic and underwent control examinations and computed tomography. The indications for frontal sinus obliteration were fracture of frontal sinus anterior and posterior walls in four cases, frontal sinus mucoceles in two cases, mucopyoceles in one case and fracture of frontal sinus anterior wall in one case. Bicoronal incision was used in all patients and then they underwent frontal sinus obliteration with lateraly based pericranial-subgaleal flap. RESULTS: In the postoperative period rhinorrhea and meningitis, which lasted for two days, developed in one patient with fracture of frontal sinus anterior-posterior walls and hypoestesia developed in the frontal skin area in one patient with fracture of frontal sinus anterior wall. No complications were observed in the other cases. CONCLUSION: Pericranial subgaleal flap is a well vascularized, close to surgical area, inexpensive, safe and effective tissue that can be used for frontal sinus obliteration. PMID- 20163333 TI - The effect of tumor width and depth on extracapsular lymp node metastases in tongue tumors. AB - OBJECTIVES: In this study, we investigate the relationship between the effects of tumor width and depth with the extracapsular nodal spread (ECS) in oral tumors. PATIENTS AND METHODS: In this study we investigate retrospectively data of 107 patients (69 males, 38 females; mean age 45 years; range 25 to 79 years) with tongue tumors, who had undergone surgery in our clinic, between 1994 and 2004. Twenty-one of them had ECS. The effects of tumor width and depth on various parameters such as nodal metastases, survival, grade and ECS are investigated. RESULTS: It was found that tumor width and depth were the most important factors that affect ECS and logistic regression analysis point out tumor width influence more than tumor depth. Receiver operating characteristic (ROC) curve analysis shows us when tumor width exceeds 3.7 cm or tumor depth exceeds 2.4 cm, rate of ECS reaches the maximum sensitivity and specificity. CONCLUSION: Tumor width and depth has affects on survival and prognosis but also they have significant relation with ECS. PMID- 20163334 TI - Larynx cancer treatment results: survive and quality of life assessment. AB - OBJECTIVES: To make a contribution to the treatment modality of larynx cancer, we evaluated our surgical outcomes of the patients with larynx cancer and their quality of life in the postoperative period. PATIENTS AND METHODS: Forty-three patients (38 males, 5 females; mean age 57.6 years; range 34 to 84 years) with larynx cancer were included in this retrospective clinical study. Total laryngectomy/near total laryngectomy (TL/NTL) was performed in 29 patients, supracricoid laryngectomy in 13 patients and supraglottic laryngectomy in one patient. Neck dissection performed in 39 patients. Two patients had preoperative and eleven patients had postoperative radiotherapy (RT). The patients were evaluated with respect to age, sex, smoking, alcohol consumption, localization differentiation-stage of the tumor, surgery and RT, postoperative complications and survival. QLQ-C30 and QLQ-H and N35 questionnaires were used and the results of 26 patients who were alive and filled in the questionnaires themselves were evaluated. RESULTS: The most frequent postoperative complication was pharyngocutaneous fistula (41.3%), which occurred only in TL/NTL patients. Mean postoperative hospitalization time was 21.2 days. Laryngeal preservation, peristomal recurrence and locoregional recurrence rates were 64.3%, 6.9% and 9.3% respectively. Overall survival rate was 88.8%. Mean survival time was 62.4 months. In quality of life assessment, speech problem (p<0.01) and cough index (p<0.05) were significantly higher in TL/NTL group than SCL group (p<0.05). There were no significant difference in both groups with respect to RT (p>0.05). CONCLUSION: Our surgical outcomes are compatible with the previous studies. Although the larynx preservation had a positive effect on the speech, it did not affect other quality of life parameters. In addition, having a permanent tracheostomy increased cough index markedly. We emphasize that multi institutional prospective quality of life studies comparing different treatment methods for similar stage tumors are essential in defining the optimal management strategy in patients with larynx cancer. PMID- 20163335 TI - [Our results with respect to uvulopalatopharyngoplasty in patients with snoring and obstructive sleep apnea syndrome]. AB - OBJECTIVES: In this study we evaluated the results of modified uvulopalatopharyngoplasty in patients with snoring and obstructive sleep apnea syndrome. PATIENTS AND METHODS: Twenty patients (9 females, 11 males; mean age 44.4 years; range 31 to 67 years) who were diagnosed to have obstructive sleep apnea syndrome and snoring and who underwent modified uvulopalatopharyngoplasty were evaluated prospectively. The patients were evaluated considering pre- and postoperative symptoms, polysomnography, and Epworth sleepiness scale. Postoperative polysomnography was performed in the 4th month at the earliest and in the 25th month at the latest. RESULTS: With respect to polysomnography, there were no significant differences between pre- and postoperative values except duration of apnea. However, there was significant decrease in postoperative values when compared to preoperative values regarding Epworth sleepiness scale. There were no significant differences between the patients followed up for four to eight months and those followed up for 12 to 25 months. CONCLUSION: Modified uvulopalatopharyngoplasty may be a method of choice in patients with obstructive sleep apne syndrome who are not compatible with continuous positive airway pressure or oral apparatus. PMID- 20163336 TI - [Assessment of internal jugular vein flow and patency with power duplex Doppler ultrasonography after functional neck dissection]. AB - OBJECTIVES: The purpose of this study was to assess the patency of the internal jugular vein after functional neck dissection. PATIENTS AND METHODS: Twenty-five patients (6 females, 19 males; mean age 53.9 years; range 30 to 71 years) who were operated on because of larynx, hypopharynx and intraoral cavity tumors in the Ear, Nose and Throat Clinic of Haseki Training and Research Hospital between January 2001 and March 2003 were included in the study. Internal jugular veins were evaluated after 42 functional neck dissections. By means of power duplex Doppler ultrasonography, the jugular blood flow, presence or absence of a thrombus, diameter of the vein, velocity of the blood flow were evaluated. RESULTS: In our study the internal jugular vein patency rate was found to be 95.2%, and thrombosis was detected only in two patients. Blood flow velocity in patients with thrombus was found to be significantly lower than that observed in patients without thrombus (p<0.05). CONCLUSION: It was observed that blood flow of the internal jugular vein was ensured in most patients after functional neck dissection. PMID- 20163337 TI - A rare case of nasal Mantle cell lymphoma. AB - A 56-year-old Caucasian man was referred to our clinic with the complaint of right sided unilateral nasal blockage which had been present for one year. Anterior rhinoscopy and computed tomograpy scan revealed a mass, filling the right nostril completely and lying in the right inferior meatus inseparable from the inferior turbinate. Following the biopsy, histopathological examination and immunohistochemical analyses, the diagnosis of Mantle cell lymphoma was established. To our knowledge, there have been no previous reports of a Mantle cell lymphoma presenting as an intranasal mass in the literature. In this article the clinical, radiological and pathological features as well as recent advances in treatment are discussed in the light of current literature. PMID- 20163338 TI - Diplopia secondary to septal infiltration anesthesia: two cases. AB - We describe two temporary diplopia cases secondary to local septal infiltration anesthesia during septoplasty operation. Both of the diplopia cases resolved without any treatment. Although diplopia was not refractory in our cases, when injecting anesthetics, special care must be taken to avoid injection either into the artery or to the vein. PMID- 20163339 TI - Modified sling snoreplasty: double triangle shaped suture uvulopalatopexy. AB - Following the uvulopalatopharyngoplasty and laser assisted uvulopalatoplasty as treatments for mild obstructive sleep apnea syndrome (OSAS) originating from the soft palate, palatal stiffening operations began to be described as causing less morbidity, interfering less with velopharyngeal and mucosal functions, and being applicable in outpatient settings. We present modified uvulopalatopexy procedure which can be used in mild OSAS patients is a simple, minimally invasive and effective new method. In this article, we present a modified form of sling snoreplasty method and two cases in whom this method was used. PMID- 20163340 TI - Suboptimal etravirine activity is common during failure of nevirapine-based combination antiretroviral therapy in a cohort infected with non-B subtype HIV-1. AB - OBJECTIVE: The primary objective of this study was to estimate etravirine activity in a cohort of patients infected with non-B subtype HIV-1 and failing nevirapine-based therapy. MATERIALS AND METHODS: Genotypic resistance testing was performed if viral load was >OR= 1,000 copies/ml after receiving at least six months of therapy. Suboptimal response to etravirine was predicted by a score >OR= 2.5 on the Tibotec weighting schema, >OR= 4 in the Monogram schema, or classification as high to low-level resistant by a modification of the Stanford HIVdb algorithm (Version 5.1.2). Bivariate and multivariate analyses were conducted to determine the risk factors for suboptimal etravirine activity. RESULTS: The patients (n=91) were receiving nevirapine and lamivudine plus stavudine (57.1%) or zidovudine (42.9%). Median duration of nevirapine exposure was 53 weeks (IQR 46-101 weeks). The most common etravirine resistance associated mutations were Y181C (42.9%), G190A (25.3%), H221Y (19.8%), A98G (18.7%), K101E (16.5%), and V90I (12.1%). Suboptimal etravirine activity was predicted in 47.3 to 56.0%. There were disparities in mutations listed in Tibotec versus Monogram Schemas. Predicted suboptimal activity was not associated with nucleoside reverse transcriptase inhibitor (NRTI) used, gender, pretreatment or current CD4 cell count or viral load, subtype or NRTI mutations. CONCLUSION: Etravirine has compromised activity in approximately half of the patients failing nevirapine based first-line treatment in this cohort, which supports guidelines that caution against using it with NRTIs alone in such patients. PMID- 20163341 TI - Is metabolic syndrome associated to HIV infection per se? Results from the HERMES study. AB - HERMES is a prospective study, including all treatment-naive patients attending scheduled visits at hospitals in the CISAI group in 2007. The present cross sectional analysis aims to assess the baseline prevalence and characteristics of Metabolic Syndrome (MS) in a population of HIV-positive treatment-naive patients. MS was diagnosed using the National Cholesterol Education Program (NCEP) definitions. A total of 292 subjects were enrolled, median age was 37 years, 75% of them were males. The prevalence of MS was 12.3%. The most frequent trio of abnormalities that led to the diagnosis of MS was high blood pressure, triglycerides and HDL. Univariate analysis showed that MS was associated with the following variables: age, education, physical activity, advanced HIV disease (CDC stage C or HIV-RNA >100,000 copies + CD4 <100 cells/mm(3)). Higher educational levels remained protectively associated with MS in multivariate analysis. A higher risk of MS was also associated with advanced HIV disease. Actually, treatment-naive HIV-positive patients in an advanced stage of the disease have a higher prevalence of abnormal levels of triglycerides, HDL cholesterol and blood glucose than those at a less advanced stage. These findings of the HERMES study suggest, therefore, that HIV infection per se is associated to MS. PMID- 20163342 TI - Hepatitis C infection on immune recovery in HIV-positive patients on successful HAART: the role of genotype 3. AB - OBJECTIVE: The primary objective of this study was to investigate the impact of HCV infection and of HCV genotypes on immune restoration in HIV-infected patients on a successful HAART regimen. METHODS: Patients from the MASTER Study were included in this current longitudinal study if they met the following criteria: being on any successful HAART, availability of CD4+ cell count and HIV RNA level before starting the suppressive HAART and 12 months after suppressive therapy, availability of HCV antibodies. The primary endpoints of the study were defined as achieving a difference above 100 cell/mmc between CD4+ at baseline and at time of HIV RNA suppression while on therapy (DeltaCD4+early), or 12 month after a suppressive therapy (DeltaCD4+late). RESULTS: 844 HIV-positive patients were included in the analysis: 673 were HCV-negative and 171 were HCV-positive [92 (53.8%) subjects had HCV genotype 1; 58 (33.9%), genotype 3; 21 (12.3%), genotype 4]. Plasma HIV RNA (both baseline as highest value), nadir CD4+, being naive, time to reach undetectable plasma HIV RNA, treatment with PI vs NNRTI were associated with an early immunological recovery; the occurrence of previous AIDS event, a history of injection drug use, and HCV infection were associated with failure to achieve an early immunological recovery. Variables associated with DeltaCD4+late immune recovery were baseline CD4+ value, plasma HIV RNA (both baseline as highest value), being naive and time to reach undetectable plasma HIV RNA. HCV infection per se was not associated with a worse probability to reach late immunologic response, although among HCV infected patients, having a genotype 3 was associated with a worse immune recovery. At multivariable analysis, factors that remained associated with failure to achieve an early immunological response were being HCV infected and history of injection drug use, while those associated with a failure to achieve a late immunological response were being infected with HCV genotype 3 and older age. CONCLUSIONS: A blunted early immune recovery was observed in HCV infected patients, compared with HCV negative subjects, while late immune recovery was not different among HCV infected as a whole and not infected subjects; only the subgroup of subjects infected with genotype 3 showed an impaired late immune recovery. PMID- 20163343 TI - Stability of dried blood spots for HIV-1 drug resistance analysis. AB - The wide scale application of dried blood spots (DBS) as a collection tool for low-cost HIV drug resistance testing requires a greater understanding of the accuracy of DBS for genotype analysis and the stability of DBS under various environmental conditions. Analysis of a 50microl DBS via a single amplicon, nested PCR-based in-house assay (the Burnet genotyping assay) showed an average nucleotide concordance of 98.9% with plasma samples, although only 65% of nucleotide mixtures detected in plasma were also detected within DBS. The analysis of three DBS resulted in the detection of a greater number of nucleotide mixtures (72 and 109 mixtures detected within one and three DBS, respectively, n=10). Two DBS extraction protocols (silica particle; NucliSENS, bioMerieux and spin column extraction; High Pure, Roche) were assessed and found to be equivalent (79% and 84% recovery success respectively, n=19). FTA Elute paper (Whatman) was an inferior DBS collection medium compared to Whatman 903 paper. DBS appeared relatively tolerant to multiple freeze/thaw cycles, with 79% of DBS subjected to ten freeze/thaw cycles successfully amplified compared to 93% of DBS defrosted once (n=14). High temperature (37 degrees C) and high humidity (>90%) substantially impaired DBS recovery within two weeks of storage (38%, n=8), whilst storage at -20 degrees C or 4 degrees C adequately preserved DBS for this period (100% recovery, n=8). Therefore, whilst DBS are suitable for HIV drug resistance surveillance, the use of multiple DBS may be required to ensure accurate detection of minor HIV quasispecies and short-term storage of samples at either 4 degrees C or -20 degrees C is recommended. PMID- 20163344 TI - Induction of SIV p27-specific multifunctional T cells in the gut following prime boost immunization with Clostridium perfringens and adenovirus vaccines expressing SIV p27. AB - A vaccine-induced cellular immune response to simian immunodeficiency virus (SIV) in the gut mucosal tissue may prevent the establishment or severity of new SIV infection. An oral Clostridium perfringens expressing SIV p27 (Cp-p27) vaccine that delivers SIV p27 to the gut was evaluated for its ability to prime multifunctional cellular immunity in the gut mucosa. Gut Peyer's patches dendritic cells matured in response to in vitro exposure to Cp-p27 and stimulated production of p27-specific IFN-gamma. In mice, the oral vaccination with the Cp p27 vaccine and systemic immunization with adenovirus expressing SIV p27 (Ad-p27) induced robust systemic and mucosal immune responses. Furthermore, the prime boost regimen induced p27-specific multifunctional CD8+ T cells in the gut. These results indicate that priming gut tissue with Cp-p27 can enhance the gut mucosal cellular immune response generated via systemic immunization with Ad-p27. PMID- 20163345 TI - Nucleoside analog stavudine depletes mitochondrial DNA with no organelle loss in mouse oocytes. AB - Nucleoside reverse transcriptase inhibitors (NRTIs) are the basis of antiretroviral treatment of HIV-positive patients. Several studies have shown decreased fertility and fecundity among HIV-positive women under antiretroviral treatment. Oocyte impaired competence has been hypothesized to be one of the main mechanisms underlying of this decreased fertility. NRTI side effects are thought to be due to the induced mitochondrial dysfunction. Stavudine, a widely used NRTI, causes persistent mitochondrial damage in various tissues. In order to gain insights into possible mechanisms of HIV-related diminished fertility, we studied the effects of stavudine on mouse oocyte mitochondria. Mitochondrial volume, protein assay and ATP contents were unaltered by stavudine treatment, but we found mitochondrial Cox I depletion in liver and oocytes. Our findings suggest that stavudine induces mtDNA depletion without organelle loss in mouse oocytes. The decrease in Cox I DNA in treated oocytes likely points to mitochondrial dysfunction, which can impair chances of pregnancy and embryo viability. We propose that the competence of oocytes depends primarily on functional capacity of mitochondria and less on their number. PMID- 20163346 TI - Does HIV VCT reduce risk behaviors? An observational study in Guatemala City. AB - OBJECTIVE: We examined the impact of HIV voluntary counseling and testing on self reported behavioral risks three months after HIV testing. DESIGN: Cohort study comparing self-reported risk behaviors prior to and three months after HIV testing. SETTING: Clinica Familiar Luis Angel Garcia, an HIV specialty clinic located in a Guatemalan National Hospital. SUBJECTS, PARTICIPANTS: 144 people undergoing HIV testing were enrolled. 44 were HIV positive. 41 HIV positive and 49 HIV negative subjects returned for follow-up interviews. INTERVENTION: All subjects were tested and received voluntary counseling regarding HIV infection, transmission, prevention, and interpretation of HIV test results. MAIN OUTCOME MEASURE: The primary study outcome measure was change in self-reported risk behaviors three months after voluntary counseling and testing. RESULTS: Men were more likely than women to report a history of sexually transmitted diseases, more than 2 sexual partners, using alcohol with sex, and receiving money for sex; they were less likely to have a regular partner. 26% of men reported non-heterosexual orientation; no woman did. Alcohol was the primary drug of abuse in both men and women. At three month follow-up HIV positive subjects showed decreases in the average number of sexual partners, use of alcohol with sex, and episodes of unprotected sex. CONCLUSIONS: Voluntary counseling and testing resulted in changes in some self-reported risk behaviors, but only among HIV positive subjects. On nearly all measures men report riskier behavior than women. Alcohol is the most commonly used drug in this population and is often used with sex. PMID- 20163347 TI - In patients with HIV-infection, chromium supplementation improves insulin resistance and other metabolic abnormalities: a randomized, double-blind, placebo controlled trial. AB - Chromium is an essential micronutrient; chromium deficiency has been reported to cause insulin resistance, hyperglycemia and hyperlipidemia. The aim was to investigate the effect of chromium supplementation on insulin-resistance, other metabolic abnormalities, and body composition in people living with HIV. This was a randomized, double-blind, placebo-controlled trial. Fifty-two HIV-positive subjects with elevated glucose, lipids, or evidence of body fat redistribution, and who had insulin-resistance based on the calculation of homeostasis model of assessment (HOMA-IR > or = 2.5) were assessed. Subjects who were on insulin or hypoglycemic medications were excluded. Subjects were randomized to receive either 400 microg/day chromium-nicotinate or placebo for 16 weeks. Forty-six subjects, 23 in each group, completed the study. Fasting blood insulin, glucose, lipid profile and body composition were measured before and after intervention. Chromium was tolerated without side effects and resulted in a significant decrease in HOMA-IR (median (IQR) (pre:4.09 (3.02-8.79); post: 3.66 (2.40-5.46), p=0.004), insulin (pre: 102 (85-226); post: 99 (59-131) pmol/L, p=0.003), triglycerides, total body fat mass (mean+/-SEM) (pre: 17.3+/-1.7; post: 16.3+/ 1.7 kg; p=0.002) and trunk fat mass (pre: 23.8+/-1.9; post: 22.7+/-2.0 %; p=0.008). Blood glucose, C-peptide, total, HDL and LDL cholesterol, and hemoglobin A1c remained unchanged. Biochemical parameters did not change in the placebo group except for LDL cholesterol which increased significantly. Body weight and medication profile remained stable throughout the study for both groups. In summary, chromium improved insulin resistance, metabolic abnormalities, and body composition in HIV+ patients. This suggests that chromium supplements alleviate some of the antiretroviral-associated metabolic abnormalities. PMID- 20163348 TI - Relationship power in the couple and sexual double standard as predictors of the risk of sexually transmitted infections and HIV: multicultural and gender differences. AB - The goal of this work is to determine whether relationship power in couples and sexual double standard can predict the risk of sexually transmitted infections/human immunodeficiency virus (STI/HIV) as a function of cultural and gender differences. The sample was made up of 689 adolescents living in Spain, of both sexes, aged between 14 and 19 years, who were sexually active in the past six months and who had a stable partner. Of them, 58.9% were native Spaniards and 41.1% were immigrants of Latin American origin. The results show that origin, age, double standard and the control over decision-making in the couple can predict the risk of STI/HIV; thus, the immigrants, the older participants, those who scored higher in double standard, and those with less control over decision making were at higher risk of STI/HIV. With regard to gender, the males displayed more double standard and more control over decision-making, and the females displayed higher control over the relationship. The need to adapt STI/HIV prevention programs to the cultural and gender inequality differences in the couple is commented on in the discussion. PMID- 20163349 TI - Results of a community-based antiretroviral treatment program for HIV-1 infection in Western Uganda. AB - OBJECTIVE: To compare the treatment outcomes and mortality in a rural community based ART (CBART) program with a hospital-based ART program in the same district. METHODS: The study design was a non-randomized cohort study consisting of 185 persons living with HIV (PLWHIV) in the CBART cohort and 200 PLWHIV in the hospital cohort. Eligibility for both cohorts was: being HIV-infected and eligible for ART, being treatment naive, age 18 years or older, and being a resident of Rwimi sub-county. The intervention consisted of a community-based program which included weekly home visits to patients by trained volunteers who delivered antiretroviral drugs (ARVs), monitored and supported adherence to treatment, and identified and reported adverse reactions and other clinical symptoms. Outcome variables were compared to patients in a hospital-based cohort who received the standard care delivered to all other HIV patients in the hospital. The main outcome measures were HIV-1 RNA viral load (VL), CD4 cell count and mortality after six months of treatment. RESULTS: Successful ART treatment outcome as measured by virological suppression (VL<400 copies/ml) in the CBART cohort were similar to those in the hospital-based cohort (90.1% vs 89.3%, p=0.47). The median CD4 cell count increased significantly in both cohorts (community-based cohort 159 cells/microl vs 145 cells/microl in the hospital based cohort). Mortality was not significantly different in both cohorts (community-based cohort 11.9%, hospital-based cohort 9.0%). CONCLUSION: The findings show that outcomes of a CBART intervention in a rural area compare favorably to outcomes of hospital-based care. If the study results are sustainable over a longer time period, this model could be considered for ART roll-out to impoverished rural/remote populations in Uganda and elsewhere. PMID- 20163350 TI - Hodgkin lymphoma in HIV positive patients. AB - Hodgkin lymphoma (HL) represents one of the most common types of a non-AIDS defining tumour that occurs in the HIV population, and its incidence is increasing in the post Highly Active Anti-retroviral Therapy (HAART) era. Despite the aggressiveness of that disease, the outcome of patients with HIV-HL has improved with better, combined antineoplastic and antiretroviral approaches. New and effective antiretroviral drugs, in conjunction with nucleoside analogs, improve the control of the underlying HIV infection when used during treatment of HL with chemotherapy. The inclusion of hematopoietic growth factors in the treatment of patients with HIV-HL may allow for the administration of higher dose intensity chemotherapy and the prolonged use of antiretroviral drugs, with the aim of improving the survival. In addition, new functional imaging tools, like the Positron Emission Tomography (PET), may help to guide treatment and minimize long term toxicity. PMID- 20163360 TI - Structural and functional analysis of amino-terminal enhancer of split in androgen-receptor-driven transcription. AB - We previously demonstrated that the Groucho protein AES (amino-terminal enhancer of split) functions as a co-repressor of the AR (androgen receptor). It physically interacts with the N-terminal domain of AR and inhibits AR-driven transcription, but the molecular mechanism of its action remained unclear. In the present paper we report that the AES protein contains one inhibitory domain, and one positive and one negative regulatory domain. The negative regulatory domain inhibits AES dimerization and AES-mediated inhibition of AR-driven transcription through an interaction with the inhibitory domain. The positive regulatory domain blocked this interaction and relieved the inhibitory effect. In addition, we discovered mechanisms by which AES regulates AR transcriptional activity, which included disruption of the interaction between the AR N-terminal and C-terminal domains, and inhibition of AR-DNA interaction. Although AES broadly inhibited the activity of androgen-dependent luciferase reporters in a transient transfection assay, it selectively regulated the expression of endogenous androgen-dependent genes in prostate cancer cells. PMID- 20163362 TI - Chronic granulomatous disease and serious unilateral keratitis with bilateral conjunctivitis: a rare case of external ocular disease. PMID- 20163363 TI - Study of clinical applications and safety for Pascal(r) laser photocoagulation in retinal vascular disorders. AB - PURPOSE: To establish safe laser parameter standards for 10-30 ms Pascal((r)) laser in clinical practice and to evaluate clinical and visual outcomes using this 532-nm multi-spot photocoagulation system. METHODS: Retrospective observational case series of 313 patients treated between 2006 and 2008. Evaluation of eight groups: A - panretinal photocoagulation (PRP) for proliferative diabetic retinopathy (PDR); B - focal laser treatment for clinically significant diabetic macular oedema; C - grid laser for diffuse diabetic macular oedema; D - sector PRP for ischaemic branch retinal vein occlusions (I-BRVO); E - full PRP for ischaemic central retinal vein occlusions (I-CRVO); F - macular laser treatment for macular oedema secondary to non ischaemic BRVO; G - full PRP for rubeosis iridis and/or neovascular glaucoma (NVG) secondary to I-BRVO, I - CRVO or PDR; H - laser retinopexy for retinal breaks/degenerations. RESULTS: Mean LogMAR visual acuity for all procedures improved postlaser (p = 0.065), and laser prevented visual loss in 85% eyes. Topical anaesthesia was only required. At mean follow-up of 5 months, 72% procedures had a successful clinical outcome. Significantly higher powers were required for PRP using Pascal((r)) compared to conventional laser (p = 0.001) in PDR, I-BRVO, I-CRVO and NVG. Sixty-seven per cent of patients (15/20) were successfully treated with single-session 20-ms PRP using a mean 1952 burns. There were no laser-associated adverse effects or ocular complications associated with multi-spot PRP or macular Pascal((r)) arrays. CONCLUSIONS: The clinical efficacy using 10- to 30-ms pulse duration Pascal((r)) laser is comparable to conventional standard protocols used for the treatment of vascular retinal disorders. Higher power, 10- to 30-ms pulse duration laser may be safely and effectively used in clinical practice. PMID- 20163364 TI - Visual outcomes 12 months after phacoemulsification cataract surgery in patients with diabetes. AB - PURPOSE: To assess cataract surgery visual outcomes 12 months postoperatively in patients with diabetes, with or without diabetic retinopathy (DR), compared to patients without diabetes. METHODS: We followed 1192 cataract surgical patients aged >=65 for 12 months postoperatively. Standardised pre- and postoperative pinhole LogMAR visual acuity (VA) measurements were taken. Mean VA improvement was determined by comparing VA after 12 months to preoperative VA. RESULTS: Of 1192 surgical patients, 324 (27.2%) had diabetes, of whom, 136 (42.0%) had DR. After adjusting for age, gender, diabetes duration and preoperative pinhole VA, the average VA gained 12 months after surgery was 10.8 letters among 868 patients without diabetes, 10.6 letters among 188 patients with diabetes but no DR, 10.0 letters among 95 patients with DR but no past laser treatment, and no letters among 41 patients with DR plus past laser treatment (p < 0.0001, compared to the other three groups). Diabetes duration >=20 years was associated with mean VA gain of 3 fewer letters than duration <10 years (7 versus 10 letters, p = 0.023), after adjusting for age, gender, DR and preoperative pinhole VA. CONCLUSION: Cataract surgery improved VA by an average two lines for patients both with and without diabetes, or with DR but no past laser treatment. No significant VA improvement was evident for patients who had preoperative DR and laser therapy. PMID- 20163365 TI - Comparison of bimanual and micro-coaxial phacoemulsification with torsional ultrasound. AB - PURPOSE: To evaluate the efficacy and postoperative outcomes of bimanual and micro-coaxial phacoemulsification with torsional ultrasound. METHODS: In this prospective randomized series, eyes with age-related cataract were randomly divided into bimanual phacoemulsification and micro-coaxial phacoemulsification groups. Data included preoperative and postoperative corrected distance visual acuity (CDVA), central/temporal corneal thickness, endothelial cell density and intraoperative ultrasound time, cumulative dissipated energy and balanced salt solution volume. RESULTS: The study evaluated 89 patients (89 eyes). When compared between micro-coaxial and bimanual phaco groups, ultrasound time (57 +/- 24 second versus 85 +/- 40 second, p < 0.01), cumulative dissipated energy (10 +/ 7 versus 14 +/- 7, p = 0.01) and balanced salt solution volume (55 +/- 19 ml l versus 75 +/- 20 ml, p < 0.01) were significantly lower in micro-coaxial phaco group. At 1 day, there were no statistically significant differences in CDVA (p = 0.68) or central corneal thickness (p = 0.48) between two groups; temporal corneal thickness was statistically significantly thicker in bimanual phaco group (1247 +/- 123 MUm) than that in micro-coaxial phaco group (1108 +/- 131 MUm, p = 0.01). There were no statistically significant differences in CDVA, central/temporal corneal thickness, or endothelial cell density between two groups 30 days postoperatively (all p values >0.05). CONCLUSION: With rapid visual rehabilitation and comparable endothelial cell loss, both bimanual and micro-coaxial phacoemulsification procedures with torsional ultrasound are efficient for moderate nuclear cataract extraction. PMID- 20163366 TI - Stargardt disease with preserved central vision: identification of a putative novel mutation in ATP-binding cassette transporter gene. PMID- 20163367 TI - Recurrent orbital compartment syndrome caused by a blow-out fracture and accumulation of air; management by orbital punctures. PMID- 20163369 TI - Concentrations of unbound bevacizumab in the aqueous of untreated fellow eyes after a single intravitreal injection in humans. AB - PURPOSE: To determine the concentration of unbound bevacizumab in untreated fellow eyes after contralateral intravitreal injection of bevacizumab. METHODS: A total of 18 eyes received intravitreal injections of 1.5 mg bevacizumab. Nine probes were obtained in the injected eye and nine in the fellow eye. Each group contained three individual eyes. Aqueous humour samples were obtained during uneventful phacoemulsification at three intervals 1-7 days (group a), 8-12 days (group b) or 13-28 days (group c). RESULTS: In untreated fellow eyes, the concentration of unbound bevacizumab was below the detectable limit of the ELISA (5 ng/ml in all samples). The mean concentration of unbound bevacizumab in the injected eye declined from 28.6 MUg/ml (group a), 16.5 MUg/ml (group b) to 7.4 MUg/ml (group c). CONCLUSIONS: There are no pharmacological indications for a significant concentration of unbound bevacizumab in the anterior chamber of contralateral eyes in humans. PMID- 20163368 TI - EXTEND-I: safety and efficacy of ranibizumab in Japanese patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration. AB - PURPOSE: To evaluate the efficacy and safety of intravitreal ranibizumab for subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) in Japanese patients. METHODS: This open-label, multicentre, Phase I/II study enroled patients into Group A (single injection of ranibizumab nonrandomized doses of 0.3 or 0.5 mg followed by 11 monthly injections of the same dose) and Group B (12 monthly injections of ranibizumab randomized to 0.3 or 0.5 mg). The primary efficacy endpoint was the mean change from baseline in best corrected visual acuity (BCVA) score at Month 6. Safety was evaluated in all patients who received ranibizumab. RESULTS: Of 88 patients enroled, 12 entered Group A (six per dose) and 76 entered Group B (0.3 mg: n = 35; 0.5 mg: n = 41). Mean change from baseline in BCVA was significantly increased for both doses (Group B) at Month 6 (0.3 mg: +8.1 letters, p = 0.0006; 0.5 mg: +9.0 letters, p < 0.0001) and Month 12 (0.3 mg: +9.5 letters, p = 0.0001; 0.5 mg: +10.5 letters, p < 0.0001). At Month 12, one patient (0.3 mg) and 0 patients (0.5 mg) lost > or =15 letters, while 37.1% (0.3 mg) and 31.7% (0.5 mg) of patients gained > or =15 letters. Ocular serious adverse events (SAEs) of the study eye were reported in 1 and 2 patients in the 0.3- and 0.5-mg groups, respectively. Nonocular SAEs were experienced by 2 and 5 patients in the 0.3- and 0.5-mg groups, respectively. No cases of endophthalmitis were reported. CONCLUSION: Ranibizumab was effective and well tolerated in Japanese patients with subfoveal CNV secondary to AMD. PMID- 20163370 TI - Can we meet the future demands for cataract surgery? PMID- 20163371 TI - Microperimetric changes after intravitreal bevacizumab injection for exudative age-related macular degeneration. AB - PURPOSE: To evaluate the effect of intravitreal bevacizumab on macular function in the cases of exudative age-related macular degeneration (AMD). METHODS: A total of 21 eyes of 21 patients with exudative AMD were included in this study. In each eye, at baseline and 1, 3 and 6 months after intravitreal bevacizumab injection, logMAR visual acuity, central 4 degrees macular sensitivity, absolute scotoma size, fixation stability and fixation location by MP-1 microperimetry and optical coherence tomography (OCT) foveal morphologic changes were assessed. After the initial treatment phase which included three consecutive injections, the decision to re-treat was based on OCT and clinical findings. Subsequent injections could be administered at least 1 month after the previous injection period according to the OCT-guided treatment regimen. RESULTS: Mean retinal sensitivity within central 4 degrees (12 points) area had increased from 3.69 +/ 3.44 dB at baseline to 7.16 +/- 3.27 dB at month 6. In all controls after the treatment, there was significant increase in logMAR visual acuity (p < 0.001) and MP-1 retinal sensitivity (p < 0.001). Mean absolute scotoma in test point location had decreased significantly from 12 of the 76 applied test point locations measured at baseline to five test point locations (-7 test point locations; p < 0.001) at month 6 showing statistical significance. Fixation properties had preserved in all patients 6 months after intravitreal bevacizumab treatment. CONCLUSION: Intravitreal bevacizumab therapy induced a significant increase in mean retinal sensitivity and significant decrease in mean absolute scotoma size during 6 months. The MP1 microperimetry proved to be a valuable tool in the evaluation of functional benefit of exudative AMD therapy with intravitreal bevacizumab. PMID- 20163372 TI - Needle-based blocks for the 21st century ophthalmology. AB - PURPOSE: This paper reviews history of the needle orbital blocks used in the earlier centuries and how they have evolved towards safer anaesthesia in the modern clinical practice. METHODS: Material is derived from literature searches from major ophthalmic and anaesthetic journals on the use of orbital needle blocks over earlier centuries. RESULTS: Needle-based anaesthetic techniques were described shortly after the invention of reliable medical needles. Atkinson popularized the classical retrobulbar block in a series of papers published in the early 20th century. This technique,which utilises a relatively long needle inserted towards the apex of the muscle cone behind the globe, has been criticized by some as unsuitable for modern 21st century ophthalmic surgery because of the extremely rare potential for serious complications. Satisfactory anaesthesia and akinesia can be obtained with short sharp or dull needles with slightly higher volumes of local anaesthetic agent placed in the farthest inferotemporal quadrant. CONCLUSION: Aside from relative safety, modern needle blocks offer the advantage of lid akinesia without a need for a second injection for the seventh nerve that is often performed con-comitantly with retrobulbar block. PMID- 20163373 TI - Detection of new respiratory viruses in hospitalized infants with bronchiolitis: a three-year prospective study. AB - AIM: We have designed a study with the objective of describing the clinical impact of other viruses different from the respiratory syncytial virus (RSV) in hospitalized infants with bronchiolitis. METHODS: A 3 year prospective study was conducted on infants admitted to the Paediatrics Department of the Severo Ochoa Hospital (Spain). We studied the frequency of 16 respiratory viruses. Clinical characteristics of RSV-only infections were compared with other single agent viral infections. RESULTS: Positive results were confirmed in 275 (86.5%) of the 318 children studied. A single virus was detected in 196 patients and 79 were dual or multiple viral infections. RSV was detected in 61.3% of total bronchiolitis. Rhinovirus (RV) was 17.4% of the identified virus, followed by human bocavirus (HBoV), adenovirus and metapneumovirus (hMPV). Only RV, HBoV and hMPV were significant as single infections. RSV patients were younger than HBoV (p > 0.0001) and hMPV (p = 0.025). Seasonality was clearly different between them. Children with RSV infection needed treatment in the intensive care unit more frequently than others. CONCLUSIONS: In hospitalized infants, RSV was the most frequent agent in bronchiolitis in winter, but other viruses were present in 47% of the patients. RV, HBoV and hMPV had a significant proportion of single infections. Clinical characteristics were similar amongst them, but seasonality was clearly different. PMID- 20163374 TI - Onset of Kleine-Levin Syndrome in association with isotretinoin treatment. AB - The synthetic retinoid isotretinoin is an effective treatment option for severe forms of acne vulgaris. However, several reports indicate that some patients experience altered central nervous system functions in association with treatment. We present here the first description of the onset of Kleine-Levin Syndrome (KLS), a rare disorder characterised by periodic hypersomnia and cognitive and behavioural symptoms, in close temporal relation to the start of isotretinoin treatment. We also discuss the biological potential of retinoids to affect sleep. CONCLUSIONS: In light of a documented potential of retinoids to modulate sleep-wake regulation, the present case suggests that isotretinoin may rarely trigger the onset of KLS. PMID- 20163375 TI - Clinical trial: renzapride treatment of women with irritable bowel syndrome and constipation - a double-blind, randomized, placebo-controlled, study. AB - BACKGROUND: Renzapride, a 5-hydroxytryptamine type-4 (5-HT(4)) receptor agonist and 5-HT(3) receptor antagonist, has been proposed as a new treatment of irritable bowel syndrome with constipation (IBS-C). AIM: To assess the efficacy and safety of renzapride in women with IBS-C. METHODS: Women with IBS-C were randomized to renzapride 4 mg daily, 2 mg b.d. or placebo for 12 weeks. The primary outcome measure was global relief of IBS symptoms. A subset of patients were enrolled in a 12-month, open-label study of renzapride 4 mg daily. RESULTS: A total of 1798 patients were included in the efficacy analysis and 971 patients entered the long-term study. The mean (S.E.M.) number of months with relief of overall IBS symptoms was 0.55 (0.04), 0.60 (0.04) and 0.44 (0.04) in the renzapride 4 mg daily, 2 mg b.d. and placebo groups (P = 0.027 and P = 0.004 respectively). Small yet statistically significant differences in favour of renzapride were observed on stool consistency and frequency, and bloating/abdominal distension scores. Renzapride was generally well tolerated; however, three episodes of ischaemic colitis were reported in the long-term study. CONCLUSION: Given the limited increase in efficacy over placebo and the incidence of ischaemic colitis observed, our data suggest that the benefit/risk ratio of renzapride is not sufficient to warrant further study in IBS-C. PMID- 20163376 TI - Clinical trial: the efficacy and safety of oral PF-03491390, a pancaspase inhibitor - a randomized placebo-controlled study in patients with chronic hepatitis C. AB - BACKGROUND: Elevated serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) reflect hepatocellular injury in patients with chronic hepatitis C virus (HCV). Increased apoptosis and activated caspases are present in these patients. PF-03491390 inhibits multiple caspases and lowers serum AST and ALT levels in patients with chronic liver diseases. AIM: To determine if treatment with an oral pancaspase inhibitor could reduce serum AST and ALT in patients with HCV. METHODS: Double-blind, randomized, placebo-controlled, parallel-dose study in 204 patients treated with placebo or PF-03491390 (5, 25 or 50 mg) orally twice daily (b.d.) for up to 12 weeks. Serum AST and ALT were monitored weekly. RESULTS: Significant reductions in serum AST and ALT were observed within 1 week of initiating PF-03491390 in all treatment groups (P < 0.0001). These reductions in AST and ALT were maintained throughout the 12 week treatment period and returned to baseline levels when PF-03491390 was discontinued. Increasing the dose did not further lower AST or ALT. The most frequently reported adverse events were headache and fatigue. CONCLUSION: PF 03491390 significantly reduced serum AST and ALT levels in patients with chronic HCV, and was well tolerated over 12 weeks. PMID- 20163377 TI - Low- and standard-dose peginterferon alfa-2a for chronic hepatitis C, genotype 2 or 3: efficacy, tolerability, viral kinetics and cytokine response. AB - BACKGROUND: Chronic infection with hepatitis C, genotype 2/3, responds better than other genotypes to peginterferon and ribavirin treatment. We hypothesized that a lower dose of peginterferon would be as effective, but less toxic than standard doses. AIM: To test the hypothesis that a lower dose of peginterferon would be as effective as, but less toxic than, standard doses. METHODS: A total of 30 patients were treated with low-dose peginterferon alfa-2a (90 microg/week) and 27 patients with standard doses (180 microg/week) for 24 weeks in combination with 800 mg/day of ribavirin. Patients who failed treatment were offered 48 weeks of standard-dose treatment. Viral and serum inducible protein 10 (IP-10) levels were measured and early viral kinetic parameters were calculated. RESULTS: Sustained virological response was achieved in 68% of the low-dose and 87% of the standard-dose patients (per protocol, P = 0.79 for non-inferiority). Re-treatment was successful in all patients who tolerated full dose and duration. The standard dose group had greater first-phase declines of viral levels and faster time to negativity. The second-phase slope was not dose-dependent. IP-10 induction was significantly greater with the standard dose. Although fatigue and general feeling during treatment were worse for standard dose, haematological toxicity and depression did not differ between groups. CONCLUSION: A lower dose of peginterferon is associated with some symptomatic benefit, but the response is not equivalent to standard dosing. PMID- 20163378 TI - Clinically significant liver injury in patients treated with natalizumab. AB - BACKGROUND: Natalizumab is a recombinant monoclonal antibody approved for the treatment of patients with multiple sclerosis and patients with Crohn's disease. Because of its immunosuppressive effects, natalizumab has been associated with a number of atypical and opportunistic infections. AIM: To describe and summarize six spontaneously reported post-marketing cases of clinically significant drug induced-liver injury associated with natalizumab use. METHODS: The FDA maintains a database of adverse event reports (AERS). We searched the AERS database for reports of serious liver injury associated with natalizumab use from November 2004, when the drug was approved, through 30 June 2008. RESULTS: The search resulted in six spontaneously reported post-marketing cases of severe drug induced liver injury. Four of six patients developed liver injury with elevations of serum transaminases and hyperbilirubinemia after only a single infusion of natalizumab. One of these patients experienced repeated increases of aminotransferases and bilirubin when natalizumab was re-administered. CONCLUSIONS: Serious hepatic injury may occur in association with natalizumab use. Health professionals should be alerted to possible serious liver injury in patients receiving natalizumab. PMID- 20163380 TI - Abnormal growth in mitochondrial disease. PMID- 20163379 TI - Indications of 'atopic bowel' in patients with self-reported food hypersensitivity. AB - BACKGROUND: An association between atopic disease and gastrointestinal complaints has been suggested. AIM: To explore the association between atopic disease, gastrointestinal symptoms, and possible gastrointestinal manifestations of atopic disease in patients with self-reported food hypersensitivity. METHODS: Symptoms, skin prick tests, serum markers of allergy and intestinal permeability were recorded in 71 adult patients. Eosinophils, tryptase- and IgE-positive cells were counted in duodenal biopsies. RESULTS: Sixty-six (93%) patients had irritable bowel syndrome (IBS) and 43 (61%) had atopic disease, predominantly rhinoconjunctivitis. All 43 were sensitized to inhalant allergens, 29 (41%) to food allergens, but food challenges were negative. Serum total IgE and duodenal IgE-positive cell counts were significantly correlated (P < 0.0001) and both were significantly higher in atopic than in non-atopic patients (P < 0.0001 and P = 0.003 respectively). IgE-positive cells appeared to be 'armed' mast cells. Intestinal permeability was significantly elevated in atopic compared with non atopic patients (P = 0.02). Gastrointestinal symptoms and numbers of tryptase positive mast cells and eosinophils did not differ between groups. CONCLUSIONS: Patients with self-reported food hypersensitivity had a high prevalence of IBS and atopic disease. Atopic patients had increased intestinal permeability and density of IgE-bearing cells compared with non-atopic patients, but gastrointestinal symptoms did not differ between groups. PMID- 20163381 TI - Age at regular drinking, clinical course, and heritability of alcohol dependence in the San Francisco family study: a gender analysis. AB - We examined gender differences in age of onset, clinical course, and heritability of alcohol dependence in 2,524 adults participating in the University of California San Francisco (UCSF) family study of alcoholism. Men were significantly more likely than women to have initiated regular drinking during adolescence. Onset of regular drinking was not found to be heritable but was found to be significantly associated with a shorter time to onset of alcohol dependence. A high degree of similarity in the sequence of alcohol-related life events was found between men and women, however, men experienced alcohol dependence symptoms at a younger age and women had a more rapid clinical course. Women were found to have a higher heritability estimate for alcohol dependence (h(2)= .46) than men (h(2)= .32). These findings suggest that environmental factors influencing the initiation of regular drinking rather than genetic factors associated with dependence may in part underlie some of the gender differences seen in the prevalence of alcohol dependence in this population. (Am J Addict 2010;00:1-10). PMID- 20163382 TI - The relationship between depression and smoking cessation outcomes in treatment seeking substance abusers. AB - The National Drug Abuse Treatment Clinical Trials Network (CTN) recently completed a randomized, open label trial comparing treatment as usual (TAU) combined with nicotine patches plus cognitive behavioral group counseling for smoking cessation (n = 153) to TAU alone (n = 72) for patients enrolled in treatment programs for drug or alcohol dependence, who were interested in quitting smoking. This report is a secondary analysis evaluating the effect of depressive symptomatology (n = 70) or history of depression (n = 110) on smoking cessation outcomes. A significant association was seen between measures of depression and difficulty quitting cigarettes. Specifically, there was a greater probability for smoking abstinence for those with lower baseline Beck Depression Inventory II (BDI-II) scores. These data suggest that evaluation and treatment of depressive symptoms may play an important role in improving smoking cessation outcomes. (Am J Addict 2010;00:1-8). PMID- 20163384 TI - Effects of sensory and behavioral substitutes following an experimentally induced stressor among abstinent smokeless tobacco users. AB - Despite the well-known health risks associated with smokeless tobacco use, much is unresolved with respect to effective treatment for use of this substance. The present study examined the impact of a nicotine-free smokeless tobacco substitute and confectionary chewing gum on craving, withdrawal, and anxiety among 24 smokeless tobacco users following 24 hours of nicotine abstinence and a laboratory stressor. Although chewing gum did not impact withdrawal, craving, or anxiety compared to a no-product control condition, smokeless tobacco substitute administration resulted in a reduction of withdrawal and craving levels compared to the control condition following 24 hours of abstinence. Furthermore, significantly lower levels of craving and withdrawal were observed in both smokeless tobacco and smokeless tobacco substitute conditions compared to the control condition following the stressor. Results indicate that although general oral stimulation (eg, chewing gum) was not effective in reducing symptoms related to nicotine withdrawal, smokeless tobacco substitute use appears to be helpful in reducing withdrawal levels post-stressor. These data suggest that use of a smokeless tobacco substitute may be an effective aid in helping individuals wishing to quit, especially when managing stressors. (Am J Addict 2010;00:1-8). PMID- 20163383 TI - Sex under the influence of drugs or alcohol: common for men in substance abuse treatment and associated with high-risk sexual behavior. AB - Sex under the influence of drugs or alcohol is associated with high-risk sexual behavior. Heterosexual men (n = 505) in substance abuse treatment completed a computer-administered interview assessing sexual risk behaviors. Most men (73.3%) endorsed sex under the influence in the prior 90 days, and 39.1% endorsed sex under the influence during their most recent sexual event. Sex under the influence at the most recent event was more likely to involve anal intercourse, sex with a casual partner, and less condom use. Patients might benefit from interventions targeting sexual behavior and substance use as mutual triggers. (Am J Addict 2010;00:1-9). PMID- 20163385 TI - Real-time craving differences between black and white smokers. AB - Black and White smokers may experience aspects of nicotine dependence, including craving, differently. This study used a naturalistic technique, ecological momentary assessment (EMA), to explore differences in craving, mood, expectancy, and smoking enjoyment between Black and White smokers. Participants carried personal digital assistants (PDAs) programmed to obtain multiple daily assessments. Black smokers reported higher craving after smoking and at random assessment times and higher cigarette enjoyment. No differences were found in mood or expectancy. Racial differences in psychological factors related to smoking are explored in the contexts of genetic, sociological, and psychophysiological distinctions. Implications for practice and research are discussed. (Am J Addict 2010;00:1-5). PMID- 20163386 TI - Conducting clinical research with prescription opioid dependence: defining the population. AB - Most treatment studies of opioid-dependent populations have focused predominantly on heroin users, despite a recent increase in those dependent upon prescription opioids. A key methodological challenge involved in studying the latter group involves defining the population. Specifically, researchers must decide whether to include (1) concurrent heroin users and (2) individuals with pain. The multi site Prescription Opioid Addiction Treatment Study is examining treatments for this population. This paper describes various inclusion criteria considered by the study team related to heroin use and pain. The goal was to recruit a distinct but generalizable population of individuals dependent upon prescription opioids. (Am J Addict 2010;00:1-6). PMID- 20163387 TI - The effects of current subsyndromal psychiatric symptoms or past psychopathology on alcohol dependence treatment outcomes and acamprosate efficacy. AB - This secondary analysis of the first U.S. acamprosate trial (N = 601) for alcohol dependence examines the effects of subsyndromal psychiatric symptoms or history of severe psychopathology on alcoholism treatment outcomes and any mitigating effects of acamprosate. Psychiatric antecedents were documented using a protocol specific interview. Current psychiatric symptoms were assessed using Hamilton Anxiety and Depression (HAM-A, HAM-D) rating scales. Predictors of good response, defined as abstinence for > or =90% of trial duration, were identified using logistic regression. Subsyndromal anxiety (as determined by HAM-A "Anxious Mood" item) and the presence of > or =1 psychiatric antecedent were significant negative predictors of good response. Lower pretreatment drinking intensity, baseline motivation to have abstinence as a goal, and treatment with acamprosate were significant positive predictors of good response. No significant interactions among predictors were detected, indicating that they are independent, additive factors. Thus, the beneficial effects of acamprosate treatment in combination with motivational therapy may offset the liabilities for alcoholism recovery that are associated with current anxiety symptoms and/or a significant past psychiatric history. (Am J Addict 2010;00:1-8). PMID- 20163388 TI - Methamphetamine and paranoia: the methamphetamine experience questionnaire. AB - Paranoia in methamphetamine (MA) users is not well characterized or understood. To investigate this phenomenon, we created the Methamphetamine Experience Questionnaire (MEQ), and tested its reliability and validity in assessing MA induced paranoia. We administered the MEQ to 274 MA-dependent subjects. Of the total subjects, 45% (123) first experienced paranoia with MA use; 55% did not. Obtaining or using a weapon while paranoid was common (37% and 11% of subjects with MA-induced paranoia, respectively). Test-retest and inter-rater reliability for MA-induced paranoia showed substantial agreement (kappa = .77, p < .05 and kappa = .80, p < .05, respectively). First episodes of paranoia occurred more often with intravenous use of MA, and subsequent episodes at higher doses. There was modest correlation between paranoia on the MEQ and the Brief Symptom Inventory (BSI) paranoid ideation scale (rho = .27, p < .05). As expected, there was a poor correlation between paranoia on the MEQ and the BSI depression scale (rho = .14, p = .07). The MEQ provides useful information on drug use variables that contribute to paranoia commonly associated with MA use. (Am J Addict 2010;00:1-14). PMID- 20163389 TI - Effect of PTSD diagnosis and contingency management procedures on cocaine use in dually cocaine- and opioid-dependent individuals maintained on LAAM: a retrospective analysis. AB - This randomized clinical trial retrospectively examined the effect of post traumatic stress disorder (PTSD) and contingency management (CM) on cocaine use in opioid and cocaine dependent individuals maintained on high or low-dose LAAM randomly assigned to CM or a yoked-control condition. Cocaine-positive urines decreased more rapidly over time in those without PTSD versus those with PTSD in the noncontingency condition. In participants with PTSD, CM resulted in fewer cocaine-positive urines compared to the noncontingent condition. This suggests that CM may help improve the potentially worse outcomes in opioid- and cocaine dependent individuals with PTSD compared to those without PTSD. (Am J Addict 2010;00:1-9). PMID- 20163391 TI - N-acetylcysteine (NAC) in young marijuana users: an open-label pilot study. PMID- 20163392 TI - Modafinil for bipolar depression with comorbid methamphetamine abuse. PMID- 20163393 TI - Drug dreams in mescaline and LSD addiction. PMID- 20163394 TI - Abuse of opium-containing Indian herbal medicines: a case report. PMID- 20163390 TI - Adolescent pathways to adult smoking: ethnic identity, peer substance use, and antisocial behavior. AB - African-Americans and Puerto Ricans were interviewed during adolescence, in their early twenties, and then again in their mid-twenties. Results indicated that earlier adolescent smoking, family conflict, and weak ethnic identity were significantly related to antisocial behavior, which in turn was related to associating with friends who smoked and/or used illegal drugs, and ultimately, to their own smoking. Results further indicate that early interventions in the development of tobacco use should focus on decreasing parental and adolescent smoking and parent-child conflict. If intervention occurs at a later time point, the emphasis should be on increasing ethnic identity and decreasing antisocial behavior. (Am J Addict 2010;00:1-9). PMID- 20163395 TI - Pharmacy willingness to partner with office-based opioid dependence treatment providers in conducting random buprenorphine pill counts. PMID- 20163399 TI - The contribution of macrophages to normal and pathological pregnancies. AB - Macrophages represent one of the major leukocyte subsets in the uterine decidua. Owing to their remarkable phenotypic plasticity, decidual macrophages can participate in diverse activities during pregnancy. At baseline, decidual macrophages are characterized by an immunosuppressive phenotype and M2 polarization, supporting feto-maternal immune tolerance. In early pregnancy, macrophage-derived pro-angiogenic factors prompt vascular remodeling within the uterine wall to ensure appropriate utero-placental circulation. Upon invasion by pathogens, pattern recognition receptors on decidual macrophages help to alter the characteristics of these malleable cells toward an M1, inflammatory phenotype. Similar inflammatory characteristics are seen in those macrophages that accumulate in the lower segment of the uterus to drive cervical ripening. Disturbances in the tight control that balances macrophage function during pregnancy can trigger the development of pregnancy complications. Here, we discuss the physiologic role of uterine macrophages at different stages of pregnancy and describe their relevance in selected pregnancy disorders. PMID- 20163402 TI - On combining family-based and population-based case-control data in association studies. AB - Combining data collected from different sources can potentially enhance statistical efficiency in estimating effects of environmental or genetic factors or gene-environment interactions. However, combining data across studies becomes complicated when data are collected under different study designs, such as family based and unrelated individual-based case-control design. In this article, we describe likelihood-based approaches that permit the joint estimation of covariate effects on disease risk under study designs that include cases, relatives of cases, and unrelated individuals. Our methods accommodate familial residual correlation and a variety of ascertainment schemes. Extensive simulation experiments demonstrate that the proposed methods for estimation and inference perform well in realistic settings. Efficiencies of different designs are contrasted in the simulation. We applied the methods to data from the Colorectal Cancer Family Registry. PMID- 20163400 TI - Interleukin-10: a multi-faceted agent of pregnancy. AB - It is widely accepted that pregnancy constitutes a unique developmental event. Unprecedented intrauterine actions of angiogenesis, immunity, and neuroendocrine regulation are juxtaposed to mechanisms of senescence that enable fetal growth and protection. The suppressive and regulatory factors that facilitate healthy pregnancy are under investigation. In non-pregnant systems of infection and inflammation, the cytokine interleukin-10 (IL-10) has been widely investigated because of its potential as a key immunosuppressant in response to a multitude of inflammatory events. In the context of pregnancy, IL-10 levels increase markedly in women during early pregnancy and remain elevated well into the third trimester immediately prior to onset of labor. The role of IL-10 during pregnancy as a suppressor of active maternal immunity to allow acceptance of the fetal allograft has been a point of study. Moreover, secretion of IL-10 by a diverse set of maternal and fetal cells has proven to aid in the orchestration of normal processes of pregnancy. Interestingly, some of the more profound findings regarding the actions of IL-10 during pregnancy have manifested from research that focuses on aberrant pregnancy outcomes as a result of inflammation, hormonal imbalances, or gene-environment interactions. This review focuses on the role of IL-10 as a facilitator of successful pregnancy both as an immune suppressive agent and a mediator of cross talk between the placenta and the decidua. Importantly, we discuss investigations on adverse pregnancy conditions to further elucidate the multifarious role of IL-10 at the maternal-fetal interface. PMID- 20163401 TI - Activation of the alternative pathway of complement is a feature of pre-term parturition but not of spontaneous labor at term. AB - PROBLEM: Plasma concentrations of fragment Bb (FBb) are a marker for activation of the alternative pathway of the complement system. High concentrations of FBb in maternal blood, as early as the first trimester, are associated with subsequent spontaneous pre-term delivery <34 weeks of gestation. The aim of this study was to determine whether spontaneous pre-term labor (PTL) with intact membranes, intra-amniotic infection/inflammation (IAI) or labor at term are associated with alterations in circulating maternal FBb concentrations. METHOD OF STUDY: This cross-sectional study included women in the following groups: (i) non pregnant (n = 40); (ii) normal pregnancy (gestational age range 20-36, 6/7 weeks, n = 63); (iii) women at term not in labor (n = 70); (iv) women at term in spontaneous labor (n = 59); (v) patients with an episode of PTL who delivered at term (n = 62); (vi) PTL without IAI who delivered pre-term (n = 30); and (vii) PTL with IAI who delivered pre-term (n = 67). Maternal plasma FBb concentrations were determined by ELISA. RESULTS: (i) Among patients with PTL, those who had a pre-term delivery either with IAI (1.21 microg/mL, IQR 0.77-2.16) or without IAI (1.13 microg/mL, IQR 0.92-2.08) had a higher median maternal plasma FBb concentration than those who delivered at term (0.86 microg/mL, IQR 0.64-1.57; P = 0.007 and P = 0.026, respectively); (ii) there was no difference in the median plasma FBb concentration between patients with and without IAI who delivered pre term (P = 0.9); (iii) in contrast, spontaneous labor at term was not associated with a significant change in the maternal plasma FBb concentration (P = 0.8); (iv) maternal plasma concentration of FBb did not differ significantly between normal pregnant women and the non-pregnant controls (P = 0.8) and were not correlated with advancing gestational age (r = -0.28, P = 0.8). CONCLUSION: (i) Pre-term parturition is associated with activation of the alternative complement pathway in maternal circulation; (ii) such activation is not detectable in spontaneous labor at term; (iii) IAI does not explain the activation of the alternative pathway of complement in PTL. Collectively, these observations suggest that pre-term and term labors have fundamental differences in the regulation of innate immunity. PMID- 20163403 TI - Biclustering via sparse singular value decomposition. AB - Sparse singular value decomposition (SSVD) is proposed as a new exploratory analysis tool for biclustering or identifying interpretable row-column associations within high-dimensional data matrices. SSVD seeks a low-rank, checkerboard structured matrix approximation to data matrices. The desired checkerboard structure is achieved by forcing both the left- and right-singular vectors to be sparse, that is, having many zero entries. By interpreting singular vectors as regression coefficient vectors for certain linear regressions, sparsity-inducing regularization penalties are imposed to the least squares regression to produce sparse singular vectors. An efficient iterative algorithm is proposed for computing the sparse singular vectors, along with some discussion of penalty parameter selection. A lung cancer microarray dataset and a food nutrition dataset are used to illustrate SSVD as a biclustering method. SSVD is also compared with some existing biclustering methods using simulated datasets. PMID- 20163404 TI - Joint variable selection for fixed and random effects in linear mixed-effects models. AB - It is of great practical interest to simultaneously identify the important predictors that correspond to both the fixed and random effects components in a linear mixed-effects (LME) model. Typical approaches perform selection separately on each of the fixed and random effect components. However, changing the structure of one set of effects can lead to different choices of variables for the other set of effects. We propose simultaneous selection of the fixed and random factors in an LME model using a modified Cholesky decomposition. Our method is based on a penalized joint log likelihood with an adaptive penalty for the selection and estimation of both the fixed and random effects. It performs model selection by allowing fixed effects or standard deviations of random effects to be exactly zero. A constrained expectation-maximization algorithm is then used to obtain the final estimates. It is further shown that the proposed penalized estimator enjoys the Oracle property, in that, asymptotically it performs as well as if the true model was known beforehand. We demonstrate the performance of our method based on a simulation study and a real data example. PMID- 20163405 TI - Continuous covariates in mark-recapture-recovery analysis: a comparison of methods. AB - Time varying, individual covariates are problematic in experiments with marked animals because the covariate can typically only be observed when each animal is captured. We examine three methods to incorporate time varying, individual covariates of the survival probabilities into the analysis of data from mark recapture-recovery experiments: deterministic imputation, a Bayesian imputation approach based on modeling the joint distribution of the covariate and the capture history, and a conditional approach considering only the events for which the associated covariate data are completely observed (the trinomial model). After describing the three methods, we compare results from their application to the analysis of the effect of body mass on the survival of Soay sheep (Ovis aries) on the Isle of Hirta, Scotland. Simulations based on these results are then used to make further comparisons. We conclude that both the trinomial model and Bayesian imputation method perform best in different situations. If the capture and recovery probabilities are all high, then the trinomial model produces precise, unbiased estimators that do not depend on any assumptions regarding the distribution of the covariate. In contrast, the Bayesian imputation method performs substantially better when capture and recovery probabilities are low, provided that the specified model of the covariate is a good approximation to the true data-generating mechanism. PMID- 20163406 TI - Robust clustering using exponential power mixtures. AB - Clustering is a widely used method in extracting useful information from gene expression data, where unknown correlation structures in genes are believed to persist even after normalization. Such correlation structures pose a great challenge on the conventional clustering methods, such as the Gaussian mixture (GM) model, k-means (KM), and partitioning around medoids (PAM), which are not robust against general dependence within data. Here we use the exponential power mixture model to increase the robustness of clustering against general dependence and nonnormality of the data. An expectation-conditional maximization algorithm is developed to calculate the maximum likelihood estimators (MLEs) of the unknown parameters in these mixtures. The Bayesian information criterion is then employed to determine the numbers of components of the mixture. The MLEs are shown to be consistent under sparse dependence. Our numerical results indicate that the proposed procedure outperforms GM, KM, and PAM when there are strong correlations or non-Gaussian components in the data. PMID- 20163407 TI - Dilating the vagina to prevent damage from radiotherapy: systematic review of the literature. AB - BACKGROUND: UK guidelines recommend routine vaginal dilation during and after pelvic radiotherapy to prevent stenosis. OBJECTIVE: To examine critically the evidence behind this guideline. SEARCH STRATEGY: Cochrane-style systematic review of the data and literature relevant to vaginal dilation and stenosis attributable to radiotherapy. SELECTION CRITERIA: Any and every measure of vaginal or sexual function after radiotherapy. DATA COLLECTION AND ANALYSIS: Numerous papers gave recommendations on dilation during or immediately after radiotherapy, but only seven contained relevant data. Case reports describe vaginal fistulas or psychological morbidity. Two trials showed that encouraging dilation increased compliance, but the first trial found no difference in sexual function scores. One comparative unmatched trial showed no advantage from inserting mitomycin C. A report of five women implied that stenosis can be treated by dilation many years after radiotherapy. One uncontrolled observational report involving 89 women showed that the median vaginal length 6-10 weeks after therapy was measured at 6 cm, but women tolerated a 9-cm measurer after 4 months of dilation experience. One retrospective report implied that dilation lowered stenosis rates, but the control group is not comparable. MAIN RESULTS: Dilation during or immediately after radiotherapy can cause damage, and there is no evidence that it prevents stenosis. Dilation might stretch the vagina if commenced after the inflammatory phase. AUTHOR'S CONCLUSIONS: Dilation might help treat the late effects of radiotherapy, but it must not be assumed that this applies to the acute toxicity phase. Routine dilation during treatment is not supported by good evidence. PMID- 20163408 TI - Clopidogrel-induced acute generalized exanthematous pustulosis with elevated Th17 cytokine levels as determined by a drug lymphocyte stimulation test. PMID- 20163409 TI - Guidance on the use of biological agents in the treatment of oral mucosal disease. PMID- 20163410 TI - Phenotypic variability associated with WNT10A nonsense mutations. PMID- 20163411 TI - Segmental pigmentation disorder. AB - BACKGROUND: There is little published information about segmental hypo- and hyperpigmentation pigmentation disorder (SegPD) although it is a relatively common problem in paediatric dermatology. OBJECTIVES: To define the spectrum of disease, clinical presentation and associations in cases of SegPD and to clarify further the terminology in defining patterned hypo- and hyperpigmentation in children. METHODS: This was a retrospective review of cases in an academic paediatric dermatology practice. Thirty-nine patients referred for dermatological evaluation were diagnosed with SegPD. Demographic and clinical features, and distribution and frequency of extracutaneous abnormalities were measured. RESULTS: Twenty female and 19 male patients were included in the study; 33 out of the 39 were referred specifically for a pigmentation abnormality. The mean age at onset was 3.4 months (median age 0.25 months). Family history was positive in two patients. Most (30/39; 77%) had segmental hyperpigmentation whereas nine of 39 (23%) had hypopigmentation. Patches were more often delineated at the ventral midline (32/39) than on the dorsal midline (7/39). The distribution of lesions was as follows: areas of the torso were most often affected (77%) and when the face, neck, arms and legs were affected pigmentation usually extended onto the torso; six patients had SegPD localized to the face. Only three of the 39 patients had extracutaneous abnormalities - atrial septal defect, strabismus with retinal hypopigmentation and a bronchogenic cyst - but the relationship to SegPD was uncertain and none had neurological abnormalities. CONCLUSIONS: SegPD is a relatively common pigmentary anomaly and most affected individuals are otherwise healthy. We propose reviving the term 'segmental pigmentation disorder' coined by Metzker and colleagues to describe children with segmental and block-like hypo /hyperpigmentation with midline demarcation. PMID- 20163412 TI - Development and successful clinical application of preimplantation genetic haplotyping for Herlitz junctional epidermolysis bullosa. AB - BACKGROUND: Herlitz junctional epidermolysis bullosa (HJEB) is a severe, life threatening, autosomal recessive blistering skin disease for which no cure is currently available. Prenatal diagnosis for couples at risk is feasible through fetal skin biopsy or analysis of DNA extracted from chorionic villi, but these methods can be applied only after pregnancy has been established. An alternative approach, which involves the analysis of single cells from embryos prior to establishment of pregnancy, is preimplantation genetic diagnosis (PGD). Until now, its clinical uptake has been hindered by lengthy delays in establishing mutation-specific protocols, and by the small amount of template DNA that can be obtained from a single cell. A new method that addresses these problems, preimplantation genetic haplotyping (PGH), relies on whole genome amplification followed by haplotyping of multiple polymorphic markers using standard DNA-based polymerase chain reaction (PCR) assays. OBJECTIVES: To design and validate a generic PGH assay for HJEB and to transfer this into clinical practice. MATERIALS AND METHODS: We established a multiplex PCR-based PGH assay involving 16 markers within and flanking the LAMB3 gene (the most frequently mutated gene in HJEB). The assay was then validated in 10 families with at least one previously affected offspring. After licensing by the Human Fertilisation and Embryology Authority (HFEA), the new test was used for PGD in a couple at risk of HJEB. RESULTS: The chromosome 1 LAMB3 markers within the assay were shown to be of sufficient heterogeneity to have widespread application for preimplantation testing of HJEB. In one couple that were heterozygous carriers of nonsense mutations in LAMB3, we used the new assay to identify unaffected embryos in a series of PGD cycles. Pregnancy was established in the third PGD cycle and a healthy, unaffected child was born. DNA analysis of cord blood confirmed the predicted single-cell mutation status of wild-type LAMB3 alleles. CONCLUSIONS: PGH represents a major step forward in widening the scope and availability of preimplantation testing for serious mapped single-gene disorders. We have established a generic test that is suitable for the majority of couples at risk of HJEB. PMID- 20163414 TI - 4-Methylumbelliferone inhibits tumour cell growth and the activation of stromal hyaluronan synthesis by melanoma cell-derived factors. AB - BACKGROUND: There is a close correlation between tumour progression and hyaluronan production, either by tumour cells or by stromal cells that are stimulated by tumour-derived factors. Inhibition of tumour stimulation of fibroblast hyaluronan may suppress tumour growth and invasion. OBJECTIVES: To examine the effect of the hyaluronan synthesis inhibitor 4-methylumbelliferone (4 MU) on the growth of and hyaluronan synthesis by fibroblasts and C8161 and MV3 melanoma cell lines, invasion, and inhibition of tumour cell-derived factor activation of fibroblasts. METHODS: Effects of 4-MU on growth and hyaluronan synthesis by fibroblasts and melanoma cells were examined in monolayer culture and fibroblast-contracted collagen lattices, and their effects on the growth and invasion of tumour cells into collagen lattices were also studied. RESULTS: 4-MU caused a dose-dependent growth inhibition of fibroblast and melanoma cells with maximum inhibition at 0.5 mmol L(-1) 4-MU. At this dose, 4-MU inhibited (3) H glucosamine incorporation into fibroblast glycosaminoglycans by 52%, and hyaluronan synthesis by 64%. The relative inhibition was more pronounced when fibroblasts were stimulated with C8161 melanoma cell-conditioned medium. 4-MU reduced the level of hyaluronan in fibroblast-contracted collagen lattices, and inhibited both the growth on and invasion into the lattices by melanoma cells. This growth inhibition appears to be predominantly independent of inhibition of hyaluronan synthesis. The effect on growth inhibition was reversible, and 4-MU had no effect on apoptosis. CONCLUSIONS: 4-MU is a potent inhibitor of hyaluronan synthesis, induction of stromal hyaluronan accumulation by tumour cells, and fibroblast and melanoma cell proliferation, and results suggest that 4-MU may have potential as a tumour cell anti-invasive and antiproliferative agent. PMID- 20163415 TI - Lip cancer: incidence, trends, histology and survival: 1970-2006. AB - BACKGROUND: High levels of lip cancer have been reported among Israelis over the last four decades. Epidemiological descriptions and analyses for this region have not previously been presented. OBJECTIVES: To establish the incidence, trends and histology of lip cancer and associated demographic variables in Israel over time. METHODS: Data for 1970-2006 were derived from the Israel National Cancer Registry. Incidence and trends over time and analyses by lip site, sex, age, origin, histology and 5-year survival were studied. RESULTS: Of 4337 new cases, most were found among men (61.4%), people aged over 53 years (75.5%), and those with lighter skin (62.6%). Lip cancer cases were 40 times more prevalent in the external than in the inner lip. The dominant tumour type was squamous cell carcinoma at the external lower lip and intraoral lip mucosa (predominantly in men) and basal cell carcinoma (originating from skin) at the external upper lip (predominantly in women). Minor salivary gland tumours, melanoma and metastases were also reported. Slight increases in the trend of upper lip cancer and decreases for lower lip cancer were reported. CONCLUSIONS: Men, fair-skinned individuals and those over 53 years of age were at higher risk for lip cancer. A higher incidence of external lip cancer, compared with internal, may indicate a major role for sun exposure rather than smoking. The effect of public awareness campaigns as well as occupational changes, both related to sun exposure, should be studied carefully as potential factors in the changing incidence of lip tumours. PMID- 20163416 TI - Modelling the seasonal variation of vitamin D due to sun exposure. AB - BACKGROUND: The current interest in vitamin D as a preventive agent in many chronic diseases has led to a reappraisal of adequate sun exposure. Yet just what constitutes adequacy remains to be clearly defined and validated. To do this requires an understanding of how behaviour outdoors during the year translates into seasonal changes in vitamin D status. OBJECTIVES: To develop a model for estimating the changes in serum 25-hydroxyvitamin D [25(OH)D] levels as a consequence of sun exposure throughout the year. METHODS: A novel mathematical model is described that incorporates the changes in serum 25(OH)D following a single, whole-body exposure to solar ultraviolet radiation with daily sun exposure in order to estimate the annual variation in serum 25(OH)D. RESULTS: The model yields results that agree closely with measured data from a large population-based study. Application of the model showed that current advice about 10-20 min of daily sun exposure during the summer months does little in the way of boosting overall 25(OH)D levels, while sufficient sun exposure that could achieve a worthwhile benefit would compromise skin health. CONCLUSIONS: There is little in the way of public health advice concerning the benefits of sun exposure that can be given as an effective means of maintaining adequate vitamin D levels throughout the year. Instead it would seem safer and more effective to fortify more foods with vitamin D and/or to consider the use of supplements during the winter months. Messages concerning sun exposure should remain focused on the detrimental effects of excessive sun exposure and should avoid giving specific advice on what might be 'optimal' sun exposure. PMID- 20163417 TI - Immune response towards the amino-terminus of desmoglein 1 prevails across different activity stages in nonendemic pemphigus foliaceus. AB - BACKGROUND: Pemphigus foliaceus (PF) is a blistering skin disease mediated by antibodies to desmoglein (Dsg) 1. The two major subtypes are nonendemic and endemic PF. A previous study in endemic PF demonstrated that changes in antibody epitope could modulate disease relapse and remission. OBJECTIVES: To characterize the frequency of immunoreactivity to various Dsg1 extracellular (EC) domains in nonendemic PF and to study if there is any change in epitope profile across various activity stages. METHODS: Sera from 34 patients with nonendemic PF were selected. To map the conformational epitopes by immunoprecipitation immunoblotting, we constructed five Dsg1/Dsg2 domain-swapped molecules, with each molecule representing one EC domain of Dsg1 on a backbone of Dsg2. RESULTS: Dsg1 EC1, EC2, EC3, EC4 and EC5 domains were recognized by 88%, 50%, 13%, 22% and 0% of active PF sera, respectively. Immunoreactivity to EC3 or EC4 often cosegregated with that to either EC1 or EC2. Longitudinal follow-up of 21 patients with PF for a median of 16 months revealed that, in most cases, immunoreactivity to the amino-terminus of Dsg1 persisted across various activity stages; only two patients lost their EC1 reactivity upon remission and changed their major epitope(s) to EC2 +/- EC3. CONCLUSIONS: Most of the anti-Dsg1 antibodies in nonendemic PF bind to the amino-terminus of Dsg1, a region critical for intercellular adhesion of cadherins, and this skewed amino-terminal immunoreactivity prevails across various activity stages in most patients, even upon remission. These findings are valuable for understanding the biology of Dsg mediated cellular adhesion as well as for the development of epitope-based monitoring and therapeutic strategies. PMID- 20163418 TI - Subungual fixed drug eruption. PMID- 20163419 TI - Effects of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and low density lipoprotein on proliferation and migration of keratinocytes. AB - BACKGROUND: Keratinocytes can obtain cholesterol either by de novo synthesis or by extraction, primarily from low-density lipoprotein (LDL). LDL is internalized following binding to the LDL receptor (LDLR). Because LDLR is expressed at a higher level in the cells of the basal layer of the epidermis, it might be assumed that LDLR upregulation is associated with keratinocyte proliferation. However, the effect of LDLR stimulation on keratinocyte function remains unclear. OBJECTIVES: To investigate the effects and mechanism of action of pitavastatin and effects of LDL on proliferation and migration of keratinocytes. METHODS: Pitavastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was used to induce upregulation of LDLR. LDLR expression was evaluated by immunofluorescence staining, fluorescence-activated cell sorting, immunohistochemical staining and real-time polymerase chain reaction (PCR). HaCaT cells and normal human keratinocytes (NHKs) were used for evaluation of migration. 5-Bromo-2'-deoxyuridine incorporation was used to evaluate keratinocyte proliferation and differentiation. C57BL6 mice were used for in vivo evaluation of the effect of topical pitavastatin or lovastatin. RESULTS: Pitavastatin was most effective in LDLR induction at a concentration of 1 micromol L(-1) in NHKs. Real-time PCR showed that pitavastatin significantly increased LDLR and liver X receptor (LXR) beta mRNA expression in these cells. Similar results were obtained in vivo. However, pitavastatin had no effect on the migration of NHKs. After the addition of LDL and/or mevalonate concomitantly with pitavastatin to NHK cultures, or topical application of pitavastatin on mouse skin, keratinocyte proliferation was significantly increased. CONCLUSIONS: Pitavastatin significantly upregulates LDLR in both NHKs and C57BL6 mouse skin, resulting in increased keratinocyte proliferation. LXRbeta may be involved in the pitavastatin-induced keratinocyte proliferation. PMID- 20163420 TI - The economic impact of high-need psoriasis in daily clinical practice before and after the introduction of biologics. AB - BACKGROUND: Although costs of biologics are high, effective treatment of patients with psoriasis may reduce the total health care costs, as it may limit the need for hospitalization. OBJECTIVES: To investigate the economic impact of psoriasis, including direct costs, before and after the introduction of biologics, with special focus on hospitalized patients, treatment effectiveness and patient satisfaction with medication. PATIENTS AND METHODS: A descriptive retrospective cohort study including 67 patients with high-need psoriasis was done. Direct costs were investigated for the biologic and pre-biologic period. Direct costs for a subgroup of hospitalized patients were analysed separately. Patient satisfaction with biologic treatment was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM) version II. Effectiveness of biologic therapy was investigated by means of the Psoriasis Area and Severity Index (PASI). RESULTS: Mean total direct costs were ?10,146 per patient per year (PPPY) in the pre-biologic treatment period, compared with ?17,712 PPPY in the biologic treatment period. For six patients in the cohort, introduction of biologics led to a reduction of direct costs, as these patients did not need long hospitalizations. Treatment with biologics led to a decrease in PASI from 19.0 at the start of biologic therapy to 6.4 at analysis (66.4%). Patient satisfaction with biologics was high, indicated by a mean TSQM score of 77.8. CONCLUSIONS: Introduction of biologic therapies may have cost-neutral or cost-saving effects for patients who otherwise require long hospitalization periods. Treatment with biologics proved effective and was accompanied by high satisfaction for the patients. PMID- 20163421 TI - 1,24-Dihydroxyvitamin D3 (tacalcitol) prevents skin T-cell infiltration. AB - BACKGROUND: 1,24-Dihydroxyvitamin D3 (tacalcitol), a vitamin D(3) compound, has been used to treat T cell-mediated inflammatory skin diseases such as psoriasis, prurigo and vitiligo. The best-known mechanism of action of this compound is inhibition of the abnormal proliferation of keratinocytes and subsequent maturation; however, its effects on skin T-cell recruitment have not yet been evaluated. Cutaneous lymphocyte-associated antigen (CLA), a surface glycoprotein expressed on T cells, plays a critical role in skin T-cell infiltration. We recently reported that 1,25-dihydroxyvitamin D3 inhibits skin infiltration of CD4+ T cells by suppressing CLA expression on T cells. OBJECTIVES: In this study, we investigated the effect of tacalcitol on CLA epitope decoration and on the levels of gut or lymph node homing receptor expression in human T cells. METHODS: We cultured human T cells with tacalcitol and analysed the effect on CLA expression and skin-homing ability, and evaluated glycosyltransferase mRNAs. We also performed an in vivo study using an antigen-dependent delayed-type hypersensitivity (DTH) mouse model and investigated the effect of tacalcitol on skin-infiltrating CD4+ T cells. RESULTS: Tacalcitol downregulated the expression of CLA and, in parallel, the E- and P-selectin ligand function; however, it exerted no effect on other homing receptors. Subcutaneously and intraperitoneally administered tacalcitol downregulated skin infiltration of effector CD4+ T cells in an in vivo DTH mouse model. CONCLUSIONS: These findings suggest that tacalcitol reduces skin inflammation by partially downregulating CLA expression levels. PMID- 20163423 TI - Vascular endothelial growth factor concentrations in serum of patients with extensive slow-flow vascular malformations. PMID- 20163424 TI - C-reactive protein as a predictor of postoperative infective complications following elective colorectal resection. AB - AIM: C-reactive protein (CRP) may be useful in predicting postoperative complications [1]. We investigated the sensitivity and specificity of postoperative CRP for infective complications after elective colorectal surgery. METHOD: One hundred and sixty consecutive patients (72 years old; interquartile range, 63-79) undergoing elective resection for colorectal cancer treated between September 2003 and October 2006 were studied. Details of the postoperative course were prospectively entered into a database. Of the 160 patients, 10 had incomplete CRP data and were excluded from further analysis. RESULTS: Infective complications occurred in 21%, with an overall complication rate of 29%. Infective complications occurred as follows: respiratory (10), wound (9), urinary tract (2) and central line infection (1), anastomotic leakage (5), intra abdominal abscess (3) and septicaemia of unknown origin (2). There were three postoperative deaths. The positive predictive value for infection of CRP > 145 mg/l on postoperative day 4 was 61%. The negative predictive value of CRP < 145 mg/l on postoperative day 4 for an infective complication was 96%. CONCLUSION: A CRP > 145 mg/l on day 4 has high specificity and sensitivity for infective complications following elective colorectal resection. PMID- 20163425 TI - Laparoscopic sphincter-preserving total mesorectal excision: 10-year report. AB - AIM: Total mesorectal excision (TME) is currently the gold standard for resection of mid or low rectal cancer and is associated with a low local recurrence rate. However, few studies have reported the long-term oncological outcome following use of a laparoscopic approach. The aim of this study was to evaluate the long term oncological outcome after laparoscopic sphincter-preserving TME with a median follow up of about 4 years. METHOD: Patients with mid or low rectal cancer who underwent laparoscopic sphincter-preserving TME with curative intent between March 1999 and March 2009 were prospectively recruited for analysis. RESULTS: During the 10-year study period, 177 patients underwent laparoscopic sphincter preserving TME with curative intent for rectal cancer. Conversion was required in two (1%) patients. There was no operative mortality. At a median follow-up period of 49 months, local recurrence had occurred in nine (5.1%) patients. The overall metastatic recurrence rate after curative resection was 22%. The overall 5-year survival and 5-year disease-free survival in the present study were 74% and 71%, respectively. CONCLUSION: The results of this study show that laparoscopic sphincter-preserving TME is safe with long-term oncological outcomes comparable to those of open surgery. PMID- 20163426 TI - Results of combined medical and surgical treatment of recto-vaginal fistula in Crohn's disease. AB - AIM: Surgical repair of recto-vaginal fistula (RVF) in Crohn's disease (CD) has been associated with high rates of failure. The aim of this study was to compare the outcome in patients with CD who underwent RVF surgery with or without infliximab infusion. METHOD: A retrospective review was carried out of 51 consecutive patients with CD treated for a symptomatic RVF between March 1998 and December 2004. RESULTS: Fifty-one patients (mean age 39 years) underwent 65 procedures, including seton drainage (n = 35), advancement flap (n = 8), fibrin glue injection (n = 8), transperineal repair (n = 6), collagen plug placement (n = 4) and bulbocavernosus flap (n = 4). All patients were on medical treatment at the time of surgery and 26 patients had received preoperative infliximab treatment (minimum of three infusions, 5 mg/kg). Ten patients underwent preoperative diversion. At a mean follow up of 38.6 months, 27 fistulas (53%) had healed and 24 (47%) had recurred. Fistula healing occurred in 60% of patients treated with preoperative diversion, whereas 51% of nondiverted repairs were successful. Neither active proctitis nor infliximab therapy significantly affected fistula healing. Fourteen (27%) patients eventually required proctectomy. CONCLUSION: RVF in CD is difficult to treat. Failure rates are significant despite repeated surgical interventions and concomitant medical treatment. PMID- 20163428 TI - Precision and content range of a parent-reported item bank assessing lower extremity and mobility skills in children with cerebral palsy. AB - AIM: The aim of this study was to determine the psychometric properties, content range, and measurement precision of a lower extremity physical functioning and mobility skills item bank (LE85) in children with cerebral palsy (CP). METHOD: Lower extremity functioning and mobility skill items were administered to 308 parents of children (169 males, 139 females; mean age 10y 8mo, SD 4y) with spastic CP (145 diplegia, 73 hemiplegia, 89 quadriplegia; [for one person type of CP was unknown]) classified using the Gross Motor Function Classification System (75 level I, 91 level II, 79 level III, 37 level IV, 26 level V). Additional legacy measures were administered to assess concurrent validity. Psychometric characteristics, differential item functioning, content range, and score precision were examined. RESULTS: The LE85 had acceptable psychometric properties. Content range matched the ability range of the sample population and exceeded legacy measures with minimal differential item functioning. The LE85 had good correlation with the Paediatric Outcomes Data Collection Instrument, Functional Independence Measure for Children, Gillette Functional Assessment Questionnaire, and Paediatric Quality of Life Inventory-CP module (range r=0.63 0.86). Precision of the LE85 and 10-item simulated computer adaptive test scores outperformed legacy measures. INTERPRETATION: The LE85 appears to be suitable to administer as a computer adaptive test to measure lower extremity physical functioning and mobility in children with CP. PMID- 20163429 TI - Walking ability and predictors of performance on the 6-minute walk test in adults with spastic cerebral palsy. AB - AIM: To describe walking ability and identify factors predicting walking capacity in adults with spastic cerebral palsy (CP) assessed with the 6-minute walk test (6MWT). METHOD: A cross-sectional clinical study as part of the recruitment process for a randomized controlled trial on the effects of botulinum toxin A. Data analysed were the 6MWT, Timed Up and Go (TUG) test, Borg Scale, spasticity, muscle strength, popliteal angle, pain, fatigue, type of CP, foot deformity, Gross Motor Function Classification System (GMFCS) levels, Functional Mobility Scale (FMS) scores, a gait questionnaire, interview, and demographic data. RESULTS: In total, 126 persons were included (53 males, 73 females; mean age 39 y [SD 12 y]; 59 with unilateral and 67 with bilateral spastic CP; GMFCS level I, n=12; level II, n=94; level III, n=20). Mean distance on the 6MWT was 485 m (SD 95 m) with FMS scores reflecting independent walking performance in daily life. Multiple regression analysis identified sex, type of CP, popliteal angle, pain, and TUG values as significant predictors, with TUG values as the strongest predictor (standardized regression coefficient=-0.57, p<0.001). INTERPRETATION: Our results demonstrate that 39% of the participants had declined one GMFCS level from adolescence to their present age, and that the TUG was the strongest predictor for the 6MWT. This implicates the importance of focusing specifically on the different elements of functional mobility in further studies. PMID- 20163430 TI - Mechanisms of disease and clinical features of mutations of the gene for mitofusin 2: an important cause of hereditary peripheral neuropathy with striking clinical variability in children and adults. AB - Mitofusin 2, a large transmembrane GTPase located in the outer mitochondrial membrane, promotes membrane fusion and is involved in the maintenance of the morphology of axonal mitochondria. Mutations of the gene encoding mitofusin 2 (MFN2) have recently been identified as the cause of approximately one-third of dominantly inherited cases of the axonal degenerative forms of Charcot-Marie Tooth disease (CMT type 2A) and of rarer variants. The latter include a severe, early-onset axonal neuropathy, which may occur in autosomal dominant or recessive forms, as well as some instances associated with pyramidal tract involvement (CMT type 5), with optic atrophy (CMT type 6), and, occasionally, with alterations of cerebral white matter. All individuals with a dominantly or recessively inherited or otherwise unexplained, chronic progressive axonal degenerative polyneuropathy should be tested for mutations of MFN2. PMID- 20163432 TI - Indications and effects of botulinum toxin A for obstetric brachial plexus injury: a systematic literature review. AB - AIM: To give an overview of indications for the use of botulinum toxin A (BoNT-A) treatment for children with obstetric brachial plexus injury (OBPI), and to present the best available evidence of the effectiveness of this treatment. METHOD: Searches were performed in Cinahl, Cochrane Library, Embase, PubMed, and Web of Science, using the keywords 'botulinum' and 'plexus', to identify articles reporting on the use of BoNT-A as a treatment for children with OBPI. Studies found through the references of related articles were also selected. RESULTS: Ten full-text papers and six congress abstracts were included, involving 343 children. Four groups of indications could be identified: internal rotation/adduction contracture of the shoulder, limited active elbow flexion, limited active elbow extension, and pronation contracture of the lower arm. Overall, positive results were reported for all except the indication for limited active elbow extension. However, only one study was comparative in nature; all others were classified as having a low level of evidence. There was a large variation in outcome measures. INTERPRETATION: To provide better evidence for the already partly promising results of BoNT-A treatment for children with OBPI, multicentre randomized controlled trials are needed. PMID- 20163431 TI - Predictors of cerebral palsy in very preterm infants: the EPIPAGE prospective population-based cohort study. AB - AIM: The aim of this study was to assess the independent role of cerebral lesions on ultrasound scan, and several other neonatal and obstetric factors, as potential predictors of cerebral palsy (CP) in a large population-based cohort of very preterm infants. METHOD: As part of EPIPAGE, a population-based prospective cohort study, perinatal data and outcome at 5 years of age were recorded for 1812 infants born before 33 weeks of gestation in nine regions of France in 1997. RESULTS: The study group comprised 942 males (52%) and 870 females with a mean gestational age of 30 weeks (SD 2 wks; range 24-32 wks) and a mean birthweight of 1367 g (SD 393 g; range 450-2645 g). CP was diagnosed at 5 years of age in 159 infants (prevalence 9%; 95% confidence interval [CI] 7-10%), 97 males and 62 females, with a mean gestational age of 29 weeks (SD 2 wks; range 24-32 wks) and a mean birthweight of 1305 g (SD 386 g; range 500-2480 g). Among this group, 67% walked without aid, 14% walked with aid, and 19% were unable to walk. Spastic, ataxic, and dyskinetic CP accounted for 89%, 7%, and 4% of cases respectively. The prevalence of CP was 61% among infants with cystic periventricular leukomalacia, 50% in infants with intraparenchymal haemorrhage, 8% in infants with grade I intraventricular haemorrhage, and 4% in infants without a detectable cerebral lesion. After controlling for cerebral lesions and obstetric and neonatal factors, only male sex (odds ratio [OR] 1.52; 95% CI 1.03-2.25) and preterm premature rupture of membranes or preterm labour (OR 1.72; 95% CI 0.95 3.14) were predictors of the development of CP in very preterm infants. INTERPRETATION: Cerebral lesions were the most important predictor of CP in very preterm infants. In addition, infant sex and preterm premature rupture of membranes or preterm labour were also independent predictors of CP. PMID- 20163433 TI - Mitochondrial diseases in childhood: a clinical approach to investigation and management. AB - Mitochondrial diseases are a common cause of inherited neurological disorders in children. Although dysfunction of the central nervous system is prominent, multisystem involvement also occurs. Diagnosis relies on characteristic clinical features, an understanding of mitochondrial genetics, and a logical, informed approach to investigations. There is a significant body of recent literature on advances in mitochondrial genetics and the investigation of mitochondrial diseases. However, to our knowledge there remains a paucity of published information on the management of these disorders. Management of the complex constellation of neurological and multisystem clinical features is challenging, and is reliant on a multidisciplinary approach. The care of the child and family is dependent on clear communication between health professionals from primary, secondary, and tertiary care as well as specialist input from quaternary services. The aim of this review is to provide paediatric neurologists, paediatricians, and allied health professionals with a structured approach to the diagnosis and management of children with suspected or confirmed mitochondrial disease. PMID- 20163434 TI - Examining the link between working memory behaviour and academic attainment in children with ADHD. AB - AIM: The aim of the present study was to investigate whether behaviours typical of working memory problems are associated with poor academic attainment in those with attention-deficit-hyperactivity disorder (ADHD), as well as a non-clinical group identified on the basis of working memory difficulties. METHOD: Children clinically diagnosed with ADHD-combined (n=31; mean age 9y 7mo, SD 12mo; 27 males) were matched with 44 low working memory children (mean age 9y 4mo, SD 15mo; 32 males) and 10 healthy controls (mean age 10y, SD 12mo; 5 males). Working memory behaviour was measured using the Working Memory Rating Scale (WMRS) and academic attainment was assessed with standardized tests of literacy and numeracy. RESULTS: The majority of children considered by their teachers to have problematic behaviours performed poorly in literacy and numeracy. When the whole sample were split into two groups on the basis of their working memory behaviour (on the WMRS), the 'At Risk' group performed significantly worse in academic attainment. INTERPRETATION: As children with ADHD and a non-clinical group exhibit classroom behaviour typical of working memory problems, early screening to prevent subsequent learning difficulties is important. The use of the WMRS allows educators to draw on their expertise in the classroom for early detection of children with working memory failures. PMID- 20163435 TI - Thickened saliva after effective management of drooling with botulinum toxin A. AB - AIM: The aim of this study was to evaluate the rheological properties of saliva after submandibular botulinum toxin type A (BoNT-A) injections. METHOD: We enrolled 15 children (11 males and six females; age range 3-17 y, mean age 9 y 10 mo) diagnosed with spastic (n=9) or dyskinetic (n=6) quadriplegic cerebral palsy (CP); Gross Motor Function Classification System level IV or V; and two children with intellectual disability (IQ<70) who experienced moderate to severe drooling. Salivary flow rate and drooling quotient were measured at baseline and at different times after BoNT-A injections up to 24 weeks. The mucin concentration of saliva was analysed before and after BoNT-A treatment. RESULTS: Both submandibular salivary flow rate (baseline 0.38 mL/min; 24 wks after injection 0.26 mL/min) and drooling quotient (baseline 42.5%; 24 wks 28.80%) were substantially reduced, with a concomitant increase in mucin concentration within 8 weeks after BoNT-A injection (from 0.612 to 1.830 U/mL). The parents of nine children observed thickened saliva. Swallowing and chewing were problematic in seven children. Two of these children needed treatment with mucolytics because of pooling of thickened saliva in the throat. INTERPRETATION: When making decisions about the use of BoNT-A, the risk of problems with masticatory and swallowing functions as a result of thickening of saliva after BoNT-A treatment should be taken into account. PMID- 20163436 TI - A prospective study of acute movement disorders in children. AB - AIM: The purpose of this study was to report a prospective cohort of children with acute-onset movement disorders. METHOD: We report on 52 individuals (31 females, 21 males; mean age 6y 5mo, range 2mo-15y) with acute-onset movement disorders managed at a busy tertiary paediatric referral hospital over a 40-month period. RESULTS: In descending order of frequency, the movement disorders reported were chorea, dystonia, tremor, myoclonus, and parkinsonism. It was possible to divide the participants into three groups: (1) those with inflammatory or autoimmune disorders (n=22), (2) those with non-inflammatory disorders (n=18), and (3) those with psychogenic disorders (n=12). The inflammatory or autoimmune aetiologies included N-methyl-D-aspartate receptor encephalitis (n=5), opsoclonus-myoclonus syndrome (n=4), Sydenham chorea (n=3), systemic lupus erythematosus (n=3), acute necrotizing encephalopathy (n=3), and other types of encephalitis (n=4). Other important non-inflammatory movement disorder aetiologies included drug-induced movement disorder (n=6), post-pump chorea (n=5), metabolic (n=3) and vascular (n=2) disease. The participants with psychogenic movement disorders (n=12) were all over 10 years of age and were more likely to be female. Tremor and myoclonus were significantly over-represented in the psychogenic movement disorder subgroup. The outcomes of the total cohort were variable, and included full recovery, severe morbidity, and death. INTERPRETATION: Acute-onset movement disorders in children are important and may be treatable. Management should focus upon identifying the cause and treating the underlying disease process, as symptomatic treatment of the abnormal movements is variably effective. PMID- 20163437 TI - High-dose intravenous levetiracetam for acute seizure exacerbation in children with intractable epilepsy. AB - We review our experience with high-dose intravenous levetiracetam (IV-LEV) for acute seizure exacerbations in nine children with medically intractable epilepsy. All children had acute repetitive seizures-while on chronic antiepileptic drugs that either led to hospitalization (eight) or occurred during hospitalization (one), and received doses of IV-LEV of 150 mg/kg/day or greater, with a mean dose of 228 +/- 48 mg/kg/day. Eight of nine children had resolution of the acute repetitive seizures. Seizure frequency was reduced to less than baseline in seven children (seizure-free in two, >/=80% reduction in four, and 50% reduction in one). Except for one child with increased seizures, IV-LEV was well tolerated in all children without complications. PMID- 20163438 TI - Respiratory changes with seizures in localization-related epilepsy: analysis of periictal hypercapnia and airflow patterns. AB - PURPOSE: The rate of sudden unexpected death in epilepsy (SUDEP) approaches 9 per 1,000 patient-years in patients with refractory epilepsy. Respiratory causes are implicated in SUDEP. We reported that ictal hypoxemia occurs in one-third of seizures in localization-related epilepsy. We now report on respiratory changes in the ictal/postictal period including changes in end-tidal CO2 (ETCO2) that correlate directly with alveolar CO(2) , allowing a precise evaluation of seizure related respiratory disturbances. METHODS: One hundred eighty-seven seizures were recorded in 33 patients with localization-related epilepsy, with or without secondarily generalized convulsions, undergoing video-electroencephalography (EEG) telemetry with recording of respiratory data. RESULTS: The ictal/postictal ETCO2 increase from baseline was 14 +/- 11 mm Hg (11, -1 to 50) [mean +/- standard deviation (SD) (median, range)]. ETCO2 peak was at or above 50 mm Hg with 35 of 94 seizures, 60 mm Hg with 15, and 70 mm Hg with five seizures. Eleven of the 33 patients had seizures with ETCO2 elevation above 50 mm Hg. The duration of ictal/postictal ETCO(2) increase above baseline was 424 +/- 807 s (154, 4 to 6225). The duration of ictal apnea was 49 +/- 46 s (31, 6-222); most ictal apneic events were central. Oxygen desaturation to 60% or less occurred with 10 seizures, including five that did not progress to generalized convulsions. Respiratory rate and amplitude increased postictally. The peak ictal ETCO2 change and duration of change were not associated with apnea duration or seizure duration. Peak ETCO2 change was significantly associated with contralateral seizure spread. CONCLUSIONS: Severe and prolonged increases in ETCO2 occur with seizures. Postictally, respiratory effort is not impaired. Ictally triggered ventilation-perfusion inequality from pulmonary shunting or transient neurogenic pulmonary edema may account for these findings. PMID- 20163439 TI - The prevalence of seizures in comatose children in the pediatric intensive care unit: a prospective video-EEG study. AB - PURPOSE: Studies in adult and neonatal intensive care units (ICUs) report a high prevalence of epileptic seizures in comatose patients. The prevalence of seizures in pediatric ICUs is variably reported in a few retrospective studies using different electroencephalography (EEG) methods. We aimed to determine prospectively the prevalence of epileptic seizures (clinical and subclinical) in comatose children in the pediatric ICU using continuous video-EEG (v-EEG) monitoring. METHODS: We performed v-EEG in consecutive children aged 2 months to 17 years admitted to the pediatric ICU with sustained depressed consciousness over a period of 15 months. RESULTS: We monitored 100 comatose children, 69% within 24 h of ICU admission. Median length of ICU stay was 5 days. Median duration of v-EEG was 20 h. Epileptic seizures were identified in only seven patients, of whom six had a history of epilepsy with witnessed seizures immediately prior to v-EEG. All epileptic seizures were recorded in the first 3 h of v-EEG. Seizures were suspected by ICU staff in 18 monitored patients, only four of whom had confirmed epileptic seizures. DISCUSSION: The lower prevalence of epileptic seizures and the shorter length of ICU stay in children compared to adults and neonates suggest a different spectrum of disease and neurologic response. Short-duration v-EEG in patients with a history of prior seizures, epilepsy, or clinical events suspected to be seizures seems more appropriate than routine v-EEG in all comatose children in the pediatric ICU. PMID- 20163440 TI - Adverse effects of valproate on bone: defining a model to investigate the pathophysiology. AB - PURPOSE: Bone disease and fractures are common with chronic antiepileptic drug (AED) therapy, but the underlying mechanisms are poorly understood. This study aimed to characterize adverse bone effects of valproate and to identify mouse strains either resistant or sensitive to these effects. METHODS: Seven mouse strains (n = 40/strain; 10/diet) were screened for the effect of chronic (8 weeks) valproate treatment (0, 2, 4, and 6 g/kg food) on total bone mineral content (BMC, by dual energy x-ray absorptiometry). In a confirmatory study the effect of valproate (0 or 4 g/kg food) over 16 weeks was assessed in five of the mouse strains (n = 60/strain; 30/diet) identified in the screening phase as either sensitive or resistant. Ex vivo volumetric bone measures and structural changes were assessed using peripheral quantitative computed tomography (pQCT) and histomorphometry. RESULTS: Chronic valproate treatment reproducibly affected bone in C3H/HeJ mice, with a 9.1% (p < 0.01) reduction in total BMC and a 10.7% (p < 0.01) reduction in trabecular volumetric density, indicating a sensitive strain to AED-induced bone loss. Histomorphometry was consistent, revealing reductions in trabecular volume (19.6%, p < 0.05) and number (14.3%, p < 0.04), and a 19.9% (p < 0.05) increase in trabecular separation. In contrast the A/J mice were reproducibly resistant to the bone effects. CONCLUSION: Mouse strains sensitive and resistant to the adverse bone effects of chronic valproate treatment were identified. The strain-specific effects suggest a role of genetic factors in the pathogenesis of AED-induced bone disease. This novel model provides a new, powerful tool to investigate the pathophysiology and therapy of AED-associated bone disease. PMID- 20163441 TI - Genetic risk perception and reproductive decision making among people with epilepsy. AB - We investigated estimated offspring risk among people with epilepsy and factors important in the family-planning process. Data were collected for 88 participants using a questionnaire assessing perceived risk of offspring to develop epilepsy, importance of factors in the reproductive decision-making process, decision to have fewer children, and association between risk perception and family planning decisions. Thirty-four percent of participants had fewer children because of their epilepsy. Concerns about the ability to care for a child (p < 0.0001) and passing epilepsy onto a child (p = 0.003) were associated with the decision to have fewer children. The mean estimated risk of offspring to develop epilepsy was 26%, a 4-fold increase over estimated population risks. Genetic counseling may be beneficial for people with epilepsy, given the considerable overestimation of offspring risk. PMID- 20163442 TI - Extrahippocampal gray matter loss and hippocampal deafferentation in patients with temporal lobe epilepsy. AB - PURPOSE: Medial temporal epilepsy (MTLE) is associated with extrahippocampal brain atrophy. The mechanisms underlying brain damage in MTLE are unknown. Seizures may lead to neuronal damage, but another possible explanation is deafferentation from loss of hippocampal connections. This study aimed to investigate the relationship between hippocampal deafferentation and brain atrophy in MTLE. METHODS: Three different MRI studies were performed involving 23 patients with unilateral MTLE (8 left and 15 right) and 34 healthy controls: (1) voxel-based morphometry (VBM), (2) diffusion tensor imaging (DTI) and (3) probabilistic tractography (PT). VBM was employed to define differences in regional gray matter volume (GMV) between controls and patients. Voxel-wise analyses of DTI evaluated differences in fractional anisotropy (FA), mean diffusivity (MD) and hippocampal PT. Z-scores were computed for regions-of interest (ROI) GMV and peri-hippocampal FA and MD (to quantify hippocampal fiber integrity). The relationship between hippocampal deafferentation and regional GMV was investigated through the association between ROI Z scores and hippocampal fiber integrity. RESULTS: Patients with MTLE exhibited a significant reduction in GMV and FA in perihippocampal and limbic areas. There was a decrease in hippocampal PT in patients with MTLE in limbic areas. A significant relationship between loss of hippocampal connections and regional GMV atrophy was found involving the putamen, pallidum, middle and inferior temporal areas, amygdala and ceberellar hemisphere. DISCUSSION: There is a relationship between hippocampal disconnection and regional brain atrophy in MTLE. These results indicate that hippocampal deafferentation plays a contributory role in extrahippocampal brain damage in MTLE. PMID- 20163443 TI - Long-term employment of adults with childhood-onset epilepsy: a prospective population-based study. AB - PURPOSE: Our aim was to determine the long-term employment and predictive factors in adults with childhood-onset epilepsy living in the community. METHODS: A population-based incidence cohort of 144 children prospectively followed since their first unprovoked seizure before the age of 16 years up to a mean age of 48. RESULTS: At a mean age of 23 years (range 18-35 years) 85 (71%) of 119 patients living in the community were employed. Predictive of employment at a mean age of 23 were normal intelligence [odds ratio (OR) 14.5, 95% confidence interval (CI) 4.5-46.8, p < 0.01], vocational education (OR 15.2, 95% CI 2.9-79.9, p < 0.01), and age at onset of epilepsy older than 6 years (OR 4.9, 95% CI 1.3-19.2, p = 0.02). At the mean age of 48 years (range 43-59 years), 45 (59%) of 76 patients living in the community were employed, as were 63 (78%) of 81 controls (patients vs. controls, p = 0.01). In 40 (53%) of 76 surviving patients employed between age 23 and 48, four factors were found to predict employment: normal intelligence (OR 15.8; 95% CI 2.4-102.4, p < 0.01), having offspring (OR 6.1; 1.5-25.0, p = 0.01), uninterrupted 5-year terminal remission (5YTR) from age 23 to age 48 (OR 4.8; 1.1-19.9, p = 0.03), and no history of status epilepticus (OR 12.8; 1.8 90.9, p = 0.01). CONCLUSIONS: Normal intelligence, onset of epilepsy at age older than 6, and good vocational education appear to predict employment in early adulthood. Normal intelligence, having offspring, uninterrupted remission, and no history of status epilepticus appear to predict lasting employment into middle age. PMID- 20163444 TI - Etomidate accurately localizes the epileptic area in patients with temporal lobe epilepsy. AB - PURPOSE: A variety of drugs have been used to activate and identify the epileptogenic area in patients during presurgical evaluation. We have evaluated the safety and usefulness of etomidate in identifying the epileptic zone by measuring bioelectrical brain activity and cerebral blood flow (CBF). METHODS: We studied 13 men and 9 women under presurgical evaluation for temporal lobe epilepsy. We applied etomidate (0.1 mg/kg) while patients were monitored by video electroencephalography (VEEG) with foramen ovale electrodes. In a subset of 15 patients, we also measured CBF with single photon emission computed tomography (SPECT). RESULTS: (1) Etomidate induced seizures in 2 of 22 patients. (2) The main side-effects observed were myoclonus (14 of 20) and moderate pain (3 of 20). (3) No changes in capillary oxygen saturation, respiration, or heart rate were observed. (4) Irritative activity specifically increased in the temporal mesial and lateral areas. No spikes were observed in other areas, aside from those observed under baseline conditions. (5) Irritative activity induced by etomidate correctly lateralized the ictal onset zone in 19 of 20 patients. In addition, the two etomidate-induced seizures appeared in the same regions as spontaneous ones. (6) The kinetics of pharmacologically induced activity was higher in the region of the ictal-onset zone. (7) Etomidate increased the CBF in the basal ganglia and especially in the posterior hippocampus of the temporal mesial region contralateral to the ictal-onset zone. DISCUSSION: Etomidate activation is a safe, specific, and quick test that can be used to identify the epileptic region in patients evaluated as candidates for temporal lobe epilepsy surgery. PMID- 20163445 TI - Insulin-like growth factor-1 is associated with cognitive outcome in infantile spasms. AB - PURPOSE: The molecular mechanisms that lead to long-term consequences of infantile spasms (IS) are poorly understood. Insulin-like growth factor-1 (IGF-1) is regulated by insults that might be stressful to the brain, and is crucial for early brain development. The aim of the present study was to correlate cerebrospinal fluid (CSF) levels of IGF-1 with antecedent insults and cognitive outcome. METHODS: We studied CSF IGF-1 and the adrenocorticotropic hormone (ACTH) concentrations in infants with idiopathic IS (IIS), symptomatic IS (SIS), and controls. RESULTS: Infants with IIS had CSF IGF-1 concentrations similar to those of the control children, but children with SIS had markedly low CSF IGF-1 concentrations. In addition, CSF ACTH concentrations were significantly lower in the children with SIS than in those with IIS. High CSF IGF-1 concentrations were associated with an idiopathic etiology, absence of early (pre- or perinatal) insults or stress, normal brain imaging studies, good response to ACTH therapy, and favorable cognitive outcome. Low CSF IGF-1 concentrations were associated with low CSF ACTH concentrations, a history of early insults or stress, cerebral atrophy, poor response to therapy, and poor cognitive outcome. DISCUSSION: In children with IS, insults or stress in early life may affect the synthesis of IGF 1, which might play a role in the reduction of certain cognitive functions. PMID- 20163446 TI - Posterior glucose hypometabolism in Lafora disease: early and late FDG-PET assessment. AB - Establishing an early diagnosis of Lafora disease (LD) is often challenging. We describe two cases of LD presenting as myoclonus and tonic-clonic seizures, initially suggesting idiopathic generalized epilepsy. The subsequent course of the disease was characterized by drug-resistant myoclonic epilepsy, cognitive decline, and visual symptoms, which oriented the diagnosis toward progressive myoclonic epilepsy and, more specifically, LD. Early in the evolution in the first case, and before histopathologic and genetic confirmation of LD in both cases, [18]Fluorodeoxyglucose positron emission tomography (FDG-PET) revealed posterior hypometabolism, consistent with the well-known posterior impairment in this disease. This suggests that FDG-PET could help to differentiate LD in early stages from other progressive myoclonic epilepsies, but confirmation is required by a longitudinal study of FDG-PET in progressive myoclonic epilepsy. PMID- 20163447 TI - The selective advantage of crypsis in mice. AB - The light color of mice that inhabit the sandy dunes of Florida's coast have served as a textbook example of adaptation for nearly a century, despite the fact that the selective advantage of crypsis has never been directly tested or quantified in nature. Using plasticine mouse models of light and dark color, we demonstrate a strong selective advantage for mice that match their local background substrate. Further our data suggest that stabilizing selection maintains color matching within a single habitat, as models that are both lighter and darker than their local environment are selected against. These results provide empirical evidence in support of the hypothesis that visual hunting predators shape color patterning in Peromyscus mice and suggest a mechanism by which selection drives the pronounced color variation among populations. PMID- 20163448 TI - The genetic architecture of wing size divergence at varying spatial scales along a body size cline in Drosophila melanogaster. AB - Latitudinal clines in quantitative traits are common, but surprisingly little is known about the genetic bases of these divergences and how they vary within and between clines. Here, we use line-cross analysis to investigate the genetic architecture of wing size divergences at varying spatial scales along a body size cline in Drosophila melanogaster. Our results revealed that divergences in wing size along the cline were due to strong additive effects. Significant nonadditive genetic effects, including epistasis and maternal effects, were also detected, but they were relatively minor in comparison to the additive effects and none were common to all crosses. There was no evidence of increased epistasis in crosses between more geographically distant populations and, unlike in previous studies, we found no significant dominance effects on wing size in any cross. Our results suggest there is little variation in the genetic control of wing size along the length of the Australian cline. They also highlight marked inconsistencies in the magnitude of dominance effects across studies, which may reflect different opportunities for mutation accumulation while lines are in laboratory culture. PMID- 20163449 TI - Host growth conditions influence experimental evolution of life history and virulence of a parasite with vertical and horizontal transmission. AB - In parasites with mixed modes of transmission, ecological conditions may determine the relative importance of vertical and horizontal transmission for parasite fitness. This may lead to differential selection pressure on the efficiency of the two modes of transmission and on parasite virulence. In populations with high birth rates, increased opportunities for vertical transmission may select for higher vertical transmissibility and possibly lower virulence. We tested this idea in experimental populations of the protozoan Paramecium caudatum and its bacterial parasite Holospora undulata. Serial dilution produced constant host population growth and frequent vertical transmission. Consistent with predictions, evolved parasites from this "high growth" treatment had higher fidelity of vertical transmission and lower virulence than parasites from host populations constantly kept near their carrying capacity ("low-growth treatment"). High-growth parasites also produced fewer, but more infectious horizontal transmission stages, suggesting the compensation of trade-offs between vertical and horizontal transmission components in this treatment. These results illustrate how environmentally driven changes in host demography can promote evolutionary divergence of parasite life history and transmission strategies. PMID- 20163450 TI - Poor statistical performance of the Mantel test in phylogenetic comparative analyses. AB - The Mantel test, based on comparisons of distance matrices, is commonly employed in comparative biology, but its statistical properties in this context are unknown. Here, we evaluate the performance of the Mantel test for two applications in comparative biology: testing for phylogenetic signal, and testing for an evolutionary correlation between two characters. We find that the Mantel test has poor performance compared to alternative methods, including low power and, under some circumstances, inflated type-I error. We identify a remedy for the inflated type-I error of three-way Mantel tests using phylogenetic permutations; however, this test still has considerably lower power than independent contrasts. We recommend that use of the Mantel test should be restricted to cases in which data can only be expressed as pairwise distances among taxa. PMID- 20163451 TI - Vitamin C attenuates ERK signalling to inhibit the regulation of collagen production by LL-37 in human dermal fibroblasts. AB - Vitamin C is used as an anti-ageing agent because of its collagen enhancing effects. The precise cellular signalling mechanism of vitamin C is not well known. Here, we investigate the profibrotic mechanism of vitamin C against LL-37. Antimicrobial peptide LL-37 decreases collagen expression at mRNA and protein levels in human dermal fibroblasts (HDFs). The ability of LL-37 to inhibit collagen expression is dependent on phosphorylation of extracellular signal regulated kinase (ERK). HDFs and human keloid fibroblasts were treated with vitamin C followed by 2 h of LL-37 treatment. Collagen mRNA expression and total soluble collagen production inhibited by LL-37 was enhanced by treatment with 0.5 mm vitamin C. Vitamin C also decreased intracellular reactive oxygen intermediates (ROI) levels that were increased by LL-37. Furthermore, the phosphorylation of ERK was analysed by Western blot following treatment with vitamin C and LL-37. Vitamin C turned off phosphorylation of ERK that was induced by LL-37. Ets-1 transcriptional factor, which is involved in the regulation of collagen expression by LL-37, was also inhibited by vitamin C. This study shows that vitamin C enhances collagen production by inhibiting the ERK pathway induced by LL-37. PMID- 20163452 TI - Novel ELISA systems for antibodies to desmoglein 1 and 3: correlation of disease activity with serum autoantibody levels in individual pemphigus patients. AB - Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are intraepidermal blistering skin diseases. PV is characterised by autoantibodies directed against desmoglein (Dsg) 3 and in patients with the mucocutaneous variant also against Dsg 1, whereas in PF, only Dsg 1 is targeted. Here, ectodomains of Dsg 3 and Dsg 1 were recombinantly expressed in a human cell line (HEK293) and applied as authentic solid phases in ELISA test systems. Autoantibodies against Dsg 3 and/or Dsg 1 could be detected in 71 (100%) of 71 PV sera and against Dsg 1 in 48 (96%) of 50 PF sera. Control sera showed reactivity with Dsg 3 and Dsg 1 in 0.2% and 0.7%, respectively, of 401 healthy blood donors and in 2.1% of 48 randomly selected patients with bullous pemphigoid. No reactivity with Dsg 1 and 3 was detected in 21 patients with linear IgA disease. For both pemphigus variants, a statistically significant correlation between clinical severity and autoantibody levels was observed as demonstrated for 10 PV and 5 PF patients. In conclusion, the use of the ectodomains of Dsg 3 and 1 as target antigens expressed in a human cell line resulted in sensitive and specific ELISA systems for both diagnosis and monitoring of PV and PF. PMID- 20163453 TI - Increased levels of serum IL-31 in chronic spontaneous urticaria. AB - IL-31 represents a novel cytokine involved in pruritic skin diseases including atopic dermatitis (AD). We, therefore, aimed at investigating IL-31 levels in chronic spontaneous urticaria (CU). We included 46 patients with CU, 26 non atopic skin healthy subjects as negative and 28 patients with AD as positive controls. IL-31 serum levels were analysed using commercial ELISA kit. IL-31 serum levels were higher in patients with CU compared to healthy controls (P < 0.001), but lower compared to patients with AD (P < 0.001). There was no difference in IL-31 serum levels in autologous serum skin test positive or negative CU patients and patients with infectious trigger factors including helicobacter pylori infection. IL-31 serum levels may play a role in the pathophysiology of CU. This is supported by the finding that not all patients with CU respond to antihistamine treatment but to the treatment with immunosuppressive drugs. PMID- 20163454 TI - Skin wound healing in MMP2-deficient and MMP2 / plasminogen double-deficient mice. AB - During healing of incisional skin wounds, migrating keratinocytes dissect their way under the crust to re-epithelialize the wounded area. The efficiency of this tissue remodelling process depends on the concomitant activity of several extracellular proteases, including members of the plasminogen activation (PA) system and the matrix metalloproteinase (MMP) family. Treatment with the broad spectrum MMP inhibitor, galardin, delays wound healing in wildtype mice and completely arrest wound healing in plasminogen (Plg)-deficient mice, indicating a functional overlap between plasmin- and galardin-sensitive MMPs during wound healing. To address whether MMP2 is accountable for the galardin-induced healing deficiency in wildtype and Plg-deficient mice, incisional skin wounds were generated in MMP2 single-deficient mice and in MMP2/Plg double-deficient mice and followed until healed. Alternatively, tissue was isolated 7 days post wounding for histological and biochemical analyses. No difference was found in the time from wounding to overt gross restoration of the epidermal surface between MMP2 deficient and wildtype control littermate mice. MMP2/Plg double-deficient mice were viable and fertile, and displayed an unchallenged general phenotype resembling that of Plg-deficient mice, including development of rectal prolapses. MMP2/Plg double-deficient mice displayed a slight increase in the wound length throughout the healing period compared with Plg-deficient mice. However, the overall time to complete healing was not significantly different between Plg deficient and MMP2/Plg double-deficient mice. These results show that MMP2 activity is not essential for wound healing and indicate that lack of MMP2 only marginally potentiates the effect of Plg deficiency. PMID- 20163455 TI - HSP70 inducers from Chinese herbs and their effect on melanin production. AB - Skin hyperpigmentation disorders as a result of abnormal melanin production induced by ultraviolet (UV) irradiation are both a clinical and a cosmetic problem. This melanin production is mediated by tyrosinase whose expression is positively regulated by microphthalmia-associated transcription factor (MITF). We recently found that expression of heat shock protein 70 (HSP70) inhibits melanin production. In this study, we searched for HSP70 inducers from Chinese herbs and selected an ethanol extract of Eupatorium lindleyanum (E. lindleyanum). Not only melanin production but also the activity and expression of tyrosinase were significantly suppressed in cells treated with E. lindleyanum extract as well as in HSP70-overexpressing cells. The expression of MITF was clearly suppressed in cells treated with E. lindleyanum extract but not in HSP70-overexpressing cells. These results suggest that E. lindleyanum extract suppresses the expression of tyrosinase and melanin production through both HSP70-dependent and HSP70 independent mechanisms. PMID- 20163456 TI - Marie Unna hereditary hypotrichosis caused by a novel mutation in the human hairless transcript. AB - Recently the causes for various forms of hypotrichosis and atrichia have been identified, increasing our understanding of the pathways involved in hair cycling and morphogenesis. Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript were found as the cause for autosomal dominant Marie Unna hereditary hypotrichosis. At present, only two studies identified several pathogenic mutations. We ascertained a Jewish Ashkenazi family with hypotrichosis simplex of the Marie Unna type in a mother and her two children. Sequencing of the upstream ORF U2HR in the 5' UTR of the hairless gene resulted in the identification of a novel heterozygous missense mutation c.74C > T resulting in the amino acid change p.P25L. Functional assays confirmed that this mutation led to increased translation of the main HR ORF. This finding extends the mutations' spectrum of U2HR, and emphasizes its major role in hair growth. PMID- 20163457 TI - Smoking but not homozygosity for CYP1A2 g-163A allelic variant leads to earlier disease onset in patients with sporadic porphyria cutanea tarda. AB - Porphyria cutanea tarda (PCT) results from decreased activity of hepatic uroporphyrinogen decarboxylase (UROD). Both sporadic and familial forms are characterised by typical cutaneous lesions triggered by genetic/environmental factors. Studies in rodents showed that cytochrome P4501A2 (CYP1A2) plays a central role in the synthesis of a competitive inhibitor of hepatic UROD, but there is little evidence in humans. The impact of smoking and CYP1A2 g-163C > A allelic variant upon first appearance of clinical signs was investigated in 102 patients (80 sporadic-PCT) and 150 healthy donors from Spain. We found an increase in the frequency of CYP1A2 g-163A allele in patients with PCT when compared with controls, although the more inducible A/A genotype had no effect on the onset age. In sporadic-PCT, smoking leads to earlier onset of clinically overt disease in moderate-to-heavy smokers (>or=10 cigarettes/day). In conclusion, this study provides evidence that smoking hastens the onset of cutaneous symptoms in sporadic-PCT patients. PMID- 20163458 TI - Association of UVRAG polymorphisms with susceptibility to non-segmental vitiligo in a Korean sample. AB - Autoimmune, self-destructive, oxidative stress and genetic theories have been proposed for the pathogenesis of vitiligo. Autophagy is essential for cellular homeostasis and is implicated in many pathophysiological conditions such as cancer, response to oxidative stress and autoimmunity. The ultraviolet (UV) radiation resistance-associated gene (UVRAG) activates the Beclin1-PI(3)KC3 complex, promoting autophagy. To evaluate whether UVRAG polymorphisms are associated with non-segmental vitiligo (NSV) patients in a Korean sample, we conducted a case-control association study of 225 NSV patients and 439 matched healthy controls. A total of five single nucleotide polymorphisms (SNPs) of UVRAG were selected for analysis. Among these, two SNPs (rs1458836, rs7933235) showed significant genotypic differences between the NSV patient group and the control group. These two SNPs were located within a strong linkage disequilibrium (LD) block. In addition, the haplotype of the UVRAG polymorphism was associated with NSV. This study suggests a possible association between UVRAG and NSV susceptibility. PMID- 20163460 TI - Heme oxygenase-1/p21WAF1 mediates peroxisome proliferator-activated receptor gamma signaling inhibition of proliferation of rat pulmonary artery smooth muscle cells. AB - Activation of peroxisome proliferator-activated receptor (PPAR)-gamma suppresses proliferation of rat pulmonary artery smooth muscle cells (PASMCs), and therefore ameliorates the development of pulmonary hypertension in animal models. However, the molecular mechanisms underlying this effect remain largely unknown. This study addressed this issue. The PPARgamma agonist rosiglitazone dose-dependently stimulated heme oxygenase (HO)-1 expression in PASMCs, 5 microm rosiglitazone inducing a 12.1-fold increase in the HO-1 protein level. Cells pre-exposed to rosiglitazone showed a dose-dependent reduction in proliferation in response to serotonin; this was abolished by pretransfection of cells with sequence-specific small interfering RNA against HO-1. In addition, rosiglitazone stimulated p21(WAF1) expression in PASMCs, a 2.34-fold increase in the p21(WAF1) protein level being achieved with 5 microm rosiglitazone; again, this effect was blocked by knockdown of HO-1. Like loss of HO-1, loss of p21(WAF1) through siRNA transfection also reversed the inhibitory effect of rosiglitazone on PASMC proliferation triggered by serotonin. Taken together, our findings suggest that activation of PPARgamma induces HO-1 expression, and that this in turn stimulates p21(WAF1) expression to suppress PASMC proliferation. Our study also indicates that rosiglitazone, a medicine widely used in the treatment of type 2 diabetes mellitus, has potential benefits for patients with pulmonary hypertension. PMID- 20163459 TI - beta-Secretase cleavage is not required for generation of the intracellular C terminal domain of the amyloid precursor family of proteins. AB - The amyloid precursor family of proteins are of considerable interest, both because of their role in Alzheimer's disease pathogenesis and because of their normal physiological functions. In mammals, the amyloid precursor protein (APP) has two homologs, amyloid precursor-like protein (APLP) 1 and APLP2. All three proteins undergo ectodomain shedding and regulated intramembrane proteolysis, and important functions have been attributed to the full-length proteins, shed ectodomains, C-terminal fragments and intracellular domains (ICDs). One of the proteases that is known to cleave APP and that is essential for generation of the amyloid beta-protein is the beta-site APP-cleaving enzyme 1 (BACE1). Here, we investigated the effects of genetic manipulation of BACE1 on the processing of the APP family of proteins. BACE1 expression regulated the levels and species of full-length APLP1, APP and APLP2, of their shed ectodomains, and of their membrane-bound C-terminal fragments. In particular, APP processing appears to be tightly regulated, with changes in beta-cleaved APPs (APPsbeta) being compensated for by changes in alpha-cleaved APPs (APPsalpha). In contrast, the total levels of soluble cleaved APLP1 and APLP2 species were less tightly regulated, and fluctuated with BACE1 expression. Importantly, the production of ICDs for all three proteins was not decreased by loss of BACE1 activity. These results indicate that BACE1 is involved in regulating ectodomain shedding, maturation and trafficking of the APP family of proteins. Consequently, whereas inhibition of BACE1 is unlikely to adversely affect potential ICD-mediated signaling, it may alter other important facets of amyloid precursor-like protein/APP biology. PMID- 20163461 TI - Methodology for the study of the hypothalamic-pituitary hormone secretion in cattle. AB - Studies on the neuroregulatory mechanisms on the secretion of anterior pituitary (AP) hormones in domestic animals are important because nearly all complex physiological and metabolic processes are regulated by the AP hormones. To examine them, this article considers in vivo approaches such as the techniques of intrahypothalamic injection, intracerebroventricular injection, push-pull perfusion, and microdialysis, which have been employed in our own research group for the study in cattle. Also, in vitro approaches such as bovine AP cell culture and the AP explants superfusion system are described. This article clarifies the potential of neuroendocrine study techniques in cattle. PMID- 20163462 TI - The evaluation of the curd forming ability of milk replacers. AB - Inadequate milk curd formation in the abomasum of newborn calves causes malnutrition and diarrhea. In order to define the factors of inadequate curd formation, we compared the curd forming ability among 9 kinds of milk replacers, bulk milk (raw milk), and skim milk both in vitro and in vivo. When rennet was added, the raw milk and one milk replacer formed firm curds. The rest of the milk replacers and skim milk did not form any curd. When a solution of HCl was added, raw milk, three milk replacers and skim milk formed the curd at pH 4.5, but the other milk replacers did not. When HCl was added following the rennet, raw milk, one milk replacer and skim milk formed the curd. In vivo, raw milk, two milk replacers and skim milk showed good curd formation whereas the other milk replacers showed poor curd formation inside the abomasums of the calves. This study showed that most of the milk replacers sold in Japan could not form the curd with rennet. PMID- 20163463 TI - Nutrient utilization and manure P excretion in growing pigs fed corn-barley soybean based diets supplemented with microbial phytase. AB - The effect of high levels of microbial phytase supplementation in diets for growing pigs was studied in a 2-week performance and nutrient digestibility trial involving 28 growing pigs weighing 16.4 +/- 1.06 (mean +/- SD) kg. Seven corn barley-soybean meal-based diets consisting of a positive control (PC) formulated to meet or exceed NRC nutrient requirements; a negative control (NC) with non phytate P reduced by 0.1% unit from NRC requirement and fed without or with 500 or 1000 U/kg; a doubled negative control (DNC) with no added inorganic P and fed without or with 2000 or 4000 U/kg. Chromic oxide was added as an indigestible marker and all diets were fed as mash. Pigs fed the PC diet had a higher P digestibility compared with those fed the NC (P < 0.02) and the DNC (P < 0.001) diets. Supplementing the NC diet with pyhtase tended to improve P digestibility (P < 0.10). However, addition of phytase to the DNC diet resulted in linear (P < 0.001) and quadratic (P < 0.03) increases in P digestibility with an overall improvement of 8% and 121% at 4000 phytase U/kg of diet, respectively, compared with the PC and DNC diets. Apparent total tract digestibility of N, OM and DM were higher (P < 0.05) in the PC diet compared with the DNC diet, but not the NC diet (P < 0.10). No effect of phytase addition to NC was observed on Ca, N, DM and OM digestibility. Phytase addition to the DNC diet resulted in a linear increase (P < 0.05) in N, DM and OM digestibility but not Ca. Increasing the levels of phytase supplementation in the NC and the DNC diets linearly decreased fecal P (P < 0.05) content by 45 and 42%, respectively. Adding phytase at 1000 or 4000 U/kg increased P retention (P < 0.05) by 14.3 or 15.6% units, respectively, compared with the PC diet. Urinary P excretion was higher in the group fed the PC diet compared with those fed the NC and DNC diets (P < 0.05). The results of this study show that complete removal of inorganic P from growing pig diets coupled with phytase supplementation improves digestibility and retention of P and N, thus reducing manure P excretion without any negative effect on pig performance. PMID- 20163464 TI - Effects of feeding fermented fish on egg cholesterol content in hens. AB - This study was conducted to investigate the effects of feeding fermented fish (FF) to layers on laying performance, and polyunsaturated fatty acid and cholesterol levels in eggs and plasma. A total of 96, 13-week-old Babcock B380 pullets were used in this study. They were randomly assigned to four numerically equal groups with eight replicates per treatment, three birds per replicate. All the birds were housed in individual cages. The dietary treatments were: Control diet, without FF; FF3 diet containing 3% (w/w) FF, FF6 diet containing 6% (w/w) FF and FF9 diet containing 9% (w/w) FF. The study was carried out for 16 weeks inclusive of two weeks of adjustment. Weekly feed intake and egg production were recorded. Blood plasma cholesterol and fatty acid profiles were assayed at the end of the experiment. FF did not enhance (P > 0.05) egg mass but (P < 0.05) decreased egg weight slightly. However, egg yolk cholesterol and plasma cholesterol concentrations were reduced (P < 0.05) by FF. The n-6:n-3 fatty acids ratio in the egg yolk (Control = 7.9, FF9 = 6.2) and plasma (Control = 10.6, FF9 = 6.2) were decreased by feeding FF. Moreover, FF was able to increase (P < 0.05) the docosahexaenoic acid (DHA) concentrations in egg yolk and plasma. In conclusion, this study demonstrated that FF increased DHA and reduced egg yolk cholesterol in poultry eggs. PMID- 20163465 TI - Effects of herbage intake on goat performance in the mediterranean type natural pastures. AB - This study aimed at identifying changes in natural pastures during the grazing season and investigating the effects of these changes on pasture feeding potential for high yielding dairy goats. During the study, 12 dairy goats were grazed on a 1.5 ha natural pasture for three months from April to June in 2003, 2004 and 2005. The goats were fed 0.5 kg/day of concentrate as a supplement during the grazing season. Botanical composition, herbage production and intake, crude protein (CP), neutral detergent fiber (NDF) and acid detergent fiber (ADF) contents of the pasture were determined. Live weight, milk yield, milk dry matter (DM) and fat content of the goats were monitored. The data were analyzed using a linear model, which evaluated the effects of grazing seasons in each year. Based on the three-year average, 87% of pasture was herbaceous plants and the remaining was shrubs in DM basis with Cistus creticus, Quercus ithaburensis, Pistacia atlantica and Asparagus acutifolius being the major shrub species. The herbage yield in June was significantly lower than in other months in all years (P = 0.001). In all experimental years, the CP content of the pasture decreased but the structural carbohydrates increased as the grazing season proceeded. While live weight was not affected by grazing periods except for 2004 (P = 0.001), milk yield significantly decreased with advancing grazing period (P = 0.001). The results of the present study indicate that natural pasture has a supportive effect in April and May on the milk yield of lactating goats which are in mid lactation, and suggested that supplementary feeding is required in consecutive grazing periods. PMID- 20163466 TI - The effect of Eucommia ulmoides leaf supplementation on the growth performance, blood and meat quality parameters in growing and finishing pigs. AB - The aim of the present study was to investigate the effect of Eucommia ulmoides leaf (EUL) supplementation on the growth performance, blood and meat quality parameters in growing and finishing pigs. Ninety gilts (L x LW x D, 20 kg initialBW) were housed 10 per pen in a front-open building with three replicate pens per treatment. Experimental treatment was started from the beginning of the growing stage (20 +/- 3 kg) by supplementing EUL at 0(C), 3(T1) and 5% (T2) to the growing and finishing diet. Pigs were slaughtered by electrical stunning at 105 +/- 3 kg live weight. Average daily feed intake (ADFI, kg/day) decreased (P < 0.05) by addition of EUL in growth performance, average daily gain (ADG, kg/day) was lower (P < 0.05) in T1 and T2 than in C. In hematology, leukocytes (WBC, 10(3)/mm(3)) decreased (P < 0.05) in T1 and T2 than in C. Erythrocytes (RBC, 10(6)/mm(3)), hemoglobin (HGB, g/dL) and hematocrit (HCT, %) increased (P < 0.05) in T1 and T2 than in C. Platelet (PLT, 10(3)/mm(3)) was lower (P < 0.05) in T2 than in C and T1. In biochemical composition of serum, total protein (g/dL), r GTP (micro/L), total cholesterol (mg/dL) and triglycerides (mg/dL) were lower (P < 0.05) in T1 and T2 than in C. On longissimus dorsi muscle, crude protein was higher (P < 0.05) in T1 than in C. Crude ash was higher (P < 0.05) in T1 and T2 than in C. Yellow to blue color scale (CIE b*) in meat color was higher (P < 0.05) in T2 than in C. CIE b* in back fat color was higher (P < 0.05) in T2 than in the other treatments. In sensory evaluation scores for fresh meat, the values of meat color, fat color, drip loss and marbling were not significantly affected by addition of EUL. In cooked meat, the values of chewiness and overall acceptability were higher (P < 0.05) in T1 and T2 than in C. The results indicate that the addition of EUL affected growth performance, blood parameters and meat quality parameters in growing and finishing pigs. PMID- 20163467 TI - Dietary phytase increases the true absorption and endogenous fecal excretion of zinc in growing pigs given a corn-soybean meal based diet. AB - We investigated the effect of dietary phytase on the true absorption and endogenous fecal excretion of zinc (Zn) using (67)Zn in growing pigs given a corn soybean meal based diet. Ten crossbred barrows were fed the control diet containing 90-mg/kg Zn, 2.3-g/kg phytate-phosphorus and 3.7-g/kg non-phytate phosphorus or the phytase diet containing similar amounts of Zn and phytate phosphorus, and 1.4-g/kg non-phytate-phosphorus with 750-PU/kg phytase for 12 h/day. On day 6, the pigs were given 200 g of the corresponding diet labeled by (67)Zn for 2 h. We measured feed intake, fecal Zn concentration and (67)Zn abundance for the determination of apparent absorption, true absorption and endogenous fecal excretion of Zn. Although the apparent absorption of Zn did not significantly differ between the dietary groups, the phytase group had significantly more (P < 0.05) true absorption of Zn than the control group. The endogenous fecal excretion of Zn tended to be more (P = 0.07) in the phytase group than in the control group. These results suggest that dietary phytase improves Zn bioavailability through increasing the true absorption of Zn in growing pigs, which results in stimulating the endogenous fecal excretion of Zn when dietary Zn satisfies its requirement. PMID- 20163468 TI - Effect of cooking time on some nutrient and antinutrient components of bambaragroundnut seeds. AB - The proximate composition, gross energy, mineral composition, percentage sugar, oligosaccharides and antinutrient substances of bambaragroundnut seeds subjected to different cooking times were determined. The seeds were cooked for 30, 60, 90 and 120 min. Results of the proximate analysis showed that only the ether extract and ash were significantly (P < 0.05) reduced as the cooking time increased. In contrast, gross energy values significantly (P < 0.05) increased with increased cooking time. Amongst, the mineral elements assayed, calcium, magnesium and iron were significantly (P < 0.05) increased, while phosphorous, potassium, sodium and copper were reduced significantly (P > 0.05) with inreased cooking time. Percentage sucrose and glucose of bambaragroundnut seeds were significantly (P < 0.05) lowest in the raw form, but increased progressively with increased of cooking time. Raffinose and stachyose levels were reduced significantly by increased cookinf time (P < 0.05) with the least value in seeds cooked for 120 min. Trypsin inhibitor, hemagglutinin and tannin were completely eliminated in seeds cooked for 60 min or longer, but the phytin level was reduced significantly (P < 0.05) by cooking. For a significant detoxification of antinutrient substances and for optimal bioavailability of the component nutrients of bambaragroundnut seeds, an optimum cooking time of 60 min at 100 degrees C is therefore recommended. PMID- 20163469 TI - Effects of dietary glucose level during late gestation on litter performance and glucose concentration in sows. AB - The effects of feeding glucose during the 5 days before parturition on litter performance and on glucose concentration in sows were studied. At day 100 of gestation, 130 multiparous sows were assigned to the treatments. Late gestating sows were fed 0 g, 150 g, 250 g, 350 g and 450 g of glucose a day, respectively. During lactation, all sows were given free access to the same lactation diet (without glucose). One day before parturition, blood samples were collected from 30 sows (6 sows per treatment) at 10 before and 20, 40, 60 and 80 min after the meal. The supply of additional dietary glucose increased piglet birth weight (P < 0.05). Feed intake in week 1 and week 1-4 of lactation was greatest in sows fed the 0% glucose diet, least by sows fed the 18% glucose diet, and intermediate by sows fed the 6, 10, 14% glucose diets (P < 0.05). Basal glucose concentration and time of maximum glucose concentration after glucose intake were not affected by dietary treatment in the last 5 days of gestation. The sows fed the 14 and 18% glucose diets had greater maximum increase in glucose concentration than sows fed diet without glucose (P < 0.05). In conclusion, feeding glucose to sows during 5 days before parturition increased birth weight of live-born piglet and decreased sows feed intake during lactation, but did not affect the performance of sows and piglets. PMID- 20163470 TI - Effects of GH gene polymorphism and sex on carcass traits and fatty acid compositions in Japanese Black cattle. AB - To investigate the effects of bovine growth hormone (bGH) gene polymorphism on carcass traits and fatty acid compositions in Japanese Black cattle caused by nucleotide substitution of CTG (allele A)/GTG (allele B) at codon 127 and of ACG (allele A and B)/ATG (allele C) at codon 172 of bGH, GH genotypes of 135 cattle were determined using allele specific-multiplex polymerase chain reaction (PCR). Allele A gave greater rib thickness and lower melting point of fat (MP) while allele B gave higher C18:1% (P < 0.05). Allele C gave higher C18:1, monounsaturated fatty acid (MUFA), unsaturated fatty acid (USFA) percentages (P < 0.05). It also gave lower saturated fatty acid (SFA) percentages, higher MUFA/SFA and USFA/SFA ratios, and lower MP (P < 0.05). Interactions of sex and GH alleles were analyzed. In heifers, allele A gave higher carcass weight, daily carcass gain, rib eye area, rib thickness, subcutaneous fat thickness, and BMS while allele B gave greater rib eye area and rib thickness (P < 0.05). Allele C gave higher C18:1 (P < 0.01), MUFA (P < 0.01), USFA percentages (P < 0.05) and MUFA/SFA and USFA/SFA ratios (P < 0.01), and lower C16:0 and SFA percentages (P < 0.05) and MP (P < 0.01). GH gene polymorphism affected carcass traits and fatty acid compositions although the effects were more pronounced in heifers. PMID- 20163471 TI - Characterization of bacteriocin produced by Streptococcus bovis J2 40-2 isolated from traditional fermented milk 'Dahi'. AB - A bacteriocin-producing strain Streptococcus bovis J2 40-2 was isolated from traditional fermented milk 'Dahi' in Bangladesh. Despite its narrow antimicrobial spectrum, it showed strong antimicrobial activity against extremely challenging and problematic organisms in foods, such as Listeria monocytogenes. Bacteriocin was sensitive to several proteolytic enzymes and showed antimicrobial activity over a wide pH range of 2.0-10.0. It was stable when heated to 110 degrees C for 20 min, but lost 25% of its activity when heated to 121 degrees C for 15 or 20 min. Optimum bacteriocin production (5600 AU/mL) was achieved when the strain was cultured at 37 degrees C for 24 h in MRS medium rather than in TYLG, GM17, or skim milk medium. Bacteriocin was partially purified by ammonium sulfate precipitation (80% saturation), dialysis (cut-off MW: 3500) and gel filtration chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that bacteriocin had a molecular weight of approximately 4.5 kDa. PMID- 20163472 TI - The effect of fermented apple diet supplementation on the growth performance and meat quality in finishing pigs. AB - The objective of the present study was to investigate the effect of fermented apple diet (FAD) supplementation on the growth performance and meat quality in finishing Berkshires. The FAD was made from dropped apple mixed with rice bran and barley bran. Until 81 +/- 1 kg live weight at 133 +/- 1 days, the animals were fed a growing diet, after which experimental samples were fixed at 0, 2, 4 and 6% FAD as C, T1, T2 and T3 in the finishing diets. Growth performance, ADG, ADFI and feed efficiency were improved in T1 than other groups. In carcass parameters, carcass weight was higher (P < 0.05) in T1 than in other groups. In meat quality, moisture and crude protein contents decreased (P < 0.05) by addition of FAD. pH(24) and WHC were higher (P < 0.05) in T1 than other groups. In sensory evaluation, marbling of fresh meat and tenderness, juiciness, flavor and overall acceptability of cooked meat were improved by the addition of FAD. According to the results of our experiment, FAD can be used for improvement of meat quality parameters. PMID- 20163473 TI - Relationships between physical and structural properties of intramuscular connective tissue and toughness of raw pork. AB - We studied the relationships between the shear-force value and physical and structural properties of the intramuscular connective tissue (IMCT) in six classes of porcine skeletal muscle to elucidate the contribution of IMCT to toughness of raw pork. The shear-force value of raw pork correlated significantly with that of the IMCT model prepared from each class of skeletal muscle (P < 0.05). The correlation suggested that the variable toughness of pork was caused by the mechanical strength of the endomysium and perimysium. The thickness of the secondary perimysium correlated significantly with the shear-force value of raw pork (P < 0.05) and with that of the IMCT model (P < 0.05). The shear-force value of raw pork correlated significantly with the total amount of collagen (P < 0.05) but not with the heat-solubility of collagen. We concluded therefore that the thickness of the secondary perimysium determines the mechanical strength of IMCT and contributes to toughness in raw pork. PMID- 20163474 TI - Determination of angiotensin-I converting enzyme inhibitory peptides in chicken leg bone protein hydrolysate with alcalase. AB - This study aims to identify peptides with angiotensin-I converting enzyme (ACE) inhibitory activity in hydrolysate from chicken leg bone protein hydrolyzed with alcalase for 4 h (A4H). The hydrolysate has demonstrated potent in vitro ACE inhibitory activity, and has been shown to attenuate the development of hypertension and cardiovascular hypertrophy in spontaneously hypertensive rats (SHR). A4H is competitive for ACE and was separated using high-performance liquid chromatography (HPLC) with a gel filtration column (Superdex Peptide HR 10/30). The results show that A4H is a mixed non-competitive inhibitor. Eighteen fractions were detected after separation of A4H, and most of them showed ACE inhibitory activity. Five fractions with strong ACE inhibitory activities (above 50%) were labeled from A to E. In addition, there were 10 peptides, consisting of 5-10 amino acid residues that were identified from fraction D that exhibited the strongest ACE inhibitory activity. Three of the identified peptides corresponded to peptides derived from collagen type I and chicken muscular protein. It is revealed that A4H has several peptides that possess ACE inhibitory activities. PMID- 20163475 TI - Ability of heifers to discriminate between familiar herdmates and members of an unfamiliar group: preference test and operant conditioning test. AB - Using a preference test and operant conditioning in a Y-maze, this experiment examined the ability of heifers to discriminate between their own familiar herdmates and member(s) of an unfamiliar group. Sixteen Danish Friesian heifers, eight older animals (360.6 +/- 24.2 days of age) and eight younger ones (190.1 +/ 14.1 days of age) were used. Each age group was further divided into two experimental groups. Members of each of these groups were housed together in small pens before the experiments began. In experiment 1, each of the 16 animals was allowed to approach either a familiar or an unfamiliar individual in the Y maze. The test was repeated 12 times, with a different unfamiliar subject for each test. In experiment 2, eight heifers were individually tested in a conditioning experiment to examine whether they could learn to discriminate between a group of their three herdmates and a group of three unfamiliar heifers. Test animals were rewarded when they chose their own group. In experiment 1, heifers did not show a preference between familiar and unfamiliar individuals. Interestingly the younger stimulus heifers but not the test animals showed an ability to discriminate between unfamiliar animals by vocalizing. In experiment 2, four of the eight test animals achieved the criterion for successful discrimination between the familiar and unfamiliar group (P < 0.003: binomial law). There was no age group difference in the ability to discriminate between familiar and unfamiliar animals. In conclusion, heifers did not show a preference toward familiar or unfamiliar individuals; but after conditioning, some heifers could learn to discriminate between familiar and unfamiliar groups. PMID- 20163476 TI - The structure of vocalization of ewes and male lambs at pasture. AB - We performed an analysis of the vocalization of 161 ewes and 50 male lambs that were pastured day and night. The vocalization structures of the phonetic notations of the opened-mouth from closed mouth /etaaee/ and /etanaeee/ and closed-mouth /etaetaetaeta/ of ewes, and the opened-mouth from closed-mouth /etaeee/ and /etaneeee/ and closed-mouth /etaetaetaeta/ of male lambs were studied in terms of their audio characteristics. The items subject to analysis included duration of each vocalization, fundamental frequency, sound pressure and first formant (F1), second formant (F2), and third formant (F3). Among the male lambs, the duration of each call type showed significant differences depending on the behavior types or the target types, and the closed-mouth to open-mouth sounds, /etaeee/ and /etaneeee/ showed a tendency to be longer than the closed mouth sound of /etaetaetaeta/. A significant correlation (r = 0.9, P < 0.05) was observed between the fundamental frequency and F1 with the /etaeee/ type of call of the male lambs when the vocalization was targeted toward the stockperson. When the ewes' behavior pattern was grazing and moving and the calling target was an ewe, the sound pressure significantly differed between /etaetaetaeta/ and /etanaeee/ (P < 0.05). From the analysis of the call durations, the fundamental frequencies, the sound pressures and formants, and the particular characteristics in sound structure were shown to vary according to the vocalization conditions and the situations, and where the animals were placed, even within the same call types. PMID- 20163477 TI - Spatio-temporal variations in protistan communities along an O/HS gradient in the anoxic Framvaren Fjord (Norway). AB - Despite its relevance for ecology and biodiversity, the stability of spatial microeukaryote diversity patterns in time has received only little attention using gene-based strategies, and there is little knowledge about the relation of spatial vs. temporal variation. We addressed this subject by investigating seasonal fluctuations in protistan communities in three ecologically distinct marine habitats. We analyzed 3360 eukaryote small subunit rRNA gene sequences collected along an O(2)/H(2)S gradient in a Norwegian fjord in order to reveal shifts in protistan community composition and structure in three different seasons. In all nine clone libraries, ciliates and stramenopiles accounted for the largest proportion. Yet, as expected, at the phylotype level, the protistan communities from distinct habitats differed significantly, with the number of shared phylotypes between two habitats being as low as 18%. This confirmed previous notions that environmental factors along the stratification gradient shape biodiversity patterns. Surprisingly, the intrahabitat community composition and structure varied at a comparable order of magnitude over time, with only 18 28% phylotypes shared within the same habitat. Our study demonstrates that the consideration of local fluctuations in microeukaryote diversity over time offers additional information for diversity surveys and can significantly contribute to the revelation of spatial protistan community patterns. PMID- 20163478 TI - Phytoplankton-bacterioplankton interactions and carbon fluxes through microbial communities in a microtidal lagoon. AB - The strength of the bacteria-phytoplankton coupling and the importance of the microbially mediated carbon fluxes have been investigated in a microtidal lagoon (Lagoon of Venice), with emphasis on the trophic variations, in a within-system perspective. The large trophic heterogeneity of the three stations considered corresponded to an elevated variability of phytoplankton biomass and production (from 0.1 up to 300 microg C L(-1) h(-1)), while bacteria standing stock and production (from 2 to 8 microg C L(-1) h(-1)) appeared, in comparison, to be much more constant. The relationships between bacteria and the phytoplankton community could not be related to the trophic state in a straightforward way; rather, some patterns common to the three stations could be evidenced. In particular, the two communities appeared to be clearly uncoupled, bacterial carbon demand (BCD) always exceeding dissolved primary production (DPP) and, mostly, also total primary production, independent of the station and the season considered. The occurrence of situations in which bacterial production was larger than primary production and the continuous prevalence of BCD over DPP implied that, quite independent of the trophic variability, sources of organic carbon other than phytoplankton production were necessary and available to sustain the bacterial metabolism in the Lagoon of Venice. PMID- 20163479 TI - Chronic headache and comorbidities: a two-phase, population-based, cross sectional study. AB - BACKGROUND: Studies using resources of a public family health program to estimate the prevalence of chronic daily headaches (CDH) are lacking. OBJECTIVES: To estimate the 1-year prevalence of CDH, as well as the presence of associated psychiatric and temporomandibular disorders (TMD) comorbidities, on the entire population of a city representative of the rural area of Brazil. METHODS: This was a cross-sectional, population-based, 2-phase study. In the first phase, health agents interviewed all individuals older than 10 years, in a rural area of Brazil. In the second stage, all individuals who reported headaches on 4 or more days per week were then evaluated by a multidisciplinary team. CDH were classified according to the second edition of the International Classification of Headache Disorders (ICHD-2). Medication overuse headache was diagnosed, as per the ICHD-2, after detoxification trials. Psychiatric comorbidities and TMD were diagnosed based on the DSM-IV and on the Research Diagnostic Criteria for Temporomandibular Disorders criteria, respectively. RESULTS: A total of 1631 subjects participated in the direct interviews. Of them, 57 (3.6%) had CDH. Chronic migraine was the most common of the CDH (21, 36.8%). Chronic tension-type headache (10, 17.5%), medication overuse headache (13, 22.8%) and probable medication overuse headache (10, 17.5%) were also common. Psychiatric disorders were observed in 38 (67.3%) of the CDH subjects. TMD were seen in 33 (58.1)% of them. CONCLUSIONS: The prevalence of CDH in the rural area of Brazil is similar to what has been reported in previous studies. A significant proportion of them have psychiatric comorbidities and/or TMD. In this sample, comorbidities were as frequent as reported in convenience samples from tertiary headache centers. PMID- 20163480 TI - Dopaminergic and non-dopaminergic pharmacological hypotheses for gait disorders in Parkinson's disease. AB - Gait disorders form one component of the axial disorders observed in Parkinson's disease (PD). Indeed, short steps with a forward-leaning stance are diagnostic criteria for PD in the early stages of the condition. Gait disorders also represent a major source of therapeutic failure in the advanced stages of PD (with the appearance of freezing of gait and falls) because they do not respond optimally to the two hand late-stage therapeutics--levodopa and electrical subthalamic nucleus (STN) stimulation. The late onset of doparesistance in these disorders may be linked to propagation of neurodegeneration to structures directly involved in gait control and to non-dopaminergic neurotransmitter systems. The coeruleus locus (a source of noradrenaline) is rapidly and severely affected, leading to a major motor impact. The pedunculopontine nucleus (PPN) and lateral pontine tegmentum (rich in acetylcholine) are both involved in gait. Degenerative damage to the serotoninergic raphe nuclei appears to be less severe, although serotonin-dopamine interactions are numerous and complex. Lastly, dopaminergic depletion leads to glutamatergic hyperactivity of the efferent pathways from the the STN to the PPN. However, the relationships between the various parkinsonian symptoms (and particularly gait disorders) and these pharmacological targets have yet to be fully elucidated. The goal of this review is to develop the various pathophysiological hypotheses published to date, in order to underpin and justify ongoing fundamental research and clinical trials in this disease area. PMID- 20163481 TI - Hepatitis C virus coinfection and the risk of cardiovascular disease among HIV infected patients. AB - BACKGROUND: Among HIV-infected patients, hepatitis C virus (HCV) coinfection is associated with lower cholesterol levels, but it remains unclear how it affects cardiovascular outcomes. METHODS: We performed logistic regression to evaluate acute myocardial infarction (AMI) and cerebrovascular disease (CVD) events by HCV status among HIV-infected US veterans in the highly active antiretroviral therapy (HAART) era (1996-2004). We then performed survival analyses to evaluate incident AMI and CVD, exploring antiretroviral therapy (ART) as a time-dependent variable. RESULTS: A total of 19 424 HIV-infected patients [31.6% of whom were HCV coinfected (HIV/HCV)] contributed 76 376 patient-years of follow-up. HCV coinfection was associated with lower rates of hypercholesterolaemia (18.0% in HIV/HCV vs. 30.7% in HIV-only patients; P<0.001), but higher rates of hypertension (43.8%vs. 35.6%; P<0.0001), type 2 diabetes mellitus (16.2%vs. 11.1%; P<0.0001) and smoking (36.7%vs. 24.7%; P=0.009). Rates of AMI and CVD were significantly higher among HIV/HCV than HIV-only patients: 4.19 vs. 3.36 events/1000 patient-years, respectively (P<0.001), for AMI; and 12.47 vs. 11.12 events/1000 patient-years, respectively (P<0.001), for CVD. When analyses were controlled for diabetes mellitus, hypertension, age and duration of ART, hazard ratios (HRs) among those with HIV/HCV (vs. HIV only) were 1.25 [95% confidence interval (CI) 0.98-1.61; P=0.072] for AMI and 1.20 (CI 1.04-1.38; P=0.013) for CVD. Hypertension (HR 2.05; P<0.001), greater age (HR 1.79; P<0.001) and longer duration (cumulative years) of antiretroviral use (HR 1.12; P=0.0411) were also associated with increased risk of AMI in the adjusted model. CONCLUSIONS: In the HAART era, HCV coinfection was associated with a significantly increased risk of CVD and a trend towards an increased risk of AMI among HIV-infected patients. PMID- 20163482 TI - HIV-1 proviral resistance mutations: usefulness in clinical practice. AB - OBJECTIVES: Transmitted HIV strains may harbour drug resistance mutations. HIV-1 drug resistance mutations are currently detected in plasma viral RNA. HIV-1 proviral DNA could be an alternative marker, as it persists in infected cells. METHODS: This was a prospective study assessing the prevalence and persistence of HIV-1 drug resistance mutations in DNA from CD4 cells before and after protease inhibitor (PI)- or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based therapy initiation in 69 drug-naive patients. RESULTS: Before therapy, 90 and 66% of detected mutations were present in CD4 cells and plasma, respectively. We detected seven key mutations, and four of these (M184M/V, M184M/I, K103K/N and M46M/I) were only found in the cells. When treatment was started, 40 patients were followed; the mutations detected at the naive stage remained present for at least 1 year. Under successful treatment, new key mutations emerged in CD4 cells (M184I, M184M/I and Y188Y/H). CONCLUSIONS: The proportion of mutations detected in the DNA was statistically significantly higher than that detected in standard RNA genotyping, and these mutations persisted for at least 1 year irrespective of therapy. The pre-existence of resistance mutations did not jeopardise treatment outcome when the drug concerned was not included in the regimen. Analysis of HIV 1 DNA could be useful in chronic infections or when switching therapy in patients with undetectable viraemia. PMID- 20163483 TI - Diagnostic value of procalcitonin for bacterial infection in elderly patients in the emergency department. AB - OBJECTIVES: To evaluate the diagnostic performance of procalcitonin (PCT) in elderly patients with bacterial infection in the emergency department (ED). DESIGN: Prospective. SETTING: ED of a tertiary care hospital. PARTICIPANTS: Elderly patients with systemic inflammatory response syndrome (SIRS) enrolled from September 2004 through August 2005. MEASUREMENTS: A serum sample for the measurement of PCT, two sets of blood cultures, and other cultures of relevant specimens from infection sites were collected in the ED. Two independent experts blinded to the PCT results classified the patients into bacterial infection and nonbacterial infection groups. RESULTS: Of the 262 patients with SIRS enrolled, 204 were classified as having bacterial infection and 48 as having bacteremia. PCT levels were significantly higher in patients with bacteremia than in those without. The area under the receiver operating characteristic curve for identification of bacteremia according to PCT was 0.817 for the old-old group (>or=75), significantly higher than 0.639 for the young-old group (65-74); P=.02). The diagnostic sensitivity, specificity, positive predictive value, and negative predictive value of PCT for bacteremia in patients aged 75 and older were 96.0%, 68.3%, 33.8%, and 98.8%, respectively, with a PCT cutoff value of 0.38 ng/mL. CONCLUSION: PCT is sensitive for diagnosing bacteremia in elderly patients with SIRS at ED admission but is helpful in excluding bacteremia only in those aged 75 and older. PCT is not an independent predictor of local infections in these patients. PMID- 20163484 TI - Characteristics and outcomes of injured older adults after hospital admission. AB - OBJECTIVES: To describe the seriously injured adult population aged 65 and older; compare the differences in injury characteristics and outcomes in three subgroups aged 65 to 74, 75 to 84, and 85 and older; and identify predictors of death, complications, and hospital discharge destination. DESIGN: Retrospective secondary analysis of data from the Queensland Trauma Registry (QTR) using all patients aged 65 and older admitted from 2003 through 2006. SETTING: Data from 15 regional and tertiary hospitals throughout Queensland, Australia. PARTICIPANTS: Six thousand sixty-nine patients: 2,291 (37.7%) aged 65 to 74, 2,265 (37.3%) aged 75 to 84, and 1,513 (24.9%) aged 85 and older. MEASUREMENTS: Outcome variables included mortality, complications, and discharge destination (usual residence, rehabilitation, nursing home, convalescence). Predictive factors incorporated demographic details, injury characteristics, and acute care factors. RESULTS: Hospital survival was 95.0%, with a median length of hospital stay of 8 days (interquartile range 5-15), and 33.8% of cases with a major injury developed a complication. Predictors of death included older age, male sex, admission to the intensive care unit (ICU), greater Injury Severity Score (ISS), injury caused by a fall, and two or more injuries; those who had surgery were less likely to die. Predictors of complications included ICU admission, older age, longer hospital stay, and two or more injuries. Predictors of discharge to a nursing home included older age, greater ISS, longer hospital stay, and injury caused by a fall, among others. CONCLUSION: Older adults with severe injuries are at risk of poor outcomes. These findings suggest opportunities for improving geriatric trauma care that could lead to better outcomes. PMID- 20163485 TI - Cardiovascular disease is associated with greater incident dehydroepiandrosterone sulfate decline in the oldest old: the cardiovascular health study all stars study. AB - OBJECTIVES: To describe cross-sectional and longitudinal associations with dehydroepiandrosterone sulfate (DHEAS) and change in DHEAS with age. DESIGN: Longitudinal cohort study. SETTING: Pittsburgh, Pennsylvania. PARTICIPANTS: Cardiovascular Health Study All Stars study participants assessed in 2005/06 (N=989, mean age 85.2, 63.5% women, 16.5% African American). MEASUREMENTS: Health characteristics were assessed in 2005/06 according to DHEAS level, mean DHEAS and DHEAS change across age categories were tested, and linear and logistic regression was used to identify factors present in 1996/97 associated with continuous and categorical DHEAS change. RESULTS: Mean +/- standard deviation DHEAS was 0.555 +/- 0.414 microg/mL in 1996/97 and 0.482 +/- 0.449 microg/mL in 2005/06 for women and 0.845 +/- 0.520 microg/mL in 1996/97 and 0.658 +/- 0.516 microg/mL in 2005/06 for men. In 2005/06, DHEAS was lower in women and subjects with cardiovascular disease (CVD) and chronic pulmonary disease and higher for African Americans and subjects with hypertension and high cholesterol. Mean DHEAS change was greater in men (-0.200 microg/mL) than in women (-0.078 microg/mL) (P<.001). Each 1-year increase in age attenuated the effect of male sex by 0.01 microg/mL (P=.009), abolishing the sex difference in DHEAS change by age 79. Presence of CVD before the study period was associated with greater absolute DHEAS change (beta=-0.04 microg/mL, P=.04) and with the fourth quartile of DHEAS change versus the first to third quartiles (odds ratio=1.46, 95% confidence interval=1.03-2.05). CONCLUSION: DHEAS change continues into very old age, is not homogenous, is affected by sex, and is associated with prevalent CVD. Future studies should investigate factors that might accelerate DHEAS decline. PMID- 20163486 TI - Depressive symptoms in middle age and the development of later-life functional limitations: the long-term effect of depressive symptoms. AB - OBJECTIVES: To determine whether middle-aged persons with depressive symptoms are at higher risk for developing activity of daily living (ADL) and mobility limitations as they advance into older age than those without. DESIGN: Prospective cohort study. SETTING: The Health and Retirement Study (HRS), a nationally representative sample of people aged 50 to 61. PARTICIPANTS: Seven thousand two hundred seven community living participants in the 1992 wave of the HRS. MEASUREMENTS: Depressive symptoms were measured using the 11-item Center for Epidemiologic Studies Depression Scale (CES-D 11), with scores of 9 or more (out of 33) classified as significant depressive symptoms. Difficulty with five ADLs and basic mobility tasks (walking several blocks or up one flight of stairs) was measured every 2 years through 2006. The primary outcome was persistent difficulty with ADLs or mobility, defined as difficulty in two consecutive waves. RESULTS: Eight hundred eighty-seven (12%) subjects scored 9 or higher on the CES D 11 and were classified as having significant depressive symptoms. Over 12 years of follow-up, subjects with depressive symptoms were more likely to reach the primary outcome measure of persistent difficulty with mobility or difficulty with ADL function (45% vs 23%, Cox hazard ratio (HR)=2.33, 95% confidence interval (CI)=2.06-2.63). After adjusting for age, sex, measures of socioeconomic status, comorbid conditions, high body mass index, smoking, exercise, difficulty jogging 1 mile, and difficulty climbing several flights of stairs, the risk was attenuated but still statistically significant (Cox HR=1.44, 95% CI=1.25-1.66). CONCLUSION: Depressive symptoms independently predict the development of persistent limitations in ADLs and mobility as middle-aged persons advance into later life. Middle-aged persons with depressive symptoms may be at greater risk for losing their functional independence as they age. PMID- 20163487 TI - Genomic and phenotypic comparison between similar wine yeast strains of Saccharomyces cerevisiae from different geographic origins. AB - AIMS: To study genomic and phenotypic changes in wine yeasts produced in short time periods analysing yeast strains possibly derived from commercial strains recently dispersed. METHODS AND RESULTS: We conducted a genomic and phenotypic comparison between the commercial yeast strain EC1118 and two novel strains (LV CB and L-957) isolated from different wine areas industrially intervened <20 years ago. Molecular analysis by amplified fragment length polymorphism (AFLP) and RAPD-PCR was not able to distinguish between these strains. However, comparative genomic hybridization (aCGH) showed discrete DNA gains and losses that allowed unequivocal identification of the strains. Furthermore, analysis of aCGH data supports the hypothesis that strains LV CB and L-957 are derivatives from strain EC1118. Finally, scarce phenotypic differences in physiological and metabolic parameters were found among the strains. CONCLUSION: The wine yeasts have a very dynamic genome that accumulates changes in short time periods. These changes permit the unique genomic identification of the strains. SIGNIFICANCE AND IMPACT OF THE STUDY: This study permits the evaluation of microevolutive events in wine yeasts and its relationship with the phenotype in this species. PMID- 20163488 TI - Enhancing the adhesion of Epicoccum nigrum conidia to peach surfaces and its relationship to the biocontrol of brown rot caused by Monilinia laxa. AB - AIMS: To find a formulation of Epicoccum nigrum conidia that enhances its adhesion to peach surfaces and improves its biocontrol efficacy against brown rot caused by Monilinia laxa. METHODS AND RESULTS: The stickers, glycerol, sodium alginate and methylcellulose; the desiccants, silica powder and talc; and a commercial adhesive (NU FILM 17) were added at two different points during the production of an E. nigrum conidial formulation to improve conidial adhesion to peach surfaces. Conidial adhesion levels were determined from the number of E. nigrum conidia that adhered to glass slides or peach surfaces and conidial viability of adherent E. nigrum conidia was determined from the number of colony forming units of glass or peach-adherent E. nigrum that grew on Petri dishes that contained potato dextrose agar. Compared to dried E. nigrum conidia without additives, the adhesion and viability of adherent E. nigrum conidia to peach surfaces were enhanced when either 1.25% sodium alginate or 2.5% methylcellulose was added to the conidial mass after fluid-bed drying, and when 2.5% methylcellulose was added to the conidial mass after its production and before fluid-bed drying. Epicoccum nigrum conidial formulations with 2.5% methylcellulose were more effective than dried E. nigrum conidia without additives in reducing the incidence of brown rot in peaches caused by M. laxa. CONCLUSIONS: When 2.5% methylcellulose is incorporated into an E. nigrum conidial formulation, the adhesion of E. nigrum conidia to peach surfaces improves and results in efficacious biocontrol of brown rot. SIGNIFICANCE AND IMPACT OF THE STUDY: A new improved formulation of a biocontrol agent has been developed to improve the control of M. laxa on peaches. PMID- 20163489 TI - Suppression of bacterial cell-cell signalling, biofilm formation and type III secretion system by citrus flavonoids. AB - AIM: This study investigated the quorum sensing, biofilm and type three secretion system (TTSS) inhibitory properties of citrus flavonoids. METHODS AND RESULTS: Flavonoids were tested for their ability to inhibit quorum sensing using Vibrio harveyi reporter assay. Biofilm assays were carried out in 96-well plates. Inhibition of biofilm formation in Escherichia coli O157:H7 and V. harveyi by citrus flavonoids was measured. Furthermore, effect of naringenin on expression of V. harveyi TTSS was investigated by semi-quantitative PCR. Differential responses for different flavonoids were observed for different cell-cell signalling systems. Among the tested flavonoids, naringenin, kaempferol, quercetin and apigenin were effective antagonists of cell-cell signalling. Furthermore, these flavonoids suppressed the biofilm formation in V. harveyi and E. coli O157:H7. In addition, naringenin altered the expression of genes encoding TTSS in V. harveyi. CONCLUSION: The results of the study indicate a potential modulation of bacterial cell-cell communication, E. coli O157:H7 biofilm and V. harveyi virulence, by flavonoids especially naringenin, quercetin, sinensetin and apigenin. Among the tested flavonoids, naringenin emerged as potent and possibly a nonspecific inhibitor of autoinducer-mediated cell-cell signalling. Naringenin and other flavonoids are prominent secondary metabolites present in citrus species. Therefore, citrus, being a major source of some of these flavonoids and by virtue of widely consumed fruit, may modulate the intestinal microflora. SIGNIFICANCE AND IMPACT OF THE STUDY: Currently, a limited number of naturally occurring compounds have demonstrated their potential in inhibition of cell-cell communications; therefore, citrus flavonoids may be useful as lead compounds for the development of antipathogenic agents. PMID- 20163490 TI - Predator-hunting success and prey vulnerability: quantifying the spatial scale over which lethal and non-lethal effects of predation occur. AB - 1. The shape of the function linking predator-attack success rate with distance to predator-concealing cover, or prey refuge, will affect population dynamics, distribution patterns and community trophic structure. Theory predicts that predator-attack success should decline exponentially with distance from predator concealing cover, resulting in a threshold distance value above which there is little change in risk. Animals should then completely avoid areas of otherwise suitable habitat below this threshold, except when starvation risk exceeds predation risk. 2. We measured the shape of the function linking attack success with distance from cover in a system of Eurasian Sparrowhawks Accipiter nisus attacking (n = 445) and killing (n = 71) Redshanks Tringa totanus. We then determined if there was a threshold value and whether redshanks avoided areas below this threshold. 3. Sparrowhawk success rate with distance to predator concealing cover declined exponentially with a threshold value of approximately 30 m. Redshanks used habitat above the threshold according to profitability and only fed below it, on average, in cold weather when starvation risk can be imminently high. Above about 5 degrees C, 26% of available habitat was avoided. 4. Our data support the hypothesis that predators create discrete areas with respect to cover that are avoided by prey. Large areas of suitable habitat may be unused, except in times of high starvation risk, when such areas may provide a foraging reserve, with large implications for population distribution and dynamics. 5. Our results are generated from a system in which predators attack their prey from concealing cover. But in the theoretically identical reverse scenario where the prey animal's distance from protective cover determines predation risk, such non-lethal effects will be equally important, especially in heavily fragmented landscapes. PMID- 20163491 TI - Mating behaviour, life history and adaptation to insecticides determine species exclusion between whiteflies. AB - 1. Negative interspecific interactions, such as resource competition or reproductive interference, can lead to the displacement of species (species exclusion). 2. Here, we investigated the effect of life history, mating behaviour and adaptation to insecticides on species exclusion between cryptic whitefly species that make up the Bemisia tabaci species complex. We conducted population cage experiments independently in China, Australia, the United States and Israel to observe patterns of species exclusion between an invasive species commonly referred to as the B biotype and three other species commonly known as biotypes ZHJ1, AN and Q. 3. Although experimental conditions and species varied between regions, we were able to predict the observed patterns of exclusion in each region using a stochastic model that incorporated data on development time, mating behaviour and resistance to insecticides. 4. Between-species variation in mating behaviour was a more significant factor affecting species exclusion than variation in development time. Specifically, the ability of B to copulate more effectively than other species resulted in a faster rate of population increase for B, as well as a reduced rate of population growth for other species, leading to species exclusion. The greater ability of B to evolve resistance to insecticides also contributed to exclusion of other species in some cases. 5. Results indicate that an integrative analysis of the consequences of variation in life-history traits, mating behaviours and adaption to insecticides could provide a robust framework for predicting species exclusion following whitefly invasions. PMID- 20163492 TI - The interacting effects of temperature and food chain length on trophic abundance and ecosystem function. AB - 1. While much is known about the independent effects of trophic structure and temperature on density and ecosystem processes, less is known about the interaction(s) between the two. 2. We manipulated the temperature of laboratory based bacteria-protist communities that contained communities with one, two, or three trophic levels, and recorded species' densities and bacterial decomposition. 3. Temperature, food chain length and their interaction produced significant responses in microbial density and bacterial decomposition. Prey and resource density expressed different patterns of temperature dependency during different phases of population dynamics. The addition of a predator altered the temperature-density relationship of prey, from a unimodal trend to a negative one. Bacterial decomposition was greatest in the presence of consumers at higher temperatures. 4. These results are qualitatively consistent with a recent model of direct and indirect temperature effects on resource-consumer population dynamics. Results highlight and reinforce the importance of indirect effects of temperature mediated through trophic interactions. Understanding and predicting the consequences of environmental change will require that indirect effects, trophic structure, and individual species' tolerances be incorporated into theory and models. PMID- 20163493 TI - Atriofascicular tract with dual pathway property. PMID- 20163495 TI - Pharmacological activation of IKr impairs conduction in guinea pig hearts. AB - INTRODUCTION: The hERG (Kv11.1) potassium channel underlies cardiac I(Kr) and is important for cardiac repolarization. Recently, hERG agonists have emerged as potential antiarrhythmic drugs. As modulation of outward potassium currents has been suggested to modulate cardiac conduction, we tested the hypothesis that pharmacological activation of I(Kr) results in impaired cardiac conduction. METHODS AND RESULTS: Cardiac conduction was assessed in Langendorff-perfused guinea pig hearts. Application of the hERG agonist NS3623 (10 microM) prolonged the QRS rate dependently. A significant prolongation (16 +/- 6%) was observed at short basic cycle length (BCL 90 ms) but not at longer cycle lengths (BCL 250 ms). The effect could be reversed by the I(Kr) blocker E4031 (1 microM). While partial I(Na) inhibition with flecainide (1 microM) alone prolonged the QRS (34 +/- 3%, BCL 250 ms), the QRS was further prolonged by 19 +/- 2% when NS3623 was added in the presence of flecainide. These data suggest that the effect of NS3623 was dependent on sodium channel availability. Surprisingly, in the presence of the voltage sensitive dye di-4-ANEPPS a similar potentiation of the effect of NS3623 was observed. With di-4-ANEPPS, NS3623 prolonged the QRS significantly (26 +/- 4%, BCL 250 ms) compared to control with a corresponding decrease in conduction velocity. CONCLUSION: Pharmacological activation of I(Kr) by the hERG agonist NS3623 impairs cardiac conduction. The effect is dependent on sodium channel availability. These findings suggest a role for I(Kr) in modulating cardiac conduction and may have implications for the use of hERG agonists as antiarrhythmic drugs. PMID- 20163496 TI - Capsule endoscopy in examination of esophagus for lesions after radiofrequency catheter ablation: a potential tool to select patients with increased risk of complications. AB - BACKGROUND: Esophageal injury can result from left atrial radiofrequency ablation (RFA) therapy, with added concern because of its possible relationship to the development of atrial-esophageal (A-E) fistulas. OBJECTIVE: Evaluate utility of esophageal capsule endoscopy to detect esophageal lesions as a complication of RFA therapy in the treatment of atrial fibrillation (AF). METHODS: Consecutive patients with AF who underwent left atrial RFA therapy and received capsule endoscopy within 48 hours postablation. Video was reviewed by a single gastroenterologist. The medical records were also reviewed for symptoms immediately postablation and at the 3-month follow-up. RESULTS: A total of 93 consecutive patients were included and 88 completed the study and were analyzed. The prevalence of esophageal lesions was 17% (15/88 patients). Nine percent (8/88) of these patients had lesions anatomically consistent with the location of the ablation catheter. Six patients with positive capsule findings had symptoms of chest pain (3/6, 50%), throat pain (2/6, 33%), nausea (1/6, 17%), and abdominal pain (1/6, 17%). An additional 24 patients were symptomatic postablation, but with normal capsule findings. All patients with identified lesions by capsule endoscopy received oral proton pump inhibitor therapy, and were instructed to contact the Cleveland Clinic in the event of worsening symptoms. No delayed complications were reported at the 3-month follow-up. CONCLUSION: This study supports the use of capsule endoscopy as a tool for the detection of esophageal injury post-RFA therapy. PillCam ESO is well tolerated and provides satisfactory images of the areas of interest in the esophagus without potential risk related to insufflation with regular esophagogastroduodenoscopy. PMID- 20163497 TI - Genetic and environmental influences on the transmission of parental depression to children's depression and conduct disturbance: an extended Children of Twins study. AB - BACKGROUND: Despite the increased risk of depression and conduct problems in children of depressed parents, the mechanism by which parental depression affects their children's behavioral and emotional functioning is not well understood. The present study was undertaken to determine whether parental depression represents a genuine environmental risk factor in children's psychopathology, or whether children's depression/conduct can be explained as a secondary consequence of the genetic liability transmitted from parents to their offspring. METHODS: Children of Twins (COT) data collected on 2,674 adult female and male twins, their spouses, and 2,940 of their children were used to address whether genetic and/or family environmental factors best account for the association between depression in parents and depression and conduct problems in their children. Data collected on juvenile twins from the Virginia Twin Study of Adolescent Behavioral Development (VTSABD) were also included to estimate child-specific genetic and environmental influences apart from those effects arising from the transmission of the parental depression itself. The fit of alternative Children of Twin models were evaluated using the statistical program Mx. RESULTS: The most compelling model for the association between parental and juvenile depression was a model of direct environmental risk. Both family environmental and genetic factors accounted for the association between parental depression and child conduct disturbance. CONCLUSIONS: These findings illustrate how a genetically mediated behavior such as parental depression can have both an environmental and genetic impact on children's behavior. We find developmentally specific genetic factors underlying risk to juvenile and adult depression. A shared genetic liability influences both parental depression and juvenile conduct disturbance, implicating child conduct disturbance (CD) as an early indicator of genetic risk for depression in adulthood. In summary, our analyses demonstrate differences in the impact of parental depression on different forms of child psychopathology, and at various stages of development. PMID- 20163498 TI - Identification of the duplicated genes for S-adenosyl-l-methionine synthetase (metK1-sp and metK2-sp) in Streptomyces peucetius var. caesius ATCC 27952. AB - AIMS: To characterize the function of both metK1-sp (sp1190) and metK2-sp (sp1566) in vitro and in vivo, and to study the regulation of doxorubicin production by overexpressing the metK. METHODS AND RESULTS: We cloned two orfs into pET32a(+) respectively, and the formation of S-Adenosyl-l-methionine was clearly observed in the in vitro enzyme assays as functional MetKs. Reverse transcriptase polymerase chain reaction (PCR) analysis indicated that the transcripts for the metK1-sp were repressed as Streptomyces cells entered the decline phase, whereas that of the metK2-sp was induced, suggesting that these MetK proteins may be important for the growth and the regulation of secondary metabolites during the stationary growth phase, whether considered together or separately. Furthermore, we found that the introduction of high-copy-number plasmids containing the metK1-sp and metK2-sp resulted in 2.1- and 1.4-fold greater levels of doxorubicin production than the control transformants containing only the vector, respectively. We also attempted to disrupt the metK sp and found that doxorubicin production from the metK1-sp-deleted mutant (Streptomyces peucetius/pNN1) was reduced when compared to the parent strain (S. peucetius var. caesius ATCC 27952). CONCLUSIONS: The results of this study indicated that two metK are differentially expressed during cell growth, and that the expressions of the two metK genes are differentially regulated under the same conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: Streptomyces peucetius var. caesius contains two genes, metK1-sp and metK2-sp, which encode functional S adenosyl-l-methionine synthetase (MetK). The degree of homology (90% identity) found between the two genes shows that metK1-sp and metK2-sp are duplicated genes. Although there is currently no evidence for the relationship of the duplicated metK genes involved in the regulation of doxorubicin production, metK1 sp and metK2-sp may play a role in controlling the stimulation of antibiotic production during secondary metabolism. PMID- 20163499 TI - Rhizobacterially induced protection of watermelon against Didymella bryoniae. AB - AIMS: To identify rhizobacteria from the Mekong Delta of Vietnam, which can systemically protect watermelon against Didymella bryoniae and elucidate the mechanisms involved in the protection conferred by isolate Pseudomonas aeruginosa 23(1-1). METHODS AND RESULTS: Bacteria were isolated from watermelon roots and their antagonistic ability tested in vitro. Of 190 strains, 68 were able to inhibit D. bryoniae by production of antibiotics. Four strains were able to reduce foliar infection by D. bryoniae when applied to watermelon seeds before sowing. Strain Ps. aeruginosa 23(1-1) was chosen for investigations of the mechanisms involved in protection and ability to control disease under field conditions. In the field, the bacterium was able to significantly reduce disease in two consecutive seasons and increase yield. Furthermore, it colonized watermelon plants endophytically, with higher numbers in plants infected by D. bryoniae than in noninoculated plants. To elucidate the mechanisms involved in protection, the infection biology of the pathogen was studied in bacterially treated and control plants. Pseudomonas aeruginosa 23(1-1) treatment inhibited pathogen penetration and this was associated with hydrogen peroxide accumulation, increased peroxidase activity and occurrence of new peroxidase isoforms, thus indicating that resistance was induced. CONCLUSIONS: The endophytic bacterium Ps. aeruginosa 23(1-1) can control D. bryoniae in watermelon by antibiosis and induced resistance under greenhouse and field conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings suggest that rhizobacteria from native soils in Vietnam can be used to control gummy stem blight of watermelon through various mechanisms including induction of resistance. PMID- 20163500 TI - Rapid quantification of viable legionellae in water and biofilm using ethidium monoazide coupled with real-time quantitative PCR. AB - AIMS: To optimize ethidium monoazide (EMA) coupled with real-time quantitative PCR (qPCR) and to evaluate its environmental applicability on quantifying viable legionellae in water and biofilm of cooling towers and hot water systems. METHODS AND RESULTS: EMA (0.9-45.5 microg ml(-1)) and propidium monoazide (PMA, 0.9 and 2.3 microg ml(-1)) combined with qPCR (i.e. EMA-qPCR and PMA-qPCR, respectively) were applied to unheated and heated (70 degrees C for 30 min) Legionella pneumophila to quantify viable cells, which was also simultaneously determined by BacLight Bacterial Viability kit with epifluorogenic microscopic enumeration (BacLight-EM). The effects of nontarget microflora and sample matrix on the performance of EMA-qPCR were also evaluated. In comparison with BacLight-EM results, qPCR with EMA at 2.3 microg ml(-1) was determined as the optimal EMA qPCR assay, which performed equally well as PMA-qPCR for unheated Leg. pneumophila but better than PMA-qPCR for heated Leg. pneumophila (P < 0.05). Moreover, qPCR with EMA at 2.3 microg ml(-1) accurately quantified viable Leg. pneumophila, Legionella anisa and Legionella-like amoebal pathogens 6 (LLAP 6) without interferences by heated legionellae, unheated nonlegionellae cells and cooling tower water matrix (P > 0.05). As for water and biofilm samples collected from cooling towers and hot water systems, the viable legionellae counts determined by EMA-qPCR were mostly greater than the culturable counts by culture assay but consistently lower than the total cell counts quantified by qPCR. CONCLUSIONS: The qPCR with EMA at 2.3 microg ml(-1) may accurately quantify viable legionellae (including fastidious LLAP 6) and Leg. pneumophila pretreated with superheating and is applicable for water and biofilm samples obtained from cooling towers and hot water systems. SIGNIFICANCE AND IMPACT OF THE STUDY: The EMA-qPCR assay may be useful in environmental surveillance for viable legionellae and in evaluation of superheating efficacy against legionellae. PMID- 20163501 TI - How do regional factors influence psoriasis patient care in Germany? AB - BACKGROUND: Two national surveys conducted in 2005 and 2007 indicated deficits in psoriasis care in Germany, although there has been a notable nationwide improvement within this period. It remained unclear whether regional differences in psoriasis health care have an influence on patient outcomes in Germany. AIM: Assessment of regional differences in the health care situation of patient with psoriasis in Germany. PATIENTS AND METHODS: Nation-wide cross-sectional study in 130 dermatological practices and clinics. Regional classification was based on the affiliation to the Associations of Statutory Health Insurance Physicians. A panel of experts developed eight criteria as indicators of quality of care, among them clinical characteristics and severity of psoriasis (PASI), previous treatments, quality of life and patient-relevant therapeutic benefits. RESULTS: Care indicators showed marked regional differences. The proportion of patients with preceding systemic or biologic treatment varied between regions. Those regions with high proportions had better results in patient-reported outcomes. CONCLUSIONS: Differences in economic and regulatory conditions of health care might account for the observed regional variations. Thus, further analyses of these factors are of great importance to assure consistent psoriasis health care in Germany. PMID- 20163502 TI - Allergic contact dermatitis caused by the blue pigment VINAMON(r) Blue BX FW - a phthalocyanine blue in a vinyl glove. AB - A 44-year-old metalworker suffered from severe hand eczema in spite of treatment with corticosteroid ointments. He had been using protective cotton gloves with blue PVC anti-slip dots on the finger tips. On clinical examination, the backs of both hands were erythematous and thickened while the finger tips showed vesicles. There was a positive patch test reaction to the blue PVC dots of an unworn cotton glove at 72, 96, 120 hours. To identify the causative chemicals, we carried out further patch tests using ingredients of the glove and cupric sulfate. The patient reacted to the blue dye VYNAMON((r)) Blue BX FW (PB 15) at two concentrations - 10% at 72 and 96 hours, and 50% at 48 and 72 hours. This dye is a very strong and brilliant blue with red-copper tones and resistant to fire and weathering. The cupric-phthalocyanine complexes are used as pigments in cosmetics (e. g. CI 74160, 74180, 74260). To the best of our knowledge, no allergic reactions to this dye have been described, particularly not in gloves. PMID- 20163503 TI - Facticious disorders in dermatology. AB - Facticious Disorders are self inflicted skin lesions and includes the creation of physical or psychiatric symptoms in oneself or other reference persons. In dermatology frequently, there are mechanical injuries by pressures, friction, occlusion, biting, cutting, stabbing, thermal burns or self-inflicted infections with wound-healing impairment, abscesses, mutilations or damages by acids and other toxic to the skin. The current classification differentiates between four groups: 1. Dermatitis artefacta syndrome in the narrower sense as unconscious/dissociated self-injury, 2. Dermatitis paraartefacta syndrome: Disorders of impulse control, often as manipulation of an existing specific dermatosis (often semi-conscious, admitted - self-injury), 3. Malingering: consciously simulated injuries and diseases to obtain material gain, 4. special forms, such as the Gardner Diamond Syndrome, Munchhausen Syndrome and Munchhausen by-Proxy Syndrome. This categorization is helpful in understanding the different pathogenic mechanisms and the psychodynamics involved, as well as in developing various therapeutic avenues and determining the prognosis. PMID- 20163504 TI - Sofa dermatitis. AB - Furniture components can cause contact allergies. In the last years several cases of eczema after sofa contact have been reported. Typically the skin lesions develop on the back, the buttocks, the dorsal aspects of the thighs and arms and are often very resistant to topical corticoid therapy. Dimethylfumarate (DMF) is postulated to be the causative agent for this Type IV hypersensitivity reaction. DMF is an antimicrobial substance, which is used in asian upholstered furniture industry amongst others. We report the case of a 65-year old patient with generalised severely itching maculopapular, partly eczematous skin lesions on the buttocks, back, abdomen and arms. The resistance to therapy, several relapses after discharge from hospital as well as the detailed history lead us to the tentative diagnosis. The sofa dermatitis was proven by positive patch testing with furniture material and dimethylfumarate. PMID- 20163506 TI - The role of phenotypic plasticity in responses of hunted thinhorn sheep ram horn growth to changing climate conditions. AB - When phenotypic change occurs over time in wildlife populations, it can be difficult to determine to what degree it is because of genetic effects or phenotypic plasticity. Here, we assess phenotypic changes over time in horn length and volume of thinhorn sheep (Ovis dalli) rams from Yukon Territory, Canada. We considered 42 years of horn growth from over 50,000 growth measurements in over 8000 individuals. We found that weather explained a large proportion of the annual fluctuation in horn growth, being particularly sensitive to spring weather. Only 2.5% of variance in horn length growth could be explained by an individual effect, and thus any genetic changes over the time period could only have had a small effect on phenotypes. Our findings allow insight into the capacity for horn morphology to react to selection pressures and demonstrate the overall importance of climate in determining growth. PMID- 20163505 TI - [A rare case of local relapsing oral melanoma]. AB - Melanoma of the oral mucosa is an extremely rare tumor. At the time of diagnosis most melanomas are in an advanced stage because of few clinical signs. Therefore the prognosis of melanoma of the oral mucosa is often very poor. We present a 48 year-old patient with melanoma of the oral mucosa first diagnosed 22 years ago. Over 20 years several wide excisions were necessary because of multiple local relapses. Eventually, the patient died from brain metastases. PMID- 20163507 TI - Selection pressures have caused genome-wide population differentiation of Anthoxanthum odoratum despite the potential for high gene flow. AB - The extent to which divergent selection can drive genome-wide population differentiation remains unclear. Theory predicts that in the face of ongoing gene flow, population differentiation should be apparent only at those markers that are directly or indirectly (i.e. through linkage) under selection. However, if reproductive barriers limit gene flow, genome-wide population differentiation may occur even in geographically proximate populations. Some insight into the link between selection and genetic differentiation in the presence of ongoing gene flow can come from long-term experiments such as The Park Grass Experiment, which has been running for over 150 years, and provides a unique example of a heterogeneous environment with a long and detailed history. Fertilizer treatments applied in the Park Grass Experiment have led to rapid evolutionary change in sweet vernal grass Anthoxanthum odoratum, but until now, nothing was known of how these changes would be reflected in neutral molecular markers. We have genotyped ten A. odoratum populations from the Park Grass Experiment using Amplified Fragment Length Polymorphisms (AFLPs). Our data show that nutrient additions have resulted in genome-wide divergence among plots despite the high potential for ongoing gene flow. This provides a well-documented example of concordance between genomes and environmental conditions that has arisen in continuous populations across a time span of fewer than 75 generations. PMID- 20163509 TI - Comparison of a food frequency questionnaire with an online dietary assessment tool for assessing preschool children's dietary intake. AB - BACKGROUND: It is important to assess the dietary habits of children as they progress from early childhood to adolescence. However, there are few validated tools available to assess the diet of this group of children. The present study aimed to investigate the relative validity of a food frequency questionnaire (FFQ) developed for use in a biennial longitudinal study. METHODS: The parents of 216 Belgian-Flemish preschool children completed a FFQ (including questions on 77 food groups) and an online dietary assessment tool for three nonconsecutive days on their child's diet. Intakes of energy, macronutrients, fibre, calcium and 20 food groups recorded by both methods were compared using Spearman's correlations, Wilcoxon's signed rank test and Bland and Altman analyses. RESULTS: At the group level, good agreement was found for energy, fat and protein intake, an overestimation was found for carbohydrates (5.6%) and fibre (13.3%), and an underestimation was found for calcium (9%). For the food groups, overestimation as well as underestimation and good agreement were found, although overestimation was most common. Good agreement was found in ranking the children's fruit (r = 0.53), beverages (r = 0.58-0.76), soup (r = 0.51), breakfast cereals (r = 0.55) and calcium (r = 0.59) intake according to both methods. CONCLUSION: The results obtained revealed that the FFQ was a useful alternative for estimating energy and macronutrient intake at a group level; however, when used to estimate fibre and calcium intake, respectively, over- and underestimation need to be considered. The short reference period (3 days) may have compromised agreement in ranking and agreement at the individual level. PMID- 20163508 TI - Bowel habit, diet and body weight in preadolescent children. AB - BACKGROUND: The possible influence of diet and body weight on bowel habit in children is unknown. The present study aimed to investigate the inter relationships between bowel function, excess body weight and dietary intake in a group of preadolescent children. METHODS: Eighty-four preadolescent children aged 7-10 years were recruited [mean (SD) age 9.7 (1.0) years]. All children completed a bowel habit diary, examining specific parameters of bowel function and a weighed food inventory concurrently for seven consecutive days. Height and weight measurements were also taken. Children were grouped according to whether they met dietary recommendations and by overweight status; differences in bowel function between the groups were then analysed. RESULTS: Children who exceeded reference values for fat were more likely to report an incidence of straining to start (P = 0.005) and pain during defaecation (P = 0.021). Subjects who met protein recommendations were less likely to report incomplete evacuation (P = 0.000) and those who met zinc recommendations were less likely to report pain during defaecation (P = 0.044). Excess body weight (according to International Obesity Task Force cut-offs) was also associated with poor bowel habit, with overweight and obese children reporting lower defaecation frequency and a higher incidence of straining and feelings of incomplete evacuation, although these findings were not statistically significant. Defaecation frequency in healthy children was 1.4 defaecations per day compared to 1.2 defaecations for overweight and obese children. CONCLUSION: A poor diet that fails to meet dietary recommendations as well as being overweight and obese appears to be associated with increased defaecation problems in preadolescent children. PMID- 20163510 TI - An expanded role for dietitians in maximising retention in nutrition and lifestyle intervention trials: implications for clinical practice. AB - The demand for clinical trials targeting lifestyle intervention has increased as a result of the escalation in obesity, diabetes mellitus and cardiovascular disease. Little is published about the strategies that dietitians have used to successfully screen potential study volunteers, implement interventions and maximise adherence and retention in large multicentre National Institutes of Health funded nutrition and lifestyle intervention clinical trials. This paper discusses an expanded role for the contributions of dietitians as members of an interdisciplinary team based on research experiences in the Diabetes Control and Complications Trial, Diabetes Prevention Program and Look AHEAD (Action for Health in Diabetes). Many of the strategies and insights discussed are also relevant to effective clinical practice. Dietitians need to broaden their scope of practice so that they are integrated proactively into the screening and intervention phases of large clinical trials to maximise retention and adherence to assigned nutrition, lifestyle and behavioural interventions. The skills of dietitians are a unique fit for this work and it is important that investigators and project managers consider including them in both the screening and intervention phases of such clinical trials to maximise retention results. PMID- 20163511 TI - An evaluation of an obesity and weight management resource pack. AB - BACKGROUND: The prevention and treatment of overweight and obesity is a priority for all health professionals and requires resources that are regularly evaluated to ensure that they meet the needs of their target population. Dietitians in Obesity Management UK (DOM UK), a specialist group of the British Dietetic Association, commissioned an evaluation of their resources. These have been developed for use by Dietitians to determine the uptake and implementation of DOM UK resources in dietetic practice, as well as the opinions and suggestions of Dietitians concerning the resource pack. METHODS: A random sample of 20% (n = 33) of the 165 Dietitians who had ordered resources were selected from the DOM UK database along with 20% of DOM UK members who had not (n = 38). Data were then collected using telephone-administered questionnaires. RESULTS: Most of the Dietitians who used the resources favoured them because they improved their consultations and were liked by patients. Resources 'j' (controlling your portions) and 'k' (planning your meals) were most frequently used. However, the cost of the pack was a deterrent to both new and repeat orders. The evaluation also revealed that 17% of DOM UK members were unaware of these resources and 23% who ordered them were unaware that online samples were available. CONCLUSION: The evaluation showed that most Dietitians who used the resources found them very useful especially resources concerning meal planning and portion sizes. However, concerns about cost and the need for greater awareness about the resources among Dietitians were highlighted. PMID- 20163512 TI - Changes in fitness, body mass index and obesity in 9-10 year olds. AB - BACKGROUND: The prevalence of obesity in children has increased substantially in recent years and, paediatric obesity and poor fitness are risk factors for disease. The present study aimed to assess changes in body mass index (BMI), the prevalence of obesity and changes in aerobic endurance over time in 9-10-year-old schoolchildren. METHODS: Participants were recruited by the SportsLinx project from primary schools across Liverpool. Height and weight data were used to calculate BMI. The prevalence of obesity and overweight were estimated using age- and sex-specific cut-off points. Performance on the 20-m multi-stage shuttle runs test (20 mMST) was used as a marker of aerobic endurance. Data were available for 13,418 (6572 boys, 6846 girls) 9-10-year-old children. Analysis of covariance was completed to assess year-on-year changes in BMI controlling for deprivation (IMD) and 20 mMST performance, and 20 mMST performance controlling for IMD and BMI. RESULTS: No significant changes in BMI from baseline were observed (P > 0.05). Obesity prevalence reduced in girls (2005 = 10.3%, 2008 = 8.52% in 2008). The data for boys showed no reductions in prevalence (2005 = 6.77%, 2008 = 7.87%). The most recent cohort for boys and two most recent cohorts for girls had lower levels of aerobic endurance than baseline (2004-2005) (P or =140 mmHg, diastolic blood pressure > or =90 mmHg or from self-reported clinical diagnosis, including the use of antihypertensive medications. Incident hypertension was defined as an absence of hypertension at baseline but presence of hypertension at the follow-up visit. RESULTS: One hundred ninety-three subjects (34.3%) had developed hypertension at 5-year follow-up. After adjusting for age, gender, baseline blood pressure and other risk factors, narrower retinal arterioles at baseline was significantly associated with an increased risk of incident hypertension (odds ratio per standard deviation decrease in arteriolar diameter: 1.53, 95% confidence interval: 1.08-2.18). CONCLUSIONS: Our findings support the concept that arteriolar narrowing, evident in the retina, signals an increased risk of developing hypertension in Japanese persons. PMID- 20163537 TI - In vivo visualization of glomerular microcirculation and hyperfiltration in streptozotocin-induced diabetic rats. AB - OBJECTIVES: Knowledge of glomerular structural and hemodynamic changes in vivo is still limited under diabetic conditions. In this study, we examined the alterations in glomerular structure and permeability of macromolecules and the effects of telmisartan using a confocal laser microscope. METHODS: Diabetes was induced by injecting streptozotocin. After 4 and 8 weeks, the filtration and permeability of differently sized compounds across the glomerular capillaries were visualized using a confocal laser microscope by injecting 500-kilodalton and 40-kilodalton dextran. At 7 weeks, some diabetic rats were treated with telmisartan for 1 week. The permeation of the 40-kilodalton dextran across the glomerular capillaries into Bowman's space was quantified. Glomerular volume, diameters of the afferent and efferent arterioles, and glomerular permeability were compared. RESULTS: Glomerular volume was significantly increased in the diabetic rats, and there was heterogeneity in the glomerular volumes. The diameter ratio of the afferent to efferent arterioles significantly increased, and there was increased glomerular permeability in the diabetic rats compared with the control rats. Telmisartan treatment reduced glomerular permeability without affecting glomerular volume. CONCLUSIONS: These data showed that glomerular hyperfiltration started from the early phase of diabetes, accompanied by dilatation of afferent arterioles and glomerular hypertrophy. PMID- 20163538 TI - Modulation of microvascular smooth muscle adhesion and mechanotransduction by integrin-linked kinase. AB - OBJECTIVE: In this study, we investigated the involvement of integrin-linked kinase (ILK) in the adhesion of arteriolar vascular smooth muscle cells (VSMC) to fibronectin (FN) and in the mechano-responsiveness of VSMC focal adhesions (FA). METHODS: ILK was visualized in VSMC by expressing EGFP-ILK and it was knocked down using ILK-shRNA constructs. Atomic force microscopy (AFM) was used to characterize VSMC interactions with FN, VSMC stiffness and to apply and measure forces at a VSMC single FA site. RESULTS: ILK was localized to FA and silencing ILK promoted cell spreading, enhanced cell adhesion, reduced cell proliferation and reduced downstream phosphorylation of GSK-3beta and PKB/Akt. AFM studies demonstrated that silencing ILK enhanced alpha5beta1 integrin adhesion to FN and enhanced VSMC contraction in response to a pulling force applied at the level of a single FN-FA site. CONCLUSIONS: ILK functions in arteriolar VSMC appear linked to multiple signaling pathways and processes that inhibit cell spreading, cell adhesion, FA formation, adhesion to FN and the mechano-responsiveness of FN-FA sites. PMID- 20163539 TI - Rapamycin inhibits VEGF-induced microvascular hyperpermeability in vivo. AB - OBJECTIVE: To test the hypothesis that rapamycin inhibits induced microvascular hyperpermeability directly in vivo. METHODS: Male golden Syrian hamsters (80-120 g) were treated with either rapamycin (at 0.1, 0.5, 2, and 10 mg/kg i.p.) or vehicle at 24 hours and at 1 hour prior to preparation of the cheek pouch. Caveolin-1 scaffolding (1 mg/kg; positive inhibitory control) was injected i.p. 24 hours prior to the experiment. 10(-8) M vascular endothelial growth factor (VEGF) or 10(-7) M platelet-activating factor (PAF) were topically applied to the cheek pouch. Microvascular permeability and arteriolar diameter were assessed using integrated optical intensity (IOI) and vascular wall imaging, respectively. RESULTS: Rapamycin at 0.1 and 0.5 mg/kg significantly reduced VEGF-stimulated mean IOI from 63.0 +/- 4.2 to 9.7 +/- 5.0 (85% reduction, P < 0.001) and 3.6 +/- 2.7 (95% reduction, P < 0.001), respectively. Rapamycin at 2 mg/kg also lowered VEGF-stimulated hyperpermeability (40% reduction, P < 0.05). However, 10 mg/kg rapamycin increased VEGF-induced microvascular hyperpermeability. Rapamycin at 0.5 mg/kg attenuated VEGF-induced vasodilation and PAF-induced hyperpermeability, but did not inhibit PAF-induced vasoconstriction. CONCLUSIONS: At therapeutically relevant concentrations, rapamycin inhibits VEGF- and PAF-induced microvascular permeability. This inhibition is (i) a direct effect on the endothelial barrier, and (ii) independent of arteriolar vasodilation. Rapamycin at 10 mg/kg stimulates effectors that increase microvascular permeability. PMID- 20163540 TI - Impact of epoxyeicosatrienoic acids in lung ischemia-reperfusion injury. AB - OBJECTIVE: Epoxyeicosatrienoic acids (EETs) are protective in both myocardial and brain ischemia, variously attributed to activation of K(ATP) channels or blockade of adhesion molecule upregulation. In this study, we tested whether EETs would be protective in lung ischemia-reperfusion injury. METHODS: The filtration coefficient (K(f)), a measure of endothelial permeability, and expression of the adhesion molecules vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) were measured after 45 minutes ischemia and 30 minutes reperfusion in isolated rat lungs. RESULTS: K(f) increased significantly after ischemia-reperfusion alone vs time controls, an effect dependent upon extracellular Ca(2+) although not on the EET-regulated channel TRPV4. Inhibition of endogenous EET degradation or administration of exogenous 11,12- or 14,-15-EET at reperfusion significantly limited the permeability response to ischemia reperfusion. The beneficial effect of 11,12-EET was not prevented by blockade of K(ATP) channels nor by blockade of TRPV4. Finally, 11,12-EET-dependent alteration in adhesion molecules expression is unlikely to explain its beneficial effect, since the expression of the adhesion molecules VCAM and ICAM in lung after ischemia-reperfusion was similar to that in controls. CONCLUSION: EETs are beneficial in the setting of lung ischemia-reperfusion, when administered at reperfusion. However, further study will be needed to elucidate the mechanism of action. PMID- 20163541 TI - Decreased arteriolar tetrahydrobiopterin is linked to superoxide generation from nitric oxide synthase in mice fed high salt. AB - OBJECTIVE: Impaired endothelium-dependent arteriolar dilation in mice fed high salt (HS) is due to local oxidation of nitric oxide (NO) by superoxide anion (O(2) (-)). We explored the possibility that "uncoupled" endothelial nitric oxide synthase (eNOS) is the source of this O(2) (-). METHODS: Levels of L-arginine (L Arg), tetrahydrobiopterin (BH(4)), and O(2) (-) (hydroethidine oxidation) were measured in spinotrapezius muscle arterioles of mice fed normal salt (0.45%, NS) or (4%, HS) diets for 4 weeks, with or without dietary L-Arg supplementation. The contribution of NO to endothelium-dependent dilation was determined from the effect of N(omega)-nitro-L-arginine methyl ester (L-NAME) on responses to acetylcholine (ACh). RESULTS: Arterioles in HS mice had lower [BH(4)] and higher O(2) (-) levels than those in NS mice. ACh further increased arteriolar O(2) (-) in HS mice only. L-Arg supplementation prevented the reduction in [BH(4)] in arterioles of HS mice, and O(2) (-) was not elevated in these vessels. Compared to NS mice, arteriolar ACh responses were diminished and insensitive to L-NAME in HS mice, but not in HS mice supplemented with L-Arg. CONCLUSIONS: These findings suggest that eNOS uncoupling due to low [BH(4)] is responsible for O(2) (-) generation and reduced NO-dependent dilation in arterioles of mice fed a HS diet. PMID- 20163542 TI - Ecology and genetics of speciation in Ficedula flycatchers. AB - Birds have for long been popular study objects in speciation research. Being easy to observe in the field, they have traditionally been particularly important in studies of behavioural and ecological factors in speciation, whereas the genetic aspects of the process have been studied in other organisms, such as Drosophila. More recently, however, a stronger genetic focus has been placed on speciation research also in birds. Here, we review ecological, behavioural and genetic studies on speciation in the pied flycatcher (Ficedula hypoleuca) and the collared flycatcher (Ficedula albicollis). These well-studied birds provide among the few proposed examples of the process of reinforcement of premating isolation, and the evidence for reinforcement is strong. They are further characterized by having strong intrinsic postzygotic barriers (female hybrid sterility), yet the two species appear to be very similar ecologically. This is in stark contrast to another well-studied bird complex, Darwin's finches, in which the species differ vastly in ecologically important traits but have no developmental problems arising from genetic incompatibilities, and where no evidence for reinforcement is found. In the flycatchers, sex chromosome linkage of genes affecting traits associated with both pre- and postzygotic barriers to gene exchange is likely to facilitate reinforcement. We discuss whether such sex-linkage may be common in birds. The contrast between flycatchers and Darwin's finches indicate that speciation in birds cannot always be understood mainly as a result of divergent natural selection ('ecological speciation'), and generalizations from one system may lead us astray. We discuss to what extent insight from research on the flycatchers may point to fruitful avenues for future research on bird speciation and specifically call for a more systematic effort to simultaneously investigate ecology, behaviour and genetics of birds caught in the process of speciation. PMID- 20163543 TI - Fine scale genetic structure in the wild ancestor of maize (Zea mays ssp. parviglumis). AB - Analysis of fine scale genetic structure in continuous populations of outcrossing plant species has traditionally been limited by the availability of sufficient markers. We used a set of 468 SNPs to characterize fine-scale genetic structure within and between two dense stands of the wild ancestor of maize, teosinte (Zea mays ssp. parviglumis). Our analyses confirmed that teosinte is highly outcrossing and showed little population structure over short distances. We found that the two populations were clearly genetically differentiated, although the actual level of differentiation was low. Spatial autocorrelation of relatedness was observed within both sites but was somewhat stronger in one of the populations. Using principal component analysis, we found evidence for significant local differentiation in the population with stronger spatial autocorrelation. This differentiation was associated with pronounced shifts in the first two principal components along the field. These shifts corresponded to changes in allele frequencies, potentially due to local topographical features. There was little evidence for selection at individual loci as a contributing factor to differentiation. Our results demonstrate that significant local differentiation may, but need not, co-occur with spatial autocorrelation of relatedness. The present study represents one of the most detailed analyses of local genetic structure to date and provides a benchmark for future studies dealing with fine scale patterns of genetic diversity in natural plant populations. PMID- 20163544 TI - The use (or misuse) of microsatellite allelic distances in the context of inbreeding and conservation genetics. AB - In line with inbreeding theory, genetic diversity at a set of molecular markers may explain variation in fitness-associated traits in partially inbred populations, and such associations will appear as 'genotype-fitness correlations'. An individual genetic diversity index specifically used for microsatellites is 'mean d(2)', i.e. the mean squared distance between alleles. The original hypothesis for mean d(2)-fitness correlations assumes that mean d(2) captures fitness effects at both ends of the inbreeding-outbreeding spectrum. This hypothesis received strong criticism from work showing that even a plain diversity estimate such as multi-locus heterozygosity (MLH) outperforms mean d(2) as a predictor of the inbreeding coefficient and fitness in most realistic situations. Despite this critique, the mean d(2)-approach is still used frequently in ecological and evolutionary research, producing results suggesting that mean d(2) sometimes provides a stronger prediction of fitness than does MLH. In light of the critique, such results are unexpected, but potential explanations for them may exist (at least hypothetically), including scenarios based on close linkage and recent admixture. Nevertheless, a major caveat is that it is very difficult to predict a priori if mean d(2) will improve the genotype-fitness correlation, which in turn makes objective interpretations difficult. Mean d(2) fitness associations are potentially interesting, but the fact that we cannot easily understand them is problematic and should be thoroughly addressed in each study. Therefore, instead of hastily reached interpretations of mean d(2)-fitness correlations, conclusions need support from complementary analyses, e.g. verifying admixture of genetically structured populations. PMID- 20163545 TI - History vs. habitat type: explaining the genetic structure of European nine spined stickleback (Pungitius pungitius) populations. AB - The genetic structure of contemporary populations can be shaped by both their history and current ecological conditions. We assessed the relative importance of postglacial colonization history and habitat type in the patterns and degree of genetic diversity and differentiation in northern European nine-spined sticklebacks (Pungitius pungitius), using mitochondrial DNA (mtDNA) sequences and 12 nuclear microsatellite and insertion/deletion loci. The mtDNA analyses identified - and microsatellite analyses supported - the existence of two historically distinct lineages (eastern and western). The analyses of nuclear loci among 51 European sites revealed clear historically influenced and to minor degree habitat dependent, patterns of genetic diversity and differentiation. While the effect of habitat type on the levels of genetic variation (coastal > freshwater) and differentiation (freshwater > coastal) was clear, the levels of genetic variability and differentiation in the freshwater sites were independent of habitat type (viz. river, lake and pond). However, levels of genetic variability, together with estimates of historical effective population sizes, decreased dramatically and linearly with increasing latitude. These geographical patterns of genetic variability and differentiation suggest that the contemporary genetic structure of freshwater nine-spined sticklebacks has been strongly impacted by the founder events associated with postglacial colonization and less by current ecological conditions (cf. habitat type). In general, the results highlight the strong and persistent effects of postglacial colonization history on genetic structuring of northern European fauna and provide an unparalleled example of latitudinal trends in levels of genetic diversity. PMID- 20163546 TI - Cytoplasmic DNA variation and biogeography of Larix Mill. in northeast Asia. AB - Range-wide variation in 54 populations of Dahurian larch (Larix gmelinii) and related taxa in Northeast Asia was assessed with four mitochondrial PCR-RFLP and five chloroplast SSR markers. Eleven mitotypes and 115 chlorotypes were detected. The highest diversity was observed in the southern Russian Far East where hybrids of L. gmelinii, L. olgensis and L. kamtschatica are distributed. In contrast, only two mitotypes occurred in L. cajanderi and L. gmelinii. The Japanese larch (L. kaempferi) was found to be closely related to populations of L. kamtschatica inhabiting the Kuril Islands and South Sakhalin, populations from the northern part of Sakhalin being more closely related to continental species. In general, both mitochondrial (G(ST) = 0.786; N(ST) = 0.823) and chloroplast (G(ST) = 0.144; R(ST) = 0.432) markers showed a strong phylogeographical structure and evidence of isolation-by-distance. Yet both markers did not allow a clear delineation of species borders. In particular, and contrary to expectations, cpDNA was not significantly better than mtDNA at delineating species borders. This lack of concordance between morphological species and molecular markers could reflect extensive ancestral haplotype sharing and past and ongoing introgression. Finally the distribution of mtDNA and cpDNA variation suggests the presence of several refugia during Pleistocene glacial intervals. In particular, mtDNA and cpDNA reveal weak but visible differentiation between L. gmelinii and L. cajanderi, suggesting independent glacial histories of these species. PMID- 20163547 TI - Spatial and temporal changes in genetic structure of greenhouse and field populations of cabbage looper, Trichoplusia ni. AB - Trichoplusia ni is a subtropical moth that migrates annually from southern California to southern British Columbia, Canada where it invades vegetable greenhouses and field crops. The heated greenhouse environment has altered the natural extinction-recolonization dynamics of T. ni populations, and allows year round persistence in some locations. In addition, the extensive use of the biopesticide, Bacillus thuringiensis subspecies kurstaki (Bt) in some greenhouses has selected for resistance. Here we investigated the genetic structure of T. ni populations in British Columbia greenhouses and in field populations in California and British Columbia using amplified fragment length polymorphisms (AFLP) as related to patterns of Bt resistance. The majority of British Columbia field populations were similar to the California field populations, the potential source of migrants. However populations in two geographic areas with high concentrations of greenhouses showed local genetic differentiation. Some of these populations experienced severe bottlenecks over-winter and following Bt sprays. Greenhouse populations showed a pattern of isolation by distance and a strong positive relationship between genetic differentiation and levels of Bt resistance. These patterns indicate that greenhouses that sometimes support year round populations of T. ni and the ensuing strong bottlenecking effects following winter cleanups and Bt application cause genetic differentiation of T. ni populations. Long distance migrants to field populations contribute to genetic homogeneity of these. PMID- 20163548 TI - Genomic diversity, population structure, and migration following rapid range expansion in the Balsam poplar, Populus balsamifera. AB - Rapid range expansions can cause pervasive changes in the genetic diversity and structure of populations. The postglacial history of the Balsam Poplar, Populus balsamifera, involved the colonization of most of northern North America, an area largely covered by continental ice sheets during the last glacial maximum. To characterize how this expansion shaped genomic diversity within and among populations, we developed 412 SNP markers that we assayed for a range-wide sample of 474 individuals sampled from 34 populations. We complemented the SNP data set with DNA sequence data from 11 nuclear loci from 94 individuals, and used coalescent analyses to estimate historical population size, demographic growth, and patterns of migration. Bayesian clustering identified three geographically separated demes found in the Northern, Central, and Eastern portions of the species' range. These demes varied significantly in nucleotide diversity, the abundance of private polymorphisms, and population substructure. Most measures supported the Central deme as descended from the primary refuge of diversity. Both SNPs and sequence data suggested recent population growth, and coalescent analyses of historical migration suggested a massive expansion from the Centre to the North and East. Collectively, these data demonstrate the strong influence that range expansions exert on genomic diversity, both within local populations and across the range. Our results suggest that an in-depth knowledge of nucleotide diversity following expansion requires sampling within multiple populations, and highlight the utility of combining insights from different data types in population genomic studies. PMID- 20163549 TI - Geographic parthenogenesis and the common tea-tree stick insect of New Zealand. AB - Worldwide, parthenogenetic reproduction has evolved many times in the stick insects (Phasmatidae). Many parthenogenetic stick insects show the distribution pattern known as geographic parthenogenesis, in that they occupy habitats that are at higher altitude or latitude compared with their sexual relatives. Although it is often assumed that, in the short term, parthenogenetic populations will have a reproductive advantage over sexual populations; this is not necessarily the case. We present data on the distribution and evolutionary relationships of sexual and asexual populations of the New Zealand stick insect, Clitarchus hookeri. Males are common in the northern half of the species' range but rare or absent elsewhere, and we found that most C. hookeri from putative-parthenogenetic populations share a common ancestor. Female stick insects from bisexual populations of Clitarchus hookeri are capable of parthenogenetic reproduction, but those insects from putative-parthenogenetic populations produced few offspring via sexual reproduction when males were available. We found similar fertility (hatching success) in mated and virgin females. Mated females produce equal numbers of male and female offspring, with most hatching about 9-16 weeks after laying. In contrast, most eggs from unmated females took longer to hatch (21-23 weeks), and most offspring were female. It appears that all C. hookeri females are capable of parthenogenetic reproduction, and thus could benefit from the numerical advantage this yields. Nevertheless, our phylogeographic evidence shows that the majority of all-female populations over a wide geographic area originate from a single loss of sexual reproduction. PMID- 20163550 TI - Genetic consequences of introducing allopatric lineages of Bluestriped Snapper (Lutjanus kasmira) to Hawaii. AB - A half century ago the State of Hawaii began a remarkable, if unintentional, experiment on the population genetics of introduced species, by releasing 2431 Bluestriped Snappers (Lutjanus kasmira) from the Marquesas Islands in 1958 and 728 conspecifics from the Society Islands in 1961. By 1992 L. kasmira had spread across the entire archipelago, including locations 2000 km from the release site. Genetic surveys of the source populations reveal diagnostic differences in the mtDNA control region (d = 3.8%; phi(ST) = 0.734, P < 0.001) and significant allele frequency differences at nuclear DNA loci (F(ST) = 0.49; P < 0.001). These findings, which indicate that source populations have been isolated for approximately half a million years, set the stage for a survey of the Hawaiian Archipelago (N = 385) to determine the success of these introductions in terms of genetic diversity and breeding behaviour. Both Marquesas and Society mtDNA lineages were detected at each survey site across the Hawaiian Archipelago, at about the same proportion or slightly less than the original 3.4:1 introduction ratio. Nuclear allele frequencies and parentage tests demonstrate that the two source populations are freely interbreeding. The introduction of 2431 Marquesan founders produced only a slight reduction in mtDNA diversity (17%), while the 728 Society founders produced a greater reduction in haplotype diversity (41%). We find no evidence of genetic bottlenecks between islands of the Hawaiian Archipelago, as expected under a stepping-stone model of colonization, from the initial introduction site. This species rapidly colonized across 2000 km without loss of genetic diversity, illustrating the consequences of introducing highly dispersive marine species. PMID- 20163551 TI - Changes in reproductive roles are associated with changes in gene expression in fire ant queens. AB - In species with social hierarchies, the death of dominant individuals typically upheaves the social hierarchy and provides an opportunity for subordinate individuals to become reproductives. Such a phenomenon occurs in the monogyne form of the fire ant, Solenopsis invicta, where colonies typically contain a single wingless reproductive queen, thousands of workers and hundreds of winged nonreproductive virgin queens. Upon the death of the mother queen, many virgin queens shed their wings and initiate reproductive development instead of departing on a mating flight. Workers progressively execute almost all of them over the following weeks. To identify the molecular changes that occur in virgin queens as they perceive the loss of their mother queen and begin to compete for reproductive dominance, we collected virgin queens before the loss of their mother queen, 6 h after orphaning and 24 h after orphaning. Their RNA was extracted and hybridized against microarrays to examine the expression levels of approximately 10,000 genes. We identified 297 genes that were consistently differentially expressed after orphaning. These include genes that are putatively involved in the signalling and onset of reproductive development, as well as genes underlying major physiological changes in the young queens. PMID- 20163552 TI - The role of the rice aquaporin Lsi1 in arsenite efflux from roots. AB - *When supplied with arsenate (As(V)), plant roots extrude a substantial amount of arsenite (As(III)) to the external medium through as yet unidentified pathways. The rice (Oryza sativa) silicon transporter Lsi1 (OsNIP2;1, an aquaporin channel) is the major entry route of arsenite into rice roots. Whether Lsi1 also mediates arsenite efflux was investigated. *Expression of Lsi1 in Xenopus laevis oocytes enhanced arsenite efflux, indicating that Lsi1 facilitates arsenite transport bidirectionally. *Arsenite was the predominant arsenic species in arsenate exposed rice plants. During 24-h exposure to 5 mum arsenate, rice roots extruded arsenite to the external medium rapidly, accounting for 60-90% of the arsenate uptake. A rice mutant defective in Lsi1 (lsi1) extruded significantly less arsenite than the wild-type rice and, as a result, accumulated more arsenite in the roots. By contrast, Lsi2 mutation had little effect on arsenite efflux to the external medium. *We conclude that Lsi1 plays a role in arsenite efflux in rice roots exposed to arsenate. However, this pathway accounts for only 15-20% of the total efflux, suggesting the existence of other efflux transporters. PMID- 20163553 TI - Salicylic acid antagonism of EDS1-driven cell death is important for immune and oxidative stress responses in Arabidopsis. AB - Reactive oxygen species (ROS) have emerged as signals in the responses of plants to stress. Arabidopsis Enhanced Disease Susceptibility1 (EDS1) regulates defense and cell death against biotrophic pathogens and controls cell death propagation in response to chloroplast-derived ROS. Arabidopsis Nudix hydrolase7 (nudt7) mutants are sensitized to photo-oxidative stress and display EDS1-dependent enhanced resistance, salicylic acid (SA) accumulation and initiation of cell death. Here we explored the relationship between EDS1, EDS1-regulated SA and ROS by examining gene expression profiles, photo-oxidative stress and resistance phenotypes of nudt7 mutants in combination with eds1 and the SA-biosynthetic mutant, sid2. We establish that EDS1 controls steps downstream of chloroplast derived O(2)(*-) that lead to SA-assisted H(2)O(2) accumulation as part of a mechanism limiting cell death. A combination of EDS1-regulated SA-antagonized and SA-promoted processes is necessary for resistance to host-adapted pathogens and for a balanced response to photo-oxidative stress. In contrast to SA, the apoplastic ROS-producing enzyme NADPH oxidase RbohD promotes initiation of cell death during photo-oxidative stress. Thus, chloroplastic O(2)(*-) signals are processed by EDS1 to produce counter-balancing activities of SA and RbohD in the control of cell death. Our data strengthen the idea that EDS1 responds to the status of O(2)(*-) or O(2)(*-)-generated molecules to coordinate cell death and defense outputs. This activity may enable the plant to respond flexibly to different biotic and abiotic stresses in the environment. PMID- 20163554 TI - A role for LORELEI, a putative glycosylphosphatidylinositol-anchored protein, in Arabidopsis thaliana double fertilization and early seed development. AB - In plants, double fertilization requires successful sperm cell delivery into the female gametophyte followed by migration, recognition and fusion of the two sperm cells with two female gametes. We isolated a null allele (lre-5) of LORELEI, which encodes a putative glycosylphosphatidylinositol (GPI)-anchored protein implicated in reception of the pollen tube by the female gametophyte. Although most lre-5 female gametophytes do not allow pollen tube reception, in those that do, early seed development is delayed. A fraction of lre-5/lre-5 seeds underwent abortion due to defect(s) in the female gametophyte. The aborted seeds contained endosperm but no zygote/embryo, reminiscent of autonomous endosperm development in the pollen tube reception mutants scylla and sirene. However, unpollinated lre 5/lre-5 ovules did not initiate autonomous endosperm development and endosperm development in aborted seeds began after central cell fertilization. Thus, the egg cell probably remained unfertilized in aborted lre-5/lre-5 seeds. The lre 5/lre-5 ovules that remain undeveloped due to defective pollen tube reception did not induce synergid degeneration and repulsion of supernumerary pollen tubes. In ovules, LORELEI is expressed during pollen tube reception, double fertilization and early seed development. Null mutants of LORELEI-like-GPI-anchored protein 1 (LLG1), the closest relative of LORELEI among three Arabidopsis LLG genes, are fully fertile and did not enhance reproductive defects in lre-5/lre-5 pistils, suggesting that LLG1 function is not redundant with that of LORELEI in the female gametophyte. Our results show that, besides pollen tube reception, LORELEI also functions during double fertilization and early seed development. PMID- 20163555 TI - The moss pentatricopeptide repeat protein with a DYW domain is responsible for RNA editing of mitochondrial ccmFc transcript. AB - In most land plants RNA editing frequently occurs in many organelle transcripts, but little is known about the molecular mechanisms of the organelle RNA editing process. In this study, we have characterized the Physcomitrella patens PpPPR_71 gene that is required for RNA editing of the ccmFc transcript. This transcript harbors two RNA editing sites, ccmF-1 and ccmF-2, that are separated by 18 nucleotides. Complementary DNA sequence analysis of ccmFc suggested that RNA editing at the ccmF-1 site occurred before ccmF-2 editing. RNA editing of the ccmF-2 downstream site was specifically impaired by disruption of the PpPPR_71 gene that encodes a polypeptide with 17 pentatricopeptide repeat motifs and a C terminal DYW domain. The recombinant PpPPR_71 protein expressed in Escherichia coli specifically bound to the 46-nucleotide sequence containing the ccmF-2 editing site. The binding affinity of the recombinant PpPPR_71 was strongest when using the edited RNA at ccmF-1. In addition, the DYW domain also binds to the surrounding ccmF-2 editing site. We conclude that PpPPR_71 is an RNA-binding protein that acts as a site recognition factor in mitochondrial RNA editing. PMID- 20163556 TI - The sweet potato IbMYB1 gene as a potential visible marker for sweet potato intragenic vector system. AB - MYB transcription factors play important roles in transcriptional regulation of many secondary metabolites including anthocyanins. We cloned the R2R3-MYB type IbMYB1 complementary DNAs from the purple-fleshed sweet potato (Ipomoea batatas L. cv Sinzami) and investigated the expression patterns of IbMYB1 gene with IbMYB1a and IbMYB1b splice variants in leaf and root tissues of various sweet potato cultivars by reverse transcription-polymerase chain reaction. The transcripts of IbMYB1 were predominantly expressed in the purple-fleshed storage roots and they were also detectable in the leaf tissues accumulating anthocyanin pigments. In addition, transcript levels of IbMYB1 gene were up-regulated by treatment with methyl jasmonate or salicylic acid in leaf and root tissues of cv. White Star. To set up the intragenic vector system in sweet potato, we first evaluated the utilization of the IbMYB1 gene as a visible selectable marker. The IbMYB1a was transiently expressed in tobacco leaves under the control of a constitutive cauliflower mosaic virus 35S promoter, a root-specific and sucrose inducible sporamin promoter, and an oxidative stress-inducible sweet potato anionic peroxidase2 promoter. We also showed that overexpression of IbMYB1a induced massive anthocyanin pigmentation in tobacco leaves and up-regulated the transcript levels of the structural genes in anthocyanin biosynthetic pathway. Furthermore, high-performance liquid chromatography analysis revealed that the expression of IbMYB1a led to production of cyanidin as a major core molecule of anthocyanidins in tobacco leaves. These results suggest that the IbMYB1 gene can be applicable to a visible marker for sweet potato transformation with intragenic vectors, as well as the production of anthocyanin as important nutritive value in other plant species. PMID- 20163557 TI - Pathogen race determines the type of resistance response in the stripe rust Triticum dicoccoides pathosystem. AB - Wild relatives of crop plants may serve as a promising source for screening for new disease resistance genes that can be utilized in breeding programs. Triticum dicoccoides, the wild progenitor of most cultivated wheats, was shown to harbor many resistance genes against the major diseases attacking cultivated wheat. Stripe rust is a devastating fungal disease that attacks wheat in many regions of the world. New races of Puccinia striiformis Westend. f. sp. tritici, the causative agent of stripe rust, have overcome most of the known Yr resistance genes in wheat. Therefore, there is a need to search for new resistance genes in the T. dicoccoides gene pool. A set of 120 T. dicoccoides accessions, collected from 13 populations representing different habitats in Israel and vicinity, was tested for resistance to three prevalent stripe rust races (38E134, 6E16 and 6E0). Of these 120 accessions, 14, 8 and 12% were resistant to races 38E134, 6E16 and 6E0, respectively, while 57, 2 and 4% were moderately resistant to these races, respectively. A unique resistance was found in the population of Mt Hermon where >80% of the accessions showed resistance to all races. Distribution of infection types (ITs) of race 38E134 showed a normal distribution that can fit a quantitative pattern of response, while the distributions of ITs of races 6E16 and 6E0 had excess of extreme values and therefore showing a qualitative pattern of response. anova testing the main factor effects and interaction showed significant effects of population, race and their interaction on IT. Significant positive correlations were obtained between the resistance to races 6E16 and 6E0 and humidity variables of the collections sites, while resistance to race 38E134 was positively correlated with temperature variables. These results show that the pathogen race can determine the type of resistance response, qualitative or quantitative, in the stripe rust-T. dicoccoides pathosystem. The obtained results also reveal that the distribution of resistance to different pathogen races can be affected by different climatic factors. PMID- 20163558 TI - Experimental evidence against the paradigm of mortality risk aversion. AB - This article deals with the question of how societal impacts of fatal accidents can be integrated into the management of natural or man-made hazards. Today, many governmental agencies give additional weight to the number of potential fatalities in their risk assessments to reflect society's aversion to large accidents. Although mortality risk aversion has been proposed in numerous risk management guidelines, there has been no evidence that lay people want public decisionmakers to overweight infrequent accidents of large societal consequences against more frequent ones of smaller societal consequences. Furthermore, it is not known whether public decisionmakers actually do such overweighting when they decide upon the mitigation of natural or technical hazards. In this article, we report on two experimental tasks that required participants to evaluate negative prospects involving 1-100 potential fatalities. Our results show that neither lay people nor hazard experts exhibit risk-averse behavior in decisions on mortality risks. PMID- 20163559 TI - The development of posterior probability models in risk-based integrity modeling. AB - There is a need for accurate modeling of mechanisms causing material degradation of equipment in process installation, to ensure safety and reliability of the equipment. Degradation mechanisms are stochastic processes. They can be best described using risk-based approaches. Risk-based integrity assessment quantifies the level of risk to which the individual components are subjected and provides means to mitigate them in a safe and cost-effective manner. The uncertainty and variability in structural degradations can be best modeled by probability distributions. Prior probability models provide initial description of the degradation mechanisms. As more inspection data become available, these prior probability models can be revised to obtain posterior probability models, which represent the current system and can be used to predict future failures. In this article, a rejection sampling-based Metropolis-Hastings (M-H) algorithm is used to develop posterior distributions. The M-H algorithm is a Markov chain Monte Carlo algorithm used to generate a sequence of posterior samples without actually knowing the normalizing constant. Ignoring the transient samples in the generated Markov chain, the steady state samples are rejected or accepted based on an acceptance criterion. To validate the estimated parameters of posterior models, analytical Laplace approximation method is used to compute the integrals involved in the posterior function. Results of the M-H algorithm and Laplace approximations are compared with conjugate pair estimations of known prior and likelihood combinations. The M-H algorithm provides better results and hence it is used for posterior development of the selected priors for corrosion and cracking. PMID- 20163560 TI - Beyond (financial) accessibility: inequalities within the medicalisation of infertility. AB - There is a significant class disparity within the provision of medical treatments for infertility in the United States. Common explanations attribute this inequality to financial inaccessibility due to sparse insurance coverage and exorbitant costs. However, little is known as to why disparities still exist without the presence of such constraints, such as in states with comprehensive insurance coverage of infertility treatments. Drawing on in-depth interviews with women of low socioeconomic status (SES), this paper aims to explore the structural and political barriers to receiving medical care for infertility within the United States context. The paper argues that much of the invisible, unidentified treatment disparities of infertility stem from the social control mechanism of medicalisation. Medicalisation perpetuates the stratified system of reproduction through its structural inaccessibility and the institutionalised classism apparent within medicine's reproductive health practices and policies. The women in this study, however, actively and creatively identified ways to overcome the reproductive limits with which they were faced. In doing so, their solutions served both to accept and reject dominant norms of motherhood and medicine. PMID- 20163561 TI - Men's business, women's work: gender influences and fathers' smoking. AB - To further understand men's continued smoking during their partner's pregnancy and the postpartum period, a study was undertaken to explore women's perspectives of men's smoking. Using a gender lens, a thematic analysis of transcribed interviews with 27 women was completed. Women's constructions of men's smoking and linkages to masculine and feminine ideals are described. The findings highlight the ways women position themselves both as defenders and regulators of men's smoking. Femininities that aligned women with hegemonic masculine principles underpinned their roles in relation to men's smoking and presented challenges in influencing their partner's tobacco reduction. By positioning the decision to quit smoking as a man's solitary pursuit, women reduced potential relationship conflict and managed to maintain their identity as a supportive partner. Insights from this study provide direction for developing gender specific tobacco reduction initiatives targeting expectant and new fathers. Indeed, a lack of intervention aimed at encouraging men's tobacco reduction has the potential to increase relationship tensions, and inadvertently maintain pressure on women to regulate fathers' smoking. This study illustrates how gender based analyses can provide new directions for men's health promotion programmes and policies. PMID- 20163562 TI - Practising medicine in two countries: South African physicians in Canada. AB - This qualitative study examines the pre- and post-migration practice experiences of 73 physicians trained in South Africa who have relocated to Canada. The aims are to explore the workings of two different healthcare systems from an insider standpoint and to address the medical autonomy debate as it relates to international medical graduates (IMGs). While study respondents reported practice frustrations in both countries, they generally preferred working in a socialised health insurance environment that grants wider accessibility than a two-tiered system that favours a privileged few. Concerns such as family safety and opportunities for children also contributed to more satisfaction with Canada. We discuss our findings in relation to a broader international context and the sociological literature on medical autonomy. We argue that IMGs face different autonomy issues from other physicians and stress the need to broaden sociological inquiry of medical work by investigating how autonomy interfaces with other neglected aspects of physicians' work and non-work lives. PMID- 20163563 TI - The (non) use of prioritisation protocols by surgeons. AB - Priority setting and rationing is a dominant feature of contemporary health policy. In New Zealand, clinical priority assessment criteria (CPAC) tools have been developed to make access to elective surgery more equitable and efficient. Research was undertaken to identify how surgeons used these tools in the consultation. Forty-seven consultations with 15 different surgeons have to date been video- and audio-recorded. There were no instances where CPAC tools were explicitly used in the consultation. Drawing on the methodology of conversation analysis and the concept of news delivery as developed by Maynard, this paper argues that the delivery of diagnoses and treatment plans can usefully be seen in part as the delivery of bad or good news. Using three case studies to illustrate the argument, it is suggested that the interactional work required in the delivery of such news challenges the ability of clinicians to use protocols such as CPAC. The analysis sheds light on important consultation processes that need to be more carefully considered when designing interventions to influence clinician behaviour. In order to influence the behaviour of clinicians to achieve policy goals, greater attention needs to be paid to the interactional demands of the consultation process. PMID- 20163564 TI - Legionella pneumophila promotes functional interactions between plasma membrane syntaxins and Sec22b. AB - Biogenesis of a specialized organelle that supports intracellular replication of Legionella pneumophila involves the fusion of secretory vesicles exiting the endoplasmic reticulum (ER) with phagosomes containing this bacterial pathogen. Here, we investigated host plasma membrane SNARE proteins to determine whether they play a role in trafficking of vacuoles containing L. pneumophila. Depletion of plasma membrane syntaxins by RNA interference resulted in delayed acquisition of the resident ER protein calnexin and enhanced retention of Rab1 on phagosomes containing virulent L. pneumophila, suggesting that these SNARE proteins are involved in vacuole biogenesis. Plasma membrane-localized SNARE proteins syntaxin 2, syntaxin 3, syntaxin 4 and SNAP23 localized to vacuoles containing L. pneumophila. The ER-localized SNARE protein Sec22b was found to interact with plasma membrane SNAREs on vacuoles containing virulent L. pneumophila, but not on vacuoles containing avirulent mutants of L. pneumophila. The addition of alpha SNAP and N-ethylmaleimide-sensitive factor (NSF) to the plasma membrane SNARE complexes formed by virulent L. pneumophila resulted in the dissociation of Sec22b, indicating functional pairing between these SNAREs. Thus, L. pneumophila stimulates the non-canonical pairing of plasma membrane t-SNAREs with the v-SNARE Sec22b to promote fusion of the phagosome with ER-derived vesicles. The mechanism by which L. pneumophila promotes pairing of plasma membrane syntaxins and Sec22b could provide unique insight into how the secretory vesicles could provide an additional membrane reserve subverted during phagosome maturation. PMID- 20163565 TI - A novel syntaxin 6-interacting protein, SHIP164, regulates syntaxin 6-dependent sorting from early endosomes. AB - Membrane fusion is dependent on the function of SNAREs and their alpha-helical SNARE motifs that form SNARE complexes. The Habc domains at the N-termini of some SNAREs can interact with their associated SNARE motif, Sec1/Munc18 (SM) proteins, tethering proteins or adaptor proteins, suggesting that they play an important regulatory function. We screened for proteins that interact with the Habc domain of Syntaxin 6, and isolated an uncharacterized 164-kDa protein that we named SHIP164. SHIP164 is part of a large (approximately 700 kDa) complex, and interacts with components of the Golgi-associated retrograde protein (GARP) tethering complex. Depletion of GARP subunits or overexpression of Syntaxin 6 results in a redistribution of soluble SHIP164 to endosomal structures. Co overexpression of Syntaxin 6 and SHIP164 produced excessive tubulation of endosomes, and perturbed the transport of cation-independent mannose-6-phosphate receptor (CI-MPR) and transferrin receptor. Thus,we propose that SHIP164 functions in trafficking through the early/recycling endosomal system. PMID- 20163566 TI - Invasive filamentous fungal infections associated with renal transplant tourism. AB - 'Transplant tourism,' the practice of traveling abroad to acquire an organ, has emerged as an issue in kidney transplantation. We treated a patient who developed invasive aspergillosis of the allograft vascular anastomosis after receiving a kidney transplant in Pakistan, prompting us to review the literature of invasive mycoses among commercial organ transplant recipients. We reviewed all published cases of infections in solid organ transplant recipients who bought their organs abroad and analyzed these reports for invasive fungal infections. Including the new case reported here, 19 cases of invasive fungal infections post commercial kidney transplant occurring in 17 patients were analyzed. Infecting organisms were Aspergillus species (12/19; 63%), Zygomycetes (5/19; 26%), and other fungi (2/19; 5%). Invasive mold infections were present at the transplanted graft in 6/17 patients (35%) with graft loss or death in 13/17 (76%) of patients and overall mortality (10/17) 59%. Invasive fungal infections, frequently originating at the graft site, have emerged as a devastating complication of commercial renal transplant and are associated with high rates of graft loss and death. PMID- 20163567 TI - Disseminated Rhizopus microsporus infection cured by salvage allogeneic hematopoietic stem cell transplantation, antifungal combination therapy, and surgical resection. AB - Invasive Zygomycetes infection complicating prolonged neutropenia is associated with high mortality in the absence of immune recovery. We report a patient who developed disseminated zygomycosis due to Rhizopus microsporus during induction chemotherapy for acute myeloid leukemia. Rescue allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed as her only chance of cure of this infection and to treat refractory leukemia. Posaconazole combined with liposomal amphotericin B contained the zygomycosis during prolonged neutropenia due to allo HSCT followed by intense immunosuppression for grade IV acute graft-versus-host disease. Surgical removal of all infected sites after immune recovery, with prolonged posaconazole treatment, ultimately cured the infection. New combination antifungal therapies might sufficiently control disseminated zygomycosis to allow allo-HSCT to be performed, assuring life-saving immune recovery. Surgery appears to be necessary for definite cure of these infections. PMID- 20163568 TI - Why is it so hard to do the right thing in wound care? AB - "Doing the right thing" in wound care is not an easy task. Studies suggest that 3 factors determine compliance with performing basic wound care from an evidence based medicine perspective: complexity, cognitive effort, and the compensation system. Two models were explored to investigate compliance with basic wound care at hospital based wound centers: offloading of diabetic foot ulcers (DFUs) and compression bandaging for venous leg ulcers. Using a very large wound-care registry it was determined that only 6% of DFU patients received the gold standard of care for offloading, i.e., total contact casting (TCC), but among those patients who received it, the average cost of treatment was half the cost of those who did not. Although inexpensive to administer, TCC is a relatively time-consuming procedure which is poorly reimbursed. Other DFU treatments such as bilaminate skin, are more costly but are reimbursed much more generously. Thus, the reimbursement system favors the use of more expensive therapies over more economical ones. In the case of venous leg ulcers (VLUs), only 17% of patients received adequate compression. Provision of adequate compression among VLU patients has been similarly hindered by inadequate reimbursement policy. Lack of familiarity with clinical practice guidelines increases the cognitive effort for clinicians. Improving the economic model to favor the provision of effective basic care, creating easier-to-use products, and making clinical practice guidelines available at the point of service may make it easier to "do the right thing(s)" in wound care. PMID- 20163569 TI - Impaired angiogenesis and mobilization of circulating angiogenic cells in HIF 1alpha heterozygous-null mice after burn wounding. AB - Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that controls vascular responses to hypoxia and ischemia. In this study, mice that were heterozygous (HET) for a null allele at the locus encoding the HIF-1alpha subunit (HET mice) and their wild-type (WT) littermates were subjected to a thermal injury involving 10% of the body surface area. HIF-1alpha protein levels were increased in burn wounds of WT but not of HET mice on day 2. The serum levels of stromal-derived factor 1alpha, which binds to CXCR4, were increased on day 2 in WT but not in HET mice. Circulating angiogenic cells were also increased on day 2 in WT but not in HET mice and included CXCR4(+)Sca1(+) cells. Laser Doppler perfusion imaging demonstrated increased blood flow in burn wounds of WT but not HET mice on day 7. Immunohistochemistry on day 7 revealed a reduced number of CD31(+) vessels at the healing margin of burn wounds in HET as compared with WT mice. Vessel maturation was also impaired in wounds of HET mice as determined by the number of alpha-smooth muscle actin-positive vessels on day 21. The remaining wound area on day 14 was significantly increased in HET mice compared with WT littermates. The percentage of healed wounds on day 14 was significantly decreased in HET mice. These data delineate a signaling pathway by which HIF-1 promotes angiogenesis during burn wound healing. PMID- 20163570 TI - Smoking attenuates wound inflammation and proliferation while smoking cessation restores inflammation but not proliferation. AB - Full-thickness 5 mm punch biopsy wounds were made lateral to the sacrum in 48 smokers and 30 never smokers. After 1 week, the wounds were excised and fixed. The smokers were then randomized to continuous smoking or abstinence with a transdermal nicotine patch or a placebo patch. The sequence of wounding and excision was repeated after 4, 8, and 12 weeks. All excised tissue was stained with hematoxylin-eosin and immunohistochemically for macrophages (CD68), procollagen 1 N-terminal propeptide (PINP) in fibroblasts, and endothelial cells (CD31). The cellularity was assessed and scored by two independent histopathologists, and for the analysis, proportional odds models and random effect models for repeated measurements were applied. Macrophages and PINP stained fibroblasts were reduced in the smokers' wounds (0.28 [0.14-0.58] [OR, 95%CI]; p=0.01 and 0.37[0.19-0.70]; p<0.01, respectively, when compared with never smokers' wounds). Inflammation scores were marginally affected. Following smoking cessation, inflammatory cell infiltration and macrophages in the wounds increased. PINP-stained fibroblasts were unaffected. Neovascularization was not affected by smoking or abstinence. Wound inflammation and fibroblast proliferation were attenuated in smokers, suggesting delayed healing. Abstinence from smoking restores inflammation, but does not affect proliferation. These findings suggest a pathophysiologic mechanism for postoperative wound infection and dehiscence in smokers and why smoking cessation appears to reduce wound infection but not dehiscence. PMID- 20163571 TI - Rab33b and Rab6 are functionally overlapping regulators of Golgi homeostasis and trafficking. AB - We used multiple approaches to investigate the coordination of trans and medial Rab proteins in the regulation of intra-Golgi retrograde trafficking. We reasoned that medially located Rab33b might act downstream of the trans Golgi Rab, Rab6, in regulating intra-Golgi retrograde trafficking. We found that knockdown of Rab33b, like Rab6, suppressed conserved oligomeric Golgi (COG) complex- or Zeste White 10 (ZW10)-depletion induced disruption of the Golgi ribbon in HeLa cells. Moreover, efficient GTP-restricted Rab6 induced relocation of Golgi enzymes to the endoplasmic reticulum (ER) was Rab33b-dependent, but not vice versa, suggesting that the two Rabs act sequentially in an intra-Golgi Rab cascade. In support of this hypothesis, we found that overexpression of GTP-Rab33b induced the dissociation of Rab6 from Golgi membranes in vivo. In addition, the transport of Shiga-like toxin B fragment (SLTB) from the trans to cis Golgi and ER required Rab33b. Surprisingly, depletion of Rab33b had little, if any, immediate effect on cell growth and multiplication. Furthermore, anterograde trafficking of tsO45G protein through the Golgi apparatus was normal. We suggest that the Rab33b/Rab6 regulated intra-Golgi retrograde trafficking pathway must coexist with other Golgi trafficking pathways. In conclusion, we provide the first evidence that Rab33b and Rab6 act to coordinate a major intra-Golgi retrograde trafficking pathway. This coordination may have parallels with Rab conversion/cascade events that regulate endosome, phagosome and exocytic processes. PMID- 20163572 TI - No emergence of Echinococcus multilocularis in foxes in Flanders and Brussels anno 2007-2008. AB - Echinococcus multilocularis is highly endemic in red foxes in southern Belgium (region of Wallonia), especially in the higher located forested areas. The north of Belgium, including the regions of Flanders and Brussels, is more urbanized and has been colonized entirely by red foxes since the 1980s. A temperospatial analysis of compiled epidemiological data from 1996 to 2003 predicted a northwest spread of the cestode from Wallonia and the Netherlands towards Flanders and Brussels (Prev. Vet. Med. 2006, 76, 137-150). In 2007-2008, none of 187 examined foxes from the north tested positive (<2.8%, alpha = 0.01), compared to 1.7% in 1996-1999. This suggests that the parasite is not emerging in the examined area and the endemic region has not significantly extended northwest during the last decade. The possible reasons are discussed in the article, including the relatively low altitude, milder climate or low abundance of suitable intermediate hosts. The low prevalence in foxes and the generally low infection rate in humans imply that the risk for public health in Flanders and Brussels is limited anno 2007-2008. PMID- 20163573 TI - Nationwide surveillance of West Nile virus targeting mosquitoes and dead birds from April 2004 through March 2007 in Japan. AB - We conducted nationwide West Nile virus (WNV) surveillance targeting mosquitoes and dead birds to reveal whether the virus and its potential vectors are present in Japan. A total of 12 766 mosquitoes and 230 dead birds were collected in April 2004-March 2005 (the 2004-2005 period), 10 755 mosquitoes and 267 dead birds in April 2005-March 2006 (the 2005-2006 period), and 8624 mosquitoes and 245 dead birds in April 2006-March 2007 (the 2006-2007 period). The species of most of the mosquitoes collected over the 3 years were Culex tritaeniorhynchus (47.82%) and Anopheles sinensis (28.49%), and other species included Aedes albopictus (6.75%), the Culex pipiens group (Cx. pipiens pallens and Cx. pipiens molestus: 5.37%), Aedes vexans nipponii (2.54%), Armigeres subalbatus (1.08%), and Aedes japonicus (0.95%). As for the dead birds, most were Passeriformes (456 specimens), which included several crow species, and the other orders included Anseriformes, Columbiformes and Ciconiiformes (78, 66 and 36 specimens, respectively). All the specimens tested negative for WNV RNA by reverse-transcriptase polymerase chain reaction (RT-PCR) in the 2004-2005 period and by real-time RT-PCR in the 2005 2006 and the 2006-2007 periods, respectively. Our surveillance provided no evidence for WNV in Japan as of the end of the surveillance period, but on the other hand, it revealed that several species of potential WNV vectors are distributed widely in Japan, which suggests that WNV in principle could be transmitted by the potential vectors if introduced. Thus, it is essential to take continued precautions against WNV introduction. PMID- 20163574 TI - Evaluation of pet-related management factors and the risk of Salmonella spp. carriage in pet dogs from volunteer households in Ontario (2005-2006). AB - The purpose of this study was to determine pet-related management factors that may be associated with the presence of Salmonella spp. in feces of pet dogs from volunteer households. From October 2005 until May 2006, 138 dogs from 84 households in Ontario were recruited to participate in a cross-sectional study. Five consecutive daily fecal samples were collected from each dog and enrichment culture for Salmonella spp. was performed. A higher than expected number of the dogs (23.2%; 32/138) had at least one fecal sample positive for Salmonella, and 25% (21/84) of the households had at least one dog shedding Salmonella. Twelve serotypes of Salmonella enterica subsp. enterica were identified, with the predominant serotypes being Typhimurium (33.3%; 13/39), Kentucky (15.4%; 6/39), Brandenburg (15.4%; 6/39) and Heidelberg (12.8%; 5/39). Univariable logistic regression models were created with a random effect for household to account for clustering. Statistically significant risk factors for a dog testing positive included having contact with livestock, receiving a probiotic in the previous 30 days, feeding a commercial or homemade raw food diet, feeding raw meat and eggs, feeding a homemade cooked diet, and having more than one dog in the household. In two-variable models that controlled for feeding raw food, the non-dietary variables were no longer statistically significant. These results highlight the potential public health risk of including raw animal products in canine diets. PMID- 20163575 TI - A qualitative study of state-level zoonotic disease surveillance in new England. AB - Zoonotic diseases are infectious diseases transmittable between animals and humans and outbreaks of these diseases in animals can signify that humans are also infected (or vice versa). Thus, communication between animal and human health agencies is critical for surveillance. Understanding how these agencies conduct surveillance and share information is important for the development of successful automated zoonotic monitoring systems. Individual interviews were conducted with 13 professionals who perform animal or human zoonotic disease surveillance in one of the New England states. Questions centred on existing surveillance methods, collaborations between animal and human health agencies, and technological and data needs. The results showed that agencies routinely communicate over suspected zoonotic disease cases, yet there are barriers preventing automated electronic linking of health data of animals and humans. These include technological barriers and barriers due to sensitivity and confidentiality of information. Addressing these will facilitate the development of electronic systems for integrating animal and human zoonotic disease surveillance data. PMID- 20163576 TI - Tularaemia in Minnesota: case report and brief epidemiology. AB - The 2008 case presented here of tularaemia in a cat and its owner occurred in an urban setting and was associated with animal contact, a relatively rare mode of transmission in Minnesota in recent years. Response to this case exemplified a 'One Health' approach involving pre-existing relationships, cooperation between multiple disciplines and laboratory infrastructure that facilitated information sharing. PMID- 20163577 TI - Diagnosis of bovine-associated parapoxvirus infections in humans: molecular and epidemiological evidence. AB - Orf virus, pseudocowpox virus and bovine papular stomatitis virus, are parapoxviruses, associated with domestic ruminants, which are capable of causing cutaneous infections in humans. Owing to virtually identical appearances in humans, clinical differentiation of these viruses is difficult. We discuss three recent occurrences of parapoxvirus infection, involving contact with domestic bovine and use a combination of molecular and epidemiological data in the diagnosis. These cases underscore the utility of modern diagnostic tools, along with species-specific contact information in acquiring a definitive diagnosis, in the case of suspected parapoxvirus infection. PMID- 20163578 TI - Molecular detection of Crimean-Congo haemorrhagic fever virus (CCHFV) but not West Nile virus (WNV) in hard ticks from provinces in northern Turkey. AB - In this study, the hard ticks collected from a variety of mammalian species (cattle, sheep, goat, buffalo) and a turtle in either coastal or inland Black Sea region of Turkey were surveyed for the presence of RNA from Crimean-Congo haemorrhagic fever virus (CCHFV) and West Nile virus (WNV). No WNV genomic RNA was detected in any tick sample. However, CCHFV RNA was found in 29 of 421 tick pools (6.88%). Positivity rates for the provinces varied and were as follows: Samsun 4.38%; Ordu 4.34%; Giresun 6.32%; Sinop 14.63%; Amasya 5.55%; Tokat 3.38% and Sivas 4.83%. Crimean-Congo haemorrhagic fever virus genomic RNA was detected in seven of eleven tick species tested. These results suggest that these hard ticks may act as a reservoir for CCHFV in northern Turkey, but probably have no role in WNV transmission. PMID- 20163579 TI - Toxicants exposures as novel zoonoses: reflections on sustainable development, food safety and veterinary public health. AB - The modern concept of zoonosis considers any detriment to the health and/or quality of human life resulting from relationships with (other) vertebrate or edible or toxic invertebrate animals. Whereas exposure to toxicants through foods of animal origin (a.o.) is a well-established issue, hereby we discuss it as novel zoonoses, from the standpoints of health implications as well as similarities and differences with classical zoonoses caused by biological agents. Novel toxicant-related zoonoses are linked with new issues in food safety, such as the environment-feed-food chain. In fact, the potential effect of the combined and repeated exposure to dietary toxicants is generally long-term and not readily discernible. Endocrine disrupting chemicals in staple foods of a.o. are discussed as a telling example of a food safety issue summing up critical points covered by the definition of sustainable development, also implicating health risks for generations to come. We suggest some critical points to implement the veterinary public health action in sustainable food safety, such as enhancement of Hazard Analysis and Critical Control Points systems for toxicological risk management. PMID- 20163580 TI - Genetic polymorphism as a background of animal behavior. AB - Various studies have shown the associations between differences in human behavioral traits and genetic polymorphism of neurotransmitter-related proteins such as receptors, transporters and monoamine oxidase. To clarify the genetic background of animal behavior, corresponding regions in animals have been analyzed. The study has been especially focused on primates, as the evolutionally closest animal to humans, and on dogs, as the socially closest animal to humans. In primates, polymorphisms were discovered between or within species, and the functional effects on neural transmission were found to be different by alleles. Even in apes, the closest species to humans, function was different from that in humans. In dogs, allele distributions of several genes were different among breeds showing different behavioral traits, and genes associated with individual differences in aggressiveness and aptitude of working dogs were surveyed. The survey of behavior-related genes has also been carried out in other mammals such as horses and cetaceans. Genes controlling various behaviors in birds have also been reported. The marker genes for behavior will provide useful information for human evolution, welfare of zoo animals and effective selection of working dogs and industry animals. PMID- 20163581 TI - Improved conception rates in sows inseminated with cryopreserved boar spermatozoa prepared with a more optimal combination of osmolality and glycerol in the freezing extender. AB - Cryoprotectant agents (CPAs) are added in freezing extenders to prevent intracellular ice crystal formation. However, it has been reported that high dose of CPAs confer toxicity on spermatozoa. Recently, the reduction of intracellular water by a high osmolality solution has also resulted in the suppression of ice crystal formation in spermatozoa, suggesting that the optimal combination of glycerol concentration and freezing extender osmolality could contribute to the development of effective sperm cryopreservation techniques. In this study, we investigated the motility, membrane and acrosomal integrity of frozen-thawed boar spermatozoa treated with freezing extender (NSF) of varying osmolalities (300, 400, 500 mOsm/kg) and final concentrations of glycerol (0.5, 1, 2, 3%). The spermatozoa that were treated at 400 mOsm/kg and 2% glycerol showed significantly higher rates of motility and membrane integrity compared with those in other treatment groups. In addition, the conception and implantation rates of swine artificially inseminated with spermatozoa frozen by the novel freezing extender (conception; 79%, implantation; 57.5%) were significantly higher than those of frozen-thawed spermatozoa treated in the conventional NSF (300 mOsm/kg, 3% glycerol) (conception; 29%, implantation; 33.8%). From these results, we concluded that the novel hyperosmotic (400 mOsm/kg) and low-glycerol (final concentration 2%) freezing extender is beneficial for the cryopreservation of boar spermatozoa. PMID- 20163582 TI - The comparative study digestion and metabolism of nitrogen and purine derivatives in male, Thai, Swamp buffalo and Thai, Brahman cattle. AB - Studies on in vivo digestion, rates of passages, metabolism of nitrogen, urinary purine derivative excretion and blood metabolites were carried out in Thai Brahman cattle and Thai swamp buffaloes (16 months old). The animals were fed mixed diets based on pineapple (Ananas comusus) waste silage containing urea-N (NPN) and true protein from a concentrate (TP). The Brahman cattle (310 +/- 15 kg) were heavier than the swamp buffaloes (195 +/- 9.4 kg) and had higher dry matter (DM), organic matter (OM) and neutral detergent fiber (NDF) intakes when compared on the basis of their metabolic body weight (BW(0.75)), but these intakes did not differ significantly when the diets of each animal species were compared. The total tract, apparent digestibilities of dry matter (DM) and organic matter (OM) were not significantly different between the animal species when comparing the two types of diets. The NDF digestibility was significantly (P < 0.01) decreased in both animal species when fed the TP diet, but was significantly (P < 0.01) greater in cattle than in swamp buffaloes. The passage rate digesta k(1) (P < 0.01) and the passage rate digesta k(2) (through the caecum and proximal colon) (P < 0.03) were significantly slower, and the total mean retention time (TMRT) (P < 0.01) was significantly longer in swamp buffaloes when compared to Brahman cattle, but the transit time (TT) showed no difference (P = 0.07) between the animal species or the diets. The N intakes were not different in both animal species and diets, but urine-N was greater (P < 0.05) in Brahman cattle than that in swamp buffaloes. Urine N and digestibility of N were significantly (P < 0.04) higher in animals fed the NPN diet than those fed the TP diet. Urinary purine derivatives (PD) and the creatinine (Cr) excretion of swamp buffaloes were significantly (P < 0.01) lower than those in Brahman cattle. Plasma urea-N (BUN) concentration was significantly (P < 0.01) higher in swamp buffaloes than that in Brahman cattle, but plasma glucose and insulin concentrations were significantly (P < 0.01) higher in Brahman cattle than in swamp buffaloes. The concentrations of non-esterified fatty acids (NEFA) were not significantly (P > 0.05) different in animals fed different diets. The present study demonstrated that Brahman cattle were better in fiber digestibility than swamp buffaloes at utilizing pineapple waste silage with both N sources. PMID- 20163583 TI - Chemical characterization, energy values, protein and carbohydrate fractions, degradation kinetics of frost damaged wheat (with severely overall weight loss) in ruminants. AB - In Canada, frost damage can result in millions of tonnes of wheat that is not suitable for human consumption (such wheat is referred to as 'frozen') each year. There is a need to systematically evaluate the nutritive value of frozen wheat for ruminants. So far, little research has been conducted to determine the magnitude of the differences in nutritive value between frozen and normal wheat. The objectives of this study were to compare frozen wheat and normal wheat (AC Barrie) in terms of (i) chemical characteristics; (ii) protein and carbohydrate fractions; (iii) energy value; and (iv) rumen degradation kinetics. The results showed that the overall yield losses of the frozen wheat were around 24%. The frozen wheat was significantly lower (P < 0.05) in starch (47 vs. 62%DM), non structural carbohydrates (60 vs. 70%DM), and non-protein N (63 vs. 93%SCP); and higher (P < 0.05) in crude fat (3 vs. 2%DM), acid (6 vs. 2%DM), neutral detergent fiber (22 vs. 10%DM), lignin (2 vs. 1%DM), acid (3 vs. 1%CP) and neutral detergent insoluble CP (19 vs. 14%CP). The frozen wheat was also lower in (P < 0.05) energy (TDN, DE(3X), ME(3X,) NEL(3X), DE(4X), ME(4X,) NEL(4X) for dairy; ME, NE(m), and NE(g) beef cattle). After partitioning of protein and carbohydrate (CHO) subfractions, the results showed that the frozen wheat was lower (P < 0.05) in the intermediately degradable CP (PB2: 47 vs. 59%CP); and higher in rapidly degradable CP (PB1: 12 vs. 2%CP) and unavailable CP (PC: 3 vs. 1%CP). The frozen wheat was also lower (P < 0.05) in intermediately degradable CHO (CB1: 60 vs. 77%CHO); and higher (P < 0.05) in slowly degradable CHO (CB2: 20 vs. 8%CHO) and unavailable CHO (CC: 5 vs. 2%CHO). The in situ results showed that the frozen wheat had different patterns in rumen degradation kinetics of protein and starch. The extent of the changes varied according to the specific nutrient examined. In conclusion, the frozen wheat differed in chemical characteristics, TDN and energy values, protein and carbohydrate fractions and in situ degradation behavior from normal wheat. The chemical and nutritional characterization of wheat was highly associated with climate condition (frost damage). The frost damage to the wheat reduced nutrient content and availability and thus reduced nutrient supply to ruminants. PMID- 20163584 TI - Hemato-biochemical changes, disease incidence and live weight gain in individual versus group reared calves fed on different levels of milk and skim milk. AB - A 2 x 3 factorial design was used to study the impact of rearing systems, individual (I) versus group (G) and different levels of milk/skim milk feeding (F1, F2 and F3) on hemato-biochemical profile, disease incidence and average daily gain of crossbred (Bos indicus x Bos taurus) calves. Six calves were taken in each group on the basis of their birth weight and housed in individual (2.20 x 1.16 m(2)/calf) or in group pens (2.20 x 1.03 m(2)/calf). After 3 days of colostrum feeding, calves were allocated to one of three different milk feeding schedules: milk fed up to 8 weeks of age (F1), milk up to 4 weeks followed by 50% replacement by skim milk up to 6 weeks and 100% thereafter (F2) and 100% replacement of milk with skim milk after 4 weeks (F3). Calf starter and cereal green fodders were fed ad libitum from the second week of age and continued for 14 weeks. Parameters on health and disease profiles of calves (disease incidence, duration of illness, response to treatment and recovery) and weekly live weight change were recorded. Calf scour predominated (52.8%), followed by joint ill (25.0%) and respiratory infections (19.4%). The disease incidence was greater (P < 0.01) in individually housed calves (94.4 vs. 55.9%). The management of navel ill required longer recovery (7.01 days) followed by joint ill (4.87 days) and respiratory infection (4.86 days). The average daily gain during 0-14 weeks of age was higher (P < 0.01) in group-housed calves (433 +/- 22 vs. 355 +/- 31 g), while the effect of feeding was not significant. Blood samples collected at 4, 8 and 14 weeks of age showed some periodic higher concentrations (but within normal range) of plasma urea and total protein in group housed calves on F2 and F3 feeding schedules in response to high protein intake. Other parameters remained non-significantly different. Thus, group-housed calves can be reared successfully with comparatively better performance and less illness than individually housed ones under the present health care and housing management system. However, the system should not be used as a substitute for good management, and frequent observations of calves should be an integral part of any successful rearing program. PMID- 20163585 TI - Effect of D-mannitol on feed digestion and cecotrophic system in rabbits. AB - This study aimed to evaluate the effect of sugar alcohol as an energy source for cecal microbes on digestibility, cecotrophy (i.e. reingestion of microbial products of cecum, cecotrophs) and performance in rabbits. Thus, we fed rabbits an experimental diet that included 5% of D-mannitol, and collected hard feces and cecotrophs to be analyzed for crude protein (CP), acid detergent fiber (ADF), ether extract (EE), crude ash (CA) and dry matter (DM). Cecotrophic behavior of the rabbits was also observed. Feeding D-mannitol increased (P < 0.01) digestibility of ADF, resulting in a decrease (P < 0.05) in the concentration in hard feces. The increase (P < 0.05) in CP concentration was attributed to lower (P < 0.05) digestibility. D-mannitol had a similar modulatory effect on CP and ADF concentrations in hard feces and cecotrophs. Accordingly, estimations of the proportion of nutrients recycled by cecotrophy to dietary intake (PR), obtained by the two calculation methods, showed an increase (P < 0.01) in PR of CP and a decrease (P < 0.05) in that of ADF. Daily weight gain and feed efficiency increased (P < 0.05) for D-mannitol-fed rabbits, while daily feed intake decreased (P < 0.05). These results suggest the possibility of using D-mannitol as a stimulator of cecal microbial growth and cellulolytic activity, and therefore, improved rabbits performance. PMID- 20163587 TI - Fecal excretion of alcohols and organic anions in neonatal dairy calves. AB - To clarify colonic fermentation during the perinatal period, 22 dairy calves less than 6 weeks old were used. They were given a milk replacer following colostrum feeding. A total 100 samples of normal feces including meconium were collected from the rectum of the calves. Fecal pH, alcohols, lactate and volatile fatty acids (VFAs) were analyzed. Higher ethanol and n-propanol concentrations were found in many fecal samples particularly in the first 2 weeks after birth, but these metabolites showed consistently lower concentrations thereafter. By contrast, higher concentrations of methanol were observed in some samples for all ages examined. Fecal VFA increased abruptly within a few days of birth, and mainly consisted of acetate and n-butyrate. During the first 2 weeks, the proportion of n-butyrate in VFAs decreased and that of propionate increased gradually. Proportions of VFAs were almost stable at 3-6 weeks of age (acetate, propionate and n-butyrate in increasing order). Higher concentrations of lactate and lower pHs were observed in the fecal samples during the first 2 weeks, and concentrations decreased thereafter. Accelerated colonic production of ethanol and n-propanol was confirmed during the early 2 weeks, in addition to organic acid fermentation as reported previously. PMID- 20163586 TI - Mobiloization of intracellular calcium ions in chicken and rat lymphocytes induced by T cell mitogens. AB - Cytosolic Ca(2+) is known to be an important factor in intracellular signaling pathways that regulate several cellular functions. The present study was designed to measure the intracellular concentrations of Ca(2+) ([Ca(2+)](i)) in T cell mitogen-stimulated chicken lymphocytes, and to compare the results with those in rat lymphocytes. [Ca(2+)](i) was increased in the thymocytes, splenocytes and bursacytes of chickens, and in the thymocytes and splenocytes of rats following exposure to the mitogens phytohaemagglutinin (PHA) and concanavalin A (ConA). Increases were greatest in the thymocytes followed by the splenocytes and bursacytes. The PHA-induced changes in the thymocytes and splenocytes were similar in chickens and rats, but the ConA-induced increases were significantly lower in the chickens than rats. Pretreatment with EGTA before the application of PHA and ConA completely suppressed the rise in [Ca(2+)](i) in all the chicken lymphocytes, indicating that the increases that occurred in PHA- and ConA-treated chicken lymphocytes could be entirely attributed to the influx of extracellular Ca(2+). On the other hand, the PHA- and ConA-induced increase in [Ca(2+)](i) in rat lymphocytes was not completely suppressed by EGTA, indicating the recruitment of Ca(2+) from the intracellular Ca(2+) pool. The results suggest species differences in the Ca(2+)-based responses to T cell mitogens between chicken lymphocytes and rat lymphocytes. PMID- 20163589 TI - Microbiota analysis of Caspian Sea yogurt, a ropy fermented milk circulated in Japan. AB - We analyzed the microbiota of domestic ropy fermented milk, Caspian Sea yogurt (or 'kasupikai yohguruto' in Japanese), circulated in Japan. We collected six varieties from five localities. Lactococcus (L) lactis ssp. cremoris was isolated from all samples as the dominant strain at levels of 10(8)-10(9) CFU/g. We show this strain produces an extracellular polysaccharide (EPS) that causes the unique characteristic viscosity of the product. From analysis of the RAPD pattern of 60 bacterial isolates from the six samples, we found that 59 strains from a total of 60 isolates were identical and produced this viscosity. Furthermore, PFGE analysis of representative strains from each sample indicated that the isolates could be classified into four subgroups. This suggests these L. lactis ssp. cremoris strains found in Caspian Sea yogurt may have been slightly mutated during subculture in Japan. In addition, Lactobacillus (L.) sakei ssp. sakei were isolated from three samples; L. plantarum, Gluconoacetobacter sacchari and Acetobacter aceti were isolated from two samples; and L. paracasei, L. kefiri, Leuconostoc (Leu.) mesenteroides were isolated from one sample. PMID- 20163588 TI - Cloning of PRL and VIP cDNAs of the Java sparrow (Padda oryzivora). AB - Complementary DNA (cDNA) of prolactin (PRL) and vasoactive intestinal polypeptide (VIP) of the Java sparrow were cloned and sequenced. The proximal region of the PRL promoter was also identified. Java sparrow PRL was found to have 88.3, 88.3, and 89.1% sequence identity at the cDNA level to PRL of chicken, turkey, and duck, respectively. The predicted amino acid sequence had an overall similarity with a comparable region of chicken (91.4%), turkey (88.9%) and duck (92.0%) PRL. Based on the cDNA sequence and genomic structure of the chicken PRL gene, the proximal promoter was characterized. Sequence analysis of the proximal region of Java sparrow PRL promoter revealed a high degree of similarity to that of chicken, turkey and duck PRL promoters. Moreover, cDNA of prepro-VIP was also cloned and sequenced. Java sparrow prepro-VIP shows high similarity to chicken and turkey prepro-VIP. However, the region upstream of the 5' untranslated region of Java sparrow prepro-VIP did not show similarity to that of chicken. These results suggest that the mechanisms, which regulate expression of the VIP gene, may be different between precocial and altricial birds, but expression of the PRL gene may be widely conserved in avian species. PMID- 20163590 TI - Relationships between tropomyosin and myosin heavy chain isoforms in bovine skeletal muscle. AB - The composition of tropomyosin (TPM) and myosin heavy chain (MyHC) isoforms was analyzed in 10 physiologically different bovine muscles (masseter, diaphragm, tongue, semispinalis, pectoralis profundus, biceps femoris, psoas major, semimembranosus, longissimus thoracis and semitendinosus) to clarify the relationships between TPM and MyHC isoforms in different muscle fiber types. The content of TPM1 and TPM3 was different in muscles according to their function in muscle contraction, although the content of TPM2 was constantly about 50% of the total TPM in all muscles. The content of TPM1 was higher in semimembranosus, longissimus thoracis and semitendinosus, while that of TPM3 was higher in masseter and diaphragm. The high positive correlation between MyHC-slow content and TPM3 content (r = 0.92) suggested a coexpression of TPM3 and MyHC-slow isoforms in a muscle fiber. MyHC-slow and TPM3 were expressed at the same level in masseter and diaphragm, whereas there was more TPM3 than MyHC-slow in tongue and semispinalis, so it appears that the excess TPM3 in tongue and semispinalis is expressed with other MyHC isoforms. MyHC-2a was the only fast type isoform expressed in tongue and semispinalis. Therefore, the excess TPM3 was composed of myofibrils with MyHC-2a. The results suggested that a fiber expressing MyHC-2a would be regulated delicately by changing the TPM isoform types. PMID- 20163591 TI - Formation of zinc protoporphyrin IX in Parma-like ham without nitrate or nitrite. AB - Zinc protoporphyrin IX (ZPP) is a characteristic red pigment in meat products that are manufactured without the addition of a curing agent such as nitrate or nitrite. To examine the effects of impurities such as mineral components in sea salt on the formation of ZPP, we manufactured Parmatype dry-cured hams that were salted with refined salt or sea salt and examined the involvement of oxidation reduction potential (ORP) in the formation of ZPP. The content of ZPP was increased drastically after 40 weeks. Microscopic observation showed strong fluorescence caused by ZPP muscle fiber after 40 weeks. Conversely, heme content varied considerably during processing. ORP increased during processing. However, there was no obvious difference between ham salted with refined salt and that salted with sea salt. Therefore, it was concluded that impurities in sea salt were not involved in the formation of ZPP. PMID- 20163592 TI - A cell preparation of Enterococcus faecalis strain EC-12 stimulates the luminal immunoglobulin A secretion in juvenile calves. AB - The immune system in juvenile calves is immature, so calves are susceptible to several diarrheal and respiratory diseases. Oral administration of lactic acid bacteria (LAB) is known to improve the growth performance and prevent diarrheal and respiratory diseases by stimulating the immune system in juvenile calves. Most of the immunostimulation by LAB is achieved by their cell wall components, and therefore we evaluated the immunostimulation of the cell preparation of Enterococcus faecalis strain EC-12 (EC-12) in juvenile calves in a clinical field. Twenty-nine 1-week old calves were used. Fourteen calves were administered 0.2% (w/w) of an EC-12 preparation that supplemented a milk replacer, and other calves were not supplemented. Feces and serum was collected at day 0, 7 and 49 after the administration to measure the IgA and IgG concentration. The fecal IgA concentration was increased by EC-12 administration at day 49, and the serum IgA concentration was also increased at day 7. These results suggested that oral administration of EC-12 in juvenile calves might have an immunostimulatory effect and provide earlier recovery of IgA levels in mucosal immunity. PMID- 20163593 TI - Goat milk acceptance and promotion methods in Japan: The questionnaire survey to middle class households. AB - A consumer questionnaire conducted with the purpose of ascertaining the acceptability of goat milk and related products in Japan was carried out on 345 guarantees of Nippon Veterinary and Life Science University in December 2006. 275 effective responses (79%) representing middle class urban households were returned. The results revealed that (1) 30% of respondents have experienced drinking goat milk and only 10% are aware of the current retail situation of goat milk and related products; (2) over 70% of goat milk drinkers raised goats by hand at some point in their past and their first experience drinking goat milk was in infancy; (3) those with experience in drinking goat milk expressed a vague evaluation and minimal understanding of drinking goat milk; (4) respondents who were inexperienced goat milk drinkers expressed a strong desire to taste and a weak desire to purchase goat milk; (5) respondents expressed low recognition regarding retailed goat milk products, but those who had already purchased goat milk products expressed a high evaluation and strong desire to purchase these products again; and (6) recognition of goat milk characteristics is low, but those with high recognition also rate goat milk highly. Goats are perceived as being 'mild and familiar.' It is necessary for those who manage goat husbandry to present goat milk and related product tasting opportunities to consumers. The key point is to make the functional differences between cow and goat milk clear and present the advantages of goat milk at the fore of this promotion. Goat milk should not be promoted merely as a drink that is similar to cow milk, but must be positioned as a functional drink or health food in order to expand the Japanese goat milk market. PMID- 20163594 TI - A simple and efficient method for extraction of PCR-amplifiable DNA from chicken eggshells. AB - Recently, we reported a method for discriminating a Japanese brand of chicken, the Hinai-jidori. As an application of this method for discriminating Hinai jidori eggs, we here report an efficient method for extracting maternal DNA from eggshells. Eggshell powder was completely decalcified with EDTA solution, and then DNA was isolated by conventional phenol-chloroform extraction and ethanol precipitation. The efficiency of DNA recovery from eggshells was 50-fold higher than that of a previously reported method. The recovered DNA could be used for PCR, and 10 markers for identifying the Hinai-jidori chicken were detected. The genotypes of the Hinai-jidori exactly matched those of the Hinai-dori breed. Using this method, Hinai-jidori and Hinai-dori eggs could be distinguished from the eggs of Rhode Island Reds. This is the first report of a technique that can be used to discriminate the eggs of Hinai-jidori from those of other chickens, and it can also be utilized to validate the labeling of Hinai-jidori eggs in the market. PMID- 20163595 TI - Health-beneficial effects of probiotics: Its mode of action. AB - It is now widely recognized that probiotics have health-beneficial effects on humans and animals. Probiotics should survive in the intestinal tract to exert beneficial effects on the host's health. To keep a sufficient level of probiotic bacteria in the gastrointestinal tract, a shorter interval between doses may be required. Although adherence to the intestinal epithelial cell and mucus is not a universal property of probiotics, high ability to adhere to the intestinal surface might strongly interfere with infection of pathogenic bacteria and regulate the immune system. The administration of probiotic Lactobacillus stimulated indigenous Lactobacilli and the production of short-chain fatty acids. This alteration of the intestinal environment should contribute to maintain the host's health. The immunomodulatory effects of probiotics are related to important parts of their beneficial effects. Probiotics may modulate the intestinal immune response through the stimulation of certain cytokine and IgA secretion in intestinal mucosa. The health-beneficial effects, in particular the immunomodulation effect, of probiotics depend on the strain used. Differences in indigenous intestinal microflora significantly alter the magnitude of the effects of a probiotic. Specific probiotic strains suitable for each animal species and their life stage as well as each individual should be found. PMID- 20163596 TI - A fine map for maternal lineage analysis by mitochondrial hypervariable region in 12 Chinese goat breeds. AB - As the fast pace of genomic research continues to identify mitochondrial lineages in animals, it has become apparent that many independent studies are needed to support a robust phylogenetic inference. The aim of this study was thus to further characterize the maternal lineage, proposed to originate in southwestern region of China, using a wider survey of diverse goat breeds in China. To this end, we sequenced the mitochondrial hypervariable region 1 (HVR1) of the mtDNA control region in 145 goats of 12 Chinese breeds. Phylogenetic analysis revealed that Chinese goats were classified into four distinct lineages (A, B, C and D) as previously reported. A Mantel test and the analysis of Analysis of Molecular Variance (ANOVA) indicated that there was not an obvious geographic structure among Chinese goat breeds. Population expansion analysis based on mismatch distribution and Fu's Fs statistic indicate that two expansion events in Chinese goats occurred respectively at about 11 and 29 mutational time units ago, revealing two star-like subclades in lineage B corresponding to two population expansion events. Moreover, lineage B sequences were presented only in the breeds of southwestern or surrounding regions of China. Multiple lines of evidence from this study and previous studies indicate that for Chinese goats mtDNA lineage B originated from the southwestern region of China. PMID- 20163597 TI - Increased blood concentration of isopropanol in ketotic dairy cows and isopropanol production from acetone in the rumen. AB - To evaluate acetone and isopropanol metabolism in bovine ketosis, the blood concentrations of isopropanol, acetone, plasma 3-hydroxybutyrate (3-HB) and other metabolites were analyzed in 12 healthy controls and 15 ketotic dairy cows including fatty liver and inferior prognosis after laparotomy for displaced abomasum. In ruminal fluid taken from 6 ketotic cows, ruminal isopropanol and acetone were also analyzed. Ketotic cows showed higher concentrations of isopropanol, acetone, 3-HB and nonesterified fatty acid, and higher activities of aspartate transaminase and gamma-glutamyl transferase than control cows. Blood samples had higher concentration of isopropanol accompanied by increased acetone. In the ketotic cows, acetone was detected not only in blood but also in ruminal fluid, while higher ruminal isopropanol did not necessarily accompany its elevation in the blood. Using 2 steers with rumen cannula, all ruminal content was emptied and then substituted with artificial saliva to evaluate the importance of ruminal microbes in isopropanol production. Under each condition of intact and emptied rumen, acetone was infused into the rumen and blood isopropanol was analyzed. The elevation in the blood isopropanol concentration after acetone infusion was markedly inhibited by the emptying. Here, increased blood concentrations of isopropanol and acetone were observed in ketotic cows, and the importance of ruminal microbes in isopropanol production was confirmed. PMID- 20163598 TI - Effect of flow parameters of rumen digesta on effective degradability and microbial yield in sheep. AB - The aim of this experiment was to examine the effect of rumen digesta flow parameters on effective degradability (EDG) and microbial nitrogen (MBN) yield in sheep fed diets of identical provision of both metabolizable energy and rumen degradable nitrogen (RDN). Ruminal degradation parameters of early-harvested perennial ryegrass hay (EH), late-harvested perennial ryegrasses hay (LH) and winter sown barley straw (BS) were determined by a nylon bag technique. Subsequently, three experimental diets (EHD, LHD and BSD) were formulated using the tested forages, sucrose and urea as supplements. An in vivo feeding study was conducted using four rumen cannulated sheep in a partial Latin square design. Digestibility, rate constants of rumen particle breakdown and passage, ruminal fermentation parameters and MBN supply to the small intestine were determined. Animals thoroughly consumed the forages fed at a restricted level. Digestion coefficients were greater for EHD than for LHD and were lowest for BSD (P < 0.05). The rate constant of large particle breakdown was 4.3, 5.9 and 6.7 %/h, respectively, and small particle passage was 5.3, 4.7 and 6.3 %/h for EHD, LHD and BSD, respectively. The estimates differed (P < 0.05) between the diets. The overall passage rate constant of total rumen particles was estimated to be higher for BSD than that for EHD or LHD (P < 0.05). Ruminal fermentation parameters were unaffected by dietary treatments (P > 0.05). Intake levels of rumen degradable organic matter (RDOM) and RDN were estimated to be greater for LHD than that for EHD or BSD (P < 0.05). Although dietary arrangements were made to give identical microbial efficiency, the estimated value was higher for EHD than that for LHD or BSD (P < 0.05); and the MBN yield for BSD was estimated to be lower than that for EHD or LHD (P < 0.05). Rumen kinetic parameters of degradation and particle flow of forage affected EDG values and MBN yield from forage-related RDN intake, although those had little effect on the efficiency of MBN yield from forage related RDOM intake. PMID- 20163599 TI - Silage preparation and nutritive value of Chinese yam by-product. AB - The objective of this experiment was to determine the ensiling characteristics, nutrient composition and nutritive value of Chinese yam by-product (CYBP) silage treated without additive (Control), with lactic acid bacteria (LY), with dried beet pulp (BY), or with mixtures of lactic acid bacteria and dried beet pulp (LBY) for a fermentation period of 150 days. The nutritive value of CYBP silage was studied in an in vivo digestibility trial using wethers in a 4 x 4 Latin square design. Addition of lactic acid bacteria and/or dried beet pulp greatly improved fermentation quality of CYBP silage. The pH was reduced to below 4.0 and lactic acid was produced at above 4.6% on dry matter basis. There were no statistical differences among treatments in the digestibilities of dry matter, organic matter, crude protein and energy in the silages, but neutral detergent fiber and acid detergent fiber digestibility were higher (P < 0.001) in wethers fed BY and LBY silages compared to the control and LY silages. It was estimated that total digestible nutrient and digestible energy in the CYBP silage averaged 79.1% and 14.3 MJ/kg on dry matter basis. The study suggests that CYBP can be well preserved by making a silage and it is a good potential energy source for ruminant diets. PMID- 20163600 TI - Effects of diets containing alfalfa hay or barley flour mixed alfalfa silage on feeding behavior, productivity, rumen fermentation and blood metabolites in lactating cows. AB - The effects of barley flour on the fermentation parameters of alfalfa silage and on the productivity of dairy cows were investigated. Alfalfa forage was ensiled either with or without barley flour. Barley flour was soaked in water for 24 h before being mixed with alfalfa (12 kg: 100 kg dry matter bases) at ensiling. Eighteen multi-parous cows were assigned to three equal treatment groups using a completely randomized design. Three isocaloric and isonitrogenous total mixed rations containing alfalfa hay, ordinary alfalfa silage or barley flour mixed alfalfa silage were then prepared. The concentrations of ammonia nitrogen, acetic acid and butyric acid were lower in barley flour mixed alfalfa silage compared to that in ordinary alfalfa silage but the concentration of lactic acid was lower in the ordinary alfalfa silage. Feeding behavior, milk yield and composition, ruminal fermentation and blood metabolites were measured. Although dry matter intake and milk production were not affected, the effect of preparation of alfalfa influenced feeding behavior and rumen fermentation parameters. Cows on alfalfa silage diets spent longer ruminating compared to those fed alfalfa hay. The ruminal ammonia nitrogen and blood urea were affected by ensiling (alfalfa hay versus alfalfa silages) while both parameters were lower in cows fed on barley flour mixed alfalfa silage than those fed on ordinary silage. Although similar blood glucose was recorded for cows fed on alfalfa silages, it was higher in cows fed on alfalfa hay. It is concluded that the addition of barely flour when making alfalfa silage may improve both the fermentation process during ensilage and the ruminal ammonia nitrogen utilization with no significant effects on productivity. PMID- 20163601 TI - Effects of the fattening period on the fatty acid composition of fat deposits and free amino acid and inosinic acid contents of the longissimus muscle in carcasses of Japanese Black steers. AB - The effects of the fattening period on carcass characteristics, fatty acid composition of fat deposits, and muscle free amino acid (FAA) and inosinic acid (IMP) contents were evaluated in Japanese Black steers. Ten castrated, 10-month old calves derived from the same sire were divided into five to be slaughtered at the age of 30 months after a 20-month fattening period (20-month group) and five to be slaughtered at the age of 34 months after a 24-month fattening period (24 month group). Concerning the fatty acid composition of subcutaneous fat, the percentage of palmitoleic acid was higher (P < 0.05) in the 24- than in the 20 month group, but no difference was noted in any other fatty acids. For intermuscular fat, no difference was observed in any fatty acids. The percentages of oleic acid and total monounsaturated fatty acid of intramuscular and perinephric fat were higher (P < 0.05) in the 24- than in the 20-month group. Of the FAAs in the longissimus thoracis muscle, the threonine and tyrosine contents were lower (P < 0.05) in the 24- than in the 20-month group. The IMP content was higher (P < 0.05) in the 24- than in the 20-month group, suggesting an effect of prolongation of the fattening period. PMID- 20163602 TI - Effects of maize (Zea mays L.) silage feeding on dry matter intake and milk production of dairy buffalo and cattle in Tarai, Nepal. AB - To identify the effects of whole crop maize silage (MS) as a substitute for rice straw (RS) on feed intake and milk production of mid-late lactating buffalo and cattle in Tarai, Nepal, eight Murrah and eight Jersey-Hariana were fed the basal diet, RS (ad libitum) with concentrate (0.68% of bodyweight [BW] on a dry matter [DM] basis). A 4 x 4 Latin square design experiment was conducted in each animal species with graded levels of MS substitution for RS (0%, T1; 33%, T2; 67%, T3 and 100%, T4). The MS had higher digestibility and total digestible nutrient (TDN) than RS. The DM intake per BW of the both species was highest in T3. The substitution of MS for RS increased the crude protein intake and the TDN intake in the both species. Although the buffalo showed the highest milking performance in T4, the cattle showed no significant differences in their milking performance among the treatments. The substitution of MS for RS improved the feed intake and milk production in the buffalo. On the other hand, the milk yield was not raised in the cattle, though the feed intake was increased by the substitution. PMID- 20163603 TI - Central L-cysteine induces sleep, and D-cysteine induces sleep and abnormal behavior during acute stress in neonatal chicks. AB - L-cysteine (L-Cys) is a non-essential and glycogenic amino acid. Previously, we reported that the intracerebroventricular (i.c.v.) injection of L-Cys induced sedative effects under isolation-induced stress in neonatal chicks. L-Cys has an optical isomer, D-Cys. The aim of this study was to clarify the effect of L-Cys and D-Cys during a stressful condition in chicks. The i.c.v. injection of L-Cys and D-Cys (0.84 micromol) decreased both distress vocalization and spontaneous activity induced by isolation. However, the two cysteine isomers induced different behaviors. L-Cys increased sleep-like behavior while D-Cys caused abnormal behavior including syncope as well as sleep-like behavior. In conclusion, while both L-Cys and D-Cys caused a sedative effect when injected i.c.v, D-Cys caused abnormal behavior and may be detrimental to neonatal chicks. PMID- 20163604 TI - Brewer's yeast efficiently degrades phytate phosphorus in a corn-soybean meal diet during soaking treatment. AB - Microbes such as yeast and Aspergillus are known to produce phytase, and Aspergillus phytase has been used as a feed additive for improving phytate phosphorus bioavailability in monogastric animals. We measured phytase activity in some by-products from fermented food and beverage productions by yeast and Aspergillus. The phytase activity was as high as 3577 and 2225 PU/kg DM in raw and dried brewer's yeasts, respectively. On the other hand, the phytase activity was approximately 400 PU/kg DM in white-wine yeast and red-wine yeast. The phytase activity was further low in natto (fermented soybean) residue, soy sauce cake, rice brewer's grain and the activity was not detected in dried corn-barley distiller's grain with soluble and sweet-potato distiller's residue. The stability of phytase against pepsin was much lower in the brewer's yeast than in an Aspergillus phytase preparation. On the other hand, the addition of raw brewer's yeast effectively degraded phytate phosphorus in a corn-soybean meal diet during soaking. These results suggest that phytase in the examined by products is not suitable for the phytase source of conventional diets, but that the soaking treatment with a raw brewer's yeast is an alternative method for improving phytate-phosphorus bioavailability in corn-soybean meal diets for pigs. PMID- 20163605 TI - Effect of high moisture storage of pearl millet (Pennisetum typhoides) with or without feed enzymes on growth and nutrient utilization in broiler chickens. AB - Effect of reconstitution of pearl millet with or without enzymes on its utilization in broiler chickens was studied. The pearl millet grains were reconstituted by adding water to raise the moisture level to 30%, followed by storage in sealed plastic buckets with or without feed enzymes (0.5 g/kg) for 21 days at room temperature (25 degrees C). Subsequently, the grains were sun-dried to reduce the moisture content up to 10% to avoid mould growth. Nine dietary treatments were formulated incorporating pearl millet either raw with or without enzymes or reconstituted with or without enzymes in maize-soya based control diet replacing maize at 50 and 75% levels. The birds fed on diets containing enzyme reconstituted pearl millet accrued higher body weight than maize based control diet. Addition of enzymes to raw pearl-millet based diet improved the body weight gain significantly. The reconstitution of pearl millet with or without enzymes increased (P < 0.01) the dietary nitrogen corrected apparent metabolizable energy (AMEn) values and the highest improvement (6.11%) was recorded in diets containing pearl millet reconstituted with enzymes at 75% level of maize replacement. The percent nitrogen retention in pearl millet based diets was comparable to maize based control diet. It may be concluded that the supplementation of the feed enzymes or reconstitution of pearl millet may improve the utilization of pearl millet in broiler chickens. PMID- 20163606 TI - Immunolocalization of lingual antimicrobial peptide (LAP) in the bovine mammary gland. AB - Lingual antimicrobial peptide (LAP), a member of the beta-defensin family in cows, is involved in the innate immune system and plays a crucial role in killing a large variety of microorganisms. The aim of the present study was to demonstrate the immunolocalization of LAP in the mammary glands of cows. A LAP antibody was raised in a rabbit by immunity with a synthetic 11 amino acid sequence out of a 42-amino acid sequence of the mature form of LAP. The specificity of the LAP antibody was checked using a competitive immunoassay and Western blotting. Paraffin sections of the mammary gland were immunostained with LAP antibody. In the competitive immunoassay, an increase of synthetic LAP concentration suppressed the optical density. Western blotting analysis for LAP revealed the presence of the LAP peptide in mammary alveolar tissue. When the mammary gland was immunostained with LAP antibody, epithelial cells of both infected and non-infected alveoli were immunopositive. These results indicate that LAP is localized in the epithelium of non-infected as well as infected alveolus in the mammary gland in cows. PMID- 20163607 TI - Immunohistochemical and scanning electron microscopic comparison of the collagen network constructions between pig, goat and chicken livers. AB - The distribution and three-dimensional architecture of collagen fibers were compared between pig, goat and chicken livers. Immunohistochemical staining revealed that collagen type I was identified in the interlobular connective tissue region and intralobular areas in pigs and goats. Type III collagen was also identified in the interlobular connective tissue region and intralobular sinusoidal walls. In the chicken liver, only the circumference region of the vessels was immunostained with collagen type I and III antibodies and the interlobular connective tissue wall could not be distinguished clearly. In the intralobular region, collagen type I antibody immunoreacted around the hepatic cells but collagen type III antibody immunoreacted weakly. In the NaOH macerated specimen, well-developed collagen bundles formed the prominent interlobular walls in pigs. In contrast, the wall in the goat liver comprised a thin layer of the bundles. In the chicken liver, there were no notable collagen septa between lobules. The intralobular collagen construction was quite different between the animals, indicating a fragile collagen fibril networks in pigs, a robust framework in goats and dense fabric-like septa in chickens. These results indicate that the distinct collagen frameworks may contribute to the histological strength of the livers in each of the animal species. PMID- 20163608 TI - Effects of crossbreeding indigenous Hair Goat with Saanen on carcass measurements and meat quality of kids under an intensive production system. AB - The aim of study was to investigate the effect of genotype on carcass measurements and meat quality characteristics of purebred Hair Goat, Saanen x Hair Goat (F(1) and B(1)) kids under an intensive production system. In total, 24 kids were slaughtered at the age of approximately 133 days. Kids were fattened for 56 days immediately after weaning. Hot carcass weights were 6.78, 7.61 and 7.02 kg and dressing percentages were 49.71, 49.27 and 48.78%, respectively (P > 0.05). Differences between genotypes for carcass measurements and indexes were not significant. Effect of genotype on pH measurements, drip loss, water holding capacity, cooking loss and Warner Bratzler shear force values were not significant. Meat lightness values at 0 h, 1 h and 1 day after cutting were higher in crossbred kids than Hair Goat kids (P < 0.05). Redness value was significantly higher in meat samples of Hair goat kids at 0 h, 1 h and 1 day measurements (P < 0.05). Kid genotype had no significant effect on meat sensory characteristics, except tenderness. Panelists gave lower scores for meat tenderness to F(1) and B(1) crosses compared to purebred Hair Goat kids. In conclusion, higher meat lightness values of crossbred kids, at particularly B(1) level, might have a positive effect on the consumer choices. PMID- 20163609 TI - Effects of dietary supplementation with conjugated linoleic acid on fatty acid composition and lipid oxidation in chicken breast meat. AB - We investigated the effects of dietary conjugated linoleic acid (CLA) on fatty acid composition and lipid oxidation in breast meat of broiler chickens. Broiler chickens (28-day-old females) were fed diets containing experimental oils at 20 g/kg diet for 28 days. The experimental oils consisted of either a 2:0, 1:1, or a 0:2 (wt : wt) ratio of safflower oil (high linoleic acid content) to a commercial CLA mixture. In this study, dietary CLA supplementation significantly increased the composition and content of CLA in chicken meat. The predominant CLA in meat from birds with supplemented diets was the cis-9, trans-11 isomer. The proportion of saturated fatty acid in meat significantly increased with increasing CLA supplementation, with a corresponding decrease in monounsaturated fatty acid. Dietary CLA also reduced thiobarbituric acid reactive substances (TBARS) values in raw meat during storage at 4 degrees C for 5 days. These results provide evidence that CLA feeding is a practical strategy not only for adding nutritional benefits to chicken meat but also for improving meat quality including oxidative stability. PMID- 20163610 TI - Nitrogen, phosphorus and potassium utilization and their cycling in a beef-forage production system. AB - The objective of this study was to quantify nitrogen (N), phosphorus (P) and potassium (K) utilization and their cycling in a beef-forage production system. A survey was conducted at the Kyoto University experimental farm in Kyoto Prefecture, Japan, and included 9.5 ha of meadow and about 160 head of beef cattle. Forages cultivated on the meadow were ensiled and offered to breeding cows. The whole farm was regarded as a beef-forage production system. The system consisted of three components: animals, manure and soil/crop. Nutrient inputs, flows through the soil-plant-animal pathway and outputs were quantified for 2 periods for the whole farm. Nutrient utilization was evaluated by nutrient balances, utilization efficiencies (ratio of nutrient export to nutrient input) and cycling index. The average nutrient balances of N, P and K for the whole farm (kg/year/ha) were 435.7, 136.3, and 262.8, and the average nutrient utilization efficiencies were 0.08, 0.06, and 0.01, respectively. The characteristics of nutrient balances and utilization efficiencies for each component differed among the nutrients. The average cycling indices for N, P and K were 0.19, 0.17 and 0.49, respectively. This study illustrates the importance of internal nutrient cycling for improving nutrient utilization in beef production systems. PMID- 20163611 TI - Novel SNP in 5' flanking region of EDG1 associated with marbling in Japanese Black beef cattle. AB - Marbling, defined by the amount and distribution of intramuscular fat, is an economically important trait of beef cattle in Japan. The endothelial differentiation, sphingolipid G-protein-coupled receptor, 1 (EDG1) gene has been considered as a positional functional candidate for the gene responsible for marbling. We have recently reported that 2 single nucleotide polymorphisms (SNPs), c.-312A>G in the 5' untranslated region (UTR) and c.*446G>A in the 3' UTR in EDG1 were associated with marbling in Japanese Black beef cattle, but this was not functional and a causal mutation for marbling. In the present study, we detected 2 novel SNPs, referred to as g.1475435G>A and g.1471620G>T, in the 5' flanking region of the EDG1 between low-marbled and high-marbled steer groups, which were previously shown to have EDG1 expression differences in musculus longissimus muscle. The g.1475435G>A SNP seemed not to segregate in Japanese Black beef cattle. The g.1471620G>T SNP was associated with the predicted breeding value for beef marbling standard number by the analyses using Japanese Black beef cattle population. Based on these findings, we hypothesized that the g.1471620G>T SNP might have an impact on EDG1 expression and also marbling. PMID- 20163612 TI - Investigation of Gibbs sampling conditions to estimate variance components from Japanese Black carcass field data. AB - The genetic evaluation using the carcass field data in Japanese Black cattle has been carried out employing an animal model, implementing the restricted maximum likelihood (REML) estimation of additive genetic and residual variances. Because of rapidly increasing volumes of the official data sets and therefore larger memory spaces required, an alternative approach like the REML estimation could be useful. The purpose of this study was to investigate Gibbs sampling conditions for the single-trait variance component estimation using the carcass field data. As prior distributions, uniform and normal distributions and independent scaled inverted chi-square distributions were used for macro-environmental effects, breeding values, and the variance components, respectively. Using the data sets of different sizes, the influences of Gibbs chain length and thinning interval were investigated, after the burn-in period was determined using the coupling method. As would be expected, the chain lengths had obviously larger effects on the posterior means than those of thinning intervals. The posterior means calculated using every 10th sample from 90,000 of samples after 10,000 samples discarded as burn-in period were all considered to be reasonably comparable to the corresponding estimates by REML. PMID- 20163613 TI - Association of BoLA-DRB3 alleles identified by a sequence-based typing method with mastitis pathogens in Japanese Holstein cows. AB - The association of the polymorphism of bovine leukocyte antigen (BoLA-DRB3) genes identified by the polymerase chain reaction sequence-based typing (PCR-SBT) method with resistance and susceptibility to mastitis caused by pathogenic bacteria was investigated. Blood samples for DNA extraction were collected from 194 Holstein cows (41 healthy cows and 153 mastitis cows including 24 mixed infection cows infected with 2 or 3 species of pathogens) from 5 districts of Chiba prefecture, Japan. Sixteen BoLA-DRB3 alleles were detected. The 4 main alleles of DRB3*0101, *1501, *1201, and *1101 constituted 56.8% of the total number of alleles detected. Mastitis cows were divided into 2 groups: group 1 with single-infection cows and group 2 with all mastitis cows including 24 mixed infection cows. The differences in the frequencies of BoLA-DRB3 alleles and the number of cows homozygous or heterozygous for each BoLA-DRB3 allele between healthy cows and the 2 groups of mastitis cows were evaluated. Furthermore, similar comparisons were performed between healthy cows and the 2 groups of mastitis cows for each mastitis pathogen. It was considered that the 4 alleles, namely, DRB3*0101, *1501, *1201, and *1101 had specific resistance and susceptibility to 4 different mastitis pathogens. Thus, DRB3*0101 might be associated with susceptibility to coagulase-negative Staphylococci and Escherichia coli, and DRB3*1501 might be associated with susceptibility to Escherichia coli. However, DRB3*1101 might be associated with resistance to Streptococci and coagulase-negative Staphylococci, and DRB3*1201, with resistance to Streptococci, Escherichia coli, and Staphylococcus aureus. PMID- 20163614 TI - Association of the amino acid motifs of BoLA-DRB3 alleles with mastitis pathogens in Japanese Holstein cows. AB - The association of the polymorphism of bovine leukocyte antigen (BoLA-DRB3) genes, identified by the polymerase chain reaction sequence-based typing (PCR SBT) method, with resistance and susceptibility to mastitis caused by Streptococci, coagulase-negative Staphylococci, Escherichia coli and Staphylococcus aureus was investigated. Blood samples for DNA extraction were collected from 170 Holstein cows (129 mastitis and 41 healthy cows) from 5 districts in Chiba prefecture, Japan. Susceptibility or resistance to the mastitis-causing pathogens was thought to vary by the presence of amino acid substitutions at the 9, 11, 13, and 30 positions. DRB3*0101 and DRB3*1501 had amino acid motifs of Glu(9), Ser(11), Ser(13), and Tyr(30), and they were considered to have susceptibility to all 4 mastitis pathogens. In contrast, DRB3*1101 and DRB3*1401 had amino acid motifs of Gln(9), His(11), Gly(13), and His(30) in these positions, and they also had Val(86), so these alleles were considered to have resistance to Streptococcal and coagulase-negative Staphylococcal mastitis. However, in the case of Escherichia coli mastitis, amino acid substitutions at the 9, 11, 13, and 30 positions had little effect, but rather substitutions at the 47, 67 positions of pocket 7, and at the 71, 74 positions of pocket 4, Tyr(47), Ile(67), Ala(71), and Ala(74), were associated with resistance. This motif was present in DRB3*1201. PMID- 20163615 TI - Gene and haplotype polymorphisms of the Prion gene (PRNP) in Japanese Brown, Japanese native and Holstein cattle. AB - Polymorphisms in the prion protein gene (PRNP) are known to be associated with transmissible spongiform encephalopathies in human, sheep and goats. There is tentative association between PRNP promoter polymorphism and bovine spongiform encephalopathy (BSE) susceptibility in cattle. In this study, we genotyped for six bovine PRNP polymorphic sites including a 23-bp indel in the promoter, a 12 bp indel in the intron 1, two nonsynonymous single nucleotide polymorphisms (SNPs), octapeptide repeats in the coding region and a 14-bp indel in the 3' untranslated region in 178 animals representing Japanese Brown, Kuchinoshima feral, Mishima, Japanese Shorthorn and Holstein. In 64 Japanese Brown cattle, three indel sites were polymorphic. All of the six sites were monomorphic in Kuchinoshima. The 23-bp and 12-bp indel sites were polymorphic in Mishima cattle. The 23-bp and 14-bp indel sites were polymorphic in Japanese Shorthorn cattle. Both SNP sites were monomorphic in all cattle examined in this study. At the 23 bp indel site, the genotype frequencies of Japanese Brown and Holstein breeds were similar to that of BSE affected cattle. We estimated 12 different haplotypes from these genotypic data. A '23-12-K6S14+' haplotype was the major haplotype in all populations, whose frequencies ranged from 0.50 to 1.00. PMID- 20163616 TI - Genetic diversity of growth hormone receptor gene in cattle. AB - Growth hormone receptor (GHR) belongs to a member of the cytokine receptor superfamily. Polymorphism of presence or absence of an approximately 1.2 kbp LINE 1 element is observed in bovine GHR gene. The present study was carried out for estimating the genetic diversity and the origin of the LINE-1 element in 10 European, Southeastern Asian and East Asian cattle breeds or populations. Genotyping of the LINE-1 revealed predominant LINE-1 presence in European breeds (0.917-0.991), absence in the Bos taurus indicus populations (0.000-0.017), and intermediate presence in Northeast Asian cattle (0.417-0.522). From genetic features of LINE families, LINE-1 of GHR could be attributed to the same origin in both European and Asian cattle, and Asian LINE-1 may not be derived from recent introgression. This result suggested that LINE-1 in bovine GHR gene could have arisen in an ancestral population of Bos taurus taurus. PMID- 20163617 TI - Effect of different levels of Quebracho tannin on nitrogen utilization and growth performance of Najdi sheep fed alfalfa (Medicago sativa) hay as a sole diet. AB - A commercial tannin source (Quebracho tannin, QT), containing 75% condensed tannins (CT) in dry matter (DM) was used to evaluate the effects of addition of different levels of QT to alfalfa hay on the in vitro degradation kinetics of organic matter (OM) and nitrogen (N) in experiment 1 (Exp. 1), N utilization and microbial N synthesis (MNS) in experiment 2 (Exp. 2) and growth performance of growing Najdi lambs in experiment 3 (Exp. 3). Alfalfa hay was treated with QT at the levels of 0, 1, 2 and 3% of DM to form four treatments of QT0, QT1, QT2 and QT3 to have actual levels of CT being 0, 0.75, 1.5 and 2.25% of DM, respectively. Degradation rate and the effective degradability of N were significantly decreased (P < 0.05) for QT2 and QT3 as compared with the QT0. In Exp. 2, digestibility coefficients for OM, neutral detergent fiber and acid detergent fiber were significantly decreased (P < 0.05) at QT3, whereas QT1 and QT2 showed no difference to QT0. In the metabolism trial (Exp. 2), digested N (DN) and urinary N (UN) excretion for QT2 and QT3 were significantly decreased (P < 0.05) compared to QT0 and QT1. The DN and UN as percentage of N intake were 79.2, 76.9, 75.5 and 69.8%; and 24.4, 22.6, 19.9 and 19.6% for QT0, QT1, QT2 and QT3, respectively. QT2 had the highest MNS and the lowest value was in QT3, the MNS of the treatments were 18.1, 18.7, 19.2 and 15.8 g/day for QT0, QT1, QT2 and QT3, respectively. In the growth trial of 56 days duration (Exp. 3, n = 24 lambs), the addition of QT at the level of QT2 enhanced (P < 0.05) the average daily gain and feed conversion rate compared with the QT0, while, QT1 and QT3 had intermediate values. It is concluded that alfalfa hay treated with QT at the level of 2% of DM could be used to protect alfalfa N from ruminal degradation that would lead to improve growth performance of lambs. PMID- 20163618 TI - Effect of fatty acids added to the milk replacer on white scour and excretion of fatty acids in Holstein calves. AB - In order to examine the relationship between white scour and fatty acids, we added fatty acids to the milk replacer. Twenty healthy Holstein calves were divided into 4 groups, five calves per group; a control group with no fortified fatty acid, and 3 groups fed either with oleic, stearic, or palmitic acid, respectively. The calves were fed milk replacer (5% of the calf's body weight) twice a day but the fatty acids (2 wt % of milk replacer) were added only once. The fecal and blood samples were obtained at 0, 12, 24, 36, and 48 h after feeding of the acids. All five calves in the palmitic acid group, and 3 out of 5 calves each in the stealic and the oleic acid groups had whitish feces after feeding fatty acid. The stearic acid group had a significantly elevated stearic acid concentration in the feces during 24-36 h compared to the pre-feeding level. The fecal concentration of palmitic acid increased significantly at 24-36 h in the palmitic acid group. We concluded that the long-chain saturated fatty acids are one of the causes of white scour in calves. PMID- 20163619 TI - The effect of dietary ratios of corn silage and alfalfa hay on carbohydrate digestion and retention time of feed particles in the gastrointestinal tract of steers. AB - Four Holstein steers fitted with duodenal cannula were used in a 4 x 4 Latin square design to investigate the effect of the combination of corn silage (CS) and alfalfa hay (AH) in different ratios on the ruminal and intestinal digestion of carbohydrates and feed particle passage rate. Steers were fed mixed diets containing both CS and AH in ratios of 80:20, 60:40, 40:60 and 20:80 on a dry matter basis at 95% of ad libitum feed intake. The increase of AH proportion in diets increased dry matter intake and ruminal digestion of dry matter, non-fiber carbohydrate, neutral and acid detergent fiber linearly. Ruminal digestibility of neutral detergent fiber showed a quadratic response, and total digestibility increased linearly with increasing AH proportion. Digestibility of acid detergent fiber in the rumen was not affected by the dietary treatments, but the total tract digestibility increased as the AH proportion increased. Mean retention time of feed particles in total compartment increased when the AH proportion increased from 20% to 60%, but decreased with further increase of the AH proportion. These results indicate that moderate combinations of CS and AH have an associative effect on ruminal fiber digestion, modifying particle movement in the rumen. PMID- 20163620 TI - An epidemiological survey on pigs showing symptoms of infectious enteric diseases and dyspepsia in Japan. AB - Diarrhea in pigs has the potential to have a serious economic impact on the swine industry. Previously, we suggested that the likely cause of the presence of non infectious diarrhea in pigs characterized by lactate accumulation was dyspepsia. In this experiment, the prevalence of enteropathogens and hyper-lactate accumulation in feces of piglets in 4 distinct growth stages was examined. The feces were collected when veterinarian experts recognized abnormalities in sporadic outbreaks. Prevalence of enteropathogens in diarrheal feces was 100% in fattening pigs (FP), 75% in weaning pigs (WP), 50% in suckling pigs (SP), and 42% in growing pigs (GP). Prevalence of enteropathogens in loose feces was 53% in WP, 50% in SP, 40% in FP, and 28% in GP. Prevalence of hyper-lactate accumulation in diarrheal feces was 33% in GP, 33% in SP, 25% in WP, and 25% in FP. Prevalence of hyper-lactate accumulation in loose feces was 40% in GP, 0% in SP, 7% in WP, and 5% in FP. Accordingly, non-infectious dyspepsia is frequent in growing pigs. In this period, pigs are potentially exposed to needless antimicrobial therapeutic treatments in sporadic cases. PMID- 20163621 TI - The molecular mechanism underlying the reduction in abdominal fat accumulation by licorice flavonoid oil in high fat diet-induced obese rats. AB - Licorice (Glycyrrhiza glabra) has been widely used in traditional medicines, and its flavonoid oil (LFO) decreases abdominal adipose tissue weight in mammals. In the present study, we investigated the molecular mechanisms underlying the decrease in abdominal adipose tissue weight by LFO. LFO significantly decreased the mRNA levels of rate-limiting enzymes in the hepatic fatty acid synthetic pathway, whereas LFO significantly increased the mRNA levels of a rate-limiting enzyme in the hepatic fatty acid oxidative pathway. LFO significantly decreased the mRNA levels of sterol regulatory element-binding protein-1c (SREBP-1c) (a transcription factor that promotes hepatic fatty acid synthesis), whereas the mRNA levels of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) (a transcription factor that promotes hepatic fatty acid oxidation) was significantly increased. All our findings suggest that the decrease in abdominal adipose tissue weight by LFO is mediated by the transcriptional regulation of SREBP-1c and PPAR-alpha in the liver. Thus, we infer that the natural ingredient LFO is a promising candidate for use as a feed additive to reduce abdominal fat accumulation in domestic animals. PMID- 20163622 TI - Effects of 5'-uridylic acid feeding on postprandial plasma concentrations of metabolites and metabolic hormones in pre-weaning goats. AB - 5'-Uridylic acid (UMP), which is present at high concentrations in cow's colostrum, has been shown to cause a reduction in increased plasma levels of insulin and glucose after ingestion of milk replacer in pre-weaning calves. However, the precise mechanisms of UMP action have not been investigated, and its action has not been investigated in other pre-weaning ruminants. In order to demonstrate whether UMP causes changes in postprandial metabolic and hormonal parameters in pre-weaning goats, 11 Saanen kids were given milk replacer (twice a day) without (n = 5) or with (n = 6) UMP (1 g for each meal, 2 g/day for each head) for 14 days. Analysis of blood samples taken in the morning of day 14 demonstrated that the feeding of milk replacer with UMP abolished the significant changes in postprandial plasma glucose, NEFA, GH and insulin concentrations induced by feeding of milk replacer alone, and demonstrated a tendency to increase IGF-I levels. However, there was no significant difference between the two groups at any sampling time. We conclude that UMP feeding with milk replacer showed a tendency to blunt the postprandial changes in levels of some plasma metabolites and hormones that are induced by replacer alone in pre-weaning goats. PMID- 20163623 TI - Extracellular signal-regulated kinase (ERK) activation in chicken heterophils stimulated with phorbol 12-myristate 13-acetate (PMA), formyl-methionylleucyl phenylalanine (fMLP) and lipopolysaccharide (LPS). AB - The signaling pathways leading to the activation of extracellular signal regulated kinase (ERK) by phorbol 12-myristate 13-acetate (PMA), formyl methionylleucyl-phenylalanine (fMLP) and lipopolysaccharide (LPS) in chicken heterophils were examined. To determine the mechanism of ERK's activation and its relation with the influx of calcium ions, heterophils were stimulated by PMA, fMLP and LPS. ERK was not activated by fMLP. LPS- and PMA-stimulated activation of ERK, based on Western blotting with antibodies against the phosphorylated form of ERK, was attenuated by the pretreatment of cells with the intracellular calcium chelator BAPTA/AM (1,2-bis (o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid) but not with the extracellular calcium chelator EGTA (glycol-bis(2 aminoethylether)-N,N,N',N'-tetraacetic acid). Exposure of cells to the protein kinase C (PKC) inhibitor GF109203X inhibited the LPS- and PMA-stimulated phosphorylation of ERK in a concentration-dependent manner. The LPS-stimulated phosphorylation was inhibited by pretreatment with the phospholipase C (PLC) inhibitor U73122 but not the phosphatidylinositol 3-kinase (PI(3)K) inhibitor LY294002. These results indicate that the LPS-induced phosphorylation of ERK in the chicken heterophils is mediated by PLC, PKC and intracellular calcium, and the PMA-stimulated phosphorylation is dependent on intracellular calcium ion and PKC. PMID- 20163624 TI - Effects of active immunization against myostatin on carcass quality and expression of the myostatin gene in pigs. AB - The study was conducted to investigate the effects of active immunization against myostatin on the titer of myostatin antibody, carcass evaluation, activity of creatine kinase and the expression of the myostatin gene in pigs. Eighteen pigs were allotted into three groups (six pigs per group), and pigs in treatment 1, 2 and 3 were immunized with physiological saline, 1 mg or 4 mg myostatin per pig, respectively. Six pigs were killed by electrical stunning followed by exsanguination at BW of 100 kg. The results indicated that the titer of myostatin antibody was increased in treated groups compared to the control group on day 42 (P < 0.01) and d 84 (P < 0.01). The carcass lean percentage was significantly increased in the treatment groups compared to the control group (P < 0.01), and intramuscular fat was significantly decreased in the 4 mg group compared to the control group (P < 0.05). The muscle creatine kinase activity of pigs treated with 1 mg and 4 mg myostatin was lower than the control group. The immunization of myostatin significantly decreased the myostatin gene expression levels in muscle. It was concluded that optimal active immunization against myostatin could increase the content of myostatin antibody, suppress the activity of creatine kinase and the expression of myostatin gene, and therefore improve the carcass lean percentage for pigs. PMID- 20163625 TI - Effects of boning method and postmortem aging on meat quality characteristics of pork loin. AB - This work investigated the effects of boning method and postmortem aging on pork loin color, shearing value and sensory attributes. Two experiments were assigned. In Experiment I, 30 Chinese native black pigs were slaughtered and their carcasses were divided into three groups: (i) hot-boning: carcasses were fabricated within 45 min postmortem just after dressing; (ii) cold boning at 24 h: carcasses were fabricated after chilling at 0 degrees C for 24 h; (iii) cold boning at 36 h: carcasses were fabricated after chilling at 0 degrees C for 36 h. In Experiment II, right sides of the second group in Experiment I were used and primal cuts were vacuum packed and aged for 1 day, 8 days and 16 days. Pork loins (Longissimus lumborum) were used for color measurement, shearing test, and sensory evaluation. Among three boning methods, cold-boning at 36 h postmortem had the advantages of giving muscles a better color, the lowest cooking loss and cooked shearing value, and the highest sensory tenderness, juiciness, flavor and overall liking. Postmortem aging could improve pork quality characteristics, but it is not the fact that the longer aging time is, the better pork quality would be. Eight days may be enough to obtain an acceptable sensory attribute. These results are meaningful for pork processing and pork consumption. PMID- 20163626 TI - Identification of a potent immunostimulatory oligodeoxynucleotide from Streptococcus thermophilus lacZ. AB - Immunostimulatory sequences of oligodeoxynucleotides (ODNs), such as CpG ODNs, are potent stimulators of innate immunity. Here, we identified a strong immunostimulatory CpG ODN, which we named MsST, from the lac Z gene of Streptococcus (S.) thermophilus ATCC19258, and we evaluated its immune functions. In in vitro studies, MsST had a similar ability as the murine prototype CpG ODN 1555 to induce inflammatory cytokine production and cell proliferation. In mouse splenocytes, MsST increased the number of CD80+CD11c+and CD86+CD11c+ dendritic cells and CD4+CD25+ regulatory T cells. We also analyzed the effects of MsST on the expression of regulatory cytokines by real-time quantitative PCR. MsST was more potent at inducing interleukin-10 expression than the ODN control 1612, indicating that MsST can augment the regulatory T cell response via Toll-like receptor 9, which plays an important role in suppressing T helper type 2 responses. These results suggest that S. thermophilus, whose genes include a strong Immunostimulatory sequence-ODN, is a good candidate for a starter culture to develop new physiologically functional foods and feeds. PMID- 20163627 TI - Display of a peer's face picture enhances the preference for a pen in preference testing in cows. AB - Using preference testing, we investigated the effect of a brush and a peer's face picture on the welfare of breeding beef cows. Four cows were used in experiment 1 and another four cows were used in experiment 2. An experimental barn consisted of two 3.5 square-meter pens, and a corridor measuring 1.6 m wide and 1.3 m long. During the experiment, either side of the pens were treated. In experiment 1, straw bedding was placed in a treated pen (condition B) in the first two trials, a brush was added in the treated pen (condition BB) in the next two trials, and a peer's face picture was displayed in the treated pen (condition BBF) in the last two trials. In experiment 2, condition B was applied for the first two trials, a peer's face picture was displayed in the treated pen (condition BF) in the next two trials, and condition BBF was applied for the last two trials. Each cow was housed alone from 09.00 hour to 15.00 h in the experimental barn during the six trials. The cows stayed in the treatment pen longer than in the non-treatment pen under all conditions in experiments 1 and 2. In experiment 1, the mean total time spent in the treatment pen was longer under condition BBF than under conditions B and BB. In experiment 2, the mean total time spent in the treatment pen was shorter under condition B than under conditions BF and BBF. The mean percentage of time spent ruminating was greater under condition BBF than under condition B. It is concluded that the cows preferred the peer's face picture in the isolated condition of preference testing in this study. PMID- 20163628 TI - Exclusion of NEU1 and PPGB from candidate genes for a lysosomal storage disease in Japanese Black cattle. AB - A case of lysosomal storage disease has been reported in a calf of Japanese Black cattle. Lysosomal storage diseases are hereditary diseases caused by deficiency of lysosomal hydrolases. The clinical and pathological features and accumulated substrates of the affected animal indicated a possibility of sialidosis or galactosialidosis caused by deficiency of neuraminidase (NEU1) or protective protein for beta-galactosidase (PPGB). In the present study, we investigated nucleotide sequences of the genes encoding these two proteins to evaluate whether mutation of these genes is involved in this disease. We determined cattle genomic sequences of these two genes by using bovine EST sequences and the nucleotide sequences of all exons of these genes were compared between affected and normal animals. The results showed several nucleotide substitutions, but none of them was a functional mutation or specific to the affected animal. Furthermore, genotyping of the microsatellite markers in the vicinity of these two genes revealed no homozygosity of the chromosomal regions including these genes in the affected animal. These findings indicated that neither NEU1 nor PPGB gene is responsible for the lysosomal storage disease of Japanese Black cattle and therefore the disease is neither sialidosis nor galactosialidosis. PMID- 20163629 TI - Effect of SCD and SREBP genotypes on fatty acid composition in adipose tissue of Japanese Black cattle herds. AB - Fatty acid composition of beef adipose tissue is one of important traits because high proportions of monounsaturated fatty acid are related to favorable beef flavor and tenderness. In this study, we investigated effects of genetic factors such as stearoyl-CoA desaturase (SCD) and sterol regulatory element binding protein (SREBP) on beef carcass traits including fatty acid composition using two cattle populations. Sire effect was significantly related to almost all traits except BMS, suggesting that the trait examined in this study is highly controlled by genetic factors. The effect of SCD genotype on fatty acid composition was detected remarkably in both cattle groups, especially on stearic and oleic acids. This result was consistent with our previous studies and suggests that SCD is associated with fatty acid composition. Unlike SCD genotyping, the effect of SREBP genotype was not identified in this study. Our results suggested that SCD genotype would contribute to improving beef quality in field populations. Further studies about the relationship among these factors will bring an insight into the molecular mechanism of fatty acid metabolism in cattle. PMID- 20163630 TI - Death losses due to stillbirth, neonatal death and diseases in cloned cattle derived from somatic cell nuclear transfer and their progeny: a result of nationwide survey in Japan. AB - To obtain the data concerning death losses due to stillbirth, neonatal death and diseases in cloned cattle derived from somatic cell nuclear transfer (SCNT) and their progeny produced by Japanese institutions, a nationwide survey was carried out in July-August, 2006. As a result, lifetime data concerning 482 SCNT cattle (97.5% of cattle produced in the country at that time) and 202 progeny of SCNT cattle were accumulated and the death loss of these cattle was analyzed. Although 1/3 of delivered SCNT calves died during the perinatal period due to stillbirth and neonatal death, incidence of death loss due to diseases in SCNT cattle surviving more than 200 days after birth seems to be the same as these in conventionally bred cattle. In contrast, progeny of SCNT cattle showed the same level in death loss as observed in conventionally bred cattle throughout their lifetime. These results suggest that robust health would be expected in SCNT cattle surviving to adulthood and their progeny. PMID- 20163631 TI - Variety diversity effect on the chemical composition and dry matter degradation characteristics of residue and by-products of oil palm fruits. AB - The materials palm press fibre (PPF), palm calyx (PCL) and palm oil sludge (POS) obtained from three varieties of oil palm: dura, oleifera and tenera were investigated for the effect of variety on their nutritive value. Analysis of proximate composition, cell wall fractions, some mineral concentration as well as in-situ dry matter degradation in the rumen of steers were carried out. Significant effects of materials (i.e. PPF, PCL and POS) as well as variety (i.e. dura, oleifera and tenera) were noticed in all the parameters studied except sodium (Na) and organic matter (OM) components. Crude protein (CP) values in all the varieties were lowest in PCL (3.15-5.48%) and highest in POS (9.02-10.02%), while crude fibre (CF) values were highest in PCL (33.00-46.19%) and lowest in POS (3.15-5.48%). The upper and lower values respectively for CP and CF in the materials were in most cases for the tenera variety. The cell wall fractions (NDF, ADF, Lignin, cellulose and hemicellulose) were all higher in PCL and lowest in POS. In the three varieties, POS had highest concentration of Mg (0.117-0.231 g/100 g), K (1.21-2.33 g/100 g) and Cu (75.07-87.34 mg/kg) but lowest content of Ca (0.016-0.089 g/100 g) while PPF had lowest concentration of Mg (0.031-0.039 g/100 g) and Cu (20.96-22.28 mg/kg). Iron (Fe, mg/kg) values were generally high, but highest in PCL (2015.41-4042.16). Dry matter degradability and effective degradability values were best in POS irrespective of the variety and least in PCL. Among the three varieties, dry matter degradation characteristics of tenera were the best and oleifera the least. Generally the residue and by-products irrespective of the variety of oil palm they are obtained from can be ranked for their nutritive value as POS > PPF > PCL, while nutritive ranking based on variety is tenera > dura > oleifera. Conclusively, POS and PPF from any variety of oil palm could be adopted directly as feed resources for ruminant livestock, while PCL will require hydrolytic nutritive value enhancement treatment. Ruminant livestock will however be at an advantage if materials from tenera variety are fed. PMID- 20163632 TI - Mineral solubility of Panicum maximum with four herbaceous forage legume mixtures incubated in the rumen of N' Dama steers. AB - This study was designed to determine the mineral concentration and bioavailability of iron (Fe), phosphorus (P), calcium (Ca) and sodium (Na) of mixtures of Panicum maximum (Panicum) with Lablab purpureus (Lablab), Centrosema pubescens (Centro), Stylosanthes guianensis (Stylo), and Aeschynomene histrix (Histrix) in a fistulated N'Dama steer. The solubility of minerals was determined by an in sacco method by incubating ground samples of these forages in the rumen at 0, 6, 12, 24, 48 and 72 h. The mineral solubility characteristics of the forages were evaluated using the equation PD = a + b (1 - e(-ct)). The result showed that Panicum intercropped with legumes had better crude protein (CP) (av. 9.22% DM) and ash content (av. 2.22% DM) than sole Panicum which gave 7.63% DM and 1.84% DM for CP and ash contents respectively. The highest value of CP of 23.29% DM and ash content (3.96% DM) was obtained for Lablab. The mineral content values of the intercrop were higher than the sole Panicum. Higher mineral content values were obtained in the sole legumes. Iron solubility values of b and potential degradation (PD) which were 58.71% and 87.92% respectively were for Panicum/Histrix mixtures. Calcium solubility values ranged from 30.0% in Panicum to 46.0% in Panicum/Lablab mixture for b fraction. P solubility ranged from 28.0% and 46.0% for b and PD fractions in Panicum to 43.0% and 71.0% in Panicum/Centro mixture respectively. The solubility of the legumes was higher in Na for b fraction (av. 42.0%) and PD fraction (av. 60.0%). Higher values of b (av. 38.0%) and PD (av. 52.0%) were obtained for the mixtures than for sole Panicum. This study revealed that intercropping Panicum with either of the herbaceous forage legumes used for this experiment would increase the Ca, P, Na and Fe contents of the grass. PMID- 20163633 TI - Influence of orally administered bovine lactoferrin on lipid metabolism in lipopolysaccharide-injected preruminant calves. AB - ABSTRACT The aim of this study was to investigate the influence of oral lactoferrin (LF) administration on lipid metabolism changes in calves given lipopolysaccharide (LPS). Twenty-one 4-day-old Holstein calves were divided into three groups, with each group receiving one of three oral doses of LF (0, 1, 3 g/day) for 10 consecutive days (day -10 to day -1). All calves were intravenously injected with LPS (50 ng/kg BW) on day 0, the day after LF treatment ended. Plasma triglyceride concentrations were lower (P < 0.05) in the LF-treated calves than in the control calves given 0 g/day of LF at 12 and 24 h after LPS injection. Plasma NEFA concentrations were elevated between 6 and 24 h after LPS treatment. At 12 h, the concentration of plasma NEFA was lower (P < 0.05) in the calves given LF 3 g/day than in the control calves. On day 0, plasma total cholesterol and phospholipid concentrations tended to be lower in the LF groups administered 1 and 3 g of LF/day than in the control group, but did not differ significantly among the groups. The plasma very-low-density and low-density lipoprotein concentrations were lower (P < 0.05) at 12, 24, and 72 h in the LF groups than in the control calves. The concentrations of plasma high-density lipoprotein tended to be lower in the LF groups than in the control group between day 0 and 96 h, though there were no significant group differences. The concentration of plasma interleukin-1beta was lower (P < 0.05) in the calves fed LF 3 g/day than in the control calves at 2 and 12-48 h after LPS injection. These data suggest that LF inhibits LPS-induced alterations in lipid metabolism in preruminant calves. PMID- 20163634 TI - Effect of fortifying concentrate supplement with fibrolytic enzymes on nutrient utilization, milk yield and composition in lactating goats. AB - Thirty lactating Beetle-sannen crossbred goats were randomly divided into 3 groups based on first fortnight milk yield, and then adjusted to body weights to study the effect of fibrolytic enzyme supplementation on digestibility and milk production. Goats in the control group (C) were fed 500 g of concentrate supplement (CS) without exogenous fibrolytic enzymes (control; CG) or CS fortified with cellulase and xylanases @ of 4000 and 12500 (EG(1)) or 8000 and 18 750 IU/kg (EG(2)), respectively. CS was offered in two equal proportions just after milking at 7 and 17 h. After feeding CS, goats were fed 1200 g of wheat straw as roughage in two equal parts at 08.00 and 18.00 hours. Milk yield was studied for 3 1/2 months. Milking was done by hand. Changes in body weight were also recorded. After a preliminary period of 60 days of feeding, a 7-day digestibility trial was conducted in two intervals with 5 animals from each group at a time. The increase in either wheat straw or NDF intake due to the enzyme mixture was only 3%. There was significant improvement (P < 0.05) in the diet digestibility of DM, OM, CP, NDF, ADF and total carbohydrates (TC) between the control and EG(1) and EG(2) goats. Improvements were greater (P < 0.05) in the latter group. Microbial protein (MBP) was estimated based on purine derivatives and creatinine excreted in spot urine samples. MBP increased about 10 and 15% in EG(1) and EG(2), but these values were statistically invalid. Phenomenally milk yield, fat and SNF were significantly (P < 0.001) changed with progression of lactation. On a temporal basis, fortnightly changes in FCM yield of this study could be grouped as 1 month each of first and last and 1 1/2 of middle phase of lactation. Repeated measure analysis showed 180 to 260 mL/day of higher FCM and 16 to 20 g/day of higher SNF yield (P < 0.001) in EG(2) than control or even EG(1) during 5 to 7th fortnight. However, no significant impact (P > 0.05) was noticed on TF. Feed intake, g/kg FCM yield was also 7% less in EG(2) than either CG or EG(1). The study concluded that apart from increased digestibility, fortification of CS with cellulase and xylanases enzymes improved FCM yield in the last quarter of lactation in goats, and improved body weights by 5% (P > 0.05). While the digestibility of the diet was higher in EG(1) and EG(2), the impact on FCM and SNF yield was noticed only on EG(2). Our study indicated that CS of lactating goats may be fortified with 8000 and 18 500 IU/kg CS in the last quarter of lactation. PMID- 20163635 TI - Using a complex non-TDN based model (the DVE/OEB system) to predict microbial protein synthesis, endogenous protein, degradation balance, and total truly absorbed protein supply of different varieties of cereal oats for ruminants. AB - Recently a new super-genotype of oat has been developed in the Crop Development Center called CDC SO-I ('SuperOat': low lignin and high fat). In a previous study, we evaluated total metabolizable protein using a TDN-based model-NRC-2001 which is popular in North America. However, the TDN-based NRC model is not accepted universally. The objectives of this study were to use a complex non-TDN based model, the DVE/OEB system, to evaluate potential nutrient supply to ruminants from the SuperOat in comparison with two normal varieties of oats (CDC Dancer and Derby) in western Canada. The quantitative predictions were made in terms of: (i) truly absorbed rumen synthesized microbial proteins in the small intestine; (ii) truly absorbed rumen undegraded feed protein in the small intestine; (iii) endogenous protein in the digestive tract; (iv) total truly absorbed protein in the small intestine; and (v) protein degraded balance. Results showed that using the DVE/OEB system to predict the potential nutrient supply, it was found that the SuperOat had similar truly absorbed rumen synthesized microbial protein levels (61, 63, 59 g/kg DM, P > 0.05, for SuperOat, CDC Dancer and Derby, respectively), higher truly absorbed rumen undegraded feed protein than CDC Dancer (22 vs. 17 g/kg DM P < 0.05, for SuperOat, CDC Dancer, respectively), but similar to Derby (22 vs. 21 g/kg DM; P > 0.05), and similar endogenous protein (16, 16, 18 g/kg DM; P > 0.05). Total truly absorbed protein in the small intestine is only numerically higher in the SuperOat (67 vs. 65, 62 g/kg DM, P > 0.05, for CDC Dancer and Derby, respectively). However, the protein degraded balance was significantly different (P < 0.05) with a positive value for the SuperOat (7.0 g/kg DM) and negative values for two normal varieties (-1.5, 6.8 g/kg DM for CDC Dancer and Derby, respectively). In conclusion, the model predicted significantly different protein degradation balance. The SuperOat had positive degradation balance but other two normal varieties had negative protein degraded balance However, the SuperOat had similar total absorbed protein value to the two normal varieties of oats. PMID- 20163636 TI - The effects of inclusion levels of urea-treated potato pulp silage in concentrate and roughage sources on finishing performance and carcass quality in cull beef cows. AB - ABSTRACT An experiment was conducted to determine the effects of inclusion levels of potato pulp silage in concentrate (0, 15, 30 or 45%; on a dry matter basis) and roughage sources (rice straw or wheat straw) on finishing performance and carcass quality of cull beef cows. Sixteen Japanese Black (Wagyu) mature cull cows (490 +/- 31 kg of BW) were used in this experiment. Increasing the levels of potato pulp silage in concentrate and roughage sources did not significantly affect feed intake in cows. In addition, the final body weight, daily gain and feed : gain ratio were not influenced by the inclusion levels of potato pulp silage in concentrate and the type of roughage. Increasing the inclusion levels of potato pulp silage in concentrate would probably decrease the marbling score. The L* values of the longissimus muscle (LM) tended to respond quadratically (P = 0.078) as the inclusion levels of potato pulp silage in concentrate increased, and was lowest for cows fed the concentrate which included 30% potato pulp silage. The a* and b* values of the LM and fat color were not affected by the inclusion levels of potato pulp silage in concentrate. No effects of roughage sources on finishing performance were observed. PMID- 20163637 TI - Intracerebroventricular injection of L-aspartic acid and L-asparagine induces sedative effects under an acute stressful condition in neonatal chicks. AB - The present study was conducted to clarify the central functions of L-aspartic acid (Asp) and L-asparagine (Asn) during an acute stressful condition in chicks. Intracerebroventricular (i.c.v.) injection of Asp and Asn (0.84 micromol) attenuated the vocalization that normally occurs during social separation stress. Asp decreased the time spent in active wakefulness and induced sedation. Asn had a similar effect to Asp, although somewhat weaker. However, i.c.v. injection of Asp and Asn further enhanced plasma corticosterone release under social separation stress. Taken together, the i.c.v. injection of Asp and Asn has sedative effects under an acute stressful condition, which does not involve the hypothalamic-pituitary-adrenal axis. PMID- 20163638 TI - Reduced glutathione decreases energy expenditure in chicks exposed to separation stress. AB - Recently, we reported that intracerebroventricular (i.c.v.) injection of reduced glutathione (GSH) induces hypnotic and sedative effects under an acute stressful condition in chicks. However, no information is available on the effects of GSH on energy expenditure (EE) under stressful conditions. The purpose of the present study was to clarify whether i.c.v. injection of GSH affects EE of neonatal chicks, and whether EE is correlated with behavioral changes after isolation induced stress. The EE was rapidly decreased by i.c.v. injection of GSH, but was increased 27 min after injection. This change in EE was correlated with behavioral changes in which GSH induced hypnotic and sedative effects shortly after injection, followed by a period in which activity increased. The present study demonstrates that central GSH initially causes lowered EE through hypnotic and sedative effects under an acute stressful condition in chicks. PMID- 20163639 TI - Water-soluble phosphorus excretion in pigs fed diets supplemented with microbial phytase. AB - Three experiments were conducted to compare the excretion of water-soluble phosphorus (P) of starter, grower, and finisher pigs fed corn-soybean meal-based P-deficient basal diet containing no added inorganic P (B), P-adequate diet (the basal diet with added dicalcium phosphate; B + P), the basal diet plus 500 units of microbial phytase/kg (B + 500), or the basal diet plus 1000 units of microbial phytase/kg (B + 1000). There were 6 barrows per diet, in a randomized complete block design, with an average initial body weight of 10.4, 20.0, or 51.1 kg for each of starter, grower, and finisher pigs in the three phosphorus balance experiments, respectively. In the experiments, the addition of dicalcium phosphate or phytase to the basal diet increased (P < 0.05) the digestibility and retention of P, and there were linear reductions (P < 0.05) in water-soluble P excretion as a result of supplementing the basal diet with phytase. In the starter pig experiment, phytase addition at 500 or 1000 units/kg reduced (P < 0.05) water-soluble P excretion by 28 or 42%, respectively when compared with the B + P diet. In the grower pig experiment, adding phytase at 500 or 1000 units/kg reduced (P < 0.05) water-soluble P excretion by 24 or 34%, respectively when compared with the B + P diet. The use of phytase at 500 or 1000 units/kg reduced (P < 0.05) water-soluble P excretion by 11 or 30%, respectively in the finisher pig experiment. The proportion of water-soluble phosphorus in total phosphorus was not affected by dietary treatment in any of the three experiments. In conclusion, adding phytase at 1000 units/kg to a corn-soybean meal-based P deficient diet basal diet containing no added inorganic P compared with B + P diet reduced the daily excretion of water-soluble P in starter, grower, and finisher pigs by 42, 34, and 30%, respectively. PMID- 20163640 TI - A study on feeding hazelnut kernel oil meal as a protein source for broiler chickens. AB - An experiment was conducted to evaluate the effect of substituting different levels of hazelnut kernel oil meal (HKM) for soybean meal (SBM) in diets for broiler. A total of 450 one-day-old female Ross 308 broiler chicks were allocated randomly to three treatment groups of 150 birds each in a randomized design. Each treatment group consisted of five replicates each of 30 chicks. All diets (in mash form) were formulated to meet nutrient concentrations recommended for broilers. The experiment lasted for six weeks. In the experiment, an SBM control (SBM) diet was compared to two HKM diets, replacing 50 (50HKM) and 100% (HKM) of SBM protein, respectively. Body weight gain, feed intake and feed conversion ratio of broilers were adversely affected (P < 0.05) by the HKM diets at 42 days of age. Broilers fed 50HKM and HKM had growth performances similar (P > 0.05). The carcass yield and abdominal fat pads of birds fed diets with SBM were higher (P < 0.05) than those of chicks fed the 50HKM and HKM diets. The edible inner organ weight of chicks fed diets with HKM was the heaviest (P < 0.05). It is concluded that SBM cannot be replaced even up to 50% with HKM in commercial broiler diet. PMID- 20163641 TI - Effect of dietary dried milky sludge on productive performance and egg quality in laying Japanese quails. AB - ABSTRACT The experiment was conducted to study the effectiveness of dried milky sludge (DMS) as a feed source for laying Japanese quails. The DMS was incorporated into the experimental diets at levels of 0, 5.0, 10.0, 15.0 and 20.0%. Four hundred quails were used in a completely randomized design. The results revealed that the daily egg-laying rate, feed cost/100 egg weight, egg width, egg length, egg weight, shell quality characteristics in terms of breaking time, Young's modulus, work, max force, fracturability, breaking stress, stiffness and power, as well as color intensity and yolk height improved significantly with increasing levels of DMS in the diet (P < 0.05), while feed intake/bird/day, mortality and eggshell thickness showed no significant differences (P > 0.05). From this experiment, it was found that DMS incorporated into the experimental diet at the 20.0% level yielded the most productive performance and best egg quality. PMID- 20163642 TI - Effect of soybean hull supplementation to finishing pigs on the emission of noxious gases from slurry. AB - Ninety six pigs were assigned on the basis of body weight (BW) to one of four dietary treatments (4 pigs per pen and 6 pens per treatment) and fed for 4 weeks. Four 14.85% CP diets were formulated to contain graded levels of soybean hulls at 0, 5, 10, or 15%, respectively. The results showed that treatments did not affect growth performance. Coefficient of total tract apparent digestibility (CTTAD) for dry matter (DM) and blood urea nitrogen (BUN) concentrations were decreased linearly (P < 0.05) with the addition level of soybean hulls. Slurry ammonia nitrogen (NH(3)-N) was not affected with the increased soybean hulls levels, but volatile fatty acids (VFA) were linearly (P < 0.05) increased. Slurry pH and ammonia (NH(3)) emissions were significantly decreased by the addition of soybean hulls (Linear, P < 0.05). Conversely, slurry hydrogen sulphide (H(2)S) emissions exhibited an increase with the addition of soybean hulls (Linear, P < 0.10). Our data indicate that soybean hulls inclusion can decrease slurry pH value and NH(3) emission without any negative influence on growth performance. PMID- 20163643 TI - Changes in peroxisome proliferator-activated receptor gamma gene expression of chicken abdominal adipose tissue with different age, sex and genotype. AB - Peroxisome proliferatior-activated receptor gamma (PPARgamma) is a transcription factor that regulates adipocyte differentiation, and the activation of PPARgamma increases fat deposition in growing chickens. The aim of the present study was to investigate whether the levels of PPARgamma gene expression were related to fat pad weight in abdominal adipose tissue in growing chickens with different genotype and sex. Body weight and abdominal adipose tissue weight in broiler chickens (Ross strain) were higher than the other genotypes (Road Island Red, White Leghorn, and Japanese native poultry (Tsushima)) at 3 and 5 weeks of age. PPARgamma mRNA expression in abdominal adipose tissue tended to increase with age, as evidenced by higher expression levels at 5 weeks than at 1 week of age in all sex and genotype of chickens. In broiler chickens, the PPARgamma expressions were significantly higher than the other genotypes. PPARgamma mRNA expression levels in abdominal adipose tissue of female chickens rapidly increased at 3 weeks, and were unchanged until 5 weeks, while those in male chickens gradually increased until 5 weeks. In addition, abdominal adipose tissue weight was correlated with PPARgamma expression levels. These results demonstrated that PPARgamma gene expression is a useful marker of fat deposition in chickens, suggesting that PPARgamma is a key factor of fat accumulation in chicken abdominal fat pad. PMID- 20163644 TI - Red jungle fowl (Gallus gallus) as a model for studying the molecular mechanism of seasonal reproduction. AB - Photoperiodism is an adaptation mechanism that enables animals to predict seasonal changes in the environment. Japanese quail is the best model organism for studying photoperiodism. Although the recent availability of chicken genome sequences has permitted the expansion from single gene to genome-wide transcriptional analysis in this organism, the photoperiodic response of the domestic chicken is less robust than that of the quail. Therefore, in the present study, we examined the photoperiodic response of the red jungle fowl (Gallus gallus), a predecessor of the domestic chicken, to test whether this animal could be developed as an ideal model for studying the molecular mechanisms of seasonal reproduction. When red jungle fowls were transferred from short-day- to long-day conditions, gonadal development and an increase in plasma LH concentration were observed. Furthermore, rapid induction of thyrotropin beta subunit, a master regulator of photoperiodism, was observed at 16 h after dawn on the first long day. In addition, the long-day condition induced the expression of type 2 deiodinase, the key output gene of photoperiodism. These results were consistent with the results obtained in quail and suggest that the red jungle fowl could be an ideal model animal for the genome-wide transcriptional analysis of photoperiodism. PMID- 20163645 TI - Plasma concentration of anti-diuretic hormone and urine volume in response to intraruminal administration of acetate, propinata and butyrate in suckling calves. AB - Acetate, propionate, and butyrate were intraruminally administered to dry feed fed suckling calves to evaluate their effects on plasma ketone bodies, anti diuretic hormone (ADH) concentrations, and urine volume. Four male Holstein calves (5-7 weeks old) were given 1.0 L of warm water or 0.5 mole of one of the acids in 1.0 L of warm water. A 4 x 4 Latin square design was adopted for the experiment. The acetate group showed significantly higher plasma acetate concentrations than the other three groups between 0.25 h and 2.0 h after administration (P < 0.01). Plasma glucose concentrations did not differ markedly among the groups. The butyrate group showed significantly higher plasma ketone body concentrations than the other three groups until the end of the experiment (P < 0.01). Plasma ADH concentrations quickly rose in the butyrate group and remained significantly higher than in the other three groups from 0.25 h to 2.5 h after administration (P < 0.05). In accordance with the elevation of plasma ADH levels, the butyrate group showed decreases in urine volume and increases in urine osmolarity (P < 0.05). Plasma osmolarity and hematocrit values (Ht) were not different among the groups. These results suggest that the administration of acetate and propionate had little effect on ADH secretion. PMID- 20163646 TI - Lactobacillus hayakitensis, L. equigenerosi and L. equi, predominant lactobacilli in the intestinal flora of healthy thoroughbreds. AB - To detect the predominant lactobacilli in the intestinal flora of healthy thoroughbreds, we isolated lactobacilli from the feces of nine thoroughbreds (five males and four females; 0-15-year-old). The isolated lactobacilli comprise 17 species (37 strains), and they were classified into five groups: Lactobacillus salivarius (6 species), L. reuteri (6 species), Lactobacillus delbrueckii (3 species), L. buchneri (1 species) and L. vitulinus (1 species). On the basis of 16S rRNA gene sequences, we identified 3 other phylogenetic relatives belonging to the genus Lactobacillus. These results suggest that the intestinal flora of thoroughbreds may comprise many species of the genus Lactobacillus. Polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) analyses of the 340-bp fragments of the 16S rRNA genes from the same nine fecal samples showed that L. hayakitensis, L. equigenerosi and L. equi are contained in all the samples, suggesting that these species are predominant lactobacilli in the intestinal flora of thoroughbreds. PMID- 20163647 TI - Effects of 'Five freedoms' environmental enrichment on the welfare of calves reared indoors. AB - We provided comfortable resting areas in pens and tools for self-grooming and suppressing aggressive behavior for environmental enrichment in Japanese black and Japanese Shorthorn calves. At the start of the experiment, the black calves (n = 10) were 164 days old and 138 kg in weight, and the Japanese Shorthorn calves (n = 10) were 176 days old and 164 kg in weight. Calves of each breed were divided into two groups (the enrichment group and the non-treatment group), and each group was housed in a 4 m x 7.2 m pen. The effect of enrichment on calf welfare was estimated on the basis of daily weight gain and behavior. The brush stimulated the grooming behavior in calves although the mean time of using the brush decreased during the experiment. The partition of the feed trough and the wooden wall in the pen decreased the agonistic behavior in Japanese Shorthorn calves (P < 0.01) and increased the affiliative behavior in Japanese black calves (P = 0.08). The cleanliness of the bedding increased sternum lying and lying with the head touching the flank or ground in Japanese black calves and decreased the standing resting behavior in both breeds (P < 0.05 in all the cases). However, the treatments did not have an effect on daily weight gain. We concluded that the treatments would improve the welfare of calves and function as environmental enrichments. PMID- 20163648 TI - Application of cycling index and input-output environs for interpretation of nutrient flows in mixed rice-beef production systems in Japan. AB - The objective of the present study was to apply two methods developed in ecology, the cycling index and input-output environs, to interpret nutrient flows in mixed rice-beef production systems. The cycling index (CI) was a quantitative measure of nutrient cycling. It was defined as the proportion of cycled nutrients to the total amount of nutrient flows. On the other hand, the input-output environs provide a quantitative distribution on a particular input or output. In this study, these methods were applied to the nutrient flows in the mixed rice-beef production systems in Japan. The results of CI provided information on the effects of nutrient cycling on the efficient conversion of nutrient imports to nutrient export. The results of input-output environs indicated that the indices represent indirect effects provided by the interaction between rice and beef production. In conclusion, these methods indicated new findings on nutrient utilization in the systems. The results of this study implied the further applicability of these two methods to the study of nutrient flows in mixed crop animal production systems. PMID- 20163649 TI - Estimation of breeding values from large-sized routine carcass data in Japanese Black cattle using Bayesian analysis. AB - Volumes of official data sets have been increasing rapidly in the genetic evaluation using the Japanese Black routine carcass field data. Therefore, an alternative approach with smaller memory requirement to the current one using the restricted maximum likelihood (REML) and the empirical best linear unbiased prediction (EBLUP) is desired. This study applied a Bayesian analysis using Gibbs sampling (GS) to a large data set of the routine carcass field data and practically verified its validity in the estimation of breeding values. A Bayesian analysis like REML-EBLUP was implemented, and the posterior means were calculated using every 10th sample from 90,000 of samples after 10,000 samples discarded. Moment and rank correlations between breeding values estimated by GS and REML-EBLUP were very close to one, and the linear regression coefficients and the intercepts of the GS on the REML-EBLUP estimates were substantially one and zero, respectively, showing a very good agreement between breeding value estimation by the current GS and the REML-EBLUP. The current GS required only one sixth of the memory space with REML-EBLUP. It is confirmed that the current GS approach with relatively small memory requirement is valid as a genetic evaluation procedure using large routine carcass data. PMID- 20163650 TI - An insertion/deletion variant of a thymine base in exon 2 of the porcine beta 3 adrenergic receptor gene associated with loin eye muscle area. AB - An insertion/deletion variant of a thymine base (T5 and T6) in exon 2 of porcine beta 3-adrenergic receptor (ADRB3) gene has been described. In the current study, we made an association study between the ADRB3 polymorphisms and production traits in 735 Duroc pigs. The allele frequencies for the T5 and T6 alleles in our study population were 0.433 and 0.567, respectively. Any associations between ADRB3 genotype and average daily weight gain during test period, or backfat thickness and intramuscular fat content were not detected in either sex. However the size of the loin eye muscle area (EMA) was significantly associated with ADRB3 genotypes in gilts. T6-homozygous gilts had a higher mean of EMA (40.6 +/- 0.6 cm(2)) than T5-homozygous (38.1 +/- 0.4 cm(2), P = 0.002) and heterozygous (38.8 +/- 0.3 cm(2), P = 0.034) gilts. This association was not detected in males. In addition, a multiple traits animal model best linear unbiased predictor (BLUP) analysis revealed that the T6-homozygous genotype had positive effects on breeding value of EMA. Accordingly, we suggest that ADRB3 polymorphism has the potential to be an important genetic marker for prediction of EMA in Duroc pigs. PMID- 20163651 TI - Association of a single nucleotide polymorphism in ribosomal protein L27a gene with marbling in Japanese Black beef cattle. AB - Marbling, defined by the amount and distribution of intramuscular fat, is an economically important trait of beef cattle in Japan. The c2-11#2 expressed sequence tag (EST) has been previously shown to possess expression difference in musculus longissimus muscle between low-marbled and high-marbled steer groups, and to be located within genomic region of a quantitative trait locus for marbling. Thus, the ribosomal protein L27a (RPL27A) gene containing the c2-11#2 EST sequence was considered as a positional candidate for the gene responsible for marbling. In the present study, a single nucleotide polymorphism (SNP) in the promoter region of the RPL27A, referred to as g.3109537C>T, was detected between the 2 steer groups. The SNP was associated with the predicted breeding value for beef marbling standard number by the analyses using Japanese Black beef cattle population. The effect of genotypes of the SNP on the predicted breeding value for subcutaneous fat thickness was not statistically significant. These findings suggest that the RPL27A SNP may be useful for effective marker-assisted selection to increase the levels of marbling in Japanese Black beef cattle. PMID- 20163652 TI - Relationship between the lactation curve and udder disease incidence in different lactation stages in first-lactation Holstein cows. AB - We examined the relationships between the shape of the first parity lactation curve and udder disease incidence at different stages of lactation in 538 Holstein cows. Data used were first-parity daily milk yields and treatment records. Each cow was classified according to whether or not it had had udder disease at least once over the whole lactation period or in one of three stages within the lactation period. We then examined the differences in the shapes of the lactation curves between the disease incidence and non-incidence group in each stage. Cows that had high rates of increase in milk yield and high milk yields in early lactation were predisposed to udder disease afterwards. Cows with high milk production over a long period but with low lactation persistency were predisposed to udder disease after the peak of lactation. There was no difference in total milk yield between incidence and non-incidence groups in all stages, suggesting that, for a comparable level of lactation, cows without udder diseases have flatter lactation curves. PMID- 20163653 TI - Embryo development of porcine oocytes after injection with miniature pig sperm and their extracts. AB - This study examined embryo development of porcine oocytes after microinjection of sperm extracts (SE) in porcine intracytoplasmic sperm injection (ICSI). SE was prepared from miniature pig sperm by a nonionic surfactant, and various concentrations (0.02, 0.04 and 0.08 mg/mL) of SE were injected into the matured oocytes with a first polar body. In the pronuclear stage, the rate of oocytes with two pronuclei and a second polar body (21.4%) in the sperm and SE (0.04 mg/mL) injection group was significantly higher (P < 0.05) compared to other groups. The rate of 2-4-cell stage in sperm and SE (0.04 mg/mL) injection group was 38.1%, and it was significantly higher than that in the sperm injection group (22.9%). The rate of blastocyst stage in sperm and SE (0.04 mg/mL) injection group was 21.4%, the value was significantly higher than those in SE (0.08 mg/mL) injection group (0%), sperm injection group (5.7%), and sperm and SE (0.08 mg/mL) injection group (2.6%). These results suggest that SE induces activation of porcine oocytes and their further embryonic development, and that SE is effective for porcine ICSI. PMID- 20163654 TI - Duration of estrus induced after GnRH-PGF2alpha protocol in dairy heifer. AB - Estrous expressions in dairy cows have been shortened and weakened. Dairy heifers, on the other hand, may not have had such changes in estrous signs as observed in cows, since they have less stresses than cows. The aim of this study was to describe the duration of estrus in a herd of dairy heifers. A total of 56 Holstein Friesian heifers estrus was synchronized using two different hormonal protocols. They were checked for primary and secondary estrous signs with the help of heat detection devices for 48 h at an interval of 4 h starting at 16.00 hour, one day after PGF(2alpha) treatment. Onset and end of standing estrus during 48 h observation period was recorded in 35 of the 44 heifers coming into estrus within 5 days after PGF(2alpha) treatment during the observation period. The duration of standing estrus on the average (+/-SD) was 9.7 +/- 5.3 h. Percentage of heifers with standing estrus longer than 12 h was 40%, and 53% showed standing estrus only for 4-8 h. It is indicated that duration of estrus in dairy heifers has been shortened recently. PMID- 20163655 TI - Concentrations of ketone body and antidiuretic hormone in cerebrospinal fluid in response to the intra-ruminal administration of butyrate in suckling calves. AB - The aim of the present study was to elucidate the mechanism by which ketone bodies increase antidiuretic hormone (ADH) secretion. Four male Holstein calves (5 weeks of age) were utilized. Four levels of butyrate (0 g, 11 g, 22 g and 44 g) were administrated intra-ruminally in a 4 x 4 Latin square design and cerebrospinal fluid (CSF, six-position lumbar puncture), blood plasma and urine were collected. The concentration of total plasma and CSF protein was 5.5-5.6 g/dL and 27.5-28.3 mg/dL, respectively. CSF concentrations of a specific ketone body, 3-hydroxybutyric acid, were significantly higher in the 22 g and 44 g butyrate groups than in the control group. CSF concentrations of ADH in the 11 g and 44 g butyrate groups were significantly higher than in the control group. Plasma concentration of 3-hydroxybutyric acid was increased by intraruminal administration of butyrate within 15 min in a dose-dependent manner, and it was higher in the 22 g and 44 g butyrate group than in the control group from 15 min to 4 h. With the exception of the 11 g butyrate group, plasma concentrations of ADH also increased in response to butyrate treatment, and it was higher in the 44 g butyrate group than in the 22 g butyrate group from 15 min to 1.5 h. The duration of the elevated plasma concentrations of ADH was shorter than that of the plasma concentration of 3-hydroxybutyric acid. The relationship between the plasma concentrations of ADH and 3-hydroxybutyric acid was statistically significant but the correlation between the two concentrations was not high. Butyrate treatment elevated the plasma concentration of ADH and also resulted in reduced urine volume and increased urine osmolality. Haematocrit (Ht) values, and the osmolality of CSF and plasma were not different among the groups. Our results suggested that the increased ADH secretion observed in suckling calves fed dry feeds was caused by butyrate-derived ketone body that crossed the blood-brain barrier rapidly. PMID- 20163656 TI - Effects of feeding level of milk replacer on body growth, plasma metabolite and insulin concentrations, and visceral organ growth of suckling calves. AB - The objective was to evaluate effects of feeding level of milk replacer on body growth, plasma metabolite and insulin concentrations, and allometric growth of visceral organs in suckling calves. Holstein bull calves (n = 8; 3-4 days of age) were fed either a low amount (average 0.63 kgDM/day, LM) or high amount (average 1.15 kgDM/day, HM) of high protein milk replacer until they were slaughtered at 6 weeks of age. Body weight (BW) at 4, 5, and 6 weeks of age, feed intake, average daily gain, and feed efficiency were higher in the HM than LM calves. The HM group had higher plasma glucose at 3 and 4 weeks of age and insulin levels after the age of 4 weeks compared with LM calves whereas no effect was detected on plasma nonesterified fatty acid or urea nitrogen concentrations. The HM calves had greater empty body weight (EBW), viscera-free BW and most of the organs dissected than LM calves. Relative weights (% of EBW) of liver, spleen, kidneys, and internal fat were higher, whereas head and large intestine was lower in HM than LM calves. The results suggest that increased milk feeding levels would accelerate the growth of the body and specific organs. PMID- 20163657 TI - B cell differentiation in the bursa of Fabricius and spleen of embryos and chicks immediately after hatching. AB - Flow cytometric analysis and immunohistochemical observation were used to qualitatively and quantitatively clarify the nature of B cell differentiation in the bursa of Fabricius of chick embryos and to determine the timing of antibody class switching in chicken spleens based on positivity of IgM and IgG on and in the cells. In the bursa, the sIgM-positive cell population formed from the 12(th) to 15(th) day of embryogenesis. The proportion of sIgM-high expressing (sIgM(high)) cells was lower among bursacytes than splenocytes of hatched chicks, suggesting that the sIgM(high) bursacytes are to be released to peripheral sites. The proportion of sIgM(high) cells was higher at 0 days old than at any other examined stage of development. Colonization of the spleen by B cells occurred between the 18(th) day of embryogenesis and 0 days old. Antibody class switching was thought to start in the spleen between 1 and 2 weeks of age, because IgG positive cells were present in the spleen of 2-week-old chicks, but not 0-day-old or 1-week-old chicks. PMID- 20163658 TI - Muscle type-specific effect of myostatin deficiency on myogenic regulatory factor expression in adult double-muscled Japanese Shorthorn cattle. AB - To clarify muscle type-specific effect of myostatin on myogenic regulatory factors (MRFs), we examined mRNA expression of MRFs in five skeletal muscles of normal (NM) and myostatin-deficient double-muscled (DM) adult Japanese Shorthorn cattle by quantitative reverse-transcribed PCR. Among the four MRFs, namely, Myf5, MyoD, myogenin, and MRF4, MyoD expression was different among the muscles of the DM cattle (P < 0.01) but not of the NM cattle. Meanwhile, MyoD expression was significantly elevated only in masseter (MS) muscle in the DM cattle due to the myostatin deficiency (P < 0.05). Myf5 and MRF4 expression in semitendinosus (ST) was higher in the DM than in the NM cattle (P < 0.05). According to analysis of myosin heavy chain (MyHC) isoform expression, more MyHC-2x and -2a and less slow isoforms were expressed in the longissimus and ST muscles compared to the MS muscle in both cattle (P < 0.05), but no significant difference in MyHC expression was observed between the NM and DM cattle. Taken together, myostatin has influences on Myf5 and MRF4 expression in faster-type muscles and on MyoD expression in slower-type muscles, suggesting a possible muscle type-specific effect of myostatin in skeletal muscle growth and maintenance. PMID- 20163659 TI - Effects of central administration of glucagon on feed intake and endocrine responses in sheep. AB - This study was conducted to investigate effects of glucagon intracerebroventricularly administered on feed intake and endocrine changes in sheep. Four male sheep (48-55 kg BW) were used. The animals were acclimatized to be fed alfalfa hay cubes at 12.00 hour. Human glucagon (40 and 80 microg/0.5 mL) was injected into the lateral ventricle at 12.00 hour. Blood samples were taken every 10 min from 30 min before to 180 min after the glucagon injection. Soon after the injection, the animals were given alfalfa hay cubes, and the amounts of the feed eaten within 2 h were measured. Feed intakes were significantly (P < 0.05) suppressed by 80 microg of glucagon. Plasma glucose levels in control animals were gradually decreased after the feeding, whilst those in glucagon treated animals were temporarily elevated just after the feeding and then kept higher than control levels. Plasma insulin was abruptly elevated after the feeding and was maintained at higher levels than before the feeding in all treatments. Plasma NEFA concentrations were decreased after the feeding in all treatments. A tendency of increase in plasma cortisol levels occurred in glucagon injected animals. The present study provides the first evidence that glucagon directly acts on the brain, then inhibiting feeding behavior and inducing endocrine responses in ruminants. PMID- 20163660 TI - The influence of fig proteases on the inhibition of angiotensin I-converting and GABA formation in meat. AB - The purposes of this research were to use fig protease for texture tenderizing, and to inhibit angiotensin I-converting enzyme (ACE) action and gamma aminobutyric acid (GABA) formation of meat. Liberated peptides by the enzymatic action of fig protease in processing meat and free amino acids were determined and ACE inhibitory activity was assayed. Meat treated with fig protease became tender as indicated by shear force value (SFV) which was half of those of non-fig treated meat during storage even at 5 degrees C. Liberated peptides, free amino acids and GABA increased while extremely low levels of Glu were detected after storage. The optimal temperature of fig protease against meat was 80 degrees C. However, the activity of fig protease decreased after pre-heating more than 40 degrees C. High ACE inhibitory activity of a mixture of fig and meat was found around 80 degrees C, and the value corresponded to the amount of liberated peptide. A lot of liberated peptides were found at 60-80 degrees C and pasterization of meat product becomes convenient to produce peptides. Production of ACE inhibitory peptides and GABA can be expected as the healthy functional meat product such as antihypertensive activity and improve brain function. PMID- 20163661 TI - Study on bioactive compounds of in vitro cultured Calculus Suis and natural Calculus Bovis. AB - The purpose of the study was to investigate bioactive compounds of in vitro cultured Calculus Suis and natural Calculus Bovis obtained as valuable by products from animals used for meat production. The results showed that the components of natural Calculus Bovis were rich in bilirubin and biliverdin and had higher content of essential amino acids. The major amino acids of in vitro cultured Calculus Suis were identified as glycine, alanine, glutamic acid and aspartic acid, and those for natural Calculus Bovis were found to be glutamic acid, aspartic acid, proline, and arginine. The methionine and cysteine contents of precursors for glutathione in natural Calculus Bovis were significantly higher than those of in vitro cultured Calculus Suis. The mineral contents of zinc, iron and manganese of natural Calculus Bovis were significantly higher than those of in vitro cultured Calculus Suis. The major bile acids in both products were cholic acid and dehydrocholic acid, respectively. The chenodeoxycholic and ursodeoxycholic acid content of in vitro cultured Calculus Suis was significantly higher than that of natural Calculus Bovis. PMID- 20163662 TI - Physiological responses of young cross-bred calves immediately after long-haul road transportation and after one week of habituation. AB - We investigated 10 suckling cross-bred calves (Japanese Black (Wagyu) x Holstein) and collected data on the physiological stress responses of the young calves to long-haul road transportation. All calves were male and 21-47 days of age. The calves were obtained at a livestock market and were transported from the market to the university in a commercial livestock vehicle. The total haul distance and time were 306.9 km and 7 h, respectively. The calves were deprived of food and water during transportation. Blood samples, electrocardiograms, and rectal temperatures were collected immediately after transportation and after one week of habituation at the university. Serum pH was significantly lower (P < 0.01), while serum triiodothyronine, aspartate aminotransferase, non-esterified fatty acids (all P < 0.05), and heart rate (P < 0.01) were significantly higher immediately after transportation. The concentrations of blood lactic acid (P = 0.08) and serum alanine aminotransferase (P = 0.06) tended to be higher after transportation. These physiological responses suggest that the stress caused by long-haul transportation causes significant effects on liver function in young calves. PMID- 20163663 TI - Oral administration of Lactobacillus plantarum Lq80 and Megasphaera elsdenii iNP 001 induces efficient recovery from mucosal atrophy in the small and the large intestines of weaning piglets. AB - Weaning causes atrophy of intestinal mucosa and a drop of IgA protection in piglets which increases vulnerability to pathogenic infections. Probiotic lactobacilli may support recovery from such weaning stresses. Butyrate-produce bacteria may support the growth of colonic mucosa. Megasphaera elsdenii, a lactate-utilizing butyrate producer, may help butyrate production particularly when combined with lactobacilli. Weaned piglets (Experiment 1: 20 days old, Experiment 2: 28 days old) were orally dosed once a day with either (L) 10(10) (cell/dose) L. plantarum Lq80, or (LM) 10(10) (cell/dose) Lq80 with 10(9) (cell/dose) M. elsdenii iNP-001. Lq80 was contained in capsules resistant to gastric digestion. M. elsdenii was contained in capsules resistant to gastric and intestinal digestion. An untreated control (C) was also prepared. After 2 weeks of administration, L. plantarum enhanced the recovery from the villous atrophy in both experiments. The rectal and colonic IgA tended to be higher in L and LM than in C in Experiment 1. Colonic butyrate was higher in LM than in the others in Experiment 1. The thickness of the colonic mucosa was greater in LM than in the others in Experiment 1. In early weaned piglets, the effects of L. plantarum and M. elsdenii were clear. PMID- 20163664 TI - Analysis of consumers' preferences and behavior with regard to horse meat using a structured survey questionnaire. AB - In this study, a structured survey questionnaire was used to determine consumers' preferences and behavior with regard to horse meat at a horse meat restaurant located in Jeju, Korea, from October 1 to December 24, 2005. The questionnaire employed in this study consisted of 20 questions designed to characterize six general attributes: horse meat sensory property, physical appearance, health condition, origin, price, and other attributes. Of the 1370 questionnaires distributed, 1126 completed questionnaires were retained based on the completeness of the answers, representing an 82.2% response rate. Two issues were investigated that might facilitate the search for ways to improve horse meat production and marketing programs in Korea. The first step was to determine certain important factors, called principal components, which enabled the researchers to understand the needs of horse meat consumers via principal component analysis. The second step was to define consumer segments with regard to their preferences for horse meat, which was accomplished via cluster analysis. The results of the current study showed that health condition, price, origin, and leanness were the most critical physical attributes affecting the preferences of horse meat consumers. Four segments of consumers, with different demands for horse meat attributes, were identified: origin-sensitive consumers, price sensitive consumers, quality and safety-sensitive consumers, and non-specific consumers. Significant differences existed among segments of consumers in terms of age, nature of work, frequency of consumption, and general level of acceptability of horse meat. PMID- 20163666 TI - Factors affecting methane production and mitigation in ruminants. AB - Methane (CH(4)) is the second most important greenhouse gas (GHG) and that emitted from enteric fermentation in livestock is the single largest source of emissions in Japan. Many factors influence ruminant CH(4) production, including level of intake, type and quality of feeds and environmental temperature. The objectives of this review are to identify the factors affecting CH(4) production in ruminants, to examine technologies for the mitigation of CH(4) emissions from ruminants, and to identify areas requiring further research. The following equation for CH(4) prediction was formulated using only dry matter intake (DMI) and has been adopted in Japan to estimate emissions from ruminant livestock for the National GHG Inventory Report: Y = -17.766 + 42.793X - 0.849X(2), where Y is CH(4) production (L/day) and X is DMI (kg/day). Technologies for the mitigation of CH(4) emissions from ruminants include increasing productivity by improving nutritional management, the manipulation of ruminal fermentation by changing feed composition, the addition of CH(4) inhibitors, and defaunation. Considering the importance of ruminant livestock, it is essential to establish economically feasible ways of reducing ruminant CH(4) production while improving productivity; it is therefore critical to conduct a full system analysis to select the best combination of approaches or new technologies to be applied under long-term field conditions. PMID- 20163667 TI - Mechano-biology of skeletal muscle hypertrophy and regeneration: possible mechanism of stretch-induced activation of resident myogenic stem cells. AB - In undamaged postnatal muscle fibers with normal contraction and relaxation activities, quiescent satellite cells of resident myogenic stem cells are interposed between the overlying external lamina and the sarcolemma of a subjacent mature muscle fiber. When muscle is injured, exercised, overused or mechanically stretched, these cells are activated to enter the cell proliferation cycle, divide, differentiate, and fuse with the adjacent muscle fiber, and are responsible for regeneration and work-induced hypertrophy of muscle fibers. Therefore, a mechanism must exist to translate mechanical changes in muscle tissue into chemical signals that can activate satellite cells. Recent studies of satellite cells or single muscle fibers in culture and in vivo demonstrated the essential role of hepatocyte growth factor (HGF) and nitric oxide (NO) radical in the activation pathway. These experiments have also reported that mechanically stretching satellite cells or living skeletal muscles triggers the activation by rapid release of HGF from its extracellular tethering and the subsequent presentation to the receptor c-met. HGF release has been shown to rely on calcium calmodulin formation and NO radical production in satellite cells and/or muscle fibers in response to the mechanical perturbation, and depend on the subsequent up-regulation of matrix metalloproteinase (MMP) activity. These results indicate that the activation mechanism is a cascade of events including calcium ion influx, calcium-calmodulin formation, NO synthase activation, NO radical production, MMP activation, HGF release and binding to c-met. Better understanding of 'mechano-biology' on the satellite cell activation is essential for designing procedures that could enhance muscle growth and repair activities in meat-animal agriculture and also in neuromuscular disease and aging in humans. PMID- 20163668 TI - The role of intramuscular connective tissue in meat texture. AB - The structure, composition and amount of intramuscular connective tissue (IMCT) vary tremendously between muscles, species and breeds, and certainly contribute to meat texture. With animal growth, collagen crosslinks become more stable, and the structural integrity of IMCT increases. These changes increase the mechanical properties of IMCT, contributing to the toughening of meat. Intramuscular fat deposits, mainly in the perimysium between muscle fiber bundles, result in marbling. This causes the remodeling of IMCT structures and reduces the mechanical strength of IMCT, contributing to the tenderization of beef. The IMCT has been thought to be rather immutable compared to myofibrils during postmortem ageing of meat. However, recent studies have shown the disintegration of IMCT during postmortem ageing of meat and its relationship to tenderization of raw meat, although its contribution to cooked meat is still controversial. Given the large influence of IMCT on meat texture, further elucidations of molecular mechanisms which change the structural integrity of IMCT during chronological ageing of animals and postmortem ageing of meat are needed. PMID- 20163669 TI - Quantitative trait loci for leg weakness traits in a Landrace purebred population. AB - Leg weakness in pigs is a serious problem in the pig industry. We performed a whole genome quantitative trait locus (QTL) analysis to find QTLs affecting leg weakness traits in the Landrace population. Half-sib progeny (n = 522) with five sires were measured for leg weakness traits. Whole genome QTL mapping was performed using a half-sib regression-based method using 190 microsatellite markers. No experiment-wide significant QTLs affecting leg weakness traits were detected. However, at the 5% chromosome-wide level, QTLs affecting leg weakness traits were detected on chromosomes 1, 3, 10 and 11 with QTL effects ranging from 0.07 to 0.11 of the phenotypic variance. At the 1% chromosome-wide level, QTLs affecting rear feet score and total leg score were detected on chromosomes 2 and 3 with QTL effects of 0.11 and 0.13 of the phenotypic variance, respectively. On chromosome 3 and 10, some QTLs found in this study were located at nearby positions. The present study is one of the first reports of QTLs affecting fitness related traits such as leg weakness traits, that segregate within the Landrace population. The study also provides useful information for studying QTLs in purebred populations. PMID- 20163670 TI - Phosphorylation of inositol 1,4,5-triphosphate receptor 1 during in vitro maturation of porcine oocytes. AB - During fertilization in mammalian species, a sperm-induced intracellular Ca(2+) signal ([Ca(2+)](i)) mediates both exit of meiosis and oocyte activation. Recently, we demonstrated in mouse oocytes that the phosphorylation levels of inositol 1,4,5 trisphosphate receptor type1 (IP(3)R1), the channel responsible for Ca(2+) release and oscillations during fertilization, changed during maturation and fertilization. Therefore, we examined the expression and phosphorylation of IP(3)R1 during in vitro maturation of pig oocytes. Here, our present study shows that expression of IP(3)R1 protein did not change during maturation, although the phosphorylation status of the receptor, specifically at an MPM-2 epitope, did. We found that while at the beginning of maturation IP(3)R1 lacked MPM-2 immunoreactivity, it became MPM-2 reactive by 24 h and reached maximal reactivity by 36 h. Interestingly, the acquisition of MPM-2 reactivity coincided with the activation of p34(cdc2) kinase and mitogen-activated protein kinase (MAPK), which are involved in meiotic progression. Following completion of maturation, inactivation of MAPK by U0126 did not affect IP(3)R1 phosphorylation, although inactivation of p34(cdc2) kinase by roscovitine dramatically reduced IP(3)R1 phosphorylation. Neither inhibitor affected total expression of IP(3)R1. Altogether, our results show that IP(3)R1 undergoes dynamic phosphorylation during maturation and this might underlie the generation of oscillations at fertilization. PMID- 20163671 TI - Possible involvement of phosphatidylinositol 3-kinase in the maintenance of metaphase II arrest in porcine oocytes matured in vitro. AB - It has been reported that phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB) pathway plays a crucial role in the meiotic resumption and progression to the metaphase II (MII) stage of oocytes. However, the role of this pathway in meiotic arrest at the MII stage (cytostatic activity) is not well understood. In this study the effect of a PI3K inhibitor, LY294002, on the MAPK and p34(cdc2) kinase activities of matured porcine oocytes was examined. After maturation culture, both the MAPK and p34(cdc2) kinase activities in the oocytes were gradually decreased in a time-dependent manner. Although 25 micromol/L LY294002 did not affect either the MAPK or p34(cdc2) kinase activities, 50 micromol/L LY294002 suppressed the PKB phosphorylation and slightly decreased MAPK activity, but not the p34(cdc2) kinase activity. Therefore the effect of 10 micromol/L Ca(2+) ionophore which was reported as inducing a transient decrease of p34(cdc2) kinase but not MAPK activities, was also examined in LY294002-treated oocytes. By additional treatment with LY294002 after Ca(2+) ionophore, both the MAPK and p34(cdc2) kinase activities were decreased in a time-dependent manner, concomitantly with improvement of pronuclear formation. Therefore, we concluded that PI3K is involved in the maintenance of MAPK activity in matured porcine oocytes. PMID- 20163672 TI - Early metaphase II oocytes treated with dibutyryl cyclic adenosine monophosphate provide suitable recipient cytoplasm for the production of miniature pig somatic cell nuclear transfer embryos. AB - We investigated the effects of in vitro maturation duration and treatment with dibutyryl cyclic adenosine monophosphate (dbcAMP) on the blind enucleation efficiency and developmental competence of miniature pig somatic cell nuclear transfer (SCNT) embryos. Oocytes were cultured for 22 h in NCSU-23 medium with or without 1 mM dbcAMP and then additionally cultured in dbcAMP-free NCSU-23 for 14, 18, or 22 h. Regardless of dbcAMP treatment, the rate of nuclear maturation reached a plateau at 36 and 40 h. However, mitochondrial distribution, a marker for cytoplasmic maturation, differed between the dbcAMP-untreated oocytes at 36 h and dbcAMP-treated oocytes at 40 h. The metaphase II chromosomes were adjacent to the first polar body in 68.8% and 63.5% of the dbcAMP-untreated oocytes at 36 h and dbcAMP-treated oocytes at 40 h, respectively. Furthermore, the blind enucleation efficiency by removing a small volume of cytoplasm was significantly higher in the dbcAMP-untreated oocytes at 36 h (82.9%) and dbcAMP-treated oocytes at 40 h (89.9%) than other groups. The rate of blastocyst formation was highest in the dbcAMP-treated oocytes at 40 h. Hence, this study demonstrated that dbcAMP treated early metaphase II oocytes are suitable for the production of miniature pig SCNT embryos. PMID- 20163673 TI - Productivity and energy partition of late lactation dairy cows during heat exposure. AB - Three late-lactation Holstein cows were used to determine the effects of environmental temperature on performance and energy partitioning. Each cow was housed in a respiratory chamber for 30 consecutive days and exposed to three different conditions of environmental temperature: (i) 20 degrees C and 20 degrees C (20 degrees C), (ii) 25 degrees C and 20 degrees C (25 degrees C), (iii) 30 degrees C and 25 degrees C (30 degrees C) during the day and night, respectively. The temperature was switched in an interval of 10 days. Humidity in the chamber was maintained at 55-65% through the entire experimental period. The daily mean as well as morning and evening rectal temperatures of Holstein cows increased linearly (P < 0.05) as chamber temperature increased. There was a significant linear reduction in dry matter (DM) intake (P < 0.05) and an increase in DM digestibility (P < 0.05). The response in milk yield, however, was not affected by heat stress. There were no significant differences among treatments for intake energy, heat production, net energy for lactation and net energy for gain. This results of this study disagreed with the assumption that late lactation cows gave priority to increasing body tissue at the expense of milk production under thermal stress. PMID- 20163674 TI - Effect of products derived from hydrolysis of wheat and flaxseed non starch polysaccharides by carbohydrase enzymes on net absorption in enterotoxigenic Escherichia coli (K88) challenged piglet jejunal segments. AB - Enterotoxigenic Escherichia coli (ETEC) infection results in fluid and electrolyte losses in the small intestine. We investigated the effect of non starch polysaccharides (NSP) hydrolysis products of wheat middlings (WM) and flaxseed (FS) on net absorption of fluid and solutes during ETEC challenge. Products were generated by incubating WM and FS with a blend of carbohydrase enzymes to produce 2 products: 80% ethanol-soluble (ES) and 80% ethanol-insoluble (EI) which were studied in 2 experiments in which 2 factors were investigated: products (EI vs. ES) and time of ETEC challenge (before vs. after perfusion). Pairs of small-intestine segments, one non-challenged and the other ETEC challenged were perfused with products for 7.5 h. ETEC reduced fluid absorption by more than 380 microL/cm(2) in saline (control) perfused segments, whereas this reduction was significantly (P < 0.05) less for the WM and FS products. Interaction (P > 0.05) between product and time of challenge was not observed. For WM, products effects on ETEC-challenged segments were such that perfusion of ES resulted in higher total solute (measured as osmolality) absorption than EI (138 vs. 103 microOsmol/cm(2)). In conclusion, hydrolysis products from WM and FS were beneficial in maintaining fluid balance during ETEC challenge, suggesting potential in controlling ETEC induced diarrhea in piglets. PMID- 20163675 TI - Detection and identification of rumen bacteria constituting a fibrolytic consortium dominated by Fibrobacter succinogenes. AB - A fibrolytic consortium, dominated by the rumen cellulolytic bacterium Fibrobacter succinogenes, was artificially constructed on hay stems to detect and identify rumen bacteria that can potentially interact with F. succinogenes. Consortium-bacterial members were determined by DGGE and sequencing analysis targeted bacterial 16S rDNA. An artificial consortium was formed in a 2-step incubation of hay stems; the first step with group 1, 2 or 3 F. succinogenes strains, the second step with rumen fluid. After consortium formation, morphologically different bacteria were observed in association with F. succinogenes. DGGE exhibited more than 30 bands, the pattern of which depended on the F. succinogenes group. Sequencing suggested that Butyrivibrio fibrisolvens, Pseudobutyrivibrio ruminis, Clostridium sp., F. succinogenes group 2, Prevotella ruminicola and unclassified Bacteroides were prominent in the group 1 consortium and that Treponema bryantii, B. fibrisolvens, Acinetobacter sp, and Wolinella succinogenes were prominent in the group 2 consortium. However, in the group 3 consortium, F. succinogenes-like bacteria were microscopically undetectable, whereas cellulolytic Ruminococcus albus and F. succinogenes group 1 were prominent, suggesting that the group 3 cannot be a core member of this consortium. This study is the first attempt to identify bacterial members of a fibrolytic consortium dominated by a specific bacterium. PMID- 20163676 TI - Effects of high potassium chloride supplementation on water intake, urine volume and nitrogen balance in mice. AB - Sixteen ICR male mice were assigned to a control diet group or a KCl diet group in metabolic cages to clarify the effects of KCl supplementation on water intake, urine volume and N balance, and 5% of KCl was supplemented in KCl diets for 4 or 8 weeks. Bodyweight of KCl supplemented mice was significantly higher than that of control mice from 24 to 28 days after treatment. Feed intake, water intake and urine volume of KCl supplemented mice were significantly higher than those of control mice, and the increased water intake and urine volume in KCl supplemented mice were 4.49 and 4.15 g, respectively. Urinary N, K and Cl excretion were significantly higher in KCl supplemented mice. Although N retention was not significantly different between control and KCl supplemented mice, N retention in KCl supplemented mice tended to be lower. Serum creatinine concentration at 8 weeks after treatment was lower in KCl supplemented mice. Histological alteration using hematoxylin-eosin and Sirius red staining was not found in the kidney of each mouse at 4 and 8 weeks after treatment. These results suggest that high KCl supplementation increases water intake, urine volume and urinary N excretion in mice. PMID- 20163677 TI - The effect of frequent milk feeding on abomasal curd formation of Holstein calves. AB - In order to understand the effects of the automatic milk replacer feeding system on calf health, we examined the effect of frequent milk feeding on curd formation in the abomasum using ultrasonographic imaging. Eight male Holstein calves were divided into a milk-replacer group and a fresh milk group. Calves were fed twice a day to 12 days after birth (Period A). From 13 days, calves were fed six times a day (Period B). The abomasal fluid was taken by paracentesis. In both periods A and B, the fresh milk group formed bigger curds faster than the milk replacer group. The curd score of the milk replacer group in period B at 2 h was significant lower than those of both groups in period A. The pH in the abomasum was lower in period B than in period A. We could not identify the location of the abomasum in the milk replacer group during period B at almost time points. Our experiment suggests the possibility that frequent feeding of milk replacer causes incomplete hydrolysis of kappa-casein as well as curd formation, thus reducing the digestibility compared to the feeding of the milk replacer twice per day or frequent feeding of fresh milk. PMID- 20163678 TI - The effect of experimental inhibition of gastric acid secretion on curd formation in abomasum and weight gain of calves. AB - Eight Holstein bull calves were divided into two groups; a non-treated control group and a famotidine treated group. Fresh milk was fed twice a day. The experiment was conducted between 7 and 14 days of age. During the experimental period the control group was injected with physiological saline, and the famotidine group was injected with famotidine, a histamine-H2-receptor blocker, into the jugular vein 30 minutes prior to each feeding. The control group showed maximum curd formation 2 h after feeding at both 7 and 14 days of age. Curd scores of 7-day-old and 14-day-old calves were significantly lower in the famotidine than in the control group at 2 and 4 h after feeding. Most fecal samples from the famotidine group exhibited an acidic smell. The famotidine group showed significantly lower values for both average weight gain and the rate of weight gain from 7 to 14 days of age. The inhibition of gastric acid secretion decreased curd formation in the abomasum as well as daily weight gain compared to non-treated control calves. This suggested that curd formation in the abomasum is important for the weight gain of newborn calves. PMID- 20163679 TI - Evaluation [corrected] of transgenic event CBH 351 (StarLink) corn in pig. AB - This study examined the influence of transgenic event CBH (StarLink; SL)-derived hybrid corn on growth, health and physiological functions of pigs, as well as the possibility of transferring the cry9C gene or Cry9C protein to the blood, liver or muscles, in comparison with pigs fed a diet with non-transgenic (isogenic) corn (non-SL). The diet for the SL group was composed of 70% SL corn, and the diet for the non-SL group was composed of 70% non-SL corn. Forty pigs approximately 3 months in age were used in the current experiment. After the pigs were acclimatized to their environment for 7 days, they were fed piglet diets for 7 weeks, and afterwards fed growing-finishing diets until the end of the experiment. There were no significant differences in bodyweight gain, feed intake or feed conversion ratio between the pigs fed SL diet and those of non-SL diet. No abnormalities were observed in the health conditions of either the SL or the non-SL group. Moreover, no significant differences were observed between the two groups in hematological values, histopathological examination and necropsy findings. Although the serum biochemical values within each group were normal, the blood urea nitrogen values of the SL group showed a tendency to be slightly higher than those of the non-SL group. Also, the blood glucose values of the SL group were significantly lower than those of the non-SL group. However, the cause of the significant differences in the blood glucose values between the two groups is unknown. The PCR and ELISA did not detect the cry9C gene and Cry9C protein in the blood, liver or muscles of the pigs at the end of the experiment. PMID- 20163680 TI - Interaction between myostatin and extracellular matrix components. AB - Myostatin, a member of the TGF-beta superfamily, is a negative regulator of skeletal muscle mass. We have recently demonstrated that decorin binds to myostatin in vitro, and that immobilized decorin within the collagen matrix prevents myostatin-mediated inhibition of myoblast proliferation. However, little is known about other ECM molecules that bind to myostatin and modulate its activity. Thus, in the present study, we investigated the interaction of several other ECM molecules with myostatin. We here show that fibromodulin, fibronectin and laminin bind to myostatin in the presence of Zn(2+) with a dissociation constant (K(D)) of 10(-10) approximately 10(-8) mol/L. Fibromodulin shows the highest affinity for myostatin among them. These results suggest that these ECM molecules may modulate myostatin activity like decorin does. PMID- 20163681 TI - Regional specialization of the ganglion cell density in the retina of the ostrich (Struthio camelus). AB - In this study, retinal whole-mount specimens were prepared and stained with 0.1% cresyl violet for the ganglion cell study in the ostrich (Struthio camelus). The total number, distribution, and size of these cells were determined in different retinal regions. The mean total number of ganglion cells (three retinas) was 1,435,052 with an average density of 652 cells/mm(2). The temporo-nasal area of the retina with high cell density were identified with the peak of 7525 cells/mm(2) in the central area. The size of most ganglion cells ranged from 113 403 microm(2), with smaller cells predominating along the temporo-nasal streak above the optic disc and larger cells comprising more of the peripheral regions. The average thickness of the retina was 196 microm. The central area was the thickest area (268.6 microm), whereas the peripheral area was the thinnest area. Thus, the specialization of ganglion cell densities, their sizes and the thickness of the retina support the notion that the conduction of visual information towards the brain from all regions of the retina is not uniform, and suggests that the temporo-nasal streak is the fine quality area for vision in ostriches. PMID- 20163682 TI - In vivo immunomodulatory effects of dietary purple sweet potato after immunization in chicken. AB - This study was intended to determine the modulatory effects of dietary supplementation of purple sweet potato (Ipomoea batats Poir., PSP) on the immune response of chickens. PSP was included in a basal starter diet by 1% (PSP(L)) or 3% (PSP(H)) and continually fed. Newcastle disease (NDV) vaccine, Brucella abortus (BA) and sheep red blood cells (SRBC) were used for chicken immunization. Antibody titers against these antigens were used to estimate humoral immunity. Concanavalin A (Con A)-induced proliferations of splenocytes, thymocytes and peripheral blood lymphocytes (PBL), ratios of CD4- and CD8-single positive and CD4-CD8-double negative (DN) cells in splenocytes, were both used to indicate cellular immunity. Relative weights of spleen, thymus and bursa and white blood cell (WBC) counts were studied. PSP(H) increased anti-NDV (P < 0.05), anti-BA (P < 0.01) and anti-SRBC titers (P < 0.05) in response to secondary immunization, whereas PSP(L) increased titers of anti-BA (P < 0.05) and anti-SRBC (P < 0.01). Proliferations of splenocytes and thymocytes were augmented with PSP(L) (P < 0.05). PSP(H)-treated chickens had lower (P < 0.05) ratios of CD4-single positive lymphocytes. Proliferation of PBL, weights of lymphoid organs and WBC counts were not affected. These results suggest that dietary PSP supplementation could enhance the immune response after immunization in chickens. PMID- 20163683 TI - Photic and non-photic entrainment on daily rhythm of locomotor activity in goats. AB - We studied the photic (L/D cycle) and non-photic (restricted feeding) entrainment on the patterns of daily rhythm of total locomotor activity in goats. Six female Maltese goats were subjected to three different artificial L/D cycles: 12/12 L/D, 12/12 D/L and constant light. During the 12/12 L/D and 12/12 D/L, food and water were available ad libitum. During constant light, animals were subjected to a restricted feeding treatment. Total activity was recorded by means of an actigraphy-based data logger (Actiwatch-Mini). Our results showed that goats exhibited clear daily rhythms of activity in 12/12 L/D cycle, 12/12 D/L cycle and constant light, although they showed FAA prior the feeding time during the restricted feeding treatment. Goats were diurnal, with activity consistently beginning promptly following the onset of light. Even when the L/D cycle was delayed by 12 h on some days, to the daily rhythm was re-established. During the constant light period, the onset of activity was linked to the time of food administration. Our study evidences two factors for the rhythm of total locomotor activity in goats: light stimuli (photic) and food access (non photic), strongly coupled to permit organisms the adaptive temporal coordination of behaviour with stable and unstable environmental periodicities. PMID- 20163684 TI - The effect of visiting zoos on human health and quality of life. AB - The increased mental stress of daily life and aging of the population are serious matters in Japan. There are many studies regarding the effects of human-animal interactions on mental and physical human health, whereas there are few studies examining the effects of visiting zoos. To determine the effect of visiting zoos on human health and quality of life, two different zoos were visited by 70 participants in Experiment 1 and 163 participants in Experiment 2. In this study we administered the WHO QOL-26 questionnaire in Japanese to assess the psychological scales of participants, and blood pressures and pulse rates were measured to assess their physical scales. We also used pedometers to count the number of steps taken during zoo visits. Both zoo visits decreased blood pressure and participants demonstrated more than 6000 steps during each visit. The quality of life sub-scale scores were improved after zoo visits. PMID- 20163685 TI - Prevalence of porcine reproductive and respiratory syndrome virus and porcine circovirus type 2 in piglets after weaning on a commercial pig farm in Japan. AB - To investigate the transition in concentration of porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) and antibody for these viruses in serum, serum samples were collected from 29 pigs on weaning day and at 7, 14, 21, 28, 53, 84, and 120 days after weaning. The concentration of circulated PRRSV and PCV2 in serum was measured by real-time RT PCR and real-time PCR, respectively. The specific antibody for PRRSV and PCV2 was measured using ELISA. PRRSV was not detected on 0 days post-weaning (dpw). The specific antibody for PRRSV began to increase as the concentration of PRRSV in serum increased, and the level of PRRSV then tended to decrease. PCV2 was detected in 12 of 28 pigs on 0 dpw. The concentration of PCV2 and the specific antibody for PCV2 showed a similar tendency to those of PRRSV. The correlation analysis suggests that a decline in the daily weight gain coincided with an increase in the PRRSV concentration. Pigs with a higher antibody titer against PRRSV or PCV2 on 0 dpw showed the lower level of PRRSV or PCV2, respectively. PMID- 20163686 TI - The T allele at the g.1471620G>T in the EDG1 gene associated with high marbling in Japanese Black cattle is at a low frequency in breeds not selected for marbling. AB - Our previous study detected a single nucleotide polymorphism (SNP), g.1471620G>T, in the 5' flanking region of the endothelial differentiation sphingolipid G protein-coupled receptor 1 (EDG1) gene, which has been considered as a positional functional candidate for the gene responsible for marbling, and showed association of the g.1471620G>T SNP with marbling in Japanese Black beef cattle. In the present study, we investigated the allele frequency distribution of the g.1471620G>T SNP among the 5 cattle breeds, Japanese Black, Japanese Brown, Japanese Short Horn, Holstein, and Brown Swiss breeds. The T allele at the g.1471620G>T SNP associated with high marbling was found at high frequency in Japanese Black breed that has been subjected to a strong selection for high marbling, while the allele was absent or at very low frequencies in the other breeds that have not been strongly selected for high marbling. Based on this finding, we hypothesized that the pressure of the strong selection for high marbling in Japanese Black breed has increased the frequency of the T allele at the g.1471620G>T SNP in the EDG1. PMID- 20163687 TI - The problem of transfusion-transmitted babesiosis. PMID- 20163688 TI - Red blood cell hemolysis: an old standard in changing times. PMID- 20163689 TI - Transfusion medicine illustrated: hydroxocobalamin-colored plasma. PMID- 20163690 TI - Red blood cell hemolysis during blood bank storage: using national quality management data to answer basic scientific questions. AB - BACKGROUND: Hemolysis of red blood cells (RBCs) during blood bank storage is the most obvious manifestation of RBC storage system failure. However, its analysis is made difficult because the largest source of interunit difference is donor specific. Availability of data from national blood systems on large numbers of RBC units used for internal quality control (QC) purposes and stored and processed in uniform ways permits statistical analysis. STUDY DESIGN AND METHODS: Measures of hemolysis during and at the end of storage on randomly selected donor units observed for QC purposes were obtained from four national blood systems. Groups of these measures from units that had undergone similar processing and storage were sorted to create histograms and the histograms were compared statistically. RESULTS: A total of 14,087 measures were obtained under seven storage conditions, including more than 12,000 measures made in a single country under four closely related conditions. Distributions of percent hemolysis are skewed normal and outliers are random. Additive solutions appear to be equivalent, except that the 42 mmol/L mannitol in AS-1 reduces hemolysis compared to conventional 30 mmol/L mannitol in saline, adenine, glucose, and mannitol. Increasing storage from 35 to 42 days increased measured hemolysis by 30% and leukoreduction decreased it by 53%. CONCLUSIONS: Large national data sets provide useful information about the distribution of hemolysis at the end of RBC storage. This information can aid blood storage system development and regulatory science. PMID- 20163691 TI - Comparison of three low-ionic-strength solutions for routine pretransfusion testing: antibody screening/identification, cross-matching, immune anti-ABO detection, and direct antiglobulin tests. PMID- 20163692 TI - Rapid tests for blood donor screening in Africa. PMID- 20163693 TI - Hepatitis B seroconversion in Japanese blood donors. PMID- 20163694 TI - A rare case of missing antibody due to anti-snake venom. PMID- 20163697 TI - Dystroglycan versatility in cell adhesion: a tale of multiple motifs. AB - Dystroglycan is a ubiquitously expressed heterodimeric adhesion receptor. The extracellular alpha-subunit makes connections with a number of laminin G domain ligands including laminins, agrin and perlecan in the extracellular matrix and the transmembrane beta-subunit makes connections to the actin filament network via cytoskeletal linkers including dystrophin, utrophin, ezrin and plectin, depending on context. Originally discovered as part of the dystrophin glycoprotein complex of skeletal muscle, dystroglycan is an important adhesion molecule and signalling scaffold in a multitude of cell types and tissues and is involved in several diseases. Dystroglycan has emerged as a multifunctional adhesion platform with many interacting partners associating with its short unstructured cytoplasmic domain. Two particular hotspots are the cytoplasmic juxtamembrane region and at the very carboxy terminus of dystroglycan. Regions which between them have several overlapping functions: in the juxtamembrane region; a nuclear localisation signal, ezrin/radixin/moesin protein, rapsyn and ERK MAP Kinase binding function, and at the C terminus a regulatory tyrosine governing WW, SH2 and SH3 domain interactions. We will discuss the binding partners for these motifs and how their interactions and regulation can modulate the involvement of dystroglycan in a range of different adhesion structures and functions depending on context. Thus dystroglycan presents as a multifunctional scaffold involved in adhesion and adhesion-mediated signalling with its functions under exquisite spatio-temporal regulation. PMID- 20163698 TI - Phenotypic effect of mutations in evolving populations of RNA molecules. AB - BACKGROUND: The secondary structure of folded RNA sequences is a good model to map phenotype onto genotype, as represented by the RNA sequence. Computational studies of the evolution of ensembles of RNA molecules towards target secondary structures yield valuable clues to the mechanisms behind adaptation of complex populations. The relationship between the space of sequences and structures, the organization of RNA ensembles at mutation-selection equilibrium, the time of adaptation as a function of the population parameters, the presence of collective effects in quasispecies, or the optimal mutation rates to promote adaptation all are issues that can be explored within this framework. RESULTS: We investigate the effect of microscopic mutations on the phenotype of RNA molecules during their in silico evolution and adaptation. We calculate the distribution of the effects of mutations on fitness, the relative fractions of beneficial and deleterious mutations and the corresponding selection coefficients for populations evolving under different mutation rates. Three different situations are explored: the mutation-selection equilibrium (optimized population) in three different fitness landscapes, the dynamics during adaptation towards a goal structure (adapting population), and the behavior under periodic population bottlenecks (perturbed population). CONCLUSIONS: The ratio between the number of beneficial and deleterious mutations experienced by a population of RNA sequences increases with the value of the mutation rate mu at which evolution proceeds. In contrast, the selective value of mutations remains almost constant, independent of mu, indicating that adaptation occurs through an increase in the amount of beneficial mutations, with little variations in the average effect they have on fitness. Statistical analyses of the distribution of fitness effects reveal that small effects, either beneficial or deleterious, are well described by a Pareto distribution. These results are robust under changes in the fitness landscape, remarkably when, in addition to selecting a target secondary structure, specific subsequences or low-energy folds are required. A population perturbed by bottlenecks behaves similarly to an adapting population, struggling to return to the optimized state. Whether it can survive in the long run or whether it goes extinct depends critically on the length of the time interval between bottlenecks. PMID- 20163699 TI - Evolutionary dynamics of U12-type spliceosomal introns. AB - BACKGROUND: Many multicellular eukaryotes have two types of spliceosomes for the removal of introns from messenger RNA precursors. The major (U2) spliceosome processes the vast majority of introns, referred to as U2-type introns, while the minor (U12) spliceosome removes a small fraction (less than 0.5%) of introns, referred to as U12-type introns. U12-type introns have distinct sequence elements and usually occur together in genes with U2-type introns. A phylogenetic distribution of U12-type introns shows that the minor splicing pathway appeared very early in eukaryotic evolution and has been lost repeatedly. RESULTS: We have investigated the evolution of U12-type introns among eighteen metazoan genomes by analyzing orthologous U12-type intron clusters. Examination of gain, loss, and type switching shows that intron type is remarkably conserved among vertebrates. Among 180 intron clusters, only eight show intron loss in any vertebrate species and only five show conversion between the U12 and the U2-type. Although there are only nineteen U12-type introns in Drosophila melanogaster, we found one case of U2 to U12-type conversion, apparently mediated by the activation of cryptic U12 splice sites early in the dipteran lineage. Overall, loss of U12-type introns is more common than conversion to U2-type and the U12 to U2 conversion occurs more frequently among introns of the GT-AG subtype than among introns of the AT-AC subtype. We also found support for natural U12-type introns with non-canonical terminal dinucleotides (CT-AC, GG-AG, and GA-AG) that have not been previously reported. CONCLUSIONS: Although complete loss of the U12-type spliceosome has occurred repeatedly, U12 introns are extremely stable in some taxa, including eutheria. Loss of U12 introns or the genes containing them is more common than conversion to the U2-type. The degeneracy of U12-type terminal dinucleotides among natural U12-type introns is higher than previously thought. PMID- 20163700 TI - Health status in patients at risk of inherited arrhythmias and sudden unexpected death compared to the general population. AB - BACKGROUND: The possibilities in the molecular genetics of long QT syndrome (LQTS) and hypertrophic cardiomyopathy (HCM) has made family screening, with diagnostic and predictive genetic testing part of the health care offer in genetic counselling of inherited arrhythmias, potentially affecting the subjective health among these individuals. The study compared health status among patients at risk of arrhythmia because of family history or clinical diagnosis of LQTS and HCM with reference health status scores of the general population. METHODS: In the period 2005-2007, 127 patients (mean age 45 years, 53.5% women), with a family history of arrhythmia (n = 95) or a clinical diagnosis of LQTS (n = 12) or HCM (n = 19) referred for genetic counselling at the medical genetic departments in Norway filled in a questionnaire (Short Form Health Survey SF-36) measuring health status on eight domains. The patient SF-36 scores were compared to expected scores of the general population by t-test, and the relationship between the socio-demographic variables, clinical status, and SF-36 domains were analysed by multiple linear regression. RESULTS: The total sample reported significant lower SF-36 score as compared to the general population scores for the domain of general health (mean difference -7.3 (<0.001). When analysing the sample in subgroups according to clinical status, the general health was still significant lower for the group of family risk and in the group of HCM. In addition the physical functioning, role physical, vitality and role emotional domains were reduced for the latter group. In general, employment, higher education and being referred to genetic counselling through a family member were associated with better scores on the health status domains. CONCLUSIONS: Having a genetic risk of arrhythmia affects general health significantly. In addition, patients with a clinical diagnosis of HCM demonstrate a significantly poorer health in both physical and mental domains. PMID- 20163701 TI - Mitf-Mdel, a novel melanocyte/melanoma-specific isoform of microphthalmia associated transcription factor-M, as a candidate biomarker for melanoma. AB - BACKGROUND: Melanoma incidence is on the rise and advanced melanoma carries an extremely poor prognosis. Treatment options, including chemotherapy and immunotherapy, are limited and offer low response rates and transient efficacy. Thus, identification of new melanocyte/melanoma antigens that serve as potential novel candidate biomarkers in melanoma is an important area for investigation. METHODS: Full length MITF-M and its splice variant cDNA were cloned from human melanoma cell line 624 mel by reverse transcription polymerase chain reaction (RT PCR). Expression was investigated using regular and quantitative RT-PCR in three normal melanocytes (NHEM), 31 melanoma cell lines, 21 frozen melanoma tissue samples, 18 blood samples (peripheral blood mononuclear cell; PBMC) from healthy donors and 12 non-melanoma cancer cell lines, including three breast, five glioma, one sarcoma, two kidney and one ovarian cancer cell lines. RESULTS: A novel splice variant of MITF-M, which we named MITF-Mdel, was identified. The predicted MITF-Mdel protein contains two in frame deletions, 56- and 6- amino acid deletions in exon 2 (from V32 to E87) and exon 6 (from A187 to T192), respectively. MITF-Mdel was widely expressed in melanocytes, melanoma cell lines and tissues, but almost undetectable in non-melanoma cell lines or PBMC from healthy donors. Both isoforms were expressed significantly higher in melanoma tissues than in cell lines. Two of 31 melanoma cell lines expressed only one isoform or the other. CONCLUSION: MITF-Mdel, a novel melanocyte/melanoma-specific isoform of MITF-M, may serve as a potential candidate biomarker for diagnostic and follow-up purposes in melanoma. PMID- 20163702 TI - TB treatment initiation and adherence in a South African community influenced more by perceptions than by knowledge of tuberculosis. AB - BACKGROUND: Tuberculosis (TB) is a global health concern. Inadequate case finding and case holding has been cited as major barrier to the control of TB. The TB literature is written almost entirely from a biomedical perspective, while recent studies show that it is imperative to understand lay perception to determine why people seek treatment and may stop taking treatment. The Eastern Cape is known as a province with high TB incidence, prevalence and with one of the worst cure rates of South Africa. Its inhabitants can be considered lay experts when it comes to TB. Therefore, we investigated knowledge, perceptions of (access to) TB treatment and adherence to treatment among an Eastern Cape population. METHODS: An area-stratified sampling design was applied. A total of 1020 households were selected randomly in proportion to the total number of households in each neighbourhood. RESULTS: TB knowledge can be considered fairly good among this community. Respondents' perceptions suggest that stigma may influence TB patients' decision in health seeking behavior and adherence to TB treatment. A full 95% of those interviewed believe people with TB tend to hide their TB status out of fear of what others may say. Regression analyses revealed that in this population young and old, men and women and the lower and higher educated share the same attitudes and perceptions. Our findings are therefore likely to reflect the actual situation of TB patients in this population. CONCLUSIONS: The lay experts' perceptions suggests that stigma appears to effect case holding and case finding. Future interventions should be directed at improving attitudes and perceptions to potentially reduce stigma. This requires a patient-centered approach to empower TB patients and active involvement in the development and implementation of stigma reduction programs. PMID- 20163703 TI - An iterative identification procedure for dynamic modeling of biochemical networks. AB - BACKGROUND: Mathematical models provide abstract representations of the information gained from experimental observations on the structure and function of a particular biological system. Conferring a predictive character on a given mathematical formulation often relies on determining a number of non-measurable parameters that largely condition the model's response. These parameters can be identified by fitting the model to experimental data. However, this fit can only be accomplished when identifiability can be guaranteed. RESULTS: We propose a novel iterative identification procedure for detecting and dealing with the lack of identifiability. The procedure involves the following steps: 1) performing a structural identifiability analysis to detect identifiable parameters; 2) globally ranking the parameters to assist in the selection of the most relevant parameters; 3) calibrating the model using global optimization methods; 4) conducting a practical identifiability analysis consisting of two (a priori and a posteriori) phases aimed at evaluating the quality of given experimental designs and of the parameter estimates, respectively and 5) optimal experimental design so as to compute the scheme of experiments that maximizes the quality and quantity of information for fitting the model. CONCLUSIONS: The presented procedure was used to iteratively identify a mathematical model that describes the NF-kappaB regulatory module involving several unknown parameters. We demonstrated the lack of identifiability of the model under typical experimental conditions and computed optimal dynamic experiments that largely improved identifiability properties. PMID- 20163704 TI - Evidence that a West-East admixed population lived in the Tarim Basin as early as the early Bronze Age. AB - BACKGROUND: The Tarim Basin, located on the ancient Silk Road, played a very important role in the history of human migration and cultural communications between the West and the East. However, both the exact period at which the relevant events occurred and the origins of the people in the area remain very obscure. In this paper, we present data from the analyses of both Y chromosomal and mitochondrial DNA (mtDNA) derived from human remains excavated from the Xiaohe cemetery, the oldest archeological site with human remains discovered in the Tarim Basin thus far. RESULTS: Mitochondrial DNA analysis showed that the Xiaohe people carried both the East Eurasian haplogroup (C) and the West Eurasian haplogroups (H and K), whereas Y chromosomal DNA analysis revealed only the West Eurasian haplogroup R1a1a in the male individuals. CONCLUSION: Our results demonstrated that the Xiaohe people were an admixture from populations originating from both the West and the East, implying that the Tarim Basin had been occupied by an admixed population since the early Bronze Age. To our knowledge, this is the earliest genetic evidence of an admixed population settled in the Tarim Basin. PMID- 20163706 TI - Intensity-based analysis of dual-color gene expression data as an alternative to ratio-based analysis to enhance reproducibility. AB - BACKGROUND: Ratio-based analysis is the current standard for the analysis of dual color microarray data. Indeed, this method provides a powerful means to account for potential technical variations such as differences in background signal, spot size and spot concentration. However, current high density dual-color array platforms are of very high quality, and inter-array variance has become much less pronounced. We therefore raised the question whether it is feasible to use an intensity-based analysis rather than ratio-based analysis of dual-color microarray datasets. Furthermore, we compared performance of both ratio- and intensity-based analyses in terms of reproducibility and sensitivity for differential gene expression. RESULTS: By analyzing three distinct and technically replicated datasets with either ratio- or intensity-based models, we determined that, when applied to the same dataset, intensity-based analysis of dual-color gene expression experiments yields 1) more reproducible results, and 2) is more sensitive in the detection of differentially expressed genes. These effects were most pronounced in experiments with large biological variation and complex hybridization designs. Furthermore, a power analysis revealed that for direct two-group comparisons above a certain sample size, ratio-based models have higher power, although the difference with intensity-based models is very small. CONCLUSIONS: Intensity-based analysis of dual-color datasets results in more reproducible results and increased sensitivity in the detection of differential gene expression than the analysis of the same dataset with ratio-based analysis. Complex dual-color setups such as interwoven loop designs benefit most from ignoring the array factor. The applicability of our approach to array platforms other than dual-color needs to be further investigated. PMID- 20163705 TI - Food-borne norovirus-outbreak at a military base, Germany, 2009. AB - BACKGROUND: Norovirus is often transmitted from person-to-person. Transmission may also be food-borne, but only few norovirus outbreak investigations have identified food items as likely vehicles of norovirus transmission through an analytical epidemiological study.During 7-9 January, 2009, 36 persons at a military base in Germany fell ill with acute gastroenteritis. Food from the military base's canteen was suspected as vehicle of infection, norovirus as the pathogen causing the illnesses. An investigation was initiated to describe the outbreak's extent, to verify the pathogen, and to identify modes of transmission and source of infection to prevent further cases. METHODS: For descriptive analysis, ill persons were defined as members of the military base with acute onset of diarrhoea or vomiting between 24 December 2008, and 3 February 2009, without detection of a pathogen other than norovirus in stools. We conducted a retrospective cohort study within the headquarters company. Cases were military base members with onset of diarrhoea or vomiting during 5-9 January. We collected information on demographics, food items eaten at the canteen and contact to ill persons or vomit, using a self-administered questionnaire. We compared attack rates (AR) in exposed and unexposed persons, using bivariable and multivariable logistic regression modelling. Stool specimens of ill persons and canteen employees, canteen food served during 5-7 January and environmental swabs were investigated by laboratory analysis. RESULTS: Overall, 101/815 (AR 12.4%) persons fell ill between 24 December 2008 and 3 February 2009. None were canteen employees. Most persons (n = 49) had disease onset during 7-9 January. Ill persons were a median of 22 years old, 92.9% were male. The response for the cohort study was 178/274 (72.1%). Of 27 cases (AR 15.2%), 25 had eaten at the canteen and 21 had consumed salad. Salad consumption on 6 January (aOR: 8.1; 95%CI: 1.5-45.4) and 7 January (aOR: 15.7; 95%CI: 2.2-74.1) were independently associated with increased risk of disease.Norovirus was detected in 8/28 ill persons' and 4/25 canteen employees' stools, 6/55 environmental swabs and 0/33 food items. Sequences were identical in environmental and stool samples (subtype II.4 2006b), except for those of canteen employees. Control measures comprised cohort isolation of symptomatic persons, exclusion of norovirus-positive canteen employees from work and disinfection of the canteen's kitchen. CONCLUSIONS: Our investigation indicated that consumption of norovirus-contaminated salad caused the peak of the outbreak on 7-9 January. Strict personal hygiene and proper disinfection of environmental surfaces remain crucial to prevent norovirus transmission. PMID- 20163707 TI - Women's experiences and views about costs of seeking malaria chemoprevention and other antenatal services: a qualitative study from two districts in rural Tanzania. AB - BACKGROUND: The Tanzanian government recommends women who attend antenatal care (ANC) clinics to accept receiving intermittent preventive treatment against malaria during pregnancy (IPTp) and vouchers for insecticide-treated nets (ITNs) at subsidized prices. Little emphasis has been paid to investigate the ability of pregnant women to access and effectively utilize these services. OBJECTIVES: To describe the experience and perceptions of pregnant women about costs and cost barriers for accessing ANC services with emphasis on IPTp in rural Tanzania. METHODS: Qualitative data were collected in the districts of Mufindi in Iringa Region and Mkuranga in Coast Region through 1) focus group discussions (FGDs) with pregnant women and mothers to infants and 2) exit-interviews with pregnant women identified at ANC clinics. Data were analyzed manually using qualitative content analysis methodology. FINDINGS: FGD participants and interview respondents identified the following key limiting factors for women's use of ANC services: 1) costs in terms of money and time associated with accessing ANC clinics, 2) the presence of more or less official user-fees for some services within the ANC package, and 3) service providers' application of fines, penalties and blame when failing to adhere to service schedules. Interestingly, the time associated with travelling long distances to ANC clinics and ITN retailers and with waiting for services at clinic-level was a major factor of discouragement in the health seeking behaviour of pregnant women because it seriously affected their domestic responsibilities. CONCLUSION: A variety of resource-related factors were shown to affect the health seeking behaviour of pregnant women in rural Tanzania. Thus, accessibility to ANC services was hampered by direct and indirect costs, travel distances and waiting time. Strengthening of user-fee exemption practices and bringing services closer to the users, for example by promoting community-directed control of selected public health services, including IPTp, are urgently needed measures for increasing equity in health services in Tanzania. PMID- 20163708 TI - Insulin-like growth factor binding protein 5 enhances survival of LX2 human hepatic stellate cells. AB - BACKGROUND: Expression of insulin-like growth factor binding protein 5 (IGFBP5) is strongly induced upon activation of hepatic stellate cells and their transdifferentiation into myofibroblasts in vitro. This was confirmed in vivo in an animal model of liver fibrosis. Since IGFBP5 has been shown to promote fibrosis in other tissues, the aim of this study was to investigate its role in the progression of liver fibrosis. METHODS: The effect of IGFBP5 was studied in LX2 cells, a model for partially activated hepatic stellate cells, and in human primary liver myofibroblasts. IGFBP5 signalling was modulated by the addition of recombinant protein, by lentiviral overexpression, and by siRNA mediated silencing. Furthermore, the addition of IGF1 and silencing of the IGF1R was used to investigate the role of the IGF-axis in IGFBP5 mediated effects. RESULTS: IGFBP5 enhanced the survival of LX2 cells and myofibroblasts via a >50% suppression of apoptosis. This effect of IGFBP5 was not modulated by the addition of IGF1, nor by silencing of the IGF1R. Additionally, IGFBP5 was able to enhance the expression of established pro-fibrotic markers, such as collagen Ialpha1, TIMP1 and MMP1. CONCLUSION: IGFBP5 enhances the survival of (partially) activated hepatic stellate cells and myofibroblasts by lowering apoptosis via an IGF1 independent mechanism, and enhances the expression of profibrotic genes. Its lowered expression may, therefore, reduce the progression of liver fibrosis. PMID- 20163709 TI - Predicting MHC class I epitopes in large datasets. AB - BACKGROUND: Experimental screening of large sets of peptides with respect to their MHC binding capabilities is still very demanding due to the large number of possible peptide sequences and the extensive polymorphism of the MHC proteins. Therefore, there is significant interest in the development of computational methods for predicting the binding capability of peptides to MHC molecules, as a first step towards selecting peptides for actual screening. RESULTS: We have examined the performance of four diverse MHC Class I prediction methods on comparatively large HLA-A and HLA-B allele peptide binding datasets extracted from the Immune Epitope Database and Analysis resource (IEDB). The chosen methods span a representative cross-section of available methodology for MHC binding predictions. Until the development of IEDB, such an analysis was not possible, as the available peptide sequence datasets were small and spread out over many separate efforts. We tested three datasets which differ in the IC50 cutoff criteria used to select the binders and non-binders. The best performance was achieved when predictions were performed on the dataset consisting only of strong binders (IC50 less than 10 nM) and clear non-binders (IC50 greater than 10,000 nM). In addition, robustness of the predictions was only achieved for alleles that were represented with a sufficiently large (greater than 200), balanced set of binders and non-binders. CONCLUSIONS: All four methods show good to excellent performance on the comprehensive datasets, with the artificial neural networks based method outperforming the other methods. However, all methods show pronounced difficulties in correctly categorizing intermediate binders. PMID- 20163710 TI - Broad spectrum microarray for fingerprint-based bacterial species identification. AB - BACKGROUND: Microarrays are powerful tools for DNA-based molecular diagnostics and identification of pathogens. Most target a limited range of organisms and are based on only one or a very few genes for specific identification. Such microarrays are limited to organisms for which specific probes are available, and often have difficulty discriminating closely related taxa. We have developed an alternative broad-spectrum microarray that employs hybridisation fingerprints generated by high-density anonymous markers distributed over the entire genome for identification based on comparison to a reference database. RESULTS: A high density microarray carrying 95,000 unique 13-mer probes was designed. Optimized methods were developed to deliver reproducible hybridisation patterns that enabled confident discrimination of bacteria at the species, subspecies, and strain levels. High correlation coefficients were achieved between replicates. A sub-selection of 12,071 probes, determined by ANOVA and class prediction analysis, enabled the discrimination of all samples in our panel. Mismatch probe hybridisation was observed but was found to have no effect on the discriminatory capacity of our system. CONCLUSIONS: These results indicate the potential of our genome chip for reliable identification of a wide range of bacterial taxa at the subspecies level without laborious prior sequencing and probe design. With its high resolution capacity, our proof-of-principle chip demonstrates great potential as a tool for molecular diagnostics of broad taxonomic groups. PMID- 20163711 TI - Suicide attempt in a rural area of Vietnam: Incidence, methods used and access to mental health care. AB - OBJECTIVES: The study aims to determine the incidence of suicide attempt, describe the methods used, and assess use of health care services including mental health care after suicide attempt in a rural area of Vietnam. METHODS: All suicide attempters (104) during 2003-2007 were listed, diagnosed and re-evaluated by trained physicians according to the research criteria of the WHO Multicentre Study of Attempted Suicide. All attempters were interviewed by trained medical staff to investigate methods used, socio-demographic characteristics and use of health services. RESULTS: The yearly incidence was 10.2 per 100000 person-years, 10.6 per 100000 in males and 9.8 per 100000 in females. 99% of cases committed suicide attempt by poisoning, 62.6% by pesticides and 36.3% by pharmaceutical drugs. 34.3% reported having been in contact with somatic care and 13.2% had received mental health care. Among those who reported some treatment received, 47.5% had been in contact with official health care services, 8.1% had pharmacy keepers' consultation or were treated by traditional healers and 4% reported self treatment. CONCLUSION: The incidence of suicide attempt was lower in this population compared to other settings. While the majority of attempters use pesticides, many had used psychotropic drugs. Contact with mental health services following the attempt was very limited in this setting. Suicide prevention for this high risk group should focus on reducing access to pesticides and psychotropic drugs. Mental health services should be made more accessible in rural areas. PMID- 20163712 TI - Body piercing and tattoo: awareness of health related risks among 4,277 Italian secondary school adolescents. AB - BACKGROUND: The awareness of health risks associated with body art among secondary school pupils has never previously been studied in depth. A large sample of secondary school adolescents from the Veneto Region (North East Italy) were investigated in order to inform health education programs. METHODS: 6 public secondary schools from each of the 7 Provinces of the Veneto Region were selected. All students attending the 1st, 3rd, and 5th school years were surveyed by an anonymous self administered questionnaire on their perception of health risks related to body art and other explanatory variables. Logistic regression analysis was employed, reporting adjusted Odds Ratios (OR) with 95% Confidence Interval (CI). RESULTS: Among 4,277 available students (aged 14-22 years), boys were consistently: less knowledgeable of infectious diseases related to body art (OR = 0.78; CI: 0.66, 0.94), less likely to be aware of the hygienic norms to be observed in a body art parlour (OR = 0.54; 0.44, 0.65), less likely to refer to a certified body art parlour (OR = 0.56; 0.48, 0.66), less likely to refer to a professional health care provider for complications related to body art (OR = 0.71; 0.59, 0.86). Students attending the first school year (baseline) had a lesser knowledge of body art related infectious diseases, were less likely to refer to a certified body art parlour, and to know the mandatory hygienic rules to be observed when performing body modifications. Interviewees from the provinces of Rovigo and Vicenza were less likely to be conscious of the health risks associated with body modifications, and those with tattoos were less knowledgeable about the infection risk (OR = 0.60; 0.42, 0.86) and less likely to refer to a professional health care provider in case of medical complication (OR = 0.68;0.48, 0.95). Students with piercings were less likely to refer to a certified practitioner for receiving body art (OR = 0.62; 0.50, 0.77) or therapy for medical complications (OR = 0.37; 0.29, 0.46). CONCLUSIONS: Health education programs should focus on males, pupils attending lower school years, living in specific Provinces of the Region, and with a positive attitude towards piercing or tattoo. PMID- 20163713 TI - Accelerated microevolution in an outer membrane protein (OMP) of the intracellular bacteria Wolbachia. AB - BACKGROUND: Outer membrane proteins (OMPs) of Gram-negative bacteria are key players in the biology of bacterial-host interactions. However, while considerable attention has been given to OMPs of vertebrate pathogens, relatively little is known about the role of these proteins in bacteria that primarily infect invertebrates. One such OMP is found in the intracellular bacteria Wolbachia, which are widespread symbionts of arthropods and filarial nematodes. Recent experimental studies have shown that the Wolbachia surface protein (WSP) can trigger host immune responses and control cell death programming in humans, suggesting a key role of WSP for establishment and persistence of the symbiosis in arthropods. RESULTS: Here we performed an analysis of 515 unique alleles found in 831 Wolbachia isolates, to investigate WSP structure, microevolution and population genetics. WSP shows an eight-strand transmembrane beta-barrel structure with four extracellular loops containing hypervariable regions (HVRs). A clustering approach based upon patterns of HVR haplotype diversity was used to group similar WSP sequences and to estimate the relative contribution of mutation and recombination during early stages of protein divergence. Results indicate that although point mutations generate most of the new protein haplotypes, recombination is a predominant force triggering diversity since the very first steps of protein evolution, causing at least 50% of the total amino acid variation observed in recently diverged proteins. Analysis of synonymous variants indicates that individual WSP protein types are subject to a very rapid turnover and that HVRs can accommodate a virtually unlimited repertoire of peptides. Overall distribution of WSP across hosts supports a non-random association of WSP with the host genus, although extensive horizontal transfer has occurred also in recent times. CONCLUSIONS: In OMPs of vertebrate pathogens, large recombination impact, positive selection, reduced structural and compositional constraints, and extensive lateral gene transfer are considered hallmarks of evolution in response to the adaptive immune system. However, Wolbachia do not infect vertebrates. Here we predict that the rapid turnover of WSP loop motifs could aid in evading or inhibiting the invertebrate innate immune response. Overall, these features identify WSP as a strong candidate for future studies of host-Wolbachia interactions that affect establishment and persistence of this widespread endosymbiosis. PMID- 20163714 TI - Antibody isotype analysis of malaria-nematode co-infection: problems and solutions associated with cross-reactivity. AB - BACKGROUND: Antibody isotype responses can be useful as indicators of immune bias during infection. In studies of parasite co-infection however, interpretation of immune bias is complicated by the occurrence of cross-reactive antibodies. To confidently attribute shifts in immune bias to the presence of a co-infecting parasite, we suggest practical approaches to account for antibody cross reactivity. The potential for cross-reactive antibodies to influence disease outcome is also discussed. RESULTS: Utilising two murine models of malaria helminth co-infection we analysed antibody responses of mice singly- or co infected with Plasmodium chabaudi chabaudi and Nippostrongylus brasiliensis or Litomosoides sigmodontis. We observed cross-reactive antibody responses that recognised antigens from both pathogens irrespective of whether crude parasite antigen preparations or purified recombinant proteins were used in ELISA. These responses were not apparent in control mice. The relative strength of cross reactive versus antigen-specific responses was determined by calculating antibody titre. In addition, we analysed antibody binding to periodate-treated antigens, to distinguish responses targeted to protein versus carbohydrate moieties. Periodate treatment affected both antigen-specific and cross-reactive responses. For example, malaria-induced cross-reactive IgG1 responses were found to target the carbohydrate component of the helminth antigen, as they were not detected following periodate treatment. Interestingly, periodate treatment of recombinant malaria antigen Merozoite Surface Protein-119 (MSP-119) resulted in increased detection of antigen-specific IgG2a responses in malaria-infected mice. This suggests that glycosylation may have been masking protein epitopes and that periodate-treated MSP-119 may more closely reflect the natural non-glycosylated antigen seen during infection. CONCLUSIONS: In order to utilize antibody isotypes as a measure of immune bias during co-infection studies, it is important to dissect antigen-specific from cross-reactive antibody responses. Calculating antibody titre, rather than using a single dilution of serum, as a measure of the relative strength of the response, largely accomplished this. Elimination of the carbohydrate moiety of an antigen that can often be the target of cross-reactive antibodies also proved useful. PMID- 20163715 TI - SoyTEdb: a comprehensive database of transposable elements in the soybean genome. AB - BACKGROUND: Transposable elements are the most abundant components of all characterized genomes of higher eukaryotes. It has been documented that these elements not only contribute to the shaping and reshaping of their host genomes, but also play significant roles in regulating gene expression, altering gene function, and creating new genes. Thus, complete identification of transposable elements in sequenced genomes and construction of comprehensive transposable element databases are essential for accurate annotation of genes and other genomic components, for investigation of potential functional interaction between transposable elements and genes, and for study of genome evolution. The recent availability of the soybean genome sequence has provided an unprecedented opportunity for discovery, and structural and functional characterization of transposable elements in this economically important legume crop. DESCRIPTION: Using a combination of structure-based and homology-based approaches, a total of 32,552 retrotransposons (Class I) and 6,029 DNA transposons (Class II) with clear boundaries and insertion sites were structurally annotated and clearly categorized, and a soybean transposable element database, SoyTEdb, was established. These transposable elements have been anchored in and integrated with the soybean physical map and genetic map, and are browsable and visualizable at any scale along the 20 soybean chromosomes, along with predicted genes and other sequence annotations. BLAST search and other infrastracture tools were implemented to facilitate annotation of transposable elements or fragments from soybean and other related legume species. The majority (> 95%) of these elements (particularly a few hundred low-copy-number families) are first described in this study. CONCLUSION: SoyTEdb provides resources and information related to transposable elements in the soybean genome, representing the most comprehensive and the largest manually curated transposable element database for any individual plant genome completely sequenced to date. Transposable elements previously identified in legumes, the third largest family of flowering plants, are relatively scarce. Thus this database will facilitate structural, evolutionary, functional, and epigenetic analyses of transposable elements in soybean and other legume species. PMID- 20163716 TI - Proteome changes of Caenorhabditis elegans upon a Staphylococcus aureus infection. AB - BACKGROUND: The success of invertebrates throughout evolution is an excellent illustration of the efficiency of their defence strategies. Caenorhabditis elegans has proven to be an appropriate model for transcriptome studies of host pathogen interactions. The aim of this paper is to complement this knowledge by investigating the worm's response to a Staphylococcus aureus infection through a 2-dimensional differential proteomics approach. RESULTS: Different types of growth media in combination with either E. coli OP50 or Staphylococcus aureus were tested for an effect on the worm's lifespan. LB agar was chosen and C. elegans samples were collected 1 h, 4 h, 8 h and 24 h post S. aureus infection or E. coli incubation. Proteomics analyses resulted in the identification of 130 spots corresponding to a total of 108 differentially expressed proteins. CONCLUSIONS: Exploring four time-points discloses a dynamic insight of the reaction against a gram-positive infection at the level of the whole organism. The remarkable upregulation after 8 h and 24 h of many enzymes involved in the citric acid cycle might illustrate the cost of fighting off an infection. Intriguing is the downregulation of chaperone molecules, which are presumed to serve a protective role. A comparison with a similar experiment in which C. elegans was infected with the gram-negative Aeromonas hydrophila reveals that merely 9% of the identified spots, some of which even exhibiting an opposite regulation, are present in both studies. Hence, our findings emphasise the complexity and pathogen-specificity of the worm's immune response and form a firm basis for future functional research. REVIEWERS: This article was reviewed by Itai Yanai, Dieter Wolf and Torben Luebke (nominated by Walter Lutz). PMID- 20163717 TI - BisoGenet: a new tool for gene network building, visualization and analysis. AB - BACKGROUND: The increasing availability and diversity of omics data in the post genomic era offers new perspectives in most areas of biomedical research. Graph based biological networks models capture the topology of the functional relationships between molecular entities such as gene, protein and small compounds and provide a suitable framework for integrating and analyzing omics data. The development of software tools capable of integrating data from different sources and to provide flexible methods to reconstruct, represent and analyze topological networks is an active field of research in bioinformatics. RESULTS: BisoGenet is a multi-tier application for visualization and analysis of biomolecular relationships. The system consists of three tiers. In the data tier, an in-house database stores genomics information, protein-protein interactions, protein-DNA interactions, gene ontology and metabolic pathways. In the middle tier, a global network is created at server startup, representing the whole data on bioentities and their relationships retrieved from the database. The client tier is a Cytoscape plugin, which manages user input, communication with the Web Service, visualization and analysis of the resulting network. CONCLUSION: BisoGenet is able to build and visualize biological networks in a fast and user friendly manner. A feature of Bisogenet is the possibility to include coding relations to distinguish between genes and their products. This feature could be instrumental to achieve a finer grain representation of the bioentities and their relationships. The client application includes network analysis tools and interactive network expansion capabilities. In addition, an option is provided to allow other networks to be converted to BisoGenet. This feature facilitates the integration of our software with other tools available in the Cytoscape platform. BisoGenet is available at http://bio.cigb.edu.cu/bisogenet-cytoscape/. PMID- 20163718 TI - High-level expression and purification of soluble recombinant FGF21 protein by SUMO fusion in Escherichia coli. AB - BACKGROUND: Fibroblast growth factor 21 (FGF21) is a promising drug candidate to combat metabolic diseases. However, high-level expression and purification of recombinant FGF21 (rFGF21) in Escherichia coli (E. coli) is difficult because rFGF21 forms inclusion bodies in the bacteria making it difficult to purify and obtain high concentrations of bioactive rFGF21. To overcome this problem, we fused the FGF21 with SUMO (Small ubiquitin-related modifier) by polymerase chain reaction (PCR), and expressed the fused gene in E. coli BL21(DE3). RESULTS: By inducing with IPTG, SUMO-FGF21 was expressed at a high level. Its concentration reached 30% of total protein, and exceeded 95% of all soluble proteins. The fused protein was purified by DEAE sepharose FF and Ni-NTA affinity chromatography. Once cleaved by the SUMO protease, the purity of rFGF21 by high performance liquid chromatography (HPLC) was shown to be higher than 96% with low endotoxin level (<1.0 EU/ml). The results of in vivo animal experiments showed that rFGF21 produced by using this method, could decrease the concentration of plasma glucose in diabetic rats by streptozotocin (STZ) injection. CONCLUSIONS: This study demonstrated that SUMO, when fused with FGF21, was able to promote its soluble expression of the latter in E. coli, making it more convenient to purify rFGF21 than previously. This may be a better method to produce rFGF21 for pharmaceutical research and development. PMID- 20163719 TI - New paradigm old thinking: The case for emergency obstetric care in the prevention of maternal mortality in Nigeria. AB - BACKGROUND: The continuing burden of maternal mortality, especially in developing countries has prompted a shift in paradigm from the traditional risk assessment approach to the provision of access to emergency obstetric care services for all women who are pregnant. This study assessed the knowledge of maternity unit operatives at the primary and secondary levels of care about the concept of emergency obstetric care (EmOC) and investigated the contents of antenatal care (ANC) counseling services they delivered to clients. It also described the operatives' preferred strategies and practices for promoting safe motherhood and averting maternal mortality in South-west Nigeria. METHODS: The study population included all the 152 health workers (doctors, midwives, nurses and community health extension workers) employed in the maternity units of all the public health facilities (n = 22) offering maternity care in five cities of 2 states. Data were collected with the aid of a self-administered, semi-structured questionnaire and non-participant observation checklist. Results were presented using descriptive statistics. RESULTS: Ninety one percent of the maternity unit staff had poor knowledge concerning the concept of EmOC, with no difference in knowledge of respondents across age groups. While consistently more than 60% of staff reported the inclusion of specific client-centered messages such as birth preparedness and warning/danger signs of pregnancy and delivery in the (ANC) delivered to clients, structured observations revealed that less than a quarter of staff actually did this. Furthermore, only 40% of staff reported counseling clients on complication readiness, but structured observations revealed that no staff did. Only 9% of staff had ever been trained in lifesaving skills (LSS). Concerning strategies for averting maternal deaths, 70% of respondents still preferred the strengthening of routine ANC services in the health facilities to the provision of access to EmOC services for all pregnant women who need it. CONCLUSION: We concluded that maternity unit operatives at the primary and secondary care levels in South-west Nigeria were poorly knowledgeable about the concept of emergency obstetric care services and they still prioritized the strengthening of routine antenatal care services based on the risk approach over other interventions for promoting safe motherhood despite a global current shift in paradigm. There is an urgent need to reorientate/retrain the staff in line with global best practices. PMID- 20163720 TI - Effects of plasma magnesium and prolactin on quantitative ultrasound measurements of heel bone among schizophrenic patients. AB - BACKGROUND: Osteoporosis is a bone disease that can reduce both bone mass and bone strength. It can cause serious fractures of bones, along with causing significant and even devastating physical, psychological and financial consequences for patients and their family members. Many reports have revealed that the prevalence of decreased bone density is higher in schizophrenic patients than in the non-psychological diseased population. The previous report of our group revealed that chronic schizophrenia patients have poorer BUA levels since they were young as compared to the general community population. Hyperprolactinemia and antipsychotics are reported to be among the risk factors for osteoporosis in chronic schizophrenic patients. METHODS: 93 schizophrenic patients with severely poor adjusted BUA values and 93 age and gender matched patients with normal adjusted BUA values from a previous survey study were selected. Data were collected via questionnaires and via reviews of antipsychotic medications. Blood samples were drawn, and serum levels of prolactin, estradiol, testosterone, magnesium, calcium, phosphate, osteocalcin, Cross-linked N teleopeptide of type I collagen (NTX), thyroid hormone and parathyroid hormone were checked. The association between BUA levels and serum levels of the above items, along with the type of received antipsychotic medication, was evaluated. RESULTS: There was no significant association found between reduced BUA levels and serum prolactin, calcium, phosphate, osteocalcin, NTX, thyroid stimulating hormone and parathyroid hormone levels. There was also no association between BUA levels and types of currently received antipsychotics. There was no association between BUA levels and menstruation condition in female patients. Hypermagnesemia had a borderline association with classical and combined (classical and atypical) antipsychotic medications in male patients. Nevertheless, hypermagnesemia is a significant protective factor of reduced BUA levels in female patients. Hyperprolactinemia had a significant association with classical and combined antipsychotic medications in female patients. Hyperprolactinemia, however, provides a protective effect on reduced BUA levels in male patients. There was no significant association found between serum prolactin level and the type of antipsychotic medication received. CONCLUSIONS: The results of this study are in contrast with literature that has reported an association between bone mass and serum prolactin levels, serum magnesium levels and type of received antipsychotics. Further study to investigate the pathophysiological process and the association between bone mass and serum prolactin level, serum magnesium level and specific antipsychotics is necessary. PMID- 20163721 TI - Gene duplication in the genome of parasitic Giardia lamblia. AB - BACKGROUND: Giardia are a group of widespread intestinal protozoan parasites in a number of vertebrates. Much evidence from G. lamblia indicated they might be the most primitive extant eukaryotes. When and how such a group of the earliest branching unicellular eukaryotes developed the ability to successfully parasitize the latest branching higher eukaryotes (vertebrates) is an intriguing question. Gene duplication has long been thought to be the most common mechanism in the production of primary resources for the origin of evolutionary novelties. In order to parse the evolutionary trajectory of Giardia parasitic lifestyle, here we carried out a genome-wide analysis about gene duplication patterns in G. lamblia. RESULTS: Although genomic comparison showed that in G. lamblia the contents of many fundamental biologic pathways are simplified and the whole genome is very compact, in our study 40% of its genes were identified as duplicated genes. Evolutionary distance analyses of these duplicated genes indicated two rounds of large scale duplication events had occurred in G. lamblia genome. Functional annotation of them further showed that the majority of recent duplicated genes are VSPs (Variant-specific Surface Proteins), which are essential for the successful parasitic life of Giardia in hosts. Based on evolutionary comparison with their hosts, it was found that the rapid expansion of VSPs in G. lamblia is consistent with the evolutionary radiation of placental mammals. CONCLUSIONS: Based on the genome-wide analysis of duplicated genes in G. lamblia, we found that gene duplication was essential for the origin and evolution of Giardia parasitic lifestyle. The recent expansion of VSPs uniquely occurring in G. lamblia is consistent with the increment of its hosts. Therefore we proposed a hypothesis that the increment of Giradia hosts might be the driving force for the rapid expansion of VSPs. PMID- 20163722 TI - Chromosomal imbalances are uncommon in chagasic megaesophagus. AB - BACKGROUND: Chagas' disease is a human tropical parasitic illness and a subset of the chronic patients develop megaesophagus or megacolon. The esophagus dilation is known as chagasic megaesophagus (CM) and one of the severe late consequences of CM is the increased risk for esophageal carcinoma (ESCC). Based on the association between CM and ESCC, we investigated whether genes frequently showing unbalanced copy numbers in ESCC were altered in CM by fluorescence in situ (FISH) technology. METHODS: A total of 50 formalin-fixed, paraffin-embedded esophageal mucosa specimens (40 from Chagas megaesophagus-CM, and 10 normal esophageal mucosa-NM) were analyzed. DNA FISH probes were tested for FHIT, TP63, PIK3CA, EGFR, FGFR1, MYC, CDKN2A, YES1 and NCOA3 genes, and centromeric sequences from chromosomes 3, 7 and 9. RESULTS: No differences between superficial and basal layers of the epithelial mucosa were found, except for loss of copy number of EGFR in the esophageal basal layer of CM group. Mean copy number of CDKN2A and CEP9 and frequency of nuclei with loss of PIK3CA were significantly different in the CM group compared with normal mucosa and marginal levels of deletions in TP63, FHIT, PIK3CA, EGFR, CDKN2A, YES and gains at PIK3CA, TP63, FGFR1, MYC, CDNK2A and NCOA3 were detected in few CM cases, mainly with dilation grades III and IV. All changes occurred at very low levels. CONCLUSIONS: Genomic imbalances common in esophageal carcinomas are not present in chagasic megaesophagus suggesting that these features will not be effective markers for risk assessment of ESCC in patients with chagasic megaesophagus. PMID- 20163723 TI - Orofacial findings in chronic granulomatous disease: report of twelve patients and review of the literature. AB - BACKGROUND: Chronic granulomatous disease is an extremely rare primary immunodeficiency syndrome that can be associated with various oral complications. This can affect high number of patients. However, data on oral complications is sparse. Here we will review the literature and describe the orofacial findings in 12 patients. FINDINGS: The age range was 5-31 years. Oral findings were variable, and reflected a low level of oral hygiene. They included periodontitis, rampant caries, gingivitis, aphthous-like ulcers, and geographic tongue. One patient had white patches on the buccal mucosa similar to lichen planus. Another patient had a nodular dorsum of the tongue associated with fissured and geographic tongue. Biopsies from the latter two lesions revealed chronic non-specific mucositis. Panoramic radiographs showed extensive periodontitis in one patient and periapical lesions in another patient. CONCLUSION: Patients with chronic granulomatous disease may develop oral lesions reflecting susceptibility to infections and inflammation. It is also possible that social and genetic factors may influence the development of this complication. Therefore, oral hygiene must be kept at an optimum level to prevent infections that can be difficult to manage. PMID- 20163724 TI - Influence of nanofibers on growth and gene expression of human tendon derived fibroblast. AB - BACKGROUND: Rotator cuff tears are a common and frequent lesion especially in older patients. The mechanisms of tendon repair are not fully understood. Common therapy options for tendon repair include mini-open or arthroscopic surgery. The use of growth factors in experimental studies is mentioned in the literature. Nanofiber scaffolds, which provide several criteria for the healing process, might be a suitable therapy option for operative treatment. The aim of this study was to explore the effects of nanofiber scaffolds on human tendon derived fibroblasts (TDF's), as well as the gene expression and matrix deposition of these fibroblasts. METHODS: Nanofibers composed of PLLA and PLLA/Col-I were seeded with human tendon derived fibroblasts and cultivated over a period of 22 days under growth-inductive conditions, and analyzed during the course of culture, with respect to gene expression of different extra cellular matrix components such as collagens, bigylcan and decorin. Furthermore, we measured cell densities and proliferation by using fluorescence microscopy. RESULTS: PLLA nanofibers possessed a growth inhibitory effect on TDF's. Furthermore, no meaningful influence on the gene expression of collagen I, collagen III and decorin could be observed, while the expression of collagen X increased during the course of cultivation. On the other hand, PLLA/Col-I blend nanofibers had no negative influence on the growth of TDF's. Furthermore, blending PLLA nanofibers with collagen had a positive effect on the gene expression of collagen I, III, X and decorin. Here, gene expression indicated that focal adherence kinases might be involved. CONCLUSION: This study indicates that the use of nanofibers influence expression of genes associated with the extra cellular matrix formation. The composition of the nanofibers plays a critical role. While PLLA/Col-I blend nanofibers enhance the collagen I and III formation, their expression on PLLA nanofibers was more comparable to controls. However, irrespective of the chemical composition of the fibres, the collagen deposition was altered, an effect which might be associated with a decreased expression of biglycanes. PMID- 20163725 TI - Genome-wide analysis of alternative splicing in Chlamydomonas reinhardtii. AB - BACKGROUND: Genome-wide computational analysis of alternative splicing (AS) in several flowering plants has revealed that pre-mRNAs from about 30% of genes undergo AS. Chlamydomonas, a simple unicellular green alga, is part of the lineage that includes land plants. However, it diverged from land plants about one billion years ago. Hence, it serves as a good model system to study alternative splicing in early photosynthetic eukaryotes, to obtain insights into the evolution of this process in plants, and to compare splicing in simple unicellular photosynthetic and non-photosynthetic eukaryotes. We performed a global analysis of alternative splicing in Chlamydomonas reinhardtii using its recently completed genome sequence and all available ESTs and cDNAs. RESULTS: Our analysis of AS using BLAT and a modified version of the Sircah tool revealed AS of 498 transcriptional units with 611 events, representing about 3% of the total number of genes. As in land plants, intron retention is the most prevalent form of AS. Retained introns and skipped exons tend to be shorter than their counterparts in constitutively spliced genes. The splice site signals in all types of AS events are weaker than those in constitutively spliced genes. Furthermore, in alternatively spliced genes, the prevalent splice form has a stronger splice site signal than the non-prevalent form. Analysis of constitutively spliced introns revealed an over-abundance of motifs with simple repetitive elements in comparison to introns involved in intron retention. In almost all cases, AS results in a truncated ORF, leading to a coding sequence that is around 50% shorter than the prevalent splice form. Using RT-PCR we verified AS of two genes and show that they produce more isoforms than indicated by EST data. All cDNA/EST alignments and splice graphs are provided in a website at http://combi.cs.colostate.edu/as/chlamy. CONCLUSIONS: The extent of AS in Chlamydomonas that we observed is much smaller than observed in land plants, but is much higher than in simple unicellular heterotrophic eukaryotes. The percentage of different alternative splicing events is similar to flowering plants. Prevalence of constitutive and alternative splicing in Chlamydomonas, together with its simplicity, many available public resources, and well developed genetic and molecular tools for this organism make it an excellent model system to elucidate the mechanisms involved in regulated splicing in photosynthetic eukaryotes. PMID- 20163726 TI - Giving tranexamic acid to reduce surgical bleeding in sub-Saharan Africa: an economic evaluation. AB - BACKGROUND: The identification of safe and effective alternatives to blood transfusion is a public health priority. In sub-Saharan Africa, blood shortage is a cause of mortality and morbidity. Blood transfusion can also transmit viral infections. Giving tranexamic acid (TXA) to bleeding surgical patients has been shown to reduce both the number of blood transfusions and the volume of blood transfused. The objective of this study is to investigate whether routinely administering TXA to bleeding elective surgical patients is cost effective by both averting deaths occurring from the shortage of blood, and by preventing infections from blood transfusions. METHODS: A decision tree was constructed to evaluate the cost-effectiveness of providing TXA compared with no TXA in patients with surgical bleeding in four African countries with different human immunodeficiency virus (HIV) prevalence and blood donation rates (Kenya, South Africa, Tanzania and Botswana). The principal outcome measures were cost per life saved and cost per infection averted (HIV, Hepatitis B, Hepatitis C) averted in 2007 International dollars ($). The probability of receiving a blood transfusion with and without TXA and the risk of blood borne viral infection were estimated. The impact of uncertainty in model parameters was explored using one-way deterministic sensitivity analyses. Probabilistic sensitivity analysis was performed using Monte Carlo simulation. RESULTS: The incremental cost per life saved is $87 for Kenya and $93 for Tanzania. In Botswana and South Africa, TXA administration is not life saving but is highly cost saving since fewer units of blood are transfused. Further, in Botswana the administration of TXA averts one case of HIV and four cases of Hepatitis B (HBV) per 1,000 surgical patients. In South Africa, one case of HBV is averted per 1,000 surgical patients. Probabilistic sensitivity analyses confirmed the robustness of the model. CONCLUSION: An economic argument can be made for giving TXA to bleeding elective surgical patients. In countries where there is a blood shortage, TXA would be a cost effective way to reduce mortality. In countries where there is no blood shortage, TXA would reduce healthcare costs and avert blood borne infections. PMID- 20163727 TI - Culture independent molecular analysis of bacterial communities in the mangrove sediment of Sundarban, India. AB - BACKGROUND: Sundarban is the world's largest coastal sediment comprising of mangrove forest which covers about one million hectares in the south-eastern parts of India and southern parts of Bangladesh. The microbial diversity in this sediment is largely unknown till date. In the present study an attempt has been made to understand the microbial diversity in this sediment using a cultivation independent molecular approach. RESULTS: Two 16 S rRNA gene libraries were constructed and partial sequencing of the selected clones was carried out to identify bacterial strains present in the sediment. Phylogenetic analysis of partially sequenced 16 S rRNA gene sequences revealed the diversity of bacterial strains in the Sundarban sediment. At least 8 different bacterial phyla were detected. The major divisions of detected bacterial phyla were Proteobacteria (alpha, beta, gamma, and delta), Flexibacteria (CFB group), Actinobacteria, Acidobacteria, Chloroflexi, Firmicutes, Planctomycetes and Gammatimonadates. CONCLUSION: The gammaproteobacteria were found to be the most abundant bacterial group in Sundarban sediment. Many clones showed similarity with previously reported bacterial lineages recovered from various marine sediments. The present study indicates a probable hydrocarbon and oil contamination in this sediment. In the present study, a number of clones were identified that have shown similarity with bacterial clones or isolates responsible for the maintenance of the S-cycle in the saline environment. PMID- 20163728 TI - Species composition, larval habitats, seasonal occurrence and distribution of potential malaria vectors and associated species of Anopheles (Diptera: Culicidae) from the Republic of Korea. AB - BACKGROUND: Larval mosquito habitats of potential malaria vectors and related species of Anopheles from three provinces (Gyeonggi, Gyeongsangbuk, Chungcheongbuk Provinces) of the Republic of Korea were surveyed in 2007. This study aimed to determine the species composition, seasonal occurrence and distributions of Anopheles mosquitoes. Satellite derived normalized difference vegetation index data (NDVI) was also used to study the seasonal abundance patterns of Anopheles mosquitoes. METHODS: Mosquito larvae from various habitats were collected using a standard larval dipper or a white plastic larval tray, placed in plastic bags, and were preserved in 100% ethyl alcohol for species identification by PCR and DNA sequencing. The habitats in the monthly larval surveys included artificial containers, ground depressions, irrigation ditches, drainage ditches, ground pools, ponds, rice paddies, stream margins, inlets and pools, swamps, and uncultivated fields. All field-collected specimens were identified to species, and relationships among habitats and locations based on species composition were determined using cluster statistical analysis. RESULTS: In about 10,000 specimens collected, eight species of Anopheles belonging to three groups were identified: Hyrcanus Group - Anopheles sinensis, Anopheles kleini, Anopheles belenrae, Anopheles pullus, Anopheles lesteri, Anopheles sineroides; Barbirostris Group - Anopheles koreicus; and Lindesayi Group - Anopheles lindesayi japonicus. Only An. sinensis was collected from all habitats groups, while An. kleini, An. pullus and An. sineroides were sampled from all, except artificial containers. The highest number of Anopheles larvae was found in the rice paddies (34.8%), followed by irrigation ditches (23.4%), ponds (17.0%), and stream margins, inlets and pools (12.0%). Anopheles sinensis was the dominant species, followed by An. kleini, An. pullus and An. sineroides. The monthly abundance data of the Anopheles species from three locations (Munsan, Jinbo and Hayang) were compared against NDVI and NDVI anomalies. CONCLUSION: The species composition of Anopheles larvae varied in different habitats at various locations. Anopheles populations fluctuated with the seasonal dynamics of vegetation for 2007. Multi-year data of mosquito collections are required to provide a better characterization of the abundance of these insects from year to year, which can potentially provide predictive capability of their population density based on remotely sensed ecological measurements. PMID- 20163729 TI - A protocol for an individualised, facilitated and sustainable approach to implementing current evidence in preventing falls in residential aged care facilities. AB - BACKGROUND: Falls are common adverse events in residential care facilities. Commonly reported figures indicate that at least 50% of residents fall in a 12 month period, and that this figure is substantially higher for residents with dementia. This paper reports the protocol of a project which aims to implement evidence based falls prevention strategies in nine residential aged care facilities (RACFs) in Australia. The facilities in the study include high and low care, small and large facilities, metropolitan and regional, facilities with a specific cultural focus, and target groups recognised as being more challenging to successful implementation of falls prevention practice (e.g. residents with dementia). METHODS: The project will be conducted from November 2007-November 2009. The project will involve baseline scoping of existing falls rates and falls prevention activities in each facility, an action research process, interactive falls prevention training, individual falls risk assessments, provision of equipment and modifications, organisation based steering committees, and an economic evaluation. In each RACF, staff will be invited to join an action research group that will lead the process of developing and implementing interventions designed to facilitate an evidence based approach to falls management in their facility. In all RACFs a pre/post design will be adopted with a range of standardised measures utilised to determine the impact of the interventions. DISCUSSION: The care gap in residential aged care that will be addressed through this project relates to the challenges in implementing best practice falls prevention actions despite the availability of best practice guidelines. There are numerous factors that may limit the uptake of best practice falls prevention guidelines in residential aged care facilities. A multi factorial individualised (to the specific requirements of each facility) approach will be used to develop and implement an action plan in each participating facility based on the best available evidence. PMID- 20163730 TI - Ethnomedicine and ethnobotany of fright, a Caribbean culture-bound psychiatric syndrome. AB - BACKGROUND: "Fright" is an English-speaking Caribbean idiom for an illness, or ethnomedical syndrome, of persistent distress. A parallel ethnopsychiatric idiom exists in the French Antilles as sesisma. Fright is distinct from susto among Hispanics, though both develop in the wake of traumatic events. West Indian ethnophysiology (ethnoanatomy) theorizes that an overload of stressful emotions (fear, panic, anguish or worry) causes a cold humoral state in which blood coagulates causing prolonged distress and increased risks of other humorally cold illnesses. METHODS: Qualitative data on local explanatory models and treatment of fright were collected using participant-observation, informal key informant interviews and a village health survey. Ethnobotanical and epidemiological data come from freelist (or "free-list") tasks, analyzed for salience, with nearly all adults (N = 112) of an eastern village in Dominica, and a village survey on medicinal plant recognition and use (N = 106). RESULTS: Along with prayer and exercise, three herbs are salient fright treatments: Gossypium barbadense L., Lippia micromera Schauer, and, Plectranthus [Coleus] amboinicus [Loureiro] Sprengel. The survey indicated that 27% of village adults had medicated themselves for fright. Logistic regression of fright suffering onto demographic variables of age, education, gender, parental status and wealth measured in consumer goods found age to be the only significant predictor of having had fright. The probability of having (and medicating for) fright thus increases with every year. CONCLUSIONS: While sufferers are often uncomfortable recalling personal fright experiences, reporting use of medicinal plants is less problematic. Inquiry on fright medical ethnobotany (or phytotherapies) serves as a proxy measurement for fright occurrence. Cross-cultural and ethnopharmacology literature on the medicinal plants suggests probable efficacy in accord with Dominican ethnomedical notions of fright. Further, the cultural salience and beliefs about these medicines may give these medications extra psychoneuroimmune (i.e. mind-body) benefits, or placebo-like effects, for this stress-related folk illness. PMID- 20163731 TI - Micro-computed tomography-based phenotypic approaches in embryology: procedural artifacts on assessments of embryonic craniofacial growth and development. AB - BACKGROUND: Growing demand for three dimensional (3D) digital images of embryos for purposes of phenotypic assessment drives implementation of new histological and imaging techniques. Among these micro-computed tomography (microCT) has recently been utilized as an effective and practical method for generating images at resolutions permitting 3D quantitative analysis of gross morphological attributes of developing tissues and organs in embryonic mice. However, histological processing in preparation for microCT scanning induces changes in organ size and shape. Establishing normative expectations for experimentally induced changes in size and shape will be an important feature of 3D microCT based phenotypic assessments, especially if quantifying differences in the values of those parameters between comparison sets of developing embryos is a primary aim. Toward that end, we assessed the nature and degree of morphological artifacts attending microCT scanning following use of common fixatives, using a two dimensional (2D) landmark geometric morphometric approach to track the accumulation of distortions affecting the embryonic head from the native, uterine state through to fixation and subsequent scanning. RESULTS: Bouin's fixation reduced average centroid sizes of embryonic mouse crania by approximately 30% and substantially altered the morphometric shape, as measured by the shift in Procrustes distance, from the unfixed state, after the data were normalized for naturally occurring shape variation. Subsequent microCT scanning produced negligible changes in size but did appear to reduce or even reverse fixation induced random shape changes. Mixtures of paraformaldehyde + glutaraldehyde reduced average centroid sizes by 2-3%. Changes in craniofacial shape progressively increased post-fixation. CONCLUSIONS: The degree to which artifacts are introduced in the generation of random craniofacial shape variation relates to the degree of specimen dehydration during the initial fixation. Fixation methods that better maintain original craniofacial dimensions at reduced levels of dehydration and tissue shrinkage lead to the progressive accumulation of random shape variation during handling and data acquisition. In general, to the degree that embryonic organ size and shape factor into microCT-based phenotypic assessments, procedurally induced artifacts associated with fixation and scanning will influence results. Experimental designs will need to address these significant effects, either by employing alternative methods that minimize artifacts in the region of focus or in the interpretation of statistical patterns. PMID- 20163732 TI - Training in childhood obesity management in the United States: a survey of pediatric, internal medicine-pediatrics and family medicine residency program directors. AB - BACKGROUND: Information about the availability and effectiveness of childhood obesity training during residency is limited. METHODS: We surveyed residency program directors from pediatric, internal medicine-pediatrics (IM-Peds), and family medicine residency programs between September 2007 and January 2008 about childhood obesity training offered in their programs. RESULTS: The response rate was 42.2% (299/709) and ranged by specialty from 40.1% to 45.4%. Overall, 52.5% of respondents felt that childhood obesity training in residency was extremely important, and the majority of programs offered training in aspects of childhood obesity management including prevention (N = 240, 80.3%), diagnosis (N = 282, 94.3%), diagnosis of complications (N = 249, 83.3%), and treatment (N = 242, 80.9%). However, only 18.1% (N = 54) of programs had a formal childhood obesity curriculum with variability across specialties. Specifically, 35.5% of IM-Peds programs had a formal curriculum compared to only 22.6% of pediatric and 13.9% of family medicine programs (p < 0.01). Didactic instruction was the most commonly used training method but was rated as only somewhat effective by 67.9% of respondents using this method. The most frequently cited significant barrier to implementing childhood obesity training was competing curricular demands (58.5%). CONCLUSIONS: While most residents receive training in aspects of childhood obesity management, deficits may exist in training quality with a minority of programs offering a formal childhood obesity curriculum. Given the high prevalence of childhood obesity, a greater emphasis should be placed on development and use of effective training strategies suitable for all specialties training physicians to care for children. PMID- 20163733 TI - Transcriptomic changes arising during light-induced sporulation in Physarum polycephalum. AB - BACKGROUND: Physarum polycephalum is a free-living amoebozoan protist displaying a complex life cycle, including alternation between single- and multinucleate stages through sporulation, a simple form of cell differentiation. Sporulation in Physarum can be experimentally induced by several external factors, and Physarum displays many biochemical features typical for metazoan cells, including metazoan type signaling pathways, which makes this organism a model to study cell cycle, cell differentiation and cellular reprogramming. RESULTS: In order to identify the genes associated to the light-induced sporulation in Physarum, especially those related to signal transduction, we isolated RNA before and after photoinduction from sporulation- competent cells, and used these RNAs to synthesize cDNAs, which were then analyzed using the 454 sequencing technology. We obtained 16,669 cDNAs that were annotated at every computational level. 13,169 transcripts included hit count data, from which 2,772 displayed significant differential expression (upregulated: 1,623; downregulated: 1,149). Transcripts with valid annotations and significant differential expression were later integrated into putative networks using interaction information from orthologs. CONCLUSIONS: Gene ontology analysis suggested that most significantly downregulated genes are linked to DNA repair, cell division, inhibition of cell migration, and calcium release, while highly upregulated genes were involved in cell death, cell polarization, maintenance of integrity, and differentiation. In addition, cell death- associated transcripts were overrepresented between the upregulated transcripts. These changes are associated to a network of actin binding proteins encoded by genes that are differentially regulated before and after light induction. PMID- 20163734 TI - Abnormalities of cell packing density and dendritic complexity in the MeCP2 A140V mouse model of Rett syndrome/X-linked mental retardation. AB - BACKGROUND: Rett syndrome (RTT), a common cause of mental retardation in girls, is associated with mutations in the MECP2 gene. Most human cases of MECP2 mutation in girls result in classical or variant forms of RTT. When these same mutations occur in males, they often present as severe neonatal encephalopathy. However, some MECP2 mutations can also lead to diseases characterized as mental retardation syndromes, particularly in boys. One of these mutations, A140V, is a common, recurring missense mutation accounting for about 0.6% of all MeCP2 mutations and ranking 21st by frequency. It has been described in familial X linked mental retardation (XLMR), PPM- X syndrome (Parkinsonism, Pyramidal signs, Macroorchidism, X-linked mental retardation) and in other neuropsychiatric syndromes. Interestingly, this mutation has been reported to preserve the methyl CpG binding function of the MeCP2 protein while compromising its ability to bind to the mental retardation associated protein ATRX. RESULTS: We report the construction and initial characterization of a mouse model expressing the A140V MeCP2 mutation. These initial descriptive studies in male hemizygous mice have revealed brain abnormalities seen in both RTT and mental retardation. The abnormalities found include increases in cell packing density in the brain and a significant reduction in the complexity of neuronal dendritic branching. In contrast to some MeCP2 mutation mouse models, the A140V mouse has an apparently normal lifespan and normal weight gain patterns with no obvious seizures, tremors, breathing difficulties or kyphosis. CONCLUSION: We have identified various neurological abnormalities in this mouse model of Rett syndrome/X-linked mental retardation which may help to elucidate the manner in which MECP2 mutations cause neuronal changes resulting in mental retardation without the confounding effects of seizures, chronic hypoventilation, or other Rett syndrome associated symptoms. PMID- 20163735 TI - SLAM algorithm applied to robotics assistance for navigation in unknown environments. AB - BACKGROUND: The combination of robotic tools with assistance technology determines a slightly explored area of applications and advantages for disability or elder people in their daily tasks. Autonomous motorized wheelchair navigation inside an environment, behaviour based control of orthopaedic arms or user's preference learning from a friendly interface are some examples of this new field. In this paper, a Simultaneous Localization and Mapping (SLAM) algorithm is implemented to allow the environmental learning by a mobile robot while its navigation is governed by electromyographic signals. The entire system is part autonomous and part user-decision dependent (semi-autonomous). The environmental learning executed by the SLAM algorithm and the low level behaviour-based reactions of the mobile robot are robotic autonomous tasks, whereas the mobile robot navigation inside an environment is commanded by a Muscle-Computer Interface (MCI). METHODS: In this paper, a sequential Extended Kalman Filter (EKF) feature-based SLAM algorithm is implemented. The features correspond to lines and corners -concave and convex- of the environment. From the SLAM architecture, a global metric map of the environment is derived. The electromyographic signals that command the robot's movements can be adapted to the patient's disabilities. For mobile robot navigation purposes, five commands were obtained from the MCI: turn to the left, turn to the right, stop, start and exit. A kinematic controller to control the mobile robot was implemented. A low level behavior strategy was also implemented to avoid robot's collisions with the environment and moving agents. RESULTS: The entire system was tested in a population of seven volunteers: three elder, two below-elbow amputees and two young normally limbed patients. The experiments were performed within a closed low dynamic environment. Subjects took an average time of 35 minutes to navigate the environment and to learn how to use the MCI. The SLAM results have shown a consistent reconstruction of the environment. The obtained map was stored inside the Muscle-Computer Interface. CONCLUSIONS: The integration of a highly demanding processing algorithm (SLAM) with a MCI and the communication between both in real time have shown to be consistent and successful. The metric map generated by the mobile robot would allow possible future autonomous navigation without direct control of the user, whose function could be relegated to choose robot destinations. Also, the mobile robot shares the same kinematic model of a motorized wheelchair. This advantage can be exploited for wheelchair autonomous navigation. PMID- 20163737 TI - Potentials 'R' Us web-server for protein energy estimations with coarse-grained knowledge-based potentials. AB - BACKGROUND: Knowledge-based potentials have been widely used in the last 20 years for fold recognition, protein structure prediction from amino acid sequence, ligand binding, protein design, and many other purposes. However generally these are not readily accessible online. RESULTS: Our new knowledge-based potential server makes available many of these potentials for easy use to automatically compute the energies of protein structures or models supplied. Our web server for protein energy estimation uses four-body potentials, short-range potentials, and 23 different two-body potentials. Users can select potentials according to their needs and preferences. Files containing the coordinates of protein atoms in the PDB format can be uploaded as input. The results will be returned to the user's email address. CONCLUSIONS: Our Potentials 'R' Us server is an easily accessible, freely available tool with a web interface that collects all existing and future protein coarse-grained potentials and computes energies of multiple structural models. PMID- 20163736 TI - Determinants of smoking initiation among women in five European countries: a cross-sectional survey. AB - BACKGROUND: The rate of smoking and lung cancer among women is rising in Europe. The primary aim of this study was to determine why women begin smoking in five different European countries at different stages of the tobacco epidemic and to determine if smoking is associated with certain characteristics and/or beliefs about smoking. METHODS: A cross-sectional telephone survey on knowledge and beliefs about tobacco was conducted as part of the Women in Europe Against Lung Cancer and Smoking (WELAS) Project. A total of 5,000 adult women from France, Ireland, Italy, Czech Republic, and Sweden were interviewed, with 1,000 from each participating country. All participants were asked questions about demographics, knowledge and beliefs about smoking, and their tobacco use background. Current and former smokers also were asked questions about smoking initiation. Basic statistics on the cross-sectional data was reported with chi-squared and ANOVA p values. Logistic regression was used to analyze ever versus never smokers. Linear regression analyses were used to analyze age of smoking initiation. RESULTS: Being older, being divorced, having friends/family who smoke, and having parents who smoke were all significantly associated with ever smoking, though the strength of the associations varied by country. The most frequently reported reason for initiation smoking was friend smoking, with 62.3% of ever smokers reporting friends as one of the reasons why they began smoking. Mean age of smoking initiation was 18.2 years and over 80% of participants started smoking by the age of 20. The highest levels of young initiators were in Sweden with 29.3% of women initiating smoking at age 14-15 and 12.0% initiating smoking younger than age 14. The lowest level of young initiators was in the Czech Republic with 13.7% of women initiating smoking at age 14-15 and 1.4% of women initiating smoking younger than age 14. Women who started smoking because their friends smoked or to look 'cool' were more likely to start smoking at a younger age. Women who started smoking to manage stress or to feel less depressed were more likely to start smoking at an older age. CONCLUSIONS: In all five participating countries, friends were the primary factor influencing ever smoking, especially among younger women. The majority of participants began smoking in adolescence and the average reported age of smoking initiation was youngest in Sweden and oldest in the Czech Republic. PMID- 20163738 TI - Methylation status of individual CpG sites within Alu elements in the human genome and Alu hypomethylation in gastric carcinomas. AB - BACKGROUND: Alu methylation is correlated with the overall level of DNA methylation and recombination activity of the genome. However, the maintenance and methylation status of each CpG site within Alu elements (Alu) and its methylation status have not well characterized. This information is useful for understanding natural status of Alu in the genome and helpful for developing an optimal assay to quantify Alu hypomethylation. METHODS: Bisulfite clone sequencing was carried out in 14 human gastric samples initially. A Cac8I COBRA DHPLC assay was developed to detect methylated-Alu proportion in cell lines and 48 paired gastric carcinomas and 55 gastritis samples. DHPLC data were statistically interpreted using SPSS version 16.0. RESULTS: From the results of 427 Alu bisulfite clone sequences, we found that only 27.2% of CpG sites within Alu elements were preserved (4.6 of 17 analyzed CpGs, A approximately Q) and that 86.6% of remaining-CpGs were methylated. Deamination was the main reason for low preservation of methylation targets. A high correlation coefficient of methylation was observed between Alu clones and CpG site J (0.963), A (0.950), H (0.946), D (0.945). Comethylation of the sites H and J were used as an indicator of the proportion of methylated-Alu in a Cac8I COBRA-DHPLC assay. Validation studies showed that hypermethylation or hypomethylation of Alu elements in human cell lines could be detected sensitively by the assay after treatment with 5-aza dC and M.SssI, respectively. The proportion of methylated-Alu copies in gastric carcinomas (3.01%) was significantly lower than that in the corresponding normal samples (3.19%) and gastritis biopsies (3.23%). CONCLUSIONS: Most Alu CpG sites are deaminated in the genome. 27% of Alu CpG sites represented in our amplification products. 87% of the remaining CpG sites are methylated. Alu hypomethylation in primary gastric carcinomas could be detected with the Cac8I COBRA-DHPLC assay quantitatively. PMID- 20163739 TI - Effects of an exercise and manual therapy program on physical impairments, function and quality-of-life in people with osteoporotic vertebral fracture: a randomised, single-blind controlled pilot trial. AB - BACKGROUND: This randomised, single-blind controlled pilot trial aimed to determine the effectiveness of a physiotherapy program, including exercise and manual therapy, in reducing impairments and improving physical function and health-related quality of life in people with a history of painful osteoporotic vertebral fracture. METHODS: 20 participants were randomly allocated to an intervention (n = 11) or control (n = 9) group. The intervention group attended individual sessions with an experienced clinician once a week for 10 weeks and performed daily home exercises with adherence monitored by a self-report diary. The control group received no treatment. Blinded assessment was conducted at baseline and 11 weeks. Questionnaires assessed self-reported changes in back pain, physical function, and health-related quality of life. Objective measures of thoracic kyphosis, back and shoulder muscle endurance (Timed Loaded Standing Test), and function (Timed Up and Go test) were also taken. RESULTS: Compared with the control group, the intervention group showed significant reductions in pain during movement (mean difference (95% CI) -1.8 (-3.5 to -0.1)) and at rest ( 2.0 (-3.8 to -0.2)) and significantly greater improvements in Qualeffo physical function (-4.8 (-9.2 to -0.5)) and the Timed Loaded Standing test (46.7 (16.1 to 77.3) secs). For the perceived change in back pain over the 10 weeks, 9/11 (82%) participants in the intervention group rated their pain as 'much better' compared with only 1/9 (11%) participants in the control group. CONCLUSION: Despite the modest sample size, these results support the benefits of exercise and manual therapy in the clinical management of patients with osteoporotic vertebral fractures, but need to be confirmed in a larger sample. TRIAL REGISTRATION: NCT00638768. PMID- 20163740 TI - Blood lipids, homocysteine, stress factors, and vitamins in clinically stable multiple sclerosis patients. AB - Multiple Sclerosis (MS) patients present a decrease of antioxidants and neuroprotective and immunoregulatory vitamins and an increase of total homocysteine (tHcy), cholesterol (CHL), HDL-cholesterol, and of cellular stress markers, variably associated with the different phases of the disease. We compared the blood levels of uric acid, folic acid, vitamins B12, A, and E, tHcy, CHL, HDL-cholesterol, and triglycerides in forty MS patients during a phase of clinical inactivity with those of eighty healthy controls, matched for age and sex. We found higher levels of tHcy (p = 0.032) and of HDL-cholesterol (p = 0.001) and lower levels of vitamin E (p = 0.001) and the ratio vitamin E/CHL (p = 0.001) in MS patients. In conclusion, modifications of some biochemical markers of cell damage were detected in MS patients during a phase of clinical inactivity. PMID- 20163741 TI - Factors associated with dental visit and barriers to utilisation of oral health care services in a sample of antenatal mothers in Hospital Universiti Sains Malaysia. AB - BACKGROUND: The aims of this study were to determine factors associated with dental visit and to describe barriers to utilisation of oral health care services among antenatal mothers attending the Obstetric and Gynaecology Specialist clinic in Hospital Universiti Sains Malaysia. METHODS: A structured, self-administered questionnaire was used obtain information on the variables of interest pertaining to the current pregnancy from 124 antenatal mothers. RESULTS: The majority of the mothers claimed that their oral health status was good (67.0%) or very good (2.4%). On the contrary, most of them admitted of having had at least one oral health problem (59.7%) including cavitated (43.5%) and painful teeth (15.3%), bleeding gum (21.0%), and bad breath (10.5%). However, only 29% of the mothers visited dentist during the current pregnancy. Factors associated with the mothers' dental visit were exposure to oral health education before the pregnancy and awareness of relationship between poor maternal oral health and adverse pregnancy outcomes with odds ratio of 4.06 (95% CI: 1.67-9.78) and 3.57 (95% CI: 1.30-9.77) respectively. Common excuses given by most mothers include perceptions of not having any oral health problems (65.9%), long waiting time at the clinic (71.6%), and no immediate treatment given by the dentist (64.8%). CONCLUSIONS: Utilisation of oral health care services among antenatal mothers was low. Mothers who reported dental visit were more likely to be those who had received oral health education before the current pregnancy and knew of the association between poor maternal oral health and adverse pregnancy outcomes. Dissatisfaction with the services rendered and perceptions of not having any oral health problems were the main barriers. PMID- 20163742 TI - Characterization of transgene expression in adenoviral vector-based HIV-1 vaccine candidates. AB - Recombinant adenovirus vectors have been extensively used in gene therapy clinical studies. More recently, the capability of inducing potent cell-mediated and humoral immunity has made these vectors equally attractive candidates for prophylactic or therapeutic vaccine applications. Merck and Co., Inc., developed HIV-1 vaccine candidates based on adenovirus serotype 5 (Ad5) vectors in which the E1 gene, a critical component for adenovirus replication, was replaced by the cytomegalovirus immediate/early promoter, followed by mutated versions of the HIV 1 gag, pol or nef genes (constructs referred to as MRKAd5gag, MRKAd5pol and MRKAd5nef, respectively). Vaccine performance was evaluated in vitro in a novel assay that measures the level of transgene expression in non-permissive A549 cells. Various combinations of vectors were studied. The results indicate that the vaccine induces a dose-dependent expression of the HIV-1 transgenes in vitro. Furthermore, the gag, pol, and nef transgenes are expressed differentially in A549 cells in an MOI-dependent and formulation-dependent manner, yielding an unexpected enhancement of protein expression in trivalent vs. monovalent formulations. Our data suggest that the presence of additional virus in multivalent formulations increases individual transgene expression in A549 cells, even when the amount of DNA encoding the gene of interest remains constant. This enhancement appears to be controlled at the transcriptional level and related to both the total amount of virus and the combination of transgenes present in the formulation. PMID- 20163743 TI - Children's tooth decay in a public health program to encourage low-income pregnant women to utilize dental care. AB - BACKGROUND: A community-based public health program to provide a dental home for women covered by the Oregon Health Plan (Medicaid) in Klamath County, Oregon USA was instituted with the long-term goal to promote preventive oral care for both mothers and their new infants provided by dental managed care companies. METHODS: As part of the evaluation of the program, children in Klamath and comparable non program counties were examined in their 2nd year of life to begin to determine if benefits accrued to the offspring of the mothers in Klamath County. RESULTS: Eighty-five and 58.9% of the children were caries free in the Klamath and comparison county samples, respectively (RR = 1.48, 95% CI 1.13, 1.93). The mean (SD) number of teeth with any decay was .75 (2.5) in the test population and 1.6 (2.5) in the comparison population (t = 2.08, p = .04). CONCLUSIONS: The assessment showed that children of mothers in the Klamath County program were about one and a half times more likely to be caries free than children in the comparison counties. Additional controlled studies are being undertaken. PMID- 20163744 TI - Prognostic stratification of patients with advanced renal cell carcinoma treated with sunitinib: comparison with the Memorial Sloan-Kettering prognostic factors model. AB - BACKGROUND: The treatment paradigm in advanced renal cell carcinoma (RCC) has changed in the recent years. Sunitinib has been established as a new standard for first-line therapy. We studied the prognostic significance of baseline characteristics and we compared the risk stratification with the established Memorial Sloan Kettering Cancer Center (MSKCC) model. METHODS: This is a retrospective analysis of patients treated in six Greek Oncology Units of HECOG. Inclusion criteria were: advanced renal cell carcinoma not amenable to surgery and treatment with Sunitinib. Previous cytokine therapy but no targeted agents were allowed. Overall survival (OS) was the major end point. Significance of prognostic factors was evaluated with multivariate cox regression analysis. A model was developed to stratify patients according to risk. RESULTS: One hundred and nine patients were included. Median follow up has been 15.8 months and median OS 17.1 months (95% CI: 13.7-20.6). Time from diagnosis to the start of Sunitinib (12 months, p = 0.001), number of metastatic sites (1 vs. >1, p = 0.003) and performance status (PS) (1, p = 0.001) were independently associated with OS. Stratification in two risk groups ("low" risk: 0 or 1 risk factors; "high" risk: 2 or 3 risk factors) resulted in distinctly different OS (median not reached [NR] vs. 10.8 [95% confidence interval (CI): 8.3 13.3], p < 0.001). The application of the MSKCC risk criteria resulted in stratification into 3 groups (low and intermediate and poor risk) with distinctly different prognosis underlying its validity. Nevertheless, MSKCC model did not show an improved prognostic performance over the model developed by this analysis. CONCLUSIONS: Studies on risk stratification of patients with advanced RCC treated with targeted therapies are warranted. Our results suggest that a simpler than the MSKCC model can be developed. Such models should be further validated. PMID- 20163745 TI - The evaluation of a Taiwanese training program in smoking cessation and the trainees' adherence to a practice guideline. AB - BACKGROUND: The Taiwanese government began reimbursement for smoking cessation in 2002. Certification from a training program was required for physicians who wanted reimbursement. The program certified 6,009 physicians till 2007. The objective of this study is to evaluate the short- and long term efficacy of the training program. METHODS: For short term evaluation, all trainees in 2007 were recruited. For long term evaluation, computer randomly selected 2,000 trainees who received training from 2002 to 2006 were recruited. Course satisfaction, knowledge, confidence in providing smoking cessation services and the adherence to a practice guideline were evaluated by questionnaires. RESULTS: Trainees reported high satisfaction with the training program. There was significant difference between pre- and post-test scores in knowledge. Confidence in providing services was lower in the long term evaluation compared to short term evaluation. For adherence to a practice guideline, 86% asked the status of smoking, 88% advised the smokers to quit, 76% assessed the smoker's willingness to quit, 59% assisted the smokers to quit, and 60% arranged follow-up visits for smokers. The incentive of reimbursement was the most significant factor affecting confidence and adherence. CONCLUSIONS: The training program was satisfactory and effective. Adherence to a practice guideline in our study was better than studies without physician training in other countries. PMID- 20163746 TI - Investigation of risk factors for Salmonella on fattening-turkey farms. AB - A cross-sectional study into risk factors for Salmonella was undertaken using data gathered from 252 fattening turkey flocks in the UK. The data was derived from the EU baseline survey conducted during 2006 and 2007, in addition to a voluntary questionnaire. Multivariate logistic regression models identified significant risk factors for Salmonella spp. and Salmonella Typhimurium. A decreased risk of Salmonella spp. infection was associated with a history of intestinal illness in the sampled flock (OR 0.17), the use of wood shavings as litter (OR 0.21), use of disinfectant in the cleaning process (OR 0.25), incineration of dead birds on farm (OR 0.29), seasonal production (OR 0.31), farm staff also working with cattle (OR 0.31), and the presence of pigs on neighbouring farms (OR 0.38). The risk of isolating Salmonella spp. varied according to the company from which the poults were sourced. A reduced risk of S. Typhimurium infection was associated with the use of wax blocks to control rodents (OR 0.09), using mains water (OR 0.19) and having a Salmonella test programme (OR 0.23). An increased risk of S. Typhimurium infection was associated with storage of items around the turkey house (OR 5.20), evidence of mice (OR 4.71) and a soil surface surrounding the turkey house (OR 2.70). This study therefore identifies a number of important practical measures which can be implemented by farmers and veterinarians within the turkey industry to assist in the control of salmonellosis at the farm level. PMID- 20163747 TI - Use of complementary and alternative medicine in head and neck cancer patients. AB - OBJECTIVE: To determine the prevalence and profile of patients who use complementary and alternative medicine, within a cohort of head and neck cancer patients. STUDY DESIGN: Cross-sectional survey. SUBJECTS AND METHODS: Ninety three consecutive head and neck cancer patients being followed up at the department of otolaryngology head and neck surgery were surveyed using an interviewer-administered questionnaire. RESULTS: The prevalence of complementary and alternative medicine use was 67.8 per cent. Patients who used complementary and alternative medicine were more likely to be female, better educated and younger, compared with non-users. A total of 82.5 per cent (52/63) perceived complementary and alternative medicine to be effective, even though they were aware of the lack of research and endorsement by their physician regarding such medicine. CONCLUSION: The use of complementary and alternative medicine by head and neck cancer patients is common, regardless of efficacy or cost. Clinicians should routinely ask patients about their use of complementary and alternative medicine, to facilitate communication and enable appropriate use of such medicine. PMID- 20163748 TI - Department of Otolaryngology and Audiology, Hopital D'Enfants Armand Trousseau, Paris, France, 2009. AB - Towards the end of my time at Trousseau, it was a huge honour to be asked if I would like to consider staying on as an observer until October, with a view to continuing on, after that, in a Chef de Clinique appointment. This was a golden opportunity that I would have dearly snapped up. Unfortunately, the timing clashed with other previously made, very solid, arrangements. I am tremendously grateful to The Journal of Laryngology & Otology for supporting this Fellowship, and also to Professor Garabedian and his team for their exceptional hospitality, approachability and generosity. I have made some excellent friends in Paris. Overall, this was an extremely positive and valuable experience both in terms of family and work. PMID- 20163749 TI - Laryngocoele as an unusual complication of supracricoid partial laryngectomy: evaluation of 62 cases. AB - BACKGROUND: This study sought to evaluate the incidence, aetiology, clinical features and treatment modalities for laryngocoele formation after supracricoid partial laryngectomy. METHODS: The medical charts of 62 patients who had undergone supracricoid partial laryngectomy were reviewed. RESULTS: Three patients developed laryngocoele, giving an incidence of 4.8 per cent. Two of these patients presented with a cervical mass, dyspnoea and fever. The mobility of the arytenoids was disturbed on the involved side. The third patient was admitted complaining only of a compressible cervical mass. In all patients, diagnosis was made by computed tomography scan. The transcervical surgical approach was preferred for resection. CONCLUSION: Laryngocoele can occur as a late complication of supracricoid partial laryngectomy. Remnants of the laryngeal ventricle may be the cause of laryngocoele formation. The integrity of the laryngeal ventricle in the resected specimen should be routinely checked in order to avoid this rare complication. Clinicians should be aware that, following supracricoid partial laryngectomy, a cervical mass presenting with dyspnoea and disturbance of arytenoid mobility does not always indicate tumour recurrence. PMID- 20163750 TI - Sodium fluoride in otosclerosis treatment: review. AB - OBJECTIVES: To review the current literature on the use of sodium fluoride in the treatment of otosclerosis. DESIGN: A literature review was conducted, searching the Medline and PubMed database from 1966 to 2009, using the terms 'otosclerosis' and 'fluoride'. Article abstracts were reviewed and relevant full articles acquired. RESULTS: There has been only one double-blind, placebo-controlled trial of the use of sodium fluoride in otosclerosis patients, and this found a reduced incidence of deterioration in hearing after two years in the treatment group. Several case-control series have described a hearing benefit in the sodium fluoride treated group. Treatment doses vary greatly, and there is no evidence regarding the optimum duration of treatment. CONCLUSIONS: There is low quality evidence suggesting that sodium fluoride may be of benefit to preserve hearing and reduce vestibular symptoms in patients with otosclerosis. PMID- 20163751 TI - Schistosoma mansoni: signal transduction processes during the development of the reproductive organs. AB - Among the topics of considerable interest concerning our understanding of the unusual biology of schistosomes is the sexual maturation of the female. The identification of genes coding for signal transduction proteins controlling essential steps of the pairing-dependent differentiation of the reproductive organs, vitellarium and ovary will help to substantiate our knowledge about this unique parasite. Furthermore, such signalling proteins could be potential targets to interfere with the development of this parasite to combat schistosomiasis since its pathology is caused by the eggs. This review summarises first post genomic steps to elucidate the function of gonad-specific signalling molecules which were identified by homology-based cloning strategies, by in silico identification or by yeast two-hybrid interaction analyses, using a combination of novel techniques. These include the in vitro culture of adult schistosomes, their treatment with chemical inhibitors to block enzyme activity, the use of RNAi to silence gene function post-transcriptionally, and confocal laser scanning microscopy to study the morphological consequences of these experimental approaches. Finally, we propose a first model of protein networks that are active in the ovary regulating mitogenic activity and differentiation. Some of these molecules are also active in the testes of males, probably fulfilling similar roles as in the ovary. PMID- 20163752 TI - Ligula intestinalis (Cestoda: Pseudophyllidea): an ideal fish-metazoan parasite model? AB - Since its use as a model to study metazoan parasite culture and in vitro development, the plerocercoid of the tapeworm, Ligula intestinalis, has served as a useful scientific tool to study a range of biological factors, particularly within its fish intermediate host. From the extensive long-term ecological studies on the interactions between the parasite and cyprinid hosts, to the recent advances made using molecular technology on parasite diversity and speciation, studies on the parasite have, over the last 60 years, led to significant advances in knowledge on host-parasite interactions. The parasite has served as a useful model to study pollution, immunology and parasite ecology and genetics, as well has being the archetypal endocrine disruptor. PMID- 20163754 TI - Physician-assisted suicide ruling in Montana: struggling with care of the dying, responsibility, and freedom in Big Sky Country. PMID- 20163753 TI - The extent of injection site infection in injecting drug users: findings from a national surveillance study. AB - Injection site infections in injecting drug users (IDUs) are associated with serious morbidity and healthcare costs. Factors associated with symptoms of these were examined through annual (2006-2008) unlinked-anonymous survey of IDUs in England, Wales and Northern Ireland. Overall 36% (1863/5209) self-reported having a symptom with no trend over time (35% 2006, 37% 2007, 34% 2008). Symptoms were less common in the North East of England; increased with years injecting; and were higher in women, those recently homeless, those recently using a needle exchange, and those injecting both opiates and stimulants. Of those injecting during the previous 4 weeks (n=3733) symptoms were associated with: injecting daily; injecting >or=10 times a day; injecting into hands, groin, or legs; sharing filters; and reusing water to flush syringes. Symptoms of injection site infections are common in IDUs. Better-targeted preventive interventions are needed, and continued surveillance should assist with assessing the impact of new initiatives. PMID- 20163755 TI - The special case of complicated grief in women at high risk for breast cancer. AB - OBJECTIVE: Exploration of complicated grief focusing on the relationship of post traumatic stress disorder (PTSD) and complicated grief in a population of women at high risk for developing breast cancer. Special reference is made to women who have experienced a material death. METHOD: We reflected on the clinical attributes of the Revlon UCLA High Risk Clinic population in terms of their own perceived risk of developing breast cancer. For part of our population, their perceived risk was coupled with their reactions to the loss of their mothers to breast cancer. We compared and contrasted this pattern of reactions to those described by Licihtenthal et al. (2004) in their developmental review of complicated grief as a distinct disorder. RESULTS: We concluded that our population of women differed from Lichtenthal et al.'s (2004) model for complicated grief. Lichtenthal's group postulated that the key element of complicated grief involves the protracted nature of separation anxiety and distress and excludes PTSD. In our populations, the daughter with complicated grief experiences a combination of separation anxiety and a type of PTSD involving anxiety over the perceived certainty of her own future diagnosis of breast cancer. It was noteworthy that Lichtenthal's model population was composed of individuals caring for terminally ill spouses. Significantly, the spousal caretakers did not have an ongoing genetic link to their partners whereas our population is genetically linked. We postulate that this accounts for the unique presentation of complicated grief and ptsd in our population. SIGNIFICANCE OF RESULTS: We submit that this combination of complicated grief and PTSD requires a cognitive reframing of their perceived inevitability of developing breast cancer and desensitization techniques to help high risk women pursue preventative health care rather than avoiding it. PMID- 20163756 TI - The experience of being next of kin to an older person in the last phase of life. AB - OBJECTIVE: The aim of the study was to investigate the experience of being next of kin to an older person in the last phase of life as narrated after the older person's death. METHOD: Qualitative interviews were performed with the next of kin (n = 17) to people aged 75 years and older who had recently died and had received help and/or care from the municipality in the last phase of life. Eleven women and six men participated, of whom seven were spouses, nine were children, and one was a grandchild. The interviews were analysed using qualitative content analysis. RESULTS: The experience of the next of kin could be understood as being a devoted companion during the transition toward the inevitable end, embracing the categories of living in the shadow of death; focusing on the needs of the dying person, making adjustments to everyday life; feeling the major responsibility; struggling with the health and social care system; and gaining strength from support. SIGNIFICANCE OF RESULTS: Being next of kin to an old person at the end of life means being a devoted companion during the transition toward the inevitable end, including the feeling of bearing the major responsibility and the need to be acknowledged by professionals. This study points to the importance of having access to professional care when it is needed, to complement and support the next of kin when his or her own resources and strength falter. This also includes support to enable the next of kin to remain involved in the care of his or her loved ones, thereby fulfilling their own wishes. PMID- 20163757 TI - Beyond communication: the development of a training program for hospital and hospice staff in the detection and management of psychological distress- preliminary results. AB - OBJECTIVE: In the United Kingdom, a Four-Tier Model of Psychological Support has been recommended for all patients with cancer and their families. This model suggests that staff at Tier 2, such as nurses, doctors, and allied health professionals, should be proficient in screening for psychological distress and intervening with techniques such as psycho-education and problem solving. Research has suggested that although communication skills training is essential for staff working in cancer services, it does not necessarily improve the detection of specific psychological disorder or staff confidence in intervening with highly distressed patients. The objective was therefore to design a training program that addressed this deficit and was easily accessible to hospital staff. METHOD: A training package was developed to train staff in the recommended skills. A literature review of teaching modalities and the effectiveness of different formats was conducted. A four-session program was developed, to be administered by staff at Tiers 3 and 4 of the model, such as clinical psychologists and counsellors. RESULTS: Over 3 years, 255 sets of data were collected from staff who attended the course. Precourse, postcourse, and 6-month follow-up data were collected through the use of confidence questionnaires, developed from the literature. The data show a significant improvement in staff confidence across all domains measured, including confidence in the detection and management of psychological distress (p =.0001). SIGNIFICANCE OF RESULTS: Although the results have limitations and the data are subjective, we can conclude that this course significantly improves staff confidence in dealing with psychological distress and that this increased confidence is maintained over a 6 month follow-up period. PMID- 20163758 TI - A longitudinal method of teaching pediatric palliative care to interns: preliminary findings regarding changes in interns' comfort level. AB - OBJECTIVE: A longitudinal pediatric palliative care curriculum was introduced into the pediatric residency program at the University of California, Los Angeles. The present study explores the possible effects of this curriculum on the interns' self-assessed comfort levels regarding caring for children with life threatening conditions. METHODS: A newly created assessment tool was administered to interns in order to rate their comfort regarding pediatric palliative care at the beginning and conclusion of their intern year. RESULTS: Twenty-two of the 29 interns completed this survey. Baseline data indicated 55% of the interns had some experience with taking care of a dying pediatric patient during their medical school training, and 79% indicated that they had taken care of a dying adult. Only 7% of the interns felt adequately prepared to deal with death and dying, but all interns indicated interest in further learning about pediatric palliative care. Comparison of the overall comfort levels of the 22 responding residents before and after the first year of training in 20 different related tasks demonstrated a significant self-assessed improvement of comfort in seven areas. There was no increase in self-reported comfort in communication related to palliative care. SIGNIFICANCE OF RESULTS: Residents indicated increased comfort in some areas of pediatric palliative care after the first year of their training. The underlying cause of this increased comfort is unclear at this time. The overall effect of longitudinal palliative care curricula on residents' level of comfort in caring for this population deserves further assessment. PMID- 20163759 TI - Art therapy with cancer patients during chemotherapy sessions: an analysis of the patients' perception of helpfulness. AB - OBJECTIVE: Art therapy has been shown to be helpful to cancer patients at different stages in the course of their illness, especially during isolation for bone marrow transplantation, during radiotherapy treatment, and after treatment. The aim of this study is twofold: (1) to assess whether patients during chemotherapy sessions perceive art therapy as helpful and (2) to outline in which way art therapy is perceived as helpful. METHOD: 157 cancer patients attending an Oncology Day Hospital (Siena, Italy) met the art therapist during their chemotherapy sessions. The art therapist used the same art therapy technique with each patient during the first encounter ("free collage"); afterward the relationship would evolve in different ways according to the patients' needs. A psychologist interviewed a randomized group of 54 patients after the chemotherapy treatment using a semistructured questionnaire. RESULTS: Out of the 54 patients, 3 found art therapy "not helpful" ("childish," "just a chat," "not interesting"). The other 51 patients described their art therapy experience as "helpful." From patients' statements, three main groups emerged: (1) art therapy was perceived as generally helpful (e.g., "relaxing," "creative"; 37.3%), (2) art therapy was perceived as helpful because of the dyadic relationship (e.g., "talking about oneself and feeling listened to"; 33.3%), and (3) art therapy was perceived as helpful because of the triadic relationship, patient-image-art therapist (e.g., "expressing emotions and searching for meanings"; 29.4%). SIGNIFICANCE OF RESULTS: These data have clinical implications, as they show that art therapy may be useful to support patients during the stressful time of chemotherapy treatment. Different patients use it to fulfil their own different needs, whether it is a need to relax (improved mood) or to talk (self-narrative) or to visually express and elaborate emotions (discovering new meanings). Some illustrations of patients using the art therapy process to fulfill these three different needs are provided. PMID- 20163760 TI - Multiple evaluation of a hospital-based palliative care consultation team in a university hospital: activities, patient outcome, and referring staff's view. AB - OBJECTIVE: Although the number of hospital-based palliative care consultation teams (PCCTs) is rapidly increasing in Japan, there is limited information available concerning the activities and usefulness of PCCT in the country. The aim of this study is to clarify the activities, patient outcome, and referring staff's view of an established PCCT in Japan. METHOD: This was a prospective study to follow patients referred to a PCCT for 28 days over a 1-year period. Patients were assessed by the Support Team Assessment Schedule-Japanese version (STAS-J) and EORTC QLQ C-30 at the time of referral and on days 7, 14, and 28. A staff survey was implemented using a questionnaire after each observation period. RESULTS: Of 180 patients referred, 53 patients were eligible for the study. Although the median of the number of the reasons for referral was 1, the PCCT provided several kinds of support: pain management, 94%; emotional support for the patient, 49%; and emotional support for the family, 36%. On day 7 after referral, of the items of STAS-J and the EORTC QLQ C-30 subscales, only insomnia improved significant whereas "other physical symptoms" and constipation were significantly exacerbated. In the staff survey, of the 98 respondents, more than 90% considered the effect of the PCCT as "excellent" or "good" and were satisfied with the support provided. SIGNIFICANCE OF RESULTS: This study showed that the PCCT performed comprehensive assessments on referred patients and provided extra support. No patient's QOL 1 week after referral was improved with the exception of insomnia. Referring staff highly evaluated the activities of the PCCT. In the evaluation of PCCTs, further research about the variation of clinical activities of PCCTs, their applicability, and benefit is needed. PMID- 20163761 TI - Health care staff's opinions about existential issues among patients with cancer. AB - OBJECTIVE: The objective of this study was to explore health care staff's opinions about what existential issues are important to patients with cancer and staff's responsibility when existential issues are raised by patients. METHOD: Four focus group interviews were conducted with health care staff (N = 23) at an in-patient hospice, on an oncology ward, on a surgical ward, and with a palliative home health care team. The focus group interviews focused on two questions, first, about health care staff's opinions about patients' important existential questions and, second, about health care staff's responsibility when existential issues are raised by the patient. The interviews were tape-recorded, transcribed verbatim, and analyzed by qualitative content analysis into subcategories and categories. RESULTS: Four categories and 11 subcategories emerged from the first question. The first category, "life and death," was based on joy of living and thoughts of dying. The second category "meaning," consisted of acceptance, reevaluation, hope, and faith. The third category, "freedom of choice," consisted of responsibility and integrity, and the fourth and last category, "relationships and solitude," consisted of alleviation, dependency, and loss. One category emerged from the second question about the health care staff's responsibility, "to achieve an encounter," which was based on the subcategories time and space, attitudes, and invitation and confirmation. SIGNIFICANCE OF RESULTS: The strength of this study was that the findings were fairly congruent in different settings and in different geographical areas. Health care staff were aware of the importance of existential issues to patients. The existential issues, mentioned by health care staff, are similar to findings from studies conducted among patients, which is another strength of the present study. Health care staff are also confident about how to act when these issues are raised by the patients. The challenge for the future is to implement the findings from this study among health care staff in different settings. PMID- 20163762 TI - Do palliative patients and carers agree about patients' psychological functioning? AB - OBJECTIVE: Palliative care clinicians and researchers often seek information about patients from informants. This research examines the extent of agreement between information from patients and family caregivers who were asked to serve as collateral sources of information about the patient. METHOD: Sixty-six patients with advanced cancer and their family caregivers participated in the study. Two measurement contexts were examined: Direct observation of patients' cognitive performance (Mini-Mental State Examination) was compared with carers' subjective reports about patients' everyday cognition (Cognitive Decline subscale of the Psychogeriatric Assessment Scale), and subjective reports about patient depression were compared between patients and carers who completed parallel forms of the same scale (Geriatric Depression Scale and Geriatric Depression Scale Collateral Source, respectively). The relationship between patient-completed and carer-completed measures was examined in four ways: the correlation between total scores in the sample, agreement about the prevalence of impaired functioning and of specific symptoms in the sample, agreement concerning whether particular patients showed impaired functioning, and agreement about the presence or absence of a specific symptom for a particular patient. RESULTS: Although most measures of agreement showed that information provided by patients and carers was related, the magnitude of discrepancies was substantial. SIGNIFICANCE OF RESULTS: There was no empirical justification for substituting information from a collateral source for information provided by the patient for any of the measures of agreement for either cognition or depression. The use of information from collateral sources is most appropriate when information from the patient is likely to be incomplete or inaccurate, when insight into caregivers' needs or understanding is sought, and when using a multi-informant approach to assessment. PMID- 20163763 TI - Differences in quality of life modalities give rise to needs of individual support in patients with ALS and their next of kin. AB - OBJECTIVE: The aim of this study was to examine health-related quality of life (HRQoL), individual QoL, anxiety and depression in patients with amyotrophic lateral sclerosis (ALS) and their next of kin in relation to patients' physical function over time. METHODS: 35 patients and their next of kin were studied using the Short Form-36 Health Survey (SF-36), Schedule for Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL-DW), and Hospital Anxiety and Depression Scale (HADS) and patients also by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised and the Norris scale every fourth to sixth month, one to four times. RESULTS: Changes were found over time in both patients and their next of kin in the SF-36 but not in the SEIQoL-DW or HADS. Patients rated worse than their next of kin in the SF-36 physical subscales and next of kin rated worse than the patients in the global QoL score in SEIQoL-DW. Health, hobbies, and total relations were important areas in the SEIQoL-DW among all participants, but some important areas also differed between the patients and their next of kin. In most important areas among the pairs, the next of kin estimated their functioning/satisfaction worse than patients estimated their functioning/satisfaction. SIGNIFICANCE OF RESULTS: There were few changes over time in the QoL among the participants. Although most of the estimates in patients and their next of kin were equal, there were also some differences. These results emphasize the importance of support for both patients and their next of kin and that support ought to be given on both individual bases and together in pairs. The SEIQoL-DW might give signposts in the care through the course of the disease about what should be focused on to increase satisfaction of the important areas of life and might help the person to find coping strategies to handle his or her life situation. PMID- 20163764 TI - Reducing the potential for suffering in older adults with advanced cancer. AB - OBJECTIVE: To deliver quality care at the end of life, understanding the impact of various changes and life transitions that occur in older age is essential. This review seeks to uncover potential sources of distress in an elder's physical, psychological, social, and spiritual well-being to shed light on the unique challenges and needs facing this age group. METHODS: Papers relating to older adults (aged 65 years and older or a mean age of 65 years and older) with advanced/terminal cancer receiving palliative, hospice, or end-of-life care published after 1998 were reviewed. RESULTS: Older adults with advanced cancer have unique needs related to changes in their physical, psychological, social, and spiritual well-being. Changes in each of these domains offer not only the risk of causing distress but also the potential for growth and development during the final stages of advanced cancer. SIGNIFICANCE OF RESULTS: Being aware of the various changes that occur with aging will help health care professionals tailor interventions to promote dignity-conserving care and greatly reduce the potential for suffering at the end of life. PMID- 20163765 TI - Bereavement dream? Successful antidepressant treatment for bereavement-related distressing dreams in patients with major depression. AB - OBJECTIVE: The death of a person is a stressful event. Such stress affects the physical and psychological well-being of the bereaved. As an associated mental disorder, major depressive disorder (MDD) is common. Some dream of the deceased, and these dreams are called bereavement dreams. Some MDD patients also experience dreams. These two types of dreams are sometimes difficult to differentiate. The dream of the bereaved might be only a bereavement-related dream, yet it might be a symptom of MDD. Herein, we report one patient who had distressing dreams after the death of her mother. METHODS: A 63-year-old woman was referred for psychiatric consultation because of generalized fatigue and insomnia. Questioning her about recent events, she said that her mother had died of colonic carcinoma 5 months previously. Two months after the death, she suddenly started dreaming of her mother, getting angry with her almost every night. Generalized fatigue, insomnia, and distressing dreams appeared simultaneously. The dream caused much distress, making her afraid to fall asleep. RESULTS: Her psychiatric features fulfilled the DSM-IV-TR criteria for MDD, single episode. The death of her mother was considered to be one of the causes of MDD. She was administered 25 mg/day of sertraline hydrochloride. After that, her symptoms gradually disappeared, and the frequency of distressing dreams was reduced. Five months later, physical and psychiatric symptoms of MDD were completely resolved. Subsequently, she has not suffered from any distressing dreams of her mother. SIGNIFICANCE OF RESULTS: This case indicates that dreams experienced after the death of a loved one should not be regarded simply as bereavement dreams. Some of the dreams may be symptoms of MDD. If the dreams are the symptoms of MDD, antidepressant treatment as well as psychotherapy may be useful. Therefore, we should avoid regarding symptoms of MDD as reactions to bereavement. PMID- 20163766 TI - Personal reflections on legacy making. PMID- 20163767 TI - Contesting the 'national interest' and maintaining 'our lifestyle': a discursive analysis of political rhetoric around climate change. AB - The release of the fourth United Nations Intergovernmental Panel on Climate Change (IPCC) report in February 2007 prompted a flood of responses from political leaders around the globe. Perhaps nowhere was this more apparent than in Australia, where its release coincided with the first sitting week of the Australian Parliament, in an election year. The current study involves a discursive analysis of climate change rhetoric produced by politicians from the major Australian political parties in the period following the release of the IPCC leading up to the national election. Data include both transcripts of parliamentary debate and statements directly broadcast in the media. The analysis focuses on the various ways in which the issue of climate change was invoked and rhetorically managed by each of the two parties in the lead up to the election. In particular, it focuses on the ways in which appeals to the 'national interest' and 'lifestyle maintenance', both regular features of political rhetoric, were mobilized by both parties to discursively manage their positions on the climate change issue. Implications of the ways in which such appeals were constructed are discussed in relation to the discursive limits of the ways in which the issue of climate change is constructed in public debate. PMID- 20163768 TI - Genetically modified vaccines augment the efficacy of cancer surgery and chemotherapy. PMID- 20163769 TI - Neocortical inhibitory system. AB - The neocortex contains two neuron types, excitatory (glutamatergic) pyramidal cells and inhibitory nonpyramidal (GABAergic) cells. GABAergic, inhibitory interneurons are morphologically distinct from excitatory pyramidal cells and account for 20-25 % of all neocortical neurons. Recent studies discovered that besides morphological features, inhibitory interneurons are molecularly and physiologically heterogenous and differ significantly in arrangement and terminations of their axonal endings. In neocortical interneurons, GABA is also co-localized with calcium-binding proteins (parvalbumin, calbindin, calretinin), with neuropeptides and nitric oxide synthase. Axons of GABAergic neurons target distinct domains of pyramidal neurons. Double-bouquet, Martinotti and neurogliaform cells (CB-IR, CR-IR) target distal dendrites of pyramidal neurons and probably regulate the vertical integration of synaptic input along the dendritic tree of pyramids. Basket cells (PV-IR) innervate soma and proximal dendrites, and Chandelier cells (PV-IR) exhibit synaptic contacts on the axon initial segment of pyramidal neurons. GABAergic neocortical interneurons are interconnected by gap junctions. Most often coupling is bidirectional and occurs between interneurons of the same type. Cortical pyramidal neurons derive from the dorsal telencephalon while the majority of interneurons derive from the ganglionic eminences of the ventral telencephalon, and tangentially migrate into cortex. Adult mammalian neurogenesis is not restricted to the hippocampus, but a small number of the new neurons is also generated in the neocortex. New cortical neurons are GABAergic and co-express calbindin and calretinin. Quantitative analysis of selected areas of the neocortex (neuropsychiatric diseases, models of epilepsy, aging) demonstrate a decrease in density of PV-IR and CB-IR neurons but not CR-IR neurons. PMID- 20163770 TI - Gradual loss of DNA-PK activity from the cytoplasm is coincident with the nuclear translocation of its activator Ku during early development of Xenopus laevis. AB - DNA-dependent protein kinase is a serine/ threonine kinase consisting of a catalytic subunit, p460, and a regulatory subunit called Ku (p80/p70). DNA dependent protein kinase plays a role in transcription, non-homologous recombination, and DNA repair. Previous data have shown the presence of DNA dependent protein kinase in Xenopus oocytes and changes in its activity during vitellogenesis. Metabolic labelling studies have shown that the increased enzyme activity in vitellogenic oocytes correlates with increased levels of Ku protein, and compared to the pre- and early-vitellogenic oocytes, vitellogenic and post vitellogenic oocytes show an increased level of DNA-dependent protein kinase activity. Whether DNA-dependent protein kinase activity is altered during early embryogenesis in Xenopus is not known. The present study demonstrates that DNA dependent protein kinase activity is gradually lost from the cytoplasm in the early embryonic cells of blastulae and gastrulae. The gradual loss of DNA dependent protein kinase activity during post-fertilization early embryogenesis in Xenopus is consistent with the reports on Arbacia punctulata. Immunohistochemistry of the oocytes at various stages and early embryos (gastrulae) shows that Ku70, a regulatory subunit of DNA-dependent protein kinase, is present both in the cytoplasm and nucleus in the pre-vitellogenic oocytes, full-grown post-vitellogenic oocytes and in the gastrula cells. However, Ku70 appears to accumulate in higher concentrations in the nuclei of gastrula cells. These results suggest that gradual loss of DNA-dependent protein kinase activity from the cytoplasm of the early embryos could be the consequence of Ku translocating to the nuclei that may be necessary for post-zygotic transcription followed by cellular differentiation. PMID- 20163771 TI - In vivo differentiation of human umbilical cord blood-derived cells into insulin producing beta cells. AB - In our study we confirmed the potential of human umbilical cord blood cells to differentiate into insulin-producing cells following transplantation into immunocompromised mice. The average number of C-peptide-positive human cells per animal was 18 +/- 13 as assessed by immunofluorescence staining and fluorescence in situ hybridization specific for human ALU sequence. Differentiation into insulin-producing cells was further confirmed by reverse transcription-polymerase chain reaction specific for human insulin mRNA. Successful differentiation required sublethal irradiation of xenogeneic recipient at least at a dose of 3 Gy. However, transplantation of human umbilical cord blood cells did not improve hyperglycaemia in diabetic animals. The results of our study show that human umbilical cord blood may be considered as a potential source of stem cells for treatment of diabetes mellitus. PMID- 20163772 TI - Morphometrical evaluation of germ cell apoptosis in infertile men. AB - Apoptosis associated with programmed cell death plays an essential role in the control of germ cell number in the testes. Although male germ cell apoptosis has been well characterized in different animal models, only a few studies of apoptosis in human testes are presently available. In 43 infertile men with azoospermia of varying aetiology, testicular tissue was obtained by testicular biopsy. Apoptosis of testicular germ cells was determined by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling method in situ. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling-positive cells were found in the testicular tissue of all patients with azoospermia, except in Sertoli cell-only syndrome. The apoptotic index was higher in germ cell hypoplasia and in normal spermatogenesis in comparison with germ cell arrest. This study was performed to confirm the presence and determine the frequency of apoptosis in infertile men. PMID- 20163773 TI - Evaluation of high-resolution melting (HRM) for mutation scanning of selected exons of the CFTR gene. AB - Hereby we present evaluation of high-resolution melting for mutation scanning applied to the cystic fibrosis transmembrane conductance regulator gene. High resolution melting was used for mutation scanning of selected samples derived from cystic fibrosis patients with a known cystic fibrosis transmembrane conductance regulator genotype. We tested 19 different disease-causing cystic fibrosis transmembrane conductance regulator mutant genotypes located within six exons of the cystic fibrosis transmembrane conductance regulator gene (4, 7, 10, 11, 14b and 22). Normalized melting curves of tested samples were compared to sequenced-verified wildtype samples. Determined mutations are as follows: p.F508del, p.I507del, p.G551D, p.R347P, c.1717- 1G>A, c.621+1G>T, p.Y122X, p.I336K, p.R553X, c.2789+5G>A, c.574delA, c.1811+1G>C, p.L1335F, p.L1335P, p.L1324P and p.M470V and represent minimally 76.5 % of all cystic fibrosis alleles detected in the Czech cystic fibrosis population. All analysed samples with mutant genotypes were unambiguously distinguished from wild-type samples. High-resolution melting analysis enabled reliable detection of all single nucleotide polymorphism classes and 1- or 3- base pair deletions. We examined the specificity, sensitivity and precision of this methodology. High-resolution melting analysis is an economical, sensitive and specific close-tube method and has a high utility for the detection of unknown mutations in cystic fibrosis DNA diagnostics. PMID- 20163774 TI - Methods of RNA purification. All ways (should) lead to Rome. AB - Ribonucleic acid (RNA) represents an important target of a wide array of laboratory anal yses. Thus, RNA purification is a critical first preceding step of a number of preparative and analytical methods, important particularly in diagnostics of dozens of viral, bacterial, and parasitic diseases, dia gnosis of inherited disorders, and tumours, as well as in basic research. To provide relevant and reliable results, techniques of molecular biology used for such purposes require pure and intact molecules of purified RNA. Moreover, RNA has to be purified effectively and reproducibly from various heterogeneous materials such as fresh or frozen tissues, cell lines, PCR products or long-term chemically preserved samples. Principally, methods of RNA purification can be divided into three groups. The first group of methods is based on organic phenol:chloroform extraction. The second group encompasses methods of RNA purification by means of its ability to bind specific surfaces in the presence of chaotropic salt, and the third group includes methods exploiting RNA isolation on isopycnic gradients. Although RNA can be isolated from either prokaryotic or eukaryotic organisms, this review is to give out a basic outline of methods available for eukaryotic, with emphasis on mammalian, tissues. PMID- 20163775 TI - Right ventricular beneficial effects of intracoronary SERCA2a gene transfer in an experimental model of heart failure. AB - SERCA2a gene transfer ameliorates heart failure pathologic processes in left ventricular myocardium. We sought to assess the simultaneous molecular changes that occur in the right ventricle. Sprague-Dawley rats underwent aortic banding and were followed by echocardiography for development of heart failure. After a decrease in fractional shortening of 25 % from baseline, intracoronary injection of adenoviral-SERCA2a or adenoviral-beta-galactosidase was performed. Successful gene transfer was confirmed by immunoblotting. Rats were randomly euthanized on post-operative day 7 or 21. Protein analysis including right ventricular levels of SERCA2a, betaARK1, inflammatory mediators (IL-1, IL-6 and TNF-alpha), apoptotic markers (Bax, Bak and Bcl-2) and MAPK (Jnk, p38 and Erk) was performed. Adenoviral-SERCA2a-treated animals showed increased right ventricular expression of SERCA2a compared with controls. Decreased levels of inflammatory markers were also demonstrated in this group. Expression of pro-apoptotic markers was similarly improved. Levels of MAPK were increased compared with the control group. These differences were most significant 7 days after gene transfer, but the majority of these changes persisted at 21 days. These results suggest that attenuation of pathologic mechanisms of calcium cycling, inflammation and apoptosis also occur in the right ventricular myocardium after SERCA2a gene transfer during heart failure. These findings support a therapeutic role for genetic manipulation of this pathway in patients with right ventricular or biventricular failure. PMID- 20163776 TI - Role of common canalicular transporter gene variations in aetiology of idiopathic gallstones in childhood. AB - Variations in genes encoding canalicular transportes, for biliary lipids may affect concentrations of biliary lipids in bile and promote cholesterol crystallization and gallstone formation. In our study we investigated the contribution of heterozygosity for common variations considered either potentially pathogenic or susceptibility alleles for cholesterol cholelithiasis in adults (c.523A>G (p.Thr175Ala) and c.1954A>G (p.Arg652Gly) in ABCB4, c.1331T>C (p.Val444Ala) in ABCB11 and c.55 G>C (p.Asp19His) in ABCG8) to the aetiology of paediatric idiopathic gallstone disease. Genotyping was performed in 35 paediatric subjects with idiopathic gallstones with positive family history for gallstones and 150 population controls. The ABCB4 variant p.Thr175Ala was found only in the controls, not in the patients. The frequency of the remaining three variant alleles and the corresponding genotypes did not differ between patients and controls. We conclude that the studied common variations in genes encoding canalicular transporters known to contribute to genetic predisposition to cholesterol gallstones in adulthood do not contribute specifically to the aetiology of paediatric idiopathic gallstones. PMID- 20163777 TI - Cardiotoxic injury caused by chronic administration of microcystin-YR. AB - Microcystins are cyclic peptide toxins. Chronic intoxication with well-known members of the microcystin family--microcystins-LR--induces liver tumour formation, injury of kidney and heart. Despite worldwide distribution in the environment, the effects of microcystins-YR have not been studied extensively. The aim of the study was to evaluate whether microcystins-YR, in relatively low doses, have a toxic effect on cardiomyocytes of chronically treated rats. Male adult Wistar rats were treated every second day for 8 months with microcystins-YR (10 microg/kg i.p., N = 5). Control groups were treated either with vehicle (ethanol and methanol 4 : 1 v/v; N = 5) or with physiologic saline (N = 4). The heart sections of microcystin-YR-treated rats revealed decreased volume density of cardiac muscle tissue (microcystins- YR = 0.485 mm3/mm3 +/- 0.003; vehicle = 0.493 mm3/mm3 +/- 0.002; saline = 0.492 mm3/mm3 +/- 0.002) due to fibrous proliferation. A few lymphocyte infiltrates were observed. Most of cardiomyocytes were enlarged (microcystins-YR = 20.19 microm +/- 1.34, vehicle = 17.45 microm +/ 0.52, saline = 16.00 microm +/- 1.43), with enlarged and often bizarre-shaped nuclei and decreased myofibril volume fraction (microcystins- YR = 0.416 mm3/mm3 +/- 0.009; vehicle = 0.472 mm3/ mm3 +/- 0.009; saline = 0.479 mm3/mm3 +/- 0.010). No TUNEL-positive cells were found in the heart sections of rats in all groups. The results allow the conclusion that chronic exposure to low doses of microcystins-YR may cause atrophy and fibrosis of the heart muscle. PMID- 20163778 TI - Polymorphisms of genes for brain-derived neurotrophic factor, methylenetetrahydrofolate reductase, tyrosine hydroxylase, and endothelial nitric oxide synthase in depression and metabolic syndrome. AB - The prevalence of metabolic syndrome as well as the occurrence of depressive disorder, which are both connected with increased risk of diabetes mellitus type 2 and cardiovascular diseases, is continually increasing worldwide. These disorders are interconnected at various levels; the genetic one seems to be promising. Contribution of genetic factors to the aetiopathogenesis of depressive disorder weighs within the range 40-50 %, whereas the genetic background for the manifestation of metabolic syndrome is more complicated. In this pilot study, we investigated the incidence of polymorphisms in several genes supposed to play a role in the development of both depressive disorder and metabolic syndrome such as brain-derived neurotrophic factor, methylenetetrahydrofolate reductase, tyrosine hydroxylase, and endothelial nitric oxide synthase. The entire group consisted of 42 patients with depressive disorder, 57 probands with metabolic syndrome and 41 control individuals. We found that genotype Met/Met of the Val66Met polymorphism of the brain-derived neurotrophic factor gene was positively associated with depressive disorder (P < 0.05), but we were not able to find any significant associations of both the depressive disorder and metabolic syndrome with the remaining polymorphisms studied (methylenetetrahydrofolate reductase 677CT, methylenetet rahydrofolate reductase 1298AC, endothelial nitric oxide synthase Glu298Asp, and tyrosine hydroxylase). PMID- 20163779 TI - MicroRNA miR-1 is up-regulated in remote myocardium in patients with myocardial infarction. AB - MicroRNAs are small regulatory RNA molecules that mediate regulation of gene expression, thus affecting a variety of physiological, developmental and pathological conditions. They are believed to be new promising therapeutic targets. In recent studies two muscle-specific microRNAs were discovered to contribute to heart diseases and development: miR-1 and miR-133, but there is little data on their expression patterns in human myocardial infarction. We performed simultaneous expression analysis of miR-1, miR-133a, miR-133b in samples of infarcted tissue and remote myocardium from twenty- four patients with acute myocardial infarction. MicroRNA expression was analysed using quantitative real-time PCR and compared to the expression patterns in myocardium of eight healthy adults who died in accidents. We found ~3.8-fold miR-1 up-regulation in remote myocardium when compared to infarcted tissue or healthy adult hearts. As miR-1 has been shown in animal models and clinical studies to contribute to arrhythmogenesis by regulating pacemaker channel genes, our finding of miR-1 up regulation in patients with myocardial infarction indicates that it might be responsible for the higher risk for arrhythmias in these patients. In addition, miR-133a/b down-regulation in infarcted tissue and remote myocardium was observed, indicating miR-133a/b involvement in the heart response to myocardial infarction. We conclude that miR-1 and miR-133 seem to be important regulators of heart adaptation after ischaemic stress. PMID- 20163780 TI - Circulating endothelial precursor cells (EPC) in patients undergoing allogeneic haematopoietic progenitor cell transplantation. AB - We have studied the number of endothelial precursor cells in eighteen patients undergoing allogeneic haematopoietic stem cell transplantation. Endothelial precursor cells were evaluated by colony-forming assay and compared to healthy controls. Patients undergoing allogeneic haematopoietic stem cell transplantation had significantly lower numbers of endothelial precursor cells before the procedure than healthy controls. The numbers of endothelial precursor cells were even lower in the first year after the treatment and seemed to recover partially after twelve months, but even then, they were lower than in healthy volunteers. On the other hand, the number of circulating CD146+CD31+ mature endothelial cells were higher than in healthy controls after more than a one-year follow-up. We hypothesize that lower numbers of endothelial precursor cells and higher numbers of endothelial cells in patients undergoing allogeneic haematopoietic stem cell transplantation reflect ongoing endothelial damage, probably caused by immunological mechanisms, and that this longterm damage may explain the higher risk of cardiovascular events in allogeneic haematopoietic stem cell transplant survivors. PMID- 20163781 TI - Aging and the speed of time. AB - Correlational and experimental methods provide evidence relevant to seven theories of humans' general impressions of the speed of time, including theories of the purported subjective acceleration of time with aging. A total of 1865 adults from two countries, ranging in age from 16 to 80, reported how fast time appears to pass over different spans of time. Other measures tapped the experience of life changes and time pressure, and experimental manipulations were used to test two models based on forward telescoping and difficulty of recall. Respondents of all ages reported that time seems to pass quickly. In contrast to widely held beliefs, age differences in reports of the subjective speed of time were very small, except for the question about how fast the last 10 years had passed. Findings support a theory based on the experience of time pressure. PMID- 20163782 TI - A probabilistic approach to the effect of water hydrogen bonds on the kinetics of protein folding and protein denaturation. AB - Previously, we presented a review of our kinetic models for the nucleation mechanism of protein folding and for the protein thermal denaturation in a barrierless way. A protein was treated as a random heteropolymer consisting of hydrophobic, hydrophilic, and neutral beads. As a crucial idea of the model, an overall potential around the cluster of native residues wherein a residue performs a chaotic motion was considered as the combination of the average dihedral, effective pairwise, and confining potentials. The overall potential as a function of the distance from the cluster has a double well shape. This allowed one to develop kinetic models for the nucleation mechanism of protein folding (NMPF) and barrierless protein denaturation (BPD) by using the mean first passage time analysis. In the original models, however, hydrogen bonding effects were taken into account only indirectly which affected the accuracy of the models because hydrogen bonding does play a crucial role in the folding, stability, and denaturation of proteins. To improve the NMPF and BPD models and explicitly take into account the hydrogen bonding "water-water" and "water-protein residue", we have developed a probabilistic hydrogen bond (PHB) model for the effect of hydrogen bond networks of water molecules around two solute particles (immersed in water) on their interaction, and have then combined the PHB model with the NMPF and BPD models. In this paper, that can be regarded as sequel of our previous review, we analyze the modified NMPF and BPD models that explicitly take into account the effect of water-water hydrogen bonding on these processes. As expected, the application of the modified models to the folding/unfolding of two model proteins (one short, consisting of 124 residues and the other large, consisting of 2500 residues) demonstrate that the hydrogen bond networks play a very important role in the protein folding/unfolding phenomena. PMID- 20163783 TI - Synoptic surgical reporting for breast cancer surgery: an innovation in knowledge translation. AB - BACKGROUND: Extensive literature identifies that the quality of surgery not only influences morbidity and mortality but also long-term survival and function. This mandates that we develop a system to capture this information on a real-time basis. METHODS: A synoptic surgical template for breast cancer was created; this was digitized and made available to all surgeons in Alberta. RESULTS: The data reference 1,392 breast cancer procedures. Ninety-one percent of reports were submitted within 1 hour and 97% of reports were submitted within 24 hours. Fifty two percent of reports were completed within 5 minutes. Information quality with respect to completeness of staging information was present in 89%. Eighty-four percent complied with practice guidelines and 89% of breast surgeons adopted the template. Seventy-five percent of users were moderately or highly satisfied with the system. CONCLUSIONS: The experience with the development and implementation of synoptic surgical reporting has proven to be a successful tool for generating quality surgical data. PMID- 20163784 TI - The Obsessive-Compulsive Inventory-Revised (OCI-R): psychometric properties of the Korean version and the order, gender, and cultural effects. AB - In this study, the psychometric properties of the Korean version of the OCI-R and the effects of order, gender, and culture on the inventory were examined in a nonclinical and in a clinical sample comprised of 702 college students and 91 patients with OCD. As a result, the original six-factor model is supported by the confirmatory factor analysis. The internal consistency, test-retest reliability, and the convergent and divergent validity of the OCI-R total and its subscales were good. Additionally, the receiver operating characteristic analyses showed that the OCI-R is an effective screening tool for OCD. For the negative results, the internal consistency of the neutralizing subscale was poor, and the hoarding and ordering subscale failed to distinguish patients with OCD from college students. Further, the divergent validity of the obsessing subscale appeared to be poor. A minor order effect on the OCI-R total score was observed-the decrease of the score when administered after another OCD symptom measure. No gender effects were found, whereas the cultural differences were found in some of the subscales. PMID- 20163785 TI - Moderators of continuation phase cognitive therapy's effects on relapse, recurrence, remission, and recovery from depression. AB - About half of patients who respond to acute-phase cognitive therapy (CT) for major depressive disorder (MDD) will relapse/recur within 2 years; continuation phase CT lowers this risk. We analyzed demographic, clinical, cognitive, social interpersonal, and personality variables to clarify which patients continuation phase CT helps to avoid relapse and recurrence and achieve remission and recovery. Participants had recurrent MDD, responded to acute-phase CT, were randomized to 8 months of continuation-phase CT (n = 41) or assessment control (n = 43), and were assessed 16 additional months (Jarrett et al., 2001). Consistent with an underlying risk-reduction model, continuation-phase CT was helpful for responders to acute-phase CT with greater risk and/or dysfunction as follows: Younger patients with earlier MDD onset who displayed greater dysfunctional attitudes and lower self-efficacy; personality traits suggesting low positive activation (e.g., reduced energy, enthusiasm, gregariousness); and transiently elevated depressive symptoms late in acute-phase CT and residual symptoms after acute-phase CT response. We emphasize the need for replication of these results before clinical application. PMID- 20163786 TI - Modulation in activation and expression of phosphatase and tensin homolog on chromosome ten, Akt1, and 3-phosphoinositide-dependent kinase 1: further evidence demonstrating altered phosphoinositide 3-kinase signaling in postmortem brain of suicide subjects. AB - BACKGROUND: Phosphoinositide 3-kinase (PI3-K) signaling plays a crucial role in neuronal growth and plasticity. Recently, we demonstrated that suicide brain is associated with decreased activation and expression of selective catalytic and regulatory subunits of PI3-K. The present investigation examined the regulation and functional significance of compromised PI3-K in suicide brain at the level of upstream phosphatase and tensin homologue on chromosome ten (PTEN) and downstream substrates 3-phosphoinositide-dependent kinase 1 (PDK1) and Akt. METHODS: Messenger RNA expression of Akt1, Akt3, PTEN, and PDK1 by competitive reverse transcription polymerase polymerase chain reaction; protein expression of Akt1, Akt3, PTEN, PDK1, phosphorylated Akt1 (Ser473 and Thr308), phosphorylated PDK1, and phosphorylated PTEN by Western blot; and catalytic activities of Akt1, Akt3, and PDK1 by enzymatic assays were determined in prefrontal cortex and hippocampus obtained from suicide subjects and nonpsychiatric control subjects. RESULTS: No significant changes in the expression of Akt1 or Akt3 were observed; however, catalytic activity of Akt1, but not of Akt3, was decreased in prefrontal cortex and hippocampus of suicide subjects, which was associated with decreased phosphorylation of Akt1 at Ser473 and Thr308. The catalytic activity of PDK1 and the level of phosphorylated PDK1 were also decreased in both brain areas without any change in expression levels of PDK1. On the other hand, messenger RNA and protein expression of PTEN was increased, whereas the level of phosphorylated PTEN was decreased. CONCLUSIONS: Our study demonstrates abnormalities in PI3-K signaling at several levels in brain of suicide subjects and suggests the possible involvement of aberrant PI3-K/Akt signaling in the pathogenic mechanisms of suicide. PMID- 20163787 TI - Developing a neurobehavioral animal model of infant attachment to an abusive caregiver. AB - BACKGROUND: Both abused and well cared for infants show attachment to their caregivers, although the quality of that attachment differs. Moreover, the infant's attachment to the abusive caregiver is associated with compromised mental health, especially under stress. In an attempt to better understand how abuse by the caregiver can compromise mental health, we explore the neural basis of attachment in both typical and abusive environments using infant rats, which form attachments to the mother through learning her odor. Here, we hypothesize that the neural circuitry for infant attachment differs based on the quality of the attachment, which can be uncovered during stressful situations. METHODS: We used infant rats to compare infant attachment social behaviors and supporting neurobiology using natural maternal odor, as well as two odor-learning attachment paradigms: odor-stroke (mimics typical attachment) and odor-.5 mA shock conditioning (mimics abusive attachment). Next, to uncover differences in behavior and brain, these pups were injected with systemic corticosterone. Finally, pups were reared with an abusive mother to determine ecological relevance. RESULTS: Our results suggest that the natural and learned attachment odors indistinguishably control social behavior in infancy (approach to the odor and interactions with the mother). However, with corticosterone injection, pups with an abusive attachment show disrupted infant social behavior with the mother and engagement of the amygdala. CONCLUSIONS: This animal model of attachment accommodates both abusive and typical attachment and suggests that pups' social behavior and underlying neural circuitry may provide clues to understanding attachment in children with various conditions of care. PMID- 20163788 TI - Yohimbine increases impulsivity through activation of cAMP response element binding in the orbitofrontal cortex. AB - BACKGROUND: Stress can increase impulsivity and has a negative impact on psychiatric outcome. Norepinephrine is heavily implicated in responses to stress, and the alpha(2) antagonist yohimbine is used clinically to study this aspect of the stress response. Yohimbine induces mild anxiety and increases impulsivity in healthy volunteers but has more detrimental effects in some psychiatric populations, triggering mania in bipolar patients and drug craving in substance dependent individuals. Understanding the mechanism by which yohimbine affects brain function could provide insight into the heightened reaction to stress in these patients. METHODS: Yohimbine's effects were assessed in rats using the five choice serial reaction time test of attention and impulse control. We then examined whether yohimbine altered activity of cyclic adenosine monophosphate response element binding (CREB) protein-a transcription factor implicated in the stress response-in brain areas that regulate impulsivity. The behavioral consequences of any changes in CREB activity were subsequently assessed using viral-mediated gene transfer to regionally overexpress CREB or the dominant negative antagonist mCREB. RESULTS: Yohimbine increased impulsive responding in rats and selectively increased CREB phosphorylation within the orbitofrontal cortex but not medial prefrontal cortex or nucleus accumbens. Overexpressing mCREB within the orbitofrontal cortex blocked yohimbine's effects on impulsivity, whereas overexpressing CREB in this region increased impulsive responding and potentiated the proimpulsive actions of yohimbine. DISCUSSION: These data suggest a novel molecular mechanism contributing to impulsivity that may be sensitive to stress. Such findings may improve our understanding of the neurobiological pathways linking the response to stress and impulsivity in both healthy and psychiatric populations. PMID- 20163789 TI - Flexible Accelerated STOP Tetracycline Operator-knockin (FAST): a versatile and efficient new gene modulating system. AB - We created the Flexible Accelerated STOP Tetracycline Operator (tetO)-knockin (FAST) system, an efficient method for manipulating gene expression in vivo to rapidly screen animal models of disease. A single gene targeting event yields two distinct knockin mice-STOP-tetO and tetO knockin-that permit generation of multiple strains with variable expression patterns: 1) knockout, 2) Cre-mediated rescue, 3) tetracycline-controlled transcriptional activator (tTA)-mediated misexpression, 4) tetracycline-controlled transcriptional activator (tTA) mediated overexpression, and 5) tetracycline-controlled transcriptional silencer (tTS)-mediated conditional knockout/knockdown. Using the FAST system, multiple gain-of-function and loss-of-function strains can therefore be generated on a time scale not previously achievable. These strains can then be screened for clinically relevant abnormalities. We demonstrate the flexibility and broad applicability of the FAST system by targeting several genes encoding proteins implicated in neuropsychiatric disorders: Mlc1, neuroligin 3, the serotonin 1A receptor, and the serotonin 1B receptor. PMID- 20163790 TI - Delayed circadian rhythm in adults with attention-deficit/hyperactivity disorder and chronic sleep-onset insomnia. AB - BACKGROUND: Previous studies suggest circadian rhythm disturbances in children with attention-deficit/hyperactivity disorder (ADHD) and sleep-onset insomnia (SOI). We investigate here sleep and rhythms in activity and melatonin in adults with ADHD. METHODS: Sleep logs and actigraphy data were collected during 1 week in 40 adults with ADHD, of whom 31 reported SOI. Salivary melatonin levels were assessed during 1 night. Sleep measures, circadian activity variables, and dim light melatonin onset were compared between groups of ADHD adults with and without SOI and with matched healthy control subjects. RESULTS: Compared with control subjects, both groups of ADHD adults had longer sleep-onset latency and lower sleep efficiency. Adults with ADHD and SOI showed a delayed start and end of their sleep period and a delayed melatonin onset compared with adults with ADHD without SOI (p = .006; p = .023; p = .02) and compared with healthy control subjects (p = .014; p = .019; p = .000). Adults with ADHD and SOI also showed an attenuated 24-hour amplitude in their rest-activity pattern, in contrast to those without SOI, who showed a higher day-to-day stability. CONCLUSIONS: These findings demonstrate diurnal rhythm deviations during everyday life in the majority of adults with ADHD that have SOI and suggest that potential benefits of rhythm-improving measures should be evaluated. PMID- 20163791 TI - Crystal structure of a new cyclomaltoheptaose hydrate: beta-cyclodextrin.7.5H2O. AB - The crystallographic study of a partially hydrated form of cyclomaltoheptaose (beta-cyclodextrin, betaCD) is reported. C(42)H(70)O(35).7.5H(2)O; space group P2(1) with unit cell constants a=15.1667(5), b=10.1850(3), c=20.9694(7)A, beta=110.993(2) degrees ; final discrepancy index R=0.0760 for the 6181 observed reflections and 784 refined parameters. One water molecule is included in the cavity and distributed over two partially occupied positions, the other 6.5 waters distributed over eight positions are located as space-filler between the macrocycles. The crystal structure belongs to the cage-type, like that observed in Form I (betaCD.12H(2)O; Lindner, K; Saenger, W. Carbohydr. Res. 1982, 99, 103 115) and Form II (betaCD.11H(2)O; Betzel, C., et al. J. Am. Chem. Soc., 1984, 106, 7545-7567). PMID- 20163792 TI - Maturation of dendritic cell precursors into IL12-producing DCs by J-LEAPS immunogens. AB - LEAPS (ligand epitope antigen presentation system) vaccines consist of a peptide containing a major histocompatibility antigen binding peptide conjugated to an immune cell binding ligand (ICBL) such as the 'J' peptide from beta-2 microglobulin. Treatment of monocytes, monocytes plus GMCSF, or monocytes plus GMCSF and IL4 with JgD (containing a peptide from gD of herpes simplex virus type 1) or JH (with a peptide from HIV p17 gag protein) was sufficient to promote their maturation into Interleukin 12 producing dendritic cells. JgD-dendritic cells supported allotypic activation of T cells to produce Th1-related cytokines. PMID- 20163793 TI - A comparison of wavelet and curvelet for breast cancer diagnosis in digital mammogram. AB - This paper presents a comparative study between wavelet and curvelet transform for breast cancer diagnosis in digital mammogram. Using multiresolution analysis, mammogram images are decomposed into different resolution levels, which are sensitive to different frequency bands. A set of the biggest coefficients from each decomposition level is extracted. Then a supervised classifier system based on Euclidian distance is constructed. The performance of the classifier is evaluated using a 2 x 5-fold cross validation followed by a statistical analysis. The experimental results suggest that curvelet transform outperforms wavelet transform and the difference is statistically significant. PMID- 20163794 TI - Phonological-lexical activation: A lexical component or an output buffer? Evidence from aphasic errors. AB - Single word production requires that phoneme activation is maintained while articulatory conversion is taking place. Word serial recall, connected speech and non-word production (repetition and spelling) are all assumed to involve a phonological output buffer. A crucial question is whether the same memory resources are also involved in single word production. We investigate this question by assessing length and positional effects in the single word repetition and reading of six aphasic patients. We expect a damaged buffer to result in error rates per phoneme which increase with word length and in position effects. Although our patients had trouble with phoneme activation (they made mainly errors of phoneme selection), they did not show the effects expected from a buffer impairment. These results show that phoneme activation cannot be automatically equated with a buffer. We hypothesize that the phonemes of existing words are kept active though permanent links to the word node. Thus, the sustained activation needed for their articulation will come from the lexicon and will have different characteristics from the activation needed for the short-term retention of an unbound set of units. We conclude that there is no need and no evidence for a phonological buffer in single word production. PMID- 20163795 TI - High-resolution ultrasound showing increased intima and media thickness of the radial artery in patients with end-stage renal disease. AB - OBJECTIVE: Although clinically relevant atherosclerosis of the upper limb arteries is rarely seen, intimal hyperplasia of the arteries may reflect global atherosclerosis and increased intima-media thickness of the brachial artery has been linked to an increased risk of cardiovascular events and to early failure of the radiocephalic arteriovenous fistula. We speculated that patients with ESRD have thickening of both the radial intimal and medial layers compared to healthy subjects. METHODS: Ultrasound biomicroscopy is a novel very high frequency (55 MHz) ultrasound technique that could accurately measure the intima and media thickness of the vessel wall. No previous study has measured intima and media thickness separately in patients with end-stage renal disease and hence, the aim of the current study was to investigate the radial arterial wall layers in patients with chronic renal failure. RESULTS: Thirty-one patients with end-stage renal disease and 41 healthy subjects underwent ultrasound biomicroscopy of the radial arteries. Blood pressures did not differ except for pulse pressures which were elevated among patients with end-stage renal disease (p<0.01). Patients with end-stage renal disease showed 39% thicker intima and 18% greater media in the radial artery compared to healthy subjects (0.117+/-0.031 mm versus 0.084+/-0.02 mm for the IT, p<0.01 and 0.205+/-0.062 mm versus 0.174+/-0.044 mm for the MT; p<0.05). CONCLUSIONS: Both the intima and the media layers of the radial arteries are increased in patients with end-stage renal disease. Whether measurements of the radial arterial intima thickness may convey valuable information on the risk of future cardiovascular events and early arteriovenous fistula failure in end stage renal disease remain to be elucidated in future studies. PMID- 20163796 TI - A numerical study of the assumptions underlying the calculation of the stationary zone mass transfer coefficient in the general plate height model of chromatography in two-dimensional pillar arrays. AB - The present study investigates the validity of one of the key assumptions underlying the general plate height model of chromatography, i.e., the presumed independency of the individual band broadening contributions. More precisely, it is investigated under which conditions the mass transfer inside the stationary zone (e.g., porous pillars) is independent from the axial transport of species outside this zone, and how strongly any such dependency would affect the validity of the general plate height model of chromatography. For this purpose, detailed calculations of the species concentration distribution inside and outside the porous pillars of a computer-mimic of a porous pillar array column have been made. These simulations revealed a clear interplay between the mass transfer inside and outside the pillars, manifesting itself as an asymmetry of the species concentration distribution inside the pillars. The latter is in disagreement with the basic assumption used to calculate the value of the C(s)-term of the general plate height model. The asymmetry-effect is largest at low reduced velocities, high retention factors and high intra-pillar diffusion coefficients. Fortunately, these are conditions where the C(s)-term is relatively small, which might explain why the general plate height model of chromatography (and based on the symmetry assumption) can represent the band broadening in a porous pillar array within an accuracy on the order of some 1-2%. PMID- 20163797 TI - Electrokinetic phenomena in wavy channels. AB - Electroosmotic flows are studied in wavy channels by expanding the solution into a double series in terms of the dimensionless amplitudes and of the dimensionless zeta potential for a binary dilute electrolyte. The expansion technique by means of formal calculations is described. Some examples are illustrated and discussed for two- and three-dimensional channels. The importance of the varicose or sinuous character of the channels as well as the role of high frequency roughness are demonstrated. These features may be used for practical purposes in order to amplify or diminish coupling effects in an algebraic way. PMID- 20163799 TI - Interface dynamics and mechanisms of nanoindented alkanethiol self-assembled monolayers using molecular simulations. AB - The interface and nanoindentation mechanisms of alkanethiol self-assembled monolayers (SAMs) chemisorbed on a gold surface are investigated using molecular dynamics simulation. The mechanisms include the nanoindentation depths, the workpiece temperatures, the numbers of SAM layers, the length of united-atoms per chain, and the shapes of the indenters. The simulation results show that the disorder and the plastic mobility of SAM chains increased with increasing indentation depth. The relaxation force and the plastic energy almost linearly increased with increasing indentation depth. The disorder region after indentation at high temperature is larger than that at low temperature. The adhesive force shows a dependence on temperature during indentation. The potential energy decreases with increasing number of SAM layers. The structural morphologies of the SAMs were not affected at the third layers for SAM film with four layers. The maximum load quickly decreases for film with two SAM layers. The structures of the SAM can be easily tilted and bent when the united-atoms per chain length is long. The SAM atoms become more disorderly and the elastic recovery is smaller when the SAM length of the united-atoms per chain is long after indentation. PMID- 20163798 TI - Polymer-lipid microbubbles for biosensing and the formation of porous structures. AB - Polymer-lipid microbubbles (PLBs) are generated by microfluidic flow-focusing devices to form a new class of long-lasting hybrid particles. The specific PLB construct developed is an elastic gas-filled microsphere with a polydimethylsiloxane (PDMS) shell containing phospholipids conjugated to functionalized polyethyleneglycol (PEG). Digital "droplet-based" microfluidics technology enables control of particle composition, size, and polydispersity (sigma<10%). Use of PDMS as a shell component improves the functionality and stability (lifetime>6 months) of the hybrid particles due to the thermally maneuverable solidification process. With a gas core, they serve as a template material for creating three-dimensional porous structures and surfaces, requiring no cumbersome post-processing removal steps. By adding biotinylated PEG-lipid derivatives that offer targeting capabilities, we demonstrate the immobilization of fluorescent IgG antibodies on stationary PDMS-lipid microbubbles through biotin-avidin interactions and on-chip trapping for immunoassays. A PDMS-lipid composition offers several advantages such as biocompatibility and biodegradability for future in vivo use as porous engineered scaffolds, packing materials, or delivery (e.g. therapeutic) agents with cell targeting capability. PMID- 20163800 TI - Charge stabilized crystalline colloidal arrays as templates for fabrication of non-close-packed inverted photonic crystals. AB - We developed a straightforward method to form non-close-packed highly ordered fcc direct and inverse opal silica photonic crystals. We utilize an electrostatically self assembled crystalline colloidal array (CCA) template formed by monodisperse, highly charged polystyrene particles. We then polymerize a hydrogel around the CCA (PCCA) and condense silica to form a highly ordered silica impregnated (siPCCA) photonic crystal. Heating at 450 degrees C removes the organic polymer leaving a silica inverse opal structure. By altering the colloidal particle concentration we independently control the particle spacing and the wall thickness of the inverse opal photonic crystals. This allows us to control the optical dielectric constant modulation in order to optimize the diffraction; the dielectric constant modulation is controlled independently of the photonic crystal periodicity. These fcc photonic crystals are better ordered than typical close-packed photonic crystals because their self assembly utilizes soft electrostatic repulsive potentials. We show that colloidal particle size and charge polydispersity has modest impact on ordering, in contrast to that for close-packed crystals. PMID- 20163801 TI - Adsorption of modified dextrins to a hydrophobic surface: QCM-D studies, AFM imaging, and dynamic contact angle measurements. AB - The adsorption of three dextrin-based polymers, regular wheat dextrin (Dextrin TY), phenyl succinate dextrin (PS Dextrin), and styrene oxide dextrin (SO Dextrin) on a model hydrophobic surface, consisting of a mixed alkanethiol layer on gold, has been characterized using the quartz crystal microbalance with dissipation monitoring (QCM-D). The three polymers exhibited varying affinities and capacity for adsorption on the hydrophobic substrate. Atomic force microscope (AFM) imaging of the polymer layers indicates that all three polymers fully cover the surface. The effect of the three polymers on the static contact angle of the surface was studied using captive bubble contact angle measurements. The three polymers were seen to reduce the receding contact angle by similar amounts (approximately 14 degrees ) in spite of having varying adsorbed amounts and differences in adsorbed layer water content. Although no differences were observed in the ability of the polymers to reduce the static contact angle, measurements of the dynamic contact angle between a rising air bubble and the polymer covered substrate yielded stark differences between the polymers, with one polymer (SO Dextrin) slowing the dewetting by an order of magnitude more than the other two polymers. The differences in dewetting behavior correlate with the adsorbed layer characteristics determined by QCM-D and AFM. The role of the dynamic and static contact angle in the performance of a polymer as depressant is discussed. PMID- 20163802 TI - Meningoencephalitis associated with Sarcocystis spp. in a free-living Japanese raccoon dog (Nyctereutes procyonoides viverrinus). AB - A free-living, young adult, male Japanese raccoon dog (Nyctereutes procyonoides viverrinus) was rescued in Gifu, Japan in March 2009. The animal was weak and emaciated with neurological signs that included head tilt, tremor and tic. The brain showed no gross abnormality at necropsy, but microscopically there was severe meningoencephalitis associated with protozoa, which were morphologically consistent with the asexual developmental stage of Sarcocystis spp. The protozoa were immunohistochemically negative for Toxoplasma gondii and Neospora caninum, but reacted weakly with antiserum specific for Sarcocystis cruzi. Analysis of the partial 18S rRNA gene sequence revealed that the protozoa were most closely related to an unidentified Sarcocystis species that was isolated from the white fronted goose (Anser albifrons). PMID- 20163804 TI - Pathology and tissue distribution of turkey coronavirus in experimentally infected chicks and turkey poults. AB - Twenty 1-day-old specific pathogen free chicks and 20 1-day-old commercially derived turkey poults were inoculated with a Brazilian strain of turkey coronavirus (TCoV) to study the pathogenicity and virus distribution up to 14 days post-inoculation by histopathology, immunohistochemistry, reverse transcriptase polymerase chain reaction and sequencing. At 2-14 dpi, TCoV antigens were detected in the paranasal sinus and lachrymal accessory gland (Harderian gland) of infected chicks and in the ileum, ileocaecal junction and caecum of infected poults. Lymphocytic inflammation was present in these tissues. TCoV was re-isolated from pooled tissue suspensions of nasal concha, Harderian gland and paranasal sinus from chicks, as well as from the ileum, ileocaecal junction and caecum of poults, after three consecutive passages in 28-day-old embryonated turkey eggs. Viral RNA corresponding to the spike gene region (1178 2073 genome position) was amplified from the upper respiratory tract of chickens and from the intestinal tract of poults and phylogenetic analysis confirmed the identity as TCoV. This is the first description of TCoV antigens and mRNA in upper respiratory tissues in experimentally infected chickens. PMID- 20163803 TI - Cross-reactivity of anti-human, anti-porcine and anti-bovine cytokine antibodies with cetacean tissues. AB - The cross-reactivity of monoclonal antibodies specific for human, porcine and bovine cytokines was evaluated for three cetacean species: Atlantic spotted dolphins (Stenella frontalis), striped dolphins (Stenella coeruleoalba) and fin whales (Balaenoptera physalus). Formalin-fixed and snap-frozen tissue sections of lung, spleen, liver and mesenteric lymph node were evaluated. T and B lymphocytes and monocytes/macrophages were detected by use of anti-human CD3, IgG and lysozyme polyclonal antibodies (pAbs), respectively. These reagents were successfully applied to both fixed and frozen tissues. Anti-human interleukin (IL)-1 alpha, IL-1 beta, IL-8, tumour necrosis factor (TNF)-alpha and CD25, anti porcine IL-2, IL-6, IL-10, and anti-bovine IL-4 and interferon (IFN)-gamma antibodies produced immunolabelling in cetacean snap-frozen lymph node sections similar to that obtained with tissue from the species of origin, but they did not react with formalin-fixed tissue sections. Anti-porcine IL-12 pAb did not react with snap-frozen cetacean tissue samples. Macrophages and lymphocytes were the most common cells immunolabelled with the anti-cytokine antibodies. This panel of anti-cytokine antibodies may be used to evaluate cytokine expression in snap frozen tissue samples from the cetacean species tested. PMID- 20163805 TI - Pathology and pathogenesis of ovine pulmonary adenocarcinoma. AB - Ovine pulmonary adenocarcinoma (OPA), also known as jaagsiekte, is a transmissible lung tumour of sheep caused by jaagsiekte sheep retrovirus (JSRV). JSRV induces neoplastic transformation of alveolar and bronchiolar secretory epithelial cells and the resulting tumours can grow to occupy a significant portion of the lung. Tumour growth is frequently accompanied by the overproduction of fluid in the lung, which further compromises normal respiration. The period between infection and the appearance of clinical signs may be several months or years and many JSRV-infected sheep do not exhibit clinical signs at all during their lifespan. This allows the spread of OPA into new flocks through contact with infected but apparently normal animals. OPA was first described in the early 19th century; however, it has still not been possible to devise effective methods for controlling its spread and it remains an important problem in most countries where sheep are farmed. This is due in part to the absence of an immunological response to JSRV in infected animals, which has hindered the development of serological diagnostic tests and vaccines. In addition to its veterinary importance, OPA is regarded as a potential large animal model for human lung adenocarcinoma and this has stimulated research into the pathogenesis of the ovine disease. This work has produced some significant results, including the finding that one of the JSRV structural proteins is directly involved in oncogenesis. The recent advances in understanding JSRV and the pathogenesis of OPA should lead to novel strategies for diagnosis and control of this disease and for its exploitation as a comparative model for human lung cancer. PMID- 20163806 TI - Children's (in)ability to recover from garden paths in a verb-final language: evidence for developing control in sentence processing. AB - An eye-tracking study explored Korean-speaking adults' and 4- and 5-year-olds' ability to recover from misinterpretations of temporarily ambiguous phrases during spoken language comprehension. Eye movement and action data indicated that children, but not adults, had difficulty in recovering from these misinterpretations despite strong disambiguating evidence at the end of the sentence. These findings are notable for their striking similarities with findings from children parsing English; however, in those and other studies of English, children were found to be reluctant to use late-arriving syntactic evidence to override earlier verb-based cues to structure, whereas here Korean children were reluctant to use late-arriving verb-based cues to override earlier syntactic evidence. The findings implicate a general cross-linguistic pattern for parsing development in which late-developing cognitive control abilities mediate the recovery from so-called "garden path" sentences. Children's limited cognitive control prevents them from inhibiting misinterpretations even when the disambiguating evidence comes from highly informative verb information. PMID- 20163807 TI - Toxic encephalopathy caused by occupational exposure to 1, 2-Dichloroethane. AB - This study describes the clinical and neuroimaging features of five patients with 1, 2-Dichloroethane (DCE) toxic encephalopathy. From January 1st 1998 to June 30th 2009, five patients who were subsequently diagnosed with DCE toxic encephalopathy were admitted to our hospital. All were female workers who had been in contact with DCE and subsequently had had seizures or symptoms of intracranial hypertension, including headache, nausea, and vomiting. The cranial MRI showed extensive brain edema in either the subcortical white matter, bilateral globus pallidus, and cerebellar nucleus dendatus, or the cortices. Of the five patients in the study, three had vasogenic edema, one had cytotoxic edema, and one had both types of edema. Following treatment with steroids and mannitol for 3 to 10 weeks, all patients made either a partial or complete recovery. The imaging findings were resolved on a follow-up MRI. It is clear that occupational exposure to DCE can cause severe toxic encephalopathy. Moreover, extensive brain edema, secondary to blood-brain barrier damage or neuronal injury, is the major neuroimaging feature and the cause of clinical manifestations. Early diagnosis and prompt treatment leads to a good outcome. PMID- 20163808 TI - The m.12316G>A mutation in the mitochondrial tRNA Leu(CUN) gene is associated with mitochondrial myopathy and respiratory impairment. AB - Mitochondrial disorders are often associated with mutations in mitochondrial tRNA. Independent observation of the same molecular defect in unrelated subjects is a generally required proof of pathogenicity. A sporadic case of chronic external ophthalmoplegia (cPEO) with ragged red fibres (RRFs) has been previously related to an m.12316G>A substitution in tRNA(Leu(CUN)). Sequencing muscle derived mtDNA, we found the m.12316G>A substitution in an adult woman with mitochondrial myopathy and respiratory impairment. Her muscle biopsy presented several cytochrome c oxidase-negative (COX-) fibres, and RRFs as signs of mitochondrial proliferation. Restriction-fragment length polymorphism (RFLP) analysis of the mutation in isolated muscle fibres showed a threshold of at least 60% of mutated mtDNA to determine a COX deficiency phenotype. This second report of the m.12316G>A mutation in a sporadic patient consolidates its pathogenic nature and provides further elements for genetic counselling. PMID- 20163809 TI - Knowing the limitations of applied deep brain stimulation technology for a clearer understanding of clinical outcomes. PMID- 20163810 TI - Guillain-Barre syndrome as leading manifestation of graft-versus-host disease in an allogeneic bone marrow transplanted patient. AB - Guillain-Barre Syndrome (GBS) is the most frequent cause of neuromuscular paralysis in industrialized countries and usually occurs after respiratory and gastrointestinal infections. However, in rare cases GBS is associated with Graft versus-Host Disease (GvHD). In the present case we report on a female allogeneic bone marrow transplanted patient who developed GBS as a leading manifestation of GvHD subsequent to discontinuation of her immunosuppressive medication with cyclosporine. In contrast to former case reports both IVIg and plasma exchange failed while resumption of immunosuppressive medication improved the condition of the patient clearly. PMID- 20163812 TI - [MRI evaluation of a supernumerary kidney fused with a horseshoe kidney]. AB - We present the case of a patient in whom a horseshoe kidney was discovered during US examination performed for abdominal pain. MRI confirmed this finding and also revealed a supernumerary kidney. The three kidneys were fused, with the supernumerary kidney forming the isthmus of the horseshoe kidney. Whereas horseshoe kidney is a relatively common renal malformation, a supernumerary kidney is one of the rarest renal malformations. The coexistence of these two malformations and especially the particular disposition of the supernumerary kidney is very rare. Knowledge of this malformation is interesting because it can lead to complications such as lithiasis, hydronephrosis, infections, and neoplasms and because it has important implications for surgical planning. PMID- 20163814 TI - Game theory based models to analyze water conflicts in the Middle Route of the South-to-North Water Transfer Project in China. AB - This study applied game theory based models to analyze and solve water conflicts concerning water allocation and nitrogen reduction in the Middle Route of the South-to-North Water Transfer Project in China. The game simulation comprised two levels, including one main game with five players and four sub-games with each containing three sub-players. We used statistical and econometric regression methods to formulate payoff functions of the players, economic valuation methods (EVMs) to transform non-monetary value into economic one, cost-benefit Analysis (CBA) to compare the game outcomes, and scenario analysis to investigate the future uncertainties. The validity of game simulation was evaluated by comparing predictions with observations. The main results proved that cooperation would make the players collectively better off, though some player would face losses. However, players were not willing to cooperate, which would result in a prisoners' dilemma. Scenarios simulation results displayed that players in water scare area could not solve its severe water deficit problem without cooperation with other players even under an optimistic scenario, while the uncertainty of cooperation would come from the main polluters. The results suggest a need to design a mechanism to reduce the risk of losses of those players by a side payment, which provides them with economic incentives to cooperate. PMID- 20163813 TI - Spectral fluorometric characterization of phytoplankton community composition using the Algae Online Analyser. AB - The utility of a multiple-fixed-wavelength spectral fluorometer, the Algae Online Analyser (AOA), as a means of quantifying phytoplankton biomass and community composition was tested using natural communities from two southeastern United States estuaries, North Inlet, South Carolina, and the Neuse River Estuary, North Carolina. Estimates of biomass (as chlorophyll a) were correlated with HPLC values and variations (usually over-estimates) were consistent with effects of light intensity and nutrient availability on fluorescence quenching. AOA estimates of taxonomic structure were consistent with those from HPLC-derived marker pigments by ChemTax, with both methods indicating domination by chromophytes and green algae in North Inlet and chromophytes and cyanobacteria in the Neuse. We recommend frequent calibration by discrete sample collection, and calibration with species representative of the region of interest. Overall, the AOA appears to be a useful tool for monitoring of phytoplankton community composition, especially as an early warning system for the detection of harmful algal blooms. PMID- 20163815 TI - Control of biofilm formation in water using molecularly capped silver nanoparticles. AB - Control of biofouling and its negative effects on process performance of water systems is a serious operational challenge in all of the water sectors. Molecularly capped silver nanoparticles (Ag-MCNPs) were used as a pretreatment strategy for controlling biofilm development in aqueous suspensions using the model organism Pseudomonas aeruginosa. Biofilm control was tested in a two-step procedure: planktonic P. aeruginosa was exposed to the Ag-MCNPs and then the adherent biofilm formed by the surviving cells was monitored by applying a model biofilm-formation assay. Under specific conditions, Ag-MCNPs retarded biofilm formation, even when high percentage of planktonic P. aeruginosa cells survived the treatment. For example, Ag-MCNPs (10 microg mL(-1)) retarded biofilm formation (>60%), when 50 percent of the planktonic P. aeruginosa cells survived the treatment. Moreover, stable low value of relative biomass has been formed in the presence of fixed Ag-MCNPs concentrations at various biofilm incubation times. Our results showed that Ag-MCNPs pretreated cells were able to produce EPS although they succeeded to form relatively low adherent biofilm. These pretreated cells appear well preserved and undamaged under TEM HPH/freeze micrographs, yet the intra cellular material seems to be pushed towards the peripheral parts of the cell, possibly indicating a survival strategy to the presence of Ag-MCNPs. The lower value of relative biomass formed in the presence of Ag-MCNPs could be associated with molecular mechanisms related to biofilm formation or continuous release of silver ions in the sample. However, further research is required to examine these factors. PMID- 20163816 TI - Electrochemical sulfide removal and recovery from paper mill anaerobic treatment effluent. AB - Sulfide can be removed from wastewater and recovered as elemental sulfur using an electrochemical process. Recently, we demonstrated this principle of product recovery on synthetic feeds. Here, we present a lab scale electrochemical reactor continuously removing sulfide from the effluent of an anaerobic treatment process operated on paper mill wastewater. The effluent contained 44+/-7 mg of sulfide-S L(-1). Sulfide was reduced to 8+/-2 mg-S L(-1), at a removal rate of 0.845+/ 0.133 kg-S m(-3) of total anodic compartment (TAC) d(-1). The removed sulfide was recovered (75+/-4% recovery) as pure concentrated alkaline sulfide/polysulfide solution, from which solid elemental sulfur was obtained. The electrochemical sulfide removal was not affected by different soluble constituents or particulate materials present in the wastewater. However, over time sulfide removal decreased due to biological sulfur reduction using the organics present in the wastewater. Therefore, a periodic switching strategy between anode and cathode was developed. Biofilm formation was avoided as the pH of the cathode solution increased to inhibitory levels during cathodic operation, while still allowing full recovery of the sulfur as end product. PMID- 20163817 TI - Removal of pharmaceuticals from water: using liquid-core microcapsules as a novel approach. AB - In recent years ever-increasing amounts of pharmaceuticals are being detected in the aquatic environment and in some cases, they have even been discovered in drinking water. Their presence is attributed mainly to the inability of sewage treatment plants to adequately remove these compounds from the sewage influent. The aim of this study was to investigate the feasibility, kinetics and efficiency of using liquid-core microcapsules as a novel methodology, termed capsular perstraction, to remove seven pharmaceuticals commonly found in the environment, from water. The process involves the envelopment of pre-selected organic solvents within a porous hydrogel membrane to form liquid-core microcapsules, which can be used to extract a large range of compounds. Results indicate that this novel approach is capable of extracting the seven chosen compounds rapidly and with a variable efficiency. The simultaneous use of both dibutyl sebacate and oleic acid liquid-core microcapsules at a liquid volume ratio of only 4% (v/v) resulted in the following extractions within 50min of capsule addition to contaminated water: furosemide 15%; clofibric acid 19%; sulfamethoxazole 22%; carbamazepine 54%; warfarin 80%; metoprolol 90% and diclofenac 100%. The effects of different agitation rates, microcapsule size and membrane thickness on the rate of mass transfer of warfarin into the liquid-core (dibutyl sebacate) of microcapsules was also examined. Results showed that the main rate-limiting step to mass transfer was due to the stagnant organic film (microcapsule size) within the core of the microcapsules. A volumetric mass transfer coefficient of 2.28x10(-6)m/s was obtained for the smallest microcapsules, which was nearly 4-fold higher compared to the value (0.6x10(-6)m/s) obtained for the largest microcapsules used in this study. Even with this resistance liquid-core microcapsules are still capable of the rapid extraction of the tested compounds and may provide a platform for the safe disposal of the pharmaceuticals after removal. PMID- 20163818 TI - Biomarkers of oxidative stress in the land snail, Theba pisana for assessing ecotoxicological effects of urban metal pollution. AB - This study investigates the biomarkers of oxidative stress and heavy metal accumulation for assessing ecotoxicological effects of urban metal pollution in Alexandria city, Egypt. This investigation was performed in the digestive gland of roadside Theba pisana snails obtained from six different sites in the city. Relationships between heavy metal (Zn, Cu, Pb and Cd) concentrations and oxidative stress indicators were also examined. The results showed that mean concentrations of the measured elements (mugg(-1) dry weight) were higher in polluted sites when compared to the background levels of the reference site. The pattern of metals accumulation at all sites was Zn>Cu>Pb>Cd. In the metal polluted sites, snails displayed higher mean of catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST) activities, lower reduced glutathione (GSH) content and higher levels of lipid peroxidation (LPO) compared to snails from the reference site. All oxidative stress parameters were positively correlated to heavy metal concentrations except GSH content which exhibits negative correlation with the concentrations of these metals. Our results suggest that the tested antioxidant defenses are sensitive parameters that could be useful as oxidative stress biomarkers in snails exposed to the actual metals in the environment. These biomarkers when complemented with metal accumulation in the digestive gland of snails may provide a powerful biomonitor for the assessment of environmental metal pollution. PMID- 20163819 TI - Are biotic indices sensitive to river toxicants? A comparison of metrics based on diatoms and macro-invertebrates. AB - Biotic indices based on macro-invertebrates and diatoms are frequently used to diagnose ecological quality in watercourses, but few published works have assessed their effectiveness as biomonitors of the concentration of micropollutants. A biological survey performed at 188 sites in the basin of the River Duero in north-western Spain. Nineteen diatom and six macro-invertebrate indices were calculated and compared with the concentrations of 37 different toxicants by means of a correlation analysis. Several chemical variables analysed correlated significantly with at least one biotic index. Sladecek's diatom index and the number of macro-invertebrate families exhibited particularly high correlation coefficients. Methods based on macro-invertebrates performed better in detecting biocides, while diatom indices showed stronger correlations with potentially toxic elements such as heavy metals. All biotic indices, and particularly diatom indices, were especially sensitive to the concentration of fats and oils and trichloroethene. PMID- 20163820 TI - Oxidative destruction of chlorinated hydrocarbons on Pt-containing fiber-glass catalysts. AB - Novel catalysts comprising noble metals (Pt), supported on fiber-glass woven materials demonstrated efficient oxidation of different chlorinated hydrocarbons (chlorobenzene, dichloroethane, dichloropropane,butyl chloride) and industrial mixed chlorinated organic wastes into HCl, CO2 and H2O at moderate temperatures without formation of highly toxic by-products (dioxins, phosgene, polychlorinated hydrocarbons,elemental chlorine). The highest oxidation activity and selectivity was observed for the platinum catalysts produced from fiber-glass supports with increased acidity and with additional introduction of promoting elements (such as Co, Mn and Cu). Long-term tests (more than 100 h) have shown no deactivation of the said catalysts. In combination with competitive catalyst price (due to the extra-low content of Pt--below 0.05% mass) it opens the way for development of highly efficient and feasible technology for utilization and detoxication of various chloro-organic wastes. PMID- 20163821 TI - Bioaugmentation of copper polluted soil microcosms with Amycolatopsis tucumanensis to diminish phytoavailable copper for Zea mays plants. AB - Amycolatopsis tucumanensis DSM 45259, the strain of a recently recognized novel species of the genus Amycolatopsis with remarkable copper resistance, was used to bioaugment soil microcosms experimentally polluted with copper and for studying the ability of this strain to effectively diminish phytoavailable copper from soils. Our results demonstrated that A. tucumanensis was capable of profusely colonizing both, copper polluted and non-polluted soil. Copper bioimmobilization ability of A. tucumanensis on soil was assessed measuring the bioavailable copper in the soil solution extracted from polluted soil by using chemical and physical methods and, in this way, 31% lower amounts of the metal were found in soil solution as compared to non-bioaugmented soil. The results obtained when using Zea mays as bioindicator correlated well with the values obtained by the chemical and physical procedures: 20% and 17% lower tissue contents of copper were measured in roots and leaves, respectively. These data confirmed the efficiency of the bioremediation process using A. tucumanensis and at the same time proved that chemical, physical and biological methods for assessing copper bioavailability in soils were correlated. These results suggest a potential use of this strain at large scale in copper soil bioremediation strategies. To our knowledge, this work is the first to apply and to probe the colonization ability of an Amycolatopsis strain in soil microcosms and constitutes the first application of an Amycolatopsis strain on bioremediation of polluted soils. PMID- 20163822 TI - Anaplastic lymphoma kinase 1 detected by immunohistochemistry in non-small cell lung cancer: a promising feature? PMID- 20163823 TI - Parameter optimization of the QUAL2K model for a multiple-reach river using an influence coefficient algorithm. AB - An influence coefficient algorithm and a genetic algorithm (GA) were introduced to develop an automatic calibration model for QUAL2K, the latest version of the QUAL2E river and stream water-quality model. The influence coefficient algorithm was used for the parameter optimization in unsteady state, open channel flow. The GA, used in solving the optimization problem, is very simple and comprehensible yet still applicable to any complicated mathematical problem, where it can find the global-optimum solution quickly and effectively. The previously established model QUAL2Kw was used for the automatic calibration of the QUAL2K. The parameter optimization method using the influence coefficient and genetic algorithm (POMIG) developed in this study and QUAL2Kw were each applied to the Gangneung Namdaecheon River, which has multiple reaches, and the results of the two models were compared. In the modeling, the river reach was divided into two parts based on considerations of the water quality and hydraulic characteristics. The calibration results by POMIG showed a good correspondence between the calculated and observed values for most of water-quality variables. In the application of POMIG and QUAL2Kw, relatively large errors were generated between the observed and predicted values in the case of the dissolved oxygen (DO) and chlorophyll-a (Chl-a) in the lowest part of the river; therefore, two weighting factors (1 and 5) were applied for DO and Chl-a in the lower river. The sums of the errors for DO and Chl-a with a weighting factor of 5 were slightly lower compared with the application of a factor of 1. However, with a weighting factor of 5 the sums of errors for other water-quality variables were slightly increased in comparison to the case with a factor of 1. Generally, the results of the POMIG were slightly better than those of the QUAL2Kw. PMID- 20163824 TI - Assessment of the anaerobic degradation of six active pharmaceutical ingredients. AB - Research examined the anaerobic degradation of 17 alpha-ethynylestradiol, acetaminophen, acetylsalicylic acid, ibuprofen, metoprolol tartrate, and progesterone by methanogenic bacteria. Using direct sample analysis and respirometric testing, anaerobic degradation was examined with (a) each compound as the sole organic carbon source and (b) each compound at a lower concentration (250 microg/L) and cellulose serving as the primary organic carbon source. The change in pharmaceutical concentration was determined following 7, 28, 56, and 112 days of anaerobic incubation at 37 degrees C. Only acetylsalicylic acid demonstrated significant degradation; the remaining compounds showed a mixture of degradation and abiotic removal mechanisms. Experimental results were compared with BIOWIN, an anaerobic degradation prediction model of the US Environmental Protection Agency. The BIOWIN model predicted anaerobic biodegradability of the compounds in the order: acetylsalicylic acid > metoprolol tartrate > ibuprofen > acetaminophen > 17 alpha-ethinylestradiol >progesterone. This corresponded well with the experimental findings which found degradability in the order: acetylsalicylic acid > metoprolol tartrate > acetaminophen > ibuprofen. PMID- 20163825 TI - Life history as a source of variation for persistent organic pollutant (POP) patterns in a community of common bottlenose dolphins (Tursiops truncatus) resident to Sarasota Bay, FL. AB - As apex predators within coastal ecosystems, bottlenose dolphins (Tursiops truncatus) are prone to accumulate complex mixtures of persistent organic pollutants (POPs). While substantial variations in POP patterns have been previously observed in dolphin populations separated across regional- and fine scale geographic ranges, less is known regarding the factors influencing contaminant patterns within localized populations. To assess the variation of POP mixtures that occurs among individuals of a population, polychlorinated biphenyl (PCB), organochlorine pesticide (OCP) and polybrominated diphenyl ether (PBDE) concentrations were measured in blubber and milk of bottlenose dolphins resident to Sarasota Bay, FL, and principal components analysis (PCA) was used to explain mixture variations in relation to age, sex and reproductive maturity. PCA demonstrated significant variations in contaminant mixtures within the resident dolphin community. POP patterns in juvenile dolphins resembled patterns in milk, the primary diet source, and were dominated by lower-halogenated PCBs and PBDEs. A significant correlation between principal component 2 (PC2) and age in male dolphins indicated that juvenile contaminant patterns gradually shifted away from the milk-like pattern over time. Metabolically-refractory PCBs significantly increased with age in male dolphins, whereas PCBs subject to cytochrome p450 1A1 metabolism did not, suggesting that changes in male POP patterns likely resulted from the selective accumulation of persistent POP congeners. Changes to POP patterns were gradual for juvenile females, but changed dramatically at reproductive maturity and gradually shifted back towards pre-parturient profiles thereafter. Congener-specific blubber/milk partition coefficients indicated that lower-halogenated POPs were selectively offloaded into milk and changes in adult female contaminant profiles likely resulted from the offloading of these compounds during the first reproductive event and their gradual re-accumulation thereafter. Overall, these results indicate that significant variations in contaminant mixtures can exist within localized populations of bottlenose dolphins, with life history factors such as age and sex driving individual differences. PMID- 20163826 TI - Characterization of roadway stormwater system residuals for reuse and disposal options. AB - The chemical characterization of sediments accumulated in catch basins and stormwater ponds provides important information for assessing risks associated with management of these residuals upon removal of accumulated deposits in stormwater systems. In this study, over a period of 15 months, more than 150 residual samples were collected from 77 catch basin units and 22 stormwater ponds from 16 municipalities throughout the state of Florida. Concentrations (mg/kg) of metals and metalloids (arsenic, barium, cadmium, chromium, copper, lead, mercury, nickel, selenium, silver, and zinc) and trace organics (volatile organics, semi volatile organics, herbicides, and pesticides) in the sediments were measured. In addition, the synthetic precipitation leaching procedure (SPLP) was utilized to evaluate pollutant leachability risk for a subset of the samples collected. Measured pollutant concentrations were compared to corresponding risk-based guidelines in Florida (i.e., Florida soil cleanup target levels) to assess potential human health risks of beneficial use of these residuals through land application. Leached concentrations were compared to risk-based water quality guidelines (i.e., Florida groundwater cleanup target levels) to examine the potential for groundwater contamination. Although several metals (arsenic, barium, chromium, copper, nickel, lead, and zinc) were routinely detected in the catch basin and stormwater pond sediments, their concentrations were generally lower than the Florida's risk-based cleanup target levels for soils. A small number of organochlorine compounds (e.g., 4,4'-DDE, 4,4'-DDT) were detected, but only in a limited number of the samples (less than 10%); leaching of trace organic pollutants above the Florida risk-based groundwater thresholds was rare. The results suggest that when land-applied or beneficially used, these residuals are not expected to pose a significant threat to human health or the environment and the results of this research will provide stormwater managers and environmental management authorities with a useful resource to examine proper disposal and beneficial use of catch basin and stormwater pond sediments. PMID- 20163827 TI - Modeling transient response of forests to climate change. AB - Our hypothesis is that a high diversity of dominant life forms in Tennessee forests conveys resilience to disturbance such as climate change. Because of uncertainty in climate change and their effects, three climate change scenarios for 2030 and 2080 from three General Circulation Models (GCMs) were used to simulate a range of potential climate conditions for the state. These climate changes derive from the Intergovernmental Panel on Climate Change (IPCC) "A1B" storyline that assumes rapid global economic growth. The precipitation and temperature projections from the three GCMs for 2030 and 2080 were related to changes in five ecological provinces using the monthly record of temperature and precipitation from 1980 to 1997 for each 1km cell across the state as aggregated into the provinces. Temperatures are projected to increase in all ecological provinces in all months for all three GCMs for both 2030 and 2080. Precipitation differences from the long-term average are more complex but less striking. The forest ecosystem model LINKAGES was used to simulate conditions for five ecological provinces from 1989 to 2300. Average output projects changes in tree diversity and species composition in all ecological provinces in Tennessee with the greatest changes in the Southern Mixed Forest province. Projected declines in total tree biomass are followed by biomass recovery as species replacement occurs in stands. The Southern Mixed Forest province results in less diversity in dominant trees as well as lower overall biomass than projections for the other four provinces. The biomass and composition changes projected in this study differ from forest dynamics expected without climate change. These results suggest that biomass recovery following climate change is linked to dominant tree diversity in the southeastern forest of the US. The generality of this observation warrants further investigation, for it relates to ways that forest management may influence climate change effects. PMID- 20163828 TI - Characteristics of two types of stabilized nano zero-valent iron and transport in porous media. AB - Nano-scale zero-valent iron (NZVI) has been shown to be suitable for remediating contaminated aquifers. However, they usually aggregate rapidly and result in a very limited migration distance that inhibits their usefulness. This study employed poly acrylic acid (PAA) and carboxymethyl cellulose (CMC) to synthesize two types of stabilized styles of NZVI with finer sizes (namely PNZVI and CNZVI). The mobility of stabilized NZVI was also demonstrated on the basis of transport in porous media. The results show that the PNZVI has a uniform particle size of 12 nm. However, tens of CNZVI particles with diameters of 1-3 nm were packed into secondary particles. Both the PNZVI and the CNZVI exhibited amorphous structures, and the stabilizer was bound to particle surfaces in the form of bidentate bridging via the carboxylic group, which could provide both electrostatic and steric repulsion to prevent particle aggregation. This study also proposes presumed stabilized configurations of PNZVI and CNZVI to reasonably illustrate their different dispersed suspension types. On the basis of the breakthrough curves and mass recovery, this study observed that the mobility of PNZVI in classic Ca(2+) concentration of groundwater was superior to CNZVI. Nonetheless, the mobility of CNZVI would be decreased less significantly than PNZVI when encountering high Ca(2+) concentrations (40 mM). Presumably, increasing the pore flow velocity would enhance the mobility of stabilized NZVI. Overall, the results of this study indicate that PNZVI has the potential to become an effective reactive material for in situ groundwater remediation. PMID- 20163829 TI - Vulnerability of organic acid tolerant wetland biota to the effects of inorganic acidification. AB - Inland waterbodies are often naturally acidic but are these ecosystems pre adapted to inorganic acidification e.g., by acid sulfate soils (ASS)? We conducted a controlled mesocosm experiment with inorganically acidified wetland water and wetland sediment replicates to pH 3 from a naturally acidic (pH 3.9, conductivity=74microScm(-1)) wetland in south-western Australia. Following acidification, dissolved organic carbon and nitrogen declined, and chlorophyll a dropped to zero. Inorganic acidification mobilised metals from sediment sods with increased water concentrations of Cu, Fe, Mn, Ca, Mg and Al. Acidification showed no significant effect on diatom assemblage. Nonetheless, greatly reduced abundance and diversity of grazing zooplankton was observed. Macroinvertebrates generally showed abundance decreases, although filterer-collector taxa increased. Decreased primary production reduced functional diversity and consumer biomasses. These results suggest likely impact to ecosystem functioning of low pH, weakly buffered and stained wetlands if exposed to inorganic acidification. PMID- 20163830 TI - Traffic-related air pollution and cardiovascular mortality in central Taiwan. AB - In this study, the relationship between cardiovascular mortality and traffic related air pollutants (NO(2), CO, PM(10), and six volatile organic compounds (VOCs), propane, iso-butane, propylene, benzene, meta-, para-, and ortho-xylenes) was investigated. The concentrations of NO(2), PM(10) and CO from 1993 to 2006 were measured at a fixed-site air monitoring station, and VOC data from 2003 to 2006 were obtained from a photochemical assessment monitoring site in an urban area in central Taiwan. Outcome variables were data on mortality due to cardiovascular diseases (ICD-9-CM 410-411, 414, 430-437) from 1993 to 2006. Cardiovascular mortality averaged 1.5 cases, ranging between 0 and 9 cases per day. Daily air pollution levels ranged from 0.5 to 80.5ppb for NO(2) and from 0.1 to 3.8ppm for CO. From the subset of data from 2003 to 2006, daily average values ranged from 0.6 to 17.5ppb for propane, 0.3 to 6.7ppb for iso-butane, 0.3 to 6.7ppb for propylene, 0.2 to 3.8ppb for benzene, 0.3 to 26.0ppb for m,p-xylene, and 0.02 to 7.6ppb for o-xylene. Poisson generalized additive model was used to estimate the effects of elevated air pollutant levels on daily mortality, adjusting for meteorological conditions and temporal trends. Single-pollutant model showed that cardiovascular mortality was significantly associated with NO(2) lagged 2 days, and with propane, iso-butane, and benzene lagged 0 day. The relative risk for an interquartile range increase in air pollutant levels was 1.053 for NO(2), 1.064 for propane, 1.055 for iso-butane, and 1.055 for benzene. In conclusion, daily cardiovascular mortality showed association with data on acute exposure to traffic air pollutants in Taichung, which is an important factor to consider in studying cardiovascular mortality in urban environments. PMID- 20163831 TI - Influence of cellular and plasma procoagulant activity on the fibrin network. AB - At the nexus of cellular and plasma procoagulant activities lies fibrin, which is necessary to provide a clot's structural support. Abnormalities in fibrin network formation or function can result in either bleeding or thrombotic complications. Understanding relationships between procoagulant activity and normal fibrin formation, as well as pathophysiologic mechanisms leading to abnormal fibrin deposition, is essential for the continued development of hemostatic and antithrombotic therapies. PMID- 20163832 TI - Role of PDI in regulating tissue factor: FVIIa activity. AB - Cell exposed tissue factor (TF) is generally in a low procoagulant ("cryptic") state, and requires an activation step (decryption) to exhibit its full procoagulant potential. Recent data suggest that TF decryption may be regulated by the redox environment through the oxidoreductase activity of protein disulfide isomerase (PDI). In this article we review PDI contribution to different models of TF decryption, namely the disulfide switch model and the phosphatidylserine dynamics, and hypothesize on PDI contribution to TF self-association and association with lipid domains. Experimental evidence debate the disulfide switch model of TF decryption and its regulation by PDI. More recently we showed that PDI oxidoreductase activity regulates the phosphatidylserine equilibrium at the plasma membrane. Interestingly, PDI reductase activity could maintain TF in the reduced monomeric form, while also maintaining low exposure of PS, both states correlated with low procoagulant function. In contrast, PDI inhibition or oxidants may promote the adverse effects with a net increase in coagulation. The relative contribution of disulfide isomerization and PS exposure needs to be further analyzed to understand the redox control of TF procoagulant function. For the moment however TF regulation remains cryptic. PMID- 20163833 TI - Association study between three polymorphisms and myocardial infarction and ischemic stroke in Chinese Han population. PMID- 20163834 TI - The VKORC1 promoter is occupied by c-Myc transcription factor in HepG2 cells. PMID- 20163835 TI - Mechanisms of estrogen-induced venous thromboembolism. AB - The use of oral contraceptives (OC) is a well established risk factor for venous thrombosis. It has been known for many years that almost all haemostatic parameters i.e. plasma levels of coagulation factors, anticoagulant proteins and proteins involved in the fibrinolytic pathway change during OC use. The discovery of several risk factors of venous thrombosis in the 1990s shed new light on the association between the effects of OC on the haemostatic system and the increased risk of venous thrombosis. In this review, we summarize the current knowledge on the effects of different kinds of hormonal contraceptives (OC, transdermal contraceptives, vaginal ring and levonorgestrel-releasing intrauterine device) on haemostatic variables and the relationship between the changes of these variables and the risk of venous thrombosis. PMID- 20163836 TI - Future directions in hemostasis: normalizing the lives of patients with hemophilia. AB - The ultimate goal of hemophilia research is to cure the disease by permanently replacing the abnormal or deficient clotting factor. The most promising current approach is to insert a functional gene into the patient that will lead to the production of either the native protein or a compatible non-immunogenic equivalent version. This protein will circulate at adequate levels to prevent spontaneous bleeds and to treat traumatic hemorrhage. While there continues to be progress in this area, there remain significant hurdles to allow the process to be done at minimal risk to the patient. In the short term the goals are: 1) to prevent spontaneous bleeding whenever possible through the provision of effective prophylactic therapy, and 2) to rapidly establish hemostasis when bleeding occurs via effective, safe and widely available treatment modalities. In addition, all therapy should be convenient and simple to use so as to allow the vast majority of hemophilia patients to routinely treat themselves. Optimally, such treatment should not require highly trained medical personnel or vascular access. Prophylactic therapy will be facilitated via the development and introduction of clotting factors with prolonged circulating times. Long acting versions of rFVIIa, rFVIII and rFIX are either already in or are about to enter clinical trials. Rapid treatment of bleeding could be facilitated by bio-engineered molecules with increased activity and/or altered binding characteristics. At least one such agent is in phase II clinical trials. Ease of administration may be accomplished by the introduction of room temperature stable products and the development of subcutaneous and even orally administered therapeutics. It is conceivable that a broad spectrum hemostatic agent capable of normalizing thrombin generation in a variety of deficiencies could be developed. If this is accomplished, the steps to a room temperature stable agent, contained within a pre-filled pen, capable of self-delivery by subcutaneous injection are already within the realm of current developmental capabilities. PMID- 20163837 TI - Isolated hemangioma causing gross painless hematuria in an adolescent male. AB - Hematuria in children is usually a benign entity, with hypercalciuria being the usual etiology; however, rarer causes also exist, including genitourinary hemangioma. Hemangioma is a benign tumor, which has a tendency to regress spontaneously by the second year of life. Involvement of the urinary tract is rare, and in patients with bladder involvement, an accompanying syndrome such as Sturge-Weber is usually found. However, there are reports of isolated bladder hemangioma in the pediatric population causing isolated gross hematuria. We report a case of bladder hemangioma causing gross painless hematuria in an otherwise healthy 14-year-old boy. PMID- 20163838 TI - Extended pelvic lymph node dissection in robotic-assisted radical prostatectomy: surgical technique and initial experience. AB - OBJECTIVES: To describe, and show in the accompanying video segments, a technique for extended pelvic lymph node dissection (ePLND) in robotic-assisted radical prostatectomy (RARP) and report our clinicopathologic and perioperative outcomes. The extent of pelvic lymphadenectomy during radical prostatectomy has not been standardized. However, evidence demonstrates that an ePLND yields a greater number of positive nodes. METHODS: A total of 32 patients with clinically localized prostate cancer underwent RARP with ePLND by a single surgeon (J.C.) between January and August 2008. The template for the ePLND included the obturator, hypogastric, external iliac, and common iliac lymph nodes up to the bifurcation of the aorta. Systematic review and grading of adverse events were performed. RESULTS: The median number of lymph nodes retrieved was 18 (interquartile range [IQR] 12-28). Four patients (12.5%) had lymph node metastases. Of the 4 patients with lymph node metastases, 1 patient (25%) had the involved lymph node exclusively in the common iliac region. Median operative time for the ePLND was 72 minutes (IQR 66-86). Median hospital length of stay was 2.0 days (IQR 2.0-2.8). Graded complications included 13 grade 1 events and 1 grade 2 event, with 1 grade 1 event being considered related to ePLND. No clinically presenting lymphoceles or thrombotic events were encountered. CONCLUSIONS: An ePLND during RARP is technically feasible and appears to have minimal morbidity. It produces a high lymph node yield and may result in improved pathologic staging. PMID- 20163839 TI - Relationship between bone mineral density and androgen-deprivation therapy in Japanese prostate cancer patients. AB - OBJECTIVES: To examine Japanese patients who had received androgen-deprivation therapy (ADT) for longer periods, as it is known that ADT of patients with prostate cancer reduces their bone mineral density (BMD). However, our previous cross-sectional study revealed that short-term ADT (average, 23.5 months) does not significantly increase the prevalence of osteoporosis in Japanese patients. METHODS: The subjects consisted of 201 native Japanese patients with prostate cancer. They comprised 113 ADT-treated and 88 hormone-naive patients. Lumbar spine, total hip, and femoral neck BMDs were measured by dual-energy x-ray absorptiometry and expressed in standard deviation units relative to the scores of young adult men (T-score) or age-matched men (Z-score). Serum levels of bone metabolism markers were also measured. RESULTS: The ADT-treated patients had significantly lower BMD values, T-scores, and even Z-scores than the hormone naive patients (P <.001). For patients who were hormone-naive, ADT-treated for less than 2 years, and ADT-treated for more than 2 years, the osteoporosis prevalence was 4.5% (4/88), 12.1% (4/33), and 10.8% (4/37), respectively. The ADT treated patients had significantly higher serum amino-terminal telopeptide levels than the hormone-naive patients (P = .014), but significantly lower serum carboxy terminal telopeptide of type-I collagen levels than the ADT-treated patients with bone metastasis (P <.001). CONCLUSIONS: Our cross-sectional study confirmed that both ADT-treated and hormone-naive Japanese patients with prostate cancer have low rates of osteoporosis. These findings are different from those of studies in western countries. Genetic and hormonal or other environmental factors may result in population differences in the characteristics of prostate cancer and BMD. PMID- 20163840 TI - An epidemiologic study of voiding and bowel habits in Korean children: a nationwide multicenter study. AB - OBJECTIVES: To evaluate the prevalence of abnormal voiding and bowel habits in healthy children, and to identify possible relationships between personal and familial factors and voiding and/or bowel habits. METHODS: A randomly selected cross-sectional study was conducted in 19,240 children (5-13 years old) nationwide in the Republic of Korea. Parents were asked to complete questionnaires, which included items about nocturnal enuresis, daytime dysfunctional voiding symptoms (DVSs), and abnormal bowel habits (ABHs). Rates and associated factors were investigated. RESULTS: The overall rates of DVS, ABH, and of both were 46.4%, 31.3%, and 18.4%, respectively, and nocturnal enuresis was reported in 919 (5.6%). Daytime dysfunctional voiding symptoms were as follows: increased voiding frequency in 419 (2.5%), decreased voiding frequency in 720 (4.4%), urgency in 2740 (16.6%), daytime incontinence in 1854 (11.2%), urge incontinence in 2775 (16.8%), and holding maneuvers or postponed voiding in 3888 (23.5%). ABHs were as follows: constipation by frequency in 1103 (6.7%), constipation by the Bristol scale in 1941 (11.8%), fecal incontinence in 1293 (7.8%), and difficult or painful defecation in 2609 (15.8%). Delayed stool control, history of urinary tract infection, and a double-income family were positively associated with DVS or ABH or both. Furthermore, fathers with a low level of education and a low income were found to be associated with higher risk of ABH or DVS or both. CONCLUSIONS: Delayed stool control, a history of urinary tract infection, a low paternal level of education, a double-income family, and a lower family income had a negative effect on voiding or bowel habits in children. PMID- 20163841 TI - Single institutional experience with nephron-sparing surgery for pathologic stage T3bNxM0 renal cell carcinoma confined to the renal vein. AB - OBJECTIVE: To assess our institution's experience with the management of pathologic stage T3bNxM0 renal cell carcinoma with tumor thrombus confined to the renal vein treated with nephron-sparing surgery (NSS). METHODS: Of the 492 patients who have undergone NSS at Columbia University from 1998 to 2009, 8 patients were found to have stage T3bNxM0 renal cell carcinoma (RCC) on final pathology. Records were reviewed for indication for NSS, imaging studies, perioperative management, surgical details, pathology, and both functional and disease-specific outcomes. Postoperative renal function was estimated by most recent glomerular filtration rate using Modification of Diet in Renal Disease formula. Recurrence of RCC was monitored using serial axial imaging. RESULTS: The 8 patients were presumed to be clinical stage T1aN0M0 RCC before surgery; however, tumor thrombus was identified in the renal vein intraoperatively and on final pathology in 4, and 4 cases, respectively, corresponding to stage T3bNxM0 RCC by current American Joint Committee on Cancer-Tumor-Necrosis-Metastasis 2002 criteria. After a median follow-up of 19.8 months, the patients experienced a mean decrease in estimated glomerular filtration rate of 27.1%. One patient developed new-onset renal failure, defined as an estimated glomerular filtration rate below 30 mL/min/1.73 m(2). Clean surgical margins were obtained in 7 patients. Carcinoma was identified at the parenchymal margin in 1 patient. No patients have evidence of recurrence of RCC by serial axial imaging. CONCLUSIONS: NSS does not seem to have had a negative impact on a small series of patients with pathologic stage T3bNxM0 RCC limited to the renal vein and may be a feasible option when the clinical situation indicates a need for preservation of renal function. PMID- 20163842 TI - Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction. AB - OBJECTIVES: To compare the safety and efficacy of the daily erectogenic therapy, tadalafil, on lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH-LUTS) in men with or without comorbid erectile dysfunction (ED). METHODS: Following a 4-week placebo run-in period, men with moderate-to-severe BPH-LUTS were randomized to placebo or tadalafil 2.5, 5, 10, or 20 mg once daily for 12 weeks. International Prostate Symptom Scores (IPSS), IPSS quality of life, and BPH Impact Index were measured every 4 weeks. Safety was mainly assessed via spontaneous reports of adverse events. Data from men with (n=716) or without (n=340) ED at baseline were compared in posthoc analyses. RESULTS: Men with ED were older and had more frequent hypertension, hyperlipidemia, coronary artery disease, and diabetes at baseline compared with men without ED. After 12 weeks, changes in IPSS in men with ED (least squares mean change from baseline, placebo: -2.4; tadalafil 2.5, 5, 10, 20 mg: -4.3, -4.8, -5.3, -5.6) and without ED (-2.4, 3.2, -5.3, -5.1, -4.5) were not significantly different (subgroup/interaction P values: .352/.644). Similar effects were observed for IPSS quality of life (with ED: -0.6, -0.9, -0.9, -1.0, -1.1; without ED: -0.6, -0.7, -0.9, -0.8, -0.8; 0.090/0.773) and BPH Impact Index (with ED: -0.7, -0.9, -1.3, -1.3, -1.4; without ED: -1.0, -0.7, -1.3, -1.3, -1.2; 0.753/0.852). Tadalafil was generally well tolerated, and men with or without ED had similar tolerability profiles. CONCLUSIONS: Changes in BPH-LUTS after 12 weeks of treatment with placebo or various doses of once daily tadalafil were similar in men with or without comorbid ED. PMID- 20163843 TI - Percutaneous biopsy of renal cell carcinoma underestimates nuclear grade. AB - OBJECTIVES: To assess the accuracy of renal biopsy for predicting the final nuclear grade and histologic subtype. Small renal masses can be safely observed in select patients who are poor surgical candidates. Renal biopsy may help identify patients who are candidates for observation. METHODS: A total of 81 patients (29 female, 52 male) underwent percutaneous biopsy of their renal mass with ultrasound or computed tomography guidance. Percutaneous 18-gauge biopsy cores were obtained, and all patients subsequently underwent radical nephrectomy or partial nephrectomy. Preoperative biopsy results were compared with postoperative specimens. RESULTS: The mean tumor size was 5.3 cm (range, 1-17). Overall, biopsy correctly identified 71 of 81 (88%) histologic subtypes. The preoperative biopsy correctly identified 62 of 64 (97%) clear cell renal carcinomas, 9 of 10 (90%) papillary carcinomas, 0 of 3 (0%) chromophobe carcinomas, and 1 of 2 (50%) oncocytomas. The final pathologies for 2 nondiagnostic biopsies were clear cell renal carcinoma and inflammatory pseudotumor. For 67 tumors, the pathologists assigned a nuclear grade for both the biopsy and the final specimen. The biopsy correctly identified 29 of 67 (43%) final nuclear grades. The biopsy underestimated the nuclear grade in 37 of 67 (55%) cases. In 7 of 67 (10%) cases, the biopsy nuclear grade increased by 2 when compared with the final grade. The biopsy rarely overestimated the nuclear grade; 1 case (1%) that was assigned a grade 2 on biopsy was assigned a grade 1 after nephrectomy. CONCLUSIONS: Core biopsies for renal masses underestimate nuclear grade in most cases; however, histologic subtype is more reliably assessed, particularly for clear cell renal tumors. PMID- 20163844 TI - Health disparities in staging of SEER-medicare prostate cancer patients in the United States. AB - OBJECTIVES: To examine whether race or age disparities affected the odds of being staged among prostate cancer (PC) patients. Accurate staging is critical for determining treatment for PC. METHODS: Multivariable logistic regression models examined race and age disparities with respect to the odds of being staged among PC patients using Surveillance, Epidemiology, and End Results-Medicare data. Similar analyses were performed to estimate the adjusted odds of being staged with distant metastatic vs in situ or local/regional disease. RESULTS: The proportion of patients without staging ranged between 3% and 16% by age and between 6% and 8% by race. Adjusted results demonstrated statistically significant lower odds ratios (P <.05) for 70-74, 75-79, and 80+-year-olds of 0.76, 0.52, and 0.23, respectively, relative to PC patients aged 65-69. The odds of being staged for African Americans are 0.78 times that of non-Hispanic Whites (95% confidence interval = 0.72-0.86). The adjusted probability of distant metastatic disease at initial diagnosis is higher for African Americans (odds ratio = 1.61; 95% confidence interval = 1.47-1.76) and older men with odds ratios of 1.25, 1.85, and 4.33 for ages 70-74, 75-79, and 80+, respectively, compared with 65-69-year-olds (all P <.05). CONCLUSIONS: Even though the overall odds of being staged increased over time, race and age disparities persisted. When staging did occur, the probability of distant metastatic disease was high for African Americans, and there were increasing odds of metastatic disease for all men with advanced age. PMID- 20163845 TI - Effect of sex hormones on crystal formation in a stone-forming rat model. AB - OBJECTIVES: To evaluate the contribution of sex hormones in urolithiasis using a stone-forming rat model. Gender differences because of sex hormones are thought to influence the incidence of urolithiasis. METHODS: We divided rats into 7 groups, such as intact males, orchidectomized males, intact males subcutaneously implanted with testosterone, intact males subcutaneously implanted with estradiol, intact females, ovariectomized females, and intact females subcutaneously implanted with testosterone. At 10 weeks old, the rats were fed 0.5% ethylene glycol in drinking water and given 0.5 microg of 1,25-dihydroxy vitamin D(3). Kidney crystal deposition and the degree of oxidative stress were examined in each group, and endogenous oxalate metabolism and antioxidant enzymes were compared among groups using real-time reverse transcription-polymerase chain reaction. RESULTS: Extensive crystal deposition was observed in intact males and testosterone-administered males, whereas few crystals were found in intact females. Crystal deposition was inhibited in orchiectomized males and in those administered estradiol, whereas ovariectomized females and testosterone administered females had slightly enhanced and very enhanced crystal deposition, respectively. Increases in urinary oxalate excretion paralleled renal crystal deposition, which were both enhanced by testosterone treatment through increased glycolate oxidase expression. Oxidative stress increased in groups with extensive crystal deposition compared with those without. Antioxidant enzyme expression was enhanced by estradiol. CONCLUSIONS: Testosterone was a promoter and estradiol an inhibitor of kidney crystal deposition, likely because of their effects on oxalate synthesis and oxidative stress. PMID- 20163847 TI - A pilot study using the Gynecologic Cancer Lymphedema Questionnaire (GCLQ) as a clinical care tool to identify lower extremity lymphedema in gynecologic cancer survivors. AB - OBJECTIVE: This study aimed to determine the feasibility and efficacy of using the Gynecologic Cancer Lymphedema Questionnaire (GCLQ) as a symptom scale for lymphedema of the lower extremity (LLE). METHODS: Twenty-eight gynecologic cancer survivors with documented LLE and 30 without a history or presence of lymphedema completed the GCLQ and provided feedback about their satisfaction with and feasibility of using the GCLQ at their oncology follow-ups. The study survey took approximately 5-10 min to complete, and it was easily understood by the majority of the sample. RESULTS: Participants had a mean age of 59.6 years (range, 28-80 years). Twenty-eight women (48%) had LLE, and 30 (52%) had no history or presence of LLE (confirmed by limb volume [LV] measurements at assessment). Type of cancer history included endometrial, 38 (66%); cervical, 13 (22%); and vulvar, 7 (12%). GCLQ scores differed significantly by lymphedema diagnosis; LLE patients had higher scores (P<0.01). The large area under the curve (AUC) of 0.95 (95% CI: 0.90-1.000) suggests that the GCLQ can distinguish between patients with and without LLE. Although all 28 (100%) of the LLE patients were aware of their LLE diagnosis, only 23 (82%) underwent treatment. The GCLQ was easily understood by most (55/58, 95%), and overall, patients showed a high willingness (56/58, 96%) to complete the questionnaire at future appointments. Twenty-five (88%) of the LLE patients found the GCLQ to be helpful in identifying symptoms of lymphedema. CONCLUSIONS: The GCLQ effectively distinguished between gynecologic cancer survivors with and those without LLE, with good sensitivity and specificity. The patients, particularly those with LLE, showed high confidence in the GCLQ's ability to detect LLE symptoms. PMID- 20163848 TI - Should epidural analgesia be dismissed in gynecologic oncology surgery? PMID- 20163849 TI - Polymorphisms involved in the miR-218-LAMB3 pathway and susceptibility of cervical cancer, a case-control study in Chinese women. AB - OBJECTIVE: Laminin-5 is required in RAS and NF-kappaB blockade induced tumorigenesis of human squamous cell carcinoma and a marker of invasiveness in cervical lesions. MicroRNA-218 (miR-218) can target laminin-5 beta3 (LAMB3), but suppressed by HPV-16 E6 protein. Therefore, we hypothesized that single nucleotide polymorphisms (SNPs) in pri-miR-218 and LAMB3 may individually and/or jointly contribute to cervical cancer carcinogenesis. METHODS: We identified one SNP rs11134527 located in pri-miR-218 sequence and one SNP rs2566 in 3'UTR of LAMB3 and genotyped these two SNPs in a case-control study of 703 cervical cancer cases and 713 cancer-free controls in Chinese women. RESULTS: Logistic regression analyses showed that the pri-miR-218 rs11134527 variant homozygote GG was associated with a decreased risk of cervical cancer compared with the AA genotype (adjusted OR=0.72, 95% CI=0.52-0.99), while the LAMB3 rs2566 variant CT/TT genotypes were associated with a significantly increased risk of cervical cancer (adjusted OR=1.57, 95% CI=1.25-1.96), compared with the wild type CC genotype. A significant dose-response effect was observed between the number of risk alleles, rs11134527A and rs2566 T, and the risk of cervical cancer (P for trend=0.0006). CONCLUSION: These findings indicate that pri-miR-218 rs11134527 and LAMB3 rs2566 may contribute to cervical cancer carcinogenesis, and further validations in diverse populations and functional characterizations are warranted. PMID- 20163850 TI - Fertility-sparing options for early stage cervical cancer. AB - OBJECTIVE: To review the literature on fertility-sparing options for women with early stage cervical cancer and outline patient selection criteria, operative, oncologic, and pregnancy outcomes. METHODS: The literature was searched using MEDLINE (OVID: 1950 through October 2009) and EMBASE (OVID: 1988 through October 2009) using combined disease-specific terms (uterine cervix neoplasms/ or cervi:.ti AND cancer:.ti or neoplasms/ or carcinoma:.ti) with treatment-specific term (trachelectomy/). The search was restricted to English or French language and humans. Additionally, Pubmed was searched with terms "cervix", "carcinoma", and "trachelectomy". Reference lists of related articles and recent review articles were also screened for additional citations. RESULTS: The largest data on fertility-sparing procedures in early stage cervical cancer has been reported with radical vaginal trachelectomy (RVT). Other fertility-sparing options have emerged recently, such as radical abdominal trachelectomy (RAT). There have been reports of more conservative methods such as simple trachelectomy or cone biopsy, with or without neoadjuvant chemotherapy. CONCLUSIONS: RVT is now well established as a safe and feasible procedure for this patient population, with low morbidity, recurrence, and mortality rates. The use of RAT in selected patients has increased, in addition to more conservative methods such as simple trachelectomy or cone biopsy, with or without neoadjuvant chemotherapy. Continued research in these areas will determine the safety and feasibility of these potential procedures, which will help give more treatment options for young women with early stage cervical cancers. PMID- 20163851 TI - The influence of nano-scale surface roughness on bacterial adhesion to ultrafine grained titanium. AB - We discuss the effect of extreme grain refinement in the bulk of commercial purity titanium (CP, Grade-2) on bacterial attachment to the mechano-chemically polished surfaces of the material. The ultrafine crystallinity of the bulk was achieved by severe plastic deformation by means of equal channel angular pressing (ECAP). The chemical composition, wettability, surface topography and roughness of titanium surfaces were characterized using X-ray photoelectron spectroscopy (XPS) and water contact angle (WCA) measurements, as well as atomic force microscopy (AFM) with 3D interactive visualization of the titanium surface morphology. It was found that physico-chemical surface characteristics of the as received and the ECAP-modified CP titanium did not differ in any significant way, while the surface roughness at the nano-scale did. Optical profilometry performed on large scanning areas of approximately 225 mum x 300 mum showed that there was no significant difference between the roughness parameters R(a) and R(q) for surfaces in the two conditions, the overall level of roughness being lower for the ECAP-processed one. By contrast, topographic profile analysis at the nano scale by AFM did reveal a difference in these parameters. This difference was sensitive to the size of the scanned surface area. A further two surface roughness parameters, skewness (R(skw)) and kurtosis (R(kur)), were also used to describe the morphology of titanium surfaces. It was found that the bacterial strains used in this study as adsorbates, viz. Staphylococcus aureus CIP 65.8 and Pseudomonas aeruginosa ATCC 9025, showed preference for surfaces of ECAP processed titanium. S. aureus cells were found to have a greater propensity for attachment to surfaces of ECAP-modified titanium, while the attachment of P. aeruginosa, while also showing some preference for the ECAP-processed material, was less sensitive to the ECAP processing. PMID- 20163852 TI - Preparation and characterization of decellularized cornea using high-hydrostatic pressurization for corneal tissue engineering. AB - To prepare acellular corneal scaffold, we used high-hydrostatic pressurization (HHP) to decellularize porcine cornea. The HHP method disrupts cells by hydrostatic pressurization, and then the disrupted cells' components are removed by washing with a cell culture medium. Porcine corneas were hydrostatically pressed at 980 MPa at 10 or 30 degrees C for 10 min to make them opaque. There was no change in the thickness of the corneas immediately after the pressurization, but they swelled during the washing process. The cornea swelling caused by HHP was suppressed when medium containing 3.5% w/v dextran was used. For H-E staining of the cornea decellularized with the HHP method, the complete removal of corneal cells was confirmed. Furthermore, when the corneas were immersed in glycerol for 1 hour, their optical properties were restored to those of native corneas. In an animal study, when acellular porcine corneas were implanted into rabbit cornea, no immune reaction occurred and the turbid corneas became clear. The decellularized corneas obtained through HHP could be useful as a corneal scaffold for tissue regeneration. PMID- 20163853 TI - Folate-PEG coated cationic modified chitosan--cholesterol liposomes for tumor targeted drug delivery. AB - In this paper, a folate-PEG coated polymeric liposome (FPL) formed from octadecyl quaternized lysine modified chitosan (OQLCS) and cholesterol has been prepared successfully. The OQLCS and its derivatives were characterized using (1)H NMR and infrared spectrum analysis. The FPLs properties were extensively studied by dynamic light scattering (DLS), fluorescence spectroscopy, and transmission electron microscopy (TEM). Due to the amphiphilic property and positive zeta potential of OQLCS, the OQLCS and cholesterol can form stable core-shell FPLs with small size (effective diameter: 163.5 nm) and narrow distribution (polydispersity: 0.108) in aqueous solutions. The PLs could form multi-lamellar structure similar to that of traditional liposomes prepared from phosphatidylcholine/cholesterol (PC/Chol). Compared with traditional liposome, calcein-loaded Polymeric Liposome exhibited high encapsulation efficiency in aqueous solution and slow, controlled release under different pH conditions. Most important, in cellular uptake experiment, folate coated FPLs showed significant higher uptake by MCF-7 cells as compared to FPLs without folate and traditional liposomes, because of the folate-receptor mediated endocytosis. The data suggest that the folate-PEG coated polymeric liposomes (FPLs) may be a useful drug delivery system. PMID- 20163854 TI - Polycation/DNA complexes coated with oligonucleotides for gene delivery. AB - Ternary nanoparticles with negatively charged surface were prepared by coating single-stranded oligonucleotides (5'-C(10)A(20)-3') on histidine-conjugated polyallylamine (PAA-HIS)/DNA complexes for gene delivery. Characterization of PAA HIS/DNA/oligonucleotide complexes demonstrated that nanoparticles possessed the negative surface charge -27 mV and size of around 100 nm when the molar ratio of oligonucleotide/PAA-HIS exceeded 1.5. The negatively charged oligonucleotide coated PAA-HIS/DNA complexes could be entirely internalized by the living HeLa cells to exhibit high gene expression with low cytotoxicity and the resistance against erythrocyte agglutination and serum inhibition. Since the gene expression of PAA-HIS/DNA complexes was significantly inhibited by coating other polyanions and oligonucleotides, the ternary PAA-HIS/DNA/deoxyadenosine-rich oligonucleotide complexes were uptaken by specific receptor-mediated process. Additionally, the deposition of a layer of oligonucleotides onto the binary PAA-HIS/DNA complexes could effectively transfect various types of cells including HEK-293, HepG2 and Hs68 cells, indicating the technology of coating specific oligonucleotides on PAA HIS/DNA complexes or other cationic binary DNA complexes might facilitate the use of nanoparticles for safe and efficient gene delivery and eventual therapy. PMID- 20163855 TI - Bactericidal and virucidal ultrathin films assembled layer by layer from polycationic N-alkylated polyethylenimines and polyanions. AB - In this work, we designed contact-killing ionically cross-linked polymeric thin films using Layer-by-Layer (LbL) technology. A polycation, N,N-dodecyl,methyl polyethylenimine, with microbicidal activity was layered with a polyanion, such as poly(acrylic acid), to create LbL films highly effective against both airborne and waterborne Escherichia coli and Staphylococcus aureus (Gram negative and positive bacteria, respectively), as well as influenza A/WSN (H1N1) virus. The dependence of the microbicidal activity on the pH during and post-assembly of LbL film formation, the nature of the polycation and polyanion, the number of layers in the LbL film, and other experimental variables was investigated quantitatively. PMID- 20163856 TI - Review: Sex chromosome evolution and the expression of sex-specific genes in the placenta. AB - Sex chromosomes have a disproportionate influence on health and disease. Both the X and Y are atypical in gene content and activity, as a result of their unique evolutionary trajectory. The X and Y chromosomes originated in a pair of autosomes, and differentiated as the Y chromosome degenerated progressively. The Y contains few active genes and is composed largely of repetitive DNA sequences. Most Y genes have copies on the X from which they evolved; this includes even the sex-determining gene SRY as well as several genes required for spermatogenesis. The X contains a disproportionate number of genes that affect reproduction and brain function (or both). It is also subject to inactivation in females, so that females are mosaics composed of patches of tissue that express only the genes on either the maternally or the paternally derived X chromosome. Several widely expressed genes on the Y chromosome code for male-specific proteins that provoke an immune reaction in females; this HY antigen has a measurable effect on maternal-fetal incompatibility. Imprinted paternal X inactivation in rodent extraembryonic tissues would be expected to mitigate the effect of foreign paternal antigens; however, paternal inactivation seems not to occur in the human placenta. PMID- 20163857 TI - Variations in heavy metal accumulation, growth and yield of rice plants grown at different sewage sludge amendment rates. AB - Use of sewage sludge in agriculture is an alternative disposal technique for this waste. The present field study was conducted to assess the suitability of sewage sludge amendment in soil for rice (Oryza sativa L. cv. Pusa sugandha 3) by evaluating the heavy metal accumulation, growth, biomass and yield responses of plants grown at 0, 3, 4.5, 6, 9, 12 kgm(-2) sewage sludge amendment (SSA) rate. Sewage sludge amendment modified the physico-chemical properties of soil, thus increasing the availability of heavy metals in soil and consequently with higher accumulation in plant parts. Root length decreased, whereas shoot length, number of leaves, leaf area and total biomass increased significantly when grown under various SSA rates. Yield of rice increased by 60%, 111%, 125%, 134% and 137% at 3, 4.5, 6, 9 and 12 kgm(-2) SSA, respectively, as compared to those grown in unamended soil. Sewage sludge amendment rates above 4.5 kgm(-2) though increased the yield of rice, but caused risk of food chain contamination as concentrations of Ni and Cd in rice grains were found to be above the Indian safe limits (1.5 mgkg(-1)) of human consumption above 4.5 kgm(-2) SSA and of Pb (2.5 mgkg(-1)) above 6 kgm(-2) SSA. Since aboveground parts of the rice also showed higher concentration than the permissible levels of Ni, Cd and Pb at 4.5 kgm(-2) SSA rate, it cannot be used as fodder. The rice husk may be used as bioresource for energy production. Efforts should be made to treat the effluents from small scale industries before discharge into the sewerage system. PMID- 20163858 TI - Theory underlying a national teacher evaluation program. AB - The paper describes a study conducted to explicate the multiple theories underlying Chile's national teacher evaluation program. These theories will serve as the basis for evaluating the intended consequences of this evaluation system, while not losing sight of emerging unintended consequences. We first analyzed legal and policy documents and then interviewed fourteen representatives of the four stakeholder groups involved in the program's design and implementation, in order to gain insight into their respective conceptions of the program's functioning and intended effects. The results show that, as to be expected and despite the long and difficult negotiation process that preceded implementation of this program, multiple political stakeholders still view the program's intended effects differently. However, there was substantial overlap regarding a number of intended effects, such as building the capacity of, and triggering change in, teachers with shortcomings, and informing the selection of new teachers and facilitating the exit of unsatisfactory teachers from the system. It was difficult to get interviewees to talk about how exactly these intended effects are supposed to be achieved. The paper draws conclusions regarding theory elaboration process involving multiple stakeholders in a highly political context. PMID- 20163859 TI - 2-(4-Chlorophenyl)benzo-1,4-quinone induced ROS-signaling inhibits proliferation in human non-malignant prostate epithelial cells. AB - Polychlorinated biphenyls (PCBs) and their metabolites are environmental chemical contaminants which can produce reactive oxygen species (ROS) by auto-oxidation of di-hydroxy PCBs as well as the reduction of quinones and redox-cycling. We investigate the hypothesis that 2-(4-chlorophenyl)benzo-1,4-quinone (4-Cl-BQ), a metabolite of 4-chlorobiphenyl (PCB3), induced ROS-signaling inhibits cellular proliferation. Monolayer cultures of exponentially growing asynchronous human non malignant prostate epithelial cells (RWPE-1) were incubated with 0-6 MUM of 4-Cl BQ and harvested at the end of 72 h of incubation to assess antioxidant enzyme expression, cellular ROS levels, cell growth, and cell cycle phase distributions. 4-Cl-BQ decreased manganese superoxide dismutase (MnSOD) activity, protein, and mRNA levels. 4-Cl-BQ treatment increased dihydroethidium (DHE) fluorescence, which was suppressed in cells pretreated with polyethylene glycol conjugated superoxide dismutase (PEG-SOD). The increase in ROS levels was associated with a decrease in cell growth, and an increase in the percentage of S-phase cells. These effects were suppressed in cells pretreated with PEG-SOD. 4-Cl-BQ treatment did not change the protein levels of phosphorylated H2AX at the end of 72 h of incubation, suggesting that the inhibition in cell growth and accumulation of cells in S-phase at the end of the treatments were probably not due to 4-Cl-BQ induced DNA double strand break. These results demonstrate that MnSOD activity and ROS-signaling perturb proliferation in 4-Cl-BQ treated in vitro cultures of human prostate cells. PMID- 20163860 TI - IntraLase-enabled astigmatic keratotomy for post-keratoplasty astigmatism: on axis vector analysis. AB - PURPOSE: To determine the refractive predictability, stability, efficacy, and complication rate of femtosecond laser-enabled astigmatic keratotomy for post keratoplasty astigmatism. DESIGN: A retrospective case series (pilot study). PARTICIPANTS: Thirty-seven eyes of 34 patients. METHODS: All eyes underwent IntraLase-enabled astigmatic keratotomy for high astigmatism (>5 diopters [D]) after penetrating keratoplasty. MAIN OUTCOME MEASURES: Uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), manifest refraction, higher-order aberrations, and complications. RESULTS: Mean follow-up was for 7.2 months. Uncorrected visual acuity improved from a mean of 1.08+/-0.34 logarithm of the minimum angle of resolution preoperatively to a mean of 0.80+/-0.42 postoperatively (P=0.0016). Best-corrected visual acuity improved from a mean of 0.45+/-0.27 preoperatively to 0.37+/-0.27 postoperatively (P=0.018). The defocus equivalent was significantly reduced by more than 1 D (P=0.025). The value of absolute astigmatism was reduced from 7.46+/-2.70 D preoperatively to 4.77+/-3.29 D postoperatively (P=0.0001). Higher-order aberrations were significantly increased. The efficacy index was 0.6+/-0.6. There were no cases of perforation, wound dehiscence, or infectious keratitis. Three eyes (8%) experienced an episode of graft rejection. Overcorrection occurred in 9 eyes (24%). CONCLUSIONS: IntraLase-enabled astigmatic keratotomy is an effective treatment for high astigmatism after penetrating keratoplasty with an encouraging refractive predictability. Future studies may help refine the treatment parameters required to achieve reduction of cylinder with greater accuracy. PMID- 20163861 TI - Combined confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography imaging of reticular drusen associated with age-related macular degeneration. AB - PURPOSE: To determine microstructural retinal alterations associated with reticular drusen in patients with age-related macular degeneration (AMD) using high-resolution in vivo imaging techniques. DESIGN: Retrospective case series. PARTICIPANTS: A total of 116 eyes of 78 AMD patients with reticular drusen were examined. METHODS: Simultaneous spectral-domain optical coherence tomography (SD OCT; 870 nm, 40,000 A-scans/sec) and near-infrared confocal scanning laser ophthalmoscopy (cSLO; 830 nm) were performed using a combined imaging instrument (Spectralis HRA+OCT, Heidelberg Engineering, Heidelberg, Germany). Individual anatomic layers in SD OCT were evaluated and correlated to en face cSLO fundus imaging. MAIN OUTCOME MEASURES: Description of corresponding structural changes in areas of reticular drusen. RESULTS: Reticular drusen appeared as an interlacing network of round or oval irregularities by near-infrared cSLO reflectance imaging. On SD OCT, reticular drusen corresponded to marked changes at a level anterior to the retinal pigment epithelium (RPE) and Bruch's membrane complex to the interface of inner and outer photoreceptor segment layer (IPRL). Individual reticular drusen correlated to focal elevations of the IPRL, accumulation of highly reflective material below the IPRL, and an increased distance between the IPRL and RPE. CONCLUSIONS: The findings indicate that the morphologic substrate of reticular drusen is the accumulation of highly reflective material within outer retinal layers anterior to the RPE. This is in contrast to previous assumptions pointing toward a localization of abnormal material at the level of the inner choroid. Although the origin of the material is unknown, the results may indicate a role for primary abnormalities in the neurosensory retina. Because reticular drusen represent high-risk markers for the progression of AMD, their ready identification is relevant both for natural history studies as well as for interventional trials. PMID- 20163862 TI - Vaulting of myopic and toric Implantable Collamer Lenses during accommodation measured with Visante optical coherence tomography. AB - PURPOSE: To study changes in vaulting of myopic and toric Implantable Collamer Lenses (ICLs) version 4 during accommodation with Visante optical coherence tomography (OCT), and analyze the relationship between vaulting and anterior subcapsular opacification. DESIGN: Cross-sectional study. PARTICIPANTS: Seventy seven eyes of 77 myopic patients were examined after implantation with an ICL (48 myopic, 29 toric). The median follow-up time was 63 months (range, 10-84). METHODS: The distance between the posterior ICL surface and the anterior surface of the crystalline lens was measured in the nonaccommodative state and during accommodation with Visante OCT. The lenses were examined for opacification using slit-lamp microscopy. MAIN OUTCOME MEASURES: The distance between the ICL and the anterior surface of the crystalline lens. RESULTS: At baseline, the mean distance between the ICL and the crystalline lens was 0.31+/-0.19 mm and during accommodation 0.31+/-0.26 mm; the difference did not reach significance (P = 0.77). The distance at baseline was significantly (P = 0.01) less in older patients and significantly (P = 0.04) greater in patients with a toric ICL. Contact was observed at baseline or during accommodation in 12 eyes; there was a significantly lower incidence of contact in eyes implanted with a toric ICL (P = 0.03). Anterior subcapsular opacification developed in 10 eyes, in 5 of these the ICL touched the crystalline lens. CONCLUSIONS: Anterior subcapsular opacification developed in 13.0% of eyes. We found no difference in vaulting of the ICL at baseline and during accommodation. There was contact between the ICL and the crystalline lens in 15.6% of the eyes. The association between anterior subcapsular opacification and contact was significant (P = 0.004). PMID- 20163863 TI - Prevalence of refractive errors and associated risk factors in subjects with type 2 diabetes mellitus SN-DREAMS, report 18. AB - PURPOSE: To report the prevalence of refractive errors and the associated risk factors in subjects with type 2 diabetes mellitus from an urban Indian population. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: One thousand eighty participants selected from a pool of 1414 subjects with diabetes. METHODS: A population-based sample of 1414 persons (age >40 years) with diabetes (identified as per the World Health Organization criteria) underwent a comprehensive eye examination, including objective and subjective refractions. MAIN OUTCOME MEASURES: One thousand eighty subjects who were phakic in the right eye with best corrected visual acuity of > or =20/40 were included in the analysis for prevalence of refractive errors. Univariate and multivariate analyses were done to find out the independent risk factors associated with the refractive errors. RESULTS: The mean refraction was +0.20+/-1.72, and the Median, +0.25 diopters. The prevalence of emmetropia (spherical equivalent [SE], -0.50 to +0.50 diopter sphere [DS]) was 39.26%. The prevalence of myopia (SE <-0.50 DS), high myopia (SE <-5.00 DS), hyperopia (SE >+0.50 DS), and astigmatism (SE <-0.50 cyl) was 19.4%, 1.6%, 39.7%, and 47.4%, respectively. The advancing age was an important risk factor for the three refractive errors: for myopia, odds ratio (OR; 95% confidence interval [CI] 4.06 [1.74-9.50]; for hyperopia, OR [95% CI] 5.85 [2.56-13.39]; and for astigmatism, OR [95% CI] 2.51 [1.34-4.71]). Poor glycemic control was associated with myopia (OR [95% CI] 4.15 [1.44-11.92]) and astigmatism (OR [95% CI] 2.01 [1.04-3.88]). Female gender was associated with hyperopia alone) OR [95% CI] 2.00 [1.42-2.82]. CONCLUSIONS: The present population-based study from urban India noted a high prevalence of refractive errors (60%) among diabetic subjects >40 years old; the prevalence of astigmatism (47%) was higher than hyperopia (40%) or myopia (20%). PMID- 20163864 TI - Eyelash growth from application of bimatoprost in gel suspension to the base of the eyelashes. AB - OBJECTIVE: To determine whether bimatoprost (Lumigan, Allergan Inc., Irvine, CA) causes increased lash length when used in gel suspension applied to the base of the eyelashes. DESIGN: Randomized controlled trial. PARTICIPANTS: Nineteen subjects were enrolled. METHODS: Subjects recruited from the Bascom Palmer Eye Institute were screened, and those who met inclusion criteria were enrolled. Each participant received 2 vials of gel suspension, which contained bimatoprost and normal saline, respectively, each mixed 1:1 with Gonak gel (Akorn Inc., Lake Forest, IL) and labeled "right eye" and "left eye" according to randomization. The suspension was applied to the upper eyelid eyelashes every evening on the designated eye for 6 weeks. MAIN OUTCOME MEASURES: Lash length was measured with a caliper at enrollment, at weekly intervals during the application of the gel, and at 1 and 3 months after discontinuation of its use. Visual acuity, ocular symptoms, intraocular pressure, and photographs were documented at these same intervals. RESULTS: The mean eyelash growth from baseline in the bimatoprost group was 2.0 mm versus a mean of 1.1 mm in the placebo group, which was a statistically significant difference (P=0.009). The average intraocular pressure decreased equally in both groups (2 mmHg). No change in visual acuity or iris discoloration was noted in any of the subjects. CONCLUSIONS: Our data showed an increase in eyelash length with the use of bimatoprost in gel suspension, suggesting the product's eyelash-lengthening properties. PMID- 20163866 TI - Long-term outcomes of autolimbal and allolimbal transplants. AB - OBJECTIVE: To evaluate the long-term results of limbal stem cell transplantation (LSCT) in patients with ocular surface (OS) disease. DESIGN: Retrospective consecutive cohort study. PARTICIPANTS: Case records of 27 eyes of 26 patients (19 males and 7 females) who presented with unilateral or bilateral total limbal stem cell deficiency and treated at the Department of Ophthalmology were examined. METHODS: All eyes that were treated with LSCT and that had at least 1 year follow-up were included. There were 12 autolimbal and 15 allolimbal transplants. Of the latter, 9 were from living related donors (LRDs) and 6 were from cadaver donors (CDs). A total of 9 eyes underwent LSCT and penetrating keratoplasty (PKP), and 11 eyes underwent LSCT and amniotic membrane transplantation (AMT). Cataract extraction with implant was carried out in 4 eyes. Some eyes had more than 1 associated procedure. Nine eyes had LSCT only. Patients with allolimbal transplants also received systemic immunosuppression. MAIN OUTCOME MEASURES: Surgical success was measured by the duration for which a healthy corneal epithelium was maintained after LSCT. Visual success was measured by improvement in visual acuity (VA) in the operated eye during the follow-up period. RESULTS: The follow-up period of all eyes was up to 119 months (mean 38+/ 35.9 months, median 24 months). Survival of LSCT, as determined by the maintenance of healthy corneal epithelium until last follow-up, was seen in 22 eyes (82%). The surface failed within 3 months in 4 eyes (1 with LRD and 3 with CD) and after 43 months in the fifth patient (with CD). Subsequently, 6 eyes required PKP to achieve their maximum visual potential. The VA (measured in decimal fraction) improved over a period of 1 year from a mean of 0.121 (standard deviation [SD] 0.184) preoperatively to a mean of 0.313 (SD 0.348) postoperatively. CONCLUSIONS: Limbal stem cell transplantation, in isolation or in combination with other procedures, is effective in improving corneal clarity and vision. Autografts have the best long-term outcome followed by LRD allografts. Cadaver donor allografts have a comparatively poor outcome. This may partly reflect the difference in case mix between unilateral and bilateral OS conditions. PMID- 20163865 TI - Use of ultra-high-resolution optical coherence tomography to detect in vivo characteristics of Descemet's membrane in Fuchs' dystrophy. AB - PURPOSE: To demonstrate the capability of ultra-high-resolution (UHR) anterior segment optical coherence tomography (OCT) to image Descemet's membrane (DM) and measure its thickness in vivo. (2) To evaluate the use of DM characteristics and thickness in the diagnosis of Fuchs' dystrophy. DESIGN: Case-control study. PARTICIPANTS: Twenty eyes of 12 Fuchs' dystrophy patients, 20 eyes of 13 young normal, and 20 eyes of 15 elderly normal subjects. METHODS: Subjects were imaged using novel, custom-built UHR-OCT. Images were used to describe the characteristics of DM. Custom-made software was used to measure DM thickness and central corneal thickness (CCT). Specimens of DM obtained from Fuchs' dystrophy patients who underwent endothelial keratoplasty (EK) were histopathologically examined. Regression analyses were used to assess the correlation of DM thickness measured by UHR-OCT in vivo and by light microscopy and to determine the intergroup correlations between age, CCT, and DM thickness. MAIN OUTCOME MEASURES: We assessed DM characteristics and thickness, CCT, and age. RESULTS: Using UHR-OCT, the DM seemed in normal young subjects as a single, opaque, smooth line and in normal elderly subjects as a band of 2 smooth opaque lines with a translucent space in between. In Fuchs' dystrophy, DM appeared as a thickened band of 2 opaque lines; the anterior line was smooth whereas the posterior line had a wavy and irregular appearance with areas of localized thickenings. The DM thickness measured in vivo by UHR-OCT correlated significantly with that measured by light microscopy in 5 Fuchs' dystrophy eyes that underwent EK. The average central thicknesses of DM in normal young, in normal elderly and in Fuchs' dystrophy eyes were 10+/-3, 16+/-2, and 34+/-11 microm, respectively (P<0.001). There was a significant correlation between age and DM thickness only in normal groups. In Fuchs' dystrophy patients, there was a significant correlation between CCT and DM thickness that was not significant for normal groups. CONCLUSIONS: Ultra-high-resolution OCT is an innovative technique for the in vivo imaging of DM. Determining DM characteristics and thickness by UHR-OCT could be a new approach for the diagnosis of Fuchs' dystrophy. PMID- 20163867 TI - Reduced application time for prophylactic mitomycin C in photorefractive keratectomy. AB - OBJECTIVE: To determine whether the duration of mitomycin C (MMC) 0.02% application affects visual outcome or the incidence of subepithelial haze in patients undergoing photorefractive keratectomy (PRK) with prophylactic administration of MMC. DESIGN: Retrospective, comparative case series. PARTICIPANTS: Two hundred sixty-nine eyes undergoing PRK. METHODS: This was a retrospective comparative case series that included 269 eyes that underwent PRK with prophylactic MMC application for 120 seconds (group 1, n = 74), 60 seconds (group 2, n = 36), or 12 seconds (group 3, n = 159). The mean preoperative spherical equivalent was -6.49 diopters (D) in group 1, -6.77 D in group 2, and 7.10 D in group 3. Photorefractive keratectomy was performed using a modified nomogram. All eyes received a single intraoperative application of MMC (0.02%) after laser ablation for the above specified durations. MAIN OUTCOME MEASURES: Best-corrected visual acuity and corneal haze score. RESULTS: Best-corrected visual acuity was 20/23 in group 1, 20/20 in group 2, and 20/21 in group 3. The mean haze score+/-standard deviation (scale, 0.00-4.00) was 0.11+/-0.31 in group 1, 0.14+/-0.28 in group 2, and 0.07+/-0.20 in group 3 throughout a mean follow-up of 31 months in group 1, 16 months in group 2, and 10 months in group 3. No eyes had a haze score of more than 1.00. CONCLUSIONS: There was no statistically significant difference in postoperative best-corrected visual acuity or haze scores among the 3 groups. Administration of prophylactic MMC 0.02% for 12 seconds after PRK seems to be equally efficacious for haze prophylaxis when compared with longer application times of 60 and 120 seconds. PMID- 20163868 TI - Evaluation of morning glory syndrome with spectral optical coherence tomography and echography. AB - PURPOSE: To evaluate eyes affected by morning glory syndrome (MGS) with spectral domain optical coherence tomography (SD OCT) and echography. DESIGN: Prospective case series. PARTICIPANTS: Nineteen patients (22 eyes) with MGS observed at the Eye Department, University of Naples Federico II, Naples, Italy. METHODS: All patients underwent a complete ophthalmologic examination that included best correct visual acuity, fundus photography, and echography. Nine patients underwent SD OCT and high-frequency B-scan echography (20 MHz). MAIN OUTCOME MEASURES: Spectral-domain optical coherence tomography and echographic findings in MGS. RESULTS: Spectral-domain optical coherence tomography revealed retinal detachment in the conus area of 5 eyes: 4 with noncontractile MGS (NCMGS) and 1 with contractile MGS (CMGS). There was evidence of a retinal break in only 2 cases. All 5 eyes had an abnormal communication between the subarachnoid space and the subretinal space. Spectral-domain optical coherence tomography did not reveal differences between CMGS and NCMGS. Echographic examination did not reveal any anatomic abnormalities of the optic nerve or orbit. CONCLUSIONS: Spectral domain optical coherence tomography provides more information than echography about the posterior pole, whereas echographic examination is the only technique that can confirm the anatomic integrity of the optic nerve in the orbital wall. Retinal detachment in MGS generally is ascribed to abnormal communication between the subretinal and subarachnoid or vitreous compartments. These data suggest that myopialike retinal detachment without a retinal break may result from tissue stretching around the peripapillary conus. PMID- 20163869 TI - A randomized trial comparing Bangerter filters and patching for the treatment of moderate amblyopia in children. AB - OBJECTIVE: To determine whether visual acuity improvement with Bangerter filters is similar to improvement with patching as initial therapy for children with moderate amblyopia. DESIGN: Randomized, clinical trial. PARTICIPANTS: We enrolled 186 children, 3 to <10 years old, with moderate amblyopia (20/40-20/80). METHODS: Children were randomly assigned to receive either daily patching or to use a Bangerter filter on the spectacle lens in front of the fellow eye. Study visits were scheduled at 6, 12, 18, and 24 weeks. MAIN OUTCOME MEASURES: Visual acuity in amblyopic eyes at 24 weeks. RESULTS: At 24 weeks, amblyopic eye improvement averaged 1.9 lines in the Bangerter group and 2.3 lines in the patching group (difference in mean visual acuities between groups adjusted for baseline acuity = 0.38 line). The upper limit of a 1-sided 95% confidence interval was 0.76 line, which slightly exceeded a prespecified noninferiority limit of <0.75 line. Similar percentages of subjects in each group improved > or =3 lines (Bangerter group 38% vs patching group 35%; P = 0.61) or had > or =20/25 amblyopic eye acuity (36% vs 31%, respectively; P = 0.86). There was a lower treatment burden in the Bangerter group as measured with the Amblyopia Treatment Index. With Bangerter filters, neither a fixation switch to the amblyopic eye nor induced blurring in the fellow eye to worse than that of the amblyopic eye was required for visual acuity improvement. CONCLUSIONS: Because the average difference in visual acuity improvement between Bangerter filters and patching was less than half a line, and there was lower burden of treatment on the child and family, Bangerter filter treatment is a reasonable option to consider for initial treatment of moderate amblyopia. PMID- 20163870 TI - Patients with Sjogren-Larsson syndrome lack macular pigment. AB - PURPOSE: Sjogren-Larsson syndrome (SLS), an autosomal recessive hereditary disorder with congenital ichthyosis, spastic diplegia or tetraplegia, and mental retardation, reveals a characteristic macular dystrophy with intraretinal crystals and foveal pseudocysts. Ophthalmic symptoms in SLS are reduced visual acuity and photophobia. This article reports the deficiency of macular pigment as a novel finding in this peculiar, congenital maculopathy. DESIGN: Cross sectional, observational case study. PARTICIPANTS: Patients with clinically and genetically proven SLS. METHODS: Besides general ophthalmologic examination, 2 different methods were used, fundus autofluorescence (FAF) and fundus reflectometry with the macular pigment reflectometer (MPR), for measuring macular pigment (MP). MAIN OUTCOME MEASURES: Distribution profiles and quantity of MP in eyes of SLS patients. RESULTS: Twenty-eight eyes of 14 patients were included. The technique to measure MP depended on the ability of the mentally handicapped patients to cooperate. Fundus autofluorescence images providing qualitative estimates were obtained from 9 eyes of 5 patients, and MPR measures providing quantitative estimates were obtained from 19 eyes of 10 patients. Fundus autofluorescence images of SLS patients lacked the typical attenuation of macular FAF signal expected in normal eyes. Mean foveal MP levels measured by MPR showed significantly lower values in SLS patients (0.10+/-0.07) than in healthy individuals (0.69+/-0.17; P<0.001, Student t test). CONCLUSIONS: The group of SLS patients studied here had significantly reduced levels of foveal MP. The crystalline macular dystrophy in SLS seems to be the first known disease with a genetically caused deficiency of MP. PMID- 20163871 TI - Benign unilateral apraxia of eyelid opening. AB - PURPOSE: To report a case series of patients with benign unilateral apraxia of eyelid opening. DESIGN: Retrospective, observational case series. PARTICIPANTS: Five patients with unilateral transient ptosis after sleep from a single neuro ophthalmology practice. METHODS: A list of 208 patients with ptosis seen at a single neuro-ophthalmology practice was drawn through the computer coding system. Transcribed reports of the outpatient visits of these patients were reviewed from this database to identify the final diagnoses. All patients with a diagnosis of ptosis resulting from underlying neurologic, myopathic, or neuromuscular problems were excluded. Five patients with ptosis that occurred on awakening and resolved after mechanical eyelid elevation were included. MAIN OUTCOME MEASURES: The main outcome measure was identifying and defining a group of patients with a benign clinical entity causing ptosis that can cause a clinical dilemma. RESULTS: Three of 5 patients were women. Ages ranged from 49 to 71 years. All patients experienced complete ptosis only on awakening after sleep. The ptosis was unilateral and did not recur after manual elevation of the eyelid. None of the patients had any underlying neurologic problem that could be contributory and were thoroughly investigated with neuroimaging and laboratory testing, including acetylcholine receptor antibodies. Examination revealed no ocular cause for the ptosis in each patient. In all patients, follow-up telephone reports noted no subsequent condition that could be responsible for ptosis. CONCLUSIONS: The identification and diagnosis of this form of isolated ptosis, which herein is termed benign unilateral apraxia of eyelid opening, is of importance in that extensive evaluation is not warranted unless there are other neurologic or ocular findings. PMID- 20163872 TI - The Central Retinal Vein Bypass Study: a trial of laser-induced chorioretinal venous anastomosis for central retinal vein occlusion. AB - PURPOSE: To evaluate the effectiveness of a laser-induced chorioretinal venous anastomosis (L-CRA) as a treatment for nonischemic central retinal vein occlusion (CRVO). DESIGN: Prospective, randomized, controlled, multicenter clinical trial. PARTICIPANTS: A total of 113 consecutive patients with a nonischemic CRVO of >3 months' duration and visual acuity of < or =20/50. METHODS: Patients were randomized to L-CRA (58 patients) or conventional care (55 patients). They underwent standardized retinal photography, fluorescein angiography, and ophthalmic examinations, together with standardized assessments of best-corrected visual acuity, performed by masked visual acuity assessors using Early Treatment Diabetic Retinopathy Study protocols. Analysis was performed by intention-to treat. MAIN OUTCOME MEASURES: The primary outcome measure was change in visual acuity at 18 months. Secondary outcomes were progression of retinal ischemia and rates of adverse events. RESULTS: A total of 53 control patients and 55 treatment patients completed the study. The 2 groups were comparable for age, age- and gender-adjusted mean visual acuity, and most other parameters. In the treated group of 55 patients, 42 (76.4%) developed an L-CRA. Over the 18-month follow-up period, treated eyes had an 8.3 letter mean improvement from baseline compared with control eyes (P = 0.03). Treated eyes that developed a functional L-CRA achieved an 11.7 letter mean improvement from baseline over the control group after 18 months (P = 0.004). Conversion to the ischemic CRVO category occurred in 20.8% of control eyes and in 9.6% of treated eyes overall (P = 0.33). Of the treated group who developed an L-CRA where the retinal ischemia was due to progression of the CRVO, 4.9% progressed to the ischemic category (P = 0.03). Neovascularization developed at the site of the L-CRA in 10 of 55 treated eyes (18.2%). Vitrectomy surgery was required by 5 of 55 treated eyes (9.1%) because of macular traction or nonresolving vitreous hemorrhage. CONCLUSIONS: Chorioretinal venous anastomosis was created in 76.4% of eyes with nonischemic CRVO in this study. Eyes that developed an anastomosis had a significant improvement (11.7 letters) in final visual acuity after 18 months, compared with eyes in the control group (P = 0.004). Complications were managed successfully with careful follow-up and early intervention. PMID- 20163873 TI - Depression in fathers in the postnatal period: assessment of the Edinburgh Postnatal Depression Scale as a screening measure. AB - BACKGROUND: Postnatal depression commonly affects women after the birth of a child, and is associated with an increased risk of adverse outcomes for their children. A wide variety of measures have been used to screen for depression in the postnatal period but little research has investigated such measures with men. However depression can also affect men at this time, and this is associated with an independently increased risk of adverse child outcomes. The present study aimed to determine whether a reliable cut off point for the Edinburgh Postnatal Depression Scale (EPDS) can be established to screen fathers. METHOD: A sample of fathers was sent the EPDS at 7 weeks after the birth of their child. A structured clinical interview was conducted with 192 men to determine whether they were suffering from depression. RESULTS: Fathers with depression scored significantly higher on the EPDS than non-depressed fathers. A score of greater than 10 was found to be the optimal cut off point for screening for depression, with a sensitivity of 89.5% and a specificity of 78.2%. LIMITATIONS: The relatively modest participation rate means the results may not be fully generalisable to the whole population. CONCLUSION: The EPDS is shown to have reasonable sensitivity and specificity at a cut off score of over 10. The study shows that it is possible to screen fathers for depression in the postnatal period and it may be valuable to administer this measure to new fathers. PMID- 20163874 TI - Predictors of mortality in patients with serious mental illness and co-occurring type 2 diabetes. AB - Persons with serious mental illness (SMI) have higher rates of chronic medical conditions such as type 2 diabetes and mortality than the general population. We assessed demographic and health related factors in the prediction of all-cause mortality among SMI patients with diabetes and a comparison group of diabetic patients without SMI. From 1999 to 2002, 201 patients with type 2 diabetes and SMI were recruited from community mental health centers and 99 persons with type 2 diabetes and no identified mental illness were recruited from nearby primary clinics. Deaths over an average seven-year period after baseline assessment were identified using the Social Security Administration's Death Master File. Twenty one percent in each group died over follow-up. Age, smoking status, duration of diabetes, and diabetes-related hospitalization in the 6months prior to baseline assessment predicted mortality in all patients. Among the non-SMI patients, those who were prescribed insulin had over a four-fold greater odds of mortality whereas this association was not found in the SMI patients. Diabetes likely contributes to mortality in persons with SMI. Providers need to be especially vigilant regarding mortality risk when patients require hospitalization for diabetes and as their patients age. Smoking cessation should also be aggressively promoted. PMID- 20163875 TI - Asocial beliefs as predictors of asocial behavior in schizophrenia. AB - Poor social and vocational outcomes have long been observed in schizophrenia, and therapeutic outcomes have been modest. Most studies have identified neurocognition and emotion perception as important contributors to social functioning. Recent research has suggested that personal beliefs, attitudes, and expectancies contribute to negative symptoms. However, the impact of specific beliefs and expectancies on social withdrawal in schizophrenia has not been examined. The present study explored: 1. whether asocial beliefs made a significant contribution to social functioning after accounting for neurocognitive performance and emotion perception; and, 2. whether asocial beliefs predicted asocial behavior in a longitudinal design. 123 outpatients diagnosed with schizophrenia or schizoaffective disorder completed tests of neurocognitive performance, emotion perception, asocial beliefs, symptomatology, and functional outcome. A subset of 13 outpatients was retested one year after the initial assessment. Hierarchical regression indicated that asocial beliefs accounted for 18% of the variability in social functioning. Depression and negative symptoms explained another 9% of the dispersion. Contrary to expectations, neurocognition and emotion perception accounted for less than 1% of the variance. In the longitudinal study, baseline asocial beliefs predicted asocial behavior one year later. Asocial beliefs predict poor social functioning in schizophrenia, and may be modifiable by psychological interventions. PMID- 20163876 TI - Comorbidity of obsessive-compulsive disorder with obsessive-compulsive personality disorder: Does it imply a specific subtype of obsessive-compulsive disorder? AB - The present study examined whether the comorbidity of obsessive-compulsive personality disorder (OCPD) and obsessive-compulsive disorder (OCD) constitute a specific subtype of OCD. The study sample consisted of 146 consecutive outpatients with a DSM-IV diagnosis of OCD. Diagnoses were established using MINI, IPDE, YBOCS and YBOCS-SC. OCD patients with comorbid OCPD were compared with OCD patients without OCPD on various sociodemographic and clinical variables. Almost one third of the OCD subjects met criteria for comorbid OCPD. OCD+OCPD patients had a significantly earlier age at onset of initial OC symptoms, earlier age at onset of OCD and more obsessions and compulsions than pure obsessions compared to the patients with OCDOCPD. OCD+OCPD patients also had a higher rate of comorbidity with avoidant personality disorder and showed more impairment in global functioning. There were not differences between the two sub groups on severity of OCD symptoms and also on type of OCD onset. Our results indicate that the comorbidity of OCD with OCPD is associated with a number of specific clinical characteristics of OCD. These findings in conjunction with of current clinical, family and genetic studies provide some initial evidence that OCD comorbid with OCPD constitute a specific subtype of OCD. PMID- 20163877 TI - Effect of carbamylated erythropoietin on major histocompatibility complex expression and neural differentiation of human neural stem cells. AB - The expression of major histocompatibility complex (MHC) on human neural stem cells (hNSCs) is tightly related to the fate of these cells in transplantation, therefore strategies to relieve rejection and promote graft survival are necessary to be applied. This study investigated the effect of carbamylated erythropoietin (CEPO) on MHC expression and differentiation of hNSCs with or without IFN-gamma incubation. Results showed that low levels of MHC molecules were expressed on hNSCs and increased by IFN-gamma. CEPO enhanced MHC-I antigens in both proliferative and differentiated hNSCs, but decreased MHC-II antigens in differentiated hNSCs and those cells exposed to IFN-gamma. Furthermore, CEPO promoted neural differentiation of hNSCs and outgrowth of neurites. Western blot analysis revealed activation of Stat3, Stat5 and Akt during these processes. These results suggest that CEPO may have immunoregulatory function in hNSCs besides its neuroprotection. PMID- 20163878 TI - Reduction of cell proliferation and potentiation of Fas-induced apoptosis by the selective kappa-opioid receptor agonist U50 488 in the multiple myeloma LP-1 cells. AB - As opioid receptors modulate proliferation and apoptosis of immune cells, we hypothesized that they could reduce malignant haematopoietic cells. After screening, we selected the human multiple myeloma LP-1 cells which express mu- (MOP-) and kappa-opioid receptors (KOP-R). U50 488 produces a modest but significant decrease in viability associated with an arrest in the G0/G1 phase, but not antagonized by NorBNI and not associated with modulation of p21(Cip1), p27(Kip1) or p53 expression. In contrast, no effect was observed with dynorphin, U69 593 and morphine. In conclusion, the anti-proliferative effects of U50 488 are not mediated by KOP-R in the LP-1 cells. PMID- 20163879 TI - Treatment patterns of pediatric nontuberculous mycobacterial (NTM) cervical lymphadenitis as reported by nationwide surveys of pediatric otolaryngology and infectious disease societies. AB - OBJECTIVE: To describe physician diagnostic and therapeutic strategies for pediatric nontuberculous mycobacterial (NTM) lymphadenitis, a disease for which surgical excision is recommended. METHODS: We surveyed members of the Infectious Diseases Society of America Emerging Infections Network (EIN) and the American Society of Pediatric Otolaryngology (ASPO). We asked them to report clinical and microbiologic details of recent cases of NTM lymphadenitis seen in their practices. RESULTS: 200 physicians reported a total of 277 NTM lymphadenitis cases. Cervical lymph nodes (84%) were most frequently involved, and a majority of patients were non-Hispanic white (62%) males (54%) with median age 3.0 years. Tissue culture (61%) or polymerase chain reaction (12%) was utilized most frequently to confirm NTM etiology. In most (59%) cases, an etiologic organism was not identified. In cases, where an NTM organism isolate was identified, Mycobacterium avium complex (n=82, 72%) was the most common. Surgical excision followed by adjunctive antibiotic therapy was favored in the majority (59%) of cases where a treatment method was reported. The use of surgical excision alone or antibiotic therapy alone was reported respectively in 24% and 17% of cases. Antibiotics were prescribed without diagnostic confirmation of infectious organisms in 28% of cases. CONCLUSION: Pediatric otolaryngologists and infectious disease specialists frequently treat cervical lymphadenitis empirically as NTM disease without bacteriologic confirmation. Antibiotic therapy is frequently employed with or without surgical excision. PMID- 20163880 TI - Laser arytenoidectomy in the management of bilateral vocal cord paralysis in children. AB - OBJECTIVE: To analyse the efficacy of CO(2) laser arytenoidectomy in the management of bilateral vocal cord paralysis in children. METHODS: Retrospective series of 17 patients who underwent laser arytenoidectomy for bilateral vocal cord between 1995 and 2008 in a tertiary care institution. All patients had bilateral laryngeal paralysis, in isolation (n=5) or associated with concomitant airway conditions (n=12). All cases had anterior prolapse of the arytenoids with partial obstruction of the airway on inspiration. 12/17 patients (70.5%) were tracheotomy-dependant, 2/17 were in-extubatable, and 3/17 had severe airway limitation, effort dyspnea and poor sleep pattern. Main outcome measures were decannulation rate for patients with tracheotomy, occurrence of aspiration and quality of voice. RESULTS: The mean age was 2.8 years old. 9/12 patients with tracheotomy (75%) were decannulated with a median delay of 2 months (2 days to 18 months). Both of the intubated patients were extubated with a median delay of 36h. One of the decannulated patients who re-presented with a residual dyspnea after the arytenoidectomy was improved by a further laser cordotomy. 2/17 patients (11.7%) had post-operative persistent aspirations (with pneumopathies in one case), 5/17 patients were dysphonic, 3 improved with speech therapy and 2 with intracordal lipoinjection. CONCLUSIONS: Laser arytenoidectomy is effective for improving the breathing in children presenting with a bilateral vocal fold paralysis associated with obstructive arytenoid prolapse. Results are good as a first-line surgery or following laryngo-tracheal surgery. Voice outcomes are satisfactory. However, aspiration is a rare complication. PMID- 20163881 TI - Exploration of the relationships among medical health history variables and aspiration. AB - OBJECTIVES: (1) Determine the relationships among a family's specific answers to health history questions and their child's risk for aspiration as determined by a swallow study. (2) Identify key factors which may predict a child's risk for aspiration. METHODS: Answers to questions and results of Functional Endoscopic Evaluation of Swallow (FEES) and/or Video Swallow Study (VSS) for a sample of 198 children were collected. Subjects were categorized into groups: "aspiration", "penetration" or "no aspiration or penetration". Logistic regression modeling was used to determine the contribution of certain characteristics to the odds of aspiration. A model for predicting aspiration or penetration based on those characteristics was assessed. The sensitivity and specificity of the model in predicting aspiration and penetration was determined. RESULTS: One hundred ninety eight subjects had a FEES or VSS. Of these, 18% (n=36) aspirated and 21% (n=42) were found to have penetration. Many of the factors identified in the health history were found to be significantly associated with aspiration or penetration. The variables "demonstrated aspiration" (this included parent or caregiver seeing food in the tracheotomy tube or aspiration noted on a previous FEES or VSS) (p=0.02), "hypotonia" (p=0.02) and "tracheotomy" (p=0.001) were most predictive of aspiration. History of tracheotomy was found to have an inverse relationship with aspiration. "gastroesophageal reflux" (GER) (p=0.0007) was most significantly associated with penetration, followed by "prematurity" (p=0.03) and "developmental delays" (p=0.04). Based on the prediction model, the probabilities for a child with a history of combinations of the above variables to have aspiration or penetration were calculated. CONCLUSIONS: Significant relationships exist between aspiration or penetration and the family's answers about their child's medical history. Practitioners should consider a swallow assessment whenever a child has a history which includes variables with a strong association with aspiration or penetration. PMID- 20163882 TI - Role of endoscopic nasal examination in reduction of nasopharyngeal adenoid recurrence rates. AB - OBJECTIVES: To evaluate the benefit of endoscopic examination after adenoidectomy in detecting residual adenoid tissue that would need completion surgery, in ultimate aim to reduce rates of adenoid recurrence. METHODS: A total of 312 children were included in the study conducted at Ain-Shams University Hospital from January till December 2007, following routine adenoidectomy, 118 had a nasal and nasopharyngeal rigid fiberoptic examination and 194 did not, randomly according to the surgical subunit that performed the surgery. Patients were followed up for a minimum of 2 years for recurrence of symptoms of adenoid enlargement. RESULTS: Endoscopic examination revealed that 14.5% of patients undergoing adenoidectomy had residual adenoid tissue that needed further removal, of these the most common site was at the lateral walls of the nasopharynx (47%). The recurrence rate of adenoid hypertrophy needing re-surgery with endoscopic examination (0.85%) approaches that of the lowest recorded (0.5%) with more expensive and costly methods, and statistically significant lower than rates when endoscopy is not performed (5.6%). Additional time needed for such examination was negligible in terms of cost-benefit relationship. CONCLUSION: Rigid fiberoptic endoscopy of the posterior choana and nasopharynx at the end of adenoidectomy provides the benefit of detecting unremoved adenoid tissue without significantly extra cost, time, nor expertise, and helps reduce significantly the rates of recurrence of adenoid enlargement, which might be attributed to residual "missed" adenoid tissue. PMID- 20163883 TI - Prognosis and outcomes of elderly (75-84 years) patients with acute myocardial infarction 1-2 years after the event: AMI-elderly study of the MONICA/KORA Myocardial Infarction Registry. AB - BACKGROUND: With increasing life expectancy the management of acute myocardial infarction (AMI) in patients of an older age is of growing importance. However, long-term data are limited regarding 'hard' endpoints and quality of life in unselected elderly patients in 'real world' settings. METHODS AND RESULTS: From March 2005 to March 2006 all 75-84-year old patients consecutively hospitalised due to an incident AMI in a large community teaching hospital were analyzed (N=235). Evidence-based therapy included the treatment with aspirin (93%), clopidogrel (65%), betablockers (93%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (84%), and statins (83%). Percutaneous coronary intervention (PCI) was performed in 45.5% and bypass grafting (CABG) in 10.2%. The 28-day-case fatality was 17.4%. Long-term follow-up was obtained in 95.9% of all hospital survivors at a mean of 18.7 +/- 6.4 months; during this time 19.9% of patients died. After multivariate analysis the only significantly negative predictor for survival and MACCE was diabetes, and the only significantly positive predictor was revascularisation during hospital stay. Patients with PCI/CABG had lower NYHA class (81% vs. 48%; p<0.04). Patients with PCI also had a higher EQ-5D index score (75 +/- 18 vs. 67 +/- 17, p<0.04) compared to patients not receiving PCI. CONCLUSION: The positive long-time effect of revascularisation procedures during hospitalisation, not only on 'hard' endpoints but also on functional outcome and quality of life emphasizes that invasive therapies should not be considered less valuable in elderly people and that age alone should not preclude aggressive treatment during AMI. PMID- 20163884 TI - What does genetic diversity of Aspergillus flavus tell us about Aspergillus oryzae? AB - Aspergillus flavus and Aspergillus oryzae belong to Aspergillus section Flavi. They are closely related and are of significant economic importance. The former species has the ability to produce harmful aflatoxins while the latter is widely used in food fermentation and industrial enzyme production. This review summarizes the current understanding of the similarity of the A. flavus and A. oryzae genomes, the genetic diversity in A. flavus and A. oryzae populations, the causes of this diversity, and the relatedness of nonaflatoxigenic A. flavus strains to A. oryzae. PMID- 20163885 TI - A review of non-invasive imaging methods and applications in contaminant hydrogeology research. AB - Contaminant hydrogeological processes occurring in porous media are typically not amenable to direct observation. As a result, indirect measurements (e.g., contaminant breakthrough at a fixed location) are often used to infer processes occurring at different scales, locations, or times. To overcome this limitation, non-invasive imaging methods are increasingly being used in contaminant hydrogeology research. Four of the most common methods, and the subjects of this review, are optical imaging using UV or visible light, dual-energy gamma radiation, X-ray microtomography, and magnetic resonance imaging (MRI). Non invasive imaging techniques have provided valuable insights into a variety of complex systems and processes, including porous media characterization, multiphase fluid distribution, fluid flow, solute transport and mixing, colloidal transport and deposition, and reactions. In this paper we review the theory underlying these methods, applications of these methods to contaminant hydrogeology research, and methods' advantages and disadvantages. As expected, there is no perfect method or tool for non-invasive imaging. However, optical methods generally present the least expensive and easiest options for imaging fluid distribution, solute and fluid flow, colloid transport, and reactions in artificial two-dimensional (2D) porous media. Gamma radiation methods present the best opportunity for characterization of fluid distributions in 2D at the Darcy scale. X-ray methods present the highest resolution and flexibility for three dimensional (3D) natural porous media characterization, and 3D characterization of fluid distributions in natural porous media. And MRI presents the best option for 3D characterization of fluid distribution, fluid flow, colloid transport, and reaction in artificial porous media. Obvious deficiencies ripe for method development are the ability to image transient processes such as fluid flow and colloid transport in natural porous media in three dimensions, the ability to image many reactions of environmental interest in artificial and natural porous media, and the ability to image selected processes over a range of scales in artificial and natural porous media. PMID- 20163886 TI - C1q induces a rapid up-regulation of P-selectin and modulates collagen- and collagen-related peptide-triggered activation in human platelets. AB - Blood platelets are emerging as important immunomodulatory cells, but complement interaction with platelets is not well understood. Several platelet structures have been described as complement protein 1q (C1q) binding receptors, such as C1qRp/CD93 and gC1qR. However, there are conflicting results whether these receptors are C1q binding structures, or even at all expressed on the cell surface. Recently, the collagen-binding integrin alphaIIbetaI was reported to bind C1q on mast cells, and this receptor is also present on platelets. The aim of this study was to further characterize the effects of C1q on platelets, by quantifying the platelet surface expression of P-selectin (CD62P) and monitoring the formation of platelet-neutrophil aggregates. Using flow cytometry, we found that C1q dose-dependently triggered a rapid but moderate and transient up regulation of P-selectin already within 5s of C1q exposure. Pre-incubation with an antibody directed against gC1qR significantly inhibited (with 57% compared to control) the up-regulation, whereas an antibody towards the alphaIIbetaI-integrin showed no effect. Stimulation with C1q did not change the cytosolic calcium levels, as measured with the fluorescent ratiometric probe Fura-2, however, a protein kinase C inhibitor (GF109203x) blocked the C1q-induced P-selectin expression. Furthermore, pre-incubation of platelets with C1q diminished both the collagen as well as the collagen-related peptide-induced up-regulation of P selectin, most evident after 90s of stimulation. This indicates that C1q may regulate platelet activation via the GPVI receptor, which is a novel finding. Moreover, C1q antagonized the collagen-induced formation of platelet-neutrophil aggregates, indicating a reduced interaction between platelet P-selectin and neutrophil P-selectin glycoprotein ligand-1(PSGL-1/CD162). In summary, C1q induces a moderate rapid platelet P-selectin expression, modulates subsequent collagen and collagen-related peptide stimulation of platelets, and inhibits the formation of platelet-neutrophil aggregates. These immuno-regulatory effects of C1q may have a crucial role in innate immunity and inflammation. PMID- 20163887 TI - HMGB1 activates nuclear factor-kappaB signaling by RAGE and increases the production of TNF-alpha in human umbilical vein endothelial cells. AB - OBJECTIVE: High mobility group box chromosomal protein 1 (HMGB1) is a lately discovered candidate molecule identified as an important extracellular mediator in systemic inflammation. Systemic inflammation results in endothelial cell activation and microvascular injury. In the present study, we investigated the effects of HMGB1 on the activation of human umbilical vein endothelial cells (HUVECs) and defined pathways activated by HMGB1. METHODS: HUVECs obtained by collagenase treatment of umbilical cord veins were stimulated in vitro with HMGB1. The activation of HUVECs was studied regarding (i) the kinetics of tumor necrosis factor-alpha (TNF-alpha) production in HUVECs, (ii) HMGB1-induced up regulation of receptor for advanced glycation end products (RAGE), (iii) HMGB1 induced nuclear translocation of nuclear factor kappa B (NF-kappaB) in HUVECs, (iv) the activation of signalling transduction pathways. RESULTS: HUVECs activation was stimulated by HMGB1 partially in a RAGE-dependent manner. Additionally, the HMGB1-induced activation of HUVECs was significantly inhibited by anti-RAGE monoclonal antibody and Ethyl pyruvate (EP) that had been shown to be an effective anti-inflammatory agent. Short-term prestimulation of HUVECs with HMGB1 caused a time-dependent increase in the secretion of TNF-alpha and expression of RAGE. Furthermore, HMGB1 stimulation resulted in nuclear translocation of transcription factor NF-kappaB. Most importantly, pretreatment with anti-RAGE monoclonal antibody significantly decreased the amounts of TNF alpha and inhibited the nuclear translocation of NF-kappaB. Additionally in HUVECs cultures, EP specifically inhibited activation of NF-kappaB signaling pathway that are critical for TNF-alpha release. CONCLUSIONS: In conclusion, Our data present a link between HMGB1and RAGE function of endothelial cells and demonstrate the pathway activated by HMGB1. These findings may provide a novel therapeutic strategy to improve the endothelial cells function. PMID- 20163888 TI - Role of idiotype-anti-idiotype interactions in the induction of collagen-induced arthritis in rats. AB - The mechanism of autoantibodies (rheumatoid factor (RF) and anti-collagen autoantibodies) induction in collagen-induced arthritis (CIA) is unknown. The study assessed the hypothesis that activation of autoantibody-producing clones is mediated by idiotype-anti-idiotype (IAI) interactions with lymphocytes on heterologous collagen. It was demonstrated that RF-containing serum of rats immunized with bovine collagen (BCII) in ELISA competes with BCII for binding to anti-BCII antibodies. Immunization of rats with Fc fragments of IgG caused not only an increase in RF levels, but also induction of antibodies to BCII and anti collagen autoantibodies. Taken together, these facts suggest that activation of RF-producing lymphocytes in CIA model occurs through IAI interactions with anti BCII lymphocytes. Three populations of antibodies were detected in the blood of arthritic rats: a population of antibodies reacting only with BCII, a population of antibodies reacting only with rat collagen (RCII) and a population of antibodies that can bind to both bovine and rat collagen. It was shown that RF in relation to anti-collagen autoantibodies act as anti-idiotype antibodies, and a comparative analysis of antibody production in arthritic and resistant rats demonstrated that the level of anti-collagen autoantibody production depends on the level of RF production. This suggests that RF and RF-producing lymphocytes are involved in regulation of anti-collagen autoreactive lymphocyte activity through an IAI interaction mechanism. A direct activation of autoreactive anti RCII lymphocytes by BCII cannot be excluded, but it can be supposed that induction of anti-collagen autoreactive lymphocytes needs a signal generated in IAI interactions by RF-producing lymphocytes. This hypothesis is based on the data obtained, and not only explains the mechanism of autoreactive lymphocytes activation in the rat CIA model, but also indicates that the key regulatory element in the development of arthritis in animals is RF-producing lymphocytes. The results allow a new insight on the role of RF in the pathogenesis of rheumatoid arthritis and on seeking more effective therapeutic means. PMID- 20163889 TI - Effects of dehydroepiandrosterone-sulfate (DHEA-S) and benznidazole treatments during acute infection of two different Trypanosoma cruzi strains. AB - A significant role for hormones in regulating the balance of Th1- and Th2 associated cytokines with a role in modulating diseases has been accumulating. Previously, we reported that dehydroepiandrosterone (DHEA), the most abundant steroid hormone synthesized by the adrenal cortex, markedly reduced the blood and tissue parasites in experimentally Trypanosoma cruzi-infected rats. Based on these findings, the main purpose of this study was to investigate the effect of dehydroepiandrosterone-sulfate ester (DHEA-S) therapy alone or in combination with benznidazole (BNZ) (recommended in Brazil for the treatment of T. cruzi infection) will be effective during the acute phase of two different lineages of T. cruzi strains: type I (Y strain) and type II (Bolivia strain) of T. cruzi. Administration of either DHEA-S or BNZ alone or in combination significantly reduced the Y strain parasite load as compared with untreated. Furthermore treatment with DHEA-S resulted in Bolivia strain clearance. This protective effect of DHEA-S was associated with the host's immune response, as evidence by enhanced levels of interferon-gamma and interleukin-2. DHEA-S treatment also increased peritoneal macrophages levels and nitrite production. DHEA-S treatment was effective in reducing the mortality rate as compared to BNZ alone or to combiner DHEA-S+BNZ treatment of T. cruzi Bolivia strain infected animals. These findings suggest that hormonal therapy may have a protective effect in the treatment of T. cruzi infection. PMID- 20163890 TI - Influence of gibberellin and daminozide on the expression of terpene synthases and on monoterpenes in common sage (Salvia officinalis). AB - Common sage (Salvia officinalis L., Lamiaceae) is one of the most important medicinal and aromatic plants, with antioxidant, antimicrobial, spasmolytic, astringent, antihidrotic and specific sensorial properties. The essential oil of the plant, composed mainly of the monoterpenes 1,8-cineole, alpha-thujone, beta thujone and camphor, is responsible for some of these effects. Gibberellins regulate diverse physiological processes in plants, such as seed germination, shoot elongation and cell division. In this study, we analyzed the effect of exogenously applied plant growth regulators, namely gibberellic acid (GA(3)) and daminozide, on leaf morphology and essential oil formation of two leaf stages during the period of leaf expansion. Essential oil content increased with increasing levels of gibberellins and decreased when gibberellin biosynthesis was blocked with daminozide. With increasing levels of gibberellins, 1,8-cineole and camphor contents increased. Daminozide blocked the accumulation of alpha- and beta-thujone. GA(3) at the highest level applied also led to a significant decrease of alpha- and beta-thujone. Monoterpene synthases are a class of enzymes responsible for the first step in monoterpene biosynthesis, competing for the same substrate geranylpyrophosphate. The levels of gene expression of the three most important monoterpene synthases in sage were investigated, 1,8-cineole synthase leading directly to 1,8-cineole, (+)-sabinene synthase responsible for the first step in the formation of alpha- and beta-thujone, and (+)-bornyl diphosphate synthase, the first step in camphor biosynthesis. The foliar application of GA(3) increased, while daminozide significantly decreased gene expression of the monoterpene synthases. The amounts of two of the end products, 1,8-cineole and camphor, were directly correlated with the levels of gene expression of the respective monoterpene synthases, indicating transcriptional control, while the formation of alpha- and beta-thujone was not transcriptionally regulated. PMID- 20163891 TI - A 20-year analysis of previous and emerging allergens that elicit photoallergic contact dermatitis. AB - BACKGROUND: Retrospective chart reviews are periodically needed to update allergen series to detect changes in photoallergic contact dermatitis (PACD) over time. OBJECTIVE: We sought to evaluate photopatch test results during a 13-year period and extend the observations to 20 years. METHODS: A retrospective chart review was conducted in patients who were photopatch tested. RESULTS: In all, 76 patients were evaluated. A total of 69 positive photopatch and 45 positive patch test reactions were detected in 30 and 23 patients, respectively. The frequencies of the positive photopatch test reactions were sunscreens 23.2%, antimicrobial agents 23.2%, medications 20.3%, fragrances 13%, plants and plant derivatives 11.6%, and pesticides 8.7%. Of the positive photopatch reactions to antimicrobial agents, 60% were caused by Fentichlor. LIMITATIONS: This study was a retrospective chart analysis, and the number of patients was small. CONCLUSIONS: Sunscreens and antimicrobial agents were the most frequent allergens eliciting PACD, and there was a decrease in PACD caused by fragrances. The number of reactions to medications increased. This study also demonstrated that pesticides can be a cause of PACD. The detection of reactions to Fentichlor was unexpected and, although they have been attributed in some studies to cross-reactions to sulfanilamides and bithionol, such a robust association was not observed in this study. This study extends our experience of the changes in the allergens that elicit PACD to 20 years. PMID- 20163892 TI - Synthesis and evaluation of some new substituted benzothiazepine and benzoxazepine derivatives as anticonvulsant agents. AB - A new series of 4-(4'-Hydroxyphenyl)-2-(3-substitutedphenyl)-3-(4 substitutedphenylamino methylene)-2,3-dihydro-1,5-benzothiazepines (3a-3j) and 4 (4'-Hydroxyphenyl)-2-(3-substituted phenyl)-3-(4-substitutedphenylaminomethylene) 2,3-dihydro-1,5-benzoxazepins (3a'-3j') were synthesized and evaluated for their anticonvulsant activity. All these compounds were screened in vivo, for their anticonvulsant activity and acute toxicity. Compound 3g was found to be most potent compound of this series and was compared with the reference drug phenytion sodium. The structures of these compounds have been established by IR, (1)H NMR and (13)C NMR spectroscopic data. PMID- 20163893 TI - Guaiane sesquiterpenes from seaweed Ulva fasciata Delile and their antibacterial properties. AB - Two new guaiane sesquiterpene derivatives, guai-2-en-10alpha-ol (1) and guai-2-en 10alpha-methanol (2), were chromatographically purified as major constituents of the CHCl3/CH3OH (1:1, v/v) soluble fraction of Ulva fasciata. Acetylation of 2 furnished guai-2-en-10alpha-methyl methanoate (3) with acetyl group at C11 position. The structures of the compounds were elucidated using one and two dimensional NMR and mass spectrometric analysis. Compounds 2 and 3 exhibited significant inhibition to the growth of Vibrio parahaemolyticus with minimum inhibitory concentrations of 25 and 35 microg/mL, respectively. The electronegative C10 acetyl group with high polarisability (7.02x10(-24) cm3) in 3 appeared to withdraw electron cloud from substituted cycloheptyl ring and (R)-3 methylcyclohept-1-ene moiety, thus acting as the nucleophilic center of the molecule resulting in high bioactivity. PMID- 20163894 TI - Naftifine-analogues as anti-Trypanosoma cruzi agents. AB - Chagas disease represents a relevant health problem in Central and South America. The first line of treatment is Nifurtimox and Benznidazole which have a great deal of disadvantages that demands the rapid generation of therapeutic alternatives. Based in our research on aza-thiaheterocycles as anti-Trypanosoma cruzi agents we identified pharmacophores that act through oxidative stress. Here, we describe the synthesis and the activity of new containing bioactive heterocycles analogues of naftifine as potential T. cruzi membrane sterol biosynthesis inhibitors. Benzimidazole 1,3-dioxides (11 and 13) and quinoxaline 1,4-dioxides (22 and 23) displayed excellent parasite/mammal selectivity indexes. Analysis of the free sterols from parasite incubated with the compounds showed that any of them are able to accumulate squalene suggesting that in the anti-T. cruzi mechanism of action is not involved the inhibition of sterol biosynthesis. Some derivatives were also tested as antifungal agents. The results obtained in the present work open potential therapeutic possibilities of new compounds for these infectious diseases. PMID- 20163895 TI - Synthesis of new pyrrolo[2,3-d]pyrimidine derivatives and evaluation of their activities against human colon cancer cell lines. AB - New pyrrolo[2,3-d]Pyrimidines with heteroaryl substitution at 5th position through sulfur linker were synthesized incorporating putative pharmacophoric moieties like benzimidazole and benzothiazole as heteroaryl groups. Cytotoxic effect of all the compounds was carried out on HCT116 colon cancer cell lines. Compounds 6c and 6h with nitrobenzimidazole and pyrimidyl heterocycles attached at 5th position via sulfur were the most potent of all with IC50 values approximately 17.6 muM. Among the four compounds tested for apoptosis induction activity, 6c induced apoptosis in a dose dependent manner. PMID- 20163896 TI - Synthesis, spectroscopic and biological studies on the new symmetric Schiff base derived from 2,6-diformyl-4-methylphenol with N-aminopyrimidine. AB - A phenol based novel Schiff base polydentate symmetric ligand was prepared. The complexes were prepared by reacting ligand and the metal chlorides of Cu (II), Ni(II), Co(II) and Fe(II) in methanol to get a series of mononuclear complexes. The complexes were characterized by elemental analyses, conductivity measurements, magnetic susceptibility data, IR, UV-Vis, NMR and API-ES mass spectral data. The mononuclear structure of the complexes was confirmed on the basis of elemental analyses, magnetic susceptibility and API-ES mass spectral data. The ligand and all the metal complexes were evaluated for their antimicrobial activity against four Gram-positive bacteria (Staphylococcus aureus ATCC 6538, S. aureus ATCC 25923, Bacillus cereus ATCC 7064 and Micrococcus luteus ATCC 9345), one Gram-negative bacterium (Escherichia coli ATCC 4230), and three yeast (Candida albicans ATCC 14053, Candida krusei ATCC 6258 and Candida parapsilosis ATCC 22019) strains. Therefore, newly synthesized the ligand and two complexes [(Cu(II) and Co(II)] showed good biological activity against all tested bacteria and yeast strains. PMID- 20163897 TI - Thiosemicarbazones, semicarbazones, dithiocarbazates and hydrazide/hydrazones: anti-Mycobacterium tuberculosis activity and cytotoxicity. AB - The aim of this study was to identify a candidate drug for the development of anti-tuberculosis therapy from previously synthesized compounds based on the thiosemicarbazones, semicarbazones, dithiocarbazates and hydrazide/hydrazones compounds. The minimal inhibitory concentration (MIC) of these compounds against Mycobacterium tuberculosis was determined. Their in vitro cytotoxicity to J774 cells (IC50) was determined to establish a selectivity index (SI) (SI=IC50/MIC). The best compounds were the thiosemicarbazones (2, 3 and 4) and the hydrazide/hydrazones (14, 15, 16 and 18). The results are comparable to or better than those of "first line" or "second line" drugs commonly used to treat TB, suggesting these compounds as anti-TB drug candidates. PMID- 20163898 TI - Indoor radon distribution of subway stations in a Korean major city. AB - The overall survey on indoor radon concentration was conducted at all subway stations in a major city, Daejeon in the central part of Korea. It was quarterly performed from September 2007 to August 2008. The annual arithmetic mean of indoor radon concentration of all the stations was 34.1+/-14.7 Bq m(-3), and the range of values was from 9.4 to 98.2 Bq m(-3). The radon concentrations in groundwater (average 31.0+/-0.8 Bq m(-3)) were not significantly high in most stations, but the concentration (177.9+/-2.3 Bq L(-1)) of one station was over the level of 148 Bq L(-1) in drinking water proposed by U.S. EPA. Based on indoor survey results, the approximate average of the annual effective dose by radon inhalation to the employees and passengers were 0.24 mSv y(-1), and 0.02 mSv y( 1), respectively. Although the effective dose based on the UNSCEAR report was potentially estimated, for more accurate assessment, the additional survey on the influence by indoor radon will be necessary. PMID- 20163899 TI - Progress in decontamination by halophilic microorganisms in saline wastewater and soil. AB - Environments with high-salt concentrations are often populated by dense microbial communities. Halophilic microorganisms can be isolated from different saline environments and different strains even belonging to the same genus have various applications. Wastewater and soil rich in both organic matter and salt are difficult to treat using conventional microorganisms typically found in wastewater treatment and soil bioremediation facilities. Studies on decontaminative capabilities and decontamination pathways of organic contaminants (i.e., aromatic compounds benzoate, cinnamate, 3-phenylpropionate, 4 hydroxybenzoic acid), heavy metals (i.e., tellurium, vanadium), and nutrients in the biological treatment of saline wastewater and soil by halophilic microorganisms are discussed in this review. PMID- 20163900 TI - Socioeconomic inequalities in suicidal ideation, parasuicides, and completed suicides in South Korea. AB - As a result of unprecedented increase in suicides over the last decade, Korea now ranks at the top of OECD countries in suicide statistics (26.1 deaths per 100,000 population in 2005). Our study sought to document socioeconomic inequalities in self-destructive behaviors including suicidal ideation, parasuicide, and completed suicide. For prevalence of suicidal ideation and parasuicide, we used four waves of data from the Korea National Health and Nutrition Examination Survey (1995, 1998, 2001, and 2005). For suicide mortality, we abstracted suicide cases from the National Death Registration records, and linked them with population denominators from the national census in 1995, 2000, and 2005. We examined variation in self-destructive behaviors according to level of educational attainment (at the individual level), as well as area-level characteristics including level of deprivation and degree of urbanicity. Age standardized rates were calculated through direct standardization using the 2005 census population as the standard. Inequalities were measured by the relative index of inequality and the slope index of inequality. The age-standardized prevalence of suicidal ideation decreased across consecutive surveys in both genders (18.0-13.5% for men, 27.5-22.9% for women). Parasuicides similarly decreased over time. By contrast, completed suicides increased over time (20.9 42.8 per 100,000 for men and 8.9-20.9 for women). The most prominent increases in completed suicides were observed among the elderly in both genders. Lower education, rural residence, and area deprivation was each associated with higher suicide rates. Both absolute as well as relative inequalities in suicide by socioeconomic position widened over time. Our findings suggest that the current suicide epidemic in Korea has social origins. In addition to clinical approaches targeted to the prevention of suicides in high risk individuals, social policies are needed to protect disadvantaged populations at risk of self-destructive behaviors. PMID- 20163901 TI - End of life care policies: do they make a difference in practice? AB - Although institutional policies related to care at the end of life (EOL) are a common feature of hospitals, there has been little examination of the ways in which these policies shape the focus and provision of care. The question asked in this study was "What effect do institutional policies relating to care at the EOL have on practice?" Data were drawn from health record reviews of 310 adults who had died in 3 acute care facilities in a major urban centre of a Western Canadian health region. Medical orders relating to care at the end of life were written for the majority of decedents, highlighting the value providers placed on care planning during this time. Relatively few providers, however, followed policy directives regarding use of care plans, terminology or documentation of discussions with patients and families about treatment plans. The findings of this study demonstrate a significant gap between institutional EOL care policies and practice in this health region, challenging institutional decision makers and front-line providers to collaborate more effectively to devise clinically relevant policies that enhance patient care at a particularly vulnerable time of life. PMID- 20163902 TI - Health disparities and the stress hypothesis: a commentary on Schwartz and Meyer. PMID- 20163903 TI - Co-operation between patient organisations and the drug industry in Finland. AB - The aim of the study was to investigate the co-operation between patient organizations and the drug industry in Finland prior to critical discussions on the topic. The data were gathered by a questionnaire survey of 85 patient organisations (response rate 65%, n = 55) and 20 drug firms (response rate 100%) in 2003, and by interviewing 13 organisations and surveying their web-pages and other documents in 2004. In the surveys, half of the patient organisations and 80% of the drug firms considered co-operation important. Most (71%) organisations reported financial support from the drug industry. Most organisations and drug firms had experienced problems. Common problems for organisations were too little or too unpredictable support from industry, and threats to independence and objectivity. Drug firms frequently mentioned unclear rules of co-operation. The patient organisation interviews exhibited similar themes and findings to those found in the surveys, revealing the complexity and importance of co-operation in organisation activities, and the variation between organisations. This case study from Finland showed that co-operation between patient organizations and the drug industry was common, many-sided and not usually transparent. The close connections between patient organizations and commercial companies, particularly drug firms, raise several policy issues and the need for action. PMID- 20163904 TI - Individual, family, and area predictors of BMI and BMI change in an adult Norwegian population: findings from the HUNT study. AB - The global obesity epidemic is a major public health concern and there is strong evidence that the drivers are varied and operate via diverse pathways. Taking a systems approach allows the contextual influences operating upon the individual to be identified and quantified. We adopt such a perspective in this study, where longitudinal data from a cohort of 24,966 settled individuals participating in two major health surveys, the Nord-Trondelag Health Study (HUNT 1 and 2) in the county of Nord-Trondelag, Norway, were used to investigate associations between individual, family and area characteristics and two outcomes: body mass index (BMI) at follow-up and BMI change over an 11 year period. Linear multilevel models were fitted, with individuals nested in 17,500 families, 447 wards and 24 municipalities. A range of putative individual, family, and area predictors were tested. We found both outcomes were strongly associated with individual characteristics, with higher BMIs generally being amongst males, unmarried participants, non-smokers, those of lower education and those undertaking physically demanding work but participating in less physical activity outside work. The characteristics of those in the sample exhibiting higher BMI gain were rather similar except that women gained more and those with no employment income gained less. Contextual influences were also found to be important: although just 1% of the unexplained variance was located on the neighbourhood and municipality levels respectively, and hence suggesting small environmental influences, between 10 and 13% could be attributed to families, highlighting the importance of the familial contextual environment. Rather little is known about the manner by which family influences may operate on bodyweight hence further work is needed to understand likely mechanisms and guide future interventions. PMID- 20163905 TI - Green space as a buffer between stressful life events and health. AB - This study investigates whether the presence of green space can attenuate negative health impacts of stressful life events. Individual-level data on health and socio-demographic characteristics were drawn from a representative two-stage sample of 4529 Dutch respondents to the second Dutch National Survey of General Practice (DNSGP-2), conducted in 2000-2002. Health measures included: (1) the number of health complaints in the last 14 days; (2) perceived mental health (measured by the GHQ-12); and (3) a single item measure of perceived general health ranging from 'excellent' to 'poor'. Percentages of green space in a 1-km and 3-km radius around the home were derived from the 2001 National Land cover Classification database (LGN4). Data were analysed using multilevel regression analysis, with GP practices as the group-level units. All analyses were controlled for age, gender, income, education level, and level of urbanity. The results show that the relationships of stressful life events with number of health complaints and perceived general health were significantly moderated by amount of green space in a 3-km radius. Respondents with a high amount of green space in a 3-km radius were less affected by experiencing a stressful life event than respondents with a low amount of green space in this radius. The same pattern was observed for perceived mental health, although it was marginally significant. The moderating effects of green space were found only for green space within 3 km, and not for green space within 1 km of residents' homes, presumably because the 3-km indicator is more affected by the presence of larger areas of green space, that are supposed to sustain deeper forms of restoration. These results support the notion that green space can provide a buffer against the negative health impact of stressful life events. PMID- 20163906 TI - Partner abuse or violence, parenting and neighborhood influences on children's behavioral problems. AB - We examined the relationship between neighborhood characteristics, parenting behaviors, experiences of intimate partner abuse or violence (IPV) and children's behavioral problems in a socioeconomically diverse sample of 383 families residing in an urban environment. Data were collected in the Fall/Winter of 2002. The census block group of residence was used as our measure of neighborhood. Census block groups typically contain 1500 residents on average. IPV was measured using a modified version of the HITS (physically Hurt, Insult, Threaten, and Screamed at) scale, a short four item tool assessing emotional and physical violence to which we added an item capturing domination or emotional control. IPV in the last year was reported by 50% of the sample with rates varying by socioeconomic position; families with the lowest and highest income reported the most IPV. Patterns of association between parenting, neighborhood and the children's behavioral problems differed for families who reported IPV in the last year compared to families who reported no IPV. While positive neighborhood characteristics such as high levels of Community Involvement with Children - based upon four scales capturing neighborhood levels of social interaction and collective socialization of children - were protective for high levels of behavioral problems among families not reporting IPV, this protective effect was not seen among families who did report IPV. Hypothesized interactions between negative neighborhood characteristics and IPV-namely that behavioral problems would be worse among families experiencing IPV in highly economically deprived or areas with negative social climates-were not supported by our data. These interactions between neighborhood factors and IPV were not explained by parental factors. PMID- 20163907 TI - Changes in interleukin-10 mRNA expression are predictive for 9-day survival of pigs in an emergency preservation and resuscitation model. AB - AIM OF THE STUDY: This study aimed at evaluating (I) the impact of different intra-arrest hypothermia levels on the expression of selected cytokines and (II) their prognostic value for 9-day survival. METHODS: Female Large White pigs (n=21, 31-38 kg) were subjected to 15 min of ventricular fibrillation, followed by intra-arrest cardiopulmonary bypass cooling for 1, 3, or 5 min achieving brain temperatures (Tbr) of 30.4+/-1.6, 24.2+/-4.6 and 18.8+/-4.0 degrees C. After 40 min of controlled rewarming, pigs were defibrillated and kept at Tbr of 34.5 degrees C for 20 h, survival was for 9 days. Plasma samples were analysed for interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha), and IL-10 levels by ELISA. Total RNA out of peripheral blood mononuclear cells was analysed by real time PCR for IL-1, IL-2, IL-4, IL-10, TNF-alpha, interferon-gamma, inducible NO synthase, and heme oxygenase-1 gene expressions. RESULTS: Plasma IL-6 and TNF alpha levels significantly (p=0.0001 and 0.0003) increased in all animals within 1h after resuscitation with no significant differences between groups. Pigs surviving exhibited a decrease in IL-10 expression between baseline and intra arrest values as compared to non-surviving animals, which showed a slight increase (p=0.0078). ROC curve analysis revealed that changes in IL-10 expression had a good prognostic power for survival to day 9 (area under the curve=0.882). CONCLUSION: The systemic inflammatory response syndrome after cardiac arrest was reflected by a remarkable increase of plasma IL-6 and TNF-alpha levels. Intra arrest hypothermia levels did not influence the expression of selected cytokines. As prognostic marker for survival IL-10 was identified with decreasing mRNA levels during cardiac arrest in survivors. PMID- 20163908 TI - Analysis of SM4 sulfatide as a P-selectin ligand using model membranes. AB - Carcinoma tumor cells express highly glycosylated mucins acting as ligands for selectin adhesion receptors and thus facilitating the metastatic process. Recently, a sulfated galactocerebroside SM4 was detected as solely P-selectin ligand on MC-38 colon carcinoma cells. Here we characterize the functionality of SM4 as selectin ligand using model membrane approaches. SM4 was found concentrated in lipid rafts of MC-38 cells indicating a local clustering that may increase the avidity of P-selectin recognition. To confirm this, SM4 was incorporated at various concentrations into POPC model membranes and lateral clustering was analyzed by fluorescence microscopy and found to be comparable to glycolipids carrying the sLe(x) epitope. SM4 containing liposomes were used as cell models, binding to immobilized P-selectin. Quartz crystal microbalance data confirmed SM4/P-selectin liposome binding that was inhibited dose-dependently by heparin. Comparable binding characteristics of SM4 and sLe(x) liposomes underscore the similarity of these epitopes. Thus, clustering of SM4 on tumor cells is a principle for binding P-selectin. PMID- 20163909 TI - Redirection of renal mesenchyme to stromal and chondrocytic fates in the presence of TGF-beta2. AB - Many members of the transforming growth factor-beta (TGF-beta) superfamily have been shown to be important regulators of metanephric development. In this study, we characterized the effect of TGF-beta2 on metanephric development. Rat and mouse metanephroi cultured in the presence of exogenous TGF-beta2 for up to 15 days were small, and contained rudimentary ureteric branches and few glomeruli. These metanephroi were mostly comprised of mesenchymal cells, with two cell populations (designated Type 1 and Type 2 cells) evident. Type 1 cells were only observed when TGF-beta2 was added from the commencement of culture, they resembled chondroblasts and were Alcian Blue and Col IIB positive. Type 2 cells were observed whenever TGF-beta2 was added to the media, formed a band at the periphery of the explants consisting of 5-10 layers of spindle-shaped cells, and were alpha-smooth muscle actin positive. Molecular and RNA in situ hybridization analysis of metanephroi cultured in the presence of TGF-beta2 for 6 days demonstrated that Type 1 and 2 cells were negative for Pax2, WT1, GDNF and FoxD1. Gene expression profiling demonstrated an upregulation of chondrocyte, myogenic and stromal genes, some of which were identified as markers of Type 1 and Type 2 cells. In addition, TGF-beta2 was capable of maintaining the survival of mouse isolated metanephric mesenchyme (iMM) in the absence of serum or inductive signals from the ureteric epithelium. TGF-beta2 also induced the differentiation of iMM into Type 1 and 2 cells. The presence of chondrocytes and muscle in these cultures is reminiscent of the cell types found in some Wilms' tumors. These studies demonstrate that TGF-beta2 is capable of differentiating metanephric mesenchyme away from a renal cell fate. PMID- 20163910 TI - EAU penile cancer guidelines 2009. AB - CONTEXT: Squamous cell carcinoma (SCC) of the penis is a relatively rare but ominous disease. OBJECTIVE: To present a condensed version of the updated 2009 European Association of Urology (EAU) guidelines on penile SCC. EVIDENCE ACQUISITION: We performed a literature search of new data available up to December 2009. No randomized study was found; consequently, level of evidence (LE) and grade of recommendations (GR) are low. EVIDENCE SYNTHESIS: More insight was gained into the etiology of SCC of the penis, together with improved staging and treatment: Human papillomavirus 16 plays an etiologic role in approximately 40-50% of cases. Similarities in etiology with SCC of the head and neck, the female genitalia, and the anal canal have been found. Improved diagnostics allowed earlier diagnosis, leading to more conservative treatments. Adjuvant and neoadjuvant chemotherapy showed promising results in patients with advanced or recurrent disease. Centralization of the disease contributed to standardization and rapid diffusion of new treatments with improved results and increased organ preservation. CONCLUSIONS: Improvements in the management of SCC of the penis are reflected in changes in the guidelines, but the rarity of the disease precluded randomized studies, leading to low level of evidence and grade of recommendation. PMID- 20163911 TI - Predictive factors for positive surgical margins and their locations after robot assisted laparoscopic radical prostatectomy. AB - BACKGROUND: Positive surgical margin (PSM) after radical prostatectomy (RP) has been shown to be an independent predictive factor for cancer recurrence. Several investigations have correlated clinical and histopathologic findings with surgical margin status after open RP. However, few studies have addressed the predictive factors for PSM after robot-assisted laparoscopic RP (RARP). OBJECTIVE: We sought to identify predictive factors for PSMs and their locations after RARP. DESIGN, SETTING, AND PARTICIPANTS: We prospectively analyzed 876 consecutive patients who underwent RARP from January 2008 to May 2009. INTERVENTION: All patients underwent RARP performed by a single surgeon with previous experience of >1500 cases. MEASUREMENTS: Stepwise logistic regression was used to identify potential predictive factors for PSM. Three logistic regression models were built: (1) one using preoperative variables only, (2) another using all variables (preoperative, intraoperative, and postoperative) combined, and (3) one created to identify potential predictive factors for PSM location. Preoperative variables entered into the models included age, body mass index (BMI), prostate-specific antigen, clinical stage, number of positive cores, percentage of positive cores, and American Urological Association symptom score. Intra- and postoperative variables analyzed were type of nerve sparing, presence of median lobe, percentage of tumor in the surgical specimen, gland size, histopathologic findings, pathologic stage, and pathologic Gleason grade. RESULTS AND LIMITATIONS: In the multivariable analysis including preoperative variables, clinical stage was the only independent predictive factor for PSM, with a higher PSM rate for T3 versus T1c (odds ratio [OR]: 10.7; 95% confidence interval [CI], 2.6-43.8) and for T2 versus T1c (OR: 2.9; 95% CI, 1.9-4.6). Considering pre-, intra-, and postoperative variables combined, percentage of tumor, pathologic stage, and pathologic Gleason score were associated with increased risk of PSM in the univariable analysis (p<0.001 for all variables). However, in the multivariable analysis, pathologic stage (pT2 vs pT1; OR: 2.9; 95% CI, 1.9-4.6) and percentage of tumor in the surgical specimen (OR: 8.7; 95% CI, 2.2-34.5; p=0.0022) were the only independent predictive factors for PSM. Finally, BMI was shown to be an independent predictive factor (OR: 1.1; 95% CI, 1.0-1.3; p=0.0119) for apical PSMs, with increasing BMI predicting higher incidence of apex location. Because most of our patients were referred from other centers, the biopsy technique and the number of cores were not standardized in our series. CONCLUSIONS: Clinical stage was the only preoperative variable independently associated with PSM after RARP. Pathologic stage and percentage of tumor in the surgical specimen were identified as independent predictive factors for PSMs when analyzing pre-, intra-, and postoperative variables combined. BMI was shown to be an independent predictive factor for apical PSMs. PMID- 20163912 TI - Annexin-1 protects MCF7 breast cancer cells against heat-induced growth arrest and DNA damage. AB - Stress proteins protect cells against the effects of heat stress, such as cell death and DNA damage. We wished to determine if Annexin-1 (ANXA1) could mediate heat-induced growth arrest and DNA damage in MCF7 breast cancer cells. Heat induced a significant growth arrest at 4h-24h. Growth arrest and heat-induced DNA damage were significantly inhibited in MCF7 cells over-expressing ANXA1. These effects were associated with enhanced ERK activation and reduction in JNK phosphorylation. This study demonstrates that ANXA1, which we recently reported as a possible tumor suppressor gene, can protect cells from heat-induced growth arrest and DNA damage. PMID- 20163913 TI - CYP1A1 and CYP1B1 gene expression and DNA adduct formation in normal human mammary epithelial cells exposed to benzo[a]pyrene in the absence or presence of chlorophyllin. AB - Benzo[a]pyrene (BP) is a potent pro-carcinogen and ubiquitous environmental pollutant. Here, we examined the induction and modulation of CYP1A1 and CYP1B1 and 10-(deoxyguanosin-N(2)-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPdG) adduct formation in DNA from 20 primary normal human mammary epithelial cell (NHMEC) strains exposed to BP (4muM) in the absence or presence of chlorophyllin (5muM). Real-time polymerase chain reaction (RT-PCR) analysis revealed strong induction of both CYP1A1 and CYP1B1 by BP, with high levels of inter-individual variability. Variable BPdG formation was found in all strains by r7, t8-dihydroxy-t-9, 10 epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)-DNA chemiluminescence assay (CIA). Chlorophyllin mitigated BP-induced CYP1A1 and CYP1B1 gene expression in all 20 strains when administered with BP. Chlorophyllin, administered prior to BP-exposure, mitigated CYP1A1 expression in 18/20 NHMEC strains (p<0.005) and CYP1B1 expression in 17/20 NHMEC strains (p<0.005). Maximum percent reductions of CYP1A1 and CYP1B1 gene expression and BPdG adduct formation were observed when cells were pre-dosed with chlorophyllin followed by administration of the carcinogen with chlorophyllin (p<0.005 for CYP1A1 and CYP1B1 expression and p<0.0005 for BPdG adducts). Therefore, chlorophyllin is likely to be a good chemoprotective agent for a large proportion of the human population. PMID- 20163914 TI - Gold(III) porphyrin 1a inhibited nasopharyngeal carcinoma metastasis in vivo and inhibited cell migration and invasion in vitro. AB - A physiologically stable gold compound, gold(III) meso-tetraphenylporphyrin (gold 1a), has been shown to be effective in inducing apoptosis and prolonging the survival of hepatocellular carcinoma (HCC)-bearing rats as well as inhibiting the tumor growth of mice bearing nasopharyngeal carcinoma (NPC), neuroblastoma and colon carcinoma. In this study, we showed that gold-1a prolonged the survival of NPC metastasis-bearing mice and inhibited intrahepatic and lung metastasis. Histologically, gold-1a markedly reduced tumor microvessel formation. Consistently, in in vitro studies, gold-1a inhibited migration and invasion of C666-1 human NPC cells. The data strongly support the use of gold(III) compounds to treat cancer metastasis. PMID- 20163915 TI - Combination with low-dose gemcitabine and hTERT-promoter-dependent conditionally replicative adenovirus enhances cytotoxicity through their crosstalk mechanisms in pancreatic cancer. AB - To overcome the limited clinical efficacy of conditionally replicative adenoviruses (CRAds), we investigated the effects of combination therapy with gemcitabine (GEM) and the hTERT-promoter-dependent CRAd (hTERT-CRAd), Ad5/3hTERTE1. This combination therapy exhibited enhanced cytotoxic effects on pancreatic cancer both in vitro and in vivo. Furthermore, we revealed that this enhancement effect was due to the multiple bidirectional interactions between hTERT-CRAd and GEM. The GEM-sensitizing effect of E1 expression derived from hTERT-CRAd, and the enhancement effect by GEM on hTERT promoter activity which led to the increase of adenovirus E1 and viral infectivity. This combination therapy may be a promising therapeutic approach for pancreatic cancer. PMID- 20163916 TI - A novel approximation method of CTF amplitude correction for 3D single particle reconstruction. AB - The typical resolution of three-dimensional reconstruction by cryo-EM single particle analysis is now being pushed up to and beyond the nanometer scale. Correction of the contrast transfer function (CTF) of electron microscopic images is essential for achieving such a high resolution. Various correction methods exist and are employed in popular reconstruction software packages. Here, we present a novel approximation method that corrects the amplitude modulation introduced by the contrast transfer function by convoluting the images with a piecewise continuous function. Our new approach can easily be implemented and incorporated into other packages. The implemented method yielded higher resolution reconstructions with data sets from both highly symmetric and asymmetric structures. It is an efficient alternative correction method that allows quick convergence of the 3D reconstruction and has a high tolerance for noisy images, thus easing a bottleneck in practical reconstruction of macromolecules. PMID- 20163917 TI - Plethora of agents, plethora of targets, plethora of side effects in metastatic renal cell carcinoma. AB - The plethora of novel agents recently approved for the management of metastatic renal cell carcinoma (RCC) has changed the therapeutic landscape in this disease. The plethora of targets some of these agents inhibit can result in a wide range of side effects. While these novel therapies can be viewed as inhibitors of angiogenesis that directly or indirectly target the vascular endothelial growth factor (VEGF) pathway, their individual mechanisms of action (MoA) are key to defining their side-effect profiles. Direct VEGF inhibition with the anti-VEGF monoclonal antibody bevacizumab, is primarily associated with side effects related to the precise inhibition of VEGF, such as proteinuria, hypertension and minor bleeding events. In contrast, non-VEGF-related side effects are observed with agents inhibiting multiple receptor tyrosine kinases (sunitinib, sorafenib, axitinib and pazopanib) and mammalian target of rapamycin inhibitors (temsirolimus and everolimus); these include diarrhoea, skin rash, stomatitis, hand-foot skin reaction, hypothyroidism, and haematological and metabolic abnormalities. This review discusses the MoA of these novel therapies and how a greater understanding of MoA may help to predict the range and type of side effects, develop combinations of agents with acceptable tolerability, enable a more rational approach to patient selection, and allow the development of effective side-effect management strategies. PMID- 20163919 TI - The influence of smokers' degree of dependence on the effectiveness of message framing for capturing smokers for a Quitline. AB - Smoking is a worldwide public health problem, and various communication strategies aimed at its cessation have been used. The objective of this paper was to explore differences over time of two communication strategies (gain-framed versus loss-framed) in encouraging calls to a Quitline, according to smoker's degree of dependence. A study was conducted for four weeks among passengers of two selected subway stations in the city of Rio de Janeiro-Brazil (N(average) = 12,500 passengers a day per station). The interventions - large posters with images and text based on central theme "shortness-of-breath" - also contained the Quitline number. Call rate differences between the strategies, overall and specific per study week, were calculated. Light smokers exposed to the positive content message called on average 2.2 times more often than those exposed to the negative-content message (p < 0.001). The absolute difference in call rates decreased after the first week of the study (p for the additive interaction between intervention and study week, 0.02). For heavy smokers, no differences between the two stations were observed. Additive interaction was found between type of smoker - light or heavy - and intervention (p = 0.02). The results suggest that short-term positive-content campaigns based on issues pertaining to individuals' daily routine could be effective in capturing light smokers. These results may have considerable public health impact, as the prevalence of less dependent smokers is much higher than that of heavier smokers. PMID- 20163918 TI - Analyzing family data: A GEE approach for substance use researchers. AB - INTRODUCTION: Analyzing data that arises from correlated observations such as husband-wife pairs, siblings, or repeated assessments of the same individuals over time requires more specialized analytic tools. Additionally, outcomes that are not normally distributed such as count data, (e.g., number of symptoms or number of problems endorsed) also require specialized analytic tools. Generalized estimating equations (GEE) are a very flexible tool for dealing with correlated data (such as data derived from related individuals such as families). The objective of this report was to compare traditional ordinary least squares regression (OLS) to a GEE approach for analyzing family data. METHODS: Using data from an ongoing five-wave longitudinal study of newlywed couples, we examined a subset of 173 families with children between the ages of 4 and 11 at two data collection points. The relation between parental risk factors (e.g., heavy drinking, aggression, marital quality) and child internalizing symptoms was examined within the context of two regression-based models: traditional OLS regression and a GEE approach. RESULTS: Overall, the GEE approach allowed a more complete use of the available data, provided more robust findings, and produced more reliable parameter estimates. CONCLUSION: GEE models are a flexible regression-based approach for dealing with related data that arises from correlated data such as family data. Further, given the availability of the models in common statistical programs, family researchers should consider these models for their work. PMID- 20163920 TI - Immigration, mental health and suicidal behavior. PMID- 20163921 TI - Gabapentin improves cold-pressor pain responses in methadone-maintained patients. AB - Individuals on methadone maintenance for the treatment of addiction (MM) are demonstrated to be hyperalgesic to cold-pressor pain in comparison to matched controls and ex-opioid addicts, a finding described as clinical evidence of opioid-induced hyperalgesia (OIH). Interestingly, opioids induce hyperalgesia via many of the same neuro-inflammatory and central sensitization processes that occur with the development of neuropathic pain. Evaluated in this study was the efficacy of a key pharmacotherapy for neuropathic pain, gabapentin (GPN), to reverse OIH in MM patients. Utilizing a clinical trial design and double blind conditions, changes in cold-pressor pain threshold and tolerance following a 5 week trial of GPN (titrated to 2400mg/day) were evaluated at peak and trough methadone plasma levels in a well-characterized MM sample. Drug abstinence was encouraged via an escalating payment schedule, and compliance monitored via pill counts and GPN plasma levels; entered into the analyses were only those subjects compliant and abstinent throughout the study (approximately 45%). Utilizing change scores from baseline, significant improvements in cold-pressor pain threshold and pain tolerance were observed at both peak and trough methadone levels (p<0.05). Notably, drop-out rates due to medication side effects were low (2%) and the medication was well-tolerated. These results support that GPN, as prescribed for the treatment of neuropathic pain, is effective in decreasing OIH in patients who are abstinent and stable in methadone treatment. PMID- 20163922 TI - HIV infection during limited versus combined HIV prevention programs for IDUs in New York City: the importance of transmission behaviors. AB - OBJECTIVES: As no single HIV prevention program has eliminated HIV transmission, there is growing interest in the effectiveness of "combined" prevention programming. To compare HIV infection among persons injecting in the initial programs environment (IPE) in New York City (self-initiated risk reduction, methadone, education/outreach, and HIV testing) to HIV infection among persons injecting in a combined programs environment (CPE) (above programs plus large scale syringe exchange). To identify potential behavioral mechanisms through which combined programs are effective. METHODS: Subjects were recruited from the Beth Israel drug detoxification program. A risk behavior questionnaire was administered and HIV testing conducted. Subjects who injected only between 1984 and 1994 (IPE) were compared to subjects who injected only between 1995 and 2008 (CPE). RESULTS: 261 IPE subjects and 1153 CPE subjects were recruited. HIV infection was significantly lower among the CPE subjects compared to IPE subjects: prevalence 6% versus 21%, estimated incidence 0.3/100 person-years versus 4/100 person-years (both p<0.001). The percentage of subjects at risk of acquiring HIV through receptive syringe sharing was similar across CPE and IPE subjects (30% versus 33%). The percentage of subjects at risk of transmitting HIV through injection-related behaviors (who were both HIV seropositive and reported passing on used needles/syringes), was much lower among the CPE subjects than among the IPE subjects (1% versus 10%, p<0.001). CONCLUSIONS: Combined prevention programs can greatly reduce HIV transmission. Reducing distributive sharing by HIV seropositive injecting drug users (IDUs) may be a critical component in reducing HIV transmission in high seroprevalence settings. PMID- 20163924 TI - Non-invasive methods of oestrus detection in captive southern hairy-nosed wombats (Lasiorhinus latifrons). AB - In order to develop a reliable method of oestrus detection in captive southern hairy-nosed (SHN) wombats, the reproductive behaviour of four groups of adult animals (1 male:2 female) was monitored using video surveillance and activity using movement-sensitive radio transmitters for a period of 12 months. During this time faecal samples were collected every 3 days and subsequently analysed for progesterone and oestradiol-17beta metabolites. In an attempt to induce and characterise oestrus-specific behaviour, each female was administered a subcutaneous injection of either 0.01 (n=2), 0.1 (n=4) or 0.2mg/kg (n=2) of oestradiol benzoate in one of two hormone trials. Remote video surveillance was an effective tool for detecting the reproductive behaviour of the captive SHN wombat. Courtship (n=426) and mating (n=46) was observed in five wombats and consisted of 13 distinctive behaviours in six consecutive phases: (1) investigation, (2) attraction, (3) chase, (4) restraint, (5) copulation and (6) recovery. Female sexual receptivity occurred at night and lasted for approximately only 13-h. Faecal progesterone metabolite analysis proved to be a reliable method for mapping oestrous cycle activity, but was not useful for the prediction of oestrus. Six out of the eight female wombats displayed periods of elevated progesterone secretion, corresponding to a mean (+/-SE) luteal phase of 20.9+/-1.1 days (n=23). Oestrous cycle length, defined as the interval between two successive luteal phases separated by a follicular phase was 31.8+/-1.1 days (n=12) and consisted of a follicular phase of 11.6+/-0.6 days (n=12). Changes in the secretion of faecal oestradiol-17beta metabolites provided little instructive information on oestrous cycle activity and were not associated with oestrus. Administration of oestradiol benzoate resulted in a spike of oestradiol-17beta metabolites in the faeces 3-4 days later, but was not dose dependent nor did it facilitate reproductive behaviour in either sex. Activity was not linked to key events in the oestrous cycle and appears not to be suitable as a method for detecting oestrus in the SHN wombat. We therefore recommend the use of 24-h video surveillance as the most reliable method for oestrus detection in captive SHN wombats. PMID- 20163923 TI - Increased error-related thalamic activity during early compared to late cocaine abstinence. AB - Altered cognitive control is implicated in the shaping of cocaine dependence. One of the key component processes of cognitive control is error monitoring. Our previous imaging work highlighted greater activity in distinct cortical and subcortical regions including the dorsal anterior cingulate cortex (dACC), thalamus and insula when participants committed an error during the stop signal task (Li et al., 2008b). Importantly, dACC, thalamic and insular activity has been associated with drug craving. One hypothesis is that the intense interoceptive activity during craving prevents these cerebral structures from adequately registering error and/or monitoring performance. Alternatively, the dACC, thalamus and insula show abnormally heightened responses to performance errors, suggesting that excessive responses to salient stimuli such as drug cues could precipitate craving. The two hypotheses would each predict decreased and increased activity during stop error (SE) as compared to stop success (SS) trials in the SST. Here we showed that cocaine dependent patients (PCD) experienced greater subjective feeling of loss of control and cocaine craving during early (average of day 6) compared to late (average of day 18) abstinence. Furthermore, compared to PCD during late abstinence, PCD scanned during early abstinence showed increased thalamic as well as insular but not dACC responses to errors (SE>SS). These findings support the hypothesis that heightened thalamic reactivity to salient stimuli co-occur with cocaine craving and loss of self control. PMID- 20163925 TI - A reduction in blood morphine concentrations amongst heroin overdose fatalities associated with a sustained reduction in street heroin purity. AB - To determine the effects of a sudden and sustained reduction in heroin purity on the toxicology of heroin overdose, 959 consecutive heroin overdose cases autopsied at the NSW Department of Forensic Medicine (1/1/1998-31/12/2006) were analysed. There was a significant reduction in blood morphine concentration across the study period (beta=-0.07), declining from a median of 0.50mg/L in the years 1998-2000 prior to 0.40mg/L in the period 2001-2006. There was no significant change in the proportion of alcohol positive cases, but the proportion of benzodiazepine positive cases increased across time (OR 1.11), as did methadone positive cases (OR 1.12). The decline in blood morphine concentrations remained significant after controlling for these factors (beta= 0.07). In determining toxic and lethal morphine concentrations, the fact that the toxicology of overdose is responsive to changes in the opioid street market needs to be borne in mind. PMID- 20163926 TI - The importance of medico-legal evaluation in a case with intraabdominal gossypiboma. AB - Data concerning the incidence of gossypiboma tend to fluctuate and is difficult to estimate because of a low reporting rate lest medico-legal implication. Gossypiboma is frequently located in the abdominal and pelvic cavities after gynecologic and upper abdominal surgical operations but can also follow thoracic, orthopedic, and urological and neurosurgical procedures. In medical literature, there are few articles about the medico-legal evaluation of gossypiboma although it is typically subjected to a medico-legal process. In this article, we reported a 22-year-old female case with intraabdominal gossypiboma following a cesarean procedure and discussed the importance of medico-legal evaluation of gossypiboma. PMID- 20163927 TI - [What are the guidelines for using a venous segment for an arterial bypass? General review]. AB - Since the first femoropopliteal bypass, performed by J. Kunlin, in 1950, the saphenous vein has remained the material of choice for arterial bypass in a wide variety of localizations. Harvesting must be adapted to vein quality and the length necessary for the bypass. A thorough knowledge of the histological structure of the graft and the impact of the harvesting process on endothelial cells is needed to understand early and late complications related to saphenous harvesting. Several experimental studies and clinical series, particularly for aortocoronary bypass, have shown the role of atraumatic harvesting, removing the perivenous fat, and/or papaverine infusion in the perivascular tissues. A venous graft can be used in six localizations. For femoropopliteal bypass, the venous graft can be used reversed or in situ, after valvular section. For bypass to tibial vessels and bypass to the ankle and the foot, the graft can be the greater saphenous vein or the lesser saphenous vein, or veins from the arm. These bypasses can be done reversed or in situ or transposed reversed or after valvular disruption. This technique has the advantage of placing the largest portion of the vein at the level of the proximal anastomosis, but with the risk of endothelial cell desquamation during vein harvesting, which can lead to late fibrosis of the graft. For aorto-iliac bypass, new prosthetic grafts and the development of endovascular techniques have overshadowed the former advantages of the saphenous vein grafts. Surgical renal revascularisations have become less frequent since the development of endovascular techniques. Nevertheless, the venous graft remains useful for some revascularisations - hepatic-renal bypass, iliorenal bypass, difficult nephrologic situations (solitary kidney, chronic occlusion). For aortocoronary bypass, long-term outcome has been studied in many studies. It is recommended to use the grafts with a no touch technique, using a portion without valves. The carotid venous graft is a useful technique when endarterectomy is difficult or not satisfactory. The graft must be harvested from the calf, without valves, have a diameter of 5mm and be harvested without injury. PMID- 20163928 TI - [Guidelines for good clinical practice: prevention and treatment of venous thromboembolism in medical patients]. PMID- 20163929 TI - IGF-1 stimulates protein synthesis by enhanced signaling through mTORC1 in bovine mammary epithelial cells. AB - Using the MAC-T cell line as a model, the effects of insulin-like growth factor (IGF)-1 on the regulation of protein synthesis through the mammalian target of rapamycin complex 1 (mTORC1) signaling in bovine mammary epithelial cells were evaluated. Global rates of protein synthesis increased by 47% within 30 min of IGF-1 treatment. The effect of IGF-1 on protein synthesis was associated with enhanced association of the eukaryotic initiation factor (eIF) 4E with eIF4G and a concomitant reduction of eIF4E association with eIF4E-binding protein-1 (4E BP1). There was a progressive increase in the phosphorylation state of ribosomal protein S6 kinase-1, a downstream target of mTORC1 in response to IGF-1. In addition, IGF-1 stimulated mTORC1 kinase activity toward 4E-BP1 in vitro. Phosphorylation on Ser473 of Akt was induced by IGF-1 within 5 min and remained elevated throughout a 30-min time course. The effect of IGF-1 on Akt phosphorylation was also concentration dependent. Activation of Akt by IGF-1 led to increased phosphorylation of tuberous sclerosis complex 2 on Thr1426, without any change in its association with tuberous sclerosis complex 1. Phosphorylation of proline-rich Akt substrate of 40-kDa (PRAS40) at Thr246 was stimulated by IGF 1. The amount of PRAS40 associated with mTORC1 decreased in response to IGF-1, and PRAS40 binding to mTORC1 was inversely related to its phosphorylation level. Overall, these results suggest that activation of the PI3K-Akt pathway by IGF-1 stimulated global protein synthesis in bovine mammary epithelial cells through changes in the phosphorylation and association state of components of the mTORC1 signaling pathway. PMID- 20163930 TI - Diagnosing occult tumour cells and their predictive value in sentinel nodes of histologically negative patients with colorectal cancer. AB - PURPOSE: Most studies on the sentinel node (SN) procedure in patients with colorectal cancer include immunohistochemical analysis of the SN only. To evaluate the real diagnostic accuracy of the SN procedure with immunohistochemical analysis, the presence of occult tumour cells in all histologically negative lymph nodes was compared to the presence of these cells in SNs. Also the reproducibility of diagnosing occult tumour cells (OTC) and the sensitivity of three different antibodies was assessed. METHODS: Between November 2006 en July 2007, an ex vivo SN procedure was performed in 58 histologically N0 patients with colorectal cancer. All lymph nodes (n = 908, mean 15.7) were step sectioned and immunohistochemistry was performed using two antibodies against cytokeratins (Cam5.2, and CK 20) and one antibody against BerEp-4. RESULTS: OTC were identified in 19 of 58 patients, with micrometastases (0.2-2 mm) in 7 and isolated tumour cells (ITC)(<0.2 mm) in 12 patients. The overall agreement in diagnosing OTC between two independent pathologists was 86%. An SN was identified in 53 of 58 patients. All micrometastases were found in SNs. In two patients with negative SNs, ITC's were demonstrated in non-SNs (sensitivity 88%, and overall accuracy 96%). CONCLUSION: Additional immunohistochemical analysis of histologically negative lymph nodes demonstrates occult tumour cells in 33% of the patients resulting in an upstaging rate of 12%. Occult tumour cells are predominantly found in the SN, therefore SN mapping has the potential to refine the staging system for patients with colorectal cancer. PMID- 20163931 TI - The use of CT derived solid modelling of the pelvis in planning cancer resections. AB - CLINICAL PROBLEM: Resection of malignant tumors of the pelvis is demanding. To avoid disabling hemipelvectomies, years ago internal hemipelvectomy combined with partial pelvic replacements had become a surgical procedure. To achieve adequate reconstructions custom-made replacements were recommended. In early stages of the surgical procedure using megaprostheses, individual pelvic models were manufactured. AIM OF THE STUDY: Since little is known about the accuracy of such models we analysed the charts of 24 patients (25 models) for whom an individual model of the osseous pelvis had been manufactured. RESULTS: Two patients refused surgery. In 23 patients partial resection of the bony pelvis was performed followed by a partial pelvic replacement (13x), hip transposition procedure (5x), ilio-sacral resection (4x), or revision surgery. In all patients who received a partial pelvic replacement, the fit of the replacement was optimal. No major unplanned resection was necessary. The same was observed in patients who received a hip transposition procedure or an ilio-sacral resection. Oncologically, in most of the patients we achieved wide resection margins (14x). In 5 patients the margins were marginal (4x) or intralesional (1x). In two cases the aim was a palliative resection because of a metastatic disease (1x) or benign entity (1x). CONCLUSION: Pelvic models are helpful tools to planning the manufacture of partial pelvic replacements and ensuring optimal osseous resection of the involved bone. Further attempts have to be made to evaluate the aim of navigational techniques regarding the accuracy of the osseous and soft-tissue resection. PMID- 20163932 TI - [Central nervous system imaging in multiple sclerosis]. AB - The diagnosis and management of patients with Multiple Sclerosis (MS) requires magnetic resonance imaging (MRI), that should be acquired according to a standardized and reproducible protocol, consistent with international guidelines. Hyperintensities on T2 or FLAIR sequences are a very sensitive finding in patients with MS but is not specific of the underlying pathology. Cerebral atrophy occurs very early in the course of the disease. Among patients with clinically isolated syndromes, the presence of spatially disseminated lesions on the initial MRI is highly predictive of the conversion to clinically definite MS. The correlations between clinical findings and radiological abnormalities identified on MRI conventional sequences remain poor, as conventional MRI doesn't accurately quantify the microscopic damage in normal appearing brain tissue. New sequences such as MR spectroscopy, diffusion tensor imaging, magnetization transfer imaging allow more sensitive quantification of such alterations. Molecular imaging by Positrons Emission Tomography is a very promising technique with high tissue specificity. It should improve our understanding of the pathophysiologic mechanisms involved in MS. PMID- 20163933 TI - Polymorphisms of genes encoding tumor necrosis factor-alpha, interleukin-10, cluster of differentiation-14 and interleukin-1ra in critically ill patients. AB - PURPOSE: The aim of the study was to determine whether distributions of tumor necrosis factor (TNF)-alpha(308), interleukin (IL)-10(1082), CD14(159), and IL 1ra gene intron 2 genotypes in critically ill patients are associated with outcome, underlying cause of sepsis, and type of microorganism. MATERIALS AND METHODS: Blood samples from 106 critically ill white patients were genotyped by method based on polymerase chain reaction for TNF-alpha(308), IL-10(1082), CD14(159), and IL-1ra gene intron 2. RESULTS: All patients with TNF-alpha(308)AA genotype survived; relative risk (RR) of death in patients with AG was 3.250 and with GG, 1.923 (P < .01). In patients with Gram-positive sepsis, IL-10(1082)AA and then AG genotypes were the most frequent ones (odds ratio [OR], 18.67 and 7.20, respectively; P < .01). When comparing IL-10(1082)AA with AG, RR of pancreatitis was 1.80 and OR was 3.40. When AA and GG were compared, RR was 7.33 and OR was 20.00. In patients with GG, RR of peritonitis was 4.07 and OR was 5.88 (P < .01). In patients with Gram-positive sepsis, CD14(159)CT was the most frequent one with OR of 5.25. Distribution of 6 IL-1ra gene intron 2 genotypes showed no significant association. CONCLUSIONS: Distribution of TNF-alpha(308) genotypes is associated with outcome, IL-10(1082) with type of microorganism and underlying cause of sepsis, and CD14(159) with type of microorganism. PMID- 20163934 TI - Deficits of visuospatial attention with reflexive orienting induced by eye-gazed cues in children with developmental coordination disorder in the lower extremities: an event-related potential study. AB - The present study aims to investigate and compare the behavioral performance and event-related potentials (ERPs) measures in children with developmental coordination disorder (DCD) and typically developing (TD) children when performing the visuospatial attention task with reflexive orienting. Thirty children with DCD and 30 TD children were recruited and presented with central eye-gazed cues. The children needed to detect and respond to laterally presented reaction signals preceded by centrally presented non-predictive directional and non-directional eye-gazed cues, which directed them to attend covertly to the right or left field location, or straight ahead, via stepping on pedals with their bilateral lower limbs, while brain ERPs were concurrently recorded. The behavioral data showed that children with DCD responded slowly and exhibited a deficit in inhibitory control capacity as compared to TD children. In terms of electrophysiological characteristics, children with DCD showed distinct modulatory effects upon longer N2 and P3 latencies, smaller P3 amplitude, an elongated interval between N2 and the motor response (N2 latency-RT), and small areas on Contingent Negative Variation (CNV). The behavioral and ERP data suggest that children with DCD could have deficits in the ventral attention network and the mechanisms on the inhibitory control difficulty, when performing such a task, could be a slower response inhibitory process and stimulus classification speed, less ability in interhemispheric and cognitive-to-motor transfer speed, and less mature abilities with regard to anticipatorily executive and motor preparatory processes. PMID- 20163935 TI - REMOVAL: Elevated serum S100B protein in first-episode drug-naive Chinese patients with schizophrenia. Retraction. PMID- 20163936 TI - Paternal age and mortality in nonaffective psychosis. AB - INTRODUCTION: Advanced paternal age (APA) is associated with an increased mortality in the general population, and is a risk factor for schizophrenia. We aimed to test if APA is associated with increased mortality in people with nonaffective psychosis. METHODS: Subjects with nonaffective psychosis who were born in Helsinki, Finland, between 1951 and 1960 (n=529) were followed until June 2006 (age 46 to 55). Hazard ratios were calculated, adjusting for subject age, age of the other parent, and gender. RESULTS: In females but not males, there was a significant increase in all-causes mortality (HR=7.04, 95% CI 1.60-31.04, p=0.01) and natural deaths (HR=7.64, 95% CI 1.20-48.66, p=0.03) in offspring of fathers age > or =40, after adjustment for potential confounders. In males but not females, there was a significant decrease in suicides (HR=0.89, 95% CI 0.81 0.97, p=0.01) with increasing maternal age (as a continuous variable). In the entire sample, there was also a trend for decreased all-cause mortality (HR=0.96, 95% CI 0.92-1.01, p=0.08) with increasing maternal age (as a continuous variable). DISCUSSION: Both paternal and maternal age may affect mortality risk in offspring with psychosis. The specific disorders and pathway(s) associated with the increase in natural cause mortality remain to be determined. PMID- 20163937 TI - Effect of hypertriglyceridemia on the pharmacokinetics and blood-brain barrier penetration of clozapine and norclozapine following administration to rats. AB - There is a long-term discussion in the literature concerning the possible link between the improved efficacy of clozapine treatment and elevated plasma triglyceride levels, but no mechanistic studies have been performed to date. The aim of this work was to investigate whether the postprandial hypertriglyceridemia affects the pharmacokinetics and brain distribution of clozapine and norclozapine. Experimental hypertriglyceridemia in rats was induced by oral administration of peanut oil and the pharmacokinetic parameters and brain penetration of clozapine and norclozapine following administration of clozapine were compared to normotriglyceridemic control animals. Moderately increased clearance of clozapine was found in hypertriglyceridemic animals compared to control group. No changes were found in penetration of compounds across the blood brain barrier (BBB). Taken together, the results do not support the hypothesis that hypertriglyceridemia improves the effect of clozapine by altered pharmacokinetics of clozapine and norclozapine and their increased penetration across the BBB. PMID- 20163938 TI - First report of Calyptospora sp. (Apicomplexa, Calyptosporidae) in forage characid fish from the Tres Marias Reservoir, Sao Francisco Basin, Brazil. AB - Coccidians are parasitic protozoans, and Calyptospora is an important genus of coccidia found in freshwater and marine fish of the Americas. This paper describes Calyptospora sp. that were found parasitizing the liver and intestine of Triportheus guentheri and the intestine of Tetragonopterus chalceus, two forage fish species from the Tres Marias Reservoir, Upper Sao Francisco River, State of Minas Gerais, Brazil. Apicomplexa found in the Sao Francisco Basin are reported here for the first time. PMID- 20163939 TI - Microangiopathy is independently associated with presence, severity and composition of carotid atherosclerosis in type 2 diabetes. AB - BACKGROUND AND AIMS: Common mechanisms for the development of micro- and macroangiopathic diabetic complications have been suggested. We aimed to cross sectionally investigate strength and characteristics of the association between carotid atherosclerosis and microangiopathy in type 2 diabetic patients. METHODS AND RESULTS: Common carotid artery intima-media thickness (cIMT), carotid plaque (CP) type and degree of stenosis were evaluated by ultrasound, along with the determination of anthropometric parameters, HbA1c, lipid profile, assessment of diabetic retinopathy and nephropathy, in 662 consecutive patients with type 2 diabetes mellitus (T2DM). Patients were divided according to high/low cIMT, presence/absence of CP and of retinopathy and nephropathy. Patients with CP were older, more prevalently males, past smokers, had longer diabetes duration, significantly lower HDL cholesterol and more prevalent ischemic heart disease (all p<0.05) as compared to those with cIMT < 1 mm. Microangiopathies were more prevalent in patients with CP than in those without. At multivariate logistic regression, factors independently associated with the presence of CP were age, past smoke, HDL cholesterol, retinopathy and retinopathy plus nephropathy. A significant independent correlation of CP stenosis with stage of retinopathy and nephropathy was found. Finally, echolucent CPs were associated with a lower prevalence of proliferative retinopathy than CP containing calcium deposits. CONCLUSION: In T2DM, retinopathy, alone or in combination with nephropathy, is independently associated to CP, and severity of microangiopathy correlates with severity of carotid atherosclerosis. These observations, together with the different prevalence of proliferative retinopathy according to CP types, point to possible common pathogenic mechanisms in micro- and macrovascular complications. PMID- 20163940 TI - Parental history of premature myocardial infarction is a stronger predictor of increased carotid intima-media thickness than parental history of hypertension. AB - An increased carotid intima-media thickness (IMT) is detectable in young subjects with parental history of premature myocardial infarction (PHPMI) or hypertension (PHH). In this study we evaluated if PHPMI and PHH exert a different influence on carotid IMT and if their conjunction produces additive effects. High-resolution B mode ultrasonographic evaluation of common carotid artery IMT was acquired from 48 subjects without PHPMI and PHH (22 males, 26 females; mean age 22.1+/-4.9 years; controls), 24 age- (+/-1 year) and sex-matched subjects with PHH without PHPMI (PHH-positive/PHPMI-negative subjects), 24 age- and sex-matched subjects with PHPMI without PHH (PHH-negative/PHPMI-positive subjects) and 24 age- and sex matched subjects with both PHPMI and PHH (PHH/PHPMI-positive subjects). Lipid profile, resting blood pressure, smoking behaviour and body mass index (BMI) were also assessed. Carotid IMT was smaller in controls (0.41+/-0.07mm) compared to PHH-positive/PHPMI-negative subjects (0.47+/-0.10, p=0.023), to PHH negative/PHPMI-positive subjects (0.54+/-0.11, p<0.001) and to PHH/PHPMI-positive subjects (0.52+/-0.10mm, p<0.001). Carotid IMT was greater in PHH-negative/PHPMI positive (p=0.006) and in PHH/PHPMI-positive (p=0.031) than in PHH-positive/PHPMI negative subjects. No difference in carotid IMT was evident between PHH negative/PHPMI-positive and PHH/PHPMI-positive subjects (p=0.549). In the comparison among subjects using multiple regression analysis, only PHPMI, age and BMI were independently associated with carotid IMT. In healthy young subjects with PHPMI and/or PHH, carotid IMT is increased. PHPMI is a stronger predictor of increased carotid IMT than PHH. PHH in conjunction with PHPMI does not add any further detrimental effect on carotid IMT. PMID- 20163941 TI - The effect of comprehensive lifestyle intervention or metformin on obesity in young women. AB - BACKGROUND AND AIM: Young women are at high risk of weight gain but few weight management interventions have been investigated in this group. This study aimed to determine the effect of metformin on body weight, body composition, metabolic risk factors and reproductive hormone levels in overweight or obese young women compared to placebo and comprehensive lifestyle intervention. METHODS AND RESULTS: 203 overweight or obese young women (BMI 33.2+/-0.3 kg/m2, age 28+/-0.3 years) were randomised to 1500 mg/day metformin (M) plus general lifestyle advice, placebo (P) plus general lifestyle advice or comprehensive lifestyle intervention including structured diet, exercise and behavioural therapy (L) for 12-weeks. At 12-weeks, linear mixed models found that L group had greater weight loss (-4.2+/-0.4 kg) compared to M (-1.0+/-0.4 kg) and P groups (-0.2+/-0.3 kg) (P < 0.0001). Weight loss between M and P groups were not significantly different. Attrition rate was 48% for L, 34% for M and 29% for P (P = 0.08). Intention-to-treat analysis showed that 10% (8/79) of the subjects in P group had gained weight (>3%), compared to 3% (2/65) from M group and none (0/59) from L group (P < 0.001). The L group had the greatest decrease in waist circumference ( 5.2+/-0.7 cm) and fat mass (-5.4+/-0.7 kg) compared to the other groups (P < 0.05). No significant time-by-group effects were seen in plasma lipids, SHBG, testosterone, blood pressure, serum folate, serum ferritin and serum vitamin B12. CONCLUSION: Lifestyle intervention was more effective in reducing body weight and improving body composition compared to metformin among healthy overweight or obese young women. PMID- 20163942 TI - Inhibitory effect of Ruta graveolens L. on oxidative damage, inflammation and aortic pathology in hypercholesteromic rats. AB - The purpose of the study was to investigate the efficacy of methanolic extract of Ruta graveolens L. in reducing oxidative damage, inflammation and aortic pathology in hypercholesteremic rats. For the study rats were divided into three groups - control group, hypercholesteremic group and treatment group (20 mg MER/kg/d orally) - and were fed for 90 days. Serum total cholesterol, LDL-C, total WBC count, CRP level, TBARS, atherogenic index, activities of COX, 15 LOX in monocyte and serum myeloperoxidase were increased in cholesterol fed rats. Activities of antioxidant enzymes and the concentration reduced glutathione in liver and heart tissue and serum HDL-C were decreased in cholesterol fed rats. The results showed that level of total cholesterol, LDL-C, atherogenic index was decreased and HDL-C was increased in MER treated rats. Activities of antioxidant enzymes were found to be increased and the activity of MPO, COX and 15 LOX were decreased on supplementation with MER. Concentration of TBARS and total WBC count were decreased and GSH was increased on supplementation with MER. Histopathology of aorta of cholesterol fed rat showed marked alterations whereas the aorta of MER administrated rat showed no significant changes. These results suggested that MER reduces oxidative stress, inflammation and aortic pathology in hypercholesteremic rats. Thus the plant may therefore be useful for therapeutic treatment of clinical conditions associated atherosclerosis. PMID- 20163943 TI - Pulmonary inflammation in asbestos-exposed subjects with borderline parenchymal changes on HRCT. AB - Many asbestos-exposed subjects have minor parenchymal changes on high resolution computed tomography (HRCT) that do not fulfil the diagnostic criteria for pulmonary fibrosis and asbestosis. We investigated if these borderline parenchymal changes in asbestos-exposed subjects are related to pulmonary inflammatory activity. Exhaled nitric oxide was measured, exhaled breath condensate collected and HRCT scanned in 104 subjects with moderate to high occupational asbestos exposure. Forty-one healthy unexposed subjects served as a comparison group. After excluding other pulmonary diseases, 35 asbestos-exposed subjects had normal parenchymal findings and 31 subjects had borderline parenchymal changes on HRCT. Lung function was poorer in the latter group, but there was no difference in the degree of asbestos exposure between these groups. As compared with the unexposed comparison group, asbestos-exposed subjects with borderline parenchymal changes had increased alveolar NO concentration (3.0 + or 0.2 vs. 2.3 + or - 0.1 ppb, p = 0.008) and increased levels of leukotriene B(4) (12.2 + or - 1.1 vs. 3.3 + or - 0.8 pg/ml, p < 0.001) and 8-isoprostane (9.4 + or - 0.7 vs. 7.3 + or - 0.6 pg/ml, p = 0.021) in breath condensate. Asbestos-exposed subjects with normal parenchymal findings had only increased breath condensate levels of leukotriene B(4) (11.4 + or - 0.9, p < 0.001). Borderline parenchymal changes on HRCT in asbestos-exposed subjects are associated with increased markers of pulmonary inflammation. Such borderline parenchymal changes are likely a mild or early form of the same pathological process that leads to asbestosis. PMID- 20163944 TI - Continuous versus on-demand pharmacotherapy of allergic rhinitis: evidence and practice. AB - This review aims to compare continuous with on-demand pharmacotherapy of allergic rhinitis by focusing on pharmacodynamic, pharmacokinetic, safety, effectiveness, cost and cost-effectiveness considerations. A working party of experts reviewed and discussed the literature and guidelines, and conducted a qualitative analysis of the Summary of Product Characteristics of specific medicines. With respect to medicines, the working party limited itself to antihistamines, nasal corticosteroids and leukotriene antagonists. Based on a review of the evidence from a multidisciplinary perspective, this article makes pharmacotherapeutic recommendations that are easy, functional and applicable to daily practice in primary care. The pharmacotherapeutic evidence for continuous versus on-demand treatment of allergic rhinitis was limited. Clearly, for corticosteroids, their mechanism of action in allergic rhinitis of reducing allergic inflammation requires continuous therapy at least for the duration of symptoms. For H(1) antihistamines, some trials suggest that continuous treatment is preferable but more studies are needed to confirm this conclusion. For both H(1)-antihistamines and nasal corticosteroids safety data indicate that continuous treatment may be given without fears of adverse consequences, although a distinction can be made between the first and the second generation antihistamines. With regard to the cost and cost-effectiveness implications of continuous therapy versus on-demand therapy, more studies are necessary before definitive conclusions may be made. PMID- 20163946 TI - Public Health and the origins of the Mersey Model of Harm Reduction. AB - In the mid-1980s in Liverpool, and the area surrounding it (Merseyside and Cheshire), harm reduction was adopted on a large scale for the first time in the UK. The harm reduction model was based on a population approach to achieve the public health goal of reducing the harm to health associated with drug use. The particular concern at that time was the risk of HIV infection, but there was also the issue of the health of a group of young people who were under-served by health services. To achieve the goal, services were developed that would attract the majority of those at risk within the community, not simply the few who wished to stop using drugs, and which would enable contact with the target group to be maintained so as to bring about the necessary changes in behaviour required to maintain health and reduce risk. This Commentary describes some of the background to the development of the Mersey Model of Harm Reduction from the memories and perspectives of two people who promoted harm reduction within the health service and the region. PMID- 20163947 TI - Use of Brazilian sugarcane bagasse ash in concrete as sand replacement. AB - Sugarcane today plays a major role in the worldwide economy, and Brazil is the leading producer of sugar and alcohol, which are important international commodities. The production process generates bagasse as a waste, which is used as fuel to stoke boilers that produce steam for electricity cogeneration. The final product of this burning is residual sugarcane bagasse ash (SBA), which is normally used as fertilizer in sugarcane plantations. Ash stands out among agroindustrial wastes because it results from energy generating processes. Many types of ash do not have hydraulic or pozzolanic reactivity, but can be used in civil construction as inert materials. The present study used ash collected from four sugar mills in the region of Sao Carlos, SP, Brazil, which is one of the world's largest producers of sugarcane. The ash samples were subjected to chemical characterization, sieve analysis, determination of specific gravity, X ray diffraction, scanning electron microscopy, and solubilization and leaching tests. Mortars and concretes with SBA as sand replacement were produced and tests were carried out: compressive strength, tensile strength and elastic modulus. The results indicated that the SBA samples presented physical properties similar to those of natural sand. Several heavy metals were found in the SBA samples, indicating the need to restrict its use as a fertilizer. The mortars produced with SBA in place of sand showed better mechanical results than the reference samples. SBA can be used as a partial substitute of sand in concretes made with cement slag-modified Portland cement. PMID- 20163948 TI - Solid waste workers and livelihood strategies in Greater Port-au-Prince, Haiti. AB - The solid waste management industry in Haiti is comprised of a formal and an informal sector. Many basic activities in the solid waste management sector are being carried out within the context of profound poverty, which exposes the failure of the socioeconomic and political system to provide sufficient job opportunities for the urban population. This paper examines the involvement of workers in the solid waste management industry in Greater Port-au-Prince and the implications for livelihood strategies. The findings revealed that the Greater Port-au-Prince solid waste management system is very inclusive with respect to age, while highly segregated with regard to gender. In terms of earning capacity, the results showed that workers hired by the State agencies were the most economically vulnerable group as more than 50% of them fell below the official nominal minimum wage. This paper calls for better salary scales and work compensation for the solid waste workers. PMID- 20163949 TI - Use of FGD gypsum in fire resistant panels. AB - Gypsum from power plant flue gas desulphurization units (FGD gypsum) is a combustion by-product produced in high quantities. In this paper, gypsum panels composed of 100% FGD gypsum from two power plants have been subjected to different physico-chemical (density, pH, humidity), mechanical (flexural and compressive strength, surface hardness, impact resistance), fire resistance and environmental tests (leaching and radioactivity). The results obtained have been compared with the requirements established in some European standards for commercial gypsum and other standards for similar products. In addition, the panels manufactured have been compared with commercial gypsum panels in order to determine the recycling possibilities of this kind of material in this application. PMID- 20163950 TI - Metabolic flux analysis in eukaryotes. AB - Metabolic flux analysis (MFA) represents a powerful tool for systems biology research on eukaryotic cells. This review describes recent advances, the challenges as well as applications of metabolic flux analysis comprising fungi, mammalian cells and plants. While MFA is widely established and applied in microorganisms, it remains still a challenge to adapt these methods to eukaryotic cell systems having a higher complexity particularly concerning compartmentation or media composition. In fungi MFA was used in the past few years to analyze a variety of conditions and factors and their effects on cellular metabolism. In mammalian cells MFA was applied mainly in cell culture technology and in medical and toxicological research. (13)C metabolic studies on native whole plants are additionally challenging by the fact that CO(2) is usually the only carbon source. PMID- 20163951 TI - Staging early ovarian cancer: impact on treatment decisions. PMID- 20163952 TI - What reasons lie behind long-term survival differences for gastric cancer within Europe? AB - BACKGROUND: Wide geographic variations in survival for gastric cancer in Europe have been reported. The aim of this study was to analyse the effect of stage at diagnosis, treatment and cancer characteristics on long-term survival for gastric cancer in populations covered by cancer registries. METHODS: We analysed survival in 4620 cases of gastric cancer from 17 European population-based cancer registries from 8 countries. Univariate and multivariate regression of relative survival were performed. RESULTS: Five-year relative survival varied between 10.6% and 24.0%, while 10-year survival ranged from 7.7% to 23.0%. After adjustment for age and sex, the regional excess hazard ratio (EHR) of death was significantly higher in Ragusa, Granada, Yorkshire, Slovakia, Slovenia and Poland than in France, Northern Italy, The Netherlands and the Basque Country. After further adjustment for surgical resection versus no resection (a proxy of stage), the EHR of death remained significantly higher only in Granada and Yorkshire than in the reference country (France). After adjustment for stage, the EHR was significantly higher only in Yorkshire (EHR: 1.51; 95% confidence interval (CI): 1.29-1.77). The EHR in this area was limited to the first year following diagnosis. CONCLUSION: Differences across Europe in gastric cancer survival depend to a large extent on differences in stage at diagnosis. However they do not explain all variations. Quality of management and treatment can explain some differences. PMID- 20163953 TI - Short-term incorporation of organic manures and biofertilizers influences biochemical and microbial characteristics of soils under an annual crop [Turmeric (Curcuma longa L.)]. AB - The study was conducted to determine whether short-term incorporation of organic manures and biofertilizers influence biochemical and microbial variables reflecting soil quality. For the study, soils were collected from a field experiment conducted on turmeric (Curcuma longa L.) involving organic nutrient management (ONM), chemical nutrient management (CNM) and integrated nutrient management (INM). The findings revealed that application of organic manures and biofertilizers (ONM and INM) positively influenced microbial biomass C, N mineralization, soil respiration and enzymes activities. Contrarily, greater metabolic quotient levels in CNM indicated a stressed soil microbial community. Principal component analysis indicated the strong relationship between microbial activity and the availability of labile and easily mineralizable organic matter. The findings imply that even short-term incorporation of organic manures and biofertilizers promoted soil microbial and enzyme activities and these parameters are sensitive enough to detect changes in soil quality due to short-term incorporation of biological fertilizers. PMID- 20163954 TI - Ammonium biosorption onto sawdust: FTIR analysis, kinetics and adsorption isotherms modeling. AB - Sawdust, an available and renewable biomass, was investigated as a novel ammonium biosorbent. Biosorption occurred over a pH range of 6-10, reached an equilibrium state within only 20 min, and can be described by a pseudo-second-order model predicting a chemisorption process. Equilibrium data were very well represented by Langmuir isotherm and confirm monolayer coverage. FTIR analysis before and after biosorption of ammonium onto sawdust suggested that the main mechanisms involved in the removal of ammonium might be the ionic exchange and complexation. The use of sawdust presents an interesting option for both tertiary wastewater treatment (as a possible non-conventional biosorbent for the removal of ammonium), and waste recycling (as a fertilizer and compost). PMID- 20163955 TI - Rapid characterization of biomass using near infrared spectroscopy coupled with multivariate data analysis: Part 1. Yellow-poplar (Liriodendron tulipifera L.). AB - This paper is the first of a two series papers on the use of near infrared (NIR) coupled with multivariate data analysis (MVDA) as a process analytical technology (PAT) tool for the rapid characterization of physical and chemical properties of two common West Virginian hardwood species, northern red oak (Quercus rubra) and yellow-poplar (Liriodendron tulipifera L.). These two wood species are potential feed stock for the bio-refinery industry. In Part 1, we report our results on yellow-poplar. The results of this study demonstrated that some preprocessing operations on the NIR spectra (first derivative) greatly improved all the prediction models developed in the study. Predictive PLS1 models developed using selective spectra regions, 1300-1800 nm and the full NIR region (800-2400 nm), were similar. The selective spectra region, 1300-1800 nm, included the first and second overtone of the NIR spectrum (1300-1800 nm). Measured and predicted physical and chemical properties of yellow-poplar yielded moderate to high correlation (R2). PMID- 20163956 TI - Three-phase partitioning of hydrolyzed levan. AB - During the fructose and polymerization to synthesize levan, smaller fructooligosaccharide (FOS) molecules are produced. FOS can also be obtained by levan hydrolysis. Three-phase partitioning (TPP) is a separation technique that has been used for polysaccharide precipitation and gathers t-butanol and ammonium sulphate to exclude the polymer from the aqueous solution. In this work TPP was tested to separate levan and FOS from aqueous solution. The FOS used was obtained from Zymomonas mobilis levan acid hydrolysis and fractionation with ethanol. The yield of low TPP fractions was higher than those obtained from the native levan. The F-90 exhibited a higher yield than other fractions. However, when applying the TPP technique to lightest fraction not precipitated by ethanol at 90% (F>90), the intermediate phase was not possible to be visualize. These results have potential application because they show that by using the levan TPP separation it is possible to separate low-molecular weight sugar. PMID- 20163957 TI - Steam plasmatron gasification of distillers grains residue from ethanol production. AB - In this study, a plasmatron reactor was used for gasifying the waste of distillers grains at different temperatures (773, 873, 973 K) and water flow rates (1, 2, 3 mL min(-1)), which were heated to produce steam. Among all the gas products, syngas was the major component (88.5 wt.% or 94.66 vol.%) with temperatures yielding maximum concentrations at 873 K with a relatively high reaction rate. The maximum concentrations regarding gaseous production occurring times are all below 1 min. With the increase of steam, the recovery mass yield of syngas also increases from 34.14 to 45.47 approximately 54.66 wt.% at 873 K. Water-gas reactions and steam-methane reforming reactions advance the production of syngas with the increase of steam. Furthermore, the water-shift reaction also increases in the context of steam gasification which leads to the decrease of CO(2) at the same time. PMID- 20163958 TI - Evaluation of the binding of iron(II) to humic substances derived from a compost sample by a colorimetric method using ferrozine. AB - In evaluating the quality of composts that include humic substances (HSs), the binding of iron(II) (conditional binding constants and binding capacities) are an important criteria. To determine the binding ability, it is necessary to determine the concentrations of free Fe(2+) and Fe(II)-HS complex species present. In the present study, we describe a colorimetric method for determining free Fe(2+) species using ferrozine in an aqueous solution of Fe(2+) and HS. It was found that the colored species in the Fe(2+) and HS mixture represented only free Fe(2+) species. Two water soluble fractions of HS, humic (HA) and fulvic (FA) acids, were isolated from a compost sample, and the conditional binding constants and binding capacities were estimated by colorimetric titration. Differences in the binding of Fe(II) to HA and FA are discussed, based on their structural features, which were characterized by acidic functional group analysis, elemental analysis and solid-state CP-MAS (13)C NMR spectral data. PMID- 20163959 TI - Wool keratin-stabilized silver nanoparticles. AB - In this paper, we explored a facile method to prepare stable silver nanoparticles (Ag NPs) using extracted wool keratin as the capping agent. The formation of Ag NPs was investigated by UV-Vis spectroscopy, X-ray photo-electron spectrometer and X-ray diffraction spectrometer. The morphology of the NPs was detected by scanning electron microscopy in vacuum and atomic force microscopy in fluid. The possible interactions between the silver core and the capping agent have been investigated using Fourier transform infrared spectroscopy. The effects of keratin concentration on the incubation of the NPs were studied by UV-Vis spectra. It was found that under alkaline condition the process of incubation was much faster than that under neutral pH condition. The photoluminescence properties of the Ag NPs were also investigated. We believe that this work is helpful for the high-value utilization of wool and other keratin-rich bioresource. PMID- 20163960 TI - Model development and simulation for predicting risk of foaming in anaerobic digestion systems. AB - Although there is not a complete agreement on the causes of foaming in anaerobic digestion, experts and operators do have valuable empirical knowledge of key factors. Based on this knowledge, a model for calculating the risk of foaming in anaerobic digestion systems due to microbiological causes has been developed. Organic loading rate, variation in organic loading rate, and the presence of filamentous microorganisms in the activated sludge system, used as a feed source for the digester, have been selected as the inputs of a knowledge-based model designed to provide as output the risk of foaming in an anaerobic digester. The performance of the model is demonstrated by means of a case study using the IWA Benchmark Simulation Model No. 2 as a framework, where risk of foaming is used as a new evaluation criterion. The simulated results of an open-loop configuration and two closed-loop control strategies illustrate the usefulness of this knowledge-based approach as a means of estimating the risk of foaming in anaerobic digestion. PMID- 20163961 TI - Radioguided occult lesion localization (ROLL) for non-palpable breast cancer: a comparison between day-before and same-day protocols. AB - BACKGROUND: Although radioguided occult lesion localization (ROLL) has become a widely accepted technique, the optimal time interval between the radioisotope injection and surgery has not yet been determined. AIM: To delineate the effects of time from the injection of the radionuclide until surgery on the ROLL success rate in a patient population diagnosed as having non-palpable breast cancer. METHODS: Between December 2004 and May 2009, 75 patients underwent ROLL procedure. The day-before protocol and same-day protocols included 50 and 25 breast cancer patients respectively. RESULTS: The two study groups were comparable in terms of age, localization technique, radiological findings and the type of surgical procedures (P > 0.05). No statistically significant difference was noticed in the pathological diagnosis, cancer size and the surgical margin clearance between the two groups (P > 0.05). CONCLUSIONS: Same-day injection of the radiotracer was not superior to the day-before injection in ROLL. The day before protocol can be scheduled for the convenience of both patients and hospital staff. PMID- 20163962 TI - Non-linear dynamical features of center of pressure extracted by recurrence quantification analysis in people with unilateral anterior cruciate ligament injury. AB - Knowledge about the non-linear dynamical pattern of postural sway may provide important insights into the adaptability (flexibility) of human postural control in response to everyday stresses imposed on the body. A commonly used non-linear tool, i.e. recurrence quantification analysis, was chosen to investigate the effect of prior anterior cruciate ligament injury on the deterministic pattern of postural sway under different conditions of postural and cognitive difficulty. In double leg stance, as postural difficulty increased from open-eyes to closed-eyes and rigid-surface to foam-surface, the centre of pressure regularity (%determinism) increased as well. In comparison to healthy counterparts, subjects with prior anterior cruciate ligament injury produced more regularity when maintaining balance on their injured leg. Also, for both the double and single leg stance balance conditions, the performance of a secondary cognitive task (a backward digit span task) caused less center of pressure regularity than the single postural task, which suggests that both study populations required the same amount of cognitive involvement for maintaining balance. Center of pressure dynamic patterns exhibited by the anterior cruciate ligament deficient patients were more regular than those of the healthy controls indicating "complexity loss" and may be indicative of the reduced adaptability (flexibility) of a balance system to sudden perturbations. PMID- 20163963 TI - Head stabilization in children of both genders during level walking. AB - Young healthy adults adopt a "head stabilization in space" strategy during walking by attenuating the acceleration going up from pelvis-to-head level. A gender difference exists in this control strategy, particularly evident in the control of medio-lateral dynamic equilibrium. This study aims at assessing whether this difference is already present at pre-pubertal age. Two groups of children (15 females and 15 males, age range: 8-11 years) were involved in the study. They were asked to walk at self-selected speed and movement data were collected using three inertial sensors firmly attached at pelvis (P), shoulder (S), and head (H) levels. The RMS of the accelerations of P, S, and H were computed along the antero-posterior (AP), medio-lateral (ML), and vertical (V) directions and used to compare the two groups. No differences were found between the two groups in the pelvis and shoulder acceleration RMS values. Conversely, lower head acceleration RMS values were found for the females in both the AP and ML directions. Both groups managed to attenuate the upper body AP and ML accelerations going from pelvis-to-head level, with higher attenuations found for the females. The results of this study suggest that the gender differences in the ability to control the head accelerations during gait, found in a previous study, are due neither to different mass distribution nor to a compensation of the greater pelvic motions, nor are they the result of gender related walking habits (e.g. use of high heels). PMID- 20163964 TI - The eukaryotic replicative DNA polymerases take shape. AB - Three multi-subunit DNA polymerase enzymes lie at the heart of the chromosome replication machinery in the eukaryotic cell nucleus. Through a combination of genetic, molecular biological and biochemical analysis, significant advances have been made in understanding the essential roles played by each of these enzymes at the replication fork. Until very recently, however, little information was available on their three-dimensional structures. Lately, a series of crystallographic and electron microscopic studies has been published, allowing the structures of the complexes and their constituent subunits to be visualised in detail for the first time. Taken together, these studies provide significant insights into the molecular makeup of the replication machinery in eukaryotic cells and highlight a number of key areas for future investigation. PMID- 20163965 TI - Arthroscopic loose body removal and cyst decompression using a posterior trans septal portal in the blind spot during knee arthroscopy--technical report. AB - Some lesions such as cyst, loose body, and mass around the knee joint tend to localize at the posterior aspect of the proximal tibia. Although arthroscopic procedures of the knee joint's posterior compartment have been developed through posteromedial, posterolateral, and posterior trans-septal portals, the posterior aspect of the proximal tibia remains difficult to access and manipulate. We report an arthroscopic loose body removal and cyst decompression on the posterolateral aspect of the proximal tibia using a posterior trans-septal portal. This area represents a blind spot in knee arthroscopy. PMID- 20163966 TI - Fibular head osteotomy: a new approach for the treatment of lateral or posterolateral tibial plateau fractures. AB - BACKGROUND: A variety of surgical approaches have been employed previously for the open reduction and internal fixation of the fractures of lateral and posterolateral tibial plateau. However, the commonly used lateral approach does not provide adequate exposure and access to the posterolateral aspect of the lateral tibial plateau. We developed a new approach with osteotomy of fibular head to solve this problem and report its preliminary result. METHODS: Eighty-two patients with lateral or posterolateral tibial plateau fractures had been treated by this approach. According to the fractures, partial or full heads of the fibula were removed, and knee joint function, including stability of the knee, was evaluated by X-ray and physical examinations. RESULTS: All 82 cases were followed up for a mean of 3.2 y 2.0-5.6 y). In each case, the fractures were completely healed and knee joint function was restored. No infection or skin and bone necrosis were found. After one year following the operation, functional assessment of the knee joints by Rasmussen's functional grading system revealed a mean score of 27.9 (24-30). In addition, the radiological assessment by Rasmussen's anatomical grading system resulted in a mean score of 16.8 (14-18). Six patients experienced occasional pain or bad wither pain around knee joints, three of which had lateral-longitudinal instability of knee joint and three lost height of the tibial plateau. CONCLUSIONS: The new approach provides excellent visualization, which can facilitate the reduction and internal fixation for lateral or posterolateral tibial plateau fractures, and shows encouraging results. PMID- 20163967 TI - Chondrogenic mRNA expression in prechondrogenic cells after blue laser irradiation. AB - Low-level laser therapy (LLLT) has been used as a method for biostimulation. Cartilage develops through the differentiation of mesenchymal cells into chondrocytes, and differentiated chondrocytes in articular cartilage maintain cartilage homeostasis by synthesizing cartilage-specific extracellular matrix. The aim of this study is to evaluate the enhancement of chondrocyte differentiation and the expression levels of chondrogenic mRNA in prechondrogenic ATDC5 cells after laser irradiation. For chondrogenic induction, ATDC5 cells were irradiated with a blue laser (405 nm, continuous wave) at 100 mW/cm(2) for 180 s following incubation in chondrogenic differentiation medium. Differentiation after laser irradiation was quantitatively evaluated by the measurement of total collagen contents and chondrogenesis-related mRNAs. The total amount of collagen and mRNA levels of aggrecan, collagen type II, SOX-9, and DEC-1 were increased relative to those of a non-laser irradiated group after 14 days of laser irradiation. On the other hand, Ap-2alpha mRNA, a negative transcription factor of chondrogenesis, was dramatically decreased after laser irradiation. In addition, intracellular reactive oxygen species (ROS) were generated after laser irradiation. These results, for the first time, provide functional evidence that mRNA expression relating to chondrogenesis is increased, and Ap-2alpha is decreased immediately after laser irradiation. As this technique could readily be applied in situ to control the differentiation of cells at an implanted site within the body, this approach may have therapeutic potential for the restoration of damaged or diseased tissue. PMID- 20163969 TI - Ventricular assist devices today and tomorrow. PMID- 20163968 TI - Elucidating the site of protein-ATP binding by top-down mass spectrometry. AB - A Fourier-transform ion cyclotron resonance (FT-ICR) top-down mass spectrometry strategy for determining the adenosine triphosphate (ATP)-binding site on chicken adenylate kinase is described. Noncovalent protein-ligand complexes are readily detected by electrospray ionization mass spectrometry (ESI-MS), but the ability to detect protein-ligand complexes depends on their stability in the gas phase. Previously, we showed that collisionally activated dissociation (CAD) of protein nucleotide triphosphate complexes yield products from the dissociation of a covalent phosphate bond of the nucleotide with subsequent release of the nucleotide monophosphate (Yin, S. et al., J. Am. Soc. Mass Spectrom. 2008, 19, 1199-1208). The intrinsic stability of electrostatic interactions in the gas phase allows the diphosphate group to remain noncovalently bound to the protein. This feature is exploited to yield positional information on the site of ATP binding on adenylate kinase. CAD and electron capture dissociation (ECD) of the adenylate kinase-ATP complex generate product ions bearing mono- and diphosphate groups from regions previously suggested as the ATP-binding pocket by NMR and crystallographic techniques. Top-down MS may be a viable tool to determine the ATP-binding sites on protein kinases and identify previously unknown protein kinases in a functional proteomics study. PMID- 20163970 TI - An experimental study on reconstruction of the condyle of the temporomandibular joint using free autogenous costal perichondrial grafts in rabbits. AB - OBJECTIVE: The purpose of this study was to develop a new method to regenerate articular cartilage of the temporomandibular joint (TMJ) by transplantation of free autogenous costal perichondrium (PC). STUDY DESIGN: In the study, 50 adult rabbits received the operation. For the surgery in the test group, the rabbits were randomly matched in pairs within the group and underwent the surgery of cross transplantation of costal PC after trimming the articular surface of the condyle. Operations were carried out in the same way in the experimental group except for PC transplantation. Instead, the suture was stitched in stratified order in the control group. Examination methods included observation of sections under the microscope, observation of specimens under the electron microscope, proliferating cell nuclear antigen (PCNA) staining, and biochemical analysis of glucuronic acid (GA) content and collagen content. The results of different groups were compared with ANOVA. RESULTS: The transplanted homologous PC escaped observable immune repulsion so that it could survive to form new joint cartilage with approximately normal tissue structure and biochemical constitution. The reproduction process was similar to the normal one, but was prolonged a little. At the later stage, the degeneration and calcification in the basal layer increased. However, because of its limited scope, no apparent effect on cartilage growth and function was observed. CONCLUSIONS: Homologous xenografting of free costal PC will not result in an apparent immunorejection of the host. Instead, the grafts can maintain their existence by obtaining nutrition from surrounding tissues and regenerate cartilage tissue. PMID- 20163971 TI - Additive effects of estrogen replacement therapy and bisphosphonates on osseointegration of hydroxyapatite-coated titanium screws in ovariectomized rats. AB - OBJECTIVE: This study investigated the effect of locally immobilized bisphosphonates and systemic estrogen replacement therapy on fixation of hydroxyapatite-coated screws in ovariectomized rats. STUDY DESIGN: Twelve weeks after being ovariectomized, each of the 20 rats received 2 hydroxyapatite-coated screws in the proximal tibia, with or without immobilized bisphosphonates. Half of the animals also received subcutaneous injections of 17beta-estradiol. Thus, there were 4 groups: control, estrogen, bisphosphonates, and estrogen plus bisphosphonates. Tibiae with screws were measured by microscopic computerized tomography and push-out test 12 weeks after implantation. RESULTS: Combined treatment had the strongest effects, with the bone volume ratio around screws and the percentage of osteointegration significantly increased by 2.3-fold and 1.9 fold and the push-out force by 3.3-fold compared with untreated control samples. Monotherapy also enhanced the fixation of screws, although less. CONCLUSIONS: Systemic estrogen replacement therapy and locally immobilized bisphosphonates had additive effects on fixation of hydroxyapatite-coated screws in ovariectomized rats. PMID- 20163972 TI - RANK/RANKL/OPG role in distraction osteogenesis. AB - Distraction osteogenesis is a fundamental pillar for craniomaxillofacial reconstruction processes. Nonetheless, although the clinical, biomechanical, and histologic changes associated with distraction osteogenesis have been widely described, this is not the case with the molecular mechanisms that regulate bone synthesis in the interfragmentary gap resulting from the gradual separation of bone segments. Recent studies have attributed a decisive role to the RANK/RANKL/OPG system in regulating bone metabolism and osteoclastogenesis. Receptor activator of nuclear factor kappa beta (RANK), belonging to the tumor necrosis factor superfamily, is present in the osteoclasts. It promotes osteoclastogenesis when it binds to RANK ligand (RANKL), which is produced by the osteoblasts and other stromal cells. Osteoprotegerin (OPG) acts as a decoy receptor by binding to RANKL and preventing RANK signaling. Osteoclast activation is thus blocked and apoptosis induced. The aim of this review is to analyze the influence of the RANK/RANKL/OPG system on the bone healing and remodeling processes that occur in distraction osteogenesis, with a view to possibly developing molecular mechanisms that stimulate bone regeneration and inhibit resorption, thereby improving the clinical outcome for distraction osteogenesis. PMID- 20163973 TI - Restoration of peri-implant defects in immediate implant installations by Choukroun platelet-rich fibrin and silk fibroin powder combination graft. AB - OBJECTIVE: The objective of this study was to determine the capability of silk fibroin powder as a biomaterial template for the restoration of peri-implant defects when mixed with Choukroun platelet-rich fibrin (PRF) in vivo. STUDY DESIGN: Ten New Zealand white rabbits were used for this study. Using a trephine bur (diameter 7.0 mm), 2 monocortical defects were prepared. Subsequently, 2 dental implants were installed into the tibia (diameter 3.0 mm, length 10.0 mm). In the experimental group, the peri-implant defect was filled with a combination graft of silk fibroin powder and Choukroun PRF. The control was left in an unfilled state. The animals were killed at 8 weeks. Subsequently, a removal torque test and a histomorphometric analysis were done. RESULTS: The removal torque for the experimental group was 30.34 +/- 5.06 N.cm, whereas it was 21.86 +/- 3.39 N.cm for the control. The difference between the 2 groups was statistically significant (P = .010). Mean new bone formation was 51.93 +/- 27.90% in the experimental group and 11.67 +/- 15.12% in the control (P = .003). Mean bone-to-implant contact was 43.07 +/- 21.96% in the experimental group and 15.37 +/- 23.84% in the control (P = .002). CONCLUSION: A peri-implant defect can be successfully repaired by the application of Choukroun PRF and silk fibroin powder. PMID- 20163974 TI - Prediction of dental implant torque with a fast and automatic finite element analysis: a pilot study. AB - OBJECTIVES: Despite its importance, implant removal torque can be assessed at present only after implantation. This paper presents a new technique to help clinicians preoperatively evaluate implant stability. STUDY DESIGN: Planning software has been combined with an in-house finite element solver. Once the clinician has chosen the implant position on the planner, a finite element analysis automatically calculates the primary stability. The process was designed to be as simple and fast as possible for clinical use. This paper describes application of the method to the prediction of removal torque. A preliminary validation has been performed in both polyurethane foam and sheep bone. RESULTS: The predicted torque is quantitatively equivalent to experimental values with correlation coefficients of >0.7 in both materials. CONCLUSIONS: This preliminary study is a first step toward the introduction of finite element models in computer-assisted surgery. The fact that the process is fast and automatic makes it suitable for a clinical use. PMID- 20163975 TI - Spectroscopic imaging with improved gradient modulated constant adiabaticity pulses on high-field clinical scanners. AB - The purpose of this work was to design and implement constant adiabaticity gradient modulated pulses that have improved slice profiles and reduced artifacts for spectroscopic imaging on 3T clinical scanners equipped with standard hardware. The newly proposed pulses were designed using the gradient offset independent adiabaticity (GOIA, Tannus and Garwood[13]) method using WURST modulation for RF and gradient waveforms. The GOIA-WURST pulses were compared with GOIA-HSn (GOIA based on nth-order hyperbolic secant) and FOCI (frequency offset corrected inversion) pulses of the same bandwidth and duration. Numerical simulations and experimental measurements in phantoms and healthy volunteers are presented. GOIA-WURST pulses provide improved slice profile that have less slice smearing for off-resonance frequencies compared to GOIA-HSn pulses. The peak RF amplitude of GOIA-WURST is much lower (40% less) than FOCI but slightly higher (14.9% more) to GOIA-HSn. The quality of spectra as shown by the analysis of lineshapes, eddy currents artifacts, subcutaneous lipid contamination and SNR is improved for GOIA-WURST. GOIA-WURST pulse tested in this work shows that reliable spectroscopic imaging could be obtained in routine clinical setup and might facilitate the use of clinical spectroscopy. PMID- 20163976 TI - Mechanism of 1H-14N cross-relaxation in immobilized proteins. AB - A resonant enhancement of the water-1H relaxation rate at three distinct frequencies in the range 0.5-3 MHz has been observed in a variety of aqueous biological systems. These so-called quadrupole (Q) peaks have been linked to a dipolar flip-flop polarization transfer from 1H nuclei to rapidly relaxing amide 14N nuclei in rotationally immobilized proteins. While the Q-peak frequencies conform to the known amide 14N quadrupole coupling parameters, a molecular model that accounts for the intensity and shape of the Q peaks has not been available. Here, we present such a model and test it against an extensive set of Q-peak data from two fully hydrated crosslinked proteins under conditions of variable temperature, pH and H/D isotope composition. We propose that polarization transfer from bulk water to amide 14N occurs in three steps: from bulk water to a so-called intermediary proton via material diffusion/exchange, from intermediary to amide proton by cross-relaxation driven by exchange-mediated orientational randomization of their mutual dipole coupling, and from amide proton to 14N by resonant dipolar relaxation 'of the second kind', driven by 14N spin fluctuations, which, in turn, are induced by restricted rigid-body motions of the protein. An essentially equivalent description of the last step can be formulated in terms of coherent 1H-->14N polarization transfer followed by fast 14N relaxation. Using independent structural and kinetic information, we show that the Q peaks from these two proteins involve approximately 7 intermediary protons in internal water molecules and side-chain hydroxyl groups with residence times of order 10(-5) s. The model not only accounts quantitatively for the extensive data set, but also explains why Q peaks are hardly observed from gelatin gels. PMID- 20163977 TI - Adsorption of naphthalene onto sonicated talc from aqueous solutions. AB - The adsorption behavior of naphthalene onto naturally hydrophobic talc from aqueous solution was investigated in this study. The natural talc was first pretreated by sonication to improve the surface characteristics and enhance the uptake capacity by increasing the specific surface area (SSA) of talc. The naphthalene uptake of talc was found as 276 mg g(-1) and increased to 359 mg g( 1) after the sonication. Adsorption studies also showed that the adsorption of naphthalene onto the sonicated talc was not affected by changes in pH suggesting that the main driving forces for naphthalene adsorption onto talc was hydrophobic bonding rather than electrostatic force. The pseudo-first and pseudo-second orders and intraparticle diffusion equation were used to evaluate the kinetic data and the constants were determined. Adsorption process of naphthalene onto talc followed the pseudo-second-order rate expression for different initial naphthalene concentrations. The Langmuir and Freundlich isotherm models were used to model the isotherm data for their applicability. The Freundlich isotherm best fitted for the adsorption of naphthalene onto talc. PMID- 20163978 TI - Influence of ultrasonic processing on the macromolecular properties of poly (D,L lactide-co-glycolide) alone and in its biocomposite with hydroxyapatite. AB - In this work poly(D,L-lactide-co-glycolide) (PLGA) and a poly(d,l-lactide-co glycolide)/hydroxyapatite (PLGA/HAp) composite processed in an ultrasonic field at higher (25 degrees C) and lower (8 degrees C) temperatures were studied with respect to the molecular properties of the obtained materials. The processing of the PLGA and the PLGA/HAp composite in an ultrasonic field resulted in a change of molar mass averages of the polymer/polymeric part of these materials, while an amorphous structure and a 50:50 lactide-to-glycolide co-monomer ratio were preserved without the formation of crystalline oligomers. However, mobility of polymeric chains obtained after ultrasonic processing was lower indicating ordering the structure of polymeric chains as a result of processing. Additionally, it was observed that the mobility of the PLGA macromolecules was lower within the composite in comparison with the mobility of the chains within the PLGA alone in the case when both were obtained after ultrasonic processing. This was a consequence of the structure formation through the interactions between the PLGA and the HAp. Based on these results different degradation rate of PLGA in composite can be expected, which is important in the application of this material for the controlled drug delivery of medicaments. PMID- 20163979 TI - Barriers to treatment adherence in physiotherapy outpatient clinics: a systematic review. AB - Poor adherence to treatment can have negative effects on outcomes and healthcare cost. However, little is known about the barriers to treatment adherence within physiotherapy. The aim of this systematic review was to identify barriers to treatment adherence in patients typically managed in musculoskeletal physiotherapy outpatient settings and suggest strategies for reducing their impact. The review included twenty high quality studies investigating barriers to treatment adherence in musculoskeletal populations. There was strong evidence that poor treatment adherence was associated with low levels of physical activity at baseline or in previous weeks, low in-treatment adherence with exercise, low self-efficacy, depression, anxiety, helplessness, poor social support/activity, greater perceived number of barriers to exercise and increased pain levels during exercise. Strategies to overcome these barriers and improve adherence are considered. We found limited evidence for many factors and further high quality research is required to investigate the predictive validity of these potential barriers. Much of the available research has focussed on patient factors and additional research is required to investigate the barriers introduced by health professionals or health organisations, since these factors are also likely to influence patient adherence with treatment. PMID- 20163980 TI - High resolution cortical bone thickness measurement from clinical CT data. AB - The distribution of cortical bone in the proximal femur is believed to be a critical component in determining fracture resistance. Current CT technology is limited in its ability to measure cortical thickness, especially in the sub millimetre range which lies within the point spread function of today's clinical scanners. In this paper, we present a novel technique that is capable of producing unbiased thickness estimates down to 0.3mm. The technique relies on a mathematical model of the anatomy and the imaging system, which is fitted to the data at a large number of sites around the proximal femur, producing around 17,000 independent thickness estimates per specimen. In a series of experiments on 16 cadaveric femurs, estimation errors were measured as -0.01+/-0.58mm (mean+/ 1std.dev.) for cortical thicknesses in the range 0.3-4mm. This compares with 0.25+/-0.69mm for simple thresholding and 0.90+/-0.92mm for a variant of the 50% relative threshold method. In the clinically relevant sub-millimetre range, thresholding increasingly fails to detect the cortex at all, whereas the new technique continues to perform well. The many cortical thickness estimates can be displayed as a colour map painted onto the femoral surface. Computation of the surfaces and colour maps is largely automatic, requiring around 15min on a modest laptop computer. PMID- 20163981 TI - Optimal embedding for shape indexing in medical image databases. AB - This paper addresses the problem of indexing shapes in medical image databases. Shapes of organs are often indicative of disease, making shape similarity queries important in medical image databases. Mathematically, shapes with landmarks belong to shape spaces which are curved manifolds with a well defined metric. The challenge in shape indexing is to index data in such curved spaces. One natural indexing scheme is to use metric trees, but metric trees are prone to inefficiency. This paper proposes a more efficient alternative. We show that it is possible to optimally embed finite sets of shapes in shape space into a Euclidean space. After embedding, classical coordinate-based trees can be used for efficient shape retrieval. The embedding proposed in the paper is optimal in the sense that it least distorts the partial Procrustes shape distance. The proposed indexing technique is used to retrieve images by vertebral shape from the NHANES II database of cervical and lumbar spine X-ray images maintained at the National Library of Medicine. Vertebral shape strongly correlates with the presence of osteophytes, and shape similarity retrieval is proposed as a tool for retrieval by osteophyte presence and severity. Experimental results included in the paper evaluate (1) the usefulness of shape similarity as a proxy for osteophytes, (2) the computational and disk access efficiency of the new indexing scheme, (3) the relative performance of indexing with embedding to the performance of indexing without embedding, and (4) the computational cost of indexing using the proposed embedding versus the cost of an alternate embedding. The experimental results clearly show the relevance of shape indexing and the advantage of using the proposed embedding. PMID- 20163983 TI - Yawning, sleep, and symptom relief in patients with multiple sclerosis. AB - BACKGROUND: Patients with multiple sclerosis (MS) suffer from thermoregulatory dysfunction, and repetitive yawning and sleep problems are symptoms of MS. Because yawning and sleep are involved in thermoregulation, we investigated the association between yawning, sleep, and symptom relief in patients with MS. METHODS: Sixty patients filled out a questionnaire about how often they yawned, whether yawning provided relief of MS symptoms, and how sleep affected these symptoms. RESULTS: Results showed that over one in three patients reported that their MS symptoms improved following a yawn, and of those experiencing relief, nearly half reported that it lasted for several minutes or longer. Not getting a good night's sleep often made MS symptoms worse, while napping during the day provided symptom relief. CONCLUSION: This is the first study showing that yawning provides symptom relief in patients with multiple sclerosis. PMID- 20163982 TI - Interaction of flavonoids, the naturally occurring antioxidants with different media: a UV-visible spectroscopic study. AB - Quantitative parameters for interaction of flavonoids-the naturally occurring antioxidants, with solvents and surfactants are determined using UV-visible absorption spectroscopy. The availability of flavonoids; kaempferol, apigenin, kaempferide and rhamnetin in micelles of sodium dodecyl sulfate (SDS) is reflected in terms of partition coefficient, K(c). Thermodynamic calculations show that the process of transfer of flavonoid molecules to anionic micelles of SDS is energy efficient. A distortion in flavonoid's morphology occurs in case of kaempferol and apigenin in surfactant and water, exhibited in terms of a new band in the UV region of electronic spectra of these flavonoids. The partition coefficients of structurally related flavonoids are correlated with their antioxidant activities. PMID- 20163984 TI - Automatic slow eye movement (SEM) detection of sleep onset in patients with obstructive sleep apnea syndrome (OSAS): comparison between multiple sleep latency test (MSLT) and maintenance of wakefulness test (MWT). AB - OBJECTIVE: To determine whether automatic slow eye movement (SEM) analysis performs comparably to standard sleep onset criteria at the multiple sleep latency test (MSLT) and at the maintenance of wakefulness test (MWT) in patients with obstructive sleep apnea syndrome (OSAS). METHODS: We compared sleep latencies obtained upon standard analysis of MSLT and MWT recordings with automatically detected SEM latencies in a population of 20 severe OSAS patients that randomly underwent the two tests 1 week apart. RESULTS: Eight of 20 OSAS patients had EDS as answered by the Epworth Sleepiness Scale (ESS). Mean SEM latency performed comparably to standard sleep onset in both the MSLT (6.4+/-5.5 min versus 7.4+/-5.1 min, p=0.25) and the MWT (25.2+/-14.5 min versus 24.4+/-14.0 min, p=0.45) settings. Mean SEM latency significantly correlated with the sleep latency at the MSLT (r=0.52, p<0.05) and at the MWT (r=0.74, p<0.001). Finally, the Epworth Sleepiness Scale score correlated with SEM latency at the MWT (r= 0.62, p<0.01), but not at the MSLT. CONCLUSIONS: Automatic SEM detection performed comparably to standard polysomnographic assessment of sleep onset, thus providing a simplified technical requirement for the MSLT and the MWT. Further studies are warranted to evaluate SEM detection of sleep onset in other sleep disorders with excessive daytime sleepiness. PMID- 20163985 TI - Peeling the artichoke. PMID- 20163986 TI - Patient expectations and preferences for follow-up after treatment for lung cancer: a pilot study. AB - INTRODUCTION: There is no robust evidence to indicate the most appropriate models of follow-up care for patients who have completed treatment for lung cancer. This pilot study aimed to assess expectations and preferences for follow-up care in a sample of patients who had completed treatment for lung cancer. METHOD: Thirty one patients who had completed treatment for primary lung cancer were recruited. A 13 item self-report survey was developed to elicit patient's preferences and expectations for follow-up. Participants completed the developed survey and clinical and demographic variables were collected. RESULTS: Factors scored as extremely important by over 80% of respondents focused on care coordination: Being able to see the same doctor or health care professional at each visit (24/83%); Knowing which doctor or nurse to contact if queries arise between follow-up appointments (23/82%); and Knowing the patient can book an appointment or contact a health care professional involved in their care regarding health concerns between visits (25/89%). Patients were supportive of nurse-led follow-up when offered in the context of a model of shared care (21/78%). CONCLUSION: This study offers new insight into the expectations and preferences for follow-up of patients with lung cancer, with participants indicated preference for intensive follow-up after the completion of treatment. PMID- 20163987 TI - Activity of a multitargeted chemo-switch regimen (sorafenib, gemcitabine, and metronomic capecitabine) in metastatic renal-cell carcinoma: a phase 2 study (SOGUG-02-06). AB - BACKGROUND: Maximum tolerated dose (MTD) chemotherapy followed by metronomic chemotherapy (low doses given on a frequent schedule) acts on tumour vascular endothelial cells by increasing the anti-tumour effect of anti-angiogenic agents. This multicentre, phase 2 study investigated the effectiveness of MTD gemcitabine combined with metronomic capecitabine plus the multikinase inhibitor sorafenib for the treatment of metastatic renal-cell carcinoma (RCC). METHODS: Patients were enrolled at eight centres across Spain between Dec 13, 2006, and April 17, 2008. Patients were aged 18 years or older, had confirmed metastatic RCC with clear-cell histology, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had not undergone previous therapy, and were unsuitable for, or intolerant to, immunotherapy. Treatment consisted of intravenous gemcitabine 1000 mg/m(2) (days 1 and 8), oral capecitabine 500 mg/m(2) twice a day (final dose after adjustment, days 1-14), and oral sorafenib 400 mg twice a day (days 1-21), for six cycles, followed by sorafenib monotherapy (at the investigator's discretion if clinical benefit was maintained). The primary endpoint was median progression-free survival (PFS) analysed in a population of all patients who received treatment. The trial is registered with ClinicalTrials.gov, number NCT00496301. FINDINGS: 44 patients enrolled in the study, 40 of whom received treatment. Median PFS for these patients was 11.1 months (95% CI 7.9-17.1). A partial response was achieved in 20 patients, and stable disease in 17 patients. Most adverse events were grade 1 or 2. Grade 3 adverse events were fatigue or asthenia (n=9), hand-foot skin reaction (n=11), mucositis (n=3), diarrhoea (n=2), infection (n=2), and allergic reaction, hypertension, and rash (all n=1). Grade 3 haematological toxicity was noted in nine patients. One death due to pulmonary embolism was reported as grade 5 dyspnoea possibly related to study drug. INTERPRETATION: PFS and response rates were greater than those previously observed with gemcitabine and capecitabine or sorafenib monotherapy in patients with metastatic RCC. Adverse events were manageable in most patients. These findings provide preliminary confirmation of the synergistic activity of the chemo-switch concept seen in preclinical studies, and merit further exploration. FUNDING: Spanish Oncology Genitourinary Group (SOGUG). PMID- 20163988 TI - New aspects in vascular gene therapy. AB - Advances in clinical gene therapy have been modest although significant progress has been made during the past few years. New viruses have been introduced and new results have been collected from preclinical and clinical studies. This review will focus on cardiovascular and especially proangiogenic gene therapy. Recent results from preclinical developments and clinical trials will be discussed. PMID- 20163991 TI - Anticipated benefits and surprising effects of daclizumab in multiple sclerosis. PMID- 20163989 TI - Chemokines and chemokine receptors: new insights into cancer-related inflammation. AB - Chemokines are involved in cellular interactions and tropism in situations frequently associated with inflammation. Recently, the importance of chemokines and chemokine receptors in inflammation associated with carcinogenesis has been highlighted. Increasing evidence suggests that chemokines are produced by tumor cells as well as by cells of the tumor microenvironment including cancer associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), endothelial cells, tumor-associated macrophages (TAMs) and more recently tumor-associated neutrophils (TANs). In addition to affecting tumor cell proliferation, angiogenesis and metastasis, chemokines also seem to modulate senescence and cell survival. Here, we review recent progress on the roles of chemokines and chemokine receptors in cancer-related inflammation, and discuss the mechanisms underlying chemokine action in cancer that might facilitate the development of novel therapies in the future. PMID- 20163990 TI - Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. AB - BACKGROUND: Daclizumab, a humanised monoclonal antibody, reduced multiple sclerosis disease activity in previous non-randomised studies. We aimed to assess whether daclizumab reduces disease activity in patients with active relapsing multiple sclerosis who are receiving interferon beta treatment. METHODS: We did a phase 2, randomised, double-blind, placebo-controlled study at 51 centres in the USA, Canada, Germany, Italy, and Spain. Patients with active relapsing multiple sclerosis who were taking interferon beta were randomly assigned to receive add on subcutaneous daclizumab 2 mg/kg every 2 weeks (interferon beta and high-dose daclizumab group), daclizumab 1 mg/kg every 4 weeks (interferon beta and low-dose daclizumab group), or interferon beta and placebo for 24 weeks. The randomisation scheme was generated by Facet Biotech. All patients and assessors were masked to treatment with the exception of Facet Biotech bioanalysts who prepared data for the data safety monitoring board or generated pharmacokinetic or pharmacodynamic data, a drug accountability auditor, and the site pharmacist. The primary endpoint was total number of new or enlarged gadolinium contrast-enhancing lesions measured on brain MRI scans every 4 weeks between weeks 8 and 24. Effects of daclizumab on prespecified subsets of lymphocytes and quantitative T-cell proliferative response were assessed in an exploratory pharmacodynamic substudy. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00109161. FINDINGS: From May, 2005, to March, 2006, 288 patients were assessed for eligibility, and 230 were randomly assigned to receive interferon beta and high-dose daclizumab (n=75), interferon beta and low dose daclizumab (n=78), or interferon beta and placebo (n=77). The adjusted mean number of new or enlarged gadolinium contrast-enhancing lesions was 4.75 in the interferon beta and placebo group compared with 1.32 in the interferon beta and high-dose daclizumab group (difference 72%, 95% CI 34% to 88%; p=0.004) and 3.58 in the interferon beta and low-dose daclizumab group (25%, -76% to 68%; p=0.51). In the pharmacodynamic substudy, daclizumab was not associated with significant changes in absolute numbers of T cells, B cells, or natural killer cells, or T cell proliferative response compared with interferon beta alone. The number of CD56(bright) natural killer cells was seven to eight times higher in both daclizumab groups than in the interferon beta and placebo group (interferon beta and low-dose daclizumab group p=0.002; interferon beta and high-dose daclizumab group p<0.0001). Common adverse events were equally distributed across groups. INTERPRETATION: Add-on daclizumab treatment reduced the number of new or enlarged gadolinium contrast-enhancing lesions compared with interferon beta alone and might reduce multiple sclerosis disease activity to a greater extent than interferon beta alone. FUNDING: Facet Biotech and Biogen Idec. PMID- 20163992 TI - Improvement of non-paraneoplastic voltage-gated potassium channel antibody associated limbic encephalitis without immunosuppressive therapy. AB - We describe a 61-year-old patient with clinical evidence of limbic encephalitis who improved with anticonvulsant treatment only, that is, without the use of immunosuppressive agents. Three years following occurrence of anosmia, increasing memory deficits, and emotional disturbances, he presented with new-onset temporal lobe epilepsy, with antibodies binding to neuronal voltage-gated potassium channels and bitemporal hypometabolism on FDG-PET scan; the MRI scan was normal. This is most likely a case of spontaneous remission, illustrating that immunosuppressive therapy might be suspended in milder courses of limbic encephalitis. It remains open whether treatment with anticonvulsant drugs played an additional beneficiary role through the direct suppression of seizures or, additionally, through indirect immunomodulatory side effects. PMID- 20163993 TI - Stimulation-based anticipation and control of state transitions in the epileptic brain. AB - We focus on the implications that the underlying neuronal dynamics might have on the possibility of anticipating seizures and designing an effective paradigm for their control. Transitions into seizures can be caused by parameter changes in the dynamic state or by interstate transitions as occur in multi-attractor systems; in the latter case, only a weak statistical prognosis of the seizure risk can be achieved. Nevertheless, we claim that by applying a suitable perturbation to the system, such as electrical stimulation, relevant features of the system's state may be detected and the risk of an impending seizure estimated. Furthermore, if these features are detected early, transitions into seizures may be blocked. On the basis of generic and realistic computer models we explore the concept of acute seizure control through state-dependent feedback stimulation. We show that in some classes of dynamic transitions, this can be achieved with a relatively limited amount of stimulation. PMID- 20163994 TI - Autoimmune hepatitis in children--impact of cirrhosis at presentation on natural history and long-term outcome. AB - Little is known regarding the natural history of autoimmune hepatitis in children. The aims of this longitudinal cohort study were to determine the long term prognosis of children with autoimmune hepatitis and to determine the effect of cirrhosis at presentation on survival. METHODS: Thirty-three children with autoimmune hepatitis who were seen at our institution over a 25-year period were studied retrospectively. RESULTS: The median age of diagnosis was 12.9 years (2.7 18.1) with a female predominance of 3:1. Liver biopsies showed cirrhosis in 18 (55%) patients at time of diagnosis. Patients with cirrhosis at baseline had a similar 10-year survival 85% (70-100%) to those without cirrhosis 75% (49-100%) (p=0.97). The overall survival was significantly lower than the expected in the age- and gender-matched U.S. population (log-rank test; p<0.001). In Cox regression models, weight loss (p=0.037), baseline elevated bilirubin (p=0.028), prolonged International Normalized Ratio (INR) (p=0.013), and positive LKM-1 antibodies (p=0.007) were associated with shorter survival. CONCLUSION: AIH in children is associated with a significant shorter survival rate than the expected in the general population. Cirrhosis on initial liver biopsy does not seem to impact long-term survival in children with AIH. PMID- 20163996 TI - The 'T' - a simple technique for finger dressings. PMID- 20163995 TI - A short version of a HRQoL questionnaire for Italian and Japanese patients with Primary Biliary Cirrhosis. AB - BACKGROUND: The available self-report questionnaire for the quality of life in patients with primary biliary cirrhosis (PBC-40) is currently validated only in the British population but it lacks an evaluation of its dimensionality. AIMS: To validate the Italian and Japanese versions of PBC-40 and to assess the dimensionality of the original structure of PBC-40 by a confirmatory factor analysis. PBC-40 was translated to Italian and Japanese using the forward backward method and then reviewed in focus groups in the framework of a large multicentric study. METHODS: A sample of 290 patients with PBC (125 Italian and 165 Japanese) was administered two questionnaires previously validated for PBC specific (PBC-40) and general quality of life (SF-36). RESULTS: The confirmatory model failed to fit adequately the original hypothesized structure. A principal component analysis led to a seven-factor structure, with exclusion of 13 items characterized by lower load; PBC-27 questionnaire was the final instrument. The validity of the PBC-27 was supported by its strong correlation with the SF-36 scores. CONCLUSION: We here propose an alternative structure of the quality of life questionnaire for PBC, namely PBC-27, which appears to be effective in detecting the impact of PBC on quality of life in Italian and Japanese patients. PMID- 20163997 TI - Prefabricated flap composed by skin and terminal gastromental vessels. Experimental study in rabbits. AB - BACKGROUND: The angiogenic induction property of the omentum makes it a promising pedicle for prefabricating flaps. Therefore, the objective of this paper is to establish the abdominal area to be prefabricated by the omental pedicle and to analyse the prefabricated potential (PP) according to the time delay between the pedicle introduction and the flap release. METHODS: Forty-four rabbits were divided into four groups (A, B, C and D). In group A, a piece of skin, subcutaneous tissue and abdominal cutaneous muscle was fully released and sutured again in place. In the other groups, a 9-cm2 omental pedicle containing the gastromental vessels distally tied was transposed and sutured to abdominal cutaneous muscle. A second procedure, consisting of incision and release of the flap that contained skin, subcutaneous and cutaneous abdominal muscle pediculated only by the omentum, was carried out. The only variation was the time delay between the two procedures: 7, 21 and 56 days for groups B, C and D, respectively. The flaps were inspected 15 days after the last procedure. The pieces of viable area were immunostained using anti-CD31 for estimation of the microvascular density. RESULTS: The mean and maximum viable areas in group D were 45.29 and 99.37cm2, respectively (average PP=5.03 and maximum PP=11.04). There was no significant difference between the viable areas in groups C and D. The mean microvascular densities of groups B, C and D were 24.54, 33.20 and 27.03 vessels/mm2, respectively. CONCLUSION: The omental tissue has great potential for prefabrication of flaps, and the delay time for the second procedure should be at least 21 days. PMID- 20163998 TI - The osmotic tissue expander: a 5-year experience. AB - Tissue expansion is a valuable technique in soft tissue reconstruction. Osmotic expanders are self-inflating and obviate the need for repeated injections. In doing so, they eliminate port site problems and may reduce the potential to introduce infection. The use of such expanders has become more common in recent years. We report on our experience with the OsmedTM osmotic expanders over the last 5-years. PMID- 20163999 TI - Choice of anesthetic technique for ear reconstruction using a tissue expander and cartilage framework. PMID- 20164000 TI - Response to Pollard RL, O'Broin E. Compartment syndrome following prolonged surgery for breast reconstruction with epidural analgesia. J Plast Reconstr Aesthet Surg 2009;62:e648-e649. PMID- 20164001 TI - Pesticide use and cutaneous melanoma in pesticide applicators in the agricultural heath study. AB - BACKGROUND: Melanoma rates continue to increase; however, few risk factors other than sun sensitivity and ultraviolet radiation (including sun exposure) have been identified. Although studies of farmers have shown an excess risk of melanoma and other skin cancers, it is unclear how much of this is related to sun exposure compared with other agricultural exposures. METHODS: We examined dose-response relationships for 50 agricultural pesticides and cutaneous melanoma incidence in the Agricultural Health Study cohort of licensed pesticide applicators, along with ever use of older pesticides that contain arsenic. Logistic regression was used to examine odds ratios (ORs) and 95% confidence intervals (CIs) associated with pesticide exposure adjusted for age, sex, and other potential confounders. RESULTS: We found significant associations between cutaneous melanoma and maneb/mancozeb (>or= 63 exposure days: OR = 2.4; 95% CI, 1.2-4.9; trend p = 0.006), parathion (>or= 56 exposure days: OR = 2.4; 95% CI, 1.3-4.4; trend p = 0.003), and carbaryl (>or= 56 exposure days: OR = 1.7; 95% CI, 1.1-2.5; trend p = 0.013). Other associations with benomyl and ever use of arsenical pesticides were also suggested. CONCLUSIONS: Most previous melanoma literature has focused on host factors and sun exposure. Our research shows an association between several pesticides and melanoma, providing support for the hypotheses that agricultural chemicals may be another important source of melanoma risk. PMID- 20164002 TI - Using residential history and groundwater modeling to examine drinking water exposure and breast cancer. AB - BACKGROUND: Spatial analyses of case-control data have suggested a possible link between breast cancer and groundwater plumes in upper Cape Cod, Massachusetts. OBJECTIVE: We integrated residential histories, public water distribution systems, and groundwater modeling within geographic information systems (GIS) to examine the association between exposure to drinking water that has been contaminated by wastewater effluent and breast cancer. METHODS: Exposure was assessed from 1947 to 1993 for 638 breast cancer cases who were diagnosed from 1983 to 1993 and 842 controls; we took into account residential mobility and drinking water source. To estimate the historical impact of effluent on drinking water wells, we modified a modular three-dimensional finite-difference groundwater model (MODFLOW) from the U.S. Geological Survey. The analyses included latency and exposure duration. RESULTS: Wastewater effluent impacted the drinking water wells of study participants as early as 1966. For > 0-5 years of exposure (versus no exposure), associations were generally null. Adjusted odds ratios (AORs) for > 10 years of exposure were slightly increased, assuming latency periods of 0 or 10 years [AOR = 1.3; 95% confidence interval (CI), 0.9 1.9 and AOR = 1.6; 95% CI, 0.8-3.2, respectively]. Statistically significant associations were estimated for ever-exposed versus never-exposed women when a 20 year latency period was assumed (AOR = 1.9; 95% CI, 1.0-3.4). A sensitivity analysis that classified exposures assuming lower well-pumping rates showed similar results. CONCLUSION: We investigated the hypothesis generated by earlier spatial analyses that exposure to drinking water contaminated by wastewater effluent may be associated with breast cancer. Using a detailed exposure assessment, we found an association with breast cancer that increased with longer latency and greater exposure duration. PMID- 20164003 TI - Effect of antioxidants on markers of apoptosis in postoperative radiotherapy of cancer cervix. AB - AIM OF THE WORK: To investigate whether a mixture of antioxidant supplementation can ameliorate damaging effects of ionizing radiation in cancer cervix patients during radiotherapy Accordingly apoptosis, lipid peroxides and Fas among cancer cervix patients undergoing postoperative radiotherapy (n=40) were measured before and after administration of a mixture of antioxidants including 60 mg vitamin C, 10 mg vitamin E, 1000 IU vitamin A and 50 mg Selenium. PATIENTS AND METHODS: Patients were divided into 2 groups each of 20 patients. Antioxidant mixture was administered to one group thrice per day during the duration of radiotherapy and one more week post cessation of radiotherapy. Twenty normal healthy women participated as controls. RESULTS: Results revealed that following the first and second sessions of radiotherapy, both the groups with and without antioxidant administration showed higher frequency of lipid peroxidation and the frequency of micronuclei compared to their level before radiotherapy as measured 24 hours and 48 hours post first session of radiotherapy. Patients undergoing radiotherapy showed a decrease in all parameters of the study after one-week, one-month post irradiation and one week post cessation of radiotherapy. However, the antioxidants group showed significantly lower levels of apoptosis and lipid peroxides and Fas compared to patients who did not receive antioxidant supplementation. CONCLUSION: The results of the present study reveals adaptation to radiation during radiotherapy and evaluate the prophylactic effect of a mixture of antioxidants during radiotherapy. PMID- 20164004 TI - A matched case-control study of Triple negative vs. HER-2 positive (irrespective of hormonal status) breast cancer: two subtypes with high risk features and poor outcome. AB - Genetic profile studies of breast cancer identified a number of biologically different subtypes. These genetic subtypes are often surrogated by estrogen receptors (ER), progesterone receptors (PR) and HER2 status as measured by immunohistochemistry (IHC). Triple negative (TN) subtype is recognized to have high risk features and poor outcome. Over expression of the HER2 is also recognized as a poor outcome marker. The characteristics and outcome of HER2 positive tumours (irrespective of hormonal status) (HER2 HR+/-) identified by IHC have not addressed in the era of surrogate genetic subtyping. Therefore, we retrospectively compared the risk features and clinical outcome of patients with TN against these with HER2 HR+/- tumours. PMID- 20164005 TI - Pattern of head and neck cancer in Yemen. AB - Head and neck cancer constitutes one of the commonest malignancies in Yemen. There may be a role for the use of Shamma and Zarda and Khat for the increase of HNC in Yemen. This study was conducted retrospectively with an overall aim to describe the pattern of head and neck cancers among Yemeni patients attending the Oncology Department of Al-Gamhouria Teaching Hospital, Aden, for the period from Jan. 2001 to Dec. 2004. The study included 183 patients with head and neck cancers (Lymphoma and thyroid were excluded), 134 were males (73.2%) and 49 were females (26.8%) , with male to female ratio of 2.7:1. The mean age was 51.3 +/- 14.9 years (range: 3 - 82 years). Statistically, there is significant difference between the mean age of male (49.5 +/- 15.1 years) and female (45.4 +/- 16.3 years) patients with head and neck cancers [t= 2.1, p: 0.03]. The common types of head and neck cancers in this study are cancers of the oral cavity (31.7%), followed by pharyngeal (22.9%) and laryngeal (19.1%). In relation to sex, there is a significant statistical relationship between certain head and neck cancers and sex (p: 0.0000). In males, the common cancers are oral cavity cancers (22.7%), laryngeal (22.1%) and pharyngeal cancers (20.8%). The common histopathological type of head and neck cancers in this study is the well differentiated squamous cell carcinoma (70.5%). This study concluded that head and neck cancers are among the common health problems affecting Yemeni patients and recommended further wide national studies to determine the real incidence and the risk factors associated with such cancer. PMID- 20164006 TI - Castleman's disease: a study of a rare lymphoproliferative disorder in a university hospital. AB - Castleman's disease (CD) is a group of rare lymphoproliferative disorders sharing characteristic clinical and histological features, and usually accompanied by a marked systemic inflammatory response. Two histological patterns of lymph nodes were described: the hyaline-vascular and plasma-cell types. The former is more common (80-90%) and tends to be localized. The plasma cell type is more aggressive and usually multicentric. It is interesting that the inflammatory manifestations seem to be related to a lymph node lesion, because the systemic symptoms and inflammatory activity can return to normal after surgical excision or successful medical treatment of the disease. We report here our 15-year experience with this rare disease in King Fahd Hospital of the University, Al Khobar, Saudi Arabia, focusing on the clinical features, therapy, and patients'outcome. PMID- 20164007 TI - Percutaneous endoscopic gastrostomy (PEG) in cancer patients; technique, indications and complications. AB - Enteral feeding is the preferred method of nutritional support in malnourished patients with inadequate oral intake but with intact gastrointestinal tract. In cancer patients, adequate nutrition plays an important role in the success of the treatment and hence the overall prognosis. Percutaneous endoscopic gastrostomy proved to be an effective means for providing enteral nutrition with easy technique, less hospital stay and cost with less morbidity and mortality. AIM OF WORK: It is a prospective study on 40 cancer patients with different indications for PEG which is done by pull technique under local anesthesia and sedation over a period of 12 months with a follow up period of 60 days. RESULTS: The procedure was successful in 38 patients (95%), 22 patients (55%) with esophageal cancer, 16 cases (40%) with head and neck cancer, and 2 cases (5%) for gastric decompression due to prepyloric gastric cancer. Mortality rate was 2.5% (1 case) due to leakage and peritonitis, and morbidity occurred in 6 cases (15%) due to port infection and minor leakage managed by dressing and systemic antibiotics. CONCLUSION: PEG is an easy procedure for providing enteral nutrition for cancer patients and associated with fewer rates of morbidity and mortality compared to gastrostomy procedures. PMID- 20164008 TI - Recurrent malignant Leydig cell tumor of testis: a case report with review of literature. AB - Malignant Testicular Leydig Cell tumors (leydigomas) are extremely rare to occur and mostly carry a bad prognosis. Here we describe the disease course of a middle aged patient with recurrent / metastatic Leydig cell tumor of testes, who needed repeated oncosurgical intervention and chemotherapy. PMID- 20164009 TI - Imaging findings in Idiopathic lobular granulomattous mastitis, case report and review of literature. AB - Idiopathic lobular granulomatous mastititis is a rare inflammatory disease of the breast. Since the clinical manifestations simulate those of mammary malignancy, it is often misdiagnosed. We report a case in a 25 yrs old Egyptian woman who had presented with complaint of a painful mass in her right breast of 3 months duration. Clinical and radiological examinations were indeterminate of its nature and the diagnosis was established by histopathogical, microbiological and serological tests. Review of relevant literature mention the features of Idiopathic lobular granulomatous mastititis, which impose significant challenge on clinical, radiological and even histopathological diagnosis. These correlate well with our case scenario also. Complete resection of the lesions and/or administration of steroids are usually the recommended treatment, however about 38% patients may experience recurrence. Hence proper post treatment follow up is mandatory. Awareness among the clinicians, radiologists and pathologists about this disease entity is required and multi disciplinary approach is imperative to establish the diagnosis. We hope to convey these facts through this article with the review of relevant literature. PMID- 20164010 TI - Solitary intra-abdominal Castleman's disease, hyaline vascular type: case report. AB - OBJECTIVE: To report a case of solitary intra-abdominal Castleman disease and highlight the importance of this entity to clinicians in the management of these patients. CASE PRESENTATION AND INTERVENTION: A 20 year old gentleman who presented with a recurrent intra-abdominal retroperitoneal mass. Previous biopsies obtained from a laparotomy showed Castleman disease- vascular hyaline type. Patient did not respond to chemotherapy and the mass was gradually increasing in size. Surgical intervention was the only option and the patient underwent complete resection of the retroperitoneal mass. Final histopathological examination confirmed the initial diagnosis of Castleman disease. CONCLUSION: Castleman's disease is a fairly rare benign tumor of lymphoid origin. It should be included in the list of differential diagnosis of retroperitoneal masses. Unicentric Castleman disease should be treated surgically when feasible and carries better prognosis compared to multicentric disease. PMID- 20164011 TI - Intravenous leiomyomatosis of the uterus. AB - Intravenous leiomyomatosis (IVL) is a rare neoplasm characterized by nodular masses of histologically benign looking smooth muscle cells growing within uterine or extrauterine venous system.The exact etiology is unclear and benign histological appearance of neoplastic smooth muscles can be deceptive since IVL might behave in a malignant fashion. Total abdominal hysterectomy and excision of any extrauterine tumor if technically feasible is the cornerstone of treatment. We report clinical, histological, and immunohistochemical features of a uterine IVL in a 48 year old lady who presented with menorrhagia. We also elaborate etiopathogenesis and conclude that knowledge about IVL is essential as it must be differentiated from malignant tumors to prevent overtreatment. Long term follow up is recommended in such cases. PMID- 20164012 TI - Ibn Sina : a tribute. AB - Idiopathic Ibn Sina, popularly known in the west as Avicenna;(980-1037 A.D.) was one of the foremost physicians and Islamic philosophers of his time. His chief medical work, Al-Qanun fi'l-tibb (The Canon of Medicine), is considered to be the most comprehensive medical encyclopedia ever written by an Arab physician. The book served as the final authority on medical matters in Europe for several centuries. It described some of the most illuminating medical thoughts that are relevant to modern medicine. In this article, we pay tribute to this great medieval Arab physician by providing a brief overview of his life and works, with special reference to his contribution to the advancement of medical science. PMID- 20164013 TI - Focus on breast and prostate cancer prevention, early detection and new trends in management highlights of the 1st National Conference on Cancer Control in Kuwait. PMID- 20164015 TI - Role of lymphangiogenesis in lung cancer. AB - Lung cancer represents one of the most frequent causes of death due to neoplastic disease in Poland and around the world. The high mortality which accompany neoplastic diseases used to be ascribed mainly to dissemination of cancerous cells. Studies on animal models suggest that tumour lymphangiogenesis represents the principal factor in the process of metastases formation. Lymphangiogenesis involves a process of formation of new lymphatic vessels from already existing lymphatic capillaries. Lymphangiogenesis is stimulated by vascular endothelial growth factors (VEGF) and other, recently reported factors, such as, e.g., cyclooxygenase 2, fibroblast growth factor 2, angiopoetin-1 and the insulin resembling growth factor. In lymphangiogenesis a key role is played by neutropilin 2 or podoplanin and this promoted development of studies on lymphangiogenesis. Activation of VEGF-C/VEGF-D/VEGFR-3 axis increases motility and invasiveness of neoplastic cells, promotes development of metastases in several types of tumours such as, e.g., lung cancer, mammary carcinoma, cancers of the neck, prostate and large intestine. In recent years lymphangiogenesis provided topic of many studies. A positive correlation was detected between expressions of VEGF-C/D and VEGFR-3 in non-small cell lung cancer. In patients with lung cancer with high expression of VEGF-C a markedly abbreviated survival was noted. Positive correlation was detected between expression of VEGF-C and VEGF-D on one hand and expression of LYVE-1 on the other in sentinel lymph nodes with metastases of neoplastic cells in patients with non-small cell lung cancer. Also, high density of lymphatic vessels and high density of intraneoplastic microvessels proved to be independent poor prognostic indices in patients with non-small cell lung cancer. Extensive hope is linked to studies on inhibitors of lymphangiogenesis, which may improve results of treatment also in tumour patients. PMID- 20164016 TI - Post-translational modifications, subcellular relocation and release in apoptotic microparticles: apoptosis turns nuclear proteins into autoantigens. AB - Autoantibodies against particular nuclear components, such as chromatin and snRNPs, are a characteristic feature of the autoimmune disease systemic lupus erythematosus. The last decade, evidence has suggested that apoptotic cells are the main source of autoantigens in this disease. Therefore, it has been proposed that protein modifications occurring during apoptosis lead to the formation of neo-epitopes, which can break the tolerance when apoptotic cells are not properly cleared. Indeed, many lupus autoantigens are prone to apoptosis-associated post translational modifications and/or cleavage by caspases. In addition, lupus autoantigens are relocated from the nucleus to apoptotic blebs on the cell surface of early apoptotic cells. Therefore, to understand why certain nuclear proteins become autoantigens during apoptosis, it is important to know the apoptotic processing of these proteins. This review summarizes the current knowledge of apoptotic processing of lupus autoantigens and the possible effects on their encounter with the immune system in normal and autoimmune situations. PMID- 20164017 TI - Review of imaging solutions for integrated quantitative immunohistochemistry in the Pathology daily practice. AB - Immunohistochemistry (IHC) plays an essential role in Pathology. In order to improve reproducibility and standardization of the results interpretation, IHC quantification methods have been developed. IHC interpretation based in whole slide imaging or virtual microscopy is of special interest. The objective of this work is to review the different computer-based programs for automatic immunohistochemistry and Fluorescence In Situ Hybridization (FISH) evaluation. Scanning solutions and image analysis software in immunohistochemistry were studied, focusing especially on systems based in virtual slides. Integrated scanning and image analysis systems are available (Bacus TMAScore, Dako ACIS III, Genetix Ariol, Aperio Image Analysis, 3DHistech Mirax HistoQuant, Bioimagene Pathiam). Other image analysis software systems (Definiens TissueMap, SlidePath Tissue Image Analysis) can be applied to several virtual slide formats. Fluorescence is the preferred approach in HistoRx AQUA, since it allows for a better compartmentalization of signals. Multispectral imaging using CRi Nuance allows multiple antibodies immunohistochemistry, and different stain unmixing. Most current popular automated image analysis solutions are aimed to brightfield immunohistochemistry, but fluorescence and FISH solutions may become more important in the near future. Automated quantitative tissue microarrays (TMA) analysis is essential to provide high-throughput analysis. Medical informatics standards in images (DICOM) and workflow (IHE) under development will foster the use of image analysis in Pathology Departments. PMID- 20164018 TI - AI (artificial intelligence) in histopathology--from image analysis to automated diagnosis. AB - The technological progress in digitalization of complete histological glass slides has opened a new door in tissue--based diagnosis. The presentation of microscopic images as a whole in a digital matrix is called virtual slide. A virtual slide allows calculation and related presentation of image information that otherwise can only be seen by individual human performance. The digital world permits attachments of several (if not all) fields of view and the contemporary visualization on a screen. The presentation of all microscopic magnifications is possible if the basic pixel resolution is less than 0.25 microns. To introduce digital tissue--based diagnosis into the daily routine work of a surgical pathologist requires a new setup of workflow arrangement and procedures. The quality of digitized images is sufficient for diagnostic purposes; however, the time needed for viewing virtual slides exceeds that of viewing original glass slides by far. The reason lies in a slower and more difficult sampling procedure, which is the selection of information containing fields of view. By application of artificial intelligence, tissue--based diagnosis in routine work can be managed automatically in steps as follows: 1. The individual image quality has to be measured, and corrected, if necessary. 2. A diagnostic algorithm has to be applied. An algorithm has be developed, that includes both object based (object features, structures) and pixel based (texture) measures. 3. These measures serve for diagnosis classification and feedback to order additional information, for example in virtual immunohistochemical slides. 4. The measures can serve for automated image classification and detection of relevant image information by themselves without any labeling. 5. The pathologists' duty will not be released by such a system; to the contrary, it will manage and supervise the system, i.e., just working at a "higher level". Virtual slides are already in use for teaching and continuous education in anatomy and pathology. First attempts to introduce them into routine work have been reported. Application of AI has been established by automated immunohistochemical measurement systems (EAMUS, www.diagnomX.eu). The performance of automated diagnosis has been reported for a broad variety of organs at sensitivity and specificity levels >85%). The implementation of a complete connected AI supported system is in its childhood. Application of AI in digital tissue--based diagnosis will allow the pathologists to work as supervisors and no longer as primary "water carriers". Its accurate use will give them the time needed to concentrating on difficult cases for the benefit of their patients. PMID- 20164019 TI - Fluvastatin increases tyrosinase synthesis induced by UVB irradiation of B16F10 melanoma cells. AB - Statins are widely used to lower plasma concentrations of lipids, e.g. cholesterol. One of the main effects of statin treatment is inhibition of hydroxymethyl glutaryl-coenzyme A reductase. The role of fluvastatin, a frequently used statin, was examined in potential modulation of tyrosinase (key enzyme of melanogenesis) synthesis. Levels of tyrosinase mRNA induced by UVB irradiation of B16F10 melanoma cell line were measured by real time PCR. Fluvastatin increases tyrosinase mRNA production induced by UVB irradiation in B16F10 melanoma cell line. Fluvastatin treatment may potentially influence melanin synthesis and protection against UV irradiation. PMID- 20164021 TI - Comparison of chromosome centromere topology in differentiating cells with myogenic potential. AB - Chromosome territories (CT's) constitute the critical element of the intranuclear architecture. Position of these compartmentalized structures plays an important role in functioning of entire genome. Present study was to examine whether the centromeres position of chromosomes 4, X and Y can be changed during differentiation from myoblasts to myotubes. Topological analysis of these centromeres was based on two-dimensional fluorescent hybridization in situ (2D FISH). During differentiation process the majority of X chromosome centromeres analyzed shifted to the peripheral part of a nucleus and similar phenomenon was observed with one of the chromosome 4 centromeres. Completely different tendency was noticed when investigating the location of the chromosome Y centromeres. Centromeres of this chromosome migrated to the centre of a nucleus. The results obtained demonstrated visible changes in chromosome topology along the myogenic stem cells differentiation. PMID- 20164020 TI - Rapid mapping of chromosomal breakpoints: from blood to BAC in 20 days. AB - Structural chromosome aberrations and associated segmental or chromosomal aneusomies are major causes of reproductive failure in humans. Despite the fact that carriers of reciprocal balanced translocation often have no other clinical symptoms or disease, impaired chromosome homologue pairing in meiosis and karyokinesis errors lead to over-representation of translocations carriers in the infertile population and in recurrent pregnancy loss patients. At present, clinicians have no means to select healthy germ cells or balanced zygotes in vivo, but in vitro fertilization (IVF) followed by preimplantation genetic diagnosis (PGD) offers translocation carriers a chance to select balanced or normal embryos for transfer. Although a combination of telomeric and centromeric probes can differentiate embryos that are unbalanced from normal or unbalanced ones, a seemingly random position of breakpoints in these IVF-patients poses a serious obstacle to differentiating between normal and balanced embryos, which for most translocation couples, is desirable. Using a carrier with reciprocal translocation t(4;13) as an example, we describe our state-of-the-art approach to the preparation of patient-specific DNA probes that span or 'extent' the breakpoints. With the techniques and resources described here, most breakpoints can be accurately mapped in a matter of days using carrier lymphocytes, and a few extra days are allowed for PGD-probe optimization. The optimized probes will then be suitable for interphase cell analysis, a prerequisite for PGD since blastomeres are biopsied from normally growing day 3--embryos regardless of their position in the mitotic cell cycle. Furthermore, routine application of these rapid methods should make PGD even more affordable for translocation carriers enrolled in IVF programs. PMID- 20164022 TI - p21/Wafl/Cipl cellular expression in chronic long-lasting hepatitis C: correlation with HCV proteins (C, NS3, NS5A), other cell-cycle related proteins and selected clinical data. AB - Studies indicate that proteins of hepatitis C virus (HCV) disturb expression of cell-cycle-related proteins. A disturbed cell-cycle control is a hepatocellular carcinoma (HCC) risk factor in patients with HCV-related liver damage. The present study aimed to analyse the cellular expression of p21/Wafl/Cipl (p21) in long-lasting chronic hepatitis C (CH-C), its correlation with the key oncogenic HCV proteins (C, NS3, NS5A), other cell-cycle-related proteins (PCNA, Ki-67, cyclin D1, p53) and selected clinical data. Archival liver biopsies, obtained from patients with CH-C, normal livers, and hepatocellular carcinoma (HCC) specimens were analysed by immunocytochemistry and ImmunoMax technique. In CH-C overexpression of p21 protein was demonstrated. Positive correlations of p21 protein expression in CH-C involved age of the patients, grading, and liver steatosis. Moreover, expression of p21 correlated significantly with expression of p53 protein, of D1 cyclin and Ki-67. Although Ki-67 antigen was related to p21 expression, only Ki-67 expression proved to be directly related to liver staging. Expression of the NS3 protein, which prevailed in CH-C patients, manifested correlation with p21 expression, and that of cyclin D1. In presence of preserved potential for regeneration, overexpression of p21 indicates inhibition of cell cycle in hepatocytes, which probably plays a protective role for the chronically damaged cells. Out of the three HCV proteins only NS3 seems to affect control of p21 protein expression in in vivo infection. Nevertheless, the studies indicate that neither expression of p21 protein nor that of viral NS3 protein can serve as a marker of progression of CH-C to HCC in vivo. PMID- 20164023 TI - An optimization of protocol for mixed chimerism induction in mice model. AB - Studies on mixed chimerism are currently focused primarily on obtaining less toxic conditioning protocols. With these issues in mind, we have undertaken the attempt to optimize the procedure of mixed chimerism induction in mice. In order to reduce toxicity, we used decreasing doses of total body irradiation (TBI) together with combination of blocking antibodies. We also tried to eliminate immunosuppression (cyclophosphamide - CP) treatment after bone marrow transplantation. B6.SJL-PtprcaPep3b mice were injected with 20-30 x 106 bone marrow cells from Balb C mice. Mice were treated with TBI (3 - 1.5 - 0 Gy) on " 1" day of the experiment and blocking antibodies against CD40L ("0", and "4" days) and additionally anti-CD8 ("-2" day) and/or anti-NK1.1 ("-3" day). Mice in certain groups also received CP (175 mg/kg) on "2" day. Presence of mixed chimerism was assessed in peripheral blood cells by flow cytometry on the 1st, 2nd, 3rd, 4th, 6th and 8th weeks of the experiment by detecting of CD45.1 (characteristic for B6.SJL-PtprcaPep3b strain) and CD45.2 (characteristic for Balb C strain) antigens expression. We also analyzed the percentage of peripheral blood CD8 T-cells (CD3e/CD8a) and NK cells (Ly-49D/NK1.1). We found that reduction of TBI dose and elimination of CP decrease the rate of mixed chimerism formation. The highest percentage of donor cells was obtained in the group of animals treated with 3 Gy of TBI, CP and combination of anti-CD40L, anti-CD8, and anti-NK1.1 antibodies. The 3 Gy TBI was necessary to induce stable mixed chimerism, but it could be obtained without the CP use. The percentage of CD3e/CD8a and Ly-49D/NK1.1 cells was significantly lower in the groups of mice treated by corresponding antibodies. Moreover, we observed the lowest number of peripheral blood Ly-49D/NK1.1 cells in the group of animals with highest mixed chimerism. Our experiments in mice model can help in better understanding of mixed chimerism phenomenon and in selecting the method of mixed chimerism induction with lowest possible toxicity. This also might improve the protocols of stable mixed chimerism induction in humans, and in the future, the effectiveness of vascularized organ transplantation. PMID- 20164024 TI - The expression of SOCS1 and TLR4-NFkappaB pathway molecules in neoplastic cells as potential biomarker for the aggressive tumor phenotype in laryngeal carcinoma. AB - Suppressor of cytokine signaling 1 (SOCS1) is the key regulator of cytokine mediated innate and adaptive immunity. One of the molecular mechanisms of SOCS1 is connected with inhibition of TLR4-NFkappaB pathway. The relationships among these molecules in laryngeal carcinoma are not exactly known. In this preliminary study we focused on their special activity and role in regulation of development and progression of laryngeal carcinoma. To investigate NFkappaB (p65 subunit) nuclear and cytoplasmic expression in 45 tumor samples of advanced laryngeal carcinoma IHC staining was performed. To determine the mRNA expression levels of TLR4, IRAK1, TRAF6 and SOCS1 in isolated neoplasm cells and non-cancerous adjacent mucosa epithelial cells RT-PCR was used. The invasiveness of laryngeal carcinomas was evaluated according to tumor front grading, TFG, which included tumor-related features (cytoplasmic differentiation, nuclear polymorphism, number of mitoses) and adjacent stroma-related characteristics of the peripheral edge of tumor infiltration (mode of infiltration, depth of invasion and plasmalymphocytic infiltration). The relationships between pT, pN status, the histological G grade, certain clinicopathological characteristics as well as postoperative observation time and the mRNA expression of the molecules mentioned earlier were investigated. Significant differences of TLR4-NFkappaB pathway molecules and SOCS1 mRNA expression in laryngeal tumor cells and normal adjacent mucosa cells as well as significant interconnections of TLR4, SOCS1 and NFkappaB(p65) in isolated tumor cells were obtained. This preliminary study demonstrated that the expression of SOCS1 and TLR4-NFkappaB pathway molecules had a strong association with the aggressiveness of laryngeal carcinoma. Positive relationships of TRAF6 in tumor margin cells with the histological grade and the mode of tumor invasion as well as the TFG total score were highlighted. Significant positive correlations were found between the TLR4 in tumor central cells and the TFG total score. Negative relationships of SOCS1 in tumor central cells with the histological grade were also noted. Significant positive correlations were found between the cytoplasmic NFkappaB(p65) and the mode of invasion as well as TFG total score. Our findings confirmed the importance of SOCS1 and TLR4-NFkappaB pathway molecules as potential biomarkers for assessment of the aggressive tumor phenotype in laryngeal carcinoma. PMID- 20164025 TI - Selected metabolites of neutrophils in patients with 2-type diabetes complicated and non complicated with diabetic foot syndrome during colonization of E. coli toxin. AB - Neutrophils play an important role in the pathogenesis of complications of diabetes mellitus. The aim of the study was to evaluate the metabolism of neutrophiles activation markers during the colonization of E. coli endotoxin in order to determine their potential role in the treatment of 2-type diabetes complicated and non-complicated with the diabetic foot syndrome and to evaluate production of peroxide anions by stimulated and non-stimulated neutrophils depending on the exposition time. 54 patients were divided into 3 groups (15 healthy volunteers--control group (1), group 2 - 17 patients with 2-type non complicated diabetes group 3 - 22 patients with diabetes and diabetic foot syndrome). Blood samples from all subjects were examined. Results show significant differences of E.coli endotoxin influence on metabolism of neutrophiles in study groups. Production of peroxide anions by non-stimulated neutrophils in 20th minute of the experiment was 15 times higher in the group with no diabetic foot and 18 times higher in the group with diabetic foot as compared to the control group. Production of peroxide anions produced by neutrophils increased significantly with the exposure time. The results correspond to data in the literature, that suggest, that type, time of exposition and concentration of pathogens may significantly interfere with neutrophiles activity in the course of diabetes. PMID- 20164026 TI - Immunohistochemical and hybridocytochemical study on ghrelin signalling in the rat seminiferous epithelium. AB - The results of presented study demonstrate expression of ghrelin, its functional receptor GHSR-1a and their genes in spermatogenic cells of rat testis suggesting their functioning within seminiferous epithelium. The immunohistochemical and hybrydocytochemical expression, of proteins and transcripts, was estimated taking into account the cycle of seminiferous epithelium and phases of spermatogenesis. Both transcripts and ghrelin was found to show nuclear expression and scarcely cytoplasmic. Expression of genes for ghrelin and GHSR-1a was shown in early spermatocytes and round spermatids representing transcriptional phases of meiosis and spermiogenesis. Ghrelin was evidenced to show nuclear expression in two stage specific windows, in late spermatogonia, in spermatocytes up to early pachytenes, and again in spermatids of acrosome and early maturation phase of spermiogenesis. In late pachytenes, secondary spermatocytes, round spermatids, maturing spermatids and spermatozoa the reaction is lacking. With two types of antibodies against the GHSR-1a used the two different patterns of immunostaining was evidenced suggesting two isoforms of GHSR-1a. The first evidenced GHSR-1a in cytoplasm of spermatocytes, cell membrane and acrosomes of spermatids, Sertoli cell processes and heads of spermatozoa. With second type of antibodies the immunostaining marks all steps of evolution of acrosome in spermatids. It is believed that site of ghrelin expression in seminiferous epithelium may indicate its role in local regulations, not excepting the intracellular signalling. Immunostaining pattern for GHSR-1a seems to suggest both its participation in the cross-talk among the cells and also process of furnishing gametes with GHSR-1a for its response to ghrelin in seminal plasma or female reproductive tract. PMID- 20164027 TI - STAT3 and hypoxia induced proteins--HIF-1alpha, EPO and EPOR in relation with Bax and Bcl-xL in nodal metastases of ductal breast cancers. AB - STAT3 contributes to increase of EPO expression which is also HIF-1 dependent. EPO receptor activates STAT3. Expressions of STAT3 and hypoxia induced proteins: HIF-1, EPO and EPOR show mutual correlations in primary ductal breast cancers, which suggest co-operation among these proteins. Moreover, EPO-EPOR signaling was reported to mediate cell survival by targeting Bcl-xL in competition with Bax dependent apoptosis. Our present study was focused on immunohistochemical evaluation of STAT3, HIF-1alpha, EPO and EPOR in relation to apoptosis regulators, Bax and Bcl-xL in 39 metastases of ductal breast cancers to lymph nodes. The proteins were abundantly expressed by cancer cells. HIF-1alpha correlated with EPOR in all and in chemotherapy treated metastases (r=0.428, p=0.007 and r=0.462, p=0.040, respectively). HIF-1 associated significantly with EPO in chemotherapy spared metastases (r=0.549, p=0.015) and comparison between those proteins almost reached statistical significance in entire number of metastatic breast cancers (r=0.309, p=0.056). Metastases from T2 primary tumors had significantly higher expressions of HIF-1alpha, EPO and EPOR compared to T1 originating metastases (p=0.020, p=0.028, p=0.021, respectively). Bax correlated with EPO and EPOR in all studied nodal metastases (r=0.449, p=0.006 and r=0.421, p=0.011, respectively) and so did Bcl-xL with HIF-1alpha (r=0.440, p=0.007), EPO and EPOR (r=0.383, p=0.021, r=0.495, p=0.002, respectively). Metastatic breast cancers seem to be areas of intensive signaling by STAT3, HIF-1, EPO and EPOR. Strong Bax and Bcl-xL labeling reflects accelerated cell turnover in nodal metastases. By means of association with Bcl-xL, HIF-1alpha, EPO and EPOR could favor growth of nodal metastases and survival of breast cancers cells. PMID- 20164028 TI - Adult Respiratory Distress Syndrome and alveolar epithelium apoptosis: an histopathological and immunohistochemical study. AB - Adult Respiratory Distress Syndrome results from a variety of different initial insults, including trauma, sepsis, pneumonia and aspiration, and represents a severe form of acute lung injury. The lung samples of a 20-year-old man who had suffered a serious motorbike accident were obtained for histological examination. He died on the seventh day as a consequence of respiratory failure. The typical histopathological features of syndrome overlapping the first exudative phase into the second proliferate phase were observed. The apoptotic index of the early apoptotic phase evaluated using M30CytoDEATH was 3.4+/-0.2. The average number of apoptotic cells in the intermediate and late phases measured using the TUNEL method was 9.8+/-0.7. Our findings indicate that alveolar epithelium apoptosis seems to be less important during the early phases of Adult Respiratory Distress Syndrome. PMID- 20164029 TI - Expression of VEGF receptors VEFGR-1 and VEGFR-2, angiopoietin receptors Tie-1 and Tie-2 in chorionic villi tree during early pregnancy. AB - The aim of this study was to determine the expression of VEGF and its receptors in placentas from normal pregnancies between 22 days p.c. and 48 days p.c. of very early pregnancy. Placental tissues carried out from 19 pregnant women were examined. Immunohistochemical technique, electron microscopy were employed to evaluate the factors expression. In the new developing mesenchymal villi and immature intermediate villi VEGF and its receptors VEGFR-1 and VEGFR-2 immunoreactivity was detected in all the placental components, while in the stem villi and in the chorionic plate with large vessels only in some components. In the mesenchymal villi and immature intermediate villi VEGFR-1 and -2, and angiopoietin receptors Tie-1 and -2 immunoreactivity was dominantly observed in the heamangiogenic cells and cells cords, whereas the matured villi showed immunoreactivity only in other components. The ultrastructural findings were higher in respect to the all of the early pregnancy days. The placental samples from all of pregnancies, showed the VEGF and its receptors in optimal expression levels, whereas the angiopoietin receptors Tie-1 and -2 showed a higher expression levels in respect to other study factors. The receptors protein levels increased from the early days to the advanced days of gestation, but this alteration was not significant. The intensity of the immunolabeling for these proteins were not significant compared to to each other of gestatin days were examined. These findings demonstrated that a dysregulation of the placental expression of the VEGF and its receptors related to the different degrees of the gestational periods. Probably, this event may be related to complete vasculugenesis and angiogenesis in placental villi. PMID- 20164030 TI - Helicobacter pylori infection and expressions of EGF, EGFR and c-erbB-2 proteins in gastric carcinoma. AB - The family of epidermal growth factor (EGF, EGFR, c-erbB-2) plays a pivotal role in gastric cancer progression, invasion and metastasizing. Helicobacter pylori infection is known to contribute significantly to the formation and progression of gastric cancer. However, the mechanisms responsible for this process have not been yet elucidated. We analysed the relationship between H. pylori infection and expression of proteins belonging to the family of epidermal growth factor (EGF, EGFR, c-erbB-2). Fifty-five patients with gastric cancer were analysed for Helicobacter pylori infection. The expressions of EGF, EGFR, c-erbB-2 proteins were determined using an immunohistochemical method. No statistically significant correlation was found between the degree of H. pylori infection and the expressions of EGF, EGFR and c-erbB-2 in gastric cancer. However, c-erbB-2 expression in the main mass of tumour correlated with tumour expression of EGF and EGFR and with c-erbB-2 expression in local lymph nodes. The expression of c erbB-2 in lymph nodes was statistically significantly related to the expressions of EGF and EGFR both in the main mass of tumour and in lymph nodes. The expression of EGF was found to correlate with EGFR in the main mass of tumour and the expression of EGF in lymph nodes was related to lymph node EGFR level. Our study did not confirm the relationship between H. pylori infection and the expression of epidermal growth factor in gastric cancer. PMID- 20164031 TI - Effect of arsenic trioxide (Trisenox) on actin organization in K-562 erythroleukemia cells. AB - Actin is one of the cytoskeletal proteins that take part in many cellular processes. The aim of this study was to show the influence of Trisenox (arsenic trioxide), on the cytoplasmic and nuclear F-actin organization. Arsenic trioxide is the proapoptotic factor. Together with increasing doses, it caused the increase in the number of cells undergoing apoptosis. Under arsenic trioxide treatment, cytoplasmic and nuclear F-actin (polymerized form of G-actin) was found reorganized. It was transformed into granulated structures. In cytometer studies fluorescence intensity of cytoplasmic F-actin after ATO treatment decreasing urgently in comparison to control. The obtained results may suggest the involvement of F-actin in apoptosis, especially in chromatin reorganization. PMID- 20164032 TI - F-actin distribution pattern in the nuclei of early mouse embryos. AB - Nuclear actin is the essential component of gene expression. Here we show that the pattern of F- actin distribution in the nuclei of early mouse embryos depends on the experimental conditions and does not represent nonspecific cell reaction for the experimental influence. PMID- 20164033 TI - Diminished production of TWEAK by the peripheral blood mononuclear cells is associated with vascular involvement in patients with systemic sclerosis. AB - Widespread vasculopathy and profound fibrosis are key features of the pathogenesis of systemic sclerosis (SSc). We hypothesized that the TNF-like weak inducer of apoptosis (TWEAK), a recently recognized multifunctional cytokine which regulates angiogenesis and tissue remodeling, may play a role in the development of SSc. The production of TWEAK by the peripheral blood mononuclear cells (PBMC) was investigated, by means of ELISA, in 24 SSc patients and 14 healthy subjects. Moreover, production of TWEAK was correlated with clinical features of SSc. PBMC were isolated using density gradient centrifugation on Histopaque and were cultured in FCS supplemented RPMI medium at 37 degrees C under 5% CO2. Production of TWEAK by PBMC was significantly diminished in patients with more severe microvascular damage, as indicated by the presence of "active" capillaroscopic pattern, compared with SSc patients with less pronounced microangiopathy ("slow" pattern), and healthy subjects. Moreover production of TWEAK correlated inversely with duration of Raynaud's phenomenon. PBMC from patients with scleroderma-related interstitial lung disease tended to produce lower amounts of TWEAK compared with SSc patients without lung involvement but the difference was not significant. The results of our study suggest that diminished production of TWEAK might play a role in the pathogenesis of vascular injury in SSc patients. Whether TWEAK may represent a new therapeutic target in SSc requires further studies. PMID- 20164034 TI - Evaluation of the memory CD4+ and CD8+ T cells homeostasis during chronic venous disease of lower limbs. AB - More and more is known about the role of venous wall abnormalities and valvular incompetence in the development of chronic venous disorders (CVD). Unfortunately detailed mechanisms of CVD pathophysiology are not well understood. Recent studies focus on involvement of the inflammatory process in the structural remodeling of venous valves and venous wall. The aim of this study is to investigate and to document the memory T cells homeostasis in CVD patients. In this study we present lymphocytic changes in blood from varicose veins in terms of total CD4+ and CD8+ T cells and their particular subsets of memory T cells: TN, TCM and TEM. Results suggest that immunological memory may be involved in the CVD development. PMID- 20164035 TI - Pituitary ACTH cells in female rats after neonatal treatment with SRIH-14. AB - The prolonged effects of neonatal SRIH-14 treatment on pituitary ACTH cells were investigated. Neonatal female rats were injected subcutaneously with SRIH (20 microg/100g b.w.) every 12 hours for five consecutive days (3rd-7th day of life). Groups of rats were then killed at the juvenile (16th day), peripubertal (38th day) or adult (80th day) stage. ACTH cells were visualized using the peroxidase antiperoxidase immunocytochemical procedure. Morphometry and stereology were used to evaluate the ACTH-immunoreactive cell volume and volume density. The histological and immunocytochemical characteristics of ACTH cells in neonatally treated females were changed in all examined periods. Thus, SRIH-14 induced significant (p<0.05) decreases of ACTH cell volume in juvenile, peripubertal and adult rats by 26%, 39% and 14%, respectively, in comparison to the corresponding controls. The volume density of ACTH cells was also diminished (by 31%; p<0.05) at the juvenile stage in comparison with the corresponding controls. In peripubertal and adult rats, the volume densities of ACTH cells were somewhat lower (17% and 14%, respectively), but the decreases did not reach statistical significance. These findings suggest that neonatal treatment with SRIH-14 exerts a marked prolonged inhibitory effect on ACTH cell morphology extending to the adult period of life. PMID- 20164036 TI - Inhibition of rhabdomyosarcoma's metastatic behavior through downregulation of MET receptor signaling. AB - Rhabdomyosarcoma (RMS) is a soft tissue sarcoma usually diagnosed in children. In advanced and metastatic stages the prognosis is often poor. RMS cell lines were used for evaluation of the role of MET receptor inhibition on chemotaxis and invasion. In vivo studies were performed using NOD-SCID xenograft model. This study shows that blocking of MET expression has strong influence on metastatic behavior of RMS. MET negative cells possess a reduced potential to migrate and to invade. Downregulation of MET suppressed the ability of RMS cells to populate bone marrow. Inhibition of MET negative tumor cells engraftment into bone marrow was observed. MET negative tumors were also two to four times smaller than their wild type counterparts. Since MET receptor plays a very important role in facilitating metastasis of RMS cells, blocking of HGF-MET axis might be considered as a therapeutic option for RMS patients, at more advanced and metastatic stages. PMID- 20164037 TI - Expression of matrix metalloproteinase-9 in the neoplastic and interstitial inflammatory infiltrate cells in gastric cancer. AB - Matrix metalloproteinases (MMPs) play an important role in the extracellular matrix degradation, that is an essential step in tumor invasion and metastases. The current study objective was to evaluate the expression of MMP-9 in the neoplastic and in the interstitial inflammatory infiltrate cells in gastric cancer (GC). Moreover, the relationship between expression of this enzyme and clinicopathological features of GC, such as TNM stage, the depth of tumor invasion, lymph node and distant metastases were assessed. The study comprised 54 patients with gastric cancer. Immunohistochemistry was used to determine the expression of MMP-9 in gastric cancer cells. The semi-quantitative scale was applied to evaluate the expression of metalloproteinase-9. Immunohistochemical testing revealed a positive reaction of MMP-9 in 98% of all cancer tissue specimens and in 93% of inflammatory cells. The expression of MMP-9 in the neoplastic and inflammatory cells increased with more advance tumor stage, depth of tumor invasion and presence of lymph node as well as distant metastases. These findings indicate the significance of interstitial inflammatory infiltrate cells in the MMP-9 synthesis and the role of this enzyme in the invasiveness and metastatic potential of GC. PMID- 20164038 TI - The aromatase expression in myomas and myometriums of women in reproduction and perimenopausal age. AB - Uterine myomas represent one of the most common female pathologies. Uterine smooth muscle myomas or fibromas are benign tumours which respond to hormones and their etiology induces wide interest. The myomas were found to contain aromatase and, in addition, cells of the myomas were found to synthesize estrogen. This study was conducted on patients with the myomas, in either generative age or in the perimenopausal period. Expression of aromatase was detected in patients of various age, with large or small uterine myomas, using an immunohistochemical technique. In addition expression of the enzyme was examined at the periphery of every myoma. PMID- 20164039 TI - Assessment of ghrelin, GHS-R, GH, and neurohormones in human fetal pituitary glands and central nervous system: an immunohistochemical study. AB - The aim of this work was evaluation of expression of ghrelin and GHS-R1a receptor in somatotrops and in neuronal cells of brain tissue in the process of human fetal ontogenesis. Relations were also looked for between GHRH and SS in the pituitary and in the CNS neurones of the studied fetuses. The study was based on 8 pituitaries and 8 brains from fetuses in different periods of intrauterine life. The immunocytochemical technique was used. The presence of ghrelin, GHS-R was shown in the glandular part of the pituitary and CNS during the whole period of intrauterine life. Neurohormones in the stalk of the pituitary were found in fetuses from the 32nd week of pregnancy whereas in the CNS neurones these hormones could be detected throughout the whole period of intrauterine life. The results obtained suggest that stimulation of GH secretion by ghrelin is independent of the feedback concentration and these two hormones act like signals of metabolic balance. GH release by ghrelin in fetal life is independent of somatostatin. The hypothalamic-pituitary axis which regulates pulsatile GH release from the pituitary matures functionally in the third trimester of pregnancy independent of the previous anatomical differentiation. PMID- 20164040 TI - Expression of tissue inhibitors of metalloproteinase 1 (TIMP-1) in gastric cancer tissue. AB - Degradation of extracellular matrix (ECM) is an essential step of invasion and metastasis of gastric cancer. The proteolysis of basement membranes depends on the balance between activities of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). The aim of the study was to assess the expression of TIMP-1 in gastric cancer (GC) and interstitial inflammatory infiltrate cells within GC tissue in relation to clinico-pathological features of tumor and to estimate the prognostic significance of TIMP-1 expression for patients' survival. The presence of TIMP-1 in 54 cases of gastric cancer samples was investigated by immunohistochemistry. The expression of TIMP-1 in cancer and interstitial inflammatory infiltrate cells was evaluated in semi-quantitative scale. The immunoreactivity of TIMP-1 in cancer and inflammatory cells was positive in 100% of cases and varied from weak to intense reaction. The intensity of TIMP-1 expression increased with more advanced tumor stages and in patients who died of cancer during 2-year observation. TIMP-1 expression in interstitial inflammatory infiltrate cells was the independent prognostic factor for patients' survival. The results suggest the role of TIMP-1 in gastric tumorigenesis, although this issue requires further investigtions. PMID- 20164041 TI - Psoriasis vulgaris and digestive system disorders: is there a linkage? AB - Psoriasis is well-known immune-mediated skin disease often associated with co morbidities, including dyslipidaemia and obesity. Few reports imply that the disease might be also related to pathology of mucosal surfaces, especially that of the digestive system. The authors present a case of psoriasis and concurrent digestive system abnormalities, and review the literature regarding the topic. A 40-year-old man suffered from an exacerbation of exudative psoriasis for about 6 months. Topical antipsoriatics proved ineffective and the disease gradually progressed to a severe disseminated form. Subsequent detailed examinations revealed persistent gastroduodenitis due to H. pylori infection, pancreatic dysfunction and fatty change of the liver, although the patient denied any gastrointestinal symptoms. As a result appropriate treatment of the diagnosed digestive system disorders was added to topical antipsoriatic therapy. Within 2 weeks of treatment clinical symptoms and laboratory signs showed a marked trend to normalisation. The presented medical history seems to suggest that there may be some kind of interplay between psoriasis and digestive system disorders. PMID- 20164042 TI - Computer aided system for segmentation and visualization of microcalcifications in digital mammograms. AB - Two methods for segmentation and visualization of microcalcifications in digital or digitized mammograms are described. First method is based on modern mathematical morphology, while the second one uses the multifractal approach. In the first method, by using an appropriate combination of some morphological operations, high local contrast enhancement, followed by significant suppression of background tissue, irrespective of its radiology density, is obtained. By iterative procedure, this method highly emphasizes only small bright details, possible microcalcifications. In a multifractal approach, from initial mammogram image, a corresponding multifractal "images" are created, from which a radiologist has a freedom to change the level of segmentation. An appropriate user friendly computer aided visualization (CAV) system with embedded two methods is realized. The interactive approach enables the physician to control the level and the quality of segmentation. Suggested methods were tested through mammograms from MIAS database as a gold standard, and from clinical praxis, using digitized films and digital images from full field digital mammograph. PMID- 20164044 TI - Alcohol consumption before and after a significant reduction of alcohol prices in 2004 in Finland: were the effects different across population subgroups? AB - AIMS: To examine trends in adult alcohol consumption by age, gender and education from 1982 to 2008 and evaluate the effects that a significant reduction in alcohol prices in 2004 had on alcohol consumption in different population subgroups. METHODS: The study population comprised respondents aged 25-64 (n = 79,100) replying to nationally representative annual postal surveys from 1982 to 2008 (average response rate 72%). The main measurements were the prevalence of respondents who had drunk at least eight (men) or five (women) drinks in the previous week ('moderate to heavy drinkers') and prevalence of those who weekly (men) or monthly (women) drank six or more drinks on a single occasion ('heavy episodic drinkers') (one 'drink' containing 11-13 g ethanol). Logistic models were used to test differences across population subgroups in the changes in drinking. RESULTS: Following the reduction of alcohol prices in 2004, drinking increased among men and women aged 45-64. Among men, both moderate to heavy drinking and heavy episodic drinking increased in the lowest educational group. Among women, moderate to heavy drinking increased mostly in the lowest and intermediate educational groups, while the highest increases for heavy episodic drinking were in the intermediate and highest female educational groups. CONCLUSION: Alcohol consumption increased especially among those aged 45-64 and among lower educated people following the reduction in alcohol prices in 2004 in Finland. PMID- 20164043 TI - Using the internet to promote health behavior change: a systematic review and meta-analysis of the impact of theoretical basis, use of behavior change techniques, and mode of delivery on efficacy. AB - BACKGROUND: The Internet is increasingly used as a medium for the delivery of interventions designed to promote health behavior change. However, reviews of these interventions to date have not systematically identified intervention characteristics and linked these to effectiveness. OBJECTIVES: The present review sought to capitalize on recently published coding frames for assessing use of theory and behavior change techniques to investigate which characteristics of Internet-based interventions best promote health behavior change. In addition, we wanted to develop a novel coding scheme for assessing mode of delivery in Internet-based interventions and also to link different modes to effect sizes. METHODS: We conducted a computerized search of the databases indexed by ISI Web of Knowledge (including BIOSIS Previews and Medline) between 2000 and 2008. Studies were included if (1) the primary components of the intervention were delivered via the Internet, (2) participants were randomly assigned to conditions, and (3) a measure of behavior related to health was taken after the intervention. RESULTS: We found 85 studies that satisfied the inclusion criteria, providing a total sample size of 43,236 participants. On average, interventions had a statistically small but significant effect on health-related behavior (d(+) = 0.16, 95% CI 0.09 to 0.23). More extensive use of theory was associated with increases in effect size (P = .049), and, in particular, interventions based on the theory of planned behavior tended to have substantial effects on behavior (d(+) = 0.36, 95% CI 0.15 to 0.56). Interventions that incorporated more behavior change techniques also tended to have larger effects compared to interventions that incorporated fewer techniques (P < .001). Finally, the effectiveness of Internet-based interventions was enhanced by the use of additional methods of communicating with participants, especially the use of short message service (SMS), or text, messages. CONCLUSIONS: The review provides a framework for the development of a science of Internet-based interventions, and our findings provide a rationale for investing in more intensive theory-based interventions that incorporate multiple behavior change techniques and modes of delivery. PMID- 20164045 TI - The pro-inflammatory effect of uraemia overrules the anti-atherogenic potential of immunization with oxidized LDL in apoE-/- mice. AB - BACKGROUND: Uraemia increases oxidative stress, plasma titres of antibodies recognizing oxidized low-density lipoprotein (oxLDL) and development of atherosclerosis. Immunization with oxLDL prevents classical, non-uraemic atherosclerosis. We have investigated whether immunization with oxLDL might also prevent uraemia-induced atherosclerosis in apolipoprotein E knockout (apoE-/-) mice. METHODS: ApoE-/- mice were immunized with either native LDL (n = 25), Cu(2+)-oxidized LDL (n = 25), PBS (n = 25), the apolipoprotein B-derived peptide P45 (apoB-peptide P45) conjugated to bovine serum albumin (BSA) (n = 25) or BSA (n = 25) prior to induction of uraemia by 5/6 nephrectomy (NX). RESULTS: Immunization with oxLDL increased plasma titres of immunoglobulin G (IgG) recognizing Cu(2+)-oxLDL and malondialdehyde-modified LDL (MDA-LDL). However, 5/6 NX induced a marked increase in plasma concentrations of anti-oxLDL antibodies as well as pro-atherogenic cytokines [interleukin (IL)-2 (IL-2), IL-4, IL-6 and IL 12)] in native mouse LDL (nLDL)-, oxLDL- and PBS-immunized mice. Even though nLDL and oxLDL-immunized mice displayed higher anti-MDA-LDL IgG titres than the PBS group, aortic atherosclerosis lesion size was not affected by immunization. Immunization with the apoB-peptide P45, which consistently reduces classical atherosclerosis in non-uraemic mice, also did not reduce lesion size in uraemic apoE-/- mice. CONCLUSION: The results suggest that the pro-inflammatory and pro atherogenic effect of uraemia overrules the anti-atherogenic potential of oxLDL immunization in apoE-/- mice. PMID- 20164046 TI - Plasma and urine leukocyte elastase-alpha1protease inhibitor complex as a marker of early and long-term kidney graft function. AB - BACKGROUND: Neutrophils are mediators of ischaemia/reperfusion (I/R) injury following kidney transplantation (kTx). Leukocyte elastase (LE) complex with alpha(1)protease inhibitor (LE-alpha(1)PI) is a marker of neutrophil degranulation. The aim of this study was to evaluate LE-alpha(1)PI as a marker of I/R kidney damage and to search for correlations between leukocyte activation and post-transplant complications. METHODS: Plasma and urine LE-alpha(1)PI were estimated in 55 deceased-donor kidney graft recipients on postoperative days (POD) 1, 3 and 7, as well as in the late post-transplant period. RESULTS: The plasma LE-alpha(1)PI level peaked on POD 1 after kTx, and the urine LE-alpha(1)PI peaked on POD 3. On POD 1 and POD 3, the urine LE-alpha(1)PI levels were higher in delayed graft function (DGF) patients than in patients with immediate graft function (IGF: P < 0.001 and P < 0.003, respectively). Urine LE-alpha(1)PI excretion on POD 1 was significantly higher in patients with longer cold ischaemia time (CIT) than in patients with shorter CIT, P < 0.002. Multivariate regression model revealed two factors influencing the occurrence of early acute rejection-urine LE-alpha(1)PI complex on POD 3 and human leukocyte antigen (HLA) mismatches. There was a significant association between the plasma LE-alpha(1)PI on POD 3 and serum creatinine level 6 and 12 months after kTx (r(2) 0.24; P < 0.005 and 0.19; P < 0.005, respectively). CONCLUSIONS: This study is the first presentation of a simple, non-invasive measurement of neutrophil activation after kTx. It also demonstrates a strong correlation between the early post-transplant LE-alpha(1)PI complex level and kidney graft function. PMID- 20164047 TI - Is Chlamydia pneumoniae the causative agent of microscopic polyangiitis? PMID- 20164052 TI - Inverse p16 and p63 expression in small cell carcinoma and high-grade urothelial cell carcinoma of the urinary bladder. AB - Small cell carcinoma (SmCC) of the urinary bladder is a rare, highly aggressive neoplasm. The diagnosis is usually made on morphologic grounds, with the help of immunohistochemistry to document neuroendocrine differentiation. However, neuroendocrine markers generally have low sensitivity, ranging between 30-70%. Recent studies have reported p16 over-expression in SmCC of the lung, suggesting that p16 immunohistochemistry may be useful in the diagnosis of bladder SmCC. This is the first study to analyze the usefulness of p16 in the distinction of small cell and high grade urothelial cell carcinoma (HG-UCC). Fourteen cases of SmCCs and sixteen cases of HG-UCC of the bladder were stained with p16, p63, cytokeratin 20 (CK20), cytokeratin 7 (CK7), chromogranin (Chr), synaptophysin (Syn), and CD56. P16 expression was significantly higher in SmCCs (92.8%) when compared to HG-UCCs (43.7%). P63 and CK20, on the other hand, were positive in the majority of HG-UCCs (81.3% and 50%, respectively), while only 14.3% of SmCCs showed focal immunoreactivity with CK20. The sensitivity of the traditional neuroendocrine markers was low, ranging between 28.6% (Chr) and 71.4% (CD56) in SmCCs. P16 positivity in the absence of p63 and CK20 is highly characteristic of SmCC, while p63 and CK20 positivity with or without p16 expression is typical of HG-UCC. PMID- 20164053 TI - Unusual snapshots of unexpected melanomas. PMID- 20164054 TI - Hernia uterine inguinale and seminoma in persistent Mullerian duct syndrome. AB - Persistent Mullerian duct syndrome (PMDS) with seminoma, hernia uterine inguinale, and transverse testicular ectopia is rare. A 41-year-old phenotypic man with 46 XY karyotype was admitted with nonpainful bulging mass in the left inguinoscrotal region. Two distinct masses were identified by sonography and computed tomography. No testis was apparent on the right side. Excisional specimens revealed seminoma and scrotal uterus. Histopathology of seminoma showed enhanced CD117 immunohistochemical staining. The other inguinal mass was consistent with uterine tissue and was associated with the vas deferens in its lateral aspect. Radiation therapy was performed after the orchiectomy and scrotal hysterectomy. The patient remains free of recurrence after 1-year follow-up assessment. The presence of a unilateral inguinal hernia with a large mass associated with a contralateral nonpalpable testis indicates the presence of PMDS with hernia uterine inguinale and transverse testicular ectopia. PMID- 20164055 TI - A tumor with many faces: metastatic malignant melanoma with extensive cartilaginous differentiation. PMID- 20164056 TI - TFE3 expression in tumors of the microphthalmia-associated transcription factor (MiTF) family. AB - The DNA-binding factor TFE3 is closely related to microphthalmia-associated transcription factor (MiTF) and is over-expressed in alveolar soft part sarcoma (ASPS) and select renal cell carcinomas. Reports of TFE3 expression in PEComa prompted investigation into TFE3 expression among other members of the putative MiTF group of neoplasms. The authors examined cases of PEComa (n = 6), conventional angiomyolipoma (AML; n = 22), metastatic melanoma (n = 16), and clear cell sarcoma (CCS; n = 9) for TFE3 expression. Nuclear immunostaining was observed in 74% (39/53) of cases, as follows: 5/6 PEComas, 18/22 AMLs, 10/16 metastatic melanomas, and 6/9 CCSs. However, with the exception of PEComas, compared with ASPS controls, TFE3 staining was significantly less intense in the tumors examined. These results illustrate that TFE3 immunoreactivity is detectable in other members of the MiTF family of neoplasms. For this reason, such neoplasms warrant consideration in the differential diagnosis with nuclear TFE3 immunoreactivity, particularly when staining is focal and less intense. PMID- 20164057 TI - The proteome of Shigella flexneri 2a 2457T grown at 30 and 37 degrees C. AB - To upgrade the proteome reference map of Shigella flexneri 2a 2457T, the protein expression profiles of log phase and stationary phase cells grown at 30 and 37 degrees C were thoroughly analyzed using multiple overlapping narrow pH range (between pH 4.0 and 11.0) two-dimensional gel electrophoresis. A total of 723 spots representing 574 protein entries were identified by MALDI-TOF/TOF MS, including the majority of known key virulence factors. 64 hypothetical proteins and six misannotated proteins were also experimentally identified. A comparison between the four proteome maps showed that most of the virulence-related proteins were up-regulated at 37 degrees C, and the differences were more notable in stationary phase cells, suggesting that the expressions of these virulence factors were not only controlled by temperature but also controlled by the nutrients available in the environment. The expression patterns of some virulence related genes under the four different conditions suggested that they might also be regulated at the post-transcriptional level. A further significant finding was that the expression of the protein ArgT was dramatically up-regulated at 30 degrees C. The results of semiquantitative RT-PCR analysis showed that expression of argT was not regulated at the transcriptional level. Therefore, we carried out a series of experiments to uncover the mechanism regulating ArgT levels and found that the differential expression of ArgT was due to its degradation by a periplasmic protease, HtrA, whose activity, but not its synthesis, was affected by temperature. The cleavage site in ArgT was between position 160 (Val) and position 161 (Ala). These results may provide useful insights for understanding the physiology and pathogenesis of S. flexneri. PMID- 20164058 TI - Template proteogenomics: sequencing whole proteins using an imperfect database. AB - Database search algorithms are the primary workhorses for the identification of tandem mass spectra. However, these methods are limited to the identification of spectra for which peptides are present in the database, preventing the identification of peptides from mutated or alternatively spliced sequences. A variety of methods has been developed to search a spectrum against a sequence allowing for variations. Some tools determine the sequence of the homologous protein in the related species but do not report the peptide in the target organism. Other tools consider variations, including modifications and mutations, in reconstructing the target sequence. However, these tools will not work if the template (homologous peptide) is missing in the database, and they do not attempt to reconstruct the entire protein target sequence. De novo identification of peptide sequences is another possibility, because it does not require a protein database. However, the lack of database reduces the accuracy. We present a novel proteogenomic approach, GenoMS, that draws on the strengths of database and de novo peptide identification methods. Protein sequence templates (i.e. proteins or genomic sequences that are similar to the target protein) are identified using the database search tool InsPecT. The templates are then used to recruit, align, and de novo sequence regions of the target protein that have diverged from the database or are missing. We used GenoMS to reconstruct the full sequence of an antibody by using spectra acquired from multiple digests using different proteases. Antibodies are a prime example of proteins that confound standard database identification techniques. The mature antibody genes result from large scale genome rearrangements with flexible fusion boundaries and somatic hypermutation. Using GenoMS we automatically reconstruct the complete sequences of two immunoglobulin chains with accuracy greater than 98% using a diverged protein database. Using the genome as the template, we achieve accuracy exceeding 97%. PMID- 20164059 TI - Site-specific phosphorylation dynamics of the nuclear proteome during the DNA damage response. AB - To investigate the temporal regulation of the DNA damage response, we applied quantitative mass spectrometry-based proteomics to measure site-specific phosphorylation changes of nuclear proteins after ionizing radiation. We profiled 5204 phosphorylation sites at five time points following DNA damage of which 594 sites on 209 proteins were observed to be regulated more than 2-fold. Of the 594 sites, 372 are novel phosphorylation sites primarily of nuclear origin. The 594 sites could be classified to distinct temporal profiles. Sites regulated shortly after radiation were enriched in the ataxia telangiectasia mutated (ATM) kinase SQ consensus sequence motif and a novel SXXQ motif. Importantly, in addition to induced phosphorylation, we identified a considerable group of sites that undergo DNA damage-induced dephosphorylation. Together, our data extend the number of known phosphorylation sites regulated by DNA damage, provides so far unprecedented temporal dissection of DNA damage-modified phosphorylation events, and elucidate the cross-talk between different types of post-translational modifications in the dynamic regulation of a multifaceted DNA damage response. PMID- 20164061 TI - Healthy men 2020. PMID- 20164062 TI - To tweet, or not to tweet: gender differences and potential positive and negative health outcomes of adolescents' social internet use. AB - Adolescents and young adults are avid Internet users. Online social media, such as social networking sites (e.g., Facebook, MySpace), blogs, status updating sites (e.g., Twitter) and chat rooms, have become integral parts of adolescents' and young adults' lives. Adolescents are even beginning to enter the world of online dating with several websites dedicated to "teenage online dating." This paper reviews recent peer-reviewed literature and national data on 1) adolescents use of online social media, 2) gender differences in online social media and 3) potential positive and negative health outcomes from adolescents' online social media use. We also examine parental monitoring of adolescents' online activities. Given that parental supervision is a key protective factor against adolescent risk-taking behavior, it is reasonable to hypothesize that unmonitored Internet use may place adolescents' at significant risk, such as cyberbullying, unwanted exposure to pornography, and potentially revealing personal information to sexual predators. PMID- 20164060 TI - Dual-color proteomic profiling of complex samples with a microarray of 810 cancer related antibodies. AB - Antibody microarrays have the potential to enable comprehensive proteomic analysis of small amounts of sample material. Here, protocols are presented for the production, quality assessment, and reproducible application of antibody microarrays in a two-color mode with an array of 1,800 features, representing 810 antibodies that were directed at 741 cancer-related proteins. In addition to measures of array quality, we implemented indicators for the accuracy and significance of dual-color detection. Dual-color measurements outperform a single color approach concerning assay reproducibility and discriminative power. In the analysis of serum samples, depletion of high-abundance proteins did not improve technical assay quality. On the contrary, depletion introduced a strong bias in protein representation. In an initial study, we demonstrated the applicability of the protocols to proteins derived from urine samples. We identified differences between urine samples from pancreatic cancer patients and healthy subjects and between sexes. This study demonstrates that biomedically relevant data can be produced. As demonstrated by the thorough quality analysis, the dual-color antibody array approach proved to be competitive with other proteomic techniques and comparable in performance to transcriptional microarray analyses. PMID- 20164063 TI - Building nursing workforce capacity--staying on course. PMID- 20164065 TI - Winners and losers: organizational impacts of a nurses pay agreement. AB - This article considers the impacts on organizations of a new national employment agreement for nurses in New Zealand. In the 1980s, local employer bargaining replaced national awards. As nurses' employment conditions deteriorated, in 2004 that trend was reversed with a new national agreement between the nurses' union and the public sector health boards. Qualitative information was collected and analyzed from two employers covered by the agreement and from five nongovernment organizations not party to the agreement. In the organizations studied, there was evidence of winners and losers within and between organizations, flow-on effects on other groups of nurses not represented by the union and on other employee groups. Although impacts on public sector nursing workforces were generally positive, some imbalances and unintended consequences arose from the agreement. Differing experiences and perspectives of a national pay agreement largely reflected local nurse market conditions. PMID- 20164064 TI - An applied simulation model for estimating the supply of and requirements for registered nurses based on population health needs. AB - Aging populations, limited budgets, changing public expectations, new technologies, and the emergence of new diseases create challenges for health care systems as ways to meet needs and protect, promote, and restore health are considered. Traditional planning methods for the professionals required to provide these services have given little consideration to changes in the needs of the populations they serve or to changes in the amount/types of services offered and the way they are delivered. In the absence of dynamic planning models that simulate alternative policies and test policy mixes for their relative effectiveness, planners have tended to rely on projecting prevailing or arbitrarily determined target provider-population ratios. A simulation model has been developed that addresses each of these shortcomings by simultaneously estimating the supply of and requirements for registered nurses based on the identification and interaction of the determinants. The model's use is illustrated using data for Nova Scotia, Canada. PMID- 20164066 TI - Fair nursing care when resources are limited: the role of patients and family members in Norwegian home-based services. AB - The purpose of the study was to investigate nurses' priority decisions and the provision of home-based nursing care services. Interviews were conducted with 17 nurses in various positions in this service. The data were interpreted and analyzed according to interpretive hermeneutic methodology. The authors particularly address the nurses' descriptions of the role of the patient and his or her family members for the provision of home-based care. Cooperative patients and family members represent an important resource for care and can make it possible for nurses to provide services for all the patients on an egalitarian basis and to prioritize those who live alone. However, demanding and resourceful patients and family members may "rule" the service at the expense of other patients who also have legitimate care needs--a practice that the nurses describe as unfair. In this article, the authors discuss how a fair and impartial distribution of common benefits can be achieved without some parties being unjustly treated. PMID- 20164067 TI - Severe abdominal pain in 2 teenage girls. PMID- 20164068 TI - Acute neonatal parotitis caused by streptococcus pyogenes: a case report. PMID- 20164069 TI - Glucocorticoid-responsive hypertension in Henoch-Schonlein purpura. PMID- 20164070 TI - Fever of unknown origin: a diagnostic approach to this vexing problem. AB - Fever is a common complaint leading families to seek medical attention. Its routine management is the bread and butter of pediatric practice. When fever is seen as prolonged beyond the expected time course (eg, 10 days for a presumed viral respiratory tract infection or 3 weeks for mononucleosis), concern for fever of unknown origin (FUO) may ensue. This diagnosis is among the most challenging for health care providers to approach and often involves referral to subspecialists. Generally, the pace of the evaluation should be guided by the severity of the disease, rather than the anxiety of the family or of the health care providers. It is useful to recognize that uncommon manifestations of common diseases are more likely than are rare diseases. Furthermore, clues to the diagnosis are frequently present in the history and physical examination but are not elicited or unappreciated (perhaps due to time constraints). Therefore, thoroughness and repetition are vitally important. Although the differential diagnosis of FUO is vast, a thoughtful, focused approach based on information gleaned from a thorough history and physical examination (together with any laboratory or other study results) is preferable to a "shotgun" or "running the list" one. Finally, FUO in special populations, including children in the hospital, those with HIV infection or other immunocompromise, and those in the developing world, require special consideration. Most children do well, compared to adults with FUO, but true FUO is not always a benign condition, necessitating the best care a health care provider can offer. PMID- 20164071 TI - False negative cystic fibrosis newborn screen. PMID- 20164072 TI - Implementing family-centered rounds: pediatric residents' perceptions. AB - PURPOSE: Many hospitals are adopting family-centered rounds (FCRs). Limited studies suggest that FCRs improve family and staff satisfaction. No study has investigated residents' opinions about FCRs. We sought to elicit house staff opinions regarding structure, teaching, and patient care with FCRs. METHOD: In fall 2006, FCRs were implemented at Alfred I duPont Hospital for Children, a freestanding children's hospital. Between March and June 2008, a cross-sectional study was mailed to pediatrics and medicine-pediatric residents. RESULTS: Nearly all (89%) respondents supported FCRs somewhat (50%) or strongly (39%). House staff cited improved relationships with other providers, increased parent/family satisfaction, decreased need for plan clarification, and improved, "nondidactic" teaching. Concerns persisted about didactic teaching and efficiency. The most important factor associated with resident satisfaction was the attending physician. CONCLUSIONS: Residents support the use of FCRs.Training for inpatient attending physicians should include facilitation of FCRs. Concerns about efficiency and didactic teaching should be considered when implementing FCRs. PMID- 20164073 TI - Reliability of parent-measured axillary temperatures. AB - BACKGROUND: Fever is a common symptom in children. Assessment of accuracy of parental temperature measurement is integral in determining proper medical management. METHODS: The authors recruited 25 afebrile and 13 febrile children from outpatient sites. Participants had rectal temperatures measured by a trained study staff, followed by axillary temperature measurements by trained study staff and parent. Analysis of variance was used to compare the afebrile and febrile groups; the paired t test was used to compare parent and study personnel's axillary temperature measurements. Analysis included the statistical significance of Pearson's correlation coefficients for the various comparisons. RESULTS: In both febrile and afebrile groups, the rectal temperatures were greater than axillary temperature measurements, but the difference was not consistent. There was a very high correlation (correlation coefficient range = .86-.96) between axillary temperature measurements performed by trained study staff and parents. CONCLUSIONS: Parental report of axillary temperature measurement can be considered reliable. PMID- 20164074 TI - Diskitis in toddlers revisited. PMID- 20164075 TI - A boy unable to move his arm. AB - An 11-year-old boy presented with inability to move his right arm, back and neck pain, and fever. He had a history of recurrent vesicular rash on his face three times over the past two years. Magnetic resonance imaging (MRI) showed diffuse expansile cervical cord, leading to a diagnosis of transverse myelitis. After 3 days of intravenous solumedrol, the patient was discharged, but returned the following day with a vesicular rash to the right arm, as well as vomiting, malaise and diffuse pruritus.Wright-Giemsa stain of the vesicles revealed herpes group virus and culture was positive for herpes simplex type 1. PMID- 20164076 TI - A neonate in septic shock. PMID- 20164077 TI - Body fat influences departure from stopover sites in migratory birds: evidence from whole-island telemetry. AB - Migration remains one of the great mysteries of animal life. Small migratory birds rely on refuelling stopovers after crossing ecological barriers such as deserts or seas. Previous studies have suggested that fuel reserves may determine stopover duration but this hypothesis could not be tested because of methodological limitations. Here, we provide evidence that subcutaneous fat stores determine stopover duration by measuring the permanence of migratory garden warblers (Sylvia borin) on a small Mediterranean island during spring migration with telemetry methods. Garden warblers with large amounts of fat stores departed the island significantly sooner than lean birds. All except one fat bird left the island on the same evening after capture, with a mean total stopover estimate of 8.8 hours. In contrast, the mean estimated total stopover duration of lean birds was 41.3 hours. To our knowledge, this is the first study that measures the true minimum stopover duration of a songbird during migration. PMID- 20164078 TI - Can eggs in a cavity be a female secondary sexual signal? Male nest visits and modelling of egg visual discrimination in blue tits. AB - Eggshell colouration is thought to function as a female-specific secondary sexual trait. While tests of this idea are rapidly accumulating in cavity-nesting birds, some fundamental underlying assumptions remain rarely investigated: namely, can males see eggshell coloration and perceive colour differences between the eggs of different females? We tested these two key assumptions in a natural population of blue tits (Cyanistes caeruleus). Using transponders, we tracked male nest visits and found that all males visited their nest-boxes while eggs were present and often visually accessible. Interestingly, some males also visited neighbouring nests. We then tested whether birds could detect eggshell coloration using models of avian colour vision; models were performed with and without limitations on visual performance owing to dim light. Both models found that differences in eggshell brightness were often easier to discriminate than differences in colour; there was more contrast in white eggshell background between clutches than within and its contrast against nest background was repeatable within clutches, suggesting these features could act as signals. Yet, the detectability of these contrasts depended entirely on model assumptions of visual limitations. Consequently, we need a better understanding of underlying visual mechanisms in dim-light environments and behavioural discrimination experiments before confirming the signalling potential of eggshell coloration. PMID- 20164079 TI - Temporal and spatial patterns of sea lice levels on sea trout in western Scotland in relation to fish farm production cycles. AB - The relationship between aquaculture and infestations of sea lice on wild sea trout (Salmo trutta) populations is controversial. Although some authors have concluded that there is a link between aquaculture and lice burdens on wild fish, others have questioned this interpretation. Lice levels have been shown to be generally higher on Atlantic salmon farms during the second years of two-year production cycles. Here we investigate whether this pattern relates to lice burdens on wild fish across broad temporal and spatial axes. Within Loch Shieldaig across five successive farm cycles from 2000 to 2009, the percentage of sea trout with lice, and those above a critical level, were significantly higher in the second year of a two-year production cycle. These patterns were mirrored in 2002-2003 across the Scottish west coast. The results suggest a link between Atlantic salmon farms and sea lice burdens on sea trout in the west of Scotland. PMID- 20164080 TI - Anthropogenic noise affects risk assessment and attention: the distracted prey hypothesis. AB - Many studies have focused on the effects of anthropogenic noise on animal communication, but only a few have looked at its effect on other behavioural systems. We designed a playback experiment to test the effect of noise on predation risk assessment. We found that in response to boat motor playback, Caribbean hermit crabs (Coenobita clypeatus) allowed a simulated predator to approach closer before they hid. Two hypotheses may explain how boat noise affected risk assessment: it masked an approaching predator's sound; and/or it reallocated some of the crabs' finite attention, effectively distracting them, and thus preventing them from responding to an approaching threat. We found no support for the first hypothesis: a silent looming object still got closer during boat motor playbacks than during silence. However, we found support for the attentional hypothesis: when we added flashing lights to the boat motor noise to further distract the hermit crabs, we were able to approach the crabs more closely than with the noise alone. Anthropogenic sounds may thus distract prey and make them more vulnerable to predation. PMID- 20164081 TI - Selection on innate immunity and body condition in Florida scrub-jays throughout an epidemic. AB - Opportunities to investigate selection in free-living species during a naturally occurring epidemic are rare; however, we assessed innate immunocompetence in Florida scrub-jays before the population suffered the greatest over-winter mortality in 20 years of study. Propitiously, three months prior to the epidemic, we had sampled a number of male breeders to evaluate a suite of physiological measures that are commonly used to estimate the overall health-state of an individual. There was a significant, positive selection gradient for both Escherichia coli bacterial killing capability and body condition, suggesting that directional selection had occurred upon each of these traits during the disease epidemic. PMID- 20164082 TI - Sickness behaviour acting as an evolutionary trap? Male house finches preferentially feed near diseased conspecifics. AB - Host behaviour towards infectious conspecifics is a crucial yet overlooked component of pathogen dynamics. Selection is expected to favour individuals who can recognize and avoid infected conspecifics in order to reduce their own risk of infection. However, evidence is scarce and limited to species employing chemical cues. Here, we experimentally examine whether healthy captive house finches (Carpodacus mexicanus) preferentially forage near a same-sex, healthy conspecific versus one infected with the directly transmissible pathogen Mycoplasma gallisepticum (MG), which causes lethargy and visible conjunctivitis. Interestingly, male house finches strongly preferred feeding near diseased conspecifics, while females showed no preference. This sex difference appeared to be the result of lower aggression rates in diseased males, but not in females. The reduced aggression of diseased males may act as an 'evolutionary trap' by presenting a historically beneficial behavioural cue in the context of a new environment, which now includes a recently emerged, potentially fatal pathogen. Since MG can be directly transmitted during feeding, healthy males may inadvertently increase their risk of contracting MG. This behaviour is likely to significantly contribute to the continued persistence of MG epidemics in wild populations. PMID- 20164083 TI - Notonecta exhibit threat-sensitive, predator-induced dispersal. AB - Dispersal is a central process determining community structure in heterogeneous landscapes, and species interactions within habitats may be a major determinant of dispersal. Although the effects of species interactions on dispersal within habitats have been well studied, how species interactions affect the movement of individuals between habitats in a landscape has received less attention. We conducted two experiments to assess the extent to which predation risk affects dispersal from an aquatic habitat by a flight-capable semi-aquatic insect (Notonecta undulata). Exposure to non-lethal (caged) fish fed conspecifics increased dispersal rates in N. undulata. Moreover, dispersal rate was positively correlated with the level of risk imposed by the fish; the greater the number of notonectids consumed by the caged fish, the greater the dispersal rate from the habitat. These results suggest that risk within a habitat can affect dispersal among habitats in a landscape and thus affect community structure on a much greater scale than the direct effect of predation itself. PMID- 20164085 TI - Analytical methods for quantifying environmental connectivity for the control and surveillance of infectious disease spread. AB - The sustained transmission and spread of environmentally mediated infectious diseases is governed in part by the dispersal of parasites, disease vectors and intermediate hosts between sites of transmission. Functional geospatial models can be used to quantify and predict the degree to which environmental features facilitate or limit connectivity between target populations, yet typical models are limited in their geographical and analytical approach, providing simplistic, global measures of connectivity and lacking methods to assess the epidemiological implications of fine-scale heterogeneous landscapes. Here, functional spatial models are applied to problems of surveillance and control of the parasitic blood fluke Schistosoma japonicum and its intermediate snail host Oncomelania haupensis in western China. We advance functional connectivity methods by providing an analytical framework to (i) identify nodes of transmission where the degree of connectedness to other villages, and thus the potential for disease spread, is higher than is estimated using Euclidean distance alone and (ii) (re)organize transmission sites into disease surveillance units based on second-order relationships among nodes using non-Euclidean distance measures, termed effective geographical distance (EGD). Functional environmental models are parametrized using ecological information on the target organisms, and pair-wise distributions of inter-node EGD are estimated. A Monte Carlo rank product analysis is presented to identify nearby nodes under alternative distance models. Nodes are then iteratively embedded into EGD space and clustered using a k-means algorithm to group villages into ecologically meaningful surveillance groups. A consensus clustering approach is taken to derive the most stable cluster structure. The results indicate that novel relationships between nodes are revealed when non Euclidean, ecologically determined distance measures are used to quantify connectivity in heterogeneous landscapes. These connections are not evident when analysing nodes in Euclidean space, and thus surveillance and control activities planned using Euclidean distance measures may be suboptimal. The methods developed here provide a quantitative framework for assessing the effectiveness of ecologically grounded surveillance systems and of control and prevention strategies for environmentally mediated diseases. PMID- 20164086 TI - Stochasticity in staged models of epidemics: quantifying the dynamics of whooping cough. AB - Although many stochastic models can accurately capture the qualitative epidemic patterns of many childhood diseases, there is still considerable discussion concerning the basic mechanisms generating these patterns; much of this stems from the use of deterministic models to try to understand stochastic simulations. We argue that a systematic method of analysing models of the spread of childhood diseases is required in order to consistently separate out the effects of demographic stochasticity, external forcing and modelling choices. Such a technique is provided by formulating the models as master equations and using the van Kampen system-size expansion to provide analytical expressions for quantities of interest. We apply this method to the susceptible-exposed-infected-recovered (SEIR) model with distributed exposed and infectious periods and calculate the form that stochastic oscillations take on in terms of the model parameters. With the use of a suitable approximation, we apply the formalism to analyse a model of whooping cough which includes seasonal forcing. This allows us to more accurately interpret the results of simulations and to make a more quantitative assessment of the predictions of the model. We show that the observed dynamics are a result of a macroscopic limit cycle induced by the external forcing and resonant stochastic oscillations about this cycle. PMID- 20164087 TI - Dynamics of infectious disease transmission by inhalable respiratory droplets. AB - Transmission of respiratory infectious diseases in humans, for instance influenza, occurs by several modes. Respiratory droplets provide a vector of transmission of an infectious pathogen that may contribute to different transmission modes. An epidemiological model incorporating the dynamics of inhalable respiratory droplets is developed to assess their relevance in the infectious process. Inhalable respiratory droplets are divided into respirable droplets, with droplet diameter less than 10 microm, and inspirable droplets, with diameter in the range 10-100 microm: both droplet classes may be inhaled or settle. Droplet dynamics is determined by their physical properties (size), whereas population dynamics is determined by, among other parameters, the pathogen infectivity and the host contact rates. Three model influenza epidemic scenarios, mediated by different airborne or settled droplet classes, are analysed. The scenarios are distinguished by the characteristic times associated with breathing at contact and with hand-to-face contact. The scenarios suggest that airborne transmission, mediated by respirable droplets, provides the dominant transmission mode in middle and long-term epidemics, whereas inspirable droplets, be they airborne or settled, characterize short-term epidemics with high attack rates. The model neglects close-contact transmission by droplet sprays (direct projection onto facial mucous membranes), retaining close-contact transmission by inspirable droplets. PMID- 20164088 TI - Consistency of myocardial deformation imaging between vendors. AB - Recent developments in echocardiographic speckle tracking have enabled the quantification of myocardial deformation. In addition to technical barriers, recent research has identified differences in strain measurements between vendors, reflecting differences in myocardial tracking, and how speckle strain is calculated and displayed. In this context, a paper in this issue of the journal emphasizes similarity of global longitudinal (but not radial and circumferential strain) between two vendors. The implications of these findings for the clinical application of strain are discussed. PMID- 20164089 TI - Prognostic value of exercise echocardiography in patients with atrial fibrillation. AB - AIMS: Non-invasive imaging techniques for the detection of coronary artery disease (CAD) may have technical problems in patients with atrial fibrillation (AF). Although the prognostic value of exercise echocardiography (ExEcho) has been well established in several subgroups of patients, it has not yet been specifically evaluated in these patients. METHODS AND RESULTS: From a population of 8095 patients with known or suspected CAD referred for ExEcho, 419 had AF at the time of the tests. Ischaemia was defined as the development of new or worsening wall motion abnormalities with exercise. Endpoints were hard cardiac events (i.e. cardiac death or non-fatal myocardial infarction). Mean age was 68.4 +/- 8.5 years, and 256 patients (61.1%) were men. Ischaemia was detected in 92 patients (22%). Over a mean follow-up of 3.10 +/- 2.98 years, 59 hard cardiac events occurred. The 5-year hard cardiac event rate was 37.3% in patients with ischaemia, when compared with 14.5% in patients without ischaemia (P < 0.001). In multivariate analysis, ischaemia on ExEcho remained an independent predictor of hard cardiac events (hazard ratio 1.99, 95% confidence interval 1.06-3.74, P = 0.03), and also provided incremental value over clinical, resting echocardiographic and treadmill exercise data for the prediction of hard cardiac events (P = 0.04). CONCLUSION: ExEcho provides significant prognostic information for predicting hard cardiac events in patients with AF. PMID- 20164090 TI - Photomodulating RNA cleavage using photolabile circular antisense oligodeoxynucleotides. AB - Caged antisense oligodeoxynucleotides (asODNs) are synthesized by linking two ends of linear oligodeoxynucleotides using a photocleavable linker. Two of them (H30 and H40) have hairpin-like structures which show a large difference in thermal stability (Delta T(m) = 17.5 degrees C and 11.6 degrees C) comparing to uncaged ones. The other three (C20, C30 and C40) without stable secondary structures have the middle 20 deoxynucleotides complementary to 40-mer RNA. All caged asODNs have restricted opening which provides control over RNA/asODN interaction. RNase H assay results showed that 40-mer RNA digestion could be photo-modulated 2- to 3-fold upon light-activation with H30, H40, C30 and C40, while with C20, RNA digestion was almost not detectable; however, photo activation triggered >20-fold increase of RNA digestion. And gel shift assays showed that it needed >0.04 microM H40 and 0.5 microM H30 to completely bind 0.02 microM 40-mer RNA, and for C40 and C30, it needed >0.2 microM and 0.5 microM for 0.02 microM 40-mer RNA binding. However, even 4 microM C20 was not able to fully bind the same concentration of 40-mer RNA. By simple adjustment of ring size of caged asODNs, we could successfully photoregulate their hybridization with mRNA and target RNA hydrolysis by RNase H with light activation. PMID- 20164091 TI - Accurate SNP and mutation detection by targeted custom microarray-based genomic enrichment of short-fragment sequencing libraries. AB - Microarray-based enrichment of selected genomic loci is a powerful method for genome complexity reduction for next-generation sequencing. Since the vast majority of exons in vertebrate genomes are smaller than 150 nt, we explored the use of short fragment libraries (85-110 bp) to achieve higher enrichment specificity by reducing carryover and adverse effects of flanking intronic sequences. High enrichment specificity (60-75%) was obtained with a relative even base coverage. Up to 98% of the target-sequence was covered more than 20x at an average coverage depth of about 200x. To verify the accuracy of SNP/mutation detection, we evaluated 384 known non-reference SNPs in the targeted regions. At approximately 200x average sequence coverage, we were able to survey 96.4% of 1.69 Mb of genomic sequence with only 4.2% false negative calls, mostly due to low coverage. Using the same settings, a total of 1197 novel candidate variants were detected. Verification experiments revealed only eight false positive calls, indicating an overall false positive rate of less than 1 per approximately 200,000 bp. Taken together, short fragment libraries provide highly efficient and flexible enrichment of exonic targets and yield relatively even base coverage, which facilitates accurate SNP and mutation detection. Raw sequencing data, alignment files and called SNPs have been submitted into GEO database http://www.ncbi.nlm.nih.gov/geo/ with accession number GSE18542. PMID- 20164092 TI - Minimizing off-target signals in RNA fluorescent in situ hybridization. AB - Fluorescent in situ hybridization (FISH) techniques are becoming extremely sensitive, to the point where individual RNA or DNA molecules can be detected with small probes. At this level of sensitivity, the elimination of 'off-target' hybridization is of crucial importance, but typical probes used for RNA and DNA FISH contain sequences repeated elsewhere in the genome. We find that very short (e.g. 20 nt) perfect repeated sequences within much longer probes (e.g. 350-1500 nt) can produce significant off-target signals. The extent of noise is surprising given the long length of the probes and the short length of non-specific regions. When we removed the small regions of repeated sequence from either short or long probes, we find that the signal-to-noise ratio is increased by orders of magnitude, putting us in a regime where fluorescent signals can be considered to be a quantitative measure of target transcript numbers. As the majority of genes in complex organisms contain repeated k-mers, we provide genome-wide annotations of k-mer-uniqueness at http://cbio.mskcc.org/ approximately aarvey/repeatmap. PMID- 20164093 TI - A cooperative and specific DNA-binding mode of HIV-1 integrase depends on the nature of the metallic cofactor and involves the zinc-containing N-terminal domain. AB - HIV-1 integrase catalyzes the insertion of the viral genome into chromosomal DNA. We characterized the structural determinants of the 3'-processing reaction specificity--the first reaction of the integration process--at the DNA-binding level. We found that the integrase N-terminal domain, containing a pseudo zinc finger motif, plays a key role, at least indirectly, in the formation of specific integrase-DNA contacts. This motif mediates a cooperative DNA binding of integrase that occurs only with the cognate/viral DNA sequence and the physiologically relevant Mg(2+) cofactor. The DNA-binding was essentially non cooperative with Mn(2+) or using non-specific/random sequences, regardless of the metallic cofactor. 2,2'-Dithiobisbenzamide-1 induced zinc ejection from integrase by covalently targeting the zinc-finger motif, and significantly decreased the Hill coefficient of the Mg(2+)-mediated integrase-DNA interaction, without affecting the overall affinity. Concomitantly, 2,2'-dithiobisbenzamide-1 severely impaired 3'-processing (IC(50) = 11-15 nM), suggesting that zinc ejection primarily perturbs the nature of the active integrase oligomer. A less specific and weaker catalytic effect of 2,2'-dithiobisbenzamide-1 is mediated by Cys 56 in the catalytic core and, notably, accounts for the weaker inhibition of the non cooperative Mn(2+)-dependent 3'-processing. Our data show that the cooperative DNA-binding mode is strongly related to the sequence-specific DNA-binding, and depends on the simultaneous presence of the Mg(2+) cofactor and the zinc effector. PMID- 20164094 TI - An intrinsic gut leptin-melanocortin pathway modulates intestinal microsomal triglyceride transfer protein and lipid absorption. AB - Fat is delivered to tissues by apoB-containing lipoproteins synthesized in the liver and intestine with the help of an intracellular chaperone, microsomal triglyceride transfer protein (MTP). Leptin, a hormone secreted by adipose tissue, acts in the brain and on peripheral tissues to regulate fat storage and metabolism. Our aim was to identify the role of leptin signaling in MTP regulation and lipid absorption using several mouse models deficient in leptin receptor (LEPR) signaling and downstream effectors. Mice with spontaneous LEPR B mutations or targeted ablation of LEPR B in proopiomelanocortin (POMC) or agouti gene related peptide (AGRP) expressing cells had increased triglyceride in plasma, liver, and intestine. Furthermore, melanocortin 4 receptor (MC4R) knockout mice expressed a similar triglyceride phenotype, suggesting that leptin might regulate intestinal MTP expression through the melanocortin pathway. Mechanistic studies revealed that the accumulation of triglyceride in the intestine might be secondary to decreased expression of MTP and lipid absorption in these mice. Surgical and chemical blockade of vagal efferent outflow to the intestine in wild-type mice failed to alter the triglyceride phenotype, demonstrating that central neural control mechanisms were likely not involved in the observed regulation of intestinal MTP. Instead, we found that enterocytes express LEPR, POMC, AGRP, and MC4R. We propose that a peripheral, local gut signaling mechanism involving LEPR B and MC4R regulates intestinal MTP and controls intestinal lipid absorption. PMID- 20164096 TI - An Alzheimer disease presenilin mutation, syndrome diversity, and a shrinking world. PMID- 20164095 TI - Worldwide distribution of PSEN1 Met146Leu mutation: a large variability for a founder mutation. AB - OBJECTIVE: Large kindreds segregating familial Alzheimer disease (FAD) offer the opportunity of studying clinical variability as observed for presenilin 1 (PSEN1) mutations. Two early-onset FAD (EOFAD) Calabrian families with PSEN1 Met146Leu (ATG/CTG) mutation constitute a unique population descending from a remote common ancestor. Recently, several other EOFAD families with the same mutation have been described worldwide. METHODS: We searched for a common founder of the PSEN1 Met146Leu mutation in families with different geographic origins by genealogic and molecular analyses. We also investigated the phenotypic variability at onset in a group of 50 patients (mean age at onset 40.0 +/- 4.8 years) by clinical, neuropsychological, and molecular methodologies. RESULTS: EOFAD Met146Leu families from around the world resulted to be related and constitute a single kindred originating from Southern Italy before the 17th century. Phenotypic variability at onset is broad: 4 different clinical presentations may be recognized, 2 classic for AD (memory deficits and spatial and temporal disorientation), whereas the others are expressions of frontal impairment. The apathetic and dysexecutive subgroups could be related to orbital-medial prefrontal cortex and dorsolateral prefrontal cortex dysfunction. CONCLUSIONS: Genealogic and molecular findings provided evidence that the PSEN1 Met146Leu families from around the world analyzed in this study are related and represent a single kindred originating from Southern Italy. The marked phenotypic variability might reflect early involvement by the pathologic process of different cortical areas. Although the clinical phenotype is quite variable, the neuropathologic and biochemical characteristics of the lesions account for neurodegenerative processes unmistakably of Alzheimer nature. PMID- 20164097 TI - Rapid viability analysis for metapopulations in dynamic habitat networks. AB - For land-use planning, numerically fast and easily applicable tools are urgently needed that allow us to assess how landscape structure and dynamics affect biodiversity. To date, such tools exist only for static landscapes. We provide an analytical formula for the mean lifetime of species in fragmented and dynamic habitat networks where habitat patches may be destroyed and created elsewhere. The formula is able to consider both patch size heterogeneity and dynamics additionally to patch number and connectivity. It is validated through comparison with a dynamic and spatially explicit simulation model. It can be used for the optimization of spatio-temporal land-use patterns in real landscapes and for advancing our general understanding of key processes affecting the survival of species in fragmented heterogeneous dynamic landscapes. PMID- 20164098 TI - Evolutionary constraints on adaptive evolution during range expansion in an invasive plant. AB - Biological invasions may expose populations to strong selection for local adaptation along geographical gradients in climate. However, evolution during contemporary timescales can be constrained by low standing genetic variation and genetic correlations among life-history traits. We examined limits to local adaptation associated with northern migration of the invasive wetland plant purple loosestrife (Lythrum salicaria) using a selection model incorporating a trade-off between flowering time and size at reproduction, and common garden experiments of populations sampled along a latitudinal transect of approximately 1200 km in eastern North America. A strong trade-off between flowering time and size at reproduction caused early-flowering plants to be smaller with reduced seed production in northern populations. Northward spread was associated with a decline in genetic variance within populations and an increase in genetic skew for flowering time and size, with limited genetic variation for small, early flowering genotypes. These patterns were predicted by our selection model of local adaptation to shorter growing seasons and were not consistent with expectations from non-adaptive processes. Reduced fecundity may limit population growth and rates of spread in northern populations. Identifying genetic constraints on key life-history traits can provide novel insights into invasion dynamics and the causes of range limits in introduced species. PMID- 20164099 TI - Interactive effects of temporal correlations, spatial heterogeneity and dispersal on population persistence. AB - It is an ecological truism that population persistence depends on a population's growth rate when rare. To understand the interplay between temporal correlations, spatial heterogeneity and dispersal on persistence, an analytic approximation for this growth rate is derived for partially mixing populations. Partial mixing has two effects on population growth. In the absence of temporal correlations in relative fitness, greater movement to patches with, on average, higher relative fitness increases population growth rates. In the absence of spatial heterogeneity in the average relative fitnesses, lower dispersal rates enhance population growth when temporal autocorrelations of relative fitness within a patch exceed temporal cross-correlations in relative fitness between patches. This approximation implies that metapopulations whose expected fitness in every patch is less than 1 can persist if there are positive temporal autocorrelations in relative fitness, sufficiently weak spatial correlations and the population disperses at intermediate rates. It also implies that movement into lower quality habitats increases the population growth rate whenever the net temporal variation in per capita growth rates is sufficiently larger than the difference in the means of these per capita growth rates. Moreover, temporal autocorrelations, whether they be negative or positive, can enhance population growth for optimal dispersal strategies. PMID- 20164100 TI - Ecological release from interspecific competition leads to decoupled changes in population and individual niche width. AB - A species's niche width reflects a balance between the diversifying effects of intraspecific competition and the constraining effects of interspecific competition. This balance shifts when a species from a competitive environment invades a depauperate habitat where interspecific competition is reduced. The resulting ecological release permits population niche expansion, via increased individual niche widths and/or increased among-individual variation. We report an experimental test of the theory of ecological release in three-spine stickleback (Gasterosteus aculeatus). We factorially manipulated the presence or absence of two interspecific competitors: juvenile cut-throat trout (Oncorhynchus clarki) and prickly sculpin (Cottus asper). Consistent with the classic niche variation hypothesis, release from trout competition increased stickleback population niche width via increased among-individual variation, while individual niche widths remained unchanged. In contrast, release from sculpin competition had no effect on population niche width, because increased individual niche widths were offset by decreased between-individual variation. Our results confirm that ecological release from interspecific competition can lead to increases in niche width, and that these changes can occur on behavioural time scales. Importantly, we find that changes in population niche width are decoupled from changes in the niche widths of individuals within the population. PMID- 20164101 TI - From spectral information to animal colour vision: experiments and concepts. AB - Many animals use the spectral distribution of light to guide behaviour, but whether they have colour vision has been debated for over a century. Our strong subjective experience of colour and the fact that human vision is the paradigm for colour science inevitably raises the question of how we compare with other species. This article outlines four grades of 'colour vision' that can be related to the behavioural uses of spectral information, and perhaps to the underlying mechanisms. In the first, even without an (image-forming) eye, simple organisms can compare photoreceptor signals to locate a desired light environment. At the next grade, chromatic mechanisms along with spatial vision guide innate preferences for objects such as food or mates; this is sometimes described as wavelength-specific behaviour. Here, we compare the capabilities of di- and trichromatic vision, and ask why some animals have more than three spectral types of receptors. Behaviours guided by innate preferences are then distinguished from a grade that allows learning, in part because the ability to learn an arbitrary colour is evidence for a neural representation of colour. The fourth grade concerns colour appearance rather than colour difference: for instance, the distinction between hue and saturation, and colour categorization. These higher level phenomena are essential to human colour perception but poorly known in animals, and we suggest how they can be studied. Finally, we observe that awareness of colour and colour qualia cannot be easily tested in animals. PMID- 20164103 TI - A content analysis of Evaluation & the Health Professions over 32 years. PMID- 20164104 TI - Smoking cessation program in outpatient clinics of Family Medicine Department in Taiwan: a longitudinal evaluation. AB - The Government of Taiwan has imposed a tobacco health tax of NT$5 (US$0.14) per pack of cigarettes since January 2002. The Department of Health has now begun to fund a smoking cessation program that provides nicotine-replacement therapy (NRT) and brief counseling by physicians in outpatient clinics. The purpose of the current study was to evaluate the smoking cessation program with a 3-year follow up review implemented at outpatient clinics, which were run by the Family Medicine Department in a medical center, with a total of 772 adult participants. The abstinence rates were 99.7%, 49.2%, 37.7%, 30.2%, and 22.7%, at the 1-, 3-, 6 , 12-, and 36-month points, respectively. The frequency of clinic visits is a major factor predicting long-term cessation. The results indicate the need to pursue implementation and evaluation of multidisciplinary interventions in smoking cessation clinics with a longer follow-up, including the promotion of compliance to increase clinic visits and prevent relapse. PMID- 20164106 TI - Psychometric properties of the Rosenberg Self-Esteem Scale: overall and across demographic groups living within the United States. AB - The purpose of this study was twofold: (a) to evaluate the scaling assumptions and component structure of and present normative data for the Rosenberg Self Esteem Scale (RSES) using a sample of US adults (N = 503), both overall and across demographic subgroups and (b) to provide new data regarding the relationship between the two RSES subcomponents of self-competence (SC) and self liking (SL), and other demographic and clinical variables. As hypothesized, all psychometric tests supported the underlying structure of the RSES. Overall RSES scores varied significantly across age, racial and ethnic, education, employment status, income, and marital status groups. Furthermore, differences between SC and SL were also found across groups differing in gender, age, employment status, and marital status groups. The implications and limitations of this study are discussed, with an emphasis on clinical relevance. PMID- 20164105 TI - A review of Alcoholics Anonymous/ Narcotics Anonymous programs for teens. AB - The investigation of the applicability of Alcoholics Anonymous/Narcotics Anonymous (AA/NA) for teens has only been a subject of empirical research investigation since the early 1990s. In the present review, the author describes teen involvement in AA/NA programming, provides an exhaustive review of the outcomes of 19 studies that used an AA/NA model as part of their formal teen substance abuse treatment programs, and provides data on the effects of AA/NA attendance on abstinence at follow-up, on which youth tend to become involved in AA/NA, and on mediation of the benefits of AA/NA participation. In addition, the author suggests the reasons for somewhat limited participation by teens in more informal, community-based 12-step meetings, and makes suggestions for maximizing participation at meetings in the community. The author concludes that AA/ NA participation is a valuable modality of substance abuse treatment for teens and that much can be done to increase teen participation, though more research is needed. PMID- 20164107 TI - Determining the number of patient charts necessary for a reliable assessment of practicing family physicians' performance. AB - In many countries, peer assessment programs based on the examination of patient charts are becoming a standard to assess physician's clinical performance. Although data on validity of the process are acceptable, reliability issues need some improvement. This article addresses the rarely studied aspect of optimal number of patient charts for an acceptable reliable assessment. Fifteen patient charts for each of a group of 20 practicing physicians were independently reviewed by 4 professional peer assessors. Generalizability (G) and decision (D) studies were applied to the data. It appears that as few as 10 patient charts are sufficient for any assessor to obtain a G coefficient of 0.80. Results of the current study suggest the possibility of getting generalizable assessments by peer reviewer with minimal information. These results are not in accordance with the concept of case specificity in which it is claimed that performance on a case is a poor predictor of performance on a different case. PMID- 20164108 TI - A method for on-site measurements of the effective spatial resolution in PET image volumes reconstructed with OSEM and Gaussian post-filters. AB - When PET image volumes are reconstructed with ordered subset expectation maximization (OSEM) and subjected to filtration with a 3D Gaussian filter the effective spatial resolution is a function of both the intrinsic scanner resolution and the user-selectable spatial width of the filter. A method was developed to derive the effective spatial resolution from such volumes obtained after acquisitions with a line source on a Siemens Biograph 64 PET/CT scanner. Assuming Gaussian distributions, the full widths at half maximum (FWHM) were derived from probit plots of cumulative spatial distributions across the line source. The effective FWHM values were also used to estimate the FWHM of the intrinsic resolution by extrapolation to a zero filter width. PMID- 20164109 TI - Cytochrome P450 1A2 detoxicates aristolochic acid in the mouse. AB - Aristolochic acids (AAs) are plant-derived nephrotoxins and carcinogens responsible for chronic renal failure and associated urothelial cell cancers in several clinical syndromes known collectively as aristolochic acid nephropathy (AAN). Mice provide a useful model for study of AAN because the renal histopathology of AA-treated mice is strikingly similar to that of humans. AA is also a potent carcinogen in mice with a tissue spectrum somewhat different from that in humans. The toxic dose of AA in mice is higher than that in humans; this difference in susceptibility has been postulated to reflect differing rates of detoxication between the species. Recent studies in mice have shown that the hepatic cytochrome P450 system detoxicates AA, and inducers of the arylhydrocarbon response protect mice from the nephrotoxic effects of AA. The purpose of this study was to determine the role of specific cytochrome P450 (P450) enzymes in AA metabolism in vivo. Of 18 human P450 enzymes we surveyed only two, CYP1A1 and CYP1A2, which were effective in demethylating 8-methoxy-6 nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAI) to the nontoxic derivative 8-hydroxy-6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAIa). Kinetic analysis revealed similar efficiencies of formation of AAIa by human and rat CYP1A2. We also report here that CYP1A2-deficient mice display increased sensitivity to the nephrotoxic effects of AAI. Furthermore, Cyp1a2 knockout mice accumulate AAI-derived DNA adducts in the kidney at a higher rate than control mice. Differences in bioavailability or hepatic metabolism of AAI, expression of CYP1A2, or efficiency of a competing nitroreduction pathway in vivo may explain the apparent differences between human and rodent sensitivity to AAI. PMID- 20164110 TI - Chlorzoxazone metabolism by porcine cytochrome P450 enzymes and the effect of cytochrome b5. AB - Chlorzoxazone (CLZ) is a commonly used nontoxic in vivo and in vitro probe for the assessment of CYP2E1 activity. Human CYP1A1 and CYP3A4 have also been shown to contribute to CLZ metabolism. For pigs to be a potential model system for humans, it is necessary that human and pig cytochromes P450 (P450) have similar metabolizing capabilities. Therefore, CLZ metabolizing capabilities and specificities of porcine P450s were investigated. In this study, the complete coding regions of six porcine P450s were amplified from liver cDNA and cloned into pcDNA3.1/V5-His TOPO vector. Expression vectors for the individual P450s and microsomal cytochrome b(5) (CYB5A) were expressed in the human embryonic kidney HEK-293FT cell line to investigate their role in CLZ metabolism. As with the human enzymes, porcine CYP2E1 (K(m) = 290.3 microM and V(max) = 4980 pmol/h/mg total protein) and CYP1A1 (K(m) = 159.5 microM and V(max) = 1650 pmol/h/mg total protein) both contribute to CLZ metabolism. In addition, porcine CYP2A19 and CYP2C33v4 also metabolize the substrate, with K(m) = 212.1 microM and V(max) = 6680 pmol/h/mg total protein and K(m) = 126.3 microM and V(max) = 2100 pmol/h/mg total protein, respectively, whereas CYP3A does not. CYB5A augmented CYP2E1 and CYP2C33v4 activity in the pig, with a significant increase in activity of 85 and 73% compared with control, respectively. Thus, CLZ should be used with caution as a probe for CYP2E1 activity in the pig. However, further information regarding the abundance of different P450 isoforms is needed to fully understand their contribution in microsomal, hepatocyte, and in vivo systems in the pig. PMID- 20164111 TI - Sex-dependent differences in cytochrome P450 3A activity as assessed by midazolam disposition in humans: a meta-analysis. AB - Controversy exists concerning the sex-dependent differences in cytochrome P450 3A activity in humans. Meta-analysis of selected studies may address this question. Meta-analysis was performed on published or unpublished data in terms of sex dependent differences in midazolam (MDZ) disposition in humans. The following pharmacokinetic parameters were included for the analysis: MDZ oral and systemic clearance, area under the concentration-time curve (AUC) of oral and intravenous MDZ, MDZ oral bioavailability (F), and MDZ gastrointestinal extraction (E(G)). Ten studies including 409 healthy volunteers were identified. Women exhibited 16% higher weight-corrected MDZ oral clearance (P < 0.001) and 20% higher systemic clearance (P = 0.002) than men. No significant difference in the AUC after oral dosing of MDZ was noted between sexes. Women showed lower AUC of intravenous MDZ than men (P = 0.02). No sex-dependent differences were observed in F and E(G). In conclusion, women showed significantly greater hepatic CYP3A activity than men, whereas no sex-dependent difference in intestinal CYP3A activity was observed. PMID- 20164112 TI - Mild hypothermia alters midazolam pharmacokinetics in normal healthy volunteers. AB - The clinical use of therapeutic hypothermia has been rapidly expanding due to evidence of neuroprotection. However, the effect of hypothermia on specific pathways of drug elimination in humans is relatively unknown. To gain insight into the potential effects of hypothermia on drug metabolism and disposition, we evaluated the pharmacokinetics of midazolam as a probe for CYP3A4/5 activity during mild hypothermia in human volunteers. A second objective of this work was to determine whether benzodiazepines and magnesium administered intravenously would facilitate the induction of hypothermia. Subjects were enrolled in a randomized crossover study, which included two mild hypothermia groups (4 degrees C saline infusions and 4 degrees C saline + magnesium) and two normothermia groups (37 degrees C saline infusions and 37 degrees C saline + magnesium). The lowest temperatures achieved in the 4 degrees C saline + magnesium and 4 degrees C saline infusions were 35.4 +/- 0.4 and 35.8 +/- 0.3 degrees C, respectively. A significant decrease in the formation clearance of the major metabolite 1' hydroxymidazolam was observed during the 4 degrees C saline + magnesium compared with that in the 37 degrees C saline group (p < 0.05). Population pharmacokinetic modeling identified a significant relationship between temperature and clearance and intercompartmental clearance for midazolam. This model predicted that midazolam clearance decreases 11.1% for each degree Celsius reduction in core temperature from 36.5 degrees C. Midazolam with magnesium facilitated the induction of hypothermia, but shivering was minimally suppressed. These data provided proof of concept that even mild and short-duration changes in body temperature significantly affect midazolam metabolism. Future studies in patients who receive lower levels and a longer duration of hypothermia are warranted. PMID- 20164113 TI - Metabolism of 2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3-[5-(trifluoromethyl) 2-pyridyloxy]propyl ether (pyridalyl) in rats after repeated oral administration and a simple physiologically based pharmacokinetic modeling in brown and white adipose tissues. AB - Male and female Sprague-Dawley rats received repeated oral administration of 14C 2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3- [5-(trifluoromethyl)-2 pyridyloxy]propyl ether (14C-pyridalyl) at 5 mg/kg/day for 14 consecutive days, and 14C excretion, 14C concentration in tissues, and the metabolic fate were determined. Most 14C was excreted into feces. The 14C concentrations in the blood and tissues attained steady-state levels at days 6 to 10, whereas those in white adipose tissues increased until day 14. Tissue 14C concentrations were highest in brown and white adipose tissue (38.37-57.50 ppm) but were 5.60 ppm or less in all the other tissues. Total 14C residues in blood and tissues on the 27th day after the first administration accounted for 2.6 to 3.2% of the total dose. A major fecal metabolite resulted from O-dealkylation. Analysis of metabolites in tissues revealed that the majority of 14C in perirenal adipose tissue and lungs was pyridalyl, accounting for greater than 90 and 60%, respectively, of the total, whereas a major metabolite in whole blood, kidneys, and liver was a dehalogenated metabolite. The experimental data were simulated with simple physiologically based pharmacokinetics using four-compartment models with assumption of lymphatic absorption and membrane permeability in adipose tissues. The different kinetics in brown and white adipose tissues was reasonably predicted in this model, with large distribution volume in adipose tissues and high hepatic clearance in liver. Sex-related difference of pyridalyl concentration in liver was considered to be a result of different unbound fraction times the hepatic intrinsic clearance (f x CL(int)) of 1.8 and 12 l/h for male and female, respectively. PMID- 20164114 TI - Comment on "Permeability, transport, and metabolism of solutes in Caco-2 cell monolayers: a theoretical study". PMID- 20164117 TI - The histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces cardiac arrhythmias in dystrophic mice. AB - AIMS: The effect of histone deacetylase inhibitors on dystrophic heart function is not established. To investigate this aspect, dystrophic mdx mice and wild-type (WT) animals were treated 90 days either with suberoylanilide hydroxamic acid (SAHA, 5 mg/kg/day) or with an equivalent amount of vehicle. METHODS AND RESULTS: The following parameters were evaluated: (i) number of ventricular arrhythmias in resting and stress conditions (restraint test) or after aconitine administration; (ii) cardiac excitability, conduction velocity, and refractoriness; (iii) expression and distribution of connexins (Cxs) and Na(v)1.5 sodium channel. Ventricular arrhythmias were negligible in all resting animals. During restraint, however, an increase in the number of arrhythmias was detected in vehicle-treated mdx mice (mdx-V) when compared with SAHA-treated mdx (mdx-SAHA) mice or normal control (WT-V). Interestingly, aconitine, a sodium channel pharmacologic opener, induced ventricular arrhythmias in 83% of WT-V mice, 11% of mdx-V, and in 57% of mdx-SAHA. Epicardial multiple lead recording revealed a prolongation of the QRS complex in mdx-V mice in comparison to WT-V and WT-SAHA mice, paralleled by a significant reduction in impulse propagation velocity. These alterations were efficiently counteracted by SAHA. Molecular analyses revealed that in mdx mice, SAHA determined Cx remodelling of Cx40, Cx37 and Cx32, whereas expression levels of Cx43 and Cx45 were unaltered. Remarkably, Cx43 lateralization observed in mdx control animals was reversed by SAHA treatment which also re-induced Na(v)1.5 expression. CONCLUSION: SAHA attenuates arrhythmias in mdx mice by a mechanism in which Cx remodelling and sodium channel re-expression could play an important role. PMID- 20164116 TI - Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. AB - The vascular system delivers oxygen and nutrients to every cell in the vertebrate organism. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of hypoxic/ischaemic vascular responses, driving transcriptional activation of hundreds of genes involved in vascular reactivity, angiogenesis, arteriogenesis, and the mobilization and homing of bone marrow-derived angiogenic cells. This review will focus on the pivotal role of HIF-1 in vascular homeostasis, the involvement of HIF-1 in vascular diseases, and recent advances in targeting HIF-1 for therapy in preclinical models. PMID- 20164118 TI - ILK mediates LPS-induced vascular adhesion receptor expression and subsequent leucocyte trans-endothelial migration. AB - AIMS: The inflammatory response to injurious agents is tightly regulated to avoid adverse consequences of inappropriate leucocyte accumulation or failed resolution. Lipopolysaccharide (LPS)-activated endothelium recruits leucocytes to the inflamed tissue through controlled expression of membrane-associated adhesion molecules. LPS responses in macrophages are known to be regulated by integrin linked kinase (ILK); in this study, we investigated the role of ILK in the regulation of the LPS-elicited inflammatory response in endothelium. METHODS AND RESULTS: This study was performed on immortalized mouse endothelial cells (EC) isolated from lung and coronary vasculature. Cells were thoroughly characterized and the role of ILK in the regulation of the LPS response was investigated by suppressing ILK expression using siRNA and shRNA technologies. Phenotypic and functional analyses confirmed that the immortalized cells behaved as true EC. LPS induced the expression of the inflammatory genes E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). ILK knockdown impaired LPS-mediated endothelial activation by preventing the induction of ICAM-1 and VCAM-1. Blockade of the LPS-induced response inhibited the inflammatory-related processes of firm adhesion and trans-endothelial migration of leucocytes. CONCLUSION: ILK is involved in the expression of cell adhesion molecules by EC activated with the inflammatory stimulus LPS. This reduced expression modulates leucocyte adhesion to the endothelium and the extravasation process. This finding suggests ILK as a potential anti-inflammatory target for the development of vascular-specific treatments for inflammation related diseases. PMID- 20164119 TI - Downregulation of microRNA-29 by antisense inhibitors and a PPAR-gamma agonist protects against myocardial ischaemia-reperfusion injury. AB - AIMS: MicroRNAs (miRNAs) regulate various cardiac processes including cell proliferation and apoptosis. Pioglitazone (PIO), a peroxisome proliferator activated receptor (PPAR)-gamma agonist, protects against myocardial ischaemia reperfusion (IR) injury. We assessed the effects of PPAR-gamma activation on myocardial miRNA levels and the role of miRNAs in IR injury. METHODS AND RESULTS: We evaluated the expression changes of miRNAs in the rat heart after PIO administration using miRNA arrays and then confirmed the result by northern blot. miR-29a and c levels decreased remarkably after 7-day treatment with PIO. In H9c2 cells, the effects of PIO and rosiglitazone on miR-29 expression levels were blocked by a selective PPAR-gamma inhibitor GW9662. Downregulation of miR-29 by antisense inhibitor or by PIO protected H9c2 cells from simulated IR injury, indicated as increased cell survival and decreased caspase-3 activity. In contrast, overexpressing miR-29 promoted apoptosis and completely blocked the protective effect of PIO. Antagomirs against miR-29a or -29c significantly reduced myocardial infarct size and apoptosis in hearts subjected to IR injury. Western blot analyses demonstrated that Mcl-2, an anti-apoptotic Bcl-2 family member, was increased by miR-29 inhibition. CONCLUSION: Downregulation of miR-29 protected hearts against IR injury. The modulation of miRNAs can be achieved by pharmacological intervention. These findings provide a rationale for the development of miRNA-based strategies for the attenuation of IR injury. PMID- 20164121 TI - High glucose, nitric oxide, and adenosine: a vicious circle in chronic hyperglycaemia? PMID- 20164120 TI - Glucose-induced endothelial heparanase secretion requires cortical and stress actin reorganization. AB - AIMS: Heparanase, which specifically cleaves carbohydrate chains of heparan sulfate, has been implicated in the pathology of diabetes-associated complications. Using high glucose (HG) to replicate hyperglycaemia observed following diabetes, the present study was designed to determine the mechanism by which HG initiates endothelial heparanase secretion. METHOD AND RESULTS: To examine the effect of HG on endothelial heparanase, bovine coronary artery endothelial cells were incubated with 25 mM glucose. Strategies using different agonists and antagonists were used to determine the mechanism behind HG-induced heparanase secretion. In endothelial cells, heparanase colocalized with lysosomes predominately around the nucleus, and HG caused its dispersion towards the plasma membrane for subsequent secretion. ATP release, purinergic receptor activation, cortical actin disassembly, and stress actin formation were essential for this HG induced heparanase secretion. With HG, phosphorylation of filamin likely contributed to the cortical actin disassembly, whereas Ca(2+)/calmodulin dependent protein kinase II and p38 mitogen-activated protein kinase /heat shock protein 25 phosphorylation mediated stress actin formation. The endothelial secreted heparanase in response to HG demonstrated endoglucuronidase activity, cleaved heparan sulfate, and released attached proteins like lipoprotein lipase and basic fibroblast growth factor. CONCLUSION: Our results suggest that HG is a potent stimulator of endothelial heparanase secretion. These data may assist in devising new therapeutic strategies to prevent or delay the cardiovascular complications associated with diabetes. PMID- 20164122 TI - Subjective loudness and reality of auditory verbal hallucinations and activation of the inner speech processing network. AB - BACKGROUND: One of the most influential cognitive models of auditory verbal hallucinations (AVH) suggests that a failure to adequately monitor the production of one's own inner speech leads to verbal thought being misidentified as an alien voice. However, it is unclear whether this theory can explain the phenomenological complexity of AVH. We aimed to assess whether subjective perceptual and experiential characteristics may be linked to neural activation in the inner speech processing network. METHODS: Twenty-two patients with schizophrenia and AVH underwent a 3-T functional magnetic resonance imaging scan, while performing a metrical stress evaluation task, which has been shown to activate both inner speech production and perception regions. Regions of interest (ROIs) comprising the putative inner speech network were defined using the Anatomical Automatic Labeling system. Correlations were calculated between scores on the "loudness" and "reality" subscales of the Auditory Hallucination Rating Scale (AHRS) and activation in these ROIs. Second, the AHRS subscales, and general AVH severity, indexed by the Positive and Negative Syndrome Scale, were correlated with a language lateralization index. RESULTS: Louder AVH were associated with reduced task-related activity in bilateral angular gyrus, anterior cingulate gyrus, left inferior frontal gyrus, left insula, and left temporal cortex. This could potentially be due to a competition for shared neural resources. Reality on the other hand was found to be associated with reduced language lateralization. CONCLUSION: Strong activation of the inner speech processing network may contribute to the subjective loudness of AVH. However, a relatively increased contribution from right hemisphere language areas may be responsible for the more complex experiential characteristics, such as the nonself source or how real AVH are. PMID- 20164123 TI - Suppression of mTOR via Akt-dependent and -independent mechanisms in selenium treated colon cancer cells: involvement of AMPKalpha1. AB - Activation of the mammalian target of rapamycin (mTOR) pathway promotes tumorigenesis, and inhibiting the mammalian target of rapamycin complex 1 (mTORC1) has emerged as an attractive target for suppressing tumor growth. We found that selenium treatment of HT-29 colon cancer cells suppressed mTORC1 through Akt-independent and -dependent pathways. In Akt-independent mTORC1 inhibition in selenium-treated colon cancer cells, adenosine monophosphate activated protein kinase (AMPK) alpha(1) was crucial for suppression of mTORC1 activity. In contrast, the Akt-dependent mTORC1 inhibition by selenium did not require AMPKalpha(1). The importance of the AMPKalpha(1)-mTORC1 pathway in mediating the antiproliferative action of selenium was examined in xenograft tumors, and the suppression of mTORC1 as well as Akt was concomitant with an increase in AMPKalpha(1) activity. These findings suggest that the antiproliferative effect of selenium is mediated by an Akt-independent AMPKalpha(1)/mTORC1 pathway or by the Akt/tuberous sclerosis complex 2 /mTORC1 pathway. PMID- 20164124 TI - Secreted protein acidic and rich in cysteine-induced cellular senescence in colorectal cancers in response to irinotecan is mediated by P53. AB - Cellular senescence is another mechanism that can be exploited to achieve better chemosensitivity and greater tumor regression. Unlike apoptosis, cellular senescence can be induced at much lower concentrations of chemotherapy that are better tolerated by patients. We previously revealed that secreted protein acidic and rich in cysteine (SPARC), a matricellular protein, may function as a modulator of chemotherapy sensitivity by enhancing apoptosis. Here, we examine the effects of SPARC on cellular senescence in the presence of chemotherapy. Cellular senescence is induced only in sensitive colorectal cancer (CRC) cells with low concentrations of irinotecan (CPT-11). However, CPT-11-resistant cells exposed to endogenous or exogenous SPARC can also be triggered into cellular senescence. This induction is associated with higher levels of p16(INK4A) and phosphorylated p53. Knock down of p16(INK4A) reduces drug-induced senescence in all cells, but knock down and overexpression of p53 modulates senescence only in cells exposed to SPARC. Furthermore, treatment of mice with SPARC and CPT-11 leads to significantly increased cellular senescence and tumor regression. The chemosensitizing effects of SPARC in CRCs are, therefore, probably mediated in part by activating cellular senescence. PMID- 20164125 TI - Spontaneous epileptic manifestations in a DCX knockdown model of human double cortex. AB - Previous reports indicate that in utero knockdown of doublecortin (DCX) results in the genesis of a subcortical heterotopia reminiscent of the doublecortex observed in female patients with DCX mutations. It has also been shown that these rats display an increased susceptibility to convulsant agents and increased cortical neurons excitability; but it is presently unknown whether they display spontaneous seizures. Furthermore, the link between the size of heterotopia and the clinical manifestation remained to be elucidated. Using video electrocorticogram recordings, we now report that DCX knockdown induces frequent spontaneous seizures commonly associated with myoclonic jerks in adult rats. Surprisingly, epilepsy occurred even in rats with very small subcortical heterotopias, as revealed by histological analysis of recorded animals. Moreover, the severity of the epileptic manifestations was positively correlated with both the size of the subcortical heterotopia and the age of recorded animals; thus, epileptic features were not detected in immature affected rats. In conclusion, our data demonstrate for the first time that subtle alterations can yield epilepsy and reveal a strong correlation between thicknesses of subcortical heterotopia, age of affected individuals and clinical impairment. PMID- 20164126 TI - Virtual model analysis as an alternative approach to plaster model analysis: reliability and validity. AB - The objective of this study was to assess the feasibility of virtual models as an alternative to orthodontic plaster models. Virtual dental models (obtained from OrthoCAD) and corresponding plaster models of 80 patients in the permanent dentition were randomly selected from patients seeking orthodontic care. Inter examiner error was assessed by measuring tooth width, overjet, overbite, intermolar width, intercanine width, and midline discrepancy. Criterion validity of virtual model analysis was determined by the agreement between the measurements from virtual and plaster models. Test-retest reliability was determined by remeasuring 10 virtual models 1 week later. Comparison analysis was assessed by calculating the mean directional differences and standardized directional differences. Correlation analysis was determined by calculating the intraclass correlation coefficients (ICCs). Both intra- and inter-examiner reliability and test-retest reliability of virtual model analysis were acceptable in measuring intercanine, intermolar, overjet, overbite, midline discrepancy, space analysis, and tooth width (ICC > 0.7). Good criterion validity was indicated by agreement between the results from the plaster and virtual models (ICC > 0.8). There were substantial agreements for canine and molar relationship classifications (kappa > 0.70). The results suggest that analysis performed on virtual models is as valid as traditional plaster models for intra- and inter arch relationship. PMID- 20164127 TI - Influence of different self-etching primers on the bond strength of orthodontic lingual buttons. AB - The aim of this study was to evaluate the influence of six self-etching primers (SEPs) on the shear/peel bond strength (SPBS) of orthodontic lingual buttons. A total of 150 extracted human premolars were randomly divided into six equal groups. In all groups, the lingual buttons were bonded with BeautyOrtho Bond and the enamel was conditioned with the following-group I (Control): Primers A & B; group II: Transbond Plus SEP; group III: Clearfil Mega Bond FATM; group IV: AdheSE; group V: Peak SE & Peak LC Bond; and group VI: Bond Force. The teeth were stored at 37 degrees C for 24 hours and the SPBS was tested (0.5 mm/minute). The results were calculated in mega pascals (MPa) and statistically analysed [mean, standard deviation, Scheffe, analysis of variance (P < 0.05)]. The adhesive remnant index (ARI) was also evaluated and statistically analysed with a chi square test. All groups demonstrated higher SPBS than the force suggested as necessary to accomplish orthodontic tooth movement, except group IV (7.7 +/- 1.7 MPa), which showed a significantly lower value than groups I (10.7 +/- 2.4 MPa), II (11.3 +/- 3.1 MPa), and V (10.9 +/- 2.8 MPa). The values of groups III (9.9 +/ 1.6 MPa) and VI (10.5 +/- 1.6 MPa) were comparable with those of groups I and V. Significant differences (P < 0.05) were found among the groups in ARI scores. The SPBS values of all groups could be clinically acceptable and lingual buttons might be successfully bonded with any of these SEPs except AdheSE since that conditioner significantly influenced bond strength. As the SPBS was lower in all groups than the value at which enamel fractures have been found, a sound enamel surface might be left after removal of lingual buttons. PMID- 20164129 TI - The prognosis for research. PMID- 20164128 TI - One-component self-etching primer: a seventh generation of orthodontic bonding system? AB - The purpose of this study was to compare the bond strengths and to evaluate the debonding site using the adhesive remnant index (ARI) provided by a conventional acid-etch conditioner and a new self-etching adhesive system, Xeno IV (Dentsply Caulk). One hundred and eighty bovine lower incisors were randomly divided into six groups (n = 30). In groups 1, 2, and 3, Transbond XT (3M Unitek) composite was used to bond the brackets to enamel samples conditioned with 37 per cent phosphoric acid + XT primer (3M Unitek), Xeno IV + XT primer, or Xeno IV only, respectively. In groups 4, 5, and 6, the bonding procedures were performed using Fuji Ortho LC (GC Corp.) resin-modified glass ionomer cement unconditioned, enamel conditioned with 37 per cent phosphoric acid, or Xeno IV, respectively. All samples underwent thermocycling and then shear bond strength (SBS) testing was performed using a universal testing machine (Emic DL 10.000). Analysis of variance was applied. For the post hoc test, the Tukey's test was used. Kruskal Wallis and Mann-Whitney U-tests were used to assess ARI scores. The results demonstrated no statistical differences between groups 1, 2, and 3. However, statistically significant differences were found between these samples and groups 4, 5, and 6. With regard to ARI score, the highest mean value was found in group 5 (Fuji Ortho LC + 37 per cent acid conditioning), whereas group 4 (Fuji Ortho LC + no conditioning) had the lowest SBS. Xeno IV self-etching bonding agent was able to bond orthodontic brackets in association with Transbond XT composite as well as with Fuji Ortho LC, thus maximizing bracket bonding. PMID- 20164135 TI - Ministers may legislate after finding 85% of labels on alcohol to be inadequate. PMID- 20164136 TI - Nearly 23,000 people in England aged under 18 have diabetes, survey shows. PMID- 20164139 TI - An unusual case of calf pain. PMID- 20164142 TI - Auxin response factor 2 (ARF2) plays a major role in regulating auxin-mediated leaf longevity. AB - Auxin regulates a variety of physiological and developmental processes in plants. Although auxin acts as a suppressor of leaf senescence, its exact role in this respect has not been clearly defined, aside from circumstantial evidence. It was found here that ARF2 functions in the auxin-mediated control of Arabidopsis leaf longevity, as discovered by screening EMS mutant pools for a delayed leaf senescence phenotype. Two allelic mutations, ore14-1 and 14-2, caused a highly significant delay in all senescence parameters examined, including chlorophyll content, the photochemical efficiency of photosystem II, membrane ion leakage, and the expression of senescence-associated genes. A delay of senescence symptoms was also observed under various senescence-accelerating conditions, where detached leaves were treated with darkness, phytohormones, or oxidative stress. These results indicate that the gene defined by these mutations might be a key regulatory genetic component controlling functional leaf senescence. Map-based cloning of ORE14 revealed that it encodes ARF2, a member of the auxin response factor (ARF) protein family, which modulates early auxin-induced gene expression in plants. The ore14/arf2 mutation also conferred an increased sensitivity to exogenous auxin in hypocotyl growth inhibition, thereby demonstrating that ARF2 is a repressor of auxin signalling. Therefore, the ore14/arf2 lesion appears to cause reduced repression of auxin signalling with increased auxin sensitivity, leading to delayed senescence. Altogether, our data suggest that ARF2 positively regulates leaf senescence in Arabidopsis. PMID- 20164143 TI - Identification and localization of a caleosin in olive (Olea europaea L.) pollen during in vitro germination. AB - In plant organs and tissues, the neutral storage lipids are confined to discrete spherical organelles called oil bodies. Oil bodies from plant seeds contain 0.6 3% proteins, including oleosins, steroleosins, and caleosins. In this study, a caleosin isoform of approximately 30 kDa was identified in the olive pollen grain. The protein was mainly located at the boundaries of the oil bodies in the cytoplasm of the pollen grain and the pollen tube. In addition, caleosins were also visualized in the cytoplasm at the subapical zone, as well as in the tonoplast of vacuoles present in the pollen tube cytoplasm. The cellular behaviour of lipid bodies in the olive pollen was also monitored during in vitro germination. The number of oil bodies decreased 20-fold in the pollen grain during germination, whereas the opposite tendency occurred in the pollen tube, suggesting that oil bodies moved from one to the other. The data suggest that this pollen caleosin might have a role in the mobilization of oil bodies as well as in the reorganization of membrane compartments during pollen in vitro germination. PMID- 20164144 TI - Mechanisms of ozone tolerance in rice: characterization of two QTLs affecting leaf bronzing by gene expression profiling and biochemical analyses. AB - High surface ozone concentration is increasingly being recognized as a factor that negatively affects crop yields in Asia. However, little progress has been made in developing ozone-tolerant genotypes of rice-Asia's major staple crop. This study aimed to identify possible tolerance mechanisms by characterizing two quantitative trait loci (QTLs) that were previously shown to influence visible leaf symptoms under ozone exposure (120 nl l(-1), 7 h d(-1), 13 d). Two chromosome segment substitution lines (SL15 and SL41) that carried introgressions of the QTLs OzT3 and OzT9, respectively, were exposed to ozone at 120 nl l(-1) along with their parent Nipponbare. In accordance with the expected QTL effect, SL15 showed stronger visible symptoms of ozone damage than Nipponbare, whereas SL41 had fewer symptoms. Gene expression profiling by microarray hybridization yielded 470 probes that were differentially expressed in SL15 and 314 in SL41. Potential tolerance mechanisms were evaluated by investigating changes in gene expression in three general categories. (i) Processes involved in programmed cell death, in which a number of genes related to ethylene or jasmonic acid metabolism or general disease resistance were identified that were differentially regulated in one of the substitution lines. (ii) Biosynthesis of antioxidants. Testing this hypothesis did not reveal any genes differentially regulated between genotypes, and it was thus rejected. (iii) Turnover of antioxidants and enzymatic detoxification of radical oxygen species (ROS), in which a number of differentially regulated genes were also identified. Genes encoding antioxidant enzymes (catalase and peroxidases) tended to be more strongly expressed in SL15. A potential tolerance gene which encodes a putative ascorbate oxidase was identified within the QTL introgression in SL41. This gene showed consistently lower expression in SL41 under ozone exposure across different points in time within independent experiments. Its expression may be involved in mechanisms leading to enhanced ascorbic acid status in SL41 under ozone exposure, and may be linked to a higher concentration of total apoplastic ascorbic acid in SL41 that was observed in an independent experiment. PMID- 20164146 TI - Flawed experimental design reveals the need for guidelines requiring appropriate positive controls in endocrine disruption research. PMID- 20164147 TI - Discrimination of porcine glycogen debranching enzyme isozymes by the ratios of their 4-alpha-glucanotransferase and amylo-alpha-1,6-glucosidase activities. AB - Glycogen debranching enzyme (GDE) is a single-chain protein containing distinct active sites that exhibit 4-alpha-glucanotransferase and amylo-alpha-1,6 glucosidase activities. The ratios of these two activities in porcine liver and muscle GDEs were compared using a set of homologous fluorogenic branched dextrins. For quantifying 4-alpha-glucanotransferase activity, 6(3)-O-alpha maltotetraosyl-PA-maltooctaose (B3/84), 6(4)-O-alpha-maltotetraosyl-PA maltooctaose (B4/84), 6(5)-O-alpha-maltotetraosyl-PA-maltooctaose (B5/84) and 6(6)-O-alpha-maltotetraosyl-PA-maltooctaose (B6/84) were used as substrates and maltohexaose (G6) as the acceptor. The substrate for amylo-alpha-1,6-glucosidase activity was 6(3)-O-alpha-glucosyl-PA-maltotetraose (B3/41). HPLC analysis of the fluorogenic branched dextrin digests in the presence of G6 revealed that GDE 4 alpha-glucanotransferases produce the corresponding 6-O-alpha-glucosyl-PA maltooctaose (GG8PA) and maltononaose (G9). The ratios of the 4-alpha glucanotransferase activity to amylo-alpha-1,6-glucosidase activity, for the liver and muscle enzymes were respectively 0.240 and 0.0840 for B3/84, 0.204 and 0.0788 for B4/84, 0.145 and 0.0592 for B5/84, and 0.109 and 0.0458 for B6/84. These data clearly indicate that porcine liver and muscle GDEs are different from each other. The ratios of porcine brain GDE were 0.155, 0.131, 0.0990 and 0.0745 for B3/84, B4/84, B5/84 and B6/84, respectively. These results indicate that porcine brain GDE is also unique from liver and muscle enzymes, suggesting that it is either a third enzyme, or a mixture of 45% liver and 55% muscle GDEs. PMID- 20164145 TI - Developmental neurotoxicity study of dietary bisphenol A in Sprague-Dawley rats. AB - This study was conducted to determine the potential of bisphenol A (BPA) to induce functional and/or morphological effects to the nervous system of F(1) offspring from dietary exposure during gestation and lactation according to the Organization for Economic Cooperation and Development and U.S. Environmental Protection Agency guidelines for the study of developmental neurotoxicity. BPA was offered to female Sprague-Dawley Crl:CD (SD) rats (24 per dose group) and their litters at dietary concentrations of 0 (control), 0.15, 1.5, 75, 750, and 2250 ppm daily from gestation day 0 through lactation day 21. F(1) offspring were evaluated using the following tests: detailed clinical observations (postnatal days [PNDs] 4, 11, 21, 35, 45, and 60), auditory startle (PNDs 20 and 60), motor activity (PNDs 13, 17, 21, and 61), learning and memory using the Biel water maze (PNDs 22 and 62), and brain and nervous system neuropathology and brain morphometry (PNDs 21 and 72). For F(1) offspring, there were no treatment-related neurobehavioral effects, nor was there evidence of neuropathology or effects on brain morphometry. Based on maternal and offspring body weight reductions, the no observed-adverse-effect level (NOAEL) for systemic toxicity was 75 ppm (5.85 and 13.1 mg/kg/day during gestation and lactation, respectively), with no treatment related effects at lower doses or nonmonotonic dose responses observed for any parameter. There was no evidence that BPA is a developmental neurotoxicant in rats, and the NOAEL for developmental neurotoxicity was 2250 ppm, the highest dose tested (164 and 410 mg/kg/day during gestation and lactation, respectively). PMID- 20164148 TI - Thermostability of striated and smooth adductor muscle tropomyosins from Yesso scallop Mizuhopecten yessoensis. AB - The striated and smooth adductor muscle tropomyosins (TMs) of Yesso scallop Mizuhopecten yessoensis have been known to express different isoforms, but have not been characterized in detail to date. In the present study, TMs from both muscles of Yesso scallop were purified and their stabilities were compared by circular dichroism (CD) spectrometry and differential scanning calorimetry (DSC). From the CD data, the apparent melting temperature and the apparent free energy of folding at 20 degrees C were calculated to be 30.5 degrees C and -13.4 kJ/mol, and 36.0 degrees C and -31.9 kJ/mol for the striated and smooth muscle TMs, respectively. From the DSC data, DeltaH values were calculated to be 1.87 x 10(3) and 2.19 x 10(3) kJ/mol for striated and smooth muscle TMs. These results suggest that smooth muscle TM has higher thermostability than striated muscle TM. The amino acid residues responsible for such stability difference were considered to be the six amino acid substitutions in the middle region of the TM molecules. PMID- 20164149 TI - Low-dose induction chemotherapy with Baby-BOP in patients with metastatic germ cell tumours does not compromise outcome: a single-centre experience. AB - BACKGROUND: In some institutions advanced metastatic germ-cell tumour (GCT) is treated with low-dose induction chemotherapy in specific settings. There is a lack of published data supporting its use. The data presented here specifically address this issue for the first time. PATIENTS AND METHODS: Twenty patients with metastatic GCT treated were with low-dose induction chemotherapy [Baby-BOP (bBOP)] between 1998 and 2009. We report the toxicity and outcome and compare it with a control group. RESULTS: bBOP was well tolerated with no treatment-related deaths and a lack of chemotherapy-related toxicity. It was associated with a significant fall in tumour markers (median HCG fell from 35 195 to 11 028 IU/l). The first subsequent cycle of standard chemotherapy was administered a median of 9.5 days after initial treatment and was not associated with excess toxicity. The 2-year overall survival of the poor-prognosis patients treated with bBOP was 79.0% [95% confidence interval (CI) 48% to 93%], which is not significantly different from the 2-year overall survival of 80% [95% CI 55% to 92%] of the poor prognosis patients, who did not receive bBOP. CONCLUSION: Low-dose induction chemotherapy can be given safely in selected individuals and does not adversely affect subsequent chemotherapy or outcome. PMID- 20164150 TI - The expression of p38, ERK1 and Bax proteins has increased during the treatment of newly diagnosed acute promyelocytic leukemia with arsenic trioxide. AB - BACKGROUND: Promising reports exist regarding the use of arsenic trioxide (ATO) as first-line treatment in acute promyelocytic leukemia (APL). Although the in vitro effect of ATO is extensively studied, the in vivo mechanism(s) of ATO action is mostly unknown. PATIENTS AND METHODS: Newly diagnosed APL patients were involved and received ATO (0.15 mg.kg/day) for 28 days as induction followed by consolidation therapy. Bone marrow (BM) aspirates were obtained on days 0, 14 and 28 of treatment for further molecular studies. Clinical findings and white blood cell counts were recorded as well. RESULTS: Complete remission was observed in 17 (85%) patients with the median duration of 28 days (18-38) and cumulative dosage of median 280 mg (180-350). Hyperleukocytosis and APL differentiation syndrome (63%), gastrointestinal disorders (30%), liver enzyme elevation and night sweating (50%) were the most prevalent side-effects. The expression of Bax, ERK1 and p38 proteins and caspase-3 activity increased significantly in promyelocytes of BM aspirates at days 14 and 28 of induction therapy. CONCLUSION(S): These findings point toward the role of p38 and Bax in the induction of apoptosis, which was confirmed by increase in caspase-3 activity. However, the increase in ERK1 expression with regard to leukocytosis could translate to a proliferative/differentiation effect. PMID- 20164151 TI - Plastoquinol is the main prenyllipid synthesized during acclimation to high light conditions in Arabidopsis and is converted to plastochromanol by tocopherol cyclase. AB - Plants have evolved various strategies to acclimate to high light conditions at different levels of organization. High light stress stimulates synthesis of different antioxidant enzymes and low molecular weight antioxidants, mainly in chloroplasts. In the present studies we showed that plastoquinol, in addition to alpha-tocopherol, is the main lipid-soluble antioxidant synthesized during acclimation of Arabidopsis plants to high light conditions. The level of plastoquinol increased >10-fold and independently of tocopherols, as revealed using tocopherol biosynthetic mutants. The high light-induced increase in plastoquinol level was mainly attributable to the photochemically non-active fraction of this compound localized in plastoglobuli, which are the storage site of prenyllipids for their antioxidant action. Our data also revealed that tocopherol cyclase is required for plastochromanol biosynthesis from plastoquinol in vivo. Plastochromanol accumulated in increasing amounts in leaves during growth and it was also identified in seeds. The obtained data suggest that plastochromanol may, similarly to other prenyllipids, fulfill antioxidant function in leaves and seeds, especially during aging. PMID- 20164152 TI - How significant is a protein structure similarity with TM-score = 0.5? AB - MOTIVATION: Protein structure similarity is often measured by root mean squared deviation, global distance test score and template modeling score (TM-score). However, the scores themselves cannot provide information on how significant the structural similarity is. Also, it lacks a quantitative relation between the scores and conventional fold classifications. This article aims to answer two questions: (i) what is the statistical significance of TM-score? (ii) What is the probability of two proteins having the same fold given a specific TM-score? RESULTS: We first made an all-to-all gapless structural match on 6684 non homologous single-domain proteins in the PDB and found that the TM-scores follow an extreme value distribution. The data allow us to assign each TM-score a P value that measures the chance of two randomly selected proteins obtaining an equal or higher TM-score. With a TM-score at 0.5, for instance, its P-value is 5.5 x 10(-7), which means we need to consider at least 1.8 million random protein pairs to acquire a TM-score of no less than 0.5. Second, we examine the posterior probability of the same fold proteins from three datasets SCOP, CATH and the consensus of SCOP and CATH. It is found that the posterior probability from different datasets has a similar rapid phase transition around TM-score=0.5. This finding indicates that TM-score can be used as an approximate but quantitative criterion for protein topology classification, i.e. protein pairs with a TM-score >0.5 are mostly in the same fold while those with a TM-score <0.5 are mainly not in the same fold. PMID- 20164153 TI - Thiazolidinediones alter growth and epithelial cell integrity, independent of PPAR-gamma and MAPK activation, in mouse M1 cortical collecting duct cells. AB - Peroxisome proliferator-activated receptor (PPAR)-gamma is highly expressed in the collecting duct (CD), yet little is known about the effects of PPAR-gamma ligands, thiazolidinediones (TZDs), on CD cell structure and function. M1 mouse cortical CD cells were treated with 5 MUM troglitazone (TRO) and rosiglitazone (ROSI). First, growth was measured by [(3)H]thymidine and [(3)H]leucine incorporation, as well as analysis of cyclin D1 and the CDK inhibitor p27 by Western blot. [(3)H]thymidine incorporation was reduced by 56 and 24% by TRO and ROSI at 6 h, and [(3)H]leucine by 21 and 10%. A similar growth inhibition was also observed after 24 h for thymidine, but leucine was reduced by 48 and 24%, respectively. Likewise, cyclin D1 was diminished 60% by TRO, and p27 was elevated 1.6- and 1.7-fold in response to TRO and ROSI. Next, epithelial cell integrity was assessed by measuring different markers by Western blot analysis. While fibronectin and alpha-smooth muscle actin levels were unchanged, by 24 h E cadherin was decreased by 50%, and beta-catenin levels were reduced 2- and 1.5 fold in response to TRO and ROSI, respectively. GW9662, a PPAR-gamma antagonist, did not reverse any of the TZD responses in M1 cells. Of interest, phosho-p38 levels were also elevated 2-fold in response to TRO and 2.3-fold to ROSI, but MAPK inhibition by PD98059 or SB203580 caused an additive inhibition of cell growth and did not alter E-cadherin or beta-catenin in response to TZDs. Finally, apoptotic death was assessed by Western blot, but cleaved caspase-3 levels were unchanged from 15 min to 24 h in response to TZDs, and TRO did not affect cell viability or reactive oxygen species generation. Our data suggest that TZDs cause a disruption of M1 cell integrity that is preceded by an inhibition of cell growth. This response is independent of p38 or PPAR-gamma activation. PMID- 20164154 TI - Reactive oxygen species differently regulate renal tubular epithelial and interstitial cell proliferation after ischemia and reperfusion injury. AB - Reactive oxygen species (ROS) function as an inducer of cell death and survival or proliferative factor, in a cell-type-specific and concentration-dependent manner. All of these roles are critical to ischemia-induced renal functional impairment and progressive fibrotic changes in the kidney. In an effort to define the role of ROS in the proliferation of tubular epithelial cells and of interstitial cells in kidneys recovering after ischemia and reperfusion (I/R) injury, experimental mice were subjected to 30 min of bilateral kidney ischemia and administered with manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin (MnTMPyP), a superoxide dismutase mimetic, from 2 to 15 days after I/R for 14 days daily (earlier and longer) and from 8 to 15 days after I/R for 8 days daily (later and shorter). Cell proliferation was assessed via 5'-bromo-2'-deoxyuridine (BrdU) incorporation assays for 20 h before the harvest of kidneys. After I/R, the numbers of BrdU-incorporating cells increased both in the tubules and interstitium. MnTMPyP administration was shown to accelerate the proliferation of tubular epithelial cells, presenting tubule-specific marker proteins along tubular segments, whereas it attenuated the proliferation of interstitial cells, evidencing alpha-smooth muscle actin, fibroblast-specific protein-1, F4/80, and NADPH oxidase-2 proteins; these results indicated that ROS attenuates tubular cell regeneration, but accelerates interstitial cell proliferation. Earlier and longer MnTMPyP treatment more effectively inhibited tissue superoxide formation, the increment of interstitial cells, and the decrement of epithelial cells compared with later and shorter treatment. After I/R, apoptotic cells appeared principally in the tubular epithelial cells, but not in the interstitial cells, thereby indicating that ROS is harmful in tubule cells, but is not in interstitial cells. In conclusion, ROS generated after I/R injury in cell proliferation and death performs a cell-type-specific and concentration-dependent role, even within the same tissues, and timely intervention of ROS is crucial for effective therapies. PMID- 20164155 TI - Expression and response of acid-sensing ion channels in urinary bladder to cyclophosphamide-induced cystitis. AB - The expression of acid-sensing ion channel (ASIC) isoforms, ASIC1, ASIC2a, and ASIC3, was examined in the urinary bladder after cyclophosphamide (CYP)-induced cystitis of varying duration (4 h, 48 h, and chronic). Immunohistochemical, Western blot, and quantitative PCR approaches were used to evaluate channel expression and effects of CYP-induced cystitis in whole urinary bladder and split bladder preparations from control (no inflammation) and CYP-treated rats. Quantitative PCR demonstrated significant (P <= 0.01) increases in ASIC2a and ASIC3 transcripts with CYP-induced cystitis (48 h and chronic) in the urothelium but no changes (e.g., ASIC3) or modest changes (e.g., ASIC2a) in detrusor smooth muscle. ASIC1 mRNA expression in the urothelium or detrusor was not affected by CYP-induced cystitis. Immunohistochemistry for ASIC2a and ASIC3 protein expression revealed significant (P <= 0.01) increases in ASIC immunoreactivity in the urothelium and suburothelial plexus with CYP-induced cystitis at all time points examined. Western blotting for ASIC2a and ASIC3 protein expression was complementary and revealed significant (P <= 0.01) increases in ASIC immunoreactivity. For the first time, these studies demonstrate that CYP-induced cystitis alters ASIC2a and ASIC3 expression in the urinary bladder; ASIC1 transcript expression is not altered by CYP-induced cystitis. Future studies are necessary to determine ASIC isoform contributions to micturition reflexes in control and inflamed urinary bladder. PMID- 20164156 TI - Regulation of renal tubular glucose reabsorption by Akt2/PKBbeta. AB - Akt/PKB is known to regulate the facilitative glucose carrier GLUT4. Nothing is known, however, of the role of Akt/PKB in the regulation of renal epithelial transport. To explore whether Akt2/PKBbeta influences the Na(+)-coupled glucose cotransporter SGLT1, human SGLT1 was expressed in Xenopus laevis oocytes with or without Akt/PKB, and electrogenic glucose transport was determined by dual electrode voltage clamp. The coexpression of Akt/PKB in SGLT1-expressing oocytes was followed by an increase in glucose-induced currents. To study the functional significance of Akt/PKB-sensitive renal glucose transport, further experiments were performed in gene-targeted mice lacking functional Akt2/PKBbeta (akt2(-/-)) and in their wild-type littermates (akt2(+/+)). Plasma glucose concentration was significantly higher in akt2(-/-) mice than in akt2(+/+) mice but was virtually identical to the plasma glucose concentration in fructose-treated akt2(+/+) mice. Urinary glucose excretion was significantly higher in akt2(-/-) mice compared with akt2(+/+) mice with or without fructose treatment. Moreover, the glucose induced depolarization of proximal tubular cells was significantly smaller in isolated, perfused renal tubules from akt2(-/-) mice than in those from akt2(+/+) mice. In conclusion, Akt2/PKBbeta plays a role in the regulation of renal glucose transport. PMID- 20164157 TI - Nicotine and its metabolites in amniotic fluid at birth--assessment of prenatal tobacco smoke exposure. AB - Amniotic fluid was collected from 78 pregnant women at birth additionally with their urine prior to delivery as well as neonatal urine and meconium. The smoking markers, nicotine and its metabolites cotinine and trans-3'-hydroxycotinine (OH cotinine), were determined using high-performance liquid chromatography (HPLC). The self-reported smoking status during pregnancy determined by means of a questionnaire was verified by measurement of maternal urine. In all smokers, nicotine metabolites were detected in amniotic fluid and in 80% of them nicotine as well. However, the sum of the nicotine metabolites (Sum(met)) was significantly lower (p < .001) in amniotic fluid (704 +/- 464 nmol/L) than in meconium (921 +/- 588 nmol/L), neonatal urine (1139 +/- 813 nmol/L) and maternal urine (4496 +/- 3535 nmol/L). Concentrations of nicotine metabolites in amniotic fluid correlated well (p < .001) with that in the other specimen types. After environmental tobacco smoke (ETS) exposure, no nicotine or nicotine metabolites were detectable in amniotic fluid but only in maternal and neonatal urine. Analysis of amniotic fluid at birth lends itself to verifying smoking habits during pregnancy and clearly discriminating from ETS exposure, but it is not a suitable approach to differentiating between ETS exposure and non-exposure. PMID- 20164158 TI - Ameliorative effect of DRDE 07 and its analogues on the systemic toxicity of sulphur mustard and nitrogen mustard in rabbit. AB - Despite extensive research efforts, there is no unanimous approval of any animal model to evaluate the toxicity of sulphur mustard [SM; bis (2-chloroethyl) sulphide] or nitrogen mustard [HN-3; tris-(2-chloroethyl) amine] and screening of various prophylactic and therapeutic agents against them. In this study, differential toxicity of mustard agents in higher animal model that is male rabbit was determined. Protective efficacy of DRDE 07 [S-2(2-aminoethylamino) ethyl phenyl sulphide] and its analogues were also evaluated against SM and HN-3 toxicity. Differential toxicity study of SM and HN-3 reveals that both the compounds were more toxic by percutaneous route as compared to subcutaneous route. Till date, there is no recommended drug to counteract SM induced toxicity or mortality in vivo. However, DRDE 07 (an amifostine analogue) and its analogues are found to be very effective protective agents against percutaneously exposed SM in rabbits. The present experiments also showed that SM does not cause skin injury alone but also can cause systemic toxicity as well. DRDE 07 and many of its analogues may prove as prototype compounds for the development of better prophylactic and therapeutic drugs to counter the toxicity of SM or HN-3. In conclusion, rodents and rabbits can be used for the screening of drugs against the blistering agents. PMID- 20164159 TI - Redotex ingestions reported to Texas poison centers. AB - Although the multi-component weight loss supplement Redotex is banned in the United States, the supplement can be obtained in Mexico. The intent of this report was to describe the pattern of Redotex calls received by a statewide poison center system. Cases were all Redotex calls received by Texas poison centers during 2000-2008. The distribution of total calls and those involving ingestion of the supplement were determined for selected demographic and clinical factors. Of 34 total Redotex calls received, 55.9% came from the 14 Texas counties that border Mexico. Of the 22 reported Redotex ingestions, 77.3% of the patients were female and 45.5% 20 years or more. Of the 17 ingestions involving no co-ingestants, 52.9% were already at or en route to a health care facility, 41.2% were managed on site, and 5.9% was referred to a health care facility. The final medical outcome was no effect in 23.5% cases, minor effect in 5.9%, moderate effect in 11.8%, not followed but minimal clinical effects possible in 47.1%, and unable to follow but judged to be potentially toxic in 11.8%. Most Redotex calls to the Texas poison center system originated from counties bordering Mexico. PMID- 20164160 TI - Up-regulation of the Apo/Fas (CD95) complex on neutrophils harvested during cardiac surgery: distinct findings in patients operated on with or without the use of cardiopulmonary bypass. AB - AIMS: In a group of patients undergoing cardiac surgery performed both with ("on pump") and without the use ("offpump") of cardiopulmonary bypass (CPB), we studied the changes of neutrophil membrane apoptosis-inducing complex Apo/Fas. METHODS: Expression of Apo/Fas (CD95) on leukocytes was evaluated by flow cytometry. RESULTS: In "on-pump" patients, we found an increase in the expression of CD95 median intensity fluorescence (MFI) on granulocytes from a baseline level median=56, (Q( 1)=45.5, Q(3)=64) to a median=88, (Q(1)=62, Q( 3)=109.5; p<0.01) at the 3(rd) postoperative day and median=74, (Q(1)=63, Q(3)=84.5; p<0.01) at the 7(th) postoperative day. In "off-pump" patients, granulocyte CD95 MFI was median=55, (Q(1)=51, Q(3)=84) before surgery. The significant increase was found on the 3(rd) postoperative day only; median=90, (Q( 1)=66; Q(3)=98; p<0.05). A similar pattern in the CD95 expression was also found if percentage changes of granulocyte CD95 MFI were followed. Moreover, the significantly increased Apo/Fas expression expressed as a percentage change of CD95 MFI was found in "on-pump" patients compared to "off-pump" patients, both at the 3(rd) postoperative day (p<0.05) and at the 7(th) postoperative day (p<0.01). CONCLUSIONS: This is the first direct evidence of increasing densities of the Apo/Fas complex on neutrophils in cardiac surgical patients. PMID- 20164161 TI - Negotiated pleasures in health-seeking lifestyles of participants of a health promoting intervention. AB - Using focus group discussion data the present article examines argumentation around pleasure from food and physical activity among participants of a health promoting intervention. The article analyses the conflicts produced by pleasure seeking and health enhancement, and the pursuits to solve these conflicts. Due to the discrepancy between the pleasure-seeking and health enhancement, pleasure was constructed not simply as a spontaneous experience but often as a planned and disciplined event. In respect of food, it was considered as appropriate to negotiate with different sources of pleasure and discipline one's inclination to simply follow one's taste. However, the tastiness of food was seen to have a value of its own and the need for pleasurable tastes was often experienced as beyond the individual's control. We term food related pleasures 'negotiated pleasures' stressing the diverse strategies used by individuals while negotiating between food related pleasures and their overall health-seeking lifestyle. In respect of physical activity, life resembled more a mosaic where passivity was occasionally interrupted with disciplined physical activity that seldom produced pleasure. The scarcity of pleasures from physical activity as well as from healthy foods is a challenge for health promoters. Instead of building more self controlling and self-denying individuals, it could be fruitful to focus health promoters' attention to the enhancement of the experiences of pleasure. No matter how self-disciplined individuals are, if the dilemma of pleasure and health is not disentangled, lifestyle change will not last long. PMID- 20164162 TI - Disrupted lives and threats to identity: the experiences of people with colorectal cancer within the first year following diagnosis. AB - In this article we focus on the experiences of 18 people with colorectal cancer, involved in a large longitudinal qualitative study to explore people's experiences of cancer within the first year following diagnosis. Three depth interviews over the course of the year were carried out. During analysis, we drew on biographically informed approaches of understanding chronic illness, particularly the work of Bury and Charmaz, to explore the extent to which people within the first year following diagnosis experience cancer as biographically disruptive. We explore the biographical work that individuals carry out in the context of an assault on their identity and discuss the relevance of the concept biographical disruption for people who experience cancer as an acute, chronic and/or life-threatening condition. We also discuss the concept's relevance for people who have lived a hard life and, hence, may anticipate these types of disruptions in their lives and experience their impact differently. We conclude that universal application of the concept biographical disruption to the experience of cancer within the first year of diagnosis is not appropriate. This study has implications for cancer services, in particular, the findings call for the development of interventions to support those people who experience cancer as an assault on their identity. PMID- 20164163 TI - 'Do you feel sorry for him?': gift relations in an HIV/AIDS on-line support forum. AB - Sociologists have debated whether meaningful emotional relationships can be formed on-line. Drawing on Mauss' concept of the gift, I explore how caregivers who participate in Hope, an on-line support forum dedicated to HIV/AIDS, incorporate moral percepts and understandings about ethics into their caregiving experiences. Their intense discussions on the essence of familial loyalties give rise to emotionally vibrant, empathic communities in which a socio-emotional economy is formulated. Can the Internet act as a moral space? How are concepts such as reciprocity, obligation, and commitment talked about and practiced in an on-line forum that exists in the ever present? PMID- 20164164 TI - Medical technocracies in liver transplantation: drawing boundaries in medical practices. AB - This article explores the ways in which the mastery of particular medical technologies plays a crucial role in drawing the boundaries between medical specialities, to form what we refer to as medical technocracies. It sets out, above all, to demonstrate how the frontiers between the different medical specialities act, on the one hand, as articulating mechanisms to be found in the division of medical work and, on the other hand, as barriers to the interaction of the various skills. Through a more searching study of the division of labour between surgeons and liver specialists (hepatologists) and surgeons and anaesthetics, we highlight the contrast between those two sets of relations.This illustrates the boundaries and articulation that exist between medical technocracies. The key theoretical guidelines are drawn from medical sociology and sociology of professions. The research methodology includes participant observation in a liver transplantation hospital unit and on site interviews. By using data gathered from physicians actually working in such areas where boundaries have been drawn between surgeons and anaesthesiologists and surgeons and liver specialists, we propose to understand how different medical skills are negotiated between the different groups and where the social arrangements are the result of processes of interaction between the different specialities, which are constantly being reorganized and redefined. PMID- 20164166 TI - Reaching the parts that other theories and methods can't reach: how and why a policy-as-discourse approach can inform health-related policy. AB - This article illustrates how conceptualizing policy-as-discourse offers opportunities for those with a vested interest in policy to 'reach the parts that other theories and methods can't reach'. First, it explores the dialogical relationship between theory and method in the context of policy analysis, summarizing contemporary writing on conceptualizing and analysing policy and drawing on the work of Bacchi to describe the theoretical underpinnings of three different policy representations along with methodological corollaries, research practices and disclosures about the world that flow from each. This involves reflecting on three different answers to the question 'what is policy?': considering how policy might be conceptualized and analysed under each and narrating the kind of research stories that emerge. Second, the article focuses on one of Bacchi's representations - policy-as-discourse - to provide readers with a case study of this dialogical relationship and drawing on published research exploring the development of primary care research policy to illustrate what elements of discursive policy analysis might look like. Last, the article concludes by reflecting on the ways in which such an approach may (and may not) prove valuable in analysing health-related policy. PMID- 20164165 TI - Revisiting biographical disruption: exploring individual embodied illness experience in people with terminal cancer. AB - Biographical accounts of illness offer useful insights into the social and adaptive processes of living with chronic illness. Yet there are concerns that the underlying theoretical assumptions of a reflexive self seeking to maintain meaning may not reflect the lived experience of individuals. A narrative emphasis may neglect the importance of emotional/felt experiences; while an analytical focus on disruptive processes may not adequately reflect the totality of actual events. In this study, we explored how well biographical theory supports understanding of individual lived experience. Narratives from 19 individuals identified from General Practice lists with a terminal diagnosis of cancer were analysed using the holistic-form approach described by Lieblich. Participants described an ongoing process of living their life, 'managing' disruptive events and maintaining an overall sense of well-being (narrative form = biographical flow). For a minority, continuity was lost when people's capacity to continue living their everyday lives was overwhelmed (narrative form = fracture). The identified emphasis was on individual creative capacity in the face of terminal illness, highlighting the importance of embodied experience in understanding outcome and need. Maintaining continuity was draining: exhaustion precipitated fracture and thus need for external help to restore continuity. By focusing on feelings associated with overall narrative form, rather than individual disruptive events, we highlight the context in which disruptive events are experienced, and individual perceptions of their relative importance. We conclude that combining narrative and emotion offers new insights into the value of understanding of biographical accounts of illness in the context of individual creative capacity. We discuss the possibilities for new approaches to clinical assessment and management of need. PMID- 20164167 TI - Review: Taking care of yourself in later life: a qualitative study into the use of non-prescription medicines by people aged 60+. AB - The last 40 years have witnessed substantial changes to the experience of later life. Health and life expectancy have improved and the emergence of a putative third age has allowed post-working life to move beyond being a residual social category to become an arena in which later life lifestyles can be constructed. Greater emphasis is now placed on expectations of self-agency and choice. Allied to this is the growing role of consumerism as a way of organizing key aspects of social life. Not only do these changes place increased emphasis on individual responsibility for health, but they also engage individuals in various forms of health consumerism.This study draws on these aspects of contemporary society to provide an explanatory framework for understanding older people's engagement with, and consumption of non-prescription medicines. We present a qualitative study in which we interviewed 22 men and women aged 60 plus who were purchasing or interested in purchasing non-prescription medicines, including complementary and alternative medicines. Our findings suggest that the use of non-prescription medicines is both pluralistic and makeshift. Moreover, while this pluralism led to tensions with conventional bio-medicine, conventional bio-medicine still maintained the legitimacy of its knowledge base. Self-care using non-prescription medicines appeared more governed by hope than by evidence or knowledge of the treatments concerned.We conclude that such pluralism of approach reflects the growing consumerism in health and self-care and that older people may in fact be similar to other age groups in terms of their approach to such commodification. PMID- 20164168 TI - Abstracts of HOPA 2010, the Hematology Oncology Pharmacy Association Annual Meeting. March 24-27, 2010. New Orleans, Louisiana, USA. PMID- 20164169 TI - Risk factors have special relevance for living kidney donors. PMID- 20164170 TI - Craving among long-abstinent smokers: an Internet survey. AB - INTRODUCTION: This survey estimated the prevalence and correlates of craving among long-abstinent smokers. METHODS: We surveyed 403 former smokers (abstinent 1-10 years) via an Internet consumer sample (www.zoomerang.com). RESULTS: Although the majority (59%) of former smokers reported a desire to smoke in the last year, this desire appeared to be clinically significant in only 11%. Those with significant prolonged craving were more nicotine dependent and appeared to have more mental health problems but did differ from other former smokers on demographics or family history of smoking. DISCUSSION: A minority of smokers appears to continue to struggle with cravings long after cessation. Replications in larger more generalizable surveys are needed. In addition, whether prolonged craving indicates risk for relapse needs to be determined. PMID- 20164171 TI - NF-kappaB activation in T cells requires discrete control of IkappaB kinase alpha/beta (IKKalpha/beta) phosphorylation and IKKgamma ubiquitination by the ADAP adapter protein. AB - NF-kappaB activation following engagement of the antigen-specific T cell receptor involves protein kinase C-theta-dependent assembly of the CARMA1-BCL10-MALT1 (CBM) signalosome, which coordinates downstream activation of IkappaB kinase (IKK). We previously identified a novel role for the adhesion- and degranulation promoting adapter protein (ADAP) in regulating the assembly of the CBM complex via an interaction of ADAP with CARMA1. In this study, we identify a novel site in ADAP that is critical for association with the TAK1 kinase. ADAP is critical for recruitment of TAK1 and the CBM complex, but not IKK, to protein kinase C theta. ADAP is not required for TAK1 activation. Although both the TAK1 and the CARMA1 binding sites in ADAP are essential for IkappaB alpha phosphorylation and degradation and NF-kappaB nuclear translocation, only the TAK1 binding site in ADAP is necessary for IKK phosphorylation. In contrast, only the CARMA1 binding site in ADAP is required for ubiquitination of IKKgamma. Thus, distinct sites within ADAP control two key activation responses that are required for NF-kappaB activation in T cells. PMID- 20164172 TI - Rho kinase-2 activation in human endothelial cells drives lysophosphatidic acid mediated expression of cell adhesion molecules via NF-kappaB p65. AB - Endothelial cells play an important role in the recruitment of immune cells to a disease locus through the induced expression of chemokines and cell adhesion molecules (CAMs). The proinflammatory lysophospholipid, lysophosphatidic acid (LPA), which is elevated in multiple inflammatory diseases, is a potent activator of the RhoA/Rho kinase signaling pathway and has been shown to induce the expression of CAMs in endothelial cells. The present study was undertaken to map signal transduction downstream of LPA and to investigate the contributions of the Rho kinase isoforms ROCK1 and ROCK2 to adhesion molecule expression in human umbilical vein endothelial cells. LPA activated Rho kinase within minutes and subsequently the NF-kappaB pathway through phosphorylation of the p65 subunit. The lipid also induced the late expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Pharmacologic inhibition of Rho kinase signaling blocked LPA-induced p65 phosphorylation and suppressed ICAM-1 and VCAM-1 expression. Inhibition of the NF-kappaB pathway had no impact on LPA-induced Rho kinase activation, but inhibited adhesion molecule expression. Small interfering RNA-facilitated knockdown of each isoform identified ROCK2 as the mediator of LPA-driven phosphorylation of NF-kappaB p65 and of ICAM-1 and VCAM-1 mRNA and protein induction. Taken collectively, our data are consistent with Rho kinase being upstream of NF-kappaB in driving LPA-mediated adhesion molecule expression. This study also provides the first evidence of the critical involvement of ROCK2 in LPA-induced CAM expression through activation of the NF kappaB pathway in human endothelial cells. PMID- 20164173 TI - Structural and functional characterization of SporoSAG: a SAG2-related surface antigen from Toxoplasma gondii. AB - Toxoplasma gondii, the etiological agent of toxoplasmosis, utilizes stage specific expression of antigenically distinct glycosylphosphatidylinositol tethered surface coat proteins to promote and establish chronic infection. Of the three infective stages of T. gondii, sporozoites are encapsulated in highly infectious oocysts that have been linked to large scale outbreaks of toxoplasmosis. SporoSAG (surface antigen glycoprotein) is the dominant surface coat protein expressed on the surface of sporozoites. Using a bioinformatic approach, we show that SporoSAG clusters with the SAG2 subfamily of the SAG1 related superfamily (SRS) and is non-polymorphic among the 11 haplogroups of T. gondii strains. In contrast to the immunodominant SAG1 protein expressed on tachyzoites, SporoSAG is non-immunogenic during natural infection. We report the 1.60 A resolution crystal structure of SporoSAG solved using cadmium single anomalous dispersion. SporoSAG crystallized as a monomer and displays unique features of the SRS beta-sandwich fold relative to SAG1 and BSR4. Intriguingly, the structural diversity is localized to the upper sheets of the beta-sandwich fold and may have important implications for multimerization and host cell ligand recognition. The structure of SporoSAG also reveals an unexpectedly acidic surface that contrasts with the previously determined SAG1 and BSR4 structures where a basic surface is predicted to play a role in binding negatively charged glycosaminoglycans. Our structural and functional characterization of SporoSAG provides a rationale for the evolutionary divergence of this key SRS family member. PMID- 20164174 TI - Impairment of embryonic cell division and glycosaminoglycan biosynthesis in glucuronyltransferase-I-deficient mice. AB - We have revealed that in Caenorhabditis elegans, non-sulfated chondroitin is required for normal cell division and cytokinesis at an early developmental stage, whereas heparan sulfate is essential for embryonic morphogenesis in the later stages of development. To clarify the roles of chondroitin sulfate and heparan sulfate in early embryogenesis in mammals, we generated glucuronyltransferase-I (GlcAT-I) knock-out mice by gene targeting. GlcAT-I is an enzyme required for the synthesis of both chondroitin sulfate and heparan sulfate. Here we report that mice with a deletion of GlcAT-I showed remarkable reduction of the synthesis of chondroitin sulfate and heparan sulfate and embryonic lethality before the 8-cell stage because of failed cytokinesis. In addition, treatment of wild-type 2-cell embryos with chondroitinase ABC had marked effects on cell division, although many heparitinase-treated embryos normally developed to blastocysts. Taken together, these results suggest that chondroitin sulfate in mammals, as with non-sulfated chondroitin in C. elegans, is indispensable for embryonic cell division. PMID- 20164175 TI - Reconstitution of a functional Toll-like receptor 5 binding site in Campylobacter jejuni flagellin. AB - Bacterial flagellin is important for intestinal immune homeostasis. Flagellins from most species activate Toll-like receptor 5 (TLR5). The principal bacterial food-borne pathogen Campylobacter jejuni escapes TLR5 recognition, probably due to an alternate flagellin subunit structure. We investigated the molecular basis of TLR5 evasion by aiming to reconstitute TLR5 stimulating activity in live C. jejuni. Both native glycosylated C. jejuni flagellins (FlaA and FlaB) and recombinant proteins purified from Escherichia coli failed to activate NF-kappaB in HEK293 cells expressing TLR5. Introduction of multiple defined regions from Salmonella flagellin into C. jejuni FlaA via a recombinatorial approach revealed three regions critical for the activation of human and mouse TLR5, including a beta-hairpin structure not previously implicated in TLR5 recognition. Surprisingly, this domain was not required for the activation of chicken TLR5, indicating a selective requirement for the beta-hairpin in the recognition of mammalian TLR5. Expression of the active chimeric protein in C. jejuni resulted in secreted glycosylated flagellin that induced a potent TLR5 response. Overall, our results reveal a novel structural requirement for TLR5 recognition of bacterial flagellin and exclude flagellin glycosylation as an additional mechanism of bacterial evasion of the TLR5 response. PMID- 20164176 TI - The single-domain globin from the pathogenic bacterium Campylobacter jejuni: novel D-helix conformation, proximal hydrogen bonding that influences ligand binding, and peroxidase-like redox properties. AB - The food-borne pathogen Campylobacter jejuni possesses a single-domain globin (Cgb) whose role in detoxifying nitric oxide has been unequivocally demonstrated through genetic and molecular approaches. The x-ray structure of cyanide-bound Cgb has been solved to a resolution of 1.35 A. The overall fold is a classic three-on-three alpha-helical globin fold, similar to that of myoglobin and Vgb from Vitreoscilla stercoraria. However, the D region (defined according to the standard globin fold nomenclature) of Cgb adopts a highly ordered alpha-helical conformation unlike any previously characterized members of this globin family, and the GlnE7 residue has an unexpected role in modulating the interaction between the ligand and the TyrB10 residue. The proximal hydrogen bonding network in Cgb demonstrates that the heme cofactor is ligated by an imidazolate, a characteristic of peroxidase-like proteins. Mutation of either proximal hydrogen bonding residue (GluH23 or TyrG5) results in the loss of the high frequency nu(Fe His) stretching mode (251 cm(-1)), indicating that both residues are important for maintaining the anionic character of the proximal histidine ligand. Cyanide binding kinetics for these proximal mutants demonstrate for the first time that proximal hydrogen bonding in globins can modulate ligand binding kinetics at the distal site. A low redox midpoint for the ferrous/ferric couple (-134 mV versus normal hydrogen electrode at pH 7) is consistent with the peroxidase-like character of the Cgb active site. These data provide a new insight into the mechanism via which Campylobacter may survive host-derived nitrosative stress. PMID- 20164177 TI - Nerve growth factor inhibits metalloproteinase-disintegrins and blocks ectodomain shedding of platelet glycoprotein VI. AB - Nerve growth factor (NGF) plays an important role in regulating mammalian neuronal/embryonic development, angiogenesis, and other physiological processes and has recently been investigated as a potential treatment for the neurodegenerative disorder, Alzheimer disease. In this study, we provide evidence that human NGF may also function as a metalloproteinase inhibitor, based on studies of NGF from snake venom. Originally, our aim was to isolate snake venom metalloproteinases targeting platelet receptors and/or ligands relevant to hemostasis and thrombosis, using Ni(2+)-agarose as a purification step based on the conserved metal ion-coordination motif in venom metalloproteinases. However, subsequent analysis of cobra (Naja kaouthia) venom led to the unexpected discovery that cobra venom NGF bound to Ni(2+)-agarose, eluting at approximately 15 mm imidazole, enabling a one-step purification. The identity of the purified protein was confirmed by mass spectrometry and N-terminal sequence analysis. Partial co-purification of NGF within metalloproteinase-enriched venom fractions led us to test whether NGF affected metalloproteinase activity. Venom NGF potently inhibited metalloproteinases isolated from the same or different venom and specifically bound to purified Nk metalloproteinase immobilized on agarose beads. Human NGF also interacted with human metalloproteinases because it blocked metalloproteinase-mediated shedding of the platelet collagen receptor, glycoprotein (GP)VI, and associated with recombinant ADAM10 by surface plasmon resonance. Together, these results suggest that NGF can function as a metalloproteinase inhibitor. PMID- 20164178 TI - A two-step process controls the formation of the bienzyme cysteine synthase complex. AB - The regulation of enzyme activity through the transient formation of multiprotein assemblies plays an important role in the control of biosynthetic pathways. One of the first regulatory complexes to be discovered was cysteine synthase (CS), formed by the pyridoxal 5'-phosphate-dependent enzyme O-acetylserine sulfhydrylase (OASS) and serine acetyltransferase (SAT). These enzymes are at the branch point of the sulfur, carbon, and nitrogen assimilation pathways. Understanding the mechanism of complex formation helps to clarify the role played by CS in the regulation of sulfur assimilation in bacteria and plants. To this goal, stopped-flow fluorescence spectroscopy was used to characterize the interaction of SAT with OASS, at different temperatures and pH values, and in the presence of the physiological regulators cysteine and bisulfide. Results shed light on the mechanism of complex formation and regulation, so far poorly understood. Cysteine synthase assembly occurs via a two-step mechanism involving rapid formation of an encounter complex between the two enzymes, followed by a slow conformational change. The conformational change likely results from the closure of the active site of OASS upon binding of the SAT C-terminal peptide. Bisulfide, the second substrate and a feedback inhibitor of OASS, stabilizes the CS complex mainly by decreasing the back rate of the isomerization step. Cysteine, the product of the OASS reaction and a SAT inhibitor, slightly affects the kinetics of CS formation leading to destabilization of the complex. PMID- 20164179 TI - Reaction mechanism and molecular basis for selenium/sulfur discrimination of selenocysteine lyase. AB - Selenocysteine lyase (SCL) catalyzes the pyridoxal 5'-phosphate-dependent removal of selenium from l-selenocysteine to yield l-alanine. The enzyme is proposed to function in the recycling of the micronutrient selenium from degraded selenoproteins containing selenocysteine residue as an essential component. The enzyme exhibits strict substrate specificity toward l-selenocysteine and no activity to its cognate l-cysteine. However, it remains unclear how the enzyme distinguishes between selenocysteine and cysteine. Here, we present mechanistic studies of selenocysteine lyase from rat. ESI-MS analysis of wild-type and C375A mutant SCL revealed that the catalytic reaction proceeds via the formation of an enzyme-bound selenopersulfide intermediate on the catalytically essential Cys-375 residue. UV-visible spectrum analysis and the crystal structure of SCL complexed with l-cysteine demonstrated that the enzyme reversibly forms a nonproductive adduct with l-cysteine. Cys-375 on the flexible loop directed l-selenocysteine, but not l-cysteine, to the correct position and orientation in the active site to initiate the catalytic reaction. These findings provide, for the first time, the basis for understanding how trace amounts of a selenium-containing substrate is distinguished from excessive amounts of its cognate sulfur-containing compound in a biological system. PMID- 20164180 TI - A novel LZAP-binding protein, NLBP, inhibits cell invasion. AB - LXXLL/leucine zipper-containing alternative reading frame (ARF)-binding protein (LZAP) was recently shown to function as a tumor suppressor through inhibition of the NF-kappaB signaling pathway. LZAP is also known as a negative regulator of cell invasion, and its expression was demonstrated to be reduced in several tumor tissues. However, the molecular mechanism of the negative effect of LZAP on cell invasion is unclear. In this study, we identify NLBP as a novel LZAP-binding protein using tandem affinity purification. We demonstrate the negative effects of NLBP on cell invasion and the NF-kappaB signaling pathway. NLBP expression was not detected in hepatocellular carcinoma cells with strong invasive activity, whereas its expression was detected in a hepatocellular carcinoma cell line with no invasive activity. We also demonstrate that these two proteins mutually affect the stability of each other by inhibiting ubiquitination of the other protein. Based on these results, we suggest that NLBP may act as a novel tumor suppressor by inhibiting cell invasion, blocking NF-kappaB signaling, and increasing stability of the LZAP protein. PMID- 20164181 TI - Critical role of the platelet-derived growth factor receptor (PDGFR) beta transmembrane domain in the TEL-PDGFRbeta cytosolic oncoprotein. AB - The fusion of TEL with platelet-derived growth factor receptor (PDGFR) beta (TPbeta) is found in a subset of patients with atypical myeloid neoplasms associated with eosinophilia and is the archetype of a larger group of hybrid receptors that are produced by rearrangements of PDGFR genes. TPbeta is activated by oligomerization mediated by the pointed domain of TEL/ETV6, leading to constitutive activation of the PDGFRbeta kinase domain. The receptor transmembrane (TM) domain is retained in TPbeta and in most of the described PDGFRbeta hybrids. Deletion of the TM domain (DeltaTM-TPbeta) strongly impaired the ability of TPbeta to sustain growth factor-independent cell proliferation. We confirmed that TPbeta resides in the cytosol, indicating that the PDGFRbeta TM domain does not act as a transmembrane domain in the context of the hybrid receptor but has a completely different function. The DeltaTM-TPbeta protein was expressed at a lower level because of increased degradation. It could form oligomers, was phosphorylated at a slightly higher level, co-immunoprecipitated with the p85 adaptor protein, but showed a much reduced capacity to activate STAT5 and ERK1/2 in Ba/F3 cells, compared with TPbeta. In an in vitro kinase assay, DeltaTM-TPbeta was more active than TPbeta and less sensitive to imatinib, a PDGFR inhibitor. In conclusion, we show that the TM domain is required for TPbeta-mediated signaling and proliferation, suggesting that the activation of the PDGFRbeta kinase domain is not enough for cell transformation. PMID- 20164182 TI - Rga4 modulates the activity of the fission yeast cell integrity MAPK pathway by acting as a Rho2 GTPase-activating protein. AB - Rho GTPase-activating proteins (GAPs) are responsible for the inactivation of Rho GTPases, which are involved in the regulation of critical biological responses in eukaryotic cells, ranging from cell cycle control to cellular morphogenesis. The genome of fission yeast Schizosaccharomyces pombe contains six genes coding for putative Rho GTPases, whereas nine genes code for predicted Rho GAPs (Rga1 to Rga9). One of them, Rga4, has been recently described as a Cdc42 GAP, involved in the control of cell diameter and symmetry in fission yeast. In this work we show that Rga4 is also a Rho2 GAP that negatively modulates the activity of the cell integrity pathway and its main effector, MAPK Pmk1. The DYRK-type protein kinase Pom1, which regulates both the localization and phosphorylation state of Rga4, is also a negative regulator of the Pmk1 pathway, but this control is not dependent upon the Rga4 role as a Rho2-GAP. Hence, two subsets of Rga4 negatively regulate Cdc42 and Rho2 functions in a specific and unrelated way. Finally, we show that Rga7, another Rho2 GAP, down-regulates the Pmk1 pathway in addition to Rga4. These results reinforce the notion of the existence of complex mechanisms determining the selectivity of Rho GAPs toward Rho GTPases and their functions. PMID- 20164183 TI - A novel protease-activated receptor-1 interactor, Bicaudal D1, regulates G protein signaling and internalization. AB - Protease-activated receptor-1 (PAR1) is a G protein-coupled receptor that plays critical roles in cancer, angiogenesis, inflammation, and thrombosis. Proteolytic cleavage of the extracellular domain of PAR1 generates a tethered ligand that activates PAR1 in an unusual intramolecular mode. The signal emanating from the irreversibly cleaved PAR1 is terminated by G protein uncoupling and internalization; however, the mechanisms of PAR1 signal shut off still remain unclear. Using a yeast two-hybrid screen, we identified Bicaudal D1 (BicD1) as a direct interactor with the C-terminal cytoplasmic domain of PAR1. BICD was originally identified as an essential developmental gene associated with mRNA and Golgi-endoplasmic reticulum transport. We discovered a novel function of BicD1 in the modulation of G protein signaling, cell proliferation, and endocytosis downstream of PAR1. BicD1 and its C-terminal CC3 domain inhibited PAR1 signaling to G(q)-phospholipase C-beta through coiled-coil interactions with the cytoplasmic 8th helix of PAR1. Unexpectedly, BicD1 was also found to be a potent suppressor of PAR1-driven proliferation of breast carcinoma cells. The growth suppressing effects of BicD1 required the ability to interact with the 8th helix of PAR1. Silencing of BicD1 expression impaired endocytosis of PAR1, and BicD1 co localized with PAR1 and tubulin, implicating BicD1 as an important adapter protein involved in the transport of PAR1 from the plasma membrane to endosomal vesicles. Together, these findings provide a link between PAR1 signal termination and internalization through the non-G protein effector, BicD1. PMID- 20164184 TI - Hepatitis B virus protein X-induced expression of the CXC chemokine IP-10 is mediated through activation of NF-kappaB and increases migration of leukocytes. AB - Interferon-gamma inducible protein 10 (IP-10) involves inflammatory cell recruitment and cellular immune damage during virus infection. Although an increase of the peripheral IP-10 level is known in HBV-infected patients, the molecular basis of HBV infection inducing IP-10 expression has remained elusive. In the present study, we demonstrate that hepatitis B virus protein X (HBx) increases IP-10 expression in a dose-dependent manner. Transfection of the HBx expressing vector into HepG2 cells results in nuclear translocation of NF-kappaB, which directly binds the promoter of IP-10 at positions from -122 to -113, thus facilitating transcription. The addition of the NF-kappaB inhibitor blocks the effect of HBx on IP-10 induction. In parallel, increase of NF-kappaB subunits p65 and p50 in HepG2 cells also augments IP-10 expression. Furthermore, we show that HBx induces activation of NF-kappaB through the TRAF2/TAK1 signaling pathway, leading to up-regulation of IP-10 expression. As a consequence, up-regulation of IP-10 may mediate the migration of peripheral blood leukocytes in a NF-kappaB dependent manner. In conclusion, we report a novel molecular mechanism of HBV infection inducing IP-10 expression, which involves viral protein HBx affecting NF-kappaB pathway, leading to transactivation of the IP-10 promoter. Our study provides insight into the migration of leukocytes in response to HBV infection, thus causing immune pathological injury of liver. PMID- 20164185 TI - Interactions among HAMP domain repeats act as an osmosensing molecular switch in group III hybrid histidine kinases from fungi. AB - The members of group III hybrid histidine kinases (HHK) are ubiquitous in fungi. Group III HHK have been implicated to function as osmosensors in the high osmolarity glycerol (HOG) pathway that is essential for fungal survival under high osmolarity stress. Recent literature suggests that group III HHK are also involved in conidia formation, virulence in several filamentous fungi, and are an excellent molecular target for antifungal agents. Thus, group III HHK constitute a very important group of sensor kinases. Structurally, group III HHK are distinct from Sln1p, the osmosensing HHK that regulates the HOG pathway in Saccharomyces cerevisiae. Group III HHK lack any transmembrane domain and typically contain HAMP domain repeats at the N terminus. Until now, it is not clear how group III HHK function as an osmosensor to regulate the HOG pathway. To investigate this, we undertook molecular characterization of DhNIK1, an ortholog from osmotolerant yeast Debaryomyces hansenii. We show here that DhNIK1 could complement sln1 mutation in S. cerevisiae thereby confirming its role as a bona fide osmosensor. We further investigated the role of HAMP domains by deleting them systematically. Our results clearly indicate that the HAMP4 domain is crucial for osmosensing by DhNik1p. Most importantly, we also show that the alternative interaction among the HAMP domains regulates the activity of DhNik1p like an "on-off switch" and thus provides, for the first time, an insight into the molecular mechanism of osmosensing by this group of HHKs. PMID- 20164186 TI - A novel glucosyltransferase is required for glycosylation of a serine-rich adhesin and biofilm formation by Streptococcus parasanguinis. AB - Fap1-like serine-rich glycoproteins are conserved in streptococci, staphylococci, and lactobacilli, and are required for bacterial biofilm formation and pathogenesis. Glycosylation of Fap1 is mediated by a gene cluster flanking the fap1 locus. The key enzymes responsible for the first step of Fap1 glycosylation are glycosyltransferases Gtf1 and Gtf2. They form a functional enzyme complex that catalyzes the transfer of N-acetylglucosamine (GlcNAc) residues to the Fap1 polypeptide. However, until now nothing was known about the subsequent step in Fap1 glycosylation. Here, we show that the second step in Fap1 glycosylation is catalyzed by nucleotide-sugar synthetase-like (Nss) protein. The nss gene located upstream of fap1 is also highly conserved in streptococci and lactobacilli. Nss deficient mutants failed to catalyze the second step of Fap1 glycosylation in vivo in Streptococcus parasanguinis and in a recombinant Fap1 glycosylation system. Nss catalyzed the direct transfer of the glucosyl residue to the GlcNAc modified Fap1 substrate in vitro, demonstrating that Nss is a glucosyltransferase. Thus we renamed Nss as glucosyltransferase 3 (Gtf3). A gtf3 mutant exhibited a biofilm defect. Taken together, we conclude that this new glucosyltransferase mediates the second step of Fap1 glycosylation and is required for biofilm formation. PMID- 20164187 TI - MicroRNA-27b contributes to lipopolysaccharide-mediated peroxisome proliferator activated receptor gamma (PPARgamma) mRNA destabilization. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) gained considerable interest as a therapeutic target during chronic inflammatory diseases. Remarkably, the pathogenesis of diseases such as multiple sclerosis or Alzheimer is associated with impaired PPARgamma expression. Considering that regulation of PPARgamma expression during inflammation is largely unknown, we were interested in elucidating underlying mechanisms. To this end, we initiated an inflammatory response by exposing primary human macrophages to lipopolysaccharide (LPS) and observed a rapid decline of PPARgamma1 expression. Because promoter activities were not affected by LPS, we focused on mRNA stability and noticed a decreased mRNA half-life. As RNA stability is often regulated via 3'-untranslated regions (UTRs), we analyzed the impact of the PPARgamma-3'-UTR by reporter assays using specific constructs. LPS significantly reduced luciferase activity of the pGL3 PPARgamma-3'-UTR, suggesting that PPARgamma1 mRNA is destabilized. Deletion or mutation of a potential microRNA-27a/b (miR-27a/b) binding site within the 3'-UTR restored luciferase activity. Moreover, inhibition of miR-27b, which was induced upon LPS exposure, partially reversed PPARgamma1 mRNA decay, whereas miR-27b overexpression decreased PPARgamma1 mRNA content. In addition, LPS further reduced this decay. The functional relevance of miR-27b-dependent PPARgamma1 decrease was proven by inhibition or overexpression of miR-27b, which affected LPS-induced expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFalpha) and interleukin (IL)-6. We provide evidence that LPS-induced miR 27b contributes to destabilization of PPARgamma1 mRNA. Understanding molecular mechanisms decreasing PPARgamma might help to better appreciate inflammatory diseases. PMID- 20164188 TI - The carboxyl-terminal domain of connexin43 is a negative modulator of neuronal differentiation. AB - Connexin43 (Cx43) is widely expressed in embryonic brain, and its expression becomes restricted mainly to astrocytes as the central nervous system matures. Recent studies have indicated that Cx43 plays important, nonchannel, roles during central nervous system development by affecting neuronal cell migration. Here, we evaluated the effects of Cx43 on neuronal differentiation. For that we used an in vitro model of neural cell development (neurospheres) to evaluate, through immunocytochemistry, electrophysiology, and molecular biology, the degree of neuronal maturation from neurospheres derived from wild-type (WT) and Cx43-null mice. Our results indicate that Cx43 is a negative modulator of neuronal differentiation. The percent neurospheres containing differentiated neurons and the number of cells displaying inward currents were significantly higher in Cx43 null than in WT littermate neurospheres. Knockdown of Cx43 with small interfering RNA increased the number of WT neurospheres generating differentiated neurons. Blockade of gap junctional communication with carbenoxolone did not induce neuronal differentiation in WT neurospheres. Transfection of Cx43-null neurospheres with Cx43 mutants revealed that Cx43 carboxyl terminus prevents neuronal maturation. In agreement with these in vitro data, in situ analysis of embryonic day 16 brains revealed increased beta-III-tubulin expression in germinal zones of Cx43-null compared with that of WT littermates. These results indicate that Cx43, and specifically its carboxyl terminus, is crucial for signaling mechanisms preventing premature neuronal differentiation during embryonic brain development. PMID- 20164189 TI - Perturbations in mitochondrial dynamics induced by human mutant PINK1 can be rescued by the mitochondrial division inhibitor mdivi-1. AB - Mutations in the mitochondrial encoded protein PTEN-induced putative kinase 1 (PINK1) cause autosomal recessive Parkinson disease (PD). In mammalian cells, mutant PINK1 has been reported to promote fission or inhibit fusion in mitochondria; however, the mechanism by which this process occurs remains elusive. Using an ecdysone-inducible expression system in mammalian dopaminergic neuronal cells, we report here that human mutant PINK1 (L347P and W437X) mediates an overall fission effect by increasing the ratio of mitochondrial fission over fusion proteins, leading to excessive dysfunctional fragmented mitochondria. Knocking down endogenous Pink1 produces similar effects. In contrast, overexpressing human wild type PINK1 produces a pro-fusion effect by increasing the ratio of mitochondrial fusion/fission proteins without resulting in functionally compromised mitochondria. Parkin knockdown blocks the imbalance in fission/fusion proteins. Furthermore, overexpressing parkin and ubiquitin increases degradation of the mitochondrial fission hFis1 protein, suggesting PINK1 and parkin maintain proper mitochondrial function and integrity via the fission/fusion machinery. Through genetic manipulations and treatment with the small molecule mitochondrial division inhibitor (mdivi-1), which inhibits DLP1/Drp1, both structural and functional mitochondrial defects induced by mutant PINK1 were attenuated, highlighting a potential novel therapeutic avenue for Parkinson disease. PMID- 20164190 TI - The acyclic 2,4-diaminopyrimidine nucleoside phosphonate acts as a purine mimetic in HIV-1 reverse transcriptase DNA polymerization. AB - The acyclic pyrimidine nucleoside phosphonate (ANP) phosphonylmethoxyethoxydiaminopyrimidine (PMEO-DAPym) differs from other ANPs in that the aliphatic alkyloxy linker is bound to the C-6 of the 2,4 diaminopyrimidine base through an ether bond, instead of the traditional alkyl linkage to the N-1 or N-9 of the pyrimidine or purine base. In this study, we have analyzed the molecular interactions between PMEO-DAPym-diphosphate (PMEO DAPym-pp) and the active sites of wild-type (WT) and drug-resistant HIV-1 reverse transcriptase (RT). Pre-steady-state kinetic analyses revealed that PMEO-DAPym-pp is a good substrate for WT HIV-1 RT: its catalytic efficiency of incorporation (k(pol)/K(d)) is only 2- to 3-fold less than that of the corresponding prototype purine nucleotide analogs PMEA-pp or (R)PMPA-pp. HIV-1 RT recognizes PMEO-DAPym pp as a purine base instead of a pyrimidine base and incorporates it opposite to thymine (in DNA) or uracil (in RNA). Molecular modeling demonstrates that PMEO DAPym-pp fits into the active site of HIV-1 RT without significant perturbation of key amino acid residues and mimics an open incomplete purine ring that allows the canonical Watson-Crick base pairing to be maintained. PMEO-DAPym-pp is incorporated more efficiently than (R)PMPA-pp by mutant K65R HIV-1 RT and is not as efficiently excised as (R)PMPA by HIV-1 RT containing thymidine analog mutations. Overall, the data revealed that PMEO- DAPym represents the prototype compound of a novel class of pyrimidine acyclic nucleoside phosphonates that are recognized as a purine nucleotide and should form the rational basis for the design and development of novel purine nucleo(s)(t)ide mimetics as potential antiviral or antimetabolic agents. PMID- 20164191 TI - A multifunctional mannosyltransferase family in Candida albicans determines cell wall mannan structure and host-fungus interactions. AB - The cell wall proteins of fungi are modified by N- and O-linked mannosylation and phosphomannosylation, resulting in changes to the physical and immunological properties of the cell. Glycosylation of cell wall proteins involves the activities of families of endoplasmic reticulum and Golgi-located glycosyl transferases whose activities are difficult to infer through bioinformatics. The Candida albicans MNT1/KRE2 mannosyl transferase family is represented by five members. We showed previously that Mnt1 and Mnt2 are involved in O-linked mannosylation and are required for virulence. Here, the role of C. albicans MNT3, MNT4, and MNT5 was determined by generating single and multiple MnTDelta null mutants and by functional complementation experiments in Saccharomyces cerevisiae. CaMnt3, CaMnt4, and CaMnt5 did not participate in O-linked mannosylation, but CaMnt3 and CaMnt5 had redundant activities in phosphomannosylation and were responsible for attachment of approximately half of the phosphomannan attached to N-linked mannans. CaMnt4 and CaMnt5 participated in N-mannan branching. Deletion of CaMNT3, CaMNT4, and CaMNT5 affected the growth rate and virulence of C. albicans, affected the recognition of the yeast by human monocytes and cytokine stimulation, and led to increased cell wall chitin content and exposure of beta-glucan at the cell wall surface. Therefore, the MNT1/KRE2 gene family participates in three types of protein mannosylation in C. albicans, and these modifications play vital roles in fungal cell wall structure and cell surface recognition by the innate immune system. PMID- 20164192 TI - Cross-phosphorylation between Arabidopsis thaliana sucrose nonfermenting 1 related protein kinase 1 (AtSnRK1) and its activating kinase (AtSnAK) determines their catalytic activities. AB - Arabidopsis thaliana sucrose nonfermenting 1-related protein kinase 1 complexes belong to the SNF1/AMPK/SnRK1 protein kinase family that shares an ancestral function as central regulators of metabolism. In A. thaliana, the products of AtSnAK1 and AtSnAK2, orthologous to yeast genes, have been shown to autophosphorylate and to phosphorylate/activate the AtSnRK1.1 catalytic subunit on Thr(175). The phosphorylation of these kinases has been investigated by site directed mutagenesis and tandem mass spectrometry. The autophosphorylation site of AtSnAK2 was identified as Thr(154), and it was shown to be required for AtSnAK catalytic activity. Interestingly, activated AtSnRK1 exerted a negative feedback phosphorylation on AtSnAK2 at Ser(261) (Ser(260) of AtSnAK1) that was dependent on AtSnAK autophosphorylation. The dynamics of these reciprocal phosphorylation events on the different kinases was established, and structural modeling allowed clarification of the topography of the AtSnAK phosphorylation sites. A mechanism is proposed to explain the observed changes in the enzymatic properties of each kinase triggered by these phosphorylation events. PMID- 20164193 TI - Hantavirus nucleocapsid protein has distinct m7G cap- and RNA-binding sites. AB - Hantaviruses, members of the Bunyaviridae family, are emerging category A pathogens that carry three negative stranded RNA molecules as their genome. Hantavirus nucleocapsid protein (N) is encoded by the smallest S segment genomic RNA (viral RNA). N specifically binds mRNA caps and requires four nucleotides adjacent to the cap for high affinity binding. We show that the N peptide has distinct cap- and RNA-binding sites that independently interact with mRNA cap and viral genomic RNA, respectively. In addition, N can simultaneously bind with both mRNA cap and vRNA. N undergoes distinct conformational changes after binding with either mRNA cap or vRNA or both mRNA cap and vRNA simultaneously. Hantavirus RNA dependent RNA polymerase (RdRp) uses a capped RNA primer for transcription initiation. The capped RNA primer is generated from host cell mRNA by the cap snatching mechanism and is supposed to anneal with the 3' terminus of vRNA template during transcription initiation by single G-C base pairing. We show that the capped RNA primer binds at the cap-binding site and induces a conformational change in N. The conformationally altered N with a capped primer loaded at the cap-binding site specifically binds the conserved 3' nine nucleotides of vRNA and assists the bound primer to anneal at the 3' terminus. We suggest that the cap binding site of N, in conjunction with RdRp, plays a key role during the transcription and replication initiation of vRNA genome. PMID- 20164195 TI - The phospholipid-binding protein SESTD1 is a novel regulator of the transient receptor potential channels TRPC4 and TRPC5. AB - TRPC4 and TRPC5 are two closely related members of the mammalian transient receptor potential cation channel family that have been implicated in important physiological functions, such as growth cone guidance and smooth muscle contraction. To further unravel the role of TRPC4 and TRPC5 in these processes in vivo, detailed information about the molecular composition of native channel complexes and their association with cellular signaling networks is needed. We therefore searched a human aortic cDNA library for novel TRPC4-interacting proteins using a modified yeast two-hybrid assay. This screen identified SESTD1, a previously uncharacterized protein containing a lipid-binding SEC14-like domain as well as spectrin-type cytoskeleton interaction domains. SESTD1 was found to associate with TRPC4 and TRPC5 via the channel's calmodulin- and inositol 1,4,5 trisphosphate receptor-binding domain. In functional studies, we demonstrate that SESTD1 binds several phospholipid species in vitro and is essential for efficient receptor-mediated activation of TRPC5. Notably, phospholipid binding to SESTD1 was Ca(2+)-dependent. Because TRPC4 and -5 conduct Ca(2+), SESTD1-channel signaling may be bidirectional and also couple TRPC activity to lipid signaling through SESTD1. The modulation of TRPC channel function by specific lipid-binding proteins, such as SESTD1, adds another facet to the complex regulation of these channels complementary to the previously described effects of direct channel phospholipid interaction. PMID- 20164194 TI - Crystal structure of human REV7 in complex with a human REV3 fragment and structural implication of the interaction between DNA polymerase zeta and REV1. AB - DNA polymerase zeta (Polzeta) is an error-prone DNA polymerase involved in translesion DNA synthesis. Polzeta consists of two subunits: the catalytic REV3, which belongs to B family DNA polymerase, and the noncatalytic REV7. REV7 also interacts with REV1 polymerase, which is an error-prone Y family DNA polymerase and is also involved in translesion DNA synthesis. Cells deficient in one of the three REV proteins and those deficient in all three proteins show similar phenotype, indicating the functional collaboration of the three REV proteins. REV7 interacts with both REV3 and REV1 polymerases, but the structure of REV7 or REV3, as well as the structural and functional basis of the REV1-REV7 and REV3 REV7 interactions, remains unknown. Here we show the first crystal structure of human REV7 in complex with a fragment of human REV3 polymerase (residues 1847 1898) and reveal the mechanism underlying REV7-REV3 interaction. The structure indicates that the interaction between REV7 and REV3 creates a structural interface for REV1 binding. Furthermore, we show that the REV7-mediated interactions are responsible for DNA damage tolerance. Our results highlight the function of REV7 as an adapter protein to recruit Polzeta to a lesion site. REV7 is alternatively called MAD2B or MAD2L2 and also involved in various cellular functions such as signal transduction and cell cycle regulation. Our results will provide a general structural basis for understanding the REV7 interaction. PMID- 20164196 TI - Dynamic regulation of CD45 lateral mobility by the spectrin-ankyrin cytoskeleton of T cells. AB - The leukocyte common antigen, CD45, is a critical immune regulator whose activity is modulated by cytoskeletal interactions. Components of the spectrin-ankyrin cytoskeleton have been implicated in the trafficking and signaling of CD45. We have examined the lateral mobility of CD45 in resting and activated T lymphocytes using single-particle tracking and found that the receptor has decreased mobility caused by increased cytoskeletal contacts in activated cells. Experiments with cells that have disrupted betaI spectrin interactions show decreased cytoskeletal contacts in resting cells and attenuation of receptor immobilization in activated cells. Applying two types of population analyses to single-particle tracking trajectories, we find good agreement between the diffusion coefficients obtained using either a mean squared displacement analysis or a hidden Markov model analysis. Hidden Markov model analysis also reveals the rate of association and dissociation of CD45-cytoskeleton contacts, demonstrating the importance of this analysis for measuring cytoskeleton binding events in live cells. Our findings are consistent with a model in which multiple cytoskeletal contacts, including those with spectrin and ankyrin, participate in the regulation of CD45 lateral mobility. These interactions are a major factor in CD45 immobilization in activated cells. Furthermore, cellular activation leads to CD45 immobilization by reduction of the CD45-cytoskeleton dissociation rate. Short peptides that mimic spectrin repeat domains alter the association rate of CD45 to the cytoskeleton and cause an apparent decrease in dissociation rates. We propose a model for CD45 cytoskeleton interactions and conclude that the spectrin-ankyrin-actin network is an essential determinant of immunoreceptor mobility. PMID- 20164198 TI - Characterization of methicillin-resistant Staphylococcus aureus ST398 from cases of bovine mastitis. AB - OBJECTIVES: Twenty-five MRSA ST398 isolates from cases of bovine clinical mastitis and two isolates from farm personnel collected from 17 dairy farms in Germany were investigated for genetic relatedness, antimicrobial resistance and virulence properties. METHODS: Genomic relationships were determined by ApaI PFGE, spa typing, SCCmec typing and dru typing. Antimicrobial resistance phenotypes were determined by broth microdilution. Resistance and virulence genes were detected via a diagnostic DNA microarray and specific PCRs. RESULTS: Nine major ApaI PFGE patterns were detected. Three spa types (t011, t034 and t2576) and two SCCmec types (IV and V) were identified. Five different dru types were seen with dt11a being predominant. All isolates were negative for Panton Valentine leucocidin, enterotoxin and exfoliative toxin genes. Ten resistance patterns were observed with 11 (40.7%) isolates being resistant to only beta lactam antibiotics and tetracyclines. Several resistance genes were detected: blaZ (penicillin resistance); tet(M), tet(K) and tet(L) (tetracycline resistance); erm(A), erm(B), erm(C) and erm(T) (macrolide/lincosamide/streptogramin B resistance); aacA-aphD, aphA3, aadD and spc (aminoglycoside or aminocyclitol resistance); fexA (phenicol resistance); dfrK (trimethoprim resistance); and vga(A) and vga(C) (pleuromutilin/lincosamide/streptogramin A resistance). The two human isolates were indistinguishable in their genotypic and phenotypic characteristics from the mastitis isolates of the same farm. CONCLUSIONS: As previously described for ST398 from swine, isolates of this sequence type from cases of bovine mastitis also demonstrated a high degree of variability when ApaI PFGE profiles and other genotypic and phenotypic characteristics were compared. A uniform virulence gene pattern appeared to be conserved between ST398 isolates from both animal species. PMID- 20164197 TI - Phosphorylation of cardiac troponin I at protein kinase C site threonine 144 depresses cooperative activation of thin filaments. AB - There is evidence for PKC-dependent multisite phosphorylation of cardiac troponin I (cTnI) at Ser-23 and Ser-24 (also PKA sites) in the cardiac-specific N-terminal extension and at Thr-144, a unique residue in the inhibitory region. The functional effect of these phosphorylations in combination is of interest in view of data indicating intramolecular interaction between the N-terminal extension and the inhibitory region of cTnI. To determine the role of PKC-dependent phosphorylation of cTnI on sarcomeric function, we measured contractile regulation at multiple levels of complexity. Ca(2+) binding to thin filaments reconstituted with either cTnI(wild-type) or pseudo-phosphorylated cTnI(S23D/S24D), cTnI(T144E), and cTnI(S23D/S24D/T144E) was determined. Compared with controls regulated by cTnI(wild-type), thin filaments with cTnI(S23D/S24D) and cTnI(S23D/S24D/T144E) exhibited decreased Ca(2+) sensitivity. In contrast, there was no significant difference between Ca(2+) binding to thin filaments with cTnI(wild-type) and with cTnI(T144E). Studies of the pCa-force relations in skinned papillary fibers regulated by these forms of cTnI yielded similar results. However, in both the Ca(2+) binding measurements and the skinned fiber tension measurements, the presence of cTnI(S23D/S24D/T144E) induced a much lower Hill coefficient than either wild type, S23D/S24D, or T144E. These data highlight the importance of thin filament-based cooperative mechanisms in cardiac regulation, with implications for mechanisms of control of function in normal and pathological hearts. PMID- 20164199 TI - Relative contributions of baseline patient characteristics and the choice of statistical methods to the variability of genotypic resistance scores: the example of didanosine. AB - BACKGROUND: Our aim was to investigate the respective role of statistical methodology and patients' baseline characteristics in the selection of mutations included in genotypic resistance scores. METHODS: As an example, the FORUM database on didanosine including 1453 patients was used. We split this population into four samples based on countries of enrolment (France n = 474, Italy n = 440, USA/Canada n = 219, others n = 320). We used both a continuous outcome measure (the viral load reduction at week 8) and a binary outcome measure (viral load decline at week 8 <0.6 log(10) or > or =0.6 log(10)) and both parametric and non parametric methods for each outcome. RESULTS: Overall, 61 distinct mutations were selected by at least one method in at least one data set. The variability due to baseline characteristics varies from 79% to 88%, i.e. for a given method applied to the four data sets >80% of the mutations are selected only once. The variability induced by the methodology varies from 49% to 56%, i.e. for a given data set approximately 50% of the mutations are selected by at least two methods. CONCLUSIONS: Baseline patient characteristics contribute more than the choice of statistical method to the variability of the mutations to be included in the genotypic resistance scores. PMID- 20164200 TI - Reduction in synaptic GABA release contributes to target-selective elevation of PVN neuronal activity in rats with myocardial infarction. AB - Neuronal activity in the paraventricular nucleus (PVN) is known to be elevated in rats with heart failure. However, the type of neurons involved and the underlying synaptic mechanisms remain unknown. Here we examined spontaneous firing activity and synaptic currents in presympathetic PVN neurons in rats with myocardial infarction (MI), using slice patch clamp combined with the retrograde labeling technique. In PVN neurons projecting to the rostral ventrolateral medulla (PVN RVLM), MI induced a significant increase in basal firing rate (1.79 to 3.02 Hz, P < 0.05) and a reduction in the frequency of spontaneous (P < 0.05) and miniature (P < 0.01) inhibitory postsynaptic currents (IPSCs). In addition, MI induced an increase in the paired-pulse ratio of evoked IPSCs (P < 0.05). Bicuculline, a GABA(A) receptor antagonist, increased the firing rate of PVN-RVLM neurons in sham-operated (1.21 to 2.74 Hz, P < 0.05) but not MI (P > 0.05) rats. In contrast, in PVN neurons projecting to the intermediolateral horn of the spinal cord (PVN-IML), MI did not induce any significant changes in the basal firing rate and the properties of spontaneous and miniature IPSCs. The properties of spontaneous excitatory postsynaptic currents (EPSCs) were not altered in either neuron group. In conclusion, our results indicate that MI induces an elevation of firing activity in PVN-RVLM but not in PVN-IML neurons and that the elevated firing rate is largely due to a decrease in GABA release. These results provide evidence for a novel target-selective synaptic plasticity in the PVN that is associated with the sympathetic hyperactivity commonly seen in heart failure. PMID- 20164201 TI - Vasoactivity of hydrogen sulfide in normoxic and anoxic turtles (Trachemys scripta). AB - Systemic vascular resistance (R(sys)) of freshwater turtles increases substantially during anoxia, but the underlying mechanisms are not fully understood. We investigated whether hydrogen sulfide (H(2)S), an endogenously produced metabolite believed to be an O(2) sensor/transducer of vasomotor tone, contributes to the increased R(sys) of anoxic red-eared slider turtles (Trachemys scripta). Vascular infusion of the H(2)S donor NaHS in anesthetized turtles at 21 degrees C and fully recovered normoxic turtles at 5 degrees C and 21 degrees C revealed H(2)S to be a potent vasoconstrictor of the systemic circulation. Likewise, wire myography of isolated turtle mesenteric and pulmonary arteries demonstrated H(2)S to mediate an anoxia-induced constriction. Intriguingly, however, NaHS did not exert vasoconstrictory effects during anoxia (6 h at 21 degrees C; 14 days at 5 degrees C) when plasma H(2)S concentration, estimated from the colorimetric measurement of plasma acid-labile sulfide concentration, likely increased by approximately 3- and 4-fold during anoxia at 21 degrees C, and 5 degrees C, respectively. Yet, blockade of endogenous H(2)S production by DL propargylglycine or hydroxylamine (0.44 mmol/kg) partially reversed the decreased systemic conductance (G(sys)) exhibited by 5 degrees C anoxic turtles. These findings suggest that the signal transduction pathway of H(2)S-mediated vasoactivity is either maximally activated in the systemic circulation of anoxic turtles and/or that it is oxygen dependent. PMID- 20164202 TI - Chronic administration of brain-derived neurotrophic factor in the hypothalamic paraventricular nucleus reverses obesity induced by high-fat diet. AB - An acute injection of brain-derived neurotrophic factor (BDNF) in the hypothalamic paraventricular nucleus (PVN) reduces body weight by decreasing feeding and increasing energy expenditure (EE), in animals on standard laboratory chow. Animals have divergent responses to a high-fat diet (HFD) exposure, with some developing obesity and others remaining lean. In the current study, we tested two hypotheses: 1) BDNF in the PVN reverses HFD-induced obesity, and 2) animals with higher body fat have a greater physiological response to BDNF than those with less body fat. Eighty-four 10-wk old rats were allowed HFD ad libitum for 9 wk and then prepared with bilateral PVN cannulas. Animals were then divided into tertiles based on their body fat rank: high, intermediate, and low (H, I, and L). Each group was further divided into 2 subgroups and then PVN injected with BDNF or control (artificial cerebrospinal fluid, aCSF) every other day for 3 wk. Energy intake (EI), body weight, and body composition were measured. At study's end, rats were killed to allow measurement of other metabolic indices. In parallel, another 12 rats were fed control diet (CD), PVN-cannulated and injected with aCSF. HFD exposure induced obesity, particularly in the H body fat group, with a significant increase in EI, body weight, fat mass, liver size, and serum glucose, triglycerides, insulin, and leptin. BDNF significantly reduced EI, body weight, body fat, lean mass, and serum metabolic indices. These BDNF effects were greatest in the H body fat group. These data indicate that BDNF reduced HFD induced obesity and metabolic syndrome-like measures, and the animals with the most body fat had the most significant response to BDNF. PMID- 20164203 TI - Effects of sex and estrogen on chicken ductus arteriosus reactivity. AB - Sex hormones have an important influence on cardiovascular physiology and pathophysiology and sex differences in vascular reactivity have been widely demonstrated. In the present study we hypothesized 1) the presence of sexual dimorphism in chicken ductus arteriosus (DA) responsiveness to contractile and relaxant stimuli and 2) that estrogens are vasoactive in the chicken DA. In vitro contractions (assessed with a wire myograph) induced by normoxia, KCl, 4 aminopyridine, norepinephrine, phenylephrine, U46619, or endothelin-1, as well as relaxations induced by ACh, sodium nitroprusside, BAY 41-2272, PGE(2), isoproterenol, forskolin,Y-27632, and hydroxyfasudil were not significantly different between males and females. The estrogen 17beta-estradiol elicited concentration-dependent relaxation of KCl-, phenylephrine-, and oxygen-induced active tone in male and female chicken DA. The stereoisomer 17alpha-estradiol showed lesser relaxant effects, and the selective estrogen receptor (ER) agonists 4,4',4''-(4-propyl-[(1)H]pyrazole-1,3,5-triyl)tris-phenol (ERalpha) and 2,3-bis(4 hydroxyphenyl)-propionitrile (ERbeta) did not show any effect. There were no sex differences in the responses to estrogen. Endothelium removal or the presence of the soluble guanylate cyclase inhibitor ODQ, the K(+) channel blockers tetraethylammonium, glibenclamide, and charybdotoxin, or the ER antagonist fulvestrant did not modify 17beta-estradiol-induced relaxation. CaCl(2) (30 muM 10 mM) induced concentration-dependent contraction in DA rings depolarized by 62.5 mM KCl or stimulated with 21% O(2) in Ca(2+)-free medium. Preincubation with 17beta-estradiol or the L-type Ca(2+) channel blocker nifedipine produced an inhibition of CaCl(2)-induced contractions. In conclusion, there are no sex related differences in chicken DA reactivity. The estrogen 17beta-estradiol induces an endothelium-independent relaxation of chicken DA that is not mediated by ER activation. This relaxant effect is, at least partially, due to inhibition of Ca(2+) entry from extracellular space. PMID- 20164204 TI - Cathepsin B is not the processing enzyme for mouse prorenin. AB - Renin, an aspartyl protease that catalyzes the rate-limiting step in the renin angiotensin system (RAS), is proteolytically activated by a second protease [referred to as the prorenin processing enzyme (PPE)] before its secretion from the juxtaglomerular cells of the kidney. Although several enzymes are capable of activating renin in vitro, the leading candidate for the PPE in the kidney is cathepsin B (CTSB) due to is colocalization with the renin precursor (prorenin) in juxtaglomerular cell granules and because of its site-selective activation of human prorenin both in vitro and in transfected tissue culture cell models. To verify the role of CTSB in prorenin processing in vivo, we tested the ability of CTSB-deficient (CTSB-/-) mice to generate active renin. CTSB-/- mice do not exhibit any overt symptoms (renal malformation, preweaning mortality) typical of an RAS deficiency and have normal levels of circulating active renin, which, like those in control animals, rise more than 15-fold in response to pharmacologic inhibition of the RAS. The mature renin enzyme detected in kidney lysates of CTSB /- mice migrates at the same apparent molecular weight as that in control mice, and the processing to active renin is not affected by chloroquine treatment of the animals. Finally, the distribution and morphology of renin-producing cells in the kidney is normal in CTSB-/- mice. In conclusion, CTSB-deficient mice exhibit no differences compared with controls in their ability to generate active renin, and our results do not support CTSB as the PPE in mice. PMID- 20164206 TI - Cholecystokinin as a regulator of cardiac function and postprandial gastrointestinal blood flow in rainbow trout (Oncorhynchus mykiss). AB - We have studied the potential role of CCK as a regulator/modulator of the postprandial increase in gastrointestinal blood flow. Rainbow trout (Oncorhynchus mykiss) were instrumented with pulsed Doppler flow probes to measure the effects of CCK on cardiac output and gastrointestinal blood flow. Furthermore, vascular preparations were used to study the direct effects of CCK on the vessels. In addition, we used in situ perfused hearts to further study the effects of CCK on the cardiovascular system. When the sulfated form of CCK-8 was injected at a physiological concentration (0.19 pmol/kg) in vivo, there was a significant increase in the gastrointestinal blood flow (18 +/- 4%). This increase in gastrointestinal blood flow was followed by a subsequent increase in cardiac output (30 +/- 6%). When the dose was increased to 0.76 pmol/kg, there was only a 14 +/- 6% increase in gastrointestinal blood flow; possibly due to a dose dependent increase in the gill vascular resistance as previously reported or a direct effect on the heart. Nevertheless, CCK did not affect the isolated vessel preparations, and thus, it seems unlikely that CCK has a direct effect on the blood vessels of the second or third order. CCK did, however, have profound effects on the dynamics of the heart, and without a change in cardiac output, there was a significant increase in the amplitude (59 +/- 4%) and rate (dQ/dt: 55 +/- 4%; -dQ/dt: 208 +/- 49%) of the phasic flow profile. If and how this might be coupled to a postprandial gastrointestinal hyperemia remains to be determined. We conclude that CCK has the potential as a regulator of the postprandial gastrointestinal blood flow in fish and most likely has its effect by inducing a gastrointestinal hyperemia. The mechanism by which CCK acts is at present unknown. PMID- 20164205 TI - Connexins and the kidney. AB - Connexins (Cxs) are widely-expressed proteins that form gap junctions in most organs, including the kidney. In the renal vasculature, Cx37, Cx40, Cx43, and Cx45 are expressed, with predominant expression of Cx40 in the endothelial cells and Cx45 in the vascular smooth muscle cells. In the tubules, there is morphological evidence for the presence of gap junction plaques only in the proximal tubules. In the distal nephron, Cx30, Cx30.3, and Cx37 are expressed, but it is not known whether they form gap junctions connecting neighboring cells or whether they primarily act as hemichannels. As in other systems, the major function of Cxs in the kidney appears to be intercellular communication, although they may also form hemichannels that allow cellular secretion of large signaling molecules. Renal Cxs facilitate vascular conduction, juxtaglomerular apparatus calcium signaling, and tubular purinergic signaling. Accordingly, current evidence points to roles for these Cxs in several important regulatory mechanisms in the kidney, including the renin angiotensin system, tubuloglomerular feedback, and salt and water reabsorption. At the systemic level, renal Cxs may help regulate blood pressure and may be involved in hypertension and diabetes. PMID- 20164207 TI - Characterization of a spinal, urine storage reflex, inhibitory center and its regulation by 5-HT1A receptors in female cats. AB - Urine storage is facilitated by somatic (pudendal nerve) and sympathetic [hypogastric nerve (HgN)] reflexes to the urethral rhabdosphincter (URS) and urethral smooth muscle, respectively, initiated by primary afferent fibers in the pelvic nerve (PelN). Inhibition of storage reflexes is required for normal voiding. This study characterizes a urine storage reflex inhibitory network that can be activated by PelN afferent fibers concurrently with the reflexes themselves. Electrical stimulation of PelN produced evoked potentials recorded by URS EMG electrodes (10-ms latency) or HgN electrodes (60-ms latency) in chloralose-anesthetized cats. When a second (i.e., paired) pulse of the same stimulus intensity was applied to the PelN 50-500 ms after the first, the reflexes evoked by the second stimulus were inhibited. The inhibition was maximal at paired-pulse intervals of 50-100 ms and remained after acute spinal transection at T10, confirming that the inhibitory center is located in the spinal cord. The 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n propylamino)tertralin (8-OH-DPAT; 3-300 mug/kg iv) consistently reduced the paired-pulse inhibition from 20% to 60% of control in spinal-intact animals but had no effect in acute spinal animals (i.e., supraspinal site of action). N-{2-[4 (2-methoxyphenyl)-1-piperazinyl]ethyl}-N-2-pyridinylcyclohexanecarboxamide maleate (300 mug/kg iv) completely reversed 8-OH-DPAT's effects. The PelN-HgN reflex paired-pulse inhibition was not affected by 8-OH-DPAT. These results indicate the presence of a spinal, urine storage reflex, inhibitory center (SUSRIC) that is activated within 50 ms after activation of the reflexes themselves. SUSRIC is inhibited (disfacilitated) by supraspinal 5-HT(1A) receptors. PMID- 20164208 TI - Cigarette exposure induces changes in maternal vascular function in a pregnant mouse model. AB - Smoking is associated with multiple adverse pregnancy outcomes, including fetal growth restriction. The objective of this study was to determine whether cigarette smoke exposure during pregnancy in a mouse model affects the functional properties of maternal uterine, mesenteric, and renal arteries as a possible mechanism for growth restriction. C57Bl/CJ mice were exposed to whole body sidestream smoke for 4 h/day. Smoke particle exposure was increased from day 4 of gestation until late pregnancy (day 16-19), with mean total suspended particle levels of 63 mg/m(3), representative of moderate-to-heavy smoking in humans. Uterine, mesenteric, and renal arteries from late-pregnant and virgin mice were isolated and studied in a pressure-arteriograph system (n = 23). Plasma cotinine was measured by ELISA. Fetal weights were significantly reduced in smoke-exposed compared with control fetuses (0.88 +/- 0.1 vs. 1.0 +/- 0.08 g, P < 0.02), while litter sizes were not different. Endothelium-mediated relaxation responses to methacholine were significantly impaired in both the uterine and mesenteric vasculature of pregnant mice exposed to cigarette smoke during gestation. This difference was not apparent in isolated renal arteries from pregnant mice exposed to cigarette smoke; however, relaxation was significantly reduced in renal arteries from smoke-exposed virgin mice. In conclusion, we found that passive cigarette smoke exposure is associated with impaired vascular relaxation of uterine and mesenteric arteries in pregnant mice. Functional maternal vascular perturbations during pregnancy, specifically impaired peripheral and uterine vasodilation, may contribute to a mechanism by which smoking results in fetal growth restriction. PMID- 20164209 TI - The lesion-mimic mutant cpr22 shows alterations in abscisic acid signaling and abscisic acid insensitivity in a salicylic acid-dependent manner. AB - A number of Arabidopsis (Arabidopsis thaliana) lesion-mimic mutants exhibit alterations in both abiotic stress responses and pathogen resistance. One of these mutants, constitutive expresser of PR genes22 (cpr22), which has a mutation in two cyclic nucleotide-gated ion channels, is a typical lesion-mimic mutant exhibiting elevated levels of salicylic acid (SA), spontaneous cell death, constitutive expression of defense-related genes, and enhanced resistance to various pathogens; the majority of its phenotypes are SA dependent. These defense responses in cpr22 are suppressed under high-humidity conditions and enhanced by low humidity. After shifting plants from high to low humidity, the cpr22 mutant, but not the wild type, showed a rapid increase in SA levels followed by an increase in abscisic acid (ABA) levels. Concomitantly, genes for ABA metabolism were up-regulated in the mutant. The expression of a subset of ABA-inducible genes, such as RD29A and KIN1/2, was down-regulated, but that of other genes, like ABI1 and HAB1, was up-regulated in cpr22 after the humidity shift. cpr22 showed reduced responsiveness to ABA not only in abiotic stress responses but also in germination and stomatal closure. Double mutant analysis with nahG plants that degrade SA indicated that these alterations in ABA signaling were attributable to elevated SA levels. Furthermore, cpr22 displayed suppressed drought responses by long-term drought stress. Taken together, these results suggest an effect of SA on ABA signaling/abiotic stress responses during the activation of defense responses in cpr22. PMID- 20164210 TI - Identification of microRNAs involved in pathogen-associated molecular pattern triggered plant innate immunity. AB - Pathogen-associated molecular patterns (PAMPs) trigger plant defenses when perceived by surface-localized immune receptors. PAMP-triggered immunity (PTI) plays a vital role in the resistance of plants to numerous potential pathogens. MicroRNA (miRNA) biogenesis is known to be important for PTI, but miRNA species involved in this process have not been fully explored. Here we show that the Arabidopsis (Arabidopsis thaliana) miRNA effector protein, Argonaute1 (AGO1), is required for a number of PTI responses including PAMP-induced callose deposition, gene expression, and seedling growth inhibition. Deep sequencing of AGO1-bound small RNAs led to the identification of a number of miRNAs that are up- or down regulated by flg22, a well-studied PAMP. Overexpression of selected miRNAs in stable transgenic plants demonstrated that miR160a positively regulate PAMP induced callose deposition, whereas miR398b and miR773 negatively regulate PAMP induced callose deposition and disease resistance to bacteria, suggesting a complexity of the miRNA regulation in plant innate immunity. PMID- 20164211 TI - Cortisol, DHEAS, their ratio and the metabolic syndrome: evidence from the Vietnam Experience Study. AB - OBJECTIVES: The aim of these analyses was to examine the association of cortisol, DHEAS and the cortisol:DHEAS ratio with the metabolic syndrome (MetS) and its components. Design The analyses were cross-sectional. METHODS: Participants were 4255 Vietnam era US army veterans. From military service files, telephone interviews and a medical examination, occupational, socio-demographic and health data were collected. MetS was ascertained from data on body mass index; fasting blood glucose or a diagnosis of diabetes; blood pressure or a diagnosis of hypertension; high-density lipoprotein cholesterol; and triglyceride levels. Contemporary morning fasted cortisol and DHEAS concentrations were determined. The outcomes were MetS and its components. Analysis was by logistic regression, first adjusting for age and then additionally for an array of candidate confounders. RESULTS: Cortisol, although not in the fully adjusted analysis, and DHEAS were both related to MetS. Whereas high cortisol concentrations were associated with an increased risk of MetS, high DHEAS concentrations appeared protective. By far, the strongest associations with MetS were observed for the cortisol:DHEAS ratio; the higher the ratio, the greater the risk of having MetS. The ratio was also significantly related to four of the five MetS components. CONCLUSIONS: The cortisol:DHEAS ratio is positively associated with MetS. Prospective analyses are needed to help untangle direction of causality, but this study suggests that the cortisol:DHEAS ratio is worthy of further study in this and other health contexts. PMID- 20164212 TI - Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations. AB - OBJECTIVE: The phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH). SUBJECTS AND METHODS: We sequenced the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes in 220 patients with HH responsive to diazoxide. The order of genetic testing was dependent upon the clinical phenotype. RESULTS: A genetic diagnosis was possible for 59/220 (27%) patients. K(ATP) channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%). Seven of the 11 probands with a heterozygous HNF4A mutation did not have a parent affected with diabetes, and four de novo mutations were confirmed. These patients were diagnosed with HI within the first week of life (median age 1 day), and they had increased birth weight (median +2.4 SDS). The duration of diazoxide treatment ranged from 3 months to ongoing at 8 years. CONCLUSIONS: In this large series, HNF4A mutations are the third most common cause of diazoxide responsive HH. We recommend that HNF4A sequencing is considered in all patients with diazoxide responsive HH diagnosed in the first week of life irrespective of a family history of diabetes, once K(ATP) channel mutations have been excluded. PMID- 20164213 TI - Therapies for the medical management of persistent hypoglycaemia in two cases of inoperable malignant insulinoma. AB - OBJECTIVE: Hypoglycaemia poses a significant management challenge in patients with unresectable functional malignant insulinoma. Novel agents such as mammalian target of rapamycin (mTOR) inhibitors and radiolabelled peptides may be effective where there is failure of conventional therapy. DESIGN: We present the cases of two men diagnosed with inoperable malignant insulinoma and hepatic metastases who developed severe symptomatic hypoglycaemia, and review potential therapies for glycaemic support. METHOD: Despite treatment with diazoxide, frequent oral carbohydrate, prednisolone and somatostatin analogue therapy, both men required hospital admission for treatment with continuous i.v. dextrose. Both were treated with Lutetium-177 octreotate. One man was also treated with everolimus, a mTOR inhibitor. RESULT: Use of Lutetium-177 octreotate, and in one case everolimus, successfully achieved normoglycaemia, facilitating safe discharge from hospital. Both men also had regression in the size and number of hepatic metastases. CONCLUSION: Lutetium-177 octreotate and everolimus are options for managing hypoglycaemia due to unresectable malignant insulinoma when refractory to conventional supportive therapies. PMID- 20164214 TI - The syndrome of inappropriate antidiuretic hormone: prevalence, causes and consequences. AB - Hyponatraemia is the commonest electrolyte abnormality found in hospital inpatients, and is associated with a greatly increased morbidity and mortality. The syndrome of inappropriate antidiuretic hormone (SIADH) is the most frequent cause of hyponatraemia in hospital inpatients. SIADH is the clinical and biochemical manifestation of a wide range of disease processes, and every case warrants investigation of the underlying cause. In this review, we will examine the prevalence, pathophysiology, clinical characteristics and clinical consequences of hyponatraemia due to SIADH. PMID- 20164215 TI - The syndrome of inappropriate antidiuretic hormone: current and future management options. AB - Hyponatraemia is the commonest electrolyte abnormality, and syndrome of inappropriate antidiuretic hormone (SIADH) is the most frequent underlying pathophysiology. Hyponatraemia is associated with significant morbidity and mortality, and as such appropriate treatment is essential. Treatment options for SIADH include fluid restriction, demeclocycline, urea, frusemide and saline infusion, all of which have their limitations. The introduction of the vasopressin-2 receptor antagonists has allowed clinicians to specifically target the underlying pathophysiology of SIADH. Initial studies have shown good efficacy and safety profiles in the treatment of mild to moderate hyponatraemia. However, studies assessing the efficacy and safety of these agents in acute severe symptomatic hyponatraemia are awaited. Furthermore, the cost of these agents at present may limit their use. PMID- 20164216 TI - Generating a panel of highly specific antibodies to 20 human SH2 domains by phage display. AB - To demonstrate the utility of phage display in generating highly specific antibodies, affinity selections were conducted on 20 related Src Homology 2 (SH2) domains (ABL1, ABL2, BTK, BCAR3, CRK, FYN, GRB2, GRAP2, LYN, LCK, NCK1, PTPN11 C, PIK3R1 C, PLCgamma1 C, RASA1 C, SHC1, SH2D1A, SYK N, VAV1 and the tandem domains of ZAP70). The domains were expressed in Escherichia coli, purified and used in affinity selection experiments. In total, 1292/3800 of the resultant antibodies were shown to bind the target antigen. Of the 695 further evaluated in specificity ELISAs against all 20 SH2 domains, 379 antibodies were identified with unique specificity (i.e. monospecific). Sequence analysis revealed that there were at least 150 different clones with 1-19 different antibodies/antigen. This includes antibodies that distinguish between ABL1 and ABL2, despite their 89% sequence identity. Specificity was confirmed for many on protein arrays fabricated with 432 different proteins. Thus, even though the SH2 domains share a common three-dimensional structure and 20-89% identity at the primary structure level, we were able to isolate antibodies with exquisite specificity within this family of structurally related domains. PMID- 20164217 TI - Role of the GTPase Rab1b in ebolavirus particle formation. AB - The Ebolavirus matrix protein VP40 is essential for virion assembly and egress. Recently, we reported that the coat protein complex II (COPII) transport system plays an important role in the transport of VP40 to the plasma membrane. Here, we show that dominant-negative mutants of the GTPase Rab1b interfere with VP40 mediated particle formation. Rab1b activates GBF1 (Golgi-specific BFA [brefeldin A] resistance factor 1), a critical factor in the assembly of COPI vesicles. Activated GBF1 stimulates ARF1 (ADP ribosylation factor 1), which recruits coat protein to cellular membranes for the assembly of COPI vesicles. Here, we demonstrate that GBF1 and ARF1 are involved in Ebolavirus virion formation, suggesting that both the COPII and COPI transport systems play a role in Ebolavirus VP40-mediated particle formation. These findings provide new insights into the cellular pathways employed for Ebolavirus virion formation. PMID- 20164218 TI - Human T-lymphotropic virus type 1 transcription and chromatin-remodeling complexes. AB - Human T-lymphotropic virus type 1 (HTLV-1) encodes the viral protein Tax, which is believed to act as a viral transactivator through its interactions with a variety of transcription factors, including CREB and NF-kappaB. As is the case for all retroviruses, the provirus is inserted into the host DNA, where nucleosomes are deposited to ensure efficient packaging. Nucleosomes act as roadblocks in transcription, making it difficult for RNA polymerase II (Pol II) to proceed toward the 3' end of the genome. Because of this, a variety of chromatin remodelers can act to modify nucleosomes, allowing for efficient transcription. While a number of covalent modifications are known to occur on histone tails in HTLV-1 infection (i.e., histone acetyltransferases [HATs], histone deacetylases [HDACs], and histone methyltransferases [HMTs]), evidence points to the use of chromatin remodelers that use energy from ATP hydrolysis to remodel nucleosomes. Here we confirm that BRG1, which is the core subunit of eight chromatin-remodeling complexes, is essential not only for Tax transactivation but also for viral replication. This is especially evident when wild-type infectious clones of HTLV-1 are used. BRG1 associates with Tax at the HTLV-1 long terminal repeat (LTR), and coexpression of BRG1 and Tax results in increased rates of transcription. The interaction of BRG1 with Tax additionally recruits the basal transcriptional machinery and removes some of the core histones from the nucleosome at the start site (Nuc 1). When using the BRG1 deficient cell lines SW13, C33A, and TSUPR1, we observed little viral transcription and no viral replication. Importantly, while these three cell lines do not express detectable levels of BRG1, much of the SWI/SNF complex remains assembled in the cells. Knockdown of BRG1 and associated SWI/SNF subunits suggests that the BRG1-utilizing SWI/SNF complex PBAF is responsible for HTLV-1 nucleosome remodeling. Finally, HTLV-1 infection of cell lines with a knockdown in BRG1 or the PBAF complex results in a significant reduction in viral production. Overall, we concluded that BRG1 is required for Tax transactivation and HTLV-1 viral production and that the PBAF complex appears to be responsible for nucleosome remodeling. PMID- 20164220 TI - Recruitment of herpes simplex virus type 1 immediate-early protein ICP0 to the virus particle. AB - Although the herpes simplex virus type 1 (HSV-1) tegument is comprised of a large number of viral and cellular proteins, how and where in the cell these proteins are recruited into the virus structure is poorly understood. We have shown previously that the immediate-early gene product ICP0 is packaged by a mechanism dependent on the major tegument protein VP22, while others have shown a requirement for ICP27. We now extend our studies to show that ICP0 packaging correlates directly with the ability of ICP0 to complex with VP22 in infected cells. ICP27 is not, however, present in this VP22-ICP0 complex but is packaged into the virion in a VP22- and ICP0-independent manner. Biochemical fractionation of virions indicated that ICP0 associates tightly with the virus capsid, but intranuclear capsids contained no detectable ICP0. The RING finger domain of ICP0 and the N terminus of VP22 were both shown to be essential but not sufficient for ICP0 packaging and complex formation. Strikingly, however, the N-terminal region of VP22, while unable to form a complex with ICP0, inhibited its translocation from the nucleus to the cytoplasm. PML degradation by ICP0 was efficient in cells infected with this VP22 mutant virus, confirming that ICP0 retains activity. Hence, we would suggest that VP22 is an important molecular partner of ICP0 that controls at least one of its activities: its assembly into the virion. Moreover, we propose that the pathway by which VP22 recruits ICP0 to the virion may begin in the nucleus prior to ICP0 translocation to its final site of assembly in the cytoplasm. PMID- 20164219 TI - The interferon-induced gene ISG15 blocks retrovirus release from cells late in the budding process. AB - The release of retroviruses from cells requires ubiquitination of Gag and recruitment of cellular proteins involved in endosome sorting, including the ESCRT-III proteins and the Vps4 ATPase. In response to infection, cells have evolved an interferon-induced mechanism to block virus replication through expression of the interferon-stimulated gene 15 (ISG15), a dimer homologue of ubiquitin, which interferes with ubiquitin pathways in cells. Previously, it has been reported that ISG15 expression inhibited the E3 ubiquitin ligase, Nedd4, and prevented association of the ESCRT-I protein Tsg101 with human immunodeficiency virus type 1 (HIV-1) Gag. The budding of avian sarcoma leukosis virus and HIV-1 Gag virus-like particles containing L-domain mutations can be rescued by fusion to ESCRT proteins, which cause entry into the budding pathway beyond these early steps. The release of these fusions from cells was susceptible to inhibition by ISG15, indicating that there was a block late in the budding process. We now demonstrate that the Vps4 protein does not associate with the avian sarcoma leukosis virus or the HIV-1 budding complexes when ISG15 is expressed. This is caused by a loss in interaction between Vps4 with its coactivator protein LIP5 needed to promote the formation of the ESCRT-III-Vps4 double-hexamer complex required for membrane scission and virus release. The inability of LIP5 to interact with Vps4 is the probable result of ISG15 conjugation to the ESCRT-III protein, CHMP5, which regulates the availability of LIP5. Thus, there appear to be multiple levels of ISG15-induced inhibition acting at different stages of the virus release process. PMID- 20164221 TI - Structure and function of a genetically engineered mimic of a nonenveloped virus entry intermediate. AB - Divalent metal ions are components of numerous icosahedral virus capsids. Flock House virus (FHV), a small RNA virus of the family Nodaviridae, was utilized as an accessible model system with which to address the effects of metal ions on capsid structure and on the biology of virus-host interactions. Mutations at the calcium-binding sites affected FHV capsid stability and drastically reduced virus infectivity, without altering the overall architecture of the capsid. The mutations also altered the conformation of gamma, a membrane-disrupting, virus encoded peptide usually sequestered inside the capsid, by increasing its exposure under neutral pH conditions. Our data demonstrate that calcium binding is essential for maintaining a pH-based control on gamma exposure and host membrane disruption, and they reveal a novel rationale for the metal ion requirement during virus entry and infectivity. In the light of the phenotypes displayed by a calcium site mutant of FHV, we suggest that this mutant corresponds to an early entry intermediate formed in the endosomal pathway. PMID- 20164222 TI - T-cell correlates of vaccine efficacy after a heterologous simian immunodeficiency virus challenge. AB - Determining the "correlates of protection" is one of the challenges in human immunodeficiency virus vaccine design. To date, T-cell-based AIDS vaccines have been evaluated with validated techniques that measure the number of CD8(+) T cells in the blood that secrete cytokines, mainly gamma interferon (IFN-gamma), in response to synthetic peptides. Despite providing accurate and reproducible measurements of immunogenicity, these methods do not directly assess antiviral function and thus may not identify protective CD8(+) T-cell responses. To better understand the correlates of vaccine efficacy, we analyzed the immune responses elicited by a successful T-cell-based vaccine against a heterologous simian immunodeficiency virus challenge. We searched for correlates of protection using a viral suppression assay (VSA) and an IFN-gamma enzyme-linked immunospot assay. While the VSA measured in vitro suppression, it did not predict the outcome of the vaccine trial. However, we found several aspects of the vaccine-induced T cell response that were associated with improved outcome after challenge. Of note, broad vaccine-induced prechallenge T-cell responses directed against Gag and Vif correlated with lower viral loads and higher CD4(+) lymphocyte counts. These results may be relevant for the development of T-cell-based AIDS vaccines since they indicate that broad epitope-specific repertoires elicited by vaccination might serve as a correlate of vaccine efficacy. Furthermore, the present study demonstrates that certain viral proteins may be more effective than others as vaccine immunogens. PMID- 20164223 TI - Reciprocal regulation of AKT and MAP kinase dictates virus-host cell fusion. AB - Viruses of the Paramyxoviridae family bind to their host cells by using hemagglutinin-neuraminidase (HN), which enhances fusion protein (F)-mediated membrane fusion. Although respiratory syncytial virus and parainfluenza virus 5 of this family are suggested to trigger host cell signaling during infection, the virus-induced intracellular signals dictating virus-cell fusion await elucidation. Using an F- or HN-F-containing reconstituted envelope of Sendai virus, another paramyxovirus, we revealed the role and regulation of AKT1 and Raf/MEK/ERK cascades during viral fusion with liver cells. Our observation that extracellular signal-regulated kinase (ERK) activation promotes viral fusion via ezrin-mediated cytoskeletal rearrangements, whereas AKT1 attenuates fusion by promoting phosphorylation of F protein, indicates a counteractive regulation of viral fusion by reciprocal activation of AKT1 and mitogen-activated protein kinase (MAPK) cascades, establishing a novel conceptual framework for a therapeutic strategy. PMID- 20164224 TI - Identification and characterization of clevudine-resistant mutants of hepatitis B virus isolated from chronic hepatitis B patients. AB - Clevudine (CLV) is a nucleoside analog with potent antiviral activity against chronic hepatitis B virus (HBV) infection. Viral resistance to CLV in patients receiving CLV therapy has not been reported. The aim of this study was to characterize CLV-resistant HBV in patients with viral breakthrough (BT) during long-term CLV therapy. The gene encoding HBV reverse transcriptase (RT) was analyzed from chronic hepatitis B patients with viral BT during CLV therapy. Sera collected from the patients at baseline and at the time of viral BT were studied. To characterize the mutations of HBV isolated from the patients, we subjected the HBV mutants to in vitro drug susceptibility assays. Several conserved mutations were identified in the RT domain during viral BT, with M204I being the most common. In vitro phenotypic analysis showed that the mutation M204I was predominantly associated with CLV resistance, whereas L229V was a compensatory mutation for the impaired replication of the M204I mutant. A quadruple mutant (L129M, V173L, M204I, and H337N) was identified that conferred greater replicative ability and strong resistance to both CLV and lamivudine. All of the CLV-resistant clones were lamivudine resistant. They were susceptible to adefovir, entecavir, and tenofovir, except for one mutant clone. In conclusion, the mutation M204I in HBV RT plays a major role in CLV resistance and leads to viral BT during long-term CLV treatment. Several conserved mutations may have a compensatory role in replication. Drug susceptibility assays reveal that adefovir and tenofovir are the most effective compounds against CLV-resistant mutants. These data may provide additional therapeutic options for CLV-resistant patients. PMID- 20164225 TI - Cultivation and serological characterization of a human Theiler's-like cardiovirus associated with diarrheal disease. AB - Cardioviruses (e.g., Theiler's murine encephalomyelitis virus [TMEV]) are members of the Picornaviridae family that cause myocarditis and encephalitis in rodents. Recently, several studies have identified human cardioviruses, including Saffold virus (SAFV) and a related virus named human TMEV-like cardiovirus (HTCV). At least eight cardiovirus genotypes are now recognized, with SAFV and most strains of HTCV belonging to genotypes 1 and 2, respectively; genotype 2 strains are the most common in the population. Although a genotype 3 cardiovirus has recently been cultured (SAFV-3), the genotype 1 and 2 cardioviruses have been difficult to propagate in vitro, hindering efforts to understand their seroprevalence and pathogenicity. Here we present the isolation and characterization of a genotype 2 human cardiovirus (HTCV-UC6). Notably, successful cultivation of HTCV-UC6 from stool required the addition of cytokine-blocking antibodies to interrupt downstream antiviral pathways. Unlike SAFV-3, HTCV-UC6 exhibited slow replication kinetics and demonstrated only a moderate cytopathic effect. Serologic assays revealed that 91% of U.S. adults carry antibodies to the genotype 2 cardioviruses, of which 80% generate neutralizing antibodies, in agreement with previous data showing that cardiovirus infection is widespread in humans. We also demonstrate an acute cardiovirus seroconversion event in a child with diarrhea and vomiting, thus reporting for the first time evidence linking cardiovirus infection to diarrheal disease in humans. PMID- 20164226 TI - Development of an intergenotypic hepatitis C virus (HCV) cell culture method to assess antiviral susceptibilities and resistance development of HCV NS3 protease genes from HCV genotypes 1 to 6. AB - Protease inhibitors (PIs) of hepatitis C virus (HCV) provide an additional or alternative therapy for chronic infection. However, assessment of their efficacy and ability to inhibit replication of different genotypes is hampered by the lack of a convenient animal model or a method for in vitro culture of HCV other than the type 1/2-based replicons and the infectious genotype 2a clone JFH1. To address this problem, we constructed a panel of replication-competent chimeric Jc1 (pFK JFH1/J6/C-846) clones containing protease and NS4A coding sequences from all six major genotypes, enabling the determination of replication and the susceptibility to PIs. Chimeras showed substantial variability in replication kinetics, attributable in part to naturally occurring polymorphisms and differing requirements for adaptive mutations in NS3 and NS4A. Through calculation of 50% inhibitory concentrations (IC(50)s) of BILN 2061, measuring reduction in the number of focus-forming units/ml (FFU/ml) and replication inhibition, consistent genotype-associated differences in antiviral susceptibilities were observed. IC(50)s for genotype 1b, 4a, and 6a-derived chimeras (1 to 3 nM) were approximately 100-fold lower than those for genotypes 2a, 3a, and 5a (range, 80 to 720 nM), implying major differences in response to therapy. In vitro passage in increasing concentrations of BILN 2061 rapidly induced resistance-associated mutations at position 168 in chimeras of all 6 genotypes and at position 156 in genotypes 1b and 4a, each with substantial variability in the identity of substituted amino acids. The system will allow future comprehensive phenotypic characterization of naturally occurring and treatment-induced mutations for PIs in trial or entering clinical use. PMID- 20164227 TI - Familial relationships in hyperthermo- and acidophilic archaeal viruses. AB - Archaea often live in extreme, harsh environments such as acidic hot springs and hypersaline waters. To date, only two icosahedrally symmetric, membrane containing archaeal viruses, SH1 and Sulfolobus turreted icosahedral virus (STIV), have been described in detail. We report the sequence and three dimensional structure of a third such virus isolated from a hyperthermoacidophilic crenarchaeon, Sulfolobus strain G4ST-2. Characterization of this new isolate revealed it to be similar to STIV on the levels of genome and structural organization. The genome organization indicates that these two viruses have diverged from a common ancestor. Interestingly, the prominent surface turrets of the two viruses are strikingly different. By sequencing and mass spectrometry, we mapped several large insertions and deletions in the known structural proteins that could account for these differences and showed that both viruses can infect the same host. A combination of genomic and proteomic analyses revealed important new insights into the structural organization of these viruses and added to our limited knowledge of archaeal virus life cycles and host-cell interactions. PMID- 20164228 TI - Rotavirus differentially infects and polyclonally stimulates human B cells depending on their differentiation state and tissue of origin. AB - We have shown previously that rotavirus (RV) can infect murine intestinal B220(+) cells in vivo (M. Fenaux, M. A. Cuadras, N. Feng, M. Jaimes, and H. B. Greenberg, J. Virol. 80:5219-5232, 2006) and human blood B cells in vitro (M. C. Mesa, L. S. Rodriguez, M. A. Franco, and J. Angel, Virology 366:174-184, 2007). However, the effect of RV on B cells, especially those present in the human intestine, the primary site of RV infection, is unknown. Here, we compared the effects of the in vitro RV infection of human circulating (CBC) and intestinal B cells (IBC). RV infected four times more IBC than CBC, and in both types of B cells the viral replication was highly restricted to the memory subset. RV induced cell death in 30 and 3% of infected CBC and IBC, respectively. Moreover, RV induced activation and differentiation into antibody-secreting cells (ASC) of CBC but not IBC when the B cells were present with other mononuclear cells. However, RV did not induce these effects in purified CBC or IBC, suggesting the participation of other cells in activating and differentiating CBC. RV infection was associated with enhanced interleukin-6 (IL-6) production by CBC independent of viral replication. The infection of the anti-B-cell receptor, lipopolysaccharide, or CpG-stimulated CBC reduced the secretion of IL-6 and IL-8 and decreased the number of ASC. These inhibitory effects were associated with an increase in viral replication and cell death and were observed in polyclonally stimulated CBC but not in IBC. Thus, RV differentially interacts with primary human B cells depending on their tissue of origin and differentiation stage, and it affects their capacity to modulate the local and systemic immune responses. PMID- 20164229 TI - Adenovirus protein E4orf4 induces premature APCCdc20 activation in Saccharomyces cerevisiae by a protein phosphatase 2A-dependent mechanism. AB - Protein phosphatase 2A (PP2A) has been implicated in cell cycle progression and mitosis; however, the complexity of PP2A regulation via multiple B subunits makes its functional characterization a significant challenge. The human adenovirus protein E4orf4 has been found to induce both high Cdk1 activity and the accumulation of cells in G(2)/M in both mammalian and yeast cells, effects which are largely dependent on the B55/Cdc55 regulatory subunit of PP2A. Thus, E4orf4 represents a unique means by which the function of a specific form of PP2A can be delineated in vivo. In Saccharomyces cerevisiae, only two PP2A regulatory subunits exist, Cdc55 and Rts1. Here, we show that E4orf4-induced toxicity depends on a functional interaction with Cdc55. E4orf4 expression correlates with the inappropriate reduction of Pds1 and Scc1 in S-phase-arrested cells. The unscheduled loss of these proteins suggests the involvement of PP2A(Cdc55) in the regulation of the Cdc20 form of the anaphase-promoting complex (APC). Contrastingly, activity of the Hct1 form of the APC is not induced by E4orf4, as demonstrated by the observed stability of its substrates. We propose that E4orf4, being a Cdc55-specific inhibitor of PP2A, demonstrates the role of PP2A(Cdc55) in regulating APC(Cdc20) activity. PMID- 20164230 TI - Dengue virus inhibits the production of type I interferon in primary human dendritic cells. AB - Dengue virus (DENV) infects human immune cells in vitro and likely infects dendritic cells (DCs) in vivo. DENV-2 productive infection induces activation and release of high levels of chemokines and proinflammatory cytokines in monocyte derived DCs (moDCs), with the notable exception of alpha/beta interferon (IFN alpha/beta). Interestingly, DENV-2-infected moDCs fail to prime T cells, most likely due to the lack of IFN-alpha/beta released by moDCs, since this effect was reversed by addition of exogenous IFN-beta. Together, our data show that inhibition of IFN-alpha/beta production by DENV in primary human moDCs is a novel mechanism of immune evasion. PMID- 20164231 TI - Cytotoxic T cells are the predominant players providing cross-protective immunity induced by {gamma}-irradiated influenza A viruses. AB - We previously demonstrated that a single dose of nonadjuvanted intranasal gamma irradiated influenza A virus can provide robust protection in mice against both homologous and heterosubtypic challenges, including challenge with an H5N1 avian virus strain. We investigated the mechanism behind the observed cross-protection to define which arms of the adaptive immune response are involved in mediating this protection. Studies with gene knockout mice showed the cross-protective immunity to be mediated mainly by T cells and to be dependent on the cytolytic effector molecule perforin. Adoptive transfer of memory T cells from immunized mice, but not of memory B cells, protected naive recipients against lethal heterosubtypic influenza virus challenge. Furthermore, gamma-irradiated influenza viruses induced cross-reactive Tc-cell responses but not cross-neutralizing or cross-protective antibodies. In addition, histological analysis showed reduced lung inflammation in vaccinated mice compared to that in unvaccinated controls following heterosubtypic challenge. This reduced inflammation was associated with enhanced early recruitment of T cells, both CD4(+) and CD8(+), and with early influenza virus-specific cytotoxic T-cell responses. Therefore, cross-protective immunity induced by vaccination with gamma-irradiated influenza A virus is mediated mainly by Tc-cell responses. PMID- 20164232 TI - Inhibition of human natural killer cell activity by influenza virions and hemagglutinin. AB - Natural killer (NK) cells keep viral infections under control at the early phase by directly killing infected cells. Influenza is an acute contagious respiratory viral disease transmitted from host-to-host in the first few days of infection. The evasion of host innate immune defenses including NK cells is important for its success as a viral pathogen of humans and animals. NK cells encounter influenza virus within the microenvironment of infected cells. It therefore is important to investigate the direct effects of influenza virus on NK cell activity. Recently we demonstrated that influenza virus directly infects human NK cells and induces cell apoptosis to counter their function (H. Mao, W. Tu, G. Qin, H. K. W. Law, S. F. Sia, P.-L. Chan, Y. Liu, K.-T. Lam, J. Zheng, M. Peiris, and Y.-L. Lau, J. Virol. 83:9215-9222, 2009). Here, we further demonstrated that both the intact influenza virion and free hemagglutinin protein inhibited the cytotoxicity of fresh and interleukin-2 (IL-2)-activated primary human NK cells. Hemagglutinin bound and internalized into NK cells via the sialic acids. This interaction did not decrease NKp46 expression but caused the downregulation of the zeta chain through the lysosomal pathway, which caused the decrease of NK cell cytotoxicity mediated by NKp46 and NKp30. The underlying dysregulation of the signaling pathway involved zeta chain downregulation, leading to decreased Syk and ERK activation and granule exocytosis upon target cell stimulation, finally causing reduced cytotoxicity. These findings suggest that influenza virus developed a novel strategy to evade NK cell innate immune defense that is likely to facilitate viral transmission and also contribute to virus pathogenesis. PMID- 20164233 TI - Role of herpes simplex virus ICP0 in the transactivation of genes introduced by infection or transfection: a reappraisal. AB - ICP0, a promiscuous transactivator that enhances the expression of genes introduced by infection or transfection, functions in both nucleus and cytoplasm. The nuclear functions include degradation and dispersal of ND10 bodies and suppression of silencing of viral DNA. Subsequently, ICP0 shifts to the cytoplasm. Transfection of DNA prior to infection has no effect on the localization of ICP0 in cells that are efficient expressers of transgenes (e.g., Vero and HEK293) but results in delayed cytoplasmic localization of ICP0 in cells (e.g., HEp-2 and HEL) that are poor transgene expressers. Here, we examined by real-time PCR (qPCR) the accumulation of a transgene and of viral gI mRNAs in Vero or HEp-2 cells that were transfected and then infected with wild-type or DeltaICP0 mutant viruses. The accumulation of transgene mRNA was unaffected by a DeltaICP0 mutant, gradually increased in HEp-2 cells, but increased and then decreased in Vero cells infected with wild-type virus. In both cell lines, accumulation of gI mRNA increased with time and was less affected by the transfected DNA in Vero cells than in HEp-2 cells. The relative kinetics of mRNA accumulation reflected continued synthesis and degradation of the transgene and gI mRNAs. We conclude that the role of ICP0 is to render the DNA templates introduced by transfection or infection accessible by transcriptional factors, that the two cell lines differ with respect to the transcription-ready status of entering foreign DNA in the nucleus, and that ICP0 is not per se the recruiter of transcriptional factors to the accessible DNA templates. PMID- 20164234 TI - Two N-linked glycosylation sites in the V2 and C2 regions of human immunodeficiency virus type 1 CRF01_AE envelope glycoprotein gp120 regulate viral neutralization susceptibility to the human monoclonal antibody specific for the CD4 binding domain. AB - A recombinant human monoclonal antibody, IgG1 b12 (b12), recognizes a conformational epitope on human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) gp120 that overlaps the CD4 binding domain. Although b12 is able to broadly neutralize HIV-1 subtype B, C, and D viruses, many HIV-1 CRF01_AE viruses are resistant to b12-mediated neutralization. In this report, we examined the molecular mechanisms underlying the low neutralization susceptibility of CRF01_AE viruses to b12, using recently established CRF01_AE Env recombinant viruses. Our results showed that two potential N-linked glycosylation (PNLG) sites in the V2 and C2 regions of Env gp120 played an important role in regulating the susceptibility of CRF01_AE Env to b12. The locations of these PNLG sites correspond to amino acid positions 186 and 197 in HXB2 Env gp120; thus, they are designated N186 and N197 in this study. Removal of N186 significantly conferred the b12 susceptibility of 2 resistant CRF01_AE Env clones, 65CC4 and 107CC2, while the introduction of N186 reduced the b12 susceptibility of a susceptible CRF01_AE Env clone, 65CC1. In addition, removal of both N186 and N197 conferred the b12 susceptibility of 3 resistant CRF01_AE Env clones, 45PB1, 62PL1, and 101PL1, whereas the removal of either N186 or N197 was not sufficient to confer the b12 susceptibility of these CRF01_AE Env clones. Finally, removal of N197 conferred the b12 susceptibility of 2 resistant CRF01_AE Env clones lacking N186, 55PL1 and 102CC2. Taken together, we propose that two PNLG sites, N186 and N197, in Env gp120 are important determinants of the b12 resistance of CRF01_AE viruses. PMID- 20164236 TI - Herpes simplex virus 1 regulatory protein ICP27 undergoes a head-to-tail intramolecular interaction. AB - Herpes simplex virus type 1 (HSV-1) regulatory protein ICP27 is a multifunction functional protein that interacts with many cellular proteins. A number of the proteins with which ICP27 interacts require that both the N and C termini of ICP27 are intact. These include RNA polymerase II, TAP/NXF1, and Hsc70. We tested the possibility that the N and C termini of ICP27 could undergo a head-to-tail intramolecular interaction that exists in open and closed configurations for different binding partners. Here, we show by bimolecular fluorescence complementation (BiFC) assays and fluorescence resonance energy transfer (FRET) by acceptor photobleaching that ICP27 undergoes a head-to-tail intramolecular interaction but not head-to-tail or tail-to-tail intermolecular interactions. Substitution mutations in the N or C termini showed that the leucine-rich region (LRR) in the N terminus and the zinc finger-like region in the C terminus must be intact for intramolecular interactions. A recombinant virus, vNC-Venus-ICP27, was constructed, and this virus was severely impaired for virus replication. The expression of NC-Venus-ICP27 protein was delayed compared to ICP27 expression in wild-type HSV-1 infection, but NC-Venus-ICP27 was abundantly expressed at late times of infection. Because the renaturation of the Venus fluorescent protein results in a covalent bonding of the two halves of the Venus molecule, the head to-tail interaction of NC-Venus-ICP27 locks ICP27 in a closed configuration. We suggest that the population of locked ICP27 molecules is not able to undergo further protein-protein interactions. PMID- 20164235 TI - Achieving a golden mean: mechanisms by which coronaviruses ensure synthesis of the correct stoichiometric ratios of viral proteins. AB - In retroviruses and the double-stranded RNA totiviruses, the efficiency of programmed -1 ribosomal frameshifting is critical for ensuring the proper ratios of upstream-encoded capsid proteins to downstream-encoded replicase enzymes. The genomic organizations of many other frameshifting viruses, including the coronaviruses, are very different, in that their upstream open reading frames encode nonstructural proteins, the frameshift-dependent downstream open reading frames encode enzymes involved in transcription and replication, and their structural proteins are encoded by subgenomic mRNAs. The biological significance of frameshifting efficiency and how the relative ratios of proteins encoded by the upstream and downstream open reading frames affect virus propagation has not been explored before. Here, three different strategies were employed to test the hypothesis that the -1 PRF signals of coronaviruses have evolved to produce the correct ratios of upstream- to downstream-encoded proteins. Specifically, infectious clones of the severe acute respiratory syndrome (SARS)-associated coronavirus harboring mutations that lower frameshift efficiency decreased infectivity by >4 orders of magnitude. Second, a series of frameshift-promoting mRNA pseudoknot mutants was employed to demonstrate that the frameshift signals of the SARS-associated coronavirus and mouse hepatitis virus have evolved to promote optimal frameshift efficiencies. Finally, we show that a previously described frameshift attenuator element does not actually affect frameshifting per se but rather serves to limit the fraction of ribosomes available for frameshifting. The findings of these analyses all support a "golden mean" model in which viruses use both programmed ribosomal frameshifting and translational attenuation to control the relative ratios of their encoded proteins. PMID- 20164237 TI - Mechanistic consequences of hnRNP C binding to both RNA termini of poliovirus negative-strand RNA intermediates. AB - The poliovirus 3' noncoding region (3' NCR) is necessary for efficient virus replication. A poliovirus mutant, PVDelta3'NCR, with a deletion of the entire 3' NCR, yielded a virus that was capable of synthesizing viral RNA, albeit with a replication defect caused by deficient positive-strand RNA synthesis compared to wild-type virus. We detected multiple ribonucleoprotein (RNP) complexes in extracts from poliovirus-infected HeLa cells formed with a probe corresponding to the 5' end of poliovirus negative-strand RNA (the complement of the genomic 3' NCR), and the levels of these RNP complexes increased during the course of viral infection. Previous studies have identified RNP complexes formed with the 3' end of poliovirus negative-strand RNA, including one that contains a 36-kDa protein later identified as heterogeneous nuclear ribonucleoprotein C (hnRNP C). We report here that the 5' end of poliovirus negative-strand RNA is capable of interacting with endogenous hnRNP C, as well as with poliovirus nonstructural proteins. Further, we demonstrate that the addition of recombinant purified hnRNP C proteins can stimulate virus RNA synthesis in vitro and that depletion of hnRNP C proteins in cultured cells results in decreased virus yields and a correspondingly diminished accumulation of positive-strand RNAs. We propose that the association of hnRNP C with poliovirus negative-strand termini acts to stabilize or otherwise promote efficient positive-strand RNA synthesis. PMID- 20164238 TI - Interaction of a host protein with core complexes of bacteriophage phi6 to control transcription. AB - Bacteriophages of the family Cystoviridae have genomes consisting of three double stranded RNA (dsRNA) segments, L, S, and M, packaged within a polyhedral capsid along with RNA polymerase. Transcription of genomic segment L is activated by the interaction of host protein YajQ with the capsid structure. Segment L codes for the proteins of the inner capsid, which are expressed early in infection. Green fluorescent protein (GFP) fusions with YajQ produce uniform fluorescence in uninfected cells and in cells infected with viruses not dependent on YajQ. Punctate fluorescence develops when cells are infected with YajQ-dependent viruses. It appears that the host protein binds to the infecting particles and remains with them during the entire infection period. PMID- 20164239 TI - Distinct patterns of 1p and 19q alterations identify subtypes of human gliomas that have different prognoses. AB - We studied the status of chromosomes 1 and 19 in 363 astrocytic and oligodendroglial tumors. Whereas the predominant pattern of copy number abnormality was a concurrent loss of the entire 1p and 19q regions (total 1p/19q loss) among oligodendroglial tumors and partial deletions of 1p and/or 19q in astrocytic tumors, a subset of apparently astrocytic tumors also had total 1p/19q loss. The presence of total 1p/19q loss was associated with longer survival of patients with all types of adult gliomas independent of age and diagnosis (P = .041). The most commonly deleted region on 19q in astrocytic tumors spans 885 kb in 19q13.33-q13.41, which is telomeric to the previously proposed region. Novel regions of homozygous deletion, including a part of DPYD (1p21.3) or the KLK cluster (19q13.33), were observed in anaplastic oligodendrogliomas. Amplifications encompassing AKT2 (19q13.2) or CCNE1 (19q12) were identified in some glioblastomas. Deletion mapping of the centromeric regions of 1p and 19q in the tumors that had total 1p/19q loss, indicating that the breakpoints lie centromeric to NOTCH2 within the pericentromeric regions of 1p and 19q. Thus, we show that the copy number abnormalities of 1p and 19q in human gliomas are complex and have distinct patterns that are prognostically predictive independent of age and pathological diagnosis. An accurate identification of total 1p/19q loss and discriminating this from other 1p/19q changes is, however, critical when the 1p/19q copy number status is used to stratify patients in clinical trials. PMID- 20164240 TI - Analysis of receptor tyrosine kinases (RTKs) and downstream pathways in chordomas. AB - We have previously demonstrated that chordomas express activated platelet-derived growth factor receptor (PDGFRB) and that treatment with imatinib, which is capable of switching off the activation of various receptor tyrosine kinases (RTKs) including PDGFRB, benefits a number of patients. The aim of this study was to identify the possible presence of other activated RTKs and their downstream signaling effectors. Cryopreserved material from 22 naive sporadic chordomas was investigated for the presence of activated RTKs and their cognate ligands and downstream signaling effectors by means of human phospho-RTK antibody arrays, Western blotting, and molecular analysis; immunohistochemistry and fluorescence in situ hybridization were used to analyze the corresponding formalin-fixed and paraffin-embedded samples. We detected activated PDGFRB, FLT3, and colony stimulating factor 1 receptor (CSF1R) of the PDGFR family and highly phosphorylated EGFR, HER2/neu, and (to a lesser extent) HER4 of the EGFR family. The detection of PDGFRB/PDGFB confirmed our previous data. The presence of activated EGFR was paralleled by the finding of high levels of epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha) and PDGFB co expression and PDGFRB co-immunoprecipitation. Of the downstream effectors, the PI3K/AKT and RAS/MAPK pathways were both activated, thus leading to the phosphorylation of mammalian target of rapamycin (mTOR) and 4E-BP1 among the regulators involved in translational control. Taken together, our results (i) provide a rationale for tailored treatments targeting upstream activated receptors, including the PDGFR and EGFR families; (ii) support the idea that a combination of upstream antagonists and mTOR inhibitors enhances the control of tumor growth; and (iii) indicate that the 4E-BP1/eIF4E pathway is a major regulator of protein synthesis in chordoma. PMID- 20164241 TI - Analysis of specialized DNA polymerases expression in human gliomas: association with prognostic significance. AB - Aberrant activation of the translesion DNA synthesis (TLS) pathway has been suggested to play a role in tumorigenesis by promoting genetic mutations. We therefore examined glioma specimens for the expression of specialized DNA polymerases involved in TLS and assessed their prognostic significance. The expression levels of DNA polymerase kappa (Pol kappa), Pol iota, and Pol eta were assessed in 40 primary glioma samples and 10 normal brain samples using quantitative real-time PCR and Western blot analysis. Their prognostic significance was evaluated using a population-based tissue microarray derived from a cohort of 104 glioma patients. Overexpression of Pol kappa and Pol iota was observed in 57.5% (23-40) and 27.5% (11-40) of patients, respectively, whereas no significant expression of Pol eta was seen in the specimens. Immunohistochemical studies revealed positive Pol kappa and Pol iota staining in 72 (69.2%) and 33 (31.7%) of the 104 glioma specimens, respectively. Pol kappa expression was associated with advanced stages of the disease. Both Pol kappa- and Pol iota-positive staining were associated with shorter survival in glioma patients (P < .001 and P = .014, respectively). A multivariate survival analysis identified Pol kappa as an independent prognostic factor for glioma patients (P < .001). These findings demonstrate, for the first time, that the expression of Pol kappa and Pol iota is deregulated in gliomas, and upregulation of Pol kappa is associated with poorer prognosis in glioma patients. PMID- 20164243 TI - Depression and cardiovascular disease: have a happy day--just smile! PMID- 20164244 TI - Don't worry, be happy: positive affect and reduced 10-year incident coronary heart disease: the Canadian Nova Scotia Health Survey. AB - AIMS: Positive affect is believed to predict cardiovascular health independent of negative affect. We examined whether higher levels of positive affect are associated with a lower risk of coronary heart disease (CHD) in a large prospective study with 10 years of follow-up. METHODS AND RESULTS: We examined the association between positive affect and cardiovascular events in 1739 adults (862 men and 877 women) in the 1995 Nova Scotia Health Survey. Trained nurses conducted Type A Structured Interviews, and coders rated the degree of outwardly displayed positive affect on a five-point scale. To test that positive affect predicts incident CHD when controlling for depressive symptoms and other negative affects, we used as covariates: Center for Epidemiological Studies Depressive symptoms Scale, the Cook Medley Hostility scale, and the Spielberger Trait Anxiety Inventory. There were 145 (8.3%) acute non-fatal or fatal ischaemic heart disease events during the 14 916 person-years of observation. In a proportional hazards model controlling for age, sex, and cardiovascular risk factors, positive affect predicted CHD (adjusted HR, 0.78; 95% CI 0.63-0.96 per point; P = 0.02), the covariate depressive symptoms continued to predict CHD as had been published previously in the same patients (HR, 1.04; 95% CI 1.01-1.07 per point; P = 0.004) and hostility and anxiety did not (both P > 0.05). CONCLUSION: In this large, population-based study, increased positive affect was protective against 10-year incident CHD, suggesting that preventive strategies may be enhanced not only by reducing depressive symptoms but also by increasing positive affect. PMID- 20164245 TI - Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79. AB - AIMS: Although the association of low serum testosterone levels with mortality has gained strength in recent research, there are few population-based studies on this issue. This study examined whether low serum testosterone levels are a risk factor for all-cause or cause-specific mortality in a population-based sample of men aged 20-79. METHODS AND RESULTS: We used data from 1954 men recruited for the prospective population-based Study of Health in Pomerania, with measured serum testosterone levels at baseline and 195 deaths during an average 7.2-year follow up. A total serum testosterone level of less than 8.7 nmol/L (250 ng/dL) was classified as low. The relationships of low serum testosterone levels with all cause and cause-specific mortality were analysed by Cox proportional hazards regression models. Men with low serum testosterone levels had a significantly higher mortality from all causes than men with higher serum testosterone levels (HR 2.24; 95% CI 1.41-3.57). After adjusting for waist circumference, smoking habits, high-risk alcohol use, physical activity, renal insufficiency, and levels of dehydroepiandrosterone sulfate, low serum testosterone levels continued to be associated with increased mortality (HR 2.32; 95% CI 1.38-3.89). In cause specific analyses, low serum testosterone levels predicted increased risk of death from cardiovascular disease (CVD) (HR 2.56; 95% CI 1.15-6.52) and cancer (HR 3.46; 95% CI 1.68-6.68), but not from respiratory diseases or other causes. CONCLUSION: Low serum testosterone levels were associated with an increased risk of all-cause mortality independent of numerous risk factors. As serum testosterone levels are inversely related to mortality due to CVD and cancer, it may be used as a predictive marker. PMID- 20164242 TI - The role of blood vessels, endothelial cells, and vascular pericytes in insulin secretion and peripheral insulin action. AB - The pathogenesis of type 2 diabetes is intimately intertwined with the vasculature. Insulin must efficiently enter the bloodstream from pancreatic beta cells, circulate throughout the body, and efficiently exit the bloodstream to reach target tissues and mediate its effects. Defects in the vasculature of pancreatic islets can lead to diabetic phenotypes. Similarly, insulin resistance is accompanied by defects in the vasculature of skeletal muscle, which ultimately reduce the ability of insulin and nutrients to reach myocytes. An underappreciated participant in these processes is the vascular pericyte. Pericytes, the smooth muscle-like cells lining the outsides of blood vessels throughout the body, have not been directly implicated in insulin secretion or peripheral insulin delivery. Here, we review the role of the vasculature in insulin secretion, islet function, and peripheral insulin delivery, and highlight a potential role for the vascular pericyte in these processes. PMID- 20164246 TI - Gender differences in incidence rates of childhood B-precursor acute lymphocytic leukemia in Mississippi. AB - The authors studied pediatric patients with B-precursor acute lymphocytic leukemia (ALL) to determine whether Mississippi's gender incidences correlate with national statistics. Furthermore, data on gender incidences in each of the risk categories of low, standard, and high were collected. A retrospective chart review was performed of pediatric B-precursor ALL patients diagnosed at the Children's Cancer Clinic at the University of Mississippi Medical Center from 1995 to 2005. The gender incidences in Mississippi were found to be comparable with the national average for ALL (1.34:1 vs 1.3:1) overall. However, the national average includes T-cell ALL, which is known to be significantly more prevalent in boys. Of greater significance, boys were noted to present with high risk B-precursor ALL 4 times more than girls, suggesting the need for further investigation into possible causes of this phenomenon. PMID- 20164247 TI - Sensitivity, specificity, and confounding factors of novel serological tests used for the rapid diagnosis of bovine tuberculosis in farmed red deer (Cervus elaphus). AB - In this study, novel serological tests were used to detect tuberculosis (TB) in groups of farmed red deer (Cervus elaphus) varying in disease status or possible confounding factors. Groups of deer naturally or experimentally infected with Mycobacterium bovis and animals vaccinated against paratuberculosis were studied, as were uninfected animals and animals naturally or experimentally infected with Mycobacterium avium subsp. paratuberculosis. Sera were assayed using two rapid lateral-flow tests, Chembio's CervidTB STAT-PAK and DPP VetTB tests, and results were compared to those from tuberculin skin tests. Both serological tests had a high sensitivity, but specificity was adversely affected after animals had received a vaccine against paratuberculosis and were subsequently skin tested. The specificity of the DPP VetTB test was higher than that of the CervidTB STAT PAK test, with natural infection with M. avium subsp. paratuberculosis adversely affecting the specificity of only the CervidTB STAT-PAK test. The sera from M. avium subsp. paratuberculosis-infected deer that produced false-positive reactions in the CervidTB STAT-PAK test were retested with a multiantigen print immunoassay (MAPIA), and some of these sera were shown to react with the MPB83 antigen. Combining the results from the serological tests and the skin tests showed only a slight increase in the sensitivity of detection of M. bovis infected animals. It is concluded that both the CervidTB STAT-PAK and DPP VetTB tests offer rapid, convenient, and easy detection of bovine tuberculosis in deer, albeit with significant interference from paratuberculosis vaccination status and subsequent skin testing. The latter finding illustrates one of the limitations of currently available vaccines against paratuberculosis. PMID- 20164248 TI - Humoral immune responses in patients with Lyme neuroborreliosis. AB - The aim of this study was to analyze and compare the humoral immune responses in serum and cerebrospinal fluid (CSF) for 34 adult patients with clinically evident Lyme neuroborreliosis, 27 patients with clinically suspected Lyme neuroborreliosis, and 32 patients with tick-borne encephalitis. Additionally, we wanted to compare the findings of two methods for the detection of intrathecally synthesized borrelial antibodies: the IDEIA Lyme neuroborreliosis test using flagellar antigen and an approach based on the Liaison indirect chemiluminescence immunoassay using the OspC and VlsE antigens. Borrelial IgM and IgG antibodies were detected by at least one of these methods in the sera of 22/34 (64.7%) and 28/34 (82.4%) patients with clinically evident Lyme neuroborreliosis, respectively, and in the cerebrospinal fluid of 22/34 (64.7%) and 20/34 (58.8%) of these patients, respectively. Intrathecal synthesis of borrelial IgM and/or IgG was found in 19/34 (55.9%) patients: IgM in 17/34 (50%) patients and IgG in 15/34 (44.1%) patients. The relatively low proportion of intrathecal synthesis of borrelial antibodies and the high ratio of IgM positivity could be explained by the short duration of neurological disease as evidenced by reported symptoms (median, 10 days). Assessment of the humoral immune response in the sera and CSF of patients with early Lyme neuroborreliosis confirmed previous findings on the relationship between the duration of illness and the proportion of patients with detectable responses. PMID- 20164249 TI - Seroprevalence of Aichi virus in a Spanish population from 2007 to 2008. AB - Viruses are among the most common causes of acute gastroenteritis. In recent years, new viruses causing outbreaks of acute gastroenteritis have been described. Among these, Aichi virus was identified in Japan in 1989. Aichi virus belongs to the Kobuvirus genus in the family Picornaviridae. This virus has been detected in outbreaks of gastroenteritis associated with oyster consumption and in pediatric stool samples, but little is known about its epidemiology or pathogenesis. In the present study, the prevalence of antibodies to Aichi virus in a Spanish population was determined between 2007 and 2008 by using an enzyme linked immunosorbent assay (ELISA). As in previous studies, a high seroprevalence of antibodies to Aichi virus (70%) was observed, with levels differing according to age. We observed significant differences in titers of antibody to Aichi virus among different age groups, grouped by decades. We report high ELISA and neutralizing antibody titers, and both titers fitted a sigmoid curve significantly. However, this virus is seldom detected; therefore, further studies are needed to gain a better understanding of its importance as a pathogenic agent. PMID- 20164250 TI - Interactive changes between macrophages and adipocytes. AB - Obesity is associated with a proinflammatory state, with macrophage infiltration into adipose tissue. We tested the hypothesis that communication between macrophages and adipocytes affects insulin resistance by disrupting insulin stimulated glucose transport, adipocyte differentiation, and macrophage function. To test this hypothesis, we cocultured 3T3-L1 adipocytes with C2D macrophages or primary peritoneal mouse macrophages and examined the impacts of macrophages and adipocytes on each other. Adipocytes and preadipocytes did not affect C2D macrophage TNF-alpha, IL-6, or IL-1beta transcript concentrations relative to those obtained when C2D macrophages were incubated alone. However, preadipocytes and adipocytes increased PEC-C2D macrophage IL-6 transcript levels, while preadipocytes inhibited IL-1beta transcript levels compared to those obtained when PEC-C2D macrophages were incubated in medium alone. We found that adipocyte coculture increased macrophage consumption of tumor necrosis factor alpha (TNF alpha), interleukin 1beta (IL-1beta), and, in some cases, IL-6. C2D macrophages increasingly downregulated GLUT4 transcript levels in differentiated adipocytes. Recombinant TNF-alpha, IL-1beta, and IL-6 also downregulated GLUT4 transcript levels relative to those for the control. However, only IL-6 was inhibitory at concentrations detected in macrophage-adipocyte cocultures. IL-6 and TNF-alpha, but not IL-1beta, inhibited Akt phosphorylation within 15 min of insulin stimulation, but only IL-6 was inhibitory 30 min after stimulation. Lastly, we found that adipocyte differentiation was inhibited by macrophages or by recombinant TNF-alpha, IL-6, and IL-1beta, with IL-6 having the most impact. These data suggest that the interaction between macrophages and adipocytes is a complex process, and they support the hypothesis that the macrophage-adipocyte interaction affects insulin resistance by disrupting insulin-stimulated glucose transport, adipocyte differentiation, and macrophage function. PMID- 20164251 TI - Randomized trial on the safety, tolerability, and immunogenicity of MenACWY-CRM, an investigational quadrivalent meningococcal glycoconjugate vaccine, administered concomitantly with a combined tetanus, reduced diphtheria, and acellular pertussis vaccine in adolescents and young adults. AB - This study evaluated the safety, tolerability, and immunogenicity of an investigational quadrivalent meningococcal conjugate vaccine, MenACWY-CRM, when administered concomitantly with a combined tetanus, reduced diphtheria, and acellular pertussis (Tdap) vaccine, in subjects aged 11 to 25 years. Subjects received either MenACWY-CRM and Tdap, MenACWY-CRM and saline placebo, or Tdap and saline placebo. No significant increase in reactogenicity and no clinically significant vaccine-related adverse events (AEs) occurred when MenACWY-CRM and Tdap were administered concomitantly. Similar immunogenic responses to diphtheria, tetanus, and meningococcal (serogroups A, C, W-135, and Y) antigens were observed, regardless of concomitant vaccine administration. Antipertussis antibody responses were comparable between vaccine groups for filamentous hemagglutinin and were slightly lower, although not clinically significantly, for pertussis toxoid and pertactin when the two vaccines were administered concomitantly. These results indicate that the investigational MenACWY-CRM vaccine is well tolerated and immunogenic and that it can be coadministered with Tdap to adolescents and young adults. PMID- 20164252 TI - A DNA vaccine-encoded nucleoprotein of influenza virus fails to induce cellular immune responses in a diabetic mouse model. AB - Influenza virus infections cause yearly epidemics and are a major cause of lower respiratory tract illnesses in humans worldwide. Influenza virus has long been recognized to be associated with higher morbidity and mortality in diabetic patients. Vaccination is an effective tool to prevent influenza virus infection in this group of patients. Vaccines employing recombinant-DNA technologies are an alternative to inactivated virus and live attenuated virus vaccines. Internal highly conserved viral nucleoprotein (NP) can be delivered as a DNA vaccine to provide heterosubtypic immunity, offering resistance against various influenza virus strains. In this study, we investigated the efficacy of an NP DNA vaccine for induction of cell-mediated immune responses and protection against influenza virus infection in a mouse model of diabetes. Healthy and diabetic BALB/c mice were immunized on days 0, 14, and 28 by injection of NP DNA vaccine. Two weeks after the last immunization, the cellular immune response was evaluated by gamma interferon (IFN-gamma), lymphocyte proliferation, and cytotoxicity assays. The mice were challenged with influenza virus, and the viral titers in the lungs were measured on day 4. Diabetic mice showed significantly smaller amounts of IFN gamma production, lymphocyte proliferation, and cytotoxicity responses than nondiabetic mice. Furthermore, higher titers of the influenza virus were detected after challenge in the lungs of the diabetic mice. The present data suggest that the NP DNA vaccine with the protocol of immunization described here is not able to induce efficient cellular immune responses against influenza virus infection in diabetic mice. PMID- 20164253 TI - Identification of and human serum reactogenicity to neutralizing epitopes within the central unglycosylated region of the respiratory syncytial virus attachment protein. AB - We identified two overlapping neutralizing epitopes within residues 151 to 172 of the central unglycosylated region of the respiratory syncytial virus (RSV) attachment protein. In approximately 40% of hospitalized and outpatient adults infected with RSV subtype A, these contiguous residues are the target of > or =4 fold increases in IgG response between acute- and convalescent-phase sera. PMID- 20164254 TI - Prevalence of protective measles virus antibody levels in umbilical cord blood samples in Catalonia, Spain. AB - The prevalence of protective antibody levels (>160 mIU/ml) in neonates was 98.5%. The mean measles virus antibody level was 3,406 mIU/ml and increased with maternal age. Measles vaccination was reported by 42% of pregnant women and decreased with age. PMID- 20164255 TI - Immunological fingerprinting method for differentiation of serum samples in research-oriented biobanks. AB - An immunoenzymatic serum fingerprinting method was developed to establish a serum sample fingerprint based on IgG titers obtained with three different antigens. Three widely expressed antigens were selected for their capacity to induce long lasting humoral immune responses. This fingerprinting method may be used to differentiate between two serum samples and to determine whether they come from the same primary blood specimen. The method showed a specificity of 99.5%. This method is suitable as a quality control method for biobanked serum samples. PMID- 20164256 TI - p23/Tmp21 differentially targets the Rac-GAP beta2-chimaerin and protein kinase C via their C1 domains. AB - The C1 domains in protein kinase C (PKC) isozymes and other signaling molecules are responsible for binding the lipid second messenger diacylglycerol and phorbol esters, and for mediating translocation to membranes. Previous studies revealed that the C1 domain in alpha- and beta-chimaerins, diacylglycerol-regulated Rac GAPs, interacts with the endoplasmic reticulum/Golgi protein p23/Tmp21. Here, we found that p23/Tmp21 acts as a C1 domain-docking protein that mediates perinuclear translocation of beta2-chimaerin. Glu227 and Leu248 in the beta2 chimaerin C1 domain are crucial for binding p23/Tmp21 and perinuclear targeting. Interestingly, isolated C1 domains from individual PKC isozymes differentially interact with p23/Tmp21. For PKCepsilon, it interacts with p23/Tmp21 specifically via its C1b domain; however, this association is lost in response to phorbol esters. These results demonstrate that p23/Tmp21 acts as an anchor that distinctively modulates compartmentalization of C1 domain-containing proteins, and it plays an essential role in beta2-chimaerin relocalization. Our study also highlights the relevance of C1 domains in protein-protein interactions in addition to their well-established lipid-binding properties. PMID- 20164258 TI - Practical evaluation of a mouse with chimeric human liver model for hepatitis C virus infection using an NS3-4A protease inhibitor. AB - A small-animal model for hepatitis C virus (HCV) infection was developed using severe combined immunodeficiency (SCID) mice encoding homozygous urokinase-type plasminogen activator (uPA) transplanted with human hepatocytes. Currently, limited information is available concerning the HCV clearance rate in the SCID mouse model and the virion production rate in engrafted hepatocytes. In this study, several cohorts of uPA(+/+)/SCID(+/+) mice with nearly half of their livers repopulated by human hepatocytes were infected with HCV genotype 1b and used to evaluate HCV dynamics by pharmacokinetic and pharmacodynamic analyses of a specific NS3-4A protease inhibitor (telaprevir). A dose-dependent reduction in serum HCV RNA was observed. At telaprevir exposure equivalent to that in clinical studies, rapid turnover of serum HCV was also observed in this mouse model and the estimated slopes of virus decline were 0.11-0.17 log(10) h(-1). During the initial phase of treatment, the log(10) reduction level of HCV RNA was dependent on the drug concentration, which was about fourfold higher in the liver than in plasma. HCV RNA levels in the liver relative to human endogenous gene expression were correlated with serum HCV RNA levels at the end of treatment for up to 10 days. A mathematical model analysis of viral kinetics suggested that 1 g of the chimeric human liver could produce at least 10(8) virions per day, and this may be comparable to HCV production in the human liver. PMID- 20164257 TI - Tight junction-associated MARVEL proteins marveld3, tricellulin, and occludin have distinct but overlapping functions. AB - In vitro studies have demonstrated that occludin and tricellulin are important for tight junction barrier function, but in vivo data suggest that loss of these proteins can be overcome. The presence of a heretofore unknown, yet related, protein could explain these observations. Here, we report marvelD3, a novel tight junction protein that, like occludin and tricellulin, contains a conserved four transmembrane MARVEL (MAL and related proteins for vesicle trafficking and membrane link) domain. Phylogenetic tree reconstruction; analysis of RNA and protein tissue distribution; immunofluorescent and electron microscopic examination of subcellular localization; characterization of intracellular trafficking, protein interactions, dynamic behavior, and siRNA knockdown effects; and description of remodeling after in vivo immune activation show that marvelD3, occludin, and tricellulin have distinct but overlapping functions at the tight junction. Although marvelD3 is able to partially compensate for occludin or tricellulin loss, it cannot fully restore function. We conclude that marvelD3, occludin, and tricellulin define the tight junction-associated MARVEL protein family. The data further suggest that these proteins are best considered as a group with both redundant and unique contributions to epithelial function and tight junction regulation. PMID- 20164259 TI - Characterization of the Ebola virus nucleoprotein-RNA complex. AB - When Ebola virus nucleoprotein (NP) is expressed in mammalian cells, it assembles into helical structures. Here, the recombinant NP helix purified from cells expressing NP was characterized biochemically and morphologically. We found that the recombinant NP helix is associated with non-viral RNA, which is not protected from RNase digestion and that the morphology of the helix changes depending on the environmental salt concentration. The N-terminal 450 aa residues of NP are sufficient for these properties. However, digestion of the NP-associated RNA eliminates the plasticity of the helix, suggesting that this RNA is an essential structural component of the helix, binding to individual NP molecules via the N terminal 450 aa. These findings enhance our knowledge of Ebola virus assembly and understanding of the Ebola virus life cycle. PMID- 20164260 TI - Pathogenesis of Lymantria dispar multiple nucleopolyhedrovirus in L. dispar and mechanisms of developmental resistance. AB - Lymantria dispar has a long historical association with the baculovirus Lymantria dispar multiple nucleopolyhedrovirus (LdMNPV), which is one of the primary population regulators of L. dispar in the field. However, host larvae exhibit strong developmental resistance to fatal infection by LdMNPV; the LD50 in newly moulted fourth instars is 18-fold lower than in the middle of the instar (48-72 h post-moult). Using a recombinant of LdMNPV expressing lacZ, we examined the key steps of pathogenesis in the host to explore mechanisms of developmental resistance. At the midgut level, we observed reduced primary midgut infections in mid-fourth instars, indicating increased sloughing of infected cells. Additional barriers were observed as the virus escaped the midgut. Mid-fourth instars had higher numbers of melanized foci of infection associated with the midgut, apoptotic tracheal epidermal cells and haemocytes, and reduced numbers of infected haemocytes later in infection. Our results show that the co-evolutionary relationship between L. dispar and LdMNPV has resulted in both midgut-based and systemic antiviral defences and that these defences are age-dependent within the instar. This age-related susceptibility may contribute to how the virus is maintained in nature and could influence management of L. dispar by using the virus. PMID- 20164261 TI - Aerosol and nasal transmission of chronic wasting disease in cervidized mice. AB - Little is known regarding the potential risk posed by aerosolized prions. Chronic wasting disease (CWD) is transmitted horizontally, almost surely by mucosal exposure, and CWD prions are present in saliva and urine of infected animals. However, whether CWD may be transmissible by the aerosol or nasal route is not known. To address this question, FVB mice transgenetically expressing the normal cervid PrP(C) protein [Tg(cerPrP) mice] were exposed to CWD prions by either nose only aerosol exposure or by drop-wise instillation into the nostrils. Mice were monitored for signs of disease for up to 755 days post-inoculation (p.i.) and by examination of tissues for lesions and PrP(CWD) after necropsy. In particular, nasal mucosa, vomeronasal organ, lungs, lymphoid tissue and the brain were assessed for PrP(CWD) by Western blotting and immunohistochemistry. Six of seven aerosol-exposed Tg(cerPrP) mice developed clinical signs of neurological dysfunction mandating euthanasia between 411 and 749 days p.i. In all these mice, CWD infection was confirmed by detection of spongiform lesions and PrP(CWD) in the brain. Two of nine intranasally inoculated Tg(cerPrP) mice also developed transmissible spongiform encephalopathy associated with PrP(CWD) between 417 and 755 days p.i. No evidence of PrP(CWD) was detected in CWD-inoculated Tg(cerPrP) mice examined at pre-terminal time points. These results demonstrate that CWD can be transmitted by aerosol (as well as nasal) exposure and suggest that exposure via the respiratory system merits consideration for prion disease transmission and biosafety. PMID- 20164262 TI - Putative emergence of classical scrapie in a background of enzootic atypical scrapie. AB - Active transmissible spongiform encephalopathy (TSE) surveillance in small ruminants across Europe was implemented in 2002 following the epizootic of bovine spongiform encephalopathy. Here, we report the potential emergence of classical scrapie in Portugal, in a background of enzootic atypical scrapie. Between 2003 and 2008, 375,459 small ruminants were screened in total, with 328 animals confirmed positive for NOR98 atypical scrapie. During this period, the prevalence rate of atypical scrapie for all years combined was 0.0874% across the country. In this scenario, classical scrapie emerged as a single outbreak in 2008, with 12 identified cases. In contrast to other European countries, where classical scrapie has been enzootic for decades, these data indicate that, in Portugal, atypical scrapie is the predominant form of TSE. The findings reported here will have implications for the control of classical scrapie in Portugal, namely in terms of keeping the country free of enzootic classical scrapie. PMID- 20164263 TI - Crimean-Congo hemorrhagic fever virus infection is lethal for adult type I interferon receptor-knockout mice. AB - Crimean-Congo hemorrhagic fever virus (CCHFV) poses a great threat to public health due to its high mortality, transmission and geographical distribution. To date, there is no vaccine or specific treatment available and the knowledge regarding its pathogenesis is highly limited. Using a small-animal model system, this study showed that adult mice missing the type I interferon (IFN) receptor (IFNAR(-/-)) were susceptible to CCHFV and developed an acute disease with fatal outcome. In contrast, infection of wild-type mice (129 Sv/Ew) was asymptomatic. Viral RNA was found in all analysed organs of the infected mice, but the amount of CCHFV RNA was significantly higher in the IFNAR(-/-) mice than in the wild type mice. Furthermore, the liver of IFNAR(-/-) mice was enlarged significantly, showing that IFN is important for limiting virus spread and protecting against liver damage in mice. PMID- 20164264 TI - Binding of monoclonal antibodies to the movement protein (MP) of Tobacco mosaic virus: influence of subcellular MP localization and phosphorylation. AB - Monoclonal antibodies (mAbs) to recombinant movement protein (MP(REC)) of Tobacco mosaic virus (TMV) were used to reveal the dependence of MP epitope accessibility to mAbs on subcellular MP localization and post-translational MP phosphorylation. Leaves of Nicotiana benthamiana or N. tabacum were inoculated mechanically with TMV or agroinjected with an MP expression vector. At different time post inoculation, ER membrane- and cell wall-enriched fractions (ER-MP and CW-MP, respectively) were isolated and analysed. The N-terminal region (residues 1-30) as well as regions 186-222 and 223-257 of MP from the CW and ER fractions were accessible for interaction with mAbs. By contrast, the MP regions including residues 76-89 and 98-129 were not accessible. The C-terminal TMV MP region (residues 258-268) was inaccessible to mAbs not only in CW-MP, but also in ER-MP fractions. Evidence is presented that phosphorylation of the majority of TMV MP C terminal sites occurred on ER membranes at an early stage of virus infection, i.e. not after, but before reaching the cell wall. C-terminal phosphorylation of purified MP(REC) abolished recognition of C-proximal residues 258-268 by specific mAbs, which could be restored by MP dephosphorylation. Likewise, accessibility to mAbs of the C-terminal MP epitope in ER-MP and CW-MP leaf fractions was restored by dephosphorylation. Substitution of three or four C-terminal Ser/Thr residues with non-phosphorylatable Ala also resulted in abolition of interaction of mAbs with MP. PMID- 20164266 TI - Pitfalls in diagnosis of pandemic (novel) A/H1N1 2009 influenza. PMID- 20164265 TI - Regulation of the subcellular distribution of key cellular RNA-processing factors during permissive human cytomegalovirus infection. AB - Alternative splicing and polyadenylation of human cytomegalovirus (HCMV) immediate-early (IE) pre-mRNAs are temporally regulated and rely on cellular RNA processing factors. This study examined the location and abundance of essential RNA-processing factors, which affect alternative processing of UL37 IE pre-mRNAs, during HCMV infection. Serine/threonine protein kinase 1 (SRPK1) phosphorylates serine/arginine-rich proteins, necessary for pre-spliceosome commitment. It was found that HCMV infection progressively increased the abundance of cytoplasmic SRPK1, which is regulated by subcellular partitioning. The essential polyadenylation factor CstF-64 was similarly increased in abundance, albeit in the nucleus, proximal to and within viral replication compartments (VRCs). In contrast, the location of polypyrimidine tract-binding protein (PTB), known to adversely affect splicing of HCMV major IE RNAs, was temporally regulated during infection. PTB co-localized with CstF-64 in the nucleus at IE times. By early times, PTB was detected in punctate cytoplasmic sites of some infected cells. At late times, PTB relocalized to the nucleus, where it was notably excluded from HCMV VRCs. Moreover, HCMV infection induced the formation of nucleolar stress structures, fibrillarin-containing caps, in close proximity to its VRCs. PTB exclusion from HCMV VRCs required HCMV DNA synthesis and/or late gene expression, whereas the regulation of SRPK1 subcellular distribution did not. Taken together, these results indicated that HCMV increasingly regulates the subcellular distribution and abundance of essential RNA-processing factors, thereby altering their ability to affect the processing of viral pre-mRNAs. These results further suggest that HCMV infection selectively induces sorting of nucleolar and nucleoplasmic components. PMID- 20164267 TI - Molecular typing of pneumococci for investigation of linked cases of invasive pneumococcal disease. AB - In winter 2007-2008, an outbreak of pediatric pneumonia caused by serotype 5 pneumococci was identified in a northeast London suburb. Variable number of tandem repeat analyses clustered these pneumococci from the other serotype 5 pneumococci in the United Kingdom, highlighting the importance of this discriminative typing method in supporting epidemiological investigations. PMID- 20164268 TI - Evaluation of chromogenic media for detection of methicillin-resistant Staphylococcus aureus. AB - Rapid laboratory diagnosis is critical for treating, managing, and preventing methicillin-resistant Staphylococcus aureus (MRSA) infections. We evaluated and compared the potential for MRSA detection of five chromogenic media, Brilliance MRSA agar (Oxoid), ChromID (bioMerieux), MRSASelect (Bio-Rad), CHROMagar (CHROMagar Microbiology), and BBL-CHROMagar (BD Diagnostics). Media were tested with log serial dilutions (10(0) to 10(6) CFU) of pure isolates of MRSA (n = 60), non-MRSA (n = 27), and defined mixtures thereof simulating clinical samples (n = 84). Further evaluations were done on pre-enriched nasal and groin screening swabs (n = 213) from 165 hospitalized patients. Randomized samples were spiral plated on each medium and independently scored by five investigators for characteristic colonies at 24 and 48 h of incubation. Confirmatory testing of up to five putative MRSA colonies recovered from each medium was done. The cumulative average sensitivity with isolates, mixtures, and clinical samples was the highest for Brilliance MRSA agar (97%) and similar for the other four media (>or=92%). The cumulative average specificity was the highest for BBL-CHROMagar (99%), followed by MRSASelect (98%), CHROMagar (97%), ChromID (89%), and Brilliance MRSA agar (86%). All of the media detected MRSA at 10 and 1 CFU, although at these low loads, few MRSA samples harboring SCCmec type III or IV were misinterpreted as non-MRSA by investigators. False-positive results were mainly due to methicillin-resistant S. epidermidis. For an arbitrary MRSA prevalence of 5% and based on patient sample evaluations, the positive predictive values for BBL-CHROMagar and CHROMagar ( approximately 84%) were the highest. The negative predictive values of all of the media were >or=92% for MRSA prevalences ranging from 5% to 30%. In conclusion, BBL-CHROMagar and CHROMagar gave the best overall results for detection of MRSA, irrespective of the sample concentration, investigator, or incubation period. PMID- 20164269 TI - Matrix-assisted laser desorption ionization-time of flight mass spectrometry for direct bacterial identification from positive blood culture pellets. AB - An ammonium chloride erythrocyte-lysing procedure was used to prepare a bacterial pellet from positive blood cultures for direct matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry analysis. Identification was obtained for 78.7% of the pellets tested. Moreover, 99% of the MALDI-TOF identifications were congruent at the species level when considering valid scores. This fast and accurate method is promising. PMID- 20164270 TI - Decreased susceptibility to teicoplanin and vancomycin in coagulase-negative Staphylococci isolated from orthopedic-device-associated infections. AB - We studied 315 coagulase-negative Staphylococcus strains recovered prospectively during 240 surgical procedures (206 subjects) from proven or suspected device associated bone and joint infections. Sixteen strains (5.1%) had decreased susceptibility to glycopeptides: 15 (12 S. epidermidis strains, 2 S. capitis strains, and 1 S. haemolyticus strain) to teicoplanin alone (MIC of 16 mg/liter, n = 9; MIC of 32 mg/liter, n = 6) and one (S. epidermidis) to both teicoplanin and vancomycin (MIC, 16 and 8 mg/liter, respectively). Decreased susceptibility to teicoplanin was more prevalent in "infecting" strains (i.e., strains recovered from >/=2 distinct intraoperative samples) than in "contaminants" (i.e., strains not fulfilling this criterion) (8.1% [12/149] versus 2.4% [4/166], respectively [P = 0.022]). One hundred percent (13/13) of S. epidermidis strains with decreased susceptibility to teicoplanin were resistant to methicillin (versus 112/173 [64.7%] for S. epidermidis strains susceptible to teicoplanin; P = 0.021). PMID- 20164271 TI - Comparison of two matrix-assisted laser desorption ionization-time of flight mass spectrometry methods with conventional phenotypic identification for routine identification of bacteria to the species level. AB - Bacterial identification relies primarily on culture-based methodologies requiring 24 h for isolation and an additional 24 to 48 h for species identification. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) is an emerging technology newly applied to the problem of bacterial species identification. We evaluated two MALDI-TOF MS systems with 720 consecutively isolated bacterial colonies under routine clinical laboratory conditions. Isolates were analyzed in parallel on both devices, using the manufacturers' default recommendations. We compared MS with conventional biochemical test system identifications. Discordant results were resolved with "gold standard" 16S rRNA gene sequencing. The first MS system (Bruker) gave high confidence identifications for 680 isolates, of which 674 (99.1%) were correct; the second MS system (Shimadzu) gave high-confidence identifications for 639 isolates, of which 635 (99.4%) were correct. Had MS been used for initial testing and biochemical identification used only in the absence of high-confidence MS identifications, the laboratory would have saved approximately US$5 per isolate in marginal costs and reduced average turnaround time by more than an 8-h shift, with no loss in accuracy. Our data suggest that implementation of MS as a first test strategy for one-step species identification would improve timeliness and reduce isolate identification costs in clinical bacteriology laboratories now. PMID- 20164272 TI - Development of a multiplex primer extension assay for rapid detection of Salmonella isolates of diverse serotypes. AB - Food-borne salmonellosis is a major manifestation of gastrointestinal disease in humans across the globe. Accurate and rapid identification methods could positively impact the identification of isolates, enhance outbreak investigation, and aid infection control. The SNaPshot multiplex system is a primer extension based method that enables multiplexing of single nucleotide polymorphisms (SNPs). Here the method has been developed for the identification of five Salmonella serotypes, commonly detected in the United Kingdom, based on serotype-specific SNPs identified in the multilocus sequence typing (MLST) database of Salmonella enterica. The SNPs, in genes hemD, thrA, purE, and sucA, acted as surrogate markers for S. enterica serovars Typhimurium, Enteritidis, Virchow, Infantis, and Braenderup. The multiplex primer extension assay (MPEA) was conducted in two separate panels and evaluated using 152 Salmonella enterica isolates that were characterized by MLST. The MPEA was shown to be 100% specific and sensitive, within this collection of isolates. The MPEA is a sensitive and specific method for the identification and detection of Salmonella serotypes based upon SNPs seen in MLST data. The method can be applied in less than 6 h and has the potential to improve patient care and source tracing. The utility of the assay for identification of Salmonella serotypes directly from clinical specimens and food samples warrants further investigation. PMID- 20164273 TI - Comparison of traditional phenotypic identification methods with partial 5' 16S rRNA gene sequencing for species-level identification of nonfermenting Gram negative bacilli. AB - Correct identification of nonfermenting Gram-negative bacilli (NFB) is crucial for patient management. We compared phenotypic identifications of 96 clinical NFB isolates with identifications obtained by 5' 16S rRNA gene sequencing. Sequencing identified 88 isolates (91.7%) with >99% similarity to a sequence from the assigned species; 61.5% of sequencing results were concordant with phenotypic results, indicating the usability of sequencing to identify NFB. PMID- 20164274 TI - Randomized, double-blind crossover study of vaginal microflora and epithelium in women using a tampon with a "winged" apertured film cover and a commercial tampon with a nonwoven fleece cover. AB - This study compared the safety of a new tampon with a four-winged apertured film cover over its nonwoven cover to improve leakage performance with that of a commercial tampon with a nonwoven cover only. Healthy women (evaluable, n = 69) were randomized to crossover between test and reference tampons in two consecutive menstrual cycles. Qualitative and quantitative analyses of vaginal cultures were conducted pre-, mid-, and postmenstrually for a broad panel of microorganisms, and colposcopy was performed. Similar to previous studies, prevalence and mean colony counts of the majority of microorganisms generally increased midmenstrually and returned or began to return postmenstrually. In contrast to most previous studies, Lactobacillus species remained at similar levels throughout the cycles with both tampons. Neither tampon was associated with clinically significant microbiological changes or abnormalities or with vaginal/cervical epithelial integrity changes on colposcopy. Microbiological and colposcopic evaluations indicate that the apertured film-covered tampon is safe. PMID- 20164275 TI - Development of real-time PCR assays for detection of the Streptococcus milleri group from cystic fibrosis clinical specimens by targeting the cpn60 and 16S rRNA genes. AB - Cystic fibrosis (CF) is a multiorgan disease, with the majority of mortalities resulting from pulmonary failure due to repeated pulmonary exacerbations. Recently, members of the Streptococcus anginosus group (S. anginosus, S. constellatus, and S. intermedius), herein referred to as the "Streptococcus milleri group" (SMG) have been implicated as important etiological pathogens contributing to pulmonary exacerbations in CF patients. This is partly due to better microbiological detection of the SMG species through the development of a novel specific medium termed "McKay agar." McKay agar demonstrated that SMG has been an underreported respiratory pathogen contributing to lung exacerbations. Our aim was to develop a real-time PCR assay to expedite the detection of SMG within diagnostic samples. The cpn60 gene was chosen as a target, with all three members amplified using a single hybridization probe set. SMG strain analysis showed that speciation based on melting curve analysis allowed for the majority of the S. constellatus (96%), S. intermedius (94%), and S. anginosus (60%) strains to be correctly identified. To increase specificity for S. anginosus, two 16S rRNA real-time PCR assays were developed targeting the 16S rRNA gene. The 16s_SA assay is specific for S. anginosus (100%), while the 16s_SCI assay is specific for S. constellatus and S. intermedius (100%). These assays can detect <10 genome equivalents in pure culture and >10(4) genome equivalents in sputum samples, making this a great tool for assessment of the presence of SMG in complex polymicrobial samples. Novel molecular methods were developed providing detection ability for SMG, an emerging opportunistic pathogen. PMID- 20164276 TI - Frequent detection of noroviruses and sapoviruses in swine and high genetic diversity of porcine sapovirus in Japan during Fiscal Year 2008. AB - A molecular biological survey on porcine norovirus (NoV) and sapovirus (SaV) was conducted in Toyama Prefecture, Japan, during fiscal year 2008. Both NoV and SaV were detected from swine fecal samples throughout the surveillance period, indicating that these viruses were circulating in this region. NoV strains detected in this study belonged to three genotypes that are known as typical swine NoVs. Although human NoVs were occasionally detected, it was unclear whether they replicated in pigs. As for SaV, genogroup VII (GVII) and other divergent genogroups were identified in addition to the dominant genogroup, GIII, which is the prototypic porcine SaV. In addition, 3 strains genetically related to human SaV were detected. Two of these 3 strains were closely related to human SaV GV. Our study showed that genetic diversification of porcine SaV is currently progressing in the swine population. PMID- 20164277 TI - Validation of factor 6d antiserum for serotyping Streptococcus pneumoniae serotype 6C. AB - Factor 6d antiserum reacts with the new Streptococcus pneumoniae serotype 6C. Serogroup 6 isolates, consisting of 49 6A, 42 6B and 98 6C strains from the United States and Israel, serotyped in parallel by PCR and capsular swelling methods, were all identified correctly. The new factor 6d antiserum accurately identifies serotype 6C. PMID- 20164279 TI - Catheter-related bacteremia caused by Staphylococcus pseudintermedius refractory to antibiotic-lock therapy in a hemophilic child with dog exposure. AB - We describe a case of catheter-related bacteremia due to Staphylococcus pseudintermedius in a child with dog exposure. The organism was confirmed as S. pseudintermedius based on 16S rRNA gene sequence analysis and positive PCR restriction fragment length polymorphism of the pta gene. PMID- 20164278 TI - Molecular identification and analysis of nonserotypeable human enteroviruses. AB - Conventional approaches to characterizing human enteroviruses (HEVs) are based on viral isolation and neutralization. Molecular typing methods depend largely on reverse transcription-PCR (RT-PCR) and nucleotide sequencing of the entire or partial VP1 gene. A modified RT-PCR-based reverse line blot (RLB) hybridization assay was developed as a rapid and efficient way to characterize common and nonserotypeable (by neutralization) HEVs. Twenty HEV serotypes accounted for 87.1% of all HEVs isolated at a reference laboratory from 1979 to 2007; these common serotypes were identified using one sense and three antisense primers and a set of 80 serotype-specific probes in VP1 (F. Zhou et al., J. Clin. Microbiol. 47:2737-2743, 2009). In this study, one HEV-specific primer pair, two probes in the 5' untranslated region (UTR), and a new set of 80 serotype-specific probes in VP1 were designed. First, we successfully applied the modified RT-PCR-RLB (using two HEV-specific probes and two sets of serotype-specific probes) to synchronously detect the 5' UTR and VP1 regions of 131/132 isolates previously studied (F. Zhou et al., J. Clin. Microbiol. 47:2737-2743, 2009). Then, this method was used to identify 73/92 nonserotypeable HEV isolates; 19 nonserotypeable isolates were hybridized only with HEV-specific probes. The VP1 region of 92 nonserotypeable HEV isolates was sequenced; 73 sequences corresponded with one or both RLB results and 19 (not belonging to the 20 most common genotypes) were identified only by sequencing. Two sets of serotype specific probes can capture the majority of strains belonging to the 20 most common serotypes/genotypes simultaneously or complementarily. Synchronous detection of the 5' UTR and VP1 region by RT-PCR-RLB will facilitate the identification of HEVs, especially nonserotypeable isolates. PMID- 20164280 TI - Rapid detection of rifampicin- and isoniazid-resistant Mycobacterium tuberculosis by high-resolution melting analysis. AB - We have developed a high-resolution melting (HRM) assay to scan for mutations in the rpoB, inhA, ahpC, and katG genes and/or promoter regions for the detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis. For assay development, 23 drug-resistant isolates of M. tuberculosis having 29 different mutations, together with 40 drug-susceptible isolates, were utilized. All 29 mutations were accurately detected by our assay. We further validated the assay with a series of 59 samples tested in a blind manner. All sequence alterations that were within the regions targeted by the HRM assay were correctly identified. Compared against results of DNA sequencing, the sensitivity and specificity of our HRM assay were 100%. For the blinded samples, the specificities and sensitivities were 89.3% and 100%, respectively, for detecting rifampin resistance and 98.1% and 83.3%, respectively, for detecting isoniazid resistance, as isolates with mutations in regions not encompassed by our assay were not detected. A C-to-T sequence alteration at position -15 of the ahpC regulatory region, which was previously reported to be associated with isoniazid resistance, may possibly be a polymorphism, as it was detected in an isoniazid-susceptible M. tuberculosis isolate. HRM is a rapid, accurate, simple, closed-tube, and low-cost method. It is thus an ideal assay to be used in countries with a high prevalence of drug-resistant M. tuberculosis and where cost-effectiveness is essential. As a mutation-scanning assay for detecting drug-resistant M. tuberculosis, it can potentially lead to better treatment outcomes resulting from earlier treatment with the appropriate antibiotics. PMID- 20164281 TI - Performance evaluation of the new Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 test version 2.0 for quantification of human immunodeficiency virus type 1 RNA. AB - Despite FDA approval and CE marking of commercial tests, manufacturer-independent testing of the technical aspects of newly developed tests is important. To evaluate the analytical performance and explore the clinical applicability of the new Roche COBAS AmpliPrep COBAS TaqMan HIV-1 test, version 2.0 (CAP/CTM v2.0), platform comparison was performed with the Roche CAP/CTM test, version 2.0, the COBAS Amplicor HIV-1 Monitor Test, version 1.5 (CAP/CA v1.5), the COBAS AmpliPrep COBAS TaqMan HIV-1 Test (CAP/CTM v1.0), and the Abbott m2000 RealTime HIV-1 assay on panels and diagnostic samples. Specificity was tested for HIV-2 samples. Furthermore, samples from HIV-1-seropositive individuals with CAP/CA v1.5 measured viral loads below 50 HIV-1 RNA copies per ml (cp/ml) and replicates of HIV-1-seronegative plasma were tested in a checkerboard analysis. CAP/CTM v2.0 is HIV-1 specific, with broad genotype inclusivity and no serious underquantification of viral load relative to the other assays used. Low viral loads below the threshold of quantification for CAP/CA v1.5 are observed with CAP/CTM v2.0. A CAP/CTM v2.0-measured viral load of >50 copies/ml in these samples correlated with therapy failure. In conclusion, CAP/CTM v2.0 is an accurate and reliable test for HIV-1 viral load measurement relative to the other assays used with respect to specificity, sensitivity, and genotype inclusivity. PMID- 20164282 TI - Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-year analysis of susceptibilities of Candida Species to fluconazole and voriconazole as determined by CLSI standardized disk diffusion. AB - Fluconazole in vitro susceptibility test results for 256,882 isolates of Candida spp. were collected from 142 sites in 41 countries from June 1997 to December 2007. Data were collected for 197,619 isolates tested with voriconazole from 2001 to 2007. A total of 31 different species of Candida were isolated. Increased rates of isolation of the common non-albicans species C. glabrata (10.2% to 11.7%), C. tropicalis (5.4% to 8.0%), and C. parapsilosis (4.8% to 5.6%) were noted when the time periods 1997 to 2000 and 2005 to 2007 were compared. Investigators tested clinical isolates of Candida spp. by the CLSI M44-A disk diffusion method. Overall, 90.2% of Candida isolates tested were susceptible (S) to fluconazole; however, 13 of 31 species identified exhibited decreased susceptibility (<75% S), similar to that seen with the resistant (R) species C. glabrata and C. krusei. Among 197,619 isolates of Candida spp. tested against voriconazole, 95.0% were S and 3% were R. About 30% of fluconazole-R isolates of C. albicans, C. glabrata, C. tropicalis, C. rugosa, C. lipolytica, C. pelliculosa, C. apicola, C. haemulonii, C. humicola, C. lambica, and C. ciferrii remained S to voriconazole. An increase in fluconazole resistance over time was seen with C. parapsilosis, C. guilliermondii, C. lusitaniae, C. sake, and C. pelliculosa. Among the emerging fluconazole-R species were C. guilliermondii (11.4% R), C. inconspicua (53.2% R), C. rugosa (41.8% R), and C. norvegensis (40.7% R). The rates of isolation of C. rugosa, C. inconspicua, and C. norvegensis increased by 5- to 10-fold over the 10.5-year study period. C. guilliermondii and C. rugosa were most prominent in Latin America, whereas C. inconspicua and C. norvegensis were most common in Eastern European countries. This survey identifies several less-common species of Candida with decreased susceptibility to azoles. These organisms may pose a future threat to optimal antifungal therapy and underscore the importance of prompt and accurate species identification and antifungal susceptibility testing. PMID- 20164283 TI - Improved diagnosis of periprosthetic joint infection by multiplex PCR of sonication fluid from removed implants. AB - The microbiological diagnosis of periprosthetic joint infection (PJI) is crucial for successful antimicrobial treatment. Cultures have limited sensitivity, especially in patients receiving antibiotics. We evaluated the value of multiplex PCR for detection of microbial DNA in sonication fluid from removed orthopedic prostheses. Cases of PJI in which the prosthesis (or part of it) was removed were prospectively included. The removed implant was sonicated, and the resulting sonication fluid was cultured and subjected to multiplex PCR. Of 37 PJI cases (17 hip prostheses, 14 knee prostheses, 4 shoulder prostheses, 1 elbow prosthesis, and 1 ankle prosthesis), pathogens were identified in periprosthetic tissue in 24 (65%) cases, in sonication fluid in 23 (62%) cases, and by multiplex PCR in 29 (78%) cases. The pathogen was detected in 5 cases in sonication fluid only (Propionibacterium acnes in all cases; none of these patients had previously received antibiotics) and in 11 cases by multiplex PCR only (all of these patients had previously received antibiotics). After exclusion of 8 cases caused by P. acnes or Corynebacterium species, which cannot be detected due to the absence of specific primers in the PCR kit, sonication cultures were positive in 17 cases and multiplex PCR sonication cultures were positive in 29 cases (59% versus 100%, respectively; P < 0.01). Among 19 cases (51%) receiving antibiotics, multiplex PCR was positive in all 19 (100%), whereas sonication cultures grew the organism in 8 (42%) (P < 0.01). Multiplex PCR of sonication fluid is a promising test for diagnosis of PJI, particularly in patients who previously received antibiotics. With modified primer sets, multiplex PCR has the potential for further improvement of the diagnosis of PJI. PMID- 20164284 TI - Correction of underquantification of human immunodeficiency virus type 1 load with the second version of the Roche Cobas AmpliPrep/Cobas TaqMan assay. AB - Initial evaluations of the Cobas AmpliPrep/Cobas TaqMan human immunodeficiency virus type 1 (HIV-1) test (CAP/CTM) demonstrated good performance but, afterwards, reports about underquantification were published. We investigated whether the problem was solved with a second version of this assay, the Cobas AmpliPrep/Cobas TaqMan HIV-1 test, version 2.0 (CAP/CTM v2.0). The remaining plasma of 375 consecutive HIV-1 positive samples with a viral load of >or=4,000 copies/ml was collected in three laboratories. The samples were diluted and retested with our routine method Cobas AmpliPrep/Cobas Amplicor HIV-1 monitor test v1.5 in ultrasensitive mode (CAP/CA PHS), as well as with the CAP/CTM and CAP/CTM v2.0 tests. An absolute difference between the results of two methods of >or=0.71 log(10) copies/ml was defined as moderately discrepant, and an absolute difference of >or=0.93 log(10) copies/ml was defined as severely discrepant. In addition, criteria for considering the new methods equivalent to the routine method were formulated. (i) For CAP/CTM compared to CAP/CA PHS, 36 (9.5%) and 20 (5.3%) samples were, respectively, considered moderately and severely underquantified by CAP/CTM. The mean difference between CAP/CTM and CAP/CA PHS was -0.32 log(10) copies/ml. Eight of nineteen of the severely underquantified samples were from patients infected with HIV-1 subtype B strain. (ii) For CAP/CTM v2.0 compared to CAP/CA PHS, no sample was moderately or severely underquantified by CAP/CTM v2.0. A mean difference of 0.08 log(10) copies/ml was found with CAP/CTM v2.0 compared to CAP/CA PHS. The underquantification problem of the CAP/CTM kit was clearly demonstrated. The criteria for the equivalence of CAP/CTM v2.0 to the routine test CAP/CA PHS were fulfilled. PMID- 20164285 TI - Performance of an agar dilution method and a Vitek 2 card for detection of inducible clindamycin resistance in Staphylococcus spp. AB - The D-zone test detects inducible clindamycin resistance in Staphylococcus spp. Two other methods not described by the Clinical and Laboratory Standards Institute (CLSI) are available to test for this resistance mechanism: an agar dilution method and new Vitek 2 cards. This study evaluated the performance of both methods in detecting inducible clindamycin resistance. Nonduplicate clinical strains of Staphylococcus spp. (111 Staphylococcus aureus and 52 coagulase negative staphylococcus strains), intermediate or resistant to erythromycin but susceptible to clindamycin, were obtained from three hospitals in Montreal, Quebec, Canada. Molecular analysis to detect resistance genes was conducted on all strains. A Mueller-Hinton agar containing 1 mg of erythromycin and 0.5 mg of clindamycin/liter was used for the dilution method, and two inocula were tested: 10(4) and 10(5) CFU per spot. Plates were read at 24 and 48 h. The Vitek 2 AST P580 card was used according to the manufacturer's recommendations. The results were compared to those of the D-zone test. The D-zone test was positive in 134 of 163 (82%) strains. With the 10(4) CFU inoculum, the sensitivities were 84 and 99% at 24 and 48 h, respectively. The 10(5) CFU inoculum increased the sensitivities at 24 and 48 h to 91 and 100%, respectively. The specificity was 100% for the 10(4) CFU inoculum at 24 h and 97% for the other combinations. The sensitivity and specificity for the Vitek 2 card were 93 and 100%, respectively. The performance of both the agar dilution method and the Vitek 2 card was good, but these methods were not as sensitive as the D-zone test at 24 h. PMID- 20164286 TI - Application of an improved enzyme-linked immunosorbent assay method for serological diagnosis of canine leishmaniasis. AB - Accurate diagnosis of canine leishmaniasis (CanL) is essential toward a more efficient control of this zoonosis, but it remains problematic due to the high incidence of asymptomatic infections. In this study, we present data on the development of enzyme-linked immunosorbent assay (ELISA)-based techniques for the detection of antibodies against the recombinant protein Leishmania infantum cytosolic tryparedoxin peroxidase (LicTXNPx) and a comparison of the results with those employing soluble Leishmania antigens from promastigote or amastigote forms and the homologue recombinant protein L. infantum mitochondrial TXNPx (LimTXNPx). Moreover, we offer an evaluation of the diagnostic potential of rK39 for CanL in the Portuguese canine population and propose an improvement to the existing ELISA based serological techniques by combining the LicTXNPx and rK39 antigens as a Leishmania antigen mixture (LAM). The data demonstrated that ELISAs based on soluble promastigote or amastigote antigens had generally higher levels of sensitivity for detection of antibodies in symptomatic or asymptomatic dogs than for detection of those against isolated recombinant proteins. Nevertheless, the specificities were found to be similar for all target antigens used. Importantly, the LAM-ELISA methodology improved the overall sensitivity, maintaining a high overall level of specificity. In addition, it was demonstrated that the detection of anti-LAM IgG2 can increase the accuracy of the serological diagnosis. Overall, the obtained results showed that the strategy of combining two well-defined Leishmania antigens, LicTXNPx and rK39, proved to be a sensitive and specific improvement to current serological diagnosis of CanL, being a useful tool for the detection of both clinical and subclinical forms of canine Leishmania infection. PMID- 20164287 TI - Prognostic factors in prolactin pituitary tumors: clinical, histological, and molecular data from a series of 94 patients with a long postoperative follow-up. AB - CONTEXT AND OBJECTIVE: Predicting pituitary tumor behavior remains a challenge. This multiparameter investigation aimed to identify markers for recurrence and progression in prolactin tumors. DESIGN: From a cohort of patients treated for prolactin tumors by surgery, we retrospectively studied clinical data, tumor characteristics, clinical outcome, and the expression of nine genes by quantitative RT-PCR. RESULTS: This study included 94 patients (62 females and 32 men), with long postoperative follow-up periods (mean, 138 +/- 46 months); 54.3% of patients had a macro or giant adenoma. Tumors were classified into three pathological groups based on their radiological and histological characteristics (noninvasive, 61; invasive, 22; and aggressive-invasive, 11). Immediately after surgery, 60 patients (63.8%) went into remission (prolactin level normalization). Persistently elevated prolactin levels (36.2%) were associated with increasing age, male sex, high preoperative prolactin levels, large tumor size on univariate analysis, and invasion and pathological classification on univariate and multivariate (P = 8 x 10(-10) and 3 x 10(-8)) analysis. During follow-up, 19 patients (20%) had tumors that recurred or progressed under dopamine agonist treatment. Invasion and pathological classification were associated with recurrence or progression on univariate analysis. Seven genes (ADAMTS6, CRMP1, PTTG, ASK, CCNB1, AURKB, and CENPE) were associated with tumor recurrence or progression and five of these (ADAMTS6, CRMP1, ASK, CCNB1, and CENPE) were associated with the pathological classification. CONCLUSION: This study identifies both the clinical and histological factors that relate to prolactin tumor recurrence or progression. Molecular markers give additional information for prognosis of such tumors. Altogether, our results could influence the management of patients with pituitary tumors. PMID- 20164288 TI - Calcium-sensing receptor (CASR) mutations in hypercalcemic states: studies from a single endocrine clinic over three years. AB - CONTEXT: Inactivating mutations of the calcium-sensing receptor (CASR) are implicated in different hypercalcemic syndromes, including familial hypocalciuric hypercalcemia (FHH), primary hyperparathyroidism (PHPT), and familial isolated hyperparathyroidism (FIHP). However, molecular diagnostics applied to large nonselected hypercalcemic cohorts from a single center have not been reported. OBJECTIVE: Our objective was to describe the prevalence, type, and potential pathogenicity of CASR mutations in a series of cases with FHH (n = 17), PHPT (n = 165), and FIHP (n = 3) and controls (n = 198) presenting at a single endocrine clinic. SUBJECTS: All were prospectively evaluated at the "Casa Sollievo della Sofferenza" Hospital in southern Italy over a 3-yr period. METHODS: CASR screening was conducted by denaturing HPLC. The variant CASRs were functionally characterized by transient transfection studies in kidney cells in vitro. RESULTS: A single novel missense variant was identified in one PHPT case. However, in FHH probands, mutations were found in eight of 17 (47%). With a hypercalcemic family member, mutation detection rate in FHH rose to seven of eight (87%), whereas only one of nine sporadic cases was positive, and none of the three FIHP cases had detectable CASR mutations. Five missense variant CASRs, identified in control subjects, performed as wild type in functional assays, whereas the missense mutant CASRs identified in the FHH patients, and in the one PHPT case, exhibited significant impairment. A novel intronic mutation (IVS4-19a- >c) found in one FHH family, created an abnormally spliced product in an in vitro minigene assay. CONCLUSION: CASR testing, with functional analysis, provides critical confirmatory evidence in the differential diagnosis of hypercalcemic states. PMID- 20164289 TI - Pseudotumor cerebri after surgical remission of Cushing's disease. AB - CONTEXT: Pseudotumor cerebri has only been described after successful surgery for Cushing's disease (CD) in case reports. We sought to establish the incidence and timing of its occurrence, identify predisposing factors, characterize the clinical presentations and their severity, and examine the effects of treatment in patients who underwent surgery for CD. SETTING: This study was conducted at two tertiary care centers: The University of Virginia and the National Institutes of Health. PATIENTS: We conducted a retrospective review of 941 surgeries for CD (723 adults, 218 children) to identify patients who developed pseudotumor cerebri after surgery for CD and examine the associated clinical features. RESULTS: Seven children (four males, three females; 3%), but no adults, developed pseudotumor cerebri postoperatively. All underwent resection of an ACTH-secreting adenoma, and postoperative serum cortisol reached a nadir of less than 2 microg/dl. After surgery, all were placed on tapering hydrocortisone replacement therapy. Within 3 52 wk, all seven patients experienced symptoms of pseudotumor cerebri and had ophthalmological examination demonstrating papilledema. One patient had diplopia from a unilateral VIth nerve palsy. Six patients were still on steroid replacement at onset of symptoms. In three patients, a lumbar puncture demonstrated elevated opening pressure. Four patients were treated successfully with a lumbar puncture, steroids, and/or Diamox. Three patients did not receive treatment, and their symptoms resolved over several months. There was no correlation between the degree of hypercortisolism (24-h urinary free cortisol) before surgery and the likelihood of developing pseudotumor cerebri after surgery (P < 0.23). CONCLUSIONS: This series demonstrates a 3% occurrence of pseudotumor cerebri in children after successful surgery for CD, but the absence of the syndrome in adults. Pseudotumor cerebri manifests itself within 1 yr of surgery, often while patients are still undergoing replacement steroid therapy. A patient exhibiting signs of intracranial hypertension after surgery for CD should undergo an evaluation for pseudotumor cerebri. Recognition of the symptoms and treatment should correct and/or prevent ophthalmological sequelae. PMID- 20164291 TI - Hypoadiponectinemia--cause or consequence of human "insulin resistance"? AB - CONTEXT: Adiponectin is a highly abundant plasma protein synthesized nearly exclusively in adipose tissue from the ADIPOQ gene. It has excited intense interest because of robust correlation of its circulating levels with indices of insulin resistance (IR) and risk of type 2 diabetes, and their unusual inverse relationship with fat mass. It has been suggested that pharmacological strategies aimed at augmenting adiponectin levels or action may generate novel insulin sensitizing drugs. EVIDENCE ACQUISITION: Relevant publications were identified by searching PubMed, with secondary searches of their bibliographies. EVIDENCE SYNTHESIS: Rodent studies suggest that adiponectin exerts a direct insulin sensitizing effect on the liver, consistent with a role in the pathogenesis of prevalent forms of IR and its sequelae. However, the complex higher-order structure of adiponectin and inconsistent reports regarding its putative receptors have complicated efforts to understand the mechanistic basis of this. No proof yet exists that adiponectin modulates insulin sensitivity in humans, and genetic, biochemical, and physiological evidence suggests that low adiponectin levels may be a consequence of IR with compensatory hyperinsulinemia. This suggests that there may be a bidirectional relationship between IR and hypoadiponectinemia in humans. CONCLUSIONS: The relationship between adiponectin and insulin action in humans is more complex than often suggested. Further investigation of the direction of causality in this relationship, allied to studies of the cellular mechanisms involved, will be central to improving understanding of the physiological role of this enigmatic protein, and to efforts to exploit it for therapeutic benefit. PMID- 20164290 TI - Vitamin D status and its relation to muscle mass and muscle fat in young women. AB - CONTEXT: Vitamin D insufficiency has now reached epidemic proportions and has been linked to increased body fat and decreased muscle strength. Whether vitamin D insufficiency is also related to adipose tissue infiltration in muscle is not known. OBJECTIVE: The objective of the study was to examine the relationship between serum 25-hydroxyvitamin D (25OHD) and the degree of fat infiltration in muscle. DESIGN: This was a cross-sectional study. OUTCOME MEASURES AND SUBJECTS: Measures were anthropometric measures, serum 25OHD radioimmunoassay values, and computed tomography (CT) values of fat, muscle mass, and percent muscle fat in 90 postpubertal females, aged 16-22 yr, residing in California. RESULTS: Approximately 59% of subjects were 25OHD insufficient (< or = 29 ng/ml), of which 24% were deficient (< or = 20 ng/ml), whereas 41% were sufficient (> or = 30 ng/ml). A strong negative relationship was present between serum 25OHD and CT measures of percent muscle fat (r = -0.37; P < 0.001). In contrast, no relationship was observed between circulating 25OHD concentrations and CT measures of thigh muscle area (r = 0.16; P = 0.14). Multiple regression analysis indicated that the relation between 25OHD and muscle adiposity was independent of body mass or CT measures of sc and visceral fat. Percent muscle fat was significantly lower in women with normal serum 25OHD concentrations than in women with insufficient levels and deficient levels (3.15 +/- 1.4 vs. 3.90 +/- 1.9; P = 0.038). CONCLUSIONS: We found that vitamin D insufficiency is associated with increased fat infiltration in muscle in healthy young women. PMID- 20164292 TI - Genome-wide association study of bone mineral density in premenopausal European American women and replication in African-American women. AB - CONTEXT: Several genome-wide association studies (GWAS) have been performed to identify genes contributing to bone mineral density (BMD), typically in samples of elderly women and men. OBJECTIVE: The objective of the study was to identify genes contributing to BMD in premenopausal women. DESIGN: GWAS using the Illumina 610Quad array in premenopausal European-American (EA) women and replication of the top 50 single-nucleotide polymorphisms (SNPs) for two BMD measures in African American (AA) women. SUBJECTS: Subjects included 1524 premenopausal EA women aged 20-45 yr from 762 sibships and 669 AA premenopausal women aged 20-44 yr from 383 sibships. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: BMD was measured at the lumbar spine and femoral neck by dual-energy x-ray absorptiometry. Age- and weight-adjusted BMD values were tested for association with each SNP, with P values determined by permutation. RESULTS: SNPs in CATSPERB on chromosome 14 provided evidence of association with femoral neck BMD (rs1298989, P = 2.7 x 10(-5); rs1285635, P = 3.0 x 10(-5)) in the EA women, and some supporting evidence was also observed with these SNPs in the AA women (rs1285635, P = 0.003). Genes identified in other BMD GWAS studies, including IBSP and ADAMTS18, were also among the most significant findings in our GWAS. CONCLUSIONS: Evidence of association to several novel loci was detected in a GWAS of premenopausal EA women, and SNPs in one of these loci also provided supporting evidence in a sample of AA women. PMID- 20164293 TI - Cathepsins in human obesity: changes in energy balance predominantly affect cathepsin s in adipose tissue and in circulation. AB - CONTEXT: Recent studies in humans and mice suggest the implication of the cysteine proteases cathepsins S, L, and K in vascular and metabolic complications of obesity. OBJECTIVE: Our objective was to identify clinically relevant forms of cathepsin in human obesity. DESIGN AND SETTING: We conducted a prospective study on two independent cohorts. PARTICIPANTS AND INTERVENTIONS: The first cohort includes 45 obese women eligible for gastric surgery (age, 39 +/- 1.6 yr; body mass index, 47 +/- 0.99 kg/m(2)) and 17 nonobese women (age, 38 +/- 1.8 yr; body mass index, 21 +/- 0.44 kg/m(2)). The second cohort comprises 29 obese women (age, 57 +/- 0.8 yr; body mass index, 34 +/- 0.69 kg/m(2)) undergoing 6 months of medically supervised caloric restriction. MAIN OUTCOMES: Cathepsin S, L, and K mRNA levels were determined in surgical adipose tissue biopsies. The proteins were measured in conditioned medium of adipose tissue explants and in circulation. RESULTS: Obese subjects had a 2-fold increase in cathepsin S mRNA in adipose tissue as compared with normal-weight subjects and an increased rate (1.5 fold) of cathepsin S release in adipose tissue explants. Cathepsin S circulating concentrations were increased with obesity (+30%) and reduced after weight reduction (P < 0.05 for both). By contrast, cathepsin L was unaffected in adipose tissue and serum; cathepsin K was undetectable in circulation and unchanged in adipose tissue. CONCLUSION: In humans, cathepsin S is more influenced than cathepsins L and K by changes in energy balance in adipose tissue and circulation. This opens new avenues to explore whether selective inhibition of this protease could reduce cardiovascular risk and ameliorate metabolic status in obese subjects. PMID- 20164294 TI - Tall stature without growth hormone: four male patients with aromatase deficiency. AB - CONTEXT: From preliminary observations, GH-IGF-I seems to be compromised in men with aromatase deficiency. The GH deficiency (GHD) coexists paradoxically with tall stature, raising the question whether or not a true GHD is part of this rare syndrome. OBJECTIVE: To evaluate the GH secretion in aromatase-deficient men, their GH response to the GHRH plus arginine (GHRH-ARG) test was compared with that of normal subjects. The effect of estrogen replacement treatment on the GH IGF-I axis in aromatase-deficient men was evaluated before and during therapy. DESIGN AND SETTING: A case-control study was conducted. PATIENTS: Four adult men with aromatase deficiency were compared with 12 normal subjects. MAIN OUTCOME MEASURES: We measured the GH response to GHRH-ARG in aromatase-deficient men (at baseline and during estrogen treatment) and in normal subjects. Basal serum IGF-I was measured in both patients and controls. RESULTS: The response of GH to GHRH ARG was severely impaired in men with aromatase deficiency and resulted in significantly lower (P < 0.001) levels than in normal subjects. Although normal, serum IGF-I levels were also significantly lower (P < 0.001) than in normal subjects. Both GH peak and IGF-I concentrations were not modified by estrogen therapy in men with aromatase deficiency. CONCLUSIONS: In aromatase-deficient men, GH response to potent provocative stimuli is impaired and is not restored by exogenous estrogens. Furthermore, a tall stature may be reached, notwithstanding the coexistence of GHD, if a prolonged time for growth is available due to a delay in bone maturation, and other growth factors different from GH (mainly insulin) promote growth. PMID- 20164295 TI - Endogenous steroids measured by high-specificity liquid chromatography-tandem mass spectrometry and prevalent cardiovascular disease in 70-year-old men and women. AB - CONTEXT: There is a need for increased knowledge about endogenous sex hormone levels and clinical outcomes of risk/benefit. Immunoassays have poor specificity to reliably measure low steroid concentrations in elderly. OBJECTIVE: The objective of the study was to evaluate plasma steroid concentrations with regard to prevalent cardiovascular disease (CVD) in elderly, using mass spectrometry. SETTING: The study was conducted at a university hospital research unit. DESIGN AND METHODS: Plasma samples were analyzed from 202 70-yr-olds as part of a large population-based study, Prospective Investigation of the Vasculature in Uppsala Seniors. Twenty-eight of these had prevalent CVD. Eleven steroids were quantified, using liquid chromatography-tandem mass spectrometry. Women with current/previous menopausal hormone therapy (n = 35) were excluded. RESULTS: Men without prevalent CVD had higher plasma 17beta-estradiol (E2), compared with women. Men with prevalent CVD, compared with those without, had lower 17 hydroxypregnenolone (17OHPregn), 17-hydroxyprogesterone, and higher estrone/androstenedione and E2/testosterone (T) (aromatase activity). Women with prevalent CVD had lower pregnenolone, 17OHPregn, and dehydroepiandrosterone (DHEA) but higher DHEA/17OHPregn, androstenedione/DHEA, E2/T, E2/estrone, and E2/SHBG. The aromatase index, E2/T, was higher for prevalent CVD in both sexes. Adjustment for statin use, smoking, and body mass index yielded additional significant differences in men, whereas some were lost in women. Logistic regression indicated strong associations between prevalent CVD and low 17OHPregn, adjusted odds ratio of 0.18, 95% confidence interval (0.06-0.61); P = 0.006, in women and low 17-hydroxyprogesterone, 0.45 (0.25-0.80); P = 0.007 in men, most likely caused by increased throughput (consumption) toward estrogen synthesis. CONCLUSIONS: Prevalent CVD was associated with indications of lower androgen precursors, increased aromatase activity, and higher estrogen levels in both sexes. Results might represent an endogenous response to a condition of developing atherosclerosis, rather than a causative relationship. Furthermore studies are needed. PMID- 20164297 TI - Progesterone receptor membrane component 1 (Pgrmc1): a heme-1 domain protein that promotes tumorigenesis and is inhibited by a small molecule. AB - Tumorigenesis requires the concerted action of multiple pathways, including pathways that stimulate proliferation and increase metabolism. Progesterone receptor membrane component 1 (Pgrmc1) is related to cytochrome b5, binds to heme, and is associated with DNA damage resistance and apoptotic suppression. Pgrmc1 is induced by carcinogens, including dioxin, and is up-regulated in multiple types of cancer. In the present study, we found that Pgrmc1 increased in vivo tumor growth, anchorage-independent growth, and migration. Pgrmc1 also promoted proliferation in the absence of serum in A549 non-small cell lung cancer cells but enhanced proliferation regardless of serum concentration in MDA-MB-468 breast cancer cells. Pgrmc1 promotes cholesterol synthesis and binds to Insig (insulin-induced gene), Scap (sterol regulatory element binding protein cleavage activating protein), and P450 proteins, but Pgrmc1 did not affect cholesterol synthesis in lung cancer cells. Pgrmc1 is also associated with progesterone signaling and plasminogen activator inhibitor (PAI1) RNA binding protein, but neither progesterone activity nor PAI1 transcript levels were altered in Pgrmc1 knockdown lung cancer cells. Pgrmc1 homologues bind to aryl ligands identified in an in silico screen, and we have found that a Pgrmc1 ligand induced cell death in a Pgrmc1-specific manner in multiple breast and lung tumor cell lines. Our data support a role for Pgrmc1 in promoting cancer-associated phenotypes and provide a therapeutic approach for targeting Pgrmc1 with a small molecule in lung and breast cancer. PMID- 20164296 TI - Effects of teriparatide, alendronate, or both in women with postmenopausal osteoporosis. AB - CONTEXT: Teriparatide increases both bone formation and bone resorption. OBJECTIVE: We sought to determine whether combining teriparatide with an antiresorptive agent would alter its anabolic action. DESIGN AND SETTING: This was a randomized controlled trial conducted in a single university hospital. PATIENTS AND INTERVENTION: We randomized 93 postmenopausal women with low bone mineral density (BMD) to alendronate 10 mg daily (group 1), teriparatide 40 microg sc daily (group 2), or both (group 3) for 30 months. Teriparatide was begun at month 6. MAIN OUTCOME MEASURES: BMD of the lumbar spine, proximal femur, proximal radius, and total body was measured by dual-energy x-ray absorptiometry (DXA) every 6 months. Lumbar spine trabecular BMD was measured at baseline and month 30 by quantitative computed tomography. Serum osteocalcin, N-terminal propeptide of type 1 collagen, and N-telopeptide levels were assessed frequently. Women who had at least one repeat DXA scan on therapy were included in the analyses (n = 69). RESULTS: DXA spine BMD increased more in women treated with teriparatide alone than with alendronate alone (18 +/- 11 vs. 7 +/- 4%; P < 0.001) or both (18+/-11 vs. 12 +/- 9%; P = 0.045). Similarly, femoral neck BMD increased more in women treated with teriparatide alone than with alendronate alone (11 +/- 5 vs. 4 +/- 4%; P < 0.001) or both (11 +/- 5 vs. 3 +/- 5%; P < 0.001). Quantitative computed tomography spine BMD increased 1 +/- 7, 61 +/- 31, and 24 +/- 24% in groups 1, 2, and 3 (P < 0.001 for all comparisons). Serum osteocalcin, N-terminal propeptide of type 1 collagen, and cross-linked N telopeptides of type I collagen increased more with teriparatide alone than with both (P < 0.001 for each marker). CONCLUSION: Alendronate reduces the ability of teriparatide to increase BMD and bone turnover in women. PMID- 20164298 TI - A naphthoquinone derivative can induce anemia through phosphatidylserine exposure mediated erythrophagocytosis. AB - A naphthoquinone derivative, beta-lapachone (betaL; 3,4-dihydro-2,2-dimethyl-2H naphthol[1,2-b]pyran-5,6-dione), is receiving huge attention for its potent therapeutic effects against various diseases. However, during the preclinical safety evaluation, repeated oral treatment of betaL in rats induced anemia, i.e., a significantly decreased erythrocyte count. In this study, in an effort to elucidate the mechanism underlying the betaL-induced anemia, we investigated the effects of betaL on erythrocytes with freshly isolated human erythrocytes in vitro and rat in vivo. betaL did not induce erythrocyte hemolysis, indicating that direct hemotoxicity was not involved in betaL-associated anemia. Meanwhile, phosphatidylserine (PS) exposure along with spherocytic shape change and microvesicle generation, important factors in the facilitation of erythrophagocytosis, were increased significantly by betaL. The PS exposure on erythrocytes was from betaL-induced reactive oxygen species generation and subsequent depletion of reduced glutathione and protein thiol, which culminated in the modified activities of phospholipid translocases, i.e., inhibition of flippase and activation of scramblase. It is important to note that coincubation of macrophage with betaL-treated erythrocyte in vitro showed increased erythrophagocytosis, demonstrating that the removal of erythrocyte by macrophage can be facilitated by betaL-induced PS exposure. In good accordance with these in vitro results, after oral administration of betaL in rats, increased PS exposure and depletion of glutathione were observed along with enhanced splenic sequestration of erythrocytes. In conclusion, these results suggest that betaL induced anemia might be mediated through the PS exposure and subsequent erythrophagocytosis, providing novel insight into the drug-induced anemia. PMID- 20164299 TI - Anti-inflammatory properties of CB1-receptor antagonist involves beta2 adrenoceptors. AB - Antagonists of the cannabinoid receptor 1 (CB1) impart anti-inflammatory activity even though, paradoxically, CB2 receptors are more predominant on cells of the immune system. We attempted to understand the mechanism of this activity by using an acute model of lipopolysaccharide-induced inflammation/stress in both rat and mouse, with selective antagonists to CB1 receptors. We demonstrate that the ability of a CB1 antagonist to inhibit release of proinflammatory cytokines is not dependent on either adrenal-derived catecholamines or corticosteroids or input from the pituitary or thymus glands but does involve the spleen. Furthermore, we show that the anti-inflammatory activity is retained without communication from the central nervous system following ganglionic blockade, suggesting a peripheral site of action. Finally, we show that the anti inflammatory activity can be inhibited with the use of a selective beta2 adrenoceptor antagonist. PMID- 20164300 TI - Butrin, isobutrin, and butein from medicinal plant Butea monosperma selectively inhibit nuclear factor-kappaB in activated human mast cells: suppression of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8. AB - Activation of mast cells in rheumatoid synovial tissue has often been associated with tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 production and disease pathogenesis by adjacent cell types. Butea monosperma (BM) is a well known medicinal plant in India and the tropics. The aim of this study was to examine whether a standardized extract of BM flower (BME) could inhibit inflammatory reactions in human mast cells (HMC) using activated HMC-1 cells as a model. Four previously characterized polyphenols--butrin, isobutrin, isocoreopsin, and butein--were isolated from BME by preparative thin layer chromatography, and their purity and molecular weights were determined by liquid chromatography/mass spectrometry analysis. Our results showed that butrin, isobutrin, and butein significantly reduced the phorbol 12-myristate 13-acetate and calcium ionophore A23187-induced inflammatory gene expression and production of TNF-alpha, IL-6, and IL-8 in HMC-1 cells by inhibiting the activation of NF kappaB. In addition, isobutrin was most potent in suppressing the NF-kappaB p65 activation by inhibiting IkappaBalpha degradation, whereas butrin and butein were relatively less effective. In vitro kinase activity assay revealed that isobutrin was a potent inhibitor of IkappaB kinase complex activity. This is the first report identifying the molecular basis of the reported anti-inflammatory effects of BME and its constituents butrin, isobutrin, and butein. The novel pharmacological actions of these polyphenolic compounds indicate potential therapeutic value for the treatment of inflammatory and other diseases in which activated mast cells play a role. PMID- 20164301 TI - Reversal of prolonged dopamine inhibition of dopaminergic neurons of the ventral tegmental area. AB - Drug abuse-induced plasticity of putative dopaminergic (pDAergic) ventral tegmental area (VTA) neurons may play an important role in changes in the mesocorticolimbic system that lead to the development of addiction. In the present study, extracellular recordings were used to examine time-dependent effects of dopamine (DA) on pDAergic VTA neurons in rat brain slices. Administration of DA (2.5-10 microM) for 40 min resulted in inhibition followed by partial or full reversal of that inhibition. The reduced sensitivity to DA inhibition lasted 30 to 90 min after washout of the long-term dopamine administration. The inhibition reversal was not observed with 40-min administration of the D2 agonist quinpirole (25-200 nM), so this phenomenon was not the result of desensitization induced solely by stimulation of D2 DA receptors. Inhibition reversal could be observed with the coapplication of quinpirole and the D1/D5 agonist SKF38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H) 3-benzazepine-7,8-diol hydrobromide], suggesting a D1/D5 mechanism for the reversal. Furthermore, D1/D5 antagonists, given in the presence of prolonged DA exposure, prevented the inhibition reversal. Application of 3 microM quinpirole caused desensitization to low quinpirole concentrations that was blocked by a D1/D5 antagonist. These data suggest that coactivation of D1/D5 receptors and D2 receptors in the VTA results in desensitization of autoinhibitory D2 receptors. Prolonged increases in pDAergic tone in the VTA that may occur in vivo with drugs of abuse could reduce the regulation of firing by D2 dopamine receptor activation, producing long-term alteration in information processing related to reward and reinforcement. PMID- 20164303 TI - Roadblocks en route to the clinical application of induced pluripotent stem cells. AB - Since the first studies of human embryonic stem cells (hESCs) and, more recently, human induced pluripotent stem cells (hiPSCs), the stem-cell field has been abuzz with the promise that these pluripotent populations will one day be a powerful therapeutic tool. Although it has been proposed that hiPSCs will supersede hESCs with respect to their research and/or clinical potential because of the ease of their derivation and the ability to create immunologically matched iPSCs for each individual patient, recent evidence suggests that iPSCs in fact have several underappreciated characteristics that might mean they are less suitable for clinical application. Continuing research is revealing the similarities, differences and deficiencies of various pluripotent stem-cell populations, and suggests that many years will pass before the clinical utility of hESCs and hiPSCs is realized. There are a plethora of ethical, logistical and technical roadblocks on the route to the clinical application of pluripotent stem cells, particularly of iPSCs. In this Essay, we discuss what we believe are important issues that should be considered when attempting to bring hiPSC-based technology to the clinic. PMID- 20164304 TI - Functional molecular imaging of ILK-mediated Akt/PKB signaling cascades and the associated role of beta-parvin. AB - Visualization and quantification of the dynamics of protein-protein interactions in living cells can be used to explore the macromolecular events involved in signal transduction processes. In this study, functional molecular imaging using a luciferase-based complementation method demonstrated how the integrin-linked kinase (ILK)-mediated protein complex controls downstream signals. The luciferase complementation assay showed that Akt1 preferentially binds to beta-parvin rather than to ILK within the complex. Moreover, photon flux from the interaction between beta-parvin and Akt1 increased following serum stimulation, and the beta parvin-Akt1 interaction was dependent on phosphoinositide 3-kinase. Intriguingly, small interfering (si)RNA-mediated beta-parvin knockdown increased photon flux from the interaction between ILK and Akt1, leading to stabilization of hypoxia inducible factor-1alpha and increased expression of vascular endothelial growth factor-A. These data from functional molecular imaging demonstrated that beta parvin plays a regulatory role in the ILK-mediated Akt (also called protein kinase B) signaling cascades, suggesting that beta-parvin might be a crucial modulator of cell survival. PMID- 20164305 TI - Retromer-mediated direct sorting is required for proper endosomal recycling of the mammalian iron transporter DMT1. AB - Endosomal recycling of the mammalian iron transporter DMT1 is assumed to be important for efficient and rapid uptake of iron across the endosomal membrane in the transferrin cycle. Here, we show that the retromer, a complex that mediates retrograde transport of transmembrane cargoes from endosomes to the trans-Golgi network, is required for endosomal recycling of DMT1-II, an alternative splicing isoform of DMT1. Bacterially expressed Vps26-Vsp29-Vsp35 trimer, a retromer cargo recognition complex, specifically binds to the cytoplasmic tail domain of DMT1-II in vitro. In particular, this binding is dependent on a specific hydrophobic motif of DMT1-II, which is required for its endosomal recycling. DMT1-II colocalizes with the Vps35 subunit of the retromer in TfR-positive endosomes. Depletion of the retromer by siRNA against Vps35 leads to mis-sorting of DMT1-II to LAMP2-positive structures, and expression of siRNA-resistant Vps35 can rescue this effect. These findings demonstrate that the retromer recognizes the recycling signal of DMT1-II and ensures its proper endosomal recycling. PMID- 20164302 TI - The catenin family at a glance. PMID- 20164306 TI - The effects of extra-articular starting point and transtibial femoral drilling on the intra-articular aperture of the tibial tunnel in ACL reconstruction. AB - BACKGROUND: The recent emphasis on more horizontal femoral tunnel placement for single-bundle anterior cruciate ligament (ACL) reconstructions requires placing a femoral tunnel lower on the lateral wall of the notch. Some surgeons have advocated moving the starting point of the tibial tunnel farther medial to achieve this more horizontal tunnel. PURPOSE: To compare tibial tunnel aperture changes with transtibial femoral tunnel drilling. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty match-paired cadaveric knees (10 specimens) were randomized into 2 groups with equal right and left knee distribution. Ten of the knees underwent tibial tunnel drilling from a medial starting point (group 1), and the corresponding opposite knee of each cadaveric specimen had the tibial tunnel drilled from a central starting point (group 2). Computerized tomography (CT) with thin slices and 3-dimensional reconstruction was used to obtain the dimensions of the apertures, area of the apertures, angles of the tunnels, and location of the starting point and ending point of the tunnels. We also determined the location of the femoral tunnels in the notch for each of the groups. The 10 knees with medial starting points underwent transtibial femoral tunnel drilling and were restudied with CT to evaluate changes in tibial tunnel characteristics. The 10 knees with central starting points underwent femoral drilling from an anteromedial arthroscopic portal. RESULTS: Central tibial tunnels were slightly larger than medial tibial tunnels before femoral drilling (106.3 mm(3) vs 92.4 mm(3)). After femoral drilling through the medial tunnels, the apertures were larger than the central tibial apertures (118.6 mm(3) vs 106.3 mm(3)). Medial tibial tunnels resulted in an intra-articular aperture that was farther from the tibial tubercle (43.1 mm vs 16.3 mm), farther from the medial tibial plateau (38.3 mm vs 32.2 mm), and more acute in the coronal plane (50.4 degrees vs 79.3 degrees ). Medial tibial tunnels resulted in an intra-articular aperture that was closer to the anterior edge of the tibia (22.6 mm vs 29.6 mm) but with a less acute sagittal plane angle (82.5 degrees vs 54.5 degrees ). The average clock-face measurement on the femur was 10:40 (+/-14 minutes) for the medial starting point and 10:14 (+/-14 minutes) for the central starting point (drilled from an anteromedial arthroscopic portal) (P = .0016). CONCLUSION: We observed significantly increased tibial aperture size and shape after transtibial femoral drilling with a medial tibial starting point. Medial tibial tunnels, compared with more central tunnels, resulted in a more acute tibial tunnel in the coronal plane and less acute tibial tunnels relative to the sagittal plane. Medial tibial tunnels started farther from the tibial tubercle but ended farther from the medial joint line and closer to the anterior edge of the tibia in comparison to central tunnels Clinical Relevance Femoral tunnel placements may be best accomplished using a technique other than transtibial drilling through a medial tibial tunnel. Tibial tunnel angle, intra-articular position, and femoral tunnel placement are affected by the choice of extra-articular starting position. PMID- 20164307 TI - Lysine requirement in parenterally fed postsurgical human neonates. AB - BACKGROUND: The lysine requirement of human neonates receiving parenteral nutrition (PN) has not been determined experimentally. OBJECTIVE: The objective was to determine the parenteral lysine requirement for human neonates by using the minimally invasive indicator amino acid oxidation technique with l-[1-(13)C] phenylalanine as the indicator amino acid. DESIGN: Eleven postsurgical neonates were randomly assigned to 15 lysine intakes ranging from 50 to 260 mg . kg(-1) . d(-1). Breath and urine samples were collected at baseline and at plateau for (13)CO(2) (F(13)CO(2)) and amino acid enrichment, respectively. The mean lysine requirement was determined by applying a 2-phase linear regression crossover analysis to the measured rates of F(13)CO(2) release and l-[1-(13)C]phenylalanine oxidation. RESULTS: The mean parenteral lysine requirement determined by F(13)CO(2) release oxidation was 104.9 mg . kg(-1) . d(-1) (upper and lower CIs: 120.6 and 89.1 mg . kg(-1) . d(-1), respectively). The mean lysine parenteral requirement determined by phenylalanine oxidation was 117.6 mg . kg(-1) . d(-1) (upper and lower CIs: 157.5 and 77.6 mg . kg(-1) . d(-1), respectively). Graded intakes of lysine had no effect on phenylalanine flux. CONCLUSION: We recommend a mean lysine requirement for the postsurgical PN-fed neonate of 104.9 mg . kg(-1) . d(-1), which is 32-43% of the lysine concentration presently found in commercial PN solutions (246-330 mg . kg(-1) . d(-1)). This trial was registered at clinicaltrials.gov as NCT00779753. PMID- 20164308 TI - Brain and high metabolic rate organ mass: contributions to resting energy expenditure beyond fat-free mass. AB - BACKGROUND: The degree to which interindividual variation in the mass of select high metabolic rate organs (HMROs) mediates variability in resting energy expenditure (REE) is unknown. OBJECTIVE: The objective was to investigate how much REE variability is explained by differences in HMRO mass in adults and whether age, sex, and race independently predict REE after adjustment for HMRO. DESIGN: A cross-sectional evaluation of 55 women [30 African Americans aged 48.7 +/- 22.2 y (mean +/- SD) and 25 whites aged 46.4 +/- 17.7 y] and 32 men (8 African Americans aged 34.3 +/- 18.2 y and 24 whites aged 51.3 +/- 20.6 y) was conducted. Liver, kidney, spleen, heart, and brain masses were measured by magnetic resonance imaging, and fat and fat-free mass (FFM) were measured by dual energy X-ray absorptiometry. REE was measured by indirect calorimetry. RESULTS: REE estimated from age (P = 0.001), race (P = 0.006), sex (P = 0.31), fat (P = 0.001), and FFM (P < 0.001) accounted for 70% (adjusted (2)) of the variability in REE. The addition of trunk HMRO (P = 0.001) and brain (P = 0.006) to the model increased the explained variance to 75% and rendered the contributions of age, sex, and race statistically nonsignificant, whereas fat and FFM continued to make significant contributions (both P < 0.05). The addition of brain to the model rendered the intercept (69 kcal . kg(-1) . d(-1)) consistent with zero, which indicated zero REE for zero body mass. CONCLUSIONS: Relatively small interindividual variation in HMRO mass significantly affects REE and reduces the role of age, race, and sex in explaining REE. Decreases in REE with increasing age may be partly related to age-associated changes in the relative size of FFM components. PMID- 20164309 TI - Low dietary choline and low dietary riboflavin during pregnancy influence reproductive outcomes and heart development in mice. AB - BACKGROUND: Embryonic development may be compromised by dietary and genetic disruptions in folate metabolism because of the critical role of folate in homocysteine metabolism, methylation, and nucleotide synthesis. Methylenetetrahydrofolate reductase (MTHFR), choline, and riboflavin play distinct roles in homocysteine detoxification and generation of one-carbon donors for methylation. The effect of low dietary choline and riboflavin on pregnancy complications and heart development has not been adequately addressed. OBJECTIVE: Our goal was to determine whether dietary deficiencies of choline and riboflavin in pregnant mice, with and without mild MTHFR deficiency, affect embryonic development. DESIGN: Female Mthfr(+/+) and Mthfr(+/-) mice were fed a control diet (CD), a choline-deficient diet (ChDD), or a riboflavin-deficient diet (RbDD) and were then mated with male Mthfr(+/-) mice. Embryos were collected 14.5 d postcoitum and examined for reproductive outcomes and cardiac defects. RESULTS: Plasma homocysteine was higher in ChDD- than in CD-fed females. Liver MTHFR enzyme activity was greater in ChDD-fed Mthfr(+/+) than in CD-fed Mthfr(+/+) females. The RbDD resulted in a higher percentage of delayed embryos and smaller embryos than did the CD. There were more heart defects, which were all ventricular septal defects, in embryos from the ChDD- and RbDD-fed females than from the CD-fed females. Dietary riboflavin and MTHFR deficiency resulted in decreased left ventricular wall thickness in embryonic hearts compared with embryos from CD-fed Mthfr(+/+) females. CONCLUSIONS: Low dietary choline and riboflavin affect embryonic growth and cardiac development in mice. Adequate choline and riboflavin may also play a role in the prevention of these pregnancy complications in women. PMID- 20164310 TI - Where is the science? What will it take to show that nutrient profiling systems work? AB - Nutrient profiling is defined as the science of ranking or categorizing foods on the basis of their nutritional composition. Validity is a general term meaning accuracy. Nutrient profiling systems in the United States have not undergone any systematic validation effort to assess their accuracy against a comparison measure or group of measures. Different types of validation studies should be conducted: content, face, convergent, criterion, and predictive. This article provides a conceptual framework for establishing the validity of nutrient profiling systems with the desired objective of assisting US consumers with food selection to improve diet quality. For a profiling system to work successfully in the American marketplace, it must function well with consumers from most or all cultural groups, from all racial groups, and with low-literate as well as highly literate people. Emphasis should be placed on conducting different types of validation studies and multiple studies with different subpopulation groups. The use of consistent standards to assess the accuracy and usefulness of multiple profiling systems is imperative to successfully identify a nutrient profiling intervention that will have the potential to lead to improved diet quality and eventually to an improved health status in US consumers. PMID- 20164311 TI - Low-fat dietary pattern and lipoprotein risk factors: the Women's Health Initiative Dietary Modification Trial. AB - BACKGROUND: The Women's Health Initiative Dietary Modification Trial tested the effects on chronic disease of a dietary pattern lower in fat and higher in vegetables, fruit, and grains. OBJECTIVE: The objective was to evaluate the effects of dietary carbohydrate changes on lipids and lipoprotein composition. DESIGN: Postmenopausal women were randomly assigned to an intervention or a comparison group for a mean of 8.1 y. Lipoprotein analyses and subclasses were based on subsamples of 2730 and 209 participants, respectively. RESULTS: At year 6, the total reported fat intake was 7.8% lower and carbohydrate intake was 7.6% higher in the intervention group than in the comparison group. Triglyceride change between groups differed by 2.3, 3.8, and -0.8 mg/dL at 1, 3, and 6 y, respectively, and HDL-cholesterol change differed by -1.6, -0.7, and -1.0 mg/dL at 1, 3, and 6 y, respectively. Changes did not differ by age, ethnicity, or obesity. In diabetic intervention women who were white, the triglyceride difference between the intervention and comparison groups was 33.8 mg/dL, whereas in black women with diabetes (n = 50 in the intervention group; n = 83 in the comparison group), the triglyceride difference was 6.4 mg/dL (P for 3-factor interaction = 0.049). No significant changes were observed in apolipoprotein or lipoprotein particles. Reductions in LDL cholesterol varied by quartile of reported lowering of saturated or trans fat. CONCLUSIONS: The replacement of 7-8% of fat intake with complex carbohydrates over 6 y was not associated with clinically adverse effects on triglycerides, HDL cholesterol, or lipoprotein subclasses. Diabetic white women with higher triglyceride concentrations may have greater increases in triglycerides. PMID- 20164312 TI - In foods, energy is cheap where it is abundant and expensive where it is scarce: this is a fact, not an artifact. PMID- 20164313 TI - High adiposity and high body mass index-for-age in US children and adolescents overall and by race-ethnic group. AB - BACKGROUND: Body mass index (BMI)-for-age has been recommended as a screening test for excess adiposity in children and adolescents. OBJECTIVE: We quantified the performance of standard categories of BMI-for-age relative to the population prevalence of high adiposity in children and adolescents overall and by race ethnic group in a nationally representative US population sample by using definitions of high adiposity that are consistent with expert committee recommendations. DESIGN: Percentage body fat in 8821 children and adolescents aged 8-19 y was measured by using dual-energy X-ray absorptiometry in 1999-2004 as part of a health examination survey. RESULTS: With the use of several different cutoffs for percentage fat to define high adiposity, most children with high BMI-for-age (> or = 95th percentile of the growth charts) had high adiposity, and few children with normal BMI-for-age (<85th percentile) had high adiposity. The prevalence of high adiposity in intermediate BMI categories varied from 45% to 15% depending on the cutoff. The prevalence of a high BMI was significantly higher in non-Hispanic black girls than in non-Hispanic white girls, but the prevalence of high adiposity was not significantly different. CONCLUSIONS: Current BMI cutoffs can identify a high prevalence of high adiposity in children with high BMI-for-age and a low prevalence of high adiposity in children with normal BMI-for-age. By these adiposity measures, less than one-half of children with intermediate BMIs-for-age (85th to <95th percentile) have high adiposity. Differences in high BMI ranges between race-ethnic groups do not necessarily indicate differences in high adiposity. PMID- 20164314 TI - Skeletal muscle loss: cachexia, sarcopenia, and inactivity. AB - Loss of skeletal muscle mass occurs during aging (sarcopenia), disease (cachexia), or inactivity (atrophy). This article contrasts and compares the metabolic causes of loss of muscle resulting from these conditions. An understanding of the underlying causes of muscle loss is critical for the development of strategies and therapies to preserve muscle mass and function. Loss of skeletal muscle protein results from an imbalance between the rate of muscle protein synthesis and degradation. Cachexia, sarcopenia, and atrophy due to inactivity are characterized by a loss of muscle mass. Each of these conditions results in a metabolic adaptation of increased protein degradation (cachexia), decreased rate of muscle protein synthesis (inactivity), or an alteration in both (sarcopenia). The clinical consequences of bedrest may mimic those of cachexia, including rapid loss of muscle, insulin resistance, and weakness. Prophylaxis against bedrest-induced atrophy includes nutrition support with an emphasis on high-quality protein. Nutritional supplementation alone may not prevent muscle loss secondary to cachexia, but, in combination with the use of an anabolic agent, it may slow or prevent muscle loss. PMID- 20164315 TI - Disposition of soy isoflavones in normal human breast tissue. AB - BACKGROUND: Despite decades of research on the relation between soy and breast cancer, questions regarding the absorption, metabolism, and distribution of isoflavones in breast tissue largely remain unanswered. OBJECTIVE: We evaluated the potential health effects of isoflavone consumption on normal breast tissue; isoflavone concentrations, metabolites, and biodistribution were investigated and compared with 17beta-estradiol exposure. DESIGN: In this dietary intervention study, healthy women were randomly allocated to a soy milk (n = 11; 16.98-mg genistein and 5.40-mg daidzein aglycone equivalents per dose), soy supplement (n = 10; 5.27-mg genistein and 17.56-mg daidzein aglycone equivalents per dose), or control (n = 10) group. After a run-in period > or = 4 d, 3 doses of soy milk or soy supplements were taken daily for 5 d before an esthetic breast reduction. Blood and breast biopsies were collected during surgery and analyzed with liquid chromatography-tandem mass spectrometry. RESULTS: After soy administration, genistein and total daidzein concentrations, which were expressed as aglycone equivalents, ranged from 135.1 to 2831 nmol/L and 105.1 to 1397 nmol/L, respectively, in hydrolyzed serum and from 92.33 to 493.8 pmol/g and 22.15 to 770.8 pmol/g, respectively, in hydrolyzed breast tissue. The major metabolites identified in nonhydrolyzed samples were genistein-7-O-glucuronide and daidzein-7 O-glucuronide, with an overall glucuronidation of 98%. Total isoflavones showed a breast adipose/glandular tissue distribution of 40:60, and their mean (+/-SEM) derived 17beta-estradiol equivalents toward estrogen receptor beta were 21 +/- 4 fold and 40 +/- 10-fold higher than the 17beta-estradiol concentrations in adipose (0.283 +/- 0.089 pmol/g, P < 0.001) and glandular (0.246 +/- 0.091 pmol/g, P = 0.001) fractions, respectively. CONCLUSION: After intake of soy milk and soy supplements, isoflavones reach exposure levels in breast tissue at which potential health effects may occur. PMID- 20164316 TI - Relation between hypomethylation of long interspersed nucleotide elements and risk of neural tube defects. AB - BACKGROUND: Impaired one-carbon metabolism is thought to be associated with the risk of neural tube defects (NTDs); however, the role of methylation in NTDs remains unclear. Long interspersed nucleotide element-1 (LINE-1) constitutes 17 25% of the human genome. LINE-1 hypomethylation correlates with global DNA methylation levels in cancerous cells, but limited information is available on LINE-1 methylation in NTDs. OBJECTIVE: We determined whether LINE-1 methylation patterns were associated with neural tube development and the possible relations between DNA methylation and key maternal metabolites involved in folate-mediated one-carbon metabolism. DESIGN: Global methylation, maternal plasma folic acid, vitamin B-12, and total homocysteine (tHcy) concentrations were assessed in 48 NTD and 49 control samples by immunoassay, and LINE-1 methylation levels were evaluated by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS: Methylation levels of genomic DNA and LINE-1 decreased significantly in the neural tissue of NTD samples. The risk of NTDs increased with decreasing levels of LINE-1 methylation, with an odds ratio of 5.246 (95% CI: 1.519, 18.124; P = 0.009) for the lowest quartile (methylation level < or = 57.94%) compared with the highest quartile (methylation level > or = 60.94%). Compared with control subjects, case subjects had lower maternal plasma concentrations of vitamin B-12. CONCLUSIONS: Hypomethylation of LINE-1 and genomic DNA was associated with an increased risk of NTDs. Functional insufficiency of maternal plasma vitamin B-12 was associated with NTDs, although no significant correlation could be established between maternal folic acid, vitamin B, tHcy, and LINE-1 methylation. PMID- 20164317 TI - On the gene-nutrient analyses of Cahill et al. PMID- 20164318 TI - Update on clinical trials of growth factors and anabolic steroids in cachexia and wasting. AB - This article and others that focused on the clinical features, mechanisms, and epidemiology of skeletal muscle loss and wasting in chronic diseases, which include chronic kidney disease, cancer, and AIDS, were presented at a symposium entitled "Cachexia and Wasting: Recent Breakthroughs in Understanding and Opportunities for Intervention," held at Experimental Biology 2009. The clinical and anabolic efficacy of specific growth factors and anabolic steroids (eg, growth hormone, testosterone, megestrol acetate) in malnutrition and other catabolic states has been the subject of considerable research during the past several decades. Research on the effects of these agents in cachexia or wasting conditions, characterized by progressive loss of skeletal muscle and adipose tissue, focused on patients with AIDS in the early 1990s, when the devastating effects of the loss of body weight, lean body mass, and adipose tissue were recognized as contributors to these patients' mortality. These same agents have also been studied as methods to attenuate the catabolic responses observed in cancer-induced cachexia and in wasting induced by chronic obstructive pulmonary disease, congestive heart failure, renal failure, and other conditions. This article provides an updated review of recent clinical trials that specifically examined the potential therapeutic roles of growth hormone, testosterone, oxandrolone, and megestrol acetate and emerging data on the orexigenic peptide ghrelin, in human cachexia and wasting. PMID- 20164319 TI - Intake during repeated exposure to low- and high-energy-dense yogurts by different means of consumption. AB - BACKGROUND: An important question in the regulation of energy intake is whether dietary learning of energy content depends on the food's characteristics, such as texture. Texture might affect the duration of sensory exposure and eating rate. OBJECTIVE: The objective was to investigate whether a long sensory exposure, due to differences in means of consumption and in viscosity, enhances learned associations between sensory signals and metabolic consequences and hence facilitates energy intake compensation. DESIGN: A total of 105 healthy young adults with a mean (+/-SD) age of 22 +/- 3 y and a body mass index (in kg/m(2)) of 21.6 +/- 1.7 participated in a parallel intervention in 3 groups: liquid yogurt with a straw (liquid/straw; n = 34), liquid yogurt with a spoon (liquid/spoon; n = 36), or semisolid yogurt with a spoon (semisolid/spoon; n = 35). Novel flavored yogurts were offered ad libitum for breakfast in 2 energy densities: low ( approximately 215 kJ/100 g) and high ( approximately 600 kJ/100 g). Subjects were repeatedly exposed to the yogurt products (10 times), and yogurt intake was measured. RESULTS: Intakes (P = 0.01) and eating rates (P = 0.01) were highest in the liquid/straw group. Average intakes over 10 exposures were 575 +/- 260 g for liquid/straw, 475 +/- 192 g for liquid/spoon, and 470 +/- 223 g for semisolid/spoon; average eating rates were 132 +/- 83 g/min for liquid/straw, 106 +/- 53 g/min for liquid/spoon, and 105 +/- 88 g/min for semisolid/spoon. No significant interaction for intake between intervention group, energy density, and repeated exposure was observed, and intakes of the low and high-energy-dense yogurts did not change over time in any of the intervention groups. CONCLUSIONS: We observed no energy intake compensation after repeated exposure to yogurt products. Differences in ad libitum yogurt intake could be explained by eating rate, which was affected by the different means of consumption. This trial was registered with the Dutch trial registration at http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1853 as NTR1853. PMID- 20164320 TI - Effect of premeal consumption of whey protein and its hydrolysate on food intake and postmeal glycemia and insulin responses in young adults. AB - BACKGROUND: Dairy protein ingestion before a meal reduces food intake and, when consumed with carbohydrate, reduces blood glucose. OBJECTIVE: The objective was to describe the effect of whey protein (WP) or its hydrolysate (WPH) when consumed before a meal on food intake, pre- and postmeal satiety, and concentrations of blood glucose and insulin in healthy young adults. DESIGN: Two randomized crossover studies were conducted. WP (10-40 g) in 300 mL water was provided in experiment 1, and WP (5-40 g) and WPH (10 g) in 300 mL water were provided in experiment 2. At 30 min after consumption, the subjects were fed an ad libitum pizza meal (experiment 1) or a preset pizza meal (12 kcal/kg, experiment 2). Satiety, blood glucose, and insulin were measured at baseline and at intervals both before and after the meals. RESULTS: In experiment 1, 20-40 g WP suppressed food intake (P < 0.0001) and 10-40 g WP reduced postmeal blood glucose concentrations and the area under the curve (AUC) (P < 0.05). In experiment 2, 10-40 g WP, but not WPH, reduced postmeal blood glucose AUC and insulin AUC in a dose-dependent manner (P < 0.05). The ratio of cumulative blood glucose to insulin AUCs (0-170 min) was reduced by > or =10 g WP but not by 10 g WPH. CONCLUSIONS: WP consumed before a meal reduces food intake, postmeal blood glucose and insulin, and the ratio of cumulative blood glucose to insulin AUCs in a dose-dependent manner. Intact WP, but not WPH, contributes to blood glucose control by both insulin-dependent and insulin-independent mechanisms. This trial was registered at clinicaltrials.gov as NCT00988377 and NCT00988182. PMID- 20164321 TI - Relation between estimates of cornstarch digestibility by the Englyst in vitro method and glycemic response, subjective appetite, and short-term food intake in young men. AB - BACKGROUND: Starch composition and rate of digestion are determinants of blood glucose concentrations and food intake (FI). OBJECTIVE: Our objective was to describe relations between estimates of digestibility of starches by the in vitro Englyst method and their effect on blood glucose concentrations, subjective appetite, and FI in young men. DESIGN: Subjects consumed 5 soups containing 50 g maltodextrin, whole-grain, high-amylose, regular cornstarch, or no added starch at 1-wk intervals. Ad libitum FI was measured at 30 min (experiment 1) or 120 min (experiment 2) later, which were the estimated times of digestion of a rapidly digestible starch (RDS) and slowly digestible starch, respectively. Blood glucose concentrations and appetite were measured pre- and postmeal. RESULTS: At 30 min, FI was reduced by maltodextrin only [86% RDS, 12% resistant starch (RS); P < 0.05], but at 120 min FI was reduced by whole-grain (24% RDS, 66% RS), high amylose corn (40% RDS, 48% RS), and regular corn (27% RDS, 39% RS) (P < 0.0001). The premeal blood glucose concentration at 30 and 120 min was highest and lowest after maltodextrin treatment, respectively (P < 0.0001). After the meal, the blood glucose area under the curve at 30 min was lower after all starch treatments (P < 0.05), but at 120 min the blood glucose area under the curve was lower only after the regular cornstarch treatment (P < 0.05). Premeal appetite decreased by all treatments (P < 0.05). CONCLUSION: The in vitro estimates of starch digestibility by the Englyst method predicted the effects of starch composition on blood glucose concentrations and FI in young men 30 and 120 min after consumption. This trial was registered at clinicaltrials.gov as NCT00980941 for experiment 1 and NCT00988689 for experiment 2. PMID- 20164322 TI - Body composition in patients with non-small cell lung cancer: a contemporary view of cancer cachexia with the use of computed tomography image analysis. AB - BACKGROUND: The prominent clinical feature of cachexia has traditionally been understood to be weight loss; however, in recognition of the potential for divergent behavior of muscle and adipose tissue, cachexia was recently defined as loss of muscle with or without loss of fat mass. Detailed assessments are required to verify body composition in patients with cancer cachexia. DESIGN: We adopted a population-based approach to study body composition in patients with cancer, with the use of diagnostic computed tomography images acquired for cancer diagnosis and follow-up. A prospective cohort of 441 patients with non-small cell lung cancer, who were referred consecutively to a regional medical oncology service in Alberta, Canada, was evaluated. RESULTS: At referral (median time to death: 265 d), mean body mass index (BMI; in kg/m(2)) was 24.9, with 47.4% of patients being overweight or obese. Only 7.5% overall were underweight as conventionally understood (BMI < 18.5). Analysis of computed tomography images showed extremely high heterogeneity of muscle mass within all strata of BMI. The overall prevalence of severe muscle depletion (sarcopenia) was 46.8% and was present in patients in all BMI categories. A much higher proportion of men (61%) than women (31%) met the criteria for sarcopenia. CONCLUSIONS: Wasting of skeletal muscle is a prominent feature of patients with lung cancer, despite normal or heavy body weights. The significance of muscle wasting in normal weight, overweight, and obese patients as a nutritional risk factor, as a prognostic factor, and as a predictor of cancer treatment toxicity is discussed in this article. PMID- 20164323 TI - Dynamic clamp: alteration of response properties and creation of virtual realities in neurophysiology. PMID- 20164324 TI - fMRI-Guided transcranial magnetic stimulation reveals that the superior temporal sulcus is a cortical locus of the McGurk effect. AB - A compelling example of auditory-visual multisensory integration is the McGurk effect, in which an auditory syllable is perceived very differently depending on whether it is accompanied by a visual movie of a speaker pronouncing the same syllable or a different, incongruent syllable. Anatomical and physiological studies in human and nonhuman primates have suggested that the superior temporal sulcus (STS) is involved in auditory-visual integration for both speech and nonspeech stimuli. We hypothesized that the STS plays a critical role in the creation of the McGurk percept. Because the location of multisensory integration in the STS varies from subject to subject, the location of auditory-visual speech processing in the STS was first identified in each subject with fMRI. Then, activity in this region of the STS was disrupted with single-pulse transcranial magnetic stimulation (TMS) as subjects rated their percept of McGurk and non McGurk stimuli. Across three experiments, TMS of the STS significantly reduced the likelihood of the McGurk percept but did not interfere with perception of non McGurk stimuli. TMS of the STS was effective at disrupting the McGurk effect only in a narrow temporal window from 100 ms before auditory syllable onset to 100 ms after onset, and TMS of a control location did not influence perception of McGurk or control stimuli. These results demonstrate that the STS plays a critical role in the McGurk effect and auditory-visual integration of speech. PMID- 20164325 TI - Hormonal modulation of sensorimotor integration. AB - Neuronal circuits commonly receive simultaneous inputs from descending, ascending, and hormonal systems. Thus far, however, most such inputs have been studied individually to determine their influence on a given circuit. Here, we examine the integrated action of the hormone crustacean cardioactive peptide (CCAP) and the gastropyloric receptor (GPR) proprioceptor neuron on the biphasic gastric mill (chewing) rhythm driven by the projection neuron modulatory commissural neuron 1 (MCN1) in the isolated crab stomatogastric ganglion. In control saline, GPR stimulation selectively prolongs the gastric mill retractor phase, via presynaptic inhibition of MCN1. In the absence of GPR stimulation, CCAP does not alter retraction duration and modestly prolongs protraction. Here, we show, using computational modeling and dynamic-clamp manipulations, that the presence of CCAP weakens or eliminates the GPR effect on the gastric mill rhythm. This CCAP action results from its ability to activate the same modulator activated conductance (G(MI)) as MCN1 in the gastric mill circuit neuron lateral gastric (LG). Because GPR prolongs retraction by weakening MCN1 activation of G(MI) in LG, the parallel G(MI) activation by CCAP reduces the impact of GPR regulation of this conductance. The CCAP-activated G(MI) thus counteracts the GPR mediated decrease in the MCN1-activated G(MI) in LG and reduces the GPR ability to regulate the gastric mill rhythm. Consequently, although CCAP neither changes retraction duration nor alters GPR inhibition of MCN1, its activation of a modulator-activated conductance in a pivotal downstream circuit neuron enables CCAP to weaken or eliminate sensory regulation of motor circuit output. PMID- 20164326 TI - Genetically determined differences in brain response to a primary food reward. AB - Combining genetic and neuroimaging techniques may elucidate the biological underpinnings of individual differences in neurophysiology and potential vulnerabilities to disease. The TaqIA A1 variant is associated with diminished dopamine D(2) receptor density, higher body mass, and food reinforcement. It also moderates the relationship between brain response to food and future weight gain. This suggests that the polymorphism is associated with a fundamental difference in the neurophysiology of food that may predispose toward overeating. An alternative possibility is that factors, such as impulsivity, eating style, reward drive, and perception, which may covary with the polymorphism, influence reward coding and eating behavior. To distinguish between these alternatives, we used functional magnetic resonance imaging to measure neural response to the ingestion of palatable and caloric milkshakes in healthy subjects with (A1+; n = 13) and without (A1-; n = 13) the TaqIA A1 allele. The groups were selected from a larger group to be matched for linked individual factors such as age, gender, education, body mass index, impulsivity, eating style, and perceptual responses to the milkshake. We demonstrate an interaction between genotype (A1+ vs A1-) and stimulus (milkshake vs a tasteless/odorless baseline) in the midbrain, thalamus, and orbital frontal cortex; whereas A1- shows increased responses to milkshake, A1+ shows decreased responses to milkshake relative to baseline. This interaction occurs despite similar ratings of milkshake pleasantness, intensity, and familiarity. We therefore conclude that there is a specific association between the TaqIA A1 polymorphism and brain response during ingestion of a palatable food. PMID- 20164327 TI - Neuronal nitric oxide synthase alteration accounts for the role of 5-HT1A receptor in modulating anxiety-related behaviors. AB - Increasing evidence suggests that 5-HT(1A) receptor (5-HT(1A)R) is implicated in anxiety disorders. However, the mechanism underlying the role of 5-HT(1A)R in these diseases remains unknown. Here, we show that 5-HT(1A)R-selective agonist 8 OH-DPAT and selective serotonin reuptake inhibitor (SSRI) fluoxetine downregulated hippocampal neuronal nitric oxide synthase (nNOS) expression, whereas 5-HT(1A)R-selective antagonist NAN-190 upregulated hippocampal nNOS expression. By assessing anxiety-related behaviors using the novelty suppressed feeding, open-field, and elevated plus maze tests, we show that mice lacking nNOS gene [knock-out (KO)] or treated with nNOS-selective inhibitor 7-nitroindazole (7 NI; i.p., 30 mg/kg/d for 28 d; or intrahippocampal microinjection, 16.31 microg/1.0 microl) displayed an anxiolytic-like phenotype, implicating nNOS in anxiety. We also show that, in wild-type (WT) mice, administrations of 8-OH-DPAT (i.p., 0.1 mg/kg/d) or fluoxetine (i.p., 10 mg/kg/d) for 28 d caused anxiolytic like effects, whereas NAN-190 (i.p., 0.3 mg/kg/d for 28 d) caused anxiogenic-like effects. In KO mice, however, these drugs were ineffective. Moreover, intrahippocampal infusion of 8-OH-DPAT (45.963 microg/100 microl) using 14 d osmotic minipump produced anxiolytic effects. Intrahippocampal microinjection of 7-NI (16.31 microg/1.0 microl) abolished the anxiogenic-like effects of intrahippocampal NAN-190 (4.74 microg/1.0 microl). Additionally, NAN-190 decreased and 8-OH-DPAT increased phosphorylated cAMP response element-binding protein (CREB) levels in WT mice but not in KO mice. Blockade of hippocampal CREB phosphorylation by microinjection of H89 (5.19 microg/1.0 microl), a PKA (protein kinase A) inhibitor, abolished the anxiolytic-like effects of 7-NI (i.p., 30 mg/kg/d for 21 d). These findings indicate that both hippocampal nNOS and CREB activity mediate the anxiolytic effects of 5-HT(1A)R agonists and SSRIs. PMID- 20164328 TI - Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer's disease. AB - Early Alzheimer's disease (AD) is marked by cholinergic hypofunction, neuronal marker loss, and decreased nicotinic acetylcholine receptor (nAChR) density from the cortex and hippocampus. alpha7 nAChRs expressed on cholinergic projection neurons and target regions have been implicated in neuroprotection against beta amyloid (Abeta) toxicity and maintenance of the septohippocampal phenotype. We tested the role that alpha7 nAChRs perform in the etiology of early AD by genetically deleting the alpha7 nAChR subunit from the Tg2576 mouse model for AD and assessing animals for cognitive function and septohippocampal integrity. Thus, Tg2576 mice transgenic for mutant human amyloid precursor protein (APP) were crossed with alpha7 nAChR knock-out mice (A7KO) to render an animal with elevated Abeta in the absence of alpha7 nAChRs (A7KO-APP). We found that learning and memory deficits seen in 5-month-old APP mice are more severe in the A7KO-APP animals. Analyses of animals in early-stage preplaque cognitive decline revealed signs of neurodegeneration in A7KO-APP hippocampus as well as loss of cholinergic functionality in the basal forebrain and hippocampus. These changes occurred concomitant with the appearance of a dodecameric oligomer of Abeta that was absent from all other genotypic groups, generating the hypothesis that increased soluble oligomeric Abeta may underlie additional impairment of A7KO-APP cognitive function. Thus, alpha7 nAChRs in a mouse model for early-stage AD appear to serve a neuroprotective role through maintenance of the septohippocampal cholinergic phenotype and preservation of hippocampal integrity possibly through influences on Abeta accumulation and oligomerization. PMID- 20164329 TI - Inhibition of FK506 binding proteins reduces alpha-synuclein aggregation and Parkinson's disease-like pathology. AB - alpha-Synuclein (alpha-SYN) is a key player in the pathogenesis of Parkinson's disease (PD). In pathological conditions, the protein is present in a fibrillar, aggregated form inside cytoplasmic inclusions called Lewy bodies. Members of the FK506 binding protein (FKBP) family are peptidyl-prolyl isomerases that were shown recently to accelerate the aggregation of alpha-SYN in vitro. We now established a neuronal cell culture model for synucleinopathy based on oxidative stress-induced alpha-SYN aggregation and apoptosis. Using high-content analysis, we examined the role of FKBPs in aggregation and apoptotic cell death. FK506, a specific inhibitor of this family of proteins, inhibited alpha-SYN aggregation and neuronal cell death in this synucleinopathy model dose dependently. Knockdown of FKBP12 or FKBP52 reduced the number of alpha-SYN aggregates and protected against cell death, whereas overexpression of FKBP12 or FKBP52 accelerated both aggregation of alpha-SYN and cell death. Thus, FK506 likely targets FKBP members in the cell culture model. Furthermore, oral administration of FK506 after viral vector-mediated overexpression of alpha-SYN in adult mouse brain significantly reduced alpha-SYN aggregate formation and neuronal cell death. Our data explain previously described neuroregenerative and neuroprotective effects of immunophilin ligands and validate FKBPs as a novel drug target for the causative treatment of PD. PMID- 20164330 TI - Neural correlates of variations in event processing during learning in basolateral amygdala. AB - The discovery that dopamine neurons signal errors in reward prediction has demonstrated that concepts empirically derived from the study of animal behavior can be used to understand the neural implementation of reward learning. Yet the learning theory models linked to phasic dopamine activity treat attention to events such as cues and rewards as static quantities; other models, such as Pearce-Hall, propose that learning might be influenced by variations in processing of these events. A key feature of these accounts is that event processing is modulated by unsigned rather than signed reward prediction errors. Here we tested whether neural activity in rat basolateral amygdala conforms to this pattern by recording single units in a behavioral task in which rewards were unexpectedly delivered or omitted. We report that neural activity at the time of reward is providing an unsigned error signal with characteristics consistent with those postulated by these models. This neural signal increased immediately after a change in reward, and stronger firing was evident whether the value of the reward increased or decreased. Further, as predicted by these models, the change in firing developed over several trials as expectations for reward were repeatedly violated. This neural signal was correlated with faster orienting to predictive cues after changes in reward, and abolition of the signal by inactivation of basolateral amygdala disrupted this change in orienting and retarded learning in response to changes in reward. These results suggest that basolateral amygdala serves a critical function in attention for learning. PMID- 20164331 TI - Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. AB - Acute leptin administration results in a depolarization and concomitant increase in the firing rate of a subpopulation of arcuate proopiomelanocortin (POMC) cells. This rapid activation of POMC cells has been implicated as a cellular correlate of leptin effects on energy balance. In contrast to leptin, insulin inhibits the activity of some POMC neurons. Several studies have described a "cross talk" between leptin and insulin within the mediobasal hypothalamus via the intracellular enzyme, phosphoinositol-3-kinase (PI3K). Interestingly, both insulin and leptin regulate POMC cellular activity by activation of PI3K; however, it is unclear whether leptin and insulin effects are observed in similar or distinct populations of POMC cells. We therefore used dual label immunohistochemistry/in situ hybridization and whole-cell patch-clamp electrophysiology to map insulin and leptin responsive arcuate POMC neurons. Leptin-induced Fos activity within arcuate POMC neurons was localized separate from POMC neurons that express insulin receptor. Moreover, acute responses to leptin and insulin were largely segregated in distinct subpopulations of POMC cells. Collectively, these data suggest that cross talk between leptin and insulin occurs within a network of cells rather than within individual POMC neurons. PMID- 20164332 TI - Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B. AB - Caspr and Caspr2 regulate the formation of distinct axonal domains around the nodes of Ranvier. Caspr is required for the generation of a membrane barrier at the paranodal junction (PNJ), whereas Caspr2 serves as a membrane scaffold that clusters Kv1 channels at the juxtaparanodal region (JXP). Both Caspr and Caspr2 interact with protein 4.1B, which may link the paranodal and juxtaparanodal adhesion complexes to the axonal cytoskeleton. To determine the role of protein 4.1B in the function of Caspr proteins, we examined the ability of transgenic Caspr and Caspr2 mutants lacking their 4.1-binding sequence (d4.1) to restore Kv1 channel clustering in Caspr- and Caspr2-null mice, respectively. We found that Caspr-d4.1 was localized to the PNJ and is able to recruit the paranodal adhesion complex components contactin and NF155 to this site. Nevertheless, in axons expressing Caspr-d4.1, Kv1 channels were often detected at paranodes, suggesting that the interaction of Caspr with protein 4.1B is necessary for the generation of an efficient membrane barrier at the PNJ. We also found that the Caspr2-d4.1 transgene did not accumulate at the JXP, even though it was targeted to the axon, demonstrating that the interaction with protein 4.1B is required for the accumulation of Caspr2 and Kv1 channels at the juxtaparanodal axonal membrane. In accordance, we show that Caspr2 and Kv1 channels are not clustered at the JXP in 4.1B-null mice. Our results thus underscore the functional importance of protein 4.1B in the organization of peripheral myelinated axons. PMID- 20164333 TI - Distinct value signals in anterior and posterior ventromedial prefrontal cortex. AB - The core feature of an economic exchange is a decision to trade one good for another, based on a comparison of relative value. Economists have long recognized, however, that the value an individual ascribes to a good during decision making (i.e., their relative willingness to trade for that good) does not always map onto the reward they actually experience. Here, we show that experienced value and decision value are represented in distinct regions of ventromedial prefrontal cortex (VMPFC) during the passive consumption of rewards. Participants viewed two categories of rewards-images of faces that varied in their attractiveness and monetary gains and losses-while being scanned using functional magnetic resonance imaging. An independent market task, in which participants exchanged some of the money that they had earned for brief views of attractive faces, determined the relative decision value associated with each category. We found that activation of anterior VMPFC increased with increasing experienced value, but not decision value, for both reward categories. In contrast, activation of posterior VMPFC predicted each individual's relative decision value for face and monetary stimuli. These results indicate not only that experienced value and decision value are represented in distinct regions of VMPFC, but also that decision value signals are evident even in the absence of an overt choice task. We conclude that decisions are made by comparing neural representations of the value of different goods encoded in posterior VMPFC in a common, relative currency. PMID- 20164334 TI - Deletion of GRK1 causes retina degeneration through a transducin-independent mechanism. AB - Rpe65(-/-) mice are unable to produce 11-cis-retinal, the chromophore of visual pigments. Consequently, the pigment is present as the apoprotein opsin with a minute level of pigment containing 9-cis-retinal as chromophore. Notably, a 10 20% fraction of this opsin is mono-phosphorylated independently of light conditions. To determine the role of rhodopsin kinase (GRK1) in phosphorylating this opsin and to test whether eliminating this phosphorylation would accelerate photoreceptor degeneration, we generated the Rpe65(-/-)Grk1(-/-) mouse. The retinae of Rpe65(-/-)Grk1(-/-) mice had negligible opsin phosphorylation, extensive degeneration with decreased opsin levels, and diminished light-evoked rod responses relative to Rpe65(-/-) mice. These data show that opsin phosphorylation in the Rpe65(-/-) mouse is due to the action of GRK1 and is neuroprotective. However, despite the higher activity of unphosphorylated opsin, the severe loss of opsin in the rapidly degenerating Rpe65(-/-)Grk1(-/-) mice resulted in lower overall opsin activity and in higher rod sensitivity compared with Rpe65(-/-) mice. In Rpe65(-/-)Grk1(-/-)Gnat1(-/-) mice where transduction activation was blocked, degeneration was only partially prevented. Therefore, increased opsin activity in the absence of phosphorylation was not the only mechanism for the accelerated retinal degeneration. Finally, the deletion of GRK1 triggered retinal degeneration in Grk1(-/-) mice after 1 month, even in the absence of apo-opsin. This degeneration was independent of light conditions and occurred even in the absence of transducin in Grk1(-/-)Gnat1(-/-) mice. Taken together, our results demonstrate a light-independent mechanism for retinal degeneration in the absence of GRK1, suggesting a second, not previously recognized role for that kinase. PMID- 20164335 TI - A G-protein-coupled neuropeptide Y-like receptor suppresses behavioral and sensory response to multiple stressful stimuli in Drosophila. AB - Recent studies suggest that human neuropeptide Y (NPY) plays a prominent role in management of stress response and emotion, and higher NPY levels observed in combat-exposed veterans may help coping with posttraumatic stress. Neuropeptide F (NPF), the counterpart of NPY in Drosophila melanogaster, also displays parallel activities, including promotion of resilience to diverse stressors and prevention of uncontrolled aggressive behavior. However, it remains unclear how NPY family peptides modulate physical and emotional responses to various stressors. Here we show that NPFR1, a G-protein-coupled NPF receptor, exerts an inhibitory effect on larval aversion to diverse stressful stimuli mediated by different subtypes of fly and mammalian transient receptor potential (TRP) family channels. Imaging analysis in larval sensory neurons and cultured human cells showed that NPFR1 attenuates Ca(2+) influx mediated by fly TRPA and rat TRPV1 channels. Our findings suggest that suppression of TRP channel-mediated neural excitation by the conserved NPF/NPFR1 system may be a major mechanism for attaining its broad anti-stress function. PMID- 20164336 TI - Overexpression of serum response factor restores ocular dominance plasticity in a model of fetal alcohol spectrum disorders. AB - Neuronal plasticity deficits underlie many of the neurobehavioral problems seen in fetal alcohol spectrum disorders (FASD). Recently, we showed that third trimester alcohol exposure leads to a persistent disruption in ocular dominance (OD) plasticity. For instance, a few days of monocular deprivation results in a robust reduction of cortical regions responsive to the deprived eye in normal animals, but not in ferrets exposed early to alcohol. This plasticity deficit can be reversed if alcohol-exposed animals are treated with a phosphodiesterase type 1 (PDE1) inhibitor during the period of monocular deprivation. PDE1 inhibition can increase cAMP and cGMP levels, activating transcription factors such as the cAMP response element binding protein (CREB) and the serum response factor (SRF). SRF is important for many plasticity processes such as LTP, LTD, spine motility, and axonal pathfinding. Here we attempt to rescue OD plasticity in alcohol treated ferrets using a Sindbis viral vector to express a constitutively active form of SRF during the period of monocular deprivation. Using optical imaging of intrinsic signals and single-unit recordings, we observed that overexpression of a constitutively active form of SRF, but neither its dominant-negative nor GFP, restored OD plasticity in alcohol-treated animals. Surprisingly, this restoration was observed throughout the extent of the primary visual cortex and most cells infected by the virus were positive for GFAP rather than NeuN. This finding suggests that overexpression of SRF in astrocytes may reduce the deficits in neuronal plasticity seen in models of FASD. PMID- 20164337 TI - Alternative splicing of the histone demethylase LSD1/KDM1 contributes to the modulation of neurite morphogenesis in the mammalian nervous system. AB - A variety of chromatin remodeling complexes are thought to orchestrate transcriptional programs that lead neuronal precursors from earliest commitment to terminal differentiation. Here we show that mammalian neurons have a specialized chromatin remodeling enzyme arising from a neurospecific splice variant of LSD1/KDM1, histone lysine specific demethylase 1, whose demethylase activity on Lys4 of histone H3 has been related to gene repression. We found that alternative splicing of LSD1 transcript generates four full-length isoforms from combinatorial retention of two identified exons: the 4 aa exon E8a is internal to the amine oxidase domain, and its inclusion is restricted to the nervous system. Remarkably, the expression of LSD1 splice variants is dynamically regulated throughout cortical development, particularly during perinatal stages, with a progressive increase of LSD1 neurospecific isoforms over the ubiquitous ones. Notably, the same LSD1 splice dynamics can be fairly recapitulated in cultured cortical neurons. Functionally, LSD1 isoforms display in vitro a comparable demethylase activity, yet the inclusion of the sole exon E8a reduces LSD1 repressor activity on a reporter gene. Additional distinction among isoforms is supported by the knockdown of neurospecific variants in cortical neurons resulting in the inhibition of neurite maturation, whereas overexpression of the same variants enhances it. Instead, perturbation of LSD1 isoforms that are devoid of the neurospecific exon elicits no morphogenic effect. Collectively, results demonstrate that the arousal of neuronal LSD1 isoforms pacemakes early neurite morphogenesis, conferring a neurospecific function to LSD1 epigenetic activity. PMID- 20164338 TI - Brain-derived neurotrophic factor regulates hedonic feeding by acting on the mesolimbic dopamine system. AB - Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, play prominent roles in food intake regulation through central mechanisms. However, the neural circuits underlying their anorexigenic effects remain largely unknown. We showed previously that selective BDNF depletion in the ventromedial hypothalamus (VMH) of mice resulted in hyperphagic behavior and obesity. Here, we sought to ascertain whether its regulatory effects involved the mesolimbic dopamine system, which mediates motivated and reward-seeking behaviors including consumption of palatable food. We found that expression of BDNF and TrkB mRNA in the ventral tegmental area (VTA) of wild-type mice was influenced by consumption of palatable, high-fat food (HFF). Moreover, amperometric recordings in brain slices of mice depleted of central BDNF uncovered marked deficits in evoked release of dopamine in the nucleus accumbens (NAc) shell and dorsal striatum but normal secretion in the NAc core. Mutant mice also exhibited dramatic increases in HFF consumption, which were exacerbated when access to HFF was restricted. However, mutants displayed enhanced responses to D(1) receptor agonist administration, which normalized their intake of HFF in a 4 h food intake test. Finally, in contrast to deletion of Bdnf in the VMH of mice, which resulted in increased intake of standard chow, BDNF depletion in the VTA elicited excessive intake of HFF but not of standard chow and increased body weights under HFF conditions. Our findings indicate that the effects of BDNF on eating behavior are neural substrate-dependent and that BDNF influences hedonic feeding via positive modulation of the mesolimbic dopamine system. PMID- 20164339 TI - Acute in vivo genetic rescue demonstrates that phosphorylation of RIM1alpha serine 413 is not required for mossy fiber long-term potentiation. AB - While presynaptic, protein kinase A (PKA)-dependent, long-term plasticity has been described in numerous brain regions, the target(s) of PKA and the molecular mechanisms leading to sustained changes in neurotransmitter release remain elusive. Here, we acutely reconstitute mossy fiber long-term potentiation (mfLTP) de novo in the mature brains of mutant mice that normally lack this form of plasticity. These results demonstrate that RIM1alpha, a presynaptic scaffold protein and a potential PKA target, can support mfLTP independent of a role in brain development. Using this approach, we study two mutations of RIM1alpha (S413A and V415P) and conclude that PKA-phosphorylation-dependent signaling by RIM1alpha serine 413 is not required for mfLTP, consistent with conclusions reached from the study of RIM1alpha S413A knockin mice. Together, these results provide insights into the mechanism of mossy fiber LTP and demonstrate a useful acute approach to genetically manipulate mossy fiber synapses in the mature brain. PMID- 20164340 TI - Redox dysregulation affects the ventral but not dorsal hippocampus: impairment of parvalbumin neurons, gamma oscillations, and related behaviors. AB - Elevated oxidative stress and alteration in antioxidant systems, including glutathione (GSH) decrease, are observed in schizophrenia. Genetic and functional data indicate that impaired GSH synthesis represents a susceptibility factor for the disorder. Here, we show that a genetically compromised GSH synthesis affects the morphological and functional integrity of hippocampal parvalbumin immunoreactive (PV-IR) interneurons, known to be affected in schizophrenia. A GSH deficit causes a selective decrease of PV-IR interneurons in CA3 and dendate gyrus (DG) of the ventral but not dorsal hippocampus and a concomitant reduction of beta/gamma oscillations. Impairment of PV-IR interneurons emerges at the end of adolescence/early adulthood as oxidative stress increases or cumulates selectively in CA3 and DG of the ventral hippocampus. Such redox dysregulation alters stress and emotion-related behaviors but leaves spatial abilities intact, indicating functional disruption of the ventral but not dorsal hippocampus. Thus, a GSH deficit affects PV-IR interneuron's integrity and neuronal synchrony in a region- and time-specific manner, leading to behavioral phenotypes related to psychiatric disorders. PMID- 20164341 TI - Stochastic transitions between neural states in taste processing and decision making. AB - Noise, which is ubiquitous in the nervous system, causes trial-to-trial variability in the neural responses to stimuli. This neural variability is in turn a likely source of behavioral variability. Using Hidden Markov modeling, a method of analysis that can make use of such trial-to-trial response variability, we have uncovered sequences of discrete states of neural activity in gustatory cortex during taste processing. Here, we advance our understanding of these patterns in two ways. First, we reproduce the experimental findings in a formal model, describing a network that evinces sharp transitions between discrete states that are deterministically stable given sufficient noise in the network; as in the empirical data, the transitions occur at variable times across trials, but the stimulus-specific sequence is itself reliable. Second, we demonstrate that such noise-induced transitions between discrete states can be computationally advantageous in a reduced, decision-making network. The reduced network produces binary outputs, which represent classification of ingested substances as palatable or nonpalatable, and the corresponding behavioral responses of "spit" or "swallow". We evaluate the performance of the network by measuring how reliably its outputs follow small biases in the strengths of its inputs. We compare two modes of operation: deterministic integration ("ramping") versus stochastic decision-making ("jumping"), the latter of which relies on state-to-state transitions. We find that the stochastic mode of operation can be optimal under typical levels of internal noise and that, within this mode, addition of random noise to each input can improve optimal performance when decisions must be made in limited time. PMID- 20164342 TI - Transient early-life forebrain corticotropin-releasing hormone elevation causes long-lasting anxiogenic and despair-like changes in mice. AB - During development, early-life stress, such as abuse or trauma, induces long lasting changes that are linked to adult anxiety and depressive behavior. It has been postulated that altered expression of corticotropin-releasing hormone (CRH) can at least partially account for the various effects of stress on behavior. In accord with this hypothesis, evidence from pharmacological and genetic studies has indicated the capacity of differing levels of CRH activity in different brain areas to produce behavioral changes. Furthermore, stress during early life or adulthood causes an increase in CRH release in a variety of neural sites. To evaluate the temporal and spatial specificity of the effect of early-life CRH exposure on adult behavior, the tetracycline-off system was used to produce mice with forebrain-restricted inducible expression of CRH. After transient elevation of CRH during development only, behavioral testing in adult mice revealed a persistent anxiogenic and despair-like phenotype. These behavioral changes were not associated with alterations in adult circadian or stress-induced corticosterone release but were associated with changes in CRH receptor type 1 expression. Furthermore, the despair-like changes were normalized with antidepressant treatment. Overall, these studies suggest that forebrain restricted CRH signaling during development can permanently alter stress adaptation leading to increases in maladaptive behavior in adulthood. PMID- 20164343 TI - eIF2alpha Phosphorylation-dependent translation in CA1 pyramidal cells impairs hippocampal memory consolidation without affecting general translation. AB - Protein synthesis inhibitor antibiotics are widely used to produce amnesia, and have been recognized to inhibit general or global mRNA translation in the basic translational machinery. For instance, anisomycin interferes with protein synthesis by inhibiting peptidyl transferase or the 80S ribosomal function. Therefore, de novo general or global protein synthesis has been thought to be necessary for long-term memory formation. However, it is unclear which mode of translation-gene-specific translation or general/global translation-is actually crucial for the memory consolidation process in mammalian brains. Here, we generated a conditional transgenic mouse strain in which double-strand RNA dependent protein kinase (PKR)-mediated phosphorylation of eIF2alpha, a key translation initiation protein, was specifically increased in hippocampal CA1 pyramidal cells by the chemical inducer AP20187. Administration of AP20187 significantly increased activating transcription factor 4 (ATF4) translation and concomitantly suppressed CREB-dependent pathways in CA1 cells; this led to impaired hippocampal late-phase LTP and memory consolidation, with no obvious reduction in general translation. Conversely, inhibition of general translation by low-dose anisomycin failed to block hippocampal-dependent memory consolidation. Together, these results indicated that CA1-restricted genetic manipulation of particular mRNA translations is sufficient to impair the consolidation and that consolidation of memories in CA1 pyramidal cells through eIF2alpha dephosphorylation depends more on transcription/translation of particular genes than on overall levels of general translation. The present study sheds light on the critical importance of gene-specific translations for hippocampal memory consolidation. PMID- 20164344 TI - Activation of the T1 neuronal circuit is necessary and sufficient to induce sexually dimorphic mating behavior in Drosophila melanogaster. AB - The molecular and cellular events mediating complex behaviors in animals are largely unknown. Elucidating the circuits underlying behaviors in simple model systems may shed light on how these circuits function. In drosophila, courtship behavior provides a tractable model for studying the underlying basis of innate behavior. The male-specific pheromone 11-cis-vaccenyl acetate (cVA) modulates courtship behavior and is detected by T1 neurons, located on the antenna of male and female flies. The T1 neurons express the odorant receptor Or67d and are exquisitely tuned to cVA pheromone. However, cVA-induced changes in mating behavior have also been reported upon manipulation of olfactory neurons expressing odorant receptor Or65a. These findings raise the issue of whether multiple olfactory-driven circuits underlie cVA-induced behavioral responses and what role these circuits play in behavior. Here, we engineered flies in which the Or67d circuit is specifically activated in the absence of cVA to determine the role of this circuit in behavior. We created transgenic flies that express a dominant-active, pheromone-independent variant of the extracellular pheromone receptor, LUSH. We found that, similar to the behaviors elicited by cVA, engineered male flies have dramatically reduced courtship, whereas engineered females showed enhanced courtship. cVA exposure did not enhance the dominant LUSH triggered effects on behavior in the engineered flies. Finally, we show the effects of both cVA and dominant LUSH on courtship are reversed by genetically removing Or67d. These findings demonstrate that the T1/Or67d circuit is necessary and sufficient to mediate sexually dimorphic courtship behaviors. PMID- 20164345 TI - Cilia organize ependymal planar polarity. AB - Multiciliated epithelial cells, called ependymal cells, line the ventricles in the adult brain. Most ependymal cells are born prenatally and are derived from radial glia. Ependymal cells have a remarkable planar polarization that determines orientation of ciliary beating and propulsion of CSF. Disruption of ependymal ciliary beating, by injury or disease, results in aberrant CSF circulation and hydrocephalus, a common disorder of the CNS. Very little is known about the mechanisms guiding ependymal planar polarity and whether this organization is acquired during ependymal cell development or is already present in radial glia. Here we show that basal bodies in ependymal cells in the lateral ventricle walls of adult mice are polarized in two ways: (1) rotational; angle of individual basal bodies with respect to their long axis and (2) translational; the position of basal bodies on the apical surface of the cell. Conditional ablation of motile cilia disrupted rotational orientation, but translational polarity was largely preserved. In contrast, translational polarity was dramatically affected when radial glial primary cilia were ablated earlier in development. Remarkably, radial glia in the embryo have a translational polarity that predicts the orientation of mature ependymal cells. These results suggest that ependymal planar cell polarity is a multistep process initially organized by primary cilia in radial glia and then refined by motile cilia in ependymal cells. PMID- 20164346 TI - Homeostatic regulation of synaptic excitability: tonic GABA(A) receptor currents replace I(h) in cortical pyramidal neurons of HCN1 knock-out mice. AB - Homeostatic control of synaptic efficacy is often mediated by dynamic regulation of excitatory synaptic receptors. Here, we report a novel form of homeostatic synaptic plasticity based on regulation of shunt currents that control dendritosomatic information transfer. In cortical pyramidal neurons from wild type mice, HCN1 channels underlie a dendritic hyperpolarization-activated cationic current (I(h)) that serves to limit temporal summation of synaptic inputs. In HCN1 knock-out mice, as expected, I(h) is reduced in pyramidal neurons and its effects on synaptic summation are strongly diminished. Unexpectedly, we found a markedly enhanced bicuculline- and L-655,708-sensitive background GABA(A) current in these cells that could be attributed to selective upregulation of GABA(A) alpha5 subunit expression in the cortex of HCN1 knock-out mice. Strikingly, despite diminished I(h), baseline sublinear summation of evoked EPSPs was unchanged in pyramidal neurons from HCN1 knock-out mice; however, blocking tonic GABA(A) currents with bicuculline enhanced synaptic summation more strongly in pyramidal cells from HCN1 knock-out mice than in those cells from wild-type mice. Increasing tonic GABA(A) receptor conductance in the context of reduced I(h), using computational or pharmacological approaches, restored normal baseline synaptic summation, as observed in neurons from HCN1 knock-out mice. These data indicate that upregulation of alpha5 subunit-mediated GABA(A) receptor tonic current compensates quantitatively for loss of dendritic I(h) in cortical pyramidal neurons from HCN1 knock-out mice to maintain normal synaptic summation; they further imply that dendritosomatic synaptic efficacy is a controlled variable for homeostatic regulation of cortical neuron excitability in vivo. PMID- 20164347 TI - Suppression of the intrinsic apoptosis pathway by synaptic activity. AB - Synaptic activity promotes resistance to diverse apoptotic insults, the mechanism behind which is incompletely understood. We show here that a coordinated downregulation of core components of the intrinsic apoptosis pathway by neuronal activity forms a key part of the underlying mechanism. Activity-dependent protection against apoptotic insults is associated with inhibition of cytochrome c release in most but not all neurons, indicative of anti-apoptotic signaling both upstream and downstream of this step. We find that enhanced firing activity suppresses expression of the proapoptotic BH3-only member gene Puma in a NMDA receptor-dependent, p53-independent manner. Puma expression is sufficient to induce cytochrome c loss and neuronal apoptosis. Puma deficiency protects neurons against apoptosis and also occludes the protective effect of synaptic activity, while blockade of physiological NMDA receptor activity in the developing mouse brain induces neuronal apoptosis that is preceded by upregulation of Puma. However, enhanced activity can also confer resistance to Puma-induced apoptosis, acting downstream of cytochrome c release. This mechanism is mediated by transcriptional suppression of apoptosome components Apaf-1 and procaspase-9, and limiting caspase-9 activity, since overexpression of procaspase-9 accelerates the rate of apoptosis in active neurons back to control levels. Synaptic activity does not exert further significant anti-apoptotic effects downstream of caspase-9 activation, since an inducible form of caspase-9 overrides the protective effect of synaptic activity, despite activity-induced transcriptional suppression of caspase-3. Thus, suppression of apoptotic gene expression may synergize with other activity-dependent events such as enhancement of antioxidant defenses to promote neuronal survival. PMID- 20164348 TI - Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. AB - Amyloid beta (Abeta)-containing plaques are surrounded by dystrophic neurites in the Alzheimer's disease (AD) brain, but whether and how plaques induce these neuritic abnormalities remain unknown. We tested the hypothesis that soluble oligomeric assemblies of Abeta, which surround plaques, induce calcium-mediated secondary cascades that lead to dystrophic changes in local neurites. We show that soluble Abeta oligomers lead to activation of the calcium-dependent phosphatase calcineurin (CaN) (PP2B), which in turn activates the transcriptional factor nuclear factor of activated T cells (NFAT). Activation of these signaling pathways, even in the absence of Abeta, is sufficient to produce a virtual phenocopy of Abeta-induced dystrophic neurites, dendritic simplification, and dendritic spine loss in both neurons in culture and in the adult mouse brain. Importantly, the morphological deficits in the vicinity of Abeta deposits in a mouse model of AD are ameliorated by CaN inhibition, supporting the hypothesis that CaN-NFAT are aberrantly activated by Abeta and that CaN-NFAT activation is responsible for disruption of neuronal structure near plaques. In accord with this, we also detect increased levels of an active form of CaN and NFATc4 in the nuclear fraction from the cortex of patients with AD. Thus, Abeta appears to mediate the neurodegeneration of AD, at least in part, by activation of CaN and subsequent NFAT-mediated downstream cascades. PMID- 20164349 TI - Stored-trace reactivation in rat prefrontal cortex is correlated with down-to-up state fluctuation density. AB - Spontaneous reactivation of previously stored patterns of neural activity occurs in hippocampus and neocortex during non-rapid eye movement (NREM) sleep. Notable features of the neocortical local field potential during NREM sleep are high amplitude, low-frequency thalamocortical oscillations including K-complexes, low voltage spindles, and high-voltage spindles. Using combined neuronal ensemble and local field potential recordings, we show that prefrontal stored-trace reactivation is correlated with the density of down-to-up state transitions of the population of simultaneously recorded cells, as well as K-complexes and low voltage spindles in the local field potential. This result strengthens the connection between reactivation and learning, as these same NREM sleep features have been correlated with memory. Although memory trace reactivation is correlated with low-voltage spindles, it is not correlated with high-voltage spindles, indicating that despite their similar frequency characteristics, these two oscillations serve different functions. PMID- 20164350 TI - Distinct functional contributions of primary sensory and association areas to audiovisual integration in object categorization. AB - Multisensory interactions have been demonstrated in a distributed neural system encompassing primary sensory and higher-order association areas. However, their distinct functional roles in multisensory integration remain unclear. This functional magnetic resonance imaging study dissociated the functional contributions of three cortical levels to multisensory integration in object categorization. Subjects actively categorized or passively perceived noisy auditory and visual signals emanating from everyday actions with objects. The experiment included two 2 x 2 factorial designs that manipulated either (1) the presence/absence or (2) the informativeness of the sensory inputs. These experimental manipulations revealed three patterns of audiovisual interactions. (1) In primary auditory cortices (PACs), a concurrent visual input increased the stimulus salience by amplifying the auditory response regardless of task-context. Effective connectivity analyses demonstrated that this automatic response amplification is mediated via both direct and indirect [via superior temporal sulcus (STS)] connectivity to visual cortices. (2) In STS and intraparietal sulcus (IPS), audiovisual interactions sustained the integration of higher-order object features and predicted subjects' audiovisual benefits in object categorization. (3) In the left ventrolateral prefrontal cortex (vlPFC), explicit semantic categorization resulted in suppressive audiovisual interactions as an index for multisensory facilitation of semantic retrieval and response selection. In conclusion, multisensory integration emerges at multiple processing stages within the cortical hierarchy. The distinct profiles of audiovisual interactions dissociate audiovisual salience effects in PACs, formation of object representations in STS/IPS and audiovisual facilitation of semantic categorization in vlPFC. Furthermore, in STS/IPS, the profiles of audiovisual interactions were behaviorally relevant and predicted subjects' multisensory benefits in performance accuracy. PMID- 20164351 TI - Distinct roles of NR2A and NR2B cytoplasmic tails in long-term potentiation. AB - NMDA receptors (NMDARs) are critical mediators of activity-dependent synaptic plasticity, but the differential roles of NR2A- versus NR2B-containing NMDARs have been controversial. Here, we investigate the roles of NR2A and NR2B in long term potentiation (LTP) in organotypic hippocampal slice cultures using RNA interference (RNAi) and overexpression, to complement pharmacological approaches. In young slices, when NR2B is the predominant subunit expressed, LTP is blocked by the NR2B-selective antagonist Ro25-6981 [R-(R,S)-alpha-(4-hydroxyphenyl)-beta methyl-4-(phenylmethyl)-1-piperidine propranol]. As slices mature and NR2A expression rises, activation of NR2B receptors became no longer necessary for LTP induction. LTP was blocked, however, by RNAi knockdown of NR2B, and this was rescued by coexpression of an RNAi-resistant NR2B (NR2B*) cDNA. Interestingly, a chimeric NR2B subunit in which the C-terminal cytoplasmic tail was replaced by that of NR2A failed to rescue LTP, whereas the reverse chimera, NR2A channel with NR2B tail, was able to restore LTP. Thus, expression of NR2B with its intact cytoplasmic tail is required for LTP induction, at an age when channel activity of NR2B-NMDARs is not required for LTP. Overexpression of wild-type NR2A failed to rescue LTP in neurons transfected with the NR2B-RNAi construct, despite restoring NMDA-EPSC amplitude to a similar level as NR2B*. Surprisingly, an NR2A construct lacking its entire C-terminal cytoplasmic tail regained its ability to restore LTP. Together, these data suggest that the NR2B subunit plays a critical role for LTP, presumably by recruiting relevant molecules important for LTP via its cytoplasmic tail. In contrast, NR2A is not essential for LTP, and its cytoplasmic tail seems to carry inhibitory factors for LTP. PMID- 20164352 TI - EEG measures index neural and cognitive recovery from sleep deprivation. AB - Sleep deprivation impairs many cognitive abilities, but these impairments can be reversed after a certain quantity and quality of sleep. The ability to inhibit responding is particularly susceptible to disruption after prolonged wakefulness. How recovery sleep (RS) alters brain activity, leading to improved performance on a variety of cognitive tasks, remains unclear. This issue was examined in the current study using spectral analysis of electroencephalogram (EEG) data during sleep. These measures of sleep physiology were acquired after both normal sleep (NS) and RS, and were related to measures of inhibitory control and concurrent brain activity. Subjects were nine young adults who underwent functional magnetic resonance imaging twice, after 9 h of NS and after 10 h of RS that followed 38 h of being awake. A multiple regression model was used to examine differences between conditions in (1) EEG spectral power during sleep, (2) probability of successful inhibition in a go/no-go task, and (3) activation within a region of right prefrontal cortex during the task. Performance recovery, as indexed by reduced performance differences between conditions, was predicted by increased delta power and decreased sigma power in RS compared with NS. These EEG variables predicted most of the variance in inhibitory performance difference between conditions. Regressions also suggested that RS improved performance because of changes in brain function including prefrontal regions that resulted from delta rebound. We thus propose that slow waves, reflected in delta power during RS, act to restore brain function, thereby improving cognitive performance that entails response inhibition. PMID- 20164354 TI - Saccade suppression by electrical microstimulation in monkey caudate nucleus. AB - It has been suggested that the caudate nucleus, the input stage of the basal ganglia, facilitates and suppresses saccade initiation based on its anatomical characteristics. Although the involvement of the caudate nucleus in saccade facilitation has been shown previously, it is still unclear whether the caudate nucleus is also involved in saccade suppression. Here, we revealed the direct involvement of the caudate nucleus in saccade suppression by electrical microstimulation in behaving monkeys. We delivered microstimulation to the caudate nucleus while monkeys performed the prosaccade (look toward a peripheral visual stimulus) and antisaccade (look away from the stimulus) paradigm. The reaction times of contralateral saccades were prolonged on both prosaccade and antisaccade trials. The suppression effects on reaction times were stronger on prosaccade trials compared with antisaccade trials. The analysis of reaction time distributions using the linear approach to threshold with ergodic rate model (LATER model) revealed that microstimulation prolonged reaction times by reducing the rate of rise to the threshold for saccade initiation. Microstimulation also worsened correct performance rates for contralateral saccades. The same microstimulation prolonged and/or shortened the reaction times of ipsilateral saccades, although the effects were not as consistent as those on contralateral saccades. We conclude that caudate signals are sufficient to suppress contralateral saccades and influence saccadic decision by controlling contralateral and ipsilateral saccade commands at the same time. PMID- 20164353 TI - Hippocampal gamma oscillations increase with memory load. AB - Although the hippocampus plays a crucial role in encoding and retrieval of contextually mediated episodic memories, considerable controversy surrounds the role of the hippocampus in short-term or working memory. To examine both hippocampal and neocortical contributions to working memory function, we recorded electrocorticographic activity from widespread cortical and subcortical sites as 20 neurosurgical patients performed working memory tasks. These recordings revealed significant increases in 48-90 Hz gamma oscillatory power with memory load for two classes of stimuli: letters and faces. Sites exhibiting gamma increases with memory load appeared primarily in the hippocampus and medial temporal lobe. These findings implicate gamma oscillatory activity in the maintenance of both letters and faces in working memory and provide the first direct evidence for modulation of hippocampal gamma oscillations as humans perform a working memory task. PMID- 20164355 TI - Diacylglycerol lipase is not involved in depolarization-induced suppression of inhibition at unitary inhibitory connections in mouse hippocampus. AB - Endocannabinoids control hippocampal inhibitory synaptic transmission through activation of presynaptic CB(1) receptors. During depolarization-induced suppression of inhibition (DSI), endocannabinoids are synthesized upon postsynaptic depolarization. The endocannabinoid 2-arachidonoylglycerol (2-AG) may mediate hippocampal DSI. Currently, the best studied pathway for biosynthesis of 2-AG involves the enzyme diacylglycerol lipase (DAGL). However, whether DAGL is necessary for hippocampal DSI is controversial and was not systematically addressed. Here, we investigate DSI at unitary connections between CB(1) receptor containing interneurons and pyramidal neurons in CA1. We found that the novel DAGL inhibitor OMDM-188, as well as the established inhibitor RHC-80267, did not affect DSI. As reported previously, effects of the DAGL inhibitor tetrahydrolipstatin depended on the application method: postsynaptic intracellular application left DSI intact, while incubation blocked DSI. We show that all DAGL inhibitors tested block slow self-inhibition in neocortical interneurons, which involves DAGL. We conclude that DAGL is not involved in DSI at unitary connections in hippocampus. PMID- 20164356 TI - Presynaptic GABA(B) receptors regulate experience-dependent development of inhibitory short-term plasticity. AB - Short-term changes in synaptic gain support information processing throughout the CNS, yet we know little about the developmental regulation of such plasticity. Here we report that auditory experience is necessary for the normal maturation of synaptic inhibitory short-term plasticity (iSTP) in the auditory cortex, and that presynaptic GABA(B) receptors regulate this development. Moderate or severe hearing loss was induced in gerbils, and iSTP was characterized by measuring inhibitory synaptic current amplitudes in response to repetitive stimuli. We reveal a profound developmental shift of iSTP from depressing to facilitating after the onset of hearing. Even moderate hearing loss prevented this shift. This iSTP change was mediated by a specific class of inhibitory interneurons, the low threshold spiking cells. Further, using paired recordings, we reveal that presynaptic GABA(B) receptors at interneuron-pyramidal connections regulate iSTP in an experience-dependent manner. This novel synaptic mechanism may support the emergence of mature temporal processing in the auditory cortex. PMID- 20164357 TI - Contribution of the global subunit structure and stargazin on the maturation of AMPA receptors. AB - Subunit assembly governs regulation of AMPA receptor (AMPA-R) synaptic delivery and determines biophysical parameters of the ion channel. However, little is known about the molecular pathways of this process. Here, we present single particle EM three-dimensional structures of dimeric biosynthetic intermediates of the GluA2 subunit of AMPA-Rs. Consistent with the structures of intact tetramers, the N-terminal domains of the biosynthetic intermediates form dimers. Transmembrane domains also dimerize despite the two ligand-binding domains (LBDs) being separated. A significant difference was detected between the dimeric structures of the wild type and the L504Y mutant, a point mutation that blocks receptor trafficking and desensitization. In contrast to the wild type, whose LBD is separated, the LBD of the L504Y mutant was detected as a single density. Our results provide direct structural evidence that separation of the LBD within the intact dimeric subunits is critical for efficient tetramerization in the endoplasmic reticulum and further trafficking of AMPA-Rs. The contribution of stargazin on the subunit assembly of AMPA-R was examined. Our data suggest that stargazin affects AMPA-R trafficking at a later stage of receptor maturation. PMID- 20164358 TI - Structural determinants of D-cycloserine efficacy at the NR1/NR2C NMDA receptors. AB - We have studied relative efficacies of NR1 agonists glycine and d-cycloserine (DCS), and found efficacy to be dependent on the NR2 subunit. DCS shows partial agonism at NR1/NR2B but has higher relative efficacy than glycine at NR1/NR2C receptor. Molecular dynamics (MD) simulations of the NR1/NR2B and NR1/NR2C agonist binding domain dimer suggest only subtle differences in the interactions of DCS with NR1 binding site residues relative to glycine. The most pronounced differences were observed in the NR1/NR2C simulation between the orientation of helices F and G of the NR1 subunit. Interestingly, Helix F was previously proposed to influence receptor gating and to adopt an orientation depending on agonist efficacy. MD simulations and site-directed mutagenesis further suggest a role for residues at the agonist binding domain dimer interface in regulating DCS efficacy. To relate the structural rearrangements to receptor gating, we recorded single-channel currents from outside-out patches containing a single active NR1/NR2C receptor. DCS increased the mean open time and open probability of NR1/NR2C receptors compared with glycine. Maximum likelihood fitting of a gating model for NR1/NR2C receptor activation to the single-channel data suggests that DCS specifically accelerates the rate constant governing a fast gating step and reduces the closing rate. These changes appear to reflect a decreased activation energy for a pregating step and increased stability of the open states. We suggest that the higher efficacy of DCS at NR1/NR2C receptors involves structural rearrangements at the dimer interface and an effect on NR1/NR2C receptor pregating conformational changes. PMID- 20164359 TI - Coordination between extrinsic extracellular matrix cues and intrinsic responses to orient the centrosome in polarizing cerebellar granule neurons. AB - Successful axon targeting during development is critically dependent on directionality of axon extension and requires coordination between the extrinsic cues that provide spatial information to the axon and the intrinsic responses that regulate structural specification of the axon during neuronal polarization. How these responses are coordinated is unclear but are known to involve aligning the centrosome with the base of the emerging axon. We have used a novel in vitro micropatterning assay that spatially segregates the extrinsic cues used by polarizing cerebellar granule cells to orient axon extension and used it to investigate the signaling mechanisms responsible for coordinating centrosome positioning with intrinsic responses. The results show that, when laminin and/or vitronectin are used as spatially restricted cues in association with substrate associated sonic hedgehog, they are sufficient to induce cell cycle arrest, that laminin and vitronectin then induce integrin-mediated signaling that upregulates phosphoinositide-3 kinase and PKC function to produce phosphatidylinositol 3,4,5 trisphosphate (PIP3) that is associated with the centrosome, that this PIP3 can interact with PKC-phosphorylated growth-associated protein GAP-43, and that PKC phosphorylated GAP-43 in turn is required for positioning Par6, Cdc42, and IQGAP1, all intrinsic response components, in proximity to the centrosome, such that, in the absence of GAP-43, they are mislocalized and microtubules are not oriented appropriately. We conclude from these results that GAP-43 plays an important role in coordinating extrinsic signaling and intrinsic responses in polarizing cerebellar granule neurons. PMID- 20164360 TI - Phase response curve analysis of a full morphological globus pallidus neuron model reveals distinct perisomatic and dendritic modes of synaptic integration. AB - Synchronization of globus pallidus (GP) neurons and cortically entrained oscillations between GP and other basal ganglia nuclei are key features of the pathophysiology of Parkinson's disease. Phase response curves (PRCs), which tabulate the effects of phasic inputs within a neuron's spike cycle on output spike timing, are efficient tools for predicting the emergence of synchronization in neuronal networks and entrainment to periodic input. In this study we apply physiologically realistic synaptic conductance inputs to a full morphological GP neuron model to determine the phase response properties of the soma and different regions of the dendritic tree. We find that perisomatic excitatory inputs delivered throughout the interspike interval advance the phase of the spontaneous spike cycle yielding a type I PRC. In contrast, we demonstrate that distal dendritic excitatory inputs can either delay or advance the next spike depending on whether they occur early or late in the spike cycle. We find this latter pattern of responses, summarized by a biphasic (type II) PRC, was a consequence of dendritic activation of the small conductance calcium-activated potassium current, SK. We also evaluate the spike-frequency dependence of somatic and dendritic PRC shapes, and we demonstrate the robustness of our results to variations of conductance densities, distributions, and kinetic parameters. We conclude that the distal dendrite of GP neurons embodies a distinct dynamical subsystem that could promote synchronization of pallidal networks to excitatory inputs. These results highlight the need to consider different effects of perisomatic and dendritic inputs in the control of network behavior. PMID- 20164361 TI - Neuronal stability and drift across periods of sleep: premotor activity patterns in a vocal control nucleus of adult zebra finches. AB - How stable are neural activity patterns compared across periods of sleep? We evaluated this question in adult zebra finches, whose premotor neurons in the nucleus robustus arcopallialis (RA) exhibit sequences of bursts during daytime singing that are characterized by precise timing relative to song syllables. Each burst has a highly regulated pattern of spikes. We assessed these spike patterns in singing that occurred before and after periods of sleep. For about half of the neurons, one or more premotor bursts had changed after sleep, an average of 20% of all bursts across all RA neurons. After sleep, modified bursts were characterized by a discrete, albeit modest, loss of spikes with compensatory increases in spike intervals, but not changes in timing relative to the syllable. Changes in burst structure followed both interrupted bouts of sleep (1.5-3 h) and full nights of sleep, implicating sleep and not circadian cycle as mediating these effects. Changes in burst structure were also observed during the day, but far less frequently. In cases where multiple bursts in the sequence changed in a single cell, the sequence position of those bursts tended to cluster together. Bursts that did not show discrete changes in structure also showed changes in spike counts, but not biased toward losses. We hypothesize that changes in burst patterns during sleep represent active sculpting of the RA network, supporting auditory feedback-mediated song maintenance. PMID- 20164362 TI - Norepinephrine directly activates adult hippocampal precursors via beta3 adrenergic receptors. AB - Adult hippocampal neurogenesis is a critical form of cellular plasticity that is greatly influenced by neural activity. Among the neurotransmitters that are widely implicated in regulating this process are serotonin and norepinephrine, levels of which are modulated by stress, depression and clinical antidepressants. However, studies to date have failed to address a direct role for either neurotransmitter in regulating hippocampal precursor activity. Here we show that norepinephrine but not serotonin directly activates self-renewing and multipotent neural precursors, including stem cells, from the hippocampus of adult mice. Mechanistically, we provide evidence that beta(3)-adrenergic receptors, which are preferentially expressed on a Hes5-expressing precursor population in the subgranular zone (SGZ), mediate this norepinephrine-dependent activation. Moreover, intrahippocampal injection of a selective beta(3)-adrenergic receptor agonist in vivo increases the number of proliferating cells in the SGZ. Similarly, systemic injection of the beta-adrenergic receptor agonist isoproterenol not only results in enhancement of proliferation in the SGZ but also leads to an increase in the percentage of nestin/glial fibrillary acidic protein double-positive neural precursors in vivo. Finally, using a novel ex vivo "slice-sphere" assay that maintains an intact neurogenic niche, we demonstrate that antidepressants that selectively block the reuptake of norepinephrine, but not serotonin, robustly increase hippocampal precursor activity via beta adrenergic receptors. These findings suggest that the activation of neurogenic precursors and stem cells via beta(3)-adrenergic receptors could be a potent mechanism to increase neuronal production, providing a putative target for the development of novel antidepressants. PMID- 20164363 TI - APOA1 and APOA4 gene polymorphisms influence the effects of dietary fat on LDL particle size and oxidation in healthy young adults. AB - We investigated whether APOA1 and APOA4 genotypes interact with diet to determine changes in LDL size and their susceptibility to oxidative modifications. A total of 97 healthy volunteers each consumed 3 diets for 4 wk: a SFA diet (38% fat, 20% SFA) followed by a low-fat and high-carbohydrate (CHO) diet (30% fat, 55% carbohydrate) or a monounsaturated fatty acid (MUFA) diet (38% fat, 22% MUFA) following a randomized crossover design. For each diet, we determined susceptibility to oxidative modifications and LDL size. To investigate the combined effects of the APOA1 G-76A and APOA4 Thr347Ser single nucleotide polymorphisms (SNP), we defined 4 combined genotype groups: GG/ThrThr, GG/ThrSer, GA/ThrThr, and GA/ThrSer. After participants consumed the CHO diet, there was a significant decrease in LDL size with respect to high-fat diets in GG homozygotes for the APOA1 G-76A SNP. However, LDL size did not differ in GA carriers among participants consuming the 3 diets. Carriers of the A allele for this polymorphism had smaller LDL size as well as increased susceptibility to oxidation after the SFA diet than the GG homozygous. Moreover, the interaction between the APO A1 and APOA4 genotypes revealed that individuals with the GA/ThrSer genotype had larger LDL particle size during consumption of the MUFA diet than when they consumed the CHO diet. No differences in LDL oxidation were found in this analysis. Our study supports the concept that SNP in APOA1and APOA4 genes influences atherogenic characteristics of LDL particles in response to diet. PMID- 20164364 TI - Postprandial cysteine/cystine redox potential in human plasma varies with meal content of sulfur amino acids. AB - Few data are available on plasma redox responses to sulfur amino acid (SAA) loads. In this study, we had 2 aims: to determine whether the SAA content of a meal affected postprandial plasma cysteine (Cys), cystine (CySS), or redox potential (E(h)CySS) in humans and whether SAA intake level (adequate or inadequate) in the days preceding the meal challenge affected these postprandial levels. Eight healthy individuals aged 18-36 y were equilibrated for 3 d to adequate SAA, fed chemically defined meals without SAA for 5 d (inadequate SAA) and then fed isoenergetic, isonitrogenous meals with adequate SAA for 5 d. On the first and last days with the chemically defined meals, a morning meal containing 60% of the daily food intake was given, and plasma Cys, CySS, and E(h)CySS were determined over an 8-h postprandial time course. Following equilibration to adequate intake, provision of the meal with SAA resulted in increased plasma Cys and CySS concentrations and more reduced plasma E(h)CySS compared with the postprandial values following the same meal without SAA. Equilibration to inadequate SAA intake for the days preceding the meal challenge did not affect this response. The magnitude of the difference in postprandial plasma E(h)CySS (10 mV) due to meal content of SAA was comparable to those which alter physiologic signaling and/or are associated with disease risk. Consequently, the SAA content of meals could affect physiologic signaling and associated disease mechanisms in the postprandial period by changes in Cys, CySS, or E(h)CySS. PMID- 20164365 TI - Sodium-dependent phosphate uptake in the jejunum is post-transcriptionally regulated in pigs fed a low-phosphorus diet and is independent of dietary calcium concentration. AB - In rodents, severe dietary P restriction increases active phosphate absorption by the intestine. However, it remains unknown if moderate dietary P restriction has a similar effect. Weanling pigs (n = 32; body weight 7.4 +/- 0.55 kg) were used in a 2 x 2 factorial design and fed dietary available P (aP) concentrations of 0.23 or 0.40% and Ca concentrations of 0.58 or 1.00% for 14 d. Diets were formulated on an aP basis instead of a total P basis, because pigs are unable to absorb phytate-P present in corn and soybean meal. Jejunal segments were mounted in modified Ussing chambers for determination of Na(+)-dependent nutrient transport. Intestinal mucosal scrapings were taken for RNA isolation and brush border membrane (BBM) vesicle isolation. Na(+)-dependent phosphate uptake and gene expression of Na-phosphate cotransporter IIb (NaPi-IIb), SGLT-1 (sodium/glucose cotransporter-1), and calbindin D(9k) and protein expression of NaPi-IIb were evaluated. Na(+)-dependent phosphate transport increased (P < 0.05) 46% as dietary aP concentration was decreased. However, increased Na(+)-dependent phosphate uptake was not accompanied by increased NaPi-IIb mRNA expression. Expression of NaPi-IIb protein in the BBM increased (P < 0.01) 84% in pigs fed low-P diets compared with pigs fed adequate-P diets. No dietary Ca effects or aP x Ca interactions were detected for Na-dependent P uptake, mRNA or protein expression of NaPi-IIb, or mRNA expression of calbindin D(9k). These data suggest that restricting dietary aP concentration by only 43% stimulates Na(+)-dependent phosphate uptake and expression of the NaPi-IIb protein in the BBM of the small intestine and through a post-transcriptional mechanism. PMID- 20164366 TI - Anemic copper-deficient rats, but not mice, display low hepcidin expression and high ferroportin levels. AB - The transmembrane protein ferroportin (Fpn) is essential for iron efflux from the liver, spleen, and duodenum. Fpn is regulated predominantly by the circulating iron regulatory hormone hepcidin, which binds to cell surface Fpn, initiating its degradation. Accordingly, when hepcidin concentrations decrease, Fpn levels increase. A previous study found that Fpn levels were not elevated in copper deficient (CuD) mice that had anemia, a condition normally associated with dramatic reductions in hepcidin. Lack of change in Fpn levels may be because CuD mice do not display reduced concentrations of plasma iron (holotransferrin), a modulator of hepcidin expression. Here, we examined Fpn protein levels and hepcidin expression in CuD rats, which exhibit reduced plasma iron concentrations along with anemia. We also examined hepcidin expression in anemic CuD mice with normal plasma iron levels. We found that CuD rats had higher liver and spleen Fpn levels and markedly lower hepatic hepcidin mRNA expression than did copper adequate (CuA) rats. In contrast, hepcidin levels did not differ between CuD and CuA mice. To examine potential mediators of the reduced hepcidin expression in CuD rats, we measured levels of hepatic transferrin receptor 2 (TfR2), a putative iron sensor that links holotransferrin to hepcidin production, and transcript abundance of bone morphogenic protein 6 (BMP6), a key endogenous positive regulator of hepcidin production. Diminished hepcidin expression in CuD rats was associated with lower levels of TfR2, but not BMP6. Our data suggest that holotransferrin and TfR2, rather than anemia or BMP6, are signals for hepcidin synthesis during copper deficiency. PMID- 20164367 TI - Postnatal hepatic fatty acid oxidative capacity of preterm pigs receiving TPN does not differ from that of term pigs and is not affected by supplemental arachidonic and docosahexaenoic acids. AB - To improve pediatric care of preterm infants, a better understanding of the metabolic processes associated with immaturity is needed. To this end, preterm and term pigs were delivered and administered either a control, a low-PUFA [0.3 and 0.6% of total lipids as docosahexaenoic acid (DHA) and arachidonic acid (AA), respectively], or a high-PUFA (5 and 11% of total lipids as DHA and AA, respectively) parenteral solution. Hepatic oxidative capacity and carnitine palmitoyltransferase (CPT) mRNA and activity in the presence or absence of malonyl-CoA were determined after 6 d. Oxidation of [1-(14)C]-palmitate or [1 (14)C]-glucose was similar in liver homogenates isolated from preterm and term pigs receiving the control solution. Oxidative capacity for either substrate did not differ with parenteral solution in preterm pigs, whereas in term pigs, glucose oxidation was 64% greater when the high-PUFA solution was administered relative to the control (P < 0.05). In preterm pigs, CPT I mRNA determined after 6 d of parenteral feeding were 1.5-fold greater (P < 0.05) than newborn estimates irrespective of solution administered, whereas CPT I mRNA were only greater for term pigs receiving the low- and high-PUFA solutions (66 and 115%, respectively; P < 0.05) relative to newborn estimates. Malonyl-CoA-sensitive CPT activity did not differ between preterm and term pigs or parenteral solution. Postnatal adaptations demonstrated by parenterally fed term neonates are present following preterm birth and are not improved by the provision of DHA and AA to parenteral solutions. PMID- 20164368 TI - Food extracts consumed in Mediterranean countries and East Asia reduce protein concentrations of androgen receptor, phospho-protein kinase B, and phospho cytosolic phospholipase A(2)alpha in human prostate cancer cells. AB - Active surveillance is an emerging management option for the rising number of men with low-grade, clinically localized prostate cancer. However, 30-40% of men on active surveillance will progress to high-grade disease over 5 y. With the ultimate aim of developing a food-based chemoprevention strategy to retard cancer progression in these otherwise healthy men, we have developed a blend of food extracts commonly consumed in Mediterranean countries and East Asia. The effect of the food extracts known as Blueberry Punch (BBP) on prostate cancer cell growth and key signaling pathways were examined in vitro and in vivo. BBP reduced prostate cancer cell growth in a dose-dependent manner (0.08-2.5%) at 72 h in vitro due to the reduction in cell proliferation and viability. Prostate cancer cell xenograft-bearing mice, administered 10% BBP in drinking water for 2 wk, had a 25% reduction in tumor volume compared with the control (water only). In vitro, BBP reduced protein concentrations in 3 signaling pathways necessary for the proliferation and survival of prostate cancer cells, namely androgen receptor, phospho-protein kinase B/protein kinase B, and phospho-cytosolic phospholipase A(2)alpha. The downstream effectors of these pathways, including prostate specific antigen and glycogen synthase kinase 3beta, were also reduced. Thus, this palatable food supplement is a potential candidate for testing in clinical trials and may ultimately prove effective in retarding the progression of low grade, early-stage prostate cancer in men managed by active surveillance. PMID- 20164370 TI - Neonatal administration of isoflavones attenuates deterioration of bone tissue in female but not male mice. AB - Neonatal exposure to soy isoflavones at levels similar to that of infants fed soy protein formula resulted in higher bone mineral density (BMD), improved bone structure, and greater bone strength at young adulthood in female CD-1 mice (1,2). Our objective in this study was to determine whether these improvements in bone quantity and quality at 4 mo of age provide protection against the deterioration of bone tissue that occurs after a decline in endogenous sex steroid production. Male and female CD-1 mice (n = 8-18 pups per group per gender) were randomized to subcutaneous injections of corn oil [negative control (CON)], daidzein + genistein (DG; 7 mg x kg body weight(-1) x d(-1)), or diethylstilbestrol [(DES); positive control, 2 mg x kg body weight(-1) x d(-1)) from postnatal d 1 to 5. At 4 mo of age, mice were ovariectomized (females) or orchidectomized (males) and studied to 8 mo of age. Females treated with DG had higher (P < 0.05) femur and vertebral bone mineral content (BMC) and BMD compared with the CON group. Microstructural analysis revealed that improvements in BMD induced by DG and DES were coupled with greater trabecular thickness at the lumbar spine. Importantly, structural improvements resulted in bones that were more resistant to fracture, as the peak load of the femoral midpoint and lumbar vertebra 2 were higher (P < 0.05) with DG compared with CON. Effects in males were not significant. In conclusion, short-term neonatal exposure to isoflavones provides protection against the deterioration of bone tissue in females but not males after a decline of endogenous sex steroid production. PMID- 20164369 TI - High dietary intake of magnesium may decrease risk of colorectal cancer in Japanese men. AB - Magnesium maintains genomic stability and is an essential cofactor for DNA synthesis and repair. Magnesium intake has been reported to be inversely associated with colorectal cancer (CRC) risk in Western populations. This study examined the association between dietary intake of magnesium and CRC risk in Japanese men and women aged 45-74 y. Data from 40,830 men and 46,287 women, at the 5-y follow-up of the Japan Public Health Center-based Prospective Study, who responded to a 138-item FFQ were used in this analysis. A total of 689 and 440 CRC events were observed during the mean follow-up of 7.9 and 8.3 y for men and women, respectively. When adjusted for potential confounders, the hazard ratio and 95% CI in the highest quintile of magnesium intake compared with the lowest quintile in men were 0.65 (95% CI, 0.40-1.03) for CRC (P-trend = 0.04), 0.48 (95% CI, 0.26-0.89) for colon cancer (P-trend = 0.01), and 0.97 (95% CI, 0.47-2.02) for rectal cancer (P-trend = 0.93). Borderline inverse associations were also observed in men who consumed alcohol regularly (P-trend = 0.07) or had a BMI <25 kg/m(2) (P-trend = 0.06). There were similar inverse associations for invasive colon cancer and distal colon cancer. There were no significant associations between magnesium intake and cancer risk in women. Higher dietary intake of magnesium may decrease the risk of CRC in Japanese men. PMID- 20164371 TI - Acute energy deprivation affects skeletal muscle protein synthesis and associated intracellular signaling proteins in physically active adults. AB - To date, few studies have characterized the influence of energy deprivation on direct measures of skeletal muscle protein turnover. In this investigation, we characterized the effect of an acute, moderate energy deficit (10 d) on mixed muscle fractional synthetic rate (FSR) and associated intracellular signaling proteins in physically active adults. Eight men and 4 women participated in a 20 d, 2-phase diet intervention study: weight maintenance (WM) and energy deficient (ED; approximately 80% of estimated energy requirements). Dietary protein (1.5 g x kg(-1) x d(-1)) and fat (approximately 30% of total energy) were constant for WM and ED. FSR and intracellular signaling proteins were measured on d 10 of both interventions using a primed, constant infusion of [(2)H(5)]-phenylalanine and Western blotting techniques, respectively. Participants lost approximately 1 kg body weight during ED (P < 0.0001). FSR was reduced approximately 19% (P < 0.05) for ED (0.06 +/- 0.01%/h) compared with WM (0.074 +/- 0.01%/h). Protein kinase B and eukaryotic initiation factor 4E binding protein 1 phosphorylation were lower (P < 0.05) during ED compared with WM. AMP activated protein kinase phosphorylation decreased (P < 0.05) over time regardless of energy status. These findings show that FSR and associated synthetic intracellular signaling proteins are downregulated in response to an acute, moderate energy deficit in physically active adults and provide a basis for future studies assessing the impact of prolonged, and perhaps more severe, energy restriction on skeletal muscle protein turnover. PMID- 20164372 TI - Oligosaccharide-induced whey-specific CD25(+) regulatory T-cells are involved in the suppression of cow milk allergy in mice. AB - Dietary intervention with a unique prebiotic nondigestible carbohydrate mixture has been shown to reduce the development of allergic disease in infants at risk. In this study, the involvement of CD25(+) regulatory T-cells (Treg) in the carbohydrate-induced effects was investigated in mice orally sensitized with whey using adoptive transfer experiments. Donor mice were sensitized with whey and fed a diet containing short-chain galacto-, long-chain fructo- and acidic oligosaccharides, or a control diet starting 2 wk before sensitization. The acute allergic skin reaction upon intradermal whey challenge was determined and whey specific Ig were measured. Splenocytes of the donor mice were transferred to naive recipient mice after partial ex vivo depletion of CD25(+) Treg. The prebiotic diet clearly diminished the acute allergic skin reaction (P < 0.001). Whey-sensitized recipient mice transferred with splenocytes from whey-sensitized, prebiotic-fed donor mice displayed almost complete prevention of the acute allergic skin reaction compared with mice receiving cells from sham-sensitized, prebiotic-fed donor mice (P < 0.001). Partial depletion of CD25(+) T-cells inhibited these effects (P < 0.001), although IgE sensitization was not prevented. This study indicates the involvement of whey-specific CD25(+) Treg in the suppression of the allergic effector response induced by dietary intervention with prebiotics. PMID- 20164373 TI - Response of adult mouse uterus to early disruption of estrogen receptor-alpha signaling is influenced by Kruppel-like factor 9. AB - Inappropriate early exposure of the hormone-responsive uterus to estrogenic compounds is associated with increased risk for adult reproductive diseases including endometrial cancers. While the dysregulation of estrogen receptor-alpha (ESR1) signaling is well acknowledged to mediate early events in tumor initiation, mechanisms contributing to sustained ESR1 activity later in life and leading to induction of oncogenic pathways remain poorly understood. We had shown previously that the transcription factor Kruppel-like factor 9 (KLF9) represses ESR1 expression and activity in Ishikawa endometrial glandular epithelial cells. We hypothesized that KLF9 functions as a tumor suppressor, and that loss of its expression enhances ESR1 signaling. Here, we evaluated the contribution of KLF9 to early perturbations in uterine ESR1 signaling pathways elicited by the administration of synthetic estrogen diethylstilbestrol (DES) to wild-type (WT) and Klf9 null (KO) mice on postnatal days (PNDs) 1-5. Uterine tissues collected at PND84 were subjected to histological, immunological, and molecular analyses. Compared with WT mice, KO mice demonstrated larger endometrial glands and lower endometrial gland numbers; DES exposure exacerbated these differences. Loss of KLF9 expression resulted in increased glandular ESR1 immunoreactivity with DES, without effects on serum estradiol levels. Quantitative RT-PCR analyses indicated altered expression of uterine genes commonly dysregulated in endometrial cancers (Akt1, Mmp9, Slpi, and Tgfbeta1) and of those involved in growth regulation (Fos, Myc, Tert, and Syk), with loss of Klf9, alone or in concert with DES. Our data support a molecular network between KLF9 and ESR1 in the uterus, and suggest that silencing of KLF9 may contribute to endometrial dysfunctions initiated by aberrant estrogen action. PMID- 20164374 TI - Hyperglycemia induces apoptosis in rat liver through the increase of hydroxyl radical: new insights into the insulin effect. AB - In this study, we analyzed the contribution of hydroxyl radical in the liver apoptosis mediated by hyperglycemia through the Bax-caspase pathway and the effects of insulin protection against the apoptosis induced by hyperglycemia. Male adult Wistar rats were randomized in three groups: control (C) (sodium citrate buffer, i.p.), streptozotocin (STZ)-induced diabetic (SID) (STZ 60 mg/kg body weight, i.p.), and insulin-treated SID (SID+I; 15 days post STZ injection, SID received insulin s.c., twice a day, 15 days). Rats were autopsied on day 30. In liver tissue, diabetes promoted a significant increase in hydroxyl radical production which correlated with lipid peroxidation (LPO) levels. Besides, hyperglycemia significantly increased mitochondrial BAX protein expression, cytosolic cytochrome c levels, and caspase-3 activity leading to an increase in apoptotic index. Interestingly, the treatment of diabetic rats with desferoxamine or tempol (antioxidants/hydroxyl radical scavengers) significantly attenuated the increase in both hydroxyl radical production and in LPO produced by hyperglycemia, preventing apoptosis by reduction of mitochondrial BAX and cytosolic cytochrome c levels. Insulin treatment showed similar results. The finding that co-administration of antioxidants/hydroxyl radical scavengers together with insulin did not provide any additional benefit compared with those obtained using either inhibitors or insulin alone shows that it is likely that insulin prevents oxidative stress by reducing the effects of hydroxyl radicals. Importantly, insulin significantly increased apoptosis inhibitor protein expression by induction of its mRNA. Taken together, our studies support that, at least in part, the hydroxyl radical acts as a reactive intermediate, which leads to liver apoptosis in a model of STZ-mediated hyperglycemia. A new anti-apoptosis signal for insulin is shown, given by an increase of apoptosis inhibitor protein. PMID- 20164375 TI - The switch of intestinal Slc26 exchangers from anion absorptive to HCOFormula secretory mode is dependent on CFTR anion channel function. AB - CFTR has been recognized to function as both an anion channel and a key regulator of Slc26 anion transporters in heterologous expression systems. Whether this regulatory relationship between CFTR and Slc26 transporters is seen in native intestine, and whether this effect is coupled to CFTR transport function or other features of this protein, has not been studied. The duodena of anesthetized CFTR , NHE3-, Slc26a6-, and Scl26a3-deficient mice and wild-type (WT) littermates were perfused, and duodenal bicarbonate (HCO(3)(-)) secretion (DBS) and fluid absorptive or secretory rates were measured. The selective NHE3 inhibitor S1611 or genetic ablation of NHE3 significantly reduced fluid absorptive rates and increased DBS. Slc26a6 (PAT1) or Slc26a3 (DRA) ablation reduced the S1611-induced DBS increase and reduced fluid absorptive rates, suggesting that the effect of S1611 or NHE3 ablation on HCO(3)(-) secretion may be an unmasking of Slc26a6- and Slc26a3-mediated Cl(-)/HCO(3)(-) exchange activity. In the absence of CFTR expression or after application of the CFTR(inh)-172, fluid absorptive rates were similar to those of WT, but S1611 induced virtually no increase in DBS, demonstrating that CFTR transport activity, and not just its presence, is required for Slc26-mediated duodenal HCO(3)(-) secretion. A functionally active CFTR is an absolute requirement for Slc26-mediated duodenal HCO(3)(-) secretion, but not for Slc26-mediated fluid absorption, in which these transporters operate in conjunction with the Na(+)/H(+) exchanger NHE3. This suggests that Slc26a6 and Slc26a3 need proton recycling via NHE3 to operate in the Cl(-) absorptive mode and Cl(-) exit via CFTR to operate in the HCO(3)(-) secretory mode. PMID- 20164376 TI - The contribution of AKAP5 in amylase secretion from mouse parotid acini. AB - A-kinase (PKA) anchoring proteins (AKAPs) are essential for targeting type II PKA to specific locales in the cell to control function. In the present study, AKAP5 (formerly AKAP150) and AKAP6 were identified in mouse parotid acini by type II PKA regulatory subunit (RII) overlay assay and Western blot analysis of mouse parotid cellular fractions, and the role of AKAP5 in mouse parotid acinar cell secretion was determined. Mice were euthanized with CO(2). Immunofluorescence staining of acinar cells localized AKAP5 to the basolateral membrane, whereas AKAP6 was associated with the perinuclear region. In functional studies, amylase secretion from acinar cells of AKAP5 mutant [knockout (KO)] mice treated with the beta-adrenergic agonist, isoproterenol, was reduced overall by 30-40% compared with wild-type (WT) mice. In contrast, amylase secretion in response to the adenylyl cyclase (AC) activator, forskolin, and the cAMP-dependent protein kinase (PKA) activator, N(6)-phenyl-cAMP, was not statistically different in acini from WT and AKAP5 KO mice. Treatment of acini with isoproterenol mimicked the effect of the Epac activator, 8-(4-methoxyphenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate (8-pMeOPT-2'-O-Me-cAMP), in stimulating Rap1. However, in contrast to isoproterenol, treatment of acini with 8-pMeOPT-2'-O-Me-cAMP resulted in stimulation of amylase secretion from both AKAP5 KO and WT acinar cells. As a scaffolding protein, AKAP5 was found to coimmunoprecipitate with AC6, but not AC8. Data suggest that isoproterenol-stimulated amylase secretion occurs via both an AKAP5/AC6/PKA complex and a PKA-independent, Epac pathway in mouse parotid acini. PMID- 20164377 TI - Influence of the extracellular matrix and integrins on volume-sensitive osmolyte anion channels in C2C12 myoblasts. AB - The purpose of this study was to determine whether extracellular matrix (ECM) composition through integrin receptors modulated the volume-sensitive osmolyte anion channels (VSOACs) in skeletal muscle-derived C2C12 cells. Cl(-) currents were recorded in whole cell voltage-clamped cells grown on laminin (LM), fibronectin (FN), or in the absence of a defined ECM (NM). Basal membrane currents recorded in isotonic media (300 mosmol/kg) were larger in cells grown on FN (3.8-fold at +100 mV) or LM (8.8-fold at +100 mV) when compared with NM. VSOAC currents activated by cell exposure to hypotonic solution were larger in cells grown on LM (1.72-fold at +100 mV) or FN (1.75-fold at +100 mV) compared with NM. Additionally, the kinetics of VSOAC activation was approximately 27% quicker on FN and LM. These currents were tamoxifen sensitive, displayed outward rectification, reversed at the equilibrium potential of Cl(-) and inactivated at potentials >+60 mV. Specific knockdown of beta(1)-integrin by short hairpin RNA interference strongly inhibited the VSOAC Cl(-) currents in cells plated on FN. In conclusion, ECM composition and integrins profoundly influence the biophysical properties and mechanisms of onset of VSOACs. PMID- 20164378 TI - Glucose downregulation of PKG-I protein mediates increased thrombospondin1 dependent TGF-{beta} activity in vascular smooth muscle cells. AB - Diabetes is a major predictor of in-stent restenosis, which is associated with fibroproliferative remodeling of the vascular wall due to increased transforming growth factor-beta (TGF-beta) action. It is well established that thrombospondin1 (TSP1) is a major regulator of TGF-beta activation in renal and cardiac complications of diabetes. However, the role of the TSP1-TGF-beta pathway in macrovascular diabetic complications, including restenosis, has not been addressed. In mesangial cells, high glucose concentrations depress protein kinase G (PKG) activity, but not PKG-I protein, thereby downregulating transcriptional repression of TSP1. Previously, we showed that high glucose downregulates PKG-I protein expression by vascular smooth muscle cells (VSMCs) through altered NADPH oxidase signaling. In the present study, we investigated whether high glucose regulation of PKG protein and activity in VSMCs similarly regulates TSP1 expression and downstream TGF-beta activity. These studies showed that high glucose stimulates both TSP1 expression and TGF-beta bioactivity in primary murine aortic smooth muscle cells (VSMCs). TSP1 is responsible for the increased TGF-beta bioactivity under high glucose conditions, because treatment with anti TSP1 antibody, small interfering RNA-TSP1, or an inhibitory peptide blocked glucose-mediated increases in TGF-beta activity and extracellular matrix protein (fibronectin) expression. Overexpression of constitutively active PKG, but not the PKG-I protein, inhibited glucose-induced TSP1 expression and TGF-beta bioactivity, suggesting that PKG protein expression is insufficient to regulate TSP1 expression. Together, these data establish that glucose-mediated downregulation of PKG levels stimulates TSP1 expression and enhances TGF-beta activity and matrix protein expression, which can contribute to vascular remodeling in diabetes. PMID- 20164379 TI - Inactivation of L-type calcium channel modulated by HCN2 channel. AB - Ca(2+) entry is delicately controlled by inactivation of L-type calcium channel (LTCC) composed of the pore-forming subunit alpha1C and the auxiliary subunits beta1 and alpha2delta. Calmodulin is the key protein that interacts with the COOH terminal motifs of alpha1C, leading to the fine control of LTCC inactivation. In this study we show evidence that a hyperpolarization-activated cyclic nucleotide gated channel, HCN2, can act as a nonchannel regulatory protein to narrow the L type Ca(2+) channel current-voltage curve. In the absence of LTCC auxiliary subunits, HCN2 can induce alpha1C inactivation. Without alpha2delta, HCN2-induced fast inactivation of alpha1C requires calmodulin. With alpha2delta, the alpha1C/HCN2/alpha2delta channel inactivation does not require calmodulin. In contrast, beta1-subunit plays a relatively minor role in the interaction of alpha1C with HCN2. The NH(2) terminus of HCN2 and the IQ motif of alpha1C subunit are required for alpha1C/HCN2 channel interaction. Ca(2+) channel inactivation is significantly slowed in hippocampus neurons (HNs) overexpressing HCN2 mutant lacking NH(2) terminus and accelerated in HNs overexpressing the wild-type HCN2 compared with HN controls. Collectively, these results revealed a potentially novel protection mechanism for achieving the LTCC inactivation via interaction with HCN2. PMID- 20164380 TI - Calcineurin activity augments cAMP/PKA-dependent activation of V-ATPase in blowfly salivary glands. AB - We have examined the role of the Ca(2+)-dependent protein phosphatase 2B (calcineurin) in the regulation of the vacuolar H(+)-ATPase (V-ATPase) in blowfly salivary glands. In response to the neurohormone serotonin [5-hydroxytryptamine (5-HT)] and under the mediation of the cAMP/PKA signaling pathway, the secretory cells assemble and activate V-ATPase molecules at the apical membrane. We demonstrate that the inhibition of calcineurin activity by cyclosporin A, by FK 506, or by prevention of the elevation of Ca(2+) diminishes the 5-HT-induced assembly and activation of V-ATPase. The effect of calcineurin on V-ATPase is mediated by the cAMP/PKA signaling pathway, with calcineurin acting upstream of PKA, because 1) cyclosporin A does not influence the 8-(4 chlorophenylthio)adenosine-3',5'-cyclic monophosphate (8-CPT-cAMP)-induced activation of V-ATPase, and 2) the 5-HT-induced rise in cAMP is highly reduced in the presence of cyclosporin A. Moreover, a Ca(2+) rise evoked by the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor cyclopiazonic acid leads to an increase in intracellular cAMP concentration and a calcineurin mediated PKA-dependent activation of V-ATPase. We propose that calcineurin activity mediates cross talk between the inositol 1,4,5-trisphosphate/Ca(2+) and the cAMP/PKA signaling pathways, thereby augmenting the 5-HT-induced rise in cAMP and thus the cAMP/PKA-mediated activation of V-ATPase. PMID- 20164381 TI - Blebbistatin, a myosin II inhibitor, suppresses contraction and disrupts contractile filaments organization of skinned taenia cecum from guinea pig. AB - To explore the precise mechanisms of the inhibitory effects of blebbistatin, a potent inhibitor of myosin II, on smooth muscle contraction, we studied the blebbistatin effects on the mechanical properties and the structure of contractile filaments of skinned (cell membrane permeabilized) preparations from guinea pig taenia cecum. Blebbistatin at 10 microM or higher suppressed Ca(2+) induced tension development at any given Ca(2+) concentration but had little effects on the Ca(2+)-induced myosin light chain phosphorylation. Blebbistatin also suppressed the 10 and 2.75 mM Mg(2+)-induced, "myosin light chain phosphorylation-independent" tension development at more than 10 microM. Furthermore, blebbistatin induced conformational change of smooth muscle myosin (SMM) and disrupted arrangement of SMM and thin filaments, resulting in inhibition of actin-SMM interaction irrespective of activation with Ca(2+). In addition, blebbistatin partially inhibited Mg(2+)-ATPase activity of native actomyosin from guinea pig taenia cecum at around 10 microM. These results suggested that blebbistatin suppressed skinned smooth muscle contraction through disruption of structure of SMM by the agent. PMID- 20164382 TI - TRPC-mediated actin-myosin contraction is critical for BBB disruption following hypoxic stress. AB - Hypoxia-induced disruption of the blood-brain barrier (BBB) is the result of many different mechanisms, including alterations to the cytoskeleton. In this study, we identified actin-binding proteins involved in cytoskeletal dynamics with quantitative proteomics and assessed changes in subcellular localization of two proteins involved in actin polymerization [vasodilator-stimulated phosphoprotein (VASP)] and cytoskeleton-plasma membrane cross-linking (moesin). We found significant redistribution of both VASP and moesin to the cytoskeletal and membrane fractions of BBB endothelial cells after 1-h hypoxic stress. We also investigated activation of actin-myosin contraction through assessment of phosphorylated myosin light chain (pMLC) with confocal microscopy. Hypoxia caused a rapid and transient increase in pMLC. Blocking MLC phosphorylation through inhibition of myosin light chain kinase (MLCK) with ML-7 prevented hypoxia induced BBB disruption and relocalization of the tight junction protein ZO-1. Finally, we implicate the transient receptor potential (TRP)C family of channels in mediating these events since blockade of TRPC channels and the associated calcium influx with SKF-96365 prevents hypoxia-induced permeability changes and the phosphorylation of MLC needed for actin-myosin contraction. These data suggest that hypoxic stress triggers alterations to cytoskeletal structure that contribute to BBB disruption and that calcium influx through TRPC channels contributes to these events. PMID- 20164383 TI - Mapping the cytoskeletal prestress. AB - Cell mechanical properties on a whole cell basis have been widely studied, whereas local intracellular variations have been less well characterized and are poorly understood. To fill this gap, here we provide detailed intracellular maps of regional cytoskeleton (CSK) stiffness, loss tangent, and rate of structural rearrangements, as well as their relationships to the underlying regional F-actin density and the local cytoskeletal prestress. In the human airway smooth muscle cell, we used micropatterning to minimize geometric variation. We measured the local cell stiffness and loss tangent with optical magnetic twisting cytometry and the local rate of CSK remodeling with spontaneous displacements of a CSK bound bead. We also measured traction distributions with traction microscopy and cell geometry with atomic force microscopy. On the basis of these experimental observations, we used finite element methods to map for the first time the regional distribution of intracellular prestress. Compared with the cell center or edges, cell corners were systematically stiffer and more fluidlike and supported higher traction forces, and at the same time had slower remodeling dynamics. Local remodeling dynamics had a close inverse relationship with local cell stiffness. The principal finding, however, is that systematic regional variations of CSK stiffness correlated only poorly with regional F-actin density but strongly and linearly with the regional prestress. Taken together, these findings in the intact cell comprise the most comprehensive characterization to date of regional variations of cytoskeletal mechanical properties and their determinants. PMID- 20164384 TI - L-Proline induces differentiation of ES cells: a novel role for an amino acid in the regulation of pluripotent cells in culture. AB - The development of cell therapeutics from embryonic stem (ES) cells will require technologies that direct cell differentiation to specific somatic cell lineages in response to defined factors. The initial step in formation of the somatic lineages from ES cells, differentiation to an intermediate, pluripotent primitive ectoderm-like cell, can be achieved in vitro by formation of early primitive ectoderm-like (EPL) cells in response to a biological activity contained within the conditioned medium MEDII. Fractionation of MEDII has identified two activities required for EPL cell formation, an activity with a molecular mass of <3 kDa and a second, much larger species. Here, we have identified the low molecular-weight activity as l-proline. An inhibitor of l-proline uptake, glycine, prevented the differentiation of ES cells in response to MEDII. Supplementation of the culture medium of ES cells with >100 M l-proline and some l-proline-containing peptides resulted in changes in colony morphology, cell proliferation, gene expression, and differentiation kinetics consistent with differentiation toward a primitive ectoderm-like cell. This activity appeared to be associated with l-proline since other amino acids and analogs of proline did not exhibit an equivalent activity. Activation of the mammalian target of rapamycin (mTOR) signaling pathway was found to be necessary but not sufficient for l-proline activity; addition of other activators of the mTOR signaling pathway failed to alter the ES cell phenotype. This is the first report describing a role for amino acids in the regulation of pluripotency and cell differentiation and identifies a novel role for the imino acid l-proline. PMID- 20164385 TI - On pitch, the ear and the brain of the beholder. Focus on "neural coding of periodicity in marmoset auditory cortex.". PMID- 20164386 TI - Glutamatergic antagonism in the NTS decreases post-inspiratory drive and changes phrenic and sympathetic coupling during chemoreflex activation. AB - For a better understanding of the processing at the nucleus tractus solitarius (NTS) level of the autonomic and respiratory responses to peripheral chemoreceptor activation, herein we evaluated the role of glutamatergic neurotransmission in the intermediate (iNTS) and caudal NTS (cNTS) on baseline respiratory parameters and on chemoreflex-evoked responses using the in situ working heart-brain stem preparation (WHBP). The activities of phrenic (PND), cervical vagus (cVNA), and thoracic sympathetic (tSNA) nerves were recorded before and after bilateral microinjections of kynurenic acid (Kyn, 5 nmol/20 nl) into iNTS, cNTS, or both simultaneously. In WHBP, baseline sympathetic discharge markedly correlated with phrenic bursts (inspiration). However, most of sympathoexcitation elicited by chemoreflex activation occurred during expiration. Kyn microinjected into iNTS or into cNTS decreased the postinspiratory component of cVNA and increased the duration and frequency of PND. Kyn into iNTS produced no changes in sympathoexcitatory and tachypneic responses to peripheral chemoreflex activation, whereas into cNTS, a reduction of the sympathoexcitation, but not of the tachypnea, was observed. The pattern of phrenic and sympathetic coupling during the chemoreflex activation was an inspiratory-related rather than an expiratory-related sympathoexcitation. Kyn simultaneously into iNTS and cNTS produced a greater decrease in postinspiratory component of cVNA and increase in frequency and duration of PND and abolished the respiratory and autonomic responses to chemoreflex activation. The data show that glutamatergic neurotransmission in the iNTS and cNTS plays a tonic role on the baseline respiratory rhythm, contributes to the postinspiratory activity, and is essential to expiratory-related sympathoexcitation observed during chemoreflex activation. PMID- 20164387 TI - Supplementary eye field activity reflects a decision rule governing smooth pursuit but not the decision. AB - Animals depend on learned rules to guide their actions. Prefrontal (PFC) and premotor (PMC) cortex of primates have been reported to display rule-related neural activity, but it is unclear how signals encoded here are utilized to enforce the decision to act. The supplementary eye field (SEF) is a candidate for enforcing rule-guided ocular decisions because the activity of neurons here is correlated with the rule in an ocular decision-making task and because this area is anatomically more proximal to movement structures than PFC and PMC and receives inputs from them. However, in the previous work, the rule encoding and ocular outcome were confounded, leaving open the question of whether SEF activity is related to the rule or the behavior. In the present study, we attempted to discriminate between these alternatives by increasing task difficulty and forcing errors, thereby putting the stimulus and the behavior at odds. Single SEF neurons were recorded while monkeys performed the task in which the rule is to pursue a moving target if it intersects a visible square and maintain fixation if it does not. A delay period was imposed to monitor neural activity while the target approached the square. Two complementary populations of go and nogo neurons were found. When task difficulty was increased, the monkeys made more errors, and the neurons took longer to encode the rule. However, in error trials, most neurons continued to reflect the rule rather the monkey's ocular decision in both the delay period and after square intersection (movement period). This was the case for both directionally tuned and nondirectional SEF neurons. The results suggest that SEF neurons encode the ocular decision rule but that the decision itself likely occurs in a different structure that sums rule information from the SEF with information from other areas. PMID- 20164388 TI - Head-free gaze shifts provide further insights into the role of the medial cerebellum in the control of primate saccadic eye movements. AB - This study examines how signals generated in the oculomotor cerebellum could be involved in the control of gaze shifts, which rapidly redirect the eyes from one object to another. Neurons in the caudal fastigial nucleus (cFN), the output of the oculomotor cerebellum, discharged when monkeys made horizontal head unrestrained gaze shifts, composed of an eye saccade and a head movement. Eighty seven percent of our neurons discharged a burst of spikes for both ipsiversive and contraversive gaze shifts. In both directions, burst end was much better timed with gaze end than was burst start with gaze start, was well correlated with eye end, and was poorly correlated with head end or the time of peak head velocity. Moreover, bursts accompanied all head-unrestrained gaze shifts whether the head moved or not. Therefore we conclude that the cFN is not part of the pathway that controls head movement. For contraversive gaze shifts, the early part of the burst was correlated with gaze acceleration. Thereafter, the burst of the neuronal population continued throughout the prolonged deceleration of large gaze shifts. For a majority of neurons, gaze duration was correlated with burst duration; for some, gaze amplitude was less well correlated with the number of spikes. Therefore we suggest that the population burst provides an acceleration boost for high acceleration (smaller) contraversive gaze shifts and helps maintain the drive required to extend the deceleration of large contraversive gaze shifts. In contrast, the ipsiversive population burst, which is less well correlated with gaze metrics but whose peak rate occurs before gaze end, seems responsible primarily for terminating the gaze shift. PMID- 20164390 TI - Multiple patterns and components of persistent inward current with serotonergic modulation in locomotor activity-related neurons in Cfos-EGFP mice. AB - Using CFos-EGFP transgenic mice (P6-P12), we targeted persistent inward current (PIC) in the spinal interneurons activated by locomotion. Following a locomotor task, whole cell patch-clamp recordings were obtained from ventral EGFP+ neurons in spinal cord slices (200-250 MUm from T13-L4). PIC was recorded by a family of 10 s voltage bi-ramps starting from -70 mV with 30 mV steps. PIC could be classified as ascending and descending forms based on the rising and falling phases of the bi-ramps. Multiple patterns of PIC with various hystereses were found in EGFP+ neurons. A novel form of PIC, single PIC crossing both phases of the bi-ramps, was described in this study. PIC was found in 82% of EGFP+ neurons (n = 129) with no significant difference in laminar distribution. PIC activated at -56.7 +/- 8 mV with an amplitude of 85.3 +/- 59 pA and time constant of 657.0 +/- 272 ms (n = 63). PIC in lamina VIII neurons activated significantly lower ( 60.2 +/- 7 mV) than in lamina VII (-54.8 +/- 6 mV) and lamina X (-55.8 +/- 9 mV) neurons. PIC could be differentiated as calcium dependent (Ca-PIC) by bath application of 1-5 MUM TTX or sodium dependent (Na-PIC) by administration of 20 30 MUM dihydropyridine. Ca-PIC activated at -40.2 +/- 19 mV (n = 49), whereas Na PIC activated at -46.8 +/- 16 mV (n = 17). Composite-, Ca-, and Na-PICs were significantly different in activation but not amplitude and time constant. Bath application of 5-HT (10-30 MUM) enhanced PIC (n = 32) by hyperpolarizing onset (4.2 +/- 6 mV) and increasing amplitude (16%). 5-HT-increased amplitude seemed to be significantly larger in lamina VII neurons (32%) than VIII (6%) and X (14%) neurons. 5-HT enhancement of Ca-PIC (n = 6) and Na-PICs (n = 4) was also observed in EGFP+ neurons. This study unveiled unique properties of PICs in EGFP+ neurons. The lamina-related PIC activation and variable effects of 5-HT on PIC amplitude provides insight into the ionic basis on which locomotion could be generated. PMID- 20164389 TI - Macaque pontine omnipause neurons play no direct role in the generation of eye blinks. AB - We recorded the activity of pontine omnipause neurons (OPNs) in two macaques during saccadic eye movements and blinks. As previously reported, we found that OPNs fire tonically during fixation and pause about 15 ms before a saccadic eye movement. In contrast, for blinks elicited by air puffs, the OPNs paused <2 ms before the onset of the blink. Thus the burst in the agonist orbicularis oculi motoneurons (OOMNs) and the pause in the antagonist levator palpabrae superioris motoneurons (LPSMNs) necessarily precede the OPN pause. For spontaneous blinks there was no correlation between blink and pause onsets. In addition, the OPN pause continued for 40-60 ms after the time of the maximum downward closing of the eyelids, which occurs around the end of the OOMN burst of firing. LPSMN activity is not responsible for terminating the OPN pause because OPN resumption was very rapid, whereas the resumption of LPSMN firing during the reopening phase is gradual. OPN pause onset does not directly control blink onset, nor does pause offset control or encode the transition between the end of the OOMN firing and the resumption of the LPSMNs. The onset of the blink-related eye transients preceded both blink and OPN pause onsets. Therefore they initiated while the saccadic short-lead burst neurons were still fully inhibited by the OPNs and cannot be saccadic in origin. The abrupt dynamic change of the vertical eye transients from an oscillatory behavior to a single time constant exponential drift predicted the resumption of the OPNs. PMID- 20164392 TI - Directional coupling from the olfactory bulb to the hippocampus during a go/no-go odor discrimination task. AB - The hippocampus and olfactory regions are anatomically close, and both play a major role in memory formation. However, the way they interact during odor processing is still unclear. In both areas, strong oscillations of the local field potential (LFP) can be recorded, and are modulated by behavior. In particular, in the olfactory system, the beta rhythm (15-35 Hz) is associated with cognitive processing of an olfactory stimulus. Using LFP recordings in the olfactory bulb and dorsal and ventral hippocampus during performance of an olfactory go/no-go task in rats, we previously showed that beta oscillations are also present in the hippocampus, coherent with those in the olfactory bulb, during odor sampling. In this study, we provide further insight into information transfer in the olfacto-hippocampal network by using directional coherence (DCOH estimate), a method based on the temporal relation between two or more signals in the frequency domain. In the theta band (6-12 Hz), coherence between the olfactory bulb (OB) and the hippocampus (HPC) is weak and can be both in the feedback and feedforward directions. However, at this frequency, modulation of the coupling between the dorsal and ventral hippocampus is seen during stimulus expectation versus odor processing. In the beta frequency band (15-35 Hz), analysis showed a strong unidirectional coupling from the OB to dorsal and ventral HPC, indicating that, during odor processing, beta oscillations in the hippocampus are driven by the olfactory bulb. PMID- 20164394 TI - Augmented sodium currents contribute to the enhanced excitability of small diameter capsaicin-sensitive sensory neurons isolated from Nf1+/- mice. AB - Neurofibromin, the product of the Nf1 gene, is a guanosine triphosphatase activating protein (GAP) for p21ras (Ras) that accelerates conversion of active Ras-GTP to inactive Ras-GDP. Sensory neurons with reduced levels of neurofibromin likely have augmented Ras-GTP activity. We reported previously that sensory neurons isolated from a mouse model with a heterozygous mutation of the Nf1 gene (Nf1+/-) exhibited greater excitability compared with wild-type mice. To determine the mechanism giving rise to the augmented excitability, differences in specific membrane currents were examined. Consistent with the enhanced excitability of Nf1+/- neurons, peak current densities of both tetrodotoxin resistant sodium current (TTX-R I(Na)) and TTX-sensitive (TTX-S) I(Na) were significantly larger in Nf1+/- than in wild-type neurons. Although the voltages for half-maximal activation (V(0.5)) were not different, there was a significant depolarizing shift in the V(0.5) for steady-state inactivation of both TTX-R and TTX-S I(Na) in Nf1+/- neurons. In addition, levels of persistent I(Na) were significantly larger in Nf1+/- neurons. Neither delayed rectifier nor A-type potassium currents were altered in Nf1+/- neurons. These results demonstrate that enhanced production of action potentials in Nf1+/- neurons results, in part, from larger current densities and a depolarized voltage dependence of steady-state inactivation for I(Na) that potentially leads to a greater availability of sodium channels at voltages near the firing threshold for the action potential. PMID- 20164395 TI - Neurophysiological correlates of nociceptive heterosynaptic long-term potentiation in humans. AB - Long-term potentiation (LTP) is a cellular model of synaptic plasticity and reflects an increase of synaptic strength. LTP is also present in the nociceptive system and is believed to be one of the key mechanisms involved in the manifestations of chronic pain. LTP manifested as an increased response in pain perception can be induced in humans using high-frequency electrical stimulation (HFS). The aim of this study was to induce spinal heterosynaptic LTP using HFS and investigate its heterotopic effects on event-related potentials (ERPs) to repeated nonpainful cutaneous stimuli as a possible electrophysiological cortical correlate of sensitization. Twenty-two healthy subjects were randomly assigned to one of the two experimental conditions: HFS and control stimulation. Before and after the stimulation, both conditions received heterotopic mechanical (pinprick) and paired nonpainful electrical test stimuli to quantify and confirm the effects of HFS on the behavioral level. ERPs to paired nonpainful electrical stimulation were measured simultaneously. Conditioning HFS resulted in significant heterotopic effects after 30 min, including increased perceived intensity in response to (pinprick) mechanical and paired nonpainful electrical stimulation compared with control. The paired nonpainful electrical stimuli were accompanied by significantly enhanced responses regarding the ERP N1-P2 peak-to-peak and P300 amplitude compared with control. These findings suggest that HFS is capable of producing heterosynaptic spinal LTP that can be measured not only behaviorally but also using ERPs. PMID- 20164393 TI - Mapping human somatosensory cortex in individual subjects with 7T functional MRI. AB - Functional magnetic resonance imaging (fMRI) is now routinely used to map the topographic organization of human visual cortex. Mapping the detailed topography of somatosensory cortex, however, has proven to be more difficult. Here we used the increased blood-oxygen-level-dependent contrast-to-noise ratio at ultra-high field (7 Tesla) to measure the topographic representation of the digits in human somatosensory cortex at 1 mm isotropic resolution in individual subjects. A "traveling wave" paradigm was used to locate regions of cortex responding to periodic tactile stimulation of each distal phalangeal digit. Tactile stimulation was applied sequentially to each digit of the left hand from thumb to little finger (and in the reverse order). In all subjects, we found an orderly map of the digits on the posterior bank of the central sulcus (postcentral gyrus). Additionally, we measured event-related responses to brief stimuli for comparison with the topographic mapping data and related the fMRI responses to anatomical images obtained with an inversion-recovery sequence. Our results have important implications for the study of human somatosensory cortex and underscore the practical utility of ultra-high field functional imaging with 1 mm isotropic resolution for neuroscience experiments. First, topographic mapping of somatosensory cortex can be achieved in 20 min, allowing time for further experiments in the same session. Second, the maps are of sufficiently high resolution to resolve the representations of all five digits and third, the measurements are robust and can be made in an individual subject. These combined advantages will allow somatotopic fMRI to be used to measure the representation of digits in patients undergoing rehabilitation or plastic changes after peripheral nerve damage as well as tracking changes in normal subjects undergoing perceptual learning. PMID- 20164396 TI - Mechanism for the universal pattern of activity in developing neuronal networks. AB - Spontaneous episodic activity is a fundamental mode of operation of developing networks. Surprisingly, the duration of an episode of activity correlates with the length of the silent interval that precedes it, but not with the interval that follows. Here we use a modeling approach to explain this characteristic, but thus far unexplained, feature of developing networks. Because the correlation pattern is observed in networks with different structures and components, a satisfactory model needs to generate the right pattern of activity regardless of the details of network architecture or individual cell properties. We thus developed simple models incorporating excitatory coupling between heterogeneous neurons and activity-dependent synaptic depression. These models robustly generated episodic activity with the correct correlation pattern. The correlation pattern resulted from episodes being triggered at random levels of recovery from depression while they terminated around the same level of depression. To explain this fundamental difference between episode onset and termination, we used a mean field model, where only average activity and average level of recovery from synaptic depression are considered. In this model, episode onset is highly sensitive to inputs. Thus noise resulting from random coincidences in the spike times of individual neurons led to the high variability at episode onset and to the observed correlation pattern. This work further shows that networks with widely different architectures, different cell types, and different functions all operate according to the same general mechanism early in their development. PMID- 20164397 TI - Voluntary control of multisaccade gaze shifts during movement preparation and execution. AB - Although the nature of gaze control regulating single saccades is relatively well documented, how such control is implemented to regulate multisaccade gaze shifts is not known. We used highly eccentric targets to elicit multisaccade gaze shifts and tested the ability of subjects to control the saccade sequence by presenting a second target on random trials. Their response allowed us to test the nature of control at many levels: before, during, and between saccades. Although the saccade sequence could be inhibited before it began, we observed clear signs of truncation of the first saccade, which confirmed that it could be inhibited in midflight as well. Using a race model that explains the control of single saccades, we estimated that it took about 100 ms to inhibit a planned saccade but took about 150 ms to inhibit a saccade during its execution. Although the time taken to inhibit was different, the high subject-wise correlation suggests a unitary inhibitory control acting at different levels in the oculomotor system. We also frequently observed responses that consisted of hypometric initial saccades, followed by secondary saccades to the initial target. Given the estimates of the inhibitory process provided by the model that also took into account the variances of the processes as well, the secondary saccades (average latency approximately 215 ms) should have been inhibited. Failure to inhibit the secondary saccade suggests that the intersaccadic interval in a multisaccade response is a ballistic stage. Collectively, these data indicate that the oculomotor system can control a response until a very late stage in its execution. However, if the response consists of multiple movements then the preparation of the second movement becomes refractory to new visual input, either because it is part of a preprogrammed sequence or as a consequence of being a corrective response to a motor error. PMID- 20164398 TI - Size of error affects cerebellar contributions to motor learning. AB - Small errors may affect the process of learning in a fundamentally different way than large errors. For example, adapting reaching movements in response to a small perturbation produces generalization patterns that are different from large perturbations. Are distinct neural mechanisms engaged in response to large versus small errors? Here, we examined the motor learning process in patients with severe degeneration of the cerebellum. Consistent with earlier reports, we found that the patients were profoundly impaired in adapting their motor commands during reaching movements in response to large, sudden perturbations. However, when the same magnitude perturbation was imposed gradually over many trials, the patients showed marked improvements, uncovering a latent ability to learn from errors. On sudden removal of the perturbation, the patients exhibited aftereffects that persisted much longer than did those in healthy controls. That is, despite cerebellar damage, the brain maintained the ability to learn from small errors and the motor memory that resulted from this learning was strongly resistant to change. Of note was the fact that on completion of learning, the motor output of the cerebellar patients remained distinct from healthy controls in terms of its temporal characteristics. Therefore cerebellar degeneration impaired the ability to learn from large-magnitude errors, but had a lesser impact on learning from small errors. The neural basis of motor learning in response to small and large errors appears to be distinct. PMID- 20164399 TI - Sensorimotor locus of the buildup activity in monkey lateral intraparietal area neurons. AB - A study in 2002 using a random-dot motion-discrimination paradigm showed that an information accumulation model with a threshold-crossing mechanism can account for activity of the lateral intraparietal area (LIP) neurons. Here, mathematical techniques were applied to the same dataset to quantitatively address the sensory versus motor representation of the neuronal activity during the time course of a trial. A technique based on Signal Detection Theory was applied to provide indices to quantify how neuronal firing activity is responsible for encoding the stimulus or selecting the response at the behavioral level. Additionally, a statistical model based on Poisson regression was used to provide an orthogonal decomposition of the neural activity into stimulus, response, and stimulus response mapping components. The temporal dynamics of the sensorimotor locus of the LIP activity indicated that there is no stimulus-response mapping-specific neuronal firing activity throughout a trial; the neural activity toward the saccadic onset reflects the development of the motor representation, and the neural activity in the beginning of a trial contains little, if any, information about the sensory representation. Sensorimotor analysis on individual neurons also showed that the neuronal activation, as a population, represent pending saccadic direction and carry little information about the direction of the motion stimulus. PMID- 20164401 TI - Intrinsic properties of mouse lumbar motoneurons revealed by intracellular recording in vivo. AB - We have developed an in vivo model for intracellular recording in the adult anesthetized mouse using sharp microelectrode electrodes as a basis for investigations of motoneuron properties in transgenic mouse strains. We demonstrate that it is possible to record postsynaptic potentials underlying identified circuits in the spinal cord. Forty-one motoneurons with antidromic spike potentials (>50 mV) from the sciatic nerve were investigated. We recorded the intrinsic properties of the neurons, including input resistance (mean: 2.4 +/ 1.2 MOmega), rheobase (mean: 7.1 +/- 5.9 nA), and the duration of the afterhyperpolarization (AHP; mean: 55.3 +/- 14 ms). We also measured the minimum firing frequencies (F(min), mean 23.5 +/- 5.7 SD Hz), the maximum firing frequencies (F(max); >300 Hz) and the slope of the current-frequency relationship (f-I slope) with increasing amounts of current injected (mean: 13 +/- 5.7 Hz/nA). Signs of activation of persistent inward currents (PICs) were seen, such as accelerations of firing frequency or jumps in the membrane potential with increasing amounts of injected current. It is likely that the particular anesthetic regime with a mixture of Hypnorm and midazolam is essential for the possibility to evoke PICs. The data demonstrate that mouse spinal motoneurons share many of the same properties that have been demonstrated previously for cat, rat, and human motoneurons. The shorter AHP duration, steeper f-I slopes, and higher F(min) and F(max) than those in rats, cats, and humans are likely to be tailored to the characteristics of the mouse muscle contraction properties. PMID- 20164400 TI - Response properties of neurons in primary somatosensory cortex of owl monkeys reflect widespread spatiotemporal integration. AB - Receptive fields of neurons in somatosensory area 3b of monkeys are typically described as restricted to part of a single digit or palm pad. However, such neurons are likely involved in integrating stimulus information from across the hand. To evaluate this possibility, we recorded from area 3b neurons in anesthetized owl monkeys with 100-electrode arrays, stimulating two hand locations with electromechanical probes simultaneously or asynchronously. Response magnitudes and latencies of single- and multiunits varied with stimulus conditions, and multiunit responses were similar to single-unit responses. The mean peak firing rate for single neurons stimulated within the preferred location was estimated to be ~26 spike/s. Simultaneous stimulation with a second probe outside the preferred location slightly decreased peak firing rates to ~22 spike/s. When the nonpreferred stimulus preceded the preferred stimulus by 10-500 ms, peak firing rates were suppressed with greatest suppression when the nonpreferred stimulus preceded by 30 ms (~7 spike/s). The mean latency for single neurons stimulated within the preferred location was ~23 ms, and latency was little affected by simultaneous paired stimulation. However, when the nonpreferred stimulus preceded the preferred stimulus by 10 ms, latencies shortened to ~16 ms. Response suppression occurred even when stimuli were separated by long distances (nonadjacent digits) or long times (500 ms onset asynchrony). Facilitation, though rare, occurred most often when the stimulus onsets were within 0-30 ms of each other. These findings quantify spatiotemporal interactions and support the hypothesis that area 3b is involved in widespread stimulus integration. PMID- 20164402 TI - Enhancement of synchronization between hippocampal and amygdala theta waves associated with pontine wave density. AB - Theta waves in the amygdala are known to be synchronized with theta waves in the hippocampus. Synchronization between amygdala and hippocampal theta waves is considered important for neuronal communication between these regions during the memory-retrieval process. These theta waves are also observed during rapid eye movement (REM) sleep. However, few studies have examined the mechanisms and functions of theta waves during REM sleep. This study examined correlations between the dynamics of hippocampal and amygdala theta waves and pontine (P) waves in the subcoeruleus region, which activates many brain areas including the hippocampus and amygdala, during REM sleep in rats. We confirmed that the frequency of hippocampal theta waves increased in association with P wave density, as shown in our previous study. The frequency of amygdala theta waves also increased with in associated with P wave density. In addition, we confirmed synchronization between hippocampal and amygdala theta waves during REM sleep in terms of the cross-correlation function and found that this synchronization was enhanced in association with increased P wave density. We further studied theta wave synchronization associated with P wave density by lesioning the pontine subcoeruleus region. This lesion not only decreased hippocampal and amygdala theta frequency, but also degraded theta wave synchronization. These results indicate that P waves enhance synchronization between regional theta waves. Because hippocampal and amygdala theta waves and P waves are known to be involved in learning and memory processes, these results may help clarify these functions during REM sleep. PMID- 20164403 TI - Activity in the barrel cortex during active behavior and sleep. AB - The rate at which neurons fire has wide-reaching implications for the coding schemes used by neural systems. Despite the extensive use of the barrel cortex as a model system, relatively few studies have examined the rate of sensory activity in single neurons in freely moving animals. We examined the activity of barrel cortex neurons in behaving animals during sensory cue interaction, during non stimulus-related activity, during various states of sleep, and during the administration of isoflurane. The activity of regular-spiking units (RSUs: predominantly excitatory neurons) and fast spiking units (FSUs: a subtype of inhibitory interneurons) was examined separately. We characterized activity by calculating neural firing rates, because several reports have emphasized the low firing rates in this system, reporting that both baseline activity and stimulus evoked activity is <1 Hz. We report that, during sensory cue interaction or non stimulus-related activity, the majority of RSUs in rat barrel cortex fired at rates significantly >1 Hz, with 27.4% showing rates above 10 Hz during cue interaction. Even during slow wave sleep, which had the lowest mean and median firing rates of any nonanesthetized state observed, 80.0% of RSUs fired above 1 Hz. During all of the nonanesthetized states observed 100% of the FSUs fired well above 1 Hz. When rats were administered isoflurane and at a depth of anesthesia used in standard in vivo electrophysiological preparations, all of the RSUs fired below 1 Hz. We also found that >80% of RSUs either upmodulated or downmodulated their firing during cue interaction. These data suggest that low firing rates do not typify the output of the barrel cortex during awake activity and during sleep and indicate that sensory coding at both the individual and population levels may be nonsparse. PMID- 20164404 TI - Differences in movement mechanics, electromyographic, and motor cortex activity between accurate and nonaccurate stepping. AB - What are the differences in mechanics, muscle, and motor cortex activity between accurate and nonaccurate movements? We addressed this question in relation to walking. We assessed full-body mechanics (229 variables), activity of 8 limb muscles, and activity of 63 neurons from the motor cortex forelimb representation during well-trained locomotion with different demands on the accuracy of paw placement in cats: during locomotion on a continuous surface and along horizontal ladders with crosspieces of different widths. We found that with increasing accuracy demands, cats assumed a more bent-forward posture (by lowering the center of mass, rotating the neck and head down, and by increasing flexion of the distal joints) and stepped on the support surface with less spatial variability. On the ladder, the wrist flexion moment was lower throughout stance, whereas ankle and knee extension moments were higher and hip moment was lower during early stance compared with unconstrained locomotion. The horizontal velocity time histories of paws were symmetric and smooth and did not differ among the tasks. Most of the other mechanical variables also did not depend on accuracy demands. Selected distal muscles slightly enhanced their activity with increasing accuracy demands. However, in a majority of motor cortex cells, discharge rate means, peaks, and depths of stride-related frequency modulation changed dramatically during accurate stepping as compared with simple walking. In addition, in 30% of neurons periods of stride-related elevation in firing became shorter and in 20 25% of neurons activity or depth of frequency modulation increased, albeit not linearly, with increasing accuracy demands. Considering the relatively small changes in locomotor mechanics and substantial changes in motor cortex activity with increasing accuracy demands, we conclude that during practiced accurate stepping the activity of motor cortex reflects other processes, likely those that involve integration of visual information with ongoing locomotion. PMID- 20164405 TI - Roles of narrow- and broad-spiking dorsal premotor area neurons in reach target selection and movement production. AB - Most visual scenes are complex and crowded, with several different objects competing for attention and action. Thus a complete understanding of the production of goal-directed actions must incorporate the higher-level process of target selection. To examine the neural substrates of target selection for visually guided reaching, we recorded the activity of isolated neurons in the dorsal premotor area (PMd) of monkeys performing a reaction-time visual search task. In this task, monkeys reached to an odd-colored target presented with three distractors. We found that PMd neurons typically discriminate the target before movement onset, ~150-200 ms after the appearance of the search array. In one subset of neurons, discrimination occurred at a consistent time after search array onset regardless of when the reaching movement occurred, suggesting that these neurons are involved in target selection. In a second group of neurons, discrimination time depended on reach reaction time, consistent with involvement in movement production but not in target selection. To look for physiological corroboration of these two functionally defined groups, we analyzed the extracellular spike waveforms of recorded neurons. This analysis showed a population of neurons with narrow action potentials that carried signals related to target selection. A second population with broader action potentials was more heterogeneous, with some neurons showing activity related to target selection and others showing only movement production activity. These results suggest that PMd contains signals related to target selection and movement execution and that different signals are carried by distinct neural subpopulations. PMID- 20164407 TI - Self-motion and the shaping of sensory signals. AB - Sensory systems must form stable representations of the external environment in the presence of self-induced variations in sensory signals. It is also possible that the variations themselves may provide useful information about self-motion relative to the external environment. Rats have been shown to be capable of fine texture discrimination and object localization based on palpation by facial vibrissae, or whiskers, alone. During behavior, the facial vibrissae brush against objects and undergo deflection patterns that are influenced both by the surface features of the objects and by the animal's own motion. The extent to which behavioral variability shapes the sensory inputs to this pathway is unknown. Using high-resolution, high-speed videography of unconstrained rats running on a linear track, we measured several behavioral variables including running speed, distance to the track wall, and head angle, as well as the proximal vibrissa deflections while the distal portions of the vibrissae were in contact with periodic gratings. The measured deflections, which serve as the sensory input to this pathway, were strongly modulated both by the properties of the gratings and the trial-to-trial variations in head-motion and locomotion. Using presumed internal knowledge of locomotion and head-rotation, gratings were classified using short-duration trials (<150 ms) from high-frequency vibrissa motion, and the continuous trajectory of the animal's own motion through the track was decoded from the low frequency content. Together, these results suggest that rats have simultaneous access to low- and high-frequency information about their environment, which has been shown to be parsed into different processing streams that are likely important for accurate object localization and texture coding. PMID- 20164408 TI - Kinesin motor activation: microtubules pull the switches. PMID- 20164409 TI - Atomic details of near-transition state conformers for enzyme phosphoryl transfer revealed by MgF-3 rather than by phosphoranes. AB - Prior evidence supporting the direct observation of phosphorane intermediates in enzymatic phosphoryl transfer reactions was based on the interpretation of electron density corresponding to trigonal species bridging the donor and acceptor atoms. Close examination of the crystalline state of beta phosphoglucomutase, the archetypal phosphorane intermediate-containing enzyme, reveals that the trigonal species is not PO-3 , but is MgF-3 (trifluoromagnesate). Although MgF-3 complexes are transition state analogues rather than phosphoryl group transfer reaction intermediates, the presence of fluorine nuclei in near-transition state conformations offers new opportunities to explore the nature of the interactions, in particular the independent measures of local electrostatic and hydrogen-bonding distributions using 19F NMR. Measurements on three beta-PGM-MgF-3 -sugar phosphate complexes show a remarkable relationship between NMR chemical shifts, primary isotope shifts, NOEs, cross hydrogen bond F...H-N scalar couplings, and the atomic positions determined from the high-resolution crystal structure of the beta-PGM-MgF--3 -G6P complex. The measurements provide independent validation of the structural and isoelectronic MgF--3 model of near-transition state conformations. PMID- 20164411 TI - International randomized clinical trial, stroke inpatient rehabilitation with reinforcement of walking speed (SIRROWS), improves outcomes. AB - BACKGROUND: Feedback about performance may optimize motor relearning after stroke. OBJECTIVES: Develop an international collaboration to rapidly test the potential efficacy of daily verbal feedback about walking speed during inpatient rehabilitation after stroke, using a protocol that requires no research funds. METHODS: This phase 2, single-blinded, multicenter trial randomized inpatients to either feedback about self-selected fast walking speed (daily reinforcement of speed, DRS) immediately after a single, daily 10-m walk or to no reinforcement of speed (NRS) after the walk, performed within the context of routine physical therapy. The primary outcome was velocity for a 15.2-m (50-foot) timed walk at discharge. Secondary outcomes were walking distance in 3 minutes, length of stay (LOS), and level of independence (Functional Ambulation Classification, FAC). RESULTS: Within 18 months, 179 participants were randomized. The groups were balanced for age, gender, time from onset of stroke to entry, initial velocity, and level of walking-related disability. The walking speed at discharge for DRS (0.91 m/s) was greater (P = .01) than that for NRS (0.72 m/s). No difference was found for LOS. LOS for both DRS and NRS was significantly shorter, however, for those who had mean walking speeds >0.4 m/s at entry. The DRS group did not have a higher proportion of FAC independent walkers (P = .1) and did not walk longer distances ( P = .09). CONCLUSIONS: An Internet-based collaboration of 18 centers found that feedback about performance once a day produced gains in walking speed large enough to permit unlimited, slow community ambulation at discharge from inpatient rehabilitation. PMID- 20164412 TI - Obesity, physical activity, and depressive symptoms in a cohort of adults aged 51 to 61. AB - OBJECTIVE: To determine associations between changes in obesity and vigorous physical activity (PA) status and depressive symptoms in a cohort aged 51 to 61 years at baseline. METHOD: Two waves (1992, 1998) of Health and Retirement Study data were used to divide participants into four obesity and four vigorous PA status categories based on change in or maintenance of their 1992 status in 1998. Depressive symptoms were defined as the upper quintile score (women >/= 4, men >/= 3) on the eight-item Center for Epidemiologic Studies-Depression Scale. Logistic regression determined adjusted odds ratios for depressive symptoms associated with obesity and vigorous PA status. RESULTS: Among men, no significant associations were found. Among women, decreasing from high vigorous PA status and maintenance of obese status were independently associated with increased odds for depressive symptoms in 1998. DISCUSSION: The findings illustrate the importance of examining gender differences in studies of risk factors for depression. PMID- 20164413 TI - Contribution of myelin autoantigen citrullination to T cell autoaggression in the central nervous system. AB - Breakdown in immunological self tolerance, leading to autoimmune diseases such as multiple sclerosis, might arise from immune recognition of self proteins that have undergone heightened posttranslational modification under pathophysiological conditions. A posttranslational modification of particular interest is the deimination of Arg to citrulline, catalyzed by peptidylarginyl deiminase (PAD) enzymes. As a CD4(+) T cell-driven model of multiple sclerosis, we used experimental autoimmune encephalomyelitis (EAE) induced with the immunodominant 35-55 peptide of myelin oligodendrocyte glycoprotein (pMOG) in C57BL/6 mice to test whether citrullination of a T cell epitope can contribute to disease etiopathology. Immunization with an altered peptide ligand (APL) of pMOG with an Arg-->citrulline conversion at a TCR contact (residue 41) led to the activation of two populations of APL-responsive T cells that either did, or did not cross react with the native pMOG peptide. This APL could induce EAE. However, this reflected the activation of T cells that cross-reacted with the native pMOG epitope, because prior tolerization of these T cells using pMOG prevented APL induced EAE. Using a passive transfer model, we found that T cells that responded specifically to the citrullinated form of pMOG were neither necessary, nor sufficient to initiate the EAE lesion. Nevertheless, these cells could provoke exacerbation of pathology if transferred into mice with ongoing EAE. The PAD2 and PAD4 enzymes were markedly upregulated in the inflamed CNS. Therefore, once inflammation is established, citrullination of target autoantigens can allow an expanded repertoire of T cells to contribute to CNS pathology. PMID- 20164414 TI - CD8 T cell cross-reactivity networks mediate heterologous immunity in human EBV and murine vaccinia virus infections. AB - In this study, we demonstrate complex networks of CD8 T cell cross-reactivities between influenza A virus and EBV in humans and between lymphocytic choriomeningitis virus and vaccinia virus in mice. We also show directly that cross-reactive T cells mediate protective heterologous immunity in mice. Subsets of T cell populations reactive with one epitope cross-reacted with either of several other epitopes encoded by the same or the heterologous virus. Human T cells specific to EBV-encoded BMLF1(280-288) could be cross-reactive with two influenza A virus or two other EBV epitopes. Mouse T cells specific to the vaccinia virus-encoded a11r(198-205) could be cross-reactive with three different lymphocytic choriomeningitis virus, one Pichinde virus, or one other vaccinia virus epitope. Patterns of cross-reactivity differed among individuals, reflecting the private specificities of the host's immune repertoire and divergence in the abilities of T cell populations to mediate protective immunity. Defining such cross-reactive networks between commonly encountered human pathogens may facilitate the design of vaccines. PMID- 20164415 TI - MyD88 adaptor-like D96N is a naturally occurring loss-of-function variant of TIRAP. AB - Signals elicited by TLRs following the detection of microbes are integrated and diversified by a group of four cytoplasmic adaptor molecules featuring an evolutionarily conserved Toll/IL-1R signaling domain. Single nucleotide polymorphisms (SNPs) in TLRs and their adaptor molecules have been shown to influence susceptibility to a range of infectious and other diseases. The adaptor MyD88 adaptor-like (Mal)/Toll/IL-1R-containing adaptor protein is involved in TLR2 and 4 signal transduction by recruiting another adaptor molecule, MyD88, to the plasma membrane. In this study, we used naturally occurring variants of Mal as tools to study the molecular biology of Mal in more detail in cellular model systems and to thereby identify functionally interesting variants whose corresponding nonsynonymous SNPs might be of further epidemiological interest. Of seven reported variants for Mal, we found Mal D96N associated with reduced NF kappaB signaling and cytokine production after overexpression in HEK293 and Huh-7 cells. The D96N mutation prevented Mal from recruiting its signaling partner MyD88 to the plasma membrane and altered posttranslational modification of Mal. These findings led us to investigate the frequency of heterozygosity for the corresponding SNP rs8177400 in a Caucasian case-control study on the etiology of lymphoma, a disease in which TLRs have been implicated. Although rs8177400 did not modify lymphoma risk in general, its frequency of heterozygosity was accurately determined to 0.97%. Our data add rs8177400 (D96N) to the list of functionally important variants of Mal and warrant further research into its immunological, epidemiological, and diagnostic relevance. PMID- 20164417 TI - Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver. AB - Regulatory T cells (T(regs)) are found at sites of chronic inflammation where they mediate bystander and Ag-specific suppression of local immune responses. However, little is known about the molecular control of T(reg) recruitment into inflamed human tissues. We report that up to 18% of T cells in areas of inflammation in human liver disease are forkhead family transcriptional regulator box P3 (FoxP3)(+) T(regs). We isolated CD4(+)CD25(+)CD127(low)FoxP3(+) T(regs) from chronically inflamed human liver removed at transplantation; compared with blood-derived T(regs), liver-derived T(regs) express high levels of the chemokine receptors CXCR3 and CCR4. In flow-based adhesion assays using human hepatic sinusoidal endothelium, T(regs) used CXCR3 and alpha4beta1 to bind and transmigrate, whereas CCR4 played no role. The CCR4 ligands CCL17 and CCL22 were absent from healthy liver, but they were detected in chronically inflamed liver where their expression was restricted to dendritic cells (DCs) within inflammatory infiltrates. These DCs were closely associated with CD8 T cells and CCR4(+) T(regs) in the parenchyma and septal areas. Ex vivo, liver-derived T(regs) migrated to CCR4 ligands secreted by intrahepatic DCs. We propose that CXCR3 mediates the recruitment of T(regs) via hepatic sinusoidal endothelium and that CCR4 ligands secreted by DCs recruit T(regs) to sites of inflammation in patients with chronic hepatitis. Thus, different chemokine receptors play distinct roles in the recruitment and positioning of T(regs) at sites of hepatitis in chronic liver disease. PMID- 20164416 TI - Matricellular protein CCN1 activates a proinflammatory genetic program in murine macrophages. AB - CCN1 (CYR61) is a matricellular protein that is highly expressed at sites of inflammation and wound repair. In these contexts, CCN1 can modify the activities of specific cytokines, enabling TNF-alpha to be cytotoxic without blocking NF kappaB activity and enhancing the apoptotic activity of Fas ligand and TRAIL. In this paper, we show that CCN1 supports the adhesion of macrophages through integrin alpha(M)beta(2) and syndecan-4, activates NFkappaB-mediated transcription, and induces a proinflammatory genetic program characteristic of classically activated M1 macrophages that participates in Th1 responses. The effects of CCN1 include upregulation of cytokines (TNF-alpha, IL-1alpha, IL 1beta, IL-6, and IL-12b), chemokines (MIP-1alpha; MCP-3; growth-related oncogenes 1 and 2; and inflammatory protein 10), and regulators of oxidative stress and complement (inducible NO synthase and C3) and downregulation of specific receptors (TLR4 and IL-10Rbeta) and anti-inflammatory factors (TGF-beta1). CCN1 regulates this genetic program through at least two distinct mechanisms: an immediate-early response resulting from direct activation of NF-kappaB by CCN1, leading to the synthesis of cytokines including TNF-alpha and inflammatory protein 10; and a delayed response resulting from CCN1-induced TNF-alpha, which acts as an autocrine/paracrine mediator to activate the expression of other cytokines including IL-1beta and IL-6. These results identify CCN1 as a novel component of the extracellular matrix that activates proinflammatory genes in macrophages, implicating its role in regulating macrophage function during inflammation. PMID- 20164418 TI - Post-endoplasmic reticulum rescue of unstable MHC class I requires proprotein convertase PC7. AB - The function of the peptide-loading complex (PLC) is to facilitate loading of MHC class I (MHC I) molecules with antigenic peptides in the endoplasmic reticulum and to drive the selection of these ligands toward a set of high-affinity binders. When the PLC fails to perform properly, as frequently observed in virus infected or tumor cells, structurally unstable MHC I peptide complexes are generated, which are prone to disintegrate instead of presenting Ags to cytotoxic T cells. In this study we show that a second quality control checkpoint dependent on the serine protease proprotein convertase 7 (PC7) can rescue unstable MHC I, whereas the related convertase furin is completely dispensable. Cells with a malfunctioning PLC and silenced for PC7 have substantially reduced MHC I surface levels caused by high instability and significantly delayed surface accumulation of these molecules. Instead of acquiring stability along the secretory route, MHC I appears to get largely routed to lysosomes for degradation in these cells. Moreover, mass spectrometry analysis provides evidence that lack of PLC quality control and/or loss of PC7 expression alters the MHC I-presented peptide profile. Finally, using exogenously applied peptide precursors, we show that liberation of MHC I epitopes may directly require PC7. We demonstrate for the first time an important function for PC7 in MHC I-mediated Ag presentation. PMID- 20164419 TI - Detailed characterization of T cell responses to herpes simplex virus-2 in immune seronegative persons. AB - In 2003, we described a small cohort of subjects (n = 6) who possessed no detectable serum Abs to HSV-1 or HSV-2 and no clinical or virological evidence of mucosal HSV infection yet possessed consistently detectable HSV-specific T cell responses measured primarily by lymphoproliferative (LP) and CTL assays to whole HSV-2 Ag. We termed these persons immune seronegative (IS). This report characterizes the T cell responses in 22 IS subjects largely recruited from studies of HSV-seronegative subjects in ongoing sexual relationships with HSV-2 seropositive (HSV-2(+)) partners using pools of overlapping peptides spanning 16 immuno-prevalent HSV-2 proteins. Overall, 77% of IS subjects had HSV-specific LP responses, 85% had IFN-gamma ELISPOT responses to at least one HSV-2 peptide pool, and 55% had both LP and IFN-gamma ELISPOT responses. In some cases, IFN gamma ELISPOT responses were in excess of 500 spot-forming cells per 10(6) PBMCs and persisted for over 5 y. Although HSV-2(+) subjects (n = 40) had frequent responses to glycoproteins and tegument and immediate-early (IE) proteins of HSV 2, T cell responses in IS subjects were directed primarily at UL39 and the IE proteins ICP4 and ICP0. These data suggest that the antigenic repertoire of T cells in IS subjects is skewed compared with that of HSV-2(+) subjects and that IS subjects had more frequent T cell responses to IE proteins and infrequent T cell responses to virion components. Understanding the mechanism(s) by which such responses are elicited may provide important insights in developing novel strategies for preventing acquisition of sexually acquired HSV-2. PMID- 20164420 TI - Antiviral response dictated by choreographed cascade of transcription factors. AB - The dendritic cell (DC) is a master regulator of immune responses. Pathogenic viruses subvert normal immune function in DCs through the expression of immune antagonists. Understanding how these antagonists interact with the host immune system requires knowledge of the underlying genetic regulatory network that operates during an uninhibited antiviral response. To isolate and identify this network, we studied DCs infected with Newcastle disease virus, which is able to stimulate innate immunity and DC maturation through activation of RIG-I signaling, but lacks the ability to evade the human IFN response. To analyze this experimental model, we developed a new approach integrating genome-wide expression kinetics and time-dependent promoter analysis. We found that the genetic program underlying the antiviral cell-state transition during the first 18 h postinfection could be explained by a single convergent regulatory network. Gene expression changes were driven by a stepwise multifactor cascading control mechanism, where the specific transcription factors controlling expression changed over time. Within this network, most individual genes were regulated by multiple factors, indicating robustness against virus-encoded immune evasion genes. In addition to effectively recapitulating current biological knowledge, we predicted, and validated experimentally, antiviral roles for several novel transcription factors. More generally, our results show how a genetic program can be temporally controlled through a single regulatory network to achieve the large scale genetic reprogramming characteristic of cell-state transitions. PMID- 20164421 TI - Diversity of the CD8+ T cell repertoire elicited against an immunodominant epitope does not depend on the context of infection. AB - The diversity of the pathogen-specific T cell repertoire is believed to be important in allowing recognition of different pathogen epitopes and their variants and thereby reducing the opportunities for mutation-driven pathogen escape. However, the extent to which the TCR repertoire can be manipulated by different vaccine strategies so as to obtain broad diversity and optimal protection is incompletely understood. We have investigated the influence of the infectious/inflammatory context on the TCR diversity of the CD8(+) T cell response specific for the immunodominant epitope in C57BL/6 mice, derived from glycoprotein B of HSV-1. To that effect, we compared TCR V segment utilization, CDR3 length, and sequence diversity of the response to natural HSV-1 infection with those elicited by either Listeria monocytogenes or vaccinia virus expressing the immunodominant epitope in C57BL/6 mice. We demonstrate that although the type of infection in which the epitope was encountered can influence the magnitude of the CD8(+) T cell responses, TCR beta-chain repertoires did not significantly differ among the three infections. These results suggest that widely different live vaccine vectors may have little impact upon the diversity of the induced CTL response, which has important implications for the design of live CTL vaccine strategies against acute and chronic infections. PMID- 20164422 TI - IFN-gamma receptor signaling regulates memory CD8+ T cell differentiation. AB - IFN-gamma regulates multiple processes in the immune system. Although its antimicrobial effector functions are well described, less is known about the mechanisms by which IFN-gamma regulates CD8(+) T cell homeostasis. With the help of adoptive T cell transfers, we show in this study that IFN-gammaR signaling in CD8(+) T cells is dispensable for expansion, contraction, and memory differentiation in response to peptide vaccination. In contrast, host IFN-gammaR signaling counterregulates CD8(+) T cell responses and the generation of effector memory T cell processes, which are partially regulated by CD11b(+) cells. Similar to vaccination-induced proliferation, host IFN-gammaR signaling limits the expansion of naive CD8(+) T cells and their differentiation into effector memory like T cells in lymphopenic mice. In contrast to peptide vaccination, IFN-gammaR signaling in CD8(+) T cells contributes to memory fate decision in response to lymphopenia, an effect that is fully reversed by high-affinity TCR ligands. In conclusion, we show that host IFN-gammaR signaling controls the magnitude of CD8(+) T cell responses and subsequent memory differentiation under lymphopenic and nonlymphopenic conditions. In contrast, IFN-gammaR signaling in CD8(+) T cells does not affect cell numbers under either condition, but it directs memory fate decision in response to weak TCR ligands. PMID- 20164423 TI - Cutting edge: Mincle is essential for recognition and adjuvanticity of the mycobacterial cord factor and its synthetic analog trehalose-dibehenate. AB - The mycobacterial cord factor trehalose-6,6-dimycolate (TDM) and its synthetic analog trehalose-6,6-dibehenate (TDB) are potent adjuvants for Th1/Th17 vaccination that activate Syk-Card9 signaling in APCs. In this study, we have further investigated the molecular mechanism of innate immune activation by TDM and TDB. The Syk-coupling adapter protein FcRgamma was essential for macrophage activation and Th17 adjuvanticity. The FcRgamma-associated C-type lectin receptor Mincle was expressed in macrophages and upregulated by TDM and TDB. Recombinant Mincle-Fc fusion protein specifically bound to the glycolipids. Genetic ablation of Mincle abolished TDM/TDB-induced macrophage activation and induction of T cell immune responses to a tuberculosis subunit vaccine. Macrophages lacking Mincle or FcRgamma were impaired in the inflammatory response to Mycobacterium bovis bacillus Calmette-Guerin. These results establish that Mincle is a key receptor for the mycobacterial cord factor and controls the Th1/Th17 adjuvanticity of TDM and TDB. PMID- 20164424 TI - A distinct subset of proinflammatory neutrophils isolated from patients with systemic lupus erythematosus induces vascular damage and synthesizes type I IFNs. AB - Neutrophil-specific genes are abundant in PBMC microarrays from lupus patients because of the presence of low-density granulocytes (LDGs) in mononuclear cell fractions. The functionality and pathogenicity of these LDGs have not been characterized. We developed a technique to purify LDGs from lupus PBMCs and assessed their phenotype, function, and potential role in disease pathogenesis. LDGs, their autologous lupus neutrophils, and healthy control neutrophils were compared with regard to their microbicidal and phagocytic capacities, generation of reactive oxygen species, activation status, inflammatory cytokine profile, and type I IFN expression and signatures. The capacity of LDGs to kill endothelial cells and their antiangiogenic potential were also assessed. LDGs display an activated phenotype, secrete increased levels of type I IFNs, TNF-alpha, and IFN gamma, but show impaired phagocytic potential. LDGs induce significant endothelial cell cytotoxicity and synthesize sufficient levels of type I IFNs to disrupt the capacity of endothelial progenitor cells to differentiate into mature endothelial cells. LDG depletion restores the functional capacity of endothelial progenitor cells. We conclude that lupus LDGs are proinflammatory and display pathogenic features, including the capacity to synthesize type I IFNs. They may play an important dual role in premature cardiovascular disease development in systemic lupus erythematosus by simultaneously mediating enhanced vascular damage and inhibiting vascular repair. PMID- 20164425 TI - The major locus for mouse adenovirus susceptibility maps to genes of the hematopoietic cell surface-expressed LY6 family. AB - Susceptibility to mouse adenovirus type 1 is associated with the major quantitative trait locus Msq1. Msq1 was originally mapped to a 13-Mb region of mouse chromosome (Chr) 15 in crosses between SJL/J and BALB/cJ inbred mice. We have now narrowed Msq1 to a 0.75-Mb interval from 74.68 to 75.43 Mb, defined by two anonymous markers, rs8259436 and D15Spn14, using data from 1396 backcross mice. The critical interval includes 14 Ly6 or Ly6-related genes, including Ly6a (encoding Sca-1/TAP), Ly6e (Sca-2/Tsa1), Ly6g (Gr-1), and gpihbp1 (GPI-anchored high-density lipoprotein-binding protein 1), as well as the gene encoding an aldosterone synthase (Cyp11b2). The Ly6 family members are attractive candidates for virus susceptibility genes because their products are GPI-anchored membrane proteins expressed on lymphoid and myeloid cells, with proposed functions in cell adhesion and cell signaling. To determine interstrain variation in susceptibility and produce additional resources for cloning Msq1, we assayed the susceptibility phenotype of four previously untested inbred mouse strains. Susceptibility of strain 129S6/SvEvTac was subsequently localized to the Ly6 complex region, using polymorphic genetic markers on Chr 15 in a population of 271 (129S6/SvEvTac x BALB/cJ)F(1) x BALB/cJ backcross mice. We identified a major 129S6/SvEvTac susceptibility allele, Msq1(129S6), on Chr 15 in the same region as Msq1(SJL). The results indicate that a major host factor in mouse adenovirus type 1 susceptibility is likely to be a member of the Ly6 gene family. PMID- 20164428 TI - Glutathione-redox balance regulates c-rel-driven IL-12 production in macrophages: possible implications in antituberculosis immunotherapy. AB - The glutathione-redox balance, expressed as the ratio of intracellular reduced glutathione (GSH) and oxidized glutathione, plays an important role in regulating cellular immune responses. In the current study, we demonstrate that alteration of glutathione-redox balance in macrophages by GSH donors like cell-permeable glutathione ethyl ester reduced or N-acetyl-L-cysteine (NAC) can differentially regulate production of IL-12 cytokine in macrophages. A low concentration of NAC increased IL-12 p40/p70 production, whereas at high concentration, IL-12 production was inhibited due to increased calmodulin expression that binds and sequesters c-rel in the cytoplasm. Although NAC treatment increased the IkappaBalpha phosphorylation, it failed to increase TNF-alpha levels due to enhanced expression of suppressor of cytokine signaling 1, which specifically prevented nuclear translocation of p65 NF-kappaB. We demonstrate that NAC at 3 mM concentration could increase bacillus Calmette-Guerin-induced IFN-gamma production by PBMCs from patients with active tuberculosis and shifts the anti bacillus Calmette-Guerin immune response toward the protective Th1 type. Our results indicate that redox balance of glutathione plays a critical role in regulating IL-12 induction in native macrophages, and NAC can be used in tailoring macrophages to induce enhanced Th1 response that may be helpful to control tuberculosis and other pathophysiological disorders. PMID- 20164426 TI - CC chemokine ligand 3 overcomes the bacteriocidal and phagocytic defect of macrophages and hastens recovery from experimental otitis media in TNF-/- mice. AB - Innate immune mechanisms are crucial in defense against bacterial illnesses in humans, as evidenced by abnormal antibacterial responses due to defects in TLR signaling, seen in children with MyD88 or IL-1R-associated kinase 4 deficiency. Otitis media (OM) is the most common disease of childhood, and the role of innate immune molecules in this disorder remains unclear. In a murine model of OM, we show that, in the absence of TNF, a key effector of innate immunity, this disease is prolonged after middle ear infection with nontypeable Haemophilus influenzae (NTHi). In the absence of TNF, mice fail to upregulate both TLRs and downstream genes and proteins, such as CCL3, resulting in defects in both inflammatory cell recruitment and macrophage function. Peritoneal macrophages of mice lacking TNF have a diminished ability to phagocytose and kill NTHi, and this defect is partially corrected in vitro by exogenous rTNF. Addition of rCCL3 alone or in combination with rTNF restores phagocytosis and killing by TNF-deficient macrophages to that of unstimulated wild-type macrophages. In vivo administration of rCCL3 to animals deficient in TNF fully restores the ability to control OM due to NTHi, whereas a CCL3-blocking Ab impaired the ability of wild-type mice to recover from OM. Thus, CCL3 is a potent downstream effector of TNF-mediated inflammation in vitro and in vivo. Manipulation of CCL3 and/or TNF may prove to be effective therapeutic approaches in OM or other conditions associated with defective TNF generation. PMID- 20164429 TI - The association of MHC class I proteins with the 2B4 receptor inhibits self killing of human NK cells. AB - The killing activity of NK cells is carried out by several activating NK receptors, which includes NKp46, NKp44, NKp30, NKp80, NKG2D, and 2B4. The ligands of these receptors are either self-derived, pathogen-derived, stress-induced ligands or tumor ligands. Importantly, none of these killer ligands are expressed on NK cells and thus self-killing of NK cells is prevented. A notable exception with this regard, is the ligand of the 2B4 receptor. This unusual receptor can exert both activating and inhibiting signals; however, in human NK cells, it serves mainly as an activating receptor. The ligand of 2B4 is CD48 and in contrast to the ligands of all the other NK activating receptors, CD48 is also present on NK cells. Thus, NK cells might be at risk for self-killing that is mediated via the 2B4-CD48 interaction. In this study, we identify a novel mechanism that prevents this self-killing as we show that the association of the MHC class I proteins with the 2B4 receptor, both present on NK cells, results in the attenuation of the 2B4-mediated self-killing of NK cells. PMID- 20164427 TI - Transfusion of nonobese diabetic mice with allogeneic newborn blood ameliorates autoimmune diabetes and modifies the expression of selected immune response genes. AB - Although allogeneic bone marrow transplantation has been shown to prevent autoimmune diabetes in heavily irradiated nonobese diabetic (NOD) mice, a similar procedure is not suitable for the treatment of patients with type 1 diabetes because of associated severe side effects. Therefore, we evaluated whether mouse newborn blood (NBB), equivalent to human umbilical cord blood, could be used for diabetes prevention without recipient preconditioning. To test this hypothesis, unconditioned, prediabetic female NOD mice were given a single injection of whole NBB derived from the allogeneic diabetes-resistant mouse strain C57BL/6. Transfusion of allogeneic NBB but not adult blood prevented diabetes incidence in a majority of treated mice for a prolonged period of time. This was accompanied by the release of insulin in response to a challenge with glucose. Invasive cellular infiltration of islets was also substantially reduced in these mice. Although NBB transfusion induced a low level of hematopoietic microchimerism, it did not strictly correlate with amelioration of diabetes. Induction of genes implicated in diabetes, such as Il18, Tnfa, and Inos but not Il4, Il17 or Ifng, was repressed in splenocytes derived from protected mice. Notably, expression of the transcription factor Tbet/Tbx21 but not Gata3 or Rorgt was upregulated in protected mice. These data indicate that allogeneic NBB transfusion can prevent diabetes in NOD mice associated with modulation of selected cytokine genes implicated in diabetes manifestation. The data presented in this study provide the proof of principle for the utility of allogeneic umbilical cord blood transfusion to treat patients with autoimmune diabetes. PMID- 20164430 TI - Cutting edge: polyinosinic:polycytidylic acid boosts the generation of memory CD8 T cells through melanoma differentiation-associated protein 5 expressed in stromal cells. AB - Polyinosinic:polycytidylic acid (poly I:C), a synthetic analog of double-stranded viral RNA, serves as a potent adjuvant for vaccination against soluble proteins, pathogens, and tumors. Poly I:C is sensed by both TLR3 in the endosomes and melanoma differentiation-associated protein 5 (MDA5) in the cytoplasm. Although it is known that TLR3 is required for cross-priming of CD8 T cells specific for viral Ags, the role of MDA5 in inducing CD8 T cell responses is still unclear. In this study, we demonstrate that in mice lacking MDA5, the majority of CD8 T cells do not survive after primary immunization with poly I:C and Ag, impairing memory response to subsequent Ag challenge. Furthermore, bone marrow chimera experiments revealed that MDA5 expression in radiation-resistant stromal cells, but not in radiation-sensitive hematopoietic cells, is essential for establishing CD8 T cell memory. We conclude that MDA5 and TLR3 mediate substantially distinct yet complementary functions during poly I:C-mediated activation of Ag-specific CD8 T cell responses. PMID- 20164431 TI - Ischemic injury enhances dendritic cell immunogenicity via TLR4 and NF-kappa B activation. AB - Ischemic (isc) injury during the course of transplantation enhances the immunogenicity of allografts and thus results in poorer graft outcome. Given the central role of dendritic cells (DCs) in mounting alloimmune responses, activation of donor DCs by ischemia may have a primary function in the increased immunogenicity of isc allografts. In this study, we sought to investigate the effect of ischemia on DC activity in vitro. Following induction of ischemia, bone marrow-derived DCs were shown to augment allogeneic T cell proliferation as well as the IFN-gamma response. Isc DCs produced greater levels of IL-6, and isc insult was concurrent with NF-kappaB activation. TLR4 ligation was also shown to occur in isc DCs, most likely in response to the endogenous ligand heat shock protein 70, which was found to be elevated in DCs following isc injury, and lack of TLR4 abrogated the observed effects of isc DCs. As compared with control DCs, isc DCs injected into the footpads of mice demonstrated enhanced migration, which was concomitant with increased recipient T cell activity. Moreover, isc DCs underwent a greater degree of apoptosis in the lymph nodes of injected mice, which may further demonstrate enhanced immunogenicity of isc DCs. We thus show that isc injury of DCs enhances DC function, augments the allogeneic T cell response, and occurs via ligation of TLR4, followed by activation of NF-kappaB. These data may serve to identify novel therapeutic targets to attenuate graft immunogenicity following ischemia. PMID- 20164432 TI - Innate and adaptive receptors interact to balance humoral immunity. PMID- 20164433 TI - Pillars Article: CD19: Lowering the threshold for antigen receptor stimulation of B lymphocytes. Science, 1992. 256: 105-107. PMID- 20164434 TI - Different bacterial pathogens, different strategies, yet the aim is the same: evasion of intestinal dendritic cell recognition. AB - Given the central role of intestinal dendritic cells (DCs) in the regulation of gut immune responses, it is not surprising that several bacterial pathogens have evolved strategies to prevent or bypass recognition by DCs. In this article, we will review recent findings on the interaction between intestinal DCs and prototypical bacterial pathogens, such as Salmonella, Yersinia, or Helicobacter. We will discuss the different approaches with which these pathogens seek to evade DC recognition and subsequent T cell activation. These diverse strategies span to include mounting irrelevant immune responses, inhibition of Ag presentation by DCs, and stretch as far as to manipulate the Th1/Th2 balance of CD4(+) T cells in the bacteria's favor. PMID- 20164435 TI - Distinct protease requirements for antigen presentation in vitro and in vivo. AB - Asparagine endopeptidase (AEP) or legumain is a potentially important Ag processing enzyme that introduces limited cleavages that trigger unfolding and class II MHC binding of different Ag substrates. AEP is necessary and sufficient for optimal processing and presentation of the tetanus toxin C fragment (TTCF) Ag in vitro, but its importance has not been tested in vivo. Surprisingly, virtually normal T cell and Ab responses to TTCF were mounted in AEP-deficient mice when examined 10 d after immunization. This was the case when TTCF was emulsified with CFA, adsorbed onto alum, or expressed within live Salmonella typhimurium. In addition, the dominant Ab and T cell determinants recognized in TTCF were essentially unchanged in AEP-deficient mice. These data are explained, at least in part, by the much lower levels of AEP expressed in primary murine APCs compared with immortalized B cell lines. Even so, the initial in vivo kinetics of TTCF presentation were slower in AEP-deficient mice and, as expected, boosting AEP levels in primary APCs enhanced and accelerated TTCF processing and presentation in vitro. Thus, AEP remains the protease of choice for TTCF processing; however, in its absence, other enzymes can substitute to enable slower, but equally robust, adaptive immune responses. Moreover, clear relationships between Ags and processing proteases identified from short-term in vitro processing and presentation studies do not necessarily predict an absolute in vivo dependency on those processing enzymes, not least because they may be expressed at strikingly different levels in vitro versus in vivo. PMID- 20164436 TI - Assessing the role of claudins in maintaining the integrity of epididymal tight junctions using novel human epididymal cell lines. AB - The epididymis is responsible for posttesticular sperm maturation. Sperm maturation is dependent on the luminal microenvironments along the epididymis. Though the role of the epididymis is well established, the molecular and cellular mechanisms responsible for sperm maturation remain to be elucidated, particularly in the human, as limited biological tools exist. We have established the first stable epithelial cell lines transformed with SV40 large T antigen (LTAg) from two regions of the human adult epididymis. The cell lines are composed of homogenous populations of diploid principal cells that possess ultrastructural characteristics similar to those of human principal cells in vivo. These cells express transcripts for adherens (cadherins CDH1 and CDH2) and tight (claudins CLDN1, CLDN2, CLDN3, CLDN4, CLDN7, and CLDN8) junctions as well as desmosomes (desmoplakin, DSP). Transepithelial resistance (TER) measurements in fertile human caput epididymal cell line 1 (FHCE1) as well as the immunolocalization of tight junctional protein 1 (TJP1), occludin, and CLDN1 indicate that these cells form functional tight junctions. Furthermore, knockdown of CLDN1, CLDN3, CLDN4, or CLDN7 using specific siRNAs resulted in significant decreases in TER, suggesting that these CLDNs are essential for the barrier function of the blood epididymis barrier. Disruption of CLDN1, CLDN3, CLDN4, and CLDN7 could, therefore, lead to epididymal dysfunction, resulting in male infertility. PMID- 20164437 TI - Transcriptional profiling of luteinizing hormone receptor-deficient mice before and after testosterone treatment provides insight into the hormonal control of postnatal testicular development and Leydig cell differentiation. AB - Luteinizing hormone (LH) is a key regulator of male fertility through its effects on testosterone secretion by Leydig cells. Transcriptional control of this is, however, currently poorly understood. Mice in which the LH receptor is knocked out (LuRKO) show reduced testicular size, reduced testosterone, elevated serum LH, and a spermatogenic arrest that can be rescued by the administration of testosterone. Using genome-wide transcription profiling of LuRKO and control testes during postnatal development and following testosterone treatment, we show that the transcriptional effects of LH insensitivity are biphasic, with an early testosterone-independent phase and a subsequent testosterone-dependent phase. Testosterone rescue re-enables the second, testosterone-dependent phase of the normal prepubertal transcription program and permits the continuation of spermatogenesis. Examination of the earliest responses to testosterone highlights six genes that respond rapidly in a dose-dependent fashion to the androgen and that are therefore candidate regulatory genes associated with the testosterone driven progression of spermatogenesis. In addition, our transcriptional data suggest a model for the replacement of fetal-type Leydig cells by adult-type cells during testicular development in which a testosterone feedback switch is necessary for adult Leydig cell production. LH signaling affects the timing of the switch but is not a strict requirement for Leydig cell differentiation. PMID- 20164438 TI - The estrous cycle of the ewe is resistant to disruption by repeated, acute psychosocial stress. AB - Five experiments were conducted to test the hypothesis that psychosocial stress interferes with the estrous cycle of sheep. In experiment 1, ewes were repeatedly isolated during the follicular phase. Timing, amplitude, and duration of the preovulatory luteinizing hormone (LH) surge were not affected. In experiment 2, follicular-phase ewes were subjected twice to a "layered stress" paradigm consisting of sequential, hourly application of isolation, restraint, blindfold, and predator cues. This reduced the LH pulse amplitude but did not affect the LH surge. In experiment 3, different acute stressors were given sequentially within the follicular phase: food denial plus unfamiliar noises and forced exercise, layered stress, exercise around midnight, and transportation. This, too, did not affect the LH surge. In experiment 4, variable acute psychosocial stress was given every 1-2 days for two entire estrous cycles; this did not disrupt any parameter of the cycle monitored. Lastly, experiment 5 examined whether the psychosocial stress paradigms of experiment 4 would disrupt the cycle and estrous behavior if sheep were metabolically stressed by chronic food restriction. Thirty percent of the food-restricted ewes exhibited deterioration of estrous cycle parameters followed by cessation of cycles and failure to express estrous behavior. However, disruption was not more evident in ewes that also encountered psychosocial stress. Collectively, these findings indicate the estrous cycle of sheep is remarkably resistant to disruption by acute bouts of psychosocial stress applied intermittently during either a single follicular phase or repeatedly over two estrous cycles. PMID- 20164439 TI - The temperature and type of intracellular ice formation in preimplantation mouse embryos as a function of the developmental stage. AB - Our studies the past 5 yr have concentrated on intracellular ice formation (IIF) in mature mouse oocytes at the metaphase stage of meiosis II. Here we report an analogous investigation of the temperature of intracellular ice nucleation in preimplantation embryo stages from one-cell to early morula suspended in 1 M ethylene glycol/PBS and cooled at 20 degrees C/min to -70 degrees C. Physical modeling indicates that oocytes and preimplantation embryos undergo very little osmotic shrinkage at that cooling rate. As a consequence, their interior becomes increasingly supercooled until the supercooling is abruptly terminated by IIF. Four categories of IIF were observed. The first two were 1) those undergoing IIF at temperatures well below the temperature of external ice formation (EIF; -7.2 degrees C) vs. 2) those undergoing IIF within 1 degrees C of the EIF temperature. The other two categories were those multicellular stages in which 3) all the blastomeres underwent IIF simultaneously vs. 4) those in which blastomeres underwent IIF sequentially. Embryos in categories 1 and 3 constituted the majority (80-90%), and for them, the mean IIF temperatures of one-cell, two-cell, four- to six-cell, and early eight-cell ranged from -37 degrees C to -43 degrees C, temperatures that indicate that IIF is a consequence of homogeneous nucleation. However, the IIF nucleation temperature of early morulae in categories 1 and 3 was markedly higher; namely, -23.1 +/- 1.5 degrees C. This marked rise in nucleation temperature coincides with the appearance of aquaporin 3 and gap junctions in early morulae (compacted eight-cell), and is presumably causally related. PMID- 20164440 TI - Human transcriptional coactivator with PDZ-binding motif (TAZ) is downregulated during decidualization. AB - Transcriptional coactivator with PDZ-binding motif (TAZ) is known to bind to a variety of transcription factors to control cell differentiation and organ development. However, its role in uterine physiology has not yet been described. To study its regulation during the unique process of differentiation of fibroblasts into decidual cells (decidualization), we utilized the human uterine fibroblast (HuF) in vitro cell model. Immunocytochemistry data demonstrated that the majority of the TAZ protein is localized in the nucleus. Treatment of HuF cells with the embryonic stimulus cytokine interleukin 1 beta in the presence of steroid hormones (estradiol-17 beta and medroxyprogesterone acetate) for 13 days did not cause any apparent TAZ mRNA changes but resulted in a significant TAZ protein decline (approximately 62%) in total cell lysates. Analysis of cytosolic and nuclear extracts revealed that the decline of total TAZ was caused primarily by a drop of TAZ protein levels in the nucleus. TAZ was localized on the peroxisome proliferator-activated receptor response element site (located at position -1200 bp relative to the transcription start site) of the genomic region of decidualization marker insulin-like growth factor-binding protein 1 (IGFBP1) in HuF cells as detected by chromatin immunoprecipitation. TAZ is also present in human endometrium tissue as confirmed by immunohistochemistry. During the secretory phase of the menstrual cycle, specific TAZ staining particularly diminishes in the stroma, suggesting its participation during the decidualization process, as well as implantation. During early baboon pregnancy, TAZ protein expression remains minimal in the endometrium close to the implantation site. In summary, the presented evidence shows for the first time to date TAZ protein in the human uterine tract, its downregulation during in vitro decidualization, and its localization on the IGFBP1 promoter region, all of which indicate its presence in the uterine differentiation program during pregnancy. PMID- 20164441 TI - Formation of the ovarian follicular antrum and follicular fluid. AB - The formation of the follicular antrum and follicular fluid has received scant attention from researchers, yet both are important processes in follicular development. The central hypothesis on follicular fluid formation suggests that production by granulosa cells of hyaluronan and the chondroitin sulfate proteoglycan versican generates an osmotic gradient. This gradient draws in fluid derived from the thecal vasculature. Inter-alpha-trypsin inhibitor is also present in follicular fluid at least in species with large follicles, and inter alpha-trypsin inhibitor and versican could additionally bind or cross-link with hyaluronan, resulting in the retention of these molecules within the follicular antrum. Barriers to the movement of fluid across the membrana granulosa are apparently minimal, as even relatively large serum proteins are present in follicular fluid. Despite the relative permeability of the follicular wall, aquaporins are present in granulosa cells and could be actively involved in the transport of water into the follicle. The formation of an antrum also requires movement of granulosa cells relative to each other to allow the fluid to accumulate. This presumably involves remodeling of cell-cell junctions and in species with small follicles may involve death of centrally located granulosa cells. Remodeling of the stroma and thecal layers also accompanies growth and expansion of the antrum and presumably involves similar processes that accompany growth of other glands. PMID- 20164442 TI - Role of ubiquitin C-terminal hydrolase-L1 in antipolyspermy defense of mammalian oocytes. AB - The ubiquitin-proteasome system regulates many cellular processes through rapid proteasomal degradation of ubiquitin-tagged proteins. Ubiquitin C-terminal hydrolase-L1 (UCHL1) is one of the most abundant proteins in mammalian oocytes. It has weak hydrolytic activity as a monomer and acts as a ubiquitin ligase in its dimeric or oligomeric form. Recently published data show that insufficiency in UCHL1 activity coincides with polyspermic fertilization; however, the mechanism by which UCHL1 contributes to this process remains unclear. Using UCHL1 specific inhibitors, we induced a high rate of polyspermy in bovine zygotes after in vitro fertilization. We also detected decreased levels in the monomeric ubiquitin and polyubiquitin pool. The presence of UCHL1 inhibitors in maturation medium enhanced formation of presumptive UCHL1 oligomers and subsequently increased abundance of K63-linked polyubiquitin chains in oocytes. We analyzed the dynamics of cortical granules (CGs) in UCHL1-inhibited oocytes; both migration of CGs toward the cortex during oocyte maturation and fertilization induced extrusion of CGs were impaired. These alterations in CG dynamics coincided with high polyspermy incidence in in vitro-produced UCHL1-inhibited zygotes. These data indicate that antipolyspermy defense in bovine oocytes may rely on UCHL1-controlled functioning of CGs. PMID- 20164443 TI - Redox regulation of auxin signaling and plant development. PMID- 20164444 TI - Interplay between the NADP-linked thioredoxin and glutathione systems in Arabidopsis auxin signaling. AB - Intracellular redox status is a critical parameter determining plant development in response to biotic and abiotic stress. Thioredoxin (TRX) and glutathione are key regulators of redox homeostasis, and the TRX and glutathione pathways are essential for postembryonic meristematic activities. Here, we show by associating TRX reductases (ntra ntrb) and glutathione biosynthesis (cad2) mutations that these two thiol reduction pathways interfere with developmental processes through modulation of auxin signaling. The triple ntra ntrb cad2 mutant develops normally at the rosette stage, undergoes the floral transition, but produces almost naked stems, reminiscent of the phenotype of several mutants affected in auxin transport or biosynthesis. In addition, the ntra ntrb cad2 mutant shows a loss of apical dominance, vasculature defects, and reduced secondary root production, several phenotypes tightly regulated by auxin. We further show that auxin transport capacities and auxin levels are perturbed in the mutant, suggesting that the NTR-glutathione pathways alter both auxin transport and metabolism. Analysis of ntr and glutathione biosynthesis mutants suggests that glutathione homeostasis plays a major role in auxin transport as both NTR and glutathione pathways are involved in auxin homeostasis. PMID- 20164445 TI - A novel role for Arabidopsis mitochondrial ABC transporter ATM3 in molybdenum cofactor biosynthesis. AB - The molybdenum cofactor (Moco) is a prosthetic group required by a number of enzymes, such as nitrate reductase, sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. Its biosynthesis in eukaryotes can be divided into four steps, of which the last three are proposed to occur in the cytosol. Here, we report that the mitochondrial ABC transporter ATM3, previously implicated in the maturation of extramitochondrial iron-sulfur proteins, has a crucial role also in Moco biosynthesis. In ATM3 insertion mutants of Arabidopsis thaliana, the activities of nitrate reductase and sulfite oxidase were decreased to approximately 50%, whereas the activities of xanthine dehydrogenase and aldehyde oxidase, whose activities also depend on iron-sulfur clusters, were virtually undetectable. Moreover, atm3 mutants accumulated cyclic pyranopterin monophosphate, the first intermediate of Moco biosynthesis, but showed decreased amounts of Moco. Specific antibodies against the Moco biosynthesis proteins CNX2 and CNX3 showed that the first step of Moco biosynthesis is localized in the mitochondrial matrix. Together with the observation that cyclic pyranopterin monophosphate accumulated in purified mitochondria, particularly in atm3 mutants, our data suggest that mitochondria and the ABC transporter ATM3 have a novel role in the biosynthesis of Moco. PMID- 20164446 TI - Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. AB - BACKGROUND: Specific populations of highly tumorigenic cells are thought to exist in many human tumors, including pancreatic adenocarcinoma. However, the clinical significance of these tumor-initiating (ie, cancer stem) cells remains unclear. Aldehyde dehydrogenase (ALDH) activity can identify tumor-initiating cells and normal stem cells from several human tissues. We examined the prognostic significance and functional features of ALDH expression in pancreatic adenocarcinoma. METHODS: ALDH expression was analyzed by immunohistochemistry in 269 primary surgical specimens of pancreatic adenocarcinoma and examined for association with clinical outcomes and in paired primary tumors and metastatic lesions from eight pancreatic cancer patients who had participated in a rapid autopsy program. The clonogenic growth potential of ALDH-positive pancreatic adenocarcinoma cells was assessed in vitro by a colony formation assay and by tumor growth in immunodeficient mice (10-14 mice per group). Mesenchymal features of ALDH-positive pancreatic tumor cells were examined by using quantitative reverse transcription-polymerase chain reaction and an in vitro cell invasion assay. Gene expression levels and the invasive potential of ADLH-positive pancreatic cancer cells relative to the bulk cell population were examined by reverse transcription-polymerase chain reaction and an in vitro invasion assays, respectively. All statistical tests were two-sided. RESULTS: ALDH-positive tumor cells were detected in 90 of the 269 primary surgical specimens, and their presence was associated with worse survival (median survival for patients with ALDH-positive vs ALDH-negative tumors: 14 vs 18 months, hazard ratio of death = 1.28, 95% confidence interval = 1.02 to 1.68, P = .05). Six (75%) of the eight patients with matched primary and metastatic tumor samples had ALDH-negative primary tumors, and in four (67%) of these six patients, the matched metastatic lesions (located in liver and lung) contained ALDH-positive cells. ALDH-positive cells were approximately five- to 11-fold more clonogenic in vitro and in vivo compared with unsorted or ALHD-negative cells, expressed genes consistent with a mesenchymal state, and had in vitro migratory and invasive potentials that were threefold greater than those of unsorted cells. CONCLUSIONS: ALDH expression marks pancreatic cancer cells that have stem cell and mesenchymal features. The enhanced clonogenic growth and migratory properties of ALDH-positive pancreatic cancer cells suggest that they play a key role in the development of metastatic disease that negatively affects the overall survival of patients with pancreatic adenocarcinoma. PMID- 20164447 TI - Neuroprotection against retinal ischemia-reperfusion injury by blocking the angiotensin II type 1 receptor. AB - PURPOSE. To investigate the effects of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II antagonist against retinal ischemia-reperfusion injury in the rat retina. METHODS. Retinal ischemia was induced by increasing intraocular pressure to 130 mm Hg. Rats were treated with an ACE inhibitor (captopril), an angiotensin II type 1 receptor (AT1-R) antagonist (candesartan), an AT2-R antagonist (PD123319), bradykinin, or a bradykinin B2 receptor antagonist (icatibant). At 7 days after the ischemia, retinal damage was evaluated. Immunohistochemistry and image analysis were used to measure changes in the levels of reactive oxygen species (ROS) and the localization of AT1-R. Dark-adapted full-field electroretinography (ERG) was also performed. RESULTS. Pretreatment with captopril or candesartan significantly inhibited the ischemic injury of the inner retina. However, PD123319, bradykinin, or icatibant did not reduce the ischemic damage. In control retinas, retinal vessels were positive for AT1-R. In contrast, 12 hours after ischemia, immunohistochemical analysis detected numerous AT1-R-positive cells in the inner retina in vehicle-treated rats. After ischemia, the production of ROS was detected in retinal cells. However, pretreatment with captopril or candesartan suppressed the production of ROS. On the seventh postoperative day, the amplitudes of the ERG b-waves were significantly lower in the vehicle group than in the groups pretreated with captopril or candesartan. CONCLUSIONS. The present findings demonstrate that ischemic damage promotes the expression of AT1-R in the inner retina. Both the ACE inhibitor and the AT1-R antagonist that were examined can block the stimulation of the AT1-R and attenuate the subsequent ischemic damage in the rat retina. PMID- 20164448 TI - Analysis of peripapillary retinal nerve fiber distribution in normal young adults. AB - PURPOSE. To determine the anatomic variations in the peripapillary retinal nerve fiber layer (RNFL) thickness distribution and the relationship between these anatomic variations and other ocular variables. METHODS. A complete ophthalmic examination, including measurement of visual acuity, refraction, and axial length, was performed on 269 subjects with no ophthalmic abnormalities. Further, fundus photographs and optic disc cube scans of the subjects' eyes were obtained with a fundus camera and spectral domain OCT (Cirrus HD-OCT; Carl Zeiss Meditec, Inc., Dubin, CA), respectively. The distance between the foveola and the center of the optic nerve head was measured. The correlations of the angles of the peaks in the RNFL thickness profile with the axial length, spherical equivalent of refractive error (SE), and distance between the foveola and optic disc center were analyzed by simple linear regression. RESULTS. Considerable interindividual variations were found in the angles of the peaks in the RNFL thickness profile. Further, the angles in the eyes in each individual showed significant differences. The angles of the superior and inferior first peak correlated significantly with the SE, axial length, and distance between the foveola and optic disc center. CONCLUSIONS. Subjects with increased distance between the foveola and optic disc center are likely to have a temporal shift in peak RNFL thickness. RNFL profiles with horizontally deviated peak RNFL thickness differ considerably from the normative data provided with the HD-OCT system. The variations in RNFL thickness profiles should be taken into account. PMID- 20164449 TI - Inhibition of histone deacetylase protects the retina from ischemic injury. AB - PURPOSE. The pathogenesis of retinal ischemia results from a series of events involving changes in gene expression and inflammatory cytokines. Protein acetylation is an essential mechanism in regulating transcriptional and inflammatory events. The purpose of this study was to investigate the neuroprotective action of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) in a retinal ischemic model. METHODS. To investigate whether HDAC inhibition can reduce ischemic injury, rats were treated with TSA (2.5 mg/kg intraperitoneally) twice daily on days 0, 1, 2, and 3. Seven days after ischemic injury, morphometric and electroretinographic (ERG) analyses were used to assess retinal structure and function. Western blot and immunohistochemical analyses were used to evaluate TSA-induced changes in histone-H3 acetylation and MMP secretion. RESULTS. In vehicle-treated animals, ERG a- and b-waves from ischemic eyes were significantly reduced compared with contralateral responses. In addition, histologic examination of these eyes revealed significant degeneration of inner retinal layers. In rats treated with TSA, amplitudes of ERG a- and b waves from ischemic eyes were significantly increased, and normal inner retina morphology was preserved. Ischemia also increased the levels of retinal TNF alpha, which was blocked by TSA treatment. In astrocyte cultures, the addition of TNF-alpha (10 ng/mL) stimulated the secretion of MMP-1 and MMP-3, which were blocked by TSA (100 nM). CONCLUSIONS. These studies provide the first evidence that suppressing HDAC activity can protect the retina from ischemic injury. This neuroprotective response is associated with the suppression of retinal TNF-alpha expression and signaling. The use of HDAC inhibitors may provide a novel treatment for ischemic retinal injury. PMID- 20164451 TI - Retinal adaptability loss in serous retinal detachment with central serous chorioretinopathy. AB - PURPOSE: To investigate the functional characteristics of the detached retina on a serous retinal detachment (SRD) in eyes with central serous chorioretinopathy (CSC) with spared visual acuity. METHODS: Multifocal electroretinograms (mfERGs) were recorded with a long recording time of 14 minutes, 34 seconds, to obtain accurate measurement of the second-order kernel (K2.1), an index of functional adaptability of the retina, from seven eyes with CSC (visual acuity, >or=1.0). The first-order kernel (K1) and the K2.1, elicited by stimulating the area of the SRD, were compared with those from the corresponding areas in eyes of 15 age matched volunteers (controls) and in 6 eyes of patients with diabetic retinopathy (DR) that have been reported to have a K2.1 attenuation. RESULTS: K2.1 was essentially flat in the SRD eye. The K2.1 amplitude and log-scaled amplitude ratio of K2.1 to K1 (K2.1/K1) were severely reduced (to <95% confidence interval [CI] of control levels) in all eyes. The value of K2.1/K1 of the SRD was less than that in any of the control and DR eyes. K1 was moderately reduced but was not smaller than the 95% CI of control eyes. The mfERGs from the area without the SRD and those from the fellow eyes did not differ significantly from those in control eyes. CONCLUSIONS: A possible cause of the flat K2.1 observed on the SRD is the separation of the sensory retina. A substantial disparity between the recovery of cones and rods could contribute to the loss of retinal adaptability, resulting in the flat K2.1 as well as the unique visual impairments in CSC eyes. PMID- 20164450 TI - Somatic mitochondrial DNA deletions accumulate to high levels in aging human extraocular muscles. AB - PURPOSE. Mitochondrial function and the presence of somatic mitochondrial DNA (mtDNA) defects were investigated in extraocular muscles (EOMs) collected from individuals covering a wide age range, to document the changes seen with normal aging. METHODS. Cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) histochemistry was performed on 46 EOM samples to determine the level of COX deficiency in serial cryostat muscle sections (mean age, 42.6 years; range, 3.0 96.0 years). Competitive three-primer and real-time PCR were performed on single fiber lysates to detect and quantify mtDNA deletions. Whole-genome mitochondrial sequencing was also performed to evaluate the contribution of mtDNA point mutations to the overall mutational load. RESULTS. COX-negative fibers were seen in EOMs beginning in the third decade of life, and there was a significant age related increase: <30 years, 0.05% (n = 17); 30 to 60 years, 1.94% (n = 13); and >60 years, 3.34% (n = 16, P = 0.0001). Higher levels of COX deficiency were also present in EOM than in skeletal muscle in all three age groups (P < 0.0001). Most of the COX-negative fibers harbored high levels (>70%) of mtDNA deletions (206/284, 72.54%) and the mean deletion level was 66.64% (SD 36.45%). The mutational yield from whole mitochondrial genome sequencing was relatively low (1/19, 5.3%), with only a single mtDNA point mutation identified among COX negative fibers with low deletion levels < or =70%. CONCLUSIONS. The results show an exponential increase in COX deficiency in EOMs beginning in early adulthood, which suggests an accelerated aging process compared with other postmitotic tissues. PMID- 20164452 TI - Detection of subclinical keratoconus by using corneal anterior and posterior surface aberrations and thickness spatial profiles. AB - PURPOSE. To assess the suitability of corneal anterior and posterior surface aberrations and thickness profile data for discrimination between eyes with early keratoconus (KC), fellow eyes of eyes with early KC, and normal eyes. METHODS. Thirty-two eyes (group 1) of 25 patients were newly diagnosed with KC; 17 eyes of 17 patients (group 2) were asymptomatic fellow eyes without clinical signs of KC. One hundred twenty-three healthy eyes of 69 patients were negative control eyes (group 3). Zernike coefficients from anterior and posterior surfaces, data from corneal thickness spatial profiles, and output values of discriminant functions based on wavefront and pachymetry data were assessed by receiver operating characteristic (ROC) curve analysis for their usefulness in discriminating between KC (groups 1, 2) eyes and control eyes. RESULTS. Vertical coma (C(3)(-1)) from the anterior surface was the coefficient with the highest ability to discriminate between groups 2 and 3 (area under the ROC curve [A(z)ROC] = 0.980; cutoff, -0.2 microm). For posterior wavefront coefficients and pachymetry data, A(z)ROC values were lower. Constructing discriminant functions from Zernike coefficients increased A(z)ROC values. The function containing first-surface data reached an A(z)ROC of 0.993; the functions containing posterior surface or pachymetry data had lower A(z)ROC values (0.932 and 0.903, respectively). The function with anterior, posterior, and pachymetry data reached an A(z)ROC of 1.0. CONCLUSIONS. Corneal wavefront and pachymetry data enabled highly accurate distinction of eyes with subclinical keratoconus from normal eyes. Posterior aberrations and thickness spatial profile data did not markedly improve discriminative ability over that of anterior wavefront data alone. PMID- 20164453 TI - Glutamate stimulation of retinal ganglion cells in normal and s334ter-4 rat retinas: a candidate for a neurotransmitter-based retinal prosthesis. AB - PURPOSE. To investigate the suitability of glutamate as a potential agent for a neurotransmitter-based retinal prosthesis. METHODS. Retinal ganglion cells (RGCs) from P35-70 albino Sprague-Dawley (normal) and P60-254 S334ter-4 (photoreceptor degeneration) rats were recorded extracellularly in flattened eye cup preparations, to assess their responses to glutamate, applied locally via micropipettes. RESULTS. Brief local application of glutamate effectively excited RGCs in both normal and degenerated retinas. Epiretinal surface application of glutamate was less likely to excite RGCs than was subsurface application (20 microm below the epiretinal surface). Glutamate evoked RGC firing rates, and the response patterns were similar for epiretinal surface and subsurface applications. Subsurface application of 2 mM glutamate effectively excited cells within 130 microm of the ejection sites. Response latencies averaged 281 ms and were significantly longer for OFF RGCs than for ON RGCs in normal retinas (P = 0.025). Suppression of activity was observed at shorter latencies ( approximately 100 ms) after glutamate application in most of the spontaneously active RGCs. Responses to each glutamate application were similar, and the duration of activity was directly dependent on the duration of application. RGC responses varied from recurrent high-frequency bursts to sustained firing at rates above 40 spikes/s, in normal and degenerated retinas. Paired, sequential applications of glutamate evoked two distinguishable responses, with interstimulus intervals as low as 200 ms. Overall, RGC response sensitivity to glutamate was similar in normal and degenerated retinas. CONCLUSIONS. Glutamate is an excellent candidate for a neurotransmitter-based retinal prosthesis, as its local application effectively stimulates RGCs with high spatial and temporal resolution. PMID- 20164454 TI - Treating amblyopia with liquid crystal glasses: a pilot study. AB - PURPOSE. To evaluate the use of liquid crystal glasses (LCG) for the treatment of amblyopia caused by refractive errors, strabismus, or both. METHODS. In this noncomparative, prospective, interventional case series, 28 children (age range, 4-7.8 years) with monocular amblyopia participated, of which 24 completed the study. In the LCG, the occluding and nonoccluding phases of the flicker were electronically set in all patients at a fixed rate. The rate was set so that accumulated occlusion was 5 hours during 8 hours' weartime. Occlusion was applied only to the good eye. All 24 children were followed up regularly for 9 months. Best corrected VA for distance and near, fixation patterns, and binocular function were measured. VA for distance was measured with the Snellen chart and for near with the Rossano/Weiss chart. RESULTS. Mean VA for distance at the end of the study (after 9 months) was 0.59 (SD, 0.16) compared with 0.27 (SD, 0.09) at the beginning (P < 0.001). Most of the children (92%) complied well with the treatment. (Good compliance was defined as wearing the LCG for at least 8 hours per day.) Stereopsis at the end of treatment was good (better than 60 sec arc) in 21% of the children compared with 8% at the beginning. No serious adverse events were recorded. CONCLUSIONS. The use of LCG in patients with amblyopia yielded an improvement in near and distance VA and in stereopsis. Treatment was well accepted by children and parents. PMID- 20164455 TI - Simultaneous measurement of tear film dynamics using wavefront sensor and optical coherence tomography. AB - PURPOSE. To investigate tear film dynamics using simultaneous measurements of ocular aberrations and lower tear meniscus. METHODS. Simultaneous measurements of wavefront aberration and lower tear meniscus were performed for 11 normal eyes and 7 eyes with short tear film break-up time (SBUT) dry eye, with a tear film break-up time shorter than 5 seconds, using a wavefront sensor and an anterior segment optical coherence tomography (OCT). During the measurement, the subjects were instructed to blink every 6 seconds for a total of 30 seconds. From the measured aberration, root mean square (RMS) wavefront error and volume modulation transfer function (vMTF) induced by changes in tear film dynamics were calculated for a 5-mm pupil. Lower tear meniscus height (TMH) and area (TMA) were estimated from the cross-sectional OCT images of lower tear meniscus. RESULTS. There was a positive correlation between RMS and tear meniscus dimensions and a negative correlation between vMTF and tear meniscus in both groups. There were moderate negative correlations between the postblink initial RMS change and baseline TMH (R = -0.61) and TMA (R = -0.54) in SBUT dry eyes that were stronger than in normal eyes (R = -0.37, R = -0.38). CONCLUSIONS. Tear meniscus dimensions increase with RMS over time, and tear quantity before blink has a significant role in maintaining initial optical integrity, especially in SBUT dry eye. Simultaneous measurement of optical quality and tear meniscus has the potential to improve understanding of tear stability in normal eyes and dry eyes. PMID- 20164456 TI - Targeting immune privilege to prevent pathogenic neovascularization. AB - PURPOSE. Current studies suggest that the immune system plays a critical role in blinding eye disorders. The eye is an immune-privileged site, and FasL expression is a major part of that mechanism because Fas/FasL interactions regulate inflammation and neovascularization, preventing damage to delicate ocular structures. These studies were undertaken to test the idea that modulating immune privilege might be an effective therapeutic approach to pathogenic angiogenesis in the eye. METHODS. C57BL/6 mice or FasL-defective B6-gld mice were laser treated to induce choroidal neovascularization (CNV). Mice were injected with cytotoxic FasL in the vitreous cavity or were treated with oral doxycycline in the drinking water. They were evaluated for CNV 7 days later. In some experiments eye tissue was harvested and evaluated for FasL expression, macrophage influx by immunohistochemistry, and release of sFasL. RESULTS. Injection of cytotoxic FasL successfully prevented neovascularization in a mouse model of CNV. Oral doxycycline increased functional FasL in the eye and substantially inhibited neovascularization. Doxycycline treatment increased FasL expression on the RPE cells and reduced circulating and tissue-associated sFasL. Treatment was ineffective in B6-gld mice, demonstrating that CNV inhibition was mediated by FasL. CONCLUSIONS. Targeting immune privilege using cytotoxic molecules or by increasing expression of the proapoptotic protein FasL may be a viable approach to treating neovascular eye disease. PMID- 20164457 TI - Identification of the IRXB gene cluster as candidate genes in severe dysgenesis of the ocular anterior segment. AB - PURPOSE: Anterior segment ocular dysgenesis (ASOD) is a broad heterogeneous group of diseases detectable at the clinical and molecular level. In a patient with bilateral congenital ASOD including aniridia and aphakia, a complex chromosomal rearrangement, inv(2)(p22.3q12.1)t(2;16)(q12.1;q12.2), was characterized at the molecular level, to identify candidate genes implicated in ASOD. METHODS: After negative sequencing of the PAX6, FOXC1, and PITX2 genes, we used fluorescence in situ hybridization (FISH) and Southern blot analysis to characterize the chromosomal breakpoints. Candidate genes were selected, and in situ tissue expression analysis was performed on human fetuses and embryos. RESULTS: Molecular analyses showed that the 16q12.2 breakpoint in this rearrangement occurs in a 625-bp region centromeric to the IRX3 gene, which belongs to the IRXB cluster. In situ hybridization expression studies showed that during early human embryonic development, the IRX3 gene is expressed in the anterior segment of the eye. Of interest, it has been shown previously that a highly conserved noncoding region (HCNCR) is located 300 kb centromeric to the IRX3 gene and induces, in a murine transgenic assay, an expression pattern fitting that of the IRX3 gene. CONCLUSIONS: The authors propose that the 16q12.2 breakpoint of this complex translocation is causally related to the ocular anterior segment dysgenesis observed in this patient. This translocation is assumed to separate the HCNCR from the IRXB cluster genes, thus deregulating the IRXB cluster and leading to the ASOD observed by a positional effect. PMID- 20164458 TI - Effects of intracranial trochlear neurectomy on the structure of the primate superior oblique muscle. AB - PURPOSE. Although cyclovertical strabismus in humans is frequently attributed to superior oblique (SO) palsy, anatomic effects of SO denervation have not been studied. Magnetic resonance imaging (MRI) and orbital histology was used to study the effects of acute trochlear (CN4) denervation on the monkey SO. METHODS. Five juvenile macaque monkeys were perfused with formalin for 5 weeks: 15 months after unilateral or bilateral 10-mm intracranial trochlear neurectomy. Denervated and fellow orbits were imaged by MRI, embedded whole in paraffin, serially sectioned at 10-mum thickness, and stained with Masson trichrome. Whole muscle and individual fiber cross sections were quantified in SO muscles throughout the orbit and traced larger fibers in one specimen where they were present. RESULTS. MRI demonstrated marked reduction in midorbital cross section in denervated SO muscles, with anterior shift of SO mass preserving overall volume. Muscle fibers exhibited variable atrophy along their lengths. Denervated orbital layer (OL) fiber cross sections were slightly but significantly reduced from control at most anteroposterior locations, but this reduction was much more profound in global layer (GL) fibers. Intraorbital and intramuscular CN4 were uniformly fibrotic. In one animal, there were scattered clusters of markedly hypertrophic GL fibers that exhibited only sparse myomyous junctions only anteriorly. CONCLUSIONS. CN4 denervation produces predominantly SO GL atrophy with relative OL sparing. Overall midorbital SO atrophy was evident by MRI as early as 5 weeks after denervation, as denervated SO volume shifted anteriorly. Occasional GL fiber hypertrophy suggests that at least some SO fibers extend essentially the full muscle length after trochlear neurectomy. PMID- 20164460 TI - Morphologic photoreceptor abnormality in occult macular dystrophy on spectral domain optical coherence tomography. AB - PURPOSE. To investigate morphologic photoreceptor layer abnormalities and their correlation with visual function in occult macular dystrophy (OMD), by using spectral-domain optical coherence tomography (SD-OCT). METHODS. This observational case series included 18 eyes of 9 patients with OMD. All patients underwent an ophthalmic evaluation, which included a fundus examination, fluorescein angiography, full-field electroretinography (ERG), multifocal ERG, time-domain optical coherence tomography (TD-OCT), and visual field testing. Morphologic photoreceptor layer abnormalities of the retinal layers were investigated with SD-OCT. The structure-function relationship was investigated regarding visual acuity, symptom duration, and multifocal ERG RESULTS: RESULTS. Best corrected visual acuity ranged from 20/200 to 20/20. Four patients had a symmetric decline of acuity in both eyes (20/200-20/100), and five had unilateral vision impairment (20/200-20/50). TD-OCT showed foveal thinning in all patients, but revealed no other retinal layer abnormality. In 15 eyes of 8 patients, SD-OCT demonstrated a well-defined disruption of the inner segment-outer segment (IS-OS) junction of the photoreceptors and of the Verhoeff membrane (cone outer segment tips). SD-OCT showed that three of five patients with presumed unilateral OMD had bilateral OMD after initial or follow-up examinations. Degrees of abnormality in the photoreceptor layer varied and correlated with visual acuity and symptom duration. CONCLUSIONS. SD-OCT can demonstrate the disruption of photoreceptors in most patients with OMD and the morphologic changes on SD-OCT correlate with visual function and disease progression. These morphologic abnormalities can be an important feature and cause of vision loss in patients with OMD. PMID- 20164459 TI - Spectrum of rhodopsin mutations in French autosomal dominant rod-cone dystrophy patients. AB - PURPOSE. To identify the prevalence of rhodopsin (RHO) mutations in French patients with autosomal dominant rod-cone dystrophies (adRPs). Methods. Detailed phenotypic characterization was performed, including precise family history, best corrected visual acuity with the ETDRS chart, slit lamp examination, kinetic and static perimetry, full-field and multifocal electroretinography (ERG), fundus autofluorescence imaging (FAF), and optical coherence tomography (OCT). For genetic diagnosis, genomic DNA of 79 families was isolated by standard METHODS: The coding exons and flanking intronic regions of RHO were PCR amplified, purified, and sequenced in the index patient. RESULTS. Of this French adRP sample, 16.5% carried an RHO mutation. Three different families showed a novel mutation (p. Leu88Pro, p.Met207Lys and p.Gln344Pro), while ten unrelated families showed recurrent, previously published mutations (p.Asn15Ser, p.Leu131Pro, p.Arg135Trp, p.Ser334GlyfsX21 and p.Pro347Leu). All mutations co-segregated with the phenotype within a family, and the novel mutations were not identified in control samples. CONCLUSIONS. This study revealed that the prevalence of RHO mutations in French adRP patients is in accordance with that in other studies from Europe. Most of the changes identified herein reflect recurrent mutations, within which p.Pro347Leu substitution is the most prevalent. Nevertheless, almost one fourth of the changes are novel, indicating that, although RHO is the first gene implicated and probably the most studied gene in RP, it is still important performing mutation analysis in RHO to detect novel changes. The detailed phenotype-genotype analyses in all available family members deliver the basis for therapeutic approaches in those families. PMID- 20164461 TI - Treatment of experimental autoimmune uveoretinitis with intravitreal injection of tacrolimus (FK506) encapsulated in liposomes. AB - PURPOSE. To evaluate the effects of intravitreal injection of liposomes encapsulating tacrolimus (FK506) on experimental autoimmune uveoretinitis (EAU) in Lewis rats. METHODS. Liposomes containing tacrolimus were prepared by reverse phase evaporation vesicles. EAU was induced in Lewis rats by subcutaneous injection of interphotoreceptor retinoid-binding protein R16 peptide emulsified in adjuvant. Ten days later, rats were intravitreally injected with saline, tacrolimus, tacrolimus-loaded liposomes, or unloaded liposomes. Clinical signs of inflammation and ocular histologic sections were observed and graded. Retinal function was evaluated by electroretinography (ERG). Tacrolimus concentration was determined in the vitreous body and serum by ELISA. Ocular biodistribution of rhodamine-conjugated liposomes containing tacrolimus (tacrolimus-Rh-lip) was analyzed with a laser scanning confocal microscope. To evaluate the systemic effect of intravitreally injected tacrolimus, delayed-type hypersensitivity (DTH) and lymphocyte proliferation assay (LPA) responses were detected. RESULTS. Treatment of EAU with intravitreal injection of liposomal tacrolimus significantly reduced intraocular inflammation and markedly inhibited the development of EAU, as determined in clinical and histopathologic analyses. No toxic effects could be detected as evaluated by ERG. The concentration of tacrolimus in ocular fluids remained for as long as 14 days after liposomal injection of tacrolimus. Confocal microscopy showed a transretinal distribution of the liposomal particles. DTH and LPA responses were not impaired in liposomal tacrolimus-treated rats. CONCLUSIONS. Intravitreal injection of liposomal tacrolimus was highly effective in suppressing the process of EAU without any side effects on retinal function or systemic cellular immunity. This treatment may represent a new option for the management of intraocular inflammation. PMID- 20164462 TI - Distribution of ocular perfusion pressure and its relationship with open-angle glaucoma: the singapore malay eye study. AB - PURPOSE. To describe the distribution of ocular perfusion pressure and its relationship with open-angle glaucoma (OAG) in a Malay population. METHODS. This was a population-based, cross-sectional study comprising 3280 (78.7% response) ethnic Malays. Intraocular pressure (IOP) was measured with Goldmann applanation tonometry. Systolic and diastolic blood pressure (SBP and DBP) was measured with a digital automatic blood pressure monitor. Mean ocular perfusion pressure (MOPP) = (2/3)(mean arterial pressure - IOP), where mean arterial pressure (MAP) = DBP + (1/3)(SBP - DBP), systolic perfusion pressure (SPP) = SBP - IOP, and diastolic perfusion pressure (DPP) = DBP - IOP, was calculated. The diagnosis of OAG was based on International Society for Geographical and Epidemiologic Ophthalmology criteria. RESULTS. A total of 3261 persons (mean age, 58.7 +/- 11 years, including 131 [4.0%] cases of OAG) were available for analyses. Among persons without glaucoma, the mean +/- SD IOP, MOPP, SPP, and DPP were 15.3 +/- 3.5, 52.8 +/- 9.3, 131.5 +/- 23.3, and 64.5 +/- 11.3 mm Hg, respectively. Among persons with OAG, the corresponding values were 16.8 +/- 5.9, 51.6 +/- 10.2, 134.5 +/- 24.6, and 61.4 +/- 11.5 mm Hg, respectively. In multiple logistic regression models adjusting for IOP, age, sex, and IOP- and BP-lowering treatments, OAG risk was significantly higher in participants with DBP, MOPP, or DPP in the lowest quartile (Q1) than in participants in the highest quartile (Q4) (Q1 vs. Q4: odds ratio [OR], 1.71 [95% confidence interval (CI), 1.04-2.96] for DBP; OR, 1.73 [95% CI, 1.05-3.15] for MOPP; OR, 1.75 [95% CI, 1.02-3.01] for DPP). CONCLUSIONS. Low DBP, low MOPP, and low DPP are independent risk factors for OAG in ethnic Malays, providing further evidence of a vascular mechanism in glaucoma pathogenesis across different populations. PMID- 20164463 TI - Mitochondrial DNA defects and selective extraocular muscle involvement in CPEO. AB - PURPOSE. Chronic progressive external ophthalmoplegia (CPEO) is a prominent, and often the only, presentation among patients with mitochondrial diseases. The mechanisms underlying the preferential involvement of extraocular muscles (EOMs) in CPEO were explored in a comprehensive histologic and molecular genetic study, to define the extent of mitochondrial dysfunction in EOMs compared with that in skeletal muscle from the same patient. METHODS. A well-characterized cohort of 13 CPEO patients harboring a variety of primary and secondary mitochondrial (mt)DNA defects was studied. Mitochondrial enzyme function was determined in EOM and quadriceps muscle sections with cytochrome c oxidase (COX)/succinate dehydrogenase (SDH) histochemistry, and the mutation load in single muscle fibers was quantified by real-time PCR and PCR-RFLP assays. RESULTS. CPEO patients with mtDNA deletions had more COX-deficient fibers in EOM (41.6%) than in skeletal muscle (13.7%, P > 0.0001), and single-fiber analysis revealed a lower mutational threshold for COX deficiency in EOM. Patients with mtDNA point mutations had a less severe ocular phenotype, and there was no significant difference in the absolute level of COX deficiency or mutational threshold between these two muscle groups. CONCLUSIONS. The more pronounced mitochondrial biochemical defect and lower mutational threshold in EOM compared with skeletal muscle fibers provide an explanation of the selective muscle involvement in CPEO. The data also suggest that tissue-specific mechanisms are involved in the clonal expansion and expression of secondary mtDNA deletions in CPEO patients with nuclear genetic defects. PMID- 20164464 TI - p38{alpha} MAP kinase controls IL-17 synthesis in vogt-koyanagi-harada syndrome and experimental autoimmune uveitis. AB - PURPOSE. Interleukin (IL)-17, which is responsible for the initial influx of leukocytes into the target tissue, was recently described as the main cytokine involved in autoimmune diseases. Vogt-Koyanagi-Harada (VKH) syndrome is a significant cause of noninfectious blindness in the world. Herein the authors aimed at unraveling the involvement of IL-17 in VKH and in experimental autoimmune uveitis, focusing on the signaling pathways involved in IL-17 synthesis. METHODS. Mice were immunized with 161-180 peptide and pertussis toxin. Draining lymph node cells, harvested 21 days after immunization, were cultured in the presence or absence of p38alpha mitogen-activated protein kinase (MAPK) inhibitor (SB203580) and assayed for cytokine production and quantification of CD4(+)IL-17(+) cells. Mice received intraocular injections of SB203580, and disease severity was evaluated by histologic examination of the enucleated eyes at day 21. CD4(+) lymphocytes from MSK-1/2-deficient mice, human CD4(+) cells silenced with MSK1 siRNA, or peripheral blood mononuclear cells (PBMCs) from VKH patients were cultured in the presence or absence of p38alpha MAPK inhibitor and then assayed for IL-17, IFN-gamma, and IL-4 production. RESULTS. The inhibition of p38alpha MAPK fully blocked the synthesis of IL-17 by PBMCs from VKH patients and lymphocytes from EAU mice. The absence of the msk1/2 gene resulted in failure to produce IL-17 by murine and human lymphocytes. Interestingly, intraocular injections of SB203580 in EAU mice did not suppress development of the disease. CONCLUSIONS. These data show that p38alpha MAPK-MSK1/2 is involved in the control of IL-17 synthesis by CD4(+) T cells and that inhibition of p38alpha MAPK in vitro suppresses IL-17 synthesis but that inhibition of this kinase in vivo did not protect from EAU. PMID- 20164465 TI - MET oncogene inhibition as a potential target of therapy for uveal melanomas. AB - PURPOSE. The purposes of this study were to investigate the frequency of MET activation in uveal melanomas (UMs), to study the potential molecular mechanism for its activation, and to assess the utility of MET inhibition as a potential therapy for UM. METHODS. The frequency of MET activation in UMs was studied by using immunohistochemistry and Western blot analysis in 46 primary UMs and six UM cell lines. Sequencing was used for detection of activating mutations in the MET gene, and the effect of selective MET inhibition was assessed by cell proliferation and migration assays. RESULTS. The results showed that the majority (82.5%) of the 46 UMs expressed activated MET protein. Three of the UM cell lines, C918, 92.1, and MEL202, showed strong MET and pMET expression, whereas the other three showed weaker expression. Sequence analysis identified no activating mutations in MET in any of the 22 tumors or in the six UM cell lines. Selective MET blocking showed inhibition of tumor cell proliferation at an IC(50) ranging from 2.5 to 5.2 microM. A significant inhibition of UM cell migration was also observed starting at 1.25 microM. CONCLUSIONS. The results indicate that MET is activated in a significant number of UMs and also that MET activation in UMs is most likely through indirect gene activation rather than copy number alteration or mutation involving the MET gene. MET inhibition could be a target of therapy for UM. PMID- 20164466 TI - Vision-specific distress and depressive symptoms in people with vision impairment. AB - PURPOSE: To determine the unique contribution of vision-specific distress in predicting depressive symptoms in people with vision impairment attending a tertiary eye care clinic. METHODS: In this cross-sectional study, interview administered surveys were conducted with 143 adult patients who had presenting visual acuity <0.3 logMAR. Depressive symptoms were assessed with the Patient Health Questionnaire-9 and vision-specific distress was assessed with the Impact of Vision Impairment (IVI) Questionnaire emotional well-being subscale. In addition, level of restriction of participation in common daily activities due to vision impairment was assessed with the IVI and measures of general physical health and social support were included. RESULTS: Twenty-one (14.7%) of 143 participants reported clinically significant depressive symptoms and an additional 27.3% (n = 39) had mild depressive symptoms. Vision-specific distress was the strongest unique predictor of depressive symptoms (beta = 0.37, P < 0.001), with physical health (beta = -0.22, P < 0.01), age (beta = -0.18, P < 0.05), and experience of a negative life event (beta = 0.15, P < 0.05) also contributing significantly to depressive symptoms. Results also indicated that vision-specific distress mediates the impact of participation restriction due to vision impairment on depressive symptoms. CONCLUSIONS: An assessment of vision specific distress may be a useful tool with which to identify those at risk of depression or in need of early intervention in eye care or rehabilitation settings. Depression treatment approaches or depression prevention strategies for people with vision impairment may benefit from a focus on vision-specific distress. PMID- 20164467 TI - Vascular endothelial growth factor stimulates protein kinase CbetaII expression in chronic lymphocytic leukemia cells. AB - Chronic lymphocytic leukemia (CLL) is a malignant disease of mature B lymphocytes. We have previously shown that a characteristic feature of CLL cells are high levels of expression and activity of protein kinase CbetaII (PKCbetaII), and that this might influence disease progression by modulating signaling in response to B-cell receptor engagement. The aim of the present work was to investigate the factors involved in stimulating PKCbetaII expression in CLL cells. Here we show that the activation of PKCbetaII in CLL cells stimulated with vascular endothelial growth factor (VEGF) can drive expression of the gene for PKCbeta, PRKCB1. We found that this effect of VEGF on PRKCB1 transcription is paralleled by high expression of PKCbetaII protein and therefore probably contributes to the malignant phenotype of CLL cells. Taken together, the data presented in this study demonstrate that VEGF, in addition to its role in providing prosurvival signals, also plays a role in overexpression of PKCbetaII, an enzyme with a specific pathophysiologic role in CLL. PMID- 20164469 TI - A survey of drug information references emergency medicine clinicians utilize for prescribing in pregnant patients. AB - BACKGROUND: Clinicians practicing in Emergency Departments (EDs) using outdated pocket guides and other non-pregnancy-specific references when prescribing in pregnancy may place the pregnancy or fetus at risk. OBJECTIVE: To identify the references that emergency medicine (EM) clinicians use for prescribing in pregnant patients, the prescribing trends when clinicians are given the pregnancy category information, and clinician awareness of access to drug information references. METHODS: This cross-sectional survey was administered to EM clinicians. In part I, clinicians listed the top 3 drug information references that they routinely use in clinical practice. In part II, clinicians ranked their willingness to prescribe a Category A, B, C, D, or X drug using a 5-point Likert scale. In part III, clinicians selected from a list of electronic and print resources those that they consider available to them in the ED to find pregnancy related drug prescribing information. Statistical analyses included frequency distribution and bivariate analysis. RESULTS: Fifty-five clinicians with an average of 5.71 +/- 7.95 years (+/- SD) in the profession completed the survey. The most commonly used references included Micromedex, Tarascon Pocket Pharmacopoeia, and Epocrates (29%, 18%, and 14%, respectively). Ten (18%) respondents stated that they would be willing to prescribe Category C drugs. Among the 5 pregnancy-specific drug information references that are available in our ED, only 20% of EM clinicians stated that these references were available to them. CONCLUSIONS: EM clinicians rely on general references to make prescribing decisions for pregnant patients and are willing to prescribe medications that have data to support safe use in pregnancy. A minority of EM clinicians acknowledged the availability of pregnancy-specific references in the ED. Increased awareness of references that incorporate human data into their pharmacotherapy recommendations is warranted to assist EM clinicians in achieving their goal of prescribing safely in the pregnant patient. PMID- 20164468 TI - CD160 signaling mediates PI3K-dependent survival and growth signals in chronic lymphocytic leukemia. AB - B-cell chronic lymphocytic leukemia (CLL) expresses CD160, a glycosylphosphatidylinositol-linked receptor found on normal natural killer (NK) and T cells, but not B cells. CD160 is a multifunctional molecule in normal lymphocytes, but its role in CLL biology is unknown. In vitro, CLL cells undergo rapid spontaneous apoptosis, which CD160 activation protected against-mean cell viability increased from 67% to 79% (P < .001). This was associated with up regulation of Bcl-2, Bcl-xL, and Mcl-1, but not Bax. As expected from these changes in Bcl-2/Bax and Bcl-xL/Bax ratios, CD160 triggering reduced mitochondrial membrane potential collapse and cytochrome c release. CD160 stimulation also induced DNA synthesis, cell cycle progression, and proliferation. B-cell antigen receptor (BCR)-induced CLL proliferation was generally greater than with CD160, but marked variation was seen. Both BCR and CD160 signaling led to CLL secretion of interleukin-6 (IL-6) and IL-8, although CD160 induced greater increases of IL-6 (51-fold) and IL-8 (15-fold). Survival and activation signals mediated by CD160 showed dose-dependent suppression by phosphoinositide-3 kinase (PI3K) inhibitors. Thus, in vitro, CLL cells can use the CD160 pathway for survival and activation, mimicking CD160 signaling in normal NK and CD8(+) T cells. Establishing the pathophysiologic relevance of these findings may reveal new therapeutic targets. PMID- 20164470 TI - Evaluation of the chronic kidney disease epidemiology collaboration equation for dosing antimicrobials. AB - BACKGROUND: Since the derivation of the Modification of Diet in Renal Disease (MDRD) equation for estimating glomerular filtration rate (GFR), investigators determined that it cannot be used for drug dosing. In 2009, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) derived an equation that was more accurate than the MDRD estimation of GFR. Therefore, questions exist about which method should be preferred in making dosage adjustments for renally eliminated antimicrobials. OBJECTIVE: To determine whether a difference exists when making antimicrobial dosage adjustments in patients with CKD based on estimation of GFR using the CKD-EPI and Cockcroft-Gault equations. METHODS: A database of 409 patients with CKD admitted to a tertiary care facility was used. GFR was calculated using both the CKD-EPI equation(s) and the Cockcroft-Gault equation and compared using correlation and Bland-Altman methodology. Dosage discordance rates of antimicrobials were determined. RESULTS: Average GFRs for all patients using the Cockcroft-Gault and CKD-EPI equations were 34.8 +/- 12 mL/min and 39.9 +/- 13 mL/min, respectively (5.09 [95% CI 4.60 to 5.59]; p < 0.001). The correlation coefficient between the 2 estimations was high (r = 0.91). The Bland Altman plot yielded limits of agreement of 15.3 and -5.1; thus, the CKD-EPI estimation may range from 5.1 mL/min below to 15.3 mL/min above the Cockcroft Gault estimation for 95% of the cases. A discordance rate of 15-25% existed among the recommended dosing adjustments of the selected antimicrobials when comparing the Cockcroft-Gault and CKD-EPI estimations. CONCLUSIONS: Though this study did not determine which equation should be selected to dose adjust antimicrobials, it demonstrated statistically significant differences between the Cockcroft-Gault and CKD-EPI equations. The clinical significance of these differences is uncertain in the absence of data assessing clinical outcomes that result from the use of the discordant doses. Clinical judgment should be employed when making renal dosage adjustments of antimicrobials. PMID- 20164471 TI - Evaluation of the impact of a tele-ICU pharmacist on the management of sedation in critically ill mechanically ventilated patients. AB - BACKGROUND: An organized and uniform approach to managing sedation in critically ill patients has been associated with improved outcomes, but the most effective means of optimizing sedative medication use in clinical practice has not been fully determined. Pharmacist interventions directed at improving sedation guideline compliance have been shown to reduce the duration of mechanical ventilation. OBJECTIVE: To determine the impact that pharmacy staffing configurations that include a tele-ICU pharmacist have on compliance with an intensive care unit (ICU) sedation guideline in critically ill mechanically ventilated patients requiring continuous-infusion sedative medications. METHODS: Compliance with an established ICU sedation guideline, the performance of daily sedative interruptions, and the number of sedative medication-related interventions were evaluated before and after expansion of the ICU pharmacist staffing model to include comprehensive off-hours pharmacist coverage supported with established tele-ICU resources. In both groups, sedation was managed by the primary ICU team. In the intervention group, a pharmacist working in the tele-ICU center performed electronic record audits and made sedative medication recommendations to the primary team. RESULTS: The addition of third shift tele ICU pharmacist support was associated with a significant increase in the percentage of patients who received a daily sedative interruption (45% vs 54%; p < 0.0001). This occurred in the context of significant increases in the total number of ICU pharmacist interventions (36 vs 49.4 per 100 patient days, p < 0.0001), the number of therapeutic interventions (20.4 vs 26.1 per 100 patient days, p < 0.001), and the number of sedative-related interventions (0.9 vs 4.4 per 100 patient days, p < 0.0001). CONCLUSIONS: Tele-ICU resources can be utilized to increase compliance with an established ICU sedation guideline and extend the benefits that daytime ICU clinical pharmacy services provide. Increased ICU pharmacist availability may have additional benefits not measured in this study. PMID- 20164472 TI - The role of pramlintide for weight loss. AB - OBJECTIVE: To evaluate the weight-loss effects of pramlintide. DATA SOURCES: A literature search was conducted in MEDLINE (1950-October week 4, 2009), International Pharmaceutical Abstracts (1970-October 2009), and Evidence Based Medicine Database (1991-2009 week 44) to identify relevant publications. Key words searched included pramlintide, weight loss, obesity, and overweight. Additional data sources were obtained through a bibliographic review of selected articles. STUDY SELECTION/DATA EXTRACTION: All studies conducted on humans and published in English that examined the effects of pramlintide on body weight as a primary or secondary endpoint were selected for analysis. DATA SYNTHESIS: Pramlintide is a human amylin analog approved by the Food and Drug Administration for use in conjunction with insulin therapy in patients with type 1 or 2 diabetes. In addition to its glucoregulatory actions, pramlintide has been shown to increase satiety and, therefore, decrease caloric intake via a central mechanism. Several studies show that this translates into statistically significant weight loss in overweight or obese patients with type 1 or 2 diabetes; patients with type 1 diabetes lost up to 1.7 kg over 1 year with pramlintide 60 microg 3 times daily, while patients with type 2 diabetes experienced a placebo-subtracted weight loss of up to 3.7 kg after 16 weeks of pramlintide 120-240 microg administered 3 times daily. Preliminary trials assessing the use of pramlintide for weight loss in obese patients without diabetes have demonstrated weight loss of up to 8 kg after 1 year. In all studies, the drug was generally well tolerated, with nausea being the most commonly reported adverse effect. CONCLUSIONS: Based on preliminary evidence, pramlintide facilitates modest weight loss in obese or overweight patients with and without diabetes. However, current trials were limited by inconsistent study design, dosing, and patient population. PMID- 20164473 TI - Internet-based interventions to change health behaviors. PMID- 20164476 TI - The GHESKIO field hospital and clinics after the earthquake in Haiti--dispatch 3 from Port-au-Prince. PMID- 20164474 TI - Effects of coaching patients with lung cancer to report cancer pain. AB - The authors have examined the effects of coaching sensory self-monitoring and reporting on pain-related variables in patients with lung cancer. Randomly assigned to coached or not-coached groups, 215 patients have their interactions with their providers audiotaped and complete study measures pre- and postintervention. Of the 151 patients who complete the 4-week study, those coached are more likely than those not coached to give their providers unsolicited sensory pain information and to mention it before their providers ask for it. The mean number of pain parameters discussed during the audiotaped clinic visit is statistically larger at study end for the coached group. Scores for analgesic adequacy, all pain indices except one, anxiety, depression, and catastrophizing coping are not significantly different. Although coaching increases the amount of pain data communicated to providers by patients with lung cancer, the magnitude is small and does not lead to improved adequacy of analgesics prescribed for each patient's pain level. PMID- 20164475 TI - Weighing risks and benefits of liraglutide--the FDA's review of a new antidiabetic therapy. PMID- 20164478 TI - Recovering from disaster--Partners in Health and the Haitian earthquake. PMID- 20164477 TI - Protecting the children of Haiti. PMID- 20164479 TI - The complexity that killed health care reform (again). PMID- 20164480 TI - Five next steps for a new national program for comparative-effectiveness research. PMID- 20164481 TI - Images in clinical medicine. Prosthetic-valve dehiscence. PMID- 20164482 TI - Looking back, moving forward. PMID- 20164483 TI - A map to bad policy--hospital efficiency measures in the Dartmouth Atlas. PMID- 20164484 TI - Dose of prophylactic platelet transfusions and prevention of hemorrhage. AB - BACKGROUND: We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia. METHODS: We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1x10(11), 2.2x10(11), or 4.4x10(11) platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria). RESULTS: In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25x10(11)) than in the medium-dose group (11.25x10(11)) or the high-dose group (19.63x10(11)) (P=0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001). CONCLUSIONS: Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1x10(11) and 4.4x10(11) platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.) PMID- 20164486 TI - Clinical practice. Small renal mass. PMID- 20164487 TI - Images in clinical medicine. Fulminant ulcerative colitis. PMID- 20164485 TI - Newborn-care training and perinatal mortality in developing countries. AB - BACKGROUND: Of the 3.7 million neonatal deaths and 3.3 million stillbirths each year, 98% occur in developing countries. An evaluation of community-based interventions designed to reduce the number of these deaths is needed. METHODS: With the use of a train-the-trainer model, local instructors trained birth attendants from rural communities in six countries (Argentina, Democratic Republic of Congo, Guatemala, India, Pakistan, and Zambia) in the World Health Organization Essential Newborn Care course (which focuses on routine neonatal care, resuscitation, thermoregulation, breast-feeding, "kangaroo" [skin-to-skin] care, care of the small baby, and common illnesses) and (except in Argentina) in a modified version of the American Academy of Pediatrics Neonatal Resuscitation Program (which teaches basic resuscitation in depth). The Essential Newborn Care intervention was assessed among 57,643 infants with the use of a before-and-after design. The Neonatal Resuscitation Program intervention was assessed as a cluster randomized, controlled trial involving 62,366 infants. The primary outcome was neonatal death in the first 7 days after birth. RESULTS: The 7-day follow-up rate was 99.2%. After birth attendants were trained in the Essential Newborn Care course, there was no significant reduction from baseline in the rate of neonatal death from all causes in the 7 days after birth (relative risk with training, 0.99; 95% confidence interval [CI], 0.81 to 1.22) or in the rate of perinatal death; there was a significant reduction in the rate of stillbirth (relative risk with training, 0.69; 95% CI, 0.54 to 0.88; P=0.003). In clusters of births in which attendants had been randomly assigned to receive training in the Neonatal Resuscitation Program, as compared with control clusters, there was no reduction in the rates of neonatal death in the 7 days after birth, stillbirth, or perinatal death. CONCLUSIONS: The rate of neonatal death in the 7 days after birth did not decrease after the introduction of Essential Newborn Care training of community-based birth attendants, although the rate of stillbirths was reduced. Subsequent training in the Neonatal Resuscitation Program did not significantly reduce the mortality rates. (ClinicalTrials.gov number, NCT00136708.) PMID- 20164488 TI - Case records of the Massachusetts General Hospital. Case 5-2010. A 51-year-old man with HIV infection, proteinuria, and edema. PMID- 20164489 TI - Darbepoetin alfa and chronic kidney disease. PMID- 20164490 TI - Vaccination against HPV-16 for vulvar intraepithelial neoplasia. PMID- 20164491 TI - A peptide-based erythropoietin-receptor agonist for pure red-cell aplasia. PMID- 20164492 TI - Rasagiline in Parkinson's disease. PMID- 20164493 TI - Thiazide diuretics. PMID- 20164494 TI - Market exclusivity for biologics. PMID- 20164495 TI - Histopathological features of the kidney after acute renal failure from melamine. PMID- 20164496 TI - Microbial risk markers for childhood caries in pediatricians' offices. AB - Dental caries in pre-school children has significant public health and health disparity implications. To determine microbial risk markers for this infection, this study aimed to compare the microbiota of children with early childhood caries with that of caries-free children. Plaque samples from incisors, molars, and the tongue from 195 children attending pediatricians' offices were assayed by 74 DNA probes and by PCR to Streptococcus mutans. Caries-associated factors included visible plaque, child age, race, and snacking habits. Species were detected more frequently from tooth than tongue samples. Lactobacillus gasseri (p < 0.01), Lactobacillus fermentum, Lactobacillus vaginalis, and S. mutans with Streptococcus sobrinus (all p < 0.05) were positively associated with caries. By multifactorial analysis, the probiotic Lactobacillus acidophilus was negatively associated with caries. Prevotella nigrescens was the only species (p < 0.05) significantly associated with caries by the 'false discovery' rate. Analysis of the data suggests that selected Lactobacillus species, in addition to mutans streptococci, are risk markers for early childhood caries. PMID- 20164497 TI - Local anesthetics inhibit Ca-ATPase in masticatory muscles. AB - Local anesthetics have myotoxic effects and inhibit Ca-ATPase activity and Ca transport in skeletal muscles. Such effects have not been fully elucidated in masticatory muscles. We tested the hypothesis that local anesthetics increase myoplasmic calcium in masticatory muscles by inhibiting Ca-ATPase at a concentration similar to that of dental cartridges. The effects of lidocaine and bupivacaine on Ca-ATPase from rabbit masseter and medial pterygoid muscles were tested with radioisotopic and colorimetric methods. Bupivacaine had an action similar to that of lidocaine on Ca-ATPase activity, but less effect on calcium transport. The pre-exposure of the membranes to the anesthetics enhanced the Ca ATPase activity in the absence of calcium ionophore, supporting their permeabilizing effect. The results demonstrate that amide-type anesthetics do not inhibit calcium binding, but do reduce calcium transport and enzyme phosphorylation by ATP, and suggest that the myoplasmic calcium increase induced by lidocaine and bupivacaine might promote masticatory muscle contraction and eventual rigidity. PMID- 20164498 TI - Persons with cleft lip and palate are looked at differently. AB - There is evidence that persons with cleft lip and palate (CLP) suffer psychosocial consequences as a result of their facial appearance. However, no data exist on how they are perceived by others. Our hypothesis was that CLP faces were looked at differently compared with faces lacking an anomaly. Eye movements of 30 healthy participants were recorded (via an eye-tracking camera) while they viewed photographs of faces with/without a CLP. Subsequently, the faces were rated for appearance, symmetry, and facial expression. When the CLP faces were viewed, there were significantly more initial fixations in the mouth and longer fixations in the mouth and nose regions, compared with reactions when control faces were viewed. Moreover, CLP faces were rated more negatively overall. When faces with CLP were viewed, attention was directed to the mouth and nose region. Together with the negative ratings, this may explain at least some of the social deprivations in persons with CLP, probably due to residual asymmetry. PMID- 20164500 TI - Epidermal growth factor-induced heparanase nucleolar localization augments DNA topoisomerase I activity in brain metastatic breast cancer. AB - Identification of molecular mechanisms responsible for brain metastatic breast cancer (BMBC) is imperative to develop novel therapies. However, current understanding of the molecular circuitry that governs BMBC dissemination remains fragmentary. Heparanase (HPSE) is the only functional mammalian endoglycosidase whose activity correlates with cancer metastasis, angiogenesis, and the reduced postoperative survival of cancer patients, making it an active target for anticancer therapeutics. We hypothesized that human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) activation promotes HPSE function in human BMBC. To address this, we examined HPSE content, activity, and intracellular trafficking in a HER2/EGFR-expressing BMBC model system and show that HPSE is present, functional, and correlates with HER2 status. Further, we showed that EGF induced nucleolar translocation of HPSE in these cells in a dose- and time-dependent manner upon activation of HER2/EGFR. Knockdowns of HER2/EGFR by small interference RNA abolished EGF-induced HPSE nucleolar translocalization. It was also noted that nucleolar HPSE modulates DNA topoisomerase I (Topo I), an enzyme that is highly present in nucleoli, essential for DNA replication and transcription in a variety of tumors, and inhibited by heparan sulfate. Evidence is provided that HPSE can regulate Topo I activity, which subsequently affects BMBC cell proliferation. Finally, we showed that the nucleolar presence of HPSE with Topo I colocalization is detected only in HER2 overexpressing BMBC patient specimens. Altogether, these findings support the notion that HPSE is a critical downstream target of HER2 mechanisms driving BMBC and is potentially relevant for BMBC therapeutic interventions. PMID- 20164501 TI - Sociodemographic and comorbidity profiles of chronic migraine and episodic migraine sufferers. AB - OBJECTIVE: To characterise and compare the sociodemographic profiles and the frequency of common comorbidities for adults with chronic migraine (CM) and episodic migraine (EM) in a large population-based sample. METHODS: The American Migraine Prevalence and Prevention (AMPP) study is a longitudinal, population based, survey. Data from the 2005 survey were analysed to assess differences in sociodemographic profiles and rates of common comorbidities between two groups of respondents: CM (ICHD-2 defined migraine; > or =15 days of headache per month) and EM (ICHD-2 defined migraine; 0-14 days of headache per month). Categories of comorbid conditions included psychiatric, respiratory, cardiovascular, pain and 'other' such as obesity and diabetes. RESULTS: Of 24 000 headache sufferers surveyed in 2005, 655 respondents had CM, and 11 249 respondents had EM. Compared with EM, respondents with CM had stastically significant lower levels of household income, were less likely to be employed full time and were more likely to be occupationally disabled. Those with CM were approximately twice as likely to have depression, anxiety and chronic pain. Respiratory disorders including asthma, bronchitis and chronic obstructive pulmonary disease, and cardiac risk factors including hypertension, diabetes, high cholesterol and obesity, were also significantly more likely to be reported by those with CM. DISCUSSION: Sociodemographic and comorbidity profiles of the CM population differ from the EM population on multiple dimensions, suggesting that CM and EM differ in important ways other than headache frequency. PMID- 20164503 TI - Treating eating disorders: a review of the evidence. PMID- 20164502 TI - Exposure to polycyclic aromatic hydrocarbons (PAHs), mutagenic aldehydes and particulate matter during pan frying of beefsteak. AB - OBJECTIVES: Cooking with gas or electric stoves produces fumes, especially during frying, that contain a range of harmful and potentially mutagenic compounds as well as high levels of fine and ultrafine particles. The aim of this study was to see if polycyclic aromatic hydrocarbons (PAHs) and higher mutagenic aldehydes which were collected in the breathing zone of the cook, could be detected in fumes from the frying of beefsteak. METHODS: The frying was performed in a model kitchen in conditions similar to those in a Western European restaurant kitchen. The levels of PAHs (16 EPA standard) and higher aldehydes (trans,trans-2,4 decadienal, 2,4-decadienal, trans-trans-2,4-nonadienal, trans-2-decenal, cis-2 decenal, trans-2-undecenal, 2-undecenal) were measured during frying on an electric or gas stove with margarine or soya bean oil as the frying fat. The number concentration of particles <100 nm in size (ultrafine) was also measured, as well as the mass concentration of total particulate matter. RESULTS: Levels of naphthalene were in the range of 0.15-0.27 microg/m(3) air. Measured levels of mutagenic aldehydes were between non-detectable and 61.80 microg/m(3) air. The exposure level of total aerosol was between 1.6 and 7.2 mg/m(3) air. Peak number concentrations of ultrafine particles were in the range of 6.0x10(4)-89.6x10(4) particles/cm(3) air. CONCLUSION: Naphthalene and mutagenic aldehydes were detected in most of the samples. The levels were variable, and seemed to be dependent on many factors involved in the frying process. However, according to the present results, frying on a gas stove instead of an electric stove causes increased occupational exposure to some of the components in cooking fumes which may cause adverse health effects. PMID- 20164504 TI - Maximising the treatment outcomes of opioid substitution treatment. PMID- 20164506 TI - Attention problems in primary school affect education achievements at high school. PMID- 20164507 TI - Conners' Teacher Rating Scale has limited ability to predict DSM-IV ADHD in referred schoolchildren. PMID- 20164508 TI - New Alzheimer's disease screening test performs well in UK outpatient settings. PMID- 20164509 TI - Video decision support affects patients' care choices in dementia care planning. PMID- 20164511 TI - Health visitor training reduces risk of postnatal depression 6 months after birth. PMID- 20164510 TI - Antidepressants combined with self-management of pain improves outcomes in people with comorbid pain and depression. PMID- 20164512 TI - School based prevention programme may reduce depressive episodes in adolescents at risk. PMID- 20164513 TI - Group CBT prevents depression in at-risk adolescents. PMID- 20164514 TI - Group therapy does not reduce repeated deliberate self-harm in adolescents. PMID- 20164515 TI - Group CBT reduces child anxiety diagnoses compared with nonspecific group support. PMID- 20164516 TI - Review: pharmacotherapy increases response and reduces symptom severity in paediatric anxiety disorders. PMID- 20164517 TI - CBT improves worry severity in older adults with GAD in primary care. PMID- 20164518 TI - Neurofeedback training improves ADHD symptoms more than attention skills training. PMID- 20164519 TI - Citalopram not effective for repetitive behaviour in autistic spectrum disorders. PMID- 20164520 TI - Haloperidol plus promethazine effective for psychosis induced aggression. PMID- 20164521 TI - Second generation antipsychotics reduce dropout rates compared with first generation antipsychotics. PMID- 20164522 TI - Subcutaneous naltrexone implants reduce opioid use in opiate dependent patients. PMID- 20164523 TI - Review: methadone increases retention and reduces heroin use compared with non pharmacological maintenance. PMID- 20164525 TI - Adding zolpidem to CBT produces limited benefits in persistent insomnia. PMID- 20164524 TI - Review: buprenorphine better than alpha2 adrenergic agonists for managing opioid withdrawal. PMID- 20164526 TI - Review: multiple session early psychological interventions after trauma do not prevent PTSD. PMID- 20164527 TI - Long term antidepressant use linked to increased risk of diabetes. PMID- 20164528 TI - Schizophrenia and comorbid substance abuse substantially increases risks of violent crime. PMID- 20164529 TI - Estimated prevalence of autism spectrum conditions in Cambridgeshire is over 1%. PMID- 20164530 TI - Structural determination and tryptophan fluorescence of heterokaryon incompatibility C2 protein (HET-C2), a fungal glycolipid transfer protein (GLTP), provide novel insights into glycolipid specificity and membrane interaction by the GLTP fold. AB - HET-C2 is a fungal protein that transfers glycosphingolipids between membranes and has limited sequence homology with human glycolipid transfer protein (GLTP). The human GLTP fold is unique among lipid binding/transfer proteins, defining the GLTP superfamily. Herein, GLTP fold formation by HET-C2, its glycolipid transfer specificity, and the functional role(s) of its two Trp residues have been investigated. X-ray diffraction (1.9 A) revealed a GLTP fold with all key sugar headgroup recognition residues (Asp(66), Asn(70), Lys(73), Trp(109), and His(147)) conserved and properly oriented for glycolipid binding. Far-UV CD showed secondary structure dominated by alpha-helices and a cooperative thermal unfolding transition of 49 degrees C, features consistent with a GLTP fold. Environmentally induced optical activity of Trp/Tyr/Phe (2:4:12) detected by near UV CD was unaffected by membranes containing glycolipid but was slightly altered by membranes lacking glycolipid. Trp fluorescence was maximal at approximately 355 nm and accessible to aqueous quenchers, indicating free exposure to the aqueous milieu and consistent with surface localization of the two Trps. Interaction with membranes lacking glycolipid triggered significant decreases in Trp emission intensity but lesser than decreases induced by membranes containing glycolipid. Binding of glycolipid (confirmed by electrospray injection mass spectrometry) resulted in a blue-shifted emission wavelength maximum (approximately 6 nm) permitting determination of binding affinities. The unique positioning of Trp(208) at the HET-C2 C terminus revealed membrane-induced conformational changes that precede glycolipid uptake, whereas key differences in residues of the sugar headgroup recognition center accounted for altered glycolipid specificity and suggested evolutionary adaptation for the simpler glycosphingolipid compositions of filamentous fungi. PMID- 20164531 TI - The N-terminal region of comparative gene identification-58 (CGI-58) is important for lipid droplet binding and activation of adipose triglyceride lipase. AB - In mammals, excess energy is stored in the form of triacylglycerol primarily in lipid droplets of white adipose tissue. The first step of lipolysis (i.e. the mobilization of fat stores) is catalyzed by adipose triglyceride lipase (ATGL). The enzymatic activity of ATGL is strongly enhanced by CGI-58 (comparative gene identification-58), and the loss of either ATGL or CGI-58 function causes systemic triglyceride accumulation in humans and mice. However, the mechanism by which CGI-58 stimulates ATGL activity is unknown. To gain insight into CGI-58 function using structural features of the protein, we generated a three dimensional homology model based on sequence similarity with other proteins. Interestingly, the model of CGI-58 revealed that the N terminus forms an extension of the otherwise compact structure of the protein. This N-terminal region (amino acids 1-30) harbors a lipophilic tryptophan-rich stretch, which affects the localization of the protein. (1)H NMR experiments revealed strong interaction between the N-terminal peptide and dodecylphosphocholine micelles as a lipid droplet-mimicking system. A role for this N-terminal region of CGI-58 in lipid droplet binding was further strengthened by localization studies in cultured cells. Although wild-type CGI-58 localizes to the lipid droplet, the N terminally truncated fragments of CGI-58 are dispersed in the cytoplasm. Moreover, CGI-58 lacking the N-terminal extension loses the ability to stimulate ATGL, implying that the ability of CGI-58 to activate ATGL is linked to correct localization. In summary, our study shows that the N-terminal, Trp-rich region of CGI-58 is essential for correct localization and ATGL-activating function of CGI 58. PMID- 20164532 TI - Weighted iterative reconstruction for magnetic particle imaging. AB - Magnetic particle imaging (MPI) is a new imaging technique capable of imaging the distribution of superparamagnetic particles at high spatial and temporal resolution. For the reconstruction of the particle distribution, a system of linear equations has to be solved. The mathematical solution to this linear system can be obtained using a least-squares approach. In this paper, it is shown that the quality of the least-squares solution can be improved by incorporating a weighting matrix using the reciprocal of the matrix-row energy as weights. A further benefit of this weighting is that iterative algorithms, such as the conjugate gradient method, converge rapidly yielding the same image quality as obtained by singular value decomposition in only a few iterations. Thus, the weighting strategy in combination with the conjugate gradient method improves the image quality and substantially shortens the reconstruction time. The performance of weighting strategy and reconstruction algorithms is assessed with experimental data of a 2D MPI scanner. PMID- 20164533 TI - Development of an MR-compatible SPECT system (MRSPECT) for simultaneous data acquisition. AB - In medical imaging, single-photon emission computed tomography (SPECT) can provide specific functional information while magnetic resonance imaging (MRI) can provide high spatial resolution anatomical information as well as complementary functional information. In this study, we developed a miniaturized dual-modality SPECT/MRI (MRSPECT) system and demonstrated the feasibility of simultaneous SPECT and MRI data acquisition, with the possibility of whole-body MRSPECT systems through suitable scaling of components. For our MRSPECT system, a cadmium-zinc-telluride (CZT) nuclear radiation detector was interfaced with a specialized radiofrequency (RF) coil and placed within a whole-body 4 T MRI system. Various phantom experiments characterized the interaction between the SPECT and MRI hardware components. The metallic components of the SPECT hardware altered the B(0) field and generated a non-uniform reduction in the signal-to noise ratio (SNR) of the MR images. The presence of a magnetic field generated a position shift and resolution loss in the nuclear projection data. Various techniques were proposed to compensate for these adverse effects. Overall, our results demonstrate that accurate, simultaneous SPECT and MRI data acquisition is feasible, justifying the further development of MRSPECT for either small-animal imaging or whole-body human systems by using appropriate components. PMID- 20164534 TI - Geometrical co-calibration of a tomographic optical system with CT for intrinsically co-registered imaging. AB - A mathematical approach for geometric co-calibration of a dual-modal small-animal imaging system is presented. The system comprises an optical imaging setup for in vivo bioluminescence and fluorescence detection, as well as an x-ray CT, both mounted on a common rotatable gantry enabling fully simultaneous imaging at axially overlapping fields-of-view. Geometric co-calibration is performed once by imaging a single cylindrical light-emitting source with both modalities over 360 degrees at two axial positions, respectively. Given the three-dimensional coordinates of the source positions in the reconstructed CT volume data along with their two-dimensional locations projected at the optical detector plane, the following intrinsic system parameters are calculated: (i) the intrinsic geometric parameters of the optical detection system-five parameters for each view and (ii) the relative positional relationship between the optical and CT systems-two parameters for each view. After co-calibration is performed, experimental studies using phantoms demonstrate the high degree of intrinsic positional accuracy between the optical and CT measurements. The most important advantage of this approach is that dual-modal data fusion is accomplished without any post registration strategies. PMID- 20164535 TI - A study of the biological effects of modulated 6 MV radiation fields. AB - The delivery of spatially modulated radiation fields has been shown to impact on in vitro cell survival responses. To study the effect of modulated fields on cell survival, dose response curves were determined for human DU-145 prostate, T98G glioma tumour cells and normal primary AGO-1552 fibroblast cells exposed to modulated and non-modulated field configurations delivered using a 6 MV Linac with multi-leaf collimator. When exposed to uniform fields delivered as a non modulated or modulated configuration, no significant differences in survival were observed with the exception of DU-145 cells at a dose of 8 Gy (p = 0.024). Survival responses were determined for exposure to non-uniform-modulated beams in DU-145 and T98G and showed no deviation from the survival response observed following uniform non-modulated exposures. The results of these experiments indicate no major deviation in response to modulated fields compared to uniform exposures. PMID- 20164536 TI - Temperature change near microbubbles within a capillary network during focused ultrasound. AB - Preformed gas bubbles can increase energy absorption from an ultrasound beam and therefore they have been proposed for an enhancer of ultrasound treatments. Although tissue temperature measurements performed in vivo using invasive thermocouple probes and MRI thermometry have demonstrated increased tissue temperature, the microscopic temperature distribution has not been investigated so far. In this study the transfer of heat between bubbles and tissue during focused ultrasound was simulated. Microbubble oscillations were simulated within a rat cortical microvascular network reconstructed from in vivo dual-photon microscopy images and the power density of these oscillations was used as an input term in the Pennes bioheat transfer equation. The temperature solution from the bioheat transfer equation was mapped onto vascular data to produce a three dimensional temperature map. The results showed high temperatures near the bubbles and slow temperature rise in the tissue. Heating was shown to increase with increasing bubble frequency and insonation pressure, and showed a frequency dependent peak. The goal of this research is to characterize the effect of various parameters on bubble-enhanced therapeutic ultrasound to allow better treatment planning. These results show that the induced temperature elevations have nonuniformities which may have a significant impact on the bio-effects of the exposure. PMID- 20164537 TI - ZAP-70, IgVh, and cytogenetics for assessing prognosis in chronic lymphocytic leukemia. AB - BACKGROUND: New prognostic factors such as IgVh mutational status, ZAP-70 protein expression and cytogenetic abnormalities have shown to offer important prognostic information for patients with chronic lymphocytic leukemia (CLL). Our aim was to evaluate the optimal cut-off for IgVh mutational status, ZAP-70 expression and cytogenetic abnormalities in association with disease progression defined as the need for treatment within 3~years from diagnosis in 170 patients with B-CLL. DESIGN AND METHODS: Receiver operating characteristics (ROC) analysis and multivariate general linear models (GLMs) were used to investigate the most significant cut-off values of these biomarkers and their prognostic impact. RESULTS: Our findings estimated that the optimal cut-off for IgVh mutation status and for ZAP-70 protein expression was 97% and 16.5% respectively and a high concordance between the two was demonstrated. We identified 30% as being the best cut-off for 17p-, 11q- and 6q-. In univariate analysis 17p- was found to be a significant predictor of the event only for the whole population. Multivariate analysis including all biological parameters, identified 11q deletion as the only significant regressor. CONCLUSIONS: We assessed that IgVh mutational status, ZAP 70 protein and 6q- are powerful prognostic markers. Analyses of all these factors revealed that 11q deletion was the strongest predictor of disease progression in B-CLL. PMID- 20164538 TI - Taurine - a possible fingerprint biomarker in non-muscle invasive bladder cancer: A pilot study by 1H NMR spectroscopy. AB - Urinary bladder cancer is a major epidemiological problem that continues to grow each year. It opens avenues for investigative research for the identification of new disease markers and diagnostic techniques. In this pilot study, utility of non-invasive (1)H NMR spectroscopy has been evaluated for probing the metabolic perturbations occurring in non-muscle invasive urinary bladder cancer. (1)H NMR spectra of urine of bladder cancer patients and controls (healthy and urinary tract infection/bladder stone) (n = 103) were acquired at 400MHz. The non overlapping resonances of citrate, dimethylamine, phenylalanine, taurine and hippurate were first identified and then quantitated by (1)H NMR spectra, with respect to an external reference sodium-3-trimethylsilylpropionate (TSP). The concentrations of these metabolites were then statistically analyzed. The cancer patients showed significant (p < 0.05) variations in concentration of hippurate and citrate as compared with healthy controls and benign controls. The significant elevation in concentration of taurine was observed in urine of bladder cancer patients, which was below the sensitivity limit of 400MHz in control cases. However, stages Ta, T1 and carcinoma in situ (CIS) cannot be differentiated on the basis of altered metabolite indices but their composition may reflect the biochemical alterations in metabolism of cancer cells. PMID- 20164539 TI - Diffusion Weighted Magnetic Resonance Imaging of metastatic bone disease: A biomarker for treatment response monitoring. AB - Diffusion Weighted Magnetic Resonance Imaging (DW-MRI) combined with conventional MRI can provide a whole body assessment of metastatic bone disease, improved lesion detection compared to other imaging techniques and a direct quantitative assessment of treatment response. In bone marrow, the presence of fat and bone trabeculae and their changing contributions with disease progression and response to treatment present unique challenges for data acquisition and image interpretation. This article discusses these challenges and reviews the potential of DW-MRI to provide a biomarker of response in metastatic bone disease. PMID- 20164541 TI - A ten markers panel provides a more accurate and complete microsatellite instability analysis in mismatch repair-deficient colorectal tumors. AB - Tumour microsatellite instability (MSI) is useful in identifying patients with hereditary non-polyposis colorectal cancer (HNPCC) with defective DNA mismatch repair (MMR) genes. A reference Bethesda panel has limitations resulting from the inclusion of dinucleotide markers, which are less sensitive and specific for detection of tumours with MMR deficiencies. We developed a multiplex PCR assay with additional four mononucleotide markers and one dinucleotide marker (NR-21, NR-24, BAT-40, TGF-BetaR and D18S58) for a rapid and proper classification of MSI H, MSI-L and MSS colorectal cancers. Two tetranucleotide markers were added to identify sample mix-ups and/or contamination. RESULTS: all the 44 cases test cases were in agreement with previous classification except for three cases: one case MSI-H-Bethesda unstable only for dinucleotides markers shifted to MSI-L category and two cases MSI-L-Bethesda unstable for mononucleotide markers shifted to MSI-H category. Immunohistochemistry analysis revealed that these two MSI-H cases did not expressed hMLH1 and they were found to be methylated at the MLH1 promoter, while the first one that shifted to MSI-L showed MMR protein expression. CONCLUSION: a complete panel of ten markers including four dinucleotide and six mononucleotide microsatellites allows accurate evaluation of tumor MSI status. PMID- 20164540 TI - Analysis of the expression of human tumor antigens in ovarian cancer tissues. AB - Biomarkers for early detection of cancer have great clinical diagnostic potential. Numerous reports have documented the generation of humoral immune responses that are triggered in response to changes in protein expression patterns in tumor tissues and these biomarkers are referred to as tumor associated antigens (TAAs). Using a high-throughput technology, we previously identified 65 proteins as diagnostically useful TAAs by profiling the humoral immune responses in ovarian cancer (OVCA) patients. Here we determined the expression status of some of those TAAs in tissues from OVCA patients. The protein expression patterns of 4 of those 65 antigens, namely NASP, RCAS1, Nijmegen breakage syndrome1 (NBS1) and eIF5A, along with p53 and Her2 (known molecular prognosticators) and two proteins that interact with NBS1, MRE11 and RAD50, were assessed by immunohistochemistry (IHC). NASP and RCAS1 proteins were more frequently expressed in ovarian cancer tissues than with normal ovarian tissue and serous cystadenomas and MRE11 was less frequently expressed. When evaluated simultaneously, only NASP and MRE11 remained statistically significant with sensitivity of 66% and specificity of 89%. None of these proteins' expression levels were prognostic for survival. Together, our results indicate that occurrence of humoral immune responses against some of these TAAs in OVCA patients is triggered by antigen protein overexpression. PMID- 20164542 TI - Applicability of antibody and mRNA expression microarrays for identifying diagnostic and progression markers of early and late stage colorectal cancer. AB - The exact molecular background and the connection between protein and mRNA expression in colorectal cancer (CRC) development and progression are not completely elucidated. Our purposes were the identification of protein markers of colorectal carcinogenesis and progression using protein arrays and validation on tissue microarrays. The connection between antibody and mRNA expression array results was also examined. Using cancerous and adjacent normal samples from 10 patients with early and 6 with advanced CRC, 67 differentially expressed genes were identified between normal and cancerous samples. A marker set containing 6 proteins (CCNA1, AR, TOP1, TGFB, HSP60, ERK1) was developed which could differentiate normal specimen, early and late stage CRC with high sensitivity and specificity. Dukes D stage samples were analyzed on HGU133plus2.0 microarrays. In these samples, mRNA and protein expression of 143 genes showed strong positive correlations (R2>0.8), while a negative correlation (R2>0.9) was found in case of 95 genes. Based on our results a correlation could be established between transcriptome and antibody array results, hence the former may be used as a high capacity screening method before applying antibody arrays containing already planned targets. Antibody microarrays may have a fundamental importance in testing of marker combinations and future application in diagnostics of tumorous diseases. PMID- 20164543 TI - Serum markers of liver fibrosis: combining the BIPED classification and the neo epitope approach in the development of new biomarkers. AB - BACKGROUND: Fibrosis is a central histological feature of chronic liver diseases and is characterized by the accumulation and reorganization of the extracellular matrix. The gold standard for assessment of fibrosis is histological evaluation of a percutaneous liver biopsy. Albeit a considerable effort have been invested in finding alternative non-invasive approaches, these have not been sufficiently successful to replace biopsy assessment. AIM: To identify the extracellular matrix proteins of interest, that as protein degradation fragments produced during extracellular matrix metabolism neo-epitopes, may be targeted for novel biochemical marker development in fibrosis. We used the recently proposed BIPED system (Burden of disease, Investigative, Prognostic, Efficacy and Diagnostic) to characterise present serological markers. METHODS: Pubmed was search for keywords; Liver fibrosis, neo-epitopes, biomarkers, clinical trail, extra cellular matrix, protease, degradation, fragment. RESULTS AND CONCLUSION: Implementation of BIPED categorization in the development and validation of fibrosis biomarkers to simplify and standardize the use of existing and future biomarkers seems advantageous. In addition, a systematic use of the neo-epitope approach, i.e. the quantification of peptide epitopes generated from enzymatic cleavage of proteins during extracellular remodeling, may prove productive in the quest to find new markers of liver fibrosis. PMID- 20164544 TI - Interleukin-6 gene promoter polymorphisms and cardiovascular risk factors. A family study. AB - Interleukin-6 (IL-6) is a cytokine involved in inflammatory process, as well as in glucose and lipid metabolism. Several studies of the biological relevance of IL-6 gene polymorphisms have indicated a relationship with cardiovascular disease. The aim of this study was to assess whether the -174 G/C and -572 G/C of IL-6 gene polymorphisms are associated with cardiovascular risk factors in Mexican families. Ninety members of 30 Mexican families, in which an index case (proband) had obesity, were included in the study. We evaluated the body composition by bioelectrical impedance. Peripheral blood samples were collected to determine biochemical and hematological parameters. High sensitivity C- reactive protein levels were measurement for nephelometric analysis. Screening for both polymorphisms studied was performed by PCR-RFLP. In the parents, both polymorphisms were in Hardy-Weinberg's equilibrium. The genotypes -174 GC/CC were associated with T2D (OR=1.23, IC(95%) 1.01-1.5) and highest levels of hsCRP (p=0.02), whereas genotype -572 GG was associated with T2D (OR=1.24, IC(95%) 1.04 1.47) with an inflammatory state determined by the increase in the leukocyte count (OR=1.24, IC(95%) 1.02-1.51). The genotypes -174 GC/CC and -572 GG may confer susceptibility for the development of subclinical inflammation and type 2 diabetes in Mexican families. PMID- 20164545 TI - A polymorphism of the corticotropin-releasing hormone receptor 2 (CRHR2) and preterm birth. AB - Our aim was to investigate whether a genetic variation in the corticotropin releasing hormone receptor 2 gene might be associated with preterm birth. In this case-control study we evaluated the G/A polymorphism (rs2267717) in intron 2 of the corticotropin-releasing hormone receptor 2 gene in one hundred women with preterm birth and one hundred healthy women with at least one uncomplicated full term pregnancy and no history of preterm birth. No significant correlation was found between the presence of the investigated polymorphism and preterm birth (p=0.9, odds ratio 0.9 [Confidence interval 0.5-1.7]). A dose dependent association of the investigated polymorphism, in women with preterm birth, with gestational age at delivery (p=0.003) and birth weight was observed (p=0.0001). However, no association between IUGR (n=10) with either one of the investigated genotypes (p=0.3) was found. Stratified analysis within case group (i.e. PPROM vs. non-PPROM) revealed no significant difference in genotype distribution (p=0.6). In conclusion, the investigated polymorphism does not increase the risk for preterm birth overall but might modulate the length of pregnancy in a dose dependent fashion in a series of Caucasian women. PMID- 20164546 TI - P2X7 gene polymorphisms and risk assessment for pulmonary tuberculosis in Asian Indians. AB - OBJECTIVE: Pulmonary tuberculosis (PTB) is a leading cause of morbidity and mortality. Macrophages play an important role in the immunopathogenesis of tuberculosis. Extracellular ATP induces macrophage bactericidal activity through activation of the purinergic P2X7 receptor. This case- control study assesses the association of -762 T/C, 1513A/C and 1729T/A P2X7 polymorphisms in patients with PTB and healthy controls to establish association if any with risk of developing the disease. MATERIALS AND METHODS: The genotyping for P2X7 was carried out using PCR and RFLP analysis in 256 individuals, which included 156 active PTB patients and 100 age and sex, matched healthy volunteers with no clinical symptoms or family history of PTB as controls. RESULTS: A chi square test showed a significant difference between the PTB patient and controls for -762 C allele; p=0.0051 (OR 1.6972, CI 95% 1.1839 to 2.4332) and 1729 T allele was found to be positively associated with the PTB; p < 0.0005 (OR- 2.4623, CI 95% 1.6376 to 3.7022). 1513A/C polymorphism did not show any significant difference between the two groups. SIGNIFICANCE: The study revealed a significant association of P2X7 762C allele and P2X7 1729T allele receptor polymorphisms with PTB in Asian Indian population. The use of these alleles as biomarkers for identifying individuals at high risk of developing TB needs to be ascertained. PMID- 20164547 TI - HLA-DR association in papillary thyroid carcinoma. AB - OBJECTIVE: Papillary thyroid carcinoma (PTC) is the most frequent types of thyroid malignancies. Several genes may be involved in susceptibility of thyroid cancer including Human Leukocyte Antigens (HLA). The association of thyroid carcinoma with HLA alleles has been previously studied in other populations and certain HLA alleles were shown to be either predisposing or protective. The aim of this study was to determine the association between HLA-DR and papillary thyroid carcinoma in an Iranian population. DESIGN: HLA-DR antigen frequencies were determined in patients with papillary thyroid carcinoma (N=70) and non related healthy controls (N=180) using PCR -SSP. MAIN OUTCOME: We found that HLA DRB1*04 frequency was significantly higher in our patients compared to the controls [P=0.02, OR; 1.9, 95% CI (1.04-3.57)]. CONCLUSIONS: Our results revealed HLA-DRB1*04 as predisposing factor in papillary thyroid carcinoma in Iranian population. This confirms the previous findings for associations between HLA-DRB1 and differentiated carcinomas in other populations. PMID- 20164548 TI - IkappaBalpha promoter polymorphisms in patients with Behcet's disease. AB - To investigate the role of IkappaBalpha promoter polymorphisms in the development of Behcet's disease, eighty-six patients with Behcet's disease and 120 healthy controls were enrolled in this study. The IkappaBalpha -881A/G, -826C/T, -550A/T, -519C/T, and -297C/T polymorphisms were measured by the method of polymerase chain reaction/ restriction fragment length polymorphism. This study demonstrated that the genotype frequencies of IkappaBalpha -826C/T and -826T/T were significantly higher in the patients with Behcet's disease than in the controls. Both in the dominant and in the recessive models, the patients with Behcet's disease have higher frequencies of the IkappaBalpha -826T containing genotype than the controls. The allele frequency of IkappaBalpha -826T was significantly increased in the patients with Behcet's disease. The frequencies of the IkappaBalpha -881A -826T -550A -519C -297C and IkappaBalpha -881A -826T -550A 519T -297C haplotypes were significantly higher in the patients with Behcet's disease than in the controls. In contrast, the haplotype frequency of IkappaBalpha -881A -826C -550A -519C -297C in the patients with Behcet's disease was significantly decreased. This study also revealed that the Behcet's disease patients with IkappaBalpha -826T/T have higher prevalence of skin lesions than those without IkappaBalpha -826T/T. In summary, the IkappaBalpha -826T allele, IkappaBalpha -881A -826T -550A -519C -297C and IkappaBalpha -881A -826T -550A 519T -297C haplotypes might be associated with susceptibility to Behcet's disease. The IkappaBalpha -826T/T genotype was related to the development of skin lesions in the patients with Behcet's disease. PMID- 20164549 TI - Altered NCAM expression associated with the cholinergic system in Alzheimer's disease. AB - Neurotransmitter system dysfunction and synapse loss have been recognized as hallmarks of Alzheimer's disease (AD). Our hypothesis is that specific neurochemical populations of neurons might be more vulnerable to degeneration in AD due to particular deficits in synaptic plasticity. We have studied, in postmortem brain tissue, the relationship between levels of synaptic markers (NCAM and BDNF), neurochemical measurements (cholinacetyltransferase activity, serotonin, dopamine, GABA, and glutamate levels), and clinical data (cognitive status measured as MMSE score). NCAM levels in frontal and temporal cortex from AD patients were significantly lower than control patients. Interestingly, these reductions in NCAM levels were associated to an ApoE4 genotype. Levels of BDNF were also significantly reduced in both frontal and temporal regions in AD patients. The ratio between plasticity markers and neurochemical measurements was used to study which of the neurochemical populations was particularly associated to plasticity changes. In both the frontal and temporal cortex, there was a significant reduction in the ChAT/NCAM ratio in AD samples compared to controls. None of the ratios to BDNF were different between control and AD samples. Furthermore, Pearson's product moment showed a significant positive correlation between MMSE score and the ChAT/NCAM ratio in frontal cortex (n=19; r=0.526*; p=0.037) as well as in temporal cortex (n=19; r=0.601*; p=0.018) in AD patients. Altogether, these data suggest a potential involvement of NCAM expressing neurons in the cognitive deficits in AD. PMID- 20164550 TI - Isolated and joint effects of tobacco and alcohol consumption on risk of Alzheimer's disease. AB - The roles of smoking and alcohol on the development of Alzheimer's disease (AD) remain unclear. We performed a case-control study on the effects of both exposures before the age of onset of the disease in the cases (and same reference age for their age-matched controls) on disease risk. Interviews were conducted with population controls (n=246) and relatives of cases (n=176) identified through local Alzheimer's Disease Associations. Logistic regression models were built adjusting by gender, age, residence, education, economic situation, employment, and history of dementia in close relatives. Risk of AD was unaffected by any measure of tobacco consumption. Alcohol consumers showed a lower risk of AD than never consumers (adjusted odds ratio, aOR = 0.53, 95% CI 0.32, 0.88), with differences by gender (women aOR =0.48, 95% CI 0.27, 0.84; men aOR=0.80, 95% CI 0.23, 2.80). Mean daily total consumption of alcohol and time consuming alcohol showed increasingly protective dose-response relationships in women. Lower AD risk was observed in alcohol drinkers of both genders who never smoked (aOR= 0.37, 95% CI 0.21, 0.65). All these associations were independent of the presence of apolipoprotein E4 allele(s) in the cases. Although the sample was small for some analyses addressing these interactions, our results suggest a protective effect of alcohol consumption, mostly in non-smokers, and the need to consider interactions between tobacco and alcohol consumption, as well as interactions with gender, when assessing the effects of smoking and/or drinking on the risk of AD. PMID- 20164552 TI - Folic Acid potentiates the effect of memantine on spatial learning and neuronal protection in an Alzheimer's disease transgenic model. AB - Folic acid deficiency and hyperhomocysteinemia potentiate amyloid-beta (Abeta) neuron toxicity. Memantine, an NMDA antagonist used in moderate to severe AD, is considered to be neuroprotective. We propose that folic acid might have a synergistic effect for memantine in protecting neurons from Abeta accumulation. We treated 8-month-old Tg2576 transgenic mice with memantine (30 mg/kg/day) with or without folic acid (8 mg/kg/day) for 4 months. Escape latencies in the Morris water maze were significantly shorter in the folic acid-memantine treatment group Tg(+)_M+F compared to both the non-treatment transgenic controls Tg(+) and the memantine-treatment group Tg(+)_M (both p < 0.05). Analysis of Abeta40 and Abeta42 showed lower brain loads in both treatment groups but this did not reach statistical significance. Histopathology analysis showed that Tg(+)_M+F had lower ratios of neuronal damage than Tg(+) (p < 0.001) and Tg(+)_M (p< 0.005). DNA analysis revealed that in the Tg(+)M_+F group, transcription was upregulated in 72 brain genes involved in neurogenesis, neural differentiation, memory, and neurotransmission compared to the Tg(+)_M group. In conclusion, we found that folic acid may potentiate the effect of memantine on spatial learning and neuronal protection. The benefit of combination therapy may be through co-action on the methylation-controlled Abeta production, and modification of brain gene expression. PMID- 20164553 TI - Radiofrequency fields, transthyretin, and Alzheimer's disease. AB - Radiofrequency field (RF) exposure provided cognitive benefits in an animal study. In Alzheimer's disease (AD) mice, exposure reduced brain amyloid-beta (Abeta) deposition through decreased aggregation of Abeta and increase in soluble Abeta levels. Based on our studies on humans on RF from wireless phones, we propose that transthyretin (TTR) might explain the findings. In a cross-sectional study on 313 subjects, we used serum TTR as a marker of cerebrospinal fluid TTR. We found a statistically significantly positive beta coefficient for TTR for time since first use of mobile phones and desktop cordless phones combined (P=0.03). The electromagnetic field parameters were similar for the phone types. In a provocation study on 41 persons exposed for 30 min to an 890-MHz GSM signal with specific absorption rate of 1.0 Watt/kg to the temporal area of the brain, we found statistically significantly increased serum TTR 60 min after exposure. In our cross-sectional study, use of oral snuff also yielded statistically significantly increased serum TTR concentrations and nicotine has been associated with decreased risk for AD and to upregulate the TTR gene in choroid plexus but not in the liver, another source of serum TTR. TTR sequesters Abeta, thereby preventing the formation of Abeta plaques in the brain. Studies have shown that patients with AD have lowered TTR concentrations in the cerebrospinal fluid and have attributed the onset of AD to insufficient sequestering of Abeta by TTR. We propose that TTR might be involved in the findings of RF exposure benefit in AD mice. PMID- 20164551 TI - Amyloid-beta peptide and oligomers in the brain and cerebrospinal fluid of aged canines. AB - The study of Alzheimer's disease (AD) pathogenesis requires the use of animal models that develop some amount of amyloid pathology in the brain. Aged canines (beagles) naturally accumulate human-type amyloid-beta peptide (Abeta) and develop parallel declines in cognitive function. However, the type and quantity of biochemically extracted Abeta in brain and cerebrospinal fluid (CSF), its link to aging, and similarity to human aging has not been examined systematically. Thirty beagles, aged 4.5-15.7 years, were studied. Abeta40 and Abeta42 were measured in CSF by ELISA, and from SDS and formic acid extracted prefrontal cortex. A sample of the contralateral hemisphere, used to assess immunohistochemical amyloid load, was used for comparison. In the brain, increases in Abeta42 were detected at a younger age, prior to increases in Abeta40, and were correlated with an increased amyloid load. In the CSF, Abeta42 decreased with age while Abeta40 levels remained constant. The CSF Abeta42/40 ratio was also a good predictor of the amount of Abeta in the brain. The amount of soluble oligomers in CSF was inversely related to brain extractable Abeta, whereas oligomers in the brain were correlated with SDS soluble Abeta42. These findings indicate that the Abeta in the brain of the aged canine exhibits patterns that mirror Abeta deposited in the human brain. These parallels support the idea that the aged canine is a useful intermediate between transgenic mice and humans for studying the development of amyloid pathology and is a potentially useful model for the refinement of therapeutic interventions. PMID- 20164554 TI - Controlled memory processes in questionable Alzheimer's disease: a view from neuroimaging research. AB - Alzheimer's disease (AD) is characterized by a progressive loss of controlled cognitive processes, and neuroimaging studies at early stages of AD provide an opportunity to tease out the neural correlates of controlled processes. Accordingly, controlled and automatic memory performance was assessed with the Process Dissociation Procedure in 50 patients diagnosed with questionable Alzheimer's disease (QAD). The patients' brain glucose metabolism was measured using FDG-PET. After a follow-up period of 36 months, 27 patients had converted to AD, while 23 remained stable. Both groups showed a similar decrease in controlled memory processes but preserved automatic processes at entry into the study. Voxel-based cognitive and metabolic correlations showed that a decrease in controlled memory processes was preferentially correlated with lower activity in the dorsomedial prefrontal and posterior cingulate cortices in very early AD patients. In stable QAD patients, reduced controlled performance in verbal memory correlated with impaired activity in the left anterior hippocampal structure. The results demonstrate the central role of a medial frontal-posterior cingulate network for controlled processing of episodic memory in the early stages of AD. PMID- 20164555 TI - Adult neurogenesis: a potential tool for early diagnosis in Alzheimer's disease? AB - Alzheimer's disease (AD) is a devastating age-related neurodegenerative disorder characterized by progressive impairment of cognition and short-term memory loss. The deposition of amyloid-beta (Abeta) 1-42 into senile plaques is an established feature of AD neuropathology. Controversy still exists about the amyloid pathway as the initiating mechanism or a mere consequence of the events leading to AD. Nevertheless, Abeta toxicity has been probed in vitro and in vivo and increased production or decreased clearance of Abeta peptides are reported to play a major role in the development of AD. Treatment of neural stem cells with Abeta in vitro induces neuronal differentiation. Increased neurogenesis has been also described in AD patients as well as in amyloid-beta protein precursor (AbetaPP) transgenic mice. Adult neurogenesis is greatly enhanced in young AbetaPP transgenic mice, before other AD-liked pathologies, and reduced in older animals. This increased neurogenesis at young ages might be the first pathology related to AD, which is detectable long before other harmful manifestation of the disease. Therefore, understanding the mechanisms of Abeta-induced neurogenesis will reveal insights into the pathogenesis of AD and may prove useful as an early AD biomarker. PMID- 20164556 TI - The Herp protein pathway is not involved in the pro-amyloidogenic effect of hyperhomocysteinemia. AB - Diet-induced high circulating levels of homocysteine, also known as hyper homocysteinemia (HHcy), is associated with an acceleration of Alzheimer's disease like amyloidosis. Herp is a homocysteine-responsive stress protein, which has been shown to increase the formation of amyloid-beta (Abeta) via interaction with presenilins in vitro. The aim of our paper was to investigate the functional role that Herp plays in HHcy-induced amyloidosis. Amyloidosis secondary to diet induced HHcy in Tg2576 mice is associated with an increase of Herp protein and mRNA levels. By contrast, no other stress-related proteins are altered by the same diet regimen. Compared to wild type animals, brains from a genetically induced HHcy mouse model did not manifest any significant change in Herp levels. Cells stably over-expressing human AbetaPP Swedish mutant incubated with high levels of homocysteine had an increase in Abeta formation, but no change in Herp level. Finally, over-expression of Herp did not result in any significant modification of Abeta levels. We conclude that the Herp protein pathway is unlikely to be directly involved in the pro-amyloidotic effect of HHcy. PMID- 20164557 TI - Meditation effects on cognitive function and cerebral blood flow in subjects with memory loss: a preliminary study. AB - This preliminary study determined if subjects with memory loss problems demonstrate changes in memory and cerebral blood flow (CBF) after a simple 8-week meditation program. Fourteen subjects with memory problems had an IV inserted and were injected with 250 MBq of Tc-99m ECD while listening to a neutral stimulus CD. They then underwent a pre-program baseline SPECT scan. Then subjects were guided through their first meditation session with a CD, during which they received an injection of 925 MBq ECD, and underwent a pre-program meditation scan. Subjects completed an 8-week meditation program and underwent the same scanning protocol resulting in a post-program baseline and meditation scan. A region of interest (ROI) template obtained counts in each ROI normalized to whole brain to provide a CBF ratio. Baseline and meditation scans and neuropsychological testing were compared before and after the program. The meditation program resulted in significant increases (p< 0.05) in baseline CBF ratios in the prefrontal, superior frontal, and superior parietal cortices. Scores on neuropsychological tests of verbal fluency, Trails B, and logical memory showed improvements after training. This preliminary study evaluated whether an 8-week meditation program resulted in improvements in neuropsychological function and differences in CBF in subjects with memory loss. While the findings are encouraging, there are a number of limitations that can be addressed in future studies with more participants and more detailed analyses. PMID- 20164559 TI - Diagnostic utility of novel MRI-based biomarkers for Alzheimer's disease: diffusion tensor imaging and deformation-based morphometry. AB - We report evidence that multivariate analyses of deformation-based morphometry and diffusion tensor imaging (DTI) data can be used to discriminate between healthy participants and patients with Alzheimer's disease (AD) with comparable diagnostic accuracy. In contrast to other studies on MRI-based biomarkers which usually only focus on a single modality, we derived deformation maps from high dimensional normalization of T1-weighted images, as well as mean diffusivity maps and fractional anisotropy maps from DTI of the same group of 21 patients with AD and 20 healthy controls. Using an automated multivariate analysis of the entire brain volume, widespread decreased white matter integrity and atrophy effects were found in cortical and subcortical regions of AD patients. Mean diffusivity maps and deformation maps were equally effective in discriminating between AD patients and controls (AUC =0.88 vs. AUC=0.85) while fractional anisotropy maps performed slightly inferior. Combining the maps from different modalities in a logistic regression model resulted in a classification accuracy of AUC=0.86 after leave-one-out cross-validation. It remains to be shown if this automated multivariate analysis of DTI-measures can improve early diagnosis of AD in predementia stages. PMID- 20164558 TI - Additional value of CSF amyloid-beta 40 levels in the differentiation between FTLD and control subjects. AB - To determine the additional value of cerebrospinal fluid (CSF)amyloid-beta1-40 (Abeta40) next to amyloid-beta1-42 (beta42), total tau (Tau), and tau phosphorylated at threonine-181 (pTau) to distinguish patients with frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), and controls, we measured CSF levels of Abeta40, Abeta42, pTau, and Tau in 55 patients with FTLD, 60 with AD, and 40 control subjects. Logistic regression was used to identify biomarkers that best distinguished the groups. Additionally, a decision tree (cost=test method; Matlab 7.7) was used to predict diagnosis selecting the best set of biomarkers with the optimal cut-off. Logistic regression showed that Abeta42 and pTau CSF levels provided optimal distinction between AD and FTLD. A combination of Abeta42, Tau, and Abeta40 optimally discriminated FTLD from controls and AD from controls. The decision tree used Abeta42 (cut-off 578 pg/ml) to identify AD (positive predictive value (PPV) 97%), followed by Tau(cut-off 336 pg/ml) to identify FTLD (PPV 67%), and in the last step,Abeta40 (cut-off 10 ng/ml) was used to differentiate controls (PPV68%). Applying CSF Abeta40 levels in the model, the PPV of diagnosis increased to 75% as opposed to 70% when only Abeta42 and Tau were used. CSF Abeta40 levels added to the conventional CSF biomarkers increases the potential to discriminate subjects with dementia from controls. Our findings favor the implementation of CSF Abeta40 in differential diagnosis between FTLD, AD, and control subjects. PMID- 20164560 TI - Joint effect of white matter lesions and hippocampal volumes on severity of cognitive decline: the 3C-Dijon MRI study. AB - Several brain magnetic resonance imaging (MRI) changes are observed in older individuals including white matter lesions (WML), silent brain infarcts (SBI), and cerebral atrophy. Few studies, however, have assessed the combined association of these changes on the severity of future cognitive decline. In the prospective population-based 3C-Dijon MRI study, 1701 non-demented participants aged 65 to 80 years at entry had a brain MRI. Information on WML, hippocampal volumes, SBI presence, and brain parenchymal fraction were obtained. At 4-year follow-up, participants were screened for cognitive decline and dementia. Severity of cognitive decline was defined as none, moderate, or severe calculated from neuropsychological test performance change. The relation between brain MRI markers and longitudinal change in cognition was studied using polytomous logistic regression and multiple linear regression models controlling for potential confounders. Two-by-two interactions were tested including with the apolipoprotein E genotype. At follow-up, 46 participants showed severe cognitive deterioration and 224 participants showed moderate cognitive deterioration. In multivariable analyses, risk of severe cognitive deterioration as well as the cognitive decline rate were significantly increased in participants with higher WML volume (p< 0.01) and smaller hippocampal volume (p< 0.01). The results suggested that WML and hippocampal volumes had a cumulative effect on the future level of cognitive decline. The APOE genotype was found to be an effect modifier of this association. Vascular brain changes and degenerative processes coexist in normal older individuals. The co-occurrence of degenerative and non-degenerative pathologies could strongly affect the course of dementia expression. PMID- 20164561 TI - PBT2 rapidly improves cognition in Alzheimer's Disease: additional phase II analyses. AB - PBT2 is a copper/zinc ionophore that rapidly restores cognition in mouse models of Alzheimer's disease (AD). A recent Phase IIa double-blind, randomized, placebo controlled trial found that the 250 mg dose of PBT2 was well-tolerated, significantly lowered cerebrospinal fluid (CSF) levels of amyloid-beta42, and significantly improved executive function on a Neuro-psychological Test Battery (NTB) within 12 weeks of treatment in patients with AD. In the post-hoc analysis reported here, the cognitive, blood marker, and CSF neurochemistry outcomes from the trial were subjected to further analysis. Ranking the responses to treatment after 12 weeks with placebo, PBT2 50 mg, and PBT2 250 mg revealed that the proportions of patients showing improvement on NTB Composite or Executive Factor z-scores were significantly greater in the PBT2 250 mg group than in the placebo group. Receiver-operator characteristic analyses revealed that the probability of an improver at any level coming from the PBT2 250 mg group was significantly greater, compared to placebo, for Composite z-scores (Area Under the Curve [AUC] =0.76, p=0.0007), Executive Factor z-scores (AUC =0.93, p=1.3 x 10(-9)), and near significant for the ADAS-cog (AUC =0.72, p=0.056). There were no correlations between changes in CSF amyloid-beta or tau species and cognitive changes. These findings further encourage larger-scale testing of PBT2 for AD. PMID- 20164562 TI - Expression of Somatostatin, cortistatin, and their receptors, as well as dopamine receptors, but not of neprilysin, are reduced in the temporal lobe of Alzheimer's disease patients. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive deficit, wherein the impairment of episodic memory is the major hallmark. AD patients exhibit augmented accumulation of amyloid-beta (Abeta) and hyperphosphorylated tau protein in specific brain regions. In addition, several neuropeptides/neurotransmitter axes clearly associated with cognitive processes, Abeta turnover, and tau phosphorylation have also been found to be impaired in AD, such as somatostatin (SST)/cortistatin (CST) and dopamine (DA) systems. However, to date there is no precise quantitative data on the expression of these systems in the human brain of AD and normal patients. Here we measured by quantitative real-time PCR the mRNA levels of SST/CST, their receptors (sst1-5 and DA receptors (drd1-5) in addition to neprilysin (a SST-regulated enzyme involved in Abeta degradation) in three regions of the temporal lobe, one of the cortical regions most severely affected by AD. Our results reveal that some components of SST/CST- and DA-axes are divergently altered in the three areas of AD patients. Despite this region specific regulation, an overall, common reduction of these systems was observed in the temporal lobe of AD patients. Conversely, neprilysin expression was not altered in AD, suggesting that Abeta accumulation observed in AD is due to a lack of neprilysin activation by SST rather than to a reduction of its expression. Collectively, our results define a comprehensive scenario wherein reduction of ssts, drds, and sst ligands SST and CST, could be involved, at least in part, in some of the more important defects observed in AD. PMID- 20164563 TI - Vascular risk aggravates the progression of Alzheimer's disease in a Chinese cohort. AB - To investigate whether vascular risk affects the progression of Alzheimer's disease (AD), 415 AD patients aged 65 years old and over without cerebrovascular diseases were enrolled and administered with a structured interview to assess demography, vascular risk factors, and cognitive and functional status at baseline, and 324 AD patients were followed up annually for 5 years. A mixed random effects regression model was used to identify the association between vascular risk, individual vascular risk factors, and the progression of AD. After adjusting for confounding factors, AD patients with vascular risk had faster cognitive and functional decline rates than the subjects without such risk factors. Individual vascular risk factors including hypertension and diabetes mellitus, transient ischemic attack and cerebrovascular accident during the follow-up were independently associated with the progression of AD. Our findings suggest that vascular risk aggravates the progression of AD and may be involved in the etiologic process of AD. As such, control of vascular risk may slow down the progression of AD. PMID- 20164564 TI - Caffeine, cognitive functioning, and white matter lesions in the elderly: establishing causality from epidemiological evidence. AB - The present study examines the epidemiological evidence for a causal relationship between caffeine consumption and cognitive deterioration in the elderly. Using a population of 641 elderly persons, we examined cognitive functioning, caffeine consumption, magnetic resonance imaging volumetrics, and other factors known to affect cognitive performance. Our findings demonstrate the association between caffeine consumption and lower cognitive change over time to be statistically significant for women only, taking into account multiple confounders, to be dose dependent and temporarily related (caffeine consumption precedes cognitive change). Mean log transformed white matter lesion/cranial volume ratios were found to be significantly lower in women consuming more than 3 units of caffeine per day after adjustment for age (-1.23 SD=0.06) than in women consuming 2-3 units (-1.04 SD=0.04) or one unit or less (-1.04 SD=0.07, -35% in cm3 compared to low drinkers). This observation is coherent with biological assumptions that caffeine through adenosine is linked to amyloid accumulation and subsequently white matter lesion formation. The significant relationship observed between caffeine intake in women and lower cognitive decline is highly likely to be a true causal relationship and not a spurious association. PMID- 20164565 TI - White matter microstructure and apathy level in amnestic mild cognitive impairment. AB - In this study, we assess white matter microstructural deficit correlates of apathy level in 20 patients with amnestic mild cognitive impairment by means of diffusion tensor imaging. Mean diffusivity correlated positively with apathy level in the right temporal portion of the uncinate, middle longitudinal and inferior longitudinal fasciculi and in the parathalamic white matter, the fornix and the posterior cingulum of the right hemisphere. Fractional anisotropy results confirmed evidence of disconnection associated with apathy in all white matter areas except the middle longitudinal fasciculus. These results support the view that alterations in the neural mechanisms underlying apathy level occur in the early phase of degenerative dementias. PMID- 20164566 TI - Caffeine and adenosine. AB - Caffeine causes most of its biological effects via antagonizing all types of adenosine receptors (ARs): A1, A2A, A3, and A2B and, as does adenosine, exerts effects on neurons and glial cells of all brain areas. In consequence, caffeine, when acting as an AR antagonist, is doing the opposite of activation of adenosine receptors due to removal of endogenous adenosinergic tonus. Besides AR antagonism, xanthines, including caffeine, have other biological actions: they inhibit phosphodiesterases (PDEs) (e.g., PDE1, PDE4, PDE5), promote calcium release from intracellular stores, and interfere with GABA-A receptors. Caffeine, through antagonism of ARs, affects brain functions such as sleep, cognition, learning, and memory, and modifies brain dysfunctions and diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, Epilepsy, Pain/Migraine, Depression, Schizophrenia. In conclusion, targeting approaches that involve ARs will enhance the possibilities to correct brain dysfunctions, via the universally consumed substance that is caffeine. PMID- 20164567 TI - The therapeutic effects of the herbal medicine, Juzen-taiho-to, on amyloid-beta burden in a mouse model of Alzheimer's disease. AB - Innate immunity, especially that involving macrophage function, reportedly diminishes with advancing age and in patients with Alzheimer's disease (AD). In this study, we tried to elicit the non-specific activation of peripheral macrophages by oral administration of the herbal medicine Juzen-taiho-to (JTT), to assess its effect as a possible treatment for AD patients. Amyloid-beta protein precursor transgenic mice were used as a model of AD to clarify the effect of JTT. Activated macrophages derived from bone marrow cross the blood brain barrier, and then develop into microglia, which phagocytose aggregated amyloid-beta (Abeta) in senile plaques. Here we show that orally administered JTT increased the number of CD11b-positive ramified microglia in the mouse brain. The immunohistochemical examination of brain sections stained with polyclonal anti Abeta antibody showed reduced Abeta burden, and Abeta levels were also decreased in the insoluble fractions of brain homogenates, as determined by ELISA. Thus, the activation of peripheral macrophages by JTT might be a potential new therapeutic strategy for AD. PMID- 20164569 TI - Colostrinin alleviates amyloid-beta induced toxicity in rat primary hippocampal cultures. AB - Colostrinin (CLN), a complex mixture of proline-rich polypeptides derived from colostrums, can alleviate cognitive decline in early Alzheimer's disease patients. The molecular basis of the action of CLN has been studied in vitro using human neuroblastoma cell lines. The aim of the present study was to use quantitative immunocytochemistry and immunoblotting to investigate the ability of CLN to relieve amyloid-beta (Abeta)-induced cytotoxicity in rat primary hippocampal neuronal cells. Our data confirm that CLN alleviates the effect of Abeta-induced cytotoxicity and causes a significant reduction in the elevated levels of the antioxidant enzyme SOD1. PMID- 20164568 TI - Caffeine protects against disruptions of the blood-brain barrier in animal models of Alzheimer's and Parkinson's diseases. AB - Sporadic Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common neurodegenerative diseases and as such they represent major public health problems. Finding effective treatments for AD and PD represents an unmet and elusive goal largely because these diseases are chronic and progressive, and have a complicated and ill-understood pathogenesis. Although the underlying mechanisms are not fully understood, caffeine, the most commonly ingested psychoactive drug in the world, has been shown in human and animal studies to be protective against AD and PD. One mechanism implicated in the pathogenesis of AD and PD is blood-brain barrier (BBB) dysfunction and we reported recently that caffeine exerts protective effects against AD and PD at least in part by keeping the BBB intact. The present review focuses on the role of BBB dysfunction in the pathogenesis of AD and PD, caffeine's protective effects against AD and PD, and potential mechanisms whereby caffeine protects against BBB leakage. PMID- 20164571 TI - Caffeine, mental health, and psychiatric disorders. AB - Caffeine intake is so common that its pharmacological effects on the mind are undervalued. Since it is so readily available, individuals can adjust their own dose, time of administration and dose intervals of caffeine, according to the perceived benefits and side effects of each dose. This review focuses on human studies of caffeine in subjects with and without psychiatric disorders. Besides the possibility of mild drug dependence, caffeine may bring benefits that contribute to its widespread use. These benefits seem to be related to adaptation of mental energy to the context by increasing alertness, attention, and cognitive function (more evident in longer or more difficult tasks or situations of low arousal) and by elevating mood. Accordingly, moderate caffeine intake (< 6 cups/day) has been associated with less depressive symptoms, fewer cognitive failures, and lower risk of suicide. However, its putative therapeutic effects on depression and ADHD have been insufficiently studied. Conversely, in rare cases high doses of caffeine can induce psychotic and manic symptoms, and more commonly, anxiety. Patients with panic disorder and performance social anxiety disorder seem to be particularly sensitive to the anxiogenic effects of caffeine, whereas preliminary data suggests that it may be effective for some patients with obsessive compulsive disorder (OCD). The threshold for the anxiogenic effect of caffeine is influenced by a polymorphism of the A2A receptor. In summary, caffeine can be regarded as a pharmacological tool to increase energy and effortful behavior in daily activities. More populational (cross-sectional and prospective) and experimental studies are necessary to establish the role of caffeine intake in psychiatric disorders, especially its putative efficacy on depressive mood and cognitive/attentional disorders. PMID- 20164572 TI - In vivo structural neuroanatomy of corpus callosum in Alzheimer's disease and mild cognitive impairment using different MRI techniques: a review. AB - The corpus callosum (CC), which connects the two cerebral hemispheres, is the largest white matter fiber bundle in the human brain. This structure presents a peculiar myelination pattern: it has small diameter fibers, located in the genu, which myelinate much later in normal development, and large diameter fibers of the splenium, which myelinate early in development. Although the pathology of AD mainly involves the cerebral gray matter structure, there is evidence that white matter may also be involved. To illustrate callosal white matter changes in AD pathology, in this review we summarize in vivo imaging studies in humans, focusing on region of interest, voxel-based morphometry, diffusion-weighted imaging, and diffusion tensor imaging techniques. Our aims were to identify where in the CC, when in the different stages of AD, and how callosal changes can be detected with different MRI techniques. Results showed that changes in the anterior (genu and anterior body) as well as in the posterior (isthmus and splenum) portions of the CC might already be present in the early stages of AD. These findings support the hypothesis that two mechanisms, Wallerian degeneration and myelin breakdown, might be responsible for the region-specific changes detected in AD patients. Wallerian degeneration affects the posterior CC subregion, which receives axons directly from those brain areas (temporo-parietal lobe regions) primarily affected by the AD pathology. Instead, the myelin breakdown process affects the later-myelinating CC subregion and explains the earlier involvement of the genu in CC atrophy. PMID- 20164573 TI - Genetic association between CALHM1, 2, and 3 polymorphisms and Alzheimer's disease in a Japanese population. AB - A recent paper reported that a variant (rs2986017) of the calcium homeostasis modulator 1 (CALHM1) gene affects risk for late-onset Alzheimer's disease (AD). This study aims to investigate whether single nucleotide polymorphisms (SNPs) of the CALHM1 gene are associated with AD. SNPs in the genes of two other CALHM subtypes, CALHM2 and CALHM3, were also studied. Our study failed to detect any association between the SNPs of the three genes and AD. Although rs729211 showed marginal association in the APOE4 negative group, the linkage disequilibrium analysis results suggest this to be a false positive. PMID- 20164574 TI - Electrophysiological studies in healthy subjects involving caffeine. AB - We review the electrophysiological studies concerning the effects of caffeine on muscle, lower and upper motor neuron excitability and cognition. Several different methods have been used, such as electromyography, recruitment analysis, H-reflex, transcranial magnetic stimulation (TMS), electroencephalography and event-related potentials. The positive effect of caffeine on vigilance, attention, speed of reaction, information processing and arousal is supported by a number of electrophysiological studies. The evidence in favor of an increased muscle fiber resistance is not definitive, but higher or lower motor neuron excitability can occur as a consequence of a greater excitation of the descending input from the brainstem and upper motor neurons. TMS can address the influence of caffeine on the upper motor neuron. Previous studies showed that cortico-motor threshold and intracortical excitatory and inhibitory pathways are not influenced by caffeine. Nonetheless, our results indicate that cortical silent period (CSP) is reduced in resting muscles after caffeine consumption, when stimulating the motor cortex with intensities slightly above threshold. We present new data demonstrating that this effect is also observed in fatigued muscle. We conclude that CSP can be considered a surrogate marker of the effect of caffeine in the brain, in particular of its central ergogenic effect. PMID- 20164570 TI - Oxidatively modified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Alzheimer's disease: many pathways to neurodegeneration. AB - Recently, the oxidoreductase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), has become a subject of interest as more and more studies reveal a surfeit of diverse GAPDH functions, extending beyond traditional aerobic metabolism of glucose. As a result of multiple isoforms and cellular locales, GAPDH is able to come in contact with a variety of small molecules, proteins, membranes, etc., that play important roles in normal and pathologic cell function. Specifically, GAPDH has been shown to interact with neurodegenerative disease-associated proteins, including the amyloid-beta protein precursor (AbetaPP). Studies from our laboratory have shown significant inhibition of GAPDH dehydrogenase activity in Alzheimer's disease (AD) brain due to oxidative modification. Although oxidative stress and damage is a common phenomenon in the AD brain, it would seem that inhibition of glycolytic enzyme activity is merely one avenue in which AD pathology affects neuronal cell development and survival, as oxidative modification can also impart a toxic gain-of-function to many proteins, including GAPDH. In this review, we examine the many functions of GAPDH with respect to AD brain; in particular, the apparent role(s) of GAPDH in AD-related apoptotic cell death is emphasized. PMID- 20164575 TI - Grb2-mediated alteration in the trafficking of AbetaPP: insights from Grb2-AICD interaction. AB - The amyloid-beta protein precursor (AbetaPP) is processed by various proteases located along the endosomal lysosomal pathway and any alteration in its trafficking would be important in the pathogenesis of Alzheimer's disease (AD). Our current study is based on the clinical evidence that an AbetaPP intracellular domain (AICD) "adaptor" protein, growth factor receptor protein binding protein 2 (Grb2), gets concentrated in neuronal cell bodies in AD patients. Here we show that both endogenous and exogenously transfected Grb2 interact with AbetaPP in Neuro 2A cells. Endogenous Grb2 partially co-localizes to late endosomal compartments along with AbetaPP and AICD. Increase in the concentration of Grb2 confines it in enlarged late endosomes leading to more sequestration of AbetaPP and AICD within these compartments. This confinement of AbetaPP due to Grb2 overexpression affects its turnover by inhibiting its release via exosomal vesicles. As a consequence, the level of intracellular AbetaPP and AICD increases. The effect of Grb2 overexpression has been verified by knocking down Grb2 as well as by overexpressing Grb2 in Grb2 knocked down cells. Having established the Grb2-mediated trafficking of AICD and its impairment, the significance of its consequence has now become apparent in the downstream events of AD pathogenesis. PMID- 20164576 TI - Early stages of pathogenesis in memory impairment during normal senescence and Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive, neurodegenerative brain disease of the elderly characterized by memory loss, cognition, and behavioral abnormalities. Aging is the single most important risk factor and there is no proven therapy. Aging invariably decreases sensory stimuli and impacts on the thalamocortical system and its connectivity to key brain regions. Memory dysfunction in senescence and early AD, a function of acetylcholine decrease, is accompanied with dysfunctional basal forebrain, parietal, prefrontal, and entorhinal cortices, and indeed hippocampus. Cholinergic neurotransmission protects neurons from amyloid-beta production and its toxicity, while cholinergic depletion enhances both. Available data on sleep disordered breathing and genioglossus dysfunction throw light on possible pathogenetic events leading to hypoxemia. Memory disturbances in normal elderly and early AD patients are intimately related to hypoxia, a reduction in blood supply, and glucose hypometabolism in the hippocampus and a number of key brain areas. The current hypothesis on memory impairment in the elderly and Alzheimer's dementia, therefore, underscores age related sensory losses, functional disconnection between strategic brain regions in conjunction with hypoxemia and hypometabolism. On the basis of available data, it is emphasized that (A) decreases in thalamocortical function decreases cholinergic activity and cerebral blood flow, while nocturnally, (B) repeated hypoxic events affect respiratory cholinergic mechanism and respiratory regulation. Consequently, the hypotrophy/atrophy of nucleus solitarius and nucleus ambiguous in pontomedullary junction affect hypoglossal nucleus, genioglossus function, upper airway patency, hypoxia, and cerebral oxygenation. These alterations may cause amyloid-beta deposition extracellularly, and neurofibrillary cytopathology in cholinergic and other neurons intracellularly. PMID- 20164578 TI - The Society for Neuroscience 2009 meeting report, part 4. PMID- 20164577 TI - Prevalent iron metabolism gene variants associated with increased brain ferritin iron in healthy older men. AB - Prevalent gene variants involved in iron metabolism [hemochromatosis (HFE) H63D and transferrin C2 (TfC2)] have been associated with higher risk and earlier age at onset of Alzheimer's disease (AD), especially in men. Brain iron increases with age, is higher in men, and is abnormally elevated in several neurodegenerative diseases, including AD and Parkinson's disease, where it has been reported to contribute to younger age at onset in men. The effects of the common genetic variants (HFE H63D and/or TfC2) on brain iron were studied across eight brain regions (caudate, putamen, globus pallidus, thalamus, hippocampus, white matter of frontal lobe, genu, and splenium of corpus callosum) in 66 healthy adults (35 men, 31 women) aged 55 to 76. The iron content of ferritin molecules (ferritin iron) in the brain was measured with MRI utilizing the Field Dependent Relaxation Rate Increase (FDRI) method. 47% of the sample carried neither genetic variant (IRON-) and 53% carried one and/or the other (IRON+). IRON+ men had significantly higher FDRI compared to IRON- men (p=0.013). This genotype effect was not observed in women who, as expected, had lower FDRI than men. This is the first published evidence that these highly prevalent genetic variants in iron metabolism genes can influence brain iron levels in men. Clinical phenomena such as differential gender-associated risks of developing neurodegenerative diseases and age at onset may be associated with interactions between iron genes and brain iron accumulation. Clarifying mechanisms of brain iron accumulation may help identify novel interventions for age-related neurodegenerative diseases. PMID- 20164579 TI - A novel mutation in the predicted TMIII domain of the PSEN2 gene in an Italian pedigree with atypical Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by accumulation of toxic amyloid-beta (Abeta) in the brain, with neuronal death, and an associated increased Abeta(42/40) ratio. Several mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid-beta precursor protein are involved in the etiology of familial AD (FAD); these mutations alter the Abeta(42/40) ratio and promote apoptosis. We describe an Italian pedigree linked to a novel mutation (S175C) at the third transmembrane domain of PSEN2. Clinical phenotype in these individuals is characterized by fast cognitive decline with progressive memory impairment, early involvement of executive functions, behavioral disturbances, and extrapyramidal signs. PMID- 20164580 TI - In vitro and in vivo activation of astrocytes by amyloid-beta is potentiated by pro-oxidant agents. AB - Alzheimer's disease (AD) is a devastating age-related neurodegenerative disease. Age is the main risk factor for sporadic AD, which is the most prevalent type. Amyloid-beta peptide (Abeta) neurotoxicity is the proposed first step in a cascade of deleterious events leading to AD pathology and dementia. Glial cells play an important role in these changes. Astrocytes provide vital support to neurons and modulate functional synapses. Therefore, the toxic effects of Abeta on astrocytes might promote neurodegenerative changes that lead to AD. Aging reduces astrocyte antioxidant defenses and induces oxidative stress. We studied the effects of Abeta(42) on cultures of human astrocytes in the presence or absence of the following pro-oxidant agents: buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, and FeSO(4), which liberates redox active iron. Pro-oxidant conditions potentiated Abeta toxicity, as shown by the generation of free radicals, inflammatory changes, and apoptosis. Similar treatments were assessed in rats in vivo. A combination of Abeta(40) and Abeta(42) or Abeta(42) alone was infused intracerebroventricularly for 4 weeks. Other animal groups were also infused with BSO and FeSO(4). A long-term analysis that ended 4 months later showed greater cognitive impairment in the Morris water maze task, which was induced by Abeta plus pro-oxidant agent treatments. Pro-oxidant agents also potentiated brain tissue pathology. This was demonstrated in histological studies that showed highly increased astrocyte reactivity in AD-vulnerable areas, Abeta deposits, and oxidative damage of AD-sensitive hippocampal neurons. To increase our understanding of AD, experimental models should be used that mimic age related brain changes, in which age-related oxidative stress potentiates the effects of Abeta. PMID- 20164581 TI - CHF5074, a novel gamma-secretase modulator, restores hippocampal neurogenesis potential and reverses contextual memory deficit in a transgenic mouse model of Alzheimer's disease. AB - The effects of compounds interfering with gamma-secretase, the enzymatic complex responsible of the formation of the amyloid-beta (Abeta) peptide from amyloid beta protein precursor (AbetaPP), on plaque deposition in transgenic mouse models of Alzheimer's disease are known but scanty data are available on the effects of these drugs on brain plasticity. We evaluated the effects of long-term treatment with CHF5074, a new gamma-secretase modulator, on hippocampal neurogenesis, cortical synaptophysin levels, and contextual memory in transgenic mice carrying the double Swedish mutation of AbetaPP (Tg2576). Six-month old Tg2576 mice were treated with CHF5074 (375 ppm in the diet) up to 15 months of age. Age-matched control transgenic and wild-type mice received standard diet. Compared to wild type animals, transgenic controls showed a significant decrease in the number of doublecortin-positive neuroblasts in dentate gyrus, synaptophysin intensity in the cortex, freezing to context in the contextual fear conditioning test. Compared to transgenic controls, CHF5074 treatment of Tg2576 mice resulted in a significant attenuation of the neurogenesis impairment in hippocampus (p=0.036), normalization of synaptophysin levels in cortex (p< 0.001), attenuation of plaque burden in the cortex (p=0.033), increases astroglial reaction around plaques (p=0.001), and attenuation of activated microglia (p=0.040). These effects were associated to a complete reversal of contextual memory deficit (p=0.006). Contextual memory significantly correlated with synaptophysin immunoreactivity in the cortex (r=0.548, p=0.0038). PMID- 20164582 TI - BACE1 activity in cerebrospinal fluid and its relation to markers of AD pathology. AB - Several studies have shown that reduced amyloid-beta 1-42 (Abeta(42)) and increased tau levels in cerebrospinal fluid (CSF) reflect increased Alzheimer's disease (AD) pathology in the brain. beta-site APP cleaving enzyme (BACE1) is thought to be the major beta-secretase involved in Abeta production in the brain, and therefore we investigated the relation between BACE1 activity and CSF markers Abeta(40), Abeta(42), total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau) in CSF of control (n=12), mild cognitive impairment (n=18), and AD (n=17) subjects. Patients were classified according to their Abeta(42), t-tau, and p-tau CSF biomarker levels, with either an AD-like biomarker profile (two or three biomarkers abnormal: Abeta(42) < 495 pg/ml in combination with t-tau > 356 pg/ml, and/or p-tau > 54 pg/ml) or a normal biomarker profile (or= 75) over a nine-year period to detect dementia and AD cases using the DSM-III-R criteria. We examined two vascular risk profiles, which were scored by counting the number of corresponding vascular factors: 1) atherosclerotic profile included systolic pressure >or= 160 mmHg, diabetes/prediabetes, and stroke; and 2) cerebral hypoperfusion profile constituted diastolic pressure < 70 mmHg, pulse pressure < 70 mmHg, and heart failure. Data were analyzed with Cox proportional hazards models controlling for major potential confounders. During the 6406 person-years of follow-up, 428 subjects developed dementia, including 328 AD cases. All components of vascular profiles were significantly or marginally associated with increased dementia risk. The risk of dementias was increased with increasing score of both risk profiles (p for trend or= 2 in either profile had an approximately twofold-increased risk for dementia and AD. These data suggest that aggregation of atherosclerotic- and hypoperfusion-related vascular factors increases the risk of dementia in very old people. Severe cerebral atherosclerosis and insufficient perfusion are involved in the development of dementia including AD. PMID- 20164586 TI - Does age matter? Behavioral and neuro-anatomical effects of neonatal and adult basal forebrain cholinergic lesions. AB - The "cholinergic hypothesis" of dementia posits that the progressive loss of basal forebrain cholinergic neurons and the consequent decrease of acetylcholine levels in the deafferented projection sites are correlated with degree of cognitive decline in dementia. It has also been proposed that early dysfunction of the basal forebrain (BF) cholinergic system may be a risk factor for subsequent cognitive decline and possibly dementia. To characterize how age when BF cholinergic system is lesioned affects behavioral performances and morphology of neocortical neurons, seven-day-old rats were bilaterally i.c.v. injected with 192 IgG-saporin. In adulthood, these animals were subjected to spatial and associative tests. Subsequently, the morphology of parietal pyramidal neurons was assessed. The same behavioral and morphological evaluations were made in 80-day old rats tested three weeks after bilateral i.c.v. injections of 192 IgG-saporin. The behavioral consequences of both cholinergic depletions were markedly similar. While both groups of lesioned animals exhibited very subtle deficits in the Morris water maze, they were significantly impaired in spatial discrimination in the open field and the radial maze. Paralleling behavioral data, the results of the morphological analysis revealed comparable increases in number and density of spines in apical and basal dendrites in layer-III parietal pyramidal neurons following both neonatal and adult cholinergic depletions. The present results demonstrate that the consequences of abnormal maturation of the cholinergic system are not substantially different from those evoked by cholinergic dysfunction in adulthood and provide a developmental psychobiological perspective of the neuronal foundations of the impaired cognitive functions. PMID- 20164588 TI - Elevation of zinc transporter ZnT3 protein in the cerebellar cortex of the AbetaPP/PS1 transgenic mouse. AB - The presence of senile plaques containing abundant amyloid-beta (Abeta) peptide is one of the major pathological hallmarks of Alzheimer's disease (AD). Recent studies support the notion that overexpression of zinc transporters (ZnT) is involved in zinc metabolic disturbances and Abeta aggregation in AD brains. Here we present data showing an elevated expression of zinc transporter 3 (ZnT3) protein, revealed by immunoblotting assay, in the cerebellum of the amyloid-beta protein precursor (AbetaPP)/presenilin 1 (PS1) transgenic mouse. Confocal microscopic and autometallographic results showed that ZnT3 immunofluorescence and zinc ions were predominantly located in the amyloid plaques. ZnT3 protein was abundantly distributed throughout the plaques, whereas zinc ions were mainly located in the peripheral parts of rosette-shaped plaques with a lightly stained center. Collectively, our results suggest that ZnT3 protein is involved in the Abeta aggregation in the cerebellum of the AbetaPP/PS1 mouse. PMID- 20164589 TI - Comprehensive genetic and mutation analysis of familial dementia with Lewy bodies linked to 2q35-q36. AB - The second most frequent form of neurodegenerative dementia after Alzheimer's disease is dementia with Lewy bodies (DLB). Since informative DLB families are scarce, little is presently known about the molecular genetic etiology of DLB. We recently mapped the first locus for DLB on chromosome 2q35-q36 in a multiplex Belgian family, DR246, with autopsy-proven DLB pathology in a region of 9.2 Mb. Here, we describe the ascertainment of additional DR246 family members and significant finemapping of the DLB locus to 3.3 Mb based on informative meiotic recombinants. Extensive sequencing of the 42 positional candidate genes within the DLB region did not identify a simple pathogenic mutation that co-segregated with disease in family DR246. Also high resolution analysis of copy number variations in the DLB locus did not provide evidence for a complex mutation. In conclusion, we confirmed the DLB locus at 2q35-q36 as a genetic entity but candidate gene-based sequencing and copy number variation analysis did not identify the pathogenic mutation in family DR246. Other detection strategies will be needed to reveal the underlying mutation explaining the linkage of DLB to 2q35 q26. Possibly the disease mutation in this family acts through a more complex mechanism than generally envisaged for monogenic disorders. Nevertheless, identifying the first familial DLB gene is likely to contribute an entry point into the pathogenic cascades underlying DLB pathology. PMID- 20164590 TI - Bis(thiosemicarbazonato) Cu-64 complexes for positron emission tomography imaging of Alzheimer's disease. AB - A bis (thiosemicarbazonato) complex radiolabeled with positron emitting Cu-64 can be used for a new and alternative method for the non-invasive diagnosis of Alzheimer's disease using positron emission tomography (PET). Most imaging agents being investigated for the diagnosis of Alzheimer's disease target amyloid-beta plaque burden but our new approach highlights altered copper homeostasis. This approach has the potential to offer complementary information to other diagnostic procedures that elucidate plaque burden. PMID- 20164591 TI - The computerized self test (CST): an interactive, internet accessible cognitive screening test for dementia. AB - The computer self test (CST) is an interactive, internet-based instrument designed to assess functional cognitive domains impaired by Alzheimer's disease (AD) and mild cognitive impairment (MCI). This study consisted of 215 total subjects with a mean age of 75.24. The 84 cognitively impaired patients (excluding patients diagnosed as MCI) met all criteria set forth by NINCDS/ADRDA for the diagnosis of AD. Control participants consisted of 104 age-matched individuals who were cognitively unimpaired. All patients completed the CST prior to other routine neurocognitive procedures. The CST accurately classified 96% of the cognitively impaired individuals as compared to controls, while the Mini Mental Status Examination (MMSE) accurately classified 71% and the Mini-Cog 69% in the same respect. In addition, the CST accurately classified 91% of the six experimental groups (control, MCI, early AD, mild to moderate, moderate to severe, and severe) as compared to 54% for the MMSE and 48% for the Mini-Cog. In conclusions, the CST demonstrates a high degree of sensitivity and specificity and is capable of accurately identifying cognitive impairment in patients with variable degrees of cognitive abnormality. This interactive internet-based cognitive screening tool may aid in early detection of cognitive impairment in the primary care setting. The ease of use and interpretation may also provide the means to obtain an accurate baseline from which to monitor cognitive changes over time. PMID- 20164593 TI - The Society for Neuroscience 2009 meeting report, part 3. PMID- 20164592 TI - CALHM1 P86L polymorphism is associated with late-onset Alzheimer's disease in a recessive model. AB - CALHM1 gene coding non-synonymous SNP P86L (rs2986017) was reported to increase the risk of Alzheimer's disease (AD) in a recent study. We have investigated this genetic variant in 2470 individuals from Spain to conduct an independent replication study of the proposed SNP marker. By applying a recessive model, we observed weak evidence of an association between P86L mutation and late-onset AD (LOAD) susceptibility in our case-control study (OR =1.38 C.I. = [1.01-1.89]). Meta-analysis of available studies also supports a recessive model for CALHM1 P86L variant and provides evidence of between study heterogeneity. Importantly, we found that adjusted mean age at AD onset in P86L homozygous LOAD patients was significantly earlier that in the rest of patients (77.01 +/- 6.1 for P86L homozygous carriers versus 79.0 +/- 6.0 for the rest of patients, p=0.002). We concluded that the CALMH1 gene may contribute to AD risk in our study population. The observed genetic model (recessive) and the estimated magnitude of the effect both imply that virtually all studies performed to date were markedly underpowered to detect this effect and underscore the importance of follow up, replication, and meta-analyses of promising genetic signals. PMID- 20164594 TI - Neuropsychiatric predictors of progression from amnestic-mild cognitive impairment to Alzheimer's disease: the role of depression and apathy. AB - The aim of the study is to evaluate whether depression or apathy in patients with amnestic-mild cognitive impairment (MCI) increases the risk of progressing to Alzheimer's disease (AD). We investigated 131 consecutive memory-clinic outpatients with newly-diagnosed amnestic-MCI (mean age 70.8, SD=6.5). Psychiatric disorders were diagnosed at baseline according to the criteria for depression and apathy in AD. Neuropsychiatric symptoms were assessed with the Neuropsychiatric Inventory (NPI). Follow-up examinations were conducted after six months and annually for four years. Neurologists diagnosed AD at follow-up using NINCDS-ADRDA criteria. Cox proportional hazard models with 95% confidence intervals were used to test the hypothesis that apathy or depression increases the risk of developing AD. At baseline, 36.6% amnestic-MCI patients had a diagnosis of depression and 10.7% had apathy. Patients with both amnestic-MCI and an apathy diagnosis had an almost sevenfold risk of AD progression compared to amnestic-MCI patients without apathy (HR=6.9; 2.3-20.6), after adjustment for age, gender, education, baseline global cognitive and functional status, and depression. Furthermore, the risk of developing AD increased 30% per point on the NPI apathy item (HR=1.3; 1.1-1.4). There was no increased risk of developing AD in amnestic-MCI patients with either a diagnosis or symptoms of depression. In conclusion, apathy, but not depression, predicts which patients with amnestic-MCI will progress to AD. Thus, apathy has an important impact on amnestic-MCI and should be considered a mixed cognitive/psychiatric disturbance related to ongoing AD neurodegeneration. PMID- 20164595 TI - Overexpression of tau proteins antagonizes amyloid-beta-potentiated apoptosis through mitochondria-caspase-3 pathway in N2a cells. AB - It has been a puzzle why the tangle-bearing neurons in Alzheimer's disease (AD) brain do not die preferentially of apoptosis even though they are actually challenged by multiple proapoptotic factors. Recently, we have reported that phosphorylation of tau can antagonize apoptosis induced by exogenous apoptotic inducers. Amyloid-beta (Abeta), a recognized endogenous proapoptotic factor, is significantly increased in the AD brains, however, it is not known whether tau could abate the Abeta-potentiated apoptosis. Here, we observed that the cells bearing high level of Abeta were more vulnerable than the controls to H2O2 induced apoptosis, and this effect of Abeta was associated with decrease of Bcl 2, elevation of Bax and cytosolic cytochrome-c, as well as activation of caspase 3, suggesting that Abeta could potentiate the oxidant-induced cell apoptosis with involvement of mitochondria-caspase-3 pathway. More importantly, we also found that expression of tau that became hyperphosphorylated could reduce the Abeta potentiated apoptosis with simultaneous preservation of Bcl-2 and suppression of Bax, cytosolic cytochrome-c, and caspase-3 activity, implying that overexpression of tau that became hyperphosphorylated can attenuate the Abeta-potentiated cell apoptosis through mitochondria-caspase-3 pathway. These findings provide an explanation of the chronic nature of neurodegeneration of neurons with neurofibrillary pathology of abnormal hyperphosphorylated tau in AD and related tauopathies. PMID- 20164596 TI - Comparison of intravenous immunoglobulins for naturally occurring autoantibodies against amyloid-beta. AB - Intravenous immunoglobulins (IVIG) are currently used for therapeutic purposes in autoimmune disorders. Recently, we demonstrated the presence of naturally occurring antibodies against amyloid-beta (nAbs-Abeta) within the pool of IVIG. In this study, we compared different brands of IVIG for nAbs-Abeta and have found differences in the specificity of the nAbs-Abeta towards Abeta(1-40) and Abeta(1 42). We analyzed the influence of a pH-shift over the course of antibody storage using ELISA and investigated antibody dimerization at acidic and neutral pH as well as differences in the IgG subclass distributions among the IVIG using both HPLC and a nephelometric assay. Furthermore, we investigated the epitope region of purified nAbs-Abeta. The differences found in Abeta specificity are not directly proportionate to the binding nature of these antibodies when administered in vivo. This information, however, may serve as a guide when choosing the commercial source of IVIG for therapeutic applications in Alzheimer's disease. PMID- 20164598 TI - Intravenous anesthetic diazepam does not induce amyloid-beta peptide oligomerization but diazepam co-administered with halothane oligomerizes amyloid beta peptide: an NMR study. AB - Amyloid-beta peptide (Abeta) oligomerization has a profound role in Alzheimer's disease pathophysiology. Biophysical studies have shown that smaller sized inhaled anesthetics promote oligomerization by inducing perturbation of three critical amino acid residues (G29, A30, and I31) located in the helix-loop-helix domain of Abeta. In this present experimental study, using state-of-the-art nuclear magnetic resonance, we have monitored the influence of a larger sized intravenous anesthetic, diazepam, as well as diazepam co-administered with halothane, on Abeta. It was concluded that diazepam (in isolation) does not interact with the G29, A30, and I31 residues, and no Abeta oligomerization occurs in the presence of 0.101 mM diazepam, even after 63 days. However, when diazepam was co-administered with halothane, profound Abeta oligomerization is observed. These results strengthen the hypothesis that the presence of smaller molecular sized anesthetic is instrumental in promoting Abeta oligomerization even when co administered with a larger sized anesthetic, namely diazepam. PMID- 20164597 TI - A novel transgenic rat model with a full Alzheimer's-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. AB - Alzheimer's disease (AD) is a neurodegenerative pathology in which amyloid-beta (Abeta) peptide accumulates in different brain areas leading to deposition of plaques and a progressive decline of cognitive functions. After a decade in which a number of transgenic (Tg) mouse models mimicking AD-like amyloid-deposition pathology have been successfully generated, few rat models have been reported that develop intracellular and extracellular Abeta accumulation, together with impairment of cognition. The generation of a Tg rat reproducing the full AD-like amyloid pathology has been elusive. Here we describe the generation and characterization of a new transgenic rat line, coded McGill-R-Thy1-APP, developed to express the human amyloid-beta precursor protein (AbetaPP) carrying both the Swedish and Indiana mutations under the control of the murine Thy1.2 promoter. The selected mono-transgenic line displays an extended phase of intraneuronal Abeta accumulation, already apparent at 1 week after birth, which is widespread throughout different cortical areas and the hippocampus (CA1, CA2, CA3, and dentate gyrus). Homozygous Tg animals eventually produce extracellular Abeta deposits and, by 6 months of age, dense, thioflavine S-positive, amyloid plaques are detected, associated with glial activation and surrounding dystrophic neurites. The cognitive functions in transgenic McGill-R-Thy1-APP rats, as assessed using the Morris water maze task, were found already altered as early as at 3 months of age, when no CNS plaques are yet present. The spatial cognitive impairment becomes more prominent in older animals (13 months), where the behavioral performance of Tg rats positively correlates with the levels of soluble Abeta (trimers) measured in the cortex. PMID- 20164599 TI - Profiling brain and plasma lipids in human APOE epsilon2, epsilon3, and epsilon4 knock-in mice using electrospray ionization mass spectrometry. AB - It is known that apolipoprotein E (ApoE) is essential for normal lipid metabolism. ApoE is the major apolipoprotein in the central nervous system and plays a key role in neurobiology by mediating the transport of cholesterol, phospholipids, and sulfatides. We therefore examined APOE epsilon2, epsilon3, and epsilon4 knock-in mice, using electrospray ionization mass spectrometry to determine if APOE genotype or age leads to altered levels in the brain of a number of glycerophospholipids (phosphatidylinositol, PI; phosphatidylethanolamine, PE; phosphatidic acid, PA, phosphatidylserine, PS; phosphatidylcholine, PC), sphingolipids (sphingomyelin, SM; ceramide, Cer), cholesterol, and triacylglycerols. We observed slight changes within individual PI, PE, PC, Cer, and SM lipid levels in APOE epsilon2 and epsilon4 mice compared to APOE epsilon3 mice. However, overall, we did not observe any major effects in APOE epsilon4 knock-in mice for the levels of the glycerophospholipids measured, as compared to APOE epsilon2 and epsilon3 mice. Our findings indicate that variations in ApoE isoforms do not per se affect bulk lipid homeostasis in the brain. These findings indicate that APOE epsilon4 is not associated with disturbances in brain sterol or sphingolipids in the absence of environmental factors. PMID- 20164600 TI - Unfolded p53 in blood as a predictive signature signature of the transition from mild cognitive impairment to Alzheimer's disease. AB - Mild cognitive impairment (MCI) is a syndrome defined as cognitive decline, but not sufficient to meet the criteria for any specific dementia. Although subjects with MCI may have an increased risk to develop AD, this clinical state encompasses several subtypes of cognitive dysfunction of different etiologies, none of which necessarily progresses to AD. The current inability of clinical criteria to accurately identify this at-risk group for AD development is fuelling the interest in biomarkers able to supplement clinical approaches. We recently described a blood-based cytofluorimetric method for conformationally altered p53 protein detection that allows the discrimination of AD patients from control subjects and patients affected by other dementias. The same protein also predicted progression to AD in preclinical patients with MCI two years before clinical diagnosis of AD was made. Herein, we describe these findings and discuss the potential of the test in diagnosing AD. PMID- 20164601 TI - NMR studies of zinc, copper, and iron binding to histidine, the principal metal ion complexing site of amyloid-beta peptide. AB - Amyloid-beta (Abeta), the major component of senile plaques in Alzheimer's disease, is known to complex transition metal ions mainly through histidine residues. In this study, using 1H NMR titration experiments, we show that histidine binds strongly to Zn(II), Cu(II), and Fe(III) ions at a biologically relevant pH (pH 7.4), with a stoichiometry of Zn(II): histidine binding of 1:2. The observed deshielding of the chemical shifts and relative line broadening indicate that Fenton-active Cu(II) and Fe(III) bind to histidine relatively more efficiently as compared to Zn(II). Parallel studies showed that glutamic acid and aspartic acid are relatively inefficient in metal ion binding. From these studies, we suggest that Abeta-chelated Zn(II) is readily displaced by Cu(II) and Fe(III) ions and leads to a propagation of oxidative stress. PMID- 20164604 TI - Editorial. PMID- 20164602 TI - Lack of implication for CALHM1 P86L common variation in Italian patients with early and late onset Alzheimer's disease. AB - A recent study identified a polymorphism (Pro86Leu) in the Calcium homeostasis modulator 1 (CALHM1) gene whose minor Leucine allele showed a higher frequency in Alzheimer's disease (AD) patients compared to controls (29% in AD and 22% in controls). Further studies provided conflicting results in different ethnic groups. In order to assess the involvement of the CALHM1 genetic variant on the risk of developing AD, we analyzed the genotype and allele distributions of the Pro86Leu polymorphism in 758 Italian subjects. Our results did not confirm an association between the CALHM1 variation and AD, thus suggesting a genetic heterogeneity among the various populations. PMID- 20164606 TI - When healthcare workers get sick: exploring sickness absenteeism in British Columbia, Canada. AB - OBJECTIVE: To determine the demographic and work characteristics of healthcare workers who were more likely to take sickness absences from work in British Columbia, Canada. METHODS: Payroll data were analyzed for three health regions. Sickness absence rates were determined per person-year and then compared across demographic and work characteristics using multivariate Poisson regression models. The direct costs to the employer due to sickness absences were also estimated. RESULTS: Female, older, full-time workers, long-term care workers and those with a lower hourly wage were more likely to take sickness absences and had similar trends with respect to the costs due to sickness absence. For occupations, licensed practical nurses, care aides and facility support workers had higher rates of sickness absence. Registered nurses, and those workers paid high hourly wages were associated with highest sickness related costs. CONCLUSION: It is important to understand the demographic and work characteristics of those workers who are more likely to take sickness absences in order to make sure that they are not experiencing additional hazards at work or facing detrimental workplace conditions. Policy makers need to establish healthy, safe and in turn more productive workplaces. Further research is needed on how interventions can reduce sickness absence. PMID- 20164607 TI - Perceptions of the work environment among people with experience of long term sick leave. AB - PURPOSE: The aims were to describe and analyze how people with experience of long term sick leave perceive that factors in their work environment support or interfere with work performance, satisfaction, and well-being. METHOD: The 53 participants were interviewed with the Work Environment Impact Scale (WEIS). The WEIS ratings and belonging notes were analyzed by descriptive statistics and qualitative analysis respectively. Differences in WEIS ratings between; women and men; participants with somatic and mental diseases; and participants working and on full-time sick leave were tested. RESULTS: The most supportive factors concerned social interactions at work, and the value and meaning of work. The factors perceived as most interfering concerned work demands and rewards. The social relations at work were perceived as more supportive by the working group than by those on full-time sick leave. The participants with somatic diseases perceived physical work factors as more interfering than did participants with mental diseases, who in turn perceived the value and meaning of work as more interfering. CONCLUSION: Knowledge about the interaction between the worker and the work environment could reveal useful information about the complex phenomenon of reducing sick leave. The WEIS seems useful in providing information about how alterations and accommodations in the work environment could support individual workers. PMID- 20164608 TI - When physicians get stuck in sick-listing consultations: a qualitative study of categories of sick-listing dilemmas. AB - OBJECTIVE: Many physicians find sick-listing tasks problematic. The aim of this study was to identify categories of dilemmas experienced by physicians in their sick-listing practice. DESIGN AND SUBJECTS: Data was collected at courses that were aimed at improving physicians' sick-listing skills, arranged in different parts of Sweden. Before the course the participants, general practitioners (GP) sent in a written report of a sick-listing case they found problematic. The material consisted of group discussions of some 100 case reports from GPs. The process of categorisation of the dilemmas was a one-step, straightforward qualitative analysis. RESULTS: Eight different categories of sick-listing dilemmas experienced by the physicians were identified. Examples of them are "Not the doctors' pigeon" (when the patients' problem was perceived as not being medical in nature), "Diagnosis as disguise" (when there is a discrepancy between how the patient describes the problems and what the physician apprehends), and "Harmed by sick listing-reversible" (when the physician perceives that the main problem is the iatrogenic adverse effects of sick listing per se). IMPLICATIONS: The contribution of the study is to provide understanding of and labels to the specific difficulties experienced by physicians in their sick-listing practice face to face with patients. PMID- 20164609 TI - Experiences of professionals participating in inter-organisational cooperation aimed at promoting clients' return to work. AB - In Sweden, the activities initiated to promote return to work (RTW) are performed in parallel by four different public organisations: the health services, the social services, the employment and the social insurance authorities. The aim was to gain deeper understanding on the experiences of professionals involved in cooperative projects aimed at promoting RTW among unemployed sickness benefit recipients. Qualitative analyses were performed of transcribed data from interviews of professionals participating in cooperative projects. First, the analysis identified that the daily collaboration on the same cases enabled development of good relationships and cooperative competence, which improved the contact with clients. Second, the cooperative projects made it possible to include only clients perceived motivated for RTW measures. Third, the closer and more frequent interaction with clients proved to be constructive in that it facilitated recognition and mobilisation of strengths and abilities. Fourth, the differences in rules and regulations between the social insurance and the unemployment insurance standards were often perceived to induce problems, for example, on how to assess the work capacity of clients. The assessments of work capacity represent important and complex tasks that professionals must perform without having access to either scientific knowledge or consensus agreement on which to base their decisions. PMID- 20164610 TI - Development and quality analysis of the Work Experience Measurement Scale (WEMS). AB - Instruments related to work are commonly illuminated from an ill-health perspective. The need for a concise and useable instrument in workplace health promotion governed the aim of this paper which is to present the development process and quality assessment of the Work Experience Measurement Scale (WEMS). A survey, using a questionnaire based on established theories regarding work and health, and a focus group study were performed in hospital settings in 2005 and 2006 respectively. A Principal Component Analysis (PCA) was used to statistically develop a model, and focus group interviews were made to compare quantitative and qualitative results for convergence and corroboration. The PCA resulted in a six factor model of dimensions containing items regarding management, reorganization, internal work experience, pressure of time, autonomy and supportive working conditions. In the analysis of the focus group study three themes appeared and their underlying content was compared to, and matched, with the dimensions of the PCA. The reliability, shown by weighted kappa values, ranged from 0.36 to 0.71, and adequate Cronbach's Alpha values of the dimensions were all above 0.7. The study validity, indicated by discriminant validity, with correlation values that ranged from 0.10 to 0.39, in relation to the content validity appeared to be good when the theoretical content of the WEMS was compared to the content of similar instruments. The WEMS presents a multidimensional picture of work experience. Its theoretical base and the psychometric properties give support for applicability and offer a possibility to measure trends in the work experience over time in health care settings. One intention of the WEMS is to stimulate the ability of organizations and the employees themselves to take action on improving their work experience. The conciseness of the instrument is intended to increase its usability. PMID- 20164611 TI - Return to work: the predictive value of the Worker Role Interview (WRI) over two years. AB - Worker Role Interview (WRI) is an assessment tool designed to identify psychosocial and environmental factors which influence a person's ability to return to work. The purpose of this study was to investigate if the Worker Role Interview (WRI) can predict return to work over a period of two years. Fifty three long-term sick-listed people were interviewed and rated with the WRI. Differences in ratings and the ability of WRI to correctly predict whether these people would fall into the working or non-working groups at 6, 12 and 24 month follow-ups were tested by Mann-Whitney test and logistic regression respectively. Eight of 17 items in WRI were rated differently between the groups at one or more of the follow-ups. The regression models based on the WRI ratings had an overall correct prediction rate ranging from 81% to 96%. 'Expectation of job success' which concerns the person's belief in abilities in relation to return to work emerged as an important predictive factor for return to work in all statistical analyses. The WRI assessment contains items that could predict return to work. This implies that the WRI could be a useful tool in vocational rehabilitation for identifying individual rehabilitation needs. PMID- 20164612 TI - Management of eWork health issues: a new perspective on an old problem. AB - Contact centres are vehicles for a rapidly growing group of knowledge workers, or eWorkers. Using computers and high-speed telecommunications connections as work tools, these employees spend long hours performing mentally demanding work while maintaining static, physically stressful, seated positions. The complex interplay between job demands, work environment, and individual differences combine to produce high levels of physical discomfort among eWorkers. This paper discusses a new view that has emerged, one that focuses on the management rather than the elimination of work related upper limb disorders (WRULD) and computer vision syndrome (CVS) issues that are prevalent among eWorkers. It also reviews a cultural shift among practitioners and business that moves towards a consultative process and the sharing of knowledge among all stakeholders. The controlled work conditions and large single location workforce found within contact centres provide the opportunity to understand the personal and industry cost of eWork injuries and the ability to develop and review new multifaceted interventions. Advances in training and workplace design aimed at decreasing discomfort and injury and reducing the associated economic burden may then be adapted for all eWorkforce groups. PMID- 20164613 TI - Significance of the 100-point scale to evaluate perceived tobacco dependence. AB - BACKGROUND: Smoking cessation is one of the primary targets for risk reduction of atherosclerotic cardiovascular disease. It also leads to the prevention of workers' illness or disability. Validation of a 100-point scale to evaluate perceived tobacco dependence was conducted using a 10-item questionnaire (the Tobacco Dependence Screener; TDS), a 6-item questionnaire (Fagerstrom Test for Nicotine Dependence; FTND), and determining the salivary levels of cotinine at Japanese workplaces. METHODS: A total of 1023 male smokers completed the TDS and FTND and scored themselves on the 100-point scale for tobacco dependence (Study 1). Of the subjects participating in Study 1, 282 male smokers from one workplace presented saliva samples, and the salivary nicotine and cotinine levels were determined by high-performance liquid chromatography (Study 2). After conducting principal axis factor analysis, multiple regression analysis was employed to clarify the association between the score on the 100-point scale for perceived tobacco dependence and several factors such as age, the TDS score, the FTND score, and the salivary cotinine level. RESULTS: The mean age for the subjects was 40.3 years. The mean salivary cotinine level was 235.4 ng/ml, and it increased significantly with increase in the number of cigarettes smoked per day. Cronbach's alpha coefficients for the TDS and FTND were 0.77 and 0.64, respectively. A ROC analysis indicated a cutoff point for the score on the 100 point scale of 61, which yielded a positive result on the TDS ( 5) with 65.7% sensitivity and 70.0% specificity. When FTND 4 was adopted as the gold standard, the sensitivity and specificity became 68.7% and 73.2%, respectively. Three factors were extracted by principal axis factor analysis, explaining 42% of the total variation. Multiple regression analysis revealed that the score on the 100 point scale for evaluating tobacco dependence was positively associated with the TDS and FTND scores, and negatively associated with the age. The adjusted multiple correlation coefficient was 0.262. CONCLUSIONS: The 100-point scale, which is a simple and easy tool to evaluate tobacco dependence, must be used in combination with other tobacco dependence questionnaires such as TDS and FTND and also the salivary cotinine level as a biological marker of tobacco exposure to conduct multi-dimensional education to promote smoking cessation. PMID- 20164614 TI - Physical assault among nursing staff employed in acute care. AB - Hospital workers are known to be at risk of physical assault. The objective of this study is to characterize injuries resulting from physical assault among hospital nursing staff and to identify associated risk factors. Workers' compensation reports linked to human resources data were used to identify a cohort of aides and nurses employed in acute care units at a major healthcare system from 1997 to 2004 and their reported physical assault events. Poisson regression methods were used to estimate rates and rate ratios (RR) by occupation, gender, race, age, tenure, and hospital unit. During the study period 220 assaults were reported; the overall incidence rate was 1.65 (95% CI: 1.45 1.89) per 100 full-time-equivalent employees (FTEs). Assault risk was higher among those with shorter tenure (< 5 years vs. 15 or more) (RR=1.35, 95% CI: 0.83 2.19) and younger workers (under age 30 vs. 50 or older) (RR=1.30, 95% CI: 0.78 2.19), and lower among Black workers (vs. non-Blacks) (RR=0.63, 95% CI: 0.45 0.90). Incidence rates were highest in Psychiatry (12.65, 95% CI: 8.90-17.99), Neurology (4.43, 95% CI: 3.17-6.20) and Rehabilitation (3.63, 95% CI: 1.51-8.71) units. Interventions targeting Psychiatry, Neurology, and Rehabilitation units, and younger and newly hired staff are warranted. More detailed data are needed to develop targeted interventions. PMID- 20164615 TI - Assessment of motor and process skills: assessing client work performance in Belgium. AB - The aim of this study is to establish whether the Assessment of Motor and Process Skills (AMPS) is an appropriate tool to evaluate the quality of work performance by comparing clients' results on the AMPS with the quality of the skills that they demonstrate on the shop floor. A convenience sample of chronically unemployed (vocationally disabled) participants (N=139) with no formal training who were seeking unskilled work through Jobcentrum West-Vlaanderen (West Flanders Job Centre, Belgium) was used. Results demonstrated that in 75.2% of cases the prediction of employment outcome was correct; it is suggested that an AMPS motor score < 2.5 and a process score < 1.2 is insufficient for regular employment, while a motor score > 3.1 and process score > 1.5 indicates that regular employment is a realistic goal. The quality of the motor skills measured by the AMPS and measured on the shop floor are comparable, but little similarity was found in the measurement of process skills. PMID- 20164616 TI - Transforming the meaning of pain: an important step for the return to work. AB - Previous studies have found illness representations to be associated with the degree to which patients adopt health behaviours. Surprisingly, pain representations, especially those in a work rehabilitation context, have rarely been explored. OBJECTIVE: To conduct a thorough investigation of the pain representations held by workers who were on sick leave due to persistent musculoskeletal pain during the process of an intensive work rehabilitation program. METHODS: Qualitative semi-structured interviews were conducted with 16 participants (male, female), three times during the program and one month after discharge. Data analysis was based on a narrative approach. RESULTS: Throughout the process, pain representation was an indicator of the type of action the participants were ready to take to control the immediate or possible consequences of their pain. Using the context of a work rehabilitation trajectory we identified the differential impact of reconstruction or status quo in pain representations that eventually led to a return to work, or not. DISCUSSION: This study highlights the importance of identifying and acknowledging workers' pain representations in facilitating their return to work. PMID- 20164617 TI - Work injury management model and implication in Hong Kong: a literature review. AB - The objective of this review is to explore the work injury management models in literatures and the essential components in different models. The resulting information could be used to develop an integrated holistic model that could be applied in the work injury management system in Hong Kong. A keyword search of MEDLINE and CINAHL databases was conducted. A total of 68 studies related to the management of an injury were found within the above mentioned electronic database. Together with the citation tracking, there were 13 studies left for selection after the exclusion screening. Only 7 out of those 13 studies met the inclusion criteria for review. It is noticeable that the most important component in the injury management model in the reviewed literatures is early intervention. Because of limitations in Employees' Compensation Ordinance in Hong Kong, there is an impetus to have a model and practice guideline for work injury management in Hong Kong to ensure the quality of injury management services. At the end of this paper, the authors propose a work injury management model based on the employees' compensation system in Hong Kong. This model can be used as a reference for those countries adopting similar legislation as in Hong Kong. PMID- 20164618 TI - Redesigning assembly stations using ergonomic methods as a lean tool. AB - With the current state of the global economy, demand for various products plummeting. To sustain in the market, companies have to reduce cost and improve quality. Today, companies have started implementing new philosophies like TQM, TPM, six sigma and lean manufacturing techniques to remain competitive in the market. Lean manufacturing is an emerging philosophy which continuously strives to reduce waste. The main objective of analyzing the assembly line with a lean perspective is to identify the areas related to human interface with other systems that could lead to the generation of waste. Improper workplace design leads to unreasonable mental or physical burden and results in waste generation like slow work (delay and inventory), and defects, which is named as muri waste. An attempt has been made in this paper to locate muri waste and create a "Lean assembly line". The proposed method, based on the use of Rapid Upper Limb Assessment (RULA) with CATIA V5 platform, has allowed the measurement of a large set of operator posture parameters and assessment of ergonomic stresses. Based on the results, the process stations in the assembly line were redesigned to prevent the generation of waste. PMID- 20164620 TI - Advancing the science and approaches for evaluating work environments. PMID- 20164621 TI - Lumbar spine movement patterns during prolonged sitting differentiate low back pain developers from matched asymptomatic controls. AB - BACKGROUND: Little is known about how lumbar spine movement influences mechanical changes and the potential injurious effects of prolonged flexion associated with seated postures. The purpose of this study was to examine the postural responses and pain scores of low back pain sufferers compared with asymptomatic individuals during prolonged sitting in order to understand the biomechanical factors that may be associated with sitting induced low back pain. METHOD: Sixteen participants with sitting-aggravated low back pain were age- and gender-matched with 16 asymptomatic participants. Tri-axial accelerometers were used to monitor lumbar spine angles during 90 minutes of seated computer work. Lumbar spine postures were examined using a movement pattern analysis of two types of postural adjustments, termed shifts (step-like adjustments larger than 5 degrees and fidgets (small change and return to approximately the same position). RESULTS: The LBP group reported large significant increases (P < 0.0001) in low back pain while asymptomatic individuals reported little to no pain. On average, every participant fidgeted every 40 to 50 seconds. However, only the LBP sufferers demonstrated a significant increase (P=0.04) in the number of shifts over 90 minutes of seated work; the LBP group shifted every 4 minutes in the last 30 minutes of sitting compared to every 10 minutes for the asymptomatic group. LBP sufferers also demonstrated larger amplitudes of shifts and fidgets when compared to the asymptomatic group. CONCLUSION: Greater and more frequent movement was not beneficial and did not reduce pain in individuals with pre-existing LBP. Future work to understand the biomechanical effects of proactively inducing movement may help to explain the paradox of the relationship between movement and pain. PMID- 20164622 TI - A systematic approach to simulating field-based occupational whole-body vibration exposure in the lab using a 6df robot. AB - BACKGROUND: Whole-body vibration is a significant workplace risk factor for discomfort and injury in many work sectors. The current approach for evaluating vibration exposures typically involves field studies of seatpan acceleration while the operators perform typical workplace activities. These vibration exposures are then compared to international standards to evaluate the risk of discomfort or injury. This approach does not enable systematic and controlled study of specific workplace factors such as the effect of seating, and it is difficult and expensive to perform. APPROACH TO PAPER: We have developed a systematic approach for studying whole-body vibration in the laboratory setting. This approach involves field studies of occupational exposures measuring the 6 degree of freedom chassis accelerations (translational and rotational) and replication of these exposures in the laboratory. FINDINGS: To date, as a research team, we have collected chassis vibration data from specific vehicles in the forestry (skidders), mining (load-haul-dump vehicles), and construction (scrapers) sectors. We have processed these exposures to develop a library of representative vibration motions, and have replicated these motions in the laboratory using a robotic platform. CONCLUSIONS: This systematic approach of combining field- and laboratory-based measures has facilitated research into specific relevant questions such as the effects of multi axis vibrations on the physical risks to operator health and direct evaluation of the vibration attenuation properties of industrial seats. PMID- 20164623 TI - Why vehicle design matters: Exploring the link between line-of-sight, driving posture and risk factors for injury. AB - Load haul dump (LHD) vehicles have been involved in workplace accidents resulting in fatal injuries and LHD operators also report high rates of musculoskeletal injury. Poor line-of-sight (LOS) and awkward postures adopted by the LHD operator increase the risk of driving related accidents and musculoskeletal injury. The purpose of this case study was to simultaneously measure point of regard (POR), driving posture and sitting position during the operation of a LHD in an underground mining environment in order to further understand the link between these variables and the design of the LHD vehicle. A 5.35 m3 bucket LHD vehicle was used and several driving tasks were analysed. The case study results showed that despite the driving task, the operator looked to the left side of the vehicle 65% of the time. Postural implications include extreme neck rotation (> 40 degrees) for 85% of the work cycle and the average peak compression at L4/L5 was 1843N. Despite changes in driving posture the average center of pressure location for the seated operator moved very little; however changes in peak pressure were observed. The design of the LHD vehicle dictated what the operator could see, which had a direct influence on driving postures adopted by the operator and resulted in several risk factors for musculoskeletal injury. PMID- 20164624 TI - Biomechanical shoulder loads and postures in light automotive assembly workers: Comparison between shoulder pain/no pain groups. AB - BACKGROUND: The number of workplace shoulder compensation claims resulting from musculoskeletal disorders (MSDs) has decreased slightly in recent years, however the median number of days off work remains unchanged, which suggests an increase in injury severity. Little information is available regarding cumulative shoulder exposures, and there is no information on their impact on shoulder pain. METHODS: Seventy-nine automotive seat frame assembly workers completed a questionnaire about the prevalence and severity of shoulder pain and were videotaped performing assembly tasks. 3DMatch, a posture-matching software program, was used to calculate the peak and cumulative shoulder moments and forces by matching postures seen in the video with predetermined ranges of posture to be used in the biomechanical model. RESULTS: Of the 45.6% who reported shoulder pain, there was a mild correlation of pain severity with posterior shear of the shoulder. There were no significant differences in peak loads between Pain and No Pain groups; however, the No Pain group experienced significantly more cumulative caudal shear. CONCLUSION: Although there was no difference in percent time spent in different flexed postures between pain groups, those working some jobs may be at an increased risk of developing MSDs based on the amount of time spent in flexed postures, as well as the peak flexion moment acting on the shoulder. PMID- 20164625 TI - Predicting discomfort scores reported by LHD operators using whole-body vibration exposure values and musculoskeletal pain scores. AB - BACKGROUND: Laboratory studies have typically been used to establish a relationship between whole body vibration (WBV) magnitude, frequency, exposure duration and reported discomfort. However, the relationship between subjective reports of discomfort, and predicted comfort response according to International Standards Organization (ISO) 2631-1, predicted health risks according to ISO 2631 1 and reported musculoskeletal discomfort has not been examined. The purpose here was to compare discomfort values predicted by ISO 2631-1 with the subjective discomfort reported by nine Load-haul-dump (LHD) operators during typical operating conditions. METHODS: Vibration exposure at the operator/seat interface was measured and processed, for one-hour duration, according to criteria established in ISO 2631-1. Vibration total values were determined for 1-minute exposure periods and the LHD operators provided a discomfort score associated with the same vibration exposure period. A linear regression analysis and correlation was carried out to determine the strength of the relationship between the predicted subjective reports of discomfort, ISO 2631-1 discomfort, objectively measured acceleration levels and reported musculoskeletal discomfort. FINDINGS: Reported discomfort was poorly correlated to ISO discomfort scores (r=0.1799). Vibration exposure values and Musculo-Skeletal Disorder (MSD) variables were related to both ISO 2631-1 discomfort and to reported discomfort. The MSD scores produced stronger relationships with reported discomfort scores than did the vibration exposure values. PMID- 20164626 TI - Exposure to whole-body vibration and seat transmissibility in a large sample of earth scrapers. AB - BACKGROUND: It is often difficult to access a large sample of vehicles in various work environments to evaluate worker exposure to vibration such as in construction and mining. Thus the main purpose of the present research was to test vibration exposure in a relatively large number of earth scrapers. The second aim was to assess vibration exposure values on seat transmissibility. STUDY DESIGN: 33earth scrapers were assessed for both exposure to whole-body vibration and seat transmissibility. METHOD: Two triaxial accelerometers, one placed on the seat and one on the floor directly below the seat, were used to gather whole-body vibration values (a(w)). Each machine was tested for a minimum of three complete work cycles: idling, scraping, travelling full, dumping, travelling empty back to the scrape site. RESULTS: Results showed that idling and scraping produced low levels of vibration when compared to travelling and dumping. Second, when the a(w) values were compared to the EU safety standards for an eight hour work day, the data (z axis) exceeded the exposure action value (0.5 m/s2) in all machines, and the exposure limit value (1.15 m/s2) in some. Implications; Operators of the scrapers were being exposed to unsafe levels of whole-body vibration. When the seats were assessed to see whether they were attenuating operator exposure to vibration, many of the seat effective amplitude transmissibility (SEAT) values exceeded 1.0. This meant that some of the seats were actually amplifying the vibration present at the floor, particularly in the y axis. CONCLUSION: Travelways should be kept smooth, operating speeds reduced, and new seats, effective in all three axes, designed. PMID- 20164627 TI - The interprofessional socialization and valuing scale: a tool for evaluating the shift toward collaborative care approaches in health care settings. AB - BACKGROUND: There is a need for tools by which to evaluate the beliefs, behaviors, and attitudes that underlie interprofessional socialization and collaborative practice in health care settings. METHOD: This paper introduces the Interprofessional Socialization and Valuing Scale (ISVS), a 24-item self-report measure based on concepts in the interprofessional literature concerning shifts in beliefs, behaviors, and attitudes that underlie interprofessional socialization. The ISVS was designed to measure the degree to which transformative learning takes place, as evidenced by changed assumptions and worldviews, enhanced knowledge and skills concerning interprofessional collaborative teamwork, and shifts in values and identities. The scales of the ISVS were determined using principal components analysis. RESULTS: The principal components analysis revealed three scales accounting for approximately 49% of the variance in responses: (a) Self-Perceived Ability to Work with Others, (b) Value in Working with Others, and (c) Comfort in Working with Others. These empirically derived scales showed good fit with the conceptual basis of the measure. CONCLUSION: The ISVS provides insight into the abilities, values, and beliefs underlying socio-cultural aspects of collaborative and authentic interprofessional care in the workplace, and can be used to evaluate the impact of interprofessional education efforts, in house team training, and workshops. PMID- 20164628 TI - Evaluating ergonomic risk factors in non-regulated stone carving units of Jaipur. AB - BACKGROUND: Stone carving at Jaipur in Rajasthan state of India, is a traditional craft employing a large number of local youths. As an unorganized sector problems are many ranging from lack of benefits to occupational ergonomic issues of Work Related Musculoskeletal Disorders(WMSDs) and injury to body parts. STUDY DESIGN: Twenty five male workers were selected in each of the three sections of a stone carving unit. The focus was to identify different ergonomic risk factors associated in this profession from the field. METHODS: Still photography and video photography was used to record different activities. Different types of non invasive tools like Rapid Entire Body Assessment (REBA), Rapid Upper Limb Assessment (RULA), Occupational Repetitive Action Index (OCRA) were used. Psychophysical measures were investigated by Body part discomfort map, rated perceived exertion scale and visual analogue scale. Objective measurements (heart arte and skin temperature) were recorded with stop watch and digital thermometer. RESULTS: The working heart rate after 30 minutes of work was 112.4 beats per minute categorizing the work as moderately heavy. Postural analysis by REBA indicated high score (13/13). Similarly postural analysis by RULA showed high score (7/7). These indicate vulnerability of many of the postures to musculoskeletal disorders and injury. CONCLUSION: The study indicates that majority of the activities are in the high risk category and demands immediate ergonomic intervention in the form of tool, workstation and process design. This could be done by involving different Non Government Organizations (NGOs), political parties, and the Human Rights Department both at the center and at the state level. PMID- 20164629 TI - Evaluating auditory perception and communication demands required to carry out work tasks and complimentary hearing resources and skills for older workers with hearing loss. AB - For older workers with acquired hearing loss, this loss as well as the changing nature of work and the workforce, may lead to difficulties and disadvantages in obtaining and maintaining employment. Currently there are very few instruments that can assist workplaces, employers and workers to prepare for older workers with hearing loss or with the evaluation of auditory perception demands of work, especially those relevant to communication, and safety sensitive workplaces that require high levels of communication. This paper introduces key theoretical considerations that informed the development of a new framework, The Audiologic Ergonomic (AE) Framework to guide audiologists, work rehabilitation professionals and workers in developing tools to support the identification and evaluation of auditory perception demands in the workplace, the challenges to communication and the subsequent productivity and safety in the performance of work duties by older workers with hearing loss. The theoretical concepts underpinning this framework are discussed along with next steps in developing tools such as the Canadian Hearing Demands Tool (C-HearD Tool) in advancing approaches to evaluate auditory perception and communication demands in the workplace. PMID- 20164630 TI - Limb bud mesenchyme cultured under tensile strain remodel collagen type I tubes to produce fibrillar collagen type II. AB - In this work, we studied the effects of tensile strain on limb bud mesenchymal cells (MSC) cultured on a collagen type I tubular scaffold. A novel bioreactor was designed to culture the cells while subjecting the tubular scaffold to tensile stress and strain. Control samples included unseeded and MSC-seeded tubes cultured for 2 weeks under unloaded, no-strain conditions, and unseeded tubes subjected to prolonged tensile stress and strain. Mechanical properties of tube specimens were measured under oscillatory compressive stress. Following mechanical testing, scaffolds were fixed for immunohistochemistry or frozen for mRNA extraction. The storage modulii of both seeded/unstrained and seeded/strained tubes were significantly less than that of unseeded tubes, suggesting that MSC disrupted the structure and elasticity of the tubes' collagen type I. At a frequency of 1.0 Hz, the loss tangent of seeded/strained tubes was more than 2.5 times greater than that of seeded/unstrained tubes, and almost 6 times greater than that of unseeded tubes. Confocal microscopy and qRT-PCR results demonstrated that collagen type II and aggrecan expression was upregulated in the seeded/strained tubes. The images also show, for the first time, that culture under tensile strain induces MSC to remodel the collagen type I tube with collagen type II and aggrecan expression into fibrils dispersed throughout the matrix. The seeded/unstrained tubes manifested less collagen type II with a more random expression pattern. Compared to seeded/unstrained tubes, qRT-PCR for collagen type II in the seeded/strained tubes showed a 4-fold increase in the message for collagen type II and a 13-fold increase in the message for aggrecan. These results demonstrate that MSC cultured for at least some period under tensile strain are able to remodel collagen type I scaffolds to produce a more viscous construct having many of the mechanical and biological features of engineered cartilage. PMID- 20164631 TI - Traumatic loading of articular cartilage: Mechanical and biological responses and post-injury treatment. AB - This review discusses a framework for studying injurious loading of articular cartilage, which can lead to post-traumatic osteoarthritis. The framework separates the mechanical from the biological response of the tissue to injury. The mechanical response is governed by the tissue's biomechanical behavior and sets off mechano-transductive pathways. These pathways then determine the biological response. The mechanical response of cartilage to injury has been studied by analytical and computational models of injurious loading, joint contact, and surface fissuring. These models have identified shear and tensile stresses as important parameters governing articular cartilage failure in response to mechanical injury. Further, measurement of cartilage's material properties during impact loading has shown that the tissue is significantly stiffer than predicted from quasi-static testing. In terms of the biological response, cell death and sulfated glycosaminoglycan (sGAG) loss from the tissue are early degradative changes that lead to decreased tissue function. These biological sequelae have also been the subject of targeted intervention strategies post-injury. Some success has been found for decreasing cell death and sGAG loss using various bioactive agents. The framework and treatments reviewed here may be useful starting points in the study of mechanical injury to other tissues. PMID- 20164632 TI - An energy-rate based blood viscosity model incorporating aggregate network dynamics. AB - Existing time-dependent blood viscosity models that involve aggregation dynamics are mainly based on structural variables and/or viscoelastic models in order to describe the bulk mechanical properties of the fluid, but the implications of important characteristics of blood microstructure, such as the time- and flow dependent characteristics of the red blood cell network developed due to aggregation at low shear rates, have not been thoroughly investigated. In this paper a time-dependent blood viscosity model is developed based on an energy-rate model previously proposed (Skalak et al., Biophys. J. 35 (1977), 771-781), which describes the total work needed to overcome the various forces developed between aggregated cells, including the adhesive, elastic and dissipative forces. Novel formulations of the forces acting on the fluid are developed and implemented in a volume-averaged version of the energy-rate model. The calculation of the viscosity is based on the relationship between the rate of energy changes and shear stress per unit volume of the fluid. The results show that network characteristics may significantly influence the viscosity blood at low shear rates and exhibit good agreement with experimental observations. PMID- 20164634 TI - Long term shear stress leads to increased phosphorylation of multiple MAPK species in cultured human aortic endothelial cells. AB - Fluid dynamics strongly influences endothelial cell function, and participates in the localization of atherosclerotic plaques at blood vessel branches. We investigated the hypothesis that wild-type human aortic endothelial cells (HAEC) exposed to prolonged pulsatile flow stimulation have levels of phosphorylated mitogen-activated protein kinases (MAPK) that are significantly greater than those observed in statically grown cultures. HAEC were exposed to pulsatile laminar shear stress in a parallel-plate flow chamber and analyzed for levels of phosphorylated ERK, JNK and p38 at 1, 10 and 20 h. While some MAPK exhibited alternating patterns of phosphorylation, others were characterized by steady increases or unchanged profiles until the terminal (20 h) time point. However, at 20 h, each MAPK demonstrated an increase in phosphorylation versus statically cultivated cells. Further, 20 h cultures from 10 dyn/cm(2) pulsatile shear stress had higher levels of phosphorylation for each MAPK than those from 2 dyn/cm(2). The finding that MAPK species can be phosphorylated in response to a prolonged pulsatile shear stress in both a time and magnitude dependent manner is an interesting result that may help to explain how the differential behaviors observed between cells from different flow environments can be generated and maintained. PMID- 20164636 TI - Dynamical structural science. PMID- 20164633 TI - A mathematical model of evolving mechanical properties of intraluminal thrombus. AB - Quantifying mechanical properties of blood clots is fundamental to understanding many aspects of cardiovascular disease and its treatment. Nevertheless, there has been little attention to quantifying the evolving composition, structure and properties when a clot transforms from an initial fibrin-based mesh to a predominantly collagenous mass. Although more data are needed to formulate a complete mathematical model of the evolution of clot properties, we propose a general constrained mixture model based on diverse data available from in vitro tests on fibrinogenesis, the stiffness of fibrin gels, and fibrinolysis as well as histological and mechanical data from clots retrieved from patients at surgery or autopsy. In particular, albeit resulting from complex kinetics involving many clotting factors, we show that the rapid (minutes) in vitro production of fibrin from fibrinogen can be modeled well by an Avrami-type relation and similarly that the fast (tens of minutes) in vitro degradation of fibrin in response to different concentrations of plasmin can be captured via a single "master function" parameterized by appropriate half-times that can be inferred from laboratory or clinical data. Accounting simultaneously for the production and removal of fibrin as well as chemo-mechano-stimulated production of fibrillar collagens yields predictions of changing mass fractions and bulk mechanical properties that correspond well to experimentally available data. Constrained mixture models thus hold considerable promise for modeling the biomechanics of clot evolution and can guide the design and interpretation of needed experiments and stress analyses. PMID- 20164637 TI - The new age of structural dynamics. AB - A perspective on the new developments of structural dynamics is presented. The scope of applications and advances, from microscopy to diffraction and spectroscopy, defines the new age of endeavour. PMID- 20164638 TI - 'Making the molecular movie': first frames. AB - Recent advances in high-intensity electron and X-ray pulsed sources now make it possible to directly observe atomic motions as they occur in barrier-crossing processes. These rare events require the structural dynamics to be triggered by femtosecond excitation pulses that prepare the system above the barrier or access new potential energy surfaces that drive the structural changes. In general, the sampling process modifies the system such that the structural probes should ideally have sufficient intensity to fully resolve structures near the single shot limit for a given time point. New developments in both source intensity and temporal characterization of the pulsed sampling mode have made it possible to make so-called 'molecular movies', i.e. measure relative atomic motions faster than collisions can blur information on correlations. Strongly driven phase transitions from thermally propagated melting to optically modified potential energy surfaces leading to ballistic phase transitions and bond stiffening are given as examples of the new insights that can be gained from an atomic level perspective of structural dynamics. The most important impact will likely be made in the fields of chemistry and biology where the central unifying concept of the transition state will come under direct observation and enable a reduction of high-dimensional complex reaction surfaces to the key reactive modes, as long mastered by Mother Nature. PMID- 20164639 TI - Non-equilibrium phonon dynamics studied by grazing-incidence femtosecond X-ray crystallography. AB - The timescales for structural changes in a single crystal of bismuth after excitation with an intense near-infrared laser pulse are studied with femtosecond pump-probe X-ray diffraction. Changes in the intensity and reciprocal-lattice vector of several reflections give quantitative information on the structure factor and lattice strain as a function of time, with a resolution of 200 fs. The results indicate that the majority of excess carrier energy that remains near the surface is transferred to vibrational modes on a timescale of about 10 ps, and that the resultant increase in the variance of the atomic positions at these times is consistent with the overall magnitude of lattice strain that develops. PMID- 20164640 TI - Photoinduced structural dynamics of polar solids studied by femtosecond X-ray diffraction. AB - Femtosecond X-ray diffraction allows for real-time mapping of structural changes in condensed matter on atomic length and timescales. Sequences of diffraction patterns provide both transient geometries and charge-density maps of crystalline materials. This article reviews recent progress in this field, the main emphasis being on experimental work done with laser-driven hard X-ray sources. Both Bragg diffraction techniques for bulk and nanostructured single crystals as well as the recently implemented powder diffraction from polycrystalline samples are discussed. In ferroelectric superlattice structures, coherent phonon motions and the driving stress mechanisms are observed in real time. In molecular crystals charge-transfer processes and the concomitant changes of the lattice geometry are analyzed. PMID- 20164641 TI - Time-resolved synchrotron diffraction and theoretical studies of very short-lived photo-induced molecular species. AB - Definitive experimental results on the geometry of fleeting species are at the time of writing still limited to monochromatic data collection, but methods for modifications of the polychromatic Laue data to increase their accuracy and their suitability for pump-probe experiments have been implemented and are reviewed. In the monochromatic experiments summarized, excited-state conversion percentages are small when neat crystals are used, but are higher when photoactive species are embedded in an inert framework in supramolecular crystals. With polychromatic techniques and increasing source brightness, smaller samples down to tenths of a micrometre or less can be used, increasing homogeneity of exposure and the fractional population of the excited species. Experiments described include a series of transition metal complexes and a fully organic example involving excimer formation. In the final section, experimental findings are compared with those from theoretical calculations on the isolated species. Qualitative agreement is generally obtained, but the theoretical results are strongly dependent on the details of the calculation, indicating the need for further systematic analysis. PMID- 20164642 TI - Structural dynamics of photoinduced molecular switching in the solid state. AB - Fast and ultra-fast time-resolved diffraction is a fantastic tool for directly observing the structural dynamics of a material rearrangement during the transformation induced by an ultra-short laser pulse. The paper illustrates this ability using the dynamics of photoinduced molecular switching in the solid state probed by 100 ps X-ray diffraction. This structural information is crucial for establishing the physical foundations of how to direct macroscopic photoswitching in materials. A key feature is that dynamics follow a complex pathway from molecular to material scales through a sequence of processes. Not only is the pathway indirect, the nature of the dynamical processes along the pathway depends on the timescale. This dictates which types of degrees of freedom are involved in the subsequent dynamics or kinetics and which are frozen or statistically averaged. We present a recent investigation of the structural dynamics in multifunctional spin-crossover materials, which are prototypes of molecular bistability in the solid state. The time-resolved X-ray diffraction results show that the dynamics span from subpicosecond molecular photoswitching followed by volume expansion (on a nanosecond timescale) and additional thermoswitching (on a microsecond timescale). PMID- 20164643 TI - Five-dimensional crystallography. AB - A method for determining a comprehensive chemical kinetic mechanism in macromolecular reactions is presented. The method is based on five-dimensional crystallography, where, in addition to space and time, temperature is also taken into consideration and an analysis based on singular value decomposition is applied. First results of such a time-resolved crystallographic study are presented. Temperature-dependent time-resolved X-ray diffraction measurements were conducted on the newly upgraded BioCARS 14-ID-B beamline at the Advanced Photon Source and aimed at elucidating a comprehensive kinetic mechanism of the photoactive yellow protein photocycle. Extensive time series of crystallographic data were collected at two temperatures, 293 K and 303 K. Relaxation times of the reaction extracted from these time series exhibit measurable differences for the two temperatures, hence demonstrating that five-dimensional crystallography is feasible. PMID- 20164645 TI - Tracking ligand-migration pathways of carbonmonoxy myoglobin in crystals at cryogenic temperatures. AB - In order to explore the ligand-migration dynamics in myoglobin induced by photodissociation, cryogenic X-ray crystallographic investigations of carbonmonoxy myoglobin crystals illuminated by continuous wave and pulsed lasers at 1-15 kHz repetition rate have been carried out. Here it is shown that this novel method, extended pulsed-laser pumping of carbonmonoxy myoglobin, promotes ligand migration in the protein matrix by crossing the glass transition temperature repeatedly, and enables the visualization of the migration pathway of the photodissociated ligands in native Mb at cryogenic temperatures. It has revealed that the migration of the CO molecule into each cavity induces structural changes of the amino-acid residues around the cavity which result in the expansion of the cavity. The sequential motion of the ligand and the cavity suggests a self-opening mechanism of the ligand-migration channel arising by induced fit. PMID- 20164646 TI - Picosecond and femtosecond X-ray absorption spectroscopy of molecular systems. AB - The need to visualize molecular structure in the course of a chemical reaction, a phase transformation or a biological function has been a dream of scientists for decades. The development of time-resolved X-ray and electron-based methods is making this true. X-ray absorption spectroscopy is ideal for the study of structural dynamics in liquids, because it can be implemented in amorphous media. Furthermore, it is chemically selective. Using X-ray absorption near-edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) in laser pump/X-ray probe experiments allows the retrieval of the local geometric structure of the system under study, but also the underlying photoinduced electronic structure changes that drive the structural dynamics. Recent developments in picosecond and femtosecond X-ray absorption spectroscopy applied to molecular systems in solution are reviewed: examples on ultrafast photoinduced processes such as intramolecular electron transfer, low-to-high spin change, and bond formation are presented. PMID- 20164644 TI - Time-resolved structural studies of protein reaction dynamics: a smorgasbord of X ray approaches. AB - Proteins undergo conformational changes during their biological function. As such, a high-resolution structure of a protein's resting conformation provides a starting point for elucidating its reaction mechanism, but provides no direct information concerning the protein's conformational dynamics. Several X-ray methods have been developed to elucidate those conformational changes that occur during a protein's reaction, including time-resolved Laue diffraction and intermediate trapping studies on three-dimensional protein crystals, and time resolved wide-angle X-ray scattering and X-ray absorption studies on proteins in the solution phase. This review emphasizes the scope and limitations of these complementary experimental approaches when seeking to understand protein conformational dynamics. These methods are illustrated using a limited set of examples including myoglobin and haemoglobin in complex with carbon monoxide, the simple light-driven proton pump bacteriorhodopsin, and the superoxide scavenger superoxide reductase. In conclusion, likely future developments of these methods at synchrotron X-ray sources and the potential impact of emerging X-ray free electron laser facilities are speculated upon. PMID- 20164647 TI - Excited-state molecular structures captured by X-ray transient absorption spectroscopy: a decade and beyond. AB - Transient molecular structures along chemical reaction pathways are important for predicting molecular reactivity, understanding reaction mechanisms, as well as controlling reaction pathways. During the past decade, X-ray transient absorption spectroscopy (XTA, or LITR-XAS, laser-initiated X-ray absorption spectroscopy), analogous to the commonly used optical transient absorption spectroscopy, has been developed. XTA uses a laser pulse to trigger a fundamental chemical process, and an X-ray pulse(s) to probe transient structures as a function of the time delay between the pump and probe pulses. Using X-ray pulses with high photon flux from synchrotron sources, transient electronic and molecular structures of metal complexes have been studied in disordered media from homogeneous solutions to heterogeneous solution-solid interfaces. Several examples from the studies at the Advanced Photon Source in Argonne National Laboratory are summarized, including excited-state metalloporphyrins, metal-to-ligand charge transfer (MLCT) states of transition metal complexes, and charge transfer states of metal complexes at the interface with semiconductor nanoparticles. Recent developments of the method are briefly described followed by a future prospective of XTA. It is envisioned that concurrent developments in X-ray free-electron lasers and synchrotron X-ray facilities as well as other table-top laser-driven femtosecond X-ray sources will make many breakthroughs and realise dreams of visualizing molecular movies and snapshots, which ultimately enable chemical reaction pathways to be controlled. PMID- 20164649 TI - Analysis of time-resolved X-ray scattering data from solution-state systems. AB - As ultrafast time-resolved studies of liquid systems with the laser pump/X-ray scattering probe method have come of age over the past decade, several groups have developed methods for the analysis of such X-ray scattering data. The present article describes a method developed primarily with a focus on determining structural parameters in the excited states of medium-sized molecules (approximately 30 atoms) in solution. The general methodology is set in a maximum likelihood framework and is introduced through the analysis of the photoactive platinum compound PtPOP, in particular the structure of its lowest triplet excited state ((3)A(2u)). Emphasis is put on structure determination in terms of model comparisons and on the information content of difference scattering signals as well as the related experimental variables. Several suggestions for improving the accuracy of these types of measurements are presented. PMID- 20164648 TI - Photolysis of Br2 in CCl4 studied by time-resolved X-ray scattering. AB - A time-resolved X-ray solution scattering study of bromine molecules in CCl(4) is presented as an example of how to track atomic motions in a simple chemical reaction. The structures of the photoproducts are tracked during the recombination process, geminate and non-geminate, from 100 ps to 10 micros after dissociation. The relaxation of hot Br(2)(*) molecules heats the solvent. At early times, from 0.1 to 10 ns, an adiabatic temperature rise is observed, which leads to a pressure gradient that forces the sample to expand. The expansion starts after about 10 ns with the laser beam sizes used here. When thermal artefacts are removed by suitable scaling of the transient solvent response, the excited-state solute structures can be obtained with high fidelity. The analysis shows that 30% of Br(2)(*) molecules recombine directly along the X potential, 60% are trapped in the A/A' state with a lifetime of 5.5 ns, and 10% recombine non-geminately via diffusive motion in about 25 ns. The Br-Br distance distribution in the A/A' state peaks at 3.0 A. PMID- 20164650 TI - Ultrafast X-ray diffraction in liquid, solution and gas: present status and future prospects. AB - In recent years, the time-resolved X-ray diffraction technique has been established as an excellent tool for studying reaction dynamics and protein structural transitions with the aid of 100 ps X-ray pulses generated from third generation synchrotrons. The forthcoming advent of the X-ray free-electron laser (XFEL) will bring a substantial improvement in pulse duration, photon flux and coherence of X-ray pulses, making time-resolved X-ray diffraction even more powerful. This technical breakthrough is envisioned to revolutionize the field of reaction dynamics associated with time-resolved diffraction methods. Examples of candidates for the first femtosecond X-ray diffraction experiments using highly coherent sub-100 fs pulses generated from XFELs are presented in this paper. They include the chemical reactions of small molecules in the gas and solution phases, solvation dynamics and protein structural transitions. In these potential experiments, ultrafast reaction dynamics and motions of coherent rovibrational wave packets will be monitored in real time. In addition, high photon flux and coherence of XFEL-generated X-ray pulses give the prospect of single-molecule diffraction experiments. PMID- 20164651 TI - Polymorphisms of 5,10-Methylenetetrahydrofolate reductase and cystathionine beta synthase genes as a risk factor for neural tube defects in Setif, Algeria. Concerning the article by Houcher et al., Pediatr Neurosurg 2009;45:472-477. PMID- 20164653 TI - Transarterial chemoembolization using doxorubicin beads for unresectable hepatocellular carcinoma. PMID- 20164652 TI - Physical and psychological burden of chronic kidney disease among older adults. AB - INTRODUCTION: The purpose of the study is to determine if functional status and quality of life (QoL) vary with glomerular filtration rate (GFR) among older adults. METHODS: We studied adults aged 45 years and older participating in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study. Data included demographic and health information, serum creatinine and hemoglobin, the 4-item Center for Epidemiologic Studies Depression Scale (CES-D 4), the 4-item Cohen's Perceived Stress Scale (PSS-4), reported health status and inactivity and the Medical Outcomes Study Short Form-12 (SF-12) QoL scores. RESULTS: CKD (GFR <60 ml/min/1.73 m(2)) was present in 11.6% of the subjects. As GFR declined, the SF-12 physical component score, adjusted for other participant attributes, declined from 38.9 to 35.9 (p = 0.0001). After adjustment for other risk factors, poorer personal health scores (p < 0.0001) and decreased physical activity (p < 0.0001) were reported as GFR declined. In contrast, after adjusting for other participant characteristics, depression scores and stress scores and the mental component score of the SF-12 were not associated with kidney function. CONCLUSION: Older individuals with CKD in the US population experience an increased prevalence of impaired QoL that cannot be fully explained by other individual characteristics. PMID- 20164654 TI - Bone marrow carcinosis and disseminated tumour cells. PMID- 20164655 TI - Time to move to targeted drugs in biliary tract cancer? PMID- 20164656 TI - Do we really need new trials on fulvestrant in prostate cancer? PMID- 20164657 TI - Postoperative follow-up for patients with non-small cell lung cancer. AB - BACKGROUND: It is unclear whether postoperative follow-up by thoracic surgeons or chest physicians for non-small cell lung cancer (NSCLC) alters survival. PATIENTS AND METHODS: The charts of 1,398 NSCLC patients, diagnosed between 1980 and 2008, were reviewed. Prognostic factors contained therein were evaluated using univariate and multivariate analyses. Patients were divided into 2 groups according to the doctor in charge of their postoperative follow-up: the thoracic surgeon group and the chest physician group. The doctors in charge of following up the patients were also analyzed for prognostic significance. RESULTS: In the univariate and multivariate analyses, age 65 years or younger, female sex, early pathological stage, Charlson Index score of 0-1, absence of adjuvant therapy, and follow-up by a chest physician were significantly favorable prognostic factors. Examined overall, NSCLC patients in the chest physician group had longer survival than those in the thoracic surgeon group. The difference in survival of patients with advanced disease was also statistically significant between these 2 groups. CONCLUSIONS: Our results indicate that early detection of asymptomatic disease by regular follow-up including chest computed tomography scan may improve the chance of treatment with curative intent and thus may increase survival, irrespective of the doctor in charge of follow-up. PMID- 20164658 TI - Impact of guideline conformity on breast cancer therapy: results of a 13-year retrospective cohort study. AB - BACKGROUND: To date, few studies have investigated whether the implementation of national breast cancer guidelines fulfills the goal to optimize the national standard of care. Therefore, we aimed to evaluate retrospectively the guideline related 13-year data on breast cancer patients treated at our institution. PATIENTS AND METHODS: In a retrospective cohort study, the records of a total of 2,231 patients with primary breast cancer treated during the period of 1992-2005 at the Department of Obstetrics and Gynecology, University of Ulm, Germany, were analyzed. Based on the German national Step 3 (S3) guideline, a model was created to classify groups according to therapy 'conforming' and 'non-conforming' to guideline recommendations. RESULTS: In 2005, 70.2% of all patients included received both surgical and systemic adjuvant therapies conforming to the guideline. Guideline-conforming treatment was accompanied with significant advantages in terms of recurrence-free survival (RFS) and overall survival (OAS) rates. CONCLUSIONS: It has to be demanded that breast cancer patients are treated in conformity with the S3 guidelines. The reasons for a treatment not conforming to the guidelines should be analyzed for the detection of barrier factors, in order to optimize adherence to the guidelines and therefore to prolong RFS and OAS. PMID- 20164659 TI - Application of DC beads in hepatocellular carcinoma: clinical and radiological results of a drug delivery device for transcatheter superselective arterial embolization. AB - AIM: Application of a drug delivery device for transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). Clinical and radiological treatment assessment. PATIENTS AND METHODS: 24 patients with liver cirrhosis and uni- or multifocal HCC underwent TACE with doxorubicin beads (DC Bead). The underly-ing cause of liver cirrhosis was hepatitis (A: n = 7; B: n = 10) or alcohol consumption (n = 7). Patients presented with Child Pugh stage A (n = 15) and B (n = 9). The mean intrahepatic tumor size, considering the sum of diameters of all lesions treated, was 3.83 cm (+/-2.4). Liver function and hematological parameters were documented before and after each TACE. Magnetic resonance imaging (MRI) was performed before and 4 weeks after TACE. The T1-w 3D volume interpolated breathhold exam (VIBE) sequence was applied for evaluation of the therapy response. RESULTS: 24 patients received a total number of 69 TACE treatments with DC beads (mean dose 160 mg). The elevation of liver function parameters after treatment did not affect the patients' clinical condition. The T1-w VIBE sequence proved very valuable for assessment of the intrahepatic tumor spread. Post-contrast images enabled delineation of the viable HCC lesions, hence facilitating the selective transcatheter approach. The tumor marker a-fetoprotein (AFP), available in 19/24 patients, dropped from 347.5 to 299.5 ng/ml, without being a reliable predictor of treatment response. A decrease of tumor size after TACE from 3.83 (+/-2.40) to 3.01 cm (+/-2.67; p < 0.0001) was evident on the T1w VIBE sequences. The mean follow-up period was 30 months. At the time of data analysis, 10 (42%) out of 14 patients were alive. CONCLUSION: TACE with DC beads in HCC offers a safe and efficient treatment resulting in tumor response within a very short time. PMID- 20164660 TI - Anagrelide for the treatment of thrombocythaemia in daily clinical practice: a post-marketing observational survey on efficacy and safety performed in Germany. AB - BACKGROUND: Myeloproliferative diseases - in particular essential thrombocythaemia (ET) - may be associated with increases in platelet count which put patients at risk of life-threatening complications such as thromboses and severe bleedings. PATIENTS AND METHODS: This multicentre post-marketing observational survey was conducted to assess the efficacy and safety of anagrelide under daily practice conditions in at-risk patients with ET who received anagrelide for the first time. RESULTS: 198 patients (median age of 64 years, range 19-88 years) were included, 61.1% of the patients were women. The mean observation time was 6.2 +/- 1.7 months. Treatment with anagrelide lowered the platelet counts by a median of 316 x 10(9)/l from a median of 797 x 10(9)/l at the beginning of the observation to 470 x 10(9)/l at the last observation (log rank test, p < 0.001). Disease-related complications were reduced during treatment compared to 6 months prior to treatment (transient ischaemic attacks from 1.5 to 0.5%; thromboses from 7.6 to 0%). The number of bleedings remained the same at 1.5%. Adverse events were documented in 46 patients (23.2%). All observed adverse events were similar to those previously reported in clinical studies. CONCLUSION: Anagrelide was effective in lowering the platelet count and was also well tolerated when used in daily clinical practice. PMID- 20164661 TI - Preliminary experience of cetuximab in the treatment of advanced-stage biliary tract cancer. AB - BACKGROUND: Cetuximab has been proved to be effective alone or in combination with other chemotherapeutic agents in the treatment of various malignancies. The aim of this report was to describe our experience of using cetuximab with chemotherapeutics agents to treat advanced-stage biliary tract cancer. CASE REPORTS: We retrospectively analyzed the outcomes of 5 biliary tract cancer patients receiving cetuximab-containing therapy. Four of them had stage IV disease, and 1 patient had incomplete resection at the time of diagnosis. Epidermal growth factor receptor (EGFR) expression and K-ras status were assessed when a specimen was available. After cetuximab treatment, complete response was achieved in 1 patient, partial response in 3 patients, and stable disease in 1 patient. Three surgical specimens were available, and all revealed positive EGFR expression. Only 1 surgical specimen was adequate for K-ras mutation test, and the wild type was confirmed. Complete response was found in the patient who had wild type K-ras. The progression-free survival of these patients varied from 4 to 16 months. CONCLUSIONS: Cetuximab-containing therapy might be an effective treatment for advanced biliary tract cancer. PMID- 20164662 TI - Primary metastatic leiomyosarcoma of the fallopian tube: a rare case report. AB - BACKGROUND: Leiomyosarcoma of the fallopian tube is an extremely unusual gynecologic neoplasm. Since 1886, only 19 of about 35 sarcomas of the fallopian tube have been identified as leiomyosarcomas. As such, clinical diagnosis and therapy management are difficult. CASE REPORT: We report on the case of a 59-year old woman with leiomyosarcoma of the fallopian tube and liver metastases at the time of diagnosis. After initial tumor debulking, she received palliative chemotherapy with gemcitabine 900 mg/m(2) (d1+8) and docetaxel 100 mg/m(2) (d8) (q21). For additional bone metastases, she started local radiation plus bisphosphonates (q28). After 2 cycles of chemotherapy, the disease progressed, and the patient died within 8 months of diagnosis. A review of the literature is given. CONCLUSIONS: Primary metastatic leiomyosarcoma of the fallopian tube is a progressive disease with limited therapy options. For better prognostic evaluation and disease management in such rare cases, it is important to report and compare more cases regarding course of disease and outcome. PMID- 20164663 TI - Long-lasting control of triple-negative metastatic breast cancer with the novel drug combination ixabepilone and capecitabine--case report. AB - BACKGROUND: The optimal duration of ixabepilone and capecitabine chemotherapy combination is currently not known and will most likely be patient-specific based on efficacy, toxicity, quality of life, and patient preference. CASE REPORT: We report an extremely long duration of chemotherapy with ixabepilone and capecitabine (42 cycles) in a patient with triple-negative metastatic breast cancer previously treated with anthracyclines and taxanes. Partial remission was achieved, and acceptable toxicity was observed. CONCLUSIONS: This report adds to the pool of knowledge regarding the use of this important new metastatic breast cancer regimen, especially with respect to the optimal duration of its use. PMID- 20164664 TI - PSA decrease with fulvestrant acetate in a hormone-resistant metastatic prostate cancer patient. AB - BACKGROUND: Androgen-independent prostate cancer (AIPCA) is a difficult disease to treat. Fulvestrant has shown activity inhibiting estrogen receptor dimerization, and the androgen receptor has been shown to stimulate growth in prostate cancer cell lines. CASE REPORT: A 79-year-old metastatic prostate cancer patient with AIPCA was treated with fulvestrant acetate with a loading dose strategy. Without recording any significant side effects, the prostate-specific antigen (PSA) level decreased from 154 ng/ml to 0.45 ng/ml 8 weeks after the first treatment administration. CONCLUSION: Fulvestrant was able to reduce the PSA level in this AIPC patient without any toxicity. PMID- 20164665 TI - Small (<10 mm) thyroid nodules; how aggressively should they be managed? AB - Most commonly, an aggressive management (including surgery) is recommended for thyroid nodules measuring >10 mm. The aim of this review is to present currently available data regarding indications for aggressive treatment of small (<10 mm) thyroid nodules. Clinical factors (history of neck irradiation; extremes of age, i.e. children or elderly patients; family history of thyroid cancer, specifically medullary thyroid cancer, and MEN 2 A or B or familial medullary thyroid cancer; rapid growth of nodule), findings from routine laboratory investigation (increased thyroglobulin or calcitonin levels) or genetic testing (specific RET gene mutations), echomorphological characteristics of the suspicious nodule, and the result of fine-needle aspiration (FNA) should be combined to select those patients with small thyroid nodules, who should be treated surgically. In conclusion, nodule size per se is not an absolute criterion of safety. Aggressive treatment may be indicated in the presence of suspicious clinical/laboratory and/or ultrasound (US) findings. US-guided FNA should be performed when malignancy is a concern, regardless of nodule size, to avoid missing or undertreating a curable cancer. PMID- 20164666 TI - Addressing the transition from curative to palliative care: concept and acceptance of a specific communication skills training for physicians in oncology -COM-ON-p. AB - BACKGROUND: There are several reasons why consultations addressing the transition to palliative care are especially challenging, and physicians are generally not very well prepared to meet these challenges. We therefore conceptualized and evaluated a concise, individualized communication skills training (CST) addressing i) communication concerning the transition to palliative care, and ii) involvement of significant others in the conversation. Core aspects of the CST and data of acceptance will be presented. METHODS: The core elements of the CST are a 1.5-day workshop held in small groups and a subsequent individual coaching session during everyday routine. The workshop is practice-oriented and highly individualized. Acceptance was assessed by using a self-developed 13-item questionnaire. RESULTS: All 41 participating physicians completed the evaluation questionnaire. The participants' overall evaluation of the workshop was very positive and indicated a high personal benefit. Individualized learning tools like 'assessment of individual learning goals' and 'closing with individual take home messages' were also seen as positive, but not as positive as other elements like practicing with actor patients and feedback from actors and facilitators. CONCLUSIONS: The presented specific, individualized, and concise CST is well accepted, and physicians see a high practical relevance and strong personal benefits. PMID- 20164667 TI - [The introduction of targeted drugs]. PMID- 20164668 TI - [Sunitinib--from paradigm shift to standard treatment of metastatic renal cell carcinoma]. AB - Targeted therapies have led to a paradigm shift in the treatment of metastatic renal cell carcinoma (mRCC). The multi-kinase inhibitor Sunitinib was rapidly established as a new standard in first-line therapy. Sunitinib was systematically developed in a comprehensive study program starting with phase II studies in second-line therapy, progressing to a phase III study of first-line therapy and ending with broad application in clinical practice. The prognosis for patients with mRCC has significantly improved with the introduction of the multi-kinase inhibitor: Sunitinib has doubled progression-free survival and quadrupled the response rate compared to Interferon alpha. This benefit is supported by more than 2 years overall survival in the Sunitinib arm of the study. In combination with the consistent results of the international Sunitinib Expanded Access Program, the substance possesses a broad evidence base on extensive practical application in all patient populations. This is also reflected in the recommendations of national and international professional associations. Sunitinib is the most frequently applied drug for mRCC in Germany. PMID- 20164669 TI - [First-line therapy of metastatic renal cell carcinoma--update 2009]. AB - Several molecular therapies have recently become available in first-line therapy of metastatic renal cell carcinoma (mRCC), thus marginalizing cytocine-based therapy. The primary aim of treatment in this situation is to delay progression with an increase in long-term life expectancy along with enhanced quality of life. At present, three new substances are available: Sunitinib, Temsirolimus, and - in combination with Interferon-alpha - Bevacizumab. To date, sufficient data is at hand for all drugs, which has resulted in a consolidation of therapeutic strategy. Selecting the best therapy is highly relevant in everyday practice, depending, among other things, on clinical evidence, guidelines, and the respective approval status. The prognostic score according to Motzer (MSKCC) plays a major role. It covers three prognostically relevant risk groups which are important for the preferential application of the new substances. Current recommendations suggest the application of Sunitinib and Bevacizumab plus Interferon-alpha for good and medium prognoses, with Sunitinib being regarded to be one therapy of first choice. It is the most frequently applied substance for this indication in Germany. The efficacy of Temsirolimus has been documented for patients with poor prognosis and it has been approved for this indication only. Hence, the mTor inhibitor should be the standard for this group of patients. PMID- 20164670 TI - [Current aspects of second-line and sequence therapy of metastatic renal cell carcinoma]. AB - The treatment objective in the metastatic situation is to delay progression while maintaining the best possible quality of life. Since several targeted therapies with different modes of action already exist, sequence therapy is increasingly being considered. Current data regarding sequential treatment is still insufficient and several approaches are being tested in ongoing clinical studies. Based on current data, guidelines, and the therapeutic algorithms supported by national and international professional associations, the German Cancer Society's interdisciplinary task force on renal cell carcinoma (RCC) recommends the following approach: since the efficacy of cytokines is very limited after a previous cytokine-based therapy has failed, Sorafenib or Sunitinib are the treatment of choice. Treatment with other targeted substances is recommended after first-line therapy has failed as a number of retrospective studies have documented relevant activity. Everolimus currently is the treatment of first choice when VEGF-directed therapy has failed. Based on the results of phase II studies, other tyrosine kinase inhibitors can alternatively be applied. PMID- 20164671 TI - [Sunitinib in clinical practice: the expanded access program for metastatic renal cell carcinoma]. AB - The preferential application of Sunitinib in the first-line therapy of metastatic renal cell carcinoma (mRCC) is based on data of a phase III study documenting a doubling of progression-free survival (PFS) with the multi-kinase inhibitor compared to Interferon- alpha. Data from clinical studies were then supplemented and supported by comprehensive experiences in everyday practice. Sunitinib was offered to a large group of patients in an expanded access program with more than 4,500 participants. Patients with no access to Sunitinib treatment due to their country-specific approval situation or patients unable to participate in the approval study on the basis of exclusion criteria could thus be included. The cohorte also encompassed patients with an unfavorable prognosis due to metastases of the brain, non-clear cell RCC, or an ECOG performance status > or =2. Priority was given to questions regarding the safety and long-term tolerability of Sunitinib in clinical practice. Regarding tolerability, these subgroups in the expanded access program did not differ from the total population. New or cumulative toxicities did not occur. In addition, even subgroups with an unfavorable prognosis were able to profit from treatment with Sunitinib. A synopsis of phase III data and the results of the expanded access program confirm the evidence for Sunitinib in all patient populations. PMID- 20164672 TI - [Monitoring of metastatic renal cell carcinoma--standards and challenges]. AB - The introduction of targeted therapies has led to a novel situation regarding monitoring of metastatic renal cell carcinoma (mRCC): patients treated with these new drugs have a significantly longer life expectancy than just a few years ago. In order to maximize the treatment benefit, new demands have come up on the assessment of tumor progression: timing and interpretation of imaging studies are crucial for optimal therapeutic management. Detailed knowledge of the new compounds' mode of action is important as it is different from that of classic cytotoxic drugs. The RECIST criteria constitute the standard for evaluation. Following recommendations made by the German Cancer Society's (DKG) interdisciplinary task force, targeted therapies should strive for a sufficient treatment duration in each line of therapy in order to achieve the best therapeutic outcome. Treatment is continued until clinical progression occurs. Assessing therapeutic efficacy with adequate imaging techniques 6-9 weeks after the beginning of therapy is recommended. Subsequent follow-up examinations should be repeated using identical imaging modalities every 2-3 months. For cyclically applied drugs such as Sunitinib, examinations should be carried out at identical time points within the treatment cycle. PMID- 20164673 TI - [Outlook: Future therapy of renal cell carcinoma]. AB - Targeted therapies have fundamentally altered the therapy of metastatic renal cell carcinoma (mRCC). Sunitinib today is an internationally recommended reference standard in first-line therapy; other drugs such as Temsirolimus, Everolimus, Bevacizumab (in combination with Interferon-alpha) and Sorafenib are part of the therapeutic arsenal. Practitioners thus have now more and better therapeutic options at hand, leading to a significantly improved prognosis for mRCC patients. Numerous ongoing research activities aim at the improvement of the benefits of the new compounds in the metastatic situation or application earlier in the course of the disease. Key aspects of future development in RCC are the optimization of the current therapy options by developing new targeted therapies, the search for the best combinations and sequences including the role of nephrectomy and the assessment in the adjuvant or neo-adjuvant setting. The following contribution provides an overview of ongoing studies, thus giving insight into the future therapy of RCC. PMID- 20164675 TI - Suppression of ROS generation by 4,4-diaminodiphenylsulfone in non-phagocytic human diploid fibroblasts. AB - The action mode of 4,4-diaminodiphenylsulfone (DDS) is still under debate, although it has long been used in treatment of several dermatologic diseases including Hansens disease. In this study, we tested the effect of DDS as an antioxidant on paraquat-induced oxidative stress in non-phagocytic human diploid fibroblasts (HDFs). Overall, preincubation of HDFs with DDS prevented the oxidative stress and the resulting cytotoxic damages caused by paraquat in these cells. The specific effects of DDS in paraquat-treated HDFs are summarized as follows: a) reducing the expression of NADPH oxidase 4 (NOX4) by inhibiting paraquat-induced activation of PKC; b) inhibiting paraquat-induced decreases in mitochondrial complex protein levels as well as in membrane potentials; c) consequently, inhibiting the generation of cytosolic and mitochondrial superoxide anions. Taken together, these findings suggest that DDS would suppress the radical generation in non-phagocytic HDFs during oxidative stress, and that DDS might have the extended potential to be used further in prevention of other oxidative stress-related pathologies. PMID- 20164676 TI - A double point mutation in PCL-gamma1 (Y509A/F510A) enhances Y783 phosphorylation and inositol phospholipid-hydrolyzing activity upon EGF stimulation. AB - Growth factor stimulation induces Y783 phosphorylation of phosphoinositide specific PLC-gamma1, and the subsequent activation of this enzyme in a cellular signaling cascade. Previously, we showed that a double point mutation, Y509A/F510A, of PLC-gamma1, abolished interactions with translational elongation factor 1-alpha. Here, we report that the Y509A/F510A mutant PLC-gamma1 displayed extremely high levels of Y783 phosphorylation and enhanced catalytic activity, compared to wild-type PLC-gamma1, upon treatment of COS7 cells with EGF. In quiescent COS7 cells, the Y509A/F510A mutant PLC-gamma1 exhibited a constitutive hydrolytic activity, whereas the wild-type counterpart displayed a basal level of activity. Upon treatment of COS7 cells with EGF, the Y783F mutation in Y509A/F510A PLC-gamma1 (Y509A/F510A/Y783F triple mutant) cells also led to an enhanced catalytic activity, whereas Y783F mutation alone displayed a basal level of activity. Our results collectively suggest that the Y509A/F510A mutant is more susceptible to receptor tyrosine kinase-induced Y783 phosphorylation than is wild type PLC-gamma1, but no longer requires Y783 phosphorylation step for the Y509A/F510A mutant PLC-gamma1 activation in vivo. PMID- 20164677 TI - Strategies for ensuring that regenerative cardiomyocytes function properly and in cooperation with the host myocardium. AB - In developed countries, in which people have nutrient-rich diets, convenient environments, and access to numerous medications, the disease paradigm has changed. Nowadays, heart failure is one of the major causes of death. In spite of this, the therapeutic efficacies of medications are generally unsatisfactory. Although whole heart transplantation is ideal for younger patients with heart failure, many patients are deemed to be unsuitable for this type of surgery due to complications and/or age. The need for therapeutic alternatives to heart transplantation is great. Regenerative therapy is a strong option. For this purpose, several cell sources have been investigated, including intrinsic adult stem or progenitor cells and extrinsic pluripotent stem cells. Most intrinsic stem cells seem to contribute to a regenerative environment via paracrine factors and/or angiogenesis, whereas extrinsic pluripotent stem cells are unlimited sources of cardiomyocytes. In this review, we summarize the various strategies for using regenerative cardiomyocytes including our recent progressions: non genetic approaches for the purification of cardiomyocytes and efficient transplantation. We expect that use of intrinsic and extrinsic stem cells in combination will enhance therapeutic effectiveness. PMID- 20164678 TI - Chronic ethanol feeding impairs AMPK and MEF2 expression and is associated with GLUT4 decrease in rat myocardium. AB - Chronic and heavy alcohol consumption is one of the causes of heart diseases. However, the effects of ethanol on insulin sensitivity in myocardium has been unclear. To investigate the effects of ethanol on the expression of AMP-activated protein kinase (AMPK), myocyte enhancer factor 2 (MEF2) and glucose transporter 4 (GLUT4), all of which are involved in the regulation of insulin sensitivity, in the myocardium, we performed three parts of experiments in vivo and in vitro. I: Rats were injected with 5-amino-4-imidazolecarboxamide ribonucleotide (AICAR, 0.8 mg.kg(-l)) for 2 h. II: Rats received different dose (0.5, 2.5 or 5 g.kg(-l).d( l)) of ethanol for 22-week. III: Primary neonatal rat cardiomyocytes were isolated and treated with or without 100 mM ethanol or 1 mM AICAR for 4 h. The cardiac protein and mRNA expression of AMPKalpha subunits, MEF2 and GLUT4 were observed by western-blotting and RT-PCR, respectively. Serum TNFalpha levels were assessed by ELISA. The results showed chronic ethanol exposure induced insulin resistance. Ethanol decreased the mRNA levels of AMPKalpha1 and alpha2, the protein levels of total- and phospho-AMPKalpha in cardiomyocytes. Similarly, ethanol showed inhibitory effects on both the mRNA and protein levels of MEF2A and 2D, and GLUT4 in a dose-response-like fashion. Correlation analysis implied an association between phospho-AMPKalpha and MEF2A or MEF2D, and between the levels of MEF2 protein and GLUT4 transcription. In addition, ethanol elevated serum TNFalpha level. Taken together, chronic ethanol exposure decreases the expression of AMPKalpha and MEF2, and is associated with GLUT4 decline in rat myocardium. PMID- 20164679 TI - ATM modulates transcription in response to histone deacetylase inhibition as part of its DNA damage response. AB - Chromatin structure has a crucial role in a diversity of physiological processes, including development, differentiation and stress responses, via regulation of transcription, DNA replication and DNA damage repair. Histone deacetylase (HDAC) inhibitors regulate chromatin structure and activate the DNA damage checkpoint pathway involving Ataxia-telangiectasia mutated (ATM). Herein, we investigated the impact of histone acetylation/deacetylation modification on the ATM-mediated transcriptional modulation to provide a better understanding of the transcriptional function of ATM. The prototype HDAC inhibitor trichostain A (TSA) reprograms expression of the myeloid cell leukemia-1 (MCL1) and Gadd45 genes via the ATM-mediated signal pathway. Transcription of MCL1 and Gadd45alpha is enhanced following TSA treatment in ATM(+) cells, but not in isogenic ATM(-) or kinase-dead ATM expressing cells, in the ATM-activated E2F1 or BRCA1- dependent manner, respectively. These findings suggest that ATM and its kinase activity are essential for the TSA-induced regulation of gene expression. In summary, ATM controls the transcriptional upregulation of MCL1 and Gadd45 through the activation of the ATM-mediated signal pathway in response to HDAC inhibition. These findings are important in helping to design combinatory treatment schedules for anticancer radio- or chemo-therapy with HDAC inhibitors. PMID- 20164680 TI - TGF-beta-treated antigen presenting cells suppress collagen- induced arthritis through the promotion of Th2 responses. AB - Collagen-induced arthritis (CIA) is mediated by self-reactive CD4(+) T cells that produce inflammatory cytokines. TGF-beta(2)-treated tolerogenic antigen presenting cells (Tol-APCs) are known to induce tolerance in various autoimmune diseases. In this study, we investigated whether collagen-specific Tol-APCs could induce suppression of CIA. We observed that Tol-APCs could suppress the development and severity of CIA and delay the onset of CIA. Treatment of Tol-APCs reduced the number of IFN-gamma- and IL-17-producing CD4(+) T cells and increased IL-4- and IL-5-producing CD4(+) T cells upon collagen antigen stimulation in vitro. The suppression of CIA conferred by Tol-APCs correlated with their ability to selectively induce IL-10 production. We also observed that treatment of Tol APCs inhibited not only cellular immune responses but also humoral immune responses in the process of CIA. Our results suggest that in vitro-generated Tol APCs have potential therapeutic value for the treatment of rheumatoid arthritis as well as other autoimmune diseases. PMID- 20164681 TI - Reactive oxygen species enhance differentiation of human embryonic stem cells into mesendodermal lineage. AB - Recently, reactive oxygen species (ROS) have been studied as a regulator of differentiation into specific cell types in embryonic stem cells (ESCs). However, ROS role in human ESCs (hESCs) is unknown because mouse ESCs have been used mainly for most studies. Herein we suggest that ROS generation may play a critical role in differentiation of hESCs; ROS enhances differentiation of hESCs into bi-potent mesendodermal cell lineage via ROS-involved signaling pathways. In ROS-inducing conditions, expression of pluripotency markers (Oct4, Tra 1-60, Nanog, and Sox2) of hESCs was decreased, while expression of mesodermal and endodermal markers was increased. Moreover, these differentiation events of hESCs in ROS-inducing conditions were decreased by free radical scavenger treatment. hESC-derived embryoid bodies (EBs) also showed similar differentiation patterns by ROS induction. In ROS-related signaling pathway, some of the MAPKs family members in hESCs were also affected by ROS induction. p38 MAPK and AKT (protein kinases B, PKB) were inactivated significantly by buthionine sulfoximine (BSO) treatment. JNK and ERK phosphorylation levels were increased at early time of BSO treatment but not at late time point. Moreover, MAPKs family-specific inhibitors could prevent the mesendodermal differentiation of hESCs by ROS induction. Our results demonstrate that stemness and differentiation of hESCs can be regulated by environmental factors such as ROS. PMID- 20164682 TI - Modulation of cartilage differentiation by melanoma inhibiting activity/cartilage derived retinoic acid-sensitive protein (MIA/CD-RAP). AB - Melanoma inhibiting activity/cartilage-derived retinoic acid-sensitive protein (MIA/CD-RAP) is a small soluble protein secreted from malignant melanoma cells and from chondrocytes. Recently, we revealed that MIA/CD-RAP can modulate bone morphogenetic protein (BMP)2-induced osteogenic differentiation into a chondrogenic direction. In the current study we aimed to find the molecular details of this MIA/CD-RAP function. Direct influence of MIA on BMP2 by protein protein-interaction or modulating SMAD signaling was ruled out experimentally. Instead, we revealed inhibition of ERK signaling by MIA/CD-RAP. This inhibition is regulated via binding of MIA/CD-RAP to integrin alpha5 and abolishing its activity. Active ERK signaling is known to block chondrogenic differentiation and we revealed induction of aggrecan expression in chondrocytes by treatment with MIA/CD-RAP or PD098059, an ERK inhibitor. In in vivo models we could support the role of MIA/CD-RAP in influencing osteogenic differentiation negatively. Further, MIA/CD-RAP-deficient mice revealed an enhanced calcified cartilage layer of the articular cartilage of the knee joint and disordered arrangement of chondrocytes. Taken together, our data indicate that MIA/CD-RAP stabilizes cartilage differentiation and inhibits differentiation into bone potentially by regulating signaling processes during differentiation. PMID- 20164684 TI - From the guest editor: Triple-negative breast cancer. PMID- 20164685 TI - What is the difference between triple-negative and basal breast cancers? AB - Triple-negative breast cancer (TNBC) represents a phenotype defined by the lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 expression. Because TNBCs have more aggressive features and lack a therapeutic target, they have become a key topic of clinical and research interest within the oncology community. With advancements in the field of molecular biology, gene expression profiling has resulted in the identification of intrinsic subtypes including basal-like breast cancers (BLBCs). Although often thought to be synonymous, TNBC and BLBC represent different biologic phenomena. Furthermore, even within the basal-like subtype, diversity exists. The purpose of this review is to outline the most current evidence in an attempt to answer the question: what is BLBC? PMID- 20164683 TI - Vitamin D: considerations in the continued development as an agent for cancer prevention and therapy. AB - Considerable preclinical and epidemiologic data suggest that vitamin D may play a role in the pathogenesis, progression, and therapy for cancer. Numerous epidemiologic studies support the hypothesis that individuals with lower serum vitamin D levels have a higher risk of a number of cancers. Measures of vitamin D level in such studies include both surrogate estimates of vitamin D level (residence in more northern latitudes, history of activity, and sun exposure) as well as measured serum 25(OH) cholecalciferol levels. Perhaps, the most robust of these epidemiologic studies is that of Giovannucci et al, who developed and validated an estimate of serum 25(OH) cholecalciferol level and reported that among >40,000 individuals in the Health Professionals Study, an increase in 25(OH) cholecalciferol level of 62.5 ng/mL was associated with a reduction in the risk of head/neck, esophagus, pancreas cancers, and acute leukemia by >50%. Unfortunately, very limited data are available to indicate whether or not giving vitamin D supplements reduces the risk of cancer. Many preclinical studies indicate that exposing cancer cells, as well as vascular endothelial cells derived from tumors, to high concentrations of active metabolites of vitamin D halts progression through cell cycle, induces apoptosis and will slow or stop the growth of tumors in vivo. There are no data that one type of cancer is more or less susceptible to the effects of vitamin D. Vitamin D also potentiates the antitumor activity of a number of types of cytotoxic anticancer agents in in vivo preclinical models. Vitamin D analogues initiate signaling through a number of important pathways, but the pathway(s) essential to the antitumor activities of vitamin D are unclear. Clinical studies of vitamin D as an antitumor agent have been hampered by the lack of a suitable pharmaceutical preparation for clinical study. All commercially available formulations are inadequate because of the necessity to administer large numbers of caplets and the poor "bioavailability" of calcitriol (the most carefully studied analogue) at these high doses. Preclinical data suggest that high exposures to calcitriol are necessary for the antitumor effects. Clinical data do indicate that high doses of calcitriol (>100 mcg weekly, intravenously, and 0.15 microg /kg weekly, orally) can be given safely. The maximum tolerated dose of calcitriol is unclear. While a 250-patient trial in men with castration-resistant prostate cancer comparing docetaxel (36 mg/sqm weekly) +/- calcitriol 0.15 microg/kg indicated that calcitriol was very safe may have reduced to death rate, an adequately powered (1000 patients) randomized study of weekly docetaxel + calcitriol versus q3 week docetaxel was negative. The limitations of this trial were the unequal chemotherapy arms compared in this study and the failure to use an optimal biologic dose or maximum tolerated dose of calcitriol. In view of the substantial preclinical and epidemiologic data supporting the potential role of vitamin D in cancer, careful studies to evaluate the impact of vitamin D replacement on the frequency of cancer and the impact of an appropriate dose and schedule of calcitriol or other active vitamin D analogue on the treatment of established cancer are indicated. PMID- 20164686 TI - Triple-negative breast cancers: a view from 10,000 feet. AB - Triple-negative breast cancer is more likely to affect younger premenopausal women and despite being responsive to traditional chemotherapy, continues to carry a poor overall prognosis. Traditional protective factors for breast cancer such as multiparity and early primaparity actually increase the risk for the triple-negative variant. Unlike other breast cancers, the incidence of this disease is also much higher in African American and West African women. Among those with triple-negative disease in the United States, the mortality rates are also highest in African American women. Variations in risk factors and socioeconomic status, lack of treatment, delays in treatment, and inadequate dosing of chemotherapy are just a few of the many reasons that may explain why this incidence and survival disparity persists. PMID- 20164687 TI - Epidermal growth factor receptor in triple-negative and basal-like breast cancer: promising clinical target or only a marker? AB - Triple-negative breast cancers represent a subset of breast cancers with a particularly aggressive phenotype and poor clinical outcomes. Recent molecular profiling of these tumors has revealed a high frequency of epidermal growth factor receptor (EGFR) dysregulation, among other abnormalities. EGFR status correlates negatively with survival in patients with triple-negative breast cancers, and thus focus has turned on this receptor as a potential clinical target. Two classes of EGFR inhibitors are currently in clinical use: the monoclonal antibodies and the small molecule tyrosine kinase inhibitors. Trials of these drugs in breast cancer, however, have been largely disappointing. It remains to be seen whether advances in our understanding of the mechanisms of EGFR dysregulation and effects of multiple compensatory pathways in breast cancer, coupled with improved targeting to appropriate patient populations, will yield meaningful improvements in clinical outcomes. PMID- 20164688 TI - Triple-negative breast cancer: role of antiangiogenic agents. AB - New blood vessel formation plays an important role in breast cancer growth, invasion, and metastasis. Tumor growth is preceded by the development of new blood vessels, which provide a pathway for metastases and nutrients essential for growth. Vascular endothelial growth factor (VEGF) is a key angiogenic mediator that stimulates endothelial cell proliferation and regulates vascular permeability. Highly proliferative tumors, such as those that are negative for the estrogen, progesterone, and HER2/neu receptors have enhanced angiogenesis that supports rapid growth and early metastases and have been found to have high levels of VEGF. Drugs developed to inhibit the angiogenic process may be particularly effective in triple-negative breast cancer. Subset analyses have demonstrated efficacy with combinations of the VEGF antibody bevacizumab in combination with chemotherapy and, to a limited degree, with other antiangiogenic agents. Many targeted biologic agents in development inhibit angiogenesis including those that inhibit the mammalian target of rapamycin, fibroblast growth factor, Notch, hypoxic inducible factor, 2-methoxyestradiol, insulin like growth factor, matrix metalloproteinase, and others. Ongoing studies are focusing on the effects of these agents in triple-negative disease, and there is an urgent need to identify markers that can predict response to specific targeted therapy. PMID- 20164689 TI - BRCA gene structure and function in tumor suppression: a repair-centric perspective. AB - Germline mutations in the BRCA1 and BRCA2 genes are characterized by deficient repair of DNA double-strand breaks by homologous recombination. Defective DNA double-strand break repair has been not only implicated as a key contributor to tumorigenesis in mutation carriers but also represents a potential target for therapy. The transcriptional similarities between BRCA1-deficient tumors and sporadic tumors of the basal-like subtype have led to the investigation of homologous recombination repair-directed therapy in triple-negative tumors, which demonstrates overlap with the basal-like subtype. We broaden the scope of this topic by addressing a "repair-defective" rather than "BRCA1-like" phenotype. We discuss structural and functional aspects of key repair proteins including BRCA1, BRCA2, BRCA1 interacting protein C-terminal helicase 1, and partner and localizer of BRCA2 and describe the phenotypic consequences of their loss at the cellular, tissue, and organism level. We review potential mechanisms of repair pathway dysfunction in sporadic tumors and address how the identification of such defects may guide the application of repair-directed therapies. PMID- 20164690 TI - Poly(ADP-ribose) polymerase inhibitors in triple-negative breast cancer. AB - Poly(ADP-ribose) polymerases (PARPs) are involved in many aspects of the cellular response to various forms of damage. PARP-1 and PARP-2, the most abundant PARPs, are central to the response to specific types of DNA damage, especially single strand breaks. Inhibition of PARP activity may sensitize the cell to exogenous agents such as chemotherapy and radiation. In circumstances where rescue pathways are deficient, particularly the homologous recombination (HR)-directed DNA repair pathway, inhibition of PARP may result in "synthetic lethality." BRCA mutation associated breast cancers are a paradigm of HR-directed repair deficient tumors. Early clinical trials have demonstrated significant activity of single-agent PARP inhibitors in BRCA-deficient breast and ovarian cancer. Because of phenotypic similarities between some "triple-negative" breast cancers (TNBC) and the most prevalent type of breast cancer seen in BRCA1 mutation carriers, some have hypothesized that TNBC might also be specifically sensitive to PARP inhibition. The activity of single-agent PARP inhibitors in TNBC has not been reported. One trial did suggest significant enhancement of the activity of platinum-based combination chemotherapy, without incremental toxicity. These studies indicate that PARP inhibition is an exciting new approach to the treatment of breast cancers in women with underlying BRCA mutations and possibly in sporadic cancers with defects in HR-directed repair. Future studies will be necessary to determine whether the effectiveness of PARP inhibitors in nonhereditary cancer requires an underlying HR defect or whether these agents may improve the activity of conventional chemotherapy by other means. In addition, studies will be required to determine whether PARP inhibitors may induce synthetic lethality in tumors with defects in pathways other than the BRCA-dependent DNA repair pathway. If either or both of these prove to be the case, then PARP inhibition may benefit a wide spectrum of cancer patients. PMID- 20164692 TI - Triple-negative breast cancer: role of the androgen receptor. AB - The androgen receptor (AR), a member of the steroid hormone receptor family, is expressed in more than 70% of breast cancers and has been implicated in breast cancer pathogenesis. The role of the AR is of particular interest in patients with estrogen- and progesterone receptor negative and HER2-negative cancers, which represent approximately 25% of all breast cancers. The "triple-negative" subset of tumors generally has a more aggressive clinical course and does not benefit from conventional endocrine targeted therapies. However, emerging evidence suggests that the AR may serve as a therapeutic target for a subset of triple-negative breast cancers. Herein, we review the role of the AR in breast cancer tumorigenesis and current progress and future directions in the development of AR-targeted therapies. PMID- 20164691 TI - Triple-negative breast cancer: role of specific chemotherapy agents. AB - Cytotoxic chemotherapy remains the mainstay of treatment for triple-negative breast cancer (TNBC) despite the promise of new targeted and biologic agents. Many studies have shown significant benefit of chemotherapy in the neoadjuvant, adjuvant, and metastatic treatment of TNBC. Neoadjuvant chemotherapy studies have consistently reported higher response rates in TNBC than non-TNBC, and pathologic complete response has been shown to predict improved long-term outcomes for TNBC. Although the specific adjuvant regimens that may be most effective for TNBC are still being determined, third-generation chemotherapy regimens using dose dense or metronomic polychemotherapy are among the most effective tools presently available. The role of specific chemotherapy agents in the treatment of TNBC remains incompletely defined and warrants careful review to ensure that the most effective therapy is delivered while minimizing unnecessary toxicity. Platinum agents have seen renewed interest in TNBC based on a growing body of preclinical and clinical data suggesting encouraging activity. Taxanes and anthracyclines are active in TNBC and remain important agents but have not shown specific benefit over non-TNBC. Capecitabine has limited reported data in TNBC, but some reports suggest differential activity in TNBC compared with hormone receptor-positive breast cancer. TNBC is itself a heterogeneous group in which subgroups such as BRCA1 mutation carriers may have particular sensitivity to platinum agents and relatively less sensitivity to taxanes. Therefore, the identification of additional molecular biomarkers to predict response to specific chemotherapy is required to further improve treatment strategies with the current menu of chemotherapy options and future combinations with targeted therapies. PMID- 20164693 TI - Carcinoma of unknown primary origin: on the cusp of a new era. PMID- 20164694 TI - Breast cancer during pregnancy: a comprehensive view. PMID- 20164695 TI - Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan in the first-line treatment of patients with carcinoma of unknown primary site: a randomized, phase III Sarah Cannon Oncology Research Consortium Trial. AB - PURPOSE: To compare the results of empiric first-line therapy with paclitaxel/carboplatin/etoposide (PCE) versus gemcitabine/irinotecan, both followed by single-agent gefitinib, in patients with carcinoma of unknown primary site. PATIENTS AND METHODS: Patients with previously untreated carcinoma of unknown primary site were randomized to receive either PCE or gemcitabine/irinotecan. Responding and stable patients continued treatment for 4 to 6 cycles. Patients with no evidence of tumor progression at that time received single-agent gefitinib until tumor progression. The trial was designed to detect an improvement in the 2-year survival rate from 20% to 30%. RESULTS: Between September 2003 and July 2008, 198 patients entered this multicenter, community based trial. Because of slow accrual, the trial was stopped short of its target accrual of 320 patients. Clinical characteristics were comparable for patients receiving PCE (N = 93) and gemcitabine/irinotecan (N = 105). PCE and gemcitabine/irinotecan produced similar 2-year survival (15% vs. 18%), median survival (7.4 months vs. 8.5 months), median progression-free survival (3.3 months vs. 5.3 months), and response rate (18% vs. 18%). Grade 3/4 neutropenia, thrombocytopenia, anemia, febrile neutropenia, and red blood cells transfusions were more common with PCE; diarrhea was more common with gemcitabine/irinotecan. The median duration of gefitinib maintenance was 3 months, suggesting no role as a maintenance therapy in this setting. DISCUSSION: The PCE and gemcitabine/irinotecan regimens have comparable efficacy in the first-line treatment of patients with carcinoma of unknown primary site. Gemcitabine/irinotecan is the preferable regimen, due to its favorable toxicity profile. However, the moderate efficacy of both regimens underscores the need for novel treatment approaches in this patient population. PMID- 20164696 TI - Breast cancer during pregnancy: maternal and fetal outcomes. AB - PURPOSE: Breast cancer is the most common malignancy occurring during pregnancy. Because more women delay childbearing, the diagnosis of cancer during pregnancy will likely increase. Case reports exist in the literature regarding the treatment of pregnant women with breast cancer, but few are prospective and few provide long-term follow-up on the neonate exposed to chemotherapy. In this report, 130 women diagnosed with breast cancer were reported to our voluntary national registry and followed up prospectively. PATIENT AND METHODS: The Cancer and Pregnancy Registry is a voluntary registry that monitors the clinical course, treatment, and disease outcome of women diagnosed with cancer during pregnancy and the perinatal and neonatal outcomes of their children. RESULTS: Of the 130 diagnosed, 120 were diagnosed with a primary tumor, 8 with a recurrence, and 2 with a new primary cancer. Mean maternal age at diagnosis was 34.8 +/- 4.2 years. Mean gestational age at diagnosis was 13.2 +/- 8.1 weeks. Gestational age was 12.8 +/- 7.8 weeks for patients with primary disease and 16.25 +/- 11 weeks for those with recurrent cancer. One hundred thirteen women were followed up for mean of 3.14 +/- 2.5 years. Of those followed up, 103 were diagnosed with primary breast cancer during pregnancy, 8 with a recurrence, and 2 with a new primary. Recurrence was reported in 30 patients at an average of 16.2 +/- 10.8 months from delivery to recurrence. Twenty-one patients are deceased with an average of 24.71 +/- 15.32 months from delivery to death. Only 42% were diagnosed with an estrogen positive tumor and 35% of cases had a progesterone receptor-positive tumor. Human epidermal growth factor receptor 2 was positive in 25% of patients. Chemotherapy was given during pregnancy in 104 cases; the first treatment was given at a mean gestational age of 20.4 +/- 5.4 weeks. The malformation rate of exposed neonates was 3 not greater than the general population. Survival by stage for a primary diagnosis in pregnancy is as follows: stage I, 100%; stage II, 86%; stage III, 86%; and stage IV, 0%. DISCUSSION: Pregnant women diagnosed with breast cancer can receive treatment comparable with nonpregnant women leading to a similar survival when matched for stage at diagnosis. The majority of children who were exposed to chemotherapy in utero did not demonstrate significant complications. We report the single largest cohort of women diagnosed with breast cancer during pregnancy. PMID- 20164697 TI - Hormone replacement therapy and messenger RNA expression of estrogen receptor coregulators after exercise in postmenopausal women. AB - The use of hormone replacement therapy (HRT) is a potential treatment to relieve symptoms of menopause in postmenopausal women; however, the effects on skeletal muscle are unclear. Specifically, it is unknown if HRT enhances estrogen receptor (ER) transcriptional activation in skeletal muscle at rest and after resistance exercise. PURPOSE: To evaluate changes in the messenger RNA (mRNA) expression of ER coregulators (steroid receptor coactivator-1 (SRC-1) and silencing mediator of retinoid and thyroid receptors (SMRT)) in postmenopausal women after a maximal eccentric exercise bout. METHODS: Fourteen postmenopausal women were divided into two groups: control, women not using HRT (n = 6, 59.2 +/- 4.2 yr, 63.1 +/- 17.4 kg); or HRT, women using traditional HRT (n = 8, 58.5 +/- 3.7 yr, 89.5 +/- 23.7 kg). Participants performed 10 sets of 10 maximal eccentric repetitions of single leg extension on the Cybex dynamometer at 60 degrees .s with 20-s rest periods between sets. Muscle biopsies of the vastus lateralis were obtained from the exercised leg at baseline and 4 h after the exercise bout. mRNA expression was determined using real-time polymerase chain reaction for SRC-1 and SMRT. RESULTS: mRNA expression of SRC-1 significantly increased (P < or = 0.01; 2.4- to 5.2-fold change) and mRNA expression of SMRT significantly decreased (P < or = 0.01; -1.3- to -4.3-fold change) after the exercise bout in both groups. We observed significantly greater changes in mRNA expression of SRC-1 and SMRT (P < or = 0.01) in the HRT group compared with controls after exercise. CONCLUSIONS: A single bout of maximal eccentric exercise enhances ER transcriptional activity with a greater response present in postmenopausal women using HRT. PMID- 20164698 TI - Is the EMG fatigue threshold a valid tool to assess muscle function? PMID- 20164700 TI - Relationship building-beyond the sandbox. PMID- 20164710 TI - 3 Bad bugs. PMID- 20164712 TI - Patient Education Series. Foot care for people with diabetes. PMID- 20164713 TI - Gathering "pearls" of knowledge for assessing older adults. PMID- 20164715 TI - Taking steps to prevent pressure ulcers. PMID- 20164716 TI - Strong medicine healing from the inside out. PMID- 20164717 TI - Staff nurses & nursing students: learning from each other. PMID- 20164718 TI - Recognizing and preventing Mycoplasmal pneumonia. PMID- 20164721 TI - What's the best way to cool my patient's burn pain? PMID- 20164723 TI - Take the lead on safety with temporary cardiac pacing. PMID- 20164725 TI - Iatrogenic pneumothorax. PMID- 20164726 TI - Collective resilience in the storms of life. PMID- 20164727 TI - Will we be included in medical home language? PMID- 20164728 TI - Febuxostat provides new gout treatment option. PMID- 20164729 TI - Vitamin D deficiency and leg pain in the elderly. PMID- 20164730 TI - Break through multidrug-resistant TB. PMID- 20164732 TI - Contraceptive for obese women: considerations. PMID- 20164734 TI - Epinephrine administration: an action plan. PMID- 20164735 TI - Parental satisfaction without antibiotics. PMID- 20164736 TI - Patient history key to diagnosing peripheral edema. PMID- 20164739 TI - Validation of the Andon KD-575 automated blood pressure monitor according to the European society of hypertension international protocol in adults. AB - OBJECTIVE: Blood pressure measuring devices should be subjected to an independent evaluation of accuracy before clinical use. The results of the validation of the Andon KD-575 automated blood pressure monitor according to the European Society of Hypertension International Protocol in adults are presented in this paper. METHODS: Sequential same-arm measurements of systolic and diastolic blood pressure were obtained in 33 participants using the mercury sphygmomanometer (two observers) and the test device (one supervisor). According to the validation protocol, 99 pairs of test device and reference blood pressure measurements were obtained during the two phases of the study (three pairs for each of the 33 participants). RESULTS: In phase 1, the Andon KD-575 device produced 26, 38 and 43 measurements within 5, 10 and 15 mmHg, respectively, for systolic blood pressure and 35, 44 and 45 mmHg, respectively, for diastolic blood pressure. However, in phase 2, the test device failed to meet the criteria for systolic blood pressure but comfortably passed all of the criteria for diastolic blood pressure with a mean (standard deviation) device-observer difference of 2.00+/ 7.12 mmHg for systolic and 1.47+/-4.71 mmHg for diastolic blood pressure. CONCLUSION: The Andon KD-575 automated blood pressure monitor cannot be recommended for clinical use in an adult population because it records systolic blood pressure inaccurately. PMID- 20164740 TI - Immunofluorescence of rabbit corneas after collagen cross-linking treatment with riboflavin and ultraviolet A. AB - PURPOSE: To assess ultrastructural modifications in keratocytes and inflammatory cell response in rabbit corneas after riboflavin and ultraviolet A exposure using immunofluorescence microscopy. METHODS: Twenty adult New Zealand albino rabbits weighing 2.0-3.0 kg were used in this study. Two rabbits served as controls.The animals had their epithelia removed and were cross-linked with riboflavin 0.1% solution (10 mg riboflavin-5-phosphate in 10 mL of 20% dextran-T-500) applied every 3 minutes for 30 minutes, and exposed to ultraviolet A (360 nm, 3 mW/cm2) for 30 minutes. Four rabbits were humanely euthanized at each time point of 1, 3, and 11 days and at 3 and 5 weeks after the procedure. Immunohistochemistry studies of thin sections of each cornea were performed using terminal deoxynucleotyl transferase-mediated uridine triphosphate biotin nick-end labeling staining, alpha smooth muscle actin (a-SMA),CD-3, myeloperoxidase antibodies, and 4',6-diamidino-2-phenylindole(DAPI) counterstaining. In another experiment, 6 additional rabbits were treated as above, and after 10 days of cross-linking, 5 mL of lipopolysaccharide endotoxin (1 mg/mL) was injected in the midstroma. RESULTS: Cross-linked corneas showed early stromal edema. By 5 weeks, complete resolution of the edema and a pronounced highly-organized anterior 200-mm fluorescent zone was observed. Terminal deoxynucleotyl transferase mediated uridine triphosphate biotin nick-end labeling staining showed keratocyte death by both necrosis and apoptosis between days 1 and 3 after cross-linking. At day 1,the limbal area close to the cross-linking zone showed some inflammatory cells and a-SMA-positive cells, indicative of the presence of myofibroblasts. By day 3, some myofibroblasts had migrated to the area beneath the cross-linked stroma. Between days 3 and 5 weeks, there was an increase in a-SMA staining in the area surrounding the cross-linked stroma. The area of cross-linking remained acellular up to 5 weeks. CONCLUSIONS: Collagen cross-linking results in early edema,keratocyte apoptosis, and necrosis, appearance of inflammatory cells in the surrounding area of treatment and transformation of surrounding keratocytes into myofibroblasts. Compaction of anterior stroma fibers, keratocyte loss, and displacement of cell nuclei including inflammatory cells may have clinical implications in the long-term risk of further corneal thinning in keratoconus and in the cross-linked corneal immune response. PMID- 20164741 TI - Where are the older patients with keratoconus? PMID- 20164743 TI - Corneal ectasia after laser in situ keratomileusis after laser thermal keratoplasty. PMID- 20164744 TI - Safety of corneal collagen cross-linking with UV-A and riboflavin in progressive keratoconus. AB - PURPOSE: To assess the possible damage to ocular tissues during treatment of keratoconus with UV-A-riboflavin corneal collagen cross-linking (CXL). DESIGN: Single center, prospective, interventional study. METHODS: Fourteen eyes of 14 patients aged 28.2 +/- 5.9 (mean +/- SD) years with progressive keratoconus were treated with UV-A-riboflavin CXL. Corneal endothelium was assessed with the endothelial specular microscope. Central retina was assessed with biomicroscopy fundus examination and with optical coherence tomography using macular thickness protocol. Patients were assessed preoperatively, at week 1, month 1, 3, 6, 9, and 12 after treatment. RESULTS: Comparative preoperative and postoperative results showed stable endothelial cell density (2730 cells/mm, 2793 cells/mm, and 2640 cells/mm, preoperatively, at month 6, and at month 12, respectively) and stable foveal thickness (203, 202, and 205 MUm, preoperatively, at month 6, and at month 12, respectively). No morphological abnormalities were noted. CONCLUSIONS: UV-A riboflavin CXL seems to be a safe procedure that does not cause damage to the corneal endothelium and central retina. PMID- 20164745 TI - Dynamic changes in the lower tear meniscus after instillation of artificial tears. AB - PURPOSE: To compare the dynamic changes in lower tear meniscus area (TMA) and height after instillation of artificial tears in patients with dry eye and healthy controls. METHODS: Twenty-two eyes of 11 patients with dry eye and twenty eyes of 10 age- and sex-matched healthy subjects were included. The inferior tear meniscus height and area measurements were taken before and after instillation of 35 MUL carboxymethyl cellulose (CMC) 0.5% and 1.0% (Allergan, Irvine, CA) on 2 consecutive days. The measurements were obtained before and 1, 5, 10, 15, and 30 minutes after instillation using anterior segment optical coherence tomography, RTVue-100 (RTVue, Optovue, Inc). RESULTS: The baseline lower TMA and height in the dry eye group were significantly lower than in the control group. A significant increase in TMA and height was found at 1 minute post instillation of 0.5% CMC in both groups, with findings returning to baseline levels at 5 and 10 minutes post instillation in the control group and dry eye group, respectively. The increase in TMA and height persisted for a longer time period in both groups with 1% CMC, versus 0.5% CMC. At 15 and 30 minutes, both tear meniscus parameters were still significantly higher in the control group and dry eye group, respectively. CONCLUSIONS: Artificial tears provide a significant yet temporary improvement in the tear meniscus. The anterior segment optical coherence tomography is valuable to measure dynamic changes in the tear meniscus. PMID- 20164746 TI - Influence of bilateral medial collateral ligament injury on mRNA expression in distal corneal tissues of control and ovariohysterectomized rabbits. AB - PURPOSE: Corneal tissues are reported to be impacted by physiological changes (eg, menopause), systemic autoimmune diseases, and osteoarthritic-like conditions. In this study, changes in specific mRNA levels in the cornea after a ligament injury in normal and rabbits subjected to surgical menopause were examined. METHODS: Skeletally mature female rabbits were either sham-operated (control) or were subjected to surgical menopause (OVX). Eight weeks post-OVX, subsets of control and OVX animals were subjected to bilateral injuries to their medial collateral ligaments (MCL) of the knee, and 6 and 14 weeks postinjury, corneal tissues were harvested. Using reverse transcriptase-polymerase chain reaction, mRNA levels for several relevant molecules, including matrix molecules, growth factors, cytokines, proteinases, and hormone receptors, were assessed. RESULTS: mRNA levels for estrogen receptor, decorin, collagens, several growth factors, and inflammatory cytokines decreased in central corneal tissue 6 weeks after distal MCL injury in control animals. The central corneal tissues of animals subjected to OVX alone also exhibited decreases in mRNA levels for a similar set of molecules. When OVX animals were further subjected to MCL injury, the mRNA levels for many of these molecules did not vary from those in the uninjured OVX group. Interestingly, mRNA levels for most molecules were still altered 14 weeks post-MCL injury in the control and OVX animals, a time when the MCL has healed. CONCLUSIONS: Corneal tissues respond to changes resulting from OVX and/or injury. OVX combined with a ligament injury does not appear to have an additive impact on corneal mRNA levels for most of the molecules assessed. PMID- 20164747 TI - An in vivo confocal microscopy and impression cytology evaluation of pterygium activity. AB - PURPOSE: To correlate pterygium activity with in vivo confocal microscopy (IVCM) and ex vivo impression cytology (IC) analyses. METHODS: Twenty-eight pterygia from 16 patients were analyzed in this study. A pterygium activity score was obtained by summing four scores of ocular discomfort, pterygium hyperemia, keratitis, and the presence of Fuchs patches. Patients underwent pterygium IVCM analysis and collection of IC specimens on the pterygium. IC specimens were analyzed quantitatively by immunohistochemistry for goblet cell and dendritiform inflammatory cell density. IVCM images and IC results were compared to search for a possible correlation with the pterygium activity score. RESULTS: The presence of inflammatory cells, numerous blood vessels, and an irregular limit between the cornea and the pterygium with infiltration of hyperreflective cells in the adjacent corneal epithelium were the signs observed with IVCM associated with pterygium activity. Using IC, the density of goblet cells and dendritiform inflammatory cells was significantly correlated to the pterygium activity score (Spearman coefficient 0.765, P < 0.0001 and 0.799, P < 0.0001, respectively). In the same pterygium, dendritic inflammatory cell density and goblet cell density were also significantly correlated (Spearman coefficient 0.952; P < 0.0001). CONCLUSIONS: The correlation of pterygium cell changes with pterygium activity supports the role of inflammation and its relationship with goblet cells in the pathogenesis of pterygium. PMID- 20164748 TI - Changing indications for penetrating keratoplasty in Greece, 1982-2006: a multicenter study. AB - PURPOSE: To evaluate the leading indications for penetrating keratoplasty (PKP) and their trends in Greece during the period 1982 to 2006. METHODS: Retrospective data review of 1,929 patients (2233 eyes) who underwent PKP in the period between 1982 and 2006 at three cornea transplantation units of three hospitals in Greece (Athens General Hospital, Heraklion University Hospital of Crete, and Thessaloniki University Hospital). Indications were classified into nine different groups: keratoconus, herpes simplex keratitis, microbial (nonviral) keratitis (fungal, bacterial, and acanthamoeba), aphakic/pseudophakic corneal edema, posttraumatic corneal scars, chemical/thermal injury, regraft, Fuchs' endothelial dystrophy, and other. RESULTS: The leading indications for PKP, in order of decreasing frequency, were aphakic/pseudophakic corneal edema (n = 649 [29.1%]), keratoconus (n = 580 [26%]), regraft (n = 265 [11.9%]), microbial (nonviral) keratitis (n = 188 [8.4%]), posttraumatic corneal scar (n = 171 [7.7%]), herpes simplex keratitis (n = 104 [4.6%]), Fuchs' endothelial dystrophy (n = 104 [4.6%]), chemical/thermal injury (n = 61 [2.7%]), and other (n = 111 [5%]). The prevalence of regrafts as an indication for PKP increased during the study period. CONCLUSIONS: Aphakic/pseudophakic corneal edema was the most common indication for PKP in a multicenter series in Greece followed by keratoconus. The number of regrafts dramatically increased during the 25-year period. PMID- 20164749 TI - Ropivacaine for topical anesthesia in pterygium surgery with fibrin glue for conjunctival autograft. AB - PURPOSE: To evaluate efficacy of ropivacaine 1% for topical anesthesia in pterygium surgery with conjunctival autograft using fibrin glue for attaching the graft to the bare sclera. METHODS: Thirty-seven patients affected by primary pterygium underwent surgical excision under topical anesthesia with ropivacaine 1%. We performed a surgical approach with dissection of the pterygium, scraping of corneal bed with a motorized burr, meticulous excision of underlying Tenon's capsule, preparation of a free autologous conjunctival graft in the superior sector, excision of the graft, and position of the same to cover the scleral bed exposed in the nasal area with respect to limbus and stromal orientation fixing the graft with fibrin glue. RESULTS: It was possible to perform all the procedures without any supplemental anesthesia and sedation. The pain reported by patients, recorded by a 0 to 10 scale, was low during the entire surgery. The technique with conjunctival autograft using a fibrin sealant allowed for short operative times and good aesthetic and functional results. CONCLUSIONS: Topical anesthesia with ropivacaine is safe and effective in pterygium surgery. The Long lasting anesthesia with this agent permitted performing our surgical procedures with autograft conjunctival graft and fibrin glue to attach the flap with low pain perceived by our patients, low surgical invasivity, and short duration of surgery. PMID- 20164750 TI - Dissection plane in deep anterior lamellar keratoplasty using the big-bubble technique. AB - PURPOSE: To find the level of dissection in keratoconic corneas undergoing deep anterior lamellar keratoplasty (DALK) using the big-bubble technique. METHODS: In 3 keratoconic eyes that underwent DALK, the operation was converted into penetrating keratoplasty after complete big-bubble formation because of extensive tear in Descemet's membrane (DM) during stromal excision. The corneal stroma and DM taken from these eyes were submitted for light and transmission electron microscopy. RESULTS: Both light and transmission electron microscope revealed a thin layer of corneal stroma adhered to DM in all cases. In 2 eyes, the residual stromal thickness was almost constant (6.4 MUm and 12.3 MUm), whereas it varied from 9.5 MUm to 25.8 MUm in the other one. CONCLUSION: Dissection plane in DALK using the big-bubble technique can be within corneal stroma rather than exactly between stroma and DM. Various corneal pathologies as well as different techniques of dissection may have influence on this level. PMID- 20164751 TI - A modified Schirmer test in dry eye and normal subjects: open versus closed eye and 1-minute versus 5-minute tests. AB - OBJECTIVE: To assess the results of 1-minute and 5-minute Schirmer test (ST) when eyes are open (STo) and closed (STc) in normal subjects and patients with dry eye disease. METHODS: In a comparative, observational case series study, 34 normal volunteers (group 1) and 34 patients with dry eye disease (DED) associated with Sjogren syndrome (group 2) were included in the study. STo and STc for 1 minute and 5 minutes were performed separately for all subjects with an interval of at least 24 hours using Whatman No. 41 (5 * 60 mm) with bended end of the paper inserted into the lateral side of the lower conjunctival fornix. RESULTS: In group 1, there were 19 females and 15 males with a mean age of 20.8 years (range 18 to 23 years). In group 2, there were 29 females and 5 males with a mean age of 53.7 years (range 35 to 75 years). Mean value of STc was significantly less than STo in both 1 minute and 5 minutes in both groups. One-minute STo and STc showed significantly less wetting than the 5-minute test in both healthy and patients with DED. Normal distribution was observed for all the values. A significant correlation between 1-minute and 5-minute tests in both STo and STc were found in the two groups. Therefore, two equations were proposed to calculate the 5-minute from 1-minute ST in each group. Statistical analysis did not provide a reliable equation for calculating the standard ST (5-minute STo) from the most comfortable state (1-minute STc). CONCLUSION: Faster and more comfortable ST (1-minute) is a reliable test to calculate the 5-minute ST in both open and closed eyes, using the provided equations. The 1-minute STc is not a reliable test to calculate the 5-minute STo. PMID- 20164752 TI - The impact of de-epithelialization of the amniotic membrane matrix on morphology of cultured human limbal epithelial cells subject to eye bank storage. AB - PURPOSE: To investigate whether human limbal epithelial cells (HLEC) that have been cultured on intact or de-epithelialized amniotic membranes (AMs) demonstrate differences in morphology after 1 week of eye bank storage. METHODS: HLEC were cultured from limbal explants for 3 weeks on intact AM and AM deprived of the amniotic epithelial cells by incubation with 0.02% ethylene diamine tetra acetic acid followed by mechanical scraping. The HLEC cultures were stored for 1 week in a closed container in a serum-based medium at 23 degrees C. The surface morphology was assessed using scanning electron microscopy, and a quantitative comparison of desmosome and hemidesmosome numbers was performed using transmission electron microscopy. RESULTS: Although most superficial epithelial cells were closely attached to each other, with tightly opposed cell junctions and distinct cell borders, there was evidence of some cell separation in HLEC that had been cultured on intact and denuded AM after 1 week of storage. In both experimental groups, the epithelia were well stratified, consisting of basal column-shaped cells, suprabasal cuboid wing cells, and flat squamous superficial cells, but dilated intercellular spaces were observed. The total number of desmosomes per micron was 1.39 +/- 0.77 in HLEC cultured on intact AM versus 0.98 +/- 0.45 in HLEC expanded on denuded AM (P = 0.76). The total number of hemidesmosomes per micron in HLEC cultured on intact AM and denuded AM was 0.87 +/- 0.34 and 0.78 +/- 0.31, respectively (P = 0.70). CONCLUSIONS: Denuding of AM does not improve the structural integrity of cultured HLEC after eye bank storage. PMID- 20164753 TI - Microbial keratitis secondary to infection with Citrobacter koseri. PMID- 20164754 TI - Induction of corneal epithelium-like cells from cynomolgus monkey embryonic stem cells and their experimental transplantation to damaged cornea. AB - PURPOSE: We previously reported the successful transplantation of corneal epithelium-like cells derived from mouse embryonic stem (ES) cells onto injured mouse cornea. Here, we tested whether nonhuman primate ES cells have ability to differentiate into corneal epithelial cells and whether monkey ES cell-derived corneal epithelium-like cells were applicable for the experimental transplantation to damaged cornea. METHODS: Monkey ES cells were cultivated on type IV collagen-coated dishes for various days to induce differentiation into corneal epithelium-like cells. The differentiation was evaluated by reverse transcription-polymerase chain reaction and immunostaining. The corneal epithelium-like cells were transplanted to the injured mouse cornea. Reconstitution of the corneal epithelium was evaluated by immunostaining. RESULTS: The cells cultured on type IV collagen showed cobblestone-like appearance resembling epithelial cells. They expressed messenger RNA of pax6, p63, E-cadherin, CD44, proliferating cell nuclear antigen, keratin 3, and keratin 12. Protein expressions of pax6, keratin 3/12, p63, proliferating cell nuclear antigen, E-cadherin, and CD44 were confirmed by immunostaining. When the corneal epithelium-like cells were transplanted, they adhered to the corneal stroma, leading to formation of multiple cell layers. The grafted cells were stained with anti-human nuclear protein antibody, which cross-reacted with nuclei of monkey cells but not with those of mouse cells. They retained the expressions of keratin 3/12, E-cadherin, and CD44. CONCLUSIONS: We induced corneal epithelium-like cells from monkey ES cells with moderate efficiency. The cells were successfully transplanted onto the injured mouse cornea. This is the first demonstration that nonhuman primate ES cells were induced to differentiate into corneal epithelium like cells, which were applicable for transplantation to an animal model of corneal injury. PMID- 20164755 TI - The white caruncle: sign of a keratinous cyst arising from a sebaceous gland duct. AB - PURPOSE: To describe an acquired, smooth white lesion of the caruncle and to underscore the role of subsurface keratinizing squamous epithelium in its formation. METHODS: Clinical photographic documentation, histopathologic evaluation, and immunohistochemical staining of an excised specimen from a 25 year-old woman. RESULTS: A cyst was found that was lined by keratinizing squamous epithelium without a keratohyaline layer (trichilemmal keratinization), typical of lesions of the pilosebaceous unit. A portion of the cyst's lining was replaced by granulomatous inflammation resulting from an earlier spontaneous partial rupture. Ki-67 immunolabeling demonstrated relatively few nuclei in S-phase (DNA synthesis) in comparison with the overlying epithelium, thereby suggesting an obstructive, nonproliferative cause for the cyst. CONCLUSION: A white caruncular lesion is a very rare finding according to the literature. It is most likely caused by a cyst lined by squamous epithelium elaborating trichilemmal-type keratin. A sebaceous gland duct was established as the source for the current lesion. PMID- 20164756 TI - Boston Ocular Surface Prosthesis for persistent epitheliopathy after treatment of conjunctival melanoma. AB - PURPOSE: To report two cases of persistent epitheliopathy after treatment of conjunctival melanoma and review management options for this condition. METHODS: Case report and literature review. RESULTS: Persistent epitheliopathy, presumably resulting from limbal stem cell deficiency, is an uncommon complication of treatment of conjunctival malignant melanoma with surgical excision, cryotherapy, and mitomycin C. The Boston Ocular Surface Prosthesis was successful in improving vision, comfort, and epithelial status in our patients. CONCLUSION: Persistent epitheliopathy is a rare complication of treatment of conjunctival melanoma. The Boston Ocular Surface Prosthesis is a viable treatment option in this situation. PMID- 20164757 TI - Recurrent herpes simplex keratitis after verteporfin photodynamic therapy for corneal neovascularization. AB - PURPOSE: To report a case of recurrent herpes simplex keratitis after verteporfin photodynamic therapy for corneal neovascularization. METHODS: A 69-year-old man who had lipid keratopathy with corneal neovascularization secondary to herpes simplex keratitis in the right eye and who was treated with topical steroid received photodynamic therapy with verteporfin. Six neovascular areas in the cornea were treated consecutively to occlude new vessels and reduce the risk of allograft rejection after subsequent keratoplasty. RESULTS: Three days after verteporfin photodynamic therapy, there was evidence of vascular occlusion. However, a herpetic epithelial ulcer was detected in the cornea. Ten days after treatment, the lesion progressed to a geographic ulcer. After topical and systemic acyclovir treatment, the lesion healed. Five months after treatment, penetrating keratoplasty and postoperative antiviral prophylaxis were performed. During a follow-up period of 12 months, the graft remained clear with visual acuity of 20/40. CONCLUSION: Herpes simplex keratitis can recur after verteporfin photodynamic therapy for corneal neovascularization. PMID- 20164758 TI - Atypical mycobacterium keratitis associated with penetrating keratoplasty: case report of successful therapy with topical gatifloxacin 0.3%. AB - PURPOSE: To report successful therapy with gatifloxacin 0.3% ophthalmic solution (Zymar) in a patient with atypical mycobacterium keratitis after penetrating keratoplasty. METHODS: A 58-year-old patient was referred for evaluation of microbial keratitis after penetrating keratoplasty. RESULTS: Clinical examination of the patient revealed an infiltrate at the inferior graft-host junction with a satellite lesion with a mild inflammatory reaction in the anterior chamber. Microbiologic evaluation confirmed the diagnosis of atypical mycobacteria keratitis. The corneal abscess was completely eradicated with a topical course of gatifloxacin 0.3% with preservation of graft clarity and good visual acuity. Topical treatment with gatifloxacin 0.3% was continued for an additional period of 5 months. CONCLUSION: Topical gatifloxacin 0.3% may be successfully used to treat microbial keratitis resulting from atypical mycobacteria. PMID- 20164759 TI - Corneal graft detachment without corneal edema after descemet stripping automated endothelial keratoplasty. AB - PURPOSE: To report the case of a patient who underwent Descemet stripping automated endothelial keratoplasty complicated by corneal graft detachment without corneal edema. METHODS: Case report. RESULTS: A 60-year-old man with bilateral decompensated endothelium 10 years after cataract extraction and anterior chamber intraocular lens implantation underwent combined anterior chamber intraocular lens explantation with iris-sutured posterior chamber intraocular lens implantation and Descemet stripping automated endothelial keratoplasty on the right eye. On the second postoperative day, the corneal graft was attached. Two weeks postoperatively, slit lamp examination revealed a double anterior chamber resulting from corneal graft detachment. The corneal graft was reattached by repositioning and injecting air. One week later, the corneal graft had detached again, creating a double anterior chamber. No corneal edema was present. Nine months postoperatively, the cornea remained clear, although a double anterior chamber was still evident as a result of the detached corneal graft. CONCLUSION: Despite post-Descemet stripping automated endothelial keratoplasty corneal graft detachment, the cornea remained without edema. PMID- 20164760 TI - Ocular surface reconstruction with cultivated limbal epithelium in a patient with unilateral stem cell deficiency caused by Epidermolysis bullosa dystrophica hallopeau-Siemens. AB - PURPOSE: To report a case of partial limbal stem cell deficiency (LSCD) caused by epidermolysis bullosa dystrophica mutilans Hallopeau-Siemens treated by transplantation of autologous ex vivo expanded limbal epithelium. METHODS: Review of the clinical findings of an 11.5-year-old boy with unilateral LSCD and epidermolysis bullosa dystrophica who underwent ocular surface reconstruction in the right eye with autologous on intact human amniotic membrane cultivated limbal epithelial cells. RESULTS: Twenty-eight months after reconstruction, the corneal surface is clear, smooth, and stable showing no signs of LSCD recurrence. Three subconjunctival bevacizumab (Avastin) injections reduced the recurrent growth of symblepharon and corneal vascularization. The visual acuity has increased from hand motion to 20/50. CONCLUSION: Autologous transplantation of cultivated human limbal epithelial cells on intact human amniotic membrane can be a safe and effective method for corneal surface reconstruction in LSCD caused by recessive epidermolysis bullosa dystrophica. PMID- 20164761 TI - Microkeratome-assisted corneal tattooing: a case report. AB - PURPOSE: The purpose of this study was to report a new technique of microkeratome assisted corneal tattooing for cosmetic improvement in a young female patient with adherent leucoma. METHODS: The para-axial adherent leucoma had resulted from penetrating corneal injury sustained at the age of 2 years. A nasal hinged partial corneal flap of 140 MUm thickness was raised using the microkeratome. The flap extended to just beyond the medial margin of the leucoma. Organic dye powder was spread on the stromal bed over the leucomatous scar as well as on the undersurface of the corneal flap corresponding to the area of opacity. The flap was then repositioned and a bandage contact lens placed. RESULTS: The staining dye powder completely concealed the leucomatous opacity with good cosmesis and patient satisfaction. Corneal topography and best-corrected visual acuity remained unchanged at last follow up of 9 months. CONCLUSIONS: Microkeratome assisted corneal tattooing appears to be a safe, effective, and precise method of corneal tattooing. PMID- 20164762 TI - Should avoidance of foods be strict in prevention and treatment of food allergy? AB - PURPOSE OF REVIEW: To discuss whether strict allergen avoidance is the most appropriate strategy for managing or preventing food allergy. RECENT FINDINGS: The standard of care for the management of food allergy has been strict allergen avoidance. This advice is based upon the suppositions that exposure could result in allergic reactions and avoidance may speed recovery. Recent studies challenge these assumptions. Studies now demonstrate that most children with milk and egg allergy tolerate extensively heated forms of these foods. Moreover, clinical trials of oral immunotherapy show that oral exposure can lead to desensitization. Additionally, recent epidemiologic studies fail to support the notion that delaying introduction of highly allergenic foods to infants and young children prevents the development of food allergy. In fact, the data suggest that delays may increase risks. SUMMARY: Recent data indicate that strict allergen avoidance is not always necessary for treatment, exposure may be therapeutic, and extended delay in introduction of food allergens to the diet of young children may increase allergy risks. However, in many circumstances strict avoidance is clearly necessary for treatment. Additional studies are needed to determine the risks and benefits of exposure to tolerated allergen, including identification of biomarkers to identify patients who may benefit. PMID- 20164763 TI - The effect of prenatal and postnatal dietary exposures on childhood development of atopic disease. AB - PURPOSE OF REVIEW: Prenatal and early life dietary factors may influence asthma and allergic disease development. We review recent studies and consensus statements regarding the effects of prenatal/early life dietary exposures on atopic disease. RECENT FINDINGS: The American Academy of Pediatrics consensus statement highlighted the inadequacy of evidence for pregnancy antigen avoidance diets or delay of infant complementary foods beyond 4-6 months. Recent studies raise the question of whether early food introduction may promote tolerance, though controlled trials are pending. A recent meta-analysis suggested that antioxidants may protect against the development of atopy. Furthermore, some of the conflicting results on the effects of vitamin E may be related to variability in the isoforms prevalent in local diet. Recent studies of vitamin D similarly suggest that it may be protective, though this remains controversial. Finally, prenatal methyl donor exposure promoted the development of allergy in an animal model. SUMMARY: There are conflicting data on the effects of most prenatal and early childhood dietary exposures on childhood atopic disease. Longitudinal prenatal/birth cohort studies with prospective measurements and clinical supplementation trials of promising dietary factors will be needed to make reliable recommendations in this vulnerable population of pregnant women and their infants. PMID- 20164764 TI - Genetic testing in cardiovascular diseases. AB - PURPOSE OF REVIEW: To review the current state and different aspects, including the yield, of genetic counseling and genetic testing in inherited heart disease. RECENT FINDINGS: The number of counselees is growing rapidly all over the world, and the first studies about patients' perspectives and follow-up have been published. Progress has been made by gene-specific studies on long QT syndrome to judge the relevance of detected mutations in the specific domains. SUMMARY: With the increasing identification of associated genes and available techniques in molecular testing of the inherited heart diseases, the diagnostic yield of mutation analysis is growing rapidly. To determine the relevance of all these mutations, ongoing research is needed. Furthermore, the process of genetic counseling can be optimized and extended with cascade screening, which leads to identifying patients at risk and timely treatment. PMID- 20164765 TI - Temporal trends in the burden of chronic kidney disease in the United States. AB - PURPOSE OF REVIEW: The public health importance of chronic kidney disease (CKD) has only recently come to be appreciated and careful examination of temporal trends is warranted. The purpose of the present review was to examine existing research on temporal trends for CKD and treated end-stage renal disease (ESRD) in the United States. RECENT FINDINGS: When the broadly representative National Health and Nutrition Examination Survey (NHANES) datasets were compared in 1988 1994 and 1999-2002, a pronounced increase in the prevalence of abnormally low glomerular filtration rate was observed when serum creatinine was used to estimate glomerular filtration rate. In contrast, glomerular filtration rate findings were almost identical when cystatin C levels were examined. Thus, although the community-wide burden of CKD is already high, uncertainty exists as to the growth rate of this problem. For treated ESRD a dramatic increase in incidence rate occurred in the 1980s and 1990s. Changing burdens of standard risk factors for CKD do not readily explain increased rates of treated ESRD, suggesting that selection criteria for dialysis and transplant programs may underlie these secular trends. If the hypothesis that nonbiological factors are major determinants of rates of treated ESRD is valid, the latter may be a poor surrogate for true ESRD and for understanding its causes and rates of progression. SUMMARY: Given its prevalence and prognostic implications, it makes intuitive sense to monitor the burden of CKD over time; the validity of the tools used to generate an answer, however, is at least as important as the direction of the answer. PMID- 20164766 TI - Long-term outcomes of acute kidney injury. AB - PURPOSE OF REVIEW: The goal of this review is to summarize the recent plethora of data that relate to long-term outcomes after acute kidney injury (AKI). RECENT FINDINGS: Surviving patients with AKI are still at high risk for long-term adverse outcomes, even if serum creatinine returns to normal. After adjusting for potential confounders, many recent studies have demonstrated that AKI is independently associated with chronic kidney disease, end-stage renal disease, and premature death. Unfortunately, definitive evidence from randomized controlled trials demonstrating that prevention or treatment of AKI prevents long term adverse outcomes is not yet available. SUMMARY: AKI is clearly a prognostic marker for poor long-term outcomes, but more studies will be needed to determine whether AKI is truly causal and whether or not the risk is modifiable. PMID- 20164767 TI - Pediatric hypertension update. AB - PURPOSE OF REVIEW: The field of childhood hypertension has been changing rapidly since publication of the most recent consensus guidelines contained in the 2004 'Fourth Report'. RECENT FINDINGS: Several epidemiologic studies have indicated that the prevalence of hypertension in children and adolescents is on the increase. A major factor behind this increase is the childhood obesity epidemic. There is substantial new information on the frequency of hypertensive target organ damage in the young, including vascular, cardiac and renal effects. These data have led some authorities to recommend changes in how hypertension is evaluated and managed in the young. SUMMARY: There has been significant new knowledge gained about many aspects of childhood hypertension over the past 5 years. Clinicians who care for children and adolescents with high blood pressure should familiarize themselves with these new data and incorporate them into their clinical decision-making. PMID- 20164768 TI - Dopamine: what's new in migraine? AB - PURPOSE OF REVIEW: Dopamine has been implicated in the pathophysiology of migraine, although its exact role remains unclear. Recent data offer some new perspective on a possible role for dopaminergic mechanisms in migraine. This review aims to summarize our current understanding of dopamine in migraine. RECENT FINDINGS: Direct application of dopamine and dopamine receptor agonists onto trigeminocervical complex neurons inhibits their activation after nociceptive stimulation. The dopaminergic A11 nucleus of the hypothalamus has been identified as the likely source of this dopamine. Recent evidence has shown that the genes for dopamine beta-hydroxylase and the dopamine transporter SLC6A3 may play a role in migraine pathophysiology, and dopamine has also been implicated in menstrual migraine. SUMMARY: Dopamine is currently considered to contribute to the pathophysiology of migraine, and dopamine receptor antagonists are prescribed in the treatment of acute migraine. Laboratory data suggest that the role of dopamine in migraine is more complex, perhaps due to the multiple receptors and levels of the brain involved in the disorder. These data suggest a reappraisal of dopaminergic therapeutic targets in migraine as our understanding of the role of this important biogenic amine is better characterized. PMID- 20164769 TI - Novel MRI approaches to assess patients with multiple sclerosis. AB - PURPOSE OF REVIEW: This review summarizes novel MRI approaches for the investigation of lesion burden and understanding of the pathophysiology of multiple sclerosis (MS). RECENT FINDINGS: Recent technical advances are improving our ability to detect and define the nature of focal lesions and 'diffuse' tissue damage in MS as well as the functional consequences of such structural abnormalities. New contrast agents allow to monitor the pluriformity of MS inflammation. Double inversion recovery sequences enable us to detect and monitor the evolution of MS lesions in the cortex. High and ultra-high field scanners are improving imaging of MS-related abnormalities at an unprecedented resolution. Furthermore, this new generation of scanners has the potential to ameliorate structural and functional MR studies of the disease. All of this has contributed, and is likely to continue to contribute, to the definition of the factors associated with the development of irreversible disability in MS. Finally, new analysis methods have allowed to track regional disease-related changes and are resulting in an increased correlation between MRI and clinical deficits. SUMMARY: Novel MR approaches highlighted previously unrecognized or neglected aspects of MS pathophysiology, which are likely to improve our understanding of the heterogeneous clinical manifestations of this condition. PMID- 20164770 TI - The growing recognition of immunotherapy-responsive seizure disorders with autoantibodies to specific neuronal proteins. AB - PURPOSE OF REVIEW: The concept of epilepsy and seizure disorders caused by autoantibodies to specific neuronal membrane proteins has developed significantly during the past few years. RECENT FINDINGS: Antibodies to cell-surface membrane proteins such as voltage-gated potassium channels or N-methyl-D-aspartate receptors, or to glutamic acid decarboxylase, are found in patients with different forms of limbic encephalitis, and in a few patients with epilepsy as their main or only condition. Many of these patients do not show a good response to conventional antiepileptic drugs, but respond to immunotherapies. By contrast, studies of other antibodies in idiopathic forms of epilepsy, or epilepsy associated with systemic lupus erythematosus or coeliac disease, have not in general disclosed consistent, clinically helpful results. SUMMARY: There are a growing number of specific antibodies associated with new onset epilepsy. These patients are likely to have an immune-mediated disorder that may benefit from immunotherapies. In autoimmune diseases such as systemic lupus erythematosus or coeliac disease, antibodies to specific membrane targets may also prove to be important in the future. PMID- 20164771 TI - Current concepts on the use of glucocorticosteroids and beta-2-adrenoreceptor agonists to treat childhood asthma. AB - PURPOSE OF REVIEW: This article reviews current concepts regarding the clinical and scientific rationale for the combined use of glucocorticosteroids and beta-2 adrenoreceptor (beta2AR) agonists in the treatment of childhood asthma. RECENT FINDINGS: Several studies have demonstrated that inhaled corticosteroids (ICS) and beta2AR agonists are the most effective medications for the management of asthma in children. Given substantial evidence of an increased clinical benefit when these agents are used together, new studies are being pursued to establish the efficacy and safety of this combinational therapy in infants and children. Ongoing research is also investigating the mechanisms of beta2AR and glucocorticosteroids signaling and their molecular interactions. This new knowledge will likely lead to novel therapeutic approaches to asthma control. SUMMARY: There is increasing evidence demonstrating that the combination of long acting beta2AR agonists and ICS may be more effective than high-dose ICS therapy alone in the management of children with uncontrolled asthma. In addition, the use of a single inhaler containing ICS and a quick-acting beta2AR agonist might be a convenient alternative to prevent and treat asthma exacerbations. Future investigations should be designed to more specifically evaluate the efficacy and safety of these therapies in the different asthmatic phenotypes of infants and children. PMID- 20164772 TI - Child abuse and neglect: a worldwide concern. AB - PURPOSE OF REVIEW: As knowledge about child abuse and neglect increases worldwide, so does the literature on abuse and neglect. The authors explore many studies published this year, with attention to the advances in understanding which are guiding prevention efforts as well as diagnosis and treatment of abuse and neglect. RECENT FINDINGS: The evidence base for many forms of child abuse continues to grow. Controversy around the diagnosis of child abuse still continues, with current debate focused on the diagnosis of abusive head injury and whether children with vitamin D deficiency are misdiagnosed with abusive fractures. As clinicians begin to understand the factors which may increase child vulnerability to abuse, more sophisticated and focused prevention efforts are being implemented, and researchers are evaluating these efforts with an eye to whether or not they really contribute to prevention. SUMMARY: The short-term and long-term impact of child maltreatment is significant not only for individuals but for families and communities in which abuse is taking place. General pediatricians have an important role to play with families and in the community as advocates for the protection of children. However, it is clear that specialists in child abuse should also play a role in order for diagnosis and management of abuse to adhere to a high standard of care. This has been validated this year by the creation of Child Abuse Pediatrics as a board certified specialty in the United States. As knowledge about abuse and neglect grows, clinicians are focusing on prevention as well as diagnosis and treatment. PMID- 20164773 TI - Cardiovascular disease in rheumatoid arthritis: a step forward. AB - PURPOSE OF REVIEW: The present review highlights the recent findings on cardiovascular disease in rheumatoid arthritis (RA), and outlines the current concepts and prospects of cardiovascular disease detection and management in RA. RECENT FINDINGS: Over the past year the knowledge of cardiovascular disease in RA has been augmented by a number of studies further explicating the interplay between RA and cardiovascular risk factors and highlighting the impact of inflammatory measures, immune mediators and other markers as early determinants of cardiovascular disease in RA. Other studies reported potential beneficial effects on cardiovascular outcomes for some antirheumatic medications. SUMMARY: Knowledge of the increased burden of cardiovascular disease in RA is substantial and is continuously growing. Early detection, control and management of cardiovascular disease in RA appear to be a rapidly advancing field of research. However, much more work is needed to develop effective interventions to reduce cardiovascular morbidity and mortality in RA patients. More studies are needed to identify specific biomarkers for cardiovascular disease in RA and to develop cardiovascular risk scoring tools and evidence-based algorithms to promote more effective cardiovascular prevention and management of cardiovascular disease in RA. PMID- 20164774 TI - Kinase inhibitors: a new approach to rheumatoid arthritis treatment. AB - PURPOSE OF REVIEW: Due to the cost and parenteral mode of administration of biologics, efforts to develop oral small molecule inhibitors to protein kinases involved in cellular signaling that impact inflammatory cytokine production have been ongoing. This article will review the recent publications on these efforts. RECENT FINDINGS: On preclinical work, p38 mitogen-activated kinases were considered attractive targets to suppress cytokine production. Three different molecules (SCIO_469, Pamapimod, VX-702) that target the p38alpha isoform have been evaluated in phase 2 trials. Unfortunately, clinical efficacy was not observed, and dose-related toxicity was seen. The future of this approach is unclear. Targeting more upstream protein tyrosine kinases such as spleen tyrosine kinase (SyK) and the JAK family of kinases has been associated with greater success in clinical trials, with efficacy demonstrated. Adverse events occurred in a dose-dependent fashion with the SyK inhibitor, such as diarrhea and hypertension. Neutropenia, elevated liver-function tests, serum creatinine elevations and lipid elevations have occurred with JAK-kinase inhibition. Dose modifications have been made based on the phase 2 trial results; phase 3 clinical trials are ongoing. SUMMARY: Inhibiting downstream proteins involved in cellular signaling, such as p38, has not been successful to date. Inhibitors of more upstream protein-tyrosine kinases involved in cellular signaling appear to be viable molecular candidates for rheumatoid arthritis. If the results seen in phase 2 studies are confirmed in larger phase 3 studies, we may soon have new, oral DMARD therapies available. PMID- 20164775 TI - Comparison of prognostic performance of scores to predict risk of stroke in ED patients with transient ischaemic attack. AB - To compare the performance of three risk scores (ABCD, ABCD2 and California) in identification of short-term stroke risk in patients with emergency department (ED) diagnosis of transient ischaemic attack. In the retrospective cohort study, information collected included features of clinical risk scores, demographic, clinical and outcome data. The outcome of interest was new stroke occurrence at 2, 7 and 30 days. Data underwent receiver operating curve analyses. Of 326 patients, 17 patients experienced a new stroke within 30 days (4.9%, 95% confidence interval: 2.9-8.0%). C-statistic for high-stroke risk was not significantly different between scores at 2, 7 or 30 days. Using cutoffs of defined risk score cutoffs, the negative predictive values for stroke within 30 days were 97.4% (California), 99.1% (ABCD) and 98.9% (ABCD2), respectively. All three risk scores predict short-term risk of stroke in patients with an ED diagnosis of transient ischaemic attack and could be an effective tool to guide clinical decision making. PMID- 20164776 TI - Hand injuries seen at an emergency department in Singapore. AB - We aim to define the characteristics of patients with hand injuries in the emergency department (ED), their management and operative findings. Decision on admission was also analyzed between the ED and the hand and reconstructive microsurgical team. We reviewed 504 patients seen at the ED over a 3-month period with isolated hand injuries and found more males (88%) who were between 20 and 30 years of age (51%). Most had industrial injuries (43%) from lacerations or crush. Left hand injuries were more common. About 62% of the patients were discharged after treatment at the ED while 38% were admitted. A high level of concurrence in the decisions made by the ED and hand and reconstructive microsurgery signifies good quality assessment performed by the ED. The operative findings of fractures, tendon, nerve and vessel injuries for those who were admitted to the wards are higher than those admitted to 'day surgery'. PMID- 20164777 TI - Prehospital ultrasound in emergency medicine: incidence, feasibility, indications and diagnoses. AB - BACKGROUND: Sonography is an established diagnostic procedure in hospitals, but is not routinely used in prehospital emergency medicine. Several studies have addressed the use of ultrasound during helicopter flights and in emergency rooms, few in prehospital settings, but most focused on abdominal blunt trauma. Several case reports describe crucial decisions distinguished by ultrasound. METHODS: In this study, four different handheld ultrasound systems in 4 helicopters and one emergency vehicle were used over a cumulative period of 3 years. Incidence, feasibility, indication, diagnoses and exploration time (in subgroups) were investigated in an overall profile of emergency patients, encompassing the area of internal medicine. RESULTS: On 971 missions ultrasound systems were available. In 17% of the cases ultrasound was considered valuable, in 144 patients (14.8%) sonographic studies were performed. Additional information could be given in 130 cases (90%). Compared with the available clinical data (return rate of 76%) there were no false-positive findings during this study, resulting in a specificity and positive predictive value of 100%, showing this technique to be reliable. Sensitivity was 85%, accuracy was 96% and negative predictive value was 95%. CONCLUSION: Ultrasound is the only imaging modality and a useful diagnostic tool in prehospital emergency medicine. Helpful information can be provided in at least one of six cases (or even more) in a trauma-dominated collective. Examination time is short; it will not significantly delay medical care. Ultrasound examination could improve triage in cases of more than one patient in disaster medicine, but further studies are necessary. PMID- 20164778 TI - Screening for cognitive impairment in older people attending accident and emergency using the 4-item Abbreviated Mental Test. AB - To determine the utility of the 4-item Abbreviated Mental Test (AMT4) for detecting cognitive impairment in accident and emergency patients aged 65 years or older. Cognitive function was assessed using the Mini Mental State Examination (MMSE), 4 and 10-point AMT and subjective judgment. Cognitive impairment was defined as an MMSE score 23/30 or less. Of 601 patients, 226 (37.6%) scored 23 or less on MMSE. Cutoffs of 3 or less for AMT4 and 7 or less for AMT had sensitivities of 80% [95% confidence interval (CI): 0.75-0.85] and 76% (95% CI: 0.69-0.81), and specificities of 88% (95% CI: 0.84-0.91) and 93% (95% CI: 0.90 0.96), respectively, for detection of cognitive impairment; subjective judgement of admitting nurse had 50.5% (95% CI: 44-57%) sensitivity and 98.6% (95% CI: 0 96 1.00%) specificity. In conclusion, the AMT4 performs as well as the 10-point AMT in screening for cognitive impairment, and will assist in the early detection of cognitive problems. PMID- 20164779 TI - Noninvasive diagnosis and prognosis of liver cirrhosis: a comparison of biological scores, elastometry, and metabolic liver function tests. AB - BACKGROUND: Recently, noninvasive methods for the diagnosis of liver cirrhosis have been extensively developed. We assessed the accuracy of liver stiffness measurement, aspartate aminotransferase-to-platelet ratio index (APRI) score, 13C aminopyrine breath test, and indocyanine green plasma clearance for the diagnosis of cirrhosis in patients with chronic liver disease and for the prediction of severe complications in cirrhotic patients. METHODS: A total of 296 consecutive patients with chronic liver diseases of various causes were studied. Diagnostic accuracy was assessed by receiver operating characteristic curve analysis. RESULTS: Areas under the receiver operating characteristic curve for the diagnosis of cirrhosis were (95% confidence interval) 0.93 (0.90-0.96) for liver stiffness measurement, 0.82 (0.77-0.87) for 13C-aminopyrine breath test, and 0.81 (0.76-0.86) for APRI score. Using cutoff values of 14.1 kPa for liver stiffness, 4.15% dose/h for 13C-aminopyrine breath test, and 1 for APRI score, the positive predictive value was approximately 90% for the diagnosis of cirrhosis. Using cutoff values of 65.2 kPa for liver stiffness, 1.17% dose/h for 13C-aminopyrine breath test, 2.82 for APRI score, and 51.1% for indocyanine green plasma clearance, the positive predictive value was approximately 80% for the occurrence of severe complications among cirrhotic patients. CONCLUSION: Liver stiffness measurement, 13C-aminopyrine breath test, indocyanine green plasma clearance, and APRI score are reliable noninvasive methods for the diagnosis of cirrhosis in patients with chronic liver diseases of various causes, and are also prognostic indicators for the occurrence of severe complications in cirrhotic patients. PMID- 20164780 TI - Membranous glomerulonephritis associated with autoimmune hepatitis and primary biliary cirrhosis overlap syndrome: a very rare condition. PMID- 20164781 TI - The role of nutritional profile in the orexigenic neuropeptide secretion in nonalcoholic fatty liver disease obese adolescents. AB - BACKGROUND: Little progress has been made to identify the central neuroendocrine pathway involved in the energy intake control in nonalcoholic fatty liver disease (NAFLD) patients. OBJECTIVE: To assess the influence of orexigenic neuropeptides in the nutritional aspects of NAFLD obese adolescents submitted to a long-term interdisciplinary approach. METHODS: Fifty adolescents aged 15-19 years, with body mass index at least 95th percentile, consisting of 25 patients without NAFLD and 25 with NAFLD. The NAFLD diagnosis was determined by ultrasonography. Blood samples were collected to analyze glycemia, hepatic transaminases, and lipid profile. Insulin resistance was estimated by Homeostasis Model Assessment Insulin Resistance Index. Neuropeptide Y (NPY) and agouti related protein concentrations were measured by enzyme-linked immunosorbent assay. Analyses of food intake were made by 3 days recordatory inquiry. RESULTS: At baseline conditions, the patients with NAFLD had significantly higher values of body mass, body mass index, visceral fat, triglycerides, VLDL-C, and hepatic transaminases. After the long term intervention, they presented a significant reduction in these parameters. In both the groups, it was observed a significant decrease in energy intake, macronutrients and dietetic cholesterol. Only the patients with NAFLD presented a positive correlation between the saturated fatty acids intake and the orexigenic neuropeptides NPY and agouti related protein, and carbohydrate with NPY. Indeed, it was observed a positive correlation between energy intake, lipid (%) and saturated fatty acids with visceral fat accumulation. CONCLUSION: Our findings showed an important influence of diet composition in the orexigenic system, being essential consider that the excessive saturated fatty acids intake could be a determinant factor to increase nonalcoholic fatty liver disease. PMID- 20164782 TI - Resistance to Simian HIV infection is associated with high plasma interleukin-8, RANTES and Eotaxin in a macaque model of repeated virus challenges. AB - Animal models for research on susceptibility to HIV are currently not available. Here we explore whether a macaque model of repeated low-dose rectal or vaginal virus challenges could be employed. We tested the hypothesis that susceptibility to Simian HIV is not merely stochastic in this model but rather is associated with identifiable host factors. Forty macaques required a median of 3.5 SHIVSF162P3 challenges for infection. We studied the association of their susceptibility with 13 predisposing plasma cytokines/chemokines (RANTES, Eotaxin, monocyte chemoattractant protein (MCP)-1, IL-7, MIP-1beta, TNF-alpha, MIP-1alpha, granulocyte colony-stimulating factor, IL-8, interferon-gamma, IL-17, IL-1beta, IL-6). Higher plasma RANTES, IL-8, and Eotaxin were associated with lower susceptibility, that is, higher resistance to infection. In a group of macaques with low IL-8 and RANTES, a median 3 exposures were required to infect; whereas, when either IL-8 or RANTES were high, a median 12 exposures were required. Thus, susceptibility was associated with identifiable discrete host factors and was not stochastic. In addition, the macaque model identified key human resistance factors (RANTES, Eotaxin), but also revealed a novel association with resistance (IL-8). Future direct evaluation of these or other factors in the animal model may be beneficial for developing new immunomodulation strategies for HIV prevention. PMID- 20164783 TI - Preprocedural score for risk of contrast-induced nephropathy in elective coronary angiography and intervention. AB - OBJECTIVES: To develop a simplified scoring system based on preprocedure clinical characteristics to predict contrast-induced nephropathy (CIN) before elective coronary angiography and percutaneous coronary intervention (PCI). BACKGROUND: CIN is associated with increased mortality and morbidity following coronary angiography and PCI and accounts for increased hospital costs. METHODS: Several baseline clinical characteristics of 1218 patients were considered as candidate univariate predictors of CIN (increase > or =0.5 mg/dl in serum creatinine within 5 days after contrast exposure). On the basis of the odds ratio at multivariate logistic regression, seven markers (with weighted scores) were identified as independent correlates of CIN: age at least 73 years (1), diabetes mellitus (2), left ventricular ejection fraction 45% or less (2), baseline serum creatinine value at least 1.5 mg/dl (2), baseline creatinine clearance 44 ml/min or less (2), posthydration creatinine > or = prehydration creatinine value (2) and one procedure effected within the past 72 h (3). RESULTS: CIN occurred in 114 (9.4%) patients [range 1.1-52.1% for a low (< or =3) and very high (> or =9) risk score, respectively]; the odds of CIN increased significantly with each class (Cochran Armitage chi-square, P < 0.0001) and the risk score allowed us to determine patients with low and high risk for postprocedure CIN (c-statistic = 0.86). These results were reproduced in a validation set. CONCLUSION: Preprocedural clinical risk factors have different influences on the likelihood of CIN. Risk classification based on the most significant parameters can be used to predict CIN before contrast exposure. The simple scoring system proposed here provides a good estimate of the risk of CIN, allowing the interventional team to make adequate adjustment to the procedures. PMID- 20164784 TI - The role of insulin resistance in the pathogenesis of atherosclerotic cardiovascular disease: an updated review. AB - Insulin resistance is the main pathologic mechanism that links the constellation of clinical, metabolic and anthropometric traits with increased risk for cardiovascular disease and type II diabetes mellitus. These traits include hyperinsulinemia, impaired glucose intolerance, endothelial dysfunction, dyslipidemia, hypertension, and generalized and upper body fat redistribution. This cluster is often referred to as insulin resistance syndrome. The progression of insulin resistance to diabetes mellitus parallels the progression of endothelial dysfunction to atherosclerosis leading to cardiovascular disease and its complications. In fact, insulin resistance assessed by homeostasis model assessment (HOMA) has shown to be independently predictive of cardiovascular disease in several studies and one unit increase in insulin resistance is associated with a 5.4% increase in cardiovascular disease risk. This review article addresses the role of insulin resistance as a main causal factor in the development of metabolic syndrome and endothelial dysfunction, and its relationship with cardiovascular disease. In addition to this, we review the type of lifestyle modification and pharmacotherapy that could possibly ameliorate the effect of insulin resistance and reverse the disturbances in insulin, glucose and lipid metabolism. PMID- 20164785 TI - Comparison of the vasoconstrictor effects of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) and zolmitriptan in human isolated coronary arteries. AB - Studies were conducted in human isolated coronary arteries to explore the vascular effects of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant and to compare its coronary vasoconstrictive potential to that of zolmitriptan. KCl precontracted coronary vessels were shown to relax to human alphaCGRP, with the CGRP-mediated vasorelaxation completely blocked with 30 microM telcagepant. In coronary vessels at basal tone, zolmitriptan caused a concentration-dependent contraction (pEC50 = 6.9 +/- 0.1; slope 0.94), with the greatest contraction obtained between 1 and 10 microM in most tissues. In contrast, telcagepant at concentrations up to 30 microM evoked no change in contractile tone. These findings suggest the potential for CGRP receptor antagonists to exert antimigraine efficacy in the absence of adverse effects on coronary tone. PMID- 20164786 TI - Effects of arginine vasopressin on differentiation of cardiac fibroblasts into myofibroblasts. AB - BACKGROUND: Differentiation of cardiac fibroblasts (CFs) into myofibroblasts is a critical event in the initiation of myocardial fibrosis (MF). Previous studies have shown that arginine vasopressin (AVP) facilitates MF. However, the effects of AVP on CFs-myofibroblasts transformation, and its possible mechanisms are still unknown. METHODS: CFs obtained from neonatal Sprague-Dawley rats were stimulated with AVP in the absence or presence of AVP V1a receptor specific antagonist [d(CH2)5Tyr(Me)]AVP. CFs-myofibroblast transformation was detected by expression of alpha-smooth muscle actin (alpha-SMA) and collagen synthesis. Western bolt and immunofluorescent staining were used to detect expression of alpha-SMA, [H]Proline incorporation was used to detect collagen synthesis. AVP induced transforming growth factor-beta1 (TGF-beta1) secretion was detected by enzyme-linked immunosorbent assay. CFs was also stimulated with exogenous TGF beta1 to find out the required dose to induce CFs-myofibroblast transformation. RESULTS: 10 mol/L AVP increased alpha-SMA expression and collagen synthesis significantly, and this effect was blocked by [d(CH2)5Tyr(Me)]AVP at the concentration of 10 mol/L. Meanwhile, AVP significantly increased TGF-beta1 secretion of CFs in a dose-dependent manner, and this effect was also blocked by 10 mol/L [d(CH2)5Tyr(Me)]AVP. However, the maximum production of biologic active TGF-beta1 induced by AVP is far less than the dose of exogenous TGF-beta1 needed to induce CFs-myofibroblast transformation. CONCLUSIONS: AVP can induce CFs myofibroblast transformation via its V1a receptor, AVP-induced increase of TGF beta1 synthesis, which also is mediated by V1a receptor, may play a minor role in the transformation. Inducing differentiation of CFs into myofibroblasts may be a mechanism of AVP contributing to MF. PMID- 20164787 TI - Candesartan decreases type III procollagen-N-peptide levels and inflammatory marker levels and maintains sinus rhythm in patients with atrial fibrillation. AB - This study has evaluated whether candesartans prevent the recurrence of atrial fibrillation (AF) and decrease type III procollagen-N-peptide (PIIINP) levels. A total of 153 patients with AF were enrolled in this study. Three groups of patients were compared; candesartan group was treated with candesartan plus bepridil (n = 52); and carvedilol group with carvedilol plus bepridil (n = 51); and bepridil group with bepridil alone (n = 50). The primary end point was length of time to the recurrence of AF and all patients were ultimately followed-up for 730 days. Serum levels of the biomarkers were measured at baseline and after 24 months. Maintenance of sinus rhythm was achieved in 25 (50%) patients in bepridil group, 37 (73%) in candesartan group, and 34 (67%) in carvedilol group, giving a bepridil group/candesartan group hazard ratio of 0.36 (95% confidence interval 0.21-0.63; P = 0.03). Candesartan significantly decreased PIIINP levels at 24 months than at baseline in sinus rhythm group (0.57 +/- 0.02 vs. 0.64 +/- 0.05 U/mL, P = 0.04) and did not decrease PIIINP levels in the recurrence group. In conclusions, PIIINP might be related to the possibility of the atrial fibrosis for AF. However, further studies are needed to clarify the relationship between PIIINP and AF. PMID- 20164788 TI - Lysimachia clethroides extract promote vascular relaxation via endothelium dependent mechanism. AB - Lysimachia clethroides is widely used in traditional herbal medicine for many purposes, especially for blood vessel-related diseases in Korea and East Asia. Experiments were undertaken to determine whether hydro-alcoholic extract obtained from L. clethroides (LCE) has vasorelaxant activity in the rat aorta rings and, if so, to elucidate the underlying mechanism. Rat aorta rings were suspended in organ chambers for the measurement of changes in isometric tension in the presence or absence of several inhibitors. LCE induced endothelium-dependent vasodilation (ED50 = 6.1 mug/mL) and that was abolished by nitric oxide synthase inhibitor, N-nitro-L-arginine, and guanylyl cyclase inhibitor, 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one, PI3-kinase inhibitor, wortmannin, and cell permeable superoxide dismutase. In addition, LCE decreased vessels contraction by phenylephrine. Prostaglandin synthesis inhibitor, indometacin, and inhibitors of endothelium-derived hyperpolarizing factor, charybdotoxin plus apamin, did not affect vasodilatory effect of LCE. In cultured endothelial cells, LCE-induced phosphorylation of serine 1177-endothelial nitric oxide synthase and serine 473 Akt. LCE inhibited strongly nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in smooth muscle cells and angiotensin II-induced contraction of rat aorta. Finally, increased oxidative stress in rat aorta-induced by angiotensin II is ameliorated by LCE. Taken together, LCE induces an endothelium dependent vasodilation and might be involved, at least in part, the activation of the nitric oxide-cyclic guanosine monophosphate pathway. In addition, LCE decreases oxidative stress in aorta by inhibition of NADPH oxidase activity. The present findings indicate that LCE could be a candidate of herbal medicine for cardiovascular diseases associated with disturbed NO production and endothelial dysfunction. PMID- 20164789 TI - Effects of sex hormones on cardiac repolarization. AB - This article reviews the current findings on the topic of gender differences derived from effects of sex steroid hormones on cardiac repolarization and drug induced torsade de pointes. Published studies have shown that sex-related differences exist in clinical cardiac electrophysiologic measurements, and that gender is an independent risk factor in vulnerability to certain types of arrhythmia. For example, women are especially susceptible to increased arrhythmia risk in response to QT-prolonging drugs. However, a number of questions remain- especially regarding the specific influence of sex steroid hormones in gender differences. Further experimental or clinical investigations are necessary to elucidate gender differences in cardiac repolarization, QT interval prolongation, and susceptibility to cardiac arrhythmias. PMID- 20164790 TI - The Ahmed Glaucoma Valve in patients with and without neovascular glaucoma. AB - PURPOSE: To evaluate the results of Ahmed Glaucoma Valve surgery in neovascular glaucoma and control patients. PATIENTS AND METHODS: In this retrospective comparative study, we reviewed 76 eyes of 76 patients, comparing the surgical outcomes in control patients (N=38) to matched neovascular glaucoma patients (N=38). Success was defined as intraocular pressure (IOP) >=6 mm Hg and <=21 mm Hg, without further glaucoma surgery, and without loss of light perception. RESULTS: Average follow-up for control and neovascular glaucoma patients was 18.4 and 17.4 months, respectively (P=0.550). The mean IOPs were 17.9+/-8.4 mm Hg and 16.5+/-15.8 mm Hg at 1-year (P=0.150), and 18.4+/-11.2 mm Hg and 9.9+/-6.3 mm Hg at 2 years (P=0.057) in controls and eyes with neovascular glaucoma, respectively. Life-table analysis showed a significantly lower success for neovascular glaucoma patients compared with controls (P=0.0096), with success at 1 year=89.2% and 73.1%, 2 years=81.8% and 61.9%, and 5 years=81.8% and 20.6% for control and neovascular glaucoma eyes, respectively. Cox proportional hazard regression analysis showed neovascular glaucoma as a risk factor for surgical failure (odds ratio=5.384, 95% CI=1.22-23.84, P=0.027). Although IOP control and complications were comparable between the 2 groups, visual outcomes were worse in neovascular glaucoma patients, with 9 (23.7%) eyes with neovascular glaucoma compared with no controls losing light perception vision (P=0.002). The majority with loss of vision (5 of 9) had successful control of IOP during the postoperative period. CONCLUSIONS: Neovascular glaucoma patients have greater risk of surgical failure after Ahmed Glaucoma Valve surgery compared with controls. Despite improved IOP with drainage implants, visual outcomes may be poor, probably owing to progression of underlying disease. PMID- 20164791 TI - Progression in primary angle closure eyes. AB - PURPOSE: To study the long-term course of primary angle closure (PAC) eyes after iridotomy. METHODS: Seventy-two eyes of 72 patients diagnosed as PAC, having occludable angles with evidence of closure, but no ocular hypertension, were studied. Laser iridotomy was carried out in all eyes at baseline. Standard achromatic perimetry and tonometry were recorded at baseline and serially every 6 months, for at least 4 years. Changes on perimetry and the intraocular pressure (IOP) were analyzed. RESULTS: At 1 year, 10 eyes and at final review, 26 eyes had developed ocular hypertension and required topical antiglaucoma medication. Eight eyes developed visual field defects on standard achromatic perimetry, over a mean period of 6.89+/-2.4 years. Eyes that progressed on perimetry, had a significantly narrower angle recess, less than or equal to 10 degrees, P=0.04, and a higher baseline MD and PSD, P=0.004 and 0.03, respectively. They also showed having a larger intervisit IOP fluctuation of 8.9+/-2.3 mm Hg, cf stable eyes, 6.2+/-3 mm Hg, P=0.003, and a longer duration of follow-up, P=0.01. CONCLUSION: A third of PAC eyes, with very narrow angles, higher global indices, intervisit IOP fluctuations, and a longer duration of follow-up were observed to develop ocular hypertension. A third of the PAC eyes with hypertension, that is 11.1% overall, went on to develop PAC glaucoma. PMID- 20164792 TI - IOP variations in the sitting and supine positions. AB - PURPOSE: The aim of this study was to assess the influence of the position (upright vs. supine) in the intraocular pressure (IOP) measured with a non contact portable tonometer. METHODS: Fifty university students with a mean age of 22.3+/-4.2 years (mean+/-SD) were recruited to participate in this study. IOP was measured with the non-contact tonometer Keeler, Pulsair EasyEye. Measurements in upright and supine positions were randomly obtained. In the upright position, 2 series of 3 measures (UP1 and UP2) and a series of 3 measures in the supine position were performed. RESULTS: The values obtained in the positions UP1 and UP2 were compared, as well as the values of the upright and supine positions. No statistically significant differences were found when comparing the values obtained in the upright position (P>0.05). Instead, when the subjects were in the supine position, IOP increased 2.47+/-2.12 mm Hg (mean+/-SD), as opposed to the value obtained in the upright position (P<0.001). CONCLUSIONS: Results from this study showed that IOP increased when measured in the supine position and that the Pulsair EasyEye tonometer can determine those variations in a healthy young population. PMID- 20164793 TI - Intraocular pressure values obtained by ocular response analyzer, dynamic contour tonometry, and goldmann tonometry in keratokonic corneas. AB - PURPOSE: To determine the agreement between dynamic contour tonometer (DCT), Goldmann applanation tonometer (GAT), and Ocular Response Analyzer (ORA) in keratoconic corneas and to find out the effect of corneal biomechanics on intraocular pressure (IOP) measurements obtained by these devices. SUBJECTS AND METHODS: IOP was measured with the ORA, DCT, and GAT in random order in 120 eyes of 61 keratoconus patients. Central corneal thickness (CCT) and keratometry were measured after all IOP determinations had been made. The mean IOP measurement by the ORA and DCT was compared with the measurement by the GAT, using Student t test. Bland-Altman analysis was performed to assess the clinical agreement between these methods. The effect of corneal hysteresis (CH), corneal resistance factor (CRF), and CCT on measured IOP was explored by multiple backward stepwise linear regression analysis. RESULTS: The mean+/-SD patient age was 30.6+/-11.2 years. The mean+/-SD IOP measurement obtained with GAT, ORA Goldmann-correlated IOP (IOPg), ORA corneal-compensated IOP (IOPcc), and DCT was 10.96+/-2.8, 10.23+/ 3.5, 14.65+/-2.8, and 15.42+/-2.7 mm Hg, respectively. The mean+/-SD CCT was 464.08+/-58.4 microns. The mean difference between IOPcc and GAT (P<0.0001), IOPcc and DCT (P<0.001), GAT and DCT (P<0.0001), IOPg and GAT (P<0.002), and IOPg and DCT (P<0.0001), was highly statistically significant. In multivariable regression analysis, DCT IOP and GAT IOP measurements were significantly associated with CH and CRF (P<0.0001 for both). CONCLUSIONS: DCT seemed to be affected by CH and CRF, and the IOP values tended to be higher when compared with GAT. ORA-measured IOPcc was found to be independent of CCT and suitable in comparison to the DCT in keratoconic eyes. PMID- 20164794 TI - Spectral-domain optical coherence tomography measurement of macular volume for diagnosing glaucoma. AB - PURPOSE: To determine the glaucoma diagnostic power of measuring the volume of the ganglion cell complex (GCC; 3 innermost retinal layers) using spectral-domain optical coherence tomography (SD-OCT). PATIENTS AND METHODS: Fifty eyes with open angle glaucoma and 35 normal partipants were included for this study. SD-OCT (RTVue-100), and time-domain (TD)-OCT were used to measure total retinal, GCC (SD OCT only), and circumpapillary retinal nerve fiber layer (cpRNFL) thicknesses in 50 eyes with open-angle glaucoma and in 35 without glaucoma. RESULTS: Total retinal and GCC volumes in a macular area correlated with visual field mean deviation (GCC: r=0.580, P<0.001; total: r=0.458, P<0.001). The area under the receiver operating characteristic curve (AROC) was greater for macular GCC volume (0.922) than for macular total retinal volume, as measured by SD-OCT (0.857; P=0.020) or TD-OCT (0.841; P=0.025). GCC AROCs were smaller than cpRNFL AROCs determined using SD-OCT (0.971; P=0.110) or TD-OCT (0.970; P=0.122), but not in a statistically significant manner. AROC for the GCC was greatest in the inferior macula. Interclass correlation coefficient values were comparable for GCC and total retinal volumes. CONCLUSION: Selective measurement of the GCC layer by SD OCT improves diagnostic performance of the macular structural analysis for glaucoma diagnosis. PMID- 20164795 TI - Elevated serum immunoglobulin G titers against Chlamydia pneumoniae in primary open-angle glaucoma patients without systemic disease. AB - PURPOSE: To determine if Chlamydia pneumoniae infection is associated with primary open-angle glaucoma (POAG). PATIENTS AND METHODS: Consecutive patients with newly diagnosed primary POAG attending the Glaucoma clinic of Keio University Hospital between June 2007 and January 2008 were considered for inclusion in this prospective case-control study. Forty consecutive POAG patients and 41 normal healthy individuals as a control population met the inclusion criteria. The exclusion criteria for both groups were; taking steroids or immunosuppressive agents, smoking, and history of any acute or chronic systemic disease including stroke, heart attack, diabetes mellitus, hypertension, asthma, and autoimmune diseases. The serum was analyzed for C. pneumoniae and C. trachomatis immunoglobulin G antibody titers by enzyme-linked immunosorbent assay. Seroactivity to each antigen between case and control groups was evaluated by Mann-Whitney U test. RESULTS: The age, male/female ratio, and intraocular pressure of the cases and control groups were not significantly different. Immunoglobulin G titers for C. pneuemoniae was significantly higher in patients with POAG than in controls (P=0.009). The titers to C. trachomatis were not significantly different between the 2 groups (P=0.99). CONCLUSION: The results suggest that higher C. pneumoniae titers are associated with POAG. If confirmed, this may indicate either a common factor that causes susceptibilities to both glaucoma and C. pneumoniae infection or that C. pneumoniae may be a causal factor for developing POAG. PMID- 20164796 TI - The SuperCrescent diamond knife: an innovative blade for glaucoma surgery. AB - Diamond blades have been used extensively in cataract surgery but their routine use in glaucoma surgery has been limited owing to the lack of controlled sharpness. The SuperCrescent knife is an ultrathin (100 MUm) diamond blade that is an innovative modification of conventional blade design. Its pentium faceted trapezoidal design along with the square front surface area affords better control during dissection and has been used with success in both traditional trabeculectomies and nonpenetrating glaucoma procedures. PMID- 20164797 TI - The influence of central corneal thickness on intraocular pressure measured by goldmann applanation tonometry among selected Ethiopian communities. AB - BACKGROUND: Estimates of intraocular pressure (IOP) are influenced directly by the central corneal thickness (CCT). We assume and apply a single value for CCT (520 MUm) in applanation tonometry estimates, although there is compelling evidence that CCT varies between individuals. OBJECTIVE: To determine the influence of CCT and other factors on IOP among Ethiopians. METHODS: A cross sectional study was conducted among 300 sampled individuals from June to July 2006. The CCT was measured using OcuScan(r) R*P Ophthalmic Ultrasound and readings of IOP were made with Goldmann applanation tonometer. The data was analyzed using SPSS version 12 and S-Plus 2000 of statistical packages. RESULTS: Out of 300 individuals, 184 (61.3%) were males. The mean age was 42.57 years (SD+/-16.71), mean IOP 13.39 mm Hg (SD+/-2.81), and mean CCT 518.68 MUm (SD+/ 32.92). There was statistically significant relationship between CCT and IOP (r=0.199, P<0.001) and a borderline statistically significant detectable change of CCT with age (r=0.012, P=0.057) with a downward trend of at least 0.001 mm decrease in CCT/decade starting from age 30 years but with pronounced change from 50 years onward. For every 30 MUm difference in CCT from the mean in either way, there was an approximately 1.1 mm Hg difference in the estimated IOP from the mean IOP (13.40 mm Hg). No significant relationship was found between IOP and age, sex or ethnicity (P>0.05). CONCLUSION: The CCT of Ethiopians is thin and hence can result in underestimation of IOP measured by GAT. PMID- 20164798 TI - The assessment of the filtering bleb function with anterior segment optical coherence tomography. AB - PURPOSE: To assess the usefulness of anterior segment optical coherence tomography (AS-OCT) in evaluating postoperative filtering bleb function. METHODS: Forty-eight eyes of 39 patients who had earlier undergone trabeculectomy were enrolled. Blebs were imaged with a commercially available AS-OCT system. The correlation between intraocular pressure (IOP) and 4 quantitative parameters, bleb height, bleb wall thickness, and the height and extent of internal cavity, and 2 qualitative parameters, bleb wall reflectivity, and the presence or absence of posterior episcleral fluid, were analyzed. RESULTS: Of the 39 participants, 25 (64.1%) were males (mean age, 65.3+/-10.0 y). The height and extent of the internal cavity and the bleb height were not correlated with the IOP. The bleb wall thickness was negatively (P=0.004) correlated with the IOP. The mean IOP in eyes with a low-reflectivity bleb wall was significantly (P=0.001) lower than in eyes with a high-reflectivity wall. The IOP levels were significantly (P=0.008) lower in eyes with posterior episcleral fluid than in eyes without it. CONCLUSIONS: AS-OCT is a useful tool to evaluate filtering bleb function. The height and extent of the total bleb and the internal cavity were not correlated with IOP control. A low-reflectivity wall and the presence of episcleral fluid were associated with lower IOP. PMID- 20164799 TI - Evaluation of Ex-PRESS mini glaucoma shunt implantation in refractory postpenetrating keratoplasty glaucoma. AB - PURPOSE: To evaluate the intraocular pressure (IOP) control and graft survival after Ex-PRESS mini glaucoma shunt implantation in refractory postpenetrating keratoplasty glaucoma. METHODS: The study included postpenetrating keratoplasty glaucoma cases unresponsive to medical antiglaucomatous therapy in whom 15 Ex PRESS mini glaucoma shunt implantation was carried out. All glaucoma shunt implantations were performed in a separate session after penetrating keratoplasty. Nine operations were performed under general anesthesia and 6 were performed under local anesthesia. Topical antibiotherapy and topical corticosteroids were used during the postoperative first month. RESULTS: Mean age of the study population was 37.4 years (range: 10 to 80 y). IOP decreased from 41.46 mm Hg (range: 26 to 80 mm Hg) to 12.06 mm Hg (range: 8 to 25 mm Hg) over a mean follow-up of 12.2 months (range: 8 to 19 mo) (P<0.001; Wilcoxon signed rank test). IOP was below 21 mm Hg in 14 of 15 eyes (93.3%) with or without antiglaucomatous drugs. Complete success (IOP<21 mm Hg without medication) rate was 86.6%. Average number of antiglaucomatous drug usage decreased from 3.20 (range: 2 to 4) preoperatively to 0.26 postoperatively (range: 0 to 3) (P<0.001; Wilcoxon signed rank test). In 93.3% of the cases, the decrease in IOP was 30% or above postoperatively. After Ex-PRESS implantation, clear grafts remained clear while edematous grafts became clearer due to IOP decrease. Neither biomicroscopy nor pachymetry showed worsening of preoperatively opaque grafts. CONCLUSION: Ex PRESS mini glaucoma shunt implantation may be an effective procedure for refractory postpenetrating keratoplasty glaucoma with acceptable graft failure rates in short term. PMID- 20164800 TI - Relief of periorbital pain after acute angle closure glaucoma attack by botulinum toxin type A. AB - PURPOSE: To assess the efficacy and safety of botulinum toxin type A (BoNT-A) injection in patients suffering from intractable periorbital pain after acute angle closure glaucoma (AACG). PATIENTS AND METHODS: In this prospective randomized intervention study, 19 patients suffering from periorbital pain after an AACG attack were injected with BoNT-A or placebo for pain relief. Patients were assessed on days 1, 2, 7, 14, 30, 60, and 90. The main outcomes were mean change of visual analog rating scale (VARS) and index scores measured through a quality-of-life questionnaire (EQ-5D), and changes in the visual analog scale (VAS), all of which were assessed at each visit. A secondary outcome was the frequency and nature of adverse events and the number of patients who withdrew from the study as a result. RESULTS: In the treatment group (n=10), the mean index score of EQ-5D and VAS changed significantly from the placebo group (by 0.299 and 2.61, respectively) from day 2 (P<0.01). The VARS of EQ-5D also disclosed significant changes from day 2 (17, P<0.01). In addition, efficacy was maintained mainly between days 2 and 60 but declined slightly by day 90. The most frequently reported treatment-related adverse events in the treatment and placebo groups were local tenderness (21%), subcutaneous hemorrhage (10.5%), and conjunctivitis (10.5%). No severe adverse events were reported during the study or follow-up period. CONCLUSIONS: BoNT-A is effective and well tolerated for the treatment of periorbital pain after an AACG attack. Its effects may be maintained for 3 months. PMID- 20164801 TI - In vitro effects of antivascular endothelial growth factors on cultured human trabecular meshwork cells. AB - PURPOSE: To investigate the effects of a neutralizing vascular endothelial growth factor antibody and antibody fragment as well as vehicle components on primary cultures of human trabecular meshwork (TM) cells. METHODS: Assays of cellular metabolism were performed using the diphenyl tetrazolium bromide assay in confluent cultures of cells. Proliferative effects were determined by measuring 5'-bromo-2'-deoxyuridine uptake in subconfluent cultures of cells. RESULTS: Twenty-four-hour treatment with 4 mg/mL bevacizumab reduced TM metabolism to 34.4 +/- 12.4% (mean +/- SD) as compared with human immunoglobulin G controls (P<0.0001). 4 mg/mL bevacizumab also reduced TM cell proliferation to 62.7 +/- 9.2% of controls (P<0.0001). No significant decrease was seen at 2 mg/mL bevacizumab, or with molar equivalents of the related anti-vascular endothelial growth factor agent ranibizumab. Exposure of TM cells to the components of bevacizumab and ranibizumab vehicle did not lead to significant antimetabolic effects. CONCLUSIONS: Our data reveal that high concentrations of bevacizumab are harmful to TM cells in vitro whereas no such effect was noted with human immunoglobulin G controls or ranibizumab. Further studies are needed to better understand the antimetabolic effects of higher concentrations of bevacizumab on intraocular cell lines and whether smaller concentrations may have a similar effect on TM cells after repeated exposures. PMID- 20164802 TI - Pigment dispersion syndrome patients do not have larger-than-normal irides. AB - PURPOSE: To compare iris cross-sectional area and thickness in the accommodated and unaccommodated states in controls versus patients with pigment dispersion syndrome (PDS) and to quantify short-term response of the iris to accommodation. PATIENTS AND METHODS: Thirty-three patients with PDS and 17 control subjects were examined with ultrasound biomicroscopy. A radial image of the iris and ciliary body was taken at the temporal quadrant before and after accommodation with the patient looking at a standardized target. Iris thickness was measured from a line perpendicular to the iris from points on the trabecular meshwork 500, 1000, and 3000 MUm from the scleral spur. Ciliary body thickness was measured 500 MUm posterior to the scleral spur. Independent sample t tests (2-sided) compared iris thickness and cross-sectional area between groups. RESULTS: All participants were of European descent. Mean age was 45.6 +/- 5.4 years (mean +/- 95% confidence interval) in the PDS group and 34.9 +/- 5.5 in the controls. Mean refractive error was -4.26 +/- 1.0 diopters in the PDS group and -4.83 +/- 1.0 diopters in the controls (P=0.499). There was no significant difference in iris cross sectional area in the accommodated and unaccommodated states between the 3 groups. For all quantities measured (iris thickness at 500, 1000, 3000 MUm; iris cross-sectional area; ciliary body thickness and area), there was no significant difference between the control group and the PDS group (P>0.35). CONCLUSIONS: Iris cross-sectional area and thickness and ciliary body thickness were similar in the accommodated and unaccommodated states in PDS and controls. This result provides further suggestive evidence that nongeometrical factors contribute to the development of PDS. PMID- 20164803 TI - The occurrence and features of the atypical birefringence pattern in scanning laser polarimetry using GD * VCC in healthy children and its impact on the retinal nerve fiber layer thickness values. AB - PURPOSE: To investigate the occurrence and features of the atypical birefringence pattern (ABP) images in scanning laser polarimetry with variable corneal compensation (GD*VCC) in healthy children and to assess their impact on the values of the retinal nerve fiber layer (RNFL) thickness. METHODS: GD*VCC scans in 120 healthy white school-aged children with mean age +/- standard deviation (SD) 12.85 +/- 3.0 years were evaluated using typical scan score (TSS) calculation and by subjective grading of the scans. Statistical analysis including the impact of ABP on the RNFL thickness in GD * VCC Temporal-Superior Nasal-Inferior-Temporal (TSNIT) parameters was done. RESULTS: The ABP was found in 18 out of 120 patients (15%) at cut-off value of TSS <80. Subjective evaluation of the scans raised the frequency of ABP to 20% of patients. The mean +/- SD values of TSNIT Average, Superior Average, and Inferior Average in 26 eyes with ABP versus 214 eyes with normal birefringence pattern were 66.99 +/- 7.29 MUm versus 58.00 +/- 6.22 MUm (P = 7.2E to -11), 78.43 +/- 9.27 MUm versus 72.33 +/- 8.72 MUm (P = 0.001) and 80.87 +/- 12.01 MUm versus 70.00 +/- 10.20 MUm (P = 0.000001), respectively. The same comparison in TSNIT SD showed minimal difference and was 25.42 +/- 5.84 MUm versus 26.41 +/- 4.81 MUm (P = 0.41). CONCLUSIONS: The occurrence of ABP in children is not rare and may significantly distort the measured values of the RNFL thickness in TSNIT parameters using GD * VCC. PMID- 20164804 TI - Reinforcement of the adrenergic overdrive in the metabolic syndrome complicated by obstructive sleep apnea. AB - BACKGROUND: Metabolic syndrome is characterized by a marked sympathetic overactivity. It is unknown, however, whether the neuroadrenergic activation can be ascribed to obstructive sleep apnoea (OSA), OSA exerts potentiating effects on the metabolic syndrome-related sympathetic activation and reflex/metabolic variables (insulin resistance) participate at the phenomenon. METHODS AND RESULTS: We conducted a cross-sectional study of healthy individuals and metabolic syndrome patients recruited in our outpatient clinic. Fifty-five middle age men classified according to Adult Treatment Panel III criteria and apnea hypopnea index (overnight polysomnographic evaluation) as healthy controls without OSA and metabolic syndrome patients without and with OSA were studied. Blood pressure (Finapres), heart rate (ECG) and muscle sympathetic nerve activity (MSNA; microneurography) were measured at rest and during baroreflex manipulation. Compared with controls, patients with metabolic syndrome with and without OSA displayed higher waist-hip ratio, blood pressure, triglycerides and homeostasis model assessment index values but lower high-density lipoprotein cholesterol. MSNA was significantly higher in patients with metabolic syndrome without OSA than in controls (61.9 +/- 3.9 vs. 37.7 +/- 4.1 bursts/100 heartbeats, respectively, P < 0.01), a further marked increase being detected in patients with metabolic syndrome with OSA (77.1 +/- 4.3 bursts/100 heart beats, P < 0.01). Compared with controls, baroreflex control of heart rate and MSNA was markedly impaired in patients with metabolic syndrome with OSA, a further impairment in baroreflex-heart rate modulation being detected in metabolic syndrome with OSA. In the metabolic syndrome group as a whole, at the multivariate analysis, MSNA was significantly related to the apnoea-hypopnoea index but not to other variables. CONCLUSION: Thus the sympathetic activation of metabolic syndrome occurs independently on OSA. OSA, however, markedly potentiates this neuroadrenergic abnormality via a hypoxic-dependent chemoreflex activation. PMID- 20164805 TI - Pulse waveform characteristics predict cardiovascular events and mortality in patients undergoing coronary angiography. AB - OBJECTIVES: Pulse waveform characteristics (Augmentation Index--AIx and pulse wave transit time) are measures of the timing and extent of arterial wave reflections. Although previous studies reported an independent association with cardiovascular morbidity, it remains to be established that waveform characteristics, derived from noninvasive pulse waveform analysis, predict cardiovascular outcomes independent of and additional to brachial blood pressure. METHODS: We prospectively assessed AIx, heart-rate corrected AIx, and pulse wave transit time, using radial applanation tonometry and a validated transfer function to generate the aortic pressure curve, in 520 male patients undergoing coronary angiography. Primary endpoint was a composite of all-cause mortality, myocardial infarction, stroke, cardiac, cerebrovascular, and peripheral revascularization. RESULTS: During a follow-up of 49 months, 170 patients reached the primary endpoint. On the basis of Cox proportional hazards regression models, all pressure waveform characteristics predicted the primary endpoint. A 10% increase of AIx and heart-rate corrected AIx was associated with a 20.5% (95% confidence interval 6.5-36.4, P = 0.003) and 31.4% (95% confidence interval 13.2 52.6, P = 0.0004) increased risk of the primary endpoint, respectively. A 10-ms increase of pulse wave transit time was associated with a 20.8% (95% confidence interval 10.8-29.6, P = 0.0001) lower risk of the primary endpoint. In multiple adjusted models, AIx, heart-rate corrected AIx, and pulse wave transit time were independently associated with the combined endpoint even after adjustments for brachial blood pressure, age, extent of coronary artery disease, clinical characteristics, and medications. CONCLUSION: The study provides evidence that pulse waveform characteristics consistently and independently predict cardiovascular events in coronary patients. PMID- 20164806 TI - Seeking patient feedback: an important dimension of quality in cancer care. AB - A patient satisfaction survey was conducted with ambulatory cancer patients to identify areas that they consider priorities for change. Wait times and telephone contact with healthcare providers were the 2 areas of lowest satisfaction. Despite previous interventions to improve wait times, it is consistently the lowest ranked item for patient satisfaction. A subset of patients who were followed by a nurse navigator was more satisfied with wait times than those who were not followed by a nurse navigator. PMID- 20164807 TI - When the 5 rights go wrong: medication errors from the nursing perspective. AB - This study describes nurses' perceptions about how and why medication errors occur and their personal experiences with medication errors. A survey was mailed to a random sample of registered nurses. Two hundred and two responded. Of those, 158 (78%) nurses admitted making medication errors and provided details about these errors. This study, by providing the perspective of frontline nurses, contributes to the body of knowledge on medication errors. PMID- 20164808 TI - Minimizing hypoglycemia in the wake of a tight glycemic control protocol in hospitalized patients. AB - Healthcare professionals are struggling with how to best balance tight glycemic control while minimizing the potential for hypoglycemia in hospitalized patients. This article details an organizational quality improvement plan to prevent and appropriately treat hypoglycemia in the acute care setting. Innovative educational modalities coupled with electronic tracking of hypoglycemic events can reduce the incidence of hypoglycemia. PMID- 20164809 TI - Effect of n-3 fatty acids and antioxidants on oxidative stress after exercise. AB - PURPOSE: n-3 fatty acids are known to exert multiple beneficial effects including anti-inflammatory actions that may diminish oxidative stress. Supplementation with antioxidant vitamins has been proposed to counteract oxidative stress and improve antioxidant status. Therefore, this project investigated the effects of daily supplementation in 48 trained cyclists over 6 wk and during 3 d of continuous exercise on F2-isoprostanes (oxidative stress), plasma n-3 fatty acids, and antioxidant status (oxygen radical absorption capacity and ferric reducing antioxidant potential). METHODS: Cyclists were randomized into n-3 fatty acids (N3) (n = 11) (2000 mg of eicosapentaenoic acid and 400 mg of docosahexaenoic acid), a vitamin-mineral (VM) complex (n = 12) emphasizing vitamins C (2000 mg), E (800 IU), A (3000 IU), and selenium (200 microg), a VM and n-3 fatty acid combination (VN3) (n = 13), or placebo (P) (n = 12). Blood was collected at baseline and preexercise and postexercise. A 4 x 3 repeated-measures ANOVA was performed to test main effects. RESULTS: After exercise, F2 isoprostanes were higher in N3 (treatment effect P = 0.014). Eicosapentaenoic acid and docosahexaenoic acid plasma values were higher after supplementation (interaction effect P = 0.001 and 0.006, respectively) in both n-3 supplemented groups. Oxygen radical absorption capacity declined similarly among all groups after exercise. Ferric-reducing antioxidant potential exhibited significant interaction (P = 0.045) and significantly increased after exercise in VN3 and VM (P < 0.01). CONCLUSIONS: This study indicates that supplementation with n-3 fatty acids alone significantly increases F2-isoprostanes after exhaustive exercise. Lastly, antioxidant supplementation augments plasma antioxidant status and modestly attenuates but does not prevent the significant n-3 fatty acid associated increase in F2-isoprostanes postexercise. PMID- 20164810 TI - Quadriceps fatigue alters human muscle performance during a novel weight bearing task. AB - Limited information is currently available regarding muscle synergistic patterns and triggered reflex responses during dynamic weight-bearing activities in the presence of muscle fatigue. PURPOSE: The purpose of this study was to examine the effects of quadriceps muscle fatigue on patterns of muscle activation and performance in response to sudden, unexpected perturbations during a weight bearing task. METHODS: Motion of the knee was measured as subjects were asked to track a visual target as accurately as possible while performing a resisted single leg squat task. Random perturbations were delivered in 20% of the trials by unexpectedly releasing the resistance during the flexion phase of the exercise. Absolute and constant errors were calculated to evaluate target tracking performance. Quadriceps and hamstring muscle activity was recorded during both perturbed and unperturbed trials. Twelve healthy women were tested before and after completing a repetitive submaximal eccentric quadriceps fatigue protocol. A second group of 12 women served as controls. Unexpected perturbations elicited long-latency responses characterized by facilitation of the quadriceps and inhibition of the hamstrings. RESULTS: Muscle fatigue increased the amplitude of the long-latency response in vastus lateralis by 4.3% maximum voluntary isometric contraction (P = 0.004). Changes in tracking error occurred in response to perturbations after fatigue in spite of significantly increased quadriceps muscle activity, especially during the extension phase of the exercise. CONCLUSION: Quadriceps muscle fatigue alters the patterns of coordinated muscle activity and may render subjects less able to cope with unexpected perturbations during weight-bearing tasks. PMID- 20164811 TI - Is generic physical activity or specific exercise associated with motor abilities? AB - PURPOSE: Evidence of the effect of leisure time physical activity (LTPA) modes on the motor abilities of a mature population is scarce. The purpose of this study was to compare the motor abilities of physically active and inactive men and women and to examine the associations of different exercise modes and former and recent LTPA (R-LTPA) with motor ability and various physical tests. METHODS: The LTPA of the participants (men n = 69, women n = 79; aged 41-47 yr) was ascertained by a modified Physical Activity Readiness Questionnaire, including questions on the frequency, duration, and intensity of R-LTPA and former LTPA and on exercise modes. Motor abilities in terms of balance, agility, and coordination were assessed with a battery of nine tests supplemented with five physical fitness tests. Multiple statistical methods were used in analyses that were conducted separately for men and women. RESULTS: The MET-hours per week of R-LTPA correlated statistically significantly with the tests of agility and static balance (rs = -0.28, P = 0.022; rs = -0.25, P = 0.043, respectively) among men and with the static balance (rs = 0.41), 2-km walking (rs = 0.36), step squat (rs = 0.36) (P < or = 0.001, respectively), and static back endurance (rs = 0.25, P = 0.024) among women. In the stepwise regression among men, the most frequent statistically significant predictor was the playing of several games. For women, a history of LTPA for more than 3 yr was the strongest predictor for good results in almost all tests. CONCLUSIONS: Participants with long-term and regular LTPA had better motor performance, and especially a variety of games improve components of motor ability. Diverse, regular, and long-term exercise including both specific training and general activity develops both motor abilities and physical fitness. PMID- 20164812 TI - Evaluation of the shoe-surface interaction using an agility maneuver. AB - PURPOSE: An increase in traction between the shoe and a playing surface can result in increased forces to be absorbed by the structures of the lower extremity. Alternately, decreased traction causes impaired performance. We hypothesized that changes in the coefficient of friction (CoF) will affect subjective and objective measures of performance for an agility maneuver. METHODS: Thirty subjects were asked to perform a functional agility maneuver under CoF conditions from 0.3 to 0.7. Subjects performed this agility maneuver over a force plate and were asked to complete a questionnaire evaluating their ability to perform the task under various CoF conditions. RESULTS: Time to complete the task decreased as CoF increased (from 3.1 +/- 0.6 s at CoF 0.3 to 2.6 +/- 0.5 s at CoF 0.5). Peak force, CoF max force plate, and subjective score all increased as CoF increased up to 0.5. CoF of 0.5 or above did not significantly change the subject's ability to perform the cutting maneuver either subjectively or objectively. CONCLUSIONS: The CoF of 0.5 was deemed adequate to complete the task for this study. Values above CoF 0.5 did not lead to better performance. More studies are needed to build on these findings to establish criteria on safe shoe-surface interactions in athletic practice and play. PMID- 20164813 TI - Short- and long-term modulation of the exercise ventilatory response. AB - The importance of adaptive control strategies (modulation and plasticity) in the control of breathing during exercise has become recognized only in recent years. In this review, we discuss new evidence for modulation of the exercise ventilatory response in humans, specifically, short- and long-term modulation. Short-term modulation is proposed to be an important regulatory mechanism that helps maintain blood gas homeostasis during exercise. PMID- 20164814 TI - Selective estrogen receptor modulator: the saga continues. PMID- 20164815 TI - White matter integrity associated with volitional motor activity. AB - Variations of white matter integrity have been associated with interindividual differences in brain function. Still, little is known about the impact of white matter integrity on quantitative motor behaviour. Diffusion tensor imaging and continuous wrist actigraphy were measured on the same day in 12 individuals. Fractional anisotropy as measure of white matter integrity was correlated with the motor activity level. Positive correlations of fractional anisotropy and activity level were detected in the cingulum and the right superior longitudinal fasciculus underneath the precentral gyrus. Negative correlations were found in the left corticobulbar tract, in the right posterior corpus callosum and in the left superior longitudinal fasciculus. Volitional motor activity was associated with white matter integrity in motor relevant fiber tracts. PMID- 20164816 TI - The KDIGO clinical practice guidelines for the care of kidney transplant recipients. AB - The clinical guideline for care of renal transplant recipients was written by a committee of 15 people from nine countries, supported by an evidence review team The scope of the review was care of the patient after a renal transplant-not evaluation or selection of recipients and donors, focusing on the issue specific to the immunosuppressed transplant patient. A total of 12,327 articles comprising 3168 randomized controlled trials, 7543 cohort studies, and 1609 reviews were selected by a formal search. Each article was formally evaluated for the quality of the data from A to D. A consistent set of statements were based on the strength of the evidence. Level 1 evidence: "we recommend" means that if you were a patient, most people would want to do this; if a clinician, you should recommend this course of action to most patients; and if a policy maker, you should adopt this as a reasonable standard. Level 2 evidence: "we suggest" means the majority of patients would want do this; to the clinician, it means that different solutions may well be needed for different patients; whereas to the health policy maker, this is a strong warning to engage stakeholders in the creation of a particular local policy. Because 69% of the advice is "suggested" on the basis of level C or D evidence, one outcome of this work is to make it clear where the current evidence for clinical decisions runs out of data. PMID- 20164817 TI - Epidemiology of infections requiring hospitalization during long-term follow-up of pancreas transplantation. AB - BACKGROUND.: Pancreas transplantation (PT) provides the best glycemic control option for diabetes mellitus but is associated with significant morbidities related to infectious disease. METHODS.: We performed a retrospective study of a cohort of consecutive PT recipients in whom PT was performed from 1998 to 2006 (n=216) and followed up them until July 2008. Data regarding infections, rejection, infection chemoprophylaxis, graft failure, absolute lymphocyte counts (ALCs), and mortalities were collected. RESULTS.: Simultaneous pancreas and kidney, pancreas transplantation alone, and pancreas after kidney (PAK) transplantations were performed in 42, 67, and 107 patients, with a mean (standard deviation) age at transplantation of 46.8 (8.03), 40.6 (10.1), and 43.7 (8.19) years. Of the simultaneous pancreas and kidney, pancreas transplantation alone, and PAK transplant recipients, 54.7%, 37.3%, and 58.8% were men. Overall, 63% developed a serious infection during the median follow-up of 6.4 years. Mean (range) number of infectious episodes was 2.3 (1-12), with mostly bacterial infections both within (68%) and after 1 year (78%). Incidence of bacterial and viral infections was greatest in the first 3 months after transplantation. Fungal infections were more constant. Bladder exocrine drainage was associated with higher risk of infection (hazard ratio=2.5, P<0.001). Infection within the first 3 months after transplantation was related to higher mortality after the first 3 months (hazard ratio=3.19). ALC was associated with the risk of first infections (P=0.005) and bacterial infections (P<0.001). CONCLUSIONS.: Incidence of infections after PT was 63% and mostly bacterial. Bladder drainage increases infection risk and low ALC partially predicts episodes. Limitations include retrospective design, unequal composition of PT groups, and lack of data between kidney and PT for PAK. PMID- 20164819 TI - Obesity was associated with inferior outcomes in simultaneous pancreas kidney transplant. AB - BACKGROUND.: In kidney transplant, obesity was reported to be associated with increased posttransplant complications and worse survival outcomes. The impact of obesity in simultaneous pancreas-kidney (SPK) transplant is less known. METHODS.: Using Organ Procurement Transplantation Network/United Network for Organ Sharing data as of August 2008, we included all adults (>18 years) type 1 diabetic SPK recipients between years 2000 and 2007 with a pretransplant body mass index (BMI) of 18.5 to 40 kg/m. The cohort was divided in three groups: normal (BMI 18.5-24.9 kg/m, reference group), overweight (BMI 25-29.9 kg/m), and obese (BMI 30-40 kg/m). Covariate-adjusted relative risk of a combination of posttransplant complications and patient, pancreas and kidney allograft outcomes were evaluated. RESULTS.: Of 5725 recipients, 56%, 33%, and 11% were in normal, overweight, and obese groups, respectively. Overweight and obese recipients were older, had a higher percent of coronary artery disease, and private health insurance coverage. Overall posttransplant complications were higher in obese group (35.7% vs. 28.6%) when compared with normal BMI group. They were mainly due to increased delayed kidney graft function (11.8% vs. 7.4%), 1-year kidney acute rejection (17.0% vs. 12.1%), and pancreas graft thrombosis (2.6% vs. 1.3%). After adjusting for possible confounders, the odds ratios for overall transplant complications were 1.03 (95% confidence interval [CI]: 0.90-1.17) for overweight and 1.38 (95% CI: 1.15-1.68) for obese. Obesity, but not overweight, was associated with patient death (hazard ratio [HR]: 1.35; 95% CI: 1.00-1.81), pancreas graft loss (HR: 1.41; 95% CI: 1.17-1.69), and kidney graft loss (HR: 1.33; 95% CI: 1.05-1.67) at 3 years. The higher rates of death and graft failure in the first 30 days posttransplant mostly accounted for the 3-year survival differences. CONCLUSION.: Obesity in SPK recipients was associated with increased risk of posttransplant complications, pancreas and kidney graft loss, and patient death. PMID- 20164818 TI - Transplantation of reprogrammed embryonic stem cells improves visual function in a mouse model for retinitis pigmentosa. AB - BACKGROUND: To study whether C57BL/6J-Tyr/J (C2J) mouse embryonic stem (ES) cells can differentiate into retinal pigment epithelial (RPE) cells in vitro and then restore retinal function in a model for retinitis pigmentosa: Rpe65/Rpe65 C57BL6 mice. METHODS: Yellow fluorescent protein (YFP)-labeled C2J ES cells were induced to differentiate into RPE-like structures on PA6 feeders. RPE-specific markers are expressed from differentiated cells in vitro. After differentiation, ES cell derived RPE-like cells were transplanted into the subretinal space of postnatal day 5 Rpe65/Rpe65 mice. Live imaging of YFP-labeled C2J ES cells demonstrated survival of the graft. Electroretinograms (ERGs) were performed on transplanted mice to evaluate the functional outcome of transplantation. RESULTS: RPE-like cells derived from ES cells sequentially express multiple RPE-specific markers. After transplantation, YFP-labeled cells can be tracked with live imaging for as long as 7 months. Although more than half of the mice were complicated with retinal detachments or tumor development, one fourth of the mice showed increased electroretinogram responses in the transplanted eyes. Rpe65/Rpe65 mice transplanted with RPE-like cells showed significant visual recovery during a 7 month period, whereas those injected with saline, PA6 feeders, or undifferentiated ES cells showed no rescue. CONCLUSIONS: ES cells can differentiate, morphologically, and functionally, into RPE-like cells. Based on these findings, differentiated ES cells have the potential for the development of new therapeutic approaches for RPE-specific diseases such as certain forms of retinitis pigmentosa and macular degeneration. Nevertheless, stringent control of retinal detachment and teratoma development will be necessary before initiation of treatment trials. PMID- 20164820 TI - Characterization of rabbit antithymocyte globulins-induced CD25+ regulatory T cells from cells of patients with end-stage renal disease. AB - BACKGROUND.: Rabbit antithymocyte globulins (rATGs) are known to convert CD4CD25FoxP3 T cells from healthy individuals to CD4CD25FoxP3 T cells. In this study, we investigated the effect of rATG on the induction of regulatory T cells (Tregs) from blood cells of patients with end-stage renal disease who are candidates for transplantation and rATG-induction therapy. The induced Tregs were analyzed and compared with naturally occurring CD4CD25FoxP3T cells. METHODS.: The CD25 T cells of pretransplant patients (n=7) and healthy controls (n=4) were stimulated with rATG or control rabbit immunoglobulins for 24 hr. The phenotype of induced Tregs was examined by flow cytometry, and their function was studied in the conventional suppression assay. Further characterization was performed by mRNA analyses. RESULTS.: After 24 hr, the percentage of CD4CD25FoxP3CD127 T cells and CD8CD25FoxP3CD127 T cells became higher in the rATG-treated samples compared with the rabbit immunoglobulin-treated samples (P<0.01). The rATG-induced CD25T cells, whether CD4 or CD8 inhibited the allogeneic responses of CD25 effector T cells as vigorously as natural CD25T cells. However, the proportion of FoxP3 within the top 2% rATG-induced CD4CD25T-cells was lower than within the natural CD4CD25T-cells (11%+/-2% vs. 95%+/-5%, P<0.01). The mRNA-expression levels of interleukin-27, interleukin-10, interferon-gamma, perforin, and granzyme B were markedly higher compared with natural CD25T-cells (all P=0.03), whereas CTLA4 (P=0.03), transforming growth factor-beta (P=0.02), and RORgammat (P=0.04) were lower. CONCLUSION.: rATG allows the induction of Tregs from patient peripheral blood mononuclear cell in vitro. In comparison with natural Tregs, the rATG induced Tregs are phenotypically distinct but have similar regulatory activities. rATG may beneficially contribute to the mechanisms that control alloreactivity. PMID- 20164822 TI - Single sensillum recordings in the insects Drosophila melanogaster and Anopheles gambiae. AB - The sense of smell is essential for insects to find foods, mates, predators, and oviposition sites. Insect olfactory sensory neurons (OSNs) are enclosed in sensory hairs called sensilla, which cover the surface of olfactory organs. The surface of each sensillum is covered with tiny pores, through which odorants pass and dissolve in a fluid called sensillum lymph, which bathes the sensory dendrites of the OSNs housed in a given sensillum. The OSN dendrites express odorant receptor (OR) proteins, which in insects function as odor-gated ion channels. The interaction of odorants with ORs either increases or decreases the basal firing rate of the OSN. This neuronal activity in the form of action potentials embodies the first representation of the quality, intensity, and temporal characteristics of the odorant. Given the easy access to these sensory hairs, it is possible to perform extracellular recordings from single OSNs by introducing a recording electrode into the sensillum lymph, while the reference electrode is placed in the lymph of the eye or body of the insect. In Drosophila, sensilla house between one and four OSNs, but each OSN typically displays a characteristic spike amplitude. Spike sorting techniques make it possible to assign spiking responses to individual OSNs. This single sensillum recording (SSR) technique monitors the difference in potential between the sensillum lymph and the reference electrode as electrical spikes that are generated by the receptor activity on OSNs. Changes in the number of spikes in response to the odorant represent the cellular basis of odor coding in insects. Here, we describe the preparation method currently used in our lab to perform SSR on Drosophila melanogaster and Anopheles gambiae, and show representative traces induced by the odorants in a sensillum-specific manner. PMID- 20164823 TI - Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial). AB - We performed a double-blind placebo-controlled trial to study whether early treatment with erythropoietin could prevent the development of acute kidney injury in patients in two general intensive care units. As a guide for choosing the patients for treatment we measured urinary levels of two biomarkers, the proximal tubular brush border enzymes gamma-glutamyl transpeptidase and alkaline phosphatase. Randomization to either placebo or two doses of erythropoietin was triggered by an increase in the biomarker concentration product to levels above 46.3, with a primary outcome of relative average plasma creatinine increase from baseline over 4 to 7 days. Of 529 patients, 162 were randomized within an average of 3.5 h of a positive sample. There was no difference in the incidence of erythropoietin-specific adverse events or in the primary outcome between the placebo and treatment groups. The triggering biomarker concentration product selected patients with more severe illness and at greater risk of acute kidney injury, dialysis, or death; however, the marker elevations were transient. Early intervention with high-dose erythropoietin was safe but did not alter the outcome. Although these two urine biomarkers facilitated our early intervention, their transient increase compromised effective triaging. Further, our study showed that a composite of these two biomarkers was insufficient for risk stratification in a patient population with a heterogeneous onset of injury. PMID- 20164824 TI - Regulatory T cells contribute to the protective effect of ischemic preconditioning in the kidney. AB - Reperfusion following ischemia is associated with acute kidney injury and inflammation. Using a mouse model, we exposed the kidney to a nonlethal period of ischemia, rendering it refractory to future ischemia-induced dysfunction. This ischemic preconditioning is partially mediated by Treg lymphocytes that suppress immune responses. We found that this maneuver significantly inhibited the accumulation of neutrophils and macrophages, tubular necrosis, and loss of kidney function caused by a subsequent ischemia/reperfusion injury 1 week later. The initial ischemia/reperfusion caused a significant increase in CD4(+)CD25(+)FoxP3(+) and CD4(+)CD25(+)IL-10(+) Treg cells within the kidney at 7 days of reperfusion. Treatment of preconditioned mice with a Treg cell-depleting antibody (PC61) reversed the effect of preconditioning on kidney neutrophil accumulation and partially inhibited the functional and histological protection of preconditioning. Adoptive transfer of Treg cells in naive mice, before ischemia/reperfusion, mimicked the protective and anti-inflammatory effects of ischemic preconditioning on the kidney. These studies highlight the role of Treg cells in ischemic preconditioning. PMID- 20164825 TI - Metformin prevents experimental gentamicin-induced nephropathy by a mitochondria dependent pathway. AB - The antidiabetic drug metformin can diminish apoptosis induced by oxidative stress in endothelial cells and prevent vascular dysfunction even in nondiabetic patients. Here we tested whether it has a beneficial effect in a rat model of gentamicin toxicity. Mitochondrial analysis, respiration intensity, levels of reactive oxygen species, permeability transition, and cytochrome c release were assessed 3 and 6 days after gentamicin administration. Metformin treatment fully blocked gentamicin-mediated acute renal failure. This was accompanied by a lower activity of N-acetyl-beta-D-glucosaminidase, together with a decrease of lipid peroxidation and increase of antioxidant systems. Metformin also protected the kidney from histological damage 6 days after gentamicin administration. These in vivo markers of kidney dysfunction and their correction by metformin were complemented by in vitro studies of mitochondrial function. We found that gentamicin treatment depleted respiratory components (cytochrome c, NADH), probably due to the opening of mitochondrial transition pores. These injuries, partly mediated by a rise in reactive oxygen species from the electron transfer chain, were significantly decreased by metformin. Thus, our study suggests that pleiotropic effects of metformin can lessen gentamicin nephrotoxicity and improve mitochondrial homeostasis. PMID- 20164826 TI - The chemokine receptor CXCR7 is expressed on lymphatic endothelial cells during renal allograft rejection. AB - CXCR7 is an atypical receptor for the chemokines CXCL11 and CXCL12, which were found to be involved in animal models of allograft injury. We studied the expression of CXCR7 and its ligands in human kidneys by first quantifying the mRNA in 53 renal allograft biopsies. Receptor and ligand mRNAs were expressed in renal allografts, with a significant induction of CXCL11 and CXCL12 in biopsies showing borderline lesions and acute rejection. Immunohistochemical analysis for CXCR7 was performed in a series of 64 indication and 24 protocol biopsies. The indication biopsies included 46 acute rejections, 6 with interstitial fibrosis and tubular atrophy, and 12 pretransplant biopsies as controls. In control biopsies, CXCR7 protein was found on smooth muscle and on endothelial cells of a small number of peritubular vessels. The number of CXCR7-positive vessels was increased in acute rejection and, using double immunofluorescence labeling, a subset of these CXCR7-positive endothelial cells were identified as lymphatic vessels. Both CXCR7-positive blood and lymphatic vessels increased during allograft rejection. We found that CXCR7 is present in both blood and lymphatic endothelial cells in human renal allografts. Whether its presence modulates the formation of chemokine gradients and the recruitment of inflammatory cells will require further experimental studies. PMID- 20164827 TI - Differential resolution of inflammation and recovery after renal ischemia reperfusion injury in Brown Norway compared with Sprague Dawley rats. AB - To investigate mechanisms conferring susceptibility or resistance to renal ischemia, we used two rat strains known to exhibit different responses to ischemia-reperfusion. We exposed proximal tubule cells isolated from Sprague Dawley or Brown Norway rats, to a protocol of hypoxia, followed by reoxygenation in vitro. The cells isolated from both rat strains exhibited comparable responses in the disruption of intercellular adhesions and cytoskeletal damage. In vivo, after 24 h of reperfusion, both strains showed similar degrees of injury. However, after 7 days of reperfusion, renal function and tubular structure almost completely recovered and inflammation resolved, but only in Brown Norway rats. Hypoxia-inducible factor-dependent gene expression, ERK1/2, and Akt activation were different in the two strains. Inflammatory mediators MCP-1, IL-10, INF gamma, IL-1beta, and TNF-alpha were similarly induced at 24 h in both strains but were downregulated earlier in Brown Norway rats, which correlated with shorter NFkappaB activation in the kidney. Moreover, VLA-4 expression in peripheral blood lymphocytes and VCAM-1 expression in kidney tissues were initially similar at 24 h but reached basal levels earlier in Brown Norway rats. The faster resolution of inflammation in Brown Norway rats suggests that this strain might be a useful experimental model to determine the mechanisms that promote repair of renal ischemia-reperfusion injury. PMID- 20164828 TI - Development and validation of equations estimating glomerular filtration rates in Chinese patients with type 2 diabetes. AB - Existing equations to calculate the estimated glomerular filtration rate (eGFR) were derived from nondiabetic Caucasian patients with chronic kidney disease. Here, we developed formulas to more accurately predict the eGFR in Chinese patients with type 2 diabetes and validated their performance in 202 type 2 diabetic and 46 nondiabetic individuals. Within the diabetic cohort, 135 were randomly assigned to a training group, whereas the remaining 67 diabetic and all of the nondiabetic patients were assigned to a validation group. Reference GFR was measured by (51)Cr-EDTA plasma clearance. The new eGFR-estimating formulas, derived using a stepwise regression model, were compared with existing prediction equations in the validation group. The formulas are: 313 x (Age)-0.494 (years) x [SCr]-1.059 (mg/dl) x [Alb]+0.485 (g/dl) for men, and 783 x (Age)-0.489 (years) x [SCr]-0.877 (mg/dl) x [SUN]-0.150 (mg/dl) for women. Compared with existing equations, the new formulas were more accurate and precise in calculating eGFR in diabetic patients, but, similar to other equations, were less accurate in the nondiabetic cohort. Our newly developed equations are simple to use and can be applied in routine clinical practice to calculate eGFR in Chinese patients with type 2 diabetes. PMID- 20164829 TI - Tetrahydrobiopterin protects the kidney from ischemia-reperfusion injury. AB - Tetrahydrobiopterin (BH4) is an essential cofactor for the nitric oxide (NO) synthases and represents a critical determinant of NO production. BH4 depletion during ischemia leads to the uncoupling of the synthases, thus contributing to reperfusion injury due to increased superoxide formation. To examine whether BH4 supplementation attenuates ischemia-reperfusion injury, we clamped the left renal arteries of male Lewis rats immediately following right-side nephrectomy. BH4 tissue levels significantly decreased after 45 min of warm ischemia compared with levels in non-ischemic controls. Histopathology demonstrated significant tubular damage and increased peroxynitrite formation. Intravital fluorescent microscopy found perfusion deficits in the microvasculature and leakage of the capillary mesh. Supplemental BH4 treatment before ischemia significantly reduced ischemia induced renal dysfunction, and decreased tubular histologic injury scores and peroxynitrite generation. BH4 also significantly improved microcirculatory parameters such as functional capillary density and diameter. These protective effects of BH4 on microvasculature were significantly correlated with its ability to abolish peroxynitrite formation. We suggest that BH4 significantly protects against acute renal failure following ischemia reperfusion. Whether BH4 has a therapeutic potential will require more direct testing in humans. PMID- 20164830 TI - Differential regulation of behavioral tolerance to WIN55,212-2 by GASP1. AB - Cannabinoid agonists have shown some promise clinically as analgesics, in particular for cancer pain, in which they have the additional benefit of decreasing nausea. However, as for most other drugs, the long-term use of cannabinoids is limited by the development of tolerance. Several molecular mechanisms have been proposed to explain drug tolerance, including receptor downregulation. The cannabinoid 1 (CB1) receptors can be downregulated in vitro through an interaction with the G-protein-coupled receptor-associated sorting protein1, GASP1, that targets CB1 receptors for degradation after their agonist mediated endocytosis. To investigate whether GASP1-mediated postendocytic sorting of the CB1 receptor contributes to tolerance to cannabinoid drugs in vivo, we generated a mouse with a disruption of GASP1. In wild-type mice, repeated administration of the cannabinoid agonist WIN55,212-2 promoted downregulation of CB1 receptor levels and concomitant tolerance to the effects of drug on antinociception, motor incoordination, and locomotor hypoactivity. In contrast, GASP1 knockout mice did not develop tolerance to any of these effects and showed no significant receptor downregulation. Taken together, this study provides evidence that GASP1 regulates CB1 receptor downregulation in vivo, and that postendocytic receptor trafficking has a key role in the development of tolerance to WIN55,212-2. PMID- 20164831 TI - The expression of VGF is reduced in leukocytes of depressed patients and it is restored by effective antidepressant treatment. AB - Major depression is a disease characterized by an inability of neuronal systems to show appropriate adaptive plasticity especially under challenging conditions, such as stress. Conversely, pharmacological intervention may normalize such defects through the modulation of factors that might act in concert for the functional recovery of depressed patients, like the neuropeptide VGF, which has previously shown to possess antidepressant like activity. We analyzed VGF mRNA levels in the brain of rodents exposed to stress or treated with antidepressant drugs. In addition, we assessed VGF expression in leukocytes obtained from 25 drug-free depressed patients before and during antidepressant treatment. We found a persistent reduction of VGF expression after exposure to prenatal stress and an upregulation of its levels following chronic treatment with different antidepressant drugs. Moreover, VGF mRNA levels were significantly reduced in drug-free depressed patients, as compared with controls, and were modulated in response to effective antidepressant treatment. Our data provide further support to the role of VGF in mood disorders and suggest that VGF could be a more specific biomarker for treatment responsiveness. PMID- 20164833 TI - Study of the efficacy, biodistribution, and safety profile of therapeutic gutless adenovirus vectors as a prelude to a phase I clinical trial for glioblastoma. AB - Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor in humans. Systemic immunity against gene therapy vectors has been shown to hamper therapeutic efficacy; however, helper-dependent high-capacity adenovirus (HC-Ad) vectors elicit sustained transgene expression, even in the presence of systemic anti-adenoviral immunity. We engineered HC-Ads encoding the conditional cytotoxic herpes simplex type 1 thymidine kinase (TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Flt3L). Flt3L expression is under the control of the regulatable Tet-ON system. In anticipation of a phase I clinical trial for GBM, we assessed the therapeutic efficacy, biodistribution, and clinical and neurotoxicity with escalating doses of HC-Ad TetOn-Flt3L + HC-Ad-TK in rats. Intratumoral administration of these therapeutic HC-Ads in rats bearing large intracranial GBMs led to long-term survival in approximately 70% of the animals and development of antiglioma immunological memory without signs of neuropathology or systemic toxicity. Systemic anti adenoviral immunity did not affect therapeutic efficacy. These data support the idea that it would be useful to develop HC-Ad vectors further as a therapeutic gene-delivery platform to implement GBM phase I clinical trials. PMID- 20164834 TI - A model-based meta-analysis of the effect of latanoprost chronotherapy on the circadian intraocular pressure of patients with glaucoma or ocular hypertension. AB - Several reports have demonstrated that the efficacy of latanoprost is influenced by the time of dosing. This model-based meta-analysis validates previous findings that evening dosing is superior to morning dosing and predicts the optimal time for dosing, based on the quantitative assessment of baseline and latanoprost treated 24-h circadian intraocular pressure (IOP) curves. The results confirm the importance of the time of dosing as a factor that influences the extent of reduction in IOP and underline the need to take this factor into consideration in the design of glaucoma trials and therapy. PMID- 20164832 TI - Regulatory T cells in many flavors control asthma. AB - That regulatory T cells (Tregs) have a crucial role in controlling allergic diseases such as asthma is now undisputed. The cytokines most commonly implicated in Treg-mediated suppression of allergic asthma are transforming growth factor beta (TGF-beta) and interleukin (IL)-10). In addition to naturally occurring Tregs, adaptive Tregs, induced in response to foreign antigens, have been shown in recent studies. The concept of inducible/adaptive Tregs (iTregs) has considerable significance in preventing asthma if generated early enough in life. This is because cytokines such as IL-4 and IL-6 inhibit Foxp3 induction in naive CD4+ T cells and therefore de novo generation of Tregs can be expected to be less efficient when it is concomitant with effector cell development in response to an allergen. However, if iTregs can be induced, the process of infectious tolerance would facilitate expansion of the iTreg pool as suggested in the recent literature. It is tempting to speculate that there is a window of opportunity in early life in the context of a relatively immature immune system that is permissive for the generation of iTregs specific to a spectrum of allergens that would regulate asthma for lifelong. The focus of this review is the relevance of nTregs and iTregs in controlling asthma from early life into adulthood, the mechanisms underlying Treg function, and the prospects for using our current concepts to harness the full potential of Tregs to limit disease development and progression. PMID- 20164835 TI - Differential innate immune signalling via Ca(2+) sensor protein kinases. AB - Innate immunity represents the first line of inducible defence against microbial infection in plants and animals. In both kingdoms, recognition of pathogen- or microbe-associated molecular patterns (PAMPs or MAMPs, respectively), such as flagellin, initiates convergent signalling pathways involving mitogen-activated protein kinase (MAPK) cascades and global transcriptional changes to boost immunity. Although Ca(2+) has long been recognized as an essential and conserved primary mediator in plant defence responses, how Ca(2+) signals are sensed and relayed into early MAMP signalling is unknown. Using a functional genomic screen and genome-wide gene expression profiling, here we show that four calcium dependent protein kinases (CDPKs) are Ca(2+)-sensor protein kinases critical for transcriptional reprogramming in plant innate immune signalling. Unexpectedly, CDPKs and MAPK cascades act differentially in four MAMP-mediated regulatory programs to control early genes involved in the synthesis of defence peptides and metabolites, cell wall modifications and redox signalling. Transcriptome profile comparison suggests that CDPKs are the convergence point of signalling triggered by most MAMPs. Double, triple and quadruple cpk mutant plants display progressively diminished oxidative burst and gene activation induced by the 22 amino-acid peptide flg22, as well as compromised pathogen defence. In contrast to negative roles of calmodulin and a calmodulin-activated transcription factor in plant defence, the present study reveals Ca(2+) signalling complexity and demonstrates key positive roles of specific CDPKs in initial MAMP signalling. PMID- 20164836 TI - Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. AB - Endogenous retroviruses (ERVs), retrovirus-like elements with long terminal repeats, are widely dispersed in the euchromatic compartment in mammalian cells, comprising approximately 10% of the mouse genome. These parasitic elements are responsible for >10% of spontaneous mutations. Whereas DNA methylation has an important role in proviral silencing in somatic and germ-lineage cells, an additional DNA-methylation-independent pathway also functions in embryonal carcinoma and embryonic stem (ES) cells to inhibit transcription of the exogenous gammaretrovirus murine leukaemia virus (MLV). Notably, a recent genome-wide study revealed that ERVs are also marked by histone H3 lysine 9 trimethylation (H3K9me3) and H4K20me3 in ES cells but not in mouse embryonic fibroblasts. However, the role that these marks have in proviral silencing remains unexplored. Here we show that the H3K9 methyltransferase ESET (also called SETDB1 or KMT1E) and the Kruppel-associated box (KRAB)-associated protein 1 (KAP1, also called TRIM28) are required for H3K9me3 and silencing of endogenous and introduced retroviruses specifically in mouse ES cells. Furthermore, whereas ESET enzymatic activity is crucial for HP1 binding and efficient proviral silencing, the H4K20 methyltransferases Suv420h1 and Suv420h2 are dispensable for silencing. Notably, in DNA methyltransferase triple knockout (Dnmt1(-/-)Dnmt3a(-/-)Dnmt3b(-/-)) mouse ES cells, ESET and KAP1 binding and ESET-mediated H3K9me3 are maintained and ERVs are minimally derepressed. We propose that a DNA-methylation-independent pathway involving KAP1 and ESET/ESET-mediated H3K9me3 is required for proviral silencing during the period early in embryogenesis when DNA methylation is dynamically reprogrammed. PMID- 20164837 TI - Remarkably ancient balanced polymorphisms in a multi-locus gene network. AB - Local adaptations within species are often governed by several interacting genes scattered throughout the genome. Single-locus models of selection cannot explain the maintenance of such complex variation because recombination separates co adapted alleles. Here we report a previously unrecognized type of intraspecific multi-locus genetic variation that has been maintained over a vast period. The galactose (GAL) utilization gene network of Saccharomyces kudriavzevii, a relative of brewer's yeast, exists in two distinct states: a functional gene network in Portuguese strains and, in Japanese strains, a non-functional gene network of allelic pseudogenes. Genome sequencing of all available S. kudriavzevii strains revealed that none of the functional GAL genes were acquired from other species. Rather, these polymorphisms have been maintained for nearly the entire history of the species, despite more recent gene flow genome-wide. Experimental evidence suggests that inactivation of the GAL3 and GAL80 regulatory genes facilitated the origin and long-term maintenance of the two gene network states. This striking example of a balanced unlinked gene network polymorphism introduces a remarkable type of intraspecific variation that may be widespread. PMID- 20164838 TI - Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. AB - Patients with dyskeratosis congenita (DC), a disorder of telomere maintenance, suffer degeneration of multiple tissues. Patient-specific induced pluripotent stem (iPS) cells represent invaluable in vitro models for human degenerative disorders like DC. A cardinal feature of iPS cells is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene (TERT). We investigated whether defects in telomerase function would limit derivation and maintenance of iPS cells from patients with DC. Here we show that reprogrammed DC cells overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self renewal. We discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DC, transcriptional silencing accompanies a 3' deletion at the TERC locus. Our results demonstrate that reprogramming restores telomere elongation in DC cells despite genetic lesions affecting telomerase, and show that strategies to increase TERC expression may be therapeutically beneficial in DC patients. PMID- 20164839 TI - The primary transcriptome of the major human pathogen Helicobacter pylori. AB - Genome sequencing of Helicobacter pylori has revealed the potential proteins and genetic diversity of this prevalent human pathogen, yet little is known about its transcriptional organization and noncoding RNA output. Massively parallel cDNA sequencing (RNA-seq) has been revolutionizing global transcriptomic analysis. Here, using a novel differential approach (dRNA-seq) selective for the 5' end of primary transcripts, we present a genome-wide map of H. pylori transcriptional start sites and operons. We discovered hundreds of transcriptional start sites within operons, and opposite to annotated genes, indicating that complexity of gene expression from the small H. pylori genome is increased by uncoupling of polycistrons and by genome-wide antisense transcription. We also discovered an unexpected number of approximately 60 small RNAs including the epsilon subdivision counterpart of the regulatory 6S RNA and associated RNA products, and potential regulators of cis- and trans-encoded target messenger RNAs. Our approach establishes a paradigm for mapping and annotating the primary transcriptomes of many living species. PMID- 20164844 TI - Acral peeling skin syndrome with TGM5 gene mutations may resemble epidermolysis bullosa simplex in young individuals. PMID- 20164843 TI - Plexin B1 suppresses c-Met in melanoma: a role for plexin B1 as a tumor suppressor protein through regulation of c-Met. AB - Melanoma arises through complex genetic and epigenetic changes, resulting in uncontrolled proliferation, invasion, and metastatic disease. Semaphorins regulate axon guidance through interaction with their receptors, plexins and neuropilins. Plexin B1, the semaphorin 4D receptor, activates oncogenic receptors c-Met and ErbB-2 in several cell types, suggesting it promotes tumor growth through stimulation of these receptors. A study by Argast et al. has shown that plexin B1 is a tumor-suppressor protein for melanoma metastasis in a mouse model. In this report, we show that plexin B1 is lost in metastatic and deeply invasive melanoma in patient samples in vivo. Unexpectedly, introduction of plexin B1 into human melanoma cell lines suppressed, rather than activated, the oncogenic receptor, c-Met, by its ligand hepatocyte growth factor (HGF). Plexin B1 also activated Akt in melanoma. Plexin B1 significantly abrogated cell migration in response to HGF but rendered cells resistant to apoptosis by cisplatin. Plexin B1 is predicted to function as a classic tumor-suppressor protein in melanoma, in part through suppression of c-Met signaling and c-Met-dependent migration. However, because plexin B1 activates Akt, a multifunctional protein involved in tumor progression in several cancers, plexin B1 may function as a tumor promoter in melanomas not driven by c-Met activation. PMID- 20164845 TI - Ultraviolet irradiation induces CYR61/CCN1, a mediator of collagen homeostasis, through activation of transcription factor AP-1 in human skin fibroblasts. AB - UV irradiation from the sun elevates the production of collagen-degrading matrix metalloproteinases (MMPs) and reduces the production of new collagen. This imbalance of collagen homeostasis impairs the structure and function of the dermal collagenous extracellular matrix (ECM), thereby promoting premature skin aging (photoaging). We report here that aberrant dermal collagen homeostasis in UV-irradiated human skin is mediated in part by a CCN-family member, cysteine rich protein-61 (CYR61/CCN1). CYR61 is significantly elevated in acutely UV irradiated human skin in vivo, and UV-irradiated human skin fibroblasts. Knockdown of CYR61 significantly attenuates UV irradiation-induced inhibition of type-I procollagen and upregulation of MMP-1. Determination of CYR61 mRNA and protein indicates that the primary mechanism of CYR61 induction by UV irradiation is transcriptional. Analysis of CYR61 proximal promoter showed that a sequence conforming to the consensus binding site for transcription factor activator protein-1 (AP-1) is required for promoter activity. UV irradiation increased the binding of AP-1-family members c-Jun and c-Fos to this AP-1 site. Furthermore, functional blockade of c-Jun or knockdown of c-Jun significantly reduced the UV irradiation-induced activation of CYR61 promoter and CYR61 gene expression. These data show that CYR61 is transcriptionally regulated by UV irradiation through transcription factor AP-1, and mediates altered collagen homeostasis that occurs in response to UV irradiation in human skin fibroblasts. PMID- 20164840 TI - Genome destabilization by homologous recombination in the germ line. AB - Meiotic recombination, which promotes proper homologous chromosome segregation at the first meiotic division, normally occurs between allelic sequences on homologues. However, recombination can also take place between non-allelic DNA segments that share high sequence identity. Such non-allelic homologous recombination (NAHR) can markedly alter genome architecture during gametogenesis by generating chromosomal rearrangements. Indeed, NAHR-mediated deletions, duplications, inversions and other alterations have been implicated in numerous human genetic disorders. Studies in yeast have provided insights into the molecular mechanisms of meiotic NAHR as well as the cellular strategies that limit it. PMID- 20164846 TI - A homozygous nonsense mutation within the dystonin gene coding for the coiled coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex. AB - Epidermolysis bullosa (EB) is a group of autosomal dominant and recessive blistering skin diseases in which pathogenic mutations have been reported in 13 different genes encoding structural proteins involved in keratinocyte integrity, as well as cell-matrix or cell-cell adhesion. We now report an inherited skin fragility disorder with a homozygous nonsense mutation in the dystonin gene (DST) that encodes the coiled-coil domain of the epithelial isoform of bullous pemphigoid antigen 1, BPAG1-e (also known as BP230). The mutation, p.Gln1124X, leads to the loss of hemidesmosomal inner plaques and a complete absence of skin immunostaining for BPAG1-e, as well as reduced labeling for plectin, the beta4 integrin subunit, and for type XVII collagen. The 38-year-old affected individual has lifelong generalized trauma-induced spontaneous blisters and erosions, particularly around the ankles. In addition, he experiences episodic numbness in his limbs, which started at the age of 37 years. These neurological symptoms may also be due to DST gene mutation, although he has a concomitant diagnosis of CADASIL (cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy), a cerebral small-vessel arteriopathy, which thus complicates the genotype-phenotype interpretation. With regard to skin blistering, the clinicopathological findings expand the molecular basis of EB by identifying BPAG1-e pathology in a new form of autosomal recessive EB simplex. PMID- 20164847 TI - Efficacy and tolerability of amlodipine plus olmesartan medoxomil in patients with difficult-to-treat hypertension. AB - Hypertension is particularly prevalent in patients aged >=65 years, those with a body mass index >=30 kg m(-2), Blacks and those with type II diabetes. Here we report a prespecified secondary analysis of the efficacy of amlodipine (10 mg day(-1)), olmesartan medoxomil (40 mg day(-1)), a combination of the two and placebo in these subgroups. Patients were randomized to treatment for 8 weeks. The primary efficacy endpoint was the change from baseline in mean seated diastolic blood pressure (DBP). Secondary efficacy endpoints included the change from baseline in mean seated systolic BP (SBP), proportions of patients achieving BP goal (<140/90 mm Hg or <130/80 mm Hg in patients with diabetes), and the number and percentage of patients achieving a range of BP targets. Safety and tolerability of amlodipine 5 and 10 mg, olmesartan medoxomil 10, 20 and 40 mg, and all possible combinations of the two were also assessed. For each prespecified subgroup, all active treatments resulted in significant BP reductions from baseline (P<0.05). The antihypertensive effect of the combination of amlodipine+olmesartan medoxomil was generally greater than the constituent amlodipine or olmesartan medoxomil monotherapies, regardless of subgroup. In general, more patients receiving combination therapy achieved BP goal than those treated with monotherapies. The safety and tolerability of combinations were similar to monotherapies across the subgroups. These results suggest that the combination of amlodipine+olmesartan medoxomil provides a safe and effective option for the treatment of hypertension in challenging patient populations. PMID- 20164849 TI - Self blood pressure monitoring: a worthy substitute for ambulatory blood pressure? AB - The European Society of Hypertension (ESH), the American Heart Association (AHA) and the American Society of Hypertension (ASH) have published guidelines for self monitoring of blood pressure (SBPM). We aimed to demonstrate the equivalence of SBPM with ambulatory blood pressure monitoring (ABPM) in the assessment of hypertension. A total of 87 consecutive subjects referred from primary care for standard ABPM underwent a 1-week period of SBPM, as defined by the ESH guidelines, either before or after ABPM. There was no difference in mean blood pressure (BP): SBPM 142/87 mm Hg, daytime average ABPM 141/86 mm Hg. The intra class correlation coefficient was 0.72 and 0.89 for systolic and diastolic pressure, respectively. SBPM is concordant with ABPM in classifying subjects as hypertensive or normotensive in 87% of cases (kappa=0.56). The coefficient of variation of SBPM compared with ABPM was 5%. In answer to a direct question 81% of subjects preferred SBPM to ABPM. The current self-monitoring schedule recommended by the ESH, AHA and ASH is valid. The mean BP obtained from SBPM is equivalent to awake-time BP on ABPM, the accepted reference standard for 'out of office' BP measurement. SBPM is simpler to carry out, preferred by patients and should be considered on a par with ABPM. PMID- 20164848 TI - Association between vascular endothelial growth factor and hypertension in children and adolescents type I diabetes mellitus. AB - The aim of the study was to analyse the relationship between the serum level of vascular endothelial growth factor (VEGF) and the incidence of hypertension (HT) in children and adolescents with type I diabetes mellitus (T1DM). One hundred and five patients with T1DM were enrolled in the study. The control group consisted of 30 healthy controls. All the T1DM patients were subjected to biochemical analyses, ophthalmologic examination and 24-h blood pressure monitoring. Besides, all the patients and healthy controls had serum VEGF levels measured with the use of the ELISA methodology. The essence of our research is that patients with T1DM and HT and with microalbuminuria (MA) and diabetic retinopathy (DR) (MA/DR) are characterized by a significantly higher level of VEGF (340.23+/-93.22 pg ml(-1)) in blood serum in comparison with the group of T1DM patients without HT and MA/DR (183.6+/-96.6 pg ml(-1)) and with healthy controls (145.32+/-75.58 pg ml(-1)). In addition, the VEGF level was significantly higher in T1DM patients, who presented all three complications, that is HT, retinopathy and MA in comparison with T1DM patients without HT, but with MA/DR (P=0.036). On the other hand, no statistically significant differences (P=0.19) were noted in the level of VEGF in serum between T1DM patients without HT and MA/DR and the healthy control group. At a further stage of analysis, using the method of multiple regression, it was shown that systolic pressure, HbA1c and duration of disease are independent factors influencing the concentration of VEGF. Summarizing, the measurement of VEGF serum levels allows for the identification of groups of patients who have the highest risk of HT and, subsequently, progression of vascular complications. PMID- 20164850 TI - Nucleoside analog ARC targets Mcl-1 to induce apoptosis in leukemia cells. PMID- 20164851 TI - Bimodal distribution of genomic MLL breakpoints in infant acute lymphoblastic leukemia treatment. PMID- 20164852 TI - Identifying candidate allogeneic NK-cell donors for hematopoietic stem-cell transplantation based on functional phenotype. PMID- 20164853 TI - AML with CBFB-MYH11 rearrangement demonstrate RAS pathway alterations in 92% of all cases including a high frequency of NF1 deletions. PMID- 20164854 TI - KANK1, a candidate tumor suppressor gene, is fused to PDGFRB in an imatinib responsive myeloid neoplasm with severe thrombocythemia. PMID- 20164855 TI - Generation of multi-functional antigen-specific human T-cells by lentiviral TCR gene transfer. AB - T-cell receptor (TCR) gene transfer is an attractive strategy to generate antigen specific T-cells for adoptive immunotherapy of cancer and chronic viral infection. However, current TCR gene transfer protocols trigger T-cell differentiation into terminally differentiated effector cells, which likely have reduced ability to mediate disease protection in vivo. We have developed a lentiviral gene transfer strategy to generate TCR-transduced human T-cells without promoting T-cell differentiation. We found that a combination of interleukin-15 (IL15) and IL21 facilitated lentiviral TCR gene transfer into non proliferating T-cells. The transduced T-cells showed redirection of antigen specificity and produced IL2, IFNgamma and TNFalpha in a peptide-dependent manner. A significantly higher proportion of the IL15/IL21-stimulated T-cells were multi-functional and able to simultaneously produce all three cytokines (P<0.01), compared with TCR-transduced T-cells generated by conventional anti-CD3 plus IL2 stimulation, which primarily secreted only one cytokine. Similarly, IL15/IL21 maintained high levels of CD62L and CD28 expression in transduced T cells, whereas anti-CD3 plus IL2 accelerated the loss of CD62L/CD28 expression. The data demonstrate that the combination of lentiviral TCR gene transfer together with IL15/IL21 stimulation can efficiently redirect the antigen specificity of resting primary human T-cells and generate multi-functional T cells. PMID- 20164856 TI - Evaluation of cross-reactive cell-mediated immune responses among human, bovine and porcine adenoviruses. AB - The absence of preexisting immunity against porcine adenovirus (Ad) serotype 3 (PAd3) and bovine Ad serotype 3 (BAd3) in humans makes them attractive alternatives to human Ad serotype 5 (HAd5) vectors. To determine whether there is significant cross-reactivity among HAd5, BAd3 and PAd3 at the level of cell mediated immune responses, BALB/c mice were inoculated intraperitoneally with wild-type (WT) or replication-defective (RD) HAd5, BAd3 or PAd3. After 35 days of the first inoculation, cross-reactive CD8+ cytotoxic T cells, as well as CD4+ Th1 and Th2-helper T cells, in the spleen were analyzed by enzyme-linked-immunospot, flow cytometry and cytotoxic T lymphocyte assays. Virus-neutralization assays were used to evaluate humoral cross-reactivity. CD8+ or CD4+ T cells primed with WT or RD HAd5, PAd3 or BAd3 showed significant (P<0.005) reactivity with homologous Ad antigens, whereas only minimal cross-reactivity was observed on stimulation with heterologous Ad antigens. Ad-neutralizing antibodies were found to be homologous Ad specific. Overall, these results suggest that there is no significant immunological cross-reactivity among HAd5, BAd3 and PAd3, thereby supporting the rationale for the use of BAd3 and PAd3 as alternative HAd vectors to circumvent anti-HAd immunity in humans. PMID- 20164857 TI - Lentiviral vectors incorporating a human elongation factor 1alpha promoter for the treatment of canine leukocyte adhesion deficiency. AB - Canine leukocyte adhesion deficiency (CLAD) provides a unique large animal model for testing new therapeutic approaches for the treatment of children with leukocyte adhesion deficiency (LAD). In our CLAD model, we examined two different fragments of the human elongation factor 1alpha (EF1alpha) promoter (EF1alphaL, 1189 bp and EF1alphaS, 233 bp) driving the expression of canine CD18 in a self inactivating (SIN) lentiviral vector. The EF1alphaS vector resulted in the highest levels of canine CD18 expression in CLAD CD34(+) cells in vitro. Subsequently, autologous CD34(+) bone marrow cells from four CLAD pups were transduced with the EF1alphaS vector and infused following a non-myeloablative dose of 200 cGy total-body irradiation. None of the CLAD pups achieved levels of circulating CD18(+) neutrophils sufficient to reverse the CLAD phenotype, and all four animals were euthanized because of infections within 9 weeks of treatment. These results indicate that the EF1alphaS promoter-driven CD18 expression in the context of a RRLSIN lentiviral vector does not lead to sufficient numbers of CD18(+) neutrophils in vivo to reverse the CLAD phenotype when used in a non myeloablative transplant regimen in dogs. PMID- 20164858 TI - Rhadinovirus vector-derived human telomerase reverse transcriptase expression in primary T cells. AB - The rhadinovirus herpesvirus saimiri (HVS) as a gene delivery vector allows large DNA insertions and long-termed gene expression. In the case of T-cell transduction, such vectors use the viral transformation-associated genes of HVS C488 for T-cell amplification. In this report, we investigated whether the gene for the catalytic telomerase subunit human telomerase reverse transcriptase (hTERT) can substitute for the transformation-associated genes in rhadinoviral T cell transduction and amplification. By using virus mutants generated by en passant mutagenesis from bacterial artificial chromosomes, we observed a very early and functional transgene expression even by virus mutants without transformation-associated genes. The markers of T-cell transformation by HVS, namely CD2 hyperreactivity, overexpression of interleukin-26, and of the tyrosine kinase Lyn could neither be induced nor enhanced by ectopic hTERT expression. When the viral transformation-associated genes were replaced by the hTERT gene, it was not sufficient for growth transformation, although hTERT was efficiently transduced and functionally expressed by the rhadinovirus vector. Thus, the transformation-associated proteins StpC and Tip are responsible for the T-cell phenotype after transduction by HVS and, additionally, modulate telomerase activity independently of hTERT expression. PMID- 20164860 TI - Anomalous energy yields in thermodynamic calculations: importance of accounting for pH-dependent organic acid speciation. PMID- 20164859 TI - Lack of humoral immune response to the tetracycline (Tet) activator in rats injected intracranially with Tet-off rAAV vectors. AB - The ability to safely control transgene expression from viral vectors is a long term goal in the gene therapy field. We have previously reported tight regulation of GFP expression in rat brain using a self-regulating tet-off rAAV vector. The immune responses against tet regulatory elements observed by other groups in nonhuman primates after intramuscular injection of tet-on encoding vectors raise concerns about the clinical value of tet-regulated vectors. However, previous studies have not examined immune responses following injection of AAV vectors into brain. Therefore, rat striatum was injected with tet-off rAAV harboring a therapeutic gene for Parkinson's disease, either hAADC or hGDNF. The expression of each gene was tightly controlled by the tet-off regulatory system. Using an ELISA developed with purified GST-tTA protein, no detectable immunogenicity against tTA was observed in sera of rats that received an intrastriatal injection of either vector. In contrast, sera from rats intradermally injected with an adenovirus containing either tTA or rtTA, as positive controls, had readily detectable antibodies. These observations suggest that tet-off rAAV vectors do not elicit an immune response when injected into rat brain and that these may offer safer vectors for Parkinson's disease than vectors with constitutive expression. PMID- 20164861 TI - Microbial secondary succession in a chronosequence of chalk grasslands. AB - Although secondary succession has been studied extensively, we have little knowledge of the succession of soil-borne microbial communities. In this study, we therefore examined the structures of the microbial communities across two separate chronosequences of chalk grasslands in Limburg, the Netherlands, which are at different stages of secondary succession after being abandoned for between 17 and >66 years. Arable fields were also included in the investigation as non abandoned references. Changes in the soil-borne microbial communities, as determined by phylogenetic microarray and quantitative PCR methodologies, were correlated with the prevailing environmental conditions related to vegetation and soil biochemistry. We observed clear patterns of microbial secondary succession related to soil age, pH and phosphate status, as exemplified by the overrepresentation of Verrucomicrobia, Acidobacteria, Gemmatimonadetes, and alpha , delta- and epsilon-Proteobacteria at late successional stages. Moreover, effects of secondary succession versus changes in soil pH could be resolved, with pH significantly altering the trajectory of microbial succession. PMID- 20164862 TI - Comparative metaproteomics reveals ocean-scale shifts in microbial nutrient utilization and energy transduction. AB - Bacteria and Archaea play critical roles in marine energy fluxes and nutrient cycles by incorporating and redistributing dissolved organic matter and inorganic nutrients in the oceans. How these microorganisms do this work at the level of the expressed protein is known only from a few studies of targeted lineages. We used comparative membrane metaproteomics to identify functional responses of communities to different nutrient concentrations on an oceanic scale. Comparative analyses of microbial membrane fractions revealed shifts in nutrient utilization and energy transduction along an environmental gradient in South Atlantic surface waters, from a low-nutrient gyre to a highly productive coastal upwelling region. The dominant membrane proteins identified (19%) were TonB-dependent transporters (TBDTs), which are known to utilize a proton motive force to transport nutrients across the outer membrane of Gram-negative bacteria. The ocean-wide importance of TonB-dependent nutrient acquisition in marine bacteria was unsuspected. Diverse light-harvesting rhodopsins were detected in membrane proteomes from every sample. Proteomic evidence of both TBDTs and rhodopsins in the same lineages suggest that phototrophic bacterioplankton have the potential to use energy from light to fuel transport activities. We also identified viral proteins in every sample and archaeal ammonia monooxygenase proteins in the upwelling region, suggesting that Archaea are important nitrifiers in nutrient-rich surface waters. PMID- 20164863 TI - Site and plant species are important determinants of the Methylobacterium community composition in the plant phyllosphere. AB - The plant phyllosphere constitutes a habitat for numerous microorganisms; among them are members of the genus Methylobacterium. Owing to the ubiquitous occurrence of methylobacteria on plant leaves, they represent a suitable target for studying plant colonization patterns. The influence of the factor site, host plant species, time and the presence of other phyllosphere bacteria on Methylobacterium community composition and population size were evaluated in this study. Leaf samples were collected from Arabidopsis thaliana or Medicago truncatula plants and from the surrounding plant species at several sites. The abundance of cultivable Methylobacterium clearly correlated with the abundance of other phyllosphere bacteria, suggesting that methylobacteria constitute a considerable and rather stable fraction of the phyllosphere microbiota under varying environmental conditions. Automated ribosomal intergenic spacer analysis (ARISA) was applied to characterize the Methylobacterium community composition and showed the presence of similar communities on A. thaliana plants at most sites in 2 consecutive years of sampling. A substantial part of the observed variation in the community composition was explained by site and plant species, especially in the case of the plants collected at the Arabidopsis sites (50%). The dominating ARISA peaks that were detected on A. thaliana plants were found on other plant species grown at the same site, whereas some different peaks were detected on A. thaliana plants from other sites. This indicates that site specific factors had a stronger impact on the Methylobacterium community composition than did plant-specific factors and that the Methylobacterium-plant association is not highly host plant species specific. PMID- 20164864 TI - Fine-scale evolution: genomic, phenotypic and ecological differentiation in two coexisting Salinibacter ruber strains. AB - Genomic and metagenomic data indicate a high degree of genomic variation within microbial populations, although the ecological and evolutive meaning of this microdiversity remains unknown. Microevolution analyses, including genomic and experimental approaches, are so far very scarce for non-pathogenic bacteria. In this study, we compare the genomes, metabolomes and selected ecological traits of the strains M8 and M31 of the hyperhalophilic bacterium Salinibacter ruber that contain ribosomal RNA (rRNA) gene and intergenic regions that are identical in sequence and were simultaneously isolated from a Mediterranean solar saltern. Comparative analyses indicate that S. ruber genomes present a mosaic structure with conserved and hypervariable regions (HVRs). The HVRs or genomic islands, are enriched in transposases, genes related to surface properties, strain-specific genes and highly divergent orthologous. However, the many indels outside the HVRs indicate that genome plasticity extends beyond them. Overall, 10% of the genes encoded in the M8 genome are absent from M31 and could stem from recent acquisitions. S. ruber genomes also harbor 34 genes located outside HVRs that are transcribed during standard growth and probably derive from lateral gene transfers with Archaea preceding the M8/M31 divergence. Metabolomic analyses, phage susceptibility and competition experiments indicate that these genomic differences cannot be considered neutral from an ecological perspective. The results point to the avoidance of competition by micro-niche adaptation and response to viral predation as putative major forces that drive microevolution within these Salinibacter strains. In addition, this work highlights the extent of bacterial functional diversity and environmental adaptation, beyond the resolution of the 16S rRNA and internal transcribed spacers regions. PMID- 20164865 TI - AMD biofilms: using model communities to study microbial evolution and ecological complexity in nature. AB - Similar to virtually all components of natural environments, microbial systems are inherently complex and dynamic. Advances in cultivation-independent molecular methods have provided a route to study microbial consortia in their natural surroundings and to begin resolving the community structure, dominant metabolic processes and inter-organism interactions. However, the utility of these methods generally scales inversely with community complexity. By applying genomics enabled methods to the study of natural microbial communities with reduced levels of species richness, a relatively comprehensive understanding of the metabolic networks and evolutionary processes within these communities can be attained. In such well-defined model systems, it is also possible to link emergent ecological patterns to their molecular and evolutionary underpinnings, facilitating construction of predictive ecosystem models. In this study, we review over a decade of research on one such system-acid mine drainage biofilm communities. We discuss the value and limitations of tractable model microbial communities in developing molecular methods for microbial ecology and in uncovering principles that may explain behavior in more complex systems. PMID- 20164866 TI - Multilevel and kin selection in a connected world. AB - Wild et al. argue that the evolution of reduced virulence can be understood from the perspective of inclusive fitness, obviating the need to evoke group selection as a contributing causal factor. Although they acknowledge the mathematical equivalence of the inclusive fitness and multilevel selection approaches, they conclude that reduced virulence can be viewed entirely as an individual-level adaptation by the parasite. Here we show that their model is a well-known special case of the more general theory of multilevel selection, and that the cause of reduced virulence resides in the opposition of two processes: within-group and among-group selection. This distinction is important in light of the current controversy among evolutionary biologists in which some continue to affirm that natural selection centres only and always at the level of the individual organism or gene, despite mathematical demonstrations that evolutionary dynamics must be described by selection at various levels in the hierarchy of biological organization. PMID- 20164871 TI - Progressive thinking. PMID- 20164872 TI - Validation required. PMID- 20164873 TI - Nature's choices. PMID- 20164884 TI - Journal club. A physical chemist is excited by the electronic potential of a new arrangement of carbon sheets. PMID- 20164886 TI - Three biologists slain on campus. PMID- 20164887 TI - Africa yields two full human genomes. PMID- 20164890 TI - Genomics firms turn to other markets. PMID- 20164888 TI - How accurate are cancer cell lines? PMID- 20164891 TI - Asian pollution delays inevitable warming. PMID- 20164892 TI - 'Climategate' scientist speaks out. PMID- 20164893 TI - Trees spit out gas from soil microbes. PMID- 20164894 TI - General relativity tested on a tabletop. PMID- 20164895 TI - Evolution: Revenge of the hopeful monster. PMID- 20164896 TI - Astronomy: The decadal dinner club. PMID- 20164897 TI - Carbon sequestration: Buried trouble. PMID- 20164898 TI - World view: Calling science to account. PMID- 20164899 TI - Transdisciplinary EU science institute needs funds urgently. PMID- 20164900 TI - Parliament needs members who are scientifically literate. PMID- 20164902 TI - University overhaul vital to end Bulgarian science's long decline. PMID- 20164901 TI - The Rubisco enzyme and agricultural productivity. PMID- 20164903 TI - Outcry stopped approved pig study of avalanche survival. PMID- 20164904 TI - China fights fraud with tough tactics and integrity training. PMID- 20164905 TI - Lessons from the Haiti earthquake. PMID- 20164910 TI - Q&A: David Brin on writing fiction. Interview by Nicola Jones. PMID- 20164911 TI - Early life: Ancient acritarchs. PMID- 20164912 TI - Astrophysics: Cosmic jet engines. PMID- 20164913 TI - Gene regulation: A chromatin thermostat. PMID- 20164914 TI - Animal behaviour: An ill wind for finches. PMID- 20164915 TI - Structural biology: Transformative encounters. PMID- 20164916 TI - Quantum measurement: A light touch. PMID- 20164917 TI - Genetics: Random expression goes binary. PMID- 20164919 TI - Signatures of mutation and selection in the cancer genome. AB - The cancer genome is moulded by the dual processes of somatic mutation and selection. Homozygous deletions in cancer genomes occur over recessive cancer genes, where they can confer selective growth advantage, and over fragile sites, where they are thought to reflect an increased local rate of DNA breakage. However, most homozygous deletions in cancer genomes are unexplained. Here we identified 2,428 somatic homozygous deletions in 746 cancer cell lines. These overlie 11% of protein-coding genes that, therefore, are not mandatory for survival of human cells. We derived structural signatures that distinguish between homozygous deletions over recessive cancer genes and fragile sites. Application to clusters of unexplained homozygous deletions suggests that many are in regions of inherent fragility, whereas a small subset overlies recessive cancer genes. The results illustrate how structural signatures can be used to distinguish between the influences of mutation and selection in cancer genomes. The extensive copy number, genotyping, sequence and expression data available for this large series of publicly available cancer cell lines renders them informative reagents for future studies of cancer biology and drug discovery. PMID- 20164920 TI - The landscape of somatic copy-number alteration across human cancers. AB - A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-kappaBeta pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types. PMID- 20164921 TI - Active site remodelling accompanies thioester bond formation in the SUMO E1. AB - E1 enzymes activate ubiquitin (Ub) and ubiquitin-like (Ubl) proteins in two steps by carboxy-terminal adenylation and thioester bond formation to a conserved catalytic cysteine in the E1 Cys domain. The structural basis for these intermediates remains unknown. Here we report crystal structures for human SUMO E1 in complex with SUMO adenylate and tetrahedral intermediate analogues at 2.45 and 2.6 A, respectively. These structures show that side chain contacts to ATP.Mg are released after adenylation to facilitate a 130 degree rotation of the Cys domain during thioester bond formation that is accompanied by remodelling of key structural elements including the helix that contains the E1 catalytic cysteine, the crossover and re-entry loops, and refolding of two helices that are required for adenylation. These changes displace side chains required for adenylation with side chains required for thioester bond formation. Mutational and biochemical analyses indicate these mechanisms are conserved in other E1s. PMID- 20164924 TI - An upper limit on the contribution of accreting white dwarfs to the type Ia supernova rate. AB - There is wide agreement that type Ia supernovae (used as standard candles for cosmology) are associated with the thermonuclear explosions of white dwarf stars. The nuclear runaway that leads to the explosion could start in a white dwarf gradually accumulating matter from a companion star until it reaches the Chandrasekhar limit, or could be triggered by the merger of two white dwarfs in a compact binary system. The X-ray signatures of these two possible paths are very different. Whereas no strong electromagnetic emission is expected in the merger scenario until shortly before the supernova, the white dwarf accreting material from the normal star becomes a source of copious X-rays for about 10(7) years before the explosion. This offers a means of determining which path dominates. Here we report that the observed X-ray flux from six nearby elliptical galaxies and galaxy bulges is a factor of approximately 30-50 less than predicted in the accretion scenario, based upon an estimate of the supernova rate from their K band luminosities. We conclude that no more than about five per cent of type Ia supernovae in early-type galaxies can be produced by white dwarfs in accreting binary systems, unless their progenitors are much younger than the bulk of the stellar population in these galaxies, or explosions of sub-Chandrasekhar white dwarfs make a significant contribution to the supernova rate. PMID- 20164922 TI - Variability in gene expression underlies incomplete penetrance. AB - The phenotypic differences between individual organisms can often be ascribed to underlying genetic and environmental variation. However, even genetically identical organisms in homogeneous environments vary, indicating that randomness in developmental processes such as gene expression may also generate diversity. To examine the consequences of gene expression variability in multicellular organisms, we studied intestinal specification in the nematode Caenorhabditis elegans in which wild-type cell fate is invariant and controlled by a small transcriptional network. Mutations in elements of this network can have indeterminate effects: some mutant embryos fail to develop intestinal cells, whereas others produce intestinal precursors. By counting transcripts of the genes in this network in individual embryos, we show that the expression of an otherwise redundant gene becomes highly variable in the mutants and that this variation is subjected to a threshold, producing an ON/OFF expression pattern of the master regulatory gene of intestinal differentiation. Our results demonstrate that mutations in developmental networks can expose otherwise buffered stochastic variability in gene expression, leading to pronounced phenotypic variation. PMID- 20164925 TI - A precision measurement of the gravitational redshift by the interference of matter waves. AB - One of the central predictions of metric theories of gravity, such as general relativity, is that a clock in a gravitational potential U will run more slowly by a factor of 1 + U/c(2), where c is the velocity of light, as compared to a similar clock outside the potential. This effect, known as gravitational redshift, is important to the operation of the global positioning system, timekeeping and future experiments with ultra-precise, space-based clocks (such as searches for variations in fundamental constants). The gravitational redshift has been measured using clocks on a tower, an aircraft and a rocket, currently reaching an accuracy of 7 x 10(-5). Here we show that laboratory experiments based on quantum interference of atoms enable a much more precise measurement, yielding an accuracy of 7 x 10(-9). Our result supports the view that gravity is a manifestation of space-time curvature, an underlying principle of general relativity that has come under scrutiny in connection with the search for a theory of quantum gravity. Improving the redshift measurement is particularly important because this test has been the least accurate among the experiments that are required to support curved space-time theories. PMID- 20164926 TI - Upside-down differentiation and generation of a 'primordial' lower mantle. AB - Except for the first 50-100 million years or so of the Earth's history, when most of the mantle may have been subjected to melting, the differentiation of Earth's silicate mantle has been controlled by solid-state convection. As the mantle upwells and decompresses across its solidus, it partially melts. These low density melts rise to the surface and form the continental and oceanic crusts, driving the differentiation of the silicate part of the Earth. Because many trace elements, such as heat-producing U, Th and K, as well as the noble gases, preferentially partition into melts (here referred to as incompatible elements), melt extraction concentrates these elements into the crust (or atmosphere in the case of noble gases), where nearly half of the Earth's budget of these elements now resides. In contrast, the upper mantle, as sampled by mid-ocean ridge basalts, is highly depleted in incompatible elements, suggesting a complementary relationship with the crust. Mass balance arguments require that the other half of these incompatible elements be hidden in the Earth's interior. Hypotheses abound for the origin of this hidden reservoir. The most widely held view has been that this hidden reservoir represents primordial material never processed by melting or degassing. Here, we suggest that a necessary by-product of whole mantle convection during the Earth's first billion years is deep and hot melting, resulting in the generation of dense liquids that crystallized and sank into the lower mantle. These sunken lithologies would have 'primordial' chemical signatures despite a non-primordial origin. PMID- 20164923 TI - A change in the optical polarization associated with a gamma-ray flare in the blazar 3C 279. AB - It is widely accepted that strong and variable radiation detected over all accessible energy bands in a number of active galaxies arises from a relativistic, Doppler-boosted jet pointing close to our line of sight. The size of the emitting zone and the location of this region relative to the central supermassive black hole are, however, poorly known, with estimates ranging from light-hours to a light-year or more. Here we report the coincidence of a gamma (gamma)-ray flare with a dramatic change of optical polarization angle. This provides evidence for co-spatiality of optical and gamma-ray emission regions and indicates a highly ordered jet magnetic field. The results also require a non axisymmetric structure of the emission zone, implying a curved trajectory for the emitting material within the jet, with the dissipation region located at a considerable distance from the black hole, at about 10(5) gravitational radii. PMID- 20164928 TI - Rapid spine stabilization and synaptic enhancement at the onset of behavioural learning. AB - Behavioural learning depends on the brain's capacity to respond to instructive experience and is often enhanced during a juvenile sensitive period. How instructive experience acts on the juvenile brain to trigger behavioural learning remains unknown. In vitro studies show that forms of synaptic strengthening thought to underlie learning are accompanied by an increase in the stability, number and size of dendritic spines, which are the major sites of excitatory synaptic transmission in the vertebrate brain. In vivo imaging studies in sensory cortical regions reveal that these structural features can be affected by disrupting sensory experience and that spine turnover increases during sensitive periods for sensory map formation. These observations support two hypotheses: first, the increased capacity for behavioural learning during a sensitive period is associated with enhanced spine dynamics on sensorimotor neurons important for the learned behaviour; second, instructive experience rapidly stabilizes and strengthens these dynamic spines. Here we report a test of these hypotheses using two-photon in vivo imaging to measure spine dynamics in zebra finches, which learn to sing by imitating a tutor song during a juvenile sensitive period. Spine dynamics were measured in the forebrain nucleus HVC, the proximal site where auditory information merges with an explicit song motor representation, immediately before and after juvenile finches first experienced tutor song. Higher levels of spine turnover before tutoring correlated with a greater capacity for subsequent song imitation. In juveniles with high levels of spine turnover, hearing a tutor song led to the rapid ( approximately 24-h) stabilization, accumulation and enlargement of dendritic spines in HVC. Moreover, in vivo intracellular recordings made immediately before and after the first day of tutoring revealed robust enhancement of synaptic activity in HVC. These findings suggest that behavioural learning results when instructive experience is able to rapidly stabilize and strengthen synapses on sensorimotor neurons important for the control of the learned behaviour. PMID- 20164927 TI - Complete Khoisan and Bantu genomes from southern Africa. AB - The genetic structure of the indigenous hunter-gatherer peoples of southern Africa, the oldest known lineage of modern human, is important for understanding human diversity. Studies based on mitochondrial and small sets of nuclear markers have shown that these hunter-gatherers, known as Khoisan, San, or Bushmen, are genetically divergent from other humans. However, until now, fully sequenced human genomes have been limited to recently diverged populations. Here we present the complete genome sequences of an indigenous hunter-gatherer from the Kalahari Desert and a Bantu from southern Africa, as well as protein-coding regions from an additional three hunter-gatherers from disparate regions of the Kalahari. We characterize the extent of whole-genome and exome diversity among the five men, reporting 1.3 million novel DNA differences genome-wide, including 13,146 novel amino acid variants. In terms of nucleotide substitutions, the Bushmen seem to be, on average, more different from each other than, for example, a European and an Asian. Observed genomic differences between the hunter-gatherers and others may help to pinpoint genetic adaptations to an agricultural lifestyle. Adding the described variants to current databases will facilitate inclusion of southern Africans in medical research efforts, particularly when family and medical histories can be correlated with genome-wide data. PMID- 20164931 TI - Whole-animal imaging: The whole picture. PMID- 20164929 TI - Rere controls retinoic acid signalling and somite bilateral symmetry. AB - One of the most notable features of the vertebrate body plan organization is its bilateral symmetry, evident at the level of vertebrae and skeletal muscles. Here we show that a mutation in Rere (also known as atrophin2) leads to the formation of asymmetrical somites in mouse embryos, similar to embryos deprived of retinoic acid. Furthermore, we also demonstrate that Rere controls retinoic acid signalling, which is required to maintain somite symmetry by interacting with Fgf8 in the left-right signalling pathway. Rere forms a complex with Nr2f2, p300 (also known as Ep300) and a retinoic acid receptor, which is recruited to the retinoic acid regulatory element of retinoic acid targets, such as the Rarb promoter. Furthermore, the knockdown of Nr2f2 and/or Rere decreases retinoic acid signalling, suggesting that this complex is required to promote transcriptional activation of retinoic acid targets. The asymmetrical expression of Nr2f2 in the presomitic mesoderm overlaps with the asymmetry of the retinoic acid signalling response, supporting its implication in the control of somitic symmetry. Misregulation of this mechanism could be involved in symmetry defects of the human spine, such as those observed in patients with scoliosis. PMID- 20164932 TI - Whole-animal imaging: Probe progress. PMID- 20164930 TI - TCR-peptide-MHC interactions in situ show accelerated kinetics and increased affinity. AB - The recognition of foreign antigens by T lymphocytes is essential to most adaptive immune responses. It is driven by specific T-cell antigen receptors (TCRs) binding to antigenic peptide-major histocompatibility complex (pMHC) molecules on other cells. If productive, these interactions promote the formation of an immunological synapse. Here we show that synaptic TCR-pMHC binding dynamics differ significantly from TCR-pMHC binding in solution. We used single-molecule microscopy and fluorescence resonance energy transfer (FRET) between fluorescently tagged TCRs and their cognate pMHC ligands to measure the kinetics of TCR-pMHC binding in situ. When compared with solution measurements, the dissociation of this complex was increased significantly (4-12-fold). Disruption of actin polymers reversed this effect, indicating that cytoskeletal dynamics destabilize this interaction directly or indirectly. Nevertheless, TCR affinity for pMHC was significantly elevated as the result of a large (about 100-fold) increase in the association rate, a likely consequence of complementary molecular orientation and clustering. In helper T cells, the CD4 molecule has been proposed to bind cooperatively with the TCR to the same pMHC complex. However, CD4 blockade had no effect on the synaptic TCR affinity, nor did it destabilize TCR pMHC complexes, indicating that the TCR binds pMHC independently of CD4. PMID- 20164940 TI - Tissues from privately owned dogs. IACUC approval required. PMID- 20164941 TI - Tissues from privately owned dogs. PMID- 20164942 TI - Tissues from privately owned dogs. A word from OLAW and USDA. PMID- 20164943 TI - Tissues from privately owned dogs. CRC is correct. PMID- 20164944 TI - Tissues from privately owned dogs. Don't rock the boat! PMID- 20164945 TI - Dermatitis in a Siberian hamster (Phodopus sungorus). Bacterial pseudomycetoma. PMID- 20164947 TI - Organic wheatgrass as environmental enrichment. AB - Environmental enrichment must be provided for the various animal species that are housed in laboratory animal facilities. Wheatgrass can be used as a natural form of enrichment that requires minimal preparation and effort. Wheatgrass is appropriate enrichment for cats, rabbits, guinea pigs, rodents and birds. PMID- 20164948 TI - Effect of intravenous ketamine and lidocaine on isoflurane requirement in sheep undergoing orthopedic surgery. AB - Intravenous ketamine and lidocaine infusions may be useful adjuncts to inhalation anesthesia for sheep undergoing orthopedic surgery. In this study, 50 female sheep underwent experimental stifle surgery (29 received a meniscal implant and 21 received sham surgery). To induce anesthesia in the sheep, the authors intravenously injected ketamine and diazepam. They administered isoflurane in oxygen to maintain anesthesia and used mechanical ventilation to maintain normal arterial carbon dioxide pressure. Some sheep received intravenous infusions of ketamine and lidocaine during surgery, whereas others did not. Sheep that received a meniscal implant without ketamine-lidocaine required approximately 23% greater isoflurane concentrations than sheep that were given ketamine-lidocaine. These findings suggest that intravenous infusion of ketamine and lidocaine decreases the requirement for isoflurane during orthopedic surgery on anesthetized sheep. PMID- 20164949 TI - Peri- and intra-operative management of the goat during acute surgical experimentation. AB - Goats are used as animal models for surgery and trauma research. The authors discuss appropriate methods for induction of anesthetics, intubation and surgical maintenance of the goat during acute experimentation. Risks imposed by the Q fever pathogen Coxiella burnetii are described, as well as measures that have proven effective in minimizing zoonotic transmission of this pathogen to laboratory personnel. With appropriate knowledge of its applications, peri- and intra-operative management and limitations, the goat is a suitable animal model for a variety of biomedical research applications. PMID- 20164950 TI - Considering Q fever when working with laboratory sheep. AB - The sheep (Ovis aries) is somewhat less common than smaller species in laboratory settings, but personnel who work with sheep or in a facility that houses sheep should be aware that certain zoonotic diseases are common in sheep. They should also know how to prevent transmission of zoonotic disease in facilities that house or work with small ruminants. Knowledge of diseases such as query fever (Q fever), which can cause severe human morbidity (and in some cases death), needs to be especially emphasized. In this paper, the author describes potential causes, transmission and manifestations of Q fever in humans and other animals and then discusses strategies for preventing the spread of Q fever. PMID- 20164951 TI - Refractive index interpolation in phase-matching. PMID- 20164953 TI - Double-beaming technique in Fourier spectroscopy. PMID- 20164952 TI - Coupling to film waveguides with reusable plastic gratings. PMID- 20164954 TI - Dielectric compound parabolic concentrators. PMID- 20164955 TI - Optical activities in industry. PMID- 20164956 TI - Meeting reports. PMID- 20164957 TI - Optical center of a glass corner cube: its measurement. PMID- 20164958 TI - Effective quantum efficiency of photodetectors for photon energies much larger than threshold. PMID- 20164960 TI - Optically stabilized power supply for mercury arc lamp far ir sources. PMID- 20164959 TI - Bimorph optical beam deflector. PMID- 20164961 TI - Cellular structure as revealed by visible light scattering: studies on suspensions of red blood cell ghosts. PMID- 20164962 TI - Multiple imaging by diffraction techniques. PMID- 20164963 TI - Structural measurement by inverse scattering in the first Born approximation. PMID- 20164964 TI - Low-visibility optical communications: received signal level as a function of receiver field of view. PMID- 20164965 TI - Reference speckle superposition technique applied to transient phenomena analysis. PMID- 20164966 TI - Modified zigzag-ray model in a dielectric slab optical waveguide. PMID- 20164967 TI - Metal diffused stripe waveguides: approximate closed form solution for lower order modes. PMID- 20164968 TI - Optical fiber splicing technique with a CO(2) laser. PMID- 20164969 TI - Light scattering particles for laser velocimeter measurements. PMID- 20164971 TI - Patents. AB - 3,813,141; 3,892,469 and 3,892,470; 3,893,751; 3,893,752; 3,895,857; 3,897,133; 3,899,242; 3,901,585; 3,902,792; 3,905,685; 3,909,115. PMID- 20164970 TI - Of optics and opticists. PMID- 20164972 TI - Optical and electrical effects during polymerization and depolymerization in liquid sulfur: indications for the nonuniformity model for covalent liquids. AB - The polymerization and depolymerization of liquid sulfur refers, respectively, to the processes of chain growth and chain scission promoted by changing thermodynamic conditions. These structural transitions cause major optical and electrical consequences, including: (1) color change from yellow to orange to red, (2) peaked high angle and low angle scattering and minimum in transmission of He-Ne laser light at the structural changes, (3) a decrease in the current induced by a pulsed ruby laser above the polymerization temperature T(p) compared with below T(p), (4) two changes in the sign of the temperature coefficient of resistance in the vicinity of T(p) and the depolymerization temperature T(d), and (5) superlinear current-voltage characteristics above T(d). The data are interpreted as being suggestive of the structure of a liquid being better described by a nonuniformity rather than random network model. PMID- 20164973 TI - Pollution monitoring systems based on resonance absorption measurements of ozone with a "tunable" CO(2) laser: some criteria. AB - Measurements have been made with a line tunable CO(2) laser on ozone in order to establish some useful criteria for pollution monitoring via the direct absorption scheme. The absorption coefficient a and the pressure dependence of the extinction coefficient k(nu)(P) at frequencies nu corresponding to the P(8) to P(36) vibration-rotation lines of the CO(2) laser have been measured. Good agreement has been found with theory (within the framework of Lorentz and Doppler broadenings) for these experimental observations. It has been found that foreign gas species lines within +/-0.1 cm(-1) of the laser line can contribute significantly to the absorption process if their absorption intensities are not more than an order of magnitude below the intensity of the gas species being monitored. PMID- 20164974 TI - Absorption coefficients of weakly absorbing solids: theory of a barothermal gas cell. AB - For the case in which a laser beam passes through the weakly absorbing windows of a cell containing a non-absorbing gas, the temperature profiles in the cell windows and the pressure and temperature profiles in the gas have been calculated. Both the transient response and steady-state behavior of the cell are examined when the barothermal conditions are valid. These calculations suggest that sufficient heat transfers by thermal conduction from the weakly absorbing windows into the gas to produce a measurable pressure rise in the gas. The theory contains the two assumptions that bulk absorption in the window is the mechanism by which energy is transferred from the laser beam to the windows and that the window and adjacent gas are in good thermal contact. Numerical examples for a laser glass and air (nitrogen) are given. PMID- 20164975 TI - Simultaneous heating and temperature measurements by an infrared laser beam. AB - A method of simultaneous heating and temperature measuring of a gas absorber by means of an ir CO(2) laser is proposed and tested. The proposed method is relatively simple and direct. In this experiment the temperature on the beam axis as a function of the beam intensity, the beam radius, and the absorber mixture is measured. A good agreement is obtained between the experimental results and theoretical predictions based on the level scheme and the physical characteristics of the absorber. The temperature measurement proposed in the present paper is an additional experimental tool in investigating excitation processes in the ir region. PMID- 20164976 TI - Atmospheric transmittance of an absorbing gas: a computationally fast and accurate transmittance model for absorbing gases with constant mixing ratios in inhomogeneous atmospheres. PMID- 20164977 TI - Theoretical atmospheric transmission in the mid-and far-infrared at four altitudes. AB - The ir transmission of the terrestrial atmosphere is calculated at four altitudes of interest: Mauna Kea at 4.2 km (2-1000 microm), aircraft at 14 km (5-1000 microm), and balloon at 28 km and 41 km (10-1000 microm). We show both high resolution spectra (0.05 cm(-1)) and broadband averages. The results are intended to serve both as a detailed guide to the interference that is expected from the atmosphere for astronomical spectroscopy and also as an indicator of the relative change in absorption and emission that can be expected at various observing altitudes. One salient result for the spectral region around 100 microm is that the absorption (and emissivity) of the atmosphere drops by a factor of 10 for each increase in altitude of 15 km throughout the aircraft and balloon range; thus balloon-borne astronomical photometry and spectroscopy should both enjoy a considerable advantage over aircraft observations in the 30-300-microm region. PMID- 20164978 TI - Inversion techniques for determining the droplet size distribution in clouds: numerical examination. AB - The Phillips-Twomey and Backus-Gilbert inversion techniques are applied to determine the size distribution of water droplets in clouds from light scattering data at backward angles. The data are generated numerically from the Mie scattering functions and an assumed cloud model. The size distribution is recovered from these data using the two inversion techniques and is compared with the assumed model. It is found that the Phillips-Twomey technique gives better agreement between the assumed and recovered size distributions than the Backus Gilbert technique. Also, it is more stable to random errors artificially introduced into the scattering data. PMID- 20164979 TI - Polarized light scattered from monodisperse randomly oriented nonspherical aerosol particles: measurements. AB - Measurements of polarized light scattered from monodisperse nonspherical randomly oriented aerosol particles are presented along with Mie theoretical results for spheres of approximately the same cross sectional area. For slightly nonspherical particles of sodium chloride and potassium sulfate with size parameter (defined as the ratio of the particle circumference to the wavelength) greater than about five, the intensity of light scattered is generally more than as predicted by Mie theory in the forward scattering lobe, but less at nonforward angles. For particles with size parameter less than five, the Mie results more closely match the measurements. Measured angular scattering patterns for randomly oriented particles are smoother than the Mie theoretical results and are nearly the same for salt and potassium sulfate particles of the same size. Measurements of particle depolarization are nearly independent of scattering angle. PMID- 20164980 TI - Ocean color spectra measured off the Oregon coast: characteristic vectors. AB - The ocean color spectrum is defined as the ratio of the spectrum of light upwelled from the sea to the spectrum of light incident on the sea surface. Ocean color spectra, observed from an airplane flown over waters off Oregon, are analyzed. The original spectra are resolved into fifty-five wavelength bands, each 5 nm wide. The shapes of these spectra are parametrized by, and shown to be accurately recoverable from, their first four principal components Y(i)(i = 1, 2, 3, 4). These Y(i) are the scalar projections of each spectrum on the first four characteristic vectors of the sample covariance matrix. Empirically determined characteristic vectors like these, but derived from a much larger and more globally representative sample of color spectra, may someday provide an efficient, standard basis for parameterizing ocean color spectra. Regression equations are found with which phytoplankton pigment concentration and water transparency may be estimated as linear functions of the parameters Y(i). Pigment concentration estimates thus obtained are imprecise. The poor fit is at least partly due to the inappropriateness of the linear regression model and the neglect of other optically important substances typically present in sea water. PMID- 20164981 TI - Laser wind sensing: the effects of saturation of scintillation. AB - We have developed a physically based extension of the first-order perturbation theory of optical scintillation that accounts for the observed variance and covariance of the amplitude fluctuations in strong integrated turbulence. We use this model to analyze the experimentally observed changes in the operation of our laser wind sensor. The theory suggests a transmitter-receiver configuration that can nearly eliminate the performance-degrading effects of strong turbulence. Based on this analysis, we have developed a saturation-resistant optical wind sensor that maintains its calibration and wind-weighting function throughout the observed range of integrated-turbulence values. PMID- 20164982 TI - Absolute oil fluorescence conversion efficiency. AB - A conceptual method has been developed to deduce the characteristic infinite thickness absolute conversion efficiencies of oils from measured finite thickness film fluorescent returns. The sea water Raman signal is used as a reference in deducing the fluorescent efficiencies. The former can be obtained absolutely by measuring its temporal behavior, from which an absolute conversion efficiency of an oil can be deduced, without any a priori knowledge of the oil. The effects of signal-to-noise and background fluorescence on the accuracy of the fluorescent efficiency measurement are considered. PMID- 20164983 TI - Hand-held spectral radiometer to estimate gramineous biomass. AB - A simple hand-held instrument has been designed and constructed to nondestructively estimate above-ground gramineous biomass using radiometric measurements. The prototype unit consists of a modified two-channel digital radiometer interfaced to a pocket calculator. A digital interface was constructed to join electronically and control the radiometer and calculator to enable the radiometer-calculator system to solve a linear conversion solution from radiometric units to estimated biomass. This instrument has been used to estimate radiometrically gramineous biomass in a more efficient fashion with a high degree of accuracy. PMID- 20164984 TI - Calibration of far-infrared spectrometers in the 100-200-cm(-1) region with the nu(5)-nu(4) band of acetylene. AB - The R branch of the nu(5)-nu(4) difference band of acetylene, 12C(2)H(2), is recommended as a calibration standard for the 100-200-cm(-1) region. The lines are split by l-type doubling into pairs with a 3:1 intensity ratio, but this can only be observed under high resolution. The position of the calculated maximum of each blended line contour is displaced by the l-type doubling from the accurately calculated wavenumber of the more intense component of each J pair, but not by more than one-fifteenth of the spectral slit width. It is recommended that values calculated from constants derived from high resolution mid-ir measurements be used for calibration. PMID- 20164985 TI - Hypersensitization by baking of certain Kodak photographic prates for use in high resolution Raman spectroscopy. AB - Hypersensitization by baking of various Kodak photographic emulsions is studied from the point of view of high-resolution Raman spectroscopy. In the 4400-4900-A region baking can increase the sensitivity of IIa-O plates to ~4 times that of 103a-O plates for long exposures. In the Raman region for Ar(+) laser excitation, 4700-5800 A, baked Ila-D plates show good sensitivity and low reciprocity failure. Baked IIIa-J plates have better resolving power than the IIa-D type, but the reciprocity failure is greater, and the useful region does not extend beyond 5300 A. PMID- 20164986 TI - Sensitivity limits of an infrared heterodyne spectrometer for astrophysical applications. AB - The sensitivity of an ideal heterodyne spectrometer approaches the quantum detection limit provided the local oscillator power is sufficiently large and the shot noise dominates all other sources of noise. The postintegration minimum detectable-number of photons/sec for an ideal heterodyne system is (B/tau)((1/2)), where B is the IF bandwidth, and tau is the integration time. For astronomical observations, however, a number of factors (Delta(i)) tend to degrade the sensitivity, a fact that becomes significant particularly when the laser power is insufficient. A discussion and an evaluation of the degradation in sensitivity are given for a heterodyne spectrometer employing a HgCdTe photodiode mixer and tunable diode lasers. The minimum detectable source brightness is considered as a function of the mixer parameters, transmission coefficient of the beam splitter, and local oscillator emission powers. The degradation in the minimum detectable line source brightness that results from the bandwidth being a fraction of the line width is evaluated and plotted as a function of the wavelength and bandwidth for various temperature to mass ratios. It is shown that the minimum achievable degradation [pi(i)(Delta(i))] in the sensitivity of a practical astronomical heterodyne spectrometer is ~30. Estimates of SNR's with which ir line emission from astronomical sources of interest may be detected are given. PMID- 20164987 TI - Rocket-borne baffled photometer: design and calibration. AB - The design of an interference filter twin photometer suitable for the observation by rocket of the daytime magnetospheric cleft aurora at 2761 A and 5200 A is presented. The two-stage baffling system test and the absolute calibration procedure are described with some detail. PMID- 20164988 TI - Vacuum ultraviolet absolute radiometry utilizing total blackbody radiation. AB - A new calibration technique is described which allows a monochromatic source and detectors to be obtained as secondary standards in the vacuum ultraviolet spectral range. The method of operation is based on the comparison, against a thermopile, between an ultraviolet flux from a monochromator and the total flux from a blackbody simulator. The over-all uncertainty does not exceed 20%. PMID- 20164989 TI - Cube corner retroreflector test and analysis. AB - Cube corner retroreflectors with nominal dihedral angles of 90 degrees 0' 1.5'' were fabricated, tested, and analyzed to determine the return energy in the annular ring of the far field diffraction pattern required by the Laser Geodynamic Satellite. Performance was assessed for variations in the dihedral angles, optical surfaces, and thermal environment. Despite relatively high independent axial and radial sensitivities, the changes caused by the anticipated thermal environment were found to be negligible; however, there were substantial variations between the analytical predictions and measured performance. PMID- 20164990 TI - Coherent detection SNR of an array of detectors. AB - General equations are derived for the SNR of a coherent (heterodyne) receiver constructed from an array of detectors and i.f. amplifiers. The equations are in terms of the distribution functions of the signal and local oscillator fields, the distributions of gain and phase shift among the i.f. amplifiers, and the sizes and shapes of the individual detectors. Such a receiver can efficiently detect any signal distribution function, no matter how badly aberrated, if the individual detectors are small enough, and the i.f. amplifier gains and phase shifts are set correctly. PMID- 20164992 TI - Frequency stability associated with a cw HF laser. AB - The frequency stability of a cw, electrically initiated HF mixing laser was investigated using heterodyne and interferometric techniques. A stability corresponding to 1 part in 10(8) was achieved over an observation time of 150 msec. The data indicated that improved performance would be achieved by increasing the mechanical stability in the optical system. Long-term stability was demonstrated by locking the laser output to the Lamb dip of the lasing transition. Based upon these experiments, the cw chemical laser shows potential as a stable frequency local oscillator for applications such as laser radar and communications. PMID- 20164991 TI - Optical field distribution in a waveguide loaded with high refractive-index film; modulation efficiency improvement in a planar-type modulator. AB - The change of optical field distribution by loading a high refractive-index film on a slab waveguide has been analyzed. It is found that the optical field is remarkably pulled to the film-waveguide boundary when the thickness of the loading film is close to the cutoff thickness. The optical energy content in the loading film has been calculated, and we have found that the energy existing in the film is easily made to be little (e.g., less than 10%) by the appropriate choice of the refractive index of the loading film. The effect is well utilized for the improvement of modulation efficiency in the waveguide modulator with planar-type electrodes. PMID- 20164993 TI - Pulse shape generator for laser fusion. AB - Current laser-fusion theory dictates the need for relatively short laser pulses that are shaped in time to implode optimally a fuel pellet. The laser pulse width and shape should be varied to match different types and sizes of targets. For current experiments, pulse widths as short as 100 psec are desirable, which eliminates the choice of relatively slow electrooptic shutters to shape the pulse, since they are limited to rise times and pulse widths longer than several hundred picoseconds. The device described here can generate a wide variety of pulse shapes and widths by stacking a set of 30-psec mode-locked pulses. This versatile pulse stacker currently shapes the pulses for the KMS Fusion neodymium doped-glass laser system that has produced over 500 neutron-yielding shots since 1 May 1974 by heating and compressing deuterium or deuterium-tritium fuel inside hollow glass spherical targets. PMID- 20164994 TI - High peak power output, high PRF by cavity dumping a Nd:YAG laser. AB - Intracavity modation of a Nd:YAG laser at high dumping efficiencies was achieved by driving an acoustooptic quartz modulator with 100 W of rf input power at 450 MHz. Stable output pulses of 25-nsec width and peak powers as high as 570 W were obtained at repetition frequencies up to 2 MHz. It is shown that the oscillation of the circulating laser power in the presence of a perturbation determines the dynamics of cavity dumping and sets a lower limit to the pulse repetition frequency of approximately 200 kHz. PMID- 20164995 TI - Tilted birefringent Fabry-Perot etalon for tuning dye lasers. AB - A tilted birefringent Fabry-Perot etalon, which is set at an angle to the axis of the dye laser cavity and rotated about the normal of end-faces of the etalon, allows the dye laser emission to be tuned with very high finesse as obtained by two cascaded conventional Fabry-Perot etalons. PMID- 20164996 TI - Leaky modes on circular optical waveguides. AB - A nonabsorbing optical waveguide of circular cross section supports leaky modes in addition to the well-known bound modes. The detailed properties of these leaky modes are determined by solving the eigenvalue equation for the modes of a circular dielectric cylinder below their cutoff frequency. The purpose of this paper is to present such solutions together with the associated characteristic mode parameters. The results are presented in graphical form for low order modes and asymptotically for higher order modes. The effects of material absorption on the attenuation of leaky modes are also discussed. PMID- 20164997 TI - Pulse broadening in graded-index optical fibers. AB - This paper reports on some theoretical and experimental investigations of the radial refractive index gradient that maximizes the information-carrying capacity of a multimode optical waveguide. The primary difference between this work and previous studies is that the dispersive nature of core and cladding materials is taken into consideration. This leads to a new expression for the index gradient parameter alpha(c) which characterizes the optimal profile. Using the best available refractive index data, it is found that in high-silica waveguides, the dispersive properties of the glasses significantly influence the pulse broadening of near-parabolic fibers, and that the parameter alpha(c) must be altered by 10 20% to compensate for dispersion differences between core and cladding glasses. These predictions are supported by pulse broadening measurements of two graded index fibers. A comparison is made between the widths and shapes of measured pulses and pulses calculated using the WKB approximation and the near-field measurement of the index profiles. The good agreement found between theory and experiment not only supports the predictions made for the value of alpha(c), but demonstrates an ability to predict pulse broadening in fibers having general index gradients. PMID- 20164998 TI - Ellipticity measurement of optical fibers. AB - The experimental aspects of a sensitive, nondestructive, and noncontacting method to measure the noncir-cularity of dielectric cylinders are presented. The technique makes use of the variation in the position of a fringe in the backscattered light arising from a beam that is incident at right angles to the cylinders axis, as the cylinder is rotated. The method has been applied to optical fibers, and ellipticities as small as 0.997 have been measured. The results are in agreement with photomicroscopy measurements and with theoretical predictions. PMID- 20164999 TI - Monochrome digital image enhancement. AB - The use of digital computers as an aid in the enhancement of monochrome imagery is explored. Point processes, spatial processes, and artifact generation are discussed. The former includes single pixel nonlinear mappings for better visual response. Spatial processes include both linear and nonlinear filtering techniques in the Fourier and singular value decomposition domains of an image. Finally, the generation of possible artifacts by enhancement processes is discussed. Numerous pictorial examples illustrating all the techniques developed are included throughout the paper. PMID- 20165000 TI - Effects of target contrast and background upon tribar threshold and resolution. AB - Effects of target contrast and background irradiance upon tribar response of optical systems have been investigated. It has been shown that these factors lead to ambiguities in the specification of tribar threshold and resolution for photooptical systems. PMID- 20165001 TI - Water pollution monitoring using matched spatial filters. AB - Presented are some results obtained from the application of matched spatial filtering techniques to the identification of biological specimens called diatoms (i.e., water algae). A prototype semiautomatic optical processor has been developed that utilizes the Vander Lugt type complex spatial filters. We describe the optical filter averaging technique employed and discuss our semi in situ developing method for the filters. The advantage of this method with regards to the critical position requirements for time sharing optical filters is also presented. The filter holder is mounted on X, Y stages and precision positioned under the control of a PDP-11-40 computer. PMID- 20165002 TI - Quality control of small mechanical pieces using optical correlation techniques. AB - A holographic matched filtering technique is used to control the contour shape of small mechanical elements. The optimization of the spatial filter leads to a well defined response curve which is used to calibrate the output of the optical correlator in terms of shape error. It is shown that the techniques of computer holograms offer the widest possibilities to perform this optimization. The basis of the technique is presented together with a few simple examples showing the possibility of detecting shape errors of a few microns (less than 1% of the controlled dimension). PMID- 20165003 TI - Optical computing and investigations on writing. AB - In previous years several methods have been developed for extracting significant information parameters contained in written, typed, or printed texts. They have shown that some models (optical, mathematical, or hybrid) could be described for linear and nonlinear operations. At first, essential features of information contained in a written page are quantitatively specified and related to legibility criteria. Then an approach to handwriting analysis is made through coherent optical processing along two distinct ways: (1) averaging permits assessing a degree of resemblance between any letter in a set and that taken as a reference, (2) as similarities cannot be extracted directly, the introduction of a form function applies to the comparison of printed letters of various types taken as a whole and other kinds of graphic signs. Finally a nonlinear model built up from polynomials can afford a complete analysis of handwriting as illustrated by various examples. PMID- 20165004 TI - Noise elimination technique in holography. AB - A method has been described for reducing speckling and the noise arising due to cosmetic defects present in the elements of the hologram recording geometry by using a multifrequency grating-diffuser-lens combination for object illumination at the time of recording the hologram. The averaging of the speckling is simulated at the plane of the object. The experimental results show that this method of object illumination is quite effective for noise reduction and may be applied to recording noise-free holograms of shortlived events. It may also be useful in holographic microscopy. PMID- 20165005 TI - Multicomponent photopolymer systems for volume phase holograms and grating devices. AB - Novel photopolymer systems for the fabrication of high-resolution volume phase holograms and grating devices are reported. Previously reported techniques use a single monomer (or a mixture of similar monomers) and rely solely on density modulation. In contrast, we have found it advantageous to use a mixture of components chosen to have differing reactivities and polarizabilities, which results in a composition modulation. During the image-forming exposure the more reactive monomer is polymerized while the less reactive species is excluded from the irradiated regions. Two-way diffusion, which must be invoked to explain our results, leads to a modulation of the chemical composition and hence of the polarizability of the final material. In some systems the polarizability effect was strong enough to exceed the density effect, even when these factors were in opposite directions. As in previous systems, an over-all exposure is used to fix the images. With appropriate monomer systems, stable images were obtained even when one component was unreactive. The peak-to-peak refractive index differentials achieved in our systems were as high as 1.5%. This is an order of magnitude larger than that reported for initially all liquid systems and 50% larger than that reported for related solid materials. The use of a liquid system enables us to fill small cavities with our materials and then record a high resolution image. We have made gratings of >3000 lines mm(-1) inside hollow fibers, with 80 microm i.d., filled with a photopolymer material. For white light guided in the core, the expected band-stop filter response was observed. PMID- 20165006 TI - Achromatic combinations of hologram optical elements. AB - Two- and three-element combinations of hologram optical elements are considered, and analytical conditions are obtained for absence of longitudinal dispersion. Solutions of the conditional equations are compared with another author's computed design results. A simple doublet design is considered for an eyepiece, and its performance is described. PMID- 20165007 TI - Computer generated holograms for testing aspheric lenses. AB - For the purpose of measuring aspheric surfaces, an improved type of computer generated hologram, named the inclined bar type hologram, is proposed. This hologram is characterized by inclined bars. The inclination angle for each bar is obtained from the calculated wavefront aberration of the test lens. A few problems with these computer generated holograms are analyzed, and the advantage of the inclined bar type hologram over the conventional one is demonstrated by experiment. PMID- 20165008 TI - Storage density limitation of a volume-type hologram memory: theory. AB - The maximum storage density of a volume-type hologram memory obtainable with a prescribed signal-to-noise ratio is discussed. In the theoretical analysis, a microscopic particle model of a phase hologram is considered; the refractive index variation is assumed to be caused by the density variation of bleached silver particles distributed spatially at random. The signal and noise intensities are derived from the analysis based upon this model. The theoretical limit of the storage density and the optimum hologram thickness are then derived in terms of the signal-to-noise ratio. The maximum storage density is finally given as a function of the average scattering cross section of the particles, the light wavelength, and the prescribed signal-to-noise ratio. Some practical cases are also discussed on the basis of measured material parameters. PMID- 20165011 TI - OSA Technical Groups. PMID- 20165012 TI - Particle model theory of diffuse reflectance: effect of nonuniform particle size. PMID- 20165009 TI - Hologram formation with red light in methylene blue sensitized dichromated gelatin. AB - The spectral sensitization of hardened dichromated gelatin to red light is carried out using methylene blue as sensitizer. The sensitized dichromated gelatin plate can be stored for over 1 month in an ammonia atmosphere without loss of photosensitivity. Holograms recorded in the sensitized dichromated gelatin using a He-Ne laser have high diffraction efficiency and low noise if they are swelled at a temperature near the gelatin gel melting point during development processing. Maximum diffraction efficiency has been found to be as high as 88%. The energy required to obtain 80% diffraction efficiency is 150-400 mJ/cm(2). PMID- 20165013 TI - Emission spectrum of nitric oxide between 5 microm and 7 microm. PMID- 20165014 TI - Ruby filter for stray light reduction in scattering experiments. PMID- 20165015 TI - Guide number for light sources that emit ultraviolet radiation. PMID- 20165016 TI - Of optics and opticists. PMID- 20165017 TI - Patents. AB - 3,794,426; 3,799,642; 3,807,828; 3,807,829; 3,809,873; 3,813,685; 3,814,503; 3,818,129; 3,818,374; 3,818,375; 3,831,105; 3,831,106; 3,831,107; 3,831,108; 3,834,809; 3,836,224; 3,837,725; 3,837,726; 3,838,903; 3,838,904; 3,843,225; 3,843,260; 3,847,465; 3,848,228; 3,849,001; 3,851,948; 3,853,384; 3,855,470; 3,856,378; 3,894,787; 3,894,788; 3,897,995; 3,899,240; 3,899,253; 3,899,254; 3,900,246; 3,901,582; 3,901,584; 3,902,061; 3,902,782; 3,902,790; 3,904,268; 3,905,019; 3,907,430; 3,909,134; 3,909,749; 3,910,680; 3,910,681 3,910,691. PMID- 20165018 TI - Optical activities in the universities. PMID- 20165019 TI - Meeting reports. PMID- 20165020 TI - Rectangular grid fringe pattern for topographic applications. PMID- 20165021 TI - Dynamic Hartmann test: comments. PMID- 20165022 TI - Photometer calibration error using extended standard sources. PMID- 20165023 TI - Laser radar measurements of atmospheric temperature profiles by use of Raman rotational backscatter. PMID- 20165024 TI - International comparison of measurements of luminance factor and reflectance of white diffusing samples: erratum. PMID- 20165025 TI - Noise spectrum caused by pointing error. PMID- 20165026 TI - Linear Polarimeter with rapid modulation, achromatic in the 0.3-1.1-microm range. PMID- 20165027 TI - Liquid argon cooled CO laser. PMID- 20165028 TI - Birefringent waveguides prepared by reactive sputtering of niobium in O(2)-N(2) mixtures. PMID- 20165029 TI - Visibility of speckle patterns: effect of the optical guide length in coherent light. PMID- 20165030 TI - Coherent optical adaptive techniques: design and performance of an 18-element visible multidither COAT system. AB - Coherent Optical Adaptive Techniques (COAT) offer promise for overcoming the deleterious effects of phase distortions experienced by optical beams propagating in a turbulent and absorbing atmosphere. An 18-element, visible wavelength, multidither COAT system is described. The all solid-state servosystem design was based on the results of an extensive computer simulation. The optical system uses a 0.488-microm argon laser and an array of beam splitters, phase shifters, and beam combiners (termed a phasor matrix) to form the output array. To date, 6- and 8-element linear arrays and an 18-element axisymmetric array have been investigated. The system has demonstrated a convergence time of 1.2 msec and can form the array with a strehl ratio of 0.67. Moving glint tracking, multiple glint discrimination, and offset pointing from a fixed reference have been demonstrated. Good agreement has been observed between measured system results and theoretical predictions. PMID- 20165031 TI - Atmospheric turbulence compensation using coherent optical adaptive techniques. AB - Measurements using an experimental, visible wavelength, eighteen-element, multidither, self-adaptive, planar, optical phased array have been made on a well characterized outdoor 100-m propagation range. The measurements have proved that this type of COAT system can remove most of the beam distortions produced by atmospheric turbulence and by fixed optical system errors. The system has demonstrated the ability to form a beam with a nearly diffraction-limited peak intensity for turbulence levels characterized by structure constants (C(N)(2)) ranging from 1 x 10(-16) cm(-2/3) to 6 x 10(-14) cm(-2/3). Convergence times for the COAT system range from 1.5 msec to 3.0 msec for a servo system with a 500-Hz unity gain bandwidth. Spectral analysis of the COAT correction signals indicates, however, that only a 50-Hz bandwidth is required for correction to within tenth wave residual wavefront errors for static targets, even in strong turbulence. The experimental phase error spectra agree well with theoretical calculations that use a Von Karman spectrum for the refractive index fluctuations. Multiple glint discrimination and tracking of the strongest glint in a multiple glint target are demonstrated in high turbulence. Good target tracking is observed at rates up to 14 mrad/sec. The convergence stability of the COAT system is good, limited only by the inability of planar, stepwise phase control to remove atmospheric beam wander and scintillation effects. Receiver aperture size has had no appreciable effect on system performance except in multiple glint cases where the glints are within 2-3 dB in net reflectance. PMID- 20165032 TI - Multiple scattered radiation emerging from Rayleigh and continental haze layers. 1: Radiance, polarization, and neutral points. AB - The complete radiation field including polarization is calculated by the matrix operator method for scattering layers of various optical thicknesses. Results obtained for Rayleigh scattering are compared with those for scattering from a continental haze. Radiances calculated using Stokes vectors show differences as large as 23% compared to the approximate scalar theory of radiative transfer, while the same differences are only of the order of 0.1% for a continental haze phase function. The polarization of the reflected and transmitted radiation is given for a wide range of optical thicknesses of the scattering layer, for various solar zenith angles, and various surface albedos. Two entirely different types of neutral points occur for aerosol phase functions. Rayleigh-like neutral points (RNP) arise from the zero polarization in single scattering that occurs for all phase functions at scattering angles of 0 degrees and 180 degrees . For Rayleigh phase functions, the position of the RNP varies appreciably with the optical thickness of the scattering layer. At low solar elevations there may be four RNP. For a continental haze phase function the position of the RNP in the reflected radiation shows only a small variation with the optical thickness, and the RNP exists in the transmitted radiation only for extremely small optical thicknesses. Another type of neutral point (NRNP) exists for aerosol phase functions. It is associated with the zeros of the single scattered polarization, which occur between the end points of the curve; these are called non-Rayleigh neutral points (NRNP). There may be from zero to four of these neutral points associated with each zero of the single scattering curve. They occur over a range of azimuthal angles, unlike the RNP that are in the principal plane only. The position of these neutral points is given as a function of solar angle and optical thickness. PMID- 20165033 TI - Suppression of scattered radiation in radiography and improvement of resolution by spatially modulated intensity. AB - In radiography a pointlike x-ray source is used to generate the picture of an object. This simple shadow projection suffers from radiation being diffusely scattered by the object itself since it reduces considerably the contrast of the picture. To avoid this drawback it is proposed in this paper to introduce a grating between source and object of an incoherent shadow projection. The primary picture is modulated by this grating while scattered radiation is essentially not, thus being nearly invariant against a shifting of the grating. After electronic scanning the primary picture can be reconstructed by electronic demodulation. A projection of the grating with the object removed serves as the carrier frequency for the demodulation. In addition to the suppression of scattered radiation the application of gratings leads to enhanced spatial resolution. Taking multiple pictures with a shifted grating, the modulation transfer function is repeated several times within the frequency plane. A detailed mathematical treatment for a point source is given. PMID- 20165034 TI - Boresighting a Gaussian beam on a specular target point: a method using conical scan. AB - A method of autoboresighting a Gaussian beam on a specular target point is presented. Closed form analysis of a staring detector output shows that the nutation frequency fundamental component in the output can be used to drive the spatial position of the nutation center to converge and lock on a target specular point. The conical scan boresighter is a combination of a reference point tracker and a beam steerer relative to the track point. The reference point must be in the field of view of the detector. The precision of tracking and hence of boresighting depends on the precision and stability of the reference point relative to the desired point on target. PMID- 20165035 TI - Secondary electron conduction camera tube for space applications. AB - A camera tube based on the SEC (secondary electron conduction) effect has been developed for space applications. The background to the initiation of this development is briefly mentioned and anticipated applications are reviewed. These comprise the use as a detector in astronomical instruments (cameras and spectrographs), in a star field camera, and in special instruments for earth observation. The tube construction is described where it concerns the modifications made to the original standard tube produced by the firm Heimann GmbH. Finally, a first assessment of the tube performance is summarized as measured in a standard test facility operating in the standard European scan format. PMID- 20165036 TI - Generating bessel functions in mie scattering calculations using continued fractions. AB - A new method of generating the Bessel functions and ratios of Bessel functions necessary for Mie calculations is presented. Accuracy is improved while eliminating the need for extended precision word lengths or large storage capability. The algorithm uses a new technique of evaluating continued fractions that starts at the beginning rather than the tail and has a built-in error check. The continued fraction representations for both spherical Bessel functions and ratios of Bessel functions of consecutive order are presented. PMID- 20165037 TI - Laser spectrophotometer for measuring differential cross sections of biological particles. AB - A tunable laser spectrophotometer is described that can accurately measure the differential scattering cross sections of small particle suspensions in the visible spectral range. The instrument was calibrated using a suspension of latex spheres of known size and index of refraction. By increasing the intensity of the illuminating laser, it should be possible to study differential scattering processes of individual particles on a microsecond time scale. PMID- 20165039 TI - Patents. AB - 3,978,429; 3,984,784; 3,986,139; 3,986,141; 3,987,373; 4,013,365; 4,016,427; 4,017,807; 4,019,151. PMID- 20165038 TI - Autocollimation-type ellipsometer for monitoring film growth through a single window. AB - Three autocollimation-type ellipsometers (ACE) are proposed for in situ study or monitoring of film growth through a single window of a vacuum chamber. An example of the monitoring is given; the growth process of a Corning 7059 glass film is monitored during rf sputtering using one of the ACE that is able to monitor directly the thickness of a transparent film. PMID- 20165040 TI - Apodization filtering applied to a bandlimited optical Fourier transformer. AB - The basic Fourier optical transform operation that exists between the front and rear focal planes of a coherently illuminated lens is examined from the viewpoint of spatial bandlimiting. It is common to regard this relationship as exact in its application to optical data processors, but in reality, finite size lens and pupil functions impose spatial bandlimiting that smooths or broadens the fields in the transform domain. To reduce these effects, shaded apertures or apodizing filters are placed in the lens plane. Experimental data are presented to demonstrate that a noticeable improvement in resolution can be obtained by use of these filters. PMID- 20165041 TI - Parametric generation processes: spectral bandwidth and acceptance angles. AB - A systematic evaluation of the spectral bandwidth and two acceptance angles of parametric generation processes is presented. The spectral bandwidth and acceptance angles are determined by expanding the wave vector mismatch in a Taylor series and retaining terms through second order. This allows a determination of these parameters even when the first order term vanishes. Conditions where the first order term vanishes are presented and compared with similar cases where the first order term does not vanish. PMID- 20165042 TI - Photoionization cross sections of metal vapors below 50 nm: an apparatus for their measurement. AB - An apparatus built for the measurement of photoionization cross sections of metallic vapors in the 30-100-nm wavelength region is described. The performance was tested by measurements of cross sections in the region of the window resonances in argon. Results in agreement with those of Madden, Codling, and Ederer were obtained. PMID- 20165043 TI - Averaging sphere for ultraviolet, visible, and near infrared wavelengths: a highly effective design. AB - Through the use of an efficient design and a newly available sphere coating material, a simple, passive, sturdy averaging sphere was made that operates effectively over the wavelength range from 200 nm to 2000 nm. Data are reported for a sphere of this type in which the sphere transmittance is 0.32 at 200 nm and rises rapidly to near the maximum theoretical value of 0.56 over the remainder of the wavelength range. The several orders of magnitude reduction in error due to beam displacement more than compensate the slight reduction in signal for many spectrophotometric and radiometric applications. PMID- 20165044 TI - Far-infrared high-resolution Fourier transform spectrometer: applications to H(2)O, NH(3), and NO(2) lines. AB - A Michelson-type Fourier transform spectrometer has been constructed for high resolution work in the far ir. The instrument has a theoretical resolution of 0.007 cm(-1) and can be used with a tunable band pass filter system for the reduction of sampling points in a specific spectral region. Separations of 0.05 cm(-1) in the inversion spectrum of NH(3) in the 200-cm(-1) spectral region have been observed with about 1000 sampling points and splittings of 0.04 cm(-1) in the NO(2) spectrum at about 100 cm(-1). PMID- 20165045 TI - Collisional narrowing: its effect on the equivalent widths of spectral lines. AB - A simple criterion is derived in terms of molecular parameters to determine whether collisional narrowing is of importance in determining the equivalent widths of spectral lines of any combination of emitting and broadening gases. The criterion is verified by numerical integration, and a simple formula is given for the maximum error obtained when the Voigt profile is used as an approximation to the Galatry profile. PMID- 20165046 TI - Image processing system using incoherent image feedback. AB - By combining a TV system with suitable optical systems an image processor which uses the technique of image feedback is constructed. The special features are the simplicity of the arrangement and the flexibility for the treatable input images as well as the ability as a real-time processor. Results for ghost image elimination under several conditions and for sharping of images are shown. PMID- 20165047 TI - Holographic strain analysis: extension of fringe-vector method to include perspective. AB - A method has been published recently that permits determination of complete strain and rotation tensors of homogeneously deformed objects directly from fringes that are observed on their surfaces. However, the illumination and observation directions had to be considered constant over the regions of interest to apply the technique. This paper presents an extension of that theory to include both observation and illumination perspectives. It is shown that bulk translations of an object combine with linear variations in the directions of observation and illumination to generate fringe vectors that add directly to those generated by the object's homogeneous transformations. These linear variations are calculable from illumination and observation geometry. PMID- 20165048 TI - Real-time holographic interferometry: a system. AB - A complete photographic system for performing real-time holographic interferometry is described. The holograms are recorded on an experimental film that permits rapid, dry, in-place processing in a specially designed chamber. The expose-process-view cycle is fully automated so that real-time interferograms can be produced with ease. The features of the system pertinent to holography are discussed and examples of real-time stroboscopic holographic interferometry are shown. PMID- 20165049 TI - Laser wavelength comparison by high resolution interferometry. AB - High resolution interferometry has been used to determine the wavelength ratio between two molecularly stabilized He-Ne lasers, one locked to a methane absorption at 3.39 microm and the other locked to the k peak of (129)I(2) at 633 nm. An optical beat frequency technique gave fractional orders while a microwave sideband method yielded the integer parts. Conventional (third derivative) peak seeking servoes stabilized both laser and cavity lengths. Reproducibility of the electronic control system and optics was a few parts in 10(12), while systematic errors associated with curvature of the cavity mirrors limited the accuracy of the wavelength ratio measurement to 2 parts in 10(10). The measured wavelength ratio of the methane stabilized He-Ne laser at 3.39 microm [P(7) line, nu(3) band] to the (129)I(2) (k peak) stabilized He-Ne laser at 633 nm was 5.359 049 260 6 (0.000 2 ppm). This ratio agrees with that calculated from the (lower accuracy) results of earlier wavelength measurements made relative to the (86)Kr standard. Its higher accuracy thus permits a provisional extension of the frequency scale based on the cesium oscillator into the visible spectrum. PMID- 20165050 TI - Mapping of optical surfaces with quarter wavelength fringes. AB - A contactless interference surface testing method is described that is capable of creating fringe patterns with fringe separations corresponding to a surface deformation of a quarter-wavelength of the illumination light. Contrary to common Fizeau fringes where the interference pattern occurs by superposing two wavefronts, the described method is based upon a superposition of four wavefronts. These wavefronts are created by a diffraction transmission grating which is contactlessly placed over the surface to be tested. Basically, this technique provides a beat frequency pattern with adaptable fringe separation. Practical applications of this method to semiconductor silicon wafers are presented. PMID- 20165051 TI - Design considerations of 2-D holographic scanners. AB - Two-dimensional holographic scanners utilizing an auxiliary reflector are described. The design equations and procedures are derived and outlined. Multiplexing techniques for increasing the resolution are proposed. Scanners of reasonable size and operating at a moderate speed can achieve a total resolution of 10(7)and a temporal signal of 100 mHz. Applications in the visible and other spectra regions including millimeter or microwave and ultrasonic wave are suggested. PMID- 20165052 TI - Pulsed uv nitrogen laser: dynamical behavior. AB - Using the time dependent rate equations, the dynamical behavior of a high power pulsed N(2) laser radiating at 337.1 nm is derived. The threshold conditions are given. The output peak power and pulse width as a function of length and initial inversion density are shown. The theoretical results derived are compared with experimental data and are found to be in good agreement. PMID- 20165053 TI - Hybrid metal mesh-dielectric mirrors for optically pumped far infrared lasers. AB - A hybrid metal metal-dielectrically coated mirror, highly reflecting in the near ir and partially transmitting in the far ir, for use in optically pumped molecular lasers, is described. Ge and CaF(2) were used for the dielectric films, along with Ni meshes deposited on Si substrates. The dielectric dispersion properties of the CaF(2) thin films were studied in the 2-15-microm range to provide design data. With a four layer dielectric coating and a metal mesh, the specular reflection of the mirror could be maintained greater than 90% over a 2 mum range in the near ir, and by choice of mesh, the transmittance in the 400-600 microm range varied from 0% to greater than 40%. PMID- 20165054 TI - Laser absorption methods for simultaneous determination of temperature and species concentrations through a cross section of a radiating flow. AB - An active laser absorption technique is proposed for simultaneous determination of temperature and species concentrations of a combustion flow. For homogeneous medium, the conventional method of ratio of the Boltzmann's population distribution factors to determine temperature is extended to include influence of the interfering species from measurements of multiple monochromatic absorptions. It is further shown that this technique may be used to retrieve two-dimensional thermodynamic variables across a selected cross section. The problem of solving a nonhomogeneous case is reduced to that of a homogeneous one if an appropriate multidirection scanning technique is employed. PMID- 20165055 TI - Improvements to a home-built nitrogen laser. AB - Several major design improvements to a previously described nitrogen laser are presented. The active region has a larger cross section but shorter length resulting in an output beam of better optical quality and a laser channel which is cheaper and easier to build. The gas flow is transverse to the channel, and the pressure is more uniform. These and other improvements result in a 9-nsec pulse FWHM (full width at half-maximum) whose peak power exceeds 0.7 MW when the laser is supplied with 24 kV and pulsed at 10 Hz. PMID- 20165056 TI - Pulse broadening caused by deviations from the optimal index profile. AB - The excess pulse broadening caused by deviations from the optimal index profile is analyzed for multimode optical fibers. First-order perturbation theory is used to evaluate the effects of arbitrary index perturbations having longitudinal spatial frequencies which are too low to cause mode coupling. A simplified expression is found for the excess pulse broadening in terms of a double integral over a weighting function. Weighting functions are evaluated and used to calculate the effects of two kinds of circularly symmetric perturbations, a Gaussian-shaped bump or dip in the index profile and an oscillating perturbation. These perturbations are found to affect the pulse broadening significantly according to the position and width of the bump and the transverse spatial frequency of the oscillating perturbation. The more narrow bumps and those located at larger core radii are found to have the greatest effect. For a typical multimode fiber, perturbations making 2-18 oscillations along the radius are found to cause significant increases in pulse broadening, while more rapid oscillations are found to have negligible effect. These results indicate the type and degree of index profile control required to keep the pulse broadening below a specified level. PMID- 20165057 TI - Propagation characteristics of GaAsP heterostructure waveguides for 1.06 microm and 0.905 mum wavelengths: an evaluation. AB - Propagation characteristics of GaAs/GaAs (1-x)P(x) and GaAs (1-y)Py/GaAs(1-x)P(x) waveguides are evaluated at 1.06-mum. and 0.905-mum wavelengths. Attenuation of the lowest order mode in single-mode and two-mode waveguides is 1.2 dB/cm at 1.06 mum. At 0.905 mum the measured attenuation rate for the GaAs(0.80)P(0.20)/GaAs(0.65)P(0.35) waveguide is 1.5 dB/cm. Multimode waveguides have considerable mode conversion due to surface undulations caused by grading dislocations. Refractive indices have also been calculated from experimental data at 1.06 mum for GaAs and GaAs(0.65)P(0.35)to be 3.47 and 3.325, respectively. PMID- 20165058 TI - Hot splices of optical waveguide fibers. AB - The application of optical waveguides in long lengths may require permanent joints (splices). The idea behind hot splices is simple and basic to glass: heat the fibers and fuse them together. This is accomplished by a small electric arc. A series of twenty splices of identical multimode fibers shows an average splice loss of 0.26 dB. Single mode fiber splices were also attempted, as well as a series of splices on different multimode fibers, and results are reported. PMID- 20165059 TI - Splicing silica fibers with an electric arc. AB - A method of making low-loss splices in silica fibers by fusing them together with the heat from an electric arc has been developed. Accurate alignment is obtained by the use of a vacuum chuck. Step-index fibers with core diameter of 75 microm and o.d. of 125 microm were spliced, with individual splice losses as low as 0.03 dB and with an average loss in forty-five splices of 0.14 dB. The splices can be made quickly and easily and add no bulk. PMID- 20165060 TI - Magnetooptical properties of index-gradient optical fibers. AB - The magnetooptical Faraday rotation of a guided He-Ne laser beam in index gradient fibers was measured. The proportionality between the rotation of the polarization vector and the length of the light path in an applied homogeneous longitudinal magnetic field is disturbed. The measuring results can be explained by means of a theoretical model combining the Faraday effect with birefringence. PMID- 20165061 TI - Propagation properties of a multilayer optical waveguide with an attenuating sheet. AB - A complex multilayer guide composed by a dielectric layer with a thin weakly attenuating sheet, embedded in a dielectric medium, has been theoretically investigated, treating also the limiting case in which the inner dielectric slab is absent. Computations for two typical cases of strong guiding are presented and discussed, from which appear the potentialities of the structure in mode selective guiding and modulation. PMID- 20165062 TI - Fast automatic lens testing for extended-field image quality. AB - Monitoring of high-volume lens manufacture for Polaroid Land photography requires an acceptance criterion that is both relevant to picture quality and suitable for automatic testing. In a hardware test based upon the modulation transfer function (MTF), the problem is to choose what not to measure, while obtaining enough information about a lens to assign it a useful figure of merit. The predominant defects of manufacture are field tilt, resulting from tilting or decentering of components, and field curvature, from small errors in spacing, thickness, radius, or index. Field tilt and curvature are not local defects of the image surface, insofar as they may be removed by a local refocus. We therefore need a test procedure that can (perhaps simultaneously) examine image quality over an extended field, but is principally called upon to evaluate focus differences. At multiple field locations a single-frequency modulation measurement adequately defines the MTF for the low spatial frequencies of interest and can be interpreted easily in terms of the rms blur of the point spread function. We will discuss the logic of 100% lens acceptance testing and two types of instrumentation we have used. PMID- 20165063 TI - Polarization states of light diffracted by acoustic surface waves. AB - The change of polarization that is produced on a transmitted light beam by acoustic surface waves propagating on a yz-LiNbO(3) plate is analyzed. When using a crossed polarizer and analyzer for optimizing the signal-to-noise ratio, the best conditions of diffraction efficiency have been found at an angle of incidence approximately equal to -10 degrees . PMID- 20165064 TI - Photodichroic recording and storage material. AB - Three techniques for recording information on NaF are reviewed. H-D exposure curves for several samples are used to record, store, and reconstruct imagery. PMID- 20165065 TI - Dynamics of photochromic conversion in optically thick samples: theory. AB - We develop a theory of the dynamics of optically induced conversion processes for samples of arbitrary optical thickness. The result is in the form of a simple first-order differential equation for the spatial variation of the state of the sample with time as an independent parameter. For the practically important case of samples that are initially homogeneous, the state of the sample is expressed in terms of a single function with the characteristics of the material, and its initial state, described by just one parameter. We present tables and plots of the function, which we call the Photochromic Function, with which one can evaluate the detailed behavior of a wide variety of systems, without requiring extensive computation. We also show that from optical transmission measurements on such samples, one can determine at most three independent constants of the material. PMID- 20165066 TI - A year in the Old Country. PMID- 20165067 TI - Spectral irradiance measurements: effect of uv-produced fluorescence in integrating spheres. PMID- 20165068 TI - Electrooptic switching response in cubic phase PLZT ceramic materials. PMID- 20165069 TI - Patents. AB - 3,814,904; 3,817,606; 3,817,627; 3,824,017; 3,826,555; 3,829,193; 3,829,827; 3,832,026; 3,832,698; 3,833,281; 3,833,301; 3,834,785; 3,834,787; 3,860,327; 3,860,940; 3,862,794; 3,864,026; 3,864,027; 3,865,470; 3,867,018; 3,874,097; 3,874,771; 3,874,774; 3,876,875; 3,877,779; 3,877,792; 3,877,795; 3,877,796; 3,879,111; 3,879,113; 3,880,498; 3,880,501; 3,881,107; 3,881,812; 3,883,228; 3,883,229; 3,883,230; 3,883,231; 3,891,311; 3,898,584; 3,898,587; 3,900,802; 3,900,803; 3,902,137; 3,902,791; 3,902,793; 3,904,982; 3,904,983; 3,904,985; 3,905,686; 3,909,106; 3,909,523; 3,910,684; 3,910,685; B315,828; B425,035; PMID- 20165070 TI - Optical activities in industry. PMID- 20165071 TI - Collecting capability of an optical system. PMID- 20165072 TI - Meeting reports. PMID- 20165074 TI - Two-hologram interferometry: a simplified sandwich technique. PMID- 20165076 TI - Real-time superresolution optical system using multiple lasers and a TV system. PMID- 20165075 TI - Holo-lens optical spatial frequency processor. PMID- 20165077 TI - Multiplying lensless Fourier holograms recorded using a multibeam reference light field. PMID- 20165078 TI - Solar energy collection using beam waveguides. PMID- 20165079 TI - Paraxial ray analysis of a cat&s-eye retroreflector: comments. PMID- 20165080 TI - Edge-on diffraction of a Gaussian laser beam by a semi-infinite plane: comments. PMID- 20165081 TI - Refractive index of liquid solutions at low temperatures: an accurate measurement. PMID- 20165083 TI - Channel electron multiplier: its quantum efficiency at soft x-ray and vacuum ultraviolet wavelengths. PMID- 20165082 TI - Optical constants of metal oxides in the far infrared region. PMID- 20165084 TI - Wavelength deviation sensing detector. PMID- 20165085 TI - Absorption cell: a modified multiple-traversal device. PMID- 20165086 TI - Spectral characteristics and atmospheric CO(2) absorption of the Ho(+3):YLF laser at 2.05 microm. PMID- 20165088 TI - Geometric optics limit of Marcuse&s coupled power equations. PMID- 20165087 TI - Real-time grey level display of velocity distributions on a surface. PMID- 20165089 TI - Reduction of pulse dispersion in imperfect multimode fibers. PMID- 20165090 TI - Real-time optical subtraction of photographic imagery for difference detection. AB - Interferometric techniques described in this paper permit real-time optical image subtraction of two input photograph transparencies without the necessity of intermediate processing steps (e.g., holograms or contact-print transparencies). These interferometric techniques allow the use of a white-light source as well as an extended light source, small input-collimator optics, and optical components with minimal requirements on wavefront quality. Experimental results with NASA LANDSAT (formerly ERTS) photographs are presented. PMID- 20165091 TI - Sharpness index and its application to focus control. AB - A sharpness index function, derived from the intensity distribution in an image aberrated by a quadratic-curvature wavefront distortion, is shown to be very effective as a measure of the correctness of focus. The function is introduced and analyzed in the spatial frequency domain. Broadly, the sharpness index belongs to a family of functions known as image sharpness functions that are potentially usable for image enhancement and restoration. The selectivity and the sensitivity of the sharpness index are theoretically derived as functions of focus error. Several sharpness index functions have been hardware implemented, and their performance as focus error signal generators have been tested in a TV imaging system in the laboratory. Finally, an outline is presented of an experimental closed-loop autofocus system using a sharpness index function, successfully implemented and tested in the laboratory. PMID- 20165092 TI - Real-time optical signal processors employing optical feedback: amplitude and phase control. AB - The development of real-time coherent optical signal processors has increased the appeal of optical computing techniques in signal processing applications. A major limitation of these real-time systems is the. fact that the optical processing material is generally of a phase-only type. The result is that the spatial filters synthesized with these systems must be either phase-only filters or amplitude-only filters. The main concern of this paper is the application of optical feedback techniques to obtain simultaneous and independent amplitude and phase control of the light passing through the system. It is shown that optical feedback techniques may be employed with phase-only spatial filters to obtain this amplitude and phase control. The feedback system with phase-only filters is compared with other feedback systems that employ combinations of phase-only and amplitude-only filters; it is found that the phase-only system is substantially more flexible than the other two systems investigated. PMID- 20165093 TI - Subsurface water parameters: optimization approach to their determination from remotely sensed water color data. AB - A method, using an optimization scheme, has been developed for the interpretation of spectral albedo (or spectral reflectance) curves obtained from remotely sensed water color data. This method used a two-flow model of the radiation flow and solves for the albedo. Optimization fitting of predicted to observed reflectance data is performed by a quadratic interpolation method for the variables chlorophyll concentration and scattering coefficient. The technique is applied to airborne water color data obtained from Kawartha Lakes, Sargasso Sea, and Nova Scotia coast. The modeled spectral albedo curves are compared to those obtained experimentally, and the computed optimum water parameters are compared to ground truth values. It is shown that the backscattered spectral signal contains information that can be interpreted to give quantitative estimates of the chlorophyll concentration and turbidity in the waters studied. PMID- 20165094 TI - Passive infrared sensors: limitations on performance. AB - The performance of passive sensors for surveillance, radiometry, spectroscopy, astronomy is analyzed using idealizations of engineering features. Sensors are characterized by a finite number of degrees of freedom in each of two angles, wavelength, and time. An optimum number of degrees of freedom is found to sense a target field in four dimensions. Degrees of freedom are quite freely interchangeable between dimensions of different kinds. An optimum number of output states is related to the sensing or measurement requirment. An optimum weighting is found for averaging degrees of freedom into output states. Simple equations relate performance to an index of cost. Examples apply the results to estimate limits to sensor performance for several applications. PMID- 20165095 TI - Photomultiplier sensitivity variation with angle of incidence on the photocathode. AB - A description is given of measurements of the variation of sensitivity and reflection coefficient of the photocathode of an EMI 9558B photomultiplier with angle of the incident beam. They were made for three wavelengths, 0.69 microm, 0.56 microm, and 0.42 microm, and both p and s polarization states. Theoretical computations for each of the experimental measurements are given and compared with the experimental data. PMID- 20165097 TI - Multiple traversal absorption cell of minimum volume: design. AB - The design oThe author is with General Electric Company, Valley Forge Space Center, P.O. Box 8555, Philadelphia, Pennsylvania 19101.f a three-mirror absorption cell, first described by White and later improved on by Bernstein and Hertzberg, was analyzed by Edwards to be a unique optical configuration where the only aberration of consequence is astigmatism and associated image curvature. Edwards derived a formula whereby the astigmatic image length could be calculated. This paper relates cell design parameters in a manner that will attain the smallest volume consistent with the design objectives of the objective optics that precede the cell. PMID- 20165096 TI - Solar irradiance: total and spectral and its possible variations. AB - The present status of our knowledge of the total and spectral irradiance of the sun is briefly reviewed. The currently accepted NASA/ASTM standard values of the solar constant and the extraterrestrial solar spectral irradiance are presented. The uncertainties in these values are relatively high. Data on the variability of the solar constant are conflicting and inconclusive. The variability of solar spectral irradiance. is almost totally unknown and unexplored. Some alleged sun weather relationships are cited in support of the need of knowing more precisely the variations in total and spectral solar irradiance. An overview of the solar monitoring program of NASA is presented, with special emphasis on the Solar Energy Monitor in Space (SEMIS) experiment which has been proposed for several of the spacecraft missions. It is a combination of a solar constant detector and a prism monochromator. PMID- 20165098 TI - Electronic stabilization of scanning interferometers. AB - A quantitative relation for the drift error of a digital scanning spectrometer in a self-stabilizing mode is developed. Using a spectral prominence as a tracking reference, it is found that the error channel gain that provides minimum error is determined by the intensity and spectral width of the prominence. It is then shown that the self-noise of photon-counting detectors limits the ability of the system to retain stabilization in the face of drift rate errors, and a scanning strategy must be employed. The characteristics and scan strategies of a typical spectrometer system are then illustrated. PMID- 20165099 TI - Luminescence of turbid materials: a theoretical model and its comparison with experiment. AB - A four-flux model describing the absorption and emission of radiation in turbid materials has been developed. Several limit cases were considered. In order to test the model, measurements of absorption, emission, and scattering were performed on samples of luminescent polymer in both transparent and turbid states. The directly measured (in transparent state) and computed (from the measurements in turbid state) spectra and quantum yields were compared. The dependence of ratios of computed values to true values of these parameters on the absorption to scattering ratio was empirically evaluated. PMID- 20165100 TI - Hemi-ellipsoidal mirror infrared reflectometer: development and operation. AB - The development and testing of an ir hemi-ellipsoidal mirror reflectometer (HEMR), operational over a wavelength interval of 2-34 microm, are described. This optical system measures the hemispherical-directional reflectance of room temperature samples relative to a specular gold-coated surface. For a source and sample area commensurate with detectable energy requirements, it is shown experimentally that the HEMR is functional with very tolerable errors. Finally, the hemispherical-directional reflectance of test samples, e.g., black paints, gold diffuser, sulfur, cesium iodide, and others, is presented for wavelengths from 2 microm to 34 microm. PMID- 20165101 TI - Reflectance spectroscopy: application of the Kubelka-Munk theory to the rates of photoprocesses of powders. AB - The Kubelka-Munk theory of reflectance spectroscopy is used to derive an approximate equation that describes the rate of the photoprocess of a powdered sample in terms of the remission function. The equation is compared with one obtained using the particle model theory of diffuse reflectance and with experimental data for the photochemical reaction of powdered K(3)[Fe(C(2)O(4))(3)]-3H(2)O. PMID- 20165102 TI - Pulsed resonance spectroscopy applied to turbulent combustion flows. AB - The application of pulsed resonance spectroscopy to the measurement of species concentrations in chemically reacting turbulent flows is discussed. The theory of such measurements is developed. An uncertainty analysis is performed and the results applied to typical combustion conditions. Experimental aspects are discussed. The method shows a significant theoretical improvement in accuracy over Raman and Rayleigh scattering techniques, and no significant barriers appear to block its development. PMID- 20165103 TI - Infrared upconversion for astronomical applications. AB - The performance of an upconversion system is examined for observation of astronomical sources in the low to middle ir spectral range. Theoretical values for the performance parmeters of an upconversion system for astronomical observations are evaluated in terms of the conversion efficiencies, spectral resolution, field of view minimum detectable source brightness, and source flux. Experimental results of blackbody measurements and molecular absorption spectrum measurements using a lithium niobate upconverter with an argon-ion laser as the pump are presented. Estimates are given of the expected optimum sensitivity of an upconversion device that may be built with presently available components. PMID- 20165104 TI - Echelle gratings: their testing and improvement. AB - Tests are described on new master echelles of very large size and on others having unusually high blaze angles, produced on interferometrically controlled ruling engines. Defects arising from the gravitational distortion of large grating blanks during ruling were reduced by the use of calibrated edge supporting springs to diminish sag. The sixth echelle in a series of the largest yet produced (400 x 600 mm, or 16 x 24 in.), ruled on a fused silica blank 127 mm thick with 79 grooves/mm blazed at 63.4 degrees , gives high speed at resolutions well in excess of 10(6). A series of 254-mm echelles ruled at blaze angles whose tangents range from 2 to 8 were compared. Because an echelle blazed at 63 degrees can theoretically give 90% of the maximum resolving power available at any blaze angle, little resolution is gained by using steeper angles, and optical defects are likely to increase with groove asymmetry. Very high blaze angles are useful for raising intrinsic dispersion, however, making possible construction of echelle spectrometers of extreme compactness. PMID- 20165105 TI - Optical antenna gain. 3: The effect of secondary element support struts on transmitter gain. AB - The effect of a secondary element spider support structure on optical antenna transmitter gain is analyzed. An expression describing the influence of the struts on the axial gain, in both the near and far fields, is derived as a function of the number of struts and their width. It is found that, for typical systems, the struts degrade the on-axis gain by less than 0.4 dB, and the first side-lobe level is not increased significantly. Contour plots have also been included to show the symmetry of the far-field distributions for three and four support members. PMID- 20165106 TI - Aerosol size distributions: remote determination from air-borne measurements of the solar aureole. AB - Aerosol size distributions were determined remotely using an airborne scanning photometer. This instrument consists of a sunshade, optics, and a large dynamic range photodetector-amplifier system that scans about the vertical, recording both the direct attenuated solar beam and the diffuse sky radiance in the almucantar of the sun at an effective wavelength of 0.54 microm. The inversion of the measured radiances determined aerosol radii from approximately 0.2 microm to 8.0 microm. Data were taken during flights in May 1973 over western Lake Superior and southwestern Wisconsin. Inverted aerosol size distributions are compared with results obtained by other methods. PMID- 20165107 TI - Thermal-blooming compensation: experimental observations using a deformable mirror system. AB - A laboratory experiment has demonstrated the effectiveness of compensating for forced-convection-dominated cw thermal blooming by using a deformable mirror to add phase corrections to the laser beam. In agreement with theoretical predictions, the peak focal-plane irradiance has been increased by a factor of 3 under severely bloomed conditions. PMID- 20165108 TI - Statistical measurement of atmospheric 6328-A attenuation using a sequential laser transmissometer. AB - A recording transmissometer for the statistical measurements of atmospheric attenuation at 6328 A has been set up. It measures attenuations greater than 1 dB/km, on a 90-m folded back path. The stability of its operation makes it useful in automatic continuous measurements. The instrument and the way in which the measurements are made are described, and typical results are presented. PMID- 20165109 TI - Analog visibility computer. AB - A simple, inexpensive, all solid-state analog computer has been developed for calculating the visual range. Using an input signal from a transmissometer, the computer calculates the visual range by repeatedly solving the Allard and Koshmieder visibility laws. It is accurate to +/-2.0% for visual ranges of between 500 ft (150 m) and 5000 ft (1500 m). PMID- 20165110 TI - Multiple scattered radiation emerging from Rayleigh and continental haze layers. 2: Ellipticity and direction of polarization. AB - The ellipticity and the direction of polarization are calculated for radiation that has undergone multiple scattering from plane parallel layers. Both the radiation emerging from the top of the layer and that transmitted through the bottom are considered. Two different phase functions are used for the scattering layer: Rayleigh and haze L. The direction of polarization of the reflected radiation shows little variation as the optical depth of the layer increases, while there is a much larger variation for the transmitted radiation. When the optical thickness is small, the direction of polarization for haze L varies rapidly with zenith angle near those angles at which the single scattered polarization is zero. The ellipticity of the radiation from haze L layers increases at first in direct proportion to the optical thickness of the layer. In general the ellipticity of the transmitted radiation is considerably greater than that of the reflected because of the greater average number of photon collisions in the frmer case. When the ellipticity is small, it is shown that the product of the polarization and the ellipticity is closely equal to -V/2I, where I and V are the first and fourth components of the Stokes vector. PMID- 20165111 TI - Transparent heat mirrors for solar-energy applications. AB - Transparent heat-mirror films, which transmit solar radiation but reflect ir thermal radiation, have potentially important applications in solar/thermal/electric conversion, solar heating, solar photovoltaic conversion, and window insulation. We have used rf sputtering to prepare two types of films: TiO(2)/Ag/TiO(2) and Sn-doped In(2)O(3). To characterize the properties of heat mirror films for solar-energy collection, we define the parameters alpha(eff), the effective solar absorptivity, and epsilon(eff), the effective ir emissivity. For our Sn-doped In(2)O(3) films, alpha(eff)/epsilon(eff) is comparable to the values of alpha/epsilon reported for the leading selective absorbers. Even higher values of alpha(eff)/epsilon(eff) are obtained for the TiO(2)/Ag/TiO(2) films. PMID- 20165112 TI - Holographic contouring by translation. AB - Holographic interference fringes caused by rigid object motion have been explained as intersections of the object by surfaces in space. These interference surfaces can be visualized as the result of a three-dimensional moire effect between two sets of the ellipsoids of the holodiagram. The angles and the curvatures of the surfaces vary rapidly in the vicinity of the foci of the ellipsoids. It is graphically explained and experimentally verified how some translations of an object placed at a certain distance from the focal points cause contouring fringes that represent intersections by surfaces that are perpendicular to the line of sight. It is also demonstrated how this angle can be changed during reconstruction by moving the eye away from the hologram plate. PMID- 20165114 TI - Computer generated polarization holograms: phase recording by polarization effect in photodichroic materials. AB - A new algorism of computer holography utilizing the anisotropic interaction of light with photodichroic materials is proposed. The most unique feature of this technique lies in the realization of phase information recording without the use of detour phase or optical path difference effect. Basic principles of information recording and reconstruction scheme using M centers in alkali halide crystals such as sodium fluoride are described in detail, and several technical merits and problems associated with the proposed algorism are discussed. This new method will provide a real-time holographic system where accurate recordability and high storage capacity are attainable due to its possibility of recording a calculated complex amplitude of wavefront only by means of controlling the polarization direction of illuminating beam. PMID- 20165113 TI - Three-dimensional imaging from a unidirectional hologram: wide-viewing-zone projection type. AB - In ordinary holography reconstructing a virtual image, the hologram must be wider than either the visual field or the viewing zone. In this paper, an economical method of recording a wide-viewing-zone wide-visual-field 3-D holographic image is proposed. In this method, many mirrors are used to collect object waves onto a small hologram. In the reconstruction, a real image from the hologram is projected onto a horizontally direction-selective stereoscreen through the same mirrors. In the experiment, satisfactory 3-D images have been observed from a wide viewing zone. The optimum design and information reduction techniques are also discussed. PMID- 20165115 TI - Economic infrared polarizer utilizing interference effects in films of polyethylene kitchen wrap. AB - An inexpensive, easily fabricated, high quality, large aperture, pile-of-plates type, ir polarizer has been constructed having a polarization constant and insertion loss of 98% and 20%, respectively, using films of polyethylene kitchen wrap, each film being tuned for maximum performance at 10.6 microm by stretching. PMID- 20165116 TI - Asymmetrical fringe broadening in a Lummer-Gehrcke interferometer. AB - This paper analyzes the effects of random surface irregularities on the intensity distribution of a Lummer-Gehrcke plate interferometer. These surface defects are distributed asymmetrically about the plane of the L-G plate and are usually caused by scratches during its use. Calculations have been conducted for typical values of parameters, and results of some specific examples have been presented graphically. PMID- 20165117 TI - Leaky modes on a dielectric waveguide: orthogonality and excitation. AB - Because they are not proper spectral modes, leaky modes do not obey the usual power orthogonality relations for an ideal waveguide. Two methods for circumventing this problem are presented in this paper. One approach is to use the fact that weakly leaky modes are approximately power orthogonal within a restricted region of space to define a new set of slightly coupled modes. The other is to abandon power orthogonality in favor of a more general, mathematically exact orthogonality relation. The relative merits of these two approaches are discussed. PMID- 20165118 TI - Mode-dependent attenuation of optical fibers: excess loss. AB - A theory is presented for calculating the excess loss produced by random perturbations of optical fibers. The theory is applicable to perturbations whose longitudinal spatial frequencies are below the range required for mode coupling. To illustrate the method, losses due to diameter variations are calculated for the case of a step-index optical fiber. The diameter variations are found to produce a strong attenuation of the higher order modes. The total excess loss is approximately wavelength independent. PMID- 20165119 TI - Automatic analysis of interferograms: optical waveguide refractive index profiles. AB - Compensation of mode velocities in optical waveguides can be achieved by fabricating fibers having graded refractive index cores. One technique for measuring these index profiles is interference microscopy. We have developed a machine aided method for analysis of interference micrographs for the rapid determination of optical waveguide refractive index profiles. Our method consists of digitizing the interference micrograph with a scanning microdensitometer, followed by computer determination of the position of the center line of each fringe. The data obtained are then converted into refractive index and fiber radius information, which is used to calculate a best fit power law function. PMID- 20165120 TI - Optical modal evolution 3-dB coupler. AB - A planar optical 3-dB coupler is proposed that uses only a single region of mode conversion followed by a region of adiabatic modal evolution. These two regions are provided by an overlay with fast and slow tapers, which makes the device synchronous at a single point. Device length is noncritical. The device was fabricated with sputtered barium silicate and fused silica films and tested experimentally. Maximum power transfer of 40% was limited by a fabrication problem with the fast taper, but agreement with theory was obtained. An approximate coupled mode representation of the coupling between local normal modes is used to estimate power transfer at an abrupt transition and to provide design requirements for the fast and slow tapers. The theoretical concepts developed are applied to describe the operation of conventional directional 3-dB couplers and channel modal evolution 3-dB couplers which use branching waveguides. PMID- 20165121 TI - Waveguide lasers with intracavity electrooptic modulators: misalignment loss. AB - Coupling from the EH(11) fundamental mode of a square, hollow bore waveguide laser to a square electrooptic modulator is treated. The misalignment loss that results from coupling of the laser fundamental mode into higher order modulator modes is calculated. Results are presented for loss from transverse displacement, angular tilt, and axial separation of the two elements. From these results, the alignment tolerances required to minimize loss for an intracavity modulator are found. PMID- 20165122 TI - Fabrication of thin periodic structures in photoresist: a model. AB - We present a technique for designing holo-graphically fabricated structures in photoresist. A method is given for obtaining a suitable initial resist thickness. The etch depth (Deltat) vs exposure (E) characteristic is determined experimentally for a fixed development time (T). The characteristics for other values of T are found using the linearity of Deltat with T. Whole families of grating profiles can then be generated by using a polynomial fit to the exposure characteristics. For example, using a single holographic exposure plus an optional uniform preexposure, a family of grating profiles is obtained by varying the parameter T. A desired profile can thus be realized by a suitable combination of initial resist thickness, exposure, and development time. Residual resist layers may be eliminated by this method thereby minimizing scattering and other losses. Experimental verification of the various features of the model is given. PMID- 20165123 TI - Approximate optical system model. AB - An analytical development is presented for on-axis far-field irradiance in terms of an optical system that specifies a laser beam quality, an optical train with both linear and nonlinear phase aberrations (power driven), and a focusing telescope with jitter. It was found that the far-field intensity does not increase linearly with laser power, in fact it turns over and decreases as nonlinear, power-driven aberrations begin to dominate. The same phenomena causes the wavelength scaling to be less than 1/lambda(2) (with decreasing wave-length) for far-field irradiance. PMID- 20165124 TI - Narrow bandwidth dye laser suitable for pumping by a short pulse duration N(2) laser. AB - The design criteria and performance characteristics are reported of a tunable, narrow bandwidth dye laser that is suitable for pumping by a short pulse duration high power N(2) laser. The dye laser system is characterized by a relatively short over-all length of 15 cm. Bandwidths of from 0.015 nm to 0.05 nm are obtained along with conversion efficiencies in the neighborhood of 10% using a 4 5 nsec pulse duration N(2) pump. Bandwidths of 0.001 nm are observed with an intracavity etalon in the system. More important, however, it is shown that the conversion efficiency of an intracavity etalon dye laser system can be greatly improved if the temporal distribution of the N(2) pump pulse is adjusted so a single dye cell in a dye laser system is used first as an oscillator and then as an amplifier. Finally, using the above technique of processing the N(2) pump pulse, a 5-nsec N(2) laser is used to pump an intracavity etalon dye laser, which is followed by a large gap external etalon and then by an amplifier; the resulting bandwidth is 0.0005 nm at 480 nm with a conversion efficiency of 4.5%. PMID- 20165125 TI - Symmetric optimization of dielectric interference filters for nonnormal incidence: erratum. PMID- 20165127 TI - Applied optics of optics and opticists. PMID- 20165126 TI - Infrared reflectance: independent measurements yield good agreement. PMID- 20165128 TI - Fiber ring interferometer. PMID- 20165130 TI - Optical activities in industry. PMID- 20165129 TI - Electromagnetic radiation, relativity, and anomalous red-shifts. PMID- 20165132 TI - Aerosol measurements since 1973 for normal and volcanic stratospheres. PMID- 20165133 TI - Absorption of DF laser radiation by propane and butane. PMID- 20165135 TI - Pulsed uv nitrogen laser: its intensity and linewidth. PMID- 20165134 TI - Atmospheric transmission measurements at HF and DF laser wavelengths. PMID- 20165136 TI - Laser feedback: its effect on laser frequency. PMID- 20165137 TI - W-type optical fiber: relation between refractive index difference and transmission bandwidth. PMID- 20165138 TI - Semitransparent tin-oxide films on Pyrex plates: measurements of reflectivity. PMID- 20165139 TI - Doubling and visibility enhancement of moire fringes of the summation type. PMID- 20165140 TI - Interferometric probing of laser produced plasmas. PMID- 20165141 TI - Velocity and depth contours with a mode-locked pulse. PMID- 20165142 TI - MTF parameters for all photographic films listed in Kodak pamphlet P-49. PMID- 20165143 TI - Laser engines operating by resonance absorption. AB - The coherence properties and power levels of lasers available at present lend themselves to the remote operation of mechanical engines by resonance absorption in a working gas. Laser radiation is capable of producing extremely high temperatures in a gas. Limits to the achievable temperatures in the working gas of an engine are imposed by the solid walls and by loss of resonance absorption due to thermal saturation, bleaching, and dissociation. However, it is shown that by proper control of the laser beam in space, time, and frequency, as well as by choice of the absorbing gas, these limits are to a great extent removed so that very high temperatures are indeed attainable. The working gas is largely monatomic, preferably helium with the addition of a few volume percent of an absorber. Such a gas mixture, internally heated, permits an optimization of the expansion ratio, with resulting thermal efficiencies and work ratios, not achievable in conventional engines. A relationship between thermal efficiency and work ratio is derived that is quite general for the optimization condition. The performance of laser piston engines, turbines, and the Stirling cycle based on these principles is discussed and compared with conventional engine operation. Finally, a brief discussion is devoted to the possibility and concepts for the direct conversion of selective vibrational or electronic excitation into mechanical work, bypassing the translational degrees of freedom. PMID- 20165144 TI - Pulsed dye laser applied to modulated spectroscopy magnetic circular dichroism. AB - A tunable jet-stream dye laser pumped by a cavity-dumped argon laser has been synchronized to a photoelastic modulator to measure magnetic circular dichroism. Gated signal amplification takes advantage of the laser's pulsed operation to detect weak dichroic signals. Comparative data show that the dye laser and gated amplification give a SNR better than that obtained with the previously used lamp, monochromator, and lockin detector. Other applications of the dye laser and gated amplification are discussed. PMID- 20165145 TI - Transfer chemical laser: modeling of a cw DF-CO(2) laser. AB - The chemical kinetics characterizing a DF-CO(2) transfer chemical laser were verified by utilizing a subsonic laser system which, for most conditions, could be approximated as premixed and at constant pressure. In such a laser, fluid dynamic effects are minimized, and the role of the kinetics model in characterizing the DF-CO(2) system is emphasized. Predictions of zero power gain, DF(v) number densities, thermocouple temperatures, and laser power were compared with data for an optical cavity pressure range of 21-79 Torr. The results show that the kinetics model gives an accurate description of the DP-CO(2) optical cavity. Mixing phenomena were found to become important at cavity pressures below 40 Torr. PMID- 20165146 TI - Spatial spikes of laser irradiance propagating over large distances in a turbulent medium. AB - Statistics of the random field of spatial spikes of laser irradiance over large distances in a turbulent medium are investigated. Formulas are obtained defining the mean value of the area of the spikes, their density, and the mean distance between the nearest spikes in a plane transverse to the direction of propagation. Numerical calculations illustrate the case of a focused Gaussian beam. PMID- 20165147 TI - Spherical particle populations: approximate analytic relationship between size distribution parameters and integral optical properties. AB - The absorption and scattering efficiencies of spherical particles in a certain size range can be approximated by a three-parameter formula. With this formula, an analytic relationship is developed between the extinction, scattering, or adsorption coefficient and the parameters of a log-normal size distribution. The technique permits approximate calculation of these coefficients from the mean radius, its standard deviation, and the total number concentration. By an inversion the size distribution parameters can be estimated from measurements of any of the coefficients at three wavelengths. The calculations require only hand calculators or slide rules. It is shown that use of the technique is justified for many cases of atmospheric aerosol particles and visible radiation. PMID- 20165148 TI - Ratio measurement of diffuse to direct solar irradiances in the middle ultraviolet. AB - The experimental details in the ratio measurement of diffuse to direct solar irradiances in the middle uv are described. Some experimental data for typical partly cloudy inland summer weather in Florida are discussed and compared with various theoretical calculations. The more extensive data for clear days from P. Bener are also compared with various calculations. We have concluded that it is feasible to improve the uv calculations with the proposed ratio measurements for various sky conditions. PMID- 20165149 TI - Ultraviolet polarimeter to record resonance-line polarization in the solar spectrum around 130-150 nm. AB - A Swedish-built uv spectropolarimeter to be launched on a Soviet satellite in the Intercosmos series is described. The scientific objective is to record linear polarization across monochromatic solar images formed in resonance lines in the 130-150-nm wavelength region. This polarization arises by coherent scattering in the chromosphere-corona transition region of the sun. The instrument uses two parallel optical channels with highly different polarizing properties. The polarization analysis is done by reflection at gold-coated mirrors. The uv calibrations of the two flight models are described. PMID- 20165150 TI - Thin slits: transmission and polarization. AB - The paper discusses measurement of the transmission ratio T ||/T? of thin slits for light polarized linearly parallel and perpendicular to the slit direction at optical wavelengths and as a function of the angle of incidence. To obtain perfectly identical geometrical beams, the plane of polarization of the linearly polarized light is rotated in the measuring setup by means of plates of optically active quartz. The results indicate that the transmissivity is higher for light polarized parallel to the slit direction. This effect is more pronounced with narrow slits than with wide slits and, moreover, increases with the wavelength. For tangential orientation of the slit, the ratio T ||/T? increases with the angle of incidence. The paper studies the effect of surface reflections. PMID- 20165151 TI - Diffraction corrections in the radiometry of extended sources. AB - The diffraction corrections associated with a circular aperture in the case of an extended source and a detector located in the fully illuminated region have been calculated in 1972 by Steel, De, and Bell. We have shown recently that the intensity distribution formula that they have used is not accurate in the central region of the diffraction pattern and greatly underestimates the diffraction corrections associated with a point source. In this paper, we take up the case of an extended source; we have followed Steel et al.'s method of calculation, but have used an intensity distribution which we have shown to be valid in the central region. We show that in the case of complex radiation, the variation of the diffraction correction with the source radius rho takes a very simple form: the diffraction correction remains approximately constant as rho increases, until the source and detector subtend equal angles at the center of the aperture; if rho is increased further, the diffraction correction decreses linearly with 1/rho over a certain range of rho. Experimental results are presented that confirm these theoretical predictions. PMID- 20165152 TI - Fresnel zones calculation. Part 2. AB - The method of the contour integral of Maggi-Rubinowicz is used to calculate exactly the contribution of a Fresnel zone taken over a general plane for the case of an incident spherical wave. PMID- 20165153 TI - Scattering by spheres with nonisotropic refractive indices. AB - Some results of experimental studies on microwave scattering by artificially constructed axially symmetric spheres with anisotropic refractive indices are presented. An approximation using Mie theory for spheres with appropriate orientation dependent indices of refraction is shown to provide a good explanation of the observed dependence of the complex forward-scattering amplitudes on target orientation. PMID- 20165154 TI - Channel electron multipliers: detection efficiencies with opaque MgF(2) photocathodes at XUV wavelengths. AB - The detection efficiencies of channel electron multipliers with opaque MgF(2) photocathodes have been measured at wavelengths between 44 A and 900 A. Efficiencies a factor of 2 greater than those of uncoated channel electron multipliers were obtained over the wavelength range from 50 A to 350 A. The absolute detection efficiencies were greater than 10% in the range from 67 A to 990 A for photocathodes illuminated at an angle of incidence of 45 degrees , with additional increases in sensitivity being obtained at short wavelengths using higher angles of incidence. Following an initial aging period, the photocathodes showed no degradation of response during storage under vacuum or in air. PMID- 20165155 TI - Infrared gas-filter correlation instrument for in situ measurement of gaseous pollutant concentrations. AB - An ir analyzer employing gas-filter correlation techniques has been designed and constructed to measure the concentrations of CO, NO, SO(2), HCl, and HF in the stacks or ducts of stationary pollutant sources. Use of a retroreflector allows the stack to be double passed, and no sample is extracted. For each gas, small interchangeable fixed-position grating polychromators are used as narrow (~1.5 cm(-1)) multiband spectral filters with the bands corresponding to locations of selected absorption lines. The approximate useful ranges (in parts per million meters) over which this analyzer operates are 10-4000 for NO, 10-1500 for CO, 50 40,000 for SO(2), 10-2000 for HC1, and 5-200 for HF. The discrimination against other gases and particulates is excellent. The analyzer has been tested in the laboratory and on a variety of pollutant sources. PMID- 20165156 TI - Opto-ultrasonic sounding system. AB - A new combination of pulsed ultrasonic waves and laser light with proper signal processing techniques is shown as a means of nondestructive testing. This method is suitable for inspection of the conditions in narrow, long regions, such as inside a pipe. The construction and basic experimental results are shown, and the effects of the signal processing are emphasized. As typical of the sensitivity of the system, an object 3 mm high placed at a 500-mm distance from the open aperture of a 26-mm diam pipe could be detected. PMID- 20165157 TI - Collimation test by double grating shearing interferometer. AB - The double grating shearing interferometry method for determination of the degree of light collimation is described. High accuracy is obtained by performing the observation of fringes in the area of the size twice as big as the one usually assumed in shearing interferometry experiments. The conditions under which such a detection mode is feasible are derived. They represent at the same time a very strong argument proving the highly diffractive (wave optics) character of the classical Ronchi test. PMID- 20165158 TI - Real time measurement of very small transverse displacements of diffuse objects by random moire. 1: Theory. AB - Illumination of a random diffuse object by a fringe pattern produced by two symmetrical laser beams leads to phenomena that are usually studied with speckle interferometric techniques. We first show that these phenomena are analogous to moire. We then propose to apply this method for measuring the transverse vibrations of a diffuse surface in real time with interferometric sensitivity. Further, we show that the discussed system can work as a linear displacement transducer; the theoretical aspects of this so-called random moire transducer are investigated. PMID- 20165159 TI - Real time measurement of very small transverse displacements of diffuse objects by random moire, 2: Experiments. AB - We first briefly describe a realization of the random moire displacement transducer (Part 1 of this paper). The principal problems arising in practical measurements, namely, stability and noise, are then discussed. Finally, results of several vibration measurements are presented, with various waveforms and amplitudes (2 A to 3 microm peak to peak). PMID- 20165160 TI - Interference filters: single crystal multilayer AlAs-GaAs. AB - High and low reflectance single crystal quarter wave stacks consisting of alternating layers of AlAs and GaAs have been grown on GaAs substrates by molecular beam epitaxy. PMID- 20165161 TI - Space charge fields: a fringe technique for observing such fields during hologram writing in LiNbO(3). AB - An interference fringe method is reported that allows rapid monitoring of the large scale (nonsinusoidal) space charge field which develops during hologram writing with nonuniform light intensity in LiNbO(3). This large scale field is distinct from the sinusoidal space charge fields that constitute the hologram. The large scale field has been shown elsewhere to be important in that it affects the efficiency of hologram writing and leads to history effects. Using the fringe method, a dielectric breakdown process associated with the large scale field was observed which may have been responsible for some effects reported by Carlsen in his work on computer applications. PMID- 20165162 TI - Volume holographic recording characteristics of an organic medium. AB - Volume holographic recording characteristics of camphorquinone in a rigid, acrylic polyester host are presented and related to the observed photoinduced refractive index changes. The dependence of the holographic recording on camphorquinone concentration, temperature, and light intensity is discussed in detail. The holograms are permanent and develop to their final efficiency slowly at room temperature. Heating after exposure can be used to accelerate fixing of the hologram. PMID- 20165163 TI - Cassegrain telescopes: limits of secondary movement in secondary focusing. AB - The maximum distance to which the secondary mirror can be moved with respect to its primary in a true Cassegrain telescope with limited image deterioration is found to be proportional to the fourth power of the focal ratio of the primary mirror. This limit is independent of all other parameters describing the system when the magnification of the secondary is greater than about 3. PMID- 20165164 TI - Cramer-Rao bounds on mensuration errors. AB - The Cramer-Rao (CR) bound is an inequality that sets a lower bound on the variance of an estimator. The paper presents an application of this bound to the problem of mensuration. Explicit results are given for the width of a pulse, incoherently imaged by an optical system. The results are given in terms of the SNR of the observed signal and the autocorrelation function of the system line spread function. The effects of another unknown parameter (pulse amplitude), an application to sampled data imagery, and the calculation of confidence limits are presented. PMID- 20165166 TI - Active imaging system: a long range scanned laser. AB - An active imaging system has been developed that utilizes a scanned Nd-YAG laser beam for target illumination. Images obtained at distances up to 1.5 km using different signal processing methods are shown. A new technique of generating a 3 D display is presented. PMID- 20165165 TI - Uniformity of film development resulting from different processing techniques. AB - The uniformity of film development was investigated for eight different film developing methods including both hand and machine processes. Film uniformity was quantitated through microdensitometry by scanning rolls of uniformly fogged and developed film with an Olympus MMSP microspectrophotometer and a Photometrics EDP scanning microscope. The results of this study showed that significant differences of uniformity were produced using the different developing methods evaluated. With the exception of the tray and hand brushing method, all the machine processors studied produced films having significantly better uniformity than any hand methods evaluated. PMID- 20165167 TI - Pulse distortion in the ultimate multimode optical fiber. AB - The shape of the impulse reponse of a step index, multimode fiber of circular cross section with material limited by Rayleigh scattering only is nearly invariant with fiber length L, unless L is so large that the signal has suffered an enormous scattering loss. The percent fraction of pulse energy responsible for distortion by scattering approximately 8.63 (1 - n(2)(CL)/n(2)(CO)) W(dB), where W(dB) is the associated energy reduction in decibels due to scattering from the core, and n(CL), n(CO) are the refractive indexes of cladding and core, respectively. WdB is nearly equal to length in kilometers for highly transparent material. PMID- 20165168 TI - Multimode optical fibers: interplay of absorption and radiation losses. AB - We present results for power transmitted when a typical multimode optical fiber is excited by a Lamber-tian source. Power attenuation is due to absorbing core and cladding materials and radiation loss due to reflections from the circular cross section. Radiation loss is responsible for a significant power reduction (20-25% for Lambertian source) over distances much less than those for which material absorption is important. PMID- 20165170 TI - Laser heating of an optical fiber. AB - For use in absorption measurements in low-attenuation glass fibers, we calculate the periodic temperature rise at the surface of a glass cylinder heated by a chopped laser beam. Specifically, we give the mean temperature, setting the operating temperature of the experiment, and the peak-to-peak temperature, determining the sensitivity of the measurements. PMID- 20165169 TI - Proximal scanning systems: improved resolution using inclined optical fibers. AB - The illumination of a plane beneath the radiating aperture of an inclined multimode optical fiber is calculated. Graphical results are presented that show, for a proximal scanning head made up of fiber triplets composed of a central sensing fiber and two illuminating fibers, inclining the illuminating fibers away from the sensing fiber provides improved illumination of the work surface. The improvement in illumination obtained allows closer spacing of the scanning head to the work surface, thus improving resolution. A simple geometrical formula is presented that enables a prediction to be made of the fiber inclination for optimum illumination. This formula holds for large variations in the shape of the fiber polar sensitivity function. PMID- 20165171 TI - Pulse separating in transmission characteristics of multimode graded index optical fibers. AB - The transmission characteristics of multimode graded index optical fibers, whose refractive index profiles were nearly parabolas, were measured. No change of the output pulse waveform could be detected at a 1-km length with a lowest-order mode excitation. In the case of mismatching excitation, output pulse waveforms separated into two pulse peaks. This was caused by the refractive index profile that was not a single function but a combination of two functions. PMID- 20165172 TI - Absorption coefficients of highly transparent solids: photoacoustic theory for cylindrical configurations. AB - The development of highly transparent solids for fiber optics, integrated optics, and high power lasers requires improved methods to measure very low absorption coefficients. For the case in which a laser beam, modulated at angular frequency omega, passes through a weakly absorbing solid which is surrounded by a confined, nonabsorbing gas, the temperature profiles in the solid and the temperature and pressure profiles in the gas have been calculated. The calculations suggest that for sufficiently low frequencies and high ambient gas pressures, enough heat transfers from the solid to the gas to produce a detectable acoustic-pressure signal at angular frequency omega in the gas. They also indicate that an absorbing layer at the solid-gas interface is not an essential mechanism for producing these detectable acoustic pressure signals. The model assumes that bulk absorption in the solid is the mechanism by which energy is transferred from the laser beam. Numerical examples for a typical laser glass are given. PMID- 20165173 TI - Parametric oscillator: HF oscillator-amplifier pumped CdSe parametric oscillator tunable from 14.1 microm to 16.4 microm. AB - A singly resonant CdSe parametric oscillator with tunable output from 14.1 microm to 16.4 microm is described. The oscillator, pumped by the 2.87-microm line from an HF oscillator-amplifier, is resonant on the signal near 3.5 microm and has produced idler outputs of 100 microJ at 16 microm. Bandwidths varied over the tuning range from 9 cm(-1) to 1.8 cm(-1). Techniques for obtaining a highly coherent HF laser pump beam are presented. The uniform beam from the gain saturated amplifier allows the use of Fresnel diffraction theory to produce a nearly uniform pump beam at the oscillator cavity. PMID- 20165174 TI - Flash evaporation of compounds with a pulsed-discharge CO(2) laser. AB - Pulsed laser radiation at 10.6 microm has been used to evaporate a number of compounds chosen for their difficulty of evaporation with conventional techniques. An average laser power of 8 W, pulsed at 50 Hz with a 1-msec duration, has been found sufficient to obtain useful evaporation rates for Al(2)O(3) and other highly refractory materials. For easily decomposed materials such as CdS and ZnS, comparison of cw and pulsed evaporation through measurement of optical and photoconductive film properties consistently indicates higher stoichiometry in pulsed evaporation, as well as higher refractive index. The dynamics of film growth during a single laser pulse has been studied by means of a unique thickness monitor. PMID- 20165175 TI - Right angle bends in light pipes: analysis. AB - An expression for the fraction of incident radiation transmitted by a right angle bend in a rectangular light pipe is derived. This expression is used to show that, in a planar light pipe structure with right angle bends, light attenuation is due only to reflection losses at the walls if the launching angle is 45 degrees . PMID- 20165176 TI - Waveguides: characteristic modes of hollow rectangular dielectric waveguides. AB - The field configurations and propagation constants of the normal modes of a hollow rectangular dielectric waveguide have been determined. In addition, the coupling coefficients of a Gaussian free-space mode into the normal modes of a square guide were calculated. The attenuation of each mode is found to be inversely proportional to the cube of the guide aperture 2alpha and proportional to the square of the free-space wavelength lambda. For a hollow dielectric square guide with 2alpha = 1 mm and lambda = 10.6 microm, an attenuation of 0.140 dB/m is predicted for SiO(2) and 0.032 dB/m for BeO. All modes are found to be hybrid modes, although they very closely approximate linearly polarized TEM modes. PMID- 20165177 TI - Resolution of a microscope: improvement using a centrally obstructed condenser aperture and a semitransparent II-phase annular aperture objective system. AB - This paper presents a study of the effects of annular sources of illumination on the resolution of two pinholes of equal brightness by a semitransparent and II phase annular aperture microscope. It has been shown that by using a centrally obstructed illuminating condenser and a semitransparent and II-phase annular aperture microscope objective the resolution of a microscope can be considerably improved. The effect of condenser blocking provides the lower values of the degree of coherence (less than zero), favoring an increase in the degree of resolution; whereas the semitransparent and II-phase annular aperture objective still lowers this limiting resolution without much loss of light by the central region of the objective. The best resolution is obtained when the central region is completely transparent. It has also been observed that the limiting separation exhibits an oscillatory behavior around the value corresponding to incoherent illumination in the particular case concerned. PMID- 20165178 TI - Patents. AB - 3,860,342; 3,861,806; 3,867,032; 3,867,038; 3,867,571; 3,900,884; 3,905,674; 3,907,402; 3,909,102; 3,909,112; 3,910,677; 3,910,680; 3,910,681; 3,910,682; 3,910,704; 3,911,206; 3,911,209; 3,912,364; 3,912,373; 3,912,376; 3,912,378; 3,912,394; 3,912,395; 3,914,020; 3,914,023; 3,914,025; 3,914,032; 3,914,054; 3,914,055; 3,914,877; 3,915,557; 3,915,564; 3,915,575; 3,916,195; 3,916,197; 3,916,205; 3,917,391; 3,917,399; 3,918,028; 3,918,791; 3,918,797; 3,918,798; B 382,783. PMID- 20165179 TI - Prism offset for optical waveguide coupling. PMID- 20165180 TI - Applied optics of optics and opticists. PMID- 20165181 TI - Threshold detection in pulsed laser ranging. PMID- 20165182 TI - Infrared photography at 5 microm and 10 microm. PMID- 20165183 TI - Optical activities in industry. PMID- 20165184 TI - Patents. AB - 3,765,753; 3,767,307; 3,767,310; 3,776,636; 3,819,270; 3,837,731; 3,838,912; 3,840,291; 3,840,298; 3,842,253; 3,842,254; 3,842,713; 3,844,645; 3,844,658; 3,860,346; 3,862,357; 3,864,016; 3,865,464; 3,866,038; 3,867,009; 3,869,193; 3,869,195; 3,871,740; 3,881,801; 3,881,802; 3,891,849; 3,892,966. PMID- 20165185 TI - Meeting reports. PMID- 20165187 TI - Pulsed CO(2) laser with combined high-current discharge. PMID- 20165188 TI - Laser frequency stabilization: combined integrating thermal-proportional servos. PMID- 20165189 TI - Silicon photodetector instabilities in the uv. PMID- 20165190 TI - Optical heterodyning ellipsometry measurements. PMID- 20165191 TI - Annular lens soft aperture for high power laser systems. PMID- 20165192 TI - Sodium in laboratory atmosphere. PMID- 20165193 TI - Clea 1975. PMID- 20165194 TI - Optical fiber fault location method. AB - An optical pulse reflection method based on the optical radar principle is discussed for optical fiber cable fault location. The optical reflection coefficient at flat surfaces of optical fibers was measured and found to be in good agreement with calculated value. The average reflection coefficient at fractures in optical fibers, which were generated by simple tensile stress, was about 0.5%. The reflected pulse signal from an optical fiber fault at a distance of 1.4 km in a SELFOC fiber having transmission loss of 17 dB/km was detected experimentally. PMID- 20165195 TI - Integrated optical silicon photodiode array. AB - We consider device design, fabrication, and operation of integrated optical photodiode arrays in which p-i-n junction photodiodes are formed in silicon. A SiO(2) layer on silicon serves as the effective substrate for a KPR waveguide. Light is coupled from the waveguide at the detector region either through the evanescent field or by multiple refraction into the detector. The waveguide photodiode structure is designed so that nearly 100% of the incident optical energy can be absorbed in the photodiode junction depletion region. A device quantum efficiency of 80% is measured compared to a theoretical value of 93%. PMID- 20165196 TI - Zinc-diffused two-dimensional optical waveguides in n-type GaAs. AB - Two-dimensional waveguides were fabricated in n-type GaAs by zinc diffusion. Experimental observation of the dependence of waveguide cutoff on channel width agrees with theoretical models of the refractive index profile. PMID- 20165197 TI - Holographic video disk: an alternative approach to optical video disks. AB - Optical video disks employing time sequential coding are superior to mechanical video disks because of their noncontact reproducing capability. One drawback in the optical systems is the necessity of precise focusing and tracking adjustments. To solve this problem, an alternative approach, using a holographic technique that makes it possible to store a frame of information in a specified area redundantly, is proposed. A design concept and experiments relating to the breakthroughs are described. A combination of random phase sampling holography and coherently superimposing holography makes it possible to store color-encoded images sufficient for about a 30-min motion picture on a disk of 300 mm in diameter. A sound recording technique suitable for the holographic video disk, constituting one-dimensional hologram-type, pulse-coded-modulation signals, is proposed. PMID- 20165198 TI - Optical sampling transient analyzer system. AB - A 1-GHz optoelectronic sampling transient analyzer system having 10(3) dynamic range has been developed and tested for diagnosing the time-amplitude characteristic of a fast, high voltage, single transient electrical pulse. Sampling rate can be tailored to individual signal analysis requirements. Primary elements are a 350-psec (FWHM) laser, a traveling-wave Kerr cell, a semiconductor detector array with charge collection circuitry, and an analog-to-digital converter with digital data memory. PMID- 20165199 TI - Polarization reference imaging systems. 2: Computer simulation studies. AB - Polarization Reference Imaging (PRIM) systems utilize the polarized and coherent output characteristics of lasers to eliminate turbulence and/or optical figure errors. Computer simulation studies of the PRIM system are presented. The simulation scheme, PRIM reconstructed images, and their image quality dependence on system parameters are shown and discussed. PMID- 20165200 TI - Optical processing: a near real-time coherent system using two Itek PROM devices. AB - A near real-time coherent optical processing system has been demonstrated using two Itek PROM devices and a TV monitor. One PROM acts as an incoherent-to coherent image converter and the other as a laser addressed, programmable Fourier plane filter. The TV monitor provides an on-line display of the filtering process. PMID- 20165201 TI - Information scanning technology: applications of cw AlGaAs injection lasers. AB - The suitability of cw room-temperature injection iasers for information retrieval systems was investigated experimentally. The results indicate that in such applications AlGaAs injection lasers compare favorably with He-Ne gas lasers. PMID- 20165202 TI - Remote measurement of distance and thickness using a deflected laser beam. AB - A remote optical technique of measuring distance and thickness is described which relies on a measurement of the time a laser beam deflected at a definite speed takes to travel from a starting point on a reference plane to a final point on the object. Its significant features are high measuring speed, high resolution, flexibility with regard to measurement range and distance between reference plane and probe, insensitivity to surface properties of the object, and rugged design. It is, therefore, suitable for a large variety of applications, especially in industrial metrology. PMID- 20165203 TI - Galvanometer deflection: a precision high-speed system. AB - An X-Y galvanometer deflection system capable of high precision in a random access mode of operation is described. Beam positional information in digitized form is obtained by employing a Ronchi grating with a sophisticated optical detection scheme. This information is used in a control interface to locate the beam to the required precision. The system is characterized by high accuracy at maximum speed and is designed for operation in a variable environment, with particular attention placed on thermal insensitivity. PMID- 20165204 TI - Low-threshold transversely excited NdP(5)O(14) laser. AB - The threshold and efficiency of a transversely excited, cw NdP(5)O(14) laser have been measured with 0.58-microm excitation from a dye laser and 0.8-microm excitation from a semiconductor laser. After fitting our data for the threshold as a function of wavelength near 0.58 microm, we have applied the calculations to the 0.80-microM Nd(3+) absorption band. With transverse excitation from high radiance LED's or laser diodes, thresholds are calculated to be 4-8.5 mW at 0.80 microm, depending on pump bandwidth. Using an A1(x)Ga(1-x)As double-hetero structure laser diode pump, we have obtained quasi-cw lasing in NdP(5)O(14), with thresholds ~7 mW and optical power conversion efficiency ~7%. PMID- 20165205 TI - High power output stages of a Nckglass laser system for fusion applications. AB - This short paper considers the advantages and disadvantages of active element apertures in the form of disks and long rectangular cross-section slabs used in laboratories in the U.S.A. and the U.S.S.R. PMID- 20165206 TI - Parasitic suppression in large aperture disk lasers employing liquid edge claddings. AB - A liquid edge cladding system for parasitic suppression in large aperture, high gain disk laser amplifiers has been developed and tested. A near-saturated aqueous solution of Znl(2) was employed for index-matching. Adequate fluorescence absorption was demonstrated using either dissolved NiCl(2) or chrome black oxide coating applied to the disk holder. Application of liquid cladding to a 20-cm aperture disk laser amplifier increased energy storage capability by approximately 20% over conventional solder glass claddings. PMID- 20165207 TI - Focusing properties of an aberrated laser beam. AB - A computation procedure using self-similar propagation modes is used to analyze the effect that nonlinear whole beam phase distortions have on the focusing properties of the beam produced by a high power solid state fusion laser. A comparison between the predicted and measured patterns for a prototype fusion laser is given. PMID- 20165208 TI - Negative-branch unstable resonator Nd:YAG laser. AB - The results of an experimental investigation of the performance characteristics of a Q-switched Nd:YAG laser utilizing a negative-branch unstable resonator is presented. Measurements indicate that near diffraction-limited beam quality has been attained with a system in the rangefinder/designator energy category. In a performance comparison with a conventional parallel-plane mirror resonator, the unstable resonator was found to produce equally efficient operation with greatly superior beam radiance and tolerance to mirror misalignment. PMID- 20165209 TI - Unstable open resonators: two-dimensional and three-dimensional losses by a waveguide analysis. AB - Previous calculations performed by a waveguide approach to unstable open resonators with cylindrical hyperbolic mirrors are further refined. By this approach, the resonator is regarded as a waveguide transverse to the resonator axis, and resonance is established by self-consistent reflection of a single waveguide mode, or of two selectively coupled waveguide modes, from the mirror edges and from the axial region. The refinement refers to improved values for the modal reflection coefficients that appear in the resonance equation. The theory is now shown to be capable of predicting the eigenmode loss behavior in resonators with large Fresnel numbers, as verified by comparisons with published numerical solutions of the resonator integral equation. The theory is also extended successfully to circular hyperbolic mirrors. Finally, the waveguide model is utilized to derive known equivalence relations, previously deduced from the integral equation, between resonators with symmetrical mirrors and those with other arrngements. Thus, the results in this paper lend further support to the validity of the coupled-mode waveguide model for unstable resonators. PMID- 20165210 TI - High power laser propagation. AB - High power laser beams propagating in the atmosphere are subjected to a variety of effects, the most important of which are absorption, scattering, turbulence induced beam spreading and wander, thermal blooming, and gas breakdown. In this paper simplified models are used to show how the various atmospheric effects interrelate and impact on the best laser choice for high power applications through their dependence on the laser wavelength and temporal mode (e.g., cw or pulsed) of operation. Results for sea level propagation at seven common laser wavelengths varying from 0.34 microm to 10.6 microm. are presented that show the mid-ir wavelengths to be favored for typical turbulence and aerosol scattering conditions. At the longer 10.6-microm CO(2) laser wavelength thermal blooming is dominant due to stronger molecular absorption, while at the shorter wavelengths turbulence induced beam spreading and aerosol absorption and scattering effects become important and tend to limit the increase in irradiance expected on the basis of diffraction effects alone. PMID- 20165211 TI - Transverse flow flashlamp pumped dye laser. AB - A high repetition rate dye laser utilizing transverse flow and linear, close coupled flashlamps has been built. Measurements and performance figures including average power, bandwidth, beam divergence, and solvent mixtures will be discussed. PMID- 20165212 TI - Ultrasonic waves: their interferometric measurement and display. AB - A system for the measurement and visualization of small displacements has been developed that features high sensitivity and acoustic-wavelength-limited resolution over apertures as large as 15 cm at frequencies up to 10 MH(z). Acoustic-wave displacement amplitudes as small as 0.07 A are measured by interferometrically detecting the motion of a thin, acoustically transparent, metallized pellicle as the ultrasonic wave passes through it. The system can also be adapted to measure and display any small vibratory motion. The basic arrangement is that of the Michelson interferometer with the addition of an open loop method to stabilize the response and a deflection system in one leg of the interferometer to scan the pellicle. Presently, the system is used in the study of the interactions of ultrasonic waves with biologic tissue and the observation and measurement of radiation patterns of acoustic transducers. PMID- 20165213 TI - Laser optoacoustic detection of explosive vapors. AB - The direct detection of nitroglycerine, ethylene glycol dinitrate, and dinitrotoluene by optoacoustic spectroscopy techniques at 6 microm, 9 microm, and 11 microm is reported. The effect of interference by normal atmospheric pollutants is investigated, and it is found that of those wavelengths used in this investigation the 9-microm and 11-/microm spectral regions, using a CO(2) laser as radiation source, are the most promising for use in explosive detection. PMID- 20165214 TI - Laser induced damage in optical materials: 7th ASTM symposium. AB - The Seventh ERDA-ASTM-ONR-NBS Symposium on Laser Induced Damage in Optical Materials was held at the National Bureau of Standards in Boulder, Colorado, on 29-31 July 1975. These Symposia are held as part of the activities in ASTM Subcommittee II on Lasers and Laser Materials, which is charged with the responsibilities of formulating standards and test procedures for laser materials, components, and devices. The Chairman of Subcommittee II is Haynes Lee, of Owens-Illinois, Inc. Co-chairmen for the Damage Symposia are Arthur Guenther of the Air Force Weapons Laboratory and Alexander J. Glass of Law-rence Livermore Laboratory. Over 150 attendees at the Symposium heard forty-five papers on topics relating fabrication procedures to laser induced damage in optical materials; on metal mirrors; in ir window materials; the multipulse, wavelength, and pulse length dependence of damage thresholds; damage in dielectric films and at exposed surfaces; as well as theoretical discussions on avalanche ionization and multiphoton processes of importance at shorter wavelengths. Of particular importance were the scaling relations developed from several parametric studies relating fundamental properties (refractive index, surface roughness etc.) to the damage threshold. This year many of the extrinsic influences tending to reduce a materials damage resistance were isolated such that measures of their egregious nature could be quantified. Much still needs to be accomplished to improve processing and fabrication procedures to allow a measurable approach to a materials intrinsic strength to be demonstrated. PMID- 20165215 TI - Passive-Q-switching at high intensities and high absorber pressures. AB - The range of operation of a CO(2) laser in pulses due to passive Q-switching is extended to high pressures of the absorber (200-800 Torr) and high intensities of the irradiation in the absorption cell (1 kW/cm(2) average power). This extension may be applied to igh power CO(2) lasers. The experimental results indicate that thermal saturation is involved in the Q-switching. The theory of passive Q switching is extended to include this effect and is compared with the experimental results. PMID- 20165216 TI - High gain ir laser in passive Q-switching: operating criterion. AB - A set of rate equations is developed for the operation of an ir laser in passive Q-switching. This set of equations includes the effect of rotational hole burning in the saturable absorber and the high gain and nonuniform losses in the cavity of the laser. Using these equations a set of criteria is developed, which states conditions on the parameters of the laser and the absorber that have to be fulfilled in order that the laser-absorber system should operate in pulses. Experimental verification of the criteria is given. The three phases of the operation of the laser (cw, pulses, and zero output) are depicted on a phase diagram that emphasizes the dependence of the operation on the parameters of the laser and the absorber. PMID- 20165217 TI - Infrared holography: an analysis of the thermal behavior of thin films. AB - This paper presents an analysis describing the thermal behavior of a thin film subjected to a spatially modulated irradiation field. The analysis shows that it is possible using a cw laser to establish a temperature field in such a film that maps the irradiation pattern with a resolution adequate for recording high quality holograms. Effects of the thermal properties of the film and substrate on such recording characteristics as linearity, sensitivity, and resolution are examined. A high diffraction efficiency recording technique based on the sublimation of a thin film situated on a constant temperature substrate is proposed as an example of the application of the analysis. PMID- 20165218 TI - Holographic storage and photoconductivity in PLZT ceramic materials. AB - The dynamics of holographic recording in quadratic electrooptic materials are analyzed. High optical quality PLZT ceramic is found to conform to the behavior predicted for quadratic materials. The operation of PLZT as a holographic store and as a photoconductor is studied, and mechanisms that limit the material sensitivity are postulated. PMID- 20165219 TI - Holographic interferometry: compensation for rigid body motion. AB - A technique producing an optical effect that is unaffected by rigid body motion is described. It is shown that the resulting interference fringe pattern is proportional to the change in model thickness, which for the case of plane stress is proportional to the sum of the principal stresses, and thus provides a full field isopachic fringe pattern. This method combines holographic interferometry and the moire effect. Double exposure holograms are made from both sides of a model before and after deformation. The two sets of holographic interferometric fringes thus obtained are treated as random grids, and the superposition of these two grids produces a moire effect that is free from the effects due to rigid body motion. The theory is experimentally confirmed with several examples, and limitations of the techniques are also discussed. PMID- 20165220 TI - Electrooptic Bragg-deflection modulators: theoretical and experimental studies. AB - We have studied the mechanism of Bragg diffraction in electrooptic thin-film lightguides and examined in detail the effectiveness of interaction between the electric field and optical field. Expressions for the full deflection voltage and the power per bandwidth are obtained and applied to various modulator structures using out-diffused, metal-diffused, epitaxial, and sputtered-film (electrooptic substrate) waveguides. An expression for minimum interaction length to ensure better than 30-dB extinction ratio is derived. The theoretical results are checked with experimental observations from an electrooptic substrate modulator we fabricated, and good agreement is obtained. PMID- 20165221 TI - Image processing by nutation: an analysis. AB - Enhancement of blurred images by nutation involves accumulation of information from displaced replicas of the degraded image. The technique is analyzed theoretically and is found to be equivalent to convolution with the weight distribution assigned to the replicas. The process is shown to improve resolution, correct certain aberrations, or reduce effects of noise, when adjustable parameters are properly selected. Plots of spectrum enhancement and of SNR calculations are presented, and tradeoffs between resolution and noise are discussed. PMID- 20165222 TI - Optical pattern recognition and clustering: Karhunen-Loeve analysis. AB - A Fourier transform gives a first dimensionally reduced description of optical data. But it is not sensitive to statistical variations characterizing class properties and allowing clustering and statistical recognition. A Karhunen-Loeve transform of Fourier spectra leads to a more classifying space: it is shown, through examples of writings, that clustering of optical data (especially recognition of scriptors) is achieved in a 2-D Karhunen-Loeve space. Inner evolution of data belonging to a given class is described in a 3-D KL space, allowing the dating of texts. PMID- 20165223 TI - Boundary layer effects in optical measurements in gas dynamics. AB - A method for including three-dimensional boundary corrections in the analysis of interferograms of two-dimensional flows is described. An effective optical pathlength is calculated using a displacement thickness concept. Expressions and methods for determining the correction to the optical pathlength are given for laminar and turbulent boundary layers in isoenergetic or diabatic flow. An exact expression is derived for the turbulent case and results given showing the correction to be of the order of 10%. PMID- 20165224 TI - Hadamard transform imager and imaging spectrometer. AB - An imager and a spectrometric imager, which achieve multiplexing by the use of binary optical encoding masks, have been built and tested. The masks are based on orthogonal, pseudorandom digital codes derived from Hadamard matrices. The spatial (and/or spectral) data are therefore obtained in the form of a Hadamard transform of the spatial (and/or spectral) scene; computer algorithms are used to decode the data and reconstruct images of the original scene. The hardware, algorithms processing and display facility are described. A number of spatial and spatial/spectral images, obtained in the laboratory, are presented. We present an analysis of the situations for which the multiplex advantage may be gained and of the limitations of the technique. Potential applications of the spectrometric imager are discussed. The spectrometric imager is covered by U.S. Patent 3,720,469 assigned to Spectral Imaging Inc., Concord, Mass. PMID- 20165225 TI - Abnormal glow discharge detection of visible radiation. AB - Extension of abnormal glow discharge detection of electromagnetic radiation to visible wavelengths is observed with inexpensive commercial indicator lamps. The spectral response and mechanisms of detection are discussed and advantages over gas-filled photodiodes noted. Responses from different discharge regions are observed and their implications considered. PMID- 20165226 TI - Light scattering measurements of particle distributions. AB - Specially designed Fraunhofer plane masks are described for passing diffracted flux in proportion to the second, third, and fourth power of the radius of spherical particles. For a distribution of particles, the total volume of the particles can be monitored using the third power mask to produce a signal proportional to the sum of the cubes of the particle radii. Ratios of signals passing through the second, third, and fourth power masks provide statistical parameters of the distribution, such as the volume mean radius, the area mean radius, and the area standard deviation. PMID- 20165227 TI - Thin metal films as applied to Schottky solar cells: optical studies. AB - Thin metal films ( approximately 100 A) have been studied for application to Schottky barrier solar cells (SBSC). Metal films having >55% transmission over the solar spectrum and resistance of 20 ?/? have been applied to Si to form a rectifying contact. A 9.5% sunlight efficient SBSC was produced using 50-A Cr adjacent to the Si for good adhesion and high open circuit voltage and a 50-A Cu overlayer to produce low sheet resistance. Film quality has been related to evaporation rate, metal layer selection, and substrate conditions. Solar cell performance is determined by the transmission and resistance of the thin metal films. Spectral response data show the SBSC to exhibit improved short wavelength sensitivity compared to the p-n Si solar cell. PMID- 20165228 TI - Keystone compensation for image storage systems. AB - Certain types of optical storage devices are preferentially read out with off axis illumination. This method, however, produces keystohing of the projected image, which is a serious disadvantage. In this paper a double Keystone system is analyzed in which a controlled distortion is introduced by the input system to compensate for the distortion by the projection system. The necessary equations to solve the system are presented in terms of a single parameter which makes a simple solution practical. PMID- 20165229 TI - Surface topography by caustics. AB - The optical method of caustics, initially developed for recording abrupt plate slopes created by singularities in elastic stress fields, was extended to incorporate the study of the general case of any type of surface. A universal technique, based on the general theory of caustics developed in this paper, was formulated to study the topography of any surface from its corresponding caustics obtained by illuminating the surface by a parallel, convergent, or divergent light beam. The special case of an axisymmetric mirror with elliptical cross section, whose ellipticity varies from zero to infinity, was studied extensively to show the potentialities of the technique developed. It was shown that the caustics obtained are very sensitive to the particular form of the surface considered. From the procedure developed in this paper it was concluded that the method of caustics can be successfully used to record the topography of any surface with large or infinitesimal slopes. PMID- 20165230 TI - Fraunhofer hologram for image multiplication by amplitude sampling spatial filtering. AB - A method of obtaining Fraunhofer holograms able to reconstruct multiplied images is presented. It consists in using an amplitude sampling spatial filter during or after the hologram recording. PMID- 20165231 TI - Diopters and eigenvalues. PMID- 20165232 TI - NO line parameters measured by CO laser transmittance. PMID- 20165233 TI - Composite prism-grating coupler for coupling light into high refractive index thin-film waveguides. PMID- 20165234 TI - Temporal coherence length and speckle: a simultaneous approach to those problems in holography; authors' reply to comment. PMID- 20165235 TI - Spontaneous laser action in laser isotope separation. PMID- 20165236 TI - Long-path monitoring: advanced instrumentation with a tunable diode laser. PMID- 20165237 TI - Lens structure for giant refractor telescopes. PMID- 20165239 TI - Of optics and opticists. PMID- 20165238 TI - Single-point diamond-turned copper mirrors: figure evaluation. PMID- 20165240 TI - Optical activities in industry. PMID- 20165241 TI - Meeting reports. PMID- 20165243 TI - Patents. AB - 3,771,124; 3,771,129; 3,773,401; 3,776,727; 3,779,631; 3,900,804; 3,903,483; 3,904,986; 3,906,397; 3,906,398; 3,911,276; 3,911,375; 3,911,376; 3,913,033; 3,920,315; 3,921,030; 3,921,136; 3,921,158; 3,922,060; 3,922,071; 3,922,072; 3,922,485; 3,922,524; 3,922,549; 3,923,369; 3,923,382; 3,924,925; 3,924,933; 3,924,934; 3,925,793; 3,926,503; 3,927,254; 3,927,933; 3,930,162; 3,931,515; 3,932,024. PMID- 20165245 TI - Temporal coherence length and speckle: a simultaneous approach to those problems in holography; comment. PMID- 20165244 TI - Wavelength dispersion in a composite volume grating. PMID- 20165246 TI - Bending losses of dielectric slab optical waveguide with double or multiple claddings: theory; correction. PMID- 20165247 TI - Magnetic stripe domain deflector in integrated optics. PMID- 20165248 TI - Optical pulsed ranging: method for improving measurement accuracy. PMID- 20165249 TI - Linear polarimeter with rapid modulation . . . .: comment. PMID- 20165250 TI - Linear polarimeter with rapid modulation ...: authors' reply to comment. PMID- 20165251 TI - Absorption coefficients for fourteen gases at CO(2) laser frequencies. PMID- 20165252 TI - Determining optimal matched filter parameters. PMID- 20165253 TI - Paraxial ray analysis of a cat's-eye retroreflector: author's reply to comments. PMID- 20165254 TI - Optical polishing with titanium dioxide. PMID- 20165255 TI - Bicentennial. AB - Like every other form of knowledge, science is grounded in tradition. The working man of science occupies himself with the knowledge that is handed down to him by his predecessors as surely as the lawyer or theologian. And if the body of scientific knowledge changes and develops more rapidly than legal or religious codes, that is but an added reason for learning something of the conditions of its change and development. This can be done only through history. Science is an organic product, and, like other results of living activity, its true nature can be discerned only in an evolutionary context. Past and present are indissolubly one. PMID- 20165256 TI - Men and milestones in optics. VI: The rise of infrared spectroscopy in the U.S.A. to World War II. AB - This survey reviews the rise of ir spectroscopy in the United States from about 1845 to about 1941 in terms of the discoveries and activities of the individuals who contributed importantly to this field. Generally speaking, the emphasis is on molecular, rather than atomic, spectra and on experimentation, rather than theory. The presentation is chronological with respect to the birth dates of the contributors, and a limited amount of biographical material is included for some of them. Some quantitative information about the institutions where ir spectroscopy was carried on, and for the journals in which the results appeared, is appended. PMID- 20165257 TI - David Alter and other spectroscopists in Western Pennsylvania. AB - The work of a few lesser known American spectroscopists in Western Pennsylvania is briefly reviewed in this paper that is based on a talk given at the Bicentennial Symposium on Analytical Chemistry and Applied Spectroscopy held during the 1976 Pittsburgh Conference. PMID- 20165258 TI - John William Draper 1811-1882 photographic scientist. AB - The scientific life of John William Draper is briefly reviewed and personally reflected upon. PMID- 20165259 TI - Lewis morris rutherfurd 1816-1892. AB - Lewis M. Rutherfurd (1816-1892) was a wealthy amateur practitioner of science, making notable contributions to the optics of astronomy and spectroscopy. He graduated from Williams College at the age of 18 and soon began a career in law. Not long thereafter he was fortunate enough to acquire sufficient wealth through marriage to permit him to pursue scientific activity, for which he had gained interest. He soon became interested in photographing the heavens to obtain quantitative data regarding star motions. A few years later he developed a spectrometer with which he obtained some of the best attainable stellar spectra of the time. Rutherfurd is not widely known because he did not fully report his work; but through correspondence and instrument development he had a profound influence on his contemporaries. He was made a trustee of Columbia College in 1858, and in 1881 he helped to found a department of Geodesy and Practical Astronomy there. PMID- 20165260 TI - Robert williams wood. AB - This short biographical paper supplements, with personal recollections, the record of the life of R. W. Wood, doyen of American physics, as given in DR. WOOD by William Seabrook, and the summary of his work, that appeared in the Journal of the Optical Society of America in 1933 on the occasion of his being awarded the Ives Medal of the Optical Society of America. PMID- 20165261 TI - Ruled gratings and wavelength tables. AB - The development of grating ruling is presented in capsule form, from the first experiment of Rittenhouse in 1876 to the ruling of large echelles under interferometric control. The evolution of wavelength tables, especially in the United States, is described. PMID- 20165262 TI - Image quality prediction: an aid to the Viking Lander imaging investigation on Mars. AB - Two Viking spacecraft scheduled to land on Mars in the summer of 1976 will return multispectral panoramas of the Martian surface with resolutions 4 orders of magnitude higher than have been previously obtained and stereo views with resolutions approaching that of the human eye. Mission constraints and uncertainties require a carefully planned imaging investigation that is supported by a computer model of camera response and surface features to aid in diagnosing camera performance, in establishing a preflight imaging strategy, and in rapidly revising this strategy if pictures returned from Mars reveal unfavorable or unanticipated conditions. PMID- 20165263 TI - Thermal modulation transfer function analysis of pyroelectric device characteristics. AB - The performance characteristics, such as responsivity and spatial resolution, of pyroelectric devices, are calculated by employing a two-dimensional thermal modulation transfer function. The thermal analysis is done for the use of a freely suspended wafer of pyroelectric material, a situation encountered in monolithic detector arrays and pyroelectric vidicon targets. Measurements of the frequency dependence of the voltage responsivity and thermal crosstalk from detector elements, fabricated on LiTaO(3) wafers, are found to be in excellent agreement with the theoretical calculations. It is concluded that for linearly scanned arrays, a minimum scanning velocity, nu(min) = (2pikappa)/a, where kappa is the material diffusivity and 2a the dimension of square array element, is desirable for good resolution in the scanning direction and acceptable levels of crosstalk between elements. The analysis also indicates that operation of pyroelectric vidicons in the chopping mode rather than the panning mode provides for better image quality. PMID- 20165264 TI - Image formation mechanism in the gamma-ruticon. AB - The gamma-ruticon is an image buffer device that has already been described in the literature. We present here the theory of its image formation mechanism and derive the total device image transfer function. We show that we can separate the ruticon imaging mechanism into three distinct and independent parts: the photo conductor mechanism that produces an electrostatic image; the elastomer mechanism that transforms the electrostatic image into a surface relief image; and the optical readout mechanism that translates the surface relief image into a conventional image. The influence of each of these mechanisms on the characteristics of the final image is investigated. PMID- 20165265 TI - Holographic image formation using phase plates with incoherent imaging property. AB - An incoherent image synthesis method using a recently developed grating modulated phase plate has been presented in order to reduce unwanted noise components in the reconstructed images. A study in connection with this method leads us to the analytical derivation of a desirable phase plate with a specified phase sequence. The analytical description presented here, with particular emphasis on obtaining the imaging property in coherent holographic imagery identical to that in incoherent imagery, shows that the derived phase plate enables us to get the reconstructions with far less undesirable irregular intensity fluctuations or noiselike pattern. Some experimental confirmations are given to make sure of the analysis. PMID- 20165266 TI - Position, rotation, and scale invariant optical correlation. AB - A new optical transformation that combines geometrical coordinate transformations with the conventional optical Fourier transform is described. The resultant transformations are invariant to both scale and rotational changes in the input object or function. Extensions of these operations to optical pattern recognition and initial experimental demonstrations are also presented. PMID- 20165267 TI - Nonlinear holographic waveguide coupler. AB - We have shown experimentally that for high exposure, higher order Bragg diffraction by volume holograms is dominated by the nonlinear refractive index modulation and proposed the application of nonlinear modulation to the construction of a high frequency volume-grating waveguide coupler. PMID- 20165268 TI - Graded index fiber waveguides with borosilicate composition: fabrication techniques. AB - Fabrication techniques for graded refractive index fibers with SiO(2)-B(2)O(3) composition are shown to be well controlled. The resulting fibers demonstrate both low loss (less than 3 dB/km) at 900 nm and 1060 nm and low dispersion (260 psec/km including 200-psec/km material dispersion) at 900 nm. PMID- 20165269 TI - Pulse transmission measurements for determining near optimal profile gradings in multimode borosilicate optical fibers. AB - Dispersive differences between B(2)O(3) and SiCO(2) constituents make nonparabolic profiles optimal equalizers of intermodal group delays in fibers with graded B(2)O(3)-SiO(2) cores and uniform B(2)O(3)-SiO(2) cladding. Pulse dispersion measurements were correlated with profile shapes in a systematic study of multimode fibers with near power law gradients. Far field spatial ray filters were used to diagnose impulse response shapes so that new fibers could be fabricated with closer-to-optimal profile gradients. One of the fibers had an alpha approximately 1.77 power law exponent that was nearly optimal for lambda = 907.5-nm wavelength and caused 2sigma = 0.26-nsec/km full rms output pulse spreading. When expected material dispersion effects were deconvolved from the output pulse spreading, the resultant pulse width was approximately 75 times less than the result expected for a comparable step-index fiber. This is the largest pulse width reduction reported yet. PMID- 20165270 TI - Calorimeters for pulsed lasers: calibration. AB - A calibration technique is developed and tested in which a calorimeter used for single-shot laser pulse energy measurements is calibrated with reference to a cw power standard using a chopped cw laser beam. A pulsed laser is required only to obtain the relative time response of the calorimeter to a pulse. With precautions as to beam alignment and wavelength, the principal error of the technique is that of the cw standard. Calibration of two thermopiles with cone receivers showed 2.5% and -3.5% agreement with previous calibrations made by the National Bureau of Standards. PMID- 20165271 TI - Atmospheric visibility measurement by a modulated cw lidar. AB - A modulated cw lidar is described for the remote sensing of atmospheric visibility. An analysis of the system response is given, optimum design parameters are established, and the theoretical capabilities of the new technique are compared with the results of previous work with similar systems. In the new technique, the output from a low power, cw laser is amplitude-modulated and transmitted by a telescope into the atmosphere where scattering and absorption occur. Backscattered light from along the visible beam path is collected and focused on a detector whose output is filtered and fed into a phase discriminator. The phase of the return signal (relative to the source) is directly related to the visibility, wherein lies the basis of this technique. PMID- 20165272 TI - Scattering and absorption of electromagnetic radiation by thin dielectric disks. AB - The scattering and absorption of incident polarized radiation by thin flat circular disks composed of homogeneous isotropic material of complex refractive index is investigated by solving an integral equation for the induced currents. The method is particularly suitable for use in the resonant region where the free space wavelength is neither very small nor very large compared to the radius. Illustrative numerical results for bistatic total, and absorption cross sections for broadside, and edge-on incidence are given, using refractive indices for ice in the ir. PMID- 20165273 TI - Cross-polarized target signature measurements. AB - Cross-polarized laser scattering cross sections were measured for twenty-four different paint samples as a function of scattering angle at four visible krypton laser frequencies. The relative magnitudes of the measured cross sections at the four frequencies were used to define a multispectral signature vector for each paint sample. Measured data confirmed the theoretical prediction that the direction of the cross-polarized multispectral signature vector is independent of the scattering geometry. PMID- 20165274 TI - Spatial coherence of light scattered by media with large correlation length of refractive index fluctuations. AB - The effect of a large spatial correlation in a scattering medium on the spatial coherence of the scattered field is presented. Theoretical curves are calculated for a specific form of the correlation function of the dielectric susceptibility. It is shown that when the spot size of the incoming coherent light is of the same order as the correlation length of fluctuations a sudden increase in the spatial coherence of the scattered light occurs. The method is applied to the study of the correlation length in a liquid crystal cell under a dc electric field. PMID- 20165275 TI - Retroreflectance measurements of photometric standards and coatings. AB - Using a technique that we have developed, the opposition effect (brightening in the retroreflection direction) has been measured for MgCO(3), BaSO(4) paint, and sulfur in the visual region with incandescent illumination and found to be 1.3,1.5, and 1.3, respectively, independent of wavelength. Nextel red, blue, white, and black paints are generally similar. However, in comparison to incoherent illumination, 0.6328-microM laser illumination shows a reduction in diffuse reflectance for angles less than 40 degrees from the incident direction. In addition, the coherent opposition effect may be very large for dark paints. The opposition effect in photometric standards can lead to calibration errors at near opposition and spurious responses in integrating spheres coated with such materials. PMID- 20165276 TI - Fabry-Perot recycling spectrometer. AB - A new type of Fabry-Perot spectrometer has been developed to achieve multichannel operation with recovery of the light that is lost in conventional systems. The light reflected from the interferometer is recycled in a predetermined way using small right angle prisms. When applied to nanosecond light pulses, the new system allows multichannel recording with a single detector. In this paper the realization of the instrument is presented. It has been tested in a prototype version with five channels. More than ten channels should be attainable. Some characteristic properties of the instrument are discussed. PMID- 20165277 TI - Far uv Absolute Intensity Measurement: Calibration Of The Brv Source By An Ion Chamber. AB - Absolute intensity of continuum from the BRV source is estimated in the 30-60-nm spectral range. The detector is an ion chamber filled with argon, and the window is an evaporated film of aluminum. The values of the radiated power show that this simple and inexpensive vacuum uv source can be compared with synchrotron radiation for a number of applications. PMID- 20165278 TI - Thermal radiation shields for radiant coolers. AB - Thermal radiation shields in the form of low-emissivity surfaces spaced on low conductance supports can be used to advantage as a replacement for multilayer insulation in radiant coolers. A view factor between adjacent shields of less than unity increases the insulation factor when the surfaces terminate with an external view. An analytical model that accounts for unequal areas as well as the reduced view factor is shown to be in good agreement with experimental measurements when the end area absorption and emission are small. The modifications to both the analytical model and the experimental evaluation are discussed for the case of significant end absorption or emission. PMID- 20165279 TI - Spectral Reference Detector For The Visible To 12-microM Region; Convenient, Spectrally Flat. AB - A convenient spectral reference detector for the visible to 12-microm region has been developed. The device consists of a large area PVF(2) pyroelectric detector enclosed in a hemispherical light trap. Based on theoretical and experimental evaluations, the detector response is independent of wavelength to +/-1% over this spectral range. PMID- 20165280 TI - Ballistic range model detection system. AB - A model detection system designed for ballistic range use is described in which a fast lens and photomultiplier detect the light reflected and/or refracted by the model as it passes through an incident light beam. The system is capable of detecting transparent as well as opaque models of various compositions with diameters as small as 1/32 in. (0.70 mm) moving with speeds up to 30,000 ft/sec (9.144 m/sec) under atmospheric or vacuum conditions. PMID- 20165281 TI - Solar concentrators with maximal concentration for cylindrical absorbers. AB - The differential equation is derived that describes the reflector of an ideal two dimensional radiation concentrator with an absorber of arbitrary convex shape. For the special case of an absorber with circular cross section, the equation can be solved in closed form if suitable coordinates are used. The effect of absorption at the reflector is considered, and formulas are presented for determining the attenuation of radiation on its passage from aperture to absorber. PMID- 20165283 TI - Three-dimensional information extraction from a coded-scan tomogram. PMID- 20165282 TI - Preparation of high-aspect ratio periodic corrugations by plasma and ion etching. PMID- 20165284 TI - X-ray microscopy with synchrotron radiation. PMID- 20165285 TI - Optical activities in the universities. PMID- 20165286 TI - Patents. AB - 3,775,602; 3,885,856; 3,891,976; 3,892,465; 3,920,312; 3,920,313; 3,920,982; 3,922,062; 3,922,089; 3,922,064; 3,922,092; 3,923,373; 3,923,375; 3,923,376; 3,924,063; 3,924,927; 3,927,253; 3,927,385; 3,930,714; 3,930,728; 3,930,729; 3,930,730; 3,932,745; 3,982,487; B398,551. PMID- 20165287 TI - Of optics and opticists. PMID- 20165288 TI - Alkali halides: their reaction with active oxygen. PMID- 20165289 TI - Dimensional stability of fused silica, Invar, and several ultralow thermal expansion materials. PMID- 20165290 TI - Doppler-shifted reflections of x rays in beamfoil spectroscopy. PMID- 20165291 TI - Adaptive control improves scanning spectrophotometers. PMID- 20165292 TI - Direct measurements of the model of the atmospheric turbulence. PMID- 20165293 TI - Spherical particle populations: approximate analytic relationship between size distribution parameters and integral optical properties; erratum. PMID- 20165294 TI - Holographic strain analysis: extension of fringe-vector method to include perspective; erratum. PMID- 20165295 TI - Optical fibers for dispersion in the time domain. PMID- 20165296 TI - Annealing procedure for self-scanned diode arrays. PMID- 20165297 TI - Resolution for a general two-bar target. PMID- 20165298 TI - X-ray 3-D coded aperture imaging: displaying the heart. AB - The coded aperture imaging technique using an array of x-ray sources for display of three-dimensional objects is applied to a relevant medical object: the coronal vascular system of an isolated heart filled with contrast medium, coded according to a nonredundant point distribution. Arbitrary layers of the heart are decoded by correlation using a holographic system. The course of the vessels in the third dimension can clearly be followed, thus presenting a completely novel tool of medical diagnosis. PMID- 20165299 TI - Far infrared imagery. AB - Active imaging experiments are described in the 300 microm-l mm-region of the far infrared (FIR) spectrum. Transmission data are presented for a wide variety of common materials indicating the range of applicability of FIR imaging to law enforcement or nondestructive testing. The FIR images of several objects are presented, and the practicality of FIR imaging is discussed in light of straightforward improvements that can be made in the simple imaging system employed in these studies. PMID- 20165300 TI - Synthetic interferometric imaging technique for moving objects. AB - It is shown, theoretically and experimentally, that an object traveling through an interference field formed by two coherent point sources can be imaged via synthetic aperture techniques. The time varying signal scattered by the object is electronically detected and then recorded spatially such that the recording is a one-dimensional hologram of the object. The synthetic angular aperture of the hologram is proportional to the angle subtended by the pathlength of the object and is dependent on the geometrical arrangement of the point sources with respect to the position and velocity of the object. PMID- 20165301 TI - W fiber design considerations. AB - The baseband frequency characteristics and the average confinement of light to core properties of a W fiber are analyzed in conjunction with corresponding singly clad (SC) fibers under some ideal assumptions It is found that the bandwidth of a W fiber is almost equal to that of the SC fiber that has no intermediate layer and is much wider than that of the other SC fiber in which the intermediate layer extends to infinity. The average fractional power flow outside the core in a W fiber is drastically reduced in comparison with both SC fibers. Practical design considerations are deduced from a typical example. PMID- 20165302 TI - Tunneling leaky modes in a parabolic index fiber. AB - Single or close to single tunneling leaky modes have been prism coupled into nominally parabolic index SEL-FOC fibers with effective efficiencies on the order of 10%. The mode parameters fit fairly well to an analytical continuation of the solutions to Gloge and Marcatili's equations for parabolic index fibers. The data can also be used in conjunction with the Gloge and Marcatili equations to obtain information about the index profile. PMID- 20165303 TI - Laser resonator: an electrooptically Q-switched Porro prism device. AB - The crossed Porro prism configuration improves the stability of the alignment of the laser resonator; however, the resultant phase shift alters the characteristics of the electrooptical Q-switch. An analysis of the operational characteristics, such as variable outcoupling, extinction ratio, and prelasing boundaries, is presented along with experimental data. An electrooptically Q switched Nd:YAG laser with a crossed Porro prism resonator, which successfully withstands severe physical environments, has been developed and demonstrated. PMID- 20165304 TI - Refractive-index profile and physical process determination in thick gratings in electrooptic crystals. AB - A method for determining the refractive index profile of thick phase gratings in linear electrooptic crystals is presented. This method also determines the effective photovoltaic electric field and the relative contributions of diffusion and drift during hologram recording. The method requires only a knowledge of the modulation ratio during hologram recording and the fundamental and the higher order diffraction efficiencies of the grating. As an illustration of the method, the refractive index profile, the effective photovoltaic field, and the relative contributions of diffusion and drift are determined from experimental measurements for a lithium niobate holographic grating. PMID- 20165305 TI - Infrared absorption in chemical laser window materials. AB - The optical absorption has been measured at DF and HF wavelengths in a wide variety of transparent materials that show promise for use as windows on high powered chemical lasers. These measurements, which were made using DF-HF chemical laser calorimetric methods, will be discussed in terms of surface and bulk contributions to the total absorption as well as in terms of the total absorption measured for each type of material studied. Materials studied include the alkaline earth fluorides, alkali halides, Ge, Si, ZnSe, MgO, Yttralox, and A1(2)O(3). PMID- 20165306 TI - Photoelastic modulator for the 0.55-13-microm range. AB - An improved photoelastic modulator (PEM) employing two piezoelectric transducers and incorporating a new ir zmc selenide (ZnSe) optical element is described. The 0.64-cm thick PEM is capable of obtaining quarter-wave retardation from 0.55 microm to 13.0 microm. Previously no single, high quality, low static strain PEM element existed for this wavelength range. We have also constructed other PEM's using optical elements composed of fused quartz, calcium fluoride, and KRS-5. The important optical and mechanical properties are measured and compared. PMID- 20165307 TI - The rayleigh: interpretation of the unit in terms of column emission rate or apparent radiance expressed in SI units. AB - The rayleigh, originally defined as a unit to express the total column light emission rate [10(10) photons sec(-1) (m(2)column) (-1)] can equivalently be defined as a unit for apparent photon radiance ((1/4)pi 10(10) photons sec(-1) m( 2) sr(-1)). The selection of the appropriate definition will depend upon the physical situation and the interests of the user. The applicability of the unit for expressing the quantitative measurement of all extended light sources, including optically thick media, is both handy and valid. PMID- 20165308 TI - Refractive indices of zinc sulfide and cryolite in multilayer stacks. AB - The refractive indices at 633 nm of ZnS and cryolite in multilayer stacks have been determined in the vacuum environment by measurements of the transmittance extrema during deposition. Estimates of the inhomogeneity of index as a function of layer thickness are given. The method gives average index measurements: (1) every lambda/4 for the first ZnS layer, (2) for an initial thickness as small as lambda/16, and thereafter every lambda/4 for the second layer, cryolite. The results are used to monitor the layer thicknesses of ZnS-cryolite multilayer stacks by theoretically predicting the transmittances of the system at the termination of each layer. PMID- 20165309 TI - Radiative transfer: a technique for simulating the ocean in satellite remote sensing calculations. AB - A method is presented for computing the radiative transfer in the ocean atmosphere system which does not require detailed knowledge of the optical properties of the ocean. The calculation scheme is based on the observation that the upwelling radiance just beneath the sea surface is approximately uniform, which implies that the effect of the ocean can be simulated by a lambertian reflector just beneath the sea surface. It is further shown that for aerosol concentrations up to ten times the normal concentration, the radiative transfer in homogeneous and vertically stratified atmospheres (of the same optical thickness) is nearly identical. Examples indicating the applicability of these results to the remote sensing of ocean color from space are discussed in detail. PMID- 20165311 TI - Sample space for particle size and velocity measuring interferometers. AB - An analysis is presented of some parameters that can affect the sampling characteristics of interferometers designed to measure particle size and/or velocity. In particular, it is demonstrated how particle size and electronic instrumentation affect the sampling capacity of the instrument. PMID- 20165310 TI - Remote measurement of wind speed using a dual beam backscatter laser Doppler velocimeter. AB - Measurements of atmospheric wind speeds at distances up to 60 m using a dual beam laser Doppler velocimeter with digital autocorrelation analysis, an unfocused argon ion laser (0.10-0.35 W) at 5145 A, and a 20-cm collecting telescope are reported. Criteria affecting the field performance of this system and an expression giving the power and range dependence of the data accumulation rate are presented. Major improvement of the system's performance can be made by focusing the laser beams and properly restricting the field of the collecting telescope. The potential of this technique for remote wind measurement at ranges of several hundred meters is discussed. PMID- 20165312 TI - Multiple scattering in atmospheric clouds: lidar observations. AB - The contribution of multiple scattering in lidar backscattering from clouds has been investigated using a ruby laser at 694 nm. The depolarization of an incident linearly polarized signal is measured with a multichannel lidar receiver. An analysis is presented whereby this information can be utilized to measure the multiple scattering in clouds in which single scattering retains the incident linear polarization. Experimental data are presented for cumulus clouds and for ground level fog, and the results are compared with some recent theoretical computations. PMID- 20165313 TI - Electromagnetic scattering from a spherical polydispersion of coated spheres. AB - The volume averaged cross sections for extinction, scattering, absorption, and radiation pressure along with the elements of the phase matrix were computed for a spherical polydispersion of water coated carbon particles. The wavelength used was 4910 A. Two cases were considered. For one we held the thickness of the water coating constant over the polydispersion, while the parameter q = r(0)/r, (the ratio of core radius to total radius) was varied. For the subsequent case we held q constant over the polydispersion, while the thickness of the coating varied. The results show that there are large differences in both the intensity and degree of polarization between dry and wet aerosols. Also interference phenomena can occur, which demonstrate that the assignment of an average refractive index to aerosols can be misleading and can lead to erroneous results. PMID- 20165314 TI - Integrated optical matrix multiplier. PMID- 20165315 TI - Birefringent coupler for integrated optics: comment 2. PMID- 20165316 TI - Propagation of ir light in flexible hollow waveguides: erratum. PMID- 20165318 TI - Waveguide H(2) Raman laser. PMID- 20165317 TI - Laser focal shift monitor. PMID- 20165319 TI - SiC, a new material for mirrors. 1: High power lasers; 2: VUV applications. PMID- 20165320 TI - Remote intensity fluctuation measurements with a laser Doppler radar. PMID- 20165321 TI - Doppler signal processing: a new technique. PMID- 20165323 TI - Microscopic color schlieren system using a wedge-type interference filter. PMID- 20165322 TI - Thermal conductance of bonding layers in HgCdTe (PC) detector arrays. PMID- 20165324 TI - Infrared holograms recorded at 10.6 microm and reconstructed at 0.6328 microm. PMID- 20165325 TI - Mode-locked, cavity-dumped laser design considerations. PMID- 20165326 TI - Polarization flipper for infrared laser beams. PMID- 20165327 TI - Far ir laser with metal-dielectric waveguide to observe the Stark effect. PMID- 20165328 TI - Focusing method used in laser damage experiments. PMID- 20165329 TI - Optoacoustic measurements of water vapor absorption at selected CO laser wavelengths in the 5-microm region. PMID- 20165330 TI - Attenuation of 33-microm laser radiation by atmospheric water vapor. PMID- 20165331 TI - Light scattering by a spheroidal particle: errata. PMID- 20165332 TI - Hollow rectangular dielectric waveguides: errata. PMID- 20165333 TI - Optical fiber wave splitting coupler. PMID- 20165334 TI - Concentrated-type directional coupler for optical fibers. PMID- 20165335 TI - Fiber optics transmittance: effect of cladding absorption. PMID- 20165336 TI - Patents. AB - 3,831,104; 3,879,109; 3,879,681; 3,883,819; 3,886,481; 3,886,482; 3,892,466; 3,912,380; 3,915,550 3,917,409 3,918,071; 3,931,594. PMID- 20165337 TI - Whiteness: photometric specification and colorimetric evaluation. AB - Though basic problems of the perception of whiteness are as yet unsolved, this paper attempts to survey the present state and the requirements of industrial whiteness measurement. Generic formulas with adjustable parameters for the evaluation of whiteness and tint are presented. PMID- 20165338 TI - Diffuse reflectance from a finite blood medium: applications to the modeling of fiber optic catheters. AB - The scattering and absorption of light by randomly oriented, discretely scattering, red blood cells imbedded in a homogeneous plasma medium can be described by the P1 approximation to the one-speed transport equation, where the cells have the dual role of anisotropic sources for first scattering events and of scattering and absorption sites for subsequent scattering events. Equations for diffuse reflectance defined for a finite size receiver in the plane of a normally incident cylindrical photon beam are derived and compared with experimental data to fundamentally justify the basic sending-receiving characteristics of a fiber optic catheter model. A model of the fiber optic catheter used for the spectrophotometric measurement of oxygen content in blood is developed from the theory and compared with experimental results to further substantiate the theoretical approach. PMID- 20165339 TI - Optical transmission and reflection properties of a pile of lossy plates. AB - Assuming no interference, recursion relations are derived, tabulated, and plotted, for the case where the number of plates is an integer power of two to form a set of graphs from which the transmission and reflection coefficients of a pile of identical, parallel, lossy plates can be obtained. Approximate closed form expressions, which are valid for any number of plates, are also derived and evaluated, giving an alternate analytical solution to the problem. PMID- 20165340 TI - Infrared bulk and surface absorption by nearly transparent crystals. AB - We present an analysis of laser calorimetric data that deduces both the bulk and the surface absorption in a single run. The method involves use of long rod geometry combined with an analytical solution of the heat equation for the temperature distribution in a sample that is heated both internally and on the surfaces. Bulk and surface absorption coefficients, heat transfer coefficient, and thermal diffusivity appear as parameters; the last is treated as known, and the thermal rise curve is fitted to the three others. The solution obtained is valid at all points and times, and measurement of the temperature during and after laser heating at different points therefore narrows the possible fit considerably. Examples illustrating the method are presented for ZnSe, CaF(2) NaF:Li, NaCl, KBr, and KC1 at 2.7 microm, 3.8 microm, and 10.6 microm. Surface absorption is found to be dominant in all cases. PMID- 20165341 TI - Remote measurements of ambient air pollutants with a bistatic laser system. AB - The ambient air pollutants ozone, nitric oxide, and ethylene have been monitored in the Pasadena area with a bistatic ir laser apparatus. These pollutants were measured with a differential absorption technique using selected wavelengths in the 9.5-microm, 5.2-microm, and 10.5-mum regions, respectively. The transmitted laser radiation was detected using both direct and heterodyne detection techniques. In the direct detection case cube corner retroreflectors provided the return, and the heterodyne detection responded to scattered radiation from various rough surfaces, ranging from 400 m to 1.9 km in distance from the apparatus. Significant departures from ambient background concentration levels were noticed in the region near a local freeway during periods of moderate and heavy traffic. PMID- 20165342 TI - Infrared continuum absorption by atmospheric water vapor in the 8-12-microm window. AB - We have carried out a detailed analysis of several long pathlength transmission measurements in the 8-12-microm atmospheric window in order to determine the extinction coefficient due to the water vapor continuum. Our results indicate that three modifications to the current LOWTRAN atmospheric transmission model are required. The first two corrections involve an improved fit to the pure water vapor continuum absorption together with the elimination of the atmospheric broadened continuum term. Finally, and most critically, a strong measured temperature dependence must be included in the water vapor continuum absorption coefficient. For pathlengths ranging from 10 km to 50 km, failure to incorporate these corrections can lead to errors in the computed transmission ranging from factors of 2 to more than 10,000. PMID- 20165343 TI - Infrared multidetector spectrometer for remote sensing of temperature profiles in the presence of clouds. AB - An infrared multidetector spectrometer with channels in the 4.3-microm and 15 microm CO(2) bands for the remote sensing of temperature profiles in the presence of clouds is described. Results obtained from aircraft flights in July 1975 over ocean sites under various conditions of cloudiness demonstrate the capability of the dual frequency technique to recover surface temperatures to an accuracy of +/ 0.5 K in the presence of up to 90% cloud cover. PMID- 20165344 TI - Active autofocusing using an apertured Gaussian beam. AB - A method of autofocusing a Gaussian beam with obscuration onto a small target, down range and on the beam axis, is presented. For a source with a sinusoidally time varying focus (dither) the temporal spectra of the reflected signal can be very accurately calculated for ranges where Fresnel approximations are valid. For such ranges certain spectral components in the reflected signal undergo significant phase and amplitude changes while passing through true focus. The closed loop control strategy naturally evolves from these properties. PMID- 20165345 TI - Temperature analysis from multispectral infrared data. AB - A technique is introduced that uses the ratios of the outputs of a multicolor ir sensor to analyze the flux from an object to determine the true temperature of the object and the relative amounts of the flux that are due to self-emission and to reflection from external sources. PMID- 20165346 TI - Remote sensing of particle size and refractive index by varying the wavelength. AB - This is a numerical study to explore the feasibility of determining particle size and refractive index from the backscattered signal combined with a signal differentially scattered at one other angle. The wavelength of the radiation is varied over a broad range (in the particular example chosen, from lambda = 0.5 micro to 1.5 micro). Three signatures of the particle size and refractive index are chosen: (1) deviation of the radiance from the inverse fourth power of the wavelength; (2) the first maximum of the variation of the angular intensity function with wavelength; and (3) the first two maxima of the variation of the phase difference of the amplitudes of the polarized radiances with wavelength. For monodisperse systems, these signatures will permit estimation of particle size in the fortyfold range of a = 0.033-1.29 micro (for m = 1.50). PMID- 20165347 TI - Fiber waveguides: a novel technique for investigating attenuation characteristics. AB - Light from a pulsed GaAs injection laser is coupled into a glass fiber via a taper coupler. The time dependence of the light backscattered within the fiber as the pulse travels down the waveguide is recorded. From these data the total loss may be determined, as well as an estimate of the scattering and mode mixing characteristics of the fiber. PMID- 20165348 TI - Multimode optical fibers: steady state mode exciter. AB - The steady state mode power distribution of the multimode graded index fiber was measured. A simple and effective steady state mode exciter was fabricated by an etching technique. Its insertion loss was 0.5 dB for an injection laser. Deviation in transmission characteristics of multimode graded index fibers can be avoided by using the steady state mode exciter. PMID- 20165349 TI - Optical fiber eigenvalue equation: plane wave derivation. AB - The asymptotic form of the eigenvalue equation for optical waveguides of circular cross section is derived using only plane wave concepts, i.e., phase changes, Fresnel's and Snell's laws. Both step and parabolic refractive index profiles are treated using this method. PMID- 20165350 TI - Thin periodic structures in photoresist: fabrication and experimental evaluation. AB - In this paper we discuss the experimental verification of an empirical photoresist model presented previously. Photoresist grating depths predicted by the model are found to be in good agreement with those obtained from diffraction efficiency measurements. Total rates of field decay alpha(T) obtained from a theoretical analysis of the photoresist grating coupler predicted by the model are also in good agreement with values measured by two independent experimental techniques. These results indicate the usefulness of the model in fabricating periodic devices in photoresist. PMID- 20165351 TI - Scattering from a localized inhomogeneity in a cladded fiber optical waveguide. 1:radiation loss. AB - An exact analysis using the Green's function formulation of the problem of scattering from a localized inhomogeneity inside a cladded fiber optical waveguide is carried out. The analysis yields radiation loss that agrees well with that evaluated from the infinite-medium approximation. However, the spatial distribution of the radiation loss, i.e., the radiation pattern, differs markedly from that predicted by the infinite-medium approximation. The same analysis also permits the study of mode conversion due to scattering to be reported separately. PMID- 20165352 TI - Annular converging wave cavity. AB - A new type of resonator that generates an annular geometric mode by use of spherical mirrors has been developed. The four-element cavity consists of an external confocal unstable resonator with a double-sided 45 degrees coupling mirror and a flat feedback mirror. The flat feedback mirror is placed on the plane wave side of the confocal cavity to form an annular mode between the feedback mirror and the coupling mirror. A plane annular wave (matched to an annular gain medium) is fed back into the unstable resonator that alternately converges and diverges to produce a diverging annular output beam. Experiments were performed on a cw HF laser. Observations of mode patterns on the flat feedback mirror and the convex mirror and of far-field beam quality were made. Far-field measurements indicated near-diffraction-limited beam quality for a peak on-axis intensity mode on the convex mirror. A nearly uniform annular mode was observed on the flat feedback mirror. PMID- 20165353 TI - Eigenmodes of optical resonators with mirrors having Gaussian reflectivity profiles. AB - A general procedure for calculating all the eigenmodes of optical resonators with mirrors having Gaussian reflectivity profiles is described. The eigenmodes are expanded in terms of the freely propagating Her-mite-Gaussian beams. The expansion enables one to apply well known matrix techniques to this kind of systems. The eigenvalues found determine the eigenfrequencies and the mode discrimination properties of such resonators. PMID- 20165354 TI - Laser scanning microscope for pyroelectric display in real time. AB - The pyroelectric probe technique is now capable of inspecting a 100 x 100-microm TGS area in a few seconds with a 2-microm limit of resolution. The method is described in detail, and a calculation of the pyroelectric signal is presented. The longitudinal growth of a cylindrical domain is mathematically simulated and also the variation of pyroelectric signal at domain boundary. These calculations are in good accordance with experiment. With a 200-kHz chopping frequency only a thin layer of the crystal surface is inspected (thermal diffusion length l = 0.64 microm), while the lateral limit of resolution is given by the laser spot radius (R(1) = 1 microm). It is possible to decrease this limit by using a smaller laser spot, but the chopping frequency ought to be increased. PMID- 20165355 TI - Off-axis unstable laser resonator: operation. AB - An experimental investigation of a novel unstable laser resonator configuration is reported. The purpose of the novel configuration is to maximize the area that can be illuminated with uniform intense flux by a given laser device. This is accomplished by displacing the optical axis of the resonator to one edge of the optical cavity. The results indicate that the change causes no loss of device output power and has little effect on the beam quality. Additional experimental results are presented indicating the sensitivity of resonator performance to misalignment of the off-axis resonator. PMID- 20165356 TI - Cusp shape reflectors to pump disk or slab lasers. AB - A two-dimensional ray tracing program is used to predict the performance of lighthouses to pump disk or slab lasers. The model is tested by comparing calculations with the results of light intensity and fluorescence measurements. Pumping efficiency and uniformity are investigated as functions of lamp spacing in a configuration employing cusp shape and plane back reflectors. It is found that doubling the number of lamps from an arrangement that provides optimal coupling brings an improvement in pumping of typically 60%. PMID- 20165357 TI - Power-limited glass amplifiers: an optimized design. AB - The optimum design of power-limited glass amplifiers may be determined by simultaneously minimizing the cost and the growth of beam perturbations leading to beam degradation and glass damage. For some simple examples, these constraints lead to a well defined laser configuration. PMID- 20165358 TI - Holographic interferometry applied to the measurement of displacements of the interior points of transparent bodies. AB - Utilizing the light scattering property of transparent media, holographic interferometry is applied to the measurement of displacement at the interior planes of three dimensional bodies. The use of a double beam illumination and the introduction of a fictitious displacement make it feasible to obtain information corresponding to components of displacement projected on the scattering plane. When the proposed techniques are invoked, it is possible to eliminate the use of a matching index of refraction fluid in many problems involving symmetrically loaded prismatic bodies. Scattered light holographic interferometry is limited in its use to small changes in the index of refraction and to low values of relative retardation. In spite of these restrictions, a large number of technical problems in both statics and dynamics can be solved. PMID- 20165359 TI - Aliasing error in digital holography. AB - The use of the discrete Fourier transform in digital holography introduces aliasing error in the reconstructed image. Spectrum shaping to reduce dynamic range may also result in a serious increase in aliasing error. The effect of aliasing in digital holography is analyzed. It is proposed that the bandwidth be constrained when shaping the image spectrum. Experimental results show the approach to be quite effective. PMID- 20165360 TI - Color-encoded focused image holograms. AB - Color-encoded focused image holograms can be reconstructed in a white light projection system to form high fidelity color images. Use of frequency encoding leads to a simple, inexpensive optical reader similar to a conventional microfiche reader. The holograms can be formed as surface-relief, phase holograms in transparent media and can be replicated by embossing into thermoplastic film. Applications include micropublishing and related fields, where they offer a considerable cost advantage over conventional color microfiche. The characteristics of color reproduction are discussed; and the hologram recording, replication, and readout are described. An optimized set of parameters is derived, which gives colorimetry comparable with that of color television and a measured screen luminous emittance of 190 lx using a standard 150-W projection lamp and x15 magnification. PMID- 20165361 TI - Laser speckle interferometry for plate bending problems. AB - A method is proposed whereby the spatial speckles created in front of a plate with an optically rough surface when illuminated by a coherent laser beam is used to generate slope contour fringes. This is done by photographing the speckles contained in a parallel plane in front of the plate before and after deformation via double exposure. The resulting speckle interferogram is then optically Fourier transformed to yield the fringe pattern of slope contours. It is shown that the method is analogous to the Ligtenberg reflection moire method with a grating of continuously variable pitch and orientation. The method can be applied to plates made of almost any material. PMID- 20165362 TI - Strain analysis by one-beam laser speckle interferometry. 1: Single aperture method. AB - A two-dimensional analysis of a double-exposed speckle pattern as created by illuminating a plane surface with a beam of laser light is presented with the role played by the aperture illumination function described in detail. Between exposures, the surface is to undergo in-plane general deformation. Two approaches (one whole field and one pointwise) are presented to delineate from the speckle pattern the three Cartesian components of strain at each point in the field. An analogy is drawn between the whole field approach and the classical in-plane moire method. Quantitative examples are included to demonstrate the validity of the methods. PMID- 20165363 TI - Optical properties of multilayer overcoated aluminum films in the uv (2000-2500 A). AB - Optical properties of high reflectance, low absorptance coatings consisting of aluminum films overcoated with multilayers of Al(2)O(3) and MgF(2) are reported in the far ultraviolet. Coating design considerations and preparation techniques are described and the potential of such reflectors for multiple-beam interferometry is considered. Transmission characteristics of experimental Fabry Perot type interference filters constructed from these Al-multilayer coatings are discussed. PMID- 20165364 TI - Side band Ronchi test. AB - Using holographic techniques a Ronchi ruling with carrier may be generated which has the property of giving highly defined Ronchi fringes, instead of the diffraction-blurred fringes produced in the normal test. This procedure can be generalized to include the case of circular fringes. PMID- 20165365 TI - Geometric parameters of moire fringes. AB - The incoherent illumination moire phenomenon between a periodic and a quasiperiodic structure is examined by the use of the spatial frequency analysis of the resultant transmittance. This approach has an advantage in that it completely explains all the fringe parameters without considering the averaging effect of the detecting system. We obtain the basic equation of the original moire pattern due to the beat phenomenon exclusively, without any external factors like, for example, the influence of the observing system. From the basic equation, we derive the fringe profile equation representing the moire fringe shape and the fringe equation expressing the spacing, the orientation, and the local displacement of the moire fringes. The fringe profile equation is experimentally verified. The sensitivity enhancement by the fringe multiplication method is readily interpreted by the use of the derived fringe equation. PMID- 20165366 TI - Fraunhofer diffraction patterns from uniformly illuminated square output apertures with noncentered square obscurations. AB - Theoretical Fraunhofer diffraction patterns are presented for uniformly illuminated square apertures with noncentered square obscurations. The energy within a given subtended solid angle in the far field is calculated. It is shown that the cornered-off-axis obscuration provides much more far-field energy in a given spot size than the centered obscuration for the same clear aperture area and total energy, for example, 82% more far-field energy in the first Airy square for 50% obscuration, thus providing superior performance for practical systems. PMID- 20165367 TI - Image quality in an optical system operating in partially coherent light: effect of parabolic motion. AB - Results of investigations on an optical system performance as affected by parabolic image motion have been presented in graphic form. The analysis has been performed using Schell's theorem, which occurs in the theory of partial coherence, under the assumption of scalar diffraction theory. Diffraction figure broadening along the direction of motion has been plotted for besinc and Gaussian forms of coherence functions across the circular aperture. Results of the present paper in case of besinc correlation have been shown to be identical with the diffraction images of uniform incoherent bright circular disks in the presence of parabolic motion. Hence the analysis of the present paper is also useful for persons engaged in work concerning aerial reconnaissance etc. PMID- 20165368 TI - Holographic representation of space-variant systems: system theory. AB - System theory for holographic representation of linear space-variant systems is derived. The utility of the resulting piecewise isoplanatic approximation (PIA) is illustrated by example application to the invariant system, ideal magnifier, and Fourier transformer. A method previously employed to holographically represent a space-variant system, the discrete approximation, is shown to be a special case of the PIA. PMID- 20165369 TI - Counting quasicircular particles by an optical-digital method. AB - A technique is presented that enables the particle-size analysis of quasicircular particles to be made. A coherent optical system is used to generate the diffraction pattern of the particle population to be analyzed, and a digital computer is used to process the information in the pattern. A similar technique has been used earlier, with success, to count circular particles of varying diameters. A scene containing three classes of particles is analyzed, and results are furnished. PMID- 20165370 TI - Acoustooptic TeO(2) tunable filter using far-off-axis anisotropic Bragg diffraction. AB - Noncollinear acoustooptic tunable filters using TeO(2) crystals are described. An anisotropic Bragg diffraction is studied applying simple design expressions to a tilt type in which an acoustic wave is launched a little off the [110] axis. Tuning property, filter bandwidth, angular aperture, required acoustic power, deflection angle, divergenceless configuration, and rapid spectrum scanning have been discussed. These filter properties have been confirmed with measurements using three kinds of filter devices: a basic type, an acoustically enhanced type, and a large angular aperture type. A 5-A bandwidth at 4000 A was obtained by slow scanning. A 32-A separation at 4000 A was observed by a rapid scanning of 0.5 msec throughout the visible region with an extremely low electric drive power. PMID- 20165371 TI - Quantum counter photodetectors: a new design. AB - A new design for quantum counter cells is described that uses total internal reflection to minimize depth-of-penetration and polarization effects. This new cell is compared to a standard 1-cm thick quantum counter cylindrical cell. Solutions of 5 g/liter of rhodamine B chloride in ethylene glycol were used in both cells. The fluorescence emission from the cell was found to be significantly less polarized and also less dependent on excitation wavelength. PMID- 20165372 TI - Slow-scan television system. AB - An unconventional, highly sensitive camera system is described, suitable for silicon or amplified silicon (SIT or EBS) vidicons. Features are a variable field size and sweep rate and a low-noise video amplifier. Used on a 91-cm telescope, it can detect 15th magnitude stars with the silicon vidicon. With an SIT tube, the limit is 17 on the 91-cm and 20.5 on the 4-m telescope. The system is briefly compared with an I-SIT camera. PMID- 20165373 TI - SNR in photocounting images of rough objects in partially coherent light. AB - Image irradiance distributions from objects illuminated with partially coherent, quasi-monochromatic light, viewed against a spatially uniform background and received with a photosensitive detector are analyzed. A general expression for the SNR at the detector output is obtained as a function of the coherence of the illuminating light, the object surface roughness, the width of the telescope point spread function, and the aperture and integration time of the detector. The expression is evaluated for several limiting cases of coherence of illumination and of object surface roughness. PMID- 20165374 TI - Lens systems: aplanatic anastigmatic two and three element. AB - In some optical applications, such as thermal imagery, chromatic aberration, correction may not be necessary. The various forms of aplantic doublet are compared with respect to high order aberrations. A set of equations is described, which generates aplanatic anastigmatic two-element single aspheric systems with any specified lens separation and back focus and, as a corollary, three-element systems with two elements in contact. The method is applied to germanium Petzval, telephoto, and inverse telephoto systems. PMID- 20165375 TI - Aberrations of a sequence of conic mirrors. AB - An interesting class of optical systems consists of conic mirrors arranged so that each mirror shares at least one focus with the optically adjacent mirrors. This paper presents simple results for several of the aberrations largely independent of the details of the configuration. Results are presented for sine law violation and third order astigmatism when the images are located at the focii of the mirrors and for astigmatism and distortion when the pupils are located at the foci. In both cases the system is equivalent to a single conic mirror having the same magnification and focal length. It is shown that there are configurations for which both the images and the pupils lie at foci, and for these all the above results apply. The exact shape of the image surface is obtained for such a system in which all the mirrors are parabolas. PMID- 20165376 TI - Statistical band model analysis and integrated intensity for the 11.8-microm band of CFCI(3). PMID- 20165377 TI - Laser feedback; its effect on laser frequency: addendum. PMID- 20165378 TI - Merit function as an aid in optical tolerancing. PMID- 20165380 TI - Meeting reports. PMID- 20165379 TI - Line spread function notation. PMID- 20165381 TI - Patents. AB - 3,711,181; 3,818,373; 3,854,044; 3,858,965; 3,858,977; 3,868,175; 3,919,662; 3,926,504; 3,928,814; 3,919,664; 3,928,816; 3,928,820; 3,928,821; 3,931,592; 3,936,147; 3,931,589; 3,936,152; 3,937,562; 3,938,883; 3,941,452; 3,942,874; 3,942,875; 3,942,876; 3,942,877. PMID- 20165383 TI - Luminescent greenhouse collector for solar radiation. PMID- 20165382 TI - Ultraviolet response of semitransparent multialkali photocathodes. PMID- 20165384 TI - Refractive indices of powdered materials: improvement of the method. PMID- 20165385 TI - Dual beam interferometer with autoequalization of path length. PMID- 20165386 TI - Asymptotic parameter realms and scintillation scales for extended sources in turbulence. PMID- 20165387 TI - Spectral covariance of scintillations. PMID- 20165388 TI - Modular optics mode converter. PMID- 20165389 TI - Mode conversion in bent step index multimode fibers. PMID- 20165390 TI - Single mode optical fiber pickoff coupler. PMID- 20165391 TI - Optical interference coatings. AB - The OSA topical meeting on Optical Interference Coatings held in February 1976 at Asilomar is briefly reported on, the state of the art surveyed, and future directions recognized. PMID- 20165392 TI - New materials for optical thin films. AB - New materials for optical thin films are presented. Zirconium oxide, titanium oxide, cerie oxide, and hafnium oxide in the form of black tablets or cones of various sizes for the electron beam evaporation technique were developed. These materials are oxygen depleted and give an uniform melt during the evaporation to give reproducible evaporation characteristics. A new mixture consisting of ZrO(2) and ZrTiO(4) for the production of high index layers is described. The evaporation conditions of the substance and the properties of thin layers of the mixture are given. The refractive index is 2.15 at 500 nm. The transmittance range is 0.4-7 microm. The layers are optically homogeneous. The application of layers of this mixture in a three-layer antireflection coating is described. PMID- 20165393 TI - Optical film materials and their applications. AB - This paper, presented at the February 1976 OSA Topical Meeting on Optical Interference Coatings, discusses the chemical aspects of the production of thin films and the packing density effects in dielectric films. Useful materials are briefly surveyed, current trends are reviewed, and some examples of applications are given. PMID- 20165394 TI - Composite material films: optical properties and applications. AB - The optical properties of the composite systems Ag-SiO(2), Si-SiC, and Ge Al(2)O(3) are compared with the predictions of the Maxwell-Garnett and the effective medium theories. Only the Maxwell-Garnett theory predicts the characteristic optical features of granular metals-a red shift relative to the pure metal in the plasma resonance and a dielectric anomaly. In the case of Si SiC, the observed red shift in the transverse optical phonon frequency is too small to allow one to discriminate between the two theories. In the case of the Ge-AI(2)O(3) films, both theories are in good agreement with the experimental results for the optical constants near the absorption edge. The use of composite films for photothermal conversion and other optical applications is discussed. PMID- 20165395 TI - Reflective multilayer coatings for the far uv region. AB - Progress in the field of reflective multilayer coatings for the wavelength region between 50 A and 2000 A is reviewed. All the coatings contain absorbing materials, absorption losses are minimized by positioning strongly absorbing materials into the nodes of the standing wave inside the coating. Above lambda = 1200 A, ideal coatings with a reflectivity approaching 100% are theoretically possible; the theoretical predictions have been confirmed for coatings up to six layers at wavelengths around 2000 A. Below lambda = 1000 A, no absorption-free material is available that can be used as a spacer layer to cover the antinodes of the standing wave field. This limits the theoretically obtainable reflectivity. However, even at the shortest wavelength a reflectivity of 30% is still possible. Experimental results have been obtained for wavelengths between 100 A and 200 A for coatings up to nine layers. Discrepancies between experiment and theory can be explained as due to insufficient knowledge of the optical constants of the films used. Extensive future work on the optical constants of materials and their dependence on film thickness and deposition conditions is required for further improvement. PMID- 20165396 TI - Electric fields in multilayers at oblique incidence. AB - The recursion equation for electric field strength in a multilayer thin film system yields only the tangential component of the field. This paper discusses the relationship between the tangential component, the peak value, and the time average value of the total electric field for the two planes of polarization. This approach leads to easy understanding of the discontinuous field strength for p polarization and the relationship between the peak and time average field strengths. The results are applied to a polarizing beam splitter of the type used with high energy lasers. PMID- 20165397 TI - Ultraprecise thermal expansion measurements of seven low expansion materials. AB - We summarize a large number of ultraprecise thermal expansion measurements made on seven different low expansivity materials. Expansion coefficients in the -150 300 degrees C temperature range are shown for Owens-Illinois Cer-Vit C-101, Corning ULE 7971 (titanium silicate) and fused silica 7940, Heraeus-Schott Zerodur low-expansion material and Homosil fused silica, Universal Cyclops Invar LR-35, and Simonds Saw and Steel Super Invar. PMID- 20165398 TI - Refractive indexes and temperature coefficients of germanium and silicon. AB - The refractive indexes and their variations with temperature for silicon and germanium have been measured over the 95-298-K and 2.5-12-microm ranges. Data are given for the refractive index that are in reasonable agreement with those of previous investigators. For dn/dT the values are independent of wavelength and are approximately 1.5 x 10(-4) (K)(-1) and 4.0 x 10(-4) (K)(-1) for silicon and germanium, respectively. PMID- 20165399 TI - Temperature dependence of the refractive index of alkaline earth fluorides. AB - The temperature coefficient of the refractive index dn/dT of CaF(2), SrF(2), and BaF(2) single crystals is measured by a laser interferometric technique at a number of frequencies over temperatures ranging from 20 degrees C to 85 degrees C. Although dn/dT is found to display little dispersion between 0.6328 microm and 3.39 mum, its magnitude shows a slight increase with temperature. A possible origin of the latter effect is discussed. PMID- 20165400 TI - Theoretical intensity uniformity from an anti-Gaussian collimating lens. AB - A plano-convex absorption glass lens proposed earlier by Ih [Appl. Opt. 11, 694 (1972)] for transforming a Gaussian intensity beam into a uniform collimated beam was analyzed theoretically on the basis of the actual paths of off-axis light rays through the lens. An analysis provided by Ih did not take into account the actual light paths. The present analysis shows that a simple spherical convex curvature results in a transmitted intensity varying less than 3% for an f/5 lens. The analysis was applied to the geometry of a lens constructed by Ih, and the corresponding theoretical maximum intensity variation is in agreement with intensity measurements reported by him. PMID- 20165401 TI - Chain reaction pulsed HF laser: a simple model. AB - With economical, yet accurate, predictions of pulsed H(2) + F(2) laser performance as a goal, a rate equation model is formulated that includes only the dominant kinetic mechanisms in the active medium. Effects of model assumptions are examined, and predictions of pulse characteristics are compared with results from a more comprehensive model presented in an earlier study. Computing costs for the present model are less than 1% of those for the comprehensive model; moreover, the present model yields laser pulse characteristics that are consistent with experiment and in excellent agreement with the more comprehensive model. In order to illustrate the model's capability, the effects of initial gas mixture composition and cavity threshold on laser performance are studied over the regime of practical interest. Some possible extensions and applications of the model are also discussed. PMID- 20165402 TI - Variable-aperture calorimeter for an unstable resonator. AB - A new technique for measuring the output power from a cw edge-coupled unstable resonator has been developed and applied to a cw DF laser. An internal-cavity calorimeter was used that permits measurement of output power with a variable rectangular mode geometry while containing the radiation inside the resonator. The variable aperture calorimeter absorbing scraper (VACAS) device consists of an absorbing copper plate calorimeter assembly, which replaces the 45 degrees output coupling mirror of a conventional edge-coupled unstable cavity. A rectangular hole in the plate of variable width w and height h defines a rectangular mode of variable width Mw and height Mh within the geometric optics approximation, where M is the magnification. Two important applications of VACAS are (1) the determination of the optimum mode geometry for a cw diffusion-type chemical laser where there is significant variation in gain across the unstable resonator mode and (2) the determination of the power tradeoff between mode width and the number of folds in a folded unstable resonator configuration. PMID- 20165403 TI - Intracavity dye laser spectroscopy as a gain probing technique. AB - A He-Ne discharge tube with gain at 6328 A , a flashed ruby rod with gain at 6943 A, and a brightly fluorescing flame were each inserted into the cavity of a flashlamp-pumped dye laser. The influence of the two gain media on the dye laser differs significantly, apparently due to their dissimilar saturation characteristics. Refractive index effects were also observed. The flame experiment demonstrates the efficacy of the intracavity technique as a simple relative population probe. PMID- 20165404 TI - Electron energy spectrum in laser-induced multiphoton ionization of atoms. AB - The energy distribution of the electrons resulting from the multiphoton ionization of air molecules by a focused ruby laser beam has been measured by a time-of-flight method. There appear to be two distinct contributions to the energy spectrum, one from electrons of mean energy below 1 eV and one from electrons of mean energy around 10 eV. Possible reasons for this are discussed. PMID- 20165405 TI - Laser beam characteristics using dc-induced second harmonic generation. AB - Previous measurements of electric field induced second harmonic generation indicated that the confocal parameter for a laser beam as calculated from the second harmonic intensity profile was in disagreement with that calculated from the measured beam diameter. In this paper, we show that this discrepancy is caused by the departure of the beam from the pure TEM(00) mode. We expand a distorted beam in terms of the component modes by using the experimental beamscan and calculate the second harmonic profile using this expansion. This calculational procedure is found to be consistent with experimental observations. PMID- 20165406 TI - Modulation contrast and coherence theory. PMID- 20165407 TI - Matched filter processing of raster-scanned images: analysis. AB - The performance of the matched filter technique on TV raster-scanned images has been analyzed and simulated with two types of input object. The output correlation is a function of bandwidth used for the matched filter. For a Nyquist bandwidth-matched filter, the output correlation does not decrease substantially (only about 3-4%) as the object becomes smaller. If the matched filter bandwidth becomes large enough to cover the total object spectrum, the correlation starts to decrease substantially when the number of scan lines per resolved image element becomes less than four. PMID- 20165408 TI - Equidensitometry by coherent optical filtering. AB - A new and simple method has been developed for fabrication of multilevel halftone screens that have proved useful for generation of equidensity contours by means of coherent optical filtering. Up to ten contours of constant brightness have been generated on a picture by coherent optical filtering of a single halftone copy of that picture. The possible application of this method to optical analog to-digital conversion using a single halftone photograph is discussed. PMID- 20165409 TI - Acoustooptic interaction for most effective deflection of unguided light via acoustic surface waves. AB - The light deflection efficiencies of surface acoustic waves propagating on YZ LiNbO(3) crystal are examined for different geometrical configurations. The optimum one is found to be the back reflection geometry, with S polarization of the impinging light beam, where a figure of ~16% of the total deflected to undeflected light intensity ratio is easily attainable with a surface corrugation amplitude of about 50 A. PMID- 20165410 TI - Photoacoustic methods for measuring surface and bulk absorption coefficients in highly transparent materials: theory of a gas cell. AB - Researchers seek improved ways to measure the surface absorption and the bulk absorption coefficients of highly transparent materials. Procedures are presented here by which one may determine separately the surface absorption and the bulk absorption coefficients. For the case in which a laser beam modulated at angular frequency omega passes through the weakly absorbing windows of a gas cell containing a nonabsorbing gas, the temperature profiles in the cell windows and the temperature and acoustic pressure or stress profiles in the gas have been calculated. These calculations indicate that for sufficiently low frequencies and high ambient gas pressure, enough heat transfers from the cell windows to the gas to produce a detectable acoustic pressure signal at angular frequency omega in the gas. These calculations also enable us to state the necessary measurements for determining the surface and bulk absorption coefficients. Measuring the acoustic stress amplitude at the fundamental and higher harmonic frequencies and measuring the phase shifts of the frequency components of the acoustic stress with respect to the modulated laser beam give sufficient data by which one can determine the surface and bulk absorption coefficients. Numerical examples for a representative laser glass and air (nitrogen) are given. PMID- 20165411 TI - Moire topography by means of a grating hologram. AB - A new method of moire topography is described. This encompasses two processes: recording of the deformed grating projected onto a 3-D object, and posterior development of contour moire from the record. The development of contour moire is realized by projecting a linear grating onto a photographic print of the record of the deformed grating, using a photographic enlarger. By this new method, a technique for describing a 3-D object by means of the slope of facets composing the object is made possible. PMID- 20165412 TI - Pressure-scanned Fabry-Perot interferometer for nightglow measurements: its construction and operation. AB - A very flexible system for pressure-scanning a Fabry-Perot interferometer is described. The pressure in the interferometer chamber is altered in small steps, allowing the frequency of transmission to stay fixed during the integration time in contrast to continuously scanning systems, which give a distortion of the line profile for long integration times. The system is highly linear, and the pressure scanning range, the pressure change per step (i.e., the resolution), and the integration time per channel are variable within wide limits. PMID- 20165413 TI - Corner cube interferometer using extended sources. AB - The corner cube interferometer employing extended sources requires very good transverse alignment of the retroreflector if the optical path difference is not to vary across the field of view. It is shown in this paper that this problem can be eliminated by the addition of a plane mirror to the interferometer forming a double pass system. For a single pass instrument, it is shown that the sensitivity to alignment errors may be exploited to obtain a powerful method of monitoring in three dimension the motion of a point otherwise inaccessible. Details of the expected performance of this method are derived. PMID- 20165414 TI - Diffraction by M centers in KCI. AB - Diffraction efficiencies as high as 15% have been measured for thick plane wave holograms consisting of grating arrays of oriented M centers in additively colored KCl. The values obtained agree well with calculated estimates based on the induced birefringence and dichroism. PMID- 20165415 TI - Highly efficient light coupling from GaAlAs lasers into optical fibers. AB - A new technique is reported for highly efficient light coupling from GaAlAs lasers into step or graded index fibers. The cladding of the fiber is etched to reduce the fiber diameter to nearly the core diameter. Then the fiber end is cut and dipped in a low melting, transparent material to form a lens. This technique is reproducible and is applicable-contrary to a flame melting process-to all types of multimode fibers. We measured 80% coupling efficiency to a 20-m long, cabled graded index fiber (silica, NA = 0.13) with a glass lens on its etched end. PMID- 20165416 TI - Solid-dielectric compound parabolic concentrators: on their use with photovoltaic devices. AB - Prototype solid dielectric compound parabolic concentrators have been made and tested. By means of the geometry and refractive properties of a transparent solid they provide a technique for increasing the power output of silicon solar cells exposed to the sun by an amount nearly equal to the increase in effective collecting area. The response is uniform over a large angle which eliminates the necessity of diurnal tracking of the sun. The technique can be applied to the construction of thin panels and has the potential for significantly reducing, their cost per unit area. PMID- 20165417 TI - Skew ray results for condensing light pipes and reflective baffles. AB - Simple criteria are presented for determining whether a general skew ray will strike an absorber at the exit of certain condensing light pipes. Several designs for ideal reflective baffles are also given and their skew ray properties discussed. PMID- 20165418 TI - Performance limitations imposed on optical waveguide switches and modulators by polarization. AB - Crosstalk in optical waveguide switches/modulators caused by having two polarizations simultaneously present is studied in this work. This situation is expected to arise when fiber optical transmission lines are coupled to integrated optical circuits. Modulator/switch performance is found to be strongly affected by having two propagating polarizations. Conditions on device design are found that minimize the polarization sensitivity of switches/modulators, making them suitable for use with fiber optic transmission lines. PMID- 20165419 TI - Determination of aerosol droplet size and concentration from simple transmittance measurements. AB - A method is described, and equations are developed for the determination of aerosol droplet size and concentration based upon simple transmittance readings. Data and experimental results are presented for water, but the method is applicable to water solutions or other materials as well for which complex indices of refraction are known at specific wavelengths in the visible or the ir. An equation is given for transmittance at 0.63 microm (He:Ne laser) which allows the interrelationship between water cloud or fog droplet size and concentration to be determined. A second equation permits specific values of concentration and droplet size to be determined knowing transmittance values at one or more ir wavelengths located in regions of spectral absorption by the liquid comprising the droplets. For water, data are given for ir wavelengths of 8.5 microm, 10.5 microm, and 12.57 microm, and specific determinations of droplet size and concentration are tabulated based upon these observation wavelengths. In addition, a composite of wavelengths in the 8-13-microm window is presented so that aerosol determinations can be made simply by comparing transmittances at 0.63 microm to those taken broadband at 8-13 microm by devices operating in the latter region without wavelength-scanning capability. For water drops, the method produces results of about +/-10% precision. The method is based upon the constancy of the product of extinction coefficient and droplet diameter in Mie calculations for water at 0.63 microm and is applicable for droplet sizes of from 6 microm to at least 30 microm. Determinations for droplets as small as 2 microm can be made at +/-30% precision. PMID- 20165420 TI - Photographic aureole measurements and the validity of aerosol single scattering. AB - A refined photographic system for solar aureole measurements is described in which a neutral density filter occulting disk blocks the direct sunlight. Experimental data for solar aureoles are presented for several wavelengths from 309 nm to 640 nm and solar zenith angles of up to 88 degrees . The results are compared with a modified single scattering calculation that includes corrections for Rayleigh multiple scattering, attenuation by ozone, ground reflection, and spherical atmosphere geometry and, at 309 nm, are compared with a Monte Carlo multiple scattering calculation. Useful analytic functions for the aerosol size distribution and for the molecular, ozone, and aerosol height distributions are given. Our near sunset calculation represents an intermediate step between single scattering and full multiple scattering for a Rayleigh-ozone-aerosol atmosphere. We show that aerosol multiple scattering may not be ignored at large solar zenith angles and long wavelengths. PMID- 20165421 TI - What property of a haze is determined by light scattering? 2: Nonuniform particles of arbitrary shape. AB - We generalize our earlier result on forward scattering of light by polydisperse hazes of uniform spheres to include nonuniform particles of arbitrary shape. The forward scattering determines a (polarizability)(2) weighted mean mean-square radius of the haze. PMID- 20165422 TI - Spatial coherence properties of light scattered by disclinations in a liquid crystal. AB - The correlation length of optical inhomogeneities near disclinations, produced by ultrasound in a liquid crystal cell, is measured as a function of the applied ultrasonic power by determining the spatial coherence of scattered light. Some preliminary indications about the behavior of disclination properties as a function of the ultrasonic power are obtained. PMID- 20165423 TI - Satellite measurement of mass of Sahara dust in the atmosphere. AB - The mass of particulates in a vertical column of dust outflow from northwestern Africa is derived with the aid of satellite measurements of nadir radiance. The measurements were made from the Landsat-1 satellite. Measurement accuracies are discussed. A radiative transfer model with a known mass of dust is developed to account for the measured radiance values. The model is constructed with knowledge of a few values of optical parameters measured from a surface ship. The accuracy of the model is discussed. The resulting mass of particulates smaller than 10 microm radius in a vertical column is 1.6 g m(-2). PMID- 20165424 TI - Water vapor absorption of carbon dioxide laser radiation. AB - An optoacoustic detector or spectrophone has been used to perform detailed measurements of the absorptivity of mixtures of water vapor in air. A C(12) O(2)(16) laser was used as the source, and measurements were made. at forty-nine different wavelengths from 9.2 microm to 10.7 microm. The details of the optoacoustic detector and its calibration are presented, along with a discussion of its performance characteristics. The results of the measurements of water vapor absorption show that the continuum absorption in the wavelength range covered is 5-10% lower than previous measurements. PMID- 20165425 TI - Radiation in the earth's atmosphere: its radiance, polarization, and ellipticity. AB - The complete radiation field including polarization is calculated by the matrix operator method for a model of the real atmosphere. The radiance, direction and amount of polarization, and ellipticity are obtained at the top and bottom of the atmosphere for three values of the surface albedo (0, 0.15, 0.90) and five solar zenith angles. Scattering and absorption by molecules (including ozone) and by aerosols are taken into account together with the variation of the number density of these substances with height. All results are calculated for both a normal aerosol number and a distribution that is one-third of the normal amount at all heights. The calculated values show general qualitative agreement with the available experimental measurements. The position of the neutral points of the polarization in the principal plane is a sensitive indicator of the characteristics of the aerosol particles in the atmosphere, since it depends on the sign and value of the single scattered polarization for scattering angles around 20 degrees and 160 degrees for transmitted and reflected photons, respectively. This, in turn, depends on the index of refraction and size distribution of the aerosols. The neutral point position does not depend appreciably on the surface albedo and, over a considerable range, depends little on the solar zenith angle. The value of the maximum polarization in the principal plane depends on the aerosol amount, surface albedo, and solar zenith angle. It could be used to measure the aerosol amount. The details of the ellipticity curves are similar to those for scattering from pure aerosol layers and, thus, are little modified by the Rayleigh scattering. Aerosols could be identified by their characteristic ellipticity curves. PMID- 20165426 TI - Detection of optical pulses: the effect of atmospheric scintillation. AB - Refractive index inhomogeneities within the path traversed by a pulse of optical energy cause a nonuniform energy distribution across the wavefront of the pulse known as scintillation. It has been shown that this energy variation has a log normal distribution, characterized by a variance sigmaE(2), which is a function of the degree of atmospheric turbulence. In this paper, we derive an expression for the detection probability of an optical pulse that has scintillation with a log normal variance sigmaE(2) in the presence of normally distributed optical noise characterized by variance sigmaN(2). The result is a convolution of scintillation and receiver detection statistics. The results of several calculations using different SNRs are presented graphically. PMID- 20165427 TI - Refractive-turbulence profiles measured by one-dimensional spatial filtering of scintillations. AB - Stellar scintillations, when appropriately analyzed, yield information about the turbulence throughout the atmosphere. We describe an instrument involving a 36-cm telescope and an on-line minicomputer that provides, after 20 min of observation, the refractive-turbulence profile of the atmosphere. The height resolution is sufficient to divide the atmosphere into about four independent regions. The principal limitation to greater accuracy and resolution is the nonstationary behavior of the atmosphere during the 20-min observing period. PMID- 20165428 TI - Phenomenological model of scintillation. AB - A model that characterizes the atmospherically induced scintillation on a signal from an exoatmospheric source is presented. A major conclusion of the analysis is that the reduction in the level of experimentally measured scintillation for targets of increasing subtense is as much influenced by the viewing geometry and isoplanatism of the atmosphere as the angular subtense of the source. Elements of the theory have been verified by comparing the model's predictions with experimental data. PMID- 20165429 TI - In situ photometric observations of angular scattering from atmospheric aerosols. AB - A large polar nephelometer was flown on a high-altitude balloon to 26.6 km over New Mexico in June 1974 just before the incursion of Fuego volcanic dust. Angular scattering intensity and polarization observations depict the vertical structure of absolute optical parameters and, as a result, the distribution of atmospheric aerosols. An uncommon phenomenon was detected at 25 km: a stratospheric cloud near the San Andres mountains. These data are compared to findings from a previous flight in November 1970 in which significant altitudinal variability in the atmospheric scattering phase function was evident. PMID- 20165430 TI - Laser beam scintillation beyond the turbulent atmosphere: a numerical computation. AB - The extended Huygens-Fresnel formulation for propagation through turbulence is used to examine scintillation of a finite laser beam. The method is demonstrated analytically for propagation beyond a weak Gaussian phase screen. A numerical integration technique is used to extend the results to a more realistic turbulence model. Results are compared with existing Gaussian beam propagation theory. PMID- 20165431 TI - Effects of random path fluctuations on the accuracy of laser ranging systems. AB - The effects of turbulence induced pathlength fluctuations on the accuracy of single color and two color laser ranging systems are examined. Correlation and structure functions for the path deviations are derived using several proposed models for the variation of C(n)(2) with altitude. For single color systems, random pathlength fluctuations can limit the accuracy of a range measurement to a few centimeters when the turbulence is strong (C(n)(2) ~ 10(-13) m(-2/3)), and the effective propagation path is long (>10 km). Two color systems can partially correct for the random path fluctuations so that in most cases their accuracy is limited to a few millimeters. However, at low elevation angles for satellite ranging (<20 degrees ) and over long horizontal paths, two color systems can also have errors approaching a few centimeters. PMID- 20165432 TI - Spectrophone measurements of infrared laser energy absorption by atmospheric dust. AB - A new method of quantitatively measuring the absorption of atmospheric dust or other particulate matter is described. The system uses a differential spectrophone KBr pellet technique and should ultimately prove useful from the uv to the far ir wavelength region. Preliminary measurement data on atmospheric dust, quartz, and soot are presented at 1.06-microm, 9.6-microm, and 10.6-microm wavelengths. PMID- 20165433 TI - Absolute integrated intensity for the 3.44-microm NO(2) band. AB - The absolute integrated intensity for the 3.44-microm NO(2) band was measured using a curve of growth technique and was determined to be 78.9 +/- 1.6 cm(-1) (atm cm)(-1)(296 K) at 296 K at the 95% confidence level. Comparison with the previous measurement showed the present determination to be about 25% higher. PMID- 20165435 TI - High resolution monochromator for the VUV radiation from the DORIS storage ring. AB - The unique properties of the DORIS storage ring at DESY as a synchrotron radiation source are exploited for high resolution spectroscopy in the vacuum ultraviolet. We describe a new experimental set up with a 3-m normal incidence monochromator for wavelengths between 3000 A and 300 A (4 100. In this region the method yields results with an accuracy of about 5%. PMID- 20165483 TI - Mie scattering, Maxwell Garnett theory, and the Giaever immunology slide. AB - The physical mechanism whereby adsorbed layers of transparent material cause a visual darkening of thin indium films is investigated. The indium is observed to be in the form of discrete islands. The wavelength of minimum optical transmission through the indium film does not vary proportionately with the size of the indium island size, as would be expected if Mie scattering were the dominant optical effect. Instead, this wavelength depends on the fractional volume of the indium film occupied by the indium islands themselves, in the manner predicted by Maxwell Garnett theory. PMID- 20165485 TI - Refractive-index profile of an optical fiber: its measurement by the scattering pattern method. AB - This paper describes a new method (the scattering-pattern method) for determining the refractive-index profile in an optical fiber from its scattering pattern for a normally incident laser beam. The proposed method is applicable to an arbitrary profile and is nondestructive. The spatial resolution is high, and the accuracy is good when the fiber diameter and the refractive-index variation are relatively small. The drawback is that a large number of data are required; however, this difficulty has been overcome by using the automated measuring system described in this paper. The profile obtained shows good agreement with design data. PMID- 20165486 TI - Multimode optical waveguides with graded refractive index: theory of power launching. AB - The power launching into multimode optical fibers with any profile of refractive index is analyzed by means of the geometrical optics. First two formulas of the numerical aperture are obtained, one including and the other excluding the contribution of leaky skew rays. Each one of these two numerical apertures has a certain domain of application, and the launching efficiencies from incoherent sources into optical fibers are calculated in both cases. Useful formulas and plots of launching efficiency for a few refractive index profiles are given. Finally the power losses due to source-fiber coupling errors (separation, displacement, or misalignment) are evaluated, and an interesting effect of virtual lengthening of the fiber is found. PMID- 20165487 TI - Leaky modes in graded index optical fibers. AB - Leaky mode attenuation coefficients for graded index optical fibers are derived using the WKB approximation. For the case of a parabolic index profile, the attenuation coefficients for explicitly evaluated and used to calculate the leaky mode contribution to near field and attenuation measurements. Failure to observe the expected leaky mode contributions in several graded index fibers is interpreted as evidence for the presence of an additional loss mechanism. PMID- 20165488 TI - Mode conversion losses of randomly bent, singly and doubly clad waveguides for single mode transmission. AB - Mode conversion effects take place when a dielectric optical guide is bent and its curvature varies along the guide. This paper considers and compares such conversion losses of singly and doubly clad slabs (adopted as analogs of corresponding fibers) for single mode transmission. It is shown that the conversion loss of a W-type slab is much smaller than that of a singly clad slab, provided that the beamwidths of both guides are equal. This property is the consequence of the wider mode spacing of the W-guide. PMID- 20165489 TI - Optical waveguide cable connection. AB - The requirements for a practical optical waveguide cable connector are reviewed. The sources of loss in fiber-to-fiber coupling, both intrinsic (fiber-related) and extrinsic (connector-related), are discussed and quantified. A multiple channel, single-fiber-per-channel connector concept, termed the overlap connector, is then described, with emphasis on the relationship of its individual design features to practical connector requirements. Experimental results with prototype overlap connectors are presented, showing that a mean extrinsic loss of less than 0.6 dB is obtained, with a standard deviation of 0.1 dB, as a result of intermating different connector halves (twelve combinations). Losses from fiber distortions are shown to account for 0.2 dB of this extrinsic loss, and, since these distortion losses are specific deficiencies of the prototype hardware (correctable in a straightforward manner), this overlap connector hardware is taken as demonstrating an extrinsic loss of 0.4 dB. Variations in joint loss and the possibility of damage to waveguides resulting from remating are also discussed. The standard deviation of joint loss obtained in a remating test is 0.09 dB. PMID- 20165490 TI - Light beam propagation along helical bands of parabolic index optical fibers. AB - The present paper analyzes the propagation behavior of light beams along parabolic index optical fibers for the cases where the center axes of the fibers are deformed along helical bends, which are caused when several optical fibers are twisted into a bundle for the purpose of cabling. The analysis is based on geometrical optics and is limited to the case where the center axes of the fibers are bent along a double helix, which arises when two fibers are twisted into a bundle, and the two bundles thus obtained are entwisted once more into a cable. It is also assumed that the center axis of the cable thus established is curved in a circular bend with a constant curvature. Ray equations for this case are derived, and their solutions are studied in detail theoretically and numerically. As a result, conditions are obtained for the occurrence of the divergence phenomenon of the beam trajectory as well as for the matched incidence of light beams to minimize the undulation amplitude of beam trajectories. Moreover, it is clarified that whether the two helices composing the double helix are twisted in the same or opposite directions has somewhat different effects upon the conditions for the divergence phenomenon and the matched incidence as well as the propagation behavior of light beams. Some problems with the application of the present cabling technique to parabolic index optical fibers are also discussed. PMID- 20165491 TI - Mode coupling by circular apertures. AB - When a freely propagating light beam passes through a limiting aperture into an interferometer a set of the interferometer modes is coupled even when the beam is matched to the interferometer. The incoming beam and the modes of the interferometer are assumed to be described by Gaussian Laguerre functions and the limiting aperture to be circular and on axis with the modes. The coupling coefficients are obtained for an arbitrary incoming mode and arbitrary expanding set. Simpler solutions are found for an incoming Gaussian beam by choosing the expanding set matched to the incoming beam parameters. PMID- 20165492 TI - Positive-permittivity-metal cladding: its effect on the modes of dielectric optical waveguides. AB - If the real part epsilon1' of the complex permittivity epsilon(1) = epsilon1' - jepsilon(1)" of the metal cladding of a dielectric optical waveguide is positive, well-guided modes can be supported by the dielectric film even if epsilon(1)' is greater than the permittivity of the dielectric film. The attenuation and phase characteristics and the field distributions of the guided modes are discussed for a number of guiding structures, and it is shown that far from cutoff most of the modes exhibit similar properties to those modes supported by the film when the metal cladding has a negative epsilon(1)'. The low order TM modes exhibit different characteristics due to a coupling between them and the surface wave supported by the metal: dielectric interface. This guide has an additional interesting characteristic in that the phase velocities of the TE(0) and TM(0) modes can be made equal. PMID- 20165494 TI - Effects of edge-rounding on geodesic lenses. AB - The effects of rounding of the edge on the focal properties of spherical depression geodesic lenses are calculated. The focal length for paraxial rays is increased very slightly for slight rounding. For greater rounding, a decrease in focal length results from the increased optical path. Edge-rounding has very little effect on lens aberrations. PMID- 20165493 TI - Light modulation by electrochromism. AB - Dyes change their absorption curve when exposed to an electric field. The conditions under which this effect can be made large enough for application to light modulation are discussed. Theoretical expectations correspond with recorded curves of a test sample. PMID- 20165495 TI - Real-time noncontacting distance measurement using optical triangulation. AB - Real-time noncontacting distance measurement systems are constructed using photogrammetric principles. The system is used to measure a distance between two points specified by sharp visible contrast change under optical illumination. Tests of the system indicate that it can measure the distance with a repeatability of better than one part in 10(4). PMID- 20165496 TI - Integration over cylindrical luminous volumes using a calibrated piston source. AB - A method is described for measuring the absolute light output from a gas or liquid in a cylindrical tube. The apparatus used is simple to build and use. The technique results in measurements of unusually high accuracy and sensitivity. The volume integration, often done with the aid of a mathematical model, is replaced by the physical measurement made by moving a calibrated luminous disk along the axis of the empty cylindrical tube. PMID- 20165497 TI - Lensless matched filter: operating principle, sensitivity to spectrum shift, and third-order holographic aberrations. AB - Synthesizing a Fresnel zone plate inside a Vander Lugt matched filter (MF) results in a lensless matched filter (LLMF) that is space-invariant from the point of view of vignetting apertures. In practice the unfocused output components of the LLMF do not degrade its SNR. A LLMF displacement appears as a combined shift of its filter and lens components. The third-order holographic aberrations of the MF and LLMF, and particularly their root-mean-square astigmatisms, are compared via computer-generated plots. PMID- 20165498 TI - Coupling efficiency between light pipes of different dimensions. AB - An expression for the transmitted fraction of the uniform and parallel radiation incident upon the coupler between two rectangular light pipes of different physical dimensions is derived. It is a function of the pipe dimension ratio and the angle of the incident radiation. It is shown that for radiation nearly parallel to the pipe axis, it is possible to design a coupler for any pipe dimension ratio so that all the radiation incident upon it is transmitted by it. Design curves for various incidence angles and the pipe dimensions are presented. PMID- 20165499 TI - Coupling between two cylindrical light pipes: a design. AB - An expression for the transmission characteristics of a conical coupling is derived. This expression is shown to be useful for choosing an optimum coupling length. PMID- 20165500 TI - Scene power spectra: the moment as an image quality merit factor. AB - Coherent optical power spectra of random scene imagery can become a powerful image evaluation technique when properly analyzed. A normalized low order moment of power spectra is set forth as a good image quality merit factor, which also has the advantageous property of taking out the spectrum analyzer's aperture effect. In addition to the relevant theory, experimental results with this merit factor of power spectra are given that demonstrate a high degree of correlation with subjective quality rankings, as well as the accurate assessment of optimum focus. PMID- 20165501 TI - Digital profile to contour converter and display. AB - A solid state scan converter is described that converts a family of profiles derived from photogrammetrically processed stereo imagery into a family of orthogonally projected contours for the purpose of display, editing, planning, and data processing. Transformations of the display of profiles such as rotation and scaling are discussed along with a stereo version of the system suitable as an on-line verification system in which orthogonally projected contours are superimposed upon the original stereo photos from which the profiles were derived. PMID- 20165502 TI - Photographic image intensification by autoradiography. AB - Images on developed photographic emulsions can be significantly intensified by making the image silver radioactive and exposing a second emulsion to this radiation. Because the print, an autoradiograph, reproduces the original with significant increases in density and contrast, the method can be used to enhance underexposed emulsions and to increase the limits of photographic detection. This paper reports a new, practical chemical method for activating the silver, using thiourea labeled with sulfur-35, a process convenient for use in photographic laboratories. Speed increases of 13 and contrast increases of 18 were achieved with Kodak Plus-X film in this initial phase. PMID- 20165503 TI - Single strip diffraction: comparison of Kirchhoff theory and geometrical theory with the exact solution in the limit of small glancing angle and width; perpendicular polarization. AB - A comparison is made between approximations using the geometrical theory of diffraction (GTD) and Kirchhoff theory and the exact solution using Maxwell's equations for the case of Fraunhofer diffraction of electromagnetic radiation incident upon a long, thin, perfectly conducting strip with the electric field vector polarized perpendicular to the strip axis. Strip widths from approximately 0.3lambda to 3lambda are considered. Glancing angles of incidence are taken from 4 degrees to 90 degrees . Irradiances are compared as a function of diffraction angle in the region on the same side of the strip as the incident radiation. PMID- 20165504 TI - Improvement in birefringent filters. 4: The alternate partial polarizer filter. AB - A design for a birefringent filter is proposed in which alternate polarizers are partial polarizers. Calculated performance characteristics of alternate partial polarizer filters (APP) are compared with those of Lyot and contrast element Lyot filters. These calculations show that the APP design has significant advantages in both transmission and profile shape. Using pulse techniques, partial polarizer systems are shown to be a natural evolution from the standard Lyot and contrast element Lyot systems. The APP filter using achromatic waveplates discussed in earlier papers of this series has been used to construct a universal alternate partial polarizer filter. This filter has a measured full width at half-maximum (FWHM) of 0.09 A at 5500 A and a transmission in polarized light of 38%. It is tunable from 4500 A to 8500 A. The measured characteristics of the filter agree well with theoretical predictions. PMID- 20165505 TI - Ideal concentrators for finite sources and restricted exit angles. AB - Design procedures for ideal radiation concentrators are described which are applicable to finite sources and/ or restricted exit angles. Finite sources are relevant for second stage concentrators which collect and further concentrate radiation from a primary focusing element (mirror or lens) in a manner similar to the field optic element in a telescope. Restricting the exit angle is useful for improving the optical efficiency of solar collectors by eliminating grazing angles of incidence of the absorber. It also serves to extend the useful range of angular acceptance values available from solid dielectric concentrators that function by total internal reflection. Concentrators of this type can be used to construct highly efficient radiation traps (spectrally selective filters). PMID- 20165506 TI - Silicon vidicon spectrometry and its infrared capabilities for solar research. AB - A rapid-scanning silicon vidicon spectrometer is described; its sensitivity extends from 300 nm to 1080 nm, where even at that wavelength it has enough sensitivity to allow observation under eclipse conditions of a pair of forbidden spectral lines from twelve-times ionized iron that are sensitive indicators of the electron density in the solar corona. Past observational work on these ir lines is reviewed, and our vidicon observations made during the 1973 total solar eclipse are discussed. The vidicon target, the scanning procedure, and the advantages of the spectrometer are described. At the 1973 eclipse, the 1074.7-nm line was detected and an upper limit set for the 1079.8-nm line at a height of 1.4 solar radii. The resultant limit to the ratio of intensities gives electron densities in agreement with those derived from other methods and is consistent with observations made at lower heights; this indicates that the only previous eclipse observation of the ratio at this height was contaminated by scattered light. Our 1973 eclipse observations were limited by the high ambient temperature of the vidicon, by the less-than-optimum match of the focal ratios of the telescope and spectrometer optics, and by problems with the pointing during totality. These difficulties can be overcome, and the silicon vidicon spectrometer will be useful in both eclipse and noneclipse solar observing to map the coronal ir spectrum and also to study the [Fe XIII] ir and interlocking uv lines. PMID- 20165507 TI - Detection of atmospheric aerosol flow using a transit-time lidar velocimeter. AB - A cross-correlation analysis of lidar echoes from an artificial tracer transported through two closely spaced atmospheric scattering volumes provides a remote measurement of the wind speed along the line joining the two volumes. A pulsed nitrogen transit-time lidar has been developed and used to make these measurements in real-time intervals of approximately 4 sec. The wind speed measurements are compared with conventional anemometer data. An extension of this technique to natural aerosol concentrations that exploits the laser wavelength dependence of the system SNR is discussed. PMID- 20165508 TI - Atmospheric temperature profiles from lidar measurements of rotational Raman and elastic scattering. AB - Criteria for optimizing system parameters in the lidar measurement of atmospheric temperature profiles from simultaneous Raman and elastic returns by use of a three-channel system are discussed and summarized. It is shown that the filter constraints of earlier techniques are removed thereby eliminating the need for the high rejection capability of spectrometers in this type of measurement. Also, SNR is improved, and a greater freedom in the choice of optimum Raman filters is demonstrated. PMID- 20165509 TI - Silicon photodiode as a detector in the rocket-borne photometry of the near infrared airglow. AB - The application of a silicon P-I-N photodiode to the dc measurement of low levels of near ir radiation is described. It is shown that the threshold of signal detection is set by the current amplifier voltage noise, the effect of which at the output is determined by the value of source resistance of the photodiode. The photodiode was used as the detector in a compact interference filter photometer designed for rocket-borne studies of the airglow. Flight results have proved the instrument's capability to provide measurements sufficiently precise to yield an accurate height profile of the (0-0) atmospheric band of O(2) night airglow at lambda762 nm. PMID- 20165510 TI - Infrared radiation extinction sensitivity to the modified gamma distribution parameters for haze and fog droplet polydispersions. AB - The volume extinction coefficients at 1.03 microm, 3.70 microm, and 10.38 microm, normalized to that at 0.50-microm wavelength, are calculated as a function of the shape parameters of the modified gamma size distribution using parameter ranges appropriate for haze and fog droplet polydispersions. Based on the sensitivity of the normalized volume extinction coefficients on the shape parameters, different procedures are proposed for utilizing the extinction features in giving form to the size distribution corresponding to the various evolutionary stages of the water droplet population. Such a methodology presents applicability in the field of fog forecast. PMID- 20165511 TI - Enhanced focal-plane irradiance in the presence of thermal blooming. AB - The use of multiple transmitter beams is shown to significantly increase the peak focal-plane irradiance that can be achieved in the presence of thermal blooming. Computer simulation studies of the beam propagation problem show over a factor of 2 increase in the irradiance of a single beam and a factor of 9 increase when three coherent beams are focused on the same target spot. Preliminary experimental results with three mutually noncoherent, nonoverlapping beams are in qualitative agreement with the computer simulation. PMID- 20165512 TI - Interaction of TEA CO(2) laser radiation with aerosol particles. AB - Some effects arising from the interaction of TEA CO(2) laser pulses with individual aerosol particles are described. The time dependence of thermal radiation emitted from aerosol particles heated with pulses from a TEA laser is shown to be related to the size of individual particles and to the distribution of sizes within an aerosol. Charge and mass changes have been determined for single particles on absorption of 10.6-microm CO(2) laser radiation. The predominant charging effect at low intensities ( approximately 10(5) W/cm(2)) involves a loss of positive charge. Splitting of particle aggregates has also been observed. PMID- 20165513 TI - Short-term average irradiance profile of an optical beam in a turbulent medium. AB - The short-term average irradiance profile of a focused laser beam transmitted through a homogeneous-isotropic medium has been determined by using the extended Huygens-Fresnel principle and by modifying the phase structure function to remove tilt. In contrast to previous analysis, no assumption is made regarding the independence of the distribution of phase with tilt removed and the random vector beta defining tilt. This analysis applies to the near field of the effective coherent transmitting aperture, where the beam wanders as a whole and does not break up into multiple patches or blobs. Central to the analysis is the short term average mutual coherence function (MCF) of a spherical wave, which has been determined from the modified phase structure function. Assuming a Kolmogorov spectrum, the modified phase structure function has been determined for three specific aperture functions. These same aperture functions are then used to determine the short-term irradiance profiles. Numerical calculations have been performed, and the results are presented for uniform and Gaussian aperture functions for various values of aperture obscuration and for various strengths of turbulence values. Comparisons are made between the long-term average, short-term average, and Fried's short-term average irradiance profiles. In particular, on axis irradiance values and beam spread, as determined by the 1/e points in irradiance, are compared. It is found, in contrast to previous analysis, that the short-term beam spread remains relatively constant as the strength of turbulence becomes large and then increases slowly. PMID- 20165514 TI - Light scattering by tenuous particles: a generalization of the Rayleigh-Gans Rocard approach. AB - We consider scattering by arbitrarily shaped particles that satisfy two conditions: (1) that the polarizability of the particle relative to the ambient medium be small compared to 1 and (2) that the phase shift introduced by the particle be less than 2. We solve the integro-differential equation proposed by Shifrin by using the method of successive iterations and then applying a Fourier transform. For the second iteration, results are presented that accurately describe scattering by a broad class of particles. The phase function and other elements of the scattering matrix are shown to be in excellent agreement with Mie theory for spherical scatterers. PMID- 20165516 TI - Dyscalculia, dyslexia, and medical students' needs for learning and using statistics. AB - Much has been written on the learning needs of dyslexic and dyscalculic students in primary and early secondary education. However, it is not clear that the necessary disability support staff and specialist literature are available to ensure that these needs are being adequately met within the context of learning statistics and general quantitative skills in the self-directed learning environments encountered in higher education. This commentary draws attention to dyslexia and dyscalculia as two potentially unrecognized conditions among undergraduate medical students and in turn, highlights key developments from recent literature in the diagnosis of these conditions. With a view to assisting medical educators meet the needs of dyscalculic learners and the more varied needs of dyslexic learners, a comprehensive list of suggestions is provided as to how learning resources can be designed from the outset to be more inclusive. A hitherto neglected area for future research is also identified through a call for a thorough investigation of the meaning of statistical literacy within the context of the undergraduate medical curriculum. PMID- 20165515 TI - Medical students' attitudes about team-based learning in a pre-clinical curriculum. AB - BACKGROUND: Team-Based Learning is relatively new in medical education. Team Based Learning was integrated into one medical school's pre-clinical curriculum in 2002. PURPOSE: This study compared how medical students' attitudes about the Team-Based Learning process changed between the first and second year of medical school. METHOD: 180 students responded to 19 statements regarding their attitudes about Team-Based Learning during their first and second year of medical school. Data were analyzed using a Mann-Whitney U test. RESULTS: Significant changes in attitudes occurred in the areas of Professional Development, Satisfaction with Team Experience, and Satisfaction with Peer Evaluation but not in the areas of Team Impact on Quality of Learning and Team Impact on Clinical Reasoning Ability. CONCLUSION: This study demonstrates that students' attitudes about working within teams, their sense of professional development, and comfort and satisfaction with peer evaluation change in a curriculum using Team-Based Learning. PMID- 20165517 TI - Integrating a hand held computer and stethoscope into a fetal monitor. AB - This article presents procedures for modifying a hand held computer or personal digital assistant (PDA) into a versatile device functioning as an electronic stethoscope for fetal monitoring. Along with functioning as an electronic stethoscope, a PDA can provide a useful information source for a medical trainee. Feedback from medical students, residents and interns suggests the device is well accepted by medical trainees. PMID- 20165518 TI - Person-oriented versus technique-oriented specialties: early preferences and eventual choice. AB - BACKGROUND: Students' selection of a specialty is an important decision in their career as a physician. While distinguishing primary care physicians from non primary care specialists has served a purpose for how medicine is practiced and managed, considering alternative ways of grouping specialties is appropriate when exploring specialty decisions. PURPOSE: This study explored how early specialty preferences correspond to eventual specialty choice using the person-oriented versus technique-oriented taxonomy. METHOD: Participants were 349 students who completed a career plan survey during the first semester of medical school and later graduated. RESULTS: Chi-square analysis showed a statistically significant difference between students' early preference for a person-oriented or technique oriented specialty and the specialty they chose for their residency. CONCLUSION: Students with an early preference for person-oriented specialties were more likely to choose a person-oriented specialty, whereas students with an early preference for technique-oriented specialties were less likely to enter a technique-oriented specialty. PMID- 20165519 TI - Merging social networking environments and formal learning environments to support and facilitate interprofessional instruction. AB - This study describes the redesign of an interprofessional team development course for health science students. A theoretical model is hypothesized as a framework for the redesign process, consisting of two themes: 1) the increasing trend among post-secondary students to participate in social networking (e.g., Facebook, Second Life) and 2) the need for healthcare educators to provide interprofessional training that results in effective communities of practice and better patient care. The redesign focused on increasing the relevance of the course through the integration of custom-designed technology to facilitate social networking during their interprofessional education. Results suggest that students in an educationally structured social networking environment can be guided to join learning communities quickly and access course materials. More research and implementation work is required to effectively develop interprofessional health sciences communities in a combined face-to-face and on line social networking context. PMID- 20165520 TI - Found in translation: exporting patient-centered communication and small group teaching skills to China. AB - The Chinese Medical Doctor's Association asked us to develop a train-the-trainers program in doctor-patient communication and in teaching skills for a select group of Chinese health care professionals, who would then serve as trainers for practicing physicians throughout China. The request came in the context of increasing doctor-patient friction related, in part, to the dissolution of the socialist health care safety net in China. In this article we recount the implementation of our 5-day training program in Beijing. We explore cross cultural issues that arose in presenting the program's two principal training domains: small group teaching and patient-centered doctor-patient communication. We also explore the linguistic challenges we encountered as non-Chinese speaking teachers. Finally, we reflect on the lessons learned from this project that may be of value to others called upon to export Western doctor-patient communications training to other cultures. In this age of increasing globalization, cross cultural sharing of medical education represents a growing trend. PMID- 20165521 TI - Standardized patient practices: initial report on the survey of US and Canadian medical schools. AB - BACKGROUND: There is currently a lack of information about the ways in which standardized patients (SPs) are used, how programs that facilitate their use are operated, the ways in which SP-based performance assessments are developed, and how assessment quality is assured. This survey research project was undertaken to describe the current practices of programs delivering SP-based instruction and/or assessment. METHOD: A structured interview of 61 individual SP programs affiliated with the Association of Standardized Patient Educators (ASPE) was conducted over a 7-month period. A web-based data entry system was used by the 11 trained interviewers. RESULTS: The two most common reported uses of SPs were learner performance assessment (88% of respondents) and small-group instruction (84% of respondents). Fifty-four percent of programs hired 51-100 SPs annually and paid an average of $15 and $16 per hour for training time and portraying a case, respectively. The average reported number of permanent program employees, excluding SPs and temporary staff, was 4.8 (sd = 3.6). The most frequently reported salary range was $30,001-$45,000. CONCLUSION: We intend for these preliminary results to inform the medical education community about the functions of SPs and the structures of programs that implement these complex educational endeavors. PMID- 20165522 TI - Sponsorship of internal medicine subspecialty fellowships since 2000: trends and community hospital involvement. AB - BACKGROUND: Since 2002, market studies have predicted a physician shortage with an increasing need for future subspecialists. A Residency Review Committee (RRC) rule that restricted sponsorship of fellowships was eliminated in 2005, but the influence of this change on the number of fellowships is not known. We believed that the rules change might make it possible for community hospitals to offer fellowships. Our objectives were to determine the extent of change in the number of fellowships in university and community hospitals from 2000 through 2008, both before and after the RRC regulation change in 2005, and to determine whether community hospitals contributed substantially to the number of new fellowships available to internal medicine graduates. METHODS: We used archived Accreditation Council for Graduate Medical Education (ACGME) data from July 2000 through June 2008. The community hospital category included multispecialty clinics, community programs, and municipal hospitals. RESULTS: Of the 94 newly approved internal medicine subspecialty fellowships in this time period, 59 (63%) were community sponsored. As of 6/02/08, all were in good standing. Thirteen programs were started as a department of medicine solo fellowship since 2005. The number of new programs approved between 2005 and 2008 was roughly three times the number approved between 2000 and 2004. CONCLUSIONS: The number of subspecialty fellowship programs and approved positions has increased dramatically in the last 8 years. Many of the new programs were at community hospitals. The change in RRC rules has been associated with increased availability of fellowship programs in the university and community hospital setting for subspecialty training. PMID- 20165523 TI - Pilot of direct observation of clinical skills (DOCS) in a medicine clerkship: feasibility and relationship to clinical performance measures. AB - PURPOSE: To assess the feasibility of Direct Observation of Clinical Skills (DOCS), a program for formative assessment of students' clinical skills during a medicine clerkship and to determine relationships between DOCS measures and other clinical performance measures. METHOD: From August, 2004 through June, 2005, Medicine Clerks assigned to the primary on-campus clinical site were asked to participate in the pilot phase of the DOCS program. Students were asked to complete at least one DOCS exercise focused on interviewing, physical examination, or oral case presentation. RESULTS: Of the 79 students who rotated on the Medicine Clerkship during the pilot period, 79% (n = 62) participated in DOCS, and 163 forms were submitted for evaluation. Seventy-seven percent (77%) of the clinical observations occurred while on-call or during daily rounds. Seventy three (73%) of observations were completed in 30 minutes or less. In 89% of encounters students received at least 5 minutes of verbal feedback. Satisfaction ratings from both students and observers were "moderately satisfied" or better. Global ratings from DOCS physical exam and case presentation sections were strongly correlated with both faculty ratings of clinical performance and final clerkship grade. DOCS measures were not statistically related to clerkship written examination scores. CONCLUSIONS: These data support the feasibility of the DOCS session for formative assessment of student interviewing, physical examination, and oral case presentation skills during a medicine clerkship. Observer ratings from DOCS physical examination and case presentation sections were found to be predictors of final clerkship grade. PMID- 20165524 TI - Knowledge translation in health research: a novel approach to health sciences education. AB - The salient role of knowledge translation process, by which knowledge is put into practice, is increasingly recognized by various research stakeholders. However, medical schools are slow in providing medical students and health professionals engaged in research with the sufficient opportunities to examine more closely the facilitators and barriers to utilization of research evidence in policymaking and implementation, or the effectiveness of their research communication strategies. Memorial University of Newfoundland now offers a knowledge translation course that equips students of community health and applied health research with the knowledge and skills necessary for conducting research, that responds more closely to the needs of their communities, and for improving the utilization of their research by a variety of research consumers. This case study illustrates how the positive research outcomes resulted from implementing the knowledge translation strategies learned in the course. Knowledge translation can be useful also in attracting more funding and support from research agencies, industry, government agencies and the public. These reasons offer a compelling rationale for the standard inclusion of knowledge translation courses in health sciences education. PMID- 20165525 TI - The effectiveness of streaming video on medical student learning: a case study. AB - Information technology helps meet today's medical students' needs by providing multiple curriculum delivery methods. Video streaming is an e-learning technology that uses the Internet to deliver curriculum while giving the student control of the content's delivery. There have been few studies conducted on the effectiveness of streaming video in medical schools. A 5-year retrospective study was conducted using three groups of students (n = 1736) to determine if the availability of streaming video in Years 1-2 of the basic science curriculum affected overall Step 1 scores for first-time test-takers. The results demonstrated a positive effect on program outcomes as streaming video became more readily available to students. Based on these findings, streaming video technology seems to be a viable tool to complement in-class delivery methods, to accommodate the needs of medical students, and to provide options for meeting the challenges of delivering the undergraduate medical curriculum. Further studies need to be conducted to continue validating the effectiveness of streaming video technology. PMID- 20165526 TI - Teaching medical students how to use interpreters: a three year experience. AB - Disparities in health exist among ethnic/racial groups, especially among members with limited English proficiency (LEP). The session described in this paper aimed to teach medical students the skills needed to communicate with patients with LEP. Description - We created a required session titled "Cross-Cultural Communication-Using an Interpreter" for third-year medical students with learning objectives and teaching strategies. The session plans evolved over three years. Program Evaluation - Students' perceived efficacy using retrospective pre/post test analysis (n = 110, 86% response rate) administered 7 weeks post-session revealed that 77.3% of students felt "more prepared to communicate with a patient with LEP", 77.3% to "give proper instructions to an untrained interpreter" and 76.4% to "access a hospital language line". Conclusion - Our curricular intervention was effective in increasing students' perceived efficacy in communicating with a patient with LEP, using untrained interpreters and accessing a hospital language line. Skills practice and discussion of using interpreters should be a part of medical education. PMID- 20165527 TI - Teaching musculoskeletal physical diagnosis using a web-based tutorial and pathophysiology-focused cases. AB - OBJECTIVE: To assess the effectiveness of an experimental curriculum on teaching first-year medical students the musculoskeletal exam as compared to a traditional curriculum. BACKGROUND: Musculoskeletal complaints are common in the primary care setting. Practitioners are often deficient in examination skills and knowledge regarding musculoskeletal diseases. There is a lack of uniformity regarding how to teach the musculoskeletal examination among sub-specialists. We propose a novel web-based approach to teaching the musculoskeletal exam that is enhanced by peer practice with pathophysiology-focused cases. We sought to assess the effectiveness of an innovative musculoskeletal curriculum on the knowledge and skills of first-year medical students related to musculoskeletal physical diagnosis as compared to a traditional curriculum. The secondary purpose of this study was to assess satisfaction of students and preceptors exposed to this teaching method. METHODS: This quasi-experimental study was conducted at a single LCME-accredited medical school and included a convenience sample from 2 consecutive classes of medical students during the musculoskeletal portion of their physical diagnosis class. We conducted a needs assessment of the traditional curriculum used to teach musculoskeletal examination. The needs assessment informed the development of an experimental curriculum. One class (control group) received the traditional curriculum while the second class (experimental group) received the experimental curriculum, consisting of a web based musculoskeletal tutorial, pathophysiology-focused cases, and facilitator preparation. We used multiple-choice questions and musculoskeletal OSCE scores to assess differences between knowledge and skills in the 2 groups. RESULTS: The sample consisted of 140 students in each medical school class. There were no statistically significant differences between the 2 groups. One hundred seven students from the control group and 120 students from the experimental group took the multiple-choice examination. The average score was 66% (95% CI= 59.7-72.3) for the control group and 66% (95% CI = 60.5-71.5) for the experimental group. There was no difference between the median musculoskeletal OSCE scores between the 2 groups. The experimental group was satisfied with the new teaching method and gained the additional benefit of a persistent resource. CONCLUSIONS: This web based experimental curriculum was as effective as the traditional curriculum for teaching the musculoskeletal exam. Additionally, users were satisfied with the web-based training and benefited from a persistent resource. PMID- 20165528 TI - Designing and implementing a skills program using a clinically integrated, multi professional approach: using evaluation to drive curriculum change. AB - The essential procedural skills that newly graduated doctors require are rarely defined, do not take into account pre-vocational employer expectations, and differ between Universities. This paper describes how one Faculty used local evaluation data to drive curriculum change and implement a clinically integrated, multi-professional skills program. A curriculum restructure included a review of all undergraduate procedural skills training by academic staff and clinical departments, resulting in a curriculum skills map. Undergraduate training was then linked with postgraduate expectations using the Delphi process to identify the skills requiring structured standardised training. The skills program was designed and implemented without a dedicated simulation center. This paper shows the benefits of an alternate model in which clinical integration of training and multi-professional collaboration encouraged broad ownership of a program and, in turn, impacted the clinical experience obtained. PMID- 20165529 TI - Integration of evidence based medicine into a medical curriculum. AB - The College of Medicine at King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) was established in January 2004. The four-year curriculum was based on the Problem Based Learning (PBL) format and involved the web-based graduate medical program adopted from the University of Sydney, Australia. At KSAU-HS, one additional semester was added to the beginning of this curriculum to prepare the students in English language skills, PBL, Information Technology and Evidence Based Medicine (EBM). EBM is part of the Personal and Professional Development (PPD) theme of the medical curriculum and is integrated into each stage of the medical curriculum. These modifications of the University of Sydney curriculum are presented here as a model of EBM integration into a college of medicine curriculum. PMID- 20165530 TI - A multi-institutional survey on faculty development needs, priorities and preferences in medical education in an Asian medical school. AB - BACKGROUND: Faculty development in medical education is crucial for maintaining academic vitality. The authors conducted a needs assessment survey in Singapore to determine the educational needs and priorities of clinical faculty. METHODS: This study implemented a questionnaire-based, anonymous, multi-institutional survey with stratified random sampling. Each question was anchored with two statements on a 9-point scale. Respondents were asked to determine their current knowledge and the knowledge they would need in future. RESULTS: The response rate was 81.9%. Overall, the participants' current knowledge was rated either "modest" (scale 4-6) or "substantial" (scale 7-9), irrespective of teaching experience. Participants reported higher knowledge in areas related to teaching and modest knowledge in educational concepts and assessment. They reported a need for higher knowledge in most areas to function well as a teacher. CONCLUSION: The need for faculty development is universal and independent of teaching experience in this group. Teaching faculty from the institutes studied understood the need for improved knowledge in pedagogical knowledge. PMID- 20165531 TI - The effect of student training on accuracy of completion of death certificates. AB - BACKGROUND: Death certificates are an invaluable source of statistical and medical information, as well as important legal documents. However, few physicians receive formal training on how to accurately complete them. PURPOSE: To determine if a simple intervention can improve the accuracy of death certificate completion by medical students. METHODS: Participants included all third year medical students undergoing their core Internal Medicine rotation at Mercer University School of Medicine at the Medical Center of Central Georgia. Participation was voluntary and participants completed an approved informed consent. Students were presented a tutorial from the National Association of Medical Examiners website. They were asked to complete a death certificate both before and after the tutorial along with subjective questionnaires. The primary outcome measurement was the difference in scores pre- and post-tutorial. RESULTS: The mean score before the tutorial was 11.75 (+/-3.20) and the mean score post tutorial was 18.85 (+/-2.56), indicating an increase in scores. The mean difference in pre- and post-tutorial scores was significant (t = 20.39, p < 0.0001). CONCLUSIONS: We found that using a tutorial to teach students how to correctly complete a death certificate was effective. PMID- 20165532 TI - Effects of Using Human Patient Simulator (HPS) versus a CD-ROM on Cognition and Critical Thinking. AB - BACKGROUND: Very little prospective randomized experimental research exists on the use of simulation as a teaching method, and no studies have compared the two strategies of using the HPS and a CD-ROM. In addition, no researchers have investigated the effects of simulation on various levels of cognition, specifically lower-level and higher-level cognition or critical thinking. OBJECTIVES: A prospective pretest-posttest experimental mixed design (within and between) was used to determine if there were statistically significant differences in HPS and CD-ROM educational strategies in lower-level, higher-level cognition and critical thinking. RESULTS: A repeated measures multivariate analysis of variance (RMANOVA) with LSD post-hoc tests were used to analyze the data. There were no significant differences between the HPS and CD-ROM groups on lower-level cognition scores. The HPS group did significantly better than the CD ROM group on higher-level cognition and critical thinking scores. CONCLUSION: This study demonstrated that the choice of teaching strategies for lower-level cognition does not make a statistically significant difference in outcome. However, the HPS is superior to using CD-ROM and should be considered as the choice in teaching. PMID- 20165533 TI - The use of professionalism scenarios in the medical school interview process: faculty and interviewee perceptions. AB - PURPOSE: The purpose of this study was to determine the impact of professionalism scenarios on the medical school admissions process from applicant and faculty perspectives. Specifically, do completing professionalism scenarios as part of the medical school interview process have an impact on both the interviewee's and the faculty's perception of the process and outcome? METHOD: Ninety-one faculty interviewed 199 applicants from January 2007 through April 2007 at The University of Toledo College of Medicine. All applicants were asked one standard professionalism scenario in each of their two interviews. A total of six scenarios were used for the entire interviewing season in rotation every two months. A survey was administered by an admissions office staff member to both the interviewed applicants as well as faculty who conducted interviews about how these scenarios impacted their interview experience. RESULTS: Asking applicants to respond to professionalism scenarios during the interview was described as having a positive influence on their interview experience. This was also associated with leaving an impression on the applicant about what our institution values in its students and contributed an element of personal reflection about what will be expected of them in the medical profession. Applicants more often reported that asking questions about professionalism was an important aspect of the interview than did faculty. Overall, there was an association between the interviewer's perception of the applicant's response and the interviewer's assessment of professionalism. CONCLUSIONS: Professionalism scenarios can be a worthwhile tool for use in the admissions process. The interview process should encourage participation from faculty who value this as an important component in the evaluation of an applicant. Determinants of faculty perception of the role of assessing professionalism in the interview process should be investigated in future research. PMID- 20165534 TI - Perceived Benefits and Barriers to Family Planning Education among Third Year Medical Students. AB - PURPOSE: The purpose of the current study is to explore third- year medical students' interest in learning about family planning, exposure to family planning (contraception and abortion) and perceived barriers and benefits to family planning education in their obstetrics and gynecology rotation. METHOD: We conducted four focus groups with 27 third-year medical students near the end of their rotation in obstetrics and gynecology. RESULTS: Students desired education in family planning but perceived limited exposure during their rotation. Most students were aware of abortion but lacked factual information and abortion procedural skills. They felt systemic and faculty-related barriers contributed to limited exposure. Students discussed issues such as lack of time for coverage of contraception and abortion in the curricula and rotation itself. Perceived benefits of clinical instruction in family planning included increased knowledge of contraceptive management and abortion the ability to care for and relate to patients, opportunity for values clarification, and positive changes in attitudes towards family planning. CONCLUSIONS: Medical students who desire full education in family planning during their obstetrics and gynecology rotation may face barriers to obtaining that education. Given that many medical students will eventually care for reproductive-age women, greater promotion of opportunities for exposure to family planning within obstetrics and gynecology rotations is warranted. PMID- 20165535 TI - Resident physician attitudes and competence about obesity treatment: need for improved education. AB - BACKGROUND: Obesity is a common problem in primary care, but little is known about Internal Medicine residents' attitudes towards obesity treatment. OBJECTIVE: To describe resident attitudes about obesity treatment. METHODS: Cross sectional survey of 101 Internal Medicine residents in Philadelphia, PA, and Bronx, NY. Responses to 18 items on a Likert scale assessed resident attitudes. Weight loss goals were assessed with open-ended questions to a clinical scenario. ANOVA with trend analysis compared questionnaire responses to resident postgraduate year (PGY) level. Associations between clinic site, PGY level, and dichotomized Likert responses were tested with chi-square analysis. RESULTS: 19% of residents felt competent in prescribing weight loss programs. Few residents (18%) considered the current recommendations of a 5-10% reduction in body weight to be successful in an obese hypothetical patient. Third-year residents reported greater feelings of negativity towards obese patients than first- and second year residents (p<.05) CONCLUSIONS: Resident physicians do not feel competent in treating obesity and have unrealistic weight loss goals; third-year residents had more negative attitudes about obese patients compared to residents in their 1(st) or 2(nd) year of training. These areas are targets for further resident education about obesity management. PMID- 20165536 TI - Resident front office experience: a systems-based practice activity. AB - PURPOSE: We set out to create and evaluate a systems-based practice experience designed to introduce residents to front office responsibilities and stimulate suggestions for front office improvements. METHODS: On two occasions in 2002 and 2006, each resident in the Obstetrics and Gynecology Department was trained by a front office staff member for one day. The residents completed pre- and post experience surveys, answered open-ended questions about their experience, and volunteered suggestions for improving the front office staff, and were evaluated by their precepting staff member. RESULTS: All but two of 23 particpating residents participated enthusiastically. These residents perceived experiencing the staff as vital to the success of the practice, reported an increased sense of appreciation for the training of staff personnel, and were evaluated favorably. CONCLUSION: This program gave our residents an appreciation for the training and responsibilities of pivotal office staff and an opportunity to suggest improvements. This program also satisfied ACGME resident education requirements regarding systems-based practice. PMID- 20165537 TI - A pilot study exploring gender differences in residents' strategies for establishing mentoring relationships. AB - BACKGROUND: Mentoring is important throughout a physician's career and has been noted to be particularly important during residency training. Other studies suggest that women may experience difficulty in finding mentors. PURPOSE: This study explored gender-specific differences in residents' mentoring experiences. METHODS: The authors conducted two focus groups at the University of Pittsburgh in July, 2004. One group was composed of 12 female residents; the other was composed of nine male residents. Discussions were audiotaped and transcribed. Two investigators coded the transcripts and identified emerging themes. RESULTS: Residents of both genders cited multiple barriers to mentoring. Men's strategies for finding mentors were more numerous than women's and included identifying mentors through research, similar interests, friendship, and networking. Female strategies were limited and included identifying mentors through "word of mouth" and work experiences. Women described more passive approaches for finding a mentor than men. CONCLUSIONS: Female residents may lack strategies and initiatives for finding mentors. Residency programs should create opportunities for residents to develop mentoring relationships, with special attention paid to gender differences. PMID- 20165538 TI - Perceptions of students in different phases of medical education of educational environment: ankara university faculty of medicine. AB - The present study was undertaken to identify the perceptions of students about their educational environment in a newly restructured curriculum. The Turkish version of the DREEM questionnaire (total score: 200) was used to diagnose the strengths and weaknesses of the curriculum which is known to be a major determinant of educational environment. Five hundred fifty three students (years 1, 3, 5) voluntarily replied to the questionnaire. The mean DREEM score was found to be 117.63 (58.8%). The mean scores for the whole DREEM questionnaire and the five essential domains were found to be significantly different in different phases of medical education. The scores were found to be highest (123.65) for year 3 students and lowest (109.39) for year 5 students. The results are the first data of a curriculum reform obtained from the students about the educational environment and give important feedback to curriculum planners and change managers of the faculty for necessary improvement. PMID- 20165539 TI - Assessing Medical Students', Residents', and the Public's Perceptions of the Uses of Personal Digital Assistants. AB - Although medical schools are encouraging the use of personal digital assistants (PDAs), there have been few investigations of attitudes toward their use by students or residents and only one investigation of the public's attitude toward their use by physicians. In 2006, the University of Louisville School of Medicine surveyed 121 third- and fourth-year medical students, 53 residents, and 51 members of the non-medical public about their attitudes toward PDAs. Students were using either the Palm i705 or the Dell Axim X50v; residents were using devices they selected themselves (referred to in the study generically as PDAs). Three survey instruments were designed to investigate attitudes of (a) third- and fourth-year medical students on clinical rotations, (b) Internal Medicine and Pediatrics residents, and (c) volunteer members of the public found in the waiting rooms of three university practice clinics. Both residents and medical students found their devices useful, with more residents (46.8%) than students (16.2%) (p < 0.001) rating PDAs "very useful." While students and residents generally agreed that PDAs improved the quality of their learning, residents' responses were significantly higher (p < 0.05) than students'. Residents also responded more positively than students that PDAs made them more effective as clinicians. Although members of the public were generally supportive of PDA use, they appeared to have some misconceptions about how and why physicians were using them. The next phase of research will be to refine the research questions and survey instruments in collaboration with another medical school. PMID- 20165540 TI - Evaluating attitudes of first-year residents to shared decision making. AB - OBJECTIVE: Shared decision making (SDM) is recognized as an ideal model of patient-physician interaction, yet clinical application occurs infrequently. The current study evaluated attitudes of first-year residents to identify potential barriers and opportunities regarding SDM. METHODS: A total of 70 residents attending orientation at the University of Utah completed a questionnaire that elicited their understanding of SDM, perceptions about the importance of SDM, confidence in utilizing SDM, and reasons for lacking confidence. RESULTS: Most residents reported no prior SDM education (N = 42, 60%) or training (N = 46, 66%), yet 67 (96%) of them could recognize it in a clinical vignette. Using a Likert scale, the majority of residents (91% to 99%) attributed importance to SDM principles, and most (79% to 90%) indicated confidence in applying them. Lack of training was reported as a barrier by 40 (57%) residents. CONCLUSIONS: A minority of residents reported formal education or training in SDM, yet the vast majority recognized and valued the model. A large percentage of residents expressed confidence in their abilities to incorporate SDM into patient care, but many also identified a need for more education and training. PMID- 20165541 TI - Evaluation of Computer-aided Strategies for Teaching Medical Students Prenatal Ultrasound Diagnostic Skills. AB - OBJECTIVE: To evaluate whether computer-based learning (CBL) improves newly acquired knowledge and is an effective strategy for teaching prenatal ultrasound diagnostic skills to third-year medical students when compared with instruction by traditional paper-based methods (PBM). STUDY DESIGN: We conducted a randomized, prospective study involving volunteer junior (3(rd) year) medical students consecutively rotating through the Obstetrics and Gynecology clerkship during six months of the 2005-2006 academic year. The students were randomly assigned to permuted blocks and divided into two groups. Half of the participants received instruction in prenatal ultrasound diagnostics using an interactive CBL program; the other half received instruction using equivalent material by the traditional PBM. Outcomes were evaluated by comparing changes in pre-tutorial and post instruction examination scores. RESULTS: All 36 potential participants (100%) completed the study curriculum. Students were divided equally between the CBL (n = 18) and PBM (n = 18) groups. Pre-tutorial exam scores (mean+/-s.d.) were 44%+/-11.1% for the CBL group and 44%+/-10.8% for the PBL cohort, indicating no statistically significant differences (p>0.05) between the two groups. After instruction, post-tutorial exam scores (mean+/-s.d.) were increased from the pre tutorial scores, 74%+/-11% and 67%+/-12%, for students in the CBL and the PBM groups, respectively. The improvement in post-tutorial exam scores from the pre test scores was considered significant (p<0.05). When post-test scores for the tutorial groups were compared, the CBL subjects achieved a score that was, on average, 7 percentage points higher than their PBM counterparts, a statistically significant difference (p < 0.05). CONCLUSION: Instruction by either CBL or PBM strategies is associated with improvements in newly acquired knowledge as reflected by increased post-tutorial examination scores. Students that received CBL had significantlyhigher post-tutorial exam scores than those in the PBM group, indicating that CBL is an effective instruction strategy in this setting. PMID- 20165542 TI - Impact of labor and delivery simulation classes in undergraduate medical learning. AB - INTRODUCATION: The aim of this study was to evaluate the impact on knowledge and learner satisfaction of adding a labour and delivery simulator-based training module versus a self-study session to the pre-existing theoretical class, in the 5(th) year undergraduate medical curriculum. METHODS: One hundred and fifty seven students attending the 5-week Obstetrics and Gynecology rotation were enrolled, and 107 completed the study. After a 90-minute "labour and delivery" theoretical interactive class, students were randomized to two groups: the first (n = 56) participated in a 30-minute supervised self-study session, while the second (n = 51) attended a 20-30 minute delivery simulator session. Tests consisting of 10 multiple-choice questions were taken before the theoretical class (pre-test), after the self-study or simulation session (1(st) post-test) and 12-15 days later (2(nd) post-test). A subgroup of 53 students participating in this study (27 from the simulation and 26 from the self-study arm) answered six additional questions on satisfaction with the learning experience, at the time of the 1(st) post-test. Wilcoxon paired rank sum test, Wilcoxon T test, and z-statistic with continuity correction were employed for statistical analysis, setting significance at p < 0.05. RESULTS: Pre-test scores were similar in both groups (p = 0.9567), but in the first post-test they were significantly higher in the simulation group (p = 0.0017). In the 2(nd) post-test, scores were again similar in both groups (p = 0.2204). Satisfaction was significantly higher in the simulation group (p < 0.0001). CONCLUSIONS: Adding a simulator-based training session for medical students in management of labour and delivery to the theoretical class led to a higher short-term increase in knowledge and student satisfaction than attending a self-study session. Significant differences in knowledge were no longer demonstrable at 12-15 days. PMID- 20165543 TI - The effect of enhanced experiential learning on the personal reflection of undergraduate medical students. AB - OBJECTIVE: This study's aim was to test the expectation that enhanced experiential learning is an effective educational method that encourages personal reflection in medical students. METHODS: Using a pre post-test follow-up design, the level of the personal reflection ability of an exposure group of first-year medical students participating in a new enhanced experiential learning program was compared to that of a control group of second- and third-year medical students participating in a standard problem-based learning program. Personal reflection was assessed using the Groningen Reflection Ability Scale (GRAS). Students' growth in reflection was analyzed with multilevel analysis. RESULTS: After one year, first-year medical students in the exposure group achieved a level of personal reflection comparable to that reached by students of the control group in their third year. This difference in growth of reflection was statistically significant (p<.001), with a small effect size (effect size = 0.18). The reflection growth curve of the control group declined slightly in the third year as a function of study time. CONCLUSION: Enhanced experiential learning has a positive effect on the personal reflection ability of undergraduate medical students. PMID- 20165544 TI - Evidence of knowledge acquisition in a cognitive flexibility-based computer learning environment. AB - BACKGROUND: A computer-based learning experience was developed using cognitive flexibility theory to overcome the pitfalls often encountered in existing medical education. An earlier study (not published) showed significant pretest-posttest increase in scores, as well as a significant positive correlation between choosing to complete the module individually or in pairs. METHOD: This experience was presented as part of a second-year course in medical school with randomized assignment for students to complete the program as pairs or individuals. RESULTS: Sixty-six scores of 101 medical students (31 from students working as singles and 35 from 70 working in pairs) were analyzed. Out of 47 possible points, the mean pretest score was 15.1 (SD = 6.4, range 13.7-15.9). The mean posttest score was 22.9 (SD = 5.2, range 21.1-24.2). Posttest scores were statistically significantly higher than pretest scores (p<.001, Cohen's d = 1.17, average gain 7.8 points). Both pairs and singles showed pre-to-post test score gains, but the score gains of pairs and singles were not significantly different. CONCLUSION: This learning module served as an effective instructional intervention. However, the effect of collaboration, measured by score gains for pairs, was not significantly different from score gains of students completing the assignment individually. PMID- 20165545 TI - Partial calcanectomy in high-risk patients with diabetes: use and utility of a "hurricane" incisional approach. AB - INTRODUCTION: Plantar heel ulcers in people with diabetes represent a difficult challenge to the treating physician. They become even more difficult with underlying osteomyelitis. When this infection is in the calcaneus it typically results in a partial or total calcanectomy or even more frequently, high-level amputation. METHODS: In this article, we describe a novel serpentine incisional approach to the plantar and (if necessary) posterior heel allowing for ample exposure and facilitating closure predominantly along relaxed skin tension lines. RESULTS: We present several representative case examples in which a hurricane incision has been used to treat and provide closure to plantar-based calcaneal ulcers. DISCUSSION: The use of this incision, which resembles a satellite view of a hurricane, was successful in achieving a desired partial calcanectomy and wound closure. This may be an additional tool in the armamentarium of the surgeon to assist in healing and amputation prevention. PMID- 20165546 TI - Avoiding the medial brachial cutaneous nerve in brachioplasty: an anatomical study. AB - OBJECTIVE: With more patients undergoing bariatric surgery procedures, there has been an increased demand on plastic surgeons to manage excess skin around the body from massive weight loss. The upper arm is one of the areas that require surgical attention. One of the complications of brachioplasty is injury to cutaneous nerves of the arm. We report our findings of the location of the medial brachial cutaneous nerve on the basis of anatomical landmarks to aid the reconstructive surgeon in planning his or her operative approach and procedure. METHODS: Eight fresh cadaver arms were dissected under loupe magnification. The brachial plexus was dissected from proximal to distal to evaluate the branching points of the cutaneous nerves. Measurements were taken from the medial epicondyle to cutaneous branches off the main nerve. RESULTS: At about 7 cm proximal to the medial epicondyle, there is an arborization of 2 to 3 cutaneous branches. This nerve sends 3 to 4 branches through the muscular fascia across the ulnar nerve to skin of the medial arm at about 15 cm proximal to the medial epicondyle. In most cadavers, this was found in the midportion of the arm. CONCLUSIONS: The plastic surgeon will be challenged to effectively manage excess skin from weight loss. Placing the incisions more posteriorly on the arm will help avoid morbidity associated with injury to these nerves, while still providing an acceptable aesthetic outcome. Knowledge of the anatomy of the course of the medial brachial cutaneous nerve can help the surgeon better plan his or her operative approach to maximize aesthetic benefit and limit nerve injury. PMID- 20165547 TI - Diagnosis and typing of systemic amyloidosis: The role of abdominal fat pad fine needle aspiration biopsy. AB - INTRODUCTION: Systemic amyloidosis (SA) has a broad nonspecific clinical presentation. Its diagnosis depends on identifying amyloid in tissues. Abdominal fat pad fine needle aspiration (FPFNA) has been suggested as a sensitive and specific test for diagnosing SA. MATERIALS AND METHODS: Thirty-nine FPFNA from 38 patients (16 women and 20 men, age range 40-88 years) during a 15-year period were reviewed. Smears and cell blocks were stained with Congo red (CR). A panel of antibodies (serum amyloid protein, serum amyloid A, albumin, transthyretin, kappa light chain and lambda light chain) was used on six cell blocks from five patients. The FNA findings were correlated with clinical and histological follow up. RESULTS: FPFNAs were positive, confirmed by CR in 5/39 (13%), suspicious in 1/39 (3%), negative in 28/39 (72%), and insufficient for diagnosis in 5/39 (13%) of cases. In all the positive cases, SA was confirmed within 2-16 weeks. Among the 28 negative cases, SA was diagnosed in 21, the rest were lost to follow-up. Among the insufficient cases, SA was diagnosed in four and one was lost to follow up. Specificity was 100%, whereas sensitivity was 19%. SA typing using cell block sections was successful in three, un-interpretable in one, and negative in two cases. CONCLUSION: FPFNA for SA is not as good as previously reported. This may be due to different practice setting, level of experience, diagnostic technique, or absence of abdominal soft tissue involvement. A negative result of FPFNA does not exclude SA. Immune phenotyping of amyloid is possible on cell block. PMID- 20165548 TI - Hepatic epithelioid hemangioendothelioma: A diagnostic pitfall in aspiration cytology. AB - Hepatic epithelioid hemangioendothelioma (EH) is a rare vascular neoplasm. An accurate radiologic diagnosis is usually difficult due to the presence of multiple nodules, simulating metastatic carcinoma. Though histologic features of this tumor are well described, cytologic reports of hepatic EH are very few in the available literature. We describe a case of a young healthy adult male who was found to have multiple hepatic masses on radiologic investigations. A guided fine needle aspiration demonstrated a poorly differentiated neoplasm. The diagnosis was made on core biopsy assisted by immunohistochemistry, which showed characteristic features of EH. He is doing well 14 months after diagnosis, without surgical excision or chemotherapy. An accurate diagnosis of hepatic EH on aspiration cytology requires an adequate specimen and awareness of its cytologic features, including discohesive atypical cells with intracytoplasmic lumina and intranuclear inclusions. Since this tumor is usually unresectable but has a favorable prognosis as compared to hepatocellular carcinoma, a correct diagnosis is essential for appropriate management and prognostication. PMID- 20165549 TI - Characterization of the structure of ultra dilute sols with remarkable biological properties. AB - Most natural waters are probably "ultra dilute": aquasols. While the composition of such waters is routinely characterized thoroughly with respect to composition, very little attention has been paid to the solid phases which are certainly suspended in most, if not all, such. Our recent work having established the importance of the structure of water on its properties, [[1]; R. Roy, W.A. Tiller, I. Bell, M.R. Hoover; Mater Res Innov. 9 (2005) 577.] we have examined the structures of many waters with easily demonstrated (e.g. silver aquasols) or long-claimed (e.g. homeopathic remedies) biological effects. The results show that such materials can be easily distinguished from the pure solvent, and from each other, by the use of UV-VIS and Raman spectroscopy, while FTIR is insensitive to these differences. This opens up a whole new field of endeavor for inorganic materials scientists interested in biological effects. PMID- 20165550 TI - Extreme polymorphism in a vaccine antigen and risk of clinical malaria: implications for vaccine development. AB - Vaccines directed against the blood stages of Plasmodium falciparum malaria are intended to prevent the parasite from invading and replicating within host cells. No blood-stage malaria vaccine has shown clinical efficacy in humans. Most malaria vaccine antigens are parasite surface proteins that have evolved extensive genetic diversity, and this diversity could allow malaria parasites to escape vaccine-induced immunity. We examined the extent and within-host dynamics of genetic diversity in the blood-stage malaria vaccine antigen apical membrane antigen-1 in a longitudinal study in Mali. Two hundred and fourteen unique apical membrane antigen-1 haplotypes were identified among 506 human infections, and amino acid changes near a putative invasion machinery binding site were strongly associated with the development of clinical symptoms, suggesting that these residues may be important to consider in designing polyvalent apical membrane antigen-1 vaccines and in assessing vaccine efficacy in field trials. This extreme diversity may pose a serious obstacle to an effective polyvalent recombinant subunit apical membrane antigen-1 vaccine. PMID- 20165551 TI - Update on Targets of Biologic Therapies for Rheumatoid Arthritis. AB - With the advent of biological therapies, considerable progress has been made in the treatment of rheumatoid arthritis (RA). These revolutionary therapies owe their origin to the role that cytokines play in the pathophysiology of the disease and are best exemplified by the wide use of tumor necrosis factor (TNF) blockade. The identification of additional pro-inflammatory factors and an understanding of their effector function now offer major possibilities for the generation of additional novel biological therapeutics to address unmet clinical needs. Such interventions will ideally fulfill several of the following criteria: control of inflammation, modulation of underlying immune dysfunction by promoting the reestablishment of immune tolerance, protection of targeted tissues such as bone and cartilage, and preservation of host immune capability to avoid profound immune suppression and amelioration of co-morbidity associated with underlying RA. The identification and characterization of the intracellular signaling pathways, in particular, the mitogen-activated protein kinase pathway, the nuclear factor-kappaB pathway and the cross-talk between these pathways offer several potential therapeutic opportunities. This review will provide an update on cytokine activities and signal transduction pathways that represent, in our opinion, optimal utility as future therapeutic targets. PMID- 20165553 TI - Towards dynamic control of magnetic fields to focus magnetic carriers to targets deep inside the body. AB - Magnetic drug delivery has the potential to target therapy to specific regions in the body, improving efficacy and reducing side effects for treatment of cancer, stroke, infection, and other diseases. Using stationary external magnets, which attract the magnetic drug carriers, this treatment is limited to shallow targets (<5 cm below skin depth using the strongest possible, still safe, practical magnetic fields). We consider dynamic magnetic actuation and present initial results that show it is possible to vary magnets one against the other to focus carriers between them on average. The many remaining tasks for deep targeting in vivo are then briefly noted. PMID- 20165552 TI - Bifunctional Gold Nanoshells with a Superparamagnetic Iron Oxide-Silica Core Suitable for Both MR Imaging and Photothermal Therapy. AB - We describe the synthesis, characterization, and use of hybrid nanoparticles with a superparamagnetic iron oxide (SPIO) core and a gold nanoshell. These multifunctional nanoparticles, designated SPIO-Au nanoshells, displayed superparamagnetic characteristics and a significant absorbance in the near infrared (NIR) region of the electromagnetic spectrum. In addition, they exhibited high transverse relaxivity, r2 , and a large r2/r1 ratio and therefore could be imaged by MRI to obtain T2-weighted images. Moreover, SPIO-Au nanoshells showed efficient photo-thermal effect when exposed to NIR light. The use of SPIO Au nanoshells, with their combination of unique magnetic and optical properties, should enhance the efficacy of nanoshell-mediated photo-thermal therapy by making it possible to direct more nanoparticles to tumors through the application of external magnetic field and by permitting real-time in vivo MRI imaging of the distribution of the nanoparticles before, during, and after photo-thermal therapy. PMID- 20165554 TI - The Role of Cell-Cell Adhesion in the Formation of Multicellular Sprouts. AB - Collective cell motility and its guidance via cell-cell contacts is instrumental in several morphogenetic and pathological processes such as vasculogenesis or tumor growth. Multicellular sprout elongation, one of the simplest cases of collective motility, depends on a continuous supply of cells streaming along the sprout towards its tip. The phenomenon is often explained as leader cells pulling the rest of the sprout forward via cell-cell adhesion. Building on an empirically demonstrated analogy between surface tension and cell-cell adhesion, we demonstrate that such a mechanism is unable to recruit cells to the sprout. Moreover, the expansion of such hypothetical sprouts is limited by a form of the Plateau-Taylor instability. In contrast, actively moving cells - guided by cell cell contacts - can readily populate and expand linear sprouts. We argue that preferential attraction to the surfaces of elongated cells can provide a generic mechanism, shared by several cell types, for multicellular sprout formation. PMID- 20165555 TI - In the Spotlight: Cardiovascular Engineering. PMID- 20165557 TI - Explaining the long reach of fathers' prenatal involvement on later paternal engagement. AB - The present study examined the association between unmarried fathers' prenatal involvement and fathers' engagement later in the child's life. The study sample consisted of 1,686 fathers from the Fragile Families and Child Wellbeing Study. Findings using multiple regressions revealed that fathers' prenatal involvement is significantly and positively associated with levels of fathers' engagement at years 1 and 3. This association was partially explained by fathers' transitions from unemployment to employment and to a greater extent by fathers' transitions from nonresidential to residential relationships with the child's mother. PMID- 20165558 TI - Tumor Necrosis Factor-alpha Suppresses Activation of Sustained Potassium Currents in Rat Small Diameter Sensory Neurons. AB - Tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine, produces pain and hyperalgesia by activating and/or sensitizing nociceptive sensory neurons. In the present study, using whole-cell patch clamp techniques, the regulation of potassium currents by TNF-alpha was examined in acutely dissociated small dorsal root ganglion neurons. We found that acute application of TNF-alpha inhibited, in a dose-dependent manner, the non-inactivating sustained potassium current without changing the rapidly inactivating transient current or the kinetics of steady-state inactivation. The effects of TNF-alpha on potassium currents were similar to that of prostaglandin E2 as reported previously and also demonstrated in the current study. Furthermore, indomethacin, a potent inhibitor for both cyclo-oxygenase (COX) -1 and COX-2, completely blocked the effect of TNF alpha on potassium currents. These results suggest that TNF-alpha may sensitize or activate sensory neurons by suppressing the sustained potassium current in nociceptive DRG neurons, possibly via stimulating the synthesis/release of endogenous prostaglandins. PMID- 20165559 TI - Membrane Electromechanics in Biology, with a Focus on Hearing. AB - Cells are ion conductive gels surrounded by a ~5-nm-thick insulating membrane, and molecular ionic pumps in the membrane establish an internal potential of approximately -90 mV. This electrical energy store is used for high-speed communication in nerve and muscle and other cells. Nature also has used this electric field for high-speed motor activity, most notably in the ear, where transduction and detection can function as high as 120 kHz. In the ear, there are two sets of sensory cells: the "inner hair cells" that generate an electrical output to the nervous system and the more numerous "outer hair cells" that use electromotility to counteract viscosity and thus sharpen resonance to improve frequency resolution. Nature, in a remarkable exhibition of nanomechanics, has made out of soft, aqueous materials a microphone and high-speed decoder capable of functioning at 120 kHz, limited only by thermal noise. Both physics and biology are only now becoming aware of the material properties of biomembranes and their ability to perform work and sense the environment. We anticipate new examples of this biopiezoelectricity will be forthcoming. PMID- 20165556 TI - Focus on flaviviruses: current and future drug targets. AB - BACKGROUND: Infection by mosquito-borne flaviviruses (family Flaviviridae) is increasing in prevalence worldwide. The vast global, social and economic impact due to the morbidity and mortality associated with the diseases caused by these viruses necessitates therapeutic intervention. There is currently no effective clinical treatment for any flaviviral infection. Therefore, there is a great need for the identification of novel inhibitors to target the virus life cycle. DISCUSSION: In this article, we discuss structural and nonstructural viral proteins that are the focus of current target validation and drug discovery efforts. Both inhibition of essential enzymatic activities and disruption of necessary protein-protein interactions are considered. In addition, we address promising new targets for future research. CONCLUSION: As our molecular and biochemical understanding of the flavivirus life cycle increases, the number of targets for antiviral therapeutic discovery grows and the possibility for novel drug discovery continues to strengthen. PMID- 20165560 TI - Search for the smallest random forest. AB - Random forests have emerged as one of the most commonly used nonparametric statistical methods in many scientific areas, particularly in analysis of high throughput genomic data. A general practice in using random forests is to generate a sufficiently large number of trees, although it is subjective as to how large is sufficient. Furthermore, random forests are viewed as "black-box" because of its sheer size. In this work, we address a fundamental issue in the use of random forests: how large does a random forest have to be? To this end, we propose a specific method to find a sub-forest (e.g., in a single digit number of trees) that can achieve the prediction accuracy of a large random forest (in the order of thousands of trees). We tested it on extensive simulation studies and a real study on prognosis of breast cancer. The results show that such sub-forests usually exist and most of them are very small, suggesting they are actually the "representatives" of the whole random forests. We conclude that the sub-forests are indeed the core of a random forest. Thus it is not necessary to use the whole forest for satisfying prediction performance. Also, by reducing the size of a random forest to a manageable size, the random forest is no longer a black-box. PMID- 20165562 TI - A Unified Approach to Conformational Statistics of Classical Polymer and Polypeptide Models. AB - We present a unified method to generate conformational statistics which can be applied to any of the classical discrete-chain polymer models. The proposed method employs the concepts of Fourier transform and generalized convolution for the group of rigid-body motions in order to obtain probability density functions of chain end-to-end distance. In this paper, we demonstrate the proposed method with three different cases: the freely-rotating model, independent energy model, and interdependent pairwise energy model (the last two are also well-known as the Rotational Isomeric State model). As for numerical examples, for simplicity, we assume homogeneous polymer chains. For the freely-rotating model, we verify the proposed method by comparing with well-known closed-form results for mean-squared end-to-end distance. In the interdependent pairwise energy case, we take polypeptide chains such as polyalanine and polyvaline as examples. PMID- 20165561 TI - Occurrences and sources of Differential Item Functioning (DIF) in patient reported outcome measures: Description of DIF methods, and review of measures of depression, quality of life and general health. AB - Examination of the equivalence of measures involves several levels, including conceptual equivalence of meaning, as well as quantitative tests of differential item functioning (DIF). The purpose of this review is to examine DIF in patient reported outcomes. Reviewed were measures of self-reported depression, quality of life (QoL) and general health. Most measures of depression contained large amounts of DIF, and the impact of DIF at the scale level was typically sizeable. The studies of QoL and health measures identified a moderate amount of DIF; however, many of these studies examined only one type of DIF (uniform). Relative to DIF analyses of depression measures, less analysis of the impact of DIF on QoL and health measures was performed, and the authors of these analyses generally did not recommend remedial action, with one notable exception. While these studies represent good beginning efforts to examine measurement equivalence in patient-reported outcome measures, more cross-validation work is required using other (often larger) samples of different ethnic and language groups, as well as other methods that permit more extensive analyses of the type of DIF, together with magnitude and impact. PMID- 20165563 TI - A Lie-Theoretic Perspective on O(n) Mass Matrix Inversion for Serial Manipulators and Polypeptide Chains. AB - Over the past several decades a number of O(n) methods for forward and inverse dynamics computations have been developed in the multi-body dynamics and robotics literature. A method was developed in 1974 by Fixman for O(n) computation of the mass-matrix determinant for a serial polymer chain consisting of point masses. In other recent papers, we extended this method in order to compute the inverse of the mass matrix for serial chains consisting of point masses. In the present paper, we extend these ideas further and address the case of serial chains composed of rigid-bodies. This requires the use of relatively deep mathematics associated with the rotation group, SO(3), and the special Euclidean group, SE(3), and specifically, it requires that one differentiates functions of Lie group-valued argument. PMID- 20165564 TI - 3,6,9,16,19,22-Hexaazatricyclo-[22.2.2.2]triaconta-1(27),11 (30), 12,14(29),24(28),25-hexaene hexakis(p-toluenesulfonate) dihydrate. AB - In the title compound, C(24)H(44)N(6) (6+).6C(7)H(7)O(3)S(-).2H(2)O, the macrocycle crystallizes in its hexaprotonated form, accompanied by six p toluenesulfonate ions and two water molecules, and lies on an inversion center. The three independent p-toluenesulfonate anions and their inversion equivalents at (1 - x, 1 - y, 1 - z) are linked to the macrocyclic cation through N-Hcdots, three dots, centeredO hydrogen bonds. Of these, two p-toluenesulfonate ions are located on opposite sides of the macrocyclic plane and are linked to bridgehead N atoms via N-Hcdots, three dots, centeredO hydrogen bonds. The remaining four p toluenesulfonate ions bridge two adjacent macrocyclic cationic units through N Hcdots, three dots, centeredO hydrogen bonding involving other N atoms, forming a chain along the a axis. The water molecules, which could not be located and may be disordered, do not interact with the macrocycle; however, they form hydrogen bonds with anions. PMID- 20165565 TI - An Interrupted Time-Series Analysis of Durkheim's Social Deregulation Thesis: The Case of the Russian Federation. AB - The dissolution of the Soviet Union resulted in sudden, widespread, and fundamental changes to Russian society. The former social welfare system-with its broad guarantees of employment, healthcare, education, and other forms of social support-was dismantled in the shift toward democracy, rule of law, and a free market economy. This unique natural experiment provides a rare opportunity to examine the potentially disintegrative effects of rapid social change on deviance, and thus to evaluate one of Durkheim's core tenets. We took advantage of this opportunity by performing interrupted time-series analyses of annual age adjusted homicide, suicide, and alcohol-related mortality rates for the Russian Federation using data from 1956 to 2002, with 1992-2002 as the postintervention time-frame. The ARIMA models indicate that, controlling for the long-term processes that generated these three time series, the breakup of the Soviet Union was associated with an appreciable increase in each of the cause-of-death rates. We interpret these findings as being consistent with the Durkheimian hypothesis that rapid social change disrupts social order, thereby increasing the level of crime and deviance. PMID- 20165566 TI - Spirituality and Cultural Identification Among Latino and Non-Latino College Students. AB - The purposes of this study were to examine (a) differences in spiritual perspectives and practices of Latino and non-Latino young adults and (b) the cultural relevance of the Latino Spiritual Perspective Scale (LSPS). Studies indicate that spiritual perspectives are embedded within cultural group norms and vary significantly across ethnic groups. A cross-sectional survey design was used with a convenience sample of 223 Latino and non-Latino university students in the Southwestern United States. The Spiritual Perspective Scale (SPS), the LSPS, the Orthogonal Cultural Identification Scale, and a demographic questionnaire were used. Latinos scored significantly higher than non-Latinos in both measures of spiritual perspectives. Self-reported behavioral measures, such as frequency of personal prayer, were also higher among the Latino group. Latino cultural identification was the only significant predictor of LSPS scores. Findings from this study indicate that spirituality among Latinos has meanings specific to the cultural group context. These findings have implications for nursing research involving the conceptualization and measurement of spirituality among multiethnic groups.Los propositos de este estudio eran examinar: (a) diferencias en perspectivas espirituales y practicas de jovenes Latinos y no Latinos; y (b) la relevancia cultural de la Escala de la Perspectiva Espiritual Latina. Estudios indican que perspectivas espirituales estan incrustadas entre normas culturales del grupo y varian considerablemente entre grupos etnicos. Un diseno transversal y de encuesta fue utilizado con una muestra de conveniencia de 233 estudiantes universitarios Latinos y no Latinos en el Suroeste de los Estados Unidos. La Escala de la Perspectiva Espiritual (EPE), la Escala de la Perspectiva Espiritual Latina (EPEL), la Escala Ortogonal de Identificacion Cultural, y un cuestionario demografico fueron utilizados. Los Latinos calificaron considerablemente mas alto que los no Latinos en ambas medidas de perspectivas espirituales. Medidas de comportamiento auto-reportadas, como la frecuencia de oracion, tambien estuvieron mas altas en el grupo Latino. La identificacion con la cultura Latina fue el unico vaticinador de las calificaciones de la EPEL. Los resultados de este estudio indican que la espiritualidad entre Latinos tiene significados especificos al contexto del grupo cultural. Estas conclusiones tienen implicaciones para las investigaciones de enfermeria que involucran la conceptualizacion y medida de la espiritualidad entre grupos multietnicos. PMID- 20165567 TI - Stroke Prevention: The Best Outcome after a Transient Ischemic Attack. Results from the Minnesota Stroke Registry and Opportunities to Improve Care. AB - A transient ischemic attack (TIA) is an opportunity for stroke prevention. We examined the care of 708 TIA patients entered into the Minnesota Stroke Registry (MSR) and analyzed the extent to which they were discharged on appropriate guideline-recommended secondary prevention treatments. We calculated the overall number of strokes prevented by multiple risk factor modifying treatments. Of the 708 TIA patients, 533 (75%) were discharged on antihypertensive treatment. Of 208 patients with an LDL-Cholesterol greater than 100 mg/dl, 131 (63%) patients were prescribed lipid-lowering medications. Anticoagulation treatment was prescribed in 76% (82 of 108) of patients diagnosed with atrial fibrillation during hospitalization. Anti-thrombotic therapy was prescribed in 94% (563 of 600) TIA patients without atrial fibrillation. We estimated that 104 strokes will be prevented over 5 years due to combining multiple treatments assuming a baseline stroke risk of 60% in atrial fibrillation patients and 17% in non-atrial fibrillation patients over 5 years. PMID- 20165568 TI - An integrated approach to cause-of-death analysis: cause-deleted life tables and decompositions of life expectancy. AB - This article integrates two methods that analyze the implications of various causes of death for life expectancy. One of the methods attributes changes in life expectancy to various causes of death; the other method examines the effect of removing deaths from a particular cause on life expectancy. This integration is accomplished by new formulas that make clearer the interactions among causes of death in determining life expectancy. We apply our approach to changes in life expectancy in the United States between 1970 and 2000. We demonstrate, and explain analytically, the paradox that cancer is responsible for more years of life lost in 2000 than in 1970 despite the fact that declines in cancer mortality contributed to advances in life expectancy between 1970 and 2000. PMID- 20165569 TI - Exact Equality and Successor Function: Two Key Concepts on the Path towards understanding Exact Numbers. AB - Humans possess two nonverbal systems capable of representing numbers, both limited in their representational power: the first one represents numbers in an approximate fashion, and the second one conveys information about small numbers only. Conception of exact large numbers has therefore been thought to arise from the manipulation of exact numerical symbols. Here, we focus on two fundamental properties of the exact numbers as prerequisites to the concept of exact numbers: the fact that all numbers can be generated by a successor function, and the fact that equality between numbers can be defined in an exact fashion. We discuss some recent findings assessing how speakers of Mundurucu (an Amazonian language), and young western children (3-4 years old) understand these fundamental properties of numbers. PMID- 20165570 TI - Using consensus guidelines effectively. PMID- 20165571 TI - Charting our course for a better CUA. PMID- 20165573 TI - Ensuring quality for radical prostatectomies in Canada. PMID- 20165572 TI - Guideline for optimization of surgical and pathological quality performance for radical prostatectomy in prostate cancer management: evidentiary base. AB - BACKGROUND: The objective is to provide surgical and pathological guidelines for radical prostatectomy (RP) with or without concurrent pelvic lymph node dissection (PLND) to achieve optimal benefit for patients, with minimal risk of harm. METHODS: For surgical questions, a literature search of MEDLINE, EMBASE and the Cochrane database was performed. A literature search for the pathological questions was not conducted since the protocol for invasive carcinomas of the prostate gland developed by the College of American Pathologists (CAP) was endorsed. Urologists and pathologists were consulted for their assessment of the surgical and pathological recommendations. RESULTS: Limited high-quality evidence from 95 primary studies was available and, therefore, the expert panel developed recommendations on the basis of a consensus of the expert opinion of the working group and through a consultation with urologists and pathologists. In addition to the CAP protocol, some technical recommendations related to the handling and processing of the specimen were made. CONCLUSION: Radical prostatectomy is recommended for the surgical treatment of prostate cancer, depending on a patient's preoperative risk profile. The panel unanimously determined that the goals for RP are to attain a positive margin rate of <25% for pT2 disease, a mortality rate of <1%, rates of rectal injury of <1% and blood transfusion rates of <10% in non-anemic patients. Standard PLND should be mandatory in high-risk patients, should be recommended for intermediate-risk patients and should be optional for low-risk patients. The quality and effectiveness of this treatment and of subsequent patient care depend on good management, effective communication and reporting between surgeons and pathologists working together as part of a multidisciplinary team. The complete guideline document is posted on the Cancer Care Ontario website (www.cancercare.on.ca); search in their Toolbox, Quality Guidelines & Standards, Clinical Program category under "surgery." PMID- 20165574 TI - Ureteral frozen sections at the time of radical cystectomy: reliability and clinical implications. AB - BACKGROUND: We hypothesized that the incidence of ureteral abnormalities on frozen section analysis (FS) at the time of radical cystectomy is much lower than historical values and that FS has minimal impact on outcomes. We also sought to determine the accuracy of FS and the associated costs. METHODS: We reviewed the records of 301 patients who underwent a radical cystectomy for urothelial carcinoma of the bladder (UC) between March 2000 and January 2007. The ureteral margins were sent for FS and subsequent permanent hematoxyllin and eosin (H&E) sections and results were compared. Analyses were performed to determine the costs of FS and if any association was present with the pathological stage of the primary bladder tumour and regional lymph nodes, the presence of urothelial carcinoma in situ of the bladder (CIS) and survival outcomes with the FS. RESULTS: We identified 602 ureters for this study. The incidence of CIS or solid urothelial carcinoma in the ureter was 2.8%. The presence of CIS of the bladder and prostatic urethra was significantly associated with a positive FS (p = 0.02). The FS were not associated with survival outcomes. The cost to pick up 1 patient with any abnormality on FS was $2080. The cost to pick up 1 patient with CIS or solid urothelial carcinoma of the ureter on FS was $6471. CONCLUSION: The incidence of CIS and tumour on FS during radical cystectomy for UC is low. The costs associated with FS are substantial. Frozen section analysis should only be performed in select patients undergoing radical cystectomy. PMID- 20165575 TI - Transobturator tape for female stress incontinence: follow-up after 24 months. AB - OBJECTIVE: The objective of this paper is to evaluate the effectiveness of transobturator vaginal tape (TOT) in the treatment of female stress urinary incontinence (SUI) and to analyze functional results and quality of life after 24 months follow-up. METHODS: The study included all women with SUI who underwent a TOT procedure in which the sling passes from the obturator foramen from the outside to the inside, under general or regional anesthesia from December 2004 to January 2006. All study patients must have had a minimal follow-up of 24 months. The patients were prospectively evaluated, and the following factors were assessed: number of pads used per day, physical examination including pelvic examination, urinalysis, urogenital distress inventory (UDI-6), analog global satisfaction scale (GSS), pad weight test, and urodynamic studies including filling cystometry and Valsalva leak point pressure (VLPP) test. RESULTS: Fifty two consecutive patients who fulfilled the inclusion criteria underwent TOT procedure by 1 surgeon. The mean age was 50 +/-9 (range 37-72) and minimal follow up was 24 months (range 24-30 months). Two patients were lost to follow-up after 12 months and 3 patients did not come for the 24-month evaluation. The mean operative time was 18 minutes +/-4 (range 15-31), with an average amount of bleeding 57 cc +/-22cc. Our results demonstrate a 92% cure or improvement rate after 12 months, and an 85% after 24 months. CONCLUSION: The transobturator approach from outside to inside is a very effective treatment of SUI with low morbidity. However, longer follow-up in larger populations should assess the long term reliability of this procedure. PMID- 20165576 TI - Patterns of computer and Internet usage among urology patients in two rural Northern Ontario communities. AB - INTRODUCTION: We wanted to determine if the Internet can be used as a potential health promotion tool among urology patients in Northern Ontario. We identified patients' computer and Internet access and use patterns in Kirkland Lake and Kapuskasing, Ontario. MATERIALS AND METHODS: This study was reviewed and approved by the ethics boards of the Kapuskasing and Kirkland Lake hospitals and Brock University. Data were collected by hand-written questionnaires in English and French. We performed a descriptive analysis of the data obtained. RESULTS: Out of the 137 questionnaires distributed and collected, we achieved a 95% response rate (7 questionnaires were incomplete). There were 67 men (52 %) and 63 women (48%) ranging in age from 24 to 84 (mean 56). Languages spoken were English (57%), French (38%) and other (5%). We divided the responses into 3 groups: non-Internet users, those with a computer but no Internet access and Internet users. Internet and non-Internet users were studied. Our results indicated that younger respondents, those with higher education and higher paying jobs, used the computer and Internet more often. The main reason behind their Internet was to seek health information for themselves, family and friends. CONCLUSION: About half of the respondents (55%) used the Internet to access health information. Patients' reactions toward online communication with their family physician were mixed. One limitation of this study is the small sample size, which inhibits making far-reaching conclusions. Our results demonstrate that individual empowerment, access to health information and access to services via emerging technologies are important issues for urology patients in rural Northern Ontario. PMID- 20165577 TI - Survey of senior resident training in urologic laparoscopy, robotics and endourology surgery in Canada. AB - INTRODUCTION: We determined the status of Canadian training during senior residency in laparoscopic, robotic and endourologic surgery. METHODS: Fifty-six residents in their final year of urology residency training were surveyed in person in 2007 or 2008. RESULTS: All residents completed the survey. Most residents (85.7%) train at centres performing more than 50 laparoscopic procedures yearly and almost all (96.4%) believe laparoscopic radical nephrectomy is the gold standard. About 82% of residents participated in a laparoscopic partial nephrectomy in 2008, compared to 64.7% in 2007. Of the respondents, 66% have participated in a laparoscopic prostatectomy and 54% believe the procedure has promising potential. Exposure and training in robotic-assisted laparoscopic procedures seem to be increasing as 35.7% of 2008 residents have access to a surgical robot and 7% consider themselves trained in robotic-assisted procedures. Most residents (71.4%) train at centres that perform percutaneous ablation. However, 65% state the procedure is performed solely by radiologists. Percutaneous nephrolithotomy is widely performed (98.2%), but only 37.5% of residents report training in obtaining primary percutaneous renal access. Despite only 12.5% of residents ranking their laparoscopic experience as below average or poor, an increasing proportion of graduating residents are pursuing fellowships in minimally-invasive urology. CONCLUSION: Laparoscopic nephrectomy is commonly performed and is considered the standard of care by Canadian urology residents. Robotic-assisted surgery is becoming more common but will require continued evaluation by educators who will ultimately define its role in the urological residency training curriculum. Minimally-invasive surgical fellowships remain popular, as Canadian residents do not feel adequately trained in certain advanced procedures. Urologists must strive to learn and adapt to new technologies or risk losing them to other specialties. PMID- 20165578 TI - The training of Canadian urology residents: Whither open surgery? PMID- 20165579 TI - Dong Quai (angelica sinensis) in the treatment of hot flashes for men on androgen deprivation therapy: results of a randomized double-blind placebo controlled trial. AB - OBJECTIVE: To determine whether Dong Quai, a Chinese herbal compound purported to be efficacious in treating menopausal vasomotor symptoms, has a therapeutic benefit in treating hot flashes among prostate cancer patients receiving androgen deprivation therapy. METHODS: A randomized double-blind placebo controlled trial was conducted involving 22 men receiving luteinizing hormone-releasing hormone agonist therapy for prostate cancer with bothersome hot flashes. After recording a baseline log of the frequency, duration and severity of daily hot flashes, patients were randomly assigned in a 1:1 ratio to receive daily placebo or Dong Quai for 3 months. Vasomotor and adverse events were recorded daily. Blood work including serum prostate-specific antigen (PSA), international normalized ratio of prothrombin time and partial thromoboplastin time were recorded at baseline and at the termination of the study. RESULTS: Seventeen of the 22 patients enrolled completed the trial. Baseline vasomotor duration and severity were equivalent between the groups, however the number of hot flashes were significantly more in the Dong Quai group (p = 0.02). With respect to the change in number of hot flashes per day, there was a slight decrease in the mean number among the Dong Quai group which was insignificant. The absolute change and average percentage change in perceived hot flash severity was similar in both groups. There was no significant decrease in the duration of the hot flashes between the 2 groups. Disease progression based on either PSA increase or change in digital rectal exam was not observed in any patient. CONCLUSION: In this small pilot study, there were no significant differences in the severity, frequency or duration of hot flashes among men receiving placebo or Dong Quai. PMID- 20165580 TI - Can alternative medicine do better than placebo?: Does it even matter? PMID- 20165582 TI - Nephrectomy is necessary in the treatment of metastatic renal cell carcinoma. PMID- 20165583 TI - Cytoreductive nephrectomy: a treatment of the past. PMID- 20165581 TI - Update on the management of non-muscle invasive bladder cancer. AB - Non-muscle invasive bladder cancer (NMIBC) is a heterogeneous population of tumours accounting for 80% of bladder cancers. Over the years, the management of this disease has been changing with improvements in results and outcomes. In this review, we focus on the latest updates on the management of NMIBC. PMID- 20165585 TI - The new-look Lung India. PMID- 20165584 TI - Tuberculosis and sarcoidosis: The continuing enigma. PMID- 20165586 TI - Sputum smear microscopy in DOTS: Are three samples necessary? An analysis and its implications in tuberculosis control. AB - OBJECTIVES: To assess relevance of spot morning spot (SMS) method of smear microscopy in tuberculosis control by directly observed treatment short course (DOTS). MATERIALS AND METHODS: Screening of smear microscopy results of 546 cases of pulmonary tuberculosis at our DOTS centre. RESULTS: Among 546 cases, 82% had all three samples positive for AFB, 98% had either morning sample or spot and morning sample positive. 2% had second spot sample positive. CONCLUSION: Examination of third sample, especially second spot sample, does not add significantly to the diagnostic yield. Examination of one spot and early morning samples were able to correctly diagnose 98% cases. This has strong implications in DOTS strategies. PMID- 20165587 TI - Significance of upper airway influence among patients of vocal cord dysfunction for its diagnosis: Role of impulse oscillometry. AB - BACKGROUND: To identify the patients of bronchial asthma (suspected or proven), not responding to optimal therapy, for the presence of vocal cord dysfunction (VCD) and to compare the diagnostic ability of flow volume (FV) loop and impulse oscillometry (IOS). MATERIALS AND METHODS: Fifty one patients of suspected/proven bronchial asthma not responding to optimal therapy were included for the study. Each patient was subjected to both FV loop and IOS studies. Direct visualization of the vocal cords with flexible fiberoptic bronchoscope for the presence of inspiratory vocal cord adduction during quiet respiration, with speech, and while performing provocative maneuvers was carried out. All patients were subjected to simple pulmonary function tests and recording of FV loop. IOS was performed on each patient to look for the site of obstruction and upper airway influence. The observations of both FV loop and IO studies were compared. RESULTS: Among 51 patients participated, 12 (23.53%) had bronchoscopical evidence of VCD and were labeled as VCD-positive group and rest 39 were designated VCD negative. No statistically significant difference in pulmonary function test (prereversibility) results between the VCD-positive and VCD-negative patients was found. Reversible airway obstruction was observed in 75% of the patients of VCD positive group and 67.65% of the patients in the VCD-negative group. Only one patient in the VCD-positive and none in VCD-negative group had inspiratory limb flattening of FV loop. Upper airway influence was evident by IOS in 58.3% of patients in the VCD-positive group and in 15.4% of patients in the VCD-negative group. This difference was statistically significant (P< 0.005). CONCLUSION: VCD was a common finding in patients with symptoms suggestive of asthma and frequently coexists with asthma. IOS was found to be a useful screening test for VCD and was more sensitive than FV loop. PMID- 20165588 TI - Tuberculosis and nutrition. AB - Malnutrition and tuberculosis are both problems of considerable magnitude in most of the underdeveloped regions of the world. These two problems tend to interact with each other. Tuberculosis mortality rates in different economic groups in a community tend to vary inversely with their economic levels. Similarly, nutritional status is significantly lower in patients with active tuberculosis compared with healthy controls. Malnutrition can lead to secondary immunodeficiency that increases the host's susceptibility to infection. In patients with tuberculosis, it leads to reduction in appetite, nutrient malabsorption, micronutrient malabsorption, and altered metabolism leading to wasting. Both, protein-energy malnutrition and micronutrients deficiencies increase the risk of tuberculosis. It has been found that malnourished tuberculosis patients have delayed recovery and higher mortality rates than well nourished patients. Nutritional status of patients improves during tuberculosis chemotherapy. High prevalence of human immunodeficiency (HIV) infection in the underdeveloped countries further aggravates the problem of malnutrition and tuberculosis. Effect of malnutrition on childhood tuberculosis and tuberculin skin test are other important considerations. Nutritional supplementation may represent a novel approach for fast recovery in tuberculosis patients. In addition, raising nutritional status of population may prove to be an effective measure to control tuberculosis in underdeveloped areas of world. PMID- 20165589 TI - Endobronchial ultrasound: A new innovation in bronchoscopy. AB - Technical development in last two decades has made it possible for pulmonologists to do endobronchial ultrasound (EBUS). With EBUS mini-probe, the multilayered structure of the tracheobronchial wall can be analyzed better than any other imaging modality. Instead of fluoroscopic guided biopsy, EBUS can be used to biopsy peripheral lesions. EBUS-transbronchial needle aspiration has proved valuable for mediastinal lymph node staging of lung cancer. Studies have shown that EBUS is cost-effective as it reduces the need for more morbid and costly invasive procedure like mediastinoscopy or thoracotomy. Prospective studies are needed in India to see how EBUS will help in populations with high prevalence of tuberculosis. PMID- 20165590 TI - Tuberculous otitis media with postaural abscess and submandibular lymphadenopathy. AB - We are reporting a case of right-sided tuberculous otitis media with postaural abscess and multiple submandibular lymphadenopathy which has been reported very infrequently. A high level of suspicion by the treating physician is mandatory to avoid long delay in diagnosis and increased complications in the modern chemotherapy era. PMID- 20165591 TI - Acquired bronchoesophageal fistula. AB - Bronchoesophageal fistula in an adult is rarely encountered in clinical practice. Most commonly, they have malignant origin. We report a case of bronchoesophageal fistula secondary to trauma caused by upper gastrointestinal endoscopy. The patient presented with recurrent chest infections and dysphagia since he underwent endoscopic procedure for obstructed denture. Barium swallow study revealed fistulous connection between right lower lobe bronchus and esophagus. PMID- 20165592 TI - Scimitar syndrome: A rare disease with unusual presentation. AB - Scimitar syndrome is a rare congenital disorder. It has a varied presentation. In adult life, it usually presents either as recurrent chest infection and/or exertional dyspnea. Pulmonary artery hypertension and hemoptysis both are uncommon features of this syndrome in adult life. PMID- 20165593 TI - Optimizing the benefit of multiple sclerosis therapy: the importance of treatment adherence. AB - Poor treatment adherence is problematic in many therapy areas, including multiple sclerosis (MS). Several immunomodulatory drugs are available for the treatment of MS, all of which require frequent parenteral administration. Current first-line therapies are two formulations of interferon (IFN) beta-1a, one of IFN beta-1b, and one of glatiramer acetate. Discontinuation of treatment is common, particularly in the first few months after initiation. Although the true effect of poor adherence to MS therapy is not known, it is likely to lead to a fall in treatment efficacy. Many factors influence a patient's adherence to treatment, including the patient's MS subtype and disability level, cognitive impairment resulting from MS, perceived lack of efficacy of the prescribed medication, and adverse events associated with MS therapy. This article summarizes the barriers to adherence to MS therapies, and discusses patient management strategies that can be employed to encourage adherence. Future advances in the field of MS treatment will be explored, including the development of orally administered drugs, which may enhance adherence. PMID- 20165594 TI - A closer look at the baseline-observation-carried-forward (BOCF). AB - PURPOSE: The baseline-observation-carried-forward (BOCF) approach is one method to handle missing data from early treatment discontinuation. We examined modifications of this approach, taking into consideration treatment-related and nontreatment-related reasons for discontinuation. METHODS: Two duloxetine chronic pain trials (placebo-controlled) were used to examine the impact of different analytical methods on study outcome. Reasons for discontinuation were categorized as treatment-related and nontreatment-related. Missing data in the primary efficacy outcome were handled using five statistical methods: mixed-model repeated measures (MMRM), last-observation-carried-forward (LOCF), BOCF, modified BOCF (mBOCF, discontinuation due to treatment-related reasons, ie, adverse events [AEs] or lack of efficacy), and aeBOCF (discontinuation due to AEs only). RESULTS: Duloxetine was superior to placebo on mean change from baseline in Brief Pain Inventory average pain rating, using MMRM (study 1, P = 0.004; study 2, P < 0.001), LOCF (study 1, P = 0.019; study 2, P < 0.001), BOCF (study 1, P = 0.019; study 2, P = 0.013), and mBOCF (study 1, P = 0.041; study 2, P = 0.005). Using aeBOCF, duloxetine was superior to placebo in study 2 (P = 0.005) and numerically better in study 1 (P = 0.075). CONCLUSION: Due to the different assumptions made by various methods regarding accounting for missing data, the analytical methods chosen may influence the interpretation of study results. Consideration should be given to the effect of actual treatment outcomes from patients. Employing different statistical approaches such as sensitivity analyses may help to assess the robustness of the study results and provide a more accurate reflection of the treatment outcome. PMID- 20165595 TI - Patient perspectives in the management of asthma: improving patient outcomes through critical selection of treatment options. AB - Asthma is a chronic inflammatory disorder of the airways that requires long-term treatment, the goal of which is to control clinical symptoms for extended periods with the least possible amount of drugs. International guidelines recommend the addition of an inhaled long-acting beta2-agonist (LABA) to a low- to medium-dose inhaled corticosteroid (ICS) when low doses of ICS fail to control asthma symptoms. The fixed combined administration of ICS/LABA improves patient compliance, reducing the risk of therapy discontinuation. The relative deposition pattern of the inhaled drug to the target site is the result of a complex interaction between the device used, the aerosol formulation and the patient's adherence to therapy. Different inhalation devices have been introduced in clinical practice over time. The new hydrofluoroalkane (HFA) solution aerosols allow for the particle size to be modified, thus leading to deeper penetration of the medication into the lung. The Modulite((R)) technology allows for the manipulation of inhaled HFA-based solution formulations, such as the fixed beclomethasone/formoterol combination, resulting in a uniform treatment of inflammation and bronchoconstriction. The success of any anti-asthmatic treatment depends on the choice of the correct device and the adherence to therapy. PMID- 20165597 TI - Footwear and foot care knowledge as risk factors for foot problems in Indian diabetics. AB - We assessed 300 diabetic and 100 age- and sex-matched controls for correlating foot wear practices and foot care knowledge and the presence of foot complications. A structured questionnaire evaluated the knowledge about foot care, type of footwear used, education level, association of tobacco abuse, and any associated symptoms of foot disease. Clinical evaluation was done by inspection of feet for presence of any external deformities, assessment of sensory function (vibration perception threshold, VPT), vascular status (foot pulses and ankle brachial ratio) and presence of any infection.In the diabetes category, 44.7% patients had not received previous foot care education. 0.6% walked barefoot outdoors and 45% walked barefoot indoors. Fourteen (4.7%) patients gave history of foot ulceration in the past and comprised the high risk group; only 2 out of 14 had received foot care education, 6 gave history of tobacco abuse, 8 had symptoms of claudication, 9 had paresthesias, 2 walked barefoot indoors. Average duration of diabetes in the high-risk and low-risk diabetes group was 10.85 +/- 6.53 and 9.83 +/- 7.99 years, respectively. In the high- and low-risk diabetic groups, VPT was 19.57 +/- 11.26 and 15.20 +/- 10.21V (P < 0.02), ankle brachial ratio was 1.05 +/- 0.19 and 1.14 +/- 0.18 (P < 0.05), and the questionnaire scores was 40.8% and 57%, respectively.In the diabetic and the control group, VPT was 15.62 +/- 10.39 and 8.36 +/- 3.61 V (P < 0.01), ankle brachial ratio was 1.14 +/- 0.18 and 1.15 +/- 0.12, and the questionnaire scores were 57% and 40.3%, respectively.In conclusion, poor knowledge of foot care and poor footwear practices were important risk factors for foot problems in diabetes. PMID- 20165596 TI - Diabetes in sub-saharan Africa: kenya, mali, mozambique, Nigeria, South Africa and zambia. AB - Until a few years ago, a limited number of epidemiologists or public health experts mentioned the words "diabetes." As new lifestyles, imported dietary practices, and globalization take roots in the developing world, as Africa is, today, diabetes and its complications are considered an epidemic in Africa, compelling African governments to start paying more attention to its impact as thousands of Africans run the risk of dying young. The potential severity of diabetes is such that some epidemiologists predict that its economic impact and death toll will surpass the ravages of HIV and AIDS in the near future. On the African sub-continent, present literature and the work of the World Diabetes Foundation have highlighted three countries, namely, Mali, Mozambique, and Zambia. However, the conditions in South Africa, Kenya, and Nigeria, some of the most developed areas of the continent, provide a clue to how people are coping and how governments are responding to diabetes and its full impact. This study is, therefore, a meta-summary of the incidence and prevalence of today's emerging silent killer or diabetes in Sub-Saharan Africa. The theme is that time is running out for Africa and that, as was for HIV/AIDS, by the time the governments wake up and stop denying the catastrophic potential of the epidemic, diabetes will simply overwhelm the continent's resources, and the world will witness the death of millions of Africans. The last section is a call for action against diabetes in terms of advocacy, promotion of awareness, and public health policies that empower people to diabetes self-management. PMID- 20165598 TI - Auditory acuity in type 2 diabetes mellitus. AB - BACKGROUND AND OBJECTIVES: The relationship between diabetes and hearing loss has been debated for many years. Hyperglycemia appears to have an effect on hearing loss and the proposed mechanisms are microangiopathy, neuropathy or a combination of both. The objective of this study was to evaluate a cross section of hyperglycemic subjects with age- and sex-matched normoglycemic controls with pure tone audiometry and compare the differences. MATERIALS AND METHODS: Forty-one type 2 diabetes mellitus subjects and 41 age- and sex-matched normoglycemic controls were subjected to a pure tone audiometric assessment followed by evaluation of their glycemic status and degree of glycemic control. The resulting data was statistically analyzed. RESULTS: The auditory thresholds in hyperglycemic subjects were higher in all age groups in all the frequencies suggestive of sensorineural hearing loss. The hyperglycemic subjects with poor control of their blood sugar levels (HbA1C > 8%) had elevated auditory thresholds in all the test frequencies. The fasting blood sugar level in hyperglycemic subjects showed a trend towards significant difference at higher frequencies, the postprandial blood sugar levels showed significant differences at higher frequencies. There was no effect of duration of diabetes mellitus on the hearing thresholds in hyperglycemic subjects. CONCLUSION: Subjects with hyperglycemia have a sensorineural hearing loss when evaluated with a pure tone audiometer in all frequencies than a normoglycemic control group. The study showed that post prandial blood sugar levels and HbA1C levels had a direct bearing on the auditory acuity of the hyperglycemic subjects. PMID- 20165599 TI - Glycohemoglobin A1c: A promising screening tool in gestational diabetes mellitus. AB - CONTEXT: Current screening tests for gestational diabetes mellitus (GDM) are inconvenient. Therefore, alternative screening tests for GDM are desirable. The use of glycohemoglobin A1c (HbA1c) in screening for GDM remains controversial. AIM: We undertook this study to evaluate the utility of HbA1c in screening for GDM. SETTINGS AND DESIGN: Retrospective study in a tertiary teaching hospital. MATERIALS AND METHODS: Laboratory records were reviewed to identify pregnant women who underwent both oral glucose tolerance test (OGTT) and HbA1c measurements over a 16-months period. The association of OGTT with HbA1c was evaluated. STATISTICAL ANALYSIS USED: Data were collected using SPSS software. Comparisons of the means and calculations of sensitivities were performed. RESULTS: Of 145 eligible patients, 124 had GDM and 21 patients did not, per OGTT. The percentages of patients with HbA1c values (reference range of 4.8%-6.0%) equal to or above sequential cut-point values of 5.0%, 5.5%, 6.0%, 6.5% and 7.0% (i.e., sensitivity values) were 100%, 98.4%, 87.1%, 62.9% and 39.5%, respectively. The mean HbA1c of the patients with GDM was 6.9 + 0.8% compared to 6.4 + 0.6% for those without GDM (P< 0.006). At an arbitrary cut-off value of 6.0% (the upper limit of normal), HbA1c would have picked up 87.1% of patients with GDM. CONCLUSIONS: This study suggests that HbA1c is a reasonably sensitive screening measure of GDM in this high-risk population. Acknowledging limitations resulting from the study design, further prospective studies are warranted to verify this conclusion, and to evaluate the specificity of HbA1c as a screening test for GDM. PMID- 20165600 TI - Impact of adhesive capsulitis on quality of life in elderly subjects with diabetes: A cross sectional study. AB - CONTEXT: Adhesive capsulitis (AC) is a common musculoskeletal manifestation in elderly having long standing history of diabetes. This hinders the function of shoulder which is crucial in many activities of daily living. This painful, functional deficit may decrease the quality of life in elderly. AIMS: The purpose of this study was to evaluate the impact of AC on quality of life in diabetic elderly subjects. SETTINGS AND DESIGN: District government Hospital, Udupi; Dr. T. M. A. Pai, Udupi, Kasturba Hospital, Manipal; and the study design is cross sectional design. MATERIALS AND METHODS: Two hundred and thirty-three diabetic elderly patients were recruited from the settings based on cluster sampling. They were evaluated for pain and restriction of range of motion in the shoulder joint and were. Severity of condition was classified on Oxford shoulder score and quality of life was calculated by SF- 36. STATISTICAL ANALYSIS USED: Descriptive statistics and spearman's correlation coefficient done in SPSS. RESULTS: Forty nine percent of women had diabetic AC. Majority of the subjects without AC fell in average quality of life. Women with AC fell in unhealthy category, whereas men were clustered in the average category. CONCLUSIONS: Adhesive capsulitis was an important factor in reducing the quality of life of the elderly with diabetes. PMID- 20165601 TI - Tropical diabetic hand syndrome. AB - Tropical diabetic hand syndrome (TDHS) is a terminology used to describe a specific complication affecting patients with diabetes mellitus in the tropics. The syndrome encompasses a localized cellulitis with variable swelling and ulceration of the hands to progressive, fulminant hand sepsis, potentially fatal. Since this syndrome is less recognized it is often under-reported. Authors present two cases of TDHS and emphasize on aggressive glycemic control and surgical therapy to prevent potential crippling or fatal complications. PMID- 20165602 TI - Pseudo "insulin allergy". AB - Allergy to human insulin is relatively rare in clinical practice. This report describes a patient referred for suspected "insulin allergy" due to lesions appearing at all sites of insulin injection. Careful evaluation confirmed contamination of the insulin syringes due to faulty techniques used by the patient. The report discusses the various types of insulin allergies and the need for proper diabetic education to avoid such infections. PMID- 20165604 TI - Basic occupational health services. PMID- 20165603 TI - Correlation between changes in blood pressure with insulin resistance in type 2 diabetes mellitus with four weeks of pioglitazone therapy. PMID- 20165606 TI - Climate change and health: Why should India be concerned? AB - Overwhelming evidence shows that climate change presents growing threats to public health security - from extreme weather-related disasters to wider spread of such vector-borne diseases as malaria and dengue. The impacts of climate on human health will not be evenly distributed around the world. The Third Assessment Report (Intergovernmental Panel on Climate Change-2001) concluded that vulnerability to climate change is a function of exposure, sensitivity, and adaptive capacity. Developing country populations, particularly in small island states, arid and high mountain zones, and in densely populated coastal areas are considered to be particularly vulnerable. India is a large developing country, with the Great Himalayas, the world's third largest ice mass in the north, 7500 km long, and densely populated coast line in the south. Nearly 700 million of her over one billion population living in rural areas directly depends on climate sensitive sectors (agriculture, forests, and fisheries) and natural resources (such as water, biodiversity, mangroves, coastal zones, grasslands) for their subsistence and livelihoods. Heat wave, floods (land and coastal), and draughts occur commonly. Malaria, malnutrition, and diarrhea are major public health problems. Any further increase, as projected in weather-related disasters and related health effects, may cripple the already inadequate public health infrastructure in the country. Hence, there is an urgent need to respond to the situation. Response options to protect health from effects of climate change include mitigation as well as adaptation. Both can complement each other and together can significantly reduce the risks of climate change. PMID- 20165605 TI - The exposure to and health effects of antimony. AB - CONTEXT: This minireview describes the health effects of antimony exposure in the workplace and the environment. AIM: To collate information on the consequences of occupational and environmental exposure to antimony on physiological function and well-being. METHODS: The criteria used in the current minireview for selecting articles were adopted from proposed criteria in The International Classification of Functioning, Disability and Health. Articles were classified from an acute and chronic exposure and toxicity thrust. RESULTS: The proportion of utilised and non utilised articles was tabulated. Antimony toxicity is dependent on the exposure dose, duration, route (breathing, eating, drinking, or skin contact), other chemical exposures, age, sex, nutritional status, family traits, life style, and state of health. Chronic exposure to antimony in the air at levels of 9 mg/m(3) may exacerbate irritation of the eyes, skin, and lungs. Long-term inhalation of antimony can potentiate pneumoconiosis, altered electrocardiograms, stomach pain, diarrhea, vomiting, and stomach ulcers, results which were confirmed in laboratory animals. Although there were investigations of the effect of antimony in sudden infant death syndrome, current findings suggest no link. Antimony trioxide exposure is predominant in smelters. Mining and exposure via glass working, soldering, and brazing are also important. CONCLUSION: Antimony has some useful but undoubtedly harmful effects on health and well-being and measures need to be taken to prevent hazardous exposure of the like. Its biological monitoring in the workplace is essential. PMID- 20165607 TI - India's National Action Plan on Climate Change. AB - Climate change is one of the most critical global challenges of our times. Recent events have emphatically demonstrated our growing vulnerability to climate change. Climate change impacts will range from affecting agriculture - further endangering food security - to sea-level rise and the accelerated erosion of coastal zones, increasing intensity of natural disasters, species extinction, and the spread of vector-borne diseases. India released its much-awaited National Action Plan on Climate Change (NAPCC) to mitigate and adapt to climate change on June 30, 2008, almost a year after it was announced. The NAPCC runs through 2017 and directs ministries to submit detailed implementation plans to the Prime Minister's Council on Climate Change by December 2008. This article briefly reviews the plan and opinion about it from different experts and organizations. PMID- 20165608 TI - Assessment of air pollution and its effects on the health status of the workers in beam rolling mills factory (Iran National Steel Industrial Group) from Ahvaz Iran. AB - BACKGROUND: Air pollutants of iron- and steel-making operations have historically been an environmental and health hazard. These pollutants include gaseous substances such as sulfur oxide, nitrogen dioxide, and carbon monoxide. The Iran National Steel Industrial Group beam rolling mills factory has two production lines viz. line 630 and line 650, with different beam production capabilities and is capable of producing different types of beams. MATERIALS AND METHODS: A retrospective cross-sectional study on 400 workers in different exposure levels to environmental pollution was performed during 2005 to determine the mean value of respirable particulate matter (RPM) concentrations and its effects on the health status of workers. To elicit information regarding the health status of the worker, the National Institute for Occupational Safety and Health standard questionnaire was used. Fisher's exact test was performed to assess the relative risk (RR) of exposure to air pollution on cardiovascular diseases, chest tightness, cough, difficulty in retention, i.e. loss of memory, tension, occupational fatigue, and occupational stress in exposed workers. RESULTS: There was significant difference in RPM pollution level between two product lines. The RR of exposure to air pollution on cardiovascular diseases, chest tightness, cough, difficulty in retention, i.e. loss of memory, tension, occupational fatigue, and occupational stress in exposed workers were 2.78, 2.44, 2.15, 1.92, 1.57, 3.90, and 2.09, respectively. PMID- 20165609 TI - Assessment of erythrocyte acetylcholine esterase activities in painters. AB - Thirty-five male painters in the age group of 20-50 years occupationally engaged in domestic and commercial painting for 5-12 years having blood lead levels (BLL) /=20 years. Two hundred and sixty diabetics, including 91 males and 169 females, were selected from the clinics of SSK Hospital and Dr RML Hospital of New Delhi. Data was analysed using SPSS for Windows, version 12. RESULTS: The mean age of the respondents was 49.7 years, with 80% of respondents being in the age-group of 40-69 years. The majority (52.1%) of female respondents were illiterate and 91.1% were economically dependent. Of the male respondents, 65.9% were skilled workers. Substance abuse was present among 41.8% male subjects. Type 2 diabetes was the commonest, with 94.6% of the subjects having this form. The mean duration of diabetes was 6.96 +/- 6.08 years. Oral hypoglycemic agents were being taken by 70.77% of the respondents. Among the diabetics the most common comorbidity was hypertension (30.8%) and the commonest complication was neuropathy (26.2%). We calculated the body mass index (BMI) of all subjects and found that, 46.2% of the male and 59.8% of the female respondents were either overweight or obese. As predicted by the waist/hip ratio (WHR), 53.8% of the male and 66.9% of the female respondents had high risk for CHD. Regular physical activity was undertaken by less than half of the subjects (46.5%). Out of eight domains of QOL in the SF-36, the two most affected were 'General Health' and 'Vitality.' Overall, males had higher QOL scores; this was found to be statistically significant (P = 0.0001). SF-36 and its eight domain scores had significant association with socioeconomic status, education, and habitual physical activity. CONCLUSION: Diabetes had an adverse effect on the QOL of these study subjects. Females had a significantly poorer QOL than males. The domains most affected were 'General Health' and 'Vitality.' Poor scores in the QOL domains were significantly associated with lower socioeconomic status, lesser education, and lesser habitual physical activity. PMID- 20165634 TI - Cascade screening for beta-thalassemia: A practical approach for identifying and counseling carriers in India. PMID- 20165635 TI - Suicidal acts reported at a teaching hospital in manipur. PMID- 20165636 TI - Community-based Study of Reproductive Tract Infections, Including Sexually Transmitted Infections, Among the Rural Population of Punjab, India. PMID- 20165637 TI - Feeding practices of children in an urban slum of kolkata. PMID- 20165638 TI - Nasal carriage of methicillin resistant staphylococci in healthy population of East sikkim. PMID- 20165639 TI - Physical activity pattern among the adolescents of a rural community in west bengal. PMID- 20165640 TI - Intra-rater and Inter-rater Reliability of Hemoglobin Color Scale Method. PMID- 20165641 TI - Consumption of iodized salt among slum households of north-East delhi, India. PMID- 20165642 TI - Introducing HPV Vaccine in Developing Countries - Addressing the Challenge. PMID- 20165643 TI - Utility of logistic regression analysis to estimate prognosis in acute myocardial infarction. PMID- 20165644 TI - Chikungunya Fever - epidemic in rural maharashtra. PMID- 20165645 TI - Investigation of death due to Fever in patrasayer block in the district of bankura, west bengal. PMID- 20165646 TI - Challenges in diabetes management with particular reference to India. AB - Diabetes was estimated to be responsible for 109 thousand deaths, 1157 thousand years of life lost and for 2263 thousand disability adjusted life years (DALYs) in India during 2004. However, health systems have not matured to manage diabetes effectively. The limited studies available on diabetes care in India indicate that 50 to 60% of diabetic patients do not achieve the glycemic target of HbA1c below 7%. Awareness about and understanding of the disease is less than satisfactory among patients, leading to delayed recognition of complications. The cost of treatment, need for lifelong medication, coupled with limited availability of anti-diabetic medications in the public sector and cost in the private sector are important issues for treatment compliance. This article attempts to highlight the current constraints in the health system to effectively manage diabetes and the need for developing workable strategies for ensuring timely and appropriate management with extensive linkage and support for enhancing the availability of trained manpower, investigational facilities and drugs. PMID- 20165647 TI - Treatment of diabetic vasculopathy with rosiglitazone and ramipril: Hype or hope? AB - Cardiovascular diseases are responsible for increased morbidity and mortality in people with diabetes. Diabetic macrovasculopathy is associated with structural and functional changes in large arteries, which causes endothelial dysfunction, increased arterial stiffness, or decreased arterial distensability. Diabetic complications can be controlled and avoided by strict glycemic control, maintaining normal lipid profiles, regular physical exercise, adopting a healthy lifestyle and pharmacological interventions. Treatment goals for patients with type 2 diabetes specify targets for glycemia and other cardiometabolic risk factors, for example, hypertension and dyslipidemia. In recent years, special attention has been devoted to both thiazolidindiones (TZDs) and angiotensin converting enzyme (ACE) inhibitors as clinical trials revealed that these drugs may reduce the rate of progression to diabetes or delay the onset of diabetes, regression of impaired glucose tolerance (IGT) to normoglycemia and reduces the composite of all-cause mortality, nonfatal myocardial infarction and stroke in patients with diabetes. This review focuses on the potential roles of rosiglitazone, a member of TZD class of antidiabetic agents, and ramipril, an ACE inhibitor, in preventing the preclinical macrovasculopathy in diabetes and IGT population. PMID- 20165648 TI - Assessing the knowledge, attitudes and practice of type 2 diabetes among patients of Saurashtra region, Gujarat. AB - As India will ranks first in diabetes now and will continue to do so in 2025, we must prevent the disease by various measures. Before setting the programmes, we should have ample data on the population's knowledge, attitude and practice (KAP) of diabetes. There are some epidemiological studies from southern India, Mumbai and north India, but there is no KAP study from Gujarat. The study was conducted between the period of June 2007 to November 2007 at three centers of Saurashtra region. Out of 300 patients who were given questionnaire, 238 patients were included for the analysis, rest were excluded due to various reasons. 52% were male. Mean age of patients was 55.82+/-10.2 years (95% CI 54.5-57.1) with mean weight of 64.52+/-10.96 Kg (95% CI 62.8-66.2). Mean duration of diabetes was 8.2+/-6.8 years (95% CI 7.2-9.1). 46% of patients knew the pathophysiology of diabetes. Nearly 50% knew the complications of diabetes. Dietary modifications were relied more than exercises among the interviewed subjects. Most of the lacunae in knowledge prevailed in drug therapy of diabetes. Insulin was not favored by most of patients. An encouraging finding in our study was that most believed in self-care and ready to change. Consultation time given by their treating doctors was less than 5 minutes in nearly 50%. Foot care and education to prevent complications were least suggested by doctors. PMID- 20165650 TI - Myths about diabetes and its treatment in North Indian population. AB - BACKGROUND: Myths prevailing about diabetes in the society have become a major hurdle for its proper treatment and control. AIM: To find out about various myths related to diabetes and its treatment in the population. MATERIALS AND METHODS: A cross sectional study was carried out in a teaching hospital of Delhi in 2008. 124 diabetic patients attending the regular diabetic clinic, 78 people who accompanied these patients and 214 non-diabetic people were included in the study. A pre-tested interview schedule with 48 questions was used to get information about sociodemographic characteristics and myths about diabetes. Data was analyzed by Epi info software version 3.2. RESULTS: The most common myth in the population (22%) was that eating more sugar causes diabetes. Others were: diabetes can only occur in old age, soaking feet in water can help control blood sugar, diabetes is a result of past sins and is cured by spiritual treatment. Myths were significantly more common in females, non-diabetics, less educated group. There was a slightly higher prevalence of myths in Muslim population. 12.1% of diabetics were taking herbal medicines. 15.9% of the diabetics and 26% of non diabetics were unaware that complications could occur if diabetes was uncontrolled. 18.5% of diabetics and 30.1% of non-diabetics were unaware about role of diet and lifestyle measures in control of diabetes. CONCLUSIONS: The prevalence of myths about diabetes is high in North Indian population which could be associated with poor early health seeking behavior and poor compliance with treatment. PMID- 20165649 TI - Lipid abnormalities in streptozotocin-diabetes: Amelioration by Morus indica L. cv Suguna leaves. AB - AIM: To observe the influence of mulberry (Morus indica L. cv Suguna) leaves on lipid abnormalities in STZ-diabetic rats. MATERIALS AND METHODS: Treatment with dried mulberry leaf powder for a period of 8 weeks in hyperglycemic and hyperlipidemic STZ-diabetic rats. RESULTS: Mulberry leaves regulated fasting blood glucose, ameliorated the abnormalities in lipid profile as indicated by significant (P<0.01) decrease in serum triglycerides, phospholipids, cholesterol and plasma free fatty acids by 50, 6, 31 and 22% respectively in STZ- diabetic rats compared to diabetic control rats which had significantly (P<0.01) raised levels of triglycerides, phospholipids, cholesterol and free fatty acids than the normal control rats. A marked increase in fecal bile acids (154%) was observed in mulberry treated diabetic rats compared to the diabetic control group indicating conversion of cholesterol to bile acids. In addition, mulberry supplementation significantly lowered LDL-C (67%) and VLDL-C (44%) levels and increased HDL-C (53%) and also decreased atherogenic index (58%) significantly when compared to the diabetic control group. CONCLUSION: Besides the diabetic rats, mulberry leaves affected lipid profile in normal rats also indicating hypolipidemic effect as a result of the synergistic action of bioactive compounds. PMID- 20165652 TI - Correlation of body mass index and total body fat with physical activity pattern in adolescents. PMID- 20165651 TI - Neurocognitive impairment and comorbid depression in patients of diabetes mellitus. AB - This study was conducted to find out the association of diabetes mellitus with cognitive functioning and depressive features. We included 50 diabetic and 30 control subjects who were screened on the basis of various inclusion and exclusion criteria. Then, a history of variables under study was taken and respective laboratory investigations were noted. First, the Becks Depression Inventory (BDI) was administrated to the patients. The cognitive function was then assessed using the digit span test, stroop Test, controlled oral word association test, visual target cancellation test, digit symbol substitution test, and visuospatial working memory matrix. The composite score on all tests was used to make cognitive index. The data was compiled and appropriate statistical methods were used. We found that 48% of elderly diabetic patients showed cognitive impairment. Poor metabolic control (hyperglycemia) was associated significantly and negatively with cognitive index in diabetic patients. Hyperglycemia was significantly and negatively correlated with immediate memory and attention, verbal memory, psychomotor functioning (DSST), and visuospatial memory. In conclusion, genesis of cognitive deficits in diabetic patients is complex. However, it appears from the study that such deficits do exist and may be associated with chronically poorly controlled diabetes. PMID- 20165653 TI - Subcutaneous emphysema from bronchocavitary subcutaneous fistula. PMID- 20165654 TI - Treatment outcomes of patients placed on treatment under directly observed therapy short-course (dots). AB - BACKGROUND: Tuberculosis continues to be a pressing health problem in India. The Revised National Tuberculosis Programme (RNTCP), an application of Directly Observed Treatment Short-course (DOTS) in India, launched in 1997 needs continuous evaluation. OBJECTIVE: To study the outcomes of treatment among the patients put on DOTS under RNTCP in Chandigarh, UT. MATERIAL #ENTITYSTARTX00026; METHODS: A Longitudinal study was conducted during 2004-2005 in 13 Microscopic centres (MC's) spread over 2 Tuberculosis Units (TU's) under District Tuberculosis Centre (DTC) in Union Territory (UT), Chandigarh. A sample of 265 respondents, selected by two-stage stratified random sampling technique, was recruited in the study cohort. Data analysis was done using SPSS-10 statistical software package. RESULTS: For Category I and Category II patients, the Success rate was 98.6% and 90.4% respectively. The overall default rate was 1.1% and failure rate was 2.6%. For re-treatment cases, failure rate was higher i.e. 5.8%. The sputum conversion rate among the new smear positive cases was 93.8% at 3 months of treatment. For the re-treatment cases, spu-tum conversion rate at 3 months was 94.1%. CONCLUSION: The study concludes that RNTCP is running successfully in UT Chandigarh, having high success rate and low default rate. The reasons for high failure rate should be explored in depth. PMID- 20165655 TI - Diagnostic Values of Electrocardiogram in Chronic Obstructive Pulmonary Disease (COPD). AB - BACKGROUND: Chronic obstructive pulmonary diseases (COPD), a broad spectrum of respiratory diseases represents a worldwide problem. Electrocardiographic (ECG) findings may help in clinical decision making regarding this disease entity. AIMS: To evaluate the extent and diagnostic values of ECG changes among COPD patients suffering from broad spectrum of respiratory diseases. MATERIAL #ENTITYSTARTX00026; METHODS: A hospital based cross-sectional study was conducted in Sworoop Rani Nehru Hospital, Allahabad in Eastern Uttar Pradesh (UP), India. A sample of 60 patients attending respiratory diseases OPD for treatment of various respiratory problems including 14 COPD patients was selected randomly during 2000 2001. Patients of respiratory diseases were also evaluated electrocardiographically along with other investigations. RESULTS: Respiratory problems were more common among rural males of low socio-economic group. COPD particularly chronic bronchitis was the commonest respiratory problem next to pulmonary tuberculosis. Inspite of normal heart rate observed in 71.4% COPD patients, ECG changes were present in 35.7% COPD patients. Peaked P-wave was observed in 35.7% COPD patients, whereas duration of QRS complex was abnormal in only 8.1% of the patients. None of the COPD patients showed abnormal P-wave duration. ECG changes were found less sensitive (35.7%) but highly specific (95.6%). CONCLUSION: Diagnostic values of ECG among patients with respiratory problems suggest that COPD patients should be screened electrocardiographically in addition to other clinical investigations. PMID- 20165656 TI - 25-year old male with pleural thickening. AB - The growth of some of the adenocarcinomas is virtually identical to that of malignant mesothelioma, also known as pseudomesotheliomatous adenocarcinoma of lung. Their differentiation on the basis of histopathology can pose diagnostic difficulties; hence immunohistochemistry and electron microscopy may be required for further differentiation. PMID- 20165657 TI - Focal eventration of the diaphragm masquerading as intrathoracic mass- "partial volume effect". PMID- 20165658 TI - Role of lifestyle in the development of chronic obstructive pulmonary disease: a review. PMID- 20165659 TI - Primary nasal tuberculosis. PMID- 20165660 TI - Smoking and the screen celebrities. PMID- 20165661 TI - Adenosine Deaminase (ADA) Level in Tubercular Pleural Effusion. AB - STUDY OBJECTIVE: To study the value of adenosine deaminase level in tuber-cular pleural effusion. DESIGN: A hospital based observational study. SETTING: Out and In patients service of department of Tuberculosis & Chest Diseases, MLN Medical College Allahabad. PATIENTS: 50 consecutive patients of pleural effusion, who were above the age of 12 years, were studied. RESULTS: Pleural fluid adenosine deaminase was more than 36 IU/L (36 to 229.7 IU/L) in tubercular pleural effusion (34 patients). In case of malignancy no. of patients was 08 and pleural fluid adenosine deaminase was more than 18.5 IU/L (18.5 to 87.6 IU/L). While in one case of hypoprotenemiea pleural fluid adenosine deaminase was 8.21 IU/L. If 36 IU/L is taken as cut of limit the sensitiv-ity and specificity of ADA for tuberculosis is 100 % and 77.7 %. More than 100 IU/L was exclusively seen in tubercular pleural effusion. CONCLUSION: ADA > 100IU/L was observed in TB only. PMID- 20165662 TI - Exercise testing in assessment and management of patients in clinical practice - present situation. PMID- 20165663 TI - A study of sputum conversion in new smear positive pulmonary tuberculosis cases at the monthly intervals of 1, 2 & 3 month under directly observed treatment, short course (dots) regimen. AB - AIMS AND OBJECTIVES: To determine sputum conversion rate at monthly intervals of 1st, 2nd and 3rd month in new smear positive cases (cat-1) under treatment under RNTCP. MATERIAL AND METHODS: The study was conducted at DOTS Center, Gauhati Medical College and Hospital; Guwahati between July 2005 to June 2006.The study is a prospective study and consists of 100 cases of new smear positive pulmonary tuberculosis cases (category 1) irrespective of age and sex. RESULTS AND OBSERVATIONS: The age & sex distribution of 100 patients showed that majority of the patients (74%) belonged to 2nd, 3rd and 4th decades & 75% were males and 25% were female with male to female ratio 3:1 respectively. The chest x-ray of 100 Smear Positive patients shows that only 60 (60%) patients had x-ray evidence of pulmonary Koch. In the present study, sputum conversion i.e. from smear positive to smear negative at the end of the 1st month is 71%, at the end of 2nd month is 84% and at the end of 3rd month is 92%. SUMMARY #ENTITYSTARTX00026; CONCLUSION: In conclusion, the overall sputum conversion rate under Directly Observed Treatment, Short Course (DOTS) chemotherapy in 100 sputum smear positive Pulmonary Tuberculosis in DOTS centre, Gauhati Medical College & Hospital was 92%.The chest x-ray evidence of pulmonary Koch in 100 patients is 60%.The sputum conversion at the end of 1st month is 71%, at the end of 2nd month it is 84% and at the end of 3rd month the same is 92%. In the present study, the infectivity decreases from the baseline with significant P value for sputum conversion of 3+, 2+ and 1+ sputum positivity. Directly Observed Treatment is an effective intervention for improving adherence to tuberculosis treatment programme in a resource-poor country. A significant decrease in conversion rate was observed with the initial high grade smear positive cases. More Prospective studies on larger number of patients are necessary to sub-stantiate our findings in this study. PMID- 20165664 TI - Contra-lateral paradoxical pleural effusion during antituberculous chemotherapy. AB - A 24-year old male developed left sided pleural effusion 10 days after the start of anti tubercular chemotherapy for right-sided pleural effusion and parenchymal lesion. This effusion seemed to be a paradoxical response as it resolved on follow up. PMID- 20165665 TI - Massive haemothorax in asymptomatic pseudocyst pancreas. AB - The case of a 35-year old man who presented with massive left sided haemothorax as a complication of an asymtomatic pancreatic pseudocyst is descibed. The diagnosis was confirmed by very high amylase content of the pleural fluid. The complications of pancreatitis and pancreatic pseudocyst are also briefly discussed. Haemothorax represents an unusual pulmonary complication of pseudocyst pancreas and should be considered in the differential diagnosis of pleural fluid collection in pancreatitis. PMID- 20165666 TI - Pulmonary mucormycosis mimicking as pulmonary tuberculosis: a case report. AB - Pulmonary Mucormycosis is an uncommon disease caused by fungi of class Zygomycetes. It occurs predminantly in an immunodeficient host most common risk factor being diabetes mellitus. The lesions are localized in the lungs or the mediastinum. We are reporting a case of 70 years old male, having cough, haemoptysis, fever and chest pain. He was on antituberculosis treatment (RHEZ) for last 10 days and was later found to have Pulmonary Mucormycosis on further evaluation. PMID- 20165667 TI - Unusual presentation of an uncommon lung malignancy. AB - Combined type of small cell lung carcinoma (SCLC) is a rare malignancy of the lung that is usually peripheral and diagnosed after resection. We report an unusual case of centrally located combined SCLC with squamous cell component that was diagnosed on endobronchial lung biopsy. PMID- 20165668 TI - Tuberculosis of the chest wall without pulmonary involvement. AB - Skeletal tuberculosis is usually seen in association with primary pulmonary form. Pulmonary tuberculosis of the chest wall is a rare entity. We herein report a case of tuberculosis of the chest wall without pulmonary involvement that presented with big ulcer in the anterior chest wall and responded completely to the antituberculosis therapy without any surgical intervention. PMID- 20165669 TI - Indian Journal of Orthopaedics: The journey so far. PMID- 20165670 TI - Scoliosis - The current concepts. PMID- 20165671 TI - The natural history of adolescent idiopathic scoliosis. AB - There have been great advances in the conservative and surgical treatment for adolescent idiopathic scoliosis in the last few decades. The challenge for the physician is the decision for the optimal time to institute therapy for the individual child. This makes an understanding of the natural history and risk factors for curve progression of significant importance. Reported rates of curve progression vary from 1.6% for skeletally mature children with a small curve magnitude to 68% for skeletally immature children with larger curve magnitudes. Although the patient's age at presentation, the Risser sign, the patient's menarchal status and the magnitude of the curve have been described as risk factors for curve progression, there is evidence that the absolute curve magnitude at presentation may be most predictive of progression in the long term. A curve magnitude of 25 degrees at presentation may be predictive of a greater risk of curve progression. Advances in research may unlock novel predictive factors, which are based on the underlying pathogenesis of this disorder. PMID- 20165672 TI - Dorsal arthrodesis in prepubertal New Zealand white rabbits followed to skeletal maturity: Effect on thoracic dimensions, spine growth and neural elements. AB - BACKGROUND: Several studies have shown that severe spinal deformity and early arthrodesis can adversely affect the development of the spine and thorax by changing their shape and reducing their normal function. This article analyzes the consequences of posterior fusion on the growth of spine, thorax and neural elements in New Zealand white rabbits and compares with similar human data. MATERIALS AND METHODS: The first section of the article analyzes the consequences of T1-T6 dorsal arthrodesis on the growth of the spine, sternum, thorax volume and neural elements in 12 prepubertal female New Zealand white rabbits, through a study of CT scans and histology specimens. The second part, evaluates thoracic dimensions in 21 children with spinal arthrodesis for treatment of deformity performed prior to nine years of age. RESULTS: Dorsal arthrodesis in prepubertal rabbits changes thoracic growth patterns. In operated rabbits thoracic depth grows more slowly than thoracic width. The sternum as well as length of thoracic vertebral bodies in the spinal segment T1-T6 show reduced growth. Children undergoing spinal arthrodesis before nine years of age were noted to have shortened height, short trunk and disproportionate body habitus at skeletal maturity. Observed spine height and chest dimension values were reduced compared to the expected norms. The ratio between chest width and chest depth was below normal values. CONCLUSIONS: The first part of the study shows that thoracic dorsal arthrodesis in prepubertal New Zealand white rabbit influences thoracic, spine growth and affects the shape of pseudo unipolar neurons of the dorsal root ganglia. The second part demonstrates that children treated before nine years of age have significantly reduced spine height and thoracic dimensions. The thorax becomes elliptical as chest depth grows less than chest width. Both experimental and clinical findings contribute to explain reduced chest growth and subsequent thoracic growth disturbance in patients treated with early arthrodesis. PMID- 20165673 TI - Results of the spine-to-rib-cage distraction in the treatment of early onset scoliosis. AB - BACKGROUND: Growing rod systems have been used in the last 30 years for the treatment of early onset scoliosis (EOS) with variable success rates. We report the results of treatment of EOS with a newly developed hybrid rod distraction system applied to the rib cage and spine with a nonfusion technique in a prospective multicenter clinical trial. MATERIALS AND METHODS: A total of 22 patients affected by progressive EOS resistant to cast and/or brace treatment were enrolled from 2004 to 2005 after informed consent into a trial of surgical treatment with a single spine-to-rib growing rod instrumentation growing spine profiler (GSP). Curves >60 degrees Cobb in the frontal plane or bending < 50% were addressed with staged anterior annulotomy and fusion and posterior implantation of a GSP rod. Less severe and rigid curves were treated with posterior implantation of GSP only. The elongation of GSP was planned according to spinal growth. Patients were kept in a brace between elongations. RESULTS: A total of 20 patients were available to follow-up with complete data. The mean follow up is 4.1 years. Mean age at time of initial surgery was 5 years (3-8). Nine patients had staged antero-posterior surgeries, 11 posterior only surgeries. Mean spinal growth was 1.9 cm (1.5-2.3) or 0.5 cm per year. Mean coronal Cobb's angle correction was from 56 degrees to 45 degrees . Major complications affected 40% of patients and included rod failure in 6/20 and crankshaft in 5/20 (all in the anteroposterior surgery group). CONCLUSION: Treatment of EOS with spine-to rib growing rod in the present form provides similar correction and complication rates to those published in the series considering traditional single or dual growing rod systems. Based on this, the authors recommend revision of the GSP design and a new clinical trial to test safety and efficacy. PMID- 20165674 TI - The evaluation of short fusion in idiopathic scoliosis. AB - BACKGROUND: Selective thoracic fusion in type II curve has been recommended by King et al. since 1983. They suggested that care must be taken to use the vertebra that is neutral and stable so that the lower level of fusion is centered over the sacrum. Since then there has been the trend to do shorter and selective fusion of the major curve. This study was conducted to find out whether short posterior pedicle instrumentation alone could provide efficient correction and maintain trunk balance comparing to the anterior instrumentation. MATERIALS AND METHODS: A prospective study was conducted during 2005-2007 on 39 consecutive cases with idiopathic scoliosis cases King 2 and 3 (Lenke 1A, 1B), 5C and miscellaneous. Only the major curve was instrumented unless both curves were equally rigid and of the same magnitude. The level of fusion was planned as the end vertebra (EVB) to EVB fusion, although minor adjustment was modified by the surgeons intraoperatively. The most common fusion levels in major thoracic curves were T6-T12, whereas the most common fusion levels in the thoraco-lumbar curves were T10-L3. Fusion was performed from the posterior only approach and the implants utilized were uniformly plate and pedicle screw system. All the patients were followed at least 2 years till skeletal maturity. The correction of the curve were assessed according to type of curve (lenke IA, IB and 5), severity of curve (less than 450, 450-890 and more than 900), age at surgery (14 or less and 15 or more) and number of the segment involved in instrumentation (fusion level less than curve, fusion level as of the curve and fusion more than the curve) RESULTS: The average long-term curve correction for the thoracic was 40.4% in Lenke 1A, 52.2% in Lenke 1B and 56.3% in Lenke 5. The factors associated with poorer outcome were younger age at surgery (<11 years or Risser 0), fusion at wrong levels (shorter than the measured end vertebra) and rigid curve identified by bending study. However, all patients had significant improved trunk balance and coronal hump at the final assessment at maturity. Two patients underwent late extension fusion because of junctional scoliosis. CONCLUSIONS: With modern instrumentations, the EVB of the major curve can be used at the end of the instrumentation in most cases of idiopathic scoliosis. In those cases with either severe trunk shift, younger than 11 years old, or extreme rigid curve, an extension of one or more levels might be safer. In particular situations, the concept of centering the lowest vertebra over the sacrum should be adopted. PMID- 20165675 TI - Adolescent idiopathic scoliosis: Retrospective analysis of 235 surgically treated cases. AB - BACKGROUND: The surgical treatment of adolescent idiopathic scoliosis (AIS) has taken great strides in the last two decades. There have been no long term reported studies on AIS from India with documented long term followup. In this study we review a single surgical team's series of 235 surgically treated cases of AIS with a follow-up from two to six years. MATERIALS AND METHODS: Pre operative charts, radiographs and MRI scans for 235 patients were collected for this study. The patients were grouped into three groups where anterior correction and fusion (n=47), posterior correction and fusion (n=123) and combined anterior release and posterior instrumentation (n=65) was performed. Each group was divided into two subgroups based on the surgical approach and instrumentation strategy (all screw construct or hybrid construct) used. Patients were followed up for coronal and saggital plane corrections, apical vertebral translation (AVT), trunk balance and back pain. The percentage of correction was calculated in each group as well as sub groups. RESULTS: The incidence of MRI detected intraspinal anomaly in this series is 5.9% with 3.4% of them requiring neurosurgical procedure along with scoliosis correction. Average coronal major curve correction was 66% in the all screw group and 58.5% in the hybrid group. The coronal plane correction was better when the all screw constructs were employed. Also, the AVT and trunk balance was better with the all screw constructs. The anterior corrections resulted in better correction of the AVT and trunk balance as compared to the posterior correction. There were eight (3.4%) complications in this series. The coronal and saggital plane correction paralleled the published international standards. CONCLUSION: The coronal plane correction was better when all screw constructs were employed. Use of all pedicle screw systems obviated the need for costoplasty in most cases. The increased incidence of intraspinal anomaly may warrant a routine pre operative MR imaging of all adolescent scoliosis needing surgical treatment. PMID- 20165676 TI - Posterior scoliosis correction for adolescent idiopathic scoliosis using side opening pedicle screw-rod system utilizing the axial translation technique. AB - BACKGROUND: Though adequate literature is present depicting the results of pedicle screw-rod instrumentation using top loading systems for correction of adolescent idiopathic scoliosis (AIS), using the rod rotation technique, few published data is available regarding side loading systems used for a similar purpose. We report a retrospective study of a cohort of patients with strict inclusion criteria who underwent surgical correction of AIS with side-opening pedicle screw-rod posterior instrumentation using the axial translation technique of curve correction to assess the efficacy of side opening system for scoliosis correction with regards to patient satisfaction, Cobb's angle correction and spinal balance. MATERIALS AND METHODS: Clinical and radiological outcomes were measured in 14 consecutive patients (3 males, 11 females) with an average age of 14.0 years (range 9 to 23 years). They were followed up for an average period of 13.0 months (range - 2.2 to 28.5). All patients underwent posterior instrumentation only with pedicle screws used as anchor points. Hybrid constructs using hooks/wires or curves requiring anterior release were excluded from the study. All levels were not instrumented - more screws were put on the concavity and in the peri-apical region. Radiological evaluation was done by whole spine standing AP, lateral radiograms preoperatively and 1, 3, 6 and12 months after surgery. Cobb's angles were measured and the spinal balance was noted. Clinical evaluation was done by SRS questionnaire. The complications were documented. RESULTS: The mean preoperative Cobb's angle was 58.35 degrees (range - 44 to 72 degrees ), which came down postoperatively to 23.45 degrees (range - 10 to 38 degrees ) signifying a mean correction of 59.57% (range - 26.92 to 76.17%). Clinical outcomes were evaluated using the SRS - 30 questionnaires. The values of mean pre- and postoperative scores are 3.68 and 4.18, showing an improvement of 0.5 points. Other than one patient of superficial wound infection, which healed with antibiotics, there was no major complication. No patient had neurological deterioration. CONCLUSION: Side-opening spinal instrumentation systems, using the axial translation technique, achieved good clinical and radiological outcome for patients of AIS. PMID- 20165677 TI - Spinal loop rectangle and sub laminar wiring as a technique for scoliosis correction. AB - BACKGROUND: Most literature popularizes the efficacy of third generation instrumentation in the surgical correction of spinal deformities. A cheap and effective scoliotic deformity correction method is reviewed in this article. The aim of this study is to evaluate the efficacy of spinal loop rectangle and sub laminar wires as a modality for spinal deformity correction and its co-relation with patients' satisfaction and clinical outcome. MATERIAL AND METHODS: Thirty six patients of scoliotic spinal deformities with various etiologies (congenital 4, idiopathic- 25, neurofibromatosis-3, neuromuscular-2 and 'syndromic'-3) with ages ranging from 8 to 23 years underwent corrective posterior spinal arthrodesis with stainless steel Hartshill loop rectangle and sublaminar wires. Clinicoradiological evaluation was done at an average follow-up of 6 (1/2) years (min-2 (1/2), years). Along with clinicoradiological outcome, patient satisfaction (as per the SRS 24), was accounted. RESULTS: Average preoperative Cobb's angle were 73.25 degrees in the entire group and 66.48 degrees in the idiopathic group. Average percentage correction was 64.34% in the entire group and the (average degree of correction was 47.13). In the idiopathic group, the respective values were 69.19% and 46 degrees . Loss of correction in the whole group was 2.2 degrees at two year follow up. Sagittal profiles, truncal balance were well corrected too; minimal complications were seen. Patient satisfaction results were encouraging in 36 patients as per - SRS24). About 80.2% patients were ready to undergo the same surgery if required. (SRS24). CONCLUSION: Segmental spinal fixation with locally made spinal loop rectangle and sublaminar wires is comparable as a modality to correct scoliotic spinal deformities. PMID- 20165678 TI - Intraspinal anomalies in scoliosis: An MRI analysis of 177 consecutive scoliosis patients. AB - BACKGROUND: The association of intraspinal neural anomalies with scoliosis is known for more than six decades. However, there are no studies documenting the incidence of association of intraspinal anomalies in scoliotic patients in the Indian population. The guide lines to obtain an magnetic resonance imaging (MRI) scan to rule out neuro-axial abnormalities in presumed adolescent idiopathic scoliosis are also not clear. We conducted a prospective study (a) to document and analyze the incidence and types of intraspinal anomalies in different types of scoliosis in Indian patients. (b) to identify clinico-radiological 'indicators' that best predict the findings of neuro-axial abnormalities in patients with presumed adolescent idiopathic scoliosis, which will alert the physician to the possible presence of intraspinal anomalies and optimize the use of MRI in this sub group of patients. MATERIALS AND METHODS: The data from 177 consecutive scoliotic patients aged less than 21 years were analyzed. Patients were categorized into three groups; Group A - congenital scoliosis (n=60), group B -presumed idiopathic scoliosis (n=94) and group C - scoliosis secondary to neurofibromatosis, neuromuscular and connective tissue disorders (n=23). The presence and type of anomaly in the MRI was correlated to patient symptoms, clinical signs and curve characteristics. RESULTS: The incidence of intraspinal anomalies in congenital scoliosis was 35% (21/60), with tethered cord due to filum terminale being the commonest anomaly (10/21). Patients with multiple vertebral anomalies had the highest incidence (48%) of neural anomalies and isolated hemi vertebrae had none. In presumed 'idiopathic' scoliosis patients the incidence was higher (16%) than previously reported. Arnold Chiari-I malformation (AC-I) with syringomyelia was the most common neural anomaly (9/15) and the incidence was higher in the presence of neurological findings (100%), apical kyphosis (66.6%) and early onset scoliosis. Isolated lumbar curves had no anomalies. In group-C, incidence was 22% and most of the anomalies were in curves with connective tissue disorders. CONCLUSION: The high incidence of intraspinal anomalies in presumed idiopathic scoliosis in our study group emphasizes the need for detailed examination for subtle neurological signs that accompany neuro-axial anomalies. Preoperative MRI screening is recommended in patients with presumed 'idiopathic' scoliosis who present at young age, with neurological findings and in curves with apical thoracic kyphosis. PMID- 20165679 TI - Multimodal intraoperative neuromonitoring in corrective surgery for adolescent idiopathic scoliosis: Evaluation of 354 consecutive cases. AB - BACKGROUND: Multimodal intraoperative neuromonitoring is recommended during corrective spinal surgery, and has been widely used in surgery for spinal deformity with successful outcomes. Despite successful outcomes of corrective surgery due to increased safety of the patients with the usage of spinal cord monitoring in many large spine centers, this modality has not yet achieved widespread popularity. We report the analysis of prospectively collected intraoperative neurophysiological monitoring data of 354 consecutive patients undergoing corrective surgery for adolescent idiopathic scoliosis (AIS) to establish the efficacy of multimodal neuromonitoring and to evaluate comparative sensitivity and specificity. MATERIALS AND METHODS: The study group consisted of 354 (female = 309; male = 45) patients undergoing spinal deformity corrective surgery between 2004 and 2008. Patients were monitored using electrophysiological methods including somatosensory-evoked potentials and motor-evoked potentials simultaneously. RESULTS: Mean age of patients was 13.6 years (+/-2.3 years). The operative procedures involved were instrumented fusion of the thoracic/lumbar/both curves, Baseline somatosensory-evoked potentials (SSEP) and neurogenic motor-evoked potentials (NMEP) were recorded successfully in all cases. Thirteen cases expressed significant alert to prompt reversal of intervention. All these 13 cases with significant alert had detectable NMEP alerts, whereas significant SSEP alert was detected in 8 cases. Two patients awoke with new neurological deficit (0.56%) and had significant intraoperative SSEP + NMEP alerts. There were no false positives with SSEP (high specificity) but 5 patients with false negatives with SSEP (38%) reduced its sensitivity. There was no false negative with NMEP but 2 of 13 cases were false positive with NMEP (15%). The specificity of SSEP (100%) is higher than NMEP (96%); however, the sensitivity of NMEP (100%) is far better than SSEP (51%). Due to these results, the overall sensitivity, specificity and positive predictive value of combined multimodality neuromonitoring in this adult deformity series was 100, 98.5 and 85%, respectively. CONCLUSION: Neurogenic motor-evoked potential (NMEP) monitoring appears to be superior to conventional SSEP monitoring for identifying evolving spinal cord injury. Used in conjunction, the sensitivity and specificity of combined neuromonitoring may reach up to 100%. Multimodality monitoring with SSEP + NMEP should be the standard of care. PMID- 20165680 TI - Validity of the DEXA diagnosis of involutional osteoporosis in patients with femoral neck fractures. AB - BACKGROUND: There exists no study comparing dual energy X-ray absorptimetry (DEXA) with histomorphometry to evaluate its accuracy and validity as an assessment tool. A prospective study was done comparing the measurements of osteoporosis in patients with femoral neck fractures using the histological method of diagnosis and in the same patients with DEXA postoperatively. PATIENTS AND METHODS: The histological method depends on histomorphometric analysis of bone biopsies taken from the neck of femur during surgical treatment of the fracture. We depend on three indices in histomorphometric analysis: these are osteoid seam width, osteoblast surface, and osteoid surface. The radiological method depends on the measurement of the bone mineral density using DEXA for fractured patients with the scan performed onto the contralateral nonfractured hips and lumbar spines. RESULTS: We found positive histological histomorphometric parameters of osteoporosis in 68% of patients with the femoral neck fracture, and there is a moderate correlation between histological histomorphometric analysis and DEXA in the diagnosis of osteoporosis in these patients. In our study, DEXA can detect up to 88.2% of possible cases of osteoporosis (sensitivity 88.2%), but the specificity of this diagnostic tool is 62.5% at a t-score of 10 mm 25.88 +/- 7.14. The difference was statistically significant. CONCLUSIONS: Pelvic ring injuries can lead to long term problems significantly. The involvement of the SI joint affects the long-term outcome adversely, more so if the residual displacement is >10 mm. The pelvic scoring system is comprehensive and depicts subtle differences in the outcome, which the individual parameters of the assessment fail to show. PMID- 20165682 TI - Gap nonunion of forearm bones treated by modified Nicoll's technique. AB - BACKGROUND: The management of an atrophic nonunion with a gap following a fracture of the radius and/or ulna is a challenging problem. Various methods of treatment available in the literature are cortical tibial graft (Boyd), ulnar segment graft (Miller and Phalen), iliac crest graft (Spira), cancellous insert graft (Nicoll), vascularized fibular graft (Jupiter), and bone transport by ring fixator (Tesworth). The present study reports the results of tricorticocancellous bone block grafts using modified Nicoll's technique, in diaphyseal defects of forearm bones. MATERIALS AND METHODS: A total of 38 forearm bones (either radius or ulna or both) in 23 patients with a gap of 1.5-7.5 cm were treated by debridement and tricorticocancellous bone block graft under compression with intramedullary nail fixation between June 1985 and June 2005. There were 15 male and 8 female patients. Sixteen patients had open and seven patients had closed fractures initially. Time of presentation since the original injury varied from 9 months to 84 months. Eighteen patients had already undergone one to three operations. RESULTS: Thirty-six bones showed union at both host graft junctions. The mean duration of union was 17.5 weeks (range, 14-60 weeks). Two bones had union only at one host graft junction and did not show any evidence of callus formation up to 9 months on the other end, hence requiring subsequent procedure in the form of phemister bone grafting. Patients were followed for a minimum period of 2 years (range, 2-7 years). Results were based on the status of union and range of motion (ROM) for elbow/wrist and grip strength at the final follow up. Complications observed were the reactivation of infection (n = 1) and herniation of the muscles at the donor site (n = 1). CONCLUSION: The tricorticocancellous strut bone grafting under optimal compression, augmented with intramedullary fixation, provides a promising solution to difficult problem of an atrophic nonunion of forearms bones with gap. PMID- 20165683 TI - Outcome of Gartland type II and type III supracondylar fractures treated by Blount's technique. AB - BACKGROUND: According to some orthopedic surgeons, almost all supracondylar humerus fractures should be treated operatively by reduction and pinning. While according to others, closed reduction and immobolization should be used for Gartland type II and some type III fractures. However, the limit of this technique remains unclear. We present 74 patients with displaced extension-type supracondylar fractures treated by closed reduction and immobilization with a collar sling fixed to a cast around the wrist. The purpose of the study is to give a more precise limitation of this technique. MATERIALS AND METHODS: Retrospective data acquisition of 74 patients with a Gartland type II or type III fractures treated by closed reduction and immobilization (Blount's technique) between January 2004 and December 2007 was done. The mean age was 6.3 years (range, 2-11). The mean time of follow-up was 6.5 months (range, 3-25). All open injuries and complex elbow fracture dislocations or T-condylar fractures were excluded from the study. All patients were evaluated with standardized anteroposterior and true lateral x-rays of the elbow, and Flynn criteria were used for functional assessment. RESULTS: Gartland type II fractures had 94% good or excellent final results. Gartland type III fractures had 73% good or excellent final result. The Gartland type III outcome depended on the displacement. The fractures remained stable in 88% for the posterior displacement, and 58% for the posteromedial displacement. These displacements were mild. However, for the posterolaterally displaced fractures, only 36% were stable; 36% had a mild displacement and 27% had a major displacement. CONCLUSION: Pure posterior displacement is more stable than posteromedial displacement which is more stable than posterolaterally displaced fractures. This study suggests that Gartland type II and pure posterior or posteromedial displaced Gartland type III fractures can be treated by closed reduction and immobilization with success. PMID- 20165684 TI - Cervical neurofibromatosis with quadriparesis: Management by fibular strut graft. AB - This is a case report of an eight-year old boy with neurofibromatosis and a 120 degrees dystrophic kyphosis of the cervical spine. He presented with progressive quadriparesis caused by spondyloptosis of the C2/C3, and was successfully treated by skull traction and one-stage anterior fibular strut graft lying between the tubercle of the atlas through the C2 body slot and lower vertebrae. At seven years follow-up there was, loosening of lower vertebral screws which allowed growth and residual mobility of lower vertebral joints while the fusion of upper cervical spines was still solid. PMID- 20165685 TI - Extramedullary hemopoiesis with undiagnosed, early myelofibrosis causing spastic compressive myelopathy: Case report and review. AB - Extramedullary hemopoiesis (EMH) is a common compensatory phenomenon associated with chronic hemolytic anemia. Abnormal hemopoietic tissue usually develops in sites responsible for fetal hemopoiesis, such as spleen, liver and kidney; however, other regions such as the spine may also become involved. In this study, a patient presenting with spastic paraparesis due to EMH in the dorsal spine is described. A 62-year-old man presented with paraparesis. Magnetic resonance imaging revealed a large lesion involving the T2-L2 vertebral levels with a large extradural component causing thecal sac compression. Laminectomy with excision of mass was carried out. The histopathology revealed EMH. The patient had no known cause for EMH at the time of diagnosis but, subsequently, a bone marrow examination revealed early myelofibrosis. This case represents the rare occurrence of a large extradural extramedullary hematopoiesis in a patient with no known predisposing factor for hemopoiesis at the time of presentation. PMID- 20165686 TI - Primary synovial osteochondromatosis of a subdeltoid bursa. AB - Primary synovial osteochondromatosis (SOC) is known to be intra-articular and wherever it is observed outside a synovial joint, it is associated with the involvement of the nearby joint. Primary SOC has not been reported to involve a subdeltoid bursa. We present a case of a 52-year-old woman having a large number of loose bodies in a large tumor in the subdeltoid bursa. The swelling was first noticed by the patient 2 years back. Plain roentgenogram revealed soft tissue swelling only with no areas of calcification. On MRI, multiple nonosseous loose bodies were visualized in the bursa deep to the deltoid muscle. A surgical excision of subdeltoid bursa was done. A biopsy confirmed it to be cartilaginous loose bodies in synovial lining sugestive of metaplastic transformation of the synovial tissue. PMID- 20165687 TI - Pseudoaneurysm as a complication of ankle arthroscopy. AB - We present a case of a pseudoaneurysm of the anterior tibial artery following ankle arthroscopy with synovectomy, an extremely rare complication when standard anteromedial and anterolateral portals are used. The patient was diagnosed and treated with appropriate interventions which led to an uneventful recovery. Nevertheless, the potential sequelae of delayed diagnosis or misdiagnosis of the complication are dangerous; therefore, a high index of suspicion for a pseudoaneurysm must be maintained in the postoperative period. PMID- 20165688 TI - Nonsecretory multiple myeloma, how to make a diagnosis? PMID- 20165690 TI - Three paths to better tyrosine kinase inhibition behind the blood-brain barrier in treating chronic myelogenous leukemia and glioblastoma with imatinib. AB - Chronic myelogenous leukemia (CML) can be controlled for years with the tyrosine kinase inhibitor imatinib but because imatinib poorly penetrates the blood-brain barrier (BBB), on occasion, the CML clone will thrive and evolve to an accelerated phase in the resulting imatinib sanctuary within the central nervous system. In this, CML resembles glioblastoma in that imatinib, which otherwise may be effective, cannot get to the tumor. Although a common street drug of abuse, methamphetamine is Food and Drug Administration-approved and marketed as a pharmaceutical drug to treat attention-deficit disorders. It has shown the ability to open the BBB in rodents. We have some clinical hints that it may do so in humans as well. This short note presents three new points potentially leading to better tyrosine kinase inhibition behind the BBB: 1) Pharmaceutical methamphetamine may have a useful role in treating both CML and glioblastoma by allowing higher imatinib concentrations behind the BBB. 2) The old antidepressant and monoamine oxidase inhibitor selegiline, used to treat Parkinson disease, is catabolized to methamphetamine. Selegiline, as a nonscheduled drug,may therefore be an easier way to open the BBB, allowing more effective chemotherapy with tyrosine kinases. 3) Dasatinib is a tyrosine kinase inhibitor with a spectrum of inhibition only partially overlapping that of imatinib and a mechanism of tyrosine kinase inhibition that is different from that of imatinib. The two should be additive. In addition, dasatinib crosses the BBB poorly, and it can therefore be expected to benefit from methamphetamine-assisted entry. PMID- 20165691 TI - Two-dimensional Fast Surface Imaging Using a Handheld Optical Device: In Vitro and In Vivo Fluorescence Studies. AB - Near-infrared (NIR) optical imaging is a noninvasive and nonionizing modality that is emerging as a diagnostic tool for breast cancer. The handheld optical devices developed to date using the NIR technology are predominantly developed for spectroscopic applications. A novel handheld probe-based optical imaging device has been recently developed toward area imaging and tomography applications. The three-dimensional (3D) tomographic imaging capabilities of the device have been demonstrated from previous fluorescence studies on tissue phantoms. In the current work, fluorescence imaging studies are performed on tissue phantoms, in vitro, and in vivo tissue models to demonstrate the fast two dimensional (2D) surface imaging capabilities of this flexible handheld-based optical imaging device, toward clinical breast imaging studies. Preliminary experiments were performed using target(s) of varying volume (0.23 and 0.45 cm(3)) and depth (1-2 cm), using indocyanine green as the fluorescence contrast agent in liquid phantom, in vitro, and in vivo tissue models. The feasibility of fast 2D surface imaging ( approximately 5 seconds) over large surface areas of 36 cm(2) was demonstrated from various tissue models. The surface images could differentiate the target(s) from the background, allowing a rough estimate of the target's location before extensive 3D tomographic analysis (future studies). PMID- 20165689 TI - Targeting p53 for Novel Anticancer Therapy. AB - Carcinogenesis is a multistage process, involving oncogene activation and tumor suppressor gene inactivation as well as complex interactions between tumor and host tissues, leading ultimately to an aggressive metastatic phenotype. Among many genetic lesions, mutational inactivation of p53 tumor suppressor, the "guardian of the genome," is the most frequent event found in 50% of human cancers. p53 plays a critical role in tumor suppression mainly by inducing growth arrest, apoptosis, and senescence, as well as by blocking angiogenesis. In addition, p53 generally confers the cancer cell sensitivity to chemoradiation. Thus, p53 becomes the most appealing target for mechanism-driven anticancer drug discovery. This review will focus on the approaches currently undertaken to target p53 and its regulators with an overall goal either to activate p53 in cancer cells for killing or to inactivate p53 temporarily in normal cells for chemoradiation protection. The compounds that activate wild type (wt) p53 would have an application for the treatment of wt p53-containing human cancer. Likewise, the compounds that change p53 conformation from mutant to wt p53 (p53 reactivation) or that kill the cancer cells with mutant p53 using a synthetic lethal mechanism can be used to selectively treat human cancer harboring a mutant p53. The inhibitors of wt p53 can be used on a temporary basis to reduce the normal cell toxicity derived from p53 activation. Thus, successful development of these three classes of p53 modulators, to be used alone or in combination with chemoradiation, will revolutionize current anticancer therapies and benefit cancer patients. PMID- 20165692 TI - Identification of genes associated with local aggressiveness and metastatic behavior in soft tissue tumors. AB - Soft tissue tumors represent a group of neoplasia with different histologic and biological presentations varying from benign, locally confined to very aggressive and metastatic tumors. The molecular mechanisms responsible for such differences are still unknown. The understanding of these molecular alterations mechanism will be critical to discriminate patients who need systemic treatment from those that can be treated only locally and could also guide the development of new drugs' against this tumors. Using 102 tumor samples representing a large spectrum of these tumors, we performed expression profiling and defined differentially expression genes that are likely to be involved in tumors that are locally aggressive and in tumors with metastatic potential. We described a set of 12 genes (SNRPD3, MEGF9, SPTAN-1, AFAP1L2, ENDOD1, SERPIN5, ZWINTAS, TOP2A, UBE2C, ABCF1, MCM2, and ARL6IP5) showing opposite expression when these two conditions were compared. These genes are mainly related to cell-cell and cell-extracellular matrix interactions and cell proliferation and might represent helpful tools for a more precise classification and diagnosis as well as potential drug targets. PMID- 20165693 TI - Evidence for DNA damage checkpoint activation in barrett esophagus. AB - Barrett esophagus is an epithelial metaplasia that predisposes to adenocarcinoma. Better markers of cancer risk are urgently needed to identify those patients who are likely to benefit most from emerging methods of endoscopic ablation. Disease progression is associated with genomic DNA changes (segmental gains, losses, or loss of heterozygosity). Although these changes are not easily assayed directly, we hypothesized that the underlying DNA damage should activate a DNA damage response (DDR), detectable by immunohistochemical (IHC) assays of checkpoint proteins and the resulting replicative phase cell cycle delays. Surgical specimens and endoscopic biopsies (N = 28) were subjected to IHC for the cell cycle markers cyclin A and phosphorylated histone H3 (P-H3), the DDR markers gammaH2AX and phosphorylated ATM/ATR substrates (P-ATM/ATRsub), and the DNA damage-responsive tumor suppressors p16 and p53. Correlations were made with histologic diagnoses. The fractions of cells that stained for cyclin A, P-H3, and gammaH2AX increased in parallel in dysplastic tissue, consistent with checkpoint mediated cell cycle delays. Foci of nuclear gammaH2AX and P-ATM/ATRsub were demonstrated by standard and confocal immunofluorescence. Staining for p16 was more prevalent in early-stage disease with lower staining for gammaH2AX and P-H3. Staining for p53 was moderately increased in some early-stage disease and strongly increased in some advanced disease, consistent with checkpoint-mediated induction and mutational inactivation of p53, respectively. We suggest that IHC for DDR-associated markers may help stratify risk of disease progression in Barrett. PMID- 20165694 TI - Inhibition of thromboxane synthase activity improves glioblastoma response to alkylation chemotherapy. AB - Thromboxane synthase (TXSA), an enzyme of the arachidonic acid metabolism, is upregulated in human glial tumors and is involved in glioma progression. Here, we analyzed the in vitro and in vivo effects of pharmacological inhibition of TXSA activity on human glioblastoma cells. Furegrelate, a specific inhibitor of TXSA, significantly inhibited tumor growth in an orthotopic glioblastoma model by inducing proapoptotic, antiproliferative, and antiangiogenic effects. Inhibition of TXSA induced a proapoptotic disposition of glioma cells and increased the sensitivity to the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea, significantly prolonging the survival time of intracerebral glioma-bearing mice. Our data demonstrate that the targeted inhibition of TXSA activity improves the efficiency of conventional alkylation chemotherapy in vivo. Our study supports the role of TXSA activity for the progression of malignant glioma and the potential utility of its therapeutic modulation for glioma treatment. PMID- 20165695 TI - Differential Effects of the Proteasome Inhibitor NPI-0052 against Glioma Cells. AB - Proteasome inhibitors are emerging as a new class of cancer therapeutics, and bortezomib has shown promise in the treatment of multiple myeloma and mantle cell lymphoma. However, bortezomib has failed to have an effect in preclinical models of glioma. NPI-0052 is a new generation of proteasome inhibitors with increased potency and strong inhibition of all three catalytic activities of the 26S proteasome. In this article, we test the antitumor efficacy of NPI-0052 against glioma, as a single agent and in combination with temozolomide and radiation using five different glioma lines. The intrinsic radiation sensitivities differed for all the lines and correlated with their PTEN expression status. In vitro, NPI 0052 showed a dose-dependent toxicity, and its combination with temozolomide resulted in radiosensitization of only the cell lines with a mutated p53. The effect of NPI-0052 as a single agent on glioma xenografts in vivo was only modest in controlling tumor growth, and it failed to radiosensitize the glioma xenografts to fractionated radiation. We conclude that NPI-0052 is not a suitable drug for the treatment of malignant gliomas despite its efficacy in other cancer types. PMID- 20165696 TI - Noninvasive assessment of tumor VEGF receptors in response to treatment with pazopanib: a molecular imaging study. AB - Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) drive angiogenesis, and several VEGFR inhibitors are already approved for use as single agents or in combination with chemotherapy. Although there is a clear benefit with these drugs in a variety of tumors, the clinical response varies markedly among individuals. Therefore, there is a need for an efficient method to identify patients who are likely to respond to antiangiogenic therapy and to monitor its effects over time. We have recently developed a molecular imaging tracer for imaging VEGFRs known as scVEGF/(99m)Tc; an engineered single-chain (sc) form of VEGF radiolabeled with technetium Tc 99m ((99m)Tc). After intravenous injection, scVEGF/(99m)Tc preferentially binds to and is internalized by VEGFRs expressed within tumor vasculature, providing information on prevalence of functionally active receptors. We now report that VEGFR imaging readily detects the effects of pazopanib, a small-molecule tyrosine kinase inhibitor under clinical development, which selectively targets VEGFR, PDGFR, and c-Kit in mice with HT29 tumor xenografts. Immunohistochemical analysis confirmed that the changes in VEGFR imaging reflect a dramatic pazopanib-induced decrease in the number of VEGFR 2(+)/CD31(+) endothelial cells (ECs) within the tumor vasculature followed by a relative increase in the number of ECs at the tumor edges. We suggest that VEGFR imaging can be used for the identification of patients that are responding to VEGFR-targeted therapies and for guidance in rational design, dosing, and schedules for combination regimens of antiangiogenic treatment. PMID- 20165697 TI - The effect of providing a USB syllabus on resident reading of landmark articles. AB - BACKGROUND: The acquisition of new knowledge is a primary goal of residency training. Retrieving and retaining influential primary and secondary medical literature can be challenging for house officers. We set out to investigate the effect of a Universal Serial Bus (USB) drive loaded with landmark scientific articles on housestaff education in a pilot study. METHODS: We created a USB syllabus that contains 187 primary scientific research articles. The electronic syllabus had links to the full-text articles and was organized using an html webpage with a table of contents according to medical subspecialties. We performed a prospective cohort study of 53 house officers in the internal medicine residency program who received the USB syllabus. We evaluated the impact of the USB syllabus on resident education with surveys at the beginning and conclusion of the nine-month study period. RESULTS: All 50 respondents (100%) reported to have used the USB syllabus. The self-reported number of original articles read each month was higher at the end of the nine-month study period compared to baseline. Housestaff rated original articles as being a more valuable educational resource after the intervention. CONCLUSIONS: An electronic syllabus with landmark scientific articles placed on a USB drive was widely utilized by housestaff, increased the self-reported reading of original scientific articles and seemed to have positively influenced residents' attitude toward original medical literature. PMID- 20165698 TI - Keeping learning central: a model for implementing emerging technologies. AB - FELT PROBLEM: Technology integration continues to be a challenge for health science faculty. While students expect emerging technologies to be used in the classroom, faculty members desire a strategic process to incorporate technology for the students' benefit. OUR SOLUTION: We have developed a model that provides faculty a strategy for integrating emerging technologies into the classroom. The model is grounded in student learning and may be applied to any technology. We present the model alongside examples from faculty who have used it to incorporate technology into their health sciences classrooms. PMID- 20165699 TI - School avoidance from the point of view of child and adolescent psychiatry: symptomatology, development, course, and treatment. AB - BACKGROUND: A considerable percentage of children and adolescents who avoid school have mental illnesses. This article reviews the typical manifestations, classification, development, course, and treatment of school-avoiding behavior. METHODS: Based on a selective review of recent literature, we present findings on the psychopathologically relevant features of school-avoiding children and adolescents, including psychiatric diagnoses, developmental, family-related, and psychological test variables. The emphasis is placed on our own studies of the subject. RESULTS: Although the evidence from the studies that have been performed to date is not definitive, the available findings show that school avoidance is associated with poor mental health and with unfavorable consequences onward into adulthood. Its causes include a number of individual and social stressors that place excessive demands on the affected children and adolescents and lead them to avoid school as a coping attempt. CONCLUSIONS: Many preventive and therapeutic interventions are now available, but the existing measures need to be better coordinated, and more effort needs to be directed to the early recognition and treatment of school-avoiding behavior. Physicians should consider the possibility of mental illness. Rather than writing sick notes or prescribing mother-child treatments at health resorts, which rather tend to sustain the problem, they should refer patients promptly to a child and adolescent psychiatrist. PMID- 20165700 TI - Judging a plethora of p-values: how to contend with the problem of multiple testing--part 10 of a series on evaluation of scientific publications. AB - BACKGROUND: When reading reports of medical research findings, one is usually confronted with p-values. Publications typically contain not just one p-value, but an abundance of them, mostly accompanied by the word "significant." This article is intended to help readers understand the problem of multiple p-values and how to deal with it. METHODS: When multiple p-values appear in a single study, this is usually a problem of multiple testing. A number of valid approaches are presented for dealing with the problem. This article is based on classical statistical methods as presented in many textbooks and on selected specialized literature. RESULTS: Conclusions from publications with many "significant" results should be judged with caution if the authors have not taken adequate steps to correct for multiple testing. Researchers should define the goal of their study clearly at the outset and, if possible, define a single primary endpoint a priori. If the study is of an exploratory or hypothesis generating nature, it should be clearly stated that any positive results might be due to chance and will need to be confirmed in further targeted studies. CONCLUSIONS: It is recommended that the word "significant" be used and interpreted with care. Readers should assess articles critically with regard to the problem of multiple testing. Authors should state the number of tests that were performed. Scientific articles should be judged on their scientific merit rather than by the number of times they contain the word "significant." PMID- 20165702 TI - Who assesses the quality of systematic reviews? PMID- 20165703 TI - High potential for addiction. PMID- 20165704 TI - Smoking--a study that leaves many questions unanswered. PMID- 20165707 TI - School as a risk factor. PMID- 20165709 TI - Alternative to crutches? PMID- 20165713 TI - What's new in Emergencies, Trauma and Shock? Coagulation is in the focus! PMID- 20165714 TI - Coagulation studies in patients with orthopedic trauma. AB - BACKGROUND: Head injury, severe acidosis, hypothermia, massive transfusion and hypoxia often complicate traumatic coagulopathy. First line investigations such as prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen level, platelet count and D-dimer levels help in the initial assessment of coagulopathy in a trauma victim. AIM: To study the coagulation profile in patients of orthopedic trauma. SETTINGS AND DESIGN: Prospective study. PATIENTS AND METHODS: Patients with head injury, severe acidosis, massive transfusion and severe hypoxia were excluded from the study. Coagulation parameters were evaluated at three intervals, at the time of admission, intra operatively and in the postoperative period. STATISTICAL ANALYSIS: Chi-square test was used for analysis of categorical variables. For comparison between groups, two- way ANOVA was used. RESULTS AND CONCLUSIONS: Of the 48 patients studied, 38 (80%) had normal DIC scores upon admission and only 10 (20%) had mild DIC scores at the time of admission. The median Injury Severity Score was 34 and they did not correlate with DIC scores. Fibrinogen levels alone were significantly different, increased progressively (mean pre op, intra op and post op levels 518 +/- 31,582 +/- 35 and 643 +/- 27 respectively; P .05). After 70 days, all pulps displayed healthy tissue. In the leakage test no specimens revealed any dye penetration. CONCLUSION: MTA showed equally good results as Ca(OH)2 and can berecommended clinically for direct pulp capping. PMID- 20165739 TI - How dentistry will look 10 years from today. PMID- 20165738 TI - Influence of loading forces on the vertical accuracy of interocclusal records. AB - OBJECTIVE: To evaluate the influence of loading forces on the vertical discrepancies caused by interocclusal recording materials. METHOD AND MATERIALS: A custom-made apparatus was used to simulate the maxilla and mandible. Eight interocclusal records were made in each of the following groups: G1-Aluwax (aluminum wax; Aluwax), G2-Beauty Pink wax (hydrocarbon wax compound; Miltex), G3 Futar D, G4-Futar D Fast, G5-Futar Scan (polyvinyl siloxanes; Kettenbach), and G6 Ramitec (polyether; 3M ESPE). The vertical discrepancies were measured by an inductive displacement transducer connected to a carrier frequency amplifier after storage of the records for 1 hour at room temperature. Different compressive loading forces up to 1 kg were applied onto the upper part of the apparatus to evaluate the influence on the vertical discrepancies of the records. Two-way ANOVA was used for statistical analysis. RESULTS: The compressive loading force had a statistically significant influence on the vertical discrepancies (P<.01) (ie, higher forces reduced the vertical discrepancies). When a compressive force of 1 kg was applied to the upper part of the apparatus, the mean vertical discrepancies for G1 (11+/-3 microm) and G2 (12+/-3 microm) were statistically significantly higher than in groups G3 (1+/-1 microm), G4 (2+/-1 microm), G5 (0+/-1 microm), and G6 (-2+/-2 microm). CONCLUSION: A compressive force of 1 kg could be used to stabilize the cast during mounting procedures in an articulator using an interocclusal record made of polyvinyl siloxane without vertically changing the interocclusal relationships. PMID- 20165740 TI - Palatal swelling as the first and only manifestation of extranodal follicular non Hodgkin lymphoma: a case presentation. AB - Non-Hodgkin lymphomas (NHLs) in the head and neck region are malignant lymphoid neoplasms that usually originate from B-lymphocytic cell lines. Primary extranodal manifestations of this hematolymphoid tumor in the oral cavity are rare and involve the maxillary jaw including the palatal soft tissues, the mandible, and gingival tissues in patients between 60 and 70 years of age without sex predilection. This case report of an extra-nodal NHL in the palate of a 75 year-old patient emphasizes the importance of accurate clinical, radiographic, and histologic diagnostic procedures to avoid delayed diagnosis or inappropriate treatment strategies. Chemotherapy, radiotherapy, or a combination of the two with a regular clinical and hemic follow-up is recommended. PMID- 20165741 TI - Hereditary gingival fibromatosis: a report of four cases in the same family. AB - Hereditary gingival fibromatosis is characterized by a slow, progressive increase in the gingival tissue that develops as either an isolated disorder or as part of the clinical characteristics of diverse syndromes. The present case report describes a Brazilian family with individuals from three generations affected. The proposed treatment was maxillary and mandibular gingivectomy with 12 months of monitoring. PMID- 20165742 TI - Dens evaginatus and dens invaginatus in all maxillary incisors: report of a case. AB - Dens evaginatus is a developmental malformation characterized by the presence of an extra cusp that takes the form of a tubercle arising from the occlusal or the lingual surface of the tooth. It is also referred to as talon cusp in the anterior teeth and Leong premolar in the premolars. Dens invaginatus is a deep surface invagination of the crown or the root lined by enamel, dentin, and pulp. Though many case reports of dens evaginatus and dens invaginatus have been found in the literature, an association of both is a rare anomaly. Only two cases of concomitance of dens invaginatus and dens evaginatus have been reported. This article is a case report of dens evaginatus and dens invaginatus involving all four maxillary incisors in a 25-year-old patient. PMID- 20165743 TI - Relationship between crowns and the periodontium: a literature update. AB - Location of the crown margin, marginal fit, crown material, and crown contour all impact periodontal tissues. This literature review evaluated available data on their relationship with the periodontium and also examines whether any changes in established knowledge and/or perspectives have been published during the past 30 years. Electronic and manual searches conducted for in vivo investigations in the English and German literature for 1953 to 2009 provided 64 studies. Findings indicate that the supragingival location remains the most advantageous from the periodontal point of view; esthetic demands, however, dictated an intracrevicular location of the margin in the anterior zone. Metal-ceramic and all-ceramic crowns show a clinically acceptable marginal fit. Ceramic materials have the lowest plaque-retaining capacity, and a normal crown contour guarantees satisfactory periodontal health and esthetics. The accompanying data confirm the results reported in the literature, revealing that nothing has substantially changed, thereby supporting current approaches. PMID- 20165744 TI - Treatment of infrabony defects with or without enamel matrix proteins: a 24-month follow-up randomized pilot study. AB - OBJECTIVE: To evaluate a comparison of open-flap debridement (OFD) with or without the use of enamel matrix proteins (EMP) for the treatment of infrabony defects. METHOD AND MATERIALS: Ten volunteers (38 infrabony defects) were randomized to receive OFD+EMP (test site) and OFD (control site). Clinical outcomes included mean changes in Plaque Index, Gingival Index, probing pocket depth (PPD), relative attachment level (RAL), gingival recession, width of keratinized tissue, and dental mobility at baseline and at 24 months. RESULTS: A significant reduction of 4.21+/-0.97 mm was observed in PPD for the OFD+EMP group (from 6.30+/-0.99 mm to 2.09+/-0.97 mm) and of 3.28+/-1.23 mm for the OFD group (from 6.13+/-0.88 mm to 2.85+/-1.42 mm) (P<.001). The reduction in PPD was statistically significantly greater for OFD+EMP compared to OFD (P=.03). The mean RAL decreased from 13.26+/-1.88 mm to 7.57+/-2.05 mm for the OFD+EMP group (a gain of 5.69+/-1.96 mm) and from 13.37+/-1.71 mm to 8.13+/-1.34 mm (P<.001) for the OFD group (a gain of 5.24+/-1.55 mm). Gingival recession was higher in the OFD+EMP group than in the OFD group. The mean keratinized tissue significantly decreased from 4.41+/-1.39 mm to 3.63+/-1.54 mm for OFD flap group (P<.01). CONCLUSION: Both treatment modalities were efficient in improving RAL and PPD. Within groups, there was a significant reduction in keratinized tissue for OFD and a significant postoperative recession for the OFD + EMP group. Infrabony defects treated with OFD + EMP showed significantly more PPD reduction when compared to OFD. PMID- 20165745 TI - Influence of white and gray endodontic posts on color changes of tooth roots, composite cores, and all-ceramic crowns. AB - OBJECTIVE: To evaluate whether post materials affect the color of roots, composite cores, and all-ceramic crowns. METHOD AND MATERIALS: Forty extracted human incisors were divided into four groups. White posts made of zirconia (Zi) or glass fiber (Gf) and gray posts made of titanium (Ti) or carbon fiber (Cf) were randomly assigned to the roots. Composite cores and glass-ceramic crowns were made. The color of the roots, cores, and crowns was captured (Spectroshade). The mean color difference (mDeltaE) among the groups was calculated for the following comparisons: A--root: empty root versus post and core; B--root: post and core with and without cement; C--core: white versus gray posts and cores; D- lower third of crown versus original ceramic ingot; E--center of crown versus ingot. Statistical analysis was performed by ANOVA, Kruskal-Wallis, and Sheffe tests. RESULTS: White, as well as gray posts, induced little changes of the root color (A, B). Gray posts led to a significant discoloration of the cores (C: mDeltaEZi 2.0+/-0.7, mDeltaEGf 1.5+/-0.6, mDeltaETi 12.9+/-5.9, mDeltaECf 11.2+/ 5.3; P<.0001, Kruskal-Wallis) resulting in a grayish discoloration of the crowns' lower thirds (D: mDeltaEZi 5.7+/-0.8, mDeltaEGf 6.0+/-1.2, mDeltaETi 3.5+/-1.1, mDeltaECf 3.9+/-0.9; P<.0001, Kruskal-Wallis). In the center of the crowns, all posts and cores induced a similar color difference (E). CONCLUSION: A grayish gingival shadowing cannot be reduced with white posts. In combination with glass ceramic crowns, white posts and cores are esthetically beneficial. PMID- 20165746 TI - In vitro evaluation of two whitening regimens using color-analyzing methods. AB - OBJECTIVES: To determine in vitro the effect of prophylaxis before tooth whitening and to evaluate a paint-on home whitening product using two methods of color analysis. METHOD AND MATERIALS: Ninety extracted human maxillary anterior teeth were randomly separated into a prophylaxis group or nonprophylaxis group of 45 teeth. The prophylaxis group received debridement and polishing before whitening. The two groups were randomly separated into three subgroups of 15 teeth each: placebo group, test group (Easy White, Dental Kosmetik), and positive control group (Colgate Simply White, Colgate-Palmolive). The 2-week whitening treatment consisted of applying one of the three gels twice daily according to the manufacturers' instructions. In vitro measurements included tooth color assessment using digital imaging analysis and evaluation of tooth shade by a colorimeter. Measurements were taken at baseline, after prophylaxis, and after whitening. RESULTS: While whitening was effective with or without prophylaxis, prior prophylaxis contributed to improved posttreatment outcomes. Both test gel and positive control gel resulted in greater shade reductions and tooth color improvements compared to placebo gel (P<.05). The positive control gel was not superior to test gel. CONCLUSIONS: Prophylaxis is highly recommended before use of paint-on home whitening gels. Colorimetric measurements and digital imaging analysis with a gray card are options to record the efficacy of whitening products. Digital imaging analysis has advantages: Numeric data can be evaluated, and an image of the outcome of the whitening procedure is available. PMID- 20165747 TI - Wear of denture teeth and their human enamel antagonists. AB - OBJECTIVES: To evaluate the wear resistance of artificial denture teeth and their human enamel antagonists in a dual-axis chewing simulator. METHOD AND MATERIALS: Four artificial denture teeth--feldspathic ceramic, nanofilled composite resin, experimental acrylic resin with UDMA/PMMA, and interpenetrating polymer networks (IPN) acrylic resin teeth--were tested in this study. Human enamel cusps were used as antagonists. Wear resistance was analyzed by measuring the vertical substance loss and the volume loss of the denture teeth using a laser scanner after 300,000 chewing cycles. In addition, the vertical substance loss of the antagonists was evaluated using an optical macroscope. Data were statistically analyzed using ANOVA. For qualitative analysis of the wear areas, the teeth were sputter coated with gold and evaluated at magnifications of 503 and 1,0003 using SEM. RESULTS: The composite resin teeth exhibited wear that was significantly higher than that of feldspathic ceramic but lower than that of acrylic resin teeth (P<.05). Acrylic resin teeth caused no measurable wear on the enamel antagonists. The wear patterns of the feldspathic ceramic and composite resin teeth can be described as attritional, while a fatigue type of wear was observed in the acrylic resin teeth. CONCLUSION: The lowest total vertical substance loss was found for the combination composite resin-enamel. Based on the results of this study, composite resin teeth seem to be more suitable for dentures opposing natural teeth than ceramic or acrylic resin teeth in terms of wear resistance. PMID- 20165748 TI - Content of urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 in oral mucosa and inflamed periodontal tissue. AB - OBJECTIVES: Recent literature has demonstrated that local proteolytic enzymes participate in periodontitis and peri-implantitis. The aim of the present study was to evaluate whether the serine proteases urokinase-type plasminogen activator (uPA) and its plasminogen activator inhibitor type 1 (PAI-1) show elevated amounts in inflamed periodontal tissues as compared to healthy oral mucosa to determine if these proteins are involved in the process of periodontal breakdown. METHOD AND MATERIALS: Fifty-eight patients with severe periodontitis were included in this study. Periodontal therapy was performed by means of modified Widman flaps. During surgery, samples of healthy oral mucosa and inflamed tissues were taken. Highly sensitive ELISAs allowed for determination of uPA and PAI-1 content in inflamed periodontal tissues and healthy oral mucosa. RESULTS: The amount of uPA and PAI-1 in diseased periodontal tissue was significantly higher than in the clinically healthy oral mucosa (P=or<.002). However, no statistically significant correlation with the sex or age of the patients or attachment loss of the teeth was seen. CONCLUSION: Serine proteases uPA and its inhibitor PAI-1 participate in periodontitis. PMID- 20165751 TI - Undoped diamond nanoparticles: origins of surface redox chemistry. AB - This article discusses some of our recent work on the origins of redox activity of undoped nanodiamond (ND) powders, as well as reviewing some properties and applications of this material. The electrochemical activity is attributed to unsaturated bonding at the ND particle surface; hence the most recent understanding of the surface chemistry of these materials is discussed. The implications of the observed redox activity, especially for use in biological applications, are highlighted, along with future avenues of research. PMID- 20165752 TI - Electrodeposition of Zn and Au-Zn alloys at low temperature in an ionic liquid. AB - In this communication, electrodeposition of Zn from 60-40 mol% ZnCl(2)-1-butyl-3 methylimidazolium chloride (BMIC) ionic liquid on Au substrates has been investigated. For the first time, initial stages of Zn electrocrystallization from BMIC has been studied by in situ X-ray diffraction (XRD) employing synchrotron radiation, which showed an initial epitaxial deposition of Zn and hexagonal Au(1.2)Zn(8.8) phases on Au(111) single crystal substrates. In the later stages of electrodeposition, phase analysis showed a formation of several Zn-Au intermetallics, namely AuZn, AuZn(3), and Au(1.2)Zn(8.8), along with the Zn phase. PMID- 20165753 TI - Amphiphilic and magnetic behavior of Fe3O4 nanocrystals. AB - Fe(3)O(4) (magnetite) nanocrystals with an average size of 13 nm were prepared using a specially synthesized polymeric stabilizer (poly-4-vinylpyridine-co acrylamidoethylamine-co-polyethyleneglycol-co-polyethyleneglycolic acid) that bears reactive groups for further functionalization. The polymer shell made the nanocrystals amphiphilic, i.e. they are soluble in pentanol, water and dichloromethane, and they distribute over the three solvents in a three phase system. The Fe(3)O(4) nanocrystals exhibited the well-known and typical magnetic properties. PMID- 20165755 TI - Spectroscopic study of the reaction between Br2 and dimethyl sulfide (DMS), and comparison with a parallel study made on Cl2 + DMS: possible atmospheric implications. AB - The reaction between molecular bromine and dimethyl sulfide (DMS) has been studied both as a co-condensation reaction in low temperature matrices by infrared (IR) matrix isolation spectroscopy and in the gas-phase at low pressures by UV photoelectron spectroscopy (PES). The co-condensation reaction leads to the formation of the molecular van der Waals adduct DMS-Br(2). This was identified by IR spectroscopy supported by results of electronic structure calculations. Calculation of the minimum energy structures in important regions of the reaction surface and computed IR spectra of these structures, which could be compared with the experimental spectra, allowed the structure of the adduct (C(s)) to be determined. The low pressure (ca. 10(-5) mbar) gas-phase reaction was studied by UV-PES, but did not yield any observable products, indicating that a third body is necessary for the adduct to be stabilised. These results are compared with parallel co-condensation and gas-phase reactions between DMS and Cl(2). For this reaction, a similar van der Waals adduct DMS-Cl(2) is observed by IR spectroscopy in the co-condensation reactions, but in the gas-phase, this adduct converts to a covalently bound structure Me(2)SCl(2), observed in PES studies, which ultimately decomposes to monochlorodimethylsulfide and HCl. For these DMS + X(2) reactions, computed relative energies of minima and transition states on the potential energy surfaces are presented which provide an interpretation for the products observed from the two reactions studied. The implications of the results obtained to atmospheric chemistry are discussed. PMID- 20165754 TI - Theoretical analysis of intermolecular interactions of selected residues of triosephosphate isomerase from Trypanosoma cruzi with its inhibitor 3-(2 benzothiazolylthio)-1-propanesulfonic acid. AB - The interaction between selected amino acid residues of the homodimeric enzyme triosephosphate isomerase from Trypanosoma cruzi with the inhibitor 3-(2 benzothiazolylthio)-1-propanesulfonic acid (BTT) was investigated by means of high level quantum chemical methods. The amino acids phe75A, arg71A and tyr102B from the enzyme monomers A and B were selected using experimental X-ray structural data. The ab initio intermolecular energies for the association of the inhibitor with the individual amino acids were calculated in two forms, namely, with a supermolecular approach and using the symmetry adapted perturbation theory. The latter also provided the contributions to the interaction energies, which were interpreted in terms of the usual van der Waals forces. The electron density for the specific interactions between BTT and the amino acids and the charge redistribution due to complex formation were also analyzed. It was found that for phe75A and tyr102B the dispersion energy is the dominant contribution to the complex stabilization followed by the induction and electrostatic energies. In addition, whereas the face-edge complex of BTT with phe75A exhibits a C-H pi bond similar to that observed for the benzene dimer, the complex with arg71A shows an important charge redistribution on the amino acid in regions far removed from those where the intermolecular specific interactions occur. PMID- 20165756 TI - Structural isotope effects in metal hydrides and deuterides. AB - Historically the extraction of high-quality crystallographic information from inorganic samples having high hydrogen contents, such as metal hydrides, has involved preparing deuterated samples prior to study using neutron powder diffraction. We demonstrate, through direct comparison of the crystal structure refinements of the binary hydrides SrH(2) and BaH(2) with their deuteride analogues at 2 K and as a function of temperature, that precise and accurate structural information can be obtained from rapid data collections from samples containing in excess of 60 at.% hydrogen using modern high-flux, medium resolution, continuous wavelength neutron powder diffraction instruments. Furthermore, observed isotope-effects in the extracted lattice parameters and atomic positions illustrate the importance of investigating compounds in their natural hydrogenous form whenever possible. PMID- 20165757 TI - Pressure-dependent deuterium reaction pathways in the Li-N-D system. AB - Neutron diffraction data from in situ deuteration and dedeuteration of Li(3)N are presented under different pressure regimes, whereby reaction pathways differing from the widely reported stoichiometric pathway of Li(3)N + 2D(2)<--> Li(2)ND + LiD + D(2)<--> LiND(2) + 2LiD are observed. At sufficiently high pressures, where the deuterium chemical potential is comparable with the heat of amide formation, the reaction appears to be driven straight to the amide plus deuteride phase mixture. At lower pressures, a cubic phase exhibiting a concentration-dependent variation in lattice parameter is observed. In dedeuteration, two sets of reflections from cubic structures with distinct lattice parameters are observed, both of which exhibit a continual decrease in cell volume. The reaction pathways are discussed in terms of the compositional variation. PMID- 20165758 TI - Electron transport properties in fluorinated copper-phthalocyanine films: importance of vibrational reorganization energy and molecular microstructure. AB - Electron transport (ET) properties of a series of fluorinated copper phthalocyanine (F(16)CuPc) thin films, which were deposited at different substrate temperatures (T(sub)) ranging from 30 to 150 degrees C, have been investigated by quantum mechanical calculations of the reorganization energy (lambda(reorg)), X-ray diffraction (XRD), atomic force microscopy (AFM), and microRaman spectroscopy. Density functional theory calculations were used to predict the vibrational frequencies, normal mode displacement vectors, and electron-vibrational lambda(reorg) for the F(16)CuPc molecule. The electron mobilities (mu(e)) of F(16)CuPc thin films are strongly dependent on the T(sub), and the value of mu(e) increases with increasing T(sub) from 30 to 120 degrees C, at which point it reaches its maximum value. The importance of electron vibrational coupling and molecular microstructures for ET properties in F(16)CuPc thin films are discussed on the basis of theoretical vibrational lambda(reorg) calculations and experimental observations of resonance Raman spectra. We observed a good correlation between mu(e) and the full-width-at-half-maximum of the vibrational bands, which greatly contributed to lambda(reorg) and/or which reflects the molecular microstructural quality of the active channel. In contrast, the crystal size analysis by XRD and surface grain morphology by AFM did not reveal a clear correlation with the ET behaviours for these different F(16)CuPc thin films. Therefore, we suggest that for organic films with weak intermolecular interactions, such as F(16)CuPc, optimized microscopic molecular scale parameters are highly important for efficient long-range charge transport in the macroscopic devices. PMID- 20165759 TI - What is the difference between the dynamics of anion- and keto-type of photochromic salicylaldehyde azine? AB - The normal and anion structures of salicylaldehyde azine (SAA) in solvents of different viscosities and polarities have been studied by means of femto- to nanosecond time-resolved emission techniques. In the normal form, an excited state intramolecular proton-transfer (ESIPT) reaction takes place with a time constant shorter than 80 fs to produce an excited keto-type tautomer in which intramolecular-vibrational energy redistribution and vibrational cooling occur in 100 fs to 2 ps. The viscosity-dependent emission decay in the red part of the spectrum with 5-11 ps reflects a twisting motion leading to rotamers of these keto-type structures, most probably of (n,pi*) nature. For the anion type, the viscosity dependent rise-times (3 to 400 ps) at the red part of the emission, and the wavelength-dependent fluorescence lifetimes (20 to 1100 ps) indicate a stepwise formation of different conformers of the anions. The results reported here should be relevant to a better understanding of the photobehaviour of photochromic compounds and charged chromophores in biological systems. PMID- 20165760 TI - The reactions of SO3 with HO2 radical and H2O...HO2 radical complex. Theoretical study on the atmospheric formation of HSO5 and H2SO4. AB - The influence of a single water molecule on the gas-phase reactivity of the HO(2) radical has been investigated by studying the reactions of SO(3) with the HO(2) radical and with the H(2)O...HO(2) radical complex. The naked reaction leads to the formation of the HSO(5) radical, with a computed binding energy of 13.81 kcal mol(-1). The reaction with the H(2)O...HO(2) radical complex can give two different products, namely (a) HSO(5) + H(2)O, which has a binding energy that is computed to be 4.76 kcal mol(-1) more stable than the SO(3) + H(2)O...HO(2) reactants (Delta(E + ZPE) at 0K) and an estimated branching ratio of about 34% at 298K and (b) sulfuric acid and the hydroperoxyl radical, which is computed to be 10.51 kcal mol(-1) below the energy of the reactants (Delta(E + ZPE) at 0K), with an estimated branching ratio of about 66% at 298K. The fact that one of the products is H(2)SO(4) may have relevance in the chemistry of the atmosphere. Interestingly, the water molecule acts as a catalyst, [as it occurs in (a)] or as a reactant [as it occurs in (b)]. For a sake of completeness we have also calculated the anharmonic vibrational frequencies for HO(2), HSO(5), the HSO(5)...H(2)O hydrogen bonded complex, H(2)SO(4), and two H(2)SO(4)...H(2)O complexes, in order to help with the possible experimental identification of some of these species. PMID- 20165761 TI - The physical chemistry of coordinated aqua-, ammine-, and mixed-ligand Co2+ complexes: DFT studies on the structure, energetics, and topological properties of the electron density. AB - Spin-unrestricted DFT-X3LYP/6-311++G(d,p) calculations have been performed on a series of complexes of the form [Co(H(2)O)(6-n)(NH(3))(n)](2+) (n = 0-6) to examine their equilibrium gas-phase structures, energetics, and electronic properties in their quartet electronic ground states. In all cases Co(2+) in the energy-minimised structures is in a pseudo-octahedral environment. The calculations overestimate the Co-O and Co-N bond lengths by 0.04 and 0.08 A, respectively, compared to the crystallographically observed mean values. There is a very small Jahn-Teller distortion in the structure of [Co(H(2)O)(6)](2+) which is in contrast to the very marked distortions observed in most (but not all) structures of this cation that have been observed experimentally. The successive replacement of ligated H(2)O by NH(3) leads to an increase in complex stability by 6 +/- 1 kcal mol(-1) per additional NH(3) ligand. Calculations using UB3LYP give stabilisation energies of the complexes about 5 kcal mol(-1) smaller and metal-ligand bond lengths about 0.005 A longer than the X3LYP values since the X3LYP level accounts for the London dispersion energy contribution to the overall stabilisation energy whilst it is largely missing at the B3LYP level. From a natural population analysis (NPA) it is shown that the formation of these complexes is accompanied by ligand-to-metal charge transfer the extent of which increases with the number of NH(3) ligands in the coordination sphere of Co(2+). From an examination of the topological properties of the electron charge density using Bader's quantum theory of atoms in molecules it is shown that the electron density rho(c) at the Co-O bond critical points is generally smaller than that at the Co-N bond critical points. Hence Co-O bonds are weaker than Co-N bonds in these complexes and the stability increases as NH(3) replaces H(2)O in the metal's coordination sphere. Several indicators, including the sign and magnitude of the Laplacian of the charge density nabla(2)rho(c), the ratio of the local potential and kinetic energy densities, |V(c)|/G(c), the sign of the total energy density H(c), and the delocalisation index delta(Co,X), X = O, N, are used to show that whilst the metal-ligand bonds are predominantly ionic in nature, they gain covalent character as NH(3) replaces H(2)O, and the Co-N bond is significantly more covalent than the Co-O bond. We have shown that the delocalisation index delta(Co,X), X = O, N, is strongly correlated with the zero point corrected stabilisation energy E demonstrating that delta can be used as a measure of the bond stability in these complexes. PMID- 20165762 TI - Comparison of the membrane-bound [NiFe] hydrogenases from R. eutropha H16 and D. vulgaris Miyazaki F in the oxidized ready state by pulsed EPR. AB - The geometric and electronic structures of the active sites in the oxidized Ni(r) B state of the [NiFe] hydrogenases from Ralstonia eutropha H16 and Desulfovibrio vulgaris Miyazaki F were investigated in pulsed EPR and ENDOR experiments at two different microwave frequencies (X- and Q-band). Two hyperfine-couplings were clearly resolved in the frozen solution spectra arising from the beta-protons of the nickel-coordinating cysteine residues Cys549 and Cys586 from the Desulfovibrio vulgaris and Ralstonia eutropha hydrogenase, respectively. ESEEM spectroscopic experiments reveal the presence of a histidine in the second coordination sphere of the Ni. The spectroscopic data indicate that the electronic structures of the [NiFe] centers in both hydrogenases are identical in the Ni(r)-B state. However, additional spin couplings of the active site to further paramagnetic centers were identified for the Ralstonia eutropha hydrogenase. The respective couplings could be clearly resolved and simulated. The results from this study are discussed in view of the exceptional O(2) tolerance of the Ralstonia hydrogenase. PMID- 20165763 TI - Chirp effects on impulsive vibrational spectroscopy: a multimode perspective. AB - The well-documented propensity of negatively-chirped pulses to enhance resonant impulsive Raman scattering has been rationalized in terms of a one pulse pump dump sequence which "follows" the evolution of the excited molecules and dumps them back at highly displaced configurations. The aim of this study was to extend the understanding of this effect to molecules with many displaced vibrational modes in the presence of condensed surroundings. In particular, to define an optimally chirped pulse, to investigate what exactly it "follows" and to discover how this depends on the molecule under study. To this end, linear chirp effects on vibrational coherences in poly-atomics are investigated experimentally and theoretically. Chirped pump-impulsive probe experiments are reported for Sulforhodamine-B ("Kiton Red"), Betaine-30 and Oxazine-1 in ethanol solutions with <10 fs resolution. Numerical simulations, including numerous displaced modes and electronic dephasing, are conducted to reproduce experimental results. Through semi-quantitative reproduction of experimental results in all three systems we show that the effect of group velocity dispersion (GVD) on the buildup of ground state wave-packets depends on the pulse spectrum, on the displacements of vibrational modes upon excitation, on the detuning of the excitation pulses from resonance, and on electronic dephasing rates. Akin to scenarios described for frequency-domain resonance Raman, within the small-displacement regime each mode responds to excitation chirp independently and the optimal GVD is mode specific. Highly-displaced modes entangle the dynamics of excitation in different modes, requiring a multi-dimensional description of the response. Rapid photochemistry and ultrafast electronic dephasing narrow the window of opportunity for coherent manipulations, leading to a reduced and similar optimal chirp for different modes. Finally, non-intuitive coherent aspects of chirp "following" are predicted in the small-displacement and slow-dephasing regime, which remain to be observed in experiment. PMID- 20165765 TI - Synthesis of hydrogen peroxide from H2 and O2 in water and ethanol catalyzed by nanoclustered Pd(0) on silica: strong selectivity enhancement exerted by the addition of ionic liquids. AB - Hydrogen peroxide (H(2)O(2)) synthesis directly from dioxygen and dihydrogen was carried out using a continuous flow reactor with a Pd catalyst. The effects of ionic liquids on the selectivity to H(2)O(2) were studied on a Pd/SiO(2) catalyst. It was found that the ionic liquid [BMIM][BF(4)] in water or ethanol is quite beneficial to the selectivity to H(2)O(2). Ca. 95% selectivity after 1 h in both solvents and a relatively high selectivity i.e. (about 50% in ethanol and 40% in water) after 5 h reaction have been achieved. On the other hand, a plausible mechanism for the effects of ion liquids on this reaction system was suggested on the basis of the preliminary results. PMID- 20165764 TI - Ultra-large single-layer graphene obtained from solution chemical reduction and its electrical properties. AB - Graphene is a promising candidate for making next-generation nanoelectronic devices. Developing methods to produce large sized graphene with high yield is the key for graphene applications. Here, we report a simple method for large scale production of ultra-large single-layer graphene sheet (up to 50 microm) reduced from graphene oxides by hydrazine in the presence of aromatic tetrasodium 1,3,6,8-pyrenetetrasulfonic acid (TPA) which efficiently disperse the resulting graphene sheet in aqueous solutions. Field-effect transistors can be readily fabricated using such large reduced graphene oxide sheets. It was found that the mobility of the reduced graphene oxide increases with the temperature of subsequent thermal reduction and reaches 3.5 cm(2) V(-1) s(-1) after reduction at 1000 degrees C. Such solution-processable method is of great potential in printable fabrication of graphene-based devices. PMID- 20165766 TI - Orientation-resolved 3d(5/2) binding energy shift of Rh and Pd surfaces: anisotropy of the skin-depth lattice strain and quantum trapping. AB - Incorporating the BOLS correlation algorithm [Y. Sun, J. Phys. Chem. C, 2009, 113, 14696] into high-resolution XPS measurements [J. N. Andersen, et al., Phys. Rev. B: Condens. Matter, 1994, 50, 17525; A. Baraldi, et al., New J. Phys., 2007, 9, 143] has produced an effective way of determining the 3d(5/2) energy levels of isolated Rh(302.163 +/- 0.003 eV) and Pd (330.261 +/- 0.004 eV eV) atoms and their respective bulk shifts (4.367 and 4.359 eV) with a refinement of the effective atomic coordination numbers of the top (100), (110), and (111) atomic layers (4.00, 3.87, and 4.26, respectively). It is further confirmed that the shorter and stronger bonds between under-coordinated atoms induce local strain and skin-depth charge-and-energy quantum trapping and, hence, dictate globally the positive core level binding energy shifts. PMID- 20165767 TI - Using supported Au nanoparticles as starting material for preparing uniform Au/Pd bimetallic catalysts. AB - One of the best methods for producing bulk homogeneous (composition) supported bimetallic AuPd clusters involves the immobilization of a protected Au seed followed by the addition of Pd. This paper investigates the importance of this gold seed in controlling the resulting bimetallic AuPd clusters structures, sizes and catalytic activities by investigating three different gold seeds. Uniform Au Pd alloy were obtained when a steric/electrostatic protecting group, poly(vinyl alcohol) (PVA), was used to form the gold clusters on activated carbon (AC). In contrast Au/AC precursors prepared using Au nanoparticles with only electrostatic stabilization (tetrakis(hydroxypropyl)phosphonium chloride (THPC)), or no stabilization (magnetron sputtering) produced inhomogeneous alloys and segregation of the gold and palladium. The uniform alloyed catalyst (Pd@Au(PVA)/AC) is the most active and selective catalyst, while the inhomogenous catalysts are less active and selective. Further study of the PVA protected Au clusters revealed that the amount of PVA used is also critical for the preparation of uniform alloyed catalyst, their stability, and their catalytic activity. PMID- 20165768 TI - Determination of the apparent transfer coefficient for CO oxidation on Pt(poly), Pt(111), Pt(665) and Pt(332) using a potential modulation technique. AB - The apparent transfer coefficient, which gives the magnitude of the potential dependence of the electrochemical reaction rates, is the key quantity for the elucidation of electrochemical reaction mechanisms. We introduce the application of an ac method to determine the apparent transfer coefficient alpha' for the oxidation of pre-adsorbed CO at polycrystalline and single-crystalline Pt electrodes in sulfuric acid. The method allows to record alpha' quasi continuously as a function of potential (and time) in cyclic voltammetry or at a fixed potential, with the reaction rate varying with time. At all surfaces (Pt(poly), Pt(111), Pt(665), and Pt(332)) we clearly observed a transition of the apparent transfer coefficient from values around 1.5 at low potentials to values around 0.5 at higher potentials. Changes of the apparent transfer coefficients for the CO oxidation with potential were observed previously, but only from around 0.7 to values as low as 0.2. In contrast, our experimental findings completely agree with the simulation by Koper et al., J. Chem. Phys., 1998, 109, 6051-6062. They can be understood in the framework of a Langmuir-Hinshelwood mechanism. The transition occurs when the sum of the rate constants for the forward reaction (first step: potential dependent OH adsorption, second step: potential dependent oxidation of CO(ad) with OH(ad)) exceeds the rate constant for the back-reaction of the first step. We expect that the ac method for the determination of the apparent transfer coefficient, which we used here, will be of great help also in many other cases, especially under steady conditions, where the major limitations of the method are avoided. PMID- 20165769 TI - A new approach to extract multiple distinct conformers and co-existing distinct electronic properties of a single molecule by point-contact method. AB - Conventionally, it is assumed that a single molecule has only one absolute electronic property. Molecular electronics, molecular machines, intelligent drugs are some of the fields that require atomic scale control of molecular properties. In spite of remarkable achievements in the last two decades, absolute control of molecular properties has not been achieved. Here, experimental evidences argue against assigning a fixed property to a molecule. A molecule might structurally accommodate itself to the new environment and its electronic properties might change accordingly. By isolating electronic properties of all the conformers of a Rose Bengal molecule one by one, a map of its complete electronic properties is drawn here. The existing concept of one absolute electronic property of a molecule is true only for those molecules, which have only one stable conformer. For others, depending on the conformer, multiple distinct electronic properties may co-exist, leading to a variable output in an electronic characterization. Thus, we present a generalized method for characterizing/resolving collective electronic properties that emerge statistically. The method could be used for designing molecular switches for collective and evolutionary information processing. PMID- 20165770 TI - Surface segregation and stability of core-shell alloy catalysts for oxygen reduction in acid medium. AB - Density functional theory is used for the evaluation of surface segregation, trends for dissolution of Pt surface atoms in acid medium, and oxygen reduction reaction activity of core-shell materials, containing a monolayer of platinum over a monometallic or bimetallic core. Two groups of cores are investigated: Pt/X with X = Ir, Au; Pd, Rh, Ag; Co, Ni, Cu; and Pt/Pd(3)X, with X = Co, Fe, Cr, V, Ti, Ir, Re. It is found that all the 4d and 5d pure cores may serve as stable cores, and their beneficial effect on the Pt monolayer may be further tuned by alloying the core to another element, here chosen from 3d or 5d groups. The Pd(3)X cores enhance the stability of the surface Pt atoms both in vacuum and under adsorbed oxygen; however the high oxygen philicity of some of the X elements induces their surface segregation that may cause surface poisoning with oxygenated species and their dissolution in acid medium. PMID- 20165771 TI - Compositional ripening of particle- and surfactant-stabilised emulsions: a comparison. AB - When beta-ionone-in-water emulsions are mixed with squalane-in-water emulsions, the slightly water-soluble, mobile beta-ionone undergoes mass transfer to the drops of highly water-insoluble, immobile oil squalane. We have investigated this compositional ripening process for emulsions stabilised either by particles or by surfactant molecules. For particle-stabilised emulsions, the swelling of the squalane-containing drops triggers droplet coalescence which causes the final swollen droplet radius to be proportional to the swelling ratio to the power of 1. Surfactant-stabilised emulsions swell without coalescence which causes the final droplet radius to be proportional to the swelling ratio to the power 1/3. Addition of excess, non-adsorbed particles to the particle-stabilised emulsions suppresses the swelling-triggered coalescence and causes a switchover from particle to surfactant behaviour. PMID- 20165772 TI - Tackling the stacking disorder of melon--structure elucidation in a semicrystalline material. AB - In this work we tackle the stacking disorder of melon, a layered carbon imide amide polymer with the ideal composition (C(6)N(7)(NH)(NH(2))). Although its existence has been postulated since 1834 the structure of individual melon layers could only recently be solved via electron diffraction and high-resolution (15)N solid-state NMR spectroscopy. With only weak van der Waals interactions between neighboring layers its long range stacking order is poorly defined preventing an efficient use of diffraction techniques. We, therefore, rely on a combination of solid-state NMR experiments and force field calculations. The key information is obtained based on heteronuclear ((1)H-(13)C) and homonuclear ((1)H-(1)H) second moments M(2) acquired from (1)H-(13)C cross polarization experiments. To allow for an interpretation of the polarization transfer rates the resonances in the (13)C MAS spectra have to be assigned and the hydrogen atoms have to be located. The assignment was performed using a two-dimensional (15)N-(13)C iDCP experiment. For the determination of the position of the hydrogen atoms NH and HH distances were measured via(1)H-(15)N Lee-Goldburg CP and (1)H-(1)H double-quantum build-up curves, respectively. Furthermore, the homogeneity of the material under examination was investigated exploiting (15)N spin-diffusion. Based on force field methods 256 structure models with varying lateral arrangements between neighboring layers were created. For each model the M(2) were calculated allowing them to be ranked by comparing calculated and measured M(2) as well as via their force field energies. This allows the creation of markedly structured hypersurfaces with two distinctly favored shift vectors for the displacement of neighboring layers. PMID- 20165773 TI - Kinetics of phase separation in polymer blends revealed by resonance light scattering spectroscopy. AB - In this work, kinetics of phase separation in the blends of polystyrene (PS) and poly(vinyl methyl ether) (PVME) was investigated by a simple and sensitive method, i.e., resonance light scattering (RLS) spectroscopy. Owing to the aggregation of chromophores (phenyl rings) in the systems when phase separation occurred, RLS intensities were drastically enhanced and hence acted as a characteristic indicator. At the early stage of phase separation, two different RLS behaviors corresponding to spinodal decomposition (SD) and nucleation and growth (NG) were observed. The Cahn-Hilliard (C-H) linearization theory was found not applicable for kinetics analysis of the scattering data at lambda < 346 nm due to RLS effect near the absorption band. Based on a decomposition reaction model, the apparent activation energy of SD phase separation was estimated by the Arrhenius equation. In view of its simplicity and sensitivity of measurement, affordability and availability of instrument, and wide application range of polymer blends, RLS proved to be an effective means for characterization of microstructural variation in polymer blends. PMID- 20165774 TI - Trapping of Rhodamine 6G excitation energy on cellulose microparticles. AB - Rhodamine 6G (R6G) was adsorbed on cellulose microparticles and fluorescence quantum yields and decays were measured as a function of dye loading. Though no spectroscopic evidence of dye aggregation was found, a noticeable decrease of quantum yield--after correction for reabsorption and reemission of fluorescence- and shortening of decays were observed at the highest loadings. These effects were attributed to the dissipation of the excitation energy by traps constituted by R6G pairs, leading to static and dynamic quenching produced by direct absorption of traps and non-radiative energy transfer from monomers, respectively. Regarding the nature of traps, two extreme approaches were considered: (a) equilibrium between monomers slightly interacting in the ground state and (b) randomly distributed monomers located below a critical distance (statistical traps). Both approaches accounted quantitatively for the observed facts. The effect of energy migration was evaluated through computational simulations. As the concentration of traps could only be indirectly inferred, in some experiments an external energy transfer quencher, Methylene Blue, was coadsorbed and the results were compared with those obtained with pure R6G. PMID- 20165775 TI - Comment on "On using a too large integration time step in molecular dynamics simulations of coarse-grained molecular models" by M. Winger, D. Trzesniak, R. Baron and W. F. van Gunsteren, Phys. Chem. Chem. Phys., 2009, 11, 1934. PMID- 20165781 TI - Separation of non-racemic mixtures of enantiomers: an essential part of optical resolution. AB - Non-racemic enantiomeric mixtures form homochiral and heterochiral aggregates in melt or suspension, during adsorption or recrystallization, and these diastereomeric associations determine the distribution of the enantiomers between the solid and other (liquid or vapour) phases. That distribution depends on the stability order of the homo- and heterochiral aggregates (conglomerate or racemate formation). Therefore, there is a correlation between the binary melting point phase diagrams and the experimental ee(I)vs. ee(0) curves (ee(I) refers to the crystallized enantiomeric mixtures, ee(0) is the composition of the starting ones). Accordingly, distribution of the enantiomeric mixtures between two phases is characteristic and usually significant enrichment can be achieved. There are two exceptions: no enrichment could be observed under thermodynamically controlled conditions when the starting enantiomer composition corresponded to the eutectic composition, or when the method used was unsuitable for separation. In several cases, when kinetic control governed the crystallization, the character of the ee(0)-ee(I) curve did not correlate with the melting point binary phase diagram. PMID- 20165782 TI - Carbo- and heterocyclisation of oxygen- and nitrogen-containing electrophiles by platinum, gold, silver and copper species. AB - In this present perspective, we summarise the recent progress on the use of gold, platinum, silver and copper complexes to activate common oxygen and nitrogen electrophiles. PMID- 20165783 TI - Multicomponent asymmetric reactions mediated by proline lithium salt. AB - The multicomponent reaction between proline lithium salt, 2-cyclohexen-1-one and aliphatic aldehydes affords the 4-alkylidene-2-cyclohexen-1-ones, which are interesting fragrances, and bicyclic amino acids that bear four additional stereocenters, obtained as single stereoisomer. PMID- 20165784 TI - Anticancer mechanism of peptide P18 in human leukemia K562 cells. AB - Studies on the anticancer mechanism of peptide P18 in human leukemia K562 cells revealed that P18 causes the death of most K562 cells by depolarizing plasma membrane potential and enhancing membrane permeability, rather than activating the classical apoptosis pathway. The mechanistic studies indicate that disrupting plasma membrane is an effective approach to kill cancer cells and help design more effective peptide analogues in future cancer therapies. PMID- 20165785 TI - Chemoselective glycosylations using 2,3-unsaturated-4-keto glycosyl donors. AB - 2,3-Unsaturated-4-keto glycosyl acetates were found to exhibit low reactivity under several glycosylation conditions. Chemoselective glycosylations were effectively performed using 2,3-unsaturated glycosyl and 2,3-dideoxy glycosyl acetates as armed glycosyl donors, and 2,3-unsaturated-4-keto glycosyl acetates as disarmed glycosyl donors. PMID- 20165786 TI - Total synthesis of (+)-chloriolide. AB - The first total synthesis of (+)-chloriolide, a 12-membered macrolide from Chloridium virescens (var. chlamydosporum), was accomplished in a longest linear sequence of 20 steps from commercial materials in 7% overall yield. PMID- 20165787 TI - Photoinduced DNA cleavage by formation of ROS from oxygen with a neurotransmitter and aromatic amino acids. AB - UV-B photoirradiation of a neurotransmitter (serotonin) and aromatic amino acids (tryptophan and tyrosine) with oxygen results in DNA cleavage by generation of reactive oxygen species (ROS) as demonstrated by agarose gel electrophoresis with pBR 322 DNA, ESR and laser flash photolysis measurements. PMID- 20165788 TI - Imaging of RNA delivery to cells by thiazole orange as a fluorescent RNA base substitution. AB - Interstrand thiazole orange (TO) dimers in RNA show a yellow colored emission that can be distinguished from the green TO monomer emission by confocal microscopy inside CHO cells. PMID- 20165789 TI - Computational calculations in microwave-assisted organic synthesis (MAOS). Application to cycloaddition reactions. AB - Computational calculations represent a very useful tool to study separately the occurrence of thermal and non-thermal effects of microwave irradiation through the determination of the thermodynamic and kinetic parameters of the reaction. In this paper, we approach the computational study of two previously reported cycloaddition reactions. All of the outcomes indicate the presence of a thermal effect alone for the microwave irradiation that produces changes in the regioselectivity or in the reaction mechanism. PMID- 20165790 TI - A quinolinium-derived turn-off fluorescent anion sensor. AB - A quinolinium-derived anion sensor has been synthesised which shows a turn-off fluorescence response in the presence of anions, with selectivity for acetate. The compound exhibits complex anion binding comprising of a host dimer, 2 : 1 and 1 : 1 host : guest species. Fluorescent quenching is due to both dynamic and static processes with charge transfer being the dominant mechanism. PMID- 20165792 TI - A fluorescent diastereoselective molecular sensor for 1,2-aminoalcohols based on the rhodamine B lactone-zwitterion equilibrium. AB - A simple yet highly sensitive diastereoselective fluorescent assay was developed, which can differentiate diastereomeric 1,2-aminoalcohols such as ephedrine, pseudoephedrine, and methylephedrine using commercially available xanthene dyes. The assay is based on the rhodamine B lactone-zwitterion equilibrium, which is highly sensitive to the presence and structure of 1,2-aminoalcohols. This is in contrast to the majority of rhodamine sensors, which are based on the pH sensitive carboxylate-lactone equilibrium. A model is proposed in which the diastereoselectivity arises from the differences in the strength of an intermolecular lone pair-pi interaction within the analyte-rhodamine zwitterion complex. An assay was developed based on this sensing mechanism in which the structure and concentration of a 1,2-aminoalcohol solution can be determined using a mixture of rhodamine B and fluorescein. The selectivity and accuracy of this two-dye system was then demonstrated by the ability to measure the diastereomeric excess of samples of methylephedrine with 98% accuracy. PMID- 20165791 TI - Nickel(II) and iron(III) selective off-on-type fluorescence probes based on perylene tetracarboxylic diimide. AB - Two novel "turn-on" fluorescent probes with perylene tetracarboxylic diimide (PDI) as the fluorophore and two different di-(2-picolyl)-amine (DPA) groups as the metal ion receptor (PDI-1 and PDI-2) were successfully synthesized with satisfactory yields. PDI-1 exhibited high selectivity toward Ni(2+) in the presence of various other metal cations including Zn(2+), Cd(2+) and Cu(2+) which were expected to interfere significantly. A 1 : 2 stoichiometry was found for the complex formed by PDI-1 and Ni(2+) by a Job's plot and by non-linear least square fitting of the fluorescence titration curves. By introducing an extra diamino ethylene group between DPA and the phenyl bridge, the receptor was modified and the high selectivity of the sensor toward Ni(2+) shifted to Fe(3+). The enhancement factor of the fluorescence response of PDI-2 to Fe(3+) was as high as 138. The binding behavior of the receptors in these two compounds is affected significantly by the PDI fluorophores. Most interestingly, both Ni(2+) and Fe(3+) are paramagnetic metal ions, which are known as fluorescence quenchers and are rarely targeted with "turn-on" fluorescence probes. This result suggests that PDIs are favorable fluorophores for a "turn-on" fluorescence probe for paramagnetic transition metal ions because of their high oxidation potential. PMID- 20165793 TI - Implementation of anion-receptor macrocycles in supramolecular tandem assays for enzymes involving nucleotides as substrates, products, and cofactors. AB - A supramolecular tandem assay for direct continuous monitoring of nucleotide triphosphate-dependent enzymes such as potato apyrase is described. The underlying principle of the assay relies on the use of anion-receptor macrocycles in combination with fluorescent dyes as reporter pairs. A combinatorial approach was used to identify two complementary reporter pairs, i.e. an amino-gamma cyclodextrin with 2-anilinonaphtalene-6-sulfonate (ANS) as dye (fluorescence enhancement factor of 17 upon complexation) and a polycationic cyclophane with 8 hydroxy-1,3,6-pyrene trisulfonate (HPTS) as dye (fluorescence decrease by a factor of more than 2000), which allow the kinetic monitoring of potato apyrase activity at different ATP concentration ranges (microM and mM) with different types of photophysical responses (switch-ON and switch-OFF). Competitive fluorescence titrations revealed a differential binding of ATP (strongest competitor) versus ADP and AMP, which constitutes the prerequisite for monitoring enzymatic conversions (dephosphorylation or phosphorylation) involving nucleotides. The assay was tested for different enzyme and substrate concentrations and exploited for the screening of activating additives, namely divalent transition metal ions (Ni(2+), Mg(2+), Mn(2+), and Ca(2+)). The transferability of the assay could be demonstrated by monitoring the dephosphorylation of other nucleotide triphosphates (GTP, TTP, and CTP). PMID- 20165794 TI - Ni-, Pd-, or Pt-catalyzed ethylene dimerization: a mechanistic description of the catalytic cycle and the active species. AB - Two key mechanistic possibilities for group 10 transition metal [M(eta(3) allyl)(PMe(3))](+) catalyzed (where M = Ni(II), Pd(II) and Pt(II)) ethylene dimerization are investigated using density functional theory methods. The nature of the potential active catalysts in these pathways is analyzed to gain improved insights into the mechanism of ethylene dimerization to butene. The catalytic cycle is identified as involving typical elementary steps in transition metal catalyzed C-C bond formation reactions, such as oxidative insertion as well as beta-H elimination. The computed kinetic and thermodynamic features indicate that a commonly proposed metal hydride species (L(n)M-H) is less likely to act as the active species as compared to a metal-ethyl species (L(n)M-CH(2)CH(3)). Of the two key pathways considered, the active species is predicted to be a metal hydride in pathway-1, whereas a metal alkyl complex serves as the active catalyst in pathway-2. A metal-mediated hydride shift from a growing metal alkyl chain to the ethylene molecule, bound to the metal in an eta(2) fashion, is predicted to be the preferred route for the generation of the active species. Among the intermediates involved in the catalytic cycle, metal alkyls with a bound olefin are identified as thermodynamically stable for all three metal ions. In general, the Ni-catalyzed pathways are found to be energetically more favorable than those associated with Pd and Pt catalysts. PMID- 20165795 TI - Optoelectronically mismatched oligophenylethynyl-naphthalenediimide SHJ architectures. AB - The objective of this study was to evaluate the possibility of photoinduced stack/rod electron transfer in surface "zipper" architectures composed of stacks of blue (B) naphthalenediimides (NDIs) along strings of oligophenylethynyl (OPE) rods. The synthesis and characterization of anionic and cationic multichromophoric OPE-B systems are reported. Absorption spectra suggest that in OPE-B systems, planarity and thus absorption and conductivity of the OPE can possibly be modulated by intramolecular stacking of the surrounding NDIs, although interfering contributions from aggregation remain to be differentiated. Among surface architectures constructed with OPE-B and POP-B systems by zipper and layer-by-layer (LBL) assembly, photocurrents generated by OPE-B zippers exhibit the best critical thickness and fill factors. These findings confirm the existence and functional relevance of topologically matching zipper architectures. In OPE-B zippers, OPEs generate much more photocurrent than the blue NDIs. Ultrafast electron transfer from OPEs to NDIs accounts for these photocurrents, providing wavelength-controlled access to rod-stack charge separation, and thus to formal supramolecular n/p-heterojunctions (SHJs). NDI excitation is not followed by the complementary hole transfer to the OPE rod. Scaffolds with higher HOMOs will be needed to integrate blue NDIs into SHJ photosystems. PMID- 20165796 TI - Antioxidant activity of alpha-pyridoin and its derivatives: possible mechanism. AB - alpha-Pyridoin (1, 1,2-di(2-pyridyl)-1,2-ethenediol) is a unique enediol antioxidant. To explore the detailed antioxidant mechanism of alpha-pyridoin, we synthesized alpha-pyridoin and its 5,5'- or 6,6'-bis-substituted derivatives (2 7) and compared their capacities to scavenge galvinoxyl radical (GO*) and protect human red blood cells (RBCs) from oxidative haemolysis. It was found that the compounds (5 and 6) with a methyl or methoxy group at the 5-position exhibit significantly higher GO*-scavenging and anti-haemolysis activities than other derivatives and vitamin C. Kinetic analysis of the GO*-scavenging reaction and the effect of added base on the reaction rate revealed that in ethyl acetate, the reaction occurs primarily by the direct hydrogen atom transfer (HAT mechanism). However, in ethanol that supports ionization, the kinetics of the process is mostly governed by sequential proton loss electron transfer (SPLET mechanism). PMID- 20165797 TI - A detailed investigation of the aza-Prins reaction. AB - The development of a Lewis acid-promoted aza-Prins reaction to form piperidines and pyrrolidines is described. Indium trichloride has been found to be a highly successful and mild Lewis acid for promoting this reaction. A thorough mechanistic investigation is described, including the factors that influence the formation of the 5- or 6-membered ring product(s). PMID- 20165798 TI - Chemoenzymatic synthesis of chiral 2,2'-bipyridine ligands and their N-oxide derivatives: applications in the asymmetric aminolysis of epoxides and asymmetric allylation of aldehydes. AB - A series of enantiopure 2,2'-bipyridines have been synthesised from the corresponding cis-dihydrodiol metabolites of 2-chloroquinolines. Several of the resulting hydroxylated 2,2'-bipyridines were found to be useful chiral ligands for the asymmetric aminolysis of meso-epoxides leading to the formation of enantioenriched amino alcohols (-->84% ee). N-oxide and N,N'-dioxide derivatives of these 2,2'-bipyridines, including separable atropisomers, have been synthesised and used as enantioselective organocatalysts in the asymmetric allylation of aldehydes to give allylic alcohols (-->86% ee). PMID- 20165799 TI - Chiral N-phosphonyl imine chemistry: an efficient asymmetric synthesis of chiral N-phosphonyl propargylamines. AB - A variety of substituted chiral propargylamines have been synthesized by reacting chiral N-phosphonylimines with lithium aryl/alkyl acetylides. Seventeen examples were studied to give excellent yields (>90%) and diastereoselectivities (96 : 4 to 99 : 1). It was found that the types of bases for generating acetylides and solvents are crucial for effectiveness of this asymmetric reaction. In addition, N,N-isopropyl group on chiral N-phosphonylimine auxiliary was proven to be superior to other protecting groups in controlling diastereoselectivity. PMID- 20165800 TI - Scandium triflate-catalyzed one-pot domino approach towards general and efficient syntheses of unsymmetrical 9-substituted xanthene derivatives. AB - A general and efficient one-pot cascade/tandem approach to synthesize unsymmetrical 9-aryl/heteroaryl xanthenes has been developed under extremely mild reaction conditions using 10 mol% Sc(OTf)(3) as a catalyst. This strategy has been further extended to synthesize 9-(thioaryl) xanthenes through tandem carbon sulfur (C-S) and carbon-carbon (C-C) bond formation. Novel C-C and C-S bond cleavage promoted by Sc(OTf)(3) is also discussed during mechanistic investigation. PMID- 20165801 TI - Subunit composition of hinokiresinol synthase controls enantiomeric selectivity in hinokiresinol formation. AB - Asparagus officinalis hinokiresinol synthase (HRS) is composed of two subunits, HRSalpha and HRSbeta. Individually, each subunit forms (E)-hinokiresinol (EHR) from 4-coumaryl 4-coumarate, whereas a mixture of both subunits forms (Z) hinokiresinol (ZHR) from the same substrate. In this study, we analyzed the enantiomeric compositions of ZHR and EHR formed after incubation of 4-coumaryl 4 coumarate with recombinant subunit proteins, recHRSalpha and/or recHRSbeta, and with naturally occurring A. officinalis ZHR. The enantiomeric composition of ZHR formed by the mixture of recHRSalpha and recHRSbeta was (+)-100% enantiomer excess (e.e.), identical to that of A. officinalis ZHR. In contrast, the enantiomeric compositions of EHR formed by recHRSalpha and recHRSbeta, individually, were (-)-20.6 and (-)-9.0% e.e., respectively. These results clearly demonstrate that the subunit composition of A. officinalis HRS controls not only cis/trans isomerism but also enantioselectivity in hinokiresinol formation. PMID- 20165802 TI - Copper-catalyzed amination of (bromophenyl)ethanolamine for a concise synthesis of aniline-containing analogues of NMDA NR2B antagonist ifenprodil. AB - An operationally simple and concise synthesis of anilinoethanolamines, as NMDA NR2B receptor antagonist ifenprodil analogues, was developed via a copper catalyzed amination of the corresponding bromoarene. Coupling was achieved with linear primary alkylamines, alpha,omega-diamines, hexanolamine and benzophenone imine, as well as with aqueous ammonia, in good yields using CuI and N,N diethylsalicylamide, 2,4-pentadione or 2-acetylcyclohexanone as catalytic systems. Amination with ethylene diamine was efficient even in the absence of an additive ligand, whereas no reaction occurred with ethanolamine whatever the conditions used. The anilinoethanolamines were evaluated as NR2B receptor antagonists in a functional inhibition assay. Aminoethylanilines displayed inhibition effects close to that of ifenprodil. PMID- 20165803 TI - BVMO-catalysed dynamic kinetic resolution of racemic benzyl ketones in the presence of anion exchange resins. AB - 4-Hydroxyacetophenone monooxygenase from Pseudomonas fluorescens ACB was employed in the presence of a weak anion exchange resin to perform dynamic kinetic resolutions of racemic benzyl ketones with high conversions and good optical purities. Different parameters that affect to the efficiency of the enzymatic Baeyer-Villiger oxidation and racemisation were analyzed in order to optimize the activity and selectivity of the biocatalytic system. PMID- 20165804 TI - A facile synthesis of pyrrolo[2,3-b]quinolines via a Rh(I)-catalyzed carbodiimide Pauson-Khand-type reaction. AB - A new straightforward synthetic method for 2,3-dihydro-1H-pyrrolo[2,3-b]quinolin 2-ones via a [RhCl(CO)(2)](2)-dppp catalyzed Pauson-Khand-type reaction of N-[2 (2-alkyn-1-yl)phenyl]carbodiimides is reported. PMID- 20165805 TI - Reconstruction of pyrrolo[2,3-b]indoles carrying an alpha-configured reverse C3 dimethylallyl moiety by using recombinant enzymes. AB - Nine reversely C3-prenylated pyrrolo[2,3-b]indoles were successfully prepared by using two recombinant enzymes involved in the biosynthesis of acetylaszonalenin from Neosartorya fischeri. The prenyltransferase AnaPT catalysed the conversion of six tryptophan-containing cyclic dipeptides to reversely C3-prenylated indoline derivatives. Using cyclo-L-Trp-L-Trp as substrate, both mono- and diprenylated indolines were obtained. Two of the AnaPT products were acetylated at position N1 by the acetyltransferase AnaAT. The structures of the obtained compounds were characterised by HR-ESI-MS, (1)H- and (13)C-NMR analyses as well as by long-range (1)H-(13)C connectivities in heteronuclear multiple-bond correlation (HMBC) spectra after preparative isolation. Their absolute configurations were determined by analysing the (1)H-(1)H spatial correlations in rotating-frame nuclear overhauser effect spectroscopy (ROESY). PMID- 20165806 TI - Vancomycin dimer formation between analogues of bacterial peptidoglycan surfaces probed by force spectroscopy. AB - Functionalised thiols presenting peptides found in the peptidoglycan of vancomycin-sensitive and -resistant bacteria were synthesised and used to form self-assembled monolayers (SAMs) on gold surfaces. This model bacterial cell-wall surface mimic was used to study binding interactions with vancomycin. Force spectroscopy, using the atomic force microscope (AFM), was used to investigate the specific rupture of interfacial vancomycin dimer complexes formed between pairs of vancomycin molecules bound to peptide-coated AFM probe and substrate surfaces. Clear adhesive contacts were observed between the vancomycin-sensitive peptide surfaces when vancomycin was present in solution, and the adhesion force demonstrated a clear dependence on antibiotic concentration. PMID- 20165807 TI - A new facile synthesis of 3-amidoindole derivatives and their evaluation as potential GSK-3beta inhibitors. AB - 3-Amidoindoles were synthesized from commercially available arylhydrazines and propargylamines over Zn-salt mediated one pot procedure in excellent regioselectivity and up to 94% yield. PMID- 20165808 TI - Tether influence on the binding properties of tRNALys3 ligands designed by a fragment-based approach. AB - A small library of 1,5-triazole derivatives linking a diaminocyclopentadiol and aromatic ketones has been prepared and screened using NMR and fluorescent techniques against tRNA(Lys)(3), the HIV reverse transcription primer. The comparison of their binding properties to those of their 1,4-triazole isomers, previously discovered in a fragment-based approach, outlines the influence of the linker on affinity and binding selectivity in such an approach. PMID- 20165809 TI - Influence of the number and distribution of NLS peptides on the photosensitizing activity of multimeric porphyrin-NLS. AB - Porphyrin-peptide conjugates bearing multiple nuclear localization sequences (NLS) could show increased tumor cell uptake and affinity for nuclear receptors, and consequently increased photodynamic activity. Previous studies suggest that an increase number of NLS might enhance the nuclear uptake of proteins and other macromolecules. We report the syntheses and investigation of a series of multimeric porphyrin-NLS conjugates bearing two, three or four peptides with the minimum sequence PKKKRKV, linked via PEG or 5-carbon linkers, and with different distributions at the porphyrin periphery. Our results show that the tumor cell uptake and phototoxicity of these conjugates is mainly determined by their amphiphilic character, and not the number of NLS residues per molecule, contrary to previous studies. The mono- and di-substituted photosensitizers bearing one or two PEG linkers and up to three peptide sequences were found to be the most phototoxic toward human carcinoma HEp2 cells, while the tetra-NLS conjugates symmetrically substituted around the porphyrin ring accumulated the least within cells and were non-phototoxic. All conjugates localized intracellularly within endosomal vesicles and lysosomes, probably as a result of an endocytic mechanism of uptake; as a consequence no nuclear uptake was detected by fluorescence microscopy. PMID- 20165810 TI - Dynamic combinatorial chemistry with hydrazones: cholate-based building blocks and libraries. AB - We describe an efficient and general strategy for the synthesis of dimethyl acetal functionalised steroidal hydrazides based on the cholic acid skeleton with the aim of using these compounds as building blocks for dynamic combinatorial chemistry. Deprotection of the acetal protected building blocks with TFA leads to formation of libraries containing macrocyclic N-acyl hydrazone oligomers. The isolation of several of these, and their characterisation using NMR is described. The effects on the equilibrium library distribution by varying the substituents at C-7 and C-12, extending the side-chain with glycine, and inverting the configuration at C-3 are discussed. Finally, we report the exchange properties of these macrocycles and demonstrate new examples of proof-reading and self-sorting in dynamic combinatorial libraries. PMID- 20165812 TI - Synthesis of phalluside-1 and Sch II using 1,2-metallate rearrangements. AB - (4E,8E,10E)-9-Methyl-4,8,10-sphingatrienine, a core component of marine sphingolipids, was synthesised for the first time using a copper(I)-mediated 1,2 metallate rearrangement of a lithiated glycal as a key step. It was converted to phalluside-1, a cerebroside isolated from the ascidian Phallusia fumigate. By an analogous route, (4E,8E)-9-methyl-4,8-sphingadiene was synthesised and converted to Sch II, a cerebroside that induces fruiting body formation in the basidiomycete Schizophyllum commune. PMID- 20165811 TI - Dynamic combinatorial chemistry with hydrazones: libraries incorporating heterocyclic and steroidal motifs. AB - We expand the possibilities in hydrazone based dynamic combinatorial chemistry with a series of new building blocks incorporating heterocyclic motifs. The synthetic procedure allows efficient access to building blocks with the general structure (MeO)(2)CH-Heterocycle-C(O)NHNH(2), originating from heterocycles with an amine and an ester functionality. The equilibrium distribution of macrocyclic N-acyl hydrazones formed upon deprotection of the building blocks with TFA in organic solvents is reported. The mixing behaviour of these heterocycle-based building blocks with our cholate-based building blocks is described, particularly the observation of kinetic intermediates that disappear following 'proof reading'. PMID- 20165813 TI - Synthesis of nucleoside and nucleotide conjugates of bile acids, and polymerase construction of bile acid-functionalized DNA. AB - Aqueous Sonogashira cross-coupling reactions of 5-iodopyrimidine or 7-iodo-7 deazaadenine nucleosides with bile acid-derived terminal acetylenes linked via an ester or amide tether gave the corresponding bile acid-nucleoside conjugates. Analogous reactions of halogenated nucleoside triphosphates gave directly bile acid-modified dNTPs. Enzymatic incorporation of these modified nucleotides to DNA was successfully performed using Phusion polymerase for primer extension. One of the dNTPs (dCTP bearing cholic acid) was also efficient for PCR amplification. PMID- 20165814 TI - Synthesis of Biginelli dihydropyrimidinone derivatives with various substituents on aluminium-planted mesoporous silica catalyst. AB - Biginelli reactions were well catalyzed on mesoporous silica MCM-41 (M41) whose activity was much greater than that of amorphous silica. Octane was the most suitable among 6 kinds of solvents examined. The addition of metal ions on M41 enhanced the catalytic activity in the order Al > Ti > Fe = In. Al-planted M41s with Si/Al ratios of 45-35 showed the highest catalytic activity and could be used repeatedly though a small loss of the activity was observed. The catalysis could widely be applied to obtain various substituted dihydropyrimidinones (DHPMs) with high yields, some of which were very difficult to prepare until now. In addition, Biginelli reactions were combined with formyl C-H insertion reactions of diazoester on mesoporous silica; that is, a tandem one-pot four component DHPM synthesis was attempted. Acetaldehyde, ethyl diazoacetate, p tolualdehyde, and urea could be condensed and the corresponding DHPM derivative was obtained with 50% yield on Al-planted M41. PMID- 20165815 TI - Generation and reaction of cyano-substituted aryllithium compounds using microreactors. AB - We developed a microflow method for the generation and reactions of aryllithiums bearing a cyano group, including o-lithiobenzonitrile, m-lithiobenzonitrile and p lithiobenzonitrile. The method was effective at much higher temperatures than are required for conventional macrobatch reactions, by virtue of rapid mixing, short residence time, and efficient temperature control. In addition, reactions of o lithiobenzonitrile with carbonyl compounds followed by trapping of the resulting lithium alkoxides with electrophiles were achieved in an integrated microflow system. PMID- 20165818 TI - Validation of new prognostic and predictive scores by sequential testing approach. AB - BACKGROUND AND PURPOSE: For practitioners, the question arises how their own patient population differs from that used in large-scale analyses resulting in new scores and nomograms and whether such tools actually are valid at a local level and thus can be implemented. A recent article proposed an easy-to-use method for the in-clinic validation of new prediction tools with a limited number of patients, a so-called sequential testing approach. The present study evaluates this approach in scores related to radiation oncology. MATERIAL AND METHODS: Three different scores were used, each predicting short overall survival after palliative radiotherapy (bone metastases, brain metastases, metastatic spinal cord compression). For each scenario, a limited number of consecutive patients entered the sequential testing approach (Table 1). The positive predictive value (PPV) was used for validation of the respective score and it was required that the PPV exceeded 80%. RESULTS: For two scores, validity in the own local patient population could be confirmed after entering 13 and 17 patients, respectively (Figures 1 and 3). For the third score, no decision could be reached even after increasing the sample size to 30 (Figure 2). CONCLUSION: In-clinic validation of new predictive tools with sequential testing approach should be preferred over uncritical adoption of tools which provide no significant benefit to local patient populations. Often the necessary number of patients can be reached within reasonable time frames even in small oncology practices. In addition, validation is performed continuously as the data are collected. PMID- 20165819 TI - Quantitative assessment of irradiated lung volume and lung mass in breast cancer patients treated with tangential fields in combination with deep inspiration breath hold (DIBH). AB - PURPOSE: Comparison of the amount of irradiated lung tissue volume and mass in patients with breast cancer treated with an optimized tangential-field technique with and without a deep inspiration breath-hold (DIBH) technique and its impact on the normal-tissue complication probability (NTCP). MATERIAL AND METHODS: Computed tomography datasets of 60 patients in normal breathing (NB) and subsequently in DIBH were compared. With a Real-Time Position Management Respiratory Gating System (RPM), anteroposterior movement of the chest wall was monitored and a lower and upper threshold were defined. Ipsilateral lung and a restricted tangential region of the lung were delineated and the mean and maximum doses calculated. Irradiated lung tissue mass was computed based on density values. NTCP for lung was calculated using a modified Lyman-Kutcher-Burman (LKB) model. RESULTS: Mean dose to the ipsilateral lung in DIBH versus NB was significantly reduced by 15%. Mean lung mass calculation in the restricted area receiving <= 20 Gy (M(20)) was reduced by 17% in DIBH but associated with an increase in volume. NTCP showed an improvement in DIBH of 20%. The correlation of individual breathing amplitude with NTCP proved to be independent. CONCLUSION: The delineation of a restricted area provides the lung mass calculation in patients treated with tangential fields. DIBH reduces ipsilateral lung dose by inflation so that less tissue remains in the irradiated region and its efficiency is supported by a decrease of NTCP. PMID- 20165820 TI - Radiotherapy for brain metastases from renal cell cancer: should whole-brain radiotherapy be added to stereotactic radiosurgery?: analysis of 88 patients. AB - PURPOSE: To evaluate the role of stereotactic radiosurgery (SRS) and whole-brain radiotherapy (WBRT) for the treatment of brain metastases in patients with renal cell cancer (RCC). PATIENTS AND METHODS: 88 patients were treated with either SRS (n = 51) or SRS + WBRT (n = 17) for one to three lesions, or with WBRT (n = 20) for more than three brain metastases. Overall survival (OS), intracerebral control (IC) and local control (LC) were retrospectively analyzed. Six potential prognostic factors were assessed: age, gender, number of brain metastases, extracerebral metastases, recursive partitioning analysis (RPA) class, and interval from tumor diagnosis to irradiation. RESULTS: The median times for OS, IC, and LC from the time of diagnosis were 11, 9, and 10 months. The median OS times for SRS, SRS + WBRT, and WBRT were 12, 16, and 2 months. Addition of WBRT to the SRS improved IC (p = 0.032) but not OS (p = 0.703). On multivariate analyses, improved OS was associated with the absence of extracerebral metastases (p < 0.001) and RPA class (p = 0.04), and IC with treatment (p = 0.019). SRS provided a 1-year, 2-year, and 3-year LC probability of 81%, 78%, and 55%, respectively. No association between LC and any of the potential prognostic factors was observed. The results of the subgroup analyses, regarding treatment modality, were similar to the entire cohort, particularly for RPA class I patients. CONCLUSION: Addition of WBRT to SRS offers better IC and should be considered for RCC patients with one to three brain metastases, especially in RPA class I group. SRS offers excellent LC rates, while WBRT should be reserved for patients with multiple metastases and poor prognosis. PMID- 20165821 TI - CT density in lung cancer patients after radiotherapy sensitized by metoclopramide. A subgroup analysis of a randomized trial. AB - PURPOSE: To investigate the lung tissue response measured with computed tomography (CT) after radiotherapy (RT) combined with metoclopramide. PATIENTS AND METHODS: Patients with non-small cell lung cancer (tumor stage IIIA and IIIB), included in a multicenter, randomized phase III trial investigating the use of metoclopramide as a radiosensitizing agent, were examined with repetitive post-RT CT scans. The analysis comprised data up to 100 days after RT for a subgroup of 16 patients treated with a total dose of 60 Gy given in 1.82 Gy per fraction. RESULTS: Large radiation doses to subvolumes were associated with denser lung tissue measured with CT (p < 0.001). Opposed to this finding, the volume of lung tissue irradiated with significant doses (V(40Gy)) was negatively correlated with the average increase in lung tissue density (p = 0.003). Patients randomized to metoclopramide injections also experienced less increase in lung tissue density (p = 0.01). CONCLUSION: There was an increase in the density of irradiated lung tissue with radiation dose and time after RT. Metoclopramide and significant radiation doses to larger lung volumes (V(40Gy)) seemed to protect against fibrosis development. PMID- 20165822 TI - Correlation of patient-related factors and dose-volume histogram parameters with the onset of radiation pneumonitis in patients with small cell lung cancer. AB - PURPOSE: To analyze the association of patient- and treatment-related factors with the onset of radiation pneumonitis in a homogeneously treated cohort of patients suffering from small cell lung cancer (SCLC). PATIENTS AND METHODS: 242 patients with SCLC staged as limited disease, who had been treated with chemotherapy and three-dimensional conformal radiotherapy, were retrospectively analyzed. Pneumonitis was defined by typical symptoms and radiographic findings and judged clinically relevant, if drug administration and hospitalization were necessary. Patient- (age, gender, smoking history, performance status, tumor localization, benign lung disease) and treatment-related parameters (V(10)-V(40), mean lung dose [MLD]) were analyzed using chi(2)-tests for categorical parameters and logistic regression for continuous variables. RESULTS: 33 patients (13.6%) developed a clinically relevant pneumonitis, of whom three patients died. All cases of pneumonitis developed within 120 days. None of the patient-related parameters correlated significantly with the onset of pneumonitis. Considering treatment-related parameters, a significant correlation of V(30) in regard to total lung and V(40) in regard to ipsilateral, contralateral and total lung to the risk of pneumonitis was found. So, the estimated risk of a clinically relevant pneumonitis increased from 10% given a V(30) of 13% to 30% given a V(30) of 35%. In contrast, no significant correlation was found for V(10) and V(20) and only a trend for MLD. CONCLUSION: In this series, high-dose radiation volume parameters, i.e., V(30) and especially V(40), were identified as the most important factors for the development of radiation pneumonitis. Low-dose radiation volume parameters and clinical parameters played an inferior role in predicting the pneumonitis risk. PMID- 20165823 TI - [Cutaneous leiomyomas. A key to the early recognition of malignant renal tumors?]. PMID- 20165824 TI - [For Professor Peter Altmeyer on his 65th birthday]. PMID- 20165825 TI - [Human papillomavirus-associated warts in organ transplant recipients. Incidence, risk factors, management]. AB - Human papillomaviruses infect the squamous epithelia of the skin and cause warts, and are occasionally found in squamous cell carcinomas. Since cell-mediated immunity plays a crucial role in the control of HPV-infections, organ transplant recipients, unable to mount an adequate T-helper 1 cell-mediated immune surveillance, frequently develop widespread and resistant induced warts. Skin tumors, especially squamous cell carcinomas, are the most common post transplantation neoplasm. Warts, actinic keratoses and invasive squamous cell carcinomas are known to develop at the same time in the areas. The role of HPV in the development of invasive squamous cell carcinoma under immunosuppression, remains to be elucidated in respect to common risk factors and increased numbers of warts potentially identifying patients at increased risk for carcinoma. We prospectively studied 1690 organ transplant recipients in the dermatology clinic at the Charite University Hospital in Berlin, to evaluate risk factors being involved in the development of HPV-induced warts and to assess a potential association of with the development of non-melanoma skin cancers in this population. The cumulative incidence of warts steadily increased throughout the post-transplant years. The presence of more than 10 verrucae was associated with the development of actinic keratoses, invasive squamous cell carcinoma and basal cell carcinoma. This study shows clear evidence that certain risk factors of skin carcinogenesis in organ transplant recipient such as increased age at transplantation, a high dose of immunosuppression related to a specific type of graft and use of azathioprine or cyclosporine are strongly associated with an increased incidence of warts. Furthermore, HPV-induced verrucae vulgares could be used as a potential predictor for the development of coincidental non melanoma skin cancer in organ transplant recipients and therefore could serve as an early identification marker of skin cancer high-risk patients. The challenging management of warts in organ transplantation patients is reviewed. PMID- 20165826 TI - [Skin infections after transplantation]. AB - Skin infections after transplantation are frequent and of special importance because they may be quite severe. The spectrum of dermatologic infections in transplant recipients includes bacterial, mycotic and viral diseases. Pyoderma, herpes virus 6/7, herpes simplex virus, varicella-zoster virus, cytomegalovirus and candida infections predominate. Rare pathogens must be also considered. Cutaneous infections can be divided into three phases following transplantation. Diagnosis and adequate early therapy together with specific prophylaxis and follow-up of transplant patients should be strived for to avoid life-threatening complications. PMID- 20165827 TI - [What can we learn from patients?]. AB - Quality management is only complete and sound when it comprehensively takes all comments from patients or staff into consideration, especially negative comments. In this manner, complaints, surveys and registered risks can be seen in a synoptic way. Every comment must be evaluated in relation to isolated cases as well as in the sense of pattern recognition. PMID- 20165828 TI - [Imaging 2010]. PMID- 20165830 TI - Cross-national comparison of the link between socioeconomic status and emotional and behavioral problems in youths. AB - INTRODUCTION: In previous longitudinal studies in the US, lower socioeconomic status (SES) was associated with more emotional and behavioral problems. It remains unclear whether these findings can be generalized outside the US, as different countries vary in their health care systems and prevention of psychopathology in youth. Therefore, we studied the same associations in a comparable sample in The Netherlands and directly tested for differences between the US and The Netherlands. METHODS: The US (N=833) and Dutch (N=708) population samples were followed-up for 9 years. Age at baseline ranged from 8 to 16 years. Parents filled out behavior checklists. RESULTS: Analyses revealed very few differences between the two countries. In both countries, SES predicted syndrome scores and cumulative prevalence rates for internalizing and externalizing problems (withdrawn and aggressive behavior) and for thought and attention Problems. The SES gradient in syndrome scores was stable over time. Only for withdrawn behavior, the gradient was larger in young adulthood. CONCLUSION: Although the health care systems differ between the US and The Netherlands, the socioeconomic disparities in emotional and behavioral problems were similar. PMID- 20165829 TI - Glucosamine-induced endoplasmic reticulum stress affects GLUT4 expression via activating transcription factor 6 in rat and human skeletal muscle cells. AB - AIMS/HYPOTHESIS: Glucosamine, generated during hyperglycaemia, causes insulin resistance in different cells. Here we sought to evaluate the possible role of endoplasmic reticulum (ER) stress in the induction of insulin resistance by glucosamine in skeletal muscle cells. METHODS: Real-time RT-PCR analysis, 2-deoxy D: -glucose (2-DG) uptake and western blot analysis were carried out in rat and human muscle cell lines. RESULTS: In both rat and human myotubes, glucosamine treatment caused a significant increase in the expression of the ER stress markers immunoglobulin heavy chain-binding protein/glucose-regulated protein 78 kDa (BIP/GRP78 [also known as HSPA5]), X-box binding protein-1 (XBP1) and activating transcription factor 6 (ATF6). In addition, glucosamine impaired insulin-stimulated 2-DG uptake in both rat and human myotubes. Interestingly, pretreatment of both rat and human myotubes with the chemical chaperones 4 phenylbutyric acid (PBA) or tauroursodeoxycholic acid (TUDCA), completely prevented the effect of glucosamine on both ER stress induction and insulin induced glucose uptake. In both rat and human myotubes, glucosamine treatment reduced mRNA and protein levels of the gene encoding GLUT4 and mRNA levels of the main regulators of the gene encoding GLUT4 (myocyte enhancer factor 2 a [MEF2A] and peroxisome proliferator-activated receptor-gamma coactivator 1alpha [PGC1alpha]). Again, PBA or TUDCA pretreatment prevented glucosamine-induced inhibition of GLUT4 (also known as SLC2A4), MEF2A and PGC1alpha (also known as PPARGC1A). Finally, we showed that overproduction of ATF6 is sufficient to inhibit the expression of genes GLUT4, MEF2A and PGC1alpha and that ATF6 silencing with a specific small interfering RNA is sufficient to completely prevent glucosamine-induced inhibition of GLUT4, MEF2A and PGC1alpha in skeletal muscle cells. CONCLUSIONS/INTERPRETATION: In this work we show that glucosamine induced ER stress causes insulin resistance in both human and rat myotubes and impairs GLUT4 production and insulin-induced glucose uptake via an ATF6-dependent decrease of the GLUT4 regulators MEF2A and PGC1alpha. PMID- 20165831 TI - The long-term psychological effect of fatal accidents at sea on survivors: a cross-sectional study of North-Atlantic seamen. AB - OBJECTIVE: This study aimed to ascertain whether disasters at sea had an enduring traumatic effect on psychological functioning, accident proneness, and on their interest to continue working at sea. METHOD: Crew members of selected sea disasters were contacted. The chosen disasters were of differing severity and in some cases fatalities had occurred. The disasters had taken place on average 8 years previously. Those who agreed to participate were interviewed in a semi structured interview. They also answered the CIDI; DIS; GHQ-30; IES, and PTSS-10. One hundred-and-twelve seamen who had been in disasters were compared with a comparison group consisting of 59 peers who had not been in a disaster. RESULTS: Survivors of fatal disasters experienced more long-lasting negative effects than did others where lives were not lost. They had more frequently unpleasant intrusive thoughts on the IES (p < 0.01) compared with their peers. On the DIS, they also more frequently experienced heightened arousal (p < 0.001), sleep problems (p < 0.01), and nightmares (p < 0.01). The duration of PTSD symptoms from the time of the disaster was on average 18 months. Over 33% of the disaster group had experienced some PTSD symptoms within the past 12 months. Disaster survivors had not quit seamanship as frequently as non-disaster seamen. CONCLUSION: The most severe and long-lasting symptoms were found among those who had been in disasters where one or more crew members had perished. Loss of life in disasters therefore seems significant in the process of creating or extending the endurance of symptoms of psychological vulnerability. PMID- 20165832 TI - High rates of psychosis for black inpatients in Padua and Montreal: different contexts, similar findings. AB - OBJECTIVE: This study tested the hypothesis that despite differences in setting, specifically in Padua or Montreal, black psychiatric inpatients will have higher rates of assigned diagnosis of psychosis than their non-black counterparts. METHODS: Data on psychotic patients admitted to the psychiatry ward were extracted from records of general hospitals in Padua and Montreal. Logistic regression analyses were conducted separately for each site to determine the relation between being black and receiving a diagnosis of psychosis, while controlling for sex and age. RESULTS: Most black patients at both sites received a diagnosis of psychosis (76% in Padua and 81% in Montreal). Being black was independently and positively associated with being diagnosed with psychosis compared to patients from other groups. CONCLUSIONS: Black patients admitted to psychiatry, whether in Padua or Montreal, were more likely to be assigned a diagnosis of psychosis than were other patients. PMID- 20165833 TI - Porcine skin collagen implants for anterior vaginal wall prolapse: a randomised prospective controlled study. AB - INTRODUCTION AND HYPOTHESIS: The effect of a Pelvicol graft compared with a conventional anterior vaginal repair was evaluated in this randomised controlled study. METHODS: Only patients with a stage II or higher (Ba >or= -1) defect were included. RESULTS: Thirty-one patients were allocated to a conventional anterior repair; 30 to Pelvicol graft. At 12 months follow-up, four patients among controls (15%) and two in the graft group (7%) had objective recurrence. Among controls, the difference at 3 months follow-up in Ba was 6.0 cm when compared with the position of Ba prior to surgery. In the graft group, the difference was 7.0 cm (P < 0.05). This difference was still present at 12 months follow-up (6.0 vs. 7.0 cm; P < 0.05). CONCLUSIONS: The implantation of a Pelvicol graft does not improve the POP-Q stage. PMID- 20165835 TI - Ultra-fast HPLC-ICP-MS analysis of oxaliplatin in patient urine. AB - A novel method for rapid HPLC-ICP-MS analysis of oxaliplatin in human urine was developed implementing a stationary HPLC phase with a particle size of 1.8 microm. The method allowed a cycle time of <1 min at a HPLC flow rate of 0.9 mL min(-1). Procedural limits of detection of 0.05 microg L(-1) oxaliplatin (150 fg on column) were obtained. Analysis of oxaliplatin in patient urine showed that accurate quantification of the intact drug demanded for storage at -80 degrees C and rapid measurement after thawing. PMID- 20165834 TI - Serum undercarboxylated osteocalcin was inversely associated with plasma glucose level and fat mass in type 2 diabetes mellitus. AB - Although recent animal studies have shown that undercarboxylated osteocalcin acts as a hormone regulating glucose metabolism and fat mass, little is known about the relationships in humans. We reported here for the first time that undercarboxylated osteocalcin were associated with glucose/fat metabolism in patients with type 2 diabetes. INTRODUCTION: Recent studies have shown that undercarboxylated osteocalcin (ucOC) acts as a hormone regulating glucose metabolism and fat mass. We investigated the relationship between ucOC as well as other bone turnover markers [serum OC, bone-specific alkaline phosphatase (BAP), and urinary N-terminal cross-linked telopeptide of type-I collagen] versus serum levels of glucose, fasting serum C-peptide, and adiponectin as well as the amount of fat mass in type 2 diabetes. METHODS: A total of 180 men and 109 postmenopausal women were consecutively recruited, and radiographic and biochemical characteristics were collected. Fat mass was measured by dual X-ray absorptiometry (DXA) and computed tomography (CT). RESULTS: In men, ucOC negatively correlated with percent trunk fat (%trunk fat; by DXA) and visceral/subcutaneous fat ratio (by CT) as well as fasting plasma glucose and HbA(1c) (at least p < 0.05). Multiple regression analysis showed that these associations were still significant independent of age, duration of diabetes, body stature, and renal function as well as glucose or fat metabolism, whereas BAP, another bone formation marker, did not correlate with any variable. On the other hand, although ucOC also negatively correlated with %fat and %trunk fat as well as HbA(1c) (at least p < 0.05) in postmenopausal women, we found no significant association in multiple regression analysis. CONCLUSIONS: These findings suggest that ucOC is associated with plasma glucose level and fat mass in men with type 2 diabetes. PMID- 20165836 TI - Ligand-protein docking studies of potential HIV-1 drug compounds using the algorithm FlexX. AB - Four compounds are docked to a pentameric bundle representing the transmembrane part of the Vpu protein from HIV-1. Employing the docking algorithm FlexX, their free energy of binding is estimated leading to the conclusion that potential drug candidates need to form H-bonds either with neighbouring or with n + 2 helices at the site of the serines within the bundle. PMID- 20165837 TI - First results on Fe solid-phase extraction from coastal seawater using anatase TiO2 nano-particles. AB - This paper describes the application of TiO(2) nano-particles (anatase form) for the solid-phase extraction of iron from coastal seawater samples. We investigated the adsorption processes by infra-red spectroscopy. We compared in batch and on (mini)column extraction approaches (0.1 and 0.05 g TiO(2) per sample, respectively), combined to external calibration and detection by inductively coupled plasma mass spectrometry at medium mass resolution. Globally, this titania phase was slightly more efficient with seawater than with ultra-pure water, although between pH 2 and pH 7, the Fe retention efficiency progressed more in ultra-pure water than in seawater (6.9 versus 4.8 times improvement). Different reaction schemes are proposed between Fe(III) species and the two main categories of titania sites at pH 2 (adsorption of [FeL(x)]((3-x)+) via possibly the mediation of chlorides) and at pH 7 (adsorption of [Fe(OH)(2)](+) and precipitation of [Fe(OH)(3)](0)). Under optimised conditions, the inlet system was pre-cleaned by pumping 6% HCl for approximately 2 h, and the column was conditioned by aspirating ultra-pure water (1.7 g min(-1)) and 0.05% ammonia (0.6 g min(-1)) for 1 min. Then 3 g seawater sample was loaded at the same flow rate while being mixed on-line with 0.05% ammonia at 0.6 g min(-1) to adjust the pH to 7. The iron retained on the oxide powder was then eluted with 3 g 6% HCl (<0.002% residual salinity in the separated samples). The overall procedural blank was 220 +/- 46 (2 s, n = 16) ng Fe kg(-1) (the titania was renewed in the column every 20 samples, with 2-min rinsing in between samples with 6% HCl at 1.5 g min(-1)). The recovery estimated from the Canadian certified reference material CASS-2 was 69.5 +/- 7.6% (2 s, n = 4). Typically, the relative combined uncertainty (k = 2) estimated for the measurement of approximately 1 microg Fe kg(-1) (0.45 microm filtered and acidified to pH 1.5) of seawater was approximately 12%. We applied our method to a similar sample, from the coastal region of the North Sea. The agreement well within stated uncertainties of our result with the value obtained independently by isotope dilution mass spectrometry further validated our method. PMID- 20165838 TI - Somatosensory effects of action inhibition: a study with the stop-signal paradigm. AB - When a weak shock is delivered to the finger immediately before a voluntary movement, or during a delay interval where subjects are prepared to make the movement, shock detection rates worsen progressively as the movement approaches. Further, we previously showed that shock detection improves again if a NoGo signal produces inhibition of a prepared response. Here, we used a somatosensory version of the stop-signal paradigm to investigate inhibitory processing during the 'horserace' period when motor excitation and inhibition processes may be simultaneously active. When subjects made a rapid keypress response to a go signal, shock detection deteriorated in a time-dependent manner, replicating sensory suppression. However, when go-signals were followed by adaptively delayed stop-signals so that subjects could not inhibit the prepared movement, and made errors of commission, we found a paradoxical brief increase in shock detection performance just after the stop-signal, as if in a NoGo trial. During this brief window, the somatosensory system showed a pattern consistent with motor inhibition, even though the motor system itself was too far advanced in movement execution for action to be inhibited. Most models of stop-signal processing propose a two-horse race between excitation and inhibition, with a winner-takes all solution. We show that there may be distinct motor and somatosensory races. Moreover, inhibitory processes may lead in the somatosensory race, at least briefly, even when excitatory processes win the motor race. PMID- 20165840 TI - Can you hear shapes you touch? AB - Shape is an inherent property of objects existing in both vision and touch but not audition. Can shape then be represented by sound artificially? It has previously been shown that sound can convey visual information by means of image to-sound coding, but whether sound can code tactile information is not clear. Blindfolded sighted individuals were trained to recognize tactile spatial information using sounds mapped from abstract shapes. After training, subjects were able to match auditory input to tactually discerned shapes and showed generalization to novel auditory-tactile pairings. Furthermore, they showed complete transfer to novel visual shapes, despite the fact that training did not involve any visual exposure. In addition, we found enhanced tactile acuity specific to the training stimuli. The present study demonstrates that as long as tactile space is coded in a systematic way, shape can be conveyed via a medium that is not spatial, suggesting a metamodal representation. PMID- 20165839 TI - Neural integration of reaching and posture: interhemispheric spike correlations in cat motor cortex. AB - To study the interlimb coordination of reaching and postural movements, chronically implanted microelectrodes were used to record single unit activity from the primary motor cortex (MI) of cats during performance of a trained reaching task. Recordings were made from both cerebral hemispheres to record neurons that modulated their activity during reaching (reach-related neurons) and supportive (posture-related neurons) movements of either forelimb. Evidence of temporal associations in the activities of simultaneously recorded reach- and posture-related neurons was evaluated using shuffle-corrected cross correlograms. The spike activity of approximately 34% of reach-related neurons was temporally correlated with the spike activity of simultaneously recorded posture-related neurons in the opposite motor cortex. Significant associations in the spike activity of neurons recorded from homotopic representational areas of the motor cortex in opposite hemispheres have not previously been reported. These interactions may have an important role in the coordination of opposite forelimbs during reaching movements and postural actions. PMID- 20165841 TI - Conotruncal cardiac defects: a clinical imaging perspective. AB - Conotruncal cardiac defects make up a significant portion of congenital heart disease. For proper diagnosis and subsequent care of patients with these defects, different and sometimes multiple imaging modalities are needed at various stages of care. This article reviews the characteristics of some of the most common conotruncal defects and the imaging options available along with the advantages and disadvantages of each. Intricate knowledge of the capabilities of each modality will aid the practitioner in making optimal clinical decisions. PMID- 20165842 TI - Aberrant left subclavian artery sparing in right-sided interrupted aortic arch repair. AB - A right-sided interrupted aortic arch is rare, and it may have an associated aberrant left subclavian artery (ALSCA). An ALSCA is most often sacrificed at biventricular repair despite the potential danger of poor left upper-extremity growth. We report a case of ALSCA preservation with extensive dissection during aortic arch repair using direct anastomosis. PMID- 20165843 TI - Late sinus and atrial tachycardia after pediatric heart transplantation might predict poor outcome. AB - Our objective was to examine clinical/electrocardiogram (ECG) predictors and outcomes of arrhythmias beyond 1 year after pediatric heart transplantation (HTx). We performed a retrospective chart review of 94 1-year HTx survivors, 1988 2006. Clinical records identified patients with arrhythmias occurring >1 year after HTx requiring pharmacotherapy, excluding acute rejection. We reviewed preoperative diagnosis, gender, age at HTx, operative details, transplant coronary artery disease (TCAD), and mortality. We analyzed serial ECGs after HTx for HR, PR, QRS, QT, and QTc intervals. Our results found complete data in 58 patients, 14 (24%) with arrhythmia and 44 controls. Arrhythmias occurred 1.1-17.9 years after HTx (mean = 6.8): 11 focal atrial tachycardia, 1 atrial fibrillation/flutter, 1 atrioventricular node reentry tachycardia; only 1 patient had ventricular tachycardia (VT). Serial ECG intervals were similar between groups, as well as surgical technique, ischemic time, and rejection history. Seven patients (50%) with arrhythmias had death or graft death versus 11% of the controls (P = 0.006). Patients with arrhythmias were more likely to be diagnosed with TCAD (P = 0.007). The patient with VT had no TCAD. In conclusion, supraventricular arrhythmias were frequent (22%) in 1-year survivors of pediatric HTx. These patients were more likely to develop TCAD and/or graft loss/mortality. PMID- 20165844 TI - The impact of prenatal diagnosis of complex congenital heart disease on neonatal outcomes. AB - Prenatal diagnosis of congenital heart disease (CHD) is increasingly common. However, the current impact of prenatal diagnosis on neonatal outcomes is unclear. Between January 2004 and January 2008, a retrospective chart review of infants who underwent surgical repair of CHD before discharge at our institution was conducted. Obstetric and perioperative variables were recorded. Of 439 neonates, 294 (67%) were diagnosed prenatally (PREdx). Infants with PREdx had a lower mean birth weight (3.0 +/- 0.6 vs. 3.1 +/- 0.6 kg, p = 0.002) and gestational age (37.9 +/- 2.1 vs. 38.6 +/- 2.4 wk, p < 0.001) than those with postnatal diagnosis (POSTdx). Severe lesions were more likely to be PREdx: Neonates with single-ventricle (SV) physiology (n = 130 patients [31.2%]) had increased odds of PREdx (n = 113/130, odds ratio [OR] 4.7; 95% confidence interval [CI] 2.7-8.2, p < 0.001). PREdx was associated with decreased preoperative intubation (OR 0.62; 95% CI 0.42-0.95, p = 0.033), administration of antibiotics (OR 0.23; 95% CI 0.15-0.36, p < 0.001), cardiac catheterization (OR 0.54; 95% CI 0.34-0.85, p = 0.01), and emergency surgery (OR 0.18; 95% CI 0.06 0.5, p < 0.001) compared with POSTdx infants. There was no difference in APGAR scores, preoperative pH, day of life of surgery, operative complications, hospital length of stay, or overall mortality in the PREdx versus POSTdx groups, even when controlling for lesion severity. PREdx was not independently associated with neonatal mortality, despite having included more severe cardiac lesions. PREdx was significantly associated with decreased neonatal morbidity in terms of decreased use of preoperative ventilator, administration of antibiotics, cardiac catheterization, and emergency surgery. PMID- 20165845 TI - Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) presenting as a complete heart block. AB - A 51-year-old previously asymptomatic man presented with complete heart block (CHB). During pacemaker implantation, fluoroscopy showed a peculiar pattern of cardiac calcification. Coronary angiography, performed to determine the origin of calcification, demonstrated an anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). A left ventriculogram showed normal ventricular contraction. Echocardiography demonstrated normal systolic function without any regional wall motion abnormality. The endocardium of the mid and basal portions of the anteroseptal, anterior and anterolateral walls as well as both of the papillary muscles were calcified. Specifically noted was a calcific bar extending across the base of the interventricular septum (IVS) on both the echocardiogram and the left ventricle angiogram. The development of CHB in the absence of transmural myocardial infarction is intriguing. It is likely that endocardial fibroelastosis during infancy led to endocardial fibrosis and scarring subsequent calcium deposition. Extension of this calcification into the conduction system may have led to CHB. This is the first report of an adult patient with ALCAPA presenting with CHB. PMID- 20165846 TI - Value of diagnostic and therapeutic laparoscopy for abdominal stab wounds. AB - BACKGROUND: The purpose of the present study was to evaluate the use of laparoscopy for the diagnosis and treatment for hemodynamically stable patients with abdominal stab wounds. METHODS: We conducted a retrospective cohort study to compare the outcomes of 86 hemodynamically stable patients with suspected intra abdominal injuries from abdominal stab wounds who underwent either exploratory laparotomy or diagnostic laparoscopy. Thirty-eight patients (group A) were treated before the adoption of laparoscopy as a diagnostic and therapeutic tool for abdominal stabbing injuries at our hospital, and 48 patients (group B) were treated after. Demographic information, injury severity, operative findings, rates of nontherapeutic interventions, operation time, length of hospital stay, and morbidity of the two groups were evaluated. RESULTS: There was no difference in the demographics and injury severity between the two groups. Laparoscopy decreased the nontherapeutic laparotomy rate from 57.9% in group A to 0% in group B (P < 0.001). The accuracy of diagnostic laparoscopy was 100% in group B. Patients in group B had a significantly shorter hospital stay (5.0 days versus 9.9 days; P < 0.001) and shorter operation time (90.7 min vs. 118.7 min; P = 0.019) than group A. For patients in group B with significant intra-abdominal injuries, therapeutic laparoscopy was successfully performed in 16 of 17 patients (94.1%), treating a total of 22 intra-abdominal injuries. CONCLUSIONS: Laparoscopy is feasible and safe for the diagnosis and treatment of hemodynamically stable patients with abdominal stab wounds. It can reduce the nontherapeutic laparotomy rate and shorten the length of hospital stay. PMID- 20165847 TI - Technical and clinical results after percutaneous angioplasty in nonmedial fibromuscular dysplasia: outcome after endovascular management of unifocal renal artery stenoses in 30 patients. AB - Although percutaneous transluminal renal angioplasty (PTRA) is associated with excellent results in medial fibromuscular dysplasia (FMD), the clinical and technical outcome in the less common nonmedial subtype of FMD is not clearly known. Angiographic PTRA results and clinical follow-up were documented, to report technical and clinical results in 30 patients with unifocal, nonmedial dysplastic stenoses. Balloon angioplasty was technically successful in only 65% of the lesions. Additional stenting, performed after PTRA failure in six patients, increased the initial technical success rate to 82%. Stenting was used in another lesion after restenosis, and long-term patency was achieved in only three of the seven stented lesions. Frequent restenoses and unusual complications were observed during follow-up. Stent fracture occurred in two cases. Overall, long-term clinical and technical successes were sustained in 70 and 76%, respectively. We conclude that nonmedial, unifocal renal artery dysplastic stenoses do not share the excellent prognosis of the medial type and that stenting should be avoided. Therefore, surgery should be considered in lesions remaining unresponsive to balloon dilatation, after a second PTRA attempt. PMID- 20165848 TI - Hypothesis: upfront use of ABL kinase inhibitor combination, either simultaneously or sequentially, in high-risk Ph+ leukemias? AB - A sequential treatment approach is the rule in CML and Ph(+) ALL with imatinib failure being followed by second-line tyrosine kinase inhibitors. The sequential strategy may be vulnerable to compound mutations. An alternative and fascinating hypothesis discussed in this paper is the upfront use, at least in very high-risk Ph(+) leukemias, of ABL kinase inhibitor combinations, either simultaneously or sequentially to target a wider range of mutations-based drug resistance. The main questions are: will TKI cocktails be able to eliminate the leukemic compartment? Which are the correct doses? Which are the long-term effects? Clinical trials have been recently initiated, and the future will give us the answer to all these questions. PMID- 20165849 TI - A phase I study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies. AB - PURPOSE: To establish the safety, maximum tolerated dose (MTD), recommended phase II dose, and preliminary antitumor activity of obatoclax mesylate (GX15-070MS), a Bcl-2 antagonist, in combination with topotecan in patients with solid tumor malignancies. PATIENTS AND METHODS: Patients with solid tumor malignancies for whom topotecan was an appropriate treatment were administered obatoclax mesylate and topotecan on a 3-week cycle in a pre-defined, standard 3 + 3 dose escalation scheme. The starting dose for obatoclax mesylate was 14 mg/m(2) by 3-h intravenous (IV) infusion. Topotecan 1.25 mg/m(2) was given concurrently as an IV infusion on days 1-5 of each cycle. RESULTS: Fourteen patients received 40 cycles of obatoclax mesylate at the following doses: 14 mg/m(2) on day 1, 14 mg/m(2) on days 1 and 3, and 20 mg/m(2) on day 1. The most common toxicities related to obatoclax were neurologic, including ataxia, mood alterations, somnolence, and cognitive dysfunction. The majority of these were grades 1 and 2 (88%). Two of five patients experienced dose-limiting grade 3 neurologic toxicity at a dose of 20 mg/m(2); no patients experienced grade 4 neurologic toxicities, and no other patients experienced grade 3 neurologic toxicity. Of the patients who experienced grade 3 neurologic events, one later developed febrile neutropenia, which was also a dose-limiting toxicity (DLT). After an additional three patients were treated without DLT at the previously tolerated dose of 14 mg/m(2) on day 1, the level was escalated to 14 mg/m(2) on days 1 and 3. Three patients were treated at this dose and, with none experiencing a DLT, 14 mg/m(2) on days 1 and 3 was defined as the recommended phase II dose. Two patients with small-cell lung cancer (SCLC) achieved partial responses and four patients had stable disease. Median time to progression (TTP) was 12 weeks. CONCLUSION: Obatoclax mesylate administered at 14 mg/m(2) IV on days 1 and 3 is safe and well tolerated when given in combination with topotecan 1.25 mg/m(2) IV on days 1-5 of an every 3 week cycle. A phase II trial to assess the efficacy of this combination for patients with relapsed SCLC is currently accruing patients. PMID- 20165850 TI - iTRAQ-coupled 2D LC-MS/MS analysis of secreted proteome of HBV-replicating HepG2 cells: potential in biomarkers for prognosis of HCC. AB - Hepatitis B virus (HBV) infection remains a major health concern with more than 350 million carriers in the world. It is associated with acute and chronic liver diseases including hepatocellular carcinoma (HCC). The early detection of severe liver diseases related to HBV is crucial for the effective treatment. This work aims to investigate the secreted proteins in our recently established cell-based HBV replication system, using isobaric tags for relative and absolute quantitation (iTRAQ)-coupled 2D LC-MS/MS proteomics approach. Such proteins are reflective of early events of HBV infection and thus may have potential as prognostic biomarkers for development of liver diseases. PMID- 20165851 TI - High-level expression of the antimicrobial peptide plectasin in Escherichia coli. AB - Plectasin is a defensin-like antimicrobial peptide isolated from a fungus, the saprophytic ascomycete Pseudoplectania nigrella. Plectasin showed marked antibacterial activity in vitro against Gram-positive bacteria, especially Streptococcus pneumoniae, including strains resistant to conventional antibiotics. Plectasin could kill the sensitive strain as efficaciously as vancomycin and penicillin and without cytotoxic effects on mammalian cell viability. In order to establish a bacterium-based plectasin production system, in the present study, the coding sequence of plectasin was optimized, and then cloned into pET32a (+) vector and expressed as a thioredoxin (Trx) fusion protein in Escherichia coli. The soluble fusion protein collected from the supernatant of the cell lysate was separated by Ni(2+)-chelating affinity chromatography. The purified protein was then cleaved by Factor Xa protease to release mature plectasin. Final purification was achieved by Ni(2+)-chelating chromatography again. The recombinant plectasin exhibited the same antimicrobial activity as reported previously. This is the first study to describe the expression of plectasin in E. coli expression system, and these works might provide a significant foundation for the following production or study of plectasin, and contribute to the development and evolution of novel antimicrobial drugs in clinical applications. PMID- 20165853 TI - Bioenergetics of torpor in the microbiotherid marsupial, monito del monte (Dromiciops gliroides): the role of temperature and food availability. AB - Torpor is the physiologically controlled reduction of metabolic rate and body temperature experienced by small birds and mammals when facing periods of low temperature and/or food shortage. In this study, we provide a first quantitative description of torpor in the relict marsupial Dromiciops gliroides by: (1) characterizing body temperature (T (B)) and torpor patterns, (2) evaluating the combined effects of ambient temperature and different levels of food restriction on torpor incidence and (3) exploring the metabolic depression during torpor. D. gliroides exhibited short bouts of torpor on a daily basis, during which T (B) decreased close to ambient temperature. During the active phase, T (B) also exhibited pronounced variation (range 34-38 degrees C). In order to evaluate the consistency of torpor, we computed the repeatability of T (B). Using the whole dataset, repeatability was significant (tau = 0.28). However, when torpid individuals were excluded from the analysis, repeatability was non-significant: some individuals were more prone to experience torpor than others. Our results indicate that this species also exhibits short bouts of daily torpor, whose depth and duration depends on the joint effects of T (A) and food availability. At T (A) = 20 degrees C, the maximum torpor incidence was found at 70-80% food reduction, while at both extremes of the food continuum (100 and 0-10% food reduction) individuals were completely active, although considerable variation in T (B) was recorded. At T (A) = 10 degrees C, individuals developed a deep form of torpor that was independent of the amount of food provided. On average, torpid D. gliroides reduced their metabolic rate up to 92% of their active values. In general, our results suggest that T (A) was the most immediate determinant of torpor, followed by energy availability. PMID- 20165855 TI - Giant secretory villous adenoma of the rectum and sigmoid presenting as McKittrick-Wheelock syndrome. PMID- 20165854 TI - Role of TGF-beta1, its receptor TGFbetaRII, and Smad proteins in the progression of colorectal cancer. AB - AIM: In the current study, we investigated the expression of TGF-beta1, its receptor TGFbetaRII, and the signaling proteins Smad4 and Smad7 in colorectal cancer tissue in relation to infiltration with antigen-presenting cells and some clinical and pathologic parameters of disease progression in patients with colorectal cancer (CRC). MATERIALS AND METHODS: The immunohistochemical expression of TGF-beta1, TGFbetaRII, Smad4, Smad7, HLA-DR antigen, CD1a, CD83, and CD68 was evaluated in 142 patients (50 females and 92 males) with CRC, followed-up for 6-8 years period. RESULTS: In our study, 127 (89.4%) out of 142 colorectal cancers displayed cytoplasmic TGF-beta1 immunoreactivity. Common mediator Smad4 was detected in the tumor cytoplasm in 124 cancers (79.5%) and inhibitory Smad7 immunostaining was observed in 110 (77.4%) tumor specimens. TGFbetaRII was expressed on tumor cell membranes in 119 (76.3%) of the cancers. The increased TGF-beta1 expression in tumor cytoplasm was related to low CD68(+)- and CD83(+)-cell infiltration in tumor tissues. Patients with TGF-beta1 overexpression had worse prognosis after surgical therapy compared to those with low expression of TGF-beta1. The observed association was more pronounced for the patients in T1-T2 stage (p = 0.0015). CONCLUSIONS: The expression of TGF-beta1, its receptor TGFbetaRII, and signaling proteins Smad4 and Smad7 was observed in the majority of colorectal cancer specimens. Our results suggest that TGF-beta1 production by tumor cells may affect the tumor environment via suppression of tumor-infiltrating immune cells and probably contributes to tumor cells aggressiveness through autocrine activation of Smad signaling. PMID- 20165856 TI - Adenovirus-mediated stem cell leukemia gene transfer induces rescue of interstitial cells of Cajal in ICC-loss mice. AB - OBJECTIVE: Interaction of c-Kit and its ligand stem cell factor (SCF) is necessary for appropriate development and survival of interstitial cells of Cajal (ICC) in the intestine. Blockade of c-Kit will cause ICC loss in vivo. Stem cell leukemia (SCL) gene acts as a positive regulator of upstream transcription of c Kit expression. This study aimed to explore whether the restoration of c-Kit expression promoted by SCL gene transfer could rescue ICC in vivo. MATERIALS AND METHODS: A modified ICC-loss mouse model was created by continual administration of anti-c-Kit antibody (ACK2) to obtain a steady status of ICC loss, and a recombinant adenovirus vector containing SCL gene (Ad-SCL) was designed to rescue ICC in these mice. Western blot analysis and immunofluorescence labeling assays were performed to analyze the SCL and c-Kit expression in vitro and in vivo. The distribution and configuration of ICC were observed with immunohistochemistry and electromicroscope. RESULTS: Western blot analysis and immunofluorescence labeling assays showed that SCL gene was successfully delivered to cultured HeLa and ICC cells in vitro. Moreover, significantly increased c-Kit expression could be detected in the colon of Ad-SCL-infected ICC-loss mice. Furthermore, rescue of the ICC network and ICC with typical ultrastructural features could be detected in Ad-SCL-infected ICC-loss mice at day 37. CONCLUSIONS: Ad-SCL was able to enhance c-Kit expression, reactivate the c-Kit/SCF pathway, and rescue ICC in ICC loss mice. Since loss and defects of ICC are associated with many human gut motility disorders, Ad-SCL may be of potential use in gene therapy of these patients. PMID- 20165857 TI - Intrathoracic impedance monitoring detecting pneumonia. PMID- 20165858 TI - Do locking plates have a role in orthopaedic oncological reconstruction. AB - BACKGROUND: Role of locking plate in skeletal reconstruction after resection of bone tumours in Indian patients. MATERIALS AND METHODS: Retrospective evaluation of skeletal reconstruction using locking plate in 20 cases of long bone tumours was done. Reconstruction was done in 12 patients following limb salvage surgery, internal fixation of pathological fracture in seven bone tumours and one angiomatous tumour. There were 12 females and 8 male patients. RESULTS: Average age at the time of surgery was 30.1 years (range 10-58). Minimum follow-up was 11 months (range 11-38). Average time for union in pathological fractures was 4 weeks and 120 days after limb salvage surgery. Vicryl mesh was used to contain the morcellized allograft and cancellous iliac crest in 17 cases. Eighteen reconstructions were intact at an average follow-up of 17 months. Two failed reconstructions included one plate breakage and one screw pull out. CONCLUSION: Use of locking plate does not ensure the bony union at the site of reconstruction but it expedite it and allow early mobilization of joints and weight bearing particularly in Indian patients with late presentations. Careful selection of patients and proper preoperative planning including length of resection are essential for optimal outcomes and to minimize complications. Reconstruction should be supported by cortico-cancellous autograft/allograft for stabilization and union at junction of host and autograft/allograft bone and should be given adequate protection. Vicryl mesh helps in containing the morcellized grafts along the long axis of reconstruction. PMID- 20165859 TI - Varus malalignment has no influence on clinical outcome in midterm follow-up after total knee replacement. AB - BACKGROUND: Varus malalignment after total knee replacement is mentioned to be a major risk factor for postoperative pain and functional impairments. This wide spread opinion is based on the historical data derived from implantations performed in the late 1970s and early 1980s. We tested the hypothesis whether significant varus malalignment leads to minor functional results and early loosening using modern implants and operating techniques. METHODS: Two hundred and eighteen knee joints (184 patients) having been replaced with a PFC Sigma or Natural Knee II with a minimum follow-up of 5 years were included in this case control study. From the 30 most varus malaligned knees (30 patients) 25 patients were available for clinical and radiographical examination (group A) and were compared with a control group without significant varus malalignment that was matched for sex, age and implant (group B). The Knee Society Score (KSS), the WOMAC and the SF36 were determined. RESULTS: No implant showed radiological signs of loosening or had been revised. The deviation from the mechanical axis was 6.3 degrees [3.9 degrees -10.7 degrees varus] in group A and 0 degrees [2.6 degrees valgus to 2.1 degrees varus] in group B (P < 0.001). The KSS was 158 [99-199] points in group A and 142 [78-198] points in group B (n.s.). The WOMAC did not reveal any significant differences between the groups either (group A 22 +/- 27 points, group B 21 +/- 21 points). Likewise in the SF36, neither in the sum nor in the individual scores was a significant difference found between groups A (56 +/- 24 [8-90] points) and B (56 +/- 18 [26-86] points). CONCLUSIONS: The present data do not support the assumption that there is a correlation between varus malalignment and a bad medium-term radiological and clinical outcome after total knee arthroplasty. This questions the indication for revision of painful and varus malaligned prostheses, since an improvement of the clinical outcome is not to be expected. PMID- 20165860 TI - Retrograde stem removal in revision hip surgery: removing a loose or broken femoral component with a retrograde nail. AB - INTRODUCTION: Removal of a cemented femoral stem during revision total hip arthroplasty is a technically demanding procedure that requires a multitude of surgical techniques and tools. To gain full access to the cement and the stem, distal fenestration or a transfemoral approach is often required. This paper presents a technique of retrograde removal of femoral stems and cement from the distal femur. MATERIALS AND METHODS: The authors present five clinical cases. In two cases the femoral component and the surrounding cement was removed using this technique. In the other three cases, due to femoral component fracture, the distal fragment of the femoral component with its cement mantle was removed using the same technique. In an experimental study, we simulated the above technique and compared it with a windowing technique on six, paired cadaveric femora (12 femurs in all). RESULTS: In all of the clinical cases the stem and the cement were removed completely without any complications. The cadaveric experiments clearly showed that the biomechanical resistance of the femur against compression and torsion forces is greatly decreased by using a window to access the proximal femur, compared with the retrograde technique, which shows no significant change. CONCLUSION: Retrograde component removal provides a simple, rapid, and less invasive technique for stem and cement extraction in elective revision hip arthroplasty. PMID- 20165861 TI - Prospective comparative study of two different autotransfusion methods versus control group in total knee replacement. AB - AIM: The aim of this study was to evaluate the efficacy of two different autotransfusion methods in total knee replacement (TKR) performed without tourniquet, in comparison to allogeneic blood transfusion (ABT) only. METHOD: In a comparative study, 248 patients with knee osteoarthritis were randomized in three groups: in control Group 85 the patients underwent only ABT post operatively, in Group 1 (n:92) an intraoperative and postoperative autotransfusion were utilized, and in Group 2 (n:71) only a postoperative autotransfusion was applied. Post-operative ABT was utilized according to predetermined criteria. RESULTS: Comparing Group 0 to Group 1 and 2 the difference in need for ABT post-operatively was statistically highly significant (p < 0.001) even when the results were analyzed classifying the patients according to the preoperative Hb levels. The difference between Group 1 and 2 was not significant. CONCLUSION: According to the results of this study, auto transfusion reduces the need for ABT in TKR performed without tourniquet. PMID- 20165862 TI - Similar developmental patterns in immunolocalisation of stem cell factor and KIT in bovine meso- and metanephros. AB - The mesonephros is often regarded as a simplified version of the terminal renal organ, the metanephros. Both renal organs result from an epithelio-mesenchymal interaction between the Wolffian duct and the nephrogenic ridge. It appears that the epithelio-mesenchymal interaction makes use of similar signal cascades for both renal organs and that key events required for the development of the metanephros occur at earlier stages. In murine metanephroi, the stem cell factor (SCF)/-KIT-signal transduction pathway has recently been shown to regulate ureteric bud branching and epithelial cell differentiation. We immunohistochemically defined the time-sequence of KIT and SCF presence in both renal organs using bovine embryos/foetuses with crown rump length (CRL) of 1.7-24 cm. In the mesonephroi, epithelial cells with strong KIT staining were scattered in distal tubules, and SCF was expressed in the epithelial wall of corpuscles and proximal tubules. KIT positivity occurred in the metanephroi of embryos prior to SCF; KIT was predominantly localised at the ureteric bud tips in the nephrogenic zone. In foetuses of 13 cm and more CRL, the SCF/KIT profile of developmentally advanced nephrons mirrored the situation in the mesonephros. Epithelial cells with strong KIT staining were scattered in the cortical areas of distal tubules, while SCF was expressed in the epithelial wall of corpuscles and proximal tubules. Our morphological findings agree with a potential role of KIT at the ureteric bud tips and demonstrate a similar expression of KIT and SCF along the areas of developmentally advanced mesonephric and metanephric nephrons. PMID- 20165863 TI - Effects of a high-fat meal on pulmonary function in healthy subjects. AB - Obesity has important health consequences, including elevating risk for heart disease, diabetes, and cancer. A high-fat diet is known to contribute to obesity. Little is known regarding the effect of a high-fat diet on pulmonary function, despite the dramatic increase in the prevalence of respiratory ailments (e.g., asthma). The purpose of our study was to determine whether a high-fat meal (HFM) would increase airway inflammation and decrease pulmonary function in healthy subjects. Pulmonary function tests (PFT) (forced expiratory volume in 1-s, forced vital capacity, forced expiratory flow at 25-75% of vital capacity) and exhaled nitric oxide (eNO; airway inflammation) were performed in 20 healthy (10 men, 10 women), inactive subjects (age 21.9 +/- 0.4 years) pre and 2 h post HFM (1 g fat/1 kg body weight; 74.2 +/- 4.1 g fat). Total cholesterol, triglycerides, and C-reactive protein (CRP; systemic inflammation) were determined via a venous blood sample pre and post HFM. Body composition was measured via dual energy X ray absorptiometry. The HFM significantly increased total cholesterol by 4 +/- 1%, and triglycerides by 93 +/- 3%. ENO also increased (p < 0.05) due to the HFM by 19 +/- 1% (pre 17.2 +/- 1.6; post 20.6 +/- 1.7 ppb). ENO and triglycerides were significantly related at baseline and post-HFM (r = 0.82, 0.72 respectively). Despite the increased eNO, PFT or CRP did not change (p > 0.05) with the HFM. These results demonstrate that a HFM, which leads to significant increases in total cholesterol, and especially triglycerides, increases exhaled NO. This suggests that a high-fat diet may contribute to chronic inflammatory diseases of the airway and lung. PMID- 20165864 TI - Angiotensin-(1-7) and angiotension II in the rostral ventrolateral medulla modulate the cardiac sympathetic afferent reflex and sympathetic activity in rats. AB - The rostral ventrolateral medulla (RVLM) plays a pivotal role in regulating sympathetic vasomotor activity. The cardiac sympathetic afferent reflex (CSAR) contributes to the enhanced sympathetic outflow in chronic heart failure and hypertension. The aim of the present study was to determine whether angiotensin (Ang) II and Ang-(1-7) in the RVLM modulate the CSAR and sympathetic activity. Bilateral sinoaortic denervation and vagotomy were carried out in anesthetized rats. The CSAR was evaluated as the renal sympathetic nerve activity (RSNA) response to epicardial application of capsaicin. The effects of bilateral microinjection of Ang II, Ang-(1-7), the AT(1) receptor antagonist losartan or the Mas receptor antagonist D: -alanine-Ang-(1-7) (A-779) into the RVLM were determined. Either Ang II or Ang-(1-7) enhanced the CSAR as well as increased RSNA and mean arterial pressure (MAP) in a dose-dependent manner. Pretreatment with losartan but not the A-779 abolished the effects of Ang II, while A-779 but not the losartan eliminated the effects of Ang-(1-7). The RVLM microinjection of losartan alone had no direct effect on the CSAR, RSNA, and MAP, but A-779 alone attenuated the CSAR and decreased RSNA and MAP. These results indicate that Ang (1-7) is as effective as Ang II in sensitizing the CSAR and increasing sympathetic outflow. In contrast to Ang II, the effects of Ang-(1-7) are not mediated by AT(1) receptors but by Mas receptors. Mas receptors, but not the AT(1) receptors, in the RVLM are involved in the tonic control of the CSAR. PMID- 20165866 TI - Meningeal hemangiopericytomas and hemangiopericytoma/solitary fibrous tumors of extracranial soft tissues: a comparison. AB - The current World Health Organization (WHO) classification of central nervous system tumors lists meningeal hemangiopericytomas (HPC) and meningeal solitary fibrous tumors (SFT) as separate entities. On the contrary, SFT and HPC of soft tissues are regarded in the WHO soft tissue fascicle as features of the same entity. The clinical data, histology, and immunohistochemistry of 18 cases of meningeal HPC and 12 cases of peripheral soft tissue HPC-SFT were compared. Both intracranial and soft tissue lesions had significant similarities that included staghorn vasculature, necrotic areas, cytologic atypia, and positivities for CD99, collagen IV, and reticulin. Nevertheless, intracranial tumors were more cellular than HPC-SFT of soft tissues and had fewer collagen bands. Meningeal HPC in addition had more mitoses, higher Ki67 index, stained less intensely for CD34 and B-cell lymphoma 2 (BCL2) than HPC-SFT of soft tissues. Meningeal HPCs recurred in 13 out of 14 cases (92.9%). One of the patients died in the postoperative period for a recurrent lesion 5 years after the diagnosis, and another patient developed an extracranial metastasis 13 years after surgery. None of the six cases of HPC-SFT of soft tissues available for follow-up recurred. Both meningeal and soft tissue tumors appear to represent different features of the same entity. A more aggressive phenotype of the tumor together with incomplete surgical resection of intracranial lesions might explain the noticeable clinical difference between HPC of the meninges and HPC-SFT of soft tissues. PMID- 20165867 TI - Soft tissue sarcomas: introduction to the Virchows Archiv review issue. PMID- 20165865 TI - Gastrointestinal stromal tumors. AB - Gastrointestinal stromal tumors (GISTs) have emerged from being poorly defined, treatment-resistant tumors to a well-recognized, well-understood, and treatable tumor entity within only one decade. The understanding of GIST biology has made this tumor a paradigm for molecularly targeted therapy in solid tumors and provides informative insights into the advantages and limitations of so-called targeted therapeutics. Approximately 85% of GISTs harbor activating mutations in KIT or the homologous receptor tyrosine kinase PDGFRA gene. These mutations are an early event in GIST development and the oncoproteins serve as a target for the small molecule tyrosine kinase inhibitors imatinib and sunitinib. The existing and emerging treatment options demand exact morphologic classification and risk assessment. Although, KIT (CD117) immunohistochemistry is a reliable diagnostic tool in the diagnosis of GIST, KIT-negative GISTs, GISTs showing unusual morphology as well as GISTs which progress during or after treatment with imatinib/sunitinib can be a challenge for pathologists and clinicians. This review focuses on GIST pathogenesis, morphologic evaluation, promising new immunohistochemical markers, risk assessment, the role of molecular analysis, and the increasing problem of secondary imatinib resistance and its mechanisms. PMID- 20165868 TI - Immunoglobulin preparations affect hyponatremia in Kawasaki disease. AB - Hyponatremia frequently occurs in Kawasaki disease (KD). The aim of this study was to investigate the effect of Na content of the intravenous immunoglobulin (IVIG) preparation on serum Na levels in KD. Seventy-eight subjects, of whom 27 had hyponatremia, were split up into two groups: group A receiving IVIG preparations containing high Na (0.9%) and group B receiving IVIG preparations containing trace Na. While the data before IVIG therapy revealed no significant differences in the median serum Na between the groups, an administration of IVIG preparations increased the serum levels of Na in group A (P < 0.01) but not in group B (P > 0.05). Furthermore, the median serum Na level was significantly higher in group A than that in group B (139.0 vs 137.0 mEq/L, respectively, P < 0.01). No significant difference was found in the prevalence of coronary artery lesions between the groups. In conclusion, we should keep it in mind that the IVIG products without Na have an adverse affect on hyponatremia in KD though their efficacy seems to be equivalent to those containing high Na. PMID- 20165869 TI - Eponym. Kostmann disease. AB - Rolf Kostmann (1909-1982) was a Swedish pediatrician and army doctor. He was the first to describe an inherited form of chronic neutropenia in childhood. In 1956, Kostmann published his article "Infantile genetic agranulocytosis" in Acta Paediatrica. "Infantile agranulocytosis," as Rolf Kostmann named this hereditary syndrome, has been known for more than half a century, yet the underlying genetic mutations have remained unknown for many decades. Fifty years later, homozygous mutations in the gene encoding the mitochondrial protein HCLS1-associated X1 were found in affected members of the original Kostmann pedigree. Therefore, the eponym "Kostmann disease" best fits this specific mutation and mode of inheritance. The identification of genetic cause now allows the analysis of genotype-phenotype correlations. After the development of recombinant human granulocyte colony-stimulating factor (G-CSF), the prognosis and quality of life improved dramatically. Hematopoietic stem cell transplantation remains the only currently available treatment for refractory cases to G-CSF and patients who have transformed into leukemia. PMID- 20165870 TI - Assessment of in vivo antimalarial activity of rifampicin, isoniazide, and ethambutol combination therapy. AB - The existing armament of drugs for the treatment and prevention of malaria is inadequate due to development of resistance. In addition to this due to lack of economic enticement the rate of new drug development and new drug discovery in the segment of parasitic diseases is very low as compared to the other segments. This has necessitated the better deployment and usage of existing antimalarial drugs as well as discovery of antimalarial activity of drugs which are well characterized for other diseases; these approaches help to reduce the time and cost required for new drug discovery. The present study evaluated the antimalarial activity of antituberculosis drugs rifampicin, isoniazide, and ethambutol in monotherapy and combination in Plasmodium berghei-infected mice. Animals were observed for mortality, parasite progression, and toxicity for a period of 1 month. Rifampicin + isoniazide and rifampicin + isoniazide + ethambutol treatment resulted in an overall survival rate of 60% compared to 0% in vehicle-fed animals by 4 weeks after post-infection without showing any toxicity. PMID- 20165871 TI - Stress-driven stage transformation of Neospora caninum. AB - Neosporiosis, a serious disease caused by the apicomplexan intracellular parasite Neospora caninum, is considered to be one of the most economically important diseases in cattle. It is associated with potentially serious complications such as abortion, stillbirth and maternal infertility. To survive in fluctuating physiological and immunological environments, N. caninum has evolved a diverse set of regulatory mechanisms that govern various adaptive responses. The most intriguing paradigm in N. caninum adaptive evolutionary biology is its ability to alternate between two phenotypically and functionally distinct stages within the host. Recent research has reinforced the notion that N. caninum tachyzoite bradyzoite stage switching on and off is correlated with its ability to form dormant cysts. Knowledge of the specific mechanisms that govern the dynamics of N. caninum phenotype switching enables a better understanding of the pathogenesis of the disease and effective control measures to be identified. Herein we review the available knowledge relating to various aspects of stage interconversion in N. caninum, with particular focus on the stress-related hypothesis presumed to be involved in this event. Finally, we put forward the postulation that N. caninum uses stage interconversion as an adaptive process to cope with the hostile environment within the host and to ensure its continuity in nature. PMID- 20165872 TI - Effects of ethanol extract of Artemisia annua L. against monogenean parasites of Heterobranchus longifilis. AB - Ethanol extract of Artemisia annua was effective in the dislodgement and mortality of monogenean parasites of juvenile Heterobranchus longifilis at concentrations ranging from 50 to 200 mg/l. Five hundred 1-week-old juvenile fish were stocked in hapa in earthen pond for 7 days to accumulate parasites. The approximate number of parasites per fish was confirmed by counting the number of parasites attached to body surfaces and the gills with a stereo-microscope before being exposed to the extract under in vivo conditions. The bioactivity of the extract was conducted in plastic Petri dishes with three replications and controls. The results obtained from A. annua extract were matched against those produced by pure artemisinin and artesunate powder, respectively, under similar experimental conditions. There was a faster effect of pure artemisinin crystals on the parasites as compared to A. annua extract and artesunate. Coagulation of parasite cells was observed with artemisinin treatment, whereas parasites were merely dislodged from their attachment organs and killed some hours later in the same concentration of A. annua. There were positive correlations between the number of parasites dislodged/killed and the concentration of A. annua extract, artemisinin, and artesunate powder, respectively, as well as the duration of exposure of affected fish to the substances. This led to the conclusion that A. annua contains substances that are effective against helminthes parasites of H. longifilis. PMID- 20165874 TI - Interactions between anomalous excretory and tegumental epithelia in aberrant Mesocestoides tetrathyridia from Apodemus sylvaticus in Spain. AB - Tetrathyridia of Mesocestoides sp. (Platyhelminthes: Cestoda) were collected from the body cavities of Apodemus sylvaticus (Rodentia: Muridae) in Murcia, Spain, and processed by routine microscopical and histological techniques, including examination with brightfield, phase-contrast, and differential-interference contrast optics. All specimens examined had solid hindbodies (i.e., lacked a primary lacuna), thus conforming to the plerocercoid metacestode type. The vast majority of tetrathyridia were highly aberrant, often lacking a scolex, varying greatly in body size, and exhibiting buds or duplexed body forms indicative of asexual proliferation. All of the aberrant forms, including those with normal scoleces and apparent absence of proliferation, possessed anomalous multi-lobed invaginations of the hindbody tegument, which were attached at many points to abnormally dilated excretory ducts. The tegumental and excretory epithelia were joined basally, but did not share a common lumen. These abnormal connections between these aberrant tegumental modifications and the abnormally dilated excretory ducts have not been described previously for any metacestode. This report contributes to understanding previously published reports of abnormalities in other plerocercoid metacestodes, including Mesocestoides spp. and diphyllobothriidean spargana. PMID- 20165873 TI - Elimination of Dirofilaria (syn. Nochtiella) repens microfilariae in dogs with monthly treatments of moxidectin 2.5%/imidacloprid 10% (Advocate, Bayer) spot-on. AB - Elimination of microfilaria in dogs infected with zoonotic Dirofilaria repens would be desirable to reduce further spread. Moxidectin has demonstrated efficacy against microfilariae and safety in dogs infected with Dirofilaria immitis and could be an option for controlling D. repens microfilariae. A field study with 64 dogs previously confirmed positive for D. repens microfilaria was conducted in Hungary, in which a spot-on product (Advocate, Bayer) was tested. Treatments were applied to 44 dogs once a month for 3 months (five dogs) or 6 months (22 dogs), alternatively every 2 weeks for 6 months (17 dogs). Twenty dogs remained untreated. Microfilaria counts were performed once a month and for a further 6 months following the last treatment. Two weeks after the first treatment, 38 of 44 dogs were microfilaria negative. Four weeks after the initial treatment, one dog still showed a low microfilaria count. Following the second treatment, all treated dogs were negative. This status was maintained during the 6-month observation period after the last treatment. These data demonstrate the successful long-lasting elimination of microfilariae. Moreover, it may be supposed that adult D. repens were killed based on the observation that no further microfilariae were seen up to 6 months after the end of the treatment period. PMID- 20165875 TI - Isolation of an antileishmanial and antitrypanosomal flavanone from the leaves of Baccharis retusa DC. (Asteraceae). AB - In the course of selection of new bioactive compounds from Brazilian flora, the crude MeOH extract from the leaves of Baccharis retusa DC. (Asteraceae) showed potential against Leishmania sp. and Trypanosoma cruzi. Chromatographic fractionation of the dichloromethane phase from MeOH extract yielded great amounts of the bioactive derivative, which was characterized as 5,6,7-trihydroxy 4'-methoxyflavanone. The structure of this compound was established on the basis of spectroscopic data analysis, mainly nuclear magnetic resonance and mass spectrometry. PMID- 20165876 TI - Chewing lice (Phthiraptera) on manakins (Passeriformes: Pipridae) from Costa Rica, with description of a new species of the genus Tyranniphilopterus (Phthiraptera: Philopteridae). AB - One hundred and seventy individuals of five species of manakins (Passeriformes: Pipridae) were examined for chewing lice (Phthiraptera) in Costa Rica. Six species of chewing lice were identified. Chewing lice or their eggs were found on 26% individuals (28 positive/109 examined) of Long-tailed Manakins (Chiroxiphia linearis), the most numerous manakin species examined. There were significant differences in prevalences and intensities of infestation between males and females. No lice were found on females (n = 28) compared to 35% (24 positive/69 examined) prevalence in males. In older males, the higher prevalence and mean intensity of infestation was found. Description and illustrations are given for a new species of the genus Tyranniphilopterus Mey, 2004 from Long-tailed Manakin Tyranniphilopterus toledo Sychra, sp. n. Both sexes of Tyranniphilopterus bruneri (Carriker, 1903) are redescribed. New host records are Long-tailed Manakin and White-collared Manakin (Manacus candei) for Ricinus invadens; White-ruffed Manakin (Corapipo altera) for Ricinus pessimalis; Long-tailed Manakin for Myrsidea andyolsoni. These are the first louse records from Long-tailed Manakin. PMID- 20165877 TI - Molecular identification of the Diphyllobothrium species causing diphyllobothriasis in Chilean patients. AB - Diphyllobothriasis caused by the infection of adult Diphyllobothrium tapeworms sporadically occurs in Chile. The occurrence of the disease is closely linked to the consumption of raw or undercooked freshwater and marine fishes. Diagnosis of diphyllobothriasis has been based on laboratory examinations of the morphological characteristics of proglottids and eggs passed in the feces. Although determination of the parasite to the species level is possible through histologic examination of proglottid specimens, the parasites of patients who only discharge eggs cannot be diagnosed to the species level. Determining the species responsible for the infection of humans and other animals in affected areas is an important component of understanding the epidemiologic and enzootic characteristics of any infectious disease. We therefore compared the classification results obtained using a molecular approach with those obtained from morphological and histopathological examination of proglottids or eggs from five Chilean individuals with diphyllobothriasis. DNA analysis confirmed that the causative Diphyllobothrium species in Chile were first identified as Diphyllobothrium latum and Diphyllobothrium pacificum at least. Furthermore, mitochondrial cytochrome c oxidase subunit 1 gene analysis also supported the hypothesis that D. latum from Chile originated from Europe. PMID- 20165878 TI - Solubilized antigen of Blastocystis hominis facilitates the growth of human colorectal cancer cells, HCT116. AB - Blastocystis hominis is one of the most common intestinal protozoan parasites in humans, and reports have shown that blastocystosis is coupled with intestinal disorders. In the past, researchers have developed an in vitro model using B. hominis culture filtrates to investigate its ability in triggering inflammatory cytokine responses and transcription factors in human colonic epithelial cells. Studies have also correlated the inflammation by parasitic infection with cancer. The present study provides evidence of the parasite facilitating cancer cell growth through observing the cytopathic effect, cellular immunomodulation, and apoptotic responses of B. hominis, especially in malignancy. Here we investigated the effect of solubilized antigen from B. hominis on cell viability, using peripheral blood mononuclear cells (PBMCs) and human colorectal carcinoma cells (HCT116). The gene expressions of cytokines namely interleukin 6 (IL-6), IL-8, tumor necrosis factor alpha, interferon gamma, nuclear factor kappa light-chain enhancer of activated B cells (a gene transcription factor), and proapoptotic genes namely protein 53 and cathepsin B were also studied. Results exhibited favor the fact that antigen from B. hominis, at a certain concentration, could facilitate the growth of HCT116 while having the ability to downregulate immune cell responses (PBMCs). Therefore, there is a vital need to screen colorectal cancer patients for B. hominis infection as it possesses the ability to enhance the tumor growth. PMID- 20165879 TI - Experimental transmission of Theileria ovis by Hyalomma anatolicum anatolicum. AB - The experimental transmission of a newly isolated Theileria ovis is described. Hyalomma anatolicum anatolicum nymphs developed from larvae engorged on sheep infected with T. ovis were able to transmit the T. ovis to splenectomized sheep. Meanwhile, H. anatolicum anatolicum adults developed from nymphs engorged on sheep infected with T. ovis were also able to transmit T. ovis to splenectomized sheep. These experiments suggested that T. ovis could be transmitted by a H. anatolicum anatolicum, and the mode of transmission is from stage to stage. PMID- 20165880 TI - Molecular evidence of intraspecific variability in different habitat-related populations of Triatoma dimidiata (Hemiptera: Reduviidae) from Costa Rica. AB - Intraspecific genetic variation among Triatoma dimidiata (Hemiptera: Reduviidae) from seven Costa Rican populations and from different domestic, peridomestic, and sylvatic ecotopes were analyzed. The complete nucleotide sequence of the nuclear ribosomal DNA internal transcribed spacer (ITS-2) and partial sequences of the cytochrome B (Cyt b) gene and the large ribosomal subunit RNA (16S) of mitochondrial DNA (mtDNA) were analyzed and compared. All ITS-2 sequences analyzed were identical and correspond to the haplotype T.dim-H1, the most common haplotype in Central American populations. Sequences of mtDNA revealed a 10.17% of polymorphism in Cyt b and 2.39% in 16S, suggesting that the Cyt b fragment is a useful marker to describe the genetic structure of populations, even at habitat related level. The analyses of the 18 new combined T. dimidiata haplotypes (Cytb/16S/ITS-2) showed that the two main geographical locations and populations studied are genetically structured showing different haplotype profiling. Only one combined haplotype was shared in the studied areas (Cytb.d/16S.a). Seven haplotypes exclusive for domestic/peridomestic populations, five for sylvatic, and six shared haplotypes for both habitat-related ecotopes are described. Although the relationship between the habitat and the haplotype profiling is less clear, there are different patterns of haplotype distribution in each geographic area between the two habitat-related ecotopes studied (domestic/peridomestic and sylvatic), some of them reflected in the phylogenetic relationships analyzed. The intraspecific variability detected may underlie the known plasticity of T. dimidiata, an important vector for Chagas disease transmission, suggesting that this species must be continuously monitored. PMID- 20165881 TI - Comparison of SYBR Green I-, PicoGreen-, and [3H]-hypoxanthine-based assays for in vitro antimalarial screening of plants from Nigerian ethnomedicine. AB - The standard method for in vitro antimalarial drug screening is based on the isotopic assay which is expensive and utilizes radioactive materials with limited availability, safety, and disposal problems in developing countries. The use of non-radioactive DNA stains SYBR Green I (SG) and PICO green (PG) for antimalarial screening had been reported. However, the use of the two DNA stains for antimalarial screening of medicinal plants has not been compared. Thus, this study compared SG, PG with the [(3)H]-hypoxanthine (HP) incorporation assays for in vitro antimalarial screening of medicinal plants. The 50% inhibitory concentration (IC(50)) values obtained using the three methods for antimalarial activity of medicinal plants and standard antimalarial drugs were similar. Data generated from this study suggests that the non-radioactive micro-flourimetric assay is sufficiently sensitive to reproducibly identify plant extracts with antimalarial activity from those lacking activity. The HP-based assay exhibited the most robust signal-to-noise ratio of 100, compared with signal-to-noise ratios of 7 for SG and 8 for PG. The SG-based assay is less expensive than the PG and HP-based assays. SG appears to be a cost-effective alternative for antimalarial drug screening and a viable technique that may facilitate antimalarial drug discovery process especially in developing countries. PMID- 20165882 TI - High-throughput assessment of CpG site methylation for distinguishing between HCV cirrhosis and HCV-associated hepatocellular carcinoma. AB - Methylation of promoter CpG islands has been associated with gene silencing and demonstrated to lead to chromosomal instability. Therefore, some postulate that aberrantly methylated CpG regions may be important biomarkers indicative of cancer development. In this study we used the Illumina GoldenGate Methylation BeadArray Cancer Panel I for simultaneously profiling methylation of 1,505 CpG sites in order to identify methylation differences in 76 liver tissues ranging from normal to pre-neoplastic and neoplastic states. CpG sites for ESR1, GSTM2, and MME were significantly differentially methylated when comparing the pre neoplastic tissues from patients with concomitant hepatocellular carcinoma (HCC) to the pre-neoplastic tissues from patients without HCC. When comparing paired HCC tissues to their corresponding pre-neoplastic non-tumorous tissues, eight CpG sites, including one CpG site that was hypermethylated (APC) and seven (NOTCH4, EMR3, HDAC9, DCL1, HLA-DOA, HLA-DPA1, and ERN1) that were hypomethylated in HCC, were identified. Our study demonstrates that high-throughput methylation technologies may be used to identify differentially methylated CpG sites that may prove to be important molecular events involved in carcinogenesis. PMID- 20165883 TI - Development of secondary palate requires strict regulation of ECM remodeling: sequential distribution of RECK, MMP-2, MMP-3, and MMP-9. AB - We have evaluated RECK (reversion-inducing-cysteine-rich protein with Kazal motifs), MMP-2 (matrix metalloproteinase-2), MMP-3, and MMP-9 involvement during palate development in mice by using various techniques. Immunohistochemical features revealed the distribution of RECK, MMP-2, and MMP-3 in the mesenchymal tissue and in the midline epithelial seam at embryonic day 13 (E13), MMPs-2, -3, and -9 being particularly expressed at E14 and E14.5. In contrast, RECK was weakly immunostained at these times. Involvement of MMPs was validated by measuring not only their protein expression, but also their activity (zymograms). In situ hybridization signal (ISH) for RECK transcript was distributed in mesenchymal and epithelial regions within palatal shelves at all periods evaluated. Importantly, the results from ISH analysis were in accord with those obtained by real-time polymerase chain reaction. The expression of RECK was found to be temporally regulated, which suggested possible roles in palatal ontogeny. Taken together, our results clearly show that remodeling of the extracellular matrix is finely modulated during secondary palate development and occurs in a sequential manner. PMID- 20165884 TI - An endocannabinoid system is localized to the hypophysial pars tuberalis of Syrian hamsters and responds to photoperiodic changes. AB - The hypophysial pars tuberalis (PT), an important interface between neuroendocrine brain centers (hypothalamus, pineal organ) and the pars distalis (PD) of the hypophysis, plays a central role in regulating seasonal reproduction and prolactin release. However, the signaling molecules that transmit photoperiodic information from the PT to the PD and control prolactin release (the so-called "tuberalins") have not yet been identified, despite an intense search for more than three decades. Here, we demonstrate an endocannabinoid system in the PT of the Syrian hamster, a photoperiodic species. By means of in situ hybrization, the PT was found to express N-acylphosphatidylethanolamine specific phospholipase D (NAPE-PLD), fatty acid amide hydrolase (FAAH), sn-1 selective diacylglycerol lipases (DAGLalpha and DAGLbeta), and monoacylglycerol lipase (MAGL), enzymes involved in endocannabinoid synthesis and degradation. The expression of NAPE-PLD, FAAH, and DAGLalpha was confirmed by immunohistochemistry. Expression and protein levels of DAGLs controlling the synthesis of 2-arachidonoyl glycerol (2-AG), a major endocannabinoid, were upregulated in the PT of Syrian hamsters kept under long-day conditions. Consequently, 2-AG levels were increased in the PT of these hamsters. A primary target of 2-AG, the cannabinoid receptor 1 (CB1), was expressed in the PD. Double immunolabeling revealed that most of the CB1-immunoreactive cells in the PD were folliculostellate cells that were also immunoreactive for S-100 protein. Thus, the PT comprises an endocannabinoid system, and 2-AG may act as a photoperiodic messenger from the PT to the PD for the regulation of hypophysial hormonal secretion. PMID- 20165885 TI - Betacellulin inhibits osteogenic differentiation and stimulates proliferation through HIF-1alpha. AB - Cellular signaling via epidermal growth factor (EGF) and EGF-like ligands can determine cell fate and behavior. Osteoblasts, which are responsible for forming and mineralizing osteoid, express EGF receptors and alter rates of proliferation and differentiation in response to EGF receptor activation. Transgenic mice over expressing the EGF-like ligand betacellulin (BTC) exhibit increased cortical bone deposition; however, because the transgene is ubiquitously expressed in these mice, the identity of cells affected by BTC and responsible for increased cortical bone thickness remains unknown. We have therefore examined the influence of BTC upon mesenchymal stem cell (MSC) and pre-osteoblast differentiation and proliferation. BTC decreases the expression of osteogenic markers in both MSCs and pre-osteoblasts; interestingly, increases in proliferation require hypoxia inducible factor-alpha (HIF-alpha), as an HIF antagonist prevents BTC-driven proliferation. Both MSCs and pre-osteoblasts express EGF receptors ErbB1, ErbB2, and ErbB3, with no change in expression under osteogenic differentiation. These are the first data that demonstrate an influence of BTC upon MSCs and the first to implicate HIF-alpha in BTC-mediated proliferation. PMID- 20165886 TI - Chitooligosaccharides enzymatic production by Metarhizium anisopliae. AB - The products of chitosan hydrolysis are chitooligosaccharides and are used mainly for medical applications due to their specific biological activities. The objective of this study was to detect and identify the products of enzymatic hydrolysis of chitosan (dimers to hexamers) using a crude extract of chitosanolytic enzymes produced by the fungus Metarhizium anisopliae. These fungus was able to produce, during 48 h cultivation in a medium containing chitosan, chitooligosaccharides ranging from dimers, trimers, tetramers and pentamers at concentrations 0.2, 0.19, 0.06, 0.04 mg/mL, respectively, and the enzymatic activity was 2.5 U/L. Using the crude enzyme extract for chitosan hydrolysis, we detected the presence of dimers to hexamers at hydrolysis times of 10, 20, 30, 40, 50 and 60 min of enzymatic reaction, but the yields were higher at 10 min (54%). The hexamers was obtained only with 30 min of reaction with concentration of 0.004 mg/mL. PMID- 20165887 TI - Treatment of Stenotrophomonas neonatal urinary tract infection with instillation of ciprofloxacin. PMID- 20165888 TI - Orthostatic proteinuria and the spectrum of diurnal variability of urinary protein excretion in healthy children. AB - The aim of this study was to characterize the 24-h and diurnal variability of urinary protein excretion and identify the prevalence of orthostatic proteinuria (OP) in healthy children. Upright, supine, and 24-h total urinary protein (UrTP) and creatinine clearance (CrCl) were measured in 91 healthy children ages 6-19 years. Urinary protein and creatinine excretions were calculated and examined by gender, age, Tanner stage, and body mass index (BMI). Orthostatic proteinuria (OP) was defined as a 24-h UrTP >100 mg/m(2) with a normal supine UrTP (<4 mg/m(2)/h). There exists a marked diurnal variability in UrTP. The upright UrTP rate was three to four-times greater than the supine rate. UrTP, adjusted for body surface area, is higher in boys than girls and increases with age and BMI. There is a similar increase in upright CrCl compared with supine. Urinary protein to creatinine ratio (UPcr) is strongly correlated with UrTP. OP is common, being found in 20% of children in this cohort, and is more common in boys and associated with age >10 years and BMI >85%. In children with OP, a first morning UPcr shows a value in the normal range, whereas a random daytime UPcr is elevated. There exists a diurnal variability in urinary protein excretion that is exaggerated in participants with OP. UPcr reliably estimates 24-h UrTP. Using current pediatric criteria, OP is very common, particularly in boys. A normal first morning UPcr ratio indicates that a child with elevated random urinary protein has OP. PMID- 20165889 TI - Anti-epoetin-antibody-induced anemia in a child with chronic renal failure. PMID- 20165891 TI - Identification and molecular characterization of a new potyvirus infecting Triteleia species. AB - Plants of Triteleia hyacinthina, Triteleia ixioides Starlight, and Triteleia laxa Corina with severe mosaic and yellow vein-banding were found to be infected with a potyvirus. The 3'-terminal region of the virus was amplified by RT-PCR from total RNA using a potyvirus-specific degenerate primer (poty5P: 5' GGN AAY AAY AGY GGN CAR CC 3') and an oligo-dTprimer. The sequence generated included the 3' NIb protein coding region (680 nucleotides), the entire coat protein coding region (840 nucleotides), and 3'-untranslated region (UTR) (253 nucleotides). Amino acid identity of the whole CP between the triteleia virus and potyvirus member ranged from 54% Apium virus Y (ApVY) to 67% Auraujia mosaic virus (ArjMV) and Twisted-stalk chlorotic streak virus (TSCSV) and the core ranged from 59% (ApVY) to 75% (ArjMV). The 3-UTR showed no significant homology with other known potyviruses. Phylogenetic relationships suggest this triteleia virus is a new member of the Potyvirus genus and the name of "Triteleia mosaic virus" (TriMV) is proposed. This is the first report of a potyvirus infecting triteleia. PMID- 20165890 TI - Coping with sexual concerns after cancer: the use of flexible coping. AB - INTRODUCTION: Although cancer treatment commonly has a negative impact on sexual functioning, sexual concerns are still largely undertreated in routine cancer care. The medical model that guides current approaches to sexual care in cancer does not adequately address key patient needs. METHODS: In this paper, we describe a broader approach to understanding and treating sexual concerns in cancer that focuses on the construct of flexibility in behavioral and cognitive coping strategies. We previously presented this model in the context of general medical conditions. We now adapt this model to the context of cancer, focusing on issues related to the benefits of flexible coping, interventions that shift perspectives following cancer, and on coping as a couple. RESULTS: We argue that coping flexibly with sexual concerns is likely to lead to improvements in mood and sexual and relationship satisfaction. We present clinical applications of the flexible coping model, including suggestions for assessment and sexual concerns and methods of introducing flexible coping into both the content and process of clinical interactions with patients. DISCUSSION: Finally, we discuss areas for future research, including the development of a validated instrument, the use of electronic methods of assessment, and intervention trials directly addressing flexibility in coping. PMID- 20165892 TI - The application of various anatomical techniques for studying the hydraulic network in tomato fruit pedicels. AB - The abscission zone in fruit pedicels plays an important role in affecting not only water uptake in the developing fruit, but also in the transport of chemical signals from root to shoot. In order to characterize the hydraulic network of tomato fruit pedicels, we applied various techniques, including light, fluorescence microscopy, electron microscopy, maceration, tissue clearing, and X ray computed tomography. Because of significant changes in xylem anatomy, the abscission zone in tomato fruit pedicels is illustrated to show a clear reduction in hydraulic conductance. Based on anatomical measurements, the theoretical axial xylem conductance was calculated via the Hagen-Poiseuille law, suggesting that the hydraulic resistance of the abscission zone increases at least two orders of magnitude compared to the pedicel zone near the stem. The advantages and shortcomings of the microscope techniques applied are discussed. PMID- 20165893 TI - Caldinitratiruptor microaerophilus, gen. nov., sp. nov. isolated from a French hot spring (Chaudes-Aigues, Massif Central): a novel cultivated facultative microaerophilic anaerobic thermophile pertaining to the Symbiobacterium branch within the Firmicutes. AB - A novel facultative microaerophilic nitrate-reducing bacterium designated CA62N(T) was isolated from a thermal spring in France. Cells were non-motile rods (2-3 x 0.2 mum) and showed low cytoplasmic density when observed under a phase contrast microscope. Strain CA62N(T) grew at temperatures between 50 and 75 degrees C (optimum 65 degrees C) and at a pH between 6.3 and 7.9 (optimum 7.0). NaCl was not required for growth but was tolerated up to 10 gl(-1). Sulfate, thiosulfate, elemental sulfur, sulfite, and nitrite were not used as electron acceptors. Nitrate was reduced to nitrite. Strain CA62N(T) used lactate, pyruvate, glucose, mannose, fructose, and casamino acids and some amino acids as electron donors only in the presence of nitrate as electron acceptor. None of these substrates was fermented. The main end-products of glucose oxidation were acetate, CO(2), and traces of H(2). The G + C content of the genomic DNA was 70.3 mol% (HPLC techniques). Phylogenetic analysis of the small-subunit (SSU) ribosomal RNA (rRNA) gene sequence indicated that strain CA62N(T) was affiliated to the Symbiobacterium branch within the Firmicutes and had Symbiobacterium thermophilum and "S. toebii" as its closest phylogenetic relatives. On the basis of phylogenetical and physiological characteristics, strain CA62N(T) is proposed to be the type strain for the novel species in the novel genus, Caldinitratiruptor microaerophilus gen. nov., sp. nov. (DSM 22660, JCM 16183). PMID- 20165894 TI - On the observation of a gem diol intermediate after O-O bond cleavage by extradiol dioxygenases. A hybrid DFT study. AB - Catalytic cycle intermediates of a representative extradiol dioxygenase, homoprotocatechuate 2,3-dioxygenase (HPCD), have recently been characterized in crystallo by Kovaleva and Lipscomb. The structures of the identified species indicate that the process of inserting oxygen into the catechol ring occurs stepwise, and involves an Fe(II)-alkylperoxo intermediate and its O-O cleavage product: a gem diol species. In general, these findings corroborate the results of our previous computational studies; however, the fact that the gem diol species is stable enough to be observed in the crystal form seems to be at odds with the computational mechanistic data, which suggest that this intermediate should very readily and spontaneously convert to the epoxide species. The key question then becomes what is actually observed in the X-ray experiments. Here we report additional computational studies undertaken with the hope of clarifying this issue. The results obtained for active site models hosting both the native and the alternative (4-sulfonylcatechol) substrate indicate that the stability of the gem diol species is substantially increased if an electron and a proton are added. If this occurs somehow, the lifetime of the intermediate should be sufficient to observe it. PMID- 20165895 TI - Complex stapes motions in human ears. AB - It has been reported that the physiological motion of the stapes in human and several animals in response to acoustic stimulation is mainly piston-like at low frequencies. At higher frequencies, the pattern includes rocking motions around the long and short axes of the footplate in human and animal ears. Measurements of such extended stapes motions are highly sensitive to the exact angulation of the stapes in relation to the measurement devices and to measurement errors. In this study, velocity in a specific direction was measured at multiple points on the footplates of human temporal bones using a Scanning Laser Doppler Vibrometer (SLDV) system, and the elementary components of the stapes motions, which were the piston-like motion and the rocking motions about the short and long axes of the footplate, were calculated from the measurements. The angular position of a laser beam with respect to the stapes and coordinates of the measurement points on the footplate plane were calculated by correlation between the SLDV measurement frame and the footplate-fixed frame, which was obtained from micro-CT images. The ratios of the rocking motions relative to the piston-like motion increased with frequency and reached a maximum around 7 kHz.A novel method for quantitatively assessing measurements of complex stapes motions and error boundaries of the motion components is presented. In the frequency range of 0.5 to 8 kHz, the magnitudes of the piston-like and two rocking motions were larger than estimated values of the corresponding upper error bounds. PMID- 20165896 TI - Supporting cell division is not required for regeneration of auditory hair cells after ototoxic injury in vitro. AB - In chickens, nonsensory supporting cells divide and regenerate auditory hair cells after injury. Anatomical evidence suggests that supporting cells can also transdifferentiate into hair cells without dividing. In this study, we characterized an organ culture model to study auditory hair cell regeneration, and we used these cultures to test if direct transdifferentiation alone can lead to significant hair cell regeneration. Control cultures (organs from posthatch chickens maintained without streptomycin) showed complete hair cell loss in the proximal (high-frequency) region by 5 days. In contrast, a 2-day treatment with streptomycin induced loss of hair cells from all regions by 3 days. Hair cell regeneration proceeded in culture, with the time course of supporting cell division and hair cell differentiation generally resembling in vivo patterns. The degree of supporting cell division depended upon the presence of streptomycin, the epithelial region, the type of culture media, and serum concentration. On average, 87% of the regenerated hair cells lacked the cell division marker BrdU despite its continuous presence, suggesting that most hair cells were regenerated via direct transdifferentiation. Addition of the DNA polymerase inhibitor aphidicolin to culture media prevented supporting cell division, but numerous hair cells were regenerated nonetheless. These hair cells showed signs of functional maturation, including stereociliary bundles and rapid uptake of FM1 43. These observations demonstrate that direct transdifferentiation is a significant mechanism of hair cell regeneration in the chicken auditory after streptomycin damage in vitro. PMID- 20165897 TI - Lamellar phase coexistence induced by electrostatic interactions. AB - Membranes containing highly charged biomolecules can have a minimal free-energy state at small separations that originates in the strongly correlated electrostatic interactions mediated by counterions. This phenomenon can lead to a condensed, lamellar phase of charged membranes that coexists in thermodynamic equilibrium with a very dilute membrane phase. Although the dilute phase is mostly water, entropy dictates that this phase must contain some membranes and counterions. Thus, electrostatics alone can give rise to the coexistence of a condensed and an unbound lamellar phase. We use numerical simulations to predict the nature of this coexistence when the charge density of the membrane is large, for the case of multivalent counterions and for a membrane charge that is characteristic of biomolecules. We also investigate the effects of counterion size and salt on the two coexisting phases. With increasing salt concentration, we predict that electrostatic screening by salt can destroy the phase separation. PMID- 20165899 TI - The cyclic nucleotide-gated ion channel CNGA3 contributes to coolness-induced responses of Grueneberg ganglion neurons. AB - Localized to the vestibule of the nasal cavity, neurons of the Grueneberg ganglion (GG) respond to cool ambient temperatures. The molecular mechanisms underlying this thermal response are still elusive. Recently, it has been suggested that cool temperatures may activate a cyclic guanosine monophosphate (cGMP) pathway in the GG, which would be reminiscent of thermosensory neurons in Caenorhabditis elegans. In search for other elements of such a cascade, we have found that the cyclic nucleotide-gated ion channel CNGA3 was strongly expressed in the GG and that expression of CNGA3 was confined to those cells that are responsive to coolness. Further experiments revealed that the response of GG neurons to cool temperatures was significantly reduced in CNGA3-deficient mice compared to wild-type conspecifics. The observation that a cGMP-activated non selective cation channel significantly contributes to the coolness-evoked response in GG neurons strongly suggests that a cGMP cascade is part of the transduction process. PMID- 20165898 TI - In front of and behind the replication fork: bacterial type IIA topoisomerases. AB - Topoisomerases are vital enzymes specialized in controlling DNA topology, in particular supercoiling and decatenation, to properly handle nucleic acid packing and cell dynamics. The type IIA enzymes act by cleaving both strands of a double helix and having another strand from the same or another molecule cross the DNA gate before a re-sealing event completes the catalytic cycle. Here, we will consider the two types of IIA prokaryotic topoisomerases, DNA Gyrase and Topoisomerase IV, as crucial regulators of bacterial cell cycle progression. Their synergistic action allows control of chromosome packing and grants occurrence of functional transcription and replication processes. In addition to displaying a fascinating molecular mechanism of action, which transduces chemical energy into mechanical energy by means of large conformational changes, these enzymes represent attractive pharmacological targets for antibacterial chemotherapy. PMID- 20165901 TI - GD2 expression is closely associated with neuronal differentiation of human umbilical cord blood-derived mesenchymal stem cells. AB - GD2 ganglioside has been identified as a key determinant of bone marrow-derived mesenchymal stem cells (BM-MSCs). Here, we characterized GD2 ganglioside expression and its implications in umbilical cord blood-derived MSCs (UCB-MSCs). Using immune-selection analysis, we showed that both GD2-positive and GD2 negative UCB-MSCs expressed general stem cell markers and possessed mesodermal lineage differentiation potential. Although the fraction of GD2-expressing cells was lower in UCB-MSC than in BM-MSC populations, inhibition of GD2 synthesis in UCB-MSCs suppressed neuronal differentiation and down-regulated basic helix-loop helix (bHLH) transcription factors, which are involved in early stage neuronal differentiation. In addition, the levels of bHLH factors in neuronally induced UCB-MSCs were significantly higher in GD2-positive than GD2-negative cells. Our data demonstrate that GD2 ganglioside expression is associated with regulation of bHLH factors and identify neurogenic-capable UCB-MSCs, providing new insights into the potential clinical applications of MSC-based therapy. PMID- 20165902 TI - Regulation of autophagy in mammals and its interplay with apoptosis. AB - A growing number of publications show that apoptosis induction is often associated with increased autophagy indicating the existence of an interplay between these two important cellular events. The simultaneous activation of both phenomena has been detected not only in experimental settings but also in vivo under physiological and pathological conditions. Despite these studies, the reciprocal influence of the two pathways in vivo has still not been completely understood. It is clear that autophagy and apoptosis are strictly interconnected, as highlighted by the finding that the two pathways share key molecular regulators. Many novel aspects of the crosstalk between apoptosis and autophagy have recently emerged showing how complex is this relationship and how critical is for the overall fate of the cell. In this mini-review we will focus on some key experiments trying to decipher as to whether autophagy contributes to apoptosis modulation in vivo. PMID- 20165900 TI - The dopamine D4 receptor: biochemical and signalling properties. AB - Dopamine is an important neurotransmitter that regulates several key functions in the brain, such as motor output, motivation and reward, learning and memory, and endocrine regulation. Dopamine does not mediate fast synaptic transmission, but rather modulates it by triggering slow-acting effects through the activation of dopamine receptors, which belong to the G-protein-coupled receptor superfamily. Besides activating different effectors through G-protein coupling, dopamine receptors also signal through interaction with a variety of proteins, collectively termed dopamine receptor-interacting proteins. We focus on the dopamine D4 receptor, which contains an important polymorphism in its third intracellular loop. This polymorphism has been the subject of numerous studies investigating links with several brain disorders, such as attention-deficit hyperactivity disorder and schizophrenia. We provide an overview of the structure, signalling properties and regulation of dopamine D4 receptors, and briefly discuss their physiological and pathophysiological role in the brain. PMID- 20165903 TI - Recent advances in lactoferrin research and development during the past two years (2007-2009): in lieu of a preface of the Special Issue Lactoferrin. AB - This is a short preface of this Special Issue Lactoferrin, it described the major points of key reporters in 'The 9th International Conference on LF Structure, Function and Applications' in Beijing in late Autumn 2009, and the major articles published in this issue. A panorama and the latest advances of lactoferrin R&D during past two years (2007-2009) was tried to extract. PMID- 20165904 TI - Overexpression of NYGGF4 (PID1) induces mitochondrial impairment in 3T3-L1 adipocytes. AB - NYGGF4 is a recently discovered gene that is involved in obesity-associated insulin resistance. The exact mechanism by which NYGGF4 induces insulin resistance has not yet been fully elucidated. In this study, we demonstrated that the overexpression of NYGGF4 in 3T3-L1 adipocytes decreased mitochondrial mass, mitochondrial DNA, and intracellular ATP synthesis. In addition, NYGGF4 overexpression also led to an imbalance of the mitochondrial dynamics and excess intracellular ROS production. Collectively, our results indicated that the overexpression of NYGGF4 caused mitochondrial dysfunction in adipocytes, which might be responsible for the development of NYGGF4-induced insulin resistance. PMID- 20165907 TI - Sex and gender in psychiatry: a view from history. AB - Although physicians have attempted for centuries to uncover the biological differences between men and women with regard to mental illness, they continue to face the challenges of untangling biological factors from social and cultural ones. This article uses examples from history to illustrate three common problems in trying to establish biological differences: identifying factors as sex-based when they are really gender-based; overlooking changes in masculine and feminine roles over time; and placing too great an emphasis on hormones. By using the benefit of hindsight to identify problems from the past, we can think more critically about these issues in the present and the future. PMID- 20165905 TI - Dichloroacetate (DCA) enhances tumor cell death in combination with oncolytic adenovirus armed with MDA-7/IL-24. AB - Dichloroacetate (DCA) is a metabolic modulator for the treatment of lactic acidosis and inherited mitochondrial diseases. A recent study showed that DCA treatment could induce apoptosis in many kinds of tumor cell lines via mitochondrial apoptotic pathway while sparing normal cells. ONYX-015 (dl 1520) is one of the oncolytic adenoviruses developed by the deletion of E1B-55kD gene of type 5 adenoviral DNA, and it replicates efficiently and selectively in tumor cells. ZD55-IL-24, an E1B-55kD deleted oncolytic adenovirus carrying interleukin 24 (IL-24, also called melanoma differentiation associated gene-7), had showed potent antitumor efficacy in a variety of tumor cells and exerted no apparent toxicity on normal cells. Given both the good therapeutic effect and low toxicity of these agents, here we investigated whether DCA in combination with ZD55-IL-24 or ONYX-015 could have more efficient antitumor activity in vitro experiments. Therefore, we tested the cytotoxicity of combination therapy in normal hepatic cells L-02 and QSG-7701 using the MTT assay. Our results showed that DCA combined with ONYX-015 or ZD55-IL-24 exhibited more potent antitumor activity than DCA or virus alone, and the combination treatment did not have superimposed toxicities in normal cells. Thus, a novel combination therapy associating oncolytic adenoviruses with relatively low toxic drug without severe side effects was proposed. PMID- 20165908 TI - Characterization of water-soluble complexes of polyacrylic acid with alpha Amylase from Aspergillus oryzae. AB - Polycomplex formation of alpha-Amylase from Aspergillus oryzae (TAKA) with polyacrylic acid (PAA) was studied by pH titration, fluorescence, and high performance liquid chromatography (HPLC) methods in water solutions. According to the our results, the complex formation and its solubility were depended on nature of enzyme and the pH of solutions. Both of them correlates isoelectric points (PI). The stability of PAA-amylase complexes was negligibly weak at pH 7 [pH > pI (isoelectric pH)]. Stable water-soluble polycomplexes were formed at pH 5 (pI approximately 4.5) and coexisted with free protein molecules. Insoluble complexes has been observed at pH < 4.5. The frozen storage stabilities of the obtained complexes were also studied by measuring the activities at different pH. PMID- 20165909 TI - Prediction of the types of membrane proteins based on discrete wavelet transform and support vector machines. AB - Membrane proteins are crucial for many biological functions and have become attractive targets for both basic research and drug discovery. With the unprecedented increasing of newly found protein sequences in the post-genomic era, it is both time-consuming and expensive to determine the types of newly found membrane proteins solely with traditional experiment, and so it is highly demanded to develop an automatic method for fast and accurately identifying the type of membrane proteins according to their amino acid sequences. In this study, the discrete wavelet transform (DWT) and support vector machine (SVM) have been used for the prediction of the types of membrane proteins. Maximum accuracy has been obtained using SVM with a wavelet function of bior2.4, a decomposition scale j = 4, and Kyte-Doolittle hydrophobicity scales. The results indicate that the proposed method may play an important complementary role to the existing methods in this area. PMID- 20165910 TI - One size does not fit all: taking diversity, culture and context seriously. AB - Evidence suggests that the current mental health system is failing in the provision of quality mental health care for diverse children and families. This paper discusses one critical domain missing to improve care: serious attention given to diversity, culture, and context. It discusses what we mean by understanding culture and context at the individual, family, organizational, and societal level. Focusing on key predictors of children's adjustment in natural contexts would increase attention to building community and family capacities that strengthen children's mental health. To conclude, we suggest changes in organizational culture to build natural supports to enhance children's mental health. PMID- 20165911 TI - Expression of the Fas-ligand gene in ejaculated sperm from adolescents with and without varicocele. AB - PURPOSE: To assess FasL mRNA levels in ejaculated sperm from adolescent patients with and without varicocele. METHODS: Semen was obtained by masturbation following 2-4 days of ejaculatory abstinence, from 14 adolescents with varicocele grades II and III (study group), and 20 adolescents without varicocele (control group). Seminal analysis was done according to World Health Organization guidelines and morphology using Kruger's strict criteria. The Fas-ligand (FasL) gene expression was performed using reverse transcription and real-time quantitative polymerase chain reaction (RQ-PCR) analysis, according to the expression level of the housekeeping cyclophilin A gene. A Student's t-test was applied to compare the groups, and Spearman's rank test in order to verify possible correlations (p < 0.05). RESULTS: Quantitative RQ-PCR demonstrated that the expression of FasL mRNA in sperm from the varicocele group was higher than in the control group. Also, sperm concentration was higher in the controls, when compared to the varicocele group. When submitted to correlation analysis, adolescents with varicocele presented a correlation between sperm concentration and FasL gene expression levels (r = -0.470), not observed in controls. CONCLUSION: Our results allow us to conclude that, in adolescents with varicocele presenting lower sperm concentration, FasL mRNA levels are higher than in adolescents without varicocele. PMID- 20165912 TI - Regulation of AMPA receptor trafficking by O-glycosylation. AB - The present study investigated the role of O-linked beta-N-acetylglucosamine (O GlcNAc) glycosylation (O-GlcNAcylation) in AMPA receptor trafficking. Alloxan, an inhibitor of O-GlcNAc transferase, potentiated responses of AMPA receptors composed of the GluR1 subunit expressed in Xenopus oocytes. No potentiating effect of alloxan was obtained with mutant GluR1 (S831A) receptor lacking CaMKII phosphorylation site. Alloxan facilitated basal synaptic transmission to approximately 120% of basal levels and enhanced Schaffer collateral-CA1 long-term potentiation (LTP) in rat hippocampal slices, especially in the late phase of the LTP. Alloxan stimulated translocation of the GluR1 and GluR2 subunit from the cytosol towards the plasma membrane in rat hippocampal slices with the LTP, although it had no effect on subcellular distribution of the NR1 subunit. Taken together, the results of the present study show that alloxan regulates AMPA receptor trafficking by inhibiting O-GlcNAcylation, to modulate hippocampal synaptic transmission and synaptic plasticity. PMID- 20165913 TI - Quadratic fractional age assumption revisited. AB - This paper introduces a quadratic fractional age assumption which makes the force of mortality and survival function continuous at all ages. The necessary and sufficient condition for the assumption to be valid is derived. Important life table parameters are estimated and applications are shown using several life table data. PMID- 20165914 TI - Supplementing transglucosidase with a high-fiber diet for prevention of postprandial hyperglycemia in streptozotocin-induced diabetic dogs. AB - Indigestible oligosaccharides have been shown to normalize blood glucose and insulin concentration thereby promoting good health and preventing diseases, such as diabetes. Transglucosidase (TG, alpha-glucosidase, enzyme code (EC) 3.2.1.20) is an enzyme capable of converting starch to oligosaccharides, such as iso-malto oligosaccharides from maltose, via the action of amylase. The aim of this study was to evaluate whether oral administration of TG with maltose or dextrin is capable of reducing post-prandial serum glucose concentration in experimentally streptozotocin (STZ)-induced diabetic dogs fed on a high-fiber diet. Five healthy and five STZ-induced diabetic dogs were employed in this study. TG supplementation with dextrin or maltose had no detrimental effect in healthy dogs. In fact, TG and dextrin exhibited a flatlined serum glucose pattern, while reducing mean post-prandial serum insulin and glucose concentration as compared to control diet alone. When TG supplementation was tested in STZ-induced diabetic dogs under the context of a high fiber diet, a 13.8% and 23.9% reduction in mean glucose concentration for TG with maltose and dextrin, respectively was observed. Moreover, TG with dextrin resulted in a 13% lower mean post-prandial glucose concentration than TG with maltose, suggesting that dextrin may be a more efficient substrate than maltose when used at the same concentration (1 g/kg). Our results indicate that TG supplementation with diet can lead to lower postprandial glucose levels versus diet alone. However, the efficacy of TG supplementation may depend on the type of diet it is supplemented with. As such, TG administration may be useful for preventing the progression of diabetes mellitus and in its management in dogs. PMID- 20165915 TI - Collaborative problem solving (CPS) as a primary method of addressing acute pediatric pathological aggression along with other modalities. AB - The answer for treating pathologic aggression (PA) in children on inpatient psychiatry units (based on various factors like severity of aggression and co morbidities) is less likely to be restrictive interventions or sedating the patient. Using seclusion and restraints or medications to calm down the aggression is not free of adverse consequences. A protocol is needed to safely and effectively address aggressive and violent children and adolescents seen very commonly in psychiatry inpatient units. PMID- 20165916 TI - Triplet state spectra and dynamics of peridinin analogs having different extents of pi-electron conjugation. AB - The Peridinin-Chlorophyll a-Protein (PCP) complex has both an exceptionally efficient light-harvesting ability and a highly effective protective capacity against photodynamic reactions involving singlet oxygen. These functions can be attributed to presence of a substantial amount of the highly-substituted and complex carotenoid, peridinin, in the protein and the facts that the low-lying singlet states of peridinin are higher in energy than those of chlorophyll (Chl) a, but the lowest-lying triplet state of peridinin is below that of Chl a. Thus, singlet energy can be transferred from peridinin to Chl a, but the Chl a triplet state is quenched before it can sensitize the formation of singlet oxygen. The present investigation takes advantage of Chl a as an effective triplet state donor to peridinin and explores the triplet state spectra and dynamics of a systematic series of peridinin analogs having different numbers of conjugated carbon-carbon double bonds. The carotenoids investigated are peridinin, which has a C(37) carbon skeleton and eight conjugated carbon-carbon double bonds, and three synthetic analogs: C(33)-peridinin, having two less double bonds than peridinin, C(35)-peridinin which has one less double bond than peridinin, and C(39)-peridinin which has one more double bond than peridinin. In this study, the behavior of the triplet state spectra and kinetics exhibited by these molecules has been investigated in polar and nonpolar solvents and reveals a substantial effect of both pi-electron conjugated chain length and solvent environment on the spectral lineshapes. However, only a small dependence of these factors is observed on the kinetics of triplet energy transfer from Chl a and on carotenoid triplet state deactivation to the ground state. PMID- 20165918 TI - DomSVR: domain boundary prediction with support vector regression from sequence information alone. AB - Protein domains are structural and fundamental functional units of proteins. The information of protein domain boundaries is helpful in understanding the evolution, structures and functions of proteins, and also plays an important role in protein classification. In this paper, we propose a support vector regression based method to address the problem of protein domain boundary identification based on novel input profiles extracted from AAindex database. As a result, our method achieves an average sensitivity of approximately 36.5% and an average specificity of approximately 81% for multi-domain protein chains, which is overall better than the performance of published approaches to identify domain boundary. As our method used sequence information alone, our method is simpler and faster. PMID- 20165919 TI - Dysregulation of autophagy and Parkinson's disease: the MEF2D link. AB - Autophagy refers to the process by which lysosomes degrade intracellular components. Three basic forms of it, macro-, micro-, and chaperon-mediated autophagy, exist in cells. Several studies have shown that dysregulation of macroautophagy compromises the viability of neurons. Recent evidence indicates that chaperone-mediated autophagy plays a role in direct degradation of neuronal transcription factor MEF2D, a protein known to promote neuronal survival. Disruption of this regulatory pathway by alpha-synuclein leads to neuronal stress, which may underlie neuronal loss in Parkinson's disease. PMID- 20165917 TI - An overview on chlorophylls and quinones in the photosystem I-type reaction centers. AB - Minor but key chlorophylls (Chls) and quinones in photosystem (PS) I-type reaction centers (RCs) are overviewed in regard to their molecular structures. In the PS I-type RCs, the prime-type chlorophylls, namely, bacteriochlorophyll (BChl) a' in green sulfur bacteria, BChl g' in heliobacteria, Chl a' in Chl a type PS I, and Chl d' in Chl d-type PS I, function as the special pairs, either as homodimers, (BChl a')(2) and (BChl g')(2) in anoxygenic organisms, or heterodimers, Chl a/a' and Chl d/d' in oxygenic photosynthesis. Conversions of BChl g to Chl a and Chl a to Chl d take place spontaneously under mild condition in vitro. The primary electron acceptors, A (0), are Chl a-derivatives even in anoxygenic PS I-type RCs. The secondary electron acceptors are naphthoquinones, whereas the side chains may have been modified after the birth of cyanobacteria, leading to succession from menaquinone to phylloquinone in oxygenic PS I. PMID- 20165920 TI - The effects of early and late bone marrow transplantation in siblings with alpha mannosidosis. Is early haematopoietic cell transplantation the preferred treatment option? AB - This article documents both the neurological and physical outcomes of the first published set of siblings undergoing transplantation at differing ages for alpha mannosidosis. The older brother, the index case, was diagnosed at the age of 3 years and underwent transplantation at 13 years for the treatment of increasing somatic problems and recurrent infections. The younger brother had undergone transplantation pre-symptomatically at 6 months of age. Their clinical, radiological and developmental outcomes are documented and compared with the previous published cases, with the case for early transplantation being weighted against other potential therapies. PMID- 20165921 TI - Chlorella infection in a sheep in Mexico and minireview of published reports from humans and domestic animals. AB - Algal infections are rare in humans and domestic animals. Prototheca spp. and Chlorella spp. are among the most commonly reported. Herein, we present a brief review on Chlorella spp. infections and related pathologies and discuss this information including a natural case in a sheep in Mexico with a disseminated form of the disease. PMID- 20165922 TI - An improved protocol for the preparation of total genomic DNA from isolates of yeast and mould using Whatman FTA filter papers. AB - Here, we present a significantly improved version of our previously published method for the extraction of fungal genomic DNA from pure cultures using Whatman FTA filter paper matrix technology. This modified protocol is extremely rapid, significantly more cost effective than our original method, and importantly, substantially reduces the problem of potential cross-contamination between sequential filters when employing FTA technology. PMID- 20165923 TI - Prevalence of known mutations in the MEFV gene in a population screening with high rate of carriers. AB - The Familial Mediterranean Fever (FMF) shows an autosomal recessive pattern of inheritance and affects certain ethnic groups. Disease is caused by mutations in MEFV gene and more than 180 mutations have been defined in affected individuals. Current study aimed to determine the frequency-type of the mutations for MEFV gene in Sivas-middle Anatolian city. The cohort was composed of 3340 patients. MEFV gene mutations were studied by multiplex PCR based reverse hybridization stripAssay method. Patients' clinical features were; family history: 68%, erysipelas-like erythema: 17.6%, fever: 89.9%, abdominal pain: 84.2%, peritonitis: 90.2%, arthritis: 33%, pleuritis: 14.2%, parental consanguinity: 21.2%. Current results revealed that M694V is the most frequent mutation (43.12%), followed by E148Q (20.18), M680I(G/C) (15.00%) and V726A (11.32%). The study population has a high rate of carriers and the E148Q mutation frequency was found to be highest when compared to the other regions of Turkey and other Mediterranean groups. PMID- 20165925 TI - The appreciation of mineral element accumulation level in some herbaceous plants species by ICP-AES method. AB - INTRODUCTION: From the metallurgic industry zone of Dambovita County, we harvested and analyzed seven herbaceous plants species (Lolium perenne, Festuca pratensis, Stipa capillata, Agrostis alba, Cynodon dactylon, Luzula campestris, and Agrostis tenuis) to establish the heavy metal accumulation levels in these species. MATERIALS AND METHOD: The heavy metal contents (for Cr, Mn, Zn, Sr, Cu, Ba, and Sn) were determined by analyzing the dry matter with an inductively coupled plasma-atomic emission spectrometer. This method has detection limits of 0.4-0.6 mg/kg for the analyzed metals. The heavy metal concentrations in plants harvested from the industrial area are in milligram per kilogram of dry matter and ranged from 10.03 to 191.98 mg/kg of dry matter for Cr, 165.89 to 1,103.92 mg/kg of dry matter for Mn, 62.09 to 921.67 mg/kg of dry matter for Zn, 29.21 to 50.12 mg/kg of dry matter for Sr, 0.99 to 113.83 mg/kg of dry matter for Cu, 58.66 to 133.51 mg/kg of dry matter for Ba, and 8.38 to 276.44 mg/kg of dry matter for Sn. The heavy metal accumulation levels in the studied species of plants were calculated by the rapport between the concentration level of the metal in plant samples and the level of the same metal in the soil, near the radicular system for each species of plants. RESULTS: The highest accumulation levels were found in A. alba for Cr (267.69%); in L. perenne for Mn (51.45%), Sr (114.35%), and Ba (60.81%); and in C. dactylon for Zn (136.62%), Cu (97.65%), and F. pratensis for Sn (704.00%). PMID- 20165926 TI - Quantitative determination of atractylon in Atractylodis Rhizoma and Atractylodis Lanceae Rhizoma by 1H-NMR spectroscopy. AB - (1)H-NMR spectroscopy was successfully applied to the quantitative determination of atractylon in Atractylodis Rhizoma (dried rhizomes of Atractylodes ovata and A. japonica) and Atractylodis Lanceae Rhizoma (dried rhizomes of Atractylodes lancea and A. chinensis). The analysis was carried out by comparing the integral of the H-12 singlet signal of atractylon, which was well separated in the range of delta 6.95-7.05 ppm in the NMR spectrum, with the integral of a hexamethyldisilane (HMD) signal at delta 0 ppm. The atractylon contents obtained by the (1)H-NMR spectroscopy were consistent with those obtained by the conventional HPLC analysis. The present method requires neither reference compounds for calibration curves nor sample pre-purification. It also allows simultaneous determination of multiple constituents in a crude extract. Thus, it is applicable to chemical evaluation of crude drugs as a powerful alternative to various chromatographic methods. PMID- 20165924 TI - Executive function in pediatric bipolar disorder and attention-deficit hyperactivity disorder: in search of distinct phenotypic profiles. AB - Often, there is diagnostic confusion between bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD) in youth due to similar behavioral presentations. Both disorders have been implicated as having abnormal functioning in the prefrontal cortex; however, there may be subtle differences in the manner in which the prefrontal cortex functions in each disorder that could assist in their differentiation. Executive function is a construct thought to be a behavioral analogy to prefrontal cortex functioning. We provide a qualitative review of the literature on performance on executive function tasks for BD and ADHD in order to determine differences in task performance and neurocognitive profile. Our review found primary differences in executive function in the areas of interference control, working memory, planning, cognitive flexibility, and fluency. These differences may begin to establish a pediatric BD profile that provides a more objective means of differential diagnosis between BD and ADHD when they are not reliably distinguished by clinical diagnostic methods. PMID- 20165927 TI - The impact of youth and family risk factors on service recommendations and delivery in a school-based system of care. AB - The present study examines the impact of child and family risk factors on service access for youth and families in a school-based system of care. Regression analyses examined the relationships between risk factors and services recommended, services received, and dosage of services received. Logistic regression analyses examined the relationship between risk factors and whether or not youth received specific types of services within the system of care. Results revealed that youth with a personal or family history of substance use had more services recommended than youth without these risk factors, while youth with a family history of substance use received more services. Youth with a history of substance use received a significantly higher dosage of services overall. Finally, history of family mental illness was associated with receiving mental health and operational services (e.g., family advocacy, emergency funds). Implications and limitations are discussed. PMID- 20165928 TI - On the reliability of frequency components in systolic arterial pressure in patients with atrial fibrillation. AB - Atrial fibrillation (AF) is characterized by desynchronization of atrial electrical activity causing a consequent irregular ventricular response. In AF, the beat-to-beat variation of blood pressure is increased because of variations in filling time and contractility. However, only a few studies have analyzed short-term blood pressure variations in AF, and we have recently observed a harmonic low-frequency (LF) component in systolic arterial pressure (SAP) during AF. Aim of the present study is to propose a method to verify the reliability of the spectral component found in SAP series, based on the position of the poles of the autoregressive spectral decomposition in the z-plane. In particular, 1,000 random permutations of the series allowed the definition of an area in the z plane where poles from random process are likely to occur. Poles lying outside this area are considered as reliable oscillations. We tested the method on 53 recordings obtained at rest from patients with persistent AF. LF component was found in, respectively, 51 and 43 recordings in SAP and RR series. High-frequency (HF) component was found in all the recordings for both SAP and RR series. Using the proposed test, the percentage of reliable components in LF and HF bands was 80 and 38 in SAP series, and 20 and 18 in RR series. We concluded that, at variance with RR ones, SAP LF components are likely to represent true physiological oscillations. PMID- 20165929 TI - Lysophosphatidylcholine containing docosahexaenoic acid at the sn-1 position is anti-inflammatory. AB - Lysophosphatidylcholine is known to be a lipid mediator in various cellular responses. In this study, we examined the anti-inflammatory actions of lysophosphatidylcholine containing docosahexaenoic acid esterified at the sn-1 position. First, in RAW 264.7 cells, DHA-lysoPtdCho suppressed the LPS-induced formation of NO concentration-dependently. However, ARA-lysoPtdCho showed a partial suppression, and LNA-lysoPtdCho had no significant effect. Additionally, DHA-lysoPtdCho also reduced the level of TNF-alpha or IL-6, but not PGE(2). In animal experiments, the i.v. administration of ARA-lysoPtdCho (150 or 500 mug/kg) prevented zymosan A-induced plasma leakage remarkably with a maximal efficacy (Emax) of 50%, in contrast to no effect with LNA-lysoPtdCho. Remarkably, DHA lysoPtdCho suppressed zymosan A-induced plasma leakage with an ED(50) value of 46 mug/kg and an Emax value of around 95%. Additionally, mechanistic studies indicated that the anti-inflammatory action of DHA-lysoPtdCho was partially related to the reduced formation of LTC(4,) TNF-alpha, and IL-6. When the interval time between lysoPtdCho administration and zymosan A challenge was extended up to 2 h, such a suppressive action of DHA-lysoPtdCho was augmented, suggesting that a DHA-lysoPtdCho metabolite is important for anti-inflammatory action. In support of this, 17-HPDHA-lysoPtdCho showed a greater anti inflammatory action than DHA-lysoPtdCho. Furthermore, a similar anti-inflammatory action was also observed with i.p. administration of DHA-lysoPtdCho or a 17(S) hydroperoxy derivative. Additionally, oral administration of DHA-lysoPtdCho also expressed a significant anti-inflammatory action. Taken together, it is proposed that DHA-lysoPtdCho and its metabolites may be anti-inflammatory lipids in vivo systems. PMID- 20165930 TI - Evaluation of hypoglycemic activity of inorganic constituents in Nelumbo nucifera seeds on streptozotocin-induced diabetes in rats. AB - The seeds of Nelumbo nucifera (Lotus) have been used in the traditional system of medicine for various ailments including diabetes. The present study was aimed at analyzing the levels of biologically important trace elements in the lotus seeds by atomic absorption spectroscopy and evaluating the hypoglycemic properties of seed ash on streptozotocin-induced diabetes in rats. Diabetic rats treated with lotus seed ash at a concentration of 200 mg/kg body weight orally for 30 days exhibited significant hypoglycemic activity. The presence of trace elements in appreciable amounts in the seeds may play a direct or indirect role on insulin secretion or its action in a synergetic manner. The hypoglycemic activity of the ash was comparable with glyclazide. The role of trace elements in disorders related to diabetes is also discussed briefly. PMID- 20165931 TI - Prophylactic role of a herbomineral drug "Thamira parpam" against cysteamine induced oxidative stress in liver and duodenum of rats. AB - Copper is known as Gunma Kaalan in Siddha literature, which means that the drug is effective for healing ulcers. The herbomineral drug "Thamira parpam" is prepared by calcining the purified copper foils with rock salt, lime juice, bracteated birth wort juice, and Alangium root decoction according to Siddha medicine. Our study investigated the possible role of Thamira parpam (TP) in the management of cysteamine-induced duodenal ulcers. Cysteamine (400 mg kg(-1) body weight(-1), two doses at 4 h interval) orally given to rats resulted in high ulcer index, increased TBARS with concomitant depletion of antioxidants such as superoxide dismutase, glutathione, glutathione peroxidase, and inflammatory markers cathepsin D, and myeloperoxidase (p < 0.01). Herbomineral drug TP (0.5, 1, and 2 mg/kg, p.o.) challenged with cysteamine attenuated the elevation of TBARS and imbalance of antioxidants. In the increases in liver inflammatory markers, tissue histopathology changes were not severe in TP treatment. Positive control omeprazole (25 mg/kg, body weight, orally) showed considerable protection against anomaly in biochemical parameters and tissue histology. Hence, our results indicate that the attenuation of oxidative stress by the herbomineral drug in experimentally induced damage to liver and duodenum of rats could be mediated by free radical quenching property. PMID- 20165932 TI - The global impact of endoscopic ultrasound (EUS) regarding the survival of a pancreatic adenocarcinoma in a tertiary hospital. AB - BACKGROUND: Pancreatic ductal adenocarcinoma is a type of neoplasm with a high mortality rate. There are a number of different procedures that may be followed in the study of the pancreas; one such procedure is endoscopic ultrasonography (EUS). OBJECTIVE: This study aimed to retrospectively evaluate the impact on patient survival of a biliopancreatic EUS performed 2 months prior to the first treatment session of the pancreatic ductal adenocarcinoma. MATERIAL AND METHODS: We carried out a retrospective evaluation of the medical case histories of our patients who had been diagnosed with pancreatic ductal adenocarcinoma over a period of 10 years (1 Jan 1999-31 Dec 2008), combining the computer archives of our Pathological Anatomy (biopsy and cytology) Dept. and those of the Digestive Department's Endoscopic Ultrasonography Unit in order to exclude any pancreatic neoplasms derived from other origins. Information regarding the patients' age, sex, tumor location, and various diagnostic tests (EUS, EUS-fine-needle aspiration (FNA), helical computed tomography (CT), multidetector-row CT (MDCT)) were recorded, along with the different treatments that had been followed in each case. RESULT: When the survival rates of patients diagnosed with and without EUS were compared, evaluating the average survival rate and the survival rate after 1, 3, and 5 years, respectively, the differences in the results proved to be statistically significant (p = 0.014) in favor of the diagnosis with EUS. However, no significant differences were found when using other diagnostic imaging methods, such as EUS-FNA (p = 0.271), helical CT (p = 0.843), or MDCT (p = 0.738). To evaluate other influencing survival factors, a study was undertaken to record data depending on the sex of the patients. Results showed a higher survival rate in the female patients with a median of 6.57 months compared to that of the male patients with a median of 4.7 months (p = 0.014). Variables, which had resulted significant prior to treatment, were included in a multivariate Cox regression model, after which only the sex and EUS remained significant. CONCLUSION: A biliopancreatic EUS carried out during the 2 months prior to the start of the treatment of the pancreatic ductal adenocarcinoma has a statistically significant impact on the patient survival rate. We believe that this is due to the possibility of a very-early-stage diagnosis of the adenocarcinoma permitted by the use of this technique. PMID- 20165933 TI - Unusual causes of fatal upper aerodigestive tract obstruction in wild Bottlenose Dolphins (Tursiops aduncus). AB - Necropsy examination of dolphins living in Gulf St Vincent, Australia is routinely undertaken to enable the evaluation of disease processes and to provide rapid medicolegal assessment of any inflicted and/or accidental injuries. Two Indo-Pacific Bottlenose Dolphins (Tursiops aduncus) are reported to demonstrate conditions that may result in unexpected death involving upper airway compromise by quite unusual mechanisms. In the first case an adult male was found with extensive soft tissue trauma suggesting human interaction. At necropsy, death was due instead to upper airway obstruction from an impacted Slender-spined Porcupine Fish (Diodon nichthemerus) in the posterior pharynx and upper esophagus. In the second case, an adult male dolphin was found to have died, following several weeks' illness, from upper airway obstruction due to extensive respiratory tract papillomatosis within the blowhole. Given the infectious etiology of this condition the local population will be monitored for similar lesions. These cases demonstrate rare causes of upper airway obstruction in wild dolphins that were identifiable only after detailed necropsy examination. The possibility of human involvement in the deaths could be excluded. PMID- 20165934 TI - 1H, 13C, and 15N NMR assignments of StnII-Y111N, a highly impaired mutant of the sea anemone actinoporin Sticholysin II. AB - Sticholysin II is an actinoporin of 175 amino acids produced by the sea anemone Stichodactyla helianthus. Several studies with different mutants have been performed to characterize its molecular properties and activity. As a first step towards a 3D structural characterization and its interaction with membrane models at a residue level, herein we report the nearly complete NMR (15)N, (13)C and (1)H chemical shifts assignments of the Y111N variant at pH 4.0 and 25 degrees C (BMRB No. 16630). The assignment is complete for the biologically relevant residues, specially for those implicated in membrane interactions. PMID- 20165935 TI - Risk of complication and revision total hip arthroplasty among Medicare patients with different bearing surfaces. AB - BACKGROUND: To address the long-term problems of bearing surface wear and osteolysis associated with conventional metal-polyethylene (M-PE) total hip arthroplasty (THA), metal-metal (M-M), and ceramic-ceramic (C-C) bearings have been introduced. These bearing surfaces are associated with unique risks and benefits and higher costs. However the relative risks of these three bearings in an older population is unknown. QUESTIONS/PURPOSES: We compared the short-term risk of complication and revision THA among Medicare patients having a primary THA with metal-polyethylene (M-PE), metal-metal (M-M), and ceramic-ceramic (C-C) bearings. METHODS: We used the 2005 to 2007 100% Medicare inpatient claim files to perform a matched cohort analysis in three separate cohorts of THA patients (M PE, M-M, and C-C) who were matched by age, gender, and US census region. Multivariate Cox proportional-hazards models were constructed to compare complication and revision THA risk among cohorts, adjusting for medical comorbidities, race, socioeconomic status, and hospital factors. RESULTS: After adjusting for patient and hospital factors, M-M bearings were associated with a higher risk of periprosthetic joint infection (hazard ratio, 3.03; confidence interval, 1.02-9.09) when compared with C-C bearings (0.59% versus 0.32%, respectively). There were no other differences among bearing cohorts in the adjusted risk of revision THA or any other complication. CONCLUSIONS: The risk of short-term complication (including dislocation) and revision THA were similar among appropriately matched Medicare THA patients regardless of bearing surface. Hard-on-hard THA bearings are of questionable value in Medicare patients, given the higher cost associated with their use and uncertain long-term benefits in older patients. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20165936 TI - Comparative study of the ramification patterns of the subclavian branches as the subclavian artery passes in front or behind the scalenus anterior muscle. AB - We investigated the ramification patterns of four subclavian branches (i.e., vertebral artery, internal thoracic artery, thyrocervical trunk, and costocervical trunk) as the subclavian artery passes in front or behind the scalenus anterior muscle. The investigation was carried out on 56 cadavers (112 cases) during student dissection practice sessions at Osaka Dental University. In 110 of the 112 cases, the subclavian artery passed behind the scalenus anterior muscle. The pattern of ramification of the subclavian branches in these cases was classified into six types (types A-F). In the remaining two cases (two cadavers), the subclavian artery passed in front of the scalenus anterior muscle. In both of these latter cases, the pattern of ramification of the subclavian branches differed from the six pattern types observed as the subclavian artery passed behind the scalenus anterior muscle: the first branch was the vertebral artery; the second, the costocervical trunk; the third, the thyrocervical trunk; the fourth, the internal thoracic artery. This same pattern of ramification was observed in three previously reported cases (two cadavers) in which the subclavian artery passed in front of the scalenus anterior muscle. Taken together, these observations indicate that the ramification pattern reported here and in a previous investigation for the subclavian artery passing in front of the scalenus anterior muscle is characteristic of this anatomical condition. PMID- 20165938 TI - [Diagnostics of vascular diseases as a cause for acute abdomen]. AB - Vascular pathologies are rare causes of an acute abdomen. If the cause is a vascular disease a rapid diagnosis is desired as vascular pathologies are associated with high mortality. A differentiation must be made between arterial and venous diseases. An occlusion of the superior mesenteric artery is the most common reason for acute mesenteric ischemia but intra-abdominal arterial bleeding is also of great importance. Venous pathologies include thrombotic occlusion of the portal vein, the mesenteric vein and the vena cava.Multi-detector computed tomography (MDCT) is predestined for the diagnostics of vascular diseases of the abdomen. Using multiphasic contrast protocols enables reliable imaging of the arterial and venous vessel tree and detection of disorders with high sensitivity and specificity. Although conventional angiography has been almost completely replaced by MDCT as a diagnostic tool, it is still of high importance for minimally invasive interventions, for example in the management of gastrointestinal bleeding. PMID- 20165939 TI - [Mechanical obstruction as a cause of acute abdomen. Radiological differential diagnosis]. AB - Mechanical obstruction is a common cause of acute abdomen. Besides the diagnosis of the obstruction itself it is crucial to recognize the cause of the obstruction for planning of conservative or operative treatment.This article gives a general overview of the methods available for imaging obstructions in the setting of an acute abdomen. In the second part the differential diagnoses of the most common causes of obstruction will be discussed. PMID- 20165940 TI - [Modern sonography in the diagnosis of acute abdomen]. AB - Acute abdomen is a serious clinical situation and prompt imaging is mandatory so that appropriate therapeutic measures can be taken. Multiple diseases can present with the clinical signs and symptoms of acute abdomen. Ultrasound is widely available and can be performed expeditiously. Recently, major technical innovations in ultrasound technology were introduced which greatly enhanced the diagnostic accuracy in the evaluation of acute abdomen. Contrast-enhanced ultrasound is among these valuable innovations. In this article the application of modern ultrasound techniques for the diagnosis of the most common causes of acute abdomen is outlined, which may be due to diseases of the gastro-intestinal tract, parenchymal organs in the upper abdomen as well as vascular disorders. Moreover, the diagnostic efficacy and the value as compared to other imaging modalities are analyzed. PMID- 20165941 TI - Greater cardiac response of colloid than saline fluid loading in septic and non septic critically ill patients with clinical hypovolaemia. AB - BACKGROUND AND OBJECTIVE: The haemodynamics of crystalloid and colloid fluid loading may depend on underlying disease, i.e. sepsis versus non-sepsis. DESIGN AND SETTING: A single-centre, single-blinded, randomized clinical trial was carried out on 24 critically ill sepsis and 24 non-sepsis patients with clinical hypovolaemia, assigned to loading with normal saline, gelatin 4%, hydroxyethyl starch 6% or albumin 5% in a 90-min (delta) central venous pressure (CVP)-guided fluid loading protocol. Transpulmonary thermodilution was done each 30 min, yielding, among others, global end-diastolic volume and cardiac indices (GEDVI, CI). RESULTS: Sepsis patients had hyperdynamic hypotension in spite of myocardial depression and dilatation, and greater inotropic/vasopressor requirements than non-sepsis patients. Independent of underlying disease, CVP and GEDVI increased more after colloid than saline loading (P < 0.018), so that CI increased by about 2% after saline and 12% after colloid loading (P = 0.029). The increase in preload-recruitable stroke work was also greater with colloids and did not differ among conditions. CONCLUSION: Fluid loading with colloids results in a greater linear increase in cardiac filling, output and stroke work than does saline loading, in both septic and non-septic clinical hypovolaemia, in spite of myocardial depression and presumably increased vasopermeability potentially decreasing the effects of colloid fluid loading in the former. PMID- 20165942 TI - Analysis of particulate contaminations of infusion solutions in a pediatric intensive care unit. AB - PURPOSE: To examine the physical properties and chemical composition of particles captured by in-line microfilters in critically ill children, and to investigate the inflammatory and cytotoxic effects of particles on endothelial cells (HUVEC) and macrophages in vitro. METHODS: Prospective, observational study of microfilters following their use in the pediatric intensive care unit. In vitro model utilizing cytokine assays to investigate the effects of particles on human endothelial cells and murine macrophages. RESULTS: Twenty filter membranes from nine patients and five controls were examined by electron microscopy (EM) and energy dispersion spectroscopy (EDX). The average number of particles found on the surface of the used membranes was 550 cm(2). EDX analysis confirmed silicon as a major particle constituent. Half of the filter membranes showed conglomerates containing an unaccountable number of smaller particles. In vitro, glass particles were used to mimic the high silicon content particles. HUVEC and murine macrophages were exposed to different contents of particles, and cytokine levels were assayed to assess their immune response. Levels of interleukin-1beta, interleukin-6, interleukin-8, and tumor necrosis factor alpha were suppressed. CONCLUSIONS: Particle contamination of infusion solutions exists despite a stringent infusion regiment. The number and composition of particles depends on the complexity of the applied admixtures. Beyond possible physical effects, the suppression of macrophage and endothelial cell cytokine secretion in vitro suggests that microparticle infusion in vivo may have immune-modulating effects. Further clinical trials are necessary to determine whether particle retention by in-line filtration has an influence on the outcome of intensive care patients. PMID- 20165944 TI - Construction of a Bacillus thuringiensis engineered strain with high toxicity and broad pesticidal spectrum against coleopteran insects. AB - A newly engineered strain, denominated BIOT185, was constructed through integrating the cry8Ca2 gene into the endogenous plasmid of BT185 (contains cry8Ea1) by homologous recombination. The thermosensitive plasmid vector was eliminated by the rising temperature of recombinant cultures. No antibiotic gene or other unnecessary genes were introduced to the new strain. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analysis demonstrated that the cry8Ca2 gene was expressed normally and produced a 130-kDa protein in the BIOT185 strain. Bioassay results showed that the new strain had high toxicity to the pests Anomala corpulenta and Holotrichia parallela, which often damage the same fields. PMID- 20165943 TI - The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen. AB - RATIONALE: Hallucinogenic serotonin 2A (5-HT(2A)) receptor partial agonists, such as (+ or -)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), induce a frontal cortex-dependent head-twitch response (HTR) in rodents, a behavioral proxy of a hallucinogenic response that is blocked by 5-HT(2A) receptor antagonists. In addition to 5-HT(2A) receptors, DOI and most other serotonin-like hallucinogens have high affinity and potency as partial agonists at 5-HT(2C) receptors. OBJECTIVES: We tested for involvement of 5-HT(2C) receptors in the HTR induced by DOI. RESULTS: Comparison of 5-HT(2C) receptor knockout and wild-type littermates revealed an approximately 50% reduction in DOI induced HTR in knockout mice. Also, pretreatment with either the 5-HT(2C) receptor antagonist SB206553 or SB242084 eradicated a twofold difference in DOI induced HTR between the standard inbred mouse strains C57BL/6J and DBA/2J, and decreased the DOI-induced HTR by at least 50% in both strains. None of several measures of 5-HT(2A) receptors in frontal cortex explained the strain difference, including 5-HT(2A) receptor density, Galpha(q) or Galpha(i/o) protein levels, phospholipase C activity, or DOI-induced expression of Egr1 and Egr2. 5-HT(2C) receptor density in the brains of C57BL/6J and DBA/2J was also equivalent, suggesting that 5-HT(2C) receptor-mediated intracellular signaling or other physiological modulators of the HTR may explain the strain difference in response to DOI. CONCLUSIONS: We conclude that the HTR to DOI in mice is strongly modulated by 5-HT(2C) receptor activity. This novel finding invites reassessment of hallucinogenic mechanisms involving 5-HT(2) receptors. PMID- 20165945 TI - Molecular mechanisms of compounds affecting bacterial biofilm formation and dispersal. AB - Bacteria can switch between planktonic forms (single cells) and biofilms, i.e., bacterial communities growing on solid surfaces and embedded in a matrix of extracellular polymeric substance. Biofilm formation by pathogenic bacteria often results in lower susceptibility to antibiotic treatments and in the development of chronic infections; thus, biofilm formation can be considered an important virulence factor. In recent years, much attention has been directed towards understanding the biology of biofilms and towards searching for inhibitors of biofilm development and of biofilm-related cellular processes. In this report, we review selected examples of target-based screening for anti-biofilm agents: We focus on inhibitors of quorum sensing, possibly the most characterized target for molecules with anti-biofilm activity, and on compounds interfering with the metabolism of the signal molecule cyclic di-GMP metabolism and on inhibitors of DNA and nucleotide biosynthesis, which represent a novel and promising class of biofilm inhibitors. Finally, we discuss the activation of biofilm dispersal as a novel mode of action for anti-biofilm compounds. PMID- 20165946 TI - Enzymatic fragmentation of the antimicrobial peptides casocidin and isracidin by Streptococcus thermophilus and Lactobacillus delbrueckii ssp. bulgaricus. AB - The cumulative effect of peptidase and protease activities associated with cells of Streptococcus thermophilus (ST) and Lactobacillus delbrueckii subsp. bulgaricus (LB) was evaluated on the milk protein-based antimicrobial peptides casocidin and isracidin. Reaction mixtures of casocidin or isracidin and nonproliferating mid-log cells of these essential yogurt starter cultures were individually incubated for up to 4 h at pH 4.5 and 7.0, and samples removed at various time points were analyzed by reverse phase-high performance liquid chromatography (RP-HPLC) and MALDI-TOF/TOF-MS. Both casocidin and isracidin remained largely unchanged following exposure to cell suspensions of ST or LB strains at pH 4.5. Casocidin was extensively degraded by both ST and LB strains at pH 7.0, whereas isracidin remained largely intact after incubation for 4 h with ST strains but was degraded by exposure to LB strains. The results showed the feasibility of using the bovine casein-based peptides casocidin and isracidin as food grade antimicrobial supplements to impart fermented dairy foods additional protection against bacterial contamination. The structural integrity and efficacy of these biodefensive peptides may be preserved by timing their addition near the end of the fermentation of yogurt-like dairy foods (at or below pH 4.5), when conditions for bacterial proteolytic activity become unfavorable. PMID- 20165947 TI - Unusual course of the common hepatic artery originating from the celiac trunk. AB - The knowledge of anatomical variations in hepatic artery is of importance to surgeons in planning effective therapeutic strategies for general surgery. Apart from the different source and number variations, the unusual course was also discovered during the angiography and anatomical dissection. The present case report shows a rare case in which the common hepatic artery arising from the celiac trunk, crossed the portal vein, positioning itself at the back of this structure, found in a male patient undergoing distal partial gastrectomy. PMID- 20165948 TI - Short pancreas: evaluation with multi-detector row CT. AB - PURPOSE: The purpose of this study was to analyze the length variations of the pancreas using computed tomography (CT) and establish a database for short pancreas. METHODS: We retrospectively reviewed CT examinations of 228 adults and rated pancreatic lengths qualitatively on a scale of 1-3 using transverse images. 1, normal pancreas length; 2, mildly short pancreas; and 3, markedly short pancreas. The length of the pancreas from head to tail was also measured using the "curved line tool" through the midline of the organ on curved planar reconstructed (CPR) images. The pancreatic neck-tail length and the abdominal radius were measured on transverse images, and the ratio of pancreatic neck-tail length to abdominal radius was calculated to avoid the effect of body mass differences. All data were analyzed statistically. RESULTS: The pancreas length was normal (group 1) in 180 (78.9%) patients, mildly short (group 2) in 38 (16.7%), and markedly short (group 3) in 10 (4.4%). The average pancreatic length on CPR evaluation was 207.5 +/- 19.1 mm in group 1, 168.9 +/- 8.5 mm in group 2, and 135.1 +/- 10.7 mm in group 3. There were statistically significant differences between three groups. Although it was not statistically significant, percentage of diabetes mellitus was higher in group 3 (20%) than other two groups (13.2% in group 2, and 8.9% in group 1). CONCLUSIONS: CT examination of the pancreas is an effective imaging method to classify the pancreatic length and to detect short pancreas. We suggest that pancreatic length variations should be reported on routine abdominal CT examinations. PMID- 20165949 TI - [Gastrointestinal stromal tumors of the stomach. Updates and differences compared to other locations]. AB - Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the gastrointestinal tract. Two thirds of them are located in the stomach, another 30% occur in the small bowel, while the remaining tumors occur in the rectum or more rarely in the oesophagus. GIST most commonly grow from the smooth muscular layer towards the serosal surface whereas development towards to the mucosal layer is less frequent. In the latter case ulceration may occur, leading to gastrointestinal bleeding as the main symptom. However, the majority of GIST of the stomach are asymptomatic, resulting in large tumors on initial diagnosis. Most gastric GIST are not visible on endoscopy but may be diagnosed by endosonography. Due to their location in the outer layers of the tubular gastrointestinal tract biopsy is often hindered of even impossible. GIST of the stomach differ from tumors in other locations with regard to their morphology, molecular pathology and prognosis. This present article provides an overview of these differences also with regard to possible therapeutic consequences. PMID- 20165950 TI - A case of psoriasis vulgaris with diffuse idiopathic skeletal hyperostosis involved with ossifications of posterior and anterior longitudinal ligament. AB - Diffuse idiopathic skeletal hyperostosis (DISH) is difficult to distinguish from various forms of inflammatory arthritis, including psoriatic arthritis (PsA), rheumatoid arthritis, and ankylosing spondylitis. A 67-year-old Japanese male had been treated for psoriasis vulgaris for 13 years. Numbness of his right arm and lower limbs and spinal stiffening had developed 7 years prior to his initial evaluation at our facility. He noticed pain mainly while exercising. There were symmetrical marginal syndesmophytes in the spine, from the thoracic vertebrae to the upper lumbar vertebrae, on radiological examinations. We therefore suspected DISH. Furthermore, ossifications of the posterior and anterior longitudinal ligaments were noted in the cervical spine. Laboratory examinations revealed a normal peripheral white blood cell count, serum C-reactive protein, and erythrocyte sedimentation rate, and he was negative for rheumatoid factor. We detected human leukocyte antigen B39 but not B27. All distal interphalangeal joints were swollen but without pain. X-ray imaging showed narrowing of the joint space, and the consolidation of the joint was recognized, but there was no new juxta-articular bone formation. Based on clinical and radiological findings, we concluded that he had DISH and not PsA. DISH was indicated by marked radiological features of the axial skeleton, particularly the thoracic spine, but may also have involved the peripheral joints. DISH is one of the entheseal disorders, and 10% of Japanese middle-aged and elderly men have DISH. Therefore, the differentiation of DISH from PsA is necessary in psoriasis patients with spinal involvement. PMID- 20165951 TI - Minimally invasive technique for the concealed penis lead to longer penile length. AB - OBJECTIVES: The aim of this study is to report a simple and minimally invasive surgical technique for congenital concealed penis repair. METHODS: Described technique includes two approaches based on common principle, which could be selected according to the degree of penis buried. Through the minimally invasive incision at the base of penis, the repair is performed combination of tacking penile base to prepubic fascia and anchoring subcutaneous penile skin to base of penile shaft. The outcome of the operation is evaluated by improvement of penile length and satisfaction of penile appearance. RESULTS: A statistically significant difference of the penile length between preoperative and postoperative was 2.6 cm for procedure I, and 2.7 cm for procedure II (P < 0.001). There were 58 parents (93.5%) satisfied with the result. No serious intraoperative or perioperative complications. Edema and swelling on the penis are common, but improves with time. All patients are followed for at least 5 months, no retractions occur in any case. CONCLUSIONS: The described technique is simple and minimally invasive. Excellent cosmetic results are achieved with low complication rate and high parent satisfaction. In our experience, there were no additional procedures required to perform deglove or reorganization of the penile skin. PMID- 20165952 TI - Pancreaticoduodenectomy for pancreatoblastoma: a case report and literature review. AB - Pancreatoblastoma (PB) is extremely rare. A 11-year-old boy, who had excision of dilated common bile duct with hepaticoduodenostomy when 9 years old was referred to our institute for further management of abdominal pain and steatorrhea. Imaging studies showed a solid 4 cm tumor in the head of the pancreas and two lesions in the liver. Needle biopsies diagnosed PB with liver metastases. After five courses of chemotherapy, the primary tumor was completely resected with pancreaticoduodenectomy (PD) and Child's pancreaticobiliary tract reconstruction. The liver metastases were resected. Postoperative recovery was uneventful. Here, we present this case and review the literature focusing on management of PB. PMID- 20165953 TI - Full-thickness skin grafts and perichondrial cutaneous grafts following surgical removal of cutaneous neoplasms of the head and neck. AB - The objective of the study is to determine efficacy in terms of survival rate and cosmesis of "normal" full-thickness skin grafts (FTSGs) as compared to perichondrial cutaneous grafts (PCCGs) in facial reconstruction. A chart review of all facial reconstructions using FTSGs and PCCGs between 1995 and 2005 was undertaken. All patients were treated by the same surgeon. A total of 121 skin grafts were included in this study (70 FTSGs and 51 PCCGs). All patients were examined at days 5 and 10 to assess the viability of the graft. For esthetic evaluation, 70 photographs were available with a minimum follow-up of 6 months (42 FTSGs/59% of total; 28 PCCGs/54% of total). The photos were randomly shown to three raters, who had no previous knowledge about the graft being a FTSG or PGCG. The complete take rate of the FTSGs and of the PCCGs was respectively, 87% (9 failures) and 94% (3 failures) .This is no statistically significant difference (P = 0.1857). The cosmetic outcome of PCCGs overall scored better by the three raters. However, the esthetic rating between PCCG and FTSG was of no statistical significant difference (P = 0.06). In conclusion, both FTSGs and PCCGS are viable options in facial reconstruction, with no statistical difference in survival and cosmesis. They are simple and one-stage procedures. The PCCG is a smooth graft, containing a few sebaceous glands and possibly has less contraction. PMID- 20165954 TI - Sequential surgical resection of hepatic and pulmonary metastases from colorectal cancer. AB - BACKGROUND: Resection of isolated hepatic or pulmonary metastases from colorectal cancer is widely accepted and associated with a 5-year survival rate of 25-40%. The value of aggressive surgical management in patients with both hepatic and pulmonary metastases still remains a controversial area. MATERIALS AND METHODS: A retrospective review of 1,497 patients with colorectal carcinoma (CRC) was analysed. Of 73 patients identified with resection of CRC and, at some point in time, both liver and lung metastases, 17 patients underwent metastasectomy (resection group). The remaining 56 patients comprised the non-resection group. Primary tumour, hepatic and pulmonary metastases of all patients were surgically treated in our department of surgery, and the results are that of a single institution. RESULTS: The resection group had a 3-year survival of 77%, a 5-year survival of 55% and a 10-year survival of 18%; median survival was 98 months. The longest overall survival was 136 months; six patients are still alive. In the resection group, overall survival was significantly higher than in the non resection group (p < 0.01). Independent from the chronology of metastasectomy, 5 year survival was 55% with respect to the primary resection, 28% with respect to the first metastasectomy and 14% with respect to the second metastasectomy. A disease-free interval (>18 months), stage III (UICC) and age (<70 years) were found to be significant prognostic factors for overall survival. CONCLUSION: Our report strongly supports aggressive surgical therapy in patients with both hepatic and pulmonary metastases from CRC. Overall survival for surgically treated selected patients with both hepatic and pulmonary metastases from CRC is comparable to hepatic or pulmonary metastasectomy. Simultaneous metastases tend to have a poorer outcome than metachronous metastases. PMID- 20165955 TI - Deregulation of HIF1-alpha and hypoxia-regulated pathways in hepatocellular carcinoma and corresponding non-malignant liver tissue--influence of a modulated host stroma on the prognosis of HCC. AB - PURPOSE: The aim of this study was to elucidate the role of HIF1A expression in hepatocellular carcinoma (HCC) and the corresponding non-malignant liver tissue and to correlate it with the clinical outcome of HCC patients after curative liver resection. METHODS: HIF1A expression was determined by quantitative RT-PCR in HCC and corresponding non-malignant liver tissue of 53 patients surgically treated for HCC. High-density gene expression analysis and pathway analysis was performed on a selected subset of patients with high and low HIF1A expression in the non-malignant liver tissue. RESULTS: HIF1A over-expression in the apparently non-malignant liver tissue was a predictor of tumor recurrence and survival. The estimated 1-year and 5-year disease-free survival was significantly better in patients with low HIF1A expression in the non-malignant liver tissue when compared to those patients with high HIF1 expression (88.9% vs. 67.9% and 61.0% vs. 22.6%, respectively, p = 0.008). Based on molecular pathway analysis utilizing high-density gene-expression profiling, HIF1A related molecular networks were identified that contained genes involved in cell migration, cell homing, and cell-cell interaction. CONCLUSION: Our study identified a potential novel mechanism contributing to prognosis of HCC. The deregulation of HIF1A and its related pathways in the apparently non-malignant liver tissue provides for a modulated environment that potentially enhances or allows for HCC recurrence after curative resection. PMID- 20165956 TI - Thymidylate synthase germline polymorphisms in rectal cancer patients treated with neoadjuvant chemoradiotherapy based on 5-fluorouracil. AB - PURPOSE: Chemoradiotherapy using 5-fluorouracil has shown to be effective treatment for rectal cancer. Thymidylate synthase (TS) is an important target enzyme for the fluoropyrimidines. However, the predictive role of TS levels in early stage rectal cancer is not yet well understood. We analyzed the value of TS gene polymorphisms as a predictive marker in patients with stage II and III rectal cancer treated with preoperative concomitant radiotherapy and fluoropyrimidine-based chemotherapy. METHODS AND MATERIALS: Between 1998 and 2007, blood samples were obtained from 51 patients with stage II/III rectal cancer. Forty patients were T2-3 (78%), 11 were T4 (22%), and 59% were N+. DNA was extracted from peripheral blood, and the genotypes were analyzed using PCR restriction fragment length polymorphism and automated sequencing techniques. RESULTS: The *3/*3 thymidylate synthase genotype was associated with a higher response rate (pathological complete remission and microfoci residual tumor; 61 vs. 22% in *2/*2 and *2/*3; P = 0.013). In the multivariate analysis, the *3/*3 thymidylate synthase genotype was also an independent prognostic factor for better survival (P < 0.05). CONCLUSIONS: The thymidylate synthase genotype might help to identify patients with stage II/III rectal cancer who could benefit from pre- and postoperative fluorouracil-based chemotherapy. PMID- 20165957 TI - Ultra deep sequencing detects a low rate of mosaic mutations in tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome caused by mutations in TSC1 and TSC2. However, 10-15% TSC patients have no mutation identified with conventional molecular diagnostic studies. We used the ultra-deep pyrosequencing technique of 454 Sequencing to search for mosaicism in 38 TSC patients who had no TSC1 or TSC2 mutation identified by conventional methods. Two TSC2 mutations were identified, each at 5.3% read frequency in different patients, consistent with mosaicism. Both mosaic mutations were confirmed by several methods. Five of 38 samples were found to have heterozygous non-mosaic mutations, which had been missed in earlier analyses. Several other possible low-frequency mosaic mutations were identified by deep sequencing, but were discarded as artifacts by secondary studies. The low frequency of detection of mosaic mutations, two (6%) of 33, suggests that the majority of TSC patients who have no mutation identified are not due to mosaicism, but rather other causes, which remain to be determined. These findings indicate the ability of deep sequencing, coupled with secondary confirmatory analyses, to detect low frequency mosaic mutations. PMID- 20165958 TI - Structure of styles and pollen tubes of distylous Turnera joelii and T. scabra (Turneraceae): are there different mechanisms of incompatibility between the morphs? AB - We investigate the anatomy and fine structure of styles and pollen tubes of two distylous Turnera species, which possess a heteromorphic self-incompatibility system. We use fluorescence and transmission electron microscopy to provide the first description of the cellular aspects of pollen-pistil interactions and ultrastructural changes to pollen tubes during the self-incompatibility response of the morphs. No obvious ultrastructural differences occur between pistils and compatible pollen tubes. Conspicuous differences were, however, observed between incompatible pollen tubes of the morphs. Incompatible pollen tubes of the long styled morph always appear to be intact, and pollen tube tips are often highly fluorescent when stained with aniline blue, a stain for callose. Swelling and loss of cristae of mitochondria, and circular rough endoplasmic reticulum, were observed for incompatible pollen tubes of the long-styled morph. For incompatible pollen tubes of the short-styled morph, the tube cell wall apex and plasma membrane often appear to be ruptured and no easily recognizable organelles, such as mitochondria, can be discerned. Our results clearly show ultrastructural differences between the morphs and support the hypothesis that different self incompatibility mechanisms might operate between them. PMID- 20165959 TI - Maize host requirements for Ustilago maydis tumor induction. AB - The biotrophic pathogen Ustilago maydis causes tumors by redirecting vegetative and floral development in maize (Zea mays L.). After fungal injection into immature tassels, tumors were found in all floral organs, with a progression of organ susceptibility that mirrors the sequential location of foci of cell division in developing spikelets. There is sharp demarcation between tumor forming zones and areas with normal spikelet maturation and pollen shed; within and immediately adjacent to the tumor zone, developing anthers often emerge precociously and exhibit a range of developmental defects suggesting that U. maydis signals and host responses are restricted spatially. Male-sterile maize mutants with defects in anther cell division patterns and cell fate acquisition prior to meiosis formed normal adult leaf tumors, but failed to form anther tumors. Methyl jasmonate and brassinosteroid phenocopied these early-acting anther developmental mutants by generating sterile zones within tassels that never formed tumors. Although auxin, cytokinin, abscisic acid and gibberellin did not impede tassel development, the Dwarf8 mutant defective in gibberellin signaling lacked tassel tumors; the anther ear1 mutant reduced in gibberellin content formed normal tumors; and Knotted1, in which there is excessive growth of leaf tissue, formed much larger vegetative and tassel tumors. We propose the hypothesis that host growth potential and tissue identity modulate the ability of U. maydis to redirect differentiation and induce tumors. PMID- 20165960 TI - Morphogenesis of complex plant cell shapes: the mechanical role of crystalline cellulose in growing pollen tubes. AB - Cellulose is the principal component of the load-bearing system in primary plant cell walls. The great resistance to tensile forces of this polysaccharide and its embedding in matrix components make the cell wall a material similar to a fiber composite. In the rapidly growing pollen tube, the amount of cellulose in the cell wall is untypically low. Therefore, we want to investigate whether the load bearing function of cellulose is nevertheless important for the architecture of this cell. Enzymatic digestion with cellulase and inhibition of cellulose crystal formation with CGA (1-cyclohexyl-5-(2,3,4,5,6-pentafluorophenoxy)-1lambda4,2,4,6 thiatriazin-3-amine) resulted in the formation of tubes with increased diameter in Solanum chacoense and Lilium orientalis when present during germination. In pre-germinated tubes, application of both agents resulted in the transient arrest of growth accompanied by the formation of an apical swelling indicating a role in the mechanical stabilization of this cellular region. Once growth resumed in the presence of cellulase, however, the cell wall in the newly formed tube showed increased amounts of pectins, possibly to compensate for the reduced amount of cellulose. Scanning electron microscopy of pollen tubes subjected to digestion of matrix polysaccharides revealed the mechanical anisotropy of the cell wall. In both Lilium and Solanum, the angle of highest stability revealed by crack formation was significantly below 45 degrees , an indication that in the mature part of the cell cellulose may not the main stress-bearing component against turgor pressure induced tensile stress in circumferential direction. PMID- 20165961 TI - Chromosome and DNA methylation dynamics during meiosis in the autotetraploid Arabidopsis arenosa. AB - Variation in chromosome number due to polyploidy can seriously compromise meiotic stability. In autopolyploids, the presence of more than two homologous chromosomes may result in complex pairing patterns and subsequent anomalous chromosome segregation. In this context, chromocenter, centromeric, telomeric and ribosomal DNA locus topology and DNA methylation patterns were investigated in the natural autotetraploid, Arabidopsis arenosa. The data show that homologous chromosome recognition and association initiates at telomeric domains in premeiotic interphase, followed by quadrivalent pairing of ribosomal 45S RNA gene loci (known as NORs) at leptotene. On the other hand, centromeric regions at early leptotene show pairwise associations rather than associations in fours. These pairwise associations are maintained throughout prophase I, and therefore likely to be related to the diploid-like behavior of A. arenosa chromosomes at metaphase I, where only bivalents are observed. In anthers, both cells at somatic interphase as well as at premeiotic interphase show 5-methylcytosine (5-mC) dispersed throughout the nucleus, contrasting with a preferential co-localization with chromocenters observed in vegetative nuclei. These results show for the first time that nuclear distribution patterns of 5-mC are simultaneously reshuffled in meiocytes and anther somatic cells. During prophase I, 5-mC is detected in extended chromatin fibers and chromocenters but interestingly is excluded from the NORs what correlates with the pairing pattern. PMID- 20165962 TI - Pollen-expressed F-box gene family and mechanism of S-RNase-based gametophytic self-incompatibility (GSI) in Rosaceae. AB - Many species of Rosaceae, Solanaceae, and Plantaginaceae exhibit S-RNase-based self-incompatibility (SI) in which pistil-part specificity is controlled by S locus-encoded ribonuclease (S-RNase). Although recent findings revealed that S locus-encoded F-box protein, SLF/SFB, determines pollen-part specificity, how these pistil- and pollen-part S locus products interact in vivo and elicit the SI reaction is largely unclear. Furthermore, genetic studies suggested that pollen S function can differ among species. In Solanaceae and the rosaceous subfamily Maloideae (e.g., apple and pear), the coexistence of two different pollen S alleles in a pollen breaks down SI of the pollen, a phenomenon known as competitive interaction. However, competitive interaction seems not to occur in the subfamily Prunoideae (e.g., cherry and almond) of Rosaceae. Furthermore, the effect of the deletion of pollen S seems to vary among taxa. This review focuses on the potential differences in pollen-part function between subfamilies of Rosaceae, Maloideae, and Prunoideae, and discusses implications for the mechanistic divergence of the S-RNase-based SI. PMID- 20165963 TI - Physical mapping of rDNA genes corroborates allopolyploid origin in apomictic Brachiaria brizantha. AB - Brachiaria (Trin.) Griseb belongs to the family Poaceae, and within the genus, apomixis or sexuality is present in different accessions of the same species. The majority of Brachiaria species are polyploid and apomictic, making strategies for crop improvement by breeding very intricate. In spite of the high frequency of apomictic polyploids, the relationship of polyploidy and hybridization with apomixis in Brachiaria is still unclear. Further analysis requires detailed knowledge regarding the genomic composition of the polyploids. The present work introduces the use of fluorescent in situ hybridization (FISH) into cytogenetic analysis of Brachiaria. Physical mapping of heterologous rDNA sequences, associated with conventional karyotyping of the B. brizantha diploid sexual (BRA 002747) and the tetraploid apomictic (BRA000591) accessions, provided evidence of the latter being of allopolyploid origin. Based on our results and on previous knowledge on apomixis in B. brizantha, we suggest that the origin of apomixis was probably a consequence of hybridization. PMID- 20165964 TI - How to shape a cylinder: pollen tube as a model system for the generation of complex cellular geometry. AB - Expansive growth in plant cells is a formidable problem for biophysical studies, and the mechanical principles governing the generation of complex cellular geometries are still poorly understood. Pollen, the male gametophyte stage of the flowering plants, is an excellent model system for the investigation of the mechanics of complex growth processes. The initiation of pollen tube growth requires first of all, the spatially confined formation of a protuberance. This process must be controlled by the mechanical properties of the cell wall, since turgor is a non-vectorial force. In the elongating tube, cell wall expansion is confined to the apex of the cell, requiring the tubular region to be stabilized against turgor-induced tensile stress. Tip focused surface expansion must be coordinated with the supply of cell wall material to this region requiring the precise, logistical control of intracellular transport processes. The advantage of such a demanding mechanism is the high efficiency it confers on the pollen tube in leading an invasive way of life. PMID- 20165965 TI - The evolution of self-fertility in apomictic plants. AB - Self-fertilization and apomixis have often been seen as alternative evolutionary strategies of flowering plants that are advantageous for colonization scenarios and in bottleneck situations. Both traits have multiple origins, but different genetic control mechanisms; possible connections between the two phenomena have long been overlooked. Most apomictic plants, however, need a fertilization of polar nuclei for normal seed development (pseudogamy). If self-pollen is used for this purpose, self-compatibility is a requirement for successful pollen tube growth. Apomictic lineages usually evolve from sexual self-incompatible outcrossing plants, but pseudogamous apomicts frequently show a breakdown of self incompatibility. Two possible pathways may explain the evolution of SC: (1) Polyploidy not only may trigger gametophytic apomixis, but also may result in a partial breakdown of SI systems. (2) Alternatively, frequent pseudo self compatibility (PSC) via aborted pollen may induce selfing of pseudogamous apomicts (mentor effects). Self-fertile pseudogamous genotypes will be selected for within mixed sexual-apomictic populations because of avoidance of interploidal crosses; in founder situations, SC provides reproductive assurance independent from pollinators and mating partners. SI pseudogamous genotypes will be selected against in mixed populations because of minority cytotype problems and high pollen discounting; in founder populations, SI reactions among clone mates will reduce seed set. Selection for SC genotypes will eliminate SI unless the apomict maintains a high genotypic diversity and thus a diversity of S alleles within a population, or shifts to pollen-independent autonomous apomixis. The implications of a breakdown of SI in apomictic plants for evolutionary questions and for agricultural sciences are being discussed. PMID- 20165968 TI - Abdominal pseudocyst complicating incisional hernia repair: our experience and literature review. AB - Giant pseudocyst is a rare complication of incisional hernia repairs whose etiology and incidence remains unknown. We have reviewed all cases of abdominal incisional hernia repair in our abdominal wall unit since its creation 6 years ago. Pseudocyst formation was observed in seven cases out of 871 incisional hernia repair operations. Four of them underwent surgical exploration with excision of the mass. To the best of our knowledge, only 18 cases of giant pseudocyst have been described in the literature. From both our personal experience and the reported literature, we understand that abdominal pseudocyst is an extremely rare or underreported late complication of hernia repair surgery. The complete excision of the cyst and its fibrous wall is the definitive treatment of choice. PMID- 20165966 TI - Retrospective analysis of orbital floor fractures--complications, outcome, and review of literature. AB - This retrospective study aimed at investigating indications, surgical approaches, and the materials used for orbital floor reconstructions, as well as the clinical follow-up, particularly with regard to postoperative complications. This study comprised 189 patients who underwent surgery for fractures of the orbital floor between 2003 and 2007. Diagnosis and treatment were based on both physical examination and computed tomography scan of the orbit. Patients were retrospectively analyzed for data, such as mechanism of injury, classification of fracture, and complications. The most common cause of injury was physical assault followed by traffic accidents. Surgery was conducted with a mean delay of 2.9 days after the incident. Mid lower eyelid incision was the most common surgical approach to the orbital floor. For orbital floor reconstruction, polydioxanone sheets (70.5%) were mainly used, followed by Ethisorb Dura (23.3%) and titanium mesh (6.2%). There were 19.0% of patients who showed postoperative complications: 5.8% suffered from persisting motility impairment, 3.7% from enophthalmos, 3.2% from consistent diplopia, 2.6% from ectropion, and 0.5% from orbital infection. Intraorbital hematoma (3.2%) represented the most severe complications, one patient suffered lasting impairment of sight and another one, complete blindness of the affected eye. If postoperative impairment of vision becomes evident, immediate surgical intervention is mandatory. Retrobulbar hematoma is more likely to occur in heavily traumatized patients with comminuted fractures and also in patients taking anticoagulative medication. The subciliary approach to the orbit and repeated operations by the same approach are associated with a higher risk of developing ectropion. PMID- 20165967 TI - The diagnostic suitability of a xerostomia questionnaire and the association between xerostomia, hyposalivation and medication use in a group of nursing home residents. AB - The study objective was to explore the diagnostic suitability of the Xerostomia Inventory and the association between xerostomia, hyposalivation and medication use in a group of nursing home residents. A cross-sectional study was carried out in 50 physically impaired nursing home residents (20 men) with a mean age of 78.1 years (range, 53-98) in The Netherlands. The Xerostomia Inventory-Dutch version was completed for all residents and the data were subjected to exploratory factor analysis to determine the diagnostic suitability. Residents' data on xerostomia, whole saliva secretion rates and hyposalivation-related medications used were collected and statistically analyzed. The diagnostic suitability of the Xerostomia Inventory-Dutch version appeared restricted. The prevalence of xerostomia was 52%, without gender and age difference. The prevalence of hyposalivation was 24% for resting, 60% for chewing-stimulated and 18% for acid stimulated whole saliva. All whole saliva secretion rates were significantly lower in women than in men and in older than in younger residents. Forty-four percent of all medications used were hyposalivation-related and women used significantly more medications than men. Xerostomia was significantly negatively correlated with the resting whole saliva secretion rate. The number of hyposalivation-related medications used was not significantly correlated with the various whole saliva secretion rates. In nursing home residents, xerostomia, hyposalivation and using hyposalivation-related medications seem common and partially associated features. PMID- 20165969 TI - Laparoscopic repair of an incarcerated right indirect sliding inguinal hernia involving a retroperitoneal ileum. AB - INTRODUCTION: Laparoscopic techniques for the repair of inguinal hernias have become an increasingly popular alternative to open techniques. No clear consensus has emerged as to the best laparoscopic technique, but the body of evidence increasingly favors a total extraperitoneal (TEP) approach. RESULTS AND DISCUSSION: We report the case of an adult man with an incarcerated right indirect inguinal sliding hernia involving the first known instance of a retroperitoneal ileum, and the novel use of a laparoscopic combined TEP approach and transabdominal preperitoneal (TAPP) approach to repair his hernia without complications. The literature is reviewed and TEP and TAPP techniques for the treatment of inguinal hernias are discussed and compared. CONCLUSION: When faced with an unforeseen anomaly during herniorrhaphy in which improved abdominal visualization is necessary, a surgeon may convert from a TEP to a transabdominal laparoscopic approach safely and effectively. PMID- 20165971 TI - Preliminary study of mother-offspring conflict in black and gold howler monkeys (Alouatta caraya). AB - Parent-offspring conflict has been scarcely studied in Neotropical primates. In this study, we explored mother-offspring conflict in a group of wild black and gold howler monkeys (Alouatta caraya) in northeastern Argentina. We used the all occurrences technique to record behaviors, completing 712 h of observation. The results showed that all immature individuals between 2 and 23 months expressed conflict with regard to suckling or traveling with their mothers. Successful suckling attempts negatively correlated with the age of the immatures, occurring least frequently with the presence of newborns. In the juvenile period, the decline in successful attempts was a consequence of juveniles reducing suckling attempts and mother rejection. PMID- 20165970 TI - Sulfatase activities towards the regulation of cell metabolism and signaling in mammals. AB - In higher vertebrates, sulfatases belong to a conserved family of enzymes that are involved in the regulation of cell metabolism and in developmental cell signaling. They cleave the sulfate from sulfate esters contained in hormones, proteins, and complex macromolecules. A highly conserved cysteine in their active site is post-translationally converted into formylglycine by the formylglycine generating enzyme encoded by SUMF1 (sulfatase modifying factor 1). This post translational modification activates all sulfatases. Sulfatases are extensively glycosylated proteins and some of them follow trafficking pathways through cells, being secreted and taken up by distant cells. Many proteoglycans, glycoproteins, and glycolipids contain sulfated carbohydrates, which are sulfatase substrates. Indeed, sulfatases operate as decoding factors for a large amount of biological information contained in the structures of the sulfated sugar chains that are covalently linked to proteins and lipids. Modifications to these sulfate groups have pivotal roles in modulating specific signaling pathways and cell metabolism in mammals. PMID- 20165972 TI - Determinants of return to work after occupational injury. AB - INTRODUCTION: The promotion of return to work (RTW) following occupational injury benefits injured workers, their families, enterprises and the society. The identification of the potential determinants would be helpful in improving RTW rate and minimizing the duration of absenteeism following injury. OBJECTIVES: The aim of the study was to identify the potential determinants of RTW following work related injury. METHODS: A historical cohort of workers with occupational injury in a state-owned locomotive vehicles company in central China was followed up on the outcomes of RTW. Demographic, employment and medical information was retrieved from the company archival documents; and post-injury information was interviewed by structured questionnaires. Univariate analysis and Cox Regression Model were used to examine the associations between potential determinants and outcomes of RTW. RESULTS: Three hundred of the 323 cases (92.9%) eventually returned to work after the median absence of 43 days. Factors from socio demographic, clinical, economic, and psychological domains affected RTW in the univariate analyses. The multivariate analysis indicated that age, injury severity, injury locus, injury nature, pain in the injury locus, self-report health status and pre-injury monthly salary were significant determinants of RTW. CONCLUSIONS: There were multidimensional factors affecting RTW after occupational injury. Proper clinical treatment and rehabilitation, as well as economic and social support to facilitate workers' RTW would be the priorities upon intervention. Future studies should be conducted in larger representative samples to confirm the findings and to develop a multidisciplinary intervention strategy towards promoting RTW. PMID- 20165974 TI - Biodegradation and seasonal variations in septage characteristics. AB - Composite samples of septage discharging at the Khirbit As-Samra municipal wastewater treatment plant were analyzed during the period from February to the end of October 2007. Septage showed difference in concentrations of pollutants between summer and winter. The average total chemical oxygen demand (COD) of 6,425 mg/L during summer was 2.16 times greater than that in winter, which is 2,969 mg/L. The total biochemical oxygen demand (5 d) represented 45% of total COD in both winter and summer. Anaerobic biodegradability was 75% after 81 d of digestion at 35 degrees C with a biodegradation rate constant (k) of 0.024 d-1, which was lower compared with 0.103 d-1 calculated for wastewater with domestic origin in Jordan. Aerobic biodegradability for septage was 48%-COD basis-after 7 d of digestion at 35 degrees C. The lower anaerobic biodegradation rate of septage compared with that of raw wastewater of domestic origin suggested that septage could have a negative effect on the performance of a domestic wastewater treatment plant if septage discharges are not taken into account in the original design of the treatment plant. PMID- 20165975 TI - Comparison of three sequential extraction protocols for the fractionation of potentially toxic metals in coastal sediments. AB - In the determination of the best sequential extraction procedures (SEP) for the speciation of metals in sediment samples from the Lagos lagoon system, three sequential extraction procedures were compared for the fractionation of Cd, Cr, Cu, Pb, and Zn. The SEP compared included a modified Tessier's procedure carried out in five steps, while the two other procedures were the three-step original Community Bureau of Reference (BCR) and the modified BCR techniques (four steps). Quantification of the metal concentration was achieved with a flame atomic absorption spectrophotometer. The results obtained by the three methods were compared, and the modified BCR and Tessier SEP were found to extract more Cu, Cr, Pb, and Zn in the reducible phase and therefore a decrease in the oxidizable phase than the original BCR SEP. The most mobile elements were found to be Cd, Pb, and Zn. These are of environmental concern, as these potentially toxic metals could be easily released into the aquatic environment with consequent ingestion by aquatic organisms, thereby entering the food chain. The mass balance (percent recovery) was found to be between 85% and 115% in most cases. Prior to the comparison, the analytical performance of the laboratory was tested using a secondary reference material, GLAURM, using the three-step modified BCR procedure. The results showed high reliability of the analytical performance of the laboratory for all the metals considered. PMID- 20165976 TI - Evaluation of a non-invasive method to detect cytomegalovirus (CMV)-DNA in stool samples of patients with inflammatory bowel disease (IBD): a pilot study. AB - BACKGROUND: A severe flare of colitis in patients with IBD treated with immunosuppressive therapy may be complicated by an underlying CMV infection. The aim of this pilot study was to investigate the diagnostic efficacy of quantitative polymerase chain reaction (PCR) to detect CMV DNA in stool samples of IBD patients. METHODS: Twenty-one patients with a severe flare of IBD, incompletely responding or refractory to either steroids or immunosuppressive agents, were included in the study. Nineteen patients completed the study according to the protocol undergoing an endoscopy with biopsies and collection of stool samples. Biopsy and stool samples were qualitatively and quantitatively analyzed for CMV DNA using real-time PCR. RESULTS: Thirty-two percent (6/19) of the patients had detectable CMV DNA in colonic biopsies and in five (83%) of those patients CMV DNA was detected in the stool. Thirteen patients had negative findings for CMV DNA in biopsy and stool samples. The sensitivity, specificity, and accuracy of the PCR-based stool test for detection of CMV DNA compared to PCR based detection of CMV in mucosal biopsies were 83, 93, and 90%, respectively. CONCLUSIONS: The pilot study suggests a high accuracy of this non-invasive testing method to detect CMV DNA in stool samples as compared to mucosal biopsies. This approach may offer a non-endoscopic testing modality for underlying CMV infection in patients with a severe flare of IBD, which could also be applied more broadly to determine the prevalence of CMV infections in patients with IBD. PMID- 20165977 TI - Risk of non-melanoma skin cancer in autoimmune hepatitis. AB - BACKGROUND: Most patients with autoimmune hepatitis (AIH) require long-term immunosuppressive therapy (IS). While it is well established that solid organ transplant recipients have a high risk of developing non-melanoma skin cancer (NMSC) as a result of immunosuppression, little is known about the risk of NMSC associated with IS in patients with AIH. OBJECTIVES: The aim of this study is to determine the incidence and risk factors for NMSC in patients on IS for AIH. METHODS: We reviewed the medical records of all patients with AIH seen at a tertiary care medical center between 1998 and 2008. We compared the incidence of NMSC to an age- and sex-matched control population and analyzed risk factors for NMSC. RESULTS: A total of forty-five patients with AIH were identified. Twenty NMSC lesions were found in eight patients. Compared to the age and sex-matched general population, the risk of SCC and BCC were increased as quantified by elevated standardized incidence ratios (28.5 and 5.0, respectively). Patients who developed NMSC were on average 24 years older (78.4 vs. 54.2 years old, p < 0.0001) and had AIH diagnosed at a more advanced age (66.0 vs. 45.4 years old, p = 0.0003). CONCLUSION: The risk of NMSC is significantly increased in patients with AIH on immunosuppression. Independent risk factors include current age and age at diagnosis of AIH. PMID- 20165978 TI - Hepatic angiomyolipoma: a clinical experience in diagnosis and treatment. AB - BACKGROUND: Hepatic angiomyolipoma is a rare mesenchyme-derived neoplasm often misdiagnosed as hepatocellular carcinoma, and the treatment for it remains controversial. AIMS: To develop the optimal preoperative diagnoses means and treatment modalities of hepatic angiomyolipoma. METHODS: Retrospective analysis of the clinical features, treatment, and prognostic data of 17 hepatic AML patients admitted to Chinese People's Liberation Army Generation Hospital between 1996 and 2006. RESULTS: Most hepatic angiomyolipoma were solitary. The overall preoperative diagnostic rate was 18% and the most common misdiagnosis was hepatocellular carcinoma (10/17, 59%). In three patients, observation was performed for 2-3 years before being admitted. The tumors increased 1-9 cm in size in all patients. All of the 17 patients finally received various liver resection procedures, and postoperative mortality and morbidity was 0 and 12% (2/17). After a median follow-up period of 73 months, the tumor recurred only in one patient 9 years post-operatively. CONCLUSIONS: Hepatic angiomyolipoma should be suspected in liver tumor patients with normal alpha-fetoprotein levels and no concomitant hepatitis. Preoperative MRI combined with percutaneous fine-needle biopsy should be the diagnostic methods of choice. Small hepatic AML proved through pathologic examination (<5 cm) may be managed by observation with close follow-up, but surgery is indicated in patients suffering from large tumors or significantly larger tumors during follow-up. PMID- 20165979 TI - Protective role of coffee in non-alcoholic fatty liver disease (NAFLD). AB - AIM: The benefits of coffee on abnormal liver biochemistry, cirrhosis and hepatocellular carcinoma have been reported, but there is a lack of satisfactory explanation. Thus, this study aims to investigate if coffee use has any relationship with bright liver, measured by ultrasound bright liver score (BLS), in patients with non-alcoholic fatty liver disease (NAFLD), and which relationship, if any, is present with BMI and insulin resistance. METHODS: This study was performed on 245 patients, 137 with NAFLD and 108 controls. Coffee drinking was defined according to the absolute number of cups of coffee (only espresso coffee), and also graded as 1 (0 cups of coffee/day), 2 (1-2 cups of coffee/day) 3 (>=3 cups of coffee/day). Insulin resistance was assessed by homoeostasis model-insulin resistance index (HOMA). RESULTS: Less fatty liver involvement is present in coffee vs. non-coffee drinkers. Odds ratios show that obesity, higher insulin resistance, lower HDL cholesterol, older age and arterial hypertension are associated with a greater risk of more severe BLS; to the contrary, coffee drinking is associated with less severe BLS. In the multiple logistic regression (MLR) model, number of cups of coffee, HOMA and BMI account for 35.8% of the variance to BLS. Coffee use is inversely associated with the degree of bright liver, along with insulin resistance and obesity, which, to the contrary, are directly associated with greater likelihood and severity of bright liver appearance. CONCLUSIONS: A possible opposite, if not antagonistic, role of coffee with regard to overweightness and insulin resistance, similar to that reported in hepatocarcinoma and cirrhosis, is envisaged in the natural history of NAFLD. PMID- 20165980 TI - Celiac disease: similar presentations in the elderly and young adults. AB - BACKGROUND/AIMS: Studies have shown that celiac disease can affect individuals in all age groups. However, few studies have described the disease in the elderly. The goal of this study is to characterize celiac disease in the elderly by comparing to a population of young adults with celiac disease. METHODS: Review of a tertiary center database of patients with celiac disease was performed to identify two groups of patients, an elderly cohort >= 65 years and a young adult cohort aged 18-30 years, with biopsy-confirmed celiac disease. Information obtained included symptom duration, clinical presentation, small intestinal pathology, associated conditions, and the presence of bone disease. RESULTS: Included in the study were 149 young adult and 125 elderly patients; the latter represented 12.4% of the patients in our database. The duration of symptoms prior to diagnosis was similar, 5.8 +/- 12 years and 6.14 +/- 12.6 years in the young adult and elderly cohorts, respectively (p = 0.119). There was no significant difference in the mode of presentation of illness. Diarrhea was the main presenting symptom (49% in young adults vs. 50% in the elderly, p = 0.921). There was a similar prevalence of autoimmune disease (19% in young adults vs. 26% in the elderly, p = 0.133). Thyroid disease and neuropathy were more prevalent in the elderly (p = 0.037 and p = 0.023, respectively). The degree of villous atrophy and prevalence of bone disease were similar in each group. CONCLUSIONS: Surprisingly, the presentation of celiac disease both clinically and histologically is similar in elderly and young adult patients. The factors triggering disease at any given age remain unclear and warrant further study. PMID- 20165981 TI - Efficacy of standard triple therapy in the treatment of Helicobacter pylori infection: experience from Kuwait. AB - INTRODUCTION: Recent studies suggest that the initial treatment success rates for H. pylori infection are falling below 80% in many parts of the world. AIM: The aim of this study was to evaluate the efficacy of standard triple therapy in the treatment of H. pylori infection in Kuwait. METHODS: Consecutive H. pylori positive patients were enrolled in the study to receive clarithromycin, amoxicillin and omeprazole for 10 days. H. pylori status was checked with 13C urea breath test 6 weeks after the end of therapy. Endoscopic findings was recorded in all patients. RESULTS: One hundred forty-one patients (82 male and 59 females; mean age 41.8 years) were enrolled in the study. A total of seven patients were excluded from the per protocol analysis. The eradication rates in intention to treat (ITT) and per protocol (PP) were 72.3% (95% CI 64.2-79.5%) and 76.1% (95% CI 68-83%), respectively. The main endoscopic findings were normal in 47.5% and gastritis in 37.6%. CONCLUSION: The efficacy of the current standard triple therapy for H. pylori eradication in our community is suboptimal. Confirmation for H. pylori eradication with noninvasive tests is recommended, especially in high-risk patients. New antimicrobial regimens for H. pylori eradication are considered necessary. PMID- 20165983 TI - The phenomenology of rooting. AB - This paper examines the attractions of passionate involvement in wanting particular outcomes, which is popularly known as rooting. The author's lifelong personal experience is the source of his analysis, along with the insights provided by spiritual literature and especially the work of Dr. Thomas Hora, with whom the author studied for 30 years. The phrase "choiceless awareness," utilized by J. Krishnamurti, and attained via meditation, is seen as the means of transcending a rooting mode of being in the world. PMID- 20165982 TI - Genes regulated by Nkx2-3 in sporadic and inflammatory bowel disease-associated colorectal cancer cell lines. AB - BACKGROUND: Nkx2-3 has been reported to be up-regulated in B cell lines and intestinal tissues from Crohn's disease patients and down-regulated in colorectal cancer. AIMS: The purpose of the current study is to determine genes regulated by Nkx2-3 in sporadic (CRS61) and inflammatory bowel disease-associated (CRS4) colorectal cancer cell lines. METHODS: Small interfering RNA-mediated knockdown of Nkx2-3 in both cell lines was generated and high-density cDNA microarrays representing over 25,000 genes were performed. Microarray results were validated by RT-PCR and immunofluorescence. Pathway analysis was used to identify gene networks associated with Nkx2-3 knockdown in these cell lines. RESULTS: A total of 1,677 genes were regulated by Nkx2-3 in CRS4 cells; 1,375 genes were regulated by Nkx2-3 in CRS61 cells. Among those genes regulated by Nkx2-3, 254 genes were similarly regulated by Nkx2-3 knockdown in both cell lines; 159 genes were differentially regulated by Nkx2-3 knockdown between the two lines. Genes regulated by Nkx2-3 were grouped primarily within the following two functional categories: (1) immune and inflammatory response; and (2) cell proliferation, growth, and oncogenesis. Among the genes with similarly changed expression in the two cell lines, the top affected pathways included antigen presentation and cell cell signaling. Among the genes with differentially changed expression between the two cell lines, ingenuity pathway analysis indicated that the top affected pathway included genes directly involved in Wnt signaling. CONCLUSIONS: Nkx2-3 may contribute to the pathogenesis of IBD-associated CRC and sporadic CRC by regulating the Wnt signaling pathway. PMID- 20165984 TI - Children consuming cassava as a staple food are at risk for inadequate zinc, iron, and vitamin A intake. AB - Cassava contains little zinc, iron, and beta-carotene, yet it is the primary staple crop of over 250 million Africans. This study used a 24-hour dietary recall to test the hypothesis that among healthy children aged 2-5 years in Nigeria and Kenya, cassava's contribution to the childrens' daily diets is inversely related to intakes of zinc, iron, and vitamin A. Dietary and demographic data and anthropometric measurements were collected from 449 Kenyan and 793 Nigerian children. Among Kenyan children 89% derived at least 25% of their dietary energy from cassava, while among the Nigerian children 31% derived at least 25% of energy from cassava. Spearman's correlation coefficient between the fraction of dietary energy obtained from cassava and vitamin A intake was r = -0.15, P < 0.0001, zinc intake was r = -0.11, P < 0.0001 and iron intake was r = 0.36, P < 0.0001. In Kenya, 59% of children consumed adequate vitamin A, 22% iron, and 31% zinc. In Nigeria, 17% of children had adequate intake of vitamin A, 57% iron, and 41% zinc. Consumption of cassava is a risk factor for inadequate vitamin A, zinc and/or iron intake. PMID- 20165985 TI - Conditional survival after surgical treatment of melanoma: an analysis of the Surveillance, Epidemiology, and End Results database. AB - BACKGROUND: Survival curves following surgical treatment of cutaneous melanoma are heavily influenced by early deaths. Therefore, survival estimates may be misleading for long-term cancer survivors. We examined whether conditional survival (CS) is more accurate in predicting long-term melanoma survival. METHODS: We used the Surveillance, Epidemiology, and End Results database (1992 2005) to identify patients who underwent surgical treatment for melanoma. We included patients with T2-T4 disease and with known nodal status. Patients were stratified into low-risk (T2-3N0M0) and high-risk (T4N0M0 or T2-4N1-3M0) categories. We defined CS as time-specific estimates conditioned on living to a certain point in follow-up, and calculated 10-year cancer-specific survival curves conditioned on annual survival. We adjusted for potential confounders using a Cox proportional hazards regression model (alpha = 0.05). RESULTS: A total of 8647 patients met inclusion criteria (low-risk, 5987 [69.2%]; high-risk, 2660 [30.8%]). At diagnosis, low-risk patients had a significantly better 10-year survival rate (low-risk, 79.6%; high-risk, 41.2%; P < 0.001). On CS analysis, survival differences remained until 8 years after treatment, after which 10-year cancer-specific survival rates were no longer significantly different (P = 0.51) for low-risk (95.4%) and high-risk (91.7%) groups. Multivariate analysis demonstrated that age, gender, location, and ulceration (initial predictors of survival) were no longer predictive after 8 years of survival. CONCLUSIONS: For patients who survive 8 years after surgical treatment of melanoma, CS data become discordant with traditionally used estimates. Our findings have important implications for patient counseling, as high-risk melanoma survivors may require no more intensive surveillance than low-risk survivors 8 years after treatment. PMID- 20165986 TI - Influence of residual tumor on outcome in ovarian cancer patients with FIGO stage IV disease: an exploratory analysis of the AGO-OVAR (Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group). AB - BACKGROUND: One of the most important prognostic factors in advanced ovarian cancer is the macroscopic absence of residual tumor after primary surgery. The impact of surgical outcome on the survival of patients with International Federation of Gynecology and Obstetrics (FIGO) stage IV disease is less clear and is the subject of this study. METHODS: Surgical and survival data were documented throughout the multicenter prospective randomized phase III trials of the AGO OVAR (OVAR-3/-5/-7) and were used for this exploratory analysis. In these studies, 573 patients with FIGO stage IV disease were first operated, then randomized and homogenously treated with a combination therapy comprising the intravenous application of platinum and paclitaxel. RESULTS: The median progression-free survival and overall survival of patients with stage IV ovarian cancer were 12.6 and 26.1 months, respectively. Multivariable Cox regression analysis for overall survival revealed that residual tumor, mucinous histological type, multiple sites of metastases, and Eastern Cooperative Oncology Group performance status were statistically significant prognostic variables. Whereas patients with macroscopically complete resection had a statistically significant improved outcome, patients with residual disease of 0.1-1 cm and patients with residual tumor of >1 cm showed similar outcome. CONCLUSIONS: Macroscopically complete resection in FIGO stage IV disease, irrespective of the site of distant tumor spread, is an important prognostic factor and the only prognosticator amenable to improvement by therapy. Our results suggest possible advantages of a reasonable attempt at complete cytoreduction even in FIGO stage IV disease. In addition, tumor biology could be an important factor for achieving complete resection. PMID- 20165987 TI - Survival analysis of intrahepatic cholangiocarcinoma after resection. AB - BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy, but the studies for the outcome after resection of ICC are rare. The aim of this study was to elucidate outcomes and prognostic factors of ICC in patients undergoing hepatic resection. METHODS: A retrospective study was conducted with a total of 63 patients who underwent surgical resection with curative intent for ICC. We performed the survival analysis with preoperative and postoperative clinicopathologic factors according to the clinical outcome. RESULTS: The cumulative 1-, 3-, and 5-year survival rates were 68.2, 50.5, and 31.8%, respectively. Univariate analysis revealed that patient's old age, high preoperative carbohydrate antigen 19-9 (CA19-9) level, major vessel invasion, T classification, lymph node metastasis, lymphatic invasion, perineural invasion, intrahepatic metastasis, and narrow resection margin were statistically significant. By multivariate analysis, patient's old age, high preoperative CA19 9 level, lymphatic invasion, and narrow resection margin were independent dismal prognostic factors. The preoperative CA19-9 level shows a significant correlation with some histopathologic factors including major vessel invasion, bile duct invasion, and perineural invasion. CONCLUSIONS: Preoperative CA19-9 level was a valuable clinical factor for predicting histopathologic invasiveness as well as clinical outcome. An adequate resection margin was the only modifiable factor by a surgeon during hepatic resection for ICC. PMID- 20165988 TI - Nanogram doses of alum-adjuvanted HBs antigen induce humoral immune response in mice when orally administered. AB - Mucosal immunity elicited by plant-based and other orally administered vaccines can serve as the first line of defense against most pathogens infecting through mucosal surfaces, but it is also considered for systemic immunity against blood borne diseases such as hepatitis B (HB). Previous oral immunization trials based on multiple administration of high doses of HBs antigen elicited an immune response; however, a reproducible and long-lasting immunization protocol was difficult to design. The objective of this study was to evaluate the effect of dose and timing of orally delivered alum-adsorbed antigen on the magnitude of the anti-HBs humoral response. Mice were immunized orally by gavage intubation or parenterally by intramuscular injection three times, once every 2 weeks, with doses of 5, 50, or 500 ng alum-adjuvanted HBsAg. A low dose (10 ng) of HBsAg was orally administered three times in different time intervals: 2, 4, 6, and 8 weeks. The three consecutive 5-ng oral doses of the antigen induced immune response at the protective level (>or=10 mIU/ml), significantly higher than the reaction elicited by three 50 or 500 ng doses. In contrast, intramuscular delivery of these doses did not differ significantly; however, they induced a five to six times higher immune response than oral immunization. The 8-week period between each of the three oral immunizations appeared to be favorable to the anti-HBs humoral responses compared with the shorter schedules. The results presented here clearly identify the importance of low doses of antigen administered orally in extended intervals for a significantly higher anti-HBs response. This finding provides some indications concerning the strategy of orally administered vaccines, including plant-based ones. PMID- 20165989 TI - Antihypertensive medication adherence, ambulatory visits, and risk of stroke and death. AB - BACKGROUND: This study seeks to determine whether antihypertensive medication refill adherence, ambulatory visits, and type of antihypertensive medication exposures are associated with decreased stroke and death for community-dwelling hypertensive patients. METHODS: This retrospective cohort study included all chronic medication-treated hypertensives enrolled in Tennessee's Medicaid program (TennCare) for 3-7 years during the period 1994-2000 (n = 49,479). Health care utilization patterns were evaluated using administrative data linked to vital records during a 2-year run-in period and 1- to 5-year follow-up period. Antihypertensive medication refill adherence was calculated using pharmacy records. RESULTS: Associations with stroke and death were assessed using Cox proportional hazards modeling. Stroke occurred in 619 patients (1.25%) and death in 2,051 (4.15%). Baseline antihypertensive medication refill adherence was associated with decreased multivariate hazards of stroke [hazard ratio (HR) 0.91; 95% confidence interval (CI), 0.86-0.97 for 15% increase in adherence]. Adherence in the follow-up period was associated with decreased hazards of stroke (HR 0.92; CI 0.87-0.96) and death (HR 0.93; CI 0.90-0.96). Baseline ambulatory visits were associated with decreased death (HR 0.99; CI 0.98-1.00). Four major classes of antihypertensive agents were associated with mortality reduction. Only thiazide type diuretic use was associated with decreased stroke (HR 0.89; CI 0.85-0.93). CONCLUSIONS: Ambulatory visits and antihypertensive medication exposures are associated with reduced mortality. Increasing adherence by one pill per week for a once-a-day regimen reduces the hazard of stroke by 8-9% and death by 7%. PMID- 20165990 TI - Comparative studies of the antiproliferative effects of ginseng polysaccharides on HT-29 human colon cancer cells. AB - Ginseng polysaccharide has anticancer activity. However, the structure-activity relationship and the activity mechanism are still unclear. Therefore, it is necessary to study the anticancer activity of structurally different ginseng polysaccharide fractions and their potential mechanisms. Ginseng polysaccharide fractions and their temperature-modified products were assayed for their effects on HT-29 cell proliferation by MTT assay, on cell cycle progression by flow cytometry, and on caspase-3 activation by western blot analysis. The HG-rich ginseng pectin inhibited cell proliferation and induced cell cycle arrest in the G2/M phase. The temperature-modified HG-rich pectin had dramatically increased antiproliferative effect and induced apoptosis accompanied by the activation of caspase-3. Starch-like glucan and arabinogalactan of ginseng exhibited no antiproliferative effects. Even after temperature modification, their inhibitory effects either remained unchanged or increased slightly. The HG-rich pectin exerts its antiproliferative effect via cell cycle arrest and the temperature modification markedly increased the antiproliferative effect. PMID- 20165991 TI - Prognostic evaluation of immunohistochemical profiles in diffuse large B-cell lymphoma: a Chinese study. AB - Diffuse large B-cell lymphoma (DLBCL) has been classified into different prognostic subgroups using immunohistochemistry in Western populations. However, the applicability in Chinese patients of these subgroups was unclear. We collected 116 specimens and performed immunohistochemical staining for CD10, BCL 6, MUM1, CD138, and CD5, and the results were classified into subgroups according to 3 different algorithms. We then analyzed the subgroups' correlation to patient survival. Expression of CD10 and BCL-6 predicted favorable 5-year OS (70 and 62.5%, respectively) and PFS (64.3 and 61.5%, respectively) rates. In contrast, the expression of MUM1 predicted unfavorable 5-year OS (23.1%) and PFS (17.9%) rates and was also independent of other markers. All algorithms led to useful subclassifications. Using Hans' algorithm based on CD10, BCL-6, and MUM1, the non germinal center (GC) subgroup (66.4%) had worse 5-year OS (29.8%) and PFS (26.7%) rates than did the GC subgroup. Likewise, using Muris' algorithm based on CD10 and MUM1, fewer non-GC cases (27%) showed poorer OS (20.3%) and PFS (16.2%) rates than did GC cases, an effect that was independent of both the International Prognostic Index, a clinical indicator, and treatment. It identified a subgroup with a high-risk of death and seemed to be applicable in our series. In conclusion, these algorithms can be used effectively in Chinese patients with DLBCL. PMID- 20165992 TI - Surveillance for post-transplant coronary artery vasculopathy: Shifting gears from diagnosis to prognosis. PMID- 20165996 TI - [Pharmacoeconomic studies - usability for reimbursement decisions]. AB - BACKGROUND AND OBJECTIVE: In Germany, cost-benefit-assessments are incorporated by law since April 2007. In this study it is examined whether published international pharmacoeconomic studies correspond to the methodological recommendations of the Institute for Quality and Efficiency in Health Care (IQWiG) and international guidelines, and whether they are usable for reimbursement decisions. METHODS: Pharmacoeconomic studies were identified by a systematic literature review and compared with the requirements of the IQWiG and 15 other international institutions. In hypothetical selection processes it was examined which and how many studies could be considered as basis for reimbursement decisions. RESULTS: 130 out of 1,982 pharmacoeconomic studies were identified as relevant and analyzed. Most frequently, the USA was mentioned as reference country (41 %) prior to UK (15 %), Canada (6 %) as well as Japan and Germany (each 4 %). In 63 % standard therapy was chosen as comparator. In 60 % of studies the payer's perspective was chosen primarily, in 22 % the societal perspective. Two thirds of the studies were modeled in most parts. Only two studies performed a comparison with standard therapy from the perspective of the statutory health insurance and could have been considered for reimbursement decisions of the G-BA. Only one German study examined the real-life effectiveness and compared it to standard therapy. CONCLUSIONS: The study revealed a congruence between the methods of iqwig and other similar international institutions. However, hitherto existing pharmacoeconomic studies do not follow international and German guidelines in many points. In consequence IQWiG will have to perform the analyses itself and the assessment process will be time-consuming and tedious so that in the short and medium term no relevant cost savings can be expected. PMID- 20165993 TI - Multi-modality imaging of diastolic function. AB - Non-invasive evaluation of diastolic function continues to play a critical role in furthering our understanding of diastole, improving the diagnosis of diastolic dysfunction, evaluating left ventricular filling pressures, and providing important prognostic information for patients with heart failure. Echocardiography, cardiovascular magnetic resonance, and nuclear cardiology each provide important tools for evaluating diastolic performance. This review will focus on the techniques from multiple cardiovascular imaging modalities which have been used for the clinical assessment of diastolic function. PMID- 20165997 TI - [A patient with chronic diarrhoe, head pigmentation and alopecia. Cronkhite Canada syndrome]. AB - HISTORY AND FINDINGS ON ADMISSION: A 70-year-old man with a 14 month history of chronic severe diarrhea treated with budenosid and mesalazin was admitted because of peripheral oedema and weight loss of about 26 kg. INVESTIGATIONS AND DIAGNOSIS: A general pigmentation of the skin, especially on scull and hands, as well as dystrophic nail changes and alopecia of scalp and facial hair were seen. The tests showed a slight macrocytotic, normochromic anemia. Total protein and the clotting factors were decreased. Endoscopy revealed multiple sessile polyps in the stomach and duodenum in appearance to colon and rectum. Endoscopic removal of a polyp showed histologically cystic dilatation of foveolae and oedematous mucosa. The histological features, the wide distribution of the polyps together with the skin changes, lead to the diagnosis of Cronkhite-Canada syndrome (CCS). TREATMENT AND COURSE: The patient was initially treated with prednisolon 60 mg/d i. v. for 2 weeks, resulting in a marked improvement of symptoms and weight gain. He is at present in good health under prednisolon 20 mg/d per os and is followed up in our outpatient department. CONCLUSION: CCS is in up to 14 % of the cases associated with a carcinoma of the gastrointestinal tract. At present there are only reports about a successful treatment by steroids, prophylactic gastrectomy and proctocolectomy. Typical myopathic lesions of CCS have not been described to date, but the demonstrated improvement of creatinin kinase with successful treatment suggests a common pathophysiological mechanism. PMID- 20165998 TI - [79-year-old woman with incidental findings]. PMID- 20165999 TI - [Usefulness of probiotics in prevention and therapy]. AB - Probiotics exert distinct effects on the intestinal mucosa and the immune system that can be used in preventive and therapeutic settings. There is evidence to support the use of probiotics in necrotizing enterocolitis in preterm infants and pouchitis. Furthermore, the immunomodulatory effects of probiotics seem to ameliorate atopic diseases, in particular atopic dermatitis. The efficacy of probiotics has been shown comparable to Mesalazine regarding the maintenance of remission in ulcerative colitis. In addition there is evidence that probiotics are useful in the prevention of pouchitis or in therapy of irritable bowel syndrome. Recent data indicate that commensals and probiotics could play a role in nutrient fermentation and energy metabolism and may be helpful in the prevention and therapy of obesity. PMID- 20166000 TI - [Survey of recent clinical trials of the prevention and immunointervention of type 1 diabetes mellitus]. AB - Immunomodulatory strategies in the management of type 1 diabetes mellitus (T1DM) have as their primary target the prevention of initiating islet autoimmunity (primary-), the secondary one is the progression to diabetes (secondary-) in non diabetic persons at risk, and the decline of beta-cell function in new-onset patients (tertiary-prevention). This article reviews four recent immunointervention trials in patients with T1DM. (1) The Pre-POINT study is a primary prevention trial that will test whether vaccination with oral or nasal insulin can prevent the progression of islet autoimmunity and of T1DM in autoantibody-negative children who are genetically at high diabetes risk. (2) The Cord Blood study is a tertiary immunointervention trial that will test whether administration of autologous umbilical cord blood to children with T1DM can lead to regeneration of pancreatic islet insulin-producing beta-cells and improved blood glucose control. (3) The GAD Vaccination study will test whether vaccination with alum-formulated rhGAD65 (recombinant human glutamic acid decarboxylate) can preserve beta-cell function in 320 children with newly diagnosed T1DM, as has been suggested in a recent phase II study. (4) The AIDA study will test the beta-cell protective effect of interleukin-1-receptor antagonist Anakinra in 80 patients with T1DM, which has recently been shown to improve beta-cell function in patients with type 2 diabetes. PMID- 20166001 TI - [Blood culture collection]. PMID- 20166002 TI - [Guidelines for the epidemiology, diagnosis, antimicrobial therapy and management of community-acquired pneumonia and lower respiratory tract infections in adults]. PMID- 20166003 TI - [Low INR-levels in certain mechanical heart valves?]. PMID- 20166004 TI - Does breathing disturb coordination in butterfly? AB - This study quantified the effects of breathing compared to non-breathing and "race pace" on arm to leg coordination in the butterfly stroke. Twelve elite male swimmers swam at four paces: 400 m, 200 m, 100 m and 50 m. The arm and leg stroke phases were identified by video analysis to calculate the total time gap (TTG), which is the sum of T1 (hands' entry in the water/high point of first kick), T2 (beginning of the hands' backward movement/low point of first kick), T3 (hands' arrival in a vertical plane to the shoulders/high point of second kick) and T4 (hands' release from the water/low point of second kick). Two strokes with breathing were compared to two strokes with breath-holding. The TTG was greater with breathing (23.3% VS. 19%), showing less propulsive continuity between arm and leg actions (p<0.05). This was due to the shorter downward leg kick and longer arm catch and upward leg kick that led to longer glide time. Conversely, breathing leads to greater coupling between the hand exit and the end of leg propulsion, which was due to a shorter arm push phase to facilitate the head exit to breathe. PMID- 20166005 TI - Age-related changes in triathlon performances. AB - The aim of this study was two-fold: i) to analyse age-related declines in swimming, cycling, and running performances for Olympic and Ironman triathlons, and ii) to compare age-related changes in these three disciplines between the Olympic and Ironman triathlons. Swimming, cycling, running and total time performances of the top 10 males between 20 and 70 years of age (in 5 years intervals) were analysed for two consecutive world championships (2006 and 2007) for Olympic and Ironman distances. There was a lesser age-related decline in cycling performance (p<0.01) compared with running and swimming after 55 years of age for Olympic distance and after 50 years of age for Ironman distance. With advancing age, the performance decline was less pronounced (p<0.01) for Olympic than for Ironman triathlon in cycling (>55 years) and running (>50 years), respectively. In contrast, an age-related decline in swimming performance seemed independent of triathlon distance. The age-related decline in triathlon performance is specific to the discipline, with cycling showing less declines in performance with age than swimming and running. The magnitude of the declines in cycling and running performance at Ironman distance is greater than at Olympic distance, suggesting that task duration exerts an important influence on the magnitude of the age-associated changes in triathlon performance. PMID- 20166006 TI - Pedometer accuracy in patients with chronic heart failure. AB - This study assesses the accuracy of the Omron HJ-720ITC pedometer at low walking intensities in patients with chronic heart failure. Step accuracy was assessed by visual observation on the treadmill and during free walking at 40, 50, 60, 70, 80 m/min, as well as during self paced walking using the 6 min walk test. A total of ninety-seven patients with heart failure (mean age: 61+/-13, NYHA I, N=30; NYHA II, N=32; NYHA III, N=35) participated in the study. At predefined walking speeds, a statistically significant % error in pedometer accuracy was evident at 60 m/min (p=0.039), and% error increased markedly below this threshold. Highest% error in pedometer accuracy was seen at 40 m/min (mean bias (% error): 28.3+/ 9.0%; 95% CI: 21.8-34.7; p<0.001). During self paced walking (6MWT) the absolute% error in pedometer readings was largest in patients with strongest functional limitations and 6 MWT distances <400 m (mean bias (% error): 10.7+/-13.6%; CI 5.6 15.4, p<0.001). The Omron HJ-720ITC pedometer is accurate for monitoring activity in individuals with normal walking behaviour, but seems unsuitable for chronically ill patients characterised by slow walking gaits. PMID- 20166007 TI - Match injuries in professional soccer: inter-seasonal variation and effects of competition type, match congestion and positional role. AB - In this prospective observational study, injuries sustained in official match play in players belonging to a professional soccer club were investigated. Incidence and patterns of injury were compared across four-seasons (2005-2006: S1, 2006-2007: S2, 2007-2008: S3 and 2008-2009: S4) and 3 match formats (domestic League/Cup games and European club competition). In addition, the effects of both fixture congestion and the positional role of players were investigated. Injury incidence (per 1 000 match-hours) did not vary between seasons (range 31.2-59.2 observed in S2 and S4, respectively, p=0.12) or fixture formats (range 32.6-40.8 observed in European and League matches, respectively, p=0.49). In contrast, rates varied in players (n=7) who participated in all four seasons as more injuries were sustained in S1 compared to S2 and S3, respectively (88.4 vs. 49.0 vs. 49.2, both p<0.05). The incidence of muscle strains was higher in S4 versus S3 (24.7 vs. 9.9, p<0.05) as were injuries sustained to the ankle region in S4 versus S2 (15.1 vs. 4.5, p<0.05). The incidence of joint sprains differed between fixture formats with a higher rate observed in League versus both Cup and European competition, respectively (10.1 vs. 3.0 vs. 3.0, both p<0.05). Injury incidence was not associated to the time delay (number of days) separating games (r=0.04, p=0.58). A very short interval (< or = 3 days) between fixtures did not result in a greater injury rate (p=0.40) or number of days lost to injury (p=0.73) compared to a longer interval (> or = 4 days). Finally, the incidence of injury and muscle strains (both p<0.001) varied across positional roles with the highest rates observed in centre-forwards. These findings provide further knowledge on the risk of injury in contemporary professional soccer match-play and may aid in the care and management of playing resources. PMID- 20166008 TI - Increasing the number of steps walked each day improves physical fitness in Japanese community-dwelling adults. AB - We aimed to investigate the effects of increasing the number of steps each day on physical fitness, and the change in physical fitness according to the angiotensin converting enzyme (ACE) genotype. A total of 174 participants were randomly assigned to two groups. Subjects in group A were instructed for 24-week trial to increase the number of steps walked each day, while subjects in group B were instructed to engage in brisk walking, at a target heart rate, for 20 min or more a day on two or more days a week. The values of the 3-min shuttle stamina walk test (SSWT) and the 30-s chair-stand test (CS-30) significantly increased, but no differences in increase were found between the groups. A significant relationship was found between the percentage increase in SSWT values and the increase in the number of steps walked by 1 500 steps or more per day over their baseline values. Our results suggest that increasing the number of steps walked daily improves physical fitness. No significant relationships were observed between the change in physical fitness and ACE genotypes. PMID- 20166009 TI - [Harlequin ichthyosis--medical and psychosocial challenges]. AB - Harlequin ichthyosis is the most severe congenital keratinizing disorder. It is caused by mutations in the ABCA12 gene leading to defective lipid transport. The infants are born with ectropion, eclabium and fissured plate-like skin. Today these infants can survive with neonatal intensive care and retinoid therapy and need long-term interdisciplinary treatment in order to improve quality of life. However, the outcome in our case is impaired by severe psychomotor developmental delay, which has not yet been associated with Harlequin Ichthyosis. PMID- 20166010 TI - Bloody nipple discharge (BND) in an 8 months old girl and a 9 months old male- rational diagnostic approach. AB - Bloody nipple discharge in adults is, in men as well as in women, often a symptom of an underlying malignant disease. In respect of this, multiple invasive and mutilating diagnostic procedures have been performed in infants and older children. Apart from individual cases in older and pubertal children, in childhood benign conditions are most common and can be diagnosed by non-invasive diagnostic procedures. Here we discuss a rational diagnostic approach on the basis of 2 patients with bloody nipple discharge at the age of 8 and 9 months which resolved spontaneously without treatment after 3 and 6 months, respectively. PMID- 20166011 TI - [Neural tube defects in Austria: Assumption and calculations on the prevention potential through folic acid enrichment and supplementation]. AB - BACKGROUND: Countries with obligatory fortification of food (USA, Canada) document a significant decrease of neural tube defects in newborns. METHODS: In this study the Daly or, respectively, the Wald method was employed for calculating the potential of fortification/and supplementation for prevention in Austria. RESULTS: According to the EUROCAT study, in Austria the overall prevalence of neural tube defects (live birth, still births and induced abortions due to neural defect) is assumed to be 7.95 per 10,000 live and still births, and the prevalence of 3.9 per 10,000 live births - that is 62 or, respectively, 30 in absolute numbers per 78,000 births per year. In 2006, 26 live-born children with neural tube defects were actually reported in Austria by Statistik Austria. CONCLUSION: Different folic acid fortification and supplementation strategies can avoid 1.2-1.4 per 10,000 (9-11 cases) of neural tube defects (live and still births). Folic acid supplements are effective to decrease the amount of neural tube defects, however, only when pregnancies are planned. Thus, evidence-based neural tube defects are more common among lower social groups. An obligatory fortification of food could therefore reach unplanned pregnancies and women facing social problems. A reason to justify this population-based intervention where people need not decide for themselves could be the reduction of social imbalances. There are, of course, advantages and disadvantages of obligatory fortification of food and, therefore, all circumstances have to be taken into consideration. PMID- 20166012 TI - [Oral health-specific stress in parents of children with orofacial clefts: an indicator for general parenting stress]. AB - AIM: Parents of children with orofacial clefts take an active part in the rehabilitation of their children. Against this background, the aim of the present study was to determine the stress in parents of orthodontically treated children with and without orofacial clefts. METHOD: For assessing oral health-specific stress in orthodontic treatment, a questionnaire was developed (FMB). General parenting stress was assessed by the Parenting Stress Index (PSI)-German Short Form. Parents of 54 orthodontically treated children with an orofacial cleft were included in the study. Parents of 44 healthy children served as controls. The questions of the FMB were generated on the basis of clinical practice and were factor analysed. The reliability was calculated and compared with the PSI for validation. RESULTS: The FMB questionnaire presented four factors regarding personal stress, stress within family life, temporal stress and financial stress. The inner consistency of each factor reached satisfactory results with a value of 0.7. Moreover, oral health-specific stress was significantly higher in parents of children with clefts compared to children without clefts. There was no difference in general parenting stress between the two groups. Moreover, both groups showed significant correlations between oral health-specific stress and general parenting stress. CONCLUSION: Oral health-specific stress of children with orofacial clefts could be a hint on general parenting stress. Regarding parents in such stressful situations, the orthodontist should be trained in psychological counselling and should be able to cooperate with a clinical psychologist. PMID- 20166013 TI - [Coercive measures: a comparison between six psychiatric departments]. AB - OBJECTIVE: Although coercive measures are one of the indicators for the quality of psychiatric in-patient care, reliable and valid data comparing the practices are hardly available. The purpose of this study was to analyse the incidence and duration of mechanical restraint and seclusion in psychiatric hospitals in Germany. We hypothesised that the duration of these coercive measures is associated not only with gender and diagnosis of the patients, but also with the clinics themselves. METHODS: Incidence and duration of coercive measures (mechanical restraint and seclusion) among patients in the year 2004 were analysed in six German psychiatric hospitals. Furthermore, the association of the length of these coercive measures with diagnosis, gender, and hospital was analysed using non-parametric statistical tests. RESULTS: 3.0% of 10,352 cases treated in 2004 were exposed to mechanical restraint and seclusion with a range from 1.9-7.4% on comparing the hospitals. On average, these measures were applied 3.7 times per patient (case) with each single intervention lasting 5.0 h (mean, range <0.1-290.8). The incidence and duration of coercive measures varied highly between different diagnostic groups and different hospitals. The length of these measures differed significantly between hospitals (p<0.001) and diagnoses (p<0.001). In patients with organic psychiatric disorders (ICD-10: F0) we observed the longest duration. Furthermore the duration of coercive measures in female patients was shorter than that for male patients (p<0.05). CONCLUSION: Data interpretation should consider numerous confounding factors such as case mix and hospital characteristics. The handling of coercive measures is an important quality feature. Therefore standardised survey methods should be developed and nationwide implemented. PMID- 20166015 TI - [Results of arthroscopically assisted refixation of fractures of the intercondylar eminence]. AB - AIM: In order to restore ACL function and therefore knee joint stability, the surgical refixation of anterior cruciate ligament avulsion fractures is a consistent recommendation in literature. The objective of this study was to evaluate the clinical results after arthroscopic fixation of dislocated avulsion fracture of the intercondylar eminence depending on patient age and refixation technique. METHOD: 24 patients (50% below 16 years) with anterior cruciate ligament avulsion fractures were treated either with arthroscopic screw fixation (n = 17) or transtibial suture refixation (n = 7). Clinical follow-up examination was conducted on average 4.1 years after operation. RESULTS: 17% of the patients presented with additional intra-articular lesions. Osseous integration of the avulsion fragment was documented on plain radiographs on average 6.1 weeks after surgery in adults and after 3.9 weeks in children. Free range of motion was accomplished after 11.3 weeks. The choice of surgical technique did not show any influence on healing period or rehabilitation. The complication rate was 16.6% in skeletally immature patients and 8.3 % in adults. IKDC scores: A10, B2 in children; A9, B3 in adults. Tegner scores: children 5.8, adults 4.1. Lysholm scores: children 93, adults 88. CONCLUSIONS: Neither the patients' age nor the refixation technique selected yielded a significant correlation to the accomplished clinical score. Both arthroscopic screw fixation and transtibial suture fixation are appropriate surgical procedures regarding results and complication rate. PMID- 20166016 TI - [Clinical and radiological outcome after trapezium resection with suspension and interposition arthroplasty]. AB - INTRODUCTION: Trapezium resection with suspension and interposition arthroplasty of the thumb-carpometacarpal joint is a common method for treatment of severe osteoarthritis of the 1st carpometacarpal joint. METHODS: We performed a single center retrospective data analysis after trapezium resection with suspension and interposition arthroplasty of the thumb-carpometacarpal joint with emphasis on quality of life and radiological parameters 3.4 years (1.2-8.7 years) after operation in 60 patients. Pre- and postoperative pain was analysed with VAS, function was measured using the DASH score, pinch grip power with a pinchmeter. RESULTS: Subjective outcome was rated excellent in 42 cases (64.6%), good in 17 (26.2%), fair in 3 (4.6%) and 3 times (4.6%) poor. 56 patients (93.3%) would like to be operated again; 4 patients (6.7%) would deny an operation retrospectively. In the VAS pain was reduced by about 75% compared to the preoperative value. The pinch grip was increased by 46.6% compared to the preoperative value. The rate of major complications was 1.5% and of minor complications 9.2 %. CONCLUSION: Trapezium resection with suspension and interposition arthroplasty can increase the quality of life and reduce pain in patients with severe osteoarthritis of the 1st carpometacarpal joint. The rate of complications is low. Outcome assessment is possible by subjective parameters. Objective values like the range of movement or the decrease of the distance between metacarpal I and scaphoid do not correlate with outcome. PMID- 20166043 TI - [Tissue engineering--synthetic tissues proven in clinical applications]. PMID- 20166044 TI - [Subacute and chronic cough]. PMID- 20166046 TI - [What is your diagnosis? Nail patella syndrome]. PMID- 20166047 TI - [What is your diagnosis? Non-erosive seronegative polyarthritis]. PMID- 20166048 TI - [Medical assessments of the years 2004 and 2005 at the Diagnostic Medical Department MEDAS, University Clinic Basel - a critical analysis]. AB - Medical assessments of patients seeking disability benefits are one of the most important services provided by MEDAS/asim Basel for the Swiss Disability Insurance scheme. An evaluation of 593 assessments from 2004 and 2005 was carried out in order to gain initial insights into the characteristics of this special patient population. Information about sociodemographic background, diagnoses and certified fitness to work was collected and evaluated. The majority of the assessed patients were immigrants (61%) from southern and south-eastern Europe, 86% of whom suffered from chronic pain conditions and depression. At the time of the assessments, only 101 patients (17% of the total) were working full- or part time. For 38% of the patient population under investigation, the last work period in mostly unskilled occupations varied from a few months to several years and had ended 1.5-2.5 years previously. PMID- 20166049 TI - [Viral infections as a cause of chronic obstructive pulmonary disease (COPD) exacerbation]. AB - COPD is a progressive disease whom course is characterized by repeated exacerbations, with a negative impact on quality of life and health costs. Although a causal link between the identification of viruses in the upper respiratory tract and exacerbation is not definitively established, there is growing evidence that viruses are important triggers of exacerbations in more than 50 percent of cases. Yet, neither clinical presentation nor biological markers permit to discriminate between viral and non viral exacerbations. PMID- 20166050 TI - [Surgery for diabetes type 2?]. AB - Diabetes mellitus type 2 is a chronic disease with increasing prevalence in western society. Obesity represents a well established risk factor for the development of diabetes mellitus type 2. Several studies on surgical procedures for the treatment of obesity have shown a postoperative reduction of obesity related co-morbidities. Thus, diabetes mellitus type 2 was shown to resolve or improve in more than 75% of morbidly obese patients (BMI >35) after bariatric surgery. These insights paved the way for the advent of metabolic surgery - a novel field with the goal to improve glucose metabolism in patients with a BMI of less than 35. Encouraging results from mostly observational studies have sparked the interest in the surgical management of diabetes mellitus type 2. PMID- 20166051 TI - [Acute anterior uveitis]. PMID- 20166052 TI - [When eating becomes dangerous...]. AB - We report the case of a 59-year-old women with idiopathic insulin auto-immune syndrome, a rare cause of endogenous hyperinsulinemic hypoglycemia. It is characterized by extremely high levels of insulin in the presence of high titers of insulin antibodies despite the absence of previous insulin injections. Early postprandial increase in glucose concentrations due to impaired insulin action resulting from the buffering effect of the antibodies and late postprandial hypoglycemia as a consequence of the dissociation of insulin from the antibodies was observed. A correct diagnosis is important to avoid unnecessary investigations and surgery in these patients who are best treated conservatively with a good prognosis - by fractionating carbohydrate intake during the day. PMID- 20166053 TI - [Pulmonary rehabilitation in COPD patients with acute exacerbation is effective]. PMID- 20166054 TI - [Strict blood glucose control not absolutely required in type 2 diabetes mellitus?]. PMID- 20166056 TI - [CME EKG 28. 3rd degree atrioventricular block]. PMID- 20166057 TI - [Work disability certificate--hindrance or catalyst for occupational reintegration?]. PMID- 20166058 TI - [Medical art column]. PMID- 20166059 TI - Neuraminidase inhibitors for preventing and treating influenza in healthy adults. AB - BACKGROUND: Neuraminidase inhibitors (NI) are recommended for use against influenza and its complications in inter-pandemic years and during pandemics. OBJECTIVES: To assess the effects of NIs in preventing and treating influenza, its transmission, and its complications in otherwise healthy adults, and to estimate the frequency of adverse effects. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 3) which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1950 to August 2009) and EMBASE (1980 to August 2009). SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi randomised placebo-controlled trials of NIs in healthy adults exposed to naturally occurring influenza. DATA COLLECTION AND ANALYSIS: Two review authors independently applied inclusion criteria, assessed trial quality, and extracted data. We structured the comparisons into prophylaxis, treatment, and adverse events, with further subdivision by outcome and dose. MAIN RESULTS: We identified four prophylaxis, 12 treatment and four post-exposure prophylaxis trials. In prophylaxis compared to placebo, NIs had no effect against influenza-like illnesses (ILI) (risk ratio (RR) ranging from 1.28 for oral oseltamivir 75 mg daily to 0.76 for inhaled zanamivir 10 mg daily). The efficacy of oral oseltamivir against symptomatic influenza was 76% (at 75 mg daily), and 73% (at 150 mg daily). Inhaled zanamivir 10 mg daily performed similarly. Neither NI had a significant effect on asymptomatic influenza. Oseltamivir induced nausea (odds ratio (OR) 1.79, 95% CI 1.10 to 2.93). Oseltamivir for post-exposure prophylaxis had an efficacy of 58% and 84% in two trials for households. Zanamivir performed similarly. The hazard ratios for time to alleviation of symptoms were in favour of the treated group 1.20 (1.06 to 1.35) for oseltamivir and 1.24 (1.13 to 1.36) for zanamivir. Because of the exclusion of a review of mainly unpublished trials of oseltamivir, insufficient evidence remained to reach a conclusion on the prevention of complications requiring antibiotics in influenza cases (RR 0.57, 95% CI 0.23 to 1.37). Analysis of the US FDA and Japan's PMDA regulators' pharmacovigilance dataset, revealed incomplete reporting and description of harms preventing us from reaching firm conclusions on the central nervous system toxicity of neuraminidase inhibitors. AUTHORS' CONCLUSIONS: Numerous inconsistencies detected in the available evidence, followed by an inability to adequately access the data, has undermined confidence in our previous conclusions for oseltamivir. Independent RCTs to resolve these uncertainties are needed. PMID- 20166060 TI - Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. AB - BACKGROUND: Individuals with chronic bronchitis or chronic obstructive pulmonary disease (COPD) may suffer recurrent exacerbations with an increase in volume and/or purulence of sputum. Because of the personal and healthcare costs associated with exacerbations, any therapy that reduces the number of exacerbations is useful. There is a marked difference between countries in terms of prescribing of mucolytics depending on whether or not they are perceived to be effective. OBJECTIVES: To assess the effects of oral mucolytics in adults with stable chronic bronchitis or COPD. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register and reference lists of articles on eight separate occasions, the most recent being in September 2008. SELECTION CRITERIA: Randomised trials that compared oral mucolytic therapy with placebo for at least two months in adults with chronic bronchitis or COPD. We excluded studies of people with asthma and cystic fibrosis. DATA COLLECTION AND ANALYSIS: One review author extracted data. We contacted study authors and drug companies for missing information. MAIN RESULTS: Twenty-eight trials involving 7042 participants were included. Compared with placebo, there was a significant reduction in the number of exacerbations per patient with oral mucolytics (weighted mean difference (WMD) -0.04 per month, 95% confidence interval -0.05 to -0.03). Using a weighted annualised rate of exacerbations in the control patients of 2.4 per year, this is a 21% reduction. The number of days of disability also fell (WMD -0.56, 95% confidence interval (CI) -0.77 to -0.35). One recent study has shown that the benefit may apply only to patients not already receiving inhaled corticosteroids. The number of patients who remained exacerbation-free was greater in the mucolytic group (odds ratio (OR) 1.93 (95% CI 1.71 to 2.17)). There is no strong evidence of improvement in lung function and treatment is not associated with any increase in adverse effects. Patients on mucolytics may be less likely to be hospitalised during the study period. AUTHORS' CONCLUSIONS: In participants with chronic bronchitis or COPD, treatment with mucolytics was associated with a small reduction in acute exacerbations and a reduction in total number of days of disability. Benefit may be greater in individuals who have frequent or prolonged exacerbations, or those who are repeatedly admitted to hospital with exacerbations with COPD. Mucolytics should be considered for use, through the winter months at least, in patients with moderate or severe COPD in whom inhaled corticosteroids (ICS) are not prescribed. PMID- 20166061 TI - Corticosteroids for Guillain-Barre syndrome. AB - BACKGROUND: Guillain-Barre syndrome is caused by inflammation of the peripheral nerves, which corticosteroids should benefit. OBJECTIVES: To examine the efficacy of corticosteroids. SEARCH STRATEGY: We searched The Cochrane Neuromuscular Disease Group Trials Specialized Register (June 2009), MEDLINE (January 1966 to June 2009) and EMBASE from (January 1980 to June 2009). SELECTION CRITERIA: We included quasi-randomised or randomised controlled trials of any form of corticosteroid or adrenocorticotrophic hormone. Our primary outcome was change in disability grade on a seven-point scale after four weeks. Secondary outcomes included time from randomisation until recovery of unaided walking, time from randomisation until discontinuation of ventilation (for those ventilated), death, death or disability (inability to walk without aid) after 12 months, relapse, and adverse events. DATA COLLECTION AND ANALYSIS: Two authors extracted the data. MAIN RESULTS: No new trials were discovered in the new search in June 2009. Six trials with 587 participants provided data for the primary outcome. According to moderate quality evidence, the disability grade change after four weeks in the corticosteroid groups was not significantly different from that in the control groups, weighted mean difference (WMD) 0.36 less improvement (95% confidence intervals (CI) 0.16 more to 0.88 less improvement). In four trials of oral corticosteroids with 120 participants in total, there was significantly less improvement after four weeks with corticosteroids than without corticosteroids, WMD 0.82 disability grades less improvement, 95% CI 0.17 to 1.47). In two trials with a combined total of 467 participants, there was no significant difference, WMD 0.17 (95% CI -0.06 to 0.39) of a disability grade more improvement after four weeks with intravenous corticosteroids. According to moderate to high quality evidence, there were no significant differences between the corticosteroid treated and the control groups in any of the secondary efficacy outcomes. Diabetes was significantly more common and hypertension significantly much less common in the corticosteroid-treated participants. AUTHORS' CONCLUSIONS: According to moderate quality evidence, corticosteroids given alone do not significantly hasten recovery from GBS or affect the long-term outcome. According to low quality evidence oral corticosteroids delay recovery. Diabetes requiring insulin was significantly more and hypertension less common with corticosteroids. PMID- 20166062 TI - Routine intracranial pressure monitoring in acute coma. AB - BACKGROUND: Studies in traumatic encephalopathy first led to the insight that the damage seen was not just due to direct consequences of the primary injury. A significant, and potentially preventable, contribution to the overall morbidity arose from secondary hypoxic-ischaemic damage. Brain swelling accompanied by raised intracranial pressure (ICP) resulted in inadequate cerebral perfusion with well-oxygenated blood. Detection of raised ICP could be useful in alerting clinicians to the need to improve cerebral perfusion, with consequent reductions in brain injury. OBJECTIVES: To determine whether routine ICP monitoring in all acute cases of severe coma reduces the risk of all-cause mortality or severe disability at final follow-up. SEARCH STRATEGY: We searched the Cochrane Injuries Group's Specialised Register (searched 7 April 2009), CENTRAL (The Cochrane Library 2009, Issue 1), MEDLINE 1950 to March week 4 2009, EMBASE 1980 to week 14 March 2009, CINAHL 1982 to March 2009, ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970 to March 2009, Conference Proceedings Citation Index Science (CPCI-S) 1990 to March 2009, PubMed (searched 7 April 2009, limit; added in last 6 months). The searches were last updated in April 2009. SELECTION CRITERIA: All randomised controlled studies of real-time ICP monitoring by invasive or semi-invasive means in acute coma (traumatic or non-traumatic aetiology) versus no ICP monitoring (that is, clinical assessment of ICP). DATA COLLECTION AND ANALYSIS: Primary outcome measures were all-cause mortality and severe disability at the end of the follow-up period. MAIN RESULTS: No studies meeting the selection criteria have been identified to date. AUTHORS' CONCLUSIONS: There are no data from randomised controlled trials that can clarify the role of ICP monitoring in acute coma. PMID- 20166063 TI - WITHDRAWN: Interventions for normal tension glaucoma. AB - BACKGROUND: Normal tension glaucoma is a clinical condition in which the optic nerve is pathologically excavated and the visual field is disturbed. Nevertheless it has been assumed that intraocular pressure plays a role in the progression of visual field defects in this disease, but other, mainly vascular factors, have been discussed as well. OBJECTIVES: The objective of this review is to assess the effects of medical and surgical treatments for normal tension glaucoma. SEARCH STRATEGY: Trials were identified from the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group trials register), MEDLINE, EMBASE and BIOSIS Previews. Bibliographies of identified trials were searched to find additional trials. In addition, investigators and pharmaceutical companies were contacted. Date of last search: January 2001. SELECTION CRITERIA: This review includes randomised controlled trials in which medical or surgical interventions were compared to no treatment, placebo or other treatment in people with normal tension glaucoma. DATA COLLECTION AND ANALYSIS: Data were extracted by two reviewers and results were compared for differences. Discrepancies were resolved by discussion. The heterogeneity of interventions, follow-up periods and outcomes did not allow for statistical combinations of the study results. MAIN RESULTS: According to the selection criteria on visual field loss, eight studies were included in this review. Only three studies focussed on patient relevant outcomes. In one trial a beneficial effect of lowering intraocular pressure was found, but only if data were corrected for cataract development. In two small studies a beneficial effect on visual field loss of brovincamine, a calcium antagonist was reported. AUTHORS' CONCLUSIONS: In one study the effect of intraocular pressure lowering on visual field outcome was only significant when data were corrected for cataract development. The results for calcium antagonists are promising, but larger trials have to be performed. Studies that focussed on reduction of intraocular pressure or haemodynamic variables are not necessarily relevant for the outcome in people with normal tension glaucoma. PMID- 20166064 TI - WITHDRAWN: Antidepressants for cocaine dependence. AB - BACKGROUND: The past decade has witnessed a sustained search for an effective pharmacotherapeutic agent for the treatment of cocaine dependence. While administration of cocaine acutely increases intercellular dopamine, serotonin, and norepinephrine levels by blocking their presynaptic reuptake, chronic cocaine abuse leads to down-regulation of monoamine systems. Post-cocaine use depression and cocaine craving may be linked to this down-regulation. Antidepressant pharmacotherapy, by augmenting monoamine levels, may alleviate cocaine abstinence symptomatology, as well as relieving dysphoria and associated craving by general antidepressant action. OBJECTIVES: To evaluate the efficacy and the acceptability of antidepressants for cocaine dependence SEARCH STRATEGY: We searched Cochrane Drug and Alcohol Group Specialised Register (July 2007), MEDLINE (1966 to July 2007), CINAHL (1982 to July 2007), SCOPUS (July 2007); reference searching; personal communication; conference abstracts; unpublished trials, ongoing trials, relevant web-sites. SELECTION CRITERIA: All randomised controlled trials and controlled clinical trials which focus on the use of any antidepressants for cocaine dependence DATA COLLECTION AND ANALYSIS: The authors independently evaluated the papers, extracted data, rated methodological quality. Doubts were solved throug discussion between all the authors. MAIN RESULTS: 18 studies were included in the review (1177 participants). Positive urine sample for cocaine metabolites was the main efficacy outcome, with no significant results obtained regardless of the type of antidepressant. Compared to other drugs, desipramine performed better but showing just a non significant trend with heterogeneity present as revealed by the chi-square test (8.6, df=3; p=0.04). One single trial showed imipramine performed better than placebo in terms of clinical response according to patient's self-report. A similar rate of patients remaining in treatment was found for both patients taking desipramine or placebo. Results from one single trial suggest fluoxetine patients on SSRIs are less likely to dropout. Similar results were obtained for trials where patients had additional diagnosis of opioid dependence and/or were in methadone maintenance treatment. AUTHORS' CONCLUSIONS: There is no current evidence supporting the clinical use of antidepressants in the treatment of cocaine dependence. Given the high rate of dropouts in this population, clinicians may consider adding psychotherapeutic supportive measures aiming to keep patients in treatment. PMID- 20166065 TI - WITHDRAWN: Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease. AB - BACKGROUND: Gastro-oesophageal reflux disease (GORD) - reflux of stomach contents +/- bile into the oesophagus causing symptoms such as heartburn and acid reflux - is a common relapsing and remitting disease which often requires long-term maintenance therapy. Patients with GORD may have oesophagitis (inflammation of the oesophagus) or a normal endoscopy (endoscopy negative reflux disease or ENRD). OBJECTIVES: To assess the effects of continuous maintenance therapy in adults with GORD (both ENRD and healed oesophagitis). SEARCH STRATEGY: We searched Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2003), MEDLINE (1966 to 2003), EMBASE (1980 to 2003), CINAHL (1982 2003), and the National Research Register (Issue 2, 2003) and reference lists of articles. We also contacted manufacturers and researchers in the field. SELECTION CRITERIA: Randomised controlled studies comparing PPIs, H2RAs, prokinetics, sucralfate and combinations either in comparison to another treatment regimen or to placebo in adults with reflux oesophagitis and ENRD. DATA COLLECTION AND ANALYSIS: One author extracted data from included trials and a second author carried out an unblinded check. Two authors independently assessed trial quality. Study authors were contacted for additional information. MAIN RESULTS: Maintenance of patients with healed oesophagitis: For a healing dose of PPI (generally the standard dose given by the manufacturer) versus placebo, the relative risk (RR) for oesophagitis relapse was 0.26 (95% confidence interval (CI) 0.19 to 0.36); versus H2RAs the RR was 0.36 (95% CI 0.28 to 0.46) and versus maintenance PPIs the RR was 0.63 (95% CI 0.55 to 0.73). However overall adverse effects were also more common and headaches were more common when comparing healing PPIs to H2RAs.For a maintenance dose of PPI (half of the standard dose) versus placebo, the RR for oesophagitis relapse was 0.46 (95% CI 0.38 to 0.57) and versus H2RAs the RR was 0.57 (95% CI 0.47 to 0.69). Overall adverse effects were more common.H2RAs were of marginal help but beneficial for symptomatic relief. Prokinetics and sucralfate were also more effective than placebo.For ENRD patients: Limited data with one RCT showed benefit for omeprazole 10 mg once daily over placebo (RR 0.4; 95% CI 0.29 to 0.53). AUTHORS' CONCLUSIONS: The findings in this review support the long-term treatment of oesophagitis to prevent relapse, both endoscopically and symptomatically. Healing doses of PPIs are more effective than all other therapies, although there is an increase in overall adverse effects compared to placebo, and headache occurrence compared to H2RAs. H2RAs prevent relapse more effectively than placebo, demonstrating a role for PPI-intolerant patients. Prokinetics and sucralfate both show benefit over placebo, but the former is no longer licenced. There is only limited data for ENRD. PMID- 20166066 TI - WITHDRAWN: Dopamine agonists for cocaine dependence. AB - BACKGROUND: Cocaine dependence is a common and serious condition, which has become a substantial public health problem. There is a wide and well documented range of consequences associated to chronic use of cocaine, such as medical, psychological and social problems.. Therapeutic management of the cocaine addicts includes an initial period of abstinence from the drug. During this phase the subjects may experience, besides the intense craving for cocaine, symptoms such as depression, fatigue, irritability, anorexia, and sleep disturbances. It was demonstrated that the acute use of cocaine may enhance dopamine transmission and chronically it decreases dopamine concentrations in the brain. Pharmacological treatment that affects dopamine could theoretically reduce these symptoms and contribute to a more successful therapeutic approach. OBJECTIVES: To evaluate the efficacy and acceptability of dopamine agonists for treating cocaine dependence. SEARCH STRATEGY: Electronic searches of Cochrane Library, EMBASE, MEDLINE, PsycLIT, Biological Abstracts and LILACS; reference searching; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence, was performed for the primary version of this review in 2001. Another search of the electronic databases was done in December of 2002 for this update. The specialised register of trials of the Cochrane Group on Drugs and Alcohol was searched until February 2003. SELECTION CRITERIA: The inclusion criteria for all randomised controlled trials were that they should focus on the use of dopamine agonists on the treatment of cocaine dependence. DATA COLLECTION AND ANALYSIS: The reviewers extracted the data independently and Relative Risks, weighted mean difference and number needed to treat were estimated. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity of the final results to this assumption. MAIN RESULTS: Seventeen studies were included, with 1224 participants randomised. Amantadine, bromocriptine, and pergolide were the drugs evaluated. The main outcomes evaluated were positive urine sample for cocaine metabolites, for efficacy, and retention in treatment, as an acceptability measure. There were no significant differences between interventions, and in trials where participants had primary cocaine dependence or had additional diagnosis of opioid dependence and/or were in methadone maintenance treatment. AUTHORS' CONCLUSIONS: Current evidence does not support the clinical use of dopamine agonists in the treatment of cocaine dependence. Given the high rate of dropouts in this population, clinicians may consider adding other supportive measures aiming to keep patients in treatment. PMID- 20166068 TI - Pharmaceutical interventions for emotionalism after stroke. AB - BACKGROUND: Antidepressants may be useful in the treatment of abnormal crying associated with stroke. This is an update of a Cochrane Review first published in 2004. OBJECTIVES: To determine whether pharmaceutical treatment reduces the frequency of emotional displays in people with emotionalism after stroke. SEARCH STRATEGY: We searched the trials registers of the Cochrane Stroke Group and the Cochrane Depression Anxiety and Neurosis Group (last searched August 2009). In addition, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2009), MEDLINE (1966 to May 2008), EMBASE (1980 to May 2008), CINAHL (1982 to May 2008), PsycINFO (1967 to May 2008), Arts and Humanities Index (1991 to May 2008), BIOSIS Previews (2002 to May 2008), Science Citation Index (1992 to May 2008), Social Sciences Citation Index (1991 to May 2008), Sociological Abstract/Sociofile (1974 to May 2008), ISI Web of Science (2002 to May 2008), reference lists, clinical trials registers, conference proceedings and dissertation abstracts. We also contacted authors, researchers and pharmaceutical companies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing psychotropic medication to placebo in people with stroke and emotionalism (also known as emotional lability or pathological crying and laughing). DATA COLLECTION AND ANALYSIS: We obtained data for people who no longer met the criteria for emotionalism, and on reduction in frequency of crying. Primary analyses were the proportion of patients who met the criteria for emotionalism at the end of treatment. Secondary outcomes included emotionalism and depression scores, cognitive function, death, activities of daily living and adverse effects. MAIN RESULTS: We included seven trials involving 239 participants. Data were available for five trials with 213 participants. Five trials showed large effects of treatment: 50% reduction in emotionalism, diminished tearfulness, improvements (reduction) in lability, tearfulness and scores on the Pathological Laughter and Crying Scale. However, confidence intervals were wide indicating that treatment may have had only a small positive effect, or even a small negative effect (in one trial). Only two studies systematically reported adverse events; no discernible differences were seen between groups. AUTHORS' CONCLUSIONS: Antidepressants can reduce the frequency and severity of crying or laughing episodes. The effect does not seem specific to one drug or class of drugs. Our conclusions must be qualified by several methodological deficiencies in the studies. More reliable data are required before recommendations can be made about the treatment of post-stroke emotionalism. PMID- 20166067 TI - Antiepileptics for aggression and associated impulsivity. AB - BACKGROUND: Aggression is a major public health issue and is integral to several mental health disorders. Antiepileptic drugs may reduce aggression by acting on the central nervous system to reduce neuronal hyper-excitability associated with aggression. OBJECTIVES: To evaluate the efficacy of antiepileptic drugs in reducing aggression and associated impulsivity. SEARCH STRATEGY: We searched CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, metaRegister of Controlled Trials (mRCT) and ClinicalTrials.gov to April 2009. We also searched Cochrane Schizophrenia Group's register of trials on aggression, National Research Record and handsearched for studies. SELECTION CRITERIA: Prospective, placebo-controlled trials of antiepileptic drugs taken regularly by individuals with recurrent aggression to reduce the frequency or intensity of aggressive outbursts. DATA COLLECTION AND ANALYSIS: Three authors independently selected studies and two authors independently extracted data. We calculated standardised mean differences (SMDs), with odds ratios (ORs) for dichotomous data. MAIN RESULTS: Fourteen studies with data from 672 participants met the inclusion criteria. Five different antiepileptic drugs were examined. Sodium valproate/divalproex was superior to placebo for outpatient men with recurrent impulsive aggression, for impulsively aggressive adults with cluster B personality disorders, and for youths with conduct disorder, but not for children and adolescents with pervasive developmental disorder. Carbamazepine was superior to placebo in reducing acts of self-directed aggression in women with borderline personality disorder, but not in children with conduct disorder. Oxcarbazepine was superior to placebo for verbal aggression and aggression against objects in adult outpatients. Phenytoin was superior to placebo on the frequency of aggressive acts in male prisoners and in outpatient men including those with personality disorder, but not on the frequency of 'behavioral incidents' in delinquent boys. AUTHORS' CONCLUSIONS: The authors consider that the body of evidence summarised in this review is insufficient to allow any firm conclusion to be drawn about the use of antiepileptic medication in the treatment of aggression and associated impulsivity. Four antiepileptics (valproate/divalproex, carbamazepine, oxcarbazepine and phenytoin) were effective, compared to placebo, in reducing aggression in at least one study, although for three drugs (valproate, carbamazepine and phenytoin) at least one other study showed no statistically significant difference between treatment and control conditions. Side effects were more commonly noted for the intervention group although adverse effects were not well reported. Absence of information does not necessarily mean that the treatment is safe, nor that the potential gains from the medication necessarily balance the risk of an adverse event occurring. Further research is needed. PMID- 20166069 TI - Interventions for preventing posterior capsule opacification. AB - BACKGROUND: Posterior capsule opacification (PCO) remains the most common long term complication after cataract surgery. It can be treated by Nd:YAG laser capsulotomy, however this may lead to other complications and laser treatment is not available in large parts of the developing world. Therefore, many studies try to find factors influencing the development of PCO. OBJECTIVES: To summarise the effects of different interventions to inhibit PCO. These include modifications of surgical technique and intraocular lens (IOL) design, implantation of additional devices and pharmacological interventions. SEARCH STRATEGY: We searched CENTRAL, MEDLINE, EMBASE, LILACS in March 2009 and reference lists of identified trial reports. SELECTION CRITERIA: We included only prospective, randomised and controlled trials with a follow-up time of at least 12 months. Interventions included modifications in surgical technique explicitly to inhibit PCO, modifications in IOL design (material and geometry), implantation of additional devices and pharmacological therapy compared to each other, placebo or standard treatment. DATA COLLECTION AND ANALYSIS: We extracted data and entered it into RevMan. We compared visual acuity data, PCO scores and YAG capsulotomy rates and performed a meta-analysis when possible. MAIN RESULTS: Sixty six studies were included in the review. The review was divided into three parts. 1. Influence of IOL optic material on the development of PCO. There was no significant difference in PCO development between the different IOL materials (PMMA, hydrogel, hydrophobic acrylic, silicone) although hydrogel IOLs tend to have higher PCO scores and silicone IOLs lower PCO scores than the other materials. 2. Influence of IOL optic design on the development of PCO. There was a significantly lower PCO score (-8.65 (-10.72 to -6.59), scale 0 to 100) and YAG rate (0.19 (0.11 to 0.35)) in sharp edged than in round edged IOLs, however not between 1-piece and 3 piece IOLs. 3. Influence of surgical technique and drugs on the development of PCO. There was no significant difference between different types of intraoperative/postoperative anti-inflammatory treatment except for treatment with an immunotoxin (MDX-A) which led to a significantly lower PCO rate. AUTHORS' CONCLUSIONS: Due to the highly significant difference between round and sharp edged IOL optics, IOLs with sharp (posterior) optic edges should be preferred. There is no clear difference between optic materials. The choice of postoperative anti-inflammatory treatment does not seem to influence PCO development. PMID- 20166070 TI - WITHDRAWN: Heparin for the prevention of venous thromboembolism in general medical patients (excluding stroke and myocardial infarction). AB - BACKGROUND: Venous thromboembolic disease has been extensively studied in surgical patients. The benefit of thromboprophylaxis is now generally accepted, but it is medical patients who make up the greater proportion of the hospital population. Medical patients differ from surgical patients with regard to their health and the pathogenesis of thromboembolism and the impact that preventative measures can have. The extensive experience from thromboprophylaxis studies in surgical patients is therefore not necessarily applicable to non-surgical patients. OBJECTIVES: To determine the effectiveness and safety of heparin thromboprophylaxis in general medical patients. SEARCH STRATEGY: The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched 24 April 2009) and the Cochrane Central Register of Controlled Trials in The Cochrane Library (last searched Issue 2, 2009)We handsearched meeting abstracts, and consulted with colleagues and investigators as well as the manufacturers of the various LMWH preparations to identify unpublished or missed studies. SELECTION CRITERIA: Randomised controlled trials comparing unfractionated heparin (UFH) or low molecular weight heparin (LMWH) with placebo or no treatment, or comparing UFH with LMWH. DATA COLLECTION AND ANALYSIS: One author identified possible trials, and the other author confirmed eligibility for inclusion in the review. Both authors extracted the data. Disagreements were resolved by discussion. We performed the meta-analysis as a fixed-effect model with relative risks. MAIN RESULTS: A significant risk reduction in deep vein thrombosis (DVT) by 60% (relative risk (RR) 0.40; 95% confidence interval CI 0.31 to 0.53; P < 0.00001) and pulmonary embolism (PE) by 42% (RR 0.58; 95% CI 0.43 to 0.80; P = 0.0007) was observed with heparin compared with placebo or no treatment. However, heparin resulted in a significant increase in major haemorrhage (RR 2.18; 95% CI 1.28 to 3.72; P = 0.004) and minor haemorrhage (RR 1.74; 95% CI 1.26 to 2.41; P = 0.0008). There was no statistically significant difference in efficacy between LMWH and UFH. There was a statistically significant 72% risk reduction in major bleeding when LMWH was compared with UFH (RR 0.28; 95% CI 0.10 to 0.78; P = 0.02). AUTHORS' CONCLUSIONS: The data from this review support the use of heparin thromboprophylaixs in medical patients presenting with an acute medical illness. Although the analysis found no significant difference in efficacy between LMWH and UFH, it did note differences in the incidence of DVT and clinical PE with a significantly reduced risk of bleeding in favour of LMWH. PMID- 20166071 TI - Exercise for dysmenorrhoea. AB - BACKGROUND: Dysmenorrhoea is characterised by cramping lower abdominal pain that may radiate to the lower back and upper thighs and is commonly associated with nausea, headache, fatigue and diarrhoea. Physical exercise has been suggested as a non-medical approach to the management of these symptoms. OBJECTIVES: To assess the evidence for the effectiveness of exercise in the treatment of dysmenorrhoea. SEARCH STRATEGY: A search was conducted using the methodology of the Menstrual Disorders and Subfertility Group (August 2009). CENTRAL (The Cochrane Library), MEDLINE, EMBASE, AMED and PsycINFO electronic databases were searched. Handsearching of relevant bibliographies and reference lists was also conducted. SELECTION CRITERIA: Randomised controlled trials comparing exercise with a control or no intervention in women with dysmenorrhoea. DATA COLLECTION AND ANALYSIS: Trials were independently selected and data extracted by two review authors. MAIN RESULTS: Four potential trials were identified of which one was included in the review. The available data could only be included as a narrative description. There appeared to be some evidence from the trial that exercise reduced the Moos' Menstrual Distress Questionnaire (MDQ) score during the menstrual phase (P < 0.05) and resulted in a sustained decrease in symptoms over the three observed cycles (P < 0.05). AUTHORS' CONCLUSIONS: The results of this review are limited to a single randomised trial of limited quality and with a small sample size. The data should be interpreted with caution and further research is required to investigate the hypothesis that exercise reduces the symptoms associated with dysmenorrhoea. PMID- 20166072 TI - Vaccines for preventing influenza in the elderly. AB - BACKGROUND: Vaccines have been the main global weapon to minimise the impact of influenza in the elderly for the last four decades and are recommended worldwide for individuals aged 65 years or older. The primary goal of influenza vaccination in the elderly is to reduce the risk of complications among persons who are most vulnerable. OBJECTIVES: To assess the effectiveness of vaccines in preventing influenza, influenza-like illness (ILI), hospital admissions, complications and mortality in the elderly. To identify and appraise comparative studies evaluating the effects of influenza vaccines in the elderly. To document types and frequency of adverse effects associated with influenza vaccines in the elderly. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register (The Cochrane Library 2009, issue 4); MEDLINE (January 1966 to October Week 1 2009); EMBASE (1974 to October 2009) and Web of Science (1974 to October 2009). SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi RCTs, cohort and case-control studies assessing efficacy against influenza (laboratory-confirmed cases) or effectiveness against influenza-like illness (ILI) or safety. Any influenza vaccine given independently, in any dose, preparation or time schedule, compared with placebo or with no intervention was considered. DATA COLLECTION AND ANALYSIS: We grouped reports first according to the setting of the study (community or long-term care facilities) and then by level of viral circulation and vaccine matching. We further stratified by co administration of pneumococcal polysaccharide vaccine (PPV) and by different types of influenza vaccines. We analysed the following outcomes: influenza, influenza-like illness, hospital admissions, complications and deaths. MAIN RESULTS: We included 75 studies. Overall we identified 100 data sets. We identified one RCT assessing efficacy and effectiveness. Although this seemed to show an effect against influenza symptoms it was underpowered to detect any effect on complications (1348 participants). The remainder of our evidence base included non-RCTs. Due to the general low quality of non-RCTs and the likely presence of biases, which make interpretation of these data difficult and any firm conclusions potentially misleading, we were unable to reach clear conclusions about the effects of the vaccines in the elderly. AUTHORS' CONCLUSIONS: The available evidence is of poor quality and provides no guidance regarding the safety, efficacy or effectiveness of influenza vaccines for people aged 65 years or older. To resolve the uncertainty, an adequately powered publicly-funded randomised, placebo-controlled trial run over several seasons should be undertaken. PMID- 20166073 TI - Influenza vaccination for healthcare workers who work with the elderly. AB - BACKGROUND: Healthcare workers' (HCWs) influenza rates are unknown, but may be similar to the general public and they may transmit influenza to patients. OBJECTIVES: To identify studies of vaccinating HCWs and the incidence of influenza, its complications and influenza-like illness (ILI) in individuals >/= 60 in long-term care facilities (LTCFs). SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2009, issue 3), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to 2009), EMBASE (1974 to 2009) and Biological Abstracts and Science Citation Index Expanded. SELECTION CRITERIA: Randomised controlled trials (RCTs) and non-RCTs of influenza vaccination of HCWs caring for individuals >/= 60 in LTCFs and the incidence of laboratory-proven influenza, its complications or ILI. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed risk of bias. MAIN RESULTS: We identified four cluster-RCTs (C-RCTs) (n = 7558) and one cohort (n = 12742) of influenza vaccination for HCWs caring for individuals >/= 60 in LTCFs. Pooled data from three C-RCTs showed no effect on specific outcomes: laboratory-proven influenza, pneumonia or deaths from pneumonia. For non-specific outcomes pooled data from three C-RCTs showed HCW vaccination reduced ILI; data from one C-RCT that HCW vaccination reduced GP consultations for ILI; and pooled data from three C-RCTs showed reduced all-cause mortality in individuals >/= 60. AUTHORS' CONCLUSIONS: No effect was shown for specific outcomes: laboratory-proven influenza, pneumonia and death from pneumonia. An effect was shown for the non-specific outcomes of ILI, GP consultations for ILI and all-cause mortality in individuals >/= 60. These non specific outcomes are difficult to interpret because ILI includes many pathogens, and winter influenza contributes < 10% to all-cause mortality in individuals >/= 60. The key interest is preventing laboratory-proven influenza in individuals >/= 60, pneumonia and deaths from pneumonia, and we cannot draw such conclusions.The identified studies are at high risk of bias.Some HCWs remain unvaccinated because they do not perceive risk, doubt vaccine efficacy and are concerned about side effects. This review did not find information on co-interventions with HCW vaccination: hand washing, face masks, early detection of laboratory-proven influenza, quarantine, avoiding admissions, anti-virals, and asking HCWs with ILI not to work. We conclude there is no evidence that vaccinating HCWs prevents influenza in elderly residents in LTCFs. High quality RCTs are required to avoid risks of bias in methodology and conduct, and to test these interventions in combination. PMID- 20166074 TI - Ad libitum or demand/semi-demand feeding versus scheduled interval feeding for preterm infants. AB - BACKGROUND: Scheduled interval feeding of prescribed enteral volumes is current standard practice for preterm infants. However, feeding preterm infants in response to their hunger and satiation cues (ad libitum or demand/semi demand) rather than at scheduled intervals might help in the establishment of independent oral feeding, increase nutrient intake and growth rates, and allow earlier hospital discharge. OBJECTIVES: To assess the effect of a policy of feeding preterm infants on an ad libitum or demand/semi-demand basis versus feeding prescribed volumes at scheduled intervals on growth rates and the time to hospital discharge. SEARCH STRATEGY: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2009), MEDLINE (1966 to Oct 2009), EMBASE (1980 to Oct 2009), CINAHL (1982 to Oct 2009), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials (including cluster randomised trials) that compared a policy of feeding preterm infants on an ad libitum or demand/semi demand basis versus feeding at scheduled intervals. DATA COLLECTION AND ANALYSIS: We used the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by two review authors. MAIN RESULTS: We found eight randomised controlled trials that compared ad libitum or demand/semi-demand regimens with scheduled interval regimes in preterm infants in the transition phase from intragastric tube to oral feeding. The trials were generally small and of variable methodological quality. The duration of the intervention and the duration of data collection and follow-up in most of the trials was not likely to have allowed detection of measurable effects on growth. Three trials reported that feeding preterm infants using an ad libitum or demand/semi-demand feeding regimen allowed earlier discharge from hospital (by about two to four days) but other trials did not confirm this finding. AUTHORS' CONCLUSIONS: Limited evidence exists that feeding preterm infants with ad libitum or demand/semi-demand regimens allows earlier attainment of full oral feeding and earlier hospital discharge. This finding should be interpreted cautiously because of methodological weaknesses in the included trials. A large randomised controlled trial is needed to confirm this finding and to determine if ad libitum of demand/semi-demand feeding of preterm infants affects other clinically important outcomes. PMID- 20166075 TI - Infraclavicular brachial plexus block for regional anaesthesia of the lower arm. AB - BACKGROUND: Several approaches exist to produce local anaesthetic blockade of the brachial plexus. It is not clear which is the technique of choice for providing surgical anaesthesia of the lower arm although infraclavicular blockade (ICB) has several purported advantages. We therefore performed a systematic review of ICB compared to the other brachial plexus blocks (BPBs). OBJECTIVES: To evaluate the efficacy and safety of ICB compared to other BPBs in providing regional anaesthesia of the lower arm. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2008, Issue 3), MEDLINE (1950 to September 22nd 2008) and EMBASE (1980 to September 22nd 2008). We also searched conference proceedings (from 2004 to 2008) and the www.clinicaltrials.gov registry. No language restriction was applied. SELECTION CRITERIA: We included any randomized controlled trials that compared ICB with other BPBs as the sole anaesthetic techniques for surgery on the lower arm. DATA COLLECTION AND ANALYSIS: The primary outcome was adequate surgical anaesthesia within 30 minutes of block completion. Secondary outcomes included sensory block of individual nerves, tourniquet pain, onset time of sensory blockade, block performance time, block-associated pain and complications related to the block. MAIN RESULTS: We identified 15 studies with 1020 participants, of whom 510 received ICB and 510 received other BPBs. The control group intervention was the axillary block in 10 studies, mid-humeral block in two studies, supraclavicular block in two studies and parascalene block in one study. Three studies employed ultrasound-guided ICB. The risk of failed surgical anaesthesia and of complications were low and similar for ICB and all other BPBs. Tourniquet pain was less likely with ICB (risk ratio (RR) 0.47, 95% CI 0.24 to 0.92, P = 0.03). When compared to a single-injection axillary block, ICB was better at providing complete sensory block of the musculocutaneous nerve (RR for failure 0.46, 95% CI 0.27 to 0.60, P < 0.0001) and the axillary nerve (RR of failure 0.37, 95% CI 0.24 to 0.58, P < 0.0001). ICB was faster to perform than multiple injection axillary (mean difference (MD) -2.7 min, 95% CI -4.2 to -1.1, P = 0.0006) or midhumeral blocks (MD -4.8 min, 95% CI -6.0 to -3.6, P < 0.00001) but this was offset by a longer sensory block onset time (MD 3.9 min, 95% CI 3.2 to 4.5, P < 0.00001). AUTHORS' CONCLUSIONS: ICB is a safe and simple technique for providing surgical anaesthesia of the lower arm, with an efficacy comparable to other BPBs. The advantages of ICB include a lower likelihood of tourniquet pain during surgery, and more reliable blockade of the musculocutaneous and axillary nerves when compared to a single-injection axillary block. PMID- 20166076 TI - Extracranial-intracranial arterial bypass surgery for occlusive carotid artery disease. AB - BACKGROUND: The EC/IC Bypass Study Group found no benefit of extracranial to intracranial (EC/IC) bypass surgery over medical therapy in patients with symptomatic carotid artery occlusion (sCAO). However, the study was criticised for many reasons and the real effect of this treatment is still not known conclusively. OBJECTIVES: To determine whether bypass surgery plus medical care is superior to medical care alone in patients with sCAO. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched June 2009). In addition, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2006), MEDLINE (1966 to June 2009) and EMBASE (1980 to June 2009). We also searched ongoing trials and research registers, checked reference lists of relevant articles, and contacted colleagues, trial authors and researchers. SELECTION CRITERIA: Randomised controlled trials (RCT) and non-random studies of EC/IC bypass surgery plus best medical treatment compared with best medical treatment alone to prevent subsequent stroke, improve cerebral haemodynamics and reduce dependency after stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, and extracted data items on the number of outcome events onto a data extraction form. We only analysed secondary outcomes if the study provided information on at least one primary outcome. We also used intention-to treat analysis where possible. MAIN RESULTS: We included 21 trials, including two RCTs, involving 2591 patients. For all endpoints, no benefit of EC/IC bypass surgery was shown either in the RCTs (any death: odds ratio (OR) 0.81, 95% confidence interval (CI) 0.62 to 1.05, P = 0.11; stroke: OR 0.99, 95% CI 0.79 to 1.23, P = 0.91; death and dependency: OR 0.94, 95% CI 0.74 to 1.21, P = 0.64), or in the non-RCTs (any death: OR 1.00, 95% CI 0.62 to 1.62, P = 0.99; stroke: OR 0.80, 95% CI 0.54 to 1.18, P = 0.25; death and dependency: OR 0.80, 95% CI 0.50 to 1.29, P = 0.37). AUTHORS' CONCLUSIONS: EC/IC bypass surgery in patients with sCAO disease was neither superior nor inferior to medical care alone. However, most studies included patients irrespective of their cerebral haemodynamics. Participation in an ongoing RCT, which is restricted to patients with impaired haemodynamics, is recommended as these patients might benefit from bypass surgery. PMID- 20166077 TI - Replacement versus repair of defective restorations in adults: amalgam. AB - BACKGROUND: Amalgam is a common filling material for posterior teeth, as with any restoration amalgams have a finite life-span. Traditionally replacement was the ideal approach to treat defective amalgam restorations, however, repair offers an alternative more conservative approach where restorations are only partially defective. Repairing a restoration has the potential of taking less time and may sometimes be performed without the use of local anaesthesia hence it may be less distressing for a patient when compared with replacement. OBJECTIVES: To evaluate the effectiveness of replacement (with amalgam) versus repair (with amalgam) in the management of defective amalgam dental restorations in permanent molar and premolar teeth. SEARCH STRATEGY: For the identification of studies relevant to this review we searched the Cochrane Oral Health Group Trials Register (to 23rd September 2009); CENTRAL (The Cochrane Library 2009, Issue 4); MEDLINE (1950 to 23rd September 2009); EMBASE (1980 to 23rd September 2009); ISI Web of Science (SCIE, SSCI) (1981 to 22nd December 2009); ISI Web of Science Conference Proceedings (1990 to 22nd December 2009); BIOSIS (1985 to 22nd December 2009); and OpenSIGLE (1980 to 2005). Researchers, experts and organisations known to be involved in this field were contacted in order to trace unpublished or ongoing studies. There were no language limitations. SELECTION CRITERIA: Trials were selected if they met the following criteria: randomised or quasi-randomised controlled trial, involving replacement and repair of amalgam restorations. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed titles and abstracts for each article identified by the searches in order to decide whether the article was likely to be relevant. Full papers were obtained for relevant articles and both review authors studied these. The Cochrane Collaboration statistical guidelines were to be followed for data synthesis. MAIN RESULTS: The search strategy retrieved 145 potentially eligible studies, after de-duplication and examination of the titles and abstracts all but three studies were deemed irrelevant. After further analysis of the full texts of the three studies identified, none of the retrieved studies met the inclusion criteria and all were excluded from this review. AUTHORS' CONCLUSIONS: There are no published randomised controlled clinical trials relevant to this review question. There is therefore a need for methodologically sound randomised controlled clinical trials that are reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement (www.consort-statement.org/). Further research also needs to explore qualitatively the views of patients on repairing versus replacement and investigate themes around pain, distress and anxiety, time and costs. PMID- 20166078 TI - Replacement versus repair of defective restorations in adults: resin composite. AB - BACKGROUND: Composite filling materials have been increasingly used for the restoration of posterior teeth in recent years as a tooth coloured alternative to amalgam. As with any filling material composites have a finite life-span. Traditionally, replacement was the ideal approach to treat defective composite restorations, however, repairing composites offers an alternative more conservative approach where restorations are partly still serviceable. Repairing the restoration has the potential of taking less time and may sometimes be performed without the use of local anaesthesia hence it may be less distressing for a patient when compared with replacement. OBJECTIVES: To evaluate the effectiveness of replacement (with resin composite) versus repair (with resin composite) in the management of defective resin composite dental restorations in permanent molar and premolar teeth. SEARCH STRATEGY: For the identification of studies relevant to this review we searched the Cochrane Oral Health Group Trials Register (to 23rd September 2009); CENTRAL (The Cochrane Library 2009, Issue 4); MEDLINE (1950 to 23rd September 2009); EMBASE (1980 to 23rd September 2009); ISI Web of Science (SCIE, SSCI) (1981 to 22nd December 2009); ISI Web of Science Conference Proceedings (1990 to 22nd December 2009); BIOSIS (1985 to 22nd December 2009); and OpenSIGLE (1980 to 2005). Researchers, experts and organisations known to be involved in this field were contacted in order to trace unpublished or ongoing studies. There were no language limitations. SELECTION CRITERIA: Trials were selected if they met the following criteria: randomised or quasi-randomised controlled trial, involving replacement and repair of resin composite restorations. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed titles and abstracts for each article identified by the searches in order to decide whether the article was likely to be relevant. Full papers were obtained for relevant articles and both review authors studied these. The Cochrane Collaboration statistical guidelines were to be followed for data synthesis. MAIN RESULTS: The search strategy retrieved 279 potentially eligible studies, after de-duplication and examination of the titles and abstracts all but four studies were deemed irrelevant. After further analysis of the full texts of the four studies identified, none of the retrieved studies met the inclusion criteria and all were excluded from this review. AUTHORS' CONCLUSIONS: There are no published randomised controlled clinical trials relevant to this review question. There is therefore a need for methodologically sound randomised controlled clinical trials that are reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement (www.consort-statement.org/). Further research also needs to explore qualitatively the views of patients on repairing versus replacement and investigate themes around pain, anxiety and distress, time and costs. PMID- 20166079 TI - Vena caval filters for the prevention of pulmonary embolism. AB - BACKGROUND: Pulmonary emboli (PE) can have potentially fatal consequences. Inferior vena caval filters (VCFs) are metal alloy devices that mechanically trap fragmented thromboemboli from the deep leg veins en route to the pulmonary circulation. Filters are designed to be introduced (and in the case of retrievable filters, removed) percutaneously. Although their deployment seems of theoretical benefit, their clinical efficacy and adverse event profile is unclear.This is an update of a Cochrane review first published in 2007. OBJECTIVES: To examine evidence for the effectiveness of VCFs in preventing pulmonary embolism (PE). Secondary outcomes were mortality, distal (to filter) thrombosis, and filter-related complications. SEARCH STRATEGY: The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched October 2009) and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library 2009, Issue 4 for randomised or controlled clinical trials of VCFs for the prevention of PE. The authors contacted filter manufacturers for information. SELECTION CRITERIA: Controlled clinical trials (CCTs) and randomised controlled trials (RCTs) that examined the efficacy of filters in preventing PE. DATA COLLECTION AND ANALYSIS: Two authors independently extracted information. MAIN RESULTS: Two studies were included involving a total of 529 people. One open quasi-randomised trial of 129 participants with traumatic hip fractures showed a reduction in PE but not mortality over a 34 day period in the filter group. The PREPIC (Prevention du Risque d'Embolie Pulmonaire par Interruption Cave) trial, was an open RCT of 400 participants with documented proximal deep vein thrombosis (DVT) or PE who received concurrent anticoagulation. Permanent VCFs prevented PE at eight years. No reduction in mortality was seen, but this reflected an older study population; the majority of deaths were due to cancer or cardiovascular causes. There was an increased incidence of (DVT) in the filter group. Adverse events were not reported. AUTHORS' CONCLUSIONS: No recommendations can be drawn from the two studies. One study showed a reduction in PE rates but not mortality, but was subject to significant biases. The PREPIC study lacked statistical power to detect a reduction in PE over shorter and more clinically significant time periods. However, the trial demonstrated that permanent VCFs were associated with an increased risk of long term lower limb DVT.There is a paucity of VCFs outcome evidence when used within currently approved indications and a lack of trials on retrievable filters. Further trials are needed to assess vena caval filter safety and effectiveness. PMID- 20166080 TI - Gamma-hydroxybutyrate (GHB) for treatment of alcohol withdrawal and prevention of relapses. AB - BACKGROUND: Chronic excessive alcohol consumption may lead to dependence, and to alcohol withdrawal syndrome (AWS) in case of abrupt drinking cessation. Gamma hydroxybutyric acid (GHB) can prevent and suppress withdrawal symptoms, and improve the medium-term abstinence rate. A clear balance between effectiveness and harmfulness has not been yet established. OBJECTIVES: To evaluate the efficacy and safety of GHB for treatment of AWS and prevention of relapse SEARCH STRATEGY: We searched Cochrane Drugs and Alcohol Group' Register of Trials (October 2008), PubMed, EMBASE, CINAHL (January 2005 - October 2008), EconLIT (1969 to February 2008), reference list of retrieved articles SELECTION CRITERIA: Randomized controlled trials (RCTs) and Controlled Prospective Studies (CPS) evaluating the efficacy and the safety of GHB vs placebo or other pharmacological treatments. DATA COLLECTION AND ANALYSIS: Three authors independently extracted data and assessed the methodological quality of studies. MAIN RESULTS: Thirteen RCTs were included. Eleven studies were conducted in Italy.For withdrawal syndrome, comparing GHB 50mg with placebo, results from 1 study, 23 participants favour GHB for withdrawal symptoms: WMD -12.1 (95% CI, -15.9 to -8.29) and side effects were more frequent in the placebo group: RR 16.2 (95% CI, 1.04 to 254.9).In the comparison with Chlormetiazole, for GHB 50mg, results from 1 study, 21 participants favour GHB for withdrawal symptoms: MD -3.40 (95% CI -5.09 to 1.71), for GHB 100mg, results from 1 study, 98 participants favour anticonvulsants for side effects: RR 1.84 (95% CI 1.19 to 2.85).At mid-term, comparing GHB with placebo, results favour GHB for abstinence rate (RR 5.35; 1.28 22.4), controlled drinking (RR 2.13; 1.07-5.54), relapses (RR 0.36; 0.21-0.63), and number of daily drinks (WMD -4.60; -6.18 to -3.02). GHB performed better than NTX and Disulfiram on abstinence (RR 2.59; 1.35-4.98, RR 1.66; 0.99-2.80 respectively). The association of GHB and NTX was better than NTX on abstinence (RR 12.2; 1.79-83.9), as well was the association of NTX, GHB and Escitalopram versus Escitalopram alone (RR 4.58; 1.28-16.5). For Alcohol Craving Scale results favour GHB versus placebo (WMD -1.90; -2.45 to 1.35) and Disulfiram (WMD -1.40; 1.86 to-0.94). AUTHORS' CONCLUSIONS: GHB 50mg is effective compared to placebo in the treatment of AWS, and in preventing relapses in previously detoxified alcoholics at 3 months follow-up, but the results of this review do not provide sufficient evidence in favour of GHB compared to benzodiazepines and Chlormethiazole for AWS prevention. GHB is better than NTX and Disulfiram in maintaining abstinence and it has a better effect on craving than placebo and Disulfiram. Side effects of GHB are not statistically different from those with BZD, NTX or Disulfiram. However, concern has been raised regarding the risk of developing addiction, misuse or abuse, especially in polydrug abusers. PMID- 20166081 TI - Cyclophosphamide versus ifosfamide for paediatric and young adult bone and soft tissue sarcoma patients. AB - BACKGROUND: Alkylating agents, such as cyclophosphamide and ifosfamide, play a major role in the improved survival of children and young adults with bone and soft tissue sarcoma. However, there is still controversy as to their comparative anti-tumour efficacy and possible adverse effects. OBJECTIVES: To compare the possible effectiveness of cyclophosphamide with that of ifosfamide for paediatric and young adult patients with sarcoma. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2008, issue 4), MEDLINE/PubMed (from 1966 to November 2008) and EMBASE/Ovid (from 1980 to November 2008) with pre-specified terms. In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing cyclophosphamide and ifosfamide for the treatment of different types of sarcoma in paediatric and young adult patients (aged less than 30 years at diagnosis). Chemotherapy other than either cyclophosphamide or ifosfamide should have been the same in both treatment groups. DATA COLLECTION AND ANALYSIS: Two authors independently performed the study selection. MAIN RESULTS: No studies meeting the inclusion criteria of the review were identified. AUTHORS' CONCLUSIONS: No RCTs or CCTs comparing the effectiveness of cyclophosphamide and ifosfamide in the treatment of bone and soft tissue sarcoma in children and young adults were identified. Therefore no definitive conclusions can be made about the effects of cyclophosphamide and ifosfamide in these patients. Based on the currently available evidence we are not able to give recommendations for clinical practice. More high quality research is needed. PMID- 20166082 TI - Chest physiotherapy for pneumonia in adults. AB - BACKGROUND: Despite conflicting evidence, chest physiotherapy has been widely used as an adjunctive treatment for adults with pneumonia. OBJECTIVES: To assess the effectiveness and safety of chest physiotherapy for pneumonia in adults. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 3); MEDLINE (1966 to August 2009); EMBASE (1974 to August 2009); CBM (1978 to August 2009); the National Research Register (August 2009) and Physiotherapy Evidence Database (PEDro) (1929 to August 2009). SELECTION CRITERIA: Randomised controlled trials (RCTs) assessing the efficacy of chest physiotherapy for treating pneumonia in adults. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility, extracted data and appraised trial quality. Primary outcomes were mortality and cure rate. We used risk ratios (RR) and mean difference (MD) for individual trial results in the data analysis. We performed meta-analysis and measured all outcomes with 95% confidence intervals (CI). MAIN RESULTS: Six RCTs (434 participants) appraised four types of chest physiotherapy (conventional chest physiotherapy; osteopathic manipulative treatment (which includes paraspinal inhibition, rib raising and myofascial release); active cycle of breathing techniques (which include active breathing control, thoracic expansion exercises and forced expiration techniques); and positive expiratory pressure).None of the physiotherapies (versus no physiotherapy or placebo) improved mortality rates of adults with pneumonia.Conventional chest physiotherapy (versus no physiotherapy), active cycle of breathing techniques (versus no physiotherapy) and osteopathic manipulative treatment (versus placebo) did not increase the cure rate or chest X ray improvement rate.Osteopathic manipulative treatment (versus placebo) and positive expiratory pressure (versus no physiotherapy) reduced mean duration of hospital stay by 2.0 days (mean difference (MD) -2.0 days, 95% CI -3.5 to -0.6) and 1.4 days (MD -1.4 days, 95% CI -2.8 to -0.0), respectively. Conventional chest physiotherapy and active cycle of breathing techniques did not.Positive expiratory pressure (versus no physiotherapy) reduced fever duration (MD -0.7 day, 95% CI -1.4 to -0.0). Osteopathic manipulative treatment did not.Osteopathic manipulative treatment (versus placebo) reduced duration of intravenous (MD -2.1 days, 95% CI -3.4 to -0.9) and total antibiotic treatment (MD -1.9 days, 95% CI 3.1 to -0.7).Limitations of this review are that the studies addressing osteopathic manipulative treatment were small, and that the six published studies which appear to meet the inclusion criteria are awaiting classification. AUTHORS' CONCLUSIONS: Based on current limited evidence, chest physiotherapy might not be recommended as routine adjunctive treatment for pneumonia in adults. PMID- 20166083 TI - Antifungal therapy in infants and children with proven, probable or suspected invasive fungal infections. AB - BACKGROUND: Invasive fungal infections are associated with significant morbidity and mortality in children. Optimal treatment strategies are yet to be defined. OBJECTIVES: This review aims to systematically identify and summarise the effects of different antifungal therapies in children with proven, probable or suspected invasive fungal infections. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 3), MEDLINE (1966 to September 2008), EMBASE (1980 to September 2008) and CINAHL (1988 to September 2008) without language restrictions. We also handsearched reference lists and abstracts of conference proceedings and scientific meetings, and contacted authors of included studies and pharmaceutical manufacturers. SELECTION CRITERIA: We included randomised clinical trials (RCTs) comparing a systemic antifungal agent with a comparator (including placebo) in children (one month to 16 years) with proven, probable or suspected invasive fungal infection. DATA COLLECTION AND ANALYSIS: Two review authors independently applied selection criteria, performed quality assessment, and extracted data using an intention-to treat approach. We synthesised data using the random-effects model and expressed results as relative risks (RR) with 95% confidence intervals (CIs). MAIN RESULTS: We included seven trials of antifungal agents in children with prolonged fever and neutropenia (suspected fungal infection) and candidaemia or invasive candidiasis (proven fungal infection). Four trials compared a lipid preparation of amphotericin B with conventional amphotericin B (395 participants), one trial compared an echinocandin with a lipid preparation of amphotericin B (82 participants) in suspected infection; one trial compared an echinocandin with a lipid preparation of amphotericin B in children with candidaemia or invasive candidiasis (109 participants) and one trial compared different azole antifungals in children with candidaemia (43 participants). No difference in all-cause mortality and other primary endpoints (mortality related to fungal infection or complete resolution of fungal infections) were observed. No difference in breakthrough fungal infection was observed in children with prolonged fever and neutropenia.When lipid preparations and conventional amphotericin B were compared in children with prolonged fever and neutropenia, nephrotoxicity was less frequently observed with a lipid preparation (RR 0.43, 95% CI 0.21 to 0.90, P = 0.02) however substantial heterogeneity was observed (I(2) = 59%, P = 0.06). Children receiving liposomal amphotericin B were less likely to develop infusion related reactions compared with conventional amphotericin B (chills: RR 0.37, 95% CI 0.21 to 0.64, P = 0.0005). Children receiving a colloidal dispersion were more likely to develop such reactions than with liposomal amphotericin B (chills: RR 1.76, 95% CI 1.09 to 2.85, P = 0.02). The rate of other clinically significant adverse reactions attributed to the antifungal agent (total reactions; total reactions leading to treatment discontinuation, dose reduction or change in therapy; hypokalaemia and hepatotoxicity) were not significantly different. When echinocandins and lipid preparations were compared, the rate of clinically significant adverse reactions (total reactions; total reactions leading to treatment discontinuation, dose reduction or change in therapy) were not significantly different. AUTHORS' CONCLUSIONS: Limited paediatric data are available comparing antifungal agents in children with proven, probable or suspected invasive fungal infection. No differences in mortality or treatment efficacy were observed when antifungal agents were compared. Children are less likely to develop nephrotoxicity with a lipid preparation of amphotericin B compared with conventional amphotericin B. Further comparative paediatric antifungal drug trials and epidemiological and pharmacological studies are required highlighting the differences between neonates, children and adults with invasive fungal infections. PMID- 20166084 TI - WITHDRAWN: Home-based HIV voluntary counseling and testing in developing countries. AB - BACKGROUND: The low uptake of HIV voluntary counseling and testing (VCT), an effective HIV prevention intervention, has hindered global attempts to prevent new HIV infections, as well as limiting the scale-up of HIV care and treatment for the estimated 38 million infected persons. According to UNAIDS, only 10% of HIV-infected individuals worldwide are aware of their HIV status. At this point in the HIV epidemic, a renewed focus has shifted to prevention, and with it, a focus on methods to increase the uptake of HIV VCT. This review discusses home based HIV VCT delivery models, which, given the low uptake of facility-based testing models, may be an effective avenue to get more patients on treatment and prevent new infections. OBJECTIVES: (1) To identify and critically appraise studies addressing the implementation of home-based HIV voluntary counseling and testing in developing countries. (2) To determine whether home-based HIV voluntary counseling and testing (HBVCT) is associated with improvement in HIV testing outcomes compared to facility-based models. SEARCH STRATEGY: We searched online for published and unpublished studies in MEDLINE (February 2007), EMBASE (February 2007), CENTRAL (February 2007). We also searched databases listing conference proceedings and abstracts; AIDSearch (February 2007), The Cochrane Library (Issue 2, 2007), LILACS, CINAHL and Sociofile. We also contacted authors who have published on the subject of review. SELECTION CRITERIA: We searched for randomized controlled trials (RCTs) and non-randomized trials (e.g., cohort, pre/post-intervention and other observational studies) comparing home-based HIV VCT against other testing models. DATA COLLECTION AND ANALYSIS: We independently selected studies, assessed study quality and extracted data. We expressed findings as odds ratios (OR), and relative Risk (RR) together with their 95% confidence intervals (CI). MAIN RESULTS: We identified one cluster-randomized trial and one pre/post-intervention (cohort) study, which were included in the review. An additional two ongoing RCTs were identified. All identified studies were conducted in developing countries. The two included studies comprised one cluster-randomized trial conducted in an urban area in Lusaka, Zambia and one pre/post-intervention (cohort) study, part of a rural community cohort in Southwestern Uganda. The two studies, while differing in methodology, found very high acceptability and uptake of VCT when testing and or results were offered at home, compared to the standard (facility-based testing and results). In the cluster-randomized trial (n=849), subjects randomized to an optional testing location (including home-based testing) were 4.6 times more likely to accept VCT than those in the facility arm (RR 4.6, 95% CI 3.6-6.2). Similarly, in the pre/post study (n=1868) offering participants the option of home delivery of results increased VCT uptake. In the intervention year (home delivery) participants were 5.23 times more likely to receive their results than during the year when results were available only at the facility. (OR 5.23 95% CI 4.02-6.8). AUTHORS' CONCLUSIONS: Home-based testing and/or delivery of HIV test results at home, rather than in clinics, appears to lead to higher uptake in testing. However, given the limited extant literature and the limitations in the included existing studies, there is not sufficient evidence to recommend large-scale implementation of the home-based testing model. PMID- 20166086 TI - Zinc supplements for preventing otitis media. AB - BACKGROUND: Otitis media (inflammation of the middle ear, usually caused by infection) affects people of all ages, but is particularly common in young children. Around 164 million people worldwide have long-term hearing loss caused by this condition, 90% of them in low-income countries. Because zinc supplements prevent pneumonia in disadvantaged children, we wondered whether they prevent otitis media. OBJECTIVES: To evaluate whether zinc supplements prevent otitis media in adults and children of different ages. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 2) which includes the Acute Respiratory Infection Groups' Specialised Register; MEDLINE (1950 to June Week 1 2009); and EMBASE (1974 to June 2009). SELECTION CRITERIA: Randomised, placebo-controlled trials of zinc supplements given at least once a week for at least a month for preventing otitis media. DATA COLLECTION AND ANALYSIS: Two review authors assessed the eligibility and methodological quality of the included trials, extracted and analysed data and wrote the review. We summarised results using risk ratios or rate ratios for dichotomous data and mean differences for continuous data. We combined trial results where appropriate. MAIN RESULTS: We identified 12 trials for inclusion, 10 of which contributed outcomes data. In trials of healthy children living in low-income communities, two trials did not demonstrate a significant difference between the zinc supplemented and placebo groups in the numbers of participants experiencing an episode of definite otitis media during follow up (3191 participants), while another trial showed a significantly lower incidence rate of otitis media in the zinc group (rate ratio 0.69, 95% confidence interval (CI) 0.61 to 0.79, n = 1621). A small trial of 39 infants undergoing treatment for severe malnutrition suggested a benefit of zinc on the mean number of episodes of otitis media (mean difference -1.12 episodes, 95% CI -2.21 to -0.03). Zinc supplements did not seem to cause any serious adverse events, but a small minority of children were reported to have vomited shortly after ingestion of the supplements. AUTHORS' CONCLUSIONS: Evidence on whether zinc supplementation can reduce the incidence of otitis media in healthy children under the age of five years living in low- and middle-income countries is mixed. There is some evidence of benefit in children being treated for marasmus, but this is based on one small trial and should therefore be treated with caution. PMID- 20166087 TI - Cesarean delivery for the prevention of anal incontinence. AB - BACKGROUND: Caesarean delivery (CD) is a common form of delivery of a baby, rising in frequency. One reason for its performance is to preserve maternal pelvic floor function, part of which is anal continence. OBJECTIVES: To assess the ability of CD in comparison to vaginal delivery (VD) to preserve anal continence in a systematic review SEARCH STRATEGY: Search terms include: "Caesarean section, Cesarean delivery, vaginal delivery, incontinence and randomised". PubMed, EMBASE and the Cochrane Central Register of Controlled Trials (Central) were searched from their inception through July, 2009. SELECTION CRITERIA: Both randomised and non-randomised studies that allowed comparisons of post partum anal continence (both fecal and flatus) in women who had had babies delivered by either CD or VD were included. DATA COLLECTION AND ANALYSIS: Mode of delivery, and when possible mode of all previous deliveries prior to the index pregnancy were extracted, as well as assessment of continence post partum of both faeces and flatus. In Non-RCTs, available adjusted odds ratios were the primary end point sought. Incontinence of flatus is reported as a separate outcome. Summary odds ratios are not presented as no study was analysed as a randomised controlled trial. Numbers needed to treat (NNT) are presented, that is, the number of CDs needed to be performed to prevent a single case of fecal or flatus incontinence, for each individual study. Quality criteria were developed, selecting studies that allowed maternal age adjustment, studies that allowed a sufficient time after the birth of the baby for continence assessment and studies in which mode of delivery of prior pregnancies was known. Subgroup analyses were done selecting studies meeting all quality criteria and in comparisons of elective versus emergency CD, elective CD versus VD and nulliparous women versus those delivered by VD or CD, in each case again, not calculating a summary risk statistic. MAIN RESULTS: Twentyone reports have been found eligible for inclusion in the review, encompassing 31,698 women having had 6,028 CDs and 25,170 VDs as the index event prior to anal continence assessment . Only one report randomised women (with breech presentation) to CD or VD, but because of extensive crossing over, 52.1%, after randomisation, it was analysed along with the other 20 studies as treated, i.e. as a non-randomised trial. Only one of these reports demonstrated a significant benefit of CD in the preservation of anal continence, a report in which incontinence incidence was extremely high, 39% in CD and 48% in VD, questioning, relative to other reports, the timing and nature of continence assessment. The greater the quality of the report, the closer its Odds ratio approached 1.0. There was no difference in continence preservation in women have emergency versus elective CD. AUTHORS' CONCLUSIONS: Without demonstrable benefit, preservation of anal continence should not be used as a criterion for choosing elective primary CD. The strength of this conclusion would be greatly strengthened if there were studies that randomised women with average risk pregnancies to CD versus VD. PMID- 20166085 TI - Neuroprotection for treatment of glaucoma in adults. AB - BACKGROUND: Glaucoma is a heterogeneous group of conditions involving progressive damage to the optic nerve, deterioration of retinal ganglion cells and ultimately visual field loss. It is a leading cause of blindness worldwide. Open angle glaucoma (OAG), the commonest form of glaucoma, is a chronic condition that may or may not present with increased intraocular pressure (IOP). Neuroprotection for glaucoma refers to any intervention intended to prevent optic nerve damage or cell death. The treatment can target extracellular factors such as reducing IOP, or cellular factors derived from the optic nerve itself such as blocking intracellular death signals. OBJECTIVES: The objective of this review was to systematically examine the evidence regarding the effectiveness of neuroprotective agents, either topical or oral, for slowing the progression of OAG in adults. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library, Issue 4, 2009), MEDLINE (January 1960 to January 2010), EMBASE (January 1980 to January 2010), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to January 2010) and ClinicalTrials.gov (http://clinicaltrials.gov). (5 January 2010). There were no language or date restrictions in the search for trials. The electronic databases were last searched on 5 January 2010. SELECTION CRITERIA: This review was limited to randomized controlled trials (RCTs) in which topical or oral treatments were used to prevent retinal ganglion cell death. Our population of interest was adults with OAG. As the primary outcome for this review was the proportion of participants who developed any progression of visual field loss at five years post intervention, only trials with at least five years of follow-up were included. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed titles and abstracts from the literature searches. Full text copies of relevant or potentially relevant studies were obtained and re-evaluated for inclusion. There were no trials identified for this review, thus we performed no data extraction or meta-analysis. Two studies comparing memantine to placebo are currently awaiting classification until additional study details are provided. Reasons for excluding studies from the review were documented. MAIN RESULTS: In accordance with the selection criteria for inclusion, we identified no studies relevant for this review. The results of short-term trials and other studies are discussed in this review. AUTHORS' CONCLUSIONS: Although neuroprotective agents are intended to act as pharmacological antagonists to prevent cell death, the evidence that they are effective in preventing retinal ganglion cell death, and thus preserving vision in patients with OAG, has not been demonstrated. Long-term RCTs are needed to determine whether or not neuroprotective agents may be beneficial for individuals with OAG. PMID- 20166088 TI - Tirilazad for aneurysmal subarachnoid haemorrhage. AB - BACKGROUND: Delayed cerebral ischaemia is a significant contributor to poor outcome (death or disability) in patients with aneurysmal subarachnoid haemorrhage (SAH). Tirilazad is considered to have neuroprotective properties in animal models of acute cerebral ischaemia. OBJECTIVES: To assess the efficacy and safety of tirilazad in patients with aneurysmal SAH. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched October 2009); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2009); MEDLINE (1966 to October 2009); EMBASE (1980 to October 2009); and the Stroke Trials Directory, the National Center for Complementary and Alternative Medicine, and the National Institute of Health Clinical Trials Database (searched October 2009). We handsearched 10 Chinese journals, searched the reference lists of relevant publications, and contacted the manufacturers of tirilazad. SELECTION CRITERIA: Randomised trials of tirilazad started within four days of SAH onset, compared with placebo or open control in patients with aneurysmal SAH documented by angiography and computerised tomography (CT) scan or cerebrospinal fluid examination, or both. DATA COLLECTION AND ANALYSIS: We extracted data relating to case fatality, poor outcome (death, vegetative state, or severe disability), delayed cerebral ischaemia (or symptomatic vasospasm), cerebral infarction and adverse events of treatments. We pooled the data using the Peto fixed-effect method for dichotomous data. MAIN RESULTS: We included five double-blind, placebo-controlled trials involving 3821 patients; there was no significant heterogeneity. Oral or intravenous nimodipine was used routinely as a background treatment in both groups in all trials. There was no significant difference between the two groups at the end of follow up for the primary outcome, death (odds ratio (OR) 0.89, 95% confidence interval (CI) 0.74 to 1.06), or in poor outcome (death, vegetative state or severe disability) (OR 1.04, 95% CI 0.90 to 1.21). During the treatment period, fewer patients developed delayed cerebral ischaemia in the tirilazad group than in the control group (OR 0.80, 95% CI 0.69 to 0.93). Subgroup analyses did not demonstrate any significant difference in effects of tirilazad on clinical outcomes. Leukocytosis and prolongation of Q-T interval occurred significantly more frequently in the treatment group in only one trial evaluating tirilazad at high dose. There was no significant difference in infusion site disorders or other laboratory parameters between the two groups. AUTHORS' CONCLUSIONS: There is no evidence that tirilazad, in addition to nimodipine, reduces mortality or improves poor outcome in patients with aneurysmal SAH. PMID- 20166089 TI - Heliox for croup in children. AB - BACKGROUND: Croup, a common acute clinical syndrome in children up to the age of six, is thought to be triggered by a viral infection, and is characterised by a varying degree of respiratory distress due to upper airway inflammation and oedema of the subglottic mucosa. Corticosteroids, now part of the standard treatment for croup, improve symptoms but it takes time for their full effect to be achieved. Meanwhile, the child remains at risk of deterioration and developing respiratory failure necessitating emergency intubation and ventilation. Helium oxygen (heliox) inhalation has been successful in the treatment of upper airway obstruction. Anecdotal evidence suggests that heliox relieves respiratory distress in children, but it remains unclear whether there is robust evidence to support the implementation of heliox for croup into clinical practice. OBJECTIVES: To examine the effect of heliox on relieving symptoms and distress, determined by a croup score (a tool for measuring the severity of croup) or clinical assessment variables, through comparisons with placebo or active treatment(s) in children with croup. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 2) which contains the Acute Respiratory Infections (ARI) Group's Specialised Register; MEDLINE (1950 to June week 3 2009); EMBASE (1974 to 2009 week 25) and CINAHL (1982 to June 2009). SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing the effect of helium-oxygen mixtures with placebo or any active treatment in children with croup. DATA COLLECTION AND ANALYSIS: Both authors independently identified and assessed citations for relevance. We assessed included trials for risk of bias using allocation concealment, blinding of intervention, completeness of outcome data, selective outcome reporting and other potential source of bias. We calculated mean differences for continuous data. We presented data not suitable for statistical analysis as descriptive data. MAIN RESULTS: Two eligible RCTs were included (22 intervention, 22 controls). Neither trial compared heliox inhalation with placebo. One study compared heliox with 30% humidified oxygen whilst the other compared it to 100% oxygen with additional racaemic epinephrine nebulisation. There was no significant difference in change of croup score between intervention and control groups. AUTHORS' CONCLUSIONS: At present there is a lack of evidence to establish the effect of heliox inhalation in the treatment of croup in children. A methodologically well-designed and adequately powered RCT is needed to assess whether there is a role for heliox therapy in the management of children with croup. PMID- 20166090 TI - Interventions for increasing ankle range of motion in patients with neuromuscular disease. AB - BACKGROUND: Reduced ankle dorsiflexion range of motion, or ankle equinus, is a common and disabling problem for patients with neuromuscular disease. Clinicians devote considerable time and resources implementing interventions to correct this problem although few of these interventions have been subject to rigorous empirical investigation. OBJECTIVES: To assess the effect of interventions to reduce or resolve ankle equinus in people with neuromuscular disease. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Specialized Register (August 2009), Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2009), MEDLINE (1966 to August 2009), EMBASE (1980 to August 2009), CINAHL 1982 to August 2009), AMED (1985 to August 2009) and The Physiotherapy Evidence Database (PEDro) (1929 to August 2009). We searched the reference lists of identified articles and also contacted known experts in the field to identify additional or unpublished data. SELECTION CRITERIA: Randomised controlled trials evaluating interventions for increasing ankle dorsiflexion range of motion in neuromuscular disease. Outcomes included ankle dorsiflexion range of motion, functional improvement, foot alignment, foot and ankle muscle strength, health-related quality of life, satisfaction with the intervention and adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently selected papers, assessed trial quality and extracted data. MAIN RESULTS: Four studies involving 149 participants met inclusion criteria for this review. Two studies assessed the effect of night splinting in a total of 26 children and adults with Charcot-Marie-Tooth disease type 1A. There were no statistically or clinically significant differences between wearing a night splint and not wearing a night splint. One study assessed the efficacy of prednisone treatment in 103 boys with Duchenne muscular dystrophy. While a daily dose of prednisone at 0.75 mg/kg/day resulted in significant improvements in some strength and function parameters compared with placebo, there was no significant difference in ankle range of motion between groups. Increasing the prednisone dose to 1.5 mg/kg/day had no significant effect on ankle range of motion. One study evaluated early surgery in 20 young boys with Duchenne muscular dystrophy. Surgery resulted in increased ankle dorsiflexion range at 12 months but functional outcomes favoured the control group. By 24 months, many boys in the surgical group experienced a relapse of achilles tendon contractures. AUTHORS' CONCLUSIONS: There is no evidence of significant benefit from any intervention for increasing ankle range of motion in Charcot-Marie-Tooth disease type 1A or Duchenne muscular dystrophy. Further research is required. PMID- 20166091 TI - Cervical preparation for first trimester surgical abortion. AB - BACKGROUND: Preparing the cervix prior to surgical abortion is intended to make the procedure both easier and safer. Options for cervical preparation include osmotic dilators and pharmacologic agents. Many formulations and regimens are available, and recommendations from professional organizations vary for the use of preparatory techniques in women of different ages, parity or gestational age of the pregnancy. OBJECTIVES: To determine whether cervical preparation is necessary in the first trimester, and if so, which preparatory agent is preferred. SEARCH STRATEGY: We searched Cochrane, Popline, Embase, Medline and Lilacs databases for randomised controlled trials investigating the use of cervical preparatory techniques prior to first trimester surgical abortion. In addition, we hand-searched key references and contacted authors to locate unpublished studies or studies not identified in the database searches. SELECTION CRITERIA: Randomised controlled trials investigating any pharmacologic or mechanical method of cervical preparation, with the exception of nitric oxide donors (the subject of another Cochrane review), administered prior to first trimester surgical abortion were included. Outcome measures must have included the amount of cervical dilation achieved, the procedure duration or difficulty, side-effects, patient satisfaction or adverse events to be included in this review. DATA COLLECTION AND ANALYSIS: Trials under consideration were evaluated by considering whether inclusion criteria were met as well as methodologic quality. Fifty-one studies were included, resulting in 24 different cervical preparation comparisons. Results are reported as odds ratios (OR) for dichotomous outcomes and weighted mean differences for continuous data. MAIN RESULTS: When compared to placebo, misoprostol (400-600 microg given vaginally or sublingually), gemeprost, mifepristone (200 or 600 mg), prostaglandin E and F(2alpha) (2.5 mg administered intracervically) demonstrated larger cervical preparation effects. When misoprostol was compared to gemeprost, misoprostol was more effective in preparing the cervix and was associated with fewer gastrointestinal side-effects. For vaginal administration, administration 2 hours prior was less effective than administration 3 hours prior to the abortion. Compared to oral misoprostol administration, the vaginal route was associated with significantly greater initial cervical dilation and lower rates of side effects; however, sublingual administration 2-3 hours prior to the procedure demonstrated cervical effects superior to vaginal administration.When misoprostol (600 microg oral or 800 microg vaginal) was compared to mifepristone (200 mg administered 24 hours prior to procedure), misoprostol had inferior cervical preparatory effects. Compared to day-prior laminaria tents, 200 or 400 microg vaginal misoprostol showed no differences in the need for further mechanical dilation or length of the procedure; similarly, the osmotic dilators Lamicel and Dilapan showed no differences in cervical ripening when compared to gemeprost, although gemeprost had cervical effects which were superior to laminaria tents. Older prostaglandin regimens (sulprostone, prostaglandin E(2) andF(2alpha)) were associated with high rates of gastrointestinal side-effects and unplanned pregnancy expulsions. Few studies reported women's satisfaction with cervical preparatory techniques. AUTHORS' CONCLUSIONS: Modern methods of cervical ripening are generally safe, although efficacy and side-effects between methods vary. Reports of adverse events such as cervical laceration or uterine perforation are uncommon overall in this body of evidence and no published study has investigated whether cervical preparation impacts these rare outcomes. Cervical preparation decreases the length of the abortion procedure; this may become increasingly important with increasing gestational age, as mechanical dilation at later gestational ages takes longer and becomes more difficult. These data do not suggest a gestational age where the benefits of cervical dilation outweigh the side-effects, including pain, that women experience with cervical ripening procedures or the prolongation of the time interval before procedure completion. Mifepristone 200 mg, osmotic dilators and misoprostol, 400microg administered either vaginally or sublingually, are the most effective methods of cervical preparation. PMID- 20166092 TI - Enhanced external counterpulsation for chronic angina pectoris. AB - BACKGROUND: Cardiovascular disease is a major cause of death in developed and developing countries. Refractory stable angina pectoris is, in general, inadequately responsive to conventional medical therapy.Enhanced external counterpulsation is a non-invasive treatment for patients with refractory angina and involves the placing of compressible cuffs around the calves and lower and upper thighs. These are inflated sequentially so that during early diastole they help propel blood back to the heart and when deflated at end of diastole allow the blood vessels to return to their normal state. It is claimed that enhanced external counterpulsation can help reduce aortic impedance and thereby alleviate some of the symptoms of angina. OBJECTIVES: To assess the effects of enhanced external counterpulsation therapy in improving health outcomes for patients with chronic stable or refractory stable angina pectoris. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (2008, Issue 1), MEDLINE (1966 to February 2008), EMBASE (1980 to February 2008), LILACS via BIREME (to February 2008) and ISI Science Citation Index on Web of Science (to February 2008). No language restrictions were applied. SELECTION CRITERIA: Randomized controlled trials and cluster-randomized trials comparing enhanced external counterpulsation therapy to sham treatment in adults, aged over 18 years, with chronic stable and stable refractory angina pectoris graded Canadian Cardiovascular Society Class III to IV at baseline. DATA COLLECTION AND ANALYSIS: Two authors independently screened papers, extracted trial details and assessed risk of bias. MAIN RESULTS: One trial (139 participants) was included in this review. Poor methodological quality, in terms of trial design and conduct, incompleteness in reporting of the review's primary outcome, limited follow up for the secondary outcomes and subsequent flawed statistical analysis, compromised the reliability of the reported data. AUTHORS' CONCLUSIONS: We found one relevant trial which failed to address the characteristics of interest satisfactorily, in terms of severity of angina, for the participants in this review. Participants with the most severe symptoms of angina were excluded, therefore the results of this study represent only a subsection of the broader population with the disorder, are not generalizable and provide inconclusive evidence for the effectiveness of enhanced external counterpulsation therapy for chronic angina pectoris. PMID- 20166093 TI - Carnitine for fatigue in multiple sclerosis. AB - BACKGROUND: Fatigue is reported to occur in up to 92% of patients with multiple sclerosis (MS) and has been described as the most debilitating of all MS symptoms by 28% to 40% of MS patients. OBJECTIVES: To assess whether carnitine (enteral or intravenous) supplementation can improve the quality of life and reduce the symptoms of fatigue in patients with MS-related fatigue and to identify any adverse effects of carnitine when used for this purpose. SEARCH STRATEGY: A literature search was performed using Cochrane MS Group Trials Register (21 May 2009), Cochrane Central Register of Controlled Trials (CENTRAL) "The Cochrane Library 2009, issue 2, MEDLINE (PubMed) (1966-21 May 2009), EMBASE (1974-21 May 2009). Reference lists of review articles and primary studies were also screened. A hand search of the abstract book of recent relevant conference symposia was also conducted. Personal contact with MS experts and a manufacturer (Source Naturals, United States) of carnitine formulation was contacted to determine if they knew of other clinical trials. No language restrictions were applied. SELECTION CRITERIA: Full reports of published and unpublished randomized controlled trials and quasi-randomized trials of any carnitine intervention in adults with a clinical diagnosis of fatigue associated with multiple sclerosis were included. DATA COLLECTION AND ANALYSIS: Data from the eligible trials was extracted and coded using a standardized data extraction form and entered into RevMan 5. Discrepancies were to be resolved by discussion with a third reviewer however this was not necessary. The quality items to be assessed were method of randomization, allocation concealment, blinding (participants, investigators, outcome assessors and data analysis), intention-to-treat analysis and completeness of follow up. MAIN RESULTS: The search identified one randomized cross-over trial. In this study patients were exposed to both acetyl L-carnitine (ALCAR(tm)) 2 grams daily and amantadine 200 mg daily in adult patients with relapsing-remitting and secondary progressive MS. The effects of carnitine on fatigue are not clear based on the one included crossover RCT. There was no difference between carnitine and amantadine for the number of patients withdrawing from the study due to an adverse event (relative risk ratio 0.20; 95% confidence interval 0.03 to 1.55. Mortality, serious adverse events, total adverse events, and quality of life were not reported. AUTHORS' CONCLUSIONS: There is insufficient evidence that carnitine for the treatment of MS-related fatigue offers a therapeutic advantage over placebo or active comparators. PMID- 20166094 TI - Efficacy of psychostimulant drugs for cocaine dependence. AB - BACKGROUND: Cocaine dependence is an increasingly prevalent disorder for which no medication is approved yet. Likewise opioid for heroin dependence, replacement therapy with psychostimulant could be efficacious for cocaine dependence. OBJECTIVES: To ascertain the efficacy of psychostimulants for cocaine dependence on cocaine use, sustained cocaine abstinence and retention in treatment. The influence of type of drug, comorbid disorders and clinical trial reporting quality over psychostimulants efficacy has also been studied. SEARCH STRATEGY: MEDLINE, EMBASE, PsycINFO, CENTRAL, references of obtained articles and experts in the field. SELECTION CRITERIA: Randomized parallel group controlled clinical trials comparing the efficacy of a psychostimulant against placebo have been included. DATA COLLECTION AND ANALYSIS: Two authors evaluated and extracted data. The Relative Risk (RR) was used to assess dichotomous outcomes except for adverse event (AE) induced dropouts for which the risk difference (RD) was preferred. The Standardized Mean Difference (SMD) was used to assess continuous outcomes. To determine the influence of moderating variables, a stratified analysis was conducted. Funnel plots were drawn to investigate the possibility of publication bias. MAIN RESULTS: Sixteen studies have been included, which have enrolled 1,345 patients. Seven drugs with psychostimulant effect or metabolized to a psychostimulant have been investigated: bupropion, dexamphetamine, methylphenidate, modafinil, mazindol, methamphetamine and selegiline. Psychostimulants did not reduce cocaine use (SMD 0.11, 95%CI: -0.07 to 0.29), showed a statistical trend over improving sustained cocaine abstinence (RR 1.41, 95%CI: 0.98 to 2.02, p=0.07) and did not improve retention in treatment (RR 0.97, 95%CI: 0.89 to 1.05). The proportion of AE induced dropouts was similar for psychostimulants and placebo (RD 0.01, 95%CI: -0.02 to 0.03). When the type of drug was included as a moderating variable, it was shown that the proportion of patients achieving sustained cocaine abstinence was higher with bupropion and dextroamphetamine, and also with modafinil, at a statistical trend of significance, than with placebo. Nevertheless, no studied drug was efficacious on any of the remaining outcomes. Besides, psychostimulants appeared to increase the proportion of patients achieving sustained cocaine and heroin abstinence amongst methadone maintained dual heroin-cocaine addicts. The main findings did not seem to be influenced by clinical trial reporting quality. No evidence of publication bias was found. AUTHORS' CONCLUSIONS: This review found mixed results, therefore evidence of the efficacy of psychostimulants for cocaine dependence is inconclusive. Nevertheless promising results exist for methadone maintained dual heroin-cocaine addicts and for some specific drugs such as dexamphetamine and bupropion. PMID- 20166095 TI - Physical examination for lumbar radiculopathy due to disc herniation in patients with low-back pain. AB - BACKGROUND: Low-back pain with leg pain (sciatica) may be caused by a herniated intervertebral disc exerting pressure on the nerve root. Most patients will respond to conservative treatment, but in carefully selected patients, surgical discectomy may provide faster relief of symptoms. Primary care clinicians use patient history and physical examination to evaluate the likelihood of disc herniation and select patients for further imaging and possible surgery. OBJECTIVES: (1) To assess the performance of tests performed during physical examination (alone or in combination) to identify radiculopathy due to lower lumbar disc herniation in patients with low-back pain and sciatica;(2) To assess the influence of sources of heterogeneity on diagnostic performance. SEARCH STRATEGY: We searched electronic databases for primary studies: PubMed (includes MEDLINE), EMBASE, and CINAHL, and (systematic) reviews: PubMed and Medion (all from earliest until 30 April 2008), and checked references of retrieved articles. SELECTION CRITERIA: We considered studies if they compared the results of tests performed during physical examination on patients with back pain with those of diagnostic imaging (MRI, CT, myelography) or findings at surgery. DATA COLLECTION AND ANALYSIS: Two review authors assessed the quality of each publication with the QUADAS tool, and extracted details on patient and study design characteristics, index tests and reference standard, and the diagnostic two-by two table. We presented information on sensitivities and specificities with 95% confidence intervals (95% CI) for all aspects of physical examination. Pooled estimates of sensitivity and specificity were computed for subsets of studies showing sufficient clinical and statistical homogeneity. MAIN RESULTS: We included 16 cohort studies (median N = 126, range 71 to 2504) and three case control studies (38 to100 cases). Only one study was carried out in a primary care population. When used in isolation, diagnostic performance of most physical tests (scoliosis, paresis or muscle weakness, muscle wasting, impaired reflexes, sensory deficits) was poor. Some tests (forward flexion, hyper-extension test, and slump test) performed slightly better, but the number of studies was small. In the one primary care study, most tests showed higher specificity and lower sensitivity compared to other settings.Most studies assessed the Straight Leg Raising (SLR) test. In surgical populations, characterized by a high prevalence of disc herniation (58% to 98%), the SLR showed high sensitivity (pooled estimate 0.92, 95% CI: 0.87 to 0.95) with widely varying specificity (0.10 to 1.00, pooled estimate 0.28, 95% CI: 0.18 to 0.40). Results of studies using imaging showed more heterogeneity and poorer sensitivity. The crossed SLR showed high specificity (pooled estimate 0.90, 95% CI: 0.85 to 0.94) with consistently low sensitivity (pooled estimate 0.28, 95% CI: 0.22 to 0.35).Combining positive test results increased the specificity of physical tests, but few studies presented data on test combinations. AUTHORS' CONCLUSIONS: When used in isolation, current evidence indicates poor diagnostic performance of most physical tests used to identify lumbar disc herniation. However, most findings arise from surgical populations and may not apply to primary care or non-selected populations. Better performance may be obtained when tests are combined. PMID- 20166096 TI - Laparoscopic versus open surgery in small bowel obstruction. AB - BACKGROUND: Acute intestinal obstruction is one of the most common surgical emergencies. The small bowel obstruction (SBO) is the site of obstruction in most patients (76%) and adhesions are the most common etiology (65%). Laparoscopy in SBO has no clear role yet as it may have a therapeutic and diagnostic function. In some settings laparoscopic or laparoscopy-assisted surgery is considered feasible and convenient more than conventional surgery for SBO; however little is known if laparoscopic or laparoscopy-assisted surgery is more suitable with respect to open surgery for patients with SBO. OBJECTIVES: The aim of this systematic review is to assess whether laparoscopic or laparoscopy-assisted surgery is feasible and safe for acute SBO, and whether laparoscopic and laparoscopy-assisted surgery present advantages compared to open surgery in terms of short-term and long-term outcomes. SEARCH STRATEGY: We searched for published randomised and prospective controlled clinical trials without language restrictions using the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950 onwards) and EMBASE (1980 onwards). SELECTION CRITERIA: Randomised controlled trials and non randomised controlled prospective trials evaluating laparoscopic and laparoscopy-assisted surgery versus traditional open surgery for acute SBO were considered. DATA COLLECTION AND ANALYSIS: We conducted the review according to the recommendations of The Cochrane Collaboration and the Cochrane Colorectal Group as well, using Review Manager 5 to conduct the review. MAIN RESULTS: No published or unpublished randomised controlled trials or prospective controlled clinical trials comparing laparoscopy with open surgery for patients with SBO were identified. AUTHORS' CONCLUSIONS: Although data from retrospective clinical controlled trials suggest that laparoscopy seems feasible and better in terms of hospital stay and mortality reduction, high quality randomised controlled trials assessing all clinically relevant outcomes including overall mortality, morbidity, hospital stay and conversion are needed. PMID- 20166097 TI - Singing for children and adults with bronchiectasis. AB - BACKGROUND: Bronchiectasis is a common respiratory disease, especially in developing countries. Its cause varies from chronic infection to rare immune deficiencies. Bronchiectasis can be present with other respiratory diseases, such as chronic obstructive pulmonary disease (COPD). People with bronchiectasis may suffer from chronic cough, fatigue, shortness of breath, chest pain and coughing up blood. Their lung function may decline with time. These can also have a negative impact on their quality of life. Thus, a holistic management is needed to provide treatment and support. Therapies which include breathing manoeuvres, such as singing, may have health benefits for respiratory function and psychological well being. OBJECTIVES: To evaluate the effects of a singing intervention as a therapy on the quality of life, morbidity, respiratory muscle strength and pulmonary function of children and adults with bronchiectasis. SEARCH STRATEGY: We searched the Cochrane Airways Group (CAG) trials register, the Cochrane Central Register of Controlled Trials, major allied complementary databases, and clinical trials registers. Professional organisations and individuals were also contacted. CAG performed searches in February, and additional searches were carried out in June 2009. SELECTION CRITERIA: Randomised controlled trials in which singing (as an intervention) is compared with either a sham intervention or no singing in patients with bronchiectasis. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed the titles, abstracts and citations to assess potential relevance for full review. No eligible trials were identified and thus no data were available for analysis. MAIN RESULTS: No meta analysis could be performed. AUTHORS' CONCLUSIONS: In the absence of data, we cannot draw any conclusion to support or refute the adoption of singing as an intervention for people with bronchiectasis. Given the simplicity of the potentially beneficial intervention, future randomised controlled trials are required to evaluate singing therapy for people with bronchiectasis. PMID- 20166098 TI - Palivizumab for prophylaxis against respiratory syncytial virus infection in children with cystic fibrosis. AB - BACKGROUND: Respiratory syncytial virus (RSV) infection causes acute lung infection in infants and young children worldwide, resulting in considerable morbidity and mortality. Children with cystic fibrosis (CF) are prone to recurrent lung inflammation, bacterial colonisation and subsequent chronic airway disease, putting them at risk for severe RSV infections requiring intensive care and respiratory support. No treatment currently exists, hence prevention is important. Palivizumab is effective in reducing RSV hospitalisation rates and is recommended for prophylaxis in high-risk children with other conditions. It is unclear if palivizumab can prevent RSV hospitalisations and intensive care unit admissions in children with CF. OBJECTIVES: To determine the efficacy and safety of palivizumab (Synagis((R))) compared with placebo, no prophylaxis or other prophylaxis, in preventing hospitalisation and mortality from RSV infection in children with CF. SEARCH STRATEGY: We searched the Cochrane CF and Genetic Disorders Group Trials Register and scanned references of the eligible study and related reviews.Last search: 20 January 2010. SELECTION CRITERIA: Randomised and quasi-randomised studies. DATA COLLECTION AND ANALYSIS: The authors independently extracted data and assessed risk of bias. MAIN RESULTS: One study (186 infants up to two years old) comparing five monthly doses of palivizumab (N=92) to placebo (N=94) over one RSV season was identified and met our inclusion criteria. At six months follow-up, one participant in each group was hospitalised due to RSV; there were no deaths in either group. In the palivizumab and placebo groups, 86 and 90 children experienced any adverse event, while 5 and 4 children had related adverse events respectively. Nineteeen children receiving palivizumab and 16 receiving placebo suffered serious adverse events; one participant receiving palivizumab discontinued due to this. At 12 months follow-up, there were no significant differences between groups in number of Pseudomonas bacterial colonisations or change in weight-to-height ratio. AUTHORS' CONCLUSIONS: We identified one randomised controlled trial comparing five monthly doses of palivizumab to placebo in infants up to two years old with CF. While the overall incidence of adverse events was similar in both groups, it is not possible to draw conclusions on the safety and tolerability of RSV prophylaxis with palivizumab in infants with CF because the trial did not specify how adverse events were classified. Six months after treatment, the authors reported no clinically meaningful differences in outcomes; however no data were provided. Additional randomised studies are needed to establish the safety and efficacy of palivizumab in children with CF. PMID- 20166099 TI - Momordica charantia for type 2 diabetes mellitus. AB - BACKGROUND: Momordica charantia is not only a nutritious vegetable, but is also used in traditional medical practices to treat type 2 diabetes mellitus. Experimental studies with animals and humans suggested that the vegetable has a possible role in glycaemic control. OBJECTIVES: To assess the effects of mormodica charantia for type 2 diabetes mellitus. SEARCH STRATEGY: Several electronic databases were searched, among these The Cochrane Library (issue 4, 2009), MEDLINE, EMBASE, CINAHL, SIGLE and LILACS (all up to November 2009), combined with handsearches. No language restriction was used. SELECTION CRITERIA: Randomized controlled trials that compared momordica charantia with a placebo or a control intervention with or without pharmacological or non-pharmacological interventions were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data. Risk of bias of trials was evaluated using the parameters of randomization, allocation concealment, blinding, completeness of outcome data, selective reporting and other potential sources of bias. A meta analysis was not performed given the quality of data and the variability of preparations of momordica charantia used in interventions (no similar preparation was tested twice). MAIN RESULTS: Three randomised controlled trials with up to three months duration and investigating 350 participants met the inclusion criteria. Risk of bias of these trials (only one study was published as a full peer-reviewed publication) was generally high. Two RCTs compared the effect of preparations from different parts of the momordica charantia plants and placebo on the glycemic control in type 2 diabetes mellitus. There was no statistically significant difference compared to placebo. The effects of preparation from the leaves of the plant and glibenclamide were comparable in the third trial. No serious adverse effects were reported in all the trials. There were no documentations of death from any cause, morbidity, (health-related) quality of life and costs. AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend momordica charantia for type 2 diabetes mellitus. Further studies are therefore required to address the issues of standardization and the quality control of preparations. For medical nutritional therapy, further observational trials evaluating the effects of momordica charantia are needed before RCTs are established to guide any recommendations in clinical practice. PMID- 20166100 TI - Flexible working conditions and their effects on employee health and wellbeing. AB - BACKGROUND: Flexible working conditions are increasingly popular in developed countries but the effects on employee health and wellbeing are largely unknown. OBJECTIVES: To evaluate the effects (benefits and harms) of flexible working interventions on the physical, mental and general health and wellbeing of employees and their families. SEARCH STRATEGY: Our searches (July 2009) covered 12 databases including the Cochrane Public Health Group Specialised Register, CENTRAL; MEDLINE; EMBASE; CINAHL; PsycINFO; Social Science Citation Index; ASSIA; IBSS; Sociological Abstracts; and ABI/Inform. We also searched relevant websites, handsearched key journals, searched bibliographies and contacted study authors and key experts. SELECTION CRITERIA: Randomised controlled trials (RCT), interrupted time series and controlled before and after studies (CBA), which examined the effects of flexible working interventions on employee health and wellbeing. We excluded studies assessing outcomes for less than six months and extracted outcomes relating to physical, mental and general health/ill health measured using a validated instrument. We also extracted secondary outcomes (including sickness absence, health service usage, behavioural changes, accidents, work-life balance, quality of life, health and wellbeing of children, family members and co-workers) if reported alongside at least one primary outcome. DATA COLLECTION AND ANALYSIS: Two experienced review authors conducted data extraction and quality appraisal. We undertook a narrative synthesis as there was substantial heterogeneity between studies. MAIN RESULTS: Ten studies fulfilled the inclusion criteria. Six CBA studies reported on interventions relating to temporal flexibility: self-scheduling of shift work (n = 4), flexitime (n = 1) and overtime (n = 1). The remaining four CBA studies evaluated a form of contractual flexibility: partial/gradual retirement (n = 2), involuntary part-time work (n = 1) and fixed-term contract (n = 1). The studies retrieved had a number of methodological limitations including short follow-up periods, risk of selection bias and reliance on largely self-reported outcome data. Four CBA studies on self-scheduling of shifts and one CBA study on gradual/partial retirement reported statistically significant improvements in either primary outcomes (including systolic blood pressure and heart rate; tiredness; mental health, sleep duration, sleep quality and alertness; self-rated health status) or secondary health outcomes (co-workers social support and sense of community) and no ill health effects were reported. Flexitime was shown not to have significant effects on self-reported physiological and psychological health outcomes. Similarly, when comparing individuals working overtime with those who did not the odds of ill health effects were not significantly higher in the intervention group at follow up. The effects of contractual flexibility on self reported health (with the exception of gradual/partial retirement, which when controlled by employees improved health outcomes) were either equivocal or negative. No studies differentiated results by socio-economic status, although one study did compare findings by gender but found no differential effect on self reported health outcomes. AUTHORS' CONCLUSIONS: The findings of this review tentatively suggest that flexible working interventions that increase worker control and choice (such as self-scheduling or gradual/partial retirement) are likely to have a positive effect on health outcomes. In contrast, interventions that were motivated or dictated by organisational interests, such as fixed-term contract and involuntary part-time employment, found equivocal or negative health effects. Given the partial and methodologically limited evidence base these findings should be interpreted with caution. Moreover, there is a clear need for well-designed intervention studies to delineate the impact of flexible working conditions on health, wellbeing and health inequalities. PMID- 20166101 TI - Somatostatin analogues for pancreatic surgery. AB - BACKGROUND: Pancreatic resections are associated with high morbidity (30% to 60%) and mortality (5%). Synthetic analogues of somatostatin are advocated by some surgeons to reduce complications following pancreatic surgery, however their use is controversial. OBJECTIVES: To determine whether prophylactic somatostatin analogues should be used routinely in pancreatic surgery. SEARCH STRATEGY: We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 4), MEDLINE, EMBASE and Science Citation Index Expanded to November 2009. SELECTION CRITERIA: We included randomised controlled trials comparing prophylactic somatostatin or one of its analogues versus no drug or placebo during pancreatic surgery (irrespective of language or publication status). DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for inclusion and independently extracted data. We analysed data with both the fixed-effect and the random-effects models using Review Manager (RevMan). We calculated the risk ratio (RR), mean difference (MD) or standardised mean difference (SMD) with 95% confidence intervals (CI) based on an intention-to treat or available case analysis. When it was not possible to perform either of the above, we performed per protocol analysis. MAIN RESULTS: We identified 17 trials (of high risk of bias) involving 2143 patients. The overall number of patients with postoperative complications was lower in the somatostatin analogue group (RR 0.71; 95% CI 0.62 to 0.82) but there was no difference in the perioperative mortality, re-operation rate or hospital stay between the groups. The incidence of pancreatic fistula was lower in the somatostatin analogue group (RR 0.64; 95% CI 0.53 to 0.78). The proportion of these fistulas that were clinically significant was not mentioned in most trials. On inclusion of trials that clearly distinguished clinically significant fistulas, there was no difference between the two groups (RR 0.69; 95% CI 0.34 to 1.41). Subgroup analysis revealed a shorter hospital stay in the somatostatin analogue group than the controls for patients with malignant aetiology (MD -7.57; 95% CI -11.29 to 3.84). AUTHORS' CONCLUSIONS: Somatostatin analogues reduce perioperative complications but do not reduce perioperative mortality. In those undergoing pancreatic surgery for malignancy, they shorten hospital stay. Further adequately powered trials with low risk of bias are necessary. Based on the current available evidence, somatostatin and its analogues are recommended for routine use in patients undergoing pancreatic resection for malignancy. There is currently no evidence to support their routine use in pancreatic surgeries performed for other indications. PMID- 20166102 TI - Inhibition of DHCR24/seladin-1 impairs cellular homeostasis in prostate cancer. AB - BACKGROUND: Seladin-1 belongs to a subgroup of androgen-dependent genes associated with anti-proliferative, pro-differentiation, and pro-apoptotic functions and plays a protective role against oncogenic stress. The present study aims to investigate the localization and expression of Seladin-1 protein in normal and tumoral human prostatic tissues as well as to explore its role in proliferation and steroid secretion in androgen-dependent (LnCaP) and androgen independent (DU145) cell lines and in human prostate primary cell culture. METHODS: Seladin-1 protein localization and expression were assessed on whole tissue sections by tissue array/immunohistochemistry and following immunofluorescence and Western blotting. Proliferation (Ki67 fluorescence labeling and cell counts) and steroid secretion (ELISA) were assessed in cell lines and primary epithelial cell cultures. RESULTS: In human prostatic tissue and cells, Seladin-1 was mostly localized within epithelial and rarely within stromal cells and primarily present in secretory luminal cells of normal and tumoral prostate cells. Its expression was increased in low-risk prostate cancer but reduced in advanced prostate cancers when compared to normal tissues. Seladin 1 was highly expressed in LnCaP, whereas its expression level was lower in DU145 cells. Seladin-1 inhibition by treatment with its specific inhibitor, U18666A (75 nM), increased proliferation in LnCaP and primary cell culture, as well as testosterone and dihydrotestosterone levels in both LnCaP and DU145 cell lines. CONCLUSIONS: Seladin-1 involvement in proliferation and secretion suggests that its downregulation may be a major mechanism causing prostate cancer evolution. Seladin-1 may thus potentially decrease cell growth and steroid dependency in low grade prostate cancer. PMID- 20166103 TI - Androgens, growth factors, and risk of prostate cancer: the Multiethnic Cohort. AB - BACKGROUND: Androgens and growth factors are thought to be associated with prostate cancer risk, although past research has produced mixed results. METHODS: We conducted a nested case-control study of biomarkers of prostate cancer risk within the Multiethnic Cohort. We compared prediagnostic levels of testosterone, dihydrotestosterone (DHT), sex hormone-binding globulin (SHBG), 3alpha androstanediol glucuronide (3alpha-diol G), insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein 1 (IGFBP-1), and IGFBP-3 in serum from 467 incident prostate cancer cases and 934 cancer-free controls. Controls were matched to the cases on geographic site (HI, LA), ethnicity, age at specimen collection (+/-1 year), date (+/-1 month) and time of day (+/-2 hr) of sample collection, and fasting status (<6, 6-7, 8-9, >10 hr). Multivariate conditional logistic regression models were used to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Serum concentrations of testosterone, DHT, SHBG, 3alpha-diol G, IGF-I, IGF-II, IGFBP-1, and IGFBP-3 were not associated with risk of prostate cancer. Tests for trend of quartiles of serum concentrations also did not show any association. Results were relatively unchanged for men with advanced prostate cancer and their matched controls. However, the follow-up period was relatively short (mean of 1.9 years). Analysis by ethnic group showed an increased risk for Latino men in the second (OR = 3.67, 95% CI: 1.63-8.24) and third (OR = 2.96, 95% CI: 1.19-7.40) tertiles of IGF-I serum levels compared with the first tertile. CONCLUSIONS: The suggested increased risk for IGF-I in Latino men merits further study, with greater statistical power. PMID- 20166104 TI - Specific fragmentation of the K-shell excited/ionized pyridine derivatives studied by electron impact: 2-, 3- and 4-methylpyridine. AB - Fragmentation of the pyridine ring upon K-shell excitation/ionization has been studied with gaseous 2-, 3- and 4-methylpyridine by the electron-impact method. Ab initio molecular orbital (MO) calculations were also carried out to explore electronic states correlating with specific fragments. Some specific fragmentation channels were identified from the ionic fragments enhanced characteristically at the N 1s edge. Yields of the C(2)HN(+) and C(5)H(5)(+)/C(5)H(6)(+) ions show that the fission of the N-C2 and C4-C5/C5-C6 bonds of the ring is likely to occur after the N 1s excitation and ionization. Ab initio MO calculations for the 2-methylpyridine molecule indicate that the dissociation channels to produce these ions are only accessible through the excited states of the parent molecular dication, which can be formed by Auger decays after the N 1s ionization. Fragment ions via hydrogen rearrangement are produced as well, but the rearrangement is not a phenomenon specific to the K shell excitation/ionization. PMID- 20166107 TI - Thiol-ene click chemistry. AB - Following Sharpless' visionary characterization of several idealized reactions as click reactions, the materials science and synthetic chemistry communities have pursued numerous routes toward the identification and implementation of these click reactions. Herein, we review the radical-mediated thiol-ene reaction as one such click reaction. This reaction has all the desirable features of a click reaction, being highly efficient, simple to execute with no side products and proceeding rapidly to high yield. Further, the thiol-ene reaction is most frequently photoinitiated, particularly for photopolymerizations resulting in highly uniform polymer networks, promoting unique capabilities related to spatial and temporal control of the click reaction. The reaction mechanism and its implementation in various synthetic methodologies, biofunctionalization, surface and polymer modification, and polymerization are all reviewed. PMID- 20166110 TI - Top-down nanomechanical machining of three-dimensional nanostructures by atomic force microscopy. PMID- 20166108 TI - Induced-fit binding of the macrocyclic noncovalent inhibitor TMC435 to its HCV NS3/NS4A protease target. PMID- 20166111 TI - Synthesis of glass-coated SERS nanoparticle probes via SAMs with terminal SiO2 precursors. PMID- 20166112 TI - The role of ELOVL1 in very long-chain fatty acid homeostasis and X-linked adrenoleukodystrophy. AB - X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). X ALD is characterized by the accumulation of very long-chain fatty acids (VLCFA; > or =C24) in plasma and tissues. In this manuscript we provide insight into the pathway underlying the elevated levels of C26:0 in X-ALD. ALDP transports VLCFacyl-CoA across the peroxisomal membrane. A deficiency in ALDP impairs peroxisomal beta-oxidation of VLCFA but also raises cytosolic levels of VLCFacyl CoA which are substrate for further elongation. We identify ELOVL1 (elongation of very-long-chain-fatty acids) as the single elongase catalysing the synthesis of both saturated VLCFA (C26:0) and mono-unsaturated VLCFA (C26:1). ELOVL1 expression is not increased in X-ALD fibroblasts suggesting that increased levels of C26:0 result from increased substrate availability due to the primary deficiency in ALDP. Importantly, ELOVL1 knockdown reduces elongation of C22:0 to C26:0 and lowers C26:0 levels in X-ALD fibroblasts. Given the likely pathogenic effects of high C26:0 levels, our findings highlight the potential of modulating ELOVL1 activity in the treatment of X-ALD. PMID- 20166113 TI - The promise and the challenge of modelling human disease in a dish. PMID- 20166116 TI - Polyoxometalates made of gold: the polyoxoaurate [Au(III)4As(V)4O20]8-. PMID- 20166117 TI - Platinum-decorated Au porous nanotubes as highly efficient catalysts for formic acid electro-oxidation. AB - Au porous nanotubes (PNTs) were synthesized by a templating technique that involves the chemical synthesis of Ag nanowire precursors, electroless surface modification with Au, and selective etching. A subsequent galvanic replacement reaction between [PtCl(6)](2-) and residual Ag generates Pt-decorated Au porous nanotubes (Pt/Au PNTs), which represents a new type of self-sustained high surface area electrocatalysts with ultra-low Pt loading. Structural characterizations with scanning electron microscopy (SEM), transmission electron microscopy (TEM) and X-ray powder diffraction (XRD) reveal a novel nanoarchitecture with multimodal open porosity and excellent structural continuity and integrity. Cyclic voltammetry (CV) demonstrates that these Pt/Au PNTs possess very high electrocatalytic activity toward formic acid oxidation with enhanced tolerance to CO poisoning. PMID- 20166114 TI - Intercellular nanotubes: insights from imaging studies and beyond. AB - Cell-cell communication is critical to the development, maintenance, and function of multicellular organisms. Classical mechanisms for intercellular communication include secretion of molecules into the extracellular space and transport of small molecules through gap junctions. Recent reports suggest that cells also can communicate over long distances via a network of transient intercellular nanotubes. Such nanotubes have been shown to mediate intercellular transfer of organelles as well as membrane components and cytoplasmic molecules. Moreover, intercellular nanotubes have been observed in vivo and have been shown to enhance the transmission of pathogens such as human immunodeficiency virus (HIV)-1 and prions in vitro. These studies indicate that intercellular nanotubes may play a role both in normal physiology and in disease. PMID- 20166118 TI - Flash chemistry extensively optimized: high-temperature Swern-Moffatt oxidation in an automated microreactor platform. AB - The generally accepted benefits of small lateral dimensions of microreactors (1 microm to 1 mm) enable a different way of performing synthetic chemistry: Extremely short contact times in the millisecond range can circumvent the need for performing highly exothermic and fast reactions at very low temperatures. In order to fully exploit this technology, such fast processes need to be redesigned and investigated for optimal reaction conditions, which can differ drastically from the ones traditionally applied. In a comprehensive study, we optimized the selective Swern-Moffatt oxidation of benzyl alcohol to benzaldehyde by varying five experimental parameters, including reaction time and temperature. Employing an ultrashort mixing and reaction time of only 32 ms, the optimal temperature was determined to be 70 degrees C, approximately 150 degrees C higher than in the conventional batch conditions. This remarkable difference shows both the potency of continuous-flow chemistry as well as the urgency of a paradigm shift in reaction design for continuous-flow conditions. PMID- 20166119 TI - Accelerated aging, natural aging, and small punch testing of gamma-air sterilized polycarbonate urethane acetabular components. AB - The objectives of this study were three-fold: (1) to determine the applicability of the small punch test to characterize Bionate 80A polycarbonate urethane (PCU) acetabular implants; (2) to evaluate the susceptibility of PCU acetabular implants to exhibit degradation of mechanical behavior following gamma irradiation in air and accelerated aging; and (3) to compare the oxidation of gamma-air sterilized PCU following accelerated aging and 5 years of natural shelf aging. In addition to attenuated total reflectance-Fourier transform infrared spectroscopy, we also adapted a miniature specimen mechanical test, the small punch test, for the deformable PCU cups. Accelerated aging was performed using ASTM F2003, a standard test that represents a severe oxidative challenge. The results of this study suggest that the small punch test is sufficiently sensitive and reproducible to discriminate slight differences in the large-deformation mechanical behavior of Bionate 80A following accelerated aging. The gamma-air sterilized PCU had a reduction of 9% in ultimate load after aging. Five years of shelf aging had little effect on the mechanical properties of the PCU. Overall, our findings suggest that the Bionate 80A material has greater oxidative stability than ultra-high molecular weight polyethylene following gamma irradiation in air and exposure to a severe oxidative challenge. PMID- 20166120 TI - Effect of calcination on microstructure and antibacterial activity of silver containing silica coatings. AB - Silver nanoparticle containing silica coatings on soda-lime glass were prepared by the sol-gel process. The effect of thermal densification treatment at different temperatures in the range of 100-700 degrees C on microstructure and antibacterial properties of the coatings were examined. The structural characterization of the coatings was performed by using scanning electron microscope, X-ray diffraction, UV-visible and X-ray photoelectron spectroscopy (XPS), and atomic force microscope (AFM). The antibacterial activity of the coatings was determined against Staphylococcus aureus by disk diffusion method. The mechanisms for formation and distribution of silver nanoparticles in the silica matrix with respect to the calcination temperature are discussed, and the correlation between the microstructural properties and antibacterial activity is described. The investigations revealed that silver nanoparticles were mainly in the metallic state during thermal treatments. AFM and XPS examinations proved that silver accumulated on the surface diffuse into glass substrate at higher calcination temperatures. A high level of antibacterial activity was observed for the coatings calcined at 300 degrees C or lower temperatures allowing accommodation of silver on the surface of the coating. Silver diffusion into bulk via ion-exchange with sodium and calcium ions from glass substrate during calcination at higher temperatures (500 or 700 degrees C) resulted in apparent degradation in the antibacterial activity. PMID- 20166121 TI - Fabrication and characterization of a porous multidomain hydroxyapatite scaffold for bone tissue engineering investigations. AB - Tissue-engineering scaffold-based strategies have suffered from limited cell depth viability when cultured in vitro, with viable cells existing within the outer periphery of the fluid-scaffold interface. This is primarily believed to be due to the lack of nutrient delivery into and waste removal from the inner regions of the scaffold construct. This work develops a hydroxyapatite trimodal porous scaffold architecture (i.e., a scaffold providing a discrete domain for cell occupancy and a separate domain for nutrient delivery) through a freeze drying process. Unidirectional channels (500 microm diameter) were incorporated through CNC machining with total combined apparent porosities of 85.1% +/- 0.22%. Effective diffusion coefficients for the bimodal phase (consisting of micro- and meso-pores, without channels) were also determined (7.9 x 10(-10) m(2) s(-1)). Trimodal scaffolds also demonstrated enhanced permeability values (approximately 18-fold increase) compared with bimodal scaffold architectures. In vitro experiments were used to assess initial seeding efficiency and distribution as well as cell viability. The presence of unidirectional channels significantly enhanced initial cell seeding distribution throughout the scaffold depth, while maintaining relatively high seeding efficiencies (67.7% +/- 2.2% for trimodal, 79.1% +/- 2.1% for bimodal scaffolds). Numerical models demonstrated the effectiveness and efficacy of incorporating channels to increase the core oxygen concentration, with the accuracy of these models improved by using experimentally measured cellular oxygen consumption rates and effective diffusion coefficients. The presence of channels had a positive influence in minimizing the concentration gradients compared with bimodal scaffolds for the same cell density distributions. PMID- 20166122 TI - Cellular inhibition produced by dental curing lights is a heating artifact. AB - Dental curing lights deliver energy in the 380-520 nm wavelength range. It has been reported that irradiation in these wavelengths may have a negative effect on cell function. We examined the effect of three dental curing lights on the viability of mouse (NIH3T3, Balb/c3T3) and human (HGF-1) fibroblastic cells, and epithelial (HT-29) cells grown in culture. Cell inhibition was observed using the MTT assay of mitochondrial function and measures of DNA fragmentation and DNA synthesis. Analyzing the experimental method and careful measurement of the temperature adjacent to the cell monolayer during irradiation showed that damage to the cells was not due to cumulative light exposure, but instead occurred when the temperature of the culture medium rose above 42 degrees C. We conclude that dental curing lights do not cause cell damage as a direct result of the light irradiation. Instead it is caused by the local temperature increase in the cells. PMID- 20166123 TI - Enhancement of octacalcium phosphate deposition on a titanium surface activated by electron cyclotron resonance plasma oxidation. AB - The present study was designed to investigate whether the formation of octacalcium phosphate (OCP) is accelerated on titanium (Ti) surface by an electron cyclotron resonance (ECR) plasma oxidation at various pressures and temperatures. X-ray diffraction (XRD) of Ti-oxidized substrates showed that the rutile TiO(2) phase on its surfaces appeared at 300 degrees C and was crystallized when the oxidation temperature increased up to 600 degrees C. The thickness of TiO(2) film on the substrates increased progressively as the temperature increased. The oxidized Ti surfaces were soaked in calcium and phosphate solutions supersaturated with respect to both hydroxyapatite (HA) and OCP but slightly supersaturated with dicalcium phosphate dihydrate (DCPD). OCP crystals with a blade-like morphology were deposited as the primary crystalline phase on Ti substrates, while DCPD was included as a minor constituent. The amount of OCP deposition was maximized under 0.015 Pa in 300 degrees C. On the other hand, the oxidation temperature did not show a significant effect on the deposit in the range examined. The phase conversion from OCP to HA, determined by XRD, was demonstrated to occur even at 1 day and to advance until 7 days by immersing the Ti substrate with the deposit in simulated body fluid at 37 degrees C. The present results suggest that ECR plasma oxidation could be used to improve a Ti surface regarding its bioactivity due to the enhancement of osteoconductive OCP deposition. PMID- 20166124 TI - Understanding specific and nonspecific toxicities: a requirement for the development of dendrimer-based pharmaceuticals. AB - Dendrimer conjugates for pharmaceutical development are capable of enhancing the local delivery of cytotoxic drugs. The ability to conjugate different targeting ligands to the dendrimer allows for the cytotoxic drug to be focused at the intended target cell while minimizing collateral damage in normal cells. Dendrimers offer several advantages over other polymer conjugates by creating a better defined, more monodisperse therapeutic scaffold. Toxicity from the dendrimer, targeted and nonspecific, is not only dependent upon the number of targeting and therapeutic ligands conjugated, but can be influenced by the repeating building blocks that grow the dendrimer, the dendrimer generation, as well as the surface termination. PMID- 20166125 TI - Multiple ligand simultaneous docking: orchestrated dancing of ligands in binding sites of protein. AB - Present docking methodologies simulate only one single ligand at a time during docking process. In reality, the molecular recognition process always involves multiple molecular species. Typical protein-ligand interactions are, for example, substrate and cofactor in catalytic cycle; metal ion coordination together with ligand(s); and ligand binding with water molecules. To simulate the real molecular binding processes, we propose a novel multiple ligand simultaneous docking (MLSD) strategy, which can deal with all the above processes, vastly improving docking sampling and binding free energy scoring. The work also compares two search strategies: Lamarckian genetic algorithm and particle swarm optimization, which have respective advantages depending on the specific systems. The methodology proves robust through systematic testing against several diverse model systems: E. coli purine nucleoside phosphorylase (PNP) complex with two substrates, SHP2NSH2 complex with two peptides and Bcl-xL complex with ABT-737 fragments. In all cases, the final correct docking poses and relative binding free energies were obtained. In PNP case, the simulations also capture the binding intermediates and reveal the binding dynamics during the recognition processes, which are consistent with the proposed enzymatic mechanism. In the other two cases, conventional single-ligand docking fails due to energetic and dynamic coupling among ligands, whereas MLSD results in the correct binding modes. These three cases also represent potential applications in the areas of exploring enzymatic mechanism, interpreting noisy X-ray crystallographic maps, and aiding fragment-based drug design, respectively. PMID- 20166127 TI - Uro-words making history: ureter and urethra. AB - PURPOSE: We comprehensively review the history of the terms "ureter" and "urethra" from 700 BC to the present. MATERIALS AND METHODS: Using a case study approach, ancient medical texts were analyzed to clarify the etymology and use of both terms. In addition, selected anatomy textbooks from the 15th to 17th centuries were searched to identify and compare descriptions, illustrations, and various expressions used by contemporary authors to designate the upper and lower parts of the urinary tract. RESULTS: The Ancient Greek words "ureter" and "urethra" appear early in Hippocratic and Aristotelian writings. However, both terms designated what we today call the urethra. It was only with increasing anatomical knowledge in Greek medical texts after the 1st century AD that definitions of these words evolved similar to those we employ today. Numerous synonyms were used which served as a basis for translation into Arabic and later Latin during the transfer of ancient knowledge to the cultures of the medieval period. When Greek original texts and their Arabic-Latin version were compared during the Renaissance, this led to terminological confusion which could only be gradually overcome. Around the year 1600, the use of the latinized terms "ureter" and "urethra" became generally accepted. The dissemination of these terms in modern national languages and the emergence of clinical derivatives complete this historical development. CONCLUSIONS: The history of the terms "ureter" and "urethra" is exemplary of the difficulties with which the development of a precise urologic terminology had to struggle. The story behind the words also clarifies why even today we still have imprecise or misleading terms. PMID- 20166126 TI - Differential regulation of steroid nuclear receptor coregulator expression between normal and neoplastic prostate epithelial cells. AB - BACKGROUND: Deregulated androgen receptor (AR) action is critical for prostate cancer (PCa) progression. Aberrant expression of AR-associated coregulators contributes to AR activity in PCa. The mechanisms underlying coregulator expression in PCa are under intense investigation as they may lead to alternative means of targeting AR activity in PCa cells. We have recently shown that over 30% of coregulator expression in the PCa cell line LNCaP is subject to androgen regulation. METHODS: Using multiple PCa cell lines as well as xenograft models, non-malignant prostate epithelial cell lines and androgen-responsive tissues derived from a male Wistar rat model system, we explored the effect of androgen stimulation and androgen deprivation on the expression of the core coactivators SRC1, SRC2, SRC3, CBP, and p300. RESULTS: Androgen stimulation of model systems representing PCa led to a decrease in the expression of SRC1, SRC2, SRC3, CBP, and p300, whereas androgen deprivation induced the expression of these coactivators. In contrast, expression of these coregulators remained largely unaffected following changes in the androgenic milieu in AR-positive models representing non-malignant prostate cells and tissues. CONCLUSIONS: Our data indicate differences in the regulation of coregulator expression between neoplastic and normal prostate cells. These findings emphasize the important potential of targeting the mechanisms regulating coregulator expression for therapeutic intervention in PCa. PMID- 20166128 TI - Effect of intermittent fasting with or without caloric restriction on prostate cancer growth and survival in SCID mice. AB - INTRODUCTION: Caloric restriction (CR) delays cancer growth in animals, though translation to humans is difficult. We hypothesized intermittent fasting (i.e., intermittent extreme CR), may be better tolerated and prolong survival of prostate cancer (CaP) bearing mice. METHODS: We conducted a pilot study by injecting 105 male individually-housed SCID mice with LAPC-4 cells. When tumors reached 200 mm(3), 15 mice/group were randomized to one of seven diets and sacrificed when tumors reached 1,500 mm(3): Group 1: ad libitum 7 days/week; Group 2: fasted 1 day/week and ad libitum 6 days/week; Group 3: fasted 1 day/week and fed 6 days/week via paired feeding to maintain isocaloric conditions to Group 1; Group 4: 14% CR 7 days/week; Group 5: fasted 2 days/week and ad libitum 5 days/week; Group 6: fasted 2 day/week and fed 5 days/week via paired feeding to maintain isocaloric conditions to Group 1; Group 7: 28% CR 7 days/week. Sera from mice at sacrifice were analyzed for IGF-axis hormones. RESULTS: There were no significant differences in survival among any groups. However, relative to Group 1, there were non-significant trends for improved survival for Groups 3 (HR 0.65, P = 0.26), 5 (0.60, P = 0.18), 6 (HR 0.59, P = 0.16), and 7 (P = 0.59, P = 0.17). Relative to Group 1, body weights and IGF-1 levels were significantly lower in Groups 6 and 7. CONCLUSIONS: This exploratory study found non-significant trends toward improved survival with some intermittent fasting regimens, in the absence of weight loss. Larger appropriately powered studies to detect modest, but clinically important differences are necessary to confirm these findings. PMID- 20166130 TI - Testing for genetic association in the presence of linkage and gene-covariate interactions. AB - In order to study family-based association in the presence of linkage, we extend a generalized linear mixed model proposed for genetic linkage analysis (Lebrec and van Houwelingen (2007), Human Heredity 64, 5-15) by adding a genotypic effect to the mean. The corresponding score test is a weighted family-based association tests statistic, where the weight depends on the linkage effect and on other genetic and shared environmental effects. For testing of genetic association in the presence of gene-covariate interaction, we propose a linear regression method where the family-specific score statistic is regressed on family-specific covariates. Both statistics are straightforward to compute. Simulation results show that adjusting the weight for the within-family variance structure may be a powerful approach in the presence of environmental effects. The test statistic for genetic association in the presence of gene-covariate interaction improved the power for detecting association. For illustration, we analyze the rheumatoid arthritis data from GAW15. Adjusting for smoking and anti-cyclic citrullinated peptide increased the significance of the association with the DR locus. PMID- 20166131 TI - Hans van Houwelingen, 40 years in biostatistics. PMID- 20166132 TI - High-dimensional Cox models: the choice of penalty as part of the model building process. AB - The Cox proportional hazards regression model is the most popular approach to model covariate information for survival times. In this context, the development of high-dimensional models where the number of covariates is much larger than the number of observations (p>>n) is an ongoing challenge. A practicable approach is to use ridge penalized Cox regression in such situations. Beside focussing on finding the best prediction rule, one is often interested in determining a subset of covariates that are the most important ones for prognosis. This could be a gene set in the biostatistical analysis of microarray data. Covariate selection can then, for example, be done by L(1)-penalized Cox regression using the lasso (Tibshirani (1997). Statistics in Medicine 16, 385-395). Several approaches beyond the lasso, that incorporate covariate selection, have been developed in recent years. This includes modifications of the lasso as well as nonconvex variants such as smoothly clipped absolute deviation (SCAD) (Fan and Li (2001). Journal of the American Statistical Association 96, 1348-1360; Fan and Li (2002). The Annals of Statistics 30, 74-99). The purpose of this article is to implement them practically into the model building process when analyzing high-dimensional data with the Cox proportional hazards model. To evaluate penalized regression models beyond the lasso, we included SCAD variants and the adaptive lasso (Zou (2006). Journal of the American Statistical Association 101, 1418-1429). We compare them with "standard" applications such as ridge regression, the lasso, and the elastic net. Predictive accuracy, features of variable selection, and estimation bias will be studied to assess the practical use of these methods. We observed that the performance of SCAD and adaptive lasso is highly dependent on nontrivial preselection procedures. A practical solution to this problem does not yet exist. Since there is high risk of missing relevant covariates when using SCAD or adaptive lasso applied after an inappropriate initial selection step, we recommend to stay with lasso or the elastic net in actual data applications. But with respect to the promising results for truly sparse models, we see some advantage of SCAD and adaptive lasso, if better preselection procedures would be available. This requires further methodological research. PMID- 20166134 TI - The Prostate Cancer Foundation 16th Annual Scientific Retreat: meeting report. AB - The 16th Annual Prostate Cancer Foundation (PCF) Scientific Retreat was held September 23-25, 2009 at Incline Village, NV. This report highlights some of the game-changing research reports from this conference. PMID- 20166133 TI - Differential expression of the alpha2 chain of the interleukin-13 receptor in metastatic human prostate cancer ARCaPM cells. AB - BACKGROUND: The alpha2 chain of the interleukin-13 receptor (IL13Ralpha2) is a high-affinity receptor and a candidate target for cytotoxic killing of cancer cells. Availability of a human prostate cancer cell line with high level of IL13Ralpha2 expression will facilitate the development of therapeutic modalities. METHODS: ARCaP(E) and ARCaP(M) human prostate cancer cell lines were subjected to comparative analyses of gene expression. Expression of the IL13Ralpha2 protein was confirmed by Western blotting and immunostaining. IL13Ralpha2 proteins in xenograft tumors and clinical human prostate cancer specimens were detected by specific antibodies. LNCaP prostate cancer cells stably transfected with IL13Ralpha2 were examined for accelerated growth in athymic mice. RESULTS: We found that IL13Ralpha2 proteins could be detected in both the ARCaP(E) and ARCaP(M) cells, but the expression level in ARCaP(M) was more than 17-fold higher than in ARCaP(E) cells. Importantly, the ARCaP lineage represented the only human prostate cancer cell line that expresses IL13Ralpha2 proteins at the level detectable by Western blotting. Expression of IL13Ralpha2 was accompanied by resistance to the anti-tumor activity of interleukin-13 (IL-13). ARCaP cells were found to be insensitive to growth inhibition upon IL-13 treatment, while overexpression of IL13Ralpha2 in LNCaP cells promoted intratibial tumor growth in athymic mice. CONCLUSIONS: Differential IL13Ralpha2 expression may account for the high tumorigenic and metastatic potential of ARCaP(M) cells. The unique expression of IL13Ralpha2 makes ARCaP lineage an attractive model for evaluating the targeting efficacy of therapeutic agents based on IL13Ralpha2 protein expression. PMID- 20166135 TI - Association of hepsin gene variants with prostate cancer risk and prognosis. AB - BACKGROUND: Hepsin (HPN) is one of the most consistently overexpressed genes in prostate cancer and there is some evidence supporting an association between HPN gene variants and prostate cancer risk. We report results from a population-based case-control genetic association study for six tagging single nucleotide polymorphisms (tagSNPs) in the HPN gene. METHODS: Prostate cancer risk was estimated using adjusted unconditional logistic regression in 1,401 incident prostate cancer cases diagnosed in 1993 through 1996 or 2002 through 2005 and 1,351 age-matched controls. Risks of disease recurrence/progression and prostate cancer-specific mortality were estimated using Cox proportional hazards (PH) regression in 437 cases with long-term follow-up. RESULTS: There were 135 recurrence/progression events and 57 cases who died of prostate cancer. Contrary to some earlier studies, we found no evidence of altered risk of developing prostate cancer overall or when clinical measures of tumor aggressiveness were considered for any of the tagSNPs, assessed either individually or by haplotypes. There was no evidence of altered risks of tumor recurrence/progression or prostate cancer death associated with variants in the HPN gene. CONCLUSIONS: Germline genetic variation of HPN does not seem to contribute to risk of prostate cancer or prognosis. PMID- 20166136 TI - Snail transcription factor regulates neuroendocrine differentiation in LNCaP prostate cancer cells. AB - BACKGROUND: Snail transcription factor induces epithelial-mesenchymal transition (EMT) via decreased cell adhesion-associated molecules like E-cadherin, and increased mesenchymal markers like vimentin. We previously established Snail mediated EMT model utilizing androgen-dependent LNCaP cells. These cells express increased vimentin protein and relocalization of E-cadherin from the cell membrane to the cytosol. Interestingly, Snail transfection in LNCaP cells resulted in cells acquiring a neuroendocrine (NE)-like morphology with long neurite-like processes. METHODS: We tested for expression of NE markers neuron specific enolase (NSE) and chromogranin A (CgA) by Western blot analysis, and performed proliferation assays to test for paracrine cell proliferation. RESULTS: LNCaP cells transfected with Snail displayed increase in the NE markers, NSE and CgA as well as translocation of androgen receptor (AR) to the nucleus. LNCaP C-33 cells that have been previously published as a neuroendocrine differentiation (NED) model exhibited increased expression levels of Snail protein as compared to LNCaP parental cells. Functionally, conditioned medium from the LNCaP-Snail transfected cells increased proliferation of parental LNCaP and PC-3 cells, which could be abrogated by NSE/CgA siRNA. Additionally, NED in LNCaP-C33 cells or that induced in parental LNCaP cells by serum starvation could be inhibited by knockdown of Snail with siRNA. CONCLUSION: Overall our data provide evidence that Snail transcription factor may promote tumor aggressiveness in the LNCaP cells through multiple processes; induction of EMT may be required to promote migration, while NED may promote tumor proliferation by a paracrine mechanism. Therefore, therapeutic targeting of Snail may prove beneficial in not only abrogating EMT but also NED. PMID- 20166138 TI - Improved disc SDS-PAGE for extraction of low molecular weight proteins from serum. AB - The low molecular weight proteins can provide a lot of valuable information of biomarkers. To study these proteins, the high abundance and high molecular weight proteins must be removed prior to analysis. In this work, a simple and inexpensive disc SDS-PAGE to extract low molecular weight proteins from human serum and cutoff proteins larger than 30 kDa was developed. Some experimental conditions were examined. The experimental results obtained by plate SDS-PAGE and MALDI-TOF MS showed that the molecular weight of extracted proteins was about in the range from 0.3 to 28 kDa. Some experiments, including precipitation of proteins in organic solvents, SPE and cytochrome C test, were carried out and the experimental results demonstrated successful recovery of proteins/peptides with molecular weight from several hundreds of dalton to about 30 kDa. The experimental results obtained by plate SDS-PAGE indicated the repeatability was satisfactory. PMID- 20166137 TI - ELL is an HIF-1alpha partner that regulates and responds to hypoxia response in PC3 cells. AB - BACKGROUND: Eleven-nineteen lysine-rich leukemia (ELL) plays an important role in tumorigenesis and animal development. HIF-1 is a transcriptional factor that functions as a master regulator of O(2) homeostasis. Our previous studies showed that a binding partner of ELL, U19/Eaf2, can modulate HIF-1alpha activity and hypoxia response, suggesting that ELL may also influence HIF-1alpha pathway and hypoxia response. METHODS: Co-localization and co-immunoprecipitation were performed to test the interaction between ELL and HIF-1alpha. PC3 cells with stable ELL knockdown and PC3 cells with stable ELL overexpression, along with their controls, were established using lentiviral expression system. Western blot and real-time PCR were performed to test the effect of ELL on HIF-1alpha protein and its down-stream gene transcription. To elucidate potential effect of hypoxia on ELL, cell growth and colony formation assays were performed using PC3 subline with stable ELL overexpression. RESULTS: ELL is associated with HIF-1alpha in transfected cells. In PC3 prostate cancer cells, ELL inhibited HIF-1alpha protein level and down-stream gene expression. As expected, ELL inhibited cell growth and colony formation under normoxia. Interestingly, the inhibition was alleviated under hypoxia. CONCLUSIONS: Our findings suggest that ELL and HIF-1alpha are binding partners and can modulate the functions of each other in hypoxia. PMID- 20166139 TI - Phosphoproteome analysis of human liver tissue by long-gradient nanoflow LC coupled with multiple stage MS analysis. AB - Reversible protein phosphorylation plays a critical role in liver development and function. Comprehensively cataloging the phosphoproteins and their phosphorylation sites in human liver tissue will facilitate the understanding of physiological and pathological mechanisms of liver. Owing to lacking of efficient approach to fractionate phosphopeptides, nanoflow-RPLC with long-gradient elution was applied to reduce the complexity of the phosphopeptides in this study. Two approaches were performed to further improve the coverage of phosphoproteome analysis of human liver tissue. In one approach, ten-replicated long-gradient LC MS/MS runs were performed to analyze the enriched phosphopeptides, which resulted in the localization of 1080 phosphorylation sites from 495 proteins. In another approach, proteins from liver tissue were first fractionated by SDS-PAGE and then long-gradient LC-MS/MS analysis was performed to analyze the phosphopeptides derived from each fraction, which resulted in the localization of 1786 phosphorylation sites from 911 proteins. The two approaches showed the complementation in phosphoproteome analysis of human liver tissue. Combining the results of the two approaches, identification of 2225 nonredundant phosphorylation sites from 1023 proteins was obtained. The confidence of phosphopeptide identifications was strictly controlled with false discovery rate (FDR) < or = 1% by a MS(2)/MS(3) target-decoy database search approach. Among the localized 2225 phosphorylated sites, as many as 70.07% (1559 phosphorylated sites) were also reported by others, which confirmed the high confidence of the sites determined in this study. Considering the data acquired from low accuracy mass spectrometer and processed by a conservative MS(2)/MS(3) target-decoy approach, the number of localized phosphorylation sites obtained for human liver tissue in this study is quite impressive. PMID- 20166140 TI - Muscle development in the Japanese flounder, Paralichthys olivaceus, with special reference to some of the larval-specific muscles. AB - We investigated muscle development in the Japanese flounder Paralichthys olivaceus, focusing primarily on the cranial muscles, using a whole mount immunohistochemical staining method. It is well established that during the very early stages of morphogenesis, until 4 days post hatching (dph), muscles required for feeding develop. Later, between 8 and 16 dph, the muscle composition in the dorsal branchial arches changes to the adult form. We discovered the presence of larval-specific muscles in this ontogenetic period, termed the larval branchial levators 2 and 3, located in the dorsal branchial arches. The larval branchial levators 2 and 3 disappear during the course of development, whereas the others remain as levator internus 1 and levator posterior, which have also been described in adult fish. In place of these regressed muscles, the levatores externi and levator internus 2 develop and regulate the branchial arches. In addition, we found that the levator posterior, which is thought to represent the fifth levator externus, and the levatores externi exhibit different origins. We also found that at least a part of the caudal fin musculature develops from the trunk myotome. PMID- 20166141 TI - CE detection of N-(3-dimethylaminopropyl)-N-carbodiimide/N-hydroxysuccinimide coupled proteins after homo- and hetero-crosslinking reactions. AB - Protein-protein conjugates formed by carbodiimide crosslinking reactions have been analyzed for the first time using CE. Lysozyme and BSA were chosen as model proteins to study the efficacy of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide and N-hydroxysuccinimide as crosslinkers. Detection of the molecular mass increase was checked by SDS-PAGE. Commercially available, PVA-coated capillaries showed appropriate selection, while phospho-deactivated and dynamic PVA-coated capillaries did not give suitable resolution. CE was found to be an efficient tool to characterize homo- (lysozyme-lysozyme) and hetero- (lysozyme-BSA) protein coupling by suitable variations of electrophoretic mobilities. PMID- 20166142 TI - High-fat diet stimulates IL-1 type I receptor-mediated inflammatory signaling in the skeletal muscle of mice. AB - Recently, substantial attention has been focused on the association between obesity and chronic inflammation. The aim of the present study was to investigate whether high-fat diet (HFD)-induced obesity induces the activation of the IL-1 type I receptor (IL-1RI)-mediated inflammatory signaling cascade in the skeletal muscle of mice. Male C57BL/6J mice were fed either an HFD or a normal diet (ND) for 12 wk. Compared with the results in mice receiving the ND, the HFD increased the expression of IL-1RI and downstream signaling proteins, such as myeloid differentiation primary response gene 88 (MyD88), IL-1R-associated kinase 4 and phospho-transforming growth factor-activated kinase 1 in the skeletal muscle. Additionally, activities of both inhibitor of kappaB kinase beta and inhibitor of kappaB degradation were significantly elevated in the skeletal muscle of mice fed with an HFD compared with mice receiving an ND. In contrast, the levels of other downstream transcription factors, such as activator protein-1 and INF regulatory factor 5, were not affected by the HFD. These results suggest that the IL-1RI MyD88-nuclear factor kappaB signaling pathway might be involved in the induction of the inflammatory response in the skeletal muscle of mice fed with an HFD. PMID- 20166143 TI - Hydroxytyrosol induces antioxidant/detoxificant enzymes and Nrf2 translocation via extracellular regulated kinases and phosphatidylinositol-3-kinase/protein kinase B pathways in HepG2 cells. AB - Hydroxytyrosol (HTy) is a natural polyphenol abundant in olive oil, which possesses multiple biological actions. Particularly, HTy has cytoprotective activity against oxidative-stress-induced cell damage, but the underlying mechanisms of action remain unclear. Here, we have investigated the molecular mechanism involved in the protection exerted by HTy on tert-butyl hydroperoxide induced damage in human HepG2 liver cells. Treatment of HepG2 cells with HTy increased the expression and the activity of glutathione-related enzymes such as glutathione peroxidase, glutathione reductase and glutathione S-transferase. HTy also induced the nuclear transcription factor erythroid 2p45-related factor (Nrf2), a transcription factor implicated in the expression of several antioxidant/detoxificant enzymes. Moreover, two important signalling proteins involved in Nrf2 translocation, the protein kinase B and the extracellular regulated kinases, were also activated by HTy. Further studies with specific inhibitors confirmed that both molecular pathways are critical for the nuclear translocation of Nrf2, the increased enzyme expression and activity and the beneficial effect against oxidative stress induced by HTy. In conclusion, together with the inherent radical scavenging activity of HTy, our results provide an additional mechanism of action to prevent oxidative stress damage through the modulation of signalling pathways involved in antioxidant/detoxifying enzymes regulation. PMID- 20166144 TI - Sulforaphane protects cortical neurons against 5-S-cysteinyl-dopamine-induced toxicity through the activation of ERK1/2, Nrf-2 and the upregulation of detoxification enzymes. AB - The degeneration of dopaminergic neurons in the substantia nigra has been linked to the formation of the endogenous neurotoxin 5-S-cysteinyl-dopamine. Sulforaphane (SFN), an isothiocyanate derived from the corresponding precursor glucosinolate found in cruciferous vegetables has been observed to exert a range of biological activities in various cell populations. In this study, we show that SFN protects primary cortical neurons against 5-S-cysteinyl-dopamine induced neuronal injury. Pre-treatment of cortical neurons with SFN (0.01-1 microM) resulted in protection against 5-S-cysteinyl-dopamine-induced neurotoxicity, which peaked at 100 nM. This protection was observed to be mediated by the ability of SFN to modulate the extracellular signal-regulated kinase 1 and 2 and the activation of Kelch-like ECH-associated protein 1/NF-E2-related factor-2 leading to the increased expression and activity of glutathione-S-transferase (M1, M3 and M5), glutathione reductase, thioredoxin reductase and NAD(P)H oxidoreductase 1. These data suggest that SFN stimulates the NF-E2-related factor 2 pathway of antioxidant gene expression in neurons and may protect against neuronal injury relevant to the aetiology of Parkinson's disease. PMID- 20166145 TI - Tocopherol production in plant cell cultures. AB - Tocopherols, collectively known as vitamin E, are lipophilic antioxidants, essential dietary components for mammals and exclusively synthesized by photosynthetic organisms. Of the four forms (alpha, beta, gamma and delta), alpha tocopherol is the major vitamin E form present in green plant tissues, and has the highest vitamin E activity. Synthetic alpha-tocopherol, being a racemic mixture of eight different stereoisomers, always results less effective than the natural form (R,R,R) alpha-tocopherol. This raises interest in obtaining this molecule from natural sources, such as plant cell cultures. Plant cell and tissue cultures are able to produce and accumulate valuable metabolites that can be used as food additives, nutraceuticals and pharmaceuticals. Sunflower cell cultures, growing under heterotrophic conditions, were exploited to establish a suitable in vitro production system of natural alpha-tocopherol. Optimization of culture conditions, precursor feeding and elicitor application were used to improve the tocopherol yields of these cultures. Furthermore, these cell cultures were useful to investigate the relationship between alpha-tocopherol biosynthesis and photomixotrophic culture conditions, revealing the possibility to enhance tocopherol production by favouring sunflower cell photosynthetic properties. The modulation of alpha-tocopherol levels in plant cell cultures can provide useful hints for a regulatory impact on tocopherol metabolism. PMID- 20166146 TI - The location and behavior of alpha-tocopherol in membranes. AB - Vitamin E (alpha-tocopherol) has long been recognized as the major antioxidant in biological membranes, and yet many structurally related questions persist of how the vitamin functions. For example, the very low levels of alpha-tocopherol reported for whole cell extracts question how this molecule can successfully protect the comparatively enormous quantities of PUFA-containing phospholipids found in membranes that are highly susceptible to oxidative attack. The contemporary realization that membranes laterally segregate into regions of distinct lipid composition (domains), we propose, provides the answer. We hypothesize alpha-tocopherol partitions into domains that are enriched in polyunsaturated phospholipids, amplifying the concentration of the vitamin in the place where it is most needed. These highly disordered domains depleted in cholesterol are analogous, but organizationally antithetical, to the well-studied lipid rafts. We review here the ideas that led to our hypothesis. Experimental evidence in support of the formation of PUFA-rich domains in model membranes is presented, focusing upon docosahexaenoic acid that is the most unsaturated fatty acid commonly found. Physical methodologies are then described to elucidate the nature of the interaction of alpha-tocopherol with PUFA and to establish that the vitamin and PUFA-containing phospholipids co-localize in non-raft domains. PMID- 20166147 TI - Vitamin E transport, membrane incorporation and cell metabolism: Is alpha tocopherol in lipid rafts an oar in the lifeboat? AB - Vitamin E is composed of closely related compounds, including tocopherols and tocotrienols. Studies of the last decade provide strong support for a specific role of alpha-tocopherol in cell signalling and the regulation of gene expression. It produces significant effects on inflammation, cell proliferation and apoptosis that are not shared by other vitamin E isomers with similar antioxidant properties. The different behaviours of vitamin E isomers might relate, at least in part, to the specific effects they exert at the plasma membrane. alpha-Tocopherol is not randomly distributed throughout the phospholipid bilayer of biological membranes, and as compared with other isomers, it shows a propensity to associate with lipid rafts. Distinct aspects of vitamin E transport and metabolism is discussed with emphasis on the interaction between alpha-tocopherol and lipid rafts and the consequences of these interactions on cell metabolism. PMID- 20166148 TI - On-plate enrichment of glycopeptides by using boronic acid functionalized gold coated Si wafer. AB - Boronic acid functionalized gold-coated Si wafer has been used as MALDI plate to isolate and enrich glycopeptides for MS analysis. This on-plate enrichment strategy offers good benefits due to the combination of specific selectivity through enrichment and direct manipulation on the wafer. First, solution transfer and eluting steps required in conventional enrichment strategies are not needed any more, thereby reducing sample loss during these steps. Second, the LODs of glycopeptides have been increased by two orders of magnitude. Third, non-specific bindings have not been detected even when non-glycopeptides are 100 times more than glycopeptides. Furthermore, the recovery of glycopeptide is up to 65.8% and glycopeptides even can be sensitively detected in the presence of 200 mM ammonium bicarbonate or physiological buffer PBS. PMID- 20166149 TI - First-trimester assessment of placenta function and the prediction of preeclampsia and intrauterine growth restriction. AB - Preeclampsia and intrauterine growth restriction (IUGR) are major contributors to perinatal mortality and morbidity worldwide. Both are characterized by impaired trophoblastic invasion of the maternal spiral arteries and their conversion from narrow muscular vessels to wide non-muscular channels. Despite improvement in the understanding of the pathophysiology of these conditions, ability to accurately identify pregnant woman who will develop them is limited. This greatly impairs the development and testing of preventive interventions. While different measures of placental dysfunction have been associated with increased risk for adverse pregnancy outcomes, the ability of any single one to accurately predict these outcomes is poor. Developing predictive tests is further challenged by difficulty in the timing of the measurements, as both the structural and biochemical characteristics of the placenta change with increasing gestational age. The ideal screening test would accurately predict the development of adverse pregnancy outcomes early enough to provide a window for preventive interventions. Improvement in ultrasound technology provides potentially useful novel tools for evaluating placental structure, but measurements need to be standardized in order to be useful. Maternal serum analyte screening is a noninvasive test of placental biochemical function, but present serum marker alone is not sufficiently accurate to suggest its routine use in clinical practice. The use of first trimester biochemical markers in combination with uterine artery Doppler screening is promising as a potential screening tool. Prospective longitudinal studies using standardized methodology are necessary to further evaluate the choice of parameters and strategies of combination to achieve the best predictive models. PMID- 20166150 TI - Induced pluripotent stem cells generate both retinal ganglion cells and photoreceptors: therapeutic implications in degenerative changes in glaucoma and age-related macular degeneration. AB - The direct reprogramming of somatic cells to a pluripotent state holds significant implications for treating intractable degenerative diseases by ex vivo cell therapy. In addition, the reprogrammed cells can serve as a model for diseases and the discovery of drugs and genes. Here, we demonstrate that mouse fibroblast induced pluripotent stem cells (iPSCs) represent a renewable and robust source of retinal progenitors, capable of generating a wide range of retinal cell types that includes retinal ganglion cells (RGCs), cone, and rod photoreceptors. They respond to simulated microenvironment of early and late retinal histogenesis by differentiating into stage-specific retinal cell types through the recruitment of normal mechanisms. The depth of the retinal potential of iPSCs suggests that they may be used to formulate stem cell approaches to understand and treat a wide range of retinal degenerative diseases from glaucoma to age-related macular degeneration (AMD). PMID- 20166151 TI - Law, ethics, religion, and clinical translation in the 21st century--a discussion with Derek Hei. Interview by Majlinda Lako, Alan O. Trounson, Susan Rainey Daher. PMID- 20166152 TI - No evidence for clonal selection due to lentiviral integration sites in human induced pluripotent stem cells. AB - Derivation of induced pluripotent stem (iPS) cells requires the expression of defined transcription factors (among Oct3/4, Sox2, Klf4, c-Myc, Nanog, and Lin28) in the targeted cells. Lentiviral or standard retroviral gene transfer remains the most robust and commonly used approach. Low reprogramming frequency overall, and the higher efficiency of derivation utilizing integrating vectors compared to more recent nonviral approaches, suggests that gene activation or disruption via proviral integration sites (IS) may play a role in obtaining the pluripotent phenotype. We provide for the first time an extensive analysis of the lentiviral integration profile in human iPS cells. We identified a total of 78 independent IS in eight recently established iPS cell lines derived from either human fetal fibroblasts or newborn foreskin fibroblasts after lentiviral gene transfer of Oct4, Sox2, Nanog, and Lin28. The number of IS ranged from 5 to 15 IS per individual iPS clone, and 75 IS could be assigned to a unique chromosomal location. The different iPS clones had no IS in common. Expression analysis as well as extensive bioinformatic analysis did not reveal functional concordance of the lentiviral targeted genes between the different clones. Interestingly, in six of the eight iPS clones, some of the IS were found in pairs, integrated into the same chromosomal location within six base pairs of each other or in very close proximity. Our study supports recent reports that efficient reprogramming of human somatic cells is not dependent on insertional activation or deactivation of specific genes or gene classes. PMID- 20166153 TI - Photodynamic therapy: new treatment for recalcitrant Malassezia folliculitis. AB - BACKGROUND: Malassezia folliculitis commonly has been treated with oral antifungal medications. However, it has many therapeutic weaknesses such as infection relapse, drug resistance, or adverse effects like hepatotoxicity and gastrointestinal discomfort. Hence, there remains an ongoing need for alternative treatments for recalcitrant Malassezia folliculitis. Recently, many dermatologists suggest photodynamic therapy (PDT) as an alternative therapeutic option for its antimicrobial effect. OBJECTIVE: To investigate the efficacy of methyl 5-aminolevulinic acid (MAL)-PDT for the treatment of recalcitrant Malassezia folliculitis. MATERIALS AND METHODS: Six Korean patients aged 23-47 years with recalcitrant Malassezia folliculitis were enrolled in this study. The patients enrolled in this study either refused oral medication or were unable to take oral antifungal agents due to hepatotoxicity concerns. Thus, we offered these patients MAL-PDT as an alternative treatment option. For all patients, photographs of the lesion(s) were taken prior to initiating treatment. MAL cream (Metvix, Galderma, France) was applied to each lesion (located on the patients' trunks) and covered with an adhesive occlusive dressing polyurethane film (Tegaderm, 3M Healthcare, St. Paul, MN). After 3 hours, the cream was wiped off and illumination was performed immediately thereafter with non-coherent red light using light-emitting diodes (Aktilite lamp, PhotoCure, Oslo, Norway, average wavelength 630 nm, light dose 37 J/cm(2)). Illumination was performed for 7.5 minutes. Patients underwent totally three sessions of MAL-PDT at 2-week intervals. One month after the last PDT treatment, patients returned to the hospital and lesions were photographed. RESULTS: After three sessions of MAL-PDT, inflammatory lesions had decreased and improved obviously in four patients, had improved slightly in one patient, and had not improved in one patient. CONCLUSION: MAL-PDT may be an effective treatment option for patients with recalcitrant Malassezia folliculitis. However, the data on MAL-PDT are still limited, and additional controlled trials including multiple patients will be necessary to verify the results of this pilot study. PMID- 20166154 TI - Fractional CO(2) laser-assisted drug delivery. AB - BACKGROUND AND OBJECTIVES: Ablative fractional resurfacing (AFR) creates vertical channels that might assist the delivery of topically applied drugs into skin. The purpose of this study was to evaluate drug delivery by CO(2) laser AFR using methyl 5-aminolevulinate (MAL), a porphyrin precursor, as a test drug. MATERIALS AND METHODS: Two Yorkshire swine were treated with single-hole CO(2) laser AFR and subsequent topical application of MAL (Metvix(R), Photocure ASA, Oslo, Norway), placebo cream and no drug. MAL-induced porphyrin fluorescence was measured by fluorescence microscopy at skin depths down to 1,800 microm. AFR was performed with a 10.6 microm wavelength prototype CO(2) laser, using stacked single pulses of 3 millisecond and 91.6 mJ per pulse. RESULTS: AFR created cone shaped channels of approximately 300 microm diameter and 1,850 microm depth that were surrounded by a 70 microm thin layer of thermally coagulated dermis. There was no porphyrin fluorescence in placebo cream or untreated skin sites. AFR followed by MAL application enhanced drug delivery with significantly higher porphyrin fluorescence of hair follicles (P<0.0011) and dermis (P<0.0433) versus MAL alone at skin depths of 120, 500, 1,000, 1,500, and 1,800 microm. AFR before MAL application also enhanced skin surface (epidermal) porphyrin fluorescence. Radial diffusion of MAL from the laser-created channels into surrounding dermis was evidenced by uniform porphyrin fluorescence up to 1,500 microm from the holes (1,000, 1,800 microm depths). Skin massage after MAL application did not affect MAL-induced porphyrin fluorescence after AFR. CONCLUSIONS: Ablative fractional laser treatment facilitates delivery of topical MAL deeply into the skin. For the conditions of this study, laser channels approximately 3 mm apart followed by MAL application could produce porphyrins throughout essentially the entire skin. AFR appears to be a clinically practical means for enhancing uptake of MAL, a photodynamic therapy drug, and presumably many other topical skin medications. PMID- 20166155 TI - Intense pulsed light (IPL): a review. AB - BACKGROUND: Intense pulsed light (IPL) devices use flashlamps and bandpass filters to emit polychromatic incoherent high-intensity pulsed light of determined wavelength spectrum, fluence, and pulse duration. Similar to lasers, the basic principle of IPL devices is a more or less selective thermal damage of the target. The combination of prescribed wavelengths, fluences, pulse durations, and pulse intervals facilitates the treatment of a wide spectrum of skin conditions. OBJECTIVE: To summarize the physics of IPL, to provide guidance for the practical use of IPL devices, and to discuss the current literature on IPL in the treatment of unwanted hair growth, vascular lesions, pigmented lesions, acne vulgaris, and photodamaged skin and as a light source for PDT and skin rejuvenation. METHODS: A systematic search of several electronic databases, including Medline and PubMed and the authors experience on intense pulsed light. RESULTS: Numerous trials show the effectiveness and compatibility of IPL devices. CONCLUSION: Most comparative trials attest IPLs similar effectiveness to lasers (level of evidence: 2b to 4, depending on the indication). However, large controlled and blinded comparative trials with an extended follow-up period are necessary. PMID- 20166156 TI - Ablative fractional lasers (CO(2) and Er:YAG): a randomized controlled double blind split-face trial of the treatment of peri-orbital rhytides. AB - BACKGROUND AND OBJECTIVE: Ablative fractional lasers were introduced for treating facial rhytides in an attempt to achieve results comparable to traditional ablative resurfacing but with fewer side effects. However, there is conflicting evidence on how well this goal has generally been achieved as well as on the comparative value of fractional CO(2) and Er:YAG lasers. The present study compares these modalities in a randomized controlled double-blind split-face study design. STUDY DESIGN/MATERIALS AND METHODS: Twenty-eight patients were enrolled and completed the entire study. Patients were randomly assigned to receive a single treatment on each side of the peri-orbital region, one with a fractional CO(2) and one with a fractional Er:YAG laser. The evaluation included the profilometric measurement of wrinkle depth, the Fitzpatrick wrinkle score (both before and 3 months after treatment) as well as the assessment of side effects and patient satisfaction (1, 3, 6 days and 3 months after treatment). RESULTS: Both modalities showed a roughly equivalent effect. Wrinkle depth and Fitzpatrick score were reduced by approximately 20% and 10%, respectively, with no appreciable difference between lasers. Side effects and discomfort were slightly more pronounced after Er:YAG treatment in the first few days, but in the later course there were more complaints following CO(2) laser treatment. Patient satisfaction was fair and the majority of patients would have undergone the treatment again without a clear preference for either method. CONCLUSIONS: According to the present study, a single ablative fractional treatment session has an appreciable yet limited effect on peri-orbital rhytides. When fractional CO(2) and Er:YAG lasers are used in such a manner that there are comparable post operative healing periods, comparable cosmetic improvement occurs. Multiple sessions may be required for full effect, which cancels out the proposed advantage of fractional methods, that is, fewer side effects and less down time. PMID- 20166157 TI - Long-term efficacy of a fractional resurfacing device. AB - BACKGROUND AND OBJECTIVE: Recently, there has been much debate regarding the long term efficacy of fractional resurfacing devices. While pulsed CO(2) laser resurfacing is considered a highly effective treatment, fractionated resurfacing is a newer modality and its long-term efficacy has yet to be assessed. We report the long-term outcomes of subjects previously treated with fractional CO(2) resurfacing for photodamaged skin and acne scars. STUDY DESIGN/MATERIALS AND METHODS: Ten subjects from our previous studies who received fractional resurfacing for the treatment of acne scarring and photodamage returned for long term follow-up visits at 1 and 2 years, respectively. Investigators graded maintenance of improvement on a quartile scale based on clinical photography. RESULTS: Subjects maintained 74% of their overall improvement at their long-term visits compared to 3-month follow-up visits. While clinical improvement was maintained long-term, the results were not as remarkable as those seen at 3-month visits. The authors speculate that results seen at 3 months may be enhanced by persistent inflammatory changes, as evidenced by heat shock protein 47 activity and ongoing collagen remodeling seen in previous histologic studies. Relaxation of tightening is to be expected with any procedure along with the natural progression of aging. However, patient satisfaction was upheld long-term. CONCLUSION: Fractional CO(2) laser resurfacing does have long-term efficacy and persistence of improvement of acne scarring and photodamage compared to baseline. However, additional treatments may be necessary to enhance long-term results. PMID- 20166158 TI - Paring and intense pulsed light versus paring alone for recalcitrant hand and foot warts: a randomized clinical trial with blinded outcome evaluation. AB - BACKGROUND AND OBJECTIVES: Treatment of recalcitrant viral warts remains a therapeutic challenge. Intense pulsed light (IPL) has been suggested effective to clear wart tissue. The objective was in a randomized controlled trial to assess the efficacy of paring followed by IPL versus paring alone for recalcitrant hand and foot warts. MATERIALS AND METHODS: Eighty-nine patients with recalcitrant hand and foot warts were included and randomized (1:1) to three treatments at 3 week intervals with either paring of warts followed by IPL or paring of warts alone. IPL was given with the Ellipse Flex IPL system (Danish Dermatologic Development A/S, Horsholm, Denmark, 400-950 nm, 5.5 millisecond pulse duration in double pulses with a 2 millisecond interval, 26.0-32.5 J/cm(2) repetitive passes). The primary outcome was complete and partial clearance of warts evaluated by blinded photo assessment at 6 weeks after final treatment. Secondary outcomes were treatment related pain and adverse reactions. RESULTS: We found no significant difference in clearance of warts between the two intervention groups (OR 1.64, 95% confidence interval 0.62-4.38). Paring followed by IPL resulted in complete or partial clearance of wart tissue in nine (22%) and five patients (12.2%) versus five (13.5%) and four patients (10.8%) from paring alone. Mostly plantar warts were treated (92.1%). The pain intensity after paring and IPL was moderate and significantly higher than the pain intensity after paring alone (P<0.0005). No adverse reactions were observed from the two interventions. CONCLUSION: Paring followed by IPL did not differ significantly from paring alone in clearance of recalcitrant hand and foot warts but caused significantly more pain. PMID- 20166159 TI - Phototoxicity is not associated with photochemical tissue bonding of skin. AB - BACKGROUND AND OBJECTIVE: We have developed a light-activated method called photochemical tissue bonding (PTB) for closing wounds using green light and a photosensitizing dye (Rose Bengal-RB) to initiate photochemical crosslinking of wound surface proteins. These studies were designed to determine whether RB causes phototoxicity during closure of skin incisions with PTB. STUDY DESIGN/MATERIALS AND METHODS: RB phototoxicity was evaluated after sealing incisions in porcine skin ex vivo and rabbit skin in vivo using PTB (1 mM RB, 100 J/cm(2), 532 nm, 0.3 or 0.5 W/cm(2).) Dead cells were identified by pyknotic nuclei and eosinophilic cytoplasm on H&E-stained sections. The influence on RB phototoxicity of penetration of RB into the wound wall (by confocal microscopy), RB concentration in the tissue (by extraction), and fluence of 532 nm reaching depths in skin (calculated from skin optical properties) were investigated. RESULTS: No significant differences were found in the percent dead cells in PTB treated and control incisions in porcine skin at 24 hours or in rabbit skin at 2 hours and 3 and 7 days after surgery. RB was retained in a approximately 100 microm wide band next to the wound wall. The mean RB concentration within this band was 0.42+/-0.03 mM. Monte Carlo modeling of light distribution indicated that the fluence rate decreased from the subsurface peak to 0.5 W/cm(2) in the mid-dermis (approximately 350 microm.) In vitro RB phototoxicity to dermal fibroblasts yielded an LD(50) of 0.50+/-0.09 J/cm(2) when the cells contained 0.46 mM RB. CONCLUSIONS: PTB does not cause phototoxicity when used to repair skin wounds even though the RB concentration and 532 nm fluence in the mid-dermis during PTB are much greater than the LD(50) for RB phototoxicity in vitro. These results indicate that phototoxicity is not a concern when using PTB for tissue repair. PMID- 20166160 TI - A split-face study of intense pulsed light on photoaging skin in Chinese population. AB - BACKGROUND AND OBJECTIVES: Intense pulsed light (IPL) is regarded as the gold standard of nonablative photo-rejuvenation. Yet there is still a need to observe its efficacy and safety on dark skin using a split-face module. STUDY DESIGN/MATERIALS AND METHODS: Twenty-four Chinese women with photoaging were enrolled in this study. Patients were randomized to receive four IPL treatments at 3- to 4-week intervals on one side of face, with the other side spared as control. Changes of photoaging were evaluated using a global evaluation, an overall self-assessment, a Mexameter and a Corneometer. Skin biopsies were taken after four sessions of treatment on one side of face. The melanocyte density and the contents of melanin, collagen fibers, and elastic fibers were stained and used to evaluate the improvement on dyschromia and other signs of photoaging. RESULTS: The global scores of photoaging on treated side decreased significantly from 3.02 to 1.22, while it remained unchanged on the untreated side. Twenty-one of 24 patients (87.5%) rated their improvement as excellent or good. The difference on the values of melanin index and erythema index on treated side were significantly larger than those on untreated side after the 1st session, the 4th session and at 3-month follow-up (P<0.05). The melanin contents were significantly decreased and the collagen fibers were obviously increased only on treated side (P<0.05). Adverse effects of treated side were limited to mild pain and transient erythema. CONCLUSION: Using this split-face module, IPL treatment is proved both clinically and histologically to be effective in treating photoaging skin in Chinese population. Adverse effects were minimal and acceptable. PMID- 20166161 TI - Long-term blood vessel removal with combined laser and topical rapamycin antiangiogenic therapy: implications for effective port wine stain treatment. AB - BACKGROUND AND OBJECTIVES: Complete blanching of port wine stain (PWS) birthmarks after laser therapy is rarely achieved for most patients. We postulate that the low therapeutic efficacy or treatment failure is caused by regeneration and revascularization of photocoagulated blood vessels due to angiogenesis associated with the skin's normal wound healing response. Rapamycin (RPM), an antiangiogenic agent, has been demonstrated to inhibit growth of pathological blood vessels. Our objectives were to (1) investigate whether topical RPM can inhibit reperfusion of photocoagulated blood vessels in an animal model and (2) determine the effective RPM concentration required to achieve this objective. STUDY DESIGN/MATERIALS AND METHODS: For both laser-only and combined laser and RPM treated animals, blood vessels in the dorsal window chambers implanted on golden Syrian hamsters were photocoagulated with laser pulses. Structural and flow dynamics of blood vessels were documented with color digital photography and laser speckle imaging to evaluate photocoagulation and reperfusion. For the combined treatment group, topical RPM was applied to the epidermal side of the window daily for 14 days after laser exposure. RESULTS: In the laser-only group, 23 out of 24 photocoagulated blood vessels reperfused within 5-14 days. In the combined treatment group with different RPM formulae and concentrations, the overall reperfusion rate of 36% was much lower as compared to the laser-only group. We also found that the reperfusion rate was not linearly proportional to the RPM concentration. CONCLUSIONS: With topical RPM application, the frequency of vessel reperfusion was considerably reduced, which implies that combined light and topical antiangiogenic therapy might be a promising approach to improve the treatment efficacy of PWS birthmarks. PMID- 20166162 TI - Enhancement of skin optical clearing efficacy using photo-irradiation. AB - BACKGROUND AND OBJECTIVES: Tissue optical clearing technique based on immersion of tissues into optical clearing agents (OCAs) can reduce the scattering and enhance the penetration of light in tissue. However, the barrier function of epidermis limits the penetration of OCAs, and hence is responsible for the poor optical clearing efficacy of skin by topical action. In this study, a variety of light irradiation was applied to increase permeability of agents in skin and improve the optical clearing efficacy. STUDY DESIGN/MATERIALS AND METHODS: Different light sources with different dose, i.e, CO(2) laser, Nd:YAG laser (532 and 1,064 nm) with different pulse modes and Intense Pulsed Light (IPL) (400-700 and 560-950 nm) were used to irradiate rat skin in vivo, and then glycerol was applied onto the irradiated zone. VIS-NIR spectrometer was utilized to monitor the changes of reflectance. In vitro skin samples were also irradiated by Q switched Nd:YAG laser (1,064 nm) and then treated by glycerol for 10-60 minutes. Based on the measurement of the reflectance and transmittance of the samples, the optical properties of skin and penetration depth of light were calculated. RESULTS: Results show that photo-irradiation with appropriate dose combining with the following glycerol treatment is able to reduce in vivo skin reflectance. Compared with the control group, the maximal changes in reflectance are ninefold at 575 nm and eightfold at 615 nm, respectively, which were caused by Q-switched 1,064-nm Nd:YAG laser irradiation and following glycerol treatment. The results for in vitro skin demonstrate that the joint action can significantly increase the optical penetration depth in samples. CONCLUSIONS: The combination of Q switched Nd:YAG (1,064 nm) laser and glycerol could enhance optical skin clearing efficacy significantly. This study provides a non-invasive way to improve the optical clearing of skin, which will benefit the skin optical therapy. PMID- 20166163 TI - Radiant near infrared light emitting Diode exposure as skin preparation to enhance photodynamic therapy inflammatory type acne treatment outcome. AB - BACKGROUND AND OBJECTIVE: An alternative approach in the treatment of acne vulgaris is photodynamic therapy (PDT) that uses light and aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) production to eradicate Propionibacterium acnes found in acne lesions. PpIX formation is dependent on ALA percutaneaous penetration. In this study, to enhance ALA penetration and subsequent accumulation of PpIX, skin temperature was increased with radiant infrared (IR) prior to ALA-PDT application and compared to ALA-PDT alone in the treatment of inflammatory acne. STUDY DESIGN/MATERIALS AND METHODS: Ten patients exhibiting inflammatory acne with a lesion count of > or =10 were assigned to a split face or split back group. One side was pre-treated for 15 minutes with radiant IR light emitting diode (LED) (970 nm), while the other side was used as control. ALA was then applied after which PDT LED (630 nm) was performed on the entire face or back surface. Blinded lesion counts and clinical global assessment of severity were performed based on digital photographs before and 4 weeks after the PDT procedure. RESULTS: This randomized, controlled, and rater-blinded trial revealed a significant difference in median reduction of inflammatory lesions on the IR pre-treated (73%, 95% confidence interval (CI) 51-81%) versus the control side (38%, 95% CI 8-55%) 1 month after PDT (P<0.0001). Clinical assessment of severity was also significantly lower on the IR-treated side than on the control side (median 1, 95% CI 0.74-1.34 vs. 2, 95% CI 1.17-1.72). No unusual treatment related adverse effects were observed. CONCLUSION: The reported therapeutic effects may be due to enhanced induction of alterations in transcutaneous diffusion kinetics of the photosensitizer at higher skin temperature and/or conversion of ALA to PpIX. Pre-PDT radiant IR LED exposure appears to be a promising method to enhance PDT efficacy for the treatment of acne lesions. PMID- 20166164 TI - Laser-mediated fixation of collagen-based scaffolds to dermal wounds. AB - BACKGROUND AND OBJECTIVE: Collagen scaffolds are popular for the reconstitution of dermal equivalents. Usually, these scaffolds are fixed with sutures or staples and in many cases these devices have to be removed in a second procedure. Laser mediated tissue welding in a wet environment is a potential alternative for collagen scaffold fixation and may be advantageous to suture, staple, and tissue glue fixation. MATERIALS AND METHODS: Welding was performed with a continuous wave diode laser system emitting radiation at a wavelength of 968 nm. Tensile strength after fixation to porcine skin and laser parameters were determined in vitro. In vivo, 24 excisional deep partial thickness wounds were created on flanks of two Goettingen mini pigs and covered with collagen scaffolds. These were randomized and fixated with either (1) staples, (2) fibrin glue, or (3) laser-mediated welding. Tissue biopsies for histological analysis were periodically performed and analyzed for wound healing progression, epidermal thickness, and extracellular matrix formation. RESULTS: Biomechanical stability after laser welding was time dependent. A dwell time of up to 10 seconds led to a strong bonding with a tensile strength of more than 30 g. In vivo, the wound healing process was macroscopically comparable in all groups and showed no significant differences. Microscopic analysis determined a more progressed and quicker wound closure in both the laser and staples group compared to the fibrin glue fixated scaffold. Laser-mediated fixation led to a significantly reduced epidermal thickness when compared with stapling or fibrin glue (P < 0.05). CONCLUSIONS: Laser tissue welding is a feasible approach for temporary fixation of collagen scaffolds to the wound bed. It improves wound healing properties and may lead to faster wound healing and cosmetically better scarring. Laser tissue welding is thus a very interesting and promising alternative to currently established fixation methods in a single step, no touch procedure. PMID- 20166165 TI - Introduction. PMID- 20166166 TI - Photodynamic photorejuvenation of the face with a combination of microneedling, red light, and broadband pulsed light. AB - BACKGROUND: High efficacy and safety, coupled with in-office, short contact protocols have made photodynamic therapy (PDT) with aminolevulenic acid (ALA) for the treatment of actinic keratoses a mainstay option over the last decade. Clinical improvement in photoaged skin has also been reported to accompany PDT treatments. The study objective was to maximize epidermal penetration and subsequent activation of ALA for the treatment of photodamaged facial skin, utilizing a microneedle roller prior to incubation and combined irradiation with red light and broadband pulsed light in a single treatment. MATERIALS AND METHODS: A full-face treatment of 21 patients was performed with 630 nm light and broadband pulsed light after multiple passes with a microneedle roller and 1-hour ALA incubation. The primary endpoint was clinical improvement, scored during two separate live assessments by three physicians blinded to previous scores, using a 5-point standardized photoaging scale. The secondary endpoint was evaluation of patient satisfaction based on a quartile scale comparing baseline to 6-month post treatment photography. RESULTS: Statistically significant improvement was seen in the global photoaging scores, as well as sub-components of the scale (fine lines, mottled pigmentation, sallowness, tactile roughness, and telangiectasias) at 3 months as compared with baseline live assessment, and at 6-month live assessment compared with the 3 months. In addition, 90% of patients judged clinical improvement to be greater than 50% at 6 months compared to baseline photography. CONCLUSION: Use of a microneedle roller to "pre-treat" prior to application of ALA appears to be well tolerated and allows for even absorption and perhaps deeper penetration of ALA following a defined incubation period. Use of red light and broadband pulsed light allowed for deeper activation of ALA, potentially accounting for marked clinical improvement in photoaging. PMID- 20166167 TI - Rapid detection of Orthopoxvirus by semi-nested PCR directly from clinical specimens: a useful alternative for routine laboratories. AB - Orthopoxvirus (OPV) has been associated with worldwide exanthematic outbreaks, which have resulted in serious economic losses as well as impact on public health. Although the current classical and molecular methods are useful for the diagnosis of OPV, they are largely inaccessible to unsophisticated clinical laboratories. The major reason for the inaccessibility is that they require both virus isolation and DNA manipulation. In this report, a rapid, sensitive and low cost semi-nested PCR method is described for the detection of OPV DNA directly from clinical specimens. A set of primers was designed to amplify the conserved OPV vgf gene. The most useful thermal and chemical conditions were selected and minimum non-inhibitory dilutions were determined. More than 100 Brazilian Vaccinia virus (VACV) field clinical specimens were tested using this semi-nested PCR in order to confirm its applicability. Cowpox virus was also detected by PCR from the ear scabs of scarified Balb/c mice. In addition, the method was highly sensitive for the detection of VACV DNA in murine blood and excreta, which are among the suggested reservoirs of OPV. Together, these data suggest that semi nested PCR can be used for initial screening for OPV and as a routine diagnostic laboratory method. PMID- 20166168 TI - Molecular characterization of Sapovirus detected in a gastroenteritis outbreak at a wedding hall. AB - Sapovirus (SaV) is an important pathogen of human acute gastroenteritis. A gastroenteritis outbreak occurred at a wedding hall in October 2007 in Ehime Prefecture, Japan. One hundred nine people who had either attended wedding parties or had eaten a box lunch at a conference held at the same hall complained of gastroenteritis symptoms. Among these 109 people, stool specimens from 56 patients were available for pathogen screening, and 20 (35.7%) of these specimens were positive for SaV, of whom 18 showed symptoms. The numbers of cDNA copies of the specimens ranged from 2.36 x 10(6) to 3.03 x 10(10) for symptomatic patients, and 2.19 x 10(6) and 1.18 x 10(9) per gram of stool for two asymptomatic food handlers. The incubation periods of the 18 symptomatic patients ranged from 14.5 to 99.5 hr. Identical nucleotide sequence types of SaV; that is, a single synonymous nucleotide difference (transition) or microheterogeneity, was detected in stool specimens from the symptomatic patients and the asymptomatic food handlers, with the direct nucleotide sequence of approximately 2.3 kb 3' end of the genome. Based on the phylogenetic analysis with the complete capsid nucleotide sequence, these strains were clustered into genogroup IV. This outbreak was thought to be caused by a single source, and underscores the importance of proper hygiene in the environment and/or in food-handling practices to control SaV outbreaks. PMID- 20166169 TI - Hepatitis C virus infection in a Japanese leprosy sanatorium for the past 67 years. AB - Oku-Komyo-En is one of the national leprosy sanatoria, located on a small island in Setouchi city, Okayama prefecture of Japan since 1938. Since autopsies were carried out routinely on almost all patients who had died in the sanatorium up to 1980, approximately 1,000 formalin-fixed autopsy tissue samples were available for analysis. When these samples were reviewed, the pathological data indicated a sharp rise in the death rate caused by cirrhosis of the liver and hepatocellular carcinoma (HCC) since 1960 and 1970, respectively. Hepatitis C virus (HCV) infection is a common cause of HCC in Japan. The presence of HCV RNA was demonstrated in paraffin sections prepared from the autopsied liver tissue fixed in formalin for a prolonged period of time, by employing nested RT-PCR using type specific primers. The data showed that HCV RNA was detectable in samples of the liver archived as early as 1940, representing the liver tissues kept in formalin for up to 67 years. HCV genotypes 1b and 2a were found by RT-PCR at 85.7% and 14.3%, respectively, in patients with leprosy. PMID- 20166170 TI - Clinical and virological effects of long-term (over 5 years) lamivudine therapy. AB - Ideally, long-term lamivudine therapy should not induce tyrosine-methionine aspartate-aspartate (YMDD) mutants (reverse transcription [rt]; rt M204I/V) in patients with chronic hepatitis B. There is little or no information on the clinical features of patients who do not develop such mutants. We analyzed 368 patients who received lamivudine therapy for more than 6 months between 1995 and 2003. Among them, 98 patients were negative for YMDD mutants during 5-year lamivudine therapy. Multivariate analysis identified hepatitis B e antigen (HBeAg) negativity, lack of cirrhosis, and high gamma glutamyltranspeptidase (GGTP) level as independent factors associated with lack of emergence of YMDD mutants during 5-year treatment. In these 98 patients, 21 patients developed YMDD mutants in the 5-year posttreatment follow-up. Old age was identified as the only factor associated with the emergence of YMDD mutants during that period. For all patients, 53 showed no elevation of alanine aminotransferase (ALT) or viral load after emergence of YMDD mutants during 5 years. Short latency to emergence of YMDD mutants, mixed (tyrosine-isoleucine-aspartate-aspartate (YIDD) [rtM204I] + tyrosine-valine-aspartate-aspartate (YVDD) [rtM204V]) type, and low ALT level were identified as independent factors associated with elevation ALT or viral load. HBeAg negativity, lack of cirrhosis, and high GGTP level were associated with lack of emergence of YMDD mutants during 5-year period. Young age protected against emergence of YMDD mutants over the 5-year period. Moreover, after the emergence of YMDD mutants, short latency to the emergence of YMDD mutant, mixed type mutants, and low baseline ALT level were associated with elevation of ALT or viral load. PMID- 20166171 TI - A comparison of the VP1, VP2, and VP4 regions for molecular typing of human enteroviruses. AB - The VP4, VP2, and VP1 gene regions were evaluated for their usefulness in typing human enteroviruses. Three published RT-PCR primers sets targeting separately these three gene regions were used. Initially, from a total of 86 field isolates (36 HEV-A, 40 HEV-B, and 10 HEV-C) tested, 100% concordance in HEV-A was identified from all three gene regions (VP4, VP2, and VP1). However, for HEV-B and HEV-C viruses, only the VP2 and VP1 regions, and not VP4, showed 100% concordance in typing these viruses. To evaluate further the usefulness of VP4 in typing HEV-A enteroviruses, 55 Japanese and 203 published paired VP4 and VP1 nucleotide sequences were also examined. In each case, typing by VP4 was 100% in concordance with typing using VP1. Given these results, it is proposed that for HEV-A enteroviruses, all three gene regions (VP4, VP2, and VP1), would be useful for typing these viruses. These options would enhance the capability of laboratories in identifying these viruses and would greatly help in outbreaks of hand, foot, and mouth disease. PMID- 20166172 TI - Incidence of hepatocellular carcinoma in patients with chronic hepatitis B virus infection who have normal alanine aminotransferase values. AB - The importance of alanine aminotransferase (ALT) levels in the progression of hepatitis B virus (HBV) infection remains a subject of debate. This study sought to identify independent risk factors involved in development of hepatocellular carcinoma (HCC), particularly in patients with chronic HBV infection who have normal ALT values. Data from 381 consecutive hepatitis B patients were analyzed with average ALT integration values < or = 40 IU/L and follow-up periods of > 3 years. Integration values were calculated from biochemical tests, and serological markers associated with the cumulative incidence of HCC were analyzed. HCC developed in 17 of the 381 patients (4.5%) during the follow-up period. Male sex (hazard ratio, 6.011 [95% confidence interval: 1.353-26.710], P = 0.018), high HBV-DNA levels (> or = 5.0 log copies/ml; 5.125 [1.880-13.973], P = 0.001), low platelet counts (< 15.0 x 10(4)/mm(3); 4.803 [1.690-13.647], P = 0.003), and low total cholesterol levels (< 130 mg/dl; 5.983 [1.558-22.979], P = 0.009) were significantly associated with greater incidence of HCC development. High HBV-DNA levels and low platelet counts are associated with the development of HCC in patients infected with hepatitis B who have normal ALT values. Therefore, maintenance of low HBV-DNA levels is important for the prevention of HCC in patients with low platelet counts, particularly in patients whose ALT values fall within the current normal range. PMID- 20166173 TI - Prevalence, evolution, and features of infection with human papillomavirus: a 15 year longitudinal study of routine screening of a women population in the north of Spain. AB - Determination of the prevalence of type-specific human papillomavirus (HPV) is important for the development of new vaccines and to prevent malignancy. The objective of this study was to determine HPV infection in two areas in the north of Spain, and their evolution in the last 15 years. Between 1991 and 2007, 7,930 fresh cervical swabs were obtained from 5,554 women (37.8 +/- 11.8 years old). From them, 425 have been followed-up for an average of 3.7 +/- 2.08 years after sampling (range 2-14.6), and 71 for 7.7 +/- 2.2 years (range 5-14). Methods based on polymerase chain reaction (PCR) were carried out. Samples from 1,598 (28.8%) women were positive for HPV: 40.9% were under 25 years of age, 34.2% in the 25-35 year age group, 27.2% in the 36-45 year age group, and 19.6% older than 45 years (P < 0.001). HPV was found in 34.4% of the women with cytological alterations versus 23% of women without cervical changes (P < 0.0001). HPV-16 was present in 25.8% of the women, although the study identified 26 different HPV genotypes. After 3 years of follow-up, HPV remained or became undetectable in 87% of the cases, and in 5 years 70.3%. The prevalence of HPV is associated with younger women and women with cytological changes in the cervix. Although HPV-16 is more prevalent, HPV types not included in available vaccines were found the most commonly. The low 3-year (even 5-year) cumulative incidence rate of HPV infection suggests that cervical screening every 3 (or even 5) years is safe and effective. PMID- 20166175 TI - Human papillomavirus (HPV) prevalence and type distribution, and HPV-associated cytological abnormalities in anal specimens from men infected with HIV who have sex with men. AB - Human papillomavirus (HPV) detection and typing using the PapilloCheck test and cytological examination were carried out in anal samples collected from 67 men seropositive for human immunodeficiency virus (HIV) who have sex with men. Fifty (74.6%) patients had anal HPV infection, 46 (68.7%) had high-risk (HR) HPV infection, and 38 (56.7%) had multiple infection involving 2-9 (median, 3) HPV types. The HPV types identified most frequently were HPV 44/55 (19.4%), HPV 53 (19.4%), HPV 16 (16.4%), HPV 39 (16.4%), and HPV 42 (14.9%). Thirty-two of the 66 interpretable smears (48.5%) revealed cytological abnormalities: 9 (13.4%) atypical cells of undetermined significance, 20 (30.3%) low-grade intraepithelial lesions, and 3 (4.5%) high-grade intraepithelial lesions. Cytological abnormalities were associated significantly with HPV detection (P < 0.001), multiple HPV infection (P < 0.001), and increased number of HPV types (P < 0.001). The HPV types associated most frequently with cytological abnormalities were HPV 39 (28.1%), HPV 42 (28.1%), HPV 53 (28.1%), HPV 16 (25.0%), HPV 44/55 (25.0%), and HPV 59 (21.9%). HPV DNA detection as well as cytological abnormalities were associated neither with HIV RNA detection in plasma nor with CD4+ T-cell count. Differences in age or in time since HIV acquisition were not observed in patients with or without cytological abnormalities. The present study confirms the high prevalence of anal HR-HPV infection and cytological abnormalities in men infected with HIV who have sex with men. HPV testing and/or cytological analysis may be helpful in selecting the patients to be referred to proctological examination. PMID- 20166174 TI - Genetic variation of G4P[6] rotaviruses: evidence for novel strains circulating between the hospital and community. AB - One hundred forty-six fecal specimens collected between 2007 and 2008 from infants with acute gastroenteritis were screened for rotavirus by ELISA with VP6 specific antibody. One hundred twenty-three of the samples (84.2%) were confirmed to be positive for group A rotavirus (community-acquired, n = 90 [73.2%] and nosocomial, n = 33 [26.8%]), and were typed subsequently using RT-PCR and sequence analysis methods. Determination of G- and P-type combinations showed that G4P[6] (78.9%) was the most common strain, followed by G3P[8] (7.3%), G1P[8] (6.5%), G2P[4] (0.8%), G2P[6] (0.8%), G1P[6] (0.8%), and G9P[8] (0.8%) strains. Of the 97 G4P[6] strains, 62 (63.8%) were responsible for community-acquired cases and 35 (36.1%) were hospital-acquired cases. Phylogenetic analysis of the VP7 gene from the G4P[6] strains revealed that both the community-acquired and nosocomial strains were segregated to the human rotaviruses circulating world wide, including the prototype vaccinal strain, ST3, which constituted a novel sublineage in lineage 1. Owing to the recent emergence of G4P[6] rotaviruses within the hospital, as well as in the community, the findings from this study are important since they provide new information concerning the community and nosocomial spread of rotaviruses. PMID- 20166176 TI - Comprehensive serotyping and epidemiology of human adenovirus isolated from the respiratory tract of Korean children over 17 consecutive years (1991-2007). AB - Among the 53 serotypes of human adenoviruses (HAdVs), identified to date, only a limited number have been associated with human respiratory infections. The epidemiology of each of the serotypes differs depending on the location and/or time of surveillance. This study was performed to elucidate the epidemiology of HAdV respiratory infections by comprehensive serotyping of the HAdVs isolated from the respiratory tract of Korean children. HAdVs isolated from respiratory specimens of Korean children over 17 consecutive years (1991-2007) were typed by the neutralization test or molecular methods, including two-sets of multiplex PCR assays, and/or sequence analysis of the hexon gene. From January 1991 through December 2007, a total of 741 isolates were obtained from nasal aspirates of children hospitalized or requiring medical treatment in the emergency room. All isolates were type-determined successfully and 13 different serotypes were identified, which included HAdV serotypes 1-8, 11, 19, 34, 37, and 41. HAdV-3 (n = 285, 37.7%) and HAdV-7 (n = 181, 23.9%) were the predominant serotypes; HAdV-8, -11, -19, -34, -37, and -41 were not usually associated with respiratory diseases. HAdV-3 was present both during outbreaks and in sporadic cases. HAdV-7 emerged in a very large outbreak, followed by smaller outbreaks. HAdV-1, -2, -4, 5, and -6 were isolated sporadically throughout the study period. In conclusion, a total of 13 different serotypes of HAdV were detected among Korean children with respiratory tract infections. HAdV-3 and HAdV-7 were the most common serotypes, and they were associated with HAdV outbreaks. PMID- 20166177 TI - Recurrent cytomegalovirus colitis with megacolon in an immunocompetent elderly man. AB - Gastrointestinal infection with cytomegalovirus (CMV) is uncommon in immunocompetent hosts. The case of a 70-year-old male with CMV colitis, who has no history of chronic inflammatory bowel disease or immunodeficiency is described. Diagnosis was aided by the identification of inclusion bodies that reacted positively for CMV by immunohistochemical testing in biopsy specimens from the colonic mucosa. His hospital course was characterized by poor improvement of his symptoms after the CMV infection was treated with ganciclovir, and the occurrence of megacolon. A repeat colonoscopy with biopsy revealed a recurrence of the CMV infection. Although CMV colitis is common in immunocompromised patients, we believe this is the first case of CMV colitis with megacolon and recurrent CMV infection in an immunocompetent patient. Colitis caused by CMV colitis should be considered in elderly people with diarrhea. PMID- 20166178 TI - Circulating human group A rotavirus genotypes in Malaysia. AB - This study examined the temporal distribution of rotavirus genotypes in Malaysia. Rotaviruses from children with diarrhea admitted to hospitals in 1996 (n = 93) and 2007 (n = 12) in two different regions of Peninsular (West) Malaysia were analyzed for their G and P genotypes using a hemi-nested RT-PCR assay. In the 2007 samples, the dominant strain was G9P[8]. It was identified in 42% of the samples. Different strains all possessing the G1 genotype were identified in the rest of the samples. In contrast, 81% of the samples collected in 1996 were the G1P[8] strain. No strains with G9 genotype were detected in samples collected in 1996. PMID- 20166179 TI - Evaluation of the performance of the novel PapilloCheck HPV genotyping test by comparison with two other genotyping systems and the HC2 test. AB - The novel PapilloCheck genotyping test was compared with SPF10 PCR LiPav1 and PGMY09/11 on hybrid capture 2 (HC2)-pretested samples. From results of 826 cervical samples detection rates and kappa values for the tests were calculated using a HPV type consensus definition. With PapilloCheck HPV types 53, 56, and 33 were found with a sensitivity of 100%. The lowest detection rate was observed for HPV 35 (72.2%). The SPF10 PCR LiPav1 was found to be 100% positive for HPV 18, 31, 53, 56, and 35 and lowest for HPV 59 (81%). The PGMY09/11 system detected only HPV 59 at 100% detection rate and showed lowest sensitivity for HPV 56 (40.5%). Multiple infection rates ranged from 25.8% (PGMY09/11 PCR-LBA), over 39.5% (PapilloCheck) to 55.9% (SPF10 PCR LiPav1). In samples with higher viral DNA load detection rates and concordance between the genotyping tests increases. The kappa values in comparison to the HPV consensus type ranged from k = 0.21 to k = 0.82 for comparing SPF10 PCR with the HPV consensus type, while values for PGMY09/11 PCR ranged from k = 0 to k = 0.96 and were best for the PapilloCheck (k = 0.49-0.98). Detection rates for the identification of high-grade cervical intraepithelial neoplasia (CIN2+) ranged from 93.7% (PGMY09/11 PCR) to 98.4% (PapilloCheck, SPF10 PCR, HC2). In conclusion, this study shows that the PapilloCheck give comparable results to established PCR methods. However, these results also show a necessity for the standardization of genotype-specific HPV detection assays. PMID- 20166180 TI - Analysis of hepatitis C virus strains circulating in Republic of the Congo. AB - The aim of this study was to assess the seroprevalence, viremia, genotype distribution, and demographic history of hepatitis C virus (HCV) in the Republic of the Congo. Testing was carried out on sera samples collected in 2005 from 807 Bantus belonging to the Kongo, Teke, and Ngala subgroups and 80 Pygmies. Positive HCV serology was found in 50 (5.6%) individuals including 31 (60%) who were viremic. Seroprevalence increased with age with a cutoff at 50 years: 2.8% <50 versus 12% >50. Twenty-one strains belonged to four described subtypes, that is, 4c in eight cases, 4h in two, 4k in three, and 4r in eight. Ten strains could not be assigned to any known subtype and may represent six new variants, that is, subtype 4 in five cases and subtype 2 in one. Evolutionary analysis of subtype 4c and 4r sequences indicated a period of enhanced transmission in the mid-twentieth century probably due to iatrogenic causes. This study underlines the high genetic diversity of strains in the Republic of the Congo with nine subtypes 4 and one subtype 2. PMID- 20166182 TI - Identification of a dengue virus-specific HLA-A*0201-restricted CD8+ T cell epitope. AB - In this study, a combination of epitope-prediction programs and in vitro assays was used to identify dengue virus (DENV)-specific CD8(+) T cell epitopes. Peripheral blood mononuclear cells (PBMCs) isolated from patients who recovered from dengue fever were stimulated with candidate epitope peptides derived from DENV, which were predicted by using SYFPEITHI and RANKpep epitope-prediction programs. The IFN-gamma ELISpot results and the results of intracellular staining of IFN-gamma showed that peptides NS4b_40 (TLYAVATTI), E_256 (QEGAMHTAL), NS3_205 (LPAIVREAI), NS5_210 (SRNSTHEMY), and NS3_207 (AIVREAIKR) could induce the recall response of CD8(+) T cells. Furthermore, the results of the MHC-peptide complex stabilization assay revealed that peptide NS4b_40 (TLYAVATTI) has a high affinity for HLA-A*0201 molecules. The IFN-gamma ELISpot results and staining of intracellular IFN-gamma confirmed that this peptide could induce high-level CD8(+) T cell response in HLA-A*0201 positive PBMCs. Peptide NS4b_40 (TLYAVATTI) was identified as a novel DENV-specific HLA-A*0201-restricted CD8(+) T cell epitope. PMID- 20166181 TI - Analysis of complete genome sequences of swine hepatitis E virus and possible risk factors for transmission of HEV to humans in Korea. AB - The hepatitis E virus (HEV) is an emerging zoonotic agent, for which pigs are the most important reservoir. Complete genome sequences of two swine HEV strains, designated swKOR-1 and swKOR-2, were determined via RT-PCR and RACE-PCR. The strains contained genomes composed of 7,222- and 7,221-bp excluding the poly(A) tails, respectively. The swKOR-1 and swKOR-2 strains were classified into subtype 3a of genotype 3 via phylogenetic analysis. These strains formed a distinctive cluster in the phylogenetic tree with human and swine HEVs isolated in the USA and human HEVs isolated in Japan. Anti-HEV antibodies were identified via ELISA in 8 of 99 (8.1%) cats, whereas, among 115 cattle and 213 dogs, no HEV-specific antibodies were detected. The conserved RNA-dependent RNA polymerase (RdRp) gene of HEV could be detected via RT-PCR in 8.7% of raw oysters collected from coastal regions in Korea. The HEV RNAs detected in oysters were identified as belonging to subtype 3a. The HEV RNAs in oysters most closely resembled that of the swKOR-2 strain. They also showed a close genetic relationship with the swKOR-1 strain and the swine and human HEVs isolated in the USA. This is the first report describing the detection in oysters of HEV that may have originated from genotype 3 swine HEV in Korea. Pigs and cats infected with HEV, as well as oysters contaminated with HEV, are potential risk factors for HEV transmission to humans. PMID- 20166183 TI - Increased proportion of the CD56(bright) NK cell subset in patients chronically infected with hepatitis C virus (HCV) receiving interferon-alpha and ribavirin therapy. AB - Natural killer (NK) cells are implicated in the regulation of a protective immune response in patients chronically infected with hepatitis C virus (HCV), but effects of interferon-alpha/ribavirin therapy on NK cell subsets and the consequences of viral clearance during therapy remain unclear. Samples were collected from chronically infected patients (n = 34) at baseline and from a subset after 3-10 months on pegylated interferon-alpha and ribavirin therapy (n = 19). NK cells present in cryopreserved PBMC were characterized by flow cytometry. Before therapy, the frequency of CD3-CD56+ NK cells was lower in patients than uninfected controls. Therapy increased proportions of CD56(bright) NK cells. Frequencies of CD56(dim) NK cells declined slightly while perforin and CD16 expression on CD56(dim) NK cells decreased compared to baseline samples. Evaluation of NK cell subsets at baseline did not identify patients able to achieve sustained virological response following therapy. However, therapy may promote the expansion of NK cells able to produce interferon-gamma, while minimizing cytotoxicity to limit liver damage. PMID- 20166184 TI - Development and comparison of molecular assays for the rapid detection of the pandemic influenza A (H1N1) 2009 virus. AB - Human infection with the novel pandemic influenza A (H1N1) virus was first identified in April 2009. Two months later, the World Health Organization (WHO) had raised the pandemic level to phase 6. Rapid case identification is essential for prompt patient management and public health actions. This study developed real-time and conventional reverse transcription-polymerase chain reaction (rRT PCR and cRT-PCR) assays for pandemic H1N1 detection, and compared their sensitivities with protocols developed by WHO reference centres. Altogether, three rRT-PCR and one cRT-PCR targeting the matrix gene for universal detection of influenza A; three rRT-PCR, one cRT-PCR targeting the hemagglutinin (HA) gene for specific detection of pandemic H1N1; and one multiplex cRT-PCR for differentiating co-circulating seasonal H1N1, H3N2, and pandemic H1N1 were examined. The lower detection limit ranged from 1.252 to 125.2 copy equivalents. In general, rRT-PCR assays were more sensitive than cRT-PCR assays. All assays showed 100% sensitivity for "optimal" specimens (nasopharyngeal samples collected within 4 days after illness onset). For the other 36 samples, cRT-PCR assays were less sensitive except that the new Protocol I-cRT-pdmH1 still retained 100% sensitivity. The new Protocol F-rRT-PCR-pdmH1 was the only pandemic virus specific rRT-PCR assay with 100% sensitivity across all specimen categories. In conclusion, rRT-PCR assays are 10-fold more sensitive than cRT-PCR assays. The newly developed cRT-PCR assay targeting the HA gene allows rapid, specific, and sensitive screening of this novel agent, which can serve as an alternative for laboratories where a real-time PCR machine is not available. PMID- 20166185 TI - Prevalence of hepatitis B and hepatitis C virus infections in France in 2004: social factors are important predictors after adjusting for known risk factors. AB - To monitor the prevalence of hepatitis B and hepatitis C a cross-sectional survey was conducted in 2004 among French metropolitan residents. A complex sampling design was used to enroll 14,416 adult participants aged 18-80 years. Data collected included demographic and social characteristics and risk factors. Sera were tested for anti-HCV, HCV-RNA, anti-HBc and HBsAg. Data were analyzed with SUDAAN software to provide weighted estimates for the French metropolitan resident population. The overall anti-HCV prevalence was 0.84% (95% CI: 0.65 1.10). Among anti-HCV positive individuals, 57.4% (95% CI: 43.2-70.5) knew their status. Factors associated independently with positive anti-HCV were drug use (intravenous and nasal), blood transfusion before 1992, a history of tattoos, low socioeconomic status, being born in a country where anti-HCV prevalence >2.5%, and age >29 years. The overall anti-HBc prevalence was 7.3% (95%: 6.5-8.2). Independent risk factors for anti-HBc were intravenous drug use, being a man who has sex with men, low socioeconomic status, a stay in a psychiatric facility or facility for the mentally disabled, <12 years of education, being born in a country where HBsAg prevalence >2%, age >29 and male sex. The HCV RNA and HBsAg prevalence were 0.53% (95% CI: 0.40-0.70) and 0.65% (95% CI: 0.45-0.93), respectively. Among HBsAg positive individuals, 44.8% (95% CI: 22.8-69.1) knew their status. Anti-HCV prevalence was close to the 1990s estimates whereas HBsAg prevalence estimate was greater than expected. Screening of hepatitis B and C should be strengthened and should account for social vulnerability. PMID- 20166186 TI - Identification of two sublineages of genotype G2 rotavirus among diarrheic children in Parauapebas, Southern Para State, Brazil. AB - On a world scale, group A human rotaviruses are the most common cause of severe acute gastroenteritis during infancy and childhood, including five (G1, G2, G3, G4, and G9) epidemiologically important genotypes. Among these, G2 denotes a different genogroup which appears to have a cyclic pattern of occurrence and yet little information is available about its genetic variability. The aim of this report was to characterize the emergence of G2 genotype in Paraupebas, Southern Para State, Brazil, some of which detected after introduction of rotavirus vaccine. A total of 241 fecal specimens from young children with acute gastroenteritis were collected from the "Yutaka Takeda Hospital," a Municipality Hospital, and at the Parauapebas' Health Unit, Para, from January to September 2006 and during March to November 2008. All samples were tested for rotavirus using immunochromatography, polyacrylamide gel electrophoresis (PAGE), and RT PCR, yielding an overall positivity of 12.45% (30/241). Rotavirus G2P[4] was identified in 27 of 30 samples (90%), followed by G1P[8] (2/30, 6.67%) and G9P[8] (1/30, 3.33%). Phylogenetic analysis was performed in 15 of the G2 strains, all of which grouped into lineage II. Four of these strains clustered into sublineage II-a (year 2006) and 11 into one possible new sublineage named II-c (year 2008, except SAL-1920-C). The recent re-emergence of G2 genotype associated with lineage II in Brazil warrants the continuous monitoring of circulating rotavirus strains following the nationwide universal use of rotavirus vaccine. PMID- 20166187 TI - Trends in HTLV-1 prevalence and incidence of adult T-cell leukemia/lymphoma in Nagasaki, Japan. AB - Most previous studies aimed at estimating the number of human T-cell leukemia virus type-1 (HTLV-1) carriers in endemic areas have been based on seroprevalence rates in blood donors; however, this may result in underestimation because of the healthy donor effect. People who have health problem do not donate blood. In the present study, the number of HTLV-1 carriers in Nagasaki City was estimated based on the seroprevalence rates in a hospital-based population from Nagasaki University Hospital. In accordance with previous reports, seroprevalence of HTLV 1 was higher in females, and year of birth-specific seroprevalence showed a significant annual decline in both genders (P for trend: <0.0001). The estimated number of HTLV-1 carriers in Nagasaki City was 36,983. The incidence of adult T cell leukemia/lymphoma (ATLL) among HTLV-1 carriers was estimated using data from the Nagasaki Prefectural Cancer Registry. The estimated annual incidence of ATLL was 61 per 100,000 HTLV-1 carriers, and the crude lifetime risk of the development was 7.29% for males and 3.78% for females. There is a large pool of HTLV-1 carriers aged over 70 years, and a continuing development of cases of ATLL among the elderly is therefore expected. PMID- 20166189 TI - Human caliciviruses detected in Mexican children admitted to hospital during 1998 2000, with severe acute gastroenteritis not due to other enteropathogens. AB - Few studies exist regarding the frequency of human caliciviruses as single etiologic agents in sporadic cases, or in outbreaks occurring in children hospitalized for acute gastroenteritis. In this study, a total of 1,129 children of <5 years of age and hospitalized due to acute diarrhea were enrolled from three main hospitals in Mexico City during a period of 3 years (March 1998 to December 2000). After analyzing all fecal samples for several enteropathogens, 396 stools that remained negative were further screened for human caliciviruses by RT-PCR using a primer set specific to norovirus and sapovirus. Human caliciviruses were detected in 5.6% (22/396) of the children. The minimum incidence rate for 1999 were 5.3% (7/132) for 1999 and 7.8% (13/167) for 2000, since only fecal specimens that tested negative to other enteric pathogens were examined. Positive samples were further characterized using specific GI and GII primers and sequencing. Norovirus GII was detected in 19/22 samples, most of them were GII/4, while sapovirus GI/2 was detected in one sample. Associations between the presence of human calicivirus and clinical and epidemiological data revealed that diarrhea occurred with a seasonal pattern, and that children hospitalized due to human calicivirus disease scored an average of 13 +/- 3.2 (SD) points on the Vesikari scale, which corresponded to severe episodes. These results highlight that human caliciviruses, by themselves, are enteropathogens of acute severe diarrhea among young Mexican children requiring hospitalization and that their detection is important in order to reduce the diagnosis gap. PMID- 20166188 TI - Amino acid substitutions in the hepatitis C virus core region of genotype 1b affect very early viral dynamics during treatment with telaprevir, peginterferon, and ribavirin. AB - Substitution of amino acid (aa) 70 and 91 in the core region of hepatitis C virus (HCV) genotype 1b can predict the response to pegylated interferon (PEG IFN)/ribavirin combination therapy, but its impact on triple therapy of telaprevir/PEG-IFN/ribavirin is not clear. The aims of this study were to investigate the rate of HCV RNA loss following 12-week triple therapy, and determine the effect of aa substitutions on very early (within 48 hr) viral dynamics. Sixty-seven patients infected with HCV genotype 1b (HCV-1b) and high viral load who received 12-week triple therapy were studied. RNA loss could be achieved in 2%, 34%, 80%, 92%, 95%, 94%, and 90% of the patients after 1, 2, 4, 6, 8, 10, and 12 weeks of triple therapy, respectively. After 24-hr treatment, the proportion of patients with Arg70 and Leu91 substitutions with > or = 3.0 log fall in HCV RNA was significantly higher than those with < 3.0 log fall (P = 0.008). However, the aa substitution patterns in the core region did not influence the fall in HCV RNA after 48-hr treatment. Multivariate analysis identified substitutions of aa 70 and 91 (P = 0.014) and level of viremia at baseline (> or = 7.0 log IU/ml; P = 0.085) as independent parameters that determined the > or = 3.0 log fall in HCV RNA level after 24-hr triple therapy. It is concluded that 12-week triple therapy achieved high rates of loss of HCV RNA in Japanese patients infected with HCV-1b and high viral load, and that the aa substitution pattern in the core region seems to influence very early viral dynamics. PMID- 20166190 TI - Persistence of high-risk human papillomavirus infection in a population-based cohort of Danish women. AB - Persisting human papillomavirus (HPV) infection is a critical step in cervical carcinogenesis. This study was conducted to determine the type-specific HPV persistence and risk factors for persistence of high-risk HPV infections in a large cohort of Danish women. The study was based on a population-based prospective cohort study of women aged 20-29 years. Participants were interviewed and underwent two gynecological examinations 2 years apart. Women with Hybrid Capture 2 results at enrolment and a follow-up visit were included in the analysis (n = 7,418). Persistence was defined as positivity for the same high risk HPV type at both examinations. Overall, 4.2% of the women had persistent HPV infection, accounting for 26.9% of the initially HPV-positive women. HPV 16, HPV 58, and HPV 31, all from species group alpha 9, were the most persistent types; however, other high-risk HPV types that are detected rarely in cancer cases were also likely to persist. The number of high-risk HPV types and detection of HPV 16 infection at baseline and ever use of oral contraceptives increased the risk for persistence. The risk factor analyses also showed that use of an intrauterine device decreased the risk for persistent high-risk HPV infection among women with one high-risk HPV type at baseline. No association was found with viral load or smoking. In conclusion, persistent high-risk HPV infection, especially HPV 16 persistence, was common among women positive for high-risk HPV. PMID- 20166191 TI - Sources of variation in fecal cortisol levels in howler monkeys in Belize. AB - High cortisol levels are known to cause low fecundity and increased mortality; thus, the prospect of using cortisol as a measure of population health is an exciting one. However, because so many factors can interact to influence cortisol release, it can be difficult to interpret what exactly is creating changes to cortisol levels. This study investigates variation in fecal cortisol levels in a population of black howlers (Alouatta pigra) from 350 fecal samples collected from 33 individuals in more than 4 years. A general linear mixed model revealed that cortisol varied significantly with fruit availability and contact with tourists. When fruit availability was low, cortisol increased, likely because when fruit availability is low monkeys eat less fruit, thus obtaining less sugar. This result may simply reflect cortisol's metabolic function of mobilizing glucose. It also indicates that these monkeys may be experiencing periods of food stress throughout the year, which was earlier thought to be minimal for a primarily folivorous species. Presence of tourists was the only other factor found to lead to high cortisol; with exposure to tourists increasing stress levels. These results highlight the importance of understanding how physiological factors can influence cortisol, making it easier to interpret results and determine the external social or ecological stressors that may increase cortisol. PMID- 20166192 TI - Association of distinctive Epstein-Barr virus variants with gastric carcinoma in Guangzhou, southern China. AB - To investigate the clinicopathologic features, Epstein-Barr virus (EBV) latency pattern and genome polymorphism of EBV-associated gastric carcinoma (EBVaGC) in Guangzhou, an endemic area of nasopharyngeal carcinoma (NPC), an in situ hybridization assay of EBV-encoded small RNA-1 (EBER-1) was used to identify the presence of EBV in 676 consecutive gastric carcinoma cases. EBV-encoded proteins EBNA1, EBNA2, LMP1, and ZEBRA were detected by immunohistochemistry. EBV genome polymorphism was also analyzed by PCR and DNA sequencing. Of the 676 cases, 45 EBV-positive cases (6.7%) were identified, including 37 (8.5%) male and 8 (3.3%) female cases. EBNA1 was detected in 42 cases (93.3%), while EBNA2, LMP1, and ZEBRA were all negative. In the EBV genome polymorphism analysis, type A strain, prototype F, type I, XhoI-, and del-LMP1 variants were predominant among EBVaGC patients, accounting for 44 (97.8%), 37 (82.2%), 45 (100%), 34 (75.6%), and 42 (93.3%) cases, respectively. Moreover, a new hotspot mutation in the BamHI-W1/I1 boundary region (148,972 T --> C) was found in 39 (86.7%) of the 45 cases. The predominant EBV variants in EBVaGC in Guangzhou are prototype F, type I, and XhoI , which are different from those in NPC in this area (predominant variant-type "f") and in EBVaGC in Latin American countries (predominant type "i" and XhoI+), suggesting that the EBV variants are not only geographically distributed but also disease restricted, and the pathogenic role of EBV in different EBV associated epithelial malignancies in different areas may be distinct. PMID- 20166193 TI - Unusual secondary electron emission behavior in carbon nanotube forests. AB - Electron yield was measured from patterned carbon nanotube forests for a wide range of primary beam energies (400-20,000 eV). It was observed that secondary and backscattered electron emission behaviors in these forests are quite different than in bulk materials. This seems to be primarily because of the increased range of electrons due to the porous nature of the forests and dependent on their structural parameters, namely nanotube length, diameter and inter-nanotube spacing. In addition to providing insight into the electron microscopy of nanotubes, these results have interesting implications on designing novel secondary electron emitters based on the structural degrees of freedom of nanomaterials. PMID- 20166194 TI - Image restoration for TV-scan moving images acquired through a semiconductor backscattered electron detector. AB - A semiconductor backscattered electron (BSE) detector has become popular in scanning electron microscopy session. However, detectors of semiconductor type have a serious disadvantage on the frequency characteristics. As a result, fast scan (e.g. TV-scan) BSE image should be blurred remarkably. It is the purpose of this study to restore this degradation by using digital image processing technology. In order to improve it practically, we have to settle several problems, such as noise, undesirable processing artifacts, and ease of use. Image processing techniques in an impromptu manner like a conventional mask processing are unhelpful for this study, because a complicated degradation of output signal affects severely the phase response as well as the amplitude response of our SEM system. Hence, based on the characteristics of an SEM signal obtained from the semiconductor BSE detector, a proper inverse filter in Fourier domain is designed successfully. Finally, the inverse filter is converted to a special convolution mask, which is skillfully designed, and applied for TV-scan moving BSE images. The improved BSE image is very effective in the work for finding important objects. PMID- 20166195 TI - Scanning: advancing DPN. PMID- 20166196 TI - Altered sex hormone concentrations and gonadal mRNA expression levels of activin signaling factors in hatchling alligators from a contaminated Florida lake. AB - Activins and estrogens participate in regulating the breakdown of ovarian germ cell nests and follicle assembly in mammals. In 1994, our group reported elevated frequencies of abnormal, multioocytic ovarian follicles in 6 month old, environmental contaminant-exposed female alligators after gonadotropin challenge. Here, we investigated if maternal contribution of endocrine disrupting contaminants to the egg subsequently alters estrogen/inhibin/activin signaling in hatchling female offspring, putatively predisposing an increased frequency of multioocytic follicle formation. We quantified basal and exogenous gonadotropin stimulated concentrations of circulating plasma steroid hormones and ovarian activin signaling factor mRNA abundance in hatchling alligators from the same contaminated (Lake Apopka) and reference (Lake Woodruff) Florida lakes, as examined in 1994. Basal circulating plasma estradiol and testosterone concentrations were greater in alligators from the contaminated environment, whereas activin/inhibin betaA subunit and follistatin mRNA abundances were lower than values measured in ovaries from reference lake animals. Challenged, contaminant-exposed animals showed a more robust increase in plasma estradiol concentration following an acute follicle stimulating hormone (FSH) challenge compared with reference site alligators. Aromatase and follistatin mRNA levels increased in response to an extended FSH challenge in the reference site animals, but not in the contaminant-exposed animals. In hatchling alligators, ovarian follicles have not yet formed; therefore, these endocrine differences are likely to affect subsequent ovarian development, including ovarian follicle assembly. PMID- 20166198 TI - Complexation of sulfonamides with beta-cyclodextrin studied by experimental and theoretical methods. AB - The complex formation between three structurally related sulfonamides (sulfadiazine (SDZ), sulfamerazine (SMR), and sulfamethazine (SMT)) and beta cyclodextrin (beta-CD) was studied, by exploring its structure affinity relationship. In all the cases, 1:1 stoichiometries were determined with different relative affinities found by phase solubility (SDZ:beta-CD > SMR:beta CD > SMT:beta-CD) and nuclear magnetic resonance (NMR) (SMT:beta-CD > SMR:beta-CD > SDZ:beta-CD) studies. The spatial configurations determined by NMR were in agreement with those obtained by molecular modeling, showing that SDZ included its aniline ring into beta-CD, while SMR and SMT included the substituted pyrimidine ring. Energetic analyses demonstrated that hydrophobicity is the main driving force to complex formation. PMID- 20166197 TI - Preclinical pharmacokinetics and in vitro metabolism of BMS-690514, a potent inhibitor of EGFR and VEGFR2. AB - BMS-690514, a potent inhibitor of human epidermal growth factor receptor (HER) 1 (EGFR), 2, and 4, and vascular endothelial growth factor receptors (VEGFR) 1-3, is currently under investigation as an oral agent for the treatment of solid tumors. In vitro and in vivo studies were conducted to characterize the pharmacokinetics and metabolism. Through integration of in vitro and in vivo pharmacokinetic data and antitumor efficacy in nude mice, human pharmacokinetics and efficacious doses were projected for BMS-690514. The oral bioavailability of BMS-690514 was 78% in mice, approximately 100% in rats, 8% in monkeys, and 29% in dogs. The low oral bioavailability in monkeys could be attributed to high systemic clearance in that species, which was also consistent with predicted clearance using in vitro data from monkey liver microsomes. Permeability of BMS 690514 in Caco-2 cells was in the intermediate range with a moderate potential to be a P-gp substrate. Experiments using recombinant human CYP enzymes and human liver microsomes suggested that CYP2D6 and CYP3A4 are likely to play a key role in the metabolic clearance of BMS-690514; in addition, direct glucuronidation of BMS-690514 was also observed in human hepatocytes. BMS-690514 was able to cross the blood-brain barrier with a brain-to-plasma ratio of approximately 1. The preclinical ADME properties of BMS-690514 suggest good oral bioavailability in humans and metabolism by multiple pathways including oxidation and glucuronidation. Based on the efficacious AUC in nude mice and predicted human pharmacokinetics, the human efficacious QD dose is predicted to be in the range of 100-200 mg. PMID- 20166199 TI - Freeze-drying in novel container system: Characterization of heat and mass transfer in glass syringes. AB - This study is aimed at characterizing and understanding different modes of heat and mass transfer in glass syringes to develop a robust freeze-drying process. Two different holder systems were used to freeze-dry in syringes: an aluminum (Al) block and a plexiglass holder. The syringe heat transfer coefficient was characterized by a sublimation test using pure water. Mannitol and sucrose (5% w/v) were also freeze-dried, as model systems, in both the assemblies. Dry layer resistance was determined from manometric temperature measurement (MTM) and product temperature was measured using thermocouples, and was also determined from MTM. Further, freeze-drying process was also designed using Smart freeze dryer to assess its application for freeze-drying in novel container systems. Heat and mass transfer in syringes were compared against the traditional container system (i.e., glass tubing vial). In the Al block, the heat transfer was via three modes: contact conduction, gas conduction, and radiation with gas conduction being the dominant mode of heat transfer. In the plexiglass holder, the heat transfer was mostly via radiation; convection was not involved. Also, MTM/Smart freeze-drying did work reasonably well for freeze-drying in syringes. When compared to tubing vials, product temperature decreases and hence drying time increases in syringes. PMID- 20166200 TI - Transdermal delivery of naltrexol and skin permeability lifetime after microneedle treatment in hairless guinea pigs. AB - Controlled-release delivery of 6-beta-naltrexol (NTXOL), the major active metabolite of naltrexone, via a transdermal patch is desirable for treatment of alcoholism. Unfortunately, NTXOL does not diffuse across skin at a therapeutic rate. Therefore, the focus of this study was to evaluate microneedle (MN) skin permeation enhancement of NTXOL's hydrochloride salt in hairless guinea pigs. Specifically, these studies were designed to determine the lifetime of MN-created aqueous pore pathways. MN pore lifetime was estimated by pharmacokinetic evaluation, transepidermal water loss (TEWL) and visualization of MN-treated skin pore diameters using light microscopy. A 3.6-fold enhancement in steady-state plasma concentration was observed in vivo with MN treated skin with NTXOL.HCl, as compared to NTXOL base. TEWL measurements and microscopic evaluation of stained MN-treated guinea pig skin indicated the presence of pores, suggesting a feasible nonlipid bilayer pathway for enhanced transdermal delivery. Overall, MN-assisted transdermal delivery appears viable for at least 48 h after MN-application. PMID- 20166201 TI - In vitro reporter gene transfection via plasmid DNA delivered by metered dose inhaler. AB - Aerosolised DNA administration could potentially advance the treatment of inheritable lung diseases, lung malignancies and provide genetic immunisation against infection. Jet nebulisation, the current standard for introducing DNA formulations into the lung, is inherently inefficient. Pressurised metered dose inhalers (pMDIs) offer a potentially more efficacious and convenient alternative, especially for repeat administration. We aim to modify a novel low-energy nanotechnology process to prepare surfactant-coated pDNA nanoparticles for pulmonary gene delivery via a pMDI. Water-in-oil microemulsions containing green fluorescent protein reporter plasmid were snap-frozen and lyophilised. Lyophilised pDNA, in some cases following a surfactant wash, was incorporated into pMDIs with hydrofluoroalkane 134a (HFA134a) propellant and ethanol as cosolvent. To assess biological functionality, A549 human lung epithelial cells were exposed to aerosolised pDNA particles in the presence of dioleoyl trimethylammonium propane (DOTAP). Transfection studies demonstrated that pDNA biological functionality was maintained following aerosolisation. In vitro toxicity assays (MTT) showed no significant cell viability loss following aerosolised pDNA treatment. We have demonstrated that pDNA particles can be incorporated into an HFA134a formulation and aerosolised using a standard valve and actuator. Particles prepared by this novel process have potential for stable and efficient delivery of pDNA to the lower respiratory tract via standard pMDI technology. PMID- 20166202 TI - Initial testing of a monoclonal antibody (IMC-A12) against IGF-1R by the Pediatric Preclinical Testing Program. AB - BACKGROUND: Many childhood malignancies including sarcomas, neuroblastoma, and Wilms tumor show the presence of both, active, type-1-insulin-like growth factor receptor (IGF-1R), and the autocrine production of its ligands IGF-1/IGF-2. IMC A12 is a fully human IgG1 antibody that prevents ligand binding to the IGF-1R. PROCEDURES: IMC-A12 was evaluated against the 23 cell lines of the Pediatric Preclinical Testing Program (PPTP) in vitro panel using 96 hr exposure at concentrations ranging from 0.01 nM to 0.1 microM. IMC-A12 was tested in vivo at a dose of 1 mg/mouse administered intraperitoneally twice weekly for 6 weeks. RESULTS: In vitro, IMC-A12-induced T/C values <50% in only three cell lines, a rhabdomyosarcoma cell line (Rh41) and two Ewing sarcoma cell lines (TC-71 and CHLA-9). In vivo, IMC-A12 induced significant differences in EFS distribution compared to control in 24 of 34 (71%) evaluable solid tumor xenografts. Using the PPTP "time to event" activity measure, IMC-A12 induced intermediate (n = 13) or high (n = 1) activity in 33 xenografts evaluable for this activity measure, including 6 of 6 rhabdomyosarcoma xenografts, 3 of 5 osteosarcoma xenografts, 2 of 5 neuroblastoma xenografts, and 1 of 5 Ewing sarcoma xenografts. The only objective response observed was observed in a rhabdomyosarcoma xenograft (Rh28) that achieved a maintained complete response. CONCLUSIONS: IMC-A12 demonstrated broad antitumor activity against the PPTP's in vivo solid tumor panels, with the activity primarily being tumor growth inhibition rather than tumor regression. IMC-A12 showed its greatest activity in vivo against the PPTP's rhabdomyosarcoma xenografts. PMID- 20166203 TI - Distribution of doxorubicin in rats undergoing ultrasonic drug delivery. AB - Ultrasound (US) increases efficacy of drugs delivered from micelles, but the pharmacokinetics have not been studied previously. In this study, US was used to deliver doxorubicin (Dox) sequestered in micelles in an in vivo rat model with bilateral leg tumors. One of two frequencies with identical mechanical index and intensity was delivered for 15 min to one tumor immediately after systemic injection of micellar Dox. Pharmacokinetics in myocardium, liver, skeletal muscle, and tumors were measured for 1 week. When applied in combination with micellar Dox, the ultrasoincated tumor had higher Dox concentrations at 30 min, compared to bilateral noninsonated controls. Initially, concentrations were highest in heart and liver, but within 24 h they decreased significantly. From 24 h to 7 days, concentrations remained highest in tumors, regardless of whether they received US or not. Comparison of insonated and noninsonated tumors showed 50% more Dox in the insonated tumor at 30 min posttreatment. Four weekly treatment produced additional Dox accumulation in the myocardium but not in liver, skeletal leg muscle, or tumors compared to single treatment. Controls showed that neither US nor the empty carrier impacted tumor growth. This study shows that US causes more release of drug at the targeted tumor. PMID- 20166204 TI - Towards prediction of in vivo intestinal absorption using a 96-well Caco-2 assay. AB - We systematically validated a robust 96-well Caco-2 assay via an extended set of 93 marketed drugs with diverse transport mechanisms and quantified by LC/MS/MS, to investigate its predictive utility while dealing with challenging discovery compounds. Utilizing nonlinear fit, the validation led to a good correlation (R(2) = 0.76) between absorptive permeability, log P(app)(A-B), from in vitro Caco-2 assay and reported human fraction of dose absorbed. We observed that paracellular compounds could be flagged by log P(app)(A-B) (<-5.5 cm/s) and physicochemical property space (c log P < 1). Of 8000 Novartis discovery compounds examined 13% were subject to low recovery (<30%). Compound loss was investigated by comparing cell monolayer and artificial membrane, while 0.5% bovine serum albumin (in both donor and acceptor compartments) was utilized to improve recovery. The second focus of this study was to investigate the advantages and limitations of the current Caco-2 assay for predicting in vivo intestinal absorption. Caco-2 measurements for compounds with high aqueous solubility and low in vitro metabolic clearance were compared to 88 in vivo rat bioavailability studies. Despite the challenges posed by discovery compounds with suboptimal physicochemical properties, Caco-2 data successfully projected low intestinal absorption. This platform sets the stage for mechanistically evaluating compounds towards improving in vitro-in vivo correlations. PMID- 20166206 TI - The treatment of recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells into the circulation. AB - BACKGROUND: Patients with recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) often have chemotherapy-resistant disease, resulting in poor prognosis. The aim of this study was to learn if inhibition of the mammalian target of rapamycin (mTOR) would produce tumor responses. METHODS: This was a phase 2 study of oral single-agent everolimus (10 mg/day) for recurrent/refractory indolent lymphoid malignancies including CLL. RESULTS: Four of 22 patients with CLL (18%; 95% confidence interval, 5%-40%) achieved a partial remission to therapy. An unanticipated finding in this study was an increase in absolute lymphocyte count (ALC) associated with a decrease in lymphadenopathy in 8 (36%) patients. ALC increased a median of 4.8-fold (range, 1.9- to 25.1-fold), and the clinically measurable lymphadenopathy decreased a median of 75.5% (range, 38%-93%) compared with baseline measurements. CONCLUSIONS: Everolimus has modest antitumor activity against CLL and can mobilize malignant cells from nodal masses into the peripheral circulation in a subset of CLL patients. Because CLL cells in lymphatic tissue and bone marrow can be more resistant to therapy than circulating CLL cells, the ability of everolimus to mobilize CLL cells into the circulation could be used in combination therapeutic regimens. PMID- 20166205 TI - Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. AB - BACKGROUND: Despite the observed association between diabetes mellitus and hepatocellular carcinoma (HCC), little is known about the effect of diabetes duration before HCC diagnosis and whether some diabetes medications reduced the risk of HCC development. This objective of the current study was to determine the association between HCC risk and diabetes duration and type of diabetes treatment. METHODS: A total of 420 patients with HCC and 1104 healthy controls were enrolled in an ongoing hospital-based case-control study. Multivariate logistic regression models were used to adjust for HCC risk factors. RESULTS: The prevalence of diabetes mellitus was 33.3% in patients with HCC and 10.4% in the control group, yielding an adjusted odds ratio (AOR) of 4.2 (95% confidence interval [95% CI], 3.0-5.9). In 87% of cases, diabetes was present before the diagnosis of HCC, yielding an AOR of 4.4 (95% CI, 3.0-6.3). Compared with patients with a diabetes duration of 2 to 5 years, the estimated AORs for those with a diabetes duration of 6 to 10 years and those with a diabetes duration >10 years were 1.8 (95% CI, 0.8-4.1) and 2.2 (95% CI, 1.2-4.8), respectively. With respect to diabetes treatment, the AORs were 0.3 (95% CI, 0.2-0.6), 0.3 (95% CI, 0.1-0.7), 7.1 (95% CI, 2.9-16.9), 1.9 (95% CI, 0.8-4.6), and 7.8 (95% CI, 1.5 40.0) for those treated with biguanides, thiazolidinediones, sulfonylureas, insulin, and dietary control, respectively. CONCLUSIONS: Diabetes appears to increase the risk of HCC, and such risk is correlated with a long duration of diabetes. Relying on dietary control and treatment with sulfonylureas or insulin were found to confer the highest magnitude of HCC risk, whereas treatment with biguanides or thiazolidinediones was associated with a 70% HCC risk reduction among diabetics. PMID- 20166207 TI - Circulating endothelial cells in patients with chronic lymphocytic leukemia: clinical-prognostic and biologic significance. AB - BACKGROUND: In patients with cancer, circulating endothelial cells (CECs) are increased and are correlated with an aggressive disease course. However, the clinical and biologic significance of CECs in chronic lymphocytic leukemia (CLL) remains uncertain. METHODS: In 170 patients with CLL, CEC levels were quantified by flow cytometry and were correlated with clinical and biologic data. In addition, CECs were characterized by immunophenotypic, fluorescence in situ hybridization (FISH), and gene expression profile analyses. RESULTS: In patients with CLL, CECs were increased compared with controls. A higher level of CECs (>20/microL) identified a subset of patients with a more aggressive disease course characterized by a shorter time to first treatment both in univariate and multivariate analyses. In FISH analysis, 7 patients had a significant proportion of CECs and presented with the same cytogenetic lesion of neoplastic lymphocytes and immunophenotypic features of endothelial progenitor cells. The gene expression profile of sorted CECs revealed a molecular pattern, suggesting a derivation from CLL leukemic cells with increased cell survival and proliferation, diminished cell adhesion to extracellular matrix, and enhanced proangiogenic function compared with their normal counterparts. CONCLUSIONS: The current data suggest that, in CLL, CECs may represent a biologic marker of aggressiveness and disease progression to be considered for new, targeted antiangiogenic treatments. PMID- 20166208 TI - Grading of nonrhabdomyosarcoma soft tissue sarcoma in children and adolescents: a comparison of parameters used for the Federation Nationale des Centers de Lutte Contre le Cancer and Pediatric Oncology Group Systems. AB - BACKGROUND: Two systems for grading soft tissue sarcoma are widely used currently: the National Cancer Institute (NCI) and the Federation Nationale des Centers de Lutte Contre le Cancer (FNCLCC) systems. Both were developed using cohorts of predominantly adult patients. The Pediatric Oncology Group (POG) system, based on the NCI system, was adapted for grading pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). The applicability and prognostic utility of the FNCLCC system in pediatric NRSTS has not been assessed or compared with the POG system. METHODS: Tumors from 130 patients with malignant NRSTS enrolled on 3 completed multi-institutional clinical trials were assessed. Of 130 tumors, 102 (78%) were localized and 28 (22%) metastatic. Of the localized tumors, 55 of 102 (54%) were >5 cm. The estimated 5-year event-free survival (EFS) for the entire group was 47%. RESULTS: As expected, stage and tumor sizes were predictive of EFS (P < .001). Both systems were predictive of 5-year EFS (POG, P = .0095 and FNCLCC, P = .0075). Patients whose tumors received discrepant grades (POG-G3 vs FNCLCC-G2/G1) (n = 44) had an intermediate outcome between those with concordant (G3 [n = 44] or G1/G2 [n = 42]) grades on both systems (P = .0018). By multivariate analysis, the mitotic index was predictive of EFS, using a cutoff of 10 mitotic figures per 10 high-power fields (P < .001). CONCLUSIONS: In conclusion, both FNCLCC and POG systems provide an adequate prognostic measure of outcome for pediatric NRSTS; albeit, a sizeable subset of cases with apparently intermediate prognosis was graded differently by the 2 systems. The mitotic index appears to be a key parameter in grading pediatric NRSTS. PMID- 20166209 TI - Radiofrequency ablation as an adjunct to systemic chemotherapy for colorectal pulmonary metastases. AB - BACKGROUND: Radiofrequency ablation (RFA) is an alternative to local treatment for pulmonary metastases in patients who are nonsurgical candidates. Based on previously documented efficacy of this treatment, the authors retrospectively studied the prognostic factors for long-term survival. METHODS: One hundred patients with unresectable colorectal pulmonary metastases underwent percutaneous RFA. Clinical and treatment variables were collected and evaluated using univariate and multivariate analyses with overall survival as the primary endpoint. RESULTS: At a median follow-up period of 23 (range, 1 to 96) months from the time of RFA treatment, 49 patients have died. The median overall survival after RFA treatment was 36 months and 5-year overall survival rates of 30%. Univariate analyses demonstrated that histopathological grade (p < .001), time to RFA treatment (p = .017), response to treatment (p < .001), repeat RFA treatments (p = .001), presence of extrapulmonary metastases (p < .001), presence of mediastinal lymphadenopathy (p = .007), and adjunct systemic chemotherapy (p < .001) were associated with overall survival. Multivariate analyses demonstrated that response to RFA treatment (p < .001), repeat RFA treatment (p = .002), presence of extrapulmonary metastases (p = .008), and use of adjunct systemic chemotherapy (p = .05) were independent predictors for survival. CONCLUSIONS: Radiofrequency ablation for colorectal pulmonary metastases represents a step forward towards a nonsurgical option of combining systemic and local treatment for metastatic disease and is a safe treatment with a low risk profile. PMID- 20166210 TI - Disrupting established tumor blood vessels: an emerging therapeutic strategy for cancer. AB - The unique characteristics of tumor vasculature represent an attractive target that may be exploited by vascular-targeting anticancer agents. A promising strategy involves the selective disruption of established tumor blood vessels by tumor-vascular disrupting agents (tumor-VDAs), which exhibit antivascular activity, resulting in inhibition of tumor blood flow and extensive necrosis within the tumor core. The tumor-VDA class can be subdivided into flavonoid compounds, which are related to flavone acetic acid, and tubulin-binding compounds. ASA404, of the flavonoid class, is the most advanced tumor-VDA in clinical development and has been evaluated preclinically and in several phase 1 and phase 2 studies. Preclinical studies have demonstrated the selective apoptosis of tumor endothelial cells and the inhibition of tumor blood flow. Synergistic activity was observed with ASA404 and with several chemotherapeutic agents, particularly taxanes. In clinical trials, compared with chemotherapy alone, ASA404 was tolerated well and produced improved activity in patients with nonsmall cell lung cancer when combined with paclitaxel and carboplatin. Phase 3 clinical trials are ongoing. Selectively targeting established tumor vasculature with tumor-VDAs represents a promising and innovative approach to improving the efficacy of standard anticancer therapies. PMID- 20166211 TI - Multiple endocrine neoplasia [corrected] syndrome type 2B in early childhood: long-term benefit of prophylactic thyroidectomy. PMID- 20166212 TI - Patient-reported acute gastrointestinal symptoms during concurrent chemoradiation treatment for rectal cancer. AB - BACKGROUND: Although it is known that standard 5-fluorouracil-based chemoradiation therapy for rectal cancer causes significant acute gastrointestinal (GI) toxicity, research on patient-reported outcomes (PROs) is limited. The authors undertook the current study to assess the feasibility of incorporating PRO measurement into routine clinical practice and to describe the trajectory of symptom development during treatment. METHODS: Seventy-seven consecutive patients who were treated between 2006 and 2008 were eligible. Patients completed the 7-item Bowel Problems Scale immediately before weekly physician visits. RESULTS: The questionnaire completion rate was 95%. Individual GI symptoms had different trajectories of development. By Week 5, approximately 40% of all patients developed clinically meaningful pain, bowel urgency, or tenesmus that was not present during Week 1; 30% developed diarrhea, abdominal cramping, and passing mucus. However, overall symptom burden was moderate. Seventy-five percent of patients who presented with rectal bleeding at Week 1 improved by Week 3 of treatment. Within each physician-assessed grade of diarrhea, patient experience varied widely. For example, of the 50 patients who developed grade 2 diarrhea on the Radiation Therapy Oncology Group Acute Morbidity Scale, the numbers of patients reporting only occasional symptoms versus those reporting frequent or very frequent symptoms were similar. CONCLUSIONS: PROs provided information on patient symptoms during chemoradiation treatment for rectal cancer that was not captured otherwise, and it was feasible to incorporate PROs into routine clinical practice. The current results may be used by physicians to counsel their patients before treatment initiation and to provide a benchmark against which trials that use new therapies may be compared. PMID- 20166213 TI - Plasma cell-free DNA in ovarian cancer: an independent prognostic biomarker. AB - BACKGROUND: Cell-free DNA reflects both normal and tumor-derived DNA released into the circulation through cellular necrosis and apoptosis. The authors sought to determine the role of preoperative total plasma cell-free DNA levels in predicting clinical outcome in patients with ovarian cancer. METHODS: After institutional review board consent, DNA was extracted from plasma of 164 women with invasive epithelial ovarian carcinoma (EOC), 49 with benign ovarian neoplasms, and 75 age-matched controls. The samples were randomly divided into training (n = 144) and validation (n = 144) sets. Quantification of cell-free DNA was performed using real-time polymerase chain reaction for beta-globin, and the number of genome equivalents (GE) per milliliter of plasma was determined. Cell free DNA was correlated with clinicopathologic parameters. RESULTS: The training and validation sets were similar in terms of demographic features. In the training set, EOC patients had a median preoperative cell-free DNA level of 10,113 GE/mL, compared with patients with benign ovarian neoplasms (median, 2365 GE/mL; P < .0001) and controls (median, 1912 GE/mL, P < .0001). Cell-free DNA >22,000 GE/mL was significantly associated with decreased patient survival (P < .001). After adjusting for other clinical variables, preoperative cell-free DNA >22,000 GE/mL was an independent predictor (P = .02) for disease-specific survival. Analysis of the validation set confirmed significantly higher cell-free DNA levels in EOC (median, 13,672 GE/mL) and that cell-free DNA >22,000 GE/mL was associated with a 2.83-fold increased risk of death from disease (P < .001). CONCLUSIONS: Preoperative plasma total cell-free DNA levels are significantly elevated in patients with EOC. Elevated plasma cell-free DNA is an independent predictor for death from disease in ovarian cancer. PMID- 20166214 TI - The role of high-dose imatinib in the management of patients with gastrointestinal stromal tumor. AB - After an era of few treatment options for patients with locally advanced or metastatic gastrointestinal stromal tumor (GIST), imatinib has emerged as the standard of care and first-line treatment for these patients. Although imatinib was initially approved at the doses of 400 and 600 mg daily, results from clinical studies established 400 mg daily as the standard initial dose for the majority of advanced GIST patients. Nevertheless, the use of high-dose imatinib (800 mg daily) has been shown to benefit patients with advanced or metastatic GIST that progresses on the standard-dose, and has been recommended in this setting by the major management guidelines in Europe and the United States. Results from the Meta-GIST meta-analysis showed that patients whose GIST harbors a KIT exon 9 mutation garner a longer progression-free survival time when treated initially with high-dose imatinib (800 mg daily) compared with those patients with KIT exon 11 or no mutations. Thus, the use of high-dose imatinib is recommended by the clinical practice guidelines in these 2 specific clinical situations. In addition, clinicians should weigh the clinical benefit of administering high-dose imatinib against the associated toxicities, as well as the proper management of dose-related side effects. PMID- 20166215 TI - Phase 2 trial of weekly intravenous 1,25 dihydroxy cholecalciferol (calcitriol) in combination with dexamethasone for castration-resistant prostate cancer. AB - BACKGROUND: Preclinical data indicate that there is substantial antitumor activity and synergy between calcitriol and dexamethasone. On the basis of these data, the authors conducted a phase 2 trial of intravenous (iv) calcitriol at a dose of 74 microg weekly (based on a recent phase 1 trial) and dexamethasone in patients with castration-resistant prostate cancer (CRPC). METHODS: A 2-stage Kepner-Chang design was used. Oral dexamethasone at a dose of 4 mg was given weekly on Days 1 and 2, and iv calcitriol (74 microg over 1 hour) was administered weekly on Day 2 from 4 to 8 hours after the dexamethasone dose in patients with CRPC. Laboratory data were monitored weekly, and renal sonograms, computed tomography scans, and bone scans were obtained every 3 months. Disease response was assessed by using the Response Evaluation Criteria in Solid Tumors (RECIST) and standard criteria for prostate-specific antigen (PSA) response. The calcitriol dose was delineated by from the authors' recent phase 1 trial. RESULTS: Of 18 evaluable patients, 15 patients were Caucasian (83%). No patients had a complete or partial response by either RECIST or PSA response criteria. Fourteen patients had progressive disease, 2 patients refused to continue treatment (after 64 days and 266 days), and 2 patients remain on the trial (for 306 days and 412 days).The median time to disease progression was 106 days (95% confidence interval, 80-182 days). Fourteen episodes of grade 3 or 4 toxicity were noted in 7 patients (hyperglycemia, hypocalemia, chest pain, dyspnea, hypercalcemia, hypophosphatemia, cardiac arrhythmia, and pain). Only 1 episode of grade 3/ 4 toxicity was related definitely to calcitriol (hypercalcemia). No treatment-related deaths were noted. CONCLUSIONS: High-dose, iv calcitriol at a dose of 74 microg weekly in combination with dexamethasone was well tolerated but failed to produce a clinical or PSA response in men with CRPC. PMID- 20166216 TI - Validation and application of a module of the M. D. Anderson Symptom Inventory for measuring multiple symptoms in patients with gastrointestinal cancer (the MDASI-GI). AB - BACKGROUND: The M. D. Anderson Symptom Inventory (MDASI) was developed as a brief yet comprehensive tool to assess patient-reported symptom severity and interference in patients with cancer. The authors report the development of an MDASI module for use in patients with gastrointestinal (GI) cancer (the MDASI GI). METHODS: Patients with GI cancer (N = 184) participated in module development and validation. The process included: 1) generating GI-specific candidate items with input from GI oncologists and from qualitative interviews with patients and adding those items to the core MDASI for testing; 2) dropping candidate GI items that lacked sensitivity; 3) validating the psychometric properties (validity, reliability, sensitivity) of the resulting MDASI-GI; and 4) conducting cognitive debriefing interviews with patients to confirm the questionnaire's ease of comprehension, relevance, and acceptability. RESULTS: Five GI-specific symptom items (constipation, diarrhea, difficulty swallowing, change in taste, and feeling bloated) were added to the original 19 MDASI symptom and interference items to form the MDASI-GI. Sixty-one percent of the sample had 1 or more moderate-to-severe symptom(s) (>or=5 on a severity scale from 0 to 10). Cronbach alpha values were .80 and .87 for symptom severity items and interference items, respectively. Known-group validity (sensitivity) was supported by the ability of the MDASI-GI to detect significant differences in symptom and interference levels according to performance status (P < .001). Cognitive debriefing demonstrated that, for patients, the MDASI-GI was an easy-to use and understandable tool. CONCLUSIONS: The current results indicated that the MDASI-GI is a valid, reliable, and concise tool for measuring symptom severity and interference with function in patients with GI cancer. PMID- 20166217 TI - Osteoblastic induction on calcium phosphate cement-chitosan constructs for bone tissue engineering. AB - Calcium phosphate cement (CPC) is osteoconductive and moldable, and it can conform to complex cavity shapes and set in situ to form hydroxyapatite. Chitosan could increase the strength and toughness of CPC, but there has been no investigation on recombinant human bone morphogenic protein-2 (rhBMP-2) delivery via CPC-chitosan composite and its effect on osteogenic induction of cells. The objective of this research was to investigate the mechanical properties and osteoblastic induction of MC3T3-E1 cells cultured on CPC-containing chitosan and rhBMP-2. Cell viability for CPC with chitosan and rhBMP-2 was comparable with that of control CPC, whereas the CPC-chitosan composite was stronger and tougher than CPC control. After 14 days, osteoblastic induction was quantified by measuring alkaline phosphatase (ALP) activity. ALP (mean +/- SD; n = 6) of cells seeded on conventional CPC without rhBMP-2 was (143 +/- 19) (mM pNpp/min)/(mug DNA). The addition of chitosan resulted in an ALP of 161 +/- 27. Further addition of rhBMP-2 to the CPC-chitosan composite increased the ALP to 305 +/- 111 (p < 0.05). All ALP activity on CPC composites was significantly higher when compared with the 10.0 +/- 3.3 of tissue culture polystyrene (p < 0.05). Flexural strength of CPC containing 15% (mass fraction) chitosan was 19.8 +/- 1.4 MPa, which is more than double the 8.0 +/- 1.4 MPa of conventional CPC (p < 0.05). The addition of chitosan to CPC increased the fracture toughness from 0.18 +/- 0.01 MPa.m(1/2) to 0.23 +/- 0.02 MPa.m(1/2) (p < 0.05). The relatively high strength, self hardening CPC-chitosan composite scaffold is promising as a moderate load-bearing matrix for bone repair, with potential to serve as an injectable delivery vehicle for osteoinductive growth factors to promote osteoblastic induction and bone regeneration. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010. PMID- 20166218 TI - Chronic inflammatory responses to microgel-based implant coatings. AB - Inflammatory responses to implanted biomedical devices elicit a foreign body fibrotic reaction that limits device integration and performance in various biomedical applications. We examined chronic inflammatory responses to microgel conformal coatings consisting of thin films of poly(N-isopropylacrylamide) hydrogel microparticles cross-linked with poly(ethylene glycol) diacrylate deposited on poly(ethylene terephthalate) (PET). Unmodified and microgel-coated PET disks were implanted subcutaneously in rats for 4 weeks and explants were analyzed by histology and immunohistochemistry. Microgel coatings reduced chronic inflammation and resulted in a more mature/organized fibrous capsule. Microgel coated samples exhibited 22% thinner fibrous capsules that contained 40% fewer cells compared to unmodified PET disks. Furthermore, microgel-coated samples contained significantly higher levels of macrophages (80%) than unmodified PET controls. These results demonstrate that microgel coatings reduce chronic inflammation to implanted biomaterials. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010. PMID- 20166219 TI - Polymethylmethacrylate particle exposure causes changes in p38 MAPK and TGF-beta signaling in differentiating MC3T3-E1 cells. AB - Periprosthetic osteolysis of joint replacements caused by wear debris is a significant complication of joint replacements. Polymethylmethacrylate (PMMA) particles have been shown to inhibit osteogenic differentiation, but the molecular mechanism has not been previously determined. In this study, we exposed differentiating MC3T3-E1 preostoblast cells to PMMA particles and determined the changes that occurred with respect to p38 mitogen-activated protein kinase (MAPK) activity and the transforming growth factor (TGF)-beta1 and bone morphogenetic protein (BMP) signaling pathways. In the absence of particles, MC3T3-E1 cells demonstrate activation of p38 MAPK on day 8 of differentiation; however, when treated with PMMA particles, differentiating MC3T3-E1 cells demonstrate the suppression of p38 activity on day 8 and show activation of p38 on days 1 and 4. On day 4 of particle exposure, the differentiating MC3T3-E1 cells show significant downregulation of TGF-beta1 expression, which is involved in osteoblast differentiation, and a significant upregulation of the expression of BMP3 and Sclerostin (SOST), which are negative regulators of osteoblast differentiation. By day 8 of particle exposure, the changes in TGF-beta1, BMP3, and SOST expression are opposite of those seen on day 4. This study has demonstrated the distinct changes in the molecular profile of MC3T3-E1 cells during particle-induced inhibition of osteoblast differentiation. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010. PMID- 20166220 TI - Polycaprolactone/hydroxyapatite composite scaffolds: preparation, characterization, and in vitro and in vivo biological responses of human primary bone cells. AB - Polycaprolactone (PCL) is a synthetic biodegradable polymer that has been approved for use as bone graft substitutes. In this study, PCL scaffolds incorporating hydroxyapatite (HAp) particles were fabricated by combined solvent casting and particulate leaching techniques. The average pore dimension was in the range of about 480-500 microm. The porosity, water absorption, and compressive modulus of the scaffold were evaluated. The responses of primary bone cells cultured on the PCL and PCL/HAp scaffolds were examined both in vitro and invivo. In comparison with the cells grown on the PCL scaffold, those cultured on the PCL/HAp counterpart positively expressed the markers of osteogenic differentiation. Cells increased the mRNA expressions of type I collagen and osteocalcin on day 10 and demonstrated a significant increase in calcium deposition. In coherence with the in vitro appearance, histomorphometric analysis in a mouse calvarial model showed a significantly greater amount of new bone formation. The results demonstrated that the prepared PCL/HAp scaffold could be a good candidate as synthetic substitute for bone tissue engineering. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010. PMID- 20166221 TI - Effects of cyclic flexural fatigue on porcine bioprosthetic heart valve heterograft biomaterials. AB - Although bioprosthetic heart valves (BHV) remain the primary treatment modality for adult heart valve replacement, continued problems with durability remain. Several studies have implicated flexure as a major damage mode in porcine-derived heterograft biomaterials used in BHV fabrication. Although conventional accelerated wear testing can provide valuable insights into BHV damage phenomena, the constituent tissues are subjected to complex, time-varying deformation modes (i.e., tension and flexure) that do not allow for the control of the amount, direction, and location of flexure. Thus, in this study, customized fatigue testing devices were developed to subject circumferentially oriented porcine BHV tissue strips to controlled cyclic flexural loading. By using this approach, we were able to study layer-specific structural damage induced by cyclic flexural tensile and compressive stresses alone. Cycle levels of 10 x 10(6), 25 x 10(6), and 50 x 10(6) were used, with resulting changes in flexural stiffness and collagen structure assessed. Results indicated that flexural rigidity was markedly reduced after only 10 x 10(6) cycles, and progressively decayed at a lower rate with cycle number thereafter. Moreover, the against-curvature fatigue direction induced the most damage, suggesting that the ventricularis and fibrosa layers have low resistance to cyclic flexural compressive and tensile loads, respectively. The histological analyses indicated progressive collagen fiber delamination as early as 10 x 10(6) cycles but otherwise no change in gross collagen orientation. Our results underscore that porcine-derived heterograft biomaterials are very sensitive to flexural fatigue, with delamination of the tissue layers the primary underlying mechanism. This appears to be in contrast to pericardial BHV, wherein high tensile stresses are considered to be the major cause of structural failure. These findings point toward the need for the development of chemical fixation technologies that minimize flexure-induced damage to extend porcine heterograft biomaterial durability. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010. PMID- 20166222 TI - Evaluation of the biocompatibility and mechanical properties of naturally derived and synthetic scaffolds for urethral reconstruction. AB - The aim of this study was to evaluate the mechanical properties and biocompatibility of biomaterials, including bladder submucosa (BAMG), small intestinal submucosa (SIS), acellular corpus spongiosum matrix (ACSM), and polyglycolic acid (PGA), to identify the optimal scaffold for urethral tissue engineering. Tensile mechanical testing was conducted to evaluate mechanical properties of each scaffold. Rabbit corporal smooth muscle cells were cultured with the extracts of biomaterials and mitochondrial metabolic activity assay was used to determine the cytotoxicity of scaffold. The pore sizes of each scaffold were measured. Additionally, smooth muscle cells were seeded on biomaterials. Cell infiltration was evaluated. Mechanical evaluation showed that Young modulus, stress at break in ACSM were prior to those in other biomaterials (p < 0.05). MTT assay confirmed that all scaffolds supported normal cellular mitochondrial metabolic without inducing cytotoxic events. SEM demonstrated that PGA has the largest pore size (>200 microm). The ACSM has different pore sizes in urethral (<5 microm) and cavernosal surfaces (>10 microm). Widespread distribution of cells could be observed in PGA 14 days after seeding. Multilayer cellular coverage developed in BAMG and urethral surface of ACSM without any sign of cellular invasion. Moderated cellular penetration could be found in SIS and cavernosal surface of ACSM. Although each scaffold demonstrated suitable mechanical properties, which is similar to normal urethra, ACSM showed better response in some parameters than those in other biomaterials. It suggested that this scaffold may be an alternative for urethral reconstruction in the future. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010. PMID- 20166223 TI - Investigation of the binding of Cr(III) complexes to bovine and human serum proteins: a proteomic approach. AB - Chromium (Cr) compounds are widely used in alloys manufacturing and forming processes. One of the main concerns in the use of cobalt-chromium (Co-Cr) alloy based implants is the long-term fate of Co and Cr ions in the blood, organs, and urine of patients. Our previous studies have shown that Cr(III) forms complexes in different cell culture media, whereas Cr(VI) does not form any detectable structure under the same conditions. Because Cr(VI) is known to be more toxic than Cr(III), we hypothesized that the presence of serum proteins in the molecular structure of Cr(III) may be responsible for the difference in toxicity. We investigated the interaction of the Cr(III) complexes with serum proteins and their internalization by U937 macrophage-like cells. By using a proteomic approach, we showed that in the presence of fetal bovine serum, Cr(III) complexes interacted only with albumin, whereas they interacted mainly with albumin, transferrin, and immunoglobulins (Ig) in the presence of human serum (HS). Cr(III) complexes were more easily engulfed by U937 macrophage-like cells when they were formed with HS. To the best of our knowledge, this is the first report on the formation of Cr(III) complexes in the presence of serum proteins and the interaction of these complexes with U937 macrophage-like cells. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010. PMID- 20166224 TI - Osteochondral repair using porous poly(lactide-co-glycolide)/nano-hydroxyapatite hybrid scaffolds with undifferentiated mesenchymal stem cells in a rat model. AB - In this study, a novel three-dimensional poly (lactide-co-glycolide) (PLGA)/nano hydroxyapatite (NHA) scaffold was fabricated by a thermally induced phase separation technique and its potential application in cartilage tissue engineering was investigated. The PLGA scaffold was used as a control and mesenchymal stem cells (MSCs) were seeded in both scaffolds. After 12-days culture, SEM images and confocal laser scanning microscopy illustrated that MSCs attached more moderately and more cells distributed in PLGA/NHA scaffolds. MTT test and DNA assay showed that the viability and proliferation of MSCs in PLGA/NHA scaffolds were significantly superior to PLGA scaffolds during in vitro culture. Through in vivo study, the efficacy of this scaffold combining with MSCs for repairing articular osteochondral defects was evaluated in a rat model. Osteochondral defects in rats knees were left untreated, or treated with PLGA/NHA MSCs composites or PLGA-MSCs composites. Twelve weeks after operation, histological examination revealed that the defects in the PLGA/NHA-MSCs treated group were filled with smooth and hyaline-like cartilage with abundant glycosaminoglycan and collagen type II deposition, but deficient in collagen type I at 12 weeks after operation. To investigate the final fate of MSCs transplanted into the defect areas, the fluorescent dye CM-DiI was used to prelabel cells. At 12 weeks after transplantation, we still observed the red fluorescence in the repair area. These findings suggest that the PLGA/NHA-MSCs composite may be potentially used for cartilage repair in clinical application. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010. PMID- 20166225 TI - Explorable three-dimensional digital model of the female pelvis, pelvic contents, and perineum for anatomical education. AB - The anatomy of the pelvis is complex, multilayered, and its three-dimensional organization is conceptually difficult for students to grasp. The aim of this project was to create an explorable and projectable stereoscopic, three dimensional (3D) model of the female pelvis and pelvic contents for anatomical education. The model was created using cryosection images obtained from the Visible Human Project, in conjunction with a general-purpose three-dimensional segmentation and surface-rendering program. Anatomical areas of interest were identified and labeled on consecutive images. Each 2D slice was reassembled, forming a three-dimensional model. The model includes the pelvic girdle, organs of the pelvic cavity, surrounding musculature, the perineum, neurovascular structures, and the peritoneum. Each structure can be controlled separately (e.g. added, subtracted, made transparent) to reveal organization and/or relationships between structures. The model can be manipulated and/or projected stereoscopically to visualize structures and relationships from different angles with excellent spatial perception. Because of its ease of use and versatility, we expect this model may provide a powerful teaching tool for learning in the classroom or in the laboratory. PMID- 20166226 TI - Introducing gross pathology to undergraduate medical students in the dissecting room. AB - Pathology and anatomy are both sciences that contribute to the foundations of a successful medical career. In the past decade, medical education has undergone profound changes with the development of a core curriculum combined with student selected components. There has been a shift from discipline-based teaching towards problem-based learning. Both anatomy and pathology are perceived to have suffered from this educational shift. The challenge is to introduce methods of learning for these subjects into an integrated student-centered curriculum. The purpose of this study was to determine the prevalence of pathology in 12 donor cadavers in the dissecting room of the Bute Medical School, University of St Andrews. All of the cadavers had multiple pathologies (between three to four conditions) ranging from common to rare disorders. A number of prostheses and surgical interventions were also noted. This small study confirms that cadaveric dissection provides an excellent opportunity for the integration of anatomy, pathology, and clinical medicine into the early clinical training of undergraduate medical students. The identification of disease in a cadaver provides an excellent introduction to the gross features of a disease process, but does not substitute for the detailed study of a process later in the curriculum. PMID- 20166227 TI - Development of a zebrafish embryo teratogenicity assay and quantitative prediction model. AB - BACKGROUND: A zebrafish (Danio rerio) teratogenicity assay has been developed and evaluated for its ability to predict the teratogenic potential of chemicals. METHODS: Zebrafish embryos were dechorionated and then exposed to a test solution from 4-6 hours post-fertilization, and embryos or larvae were assessed up to 5 days post-fertilization (dpf) for viability and morphology. In preliminary experiments, the potential time points for assessment of compound-induced dysmorphology and general toxicity parameters were evaluated, and 5 dpf was found to be the optimum developmental stage for evaluation. Additionally, a morphological scoring system was devised to identify the developmental no observed-adverse-effect level (NOAEL). For assay evaluation, 34 compounds with adequate in vivo developmental toxicity data were chosen. The compound set represented diversity in teratogenic potencies, structural classes, and pharmacologic targets. For 31 test compounds, each was evaluated over a concentration range, while 3 others were insufficiently aqueous-soluble to be fully tested. For each of the 31 tested compounds, the 5 dpf NOAEL was determined, and the concentration resulting in 25% lethality (LC25) was calculated by curve-fitting. Teratogenic potential of each compound was predicted based on the ratio of the LC25 to the NOAEL. LC25/NOAEL ratios of 10 or greater were considered predictive of teratogenicity. RESULTS: The model successfully categorized 87% of the compounds as teratogens or non-teratogens, with only 2 false-positives (dimethyl phthalate and a Bristol-Myers Squibb (BMS) investigative compound) and 2 false-negatives (valproic acid and a BMS compound). CONCLUSIONS: The results indicate that this assay is promising for screening compounds for teratogenic potential. Birth Defects Res (Part B) 89:66-77, 2010. (c) 2010 Wiley-Liss, Inc. PMID- 20166228 TI - Introduction to special issue on developmental and reproductive toxicology in China. PMID- 20166229 TI - Self-assemblies on chitosan nanohydrogels. AB - Nanohydrogels of pure chitosan, containing neither potentially toxic solvent nor chemical cross-linker, were obtained by an ammonia-induced physical gelation of a reverse emulsion of a chitosan solution in a triglyceride mixture as an organic phase. The resulting colloids were obtained with a controlled size distribution and displayed a positive surface charge. Assemblies with various macromolecules were investigated as a first step toward new nano-carriers for bioactive molecules. Chondroitin sulfate formed polyelectrolyte complexes with the positively charged surface of the nanogels, leading to negative chitosan-based colloidal hydrogels with preservation of the original average size of the dispersion. The mode of assembly of HIV-1 p24 protein with these colloids relied on multiple interactions between the protein and the hydrogels, irrespective of their surface charges. Anyhow, the amounts of loaded protein remained limited, suggesting a surface association. The assembly of an immunoglobulin (IgG) was markedly different from p24. No association was detected with the positive colloidal hydrogels whereas a very high loading capacity could be obtained with the negative ones. So, this work reports that fully biodegradable submicrometric physical hydrogels could be obtained from naturally occurring polymers. These gels could cargo a variety of biomolecules making them versatile carriers with many potential applications in Life Sciences. PMID- 20166230 TI - Reinforcing silk scaffolds with silk particles. AB - Silk fibroin is a useful protein polymer for biomaterials and tissue engineering. In this work, porogen leached scaffolds prepared from aqueous and HFIP silk solutions were reinforced through the addition of silk particles. This led to about 40 times increase in the specific compressive modulus and the yield strength of HFIP-based scaffolds. This increase in mechanical properties resulted from the high interfacial cohesion between the silk matrix and the reinforcing silk particles, due to partial solubility of the silk particles in HFIP. The porosity of scaffolds was reduced from approximately 90% (control) to approximately 75% for the HFIP systems containing 200% particle reinforcement, while maintaining pore interconnectivity. The presence of the particles slowed the enzymatic degradation of silk scaffolds. PMID- 20166231 TI - Multicompartmental micro- and nanocapsules: hierarchy and applications in biosciences. AB - Multicompartmentalized micro- and nanocapsules allow simultaneous delivery of several vectors or biomolecules; they are the next generation of carriers with increased complexity. Here we overview multicompartment micro- and nanocapsules and present a road-map for future developments in the field. Four basic building block structures are demonstrated, three isotropic: concentric, pericentric, and innercentric, and one anisotropic: acentric. As an elaborate implementation of multicompartmentalization, an enzyme-catalyzed reaction inside the same capsule carrying both an enzyme and a substrate is shown. Applications of multicompartmentalized microcapsules for simultaneous multiple drug delivery in bio-medicine are discussed. PMID- 20166232 TI - Aerogels from unaltered bacterial cellulose: application of scCO2 drying for the preparation of shaped, ultra-lightweight cellulosic aerogels. AB - Bacterial cellulose produced by the gram-negative bacterium Gluconacetobacter xylinum was found to be an excellent native starting material for preparing shaped ultra-lightweight cellulose aerogels. The procedure comprises thorough washing and sterilization of the aquogel, quantitative solvent exchange and subsequent drying with supercritical carbon dioxide at 40 degrees C and 100 bar. The average density of the obtained dry cellulose aerogels is only about 8 mg x cm(-3) which is comparable to the most lightweight silica aerogels and distinctly lower than all values for cellulosic aerogels obtained from plant cellulose so far. SEM, ESEM and nitrogen adsorption experiments at 77 K reveal an open-porous network structure that consists of a comparatively high percentage of large mesopores and smaller macropores. PMID- 20166234 TI - [Radiologic findings in patients with common variable immunodeficiency]. PMID- 20166233 TI - Thermosensitive nanoparticles self-assembled from PCL-b-PEO-b-PNIPAAm triblock copolymers and their potential for controlled drug release. AB - Thermosensitive nanoparticles with a core-shell structure were prepared by self assembly of PCL-b-PEO-b-PNIPAAm triblock copolymers, which were synthesized by anionic ring-opening polymerization and reversible addition fragmentation chain transfer (RAFT) polymerization. At temperatures above the lower critical solution temperature (LCST), the collapse of PNIPAAm chains in the outer shell and in the core of nanoparticle caused a decrease in size, while the constantly hydrophilic PEO chains in the shell endowed nanoparticles with excellent stability in water. The release of doxorubicin from these nanoparticles showed that both the length of PNIPAAm chains and temperature have great influence on drug release, which indicates the great potential of thermosensitive nanoparticles as drug carriers. PMID- 20166235 TI - An interview with... Kevin Campbell. Interview by Louisa Flintoft. PMID- 20166236 TI - Poor outcome in patients with spine-related leg or arm pain who are involved in compensation claims: a prospective study of patients in the secondary care sector: comment on the article by Rasmussen et al. PMID- 20166237 TI - Chronic systemic capillary leak syndrome: a case responding to prednisolone treatment. PMID- 20166238 TI - Minimisation of the wall shear stress gradients in bypass grafts anastomoses using meshless CFD and genetic algorithms optimisation. AB - The wall shear stress (WSS) spatial and temporal gradients are two hemodynamics parameters correlated with endothelial damage. Those two gradients become well pronounced in a bypass graft anastomosis geometry where the blood flow patterns are quite disturbed. The WSS gradient minimisation on the host artery floor can be achieved by optimising the anastomosis shape and hence may lead to an improved long-term post-surgical performance of the graft. The anastomosis shape optimisation can be executed via an integrated computational tool comprised of a meshless computational fluid dynamics (CFD) solver and a genetic algorithm (GA) shape optimiser. The meshless CFD solver serves to evaluate the WSS gradients and the GA optimiser serves to search for the end-to-side distal anastomosis (ETSDA) optimal shape that best minimises those gradients. We utilise a meshless CFD method to resolve hemodynamics and a GA for the purpose of optimisation. We consider three different anastomotic models: the conventional ETSDA, the Miller Cuff ETSDA and the hood ETSDA. The results reported herein demonstrate that the graft calibre should always be maximised whether a conventional or Miller Cuff ETSDA model is utilised. Also, it was noted that the Miller Cuff height should be minimised. The choice of an optimal anastomotic angle should be optimised to achieve a compromise between the concurrent minimisations of both the spatial WSS gradient and the temporal WSS gradient. PMID- 20166239 TI - Cardiorenal syndrome and heart failure. AB - PURPOSE OF REVIEW: Concomitant anemia, heart failure, and renal disease can be seen in a large proportion of patients with heart failure. The purpose of this review is to discuss the current definitions and mechanisms involved in this pathophysiological relationship, as well as the potential management and treatment options available for these patients. RECENT FINDING: Dysfunctional heart can promote the dysfunction of the kidneys through a variety of pathophysiological mechanism, the reciprocal holds true as well. Heart failure has been considered as the most common type of cardiovascular complication seen in patients with renal failure. Central to this relationship lies anemia, which can be the result or the cause of either heart or kidney disease. SUMMARY: Cardiorenal syndrome is a complex condition, which requires the collaboration and resources from cardiology, cardiac surgery, nephrology, and critical care. Of great importance is recognizing the presence of cardiorenal syndrome and appreciating the impact it can play on treatment options and survival. PMID- 20166240 TI - Cagan H. Sekercioglu. PMID- 20166241 TI - Safety evaluation and pharmacokinetics of a novel human tumor necrosis factor alpha exhibited a higher antitumor activity and a lower systemic toxicity. AB - We had prepared earlier a prokaryotic-expressed tumor necrosis factor-alpha (TNF [alpha]) mutant that exhibited a higher antitumor activity and a lower systemic toxicity compared with that of wild-type TNF-[alpha] in both syngeneic murine tumor models and human tumor xenografts models. For its clinical use as an antitumor agent, we evaluated repeated-dose toxicity, anaphylaxis, genetic toxicity, pharmacokinetic, and metabolism in different animals according to the criteria of the biological investigational new drug application. It was found to be safe at a dose of 4x10(6) IU/kg/day for 60 days after administration in rhesus monkeys, but the TNF-[alpha] antibody level and liver toxicity needed to be monitored. No systemic anaphylaxis or genetic toxicity was found and the pharmacokinetic characteristics of the recombinant mutated human TNF-[alpha] (rmhTNF-[alpha]) were suited for clinical use. More than 96.3% of rmhTNF-[alpha] could be reclaimed from the urine and feces in 24 h after administration, which indicated the main excretion route. The results proved that the characteristics of this rmhTNF-[alpha] satisfied clinical trial requirements. The related positive clinical trial results will be reported in future. This study of novel rmhTNF-[alpha] is of considerable importance, not only given the proven usefulness of TNF-[alpha] local application therapies under isolated limp perfusion and isolated hepatic perfusion conditions for selected indications, but also implicated for systemic application of TNF-[alpha]. PMID- 20166243 TI - [Adverse drug effects on the eye]. PMID- 20166242 TI - Silibinin inhibits invasive properties of human glioblastoma U87MG cells through suppression of cathepsin B and nuclear factor kappa B-mediated induction of matrix metalloproteinase 9. AB - Glioblastoma multiforme remains one of the most devastating human malignancies because of its high infiltrative capacity. This study aimed to investigate the effects of silibinin on human glioblastoma U87MG cells. The microculture tetrazolium test, bromodeoxyuridine cell proliferation assay, cell-based nuclear factor kappa B (NF-[kappa]B) activation assessment, cathepsin B activity assay, gelatin zymography, and quantitative real-time reverse transcription-PCR were performed to appraise the effects of silibinin on the metabolic activity, DNA synthesis, NF-[kappa]B phosphorylation, cathepsin B activity, and gelatinolytic activity of U87 cells. Silibinin inhibited metabolic activity, cell proliferation, NF-[kappa]B activation, cathepsin B enzymatic levels, and gelatinase B activity in U87 cells. In addition, an expressive decrease in mRNA levels of matrix metalloproteinase-9, cathepsin B, urokinase plasminogen activator receptor, urokinase plasminogen activator, and intercellular adhesion molecule 1 coupled with a significant induction in transcriptional levels of stefin A was observed. Altogether, these issues show for the first time that silibinin treatment could trammel invasive features of a highly invasive human glioma cell line, U87, through suppression of NF-[kappa]B-mediated stimulation of matrix metalloproteinase-9. Furthermore, silibinin might cripple the activation of gelatinase B by cramping transcriptional and enzymatic activities of cathepsin B in U87 cells. PMID- 20166245 TI - Elephants I--new PIs. By Caveman. PMID- 20166246 TI - Mitral valve repair for functional mitral regurgitation: is annuloplasty alone enough? AB - PURPOSE OF REVIEW: To outline indications and contraindications to mitral valve surgery in the clinical context of dilated cardiomyopathy and the surgical principles to follow in performing an undersized annuloplasty. Moreover, we will describe the characteristics of the patients for whom an annuloplasty alone is unlikely to provide an effective result and for whom,therefore, some other procedures or mitral valve replacement should be preferred. RECENT FINDINGS: In functional mitral regurgitation, competence of the mitral valve can be restored by using a restrictive annuloplasty. This procedure leads to symptomatic improvement and reverse left ventricular remodeling in a substantial proportion of patients. However, the failure rate of undersized annuloplasty is still high and is mainly due to inappropriate patient selection and to technical issues that have been progressively identified. SUMMARY: In the treatment of functional mitral regurgitation, annuloplasty alone should only be carried out in the early phase of the disease before the occurrence of advanced left ventricular remodeling and echocardiographic predictors of unfavorable outcome should be taken into account. Under certain circumstances, surgery should include additional procedures apart from annuloplasty to enhance the durability of the repair. Mitral valve replacement should be considered when unsatisfactory results are expected with mitral valve repair due to advanced left ventricular remodeling and long-lasting heart failure. PMID- 20166247 TI - Ethical practice: serving the aging community. PMID- 20166248 TI - Focus: Darwin as a cultural icon. AB - Since his death in 1882, if not before, Charles Darwin has been a key icon of the modern era. The bearded sage of Down House has been invoked in a wide range of contexts in the English-speaking world, from eugenics and social policy to debates about the implications of science for religious belief. The essays in this Focus section explore the Darwinian image in an unusual diversity of media, examining portrait photographs, portable sculptures,newspaper caricatures, cartoons, after-dinner drinking songs, and long-playing records. They suggest that Darwin's celebrity needs to be understood not as the outcome of the unique qualities of his life and work, but as an aspect of the emergence of the idea of the scientist, a process closely tied to the developing communication and entertainment industries of the late nineteenth and early twentieth centuries. PMID- 20166249 TI - Looking at Darwin: portraits and the making of an icon. AB - With increased attention on the visual in the history of science, there is renewed interest in the role of portraiture and other forms of personal imagery in constructing scientific reputation and the circulation of scientific ideas. This essay indicates some directions in which researchers could push forward by studying the dissemination of pictures and portraits of Charles Darwin. Selected portraits are discussed, with particular attention paid to their circulation. The mode of production and original intent of these portraits is briefly addressed, but the thrust of the argument is to highlight subsequent shifts in usage. While self-fashioning is an important part of the story, it is useful also to dwell on the rise and diversification of printed media in conjunction with escalating interest in Darwin as a celebrity figure. Historicizing the variety of opportunities that people have had of "looking"at Darwin adds considerably to our understanding of scientific fame. PMID- 20166250 TI - "You are here": Missing links, chains of being, and the language of cartoons. AB - Evolution cartoons served polemical and satirical purposes even before Darwin published On the Origin of Species, and they proliferated afterward. Yet even though Victorian evolution cartoons often pictured Darwin himself as a personification of his theory, by the time of the Scopes trial controversy in the 1920s cartoons about evolution had come to popularize ironically non-Darwinian views of evolution. Cartoons repeated, reflected, and perpetuated teleological views of evolution and often implicitly associated evolution with prevalent attitudes about race, gender, and social hierarchies. Cartoons drew on old iconographic traditions, expanding them to fit changing historical circumstances, forming a lasting cartoon lexicon. Though adaptable and protean, the language of evolution cartoons, like any language, carries its history with it, and in them we can read the history of the cultural context of evolution controversies. PMID- 20166251 TI - Singing his praises: Darwin and his theory in song and musical production. AB - This essay offers a chronological survey of the range of songs and musical productions inspired by Darwin and his theory since they entered the public sphere some 150 years ago.It draws on an unusual set of historical materials, including illustrated sheet music, lyrics and librettos, wax cylinder recordings, vinyl records, and video recordings located in digital and sound archives and on the Internet. It also offers a characterization of the varied genres and a literary analysis of the forms as a way of understanding the diverse audiences engaging, and indeed "entertaining," Darwin and the implications of his theory. It argues that the engagement with Darwin and his celebrated theory is far more creative than has been appreciated and recommends that historians of science further explore Darwin and his theory as embodied ina fuller range of cultural expressions. This will lead to an understanding of Darwin's "iconic"status that draws on a fuller range of human sensory experience and that also enables us to appreciate his--and his theory's-enduring power to engage the human imagination. PMID- 20166252 TI - [Measurement of pulmonary function with body plethysmograph in infants]. AB - OBJECTIVE: To observe the alterations of pulmonary function in infants with respiratory diseases. METHODS: A total of 900 infants with respiratory diseases were recruited and pulmonary function measured in 30 healthy infants. The tests were performed in the sleeping infants with sedation. Tidal breathing flow-volume (TBFV) loops were recorded when infants were breathing quietly. Passive flow volume technique was used to obtain static respiratory system compliance and resistance. Functional residual capacity was measured by body plethysmograph. RESULTS: The TBFV loop showed proximate round or oval curve in healthy infants. The shape and parameters of TBFV loop had significant differences in infants with respiratory diseases as compared with healthy controls. The TBFV loop displayed a concave expiratory curve and ratio of time to reach tidal peak flow to total expiratory time, the expiratory volume till peak flow divided by the total expiratory volume significantly decreased in infants with small airway obstruction. The expiratory or inspiratory curve showed a plateau and the ratio of mid-expiratory to mid-inspiratory flow was less than 60% or over 150% in infants with upper airway obstruction. The TBFV loop turned narrow and lung volume decreased in infants with restrictive diseases. CONCLUSION: The TBFV loop show proximate round or oval curve in healthy infants. Pulmonary function has significant differences between healthy controls and infants with respiratory diseases. Pulmonary function test is useful in the assessment of respiratory diseases. PMID- 20166253 TI - [Exploring the biological effects of electromagnetic fields systematically, and setting electromagnetic environment management policy reasonably]. PMID- 20166254 TI - [Power line health risk of exposure to power line electromagnetic fields in rats]. PMID- 20166255 TI - [Effect of electromagnetic radiation on blood-brain barrier and its mechanism]. PMID- 20166256 TI - [Status quo of international power frequency electromagnetic field exposure limit]. PMID- 20166257 TI - [Green grid and harmonious home: development of grid environmental protection in China]. PMID- 20166258 TI - [Magnetic field limit and status quo of high-voltage transmission and transformation power facilities]. PMID- 20166259 TI - [Environmental electromagnetic fields and their potential health impact]. PMID- 20166260 TI - [Exercise, physical activity and public health (19) How do we evaluate the amount of physical activities?]. PMID- 20166261 TI - [The current status and challenge in anti-tuberculosis campaign in Japan (12) A new strategy in anti-tuberculosis campaign--Stop TB partnership]. PMID- 20166262 TI - [Revision of the laws concerning public health nurses, midwives and nurses and an overview on education of public health nurses (3). Keypoints in the curriculum for public health nursing education at universities--from the viewpoint of the achievement at graduation]. PMID- 20166263 TI - Share with Women. Menopause--what's it all about? PMID- 20166264 TI - [What is a midwife? ]. PMID- 20166265 TI - [Environmental hazards during pregnancy]. PMID- 20166266 TI - [Eating safely during pregnancy]. PMID- 20166267 TI - [Nausea and vomiting during pregnancy]. PMID- 20166268 TI - [Prenatal tests for Down syndrome]. PMID- 20166269 TI - [Epidural analgesia]. PMID- 20166271 TI - GRACE campaign raises awareness for women and people of color. PMID- 20166270 TI - The syndrome of delayed post-hypoxic leukoencephalopathy. AB - Delayed post-hypoxic leukoencephalopathy (DPHL) is a demyelinating syndrome characterized by acute onset of neuropsychiatric symptoms days to weeks following apparent recovery from coma after a period of prolonged cerebral hypo oxygenation. It is diagnosed, after excluding other potential causes of delirium, with a clinical history of carbon monoxide poisoning, narcotic overdose, myocardial infarction, or another global cerebral hypoxic event. The diagnosis can be supported by neuroimaging evidence of diffuse hemispheric demyelination sparing cerebellar and brainstem tracts, or by an elevated cerebrospinal fluid myelin basic protein. Standard or hyperbaric oxygen following CO poisoning may reduce the likelihood of DPHL or other neurologic sequelae. Bed rest and avoidance of stressful procedures for the first 10 days following any prolonged hypoxic event may also lower the risk. Gradual recovery over a 3 to 12 month period is common, but impaired attention or executive function, parkinsonism, or corticospinal tract signs can persist. Stimulants, amantadine or levodopa may be considered for lasting cognitive or parkinsonian symptoms. Anticipation and recognition of DPHL should lead to earlier and more appropriate utilization of health care services. PMID- 20166272 TI - The economic benefits of breastfeeding. PMID- 20166273 TI - Special anniversary volume - issue 5: replacement - focus on in silico methods. PMID- 20166274 TI - The longevity dividend: why invest in basic aging reserach? PMID- 20166275 TI - HIPAA administrative simplification: enforcement. Interim final rule; request for comments. AB - The Secretary of the Department of Health and Human Services (HHS) adopts this interim final rule to conform the enforcement regulations promulgated under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) to the effective statutory revisions made pursuant to the Health Information Technology for Economic and Clinical Health Act (the HITECH Act), which was enacted as part of the American Recovery and Reinvestment Act of 2009 (ARRA). More specifically, this interim final rule amends HIPAA's enforcement regulations, as they relate to the imposition of civil money penalties, to incorporate the HITECH Act's categories of violations, tiered ranges of civil money penalty amounts, and revised limitations on the Secretary's authority to impose civil money penalties for established violations of HIPAA's Administrative Simplification rules (HIPAA rules). This interim final rule does not make amendments with respect to those enforcement provisions of the HITECH Act that are not yet effective under the applicable statutory provisions. Such amendments will be subject to forthcoming rulemaking(s). PMID- 20166276 TI - Medical examination of aliens--removal of human immunodeficiency virus (HIV) infection from definition of communicable disease of public health significance. Final rule. AB - Through this final rule, the Centers for Disease Control and Prevention (CDC), within the U.S. Department of Health and Human Services (HHS), is amending its regulations to remove "Human Immunodeficiency Virus (HIV) infection" from the definition of communicable disease of public health significance and remove references to "HIV" from the scope of examinations for aliens. Prior to this final rule, aliens with HIV infection were considered to have a communicable disease of public health significance and were thus inadmissible to the United States per the Immigration and Nationality Act (INA). While HIV infection is a serious health condition, it is not a communicable disease that is a significant public health risk for introduction, transmission, and spread to the U.S. population through casual contact. As a result of this final rule, aliens will no longer be inadmissible into the United States based solely on the ground they are infected with HIV, and they will not be required to undergo HIV testing as part of the required medical examination for U.S. immigration. PMID- 20166277 TI - Presumption of service connection for amyotrophic lateral sclerosis. Final rule. AB - This document adopts as a final rule the interim final rule amending the Department of Veterans Affairs (VA) adjudication regulations to establish a presumption of service connection for amyotrophic lateral sclerosis (ALS) for any veteran who develops the disease at any time after separation from service. This amendment implements the decision by the Secretary of Veterans Affairs to establish such a presumption based on a November 2006 report by the National Academy of Sciences Institute of Medicine on the association between active service and ALS. PMID- 20166278 TI - Medicare program; home health prospective payment system; rate update for calendar year 2010. Final rule. AB - This final rule sets forth an update to the Home Health Prospective Payment System (HH PPS) rates; the national standardized 60-day episode rates, the national per-visit rates, the non-routine medical supply (NRS) conversion factors, and the low utilization payment amount (LUPA) add-on payment amounts, under the Medicare prospective payment system for home health agencies effective January 1, 2010. This rule also updates the wage index used under the HH PPS. In addition, this rule changes the HH PPS outlier policy, requires the submission of OASIS data as a condition for payment under the HH PPS, implements a revised Outcome and Assessment Information Set (OASIS-C) for episodes beginning on or after January 1, 2010, and implements a Consumer Assessment of Healthcare Providers and Systems (CAHPS) Home Health Care Survey (HHCAHPS) affecting payment to HHAs beginning in CY 2012. Also, this rule makes payment safeguards that will improve our enrollment process, improve the quality of care that Medicare beneficiaries receive from HHAs, and reduce the Medicare program's vulnerability to fraud. This rule also adds clarifying language to the "skilled services" section and Conditions of Participation (CoP) section of our regulations. This rule also clarifies the coverage of routine medical supplies under the HH PPS. PMID- 20166279 TI - Medicare program: changes to the hospital outpatient prospective payment system and CY 2010 payment rates; changes to the ambulatory surgical center payment system and CY 2010 payment rates. Final rule with comment period. AB - This final rule with comment period revises the Medicare hospital outpatient prospective payment system (OPPS) to implement applicable statutory requirements and changes arising from our continuing experience with this system. In this final rule with comment period, we describe the changes to the amounts and factors used to determine the payment rates for Medicare hospital outpatient services paid under the prospective payment system. These changes are applicable to services furnished on or after January 1, 2010. In addition, this final rule with comment period updates the revised Medicare ambulatory surgical center (ASC) payment system to implement applicable statutory requirements and changes arising from our continuing experience with this system. In this final rule with comment period, we set forth the applicable relative payment weights and amounts for services furnished in ASCs, specific HCPCS codes to which these changes will apply, and other pertinent ratesetting information for the CY 2010 ASC payment system. These changes are applicable to services furnished on or after January 1, 2010. PMID- 20166280 TI - Introduction. ARCTIC program & other initiatives bring more science into the field. PMID- 20166281 TI - Beyond ventricular fibrillation. PMID- 20166282 TI - In my own words. PMID- 20166283 TI - Evolving AMI care, 2010. AB - The care of the patient with an acute coronary syndrome, specifically STEMI, continues to evolve. Although the goal of caring for any patient with STEMI is a D2B time of less than 90 minutes, research shows that every minute counts, and "time is muscle". Thus, even if a hospital has an acceptable D2B time, EMS on scene and transport times must be minimized to ensure optimal treatment and recovery of a dying heart. All EMS systems should work with their destination hospitals to ensure E2B times are optimally lowered and aim for an E2B of under 90 minutes when possible. MOreover, a team approach to PCI activation involving both the paramedic and ED physician whenever possible appears to be the best way to decrease false activations and increase recognition of STEMI patients. As research into myocardial infarction and treatment continues, EMS personnel should expect more critical care transports of patients who have already received lytic therapy. The in-hospital care of patients with acute coronary syndromes continues to evolve, and similarly EMS care for ACS patients continues to change at an ever increasing rate. PMID- 20166284 TI - [Cancer stem cells]. PMID- 20166285 TI - Effective public-private partnership in healthcare: Apollo as a cautionary tale. PMID- 20166286 TI - World trade, the poor and swine flu. PMID- 20166287 TI - Should the Bt brinjal controversy concern healthcare professionals and bioethicists? AB - The Genetic Engineering Approval Committee's approval of Bt brinjal, the first genetically modified crop for human consumption in India, has sparked off protests across the country. This article questions the so-called benefits of GM crops and highlights some major concerns. These include: inadequately addressed health and environmental risks, inadequate safety guidelines, a lack of transparency in sharing test data, the implications to seed sovereignty of farmers and the lack of informed choice for consumers. Some concerns about field testing by Mahyco, the developer of Bt-brinjal, and the process of evaluation by GEAC remain unresolved. With inadequate information about the crop's long-term safety, a precautionary approach is advocated before national policy allows commercial release of the seeds. A fair process is also needed in the public consultations being proposed by the minister of state for environment and forests. In addition to issues of procedural justice, a basic ethical question remains: do humans have a right to dominate the land and make expendable those creatures that they deem "undesirable"? PMID- 20166288 TI - Was the gadchiroli trial ethical? Response from the principal investigator. PMID- 20166289 TI - Impact of bioethics on patentability of inventions. AB - This paper examines the impact of bioethics on patent claims. The increase in research activities involving human biological materials, and the rush to commercialise inventions derived from such biological materials, can at times result in unethical conduct of research. Questions arise as to whether patent law should concern itself with tainted research that has resulted in an invention or whether it should grant patent rights solely on the basis of the technical improvements resulting from such research. This paper highlights the significance of ethical practice in biomedical research, an issue that may influence the decision to grant patents on inventions. It explores the relation between morality, bioethics and patents from the perspective of the objectives of the patent system and current developments in the law on patents. The inclusion of the morality provision in patent law introduces a mechanism through which inventions derived from tainted research can be filtered at an early stage. PMID- 20166290 TI - White coated corruption. AB - This essay documents the state of the medical profession which was once a respected line of work but today is corrupted at every level, from medical education to medical practice, and ir both the private and government sectors. It calls for doctors, thE government and the public to act against dishonest doctors restore the dignity of the profession and work for the benefit of society. PMID- 20166291 TI - A farce called the National Board of Examinations. AB - The National Board of Examinations is a body formed to enhance the standards of post graduate examinations in modern medicine in India. Unfortunately, the outdated mode of examinations and the arbitrarily set high cut-off marks for passing the examinations defeat the very purpose of its formation and functioning. PMID- 20166292 TI - Diplomate of the National Board: inefficient parallel education. AB - The National Board of Examinations conducts the Diplomate of the National Board in broad specialities as well as in core super specialities. The programme was meant to provide a common standard and a mechanism of evaluation the These programmes, as per the prospectus of the DNB course are meant to provide the basic level ofcompetence required for the postgraduate qualification in that subject. However, it has failed to meet these objectives. It is imperative to re examine and revamp the system to improve its credibility and acceptability at both the national and international levels. PMID- 20166293 TI - Medicine, merit, money and caste: the complexity of medical education in India. AB - Private medical colleges in India are under the scanner. There is a longstanding debate about the selection methodology that should be followed for admissions in medical colleges. A significant proportion of aspirants are able to afford medical education in private colleges despite not clearing entrance examinations. Others gain entry purely on the basis of caste. Medicine deals with human life and, consequently, there is a widespread feeling that admission criteria in medical schools should be based only on merit as assessed in entrance examinations. This article examines some of these contentious issues. PMID- 20166294 TI - Financial incentives and the prescription of newer vaccines by doctors in India. PMID- 20166295 TI - Vaccines: for whose benefit? PMID- 20166296 TI - Disability and the Medical Termination of Pregnancy Act, 1972. PMID- 20166297 TI - A legal precedent: reproductive rights of mentally retarded persons in India. PMID- 20166298 TI - Right to human dignity. PMID- 20166299 TI - Concerns around the human papilloma virus (HPV) vaccine. PMID- 20166300 TI - Cervical cancer screening and vaccination in India. PMID- 20166301 TI - The HPV vaccine demonstration projects: we should wait, watch and learn. PMID- 20166302 TI - Assessing the social value of research involving "minimal risks": who is accountable? PMID- 20166303 TI - Process, pitfalls and probity: sharing experiences on setting up and running ethics committees in India. PMID- 20166304 TI - Use of blanket consent for retrospective research in academic institutions: need for scrutiny and integrating safeguards. PMID- 20166305 TI - This is no low risk game: social science researchers reflect on their work. PMID- 20166306 TI - HPV vaccines: separating real hope from drug company hype. PMID- 20166307 TI - Need reforms in medical education. PMID- 20166308 TI - More on complexity. PMID- 20166309 TI - Takotsubo cardiomyopathy and canalith repositioning procedure for benign paroxysmal positional vertigo. AB - BACKGROUND: Takotsubo cardiomyopathy, also known as left ventricular apical ballooning syndrome, ampulla cardiomyopathy, or transient left ventricular dysfunction is characterized by chest pain, electrocardiographic changes, transient left ventricular apical aneurysm, and normal coronary arteries. Takotsubo is a round-bottomed, narrow-necked Japanese octopus trap and lends its name to takotsubo cardiomyopathy because of its resemblance to echocardiographic and ventricular angiographic images of the left ventricle in this condition. This appearance takes its source from peculiar, transient regional systolic dysfunction involving the left ventricular apex and mid-ventricle with hyperkinesis of the basal left ventricular segments. Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo caused by peripheral vestibular dysfunction. The symptoms of BPPV are attributed to intralabyrinthine particles, presumed displaced otoconia. Thus, the treatment recommended for BPPV is head repositioning maneuvers. PURPOSE: To present the first takotsubo cardiomyopathy case in the English literature related to BPPV undergoing canalith repositioning procedure. CONCLUSION: This report will provide additional information for physicians encountering acute-onset chest pain and vertigo. It will also expand the spectrum of clinical correlates of the increasingly well recognized but poorly understood syndrome, takotsubo cardiomyopathy. PMID- 20166310 TI - Effect of age on directional microphone hearing aid benefit and preference. AB - BACKGROUND: Despite the recognition that the directional microphone hearing aid (DMHA) is an important intervention aimed at helping older hearing-impaired adults understand speech in noisy environments, there is little evidence that older listeners can actually benefit from directional processing. PURPOSE: The objective of this study was to determine if older and younger adults can obtain and perceive comparable benefit afforded by DMHAs. STUDY SAMPLE: Twenty-four hearing-impaired adults aged 36 through 79 yr were fit with switchable-microphone hearing aids and tested in the laboratory and the field. DATA COLLECTION AND ANALYSIS: In the laboratory, the listeners' directional benefit and preferences for microphone modes (directional vs. omnidirectional) were assessed using various speech-recognition-in-noise tests. In the four-week field trial, a paired comparison technique and paper-and-pencil journals were used to determine the benefit provided by directional processing. The effects of age on directional benefit/preference were analyzed using generalized linear models with controlling for the effect of hearing loss. RESULTS: The results revealed that age did not have a significant effect on directional benefit and preference as measured in the laboratory. However, the field data showed that older age was significantly associated with a lower preference for the directional mode. CONCLUSION: These results indicate that although listeners of different ages may obtain and perceive comparable benefit from DMHAs in laboratory testing, older users tend to perceive less benefit than do younger users in the real world. The implications of these findings are discussed. PMID- 20166311 TI - Word-recognition performance in interrupted noise by young listeners with normal hearing and older listeners with hearing loss. AB - BACKGROUND: The most common complaint of adults with hearing loss is understanding speech in noise. One class of masker that may be particularly useful in the assessment of speech-in-noise abilities is interrupted noise. Interrupted noise usually is a continuous noise that has been multiplied by a square wave that produces alternating intervals of noise and silence. Wilson and Carhart found that spondaic word thresholds for listeners with normal hearing were 28 dB lower in an interrupted noise than in a continuous noise, whereas listeners with hearing loss experienced only an 11 dB difference. PURPOSE: The purpose of this series of experiments was to determine if a speech-in-interrupted noise paradigm differentiates better (1) between listeners with normal hearing and listeners with hearing loss and (2) among listeners with hearing loss than do traditional speech-in-continuous-noise tasks. RESEARCH DESIGN: Four descriptive/quasi-experimental studies were conducted. STUDY SAMPLE: Sixty young adults with normal hearing and 144 older adults with pure-tone hearing losses participated. DATA COLLECTION AND ANALYSIS: A 4.3 sec sample of speech-spectrum noise was constructed digitally to form the 0 interruptions per second (ips; continuous) noise and the 5, 10, and 20 ips noises with 50% duty cycles. The noise samples were mixed digitally with the Northwestern University Auditory Test No. 6 words at selected signal-to-noise ratios and recorded on CD. The materials were presented through an earphone, and the responses were recorded and analyzed at the word level. Similar techniques were used for the stimuli in the remaining experiments. RESULTS: In Experiment 1, using 0 ips as the reference condition, the listeners with normal hearing achieved 34.0, 30.2, and 28.4 dB escape from masking for 5, 10, and 20 ips, respectively. In contrast, the listeners with hearing loss only achieved 2.1 to 2.4 dB escape from masking. Experiment 2 studied the 0 and 5 ips conditions on 72 older listeners with hearing loss, who were on average 13 yr younger and more varied in their hearing loss than the listeners in Experiment 1. The mean escape from masking in Experiment 2 was 7dB, which is 20-25 dB less than the escape achieved by listeners with normal hearing. Experiment 3 examined the effects that duty cycle (0-100% in 10% steps) had on recognition performance in the 5 and 10 ips conditions. On the 12 young listeners with normal hearing, (1) the 50% correct point increased almost linearly between the 0 and 60% duty cycles (slope = 4.2 dB per 10% increase in duty cycle), (2) the slope of the function was steeper between 60 and 80% duty cycles, and (3) about the same masking was achieved for the 80-100% duty cycles. The data from the listeners with hearing loss were inconclusive. Experiment 4 varied the interburst ratios (0, -6, -12, -24, -48, and -infinity dB) of 5 ips noise and evaluated recognition performance by 24 young adults. The 50% points were described by a linear regression (R2 = 0.98) with a slope of 0.55 dB/dB. CONCLUSION: The current data indicate that interrupted noise does provide a better differentiation both between listeners with normal hearing and listeners with hearing loss and among listeners with hearing loss than is provided by continuous noise. PMID- 20166312 TI - The effect of reducing the number of electrodes on spatial hearing tasks for bilateral cochlear implant recipients. AB - BACKGROUND: Many studies have documented the effect of reducing spectral information for speech perception in listeners with normal hearing and hearing impairment. While it is understood that more spectral bands are needed for unilateral cochlear implant listeners to perform well on more challenging listening tasks such as speech perception in noise, it is unclear how reducing the number of spectral bands or electrodes in cochlear implants influences the ability to localize sound or understand speech with spatially separate noise sources. PURPOSE: The purpose of this study was to measure the effect of reducing the number of electrodes for patients with bilateral cochlear implants on spatial hearing tasks. RESEARCH DESIGN: Performance on spatial hearing tasks was examined as the number of bilateral electrodes in the speech processor was deactivated equally across ears and the full frequency spectrum was reallocated to a reduced number of active electrodes. Program parameters (i.e., pulse width, stimulation rate) were held constant among the programs and set identically between the right and left cochlear implants so that only the number of electrodes varied. STUDY SAMPLE: Nine subjects had used bilateral Nucleus or Advanced Bionics cochlear implants for at least 12 mo prior to beginning the study. Only those subjects with full insertion of the electrode arrays with all electrodes active in both ears were eligible to participate. DATA COLLECTION AND ANALYSIS: Two test measures were utilized to evaluate the effect of reducing the number of electrodes, including a speech-perception-in-noise test with spatially separated sources and a sound source localization test. RESULTS: Reducing the number of electrodes had different effects across individuals. Three patterns emerged: (1) no effect on localization (two of nine subjects), (2) at least two to four bilateral electrodes were required for maximal performance (five of nine subjects), and (3) performance gradually decreased across conditions as electrode number was reduced (two of nine subjects). For the test of speech perception in spatially separated noise, performance was affected as the number of electrodes was reduced for all subjects. Two categories of performance were found: (1) at least three or four bilateral electrodes were needed for maximum performance (five of seven subjects) and (2) as the number of electrodes were reduced, performance gradually decreased across conditions (two of seven subjects). CONCLUSION: Large individual differences exist in determining maximum performance using bilateral electrodes for localization and speech perception in noise. For some bilateral cochlear implant users, as few as three to four electrodes can be used to obtain maximal performance on localization and speech-in-noise tests. However, other listeners show a gradual decrement in performance on both tasks when the number of electrodes is reduced. PMID- 20166313 TI - Short and long compression release times: speech understanding, real-world preferences, and association with cognitive ability. AB - BACKGROUND: Several previous investigations have explored the relationship between cognitive abilities and speech understanding with short and long hearing aid compression release times in adult hearing aid wearers. Although there was consensus that such a relationship exists, the details have not been consistent across studies. This investigation was designed to further explore, extend, and generalize this topic. PURPOSE: Questions addressed: (1) the association between cognitive abilities and speech understanding with short and long release times for more ecologically valid speech than in previous studies, (2) the presence or absence of release time preferences in daily life, and (3) the association between the laboratory measures and real-world release time preferences. RESEARCH DESIGN: The study was a blinded randomized crossover trial. STUDY SAMPLE: Twenty four subjects with mean age of 72yr completed the study. They were experienced users of bilateral amplification with mild to moderately-severe symmetrical hearing losses. They were healthy, English-speaking active seniors recruited using advertisements and letters. DATA COLLECTION AND ANALYSIS: There were five test sessions. They included audiometric and cognitive testing, fitting bilateral Oticon Adapto hearing aids, a four-week trial with either short or long release time, outcome measures, a four-week trial with the other release time, further outcome measures, and a final interview. RESULTS: Taken together with the previous studies, the results suggest that compression processing release time is more critical for patients with lower cognitive abilities than for those with higher cognitive abilities. Further, we postulate that the best release time for listeners with lower cognitive abilities depends on the redundancy of the tested speech. Those with lower cognitive abilities might benefit from short release time when contextual speech is used, or when speech is rich in context, release time might not be important; however, when speech is low in semantic context, listeners with lower cognitive abilities might require long release time for best performance. Listeners do appear to be able to distinguish between long and short release time processing in daily life listening. However, release time preference was not predictable from cognitive abilities or aided measures of speech understanding. About two-thirds preferred long release time, and one-third preferred short release time. CONCLUSION: The relationship between cognitive abilities and performance with short and long release time processing was supported and further elucidated in this research. In addition, release time was seen to be a salient variable in subjective performance with amplification in daily life. Accurate prospective prescription of release time has the potential to make a material contribution to successful amplification provision. PMID- 20166315 TI - Why don't pesticide applicators protect themselves? Exploring the use of personal protective equipment among Colombian smallholders. AB - The misuse of personal protective equipment (PPE) during pesticide application was investigated among smallholders in Colombia. The integrative agent-centered (IAC) framework and a logistic regression approach were adopted. The results suggest that the descriptive social norm was significantly influencing PPE use. The following were also important: (1) having experienced pesticide-related health problems; (2) age; (3) the share of pesticide application carried out; and (4) the perception of PPE hindering work. Interestingly, the influence of these factors differed for different pieces of PPE. Since conformity to the social norm is a source of rigidity in the system, behavioral change may take the form of a discontinuous transition. In conclusion, five suggestions for triggering a transition towards more sustainable PPE use are formulated: (1) diversifying targets/tools; (2) addressing structural aspects; (3) sustaining interventions in the long-term; (4) targeting farmers' learning-by-experience; and (5) targeting PPE use on a collective level. PMID- 20166314 TI - Assessing agreement of self-reported and observed physical exposures of the upper extremity. AB - Assessment of workplace physical exposures by self-reported questionnaires has logistical advantages in population studies, but is subject to exposure misclassification. This study measured agreement between eight self-reported and observer-rated physical exposures to the hands and wrists, and evaluated predictors of intermethod agreement. Workers (n = 341) from three occupational categories (clerical/technical, construction, and service) completed self administered questionnaires and worksite assessments. Analyses compared self reported and observed ratings using a weighted kappa coefficient. Personal and psychosocial factors, presence of upper extremity symptoms, andjob type were evaluated as predictors of agreement. Weighted kappa values were substantial for lifting (0.67) and holding vibrating tools (0.61), moderate for forceful grip (0.58), and fair to poor for all other exposures. Upper extremity symptoms did not predict greater disagreement between self-reported and observed exposures. Occupational category was the only significant predictor of inter-method agreement. Self-reported exposures may provide a useful estimate of some work exposures for population studies. PMID- 20166316 TI - Double standards and the international trade of pesticides: the Brazilian case. AB - Despite bans on certain pesticides and their replacement by others considered less hazardous, the widespread use of these substances in agriculture continues to threaten the environment and the health of millions of people. This article discusses the current double standard in the international trade of pesticides and focuses on Brazil, one of the main users of pesticides in the world, analyzing the trends in foreign trade (imports and exports) of selected pesticides as a function of changes in legislation in the United States, the European Union, and Brazil from 1989 to 2006. We applied time line analysis to eight organochlorines already banned in Brazil and conducted a case-by-case qualitative and quantitative analysis of nine other pesticides. The results indicate the existence of double standards, as demonstrated by the continued exports to Brazil of some pesticides banned in the United States and Europe. PMID- 20166317 TI - Epidemiological surveillance of informal workers' health in two cities in southeastern Brazil: the experience of the TRAPP-TRAPPURA projects. AB - Informal labor markets have grown in peripheral countries, accounting for more than 50% of jobs. There is anecdotal evidence of a direct relation between informal sector growth and an increase in the frequency and severity of work related diseases and injuries. Two sister pilot projects were conducted in Uberaba and Campinas, Brazil to develop population-based epidemiological surveillance of workplace injuries in the informal sector. Results for Campinas and Uberaba found cumulative yearly incidences of 5.1% and 10.4%, with incidence rates of 2.2 and 6.5 injuries per 100,000 worked hours, respectively. The proportions of lost work time were 0.3% and 0.31%. Rates found were comparable to those found in the literature for both formal and informal jobs. These results suggest that bad working conditions in the formal labor market are replicated in the informal market as subcontracting and outsourcing contribute to the growth of informal jobs. PMID- 20166318 TI - Lower respiratory symptoms among residents living near the World Trade Center, two and four years after 9/11. AB - We investigated whether residents living near the World Trade Center (WTC) continued to experience respiratory problems several years after September 11, 2001 (9/11). Residents living within one mile of the WTC surveyed after 9/11 responded two and four years later to follow-up surveys that asked about lower respiratory symptoms (LRS), medical history, psychological stress, and indoor environmental characteristics. There were declines in the proportion of residents reporting LRS, new lower respiratory diagnoses, unplanned medical visits, and asthma medication use. However, the proportion of residents reporting any LRS in the affected area at follow-up remained higher than the original proportion in the control area; residents with multiple sources of potential 9/11-related exposures were at greatest risk for LRS at follow-up. Psychological stress, dust/odors, and moisture were significantly associated with LRS at follow-up. These data demonstrate that LRS continue to burden residents living in the areas affected by the WTC disaster. PMID- 20166319 TI - Hospital workers' awareness of health and environmental impacts of poor clinical waste disposal in the Northwest Region of Cameroon. AB - Due to the infectious nature of some clinical waste, poor disposal practices have sparked concern regarding the impact on public health and the environment. Lack of sufficient knowledge of the associated risks may be a strong factor contributing to inadequate disposal practices. We conducted a survey to evaluate hospital workers' awareness of health and environmental impacts of poor clinical waste disposal in Cameroon. We randomly distributed 500 questionnaires to hospital workers in three hospitals in the Northwest Region of Cameroon in April 2008. In addition, we observed collection, segregation, transportation, and disposal of clinical waste at the three hospitals. Of 475 total respondents, most lacked sufficient awareness of any environmental or public health impacts of poor clinical waste disposal and had never heard of any policy--national or international--on safe clinical waste management. Methods of collecting, segregating, transporting and disposing clinical waste at the three hospitals was poor. The development of a comprehensive policy on efficient clinical waste management in Cameroon is imperative. PMID- 20166320 TI - Associations of fertility and pregnancy outcomes with leather tannery work in Mongolia: a pilot study. AB - To our knowledge, reproductive health effects among male leather tannery workers have not been previously investigated. Tannery work involves exposure to chromium, solvents, and other chemicals, which has been associated with adverse pregnancy and fertility outcomes in animals or humans in some studies. This study retrospectively investigates the association of male leather tannery work with preterm delivery, spontaneous abortion, time to pregnancy, and infertility by comparing tannery employees to other workers in Ulaanbaatar, Mongolia. Participants were randomly selected from current employee rosters at eight tanneries and two bread-making companies. The results of this research suggest that tannery work may be associated with reduced fertility in males. The study had limited statistical power, and some factors are likely to have biased findings toward the null hypothesis; other limitations and possible sources of undetermined bias give reason for cautious interpretation. Additional studies should be conducted to further examine fertility among tannery workers. PMID- 20166321 TI - Rubberwood dust and lung function among Thai furniture factory workers. AB - The objective of this study was to assess factors affecting lung function among 685 workers in the rubberwood (Hevea brasiliensis) furniture industry in the Chonburi and Rayung provinces of eastern Thailand. Study data were gathered using questionnaires, by sampling wood dust, and by spirometry. The mean wood dust exposure level in the factories was 4.08 mg/m3 (SD = 1.42, range: 1.15-11.17 mg/m3). The mean overall percent of predicted forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and FEV1/FVC values were 84 % (SD = 13.41), 86 % (SD = 14.40), and 99% (SD = 10.42), respectively. Significant negative correlations were found between mean dust exposure levels and FVC (p = 0.0008), and FEV1/FVC% (p < 0.001), but not FEV1 (p = 0.074). An association between decline in lung function and wood dust levels among wood workers suggests that rubberwood dust exposure negatively affects lung function. PMID- 20166322 TI - Temporal and demographic patterns of non-Hodgkin's lymphoma incidence in Pennsylvania. AB - Our study analyzed temporal and demographic patterns of non-Hodgkin's lymphoma (NHL) incidence in Pennsylvania and compared Pennsylvania time trends with national trends. Joinpoint and age-period-cohort analyses summarized sex- and race-specific NHL incidence time trends between 1985 and 2004. Ecologic analysis identified demographic factors associated with age-adjusted county-specific NHL incidence. NHL incidence in Pennsylvania increased annually: 1.6% and 2.5% in white and black men and 1.6% and 3.2% in white and black women. National trends were similar, except for smaller increases in white men. Diffuse lymphoma appeared to be the major contributor to the increases. NHL incidence was higher in Pennsylvania counties with greater percentages of urban residents. NHL incidence patterns in Pennsylvania were parallel to those seen nationally, with the highest rates occurring in white men and in persons residing in urban areas. PMID- 20166323 TI - Libby trial ends but asbestos hazards remain in buildings. AB - The largest criminal trial ever involving environmental hazards came to a close in early May, but the dangers from the asbestos-containing materials mined in Libby, Montana that were the subject of the case continue to go unregulated. The jury's decision finding all defendants not guilty does not diminish the need to protect workers and the public from this hazard. Instead the trial highlighted the U.S. government's continuing failure to regulate these materials. PMID- 20166324 TI - Inadequate toxicity tests of food additive acesulfame. AB - Despite poor-quality toxicity tests, acesulfame potassium was approved by the US Food and Drug Administration (FDA) for use as an artificial sweetener. At present, acesulfame is very widely used, most frequently in blends with the most popular artificial sweetener in the US, sucralose (Splenda). Acesulfame was nominated twice (in 1996 and again in 2006) for testing in the National Toxicology Program (NTP) bioassay program. Both nominations were rejected by NTP. Rather than carry out bioassays, NTP subjected acesulfame to tests in genetically modified mice (GMM). Those GMM tests yielded results that provided no insight into potential carcinogenicity of acesulfame. It is possible that FDA discouraged NTP from conducting bioassays of acesulfame. Acesulfame should be tested in the bioassay program as soon as possible, and steps should be taken to ensure the objectivity of the bioassay nomination process. PMID- 20166325 TI - Basic occupational health services and stakeholders' participation. PMID- 20166326 TI - Chronic pleuritic pain and the inhalation of taconite fibers. PMID- 20166327 TI - Everything old is new again. PMID- 20166328 TI - Ambient advertising. Healthcare media in a new context. PMID- 20166329 TI - Marketing to the mature marketplace. Six pathways to success in challenging times. PMID- 20166330 TI - Doing more with less. Search engine optimization can enhance your credibility. PMID- 20166331 TI - Go where the customers are. Marketing (and managing) your patient experience with social media. PMID- 20166332 TI - Outsourcing is not a dirty word. Strategic outsourcing can create better healthcare Web sites. PMID- 20166333 TI - An easy way to track ROI. Does it really have to be that complicated? PMID- 20166334 TI - Get ready. Marketers need to prepare for the upcoming healthcare upheaval. PMID- 20166335 TI - Pancreatic cancer in Israel: the epidemiology, possibilities of prevention, early detection and screening. AB - Pancreatic cancer is not a common malignancy in Israel, but it is the third most common cause of cancer mortality, attributable to a lack of screening tests, inaccessibility of the pancreas, and late cancer stage at diagnosis. We reviewed the epidemiology, known risk factors and screening methods available in Israel and describe the Israeli national consortium that was established to identify persons at risk and decide on screening methods to detect and treat their early stage pancreatic cancer. In collaboration with the Israel National Cancer Registry, we evaluated the incidence and trends of the disease in the Jewish and non-Jewish populations. The consortium reviewed known lifestyle risk habits, genetic causes, and screening methodologies used and available in Israel. Overall, there are about 600 new patients per year, with the highest incidence occurring in Jewish men of European birth (age-standardized rate 8.11/10(5) for 2003-06). The 5 year survival is about 5%. The consortium concluded that screening will be based on endoscopic ultrasonography. Pancreatic cancer patients and families at risk will be enrolled, demographic and lifestyle data collected and a cancer pedigree generated. Risk factors will be identified and genetic tests performed as required. This concerted national program to identify persons at risk, recommend which environmental risk factors to avoid and treat, and perform endoscopic ultrasound and genetic screening where appropriate, might reduce the incidence of invasive pancreatic cancer and/or improve its prognosis. PMID- 20166336 TI - Lessons learned from 2 years experience in intravenous thrombolysis for acute ischemic stroke in a single tertiary medical center. AB - BACKGROUND: Intravenous tissue plasminogen activator has been approved treatment for acute (< or = 3 hours) ischemic stroke in Israel since late 2004. The Israeli experience with IV tPA is still limited. Several factors may influence the response to IV thrombolysis, including time-to-treatment parameters and tandem internal carotid artery/middle cerebral artery stenosis/occlusion. OBJECTIVES: To compare our experience with IV tPA treatment of patients with acute ischemic stroke to the findings of the SITS-MOST (Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy, international data) and of the Sheba Medical Center (national data) and to compare the early outcome among patients with ischemic stroke in the MCA with and without severe ICA stenosis. METHODS: We obtained demographic data, timing details, stroke severity, hemorrhagic complications, mortality, and early outcome from the records of IV tPA-treated acute ischemic stroke patients. RESULTS: Fifty-eight patients (median age 69 years, 26 females) with acute ischemic stroke were treated by IV tPA at the Tel Aviv Sourasky Medical Center in 2006-2007. Median time between stroke onset and IV tPA administration was 148 minutes for the Sourasky center, 150 minutes for the Sheba center, and 140 minutes for SITS-MOST. The Sourasky mortality rate was 10.5%. Of the 31 patients who suffered MCA stroke, 8 had severe ipsilateral ICA stenosis. These 8 had significantly lower neurological improvement than the 23 without ipsilateral ICA stenosis (1/8 versus 15/23, P < 0.001). CONCLUSIONS: Our data demonstrate fairly similar parameters of IV tPA treatment compared to other centers and suggest that patients with severe ICA stenosis might be less likely to benefit from IV tPA. PMID- 20166337 TI - Improving combined diabetes outcomes by adding a simple patient intervention to physician feedback: a cluster randomized trial. AB - BACKGROUND: Research on synergistic effects of patient targeted interventions combined with physician-targeted interventions has been limited. OBJECTIVES: To compare a combined physician-patient intervention to physician feedback alone on a composite outcome of glycemic, lipid and blood pressure control. METHODS: In this cluster study 417 patients with adult-type 2 diabetes from four primary care clinics were randomized to receive either a physician-only intervention or a combined physician-plus-patient intervention. Physicians in all clinics received diabetes-related quality performance feedback during staff meetings. Patients at combined-intervention clinics also received a letter encouraging them to remind their doctors to address essential aspects of diabetes care at the next visit. At 1 year follow-up, outcome measurements included hemoglobin A1c, low density lipoprotein-cholesterol and systolic blood pressure: namely, the proportion of patients with HbA1c 9%, LDL <130 mg/dl and SBP <140 mmHg both as separate outcomes and combined. RESULTS: After adjusting for patient characteristics and baseline measures, follow-up levels of HbA1c (7.5% vs. 7.8%, P = 0.09), LDL (104.7 vs. 110.7 mg/dl, P < 0.05) and SBP (135.6 vs. 139.9, P = 0.10) were marginally better for combined-intervention patients compared to physician-only intervention patients. Significantly more patients in the combined-intervention (38.8%) than physician-only intervention (24.2%) met all three targets (HbA1c (9%, LDL (130 mg/dl and SBP <140 mmHg) as a single combined outcome (adjusted odds ratio 2.4, P < .01). CONCLUSIONS: Compared to physician-feedback alone, a dual intervention combining a patient letter with physician feedback produced modest improvements in glycemic, lipid and blood pressure control individually, but substantial improvement in a combined measure of these three outcomes together. Using composite outcomes may detect meaningful improvements in the management of complex chronic disease. PMID- 20166338 TI - Alcohol and driver fatalities in Israel: an examination of the current problem. AB - BACKGROUND: The role of alcohol in driver fatalities in Israel is unknown, and monitoring blood alcohol concentration among drivers is not routine. Moreover, over the past decade, self-reported access to and consumption of alcohol in Israel has been on the rise. OBJECTIVES: To use available data to characterize alcohol-related driver fatalities. METHODS: The prevalence of alcohol-related driver fatalities were estimated for 443 drivers, aged 17+ years, using data from Israel's National Center for Forensic Medicine for 2000-2004. RESULTS: Between 8% and 17% of driver fatalities had a BAC > or = 0.05 g/dl. Most drivers with alcohol exceeding this level were males aged 21-30 years who died on weekends. Recreational and/or medicinal drugs were found in 6%-11% of driver fatalities. Mean BAC among driver fatalities with BAC > or = 0.05 g/dl was threefold higher than the legal driving limit and appears to be increasing with time. CONCLUSIONS: In light of the evidence suggesting an increasing mean BAC over time as well as reported increasing trends in access to alcohol and consumption, this study should serve as a basis for future research to comprehensively characterize the extent of this problem. PMID- 20166339 TI - Aspirin promotes low density lipoprotein susceptibility to oxidative modification in healthy volunteers. AB - BACKGROUND: Low density lipoprotein oxidation is a major pathogenic pathway in atherosclerosis. Previous studies suggested that aspirin, a commonly prescribed drug in patients with atherosclerosis, when given in a dose of 300 mg/day may decrease LDL susceptibility to oxidative modification. However, the effect of the more common lower dose aspirin on LDL oxidation is not known. OBJECTIVES: To examine the effect of aspirin administration (low dosage) on the susceptibility of LDL to oxidative modification in healthy volunteers. METHODS: Aspirin 75 mg was administered daily for 2 weeks to 10 healthy volunteers selected from the medical staff and students at the faculty of medicine. The main outcome measure was ex vivo oxidation of LDL by ultraviolet C irradiation or by peroxyl free radicals generated by AAPH (2,2'-azobis 2-amidinopropane hydrochloride). The extent of LDL oxidation was determined by measuring the formed amounts of thiobarbituric acid-reactive substances, lipid peroxides and conjugated dienes. RESULTS: Following exposure to UVc irradiation there was a significant (P 0.01) increase (10.8%) in TBARS concentrations and a significant (P < 0.05) increase (5.4%) in PD concentrations in LDL withdrawn after aspirin treatment as compared to LDL withdrawn before aspirin treatment. Following incubation with AAPH there was a significant (P < 0.05) increase (15%) in PD concentrations and a significant (P < 0.05) reduction (10%) of the LDL oxidation lag time in LDL withdrawn after aspirin intake as compared to LDL withdrawn before aspirin treatment. CONCLUSIONS: Aspirin treatment given to healthy volunteers at a dose of 75 mg/day increased the susceptibility of their plasma LDL to oxidative modification ex vivo. Our study provides, for the first time, in vivo evidence of pro-oxidative properties of aspirin already suggested by previous in vitro trials. PMID- 20166340 TI - Reduced rate of side effects associated with separate administration of MMR and DTaP-Hib-IPV vaccinations. AB - BACKGROUND: According to the Israeli immunization schedule, 1 year old babies should receive two concomitant vaccinations: MMR (measles-mumps-rubella), and DTap-Hib-IPV (diphtheria tetanus acellular pertussis-Haemophilus influenzae type b-poliomyelitis). However, about one-third of infants in Israel receive these vaccinations separately. Nurses at a primary care prevention clinic in Israel observed that the separate mode of vaccination is associated with a lower rate of side effects. OBJECTIVES: To validate this observation and determine whether it represents an exception or the rule. METHODS: A nested prospective follow-up study was conducted in a primary care clinic in Israel. The survey included 191 mothers and their offspring born during 2004/2005. The mothers were interviewed over the telephone 2 weeks after the day of vaccination. RESULTS: The rate of adverse effects in children who received the injections separately was significantly lower than among those who were vaccinated simultaneously (40% vs. 57%). CONCLUSIONS: It may be necessary to reconsider the current vaccination policy regarding concomitant injections. PMID- 20166341 TI - Conservative treatment for acute cholecystitis: clinical and radiographic predictors of failure. AB - BACKGROUND: Current treatment options for acute calculous cholecystitis include either early cholecystectomy, or conservative treatment consisting of intravenous antibiotics and an interval cholecystectomy several weeks later. Percutaneous drainage is reserved for patients in whom conservative therapy failed or as a salvage procedure for high risk patients. OBJECTIVE: To identify clinical and radiographic factors leading to failure of conservative treatment. METHODS: We prospectively collected data on consecutive patients admitted with the diagnosis of acute cholecystitis. Parameters were compared between patients who were successfully treated conservatively and those who required percutaneous cholecystostomy. Logistic regression analysis was performed to identify predictors for failure of conservative treatment. RESULTS: The study population comprised 103 patients with a median age of 60 who were treated for acute cholecystitis. Twenty-seven patients (26.2%) required PC. On univariate analysis, age above 70 years, diabetes, elevated white blood cell count, tachycardia (> 100 beats/min) at admission, and a distended gallbladder (> 5 cm transverse diameter) were found to be significantly more common in the PC group (P < 0.001). WBC was higher in the PC group throughout the initial 48 hours. On multivariate analysis, age above 70 (odds ratio 3.6), diabetes (OR 9.4), tachycardia at admission (OR 5.6), and a distended gallbladder (OR 8.5) were predictors for cholecystostomy (P < 0.001). Age above 70 (OR 5.2) and WBC $15,000 (OR 13.7) were predictors for failure of conservative treatment after 24 and 48 hours (P < 0.001). CONCLUSIONS: Age above 70, diabetes, and a distended gallbladder are predictors for failure of conservative treatment and such patients should be considered for early cholecystostomy. Persistently elevated WBC (> 15,000) suggests refractory disease and should play a central role in the clinical follow-up and decision-making process for elderly patients with acute cholecystitis. PMID- 20166342 TI - Incidence and clinical manifestations of adenoviral infection among children undergoing allogeneic stem cell transplantation. AB - BACKGROUND: Adenoviral infection in children undergoing stem cell transplantation is associated with significant morbidity and mortality. Identification of adenoviral infection by polymerase chain reaction from blood facilitates accurate and rapid diagnosis and surveillance. The incidence of adenoviral infection among children undergoing SCT in Israel is not known. OBJECTIVE: To estimate the incidence of adenoviral infection in pediatric SCT patients and to characterize the morbidity associated with proven infection. METHODS: Blood samples obtained weekly from children who underwent allogeneic SCT were retrospectively tested for adenovirus using standard PCR. A total of 657 samples collected from 32 patients were examined. Correlation was made between the presence of adenovirus in samples and clinical records. RESULTS: Of the 32 patients 4 had adenoviral infection by PCR (12.5%). Clinical disease was present in all four patients concurrent with positive PCR. Gastrointestinal complaints and abnormal hepatocellular enzymes were uniformly present. One patient died due to disseminated disease. T cell depletion was a significant risk factor for adenoviral infection (P = 0.03). CONCLUSIONS: In the patient population studied, the incidence of adenoviral infection in children undergoing SCT was 12.5%. The combination of gastrointestinal symptoms and abnormal hepatocellular enzymes should raise the suspicion of adenoviral infection, especially when occurring during the first few months after SCT. PMID- 20166343 TI - Tissue plasminogen activator in Israel: are we there yet? PMID- 20166344 TI - In anticipation of patient participation. PMID- 20166345 TI - Prevention of venous thromboembolism in medical patients: recent advances and future directions. PMID- 20166346 TI - Post-infectious glomerulonephritis associated with adenovirus infection. PMID- 20166347 TI - New-onset psoriasis following treatment with pegylated interferon-alpha 2b and ribavirin for chronic hepatitis C. PMID- 20166348 TI - Fortunate retention of an endoscopic video capsule by primary small bowel carcinoma. PMID- 20166349 TI - Cardiac manifestations of ulcerative colitis. PMID- 20166350 TI - Acute pulmonary disease in a young woman with sickle cell anemia and moyamoya disease. PMID- 20166351 TI - Isolated coronary vasculitis as a cause of unexpected sudden death. PMID- 20166352 TI - Treatment options in Kienbock's disease. PMID- 20166353 TI - Improved range of motion after medial-based T capsular shift for recurrent post traumatic anterior shoulder dislocation. AB - Postoperative function and recurrence rates are reportedly similar following open and arthroscopic procedures for recurrent anterior instability of the shoulder. However, various studies have reported greater restriction of shoulder mobility with open stabilisation. Sixty-two patients with post-traumatic recurrent anterior instability of the shoulder underwent anatomic reconstruction of the capsular-labral complex using a medial-based T capsular shift. They were investigated preoperatively and 53 of them were reexamined at an average of 41.5 months after operation. Function and stability improved: the Rowe score increased from 33.2 to 80.6, the Constant score from 81.5 to 89.8 points. Pre- and post operative mobility of the affected shoulder was reduced in all planes of movement compared to the contralateral side. Passive mobility did not deteriorate in any direction with surgery. Passive adduction, forward flexion and external rotation in 90 degrees abduction of the arm improved significantly and active mobility rose to the values of the contralateral side. The restriction of mobility noted postoperatively thus appears as a consequence of the underlying pathology rather than of the surgical procedure. The recurrence rate after primary stabilisation was 1.6%. Based on these findings, the medial-based T capsular shift remains an appropriate surgical option in the treatment of chronic post-traumatic anterior instability of the shoulder. PMID- 20166354 TI - Is the bare spot a valid landmark for glenoid evaluation in arthroscopic Bankart surgery? AB - The "bare spot "of the glenoid cavity has recently been described as a consistent reference point to identify the center of the glenoid and to quantify the extent of antero-inferior bone loss of the glenoid following anterior shoulder dislocation. The spot should help the surgeon to determine arthroscopically the width of the remaining inferior glenoid cavity. In this study we prospectively compared arthroscopic images and the multidetector spiral CT arthrographic findings recorded in 58 consecutive patients (mean age, 47 years; range: 17-72 years) with respect to glenohumeral cartilage quality and the presence of a "bare spot". At arthroscopy the "bare spot" was visible in less than 48% of cases and with spiral CT arthrography in less than 26% of cases. We concluded that the "bare spot" seems to be an unreliable landmark to determine the center of the inferior glenoid cavity, as it was present in only half of the shoulders studied. PMID- 20166355 TI - Correction of forearm deformities in children with multiple osteochondroma, by corrective radial osteotomy and ulnar lengthening by distraction osteogenesis. AB - We retrospectively evaluated the results after ulnar lengthening and radial deformity correction using an external fixator for forearm deformities caused by osteochondromas. Eight forearms were treated surgically in seven patients with multiple hereditary osteochondroma. The mean follow-up time was 40 months (range, 20 to 60 months). The average radial articular angle improved from 43 degrees to 35.5 degrees (range, 28 to 56 degrees) and the carpal slip improved from 69.5% to 55% (range, 40 to 60%) postoperatively. The average shortening of the ulna was reduced from 2.06 cm to 0.44 cm (range 0 to 1 cm) after the treatment. There were no serious complications associated with the surgery; two minor pin track infections were successfully treated by local wound care and antibiotics. Although technically demanding, ulnar osteotomy and gradual lengthening by an external fixator provided promising results in the treatment of forearm deformities in children with multiple osteochondroma. PMID- 20166356 TI - External fixation of intertrochanteric fractures in elderly high-risk patients. AB - Intertrochanteric fractures of the femur were treated with an external fixator in 38 elderly high-risk patients between November 2005 and February 2007. The mean operation time was 25 min (range: 20 to 32 min), the mean fluoroscopy time was 15 sec (range: 10 to 18 sec), and the mean hospital stay was four days (range: 3 to 7 days). The average time to union was 9.5 weeks. No deep pin track infections occurred; superficial skin inflammation was seen in 30%. Implant failure or knee stiffness were noted in no instance. At the latest follow-up, the mean femoral shaft-neck angle was 130 degrees (range: 116 degrees to 138 degrees), the average Harris hip score was 64 (range: 50-80). Mortality rate was 8% at 6 months from causes unrelated to the operation. The use of a multiplanar external fixator in these patients provided a satisfactory stability, reduced their time in hospital and facilitated their postoperative rehabilitation. PMID- 20166357 TI - Clinical presentation of young adults after Legg-Calve-Perthes disease. AB - The purpose of the present study was to review the clinical and radiological outcome of young adult individuals who had Legg-Calve-Perthes disease (LCPD) during child age. After a mean follow-up of 18.7 +/- 6.2 years, 25 young adults with various morphological deformity grades were assessed clinically and radiologically. Deterioration of hip joint function and onset of pain were found to manifest early in the intermediate follow-up of LCPD and to correlate with the residual hip deformity. PMID- 20166358 TI - No change detected by DEXA in bone mineral density after periacetabular osteotomy. AB - The purpose of this study was to assess acetabular bone mineral density after periacetabular osteotomy and to examine whether bone mineral density correlates with postoperative migration of the osteotomised acetabular fragment. Twenty-five female and three male patients scheduled for periacetabular osteotomy were consecutively included. The patients were scanned by dual energy X-ray absorptiometry (DEXA) at 1 week, 1 year, and 2 1/2 years after surgery. Radiostereometric analyses (RSA) were done at 1, 4, 8, and 24 weeks after surgery. Two and a half years after periacetabular osteotomy, no significant changes in bone mineral density or any biological effect on bone remodelling due a changed loading pattern in the acetabulum could be detected. There was no significant correlation between bone mineral density and migration of the acetabulum. Dual energy X-ray absorptiometry is not an appropriate method to demonstrate the changes in bone mineral density after periacetabular osteotomy or to predict postoperative acetabular migration. PMID- 20166359 TI - Ten-year survival of the cemented MS-30 femoral stem: increased revision rate in male patients. AB - This retrospective study evaluated the clinical and radiographic results of 337 consecutive matte surfaced, straight cemented MS-30 femoral stems implanted with first -to second-generation cementing technique. The median age of the patients at time of surgery was 72 (27-91) years. The median duration of follow-up was 10 (0.1-14) years. A Kaplan Meier survival analysis was performed. At follow-up, 113 patients (120 stems) had died and 13 (13 hips) were lost to follow-up. Twenty-one hips had undergone femoral revision, 13 for aseptic loosening, five for infection, two for dislocation and one for periprosthetic fracture. Survival analysis with revision of the femoral component for any reason as the end point was 91% (95% CI: 87-96) and for aseptic loosening 94% (95% CI: 90-97) at 12 years. Females (n = 245) with 99% (95% CI: 97-100) had significantly better survival compared to males (n = 92) showing 80% stem survival (95% CI: 67-91) at 12 years (p < 0.001). Median Harris Hip score (HHS) was 82 (25-100) points. Male patients had a higher activity score than female patients (p = 0.04). Femoral Dorr type A was associated with a higher risk of failure. THA with the MS-30 stem revealed satisfactory midterm results despite relatively crude cementing techniques. However, the higher revision rate in males and Dorr Type A is of concern. PMID- 20166360 TI - Periprosthetic femoral fractures: outcome after treatment with LISS internal fixation or stem replacement in 36 patients. AB - Periprosthetic fractures of the femur present a challenging surgical problem. The aim of this study was to evaluate the outcome of periprosthetic femoral fractures (PFF) which were treated with internal fixation or stem revision. Depending on the fracture type in the Duncan-Vancouver-Classification, 42 patients with PFF were treated either with a Fixateur interne (n = 23) in cases with type B1 or C fractures, or with stem revision (n = 19) in cases with type B2/B3 fractures. Follow-up rate was 78% over 24 months. All but two fractures showed radiological signs of healing. Implant failure was noted in 4 cases in the LISS group. The Lysholm and Larson scores were respectively 75.5 and 71 in patients undergoing stem revision, versus 74.5 and 69 in those treated with LISS fixation. Even taking into account the higher risk of implant failure, the treatment with LISS internal fixation has shown to be a reasonable method in the treatment of periprosthetic fractures without stem loosening. PMID- 20166361 TI - Ilizarov gradual correction of genu varum deformity in adults. AB - Valgus producing high tibial osteotomy (HTO) is an effective treatment option for medial compartment osteoarthrosis with varus deformity in young patients. The most common complications of conventional high tibial osteotomy techniques are related to accuracy of correction. Major angle correction of more than 15 degrees with an osteotomy proximal to the tibial tuberosity may cause significant change in patellofemoral mechanics and patellar height. Valgus HTO was performed in 11 lower limbs of 9 patients with gradual correction of the varus deformity using an Ilizarov external fixator, with the osteotomy at the distal border of the tibial tuberosity. The mean age of the patients was 38.5 years. The average correction was 17 degrees. They were followed up for an average of 25 months. The mean preoperative "Hospital for Special Surgery" (HSS) score was 68 and improved to a mean of 90 at follow-up. Nine limbs had excellent or good HSS scores. Disadvantages of this technique were mainly pin tract infection and poor patient acceptance and noncompliance. PMID- 20166362 TI - Early results with the Genesis II Posterior Stabilized High Flexion knee prosthesis. A one year follow-up study. AB - The aim of this prospective study was to assess the range of motion (ROM) achieved with the Genesis II Posterior Stabilized High Flexion knee prosthesis. The ROM was compared with that of a historical study group with the standard PS insert and an identical study design. Sixty three patients with primary knee osteoarthritis (37 female, 26 male; average age: 67.0 years, average BMI 31.2) underwent primary cemented TKA with a PS high flex insert. The surgery was performed by one senior author using a mini-midvastus approach. During the follow up no statistically significant difference in maximal flexion was found between 14 weeks (average flexion = 120 degrees, SD = 11.2) and 65 weeks postoperatively (average flexion = 122 degrees, SD = 8.9). The radiographic evaluation showed no influence of the implant positioning on the final flexion. Compared to the results obtained in a 5 year follow-up study of 100 cases in combination with the PS standard insert, the improvement in final flexion range found in this study did not appear not to be great enough to generally recommend the PS high flex insert in terms of a proven higher flexion result. PMID- 20166363 TI - Improving maximum flexion with a posterior cruciate retaining total knee arthroplasty: a fluoroscopic study. AB - Achieving a large range of motion (ROM) is a much-desired clinical outcome after total knee arthroplasty (TKA), especially in Asian and Middle Eastern cultures. TKA design plays an important role in providing the post-operative ROM. This study investigated the kinematics of a new high-flexion posterior cruciate ligament retaining total knee replacement, featuring an enlarged posterior condylar offset and a more conforming tibiofemoral articulation. Two flexion activities were compared to determine which provides higher flexion kinematics. Sixteen North American patients with 20 total knee implants were studied using fluoroscopy and shape matching techniques. Maximum skeletal flexion during a lunge activity averaged 120 degrees +/- 11 degrees, with 11 degrees +/- 4 degrees tibial internal rotation. Kneeling activities showed 11 degrees greater average maximum skeletal flexion (131 degrees +/- 13 degrees, p < 0.05) and 1 degrees less tibial internal rotation (10 degrees +/- 4 degrees, p > 0.05) than lunge activities. We conclude that specific knee implant design features can facilitate high flexion in fixed-bearing cruciate retaining TKA, and that kneeling activities provide higher flexion than lunge activities. PMID- 20166364 TI - Does tendon lengthening surgery affect muscle tone in children with cerebral palsy? AB - The objective of this study was to determine if surgical lengthening of the hamstrings and gastrocnemius/Achilles complex affects muscle tone in patients with cerebral palsy. The question was if the dynamic component of muscle length changes after orthopedic surgery. A retrospective study was performed on ambulatory children with cerebral palsy who underwent either hamstring lengthening or gastrocnemius/Achilles tendon lengthening. A total of 135 consecutive patients with an average age of 13 years were included in the study. A single random side was selected for children with bilateral surgery and the affected limb was analyzed for those undergoing unilateral surgery. The popliteal angle measurement was performed with a quick and slow stretch, as well as the ankle dorsiflexion, and measurements were made using a goniometer. The difference (delta ml) between initial grab with fast stretch and end of range (EOR) with slow stretch was used as a measure of spasticity. The Bohannon modification of the Ashworth score was also assessed. Postoperatively, 18 degrees popliteal angle improvement in end-of-range and 32 degrees improvement in quick stretch in the hamstrings group were noted, with change in slow stretch, quick stretch and delta ml (comparison between quick and slow stretch) being significant at p < .0001. In the triceps surae group, 14 degrees ankle dorsiflexion improvement in end-of range, and 18 degrees improvement in quick stretch were noted postoperatively, with change in slow stretch, quick stretch and delta ml at p < .0001, p < .0001, and p < .0180 respectively. Ashworth scale was reduced by at least one grade in 89% of subjects in the hamstring group and 78% of subjects in the triceps surae group of the children with preoperative Ashworth 3 and above. PMID- 20166365 TI - Transpedicular bone grafting as a supplement to posterior pedicle screw instrumentation in thoracolumbar burst fractures. AB - The objective of the present study was to investigate whether transpedicular bone grafting as a supplement to posterior pedicle screw fixation in thoracolumbar fractures results in a stable reconstruction of the anterior column, that allows healing of the fracture without loss of correction. Posterior instrumentation using an internal fixator is a standard procedure for stabilizing the injured thoracolumbar spine. Transpedicular bone grafting was first described by Daniaux in 1986 to achieve intrabody fusion. Pedicle screw fixation with additional transpedicular fusion has remained controversial because of inconsistent reports. A retrospective single surgeon cohort study was performed. Between October 2001 and May 2007, 30 consecutive patients with 31 acute traumatic burst fractures of the thoracolumbar spine (D12-L5) were treated operatively. The mean age of the patients was 45.7 years (range: 19-78). There were 23 men and 7 women. Nineteen thoracolumbar fractures were sustained in falls from a height; the other fractures were the result of motor vehicle accidents. The vertebrae most often involved were L1 in 13 patients and L2 in 8 patients. According to the Magerl classification, 25 patients sustained Type A1, 4 Type A2 and 2 Type A3 fractures. The mean time from injury to surgery was 6 days (range 2-14 days). Two postoperative complications were observed: one superficial and one deep infection. Mean Cobb's angle improved from +7.16 degrees (SD 12.44) preoperatively to -5.48 degrees (SD 11.44) immediately after operation, with a mean loss of correction of 1.00 degrees (SD 3.04) at two years. Reconstruction of the anterior column is important to prevent loss of correction. In our experience, the use of transpedicular bone grafting has efficiently restored the anterior column and has preserved the post-operative correction of kyphosis until healing of the fracture. PMID- 20166366 TI - Short segment pedicle screw fixation for unstable T11-L2 fractures: with or without fusion? A three-year follow-up study. AB - In unstable thoracolumbar fractures T11-L2, exaggerated kyphosis at the end of treatment may predispose to late back pain and poor functional outcome. Short segment (SS) (3 vertebrae) pedicle instrumentation has become a popular method of treatment. However the question to add a fusion or not is still under debate. The authors retrospectively evaluated the radiological and functional results in 74 patients who had undergone an SS pedicle screw fixation. They were divided into two groups: group 1 (39 patients) was the non-fusion group; group 2 (35 patients) was the fusion group. In the non-fusion group the mean preoperative, immediate postoperative and final kyphosis angles at the fracture site were respectively 20.8 degrees +/- 6.4, 8.2 degrees +/- 4.8, and 15.2 degrees +/- 6.0. In the fusion group the corresponding angles were 26.6 degrees +/- 4.1, 7.9 degrees +/- 2.1, and 8.4 degrees +/- 2.4, which demonstrated a distinctly better final result (p < 0.0001). In the non-fusion group the preoperative, immediate postoperative and final follow-up visual analog scores (VAS) for back pain were respectively 7.3 +/- 0.8, 3.9 +/- 0.8, and 3.4 +/- 0.9. In the fusion group the corresponding scores were 7.5 +/- 1.0, 3.9 +/- 1.1, and 1.6 +/- 0.7; the final result pleaded again in favour of fusion (p < 0.0001). Moreover, there were significantly more implant-related complications (screw loosening and breakage) in the non-fusion group (p < 0.0001). The authors conclude that fusion is advisable to obtain a better final outcome with respect to kyphosis and pain, and to avoid implant related complications. However, at least one other study has led to the opposite conclusion: the issue remains controversial. PMID- 20166367 TI - Open anatomical coracoclavicular ligament reconstruction using a tendon graft with an Endobutton loop. AB - We describe a technique of open anatomical coracoclavicular ligament reconstruction restoring both parts of the native ligament, aiming at achieving maximum stability of the acromioclavicular joint without disturbing the normal anatomy. Using the same anatomical principle of ligament reconstruction as in other joints, transosseous tunnels are created at the native footprints of the conoid and trapezoid ligaments. An autologous graft is fixed using an Endobutton continuous loop and a PEEK screw; adequate healing of the ligament is ensured with an appropriate working length. Although an open procedure, this technique offers several advantages. It can be easily reproduced using basic anatomical principles and simple cost-effective instrumentation. The implant does not have to be removed, important anatomical structures are respected, normal acromioclavicular joint kinematics are restored, the scar is cosmetically acceptable and post-operative morbidity is very low. PMID- 20166368 TI - Kienbock's disease in a 6-year-old boy. AB - A case of avascular necrosis of the lunate bone in a 6-year-old boy is reported. This is the youngest child reported in literature with Kienbock's disease. Clinical and radiological healing was obtained with conservative treatment. Non operative management is recommended in children with avascular necrosis of the lunate bone. PMID- 20166369 TI - Cystic presentation of Ewing's sarcoma with indolent clinico-radiologic behaviour. AB - Ewing's sarcoma is a high-grade malignant primary bone tumour with aggressive clinico-radiologic features. Rarely, it exhibits a benign pattern, but presentation as a solitary bone cyst in a long bone is rather unusual. The purpose of this paper is to document such a cystic presentation with relatively benign clinico-radiologic course and to review the pertinent literature. A 27 year-old male presented with a pathologic fracture through a radiologically benign appearing solitary bone cyst in the distal tibial metaphysis. The fracture healed on conservative treatment, but the patient presented again a year later with pain and difficulty with weight bearing. Curetting and bone grafting done elsewhere was suggestive of an Ewing's sarcoma, which was later confirmed by a second biopsy. He was treated by standard neoadjuvant chemotherapy followed by wide local excision and reconstruction with an intercalary allograft. At 2 years postoperative follow-up, the patient is without any evidence of local or distant recurrence. Awareness of this atypical presentation is important because it may help in an earlier diagnosis, avoid diagnostic confusion and thus may contribute to improved survival. PMID- 20166370 TI - Isolated congenital anterolateral bowing of the fibula: a case report with 24 years follow-up. AB - Only very few cases of congenital anterolateral bowing of the fibula have been described in literature. We report a girl with congenital anterolateral bowing of the fibula with a 24 year follow-up. Asymptomatic bowing of her left leg below the knee was noted at the age of three years. Radiographs showed an isolated anterolateral bowing of the fibula with a normal ipsilateral tibia. Supervised neglect was advised. A spontaneous fracture occurred one year later. A shortening osteotomy resulted in solid consolidation of the fracture. At the age of 27 years the deformity had progressed into a two-level fracture of the fibular diaphysis with pseudoarthrosis. The segment in-between the fractures was resected. Following this, the patient returned to a normal level of activities in just a matter of weeks. She could even participate in recreational tennis six weeks after surgery and was then discharged from the outpatient clinic. Isolated congenital anterolateral bowing of the fibula is a very rare condition and there is no consensus on its treatment. In this case, removal of the painful pseudarthrotic fragment of the fibula led to a good result. PMID- 20166371 TI - Hypophosphataemic osteomalacia in neurofibromatosis. AB - Oncogenic Osteomalacia syndrome is associated with mesenchymal tumours, caused by a protein secreted from tumours which inhibits tubular renal phosphate absorption and reduces 1,25 dihydroxy vitamin-D renal conversion. It manifests as osteomalacia with hypophosphataemia and hyperphosphaturia. Association of neurofibromatosis with oncogenic osteomalacia is unusual. We report a rare case of oncogenic osteomalacia with generalized neurofibromatosis which presented to us as pathological fracture. PMID- 20166372 TI - Monocular blindness following elective hip arthroplasty. AB - Visual loss is a devastating complication of non-ophthalmic surgery. It is documented following cardiac, spinal, and transplant surgery. Patients with carotid artery occlusion are at increased risk for ocular ischaemia. Pre operative assessment as well as early diagnosis and treatment is essential in cases of high-risk patients. We discuss the case of an 82-year-old man who underwent an elective total hip replacement and was left with monocular hemispherical blindness as a result of branch retinal artery occlusion. PMID- 20166373 TI - Anterior sacral meningocoele presenting as acute urinary retention. A case report. AB - Anterior sacral meningocoele is caused by a congenital hiatus in the anterior sacrum. We report a very rare case which presented as acute urinary retention. The common findings of anterior sacral meningocele include atypical low back pain, urological and gynaecological symptoms. Acute urinary retention as a presenting symptom does not appear to have been mentioned in the English literature. PMID- 20166374 TI - Still current after all these years. PMID- 20166375 TI - Effect of malignant disease and treatments on oral structures. AB - There has been an increase in the diagnosis and treatment options for malignant diseases. In this article we provide an overview of the impact of the treatments of malignant diseases on the oral structures. Whilst some of the complications, such as oral mucositis and oral infection, are of short duration and respond once chemotherapy has been completed, other treatments have a prolonged effect. Of particular concern is the effect of bisphosphonates on bone turnover and the risk of osteonecrosis on the jaw and hormones affecting the periodontal tissues. These unwanted effects all impact upon the quality of life of many patients diagnosed with malignant disease. CLINICAL RELEVANCE: Treatments of malignant diseases can have a profound effect on oral structures and functions. All members of the dental team need to be aware of adverse effects arising from such treatments and how they can affect oral function and quality of life. PMID- 20166376 TI - A review of the safety of tooth bleaching. AB - This article considers the safety of tooth bleaching based on a Medline search of clinical, animal and in vitro studies between 1986 and 2007. CLINICAL RELEVANCE: Bleaching is the least invasive option for improving tooth colour compared to alternatives such as crowns and veneers. However, no dental procedure is without risk and the clinician should be aware of the safety issues and adverse effects of tooth bleaching so that patients can be fully informed. PMID- 20166377 TI - Consequences of tooth loss: 1. The patient perspective--aesthetic and functional implications. AB - Tooth loss in adults is becoming less common, and the attitudes of patients and professionals towards it have changed dramatically over the last quarter of a century. This paper explores these changes, from the patient's perspective, in terms of psychological perspectives, aesthetics, function and the need or desire for tooth replacement. A second paper will examine the evidence available on the positional and functional changes following tooth loss. CLINICAL RELEVANCE: Clinicians need to have an awareness of changes in disease patterns, trends in patient expectations and the demand for restorative interventions. PMID- 20166378 TI - Case study: limitations of panoramic radiography in the anterior mandible. AB - Dental Panoramic Tomography (DPT) is a widely used and valuable examination in dentistry. One area prone to artefacts and therefore misinterpretation is the anterior region of the mandible. This case study discusses a periapical radiolucency related to lower anterior teeth that is discovered to be a radiographic artefact. Possible causes of the artefact include a pronounced depression in the mental region of the mandible or superimposition of intervertebral spaces. Additional limitations of the DPT image include superimposition of radio-opaque structures, reduced image detail compared to intra-oral views and uneven magnification. These problems often make the DPT inappropriate for imaging the anterior mandible. CLINICAL RELEVANCE: Panoramic radiography is often unsuitable for radiographic examination of the anterior mandible. PMID- 20166379 TI - Adherence in dental settings. AB - Adherence is of central importance to promoting positive oral health behaviours. Understanding the processes involved in behaviour change and how change may be sustained is essential to support patients to change their behaviour successfully. We review the concept of adherence, the oral health behaviours of interest to the dental team and how change around these behaviours is currently managed. Theoretical models of behaviour change are reviewed and their possible implications for every day practice described. CLINICAL RELEVANCE: This paper will help the dental team to understand the processes involved in behaviour change and support their patients to adopt and sustain positive oral health behaviours. PMID- 20166380 TI - Chondrosarcoma of the jaws. AB - Chondrosarcomas are rare lesions within the head and neck. They are most common in the 4th to 5th decade of life and usually present as a painless swelling. The purpose of this paper is to present a case and review the literature with regard to the radiographic appearance. Although the radiographic appearance is variable, there are some features that are common to most cases, the most important feature being that of an ill-defined radiolucent lesion with scattered radio-opacities. Although these features are seen in other malignant diseases, these features should alert the clinician to the possibility of a chondrosarcoma. CLINICAL RELEVANCE: Chondrosarcomas of the jaw are rare but important malignant lesions that require prompt diagnosis and treatment for improved outcomes. PMID- 20166381 TI - Vaccines and periodontal diseases--an insight. AB - Vaccination against periodontal diseases is an innovative approach to combating periodontal diseases. Although discussed briefly some 50 years ago by Bibby, it has been popularized with the late twentieth century technologies and current understanding of periodontal microbiology. This review discusses the potential for a vaccine against periodontitis. CLINICAL RELEVANCE: A vaccine is a possible protection strategy for primary prevention of periodontitis. PMID- 20166382 TI - Current strategies and applications of tissue engineering in dentistry--a review Part 2. AB - The three main key elements used in tissue engineering are the stem cells, morphogens and the scaffolds that, under a conductive external influence (environment) combine in the engineering of tissues. Part 1 of this two-part review article described in detail the various stem cells, morphogens and scaffolds that can be used in tissue engineering. This second article describes the various ways in which these three key elements can be used to engineer biological tissues. A number of strategies and technologies (Figure 1) such as, stem cell therapy, gene therapy, guided tissue regeneration, self-assembling systems, etc have been proposed. CLINICAL RELEVANCE: The field of tissue engineering has recently shown promising results and good future prospects in dentistry for the development of restorations to replace lost tooth structure with a functional replacement. PMID- 20166383 TI - Hot topics in special care dentistry. 8. Warfarin. PMID- 20166385 TI - Aspects of human disease. 42. Gout. PMID- 20166384 TI - Medical conditions in dental practice. Case 70. Physical signs for the general dental practitioner. Diagnosis: Massive diffuse 'goitre'. PMID- 20166386 TI - Magic angle effect in normal collateral ligaments of the distal interphalangeal joint in horses imaged with a high-field magnetic resonance imaging system. AB - Distal forelimb specimens of eight skeletally mature horses were imaged using proton density turbo spin echo, T1-weighted spoiled gradient echo, T2*-weighted gradient echo, short tau inversion recovery and T2-weighted fast spin echo sequences with the limb parallel to the main magnetic field, and with angulation of the limb relative to the main magnetic field. The magic angle effect can be identified in the collateral ligaments of the distal interphalangeal joint when imaged in a high-field magnetic resonance (MR) imaging system with a horizontally oriented main magnetic field. This effect has previously been described in the collateral ligaments of the distal interphalangeal joint in a low-field system with a vertically oriented main magnetic field. The curvature of the ligaments places the fibers at the magic angle in both horizontally and vertically orientated main magnetic fields. This effect can be identified on short time of echo sequences and impacts the signal pattern of the ligaments at the level of the middle phalanx with the limb in a neutral position and with angulation of the limb. Magic angle effect should be considered as a possible cause of an asymmetrical signal pattern, depending on the positioning of the limb and the sequences used for imaging, when evaluating the collateral ligaments of the distal interphalangeal joint on images acquired with a high-field MR imaging system that has a horizontally oriented main magnetic field. PMID- 20166387 TI - Clinical, magnetic resonance, and sonographic imaging findings in horses with proximal plantar metatarsal pain. AB - Sonography is commonly used for diagnosis of desmopathy of the proximal part of the suspensory ligament in horses. However, magnetic resonance (MR) imaging has been stated to be superior for detecting disease and localizing lesions. In this retrospective study of 39 horses or 46 hind limbs with lameness due to proximal plantar metatarsal pain, the clinical and diagnostic findings are discussed and sonography and MR imaging compared for examination of the proximal part of the suspensory ligament. With MR imaging interpreted as the clinical gold standard, desmopathy of the proximal part of the suspensory ligament was diagnosed in 21 hind limbs, proximal plantar metatarsal pain of unknown cause in 12, an osseous injury at the origin of the suspensory ligament in four and a condition unrelated to the suspensory ligament in nine. Based on these findings, sonography had a sensitivity of 0.77 and 0.66 and specificity of 0.33 and 0.31 for diagnosing proximal suspensory desmopathy and for accurately localizing lesions, respectively. MR imaging changes consistent with proximal suspensory desmopathy were signal hyperintensities and an increase in cross-sectional area compared with the contralateral limb. Anesthesia of the deep branch of the lateral plantar nerve is not specific neither for proximal suspensory desmopathy, as conditions unrelated to the suspensory ligament were diagnosed, nor for diagnosis of proximal plantar metatarsal pain, as conditions outside the proximal plantar metatarsal region were also diagnosed. PMID- 20166388 TI - Magnetic resonance signal changes during time in equine limbs refrigerated at 4 degrees C. AB - When ex vivo magnetic resonance (MR) imaging studies are undertaken, specimen conservation should be taken into account when interpreting MR imaging results. The purpose of this study was to assess MR changes during time in the anatomic structures of the equine digit on eight cadaver limbs stored at 4 degrees C. The digits were imaged within 12 h after death and then after 1, 2, 7, and 14 days of refrigeration. After the last examination, four feet were warmed at room temperature for 24 h and reimaged. Sequences used were turbo spin echo (TSE) T1, TSE T2, short tau inversion recovery (STIR), and double-echo steady state (DESS). Images obtained were compared subjectively side by side for image quality and signal changes. Signal-to-noise ratio (SNR) was measured and compared between examinations. There were no subjective changes in image quality. A mild size reduction of the synovial recesses was detected subjectively. No signal change was seen subjectively except for bone marrow that appeared slightly hyperintense in STIR and slightly hypointense in TSE T2 sequence after refrigeration compared with day 0. Using quantitative analysis, significant SNR changes in bone marrow of refrigerated limbs compared with day 0 were detected in STIR and TSE T2 sequences. Warming at room temperature for 24 h produced a reverse effect on SNR compared with refrigeration with a significant increase in SNR in TSE T2 images. After 14 days of refrigeration a statistically significant decrease of SNR was found in bone marrow in TSE T2 and DESS sequences. The SNR in the deep digital flexor tendon was not characterized by significant change in SNR. PMID- 20166389 TI - Acquired portal collateral circulation in the dog and cat. AB - We describe patterns of acquired portal collateral circulation in dogs and in a cat using multidetector row computed tomography angiography. Large portosystemic shunts included left splenogonadal shunts in patients with portal hypertension. Small portal collaterals were termed varices; these collaterals had several patterns and were related either to portal vein or cranial vena cava obstruction. Varices were systematized on the basis of the venous drainage pathways and their anatomic location, namely left gastric vein varix, esophageal and paraesophageal varices, gastroesophageal and gastrophrenic varices, gallbladder and choledocal varices, omental varices, duodenal varices, colic varices, and abdominal wall varices. As reported in humans and in experimental dog models, esophageal and paraesophageal varices may result from portal hypertension that generates reversal of flow, which diverts venous blood in a cranial direction through the left gastric vein to the venous plexus of the esophagus. Blood enters the central venous system through the cranial vena cava. Obstructions of the cranial vena cava can lead to esophageal and paraesophageal varices formation as well. In this instance, they drain into the azygos vein, the caudal vena cava, or into the portal system, depending on the site of the obstruction. Gallbladder and choledocal varices, omental varices, duodenal varices, phrenico-abdominal varices, colic varices, abdominal wall varices drain into the caudal vena cava and result from portal hypertension. Imaging plays a pivotal role in determining the origin, course, and termination of these vessels, and the underlying causes of these collaterals as well. Knowledge about these collateral vessels is important before interventional procedures, endosurgery or conventional surgery are performed, so as to avoid uncontrollable bleeding if they are inadvertently disrupted. PMID- 20166390 TI - Computed tomographic analysis of calvarial hyperostosis in captive lions. AB - Osseous malformations in the skull and cervical vertebrae of lions in captivity are believed to be caused by hypovitaminosis A. These often lead to severe neurologic abnormalities and may result in death. We describe the characterization of these abnormalities based on computed tomography (CT). CT images of two affected and three healthy lions were compared with define the normal anatomy of the skull and cervical vertebrae and provide information regarding the aforementioned osseous malformations. Because bone structure is influenced by various factors other than the aforementioned disease, all values were divided by the skull width that was not affected. The calculated ratios were compared and the most pronounced abnormalities in the affected lions were, narrowing of the foramen magnum, thickening of the tentorium osseus cerebelli and thickening of the dorsal arch of the atlas. CT is useful for detection of the calvarial abnormalities in lions and may be useful in further defining this syndrome. PMID- 20166391 TI - Imaging diagnosis--magnetic resonance imaging pseudolesion associated with the petrous temporal bone. AB - Normal anatomic variation in the amount of fat within the petrous temporal bone of dogs can result in a magnetic resonance (MR) imaging pseudolesion. Focal hyperintense areas in the region of the hippocampus on T1-weighted, T1-weighted, and fluid-attenuated inversion recovery imaging sequences were noted in a dog being imaged for seizure activity. Further investigation of this region, aided by the use of cadaveric specimens, led to the identification of normal anatomic variability in the amount of fat in the substantia spongiosa of the petrous temporal bone. The presence of normal adipose tissue was confirmed histopathologically. Fat suppression MR imaging sequences can be used to differentiate whether hyperintensity ventral to the hippocampus is a result of a pathologic process, or fat in the substantia spongiosa of the petrous temporal bone. PMID- 20166392 TI - Comparison of Gastrografin to barium sulfate as a gastrointestinal contrast agent in red-eared slider turtles (Trachemys scripta elegans). AB - Red-eared slider turtles (Trachemys scripta elegans) commonly develop intestinal obstruction. The gastrointestinal transit time in turtles tends to be longer than in other animals, making a rapid diagnosis of obstruction difficult. Fifteen red eared sliders were given either Gastrografin or 30% w/v barium sulfate orally to compare ease of administration, transit time, and image quality. Each contrast medium was easy to administer but barium sulfate had to be administered more slowly (mean = 40s) than Gastrografin (mean = 20s) to prevent regurgitation. The mean transit and emptying time of Gastrografin was at least 9 h faster than barium sulfate at all time points except gastric transit. Both contrast media had a smooth, uniform appearance that outlined the mucosa with well-defined margins within the stomach and proximal small intestine. Dilution of Gastrografin occurred as it progressed through the intestines, resulting in decreased opacity in the distal small intestine and colon. Pre-administration packed cell volume and total serum protein levels of four turtles receiving Gastrografin were compared with levels at 24-, 96-, and 168-hours postadministration as well as to four control turtles not receiving contrast medium. Packed cell volume and total serum protein levels did not significantly differ among the Gastrografin and control group. From a clinical perspective, administration of Gastrografin allows for quicker results with only minor hematologic changes in red-eared sliders, but visualization of this contrast medium in the lower gastrointestinal tract may be insufficient for an accurate diagnosis. PMID- 20166393 TI - Assessment of three radiographic projections for detection of fluid in the rabbit tympanic bulla. AB - Otitis media in the rabbit commonly results in fluid accumulation in the tympanic bulla. Radiographic detection of fluid in the tympanic bulla is only moderately sensitive in the dog and cat. The purpose of this study was to investigate the accuracy of radiographic detection of fluid in the rabbit tympanic bulla for three different radiographic projections. Forty rabbit cadavers were used. Half of the tympanic bullae were randomly allocated to be filled with soft tissue material. Following this procedure, each specimen was radiographed in three projections: dorsoventral (DV), rostro 40 degrees ventral-caudodorsal (R40 degrees V-CdDO), and left and right latero 40 degrees ventral-laterodorsal (Lat40 degrees V-LatDO). After imaging, each specimen was frozen and sectioned to determine the content of the tympanic bullae. Images were interpreted and scored independently by two board-certified radiologists. There was no significant difference in sensitivity or specificity between the three projections when compared with the gross findings following sectioning, but observer confidence was highest for the DV projection. Accuracy of radiographic fluid detection was similar to that reported in the dog and cat. The DV and R40 degrees V-CdDO allow comparison of both tympanic bullae on a single radiograph, but the DV was subjectively easier to position, while the Lat40 degrees V-LatDO requires two radiographs for comparison. PMID- 20166394 TI - Imaging diagnosis--left retrocaval ureter and transposition of the caudal vena cava in a dog. AB - Retrocaval ureter and transposition of the caudal vena cava are each, rare developmental anomalies. We describe the usefulness of static fluid magnetic resonance urography and dynamic contrast-enhanced magnetic resonance urography in the diagnosis of these anomalies. Basic techniques, benefits, and drawbacks of magnetic resonance urography are presented. PMID- 20166395 TI - Imaging diagnosis--split cord malformation. AB - The features of a calf with a split cord malformation are described. Clinically, there was severe cervicothoracic kyphoscoliosis and an interscapular dermal sinus associated with cerebrospinal fluid drainage. Using magnetic resonance imaging, complete duplication of the spinal cord at the cervical intumescence was detected. There was associated syringohydromyelia, multiple cervicothoracic vertebral malformations resulting in kyphoscoliosis and rachischisis, herniation of the cerebellar vermis, meningoencephalocele, and calvarial defects. PMID- 20166396 TI - Imaging diagnosis--duodenal diverticulum in a dog. AB - A young female Boxer had a history of chronic soft stool. Survey abdominal radiographs were unremarkable. A duodenal diverticulum was identified in abdominal ultrasound and barium upper-gastrointestinal contrast examinations. Before surgery a 99mTc-pertechnetate study was performed to evaluate for ectopic gastric mucosa in the duodenal diverticulum. Focal abnormal increased radioactivity was identified in the right caudal abdominal quadrant. The diverticulum was excised. Upon histopathologic examination of the duodenal diverticulum, ectopic gastric mucosa was not identified but ectopic pancreatic tissue was found. Mild eosinophilic inflammation within the diverticulum was suspected to be the cause of the mild 99mTc uptake seen in this dog. PMID- 20166397 TI - Imaging diagnosis--equine nasal septal thickening due to chronic chondritis. AB - We describe the use of computed tomography (CT) in a 6-year-old mare with upper airway obstruction due to an abnormally thick nasal septum. Upon CT imaging, multifocal, expansile cyst-like lesions were detected in the nasal septum. The histopathologic diagnosis was chronic dissecting chondritis. Resection of the abnormal nasal septum resulted in resolution of the clinical signs. PMID- 20166398 TI - Ultrasonographic appearance of canine parvoviral enteritis in puppies. AB - The ultrasonographic appearance of the gastrointestinal tract of puppies suffering from parvoviral enteritis was characterized. Forty puppies between 6 and 24 weeks of age with confirmed canine parvoviral enteritis were examined ultrasonographically within 24 h of admission. Sonographic findings included fluid-filled small intestines in 92.5% of subjects, and stomach and colon in 80% and 62.5% of subjects, respectively. Generalized atony was present in 30 subjects and weak peristaltic contractions indicative of functional ileus observed in the remaining 10 subjects. The duodenal and jejunal mucosal layer thicknesses were significantly reduced when compared with normal puppies with mean duodenal mucosal layer measuring 1.7 mm and jejunal mucosal layer 1.0 mm. Additionally, a mucosal layer with diffuse hyperechoic speckles was seen in the duodenum (15% of subjects) and the jejunum (50% of subjects). The luminal surface of the duodenal mucosa was irregular in 22.5% of subjects and the jejunal mucosa in 42.5% of subjects. In all of these subjects, changes were accompanied by generalized indistinct wall layering. Small intestinal corrugations were seen within the duodenum in 35% of subjects and within the jejunum in 7.5%. A mild amount of anechoic free peritoneal fluid was observed in 26 subjects and was considered within normal limits and a moderate amount of anechoic free peritoneal fluid was observed in six subjects. The jejunal lymph node size was within normal limits. None of the above changes are pathognomonic for canine parvoviral enteritis but finding them in combination is highly suggestive. PMID- 20166399 TI - Normal canine pediatric gastrointestinal ultrasonography. AB - The normal sonographic appearance of the adult canine gastrointestinal tract has been described. Interpretation of abdominal ultrasonographic findings in puppies is difficult due to the lack of information on normal ultrasonographic findings. The gastrointestinal tract, jejunal lymph node size and the presence and appearance of abdominal fluid were investigated in 23 normal, 7-12-week-old Beagle puppies. The duodenal wall thickness was greater than in other parts of the gastrointestinal tract (mean 3.8 +/- standard deviation [SD] 5 mm, range 3.2 4.8 mm). The mean stomach wall thickness was 2.7 +/- SD 0.4 mm (range 2.2-3.7 mm), the mean jejunal wall thickness was 2.5 +/- SD 0.5 mm (range 1.2-3.4 mm), and the mean colonic wall thickness was 1.3 +/- SD 0.3 mm (range 0.7-2.0 mm). In addition, mean duodenal and jejunal mucosal layer thicknesses measured 2.7 +/- SD 0.5 mm (range 2.0-3.8 mm) and 1.5 +/- SD 0.4 mm (range 0.6-2.5 mm), respectively. Homogenous, hypoechoic jejunal lymph nodes were easily found and the mean thickness was 7.1 +/- SD 2.2 mm (range 1.5-12.5 mm). A mild amount of anechoic free peritoneal fluid was present in all puppies. PMID- 20166400 TI - Contrast-enhanced ultrasonography for characterization of canine focal liver lesions. AB - In six normal beagles and 27 dogs with spontaneous focal or multifocal liver lesions, contrast-enhanced ultrasonography using Sonazoid was performed. Sonazoid is a newly developed second-generation contrast agent with the ability to be used for real-time contrast imaging along with parenchymal imaging. An appropriate protocol for the evaluation of all three phases (arterial, portal, and parenchymal) was established based on the results for normal beagles. By evaluation of the echogenicity of hepatic nodules during the arterial and parenchymal phases it was possible to differentiate malignant tumors from benign nodules with very high accuracy. In 15 of 16 dogs diagnosed as malignant tumors, nodules were clearly hypoechoic to the surrounding normal liver during the parenchymal phase. Additionally, malignant tumors had different echogenicity compared with the surrounding normal liver during the arterial phase in 14 of 15 dogs. In the portal phase, there were no characteristic findings. Contrast enhanced ultrasonography with Sonazoid appears to improve the characterization of canine focal and multifocal hepatic lesions. PMID- 20166401 TI - Ultrasonographic observation of secretin-induced pancreatic duct dilation in healthy cats. AB - Secretin is a polypeptide hormone that stimulates secretion of bicarbonate from the exocrine pancreas and, in healthy human subjects, causes transient pancreatic duct dilation observable sonographically. In humans with chronic pancreatitis, secretin administration fails to cause pancreatic duct dilation, theoretically due to the restrictive effects of periductal fibrosis. We characterized the effect of exogenous secretin administration on the width of the pancreatic duct in nine healthy domestic cats. Cats were given a commercially available secretin product (ChiRho Stim) while the pancreatic duct was monitored sonographically. Mean pancreatic duct diameter increased from 0.77 +/- 0.33 to 1.42 +/- 0.40 mm after secretin administration (P = 0.0017). The mean percent increase in pancreatic duct diameter over basal diameter for all time points up to 15 min postsecretin administration was 101.9 +/- 58.8%. Applicability of this technique to diagnose chronic pancreatitis in cats will need to be investigated. PMID- 20166402 TI - Dosimetric impact of daily setup variations during treatment of canine nasal tumors using intensity-modulated radiation therapy. AB - Intensity-modulated radiation therapy (IMRT) can be employed to yield precise dose distributions that tightly conform to targets and reduce high doses to normal structures by generating steep dose gradients. Because of these sharp gradients, daily setup variations may have an adverse effect on clinical outcome such that an adjacent normal structure may be overdosed and/or the target may be underdosed. This study provides a detailed analysis of the impact of daily setup variations on optimized IMRT canine nasal tumor treatment plans when variations are not accounted for due to the lack of image guidance. Setup histories of ten patients with nasal tumors previously treated using helical tomotherapy were replanned retrospectively to study the impact of daily setup variations on IMRT dose distributions. Daily setup shifts were applied to IMRT plans on a fraction by-fraction basis. Using mattress immobilization and laser alignment, mean setup error magnitude in any single dimension was at least 2.5 mm (0-10.0 mm). With inclusions of all three translational coordinates, mean composite offset vector was 5.9 +/- 3.3 mm. Due to variations, a loss of equivalent uniform dose for target volumes of up to 5.6% was noted which corresponded to a potential loss in tumor control probability of 39.5%. Overdosing of eyes and brain was noted by increases in mean normalized total dose and highest normalized dose given to 2% of the volume. Findings suggest that successful implementation of canine nasal IMRT requires daily image guidance to ensure accurate delivery of precise IMRT distributions when non-rigid immobilization techniques are utilized. Unrecognized geographical misses may result in tumor recurrence and/or radiation toxicities to the eyes and brain. PMID- 20166403 TI - Radiation therapy communication: nasal passage and paranasal sinus lymphoma in a pony. AB - An aged pony with extensive paranasal sinus and nasal passage B-cell lymphoma was treated with palliative radiation therapy. Sixteen gray were administered in two fractions, 7 days apart. A lateral field was used for the first fraction and a dorsal field for the second. Because of tumor being present in the left frontal sinus, gross tumor was knowingly excluded from the treated volume in the lateral field. The tumor regressed within 2 months and the pony remained free of clinical disease for 2.5 years. Acute, temporary blindness developed shortly after the second radiation fraction, but a direct causal relationship with the radiation therapy was not confirmed. The only radiation side effect was leukotrichia. Palliative treatment was successful in improving and prolonging the quality of life. These results suggest that localized equine B-cell lymphoma is radiosensitive, and that palliative radiation therapy is a reasonable consideration for large tumors, even when tumor volume prevents all gross tumor from being irradiated. PMID- 20166404 TI - Remembering the past, an eye to the future. PMID- 20166405 TI - Clinical performance of vital bleaching techniques. AB - This study compared the clinical outcome of bleaching techniques in vital teeth. After IRB approval and informed consent, 90 subjects were selected based on the shade of their anterior teeth (A2 or darker, Vita Classic shade guide). Subjects were assigned to three treatment groups in a split-mouth study design: Group I: HB (at-home bleaching with 10% carbamide peroxide for two weeks) vs OBL (in office bleaching with 35% hydrogen peroxide, two sessions, two-week intervals, with light irradiation); Group II: OB (in-office bleaching without light irradiation) vs OBL; Group III: HB vs combination (one session plus HB). Color change and color rebound (deltaE) were measured for a 16-week period. Color measurements were carried out with both a spectrophotometer and a shade guide at baseline, 1, 2, 4, 8 and 16 weeks. Tooth sensitivity was evaluated using a VAS scale for 15 days. Both the Student's t-test and Tukey-Kramer test were used to analyze the results (p < 0.05). After one week, one session of OBL followed by HB resulted in lower color values, compared with the other bleaching methods. Group III resulted in the least shade values at one-week evaluation, when compared with the other bleaching methods. After two weeks, HE alone resulted in similar color changes as OB, OBL and OBL+HB. The use of light irradiation did not improve bleaching efficacy (OB = OBL). OBL and OB resulted in higher sensitivity rates than HB. PMID- 20166406 TI - Evaluation of packable and conventional hybrid resin composites in Class I restorations: three-year results of a randomized, double-blind and controlled clinical trial. AB - The clinical performance of packable and conventional hybrid resin composites in Class I restorations for a period of three years was compared using a randomized controlled double-blind clinical trial with self-matching design. A total of 50 pairs of Class I restorations were placed in 32 adult patients by one dentist in a self-matching prospective clinical trial. The paired teeth were divided into the TPH Spectrum/XenoIII (TS) restoration group and the Synergy Compact/One Coat (SC) restoration group according to a random number table. Application of the materials followed the manufacturer's instructions. The restorations were evaluated by two independent evaluators using US Public Health Service (USPHS) Ryge modified criteria. Statistical analysis was performed using the McNemar's test with Yates' continuity correction. After three years, 40 pairs of restorations were available for evaluation. Four TS and two SC restorations failed due to fracture. Only one TS-restored tooth showed postoperative sensitivity at baseline and the symptom disappeared one week later. Alpha ratings of TS vs SC restorations were as follows: 95% vs 98% for color match, 85% vs 88% for marginal integrity, 88% vs 90% for anatomical form, 85% vs 83% for marginal discoloration, 88% vs 93% for occlusal contact. For both materials, Alpha ratings were 88% for surface texture. The three-year clinical performances of the two restorative materials were satisfactory and not significantly different for each of the parameters evaluated. PMID- 20166407 TI - Pulp capping with mineral trioxide aggregate (MTA): a retrospective analysis of carious pulp exposures treated by undergraduate dental students. AB - The current study estimated pulpal vitality after MTA pulp caps were performed by undergraduate student clinicians. At recall after 12 to 27 months, 51 pulp caps were clinically and radiographically assessed. Kaplan-Meier analyses were used to estimate overall success at 12 and 24 months, determined as the presence of a vital pulp, as well as impact of preoperative variables on pulp vitality at recall. Overall, one-year pulp survival was 67.7%, while the two-year survival rate was 56.2%. Tarone-Ware statistics indicated that neither age of the patient nor size of the exposure ("minimal" or "moderate") and the amount of bleeding ("none," "minimal" or "moderate") had a significant effect on survival rates. Within the limitations of the current study on procedures performed by student clinicians, it may be concluded that, for MTA pulp caps applied to carious exposures in adults, certain preoperative conditions--patient age, exposure size and amount of bleeding--are not predictive of clinical outcome. Considering the comparatively low success rate for the current cohort, more research is needed to define predictive criteria for successful pulp capping with MTA. PMID- 20166408 TI - The use of warm air stream for solvent evaporation: effects on the durability of resin-dentin bonds. AB - This study evaluated the effect of a warm (W) or cold (C) air-dry stream for solvent evaporation on the immediate (IM) and six-month (6M) resin-dentin bond strength (microTBS) and silver nitrate uptake pattern (SNU) of two-step etch-and rinse adhesive system (Adper Single Bond [SB] and Prime & Bond 2.1 [PB]). The adhesives were applied on demineralized dentin surfaces and a warm or cold air dry stream (10 seconds) was applied followed by light-activation (10 seconds). After 24-hours of water storage, the specimens were serially sectioned in the "x" and "y" directions to obtain bonded sticks around 0.8 mm2 to be tested immediately or after six months of water storage. The specimens at each period were immersed in a 50% solution of silver nitrate, photodeveloped and analyzed by SEM for SNU. Higher IM microTBS values were observed for SB under W conditions. Both adhesives showed reductions in microTBS after 6M in both air temperatures. Regarding SEM, a low silver nitrate uptake was observed in the W groups either in IM or 6M for both adhesives. PMID- 20166409 TI - Evaluation of proximal contact tightness of Class II resin composite restorations. AB - OBJECTIVE: The objective of the current study was to compare in-vitro the proximal contact tightness (PCT) of Class II resin composite restorations (RCR) placed with different established and new placement techniques. METHODS: 105 ivorine lower left first molars with standardized MO cavities were randomly divided into seven groups (n = 15) as follows: SRing: sectional matrix and separation ring (Garrison Dental); CRing: circumferential matrix (1101-c, KerrHawe SA) with separation ring; CWedge: circumferential matrix with a wedge only; COptra: circumferential matrix and OptraContact (Vivadent); CCerana: circumferential matrix and a Cerana insert (Nordiska Dental); CElliot: circumferential matrix and Elliot separator (PFINGST & Co) and Walser: Walser matrix O-type (Dr Walser Dental GmbH). In all the groups, the matrix band was secured using a wooden wedge except for the Walser group, following manufacturer's recommendations. A Tofflemire retainer (Kerr Corporation) was used to apply the circumferential matrix band whenever it was used. All the prepared teeth were restored with resin composite (Premise, Kerr) mounted in a manikin head to simulate the clinical environment. PCT was measured using the Tooth Pressure Meter (University of Technology, Delft). The data were analyzed using one-way ANOVA and Tukey post-hoc tests (p < 0.05). RESULTS: Compared to the control group (SRing) (6.64 +/- 1.06N), all other systems resulted in significantly lower PCT values (p < 0.001). Within the circumferential matrix groups, CRing (4.01 +/- 0.53N) and CElliot (4.29 +/- 1.08N) showed significantly tighter contacts compared to the CWedge (0.37 +/- 0.22N), COptra (0.91 +/- 0.49N), CCerana (2.99 +/- 1.98N) and Walser (1.34 +/- 0.55N) (p < 0.05) group. Between CWedge and COptra, no significant difference was found (p = 0.57). CONCLUSION: The use of separation rings with sectional matrices provides superior contacts when placing Class II RCRs. PMID- 20166410 TI - Chromatic influence of value resin composites. AB - The current study evaluated the chromatic influence of high, medium and low value composites on a dentin composite substrate (A2 shade) using spectrophotometric analysis. The specimens were divided into the following four groups: a) control (CG), entirely composed of dentin composite (n = 5); b) high value (GHV), dentin composite and high value composite (n = 20); c) medium value (GMV), dentin composite and medium value composite (n = 20) and d) low value (GLV), dentin composite and low value composite (n = 20). The dentin composite was 2.0 mm thick and the value composite was added in four different thicknesses, dividing the groups into four subgroups: S1 = 1.0 mm, S2 = 0.8 mm, S3 = 0.6 mm and S4 = 0.4 mm. The results were determined using the CIELAB system and differences in brightness of the specimens were analyzed using two-way ANOVA. Significant differences were found between different value resin composites, thicknesses and interactions, as revealed by the Tukey's test (HSD). Adding value composite produced lower brightness, and a gray shade was observed, compared to the control, regardless of the value or thickness of the primary composite. Eleven of the 12 subgroups presented clinically unacceptable chromatic changes, except when the 0.4 mm thickness of high value composite was used. PMID- 20166411 TI - Shear bond strength of three different nano-restorative materials to dentin. AB - OBJECTIVES: To evaluate the shear bond strength (SBS) of a nano-composite, a flowable nano-composite and a nano glass ionomer to dentin in vitro. MATERIALS AND METHODS: Sixty human molars were ground flat, exposing the dentin surfaces, and they were randomly divided into five groups according to the restorative materials and adhesive systems used (n = 12/group). The restoratives were applied to all dentin surfaces according to the manufacturer's instructions, using a special jig (Ultradent) in the following manner: Group 1: a nano-composite (NC) (Filtek Supreme XT-3M ESPE) was applied with a two-step self-etch adhesive (SE) (Adper SE Plus-3M ESPE); Group 2: NC was applied with an etch&rinse adhesive (SB) (Adper Single Bond 2-3M ESPE); Group 3: a flowable nano-composite (FNC, Filtek Supreme XT Flow-3M ESPE) was applied with SE; Group 4: FNC was applied with SB and Group 5: a nanofilled resin-modified glass ionomer (Ketac N100-3M ESPE) was applied with Ketac Nano Primer (3M ESPE). The bonded specimens were stored in distilled water (37 degrees C, 24 hours) and tested for SBS in a universal testing machine (1 mm/minute). Two specimens from each group were subjected to SEM evaluations of the adhesive interfaces. Failure modes were determined using a stereomicroscope. The mean SBS values were calculated and the data were analyzed with the Kruskal Wallis and Mann-Whitney-U tests (p < 0.05). RESULTS: Mean SBS values (MPa) for the groups were 13.64; 7.83; 11.20; 4.12 and 0.64 for Groups 1, 2, 3, 4 and 5, respectively. Group 1 exhibited a significantly higher value than all the other groups; whereas, Group 5 had the lowest value (p < 0.05). The SE adhesive yielded higher bond values than the SB adhesive with NC and FNC restorative materials. Failure modes in all the groups were primarily adhesive. CONCLUSION: The results demonstrate the capacity of the current two-step self etch adhesive to outperform the etch&rinse adhesive in conjunction with the two nano-restoratives tested. PMID- 20166412 TI - Knoop microhardness mapping used to compare the efficacy of LED, QTH and PAC curing lights. AB - This study used a hardness mapping technique to compare the ability of seven curing lights to polymerize five composites. Six curing lights (Sapphire [plasma arc: PAC], Bluephase16i [light emitting diode: LED], LEDemetron II [LED], SmartLite IQ [LED], Allegro [LED] and UltraLume-5 [Polywave LED]) were compared to an Optilux 501 (halogen: QTH) light. Five resin composites (Vit-1-escence, Tetric Evoceram, Filtek Z250, 4 Seasons and Solitaire 2) were polymerized at 4 mm and 8 mm from the end of the light guide. Four composites were light cured for the following times using these lights: Sapphire (5 seconds), Bluephase16i (5 seconds), LEDemetron II (5 seconds), SmartLite IQ (10 seconds), UltraLume-5 (10 seconds), Allegro (10 seconds) and Optilux 501 (20 seconds). Solitaire 2 required double these irradiation times. On each specimen, the Knoop microhardness (KHN) was measured at 49 locations across a 3 x 3 mm grid to determine the ability of each light to cure each brand of composite. The PAC light delivered the broadest spectrum of wavelengths, the greatest irradiance and hardness values that were 4.7 to 18.1 KHN(50gf) harder than the other lights. The ability of the lights to cure these five composites was ranked from highest to lowest: Sapphire, Optilux 501, Allegro, UltraLume-5, SmartLite IQ, LEDemetron II and Bluephase16i (ANOVA with REGWQ multiple comparison adjustment, p < 0.01). PMID- 20166413 TI - Evaluation of bond strength and internal adaptation between the dental cavity and adhesives applied in one and two layers. AB - This research evaluated the influence of the number of adhesive layers of three adhesive systems on microtensile bond strength (microTBS) to dentin and the internal adaptation between the dental structure and the resin composite restoration. Two cavities (C-factor = 3) were made on the buccal surfaces of 30 bovine incisors. Scotchbond Multi-Purpose (MP), Adper Single Bond 2 (SB) and Clearfil SE Bond (CSB) were applied in one layer (MP-I, SB-I and CSB-I) and in two layers (MP-II, SB-II and CSB-II). The cavities were restored with Z250 resin composite. After 48 hours, beams were obtained (n = 15/group) for microTBS testing, and slices containing the two restorations were obtained for internal adaptation analysis. The beams were submitted to the microTBS test on a universal testing machine (EMIC DL-2000) and the failures were analyzed by SEM. The slices were analyzed under an optical microscope and the types and amounts of internal failures (gap, crack, rupture) were classified. The mean values of microTBS (MPa) were: MP-II: 56.92; MP-I: 52:23; CSB-II: 47:71; CSB-I: 42.25; SB-I: 35.12 and SB II: 34.69. According to two-way ANOVA (alpha = 0.05), the independent variables adhesive system (p = 0.001) and the number of layers (p = 0.025) presented significant difference. The mixed failure was predominant in all groups. For the internal adaptation analysis, the Kruskal-Wallis test (alpha = 0.05) showed statistical differences for cracks and ruptures between the adhesive systems. SB I and II were shown to have the highest values for cracks, and MP-I demonstrated the lowest. SB-II showed significantly higher values for rupture. The application of two layers promoted a slight increase in microTBS for Scotchbond MP and Clearfil SE Bond, but it did not improve the internal adaptation for the tested adhesive systems. PMID- 20166414 TI - Influence of adhesive application time on enamel bond strength of single-step self-etch adhesive systems. AB - This study examined the relationship between the adhesive application time and enamel bond strength of several single-step self-etch adhesive systems. The adhesives used were: Bond Force (BF, Tokuyama Dental Corporation, Tokyo, Japan), Clearfil tri-S Bond (CT, Kuraray Medical Inc, Tokyo, Japan), iBond Self-Etch (IB, Heraeus Kulzer, Armonk, NY) and OptiBond All-in-One (OB, sds Kerr). Bovine mandibular incisors were mounted in self-curing resin and wet ground with #600 grit silicon carbide paper to expose labial enamel. Adhesives were applied for 10, 20 or 40 seconds and the resin composites were condensed into a mold (phi4 x 2 mm) on the enamel and light irradiated. Ten samples per test group were stored in 37 degrees C water for 24 hours, then shear tested at a crosshead speed of 1.0 mm/minute. One-way ANOVA and the Tukey HSD test (alpha = 0.05) were performed within each adhesive system. The enamel surfaces after adhesive application were also observed in a Field Emission Electron Probe Surface Roughness Analyzer and the Ra value was calculated. The enamel bond strength ranged from 13.6 to 17.8 MPa for BF, 13.6 to 15.9 MPa for CT, 14.3 to 16.2 MPa for IB and 13.4 to 19.8 MPa for OB. Significant increases in bond strength were found for the 40-second application groups, except for IB. No changes in Ra value were found for BF and IB, while significant decreases in Ra value were recorded with 40-second application for CT and OB. The data suggested that the duration of the single step self-etch adhesive application was a crucial factor for determining the enamel bond strengths of some of the single-step self-etch adhesives employed in the current study. PMID- 20166415 TI - Effect of configuration factor on shear bond strengths of self-etch adhesive systems to ground enamel and dentin. AB - Self-etch bonding systems are easy to use and popular in dental practice. The current study examined the in vitro shear bond strengths to dentin and ground enamel of four self-etch bonding systems and a two-step etch-and-rinse bonding system. Two hundred extracted non-carious human molars were used. Approximately 0.5 mm of enamel was removed from the buccal surface of 100 teeth and the bond strengths of this enamel surface were determined. The buccal surface of the remaining 100 teeth was ground away to create a standardized smear layer on dentin. Five adhesive systems were used: Adper Single Bond Plus (ASB): two-step etch-and-rinse); Adper Scotchbond SE (AS), Clearfil SE Bond (CSE-both two-step self-etch); XENO V (X) and Adper Easy Bond (AE): both one-step self-etch). Filtek Z250 composite was bonded to the tooth using each adhesive system in a low configuration (C) factor (0.2) and a high C-factor (4.4) mold (10 teeth in each group). The specimens were thermal cycled 2,000x, then subjected to a shear bond strength test. The data were compared with analysis of variance using the Fisher's PLSD multiple comparison tests. A three-factor ANOVA showed that, overall, the shear bond strength was significantly higher in the low C-factor group 4.33 MPa (p < 0.0001). There was also a significant difference in the shear bond strengths among the bonding systems (p < 0.0001). The higher C-factor molds had the same adverse effect on all bonding systems and on both enamel and dentin, but the bonding systems acted differently on enamel and dentin (three-factor ANOVA p < 0.0001). The two-step etch-and-rinse system (ASB) consistently delivered the highest bond strengths (34.6-41.5 MPa). Fisher's PLSD comparisons showed that, in the high C-factor mold, there was no significant difference between the shear bond strengths of SB, EB and CSE to dentin, and SB, X and SE to enamel (p > 0.05). The one-step self-etch AE system delivered the lowest shear bond strengths (23.9 MPa) to enamel (p < 0.05). The two-step self-etch system AS delivered the lowest shear bond strengths (23.9 MPa) to dentin (p < 0.05). PMID- 20166416 TI - Microtensile bond strength and interfacial characterization of 11 contemporary adhesives bonded to bur-cut dentin. AB - OBJECTIVES: This study evaluated mechanically and ultra-morphologically 11 different adhesive systems bonded to dentin. METHODS: The microtensile bond strength (microTBS) of 11 contemporary adhesives, including two three-step etch&rinse, three two-step etch&rinse, two two-step self-etch and four one-step self-etch adhesives to dentin, were measured. The resultant interfacial ultra structure at dentin was characterized by transmission electron microscopy (TEM). Human third molars had their superficial dentin surface exposed, after which a standardized smear layer was produced using a medium-grit diamond bur. The selected adhesives were applied according to their respective manufacturer's instructions for microTBS measurement after storage in water at 37 degrees C for 24 hours or for TEM interfacial characterization. RESULTS: The microTBS varied from 11.1 to 63.6 MPa; the highest bond strengths were obtained with the three step etch&rinse adhesives and the lowest with one-step self-etch adhesives. TEM evaluation showed very different interaction patterns, especially for the self etch adhesives. "Mild" self-etch adhesives demineralized the dentin surface sufficiently to provide micro-mechanical retention, while preserving hydroxyapatite within the hybrid layer to enable additional chemical interaction. CONCLUSIONS: When bonded to dentin, the adhesives with simplified application procedures (in particular, one-step self-etch adhesives) still underperform as compared to conventional three-step adhesives. "Mild" two-step self-etch adhesives that provide additional chemical bonding appear to most optimally combine bonding effectiveness with a simplified application protocol. PMID- 20166417 TI - The effect of mouthrinses on salivary sorption, solubility and surface degradation of a nanofilled and a hybrid resin composite. AB - This in vitro study evaluated the effect of mouth rinses on salivary sorption (Sp), solubility (Sl) and surface degradation of a nanofilled (Z350) and hybrid (P60) resin composite. Specimens (6 mm in diameter and 1 mm thick) of a nanofilled and hybrid resin composite were immersed in artificial saliva at 37 degrees C for seven days. Twice a day, the samples (n = 5) were immersed in 20 ml of three mouth rinses: Listerine, Plax Mint and Plax. A control group was maintained in artificial saliva. Sp and Sl were evaluated based on ISO 4049:2000(E) and surface degradation by scanning electron microscopy-SEM. The degree of conversion (DC%) of resin composites was obtained by using an FT-IR spectrometer equipped with an attenuated total reflectance crystal (ATR). The data were analyzed using the Student's t-test, ANOVA and Tukey test for multiple comparisons. No significant difference in DC% was found between the two resin composites (p < 0.05). The highest sorption rate was presented by the nanofilled composite exposed to Listerine (p < 0.05). The hybrid composite in the control group (artificial saliva) and Plax presented the lowest sorption (p < 0.05). The highest solubility was presented by the two resin composites exposed to Listerine (p < 0.05). SEM analysis showed that mouth rinses produced more severe surface degradation in the nanofilled composite. PMID- 20166418 TI - Adhesive bond strengths to enamel and dentin using recommended and extended treatment times. AB - This study examined the effect of different enamel and dentin conditioning times on the shear bond strength of a resin composite using etch-and-rinse and self etch adhesive systems. Shear bond strengths were determined following treatment of flat ground human enamel and dentin surfaces (4000 grit) with 11 adhesive systems: 1) AdheSE One Viva Pen-(ASE), 2) Adper Prompt L-Pop-(PLP), 3) Adper Single Bond Plus-(SBP), 4) Clearfil SE Bond-(CSE), 5) Clearfil S3 Bond-(CS3), 6) OptiBond All-In-One-(OBA), 7) OptiBond Solo Plus-(OBS), 8) Peak SE-(PSE), 9) Xeno IV-(X4), 10) Xeno V-(X5) and 11) XP Bond-(XPB) using recommended treatment times and an extended treatment time of 60 seconds (n = 10/group). Composite (Z100) to enamel and dentin bond strengths (24 hours) were determined using Ultradent fixtures and debonded with a crosshead speed of 1 mm/minute. The data were analyzed with a three-way Analysis of Variance (ANOVA) and Fisher's LSD post hoc test. The highest shear bond strengths (MPa) to enamel were achieved by the three etch-and-rinse systems at both the recommended treatment time (SBP-40.5 +/- 6.1; XPB-38.7 +/- 3.7; OBS- 35.2 +/- 6.2) and the extended treatment time (SBP-44.5 +/ 8.1; XPB-40.9 +/- 5.7; OBS-35.0 +/- 4.5). Extending the enamel treatment time did not produce a significant change (p > 0.05) in bond strength for the 11 adhesive systems tested. OBS generated the highest (46.2 +/- 7.9) bond strengths to dentin at the recommended treatment time. At the extended treatment time X4 (42.2 +/- 11.7), PSE (42.1 +/- 9.7) and OBS (41.4 +/- 8.0) produced the highest bond strengths to dentin. The bond strength change between recommend and extended treatment times was significant (p < 0.05) for PSE, but the other 10 systems did not exhibit any significant change. PMID- 20166419 TI - Effect of light energy density on conversion degree and hardness of dual-cured resin cement. AB - This study evaluated the effect of different light energy densities on conversion degree (CD) and Knoop hardness number (KHN) of RelyX ARC (RLX) resin cement. After manipulation according to the manufacturer's instructions, RLX was inserted into a rubber mold (0.8 mm x 5 mm) and covered with a Mylar strip. The tip of the light-curing unit (LCU) was positioned in contact with the Mylar surface. Quartz tungsten-halogen (QTH) and light-emitting diode (LED) LCUs with light densities of 10, 20 and 30 J/cm2 were used to light-cure the specimens. After light curing, the specimens were stored dry in lightproof containers at 37 degrees C. After 24 hours, the CD was analyzed by FT-Raman and, after an additional 24-hours, samples were submitted to Knoop hardness testing. The data of the CD (%) and KHN were submitted to two-way ANOVA and the Tukey's test (alpha = 0.05). QTH and LED were effective light curing units. For QTH, there were no differences among the light energy densities for CD or KHN. For LED, there was a significant reduction in CD with the light energy density set at 10 J/cm2. KHN was not influenced by the light-curing unit and by its light energy density. PMID- 20166420 TI - Restoration of occlusal vertical dimension in dental erosion caused by gastroesophageal reflux: case report. AB - The authors describe a minimally invasive procedure for occlusal rehabilitation in a young patient presenting with mild mandibular prognathism and loss of occlusal vertical dimension caused by dental erosion from chronic gastroesophageal reflux. PMID- 20166421 TI - American Academy of Gold Foil Operators. Clinician of the Year Award Dr. Dan Henry. PMID- 20166422 TI - American Academy of Gold Foil Operators. Distinguished Member Award Dr Craig Bridgeman. PMID- 20166423 TI - Emergency department decreases 4-hour wait times to 9 minutes. AB - The ED at Palisades Medical Center in North Bergen, NJ, has slashed its door-to doc times down to nine minutes with the implementation of a new rapid evaluation unit model and other improved efficiencies. Here are some of the keys to their success: Triage was moved to the bedside, where specially trained nurses' aides perform point-of-care testing following evaluation by a nurse, a physician's assistant, or a doctor. Discussions with other departments made them aware of how their processes affected ED wait times. A discharge area was created to free up more beds in the ED proper. PMID- 20166424 TI - Flow strategies cover processes in and out of ED. AB - With changes in place only about six months, Cincinnati Children's Hospital Medical Center, compared the May-July period door-to-doc times and found they had dropped from 61 minutes in 2008 to 45 minutes in 2009. The ED manager interfaces with the hospital's director of patient flow, and they have initiated new processes inside and outside the department: Nurses have been placed at the ED entrance to take a "quick look" at patients. Handoffs are handled via fax, so ED nurses no longer have to track down their inpatient counterparts for a telephone conversation. Mathematical formulas have been created to predict admissions and discharges. PMID- 20166425 TI - Predicting admits, discharges vital. PMID- 20166426 TI - ED improves on already impressive wait times. AB - LEAN methodology, known for uncovering opportunities to improve by eliminating "wasteful" process steps, has helped the ED at Good Samaritan Hospital in Kearney, NE, make good patient flow numbers even better. The hospital went from a door-to-doc time of 28 minutes and length of stay (LOS) of 103 minutes to a door to-doc time of 16 minutes and a LOS of 93 minutes. Here are some efficiencies that were implemented: standardized bedside carts and procedure carts that can be pulled into any room as needed; a manual-entry whiteboard with magnetized color coded symbols to indicate patient status; a new documentation system that standardized the ED charting decreased the time required for documentation. PMID- 20166427 TI - Emergency departments post wait times on the web. AB - The two EDs of Sacred Heart Medical Center in Oregon have been posting their wait times online for several months now, but the introduction of this service didn't come without a great deal of preparation. For example: ED charge nurses at facilities that already had posted wait times online were contacted to see if there had been any problems. A communitywide education effort was put in place to let potential patients know what was coming. PMID- 20166428 TI - Pharmacokinetics and pharmacodynamics of a new ACT formulation: Artesunate/Amodiaquine (TRIMALACT) following oral administration in African malaria patients. AB - A new fixed-dose combination of artesunate (AS) plus amodiaquine (AQ) (TRIMALACT) was recently developed for the treatment of uncomplicated falciparum malaria. The originality of this combination lies in its galenic formulation which consists of a three-layer tablet with two layers containing each of the active ingredients, i.e. AS and AQ, and these are separated by a middle layer containing an antioxidant compound. To evaluate the efficacy and tolerability of this combination, adults with uncomplicated malaria received three administrations of two tablets (100:300 mg AS/AQ) in a 24-h interval, in Democratic Republic of Congo. Parasitemia and fever were measured and the plasma levels of parent compounds and metabolites [dihydroartemisinin (DHA) and monodesethylamodiaquine (MdAQ)] were determined by high-performance liquid chromatography. In addition, we determined the prevalence of molecular markers of resistance to chloroquine (CQ) and sulfadoxine/pyrimethamine (SP). The AS/AQ combination TRIMALACT demonstrated a good efficacy resulting in an excellent clinical and parasitological response rate of 100% after correction for PCR results. Treatment regimen was well tolerated. The main disposition parameters to AS+AQ were: for DHA, AUC = 632 +/- 475 ng h/ml and Cmax = 432 +/- 325 ng/ml, and for MdAQ = 14268 +/- 4114 ng h/ml and Cmax = 336 +/- 225 ng/ml (mean +/- standard deviation). Parasite genotyping show high frequencies of molecular SP- and CQ-resistance markers with more 80% of the samples showing more than three mutations linked to SP resistance and 93.48% carrying parasite with the CQ-resistant haplotype. This study shows that the AS/AQ combination TRIMALACT is safe and effective in the treatment of highly drug-resistant falciparum malaria. PMID- 20166429 TI - Changes of lidocaine levels in rat serum and tissue under stress and hyperlipidaemic diets. AB - Hyperlipidaemic diets induce increase in serum lipid profile (total cholesterol, triglycerides, LDL etc). It has also been proven that stress interferes in lipid metabolism. Many drugs modify their pharmacokinetic properties in presence of lipoproteins, as a result of alterations in their plasma protein and tissue binding. Lidocaine, a synthetic amide, used as a local anesthetic and secondary as antiarrhythmic agent is also protein bound and therefore conditions, which favor lidocaine dissociation from plasma proteins, modify its pharmacokinetic profile. The purpose of this study was: To investigate and compare the effects of stress( cold water 4 degrees C swimming of 20 days duration) and various high lipid diets (olive oil, butter, sunflower oil) on the serum and tissue (liver and tongue) levels of 14C lidocaine. PMID- 20166430 TI - Genetic CYP2C19 polymorphism dependent non-responders to clopidogrel therapy- does structural design, dosing and induction strategies have a role to play? AB - Recent evidences suggest that genetic CYP2C19 polymorphism plays a role in the development of treatment resistance for clopidogrel's antiplatelet therapy. This short communication puts forward some strategies that could be potentially used to overcome the genetic polymorphism associated hurdles. While there is some established evidence for an induction strategy and design of chemical structure, the proposed dosing input strategy is speculative in nature. Such thought process and novel explorations are important for delivering medicines in genetically and ethnically diverse populations. PMID- 20166431 TI - Effect of phytomedicines, AM-1, niprisan and nifadin on the pharmacokinetics of chloroquine in rats. AB - The single oral dose pharmacokinetics of chloroquine was studied alone and after coadministration with phytomedicines NIPRID?92?001?1-1 (AM-1), Niprisan, and Nifadin in rats. Plasma chloroquine concentrations were measured using High performance liquid chromatography (HPLC) method developed earlier in our laboratory. The data were fitted into a WinNonlin standard non-compartmental programme. The co-administration of the herbal medicines with chloroquine produced decrease in the serum concentration of chloroquine at each sampling time. The highest decrease of 85% occurring at the time of peak concentration (1 h) was recorded with Nifadin, followed by 75% with Niprisan the least was 50% with AM-1. Significant reduction was also observed in some other parameters, such as area under the serum concentration- time curve (AUC(0-24)) and maximum serum concentration (Cmax) while the apparent volume of distribution (Vd) and elimination half-life (t 1/2beta) increased significantly (P< 0.05). It was concluded that the gastric presence of the herbal medicines significantly impaired the absorption of chloroquine in rats. PMID- 20166432 TI - Pharmacokinetics and bioequivalence studies of cefteram pivoxil in healthy Chinese volunteers. AB - A simple, sensitive and specific method has been developed for the determination of cefteram in human plasma. Sample preparation was accomplished through protein precipitation with 20% trichloroacetic acid (v/v) and chromatographic separation was performed on a C18 column at 25 degrees C. The mobile phase consisted of methanol-aqueous 20 mM ammonium acetate (18:82, v/v) at flow rate of 1.0 mL/min. Wavelength was set at 235 nm. The lower limit of quantification was 0.04 microg/mL and the assay exhibited a linear range of 0.04-3.2 microg/mL (r=0.9996). The relative recoveries of cefteram from human plasma at three different concentrations were more than 90%. The method was successfully applied to investigate the bioequivalence between two kinds of cefteram pivoxil preparations (test vs reference) in 24 healthy Chinese volunteers. After a single 100 mg dose for the test and reference product, the resulting means of major pharmacokinetic parameters such as AUC(0-t), AUC(0-infinity), Cmax and Tmax of cefteram pivoxil were 4.75 +/- 1.35 vs 4.76 +/- 1.29 microg h/mL, 4.89 +/- 1.36 vs 4.91 +/- 1.29 microg h/mL, 1.65 +/- 0.45 vs 1.73 +/- 0.45 microg/mL and 1.48 +/- 0.59 vs 1.73 +/- 0.45 h, respectively, indicating that these two kinds of preparations were bioequivalent. PMID- 20166433 TI - Effects of simvastatin on the pharmacokinetics of verapamil and its main metabolite, norverapamil, in rats. AB - The aim of this study was to investigate the effect of simvastatin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were determined after the oral administration of verapamil (9 mg/kg) in the presence or absence of simvastatin (0.3 and 1.0 mg/kg). The pharmacokinetics of verapamil were significantly altered by the coadministration of simvastatin compared with those in the control group (given verapamil alone). The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of verapamil were significantly increased (P < 0.05 at 0.3 mg/kg; P < 0.01 at 1.0 mg/kg) by simvastatin. Consequently, the absolute bioavailability (A.B.) of verapamil with simvastatin (7.3% at 0.3 mg/kg, 9.3% at 1.0 mg/kg) were significantly higher than those in the control group (P < 0.05, 5.2%). The AUC and Cmax of norverapamil were not significantly increased in the rats coadministered with simvastatin compared with those in the control group. Moreover, the metabolite-parent ratio (M.R.) of norverapamil were significantly decreased in rats coadministered with simvastatin. These results implied that simvastatin significantly enhanced the oral bioavailability of verapamil by inhibiting the CYP3A-mediated metabolism in small intestine or in the liver and P glycoprotein (P-gp) efflux pump in small intestine. Therefore, concurrent use of verapamil and simvastatin should be monitored closely to potential drug interactions for safe therapy of cardiovascular diseases. PMID- 20166434 TI - Urinary elimination kinetics of pyrimethamine. AB - In this study, the kinetics of pyrimethamine elimination via the urine was investigated. The experiments were carried out on six healthy male volunteers aged 23-32 years. The drug was administered orally (p.o.) in a single dose at three different concentrations i.e.: 50, 75 and 100 mg. The concentration of the drug in the urine was determined via the modified method of Bonini et al. and Garber et al. It was found that 13.4 +/- 1.3% of the dose eliminated via the urine was in unchanged form. The process of pyrimethamine elimination may be described according to an open kinetic two-compartmental model: the formula showing the course of pyrimethamine elimination over time has been given. Several examples of the quantitative exposure test have been proposed, which allow the calculation of the drug dose absorbed and thus the degree of toxicity to be determined. This test can also be useful in a controlled clinical setting. PMID- 20166435 TI - Kinetics of pyrimethamine in young and adult rats on a standard diet and on a low protein diet. AB - A pharmacokinetic study of pyrimethamine was carried out in 4- (103-115 g) and 12 week-old (260-280 g) white male Wistar rats fed a standard diet containing 24% protein, and a low-protein diet containing 8% protein. After intragastric administration of the drug in a single dose of 40 mg/kg body weight, the concentrations of pyrimethamine in the blood were determined at different time points from 15 min to 20 hours post-dose. On the basis of the results obtained, a number of parameters characterizing the course of absorption and elimination of the drug from the blood were calculated. The majority of parameters were dependent on both age and type of diet. The greatest bioavailability was observed in the 4-week-old rats: for the animals fed the low-protein diet, the area under the concentration-time curve (AUC) amounted to 593.0 and for those on the standard diet the AUC was 503.1. In the older rats, this parameter was 339.3 and 228.1 respectively. The k(e) values were lower in the younger rats (i.e. 0.0121 h(-1) and 0.0135 h(-1)) than in the older animals (i.e. 0.0164 h(-1) and 0.0193 h(-1) respectively). The elimination half-life (t1/2) was higher in the 4-week old rats (i.e. 57.1 h; 8% protein, and 51.2 h; 24% protein) than in the 12-week old animals (i.e. 42.4 h; 8% protein, and 36.0 h; 24% protein). PMID- 20166436 TI - Development and validation of a sensitive LC-MS method for the determination of promethazine hydrochloride in human plasma and urine. AB - We developed and validated a sensitive and low sample volume liquid chromatographic-mass spectrometric (LC-MS) method for determination of Promethazine hydrochloride in human plasma (0.5 ml) or urine (0.1 ml). The lower limit of quantification in human plasma and urine was 1.00 ng/ml. The inter- and intra-day precisions (CV %) in both plasma and urine were lower than 10%, the mean method accuracies and recoveries from spiked plasma samples at three concentrations were more than 97%. The developed method was successfully applied to determine Promethazine hydrochloride in human plasma and urine, and proved suitable to clinical pharmacokinetic study. PMID- 20166437 TI - Development and validation of a sensitive LC-MS method for the determination of tramadol in human plasma and urine. AB - A sensitive and selective liquid chromatography-tandem mass spectrometric (LC-MS) method was developed and validated for the determination of Tramadol in human plasma and urine. The analyte was separated on a Diamonsil C18 column with ammonium acetate (5 mmol x L(-1))-methanol (50:50,v:v) adjusted PH by caustic soda at a flow rate of 0.8 ml min(-1), and analyzed by mass spectrometry is in positive ion mode. The ion mass spectrum of m/z were 264.1 for Tramadol and 248.0 for Tinidazole (I.S.), respectively. The weighted (1/x2) calibration curve was linear over plasma concentration range 1.00-400.00 ng/ml and urine concentration range 0.01-16.00 microg/ml, with a correlation coefficient (r) of 0.9995 and 0.9997, respectively. The lower limit of quantification in human plasma was 1.00 ng/ml. The inter-and intra-day precisions (CV%) in both plasma and urine were lower than 10%, the mean method accuracies and recoveries from spiked plasma samples at three concentrations ranged from 98.2 to 100.1% and 61.6 to 62.9%, respectively. The developed method was successfully applied to determine Tramadol in human plasma and urine, and provided suitable profiles for clinical pharmacokinetic study of Tramadol. PMID- 20166438 TI - Pharmacokinetics, safety and tolerance of single- and multiple-dose of a novel compound tramadol hydrochloride injection (35 mg tramadol hydrochloride, 45 mgl promethazine hydrochloride) in Chinese healthy subjects. AB - The pharmacokinetics of Tramadol and Promethazine after a single dose of 40, 80 and 120 mg intramuscular injecting CTHI was evaluated in healthy volunteers. Physical exam, vital signs, clinical laboratory tests and electrocardiogram measurements were monitored to assess the safety and tolerance of the drug. The plasma levels of Tramadol and Promethazine in serial samples were measured by a validated HPLC-MS method. No subject showed any drug-related clinically significant changes on physical examination, vital signs or laboratory tests. PMID- 20166439 TI - Change in blood tacrolimus concentration by fluctuation of renal function in a bone marrow transplant patient. AB - The authors report a case showing a marked change in blood tacrolimus concentration due to modification of renal function in a bone marrow transplant recipient. Blood tacrolimus concentration was well controlled after transplantation, but an approximately threefold increase in the concentration was observed on day 10 even though the dosage was unchanged. Although there were no pronounced changes in hepatic enzyme activities in serum, marked elevations of renal function test values were noted; concentrations of serum creatinine (SCr) and blood urea nitrogen (BUN) were increased by more than 300% from the original levels. The tacrolimus concentration was gradually decreased by the dose reduction, but the dose-adjusted tacrolimus blood concentration (C/D) was increased contrary to the decreased tacrolimus concentration. The C/D of tacrolimus also began to decline from several days after the recovery of Scr and BUN levels and returned to the basal level. Our finding suggests that renal function has a significant effect on the pharmacokinetic disposition of tacrolimus, although this agent is almost completely eliminated by hepatic metabolism. Careful attention should be paid to alteration in tacrolimus blood concentration, especially when renal function fluctuates during post-transplant immunosuppressive therapy. PMID- 20166441 TI - The toxicity of aconitine, emodin on ICC cell and the antagonist effect of the compatibility. AB - The study was to investigate the effect and action mechanism of aconitine and emodin on the function of the interstitial cells of Cajal (ICC) cultured in vitro. ICC cells were treated with aconitine (0.05-8%) and emodin (0.001-2%) in single or combined synchronous experiments and the effect of emodin on aconitine was evaluated using cell viability as end-point. Both the two compounds had toxicity on ICC cell. The cell membrane integrity impairment caused by the exposure lead to the efflux of intracellular ionic ([Na+], [Ca2+] and [K+]) and the deactivation of the Na+-K+-ATPase. The ionic disturbance caused the interruption of the cellular breathing chain and resulted in anaerobic metabolism increase and the glycogen massive decomposition, at last the energy metabolism in the cells was obstructed. But the antagonist effect existed when the two compounds were exposed to ICC cells together. The compatibility (aonitine:emodin as 2:1), can significantly reversed the toxicity of aconition. In addition, synergistic effects were never observed in the range of concentrations considered. Although emodin can defer the aconition's toxicity on ICC cell, the impairment can't be totally inhibited by the compatibility with time went on. The results of our work represent a starting point to generate novel information on the interactions between aconitine and emodin in vitro, as well as a new relevant experimental approach useful to investigate the Herb compatibility with aconite and rhubarb and reference for the clinic. PMID- 20166440 TI - Construction of expression system of rabbit aldehyde oxidase cDNA for the clarification of species differences. AB - A remarkably large species difference in cinchonidine oxidation activity catalyzed by aldehyde oxidase (AO) has been known, in particular between rabbit and monkey. As the first step in clarifying the phenomenon from the view point of structures of the active site, we attempted to construct an expression system of rabbit AO cDNA. The nucleotide sequences of cloned full-length rabbit AO cDNA were determined and confirmed to agree completely with those of genome DNA. The expression system in Escherichia coli was constructed in reference to the previously established method for monkey AO. Both expressed rabbit and monkey AO proteins correctly reproduced the remarkable species differences observed in their liver cytosols towards cinchonidine and methotrexate. Namely, the expressed rabbit AO protein showed extremely high activities than did that of monkey AO. A difference in the structure of the active site might be responsible for the substrate-dependent species difference towards the relatively bulky molecules of cinchonidine and methotrexate. The use of molecular biology techniques will be very useful to verify the hypothesis. PMID- 20166442 TI - Comparative single- and multiple-dose pharmacokinetics of rosuvastatin following oral administration in Chinese volunteers. AB - The objective of this study was to determine and compare the plasma concentrations of rosuvastatin following single- and multiple-dose administration in Chinese volunteers. The study was of an open label, randomized, three-way cross-over design and was conducted in 12 subjects. Single dose administration of the rosuvastatinon was characterized by a rapid absorption (2.045 +/- 0.891 h, 2.273 +/- 1.009 h and 1.667 +/- 0.651 h) and a marked peak plasma concentration (9.938 +/- 4.438, 28.09 +/- 12.075 and 43.092 +/- 22.09 ng/ml) for the three different doses (5 mg, 10 mg and 20 mg) of rosuvastatin. The apparent elimination half-life amounted to 7.914 +/- 3.813 h, 8.445 +/- 4.994 h and 15.401 +/- 5.429 h following administration, respectively. Similar findings were obtained after multiple dosing. A rapid absorption (3 +/- 1.365 h, 3.042 +/- 1.054 h and 2.375 +/- 0.829 h) and a marked peak plasma concentration (9.288 +/- 5.314, 18.808 +/- 6.687 and 49.808 +/- 23.516 ng/ml) for the three different doses (5 mg, 10 mg and 20 mg) of rosuvastatin were observed. The apparent elimination half-life amounted to 13.181 +/- 5.492 h, 8.035 +/- 3.331 h and 15.509 +/- 6.43 h following administration, respectively. Small differences in gender are not considered clinically relevant, and dose adjustments based on gender are not anticipated. But the state of fed or fasting will affect the pharmacokinetic of rosuvastatin. PMID- 20166444 TI - Facilities & physicians: working together. PMID- 20166445 TI - Ownership successor liability. PMID- 20166446 TI - Handle with care. PMID- 20166443 TI - Clonidine changes lidocaine free concentrations in rat myocardium without affecting heart function measured by echocardiography. AB - Lidocaine is a local anaesthetic widely used in regional and epidural anaesthesia. Clonidine a alpha2-adrenergic agonist is an antihypertensive agent, regulating the production of catecholamines (epinephrine and norepinephrine) and added to local anesthetic infusions in order to improve postoperative analgesia. The aim of the study was to investigate the influence of clonidine co administration on the binding of 14C lidocaine to rat serum and heart tissue protein as well as its pharmacodynamic effects in the heart. Four groups of Wistar rats (n=7) were used; Groups I and II received 4 mg/kg lidocaine i.m. Groups III and IV received lidocaine and 1 microg/kg clonidine i.m. In group I and III fifteen minutes and in groups II and IV thirty minutes after the initial treatment, ultrasound examination of heart function (heart rate, diameter of left ventricle in systole and diastole, ejection fraction) was performed. The animals were then sacrificed in all groups. Lidocaine free fraction in serum and heart was evaluated via ultrafiltration. The kinetics of lidocaine was altered by clonidine co-administration probably by mechanisms related to protein binding alterations. However, the pharmacokinetic interactions were not accompanied by changes of pharmacodynamic parameters including those of heart function as measured by echocardiography. PMID- 20166447 TI - Providers agree: HIT beats paper. PMID- 20166448 TI - Meet 2010 CDS President Michael Stablein. Interview by Walter Lamacki. PMID- 20166449 TI - How to master information overload. PMID- 20166450 TI - License problems that don't need to happen. PMID- 20166451 TI - Prevent flu with a healthy dose of fruits and vegetables. PMID- 20166452 TI - 'Watson, come here'! PMID- 20166453 TI - Dental tourism. PMID- 20166454 TI - Golden years. PMID- 20166455 TI - Hospice myths: what is hospice really about? AB - Hospice. The word alone can incite fear in those who hear it. Why? Often, when people hear the word "hospice," certain images come to mind: a loved one in bed- a loved one dying without food or water--a loved one who is lacking skilled care. With these images also comes the ideology that hospice "kills" patients or "starves" them. Many people have the impression that once their loved one enters an acute hospice care facility, they will only leave by death. Many myths surround hospice. Families often have a preconceived negative notion of hospice, but when they experience the hospice philosophy and the interaction of the Hospice Interdisciplinary Team, those negative connotations are dispelled. In this article, prevalent hospice myths will be explored. The goal is to bring a clearer understanding of hospice care, and in turn, encourage readers to think about how they would want themselves, their families, and their patients to experience care at the end of life. PMID- 20166456 TI - Understanding childhood obesity. PMID- 20166457 TI - Durable power of attorney for healthcare. PMID- 20166458 TI - Understanding Pennsylvania living wills: the 5 Ws. AB - The working world of nurses is often filled with deep-running emotions and physical exhaustion as we care for our dying patients. We feel the need to step back and gain perspective when faced with a dying patient, or more appropriately, a dying person. We must also keep in mind the family of the dying who may have similar feelings. It is nearly impossible to be a nurse and not have to care for a dying patient; thus, we often find ourselves dealing with living wills. The living will is the more common of the two forms of an advance directive; the other is the durable power of attorney for healthcare. Since living wills are so common, and laws about them vary from state-to-state, it is important for the professional nurse in Pennsylvania to understand how living wills work in our state. This may best be approached by considering the 5 Ws related to living wills. PMID- 20166459 TI - The Museum of Nursing History, Inc.: a sense of pride. PMID- 20166460 TI - Evaluation of Hospital Compare website for identifying risk. PMID- 20166461 TI - Globalization: from geopolitical perspective to personal connections. PMID- 20166462 TI - Pediatric influenza. AB - Influenza viruses cause annual epidemics in the United States. Although the severity of influenza epidemics vary by season, the morbidity associated with annual influenza epidemics in children is considerable from year to year. Excess pediatric outpatient clinic visits, emergency department visits, hospitalizations, and deaths occur each influenza season and are more common among younger children and those with conditions that increase their risk for developing influenza-related complications. Vaccination is the most effective way to prevent influenza and its complications and is recommended for all children 6 months through 18 years of age. Antiviral treatment is another tool to prevent influenza and reduce the duration of illness and complications. This article will review the virological, clinical, and epidemiological features of seasonal influenza, as well as discuss seasonal influenza vaccination and antiviral therapy. PMID- 20166463 TI - Trans fat intake in children: risks and recommendations. AB - Partially hydrogenated oils, also known as trans fat, are found in many baked goods, snack foods, fast foods, margarines, and shortening. Partially hydrogenated oil is vegetable oil that has been modified to be solid at room temperature and lengthens the shelf life of products in which it is used. Consumption of trans fat has been linked to negative changes in lipoproteins, systemic inflammation, coronary heart disease, and diabetes mellitus. Evidence of processes leading to these conditions has also been found in children. Dietary habits and preferences are established in early childhood; therefore, it is important to intervene early with parents to help them make healthier food choices for their families. Educational intervention should reflect successful programs, be based on a theoretical model, and focus on the adverse health effects of consuming trans fat and the importance of choosing a diet that favors unprocessed foods. PMID- 20166464 TI - Hispanic children and overweight: causes and interventions. AB - The incidence and prevalence of overweight is increasing to alarming rates in children and adolescents in the United States. Hispanic children are one of the highest risk groups for overweight. Many different factors are positively correlated with childhood overweight in Hispanics: lower socioeconomic status, lacking health insurance or being under-insured, poor diet, decreased physical activity, overweight status of parents, mother's perception of overweight, and degree of acculturation. Pediatric nurses are in a pivotal position to assist in curtailing the epidemic. Various evidence-based practices to prevent and treat pediatric overweight are discussed with recommendations to intervene, particularly with Hispanic youth. PMID- 20166465 TI - Exploring the meaning of excess child weight and health: shared viewpoints of Mexican parents of preschool children. AB - In the United States, the prevalence of childhood overweight and obesity has reached epidemic levels, with U.S. Hispanic children, a sub-group mainly composed of children of Mexican decent, disproportionately affected. Prior research has suggested that Mexican parents may view overweight in early childhood as desirable; however, it is unclear if this is still the case. Therefore, this qualitative study explored the beliefs of 11 Mexican parents of preschoolers regarding weight and health. Following coding and clustering of themes from the transcribed audio-recorded meetings, six patterns were identified: (a) meanings and relationships about excess weight in childhood and child health, (b) causes of overweight and obesity, (c) uncertainty about knowing and not knowing, (d) from Mexico to America: enticements of a new land and time as a commodity, (e) the effects of society on personal and parental goals: the work of parenting in the United States, and (f) identified needs and action strategies. In summary, parents involved in this group discussion readily associated overweight/obesity with poor mental and physical health; however, they were uncertain how they would "know" if their children were overweight. PMID- 20166466 TI - Pharmacokinetic considerations in the treatment of pediatric behavioral issues. AB - TOPIC: A review of psychopharmacology and the genetic considerations with pharmokinetics is followed through a case study to demonstrate the optimal clinical treatment of the child with pediatric behavioral issues. PURPOSE: The knowledge of the pharmacokinetic and pharmacodynamic consequences of medications in clinical practice is of the utmost importance for all pediatric nurse practitioners. Drug interactions occur when the efficacy or toxicity of a medication is changed with the addition of another medication or dosage change. SOURCES: An integrative literature review from nursing, medicine, psychology, and child psychiatry. CONCLUSIONS: The current climate of a child psychiatric specialist shortage leaves the charge of this vulnerable population in the hands of the primary care provider. Pediatric primary care now requires a clear understanding of the psychostimulant and non-stimulant medications, thorough screening of each child, appropriate dosage regulation, and close monitoring of all outcomes. It is imperative that pediatric nurse practitioners understand the pharmacological interactions and safety in the treatment of children with behavioral issues. PMID- 20166467 TI - Parental presence in pediatric trauma resuscitation: one hospital's experience. AB - Although parental presence during medical resuscitation of children has been a common practice for years, the same opportunity has rarely been available for families in pediatric trauma resuscitation. Blank Children's Hospital is an exception; for three years, the hospital has had a successful program for family presence in pediatric trauma resuscitation. Beginning with the efforts of one nurse, a task force was established that developed guidelines for this practice in conjunction with nursing and allied health staff, as well as trauma surgeons. Chaplains were approached and then trained to serve as family support persons during trauma resuscitation. Families have been receptive to and pleased with the opportunity to be present during trauma resuscitation of their children. PMID- 20166468 TI - Transition from pediatric to adult health care for adolescents with congenital heart disease: a review of the literature and clinical implications. AB - As medical and surgical techniques advance in modern health care, children and adolescents with congenital heart disease (CHD) are living well into their adult years. Their complex cardiac anatomy, physiology, and medical histories present a challenge to adult health care providers who are not traditionally educated and trained in CHD. Growing evidence demonstrates that adolescents and young adults with CHD are at risk for extensive complications and sequelae from their heart condition and surgical treatments. Many of these young adults either continue to be cared for by their pediatric cardiologist or are lost to follow up as they age out of pediatric care. There are little data on the most successful way to transition adolescents and young adults into adult-centered CHD programs. The purpose of this review is to reveal the need for transition into appropriate care and lifelong follow up for adolescents and young adults with CHD, and highlight the role of a pediatric nurse practitioner as a transition coordinator in a pediatric cardiology clinic. PMID- 20166469 TI - Ethical dimensions in the case of the 'octomom': two perspectives. PMID- 20166470 TI - Overactive bladder syndrome in the older woman: conservative treatment. AB - Over active bladder syndrome (OAB) is the most common cause of urinary incontinence in the older population (Gadgil and Wagg, 2008). Many women do not seek medical help and advice as they consider it to be an inevitable part of ageing. It can have significant impact on sufferers' lives and can contribute to an increased risk of falls, reduced quality of life, social isolation and depression. It is also known to be hugely underreported as patients are often too embarrassed to discuss their symptoms with members of their family or health professionals. OAB syndrome can however, be treated effectively in primary care with conservative, nurse-led treatments. This article will discuss the causes, implications, assessment and conservative treatments available to women over 65 years old presenting with OAB syndrome in primary care. PMID- 20166471 TI - Lower urinary tract dysfunction in MS: management in the community. AB - Lower urinary tract dysfunction in multiple sclerosis is common and is highly amenable to treatment. Individuals may have bladder storage and/or voiding dysfunction. The risk of progression to renal failure is low and hence lower urinary tract dysfunction should be considered medically manageable in most individuals. Evaluation begins with history taking and is supplemented by using a bladder diary. Ultrasonography is used to assess the degree of incomplete bladder emptying, and for assessing upper urinary tract damage. Incomplete bladder emptying is most often managed by clean intermittent self-catheterization and should be initiated if post-void residual urine is greater than 100 mls. Storage symptoms are most often managed using antimuscarinic medications. Other options include desmopressin or detrusor muscle injection of botulinum toxin type A. There are specific situations where specialist urology services should be involved. PMID- 20166472 TI - Mentoring a student immediately prior to registration: a qualitative study. AB - A literature search revealed limited research exploring the experience of the community nurse mentoring the student nurse immediately prior to registration. This qualitative study was undertaken in order to describe the lived experience of the community nurse when mentoring a final placement student. The study was conducted in compliance with relevant ethical procedures and institutional guidelines. Three focus groups were convened and the experiences of twelve community nurses working within a large city-based community health practice in Scotland who had mentored a student nurse immediately prior to registration were explored. Analysis suggests the community nurse mentors require support and development opportunities in relation to mentoring and assessing final placement pre-registration students. PMID- 20166473 TI - Informing patients of risks inherent in treatment. AB - Consent to treatment lies at the heart of autonomous decision making by patients who are entitled to make a free choice about whether to accept or refuse treatment. To help patients arrive at their decision district nurses must ensure that they give sufficient information about the nature and risks inherent in the treatment to allow an informed choice to be made. This article considers how much information regarding risks needs to be disclosed. It discusses how the law requires a different level of disclosure for patients who ask no questions about risks, those who make general enquiries about risks and those who ask specific questions about the risks inherent in treatment. PMID- 20166474 TI - What does enhanced recovery mean for the community nurse? AB - The enhanced recovery programme (ERP) is being increasingly performed in hospitals in the UK. This article discusses the principles of enhanced recovery and aims to dispel myths and concerns that the ERP might increase the workload for the community nurse. Enhanced recovery can be used after colorectal and other surgery; this article will focus on colorectal issues, particularly stoma care. With enhanced recovery hospital stays can be reduced to approximately 4 days for resections of the colon. To achieve this care a number of elements are required including early feeding and early mobilization and this results in patients getting better quicker than they would with traditional hospital care. PMID- 20166475 TI - Triggers for weight gain and loss among participants in a primary care-based intervention. AB - Numerous studies have sought to investigate the causes of obesity and the effectiveness of interventions for its treatment. However, there is little published evidence to describe patients' experiences of becoming and being obese. This paper reports on a qualitative study to explore the views and experiences of patients who had recently completed a primary care-based weight management intervention. Weight gain was often attributed to life events that caused changes in appetite and activity levels, rather than directly attributed to over-eating or inactivity. Triggers to help-seeking included health concerns, image factors and past experiences of stigmatization. Personalized messages and ongoing support from professionals and peers were identified as facilitators to successful weight management. This paper has implications for the role of primary and community care staff in the prevention, treatment and management o obesity, in terms of supporting patients through significant life events and encouraging them to access services. PMID- 20166476 TI - Ileoanal pouch dysfunction and the use of a Medena catheter following hospital discharge. AB - With the advent of new surgical techniques to manage colorectal disease, the number of ileoanal pouch operations has amplified and therefore increased numbers of pouch patients are being discharged into the community setting. Community nurses will now encounter the ileoanal pouch patient and may be required to manage related complications. Restorative proctocolectomy with ileoanal pouch anastomosis (RPC) has become established as the gold standard operation for patients with ulcerative colitis (UC) and selected patients with familial adenomatous polyposis (FAP). Using a reservoir constructed from small bowel as a substitute rectum is a medical triumph which in the majority of cases improves the quality of life for patients, not only by eradicating disease and preserving anal sphincter function but also by avoiding a permanent ileostomy. Recent investigation into the use of Medena catheterization for pouch dysfunction has found that it is tolerated in the long-term and is associated with satisfactory quality of life in pouch patients with outflow obstruction. PMID- 20166477 TI - Funding to attract the best. PMID- 20166478 TI - 2010 consumer guide. Understanding your options. PMID- 20166479 TI - Remixed nuts. PMID- 20166480 TI - A contrast in care. PMID- 20166481 TI - Dentist, yes; ED, no. PMID- 20166482 TI - Finance. Portfolios recovering from market trouncing. PMID- 20166483 TI - Information exchange. Health information exchanges hold promise, pose perils. PMID- 20166484 TI - Supply chain. Teaming with physicians can drive down costs. PMID- 20166485 TI - Behave yourself! PMID- 20166486 TI - Electronic health records. Health system hopes to buiId physician loyalty with EHR program. PMID- 20166487 TI - Operation Mend: healing the body and the spirit. Interview by Laura Putre. PMID- 20166488 TI - Health care's Most Wired gets redesigned. PMID- 20166489 TI - The Medicaid trap. AB - Even as the economy rebounds, unemployment remains high and tax revenues low. States face enormous deficits, and many could cut Medicaid reimbursements or levy fees on providers to help fund the program, typically among their largest budget items. If and how the federal government will help is unclear. "We're looking at tremendous pressure over the next two years, making institutional players, especially hospitals, very vulnerable," one expert warns. PMID- 20166491 TI - Shutting the door on readmissions. PMID- 20166490 TI - Doing double duty. Interview by Charlotte Huff. AB - In a number of rural areas, one executive leads two, or even three, hospitals. They have to juggle staffs, boards of trustees and where to spend their time. PMID- 20166492 TI - Most improved winners follow varied paths. PMID- 20166493 TI - Tackling barriers. PMID- 20166494 TI - Dealing with pregnancy in radiology: a thin line between science, social and regulatory aspects. AB - The participation of pregnant women in radiology can be an emotional experience. The word "radiation" understandably invokes fear and uncertainty. Irradiation of a foetus should be avoided whenever possible. However, radiological examinations of pregnant women are often justified and unintended exposures do occur. Also pregnant radiology staff may remain working in the department. Lack of knowledge about the effects of both ionising (X-rays) and non-ionising (MRI) radiation is responsible for anxiety of patients and workers. If foetal exposures occur, they must be quantitatively evaluated and the risk put into perspective. This paper is intended to inform radiology managers, radiologists, technologists and referring clinicians in their management with pregnant patients and co-workers. The paper describes conceptus doses for both patient and worker that are associated with radiology practice, reviews the risks and effects of in utero irradiation, and discusses current national policies, international guidelines and practical aspects. PMID- 20166495 TI - Lipoid pneumonia secondary to Vaseline use in a patient with tympanic membrane perforation. AB - Exogenous lipoid pneumonia is a rare condition caused by aspiration of mineral, vegetable or animal oils. The aspiration of mineral oil is the most common cause of lipoid pneumonia in children. We present a 27-year-old man with a lipoid pneumonia with a history of daily use of Vaseline applied to cotton balls for ear plugging before swimming and shower. PMID- 20166496 TI - Aryepiglottic fold and subcutaneous metastases from breast carcinoma. AB - We report the CT findings in a 77-year-old woman with left-sided aryepiglottic fold metastasis from breast cancer diagnosed 7 years previously. The lesion obliterated the left piriform sinus, had a lobulated contour and showed mild and heterogeneous enhancement on a post-contrast CT examination. Biopsy of the lesion revealed metastasis from poorly differentiated adenocarcinoma, compatible with metastasis of the breast carcinoma. Before detection of the laryngeal lesion, a second primary tumor in the right ovary was diagnosed. After right oopherectomy, histopathology revealed clear cell adenocarcinoma. The patient also had multiple subcutaneous metastases and bilateral cervical lymphadenopathies. Chemotherapy was applied to the patient. PMID- 20166497 TI - Imaging findings of a cutaneous B-cell lymphoma. AB - We report a case of a slowly growing primary cutaneous B-cell lymphoma of the right upper arm in an 81-old-year-old female. Although primary cutaneous lymphoma is the second most common group of extranodal non-Hodgkin lymphomas, reports on the potential value of imaging in the diagnosis are very scarce in the radiological literature. Although the dermatologist usually relies on clinical and histological findings for a correct diagnosis, MR imaging may be useful in local staging of the tumor, whereas 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) is the imaging technique of choice for initial distant staging and follow-up after treatment. PMID- 20166498 TI - Bleeding duodenal varices, an unusual presentation of portal hypertension: 3D MSCT of the feeding branches facilitates temporizing treatment by percutaneous transhepatic embolization. AB - Though duodenal varix ruptures account for only 5% of variceal hemorrhages, they often have a fatal outcome with a mortality as high as 40%. Their detection and treatment, which often prove quite difficult endoscopically, benefit of CT imaging and percutaneous endovascular radiological techniques. PMID- 20166499 TI - Retroesophageal aortic arch in a patient with pulmonary embolism. AB - The authors report an interesting case of right retroesophageal aortic arch (REAA) with pulmonary embolism that presented like the dissection of the aortic aneurysm but eventually diagnosed by means of spiral CT. Right REAA should be considered as a rare cause of mediastinal widening in the patients in whom significant difference between the blood pressure and pulse intensity of both extremities is evident to prevent the erroneous diagnosis and treatment. PMID- 20166500 TI - MRI of abducens nerve paralysis of non-traumatic origin. PMID- 20166501 TI - Madelung's disease. PMID- 20166502 TI - Ameloblastoma. PMID- 20166503 TI - Infarctus of the azygos lobe due to acute pulmonary embolism. PMID- 20166504 TI - Hepatic epithelioid hemangioendothelioma. PMID- 20166505 TI - Presumptive schwannoma of the trochlear nerve (IV). PMID- 20166506 TI - Kiloh-Nevin syndrome. PMID- 20166507 TI - Toward global justice through benefit-sharing. PMID- 20166508 TI - Vulnerability: a contentious and fluid term. PMID- 20166509 TI - Two masters. PMID- 20166510 TI - Too few physicians, or too many? PMID- 20166511 TI - Case study. Just another test? Commentary. PMID- 20166513 TI - Cryptic coercion. PMID- 20166512 TI - Moral distress: a growing problem in the health professions? PMID- 20166514 TI - Medicalized weapons & modern war. AB - "Medicalized" weapons--those that rely on advances in neuroscience, physiology, and pharmacology--offer the prospect of reducing casualties and protecting civilians. They could be especially useful in modern asymmetric wars in which conventional states are pitted against guerrilla or insurgent forces. But may physicians and other medical workers participate in their development? PMID- 20166515 TI - New standards for gene synthesis screening. PMID- 20166516 TI - Political, policy and social barriers to health system interoperability: emerging opportunities of Web 2.0 and 3.0. AB - Achieving effective health informatics interoperability in a fragmented and uncoordinated health system is by definition not possible. Interoperability requires the simultaneous integration of health care processes and information across different types and levels of care (systems thinking). The fundamental argument of this paper is that information system interoperability will remain an unfulfilled hope until health reforms effectively address the governance (accountability), structural and process barriers to interoperability of health care delivery. The ascendency of Web 2.0 and 3.0, although still unproven, signals the opportunity to accelerate patients' access to health information and their health record. Policy suggestions for simultaneously advancing health system delivery and information system interoperability are posited. PMID- 20166517 TI - The art and science of transforming Canada's health system. AB - This article considers whether greater attention to the art and the science aspects of organizational change can help achieve a smoother transition to future regionalized health services in Canada. The reported problems with the current system are considered and a key-point checklist based on the art and science of transformation is proposed for adoption by health system planners. It is argued that this will help address the current shortcomings of Canada's health system and improve the future delivery of Canada's health care services. PMID- 20166518 TI - How to control the costs of health care services--an inventory of strategic options. AB - This paper has two objectives: (1) to provide an inventory of popular strategies for cost reduction or cost containment in the health services research literature and (2) to propose a coherent framework to organize this inventory. The purpose of this framework is to inform decision-makers when grappling with the opposing forces they face in choosing a cost reduction strategy. The trade-off is clear: to access progressively more possible strategies, the decision-maker must be ready to expose the population and patients to more significant changes in services provided. On one hand, more choices are preferable because each strategy attacks the problem from a different angle and being restricted to fewer "angles" increases the likelihood that a specific "well" may have dried up. On the other hand, we know that change is often viewed, a priori, negatively in health care management, so there are pressures to limit the impact on services. PMID- 20166519 TI - The chronic care model: which physician practice organizations adapt best? AB - Chronic diseases remain among the major causes of death and disability in Canada as well as in other western industrialized nations. The episodic, punctuated, acute care model of health service delivery that describes the organization and orientation of care delivery is ill prepared to meet the needs of society burdened by chronic illness. The chronic care model (CCM) has been advanced as a way by which primary care practices can be transformed to meet the challenge of chronic illness. The objective of this research is to examine how well primary care physician practices, including walk-in clinics, solo family practices, group family practices, community health centres and physicians practicing in primary care networks, are succeeding at implementing the components of the CCM. Results suggest that physician primary care practices have considerable way to go in implementing the model, with walk-in clinics and solo family practices showing the least progress in inculcating its components. PMID- 20166520 TI - Measuring patient satisfaction with radiation therapy service delivery. AB - Patient satisfaction is an important component in the evaluation of health services provided to patients. This study evaluates the results of a patient satisfaction survey collected over five years in a radiation therapy department. The analysis identifies that satisfaction has improved in almost all areas, but there is room for improvement in others. The key findings are the importance of treating patients with courtesy and respect and the relatively lower levels of satisfaction noted for patients treated with palliative intent, an area of concern given these patients' greater needs. We provide aggregate results, identify factors that influence overall satisfaction and demonstrate how the survey results have led to quality improvement initiatives, which in turn have resulted in improved levels of satisfaction for patients. PMID- 20166521 TI - Reflections on health care leadership ethics. PMID- 20166523 TI - [Neuroscientific application of ultra high-field (7 tesla) MRI]. PMID- 20166522 TI - Leading patient-centred change in the Swedish health system: lessons from the 2009 Sweden Study Tour. AB - In May 2009, 17 senior health leaders from Canada travelled to Sweden as part of a Canadian College of Health Service Executives study tour. This paper provides an overview of the tour, outlines a number of health service reform practices in Sweden and proposes five "lessons learned" with regard to the practice of leading reform. Knowledge of the current Swedish practices of "leading change" based on the itinerary shows that a patient-centred vision, when combined with effective leadership practice, can bring about significant change. Ongoing dialogue between the Swedish and Canadian leaders provided the substance for this paper. PMID- 20166524 TI - [Surgery for lumbosacral lipoma: usefulness of 3D heavily T2 weighted MR image]. PMID- 20166526 TI - [Strategy for revascularization of chronic carotid occlusion with contralateral carotid stenosis]. AB - BACKGROUND AND PURPOSE: The optimal therapeutic approach for chronic carotid occlusion with contralateral carotid stenosis (ICO-ICS) remains uncertain. The aim of this study was to elucidate the safety and efficacy of initial vascular reconstruction for ICS in patients with ICO-ICS. PATIENTS AND METHODS: Eleven patients with ICO-ICS who demonstrated severe cerebral hypoperfusion in the hemisphere ipsilateral to ICO were treated in our institution between February 2003 and November 2007. Revascularization for ICS after measuring cerebral blood flow (CBF) by single photon emission computed tomography (SPECT) was performed either by carotid endarterectomy or carotid stenting. External carotid artery internal carotid artery (EC-IC) bypass for ICO was also performed when SPECT after revascularization for ICS still demonstrated marked hypoperfusion. RESULTS: In 6 patients with collateral flow via the anterior communicating artery and/or who had high-grade ICS (>70%), sufficient improvement of CBF solely by revascularization for ICS was confirmed. With regard to perioperative complications, 2 patients suffered bradycardia and hypotension and another 2 showed asymptomatic cerebral infarction on diffusion-weighted magnetic resonance imaging. CONCLUSIONS: Overall results for revascularization of ICS prior to that for ICO in patients with ICO-ICS were acceptable. CBF of bilateral hemispheres was sufficiently improved in more than half of the patients solely by revascularization for ICS. This strategy might be both efficient and effective for ICO-ICS. PMID- 20166525 TI - [Effect of Chai-ling-tang (Sairei-to) for methotrexate concentration degradation delay by methotrexate high-dose therapy]. AB - When methotrexate (MTX) salvage chemotherapy is performed for primary brain malignant lymphoma, use of leucovonrin rescue must often be extended due to delays in the degradation of blood concentration. We examined whether delay in MTX blood concentration degradation could be prevented by chai-ling-tang (Sairei to) which has diuretic action. In the five cases examined were MTX blood concentration 72 hours after MTX administration was more than 1 x 10(-7) M. A single dose of 3 g of chai-ling-tang was administered three times on the day the MTX salvage chemotherapy was subsequently performed. MTX blood concentration at 72 hours post MTX administration and subsequent chai-ling-tang administration was less than 1 x 10(-7) M in all five cases. In addition, urea nitrogen and creatinine levels in serum increased and creatinine clearance decreased following MTX administration, however these changes induced by MTX administration were reduced by chai-ling-tang administration. Chai-ling-tang was effective in preventing an MTX deferent delay in MTX high-dose therapy by improving renal blood flow. PMID- 20166527 TI - [Three pediatric cases with choroid plexus papilloma in the fourth ventricle]. AB - Choroid plexus papillomas are rare; they comprise less than 1% of all intracranial tumors. In children, most of these neoplasms arise in the lateral ventricle while in adults they are primarily located in the fourth ventricle. We report 3 children with choroid plexus papilloma in the fourth ventricle; they were one 5-month-old girl and 2 boys aged 8-and 15-years. The baby girl presented with macrocephaly and signs of raised intracranial pressure, the 2 boys exhibited cerebellar signs. On magnetic resonance imaging (MRI) the tumors were well enhanced with a cauliflower-like contour and hydrocephalus. In one case, diffusion weighted images (DWIs) showed an isointense tumor signal clearly different from the well-known hyperintensity of medulloblastomas, Via suboccipital craniotomy we succeeded in the total or subtotal surgical resection of these tumors and there were no sequela. None of the tumors have recurred in the intervening 2-9 years. In conclusion, choroid plexus papilloma should be included as a differential diagnosis in children presenting with tumors in the fourth ventricle. The contour of the tumor on MRI and its intensity on DWI may be clues for a correct preoperative diagnosis. PMID- 20166528 TI - [A case of symptomatic arachnoid cyst, that had been growing for 14 years, at the posterior part of the left temporal lobe]. AB - The authors report a 54-year-old woman with headache in whom a cyst was detected at the posterior part of the left temporal lobe following a traffic accident in 1993. Symptoms had recently worsened and computed tomography demonstrated an enlarged cyst in 2007. Thereafter, the patient underwent cyst fenestration. Intraoperative findings showed multilocular cysts with calcification. Symptoms improved immediately. Histological findings showed that the cyst was composed of collagenous membrane and a monolayer of cells compatible with arachnoid cyst. These findings also showed calcification and we considered that growth of the arachnoid cyst had been induced by trauma. We expected an arachnoid cyst with a single cavity, but this lesion was multilocular. Retrospectively, cine magnetic resonance image (MRI) seemed to show multilocular cysts. Cine MRI might be an effective tool to determine whether a cyst is multilocular. PMID- 20166529 TI - [Cerebral complications induced by neurotoxity of nonionic contrast medium after embolization of unruptured cerebral aneurysms: report of 2 cases]. AB - We successfully performed endovascular coil embolization for 2 patients with unruptured saccular aneurysms. However, transient cortical blindness and generalized seizure associated with CNS neurotoxity of contrast medium were noted for each patient after the procedure. In the first case of a 62-year-old woman with a right BA-SCA aneurysm, she complained of blindness with restlessness one day after the intervention but no evidence of embolism on MRA. Abnormal EEG with slow, large amplitudes and 99mTc-HMPAO SPECT-evidenced hyperperfusion were observed in the occipital area. Accompanied by resolution of the edematous changes on MRI in conjunction with normalization of EEG and rCBF by anticonvulsant administration, her visual acuity completely recovered 8 days after the onset. According to these findings, we considered this case as transient cortical blindness. In the second case of a 68-year-old man with a left MCA aneurysm, he exhibited generalized seizure 8 hours after the procedure. CT scan revealed retention of the contrast medium over the left hemisphere. Postictal EEG one day after the seizure showed left frontal slowing but had no evidence of contrast medium retention or hyperperfusion. He recovered well with corticosteroid, anticonvulsant, and intravenous hydration. His follow-up DSA 2 years after the coiling was performed without trouble by reducing the amount/concentration of the contrast medium and by prophylactic steroid and hydration. Non-ionic contrast medium-related neurotoxity as represented by transient cortical blindness or generalized seizure should be recognized as a possible complication of endovascular surgery where patients' brain areas are locally vulnerable to contrast medium exposure. PMID- 20166530 TI - [A case of herpetic meningoencephalitis associated with massive intracerebral hemorrhage during acyclovir treatment: a rare complication]. AB - We report a case of a 35-year-old female with herpetic meningoencephalitis confirmed by polymerase chain reaction and immunohistochemical study for herpes simplex virus-1 accompanied with a massive intracerebral hematoma as a complication. A hematoma localized at the medial temporal lobe and the medial frontal lobe occurred on the 11th day after initiation of acyclovir treatment. She subsequently required emergency surgery for temporal lobectomy, as well as hematoma and external decompression. Intracerebral hematoma with MR imaging showed gyral pattern along the cortex of the medial temporal lobe and the base of the medial frontal lobe. We speculate that the hemorrhage occurred by rupture of small vessels affected by vasculitis in addition to hypertension caused by increased intracranial pressure. We therefore emphasize the risk of intracerebral hemorrhage at an early stage or during acyclovir treatment, especially during one or two weeks after initiation of the treatment, and the necessity of careful observation during these periods. PMID- 20166531 TI - [Evolution of Egyptian neurosurgery: an overview]. AB - This article describes the evolution of Egyptian neurosurgery. It highlights the experiences of the ancient Egyptians in treatment of the central nervous system diseases. These experiences were documented through their papyrus writings and their drawings over the walls in ancient temples. The aim of this article is not only to search for the roots of neurosurgery in Egypt but also to showcase the present and future status of neurosurgery. Neurosurgery developed as a specialty earlier in Egypt and has led the development of this specialty in Africa and the Middle East. It is worthwhile tracing the history of neurosurgery of past civilizations, ancient medicine, and the work of pioneers. PMID- 20166532 TI - [Clinical standard of neurosurgical disorder (15) parasellar tumor including craniopharyngioma]. PMID- 20166533 TI - [Immunosuppressive therapy update 2010 for ANCA-associated glomerulonephritis and intractable nephrotic syndrome]. PMID- 20166534 TI - [Hot topics in renal physiology]. PMID- 20166536 TI - [Preface: Time to act for the higher impact factor of Clinical and Experimental Nephrology]. PMID- 20166535 TI - [Clinical study on nephrology]. PMID- 20166537 TI - [Brief history of launching Clinical and Experimental Nephrology]. PMID- 20166538 TI - [History of Clinical and Experimental Nephrology from 2002 to 2006]. PMID- 20166539 TI - [Progress of Clinical and Experimental Nephrology (CEN): CEN is increasing its presence in Web of Science]. PMID- 20166540 TI - [Springer Journal's global perspectives and CEN]. PMID- 20166541 TI - [History of Clinical and Experimental Nephrology: afterword]. PMID- 20166542 TI - [Clinico-pathological features and outcome in adult patients with Henoch Schonlein purpura nephritis]. AB - We examined the data of 24 patients with Henoch-Schonlein purpura nephritis (HSPN) over a 5-year follow-up period. Proteinuria, sediment RBC and CRP significantly decreased between the time of diagnosis and the end of the 5-year period. In the steroid usage group (n = 16), proteinuria was significantly higher, and crescent formation was significant higher at the time of diagnosis than in the non-steroid usage group (n = 8). However, there was no significant difference in the decrease in eGFR from the baseline at the end of the 5-year period between the two groups. Furthermore, to clarify the factors influencing the risk of renal function deterioration, we divided the patients into two groups, the (delta eGFR/pre eGFR) <0.25 group (n = 13) and (delta eGFR/pre eGFR) >0.25 group (n = 11), and compared the clinico-pathophysiological characteristics between the two groups. In the (delta eGFR/pre eGFR) >0.25 group, the ratio of glomerular obsolescence at the time of diagnosis was significantly higher than in the (delta eGFR/pre eGFR) <0.25 group. Glomerular obsolescence was identified as an independent risk factor for renal function deterioration. In this study, the prognosis of HSPN was related to glomerular obsolescence rather than to the disease activity. It may be necessary to consider the decrease in nephrons, in accordance with non-immunological glomerular obsolescence, in addition to immunological treatment to clarify the prognosis. PMID- 20166543 TI - [Retardation of hemodialysis by recombinant human erythropoietin in patients with chronic kidney disease]. AB - Renal anemia is a serious complication of chronic kidney disease (CKD) and accelerates its progress. Recombinant human erythropoietin (rHuEPO) therapy not only improves anemia but also has a renoprotective effect. This study aimed to determine whether treatment with rHuEPO can retard the initiation of hemodialysis (HD) in patients with CKD. METHODS: Clinical data of CKD patients who had already been treated with HD were analyzed retrospectively. Twenty-one patients who had received rHuEPO therapy constituted the treated group (EPO(+) group), and twenty one other patients without rHuEPO constituted the non-treated group (EPO(-) group). The study start-point was the day of kidney function deterioration, judged as CKD stage 5. The end-point of the study was the initiation of HD. RESULTS: During the evaluation period, mean values of hemoglobin (Hb) in the EPO(+) group remained lower than those in the EPO(-) group. Survival analysis limited to the two-year period from the beginning of evaluation showed that the renal survival rate of the EPO(+) group was significantly better than that of the EPO(-) group [EPO(+): 42.1% vs. EPO(-): 12.5%, p<0.05]. Duration of renal survival was 29.8 +/- 4.07 months in the EPO(+) group and 19.1 +/- 3.27 months in the EPO(-) group (p<0.05). CONCLUSION: Although the mean values of Hb remained lower in the EPO(+) group than in the EPO(-) group during the observation period, the renal survival rate and duration of renal survival in the EPO(+) group were significantly superior than in the EPO(-) group. The study suggests that rHuEPO exerts a renoprotective effect via a mechanism other than the correction of anemia. PMID- 20166544 TI - [Adult case of severe Henoch-Schonlein purpura associated with steroid-resistant nephrotic syndrome successfully treated with intravenous cyclophosphamide]. AB - Henoch-Schonlein purpura (HSP) is a systemic disorder characterized by small vessel vasculitis with the deposition of IgA immune complexes. Renal involvement is the major cause of morbidity and mortality in patients with HSP. We report here a 37-year-old female patient with HSP nephritis (HSPN) associated with steroid-resistant nephrotic syndrome and renal dysfunction despite conventional therapy. The patient was successfully treated with intravenous cyclophosphamide following treatment with intravenous pulse methylprednisolone and oral prednisolone. The combination therapy resulted in a significant decrease in proteinuria, together with improvement of renal function. The patient finally reached a stage of clinical remission. PMID- 20166545 TI - [Case of IgG4-related tubulointerstitial nephritis showing the progression of renal dysfunction after a cure for autoimmune pancreatitis]. AB - A 78-year-old-man was admitted to our hospital because of renal insufficiency 20 months after the onset of autoimmune pancreatitis. He had cerebral infarction and prostatic hypertrophy as complications. He had been previously diagnosed with autoimmune pancreatitis (AIP). The initial therapy was started with oral prednisolone at the dose of 0.8 mg/kg (40 mg/day). Prednisolone had been tapered off gradually through a one-year period. Four months later from terminating prednisolone, a follow-up CT showed multiple low-density areas in both kidneys without swelling of the pancreas. Furthermore, 4 months later, laboratory findings showed progressive renal insufficiency. On admission, BP was 167/77 mmHg, and the bilateral submaxillary glands were swollen. He did not have pretibial edema. Laboratory findings were as follows. BUN 55.9 mg/dL, Cre 6.17 mg/dL, Amy 65 mg/dL, TP/Alb 9.5/4 g/dL, gamma-gl 43.7%, IgG/IgA/IgM 3,395/112/74 mg/dL, IgG4 1,460 mg/dL, urinary protein 1.38 g/day, and 24 hr-Ccr 11.8 mL/min/1.73 m2. Percutaneous renal needle biopsy was conducted. Light microscopic findings demonstrated tubulointerstitial nephritis (TIN) and membranous change. Immunofluorescent microscopic findings indicated diffuse deposition of IgG2 and IgG4 in the renal interstitium. On the basis of these findings, the condition was diagnosed as IgG4-related tubulointerstitial nephritis. As renal insufficiency was progressing, hemodialysis was started soon after admission and oral prednisolone was also started at the dose of 0.4 mg/kg (20 mg/day). However, improvement of renal function has not been obtained and hemodialysis and prednisolone tapering are still being conducted. This case showed severe tubulointerstitial nephritis requiring hemodialysis after a cure for autoimmune pancreatitis. IgG4-related renal disease rarely needs hemodialysis. This case indicates that the prognosis of IgG4-related systemic disease is not necessarily good and further accumulation of cases is required. PMID- 20166546 TI - [Clinical characteristics of five elderly patients with severe hypokalemia induced by glycyrrhizin derivatives]. AB - Although hypokalemia is a common clinical problem, symptoms generally do not become manifest unless the serum potassium (K) falls rapidly. We encountered five cases with symptomatic severe hypokalemia (K<2.0 mEq/L) hospitalized for the past 15 months at our hospital. We examined the clinical characteristics and treatment of these patients. All five patients were women, and their mean age was 77.8 (73 82)years. They suffered from hypertension. Mean K level at admission was 1.66 (1.4-1.9) mEq/L and HCO3(-) was 48.3 (33.6-56.1) mmol/L. Plasma aldosterone level was low and plasma rennin activity was suppressed. All patients developed progressive muscle weakness with elevated creatinine phosphokinase. Three of the patients had received Chinese medicine which contained licorice, one received glycyrrhizin and the other one had received both. We diagnosed these cases as pseudoaldosteronism induced by glycyrrhizin. With discontinuation of the drugs and intravenous as well as oral K supplementation, serum K were normalized and clinical symptoms improved within 12 days. For one patient who developed cardiac dysfunction, concentrated K solution (230 mEq/L) was infused into the central vein. These findings show that glycyrrhizin ingestion should be kept in mind as a cause of an extreme degree of an hypokalemia, especially in elderly patients. PMID- 20166547 TI - Budding and direct division of adult human erythrocytes in serum-free cultures. AB - This paper documents the budding and division process of human erythrocytes in vitro using time-lapse light microscopy of hanging-drop preparations. The erythrocytes were prepared from normal adult human peripheral blood. Red blood cells showed cytoplasmic budding, segmentation, and direct division with delayed addition of erythropoietin in serum-free Dulbecco's modified Eagle's medium/nutrient mixture F-12 Ham. These observations are thought to be useful for developing model of definitive erythropoiesis and simple expansion of human erythrocytes. PMID- 20166548 TI - The pattern of the arterial supply of the pancreas in anthropoid apes, catarrhine monkeys and platyrrhine monkeys. AB - To get the full understanding of the arterial distribution to the pancreas, the analysis of the distribution of the variety of monkey species would be helpful. In this study, we studied the layout of the pancreatic artery in anthropoids (1 gorilla, 3 chimpanzees and 2 white-handed gibbons), in catarrhine monkeys (1 hamadryas baboon, 2 anubid baboons, 10 savannah monkeys) and in platyrrhine monkeys (6 squirrel monkeys). The pancreas of the monkeys was supplied by the arteries originating from the celiac trunk and/or superior mesenteric artery. There were three patterns in the arterial distribution; (1) the celiac artery supplied the major area of the pancreas. (2) the superior mesenteric artery supplied the major area of the pancreas. (3) the celiac artery supplied the whole pancreas. The pattern of the arterial distribution to the monkey pancreas had a wide variety. The result would be helpful for the elucidation of the development of the vascular distribution in the pancreas. PMID- 20166549 TI - Modulation mechanism of c-Mpl promoter activity in megakaryoblastic cells. AB - Thrombopoietin receptor (c-Mpl) is considered to regulate megakaryocytopoiesis. In this study, we investigated an effect of activation of a protein kinase C (PKC) on c-mpl promoter activity to elucidate the underlying mechanisms of c-mpl gene expression in megakaryoblastic cells. PKC is a member of a family of serine/threonine protein kinases in the cytosol involved in cell growth and differentiation. Phorbol 12-myristate 13-acetate (PMA) is known as PKC activator, significantly enhanced the c-mpl promoter activity and PKC inhibitors (H7, GF109203) suppressed the up-regulation of PMA-induced promoter activity and reduced the steady level of its activity. These results strongly suggest that PKC plays the essential role in the modulation of c-mpl promoter activity of megakaryoblastic cells. PMID- 20166550 TI - Expression of respiratory chain enzyme mRNA and the morphological properties of mitochondria in the masseter muscles of klotho mutant mice. AB - The activity of respiratory chain enzymes in a rat's masseter muscle changes as the animal ages; however, there is little information about the RNA transcript levels of mitochondrial enzymes in klotho mutant mice as they age. We measured the activities of NADH-ferricyanide oxidoreductase and NADH-O2 oxidoreductase, and the RNA transcript levels of NADH dehydrogenase, the mitochondrial isoform of ND1, the nuclear isoforms of the 51 kDa and 75 kDa subunits of Complex I, the nuclear isoform of cytochrome c, and the mitochondrial isoform of beta subunits of ATPase (Complex V). In addition, we measured the RNA transcript levels of catalase (CAT) and superoxide dismutase (SOD), which are associated with antioxidant proteins. Moreover, we measured ATP concentrations using a luciferin luciferase assay, and we determined the amount of cytochrome c associated with mitochondria in both klotho mutant mice and wild-type mice. However, the mRNA levels of cytochrome c and Complex V components, the mRNA levels of CAT, SOD, and apoptosis-inducing factor (Aifm), and the protein level of cytochrome c remained constant as klotho mutant mice aged from 5 weeks to 7 weeks. In wild-type mice, these components (except for those of Complex I) increased over time. NADH ferricyanide oxidoreductase and NADH-O2 oxidoreductase activities decreased in klotho mutant mice as they aged from 5 weeks to 7 weeks. A few large mitochondria were scattered between myofibrils, and 7-week-old klotho mutant mice displayed an increased number of irregular mitochondria with fewer cristae. Our results indicate that the klotho protein plays a role in the diminished functional adaptability of enzymes in the masseter muscle of klotho mutant mice throughout the aging process. PMID- 20166552 TI - Understanding the retention mechanism in reversed-phase liquid chromatography: insights from molecular simulation. PMID- 20166553 TI - Thermodynamic modeling of chromatographic separation. PMID- 20166551 TI - Expression of myosin heavy chain isoforms in the postnatal mouse masseter muscle. AB - We investigated the properties of the masseter muscle in mice from five to seven weeks of age. Myosin heavy chain (MyHC) isoforms were measured in the masseter muscle. The three types of muscle fibers (Type I, strong reaction; Type IIA, intermediate reaction; and Type IIB, weak reaction) were all present in the masseter muscle in five-weeks-old mice and seven-weeks-old mice, the three types could be clearly distinguished by their enzyme activity. The percentage of Type IIB fibers (above 50%) was the highest among all fiber types both 5- and 7-weeks old mice. The mRNA levels for myosin slow and myosin IIb increased significantly between 5 and 7 weeks. These observations suggest that muscle fiber size, muscle fiber types and mRNA levels of the MyHC isoforms all contribute to the diminished functional adaptability of enzyme activity in the masseter muscle. PMID- 20166554 TI - Ultra-performance liquid chromatography technology and applications. PMID- 20166556 TI - Characterization of stationary phases in supercritical fluid chromatography with the solvation parameter model. PMID- 20166555 TI - Biointeraction affinity chromatography: general principles and recent developments. PMID- 20166557 TI - Silica hydride--chemistry and applications. PMID- 20166558 TI - Multidimensional gas chromatography. PMID- 20166559 TI - Sample preparation for chromatographic analysis of environmental samples. PMID- 20166560 TI - Sample preparation for gas chromatography using solid-phase microextraction with derivatization. AB - The development of SPME over the past 20 years, and the more recent wide availability of automated SPME systems, has generated renewed interest in derivatization with gas chromatography for the analysis of highly polar or labile analytes. By using an SPME fiber as the extracting phase, the derivatization process is straightforward and readily automated. From anecdotal examination of the literature, it appears that the fiber may offer benefits over traditional liquid phase reactions in that control over the selectivity of the reaction for the desired product and fewer interfering byproducts may be more readily achieved. Nearly all authors have reported that SPME-based derivatization methods provide equivalent or superior analytical performance to their traditional counterparts. While attention to derivatization in general has waned among gas chromatographers, the advent of procedures in combination with SPME makes derivatization again attractive and worthy of consideration in analytical method development. PMID- 20166561 TI - Drugging the "undruggable". PMID- 20166563 TI - Protein transport in and out of the endoplasmic reticulum. PMID- 20166562 TI - Basal bodies: their roles in generating asymmetry. PMID- 20166564 TI - Signaling networks that control synapse development and cognitive function. PMID- 20166565 TI - Cilia and Hedgehog signaling in the mouse embryo. PMID- 20166566 TI - Derivation of adult stem cells during embryogenesis. PMID- 20166567 TI - Tracking the road from inflammation to cancer: the critical role of IkappaB kinase (IKK). PMID- 20166568 TI - Pens. PMID- 20166569 TI - What is your diagnosis? Tinea nigra. PMID- 20166570 TI - Eruptive vellus hair cysts: report of a pediatric case with partial response to calcipotriene therapy. AB - Eruptive vellus hair cysts (EVHCs) are characterized by asymptomatic, follicular, comedonelike papules usually located on the anterior chest and abdomen. We present a pediatric case of EVHC associated with attention deficit hyperactivity disorder that partially responded to calcipotriene cream within 2 months. Our aim is to refamiliarize clinicians with a common albeit frequently unrecognized disorder of vellus hair follicles. PMID- 20166571 TI - Necrolytic acral erythema: an expanding spectrum. AB - Hepatitis C virus (HCV) infection is the most common chronic blood-borne viral infection in the United States. Well-described cutaneous manifestations of HCV infection include polyarteritis nodosa, porphyria cutanea tarda, type II cryoglobulinemia-associated vasculitis, pruritus, erythema nodosum, urticaria and urticarial vasculitis, lichen planus, and erythema multiforme. First described in 1996, necrolytic acral erythema (NAE) is now recognized as a cutaneous acral eruption uniquely associated with HCV infection. Most patients present with chronic, acral, erythematous, and psoriasiform lesions. Acute presentations of NAE are rare and patients may present with atypical clinical features; in these cases, suspicion for HCV infection may be delayed for weeks to months until more classic chronic lesions develop. In many cases, NAE presents before the patient has been diagnosed with HCV infection, which allows dermatologists the unique opportunity to suspect and diagnose HCV infection based on skin findings alone. PMID- 20166572 TI - Syphilitic palmoplantar keratoderma and ocular disease: a rare combination in an HIV-positive patient. AB - Approximately 349 million individuals worldwide are actively infected with syphilis. The incidence of syphilis in North America and Europe is low but has been rising in recent years. The rate of concomitant infection with human immunodeficiency virus (HIV) and syphilis also has been increasing. Concomitant infection with HIV can cause syphilis to have atypical characteristics. These atypical findings can involve the skin as well as organs that rarely are affected in HIV-negative individuals such as the eyes. We present a case of syphilis causing palmoplantar keratoderma and ocular disease in a patient with HIV infection, and discuss the differences in diagnosis and treatment of patients with both diseases. PMID- 20166573 TI - Pulmonary cutaneous metastasis: a case report and review of common cutaneous metastases. AB - The literature on cutaneous metastatic disease can be difficult to interpret because of inconsistent study design and analysis among authors. Furthermore, one should be careful when reviewing the statistics in the literature, as reported patient populations tend to vary and are not representative of the whole population. However, certain trends are notable and should be reported. Diagnosis of cutaneous metastatic disease carries a grave prognosis. We describe a patient with pulmonary cutaneous metastasis and provide a review of the literature on nonmelanomatous solid tumor malignancies that most commonly have cutaneous metastases. The review will focus on epidemiology, clinical presentation, histology and immunohistochemical staining, and prognosis and management. The most common cutaneous metastasizing carcinomas--breast, lung, and colorectal cancer--also are discussed. PMID- 20166574 TI - Adalimumab in the management of cutaneous and oral lichen planus. AB - Lichen planus (LP) is a common, chronic, inflammatory dermatosis that may involve the skin as well as oral and genital mucosa. Characterized by distinctive purplish papules often featuring white reticular scale, LP commonly is resistant to treatment. My patient presented with extensive, violaceous, and lacelike whitish lesions on the distal extremities, including the hands and feet, and the vulva. Approximately 10% to 12% of her body surface area (BSA) was involved, and her condition became progressively worse over time, with thick plaques developing on the buccal mucosa and tongue. After several conventional therapies failed, the patient underwent treatment with adalimumab, a tumor necrosis factor (TNF) antagonist. An almost clear response was noted by week 6, and the patient's lesions remained almost fully resolved after week 22. Additional studies are warranted to investigate the efficacy and safety of adalimumab for the treatment of LP. PMID- 20166575 TI - New column liquid and gas chromatography instruments. PMID- 20166576 TI - Single-laboratory validation of an NMR method for the determination of aloe vera polysaccharide in pharmaceutical formulations. AB - This report presents a single-laboratory-validated NMR method for determining the quantity of aloe vera polysaccharide in product formulations. The ratio of signal intensities of the acetyl methyl protons to methyl protons of an internal reference varied linearly with concentration (r2 > 0.99) with a lower LOQ of 0.2 g/100 mL for two commercial aloe polysaccharide standards, Acemannan Hydrogel (AH) and Immuno-10 (I-10). The assay was used to quantify these standards in two nonacetylated polysaccharide matrices, dextrin and arabinogalactan, and in a pharmaceutical product. The concentrations of AH in samples containing the polysaccharide matrices agreed within 7% of values determined on the basis of weight and showed within- and between-run RSD values of < 3.5%. The assay of I-10 in the pharmaceutical product was within 7% of the expected values over a range from 50 to 125% of the targeted I-10 concentration, with a between-run RSD of < 7%. The assay showed no interference from other added polysaccharides or from other components of the pharmaceutical formulation and was independent of the molecular size distribution of the aloe polysaccharide present. The NMR assay can be used to validate aloe polysaccharide contained in a product and to follow any chemical degradation that may occur over time. PMID- 20166577 TI - Selective determination of aconitine in polyherbal oils containing Aconitum chasmanthum using high-performance thin-layer chromatography. AB - Many polyherbal oil formulations in traditional systems of medicine contain aconite root. This paper reports the development and validation of a simple, rapid, and sensitive HPTLC method for identification and quantification of aconitine from polyherbal oil formulations. Chromatography of methanolic extract of these formulations was performed on silica gel 60F254 aluminum-backed HPTLC plates with a 0.2 mm layer thickness. The plates were developed up to 85 mm with the binary mobile phase ethyl acetate-ethanol (7.5 + 2.5, v/v) at 22 +/- 2 degrees C with 20 min of chamber saturation. The system produced a compact band of the marker aconitine at an R(f) value of 0.33 that was quantified at its maximum absorbance of 238 nm. The LOD and LOQ values were found to be 20 and 70 ng/band, respectively. The linearity with respect to peak area was in the range of 300 to 1800 ng/band with an r of 0.9991. Polyherbal oil formulations were analyzed with reasonable accuracy, and no matrix interference was observed. The developed HPTLC method is accurate, precise, and cost-effective, and can be used for marker-based QA of polyherbal oil formulations containing Aconitum chasmanthum as one of the active ingredients. PMID- 20166578 TI - Stability-indicating simultaneous determination of paracetamol and three of its related substances using a direct GC/MS method. AB - A simple, direct, and selective stability-indicating GC/MS procedure was developed for the simultaneous determination of paracetamol (PR) and three of its related substances: 4-aminophenol (4-AP), acetanilide (AD), and 4' chloroacetanilide (4-CA). The method involved resolution of the underivatized compounds using a 100% dimethylpolysiloxane (Rtx-1) column, and MS detection was carried out in the electron-impact mode. The four compounds were completely resolved in less than 11 min. The fragmentation pathways for the four compounds were described, and the structures of the major fragment ions peaks were proposed. Quantification of the analytes was based on measuring their peak areas. The reliability and analytical performance of the proposed method including linearity, range, precision, accuracy, and detection and quantification limits were statistically validated. Calibration curves were linear over the ranges 75 500, 25-350, 25-350, and 25-350 microg/mL for PR, 4-AP, AD, and 4-CA, respectively. The proposed method was successfully applied for the determination of PR and its related substances in laboratory-prepared mixtures of different proportions. Also, it was applied for the assay of PR in several commercially available pharmaceutical formulations with recoveries of 98.95-100.76%. PMID- 20166580 TI - Reversed-phase liquid chromatographic determination of two manufacturing intermediates in D&C Red No. 34 and its lakes. AB - A reversed-phase LC method was developed to determine two manufacturing intermediates in the monosulfo monoazo color additive D&C Red No. 34 and its lakes. The analytes are 2-amino-1-naphthalenesulfonic acid (Tobias acid) and 3 hydroxy-2-naphthalenecarboxylic acid (3-hydroxy-2-naphthoic acid). This method can be used for batch certification of the color additives by the U.S. Food and Drug Administration to ensure that each lot meets published specifications for coloring drugs and cosmetics. The new method uses lithium oxalate in methanol water to dissolve the color additives for analysis. The analytes were identified by comparison of their LC retention times and UV absorption spectra with those of standards. Peak area calibrations were generally linear (R > 0.999) and recoveries were 105% for Tobias acid and 103% for 3-hydroxy-2-naphthoic acid. The limits of determination (LOD) were 0.01% for Tobias acid and 0.03% for 3-hydroxy 2-naphthoic acid. The RSDs at the specification levels were 0.9% for Tobias acid and 3.2% for 3-hydroxy-2-naphthoic acid. Survey analyses of 14 samples of certified D&C Red No. 34 straight colors and lakes from six domestic and foreign manufacturers yielded results for Tobias acid that generally agreed with results previously obtained by using a gravity elution column chromatographic method. Nine of the results for 3-hydroxy-2-naphthoic acid were 2 to 5 times higher than the results obtained using the column chromatographic method. We attribute the lower accuracy of the column chromatographic method to incomplete solubility of the samples using the method conditions and difficulty with interpreting the UV spectrophotometric results. PMID- 20166579 TI - Membrane electrodes for the determination of pyridostigmine bromide. AB - Two pyridostigmine bromide (PB) selective electrodes were investigated with 2 nitrophenyl octyl ether as a plasticizer in a polymeric matrix of carboxylated polyvinyl chloride (PVC-COOH), based on the interaction between the drug solution and the dissociated COOH groups in the PVC-COOH. One of the sensors was fabricated by using PVC-COOH only as anionic site without incorporation of an ionophore (sensor 1). The second sensor was constructed by using 2-hydroxy propyl beta-cyclodextrin as an ionophore (sensor 2). Linear responses of PB within a concentration range of 10(-3)-10(-2) and 10(-5)-10(-2) M, with slopes of 51.9 +/- 0.31 and 56.7 +/- 0.40 mV/decade over pH range of 5-10 were obtained using sensors 2 and 1, respectively. The proposed method displayed useful analytical characteristics for determination of PB in tablets with average recoveries of 100.22 +/- 0.62, and 100.15 +/- 0.72, and in plasma with average recoveries of 99.14 +/- 1.19 and 99.79 +/- 0.72, for sensors 2 and 1, respectively. The utility of 2-hydroxy propyl beta-cyclodextrin as an ionophore has a significant influence on increasing both membrane sensitivity and selectivity of sensor 2 in comparison with sensor 1. The methods were also used to determine the intact drug in the presence of its degradate, and thus could be used as stability-indicating methods. The results obtained by the proposed procedures were statistically analyzed and compared with those obtained by the U.S. Pharmacopeia method. No significant difference for either accuracy or precision was observed. PMID- 20166581 TI - Determination of individual homologues and total content of benzalkonium chloride by reversed-phase high-performance liquid chromatography using a short butyl column. AB - Benzalkonium chloride (a mixture of alkylbenzyldimethylammonium chlorides that usually contains C-10, C-12, C-14, and C-16 homologues), commonly known as BKC, is used as a bacteriostatic agent in many household, food, and drug products. In this paper, we report a simple, rapid, robust, and stability-indicating reversed phase HPLC method using a short butyl (C4) column for the simultaneous determination of each individual homologue content, as well as the total concentration of individual homologues in commercial bulk raw material batches of BKC samples. The chromatographic separation was performed on a 5 cm ACE C4 column with mobile phase consisting of water, acetonitrile, and potassium chloride. Even though using a short column can potentially cause some challenges to resolving certain critical pairs of peaks, we have successfully separated all of the analyte peaks (including those from stressed, degraded products) on a short column using an optimal mobile phase. PMID- 20166582 TI - Assessment of suitability of magnetic beads for purification of rat plasma in proteomic analyses by matrix-assisted laser desorption ionization-time-of-flight MS. AB - Plasma is a complex matrix and has to be clarified or fractionated to obtain informative MS data. Although there are a number of prefractionation methods to clean up complex biological matrixes before proteomic analysis, these methods require large sample volumes and are costly and time-consuming. Alternatively, recently introduced magnetic beads (MB) appear to be attractive in overcoming these difficulties. Therefore, we were interested in investigating the applicability of MB in the clarification of rat plasma samples for proteome analyses. For this purpose, we used complementary supports, such as hydrophobic interaction chromatography-based MB (MB-C18) and weak cation-exchange chromatography-based MB (MB-WCX). MB-based fractionated samples were either spotted directly or underwent tryptic digestion before matrix-assisted laser desorption ionization (MALDI) spotting. Samples from both MB separation techniques gave clean and well-resolved MALDI-time-of-flight MS spectra in the low molecular mass range of 1-10 kDa with alpha-cyano-4-hydroxycinnamic acid as the matrix. Both techniques gave approximately 300 analyte peaks in this mass range. Our results showed that both MB-based separation procedures gave complementary mass spectral information. This approach provided information on the identity of a number of less-abundant and more-abundant proteins in plasma. Our findings suggest that this MB-based proteomic approach can be valuable in conducting faster screening of plasma samples for protein profiling. PMID- 20166583 TI - Determination of linezolid in human breast milk by high-performance liquid chromatography with ultraviolet detection. AB - A rapid and simple HPLC method was developed for the determination of linezolid (LNZ) in human breast milk after a simple protein precipitation with methanol. The chromatographic separation was achieved on a C18 column (5 microm, 250 x 4.6 mm id) using a mobile phase of acetonitrile-10 mM acetic acid (25:75, v/v) at a flow rate of 1 mL/min. The LNZ peak was measured by photodiode array detection at 250 nm. The calibration graph was linear over the range of 0.5-20.0 microg/mL. The limits of detection and quantitation were found to be 0.1 and 0.5 microg/mL, respectively. The precision of the assay and the recovery of LNZ from breast milk at three different concentrations were assessed. The intraday and interday RSD values were found to be < 5%. The mean absolute recovery was 85.33%. The developed method was successfully applied to the determination of LNZ in breast milk obtained from the breastfeeding mother after oral administration of LNZ. PMID- 20166584 TI - Determination of atropine enantiomers in ophthalmic solutions by liquid chromatography using a Chiral AGP column. AB - Many therapeutic agents are commercialized under their racemic form. The enantiomers can show differences in the pharmacokinetic and pharmacodynamic profile. The use of a pure enantiomer in pharmaceutical formulations may result in a better therapeutic index and fewer adverse effects. Atropine, an alkaloid of Atropa belladonna, is a racemic mixture of l-hyoscyamine and d-hyoscyamine. It is widely used to dilate the pupil. To quantify these enantiomers in ophthalmic solutions, an HPLC method was developed and validated using a Chiral AGP column at 20 degrees C. The mobile phase consisted of a buffered phosphate solution (containing 10 mM 1-octanesulfonic acid sodium salt and 7.5 mM triethylamine, adjusted to pH 7.0 with orthophosphoric acid) and acetonitrile (99 + 1, v/v). The flow rate was 0.6 ml/min, with UV detection at 205 nm. In the concentration range of 14.0-26.0 microg/mL, the method was found to be linear (r > 0.9999), accurate (with recovery of 100.1-100.5%), and precise (RSD system < or = 0.6%; RSD intraday < or = 1.1%; RSD interday < or = 0.9%). The method was specific, and the standard and sample solutions were stable for up to 72 h. The factorial design assures robustness with a variation of +/- 10% in the mobile phase components and 2 degrees C of column temperature. The complete validation, including stress testing and factorial design, was studied and is presented in this research. PMID- 20166585 TI - Development of an ultraviolet spectrophotometric method for the determination of ceftiofur sodium powder. AB - A UV spectrophotometric method was developed for determination of ceftiofur sodium in the drug substance and sterile powder for injection. The method validation, which yielded good results, included evaluation of the range, linearity, intra- and interday precision, accuracy, recovery, specificity, robustness, LOQ, and LOD. The UV spectrophotometric determinations were performed at 292 nm. Good linearity was obtained between 2.5 and 20.0 microg/mL. A prospective validation showed that the method is linear (r = 0.9999) and precise, with RSD values of 0.3% for product A and 0.4% for product B. The intra- and interday precision values were < 2% for all samples analyzed. Comparison of UV spectrophotometry and LC by analysis of variance and Student's t-test showed no significant difference between methodologies. Moreover, the accuracy and precision obtained with the UV method correlated well with the values obtained with the LC method, and this correlation suggests that UV spectrophotometric analysis can be an inexpensive, reliable, and less time-consuming alternative to chromatographic analysis. The results demonstrated the validity of the proposed method as a simple and useful alternative for the determination of ceftiofur in routine QC analyses. PMID- 20166586 TI - Microdetermination of emtricitabine in human plasma by liquid chromatography/tandem mass spectrometry. AB - A simple, precise, and rapid LC/MS/MS method was developed and validated for the quantification of emtricitabine in human plasma using lamivudine as the internal standard (IS). The method involves liquid-liquid extraction of emtricitabine and the IS in diethyl ether-ethyl acetate (50 + 50, v/v) from 0.1 mL human plasma. A Kromasil C18 (150 x 4.6 mm, 5 microm particle size) analytical column was used for the chromatographic separation under isocratic conditions. The parent --> product ion transitions for emtricitabine (m/z 248.0 --> 130.0) and the IS (m/z 230.1 --> 112.0) were monitored on a triple-quadrupole mass spectrometer, operated in the multiple reaction monitoring positive ion mode. The method was validated over the concentration range of 29.2-3110 ng/mL for emtricitabine, with a total chromatographic run time of 1.5 min. Acceptable precision and accuracy were obtained for the concentrations used to prepare the standard curves. The applicability of the method was demonstrated by a pharmacokinetic study conducted with 43 healthy volunteers who were administered a capsule formulation containing 200 mg emtricitabine. PMID- 20166587 TI - Liquid chromatographic post-column oxidation method for analysis of paralytic shellfish toxins in mussels, clams, scallops, and oysters: single-laboratory validation. AB - A single-laboratory validation study was conducted for the LC post-column oxidation analysis of paralytic shellfish toxins (PST): saxitoxin (STX); neosaxitoxin (NEO); gonyautoxins (GTX) 1-5; decarbamoyl gonyautoxins (dcGTX) 2 and 3; decarbamoyl saxitoxin (dcSTX); and N-sulfocarbamoyl-gonyautoxin-2 and 3 (C1 and C2) in mussels (Mytilus edulis), soft shell clams (Mya arenaria), scallops (Placopectin magellanicus), and oysters (Crassostrea virginicus). The instrumental technique was developed for the analysis of PST in shellfish as an alternative to the precolumn oxidation method, AOAC Official Method 2005.06, and a replacement for the current AOAC biological method 959.08. The method used reversed-phase LC with post-column oxidation and fluorescence detection. Test materials for method recovery were prepared by fortification of blank material with a cocktail of PST. Materials used to determine method repeatability and intermediate precision were prepared by blending blank material with naturally incurred material. The target total toxicity levels evaluated in the study were 0.40, 0.80, and 1.60 mg STX x diHCl equivalents per kilogram [(eq/kg) 1%, 1, and 2 times the regulatory limit]. Linearity, recovery, and within-laboratory precision parameters of the method were evaluated. Correlation coefficients of the calibration curves for all toxins studied were > 0.99. Total toxin recovery ranged from 94 to 106% at the three levels of interest. Repeatability and intermediate precision RSD ranged from 2 to 7% and 2 to 8%, respectively. The method LOD and LOQ (assuming the presence of all toxins) were determined to be equivalent to 0.18 and 0.39 mg STX x diHCl eq/kg. The method is intended for a regulatory framework and will be submitted for an AOAC collaborative study. PMID- 20166589 TI - A square-wave adsorptive stripping voltammetric method for determination of fast green dye. AB - Square-wave adsorptive stripping voltammetric (SW-AdSV) determinations of trace concentrations of the coloring agent fast green were described. The analytical methodology used was based on the adsorptive preconcentration of the dye on the hanging mercury drop electrode, and then a negative sweep was initiated. In pH 10 carbonate supporting electrolyte, fast green gave a well-defined and sensitive SW AdSV peak at -1220 mV. The electroanalytical determination of this dye was found to be optimized in carbonate buffer (pH 10) with the following experimental conditions: accumulation time (120 s); accumulation potential (-0.8 V); scan rate (800 mV/s); pulse amplitude (90 mV); frequency (90 Hz); surface area of the working electrode (0.6 mm2); and the convection rate (2000 rpm). Under these optimized conditions, the AdSV peak current was proportional over the concentration range 2 x 10(-8) -6 x 10(-7) M (r = 0.999), with an LOD of 1.63 x 10(-10) M (0.132 ppb). This analytical approach possessed more enhanced sensitivity than conventional chromatography or spectrophotometry, and was simple and quick. The precision of the method in terms of RSD was 0.17%, whereas the accuracy was evaluated via the mean recovery of 99.6%. Possible interferences by several substances usually present as food additive azo dyes (E110, E102, E123, and E129), natural and artificial sweeteners, and antioxidants were also investigated. Applicability of the developed electroanalysis method was illustrated via the determination of fast green in ice cream and soft drink samples. PMID- 20166588 TI - Single-laboratory validation of the microplate receptor binding assay for paralytic shellfish toxins in shellfish. AB - A single-laboratory validation (SLV) study was conducted for the microplate receptor binding assay (RBA) for paralytic shellfish poisoning (PSP) toxins in shellfish. The basis of the assay is the competition between [3H]saxitoxin (STX) and STX in a standard or sample for binding to the voltage dependent sodium channel. A calibration curve is generated by the addition of 0.01-1000 nM STX, which results in the concentration dependent decrease in [3H]STX-receptor complexes formed and serves to quantify STX in unknown samples. This study established the LOQ, linearity, recovery, accuracy, and precision of the assay for determining PSP toxicity in shellfish extracts, as performed by a single analyst on multiple days. The standard curve obtained on 5 independent days resulted in a half-maximal inhibition (IC50) of 2.3 nM STX +/- 0.3 (RSD = 10.8%) with a slope of 0.96 +/- 0.06 (RSD = 6.3%) and a dynamic range of 1.2-10.0 nM. The LOQ was 5.3 microg STX equivalents/100 g shellfish. Linearity, established by quantification of three levels of purified STX (1.5, 3, and 6 nM), yielded an r2 of 0.97. Recovery from mussels spiked with three levels (40, 80, and 120 microg STX/100 g) averaged 121%. Repeatability (RSD(r)), determined on six naturally contaminated shellfish samples on 5 independent days, was 17.7%. A method comparison with the AOAC mouse bioassay yielded r2 = 0.98 (slope = 1.29) in the SLV study. The effects of the extraction method on RBA-based toxicity values were assessed on shellfish extracted for PSP toxins using the AOAC mouse bioassay method (0.1 M HCI) compared to that for the precolumn oxidation HPLC method (0.1% acetic acid). The two extraction methods showed linear correlation (r2 = 0.99), with the HCl extraction method yielding slightly higher toxicity values (slope = 1.23). A similar relationship was observed between HPLC quantification of the HCI and acetic acid-extracted samples (r2 = 0.98, slope 1.19). The RBA also had excellent linear correlation with HPLC analyses (r2 = 0.98 for HCl, r2 = 0.99 for acetic acid), but gave somewhat higher values than HPLC using either extraction method (slope = 1.39 for HCl extracts, slope = 1.32 for acetic acid). Overall, the excellent linear correlations with the both mouse bioassay and HPLC method and sufficient interassay repeatability suggest that the RBA can be effective as a high throughput screen for estimating PSP toxicity in shellfish. PMID- 20166590 TI - Determination of total iodine in food samples using inductively coupled plasma mass spectrometry. AB - A method was developed and validated for the extraction and determination of total iodine (I) in food composite samples, representing different foods available on the Canadian market, by inductively coupled plasma-mass spectrometry (ICP-MS). Prior to analysis, samples were digested in a closed microwave system using a mixture of nitric acid and perchloric acid. The detection limit for iodine determination was 29 nglg and precisions of 10 and 1.3% were obtained for 10 replicate measurements of 100 and 1000 ng/g standards, respectively. The method was validated using Certified Reference Materials and spike recovery measurements in food samples and was applied for the determination of iodine in a variety of food composite samples from the Canadian Total Diet Study. The high sample throughput of ICP-MS makes the method suitable for analysis of large numbers of food samples with varying matrixes, such as for Total Diet Studies. PMID- 20166591 TI - Measurement of water-soluble B vitamins in infant formula by liquid chromatography/tandem mass spectrometry. AB - A method has been developed for the simultaneous measurement of multiple B vitamins (i.e., B1, B2, B3, B5, and B6) in infant formulas by LC-MSIMS. The vitamins were extracted with acidic solvent, followed by protein precipitation at a pH range of 4.5 to 5.5, and filtered. This simplified procedure eliminates many of the potential sources of laboratory error and facilitates rapid and efficient analysis. As is common in most cases, isotope internal standards were added to account for variations in sample preparation, as well as changes in MS measurement. In this method, isotope-labeled internal standards of B1, B3, B5, and B6 were used. The factors affecting analytical performance were investigated and optimized. In addition, the stability of these vitamins in the extraction solution was investigated. An acidic condition (5 mM HCl) was applied to successfully stabilize B1, which had shown a decrease in signal when other solvents were used. The quantitative extraction and good stability allowed isotope standards to be added to the filtered sample solution, instead of to the extraction solvent. The addition of the isotope to the small portion of the filtered sample solution significantly reduces cost. A comprehensive evaluation of the analysis of the standard reference material and good spike recovery of the vitamins (100 +/- 6%) demonstrates the accuracy of the method. The results for commercially available infant formula samples were also compared with those obtained using the current microbiological method. PMID- 20166592 TI - GMOtrack: generator of cost-effective GMO testing strategies. AB - Commercialization of numerous genetically modified organisms (GMOs) has already been approved worldwide, and several additional GMOs are in the approval process. Many countries have adopted legislation to deal with GMO-related issues such as food safety, environmental concerns, and consumers' right of choice, making GMO traceability a necessity. The growing extent of GMO testing makes it important to study optimal GMO detection and identification strategies. This paper formally defines the problem of routine laboratory-level GMO tracking as a cost optimization problem, thus proposing a shift from "the same strategy for all samples" to "sample-centered GMO testing strategies." An algorithm (GMOtrack) for finding optimal two-phase (screening-identification) testing strategies is proposed. The advantages of cost optimization with increasing GMO presence on the market are demonstrated, showing that optimization approaches to analytic GMO traceability can result in major cost reductions. The optimal testing strategies are laboratory-dependent, as the costs depend on prior probabilities of local GMO presence, which are exemplified on food and feed samples. The proposed GMOtrack approach, publicly available under the terms of the General Public License, can be extended to other domains where complex testing is involved, such as safety and quality assurance in the food supply chain. PMID- 20166593 TI - 13C nuclear magnetic resonance spectroscopic detection of the adulteration of extra virgin olive oils extracted from different cultivars with cold-pressed hazelnut oil. AB - 13C NMR spectroscopy was applied to detect the adulteration of olive oils with hazelnut oil. Considering that the linolenate chain and the squalene hydrocarbon were absent in hazelnut oil, unlike olive oil, a 13C NMR spectroscopy method was developed to measure in addition to the triglyceride normal chains (i.e., saturated, oleate, and linoleate chains), the resonances of the linolenate chain and of squalene hydrocarbon. Acyl chain and squalene resonances highly discriminated olive oil samples by cultivars. Nevertheless, the "hazelnut oil percentage factor" prevailed over the "cultivar factor," thus correctly classifying 86% of the authentic and adulterated olive oil samples according to the hazelnut oil percentages. In particular, 85.7, 73.7, and 100.0% of the authentic olive oil samples, and the samples adulterated with 5 and 20% of hazelnut oil, were correctly classified through cross-validation. PMID- 20166594 TI - Checking the validity of the harvesting and disaggregating steps in laboratory tests of surface disinfectants. AB - A chemical disinfectant against surface-associated bacteria typically uses carriers (e.g., glass disks) that are purposely contaminated with bacteria prior to disinfection. After disinfection, the bacteria are harvested by mechanically separating them from the carrier surface to form a suspension of cells in a dilution tube. Bacterial clumps in the tube are disaggregated using mechanical or chemical techniques, thereby creating a well-mixed suspension of single cells suitable for enumeration. Efficacy is quantified by comparing the viable cell count for a disinfected carrier to the viable cell count for sham-disinfected (control) carrier. A test is said to be biased (invalid) if the observed efficacy measure is systematically higher or lower than the true efficacy. It is shown here for the first time that the bias attributable to the harvesting and disaggregating steps of a disinfectant test can be measured. For some conventional biofilm harvesting and disaggregating techniques, laboratory checks showed either negligible bias or important bias, depending on the disinfectant. Quantitative bias checks on the harvesting and disaggregating steps are prudent for each combination of carrier material, microorganism, and disinfectant. The quantitative results should be augmented by microscopic examination of harvested disinfected and control carriers and of the disaggregated suspensions. PMID- 20166595 TI - Estimation of the POD function and the LOD of a qualitative microbiological measurement method. AB - Qualitative microbiological measurement methods in which the measurement results are either 0 (microorganism not detected) or 1 (microorganism detected) are discussed. The performance of such a measurement method is described by its probability of detection as a function of the contamination (CFU/g or CFU/mL) of the test material, or by the LOD(p), i.e., the contamination that is detected (measurement result 1) with a specified probability p. A complementary log-log model was used to statistically estimate these performance characteristics. An intralaboratory experiment for the detection of Listeria monocytogenes in various food matrixes illustrates the method. The estimate of LOD50% is compared with the Spearman-Kaerber method. PMID- 20166596 TI - Characterization of hapten-protein conjugates: antibody generation and immunoassay development for chlorophenoxyacetic acid pesticides. AB - The generation of specific and sensitive antibodies against small molecules is greatly dependent upon the characteristics of the hapten-protein conjugates. In this study, we report a new fluorescence-based method for the characterization of hapten-protein conjugates. The method is based on an effect promoted by hapten protein conjugation density upon the fluorescence intensity of the intrinsic tryptophan chromophore molecules of the protein. The proposed methodology is applied to quantify the hapten-protein conjugation density for two different chlorophenoxyacetic acid pesticides, 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4-dichlorophenoxybutyric acid (2,4-DB), coupled to carrier protein. Highly sensitive anti-2,4-D and anti-2,4-DB antibodies were obtained using these well characterized hapten-protein conjugates. The generated antibodies were used in an immunoassay format demonstrating inhibitory concentration (IC50) values equal to 30 and 7 ng/mL for 2,4-D and 2,4-DB, respectively. Linearity was observed in the concentration range between 0.1-500 nglmL with LODs around 4 and 3 ng/mL for 2,4 D and 2,4-DB, respectively, in standard water samples. The proposed method was successfully applied for the determination of the extent of hapten-protein conjugation to produce specific antibodies for immunoassay development against pesticides. PMID- 20166597 TI - Levels of bisphenol A diglycidyl ether (BADGE) and bisphenol F diglycidyl ether (BFDGE) in canned liquid infant formula products in Canada and dietary intake estimates. AB - A method based on solid-phase extraction followed by HPLC analysis with fluorescence detection was developed for the determination of bisphenol A diglycidyl ether (BADGE) and bisphenol F diglycidyl ether (BFDGE) in liquid infant formula. In this method, instead of trying to isolate and measure each individual form of the molecules, hydrolysis of BADGE, BFDGE, BADGE x H2O, and BFDGE x H2O was forced to completion to their stable forms, BADGE x 2H2O and BFDGE x 2H2O, before extraction. The method LODs were 2.0 ng/g for BADGE and 3.0 ng/g for BFDGE. Extraction recoveries were 61-91% for BADGE, and 55-82% for BFDGE over the concentration range of 10 to 50 ng/g. The method was used to analyze samples of 21 canned liquid infant formula products for BADGE and BFDGE. BADGE was detected in samples of all products at levels ranging from as low as 2.4 ng/g to as high as 262 ng/g. BFDGE was detected in only one product (40 ng/g), and this product also had the highest BADGE level (262 ng/g). HPLC/MS/MS with a similar LOD was also used to confirm the results. The probable daily intakes (PDI) of BADGE and BFDGE due to consumption of canned liquid infant formula were estimated for infants from premature to 12-18 months of age. The maximum PDI of BADGE was 22 microg/kg body weight/day for the 12-18 months old with the maximum formula intake. The maximum PDI of BFDGE was < 3.4 microg/kg body weight/day. PMID- 20166599 TI - Simultaneous spectrophotometric determination of benzoic acid, sorbic acid, and ascorbic acid using a net analyte signal-based method. AB - The net analyte preprocessing/classical least-squares (NAP/CLS) method is a simple chemometric method that has been used for the simultaneous spectrophotometric determination of benzoic acid, sorbic acid, and ascorbic acid. The obtained results indicated that the performances of the NAP/CLS and partial least-squares methods were almost identical. The net analyte signal (NAS) concept was also used to calculate multivariate analytical figures of merit, such as LOD, selectivity, and sensitivity. Wavelength selection was applied based on the concept of NAS regression, and improved the method performance in samples containing nonmodeled interferences. The method afforded recoveries in the range of 98-105%. The proposed method was successfully applied to determination of the analytes in an Iranian soft drink. PMID- 20166598 TI - Simultaneous screening and target analytical approach by gas chromatography quadrupole-mass spectrometry for pesticide residues in fruits and vegetables. AB - A full-scan GC/quadrupole/MS method has been developed to perform large-scale screenings of pesticides and simultaneous quantification of 95 target compounds in a single run of 21 min. The screening method was performed by using a deconvolution of the spectrum of the full-scan data files acquired under a retention time locked method. The identification performance of the screening method was evaluated in eight different food matrixes at three different concentrations. The system was equipped with a programmable temperature vaporizing inlet, allowing 10 microL injections. The LOQ in the full-scan mode and linearity were studied for four different matrixes. Correlation coefficients > 0.99 were achieved in all cases, and the LOD was < 20 microg/kg for 80% of the studied pesticides. Maintenance of the system was reduced by the use of a QuickSwap device that provided backflush capabilities by reversing column flow immediately after elution of the last compound of interest. The combined screening and target method was used in the analysis of more than 100 food samples, including a carrot sample from the European Proficiency Test FV 10, with good results. PMID- 20166600 TI - Analysis of photochemically induced cotton bound residues of deltamethrin by an immunoassay technique. AB - A sensitive and selective indirect competitive ELISA was developed for the detection of deltamethrin bound residues on cotton texture. Cross-reactivity studies with the main deltamethrin photodegradation products showed high specificity of deltamethrin polyclonal antibody to the parent compound. No cross reactivity was measured with deltamethrin photodegradtion products derived from the alcohol moiety (3-phenoxybenzaldhyde, phenoxybenzyl alcohol, cyanohydrin, and 3-phenoxybenzoic acid), and lesser amounts were observed with the acid moiety (deltamethric acid). The dot-blot immunoassay was performed on cotton fabric discs spiked with deltamethrin and irradiated to assess the suitability of this system to detect bound residue. The dot-blot immunoassay results revealed that the bound form of deltamethrin has binding affinity with deltamethrin antibody similar to the parent compound. In addition, the test system was used to detect bound and free residues of deltamethrin on cotton samples exposed to three cycles of simulated sunlight and water wash. The results obtained suggest that the competitive ELISA format can be used as a tool for monitoring free and bound residues of deltamethrin impregnated on cotton targets. PMID- 20166601 TI - Toward a quality guide to facilitate the transference of analytical methods from research to testing laboratories: a case study. AB - At present, there is no single viewpoint that defines QA strategies in analytical chemistry. On the other hand, there are no unique protocols defining a set of analytical tasks and decision criteria to be performed during the method development phase (e.g., by a single research laboratory) in order to facilitate the transference to the testing laboratories intending to adapt, validate, and routinely use this method. This study proposes general criteria, a priori valid for any developed method, recommended as a provisional quality guide containing the minimum internal tasks necessary to publish new analytical method results. As an application, the selection of some basic internal quality tasks and the corresponding accepted criteria are adapted to a concrete case study: indirect differential pulse polarographic determination of nitrate in water samples according to European Commission requisites. Extra tasks to be performed by testing laboratories are also outlined. PMID- 20166602 TI - Comparison of signal-to-noise, blank determination, and linear regression methods for the estimation of detection and quantification limits for volatile organic compounds by gas chromatography. AB - LOD and LOQ are two important performance characteristics in method validation. This work compares three methods based on the International Conference on Harmonization and EURACHEM guidelines, namely, signal-to-noise, blank determination, and linear regression, to estimate the LOD and LOQ for volatile organic compounds (VOCs) by experimental methodology using GC. Five VOCs, toluene, ethylbenzene, isopropylbenzene, n-propylbenzene, and styrene, were chosen for the experimental study. The results indicated that the estimated LODs and LOQs were not equivalent and could vary by a factor of 5 to 6 for the different methods. It is, therefore, essential to have a clearly described procedure for estimating the LOD and LOQ during method validation to allow interlaboratory comparisons. PMID- 20166603 TI - The AOAC Research Institute Emergency Response Validation Program. PMID- 20166604 TI - GeneQuence" Salmonella assay. Performance Tested Method 030201. AB - A study was conducted to validate the GeneQuence Salmonella DNA hybridization assay, Performance Tested Method 030201, for detection of Salmonella spp. in peanut butter. The study was organized by the AOAC Research Institute under its Emergency Response Validation program. Peanut butter samples inoculated with S. Typhimurium were prepared by an independent laboratory and shipped to study participants for testing. The set of blind-coded test samples consisted of five uninoculated controls, 20 portions inoculated with S. Typhimurium at a low level [determined by most probable number (MPN) analysis to contain 1.1 CFU/25 g portion], and 20 portions inoculated with S. Typhimurium at a higher level (11 CFU/25 g portion by MPN analysis). Samples were tested in parallel by the GeneQuence method and by the U.S. Food and Drug Administration's Bacteriological Analytical Manual reference culture procedure. All five control samples were negative by both methods. For the low-level samples, the same two samples were positive by both the GeneQuence and reference methods. For the high-level samples, the same 19 samples were positive by both methods. All positive GeneQuence assays were confirmed by plating from associated broth cultures. Agreement between the GeneQuence and reference methods was 100%. Sensitivity and specificity of the GeneQuence method were both 100%. Because neither the low- nor the high-level samples yielded the desired fractional positive results (5-15 positives out of 20 samples), a second trial was conducted. Samples in the second trial contained 0.1 and 0.5 CFU/25 g portion for the low and high levels, respectively. All five control samples were negative by both methods. For the low level samples, the same two samples were positive by both the GeneQuence and reference methods. For the high-level samples, the same three samples were positive by both methods. All positive GeneQuence assays were confirmed by plating from associated broth cultures. Sensitivity and specificity of the GeneQuence method were both 100%. Although once again the desired level of fractional positive results was not obtained, there was 100% agreement between the GeneQuence and reference methods. Based on the results of both trials, it is recommended that the validated claims for Performance Tested Method 030201 be expanded to include peanut butter. PMID- 20166605 TI - 1-2 Test. AB - A study was conducted to determine the efficacy of detecting low contamination levels of Salmonella in peanut butter using the 1-2 Test. This study was conducted under the AOAC Research Institute Emergency Response Validation program. A set of samples was analyzed by the 1-2 Test and the U.S. Food and Drug Administration's Bacteriological Analytical Manual reference method. Among the 90 total samples and controls, 32 samples were positive by the 1-2 Test and the reference method. Statistical analyses of these paired samples indicated that for all levels analyzed, the difference between the 1-2 Test and reference method results were not statistically different at the 5% level. PMID- 20166606 TI - Assurance GDS for Salmonella. Performance Tested Method 050602. AB - A study was conducted to determine the efficacy of detecting low contamination levels of Salmonella in peanut butter using Assurance GDS for Salmonella (GDS). This study was conducted under the AOAC Research Institute Emergency Response Validation program. A set of samples was each analyzed by the GDS and the U.S. Food and Drug Administration's Bacteriological Analytical Manual reference method. Among the 45 total samples and controls, 26 samples were positive by the GDS and 24 were positive by the reference method. Statistical analyses of these unpaired samples indicated that, for all levels analyzed, the differences between the GDS and reference method results were not statistically different at the 5% level. PMID- 20166607 TI - TRANSIA PLATE Salmonella Gold. Performance Tested Method 010602. AB - A study was conducted to determine the efficacy of detecting low contamination levels of Salmonella in peanut butter using TRANSIA PLATE Salmonella Gold (TPSG). This study was conducted under the AOAC Emergency Response Validation program. A set of samples was each analyzed by the TPSG method and the U.S. Food and Drug Administration's Bacteriological Analytical Manual reference method. Among the 45 total samples and controls, 26 were positive by the TPSG and 24 were positive by the reference method. Statistical analyses of these unpaired samples indicated that for all levels analyzed, the difference between the TPSG and reference method results were not statistically different at the 5% level. PMID- 20166608 TI - VIDAS Salmonella (SLM) assay method EasySLM with ChromID Salmonella (SM2) Agar. Performance Tested Method 020901. AB - A method modification study was conducted for the VIDAS Salmonella (SLM) assay (AOAC Performance Tested Method 020901) using the EasySLM method to validate a matrix extension for peanut butter. The VIDAS EasySLM method is a simple enrichment procedure compared to traditional Salmonella methods, requiring only pre-enrichment and a single selective enrichment media, Salmonella Xpress 2 (SX2) broth. SX2 replaces the two selective broths in traditional methods and eliminates the M broth transfer, incubation, and subsequent pooling of M broths prior to VIDAS assay. The validation study was conducted under the AOAC Research Institute Emergency Response Validation program. VIDAS SLM was compared to the U.S. Food and Drug Administration's Bacteriological Analytical Manual (FDA-BAM) method for detection of S. enterica ser. Typhimurium in peanut butter. All peanut butter samples were prepared, blind-coded, and shipped to the method developers' laboratory by Q Laboratories. In addition, Q Laboratories performed most probable number and reference method analyses on peanut butter samples. The VIDAS EasySLM ChromID Salmonella (SM2) Agar was previously validated in the Performance Tested Methods program for the detection of Salmonella in roast beef, raw ground pork, turkey, pork sausage, raw chicken breast, dry pet food, whole milk, ice cream, bagged spinach, shrimp (raw, peeled), raw cod, spent irrigation water, pecans, peanut butter, dry pasta, cake mix, ground black pepper, nonfat dry milk, liquid eggs, cantaloupe, and orange juice. In the matrix extension study for peanut butter, the VIDAS EasySLM method was shown to be equivalent to the appropriate reference culture procedure using both buffered peptone water pre-enrichment and the FDA-BAM lactose pre-enrichment in the two-step enrichment method with SX2 media. The current study extends the validation to include peanut butter. PMID- 20166609 TI - iQ-Check Salmonella II: real-time polymerase chain reaction test kit. Performance Tested Method 010803. AB - iQ-Check Salmonella II is a real-time PCR kit for detection of Salmonella in foods. Specific oligonucleotide probes are used to detect target DNA during the amplification, by hybridizing to the amplicons. These probes are linked to a fluorophore, which fluoresces only when hybridized to the target sequence. As part of an Emergency Response Validation due to a massive outbreak and subsequent recall, peanut butter was tested to compare the performance of iQ-Check Salmonella II to the U.S. Food and Drug Administration's Bacteriological Analytical Manual (FDA-BAM) reference method for detection of Salmonella. A single enrichment in buffered peptone water was used for a reduced enrichment time of 21 +/- 1 h over the 48 h reference method. There was no significant difference in the performance of the iQ-Check kit when compared to the FDA-BAM method, as determined by Chi-square analysis. All samples identified as positive by iQ-Check were confirmed by reference method protocol. PMID- 20166610 TI - RAPID'Salmonella chromogenic medium. Performance Tested Method 050701. AB - RAPID'Salmonella is a chromogenic medium for isolation and detection of Salmonella spp. in food, based on two enzymatic activities. All presumptive Salmonella-positive colonies are magenta, including lactose-positive Salmonella. S. Typhi, and S. Paratyphi serotypes, due to detection of C8 esterase activity. In order to differentiate Salmonella from other Enterobacteriaceae, the medium includes a second chromogenic substrate. As part of an Emergency Response Validation due to a massive outbreak and subsequent recall, peanut butter was tested to compare the performance of RAPID'Salmonella to the U.S. Food and Drug Administration's Bacteriological Analytical Manual reference method for detection of Salmonella. Sensitivity and specificity for RAPID'Salmonella were 100%. PMID- 20166611 TI - Foodproof Salmonella Detection Kit. Performance Tested Method 120301. AB - The foodproof Salmonella Detection Kit was previously validated in the Performance Tested Methods program for the detection of Salmonella species in a variety of foods, including milk powder, egg powder, coconut, cocoa powder, chicken breast, minced meat, sliced sausage, sausage, smoked fish, pasta, white pepper, cumin, dough, wet pet food, dry pet food, ice cream, watermelon, sliced cabbage, food dye, and milk chocolate. The method was shown to be equivalent to the U.S. Food and Drug Administration's Bacteriological Analytical Manual (FDA BAM) and the U.S. Department of Agriculture, Food Safety and Inspection Service's Microbiology Laboratory Guidebook reference culture procedures. In the first Emergency Response Validation (ERV) extension study, peanut butter was inoculated with S. enterica. ser Typhimurium. For the low inoculation level (1.08 CFU/25 g), a Chi-square value of 2.25 indicated that there was no significant performance difference between the foodproof Salmonella Detection Kit and the FDA-BAM reference method. For high-level inoculation (11.5 CFU/25 g) and uninoculated control, there was 100% agreement between the methods. In the second ERV extension study, peanut butter was inoculated with S. enterica. ser Typhimurium. For both inoculation levels (0.1 and 0.5 CFU/25 g by most probable number), Chi square values of 0 indicated that there was no significant performance difference between foodproof Salmonella Detection Kit and the FDA-BAM reference method. PMID- 20166612 TI - Singlepath Salmonella. Performance Tested Method 060401. AB - Singlepath Salmonella is an immunochromatographic (lateral flow) assay for the presumptive qualitative detection of Salmonella spp. in food. A previous AOAC Performance Tested Method study evaluated Singlepath Salmonella as an effective method for the detection of Salmonella spp. in the following selected foods: dried skimmed milk, black pepper, dried pet food, desiccated coconut, cooked peeled frozen prawns, raw ground beef, and raw ground turkey. In this Emergency Response Validation extension, creamy peanut butter was inoculated with S. enterica. ser. Typhimurium. For low contamination level (1.08 CFU/25 g), a Chi square value of 0.5 indicated that there was no significant difference between Singlepath Salmonella and the U.S. Food and Drug Administration's Bacteriological Analytical Manual (FDA-BAM) reference method. For high-level and uninoculated control there was 100% agreement between the methods. PMID- 20166613 TI - RapidChek SELECT Salmonella. Performance Tested Method 080601. AB - RapidChek SELECT Salmonella was previously validated in the Performance Tested Methods program for the detection of Salmonella spp. in raw ground chicken, chicken carcass rinse, sliced cooked turkey, and liquid eggs. The present matrix extension study conducted under the AOAC Research Institute Emergency Response Validation program compared the RapidChek SELECT Salmonella method to the U.S. Food and Drug Administration's Bacteriological Analytical Manual (FDA-BAM) method for the detection of Salmonella Typhimurium in peanut butter. Overall, 27 samples were found positive by the RapidChek SELECT Salmonella method and 27 were found to be positive by the reference method. All RapidChek SELECT Salmonella presumptive positives were confirmed positive by the cultural reference method; additionally, all presumptive negative results were confirmed negative by the cultural reference method. Accordingly 0% false-negative rate and 0% false positive rate were found. No significant difference between the RapidCheck SELECT Salmonella and FDA-BAM reference method was found; calculated Chi-square was 0. Results indicate that a low level of Salmonella in peanut butter can be successfully recovered and detected in the minimum 24 h enrichment protocol. PMID- 20166614 TI - TaqMan Salmonella enterica Detection Kit. Performance Tested Method 020803. AB - Peanut butter spiked with Salmonella enterica ser. Typhimurium was prepared by an independent laboratory and sent to Applied Biosystems to determine the sensitivity and specificity of the TaqMan Salmonella enterica Detection Kit for detecting Salmonella in peanut butter. The samples were spiked at three levels: five no-spike (0 CFU/25 g); 20 low-spike (0.2 CFU/25 g); and 20 high-spike (2 CFU/25 g). They were coded to create a blind set of 45 samples. The samples were processed based on an unpaired test design that included enrichment in buffered peptone water for the candidate method and lactose broth for the reference method. In the candidate method, a 1 mL aliquot of enriched sample was extracted using PrepMan Ultra Sample Preparation Reagent; the sample was amplified on the Applied Biosystems 7500 real-time PCR system, and analyzed for detection of Salmonella using RapidFinder Version 1.0 software. All samples processed by the candidate method were confirmed by culture according to the U.S. Food and Drug Administration's Bacteriological Analytical Manual procedures. Sensitivity, specificity, and Chi-square analysis were calculated by combining candidate method results with those of the reference method that were collected by the independent laboratory. The TaqMan Salmonella enterica Detection Kit showed 40% sensitivity, 100% specificity, and a Chi-square value equal to 1.52. Chi-square analysis indicated the candidate method and the reference method were comparable. Although the candidate method sensitivity was only 40% when compared with the reference method (unpaired samples), the sensitivity was > 100% when the candidate method results were compared with those of the confirmation method (same sample enrichment). PMID- 20166615 TI - DuPont Qualicon BAX System polymerase chain reaction assay. Performance Tested Method 100201. AB - A recent outbreak of Salmonella in peanut butter has highlighted the need for validation of rapid detection methods. A multilaboratory study for detecting Salmonella in peanut butter was conducted as part of the AOAC Research Institute Emergency Response Validation program for methods that detect outbreak threats to food safety. Three sites tested spiked samples from the same master mix according to the U.S. Food and Drug Administration's Bacteriological Analytical Manual (FDA BAM) method and the BAX System method. Salmonella Typhimurium (ATCC 14028) was grown in brain heart infusion for 24 h at 37 degrees C, then diluted to appropriate levels for sample inoculation. Master samples of peanut butter were spiked at high and low target levels, mixed, and allowed to equilibrate at room temperature for 2 weeks. Spike levels were low [1.08 most probable number (MPN)/25 g]; high (11.5 MPN/25 g) and unspiked to serve as negative controls. Each master sample was divided into 25 g portions and coded to blind the samples. Twenty portions of each spiked master sample and five portions of the unspiked sample were tested at each site. At each testing site, samples were blended in 25 g portions with 225 mL prewarmed lactose broth until thoroughly homogenized, then allowed to remain at room temperature for 55-65 min. Samples were adjusted to a pH of 6.8 +/- 0.2, if necessary, and incubated for 22-26 h at 35 degrees C. Across the three reporting laboratories, the BAX System detected Salmonella in 10/60 low-spike samples and 58/60 high-spike samples. The reference FDA-BAM method yielded positive results for 11/60 low-spike and 58/60 high-spike samples. Neither method demonstrated positive results for any of the 15 unspiked samples. PMID- 20166616 TI - CHROMagar Salmonella Detection Test Kit. Performance Tested Method 020502. AB - BBL CHROMagar Salmonella was evaluated by an external food testing laboratory for the recovery of Salmonella in peanut butter using the U.S. Food and Drug Administration's Bacteriological Analytical Manual (FDA-BAM) procedure. The peanut butter was found to be negative for the presence of Salmonella and, therefore, was seeded with heat-stressed Salmonella at target concentrations of 0.2 and 2 CFU/25 g. The Salmonella-seeded samples remained at room temperature for 14 days before analysis to stabilize the Salmonella in the food environment. Twenty 25 g test portions from each seeded level and five 25 g samples of uninoculated control samples were processed using enrichment broths as outlined in the FDA-BAM procedure. BBL CHROMagar Salmonella-prepared plates were evaluated with the FDA reference method media (bismuth sulfite, xylose lysine desoxycholate, and Hektoen enteric agars). Fractionally positive results were obtained from the lower inoculum level of peanut butter samples. Five positive cultures were recovered from both the BBL CHROMagar Salmonella and reference methods. The two methods gave identical results for all cultures resulting in a method agreement of 100%. McNemar's chi2 test, which assesses the evidence for difference in marginal proportions between two methods, could not be evaluated because it requires one or more discrepant cultures. However, because there were no discrepant cultures, the marginal proportions for the two methods were identical; therefore, there is no evidence of a difference between the methods. This study demonstrates that the results from BBL CHROMagar Salmonella are comparable to the three reference method media for the detection of Salmonella in peanut butter using the FDA-BAM procedures. PMID- 20166617 TI - Outcomes of corneal spherical aberration-guided cataract surgery measured by the OPD-scan. AB - PURPOSE: To determine based on preoperative corneal spherical aberration, the practicality of targeting zero total ocular postoperative spherical aberration when selecting an aspheric intraocular lens (IOL). METHODS: Consecutive cataract patients were selected to receive an aspheric IOL based on corneal spherical aberration. A target of zero postoperative total spherical aberration Z(4,0) was calculated. One of three IOLs was chosen, based on the corneal spherical aberration Z(4,0) measurement at the 6-mm optical zone. The IOL was selected based on the summation of the corneal spherical aberration and the aspheric value of the prolate optic. The intention was an absolute value of zero total spherical aberration. Statistical analysis of the postoperative total ocular wavefront profile was performed to assess the accuracy of aspheric IOL selection. RESULTS: Forty eyes of 40 patients were available for postoperative assessment. The Tecnis Z9003 (Abbott Medical Optics) was implanted in 25 eyes with a preoperative corneal spherical aberration of +0.311+/-0.054 MUm, the AcrySof IQ (Alcon Laboratories Inc) in 13 eyes (+0.188+/-0.034 MUm), and the SofPort-Advanced Optic with Violet Shield (Bausch & Lomb) was implanted in 2 eyes (+0.0915 MUm). Total postoperative ocular spherical aberration for the entire group measured +0.019+/ 0.051 MUm (Tecnis: +0.024+/-0.058 MUm; AcrySof IQ: +0.010+/-0.035 MUm; and SofPort AOV: +0.037 MUm). Mean absolute predictive error, for the entire group, measured +0.025+/-0.020 MUm. CONCLUSIONS: Skiascopy-derived total wavefront measurement of spherical aberration is a reproducible method of aspheric IOL selection and permits more precise control of total ocular spherical aberration. PMID- 20166618 TI - Decision Assistant Wizard to standardize optimal outcomes in excimer laser refractive corneal surgery. AB - PURPOSE: To assess a decision tree analysis system to further optimize refractive surgery outcomes. METHODS: A 5-step decision tree, the Decision Assistant Wizard, based on previous experience with the SCHWIND AMARIS laser, was applied for selecting a customized refractive surgery treatment mode (aspheric aberration neutral, corneal wavefront-guided, or ocular wavefront-guided) to eliminate or reduce total aberration. RESULTS: Using the Decision Assistant Wizard, 6467 LASIK treatments were performed over a 30-month period; 5262 and 112 for myopic and hyperopic astigmatism, respectively, using aspheric aberration neutral (AF) profiles, 560 using corneal wavefront-guided profiles, and 533 using ocular wavefront-guided profiles. Twenty-two (0.3%) retreatments were performed overall; 18 (0.3%) and 0 (0%) after myopic and hyperopic astigmatism, respectively, using AF, 3 (0.5%) after corneal wavefront-guided profiles, and 1 (0.2%) after ocular wavefront-guided profiles. CONCLUSIONS: Decision Assistant Wizards may further optimize refractive surgical outcomes by providing the most appropriate ablation pattern based on an eye's anamnesis, diagnosis, and visual demands. The general principles may be applied to other laser systems; however, specifics will depend on manufacturers' specifications. PMID- 20166619 TI - Implantation of a complete corneal ring in an intrastromal pocket for keratoconus. AB - PURPOSE: to evaluate the refractive and visual results of a new treatment for keratoconus using the corneal intrastromal implantation system (CISIS). METHODS: six eyes of four patients with keratoconus were treated with CISIS. Follow-up was 1, 3, and 6 months. After creating an intracorneal pocket of 9-mm diameter and 300-microm depth, a flexible full-ring implant was inserted via a 4-mm-wide corneal tunnel. RESULTS: no eyes showed loss of lines in uncorrected distance visual acuity (UDVA) or spectacle corrected distance visual acuity (CDVA) at any follow-up examination. Uncorrected and distance corrected visual acuity, keratometry, spherical and cylindrical refractive error as well as spherical equivalent refraction improved significantly (P<.05). Mean UDVA improved from 20/260 to 20/48 and mean CDVA improved from 20/41 to 20/27. A significant centralization and decrease of the corneal apex was found. No intra- or postoperative complications were observed. CONCLUSIONS: the corneal intrastromal implantation system using a complete ring implanted in a stromal pocket can achieve significant improvements in the visual function of patients with keratoconus. Uncorrected distance visual acuity improved by more than seven lines on average and CDVA improved by two lines. PMID- 20166620 TI - Conductive keratoplasty to treat hyperopic overcorrection after LASIK for myopia. AB - PURPOSE: to investigate the refractive outcomes and stability of conductive keratoplasty (CK) for retreatment of myopic LASIK overcorrection. METHODS: seven eyes (six patients) that were overcorrected after myopic LASIK by +1.00 to +2.75 diopters (D) manifest refraction spherical equivalent (MRSE) were retreated using CK. All eyes had insufficient stromal thickness for LASIK retreatment. LightTouch CK was performed at least 1 year after LASIK. Either 8 or 16 spots were applied at 7- and/or 8-mm zones on the cornea. Uncorrected distance visual acuity, manifest refraction, corrected distance visual acuity (CDVA), and postoperative complications were analyzed. RESULTS: mean MRSE after CK at last follow-up was +0.38 +/- 0.52 D (range: -0.38 to +1.13 D). The change in MRSE ranged from -0.63 to -2.38 D. Mean MRSE after CK changed from -0.60 +/- 2.07 D (range: -3.38 to +1.50 D) at 1 week to +0.45 +/- 0.69 D (range: -0.38 to +1.38 D) at 12 months. Two eyes experienced an initial overcorrection of -2.75 D and -3.38 D, respectively, at 1 week after CK. Cylinder <=0.75 D was induced in four eyes, whereas one eye had a 0.75-D reduction in cylinder. All eyes had CDVA of logMAR 0.10 or better. Two eyes lost one line of CDVA and no eyes lost more than one line. CONCLUSIONS: lighttouch CK retreatment for over-corrected myopic LASIK can reduce the hyperopia but produces minimal change in cylinder, and may be appropriate for eyes with insufficient stromal tissue for repeated excimer laser surgery. Early regression occurs commonly. PMID- 20166621 TI - Transepithelial corneal collagen cross-linking in keratoconus. AB - PURPOSE: To evaluate the clinical effects of transepithelial corneal cross linking (CXL) on keratoconic eyes pre-treated with substances enhancing epithelial permeability. METHODS: Prospective, consecutive, single-masked, paired eye study on 51 patients. The eye with more severe keratoconus was treated; the fellow eye served as the control. Gentamicin, benzalkonium chloride, and ethylenediaminetetraacetic acid were instilled for 3 hours, then oxybuprocaine for 30 minutes. Riboflavin 0.1% in 20% dextran T500 and oxybuprocaine were instilled for 30 minutes. Finally, ultraviolet A irradiation to the central 7.5 mm of the cornea was applied for 30 minutes, while riboflavin was instilled every 5 minutes. RESULTS: Mean corrected distance visual acuity improved by 0.036 logMAR after CXL and worsened by 0.039 logMAR in the control eyes (P<.05). Safety index was 1.05 after CXL and 0.96 in the control group. Mean spherical equivalent refraction decreased by 0.35 D (less myopic) after CXL and increased by 0.83 diopters (D) in the control eyes (P<.05). Mean apex curvature on tangential videokeratography increased by 0.51 D after CXL and by 1.61 D in the control eyes (P=.16). Mean average simulated keratometry decreased by 0.10 D after CXL and increased by 0.88 D in the control eyes (P<.05). Mean index of surface variance increased (worsened) by 0.9 after CXL and 5.3 in the control eyes (P<.05). Mean endothelial cell density was unchanged. CONCLUSIONS: A limited but favorable effect of transepithelial CXL was noted on keratoconic eyes, without complications. The effect appears to be less pronounced than described in the literature after CXL with de-epithelialization. PMID- 20166622 TI - Pentacam characterization of corneas with Fuchs dystrophy treated with Descemet membrane endothelial keratoplasty. AB - PURPOSE: To characterize central corneal thickness, curvature, and posterior surface elevation in eyes with Fuchs dystrophy that underwent Descemet membrane endothelial keratoplasty (DMEK) for endothelial decompensation and to compare these characteristics with those in normal eyes. METHODS: Pre- and postoperative corneal tomography was prospectively evaluated using Pentacam (Oculus Optikgerate GmbH) imaging on 29 eyes with Fuchs dystrophy treated with DMEK. Results were compared with data from a separate cohort of 198 normal eyes. RESULTS: In the Fuchs cohort, the mean preoperative central corneal thickness was 656 MUm (range: 574 to 731 MUm). This significantly exceeded the mean thickness of 542 MUm in the normal cohort (range: 439 to 611 MUm, P<.0001) although the cohort thickness ranges overlapped. One month after DMEK, mean central corneal thickness decreased significantly to 539 MUm (range: 465 to 669 MUm, P<.0001) with no further significant decrease between 1 and 3 months after DMEK (mean difference = -4 MUm, P=.39). In the Fuchs cohort, keratometry (average Sim K and delta K) did not change significantly after DMEK (P=.41 and P=.44, respectively); pre- and postoperative values were comparable to those in the normal cohort. The mean forward displacement of the posterior surface increased by 69 MUm 1 month after DMEK (P<.0001) without further significant change between 1 and 3 months. CONCLUSIONS: After DMEK, central corneal thickness in the Fuchs dystrophy cohort decreased significantly and the posterior corneal surface displaced forward, without significant change in anterior keratometric values or keratometric astigmatism. The preoperative central corneal thickness range in eyes with confluent central guttata overlapped the range in normal corneas. PMID- 20166623 TI - Factors related to the correction of astigmatism by LASIK after penetrating keratoplasty. AB - PURPOSE: To analyze the preoperative factors related to successful correction of astigmatism by LASIK after penetrating keratoplasty (PKP). METHODS: This retrospective chart review included 71 patients (75 eyes) undergoing LASIK after PKP. The full refractive cylindrical (thus near-spherical) errors were treated by laser ablation. Postoperative follow-up examinations included uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest autorefraction, slit-lamp examination, topography, specular microscopy, and simple questionnaire regarding satisfaction with LASIK at 1 day, 1 week, and 1, 6, and 12 months. RESULTS: Before surgery, no eye had UDVA of 20/60 or better and 42 (56%) eyes had CDVA of 20/40 or better. At 1 year, 45 (60%) eyes had UDVA of 20/60 or better and 57 (76%) eyes had CDVA of 20/40 or better. The mean astigmatism was 6.80+/-2.10 diopters (D) preoperatively. The mean reduction of astigmatism was 3.80+/-2.30 D (53.9+/-28.7%) at 12 months after LASIK and was relatively stable between 6 and 12 months. Although mean achieved correction showed a tendency toward undercorrection, CDVA and contact lens/spectacle tolerance were significantly increased. The younger the patient, the lesser magnitude of refractive cylinder, and greater endothelial cell density showed better astigmatism reduction in the multiple regression analysis. CONCLUSIONS: LASIK is a safe and effective procedure with stability for reducing astigmatism following PKP and increasing spectacle or contact lens tolerance. For optimal predictability and visual outcomes after LASIK, we recommend the full identification of astigmatism after PKP and preoperative analysis of the endothelial cell density. PMID- 20166624 TI - Effect of topical 0.5% morphine on postoperative pain after photorefractive keratectomy. AB - PURPOSE: To investigate safety and efficacy of 0.5% morphine drops for pain control after photorefractive keratectomy (PRK). METHODS: In a double-blind prospective study, 40 patients were randomized to either 0.5% morphine drops (n=20) or vehicle control (n=20). Treatment occurred every 2 hours following PRK on the day of the procedure, then four times daily on postoperative days 1 through 3. Patients completed pain assessment questionnaires (visual descriptor, numerical rating, visual analog scales, and oral analgesic consumption) every 2 hours while awake during the treatment period. Daily average and maximum scores were compared between the two groups. Patients were examined daily for 4 days after PRK, weekly for 4 weeks, then monthly for 3 months. Epithelial healing, corneal haze, and refractive outcomes were compared. RESULTS: Both average and maximum pain scores were lower in the morphine group than in the vehicle control group on all scales and during all 4 days after PRK. Statistical significance (P<.05) was reached on numeric rating scale on procedure day and on postoperative day 1. The difference between the groups on the visual analog scale was statistically significant on procedure day, and on postoperative days 1 and 2. Oral analgesic consumption was higher in the vehicle control group on postoperative day 2. No difference between groups was noted in epithelial healing or refractive outcomes. Stromal haze scores were lower in the morphine group, but the difference was not statistically significant. CONCLUSIONS: Topical 0.5% morphine may be an effective and safe method of pain control after PRK. PMID- 20166625 TI - Treatment of highly aberrated eyes using the NIDEK CXIII excimer laser. AB - PURPOSE: To describe the treatment of highly aberrated eyes due to previous excimer laser surgery or trauma. METHODS: Three eyes (three patients) with reduced visual quality due to previous decentration or corneal laceration (one eye) underwent topography-guided ablation using the CXIII excimer laser (NIDEK Co Ltd) to correct residual refractive error and/or wavefront aberrations. RESULTS: Postoperatively, one patient had a one-line increase in corrected distance visual acuity (CDVA) with a reduction in visual symptoms. At 2 months postoperatively, one patient maintained CDVA, increased uncorrected distance visual acuity from 20/20 to 20/15, and reported resolution of monocular diplopia. In all cases, the functional optical zone increased and wavefront aberrations decreased with selective flattening of the intended corneal region. CONCLUSIONS: Topography guided ablation is an effective treatment of severe corneal aberrations due to surgery or trauma and can be selectively used to treat higher order aberrations with or without refractive error. PMID- 20166626 TI - Corneal spherical aberration of eyes with cataract in a Japanese population. AB - PURPOSE: To investigate the distribution of corneal spherical aberration in Japanese eyes with cataract for implantation of aspheric intraocular lenses (IOLs). METHODS: Corneal spherical aberration (Zernike coefficient Z04) in the central 6-mm zone was measured with a wavefront analyzer (KR9000PW, Topcon) in 257 eyes of 168 Japanese patients with cataract. Axial length was also measured for each eye. RESULTS: Mean corneal spherical aberration was 0.203+/-0.100 microm (range: -0.103 to 0.497 microm). A significant negative correlation was found between axial length and corneal spherical aberration (r =/-0.135, P=.036). CONCLUSIONS: Corneal spherical aberration varied among cataract patients and correlated with axial length. Japanese patients showed a relatively smaller corneal spherical aberration than previous studies of Caucasians. Preoperative measurement of wavefront aberrations is thus important in using aspheric IOLs. PMID- 20166628 TI - Effect of pupil size on visual acuity in a laboratory model of pseudophakic monovision. AB - PURPOSE: To investigate the effect of pupil size on visual acuity in pseudophakic monovision. METHODS: For the simulation, a modified Liou-Brennan model eye was used. The model eye was designed to include a centered optical system, corneal asphericity, an iris pupil, a Stiles-Crawford effect, an intraocular lens, and chromatic aberration. Calculation of the modulation transfer function (MTF) was performed with ZEMAX software. Visual acuity was estimated from the MTF and the retinal threshold curve. The sizes of the entrance pupil were 2.0, 2.5, 3.0, and 4.0 mm. RESULTS: Decreasing pupil diameter and increasing myopia progressively improved near visual acuity. For an entrance pupil size of 2.5 mm and a refractive error of -1.50 diopters, the logMAR value (Snellen; metric) in the non dominant eye at 40 cm was 0.06 (20/23; 6/6.9). CONCLUSIONS: Knowledge of the patient's pupil diameter at near fixation can assist surgeons in determining the optimum degree of myopia for successful monovision. PMID- 20166627 TI - Evaluation of a risk factor scoring system for corneal ectasia after LASIK in eyes with normal topography. AB - PURPOSE: To assess a previously published risk score system for predicting postoperative LASIK ectasia in eyes with normal preoperative topography. METHODS: A retrospective review of one surgeon's LASIK database was performed for eyes with Randleman ectasia risk scores based on patient age <30 years, preoperative central corneal thickness <510 microm, residual stromal bed thickness <300 microm, and/or a preoperative manifest refraction spherical equivalent >-8.00 diopters that had a minimum follow-up of 1 year. RESULTS Of 1702 eyes with myopic errors and normal topographies, 35 (2.0%) eyes had a combined risk score between 5 and 9 points, 92 (5.4%) eyes had a combined risk score of 4 or higher, and 208 (12.2%) eyes had a combined score of 3 or higher. None of these eyes developed ectasia, whereas 3 eyes with preoperative topographic keratoconus with no other risk factors developed ectasia. CONCLUSIONS: The current risk score system would have eliminated 5.4% of eyes with 4 or more points from LASIK surgery, and would have also required the surgeon to advise an additional 6.8% of eyes with a score of 3 that they were at "moderate risk" and should "proceed with caution." In eyes with normal preoperative topographies, the scoring system may not accurately predict whether patients are at increased risk for developing postoperative LASIK ectasia. PMID- 20166629 TI - INTACS followed by KeraRing intrastromal corneal ring segment implantation for keratoconus. AB - PURPOSE: To describe the visual and refractive outcomes in three eyes (two keratoconic patients) with previous intrastromal corneal ring segments (INTACS, Addition Technology Inc) that underwent adjuvant single KeraRing (Mediphacos) intrastromal corneal ring segment implantation. METHODS: Two keratoconic patients (three eyes) with implanted INTACS segments underwent an additional (without explanting previous INTACS) single KeraRing segment implantation. RESULTS: No intraoperative complications occurred. Six months postoperatively, uncorrected distance visual acuity improved from 20/100 and 20/200 to 20/32 and 20/40 in the right and left eyes, respectively, of patient 1, and from 20/400 to 20/50 in the treated right eye of patient 2. Corrected distance visual acuity improved from 20/50 and 20/100 to 20/30 and 20/32 in the right and left eyes, respectively, of patient 1 and from 20/200 to 20/40 in patient 2. Keratometric measurements improved from 51.00/45.70 to 47.00/44.60 diopters (D) and from 50.80/48.80 to 42.70/40.30 D in the right and left eyes, respectively, of patient 1, and from 49.30/45.70 to 45.60/44.10 D in patient 2. CONCLUSIONS: In keratoconic patients with INTACS in place, adjuvant single intrastromal corneal ring segment (KeraRing) implantation could improve visual and refractive outcome. PMID- 20166630 TI - Learning the teaching of pediatrics. PMID- 20166631 TI - This issue: medical education. PMID- 20166632 TI - A 7-month-old boy with failure to thrive. PMID- 20166633 TI - A 7-day-old boy with a congenital vascular nodule. PMID- 20166634 TI - Pediatric education in office settings. AB - Pediatric training in community office-based settings has been demonstrated to be an effective means of providing "real-world" experiences to students and residents. Although it is often challenging with regards to addressing logistic and conceptual issues, such training provides important practical experiences that may prove critical to the future practice of not only primary care pediatrics but also pediatric subspecialty care. It also may be the key to enhancing the interaction between the two. PMID- 20166635 TI - Microskills in office teaching. PMID- 20166636 TI - Challenges and options for patient education in the office setting. PMID- 20166637 TI - Primary care physicians and hospitalists: two branches of the same tree. AB - The success of the evolving filed of pediatric hospitalist medicine should be judged on the health outcomes achieved for the more than 6 million children who are hospitalized annually. The focused approach hospitalists bring to defining the best knowledge that their role is important but is limited in the overall health of most children. In order to achieve the best health outcomes, hospitalists must fully partner with the child's primary care provider. By consistently communicating well during pre-admission, hospitalization, and discharge intervals, hospitalists and primary care pediatricians can enhance learning, as well as maximize outcomes for shared patients. PMID- 20166638 TI - Attempting to meet our nation's pediatric workforce needs. PMID- 20166639 TI - Community-oriented primary care: an often overlooked option for community pediatrics practice and training. PMID- 20166640 TI - Teaching scholarship and the clinician/educator. PMID- 20166641 TI - Out with the old and in with the new. PMID- 20166642 TI - Planning committees: value for continuing nursing education. AB - Accreditation criteria require the use of planning committees for continuing nursing education activities. More than just meeting a requirement, though, these committees can be valuable tools in guiding development of helpful, effective continuing nursing education learning activities. PMID- 20166643 TI - Using reusable learning objects. AB - Reusable learning objects (RLOs) are predeveloped digital learning activities that can be integrated into lessons, modules, and courses. Several repositories have nursing-specific RLOs waiting to be used by nurse educators. PMID- 20166644 TI - Open access is almost here: navigating through copyright, fair use, and the TEACH Act. AB - Dealing with the complexities of copyright, fair use, the TEACH Act, and the concept of open access can confuse even the most experienced educator. Online education has added to the dilemma. This article discusses the latest information on copyright issues, current guidelines for interpreting fair use and incorporating the TEACH Act, and recent developments in open access publishing. PMID- 20166646 TI - Bioterrorism knowledge and educational participation of nurses in Missouri. AB - BACKGROUND: Nurses are integral to bioterrorism preparedness, but nurses' bioterrorism preparedness knowledge has not been evaluated well. METHODS: Missouri Nurses Association members (1,528) were studied in the summer of 2006 to assess their bioterrorism knowledge and the perceived benefits of education as well as barriers to education. RESULTS: The response rate was 31%. Most respondents (60%, n = 284) received no bioterrorism education. Nurses who were nurse practitioners (t = -2.42, p < .05), were male (t = -2.99, p < .01), or were on a planning committee (t = -1.96, p = .05) had received more education than other nurses. The most commonly cited barrier to education (46.6%, n = 221) was not knowing where to obtain training. One third of respondents (31.2%) reported no interest in receiving bioterrorism education in the future. Nurses' average score on the knowledge test was 73%. The most commonly missed questions pertained to infection control and decontamination procedures. CONCLUSION: Bioterrorism preparedness training should be offered through continuing education and nursing school curricula. PMID- 20166647 TI - Creating a paperless documentation system for nursing continuing education activities. AB - This article describes the process used to convert the required communication, documentation, and peer review process required by the Ohio State Board of Nursing, as well as program evaluation documents, to a completely online "live document" system. Creation of the documentation and review system was accomplished with custom Microsoft Word templates created with Visual Basic for Applications. All templates were created according to nursing continuing education specifications by a constituent member association-approved provider unit within the American Nurses Credentialing Center Accreditation system. Examples of the templates, program review process, and documentation system are included. PMID- 20166648 TI - From practice to education: perspectives from three nurse leaders. AB - Three nurse leaders recount their experiences transitioning from a practice career to an academic career. These nurse leaders discuss their experiences with role transition and gaining new competencies, comparing and contrasting the competencies of nurse educators and nurse leaders. Specific examples are presented addressing collaborative efforts between practice and education. PMID- 20166649 TI - The importance of tobacco cessation training for nurses in Serbia. AB - BACKGROUND: This study assessed smoking prevalence, attitudes, and perceived patient counseling responsibilities among practicing nurses in Serbia. The need for nurses to receive tobacco cessation training is explored. METHODS: Data were collected through a cross-sectional survey of 230 nurses at public institutions in Belgrade, a health care center in Belgrade, and public health care facilities throughout Serbia. RESULTS: The smoking prevalence was 52% for male nurses and 47% for female nurses. Nurses had the greatest mean level of agreement with statements about controlling smoking through policy, followed by statements about being role models. Only 15% (n = 35) of nurses regularly counseled their patients about smoking, and only 16% of nurses (45% of males vs. 12% of females, p < .0001) had received training in counseling patients about smoking. Nurses' training in counseling patients about smoking was positively associated with the nurses' belief that their counseling could help patients stop smoking or never start smoking. In addition, nurses with training in counseling patients about smoking considered themselves significantly better prepared to assist patients to quit smoking. Nurses who smoked were significantly less likely to believe that their counseling about smoking could be effective. They also felt significantly less well prepared to assist patients to quit smoking. CONCLUSION: These findings show that nurses' training in tobacco cessation counseling results in greater self-perceived confidence and frequency of regular tobacco cessation counseling in Serbia. PMID- 20166650 TI - Health reform and politics 101 for psychiatric nurse therapists. PMID- 20166651 TI - When is a "generic" medication not really a generic? AB - The distinction between pharmaceutical equivalent and pharmaceutical alternative drug products can lead to considerable confusion, especially with the proliferation of various branded, alternative, and generic medications that contain the same active ingredient. To illustrate this problem, four examples of medication products containing the active ingredients paroxetine, venlafaxine, bupropion, and valproate will be described. Understanding these differences is important for nurses providing patient care. Only generic drugs can be freely substituted for a brand-name product. Switching to a pharmaceutical alternative requires a change in prescription. Finally, the use, labeling, and cost of branded, alternative, and generic medications may be different. PMID- 20166652 TI - Drinking games and college students. Part 1: problem description. AB - College students seek peer acceptance and opportunities for social interaction. For many, it may be the first time away from home, away from the supervision and watchful eyes of parents and other family members. Whether for fun, thrill, competition, or the need to socialize with others, approximately two thirds of U.S. college students participate in the risky binge drinking behavior called drinking games. Regardless of the game type, the goal of this behavior is to become intoxicated in a short period of time. Significant consequences and harm can result form this dangerous social behavior. This article, the first of two parts, will describe the problem; Part 2 will discuss the implications for community and mental health nurses. PMID- 20166653 TI - A signature wound of war: mild traumatic brain injury. AB - Improvised explosive devices are the weapons of choice for the insurgent enemy in Iraq and Afghanistan. More soldiers are surviving these blast injuries due to improved torso protection yet are sustaining head and neck wounds in numbers that exceed those from previous wars. Although moderate and severe traumatic head injuries are easily identified and aggressively treated, mild traumatic brain injuries (m-TBIs), or concussions, had previously been deemed inconsequential and often overlooked. Recently, however, the U.S. Department of Defense and Veterans Health Administration have placed emphasis on identifying service members at risk for m-TBI because a select number continue to have disabling symptoms that can negatively affect quality of life. Research regarding the effects and treatment of blasts injury are gaining momentum, but further work needs to be accomplished. This article provides a three-question screening tool that can be used to identify these at-risk veterans. PMID- 20166654 TI - Psychotropic medication-induced rabbit syndrome. AB - Rabbit syndrome (RS) is an involuntary movement disorder characterized by rapid, fine movements of an individual's mouth, similar to the chewing movements of a rabbit, and has most frequently been associated with the use of antipsychotic medications. RS is often unrecognized or misdiagnosed as tardive dyskinesia or pseudoparkinsonism. Although rare, RS is easily treatable if recognized. It is essential that nurses are able to distinguish this syndrome from other movement disorders; however, a lack of information exists in the nursing literature about this syndrome. The aims of this article are to describe the clinical symptoms of RS, its prevalence and etiology, and recommended treatment. Clinical and education implications regarding RS are also provided. PMID- 20166655 TI - Secondary organic aerosol formation from high-NO(x) photo-oxidation of low volatility precursors: n-alkanes. AB - Smog chamber experiments were conducted to investigate secondary organic aerosol (SOA) formation from photo-oxidation of low-volatility precursors; n-alkanes were chosen as a model system. The experiments feature atmospherically relevant organic aerosol concentrations (C(OA)). Under high-NO(x) conditions SOA yields increased with increasing carbon number (lower volatility) for n-decane, n dodecane, n-pentadecane, and n-heptadecane, reaching a yield of 0.51 for heptadecane at a C(OA) of 15.4 microg m(-3). As with other photo-oxidation systems, aerosol yield increased with UV intensity. Due to the log-linear relationship between n-alkane carbon number and vapor pressure as well as a relatively consistent product distribution it was possible to develop an empirical parametrization for SOA yields for n-alkanes between C(12) and C(17). This parametrization was implemented using the volatility basis set framework and is designed for use in chemical transport models. For C(OA) < 2 microg m(-3), the SOA mass spectrum, as measured with an aerosol mass spectrometer, had a large contribution from m/z 44, indicative of highly oxygenated products. At higher C(OA), the mass spectrum was dominated by m/z 30, indicative of organic nitrates. The data support the conclusion that lower volatility organic vapors are important SOA precursors. PMID- 20166656 TI - Minimising alkalinity and pH spikes from Portland cement-bound Bauxsol (seawater neutralized red mud) pellets for pH circum-neutral waters. AB - Bauxsol reagents (powder, slurry, or pellet forms) are powerful tools in environmental remediation and water and sewage treatment However, when used in circum-neutral water treatments, cement-bound Bauxsol pellets produce a sustained pH and alkalinity spike due to the presence of unreacted CaO in the cement binder. This study developed a pellet treatment system to minimize the alkalinity/pH spike. The recipe for pelletization consisted of Bauxsol powder, ordinary Portland cement (OPC), hydrophilic fumed silica, aluminum powder, a viscosity modifier, and water. Several batches (including different ratios and sizes) were run using modified makeup waters (H(2)0 + CO(2) or NaHCO(3)) or curing brines (CO(2), NaHCO(3), or Mg/CaCl(2)). Alkalinity, pH stability, and slake durability tests were performed on pellets before and/or after curing. The best result for reducing the alkalinity/pH spike was obtained from a MgCl(2), CaCl(2) bath treatment using a Bauxsol:cement ratio of 2.8:1 (pH 8.28; alkalinity 75.1 mg/L) for a 100 g batch or 245:1 (pH 8.05; alkalinity 35.4 mg/L) for a 1 kg batch. Although brine curing does provide a control on pH/alkalinity release, the pellets may still contain unreacted CaO. Therefore, a freshwater rinse of pellets before treating circum-neutral waters is recommended as is the continued investigation of alternative pellet binders. PMID- 20166657 TI - Reliance on (210)Pb chronology can compromise the inference of preindustrial Hg flux to lake sediments. AB - Lake sediments are frequently used to reconstruct the rate and magnitude of human impacts on the biogeochemical cycle of mercury (Hg). The vast majority of these studies rely on excess (210)Pb inventories in short cores to temporally constrain recent trends in Hg deposition, revealing an approximately 3-fold increase in Hg deposition since preindustrial times. However, the exhaustion of unsupported (210)Pb and the onset of widespread global Hg pollution converge temporally in the late 19th century, raising the possibility that preindustrial Hg fluxes are poorly constrained. Here, we combine (210)Pb and accelerator mass spectrometry (AMS) (14)C dated lake sediment records from arctic and Andean lakes to assess the reliability of (210)Pb-derived chronologies in the estimation of preindustrial Hg fluxes. For all four studied lakes, relying on (210)Pb chronologies results in an overestimate of preindustrial Hg fluxes, because extrapolated basal (210)Pb sedimentation rates are systematically overestimated in comparison to accumulation models that include (14)C dates. In the Andes, the use of (14)C dates is critical toward assessing the full history of Hg pollution, which extends beyond the industrial era. In the Arctic, (14)C dating suggests that Hg deposition may have increased >10-fold since the Industrial Revolution, rather than the commonly quoted 3-fold increase. The incorporation of (14)C dates may therefore be necessary if accurate Hg flux histories are sought from oligotrophic lake sediments. PMID- 20166658 TI - Application of porcine lipase secreted by pichia pastoris to improve fat digestion and growth performance of postweaning piglets. AB - The aim of the study was to use Pichia pastoris to express a recombinant porcine lipase gene (pLip). The expression-secretion cassette was constructed using the P. pastoris GAPDH (glyceraldehyde-3-phosphate-dehydrogenase) promoter and an 89 residue prepro-alpha-factor secretion signal fused to the AOX1 terminator (the pGAPZalphaA vector). A total of 1,408 bp of pancreatic lipase cDNA was produced, which was located from the position of 4-nt upstream of ATG to 1408-nt inside the intact coding region of the pLip sequence. In an animal trial, three concentrations of recombinant lipase activity (0, 5,000 and 10,000 U/kg) were blended with the basal diet and fed to weaned piglets for six weeks. During the experimental period, the growth performance (bodyweight, feed intake, and feed efficiency) of the test groups was superior to that of the control group (p < 0.05). Furthermore, the group fed the diet blended with 10,000 U/kg of recombinant lipase showed significant (p < 0.05) increases in blood triglyceride (TG) concentration on the seventh day postweaning. These results suggested that the porcine lipase protein yielded by transformed yeast cells may improve fat digestibility and enhance the growth performance in postweaning piglets. PMID- 20166659 TI - Inhibition of epidermal growth factor receptor signaling by Saussurea involucrata, a rare traditional Chinese medicinal herb, in human hormone resistant prostate cancer PC-3 cells. AB - Prostate carcinoma is the most frequently diagnosed malignancy and the second leading cause of death of men in the United States. To date, no effective therapeutic treatment allows abrogation of the progression of prostate cancer to more invasive forms. In this study, we identified Saussurea involucrata Kar. et Kir., a rare traditional Chinese medicinal herb, as a potential agent for androgen-independent prostate cancer patients and investigated its biological mechanism as an antineoplastic agent. S. involucrata caused a concentration- and time-dependent inhibition of cell proliferation in human hormone-resistant prostate cancer PC-3 cells. Moreover, in vitro studies in a panel of several types of human cancer cell lines revealed that S. involucrata inhibited cell proliferation with high potency. To evaluate the bioactive compounds, we successively extracted the S. involucrata with fractions of methanol (SI-1), ethyl acetate (SI-2), n-butanol (SI-3), and water (SI-4). Among these extracts, SI-2 contains the most effective bioactivity. SI-2 treatment resulted in significant time-dependent growth inhibition together with G1 phase cell cycle arrest and apoptosis in PC3 cells. In addition, SI-2 treatment strongly induced p21WAF1/CIP and p27KIP1 expression, independent of the p53 pathway, and downregulated expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4). SI-2 treatment increased levels of Bax, cytochrome c, activated caspase-3, and active caspase-9 and decreased Bcl-2 expression level. One of the major targets for the therapy in prostate cancer can be epidermal growth factor receptor (EGFR). SI-2 markedly reduced phosphorylation of EGFR and inhibited activation of AKT and STAT3. Moreover, p.o. administration of SI-2 induced a dose-dependent inhibition of PC-3 tumor growth in vivo. In summary, our study identifies S. involucrata as an effective inhibitor of EGFR signaling in human hormone-resistant prostate cancer PC-3 cells. We suggest that S. involucrata could be developed as an agent for the management of EGFR-positive human cancers. PMID- 20166660 TI - Postinfection activity, residue levels, and persistence of azoxystrobin, fludioxonil, and pyrimethanil applied alone or in combination with heat and imazalil for green mold control on inoculated oranges. AB - The postinfection activity of azoxystrobin (AZX), fludioxonil (FLU), and pyrimethanil (PYR), applied alone or in combination with imazalil (IMZ), in controlling postharvest green mold in 'Salustiana' oranges inoculated with Penicillium digitatum was studied. Fruits were immersed for 30 or 60 s in (i) water or water mixtures at 20 degrees C containing AZX, FLU, or PYR at 600 mg/L; and (ii) IMZ at 600 mg/L, alone or in combination with AZX, FLU, or PYR at 600 mg/L. Similar treatments were performed at 50 degrees C using the active ingredients at half rates with respect to the treatments at 20 degrees C. Fungicide residues in fruits were analyzed following treatments and after 14 days of simulated shelf life at 17 degrees C. AZX or FLU mixtures at 20 degrees C for 30-60 s similarly but moderately reduced green mold decay with respect to control fruit; differences due to dip time were not significant. Superior control of decay was achieved by PYR and, especially, IMZ, applied alone or in combination with AZX, FLU, or PYR. The activity of PYR at 20 degrees C was significantly dependent on treatment time, whereas that of IMZ and combined treatments at 20 degrees C was not. The effectiveness of FLU or PYR mixtures at 50 degrees C in controlling decay was similar and superior to that of AZX. The action of single- or double-fungicide application was not dependent on dip time in most samples. IMZ or combined mixtures at 50 degrees C were consistently more effective with respect to single-fungicide treatments with AZX, FLU, or PYR. The application of heated fungicide mixtures resulted in significantly higher residue accumulation in most fruit samples compared to treatments performed at 20 degrees C. The degradation rate of fungicides was generally low and dependent on treatment conditions such as time, temperature, and the presence or not of other fungicides. PMID- 20166661 TI - Changes in composition and amino acid profile during dry grind ethanol processing from corn and estimation of yeast contribution toward DDGS proteins. AB - Three sets of samples, consisting of ground corn, yeast, intermediate products, and DDGS, were provided by three commercial dry grind ethanol plants in Iowa and freeze dried before chemical analysis. On average, ground corn contained 70.23% starch, 7.65% protein, 3.26% oil, 1.29% ash, 87.79% total carbohydrate (CHO), and 17.57% total nonstarch CHO, dry matter basis. Results from Plant 1 samples showed that compared to ground corn, there was a slight but significant increase in the contents of protein, amino acids (AA), oil, and ash before fermentation, although starch/dextrin decreased sharply upon saccharification. After fermentation, starch content further decreased to about 6.0%, while protein, oil, and ash contents increased over 3-fold. AA increased 2.0-3.5-fold. Total CHO content decreased by 40%, and the content of total nonstarch CHO increased over 2.5-fold. Concentrations of these attributes fluctuated slightly in the remaining downstream products, but oil and ash were concentrated in thin stillage, while protein was concentrated in distiller grains upon centrifugation. When AA composition is expressed in relative % (protein basis), its changes did not follow that of protein concentration, but the influence of yeast AA profiles on those of downstream products became apparent. Accordingly, a multiple linear regression model for the AA profile of a downstream product as a function of AA profiles of ground corn and yeast was proposed. Regression results indicated that, with an r(2) = 0.95, yeast contributed about 20% toward DDGS proteins, and the rest came from corn. Data from Plants 2 and 3 confirmed those found with Plant 1 samples. PMID- 20166662 TI - Characterization of acetylated corn starch prepared under ultrahigh pressure (UHP). AB - To investigate the impact of ultrahigh pressure (UHP) on the physicochemical properties of the UHP-assisted starch acetate, common corn starch was subjected to either conventional (0.1 MPa, 30 degrees C, 60 min) or UHP-assisted (400 MPa, 25 degrees C, 15 min) acetylation reactions at three levels (4, 8, or 12%) of acetic anhydride. Without significant changes in starch granule crystal structure, UHP-assisted reaction exhibited lower degree of substitution values than conventional reaction across reagent addition levels. An increase in reagent addition levels exhibited common trends in starch solubility/swelling power, gelatinization, and pasting properties for the conventional and UHP-assisted starch acetates relative to native starch. Within an equivalent derivatization level, however, the UHP-assisted (relative to conventional) starch acetates revealed restricted starch solubility/swelling power, reduced gelatinization temperatures, and lower pasting viscosities. Overall, this result suggested that UHP treatment in acetylation reaction might influence the physicochemical properties of starch acetate by facilitating the formation of lipid-complexed amylose or altering granular reaction patterns to acetic anhydride. PMID- 20166663 TI - Kinetics of the 5-hydroxymethylfurfural formation reaction in Chinese rice wine. AB - The kinetics of 5-hydroxymethylfurfural (HMF) formation in Chinese rice wine was investigated under different treatment conditions. Samples I and II were the rough rice wine and outflow fraction of the rice wine from the macroporous resin, respectively. Sample III was the fraction derived from sample II loaded through ion-exchange resin. The HMF content of the different samples under a range of temperature values from 323.15 to 363.15 K was measured by high-performance liquid chromatography. The results demonstrated that the kinetics of HMF formation in sample I was determined as first-order [C(t) = C(0) exp(kt)], but those for samples II and III were found to be the zero-order reaction [C(t) = C(0) + kt]. For all three samples, the relationships of reaction rates (k) and temperature (T) were computed as follows: k(1) = 2.81 x 10(5) exp(-43.01/RT), k(2) = 2.33 x 10(18) exp(-123.90/RT), and k(3) = 1.79 x 10(13) exp(-89.16/RT). By applying the Arrhenius equation k = k(f) exp(-E(a)/RT), the activation energy was 43.01, 123.90, and 89.16 kJ mol(-1), respectively. On the basis of these kinetics equations, weak polar components such as phenolic groups may be involved in HMF formation. PMID- 20166664 TI - Mechanical reconfiguration of stereoisomers. AB - Poly(methyl acrylate) of varying molecular weight was grown from the enantiopure ditopic initiator (R)- or (S)-1,1'-binaphthyl-2,2'-bis-(2-bromoisobutyrate). Subjecting CH(3)CN solutions of high-molecular-weight derivatives (M(N) > 25 kDa) to sonication at 0 degrees C resulted in >95% racemization after 24 h, as determined by circular dichroism; no appreciable racemization was observed in low molecular-weight derivatives. Control experiments excluded the possibility of a thermal racemization mechanism. PMID- 20166665 TI - Catalytic carbon-carbon bond-forming reactions of aminoalkane derivatives with imines. AB - Catalytic C-C bond-forming reactions of aminoalkanes with imines were successfully performed using 9-fluorenylidene as a protecting and activating group of the nitrogen atom. The desired products were obtained in high yields with high diastereoselectivities using KO(t)Bu/18-crown-6 or potassium 2,6 dimethylphenoxide as a catalyst. A wide substrate scope, including simple aminoalkanes and a variety of imines, has been demonstrated. For the products obtained, selective deprotection was possible under acidic conditions to give the desired monoamine and diamine derivatives in high yields with quantitative recovery of 9-fluorenone. A preliminary study of a catalytic asymmetric variant showed promising enantioselectivity in the desired product. PMID- 20166666 TI - Toward structural dynamics: protein motions viewed by chemical shift modulations and direct detection of C'N multiple-quantum relaxation. AB - Multiple quantum relaxation in proteins reveals unexpected relationships between correlated or anti-correlated conformational backbone dynamics in alpha-helices or beta-sheets. The contributions of conformational exchange to the relaxation rates of C'N coherences (i.e., double- and zero-quantum coherences involving backbone carbonyl (13)C' and neighboring amide (15)N nuclei) depend on the kinetics of slow exchange processes, as well as on the populations of the conformations and chemical shift differences of (13)C' and (15)N nuclei. The relaxation rates of C'N coherences, which reflect concerted fluctuations due to slow chemical shift modulations (CSMs), were determined by direct (13)C detection in diamagnetic and paramagnetic proteins. In well-folded proteins such as lanthanide-substituted calbindin (CaLnCb), copper,zinc superoxide dismutase (Cu,Zn SOD), and matrix metalloproteinase (MMP12), slow conformational exchange occurs along the entire backbone. Our observations demonstrate that relaxation rates of C'N coherences arising from slow backbone dynamics have positive signs (characteristic of correlated fluctuations) in beta-sheets and negative signs (characteristic of anti-correlated fluctuations) in alpha-helices. This extends the prospects of structure-dynamics relationships to slow time scales that are relevant for protein function and enzymatic activity. PMID- 20166667 TI - Nanocrystal growth on graphene with various degrees of oxidation. AB - We show a general two-step method for growing hydroxide and oxide nanocrystals of the iron family elements (Ni, Co, Fe) on graphene with two degrees of oxidation. Drastically different nanocrystal growth behaviors were observed on low-oxidation graphene sheets (GS) and highly oxidized graphite oxide (GO) in hydrothermal reactions. Small particles precoated on GS with few oxygen-containing surface groups diffused and recrystallized into single-crystalline Ni(OH)(2) hexagonal nanoplates or Fe(2)O(3) nanorods with well-defined morphologies. In contrast, particles precoated on GO were pinned by the high-concentration oxygen groups and defects on GO without recrystallization into well-defined shapes. Adjusting the reaction temperature can be included to further control materials grown on graphene. For materials with weak interactions with graphene, increasing the reaction temperature can lead to diffusion and recrystallization of surface species into larger crystals, even on highly oxidized and defective GO. Our results suggest an interesting new approach for controlling the morphology of nanomaterials grown on graphene by tuning the surface chemistry of graphene substrates used for crystal nucleation and growth. PMID- 20166668 TI - Alkynes as equivalents of alpha-diazo ketones in generating alpha-oxo metal carbenes: a gold-catalyzed expedient synthesis of dihydrofuran-3-ones. AB - An expedient and reliable method for accessing reactive alpha-oxo gold carbenes via gold-catalyzed intermolecular oxidation of terminal alkynes has been developed. Significantly, this method offers a safe and economical alternative to the strategies based on diazo substrates. Its synthetic potential is demonstrated by expedient preparation of dihydrofuran-3-ones containing a broad range of functional groups. PMID- 20166670 TI - Enhanced cell surface polymer grafting in concentrated and nonreactive aqueous polymer solutions. AB - Macromolecular cell surface modification techniques have shown tremendous utility in various biomedical applications. However, a major drawback concerns inefficient cell surface modification caused by the poor association of hydrophilic macromolecules with cell surfaces. Here, a novel, highly efficient, and universal strategy in which nonreactive "additive" macromolecules are used to modulate the grafting efficiency of cell surface reactive, hydrophilic macromolecules is described. Unprecedented enhanced cell surface modifications by up to 10-fold were observed when various concentrations of a suitable "additive" polymer was present with a constant and low concentration of a "reactive" macromolecule. The importance of this increased efficiency and the possible mechanisms involved are discussed. The cell compatible technique is demonstrated in the case of four different cell types--red blood cells (RBC), leukocytes, platelets, and Jurkat cells. A practical application of grafting macromolecules to cell surfaces in concentrated polymer solutions is demonstrated by the enhanced camouflage of RBC surface antigens for the development of RhD null RBC. In principle, the technique can be adapted to various macromolecular systems and cell types, with significant potential for biomedical applications such as live cell based technologies. PMID- 20166669 TI - Synthetic and mechanistic studies on Pd(0)-catalyzed diamination of conjugated dienes. AB - Various dienes and a triene can be regioselectively diaminated at the internal double bond with good yields and high diastereoselectivity using di-tert butyldiaziridinone (5) as the nitrogen source and Pd(PPh(3))(4) (1-10 mol %) as the catalyst. Kinetic studies with (1)H NMR spectroscopy show that the diamination is first-order in total Pd catalyst and inverse first-order in PPh(3). For reactive dienes, such as 1-methoxybutadiene (6g) and alkyl 1,3 butadienes (6a, 6j), the diamination is first-order in di-tert-butyldiaziridinone (5) and zero-order in the olefin. For olefins with relatively low reactivity, such as (E)-1-phenylbutadiene (6b) and (3E,5E)-1,3,5-decatriene (6i), similar diamination rates were observed when 3.5 equiv of olefins were used. Pd(PPh(3))(2) is likely to be the active species for the insertion of Pd(0) into the N-N bond of di-tert-butyldiaziridinone (5) to form a four-membered Pd(II) complex (A), which can be detected by NMR spectroscopy. The olefin complex (B), formed from intermediate A via ligand exchange between the olefin substrate and the PPh(3), undergoes migratory insertion and reductive elimination to give the diamination product and regenerate the Pd(0) catalyst. PMID- 20166671 TI - Selectively nonselective kinase inhibition: striking the right balance. PMID- 20166672 TI - Positive frequency shifts observed upon adsorbing micron-sized solid objects to a quartz crystal microbalance from the liquid phase. AB - By specifically binding derivatized colloidal particles and physisorbing nonderivatized particles to the surface of a quartz crystal microbalance (QCM), we have observed positive shifts of frequency, Deltaf, in contrast to the negative frequency shifts typically found in adsorption experiments. Evidently, the Sauerbrey relation does not apply to this situation. A comparison of frequencies shifts and bandwidths on different overtones reveals a coupled resonance: at low overtones, Deltaf is negative, whereas it is positive at high overtones, with maximal resonance bandwidth observed at the crossover point. As predicted by the Dybwad model, the spheres bound to the surface form resonating systems on their own. A composite resonator is formed, consisting of a large crystal with resonance frequency omega and the adsorbed spheres with resonance frequency omega(S). In the case in which the resonance frequency of the small spheres (firmly attached to crystal), omega(S), is higher than the resonance frequency of the crystal, omega, Deltaf of the composite system is negative (leading to the Sauerbrey limit). In the opposite limit (that is, in the case of large adsorbed particles bound to the sensor surface via a sufficiently weak bridge) Deltaf is positive. Such a behavior is known from sphere-plate contacts in the dry state. Finite element calculation demonstrates that this phenomena is also plausible in liquid phase media, with Deltaf critically dependent on the strength of the sphere-plate contact. Operated in this mode, the QCM most likely probes the contact strength, rather than the mass of the particle. PMID- 20166673 TI - Histochemical application of a peroxidase DNAzyme with a covalently attached hemin cofactor. AB - The enzyme horseradish peroxidase is routinely used in immunohistochemistry to facilitate the chromogenic oxidation of 3,3'-diaminobenzidine, producing an insoluble brown precipitate marking the location and quantity of a tissue protein. In an effort to develop non-protein reagents for tissue diagnostics, we have developed a peroxidase DNAzyme construct that can be used as a chromogenic functional group in immunohistochemistry assays. The DNAzyme is based on a reported 18-mer G-quadruplex-forming DNA sequence, PS2.M, and has been covalently linked to its catalytically active moiety, hemin, to avoid the high background signal associated with the use of free hemin in histochemical studies. The activity of the covalent construct is maintained under conditions where G quadruplex formation is unfavored and where the noncovalent DNAzyme-hemin complex has no activity. PMID- 20166675 TI - Specific effects of surface amines on polystyrene nanoparticles in their interactions with mesenchymal stem cells. AB - We have investigated the uptake of cationic polystyrene nanoparticles by mesenchymal stem cells (MSCs) using confocal fluorescence microscopy and flow cytometry. Two types of nanoparticles of about 100 nm diameter with similar zeta potentials were employed in this study, plain polystyrene (PS) nanoparticles and amino-functionalized polystyrene (NPS) nanoparticles, each carrying about 6000 amino groups on the surface. To assess the relative importance of specific endocytosis mechanisms, uptake was observed in the presence of the drugs dynasore and chlorpromazine. NPS nanoparticles were rapidly internalized and accumulated to a much higher level in MSCs than PS nanoparticles, predominantly via the main clathrin-mediated pathway. PS nanoparticles were internalized mainly via clathrin independent endocytosis. The pronounced difference in the internalization behavior of PS and NPS nanoparticles points to specific interactions of the amino groups on the nanoparticle surface with the endocytosis machinery of the cells. PMID- 20166676 TI - Linker chemistry determines secondary structure of p5314-29 in peptide amphiphile micelles. AB - Biofunctional micelles formed via self-assembly of synthetic peptide-lipid conjugates are a class of promising biomaterials with applications in drug delivery and tissue engineering. The micelle building block, termed peptide amphiphile, consists of a lipid-like chain covalently linked through a spacer to a peptide headgroup. Self-assembly results in formation of a hydrophobic core surrounded by a dense shell with multiple, functional peptides. We report here on the effect that different linkers between a palmitic tail and a bioactive peptide (p5314-29) have on headgroup secondary structure. Peptide p5314-29 may act as an inhibitor of the interaction between tumor suppressor p53 and human double minute 2 (hDM2) proteins by binding hDM2 in a partially helical form, leading to the release of p53 and the induction of apoptosis in certain tumors. Circular dichroism and fluorescence spectroscopy data revealed that the extent and type of secondary structure of p5314-29 are controlled through size and hydrogen bond potential of the linker. In addition, the structure of the self-assembled micelles was influenced through linker-dependent altered headgroup interactions. This study provides insight into the mechanisms through which headgroup structuring occurs on peptide amphiphile micelles, with implications on the bioactivity, stability, and morphology of the self-assembled entities. PMID- 20166677 TI - Synthesis and AFM characterization of poly(dG)-poly(dC)-gold nanoparticle conjugates. AB - In the present work, we have synthesized conjugates between the 5 nm gold nanoparticles (Au-NP) and 5' thiol-functionalized, 700 bp poly(dG)-poly(dC). We have completely separated and purified to homogeneity conjugates bearing different number of poly(dG)-poly(dC) molecules per Au-NP by electrophoresis and HPLC. The conjugates were directly visualized by atomic force microscopy. We have demonstrated that Au NP-bound poly(dG)-poly(dC) can be considerably extended by Klenow exo(-) polymerase in the presence of dCTP and dGTP. PMID- 20166678 TI - Bioinspired synthesis and characterization of gadolinium-labeled magnetite nanoparticles for dual contrast t1- and T2-weighted magnetic resonance imaging. AB - Gadolinium-labeled magnetite nanoparticles (GMNPs) were synthesized via a bioinspired manner to use as dual contrast agents for T1- and T2-weighted magnetic resonance imaging. A mussel-derived adhesive moiety, 3,4-dihydroxy-l phenylalanine (DOPA), was utilized as a robust anchor to form a mixed layer of poly(ethylene glycol) (PEG) chains and dopamine molecules on the surface of iron oxide nanoparticles. Gadolinium ions were subsequently complexed at the distal end of the dopamine molecules that were prefunctionalized with a chelating ligand for gadolinium. The resultant GMNPs exhibited high dispersion stability in aqueous solution. Crystal structure and superparamagnetic properties of magnetite nanocrystals were also maintained after the complexation of gadolinium. The potential of GMNPs as dual contrast agents for T1 and T2-weighted magnetic resonance imaging was demonstrated by conducting in vitro and in vivo imaging and relaxivity measurements. PMID- 20166679 TI - Supramolecular hydrogels exhibiting fast in situ gel forming and adjustable degradation properties. AB - Fast in situ forming supramolecular hydrogels consisted of the tyramine conjugated supramolecular structures and chitosan derivative were prepared via an enzymatic reaction with horseradish peroxidase (HRP) and hydrogen peroxide (H(2)O(2)). The gel formation was varied within a time period of 5 s to 10 min by controlling the concentrations of HRP, H(2)O(2), and polymers. Tyramine conjugation at different sites of the supramolecular structure resulted in significant changes in physical properties and the degradation time of the hydrogels that were confirmed by water uptake, compressive strength and degradation tests. In addition, the hydrogels showed a good cytocompatibility in vitro. These hydrogels could be promising injectable biomaterials with adjustable degradation times to control both the cellular behaviors as a regenerative cell matrix and the drug release behavior as a drug delivery vehicle. PMID- 20166680 TI - Complement protein C1q recognizes enzymatically modified low-density lipoprotein through unesterified fatty acids generated by cholesterol esterase. AB - We previously reported that enzymatically modified low-density lipoprotein (E LDL) particles obtained by LDL treatment with trypsin and then cholesterol esterase are recognized by C1q and activate the C1 complex of complement. The objective of this study was to identify the E-LDL component(s) recognized by C1q. In addition to trypsin, plasmin, thrombin, tryptase, and matrix metalloprotease-2 each yielded E-LDL particles with high C1-activating efficiency, and the C1 activation extent was strictly dependent on cholesterol esterase treatment in all cases. When incorporated into vesicles, the lipid fraction of E-LDL, but not of native LDL, triggered C1 activation, and activation correlated with the amount of unesterified cholesterol generated by cholesterol esterase. Whereas treatment of E-LDL particles with human serum albumin reduced their fatty acid content, both cholesterol and unesterified fatty acids were decreased by methyl-beta cyclodextrin, both treatments resulting in dose-dependent inhibition of the C1 activating ability of the particles. Incorporation of linoleic acid into phosphatidylcholine-containing model vesicles enabled them to interact with the C1q globular domain and to trigger C1 activation, and cholesterol enhanced both processes by facilitating incorporation of the fatty acid into the vesicles. Direct evidence that C1q binds E-LDL through its globular domains was obtained by electron microscopy. This study demonstrates that C1 binding to E-LDL particles involves recognition by the C1q globular domain of the unesterified fatty acids generated by cholesterol esterase. The potential implications of these findings in atherogenesis are discussed. PMID- 20166681 TI - Coassembly of oppositely charged short peptides into well-defined supramolecular hydrogels. AB - Two types of oppositely charged short peptides comprised of a hydrophobic N fluorenyl-9-methoxycarbonyl (FMOC) tail and a peptide backbone were designed and prepared via a standard solid phase peptide (SPPS) technique. When mixing these two oppositely charged peptides in water at a neutral pH, a supramolecular hydrogel with fibroid morphology could be formed via the electrostatic attraction triggered coassembly. The spectroscopic techniques indicated that the hydrogen bonding interactions of the peptide backbones resulted in the formation of antiparallel beta-sheet like superstructure, and the fluorenyl rings connected to the peptide backbones were thus pi-stacked with each other through an antiparallel fashion in the formed nanofibers. Due to the weak flexibility of peptide chains and steric hindrance of rigid fluorenyl rings during the initial process of the coassembly of the oppositely charged peptides, a relatively slow self-assembly was presented, and a higher concentration of the oppositely charged peptides was necessary for this supramolecular hydrogel formation. The strategy demonstrated in this study can be developed as a convenient approach for different types of short peptides to coassemble into a supramolecular hydrogel with multiple functions for the biomedical applications. PMID- 20166682 TI - Implicit electrostatic solvent model with continuous dielectric permittivity function. AB - The modification of the electrostatic continuum solvent model considered in the present work is based on the exact solution of the Poisson equation, which can be constructed provided that the dielectric permittivity epsilon of the total solute and solvent system is an isotropic and continuous spatial function. This assumption allows one to formulate a numerically efficient and universal computational scheme that covers the important case of a variable epsilon function inherent to the solvent region. The obtained type of solution is unavailable for conventional dielectric continuum models such as the Onsager and Kirkwood models for spherical cavities and the polarizable continuum model (PCM) for solute cavities of general shape, which imply that epsilon is discontinuous on the boundary confining the excluded volume cavity of the solute particle. Test computations based on the present algorithm are performed for water and several nonaqueous solvents. They illustrate specific features of this approach, called the "smooth boundary continuum model" (SBCM), as compared to the PCM procedure, and suggest primary tentative results of its parametrization for different solvents. The calculation for the case of a binary solvent mixture with variable epsilon in the solvent space region demonstrates the applicability of this approach to a novel application field covered by the SBCM. PMID- 20166683 TI - Evaluating binuclear copper(II) complexes for glycoside hydrolysis. AB - Three binuclear copper(II) complexes were characterized as solids by X-ray diffraction and in solution by UV/vis spectrophotometric titration, and subsequently evaluated for their glycosidase-like activity. The structure analysis revealed comparable intermetallic Cu...Cu distances (approximately 3.5 A) for the complexes 2 and 3. Despite this similarity, the composition of the complexes differs significantly in aqueous solution as revealed by spectrophotometric titrations. The hydrolysis of selected nitrophenylglycopyranosides is up to 11,000-fold accelerated over background in the presence of the copper(II) complexes in 3-(cyclohexylamino)-1-propanesulfonic acid (CAPS) buffer at pH 10.5 and 30 degrees C. PMID- 20166684 TI - Structure determination and relative properties of novel chiral orthoborate KMgBO3. AB - A novel chiral orthoborate, KMgBO(3), has been successfully synthesized via a standard solid-state reaction, and the crystal structure has been determined from powder X-ray diffraction data. It crystallizes in the cubic chiral space group P2(1)3. Isolated [BO(3)](3-) anionic groups, which are the fundamental building units, are distributed around the 111 crystallographic direction in an axial C(3) symmetry, and the configuration of O(3) planes is helical, similar to the aplanar ClO(3) groups in NaClO(3), which indicates an optical activity in it and is validated by the circular dichroism spectrum. The chiral feature of the borate is unique, and because of the noncentrosymmetric structure, the compound exhibits nonlinear optical properties, which are validated by second harmonic generation powder measurement. It has a wide transparency, including the vacuum ultraviolet region. The relations between the structures of KMgBO(3) and NaClO(3) and structural conversion form KMgBO(3) to NaMgBO(3) are also discussed. The ionic radii, interatomic distance, and the rigid tilting of BO(3) groups are considered to be the main factors in the crystallization of different structures. PMID- 20166685 TI - Halogen photoreductive elimination from metal-metal bonded iridium(II)-gold(II) heterobimetallic complexes. AB - Halogen oxidation of [Ir(I)Au(I)(dcpm)(2)(CO)X](PF(6)) (dcpm = bis(dicyclohexylphosphino)methane, X = Cl, Br) and [Ir(I)Au(I)(dppm)(2)(CN(t)Bu)(2)](PF(6))(2) (dppm = bis(diphenylphosphino)methane) furnishes the heretofore unknown class of d(7) d(9) compounds comprising an Ir(II)Au(II) heterobimetallic core. A direct metal metal bond is evident from a 0.2 A contraction in the intermetallic distance, as determined by X-ray crystallography. The photophysical consequence of iridium gold bond formation, as elucidated by experimental and computational investigations, is an electronic structure dominated by a sigma --> sigma* transition that possesses significant ligand-to-metal charge transfer (LMCT) character. Accordingly, these compounds are non-emissive but photoreactive. Excitation of Ir(II)Au(II) complexes in the presence of a halogen trap prompts a net photoreductive elimination of halogen and the production of the two-electron reduced Ir(I)Au(I) species with about 10% quantum efficiency. The Ir(II)Au(II) complexes add to a growing library of d(7)-d(9) heterobimetallic species from which halogen elimination may be driven by a photon. PMID- 20166686 TI - Electronic structure of a paramagnetic {MNO}6 complex: MnNO 5,5-tropocoronand. AB - Using density functional theory (OLYP/STO-TZP) calculations, we have investigated the electronic structure of [Mn(5,5-tropocoronand)(NO)], a rare paramagnetic {MNO}(6) complex. Experimental methods, including magnetic susceptibility measurements and high-field electron paramagnetic resonance spectroscopy, have not provided an unambiguous spin state assignment for this complex. In other respects, however, the compound was fully characterized, including by means of single-crystal X-ray structure determination. The optimized S = 1 OLYP geometry reproduced all key aspects of the trigonal-bipyramidal molecular structure, including a short Mn-N(O) distance (approximately 1.7 A) and an essentially linear MnNO angle. In contrast, the S = 0 and S = 2 optimized structures disagreed with the crystal structure in critical respects. Moreover, three different exchange-correlation functionals (OLYP, B3LYP, and B3LYP*) indicated an S = 1 ground state by a clear margin of energy. An examination of the Kohn-Sham MOs of this state indicated a primarily d(xz)(2)d(yz)(2)d(xy)(1)d(x(2)-z(2))(1) electronic configuration, where the z axis is identified with the nearly linear MnNO axis. The d(y(2)) orbital is formally unoccupied in this state, interacting, as it does, head-on with two tropocoronand nitrogens lying along the y axis, the pseudo-3-fold axis of the trigonal bipyramid. The doubly occupied d(xz) and d(yz) orbitals are in actuality d(pi)(Fe)-pi*(NO)-based pi-bonding molecular orbitals, the alpha and beta "components" of which are significantly offset spatially. This offset results in excess minority spin density on the NO unit. Thus, the OLYP/TZP atomic spin populations are Mn, 2.85; N(O), -0.52; and O, -0.35. PMID- 20166687 TI - Interaction of SbCl5(2-) and thioether groups at the open coordination sites of platinum(II) diimine complexes. AB - In the solid-state, the approximately square planar cation in orange crystals of [Pt(NO(2)phen)(ttcn)](PF(6))(2) (NO(2)phen = 5-nitro-1,10-phenanthroline; ttcn = 1,4,7-trithiacyclononane) has a short apical Pt...S(ttcn) distance (2.9415(15) A). In acetonitrile solution, the electronic spectrum shows a long-wavelength absorption band (412 nm; 2200 M(-1) cm(-1)), consistent with the notion that the axial Pt...S(ttcn) interactions stabilize states having metal-to-ligand charge transfer (MLCT) character. Reaction with the hexachloroantimonate(V) salt of tris(4-bromophenyl)aminium (TBPA(+)) results in complex redox chemistry, involving the platinum complex, SbCl(5)(2-) and TBPA(+). In the case of Pt(bpy)(ttcn)(2+), orange-yellow crystals of [Pt(bpy)(ttcn)](2)(Sb(4)Cl(16)) were isolated from the reaction, whereas the reaction with Pt(NO(2)phen)(ttcn)(2+) consistently yielded red crystals of [Pt(NO(2)phen)(ttcn)](SbCl(5)) x 2 CH(3)CN. In the latter case, the geometry of the cation, including the apical Pt...S(ttcn) distance (2.9390(12) A), is very similar to that of the PF(6)(-) salt. However, the basal plane of each square pyramidal SbCl(5)(2-) opposes the nearly parallel coordination plane of an adjacent Pt(NO(2)phen)(ttcn)(2+) complex, resulting in an unusually short intermolecular Pt...Sb distance of 3.4259(3) A. The longest wavelength maximum in the diffuse reflectance spectrum and the solid-state emission maximum are shifted by approximately 1200 cm(-1) and approximately 700 cm(-1), respectively, to the red of those of the PF(6)(-) salt, consistent with perturbation of the complex's electronic structure because of the Pt...Sb interaction. PMID- 20166688 TI - Computational study of factors controlling the boat and chair transition states of Ireland-Claisen rearrangements. AB - The origins of the boat transition state preference in the Ireland-Claisen rearrangements studied experimentally by Kishi and co-workers have been explored computationally with Density Functional Theory. Steric interactions in the chair transition states were identified as the principal reason for the boat transition state preference. PMID- 20166689 TI - A new class of C3-symmetrical hemicryptophane hosts: triamide- and tren hemicryptophanes. AB - The first hemicryptophanes derived from tris(N-alkyl-carbamoylmethyl)amine and tris(2-aminoethyl)amine (tren) have been synthesized following a single synthetic pathway that allows the subsequent formation of the two heteroditopic hosts 3 and 4. X-ray crystal structures show a well-defined cavity encapsulating a solvent guest for both compounds emphasizing their complexation properties. PMID- 20166690 TI - Controlling the equilibrium of formic acid with hydrogen and carbon dioxide using ionic liquid. AB - The equilibrium for the reversible decomposition of formic acid into carbon dioxide and hydrogen is studied in the ionic liquid (IL) 1,3-dipropyl-2 methylimidazolium formate. The equilibrium is strongly favored to the formic acid side because of the strong solvation of formic acid in the IL through the strong Coulombic solute-solvent interactions. The comparison of the equilibrium constants in the IL and water has shown that the pressures required to transform hydrogen and carbon dioxide into formic acid can be reduced by a factor of approximately 100 by using the IL instead of water. The hydrogen transformation in such mild conditions can be a chemical basis for the hydrogen storage and transportation using formic acid. PMID- 20166691 TI - Matrix isolation and ab initio study of trans-trans and trans-cis dimers of formic acid. AB - Six trans-trans and five trans-cis dimeric structures of formic acid (HCOOH) are revealed by ab initio calculations. Four trans-trans and two trans-cis dimers are identified in the IR absorption spectra in argon matrices. The trans-cis dimers are obtained by narrow-band IR excitation of the vibrational transitions of the trans-trans dimers. Two trans-trans (tt3 and tt6) and one trans-cis (tc4) dimer are characterized experimentally for the first time. The tunneling decay rates of two trans-cis dimers (tc1 and tc4) are evaluated at different temperatures. A greater lifetime of the trans-cis dimers at elevated temperatures compared to the cis-monomer suggests that the high-energy conformers can be stabilized upon hydrogen bonding. PMID- 20166692 TI - Theoretical studies for the rates and kinetic isotope effects of the excited state double proton transfer in the 1:1 7-azaindole:H2O complex using variational transition state theory including multidimensional tunneling. AB - Variational transition state theory calculations including multidimensional tunneling (VTST/MT) for excited-state tautomerization in the 1:1 7 azaindole:H(2)O complex were performed. Electronic structures and energies for reactant, product, transition state, and potential energy curves along the reaction coordinate were computed at the CASSCF(10,9)/6-31G(d,p) level of theory. The potential energies were corrected by second-order multireference perturbation theory to take the dynamic electron correlation into consideration. The final potential energy curves along the reaction coordinate were generated at the MRPT2//CASSCF(10,9)/6-31G(d,p) level. Two protons in the excited-state tautomerization are transferred concertedly, albeit asynchronously. The position of the variational transition state is very different from the conventional transition state, and is highly dependent on isotopic substitution. Rate constants were calculated using VTST/MT, and were on the order of 10(-6) s(-1) at room temperature. The HH/DD kinetic isotope effects are consistent with experimental observations; consideration of both tunneling and variational effects was essential to predict the experimental values correctly. PMID- 20166693 TI - Anion influence on thermophysical properties of ionic liquids: 1-butylpyridinium tetrafluoroborate and 1-butylpyridinium triflate. AB - The thermophysical properties of two pyridinium-based ionic liquids, 1 butylpyridinium tetrafluoroborate and 1-butylpyridinium triflate, have been measured. Thus, densities, refractive indices, speeds of sound, viscosities, surface tensions, isobaric molar heat capacities, and thermal properties have been experimentally determined over a wide range of temperatures. The comparison of the properties of the two ionic liquids has allowed us to analyze in detail the anion influence. Moreover, useful derived properties have been calculated from the results. On the other hand, the influence of the lack of a substituent in the cation has been evaluated when properties of 1-butylpyridinium tetrafluoroborate have been contrasted to those of 1-butyl-n-methylpyridinium tetrafluoroborate, (n = 2, 3, or 4). The study has been carried out paying special attention to interactions between ions in order to elucidate the desired relationship between properties and structural characteristics of ionic liquids. PMID- 20166694 TI - 2D-IR study of a photoswitchable isotope-labeled alpha-helix. AB - A series of photoswitchable, alpha-helical peptides were studied using two dimensional infrared spectroscopy (2D-IR). Single-isotope labeling with (13)C(18)O at various positions in the sequence was employed to spectrally isolate particular backbone positions. We show that a single (13)C(18)O label can give rise to two bands along the diagonal of the 2D-IR spectrum, one of which is from an amide group that is hydrogen-bonded internally, or to a solvent molecule, and the other from a non-hydrogen-bonded amide group. The photoswitch enabled examination of both the folded and unfolded state of the helix. For most sites, unfolding of the peptide caused a shift of intensity from the hydrogen-bonded peak to the non-hydrogen-bonded peak. The relative intensity of the two diagonal peaks gives an indication of the fraction of molecules hydrogen-bonded at a certain location along the sequence. As this fraction varies quite substantially along the helix, we conclude that the helix is not uniformly folded. Furthermore, the shift in hydrogen bonding is much smaller than the change of helicity measured by CD spectroscopy, indicating that non-native hydrogen-bonded or mis folded loops are formed in the unfolded ensemble. PMID- 20166695 TI - Transport and modeling of estrogenic hormones in a dairy farm effluent through undisturbed soil lysimeters. AB - The presence of endocrine-disrupting chemicals, including estrone (E1) and 17beta estradiol (E2), in surface waters has been associated with physiological dysfunction in a number of aquatic organisms. One source of surface and groundwater contamination with E1 and E2 is the land application of animal wastes. The processes involved in the transport of these hormones in the soil, when applied with animal wastes, are still unclear. Therefore, a field-transport experiment was carried out, where a dairy farm effluent spiked with E1 and E2 was applied on large (50 cm diameter and 70 cm depth) undisturbed soil lysimeters. The concentrations of E1 and E2 in the leachate were monitored over a 3-month period, during which irrigation was applied. The experimental data suggest that E1 and E2 were transported through preferential/macropore flow pathways. The data from the experiment also show that E1 and E2 are leached earlier than the inert tracer (bromide). This observation can be explained either by the presence of antecedent concentrations in the soil or by an enhanced transport of E1 and E2 through the soil. A state-space mixing-cell model was further developed in order to describe the transport of E1 and E2 by three transport processes in parallel. The inverse modeling of the leaching data did not support the hypothesis that antecedent concentrations of estrogens could be responsible for the observed breakthrough curves but confirmed that estrogens were transported mainly via preferential/macropore flow and also via an enhanced transport. The parameter values that characterized this enhanced transport strongly suggest that this enhanced transport is mediated by colloids. For the first time, the simultaneous transport of E1 and E2 was modeled under transient conditions, taking into account the advection-dispersion, preferential/macropore flow, and colloidal enhanced transport processes as well as E1 and E2 dissipation in the soil. These findings have major implications in terms of management practices to decrease E1 and E2 transport and water contamination. PMID- 20166696 TI - Copper-transfer mechanism from the human chaperone Atox1 to a metal-binding domain of Wilson disease protein. AB - The molecular details of how copper (Cu) is transferred from the human Cu chaperone Atox1 to metal-binding domains (MBDs) of P(1B)-type ATPases are still unclear. Here, we use a computational approach, employing quantum mechanics/molecular mechanics (QM/MM) methods, to shed light on the reaction mechanism [probable intermediates, Cu(I) coordination geometries, activation barriers, and energetics] of Cu(I) transfer from Atox1 to the fourth MBD of Wilson disease protein (WD4). Both Atox1 and WD4 have solvent-exposed metal binding motifs with two Cys residues that coordinate Cu(I). After assessing the existence of all possible 2-, 3- and 4-coordinate Cu-intermediate species, one dominant reaction path emerged. First, without activation barrier, WD4's Cys1 binds Cu(I) in Atox1 to form a 3-coordinated intermediate. Next, with an activation barrier of about 9.5 kcal/mol, a second 3-coordinated intermediate forms that involves both of the Cys residues in WD4 and Cys1 of Atox1. This species can then form the product by decoordination of Atox1's Cys1 (barrier of about 8 kcal/mol). Overall, the Cu-transfer reaction from Atox1 to WD4 appears to be kinetically accessible but less energetically favorable (DeltaE = 7.7 kcal/mol). Our results provide unique insights into the molecular mechanism of protein-mediated Cu(I) transfer in the secretory pathway and are in agreement with existing experimental data. PMID- 20166698 TI - Nanoscale shape and size control of cubic, cuboctahedral, and octahedral Cu-Cu2O core-shell nanoparticles on Si(100) by one-step, templateless, capping-agent-free electrodeposition. AB - Cu-Cu2O core-shell nanoparticles (NPs) of different shapes over an extended nanosize regime of 5-400 nm have been deposited on a H-terminated Si(100) substrate by using a simple, one-step, templateless, and capping-agent-free electrochemical method. By precisely controlling the electrolyte concentration [CuSO4 x 5H2O] below their respective critical values, we can obtain cubic, cuboctahedral, and octahedral NPs of different average size and number density by varying the deposition time under a few seconds (<6 s). Combined glancing incidence X-ray diffraction and depth-profiling X-ray photoelectron spectroscopy studies show that these NPs have a crystalline core-shell structure, with a face centered cubic metallic Cu core and a simple cubic Cu2O shell with a CuO outerlayer. The shape control of Cu-Cu2O core-shell NPs can be understood in terms of a diffusion-limited progressive growth model under different kinetic conditions as dictated by different [CuSO4 x 5H2O] concentration regimes. PMID- 20166697 TI - Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. AB - The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4 (dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5 triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described. PMID- 20166699 TI - Single-step assembly of homogenous lipid-polymeric and lipid-quantum dot nanoparticles enabled by microfluidic rapid mixing. AB - A key challenge in the synthesis of multicomponent nanoparticles (NPs) for therapy or diagnosis is obtaining reproducible monodisperse NPs with a minimum number of preparation steps. Here we report the use of microfluidic rapid mixing using hydrodynamic flow focusing in combination with passive mixing structures to realize the self-assembly of monodisperse lipid-polymer and lipid-quantum dot (QD) NPs in a single mixing step. These NPs are composed of a polymeric core for drug encapsulation or a QD core for imaging purposes, a hydrophilic polymeric shell, and a lipid monolayer at the interface of the core and the shell. In contrast to slow mixing of lipid and polymeric solutions, rapid mixing directly results in formation of homogeneous NPs with relatively narrow size distribution that obviates the need for subsequent thermal or mechanical agitation for homogenization. We identify rapid mixing conditions that result in formation of homogeneous NPs and show that self-assembly of polymeric core occurs independent of the lipid component, which only provides stability against aggregation over time and in the presence of high salt concentrations. Physicochemical properties of the NPs including size (35-180 nm) and zeta potential (-10 to +20 mV in PBS) are controlled by simply varying the composition and concentration of precursors. This method for preparation of hybrid NPs in a single mixing step may be useful for combinatorial synthesis of NPs with different properties for imaging and drug delivery applications. PMID- 20166700 TI - Solid nanotubes comprising alpha-Fe2O3 nanoparticles prepared from ferritin protein. AB - Solid nanotubes comprising alpha-Fe2O3 nanoparticles were prepared from iron storage protein ferritin. Their structure, magnetic properties, and photocatalytic activities were characterized. The initial ferritin nanotube precursors were fabricated using alternating layer-by-layer depositions of poly-L arginine (PLA) and ferritin into a track-etched polycarbonate membrane (pore diameter, 400 nm) with subsequent dissolution of the template. The obtained uniform cylinders of (PLA/ferritin)3 (outer diameter, 410 +/- 14 nm) were calcinated at 500 degrees C under air, yielding reddish-brown iron oxide nanotubes. The one-dimensional hollow structure remained perfect, but its diameter, wall thickness, and maximum length were markedly diminished. Disappearance of the protein shell and the PLA layers were confirmed using IR and EDX spectroscopy. Subsequent SEM, TEM, and XPS measurements showed that the tubular walls comprise fine alpha-Fe2O3 nanoparticles with a 5 nm diameter. These alpha-Fe2O3 nanotubes demonstrated superparamagnetic properties with a blocking temperature of 37 K and efficient photocatalytic activity for degradation of 4 chlorophenol. PMID- 20166701 TI - Isolation and biological evaluation of 8-epi-malyngamide C from the Floridian marine cyanobacterium Lyngbya majuscula. AB - A new stereoisomer of malyngamide C, 8-epi-malyngamide C (1), and the known compound lyngbic acid [(4E,7S)-7-methoxytetradec-4-enoic acid] were isolated from a sample of Lyngbya majuscula collected near Bush Key, Dry Tortugas, Florida. The structure of 1 was determined by NMR and MS experiments. The absolute configuration of 1 was determined by selective Mitsunobu inversion of C-8 to give malyngamide C, as determined by NMR, MS, and comparison of specific rotation. Both 1 and malyngamide C were found to be cytotoxic to HT29 colon cancer cells (IC(50) 15.4 and 5.2 microM, respectively) and to inhibit bacterial quorum sensing in a reporter gene assay. PMID- 20166702 TI - Isomeric tropane alkaloids from the aerial parts of Schizanthus tricolor. AB - Investigation of the aerial parts of Schizanthus tricolor yielded seven isomeric tropane alkaloids: 3alpha-(1-methylitaconyl)-6beta-senecioyloxytropane (1), 3alpha-(1-methylitaconyl)-6beta-angeloyloxytropane (2), 3alpha-(1 methylmesaconyl)-6beta-senecioyloxytropane (3), 3alpha-(1-methylmesaconyl)-6beta angeloyloxytropane (4), 3alpha-(1-methylmesaconyl)-6beta-tigloyloxytropane (5), 3alpha-(1-methylcitraconyl)-6beta-senecioyloxytropane (6), and 3alpha-(1 methylcitraconyl)-6beta-angeloyloxytropane (7). Their structures were established by NMR including (1)H, (13)C NMR, HSQC, HMBC, COSY, and NOESY experiments, UV, IR, and mass spectrometry. Compounds 1, 6, and 7 are new to the literature. Alkaloids 1, 3, 4, and 5 and a mixture of 3, 4, and 5 were evaluated for in vitro antiplasmodial and cytotoxic activity. Compounds 1, 4, and 5 showed marginal inhibition of Plasmodium falciparum strain K1 with IC(50) values of 22.8, 24.8, and 36.0 microM and displayed no cytotoxicity on MRC-65 cells (CC(50) > 64 microM). Alkaloid 3 was inactive (IC(50) 63.5 microM). The alkaloid mixture exhibited slightly higher activity (IC(50) 17.0 microM) than the pure compounds, indicating some synergy between the different isomers. PMID- 20166703 TI - Synthesis and characterization of an epimer of tacrolimus, an immunosuppressive drug. AB - 8-Epitacrolimus (2), a new l-pipecolic acid macrolide lactone, was obtained by base-catalyzed epimerization of tacrolimus (FK-506, 1), an important immunosuppressive drug, and its structure determined by a single-crystal X-ray diffraction method. The compound was fully characterized by spectroscopic techniques. The epimer is of importance due to its potential biological effects as well as because of its possible formation during formulation, handling, and use of tacrolimus products. PMID- 20166704 TI - Regioselective reactions of highly substituted arynes. AB - The fully regioselective reactivity of four new highly substituted silyl aryl triflate aryne precursors in aryne acyl-alkylation, acyl-alkylation/condensation, and heteroannulation reactions is reported. The application of these more complex arynes provides access to diverse natural product scaffolds and obviates late stage functionalization of aromatic rings. PMID- 20166705 TI - Two-component mixed and patterned films on carbon surfaces through the photografting of arylazides. AB - Organic films have been grafted to glassy carbon surfaces by the photolysis of arylazides. Atomic force microscopy and electrochemical measurements reveal that the films are loosely packed. The methodology was expanded to prepare two component thin films incorporating either a reactive tether species and a nonreactive background film or two different reactive tethers. Strategies were developed to generate both continuous mixed films and surfaces presenting patterns of two components. For patterning, the arylazide derivative was grafted onto previously modified glassy carbon surfaces. In this case, the first modification step is not limited to photografting, which increases the scope of the methods. For all grafted surfaces, the reactivity of tether species was confirmed by coupling electroactive targets to the tethers, followed by electrochemical monitoring. The ease of preparing surfaces with spatially controlled functionality offers promise for the design of sensing platforms on graphitic carbon substrates. PMID- 20166706 TI - Conformational behavior of CH3OC(O)SX (X = CN and SCN) pseudohalide congeners. A combined experimental and theoretical study. AB - Pure methoxycarbonylsulfenyl cyanide, CH(3)OC(O)SCN (I), and methoxycarbonylsulfenyl thiocyanate, CH(3)OC(O)SSCN (II), were prepared by reacting liquid CH(3)OC(O)SCl with either AgCN or AgSCN, respectively. Compounds I and II were characterized by (1)H NMR, CG-MS, and vibrational (FTIR and FT Raman) techniques. The conformational properties have been studied by using vibrational spectroscopy [infrared (gaseous, liquid, and Ar matrix isolated), Raman (liquid) spectroscopy] together with quantum chemical calculations at the B3LYP and MP2 methods with the extended 6-311++G** and aug-cc-pVTZ basis sets. Compound I exhibits a conformational equilibrium at room temperature having the most stable form C(s) symmetry with a synperiplanar (syn) orientation of the carbonyl double bond (C=O) with respect to both the CH(3)O- and -SCN groups (syn syn). Several bands assigned to a second conformer have been observed in the IR matrix spectra. This rotamer presents an antiperiplanar orientation of the thiocyanate group (syn-anti). Evaluating the equilibrium compositions at different temperatures by quenching the gas phase mixtures as Ar matrices allowed us to determine the conformational enthalpy difference DeltaH(0) = H(0)((syn anti)) - H(0)((syn-syn)) = 0.80(18) kcal mol(-1). A similar conformational behavior has been determined for compound II. Thermodynamic properties were also computed at the high-level G2MP2 and G3 model chemistry methods. The importance of mesomeric (resonance) and anomeric (hyperconjugation) electronic interaction in the conformational behavior is evaluated by using the NBO approach for both species. PMID- 20166707 TI - Omega-ethylenic allylic substrates as alternatives to cyclic substrates in copper and iridium-catalyzed asymmetric allylic alkylation. AB - A new strategy to access highly enantioenriched cyclic compounds (up to 98%) is proposed using omega-ethylenic allylic substrates through a one-pot asymmetric allylic alkylation and ring-closing metathesis. Such starting compounds can be seen as synthetic equivalents of cyclic allylic substrates. PMID- 20166708 TI - Refinements to label free proteome quantitation: how to deal with peptides shared by multiple proteins. AB - Quantitative shotgun proteomics is dependent on the detection, identification, and quantitative analysis of peptides. An issue arises with peptides that are shared between multiple proteins. What protein did they originate from and how should these shared peptides be used in a quantitative proteomics workflow? To systematically evaluate shared peptides in label-free quantitative proteomics, we devised a well-defined protein sample consisting of known concentrations of six albumins from different species, which we added to a highly complex yeast lysate. We used the spectral counts based normalized spectral abundance factor (NSAF) as the starting point for our analysis and compared an exhaustive list of possible combinations of parameters to determine what was the optimal approach for dealing with shared peptides and shared spectral counts. We showed that distributing shared spectral counts based on the number of unique spectral counts led to the most accurate and reproducible results. PMID- 20166710 TI - Tuning the charge-transport parameters of perylene diimide single crystals via end and/or core functionalization: a density functional theory investigation. AB - Perylene tetracarboxylic diimide (PTCDI) derivatives stand out as one of the most investigated families of air-stable n-type organic semiconductors for organic thin-film transistors. Here, we use density functional theory to illustrate how it is possible to control the charge-transport parameters of PTCDIs as a function of the type, number, and positions of the substituents. Specifically, two strategies of functionalization related to core and end substitutions are investigated. While end-substituted PTCDIs present the same functional molecular backbone, their molecular packing in the crystal significantly varies; as a consequence, this series of derivatives constitutes an ideal test bed to evaluate the models that describe charge-transport in organic semiconductors. Our results indicate that large bandwidths along with small effective masses can be obtained with the insertion of appropriate substituents on the nitrogens, in particular halogenated aromatic groups. PMID- 20166709 TI - Molecular recognitive photocatalysis driven by the selective adsorption on layered titanates. AB - The composition of layered alkali titanates (M(x)Ti(2-x/3)Li(x/3)O(4); M = K(+), Li(+), Na(+)) was tuned to control the swelling of the titanates in water and subsequently achieve molecular-sieve-like molecular recognitive photocatalytic decomposition of aqueous organic compounds on the titanates. Layered potassium lithium titanates with different layer charge density, K(x)Ti(2-x/3)Li(x/3)O(4) (x = 0.61, 0.67, and 0.74), was first synthesized and then the interlayer K(+) was quantitatively exchanged with Li(+) and Na(+) to form Li(x)Ti(2 x/3)Li(x/3)O(4) (x = 0.61, 0.67, and 0.76) and Na(x)Ti(2-x/3)Li(x/3)O(4) (x = 0.61, 0.67, and 0.76). The water adsorption/desorption isotherms and X-ray diffraction patterns of the titanates revealed that the pristine K(+)-type titanates hardly hydrated, while the Li(+)- and Na(+)-exchanged titanates expanded the interlayer space upon the hydration and the degree in the hydration was larger for the Na forms than for the Li ones and depended on the layer charge density. The present titanates were found to selectively adsorb benzene from an aqueous mixture of benzene, phenol, and 4-butylphenol and subsequently decompose benzene upon UV irradiation. The efficiency of the molecular recognitive photocatalytic benzene decomposition was related to the degree in the swelling of the titanates in water. PMID- 20166712 TI - Probing the solvent shell with 195Pt chemical shifts: density functional theory molecular dynamics study of Pt(II) and Pt(IV) anionic complexes in aqueous solution. AB - Ab initio molecular dynamics (aiMD) simulations based on density functional theory (DFT) were performed on a set of five anionic platinum complexes in aqueous solution. (195)Pt nuclear magnetic shielding constants were computed with DFT as averages over the aiMD trajectories, using the two-component relativistic zeroth-order regular approximation (ZORA) in order to treat relativistic effects on the Pt shielding tensors. The chemical shifts obtained from the aiMD averages are in good agreement with experimental data. For Pt(II) and Pt(IV) halide complexes we found an intermediate solvent shell interacting with the complexes that causes pronounced solvent effects on the Pt chemical shifts. For these complexes, the magnitude of solvent effects on the Pt shielding constant can be correlated with the surface charge density. For square-planar Pt complexes the aiMD simulations also clearly demonstrate the influence of closely coordinated non-equatorial water molecules on the Pt chemical shift, relating the structure of the solution around the complex to the solvent effects on the metal NMR chemical shift. For the complex [Pt(CN)(4)](2-), the solvent effects on the Pt shielding constant are surprisingly small. PMID- 20166713 TI - Structure-based calculations of optical spectra of photosystem I suggest an asymmetric light-harvesting process. AB - Optical line shape theory is combined with a quantum-chemical/electrostatic calculation of the site energies of the 96 chlorophyll a pigments and their excitonic couplings to simulate optical spectra of photosystem I core complexes from Thermosynechococcus elongatus. The absorbance, linear dichroism and circular dichroism spectra, calculated on the basis of the 2.5 A crystal structure, match the experimental data semiquantitatively allowing for a detailed analysis of the pigment-protein interaction. The majority of site energies are determined by multiple interactions with a large number (>20) of amino acid residues, a result which demonstrates the importance of long-range electrostatic interactions. The low-energy exciton states of the antenna are found to be located at a nearest distance of about 25 A from the special pair of the reaction center. The intermediate pigments form a high-energy bridge, the site energies of which are stabilized by a particularly large number (>100) of amino acid residues. The concentration of low energy exciton states in the antenna is larger on the side of the A-branch of the reaction center, implying an asymmetric delivery of excitation energy to the latter. This asymmetry in light-harvesting may provide the key for understanding the asymmetric use of the two branches in primary electron transfer reactions. Experiments are suggested to check for this possibility. PMID- 20166714 TI - Prussian blue analogues for CO(2) and SO(2) capture and separation applications. AB - Adsorption isotherms of pure gases present in flue gas including CO(2), N(2), SO(2), NO, H(2)S, and water were studied using prussian blues of chemical formula M(3)[Co(CN)(6)](2).nH(2)O (M = Co, Zn) using an HPVA-100 volumetric gas analyzer and other spectroscopic methods. All the samples were characterized, and the microporous nature of the samples was studied using the BET isotherm. These materials adsorbed 8-10 wt % of CO(2) at room temperature and 1 bar of pressure with heats of adsorption ranging from 200 to 300 Btu/lb of CO(2), which is lower than monoethanolamine (750 Btu/lb of CO(2)) at the same mass loading. At high pressures (30 bar and 298 K), these materials adsorbed approximately 20-30 wt % of CO(2), which corresponds to 3 to 5 molecules of CO(2) per formula unit. Similar gas adsorption isotherms for SO(2), H(2)S, and NO were collected using a specially constructed volumetric gas analyzer. At close to 1 bar of equilibrium pressure, these materials sorb around 2.5, 2.7, and 1.2 mmol/g of SO(2), H(2)S, and NO. In particular, the uptake of SO(2) and H(2)S in Co(3)[Co(CN)(6)](2) is quite significant since it sorbs around 10 and 4.5 wt % at 0.1 bar of pressure. The stability of prussian blues before and after trace gases was studied using a powder X-ray diffraction instrument, which confirms these materials do not decompose after exposure to trace gases. PMID- 20166715 TI - Structural variety within gallium diphosphonates affected by the organic linker length. AB - Three new gallium diphosphonates: Ga(3)(OH)(O(3)PC(3)H(6)PO(3))(2) (1), Ga(4)(O(3)PC(5)H(10)PO(3))(3)(C(5)H(5)N)(2) (2), and Ga(HO(3)PC(10)H(20)PO(3)) (3), in which the diphosphonate bridging ligands have 3, 5, and 10 methylene units, respectively, have been synthesized using solvothermal methods and their structures determined using single-crystal laboratory and synchrotron X-ray diffraction data. All three materials contain Ga-centered tetrahedra and octahedra linked together through the -PO(3) groups of the diphosphonate ligands to form two-dimensional pillared slab (1) and three-dimensional pillared (2 and 3) materials. Compound 1 contains bridging hydroxide anions that connect Ga centered octahedra and tetrahedra, and contains pillared slabs in which one side of the Ga-P-O/OH/CH hybrid layers are connected by the propylenediphosphonate groups only. This slab also contains propylenediphosphonate groups arranged orthogonally to the pillaring direction in the outermost layer of the Ga-P O/OH/CH hybrid layers. Compound 2 is a framework structure that contains framework pyridine molecules between alternate layers of diphosphonate-pillared Ga-P-O layers and is structurally stable to loss of 1 equiv of pyridine molecules from the structure. Compound 3 is a partially condensed pillared framework structure with one P-O-H bond per diphosphonate group remaining in the resulting material. The structural changes observed as the alkylene chain in the diphosphonate ligand is increased in these compounds is compared to other members of the gallium diphosphonate family synthesized in a similar manner, and other metal diphosphonate series, to gain some general oversight of the structural trends observed in series of metal diphosphonate materials in which the alkylene chain length is varied systematically. PMID- 20166716 TI - Synthesis of chiral 3-alkyl-3,4-dihydroisocoumarins by dynamic kinetic resolutions catalyzed by a Baeyer-Villiger monooxygenase. AB - Baeyer-Villiger monooxygenases have been tested in the oxidation of racemic benzofused ketones. When employing a single mutant of phenylacetone monooxygenase (M446G PAMO) under the proper reaction conditions, it was possible to achieve 3 substituted 3,4-dihydroisocoumarins with high yields and optical purities through regioselective dynamic kinetic resolution processes. PMID- 20166717 TI - Low-temperature protein dynamics of the B800 molecules in the LH2 light harvesting complex: spectral hole burning study and comparison with single photosynthetic complex spectroscopy. AB - Previously published and new spectral hole burning (SHB) data on the B800 band of LH2 light-harvesting antenna complex of Rps. acidophila are analyzed in light of recent single photosynthetic complex spectroscopy (SPCS) results (for a review, see Berlin et al. Phys. Life Rev. 2007, 4, 64.). It is demonstrated that, in general, SHB-related phenomena observed for the B800 band are in qualitative agreement with the SPCS data and the protein models involving multiwell multitier protein energy landscapes. Regarding the quantitative agreement, we argue that the single-molecule behavior associated with the fastest spectral diffusion (smallest barrier) tier of the protein energy landscape is inconsistent with the SHB data. The latter discrepancy can be attributed to SPCS probing not only the dynamics of of the protein complex per se, but also that of the surrounding amorphous host and/or of the host-protein interface. It is argued that SHB (once improved models are developed) should also be able to provide the average magnitudes and probability distributions of light-induced spectral shifts and could be used to determine whether SPCS probes a set of protein complexes that are both intact and statistically relevant. SHB results are consistent with the B800 --> B850 energy-transfer models including consideration of the whole B850 density of states. PMID- 20166718 TI - Adjustable mutations in lactate (LA)-polymerizing enzyme for the microbial production of LA-based polyesters with tailor-made monomer composition. AB - Lactate (LA)-polymerizing enzyme (LPE) is a newly established class of polyhydroxyalkanoate (PHA) synthase, which can incorporate LA units into a polymer chain. We previously synthesized P(LA-co-3-hydroxybutyrate)s [P(LA-co 3HB)s] in recombinant Escherichia coli using the first LPE, which is the Ser325Thr/Glu481Lys mutant of PHA synthase from Pseudomonas sp. 61-3 [PhaC1(Ps)ST/QK]. In this study, we finely regulated LA fraction in the copolymer by saturated mutations at position 392 (F392X), which corresponds to the activity enhancing mutations at position 420 of PHA synthase from Ralstonia eutropha. Among the 19 saturated mutants of LPE at position 392, 17 mutants produced P(LA co-3HB)s with various LA fractions (16-45 mol %), whereas PhaC1(Ps)ST/QK produced P(LA-co-3HB) with 26 mol % LA under the same culture condition. In particular, the F392S mutation exhibited the highest LA fraction of 45 mol %, and also increased polymer content (62 wt %) compared with PhaC1(Ps)ST/QK (44 wt %). Combination of the F392S mutant and anaerobic culture conditions, which promote LA production, led to a further increase in LA fraction up to 62 mol %. The P(LA co-3HB)s with various LA fractions exhibited altered melting temperatures and melting enthalpy depending on their monomer composition. Accordingly, the mutations at position 392 in LPE greatly contributed to fine-tuning of the LA fraction in the copolymers that is useful for regulating LA fraction-dependent thermal properties. PMID- 20166719 TI - Reverse of mixing process with a two-dimensional electro-fluid-dynamic device. AB - Mixing of two solutions into one is a spontaneous process with a net increase in entropy. However, the reverse of the mixing process is usually not possible unless certain conditions are met. A continuous solution stream containing a mixture of two compounds can be separated into two channels, each containing a pure compound, thus reversing the mixing process using a two-dimensional microfluidic electro-fluid-dynamic (EFD) device. When the electric field is strategically applied in the interconnecting channels of an EFD device, the pressure required to direct an analyte into a certain channel can be calculated by using the solutions of electric field and fluid dynamics in the mass balance equation. If the pressure and electric potential at various inlets and outlets satisfy these predetermined conditions, the reverse of a mixing process is observed. Conventional microfluidic devices have been used to introduce samples from interconnecting channels or efficiently mix different solutions into a single channel. The EFD devices expand the spatial separation of analytes from one dimension to two using both the differential migration behavior of analytes and the velocity field distribution in different channel geometries. The devices designed according to these basic physicochemical principles can be used for complete processing of minute samples and to obtain pure chemical species from complex mixtures. PMID- 20166720 TI - Microfluidic capillary separation and real-time spectroscopic analysis of specific components from multiphase mixtures. AB - We present a technique of phase separation suitable for microfluidic systems and demonstrate its efficient integration with a microfluidic optical cell for performing real-time spectrometric measurements on one specific phase from a mixture. We demonstrate that efficient and robust phase separation based on capillarity is possible within a microfluidic chip using either microfabricated capillary channels in polydimethylsiloxane (PDMS) or oil-wet fluoropolymer membranes, allowing for extraction of either the continuous or of the dispersed phases from a multiphase mixture. We analyze the dependence of phase separation efficiency on the operating parameters of the device and observe the presence of a hysteresis cycle during pressure sweeps above a water breakthrough pressure (P(b)); we also observe and analyze the reversibility of the oil-wet state of the membrane upon pressure reduction below a reset pressure (P(r) < P(b)). We test the capillary separation method extensively with several types of organic/water mixtures and emulsions and derive criteria for design and operation of a robust microfluidic capillary separator. As an example of monitoring application we describe the design and manufacturing of a microfluidic spectrometer cell optimized for fast response time, which was used to analyze the oil extracted from an oil/water emulsion using a capillary separator. The complete separator sensor system is characterized in terms of response and cleanup times to instantaneous changes in the dye concentration of the phase of interest. PMID- 20166721 TI - Synthesis and fungicidal activity of novel aminophenazine-1-carboxylate derivatives. AB - A series of novel 6-aminophenazine-1-, 7-aminophenazine-1- and 8-aminophenazine-1 carboxylate derivatives were synthesized by a facile method, and their structures were characterized by (1)H NMR, (13)C NMR and high-resolution mass spectrometry. Some unexpected byproducts V-7b-V-8d were noticed and isolated, and their structures were identified by 2D NMR spectra including heteronuclear multiple quantum coherence (HMQC), heteronuclear multiple-bond correlation (Hmbc) and H-H correlation spectrometry (H-H COSY) approach. Their fungicidal activities against five fungi were evaluated, which indicated that most of the title compounds showed low fungicidal activities in vitro against Alternaria solani, Cercospora arachidicola, Fusarium omysporum, Gibberella zeae, and Physalospora piricola at a dosage of 50 microg mL(-1), while compounds IV-6a and IV-6b exhibited excellent activities against P. piricola at that dosage. Compound IV-6a could be considered as a leading structure for further design of fungicides. PMID- 20166722 TI - Contribution of flavonoids to the overall radical scavenging activity of olive (Olea europaea L.) leaf polar extracts. AB - The contribution of flavonoids to the overall radical scavenging activity of olive leaf polar extracts, known to be good sources of oleuropein related compounds, was examined. Off line and on line HPLC-DPPH(*) assays were employed, whereas flavonoid content was estimated colorimetrically. Individual flavonoid composition was first assessed by RP-HPLC coupled with diode array and fluorescence detectors and verified by LC-MS detection system. Olive leaf was found a robust source of flavonoids regardless sampling parameters (olive cultivar, leaf age or sampling date). Total flavonoids accounted for the 13-27% of the total radical scavenging activity assessed using the on line protocol. Luteolin 7-O-glucoside was one of the dominant scavengers (8-25%). Taking into consideration frequency of appearance the contribution of luteolin (3-13%) was considered important, too. Our findings support that olive leaf, except for oleuropein and related compounds, is also a stable source of bioactive flavonoids. PMID- 20166724 TI - Study of the interface between rhodium and carbon nanotubes. AB - X-ray photoelectron spectroscopy at 3.5 keV photon energy, in combination with high-resolution transmission electron microscopy, is used to follow the formation of the interface between rhodium and carbon nanotubes. Rh nucleates at defect sites, whether initially present or induced by oxygen-plasma treatment. More uniform Rh cluster dispersion is observed on plasma-treated CNTs. Experimental results are compared to DFT calculations of small Rh clusters on pristine and defective graphene. While Rh interacts as strongly with the carbon as Ti, it is less sensitive to the presence of oxygen, suggesting it as a good candidate for nanotube contacts. PMID- 20166725 TI - Regulating volume transitions of highly responsive hydrogel scaffolds by adjusting the network properties of microgel building block colloids. AB - We present a simple method to control the volume change of thermally responsive hydrogel scaffolds, providing a remarkably fast swelling and deswelling response to temperature changes. These scaffolds have 3-dimensional colloidal-network structures which are made from microgel particles while they are above their deswelling transition temperatures. By tuning the cross-link density of the microgel particles, we achieve controllable changes of the volume of the scaffolds in response to temperature. Their fast response rate is determined by the length scale of the unit microgel particles and is not influenced by the properties of the network. The release profile of a model drug (Rhapontin) loaded within the scaffolds can also be regulated by the cross-linking density of the microgel particles. These results offer a new way of fabricating hydrogel scaffolds with tunable matrix geometry and function by adjusting the properties of the unit microgel colloids, without loss of their fast response to temperature change. PMID- 20166726 TI - Nanochemistry in confined environments: polyelectrolyte brush-assisted synthesis of gold nanoparticles inside ordered mesoporous thin films. AB - A robust and straightforward strategy allowing the controlled confinement of metal nanoparticles within the 3D framework of mesoporous films is presented. The chemical methodology is based on the inner surface modification of mesoporous silica films with polyelectrolyte brushes. We demonstrate that the macromolecular building blocks significantly enhance the site-selective preconcentration of nanoparticle precursors in the inner environment of the mesoporous film. Then, chemical reduction of the preconcentrated precursors led to the formation of metal nanoparticles locally addressed in the mesoporous structure. We show that the synergy taking place between two versatile functional nanobuilding blocks (ordered mesocavities and polymer brushes) can produce stable embedded nanoparticles with tuned optical properties in a very simple manner. As a general framework, the strategy can be easily adapted to different sets of polymer brushes and mesoporous films in order to regulate the monomer-precursor interactions and, consequently, manipulate the site-selective character of the different chemistries taking place in the film. We consider that the "integrative chemistry" approach described in this work provides new pathways to manipulate the physicochemical characteristics of hybrid organic-inorganic advanced functional assemblies based on the rational design of chemistry and topology in confined environments. PMID- 20166727 TI - Orthogonal, three-component, alkanethiol-based surface-chemical gradients on gold. AB - An orthogonal surface-chemical gradient composed of self-assembled monolayers on gold has been prepared by successive, controlled immersions in orthogonal directions into dilute solutions of dodecanethiol and perfluorododecanethiol. The resulting two-component orthogonal gradient in surface coverage was backfilled with 11-mercaptoundecanol, leading to a two-directional, three-component surface chemical gradient. Water and hexadecane show distinctly different wetting behaviors on the gradient surface because of the differences in the hydrophobic and oleophobic natures of the three different constituents. These results are correlated with the chemical composition maps of the surface obtained by X-ray photoelectron spectroscopy. The homogeneity and the ordering of the self assembled monolayer were investigated by dynamic water contact angle measurements and polarization-modulation infrared reflection-absorption spectroscopy. PMID- 20166728 TI - Effect of ligands on thermal dissipation from gold nanorods. AB - Thermal interface conductance was measured for soluble gold nanorods (NRs) coated with mercaptocarboxylic acids (HS-(CH(2))(n)COOH, n = 5, 10, 15), thiolated polyethylene glycols (MW = 356, 1000, 5000), and HS-(CH(2))(15)-COOH-coated NRs further coated with alternating layers of poly(diallyldimethylammonium chloride) and poly(sodium styrenesulfonate). Ferguson analysis determined ligand thickness. The thermal-diffusion-dominated regime of transient absorption spectra was fit to a continuum heat diffusion finite element model to obtain the thermal interface conductance, G, which varied with ligand chemistry but not molecule length. The results suggest that the ability to exclude water from the NR surface governs ligand G values. PMID- 20166729 TI - High yield, single droplet electrode arrays for nanoscale printed electronics. AB - In this work we demonstrate two building blocks of a scalable manufacturing technology for nanoscale electronic devices based on direct-write printing: an architecture for high-yield printing of electrode gaps with 100 nm dimension and a low-temperature silver complex ink for integration of organic materials with high conductivity metal interconnects. We use single printed droplets that are made to dewet slowly from each other to allow reliable, high yield patterning even in the presence of certain surface defects. PMID- 20166730 TI - Sequence-specific Ni(II)-dependent peptide bond hydrolysis for protein engineering. Combinatorial library determination of optimal sequences. AB - Previously we demonstrated for several examples that peptides having a general internal sequence R(N)-Yaa-Ser/Thr-Xaa-His-Zaa-R(C) (Yaa = Glu or Ala, Xaa = Ala or His, Zaa = Lys, R(N) and R(C) = any N- and C-terminal amino acid sequence) were hydrolyzed specifically at the Yaa-Ser/Thr peptide bond in the presence of Ni(II) ions at alkaline pH (Krezel, A., Mylonas, M., Kopera, E. and Bal, E. Acta Biochim. Polon. 2006, 53, 721-727 and references therein). Hereby we report the synthesis of a combinatorial library of CH(3)CO-Gly-Ala-(Ser/Thr)-Xaa-His-Zaa-Lys Phe-Leu-NH(2) peptides, where Xaa residues included 17 common alpha-amino acids (except Asp, Glu, and Cys) and Zaa residues included 19 common alpha-amino acids (except Cys). The Ni(II)-dependent hydrolysis at 37 and 45 degrees C of batches of combinatorial peptide mixtures randomized at Zaa was monitored by MALDI-TOF mass spectrometry. The correctness of library-based predictions was confirmed by accurate measurements of hydrolysis rates of seven selected peptides using HPLC. The hydrolysis was strictly limited to the Ala-Ser/Thr bond in all library and individual peptide experiments. The effects of individual residues on hydrolysis rates were quantified and correlated with physical properties of their side chains according to a model of independent contributions of Xaa and Zaa residues. The principal component analysis calculations demonstrated partial molar side chain volume and the free energy of amino acid vaporization for both Xaa and Zaa residues and the amine pK(a) for Zaa residues to be the most significant empirical parameters influencing the hydrolysis rate. Therefore, efficient hydrolysis required bulky and hydrophobic residues at both variable positions Xaa and Zaa, which contributed independently to the hydrolysis rate. This relationship between the peptide sequence and the hydrolysis rate provides a basis for further research, aimed at the elucidation of the reaction mechanism and biotechnological applications of Ni(II)-dependent peptide bond hydrolysis. PMID- 20166731 TI - Reaction pathways and possible path bifurcation for the Schmidt reaction. AB - The N(2) liberation from iminodiazonium ion (2-X) is a key step of the Schmidt rearrangement of ketones. Molecular orbital calculations showed that two concurrent reaction channels, syn-benzyl fragmentation and anti-Me rearrangement, exist for syn-2, whereas anti-2-X proceeds via a single TS. Substituent effect analyses of the reactions of syn-2-X gave concave-upward plots, typical for a concurrent reaction mechanism. On the other hand, the reactions of anti-2-X gave linear Hammett plots, indicative of a single reaction mechanism for all anti-2-X. IRC calculations, however, revealed that the TS led to either an anti-benzyl rearrangement or an anti-benzyl fragmentation product depending on the substituent. Thus, the change of the mechanism (identity of the product) could not be detected by the Hammett plots. Ab initio dynamics simulations for anti-2-X were found to follow the IRC path for X = p-NO(2), giving the rearrangement product, and almost so for X = p-MeO, giving the fragmentation products. However, in borderline cases where X is less donating than p-MeO and less withdrawing than p-NO(2), the trajectories did not follow the minimum energy path on the potential energy surface but gave both rearrangement and fragmentation products directly from the single TS. This is a novel example of path bifurcation for a closed shell anionic reaction. It was concluded that a reactivity-selectivity argument based on the traditional TS theory might not always be applicable even to a well known textbook organic reaction. PMID- 20166732 TI - DNA (6-4) photolyases reduce Dewar isomers for isomerization into (6-4) lesions. AB - Repair of the Dewar valence isomers by (6-4) photolyases proceeds via an enzyme catalyzed ring-opening reaction of the Dewar lesion to the (6-4) photoproduct. PMID- 20166733 TI - Highly efficient chromatin transcription induced by superhelically curved DNA segments: the underlying mechanism revealed by a yeast system. AB - Superhelically curved DNA structures can strongly activate transcription in mammalian cells. However, the mechanism underlying the activation has not been clarified. We investigated this mechanism in yeast cells, using 108, 180, and 252 bp synthetic curved DNA segments. Even in the presence of nucleosomes, these DNAs activated transcription from a UAS-deleted CYC1 promoter that is silenced in the presence of nucleosomes. The fold-activations of transcription by these segments, relative to the transcription on the control that lacked such segments, were 51.4, 63.4, and 56.4, respectively. The superhelically curved DNA structures favored nucleosome formation. However, the translational positions of the nucleosomes were dynamic. The high mobility of the nucleosomes on the superhelically curved DNA structures seemed to influence the mobility of the nucleosomes formed on the promoter and eventually enhanced the access to the center region of one TATA sequence. Functioning as a dock for the histone core and allowing nucleosome sliding seem to be the mechanisms underlying the transcriptional activation by superhelically curved DNA structures in chromatin. The present study provides important clues for designing and constructing artificial chromatin modulators, as a tool for chromatin engineering. PMID- 20166734 TI - The vibrational spectrum of parabanic acid by inelastic neutron scattering spectroscopy and simulation by solid-state DFT. AB - The incoherent inelastic neutron scattering spectrum of parabanic acid was measured and simulated using solid-state density functional theory (DFT). This molecule was previously the subject of low-temperature X-ray and neutron diffraction studies. While the simulated spectra from several density functionals account for relative intensities and factor group splitting regardless of functional choice, the hydrogen-bending vibrational energies for the out-of-plane modes are poorly described by all methods. The disagreement between calculated and observed out-of-plane hydrogen bending mode energies is examined along with geometry optimization differences of bond lengths, bond angles, and hydrogen bonding interactions for different functionals. Neutron diffraction suggests nearly symmetric hydrogen atom positions in the crystalline solid for both heavy atom and N-H bond distances but different hydrogen-bonding angles. The spectroscopic results suggest a significant factor group splitting for the out-of plane bending motions associated with the hydrogen atoms (N-H) for both the symmetric and asymmetric bending modes, as is also supported by DFT simulations. The differences between the quality of the crystallographic and spectroscopic simulations by isolated-molecule DFT, cluster-based DFT (that account for only the hydrogen-bonding interactions around a single molecule), and solid-state DFT are considered in detail, with parabanic acid serving as an excellent case study due to its small size and the availability of high-quality structure data. These calculations show that hydrogen bonding results in a change in the bond distances and bond angles of parabanic acid from the free molecule values. PMID- 20166735 TI - Combining very large quadratic and cubic nonlinear optical responses in extended, tris-chelate metallochromophores with six pi-conjugated pyridinium substituents. AB - We describe a series of nine new complex salts in which electron-rich Ru(II) or Fe(II) centers are connected via pi-conjugated bridges to six electron-accepting N-methyl-/N-arylpyridinium groups. This work builds upon our previous preliminary studies (Coe , B. J. J. Am. Chem. Soc. 2005, 127, 13399-13410; J. Phys. Chem. A 2007, 111, 472-478), with the aims of achieving greatly enhanced NLO properties and also combining large quadratic and cubic effects in potentially redox switchable molecules. Characterization has involved various techniques, including electronic absorption spectroscopy and cyclic voltammetry. The complexes display intense, visible d --> pi* metal-to-ligand charge-transfer (MLCT) bands, and their pi --> pi* intraligand charge-transfer (ILCT) absorptions in the near-UV region show molar extinction coefficients as high as ca. 3.5 x 10(5) M(-1) cm( 1). Molecular quadratic nonlinear optical (NLO) responses beta have been determined by using hyper-Rayleigh scattering at 800 and 1064 nm and also via Stark (electroabsorption) spectroscopic studies. The directly and indirectly derived beta values are very large, with the Stark-based static first hyperpolarizabilities beta(0) reaching as high as ca. 10(-27) esu, and generally increase on extending the pi-conjugation and enhancing the electron-accepting strength of the ligands. Cubic NLO properties have also been measured by using the Z-scan technique, revealing relatively high two-photon absorption cross sections of up to 2500 GM at 750 nm. PMID- 20166736 TI - Agelastatin E, agelastatin F, and benzosceptrin C from the marine sponge Agelas dendromorpha. AB - The study of the n-butanol extract of the New Caledonian sponge Agelas dendromorpha led to the isolation and identification of three new pyrrole-2 aminoimidazole (P-2-AI) alkaloids, named agelastatins E (3) and F (4) and benzosceptrin C (5), together with 10 known metabolites, agelastatin A (1), agelastatin D (2), sceptrin (6), manzacidin A, tauroacidin A, taurodispacamide A, nortopsentin D, thymine, longamide, and 4,5-dibromopyrrole-2-carboxamide. Their structures were assigned by spectroscopic data interpretation. All the compounds were tested for cytotoxic activity. PMID- 20166737 TI - Coefficients of evaporation and gas phase diffusion of low-volatility organic solvents in nitrogen from interferometric study of evaporating droplets. AB - Evaporation of motionless, levitating droplets of pure, low-volatility liquids was studied with interferometric methods. Experiments were conducted on charged droplets in the electrodynamic trap in nitrogen at atmospheric pressure at 298 K. Mono-, di-, tri-, and tetra(ethylene glycols) and 1,3-dimethyl-2-imidazolidinone were studied. The influence of minute impurities (<0.1%) upon the process of droplet evaporation was observed and discussed. The gas phase diffusion and evaporation coefficients were found from droplet radii evolution under the assumption of known vapor pressure. Diffusion coefficients were compared with independent measurements and calculations (in air). Good agreement was found for mono- and di(ethylene glycols), and for 1,3-dimethyl-2-imidazolidinone, which confirmed the used vapor pressure values. The value of equilibrium vapor pressure for tri(ethylene glycol) was proposed to be 0.044 +/- 0.008 Pa. The evaporation coefficient was found to increase from 0.035 to 0.16 versus the molecular mass of the compound. PMID- 20166739 TI - Ions at the water-vapor interface. AB - We obtain the electrostatic free energy of finite-sized ions near a dielectric interface within the framework of the classical continuum dielectric theory. The ion is modeled as a dielectric sphere with a fixed uniform surface charge density. In order to avoid the generation of additional induced charges on the ionic surface, it is assumed there is no dielectric contrast between the ion core and the external dielectric medium where it is embedded, which allows an exact solution of the electrostatic problem by the image-charge method. It is shown that earlier results reported in the literature, especially when there is partial ionic penetration into the interface, always underestimate the electrostatic free energy associated with nonpolarizable ions. For an ion modeled as a vacuum cavity at the water-vapor interface, it is estimated that the free energy is an order of magnitude larger than prior predictions. PMID- 20166738 TI - Investigation of protein folding by coarse-grained molecular dynamics with the UNRES force field. AB - Coarse-grained molecular dynamics simulations offer a dramatic extension of the time-scale of simulations compared to all-atom approaches. In this article, we describe the use of the physics-based united-residue (UNRES) force field, developed in our laboratory, in protein-structure simulations. We demonstrate that this force field offers about a 4000-times extension of the simulation time scale; this feature arises both from averaging out the fast-moving degrees of freedom and reduction of the cost of energy and force calculations compared to all-atom approaches with explicit solvent. With massively parallel computers, microsecond folding simulation times of proteins containing about 1000 residues can be obtained in days. A straightforward application of canonical UNRES/MD simulations, demonstrated with the example of the N-terminal part of the B-domain of staphylococcal protein A (PDB code: 1BDD, a three-alpha-helix bundle), discerns the folding mechanism and determines kinetic parameters by parallel simulations of several hundred or more trajectories. Use of generalized-ensemble techniques, of which the multiplexed replica exchange method proved to be the most effective, enables us to compute thermodynamics of folding and carry out fully physics-based prediction of protein structure, in which the predicted structure is determined as a mean over the most populated ensemble below the folding-transition temperature. By using principal component analysis of the UNRES folding trajectories of the formin-binding protein WW domain (PDB code: 1E0L; a three-stranded antiparallel beta-sheet) and 1BDD, we identified representative structures along the folding pathways and demonstrated that only a few (low-indexed) principal components can capture the main structural features of a protein-folding trajectory; the potentials of mean force calculated along these essential modes exhibit multiple minima, as opposed to those along the remaining modes that are unimodal. In addition, a comparison between the structures that are representative of the minima in the free-energy profile along the essential collective coordinates of protein folding (computed by principal component analysis) and the free-energy profile projected along the virtual-bond dihedral angles gamma of the backbone revealed the key residues involved in the transitions between the different basins of the folding free-energy profile, in agreement with existing experimental data for 1E0L . PMID- 20166741 TI - Hierarchical orientational relaxation inducing shish-kebab formations in polymer melt crystallization. AB - We studied athermal relaxation of bulk extended chains by means of dynamic Monte Carlo simulations, and we got intermediately relaxed melts with a memory of chain orientations but no more crystalline order. The orientational memory in the melts dominated the crystal orientation and nucleation types. The difference in crystallization behaviors induced by orientational relaxation suggested the mechanism of hierarchical crystallization. Thus, we studied the isothermal crystallization of a binary blend of different relaxed chains. We observed the prior crystallization of less relaxed chains could act as a shish to induce epitaxial crystallization of more relaxed chains to form kebabs. This mechanism had demonstrated the structure of precursors and gave insight into the formation of shish-kebab crystals in polymer melts. The results suggested that in flow induced polymer crystallization the hierarchical orientational relaxation of chains decided the formation of shish-kebabs. PMID- 20166740 TI - Direct interaction of the mouse cytomegalovirus m152/gp40 immunoevasin with RAE-1 isoforms. AB - Cytomegaloviruses (CMVs) are ubiquitous species-specific viruses that establish acute, persistent, and latent infections. Both human and mouse CMVs encode proteins that inhibit the activation of natural killer (NK) cells by downregulating cellular ligands for the NK cell activating receptor, NKG2D. The MCMV glycoprotein m152/gp40 downregulates the surface expression of RAE-1 to prevent NK cell control in vivo. So far, it is unclear if there is a direct interaction between m152 and RAE-1 and, if so, if m152 interacts differentially with the five identified RAE-1 isoforms, which are expressed as two groups in MCMV-susceptible or -resistant mouse strains. To address these questions, we expressed and purified the extracellular domains of RAE-1 and m152 and performed size exclusion chromatography binding assays as well as analytical ultracentrifugation and isothermal titration calorimetry to characterize these interactions quantitatively. We further evaluated the role of full-length and naturally glycosylated m152 and RAE-1 in cotransfected HEK293T cells. Our results confirmed that m152 binds RAE-1 directly, relatively tightly (K(d) < 5 microM), and with 1:1 stoichiometry. The binding is quantitatively different depending on particular RAE-1 isoforms, corresponding to the susceptibility to downregulation by m152. A PLWY motif found in RAE-1beta, although contributing to its affinity for m152, does not influence the affinity of RAE-1gamma or RAE-1delta, suggesting that other differences contribute to the RAE-1-m152 interaction. Molecular modeling of the different RAE-1 isoforms suggests a potential site for the m152 interaction. PMID- 20166742 TI - Hybrid polyoxotungstate/MIL-101 materials: synthesis, characterization, and catalysis of H2O2-based alkene epoxidation. AB - Polyoxotungstates [PW(4)O(24)](3-) (PW(4)) and [PW(12)O(40)](3-) (PW(12)) have been inserted into nanocages of the metal organic framework MIL-101. The hybrid materials PW(x)/MIL-101 (x = 4 or 12) containing 5-14 wt % of polyoxotungstate have been obtained and characterized by elemental analysis, N(2) adsorption, FT IR, Raman, and (31)P NMR MAS spectroscopic techniques. Their catalytic performance was assessed in the selective oxidation of alkenes with aqueous hydrogen peroxide under mild reaction conditions ([H(2)O(2)] = 0.1-0.2 M, 50 degrees C, MeCN). PW(x)/MIL-101 enclosing 5 wt % of polyoxotungstate demonstrated fairly good catalytic activities in the epoxidation of various alkenes (3-carene, limonene, alpha-pinene, cyclohexene, cyclooctene, 1-octene), the turnover frequencies (TOF) and alkene conversions were close to the corresponding parameters achieved with homogeneous PW(x). For the oxidation of substrates with aromatic groups (styrene, cis- and trans-stilbenes), a higher level of olefin conversion was attained using PW(12)/MIL-101. Moreover, confinement of PW(12) within MIL-101 nanocages allowed us to reach higher epoxide selectivities at higher alkene conversions. The hybrid PW(x)/MIL-101 materials were stable to leaching, behaved as true heterogeneous catalysts, were easily recovered by filtration, and reused several times with the maintenance of the catalytic performance. PMID- 20166743 TI - Aptamer-based tumor-targeted drug delivery for photodynamic therapy. AB - A specialized G-rich DNA structure, G-quadruplex, has been studied for its special physical characteristics and biological effects. Herein we report a novel strategy of using G-quadruplex as a drug carrier to target cancer cells for photodynamic therapy (PDT). A G-quadruplex forming AS1411 aptamer could be physically conjugated with six molecules of porphyrin derivative, 5,10,15,20 tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP4), to fabricate the apt-TMP complex. The TMPyP4 molecules in the complex were identified to bind tightly to the aptamer by intercalation and outside binding. Because the G-quadruplex structure is known to target the overexpressed nucleolin in cancer cells, in this study, the effect of the G-quadruplex structure as a carrier for the delivery of TMPyP4 into cancer cells by nucleolin-mediated internalization was investigated. The results showed that the apt-TMP complex exhibited a higher TMPyP4 accumulation in MCF7 breast cancer cells than in M10 normal epithelium cells. After treated with light for 180 s, the photodamage in MCF7 cells was larger than in M10 cells. These results indicated that the TMPyP4 delivery and uptake were mediated by the specific interaction of the apt-TMP complex with nucleolin on the cellular surface and that the use of the AS1411 aptamer as a drug carrier may be a potential tactic in cancer therapy. PMID- 20166744 TI - Four-coordinate As(III)-N,S complexes: synthesis, structure, properties, and biological relevance. AB - Air-stable four-coordinate As(III) complexes, [As(L4)Cl] (1) and [As(L4)I] (2), were prepared using a rearranged form of the deprotonated benzothiazoline ligand, 2-(pyridin-2-yl)-2,3-dihydrobenzo[d]thiazole. Complexes 1 and 2 have been characterized by FTIR, (1)H NMR, UV-vis, and elemental microanalysis. The solid state structure of 2 was also solved. The unusual and rare four-coordinate geometry of 2 elucidates possible binding modes and properties of N,S-ligated As(III) that may be encountered in biology. PMID- 20166746 TI - Charge transfer in uranyl(VI) halides [UO2X4]2- (X = F, Cl, Br, and I). A quantum chemical study of the absorption spectra. AB - The electronic spectra of uranyl(VI) coordinated with four equatorial halide ligands, [UO2X4]2- (X = F, Cl, Br, and I), have been calculated at the all electron level using the multiconfigurational CASPT2 method, with spin-orbit coupling included through the variational-perturbational method. The halide-to uranyl charge-transfer states were taken into account in the calculation by including ligand orbitals in the active space. In order to do that, it is assumed that the charge transfer takes place from only one of the four ligands. Two models, which in principle can describe this, were investigated: the first one makes use of a localizing technique and the second one replaces three ligands by ab initio model potentials (AIMPs). The basis set dependence was investigated by using two different basis sets for the halides, of triple-zeta and quadruple-zeta quality. The localization procedure turned out to be strongly basis set dependent, and the most stable results were obtained with ab initio model potentials. The ground state is a closed shell singlet state, and the first excitation is from the bonding sigma(u) orbital on uranyl to the nonbonding delta(u) orbitals, except for the [UO2I4]2- complex, where the first excited state has a mixed character of charge transfer from the I- and the sigma(u)(1)phi(u)(1) configuration. In [UO2F4]2- there is no charge transfer excitation below 50,000 cm(-1) , while in [UO2Cl4]2- it appears around 33,000 cm( 1) and in [UO2Br4]2- around 23,000 cm(-1) . A blueshift of the spectra, from F- to I-, is observed. The calculations compare reasonably well with available experimental results. PMID- 20166745 TI - Light-induced local heating for thermophoretic manipulation of DNA in polymer micro- and nanochannels. AB - We present a method for making polymer chips with a narrow-band near-infrared absorber layer that enables light-induced local heating of liquids inside fluidic micro- and nanochannels fabricated by thermal imprint in polymethyl methacrylate. We have characterized the resulting liquid temperature profiles in microchannels using the temperature dependent fluorescence of the complex [Ru(bpy)(3)](2+). We demonstrate thermophoretic manipulation of individual YOYO-1 stained T4 DNA molecules inside micro- and nanochannels. PMID- 20166747 TI - Stacking and spreading interaction in N-heteroaromatic systems. AB - pi-pi interactions in heteroaromatic systems are ubiquitous in biological systems. In the present study, stabilization energies of stacked and hydrogen bonded dimers of N-heteroaromatic systems (pyridine, pyrazine, sym-triazine, and sym-tetrazine) have been computed using a benchmark quality coupled cluster through the perturbative triples (CCSD(T)) method at the estimated complete basis set (CBS) limit. In the case of stacking, monomer units are found to be stacked in parallel planes with displaced geometries. The stabilization energies for the most stable stacked geometry of pyridine, pyrazine, sym-triazine, and sym tetrazine dimers are found to be -3.39, -4.14, -4.02, and -3.90 kcal/mol, respectively at the est. CCSD(T)/CBS level of theory, which is clearly larger than the stabilization energy for the most stable geometry of the benzene dimer. In the case of spreading, hydrogen bonded dimers and trimers are stabilized by weak C-H...N interactions. The stabilization energies for the stacked and the spread out complexes are found to be comparable. The stabilization energy for the trimers is computed using the MP2, MP3, and B3LYP-D methods. The present study is aimed at unraveling the basis of preferred conformations of N-heteroaromatic dimers. These model systems explain partly the stability of double helical DNA and RNA structures that are formed by stacking and hydrogen bonding between nucleic acid bases. PMID- 20166749 TI - Visual indicator for trace organic volatiles. AB - We describe herein a novel approach for visual indication of trace organic vapors. The sensor utilizes a microporous material within a visual thin film transducer to produce changes in color upon exposure to a very wide range of volatile organic compounds. Visual indication at 5 parts per million (ppm) is demonstrated, with optoelectronic detection achieved to below 50 parts per billion (ppb). Through a thoughtful design of the sensor, we are able to avoid interference from water vapor, a critical attribute needed for practical application. PMID- 20166748 TI - Kinetics of mismatch formation opposite lesions by the replicative DNA polymerase from bacteriophage RB69. AB - The fidelity of DNA replication is under constant threat from the formation of lesions within the genome. Oxidation of DNA bases leads to the formation of altered DNA bases such as 8-oxo-7,8-dihydroguanine, commonly called 8-oxoG, and 2 hydroxyadenine, or 2-OHA. In this work we have examined the incorporation kinetics opposite these two oxidatively derived lesions as well as an abasic site analogue by the replicative DNA polymerase from bacteriophage RB69. We compared the kinetic parameters for both wild type and the low fidelity L561A variant. While nucleotide incorporation rates (k(pol)) were generally higher for the variant, the presence of a lesion in the templating position reduced the ability of both the wild-type and variant DNA polymerases to form ternary enzyme-DNA-dNTP complexes. Thus, the L561A substitution does not significantly affect the ability of the RB69 DNA polymerase to recognize damaged DNA; instead, the mutation increases the probability that nucleotide incorporation will occur. We have also solved the crystal structure of the L561A variant forming an 8-oxoG.dATP mispair and show that the propensity for forming this mispair depends on an enlarged polymerase active site. PMID- 20166750 TI - Specific oxygen-containing functional groups on the carbon surface underlie an enhanced sensitivity to dopamine at electrochemically pretreated carbon fiber microelectrodes. AB - The in vivo use of carbon-fiber microelectrodes for neurochemical investigation has proven to be selective and sensitive when coupled with background-subtracted fast-scan cyclic voltammetry (FSCV). Various electrochemical pretreatments have been established to enhance the sensitivity of these sensors; however, the fundamental chemical mechanisms underlying these enhancement strategies remain poorly understood. We have investigated an electrochemical pretreatment in which an extended triangular waveform from -0.5 to 1.8 V is applied to the electrode prior to the voltammetric detection of dopamine using a more standard waveform ranging from -0.4 to 1.3 V. This pretreatment enhances the electron-transfer kinetics and significantly improves sensitivity. To gain insight into the chemical mechanism, the electrodes were studied using common analytical techniques. Contact atomic force microscopy (AFM) was used to demonstrate that the surface roughness was not altered on the nanoscale by electrochemical pretreatment. Raman spectroscopy was utilized to investigate oxide functionalities on the carbon surface and confirmed that carbonyl and hydroxyl functional groups were increased by electrochemical conditioning. Spectra collected after the selective chemical modification of these groups implicate the hydroxyl functionality, rather than the carbonyl, as the major contributor to the enhanced electrochemical signal. Finally, we have demonstrated that this electrochemical pretreatment can be used to create carbon microdisc electrodes with sensitivities comparable to those associated with larger, conventionally treated cylindrical carbon fiber microelectrodes. PMID- 20166751 TI - Cold adaptation in DEAD-box proteins. AB - Spontaneous rearrangements of RNA structures are usually characterized by large activation energies and thus become very slow at low temperatures, yet RNA structure must remain dynamic even in cold-adapted (psychrophilic) organisms. DEAD-box proteins constitute a ubiquitous family of RNA-dependent ATPases that can often unwind short RNA duplexes in vitro (helicase activity), hence the belief that one of their major (though not exclusive) roles in vivo is to assist in RNA rearrangements. Here, we compare two Escherichia coli DEAD-box proteins and their orthologs from the psychrophilic bacteria Pseudoalteromonas haloplanktis and Colwellia psychrerythraea from the point of view of enzymatic properties. One of these proteins (SrmB) is involved in ribosome assembly, whereas the other (RhlE) presumably participates in both mRNA degradation and ribosome assembly; in vitro, RhlE is far more active as a helicase than SrmB. The activation energy associated with the ATPase activity of the psychrophilic SrmB is lower than for its mesophilic counterpart, making it more active at low temperatures. In contrast, in the case of psychrophilic RhlE, it is the RNA unwinding activity, not the ATPase activity, that has a reduced activation energy and is therefore cold-adapted. We argue that these different modes of cold adaptation reflect the likely function of these proteins in vivo: RNA helicase for RhlE and ATP-dependent RNA binding for SrmB. The cold adaptation of helicases like RhlE presumably facilitates RNA metabolism in psychrophilic bacteria. PMID- 20166752 TI - Crystal structure of a replicative DNA polymerase bound to the oxidized guanine lesion guanidinohydantoin. AB - The oxidation of guanine generates one of the most common DNA lesions, 8-oxo-7,8 dihydroguanine (8-oxoG). The further oxidation of 8-oxoG can produce either guanidinohydantoin (Gh) in duplex DNA or spiroiminodihydantoin (Sp) in nucleosides and ssDNA. Although Gh can be a strong block for replicative DNA polymerases such as RB69 DNA polymerase, this lesion is also mutagenic: DNA polymerases bypass Gh by preferentially incorporating a purine with a slight preference for adenine, which results in G.C --> T.A or G.C --> C.G transversions. The 2.15 A crystal structure of the replicative RB69 DNA polymerase in complex with DNA containing Gh reveals that Gh is extrahelical and rotated toward the major groove. In this conformation Gh is no longer in position to serve as a templating base for the incorporation of an incoming nucleotide. This work also constitutes the first crystallographic structure of Gh, which is stabilized in the R configuration in the two polymerase/DNA complexes present in the crystal asymmetric unit. In contrast to 8-oxoG, Gh is found in a high syn conformation in the DNA duplex and therefore presents the same hydrogen bond donor and acceptor pattern as thymine, which explains the propensity of DNA polymerases to incorporate a purine opposite Gh when bypass occurs. PMID- 20166753 TI - Structural analysis and functional implications of the negative mTORC1 regulator REDD1. AB - REDD1 is a conserved stress-response protein that regulates mTORC1, a critical regulator of cell growth and proliferation that is implicated in cancer. REDD1 is induced by hypoxia, and REDD1 overexpression is sufficient to inhibit mTORC1. mTORC1 is regulated by the small GTPase Rheb, which in turn is regulated by the GTPase-activating protein complex, TSC1/TSC2. REDD1 induced-mTORC1 inhibition requires the TSC1/TSC2 complex, and REDD1 has been proposed to act by directly binding to and sequestering 14-3-3 proteins away from TSC2 leading to TSC2 dependent inhibition of mTORC1. Structure/function analyses have led us to identify two segments in REDD1 that are essential for function, which act in an interdependent manner. We have determined a crystal structure of REDD1 at 2.0 A resolution, which shows that these two segments fold together to form an intact domain with a novel fold. This domain is characterized by an alpha/beta sandwich consisting of two antiparallel alpha-helices and a mixed beta-sheet encompassing an uncommon psi-loop motif. Structure-based docking and functional analyses suggest that REDD1 does not directly bind to 14-3-3 proteins. Sequence conservation mapping to the surface of the structure and mutagenesis studies demarcated a hotspot likely to interact with effector proteins that is essential for REDD1-mediated mTORC1 inhibition. PMID- 20166754 TI - Conformation-dependent formation of the G[8-5]U intrastrand cross-link in 5 bromouracil-containing G-quadruplex DNA induced by UVA irradiation. AB - G-quadruplex motifs are known to be present in telomeres of human and other organisms. Recent bioinformatic studies also revealed the widespread existence of these motifs in promoter regions of human genes. Treatment of cultured cells with 5-bromo-2'-deoxyuridine ((Br)dU) is known to result in the substitution of DNA thymidine with (Br)dU; such replacement has been shown to sensitize cells to killing induced by UV light. Our previous studies revealed that the exposure of (Br)dU-carrying duplex DNA or (Br)dU-treated MCF-7 cells to UVB light could lead to the facile formation of intrastrand cross-link products initiated from (Br)dU. Here we found that the exposure of (Br)dU-bearing G-quadruplex DNA to UVA light could also give rise to the efficient formation of the G[8-5]U intrastrand cross link, where the C8 of guanine in the external G-tetrad is covalently linked with the C5 of its adjacent 3' uracil in the loop region. In addition, the yield for the cross-link product is dependent on the conformation of the G-quadruplex. Together, the formation of intrastrand cross-link in G-quadruplex motifs may account for the photocytotoxic effect induced by (Br)dU incorporation, and the (Br)dU-mediated photo-cross-linking may constitute a useful method for monitoring the different conformations of G-quadruplex folding. PMID- 20166755 TI - Bioresponsive dextrin-rhEGF conjugates: in vitro evaluation in models relevant to its proposed use as a treatment for chronic wounds. AB - We recently developed a bioresponsive dextrin-recombinant human epidermal growth factor (rhEGF) conjugate as a polymer therapeutic with potential for use in the promotion of tissue repair. The aim of these studies was to use patient-derived wound fluid and fibroblasts to evaluate its potential for further development as a treatment for chronic wounds, such as venous leg ulceration, a growing clinical challenge in the aging population. First, the levels of EGF (ELISA assay), alpha amylase and elastase (enzyme assays) were measured in patient-derived acute and chronic wound fluid. EGF was detected in acute, but not in chronic wound fluid. alpha-Amylase concentrations were higher in acute (188 IU/L), compared to chronic wound fluid (52 IU/L), but both were in the range of human serum levels. Although elastase was present in chronic wound fluid (2.1 +/- 1.2 RFU/min), none was detected in acute wound fluid. Dextrin-rhEGF incubation in chronic wound fluid led to endogenous alpha-amylase-mediated release of rhEGF (ELISA) that was maximal at 48 h. When the migration of HaCaT keratinocytes and of human fibroblasts (isolated from patient-matched, normal skin and chronic dermal wounds) was studied in vitro using the scratch wound assay, enhanced cell migration was observed in response to both free rhEGF and alpha-amylase-activated dextrin-rhEGF conjugate compared to controls. In addition, fibroblasts displayed increased proliferation (normal dermal fibroblasts approximately 160%; chronic wound fibroblasts approximately 140%) following incubation (72 h) with dextrin rhEGF that had been exposed to physiological levels of alpha-amylase (93 IU/L). These results suggest further preclinical in vivo evaluation of dextrin-rhEGF is warranted to determine whether conjugate pharmacokinetics and rhEGF liberation into such a complex and aggressive environment can still lead to bioactivity. PMID- 20166756 TI - Mechanisms of phospholipid complex loaded nanoparticles enhancing the oral bioavailability. AB - The purpose of the present study was to study the mechanisms of salvianolic acid B phospholipid complex loaded nanoparticles (SalB-PLC-NPs) enhancing the oral bioavailability of SalB by in situ perfusion model in rats and to evaluate the potential of phospholipid complex loaded nanoparticles (PLC-NPs) serving as an efficient oral delivery system to enhance the bioavailability of highly water soluble drugs. SalB-PLC-NPs, prepared by a solvent evaporation method, exhibited a spherical shape with a mean particle size and a zeta potential of 112.2 nm and 44.2 mV, respectively. The drug entrapment efficiency and drug loading were 86.19% and 3.21%, respectively. The lyophilized SalB-PLC-NPs, prepared with 10% maltose as the cryoprotectant, presented sustained release profiles in artificial gastric juice (0.1 M HCl with pH 1.2) and intestinal juice (PBS with pH 6.8 and 7.4). The absorption mechanisms were studied using a modified in situ perfusion method in rats, which showed the segment dependent absorption characteristics of SalB, SalB-PLC as well as SalB-PLC-NPs. The greatest absorption was obtained when SalB-PLC-NPs were perfused in colon. The possibility of intestinal lymphatic transport of SalB-PLC-NPs was investigated using mesenteric lymph vessel cannulation. Microscope (fluorescence and natural light) observation of lymph indicated that nanoparticles underwent intestinal lymphatic transport. In conclusion, the enhanced oral bioavailability of SalB was contributed to both the PLC and NPs. Importantly, our studies indicate that PLC-NPs may be a promising delivery system to enhance the oral bioavailability of highly water-soluble drugs. PMID- 20166757 TI - Twitter for scientists. PMID- 20166761 TI - Swimming into the future of drug discovery: in vivo chemical screens in zebrafish. AB - In recent years in vivo chemical screening in zebrafish has emerged as a rapid and efficient method to identify lead compounds that modulate specific biological processes. By performing primary screening in vivo, the bioactivity, toxicity, and off-target side effects are determined from the onset of drug development. A recent study demonstrates that in vivo screening can be used successfully to perform structure-activity relationship (SAR) studies. This work validates the zebrafish as an effective model for not only drug discovery but also drug optimization. PMID- 20166762 TI - ABA-regulated G protein signaling in Arabidopsis guard cells: a proteomic perspective. AB - Signaling cascades mediated by heterotrimeric G proteins are ubiquitous and important signal transduction mechanisms in both metazoans and plants. In the model plant Arabidopsis thaliana, the sole canonical G protein alpha subunit, GPA1, has been implicated in multiple signaling events, including guard cell movement regulated by the plant stress hormone abscisic acid (ABA). However, only a handful of proteins have been demonstrated to be involved in GPA1 signaling to date. Here, we compared the proteome composition of guard cells from wild type Col vs gpa1-4 null mutants with and without ABA treatment using iTRAQ technology to identify guard cell proteins whose abundance was affected by ABA and/or GPA1. After imposition of strict selection criteria, the abundance of two proteins in Col and six proteins in gpa1-4 was found to be affected by ABA in guard cells, and 18 guard cell proteins were quantitatively affected by the mutation of GPA1. On the basis of known functions of the differentially expressed proteins, our data suggest that GPA1 inhibits guard cell photosynthesis and promotes the availability of reactive oxygen species (ROS) in guard cells. These results exemplify how iTRAQ can be used to quantitatively study single cell signaling pathways in Arabidopsis. PMID- 20166763 TI - Naturally occurring variability in the envelope glycoprotein of HIV-1 and development of cell entry inhibitors. AB - Naturally occurring genetic variability across HIV-1 subtypes causes amino acid polymorphisms in encoded HIV-1 proteins including the envelope glycoproteins associated with viral entry. The effects of amino acid polymorphisms on the mechanism of HIV-1 entry into cells, a process initiated by the binding of the viral envelope glycoprotein gp120 to the cellular CD4 receptor, are largely unknown. In this study, we demonstrate that amino acid polymorphisms affect the structural stability and domain cooperativity of gp120 and that those differences are reflected in the binding mechanism of the viral envelope glycoprotein to the cell surface receptor and coreceptor. Moreover, subtype differences also affect the binding behavior of experimental HIV cell entry inhibitors. While gp120-A has a slightly lower denaturation temperature than gp120-B, the most notable stability difference is that for gp120-B the van't Hoff to calorimetric enthalpy ratio (DeltaH(vH)/DeltaH) is 0.95 whereas for gp120-A is 0.6, indicative of more cooperative domain/domain interactions in gp120-B, as this protein more closely approaches a two-state transition. Isothermal titration calorimetry demonstrates that CD4 and 17b (a surrogate antibody for the chemokine coreceptor) exhibit 7- and 3-fold weaker binding affinities for gp120-A. The binding of these proteins as well as that of the experimental entry inhibitor NBD-556 induces smaller conformational changes in gp120-A as evidenced by significantly smaller binding enthalpies and binding entropies. Together, these results describe the effects of gp120 polymorphisms on binding to host cell receptors and emphasize that guidelines for developing future entry inhibitors must recognize and deal with genomic differences between HIV strains. PMID- 20166765 TI - Rituximab for the treatment of non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. AB - Rituximab is a monoclonal antibody that is widely utilized in the treatment of a number of B-cell-derived haematological malignancies. Rituximab, in combination with chemotherapy, has significantly improved survival outcomes for patients diagnosed with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), the two most commonly diagnosed subtypes of non-Hodgkin's lymphoma. Furthermore, chemoimmunotherapy containing rituximab has led to significant increases in complete response and progression-free survival rates for patients with both previously untreated and relapsed or refractory chronic lymphocytic leukaemia (CLL). This article reviews the efficacy data from clinical trials demonstrating the significant survival benefits associated with rituximab use in the treatment of FL, DLBCL and CLL. PMID- 20166764 TI - Cystic fibrosis transmembrane conductance regulator modulators for personalized drug treatment of cystic fibrosis: progress to date. AB - This article considers the issue of personalized drug discovery for the orphan disease cystic fibrosis (CF) to deliver a candidate for therapeutic development. CF is a very complicated disease due to numerous anomalies of the gene leading to progressive severity and morbidity. Despite extensive research efforts, 20 years after the cloning of the CF gene, CF patients are still waiting for a curative treatment as prescribed medications still target the secondary manifestations of the disease rather than the gene or the CF transmembrane conductance regulator (CFTR) protein. New therapeutics aimed at improving mutant CFTR functions, also known as 'protein repair therapy' are nevertheless hoped and predicted to replace some of the currently used therapy, while improving the quality of life as well as life expectancy of CF patients. Although there is substantial variability in the cost of treating CF between countries, a protein repair therapy should also alleviate the financial burden of medical costs for CF patients and their families. Finding new drugs or rediscovering old ones for CF is critically dependent on the delivery of molecular and structural information on the CFTR protein, on its mutated version and on the network of CFTR-interacting proteins. The expertise needed to turn compounds into marketable drugs for CF will depend on our ability to provide biological information obtained from pertinent models of the disease and on our success in transferring safe molecules to clinical trials. Predicting a drug-induced response is also an attractive challenge that could be rapidly applied to patients. PMID- 20166766 TI - Current and emerging treatment strategies for cutaneous T-cell lymphoma. AB - Cutaneous T-cell lymphomas (CTCLs) are a rare group of mature T-cell lymphomas presenting primarily in the skin. The most common subtypes of CTCL are mycosis fungoides and its leukaemic variant Sezary's syndrome. Patients with early-stage disease frequently have an indolent clinical course; however, those with advanced stages have a shortened survival. For the treating physician, the question of how to choose a particular therapy in the management of CTCL is important. These diseases span the disciplines of dermatology, medical oncology and radiation oncology. Other than an allogeneic stem cell transplant, there are no curative therapies for this disease. Hence, many treatment modalities need to be offered to the patient over the course of their life. An accepted treatment approach has been to delay traditional chemotherapy, which can cause excessive toxicity without durable benefit. More conservative treatment strategies in the initial management of CTCL have led to the development of newer biological and targeted therapies. These therapies include biological immune enhancers such as interferon alpha and extracorporeal photopheresis that exert their effect by stimulating an immune response to the tumour cells. Retinoids such as bexarotene have been shown to be effective and well tolerated with predictable adverse effects. The fusion toxin denileukin diftitox targets the interleukin-2 receptor expressed on malignant T cells. Histone deacetylase inhibitors such as vorinostat and romidepsin (depsipeptide) may reverse the epigenetic states associated with cancer. Forodesine is a novel inhibitor of purine nucleoside phosphorylase and leads to apoptosis of malignant T cells. Pralatrexate is a novel targeted antifolate that targets the reduced folate carrier in cancer cells. Lastly, systemic chemotherapy including transplantation is used when rapid disease control is needed or if all other biological therapies have failed. As response rates to most of the biological agents used to treat CTCL are 25-30%, it is also reasonable to consider clinical trials with novel agents if one or two front-line therapies have failed, especially before considering chemotherapy. CTCL is largely an incurable disease with significant morbidity and more active agents are needed. PMID- 20166767 TI - Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders. AB - There is an increasing interest in nootropic drugs for the treatment of CNS disorders. Since the last meta-analysis of the clinical efficacy of piracetam, more information has accumulated. The primary objective of this systematic survey is to evaluate the clinical outcomes as well as the scientific literature relating to the pharmacology, pharmacokinetics/pharmacodynamics, mechanism of action, dosing, toxicology and adverse effects of marketed and investigational drugs. The major focus of the literature search was on articles demonstrating evidence-based clinical investigations during the past 10 years for the following therapeutic categories of CNS disorders: (i) cognition/memory; (ii) epilepsy and seizure; (iii) neurodegenerative diseases; (iv) stroke/ischaemia; and (v) stress and anxiety. In this article, piracetam-like compounds are divided into three subgroups based on their chemical structures, known efficacy and intended clinical uses. Subgroup 1 drugs include piracetam, oxiracetam, aniracetam, pramiracetam and phenylpiracetam, which have been used in humans and some of which are available as dietary supplements. Of these, oxiracetam and aniracetam are no longer in clinical use. Pramiracetam reportedly improved cognitive deficits associated with traumatic brain injuries. Although piracetam exhibited no long-term benefits for the treatment of mild cognitive impairments, recent studies demonstrated its neuroprotective effect when used during coronary bypass surgery. It was also effective in the treatment of cognitive disorders of cerebrovascular and traumatic origins; however, its overall effect on lowering depression and anxiety was higher than improving memory. As add-on therapy, it appears to benefit individuals with myoclonus epilepsy and tardive dyskinesia. Phenylpiracetam is more potent than piracetam and is used for a wider range of indications. In combination with a vasodilator drug, piracetam appeared to have an additive beneficial effect on various cognitive disabilities. Subgroup 2 drugs include levetiracetam, seletracetam and brivaracetam, which demonstrate antiepileptic activity, although their cognitive effects are unclear. Subgroup 3 includes piracetam derivatives with unknown clinical efficacies, and of these nefiracetam failed to improve cognition in post-stroke patients and rolipram is currently in clinical trials as an antidepressant. The remaining compounds of this subgroup are at various preclinical stages of research. The modes of action of piracetam and most of its derivatives remain an enigma. Differential effects on subtypes of glutamate receptors, but not the GABAergic actions, have been implicated. Piracetam seems to activate calcium influx into neuronal cells; however, this function is questionable in the light of findings that a persistent calcium inflow may have deleterious impact on neuronal cells. Although subgroup 2 compounds act via binding to another neuronal receptor (synaptic vesicle 2A), some of the subgroup 3 compounds, such as nefiracetam, are similar to those of subgroup 1. Based on calculations of the efficacy rates, our assessments indicate notable improvements in clinical outcomes with some of these agents. PMID- 20166769 TI - Trabectedin: a review of its use in soft tissue sarcoma and ovarian cancer. AB - Trabectedin (Yondelis) is a tetrahydroisoquinoline molecule that was originally derived from a marine organism. It is indicated in the EU and many other countries for use in patients with advanced soft-tissue sarcoma (STS) who have progressed despite receiving previous treatment with anthracyclines and ifosfamide or in those who are unable to receive these agents. It is also approved in the EU in combination with pegylated liposomal doxorubicin for the treatment of platinum-sensitive, recurrent ovarian cancer. In addition, trabectedin holds orphan drug status for the treatment of advanced, recurrent STS in the US, Switzerland and Korea, and for the treatment of advanced, recurrent ovarian cancer in the US and Switzerland. Clinical trials showed that intravenous trabectedin was effective in chemotherapy-experienced patients with advanced, recurrent liposarcoma or leiomyosarcoma, and results from a retrospective analysis suggest that the drug may be particularly effective in patients with advanced myxoid liposarcoma. In addition, coadministration of trabectedin with pegylated liposomal doxorubicin was associated with a significantly longer progression-free survival (6 weeks) than pegylated liposomal doxorubicin monotherapy in patients with recurrent ovarian cancer after failure of first line, platinum-based chemotherapy. The tolerability profile of trabectedin was manageable in clinical trials, and the tolerability profile of concomitant trabectedin and pegylated liposomal doxorubicin was generally consistent with that of each agent alone. Results to date indicate that trabectedin is a valuable addition to the group of second-line antineoplastic agents available for the treatment of advanced, recurrent STS, and that it is a beneficial treatment for recurrent ovarian cancer after failure of first-line, platinum-based chemotherapy when administered in conjunction with pegylated liposomal doxorubicin. PMID- 20166768 TI - Infections with extended-spectrum beta-lactamase-producing enterobacteriaceae: changing epidemiology and drug treatment choices. AB - Since 2000, Escherichia coli producing CTX-M enzymes (especially CTX-M-15) have emerged worldwide as important causes of community-onset urinary tract infections (UTIs) and bloodstream infections due to extended-spectrum beta-lactamase (ESBL) producing bacteria. Molecular epidemiology studies suggested that the sudden worldwide increase of CTX-M-15-producing E. coli is mostly due to a single clone named ST131 and that foreign travel to high-risk areas such as the Indian subcontinent might in part play a role in the spread of this clone across different continents. Empirical antibacterial coverage for these resistant organisms should be considered in community patients presenting with sepsis involving the urinary tract especially if a patient recently travelled to a high risk area. Infections due to ESBL-producing Enterobacteriaceae are associated with a delay in initiation of appropriate antibacterial therapy, which consequently prolongs hospital stays and increases hospital costs. Failure to initiate appropriate antibacterial therapy from the start appears to be responsible for higher patient mortality. The carbapenems are widely regarded as the drugs of choice for the treatment of severe infections due to ESBL-producing Enterobacteriaceae, although comparative clinical trials are lacking. Agents that may be useful for the treatment of ESBL-associated UTIs include fosfomycin, nitrofurantoin and temocillin. If this emerging public health threat is ignored, it is possible that clinicians may be forced in the near future to use the carbapenems as the first choice for empirical treatment of serious infections associated with UTIs originating from the community. PMID- 20166771 TI - Triptorelin embonate (6-month formulation). AB - A 6-month formulation of the gonadotropin-releasing hormone agonist triptorelin embonate (designed to deliver 22.5 mg of triptorelin over a 6-month period) has been developed for use in the treatment of advanced prostate cancer. Following intramuscular administration of the 6-month formulation of triptorelin embonate 22.5 mg to men with advanced prostate cancer (subset of 15 patients from the pivotal clinical trial), serum testosterone levels initially increased, followed by a rapid, sustained decrease. Castrate serum testosterone levels (i.e. < or =1.735 nmol/L) were achieved in a geometric mean time of 18.8 days. The 6-month formulation of triptorelin embonate achieved and maintained castrate serum testosterone levels in patients with advanced prostate cancer (n = 120), according to the results of the pivotal, noncomparative, multicentre trial (patients received intramuscular triptorelin embonate 22.5 mg on day 1 and at month 6 [week 24]). By day 29, 97.5% of patients had castrate serum testosterone levels. Castrate serum testosterone levels were maintained from months 2 to 12 in 93.0% of patients. Prior to the second injection at month 6, 98.3% of patients had castrate serum testosterone levels, and 98.3% of patients had castrate serum testosterone levels at study completion. The 6-month formulation of triptorelin embonate 22.5 mg was generally well tolerated in patients with advanced prostate cancer; adverse events were of mild severity in the majority of patients. Drug related adverse events (e.g. hot flushes) were consistent with the pharmacological action of triptorelin. Injection-site reactions occurred in 6.7% of triptorelin embonate recipients. PMID- 20166770 TI - Pharmacotherapy and weight-loss supplements for treatment of paediatric obesity. AB - Childhood obesity has become the most common paediatric disorder in the developed world. Treatment of obesity in children may include lifestyle interventions, pharmacotherapy and weight-loss supplements. The outcome of lifestyle interventions, which classically include dietary modifications, increased activity and behavioural modifications, remains insufficient and the adjuvant role of pharmacological agents has been proposed. Among the group of weight-loss medications, orlistat is the only pharmaceutical approved by the US FDA for the treatment of overweight and obese adolescents. The role of metformin needs to be established in larger studies and sibutramine remains an experimental product because of its potential adverse events. Weight-loss supplements lack sufficient data supporting their efficacy and safety, even in adults, and cannot be recommended at this time for adolescents. Preliminary data suggest that the use of fibre supplements, such as glucomannan, provides additional weight loss in individuals receiving a lifestyle intervention. No single approach will successfully treat obesity, and lifestyle modification presently remains the main pillar of any intervention aiming at decreasing bodyweight. PMID- 20166772 TI - [The sanitary conditions in the old Korcula Statute]. AB - Korcula's Code of Statutory regulations (from 1214, 1265, 1271 and later) contained very interesting rules of sanitary conditions in Korcula of that time. To protect the spreading of plague is prohibited contact with persons from the contaminated areas; it prohibited also entry into contaminated regions and rivers. The persons from the plague-stricken places were not allowed to enter the city. As was the custom, to preserve sanitary-hygienic conditions the shoe markers were forbidden to pollute the town with leather tanning. It was also forbidden to keep pigs in the city and to do washing in the pools. The place and time for throwing rubbish away were strictly controlled. To protect the citizens' lives and health the preparing of plant poisons was considered a felony. Capital punishment, burning at the stake, followed a case where somebody died or lost a limb as a result of plant poisoning. In a case less serious, such as fainting, the Prince meets out punishment according to his judgement of the crime. If the criminal absconds with exile the confiscation of all his property could follow. PMID- 20166773 TI - [Dr. Bruno Curinaldi (1854-1944): from Zadar over Mostar to Sarajevo]. AB - Dr Curinaldi was a fortunate combination of Italian background, Austro-Hungarian education, and life in a Croatian community where Catholicism met Islam. In a word, he was a genuine European multicultural intellectual. Ninety years of life and sixty-six years of medical career from Zadar to Mostar and to Sarajevo at the turn of the 20th century speak not only about his personal development and dilemmas, but also about social turmoils of the times. His life teaches us that a physician, in addition to his calling to always strive to help the sick and weak, must never forget his role of educator and active member of the community. PMID- 20166774 TI - On the water transport of animals with special reference to Denmark. AB - Transport of animals by water is a very old way of transport because it is relatively cheap and safe, with a minimum loss of animals. Waterways have been used for the transport of living animals and various goods from ancient times, for example in Ancient Egypt and the Roman Empire. Later, Vikings were so successful in their conquests because they always had trained horses aboard. It is believed that the colonization of America was possible because Spaniards were also bringing many horses with them. Danish possessions in the Caribbean owe much of their economic success in the period between 1820 and 1920 to permanent supply of cheap mules and other equides from South America. Mules were used for agricultural purposes and for work in sugar-cane mills. In the 20th century, a significant number of animals was transported to German and British colonies in South Africa. During the First and the Second World War, animals were also transported by water; measures were taken to meet the fundamental physiological requirements, and a veterinarian accompanied animals on long voyages. These precautions resulted in minimum transport losses. PMID- 20166775 TI - [The tribute of the pioneer of hypnotherapy--Franz Anton Mesmer, MD, PhD in the history of psychotherapy and medicine]. AB - Modern hypnosis started with the Austrian physician Franz Anton Mesmer (1734 1815), who believed that the phenomenon known as mesmerism, or animal magnetism, or fluidum was related to an invisible substance--a fluid that runs within the subject or between the subject and the therapist, that is, the hypnotist, or the "magnetizer". The term hypnosis was introduced in the 1840s by a Scottish surgeon James Braid (1795-1860), who believed the subject to be in a particular state of sleep--a trance. In the late 19th century, a French neurologist Jean Martin Charcot (1825-1893) thought hypnotism to be a special physiological state, and his contemporary Hyppotite-Marie Bernheim (1840-1919) believed it to be a psychological state of heightened suggestibility. Sigmund Freud, who studied with Charcot, used hypnosis early in his career to help patients recover repressed memories. He noted that patients would relive traumatic events while under hypnosis, a process know as abreaction. Freud later replaced hypnosis with the technique of free associations. Today, hypnosis is used as a form of therapy (hypnotherapy), a method of investigation to recover lost memories, and research tool. According to Caplan & Sadock, F.A. Mesmer is generally thought of as the fons et origo of modern psychotherapy; and from the early techniques of mesmerism, it is said, have evolved the more elaborate and sophisticated therapeutic measures of the analyst and his colleagues. Although Mesmer was certainly dealing with individuals suffering from a variety of neurotic disorders, and though the clinical successes he achieved were the result of psychological processes that his procedures induced in his patients, Mesmer's theoretical formulations, his understanding of the nature of the treatment he developed, and his specific procedures were all totally different from those of the 20th century analyst. He was one of the corne stones in the development of psychoanalysis through hypnosis mainly of hysterical patients. PMID- 20166776 TI - [Institutionalisation of Croatian medicine by the first World War]. AB - Unfavourable socioeconomic and political conditions delayed stronger development of medicine in Croatia until the last decades of the 19th century and the turn of the 20th century. This relatively short period saw the establishment of a number of key healthcare institutions such as the institute for smallpox vaccine production, department of bacteriology and hygiene, tuberculosis sanatorium, paediatric outpatient clinic, emergency medical facility, and dissection facility. Hospitals became centres of medical research and started to develop specific clinical professions. New medical associations saw the light of day [Sbor liecnika kr. Hrvatske i Slavonije (Association of Physicians of the Kingdom of Croatia and Slavonia) in Zagreb and DruZtvo slavonskih liecnika (Society of Physicians of Slavonia) in Osijek] and started their own bulletins Liecnicki viestnik and Glasnik DruZtva slavonskoh liecnika, respectively. Medical training was then provided by a midwifery school and a university school of pharmacy, while the Austrian government discouraged medical studies at the local level for decades, as it feared it would create a new class of free-thinking intellectuals. Those times also saw the first welfare institutions. Croatia was not producing pharmaceuticals at the time, but there was a new factory producing medical instruments, orthopaedic devices, and bandages. PMID- 20166777 TI - Distinguished figures in the development of the dental care in Croatian Littoral and the foundation of a Dentist Association in Rijeka. AB - Until the early 19th century, dental illnesses in the Croatian Littoral were treated by barbers and quacks. Mid 19th century saw the first seasonal dentists come from Vienna, Graz, and Trieste, and the first local dentists started to work full-time in the second half of the 19th century. Dr Frano Dabrovic, Dr Niko Gjivovic, Dr Dezider Dalma, and Dr Edmund Krausz were the first promoters of the profession, research, and education in dental hygiene of the local population. To further improve their profession, the dentists of Rijeka established a Society of the Littoral on 16 January 1909. There were other dentists outside Rijeka, such as Dr Ljudevit Korewa who ran his office in Senj, and Dr Hans Pichler who worked in the Navy Hospital of Pula during the First World War. The first teacher of dental medicine at the Zagreb University School of Medicine was professor Eduard Radosevic, and the first dean of the Zagreb University School of Dental Medicine was professor zivko Bolf, both born in Gorski kotar ( an inland region with close ties with Rijeka). PMID- 20166778 TI - Antonio Grossich- on the centenary of his introduction of iodine tincture painting in the preoperative infection control. AB - The article presents the life and achievements of Doctor Antonio Grossich, the head of the Department of surgery and gynecology of the Civic hospital in Rijeka. He wrote several literary works, but deserves to be remembered for his clinical and experimental work on antiseptic and aseptic procedure. He introduced the method of painting the operative field with 10% iodine tincture at first in traumas, then in general surgery. The method, for its rapidity, efficacy and not expensive had soon a worldwide success. He also participated actively in the political life of Rijeka before and after the World War I. PMID- 20166779 TI - [Dr Ante Svalba (1903-1989): promotor of social medicine and public health]. AB - When a healthcare professional sticks to one area of activity, such as protection of human environment, for his entire career, he must leave an indelible mark on his colleagues and local population. Dr Ante Svalba was this kind of a man; he was a physician specialised in hygiene, who persisted in his commitment to improve public health in the wide Rijeka area for nearly sixty active years. He was a true field worker and tireless educator dedicated to improving health culture in all age groups, but especially in schoolchildren. For decades, and nearly to the day he died, he was active in Red Cross work. Ante Svalba was born in Rijeka, and completed primary and secondary school in Rijeka and Susak, respectively. He graduated from the School of Medicine in Zagreb in 1927. For three years he worked at the School of Public Health in Zagreb, and between 1931 and 1942 he was town physician of Susak, until he was interned in Italy with his family. When Italy capitulated he went to Bari and joined anti-fascist resistance. In a place called Grumo he set up a hospital and a medical corps school of the National Liberation Army of Yugoslavia. Having returned to Rijeka, he performed a number of healthcare public offices, of which sanitation inspection was the longest lasting. When he retired in 1965, he took up a position of the head of Hygiene and Epidemiology Department of the Community Health Centre of Opatija until 1972. PMID- 20166780 TI - [The 60th anniversary of the Croatian Balneological and Climatological Institute]. AB - Sixty years ago, more precisely on 28 August 1949, Croatian Ministry of Health founded the Balneological and Climatological Institute as a result of a long-term endeavor and attempts to provide Croatia with an institution of this type, already existing in many European countries. In 1953, the Institute came under the management of the Yugoslav Academy of Arts and Sciences/YAAS [today Croatian Academy of Sciences and Arts and became the Department of Balneoclimatology of the Medical Research Institute of YAAS. In 1958, it was transferred to the Medical School of the University of Zagreb, continuing to function first as the Institute of Balneoclimatology and Physical Therapy and, since 1963, as the Institute of Physical Medicine and Rehabilitation. In spite of financial difficulties and occasional lack of understanding from the officials in this field, significant contributions have been made to balneology during this time, justifying the need for such an institution. On 15 April 2008, the Institute of Physical Medicine and Rehabilitation became Department for Balneoclimatology, under the Department of Environmental and Occupational Health of Andrija Stampar School of Public Health, Rockfellerova 4, Zagreb. PMID- 20166781 TI - Bioethics of handedness: from evolution to resolution? AB - Departing from historical facts and speculations on the evolution of human right hand dominance (including theories on the development of right-handedness and cultural and linguistic sequellae of such a phenomenon), the present work stresses the delicate problem of the traditional favouring of one particular subpopulation, escalating into a real eugenic practice present sporadically even in modern times. The major hypothesis of the paper would be that the problem of forced handedness had been neglected by (bio)ethical theory, practice, and literature, and that it was absolved only recently by the results of modern neuroscientific research on handedness. According to that hypothesis, ending the discrimination took too much time precisely because the initial lack of the problem insight, which certainly should invoke cautiousness for any potentially similar phenomena in the future. PMID- 20166782 TI - [Croatian Catholic Movement and Vladimir Hudolin (1922-1996): formation of one world known alcohologist]. AB - Vladimir Hudolin was born in Ogulin in 1922 and died in Zagreb in 1996. He was one of the best students of the Susak grammar school and distinguished himself in a Catholic youth association Domagoj. In 1940, he moved to Zagreb to study medicine. In 1948 he graduated, and in 1951 specialised in psychiatry. His field of expertise was social psychiatry, alcohology in particular. In developing his own original preventive and remedial programmes, he much relied on the concepts of Community Psychiatry and alike, and managed to encourage their implementation on a variety of community levels, from local to national. His concept was recognised in a number of countries around the world; over 650 articles speak about how successful it was. This article focuses on Vladimir Hudolin's grammar school years in Susak, proposing that particular circumstances and figures from his formative years played a key role in his humanistic and scientific development. Early on it was his social activity in the Catholic youth association Domagoj and Bonifacije Perovic, a theologist-sociologist who was a member of the Croatian Catholic Movement. The key figures who made him aware of the alcoholism issue were Fran Gudrum, Mirko Cunko, Maksimilijan Benkovic, Andrija Stampar, Josip Silovic, and the Bishop of Senj Josip Marusic. Regardless of the controversies and controversial activities of some of the members of the Croatian Catholic Movement between the two world wars, there is no doubt that this movement has played a major role in the development of one of the most distinct figures in world alcohology, Vladimir Hudolin. PMID- 20166783 TI - Predictors of condom use in a multisite study of high-risk youth living with HIV. AB - Young people between the ages of 13 to 24 are at persistent risk for HIV infection in the United States (Centers for Disease Control and Prevention [CDC], 2006). Young adulthood is a period characterized by experimentation, including engagement in risky behaviors (e.g., substance use and sexual behavior) (Moore & Parsons, 2000). Most young adults are sexually active, with the highest rates of sexual activity reported among youth of color (Park, Mulye, Adams, Brindis, & Irwin, 2006). The prevalence of sexually transmitted infections (STIs), especially chlamydia and gonorrhea, peak in young adulthood and are highest among youth of color (CDC, 2003). PMID- 20166784 TI - Mobilizing communities around HIV prevention for youth: how three coalitions applied key strategies to bring about structural changes. AB - Increasingly, HIV prevention efforts must focus on altering features of the social and physical environment to reduce risks associated with HIV acquisition and transmission. Community coalitions provide a vehicle for bringing about sustainable structural changes. This article shares lessons and key strategies regarding how three community coalitions located in Miami and Tampa, Florida, and San Juan, Puerto Rico engaged their respective communities in bringing about structural changes affecting policies, practices and programs related to HIV prevention for 12-24-year-olds. Outcomes of this work include increased access to HIV testing and counseling in the juvenile correctional system (Miami), increased monitoring of sexual abuse between young women and older men within public housing, and support services to deter age discordant relationships (Tampa) and increased access to community-based HIV testing (San Juan). PMID- 20166786 TI - The Bruthas Project: evaluation of a community-based HIV prevention intervention for African American men who have sex with men and women. AB - The Bruthas Project is a community-collaborative intervention to reduce HIV risk behavior among African American men who have sex with men and women (MSMW) but who do not form an identity around their same-sex behavior. The intervention was developed based on formative qualitative research with members of the population and involved four individualized risk reduction counseling sessions. Participants review general risk factors for HIV and are offered HIV testing and counseling (Session 1); discuss sexual dynamics and risk behaviors with female partners (Session 2); discuss sexual dynamics and risk behaviors with male partners (Session 3); review motivations and situational triggers for unsafe sex, and engage in role-play exercises that aim to reach personal risk reduction goals (Session 4). Community outreach and counseling are provided by African American men with whom participants can identify, and counseling is designed to respond to men's need for privacy, cultural affirmation, and masculine values. Thirty-six African American MSMW completed a pilot intervention, including baseline and 3 month follow-up assessments of sexual risk behaviors and psychosocial factors. Preanalysis and postanalysis found significant reductions in unprotected receptive and insertive anal sex with male partners, fewer numbers of female and male unsafe sex partners, and decreased sex while under the influence of drugs. Men also reported significantly increased social support, self-esteem, and reduced loneliness at follow-up. Positive outcomes suggest this is a promising approach for reducing HIV risk in this population. PMID- 20166785 TI - Recruitment of men who have sex with men for large HIV intervention trials: analysis of the EXPLORE Study recruitment effort. AB - Testing HIV prevention strategies requires that researchers recruit participants at high risk of HIV infection. Data from the EXPLORE Study, a behavioral intervention trial involving men who have sex with men (MSM), were used to examine the relationship between recruitment strategies and participant characteristics, sexual risk behaviors and HIV incidence. The EXPLORE Study used a wide variety of recruitment strategies; no one strategy accounted for more than 20% of enrolled men. Younger men and men of color were more likely to be recruited through club and bar outreach, friend referral, and street outreach. Men reporting 10 or more sexual partners were more likely to be recruited through advertising and street outreach. Men reporting unprotected sex were more likely to be recruited through clinic referrals. HIV incidence did not significantly differ by recruitment strategy. Our findings support the need for a wide range of recruitment strategies in attracting MSM at high risk for HIV into clinical studies. PMID- 20166787 TI - Outcomes of AIDS Education and Training Center HIV/AIDS skill-building workshops on provider practices. AB - The Midwest AIDS Training and Education Center (MATEC) implemented a Web-based survey method to measure impact on practitioners of HIV/AIDS skill-building workshops offered in seven midwestern states. Surveys were sent to 2,949 participants from 230 workshops 4-6 weeks after each workshop. Of those surveyed, 631 respondents provided usable data (22.4%). Self-reported narrative responses described practice changes attributed to training. Changes were categorized as (a) practitioner attitude/knowledge, (b) practitioner practice behavior, (c) planning system change, and (d) implemented adaptations to the clinical care system. Other outcome measures were attending more programs and consulting with colleagues. Change was reported by 341 (54.0%) individuals, with a total of 411 change events/activities documented. Of the change events, 302 (73%) related to changes in health provider practices and 109 (27%) related to the care systems. Findings from this evaluation project provide evidence that MATEC workshops do impact practitioners' behaviors and care systems consistent with the literature about translating research into practice. PMID- 20166788 TI - Violence, coping, and consistent medication adherence in HIV-positive couples. AB - The purpose of this study was to investigate the extent to which intimate partner violence (IPV) influences antiretroviral medication adherence. Furthermore, it was hypothesized that adherence would differ for men and women based on degree of violence and coping strategies employed by each gender. A sample of HIV seroconcordant and serodiscordant heterosexual couples was recruited from the Miami area and assessed on rates of medication adherence, conflict resolution tactics, and coping strategies. Of these, 190 individual participants were prescribed antiretroviral medication. Baseline rates of adherence were 90.29% for men and 87.77% for women. Acts of violence were found to have negative effects on adherence for women but not for men. However, negative coping strategies were predictive of poor adherence for men but not women. Violence was found to be related to poor coping styles for both men and women. This study offers support for the inclusion of partners in conducting interventions. Furthermore, it underlines the importance of recognizing IPV as a barrier to medication adherence. PMID- 20166789 TI - Social influence and individual risk factors of HIV unsafe sex among female entertainment workers in China. AB - Female entertainment workers in China are at increased sexual risk of HIV, but causes of their unprotected sex remain poorly understood. We develop a model that integrates information-motivation-behavioral skills (IMB) with social influences and test the model in a venue-based sample of 732 female entertainment workers in Shanghai. Most IMB and social influence measures are statistically significant in bivariate relationships to condom use; only HIV prevention motivation and behavioral self-efficacy remain significant in the multiple regressions. Self efficacy in condom use is the most proximate correlate, mediating the relationship between information and motivation and condom use. Both peer and venue supports are important, but their influences over condom use are indirect and mediated through prevention motivation and/or self-efficacy. Behavioral intervention is urgently needed and should take a multilevel approach, emphasizing behavioral skills training and promoting a supportive social/working environment. PMID- 20166790 TI - Possible influence of variant of the P-glycoprotein gene (MDR1/ABCB1) on clinical response to guanfacine in children with pervasive developmental disorders and hyperactivity. AB - OBJECTIVE: Guanfacine has been shown to reduce hyperactive behaviors in children with attention-deficit/hyperactivity disorder (ADHD) and possibly in children with pervasive developmental disorder (PDD) and hyperactivity. The aim of this exploratory study was to examine whether gene variants encoding the multidrug resistance protein (MDR1 or ABCB1) , a drug transporter at the blood-brain barrier, are associated with variability in the efficacy of guanfacine in children with PDD and hyperactivity. METHODS: Children with PDD who participated in an 8-week open-label trial of guanfacine were genotyped for the C3435T single nucleotide polymorphism (SNP) variant of the MDR1 gene, a variant reported to alter function of the transporter. The decrease from baseline to 8 weeks in parent-rated Aberrant Behavior Checklist (ABC) hyperactivity and Swanson, Nolan, and Pelham (SNAP) scores were analyzed by MDR1 genotype. Response was compared between subjects homozygous for the minor allele T of the C34535T MDR1 variant (T/T) versus other genotypes (C/T and C/C). RESULTS: Disruptive behavior decreased during guanfacine treatment as assessed by several end points in the 25 enrolled children (23 boys and 2 girls). Genotype data were available from 22 children. Subjects with either C/T or C/C (n = 16) genotypes showed a three-fold greater improvement than T/T MDR1 C3435T genotype (n = 6) (mean decrease of 15.1 +/- 12.6, or 50.7% from baseline, versus 4.5 +/- 5.1, or 15.6% from baseline) in parent-rated ABC Hyperactivity scores over 8 weeks (p = 0.03). Parent-rated ADHD SNAP scores also differed by genotype (p = 0.05). CONCLUSIONS: Gene variants in MDR1 may influence guanfacine response on hyperactive-impulsive behaviors via altered membrane transport. If replicated in larger samples, additional studies would be important to clarify the mechanisms underlying this effect and to determine its clinical significance. 2. PMID- 20166791 TI - A prospective open-label trial of extended-release carbamazepine monotherapy in children with bipolar disorder. AB - OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of extended release carbamazepine (CBZ-ER) monotherapy in the treatment of pediatric bipolar disorder (BD). METHOD: This was an 8-week, open-label, prospective trial of CBZ-ER monotherapy (788 +/- 252 mg/day) to assess the effectiveness and tolerability of this compound in treating pediatric bipolar spectrum disorders. Assessments included the Young Mania Rating Scale (YMRS), Clinical Global Impressions-Improvement scale, Children's Depression Rating Scale, and Brief Psychiatric Rating Scale. Adverse events were assessed through spontaneous self reports, vital signs weight monitoring, and laboratory analysis. RESULTS: Of the 27 participating children with BD, 16 (59.%) completed the study. CBZ-ER treatment was associated with statistically significant, but modest, levels of improvement in mean YMRS scores (-10.1 +/- 10.2, p < 0.001) with end-point mean YMRS score (21.8 +/- 12.2) suggesting a lack of complete resolution of mania. CBZ ER treatment also resulted in significant improvement in the severity of depressive, attention-deficit/hyperactivity disorder, and psychotic symptoms. With the exception of 2 participants who discontinued due to skin rash, CBZ-ER was well tolerated with marginal increase in body weight (0.8 +/- 2.5 kg, p = 0.04) and was not associated with any abnormal changes in laboratory parameters. CONCLUSIONS: Open-label CBZ-ER treatment was beneficial for the treatment of BD in children. Future controlled trials are warranted. PMID- 20166792 TI - Neural correlates of response inhibition in pediatric bipolar disorder. AB - OBJECTIVES: Pediatric bipolar disorder is characterized by core deficits in mood and executive function and commonly co-occurs with attention deficit/hyperactivity disorder (ADHD). We aimed to examine response inhibition in this population, as an element of executive function, which, if aberrant, may interfere with learning and information processing. METHODS: Children (9-18 years) with bipolar I or II disorder (BD, n = 26) and age, gender, and intelligence quotient (IQ) comparable healthy children (HC, n = 22) without any psychopathology were given a standardized Go/NoGo computerized task measuring response inhibition. A whole-brain functional magnetic resonance imaging (MRI) group analysis was performed using statistical parametric mapping software (SPM2) for comparing NoGo to Go epochs. RESULTS: There were no statistically significant group differences between groups in age, gender, or ethnicity. The BD group had high rates of co-morbid disorders, including 81% with ADHD, 62% with oppositional defiant disorder (ODD), and 46% with anxiety disorders. This BD group had fewer correct responses on Go (84% vs. 96%, T[46] = 3.35, p = 0.002) and overall (85% vs. 94%, T[46] = 4.12, p = 0.0002) trials as compared to the HC group. However, there were no statistically significant group differences in response inhibition on NoGo trials (p = 0.11). In the NoGo-Go contrast, the BD group showed increased neural activation in the right dorsolateral prefrontal cortex (DLPFC) compared to HC (T[46] = 4.21, p < 0.001). CONCLUSIONS: During accurate NoGo but impaired Go trial performance, children with BD showed increased right DLPFC activation versus controls, suggesting increased recruitment of executive control regions for accurate response inhibition. Studies relating these results to mood regulation in pediatric BD are warranted. PMID- 20166794 TI - Changes in positive and negative syndrome scale-derived hostility factor in adolescents with schizophrenia treated with aripiprazole: post hoc analysis of randomized clinical trial data. AB - INTRODUCTION: This post hoc analysis evaluated the effects of aripiprazole on Positive and Negative Syndrome Scale (PANSS) Hostility factor scores in adolescents with schizophrenia. METHODS: In total, 302 adolescents (13-17 years) with schizophrenia were enrolled in a 6-week, multicenter, double-blind, randomized, placebo-controlled trial comparing aripiprazole (10 or 30 mg/day) with placebo. The PANSS was the primary outcome measure. To determine the effect of aripiprazole on hostility, a post hoc analysis of the PANSS Hostility factor and individual items was performed. RESULTS: Aripiprazole was superior to placebo in reducing PANSS Hostility factor scores in adolescents with schizophrenia. After 6 weeks, aripiprazole 10 mg/day and aripiprazole 30 mg/day showed a statistically significant improvement versus placebo (-3.0, -3.7, versus -2.1; p < 0.05; last observation carried forward [LOCF]) in the PANSS Hostility factor. For aripiprazole 30 mg/day, statistically significant separation from placebo was evident from week 3 through week 6 and at week 6 for aripiprazole 10 mg/day. Individual PANSS Hostility, Uncooperativeness, and Poor Impulse Control Items showed statistically significant improvement with aripiprazole 30 mg/day over placebo at end point. CONCLUSIONS: This post hoc analysis shows that aripiprazole (10 and 30 mg/day) is an effective treatment for hostility symptoms in adolescents with schizophrenia. Clinical trials information: ClinicalTrials.gov identifier: NCT00102063. PMID- 20166793 TI - Psychotropic medication exposure and age at onset of bipolar disorder in offspring of parents with bipolar disorder. AB - OBJECTIVE: Exposure to psychotropic medications before the onset of bipolar disorder (BD) in children may have profound effects on the course of illness. Both antidepressant and stimulant exposure have been proposed to hasten the course of BD development, whereas mood stabilizers have been proposed as protective. We sought to describe psychotropic medication exposure in a cohort of children at risk for BD and retrospectively determine the effect of medication exposure on age at onset (AAO) of BD. METHODS: Subjects were 106 children and adolescents who had at least 1 parent with BD. Of these, 63 had BD I or BD II and 43 had subsyndromal symptoms of BD. AAO was determined as nearest month of first manic or hypomanic episode. Past psychotropic medication exposure prior to AAO was determined through interview and chart review. RESULTS: Both groups had high rates of exposure to psychotropic medications. Antidepressant or stimulant exposure was not correlated with an earlier AAO of BD. However, mood stabilizer exposure was associated with a later AAO. CONCLUSIONS: Children with full or subsyndromal BD are frequently exposed to a variety of psychotropic medications before their first manic episode. Our findings do not support that early stimulant or antidepressant exposure leads to an earlier AAO of BD. However, early mood stabilizer exposure may be associated with delayed AAO. Longitudinal studies are needed to clarify these results. PMID- 20166795 TI - Predictors of placebo response in randomized controlled trials of psychotropic drugs for children and adolescents with internalizing disorders. AB - OBJECTIVE: The aim of this study was to assess predictors of placebo response in all available short-term, placebo-controlled trials of psychotropic drugs for children and adolescents with internalizing disorders, major depressive disorder (MDD), obsessive compulsive disorder (OCD,) and anxiety disorders (ANX) exclusive of OCD and posttraumatic stress disorder (PTSD). METHOD: We reviewed the literature relevant to the use of psychotropic medication in children and adolescents with internalizing disorders, restricting our review to double-blind studies including a placebo arm. Placebo response, defined according to each trial's primary response outcome variable and Clinical Global Impressions Improvement, when available, and potential predictive variables were extracted from 40 studies. RESULTS: From 1972 to 2007, we found 23 trials that evaluated the efficacy of psychotropic medication involving youth with MDD, 7 pertaining to youths with OCD, and 10 pertaining to youths with ANX (N = 2,533 patients in placebo arms). For all internalizing disorders combined, predictors of nonresponse to placebo were the percentage of Caucasian patients included in the study and the duration of the disorder: Both variables were negatively correlated with the percent of placebo responders. The type of disorder was found to predict the robustness of placebo response: (OCD < ANX < MDD). For a subset of MDD studies, we found that baseline illness severity tended to be negatively correlated with placebo response. Finally, trial "success" was significantly associated with lower placebo response rate. CONCLUSION: Predictors of placebo response in internalizing disorders of youths parallel those in adult studies, with the exception of race. These predictors should be considered when designing placebo-controlled trials in youths to enhance findings of true drug-placebo differences. PMID- 20166796 TI - Plasma methylphenidate concentrations in youths treated with high-dose osmotic release oral system formulation. AB - BACKGROUND: Children and adolescents are being treated increasingly for attention deficit/hyperactivity disorder (ADHD) with a variety of stimulants in higher than Food and Drug Administration (FDA)-approved doses and in combination with other medications. OBJECTIVE: We sought to determine methylphenidate (MPH) concentrations in children and adolescents treated with high-dose, extended release osmotic release oral system (OROS) MPH plus concomitant medications, and to examine MPH concentrations with respect to the safety and tolerability of treatment. METHODS: Plasma MPH concentrations were measured by liquid chromatography-mass spectrometry 4-5 hours after administration of medication in a sample of youths diagnosed with ADHD. These youths were treated naturalistically with higher than FDA-approved doses of OROS MPH in addition to their concomitant medications. Markers of safety and tolerability (e.g., measures of blood pressure and heart rate) were also examined. RESULTS: Among the 17 patients (with a mean age of 16.2 +/- 2 years and a mean number of concurrent medications of 2.23 +/- 0.94), the mean plasma MPH concentration was 28 +/- 9.1 ng/mL, despite a mean daily dose of OROS MPH of 169 +/- 5 mg (3.0 +/- 0.8 mg/kg per day). No patient had a plasma MPH level >or=50 ng/mL or clinical signs of stimulant toxicity. No correlation was found between plasma MPH concentrations and OROS MPH dose or changes in vital signs. CONCLUSIONS: High-dose OROS MPH, used in combination with other medications, was not associated with either unusually elevated plasma MPH concentrations or with clinically meaningful changes in vital signs. Study limitations include a single time-point sampling of MPH concentrations, a small sample size, and a lack of outcome measures to address treatment effectiveness. PMID- 20166797 TI - Trends in incidence and characteristics of children, adolescents, and adults initiating immediate- or extended-release methylphenidate or atomoxetine in the Netherlands during 2001-2006. AB - BACKGROUND: Previous Dutch studies showed increasing psychostimulant use, especially methylphenidate immediate-release (MPH-IR), between 1995 and 2003. In 2003 the extended-release (ER) formulation of MPH and in 2005 atomoxetine (ATX) were introduced in The Netherlands, which increased treatment options. OBJECTIVE: The aim of this study was to describe the change in incidence of attention deficit/hyperactivity disorder (ADHD) drugs and the prescription profiles of patients younger than 45 years starting treatment with these medicines between 2001 and 2006. METHODS: Data were obtained from Dutch community pharmacies as collected by the Foundation for Pharmaceutical Statistics, covering 97% of all dispenses for prescription medicines to outpatients in The Netherlands. RESULTS: The overall incidence of ADHD drugs use increased 6.5-fold from 2001 to 2006 in men as well as in women. The absolute incidence was highest among 6- to 11-year old boys. The percentage of first-time MPH-IR users decreased from 98.3% in 2001 to 75.9% in 2006. Likewise, MPH-ER use increased from 0% in 2001 to 18.9% in 2006, and ATX use increased from 0% in 2001 to 3.9% in 2006. The new nonstimulant drug ATX was prescribed more often to adults if they had been previously treated with selective serotonin reuptake inhibitors (SSRIs), benzodiazepines, or antipsychotics. Youngsters <17 years initiated on ATX were often previously treated with antipsychotics or clonidine/guanfacine. CONCLUSION: These findings demonstrate an increase in incidence in use of ADHD drugs between 2001 and 2006 in The Netherlands. The major proportion of all treated patients comprised boys, 6-11 years old; most of them were treated with MPH-IR. In a few years time, the use of extended-release drugs as part of all ADHD drug prescriptions increased considerably, despite the lack of full reimbursement of these extended-release drugs. Psychostimulants and atomoxetine in children, adolescents, and adults are probably used to address different treatment needs. PMID- 20166798 TI - Report of an initial pilot study on the feasibility of using the MacArthur competence assessment tool for clinical research in children and adolescents with attention-deficit/hyperactivity disorder. AB - INTRODUCTION: The MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) was used in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and co-morbid oppositional defiant disorder (ODD) and in their parents. The aims were to test feasibility and to determine children's understanding of the elements of disclosure for a clinical drug trial and their competence to assent. METHOD: The contents and language of MacCAT-CR were adapted to be age appropriate for the children. Twelve children (mean age, 9.87 [7.7-12.2]; mean intelligence quotient [IQ], 97 [72-122]) and either the mother or father of each child were interviewed. Psychologists rated the interviews and, in addition to MacCAT-CR, competence was assessed by trained clinicians. RESULTS: The MacCAT-CR was practicable, and the time required was acceptable. Interrater reliability was excellent in children. Children performed less well than parents on this test (children;s vs. parents' scores: Understanding 5.86 vs. 9.08, appreciation 2.64 vs. 4.96, reasoning 3.05 vs. 4.63, respectively). Whereas clinicians assessed all children as competent, lack of competence became apparent in the MacCAT-CR. CONCLUSIONS: The practicability and the interrater reliability suggest that the MacCAT-CR is feasible in children, but the question of whether competence is assessed validly remains unsolved in the absence of external validation. The differences between assessment by clinicians and the low scores obtained in the MacCAT-CR suggest that children may give assent even if they do not understand completely. The results of this initial pilot study may help in the planning of further investigations intended to improve information about studies and assessment of assent/consent. PMID- 20166800 TI - Compulsive spitting in a child with pervasive developmental disorder and Tourette's disorder: tic or compulsion? PMID- 20166801 TI - Paliperidone for irritability in autistic disorder. PMID- 20166802 TI - Effectiveness of clozapine for the treatment of aggression in an adolescent with autistic disorder. PMID- 20166804 TI - Novel glimepiride derivatives with potential as double-edged swords against type II diabetes. AB - Sulphonylurea drugs have been widely used in the safe and efficacous therapy of type II diabetes during the past five decades. They lower blood glucose predominantly via the stimulation of insulin release from pancreatic beta-cells. However, a moderate insulin-independent regulation of fatty acid esterification and release in adipose tissue cells has been reported for certain sulphonylureas, in particular for glimepiride. On basis of the known pleiotropic pathogenesis of type II diabetes with a combination of beta-cell failure and peripheral, including adipocyte, insulin resistance, anti-diabetic drugs exerting both insulin releasing- and fatty acid-metabolizing activities in a more balanced and potent fashion may be of advantage. However, the completely different molecular mechanisms underlying the insulin-releasing and fatty acid-metabolizing activities, as have been delineated so far for glimepiride, may hamper their optimization within a single sulphonylurea molecule. By analyzing conventional sulphonylureas and novel glimepiride derivatives for their activities at the primary targets and downstream steps in both beta-cells and adipocytes in vitro we demonstrate here that the insulin-releasing and fatty acid-metabolizing activities are critically dependent on both overlapping and independent structural determinants. These were unravelled by the parallel losses of these two activities in a subset of glimepiride derivatives and the impairment in the insulin-releasing activity in parallel with elevation in the fatty acid metabolizing activity in a different subset. Together these findings may provide a basis for the design of novel sulphonylureas with blood glucose-lowering activity relying on less pronounced stimulation of insulin release from pancreatic beta-cells and more pronounced insulin-independent stimulation of esterification as well as inhibition of release of fatty acids by adipocytes than provoked by the sulphonylureas currently used in therapy. PMID- 20166805 TI - Distribution of liposomal bifendate in liver following intravenous injection in mice. AB - The purpose of this study was to develop and study the behaviors of bifendate (DDB) liposome in vivo. DDB liposome was prepared by the rotary evaporationextrusion method. The particle size, zeta-potential, encapsulation efficiency (EE), and in vitro drug release from liposome were determined and the in vivo studies were tested in mice and rats. The concentrations of DDB in plasma and liver at different sampling time points were determined by RP-HPLC. The liver concentration-time curves of DDB liposome and free drug solution in mice were determined, and the pharmacokinetic parameters in rats and mice were calculated and compared by statistical analysis. The average liposome diameter was 323 +/- 29 nm (n = 3) and the EE was 91.52 +/- 2.38%. There were significantly different parameters of k10 and area under the plasma concentrationtime curve (AUC(0-T)) between liposome and solution. The mean residence time (MRT(0-T)) in plasma of liposomal formulation was 3.72 times longer than that of solution. Compared with solution, DDB liposome delivered about 2.57 times higher DDB into liver. Thus, an optimum intravenous liposome formulation for DDB could be developed as an alternative to the commercial DDB preparations. PMID- 20166806 TI - Blockade of acute microglial activation by minocycline promotes neuroprotection and reduces locomotor hyperactivity after closed head injury in mice: a twelve week follow-up study. AB - Traumatic brain injury (TBI) causes a wide spectrum of consequences, such as microglial activation, cerebral inflammation, and focal and diffuse brain injury, as well as functional impairment. In this study we aimed to investigate the effects of acute treatment with minocycline as an inhibitor of microglial activation on cerebral focal and diffuse lesions, and on the spontaneous locomotor activity following TBI. The weight-drop model was used to induce TBI in mice. Microglial activation and diffuse axonal injury (DAI) were detected by immunohistochemistry using CD11b and ss-amyloid precursor protein (ss-APP) immunolabeling, respectively. Focal injury was determined by the measurement of the brain lesion volume. Horizontal and vertical locomotor activities were measured for up to 12 weeks post-injury by an automated actimeter. Minocycline or vehicle were administered three times post-insult, at 5 min (90 mg/kg i.p.), 3 h, and 9 h post-TBI (45 mg/kg i.p.). Minocycline treatment attenuated microglial activation by 59% and reduced brain lesion volume by 58%, yet it did not affect DAI at 24 h post-TBI. More interestingly, minocycline significantly decreased TBI induced locomotor hyperactivity at 48 h post-TBI, and its effect lasted for up to 8 weeks. Taken together, the results indicate that microglial activation appears to play an important role in the development of TBI-induced focal injury and the subsequent locomotor hyperactivity, and its short-term inhibition provides long lasting functional recovery after TBI. These findings emphasize the fact that minocycline could be a promising new therapeutic strategy for head-injured patients. PMID- 20166807 TI - Simulations of exercise and brain effects of acute exposure to carbon monoxide in normal and vascular-diseased persons. AB - At some level, carboxyhemoglobin (COHb) due to inhalation of carbon monoxide (CO) reduces maximum exercise duration in both normal and ischemic heart patients. At high COHb levels in normal subjects, brain function is also affected and behavioral performance is impaired.These are findings from published experiments that are, due to ethical or practical considerations, incomplete in that higher or lower ranges of COHb, and exercise have not been well studied. To fill in this knowledge base, a whole-body human physiological model was used to make estimates of physiological functioning by the simulation of parametric exposures to CO and various exercise levels. Ischemic heart disease was simulated by introducing a stenosis in the left heart arterial supply. Brain blood flow was also limited by such a stenosis. To lend credibility to such estimation, the model was tested by simulating experiments from the published literature. Simulations permitted several new conclusions. Increases in COHb produced the largest decreases in exercise duration when exercise was least strenuous and when COHb was smallest. For ischemic heart disease subjects, the greatest change in exercise duration produced by COHb increase was when ischemia and COHb was smallest. Brain aerobic metabolism was unaffected until COHb exceeded 25%, unless the maximum brain blood supply was limited by a stenosis greater than 50% of normal. For higher levels of stenosis, aerobic brain metabolism was reduced for any increase in COHb level, implying that behavior would be impaired with no "threshold" for COHb. PMID- 20166809 TI - Inhibition and binding studies of carbonic anhydrase isozymes I, II and IX with benzimidazo[1,2-c][1,2,3]thiadiazole-7-sulphonamides. AB - The binding and inhibition strength of a series of benzimidazo[1,2 c][1,2,3]thiadiazole-7-sulphonamides were determined for recombinant human carbonic anhydrase isoforms I, II, and IX. The inhibition strength was determined by a stop-flow method to measure carbon dioxide hydration. Inhibitor-enzyme binding was determined by two biophysical techniques--isothermal titration calorimetry and thermal shift assay. The co-crystal structure was determined by X ray crystallography. Comparing the results obtained using three different inhibition and binding methods increased the accuracy of compound affinity ranking and the ability to determine compound inhibitory specificity towards a particular carbonic anhydrase isoform. In most cases, all three methods yielded the same results despite using very different approaches to measure the binding and inhibition reactions. Some of the compounds studied are submicromolar inhibitors of the isoform IX, a prominent cancer target. PMID- 20166811 TI - The outcome for secondary alveolar bone grafting in the South West UK region post CSAG. AB - OBJECTIVE: In 1998 the delivery of cleft care in the United Kingdom was examined by the Clinical Standards Advisory Group, the outcomes of which led to the wide restructuring of cleft services in the United Kingdom. We present a retrospective study evaluating the radiographic outcome of 53 consecutively performed alveolar bone grafts following the regional centralization of secondary alveolar bone grafting to the South West Cleft Centre between 2004 and 2006. METHODS: A retrospective audit of one surgeon's outcome of 53 consecutively performed alveolar bone grafts, assessed radiographically using the Kindelan method. RESULTS: That 94% of bone-grafted sites achieved a successful radiographic outcome compares favorably with the previously published Clinical Standards Advisory Group data of 58% with Bergland scores. CONCLUSION: The radiographic outcome for alveolar bone grafting has improved with centralization. A small number of patients are being grafted after the ideal chronological age, and this needs to be addressed throughout the region. The Kindelan assessment provides a reliable method of early assessment for alveolar bone grafting. PMID- 20166813 TI - Extraintestinal manifestations of inflammatory bowel disease: epidemiology, diagnosis, and management. AB - Abstract Extraintestinal manifestations occur rather frequently in inflammatory bowel disease (IBD), e.g. ulcerative colitis (UC) and Crohn's disease (CD). The present paper provides an overview of the epidemiology, clinical characteristics, diagnostic process, and management of rheumatic, metabolic, dermatologic (mucocutaneous), ophthalmologic, hepatobiliary, hematologic, thromboembolic, urinary tract, pulmonary, and pancreatic extraintestinal manifestations related to IBD. Articles were identified through search of the PubMed and Embase databases, the Cochrane Library, and the web sites of the European Agency for the Evaluation of Medicinal Products (EMEA) and the US Food and Drug Administration (FDA) (cut-off date October 2009). The search terms 'Crohn's disease', 'inflammatory bowel disease', or 'ulcerative colitis' were combined with the terms 'adalimumab', 'anemia', 'arthritis', 'bronchiectasis', 'bronchitis', 'cutaneous manifestations', 'erythema nodosum', 'extraintestinal manifestations', 'hyperhomocysteinemia', 'infliximab', 'iridocyclitis', 'lung disease', 'ocular manifestations', 'osteomalacia', 'pancreatitis', 'primary sclerosing cholangitis', 'renal stones', 'sulfasalazine', 'thromboembolism', and 'treatment'. The search was performed on English-language reviews, practical guidelines, letters, and editorials. Articles were selected based on their relevance, and additional papers were retrieved from their reference lists. Since some of the diseases discussed are uncommon, valid evidence of treatment was difficult to obtain, and epidemiologic data on the rarer forms of extraintestinal manifestations are scarce. However, updates on the pathophysiology and treatment regimens are given for each of these disorders. This paper offers a current review of original research papers and randomized clinical trials, if any, within the field and makes an attempt to point out practical guidelines for the diagnosis and treatment of various extraintestinal manifestations related to IBD. PMID- 20166810 TI - Adipose tissue engineering for soft tissue regeneration. AB - Current treatment modalities for soft tissue defects caused by various pathologies and trauma include autologous grafting and commercially available fillers. However, these treatment methods present a number of challenges and limitations, such as donor-site morbidity and volume loss over time. As such, improved therapeutic modalities need to be developed. Tissue engineering techniques offer novel solutions to these problems through development of bioactive tissue constructs that can regenerate adipose tissue in both structure and function. Recently, a number of studies have been designed to explore various methods to engineer human adipose tissue. This review will focus on these developments in the area of adipose tissue engineering for soft tissue replacement. The physiology of adipose tissue and current surgical therapies used to replace lost tissue volume, specifically in breast tissue, are introduced, and current biomaterials, cell sources, and tissue culture strategies are discussed. We discuss future areas of study in adipose tissue engineering. PMID- 20166814 TI - Prevalence and prognostic value of poor R-wave progression in standard resting electrocardiogram in a general adult population. The Health 2000 Survey. AB - AIMS: We examined the prevalence and prognostic impact of poor R-wave progression (PRWP) in a standard electrocardiogram (ECG) in a general population. METHODS: Data and standard resting ECG recording were collected from a large nationally representative (random sample) health examination survey conducted in Finland in 2000-2001. The final study population consisted of 5613 individuals. RESULTS: The prevalence of PRWP (defined as RV3 < or = 3 mm and RV2 < or = RV3) was 7.0% in women and 2.7% in men (P< or = 0.001 for difference). During follow-up of 70 +/- 9 months (mean +/- SD), 317 patients died (5.6%). Both all-cause and cardiovascular mortality was higher in the group with PRWP than in those without PRWP in both women and men. In Cox regression analysis after adjustment for age, hypertension, diabetes, previous myocardial infarction, and coronary heart disease, the relative risk for all-cause mortality for PRWP was 1.69 (95% CI 0.89 3.22, P=0.112) for men and 2.00 (95% CI 1.28-3.13, P=0.002) for women. For cardiovascular mortality the relative risk for individuals with PRWP was 1.85 (0.74-4.65, P=0.19) for men and 3.02 (1.54-5.93, P=0.001) for women. CONCLUSIONS: PRWP is a common ECG finding and predicts risk for total and cardiovascular mortality in women in a general population. PMID- 20166812 TI - Brain-derived neurotrophic factor and suicide pathogenesis. AB - Abstract Suicide is a major public health concern. The etiology and pathogenic mechanisms associated with suicidal behavior are poorly understood. Recent research on the biological perspective of suicide has gained momentum and appears to provide a promising approach for identifying potential risk factors associated with this disorder. One of the areas that have gained the most attention in suicide research is the role of brain-derived neurotrophic factor (BDNF), which participates in many physiological functions in the brain, including synaptic and structural plasticity. Several studies consistently show that expression of BDNF is reduced in blood cells of suicidal patients and in brains of subjects who committed suicide. Recent studies also demonstrate abnormalities in the functioning of BDNF, because its cognate receptors (tropomycin receptor kinase B and pan75 neurotrophin receptor) are abnormally active and/or expressed in the post-mortem brains of suicide subjects. There is further evidence of the role of BDNF in suicide as numerous studies show a strong association of suicidal behavior with BDNF functional polymorphism. Overall, it appears that abnormalities in BDNF signaling may serve as an important biological risk factor in the etiology and pathogenesis of suicide. PMID- 20166815 TI - Plasma adiponectin levels are associated with left ventricular hypertrophy in a random sample of middle-aged subjects. AB - BACKGROUND: A low adiponectin level is associated with high blood pressure which, in turn, often results in left ventricular hypertrophy. We evaluated the association between plasma adiponectin concentrations and echocardiographic measurements, including left ventricular mass index (LVMI), in 933 middle-aged subjects consisting of 453 hypertensives and 480 controls. METHODS: Plasma adiponectin concentrations were measured with an enzyme-linked immunosorbent assay (ELISA) method. One experienced cardiologist performed echocardiographic examinations, and LVMI was calculated according to Devereux's method. RESULTS: Low plasma adiponectin levels were independently associated with increased intraventricular septum thickness, posterior ventricular wall thickness, and left ventricular mass index (P<0.001) in the whole cohort. In the subgroup analysis, the association between these echocardiographic parameters and adiponectin concentrations was observed only in the hypertensive cohort although fractional shortening revealed an association with adiponectin levels also in the control cohort (P=0.021). Findings remained significant after adjustment for the major risk factors for LVMI, such as age, sex, smoking, and systolic blood pressure. CONCLUSIONS: This study in a large population sample detected an association between low plasma adiponectin concentration and LVMI, a marker of left ventricular hypertrophy. This association may be one of the factors that could explain the reported increased cardiovascular risk in subjects with low adiponectin levels. PMID- 20166816 TI - Entropy maximization and the spatial distribution of species. AB - Entropy maximization (EM, also known as MaxEnt) is a general inference procedure that originated in statistical mechanics. It has been applied recently to predict ecological patterns, such as species abundance distributions and species-area relationships. It is well known in physics that the EM result strongly depends on how elementary configurations are described. Here we argue that the same issue is also of crucial importance for EM applications in ecology. To illustrate this, we focus on the EM prediction of species-level spatial abundance distributions. We show that the EM outcome depends on (1) the choice of configuration set, (2) the way constraints are imposed, and (3) the scale on which the EM procedure is applied. By varying these choices in the EM model, we obtain a large range of EM predictions. Interestingly, they correspond to spatial abundance distributions that have been derived previously from mechanistic models. We argue that the appropriate choice of the EM model assumptions is nontrivial and can be determined only by comparison with empirical data. PMID- 20166817 TI - Blastomycosis of the central nervous system: a multicenter review of diagnosis and treatment in the modern era. AB - BACKGROUND: Central nervous system (CNS) involvement with Blastomyces dermatitidis is an uncommon and potentially fatal complication of blastomycosis. METHODS: We retrospectively reviewed 22 patients with CNS blastomycosis at our institutions from 1990 through 2008 (13 proven, 5 probable, and 4 possible cases). RESULTS: Magnetic resonance imaging was used in most patients, alone or in addition to computed tomography. CNS blastomycosis manifested as epidural abscess (1 of 22), meningitis (7 of 22), intracranial mass lesions (10 of 22), and concomitant intracranial mass lesions and meningitis (4 of 22). All patients received amphotericin B deoxycholate or a lipid formulation of amphotericin B as part of their treatment regimens. Most patients received amphotericin B followed by a prolonged course of oral azole therapy (voriconazole, fluconazole, or itraconazole). Four (18%) of 22 patients died during follow-up. CONCLUSIONS: On the basis of these data, we recommend initial treatment with a lipid formulation of amphotericin B followed by a prolonged course of oral azole therapy, preferably voriconazole. PMID- 20166818 TI - Increasing incidence of empyema complicating childhood community-acquired pneumonia in the United States. AB - BACKGROUND: The incidence of childhood pneumonia decreased following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in the United States. Recent regional reports suggest an increase in the incidence of childhood pneumonia complicated by empyema. We assessed whether early decreases in pneumonia hospitalization rates were sustained and trends in such hospitalizations complicated by empyema in United States children aged <5 years. METHODS: Nationwide Inpatient Sample and Census data were used to calculate annual all cause and pneumococcal pneumonia hospitalization rates for pre-PCV7 (1996-1999) and post-PCV7 years (2001-2007) and to analyze national trends in total and pathogen-specific pneumonia-associated empyema. RESULTS: Among children aged <2 years, all-cause pneumonia hospitalizations decreased 33% (95% confidence interval, 28%-37%) from 1267 cases per 100,000 children in pre-PCV7 years to 852 cases per 100,000 children in post-PCV7 years. Pneumococcal pneumonia hospitalization rates decreased 61% (95% confidence interval, 55%-67%) post-PCV7, compared with pre-PCV7 years. Pneumonia hospitalizations complicated by empyema increased 2.01-fold from 3.5 cases per 100,000 children in 1996-1998 to 7.0 cases per 100,000 children in 2005-2007. Rates of pneumococcal and streptococcal empyema remained stable, whereas rates of staphylococcal and other or unspecified empyema increased 4.08- and 1.89-fold, respectively. Among children aged 2-4 years, all-cause pneumonia rates remained stable, whereas pneumococcal pneumonia decreased by 26% (95% confidence interval, 16-34). Pneumonia complicated by empyema increased 2.81-fold from 3.7 cases per 100,000 children in 1996-1998 to 10.3 cases per 100,000 children in 2005-2007. In this age group, there were 2.17 , 2.80-, 3.76-, and 3.09-fold increases in rates of pneumococcal, streptococcal, staphylococcal, and other or unspecified empyema, respectively. CONCLUSION: Decreases in childhood pneumonia hospitalization rates following PCV7 introduction were sustained. Although empyema complicated only a small fraction of pneumonia hospitalizations, its prevalence increased substantially. This increase was due to several pathogens and warrants continuing monitoring. PMID- 20166819 TI - Impact of the novel influenza A (H1N1) during the 2009 autumn-winter season in a large hospital setting in Santiago, Chile. AB - BACKGROUND: In Chile, the novel influenza A (H1N1) epidemic began in the middle high income area of Santiago. Clinical and laboratory surveillance was intensified with the aim to characterize the epidemic and determine its impact in a large hospital setting. METHODS: Demographic and clinical data were obtained from all patients whose symptoms met the clinical definition of influenza A (H1N1) infection during the epidemic period. Laboratory confirmation was obtained by use of a nasopharyngeal antigen detection test for influenza A and/or influenza A (H1N1) polymerase chain reaction (PCR). A case was considered confirmed if the antigen detection test result for influenza A and/or the PCR test result were positive. RESULTS: The total number of emergency department (ED) visits increased by 88.5% from a mean of 14,489 ED visits in 2006-2008 to a mean of 27,308 ED visits in 2009, during the epidemic period. There were 10,048 patients who were clinically diagnosed with influenza A (H1N1), and they represented 78% of all visits, of which 4591 (45.6%) were laboratory confirmed. The median time from symptom onset to diagnosis was 1 day, and 99.7% of individuals received antiviral treatment. School-aged children represented 67% of ED visits at the beginning of the epidemic and 24% of ED visits at the end of the epidemic. Only 2% of cases were hospitalized; of these, 70% of cases occurred in patients 6-50 years of age, and 32% of cases occurred in patients who had an underlying medical condition. Eleven patients (age range, 1-53 years) required admission to the intensive care unit (ICU); 6 of these patients had pneumonia with or without hemodynamic shock. No influenza-associated deaths occurred. CONCLUSIONS: Many cases of influenza A (H1N1) occurred in school-aged and adult individuals who required an ED visit; these visits resulted in a low impact on the use of hospital beds. Aggressive ICU management and/or experience in extracorporeal membrane oxygenation significantly improved outcomes. Early antiviral treatment may have played an important role in the low number of severe cases. Vaccines targeted for school-aged children and young adults may modify the first epidemic wave in the northern hemisphere. PMID- 20166820 TI - A 79-year-old man with swelling and crusted cutaneous ulceration of both hands. PMID- 20166821 TI - Protease inhibitor-based antiretroviral prophylaxis during pregnancy and the development of drug resistance. AB - BACKGROUND: The aim of this study was to determine the development of drug resistance among pregnant women receiving a protease inhibitor-based antiretroviral prophylaxis for the prevention of mother-to-child transmission of human immunodeficiency virus (HIV). METHODS: HIV-infected pregnant women without maternal indication for antiretroviral therapy were enrolled prospectively. Genotypic resistance testing was performed prior to initiation of antiretroviral prophylaxis and was repeated 4-8 weeks after cessation of antiretroviral therapy at the time of delivery. RESULTS: Forty pregnant women with HIV infection (Centers for Disease Control and Prevention stage A1 or A2) were included. All women received an antiretroviral regimen including either fixed-dose lopinavir/ritonavir (n = 33) or ritonavir-boosted saquinavir (n = 7) and a backbone consisting of 2 nucleoside reverse-transcriptase inhibitors. The mean duration of antiretroviral treatment was 8.4 weeks (range, 5-22 weeks). Primary resistance mutations were found in 2 patients (nonnucleoside reverse transcriptase inhibitor resistance, K103N; protease inhibitor resistance, G48V). Postpartum genotypic resistance revealed no new relevant resistance mutations. CONCLUSIONS: In our study no clinically significant resistance mutations developed in pregnant women receiving a short-term protease inhibitor-based antiretroviral regimen for prophylaxis of mother-to-child transmission of HIV. Future therapeutic options are therefore preserved. PMID- 20166822 TI - High genetic barrier antiretroviral drugs in human immunodeficiency virus positive pregnancy. PMID- 20166824 TI - Pre-analytical errors in rapid influenza testing. PMID- 20166825 TI - When is rapid testing for influenza useful? PMID- 20166827 TI - Is phenolic glycolipid-I really a specific antigen for leprosy? PMID- 20166828 TI - Cover image and description for the 1 November 2009 issue. PMID- 20166829 TI - Rifampin and posaconazole coadministration leads to decreased serum posaconazole concentrations. PMID- 20166835 TI - Headache and medication overuse: are clinical case series appropriate to reveal differential risks of different medications? AB - IMPORTANCE OF THE FIELD: The question of whether different migraine and headache medications show a differential risk of medication overuse headache (MOH) induction has been discussed extensively but has not been definitively answered to date. AREAS COVERED IN THIS REVIEW: Clinical case series of interest that include statements on a differential risk of MOH development due to the use of different headache medications are identified by systematic literature research and analyzed. WHAT THE READER WILL GAIN: In the present work, an expert evaluation is made of the existing evidence for different risks of different headache and migraine medications with regard to MOH occurrence, as has been claimed in various publications. TAKE HOME MESSAGE: Despite several different attempts to obtain direct or indirect answers from clinical case series, the fact is that due to the intrinsic selection bias, confounding and other limitations inherent to clinical case series, they are not suitable to answer this question reliably. Thus, the repeated claims of a differential risk of different drugs and drug groups are simply not scientifically sound. PMID- 20166836 TI - Varenicline use in patients with mental illness: an update of the evidence. AB - IMPORTANCE OF THE FIELD: Patients with a psychiatric diagnosis have a higher prevalence of smoking compared to the general population. Varenicline is a first line pharmacotherapy option to assist in smoking cessation. Clinical trials during drug development excluded patients with active psychiatric illnesses leaving the risks associated with varenicline use in this patient population unknown. AREAS COVERED IN THIS REVIEW: Literature published in English up to December 2009 were identified and include neuropsychiatric adverse drug events reported in pre-marketing trials and post-marketing surveillance, varenicline case reports, evidence surrounding the use of varenicline in patients with psychiatric diagnoses, and varenicline and suicidality. WHAT THE READER WILL GAIN: Although the risk of potential neuropsychiatric events is evident through voluntary reporting systems and reported cases in the literature, multiple studies and case reports support the use of varenicline in the mental health population. Reviewing the literature will enable clinicians to optimize patient care by weighing the risks and benefits associated with varenicline use against the risk of continued smoking. TAKE HOME MESSAGE: Cautious treatment initiation, patient education, and close follow-up, monitoring for mood and behavior changes during therapy are recommended, especially in the psychiatric setting. PMID- 20166837 TI - Delayed-onset and recurrent limb weakness associated with West Nile virus infection. AB - Human neurologic illness following infection with West Nile virus (WNV) may include meningitis, encephalitis, and acute flaccid paralysis (AFP). Most WNV associated AFP is due to involvement of the spinal motor neurons producing an anterior (polio)myelitis. WNV poliomyelitis is typically characterized by acute and rapidly progressing limb weakness occurring early in the course of illness, which is followed by death or clinical plateauing with subsequent improvement to varying degrees. We describe four cases of WNV poliomyelitis in which the limb weakness was characterized by an atypical temporal pattern, including one case with onset several weeks after illness onset, and three cases developing relapsing or recurrent limb weakness following a period of clinical plateauing or improvement. Delayed onset or recurrent features may be due to persistence of viral infection or delayed neuroinvasion with delayed injury by excitotoxic or other mechanisms, by immune-mediated mechanisms, or a combination thereof. Further clinical and pathogenesis studies are needed to better understand the mechanisms for these phenomena. Clinicians should be aware of these clinical patterns in patients with WNV poliomyelitis. PMID- 20166838 TI - Inferior vena cava occluder for remote access perfusion in robotic cardiac surgery. AB - Robotic cardiac surgery requires remote access perfusion. We have developed an inferior vena cava (IVC) occluder that can safely and conveniently drain blood from the IVC. This device has been clinically applied in one patient, as described herein. The framework for this device is made from a single superelastic nitinol wire, 0.30 mm in diameter. Diameter of the spreading site of the device is decided from computed tomographic images. A polyester fabric membrane (thickness 0.10 mm) is set at the tip of this framework. The occluder is deployed through an 18-F sheath. This device was used in a 64-year-old woman with lipoma in the right atrial wall near the IVC-right atrium interface. In this patient, it might not have been possible to completely reset the tumour by conventional IVC occlusion using a snare. The occluder was smoothly and safely deployed and retracted. During placement of the occluder, blood did not flow from the IVC into the right atrium. During extracorporeal circulation, vacuum drainage was performed with no air contamination. The tumour was resected by a three-arm da Vinci Surgical System. The IVC occluder needs to completely block the IVC and avoid obstructing the inflow region of the hepatic vein. This device obviates the need to place a snare on the IVC, and thus should directly improve the safety of robotic cardiac surgery and shorten the operating time. PMID- 20166839 TI - Materials and techniques for osseous skull reconstruction. AB - This review paper gives an overview and summarizes the different methods of cranioplasty for reconstruction of the bony skull. There are various origins of cranial defects including trauma, tumours, congenital deformities or postoperative defects due to the surgical procedure itself. The overall goal of skull reconstruction is, on the one hand, appropriate closure, and on the other hand, the perfect cosmetic result. The cranioplasty should be safe, fast and easy to handle. Cost-effectiveness of the procedure represents a further important point. To solve these complex and multimodal problems, different techniques and also various materials for the reconstruction are available. This report details the usual procedures for skull reconstruction, as well as the advantages and limitations of the different materials and operative strategies. PMID- 20166840 TI - Assessment of vitamin D status in healthy children and adolescents living in Tehran and its relation to iPTH, gender, weight and height. AB - This study was conducted to determine the frequency of vitamin D deficiency and its correlation with different factors. Three hundred and thirteen healthy children and adolescents (192 females and 121 males aged 8-18 years, mean +/- SD, 12.7 +/- 2.3 years) were enrolled, and measurements of serum 25-hydroxyvitamin D [25(OH)D] (using EIA) and intact parathyroid hormone (iPTH) (using immunoradiometric assay (IRMA)) were conducted. The grades of vitamin D status were defined according to blood level of 25(OH)D as follows: severely deficient < 12.5; deficient, > or = 12.5 and < 25; insufficient, > or = 25 and < 50; normal > or = 50 and < 250 nmol/L. Severe deficiency was detected in 25% of subjects (males 8%; females 92%), deficiency in 27% (males 34%; females 66%) and insufficiency in 26% (males 58%; females 42%). The mean 25(OH)D level in males was significantly greater than that in females (p < 0.001), and this level was significantly higher in prepubertal compared to pubertal subjects (p < 0.001). 25(OH)D had a negative correlation with iPTH (p < 0.001). The curve of iPTH began to rise when 25(OH)D reached 75 nmol/L. The level of 25(OH)D had a negative correlation with BMI-SDS and height-SDS in females (p-value, 0.01 and 0.039, respectively). The subjects did not have any signs or symptoms of rickets. Frequency of vitamin D deficiency did not have any significant seasonal variation. Furthermore, vitamin D deficiency was not found to be related to the type or location of the subjects' homes. In this study, subclinical vitamin D deficiency was significantly more prevalent in females, particularly those undergoing puberty. Children who were obese and taller than average, had lower levels of 25(OH)D, and level of 25(OH)D should be maintained > 75 nmol/L in order to prevent PTH rising. PMID- 20166841 TI - Treatment of HBV/HCV coinfection. AB - IMPORTANCE OF THE FIELD: Hepatitis B (HBV) and hepatitis C (HCV) virus infections are among the most common causes of advanced chronic liver disease worldwide. HBV/HCV coinfection is not uncommon with an estimated 7 - 20 million individuals affected worldwide. Patients with HBV/HCV coinfection have an increased risk for cirrhosis, hepatocellular carcinoma (HCC) and even death. AREAS COVERED IN THIS REVIEW: The pathophysiology of HBV/HCV coinfection is complex, as different patterns of virological dominance may occur, which can even fluctuate over time. Recently, combination of pegylated interferon (PEG-IFN) plus ribavirin has been explored in HBV/HCV coinfected patients who are positive for HCV-RNA. HBV polymerase inhibitors may be indicated if HBV-DNA concentrations are above 2000 IU/ml. In this review, we summarize the epidemiology, viral interaction, its clinical features and the available treatment options. WHAT THE READER WILL GAIN: Insights into viral interaction of HBV/HCV coinfection and treatment individualization strategies are provided in the review. TAKE HOME MESSAGE: Detailed serological and virological evaluations are required for HBV/HCV coinfected patients before initiation of antiviral therapy. At present, PEG-IFN alpha plus ribavirin should be the treatment of choice in patients with dominant HCV replication. However, HBV rebound may occur after elimination of HCV, and thus close monitoring for both viruses is recommended even for patients with initially suppressed HBV-DNA. PMID- 20166842 TI - Pharmacotherapy of diabetes in cystic fibrosis patients. AB - IMPORTANCE OF THE FIELD: Cystic fibrosis-related diabetes (CFRD) is a unique type of diabetes. In this article I review the pathophysiology of CFRD to gain insight as to why these patients have clinical features of both type 1 and 2 diabetes (DM). The reader will also learn that, although CFRD is different from type 1 and 2 DM, the development of diabetes-induced complications is similar to other types of DM. These complications can include retinopathy, nephropathy and neuropathy resulting from uncontrolled hyperglycemia; however, hyperglycemia and/or insulin deficiency in people with CFRD may exacerbate underlying CF problems, such as decreased pulmonary function and weight loss. AREAS COVERED IN THIS REVIEW: Review medical therapy of CFRD including the over-riding goal of maintaining blood glucose levels in a range as close to normal as possible. The other important goal for diabetes management is to prevent diabetes complications and to encourage psychological wellbeing of the patient. However, as reviewed in this article, the underlying medical condition of people with CF and the basic metabolic differences caused by the disease often provide challenges in maintaining optimal diabetes control. WHAT THE READER WILL GAIN: The reader will gain an understanding of how CFRD physically affects the patient with CF and the various pharmacologic therapies available for treatment of this type of diabetes. Furthermore they will gain insight into areas where more research is needed. TAKE HOME MESSAGE: Cystic fibrosis-related diabetes is unique to CF and thus deserves disease specific medical therapy. PMID- 20166843 TI - Comparison of the protective effects of papaverine, lidocaine and verapamil on the sperm quality of the testis after induced torsion-detorsion in rats. AB - OBJECTIVE: Spermatic cord torsion is a true urological emergency. Significant subfertility exists in patients following unilateral testicular torsion. Several studies have tested several agents such as vasodilators and antioxidants to inhibit or temper testicular damage. MATERIAL AND METHODS: Sprague-Dawley rats were divided into five groups; in group 1 (control) no operation or drug injection was done. In groups 2-5 the left testis was subjected to 270 torsions. Two hours after induced torsion, drugs were injected intraperitoneally. Rats in group 2 received no drug, whereas those in groups 3, 4 and 5 were administered a single dose of papaverine (35 mg/kg), lidocaine (4 mg/kg) and verapamil (0.1 mg/kg), respectively. Thirty minutes after drug injection (2.5 h after torsion), testis detorsion was performed in all groups. The drug injections continued for 1 week. After 20 days, bilateral orchiectomy was carried out and semen from both testes was evaluated. RESULTS: In animals treated with verapamil, left testis sperm count and the percentage of motile sperm were increased significantly in comparison with the sham-operated animals. Sperm morphology in all groups was in the normal range. Mean sperm count and motility in the right testes were not significantly different in different groups. CONCLUSIONS: Verapamil can induce beneficial effects on semen analysis parameters after testicular torsion in rats. PMID- 20166844 TI - Societal costs for irritable bowel syndrome--a population based study. AB - OBJECTIVE: Irritable bowel syndrome (IBS) is associated with increased use of health care services. This study aims to estimate the costs of IBS in relation to differing diagnostic criteria of IBS, duration of symptoms, gender, and age. MATERIAL AND METHODS: A two-phase postal survey. Questionnaire I covering gastrointestinal (GI) symptoms by Manning and Rome II criteria was mailed to 5000 randomly selected adults. Questionnaire II, mailed to those fulfilling IBS criteria of Questionnaire I, recorded data on physician visits, medications, and diagnostic procedures performed. RESULTS: Proportion of GI consulters was 48% (95% CI 41-55%) and 32% (95% CI 28-36%) for Rome II and Manning groups. Annual GI related individual costs were euro 497 (95% CI euro 382-621) and euro 295 (95% CI euro 246-347) by Rome II and Manning criteria. Societal GI costs were euro 82 million and euro 154 million by Rome II and Manning criteria. Direct non-GI costs amounted to euro 43 million and euro 126 million by Rome II and Manning criteria. Duration of GI symptoms, gender, or age had no impact on GI costs. CONCLUSIONS: IBS incurs substantial GI and non-GI costs corresponding to a share of up to 5% of the national direct outpatient and medicine expenditures. The more restrictive Rome II criteria identify an IBS population incurring higher GI related individual costs than Manning criteria. Costs due to GI endoscopies are not lower for those with a long history of symptoms suggesting that guideline recommendations for avoiding repeated diagnostic procedures may not be followed. PMID- 20166845 TI - Inhibitors of Cdc25 phosphatases as anticancer agents: a patent review. AB - IMPORTANCE OF THE FIELD: The cell division cycle 25 (Cdc25) family of proteins are highly conserved dual specificity phosphatases that regulate cyclin-dependent kinases, the main gatekeepers of the eukaryotic cell division cycle. The three isoforms of Cdc25, including Cdc25A, Cdc25B and Cdc25C, appear to act on different cyclin-dependent kinase/cyclin complexes at different stages of the cell cycle. Overexpression of Cdc25A and/or Cdc25B, but not Cdc25C, has been detected in numerous cancers and is often correlated with a poor clinical prognosis. Thus, inhibition of these phosphatases may represent a promising therapeutic approach in oncology. AREAS COVERED IN THIS REVIEW: The main focus of the present review is to describe the development of Cdc25 inhibitors over the years. We describe different compounds according to the decade of discovery and focus attention on molecules that were published in patents. WHAT THE READER WILL GAIN: Insight into the most clinically relevant therapeutic Cdc25 analogues that have been published in over 40 patents over the past 19 years. TAKE HOME MESSAGE: Some Cdc25 inhibitors have suppressed in vivo the growth of human tumor xenografts in animals; this confirmed the validity of using Cdc25 phosphatase inhibition as an anticancer strategy, but side effects and toxicity remain to be investigated. PMID- 20166846 TI - Effect of retorting and oven cooking on the nutritional properties of beef frankfurters blended with palm oils. AB - The effect of retorting and oven cooking on the nutritional properties of beef frankfurters blended with palm oil (PO), red PO35 and red PO48 were compared against the control beef fat treatment. Red PO oven-cooked beef frankfurters resulted in a significant loss of vitamin E from 538.5 to 287.5 microg after 6 months. Oven cooked sausages stored at -18 degrees C and retorted sausages stored for the 6 months of shelf studies resulted in more than 90% loss of alpha carotene and beta-carotene in red PO beef frankfurters. Cholesterol was reduced at the range of 29.0-32.2 mg/100 g when beef fat was substituted with palm-based oils, in beef frankfurters. Differences of heat treatments did not significantly change THE cholesterol content, within all treatments. This study showed the potential of utilizing red palm oils as animal fat analogues in improving vitamin E, reducing cholesterol but not carotenes in beef frankfurters. PMID- 20166847 TI - Minimal mesangial lupus nephritis: a systematic review. AB - OBJECTIVES: To summarize the clinical presentation, histological features, treatment, and outcome of minimal change nephropathy (MCN) in patients with systemic lupus erythematosus (SLE). METHODS: We performed a systematic review of cases of MCN in SLE patients reported in the English literature from January 1985 to May 2009 by a Medline search. RESULTS: The estimated prevalence of MCN in biopsy-proven lupus nephritis is 2.3% in childhood and 1.1% in adults. There are 13 individual cases (12 women, one man) of SLE-related MCN reported in the literature. The mean age of nephritis onset was 32.7 years. In six (46%) patients, MCN was the initial manifestation of SLE. All patients presented with nephrotic syndrome and two (15%) had active urinary sediments. Renal function was impaired in eight (62%) patients and six (46%) patients had active lupus serology. All patients responded promptly to high-dose glucocorticoids but four (31%) had relapse of proteinuria during their course of SLE. None of the patients developed thromboembolic or infective complications. CONCLUSIONS: MCN is an uncommon histological class of lupus nephritis. Typically, patients present with heavy proteinuria, and transient renal dysfunction is common. The prognosis of MCN in SLE appears to be good because of its rapid response to glucocorticoids. Relapses of proteinuria may be reduced by the use of maintenance immunosuppression. Alkylating agents, calcineurin inhibitors, mycophenolate mofetil, and rituximab can be considered in glucocorticoid-dependent or refractory cases of SLE-related MCN. PMID- 20166848 TI - Comparison of the Psoriatic Arthritis Quality of Life (PsAQoL) questionnaire, the functional status (HAQ) and utility (EQ-5D) measures in psoriatic arthritis: results from a cross-sectional survey. AB - OBJECTIVES: To compare the Psoriatic Arthritis Quality of Life (PsAQoL) instrument, the Health Assessment Questionnaire (HAQ) as a measure of functional status, and the generic health status (utility) measure the EuroQoL (EQ-5D) in terms of ability to assess disease severity in psoriatic arthritis (PsA). METHODS: The differences between known groups and correlations of the PsAQoL, the HAQ and the EQ-5D with clinical measures were analysed in a sample of 183 PsA patients. RESULTS: Different severities of PsA determined by known groups were distinguished well by all three questionnaires; more severe disease was associated with significantly worse values of the instruments. The correlations revealed a strong relationship between each of the measures, and with the patients' pain on the visual analogue scale (VAS), the patient global VAS, and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and a weak relationship with the disease duration and the Psoriasis Area Severity Index (PASI). The PsAQoL also correlated strongly with the 28-joint Disease Activity Score (DAS28). CONCLUSIONS: The PsAQoL, the HAQ, and the EQ-5D are able to distinguish well across levels of PsA severity. PMID- 20166849 TI - Serum peptidome patterns of human systemic lupus erythematosus based on magnetic bead separation and MALDI-TOF mass spectrometry analysis. AB - OBJECTIVES: Currently few studies have been reported to utilize matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) in rheumatic disease, especially in systemic lupus erythematosus (SLE). Our aim was to find differentially expressed disease-related and condition-specific peptides in sera from patients with SLE, as well as to develop and validate the peptide classification model for the diagnosis of SLE. METHODS: Based on the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 2000, 50 SLE patients were divided into two subgroups: 25 were defined as stable SLE (SLEDAI < or = 8) and 25 as active SLE (SLEDAI > 8). Twenty-five patients with rheumatoid arthritis (RA) and 24 healthy donors were also included and underwent analysis. We performed magnetic beads-based weak cation exchange chromatography (MB-WCX) for sample processing and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) for peptide profiling. ClinProt software 2.1 was used for data analysis and a genetic algorithm was modelled for class prediction. RESULTS: A series of significant short peptides was detected. Classification models were developed to classify samples across normal controls, active SLE patients, and stable SLE patients, and achieved high capability of prediction and cross-validation. Blinded verification of the classification model showed 91.7% sensitivity in active SLE, 83.3% sensitivity in stable SLE, and 86.7% specificity in normal controls. CONCLUSION: We have completed a preliminary study to describe the serum peptide profile of SLE and improve the diagnosis of SLE from an integrated perspective of peptide mass patterns. PMID- 20166850 TI - Heritability estimates and linkage analysis of 23 short tandem repeat loci on chromosomes 2, 11, and 12 in an endemic osteochondropathy in China. AB - OBJECTIVE: To estimate the heritability of Kashin-Beck disease (KBD) in first degree relatives and to identify chromosome regions likely to contain susceptibility loci for KBD. METHODS: A total of 331 probands with confirmed KBD in their pedigrees were selected from 9331 residents in 17 KBD villages of Linyou county, northwestern China. The heritability (h(2)) in first-degree relatives was estimated by using Falconer's formula. The segregation ratio was calculated by the Li-Mantel-Gart method. A total of 23 short tandem repeat (STR) loci on chromosomes 2, 11, and 12 were used to identify the susceptibility genes for KBD by linkage analysis using the GENEHUNTER program in 19 KBD pedigrees. RESULTS: The general prevalence rate of KBD was 13.75% in the 17 KBD villages, lower than that of 20.88% in the first-degree relatives of the KBD probands. In the first degree relatives, the heritability was 0.064 and the segregation ratio 35.10% (p < 0.05). Slight evidence for heritability was detected only in locus D12S1725 with a logarithm of odds (LOD) score of 1.95. However, the nonparametric linkage (NPL) scores showed no linkage between KBD and the 23 loci; the maximum NPL score was 1.59 for locus D12S1725. CONCLUSIONS: Our results show that 35.10% of the heritability is attributable to genetic variation for the KBD phenotype among individuals of Linyou county, and the segregation ratio supports a multifactorial inheritance of KBD. There is no significant linkage between KBD and the 23 markers in the Linyou population examined; however, markers near the locus D12S1725 may indicate loci for further study. PMID- 20166851 TI - Emerging treatments for narcolepsy and its related disorders. AB - IMPORTANCE OF THE FIELD: Narcolepsy is a chronic sleep disorder, characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis and nocturnal sleep disruption. Non-pharmacological treatments (i.e., behavioral modification) are often helpful for the clinical management of narcoleptic patients. As these symptoms are often disabling, most patients need life-long treatments. Over 90% of diagnosed narcoleptic patients are currently prescribed medications to control their symptoms; however, available treatments are merely symptomatic. AREAS COVERED IN THIS REVIEW: This review presents a description of the clinical symptoms of narcolepsy, followed by a discussion of the state-of-the-art knowledge regarding the disorder and related emerging treatments. In preparing this review, an extensive literature search was conducted using Pubmed. Only selected references from 1970 to 2008 are cited. WHAT THE READER WILL GAIN: This review focuses on emerging treatments for human narcolepsy, and the reader will gain significant knowledge of current and future treatment for this and related disorders. Traditionally, amphetamine-like stimulants (i.e., dopaminergic release enhancers) have been used for clinical management to improve EDS, and tricyclic antidepressants have been used as anticataplectics. However, treatments have recently evolved which utilize better tolerated compounds, such as modafinil (for EDS) and adrenergic/serotonergic selective reuptake inhibitors (as anticataplectics). In addition, night time administration of a short-acting sedative, gamma-hydroxybutyrate, has been used for the treatment for EDS and cataplexy. As a large majority of human narcolepsy is hypocretin peptide deficient, hypocretin replacement therapy may also be a new therapeutic option; yet, this option is still unavailable. In addition to the hypocretin-based therapy, a series of new treatments are currently being tested in animal and/or humans models. These potential options include novel stimulant and anticataplectic drugs as well as immunotherapy, based on current knowledge of the pathophysiology of narcolepsy with cataplexy. TAKE HOME MESSAGE: We expect that more pathophysiology-based treatments, capable of curing and/or preventing narcolepsy and related diseases, will be available in near future. As cases of EDS, associated with other neurological conditions (i.e., symptomatic narcolepsy or narcolepsy due to medical conditions), are often linked with hypocretin deficiency, these novel therapeutic options may also be applied to treatment of these disabling conditions. PMID- 20166852 TI - Menstrual characteristics: a study of the adolescents of rural and urban West Bengal, India. AB - BACKGROUND: It has been observed that menstrual characteristics are generally influenced by lifestyle, socio-cultural and biological factors. AIM: The present study examines: (a) variation in menstrual characteristics between rural and urban adolescents; and (b) whether these characteristics can be predicted from various socio-economic variables related to place of residence. SUBJECTS AND METHODS: The sample of the present study constituted 715 adolescent girls from rural (325) and urban (390) areas of West Bengal, a State of India. These girls belong to a Bengali-speaking Hindu ethnic group. Data on socio-economic variables and menstrual characteristics were collected using pretested questionnaires. RESULTS: Rural and urban adolescents differed significantly (p < or = 0.05) with respect to age at menarche, skipped and irregular cycles, premenstrual syndrome, duration of menstrual discharge, mean number of days of peak discharge and problems related to menstrual discharge. Place of residence was found to be a significant predictor of age at menarche (beta = 0.27, p < 0.01). Significant association was observed between some of the socio-economic variables and various menstrual characteristics among the study participants. CONCLUSIONS: Menstrual characteristics differ significantly between rural and urban adolescents. Moreover, various socio-economic variables pertaining to place of residence significantly affect the menstrual characteristics among adolescents. PMID- 20166854 TI - Ultrasound-mediated gene delivery. AB - IMPORTANCE OF THE FIELD: The use of ultrasound with microbubbles raises the possibility of an efficient and safe gene delivery. AREAS COVERED IN THIS REVIEW: This review summarizes the current state of the art of gene delivery by sonoporation under the following topics. First, the basic ultrasound parameters and the characteristics of microbubble in biological systems are discussed. Second, the extensions of sonoporation to other fields of gene delivery such as viral and non-viral vector are briefly reviewed. Finally, recent applications in an animal model for various diseases are introduced. WHAT THE READER WILL GAIN: Information and comments on gene delivery by sonoporation or enhanced cell membrane permeability by means of ultrasound. TAKE HOME MESSAGE: Ultrasound mediated gene delivery combined with microbubble agents provides significant safety advantages over other methods of local gene delivery. PMID- 20166858 TI - Estrogen and mental illness--a new frontier. PMID- 20166853 TI - Suppressive and pro-inflammatory roles for IL-4 in the pathogenesis of experimental drug-induced liver injury: a review. AB - IMPORTANCE OF THE FIELD: Idiosyncratic drug reactions resulting in drug-induced liver injury (DILI) account for approximately 13% of acute liver failure cases in the US. Idiosyncratic drug reactions are the third most common cause of liver transplantation, exceeded only by acetaminophen and indeterminate causes. Clinical evidence suggests that idiosyncratic DILI is triggered by drug hapten altered self proteins resulting in hepatocellular injury. An example of this type of DILI is hepatitis that develops in susceptible individuals following administration of halogenated volatile anesthetics, dihydralazine, carbamazepine or diclofenac. AREAS COVERED IN THIS REVIEW: In this review, we describe research in animal models that supports a critical role for suppressive and pro inflammatory roles for IL-4 in the pathogenesis of immune-mediated DILI. WHAT THE READER WILL GAIN: The reader will gain insights into the roles of IL-4 in the development of experimental DILI. The reader will gain tools to assist in the translation of these findings to those in patients with immune-mediated DILI, as well as other inflammatory diseases of the liver. The reader will then be made aware of gaps in knowledge in the pathogenesis of DILI where research could result in significant advances in the care of these complicated patients. TAKE HOME MESSAGE: In experimental immune-mediated DILI, IL-4 suppresses regulatory responses to CYP2E1 autoantigens but induces pro-inflammatory responses to drug haptens. PMID- 20166859 TI - Testosterone treatment of HSDD in naturally menopausal women: the ADORE study. AB - OBJECTIVE: To evaluate the efficacy and safety of a transdermal testosterone patch (TTP, 300 microg/day) in naturally menopausal women with hypoactive sexual desire disorder (HSDD). METHODS: A total of 272 naturally menopausal women, predominantly not using hormone therapy, were randomized in this 6-month, placebo controlled, double-blind, multicenter study to receive twice weekly either TTP or an identical placebo. Efficacy endpoints measured were the 4-week frequency of satisfying sexual episodes (SSE) using the Sexual Activity Log, the sexual desire domain of the Profile of Female Sexual Function and distress by the Personal Distress Scale. Safety was assessed by adverse events, laboratory parameters and hormone levels. RESULTS: The TTP group demonstrated significant improvements in SSE (p = 0.0089) as well as in sexual desire (p = 0.0007) and reduced personal distress (p = 0.0024) versus placebo at 6 months (intent-to-treat analysis, n = 247). The results were significant for all three endpoints in the subgroup (n = 199) not using hormone therapy. Similar numbers of women treated with placebo and TTP discontinued (n = 39, 27.5% vs. n = 26, 20%), reported adverse events (including application site reactions) (n = 101, 71.1% vs. n = 81, 62.3%) and withdrew due to adverse events (n = 20, 14.1% vs. n = 9, 6.9%). No clinically relevant changes were noted in laboratory parameters. Serum free and total testosterone levels increased from baseline in the TTP group (geometric means 5.65 pg/ml and 67.8 ng/dl, respectively, at week 24) within the physiological range; no changes were seen in estradiol and sex hormone binding globulin levels. CONCLUSIONS: TTP was effective in treating HSDD and improving sexual function in this study of naturally menopausal women with and without concurrent hormone therapy. PMID- 20166861 TI - Treating the hypertensive patient in a nurse-led hypertension clinic. AB - AIMS: This manuscript presents results from 4 years experience in a nurse-led hypertension clinic. The aim of the hypertension clinic was to optimize hypertension treatment and to reduce the number of physician consultations. MATERIALS AND METHODS: All patients were initially examined by cardiologists. All follow-up visits were performed by nurses. They initiated and titrated antihypertensive medication according to a stepwise treatment algorithm or the physicians' instructions. The blood pressure (BP) measurement technique and the recording of risk profile were performed as instructed by guidelines from the European Hypertension Society. RESULTS: During the first 4 years, 186 patients were treated in the hypertension clinic. One hundred and thirty patients were treated by the nurses alone and hereafter discharged to general practitioners; 95% of these patients reached target BP. Most of the patients received combination therapy with two to seven different antihypertensive drugs. The three primary antihypertensive drugs (calcium-channel blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and diuretics) were the first drugs to be used and they made up the main part of the combination therapy. CONCLUSION: In spite of many risk factors, co-existing cardiovascular diseases and severe hypertension, 95% of the patients achieved target BP when treated in a nurse-led hypertension clinic. We suggest that the data serves as an inspiration for other clinics and GPs to implement the concept. PMID- 20166862 TI - Evaluation of clinical and laboratory predictors of fatality in patients with Crimean-Congo haemorrhagic fever in a tertiary care hospital in Turkey. AB - The fatality rate of Crimean-Congo haemorrhagic fever (CCHF) disease has been reported as 5.4-80%. In this prospective study our aim was to evaluate the clinical and laboratory predictors of fatality in patients with CCHF. Among probable CCHF patients admitted to our clinic between 2005 and 2008, patients with positive IgM antibodies and/or polymerase chain reaction for CCHF virus were included in the study. To determine the predictors of fatality, we compared epidemiological, clinical and laboratory findings of the fatal cases with survivors. Ninety-three confirmed CCHF patients were included in the study; 56 (60.2%) of them were female. Mean patient age was 48.4+/-17.7 y and mean hospital stay was 7.9+/-3.0 days. Five patients died (5.4%). The rates of haemorrhage, diarrhoea and confusion were higher in fatal cases compared with non-fatal cases (p<0.05). Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, lactate dehydrogenase (LDH), and C-reactive protein levels were higher in fatal cases; the international normalized ratio (INR) and activated partial thromboplastin time (aPTT) were longer and mean platelet counts were lower (p<0.05). By multivariate analysis, diarrhoea, melena, haematemesis, haematuria, elevated ALT and LDH, and prolongation of aPTT were independent clinical and laboratory predictors associated with fatality. We suggest that for patients who have diarrhoea, melena, haematemesis, haematuria, elevated AST and LDH, and a prolonged aPTT, physicians should be aware of the high fatality risk. PMID- 20166863 TI - Phylogenetic analysis of human bocavirus isolated from children with acute respiratory illnesses and gastroenteritis in Iran. AB - Human bocavirus (hBoV) was first discovered in respiratory samples from children in 2005, and has been classified in the Parvoviridae family. hBoV has also been detected in children with acute gastroenteritis. This study was performed to analyze the frequency and phylogeny of hBoV in the respiratory and stool samples of children with acute respiratory tract illnesses and gastroenteritis during the time period beginning 2006 and ending 2008, at the Virology Research Centre, Masih Daneshvari Hospital, NRITLD, Tehran, Iran. Respiratory and stool samples were screened for hBoV by nested polymerase chain reaction with primers from the NS-1 gene. Nine out of 133 respiratory samples (6.8%) and 6 out of 47 stool samples (12.8%) were positive for hBoV. Ten positive samples (7 respiratory and 3 stool samples) were subjected to phylogenetic analysis by sequencing a fragment of the VP1/VP2 gene junction. The results showed a high similarity among isolates (>or=99%). It was found that hBoV isolates can be divided into 3 genetic groups. PMID- 20166864 TI - Early telephone intervention for psychiatric outpatients starting antidepressant treatment. AB - BACKGROUND: The article addresses the hypothesis that early telephone intervention for psychiatric outpatients starting antidepressant treatment would increase compliance with pharmacological treatment and retention time in the study, and thus allow for a more favourable clinical outcome. METHODS: The study focuses on 131 depressed outpatients who participated in a study aiming to obtain full remission. Patients who benefited from three early structured telephone interventions (n=81) were compared with participants who benefited from the usual care (n=50) with no clinical contact before the first clinical assessment at 2 weeks. RESULTS: The intervention proved to have no significant effect on treatment adherence, attrition rate, exclusion rate for adverse events or improvement of depression severity. It was nevertheless associated with increased retention time in the present study. CONCLUSIONS: These results suggest that motivational phone calls may reinforce adhesion in psychiatric patients and provide early opportunities to adapt treatment to individual needs. CLINICAL IMPLICATION: These results suggest that motivational phone calls may reinforce adhesion in psychiatric patients and provide early opportunities to adapt treatment to individual needs. PMID- 20166865 TI - Variable recognition of Candida albicans strains by TLR4 and lectin recognition receptors. AB - The role of TLR4 in the recognition of Candida albicans has been brought into question. In order to assess whether discrepancies in the literature are due to differences in the recognition of various C. albicans strains, we selected 14 different isolates of C. albicans to evaluate their recognition by TLR4 and lectin receptors. We demonstrate that recognition of cell wall structures by lectin receptors is a consistent characteristic independent of the C. albicans strain selected, while recognition by TLR4 is a more variable feature. These data were corroborated by the increased susceptibility of TLR4-/- mice to a C. albicans strain recognized by TLR4, but not to a strain in which recognition has been shown to be independent of this receptor. This suggests a heavier reliance of in vivo antifungal host defense on lectin receptors than on TLRs, a notion compatible with the clinical picture in individuals deficient in MyD88/TLRs or dectin-1/CARD9. PMID- 20166870 TI - Immunosuppressive therapies in myasthenia gravis. AB - Immunosuppression is the mainstay of treatment for myasthenia gravis (MG). In this paper, we review the mechanisms of action and clinical application of corticosteroids and different classes of immunosuppressive drugs that are currently used in MG patients, and present the results of their use in more than 1000 patients with MG seen at our two centers. Immunosuppressive treatment was considered along with, or as an alternative to thymectomy in MG patients with disabling weakness, not adequately controlled with anticholinesterase drugs. Overall, 82% of our patients received immunosuppressants for at least 1 year, with frequencies varying according to disease severity, from 93-95% of those with thymoma or MuSK antibodies to 72% in ocular myasthenia. Prednisone was used in the great majority of patients, azathioprine was the first-choice immunosuppressant; mycophenolate mofetil and cyclosporine were used as second choice agents. All clinical forms of MG benefited from immunosuppression: the rate of remission or minimal manifestations ranged from 85% in ocular myasthenia to 47% in thymoma-associated disease. Treatment was ultimately withdrawn in nearly 20% of anti-AChR positive early-onset patients, but in only 7% of thymoma cases. The risk of complications appears to depend on drug dosage, treatment duration, and patient characteristics, the highest rate of serious side effects (20%) having been found in late-onset MG and the lowest (4%) in early-onset disease. Although nonspecific, current immunosuppressive treatment is highly effective in most MG patients. Lack of randomized evidence, the need for prolonged administration, and unwanted effects are still relevant limitations to its use. PMID- 20166871 TI - Interferon-alpha as angiogenesis inhibitor: learning from tumor models. AB - Interferon-alpha (IFN-alpha), a cytokine with marked therapeutic activity in transplantable tumor models, has been identified as powerful angiogenesis inhibitor. The effects of IFN-alpha on the vasculature have been mainly attributed to inhibition of basic fibroblast growth factor production by tumor cells or downregulation of IL-8 and vascular endothelial growth factor gene expression. Moreover, IFN-alpha has direct effects on endothelial cells (EC), including impairment of their proliferation and migration. The gene expression profile induced by IFN-alpha in EC has recently been defined, and it was found that several genes encoding negative regulators of angiogenesis are upmodulated, thus providing a potential amplification mechanism for this biological activity. The anti-angiogenic effects of IFN-alpha appear to be associated with increased hypoxia and ischemic necrosis in subcutaneous xenograft models, whereas in transgenic mouse models, IFN-alpha may simultaneously interfere with both blood vessels and tumor cell proliferation, leading to regression of tumors without necrosis. The consequences of IFN-alpha therapy on the invasive and metastatic behavior of tumor cells are currently unknown. Finally, as effective anti angiogenic therapy with IFN-alpha demands sustained localized production of this cytokine, innovative strategies of targeted delivery of the IFN-alpha gene into tumors are discussed. PMID- 20166872 TI - The type I IFN system in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder characterized by joint inflammation, immune cell infiltration of the synovia, and cartilage/bone destruction. Despite noteworthy progress in the treatment of RA in recent years, many patients remain refractory to current therapeutic strategies that target either the adaptive immune system or mediators of the innate system. Type I interferons (IFNs) play a significant role in regulation of the innate immune system, originally being discovered as part of intracellular immune defence against viral infection. IFNs are pleiotropic cytokines, mediating both immunostimulatory and immunosuppressive effects. IFN-alpha and beta have been detected in RA synovial fluid and tissue and subsequent therapeutic approaches using type I IFN in murine models of arthritis and in human RA have produced different and controversial results. Great interest has been directed toward principally plasmacytoid dendritic cells (pDCs), although also toward myeloid dendritic cells, as sources of type I IFN. Furthermore, manipulation of DC populations in murine RA models demonstrated that pDCs could suppress the development of arthritis and autoimmunity and may offer an attractive therapy for T-cell-mediated autoimmune diseases. Finally, dendritic cells (DCs) are vehicles for the delivery of therapeutic vaccines, and clinical trials are ongoing in RA with "tolerogenic" DC populations. Further, studies on animal models of RA will elucidate how IFN and DCs contribute to the establishment of autoimmune arthritis and the potential for manipulation of these cell populations and products to re establish the immune tolerance. PMID- 20166873 TI - Tumoral aspects of plasmacytoid dendritic cells: what do we know in 2009? AB - Plasmacytoid dendritic cell (PDC) is a Th2-type dendritic cell precursor. It is an important professional effector cell characterized by its capacities to produce large amount of alpha interferon and to differentiate into dendritic cell. PDCs are scarce in normal condition. They circulate in the blood as veiled cells and enter the lymph node and mucosal site in response to immune stimulation. Besides the recent and wide-open field of the implication of PDCs in inflammatory diseases and in the microenvironment of solid or lymphoid tumours it has also been observed that PDCs can also be tumoral cells. In this paper, the authors present the different tumours thought to be originating from tumoral PDCs. To date, two kinds of tumoral conditions are recognized: the so-called PDCs proliferations in patients with myeloid disorders and the blastic plasmacytoid dendritic cell neoplasm. These two entities are exposed and discussed. PMID- 20166874 TI - Immune functions and recruitment of plasmacytoid dendritic cells in psoriasis. AB - Psoriasis is one of the most common chronic T cell-mediated diseases in humans. Among the most proximal event in the innate immunity cascade driving psoriatic inflammation is the secretion of type I IFN by activated plasmacytoid dendritic cells (pDC), a special DC subset strategically positioned in pre-psoriatic symptomless skin. There is an IFN-alpha signature in primary psoriatic plaques, and blocking of type I IFN signalling can prevent the expansion of pathogenetic T cells and development of psoriatic phenotype. Recently, we have demonstrated that pDC infiltration in psoriatic skin correlates with the expression of markers typical of early phases of psoriasis, whereas it is almost absent in long-lasting lesions. Importantly, pDC recruitment in psoriatic skin is strictly associated with the chemerin/ChemR23 axis, and is temporally active during psoriatic plaque development. Pro-chemerin is produced primarily by dermal fibroblasts, but also by mast cells and endothelial cells. Once secreted, it can be activated by enzymes produced by neutrophils and mast cells, which infiltrate early psoriasis lesions. These findings propose the chemerin/ChemR23 axis as a potential novel therapeutic target in psoriasis. PMID- 20166875 TI - New acquirements on an old molecule: type I interferon. PMID- 20166876 TI - Meta-analysis of TNF-alpha promoter - 238A/G polymorphism and SLE susceptibility. AB - The tumor necrosis factor-alpha (TNF-alpha) promoter--238A/G polymorphism has been repeatedly associated with systemic lupus erythematosus (SLE), but findings are not consistent across studies. Our aim was to do a meta-analysis to assess the association between TNF-alpha promoter--238A/G polymorphism and SLE. Eleven published studies of this polymorphism with SLE in different ethnic groups were identified using a Medline search. Meta-analysis was performed for genotypes AA versus GG, GA versus GG, AA versus GG+GA, GA+AA versus GG, and A allele versus G allele in a fixed/random effect model. The overall odds ratio (OR) of the AA versus GG+GA genotypes was 3.46 (95% CI = 1.35-8.83, P = 0.01), and a similar result was found in Caucasian population (OR = 4.62, 95% CI = 1.20-17.80, P = 0.03); the overall OR of the AA versus GG genotypes was 3.36 (95% CI = 1.32-8.55, P = 0.01), and a similar result was found in Caucasian population (OR = 4.29, 95% CI = 1.11-16.53, P = 0.03); the OR of the GA versus GG genotypes was 0.48 (95% CI = 0.30-0.75, P = 0.001) in Caucasian population. In conclusion, this meta analysis demonstrates the association between TNF-alpha promoter - 238A/G polymorphism and SLE, especially in Caucasian population. PMID- 20166877 TI - Allele and haplotype frequency distribution in PTPN22 gene across variable ethnic groups: Implications for genetic association studies for autoimmune diseases. AB - The rs2476601-T allele at the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene has been consistently associated with several autoimmune diseases in European-derived populations. However, little is known about the allele and haplotype frequency distributions in PTPN22 among populations derived from other ethnic groups. In the present study, the allele and haplotype frequency distributions of six single nucleotide polymorphisms (SNPs) in the PTPN22 gene were compared among Brazilian populations and HapMap phase 3 dataset. A total of 10 different population samples were evaluated. Additionally, in admixed populations, individual genetic ancestries were estimated for Native American, African, and European contributions. Estimated individual ancestries were used as quantitative traits in a conditional approach for single-marker and haplotype specific regression analyses. It was shown that several SNPs and haplotypes have different frequencies among different ethnic populations. Individual genetic ancestries were not associated with the rs2476601-T allele, but were associated with PTPN22 haplotypes in Brazilian, Mexican, and African-American admixed populations. Our results suggest caution in the interpretation of results found in association studies involving PTPN22 polymorphisms in admixed populations. Correction for stratification generated by admixture should be mandatory to minimize or avoid chances of spurious association. PMID- 20166878 TI - Memory T-cells and characterization of peripheral T-cell clones in acute Kawasaki disease. AB - Kawasaki disease (KD) is a pediatric self-limited vasculitis characterized by immune-mediated destruction of the arterial wall and myocardium. Neither the trigger that incites the inflammation nor the switch that turns it off is known. To further our understanding of KD pathogenesis and the role of regulatory T cells in modulating the inflammatory response, we studied circulating effector memory T-cells (CCR7- and IL-15+ T(em)) and central memory T-cells (CCR7+ and IL 15+ T(cm)) in six KD subjects. In two of the subjects, we cloned the remaining T cell population by limiting dilution. TaqMan analysis of T(em) studied in two KD subjects suggested that T(em) are pro-inflammatory CD4+T-helper 1 cells and CD8+ cytotoxic T-cells. Following memory T-cells over time, we defined that circulating T(em) and T(cm) are detectable during the acute phase in some KD subjects before treatment with intravenous immunoglobulin. Both T(em) and T(cm) expand rapidly within 2 weeks of treatment. The circulating T(em) pool contracts, while T(cm) further proliferate in the convalescent phase. Following depletion of memory T-cells, numerous T-cell clones were derived from two acute KD subjects. The large majority of these T-cells displayed the functional phenotype of peripherally induced regulatory T-cells (T(reg)). These findings provide insight into the nature and kinetics of the adaptive immune response in KD. PMID- 20166879 TI - Foxp3-transduced polyclonal regulatory T cells suppress NK cell functions in a TGF-beta dependent manner. AB - CD4(+)CD25(+) regulatory T cells (Treg) are a unique population of T cells that maintain immune tolerance and are essential in host suppression of autoimmune diseases. Natural killer (NK) cells are an important component of the innate immune system and respond to insults. Recent studies demonstrate that NK cells may play a vital role during the onset and progression of certain autoimmune diseases. The decreased or abolished regulation by Treg cells on NK cells may lead to the abnormal autoimmune response. The purpose of this study was to investigate the suppressive effect of Foxp3-transduced CD4(+) T cells on NK cell functions, and thus to present a possible method for managing NK cell-related autoimmune abnormalities. This study showed that forced Foxp3 expression in polyclonal CD4(+) T cells could obtain Treg cells phenotype, including specifically expressing CD25, transforming growth factor (TGF-beta) and CTLA-4. Since NK cells have two major immunological properties--cytotoxicity and cytokine production, we observed that transduction-induced Treg cells decreased NK cell cytotoxicity obviously, and dramatically downregulated the interferon-gamma secretion of NK cell responding to IL-12 stimulation. Moreover, it was found that cell-cell interaction was essential for suppression of NK cell functions, and TGF beta played a vital role in the inhibition process. These results indicate that the forced Foxp3 expression in polyclonal CD4(+) T cells could induce Treg cells and potentially inhibit NK cell functions. PMID- 20166880 TI - Altered expression of the lymphocyte activation antigen CD30 in active celiac disease. AB - Interleukin (IL)-15 and CD30 may be associated with the ongoing intestinal immunologic activation in celiac disease (CD). We studied duodenal biopsies and blood samples of patients with active CD (Cel) and controls in order to determine the regulatory role proposed for CD30(+) T cells in this Th1-driven disease and the potential influences of IL-15 on CD30 expression. We detected that a CD30(+) T-cell subpopulation persists longer in Cel after a 5 day incubation with anti CD3 antibody than in controls (p = 0.0063). CD30 upregulation by IL-15 in T blasts was greater in Cel than in controls (p = 0.0062). At the mucosal compartment, the CD30 antigen was examined by immunohistochemistry and quantified on isolated lamina propria (LP) and epithelial T cells by flow cytometry. For Cel and controls, similar mean percentages of CD3(+)CD30(+) intraepithelial T cells (5.88 vs. 5.51, p = ns) and LP T cells (7.38 vs. 7.49, p = ns) were observed at baseline and after in vitro gliadin challenge of duodenal biopsy samples. Our study demonstrates the occurrence of potentially important alterations of the immune response at the peripheral compartment. Our findings also allow us to speculate that a negative effect of soluble mediators at the mucosal compartment might counteract the latent influence of IL-15 on CD30 expression precluding a more severe course of active CD. PMID- 20166881 TI - Reassessment of antioxidant activity of arbutin: multifaceted evaluation using five antioxidant assay systems. AB - Arbutin, a practically used skin-lightening agent, has been reported to possess a weak antioxidant activity compared to that of its precursor, hydroquinone. However, its antioxidant activity has not been systematically evaluated. Hence, this study reassessed its activity using five assay systems. Assays were first performed using model radicals, DPPH radical and ABTS(*+). Arbutin showed weak DPPH radical-scavenging activity compared to that of hydroquinone, but showed strong ABTS(*+)-scavenging activity. Its activity by ORAC assay was then evaluated using a physiologically relevant peroxyl radical. Arbutin exerted weak but long-lasting radical-scavenging activity and showed totally the same antioxidant activity as that of hydroquinone. Finally, it was shown that, in two cell-based antioxidant assays using erythrocytes and skin fibroblasts, arbutin exerted strong antioxidant activity comparable or even superior to that of hydroquinone. These findings indicate that the antioxidant activity of arbutin may have been under-estimated and suggest that it acts as a potent antioxidant in the skin. PMID- 20166882 TI - Lipid peroxidation product acrolein as a predictive biomarker of prostate carcinoma relapse after radical surgery. AB - Cancer recurrence after radical surgery might happen even in the case of patients with localized prostate carcinoma treated by radical prostatectomy. Therefore, identifying predictive markers of tumour recurrence is very important, so this study evaluated the presence of lipid peroxidation product acrolein in primary prostate carcinomas, assuming that acrolein could be involved in prostate carcinogenesis as was recently shown for colon cancer. Samples obtained by radical prostatectomy of 70 patients were analysed, out of which 27 patients suffered afterwards from tumour recurrence, while 43 patients were disease free. Immunohistochemistry using genuine monoclonal antibodies against acrolein-protein adducts revealed the association of acrolein with progression of carcinoma. The logistic regression combining clinical parameters together with the biochemical markers of disease and acrolein immunohistochemistry has shown that the relapse might be predicted with 90% accuracy if tumour-positive surgical margins, stage of disease and the intensity of acrolein presence in tumour stroma were taken together. PMID- 20166883 TI - Cytochrome P450 induction by phenobarbital exacerbates warm hepatic ischemia reperfusion injury in rat livers. AB - Recent studies have shown that cytochrome P450 inhibitors reduce oxidative stress and injury to the liver following warm ischemia-reperfusion (IR). The aim here was to test the effect of P450 induction by phenobarbital on the IR injury in rat livers. Rats were pre-treated with saline or phenobarbital and subjected to IR or sham operation. IR significantly increased the plasma alanine aminotransferase concentrations. Phenobarbital further exacerbated the injury by an additional 50% increase in the alanine aminotransferase levels. Phenobarbital also caused an approximately 40% increase in the total P450 content of the liver, which was also associated with a 75% increase in the reactive oxygen species (ROS) generation in the IR group. There was a strong correlation between the microsomal ROS generation and total P450 content, CYP3A2 activity or CYP2B1 activity. It is concluded that the induction of P450 by phenobarbital significantly increases hepatic production of ROS, leading to significantly higher hepatic IR injury. PMID- 20166884 TI - Thiol redox systems and protein kinases in hepatic stellate cell regulatory processes. AB - Hepatic stellate cells (HSC) are the major producers of collagen in the liver and their conversion from resting cells to a proliferating, contractile and fibrogenic phenotype ('activation') is a critical step, leading to liver fibrosis characterized by deposition of excessive extracellular matrix. Cytokines, growth factors, reactive oxygen and nitrogen species (ROS/RNS), lipid peroxides and their products deriving from hepatocytes, Kupffer cells and other cells converge on HSC and influence their activation. This review focuses on glutathione and thioredoxin pathways, with particular emphasis on their role in HSC. These two systems have been shown to act in the metabolism of hydrogen peroxide, control of thiol redox balance and regulation of signalling pathways. Particular attention is paid to mitochondria and NADPH oxidase. Detailed knowledge of specific signalling, redox conditions and apoptotic processes will be of help in devising proper pharmacological treatments for liver fibrosis. PMID- 20166885 TI - High cerebrospinal fluid antioxidants and interleukin 8 are protective of hypoxic brain damage in newborns. AB - The objective was to explain the discrepancy in the development of hypoxic ischemic brain injury (HIE) in some asphyxiated newborns rather than others. Forty newborns were classified according to their cerebrospinal neuron-specific enolase (CSF-NSE) levels on their 5th-day of life; group 1 with low-NSE (n = 25). The remaining 15 newborns had high-NSE and were further divided into a group with no HIE (n = 10, group 2) and another with HIE (n = 5, group 3). CSF-NSE, total hydroperoxide (TH), biological-antioxidant-potentials (BAPs), 12 cytokines and erythropoietin (EPO) were measured. The TH/BAP gave the oxidative-stress-index (OSI). The BAPs of serial dilutions of three types of EPO were tested. CSF-NSE and TH and mean OSIs were higher in group 3. IL-8 and mean BAPs were higher in group 2 than in group 1. EPO was less detected in group 3. Serial EPO dilutions correlated with their BAPs. Compensatory antioxidants and IL-8 elevation could be protective of perinatal asphyxic brain injury. Antioxidative effect of EPO could be neuroprotective. PMID- 20166887 TI - The influence of inhibition of the epidermal growth factor receptor on tympanic membrane wound healing in rats. AB - Recently, a report on a bilateral tympanic membrane (TM) perforation in a patient after long-term treatment with erlotinib was published. The object of this study was to investigate the destructive potential of topical applied epidermal growth factor receptor (EGFR) inhibitors on wound healing of experimental TM perforation in rats by evaluating closure rates and histology. In 12 rats, erlotinib (10 mg/ml) was applied to one TM of each animal and cetuximab (5 mg/ml) to the other side daily for 12 consecutive days. Both the erlotinib group (11.8 days) and cetuximab group (9 days) had prolonged healing latencies compared to a reference value (7 days). We observed differences in the histologic parameters between both groups. Our results suggest that in normal TM, the inhibition of EGFR does not lead to a persistent perforation. However, in case of preexisting TM pathology, a spontaneous perforation in patients under long-term treatment of EGFR inhibitors seems to be possible. PMID- 20166886 TI - S100A8 and S100A9 inhibit neutrophil oxidative metabolism in-vitro: involvement of adenosine metabolites. AB - Neutrophils are short-lived granulocytic cells of the innate immune system specialized in the production of reactive oxygen species. S100A8 and S100A9 and their heterocomplex calprotectin play a role in neutrophil recruitment and represent 40% of neutrophil cytosolic protein weight. The present study was designed to test the effect of S100A8 and S100A9 on the rate of neutrophil oxidative metabolism. It is hypothesized that the two S100 proteins inhibit neutrophil associated oxidation. Granulocytes freshly isolated from healthy volunteers were tested for their ability to oxidize dichlorofluorescindiacetate (DCFH-DA) in-vitro. The data showed that S100A8 and S100A9 inhibited spontaneous and stimulated oxidation of the DCFH-DA probe by neutrophils. The inhibition of neutrophil oxidative metabolism by S100A8 and S100A9 was markedly reduced by the enzymatic activity of adenosine deaminase. Inhibitors of the P1 adenosine receptors also reduced the anti-oxidative effect of S100A8/A9 providing further support for the involvement of adenosine metabolites in S100A8/ A9 anti-oxidative effect. PMID- 20166888 TI - Sorafenib protects human optic nerve head astrocytes from light-induced overexpression of vascular endothelial growth factor, platelet-derived growth factor, and placenta growth factor. AB - OBJECTIVES: Growth factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and placenta growth factor (PlGF) are key players in the development of diabetic retinopathy, age-related macular degeneration, and other retinal neovascular diseases. Glial cells provide a significant source of retinal growth factor production under physiologic and pathologic conditions. Cumulative light exposure has been linked to increased retinal growth factor expression. Previous reports indicate that sorafenib, an oral multikinase inhibitor, might have a beneficial effect on retinal neovascularization. This study was designed to investigate the effects of sorafenib on light-induced overexpression of growth factors in human retinal glial cells. METHODS: Primary human optic nerve head astrocytes (ONHAs) were exposed to white light and incubated with sorafenib. Viability, expression, and secretion of VEGF-A, PDGF-BB, and PlGF and their mRNA were determined by reverse transcription-polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay. RESULTS: Light exposure decreased cell viability and increased VEGF-A, PDGF-BB, and PlGF expression and secretion. These light-induced effects were significantly reduced when cells were treated with sorafenib at a concentration of 1 microg/ml. CONCLUSION: Sorafenib significantly reduced light induced overexpression of VEGF-A, PDGF-BB, and PlGF in primary human ONHAs. Sorafenib has promising properties as a potential supportive treatment for retinal neovascularization. PMID- 20166890 TI - Vascular endothelial growth factor A is a putative paracrine regulator in seasonally controlled spermatogenesis: insights from a ruminant model, the roe deer. AB - Vascular endothelial growth factor A (VEGFA) influences spermatogenesis, but its impact on seasonally regulated sperm production is still not fully understood. Thus, we investigated both expression levels and localisation of VEGFA and its receptors VEGFR1 and 2 in roe buck testis via real-time reverse transcription polymerase chain reaction and immunohistochemistry in relation to seasonal changes in the cellular composition of the testis. VEGFA was expressed by interstitial cells while its receptors were found on endothelial and perivascular cells. Inside the tubules, VEGFA was located in spermatogonia and spermatocytes, VEGFR1 was present on elongating spermatids and VEGFR2 on Sertoli cells. VEGFR1 mRNA was expressed tenfold lower than VEGFR2 and VEGF mRNAs. Relative VEGF and VEGFR2 expression (divided by the number of VEGFA and VEGFR2 expressing cells) showed an increase towards the rut (July/August) and a decrease thereafter. The results suggest involvement of VEGFA in the adjustment of vascular permeability as well as in spermiogenesis and the proliferation of spermatogonia. PMID- 20166889 TI - The applied biochemistry of PEDF and implications for tissue homeostasis. AB - Pigment epithelium-derived factor (PEDF) is an endogenously produced glycoprotein with a spectrum of biological roles across diverse pathologies. Recent research has focused on the biochemical properties of PEDF and its associated receptors. This review discusses the recent developments in PEDF biochemistry and how this new knowledge will help progress our understanding of PEDF as a molecular mediator for anti-angiogenesis and -tumorigenesis. Additionally, pathophysiological roles for PEDF in healing and tissue homeostasis are being revealed and our enhanced understanding of the interactions between PEDF and its receptors may yet prove useful in propelling PEDF towards clinical application. PMID- 20166891 TI - Oxidative LDL modification is increased in vascular dementia and is inversely associated with cognitive performance. AB - It is not known whether the association between increased plasma homocysteine (Hcy) associated with LDL modification and propensity for LDL uptake by macrophages in cardiovascular disease patients holds true in vascular dementia (VaD). Plasma from 83 subjects diagnosed with Alzheimer's disease (AD), VaD, mild cognitive impairment (MCI) and from controls was analysed to examine (1) whether LDL isolated from the plasma of VaD is biochemically and functionally distinct from that isolated from AD, MCI or controls; and (2) whether such biomarkers of LDL phenotype are related to plasma folate levels, Hcy levels and/or to disease severity. Folate and vitamin B6 levels were significantly lower in VaD subjects than in controls. VaD-LDL showed increased protein carbonyl content (p < 0.05) and was more susceptible to scavenging by macrophages (p < 0.05) than AD- or control-LDL. Patients from the VaD cohort were more prevalent in the lowest tertile for HDL:LDL and the upper tertile for LDL oxidation; the combined parameters of HDL cholesterol, LDL oxidation and scavenging by macrophages show 87% sensitivity towards VaD detection. The association between folate deficiency, LDL modification and dysfunction in VaD but not in AD may provide a novel biomarker assessment to discriminate between the diseases. PMID- 20166892 TI - Radioprotective effect of hydrogen in cultured cells and mice. AB - It has been demonstrated that hydrogen can selectively reduce hydroxyl and peroxynitrite in vitro. Since most of the ionizing radiation-induced cellular damage is caused by hydroxyl radicals, this study was designed to test the hypothesis that hydrogen may be an effective radioprotective agent. This paper demonstrates that treating cells with hydrogen before irradiation could significantly inhibit ionizing irradiation(IR)-induced Human Lymphocyte AHH-1 cells apoptosis and increase cells viability in vitro. This paper also shows that hydrogen can protect gastrointestinal endothelia from radiation-induced injury, decrease plasma malondialdehyde (MDA) intestinal 8-hydroxydeoxyguanosine (8-OHDG) levels and increase plasma endogenous antioxidants in vivo. It is suggested that hydrogen has a potential as an effective and safe radioprotective agent. PMID- 20166893 TI - Dehydroascorbic acid as pre-conditioner: protection from lipopolysaccharide induced mitochondrial damage. AB - Oxidative stress-induced mitochondrial dysfunction is a common consequence of severe sepsis. However, oxidative stress also activates signalling cascades which enable protection of cells against subsequent oxidative damage. This study hypothesized that cellular uptake of vitamin C as dehydroascorbic acid rather than ascorbic acid would up-regulate antioxidant enzyme systems and impart a protective effect to mitochondria in cells subsequently exposed to lipopolysaccharide (LPS) in an iron free environment. Treatment of monocytes with dehydroascorbic acid, but not ascorbic acid, caused oxidative stress (p< 0.001). Dehydroascorbic acid exposure also resulted in increased manganese superoxide dismutase (p= 0.018) and catalase (p= 0.003) expression. Pre-treatment of monocytes with dehydroascorbic acid followed by LPS resulted in higher mitochondrial membrane potentials than cells without pre-treatment (p< 0.0001). Lower cytochrome c in cytosol (p< 0.05) and higher mitochondrial expression of the anti-apoptotic Bcl-2 protein (p= 0.029) was also found in monocytes pre treated before subsequent LPS exposure, compared to cells without pre-treatment. In conclusion, acute exposure of monocytes to dehydroascorbic acid in an iron free environment induces cytoprotective antioxidant enzymes and protected mitochondria from the harmful effects of oxidative stress prior to a septic insult, which was abrogated when cells were pre-incubated with the DHA uptake inhibitor cytocholasin B. PMID- 20166894 TI - Formation of nitric oxide, ethyl nitrite and an oxathiolone derivative of caffeic acid in a mixture of saliva and white wine. AB - Reactions of salivary nitrite with components of wine were studied using an acidic mixture of saliva and wine. The formation of nitric oxide (NO) in the stomach after drinking wine was observed. The formation of NO was also observed in the mixture (pH 3.6) of saliva and wine, which was prepared by washing the oral cavity with wine. A part of the NO formation in the stomach and the oral cavity was due to the reduction of salivary nitrite by caffeic and ferulic acids present in wine. Ethyl nitrite produced by the reaction of salivary nitrite and ethyl alcohol in wine also contributed to the formation of NO. In addition to the above reactions, caffeic acid in wine could be transformed to the oxathiolone derivative, which might have pharmacological functions. The results obtained in this study may help in understanding the effects of drinking wine on human health. PMID- 20166895 TI - Acetaminophen induced acute liver failure via oxidative stress and JNK activation: protective role of taurine by the suppression of cytochrome P450 2E1. AB - The present study was carried out to investigate whether taurine plays any beneficial role in acetaminophen (APAP)-induced acute hepatotoxicity. APAP exposure increased the plasma levels of ALT, ALP, LDH, TNF-alpha and NO production. Moreover, APAP treatment reduced the glutathione level and antioxidant enzyme activities, increased lipid peroxidation and caused hepatic DNA fragmentation which ultimately leads to cellular necrosis. Also, incubation of hepatocytes with APAP reduced cell viability, enhanced ROS generation and increased CYP2E1 activity. APAP overdose caused injury in the hepatic tissue and hepatocytes via the upregulation of CYP2E1 and JNK. Taurine treatment was effective in counteracting APAP-induced hepatic damages, oxidative stress and cellular necrosis. Results indicate that APAP overdose caused hepatic injury due to its metabolism to hepatotoxic NAPQI (N-acetyl-p-benzoquinone imine), usually catalysed by CYP2E1, and via the direct activation of JNK-dependent cell death pathway. Taurine possesses prophylactic as well as therapeutic potentials against APAP-induced hepatic injury. PMID- 20166898 TI - ZFP36L1 is regulated by growth factors and cytokines in keratinocytes and influences their VEGF production. AB - Keratinocyte-derived growth factors and cytokines play an important role in epidermal homeostasis and particularly in cutaneous wound repair. Thus, we analyzed a potential role of the ZFP36/tristetraprolin family of zinc finger proteins, which are targets of these factors, but also regulate their production, in keratinocytes. We show that expression of ZFP36, ZFP36L1, and ZFP36L2 is induced by a broad variety of growth factors and cytokines, and by scratch wounding. Since ZFP36L1 is a modulator of vascular endothelium growth factor (VEGF) mRNA stability, we subsequently used siRNA technology to inhibit ZFP36L1 gene expression. Notably, this treatment resulted in prolonged maintenance of elevated VEGF levels in HaCaT keratinocytes upon epidermal growth factor stimulation of these cells. Taken together, our results suggest an important role of ZFP36L1 in wound healing. PMID- 20166899 TI - Nerve growth factor signaling in prostate health and disease. AB - The prostate is one of the most abundant sources of nerve growth factor (NGF) in different species, including humans. NGF and its receptors are implicated in the control of prostate cell proliferation and apoptosis and it can either support or suppress cell growth. The co-expression of both NGF receptors, p75(NGFR) and tropomyosin-related kinase A (trkA), represents a crucial condition for the antiproliferative effect of NGF; indeed, p75(NGFR) is progressively lost during prostate tumorigenesis and its disappearance represents a malignancy marker of prostate adenocarcinoma (PCa). Interestingly, a dysregulation of NGF signal transduction was found in a number of human tumors. This review summarizes the current knowledge on the role of NGF and its receptors in prostate and in PCa. Conclusions bring to the hypothesis that the NGF network could be a candidate for future pharmacological manipulation in the PCa therapy: in particular the re expression of p75(NTR) and/or the negative modulation of trkA could represent a target to induce apoptosis and to reduce proliferation and invasiveness of PCa. PMID- 20166900 TI - Effects of epidermal growth factor on proliferation and migration of cardiosphere derived cells expanded from adult human heart. AB - Recent studies have provided evidence that the human heart has an endogenous reserve of cardiac stem cells (CSCs) that can be activated to reconstitute the dead myocardium. Current efforts are now directed towards the identification of factors favoring the growth and expansion of the CSC pool in the heart. Accordingly, in the present study, effects of different growth factors on cardiosphere-derived cells (CDCs), expanded from atrial biopsies from patients undergoing elective coronary artery bypass surgery, were analyzed. CSCs appear to respond to epidermal growth factor (EGF) more efficiently than other widely used growth factors such as vascular endothelial growth factor, insulin-like growth factor, basic fibroblast growth factor, hepatocyte growth factor, transforming growth factor, and platelet-derived growth factor. EGF significantly promoted cardiosphere formation (p < 0.05) and proliferation (p < 0.005), migration (p < 0.0005), and wound healing (p < 0.005) activities of CDCs in comparison to the other growth factors studied. Pretreatment with EGF enhanced the expression of cardiac markers cTN1(+) and MHC(+) in CDCs in comparison to untreated controls. PMID- 20166901 TI - Trends in the paramedic workforce: a profession in transition. PMID- 20166902 TI - Anger and depression predict hospital use among chronic heart failure patients. AB - Costly hospital readmissions among chronic heart failure (CHF) patients are expected to increase dramatically with the ageing population. This study investigated the prognostic ability of depression, anger and anxiety, prospectively, and after adjusting for illness severity, on the number of readmissions to hospital and the total length of stay over one year. Participants comprised 175 inpatients with CHF. Depression, anger, anxiety, and illness severity were measured at baseline. One year later, the number of readmissions and length of stay for each patient were obtained from medical records. Depression and anger play a detrimental role in the health profile of CHF patients. PMID- 20166903 TI - Exploring the impact of an Aboriginal Health Worker on hospitalised Aboriginal experiences: lessons from cardiology. AB - To enhance Aboriginal inpatient care and improve outpatient cardiac rehabilitation utilisation, a tertiary hospital in Western Australia recruited an Aboriginal Health Worker (AHW). Interviews were undertaken with the cardiology AHW, other hospital staff including another AHW, and recent Aboriginal cardiac patients to assess the impact of this position. The impact of the AHW included facilitating culturally appropriate care, bridging communication divides, reducing discharges against medical advice, providing cultural education, increasing inpatient contact time, improving follow-up practices and enhancing patient referral linkages. Challenges included poor job role definition, clinical restrictions and limitations in AHW training for hospital settings. This study demonstrates that AHWs can have significant impacts on Aboriginal cardiac inpatient experiences and outpatient care. Although this study was undertaken in cardiology, the lessons are transferable across the hospital setting. PMID- 20166904 TI - The Breast Service psychosocial model of care project. AB - OBJECTIVE: It has been consistently demonstrated that many women with breast disease will experience psychosocial distress at some stage along the patient journey. Psychosocial care has recently gained more prominence and is increasingly recognised as an important aspect of care offered to patients with breast cancer. The purpose of this project was to develop a model that improved the way psychosocial services were provided to patients. The aim of this paper is to describe the process in developing this psychosocial model of care for patients with breast disease. METHODS: Using in-depth semi-structured interviews with a sample of patients and staff, we examined psychosocial concerns experienced by breast patients and the factors associated with the effective assessment and delivery of psychosocial care. The project was approved by the Royal Women's hospital ethics secretariat as a quality assurance project. RESULTS: An inductive analysis of staff responses indicated that a standardised screening and referral pathway was needed in a context of well defined staff roles and a multidisciplinary team environment. An inductive analysis of patient responses indicated that psychosocial concerns were common, but varied, and a tailored approach to the provision of psychosocial care was warranted. DISCUSSION: In line with these findings, a standardised assessment and referral pathway was developed for The Breast Service that may be extended for use in other clinical settings and tumour streams. PMID- 20166905 TI - Perceptions of multidisciplinary case conferencing in residential aged care facilities. AB - OBJECTIVE: To explore the understanding about and perceptions of, multidisciplinary case conferencing in residential aged care from the perspective of residential facility staff, residents, carers and general practitioners. METHODS: Focus groups and in-depth interviews were conducted with nurses, residents, carers, allied health workers and general practitioners from two residential aged care facilities during February-March 2008. Conversations were analysed using thematic analysis techniques. RESULTS: Thematic analyses highlighted four key themes. Most notably, respondents identified a degree of confusion regarding the purpose of case conferencing and its role in resident health care. The ad hoc development of the conferencing model led to unclear role descriptions for participants that contributed to role confusion and the lack of a collaborative culture. Underpinning much of the discussion was the need for a framework to support the organisation of the conference process. CONCLUSIONS: While the process of multidisciplinary case conferencing in residential aged care has significant potential to improve resident care and health outcomes, the development of an explicit framework is required to support the effective conduct of these meetings. Key stakeholders need to be engaged to develop a team approach to conducting case conferences that facilitates the active participation of providers, residents and their carers. PMID- 20166906 TI - The distribution of health services for older people in Australia: where does transition care fit? AB - INTRODUCTION: The purpose of this study was to describe the distribution of hospital and aged care services for older people, with a particular focus on transition care places, across Australia and to determine the relationships between the provision of these services. METHODS: Aggregation of health and aged care service indicators by Aged Care Assessment Team (ACAT) region including: public and private acute and subacute (rehabilitation and geriatric evaluation and management) hospital beds, flexible and mainstream aged care places as at 30 June 2006. RESULTS: There was marked variation in the distribution of acute and subacute hospital beds among the 79 ACAT regions. Aged care places were more evenly distributed. However, the distribution of transition care places was uneven. Rural areas had poorer provision of all beds. There was no evidence of coordination in the allocation of hospital and aged care services between the Commonwealth and state/territory governments. There was a weak relationship between the allocation of transition care places and the distribution of health and aged care services. DISCUSSION: Overall, the distribution of services available to older persons is uneven across Australia. While the Transition Care Program is flexible and is providing rural communities with access to rehabilitation, it will not be adequate to address the increasing needs associated with the ageing of the Australian population. An integrated national plan for aged care and rehabilitation services should be considered. PMID- 20166907 TI - The impact of the Coronial Communique on changing patient safety: a subscriber survey. AB - To determine whether the Coronial Communique prompted subscribers to initiate changes to clinical practice for patient safety an anonymous, online cross sectional population survey questionnaire was provided to all registered subscribers to the Communique. The main outcome measure was self-reported review and change to practice. From 1325 subscribers invited to participate, 697 complete and valid responses were received (52.6%). Most of the respondents (588; 84.4%) reported the Communique provided ideas for improving patient safety, 429 (61.5%) reviewed their practice, and 290 (41.6%) changed their practice. The characteristic most associated with a change in practice was if the subscriber was in clinical practice. This association was evident for ideas (odds ratio [OR], 3.42; 95% CI, 2.24-5.23), review (OR, 2.63; 95% CI, 1.91-3.61) and change to improve practice (OR, 2.40; 95% CI, 1.73-3.32). PMID- 20166908 TI - How far can systematic reviews inform policy development for "wicked" rural health service problems? AB - Policy makers and researchers increasingly look to systematic reviews as a means of connecting research and evidence more effectively with policy. Based on Australian research into rural and remote primary health care services, we note some concerns regarding the suitability of systematic review methods when applied to such settings. It suggests that rural and other health services are highly complex and researching them is akin to dealing with "wicked" problems. It proposes that the notion of "wicked" problems may inform our understanding of the issues and our choice of appropriate methods to inform health service policy. Key issues including the complexity of health services, methodological limitations of traditional reviews, the nature of materials under review, and the importance of the service context are highlighted. These indicate the need for broader approaches to capturing relevant evidence. Sustained, collaborative synthesis in which complexity, ambiguity and context is acknowledged is proposed as a way of addressing the wicked nature of these issues. PMID- 20166910 TI - Global warming and Australian public health: reasons to be concerned. AB - Studies in global warming and climate change indicate that human populations will be deleteriously affected in the future. Studies forecast that Australia will experience increasing heat waves and droughts. Heat stress caused by frequent heat waves will have a marked effect on older Australians due to physiological and pharmacological factors. In this paper we present an overview of some of the foreseeable issues which older Australians will face from a public health perspective. PMID- 20166909 TI - Projecting subacute inpatient activity in New South Wales. AB - We describe the development of a method for estimating and modelling future demand for sub- and non-acute inpatient activity across New South Wales, Australia to 2016. A time series linear regression equation was used, which is consistent with projection models found in the literature. Results of the modelling indicated an increase in rehabilitation, palliative care and maintenance episodes and bed-days. Projections for other categories of care are problematic due to smaller levels of activity and data quality issues. This project indicated a need for ongoing monitoring of type-changing by facilities and management of data quality. Local planners will need to consider a range of factors when considering the applicability activity projections at a local level, particularly within the specific age and clinical groupings. PMID- 20166912 TI - Science, research and social change in Indigenous health--evolving ways of knowing. AB - History tells us of the overwhelming destructive influence of exotic culture, politics and knowledge forms upon the worldview and wellbeing of Indigenous Australians. The power of dominant culture to oppress, control and dominate traditional Indigenous ways of knowing and being has been identified as a being a crucial influence on the health status, future hopes and aspirations of Indigenous Australians. Fundamental to this assertion is that the alienating effect of the belief in and application of the scientific method in relation to learning and knowing is a phenomenon that is incompatible with the law and cultural ways of traditional Indigenous people. The establishment of the Centre of Clinical Research Excellence (CCRE) is predicated upon and responds to a deep need in our community today to synthesise the ideological and epistemological premises of an increasing range of cultures and world views. It recognises that clinical research, for example, is important to the health of Aboriginal and Torres Strait Islander peoples, but also that the way such research is designed and carried out is also crucial to its potential to effect change in and improve the state of Indigenous health in Australia. This paper examines knowledge principles and processes associated with research in Indigenous communities, explores emerging research trends in science and proposes an epistemological framework for synthesis of traditional approaches with those of the scientific paradigm. PMID- 20166911 TI - Refugees and oral health: lessons learned from stories of Hazara refugees. AB - Australia is one of a few countries with a resettlement program for refugees. The organisation and provision of health services for refugees pose challenges to health service managers and service providers. Some groups have experienced severe trauma and, in the case of Hazara refugees, years of persecution and displacement. This qualitative study gained access to Hazara refugees in order to gain an understanding of their oral health experiences and to seek participant views on factors that impacted on their oral health status. All participants had poor oral health status, multiple tooth extractions, and had placed a low priority on their oral health. They had experienced violence and traumatic events associated with war and looting. Participants reported that they had limited access to dental practitioners and oral education; lived for extended periods with oral pain and untreated oral problems; and treated oral pain with traditional pain remedies and tooth extractions. Service providers need to consider that elements of the refugee experience may affect health-seeking behavior and adherence to treatment. PMID- 20166913 TI - Insights from the Northern Territory on factors that facilitate effective palliative care for Aboriginal peoples. AB - This article aims to assist remote communities to develop their own palliative care services by providing findings on successful strategies identified through a 2-year research project which developed an innovative model for Indigenous palliative care. The discussion is set in the context of an understanding of the notion of cultural safety and discusses the positive experiences of the benefits of palliative care from the perspectives of both consumers and health professionals. The findings show that successful outcomes are derived from generic factors associated with palliative care philosophy and practice and from more specific factors, including the provision of pragmatic support to overcome practical problems, and community visits by health professionals. Factors specific to cultural respect are important, including familiarity and continuity of health care providers, cultural respect for grieving practices, provision of comfort food and bush tucker, development of culturally appropriate built environments, use of traditional healers and respect for spiritual practices. PMID- 20166914 TI - Patient and carer perceptions of cancer care in South Australia. AB - Quality of care from the patient's perspective is an increasingly important outcome measure for cancer services. Patients' and carers' perceptions of cancer care were assessed through structured telephone interviews, 4-10 months post discharge, which focused on experiences during the most recent hospital admission. A total of 481 patients with a primary diagnosis of cancer (ICD-10 C codes) were recruited, along with 345 carers nominated by the patients. Perceptions of clinical care were generally positive. Less positive aspects of care included not being asked how they were coping, not being offered counselling, and not receiving written information about procedures. Results also highlighted inadequate discharge processes. Carers were more likely than patients to report negative experiences. Perceptions of care also differed by cancer type. PMID- 20166915 TI - Delirium in the elderly. A survey of environmental policies and procedures in Melbourne hospitals. AB - This study aimed to review the presence of policies for management of behavioural symptoms and physical restraints, the availability of delirium management protocols and educational programs, and accessibility of a physical environment appropriate for the management of delirium in Melbourne hospitals. A structured survey tool was developed, and 70 Melbourne hospitals were surveyed seeking responses from a senior member of the nursing staff. Overall, 90% of Melbourne hospitals responded to the survey. It was found that smaller hospitals have fewer policies relating to the management of behavioural symptoms, and fewer delirium management protocols. Some education is available for nursing staff; however, less for the night staff, who often manage behavioural symptoms associated with delirium. Physical restraint policies exist at most hospitals. Single rooms and night lights are generally available, but low-low beds and orientation devices are relatively uncommon. PMID- 20166916 TI - Physiotherapy-led triage clinic for low back pain. AB - The aims of this study were to evaluate a physiotherapy-led triage clinic (PLTC) and investigate general practitioner satisfaction with the PLTC. A retrospective cohort study was undertaken from January to December 2005 at a Melbourne tertiary teaching hospital. Outcomes assessed included waiting times to first appointment, patient attendance and surgery conversion rates. Outcomes were compared with the hospital 2002 benchmark data. GP satisfaction was evaluated by a survey. One hundred and five new patients attended the PLTC clinic during the evaluation period. Patients waited 9 weeks for a PLTC appointment compared with 26 weeks for the general orthopaedic clinic and 23 weeks for the spinal orthopaedic clinic. Sixty-seven percent of the patients triaged in the PLTC were discharged from the orthopaedic outpatient department without requiring an orthopaedic surgeon consultation. Referring GPs were at least as satisfied with the management of their patients through the PLTC as with usual management in the general orthopaedic clinic. A PLTC can significantly reduce waiting times for orthopaedic outpatient appointments in a public hospital. Many patients can be managed by these experienced physiotherapists and their GPs, without the need for face-to face contact with an orthopaedic surgeon. Pilot results indicated that GPs whose patients are managed in this PLTC were satisfied with this model for their patients with low back conditions. PMID- 20166917 TI - An evaluation of community-based resources for management of diabetes-related foot disorders in an Australian population. AB - We aimed to evaluate service model configuration, service capacity and accessibility of diabetes-related footcare in an Australian community health setting. Eighty-eight community-based podiatry clinics were surveyed using the self-administered Footcare Provider Survey. Survey domains included communication, resources, service coordination and barriers to service provision. Sixty-nine from a possible 88 Victorian community podiatry clinics (78%) responded. Sixty-one (88%) provided ongoing care to individuals with diabetes related foot disorders. Communication with vascular and orthopaedic specialists was reported to be readily available in 37% and 27% of cases respectively. Overall, communication with general practitioners was deemed readily available in 62% of cases. Just 39% of podiatrists statewide agreed overall resources were sufficient, with 26% agreeing staffing levels were adequate. Thirty-nine percent of community podiatrists used clinical care pathways, and onsite collaboration was deemed appropriate in just 30% of cases. Perceived barriers to provision of care included inadequate staffing and resources, lack of confidence from other health professionals in the podiatrists' ability to manage diabetes-related foot disorders, and lack of access to specialists. PMID- 20166918 TI - The status of Australian nurse practitioners: the first national census. AB - A five-section questionnaire was mailed to all 234 authorised Australian nurse practitioners in late 2007. An 85% response rate was achieved (202 responses). Respondents had a mean age of 47.0 years and 84.2% were women. Only 145 nurse practitioners (72% of respondents) reported being employed in Australia at the time of the census. Emergency nurse practitioners were the most commonly employed nationally (26.9%). Nearly one third of employed nurse practitioners reported that they were still awaiting approval to prescribe medications despite this being a core legislated skill. Over 70% stated that lack of Medicare provider numbers and lack of authority to prescribe through the Pharmaceutical Benefits Scheme was extremely limiting to their practice. These findings are consistent with the international literature describing establishment of reformative health care roles. PMID- 20166919 TI - Is there a role for podiatric surgeons in public hospitals? An audit of surgery to the great toe joint in Victoria, 1999-2003. AB - This project aimed to describe and compare the frequencies of procedures performed by podiatric surgeons and orthopaedic surgeons for elective surgery to the great toe joint, an area of identified clinical need. The objective was to determine whether podiatric surgeons in the Australian context possess a surgical skill set which can be utilised in the public health sector. The Medicare Benefits Schedule (Medicare Australia) was reviewed to identify all codes relating to great toe joint surgery and frequency data were obtained for the period July 1999 to June 2003. A separate audit of the activity of Victorian podiatric surgeons was conducted. During the 4 years in Victoria, the number of procedures performed on this joint by 152 orthopaedic surgeons was 5882. Two podiatric surgeons in Victoria performed 1260 operations on this joint over this period (17.6% of great toe joint surgery on average each year in the private sector). Utilising orthopaedic workforce figures and on a per-surgeon basis, during this period the podiatric surgeons performed this type of surgery between 2 and 16 times more often than the orthopaedic surgeons, and consideration should be given to using these skills in the public sector to address the growing demand. PMID- 20166920 TI - Interaction of endocannabinoid receptors with biological membranes. AB - Cellular signaling is regulated by several biochemical reactions, whose dynamics depends on changes in the fluxes of specific ligands through the containment barriers that are the biological membranes. The regulation of this complex dynamic equilibrium is mainly due to the activity of border proteins, that must be able to interact simultaneously with the lipid bilayer and the extracellular milieu. Endocannabinoid receptors, that include type-1 and type-2 cannabinoid receptors, the transient vanilloid potential receptors and the peroxisome proliferator-activated receptors, represent one of the most intriguing examples of "border" proteins. They have also been identified as important drug discovery targets with potential therapeutic applications, from antiemesis, appetite enhancement, analgesia, glaucoma treatment, and immune suppression. However, as yet the molecular details of endocannabinoid receptor regulation remain elusive. In this review we summarize the most relevant aspects of the structural/functional characterization of these receptors, with a focus on the active role played by biological membranes (in particular lipid rafts) in the modulation of their accessibility and mode of ligand binding. Based on available evidence, we propose that endocannabinoid receptors can be regulated by the rate of interlayer exchange and lateral diffusion of endocannabinoid/cholesterol complexes within lipid bilayers, thus suggesting innovative approaches for the therapeutic exploitation of the membrane component of endocannabinoid signaling. PMID- 20166922 TI - From surface to nuclear receptors: the endocannabinoid family extends its assets. AB - Peroxisome proliferator-activated receptors (PPARs) have long been known as mediators of several physiological functions, among which the best characterized are lipid metabolism, energy balance and anti-inflammation. Their rather large and promiscuous ligand binding site has been recently discovered to accommodate, among a plethora of lipid molecules and metabolic intermediates, endocannabinoids and their cognate compounds, specifically belonging to the Nacylethanolamine group. In fact, oleoylethanolamide, palmitoylethanolamide and probably anandamide bind with relatively high affinity to PPARs and have now been included among their endogenous ligands. Through activation of PPARs these molecules exert a variety of physiological processes. Particularly, both long-term effects via genomic mechanisms and rapid non-genomic actions have been described, which in several instances are opposite to those evoked by activation of "classical" surface cannabinoid receptors. In this review, we describe how these effects are relevant under diverse physiological and pathophysiological circumstances, such as lipid metabolism and feeding behaviour, neuroprotection and epilepsy, circadian rhythms, addiction and cognition. A picture is emerging where nuclear receptors are involved in anorexiant, anti-inflammatory, neuroprotective, anti epileptic, wakefulness- and cognitive-enhancing, and anti-addicting properties of endocannabinoid-like molecules. Further studies are necessary to fully understand cellular mechanisms underlying the interactions between endocannabinoids and PPARs, but also between their surface and nuclear receptors, and to exploit their potential therapeutic applications. PMID- 20166923 TI - Endocannabinoids as regulators of transient receptor potential (TRP) channels: A further opportunity to develop new endocannabinoid-based therapeutic drugs. AB - In the late 1990's, a series of experiments carried out independently in two laboratories led to establish an important connection between the function of the endocannabinoids, which, as exemplified in this special issue, is per se very complex and ubiquitous in animals, and that of the transient receptor potential (TRP) channels, a large family of plasma membrane cation channels involved in several mammalian and non-mammalian physiological and pathological conditions, overlapping only in part with those in which the cannabinoid receptors participate. These experiments were initially based on the observation that the endocannabinoid anandamide and the xenobiotic ligand of TRP channels of V1 type (TRPV1), capsaicin, are somehow chemically similar, both compounds being fatty acid amides, as are also synthetic activators of these channels and inhibitors of anandamide cellular re-uptake. As discussed in this article, the same type of "chemical thoughts" led to the discovery of N-arachidonoyl-dopamine, an endogenous ligand of TRPV1 channels that behaves also an endocannabinoid. The overlap between the ligand recognition properties of some TRP channels and proteins of the endocannabinoid system, namely the cannabinoid receptors and the proteins and enzymes catalyzing anandamide cellular re-uptake and hydrolysis, is being actively explored through the rational design and synthesis of new endocannabinoid-based drugs with multiple mechanisms of action. These aspects are discussed in this review article, together with the possible functional and pharmacological consequences of endocannabinoid-TRP channel interactions. PMID- 20166924 TI - GPR55: Current knowledge and future perspectives of a purported "Type-3" cannabinoid receptor. AB - In the last decade, accumulated evidence highlighted that GPR55 might be activated by several classical cannabinoid ligands, making this orphan receptor the main candidate to be considered as the "third" cannabinoid receptor. The investigation of its pharmacology has often provided divergent and more intricate results that have complicated the understanding of the physiological role of GPR55. Nevertheless, the patent analysis regarding GPR55 outlines the fair interest of big pharmaceutical companies, especially in the first years of this decade. This investigation provides a brief overview of the current "state of the art" of our knowledge of GPR55, giving particular emphasis to its functional selectivity. This property could account for controversial roles of GPR55, whose pharmacology and downstream signaling is known to vary significantly both in ligand- and system-dependent manners. In addition, we gain insights into the challenging aspect of finding out novel GPR55 modulators, by analyzing conserved structural and functional motifs that, together with future studies, could help to elucidate its mechanism of action and to design more selective and potent small-molecules directed towards GPR55. Preliminary data highlight remarkable differences, but also intriguing commonalities, between GPR55 and other members of class A G protein-coupled receptors. It is anticipated that, in the next future, novel lead candidates targeting GPR55 could represent new tools to better understand GPR55-mediated human diseases and, hopefully, generate an innovative class of effective next-generation therapeutics. PMID- 20166921 TI - Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown. AB - The cannabinoid CB1 and CB2 receptors are Class A G protein-coupled receptors (GPCRs). While many Class A GPCRs have endogenous ligands that are hydrophilic cations (e.g., the serotonin and dopamine receptors), the cannabinoid receptors have neutral, highly lipophilic ligands derived from the fatty acid, arachidonic acid. The most well-studied of these are N-arachidonoylethanolamine (anandamide, AEA) and sn-2-arachidonoylglycerol (2-AG). This review focuses on the experimental and computational studies that have been used to probe the nature of endocannabinoid interaction with the cannabinoid receptors. These studies include mutation, SAR and NMR studies, as well as, QSAR, docking and molecular dynamics simulations. Gaps in our knowledge are identified. The review begins more generally, however, by discussing the entire endocannabinoid system, of which the cannabinoid receptors are part. For in order to understand endocannabinoid action, one needs an appreciation for the environments for which these ligands have been designed and the conformational changes these ligands must undergo in order to act on the cannabinoid receptors. PMID- 20166925 TI - Cannabinoid CB(2) receptors in health and disease. AB - Marijuana has been used for thousands of years to affect human health. Dissecting the peripheral effects from the central psychotropic effects has revealed a complex interplay between cannabinoids, endocannabinoids and their receptors. This review examines recent advances in understanding the expression, regulation and utilization of the CB(2) receptor. Here we highlight the molecular aspects of the CB(2) receptor, CB(2) receptor signaling and new ligands for this receptor. We focus in the rest of the review on recent findings in the immune system, the gastrointestinal tract and liver, the brain and the cardiovascular system and airways as examples of areas where new developments in our understanding of the CB(2) receptor have occurred. Early studies focused on expression of this receptor under baseline physiologic conditions; however, perturbations such as those that occur during inflammation, ischemia/reperfusion injury and cancer are revealing a critical role for the CB(2) receptor in regulating these disease processes amongst others. As a result, the CB(2) receptor is an appealing therapeutic target as well as a useful tool for shedding new light on physiological regulatory processes throughout the body. PMID- 20166928 TI - Novel natural and synthetic ligands of the endocannabinoid system. AB - In this review we describe recent advances in the chemistry of novel CB(1)/CB(2) agonists, CB(1) antagonists, selective CB(2) agonists, fatty acid amide hydrolase inibitors, monoglyceride (MGL) and diglyceride (DAGL) inhibitors and cannabinoid type agonists and antagonists of non CB(1)/CB(2) receptors. In view of recent interest in the activities of fatty acid amides of amino acids (N-acyl amino acids) a list of this type of compounds was compiled and is presented as a Table. We conclude that further synthetic work based on both the plant cannabinoids and on the endocannabinoids may lead to novel therapeutics and that the identification and the elucidation of the biological profile of the myriad of endogenous N-acyl amino acids and related compounds may enhance the already wide spectrum of lipidomics. PMID- 20166927 TI - Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists. AB - It is widely accepted that non-endogenous compounds that target CB(1) and/or CB(2) receptors possess therapeutic potential for the clinical management of an ever growing number of disorders. Just a few of these disorders are already treated with Delta(9)-tetrahydrocannabinol or nabilone, both CB(1)/CB(2) receptor agonists, and there is now considerable interest in expanding the clinical applications of such agonists and also in exploiting CB(2)-selective agonists, peripherally restricted CB(1)/CB(2) receptor agonists and CB(1)/CB(2) antagonists and inverse agonists as medicines. Already, numerous cannabinoid receptor ligands have been developed and their interactions with CB(1) and CB(2) receptors well characterized. This review describes what is currently known about the ability of such compounds to bind to, activate, inhibit or block non-CB(1), non- CB(2) G protein-coupled receptors such as GPR55, transmitter gated channels, ion channels and nuclear receptors in an orthosteric or allosteric manner. It begins with a brief description of how each of these ligands interacts with CB(1) and/or CB(2) receptors. PMID- 20166929 TI - Drug design studies of the novel antitumor targets carbonic anhydrase IX and XII. AB - The carbonic anhydrase (CA, EC 4.2.1.1) isozymes IX and XII are predominantly found in tumor cells and show a restricted expression in normal tissues. By efficiently hydrating carbon dioxide to protons and bicarbonate, these CAs contribute significantly to the extracellular acidification of solid tumors. CA IX and XII are overexpressed in many such tumors in response to the hypoxia inducible factor (HIF) pathway, and research on the involvement of these isozymes in cancer has progressed in recent years. The report of the X-ray crystal structure of CA IX, which is a dimeric protein with a quaternary structure not evidenced earlier for this family of enzymes, allows for structure-based drug design campaigns of inhibitors against this novel antitumor target. Indeed, it has been known for some time that aromatic/ heterocyclic sulfonamides and sulfamates have good affinity for this isoform, but generally they do not show specificity for the inhibition of the tumor-associated isoform versus the remaining CA isozymes (CA I-VII, and XII-XV) found in mammals. Recently, we reported several classes of compounds with good selectivity for the tumor associated CAs, being shown that CA IX/XII inhibition reverses the effect of tumor acidification, leading to inhibition of the cancer cells growth. CA IX/XII are now proposed as novel therapeutic antitumor targets. Furthermore, as some types of CA inhibitors (CAIs), such as the fluorescent sulfonamides accumulate only in hypoxic tumor cells overexpressing these enzymes, CAIs may be also used as diagnostic tools for imaging of hypoxic cancer cells. Work from several laboratories recently reported the proof-of-concept studies for the use of CA IX/XII inhibitors as well as antibodies both in the therapy and imaging of hypoxic tumors. PMID- 20166926 TI - CB(1) cannabinoid receptors and their associated proteins. AB - CB1 receptors are G-protein coupled receptors (GPCRs) abundant in neurons, in which they modulate neurotransmission. The CB(1) receptor influence on memory and learning is well recognized, and disease states associated with CB(1) receptors are observed in addiction disorders, motor dysfunction, schizophrenia, and in bipolar, depression, and anxiety disorders. Beyond the brain, CB(1) receptors also function in liver and adipose tissues, vascular as well as cardiac tissue, reproductive tissues and bone. Signal transduction by CB(1) receptors occurs through interaction with Gi/o proteins to inhibit adenylyl cyclase, activate mitogen-activated protein kinases (MAPK), inhibit voltage-gated Ca(2+) channels, activate K(+) currents (K(ir)), and influence Nitric Oxide (NO) signaling. CB(1) receptors are observed in internal organelles as well as plasma membrane. beta Arrestins, adaptor protein AP-3, and G-protein receptor-associated sorting protein 1 (GASP1) modulate cellular trafficking. Cannabinoid Receptor Interacting Protein1a (CRIP1a) is an accessory protein whose function has not been delineated. Factor Associated with Neutral sphingomyelinase (FAN) regulates ceramide signaling. Such diversity in cellular signaling and modulation by interacting proteins suggests that agonists and allosteric modulators could be developed to specifically regulate unique, cell type-specific responses. PMID- 20166930 TI - Progress in COX-2 inhibitors: a journey so far. AB - The non-steroidal anti-inflammatory drugs (NSAIDs) are diverse group of compounds used for the treatment of inflammation, since the introduction of acetylsalicylic acid in 1899. Traditional (first generation) NSAIDs exert antiinflammatory, analgesic, and antipyretic effects through the blockade of prostaglandin synthesis via non-selective inhibition of cyclooxygenase (COX-1 and COX-2) isozymes. Their use is associated with side effects such as gastrointestinal and renal toxicity. A number of selective (second generation) COX-2 inhibitors (rofecoxib, celecoxib, valdecoxib etc.) were developed as safer NSAIDs with improved gastric safety profile. Observation of increased cardiovascular risks in APPROVe (Adenomatous Polyp Prevention on Vioxx) study sent tremors and led to voluntary withdrawn of Vioxx (rofecoxib) by Merck from the market in September 2004 followed by Bextra (valdecoxib) in 2005 raising a question on the safety of selective COX-2 inhibitors. This leads to the belief that these effects are mechanism based and may be class effect. However, some studies suggested association of traditional NSAIDs with similar effects requiring a relook into the whole class of NSAIDs rather than simply victimizing the selective COX-2 inhibitors. Recognition of new avenues for selective COX-2 inhibitors such as cancer, Alzheimer's disease, Parkinson's disease, schizophrenia, major depression, ischemic brain injury and diabetic peripheral nephropathy has kindled the interest in these compounds. This review highlights the various structural classes of selective COX-2 inhibitors developed during past seven years (2003 2009) with special emphasis on diaryl-hetero/carbo-cyclic class of compounds. Molecular modeling aspects are also briefly discussed. PMID- 20166931 TI - In silico prediction of binding sites on proteins. AB - The majority of biological processes involve the association of proteins or binding of other ligands to proteins. The accurate prediction of putative binding sites on the protein surface can be very helpful for rational drug design on target proteins of medical relevance, for predicting the geometry of protein protein as well as protein-ligand complexes and for evaluating the tendency of proteins to aggregate or oligomerize. A variety of computational methods to rapidly predict protein-protein binding interfaces or binding sites for small drug-like molecules have been developed in recent years. The principles of methods available for protein interface and pocket detection are summarized, including approaches based on sequence conservation, as well as geometric and physicochemical surface properties. The performance of several Webaccessible methods for ligand binding site prediction has been compared using protein structures in bound and unbound conformation and homology modeled proteins. All methods tested gave very promising predictions even on unbound and homology modeled protein structures, thus indicating that current methods are robust in relation to modest conformational changes associated with the ligand binding process. PMID- 20166932 TI - Tyrosyl-DNA phosphodiesterase 1 targeting for modulation of camptothecin-based treatment. AB - The targeting of specific DNA repair mechanisms may be a promising strategy to improve the efficacy of antitumor therapy. The cytotoxic effects of the clinically relevant topoisomerase 1 (Top1) poison camptothecins are related to the generation of DNA lesions and tumor cells may be resistant to DNA damaging agents due to increased repair. Tyrosyl- DNA phosphodiesterase 1 (TDP1) is implicated in the repair of strand breaks by removing abortive Top1/DNA complexes. Thus, a role for TDP1 in counteracting DNA damage induced by camptothecins has been proposed. Here, we review the role of TDP1 in DNA repair with particular reference to TDP1 function, its cooperation with other pathways and the development of pharmacological inhibitors. PMID- 20166933 TI - Recent advances in anti-survivin treatments for cancer. AB - Apoptosis occurs via extrinsic or intrinsic signalling each triggered and regulated by many different molecular pathways. In recent years, the selective induction of apoptosis through survivin in tumour cells has been increasingly recognized as a promising approach for cancer therapy. Survivin has multiple functions including cytoprotection, inhibition of cell death, and cell-cycle regulation, especially at the mitotic process stage, all of which favour cancer survival. Many studies on clinical specimens have shown that survivin over expression is invariably up regulated in human cancers, associated with resistance to chemotherapy or radiation therapy, and linked to poor prognosis, suggesting that cancer cells survive with survivin. On the basis of these findings, survivin has been proposed as an attractive target for new anticancer interventions. Survivin inhibitors recently entered clinical trials. Recent studies suggest a possible role for survivin in regulating the function of normal adult cells. However, the expression and function of survivin in normal tissues are still not well characterized and understood. Still better understandings of survivin's role in tumour versus normal cells are needed for designing the strategies to selectively disrupt survivin in cancers. In the present review, we summarise the importance of recent survivin-targeted cancer therapy for future clinical application. PMID- 20166934 TI - Trypanosomatid parasites causing neglected diseases. AB - Parasitic diseases such as Kala azar (visceral leishmaniasis), Chagas disease human (American trypanosomiasis) and African sleeping sickness (African trypanosomiasis) are affecting more than 27 million people worldwide. They are categorized amongst the most important neglected diseases causing approximately 150,000 deaths annually. As no vaccination is available, treatment is solely dependent on chemotherapeutic drugs. This review provides a comprehensive insight into the treatment of Kala azar, Chagas disease and African sleeping sickness. In addition to established drugs, novel small molecule- based therapeutic approaches are discussed. Drugs currently used for the treatment of Kala azar include pentavalent antimonials, Amphotericin B, Miltefosine, and Paromomycin. Liposomal formulations such as AmBisome provide promising alternatives. Furthermore, antiproliferative compounds might open new avenues in Kala azar treatment. Regarding Chagas disease, chemotherapy is based on two drugs, Nifurtimox and Benznidazole. However, sequencing of T. cruzi genome in the year 2005 raises a hope for new drug targets. Proteases, sterols and sialic acids are potential promising drug targets. Suramin, Pentamidine, Melarsporol and Eflornithine are well-established drugs to treat African sleeping sickness. New treatment options include combination therapy of Eflornithine and Nifurtimox, a Chagas disease therapeutic.. However, all approved chemotherapeutic compounds for trypanosomatid diseases suffer from high toxicity. Further, increasing resistance limits their efficacy and compliance. PMID- 20166935 TI - Potential and perspectives of cyclonucleosides. AB - Cyclonucleosides are defined as analogs of natural nucleosides with an additional covalent bond between the nucleobase and the sugar moiety. They differ from classical nucleosides in more rigid structure and fixed conformation, which are responsible for unique properties and further applications. For instance, rigid structure can determine better interaction of the molecule with the acceptor, which is important in the design new bioactive of compounds. This class of nucleosides is known from the early fifties, when Todd et al. obtained cyclic salts of nucleosides. Although the formation of cyclic salts by purine nucleosides is quite common, the variety of cyclonucleosides is not only limited to this group. Up to now, various miscellaneous purine and pyrimidine cyclonucleosides and their analogs with great structural diversity were obtained; they differ from each other in position, length and type of linkage. Purine cyclonucleosides form a large group of artificially obtained derivatives. However, recently turned out cyclonucleosides also exist in nature. In fact, cyclopurine N(3),5-cycloxanthine was isolated from a marine sponge of genus Eryus sp. The aim of this review is to give an overview of the synthesis of some cyclonucleosides according to their structural types and to underline their biological activities. The article also refers to other relevant review articles that have covered particular areas of investigation or have dealt in depth with a single compound. PMID- 20166936 TI - Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. The COL4A1 stroke syndrome. AB - Type IV collagens are basement membrane (BM) proteins expressed in all tissues including the vasculature. COL4A1 and COL4A2, the most abundant type IV collagens, form heterotrimers with a 2:1 stoichiometry and each heterotrimer forms a triple helix along the length of the collagenous domains. Recently, mutations in COL4A1 on chromosome 13q34, encoding the alpha1 chain of type IV collagen, have been linked to a spectrum of cerebral small-vessel disease in humans, including perinatal intracerebral hemorrhage (ICH) with consequent porencephaly, adult-onset ICH, microbleeds, lacunar strokes, and leukoaraiosis, which follows an autosomal dominant pattern of inheritance. This variable phenotype has been named the "COL4A1 stroke syndrome". In COL4A1 stroke syndrome most mutations are missense mutations involving a glycine residue, including G562E, G749S, G805R, G1130D, G1236R, G1423R, G720D, G1580R, and G755R. Mutations replacing a highly conserved hydrophobic glycine residue likely lead to synthesis of an abnormal protein with abnormal structure and inhibit heterotrimer secretion into the vascular BM, modify its structural properties (when imaged with electron microscopy BM is uneven, with inconsistent density and focal disruptions), and, thus, increase the fragility of the vessel wall when exposed to environmental factors. Although pathological changes in BM also occur in other tissues (mostly retina and kidney), the major site of vessel damage is the brain. In the present review article we will focus on the molecular basis of the COL4A1 stroke syndrome, summarize data on its variable phenotype, and explore additional questions concerning the possible genotype-phenotype correlations and the mechanisms leading to cerebral small-vessel disease in this clinically heterogeneous condition. PMID- 20166937 TI - New opportunities to treat the T315I-Bcr-Abl mutant in chronic myeloid leukaemia: tyrosine kinase inhibitors and molecules that act by alternative mechanisms. AB - Resistance to the Bcr-Abl inhibitors approved for the treatment of chronic myeloid leukaemia (CML) may arise from different mechanisms, including Bcr-Abl amino acid mutations, gene amplification and mechanisms independent of Bcr-Abl. The T315I mutation at the gatekeeper residue is very frequent in advanced phases of the disease and is one of the main causes of resistance, disrupting important contact points between the inhibitors and the enzyme. Different strategies have been implemented to overcome this resistance, including the synthesis of new Bcr Abl ATPcompetitive or non-ATP-competitive inhibitors, dual Aurora/Bcr-Abl inhibitors and multi-targeted kinase inhibitors. An alternative approach is the use of other compounds that do not bind directly to the Bcr-Abl protein; instead, these molecules act on several downstream pathways, regulated by or linked in different ways to Bcr-Abl, that lead to the malignant transformation of the cells. For this reason, farnesyl transferase inhibitors, MAPK inhibitors, Rac guanosine triphosphatase inhibitors, PI3K inhibitors, JAK inhibitors, Hsp90 inhibitors, mTOR inhibitors, PP2A activators and apoptosis inducers have been tested, alone or in combination with ATP-competitive inhibitors, against CML cell lines. This review discusses compounds that act on Bcr-Abl or different cell pathways and reports on the molecules active against the T315I mutation, particularly the most recent findings in this field. New molecules that are claimed by recent patents to be active on this mutation are also reported. When possible, the review will focus on medicinal chemistry in terms of chemical structure, mechanism of action and structure-activity relationships. PMID- 20166938 TI - Coumarins: old compounds with novel promising therapeutic perspectives. AB - Natural as well as synthetic coumarins have recently drawn much attention due to its broad pharmacological activities. Many coumarins and their derivatives exert anti-coagulant, anti-tumor, anti-viral, anti-inflammatory and anti-oxidant effects, as well as anti-microbial and enzyme inhibition properties. The recognition of key structural features within coumarin family is crucial for the design and development of new analogues with improved activity and for the characterization of their mechanism of action and potential side effects. The different substituents in the coumarin nucleus strongly influence the biological activity of the resulting derivatives. Although some coumarins have been already characterized to evoke a particular biological activity, the challenge would be the design and synthesis of new derivatives with high specific activity for other pharmacological targets and define their mechanism of action to achieve new therapeutic drugs. The present review highlights the current progress in the development of coumarin scaffolds for drug discovery as novel anti-cancer agents. The major challenges about coumarins include the translation of current knowledge into new potential lead compounds and the repositioning of known compounds for the treatment of cancer. PMID- 20166939 TI - Reversing aberrant methylation patterns in cancer. AB - Changes to the epigenetic information within a cell play a significant role in cancer development and progression. These epigenetic changes are important in establishing the aberrant gene expression patterns that are a feature of cancer cell biology. We are currently experiencing a rapid advance in our understanding of how epigenetic information is written and interpreted in the cell, and the enzymes involved in these processes have been recognised as prime targets for therapeutic intervention. Reagents that target these enzymes have the potential to inhibit or reverse epigenetic changes in cancer cells. Evidence suggests that the aberrant regulation of two gene silencing pathways; involving DNA methylation and histone methylation, play an important role in cancer development. Considerable effort is being exerted in the development of inhibitors of these pathways. However, complex functional interactions exist between the DNA and histone methylation pathways, and these interactions will need to be considered in the design of inhibitory molecules. This review details current research into agents developed as inhibitors of these epigenetic pathways, focusing on the types of epigenetic modifications being targeted, interactions between these modifications and the use of these inhibitory agents in cancer treatment. PMID- 20166941 TI - Targeting alphavbeta3 integrin: design and applications of mono- and multifunctional RGD-based peptides and semipeptides. AB - The outstanding physio-pathological role played by integrin receptors in living subjects motivates the enormous interest shown by scientists worldwide for this topic. More than twenty years of research has spanned across the structural and functional elucidation of these proteins and over their antagonism-based biomedical applications. The proof-of concept stage, aimed at identifying potent inhibitors, covered a decade of studies, and paved the way for a more advanced era of research where these antagonist molecules were thrown into the deep end of applicative studies. This review intends to summarize the major efforts conducted thus far and focuses on the design, synthesis and biomedical applications of cyclic RGD-containing alpha(v)beta(3) integrin antagonists, in both their small and macromolecular formats. In particular, Chapters 1 and 2 offer a comprehensive outlook on the rational basis for the design of integrin inhibitors, Chapter 3 chronicles the biological and medical applications of monofunctional RGD integrin ligands both in their monomeric and multimeric asset, and Chapter 4 illustrates the potential of RGD-based multifunctional systems in molecular medicine. PMID- 20166940 TI - Primate-accelerated evolutionary genes: novel routes to drug discovery in psychiatric disorders. AB - Novel molecular genetic approaches, at genome-scale in different species allowed characterizing genes that have undergone recent selection. The interest in this research field is not limited to the natural curiosity about our evolutionary past, but it is also to identify novel susceptibility genes for neuropsychiatic disorders by pointing specific human traits, such as behavioral and cognitive abilities. Hypotheses have been proposed to relate specific psychiatric disorders to the origin of modern humans, as evidenced by the theory of Crow about schizophrenia. In the present review, we will focus on genes that underwent positive selection in humans or displayed a human specific evolutionary pattern and which were reported as associated with psychiatric disorders. This will include the (1) DRD4 gene associated with attentiondeficit/ hyperactivity disorder, located in a locus that underwent a positive selection; the (2) GABRB2 gene, a gene associated with schizophrenia and recently reported as the target of a positive selection; (3) MARK1, a candidate gene for autism that was reported as displaying a signature of adaptative evolution in the human lineage, and (4) the ADH and ALDH2 genes which are associated with alcoholism, and for which evidence of positive selection was identified in the human lineage since the divergence between humans and chimpanzees. Identification of novel candidate genes based on recent evolution selection, coupled to genome-wide strategies designed to detect rare structural variants, could lead to a better knowledge of the molecular mechanisms of neurodevelopmental disorders and might therefore help to develop new medical chemistry. PMID- 20166942 TI - Exploration of structure-activity relationships for dual serotonin transporter reuptake inhibitors-histamine H3 receptor antagonists. AB - Depression is a major health issue, which is routinely treated with selective serotonin reuptake inhibitors. However, although these agents display a favorable effect on mood, they often fail to improve conditions that accompany depression including cognitive impairment and fatigue. In pre-clinical studies histamine H(3) receptor antagonists have demonstrated both pro-cognitive and wake-promoting effects suggesting that the combination of a histamine H(3) receptor antagonist and a serotonin reuptake inhibitor may have utility as an antidepressant therapy. To this end we sought to introduce histamine H(3) receptor antagonist activity into both known selective serotonin reuptake inhibitors and novel templates. These efforts have afforded several series of compounds with the desired activities. Selected examples demonstrated in vivo efficacy both in pre-clinical models of depression and wakefulness. PMID- 20166943 TI - Review of 5-HT4R ligands: state of art and clinical applications. AB - This article reviews the medicinal implications of 5-HT(4)R in the peripheral and central nervous systems, based on data from two hundred bibliographic references. An exhaustive compilation of molecules reported to be antagonists or agonists for 5-HT(4)R is presented, including chemical structures, binding properties and pharmacological profiles. In the last part of the review, some key concepts concerning structure-activity relationships are highlighted. PMID- 20166944 TI - Emerging opportunities and concerns for drug discovery at serotonin 5-HT2B receptors. AB - 5-HT(2B) receptors have been reported to play an important role at cardiac, intestinal and central levels, as well as in bone marrow formation and growth. In the last decade, 5-HT(2B) receptors have also gained much attention as new targets in therapeutics, but also as off-targets because their activation along with the inhibition of serotonin transporters plays a significant role in the pathogenesis of 5-HT induced valvulopathy. Taking this into account, the present review focuses on the new therapeutic applications of 5-HT(2B) receptor ligands as well as on the potential concerns. PMID- 20166946 TI - Medicinal chemistry of 5-HT5A receptor ligands: a receptor subtype with unique therapeutical potential. AB - Although the 5-HT(5) receptor subfamily was discovered more than 15 years ago, it is unambiguously the least known 5-HT receptor subtype. The G(i)/G(0)-mediated signal transduction and its intensive presence in raphe and other brainstem and pons nuclei suggest mechanisms similar to those of 5-HT(1) receptors, the ligands of which are already applied in the treatment of e.g. anxiety and migraine. In addition, a unique coupling and inhibition of adenosine diphosphate-ribosyl cyclase have also been described. High concentrations of 5-HT(5) receptor in other key regions including, e.g. locus coeruleus, nucleus of the solitary tract, arcuate and suprachiasmatic nuclei of the hypothalamus indicate a wide range of physiological effects, thus its ligands are potential drug candidates in various areas, e.g. anxiety, sleep, incontinence, food intake, learning and memory, pain or chemoreception pathways. These findings have motivated several institutes and pharmaceutical companies to participate in the research of this field. Despite extensive research, no selective agonist and only two selective antagonists have been identified until now. Beyond these compounds, the present review provides a complete overview on all other published 5-HT(5A) receptor ligands as well as on the structure, function, distribution, genetics and possible therapeutic applications of this receptor. PMID- 20166945 TI - The medicinal chemistry of 5-HT6 receptor ligands with a focus on arylsulfonyltryptamine analogs. AB - Arylsulfonyl analogs of aminopyrimidines (e.g. Ro 04-6790; 2), aminopyridines (e.g. Ro 63-0563; 3), 1-phenylpiperazines (e.g. SB-271046; 4), and tryptamines (e.g. MS-245; 5) were described as the first examples of selective 5-HT(6) receptor antagonists only ten years ago. Today, hundreds of compounds of seemingly diverse structure have been reported. The early antagonists featured an arylsulfonyl group leading to the wide notspread assumption that an arylsulfonyl moiety might be critical for binding and antagonist action. With respect to the arylsulfonyltryptamines, it seems that neither the "arylsulfonyl" nor the "tryptamine" portion of these compounds is essential for binding or for antagonist action, and some such derivatives even display agonist action. The present review describes many of the currently available 5-HT(6) receptor ligands and, unlike prior reviews, provides a narrative of the thinking (where possible) that led to their design, synthesis, and evaluation. The arylsulfonyltryptamines are also used as the structural basis of attempts to relate various structure types to one another to afford a better understanding of the overall structural requirements for 5-HT(6) receptor binding. PMID- 20166947 TI - Recent advances in the discovery of selective and non-selective 5-HT(1D) receptor ligands. AB - This article highlights recent advances in the discovery of new agonists, antagonists and partial agonists of the 5-HT(1D) receptor. The field of 5-HT(1D) agonists continues to deliver a number of new potential therapeutic agents, although advances in this field are now more focussed on the clinical evaluation phase. The identification of novel compounds is greater for the 5-HT(1D) receptor antagonists, and whilst few truly selective ligands have been identified, a number of approaches are discussed towards defined mixed-pharmacology profiles. An overview is also given of recent advances in biological and clinical understanding of the receptor. PMID- 20166948 TI - The interactions of the 5-HT3 receptor with quipazine-like arylpiperazine ligands: the journey track at the end of the first decade of the third millennium. AB - The 5-HT(3) receptor (5-HT(3)R) occupies a special place among the serotonin receptor subtypes because it has been shown to be a ligand-gated ion channel, which is involved in a number of physiological functions and important pathologies. 5-HT(3)R antagonists have shown an outstanding efficacy in the control of the emesis induced by anticancer chemotherapy and few adverse side effects, so as to revolutionize the treatment of nausea in cancer patients. This review covers the authors' work performed during the past decade in the development of 5-HT(3)R ligands belonging to the class of arylpiperazine derivatives related to quipazine (quipazine-like arylpiperazines, QLAs) and represents the extension of the review previously published in Current Topics in Medicinal Chemistry in 2002. The discussion is focused mainly on the most significant structure-affinity relationships emerged in the progress of the work and shows how the original ideas have evolved in the recent years. PMID- 20166949 TI - Enzyme kinetics and hit validation in fluorimetric protease assays. AB - Fluorimetric assays are convenient and efficient to determine the inhibitory potency of enzyme inhibitors. Since enzyme activity can be blocked in a number of ways, it is important to determine the exact mode of inhibition. The first part of the review deals with kinetic methods to distinguish among the different modes of inhibition. In addition to that, pitfalls are discussed that can be encountered if the mode of inhibition was not thoroughly investigated. The second part of the review deals with some basic techniques of hit validation. Specifically, three error sources that may result in misleadingly strong inhibitors are scrutinized and exemplified for two different typical protease assays (cathepsin B, chymotrypsin). The studied error sources are attenuation of the fluorescence signal, aggregation of the analysed molecules, and irreversible binding of the inhibitor to the enzyme. A simple experimental protocol to detect the aforementioned problems is proposed. PMID- 20166950 TI - Proteases of Plasmodium falciparum as potential drug targets and inhibitors thereof. AB - Malaria, caused by protozoa of the genus Plasmodium, remains one of the most dreadful infectious diseases worldwide killing more than 1 million people per year. The emergence of multidrug-resistant parasites highly demands a steadfast and continuous search not only for new targets but also for new anti-infectives addressing the known ones. As proteases in general have been proven to be excellent drug targets and the development of inhibitors has frequently resulted in approved drugs, this review will only focus on the proteases of Plasmodium falciparum as drug targets. The completion of the sequencing of the Plasmodium falciparum genome in 2002 lead to the discovery of nearly 100 putative proteases encoded therein. Within this review, only those proteases and inhibitors thereof will be discussed in more detail, in which their biological function has been determined undoubtedly or in those cases, in which the development of specific inhibitors has significantly contributed to the understanding of the underlying biological role of the respective protease thus validating the role as promising drug target. PMID- 20166951 TI - Recent advances in targeting viral proteases for the discovery of novel antivirals. AB - The occurrence of life-threatening viral infections and the establishment of appropriate defense strategies exhibit major challenges to the disease management in our society. The unpredictable character of viral outbreaks will even be enhanced in the future due to human activities such as increasing international travel, deforestation, changes in social conditions, or influences induced by the climate change. The defense against these pathogenic agents requires preparedness, including successful drug design strategies. Viral proteases represent attractive targets for the design of anti-infective lead compounds, as in case that a viral mRNA encoding several types of proteins is recognized as a monocistronic template by the host-cell translation machinery, the presence of protease activities is required for processing the viral polyprotein precursor into structural or non-structural components essential for the formation of new virion particles. In addition, viral proteases can be involved in further processes relevant for viral replication. Numerous efforts have been made to develop potent small-molecule inhibitors of viral proteases, however, until now only a limited number reached the market. In the present contribution, functional aspects of the target proteases, their structural properties, drug design strategies, resulting inhibitors, and resistance management are reviewed and discussed by means of the four essential representative cases of HIV, HCV, SARS coronavirus, and the flaviviruses Dengue and West Nile virus. PMID- 20166952 TI - Development of nitrile-based peptidic inhibitors of cysteine cathepsins. AB - It is now becoming clear that several papain-like cysteine cathepsins are involved in the pathophysiology of diseases such as osteoporosis, autoimmune disorders, and cancer. Therefore, the development of potent and selective cathepsin inhibitors is an attractive subject for medicinal chemists. New advances have been made for nitrile-based inhibitors, leading to the identification of the cathepsin K inhibitor odanacatib and other candidates with potential for therapeutic use. This review summarizes the development of peptidic and peptidomimetic compounds with an electrophilic nitrile 'warhead' as inhibitors of the cysteine cathepsins B, S, L, C, and K. Peptide nitriles have been shown to reversibly react with the active site cysteine under formation of a covalent thioimidate adduct. The structural optimization with respect to the positions P3, P2, P1, P1', and P2' resulted in the identification of potent and selective inhibitors of the corresponding cathepsins. The underlying structure activity relationships are discussed herein. PMID- 20166953 TI - Calpains: attractive targets for the development of synthetic inhibitors. AB - The physiological roles of calpains are discussed, as are the associated pathological disorders that result from their over-activation. We also present practical information for establishing functional inhibition assays and an overview of X-ray crystal structures of calpain-inhibitor complexes to aid inhibitor design. These structures reveal the expected extended beta-strand conformation for the inhibitor backbone, a geometry that has been engineered into inhibitors with the introduction of either an N-terminal heterocycle or a macrocycle that links the P(1) and P(3) residues. The structure and function of all the main classes of inhibitors are reviewed, with most examples being classified according to the nature of the C-terminal reactive warhead group that reacts with the active site cysteine of calpains. These inhibitor classes include epoxysuccinate derivatives, aldehydes, aldehyde prodrugs (hemiacetals) and alpha keto carbonyl compounds. Inhibitors derived from the endogenous inhibitor calpastatin and examples lacking a warhead, are now known and these are also discussed. PMID- 20166954 TI - Entering the era of non-basic p1 site groups: discovery of Xarelto (Rivaroxaban). AB - Several clinical candidates have now emerged as a result of an intense search for orally available, antithrombotic factor Xa inhibitors. This review highlights the discovery of XareltoTM (Rivaroxaban) starting from an initial tetrahydrophthalimide screening hit. The major breakthrough was the finding that a chlorothiophene moiety can undergo an interaction in the S1 binding site thus leading to high potency combined with favorable oral bioavailability. The binding mode of this P1 moiety is discussed, and further non-basic S1 binders of this new type are reviewed. PMID- 20166955 TI - Proteasome inhibitors: recent advances and new perspectives in medicinal chemistry. AB - The search for proteasome inhibitors began fifteen years ago. These inhibitors proved to be powerful tools for investigating many important cellular processes regulated by the ubiquitin-proteasome pathway. Targeting the proteasome pathway can also lead to new treatments for disorders like cancer, muscular dystrophies, inflammation and immune diseases. This is already true for cancer; the FDA approved bortezomib, a potent proteasome inhibitor, for treating multiple myeloma in 2003, and mantle cell lymphoma in 2006. The chemical structures identified in some of the early proteasome inhibitors have led to the development of new anti cancer drugs (CEP-18770, Carfilzomib, NPI-0052). All these molecules are covalent bonding inhibitors that react with the catalytic Thr1-O(gamma) of the three types of active site. This review covers recent developments in medicinal chemistry of natural and synthetic proteasome inhibitors. Advances in non-covalent inhibitors that have no reactive group will be highlighted as they should minimize side effects. New structures and new modes of action have been recently identified that open the door to new drug candidates for treating a range of diseases. PMID- 20166956 TI - Recent progress in the discovery of non-sarcosine based GlyT1 inhibitors. AB - The simple amino acid glycine is implicated in both inhibitory and excitatory neurotransmission in mammalian central nervous system, and it modulates excitatory neurotransmission through its role as a necessary co-agonist for glutamatergic N-methyl-D-aspartate (NMDA) receptors. Given the involvement of NMDA receptor-mediated neurotransmission in complex cerebral processes such as cognition, pharmacological manipulation of extracellular synaptic glycine biology is an active area of pharmaceutical research to develop novel treatments for neuropsychiatric disorders. A key component of cerebral glycine metabolism is the glycine transporter type 1 (GlyT1) and elevation of extracellular synaptic glycine concentration by blockade of GlyT1 has been hypothesized to potentiate NMDA receptor function in vivo and to represent a rational approach for the treatment of schizophrenia and cognitive disorders. The present article will review the wealth of scientific evidence supporting that hypothesis and the medicinal chemistry effort by many pharmaceutical companies and academic institutions to develop potent and selective GlyT1 inhibitors. PMID- 20166957 TI - Phosphodiesterase inhibitors as potential cognition enhancing agents. AB - As might be predicted for an organ designed for cell to cell communication, cyclic nucleotide signaling in the brain is highly organized and regulated. Augmentation of cyclic nucleotide signaling by means of phosphodiesterase inhibition appears to be a viable and tractable means of enhancing neuronal communication. Of the various CNS disorders that have been considered as target indications for phosphodiesterase inhibitors, no condition has received more attention than cognitive dysfunction. This review provides a background for understanding the expanding literature in this field as well as a brief update on the rationale driving the search for selective inhibitors of targets such as PDE1B, PDE2, PDE5 and PDE9. PMID- 20166958 TI - 5-HT6 receptor antagonists as potential therapeutics for cognitive impairment. AB - Cognitive impairment (CI) has been recognized as a core feature of Alzheimer's disease (AD) and schizophrenia. The 5-HT(6) receptor is an attractive target for the development of cognitive enhancers due to its unique localization and pharmacology. 5-HT(6) receptor antagonists have been shown to modulate multiple neurotransmitter systems and therefore enhance cognition in preclinical studies. This premise translated into the clinical efficacy of the 5-HT(6) receptor antagonist SB-742457 in mild-to-moderate AD patients. Advances in the understanding of the structure-activity-relationship, the design of novel 5-HT(6) receptor ligands and their potential application for the treatment of CI are reviewed. PMID- 20166959 TI - Neuronal nicotinic acetylcholine receptors - targets for the development of drugs to treat cognitive impairment associated with schizophrenia and Alzheimer's disease. AB - Nicotinic acetylcholine receptors (nAChR) have been strongly implicated as therapeutic targets for treating cognitive deficits in disorders such as schizophrenia and Alzheimer's disease (AD). In particular alpha7 and alpha4beta2 subtype-selective nAChR agonists and partial agonists have been developed as potential candidates for the treatment of schizophrenia, cognitive disorders (including Alzheimer's disease), and inflammation. Further development of positive allosteric modulators and antagonists were also recently reported in the literature. In this review we will cover recent developments focused on the above mentioned nAChR subtypes, starting from the most advanced clinical candidate followed by an overview of literature compounds where potency, selectivity, central nervous system access, pharmacological activity and pharmacokinetic properties are disclosed. PMID- 20166960 TI - Histamine H3 antagonists for treatment of cognitive deficits in CNS diseases. AB - The H(3) histamine receptor is expressed in many brain regions, including those involved in sleep/wake regulation and cognitive functions. Inhibition of the H(3) receptor leads to increased release of multiple neurotransmitters in these regions, making this receptor an ideal target for the potential enhancement of arousal and/or cognitive processes. The high interest level by several pharmaceutical companies in H(3) receptors as potential drug targets has produced rapid advancement in novel compound series with different properties, providing a variety of preclinical tools as well as advancing several candidates into clinical trials. Multiple chemotypes have demonstrated efficacy in preclinical models covering a range of cognitive deficits, suggesting the potential value of H(3) antagonists as cognition enhancers in a variety of disease states. These studies have revealed the actions of this class of compounds at the cellular, neuronal systems and behavioral levels. Recently, compounds with improved selectivity, pharmacokinetics and preclinical safety profiles have advanced into clinical trials for a number of potential indications. The results of these clinical trials are eagerly awaited and will increase our understanding of the properties of H(3) receptor antagonists that will provide therapeutic value. PMID- 20166961 TI - Heat shock proteins: therapeutic drug targets for chronic neurodegeneration? AB - Intra- and extracellular protein misfolding and aggregation is likely to contribute to a number of age-related central nervous system diseases ("proteinopathies"). Therefore, molecular chaperones, such as heat shock proteins (HSPs), that regulate protein folding, misfolding and adaption to cellular stress are emerging as therapeutic targets. Here we review the current knowledge of HSP modulating drugs and discuss the opportunities and difficulties of their therapeutic use to treat proteinopathies such as Alzheimer's- and Parkinson's disease, the polyglutamine- and prion disorders and Amyotrophic Lateral Sclerosis. PMID- 20166962 TI - Induction of molecular chaperones as a therapeutic strategy for the polyglutamine diseases. AB - Protein misfolding and aggregation in the brain have been implicated as a common molecular pathogenesis of various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and the polyglutamine (polyQ) diseases. The polyQ diseases are a group of nine hereditary neurodegenerative diseases, including Huntington's disease (HD) and various types of spinocerebellar ataxia (SCA), which are caused by abnormal expansions of the polyQ stretch (> 35-40 repeats) in unrelated disease-causative proteins. The expanded polyQ stretch is thought to trigger misfolding of these proteins, leading to their aggregation and accumulation as inclusion bodies in affected neurons, eventually resulting in neurodegeneration. Misfolding and aggregation of the polyQ protein are the most ideal therapeutic targets since they are the most upstream events in the pathogenic cascade, and therefore, therapeutic approaches using molecular chaperones, which prevent protein misfolding and assist the refolding of misfolded proteins, are being extensively investigated. Indeed, a variety of molecular chaperones such as Hsp70 and Hsp40 have been demonstrated to exert therapeutic effects against various experimental models of the polyQ diseases. Furthermore, toward developing pharmacological therapies, small chemical activators of heat shock transcription factor 1 (HSF1) such as geldanamycin and its derivative 17-AAG, which induce multiple endogenous molecular chaperones, have been proven to be effective not only in polyQ disease models, but also in other neurodegenerative disease models. We hope that brain permeable molecular chaperone inducers will be developed as drugs against a wide range of neurodegenerative diseases in the near future. PMID- 20166963 TI - Collective roles of molecular chaperones in protein degradation pathways associated with neurodegenerative diseases. AB - The homeostasis of the protein synthesis and degradation is crucial for cell survival. Most age-related neurodegenerative diseases are characterized by accumulation of aberrant protein aggregates in affected brain regions. The principal routes of intracellular protein metabolism are the ubiquitin proteasome system (UPS) and the autophagy-lysosome pathway (ALP). They collaborate to degrade wasted proteins and interact each other to cope with the pathological conditions, in which molecular chaperones play collective roles by assisting the protein targeting to the proteasome or autophagy. It is known that intracellular protein degradation functions are decreased with aging in many tissues and organs. Failure to perform their functions could underlie the inability of cells to adapt to stress conditions, lead to accelerated course of misfolding protein deposit and the inclusion body formation, and eventually result in neurodegeneration.One of the functions of the molecular chaperones is to help the new synthesized or the misfolding toxic proteins fold to their native and nontoxic formation, as our common conception. In this review, we analyze the recent perceptions and findings of molecular chaperones biology in the two degradation pathways and their pathological attribution in several neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and others. It is worthy noticing that some of the HSPs can not only block the protein aggregation in the early stages, but also have promising effect on attenuating the formation of fibrils. Further more, when the degradation pathways are too weak to degrade all the toxic soluble proteins, molecular chaperones can also help to sequenstrate the toxic proteins into inclusion bodies. However, whether it is good or bad is still unclear. Therefore, the study of HSPs might shed new light on not only the mechanisms of protein synthesis and degradation, but also the possible therapeutic targets of fibril formation associating diseases. PMID- 20166964 TI - Heat shock proteins and ion channels. Functional interactions and therapeutic consequences. AB - Screening for protein interaction partners of ion channels helps to elucidate signaling cascades to cellular targets and processes for a better understanding of the origin of diseases. Most important are the cytosolic segments of membrane bound voltage- and ligand-gated ion channels or from ion channel regulators, which may connect to specific signaling complexes. So far, not much is known about those interactions. Molecular chaperones are proteins, which support the biosynthesis of proteins during maturation without being part of the final protein complex or which support the degradation of targeted proteins within the cellular protein quality control. PMID- 20166965 TI - Cell-penetrating peptide technology to deliver chaperones and associated factors in diseases and basic research. AB - Cell-penetrating peptides (CPP), also called protein transduction domains (PTD), membrane-permeable peptides (MPP), or Trojan horse peptides, have been used in many different research areas. The delivery of heat shock proteins (Hsp) using CPP has been applied in models for apoptosis, necrosis, oxidative stress, neurodegenerative diseases, stroke, cystic fibrosis, smooth muscle relaxation, myocardial injury, scar formation, and others. This review summarizes the accomplishments of the field over the last years and discusses why Hsp are particularly suitable for CPP-mediated delivery. PMID- 20166966 TI - Small heat shock proteins and protein-misfolding diseases. AB - Small heat shock proteins (sHsps) are molecular chaperones ubiquitously distributed in numerous species, from bacteria to humans. A conserved C-terminal "alpha-crystallin" domain organized in a beta-sheet sandwich and oligomeric structure are common features of sHsps. sHsps protect cells against many kinds of stresses including heat shock, oxidative and osmotic stress. sHsps recognize unfolded proteins, prevent their irreversible aggregation and facilitate refolding of bound substrates in cooperation with ATP-dependent molecular chaperones (Hsp70/Hsp40). Mammalian sHsps (HSPBs) are multifunctional proteins involved in many cellular processes including those which are not directly related to protein folding and aggregation. HSPBs participate in cell development and cancerogenesis, regulate apoptosis and control cytoskeletal architecture. Recent data revealed that HSPBs also play an important role in membrane stabilization. Mutation in HSPB genes have been identified, which are responsible for the development of cataract, desmin related myopathy and neuropathies. HSPBs are often found as components of protein aggregates associated with protein misfolding disorders, such as Parkinson's, Alzheimer's, Alexander's and prion diseases. It is supposed that the presence of HSPBs in intra- or extracellular protein deposits is a consequence of the chaperone activity of HSPBs, however more studies are needed to reveal the exact function of HSPBs during the formation (or removal) of disease-related aggregates. PMID- 20166967 TI - The heat shock connection of metabolic stress and dietary restriction. AB - Molecular chaperones and the heat shock response guard and modulate protein conformation, protect proteins from misfolding and aggregation, and maintain signalling and organellar networks. Overnutrition and the metabolic syndrome represent a pro-aging condition, and dietary restriction is the most robust environmental intervention that induces longevity from yeast to mammals. In recent years a considerable effort has been made to elucidate the signaling pathways involved in metabolic signaling. Here we review the current understanding on the connection between metabolic stress, dietary restriction and the heat shock response and highlight results showing chaperone induction as a promising therapeutic strategy to promote healthy aging and to prevent metabolic disorders. PMID- 20166968 TI - Influenza and stroke risk: a key target not to be missed? AB - There is increasing evidence that acute bacterial and viral infection represent trigger factors that temporarily elevate the risk of ischemic stroke. During and after influenza epidemics vascular death rates and hospitalizations for stroke are increased. Influenza vaccination is an effective measure to reduce hospitalization and mortality in the elderly and work incapacity in adults of working age. Results of several observational studies support the hypothesis that influenza vaccination is associated with reduced odds of stroke. As randomized studies are lacking, a causal role of influenza vaccination in stroke prevention is not proven, however. According to current guidelines in many countries, that recommend the vaccination in all patients with chronic vascular disease, all patients with a history of stroke or TIA should receive an influenza vaccination annually. Furthermore, patients with diabetes mellitus or with a combination of risk factors that increase stroke risk should obtain the vaccination. In addition, there is evidence from observational data that the neuraminidase inhibitor oseltamivir reduces the risk of stroke within 6 months after influenza infection. PMID- 20166969 TI - Current and emerging treatments for acute stroke: relationships with infection. AB - Infection is the commonest complication of stroke and has a major impact on morbidity and mortality. The relationships between susceptibility to infection after stroke and the influence of infection on stroke outcome are complex, but have considerable clinical relevance. Both pharmacological and non pharmacological interventions in acute stroke may affect the risk of developing infection by influencing potentially modifiable risk factors, for example exposure to infectious organisms (dysphagia/aspiration), or immune susceptibility to infectious challenge. Treatment of infection itself may also reduce ischaemic injury, and influence outcome following stroke. In this review we discuss the role of current and emerging treatments for stroke and their effects on infection, considering possible underlying mechanisms and implications for the development of new therapies. PMID- 20166971 TI - Models of infection before and after stroke: investigating new targets. AB - Infectious diseases are the most common medical complication after cerebral ischemia, inpairing both the neurological and the general medical outcome. The most frequent infectious complications are bacterial pneumonia and urinary tract infections. There is a growing body of evidence that a secondary immunosuppressive state accounts for the increased risk of infection following stroke. Infections do not only have an important impact on outcome after stroke but also are known risk factors for stroke. Thus, suitable models for investigating the relation between infections and stroke are urgently needed. Elucidating the underlying mechanisms might facilitate the development of new therapeutic strategies and improve patient outcome. Here we present recent insights into the relationship between infections and stroke, based on experimental models of post-stroke infection. In addition we give a brief overview of models that explore the impact on stroke of preceding infections. PMID- 20166972 TI - Post-stroke immunodepression and infection: an emerging concept. AB - Infections occur commonly following stroke and adversely influence outcome. Dysphagia, greater stroke severity and increasing age are associated with post stroke infection, but post-stroke immunodepression is now recognised as an independent factor associated with increased susceptibility. Counter-regulatory responses, triggered by the pro-inflammatory response to stroke, appear to effect systemic immunodepression via suppression of both innate and adaptive immune responses. Experimental and clinical studies have identified a range of anti inflammatory and immunosuppressive changes, including reduced mononuclear phagocyte and natural killer cell function, induction of anti-inflammatory cytokines, apoptotic lymphocyte loss and altered T lymphocyte activity. A range of mechanisms has been proposed, including hypothalamo-pituitary-adrenal axis (HPAA) and sympathetic nervous system (SNS) activation. The post-stroke balance of pro- and anti- inflammatory mechanisms may be aimed at restricting the extent of inflammation and contributing to the restoration of immune homeostasis. However, severe inflammation in the brain may trigger major systemic, counter inflammatory responses that ultimately compromise immune mechanisms required to combat pathogens. Although key pathways have been identified, the extent to which the various elements of post-stroke immunodepression are clinically relevant remains to be discovered. The identification of markers of immunodepression in the early post-stroke phase may prove useful for identifying patients that may have increased susceptibility to infection. It also seems likely that post-stroke immunodepression will need to be taken into account where stroke treatments impact upon inflammatory and immune pathways. PMID- 20166970 TI - Virus vasculopathy and stroke: an under-recognized cause and treatment target. AB - While arteriosclerotic disease and hypertension, with or without diabetes, are the most common causes of stroke, viruses may also produce transient ischemic attacks and stroke. The three most-well studied viruses in this respect are varicella zoster virus (VZV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV), all of which are potentially treatable with antiviral agents. Productive VZV infection in cerebral arteries after reactivation (zoster) or primary infection (varicella) has been documented as a cause of ischemic and hemorrhagic stroke, aneurysms with subarachnoid and intracerebral hemorrhage, arterial ectasia and as a co-factor in cerebral arterial dissection. CMV has been suggested to play a role in the pathogenesis of arteriosclerotic plaques in cerebral arteries. HIV patients have a small but definite increased incidence of stroke which may be due to either HIV infection or opportunistic VZV infection in these immunocompromised individuals. Importantly, many described cases of vasculopathy in HIV-infected patients were not studied for the presence of anti VZV IgG antibody in CSF, a sensitive indicator of VZV vasculopathy. Unlike the well-documented role of VZV in vasculopathy, evidence for a causal link between HIV or CMV and stroke remains indirect and awaits further studies demonstrating productive HIV and CMV infection of cerebral arteries in stroke patients. Nonetheless, all three viruses have been implicated in stroke and should be considered in clinical diagnoses. PMID- 20166974 TI - Human immunodeficiency virus (HIV) and stroke: targets for intervention. AB - Human immunodeficiency virus (HIV) infection causes stroke through several mechanisms. Stroke results from opportunistic infection and neoplasia, HIV induced cardiac disease, HIV associated cerebral vasculopathy, and perhaps of HIV induced facilitation of some forms of systemic vasculitis and prothrombotic haematological conditions. HIV causes more ischaemic stroke than cerebral haemorrhage. Although stroke is currently a relatively infrequent manifestation of HIV infection, the incidence of stroke in HIV infected individuals is likely to increase with current combination antiretroviral therapy. HIV infection per se induces endothelial activation and dyslipidaemia, predisposing to accelerated atherosclerosis. Antiretroviral therapy, which increases life expectancy and therefore inherently increases ischaemic stroke risk with advancing age and length of exposure to traditional risk factors, also causes pro-atherosclerotic metabolic and endothelial dysfunction. Antiretroviral induced vascular dysfunction together with pre-existing HIV induced vascular disease has the potential to increase atherosclerotic causes of ischaemic stroke. New antiretroviral agents should ideally eradicate the human immunodeficiency virus thereby reducing vascular risk and HIV related causes of stroke without inducing metabolic or endothelial dysfunction. Future studies of vascular disease in HIV infected individuals, particularly studies investigating the impact of current and future antiretroviral agents, should ideally assess stroke as a specific outcome, and provide data by pathological stroke type and ischaemic stroke subtype, to clarify the mechanisms of stroke and guide the approach to treatment and prevention of stroke. PMID- 20166975 TI - Rashes, sniffles, and stroke: a role for infection in ischemic stroke of childhood. AB - Major infections-sepsis, meningitis, encephalitis-have long been recognized as causes of pediatric arterial ischemic stroke. However, minor infections may also contribute to the pathogenesis of stroke, either by causing a systemic prothrombotic state or direct or indirect vascular injury. A focal cerebral arteriopathy has been identified in a large proportion of otherwise healthy children present with a first ischemic stroke. Both histologic data and small association studies suggest that varicella zoster virus can cause this childhood arteriopathy. Other viruses have been implicated in case reports. New data demonstrate an association between recent upper respiratory infection and this arteriopathy, suggesting a non-specific effect of infection. This manuscript reviews the evidence supporting a role for infection in ischemic stroke of childhood. PMID- 20166973 TI - Infectious burden: a new risk factor and treatment target for atherosclerosis. AB - Atherosclerosis is a chronic inflammatory process, and several common bacterial and viral infections have been hypothesized to contribute to the inflammation of the vascular wall that leads to atherosclerosis. More recently, investigators have found preliminary evidence that the aggregate burden of these chronic infections, rather than any single organism, may contribute to atherosclerosis and risk of clinical vascular events, including ischemic stroke. This aggregate burden of infections, which has been variably labeled "infectious burden" or "pathogen burden," may be associated with stroke through mechanisms independent of atherosclerosis, as well, including platelet aggregation and endothelial dysfunction. Host factors, moreover, may interact with infectious burden to modify the risk of disease associated with these infections. Currently there is no commonly accepted group of organisms or method of assessing infectious burden, and not all studies confirm an association of infection and stroke risk. Nonetheless, if infectious burden does play a role in atherosclerosis or stroke, it is plausible that preventive anti-infective treatment, such as vaccination, or antibiotics, would reduce the risk of incident or recurrent stroke. While influenza vaccination has been recommended to prevent recurrence among those with coronary disease, similar recommendations for stroke patients have not yet been made. Large scale randomized clinical trials of macrolide antibiotics for coronary patients, moreover, have been negative. Further studies are needed, however, to determine whether an association between infectious burden and stroke exists, and whether infectious burden may be a target for intervention. PMID- 20166976 TI - Bisphosphonates as treatment of bone metastases. AB - Accelerated bone loss is a common clinical feature of advanced breast cancer, and anti-resorptive bisphosphonates are the current standard therapy used to reduce the number and frequency of skeletal-related complications experienced by patients. Bisphosphonates are potent inhibitors of bone resorption, acting by inducing osteoclast apoptosis and thereby preventing the development of cancer induced bone lesions. In clinical use bisphosphonates are mainly considered to be bone-specific agents, but anti-tumour effects have been reported in a number of in vitro and in vivo studies. By combining bisphosphonates with chemotherapy agents, growth and progression of breast cancer bone metastases can be virtually eliminated in model systems. Recent clinical trials have indicated that there may be additional benefits from bisphosphonate treatment, including positive effects on recurrence and survival when added to standard endocrine therapy. Whereas the ability of bisphosphonates to reduce cancer-induced bone disease is well established, their potential direct anti-tumour effect remain controversial. Ongoing clinical trials will establish whether bisphosphonates can inhibit the development of bone metastases in high-risk breast cancer patients. This review summarizes the main studies that have investigated the effects of bisphosphonates, alone and in combination with other anti-cancer agents, using in vivo model systems of breast cancer bone metastases. We also give an overview of the use of bisphosphonates in the treatment of breast cancer, including examples of key clinical trials. The potential side effects and future clinical applications of bisphosphonates will be outlined. PMID- 20166977 TI - Tgf-Beta pathway as a therapeutic target in bone metastases. AB - Breast and prostate cancer frequently metastasizes to the skeleton and causes bone destruction. In skeletal tissue, transforming growth factor-beta (TGF-beta) is a major bone-derived factor responsible for driving a feed-forward vicious cycle of breast cancer growth in bone. TGF-beta is released from bone in active form by osteoclastic resorption and increases the tumor secretion of factors, which stimulate osteolytic destruction of the bone adjacent to the tumor. Moreover it activates epithelial-mesenchymal transition and tumor cell invasion, increases angiogenesis and induces immunosuppression. Blocking the TGF-beta signaling pathway to interrupt this vicious cycle between tumor and bone offers a target for therapeutic intervention to decrease skeletal metastasis. Here we summarize the current knowledge of TGF-beta in bone metastases, the use of TGF beta inhibitors and its potential for clinical use and consequences. PMID- 20166978 TI - The CXCR4/SDF-1 chemokine axis: a potential therapeutic target for bone metastases? AB - Chemokines and chemokine receptors play diverse roles in homeostasis. The chemokine stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 have critical functions in the immune, circulatory, and central nervous systems and have also been implicated in tumor biology and metastasis. Here we review the current data regarding the role of the CXCR4/SDF-1 chemokine axis in the development of bone metastases, derived from tumor models of breast or prostate cancers. There is substantial evidence that CXCR4 and SDF-1 directly influence the survival and proliferation of tumor cells. In regards to bone metastases, the CXCR4/SDF-1 axis also appears to facilitate tumor cell recruitment to the bone marrow microenvironment via a homing mechanism. This makes disruption of the chemokine axis an attractive therapeutic target for the prevention of tumor cell spread to bone. However, within the bone microenvironment, SDF-1 and CXCR4 appear to have conflicting roles. While genetic disruption of CXCR4 enhances osteoclast activity and therefore stimulates tumor cell growth in the bone - likely via release of bone-derived growth factors - SDF-1 has been shown to have either a stimulatory effect or no effect on osteoclasts. In short, the effects of the CXCR4/SDF-1 axis on tumor cell growth within the bone are not yet fully defined. Further, there are theoretical risks that blockade of this chemokine axis could impair immune function or mobilize tumor cells leading to other sites of metastasis. As such, caution should be taken when designing therapeutic strategies targeting this chemokine axis. PMID- 20166979 TI - Bone morphogenetic proteins and its receptors; therapeutic targets in cancer progression and bone metastasis? AB - Breast and prostate cancer are osteotropic cancers, i.e., carcinomas that have a special predilection to form bone metastases. At postmortem examination, approximately 70% of patients dying of these cancers have evidence of metastatic bone disease. Bone Morphogenetic Proteins (BMPs) were first identified by their ability to induce ectopic bone formation in vivo. Since prostate cancer cells express several BMPs, BMPs have been implicated in the osteoblastic phenotype of bone metastases. In addition to their osteogenic function, BMPs turned out to be multifunctional proteins regulating cell growth, differentiation, migration, and apoptosis in various target cells, including breast and prostate cancer cells. Especially in the last decade, studies have focused on the role of several BMPs in osteotropic cancers. In this review, the role of BMPs, particularly that of BMP7, in breast and prostate cancer will be discussed. PMID- 20166980 TI - Targeting RANK/RANKL in the treatment of solid tumours and myeloma. AB - Cancers which damage the human skeleton include multiple myeloma, where the primary tumour colonises bone directly, or breast and prostate cancer, where malignant cells travel from the primary tumour to form clonal outgrowths within the bone. Owing to the interaction of tumour cells with those normally found in the bone microenvironment, such as osteoclasts and osteoblasts, these cancers affect the closely linked processes of bone formation and resorption. As a result, these twin processes contribute to the clinical manifestations of cancer metastasis, including bone pain and pathological fractures. A critical component of physiologically normal bone remodelling, the RANK/RANKL/OPG pathway, has been implicated in the formation of osteolytic, and possibly osteoblastic, lesions, which characterise the bone disease associated with these malignancies. In these cancers that affect the skeleton in this way the abnormally regulated RANK/RANKL system appears to be the final effector pathway. As a result, there has been much research focused upon targeting these molecules using OPG constructs, peptidomimetics, soluble receptor constructs and antibodies to RANKL, in pre clinical studies. The success of these studies has paved the way for a clinical programme, the success of which is likely to lead to a new therapeutic approach to treating cancers that develop in the skeleton. PMID- 20166981 TI - Most efficient routes for the synthesis of alpha,beta-diamino acid-derived compounds. AB - Alpha,beta-Diamino acids have attracted considerable attention recently due to their growing importance in pharmaceutical and biochemical research. For example, this special class of alpha,beta-diamino acids has become the components of enzyme inhibitors, and has been incorporated into peptides which are used to modulate secondary and tertiary structural conformations. Although their widely occurrence in nature, optically active diamino acids are hard to isolate and purify from available natural resources on large scale. Therefore, their asymmetric synthesis becomes a great interest for organic and medicinal chemists. However, there still exist great challenges for enantioselective synthesis of diamino acids, especially those with two vicinal chiral centers. This review highlights the recent promising methodologies for enantioselective synthesis of alpha,beta-diamino acids, with special emphasis on catalytic asymmetric reactions, as well as methods for natural chiral compound derivatization, and chiral auxiliaries. PMID- 20166982 TI - Nutlins and ionizing radiation in cancer therapy. AB - Radioresistance stands as a fundamental barrier that limits the effectiveness of radiotherapy in cancer treatment. Recent evidences suggest that radioresistance is due to tumour repopulation and involves several signalling pathways, including p53/MDM2 interaction. Ionizing radiation induces p53-dependent MDM2 gene transcription that, in turn, inhibits p53 transcriptional activity, favouring its nuclear export and stimulating its degradation. In light of the observation that in many human tumours the inadequate function of p53 is the result of MDM2 over expression, several authors have considered as an attractive therapeutic strategy to activate p53 signalling in tumours by inhibiting MDM2 activities or p53/MDM2 interaction. We retain that, by preventing the interaction p53/MDM2 with Nutlin, a small molecule that bind at the interface between these two proteins, the effectiveness of ionizing radiation treatment could be improved. Promising results have recently emerged from in vitro studies performed on laryngeal, prostate and lung cancer cell lines treated with Nutlin in combination with ionizing radiation. Based on these findings, we believe that the combined approach Nutlin/ionizing radiation should be further investigated for efficacy on both solid tumours and lymphoproliferative disorders as well as for side effects on normal cells and tissues. Therefore, the purpose of this review is to report the first results obtained by using Nutlins alone or in combination with other therapeutic agents on primary tumour cells, in vitro cell lines or tumour xenografts and to present the most recent advances in the understanding of the molecular mechanisms underlining ionizing radiation cytotoxicity and resistance. PMID- 20166983 TI - Cell cycle as a target of antineoplastic drugs. AB - The cell cycle consists of a number of complex biochemical pathways that ensure that the start of a particular event depends on the successful and right end of previous steps in the pathway. An important role is played by cyclin/cyclin dependent kinase (cdk) complexes which are critical regulators of cell cycle progression and RNA transcription. To ensure proper progression through each phase, cells have developed a series of orchestrated checkpoints that govern the different cellular kinases required for distinct cell cycle events. In particular, several cell cycle protein kinases, including members of the Aurora family and the Polo-like kinases, play critical roles in mitotic entry and chromosome segregation that ensure the correct formation of daughter cells. Tumour cell proliferation is frequently associated to both genetic and epigenetic mechanisms commonly affecting the expression of cell cycle regulatory proteins or causing an incompetent checkpoint control, resulting in aberrant responses to cellular damage. These alterations result not only in proliferative advantages but also in an increased susceptibility to the accumulation of additional genetic alterations that contribute to tumour progression and acquisition of more aggressive phenotypes. In the last years, the identification of anticancer drugs directed against critical cell cycle regulators has received particular attention. Specifically, several preclinical and clinical trials are addressing cdks or cell cycle protein kinase inhibitors. Starting from a description of cell cycle, this review summarizes the most recent studies on drugs targeting cell cycle regulators that are being used in cancer therapy. PMID- 20166984 TI - PI3K/Akt signalling pathway specific inhibitors: a novel strategy to sensitize cancer cells to anti-cancer drugs. AB - The resistance of many types of cancer to chemotherapies represents the major hurdle in successful cancer treatment. Cancer cells can escape the toxic effect of most commonly used drugs despite their different chemical structure and intracellular targets. The mechanisms underlying the failure of chemotherapeutic drugs have been well studied. Here I review the role of a signalling pathway activated by the lipid kinase phosphoinositide 3-kinase (PI3K) and the serine/threonine kinase, protein kinase B (PKB) or Akt, in chemotherapeutic resistance. Activation of this pathway plays a key role in different cellular functions such as growth, migration survival and differentiation. Data accumulated in the last decade have established that this pathway plays a key role in cancer development and progression. More recently it has been shown that this pathway plays also a key role in resistance to chemotherapy. Therefore drugs designed to specifically target this pathway are under development to be used as single agent and in combination to chemotherapy to overcome therapeutic resistance. PMID- 20166985 TI - Tyrosine kinases as molecular targets to inhibit cancer progression and metastasis. AB - During the last decades, the improvement of our knowledge of the mechanisms responsible for cancer development has led to the introduction of new promising strategies of treatment, based on "molecular targeted" drugs. These drugs are designed to act on specific molecules, identified as major players in the maintenance of the malignant status. The development of inhibitors, mainly monoclonal antibodies and small-molecules, directed against activated oncogenes has been the most widely used approach for this kind of treatment. Among the oncogenes implicated in human cancers, tyrosine kinases play a critical role. This observation, together with the discovery that cancer cells can be dependent for their survival from the continuous expression of activated oncogenes (a concept defined as "oncogene addiction"), has made protein kinases ideal targets for targeted therapy in cancer. As the field of targeted therapies is now rapidly growing and a comprehensive survey would be too wide, this review will thus mainly focus on strategies aimed at inhibiting tyrosine kinases and their signal transduction pathways. PMID- 20166986 TI - Cell responses to oxidative stressors. AB - Stress is a stimulus or a succession of stimuli tending to disrupt the homeostasis of an organism. An organism is consisting of a multitude of cells that singly undergo the effects of external factors that disturb or upset their homeostatic regulation. Stimuli acting as potential stressors are numerous, and include physical agents (ionizing radiation), non-physiological oxygen levels (hypoxia, hyperoxia) and chemotherapeutics. Lastly, also senescence, a physiological process occurring in all organisms, can be considered as a potential stressor. The cell response to multiple oxidative stresses involves mitochondria, since these organelles represent the major source of Reactive Oxygen Species (ROS) that drive the occurrence of pathological conditions and ageing by activating specific signalling pathways. Nevertheless, under physiological conditions the cells are able to exert an antioxidant response which, controlling ROS/Reactive Nitrogen Species (RNS) homeostasis, is involved in mediating cell differentiation, proliferation and migration. Thus, this review focuses the attention to the role played by mitochondria in the physiological and non-physiological signalling responses of eukaryotic cells to some oxidative stresses, in order to identify potential therapeutic targets to counteract oxidative stress effects and mitochondrial-related pathologies. PMID- 20166987 TI - Morpho-functional features of in-vitro cell death induced by physical agents. AB - Based on the study of the recent literature, the aim of this report is to present and discuss in vitro cell death, and, more specifically, apoptosis appearing after exposure to physical conditions such as hyperthermia, hypothermia, UVB radiation and static magnetic fields. Hyperthermia (i.e. variable exposures to 42 degrees C) as well as hypothermia conditions (i.e. variable exposures to 0 degrees C) were considered mild and were both followed by incubation at physiological conditions. Heat exposure can be considered as a powerful apoptotic inducer in a variety of cells, where it induces classical apoptotic changes and well known biochemical pathways. The effect of hyperthermia has been described in adherent human tumour cells that undergo cell rounding and progressively detach from the substrate, due to the concomitant down-regulation of adhesion molecules. Hypothermia instead, as a cold treatment, only occasionally triggers apoptosis, but more frequently induces cell necrosis. UVB radiation induces oxidative stress, leading, in most experimental models, to apoptotic cell death, generally through the intrinsic apoptotic pathway, even if the extrinsic pathway cannot be excluded. Interestingly, UVB radiation appears effective also on cell systems that are normally apoptosis-resistant, such as muscle cells. Most cell alterations induced by static magnetic fields result from alterations at the plasma membrane and microvilli; in this case, apoptotic cell death is rarely detected. Therefore, cell death can be induced with physical agents in dependence on the treatment and cell model employed. In particular, hyperthermia and UVB can be considered a reliable and reproducible apoptotic trigger. PMID- 20166988 TI - Signalling pathways activated by ultraviolet radiation: role in ocular and cutaneous health. AB - The eye and the skin are protected by a multi-layered epithelial barrier that provides the first line of defence against invading pathogens and environmental stresses such as damaging solar ultraviolet radiation. Extensive epidemiological findings supported by compelling experimental evidence in culture and animal models suggest that ultraviolet radiation is the most important environmental carcinogen leading to the development of a variety of benign and malignant ocular and cutaneous conditions. Epithelial cells have evolved several key defence mechanisms to prevent ultraviolet radiation-induced DNA mutations from stably entering the genome and ultraviolet radiation-damaged cells from establishing themselves in an otherwise normal microenvironment. Firstly, through the process excision repair, cells have the ability to correct carcinogen-induced DNA damage. Secondly, severely damaged cells are eliminated from healthy tissues by molecular programs that trigger cell death. These processes are activated through complex intracellular signalling circuits that ensure that organs such as the eyes and skin are maintained in a disease-free state. Finally, abnormal cells can be recognized, targeted and destroyed by surveillance from the immune system, however this is complicated further by the immunosuppressive effects of ultraviolet radiation that promote tumour growth. This review will discuss in greater detail some of the processes and pathways that are activated in response to ultraviolet radiation and their effect on ocular and cutaneous health. PMID- 20166989 TI - Development of peptides as potential drugs for cancer therapy. AB - The development of more selective agents focused on targeted delivery of imaging probes and drugs to different tumor sites is the current trend in cancer diagnosis and therapies. Peptides are small amino acid sequences that can be isolated to bind to a predetermined target and are potentially capable of interfering with its function. These specific peptides isolated can inhibit individual signaling components, which are essential in cancer development and progression. Phage display is a powerful technology for selecting and cloning peptides displayed on the surface of bacteriophage. Billionclone-peptide libraries can be rapidly and simultaneously selected by phage biopanning, leading to large numbers of hits. Although peptides account for only a small part of current therapeutic agents, their potential is being improved by new technologies affecting their modification, delivery, stability and their application in preclinical settings. This review will highlight how to isolate peptides that target pivotal molecules in cancer development and progression through phage library biopanning and how to modify these peptides to enhance their anticancer efficacy. PMID- 20166990 TI - HSP-dependent protection against gastrointestinal diseases. AB - It is well known that heat shock proteins (HSPs) are induced by various stressors in order to confer protection against such stressors. Since stressor-induced tissue damage is involved in various diseases, especially gastrointestinal diseases, such as gastric ulcer, it has been thought that HSPs are protective against these diseases. Indirect lines of evidence, such as identification of geranylgeranylacetone (GGA, a leading anti-ulcer drug in Japanese market) as non toxic HSP-inducer, suggest that HSPs provide a major protective mechanism against irritant-induced gastric lesions. However, no direct evidences that support this notion exits. Furthermore, because GGA has other gastroprotective effects, it was not clear whether HSP-induction by GGA is the main mechanism for its anti-ulcer effect. In this article, I review our recent work on protective roles of HSPs against gastrointestinal diseases, using transgenic mice. We obtained genetic evidence showing not only that HSPs are protective against irritant-induced gastric lesions but also that GGA achieves its anti-ulcer effect through induction of HSPs. We also obtained genetic evidence that HSPs are protective against inflammatory bowel disease (IBD)-related colitis and lesions of small intestine. Furthermore, we found that GGA is effective against these diseases. Based on these observations, we propose that non-toxic HSP-inducers, such as GGA are therapeutically beneficial for these diseases. PMID- 20166991 TI - Involvement of orexigenic peptides in the mechanism of gastric mucosal integrity and healing of chronic gastric ulcers. AB - Orexigenic peptides are group of endocrine hormones exerting a pleiotropic influence on many physiological functions including regulation of the feeding behaviour and energy expenditure, release of growth hormone (GH) and inotropic effects on the heart. Some of these peptides such as ghrelin, originally identified in the gastric mucosa, has been involved not only in control of food intake and growth hormone release but also exerts the immunomodulatory and anti inflammatory properties. This review summarizes the recent attempts to prove the concept that orexigenic peptides such as ghrelin, orexin-A and obestatin besides playing an important role in the mechanism of food intake, exhibit a potent gastroprotective action against the formation of acute gastric mucosal injury induced by various ulcerogens. This protective effect depends upon vagal activity and hyperemia mediated by NOS/NO and COX/PG systems and CGRP released from sensory afferent nerves. In addition, the appetite peptides such as ghrelin and orexin-A are implicated in the mechanism of the healing of preexisting gastric ulcers due to an activation of specific GHS-R1a and OX-R1 receptors and PG/COX system. PMID- 20166992 TI - Role of dietary fiber in formation and prevention of small intestinal ulcers induced by nonsteroidal anti-inflammatory drug. AB - Recent advances in endoscopic techniques such as capsule endoscopy have revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) often cause ulcers in the small intestine in humans, but there are few effective agents for treatment of small intestinal ulcers. Although the pathogenesis of NSAID-induced intestinal ulcer has been widely studied, dietary factors have seldom been considered. In the present review, the role of dietary fiber (DF) in the formation of NSAID induced intestinal ulcers is discussed. In previous studies, small intestinal lesions were not observed when NSAIDs were administered to fasted rats, dogs, and cats, but were observed in conventionally-fed animals, suggesting the importance of feeding in the formation of intestinal lesions induced by NSAIDs. However, in animals fed diets containing low or no DF, indomethacin (IND) did not produce lesions in the small intestine, but did produce lesions in animals fed diets supplemented with insoluble dietary fiber (IDF, cellulose). The results suggest that IDF in the diet plays an important role in the formation of NSAID-induced intestinal lesions. On the other hand, addition of soluble dietary fibers (SDFs) such as pectin or mucin to regular diet markedly decreased NSAID-induced intestinal lesions. Thus, IDF and SDF have opposing effects on IND-induced intestinal lesions, i.e., IDF is harmful while SDF is protective. SDFs potentially represent a novel and safe means for protecting the small intestine against NSAID-induced intestinal lesions. PMID- 20166993 TI - Revised Robert's cytoprotection and adaptive cytoprotection and stable gastric pentadecapeptide BPC 157. Possible significance and implications for novel mediator. AB - The significance of cytoprotection and adaptive cytoprotection and the peptides importance remained to be not completely determined. BPC 157 is an anti-ulcer peptidergic agent, proven in clinical trials to be both safe in inflammatory bowel disease (PL-10, PLD-116, PL 14736) and wound healing, and stable in human gastric juice, with no toxicity being reported. It has a prominent effect on alcohol- lesions (i.e., induced acutely and chronically) and non-steroidal anti inflammatory drugs-lesions (while interestingly BPC 157 may both prevent and reverse adjuvant arthritis). To review the importance of BPC 157, this review focused on Robert's cytoprotection concept described in rat stomach, reviewing our evidence that may resolve whether the cytoprotection and adaptive cytoprotection is an uniform phenomenon or not; whether the phenomenon or phenomena are endogenous or not, depending on nature of the irritants (mild or strong); whether this may contribute to stomach mucosa defense either when threaten by various ulcerogens or afforded by various antiulcer agents; whether these phenomena are uniform in whole gastrointestinal tract or not; whether they are interrelated or not. Finally, the importance of the cytoprotection phenomena and cytoprotection activity for skin wound healing, and wound healing in general was challenged. Thereby, this review focused on BPC 157 role in cytoprotection and adaptative cytoprotection suggesting that it may be the essential endogenous mediator able to mediate both cytoprotective and adaptive cytoprotective response in stomach and the whole gastrointestinal tract with significant importance in wound healing as well. PMID- 20166994 TI - Complexity of gastric acid secretion revealed by targeted gene disruption in mice. AB - Physiology of gastric acid secretion is one of the earliest subjects in medical research and education. Gastric acid secretion has been sometimes inadequately expressed as pH value rather than amount of gastric H(+) secreted per unit time. Gastric acid secretion is regulated by endocrine, paracrine and neurocrine signals via at least three messenger pathways: gastrin-histamine, CCK somatostatin, and neural network. These pathways have been largely validated and further characterized by phenotyping a series of knockout mouse models. The complexity of gastric acid secretion is illustrated by both expected and unexpected phenotypes of altered acid secretion. For examples, in comparison with wild-type mice, gastrin and CCK double knockout and SSTR(2) knockout mice displayed a shift in the regulation of ECL cells from somatostatin-SSTR(2) pathway to galanin-Gal1 receptor pathway; a shift in the regulation of parietal cells from gastrin-histamine pathway to vagal pathway; and a shift in the CCK(2) receptors on parietal cells from functional silence to activation. The biological function of glycine-extended gastrin in synergizing gastrin-17 has been revealed in gastrin knockout mice. The roles of gastric acid secretion in tumorigenesis and ulceration have not been fully understood. Transgenic hypergastrinemic INS GAS mice developed a spontaneous gastric cancer, which was associated with an impaired acid secretion. Gastrin knockout mice were still able to produce acid in response to vagal stimulation, especially after H. pylori infection. Taken together, phenotyping of a series of genetically engineered mouse models reveals a high degree of complexity of gastric acid secretion in both physiological and pathophysiological conditions. PMID- 20166995 TI - Prostaglandin EP receptor subtypes involved in regulating HCO(3)(-) secretion from gastroduodenal mucosa. AB - Gastroduodenal HCO(3)(-) secretion is a key process that aids in preventing acid peptic injury. The HCO(3)(-) secretion in rats and mice was increased in response to PGE(2) as well as mucosal acidification, the latter response occurring with a concomitant enhancement of mucosal PG production. The duodenal responses to PGE(2) and acid were decreased in mice lacking EP3 receptors and reduced by coadministration of an EP3 or EP4 antagonist in rats, complete inhibition being observed when the EP3 and EP4 antagonists were given together. By contrast, the gastric responses disappeared in EP1-knockout mice and were prevented by an EP1 antagonist but not other EP antagonists. Furthermore, duodenal HCO(3)(-) secretion was stimulated by the EP3 and EP4 agonists, whereas gastric HCO(3)(-) secretion was increased only by the EP1 agonist. In addition, the HCO(3)(-) stimulatory effect of sulprostone (an EP1/EP3 agonist) in the duodenum was inhibited by verapamil, a Ca(2+) antagonist, and enhanced by isobutyl- methylxanthine, a phosphodiesterase (PDE) inhibitor, but the response in the stomach was inhibited by verapamil and not affected by isobutylmethylxanthine. In the mouse duodenum but not stomach, the response to PGE(2) was potentiated by both vinpocetine (a PDE1 inhibitor) and cilostamide (a PDE3 inhibitor). These results suggest that the HCO(3)(-) stimulatory effect of PGE(2) in the duodenum is mediated by both EP3 and EP4 receptors, being coupled intracellularly with Ca(2+) and cAMP, while that in the stomach is mediated by EP1 receptors, coupled with Ca(2+). In addition, both PDE1 and PDE3 are involved in the regulation of duodenal HCO(3)(-) secretion. PMID- 20166996 TI - Production of orally applicable new drug or drug combinations from natural origin capsaicinoids for human medical therapy. AB - It is well known that the capsaicin stimulates (in small doses) or impairs (in high doses) the capsaicin-sensitive afferent nerves and the final effects of capsaicin depend on its applied doses. The effects of capsaicin were analyzed on the gastrointestinal mucosal protection and injury in animal experiments and in human beings (from 1980 up to now). From 2005 to 2008 an interdisciplinary group (21 researchers) participated in the production of orally applicable drug or drug combinations from capsaicin for human medical therapy of patients suffering from cardiovascular, degenerative joint and locomotor diseases, who received in their treatments non-steroidal anti-inflammatory compounds (NSAIDs). Our studies were based on the results of the NSAIDs-induced gastrointestinal side effects could be detected by application of small doses of capsaicin. Because natural (plant origin) capsaicin is chemically does not represent a uniform entity and used in the international research, consequently the authors met a lot of unpredictable scientific problems during the time of production of new capsaicin containing (alone or in combinations) drug before receiving official permissions from the different national and international authorities to start the classical human clinical pharmacological studies. This paper summarizes the different steps from the basic physiological and pharmacological notes (in animals), plant cultivation, chemistry of substance(s), animal (general and germinative) acute and chronic toxicology, human actions, basic clinical pharmacology of natural capsaicin (capsaicinoids) to introduce and to develop a new drug (or drug combinations) in the human medical therapy. PMID- 20166998 TI - Predicting aqueous solubility: the role of crystallinity. AB - This paper revisits the role of crystallinity in predicting the aqueous solubility of a wide variety of organic compounds. Box and Comer (Current Drug Metabolism, 2008, 9, 869-878) fitted solubility data for 86 drugs to an equation based solely on log P. The General Solubility Equation of Jain and Yalkowsky, which accounts for the crystal lattice energy, was applied to the same data set and gives more accurate solubility predictions. In this simple comparison between two solubility prediction methods, we show that log P alone is only half of the solution, and that there is a need to include the melting point when dealing with crystalline solutes. PMID- 20166997 TI - Design and application of microfluidic systems for in vitro pharmacokinetic evaluation of drug candidates. AB - One of the fundamental challenges facing the development of new chemical entities within the pharmaceutical industry is the extrapolation of key in vivo parameters from in vitro cell culture assays and animal studies. Development of microscale devices and screening assays incorporating primary human cells can potentially provide better, faster and more efficient prediction of in vivo toxicity and clinical drug performance. With this goal in mind, large strides have been made in the area of microfluidics to provide in vitro surrogates that are designed to mimic the physiological architecture and dynamics. More recent advancements have been made in the development of in vitro analogues to physiologically-based pharmacokinetic (PBPK) models - a mathematical model that represents the body as interconnected compartments specific for a particular organ. In this review we highlight recent advancements in human hepatocyte microscale culture, and describe the next generation of integrated devices, whose potential allows for the high throughput assessment of drug metabolism, distribution and pharmacokinetics. PMID- 20166999 TI - Expression, function and regulation of mouse cytochrome P450 enzymes: comparison with human P450 enzymes. AB - The present review focuses on the expression, function and regulation of mouse cytochrome P450 (Cyp) enzymes. Information compiled for mouse Cyp enzymes is compared with data collected for human CYP enzymes. To date, approximately 40 pairs of orthologous mouse-human CYP genes have been identified that encode enzymes performing similar metabolic functions. Recent knowledge concerning the tissue expression of mouse Cyp enzymes from families 1 to 51 is summarized. The catalytic activities of microsomal, mitochondrial and recombinant mouse Cyp enzymes are discussed and their involvement in the metabolism of exogenous and endogenous compounds is highlighted. The role of nuclear receptors, such as the aryl hydrocarbon receptor, constitutive androstane receptor and pregnane X receptor, in regulating the expression of mouse Cyp enzymes is examined. Targeted disruption of selected Cyp genes has generated numerous Cyp null mouse lines used to decipher the role of Cyp enzymes in metabolic, toxicological and biological processes. In conclusion, the laboratory mouse is an indispensable model for exploring human CYP-mediated activities. PMID- 20167000 TI - New insights into the structural features and functional relevance of human cytochrome P450 2C9. Part II. AB - Part I of this article published in the previous issue of Current Drug Metabolism discussed the substrate specificity, inhibitor selectivity and structure-activity relationship (SAR) of human CYP2C9. The features of CYP2C9 pharmacophore and SAR models have been elaborated. Part II of this article will address the homology models of CYP2C9, data from site-directed mutagenesis studies, and crystal structural features of CYP2C9. The heteroactivation of CYP2C9 and its interactions with other CYPs will also be discussed. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Site-directed mutagenesis studies have revealed that a number of residues (e.g. R97, F110, F114, R132, R144, D293, F476 and A477) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. Currently, there are three X-ray structures of the human CYP2C9 in Protein Database (PDB): one ligand-free protein (1OG2), and two in complex with S-warfarin (1OG5) or flurbiprofen (1R9O). The published structures of 1OG2 and 1OG5 differ in comparison with 1R9O in residues 30-53 of N-termini, residues 97-121 of B/C-loops, and residues 196-233 of helix F and F/G-loops. CYP2C9 is a two-domain protein with typical fold characteristics of the CYPs. The B-C loop forms part of the active site and contributes to substrate specificity. In the structures of CYP2C9 without ligand bound or with bound S-warfarin, residues 101-106 in the B-C loop form helix B'. In addition, residues 212-222 in the F-G loop form helices F' and G', which was not observed in rabbit CYP2C5 and bacterial CYPs. In the 1OG2 and 1OG5 structures, the heme is stabilized by hydrogen bonds between the propionates and the side chains of W120, R124, H368 and R433. In addition, R97 forms hydrogen bonds to the propionates as well as the carbonyl oxygen atoms of V113 and P367. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. Further studies are needed to investigate the molecular determinants for ligand CYP2C9 interactions. PMID- 20167001 TI - New insights into the structural features and functional relevance of human cytochrome P450 2C9. Part I. AB - CYP2C9 is one of the most abundant CYP enzymes in the human liver ( approximately 20% of hepatic total CYP content). CYP2C9 metabolizes approximately 20% clinical drugs (>120 drugs), including a number of drugs with narrow therapeutic ranges. Some natural compounds are also metabolized, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Typical substrates of CYP2C9 such as celecoxib, ibuprofen, flurbiprofen, and diclofenac are relatively small, lipophilic and contain acidic groupings with pK(a) values in the range 3.8-8.1 which will be ionized at physiological pH. The carboxylate groups of tienilic acid and diclofenac have been shown to be responsible for substrate preference and orientation in the active site of CYP2C9. Therefore, a typical CYP2C9 substrate should contain an anionic site and a hydrophobic site. However, neutral or positively charged compounds may also be substrates of CYP2C9. CYP2C9 is subject to inhibition by a number of drugs and other compounds and this may provide an explanation for some clinical drug-drug interactions. With regard to prodrugs that need CYP2C9 for activation, inhibition of CYP2C9 may cause a decrease in the amount of the active metabolite, leading to therapeutic failure. Pharmacophore models have revealed that hydrogen bonding, ion-pair interactions, and probably hydrophobic interactions play a major role in determining the substrate specificity and inhibitor selectivity of CYP2C9. A number of structure-activity relationship studies have identified the structural determinants of compounds for their binding affinity to CYP2C9 and inhibitory potency for CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates and/or inhibitors of CYP2C9 in drug development and drugs with minimal interactions with this enzyme should be chosen for further development. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships. PMID- 20167002 TI - Investigation of the CYP2C9 induction profile in human hepatocytes by combining experimental and modelling approaches. AB - The goal of the present review is to characterise the induction profile of CYP2C9, a member of the cytochrome P450 superfamily. Since the mechanism of CYP2C9 induction is fairly complex, with parallel processes triggered by various inducers, an evaluation of the experimental results is often a great challenge. At least three nuclear receptors, the glucocrticoid receptor (GR), the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), are known to mediate the CYP2C9 gene induction in man. However, mathematical modelling and simulation can provide an appropriate tool for the interpretation of CYP2C9 regulatory mechanisms. As an example, we present modelling and simulation approaches of the CYP2C9 gene expression in human hepatocytes treated with well known CYP2C9 inducers: the steroid hormone precursor dehydroepiandrosterone (DHEA) and the synthetic glucocorticoid dexamethasone (DXM). The results of the analysis suggest that in addition to the potent function of GR and the further involvement of PXR and CAR activated by DXM or DHEA, an additional factor might play a role in CYP2C9 regulation by DHEA. The novel potential candidate for DHEA action in CYP2C9 induction is likely to be the estrogen receptor. Additionally, the balance of DHEA sulphation-desulphation processes should also be considered in any description of DHEA-induced CYP2C9 profiles. PMID- 20167003 TI - Effects of estrogen in the brain: is it a neuroprotective agent in Alzheimer's disease? AB - Over the last decades estrogen has been recognized to be involved in normal brain function due to its neurothrophic and neuroprotective effects. Estrogen is intimately associated with neuronal survival, mitochondrial function, neuroinflammation and cognition through genomic as well as non-genomic pathways. It is also known that the neuroprotective actions mediated by estrogens are interlinked with the insulin-like growth factor-1 (IGF-1) signaling pathway. This review is mainly devoted to explore the physiological and pathophysiological effects of estrogen and its signaling pathways in the brain. The molecular mechanisms underlying these effects are also debated. Finally, we discuss the potential neuroprotection afforded by estrogens in Alzheimer's disease pathophysiology focusing in the "window of opportunity" for the initiation of estrogen therapy as a critical factor in the fight against neurodegeneration. PMID- 20167004 TI - Niacin: from mechanisms of action to therapeutic uses. AB - Niacin has broad spectrum lipid modifying and anti-atherosclerotic properties. It is the most effective medication available for raising raise high density lipoprotein (HDL) levels. Despite statin therapy there remains a considerable residual cardiovascular risk attributed to low HDL levels. Currently, statins decrease cardiovascular events and death by about 25-40%. Trials with surrogate endpoints have shown a decrease in endpoints by 60-90% when a combination of statin and niacin has been used. There is a growing interest in niacin in combination therapy to fill the treatment gap by modifying lipid parameters other than low density lipoprotein cholesterol. This review addresses the role of niacin in comprehensive lipid management with an emphasis on its mechanism of action, formulations, side effects, evidence from clinical trials and also focuses on practical issues related to niacin therapy. PMID- 20167005 TI - The injured cochlea as a target for inflammatory processes, initiation of cell death pathways and application of related otoprotectives strategies. AB - One of the causes of sensorineural hearing loss is the loss of auditory hair cells following exposure to environmental stresses. Auditory hair cell death in response to cochlear trauma occurs via both necrosis and apoptosis. Apoptosis of hair cells involves the caspase and MAPK/JNK pathways which are activated by oxidative stress and secretion of inflammatory cytokines in response to trauma. Identification of the pathways that lead to apoptosis provides therapeutic targets for the conservation of hearing. Antioxidants reduce the level of reactive oxygen species and reactive nitrogen species generated by oxidative stress in response to acoustic trauma, aminoglycoside and platinum-based drugs. Caspase inhibitors affect both the extrinsic and intrinsic apoptotic pathways thereby reducing cisplatin, aminoglycoside, hydraulic trauma and ischemia-induced hearing losses. Corticosteroid therapy reduces inflammation and inhibits apoptosis while activating pro-survival pathways in the organ of Corti following exposure to noise, vibration, cisplatin, aminoglycoside, ischemia/reperfusion injury, bacterial meningitis and electrode insertion trauma. Inhibitors of JNK signaling pathway prevent apoptosis of auditory hair cells following electrode insertion trauma, acute labyrinthitis, acoustic trauma and aminoglycoside ototoxicity. This review provides an overview of the different pathways involved in auditory hair cell death following an environmental stress and both traditional and newly developed drugs that are currently being studied or used for the treatment of acute hearing loss. Recent patents related to otoprotective strategies to conserve hearing and auditory hair cells are also discussed in this review. PMID- 20167006 TI - Molecular diversity within clonal complex 22 methicillin-resistant Staphylococcus aureus encoding Panton-Valentine leukocidin in England and Wales. AB - Panton-Valentine leukocidin (PVL)-positive methicillin-resistant Staphylococcus aureus (MRSA) that are multi-locus sequence type clonal complex 22 (CC22) comprise a significant public health problem in the UK. In the present study we sought to determine the genetic diversity, and the respective patient demographics, among 47 PVL-MRSA with a CC22 pulsotype that occurred sporadically or in clusters in community and healthcare settings in eight of nine geographic regions in England and Wales between January 2005 and September 2007. Patient demographics and disease presentations were typical for PVL-S. aureus infections (mostly skin and soft tissue infections in individuals <40 years old); one patient with community-acquired pneumonia died. Although the isolates were closely genotypically related by spa typing and pulsed field gel electrophoresis, at least two variant groups were suggested. PCR detections demonstrated that the majority of the CC22 PVL-MRSA identified (n = 42; 89%) harboured SCCmecIVc, three had SCCmecIVd, one had SCCmecIV but was non-subtypeable, and one isolate harboured SCCmecV. At least three different PVL-encoding phages were detected: FPVL, F108PVL and an unidentified icosahedral phage. Agar dilution MIC determinations showed that the CC22 PVL-MRSA identified were typically resistant to gentamicin and trimethoprim (43 of 47 isolates) and ciprofloxacin resistance was also noted in six isolates. In conclusion, the CC22 PVL-MRSA tested were geographically disseminated but highly genetically related. The observed variances in acquired elements (most notably SCCmec and PVL-encoding phages) suggested that CC22 PVL-MRSA in England and Wales have evolved on multiple occasions. PMID- 20167007 TI - PCR amplification and high-resolution melting curve analysis as a rapid diagnostic method for genotyping members of the Mycobacterium avium intracellulare complex. AB - Some of the members of the Mycobacterium avium-intracellulare (MAI) complex are recognized as human pathogens in both immunocompromised and immunocompetent patients. The current molecular methods that are available for genotyping the MAI complex members can be both expensive and technically demanding. In this report, we describe for the first time the application of a real-time PCR and high resolution melt approach to differentiate between the complex members by targeting a member of the Pro- Pro-Glu gene family, MACPPE24. To this end, reference strains of the M. avium subspecies and Mycobacterium intracellulare were used to optimize the technique. Then, this real-time PCR-high-resolution melt approach was used to distinguish ten M. avium ssp. hominissuis field isolates from the M. intracellulare reference strain. PMID- 20167008 TI - Effect of time to onset on clinical features and prognosis of post-sternotomy mediastinitis. AB - Incubation time affects the clinical features and outcome of many nosocomial infections. However, its role in the setting of post-sternotomy mediastinitis (PSM) has not been specifically studied. The present study aimed to evaluate the impact of time to onset of PSM on the clinical presentation and outcomes of patients. Hospital records of 197 patients who developed PSM over a 10-year period and were treated by closed drainage using Redon catheters were reviewed retrospectively. Follow-up was complete for all included patients (median of 19 months); 98 patients developed early-onset PSM (time from initial operation to PSM <14 days) and 99 patients had late-onset PSM (>=14 days). Patients with late onset PSM had a higher rate of internal thoracic artery harvest and mediastinal re-exploration after initial operation. Patients with early-onset PSM presented more frequently with septic shock. Microbiological findings differed between early- and late-onset PSM by a higher incidence of Enterococcus species in the former and of Staphylococcus aureus in the latter. Overall mortality reached 34% (n = 66). Rates of superinfection, treatment failure, mediastinitis-related death, mortality at 1 year and overall mortality were all significantly higher in patients with early-onset PSM. Multiple regression procedures identified early onset PSM as a significant and independent risk factor for both 1-year (OR 2.40; 95% CI 1.12-5.11) and overall (OR 2.11; 95% 1.26-3.53) mortality. In conclusion, the results obtained in the present study support the distinction between early- and late-onset PSM with different clinical and pathophysiological features. Early onset PSM is associated with a significantly higher morbidity and mortality compared to late-onset PSM. PMID- 20167009 TI - Fatal case of Reye's syndrome associated with H3N2 influenza virus infection and salicylate intake in a 12-year-old patient. AB - We describe a fatal case of Reye's syndrome in a 12-year-old male patient during an influenza A (H3N2) infection for which he received salicylates. In the current situation of the novel A/H1N1 virus pandemic, we believe that it is of high importance to emphasize the risks associated with salicylate intake to avoid the reappearance of Reye's syndrome. PMID- 20167010 TI - Capnocytophaga canimorsus infections in The Netherlands: a nationwide survey. AB - A retrospective nationwide survey on the occurrence of Capnocytophaga canimorsus and Capnocytopaga cynodegmi infections in The Netherlands over 3 years showed 32 cases, of which 31 were caused by C. canimorsus and one by an unspecified oxidase positive Capnocytophaga strain. Twenty-eight patients had been diagnosed by blood culture, one by culture from both blood and cerebrospinal fluid (CSF), one by culture from a conjunctival swab, and two patients by 16S rRNA gene amplification by PCR directly from a blood or CSF specimen. The incidence rate was 0.67 infections per million population. Bacteraemia was found in 94% of the cases. The age range of patients was 38-80 years; 72% of them were male. Among 26 patients from whom clinical data were available, splenectomy was not reported, but alcoholism was reported in five. Nine patients (35%) had been admitted to the intensive-care unit, and three patients (13%) died. The mortality rate was much lower than observed in previous studies. PMID- 20167012 TI - The Nasonia genome sequence: finding gems in the jewel (wasp) box. PMID- 20167013 TI - Two novel proteins expressed by the venom glands of Apis mellifera and Nasonia vitripennis share an ancient C1q-like domain. AB - An in-depth proteomic study of previously unidentified two-dimensional polyacrylamide gel electrophoresis spots of honey bee (Apis mellifera, Hymenoptera) venom revealed a new protein with a C1q conserved domain (C1q-VP). BlastP searching revealed a strong identity with only two proteins from other insect species: the jewel wasp, Nasonia vitripennis (Hymenoptera), and the green pea aphid, Acyrthosiphon pisum (Hemiptera). In higher organisms, C1q is the first subcomponent of the classical complement pathway and constitutes a major link between innate and acquired immunity. Expression of C1q-VP in a variety of tissues of honey bee workers and drones was demonstrated. In addition, a wide spatial and temporal pattern of expression was observed in N. vitripennis. We suggest that C1q-VP represents a new member of the emerging group of venom trace elements. Using degenerate primers the corresponding gene was found to be highly conserved in eight hymenopteran species, including species of the Aculeata and the Parasitica groups (suborder Apocrita) and even the suborder Symphyta. A preliminary test using recombinant proteins failed to demonstrate Am_C1q-VP specific immunoglobulin E recognition by serum from patients with a documented severe bee venom allergy. PMID- 20167015 TI - Transfers of mitochondrial DNA to the nuclear genome in the wasp Nasonia vitripennis. AB - Many organisms carry nuclear sequences of mitochondrial origin (NUMTs). We have identified 76 NUMTs in 25 genomic locations in the jewel wasp Nasonia vitripennis. The total amount of NUMTs in Nasonia is 42 972 bp exceeding over four-fold that found in Tribolium castaneum and almost fifty-fold that found in Drosophila melanogaster, whereas Apis mellifera has an even larger number of NUMTs in its genome (over 230 kb). The Nasonia NUMTs were inserted by multiple independent events and frequently involved large fragments spanning multiple mitochondrial genes. Most of the NUMTs are recent transfers that occurred less than one million years ago after the speciation of N. vitripennis. Duplications and rearrangements in the nucleus have also occurred. Data suggest that NUMTs may be more common in hymenoptera than in other insect genomes. PMID- 20167016 TI - Maintenance of multiple lineages of R1 and R2 retrotransposable elements in the ribosomal RNA gene loci of Nasonia. AB - Sequencing reads from the Nasonia genome project were used to study the ribosomal RNA gene loci and the retrotransposons R1 and R2 that insert specifically into the 28S genes. Five highly divergent R1 and five highly divergent R2 families were identified in the three sequenced species, as well as a non-autonomous element that appears to use the retrotransposition machinery of R1. A duplication of the R1 target site within the spacer region of the rDNA units was also found to be extensively utilized by R1 elements. We document numerous instances where the R1 and R2 families appropriated parts of the retrotransposition machinery of other lineages and speculate that this enables rapid adaptation and the maintenance of multiple R1 and R2 families. PMID- 20167014 TI - Insights into the venom composition of the ectoparasitoid wasp Nasonia vitripennis from bioinformatic and proteomic studies. AB - With the Nasonia vitripennis genome sequences available, we attempted to determine the proteins present in venom by two different approaches. First, we searched for the transcripts of venom proteins by a bioinformatic approach using amino acid sequences of known hymenopteran venom proteins. Second, we performed proteomic analyses of crude N. vitripennis venom removed from the venom reservoir, implementing both an off-line two-dimensional liquid chromatography matrix-assisted laser desorption/ ionization time-of-flight (2D-LC-MALDI-TOF) mass spectrometry (MS) and a two-dimensional liquid chromatography electrospray ionization Founer transform ion cyclotron resonance (2D-LC-ESI-FT-ICR) MS setup. This combination of bioinformatic and proteomic studies resulted in an extraordinary richness of identified venom constituents. Moreover, half of the 79 identified proteins were not yet associated with insect venoms: 16 proteins showed similarity only to known proteins from other tissues or secretions, and an additional 23 did not show similarity to any known protein. Serine proteases and their inhibitors were the most represented. Fifteen nonsecretory proteins were also identified by proteomic means and probably represent so-called 'venom trace elements'. The present study contributes greatly to the understanding of the biological diversity of the venom of parasitoid wasps at the molecular level. PMID- 20167017 TI - Comparative analysis of nuclear tRNA genes of Nasonia vitripennis and other arthropods, and relationships to codon usage bias. AB - Using bioinformatics methods, we identified a total of 221 and 199 tRNA genes in the nuclear genomes of Nasonia vitripennis and honey bee (Apis mellifera), respectively. We performed comparative analyses of Nasonia tRNA genes with honey bee and other selected insects to understand genomic distribution, sequence evolution and relationship of tRNA copy number with codon usage patterns. Many tRNA genes are located physically close to each other in the form of small clusters in the Nasonia genome. However, the number of clusters and the tRNA genes that form such clusters vary from species to species. In particular, the Ala-, Pro-, Tyr- and His-tRNA genes tend to accumulate in clusters in Nasonia but not in honey bee, whereas the bee contains a long cluster of 15 tRNA genes (of which 13 are Gln-tRNAs) that is absent in Nasonia. Though tRNA genes are highly conserved, contrasting patterns of nucleotide diversity are observed among the arm and loop regions of tRNAs between Nasonia and honey bee. Also, the sequence convergence between the reconstructed ancestral tRNAs and the present day tRNAs suggests a common ancestral origin of Nasonia and honey bee tRNAs. Furthermore, we also present evidence that the copy number of isoacceptor tRNAs (those having a different anticodon but charge the same amino acid) is correlated with codon usage patterns of highly expressed genes in Nasonia. PMID- 20167018 TI - The draft genome sequence of Arsenophonus nasoniae, son-killer bacterium of Nasonia vitripennis, reveals genes associated with virulence and symbiosis. AB - Four percent of female Nasonia vitripennis carry the son-killer bacterium Arsenophonus nasoniae, a microbe with notably different biology from other inherited parasites and symbionts. In this paper, we examine a draft genome sequence of the bacterium for open reading frames (ORFs), structures and pathways involved in interactions with its insect host. The genome data suggest that A. nasoniae carries multiple type III secretion systems, and an array of toxin and virulence genes found in Photorhabdus, Yersinia and other gammaproteobacteria. Of particular note are ORFs similar to those known to affect host innate immune functioning in other bacteria, and four ORFs related to pro-apoptotic exotoxins. The genome sequences for both A. nasoniae and its Nasonia host are useful tools for examining functional genomic interactions of microbial survival in hostile immune environments, and mechanisms of passage through gut epithelia, in a whole organism context. PMID- 20167019 TI - Characteristics of the genome of Arsenophonus nasoniae, son-killer bacterium of the wasp Nasonia. AB - We report the properties of a draft genome sequence of the bacterium Arsenophonus nasoniae, son-killer bacterium of Nasonia vitripennis. The genome sequence data from this study are the first for a male-killing bacterium, and represent a microorganism that is unusual compared with other sequenced symbionts, in having routine vertical and horizontal transmission, two alternating hosts, and being culturable on cell-free media. The resulting sequence totals c. 3.5 Mbp and is annotated to contain 3332 predicted open reading frames (ORFs). Therefore, Arsenophonus represents a relatively large genome for an insect symbiont. The annotated ORF set suggests that the microbe is capable of a broad array of metabolic functions, well beyond those found for reproductive parasite genomes sequenced to date and more akin to horizontally transmitted and secondary symbionts. We also find evidence of genetic transfer from Wolbachia symbionts, and phage exchange with other gammaproteobacterial symbionts. These findings reflect the complex biology of a bacterium that is able to live, invade and survive multiple host environments while resisting immune responses. PMID- 20167020 TI - The distribution of microsatellites in the Nasonia parasitoid wasp genome. AB - Microsatellites are important molecular markers used in numerous genetic contexts. Despite this widespread use, the evolutionary processes governing microsatellite distribution and diversity remain controversial. Here, we present results on the distribution of microsatellites of three species in the parasitic wasp genus Nasonia generated by an in silico data-mining approach. Our results show that the overall microsatellite density in Nasonia is comparable to that of the honey bee, but much higher than in eight non-Hymenopteran arthropods. Across the Nasonia vitripennis genome, microsatellite density varied both within and amongst chromosomes. In contrast to other taxa, dinucleotides are the most abundant repeat type in all four species of Hymenoptera studied. Whether the differences between the Hymenoptera and other taxa are of functional significance remains to be determined. PMID- 20167021 TI - Data mining cDNAs reveals three new single stranded RNA viruses in Nasonia (Hymenoptera: Pteromalidae). AB - We report three novel small RNA viruses uncovered from cDNA libraries from parasitoid wasps in the genus Nasonia. The genome of this kind of virus is a positive-sense single-stranded RNA with a 3' poly(A), which facilitates cloning from cDNAs. Two of the viruses, NvitV-1 and NvitV-2, possess a RNA-dependent RNA polymerase that associates them with the family Iflaviridae of the order Picornavirales. A third virus, NvitV-3, is most similar to the Nora virus from Drosophila. A reverse transcription-PCR method developed for NvitV-1 indicates that it is a persistent commensal infection of Nasonia. PMID- 20167023 TI - The insect chemoreceptor superfamily of the parasitoid jewel wasp Nasonia vitripennis. AB - Chemoreception is important for locating food, mates and other resources in many insects, including the parasitoid jewel wasp Nasonia vitripennis. In the insect chemoreceptor superfamily, Nasonia has 58 gustatory receptor (Gr) genes, of which 11 are pseudogenes, leaving 47 apparently intact proteins encoded. No carbon dioxide receptors, two candidate sugar receptors, a DmGr43a orthologue, and several additional Gr lineages were identified, including significant gene subfamily expansions related to the 10 Grs found in the honey bee Apis mellifera. Nasonia has a total of 301 odorant receptor (Or) genes, of which 76 are pseudogenes, leaving 225 apparently intact Ors. Phylogenetic comparison with the 174 honey bee Ors reveals differential gene subfamily expansion in each hymenopteran lineage, along with a few losses from each species. The only simple orthologous relationship is the expected single DmOr83b orthologue. The large number of Nasonia Ors is the result of several major subfamily expansions, including one of 55 genes. Nasonia does not have the elaborate social chemical communication of honey bees, nor the diversity of floral odours honey bees detect, however, Nasonia wasps might need to detect a diversity of odours to find potential mates and hosts or avoid harmful substances in its environment. PMID- 20167024 TI - Organization, evolution and transcriptional profile of hexamerin genes of the parasitic wasp Nasonia vitripennis (Hymenoptera: Pteromalidae). AB - Hexamerins and prophenoloxidases (PPOs) proteins are members of the arthropod haemocyanin superfamily. In contrast to haemocyanin and PPO, hexamerins do not bind oxygen, but mainly play a role as storage proteins that supply amino acids for insect metamorphosis. We identified seven genes encoding hexamerins, three encoding PPOs, and one hexamerin pseudogene in the genome of the parasitoid wasp Nasonia vitripennis. A phylogenetic analysis of hexamerins and PPOs from this wasp and related proteins from other insect orders suggests an essentially order specific radiation of hexamerins. Temporal and spatial transcriptional profiles of N. vitripennis hexamerins suggest that they have physiological functions other than metamorphosis, which are arguably coupled with its lifestyle. PMID- 20167022 TI - Identification and characterization of Nasonia Pax genes. AB - Pax genes are a group of critical developmental transcriptional regulators in both invertebrates and vertebrates, characterized by the presence of a paired DNA binding domain. Pax proteins also often contain an octapeptide motif and a C terminal homeodomain. The genome of Nasonia vitripennis (Hymenoptera) has recently become available, and analysis of this genome alongside Apis mellifera allowed us to contribute to the phylogeny of this gene family in insects. Nasonia, a parasitic wasp, has independently evolved a similar mode of development to that of the well-studied Drosophila, making it an excellent model system for comparative studies of developmental gene networks. We report the characterization of the seven Nasonia Pax genes. We describe their genomic organization, and the embryonic expression of three of them, and uncover wider conservation of the octapeptide motif than previously described. PMID- 20167025 TI - Metabolic enzymes associated with xenobiotic and chemosensory responses in Nasonia vitripennis. AB - The numbers of glutathione S-transferase, cytochrome P450 and esterase genes in the genome of the hymenopteran parasitoid Nasonia vitripennis are about twice those found in the genome of another hymenopteran, the honeybee Apis mellifera. Some of the difference is associated with clades of these families implicated in xenobiotic resistance in other insects and some is in clades implicated in hormone and pheromone metabolism. The data support the hypothesis that the eusocial behaviour of the honeybee and the concomitant homeostasis of the nest environment may obviate the need for as many gene/enzyme systems associated with xenobiotic metabolism as are found in other species, including N. vitripennis, that are thought to encounter a wider range of potentially toxic xenobiotics in their diet and habitat. PMID- 20167026 TI - Inventory and phylogenomic distribution of meiotic genes in Nasonia vitripennis and among diverse arthropods. AB - The parasitoid jewel wasp Nasonia vitripennis reproduces by haplodiploidy (arrhenotokous parthenogenesis). In diploid females, meiosis occurs during oogenesis, but in haploid males spermatogenesis is ameiotic and involves a single equational division. Here we describe the phylogenomic distribution of meiotic genes in N. vitripennis and in 10 additional arthropods. Homologues for 39 meiosis-related genes (including seven meiosis-specific genes) were identified in N. vitripennis. The meiotic genes missing from N. vitripennis are also sporadically absent in other arthropods, suggesting that certain meiotic genes are dispensable for meiosis. Among an additional set of 15 genes thought to be specific for male meiosis in Drosophila, two genes (bol and crl) were identified in N. vitripennis and Apis mellifera (both for which canonical meiosis is absent in males) and in other arthropods. The distribution of meiotic genes across arthropods and the impact of gene duplications and reproductive modes on meiotic gene evolution are discussed. PMID- 20167027 TI - Development of bacterial artificial chromosome library resources for parasitoid Hymenoptera (Nasonia vitripennis and Nasonia giraulti: Pteromalidae). AB - The species of the genus Nasonia possess qualities that make them excellent candidates for genetic and genomic studies. To increase the wealth of genomic resources for the genus we constructed publicly available bacterial artificial chromosome (BAC) libraries for Nasonia vitripennis and Nasonia giraulti. Libraries have 36 864 clones each, empty-vector contents of approximately 2% and average insert sizes of 113.1 and 97.7 Kb, respectively, representing 12 and 11 genome equivalents. The N. vitripennis library was used for genome sequence assembly and in efforts at positional cloning of a developmental gene. The genome assembly of N. vitripennis is currently composed on 6181 un-joined scaffolds. These BAC libraries can be used to identify and close regions between scaffolds of the genome assemblies of both species. PMID- 20167028 TI - Great expectations fulfilled. PMID- 20167029 TI - Hypertension prevalence and prescribing trends in older US adults: 1999-2004. AB - To describe hypertension trends in US adults aged 65 years and older using Medicare Current Beneficiary Survey (MCBS) data, a cross-sectional, nationally representative health examination survey from MCBS files between 1999 and 2004 was investigated. Overall, 62% of beneficiaries, or an estimated 20 million US adults aged 65 years and older, were hypertensive as extrapolated from MCBS data. From 1999 to 2004, the prevalence rate of hypertension increased from 59% to 65% (P<.001). Nonwhite persons and women had a higher prevalence of hypertension than whites and men. A history of diabetes mellitus, prior myocardial infarction, coronary artery disease, or stroke was significantly associated with hypertension treatment. In addition, significant geographic variation in treatment was noted. There was a significant increase in hypertension prevalence in older Medicare beneficiaries from 1999 to 2004. Women, patients 85 years and older, and nonwhite patients were less likely to be treated with antihypertensive medications, and significant geographic variation existed in treatment. PMID- 20167030 TI - Does "hidden undercuffing" occur among obese patients? Effect of arm sizes and other predictors of the difference between wrist and upper arm blood pressures. AB - Arm size can affect the accuracy of blood pressure (BP) measurement, and "undercuffing" of large upper arms is likely to be a growing problem. Therefore, the authors investigated the relationship between upper arm and wrist readings. Upper arm and wrist circumferences and BP were measured in 261 consecutive patients. Upper arm auscultation and wrist BP was measured in triplicate, rotating measurements every 30 seconds between sites. Upper arm BP was 131.9+/ 20.6/71.6+/-12.6 mm Hg in an obese population (body mass index, 30.6+/-6.6 kg/m(2)) with mean upper arm size of 30.7+/-5.1 cm. Wrist BP was higher (2.6+/ 9.2 mm Hg and 4.9+/-6.6 mm Hg, respectively, P<.001); however, there was moderate concordance for the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) strata (kappa value=0.27-0.71), and the difference was >or=5 mm Hg in 72% of the patients. The authors conclude that there was poor concordance between arm and wrist BP measurement and found no evidence that "hidden undercuffing" was associated with obesity; therefore, they do not support routine use of wrist BP measurements. PMID- 20167031 TI - Health care services provided during physician office visits for hypertension: differences by specialty. AB - The changing health care system has reduced patients' access to specialty care. Often, patients with hypertension visit noncardiologists. The objective of this study is to compare differences by physician specialty in the provision of health care services during office visits for hypertension. The authors examined office visits for US physicians by using data from the National Ambulatory Medical Care Survey for 2003 to 2005. Of more than 274 million hypertension visits, 35.5%, 43.9%, 8.5%, and 12.1% visits were made to general practitioners/family physicians, internists, cardiologists, and other specialties, respectively. Visitors to cardiologists were more likely to have coronary heart disease and heart failure than visitors to other physicians. While prescriptions for antihypertensive drugs overall were similar by specialty, cardiologists were more likely to prescribe lipid-lowering drugs (odds ratio [OR], 1.60; 95% confidence interval [CI], 1.14-2.24) and aspirin (OR, 2.76; 95% CI, 1.81-4.20), calcium channel blockers (OR, 1.48; 95% CI, 1.12-1.96), beta-blockers (OR, 1.83; 95% CI, 1.35-2.48), and alpha-blockers (OR, 2.10; 95% CI, 1.46-2.95) than general practitioners/family physicians after adjusting for relevant risk factors. There was no difference by specialty in providing/making a referral for nutrition/exercise counseling among physicians. Among hypertension office visits in the United States, cardiologists were more likely to provide lipid-lowering drugs, aspirin, calcium channel blocker, beta-blockers, and alpha-blockers than other physicians. PMID- 20167032 TI - Association of calcium-phosphorus product with blood pressure in dialysis. AB - Hypertension is very common in dialysis patients. Disorders of mineral metabolism have been linked to vascular calcification and hypertension in dialysis. Fifty four hemodialysis patients were included in a cross-sectional study in a dialysis unit during a 6-month period. Linear regression analysis was done between averages of calcium and phosphorus (ca x ph) product and blood pressures (BPs). Ca x ph was significantly associated with systolic BP predialysis (P=.03, R=0.28), diastolic BP predialysis (P=.001, R=0.44), predialysis mean arterial pressure (MAP) (P=.002, R=0.4), and diastolic BP postdialysis (P=.03, R=0.26). No relationship was found with pulse pressures. Multilinear regression analysis was then done between ca x ph product and BPs adjusting for age, sex, hemoglobin, diabetes, albumin, parathyroid hormone, ultrafiltration volume, and average BP medications per patient. There was a strong positive association with predialysis systolic BP (P=.003, R(2)=0.49), predialysis MAP (P=.001, R(2)=0.51), and postdialysis MAP (P=.02, R(2)=0.65). No associations with pulse pressures were detected. The study findings suggest that ca x ph product is significantly associated with dialysis MAP and not pulse pressure. This is likely secondary to the stronger relationship with diastolic BP than with systolic BP. Prospective studies looking into the associated hemodynamic parameters related to arterial stiffness and endothelial dysfunction along with measures for calcifications would be very beneficial. PMID- 20167033 TI - The hypertension paradox. PMID- 20167034 TI - Malignant pheochromocytoma presenting with uncontrolled hypertension after kidney transplant. PMID- 20167035 TI - A lower blood pressure goal in patients without diabetes lessens the occurrence of left ventricular hypertrophy. PMID- 20167036 TI - Leadership message. Maintaining core values. PMID- 20167039 TI - Serial changes in norepinephrine kinetics associated with feeding dogs a high-fat diet. AB - The role of increased sympathetic nervous system (SNS) activity in the pathogenesis of obesity hypertension and insulin resistance is controversial. Eight dogs were instrumented and fed a high-fat diet (HFD) for 6 weeks. Dogs were evaluated for changes in weight, blood pressure, insulin resistance, and norepinephrine (NE) kinetics using a two-compartment model. The HFD resulted in weight gain, hypertension, and insulin resistance. During the 6 weeks of the HFD, although plasma NE concentration trended toward increasing (P=.09), SNS, assessed by NE kinetic studies, significantly increased (P=.009). Within 1 week of starting the HFD, NE release into the extravascular compartment (NE(2)) increased from 3.44+/-0.59 microg/mL to 4.87+/-0.80 microg/mL (P<.01) and this increase was maintained over the next 5 weeks of the HFD (NE(2) at week 6 was 4.66+/-0.97 microg/mL). In addition to the increased NE(2) there was also a significant increase in NE clearance (P=.04). There were significant correlations between the increase in NE(2) and both the development of insulin resistance and hypertension. This study supports the hypothesis that activation of the SNS plays a pivotal role in the metabolic and hemodynamic changes that occur with weight gain induced by HFD. PMID- 20167040 TI - Association of capillary density and function measures with blood pressure, fasting plasma glucose, and insulin sensitivity. AB - The pathophysiology underlying the association between hypertension and insulin resistance remains unclear. The study purpose was to determine whether reduced capillary density and/or function underlie, and may therefore explain, this association. The study was conducted on 115 black and non-black participants aged 18 to 55 years: 91 with normal blood pressure (systolic blood pressure [SBP] <130 mm Hg) and 24 with mild blood pressure elevation (SBP 130-159 mm Hg). Capillary density and function were quantified using direct capillaroscopy measures. Insulin sensitivity (IS) was estimated using the Quantitative Insulin Sensitivity Check Index (QUICKI). Endothelial function (EF) was measured using strain-gauge plethysmography. Data were analyzed by linear regression adjusted for age, sex, race, and body mass index (BMI). After adjustment for BMI, capillary density and function measures were significant predictors of SBP ( P<.01), fasting plasma glucose (P=.012, P=.03, and P=.004, respectively), and EF (P=.033, P=.001, and P=.009, respectively). However, none of the capillary measures were significant predictors of fasting insulin or IS. These capillaroscopy data demonstrated an association with SBP but not insulin resistance, suggesting that capillary measures are unlikely to explain the association between hypertension and insulin resistance, at least with modest degrees of blood pressure elevation. PMID- 20167041 TI - High inflammatory activity related to the number of metabolic syndrome components. AB - It has been known that each component of the metabolic syndrome (MS) has an atherogenic potential and increases the risk of cardiovascular events. Therefore, patients who have MS are candidates for the development of atherosclerosis and accompanying complications. In this study, the authors assessed the levels of acute phase reactants as an indicator of inflammation in patients with MS. Twenty five patients with recently diagnosed MS and not treated before who had at least 3 of 5 diagnostic criteria of MS listed in the Third Report of the Adult Treatment Panel National Cholesterol Education Program (NCEP-ATP III) guidelines were included in the study. Twenty healthy patients constituted the control group. Inflammatory parameters were compared between the groups. There was no significant difference between the MS and control group with regard to age and sex. White blood cell count (/mm(3)), high-sensitivity C-reactive protein (hs CRP), uric acid, interleukin (IL) 6, and fibrinogen levels were found to be significantly higher in the MS group. Number of MS components was strongly correlated with serum levels of hs-CRP (r=0.688, P=.0001), IL-6 (r=0.546, P=.0001), fibrinogen (r=0.551, P=.0001), uric acid (r=0.517, P=.0001), and leucocyte count (/mm(3)) (r=0.456, P=.002). Inflammation plays an important role in atherosclerotic complications, which is activated in MS. Increased number of MS components are strongly associated with elevated inflammatory and metabolic markers. Measurement of serum inflammatory parameters in patients with MS may be beneficial in detection and management of cardiovascular events and in the assessment of efficacy of treatment. PMID- 20167042 TI - News from recent clinical trials: Implications for clinical practice and the treatment of hypertension. PMID- 20167043 TI - Rewards for commitment and success. PMID- 20167044 TI - An early report from newly established laboratory-based influenza surveillance in Lao PDR. AB - BACKGROUND: Prior to 2007, little information was available about the burden of influenza in Laos. We report data from the first laboratory-based influenza surveillance system established in the Lao People's Democratic Republic. METHODS: Three hospitals in the capital city of Vientiane began surveillance for influenza like illness (ILI) in outpatients in 2007 and expanded to include hospitalized pneumonia patients in 2008. Nasal/throat swab specimens were collected and tested for influenza and other respiratory viruses by multiplex ID-Tag respiratory viral panel (RVP) assay on a Luminex 100x MAP IS instrument (Qiagen, Singapore). RESULTS: During January 2007 to December 2008, 287 of 526 (54.6%) outpatients with ILI were positive for at least one respiratory virus. Influenza was most commonly identified, with 63 (12.0%) influenza A and 92 (17.5%) influenza B positive patients identified. In 2008, six of 79 (7.6%) hospitalized pneumonia patients were positive for influenza A and four (5.1%) were positive for influenza B. Children <5 years represented 19% of viral infections in outpatients and 38% of pneumonia inpatients. CONCLUSION: Our results provide the first documentation of influenza burden among patients with febrile respiratory illness and pneumonia requiring hospitalization in Laos. Implementing laboratory-based influenza surveillance requires substantial investments in infrastructure and training. However, continuing outbreaks of avian influenza A/H5N1 in poultry and emergence of the 2009 influenza A(H1N1) pandemic strain further underscore the importance of establishing and maintaining influenza surveillance in developing countries. PMID- 20167045 TI - Experimental inoculation of pigs with pandemic H1N1 2009 virus and HI cross reactivity with contemporary swine influenza virus antisera. AB - BACKGROUND: A novel A/H1N1 was identified in the human population in North America in April 2009. The gene constellation of the virus was a combination from swine influenza A viruses (SIV) of North American and Eurasian lineages that had never before been identified in swine or other species. OBJECTIVES: The objectives were to (i) evaluate the clinical response of swine following experimental inoculation with pandemic H1N1 2009; (ii) assess serologic cross reactivity between H1N1 2009 and contemporary SIV antisera; and (iii) develop a molecular assay to differentiate North American-lineage SIV from H1N1 2009. METHODS: Experiment 1: Weaned pigs were experimentally infected with A/California/04/2009 (H1N1). Experiment 2: The cross-reactivity of a panel of US SIV H1N1 or H1N2 antisera with three isolates of pandemic A/H1N1 was evaluated. Experiment 3: A polymerase chain reaction (PCR)-based diagnostic test was developed and validated on samples from experimentally infected pigs. RESULTS AND CONCLUSIONS: In experiment 1, all inoculated pigs demonstrated clinical signs and lesions similar to those induced by endemic SIV. Viable virus and antigen were only detected in the respiratory tract. In experiment 2, serologic cross reactivity was limited against H1N1 2009 isolates, notably among virus antisera from the same HA phylogenetic cluster. The limited cross-reactivity suggests North American pigs may not be fully protected against H1N1 2009 from previous exposure or vaccination and novel tests are needed to rapidly diagnose the introduction of H1N1 2009. In experiment 3, an RT-PCR test that discriminates between H1N1 2009 and endemic North American SIV was developed and validated on clinical samples. PMID- 20167046 TI - Protecting health care workers: a pandemic simulation based on Allegheny County. AB - BACKGROUND AND OBJECTIVES: The Advisory Committee on Immunization Practices has identified health care workers (HCWs) as a priority group to receive influenza vaccine. Although the importance of HCW to the health care system is well understood, the potential role of HCW in transmission during an epidemic has not been clearly established. METHODS: Using a standard SIR (Susceptible-Infected Recovered) framework similar to previously developed pandemic models, we developed an agent-based model (ABM) of Allegheny County, PA, that incorporates the key health care system features to simulate the spread of an influenza epidemic and its effect on hospital-based HCWs. FINDINGS: Our simulation runs found the secondary attack rate among unprotected HCWs to be approximately 60% higher (54.3%) as that of all adults (34.1%), which would result in substantial absenteeism and additional risk to HCW families. Understanding how a pandemic may affect HCWs, who must be available to treat infected patients as well as patients with other medical conditions, is crucial to policy makers' and hospital administrators' preparedness planning. PMID- 20167047 TI - A novel electrochemical device to differentiate pandemic (H1N1) 2009 from seasonal influenza. AB - BACKGROUND: One of the challenges of the recent pandemic (H1N1) 2009 influenza outbreak was to differentiate the virus from seasonal influenza when confronting clinical cases. The determination of the virus has implications on treatment choice, and obvious epidemiologic significance. OBJECTIVES: We set out to apply a novel electrochemical device to samples derived from clinical cases of pandemic (H1N1) 2009 influenza to examine the ability of the device to differentiate these samples from cases of seasonal influenza. PATIENTS/METHODS: An IRB approved protocol allowed for the use of original nasal wash samples from 24 confirmed human cases pandemic (H1N1) 2009 influenza. Clinical samples from cases of seasonal influenza (Influenza A/H1N1, A/H3N2, and B) were included as controls. Nucleic acids were extracted and samples examined by the ElectraSense Influenza A assay (CombiMatrix, Inc). Samples were also examined by RT-PCR or Luminex assays as a comparator. RESULTS AND CONCLUSIONS: The ElectraSense Influenza A assay correctly identified 23 of 24 samples of laboratory-confirmed pandemic (H1N1) 2009 Influenza. The assay correctly identified all samples of influenza A/H1N1 and A/H3N2, and differentiated these from pandemic (H1N1) 2009 Influenza in all cases. The ElectraSense Influenza A assay proved to be a useful assay to quickly and accurately differentiate pandemic (H1N1) 2009 influenza from seasonal influenza. PMID- 20167048 TI - The Spanish influenza pandemic in occidental Europe (1918-1920) and victim age. AB - BACKGROUND: Studies of the Spanish Influenza pandemic (1918-1920) provide interesting information that may improve our preparation for present and future influenza pandemic threats. METHODS: We studied archives from France, Italy, Spain and Portugal, obtaining high-quality data that allowed us to calculate mortality rates associated with the Spanish flu and to characterize the proportional distribution of influenza deaths by age in the capital cities of these countries. RESULTS: French and American troops who fought in the First World War began to be affected from April 1918 onwards by a benign influenza epidemic, which hardly caused any deaths. The first occidental European country in which the pandemic spread to large sectors of the population, causing serious mortality, was Spain. The associated influenza provoked in Madrid a mortality rate of 1.31 per 1000 inhabitants between May and June (1918). In the following months of June and July, the epidemic spread to Portugal, but did not reach the Pyrenees. In September 1918, the influenza pandemic spread with tremendous virulence, presenting itself simultaneously during the month of October in South Western European countries. In Madrid, the 1918 excess mortality due in large part to the influenza pandemic is estimated at 5.27 per 1000. In Paris, the 1918 mortality rate provoked by the influenza and pathologies of the respiratory system was 6.08 per 1000. In South Western European countries, mortality rates oscillated between 10.6 and 12.1 per 1000 inhabitants. A study of the age distribution of deaths due to influenza between 1916 and 1921 reveals that the Spanish influenza principally affected men and women between 15 and 44 years of age. Deaths associated with the seasonal influenza of 1916, 1917 and 1921 represented 19.7%, 12.5% and 21.0% of all deaths respectively, whereas during the rawest moments of the Spanish influenza, in 1918, the proportion of deaths due to flu for those aged between 15 and 44 years of age reached 68.2% in Paris and 66.3% in Madrid. CONCLUSION: Victim age is an important criterion that can be used to evaluate the phase and evolution of pandemic influenza. The Spanish Influenza affected particularly the 25- to 34-year-old and 15- to 24-year-old age groups. PMID- 20167049 TI - Low-pathogenic notifiable avian influenza serosurveillance and the risk of infection in poultry - a critical review of the European Union active surveillance programme (2005-2007). AB - BACKGROUND: Since 2003, Member States (MS) of the European Union (EU) have implemented serosurveillance programmes for low pathogenic notifiable avian influenza (LPNAI) in poultry. To date, there is the need to evaluate the surveillance activity in order to optimize the programme's surveillance design. OBJECTIVES: To evaluate MS sampling operations [sample size and targeted poultry types (PTs)] and its relation with the probability of detection and to estimate the PTs relative risk (RR) of being infected. METHODS: Reported data of the surveillance carried out from 2005 to 2007 were analyzed using: (i) descriptive indicators to characterize both MS sampling operations and its relation with the probability of detection and the LPNAI epidemiological situation, and (ii) multivariable methods to estimate each PTs RR of being infected. RESULTS: Member States sampling a higher sample size than that recommended by the EU had a significantly higher probability of detection. Poultry types with ducks & geese, game-birds, ratites and "others" had a significant higher RR of being seropositive than chicken categories. The seroprevalence in duck & geese and game bird holdings appears to be higher than 5%, which is the EU-recommended design prevalence (DP), while in chicken and turkey categories the seroprevalence was considerably lower than 5% and with that there is the risk of missing LPNAI seropositive holdings. CONCLUSION: It is recommended that the European Commission discusses with its MS whether the results of our evaluation calls for refinement of the surveillance characteristics such as sampling frequency, the between holding DP and MS sampling operation strategies. PMID- 20167050 TI - Pre-dispensing of antivirals to high-risk individuals in an influenza pandemic. AB - We consider the net benefits of pre-dispensing antivirals to high-risk individuals during an influenza pandemic, where the measure of the benefit is the number of severe outcomes (such as deaths or hospitalizations) prevented by antivirals in the whole population. One potential benefit of pre-dispensing is that individuals to whom antivirals have been pre-dispensed may be able to initiate treatment earlier than if they had to wait to obtain and fill a prescription, reducing their risk of progression to severe disease. If this benefit exceeds the side effects of misuse for the category of individuals to whom antivirals were pre-dispensed, and if antiviral supply exceeds overall population demand (which appears relevant for several countries including US in the 2009 H1N1 pandemic), pre-dispensing a quantity of antivirals not exceeding the difference between supply and demand is always beneficial. In this study, we consider the net benefits of pre-dispensing antivirals under various scenarios, including demand exceeding supply, and derive mathematical conditions under which antiviral pre-dispensing is advantageous on balance. For individuals whose relative risk of severe outcome is high enough, such as immunosuppressed individuals (particularly children) and possibly individuals with neurological disorders, pre-dispensing is always beneficial at a given level of antiviral stockpile with modest assumptions on the relative benefit of early treatment by a pre-dispensed course, regardless of the overall population demand for antivirals during the course of an epidemic. Making additional assumptions on either the overall population demand for antivirals (which appear relevant for the 2009 H1N1 pandemic) or on the relative benefit of pre-dispensing would make pre-dispensing net beneficial with inclusion of a larger number of persons such as pregnant women and morbidly obese adults. PMID- 20167051 TI - Genomic sequencing and analyses of Lymantria xylina multiple nucleopolyhedrovirus. AB - BACKGROUND: Outbreaks of the casuarina moth, Lymantria xylina Swinehoe (Lepidoptera: Lymantriidae), which is a very important forest pest in Taiwan, have occurred every five to 10 years. This moth has expanded its range of host plants to include more than 65 species of broadleaf trees. LyxyMNPV (L. xylina multiple nucleopolyhedrovirus) is highly virulent to the casuarina moth and has been investigated as a possible biopesticide for controlling this moth. LdMNPV like virus has also been isolated from Lymantria xylina larvae but LyxyMNPV was more virulent than LdMNPV-like virus both in NTU-LY and IPLB-LD-652Y cell lines. To better understand LyxyMNPV, the nucleotide sequence of the LyxyMNPV DNA genome was determined and analysed. RESULTS: The genome of LyxyMNPV consists of 156,344 bases, has a G+C content of 53.4% and contains 157 putative open reading frames (ORFs). The gene content and gene order of LyxyMNPV were similar to those of LdMNPV, with 151 ORFs identified as homologous to those reported in the LdMNPV genome. Two genes (Lyxy49 and Lyxy123) were homologous to other baculoviruses, and four unique LyxyMNPV ORFs (Lyxy11, Lyxy19, Lyxy130 and Lyxy131) were identified in the LyxyMNPV genome, including a gag-like gene that was not reported in baculoviruses. LdMNPV contains 23 ORFs that are absent in LyxyMNPV. Readily identifiable homologues of the gene host range factor-1 (hrf-1), which appears to be involved in the susceptibility of L. dispar to NPV infection, were not present in LyxyMNPV. Additionally, two putative odv-e27 homologues were identified in LyxyMNPV. The LyxyMNPV genome encoded 14 bro genes compared with 16 in LdMNPV, which occupied more than 8% of the LyxyMNPV genome. Thirteen homologous regions (hrs) were identified containing 48 repeated sequences composed of 30-bp imperfect palindromes. However, they differed in the relative positions, number of repeats and orientation in the genome compared to LdMNPV. CONCLUSION: The gene parity plot analysis, percent identity of the gene homologues and a phylogenetic analysis suggested that LyxyMNPV is a Group II NPV that is most closely related to LdMNPV but with a highly distinct genomic organisation. PMID- 20167052 TI - Cellular toxicity following application of adeno-associated viral vector-mediated RNA interference in the nervous system. AB - BACKGROUND: After a spinal cord lesion, axon regeneration is inhibited by the presence of a diversity of inhibitory molecules in the lesion environment. At and around the lesion site myelin-associated inhibitors, chondroitin sulfate proteoglycans (CSPGs) and several axon guidance molecules, including all members of the secreted (class 3) Semaphorins, are expressed. Interfering with multiple inhibitory signals could potentially enhance the previously reported beneficial effects of blocking single molecules. RNA interference (RNAi) is a tool that can be used to simultaneously silence expression of multiple genes. In this study we aimed to employ adeno-associated virus (AAV) mediated expression of short hairpin RNAs (shRNAs) to target all Semaphorin class 3 signaling by knocking down its receptors, Neuropilin 1 (Npn-1) and Neuropilin 2 (Npn-2). RESULTS: We have successfully generated shRNAs that knock down Npn-1 and Npn-2 in a neuronal cell line. We detected substantial knockdown of Npn-2 mRNA when AAV5 viral vector particles expressing Npn-2 specific shRNAs were injected in dorsal root ganglia (DRG) of the rat. Unexpectedly however, AAV1-mediated expression of Npn-2 shRNAs and a control shRNA in the red nucleus resulted in an adverse tissue response and neuronal degeneration. The observed toxicity was dose dependent and was not seen with control GFP expressing AAV vectors, implicating the shRNAs as the causative toxic agents. CONCLUSIONS: RNAi is a powerful tool to knock down Semaphorin receptor expression in neuronal cells in vitro and in vivo. However, when shRNAs are expressed at high levels in CNS neurons, they trigger an adverse tissue response leading to neuronal degradation. PMID- 20167054 TI - The relationship of cerb B 2 expression with estrogen receptor and progesterone receptor and prognostic parameters in endometrial carcinomas. AB - BACKGROUND: Endometrial carcinoma (EC) is the most common malignancy of the female genital tract. Gene alterations and overexpression of various oncogenes are important in tumor development. The human HER 2 neu (c-erbB-2) gene product is a transmembrane receptor with an intracellular tyrosine kinase that plays an important role in coordinating the endometrial growth factor receptor signaling network. The aim of this study was to investigate the expression of c-erbB-2 in endometrial cancer, to study its correlation to established prognostic parameters and estrogen receptor (ER) and progesterone receptor (PR) status. METHODS: Immunohistochemical (IHC) analyses of ER, PR and c-erbB-2 were performed in 72 EC cases. RESULTS: We detected a positive staining with c erbB 2 in 18.1% of the cases and determined a statistically significant relation between c-erbB-2 and PR. We could not find a statistically significant relation between c-erbB-2 staining and ER. There was not a statistically significant difference between c erbB-2 and histological grade. The highest level of c-erbB-2 was found in grade 2 cases. There was not any statistically significant relation between c-erbB-2 and menstrual status, myometrial invasion, lymph node status, stage and survival. CONCLUSIONS: Although our study provides additional evidence of the potential prognostic role of c-erbB-2, further prospective and controlled studies are required to validate their clinical usefulness. PMID- 20167053 TI - General and species-specific transcriptional responses to downy mildew infection in a susceptible (Vitis vinifera) and a resistant (V. riparia) grapevine species. AB - BACKGROUND: Downy mildew is a destructive grapevine disease caused by Plasmopara viticola (Berk. and Curt.) Berl. and de Toni, which can only be controlled by intensive fungicide treatments. Natural sources of resistance from wild grapevine (Vitis) species are used in conventional breeding approaches, but the signals and effectors involved in resistance in this important crop species are not well understood. RESULTS: Early transcriptional changes associated with P. viticola infection in susceptible V. vinifera and resistant V. riparia plants were analyzed using the Combimatrix microarray platform. Transcript levels were measured 12 and 24 h post-inoculation, reflecting the time points immediately preceding the onset of resistance in V. riparia, as determined by microscopic analysis. Our data indicate that resistance in V. riparia is induced after infection, and is not based on differences in basal gene expression between the two species. The strong and rapid transcriptional reprogramming involves the induction of pathogenesis-related proteins and enzymes required for the synthesis of phenylpropanoid-derived compounds, many of which are also induced, albeit to a lesser extent, in V. vinifera. More interestingly, resistance in V. riparia also involves the specific modulation of numerous transcripts encoding components of signal transduction cascades, hypersensitive reaction markers and genes involved in jasmonate biosynthesis. The limited transcriptional modulation in V. vinifera represents a weak attempted defense response rather than the activation of compatibility-specific pathways. CONCLUSIONS: Several candidate resistance genes were identified that could be exploited in future biotechnological approaches to increase disease resistance in susceptible grapevine species. Measurements of jasmonic acid and methyl jasmonate in infected leaves suggest that this hormone may also be involved in V. riparia resistance to P. viticola. PMID- 20167055 TI - Traditional agroecosystems as conservatories and incubators of cultivated plant varietal diversity: the case of fig (Ficus carica L.) in Morocco. AB - BACKGROUND: Traditional agroecosystems are known to host both large crop species diversity and high within crop genetic diversity. In a context of global change, this diversity may be needed to feed the world. Are these agroecosystems museums (i.e. large core collections) or cradles of diversity? We investigated this question for a clonally propagated plant, fig (Ficus carica), within its native range, in Morocco, but as far away as possible from supposed centers of domestication. RESULTS: Fig varieties were locally numerous. They were found to be mainly highly local and corresponded to clones propagated vegetatively. Nevertheless these clones were often sufficiently old to have accumulated somatic mutations for selected traits (fig skin color) and at neutral loci (microsatellite markers). Further the pattern of spatial genetic structure was similar to the pattern expected in natural population for a mutation/drift/migration model at equilibrium, with homogeneous levels of local genetic diversity throughout Moroccan traditional agroecosystems. CONCLUSIONS: We conclude that traditional agroecosystems constitue active incubators of varietal diversity even for clonally propagated crop species, and even when varieties correspond to clones that are often old. As only female fig is cultivated, wild fig and cultivated fig probably constitute a single evolutionary unit within these traditional agroecosystems. Core collections, however useful, are museums and hence cannot serve the same functions as traditional agroecosystems. PMID- 20167056 TI - Metal on metal hip resurfacing versus uncemented custom total hip replacement- early results. AB - INTRODUCTION: There is no current consensus on the most appropriate prosthesis for treating symptomatic osteoarthritis (OA) of the hip in young, active patients. Modern metal on metal hip resurfacing arthroplasty (HR) has gained popularity as it is theoretically more stable, bone conserving and easier to revise than total hip arthroplasty. Early results of metal on metal resurfacing have been encouraging. We have compared two well matched cohorts of patients with regard to function, pain relief and patient satisfaction. METHODS: This prospective study compares 2 cohorts of young, active patients treated with hip resurfacing (137 patients, 141 hips) and custom uncemented (CADCAM) stems (134 patients, 141 hips). All procedures were performed by a single surgeon. Outcome measures included Oxford, WOMAC and Harris hip scores as well as an activity score. Statistical analysis was performed using the unpaired student's t-test. RESULTS: One hundred and thirty four and 137 patients were included in the hip replacement and resurfacing groups respectively. The mean age of these patients was 54.6 years. The mean duration of follow up for the hip resurfacing group was 19.2 months compared to 13.4 months for the total hip replacement group.Pre operative oxford, Harris and WOMAC scores in the THA group were 41.1, 46.4 and 50.9 respectively while the post operative scores were 14.8, 95.8 and 5.0. In the HR group, pre- operative scores were 37.0, 54.1 and 45.9 respectively compared to 15.0, 96.8 and 6.1 post operatively. The degree of improvement was similar in both groups. CONCLUSION: There was no significant clinical difference between the patients treated with hip resurfacing and total hip arthroplasty in the short term. PMID- 20167058 TI - Comparing two intramedullary devices for treating trochanteric fractures: a prospective study. AB - BACKGROUND: Intertrochanteric fractures are surgically treated by using different methods and implants. The optional type of surgical stabilization is still under debate. However, between devices with the same philosophy, different design characteristics may substantially influence fracture healing. This is a prospective study comparing the complication and final functional outcome of two intramedullary devices, the intramedullary hip screw (IMHS) and the ENDOVIS nail. MATERIALS AND METHODS: Two hundred fifteen patients were randomized on admission in two treatment groups. Epidemiology features and functional status was similar between two treatment groups. Fracture stability was assessed according to the Evan's classification. One hundred ten patients were treated with IMHS and 105 with ENDOVIS nail. RESULTS: There were no significant statistical differences between the two groups regarding blood loss, transfusion requirements and mortality rate. In contrast, the number of total complications was significantly higher in the ENDOVIS nail group. Moreover, the overall functional and walking competence was superior in the patients treated with the IMHS nail. CONCLUSIONS: These results indicate that the choice of the proper implant plays probably an important role in the final outcome of surgical treatment of intertrochanteric fractures. IMHS nail allows for accurate surgical technique, for both static and dynamic compression and high rotational stability. IMHS nail proved more reliable in our study regarding nail insertion and overall uncomplicated outcome. PMID- 20167057 TI - Pentosan polysulfate promotes proliferation and chondrogenic differentiation of adult human bone marrow-derived mesenchymal precursor cells. AB - INTRODUCTION: This study was undertaken to determine whether the anti osteoarthritis drug pentosan polysulfate (PPS) influenced mesenchymal precursor cell (MPC) proliferation and differentiation. METHODS: Human MPCs were maintained in monolayer, pellet or micromass cultures (MMC) for up to 10 days with PPS at concentrations of 0 to 20 microg/ml. MPC viability and proliferation was assessed using the WST-1 assay and 3H-thymidine incorporation into DNA, while apoptosis was monitored by flow cytometry. Proteoglycan (PG) biosynthesis was determined by 35SO42- incorporation and staining with Alcian blue. Proteoglycan and collagen type I and collagen type II deposition in pellet cultures was also examined by Toluidine blue and immunohistochemical staining, respectively. The production of hyaluronan (HA) by MPCs in MMC was assessed by ELISA. The relative outcome of PPS, HA, heparin or dextran sulfate (DS) on PG synthesis was compared in 5-day MMC. Gene expression of MPCs in 7-day and 10-day MMC was examined using real-time PCR. MPC differentiation was investigated by co-culturing with PPS in osteogenic or adipogenic inductive culture media for 28 days. RESULTS: Significant MPC proliferation was evident by day 3 at PPS concentrations of 1 to 5 microg/ml (P < 0.01). In the presence of 1 to 10 microg/ml PPS, a 38% reduction in IL-4/IFNgamma induced MPC apoptosis was observed. In 5-day MMC, 130% stimulation of PG synthesis occurred at 2.5 microg/ml PPS (P < 0.0001), while 5.0 microg/ml PPS achieved maximal stimulation in the 7-day and 10-day cultures (P < 0.05). HA and DS at > or = 5 microg/ml inhibited PG synthesis (P < 0.05) in 5-day MMC. Collagen type II deposition by MMC was significant at > or = 0.5 microg/ml PPS (P < 0.001 to 0.05). In MPC-PPS pellet cultures, more PG, collagen type II but less collagen type I was deposited than in controls. Real-time PCR results were consistent with the protein data. At 5 and 10 microg/ml PPS, MPC osteogenic differentiation was suppressed (P < 0.01). CONCLUSIONS: This is the first study to demonstrate that PPS promotes MPC proliferation and chondrogenesis, offering new strategies for cartilage regeneration and repair in osteoarthritic joints. PMID- 20167059 TI - Thermal stability and inactivation of hepatitis C virus grown in cell culture. AB - BACKGROUND: Hepatitis C virus (HCV) is a blood-borne flavivirus that infects many millions of people worldwide. Relatively little is known, however, concerning the stability of HCV and reliable procedures for inactivating this virus. METHODS: In the current study, the thermostability of cell culture-derived HCV (HCVcc, JFH-1 strain) under different environmental temperatures (37 degrees C, room temperature, and 4 degrees C) and the ability of heat, UVC light irradiation, and aldehyde and detergent treatments to inactivate HCVcc were evaluated. The infectious titers of treated viral samples were determined by focus-forming unit (FFU) assay using an indirect immunofluorescence assay for HCV NS3 in hepatoma Huh7-25-CD81 cells highly permissive for HCVcc infection. MTT cytotoxicity assay was performed to determine the concentrations of aldehydes or detergents at which they were no longer cytotoxic. RESULTS: HCVcc in culture medium was found to survive 37 degrees C and room temperature (RT, 25 +/- 2 degrees C) for 2 and 16 days, respectively, while the virus was relatively stable at 4 degrees C without drastic loss of infectivity for at least 6 weeks. HCVcc in culture medium was sensitive to heat and could be inactivated in 8 and 4 min when incubated at 60 degrees C and 65 degrees C, respectively. However, at 56 degrees C, 40 min were required to eliminate HCVcc infectivity. Addition of normal human serum to HCVcc did not significantly alter viral stability at RT or its susceptibility to heat. UVC light irradiation (wavelength = 253.7 nm) with an intensity of 450 microW/cm2 efficiently inactivated HCVcc within 2 min. Exposures to formaldehyde, glutaraldehyde, ionic or nonionic detergents all destroyed HCVcc infectivity effectively, regardless of whether the treatments were conducted in the presence of cell culture medium or human serum. CONCLUSIONS: The results provide quantitative evidence for the potential use of a variety of approaches for inactivating HCV. The ability of HCVcc to survive ambient temperatures warrants precautions in handling and disposing of objects and materials that may have been contaminated with HCV. PMID- 20167060 TI - The epidemiology of medical emergency contacts outside hospitals in Norway--a prospective population based study. AB - INTRODUCTION: There is a lack of epidemiological knowledge on medical emergencies outside hospitals in Norway. The aim of the present study was to obtain representative data on the epidemiology of medical emergencies classified as "red responses" in Norway. METHOD: Three emergency medical dispatch centres (EMCCs) were chosen as catchment areas, covering 816 000 inhabitants. During a three month period in 2007 the EMCCs gathered information on every situation that was triaged as a red response, according to The Norwegian Index of Medical Emergencies (Index). Records from ground ambulances, air ambulances, and the primary care doctors were subsequently collected. International Classification of Primary Care-2 symptom codes (ICPC-2) and The National Committee on Aeronautics (NACA) Score System were given retrospectively. RESULTS: Total incidence of red response situations was 5 105 during the three month period. 394 patients were involved in 138 accidents, and 181 situations were without patients, resulting in a total of 5 180 patients. The patients' age ranged from 0 to 107 years, with a median age of 57, and 55% were male. 90% of the red responses were medical problems with a large variation of symptoms, the remainder being accidents. 70% of the patients were in a non-life-threatening situation. Within the accident group, males accounted for 61%, and 35% were aged between 10 and 29 years, with a median age of 37 years. Few of the 39 chapters in the Index were used, A10 "Chest pain" was the most common one (22% of all situations). ICPC-2 symptom codes showed that cardiovascular, syncope/coma, respiratory and neurological problems were most common. 50% of all patients in a sever situation (NACA score 4-7) were > 70 years of age. CONCLUSIONS: The results show that emergency medicine based on 816 000 Norwegians mainly consists of medical problems, where the majority of the patients have a non-life-threatening situation. More focus on the emergency system outside hospitals, including triage and dispatch, and how to best deal with "everyday" emergency problems is needed to secure knowledge based decisions for the future organization of the emergency system. PMID- 20167061 TI - Rumen-protected conjugated linoleic acid supplementation to dairy cows in late pregnancy and early lactation: effects on milk composition, milk yield, blood metabolites and gene expression in liver. AB - BACKGROUND: Conjugated linoleic acid (CLA) is a collective term for isomers of octadecadienoic acid with conjugated double-bond system. Thus, it was the objective to investigate whether milk composition and metabolic key parameters are affected by adding CLA to the diet of dairy cows in the first four weeks of lactation. METHODS: A study was carried out with five primiparous cows fed a CLA supplemented diet compared to five primiparous cows without CLA supplementation. CLA supplemented cows received 7.5 g CLA/day (i.e. 50% cis(c)9,trans(t)11- and 50% t10,c12-CLA) starting two weeks before expected calving and 20 g CLA/day (i.e. 50% c9,t11- and 50% t10,c12-CLA) throughout day 1 to 28 of lactation. RESULTS: The CLA supplement was insufficiently accepted by the animals: only 61.5% of the intended amount was ingested. Fed CLA were detectable in milk fat, whereas contents of c9,t11-CLA and t10,c12-CLA in milk fat were higher for CLA supplemented cows compared to the control group. On average over the entire treatment period, there was a decrease of saturated fatty acids (FA) in milk fat of CLA supplemented cows, combined with a higher content of monounsaturated and trans FA.Our study revealed no significant effects of c9,t11- and t10,c12-CLA supplementation either on milk yield and composition or on metabolic key parameters in blood. Furthermore the experiment did not indicate significant effects of c9,t11- and t10,c12-CLA-supplementation on gene expression of peroxisome proliferator-activated receptor-alpha (PPARalpha), PPARgamma, sterol regulatory element-binding protein-1 and tumor necrosis factor-alpha in liver tissue. CONCLUSIONS: Feeding c9,t11- and t10,c12-CLA during the first weeks after calving did not affect metabolic key parameters of blood serum or milk composition of fresh cows. Milk fatty acid composition was changed by feeding c9,t11- and t10,c12-CLA resulting in higher contents of these isomers in milk fat. High contents of long chain FA in milk fat indicate that CLA supplementation during the first four weeks of lactation did not affect massive peripheral lipomobilization. PMID- 20167062 TI - Cerebral misery perfusion diagnosed using hypercapnic blood-oxygenation-level dependent contrast functional magnetic resonance imaging: a case report. AB - INTRODUCTION: Cerebral misery perfusion represents a failure of cerebral autoregulation. It is an important differential diagnosis in post-stroke patients presenting with collapses in the presence of haemodynamically significant cerebrovascular stenosis. This is particularly the case when cortical or internal watershed infarcts are present. When this condition occurs, further investigation should be done immediately. CASE PRESENTATION: A 50-year-old Caucasian man presented with a stroke secondary to complete occlusion of his left internal carotid artery. He went on to suffer recurrent seizures. Neuroimaging demonstrated numerous new watershed-territory cerebral infarcts. No source of arterial thromboembolism was demonstrable. Hypercapnic blood-oxygenation-level dependent-contrast functional magnetic resonance imaging was used to measure his cerebrovascular reserve capacity. The findings were suggestive of cerebral misery perfusion. CONCLUSIONS: Blood-oxygenation-level-dependent-contrast functional magnetic resonance imaging allows the inference of cerebral misery perfusion. This procedure is cheaper and more readily available than positron emission tomography imaging, which is the current gold standard diagnostic test. The most evaluated treatment for cerebral misery perfusion is extracranial-intracranial bypass. Although previous trials of this have been unfavourable, the results of new studies involving extracranial-intracranial bypass in high-risk patients identified during cerebral perfusion imaging are awaited.Cerebral misery perfusion is an important and under-recognized condition in which emerging imaging and treatment modalities present the possibility of practical and evidence-based management in the near future. Physicians should thus be aware of this disorder and of recent developments in diagnostic tests that allow its detection. PMID- 20167063 TI - 4beta-Hydroxywithanolide E from Physalis peruviana (golden berry) inhibits growth of human lung cancer cells through DNA damage, apoptosis and G2/M arrest. AB - BACKGROUND: The crude extract of the fruit bearing plant, Physalis peruviana (golden berry), demonstrated anti-hepatoma and anti-inflammatory activities. However, the cellular mechanism involved in this process is still unknown. METHODS: Herein, we isolated the main pure compound, 4beta-Hydroxywithanolide (4betaHWE) derived from golden berries, and investigated its antiproliferative effect on a human lung cancer cell line (H1299) using survival, cell cycle, and apoptosis analyses. An alkaline comet-nuclear extract (NE) assay was used to evaluate the DNA damage due to the drug. RESULTS: It was shown that DNA damage was significantly induced by 1, 5, and 10 microg/mL 4betaHWE for 2 h in a dose dependent manner (p < 0.005). A trypan blue exclusion assay showed that the proliferation of cells was inhibited by 4betaHWE in both dose- and time-dependent manners (p < 0.05 and 0.001 for 24 and 48 h, respectively). The half maximal inhibitory concentrations (IC50) of 4betaHWE in H1299 cells for 24 and 48 h were 0.6 and 0.71 microg/mL, respectively, suggesting it could be a potential therapeutic agent against lung cancer. In a flow cytometric analysis, 4betaHWE produced cell cycle perturbation in the form of sub-G1 accumulation and slight arrest at the G2/M phase with 1 microg/mL for 12 and 24 h, respectively. Using flow cytometric and annexin V/propidium iodide immunofluorescence double-staining techniques, these phenomena were proven to be apoptosis and complete G2/M arrest for H1299 cells treated with 5 microg/mL for 24 h. CONCLUSIONS: In this study, we demonstrated that golden berry-derived 4betaHWE is a potential DNA-damaging and chemotherapeutic agent against lung cancer. PMID- 20167064 TI - Effects of weaning biscuits on the nutritional profile and the cognitive development in preschool children. AB - AIM: To study the effect of weaning biscuits supplementation of the nutritional parameters and cognitive performance of the selected children. METHODS: Three primary schools situated in Salem District, Tamilnadu, India were selected. A total number of 150 school children, 61 from primary school I, 46 from primary school II and 43 from primary school III comprised the study sample. About 80 primary school children with Grade II malnutrition were selected for the experimental study. Home diet without any supplementation was followed by Group I (n=20, control group), potato flour biscuit was supplemented to Group II (n=20), wheat biscuits was given to Group III (n=20) and ragi biscuits were given to Group IV (n=20) for the period of 3 months. Parameters like anthropometric measurements, hemoglobin content clinical picture and cognitive performance were analyzed before and after supplementation. RESULTS: Results about Group I (control group) showed no significant difference in height, weight and clinical picture and cognitive performance after three months on their home diet. In Group II, III and IV significant increase in all the above parameters was noticed. More increase was found in Group II children supplemented with potato flour biscuits for a period of 3 months. About cognitive performance better results was obtained in Group II followed by Group III (supplemented with wheat biscuits) and Group IV (supplemented with ragi biscuits). Least was obtained by control group children who are in their home diet. CONCLUSION: All these observations evident that if such weaning biscuits made with potato flour, wheat and Ragi can form a daily ingredient in their diets, it will bring out better all round development of the children. PMID- 20167065 TI - Transcriptional regulation of respiration in yeast metabolizing differently repressive carbon substrates. AB - BACKGROUND: Depending on the carbon source, Saccharomyces cerevisiae displays various degrees of respiration. These range from complete respiration as in the case of ethanol, to almost complete fermentation, and thus very low degrees of respiration on glucose. While many key regulators are known for these extreme cases, we focus here on regulators that are relevant at intermediate levels of respiration. RESULTS: We address this question by linking the functional degree of respiration to transcriptional regulation via enzyme abundances. Specifically, we investigated aerobic batch cultures with the differently repressive carbon sources glucose, mannose, galactose and pyruvate. Based on 13C flux analysis, we found that the respiratory contribution to cellular energy production was largely absent on glucose and mannose, intermediate on galactose and highest on pyruvate. In vivo abundances of 40 respiratory enzymes were quantified by GFP-fusions under each condition. During growth on the partly and fully respired substrates galactose and pyruvate, several TCA cycle and respiratory chain enzymes were significantly up-regulated. From these enzyme levels and the known regulatory network structure, we determined the probability for a given transcription factor to cause the coordinated expression changes. The most probable transcription factors to regulate the different degrees of respiration were Gcr1p, Cat8p, the Rtg-proteins and the Hap-complex. For the latter three ones we confirmed their importance for respiration by quantifying the degree of respiration and biomass yields in the corresponding deletion strains. CONCLUSIONS: Cat8p is required for wild-type like respiration, independent of its known activation of gluconeogenic genes. The Rtg-proteins and the Hap-complex are essential for wild-type like respiration under partially respiratory conditions. Under fully respiratory conditions, the Hap-complex, but not the Rtg-proteins are essential for respiration. PMID- 20167066 TI - Relationships between magnitude representation, counting and memory in 4- to 7 year-old children: a developmental study. AB - BACKGROUND: The development of an evolutionarily grounded analogue magnitude representation linked to the parietal lobes is frequently thought to be a major factor in the arithmetic development of humans. We investigated the relationship between counting and the development of magnitude representation in children, assessing also children's knowledge of number symbols, their arithmetic fact retrieval, their verbal skills, and their numerical and verbal short-term memory. METHODS: The magnitude representation was tested by a non-symbolic magnitude comparison task. We have perfected previous experimental designs measuring magnitude discrimination skills in 65 children kindergarten (4-7-year-olds) by controlling for several variables which were not controlled for in previous similar research. We also used a large number of trials which allowed for running a full factorial ANOVA including all relevant factors. Tests of verbal counting, of short term memory, of number knowledge, of problem solving abilities and of verbal fluency were administered and correlated with performance in the magnitude comparison task. RESULTS AND DISCUSSION: Verbal counting knowledge and performance on simple arithmetic tests did not correlate with non-symbolic magnitude comparison at any age. Older children performed successfully on the number comparison task, showing behavioural patterns consistent with an analogue magnitude representation. In contrast, 4-year-olds were unable to discriminate number independently of task-irrelevant perceptual variables. Sensitivity to irrelevant perceptual features of the magnitude discrimination task was also affected by age, and correlated with memory, suggesting that more general cognitive abilities may play a role in performance in magnitude comparison tasks. CONCLUSION: We conclude that young children are not able to discriminate numerical magnitudes when co-varying physical magnitudes are methodically pitted against number. We propose, along with others, that a rather domain general magnitude representation provides the later basis for a specialized representation of numerical magnitudes. For this representational specialization, the acquisition of the concept of abstract numbers, together with the development of other cognitive abilities, is indispensable. PMID- 20167067 TI - 8p23.1 duplication syndrome differentiated from copy number variation of the defensin cluster at prenatal diagnosis in four new families. AB - BACKGROUND: The 8p23.1 duplication syndrome and copy number variation of the 8p23.1 defensin gene cluster are cytogenetically indistinguishable but distinct at the molecular level. To our knowledge, the 8p23.1 duplication syndrome has been described at prenatal diagnosis only once and we report our experience with four further apparent duplications ascertained at prenatal diagnosis. METHODS: Additional material at band 8p23.1 was detected using conventional G-banded cytogenetics in each case. Multiplex Ligation-dependent Probe Amplification (MLPA) or Fluorescence In Situ Hybridisation (FISH) were used depending on whether only DNA (Cases 1 and 4) or cytogenetic preparations (Cases 2 and 3) were available from the laboratory of origin. The extent of the duplication in Case 1 was retrospectively determined using array Comparative Genomic Hybridisation (array CGH). RESULTS: Three cases of 8p23.1 duplication syndrome were found (Cases 1 to 3). Two were de novo and continued to term and the third, a paternally transmitted duplication, was terminated because of a previous child with psychomotor delay and 8p23.1 duplication syndrome. Case 1 was ascertained with a hypoplastic left heart but the ventricular septal and interventricular defects, in Cases 2 and 3 respectively, were found after ascertainment for advanced maternal age. By contrast, case 4 was a maternally transmitted copy number variation of the defensin cluster with normal outcome. CONCLUSIONS: Our data underline the need to differentiate 8p23.1 duplications from copy number variation of the defensin cluster using FISH, MLPA or array CGH. Cardiac defects were ascertained by ultrasound in only one of the three duplication 8p23.1 pregnancies but were visible in two of the three at 21 to 22 weeks gestation. Our results provide further evidence that both deletion and duplication of the GATA4 transcription factor can give rise to a variety of conotruncal heart defects with variable penetrance and expressivity. PMID- 20167068 TI - Drugs of abuse and the adolescent athlete. AB - Doping with endocrine drugs is quite prevalent in amateur and professional athletes. The World Anti-Doping Agency (WADA) has a list of banned drugs for athletes who compete and a strategy to detect such drugs. Some are relatively easy, anabolic steroids and erythropoietin, and others more difficult, human growth hormone (rhGH) and insulin like growth factor I (IGF-I). The use of such compounds is likely less in adolescent athletes, but the detection that much more difficult given that the baseline secretion of the endogenous hormone is shifting during pubertal development with the greatest rise in testosterone in boys occurring about the time of peak height velocity and maximal secretion of hGH and IGF-I. This review notes the rationale, physiology, performance enhancement, adverse events and the detection of doping with insulin, rhGH, rhIGF-I, erythropoietin, and anabolic-androgenic steroids. PMID- 20167069 TI - Strengthening the Paediatricians Project 2: The effectiveness of a workshop to address the Priority Mental Health Disorders of adolescence in low-health related human resource countries. AB - BACKGROUND: Paediatricians can be empowered to address the Priority Mental Health Disorders at primary care level. To evaluate the effectiveness of a collaborative workshop in enhancing the adolescent psychiatry knowledge among paediatricians. METHODS: A 3-day, 27-hours workshop was held for paediatricians from different regions of India under the auspices of the National Adolescent Paediatric Task Force of the Indian Academy of Paediatrics. A 5-item pretest-posttest questionnaire was developed and administered at the beginning and end of the workshop to evaluate the participants' knowledge acquisition in adolescent psychiatry. Bivariate and multivariate analyses were performed on an intention-to participate basis. RESULTS: Forty-eight paediatricians completed the questionnaire. There was significant enhancement of the knowledge in understanding the phenomenology, identifying the psychopathology, diagnosing common mental disorder and selecting the psychotropic medication in the bivariate analysis. When the possible confounders of level of training in paediatrics and number of years spent as paediatrician were controlled, in addition to the above areas of adolescent psychiatry, the diagnostic ability involving multiple psychological concepts also gained significance. However, both in the bivariate and multivariate analyses, the ability to refer to appropriate psychotherapy remained unchanged after the workshop. CONCLUSIONS: This workshop was effective in enhancing the adolescent psychiatry knowledge of paediatricians. Such workshops could strengthen paediatricians in addressing the priority mental health disorders at the primary-care level in countries with low-human resource for health as advocated by the World Health Organization. However, it remains to be seen if this acquisition of adolescent psychiatry knowledge results in enhancing their adolescent psychiatry practice. PMID- 20167070 TI - Finding sRNA generative locales from high-throughput sequencing data with NiBLS. AB - BACKGROUND: Next-generation sequencing technologies allow researchers to obtain millions of sequence reads in a single experiment. One important use of the technology is the sequencing of small non-coding regulatory RNAs and the identification of the genomic locales from which they originate. Currently, there is a paucity of methods for finding small RNA generative locales. RESULTS: We describe and implement an algorithm that can determine small RNA generative locales from high-throughput sequencing data. The algorithm creates a network, or graph, of the small RNAs by creating links between them depending on their proximity on the target genome. For each of the sub-networks in the resulting graph the clustering coefficient, a measure of the interconnectedness of the subnetwork, is used to identify the generative locales. We test the algorithm over a wide range of parameters using RFAM sequences as positive controls and demonstrate that the algorithm has good sensitivity and specificity in a range of Arabidopsis and mouse small RNA sequence sets and that the locales it generates are robust to differences in the choice of parameters. CONCLUSIONS: NiBLS is a fast, reliable and sensitive method for determining small RNA locales in high throughput sequence data that is generally applicable to all classes of small RNA. PMID- 20167071 TI - Community annotation in biology. AB - Attempts to engage the scientific community to annotate biological data (such as protein/gene function) stored in databases have not been overly successful. There are several hypotheses on why this has not been successful but it is not clear which of these hypotheses are correct. In this study we have surveyed 50 biologists (who have recently published a paper characterizing a gene or protein) to better understand what would make them interested in providing input/contributions to biological databases. Based on our survey two things become clear: a) database managers need to proactively contact biologists to solicit contributions; and b) potential contributors need to be provided with an easy-to-use interface and clear instructions on what to annotate. Other factors such as 'reward' and 'employer/funding agency recognition' previously perceived as motivators was found to be less important. Based on this study we propose community annotation projects should devote resources to direct solicitation for input and streamlining of the processes or interfaces used to collect this input. REVIEWERS: This article was reviewed by I. King Jordan, Daniel Haft and Yuriy Gusev. PMID- 20167072 TI - Inositol monophosphate phosphatase genes of Mycobacterium tuberculosis. AB - BACKGROUND: Mycobacteria use inositol in phosphatidylinositol, for anchoring lipoarabinomannan (LAM), lipomannan (LM) and phosphatidylinosotol mannosides (PIMs) in the cell envelope, and for the production of mycothiol, which maintains the redox balance of the cell. Inositol is synthesized by conversion of glucose-6 phosphate to inositol-1-phosphate, followed by dephosphorylation by inositol monophosphate phosphatases (IMPases) to form myo-inositol. To gain insight into how Mycobacterium tuberculosis synthesises inositol we carried out genetic analysis of the four IMPase homologues that are present in the Mycobacterium tuberculosis genome. RESULTS: Mutants lacking either impA (Rv1604) or suhB (Rv2701c) were isolated in the absence of exogenous inositol, and no differences in levels of PIMs, LM, LAM or mycothiol were observed. Mutagenesis of cysQ (Rv2131c) was initially unsuccessful, but was possible when a porin-like gene of Mycobacterium smegmatis was expressed, and also by gene switching in the merodiploid strain. In contrast, we could only obtain mutations in impC (Rv3137) when a second functional copy was provided in trans, even when exogenous inositol was provided. Experiments to obtain a mutant in the presence of a second copy of impC containing an active-site mutation, in the presence of porin-like gene of M. smegmatis, or in the absence of inositol 1-phosphate synthase activity, were also unsuccessful. We showed that all four genes are expressed, although at different levels, and levels of inositol phosphatase activity did not fall significantly in any of the mutants obtained. CONCLUSIONS: We have shown that neither impA, suhB nor cysQ is solely responsible for inositol synthesis. In contrast, we show that impC is essential for mycobacterial growth under the conditions we used, and suggest it may be required in the early stages of mycothiol synthesis. PMID- 20167073 TI - Hfq affects mRNA levels independently of degradation. AB - BACKGROUND: The bacterial Lsm protein, Hfq, is an RNA chaperone involved in many reactions related to RNA metabolism, such as replication and stability, control of small RNA activity and polyadenylation. Despite this wide spectrum of known functions, the global role of Hfq is almost certainly undervalued; its capacity to bind DNA and to interact with many other proteins are only now beginning to be taken into account. RESULTS: The role of Hfq in the maturation and degradation of the rpsO mRNA of E. coli was investigated in vivo. The data revealed a decrease in rpsO mRNA abundance concomitant to an increase in its stability when Hfq is absent. This indicates that the change in mRNA levels in hfq mutants does not result from its modification of RNA stability. Moreover, a series of independent experiments have revealed that the decrease in mRNA level is not a consequence of a reduction of translation efficiency and that Hfq is not directly implicated in translational control of rpsO expression. Reduced steady-state mRNA levels in the absence of Hfq were also shown for rpsT, rpsB and rpsB-tsf, but not for lpp, pnp or tRNA transcripts. The abundance of chimeric transcripts rpsO-lacZ and rpsB lacZ, whose expression was driven by rpsO and rpsB promoters, respectively, was also lower in the hfq null-mutants, while the beta-galactosidase yield remained about the same as in the parent wild-type strain. CONCLUSIONS: The data obtained suggest that alteration of rpsO, rpsT and rpsB-tsf transcript levels observed under conditions of Hfq deficiency is not caused by the post-transcriptional events, such as mRNA destabilization or changes in translation control, and may rather result from changes in transcriptional activity. So far, how Hfq affects transcription remains unclear. We propose that one of the likely mechanisms of Hfq-mediated modulation of transcription might operate early in the elongation step, when interaction of Hfq with a nascent transcript would help to overcome transcription pauses and to prevent preliminary transcript release. PMID- 20167074 TI - Novel genetic variants in miR-191 gene and familial ovarian cancer. AB - BACKGROUND: Half of the familial aggregation of ovarian cancer can't be explained by any known risk genes, suggesting the existence of other genetic risk factors. Some of these unknown factors may not be traditional protein encoding genes. MicroRNA (miRNA) plays a critical role in tumorigenesis, but it is still unknown if variants in miRNA genes lead to predisposition to cancer. Considering the fact that miRNA regulates a number of tumor suppressor genes (TSGs) and oncogenes, genetic variations in miRNA genes could affect the levels of expression of TSGs or oncogenes and, thereby, cancer risk. METHODS AND RESULTS: To test this hypothesis in familial ovarian cancer, we screened for genetic variants in thirty selected miRNA genes, which are predicted to regulate key ovarian cancer genes and are reported to be misexpressed in ovarian tumor tissues, in eighty-three patients with familial ovarian cancer. All of the patients are non-carriers of any known BRCA1/2 or mismatch repair (MMR) gene mutations. Seven novel genetic variants were observed in four primary or precursor miRNA genes. Among them, three rare variants were found in the precursor or primary precursor of the miR 191 gene. In functional assays, the one variant located in the precursor of miR 191 resulted in conformational changes in the predicted secondary structures, and consequently altered the expression of mature miR-191. In further analysis, we found that this particular variant exists in five family members who had ovarian cancer. CONCLUSIONS: Our findings suggest that there are novel genetic variants in miRNA genes, and those certain genetic variants in miRNA genes can affect the expression of mature miRNAs and, consequently, might alter the regulation of TSGs or oncogenes. Additionally, the variant might be potentially associated with the development of familial ovarian cancer. PMID- 20167075 TI - The impact of gender and parenthood on physicians' careers--professional and personal situation seven years after graduation. AB - BACKGROUND: The profile of the medical profession is changing in regard to feminization, attitudes towards the profession, and the lifestyle aspirations of young physicians. The issues addressed in this study are the careers of female and male physicians seven years after graduation and the impact of parenthood on career development. METHODS: Data reported originates from the fifth assessment (T5) of the prospective SwissMedCareer Study, beginning in 2001 (T1). At T5 in 2009, 579 residents (81.4% of the initial sample at T1) participated in the questionnaire survey. They were asked about occupational factors, career-related factors including specialty choice and workplace, work-life balance and life satisfaction. The impact of gender and parenthood on the continuous variables was investigated by means of multivariate and univariate analyses of variance; categorical variables were analyzed using Chi-square tests. RESULTS: Female physicians, especially those with children, have lower rates of employment and show lower values in terms of career success and career support experiences than male physicians. In addition, parenthood has a negative impact on these career factors. In terms of work-life balance aspired to, female doctors are less career oriented and are more inclined to consider part-time work or to continue their professional career following a break to bring up a family. Parenthood means less career-orientation and more part-time orientation. As regards life satisfaction, females show higher levels of satisfaction overall, especially where friends, leisure activities, and income are concerned. Compared to their male colleagues, female physicians are less advanced in their specialty qualification, are less prone to choosing prestigious surgical fields, have a mentor less often, more often work at small hospitals or in private practice, aspire less often to senior hospital or academic positions and consider part-time work more often. Any negative impact on career path and advancement is exacerbated by parenthood, especially as far as women are concerned. CONCLUSION: The results of the present study reflect socially-rooted gender role stereotypes. Taking into account the feminization of medicine, special attention needs to be paid to female physicians, especially those with children. At an early stage of their career, they should be advised to be more proactive in seeking mentoring and career planning opportunities. If gender equity in terms of career chances is to be achieved, special career-support measures will have to be provided, such as mentoring programs, role models, flexitime and flexible career structures. PMID- 20167076 TI - Strengthening the Paediatricians Project 1: The need, content and process of a workshop to address the Priority Mental Health Disorders of adolescence in countries with low human resource for health. AB - OBJECTIVE: World Health Organization has identified Priority Mental Health Disorders (PMHD) of adolescence. To effectively address these disorders at the primary care level paediatricians have to be trained in the low-income countries, which often have paucity of mental health resources. We studied: (1) the need of psychiatric training required among paediatricians; (2) if the content and process of the model workshop suits them to identify and treat these disorders. METHODS: Forty-eight paediatricians completed evaluation questionnaire at the end of a 3-day workshop on adolescent psychiatry. They participated in a focused group discussion addressing the areas in psychiatry that needs to be strengthened in these workshops, the changes in the content and process of the workshop to bolster their learning. Qualitative and descriptive analyses were appropriately used. RESULTS: Training in adolescent psychiatry was considered necessary among the paediatricians at zonal level frequently to develop their private practice, treat psychiatric disorders confidently, make correct referrals, and learn about counselling. Prioritizing training from under and postgraduate training, integrate psychiatry training with conference, conducting special workshops or Continuing Medical Education were suggested as ways of inculcating adolescent psychiatry proficiency. Mental status examination, psychopathology and management of the PMHD were considered by the respondents as important content that need to be addressed in the program but aspects of behavioural problems and developmental disabilities were also identified as areas of focus to gain knowledge and skill. Appropriate group size, flexibility in management decisions to fit the diverse clinical practice- settings was appreciated. Lack of skills in giving clinical reasoning in relation to PMHD, time management and feedback to individuals were identified as required components in the collaborative effort of this manner. Providing delegates with basic information on adolescent psychiatry prior to the workshop was suggested to make the workshop more valuable. CONCLUSIONS: There is a need to expand training for paediatricians from various backgrounds in adolescent psychiatry to strengthen their clinical skills to address the PMHD at the primary-care level. The evaluation suggests that the design and collaborative approach evident in this programme have merit as a model for training paediatricians in adolescent psychiatry in countries with low human resource for health. PMID- 20167077 TI - Characterization of a molecular switch system that regulates gene expression in mammalian cells through a small molecule. AB - BACKGROUND: Molecular switch systems that activate gene expression by a small molecule are effective technologies that are widely used in applied biological research. Nuclear receptors are valuable candidates for these regulation systems due to their functional role as ligand activated transcription factors. Previously, our group engineered a variant of the retinoid x receptor to be responsive to the synthetic compound, LG335, but not responsive to its natural ligand, 9-cis-retinoic acid. RESULTS: This work focuses on characterizing a molecular switch system that quantitatively controls transgene expression. This system is composed of an orthogonal ligand/nuclear receptor pair, LG335 and GRQCIMFI, along with an artificial promoter controlling expression of a target transgene. GRQCIMFI is composed of the fusion of the DNA binding domain of the yeast transcription factor, Gal4, and a retinoid x receptor variant. The variant consists of the following mutations: Q275C, I310M, and F313I in the ligand binding domain. When introduced into mammalian cell culture, the switch shows luciferase activity at concentrations as low as 100 nM of LG335 with a 6.3 +/- 1.7-fold induction ratio. The developed one-component system activates transgene expression when introduced transiently or virally. CONCLUSIONS: We have successfully shown that this system can induce tightly controlled transgene expression and can be used for transient transfections or retroviral transductions in mammalian cell culture. Further characterization is needed for gene therapy applications. PMID- 20167079 TI - Ophthalmic complications of endoscopic ethmoidectomy: a case report. AB - Damage to ethmoid structures following removal of nasal polyps can cause severe complications. A patient aged 48 years with damage to right orbital structures sustained in the course of transnasal endoscopic surgery for ethmoid polyps was operated. After operation were complications. PMID- 20167078 TI - Mitochondrial phylogenomics of the Bivalvia (Mollusca): searching for the origin and mitogenomic correlates of doubly uniparental inheritance of mtDNA. AB - BACKGROUND: Doubly uniparental inheritance (DUI) is an atypical system of animal mtDNA inheritance found only in some bivalves. Under DUI, maternally (F genome) and paternally (M genome) transmitted mtDNAs yield two distinct gender-associated mtDNA lineages. The oldest distinct M and F genomes are found in freshwater mussels (order Unionoida). Comparative analyses of unionoid mitochondrial genomes and a robust phylogenetic framework are necessary to elucidate the origin, function and molecular evolutionary consequences of DUI. Herein, F and M genomes from three unionoid species, Venustaconcha ellipsiformis, Pyganodon grandis and Quadrula quadrula have been sequenced. Comparative genomic analyses were carried out on these six genomes along with two F and one M unionoid genomes from GenBank (F and M genomes of Inversidens japanensis and F genome of Lampsilis ornata). RESULTS: Compared to their unionoid F counterparts, the M genomes contain some unique features including a novel localization of the trnH gene, an inversion of the atp8-trnD genes and a unique 3'coding extension of the cytochrome c oxidase subunit II gene. One or more of these unique M genome features could be causally associated with paternal transmission. Unionoid bivalves are characterized by extreme intraspecific sequence divergences between gender-associated mtDNAs with an average of 50% for V. ellipsiformis, 50% for I. japanensis, 51% for P. grandis and 52% for Q. quadrula (uncorrected amino acid p-distances). Phylogenetic analyses of 12 protein-coding genes from 29 bivalve and five outgroup mt genomes robustly indicate bivalve monophyly and the following branching order within the autolamellibranch bivalves: ((Pteriomorphia, Veneroida) Unionoida). CONCLUSION: The basal nature of the Unionoida within the autolamellibranch bivalves and the previously hypothesized single origin of DUI suggest that (1) DUI arose in the ancestral autolamellibranch bivalve lineage and was subsequently lost in multiple descendant lineages and (2) the mitochondrial genome characteristics observed in unionoid bivalves could more closely resemble the DUI ancestral condition. Descriptions and comparisons presented in this paper are fundamental to a more complete understanding regarding the origins and consequences of DUI. PMID- 20167080 TI - Chest computed tomography of a patient revealing severe hypoxia due to amniotic fluid embolism: a case report. AB - INTRODUCTION: Amniotic fluid embolism is one of the most severe complications in the peripartum period. Because its onset is abrupt and fulminant, it is unlikely that there will be time to examine the condition using thoracic computed tomography (CT). We report a case of life-threatening amniotic fluid embolism, where chest CT in the acute phase was obtained. CASE PRESENTATION: A 22-year-old Asian Japanese primiparous woman was suspected of having an amniotic fluid embolism. After a Cesarean section for cephalopelvic disproportion, her respiratory condition deteriorated. Her chest CT images were examined. CT findings revealed diffuse homogeneous ground-glass shadow in her bilateral peripheral lung fields. She was therefore transferred to our hospital. On admission to our hospital's intensive care unit, she was found to have severe hypoxemia, with SpO2 of 50% with a reservoir mask of 15 L/min oxygen. She was intubated with the support of noninvasive positive pressure ventilation. She was successfully extubated on the sixth day, and discharged from the hospital on the twentieth day. CONCLUSION: This is the first case report describing amniotic fluid embolism in which CT revealed an acute respiratory distress syndrome-like shadow. PMID- 20167081 TI - Anti-tetherin activities in Vpu-expressing primate lentiviruses. AB - BACKGROUND: The anti-viral activity of the cellular restriction factor, BST 2/tetherin, was first observed as an ability to block the release of Vpu-minus HIV-1 from the surface of infected cells. However, tetherin restriction is also counteracted by primate lentiviruses that do not express a Vpu protein, where anti-tetherin functions are provided by either the Env protein (HIV-2, SIVtan) or the Nef protein (SIVsm/mac and SIVagm). Within the primate lentiviruses, Vpu is also present in the genomes of SIVcpz and certain SIVsyk viruses. We asked whether, in these viruses, anti-tetherin activity was always a property of Vpu, or if it had selectively evolved in HIV-1 to perform this function. RESULTS: We found that despite the close relatedness of HIV-1 and SIVcpz, the chimpanzee viruses use Nef instead of Vpu to counteract tetherin. Furthermore, SIVcpz Nef proteins had activity against chimpanzee but not human tetherin. This specificity mapped to a short sequence that is present in the cytoplasmic tail of primate but not human tetherins, and this also accounts for the specificity of SIVsm/mac Nef for primate but not human tetherins. In contrast, Vpu proteins from four diverse members of the SIVsyk lineage all displayed an anti-tetherin activity that was active against macaque tetherin. Interestingly, Vpu from a SIVgsn isolate was also found to have activity against human tetherin. CONCLUSIONS: Primate lentiviruses show a high degree of flexibility in their use of anti-tetherin factors, indicating a strong selective pressure to counteract tetherin restriction. The identification of an activity against human tetherin in SIVgsn Vpu suggests that the presence of Vpu in the ancestral SIVmus/mon/gsn virus believed to have contributed the 3' half of the HIV-1 genome may have played a role in the evolution of viruses that could counteract human tetherin and infect humans. PMID- 20167082 TI - A novel paradigm for cell and molecule interaction ontology: from the CMM model to IMGT-ONTOLOGY. AB - BACKGROUND: Biology is moving fast toward the virtuous circle of other disciplines: from data to quantitative modeling and back to data. Models are usually developed by mathematicians, physicists, and computer scientists to translate qualitative or semi-quantitative biological knowledge into a quantitative approach. To eliminate semantic confusion between biology and other disciplines, it is necessary to have a list of the most important and frequently used concepts coherently defined. RESULTS: We propose a novel paradigm for generating new concepts for an ontology, starting from model rather than developing a database. We apply that approach to generate concepts for cell and molecule interaction starting from an agent based model. This effort provides a solid infrastructure that is useful to overcome the semantic ambiguities that arise between biologists and mathematicians, physicists, and computer scientists, when they interact in a multidisciplinary field. CONCLUSIONS: This effort represents the first attempt at linking molecule ontology with cell ontology, in IMGT-ONTOLOGY, the well established ontology in immunogenetics and immunoinformatics, and a paradigm for life science biology. With the increasing use of models in biology and medicine, the need to link different levels, from molecules to cells to tissues and organs, is increasingly important. PMID- 20167083 TI - Fibrinogen beta variants confer protection against coronary artery disease in a Greek case-control study. AB - BACKGROUND: Although plasma fibrinogen levels are related to cardiovascular risk, data regarding the role of fibrinogen genetic variation in myocardial infarction (MI) or coronary artery disease (CAD) etiology remain inconsistent. The purpose of the present study was to investigate the effect of fibrinogen A (FGA), fibrinogen B (FGB) and fibrinogen G (FGG) gene SNPs and haplotypes on susceptibility to CAD in a homogeneous Greek population. METHODS: We genotyped for rs2070022, rs2070016, rs2070006 in FGA gene, the rs7673587, rs1800789, rs1800790, rs1800788, rs1800787, rs4681 and rs4220 in FGB gene and for the rs1118823, rs1800792 and rs2066865 SNPs in FGG gene applying an arrayed primer extension-based genotyping method (APEX-2) in a sample of CAD patients (n = 305) and controls (n = 305). Logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), before and after adjustment for potential confounders. RESULTS: None of the FGA and FGG SNPs and FGA, FGB, FGG and FGA-FGG haplotypes was associated with disease occurrence after adjustment. Nevertheless, rs1800787 and rs1800789 SNPs in FGB gene seem to decrease the risk of CAD, even after adjustment for potential confounders (OR = 0.42, 95%CI: 0.19 0.90, p = 0.026 and OR = 0.44, 95%CI:0.21-0.94, p = 0.039, respectively). CONCLUSIONS: FGA and FGG SNPs as well as FGA, FGB, FGG and FGA-FGG haplotypes do not seem to be important contributors to CAD occurrence in our sample. On the contrary, FGB rs1800787 and rs1800789 SNPs seem to confer protection to disease onset lowering the risk by about 50% in homozygotes for the minor alleles. PMID- 20167084 TI - Daptomycin for methicillin-resistant Staphylococcus epidermidis native-valve endocarditis: a case report. AB - Coagulase-negative staphylococci (CoNS) have been increasing in importance as a cause of native valve endocarditis (NVE). Most cases of NVE caused by CoNS are attributable to Staphylococcus epidermidis. NVE caused by CoNS acquired in a nosocomial setting may differ from cases acquired in the community in several ways. It may be associated with hemodialysis, the presence of a long-term indwelling central catheter or pacemaker, or a recent invasive procedure; nosocomial cases may have a higher rate of methicillin resistance among CoNS isolates, and so be more likely to be treated with vancomycin. Unfortunately, NVE caused by methicillin-resistant CoNS has been associated with significantly higher rates of persistent bacteremia and in-hospital mortality than methicillin susceptible isolates. The poor outcomes in these cases point to the need for alternative therapies with potent activity against methicillin-resistant CoNS. In our medical center, a 76-year-old man presented with native-valve endocarditis and positive blood cultures for methicillin-resistant Staphylococcus epidermidis (MRSE). During each of three 6-week courses of treatment with vancomycin, blood cultures were negative, but they once again became positive for MRSE when vancomycin was discontinued. The minimum inhibitory concentration of the MRSE isolates for vancomycin remained stable at 2 microg/mL. Eventually, treatment with daptomycin was initiated (500 mg [7 mg/kg]) 3 times/week for 6 weeks. Over the following year, no positive cultures for MRSE were detected. PMID- 20167085 TI - Genetic adaptation of Streptococcus mutans during biofilm formation on different types of surfaces. AB - BACKGROUND: Adhesion and successful colonization of bacteria onto solid surfaces play a key role in biofilm formation. The initial adhesion and the colonization of bacteria may differ between the various types of surfaces found in oral cavity. Therefore, it is conceivable that diverse biofilms are developed on those various surfaces. The aim of the study was to investigate the molecular modifications occurring during in vitro biofilm development of Streptococcus mutans UA159 on several different dental surfaces. RESULTS: Growth analysis of the immobilized bacterial populations generated on the different surfaces shows that the bacteria constructed a more confluent and thick biofilms on a hydroxyapatite surface compared to the other tested surfaces. Using DNA microarray technology we identified the differentially expressed genes of S. mutans, reflecting the physiological state of biofilms formed on the different biomaterials tested. Eight selected genes were further analyzed by real time RT PCR. To further determine the impact of the tested material surfaces on the physiology of the bacteria, we tested the secretion of AI-2 signal by S. mutans embedded on those biofilms. Comparative transcriptome analyses indicated on changes in the S. mutans genome in biofilms formed onto different types of surfaces and enabled us to identify genes most differentially expressed on those surfaces. In addition, the levels of autoinducer-2 in biofilms from the various tested surfaces were different. CONCLUSIONS: Our results demonstrate that gene expression of S. mutans differs in biofilms formed on tested surfaces, which manifest the physiological state of bacteria influenced by the type of surface material they accumulate onto. Moreover, the stressful circumstances of adjustment to the surface may persist in the bacteria enhancing intercellular signaling and surface dependent biofilm formation. PMID- 20167086 TI - Promoter methylation analysis of O6-methylguanine-DNA methyltransferase in glioblastoma: detection by locked nucleic acid based quantitative PCR using an imprinted gene (SNURF) as a reference. AB - BACKGROUND: Epigenetic silencing of the MGMT gene by promoter methylation is associated with loss of MGMT expression, diminished DNA-repair activity and longer overall survival in patients with glioblastoma who, in addition to radiotherapy, received alkylating chemotherapy with carmustine or temozolomide. We describe and validate a rapid methylation sensitive quantitative PCR assay (MS qLNAPCR) using Locked Nucleic Acid (LNA) modified primers and an imprinted gene as a reference. METHODS: An analysis was made of a database of 159 GBM patients followed between April 2004 and October 2008. After bisulfite treatment, methylated and unmethylated CpGs were recognized by LNA primers and molecular beacon probes. The SNURF promoter of an imprinted gene mapped on 15q12, was used as a reference. This approach was used because imprinted genes have a balanced copy number of methylated and unmethylated alleles, and this feature allows an easy and a precise normalization. RESULTS: Concordance between already described nested MS-PCR and MS-qLNAPCR was found in 158 of 159 samples (99.4%). The MS qLNAPCR assay showed a PCR efficiency of 102% and a sensitivity of 0.01% for LNA modified primers, while unmodified primers revealed lower efficiency (69%) and lower sensitivity (0.1%). MGMT promoter was found to be methylated using MS qLNAPCR in 70 patients (44.02%), and completely unmethylated in 89 samples (55.97%). Median overall survival was of 24 months, being 20 months and 36 months, in patients with MGMT unmethylated and methylated, respectively. Considering MGMT methylation data provided by MS-qLNAPCR as a binary variable, overall survival was different between patients with GBM samples harboring MGMT promoter unmethylated and other patients with any percentage of MGMT methylation (p = 0.003). This difference was retained using other cut off values for MGMT methylation rate (i.e. 10% and 20% of methylated allele), while the difference was lost when 50% of MGMT methylated allele was used as cut-off. CONCLUSIONS: We report and clinically validate an accurate, robust, and cost effective MS-qLNAPCR protocol for the detection and quantification of methylated MGMT alleles in GBM samples. Using MS-qLNAPCR we demonstrate that even low levels of MGMT promoter methylation have to be taken into account to predict response to temozolomide chemotherapy. PMID- 20167087 TI - The morbidity of urethral stricture disease among male medicare beneficiaries. AB - BACKGROUND: To date, the morbidity of urethral stricture disease among American men has not been analyzed using national datasets. We sought to analyze the morbidity of urethral stricture disease by measuring the rates of urinary tract infections and urinary incontinence among men with a diagnosis of urethral stricture. METHODS: We analyzed Medicare claims data for 1992, 1995, 1998, and 2001 to estimate the rate of dual diagnoses of urethral stricture with urinary tract infection and with urinary incontinence occurring in the same year among a 5% sample of beneficiaries. Male Medicare beneficiaries receiving co-incident ICD 9 codes indicating diagnoses of urethral stricture and either urinary tract infection or urinary incontinence within the same year were counted. RESULTS: The percentage of male patients with a diagnosis of urethral stricture who also were diagnosed with a urinary tract infection was 42% in 2001, an increase from 35% in 1992. Eleven percent of male Medicare beneficiaries with urethral stricture disease in 2001 were diagnosed with urinary incontinence in the same year. This represents an increase from 8% in 1992. CONCLUSIONS: Among male Medicare beneficiaries diagnosed with urethral stricture disease in 2001, 42% were also diagnosed with a urinary tract infection, and 11% with incontinence. Although the overall incidence of stricture disease decreased over this time period, these rates of dual diagnoses increased from 1992 to 2001. Our findings shed light into the health burden of stricture disease on American men. In order to decrease the morbidity of stricture disease, early definitive management of strictures is warranted. PMID- 20167088 TI - miR-17-92 expression in differentiated T cells - implications for cancer immunotherapy. AB - BACKGROUND: Type-1 T cells are critical for effective anti-tumor immune responses. The recently discovered microRNAs (miRs) are a large family of small regulatory RNAs that control diverse aspects of cell function, including immune regulation. We identified miRs differentially regulated between type-1 and type-2 T cells, and determined how the expression of such miRs is regulated. METHODS: We performed miR microarray analyses on in vitro differentiated murine T helper type 1 (Th1) and T helper type-2 (Th2) cells to identify differentially expressed miRs. We used quantitative RT-PCR to confirm the differential expression levels. We also used WST-1, ELISA, and flow cytometry to evaluate the survival, function and phenotype of cells, respectively. We employed mice transgenic for the identified miRs to determine the biological impact of miR-17-92 expression in T cells. RESULTS: Our initial miR microarray analyses revealed that the miR-17-92 cluster is one of the most significantly over-expressed miR in murine Th1 cells when compared with Th2 cells. RT-PCR confirmed that the miR-17-92 cluster expression was consistently higher in Th1 cells than Th2 cells. Disruption of the IL-4 signaling through either IL-4 neutralizing antibody or knockout of signal transducer and activator of transcription (STAT)6 reversed the miR-17-92 cluster suppression in Th2 cells. Furthermore, T cells from tumor bearing mice and glioma patients had decreased levels of miR-17-92 when compared with cells from non tumor bearing counterparts. CD4+ T cells derived from miR-17-92 transgenic mice demonstrated superior type-1 phenotype with increased IFN-gamma production and very late antigen (VLA)-4 expression when compared with counterparts derived from wild type mice. Human Jurkat T cells ectopically expressing increased levels of miR-17-92 cluster members demonstrated increased IL-2 production and resistance to activation-induced cell death (AICD). CONCLUSION: The type-2-skewing tumor microenvironment induces the down-regulation of miR-17-92 expression in T cells, thereby diminishing the persistence of tumor-specific T cells and tumor control. Genetic engineering of T cells to express miR-17-92 may represent a promising approach for cancer immunotherapy. PMID- 20167089 TI - Functional evolution of the trace amine associated receptors in mammals and the loss of TAAR1 in dogs. AB - BACKGROUND: The trace amine associated receptor family is a diverse array of GPCRs that arose before the first vertebrates walked on land. Trace amine associated receptor 1 (TAAR1) is a wide spectrum aminergic receptor that acts as a modulator in brain monoaminergic systems. Other trace amine associated receptors appear to relate to environmental perception and show a birth-and-death pattern in mammals similar to olfactory receptors. RESULTS: Across mammals, avians, and amphibians, the TAAR1 gene is intact and appears to be under strong purifying selection based on rates of amino acid fixation compared to neutral mutations. We have found that in dogs it has become a pseudogene. Our analyses using a comparative genetics approach revealed that the pseudogenization event predated the emergence of the Canini tribe rather than being coincident with canine domestication. By assessing the effects of the TAAR1 agonist beta phenylethylamine on [3H]dopamine uptake in canine striatal synaptosomes and comparing the degree and pattern of uptake inhibition to that seen in other mammals, including TAAR1 knockout mice, wild type mice and rhesus monkey, we found that the TAAR1 pseudogenization event resulted in an uncompensated loss of function. CONCLUSION: The gene family has seen expansions among certain mammals, notably rodents, and reductions in others, including primates. By placing the trace amine associated receptors in an evolutionary context we can better understand their function and their potential associations with behavior and neurological disease. PMID- 20167090 TI - MosquitoMap and the Mal-area calculator: new web tools to relate mosquito species distribution with vector borne disease. AB - BACKGROUND: Mosquitoes are important vectors of diseases but, in spite of various mosquito faunistic surveys globally, there is a need for a spatial online database of mosquito collection data and distribution summaries. Such a resource could provide entomologists with the results of previous mosquito surveys, and vector disease control workers, preventative medicine practitioners, and health planners with information relating mosquito distribution to vector-borne disease risk. RESULTS: A web application called MosquitoMap was constructed comprising mosquito collection point data stored in an ArcGIS 9.3 Server/SQL geodatabase that includes administrative area and vector species x country lookup tables. In addition to the layer containing mosquito collection points, other map layers were made available including environmental, and vector and pathogen/disease distribution layers. An application within MosquitoMap called the Mal-area calculator (MAC) was constructed to quantify the area of overlap, for any area of interest, of vector, human, and disease distribution models. Data standards for mosquito records were developed for MosquitoMap. CONCLUSION: MosquitoMap is a public domain web resource that maps and compares georeferenced mosquito collection points to other spatial information, in a geographical information system setting. The MAC quantifies the Mal-area, i.e. the area where it is theoretically possible for vector-borne disease transmission to occur, thus providing a useful decision tool where other disease information is limited. The Mal-area approach emphasizes the independent but cumulative contribution to disease risk of the vector species predicted present. MosquitoMap adds value to, and makes accessible, the results of past collecting efforts, as well as providing a template for other arthropod spatial databases. PMID- 20167093 TI - Modified lateral rhinotomy for fronto-ethmoid schwannoma in a child: a case report. AB - Schwannoma of frontoethmoid region is a rare presentation. We report a case of 11-year-old girl with a swelling at the root of nose and nasal dorsum. Based on clinical picture and radiological findings it was not possible to establish a definitive diagnosis. But the histopathological picture was suggestive of schwannoma. A novel surgical approach was adopted to facilitate complete removal of the tumor and provide best possible cosmetic results. PMID- 20167092 TI - Acute NMDA toxicity in cultured rat cerebellar granule neurons is accompanied by autophagy induction and late onset autophagic cell death phenotype. AB - BACKGROUND: Autophagy, an intracellular response to stress, is characterized by double membrane cytosolic vesicles called autophagosomes. Prolonged autophagy is known to result in autophagic (Type II) cell death. This study examined the potential role of an autophagic response in cultured cerebellar granule neurons challenged with excitotoxin N-methyl-D-aspartate (NMDA). RESULTS: NMDA exposure induced light chain-3 (LC-3)-immunopositive and monodansylcadaverine (MDC) fluorescent dye-labeled autophagosome formation in both cell bodies and neurites as early as 3 hours post-treatment. Elevated levels of Beclin-1 and the autophagosome-targeting LC3-II were also observed following NMDA exposure. Prolonged exposure of the cultures to NMDA (8-24 h) generated MDC-, LC3-positive autophagosomal bodies, concomitant with the neurodegenerative phase of NMDA challenge. Lysosomal inhibition studies also suggest that NMDA-treatment diverted the autophagosome-associated LC3-II from the normal lysosomal degradation pathway. Autophagy inhibitor 3-methyladenine significantly reduced NMDA-induced LC3-II/LC3-I ratio increase, accumulation of autophagosomes, and suppressed NMDA mediated neuronal death. ATG7 siRNA studies also showed neuroprotective effects following NMDA treatment. CONCLUSIONS: Collectively, this study shows that autophagy machinery is robustly induced in cultured neurons subjected to prolonged exposure to excitotoxin, while autophagosome clearance by lysosomal pathway might be impaired. Our data further show that prolonged autophagy contributes to cell death in NMDA-mediated excitotoxicity. PMID- 20167091 TI - The influence of heart disease on characteristics, quality of life, use of health resources, and costs of COPD in primary care settings. AB - BACKGROUND: To evaluate the influence of heart disease on clinical characteristics, quality of life, use of health resources, and costs of patients with COPD followed at primary care settings under common clinical practice conditions. METHODS: Epidemiologic, observational, and descriptive study (EPIDEPOC study). Patients > or = 40 years of age with stable COPD attending primary care settings were included. Demographic, clinical characteristics, quality of life (SF-12), seriousness of the disease, and treatment data were collected. Results were compared between patients with or without associated heart disease. RESULTS: A total of 9,390 patients with COPD were examined of whom 1,770 (18.8%) had heart disease and 78% were males. When comparing both patient groups, significant differences were found in the socio-demographic characteristics, health profile, comorbidities, and severity of the airway obstruction, which was greater in patients with heart disease. Differences were also found in both components of quality of life, physical and mental, with lower scores among those patients with heart disease. Higher frequency of primary care and pneumologist visits, emergency-room visits and number of hospital admissions were observed among patients with heart diseases. The annual total cost per patient was significantly higher in patients with heart disease; 2,937 +/- 2,957 vs. 1,749 +/- 2,120, p < 0.05. Variables that were showed to be independently associated to COPD in subjects with hearth conditions were age, being inactive, ex-smokers, moderate physical exercise, body mass index, concomitant blood hypertension, diabetes, anxiety, the SF-12 physical and mental components and per patient per year total cost. CONCLUSION: Patients with COPD plus heart disease had greater disease severity and worse quality of life, used more healthcare resources and were associated with greater costs compared to COPD patients without known hearth disease. PMID- 20167094 TI - The use of tibial Less Invasive Stabilization System (LISS) plate [AO-ASIF] for the treatment of paediatric supracondylar fracture of femur: a case report. AB - Paediatric supracondylar fractures of the femur are not common. The treatment options depend on the age of child, the site of the fracture, the pattern of injury and the surgeon's preference. We report a case of an 11-year old boy who sustained a comminuted displaced supracondylar fracture of the femur and was treated with indirect reduction and internal fixation with the Less Invasive Stabilization System (LISS) tibial plate. PMID- 20167095 TI - Keratin 19 marks poor differentiation and a more aggressive behaviour in canine and human hepatocellular tumours. AB - BACKGROUND: The expression of Keratin 19 (K19) was reported in a subset of hepatocellular carcinomas (HCCs). K19 positive HCCs are associated with an increased malignancy compared to K19 negative HCCs. No suitable mouse models exist for this subtype of HCC, nor is the incidence of K19 expression in hepatocellular neoplasia in model animals known. Therefore, we compared the occurrence and tumour behaviour of K19 positive hepatocellular neoplasias in dog and man. RESULTS: The expression of hepatocellular differentiation (HepPar-1), biliary/progenitor cell (K7, K19), and malignancy (glypican-3) markers was semi quantitatively assessed by immunohistochemistry. The histological grade of tumour differentiation was determined according to a modified classification of Edmondson and Steiner; the staging included intrahepatic, lymph node or distant metastases. Four of the 34 canine hepatocellular neoplasias showed K19 positivity (12%), of which two co-expressed K7. K19 positive tumours did not express HepPar 1, despite the histological evidence of a hepatocellular origin. Like in human HCC, all K19 positive hepatocellular neoplasias were glypican-3 positive and histologically poorly differentiated and revealed intra- or extrahepatic metastases whereas K19 negative hepatocellular neoplasias did not. CONCLUSIONS: K19 positive hepatocellular neoplasias are highly comparable to man and occur in 12% of canine hepatocellular tumours and are associated with a poorly differentiated histology and aggressive tumour behaviour. PMID- 20167096 TI - Bilateral rectus femoris intramuscular haematoma following simultaneous quadriceps strain in an athlete: a case report. AB - INTRODUCTION: Bilateral rectus femoris haematoma following a simultaneous strain of the quadriceps muscles is a very rare condition. CASE PRESENTATION: We report the case of a 21-year-old Greek Caucasian female rowing athlete who was injured on both thighs. She complained of pain and inability to walk. Physical examination revealed tenderness over the thighs and restriction of knee movement. The result of a roentgenogram was normal, and there was no evidence of fracture or patella displacement. Magnetic resonance imaging revealed haematoma formation in both the rectus femoris muscles. The diameters of the left and right haematomas within the muscles were 6 cm and 5 cm, respectively. Therapeutic approaches included compression bandages, ice application, rest, elevation, and administration of muscle relaxant drugs. Active stretching and isometric exercises were performed after three days. The patient was able to walk using crutches two days after the initiation of treatment. On the seventh day, she had regained her full ability to walk without crutches. Non-steroidal anti inflammatory drugs were administered on the fifth day and continued for one week. Six weeks later, she had pain-free function and the result of magnetic resonance imaging was normal. She was able to resume her training programme and two weeks later, she returned to her previous sport activities and competitions. CONCLUSION: There are references in the literature regarding the occurrence of unilateral quadriceps haematomas following strain and bilateral quadriceps tendon rupture in athletes. Simultaneous bilateral rectus femoris haematomas after a muscle strain is a rare condition. It must be diagnosed early. The three phases of treatment are rest, knee mobilization, and restoration of quadriceps function. PMID- 20167097 TI - Degeneracy: a link between evolvability, robustness and complexity in biological systems. AB - A full accounting of biological robustness remains elusive; both in terms of the mechanisms by which robustness is achieved and the forces that have caused robustness to grow over evolutionary time. Although its importance to topics such as ecosystem services and resilience is well recognized, the broader relationship between robustness and evolution is only starting to be fully appreciated. A renewed interest in this relationship has been prompted by evidence that mutational robustness can play a positive role in the discovery of adaptive innovations (evolvability) and evidence of an intimate relationship between robustness and complexity in biology.This paper offers a new perspective on the mechanics of evolution and the origins of complexity, robustness, and evolvability. Here we explore the hypothesis that degeneracy, a partial overlap in the functioning of multi-functional components, plays a central role in the evolution and robustness of complex forms. In support of this hypothesis, we present evidence that degeneracy is a fundamental source of robustness, it is intimately tied to multi-scaled complexity, and it establishes conditions that are necessary for system evolvability. PMID- 20167098 TI - Toxicity of unsaturated fatty acids to the biohydrogenating ruminal bacterium, Butyrivibrio fibrisolvens. AB - BACKGROUND: Health-promoting polyunsaturated fatty acids (PUFA) are abundant in forages grazed by ruminants and in vegetable and fish oils used as dietary supplements, but only a small proportion of PUFA finds its way into meat and milk, because of biohydrogenation in the rumen. Butyrivibrio fibrisolvens plays a major role in this activity. The aim of this study was to investigate the mechanisms by which PUFA affect the growth of B. fibrisolvens, how PUFA are metabolized and the metabolic response to growth in the presence of PUFA. RESULTS: Linoleic acid (LA; cis-9, cis-12-18:2) and alpha-linolenic acid (LNA; cis-9, cis-12, cis-15-18:3) increased the lag phase of B. fibrisolvens JW11, LNA having the greater effect. Growth was initiated only when the PUFA had been converted to vaccenic acid (VA; trans-11-18:1). The major fish oil fatty acids, eicosapentaenoic acid (EPA; 20:5(n-3)) and docosahexaenoic acid (DHA; 22:6(n-3)), were not metabolized and prevented growth. Cellular integrity, as determined fluorimetrically by propidium iodide (PI) ingression, was affected as much by 18:1 fatty acids, including VA, as 18:2 fatty acids. The methyl esters of LNA, LA, EPA and DHA had no effect on growth or other measurements. The ATP pool decreased by 2/3 when LA was added to growing bacteria, whereas most acyl CoA pools decreased by >96%. CONCLUSIONS: It was concluded that biohydrogenation occurs to enable B. fibrisolvens to survive the bacteriostatic effects of PUFA, and that the toxicity of PUFA is probably mediated via a metabolic effect rather than disruption of membrane integrity. PMID- 20167099 TI - Dietary intake of Senegalese adults. AB - The aim of this work is to identify major food sources and dietary constituents of Senegalese adults. We conducted a cross-sectional study, using a single 24 hour dietary recall interview. Foods were classified into food groups based on similarities in nutrient content or use. Food groups included foods consumed individually, or as part of food mixtures such as stews, soups, or sandwiches. Median consumption (amount/day) of each food was determined and examined by relevant subgroups. Participants were 50 healthy Senegalese men, aged 20-62 years recruited at the Hopital General de Grand Yoff in Dakar, Senegal and from Sendou village, a rural area outside Dakar. A total of 90 foods and beverages were identified and classified into 11 groups. Sixty-five percent of foods identified could be classified as meats, grains, or fruits/vegetables. Fruits and vegetables comprised 42% (38/90) of all foods; meats 12% (11/90); and grains 11% (10/90). Sauces (6%, 5/90), sweets (4%, 4/90), and desserts (4%, 4/90) were also reported. The most common fruits/vegetables reported were potato, carrot, mango, and lettuce; commonly reported grains were bread and rice; and commonly reported meats were fish, beef, and ox. There were no differences in reported daily intake of each food by age, ethnicity, education, or residence. Most foods reported were traditional to the Senegalese diet, despite the increasing availability of Western foods in Senegal. PMID- 20167100 TI - Antibody dependent enhancement of frog virus 3 infection. AB - BACKGROUND: Viruses included in the family Iridoviridae are large, icosahedral, dsDNA viruses that are subdivided into 5 genera. Frog virus 3 (FV3) is the type species of the genus Ranavirus and the best studied iridovirus at the molecular level. Typically, antibodies directed against a virus act to neutralize the virus and limit infection. Antibody dependent enhancement occurs when viral antibodies enhance infectivity of the virus rather than neutralize it. RESULTS: Here we show that anti-FV3 serum present at the time of FV3 infection enhances infectivity of the virus in two non-immune teleost cell lines. We found that antibody dependent enhancement of FV3 was dependent on the Fc portion of anti-FV3 antibodies but not related to complement. Furthermore, the presence of anti-FV3 serum during an FV3 infection in a non-immune mammalian cell line resulted in neutralization of the virus. Our results suggest that a cell surface receptor specific to teleost cell lines is responsible for the enhancement. CONCLUSIONS: This report represents the first evidence of antibody dependent enhancement in iridoviruses. The data suggests that anti-FV3 serum can either neutralize or enhance viral infection and that enhancement is related to a novel antibody dependent enhancement pathway found in teleosts that is Fc dependent. PMID- 20167101 TI - AMPK exerts dual regulatory effects on the PI3K pathway. AB - BACKGROUND: AMP-activated protein kinase (AMPK) is a fuel-sensing enzyme that is activated when cells experience energy deficiency and conversely suppressed in surfeit of energy supply. AMPK activation improves insulin sensitivity via multiple mechanisms, among which AMPK suppresses mTOR/S6K-mediated negative feedback regulation of insulin signaling. RESULTS: In the present study we further investigated the mechanism of AMPK-regulated insulin signaling. Our results showed that 5-aminoimidazole-4-carboxamide-1 ribonucleoside (AICAR) greatly enhanced the ability of insulin to stimulate the insulin receptor substrate-1 (IRS1)-associated PI3K activity in differentiated 3T3-F442a adipocytes, leading to increased Akt phosphorylation at S473, whereas insulin stimulated activation of mTOR was diminished. In 3T3-F442a preadipocytes, these effects were attenuated by expression of a dominant negative mutant of AMPK alpha1 subunit. The enhancing effect of ACIAR on Akt phosphorylation was also observed when the cells were treated with EGF, suggesting that it is regulated at a step beyond IR/IRS1. Indeed, when the cells were chronically treated with AICAR in the absence of insulin, Akt phosphorylation was progressively increased. This event was associated with an increase in levels of phosphatidylinositol -3,4,5 trisphosphate (PIP3) and blocked by Wortmannin. We then expressed the dominant negative mutant of PTEN (C124S) and found that the inhibition of endogenous PTEN per se did not affect phosphorylation of Akt at basal levels or upon treatment with AICAR or insulin. Thus, this result suggests that AMPK activation of Akt is not mediated by regulating phosphatase and tensin homologue (PTEN). CONCLUSION: Our present study demonstrates that AMPK exerts dual effects on the PI3K pathway, stimulating PI3K/Akt and inhibiting mTOR/S6K. PMID- 20167102 TI - Immunohistochemical detection of transgene expression in the brain using small epitope tags. AB - BACKGROUND: In vivo overexpression of proteins is a powerful approach to study their biological function, generate disease models or evaluate gene therapy approaches. In order to investigate an exogenously expressed protein, specific and sensitive detection is essential. Unfortunately, antibodies that allow histological detection of the protein of interest are not always readily available. The use of an epitope tag fused to the protein can circumvent this problem as well as provide the possibility to discriminate endogenous from overexpressed proteins. In order to minimize impact on the bioactivity and biodistribution of the overexpressed protein, preference is given to small tags. RESULTS: In the present study, we evaluated several small epitope tags together with corresponding anti-tag antibodies for the detection of overexpressed proteins in rat brain, using eGFP as a reference. We generated several lentiviral vectors encoding eGFP with different N-terminally fused small epitope tags (AU1, flag, 3flag, HA, myc and V5). After confirmation of their functionality in cell culture, we injected these lentiviral vectors stereotactically into the striatum of rats and prepared paraformaldehyde fixed floating sections for immunohistochemical analysis. Using multiple antibodies and antibody dilutions per epitope tag, we extensively assessed the efficiency of several anti-tag antibodies for chromogenic immunohistochemical detection of the epitope tagged eGFPs by determining the proportion of immunoreactivity detected by anti-tag antibodies compared to anti-GFP antibody. Using fluorescence immunohistochemistry and confocal microscopy, we also quantified the proportion of eGFP-positive cells detected by anti-tag antibodies. Our results show that all the examined small epitope tags could be detected by anti-tag antibodies both in cell extracts as well as in vivo, although to varying degrees depending on the tag and antibody used. Using the presented protocol, V5/anti-V5 and HA/HA11 tag/antibody combinations provided the most sensitive detection in brain tissue. We confirmed the applicability of these optimized in vivo tag detection conditions for a difficult to detect protein, firefly luciferase (fLuc), using lentiviral vector constructs expressing V5 tagged and 3flag tagged fLuc protein. CONCLUSIONS: We show here that several small epitope tags are useful for immunohistochemical detection of exogenous proteins in vivo. Our study also provides a generic methodology which is broadly applicable for the detection of overexpressed transgenes in mammalian brain tissue. PMID- 20167104 TI - Severe hydrops in the infant of a Rhesus D-positive mother due to anti-c antibodies diagnosed antenatally: a case report. AB - INTRODUCTION: Rhesus haemolytic disease of the newborn is a prototype of maternal isoimmunisation and fetal haemolytic disease. There are other rare blood group antigens capable of causing alloimmunisation and haemolytic disease such as c, C, E, Kell and Duffy. In India, after the confirmation of a newborn's blood group, antibodies are screened only if the mother is Rehsus D-negative negative and the father is Rhesus D-positive. Hydrops in Rhesus positive women are investigated along the lines of non-immune hydrops. CASE PRESENTATION: We report the case of a patient from India where irregular antibodies were requested for an O-positive 26 year-old mother in order to investigate fetal hydrops. Anti-c antibody was revealed and the fetus was treated successfully with compatible O negative and c negative intrauterine blood transfusions. The baby was treated postnatally with double volume exchange transfusion with the same compatible blood, and was discharged 30 days after birth. CONCLUSION: We highlight the importance of conducting irregular antibody screening for women with significant obstetric history and fetal hydrops. This could assist in diagnosing and successfully treating the fetus with appropriate antigen negative cross-matched compatible blood. We note, however, that anti-c immunoglobulin is not yet readily available. PMID- 20167103 TI - The role of social support and social networks in smoking behavior among middle and older aged people in rural areas of South Korea: a cross-sectional study. AB - BACKGROUND: Although the number of studies on anti-smoking interventions has increased, studies focused on identifying social contextual factors in rural areas are scarce. The purpose of this study was to explore the role of social support and social networks in smoking behavior among middle and older aged people living in rural areas of South Korea. METHODS: The study employed a cross sectional design. Participants included 1,057 adults, with a mean age of 60.7 years, residing in rural areas. Information on participants' tobacco use, stress, social support, and social networks was collected using structured questionnaires. The chi-square test, the t-test, ANOVA, and logistic regression were used for data analysis. RESULTS: The overall smoking prevalence in the study was 17.4% (men, 38.8%; women, 5.1%). Overall, stress was high among women, and social support was high among men. Smokers had high levels of social support (t = -2.90, p = .0038) and social networks (t = -2.22, p = .0271), as compared to non- and former smokers. Those in the high social support group were likely to be smokers (AOR = 2.21, 95% CI 1.15-4.26). Women with moderate social ties were less likely to smoke (AOR = 0.18, 95% CI 0.05-0.61). CONCLUSION: There was a protective role of a moderate social network level among women, and a high level of social support was associated with smoking behaviors in rural areas. Findings suggest the need for a comprehensive understanding of the functions and characteristics of social contextual factors including social support and social networks in order to conduct more effective anti-smoking interventions in rural areas. PMID- 20167106 TI - Exposure of beta-tubulin regions defined by antibodies on an Arabidopsis thaliana microtubule protofilament model and in the cells. AB - BACKGROUND: The function of the cortical microtubules, composed of alphabeta tubulin heterodimers, is linked to their organizational state which is subject to spatial and temporal modulation by environmental cues. The role of tubulin posttranslational modifications in these processes is largely unknown. Although antibodies against small tubulin regions represent useful tool for studying molecular configuration of microtubules, data on the exposure of tubulin epitopes on plant microtubules are still limited. RESULTS: Using homology modeling we have generated an Arabidopsis thaliana microtubule protofilament model that served for the prediction of surface exposure of five beta-tubulin epitopes as well as tyrosine residues. Peptide scans newly disclosed the position of epitopes detected by antibodies 18D6 (beta1-10), TUB2.1 (beta426-435) and TU-14 (beta436 445). Experimental verification of the results by immunofluorescence microscopy revealed that the exposure of epitopes depended on the mode of fixation. Moreover, homology modeling showed that only tyrosines in the C-terminal region of beta-tubulins (behind beta425) were exposed on the microtubule external side. Immunofluorescence microscopy revealed tyrosine phosphorylation of microtubules in plant cells, implying that beta-tubulins could be one of the targets for tyrosine kinases. CONCLUSIONS: We predicted surface exposure of five beta-tubulin epitopes, as well as tyrosine residues, on the surface of A. thaliana microtubule protofilament model, and validated the obtained results by immunofluorescence microscopy on cortical microtubules in cells.The results suggest that prediction of epitope exposure on microtubules by means of homology modeling combined with site-directed antibodies can contribute to a better understanding of the interactions of plant microtubules with associated proteins. PMID- 20167107 TI - Whole brain radiotherapy with a conformational external beam radiation boost for lung cancer patients with 1-3 brain metastasis: a multi institutional study. AB - BACKGROUND: To determine the outcome of patients with brain metastasis (BM) from lung cancer treated with an external beam radiotherapy boost (RTB) after whole brain radiotherapy (WBRT). METHODS: A total of 53 BM patients with lung cancer were treated sequentially with WBRT and RTB between 1996 and 2008 according to our institutional protocol. Mean age was 58.8 years. The median KPS was 90. Median recursive partitioning analysis (RPA) and graded prognostic assessment (GPA) grouping were 2 and 2.5, respectively. Surgery was performed on 38 (71%) patients. The median number of BM was 1 (range, 1-3). Median WBRT and RTB combined dose was 39 Gy (range, 37.5-54). Median follow-up was 12.0 months. RESULTS: During the period of follow-up, 37 (70%) patients died. The median overall survival (OS) was 14.5 months. Only 13 patients failed in the brain. The majority of patients (n = 29) failed distantly. The 1-year OS, -local control, extracranial failure rates were 61.2%, 75.2% and 60.8%, respectively. On univariate analysis, improved OS was found to be significantly associated with total dose (< or = 39 Gy vs. > 39 Gy; p < 0.01), age < 65 (p < 0.01), absence of extracranial metastasis (p < 0.01), GPA > or = 2.5 (p = 0.01), KPS > or = 90 (p = 0.01), and RPA < 2 (p = 0.04). On multivariate analysis, total dose (p < 0.01) and the absence of extracranial metastasis (p = 0.03) retained statistical significance. CONCLUSIONS: The majority of lung cancer patients treated with WBRT and RTB progressed extracranially. There might be a subgroup of younger patients with good performance status and no extracranial disease who may benefit from dose escalation after WBRT to the metastatic site. PMID- 20167108 TI - Functional characterization of Arabidopsis thaliana transthyretin-like protein. AB - BACKGROUND: Arabidopsis thaliana transthyretin-like (TTL) protein is a potential substrate in the brassinosteroid signalling cascade, having a role that moderates plant growth. Moreover, sequence homology revealed two sequence domains similar to 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU) decarboxylase (N-terminal domain) and 5-hydroxyisourate (5-HIU) hydrolase (C-terminal domain). TTL is a member of the transthyretin-related protein family (TRP), which comprises a number of proteins with sequence homology to transthyretin (TTR) and the characteristic C-terminal sequence motif Tyr-Arg-Gly-Ser. TRPs are single domain proteins that form tetrameric structures with 5-HIU hydrolase activity. Experimental evidence is fundamental for knowing if TTL is a tetrameric protein, formed by the association of the 5-HIU hydrolase domains and, in this case, if the structural arrangement allows for OHCU decarboxylase activity. This work reports about the biochemical and functional characterization of TTL. RESULTS: The TTL gene was cloned and the protein expressed and purified for biochemical and functional characterization. The results show that TTL is composed of four subunits, with a moderately elongated shape. We also found evidence for 5-HIU hydrolase and OHCU decarboxylase activities in vitro, in the full-length protein. CONCLUSIONS: The Arabidopsis thaliana transthyretin-like (TTL) protein is a tetrameric bifunctional enzyme, since it has 5-HIU hydrolase and OHCU decarboxylase activities, which were simultaneously observed in vitro. PMID- 20167109 TI - Role of PPAR-delta in the development of zymosan-induced multiple organ failure: an experiment mice study. AB - BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-beta/delta is a nuclear receptor transcription factor that regulates gene expression in many important biological processes. It is expressed ubiquitously, especially white adipose tissue, heart, muscle, intestine, placenta and macrophages but many of its functions are unknown. Saturated and polyunsaturated fatty acids activate PPAR-beta/delta, but physiological ligands have not yet been identified. In the present study, we investigated the anti-inflammatory effects of PPAR-beta/delta activation, through the use of GW0742 (0,3 mg/kg 10% Dimethyl sulfoxide (DMSO) i.p), a synthetic high affinity ligand, on the development of zymosan-induced multiple organ failure (MOF). METHODS: Multiple organ failure (MOF) was induced in mice by administration of zymosan (given at 500 mg/kg, i.p. as a suspension in saline). The control groups were treated with vehicle (0.25 ml/mouse saline), while the pharmacological treatment was the administration of GW0742 (0,3 mg/kg 10% DMSO i.p. 1 h and 6 h after zymosan administration). MOF and systemic inflammation in mice was assessed 18 hours after administration of zymosan. RESULTS: Treatment with GW0742 caused a significant reduction of the peritoneal exudate formation and of the neutrophil infiltration caused by zymosan resulting in a reduction in myeloperoxidase activity. The PPAR-beta/delta agonist, GW0742, at the dose of 0,3 mg/kg in 10% DMSO, also attenuated the multiple organ dysfunction syndrome caused by zymosan. In pancreas, lung and gut, immunohistochemical analysis of some end points of the inflammatory response, such as inducible nitric oxide synthase (iNOS), nitrotyrosine, poly (ADP-ribose) (PAR), TNF- and IL-1as well as FasL, Bax, Bcl-2 and apoptosis, revealed positive staining in sections of tissue obtained from zymosan-injected mice. On the contrary, these parameters were markedly reduced in samples obtained from mice treated with GW0742 CONCLUSIONS: In this study, we have shown that GW0742 attenuates the degree of zymosan-induced non-septic shock in mice. PMID- 20167110 TI - Evaluation of statistical methods for normalization and differential expression in mRNA-Seq experiments. AB - BACKGROUND: High-throughput sequencing technologies, such as the Illumina Genome Analyzer, are powerful new tools for investigating a wide range of biological and medical questions. Statistical and computational methods are key for drawing meaningful and accurate conclusions from the massive and complex datasets generated by the sequencers. We provide a detailed evaluation of statistical methods for normalization and differential expression (DE) analysis of Illumina transcriptome sequencing (mRNA-Seq) data. RESULTS: We compare statistical methods for detecting genes that are significantly DE between two types of biological samples and find that there are substantial differences in how the test statistics handle low-count genes. We evaluate how DE results are affected by features of the sequencing platform, such as, varying gene lengths, base-calling calibration method (with and without phi X control lane), and flow-cell/library preparation effects. We investigate the impact of the read count normalization method on DE results and show that the standard approach of scaling by total lane counts (e.g., RPKM) can bias estimates of DE. We propose more general quantile based normalization procedures and demonstrate an improvement in DE detection. CONCLUSIONS: Our results have significant practical and methodological implications for the design and analysis of mRNA-Seq experiments. They highlight the importance of appropriate statistical methods for normalization and DE inference, to account for features of the sequencing platform that could impact the accuracy of results. They also reveal the need for further research in the development of statistical and computational methods for mRNA-Seq. PMID- 20167111 TI - JC virus in the pathogenesis of colorectal cancer, an etiological agent or another component in a multistep process? AB - JCV infection occurs early in childhood and last throughout life. JCV has been associated to colorectal cancer and might contribute to the cancer phenotype by several mechanisms. Among JCV proteins, particularly two of them, large T-antigen and agnoprotein, can interfere with cell cycle control and genomic instability mechanisms, but other viral proteins might also contribute to the process. Part of viral DNA sequences are detected in carcinoma lesions, but less frequently in adenomas, and not in the normal surrounding tissue, suggesting they are integrated in the host cell genome and these integrations have been selected; in addition viral integration can cause a gene, or chromosomal damage. The inflammatory infiltration caused by a local chronic viral infection in the intestine can contribute to the selection and expansion of a tumor prone cell in a cytokine rich microenvironment. JCV may not be the cause of colorectal cancer, but it can be a relevant risk factor and able to facilitate progression at one or several stages in tumor progression. JCV transient effects might lead to selective expansion of tumor cells. Since there is not a direct cause and effect relationship, JCV infection may be an alternative to low frequency cancer predisposition genes. PMID- 20167112 TI - Multiple controls affect arsenite oxidase gene expression in Herminiimonas arsenicoxydans. AB - BACKGROUND: Both the speciation and toxicity of arsenic are affected by bacterial transformations, i.e. oxidation, reduction or methylation. These transformations have a major impact on environmental contamination and more particularly on arsenic contamination of drinking water. Herminiimonas arsenicoxydans has been isolated from an arsenic- contaminated environment and has developed various mechanisms for coping with arsenic, including the oxidation of As(III) to As(V) as a detoxification mechanism. RESULTS: In the present study, a differential transcriptome analysis was used to identify genes, including arsenite oxidase encoding genes, involved in the response of H. arsenicoxydans to As(III). To get insight into the molecular mechanisms of this enzyme activity, a Tn5 transposon mutagenesis was performed. Transposon insertions resulting in a lack of arsenite oxidase activity disrupted aoxR and aoxS genes, showing that the aox operon transcription is regulated by the AoxRS two-component system. Remarkably, transposon insertions were also identified in rpoN coding for the alternative N sigma factor (sigma54) of RNA polymerase and in dnaJ coding for the Hsp70 co chaperone. Western blotting with anti-AoxB antibodies and quantitative RT-PCR experiments allowed us to demonstrate that the rpoN and dnaJ gene products are involved in the control of arsenite oxidase gene expression. Finally, the transcriptional start site of the aoxAB operon was determined using rapid amplification of cDNA ends (RACE) and a putative -12/-24 sigma54-dependent promoter motif was identified upstream of aoxAB coding sequences. CONCLUSION: These results reveal the existence of novel molecular regulatory processes governing arsenite oxidase expression in H. arsenicoxydans. These data are summarized in a model that functionally integrates arsenite oxidation in the adaptive response to As(III) in this microorganism. PMID- 20167114 TI - Characteristics of ambulatory anticoagulant adverse drug events: a descriptive study. AB - BACKGROUND: Despite the high frequency with which adverse drug events (ADEs) occur in outpatient settings, detailed information regarding these events remains limited. Anticoagulant drugs are associated with increased safety concerns and are commonly involved in outpatient ADEs. We therefore sought to evaluate ambulatory anticoagulation ADEs and the patient population in which they occurred within the Duke University Health System (Durham, NC, USA). METHODS: A retrospective chart review of ambulatory warfarin-related ADEs was conducted. An automated trigger surveillance system identified eligible events in ambulatory patients admitted with an International Normalized Ratio (INR) >3 and administration of vitamin K. Event and patient characteristics were evaluated, and quality/process improvement strategies for ambulatory anticoagulation management are described. RESULTS: A total of 169 events in 167 patients were identified from December 1, 2006-June 30, 2008 and included in the study. A median supratherapeutic INR of 6.1 was noted, and roughly half of all events (52.1%) were associated with a bleed. Nearly 74% of events resulted in a need for fresh frozen plasma; 64.8% of bleeds were classified as major. A total of 59.2% of events were at least partially responsible for hospital admission. Median patient age was 68 y (range 36-95 y) with 24.9% initiating therapy within 3 months prior to the event. Of events with a prior documented patient visit (n = 157), 73.2% were seen at a Duke clinic or hospital within the previous month. Almost 80% of these patients had anticoagulation therapy addressed, but only 60.0% had a follow-up plan documented in the electronic note. CONCLUSIONS: Ambulatory warfarin-related ADEs have significant patient and healthcare utilization consequences in the form of bleeding events and associated hospital admissions. Recommendations for improvement in anticoagulation management include use of information technology to assist monitoring and follow-up documentation, avoid drug interactions, and engage patients in their care. PMID- 20167113 TI - R-Ras regulates beta1-integrin trafficking via effects on membrane ruffling and endocytosis. AB - BACKGROUND: Integrin-mediated cell adhesion and spreading is dramatically enhanced by activation of the small GTPase, R-Ras. Moreover, R-Ras localizes to the leading edge of migrating cells, and regulates membrane protrusion. The exact mechanisms by which R-Ras regulates integrin function are not fully known. Nor is much known about the spatiotemporal relationship between these two molecules, an understanding of which may provide insight into R-Ras regulation of integrins. RESULTS: GFP-R-Ras localized to the plasma membrane, most specifically in membrane ruffles, in Cos-7 cells. GFP-R-Ras was endocytosed from these ruffles, and trafficked via multiple pathways, one of which involved large, acidic vesicles that were positive for Rab11. Cells transfected with a dominant negative form of GFP-R-Ras did not form ruffles, had decreased cell spreading, and contained numerous, non-trafficking small vesicles. Conversely, cells transfected with the constitutively active form of GFP-R-Ras contained a greater number of ruffles and large vesicles compared to wild-type transfected cells. Ruffle formation was inhibited by knock-down of endogenous R-Ras with siRNA, suggesting that activated R-Ras is not just a component of, but also an architect of ruffle formation. Importantly, beta1-integrin co-localized with endogenous R-Ras in ruffles and endocytosed vesicles. Expression of dominant negative R-Ras or knock down of R-Ras by siRNA prevented integrin accumulation into ruffles, impaired endocytosis of beta1-integrin, and decreased beta1-integrin-mediated adhesion. Knock-down of R-Ras also perturbed the dynamics of another membrane-localized protein, GFP-VSVG, suggesting a more global role for R-Ras on membrane dynamics. However, while R-Ras co-internalized with integrins, it did not traffic with VSVG, which instead moved laterally out of ruffles within the plane of the membrane, suggesting multiple levels of regulation of and by R-Ras. CONCLUSIONS: Our results suggest that integrin function involves integrin trafficking via a cycle of membrane protrusion, ruffling, and endocytosis regulated by R-Ras, providing a novel mechanism by which integrins are linked to R-Ras through control of membrane dynamics. PMID- 20167115 TI - Microarray analysis of Foxl2 mediated gene regulation in the mouse ovary derived KK1 granulosa cell line: Over-expression of Foxl2 leads to activation of the gonadotropin releasing hormone receptor gene promoter. AB - BACKGROUND: The Foxl2 transcription factor is required for ovarian function during follicular development. The mechanism of Foxl2 regulation of this process has not been elucidated. Our approach to begin to understand Foxl2 function is through the identification of Foxl2 regulated genes in the ovary. METHODS: Transiently transfected KK1 mouse granulosa cells were used to identify genes that are potentially regulated by Foxl2. KK1 cells were transfected in three groups (mock, activated, and repressed) and twenty-four hours later RNA was isolated and submitted for Affymetrix microarray analysis. Genesifter software was used to carry out analysis of microarray data. One identified target, the gonadotropin releasing hormone receptor (GnRHR) gene, was chosen for further study and validation of Foxl2 responsiveness. Transient transfection analyses were carried out to study the effect of Foxl2 over-expression on GnRHR gene promoter-luciferase fusion activity. Data generated was analyzed with GraphPad Prism software. RESULTS: Microarray analysis identified 996 genes of known function that are potentially regulated by Foxl2 in mouse KK1 granulosa cells. The steroidogenic acute regulatory protein (StAR) gene that has been identified as Foxl2 responsive by others was identified in this study also, thereby supporting the effectiveness of our strategy. The GnRHR gene was chosen for further study because it is known to be expressed in the ovary and the results of previous work has indicated that Foxl2 may regulate GnRHR gene expression. Cellular levels of Foxl2 were increased via transient co-transfection of KK1 cells using a Foxl2 expression vector and a GnRHR promoter-luciferase fusion reporter vector. The results of these analyses indicate that over-expression of Foxl2 resulted in a significant increase in GnRHR promoter activity. Therefore, these transfection data validate the microarray data which suggest that Foxl2 regulates GnRHR and demonstrate that Foxl2 acts as an activator of the GnRHR gene. CONCLUSIONS: Potential Foxl2 regulated ovarian genes have been identified through microarray analysis and comparison of these data to other microarray studies. The Foxl2 responsiveness of the GnRHR gene has been validated and provided evidence of Foxl2 transcriptional activation of the GnRHR gene promoter in the mouse ovary derived KK1 granulosa cell line. PMID- 20167116 TI - Increased incidence of rare codon clusters at 5' and 3' gene termini: implications for function. AB - BACKGROUND: The process of translation can be affected by the use of rare versus common codons within the mRNA transcript. RESULTS: Here, we show that rare codons are enriched at the 5' and 3' termini of genes from E. coli and other prokaryotes. Genes predicted to be secreted show significant enrichment in 5' rare codon clusters, but not 3' rare codon clusters. Surprisingly, no correlation between 5' mRNA structure and rare codon usage was observed. CONCLUSIONS: Potential functional roles for the enrichment of rare codons at terminal positions are explored. PMID- 20167117 TI - Antenatal allopurinol for reduction of birth asphyxia induced brain damage (ALLO Trial); a randomized double blind placebo controlled multicenter study. AB - BACKGROUND: Hypoxic-ischaemic encephalopathy is associated with development of cerebral palsy and cognitive disability later in life and is therefore one of the fundamental problems in perinatal medicine. The xanthine-oxidase inhibitor allopurinol reduces the formation of free radicals, thereby limiting the amount of hypoxia-reperfusion damage. In case of suspected intra-uterine hypoxia, both animal and human studies suggest that maternal administration of allopurinol immediately prior to delivery reduces hypoxic-ischaemic encephalopathy. METHODS/DESIGN: The proposed trial is a randomized double blind placebo controlled multicenter study in pregnant women at term in whom the foetus is suspected of intra-uterine hypoxia.Allopurinol 500 mg IV or placebo will be administered antenatally to the pregnant woman when foetal hypoxia is suspected. Foetal distress is being diagnosed by the clinician as an abnormal or non reassuring foetal heart rate trace, preferably accompanied by either significant ST-wave abnormalities (as detected by the STAN-monitor) or an abnormal foetal blood scalp sampling (pH < 7.20).Primary outcome measures are the amount of S100B (a marker for brain tissue damage) and the severity of oxidative stress (measured by isoprostane, neuroprostane, non protein bound iron and hypoxanthine), both measured in umbilical cord blood. Secondary outcome measures are neonatal mortality, serious composite neonatal morbidity and long-term neurological outcome. Furthermore pharmacokinetics and pharmacodynamics will be investigated.We expect an inclusion of 220 patients (110 per group) to be feasible in an inclusion period of two years. Given a suspected mean value of S100B of 1.05 ug/L (SD 0.37 ug/L) in the placebo group this trial has a power of 90% (alpha 0.05) to detect a mean value of S100B of 0.89 ug/L (SD 0.37 ug/L) in the 'allopurinol-treated' group (z-test2-sided). Analysis will be by intention to treat and it allows for one interim analysis. DISCUSSION: In this trial we aim to answer the question whether antenatal allopurinol administration reduces hypoxic ischaemic encephalopathy in neonates exposed to foetal hypoxia. TRIAL REGISTRATION NUMBER: Clinical Trials, protocol registration system: NCT00189007. PMID- 20167118 TI - Empirical aspects of record linkage across multiple data sets using statistical linkage keys: the experience of the PIAC cohort study. AB - BACKGROUND: In Australia, many community service program data collections developed over the last decade, including several for aged care programs, contain a statistical linkage key (SLK) to enable derivation of client-level data. In addition, a common SLK is now used in many collections to facilitate the statistical examination of cross-program use. In 2005, the Pathways in Aged Care (PIAC) cohort study was funded to create a linked aged care database using the common SLK to enable analysis of pathways through aged care services. Linkage using an SLK is commonly deterministic. The purpose of this paper is to describe an extended deterministic record linkage strategy for situations where there is a general person identifier (e.g. an SLK) and several additional variables suitable for data linkage. This approach can allow for variation in client information recorded on different databases. METHODS: A stepwise deterministic record linkage algorithm was developed to link datasets using an SLK and several other variables. Three measures of likely match accuracy were used: the discriminating power of match key values, an estimated false match rate, and an estimated step specific trade-off between true and false matches. The method was validated through examining link properties and clerical review of three samples of links. RESULTS: The deterministic algorithm resulted in up to an 11% increase in links compared with simple deterministic matching using an SLK. The links identified are of high quality: validation samples showed that less than 0.5% of links were false positives, and very few matches were made using non-unique match information (0.01%). There was a high degree of consistency in the characteristics of linked events. CONCLUSIONS: The linkage strategy described in this paper has allowed the linking of multiple large aged care service datasets using a statistical linkage key while allowing for variation in its reporting. More widely, our deterministic algorithm, based on statistical properties of match keys, is a useful addition to the linker's toolkit. In particular, it may prove attractive when insufficient data are available for clerical review or follow-up, and the researcher has fewer options in relation to probabilistic linkage. PMID- 20167119 TI - Identification of microRNAs expressed in two mosquito vectors, Aedes albopictus and Culex quinquefasciatus. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs that post transcriptionally regulate gene expression in a variety of organisms, including insects, vertebrates, and plants. miRNAs play important roles in cell development and differentiation as well as in the cellular response to stress and infection. To date, there are limited reports of miRNA identification in mosquitoes, insects that act as essential vectors for the transmission of many human pathogens, including flaviviruses. West Nile virus (WNV) and dengue virus, members of the Flaviviridae family, are primarily transmitted by Aedes and Culex mosquitoes. Using high-throughput deep sequencing, we examined the miRNA repertoire in Ae. albopictus cells and Cx. quinquefasciatus mosquitoes. RESULTS: We identified a total of 65 miRNAs in the Ae. albopictus C7/10 cell line and 77 miRNAs in Cx. quinquefasciatus mosquitoes, the majority of which are conserved in other insects such as Drosophila melanogaster and Anopheles gambiae. The most highly expressed miRNA in both mosquito species was miR-184, a miRNA conserved from insects to vertebrates. Several previously reported Anopheles miRNAs, including miR-1890 and miR-1891, were also found in Culex and Aedes, and appear to be restricted to mosquitoes. We identified seven novel miRNAs, arising from nine different precursors, in C7/10 cells and Cx. quinquefasciatus mosquitoes, two of which have predicted orthologs in An. gambiae. Several of these novel miRNAs reside within a ~350 nt long cluster present in both Aedes and Culex. miRNA expression was confirmed by primer extension analysis. To determine whether flavivirus infection affects miRNA expression, we infected female Culex mosquitoes with WNV. Two miRNAs, miR-92 and miR-989, showed significant changes in expression levels following WNV infection. CONCLUSIONS: Aedes and Culex mosquitoes are important flavivirus vectors. Recent advances in both mosquito genomics and high-throughput sequencing technologies enabled us to interrogate the miRNA profile in these two species. Here, we provide evidence for over 60 conserved and seven novel mosquito miRNAs, expanding upon our current understanding of insect miRNAs. Undoubtedly, some of the miRNAs identified will have roles not only in mosquito development, but also in mediating viral infection in the mosquito host. PMID- 20167120 TI - Interleukin-17A upregulates receptor activator of NF-kappaB on osteoclast precursors. AB - INTRODUCTION: The interaction between the immune and skeletal systems is evidenced by the bone loss observed in autoimmune diseases such as rheumatoid arthritis. In this paper we describe a new mechanism by which the immune cytokine IL-17A directly affects osteoclastogenesis. METHODS: Human CD14+ cells were isolated from healthy donors, cultured on dentine slices and coverslips and stimulated with IL-17A and/or receptor activator of NF-kappaB ligand (RANKL). Osteoclast differentiation was evaluated by gene expression, flow cytometry, tartrate-resistant acid phosphatase staining, fluorescence and electron microscopy. Physiologic bone remodelling was studied in wild-type (Wt) and IL-17A /- mice using micro-computer tomography and serum RANKL/osteoprotegerin concentration. Functional osteoclastogenesis assays were performed using bone marrow macrophages isolated from IL-17A-/- and Wt mice. RESULTS: IL-17A upregulates the receptor activator for NF-kappaB receptor on human osteoclast precursors in vitro, leading to increased sensitivity to RANKL signalling, osteoclast differentiation and bone loss. IL-17A-/- mice have physiological bone homeostasis indistinguishable from Wt mice, and bone marrow macrophages isolated from these mice develop fully functional normal osteoclasts. CONCLUSIONS: Collectively our data demonstrate anti-IL-17A treatment as a selective therapeutic target for bone loss associated with autoimmune diseases. PMID- 20167121 TI - High-throughput genome sequencing of two Listeria monocytogenes clinical isolates during a large foodborne outbreak. AB - BACKGROUND: A large, multi-province outbreak of listeriosis associated with ready to-eat meat products contaminated with Listeria monocytogenes serotype 1/2a occurred in Canada in 2008. Subtyping of outbreak-associated isolates using pulsed-field gel electrophoresis (PFGE) revealed two similar but distinct AscI PFGE patterns. High-throughput pyrosequencing of two L. monocytogenes isolates was used to rapidly provide the genome sequence of the primary outbreak strain and to investigate the extent of genetic diversity associated with a change of a single restriction enzyme fragment during PFGE. RESULTS: The chromosomes were collinear, but differences included 28 single nucleotide polymorphisms (SNPs) and three indels, including a 33 kbp prophage that accounted for the observed difference in AscI PFGE patterns. The distribution of these traits was assessed within further clinical, environmental and food isolates associated with the outbreak, and this comparison indicated that three distinct, but highly related strains may have been involved in this nationwide outbreak. Notably, these two isolates were found to harbor a 50 kbp putative mobile genomic island encoding translocation and efflux functions that has not been observed in other Listeria genomes. CONCLUSIONS: High-throughput genome sequencing provided a more detailed real-time assessment of genetic traits characteristic of the outbreak strains than could be achieved with routine subtyping methods. This study confirms that the latest generation of DNA sequencing technologies can be applied during high priority public health events, and laboratories need to prepare for this inevitability and assess how to properly analyze and interpret whole genome sequences in the context of molecular epidemiology. PMID- 20167122 TI - Massive gene losses in Asian cultivated rice unveiled by comparative genome analysis. AB - BACKGROUND: Rice is one of the most important food crops in the world. With increasing world demand for food crops, there is an urgent need to develop new cultivars that have enhanced performance with regard to yield, disease resistance, and so on. Wild rice is expected to provide useful genetic resources that could improve the present cultivated species. However, the quantity and quality of these unexplored resources remain unclear. Recent accumulation of the genomic information of both cultivated and wild rice species allows for their comparison at the molecular level. Here, we compared the genome sequence of Oryza sativa ssp. japonica with sets of bacterial artificial chromosome end sequences (BESs) from two wild rice species, O. rufipogon and O. nivara, and an African rice species, O. glaberrima. RESULTS: We found that about four to five percent of the BESs of the two wild rice species and about seven percent of the African rice could not be mapped to the japonica genome, suggesting that a substantial number of genes have been lost in the japonica rice lineage; however, their close relatives still possess their counterpart genes. We estimated that during evolution, O. sativa has lost at least one thousand genes that are still preserved in the genomes of the other species. In addition, our BLASTX searches against the non-redundant protein sequence database showed that disease resistance-related proteins were significantly overrepresented in the close relative-specific genomic portions. In total, 235 unmapped BESs of the three relatives matched 83 non-redundant proteins that contained a disease resistance protein domain, most of which corresponded to an NBS-LRR domain. CONCLUSION: We found that the O. sativa lineage appears to have recently experienced massive gene losses following divergence from its wild ancestor. Our results imply that the domestication process accelerated large-scale genomic deletions in the lineage of Asian cultivated rice and that the close relatives of cultivated rice have the potential to restore the lost traits. PMID- 20167123 TI - The breast feeding mother and xenon anaesthesia: four case reports. Breast feeding and xenon anaesthesia. AB - BACKGROUND: Four nursing mothers consented to anaesthesia for urgent surgery only on condition that their ability to breast feed would not be impaired. METHODS: Following induction of general anaesthesia with propofol and remifentanil, 65-69% xenon supplemented with remifentanil was used as an inhalational anaesthetic for maintenance. RESULTS: After finishing surgery the women could be extubated between 2:52 and 7:22 minutes. The women were fully alert just minutes after extubation and spent about 45 minutes in the recovery room before discharge to a regular ward. They resumed regular breast feeding some time later. The propofol concentration in the blood was measured after 0, 30, 90, and 300 minutes and in the milk after 90 and 300 minutes. Just 90 minutes after extubation, the concentration of propofol in the milk was limited (> 3 mg/l) so that pharmacological effects on the babies were excluded after oral intake. Also, no traces of xenon gas were found in the maternal milk at any time. After propofol induction and maintenance of anaesthesia with xenon in combination with a water soluble short-acting drug like remifentanil, the concentration of propofol in maternal milk is low (> 3 mg/l 90 min after anesthesia) and harmless after oral intake. CONCLUSIONS: These results, as well as the rapid elimination and absence of metabolism of xenon, are of great interest to nursing mothers. General anaesthesia with propofol for induction only, combined with remifentanil and xenon for maintenance, has not yet been described in breast feeding mothers. PMID- 20167124 TI - The population approach to falls injury prevention in older people: findings of a two community trial. AB - BACKGROUND: There is a sound rationale for the population-based approach to falls injury prevention but there is currently insufficient evidence to advise governments and communities on how they can use population-based strategies to achieve desired reductions in the burden of falls-related injury. The aim of the study was to quantify the effectiveness of a streamlined (and thus potentially sustainable and cost-effective), population-based, multi-factorial falls injury prevention program for people over 60 years of age. METHODS: Population-based falls-prevention interventions were conducted at two geographically-defined and separate Australian sites: Wide Bay, Queensland, and Northern Rivers, NSW. Changes in the prevalence of key risk factors and changes in rates of injury outcomes within each community were compared before and after program implementation and changes in rates of injury outcomes in each community were also compared with the rates in their respective States. RESULTS: The interventions in neither community substantially decreased the rate of falls related injury among people aged 60 years or older, although there was some evidence of reductions in occurrence of multiple falls reported by women. In addition, there was some indication of improvements in fall-related risk factors, but the magnitudes were generally modest. CONCLUSIONS: The evidence suggests that low intensity population-based falls prevention programs may not be as effective as those that are intensively implemented. PMID- 20167125 TI - Mental Health First Aid guidelines for helping a suicidal person: a Delphi consensus study in India. AB - BACKGROUND: This study aimed to develop guidelines for how a member of the Indian public should provide mental health first aid to a person who is suicidal. METHODS: The guidelines were produced by developing a questionnaire containing possible first aid actions and asking an expert panel of Indian mental health clinicians to rate whether each action should be included in the guidelines. The content of the questionnaire was based on a systematic search of the relevant evidence and claims made by authors of consumer and career guides and websites. Experts were recruited by SC, EC and HM. The panel members were asked to complete the questionnaire by web survey. Three rounds of the rating were carried and, at the end of each round, items that reached the consensus criterion were selected for inclusion in the guidelines. During the first round, panel members were also asked to suggest any additional actions that were not covered in the original questionnaire (to include items that are relevant to local cultural circumstances, values, and social norms.). Responses to the open-ended questions were used to generate new items. RESULTS: The output from the Delphi process was a set of agreed upon action statements. The Delphi process started with 138 statements, 30 new items were written based on suggestions from panel members and, of these 168 items, 71 met the consensus criterion. These statements were used to develop the guidelines appended to this paper. Translated versions of the guidelines will be produced and used for training. CONCLUSIONS: There are a number of actions that are considered to be useful for members of the public when they encounter someone who is experiencing suicidal thoughts or engaging in suicidal behaviour. Although the guidelines are designed for members of the public, they may also be helpful to non-mental health professionals working in health and welfare settings. PMID- 20167126 TI - Lineage-specific positive selection at the merozoite surface protein 1 (msp1) locus of Plasmodium vivax and related simian malaria parasites. AB - BACKGROUND: The 200 kDa merozoite surface protein 1 (MSP-1) of malaria parasites, a strong vaccine candidate, plays a key role during erythrocyte invasion and is a target of host protective immune response. Plasmodium vivax, the most widespread human malaria parasite, is closely related to parasites that infect Asian Old World monkeys, and has been considered to have become a parasite of man by host switch from a macaque malaria parasite. Several Asian monkey parasites have a range of natural hosts. The same parasite species shows different disease manifestations among host species. This suggests that host immune responses to P. vivax-related malaria parasites greatly differ among host species (albeit other factors). It is thus tempting to invoke that a major immune target parasite protein such as MSP-1 underwent unique evolution, depending on parasite species that exhibit difference in host range and host specificity. RESULTS: We performed comparative phylogenetic and population genetic analyses of the gene encoding MSP 1 (msp1) from P. vivax and nine P. vivax-related simian malaria parasites. The inferred phylogenetic tree of msp1 significantly differed from that of the mitochondrial genome, with a striking displacement of P. vivax from a position close to P. cynomolgi in the mitochondrial genome tree to an outlier of Asian monkey parasites. Importantly, positive selection was inferred for two ancestral branches, one leading to P. inui and P. hylobati and the other leading to P. vivax, P. fieldi and P. cynomolgi. This ancestral positive selection was estimated to have occurred three to six million years ago, coinciding with the period of radiation of Asian macaques. Comparisons of msp1 polymorphisms between P. vivax, P. inui and P. cynomolgi revealed that while some positively selected amino acid sites or regions are shared by these parasites, amino acid changes greatly differ, suggesting that diversifying selection is acting species specifically on msp1. CONCLUSIONS: The present results indicate that the msp1 locus of P. vivax and related parasite species has lineage-specific unique evolutionary history with positive selection. P. vivax and related simian malaria parasites offer an interesting system toward understanding host species-dependent adaptive evolution of immune-target surface antigen genes such as msp1. PMID- 20167127 TI - The ClpP protease homologue is required for the transmission traits and cell division of the pathogen Legionella pneumophila. AB - BACKGROUND: Legionella pneumophila, the intracellular bacterial pathogen that causes Legionnaires' disease, exhibit characteristic transmission traits such as elevated stress tolerance, shortened length and virulence during the transition from the replication phase to the transmission phase. ClpP, the catalytic core of the Clp proteolytic complex, is widely involved in many cellular processes via the regulation of intracellular protein quality. RESULTS: In this study, we showed that ClpP was required for optimal growth of L. pneumophila at high temperatures and under several other stress conditions. We also observed that cells devoid of clpP exhibited cell elongation, incomplete cell division and compromised colony formation. Furthermore, we found that the clpP-deleted mutant was more resistant to sodium stress and failed to proliferate in the amoebae host Acanthamoeba castellanii. CONCLUSIONS: The data present in this study illustrate that the ClpP protease homologue plays an important role in the expression of transmission traits and cell division of L. pneumophila, and further suggest a putative role of ClpP in virulence regulation. PMID- 20167128 TI - Characterization of the tandem CWCH2 sequence motif: a hallmark of inter-zinc finger interactions. AB - BACKGROUND: The C2H2 zinc finger (ZF) domain is widely conserved among eukaryotic proteins. In Zic/Gli/Zap1 C2H2 ZF proteins, the two N-terminal ZFs form a single structural unit by sharing a hydrophobic core. This structural unit defines a new motif comprised of two tryptophan side chains at the center of the hydrophobic core. Because each tryptophan residue is located between the two cysteine residues of the C2H2 motif, we have named this structure the tandem CWCH2 (tCWCH2) motif. RESULTS: Here, we characterized 587 tCWCH2-containing genes using data derived from public databases. We categorized genes into 11 classes including Zic/Gli/Glis, Arid2/Rsc9, PacC, Mizf, Aebp2, Zap1/ZafA, Fungl, Zfp106, Twincl, Clr1, and Fungl-4ZF, based on sequence similarity, domain organization, and functional similarities. tCWCH2 motifs are mostly found in organisms belonging to the Opisthokonta (metazoa, fungi, and choanoflagellates) and Amoebozoa (amoeba, Dictyostelium discoideum). By comparison, the C2H2 ZF motif is distributed widely among the eukaryotes. The structure and organization of the tCWCH2 motif, its phylogenetic distribution, and molecular phylogenetic analysis suggest that prototypical tCWCH2 genes existed in the Opisthokonta ancestor. Within-group or between-group comparisons of the tCWCH2 amino acid sequence identified three additional sequence features (site-specific amino acid frequencies, longer linker sequence between two C2H2 ZFs, and frequent extra sequences within C2H2 ZF motifs). CONCLUSION: These features suggest that the tCWCH2 motif is a specialized motif involved in inter-zinc finger interactions. PMID- 20167129 TI - Study Protocol--accurate assessment of kidney function in Indigenous Australians: aims and methods of the eGFR study. AB - BACKGROUND: There is an overwhelming burden of cardiovascular disease, type 2 diabetes and chronic kidney disease among Indigenous Australians. In this high risk population, it is vital that we are able to measure accurately kidney function. Glomerular filtration rate is the best overall marker of kidney function. However, differences in body build and body composition between Indigenous and non-Indigenous Australians suggest that creatinine-based estimates of glomerular filtration rate derived for European populations may not be appropriate for Indigenous Australians. The burden of kidney disease is borne disproportionately by Indigenous Australians in central and northern Australia, and there is significant heterogeneity in body build and composition within and amongst these groups. This heterogeneity might differentially affect the accuracy of estimation of glomerular filtration rate between different Indigenous groups. By assessing kidney function in Indigenous Australians from Northern Queensland, Northern Territory and Western Australia, we aim to determine a validated and practical measure of glomerular filtration rate suitable for use in all Indigenous Australians. METHODS/DESIGN: A cross-sectional study of Indigenous Australian adults (target n = 600, 50% male) across 4 sites: Top End, Northern Territory; Central Australia; Far North Queensland and Western Australia. The reference measure of glomerular filtration rate was the plasma disappearance rate of iohexol over 4 hours. We will compare the accuracy of the following glomerular filtration rate measures with the reference measure: Modification of Diet in Renal Disease 4-variable formula, Chronic Kidney Disease Epidemiology Collaboration equation, Cockcroft-Gault formula and cystatin C- derived estimates. Detailed assessment of body build and composition was performed using anthropometric measurements, skinfold thicknesses, bioelectrical impedance and a sub-study used dual-energy X-ray absorptiometry. A questionnaire was performed for socio-economic status and medical history. DISCUSSION: We have successfully managed several operational challenges within this multi-centre complex clinical research project performed across remote North, Western and Central Australia. It seems unlikely that a single correction factor (similar to that for African Americans) to the equation for estimated glomerular filtration rate will prove appropriate or practical for Indigenous Australians. However, it may be that a modification of the equation in Indigenous Australians would be to include a measure of fat-free mass. PMID- 20167130 TI - Analysis of an alternative human CD133 promoter reveals the implication of Ras/ERK pathway in tumor stem-like hallmarks. AB - BACKGROUND: An increasing number of studies support the presence of stem-like cells in human malignancies. These cells are primarily responsible for tumor initiation and thus considered as a potential target to eradicate tumors. CD133 has been identified as an important cell surface marker to enrich the stem-like population in various human tumors. To reveal the molecular machinery underlying the stem-like features in tumor cells, we analyzed a promoter of CD133 gene using human colon carcinoma Caco-2 and synovial sarcoma Fuji cells, which endogenously express CD133 gene. RESULTS: A reporter analysis revealed that P5 promoter, located far upstream in a human CD133 gene locus, exhibits the highest activity among the five putative promoters (P1 to P5). Deletion and mutation analysis identified two ETS binding sites in the P5 region as being essential for its promoter activity. Electrophoretic mobility shift assays demonstrated the specific binding between nuclear factors and the ETS binding sequence. Overexpression of dominant-negative forms of Ets2 and Elk1 resulted in the significant decrease of P5 activity. Furthermore, treatment of Fuji cells with a specific MEK/ERK inhibitor, U0126, also markedly decreased CD133 expression, but there was no significant effect in Caco-2 cells, suggesting cell type-specific regulation of CD133 expression. Instead, the side population, another hallmark of TSLCs, was dramatically diminished in Caco-2 cells by U0126. Finally, Ras mediated oncogenic transformation in normal human astrocytes conferred the stem like capability to form neurosphere-like colonies with the increase of CD133 mRNA expression. CONCLUSIONS: In conclusion, the Ras/ERK pathway at least in part contributes to the maintenance and the acquisition of stem-like hallmarks, although the extent of its contribution is varied in a cell type-specific manner. These findings could help our comprehensive understanding of tumor stemness, and also improve the development of eradicative therapies against human malignancies. PMID- 20167131 TI - A novel fed-batch based cultivation method provides high cell-density and improves yield of soluble recombinant proteins in shaken cultures. AB - BACKGROUND: Cultivations for recombinant protein production in shake flasks should provide high cell densities, high protein productivity per cell and good protein quality. The methods described in laboratory handbooks often fail to reach these goals due to oxygen depletion, lack of pH control and the necessity to use low induction cell densities. In this article we describe the impact of a novel enzymatically controlled fed-batch cultivation technology on recombinant protein production in Escherichia coli in simple shaken cultures. RESULTS: The enzymatic glucose release system together with a well-balanced combination of mineral salts and complex medium additives provided high cell densities, high protein yields and a considerably improved proportion of soluble proteins in harvested cells. The cultivation method consists of three steps: 1) controlled growth by glucose-limited fed-batch to OD600 approximately 10, 2) addition of growth boosters together with an inducer providing efficient protein synthesis within a 3 to 6 hours period, and 3) a slow growth period (16 to 21 hours) during which the recombinant protein is slowly synthesized and folded. Cell densities corresponding to 10 to 15 g l(-1) cell dry weight could be achieved with the developed technique. In comparison to standard cultures in LB, Terrific Broth and mineral salt medium, we typically achieved over 10-fold higher volumetric yields of soluble recombinant proteins. CONCLUSIONS: We have demonstrated that by applying the novel EnBase Flo cultivation system in shaken cultures high cell densities can be obtained without impairing the productivity per cell. Especially the yield of soluble (correctly folded) proteins was significantly improved in comparison to commonly used LB, Terrific Broth or mineral salt media. This improvement is thought to result from a well controlled physiological state during the whole process. The higher volumetric yields enable the use of lower culture volumes and can thus significantly reduce the amount of time and effort needed for downstream processing or process optimization. We claim that the new cultivation system is widely applicable and, as it is very simple to apply, could widely replace standard shake flask approaches. PMID- 20167132 TI - Avian influenza virus monitoring in wintering waterbirds in Iran, 2003-2007. AB - BACKGROUND: Virological, molecular and serological studies were carried out to determine the status of infections with avian influenza viruses (AIV) in different species of wild waterbirds in Iran during 2003-2007. Samples were collected from 1146 birds representing 45 different species with the majority of samples originating from ducks, coots and shorebirds. Samples originated from 6 different provinces representative for the 15 most important wintering sites of migratory waterbirds in Iran. RESULTS: Overall, AIV were detected in approximately 3.4% of the samples. However, prevalence was higher (up to 8.3%) at selected locations and for certain species. No highly pathogenic avian influenza, including H5N1 was detected. A total of 35 AIVs were detected from cloacal or oropharyngeal swab samples. These positive samples originated mainly from Mallards and Common Teals.Of 711 serum samples tested for AIV antibodies, 345 (48.5%) were positive by using a nucleoprotein-specific competitive ELISA (NP-C ELISA). Ducks including Mallard, Common Teal, Common Pochard, Northern Shoveler and Eurasian Wigeon revealed the highest antibody prevalence ranging from 44 to 75%. CONCLUSION: Results of these investigations provide important information about the prevalence of LPAIV in wild birds in Iran, especially wetlands around the Caspian Sea which represent an important wintering site for migratory water birds. Mallard and Common Teal exhibited the highest number of positives in virological and serological investigations: 43% and 26% virological positive cases and 24% and 46% serological positive reactions, respectively. These two species may play an important role in the ecology and perpetuation of influenza viruses in this region. In addition, it could be shown that both oropharyngeal and cloacal swab samples contribute to the detection of positive birds, and neither should be neglected. PMID- 20167133 TI - A comparison of experience-dependent locomotory behaviors and biogenic amine neurons in nematode relatives of Caenorhabditis elegans. AB - BACKGROUND: Survival of an animal depends on its ability to match its responses to environmental conditions. To generate an optimal behavioral output, the nervous system must process sensory information and generate a directed motor output in response to stimuli. The nervous system should also store information about experiences to use in the future. The diverse group of free-living nematodes provides an excellent system to study macro- and microevolution of molecular, morphological and behavioral character states associated with such nervous system function. We asked whether an adaptive behavior would vary among bacterivorous nematodes and whether differences in the neurotransmitter systems known to regulate the behavior in one species would reflect differences seen in the adaptive behavior among those species. Caenorhabditis elegans worms slow in the presence of food; this 'basal' slowing is triggered by dopaminergic mechanosensory neurons that detect bacteria. Starved worms slow more dramatically; this 'enhanced' slowing is regulated by serotonin. RESULTS: We examined seven nematode species with known phylogenetic relationship to C. elegans for locomotory behaviors modulated by food (E. coli), and by the worm's recent history of feeding (being well-fed or starved). We found that locomotory behavior in some species was modulated by food and recent feeding experience in a manner similar to C. elegans, but not all the species tested exhibited these food modulated behaviors. We also found that some worms had different responses to bacteria other than E. coli. Using histochemical and immunological staining, we found that dopaminergic neurons were very similar among all species. For instance, we saw likely homologs of four bilateral pairs of dopaminergic cephalic and deirid neurons known from C. elegans in all seven species examined. In contrast, there was greater variation in the patterns of serotonergic neurons. The presence of presumptive homologs of dopaminergic and serotonergic neurons in a given species did not correlate with the observed differences in locomotory behaviors. CONCLUSIONS: This study demonstrates that behaviors can differ significantly between species that appear morphologically very similar, and therefore it is important to consider factors, such as ecology of a species in the wild, when formulating hypotheses about the adaptive significance of a behavior. Our results suggest that evolutionary changes in locomotory behaviors are less likely to be caused by changes in neurotransmitter expression of neurons. Such changes could be caused either by subtle changes in neural circuitry or in the function of the signal transduction pathways mediating these behaviors. PMID- 20167135 TI - Taking the "human" out of human rights. PMID- 20167134 TI - Dominance of highly divergent feline leukemia virus A progeny variants in a cat with recurrent viremia and fatal lymphoma. AB - BACKGROUND: In a cat that had ostensibly recovered from feline leukemia virus (FeLV) infection, we observed the reappearance of the virus and the development of fatal lymphoma 8.5 years after the initial experimental exposure to FeLV A/Glasgow-1. The goals of the present study were to investigate this FeLV reoccurrence and molecularly characterize the progeny viruses. RESULTS: The FeLV reoccurrence was detected by the presence of FeLV antigen and RNA in the blood and saliva. The cat was feline immunodeficiency virus positive and showed CD4+ T cell depletion, severe leukopenia, anemia and a multicentric monoclonal B-cell lymphoma. FeLV-A, but not -B or -C, was detectable. Sequencing of the envelope gene revealed three FeLV variants that were highly divergent from the virus that was originally inoculated (89-91% identity to FeLV-A/Glasgow-1). In the long terminal repeat 31 point mutations, some previously described in cats with lymphomas, were detected. The FeLV variant tissue provirus and viral RNA loads were significantly higher than the FeLV-A/Glasgow-1 loads. Moreover, the variant loads were significantly higher in lymphoma positive compared to lymphoma negative tissues. An increase in the variant provirus blood load was observed at the time of FeLV reoccurrence. CONCLUSIONS: Our results demonstrate that ostensibly recovered FeLV provirus-positive cats may act as a source of infection following FeLV reactivation. The virus variants that had largely replaced the inoculation strain had unusually heavily mutated envelopes. The mutations may have led to increased viral fitness and/or changed the mutagenic characteristics of the virus. PMID- 20167136 TI - Assessment of social cognition in patients with multiple sclerosis. AB - We examined the capacity of patients with multiple sclerosis (MS) to attribute mental states to others and to identify cognitive abilities that subserve theory of mind (ToM). In this article, we report findings on 41 out-patients with diagnosed MS who underwent detailed neuropsychological and social-cognitive assessment. They were subdivided into a cognitively intact (n=15) and cognitively impaired (n=26) group according to their neuropsychological test results. Their results were compared with those of 20 age- and education-matched controls. MS patients with cognitive impairments were found to have more difficulties attributing mental states to others than did cognitively intact MS patients and normal controls on two ToM measures; short stories (Happe, Winner, & Brownell, 1998) and video clips (Ouellet, Bedirian, Charbonneau, & Scherzer, 2009). When attention, memory, and working memory were controlled, performance on the WAIS III Picture Arrangement task accounted for 17.3% of the variance in performance on the video clips task. Performance on a WAIS-III index composed of Similarities and Comprehension subtests, accounted for 7.0% of the variance in performance on the short stories task. These results provide some preliminary information on the effect of MS-related cognitive deficits on the ability to attribute mental states to others. PMID- 20167137 TI - Organic more healthy? Green shoots in a scientific semi-desert. PMID- 20167138 TI - Safety of a depigmented, polymerized vaccine for the treatment of allergic rhinoconjunctivitis and allergic asthma. AB - BACKGROUND: Clinical efficacy of specific immunotherapy (SIT) with depigmented, polymerized allergen extracts is well documented in placebo-controlled trials, and safety data are encouraging although further data are required. METHODS: We enrolled 768 patients (51% men; mean age, 31 years) in this prospective multicenter study on safety and clinical effects of Depigoid (Laboratorios LETI, S.L., Madrid, Spain). Immunotherapy consisted of four injections of increasing doses of Depigoid at weekly intervals followed by monthly maintenance injections. All adverse events were documented. Moreover, nose, eye, and lung symptoms were assessed at baseline after 3 and 6 months. Results were compared with the scores of the preceding season. RESULTS: Rates for local and systemic reactions that might possibly be related to the study medication were 2.36 and 4.56/1000 injections, respectively. With 5923 injections given, 14 local reactions were reported (5 patients), and 27 systemic reactions were reported, including 20 of grade 1 (6 patients) and 7 of grade 2 (4 patients). The best safety profile was seen for patients vaccinated against house-dust mites. Reductions in nose, eye, and lung symptoms as well as in concomitant medication compared with either the preceding season (pollen-sensitized patients) or the baseline (house-dust mite sensitized patients) were observed at the end of study. CONCLUSION: In this large multicenter study on 768 patients with allergic rhinoconjunctivitis and allergic asthma under daily practice conditions SIT with Depigoid was well tolerated with low rates of local and systemic reactions. Furthermore, SIT resulted in considerable reductions in symptoms and concomitant medication. PMID- 20167139 TI - Forensic approach to medical causation when allergic disease is in the differential diagnosis. AB - As physicians, we are advocates for our patients. As allergists, we probe patient exposures. Occasionally, our good intentions find us entwined with forensic matters. Unfortunately, we have little formal training in toxicological, epidemiological, or evidence-based medicine methodology when determining exposure related medical causation. This article provides such an approach and suggests helpful hints of conduct. PMID- 20167140 TI - A comparison of intranasal corticosteroid, leukotriene receptor antagonist, and topical antihistamine in reducing symptoms of perennial allergic rhinitis as assessed through the Rhinitis Severity Score. AB - Rhinitis symptom complex consists of rhinorrhea, congestion, itchy mucosa, itchy eyes, and sneezing. Available medications vary in their benefit for each of these symptoms. It was the purpose of this article to compare symptom reduction with three different classes of medications. Montelukast, azelastine, and budesonide were compared to determine the effect on individual, as well as total, symptom scores using the Rhinitis Severity Score (RSS). All three medications were compared with placebo and showed efficacy in prior studies using Balaam's crossover design. The inclusion and exclusion criteria and all procedures were identical for all three studies. In analyzing the data from the RSS questionnaire, we used the procedure PROC MIXED in SAS specific for Balaam's crossover design (SAS Institute, Inc., Cary, NC). Although all three medications were effective compared with placebo, montelukast had the greatest effect of the three medications on reduction of ocular itching and throat and palate itching. Azelastine's effect was greater than budesonide and montelukast for reduction of rhinorrhea. Systemic medication, montelukast, as expected, provided better relief for symptoms distant from the nasal cavity, and the antihistamine, azelastine, reduced rhinorrhea, more than either montelukast or budesonide. PMID- 20167141 TI - Effect of therapeutic doses of mometasone furoate on cortisol levels in children with mild asthma. AB - Corticosteroids are the foundation of pharmacologic treatment for children with asthma. However, high-dose inhaled corticosteroid treatment can cause hypothalamic-pituitary-adrenal (HPA) axis suppression. We investigated the effect of three doses of mometasone furoate administered via dry-powder inhaler (MF-DPI) on the HPA axis in children. Fifty children (6-11 years) with mild asthma of > or =6 months' duration were randomized to MF-DPI, 100 (n = 13), 200 (n = 13), or 400 micrograms b.i.d. (n = 12), or placebo (n = 12) for 29 days. The primary end point was change from baseline in the 12-hour area under the plasma-cortisol concentration-time curve (AUC). Secondary parameters included plasma cortisol response to cosyntropin stimulation and 24-hour urinary free cortisol concentrations. Compared with placebo, AUC changes associated with treatments of MF-DPI, 100 or 200 micrograms b.i.d., were not significant, whereas a significant change was observed with MF-DPI, 400 micrograms b.i.d. (27%; p = 0.05). Responses to cosyntropin stimulation and urinary cortisol measurements were similar to placebo with all MF-DPI doses. All regimens were well tolerated. MF-DPI did not have a significant effect on plasma or urinary cortisol levels at doses up to 200 micrograms b.i.d. in children with mild asthma. Higher MF-DPI doses may potentially suppress the HPA axis. PMID- 20167142 TI - Comparative effect of body mass index on response to asthma controller therapy. AB - Increases in body mass index (BMI) are reported to influence asthma severity and response to treatment. This analysis was designed to explore whether increasing BMI altered the comparative response to treatment with either fluticasone propionate (FP) or montelukast. Two double-blind, randomized, parallel-group trials of 12-weeks duration comparing FP, 88 micrograms, twice daily or montelukast, 10 mg, daily were evaluated. Subjects with mild-moderate persistent asthma were retrospectively stratified by BMI of <20 kg/m(2) (underweight), 20 24.9 kg/m(2) (normal weight), 25-29.9 kg/m(2) (overweight), and > or =30 kg/m(2) (obese). Outcomes included mean changes in forced expiratory volume in 1 second (FEV(1)) and morning peak flow, daily albuterol use, and daily symptom scores. There were 1052 subjects evenly distributed between FP and montelukast by baseline parameters, including BMI. FP was statistically superior to montelukast for all BMI categories of normal, overweight, and obese subjects for FEV(1) (p < 0.008), morning peak flow (p < 0.002), albuterol use (p < 0.02), and symptom scores (p < 0.05). FP produced a significantly greater clinical response for normal, overweight, and obese subjects compared with montelukast. Irrespective of BMI, FP appears to be the more effective asthma controller therapy. PMID- 20167143 TI - The safety and clinical benefit of budesonide/formoterol pressurized metered-dose inhaler versus budesonide alone in children. AB - Few studies have evaluated inhaled corticosteroid (ICS)/long-acting beta(2) adrenergic agonist combination therapy in asthmatic children. This study was designed to evaluate the safety (primary) and clinical benefits (secondary) of budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus budesonide dry powder inhaler (DPI) in children with persistent asthma. This was a 26-week, multicenter, randomized, open-label U.S. study of 187 children 6-11 years of age previously receiving ICS. After 1 week of usual ICS therapy, subjects received twice-daily budesonide/formoterol pMDI 160/4.5 micrograms x 2 inhalations (320/9 micrograms; n = 124) or budesonide DPI 200 micrograms x 2 inhalations (400 micrograms [320 micrograms delivered ex-mouthpiece]; n = 63). Budesonide/formoterol and budesonide were well tolerated with a similar incidence of adverse events (AEs) (84.6% and 85.7%, respectively), most of mild or moderate intensity. Treatment-related AE incidence was low (5.4%) and similar across groups (budesonide/formoterol, 4.9%; budesonide, 6.3%). No clinically important treatment differences were observed for 12-lead electrocardiograms, hematology, serum glucose and potassium, and 24-hour urinary cortisol. Compared with budesonide, budesonide/formoterol decreased health care use (urgent care visits and interference with daily activities [child] or work [caregiver]; p < or = 0.012) and improved health-related quality of life (Pediatric Asthma Quality of Life Questionnaire [standardized] and Pediatric Asthma Caregiver Quality of Life Questionnaire overall scores; p < or = 0.006) and pulmonary function (predose forced expiratory volume in 1 second and forced expiratory flow during the middle half of exhalation; p < or = 0.007). In this 26-week study of asthmatic children (6-11 years), safety profiles were similar and clinical benefits were greater with budesonide/formoterol than with budesonide. PMID- 20167144 TI - The functionality of a budesonide/formoterol pressurized metered-dose inhaler with an integrated actuation counter. AB - Integration of an actuation counter into pressurized metered-dose inhalers (pMDIs) can allow patients to accurately determine the remaining number of medication doses. This study was designed to assess the functionality of budesonide/formoterol (Symbicort; AstraZeneca, Dunkerque, France) pMDI with an integrated actuation counter in a clinical setting. Children aged > or =6 years, adolescents, and adults with inhaled corticosteroid-dependent asthma participated in this 6-week, randomized, open-label, multicenter study (SD-039-0743; D5896C00743). Patients were treated with budesonide/formoterol pMDI with no actuation counter (80/4.5 micrograms x 2 inhalations [160/9 micrograms] twice daily) during a 7- to 10-day run-in period. Qualifying patients were then randomized into one of three groups treated with budesonide/formoterol pMDI with actuation counter (80/4.5 micrograms x 2 inhalations [160/9 micrograms] twice daily): group 1, 96 actuations (24 days); group 2, 120 actuations (30 days); or group 3, 128 actuations (32 days). Actuation count was assessed using position of the counter arrow, patient/caregiver reports (daily log and actuation counter final reading), and device (canister plus actuation counter assembly) weight change. Patients/caregivers rated ease of device use. There was good agreement across treatment groups (n = 254) between patient/caregiver-reported actuation counts and counts determined by the angular position of the arrow. Analysis of device weight change versus other estimates of actuation counts in groups 1 and 2 indicated that the device did not undercount the number of actuations sprayed. Most patients (93%) indicated the device was "extremely easy" or "very easy" to use. Clinical functionality and reliability of the budesonide/formoterol pMDI device with an actuation counter were established. PMID- 20167145 TI - Efficacy and safety of budesonide/formoterol pressurized metered-dose inhaler: randomized controlled trial comparing once- and twice-daily dosing in patients with asthma. AB - Asthma guidelines recommend titrating maintenance medications to the lowest effective dose. This study assessed the efficacy and tolerability of reducing the frequency of dosing in patients previously controlled with twice-daily budesonide/formoterol (BUD/FM) pressurized metered-dose inhaler (pMDI) to once daily regimens of BUD/FM pMDI or BUD pMDI. This was a 12-week, randomized, double blind, double-dummy, placebo (PBO)/active-controlled, multicenter study (N = 752) of patients aged > or =16 years with mild to moderate asthma. After 4-5 weeks on single-blind BUD/FM pMDI 160/9 micrograms twice daily (320/18 micrograms daily), patients with stable asthma received BUD/FM pMDI 160/9 micrograms twice daily (320/18 micrograms daily; morning and evening), BUD/FM pMDI 320/9 micrograms once daily (evening), BUD/FM pMDI 160/9 micrograms once daily (evening), BUD pMDI 320 micrograms once daily (evening), or PBO. BUD/FM (once or twice daily) was more effective (p < or = 0.003) than BUD and PBO on evening peak expiratory flow (primary variable), morning pulmonary function assessments, daily symptoms, and nighttime rescue medication use. Twice-daily BUD/FM was more effective (p < or = 0.05) than both once-daily doses for evening pulmonary function assessments and daytime rescue medication use. All treatments were well tolerated. Once- or twice daily BUD/FM showed better efficacy than BUD once daily or PBO; results generally were more favorable with twice-daily dosing compared with both once-daily dosing regimens, which had one-half the daily FM dose. PMID- 20167146 TI - Poor disease control among insured users of high-dose combination therapy for asthma. AB - Adherence to asthma treatment may not completely prevent exacerbations. Clinical trial results indicate that many highly adherent asthma patients still have symptoms. Little is known about the level of control achieved by adherent patients outside clinical trials. This study was designed to evaluate the extent of asthma control among insured patients who were highly adherent to combination controller therapy. We used an administrative claims database for this cohort study of patients aged 12-64 years. Patients were newly treated with fluticasone, 500 micrograms/salmeterol, 50 micrograms, between January 1, 2003 and June 30, 2004. Patients were stratified according to adherence levels: low (<50%), moderate (50-74%), and high (> or =75%). We compared rates of poor control. A logistic regression model was used to control for baseline differences. Among 3357 patients, the mean age was 40.5 +/- 13.6 years, and 64.1% were women. Sixty one percent had low adherence, 20% had moderate adherence, and 19% had high adherence. Highly adherent patients were older, and more used fluticasone, 250 micrograms/salmeterol, 50 micrograms, during the preindex period than the other groups. Even after starting high-dose fluticasone/salmeterol, many patients with low, moderate, and high adherence had indicators of poor symptom control (28.9% [587/2030], 30.6% [209/682], and 30.7% [198/645], respectively). Patients who were highly adherent and used additional controller medications had rates of poor control that ranged from 23.1 to 31.2%. After adjusting for age, gender, and baseline characteristics, results were similar. Many patients continue to have poor asthma control despite being adherent to high-dose combination therapy or using additional controller medications. PMID- 20167147 TI - Adding montelukast to fluticasone propionate/salmeterol for control of asthma and seasonal allergic rhinitis. AB - Limited information exists comparing fluticasone propionate/salmeterol combination (FSC) versus montelukast (MON) in patients with coexistent asthma and allergic rhinitis. The purpose of this study was to compare the addition of MON to patients receiving FSC on asthma control while experiencing asthma and allergy symptoms. Additionally, the effect of fluticasone propionate aqueous nasal spray (FPANS) and MON were assessed in allergic rhinitis control. Symptomatic patients (n = 1385) with asthma and seasonal allergic rhinitis were randomized to receive FSC, 100/50 micrograms twice daily; FSC twice daily + FPANS, 200 micrograms once daily; FSC twice daily + MON, 10 mg once daily; or MON once daily for 4 weeks during the allergy pollen season. Patients recorded peak expiratory flow, rescue albuterol use, and asthma and rhinitis symptoms. No additional improvements in overall asthma control were seen when MON was added to FSC. Treatment with FSC produced significant (p < 0.001) improvements in all clinical and patient reported measures versus MON. FSC + FPANS was superior to FSC + MON (p < or = 0.001) in improving daytime and nighttime total nasal symptom scores. Adverse events were similar. In patients with asthma and allergic rhinitis, adding MON to FSC provided no additional benefit in asthma control. FSC resulted in superior improvement in asthma control compared with MON. FPANS also provided superior nasal symptom control versus MON in allergic patients treated with FSC for asthma. Optimal disease control in patients with asthma and allergic rhinitis should be achieved by the most effective therapy directed toward each disease component. PMID- 20167149 TI - Small bowel intussusception: an unusual presentation of angioedema. AB - This article presents a case report of a 13-year-old boy who presented to the Emergency Department with abdominal pain and vomiting. He had a known history of recurrent swelling but no previous abdominal episodes. A computed tomography scan revealed small bowel intussusception and he was scheduled for surgery. The patient had a history of multiple episodes of swelling of extremities, face, and genitalia. The Allergy Consult Service was consulted for perioperative management of his angioedema. PMID- 20167148 TI - Effects of omalizumab in patients with food allergy. AB - Omalizumab is a novel therapy approved for treating patients with moderate to severe persistent allergic asthma with a serum IgE ranging from 30 to 700 IU/mL. We examined the efficacy of omalizumab as a treatment for IgE-mediated food allergy. An Institutional Review Board-approved prospective pilot study was performed to assess the efficacy of omalizumab in 22 patients with persistent asthma and concomitant IgE-mediated food allergy. All patients showed skin test positivity to foods and experienced allergic food reactions based on history. Patients were interviewed on unintentional and/or unauthorized exposures to sensitized foods. Thirteen female and nine male patients (range, 4-66 years old; mean, 38 years) were evaluated in a private practice setting. Mean IgE level was 1120.74 IU/mL. Sensitized allergens included fish, shellfish, peanuts, tree nuts, egg, soybean, and wheat. All 22 (100%) patients maintained significant improvement as shown by a decrease/lack of clinical symptoms on reexposure to sensitized foods. Clinical improvement by the sixth dosage of omalizumab (150-300 mg q. 2-4 weeks) was noted by history and physical examination. Eight patients noted a decrease in their food-induced atopic dermatitis, 13 patients noted a decrease in their food-induced asthma symptoms, 3 patients noted a decrease in their food-induced urticaria, 6 patients noted a decrease in their food-induced rhinosinusitis symptoms, and 9 patients showed efficacy for angioedema and/or anaphylaxis. While treating asthma patients with omalizumab, patients subjectively observed a reduction in their concomitant IgE-mediated food allergy symptoms. PMID- 20167150 TI - Impact of type of insurance plan on access and utilization of health care services for adults aged 18-64 years with private health insurance: United States, 2007-2008. AB - KEY FINDINGS: Data from the National Health Interview Survey. Almost 18% of adults under age 65 with private health insurance were enrolled in some type of high deductible health plan (HDHP), including 5% who were enrolled in a consumer directed health plan (CDHP), 2% with a flexible spending account (FSA) for medical expenses, and 12% in a HDHP-only plan. Approximately 17% of adults aged 18-64 years enrolled in an HDHP had unmet medical or prescription drug needs due to cost, compared with 10% among adults aged 18-64 years enrolled in a traditional health plan only (no FSA). Privately insured adults aged 18-64 years with an FSA or health savings account (HSA) were more likely to receive a flu shot or have contact with an eye doctor in the past 12 months than those with neither an FSA nor an HSA. PMID- 20167151 TI - Getting your research information out there quickly. PMID- 20167152 TI - Rare ATGL haplotypes are associated with increased plasma triglyceride concentrations in the Greenland Inuit. AB - OBJECTIVES: To genotype common genetic variants found in the adipose triglyceride lipase (ATGL) gene and test them for association with cardiovascular disease risk factors in the Greenland Inuit. STUDY DESIGN: Candidate gene association study of discrete and quantitative traits related to cardiovascular health. METHODS: ATGL was sequenced in 10 European subjects to identify DNA sequence variants. The identified polymorphisms were subsequently genotyped in a population-based cohort of 1,218 unrelated Greenland Inuit subjects, ascertained from the Greenland Population Study. Genotypes and reconstructed haplotypes were tested for association with cardiovascular disease risk factors using additive, dominant or recessive models, corrected for age, sex and body mass index. RESULTS: Five single nucleotide polymorphisms and one 4-base pair deletion were identified in the European sample and were similarly polymorphic in the Greenland Inuit. Independently, variants were not associated with any cardiovascular traits. However, reconstructed rare ATGL haplotypes were associated with increased plasma triglyceride (TG) concentrations compared to the major haplotype under a dominant model (1.21+/-0.7 mmol/L and 1.11+/-0.6 mmol/L, respectively, p=0.006). CONCLUSIONS: Rare ATGL haplotypes are associated with increased plasma TG concentrations in the Greenland Inuit. PMID- 20167153 TI - Inuit dietary patterns in modern Greenland. AB - OBJECTIVES: The purpose of the study was to apply two different approaches of dietary pattern definition to data from Greenland and to analyse the contemporary dietary patterns of the Inuit in Greenland in relation to urbanization and socio economic positions. STUDY DESIGN: Cross-sectional population survey. METHODS: A total of 2,247 Inuit aged 18+ from 15 towns and villages in West Greenland (25% of all communities) were interviewed about their diet as part of a general health survey. A 67-item Food Frequency Questionnaire (FFQ) with portion sizes was used as the survey instrument. The analyses were based on 2,026 individuals who reported realistic daily energy intakes. Dietary patterns were determined by two different methods: a factor-cum-cluster analysis, and a normative approach based on adherence to dietary recommendations. RESULTS: The 2 approaches resulted in 6 respective and 5 partly overlapping dietary patterns. The distribution of patterns varied significantly according to age, gender, urbanization and socio economic position. A healthy diet was most often reported by women aged 35+, who lived in towns and who belonged to the upper social stratum; an unhealthy diet was reported by young men and women irrespective of urbanization or social position; and a traditional diet was reported increasingly with age, among village residents and by hunters/fishermen and their families. CONCLUSIONS: The two methodological approaches gave comparable results. The normative approach can be extended to other data sets and its results are directly applicable to dietary intervention, while the data-driven approach can identify novel patterns but is tied to the actual data set. PMID- 20167154 TI - Developing a culturally competent and socially relevant sexual health survey with an urban Arctic community. AB - OBJECTIVES: To develop a culturally competent and socially relevant sexual health survey for people living in Nuuk, Greenland, aged 15 years and older. STUDY DESIGN: Qualitative study with interviews. METHODS: Community and research informants (n=10) were interviewed informally to identify survey topics. A sexual health survey was constructed combining local knowledge from informants with a review of sexual health literature for the Arctic and other Indigenous locations. The draft survey was distributed to community partners for commentary and revision. After translation into Danish and Greenlandic, cognitive interviews were conducted with 11 Nuuk residents, identified through snowball sampling, to both pilot test the survey and exchange social and cultural knowledge relevant to sexual health in Nuuk. The utility of this process was evaluated against implementation of the final survey to Nuuk residents enrolled in Inuulluataarneq (n=149). RESULTS: Theme saturation was reached by the ninth interview. STI risk and self-efficacy, co-occurrence of alcohol use and sex and STI knowledge were identified as most relevant. Questions about community efficacy, culture/community involvement and identity were most sensitive. Upon implementation of the final survey, 146 of 149 participants answered all survey questions. Two Elder participants refused to answer questions about sex. Some questions had low response variability but still added to our contextual understanding and helped to build rapport with participants. CONCLUSIONS: Combining an iterative process with community-based participatory research principles and cognitive interview techniques was an effective method for developing a sexual health survey with Nuuk residents. PMID- 20167155 TI - Causes and contributions to differences in life expectancy for Inuit Nunangat and Canada, 1994-2003. AB - OBJECTIVES: The objective of this article is to measure the contributions of age groups and causes of death to differences in mortality and life expectancy between residents of Inuit Nunangat and the rest of Canada. STUDY DESIGN: The geographic area of coverage includes communities within Inuit Nunangat, with the addition of Inuvik in the Northwest Territories. Deaths were compiled for 2 5 year periods, 1994 through 1998 and 1999 through 2003, with the mid-year centred on the 1996 and 2001 censuses. METHODS: Abridged life tables were constructed according to the revised Chiang method. Age decomposition of differences in life expectancy and cause-deleted life tables were calculated using a discrete approach. The age groups and causes contributing to differences in life expectancy between Inuit Nunangat and the rest of Canada were calculated. RESULTS: Specific age groups contribute more to the difference in life expectancy between Inuit Nunangat and the rest of Canada. For males, over 50% of the difference in life expectancy is due to excess mortality before 25 years of age, while for females nearly 65% is due to excess mortality after the age of 60. CONCLUSIONS: Cancer is a major contributor to the difference in life expectancy between residents of Inuit Nunangat and the rest of Canada; reduction in cancer rates would make the greatest contribution to gains in life expectancy. There are clear gender differences in life expectancy and mortality, with the total effect of mortality being greatest for males between 15 and 25 years of age and for females over the age of 60. PMID- 20167156 TI - Blood pressure 2 years after a chronic disease management intervention study. AB - OBJECTIVES: To follow blood pressure change over time in participants who had participated in a 1- year chronic disease management program focused on blood pressure reduction. The expectation was that blood pressure would return back to the baseline once the study was completed. STUDY DESIGN: Prospective, single-arm observational study. METHODS: Study participants were Status Indians living on reserve with type 2 diabetes and persistent hypertension who had participated in the DREAM3 study. Blood pressure was measured with the BpTRU automated device every 6 months for 2 years. The primary endpoint was the change in systolic blood pressure over the follow-up period. RESULTS: Sixty of the original 96 participants agreed to participate in the follow-up. Mean blood pressure at the beginning of the follow-up was 130/76 (SD 18/12) mmHg. Mean blood pressure at the end of the follow-up period was 132/76 (17/9 SD) mmHg. Target blood pressure (<130/80 mmHg) was present in 53%. The 99% confidence limit around change of blood pressure over the 24 months of follow-up was +/-4.7 mmHg. CONCLUSIONS: Contrary to expectations, the participants maintained their blood pressure control and did not revert to baseline levels. Community awareness and engagement resulting from the chronic disease management program led to a sustainable improvement in the health parameters of the participants and the community that lasted beyond the duration of the 1-year DREAM3 project. PMID- 20167157 TI - Unintentional injuries among children and adolescents in Aboriginal and non Aboriginal communities, Newfoundland and Labrador, Canada. AB - OBJECTIVES: To compare epidemiologic characteristics of unintentional injuries among children and adolescents in Aboriginal and non-Aboriginal communities in the Province of Newfoundland and Labrador (NL), Canada. STUDY DESIGN: A comparative population-based study of unintentional injuries among individuals 0 19 years was conducted among Aboriginal and non-Aboriginal communities in NL. METHODS: The provincial hospital discharge and mortality data were analyzed for a 6-year period, April 1995 to March 2001. Rates and rate ratios related to hospital discharge and mortality due to unintentional injuries were calculated to assess variation of rates. The 2-independent sample binomial proportion test was used to compare rates between Aboriginal and non-Aboriginal communities. RESULTS: The overall hospital discharge rates of unintentional injury in Aboriginal and non-Aboriginal communities were 1,132.0 and 614.2 per 100,000 population, respectively (p(2)<0.001). For both Aboriginal and non-Aboriginal communities, the rate among males was higher than that of females (p(2)<0.001). The mortality rate was found to be higher in Aboriginal communities than non-Aboriginal communities (84.3 vs. 10.2 per 100,000 population) (p(2)<0.001). CONCLUSIONS: The rate of unintentional injury among children and adolescents in Aboriginal communities is higher than non-Aboriginal communities. Sex (male) and place of residence (Aboriginal communities) were strong predictors of unintentional injury in NL. PMID- 20167158 TI - Cancers of the breast, uterus, ovary and cervix among Alaska Native women, 1974 2003. AB - OBJECTIVES: Alaska Native (AN) women have exhibited some of the highest incidence rates of cancer overall, and different patterns of site-specific incidence compared to other U.S. populations. This study compares incidence rates between AN and U.S. white women (USW) for cancers of the breast, uterus, ovary and cervix, and examines effects of time period and birth cohort as determinants of incidence trends among AN women. STUDY DESIGN: Observational, population-based study. METHODS: Cancer incidence data from the Alaska Native Tumor Registry and SEERStat, 1974-2003. Age-adjusted World Standard Population rates were calculated for a current 5-year period and over time (30 years), and compared to other populations using rate ratios with 95% confidence intervals. Log-linear regression models used to assess impact on trend of age, time period and birth cohort. RESULTS: Compared to U.S. white women, current cancer rates among AN women are not significantly different for cancer of the breast and cervix, and significantly lower for cancers of the ovary and uterus. Trends over time over a 30-year time period also differ for these cancer sites. There were significant increases in breast and uterine cancer, and in contrast, a marked decline in cervical cancer. There was no significant change for cancer of the ovary. Changes appear to be due largely to period, not birth cohort effects. CONCLUSIONS: Increases in breast cancer may be due to a combination of modifiable behaviours; increased BMI and a shift to a non-traditional diet. Increases in uterine cancer could be associated with increased BMI and diabetes. Cervical cancer rates have declined to USW levels. The marked decline is likely due to enhanced screening and control efforts within the Alaska Native Women's cancers among Alaska Natives Tribal Health System (formerly Alaska Area USPHS, Indian Health Service utilizing resources available from the Centers for Disease Control tribal and state Breast and Cervical Cancer Early Detection Programs). PMID- 20167159 TI - Impaired fasting glucose and the metabolic syndrome in an indigenous Siberian population. AB - OBJECTIVES: This study investigated the lifestyle and anthropometric correlates of impaired fasting glucose and the presence of metabolic syndrome (MetS) among an Indigenous high-latitude herding population from north-eastern Siberia. STUDY DESIGN: Cross-sectional study of Yakut (Sakha) adult volunteers. METHODS: We collected health, lifestyle and anthropometric data among 166 Yakut adults (>or=18 years old; 101 females, 65 males) from the rural village of Tyungyulyu (62 degrees N, 130 degrees E; population 2,500), Sakha Republic (Yakutia), Russia. Measurements of fasting glucose, triglycerides, HDL cholesterol, blood pressure and waist circumference were used to document the presence of MetS based on the updated Adult Treatment Panel (ATP) III definition. RESULTS: Metabolic syndrome was relatively uncommon among study participants, with only 10% of participants classified as having MetS, including 8% of females and 12% of males. Elevated blood pressure and low HDL cholesterol were the most common features of MetS in Yakut men and women, while elevated fasting glucose and high triglycerides were uncommon in both sexes. Relatively low mean fasting glucose concentrations were documented among Yakut women (4.46+/-0.65 mmol/L) and men (4.41+/-0.76 mmol/L); no participants were classified as diabetic. CONCLUSIONS: Fasting glucose and MetS are at relatively low levels in this population; however, rising rates of obesity are likely to lead to future increases in MetS and impaired fasting glucose in this population. Further, increasing consumption of market foods, many high in refined sugars, is likely to contribute to an increased presence of impaired fasting glucose and MetS. PMID- 20167160 TI - Sustainable development, climate change and human health in the Arctic. PMID- 20167161 TI - The need for a glycemia modeling comparison workshop to facilitate development of an artificial pancreas. PMID- 20167162 TI - Modeling the error of continuous glucose monitoring sensor data: critical aspects discussed through simulation studies. AB - BACKGROUND: Knowing the statistical properties of continuous glucose monitoring (CGM) sensor errors can be important in several practical applications, e.g., in both open- and closed-loop control algorithms. Unfortunately, modeling the accuracy of CGM sensors is very difficult for both experimental and methodological reasons. It has been suggested that the time series of CGM sensor errors can be described as realization of the output of an autoregressive (AR) model of first order driven by a white noise process. The AR model was identified exploiting several reference blood glucose (BG) samples (collected frequently in parallel to the CGM signal), a procedure to recalibrate CGM data, and a linear time-invariant model of blood-to-interstitium glucose (BG-to-IG) kinetics. By resorting to simulation, this work shows that some assumptions made in the Breton and Kovatchev modeling approach may significantly affect the estimated sensor error and its statistical properties. METHOD: Three simulation studies were performed. The first simulation was devoted to assessing the influence of CGM data recalibration, whereas the second and third simulations examined the role of the BG-to-IG kinetic model. Analysis was performed by comparing the "original" (synthetically generated) time series of sensor errors vs its "reconstructed" version in both time and frequency domains. RESULTS: Even small errors either in CGM data recalibration or in the description of BG-to-IG dynamics can severely affect the possibility of correctly reconstructing the statistical properties of sensor error. In particular, even if CGM sensor error is a white noise process, a spurious correlation among its samples originates from suboptimal recalibration or from imperfect knowledge of the BG-to-IG kinetics. CONCLUSIONS: Modeling the statistical properties of CGM sensor errors from data collected in vivo is difficult because it requires perfect calibration and perfect knowledge of BG-to IG dynamics. Results suggest that correct characterization of CGM sensor error is still an open issue and requires further development upon the pioneering contribution of Breton and Kovatchev. PMID- 20167163 TI - Hypoglycemia detection in critical care using continuous glucose monitors: an in silico proof of concept analysis. AB - BACKGROUND: Tight glycemic control (TGC) in critical care has shown distinct benefits but has also been proven difficult to obtain. The risk of severe hypoglycemia (<40 mg/dl) has been increased significantly in several, but not all, studies, raising significant concerns for safety. Continuous glucose monitors (CGMs) offer frequent measurement and thus the possibility of using them for early detection alarms to prevent hypoglycemia. METHODS: This study used retrospective clinical data from the Specialized Relative Insulin Nutrition Titration TGC study covering seven patients who experienced severe hypoglycemic events. Clinically validated metabolic system models were used to recreate a continuous blood glucose profile. In silico analysis was enabled by using a conservative single Gaussian noise model based on reported CGM clinical data from a critical care study [mean absolute percent error (MAPE) 17.4%]. A novel median filter was implemented and further smoothed with a least mean squares-fitted polynomial to reduce sensor noise. Two alarm approaches were compared. An integral-based method is presented that examined the area between a preset threshold and filtered simulated CGM data. An alarm was raised when this value became too low. A simple glycemic threshold method was also used for comparison. To account for random noise skewing the results, each patient record was Monte Carlo simulated 100 times with a different random noise profile for a total of 700 runs. Different alarm thresholds were analyzed parametrically. Results are reported in terms of detection time before the clinically measured event and any false alarms. These retrospective clinical data were used with approval from the New Zealand South Island Regional Ethics Committee. RESULTS: The median filter reduced MAPE from 17.4% [standard deviation (SD) 13%] to 9.3% (SD 7%) over the cohort. For the integral-based alarm, median per-patient detection times ranged, t, from -35 minutes (before event) to -170 minutes, with zero to two false alarms per patient over the cohort and different alarm parameters. For a simple glycemic threshold alarm (three consecutive values below threshold), median per-patient alarm times were -10 to -75 minutes and false alarms were zero to seven; however, in one case, five of seven subjects never alarmed at all, despite the hypoglycemic event. CONCLUSIONS: A retrospective study used clinical hypoglycemic events from a TGC study to develop and analyze an integral-based hypoglycemia alarm for use in critical care TGC studies. The integral-based approach was accurate, provided significant lead time before a hypoglycemic event, alarmed at higher glycemic levels, was robust to sensor noise, and had minimal false alarms. The approach is readily generalizable to similar scenarios, and results would justify a pilot clinical trial to verify this study. PMID- 20167164 TI - Hypoglycemia prediction with subject-specific recursive time-series models. AB - BACKGROUND: Avoiding hypoglycemia while keeping glucose within the narrow normoglycemic range (70-120 mg/dl) is a major challenge for patients with type 1 diabetes. Continuous glucose monitors can provide hypoglycemic alarms when the measured glucose decreases below a threshold. However, a better approach is to provide an early alarm that predicts a hypoglycemic episode before it occurs, allowing enough time for the patient to take the necessary precaution to avoid hypoglycemia. METHODS: We have previously proposed subject-specific recursive models for the prediction of future glucose concentrations and evaluated their prediction performance. In this work, our objective was to evaluate this algorithm further to predict hypoglycemia and provide early hypoglycemic alarms. Three different methods were proposed for alarm decision, where (A) absolute predicted glucose values, (B) cumulative-sum (CUSUM) control chart, and (C) exponentially weighted moving-average (EWMA) control chart were used. Each method was validated using data from the Diabetes Research in Children Network, which consist of measurements from a continuous glucose sensor during an insulin induced hypoglycemia. Reference serum glucose measurements were used to determine the sensitivity to predict hypoglycemia and the false alarm rate. RESULTS: With the hypoglycemic threshold set to 60 mg/dl, sensitivity of 89, 87.5, and 89% and specificity of 67, 74, and 78% were reported for methods A, B, and C, respectively. Mean values for time to detection were 30 +/- 5.51 (A), 25.8 +/- 6.46 (B), and 27.7 +/- 5.32 (C) minutes. CONCLUSIONS: Compared to the absolute value method, both CUSUM and EWMA methods behaved more conservatively before raising an alarm (reduced time to detection), which significantly decreased the false alarm rate and increased the specificity. PMID- 20167165 TI - Hypoglycemia alarm enhancement using data fusion. AB - BACKGROUND: The acceptance of closed-loop blood glucose (BG) control using continuous glucose monitoring systems (CGMS) is likely to improve with enhanced performance of their integral hypoglycemia alarms. This article presents an in silico analysis (based on clinical data) of a modeled CGMS alarm system with trained thresholds on type 1 diabetes mellitus (T1DM) patients that is augmented by sensor fusion from a prototype hypoglycemia alarm system (HypoMon). This prototype alarm system is based on largely independent autonomic nervous system (ANS) response features. METHODS: Alarm performance was modeled using overnight BG profiles recorded previously on 98 T1DM volunteers. These data included the corresponding ANS response features detected by HypoMon (AiMedics Pty. Ltd.) systems. CGMS data and alarms were simulated by applying a probabilistic model to these overnight BG profiles. The probabilistic model developed used a mean response delay of 7.1 minutes, measurement error offsets on each sample of +/- standard deviation (SD) = 4.5 mg/dl (0.25 mmol/liter), and vertical shifts (calibration offsets) of +/- SD = 19.8 mg/dl (1.1 mmol/liter). Modeling produced 90 to 100 simulated measurements per patient. Alarm systems for all analyses were optimized on a training set of 46 patients and evaluated on the test set of 56 patients. The split between the sets was based on enrollment dates. Optimization was based on detection accuracy but not time to detection for these analyses. The contribution of this form of data fusion to hypoglycemia alarm performance was evaluated by comparing the performance of the trained CGMS and fused data algorithms on the test set under the same evaluation conditions. RESULTS: The simulated addition of HypoMon data produced an improvement in CGMS hypoglycemia alarm performance of 10% at equal specificity. Sensitivity improved from 87% (CGMS as stand-alone measurement) to 97% for the enhanced alarm system. Specificity was maintained constant at 85%. Positive predictive values on the test set improved from 61 to 66% with negative predictive values improving from 96 to 99%. These enhancements were stable within sensitivity analyses. Sensitivity analyses also suggested larger performance increases at lower CGMS alarm performance levels. CONCLUSION: Autonomic nervous system response features provide complementary information suitable for fusion with CGMS data to enhance nocturnal hypoglycemia alarms. PMID- 20167166 TI - Alarm characterization for continuous glucose monitors used as adjuncts to self monitoring of blood glucose. AB - BACKGROUND: Continuous glucose monitoring (CGM) devices available in the United States are approved for use as adjuncts to self-monitoring of blood glucose (SMBG). Alarm evaluation in the Clinical and Laboratory Standards Institute (CLSI) guideline for CGM does not specifically address devices that employ both CGM and SMBG. In this report, an alarm evaluation method is proposed for these devices. METHOD: The proposed method builds on the CLSI method using data from an in-clinic study of subjects with type 1 diabetes. CGM was used to detect glycemic events, and SMBG was used to determine treatment. To optimize detection of a single glucose level, such as 70 mg/dl, a range of alarm threshold settings was evaluated. The alarm characterization provides a choice of alarm settings that trade off detection and false alarms. Detection of a range of high glucose levels was similarly evaluated. RESULTS: Using low glucose alarms, detection of 70 mg/dl within 30 minutes increased from 64 to 97% as alarm settings increased from 70 to 100 mg/dl, and alarms that did not require treatment (SMBG >85 mg/dl) increased from 18 to 52%. Using high glucose alarms, detection of 180 mg/dl within 30 minutes increased from 87 to 96% as alarm settings decreased from 180 to 165 mg/dl, and alarms that did not require treatment (SMBG <180 mg/dl) increased from 24 to 42%. CONCLUSION: The proposed alarm evaluation method provides information for choosing appropriate alarm thresholds and reflects the clinical utility of CGM alarms. PMID- 20167167 TI - Alarm characterization for a continuous glucose monitor that replaces traditional blood glucose monitoring. AB - BACKGROUND: Continuous glucose monitoring (CGM) devices available in the United States are approved for use as adjuncts to self-monitoring of blood glucose (SMBG); all CGM alarms require SMBG confirmation before treatment. In this report, an analysis method is proposed to determine the CGM threshold alarm accuracy required to eliminate SMBG confirmation. METHOD: The proposed method builds on the Clinical and Laboratory Standards Institute (CLSI) guideline for evaluating CGM threshold alarms using data from an in-clinic study of subjects with type 1 diabetes. The CLSI method proposes a maximum time limit of +/-30 minutes for the detection of hypo- and hyperglycemic events but does not include limits for glucose measurement accuracy. The International Standards Organization (ISO) standard for SMBG glucose measurement accuracy (ISO 15197) is +/-15 mg/dl for glucose <75 mg/dl and +/-20% for glucose > or = 75 mg/dl. This standard was combined with the CLSI method to more completely characterize the accuracy of CGM alarms. RESULTS: Incorporating the ISO 15197 accuracy margins, FreeStyle Navigator CGM system alarms detected 70 mg/dl hypoglycemia within 30 minutes at a rate of 70.3%, with a false alarm rate of 11.4%. The device detected high glucose in the range of 140-300 mg/dl within 30 minutes at an average rate of 99.2%, with a false alarm rate of 2.1%. CONCLUSION: Self-monitoring of blood glucose confirmation is necessary for detecting and treating hypoglycemia with the FreeStyle Navigator CGM system, but at high glucose levels, SMBG confirmation adds little incremental value to CGM alarms. PMID- 20167168 TI - Methods of evaluating the utility of continuous glucose monitor alerts. AB - BACKGROUND: The evaluation of continuous glucose monitor (CGM) alert performance should reflect patient use in real time. By evaluating alerts as real-time events, their ability to both detect and predict low and high blood glucose (BG) events can be examined. METHOD: True alerts (TA) were defined as a CGM alert occurring within +/- 30 minutes from the beginning of a low or a high BG event. The TA time to detection was calculated as [time of CGM alert] - [beginning of event]. False alerts (FA) were defined as a BG event outside of the alert zone within +/- 30 minutes from a CGM alert. Analysis was performed comparing DexCom SEVEN PLUS CGM data to BG measured with a laboratory analyzer. RESULTS: Of 49 low glucose events (BG < or =70 mg/dl), with the CGM alert set to 90 mg/dl, the TA rate was 91.8%. For 50% of TAs, the CGM alert preceded the event by at least 21 minutes. The FA rate was 25.0%. Similar results were found for high alerts. CONCLUSION: Continuous glucose monitor alerts are capable of both detecting and predicting low and high BG events. The setting of alerts entails a trade-off between predictive ability and FA rate. Realistic analysis of this trade-off will guide patients in the effective utilization of CGM. PMID- 20167169 TI - Clinical evaluation of a noninvasive alarm system for nocturnal hypoglycemia. AB - BACKGROUND: The aim of this study was to evaluate the performance of a prototype noninvasive alarm system (HypoMon) for the detection of nocturnal hypoglycemia. A prospective cohort study evaluated an alarm system that included a sensor belt, a radio frequency transmitter for chest belt signals, and a receiver. The receiver incorporated integrated "real-time" algorithms designed to recognize hypoglycemia "signatures" in the physiological parameters monitored by the sensor belt. METHODS: Fifty-two children and young adults with type 1 diabetes mellitus (T1DM) participated in this blinded, prospective, in-clinic, overnight study. Participants had a mean age of 16 years (standard deviation 2.1, range 12-20 years) and were asked to follow their normal meal and insulin routines for the day of the study. Participants had physiological parameters monitored overnight by a single HypoMon system. Their BG levels were also monitored overnight at regular intervals via an intravenous cannula and read on two independent Yellow Springs Instruments analyzers. Hypoglycemia was not induced by any manipulations of diabetes management, rather the subjects were monitored overnight for "natural" occurrences of hypoglycemia. Performance analyses included comparing HypoMon system alarm times with allowed time windows associated with each hypoglycemic event. RESULTS: The primary recognition algorithm in the prototype alarm system performed at a level consistent with expectations based on prior user surveys. The HypoMon system correctly recognized 8 out of the 11 naturally occurring overnight hypoglycemic events and falsely alarmed on 13 out of the remaining 41 normal nights [sensitivity 73% (8/11), specificity 68% (28/41), positive predictive value 38%,negative predictive value 90%]. CONCLUSION: The prototype HypoMon shows potential as an adjunct method for noninvasive overnight monitoring for hypoglycemia events in young people with T1DM. PMID- 20167170 TI - A review of standards and statistics used to describe blood glucose monitor performance. AB - Glucose performance is reviewed in the context of total error, which includes error from all sources, not just analytical. Many standards require less than 100% of results to be within specific tolerance limits. Analytical error represents the difference between tested glucose and reference method glucose. Medical errors include analytical errors whose magnitude is great enough to likely result in patient harm. The 95% requirements of International Organization for Standardization 15197 and others make little sense, as up to 5% of results can be medically unacceptable. The current American Diabetes Association standard lacks a specification for user error. Error grids can meaningfully specify allowable glucose error. Infrequently, glucose meters do not provide a glucose result; such an occurrence can be devastating when associated with a life threatening event. Nonreporting failures are ignored by standards. Estimates of analytical error can be classified into the four following categories: imprecision, random patient interferences, protocol-independent bias, and protocol-dependent bias. Methods to estimate total error are parametric, nonparametric, modeling, or direct. The Westgard method underestimates total error by failing to account for random patient interferences. Lawton's method is a more complete model. Bland-Altman, mountain plots, and error grids are direct methods and are easier to use as they do not require modeling. Three types of protocols can be used to estimate glucose errors: method comparison, special studies and risk management, and monitoring performance of meters in the field. Current standards for glucose meter performance are inadequate. The level of performance required in regulatory standards should be based on clinical needs but can only deal with currently achievable performance. Clinical standards state what is needed, whether it can be achieved or not. Rational regulatory decisions about glucose monitors should be based on robust statistical analyses of performance. PMID- 20167171 TI - Analytical and clinical performance of blood glucose monitors. AB - BACKGROUND: The objective of this study was to understand the level of performance of blood glucose monitors as assessed in the published literature. METHODS: Medline from January 2000 to October 2009 and reference lists of included articles were searched to identify eligible studies. Key information was abstracted from eligible studies: blood glucose meters tested, blood sample, meter operators, setting, sample of people (number, diabetes type, age, sex, and race), duration of diabetes, years using a glucose meter, insulin use, recommendations followed, performance evaluation measures, and specific factors affecting the accuracy evaluation of blood glucose monitors. RESULTS: Thirty-one articles were included in this review. Articles were categorized as review articles of blood glucose accuracy (6 articles), original studies that reported the performance of blood glucose meters in laboratory settings (14 articles) or clinical settings (9 articles), and simulation studies (2 articles). A variety of performance evaluation measures were used in the studies. The authors did not identify any studies that demonstrated a difference in clinical outcomes. Examples of analytical tools used in the description of accuracy (e.g., correlation coefficient, linear regression equations, and International Organization for Standardization standards) and how these traditional measures can complicate the achievement of target blood glucose levels for the patient were presented. The benefits of using error grid analysis to quantify the clinical accuracy of patient-determined blood glucose values were discussed. CONCLUSIONS: When examining blood glucose monitor performance in the real world, it is important to consider if an improvement in analytical accuracy would lead to improved clinical outcomes for patients. There are several examples of how analytical tools used in the description of self-monitoring of blood glucose accuracy could be irrelevant to treatment decisions. PMID- 20167172 TI - Siphon effects on continuous subcutaneous insulin infusion pump delivery performance. AB - BACKGROUND: The objective was to quantify hydrostatic effects on continuous subcutaneous insulin infusion (CSII) pumps during basal and bolus insulin delivery. METHODS: We tested CSII pumps from Medtronic Diabetes (MiniMed 512 and 515), Smiths Medical (Deltec Cozmo 1700), and Insulet (OmniPod) using insulin aspart (Novolog, Novo Nordisk). Pumps were filled and primed per manufacturer's instructions. The fluid level change was measured using an inline graduated glass pipette (100 microl) when the pipette was moved in relation to the pump (80 cm Cosmo and 110 cm Medtronics) and when level. Pumps were compared during 1 and 5 U boluses and basal insulin delivery of 1.0 and 1.5 U/h. RESULTS: Pronounced differences were seen during basal delivery in pumps using 80-100 cm tubing. For the 1 U/h rate, differences ranged from 74.5% of the expected delivery when the pumps were below the pipettes and pumping upward to 123.3% when the pumps were above the pipettes and pumping downward. For the 1.5 U/h rate, differences ranged from 86.7% to 117.0% when the pumps were below or above the pipettes, respectively. Compared to pumps with tubing, OmniPod performed with significantly less variation in insulin delivery. CONCLUSIONS: Changing position of a conventional CSII pump in relation to its tubing results in significant changes in insulin delivery. The siphon effect in the tubing may affect the accuracy of insulin delivery, especially during low basal rates. This effect has been reported when syringe pumps were moved in relation to infusion sites but has not been reported with CSII pumps. PMID- 20167173 TI - Compatibility of insulin Lispro, Aspart, and Glulisine with the Solo MicroPump, a novel miniature insulin pump. AB - BACKGROUND: This study compared the stability of commercially available, rapid acting insulin in the novel tubeless, skin-adhering Solo insulin pump over 6 days at extreme environmental conditions. METHODS: Forty-eight pumps for each tested analog were loaded with three different insulin lots and operated at 30 U/day (three sets of 12 pumps) and 15 U/day (one set of 12 pumps) with basal/bolus delivery patterns for 6 days under extreme climatic (37 degrees C, 40% relative humidity) and mechanical (35 strokes/min) stresses. The insulin solutions dispensed were sampled periodically and analyzed for potency, related substances, high molecular weight proteins (HMWP), and preservative content by high performance liquid chromatography techniques. Biological activity (bioidentity) was demonstrated by an abrupt decrease in blood glucose in rabbits. Solutions were inspected for visual appearance and measured for pH levels. RESULTS: During the 6-day sampling period, the potency of all insulin samples was maintained at 95.0-105.0% of the bulk solution concentration of the insulin vials. The levels of HMWP and related substances remained well below labeling limits. The preservative concentration decreased with time but remained bacteriostatic effective. Solutions maintained pH and clarity and were particulate free. The biological activity was verified. CONCLUSIONS: Insulin analogs lispro, aspart, and glulisine maintained physical, chemical, and biological properties for 6 days when used in the Solo MicroPump device. PMID- 20167174 TI - Accuracy of a new real-time continuous glucose monitoring algorithm. AB - BACKGROUND: Through minimally invasive sensor-based continuous glucose monitoring (CGM), individuals can manage their blood glucose (BG) levels more aggressively, thereby improving their hemoglobin A1c level, while reducing the risk of hypoglycemia. Tighter glycemic control through CGM, however, requires an accurate glucose sensor and calibration algorithm with increased performance at lower BG levels. METHODS: Sensor and BG measurements for 72 adult and adolescent subjects were obtained during the course of a 26-week multicenter study evaluating the efficacy of the Paradigm REAL-Time (PRT) sensor-augmented pump system (Medtronic Diabetes, Northridge, CA) in an outpatient setting. Subjects in the study arm performed at least four daily finger stick measurements. A retrospective analysis of the data set was performed to evaluate a new calibration algorithm utilized in the Paradigm Veo insulin pump (Medtronic Diabetes) and to compare these results to performance metrics calculated for the PRT. RESULTS: A total of N = 7193 PRT sensor downloads for 3 days of use, as well as 90,472 temporally and nonuniformly paired data points (sensor and meter values), were evaluated, with 5841 hypoglycemic and 15,851 hyperglycemic events detected through finger stick measurements. The Veo calibration algorithm decreased the overall mean absolute relative difference by greater than 0.25 to 15.89%, with hypoglycemia sensitivity increased from 54.9% in the PRT to 82.3% in the Veo (90.5% with predictive alerts); however, hyperglycemia sensitivity was decreased only marginally from 86% in the PRT to 81.7% in the Veo. CONCLUSIONS: The Veo calibration algorithm, with sensor error reduced significantly in the 40- to 120-mg/dl range, improves hypoglycemia detection, while retaining accuracy at high glucose levels. PMID- 20167175 TI - The accuracy of a new real-time continuous glucose monitoring algorithm: an analysis. AB - In this issue of Journal of Diabetes Science and Technology, Keenan and colleagues used archival data from the STAR 1 clinical trial (Medtronic Diabetes) to support the claim that the new Veo calibration algorithm improves the accuracy of continuous glucose monitoring, particularly in the critical hypoglycemic range. Extensive data analyses are presented to support this claim; the results are convincing, and the estimated improvement in hypoglycemic detection from 55% for the standard calibration to 82% for the Veo is particularly impressive. We can therefore conclude that the Veo algorithm has the potential to improve the accuracy of hypoglycemia alarms and ultimately contribute to closed-loop control. However, the presented results should be interpreted cautiously because they are based on retrospective analysis and are heavily dependent on the distribution of blood glucose levels observed in a particular data set. PMID- 20167176 TI - Continuous glucose monitoring during exercise in patients with type 1 diabetes on continuous subcutaneous insulin infusion. AB - AIM: Exercise is associated with an increased risk of hypoglycemic or hyperglycemic events. The aim of this study was to assess glucose changes during and after physical exercise in patients with type 1 diabetes managed by continuous subcutaneous insulin infusion before and after a 14-day moderate or intense exercise program. METHODS: Sixteen male patients [hemoglobin A1c 7.3 +/- 0.8% (mean +/- standard deviation), age 39 +/- 11 years, body mass index 26.0 +/- 2.7 kg/m(2)] were enrolled in this single-center, randomized, open-label study. They underwent exercise challenges before and after a 14-day moderate (group A, n = 8) and intense (group B) exercise program. Changes in glucose levels were monitored continuously by means of a microdialysis technique. RESULTS: Patients in group A trained less intensively than the patients in group B. The treadmill exercise led to a comparable level of challenge in both patient groups. Neither heart rate nor energy consumption differed within the groups or between the groups. Patients in both groups had a comparable basal insulin infusion rate. Prandial insulin doses were higher pretraining than posttraining in both groups. Identical amounts of additional carbohydrates were consumed by the patients in both groups during the 21 h after the exercise challenge. Glucose profiles recorded showed a wide variability. No differences in the glucose profiles with respect to the training intensity could be observed within and between the groups. Patients in group A tended to spend a shorter period of time in hypoglycemia after the exercise challenge posttraining compared to pretraining, but not the patients in group B. The number of hypoglycemic episodes was not different between the groups. CONCLUSIONS: The patients with type 1 diabetes exhibit the expected wide variability in glucose profiles before, during, and after physical exercise. Use of continuous glucose monitoring allows handling of this situation without running into the risk of acute metabolic deteriorations. PMID- 20167177 TI - Simulation environment to evaluate closed-loop insulin delivery systems in type 1 diabetes. AB - BACKGROUND: Closed-loop insulin delivery systems linking subcutaneous insulin infusion to real-time continuous glucose monitoring need to be evaluated in humans, but progress can be accelerated with the use of in silico testing. We present a simulation environment designed to support the development and testing of closed-loop insulin delivery systems in type 1 diabetes mellitus (T1DM). METHODS: The principal components of the simulation environment include a mathematical model of glucose regulation representing a virtual population with T1DM, the glucose measurement model, and the insulin delivery model. The simulation environment is highly flexible. The user can specify an experimental protocol, define a population of virtual subjects, choose glucose measurement and insulin delivery models, and specify outcome measures. The environment provides graphical as well as numerical outputs to enable a comprehensive analysis of in silico study results. The simulation environment is validated by comparing its predictions against a clinical study evaluating overnight closed-loop insulin delivery in young people with T1DM using a model predictive controller. RESULTS: The simulation model of glucose regulation is described, and population values of 18 synthetic subjects are provided. The validation study demonstrated that the simulation environment was able to reproduce the population results of the clinical study conducted in young people with T1DM. CONCLUSIONS: Closed-loop trials in humans should be preceded and concurrently guided by highly efficient and resource-saving computer-based simulations. We demonstrate validity of population-based predictions obtained with our simulation environment. PMID- 20167178 TI - Individuals achieve more accurate results with meters that are codeless and employ dynamic electrochemistry. AB - BACKGROUND: Studies have shown that controlling blood glucose can reduce the onset and progression of the long-term microvascular and neuropathic complications associated with the chronic course of diabetes mellitus. Improved glycemic control can be achieved by frequent testing combined with changes in medication, exercise, and diet. Technological advancements have enabled improvements in analytical accuracy of meters, and this paper explores two such parameters to which that accuracy can be attributed. METHODS: Four blood glucose monitoring systems (with or without dynamic electrochemistry algorithms, codeless or requiring coding prior to testing) were evaluated and compared with respect to their accuracy. RESULTS: Altogether, 108 blood glucose values were obtained for each system from 54 study participants and compared with the reference values. The analysis depicted in the International Organization for Standardization table format indicates that the devices with dynamic electrochemistry and the codeless feature had the highest proportion of acceptable results overall (System A, 101/103). Results were significant when compared at the 10% bias level with meters that were codeless and utilized static electrochemistry (p = .017) or systems that had static electrochemistry but needed coding (p = .008). CONCLUSIONS: Analytical performance of these blood glucose meters differed significantly depending on their technologic features. Meters that utilized dynamic electrochemistry and did not require coding were more accurate than meters that used static electrochemistry or required coding. PMID- 20167179 TI - No higher dose requirements with insulin detemir than glargine in type 2 diabetes: a crossover, double-blind, and randomized study using continuous glucose monitoring. AB - BACKGROUND: In a previous publication we reported no difference in the 24-hour glucose response between two basal analog insulins, detemir and glargine, when taken once a day in type 2 diabetes mellitus (T2DM). We now report the dose comparison observed within this randomized, double-blind, crossover study. METHOD: Of 36 patients on basal insulin and other noninsulin treatments, 29 completed the study. Both insulins were given once a day at 8 pm and no food was taken between 6 pm and the following morning. The dose was titrated daily by continuous glucose monitoring (CGM) until the basal glucose (between 12 and 6 am) was <120 mg/dl but not >5% of CGM readings <70 mg/dl. Subjects were then crossed over to the other insulin and titrated similarly. RESULTS: Glucose goals were achieved in all subjects. The mean dosage was 0.26 U/kg with very few subjects requiring >0.4 U/kg. Only 2 required an absolute dose less than 10 U/day and all others required more, some considerably higher. Of the 29 subjects, 7 required a greater, 6 a smaller, and 16 the same dose of detemir compared to glargine. CONCLUSIONS: When given once daily in T2DM and titrated using CGM to the same fasting glucose, there was no difference in the glucose response between basal insulins during the basal titration period (4-10 hours after injection) nor during the entire 24-hour period following the injection. Further, the mean dosage to achieve this glucose goal was the same with both insulins. PMID- 20167180 TI - An analysis of dosing equivalence of insulin detemir and insulin glargine: more evidence? AB - Current guidelines for the management of type 2 diabetes call for the use of basal insulin when glycemic targets are not achieved. Previous studies have demonstrated noninferiority of insulin detemir, dosed once or twice daily, and insulin glargine, dosed once daily. In this issue of Journal of Diabetes Science and Technology, Dr. Allen King provides additional data of his previously published randomized, double-blinded, crossover trial in which both insulins were restricted to once-daily use. In this trial of 29 patients, 24-hour continuous glucose monitoring profiles (published previously) and dosing requirements (in this publication) were shown to be statistically equivalent between the two insulins. The shortcomings of this trial are its short duration, small number of patients, and potential interference from endogenous insulin. Longer trials with more patients, studying once-daily use of these medications, will help better determine if any significant differences exist. PMID- 20167181 TI - Epidemiology of cardiovascular disease in type 2 diabetes: the Indian scenario. AB - Noncommunicable diseases, of which coronary artery disease (CAD) and diabetes top the list, have overtaken communicable diseases with respect to overall mortality, even in developing countries like India. High prevalence rates of diabetes and CAD are seen not only in affluent migrant Indians, but also in those living within the subcontinent. Indeed the epidemic of diabetes and CAD is now spreading to the middle- and lower-income groups in India. The risk for CAD is two to four times higher in diabetic subjects, and in Indians, CAD occurs prematurely, i.e., one to two decades earlier than in the West. Thus there is an urgent need for studies on CAD in diabetic and nondiabetic subjects in India. The Chennai Urban Population Study, a population-based study in Chennai, in South India, showed a prevalence of CAD of 11%, which is 10 times more than what it was in 1970. Clustering of risk factors for CAD such as hyperglycemia, central body obesity, dyslipidemia, and hypertension tends to occur, and interplay of these risk factors could explain the enhanced CAD risk in Indians. Additionally, low-grade inflammation and a possible inherent genetic susceptibility are other contributing factors. Preventive measures such as lifestyle modification with healthy diet, adequate physical activity, and decrease in stress could help prevent the twin epidemics of diabetes and CAD. PMID- 20167182 TI - Aluminum gallium nitride (GaN)/GaN high electron mobility transistor-based sensors for glucose detection in exhaled breath condensate. AB - BACKGROUND: Immobilized aluminum gallium nitride (AlGaN)/GaN high electron mobility transistors (HEMTs) have shown great potential in the areas of pH, chloride ion, and glucose detection in exhaled breath condensate (EBC). HEMT sensors can be integrated into a wireless data transmission system that allows for remote monitoring. This technology offers the possibility of using AlGaN/GaN HEMTs for extended investigations of airway pathology of detecting glucose in EBC without the need for clinical visits. METHODS: HEMT structures, consisting of a 3 microm-thick undoped GaN buffer, 30-A-thick Al(0.3)Ga(0.7)N spacer, and 220-A thick silicon-doped Al(0.3)Ga(0.7)N cap layer, were used for fabricating the HEMT sensors. The gate area of the pH, chloride ion, and glucose detection was immobilized with scandium oxide (Sc(2)O(3)), silver chloride (AgCl) thin film, and zinc oxide (ZnO) nanorods, respectively. RESULTS: The Sc(2)O(3)-gated sensor could detect the pH of solutions ranging from 3 to 10 with a resolution of approximately 0.1 pH. A chloride ion detection limit of 10(-8) M was achieved with a HEMT sensor immobilized with the AgCl thin film. The drain-source current of the ZnO nanorod-gated AlGaN/GaN HEMT sensor immobilized with glucose oxidase showed a rapid response of less than 5 seconds when the sensor was exposed to the target glucose in a buffer with a pH value of 7.4. The sensor could detect a wide range of concentrations from 0.5 nM to 125 microM. CONCLUSION: There is great promise for using HEMT-based sensors to enhance the detection sensitivity for glucose detection in EBC. Depending on the immobilized material, HEMT-based sensors can be used for sensing different materials. These electronic detection approaches with rapid response and good repeatability show potential for the investigation of airway pathology. The devices can also be integrated into a wireless data transmission system for remote monitoring applications. This sensor technology could use the exhaled breath condensate to measure the glucose concentration for diabetic applications. PMID- 20167183 TI - Stomach dysfunction in diabetes mellitus: emerging technology and pharmacology. AB - Gastroparesis and other types of gastric dysfunction result in substantial morbidity in diabetes patients. The pathophysiology of these disorders is incompletely understood. This article reviews techniques applicable to the assessment of gastric function in diabetes patients, including the measurement of emptying, accommodation, and contractility. Available treatment options are also reviewed, including novel yet unapproved serotonin 5-HT(4) agonist pharmacological treatments, as well as the role of endoscopic, surgical, and device treatments of gastroparesis. PMID- 20167185 TI - Telehealth behavior therapy for the management of type 1 diabetes in adolescents. AB - BACKGROUND: Poor management of type 1 diabetes mellitus (T1DM) may result in serious medical complications. Psychological intervention may improve adherence to medical regimens; however, access to trained professionals is limited, particularly in rural communities. Telehealth interventions may address this by allowing families to access services at home; however, little is known about the efficacy of such services. METHOD: This study presents results from a pilot trial of a randomized waitlist controlled trial of Telehealth Behavioral Therapy (TBT) for youths with T1DM. Primary outcome measures were adherence to the diabetes regimen, glycemic control, and level of family discord. Thirty-two youths (23 female) with T1DM (aged 9 to 17 years) and one parent or caregiver participated. Telehealth Behavioral Therapy sessions were conducted thrice weekly for 12 weeks by phone and lasted an average of 15 min each. RESULTS: Results indicated that youths in treatment decreased their hemoglobin A1c by 0.74 compared to 0.09 in the waitlist, though this was not statistically significant. Youths in treatment reported increased unsupportive and decreased caring parental behaviors. CONCLUSION: Telehealth Behavioral Therapy improves access to knowledgeable providers and results in a clinically significant improvement in glycemic control. Despite some youths experiencing an increase in unsupportive parental behaviors, TBT is a promising method of service delivery that warrants further investigation. PMID- 20167184 TI - Essential elements of the native glucoregulatory system, which, if appreciated, may help improve the function of glucose controllers in the intensive care unit setting. AB - In 2001, Van den Berghe and colleagues were able to show that tight glucose control decreases morbidity and mortality rates in the intensive care unit (ICU) setting. Several large, prospective, randomized controlled trials have failed to confirm these results. All of these studies attempted tight glucose control using expert-designed algorithms to adjust the rate of intravenous insulin. Unfortunately, these studies each had high rates of hypoglycemia, a high percentage of glucose values outside of the target range, and increased glucose variability. These three measurements have been shown to increase mortality rates in ICU patients. In order to achieve a high rate of success with regards to tight glucose control, a closed-loop system will need to be created. The two main elements of such a system are a continuous glucose sensor and a recursive glucose control algorithm. This review highlights the important elements of the native glucoregulatory system, which, if utilized, may help create a successful glucose control algorithm for a closed-loop system. PMID- 20167186 TI - An intensive insulinotherapy mobile phone application built on artificial intelligence techniques. AB - BACKGROUND: Software to help control diabetes is currently an embryonic market with the main activity to date focused mainly on the development of noncomputerized solutions, such as cardboard calculators or computerized solutions that use "flat" computer models, which are applied to each person without taking into account their individual lifestyles. The development of true, mobile device-driven health applications has been hindered by the lack of tools available in the past and the sheer lack of mobile devices on the market. This has now changed, however, with the availability of pocket personal computer handsets. METHOD: This article describes a solution in the form of an intelligent neural network running on mobile devices, allowing people with diabetes access to it regardless of their location. Utilizing an easy to learn and use multipanel user interface, people with diabetes can run the software in real time via an easy to use graphical user interface. The neural network consists of four neurons. The first is glucose. If the user's current glucose level is within the target range, the glucose weight is then multiplied by zero. If the glucose level is high, then there will be a positive value multiplied to the weight, resulting in a positive amount of insulin to be injected. If the user's glucose level is low, then the weights will be multiplied by a negative value, resulting in a decrease in the overall insulin dose. RESULTS: A minifeasibility trial was carried out at a local hospital under a consultant endocrinologist in Belfast. The short study ran for 2 weeks with six patients. The main objectives were to investigate the user interface, test the remote sending of data over a 3G network to a centralized server at the university, and record patient data for further proofing of the neural network. We also received useful feedback regarding the user interface and the feasibility of handing real-world patients a new mobile phone. Results of this short trial confirmed to a large degree that our approach (which also can be known as intensive insulinotherapy) has value and perhaps that our neural network approach has implications for future intelligent insulin pumps. CONCLUSIONS: Currently, there is no software available to tell people with diabetes how much insulin to inject in accordance with their lifestyle and individual inputs, which leads to adjustments in software predictions on the amount of insulin to inject. We have taken initial steps to supplement the knowledge and skills of health care professionals in controlling insulin levels on a daily basis using a mobile device for people who are less able to manage their disease, especially children and young adults. PMID- 20167188 TI - Obesity epidemic requires federal intervention: "Healthy Kids" key to nation's healthy future. AB - The Healthy Kids Act (H.R. 4053) legislation does three things: (1) establishes an office of Childhood Overweight and Obesity Prevention and Treatment within the Department of Health and Human Services to provide information and promote action on healthy eating, (2) institutes a three-tier system for labeling foods, and (3) enables regulatory action to curb food commercials targeting children. PMID- 20167187 TI - Amperometric glucose sensors: sources of error and potential benefit of redundancy. AB - Amperometric glucose sensors have advanced the care of patients with diabetes and are being studied to control insulin delivery in the research setting. However, at times, currently available sensors demonstrate suboptimal accuracy, which can result from calibration error, sensor drift, or lag. Inaccuracy can be particularly problematic in a closed-loop glycemic control system. In such a system, the use of two sensors allows selection of the more accurate sensor as the input to the controller. In our studies in subjects with type 1 diabetes, the accuracy of the better of two sensors significantly exceeded the accuracy of a single, randomly selected sensor. If an array with three or more sensors were available, it would likely allow even better accuracy with the use of voting. PMID- 20167189 TI - Do incretin-based therapies cause acute pancreatitis? AB - In 2007 a question was raised about the causal relationship between the first of the glucagon-like peptide 1 receptor agonists, exenatide, and pancreatitis, as postmarketing reports of pancreatitis in patients treated with this agent had been received by the Food and Drug Administration (FDA). There had been six reports of hemorrhagic pancreatitis, with two of the cases resulting in death. An update of the package insert for Byetta was mandated. Sitagliptin entered the market about a year and a half later, and now there are similar reports of acute pancreatitis. As the number of patients treated with these agents increases, is it uncovering a risk not appreciated in the premarket phase or just what should be expected from the population treated with these agents? To date, 88 cases of acute pancreatitis have been reported to the FDA in patients taking sitagliptin (Januvia/Janumet). Of these, two cases have been hemorrhagic or necrotizing pancreatitis. A revision of the package insert for sitagliptin has been made recently. An examination of available data should help shed light on whether the relation is likely causal or merely incidental. PMID- 20167190 TI - Ensuring valid measurements for a disabled population: an insulin pen pilot study. PMID- 20167191 TI - Interferon-induced Sus scrofa Mx1 blocks endocytic traffic of incoming influenza A virus particles. AB - The interferon-induced Mx proteins of vertebrates are dynamin-like GTPases, some isoforms of which can additionally inhibit the life cycle of certain RNA viruses. Here we show that the porcine Mx1 protein (poMx1) inhibits replication of influenza A virus and we attempt to identify the step at which the viral life cycle is blocked. In infected cells expressing poMx1, the level of transcripts encoding the viral nucleoprotein is significantly lower than normal, even when secondary transcription is prevented by exposure to cycloheximide. This reveals that a pretranscriptional block participates to the anti-influenza activity. Binding and internalization of incoming virus particles are normal in the presence of poMx1 but centripetal traffic to the late endosomes is interrupted. Surprisingly but decisively, poMx1 significantly alters binding of early endosome autoantigen 1 to early endosomes and/or early endosome size and spatial distribution. This is compatible with impairment of traffic of the endocytic vesicles to the late endosomes. PMID- 20167192 TI - Attenuated Salmonella choleraesuis-mediated RNAi targeted to conserved regions against foot-and-mouth disease virus in guinea pigs and swine. AB - In this study, specific sequences within three genes (3D, VP4 and 2B) of the foot and-mouth disease virus (FMDV) genome were determined to be effective RNAi targets. These sequences are highly conserved among different serotype viruses based on sequence analysis. Small interfering RNA (siRNA)-expressing plasmids (p3D-NT19, p3D-NT56, pVP4-NT19, pVP4-NT65 and p2B-NT25) were constructed to express siRNA targeting 3D, VP4 and 2B, respectively. The antiviral potential of these siRNA for various FMDV isolates was investigated in baby hamster kidney (BHK-21) cells and suckling mice. The results show that these siRNA inhibited virus yield 10- to 300-fold for different FMDV isolates of serotype O and serotype Asia I at 48 h post infection in BHK-21 cells compared to control cells. In suckling mice, p3D-NT56 and p2B-NT25 delayed the death of mice. Twenty percent to 40% of the animals that received a single siRNA dose survived 5 days post infection with serotype O or serotype Asia I. We used an attenuated Salmonella choleraesuis (C500) vaccine strain, to carry the plasmid that expresses siRNA directed against the polymerase gene 3D (p3D-NT56) of FMDV. We used guinea pigs to evaluate the inhibitory effects of recombinant S. cho (p3D-NT56/S. cho) on FMDV infection. The results show that 80% of guinea pigs inoculated with 10(9) CFU of p3D-NT56/S. cho and challenged 36 h later with 50 ID(50) of homologous FMDV were protected. We also measured the antiviral activity of p3D-NT56/S. cho in swine. The results indicate that 100% of the animals treated with 5 x 10(9) CFU of p3D-NT56/S. cho were protected in 9 days. PMID- 20167193 TI - Porcine circovirus type 2 (PCV2)-infection and re-inoculation with homologous or heterologous strains: virological, serological, pathological and clinical effects in growing pigs. AB - Long-term PCV2 infection and/or concurrent infection with genotypes PCV2a and PCV2b may play a role in the development of clinical porcine circovirus associated disease (PCVAD). To evaluate this premise, 24 11-week-old specific pathogen-free (SPF) pigs were randomly assigned to 1 of 4 treatments: negative controls, a single inoculation with PCV2a, single inoculation followed by re inoculation with a homologous PCV2a strain, or repeated inoculations with heterologous strains (PCV2a, PCV2b). Pigs were evaluated for clinical signs daily through 140 days post inoculation (dpi). Serum samples were collected every other day from dpi 0 through 14 and weekly thereafter. PCV2-inoculated pigs were viremic by dpi 2 and 13 of 18 pigs remained viremic at 140 dpi. No statistical differences in the onset, level, or duration of PCV2 viremia were detected among treatment groups. Anti-PCV2 antibodies were detected between 14 and 28 dpi and were present through 140 dpi without statistical differences in antibody response among treatment groups. In the current study, pigs had extended viremia combined with detectable tissue PCV2 antigen levels despite the presence of high levels of anti-PCV2 antibody; however, no clinical disease was observed. PMID- 20167194 TI - A metapopulation model to simulate West Nile virus circulation in Western Africa, Southern Europe and the Mediterranean basin. AB - In Europe, virological and epidemiological data collected in wild birds and horses suggest that a recurrent circulation of West Nile virus (WNV) could exist in some areas. Whether this circulation is permanent (due to overwintering mechanisms) or not remains unknown. The current conception of WNV epidemiology suggests that it is not: this conception combines an enzootic WNV circulation in tropical Africa with seasonal introductions of the virus in Europe by migratory birds. The objectives of this work were to (i) model this conception of WNV global circulation; and (ii) evaluate whether the model could reproduce data and patterns observed in Europe and Africa in vectors, horses, and birds. The model was calibrated using published seroprevalence data obtained from African (Senegal) and European (Spain) wild birds, and validated using independent, published data: seroprevalence rates in migratory and resident wild birds, minimal infection rates in vectors, as well as seroprevalence and incidence rates in horses. According to this model, overwintering mechanisms are not needed to reproduce the observed data. However, the existence of such mechanisms cannot be ruled out. PMID- 20167195 TI - Experimental inoculation study indicates swine as a potential host for Hendra virus. AB - Hendra virus (HeV) is a zoonotic virus from the family Paramyxoviridae causing fatal disease in humans and horses. Five-week-old Landrace pigs and 5-month-old Gottingen minipigs were inoculated with approximately 10(7) plaque forming units per animal. In addition to fever and depression exhibited in all infected pigs, one of the two Landrace pigs developed respiratory signs at 5 days post inoculation (dpi) and one of the Gottingen minipigs developed respiratory signs at 5 dpi and mild neurological signs at 7 dpi. Virus was detected in all infected pigs at 2-5 dpi from oral, nasal, and rectal swabs and at 3-5 dpi from ocular swabs by real-time RT-PCR targeting the HeV M gene. Virus titers in nasal swab samples were as high as 10(4.6) TCID(50)/mL. The viral RNA was mainly distributed in tissues from respiratory and lymphoid systems at an early stage of infection and the presence of virus was confirmed by virus isolation. Pathological changes and immunohistochemical staining for viral antigen were consistent with the tissue distribution of the virus. This new finding indicates that pigs are susceptible to HeV infections and could potentially play a role as an intermediate host in transmission to humans. PMID- 20167196 TI - Identification of full length bovine TLR1 and functional characterization of lipopeptide recognition by bovine TLR2/1 heterodimer. AB - Toll-like receptors (TLR) are highly conserved pattern recognition receptors of the innate immune system. Toll-like receptor 2 (TLR2) recognizes bacterial lipopeptides in a heterodimeric complex with TLR6 or TLR1, thereby discriminating between di- or triacylated lipopeptides, respectively. Previously, we found that HEK293 cells transfected with bovine TLR2 (boTLR2) were able to respond to diacylated lipopeptides but did not recognize triacylated lipopeptides, even after cotransfection with the so far published sequence of boTLR1. In this study we now could show that primary bovine cells were in general able to detect triacylated lipopetides. A closer investigation of the boTLR1 gene locus revealed an additional ATG 195 base pairs upstream from the published start codon. Its transcription would result in an N-terminus with high identity to human and murine TLR1 (huTLR1, muTLR1). Cloning and cotransfection of this longer boTLR1 with boTLR2 now resulted in the recognition of triacylated lipopeptides by HEK293 cells, thereby resembling the ex vivo observation. Analysis of the structure activity relationship showed that the ester-bound acid chains of these lipopeptides need to consist of at least 12 carbon atoms to activate the bovine heterodimer showing similarity to the recognition by huTLR2/huTLR1. In contrast, HEK293 cell cotransfected with muTLR2 and muTLR1 could already be activated by lipopeptides with shorter fatty acids of only 6 carbon atoms. Thus, our data indicate that the additional N-terminal nucleotides belong to the full length and functionally active boTLR1 (boTLR1-fl) which participates in a species-specific recognition of bacterial lipopeptides. PMID- 20167197 TI - Hsp70 enhances presentation of FMDV antigen to bovine CD4+ T cells in vitro. AB - Foot-and-mouth disease virus (FMDV) is the causative agent of a highly contagious acute vesicular disease affecting cloven-hoofed animals, including cattle, sheep and pigs. The current vaccine induces a rapid humoral response, but the duration of the protective antibody response is variable, possibly associated with a variable specific CD4+ T cell response. We investigated the use of heat shock protein 70 (Hsp70) as a molecular chaperone to target viral antigen to the Major Histocompatibility Complex (MHC) class II pathway of antigen presenting cells and generate enhanced MHC II-restricted CD4+ T cell responses in cattle. Monocytes and CD4+ T cells from FMDV vaccinated cattle were stimulated in vitro with complexes of Hsp70 and FMDV peptide, or peptide alone. Hsp70 was found to consistently improve the presentation of a 25-mer FMDV peptide to CD4+ T cells, as measured by T cell proliferation. Complex formation was required for the enhanced effects and Hsp70 alone did not stimulate proliferation. This study provides further evidence that Hsp70:peptide complexes can enhance antigen specific CD4+ T cell responses in vitro for an important pathogen of livestock. PMID- 20167198 TI - Immune cell kinetics in the ovine abomasal mucosa following hyperimmunization and challenge with Haemonchus contortus. AB - Sheep were sensitized by repeated infection with Haemonchus contortus L3, followed by a 12 week rest period, and an abomasal cannula was surgically implanted in all sheep. Seven of the sensitized sheep were subsequently challenged with 50 000 H. contortus L3 while 4 control sheep were challenged with saline. Biopsy samples were taken using a fibreoptic endoscope on days 0, 1, 2, 3, 5, 7 and 28 after challenge and leukocyte subpopulations quantified by (immuno)histology. Differential blood cell counts were performed on the same days. At the end of the trial, sheep showed significantly reduced worm burdens compared to unsensitized control sheep, confirming their resistance status. Both blood and tissue eosinophils, as well as tissue gammadelta TCR+ cells were rapidly elevated by day 1 post L3 challenge (pc), peaking at day 3 pc. There was a slight increase in tissue CD4 T cells at day 2 pc, peaking at day 3 pc while no significant changes in CD8 T cells were observed. B cells (CD45R+) increased later into challenged tissues with a peak at 5 days pc. All tissue lymphocyte subpopulations as well as tissue and blood eosinophils were reduced by day 7 pc before increasing again at day 28 pc, suggesting separate responses to larval and adult antigens. In contrast, globule leukocytes and mucosal mast cells only showed one peak at day 5 pc and 28 pc, respectively. Unexpectedly, globule leukocytes correlated significantly with tissue eosinophils but not mucosal mast cells. The results are consistent with an early eosinophil-mediated killing of L3, possibly recruited by IL-5 produced by gammadelta T cells. In contrast to post-mortem studies, abomasal cannulation allowed sequential analysis of both early and late time points in the same animal, providing a more complete picture of cellular interactions at both peripheral and local sites, and their correlation with the different stages of parasite development. PMID- 20167199 TI - Re-emergence of bluetongue, African horse sickness, and other orbivirus diseases. AB - Arthropod-transmitted viruses (Arboviruses) are important causes of disease in humans and animals, and it is proposed that climate change will increase the distribution and severity of arboviral diseases. Orbiviruses are the cause of important and apparently emerging arboviral diseases of livestock, including bluetongue virus (BTV), African horse sickness virus (AHSV), equine encephalosis virus (EEV), and epizootic hemorrhagic disease virus (EHDV) that are all transmitted by haematophagous Culicoides insects. Recent changes in the global distribution and nature of BTV infection have been especially dramatic, with spread of multiple serotypes of the virus throughout extensive portions of Europe and invasion of the south-eastern USA with previously exotic virus serotypes. Although climate change has been incriminated in the emergence of BTV infection of ungulates, the precise role of anthropogenic factors and the like is less certain. Similarly, although there have been somewhat less dramatic recent alterations in the distribution of EHDV, AHSV, and EEV, it is not yet clear what the future holds in terms of these diseases, nor of other potentially important but poorly characterized Orbiviruses such as Peruvian horse sickness virus. PMID- 20167200 TI - Mechanisms of viral emergence. AB - A number of virologic and environmental factors are involved in the emergence and re-emergence of viral disease. Viruses do not conservatively occupy a single and permanent ecological niche. Rather, due to their intrinsic capacity for genetic change, and to the evolvability of fitness levels, viruses display a potential to parasitize alternative host species. Mutation, recombination and genome segment reassortment, and combination of these molecular events, produce complex and phenotypically diverse populations of viruses, which constitute the raw material on which selection acts. The majority of emerging viral diseases of humans have a zoonotic origin. Sociologic and ecologic factors produce diverse and changing environments in which viral subpopulations have ample opportunities to be selected from intrinsically heterogeneous viral populations, particularly in the case of RNA viruses. In this manner, new human, animal and plant viruses have emerged periodically and, from all evidence, will continue to emerge. This article reviews some of the mechanisms that have been identified in viral emergence, with a focus on the importance of genetic variation of viruses, and on the general concept of biological complexity. PMID- 20167201 TI - Comparative analysis of canine monocyte- and bone-marrow-derived dendritic cells. AB - Dendritic cells (DC) represent a heterogeneous cell family of major importance for innate immune responses against pathogens and antigen presentation during infection, cancer, allergy and autoimmunity. The aim of the present study was to characterize canine DC generated in vitro with respect to their phenotype, responsiveness to toll-like receptor (TLR) ligands and T-cell stimulatory capacity. DC were derived from monocytes (MoDC) and from bone marrow hematopoietic cells cultured with either Flt3-ligand (FL-BMDC) or with GM-CSF (GM BMDC). All three methods generated cells with typical DC morphology that expressed CD1c, CD11c and CD14, similar to macrophages. However, CD40 was only found on DC, CD206 on MPhi and BMDC, but not on monocytes and MoDC. CD1c was not found on monocytes but on all in vitro differentiated cells. FL-BMDC and GM-BMDC were partially positive for CD4 and CD8. CD45RA was expressed on a subset of FL BMDC but not on MoDC and GM-BMDC. MoDC and FL-DC responded well to TLR ligands including poly-IC (TLR2), Pam3Cys (TLR3), LPS (TLR4) and imiquimod (TLR7) by up regulating MHC II and CD86. The generated DC and MPhi showed a stimulatory capacity for lymphocytes, which increased upon maturation with LPS. Taken together, our results are the basis for further characterization of canine DC subsets with respect to their role in inflammation and immune responses. PMID- 20167202 TI - Restoring catalase activity in Staphylococcus aureus subsp. anaerobius leads to loss of pathogenicity for lambs. AB - Staphylococcus aureus subsp. anaerobius, a microaerophilic and catalase-negative bacterium, is the etiological agent of abscess disease, a specific chronic condition of sheep and goats, which is characterized by formation of necrotic lesions that are located typically in superficial lymph nodes. We constructed an isogenic mutant of S. aureus subsp. anaerobius (RDKA84) that carried a repaired and functional catalase gene from S. aureus ATCC 12600, to investigate whether the lack of catalase in S. aureus subsp. anaerobius plays a role in its physiological and pathogenic characteristics. The catalase activity had no apparent influence on the in vitro growth characteristics of RDKA84, which, like the wild-type, did not grow on aerobically incubated agar plates. Restoration of catalase activity in RDKA84 substantially increased resistance to H2O2 when analyzed in a death assay. The intracellular survival rates of the catalase positive mutant RDKA84 in polymorphonuclear neutrophils (PMN) isolated from adult sheep were significantly higher than those of the wild-type, while no differences were found with PMN isolated from lambs. RDKA84 showed significantly lower survival rates in murine macrophages (J774A.1 cells) than the wild-type strains did, whereas, in bovine mammary epithelial cells (MAC-T), no differences in intracellular survival were observed. Interestingly, the virulence for lambs, the natural host for abscess disease, of the catalase-positive mutant RDKA84 was reduced dramatically in comparison with wild-type S. aureus subsp. anaerobius in two experimental models of infection. PMID- 20167203 TI - Determination of the specific activities of methionine sulfoxide reductase A and B by capillary electrophoresis. AB - A capillary electrophoresis (CE) method for the determination of methionine sulfoxide reductase A and methionine sulfoxide reductase B activities in mouse liver is described. The method is based on detection of the 4 (dimethylamino)azobenzene-4'-sulfonyl derivative of l-methionine (dabsyl Met), the product of the enzymatic reactions when either dabsyl l-methionine S sulfoxide or dabsyl l-methionine R-sulfoxide is used as a substrate. The method provides baseline resolution of the substrates and, therefore, can be used to easily determine the purity of the substrates. The method is rapid ( approximately 20min sample to sample), requires no column regeneration, and uses very small amounts of buffers. Separation was performed by using a 75-mum internal diameter polyimide-coated fused silica capillary (no inside coating) with 60cm total length (50cm to the detector window). Samples were separated at 22.5kV, and the separation buffer was 25mM KH(2)PO(4) (pH 8.0) containing 0.9ml of N-lauroylsarcosine (sodium salt, 30% [w/v] solution) per 100ml of buffer. Prior to use, the capillary was conditioned with the same buffer that also contained 25mM sodium dodecyl sulfate. The CE method is compared with high performance liquid chromatography (HPLC) as determined by comparing results from measurements of hepatic enzyme activities in mice fed either deficient or adequate selenium. PMID- 20167204 TI - Identification of protein domains required for makorin-2-mediated neurogenesis inhibition in Xenopus embryos. AB - Makorin-2, consisting of four highly conserved C(3)H zinc fingers, a Cys-His motif and a C(3)HC(4) RING zinc finger domain, is a putative ribonucleoprotein. We have previously reported that Xenopus makorin-2 (mkrn2) is a neurogenesis inhibitor acting upstream of glycogen synthase kinase-3beta (GSK-3beta) in the phosphatidylinositol 3-kinase/Akt pathway. In an effort to identify the functional domains required for its anti-neurogenic activity, we designed and constructed a series of N- and C-terminal truncation mutants of mkrn2. Concurred with the full-length mkrn2, we showed that overexpression of one of the truncation mutants mkrn2(s)-7, which consists of only the third C(3)H zinc finger, Cys-His motif and C(3)HC(4) RING zinc finger, is essential and sufficient to produce the phenotypical dorso-posterior deficiencies and small-head/short tail phenotype in tadpoles. In animal cap explant assay, we further demonstrated that mkrn2(s)-7 not only inhibits activin and retinoic acid-induced animal cap neuralization and the expression of a pan-neural marker neural cell adhesion molecule, but also induces GSK-3beta expression. These results collectively suggest that the third C(3)H zinc finger, Cys-His motif and C(3)HC(4) RING zinc finger are indispensable for the anti-neurogenic activity of mkrn2. PMID- 20167205 TI - Effect of immunomodulatory medication on regional gray matter loss in relapsing remitting multiple sclerosis--a longitudinal MRI study. AB - Prevention of global gray matter (GM) volume changes in multiple sclerosis (MS) are an objective in clinical trials, but the effect of immunomodulatory medication on regional GM atrophy progression is unclear. MRIs from 86 patients with relapsing-remitting MS (RRMS) followed up for 24 months were analyzed using voxel-based morphometry. An analysis of covariance model (cluster threshold, corrected p<0.05) was used to compare GM volumes between baseline and follow-up while stratified by immunomodulatory medication (IM): Interferone INF-beta-1a (n=34), INF-beta-1b (n=16), glatiramer acetate (GA) (n=15), and no immunomodulatory treatment (n=21). In the INF-beta-1a/1b group (n=50), significant GM volume reductions were observed during follow-up in fronto temporal, cingulate and cerebellar cortical brain regions, without significant differences between the INF-beta-1a and INF-beta-1b patients. In the GA group and in unmedicated patients, no significant regional GM volume reductions were observed. In contrast to GA, INF-beta-1a/1b treatment was associated with GM volume reductions in hippocampal/parahippocampal and anterior cingulate cortex. This is the first longitudinal study investigating the effects of IMs on GM in RRMS. Results suggest differences in the dynamics of regional GM volume atrophy in differentially treated or untreated RRMS patients. PMID- 20167206 TI - Resveratrol attenuates 6-hydroxydopamine-induced oxidative damage and dopamine depletion in rat model of Parkinson's disease. AB - The present study was undertaken to investigate the neuroprotective effects of resveratrol (RES) on 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) in rats. PD is an age-related neurodegenerative disorder in which the role of reactive oxygen species (ROS) is strongly implicated. RES, a polyphenolic antioxidant compound enriched in grapes, has been shown to have antioxidant and anti-inflammatory actions and thus was tested for its beneficial effects using 6 OHDA-induced PD rat model. Male Wistar rats were pretreated with RES (20mg/kg body weight i.p.) once daily for 15 days and subjected to unilateral intrastriatal injection of 6-OHDA (10 microg in 0.1% ascorbic acid in normal saline). Three weeks after 6-OHDA infusion, rats were tested for neurobehavioral activity and were killed after 4 weeks of 6-OHDA infusion for the estimation of lipid peroxidation, glutathione content, and activity of antioxidant enzymes (glutathione peroxidase [GPx], glutathione reductase [GR], catalase [CAT], and superoxide dismutase [SOD]. RES was found to be successful in upregulating the antioxidant status and lowering the dopamine loss. Conversely, the elevated level of thiobarbituric acid reactive substances (TBARS), protein carbonyl (PC), and activity of phospholipase A2 in 6-OHDA group was attenuated significantly in RES pretreated group when compared with 6-OHDA-lesioned group. These results were supported by the immunohistochemical findings in the substantia nigra that has shown the protection of neurons by RES from deleterious effects of 6-OHDA. Thus, RES may be used to reduce the deterioration caused by free radicals thereby preventing subsequent behavioral, biochemical, and histopathological changes that occur during PD. PMID- 20167207 TI - Neuroprotection of early and short-time applying atorvastatin in the acute phase of cerebral ischemia: down-regulated 12/15-LOX, p38MAPK and cPLA2 expression, ameliorated BBB permeability. AB - BACKGROUND: It has been proved that chronic administration and pre-treatment with atorvastatin could protect brain tissue against ischemic injury. However, little is known regarding the effect of atorvastatin in the acute phase of ischemic stroke. This study investigated the potential neuroprotective effects of atorvastatin and underlying mechanisms in vivo. METHODS: Male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO). Experiment 1 was used to evaluate time course expressions of 12/15-LOX, mitogen-activated protein kinase (MAPK), phosphorylated-p38MAPK (phospho-p38MAPK) and cytosolic phospholipase A2 (cPLA2) after cerebral ischemia, seven time points were included. Experiment 2 was used to detect atorvastatin's neuroprotection in the acute phase of ischemic stroke; atorvastatin was administered immediately after MCAO. Neurological deficit, brain water content and infarct size were measured at 24h after stoke. Immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to analyze the expression of 12/15 LOX, p38MAPK, phospho-p38MAPK and cPLA2. Experiment 3 was used to detect atorvastatin's influence on blood-brain barrier (BBB). RESULTS: 12/15-LOX, p38MAPK, phospho-p38MAPK and cPLA2 were up-regulated after cerebral ischemia. Compared with MCAO group, atorvastatin dramatically reduced brain water content and infarct sizes, and the over-expressions of 12/15-LOX, p38MAPK, phospho p38MAPK and cPLA2 were significantly decreased in high dose group (20mg/kg, P<0.05). Meanwhile, extra-vascular IgG was not only reduced, but BBB permeability was also ameliorated. CONCLUSIONS: Atorvastatin protected brain from damage caused by MCAO at the early stage; this effect may be through down-regulation of 12/15-LOX, p38MAPK and cPLA2 expressions, and ameliorating BBB permeability. PMID- 20167208 TI - Motivational effects on interval timing in dopamine transporter (DAT) knockdown mice. AB - We examined interval timing in mice that underexpress the dopamine transporter (DAT) and have chronically higher levels of extracellular dopamine (Zhuang et al., 2001). The dopaminergic system has been proposed as a neural substrate for an internal clock, with transient elevations of dopaminergic activity producing underestimation of temporal intervals. A group of DAT knockdown (KD) and littermate wild type (WT) mice were tested with a dual peak procedure. Mice obtained reinforcement by pressing one of two levers after a fixed amount of time (30 or 45 s) had elapsed since lever extension. Only one lever was available at a time, and each lever was associated with a single duration. On occasional probe trials, the DAT KD mice began responding earlier in the interval than WT mice, but showed maximal responding and terminated responding around the same time as the WT mice. Administration of raclopride (0.2, 0.6, and 1.2 mg/kg), a D2 antagonist, eliminated most of the differences between DAT KD and WT mice, suggesting that the effects of chronic DAT downregulation on interval timing were mediated by the D2 receptors. Another cohort of DAT KD mice was trained on a visual attention task, and no deficits were observed, confirming that the changes in timed behavior were not attentionally mediated. Our data are consistent with the view that tonic dopamine affects the sensitivity of an organism to external reward signals, and that this increased motivation for reward of DAT KD mice lowers the threshold for initiating responding in a timing task. PMID- 20167209 TI - Developmental distribution of vestibular nuclear neurons responsive to different speeds of horizontal translation. AB - To examine whether subgroups of vestibular nuclear neurons encode different frequency oscillation of horizontal linear motion, Fos immunohistochemistry was used to document neuronal subpopulations that were functionally activated by such otolithic stimulations. Conscious rats at P7, P14 and adult were subjected to sinusoidal linear acceleration along the transverse axis on the horizontal plane. Labyrinthectomized and/or stationary controls showed only sporadically scattered Fos-labeled neurons in the vestibular nuclei, confirming otolithic origin of c fos expression. In each age group, Fos-labeled neurons responsive to high frequency stimulation (>1.5 Hz) were clustered in the lateral region of the medial vestibular nucleus while those to low frequency stimulation (0.5-1.0 Hz) were found in the medial portion of the medial vestibular nucleus. The number of these neurons increased with age. No apparent frequency-related distribution pattern of Fos-labeled neurons was observed in other vestibular nuclei and subgroups. Our findings therefore reveal subpopulations of central vestibular neurons responsive to different stimulus frequencies that correspond to head motions ranging from tilt to translation. PMID- 20167210 TI - Neuroprotective effects of NSTyr on cognitive function and neuronal plasticity in rats of chronic cerebral hypoperfusion. AB - The neuroprotective effects of N-stearoyl-L-tyrosine (NSTyr) on cognitive function and neuronal plasticity during chronic cerebral hypoperfusion (CCH) in rats were investigated. After induction of CCH, NSTyr was administered daily for 3 months intraperitoneally. Cognitive functions were evaluated by Morris water maze and hippocampal long-term potentiation (LTP). Neuropathological changes were examined using light micrograph and Fluoro-Jade B staining. Neuronal plasticity was assessed by measuring the expression of MAP-2, GAP-43 and synaptophysin on hippocampal regions of rats with immunohistochemistry and western blotting. CCH resulted in significant spatial memory impairment and inhibition of LTP, and led to neurodegeneration in the CA1 region of the hippocampus in the model rats compared with the sham-operated rats. In the model rats treated with NSTyr, cognitive function improved. The expression levels of MAP-2 and synaptophysin protein in hippocampal areas in the model rats were less than those in the sham operated rats, and increased in the model rats treated with NSTyr. However, no statistical significance of GAP-43 expression among the sham, model and NSTyr groups was observed. These data indicate that NSTyr exerts protective effects on cognitive function of rats after CCH, which may be related to the changes of neurodegeneration and neuronal plasticity in the hippocampal area of rats. PMID- 20167212 TI - Tabun-inhibited rat tissue and blood cholinesterases and their reactivation with the combination of trimedoxime and HI-6 in vivo. AB - Up to now, intensive attempts to synthesize a universal reactivator able to reactivate cholinesterases inhibited by all types of nerve agents/organophosphates were not successful. Therefore, another approach using a combination of two reactivators differently reactivating enzyme was used: in rats poisoned with tabun and treated with combination of atropine (fixed dose) and different doses of trimedoxime and HI-6, changes of acetylcholinesterase activities (blood, diaphragm and different parts of the brain) were studied. An increase of AChE activity was observed following trimedoxime treatment depending on its dose; HI-6 had very low effect. Combination of both oximes showed potentiation of their reactivation efficacy; this potentiation was expressed for peripheral AChE (blood, diaphragm) and some parts of the brain (pontomedullar area, frontal cortex); AChE in the basal ganglia was relatively resistant. These observations suggest that the action of combination of oximes in vivo is different from that observed in vitro. PMID- 20167211 TI - Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates. AB - Two novel families of dual binding site acetylcholinesterase (AChE) inhibitors have been developed, consisting of a tacrine or 6-chlorotacrine unit as the active site interacting moiety, either the 5,6-dimethoxy-2-[(4 piperidinyl)methyl]-1-indanone fragment of donepezil (or the indane derivative thereof) or a 5-phenylpyrano[3,2-c]quinoline system, reminiscent to the tryciclic core of propidium, as the peripheral site interacting unit, and a linker of suitable length as to allow the simultaneous binding at both sites. These hybrid compounds are all potent and selective inhibitors of human AChE, and more interestingly, are able to interfere in vitro both formation and aggregation of the beta-amyloid peptide, the latter effects endowing these compounds with the potential to modify Alzheimer's disease progression. PMID- 20167213 TI - Genotoxic effect of 6-gingerol on human hepatoma G2 cells. AB - 6-gingerol, a major component of ginger, has antioxidant, anti-apoptotic, and anti-inflammatory activities. However, some dietary phytochemicals possess pro oxidant effects as well, and the risk of adverse effects is increased by raising the use of doses. The aim of this study was to assess the genotoxic effects of 6 gingerol and to clarify the mechanisms, using human hepatoma G2 (HepG2) cells. Exposure of the cells to 6-gingerol caused significant increase of DNA migration in comet assay, increase of micronuclei frequencies at high concentrations at 20 80 and 20-40 microM, respectively. These results indicate that 6-gingerol caused DNA strand breaks and chromosome damage. To further elucidate the underlying mechanisms, we tested lysosomal membrane stability, mitochondrial membrane potential, the intracellular generation of reactive oxygen species (ROS) and reduced glutathione (GSH). In addition, the level of oxidative DNA damage was evaluated by immunocytochemical analysis on 8-hydroxydeoxyguanosine (8-OHdG). Results showed that lysosomal membrane stability was reduced after treatment by 6 gingerol (20-80 microM) for 40 min, mitochondrial membrane potential decreased after treatment for 50 min, GSH and ROS levels were significantly increased after treatment for 60 min. These suggest 6-gingerol induces genotoxicity probably by oxidative stress; lysosomal and mitochondrial damage were observed in 6-gingerol induced toxicity. PMID- 20167214 TI - Identification and properties of complexes formed by myeloperoxidase with lipoproteins and ceruloplasmin. AB - The first evidence of multi-component complexes formed by myeloperoxidase (MPO), ceruloplasmin (CP), and very low/low density lipoproteins (VLDL/LDL) obtained by electrophoresis, gel filtration, and photon-correlation spectroscopy (PCS) is presented in this paper. Complexes were observed when isolated MPO, CP, and VLDL/LDL were mixed and/or when MPO was added to the blood plasma. Complex LDL MPO-CP was detected in 44 of 100 plasma samples taken from patients with atherosclerosis, and 33 of 44 samples also contained the VLDL-MPO-CP complex. MPO concentration in these patients' plasma exceeded 800 ng/ml. Interaction of MPO with high density lipoproteins (HDL) was not revealed, as well as binding of CP to lipoproteins in the absence of MPO. Adding antibodies against apoB-100 to VLDL MPO-CP and LDL-MPO-CP complexes results in release of lipoproteins. Using PCS the diameters of complexes under study were evaluated. By comparing concentrations of the components in complexes formed by MPO, CP, and lipoproteins their stoichiometry was assessed as 2VLDL:1MPO:2CP and 1LDL:1MPO:2CP. Lipoproteins affected the inhibition of MPO peroxidase activity by CP. The affinity of lipoproteins to MPO-CP complex was assessed using apparent dissociation constants determined as approximately 0.3 nM for VLDL and approximately 0.14 nM for LDL. PMID- 20167215 TI - The separate roles of endothelin receptors participate in remodeling of matrix metalloproteinase and connexin 43 of cardiac fibroblasts in maladaptive response to isoproterenol. AB - Stress may affect gap junction connexin 43 and matrix metalloproteinase-2/9 (MMP 2/9) in cardiac fibroblasts, potentially contributing to worsening cardiac function and arrhythmias. Cardiac fibroblasts isolated from neonatal rat were incubated with isoproterenol at 3 x 10(-7) M to mimic stress and were treated with either PD156707 or IRL-1038 (selective antagonists for endothelin A and B receptor respectively) and CPU0213 (a dual endothelin A/B receptor antagonist) at 1 x 10(-8) M, 3 x 10(-8) M or 1 x 10(-7) M. RT-PCR and Western blotting were conducted. Upregulation of the two endothelin receptors, MMP-2/9 and NADPH oxidase subunits (p22phox and p47phox), and downregulation of connexin 43 in cardiac fibroblasts were found in the presence of isoproterenol and were attenuated by the selective blockers PD156707 and IRL-1038 in a dose-dependent manner. IRL-1038 was less effective. CPU0213 appeared to be more effective than the two selective blockers in blocking these changes. Changes in cardiac fibroblasts in response to isoproterenol mediated by upregulation of the endothelin-NADPH oxidase pathway may play a role in deteriorating cardiac function and arrhythmias. The endothelin A receptor has a major role, relative to the endothelin B receptor, in the remodeling of cardiac fibroblasts during isoproterenol stimulation. CPU0213, a dual endothelin receptor A/B blocker, seems to be more effective in normalizing these changes than do the selective endothelin receptor antagonists. PMID- 20167216 TI - Progress and challenges in colorectal cancer screening and surveillance. AB - Colorectal cancer is a leading cause of cancer death throughout the world. There is evidence that screening of average-risk individuals can result in mortality reduction with early cancer detection and cancer prevention by detection and removal of cancer precursor lesions. The optimal form of screening is not clear. Fecal screening tests can be performed at home at low initial cost, but current versions lack high sensitivity for cancer precursor lesions, and tests need to be repeated at regular intervals. Adherence to repeat testing for negative tests and referral for colonoscopy for positive tests are important elements of program effectiveness. Structural examinations of the colon are more invasive and may result in detection of both early cancer and cancer precursor lesions. Every screening program has advantages and limitations, but each program ultimately depends on quality and patient adherence. PMID- 20167217 TI - Inflammatory bowel disease confers a lower risk of colorectal cancer to females than to males. AB - BACKGROUND & AIMS: Reported differences in cancer risk between male and female animals after chronic inflammation suggest that estrogen has inflammation modifying properties. Little is known about these effects in human beings. Inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (CRC); we studied differences in inflammation-associated CRC between men and women patients with IBD. METHODS: By using a large population based cohort (n = 7607) of individuals diagnosed with IBD from 1954 to 1989, we assessed the sex-specific incidence of CRC from 1960 to 2004. Incidence was determined within the cohort (modeled using Poisson regression) and compared with the general population (assessed as standardized incidence ratios) using data from national Swedish health and census registers. RESULTS: During 171,000 person years of follow-up evaluation, 196 new cases of CRC were observed (123 in males, 73 in females). Males with IBD had a 60% higher risk of CRC (relative risk [RR], 1.6; 95% confidence interval [CI], 1.2-2.2) than females (cumulative incidence 40 years after IBD diagnosis, 8.3% vs 3.5%). Compared with the rate of CRC among the general population, in males with IBD the RR was 2.6 and the 95% CI was 2.2-3.1, whereas in females the RR was 1.9 and the 95% CI was 1.5-2.4. The effect of sex was limited to the period after 10 years of follow-up evaluation (RR, 0.8 before vs 2.2 after), and to patients diagnosed before age 45 (RR, 2.1 before vs 1.0 after). CONCLUSIONS: IBD confers a lower risk of CRC to females than to males. PMID- 20167218 TI - Characterization of resistance to Bacillus thuringiensis toxin Cry1Ac in Plutella xylostella from China. AB - A field population (SZ) of Plutella xylostella, collected from the cabbage field in Shenzhen, Guangdong Province of China in 2002, showed 2.3-fold resistance to Cry1Aa, 110-fold to Cry1Ab, 30-fold to Cry1Ac, 2.1-fold to Cry1F, 5.3-fold to Cry2Aa and 6-fold resistance to Bacillus thuringiensis var. kurstaki (Btk) compared with a susceptible strain (ROTH). The SZBT strain was derived from the SZ population through 20 generations of selection with activated Cry1Ac in the laboratory. While the SZBT strain developed 1200-fold resistance to Cry1Ac after selection, resistance to Cry1Aa, Cry1Ab, Cry1F, and Btk increased to 31-, 1900 ,>33- and 17-fold compared with the ROTH strain. However, little or no cross resistance was detected to Cry1B, Cry1C and Cry2Aa in the SZBT strain. Genetic cross analyses between the SZBT and ROTH strains revealed that Cry1Ac-resistance in the SZBT strain was controlled by a single, autosomal, incompletely recessive gene. Binding studies with (125)I-labeled Cry1Ac showed that the brush border membrane vesicles (BBMVs) of midguts from the resistant SZBT insects had lost binding to Cry1Ac. Allelic complementation tests demonstrated that the major Bt resistance locus in the SZBT strain was same as that in the Cry1Ac-R strain which has "mode 1" resistance to Bt. An F(1) screen of 120 single-pair families between the SZBT strain and three field populations collected in 2008 was carried out. Based on this approach, the estimated frequencies of Cry1Ac-resistance alleles were 0.156 in the Yuxi population from Yunnan province, and 0.375 and 0.472 respectively in the Guangzhou and Huizhou populations from Guangdong province. PMID- 20167219 TI - Establishment of a neonate cell line from Epiphyas postvittana (Walker) (Lepidoptera: Tortricidae) that supports replication of E. postvittana nucleopolyhedrovirus. AB - The lightbrown apple moth (Epiphyas postvittana) is a leafroller pest that damages horticultural crops in New Zealand. This paper documents the establishment of a primary cell line from neonate E. postvittana larvae to facilitate the development of E. postvittana nucleopolyhedrovirus (EppoNPV) for control of this pest. The cell line was cultured for 36 passages and a clonal derivative designated EpN1.10 was generated that had a doubling time of 36h at 21 degrees C. The EpN1.10 cell line allowed for recovery of EppoNPV from transfected genomic DNA and virus passage, as determined by occlusion body production and restriction endonuclease analysis. PMID- 20167220 TI - CAMBIUM, a process-based model of daily xylem development in Eucalyptus. AB - In hardwoods such as Eucalyptus spp., xylem (wood) is a heterogeneous tissue consisting of multiple cell types. As such, xylem development involves multiple complex interactions. To describe and understand xylem development, and ultimately predict the resultant wood properties, a process-based approach to modelling wood property variation is potentially very useful. In this paper, a new model (CAMBIUM), which incorporates concepts of these processes, is described. CAMBIUM predicts how wood density and fibre and vessel anatomical properties vary from pith-to-bark at a daily time step as a function of changing environmental conditions and a set of simulated physiological processes. Simulations from an existing process-based model of stand development (CABALA) are used as inputs. A key feature of CAMBIUM is a model of the interaction between different xylem cell types. Some weaknesses were identified in the ability of the model to simulate vessel spatial patterns and frequencies, emphasizing the complexities inherent in this aspect of angiosperm wood formation. The model was, however, able to provide realistic estimates of short term variation and temporal ranges in eucalypt fibre diameter and secondary wall development and wood density. PMID- 20167221 TI - Exact analytic solutions for a global equation of plant cell growth. AB - A generalization of the Lockhart equation for plant cell expansion in isotropic case is presented. The goal is to account for the temporal variation in the wall mechanical properties--in this case by making the wall extensibility a time dependent parameter. We introduce a time-differential equation describing the plant growth process with some key biophysical aspects considered. The aim of this work was to improve prior modeling efforts by taking into account the dynamic character of the plant cell wall with characteristics reminiscent of damped (aperiodic) motion. The equations selected to encapsulate the time evolution of the wall extensibility offer a new insight into the control of cell wall expansion. We find that the solutions to the time dependent second order differential equation reproduce much of the known experimental data for long- and short-time scales. Additionally, in order to support the biomechanical approach, a new growth equation based on the action of expansin proteins is proposed. Remarkably, both methods independently converge to the same kind, sigmoid-shaped, growth description functional V(t) proportional, exp(-exp(-t)), properly describing the volumetric growth and, consequently, growth rate as its time derivative. PMID- 20167222 TI - Buckling and postbuckling of radially loaded microtubules by nonlocal shear deformable shell model. AB - This paper presents an investigation on the buckling and postbuckling of microtubules (MTs) subjected to a uniform external radial pressure in thermal environments. The microtubule is modeled as a nonlocal shear deformable cylindrical shell which contains small scale effects. The governing equations are based on higher order shear deformation shell theory with a von Karman-Donnell type of kinematic nonlinearity and include the extension-twist and flexural-twist couplings. The thermal effects are also included and the material properties are assumed to be temperature-dependent. A singular perturbation technique is employed to determine the buckling pressure and postbuckling equilibrium paths. The small scale parameter e(0)a is estimated by matching the buckling pressure of MTs measured from the experiments with the numerical results obtained from the nonlocal shear deformable shell model. The numerical results show that buckling pressure and postbuckling behavior of MTs are very sensitive to the small scale parameter e(0)a. The results reveal that the 13_3 microtubule has a stable postbuckling path, whereas the 13_2 microtubule has an unstable postbuckling behavior due to the presence of skew angles. PMID- 20167223 TI - Evolutionary game theory meets social science: is there a unifying rule for human cooperation? AB - Evolutionary game theory has shown that human cooperation thrives in different types of social interactions with a PD structure. Models treat the cooperative strategies within the different frameworks as discrete entities and sometimes even as contenders. Whereas strong reciprocity was acclaimed as superior to classic reciprocity for its ability to defeat defectors in public goods games, recent experiments and simulations show that costly punishment fails to promote cooperation in the IR and DR games, where classic reciprocity succeeds. My aim is to show that cooperative strategies across frameworks are capable of a unified treatment, for they are governed by a common underlying rule or norm. An analysis of the reputation and action rules that govern some representative cooperative strategies both in models and in economic experiments confirms that the different frameworks share a conditional action rule and several reputation rules. The common conditional rule contains an option between costly punishment and withholding benefits that provides alternative enforcement methods against defectors. Depending on the framework, individuals can switch to the appropriate strategy and method of enforcement. The stability of human cooperation looks more promising if one mechanism controls successful strategies across frameworks. PMID- 20167224 TI - A computational model of cerebral cortex folding. AB - The geometric complexity and variability of the human cerebral cortex have long intrigued the scientific community. As a result, quantitative description of cortical folding patterns and the understanding of underlying folding mechanisms have emerged as important research goals. This paper presents a computational 3D geometric model of cerebral cortex folding initialized by MRI data of a human fetal brain and deformed under the governance of a partial differential equation modeling cortical growth. By applying different simulation parameters, our model is able to generate folding convolutions and shape dynamics of the cerebral cortex. The simulations of this 3D geometric model provide computational experimental support to the following hypotheses: (1) Mechanical constraints of the skull regulate the cortical folding process. (2) The cortical folding pattern is dependent on the global cell growth rate of the whole cortex. (3) The cortical folding pattern is dependent on relative rates of cell growth in different cortical areas. (4) The cortical folding pattern is dependent on the initial geometry of the cortex. PMID- 20167225 TI - Genetic probing of homologous recombination and non-homologous end joining during meiotic prophase in irradiated mouse spermatocytes. AB - This study was designed to obtain a better insight into the relative contribution of homologous recombination (HR) and non-homologous end joining (NHEJ) to the repair of radiation-induced DNA double-strand breaks (DSBs) at first meiotic prophase. Early and late pachytene and early diplotene spermatocytes that had completed crossing over were sampled. We studied the kinetics of gamma-H2AX chromatin foci removal after irradiation of mice deficient for HR and mice deficient for NHEJ. Analyzing gamma-H2AX signals in unirradiated RAD54/RAD54B deficient spermatocytes indicated incomplete meiotic recombination repair due to the pronounced increase of gamma-H2AX foci in late prophase primary spermatocytes. In these mice, 8h after irradiation, early pachytene spermatocytes showed a reduction of the numbers of gamma-H2AX foci by 52% compared to 82% in the wild type, the difference being significant. However, after crossing over (in late pachytene and early diplotene), no effect of RAD54/RAD54B deficiency on the reduction of irradiation-induced foci was observed. In NHEJ deficient SCID mice, repair kinetics in early spermatocytes were similar to those in wild type mice. However, 1h after irradiation in late pachytene and early diplotene spermatocytes 1.7 times more foci were found than in wild type mice. This difference might be related to the absence of a DNA-PKcs dependent fast repair component in SCID mice. As subsequent repair is normal, HR likely is taking over. Taken together, the results obtained in RAD54/RAD54B deficient mice and in SCID mice indicate that DSB repair in early pachytene spermatocytes is mainly carried out through HR. In late spermatocytes (late pachytenes and early diplotenes) NHEJ is active. However, probably there is an interplay between these repair pathways and when in late spermatocytes the NHEJ pathway is compromised HR may take over. PMID- 20167226 TI - Enzymatic recognition of DNA damage induced by UVB-photosensitized titanium dioxide and biological consequences in Saccharomyces cerevisiae: evidence for oxidatively DNA damage generation. AB - Although titanium dioxide (TiO(2)) has been considered to be biologically inert, finding use in cosmetics, paints and food colorants, recent reports have demonstrated that when TiO(2) is attained by UVA radiation oxidative genotoxic and cytotoxic effects are observed in living cells. However, data concerning TiO(2)-UVB association is poor, even if UVB radiation represents a major environmental carcinogen. Herein, we investigated DNA damage, repair and mutagenesis induced by TiO(2) associated with UVB irradiation in vitro and in vivo using Saccharomyces cerevisiae model. It was found that TiO(2) plus UVB treatment in plasmid pUC18 generated, in addition to cyclobutane pyrimidine dimers (CPDs), specific damage to guanine residues, such as 8-oxo-7,8 dihydroguanine (8-oxoG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG), which are characteristic oxidatively generated lesions. In vivo experiments showed that, although the presence of TiO(2) protects yeast cells from UVB cytotoxicity, high mutation frequencies are observed in the wild-type (WT) and in an ogg1 strain (deficient in 8-oxoG and FapyG repair). Indeed, after TiO(2) plus UVB treatment, induced mutagenesis was drastically enhanced in ogg1 cells, indicating that mutagenic DNA lesions are repaired by the Ogg1 protein. This effect could be attenuated by the presence of metallic ion chelators: neocuproine or dipyridyl, which partially block oxidatively generated damage occurring via Fenton reactions. Altogether, the results indicate that TiO(2) plus UVB potentates UVB oxidatively generated damage to DNA, possibly via Fenton reactions involving the production of DNA base damage, such as 8-oxo-7,8-dihydroguanine. PMID- 20167227 TI - The functional neurophysiology of the amyloid precursor protein (APP) processing pathway. AB - Amyloid beta (Abeta) peptides derived from proteolytic cleavage of amyloid precursor protein (APP) are thought to be a pivotal toxic species in the pathogenesis of Alzheimer's disease (AD). Furthermore, evidence has been accumulating that components of APP processing pathway are involved in non pathological normal function of the CNS. In this review we aim to cover the extensive body of research aimed at understanding how components of this pathway contribute to neurophysiological function of the CNS in health and disease. We briefly outline changes to clinical neurophysiology seen in AD patients before discussing functional changes in mouse models of AD which range from changes to basal synaptic transmission and synaptic plasticity through to abnormal synchronous network activity. We then describe the various neurophysiological actions that are produced by application of exogenous Abeta in various forms, and finally discuss a number or other neurophysiological aspects of the APP pathway, including functional activities of components of secretase complexes other than Abeta production. PMID- 20167228 TI - DHEA prevents Abeta25-35-impaired survival of newborn neurons in the dentate gyrus through a modulation of PI3K-Akt-mTOR signaling. AB - Infusion (i.c.v.) of beta-amyloid 25-35 (Abeta(25-35)) stimulates proliferation of progenitor cells in the hippocampal dentate gyrus (DG) of adult male mice, but a large population of the newborn cells will die in the 2nd week after birth, a critical period for neurite growth. Neurosteroid dehydroepiandrosterone (DHEA) has been demonstrated to promote neurite growth. Herein, we report that the DHEA treatment on 6-12 days after BrdU-injection (BrdU-D(6-12)) dose-dependently attenuates the loss of newborn neurons induced by Abeta(25-35)-infusion. The DHEA neuroprotection was blocked by the sigma(1) receptor antagonist NE100 and mimicked by the sigma(1) receptor agonist PRE084 when administered on BrdU-D(6 12). The DHEA-action was sensitive to the PI3K inhibitor LY294002 and the mammalian target of rapamycin (mTOR) inhibitor rapamycin. The Abeta(25-35) infusion decreased the levels of Akt, mTOR and p70S6k phosphorylation, which could be rescued by DHEA-treatment in a sigma(1) receptor-dependent manner. Furthermore, the Abeta(25-35)-infusion led to a decrease in the dendritic density and length of doublecortin positive cells in the DG, which also was improved by the DHEA-treatment on BrdU-D(6-12). These findings suggest that DHEA prevents the Abeta(25-35)-impaired survival and dendritic growth of newborn neurons through a sigma(1) receptor-mediated modulation of PI3K-Akt-mTOR-p70S6k signaling. PMID- 20167229 TI - Mirror-image discrimination and reversal in the disconnected hemispheres. AB - Two callosotomized patients and 24 neurologically normal subjects performed simple binary discriminations between upright letters flashed in one or other visual field. Where discrimination of the letters F and R by name either showed a left-hemisphere advantage or no hemispheric effect, discrimination of whether the same letters were normal or backward showed a right-hemisphere advantage. These results suggest that discrimination of mirror-image letters depends on matching to an exemplar, for which the right-hemisphere is dominant, while letter naming depends on abstract category recognition. One commissurotomized patient, DDV, showed systematic left-right reversal of the letters in the left visual field, classifying the normal letters as reversed and reversed ones as normal, and persisted with this reversal when the letters were shown in free vision. This suggests that reversed exemplars of the letters may be laid down the right cerebral hemisphere. There was no such reversal in the other patient (DDC). PMID- 20167230 TI - Tissue distribution of tetrodotoxin in the red-spotted newt Notophthalmus viridescens. AB - High levels of tetrodotoxin (TTX) and of its analogue 6-epi-tetrodotoxin have been detected in skin and liver extracts of the red-spotted newt Notophthalmus viridescens assayed by a post-column fluorescent-HPLC system. Using a monoclonal antibody-based immunoenzymatic technique, TTX was localized in the granular glands of the epidermis as well as in the muscle layer between the muscle fibres, but also in most organs suggesting that TTX is stored in the whole body of the newt and is secreted by skin glands. PMID- 20167231 TI - Microcystin production in epiphytic cyanobacteria on submerged macrophytes. AB - Cyanotoxins have been largely studied in planktonic and benthic cyanobacteria, but microcystin (MCYST) production in epiphytic cyanobacteria has not been reported yet. The present study reports for the first time the MCYST production in epiphytic cyanobacteria on submerged macrophytes. During this study, four common submerged macrophytes in eutrophic pond in Saudi Arabia were surveyed for the presence of toxic epiphytic cyanobacteria. The results showed that chlorophyll-a and total biovolume of epiphytic cyanobacteria differed significantly among submerged plants with highest values obtained in Stratiotes aloides and lowest in Elodea canadensis. Epiphytic materials collected from Ceratophyllum demersum and S. aloides had higher species diversities than materials collected from E. canadensis and Myriophyllum verticillatum. The cyanobacteria, Merismopedia tenuissima and Leptolyngbya boryana were recorded with a high abundance in epiphytic materials collected from all submerged macrohpytes. Based on Enzyme-linked immunosorbent assay (ELISA), these two species were found to produce MCYSTs (MCYSTs) with concentrations of 1438 and 630 microg g(-1) dry weight, respectively. HPLC analysis of the methanolic extracts of the two species showed that M. tenuissima extract contained MCYST-RR and LR/demethyl LR plus 3 minor unidentified MCYSTs, while L. boryana extract contained MCYST-YR, -LR/demethyl LR, and 2 minor unidentified MCYSTs. This study suggests that epiphytic species should be considered during monitoring of toxic cyanobacteria in water sources. PMID- 20167232 TI - Anxiolytic-like property of risperidone and olanzapine as examined in multiple measures of fear in rats. AB - Atypical antipsychotics are also used in the treatment of anxiety-related disorders. Clinical and preclinical evidence regarding their intrinsic anxiolytic efficacy has been mixed. In this study, we examined the potential anxiolytic-like effects of risperidone and olanzapine, and compared them with haloperidol, chlordiazepoxide (a prototype of sedative-anxiolytic drug) or citalopram (a selective serotonin reuptake inhibitor). We used a composite of two-way avoidance conditioning and acoustic startle reflex model and examined the effects of drug treatments during the acquisition phase (Experiment 1) or extinction phase (Experiments 2 and 3) on multiple measures of conditioned and unconditioned fear/anxiety-like responses. In Experiment 4, we further compared risperidone, olanzapine, haloperidol, citalopram and chlordiazepoxide in a standard elevated plus maze test. Results revealed three distinct anxiolytic-like profiles associated with risperidone, olanzapine and chlordiazepoxide. Risperidone, especially at 1.0mg/kg, significantly decreased the number of avoidance responses, 22kHz ultrasonic vocalization, avoidance conditioning-induced hyperthermia and startle reactivity, but did not affect defecations or time spent on the open arms. Olanzapine (2.0mg/kg, sc) significantly decreased the number of avoidance responses, 22kHz vocalization and amount of defecations, but it did not inhibit startle reactivity and time spent on the open arms. Chlordiazepoxide (10mg/kg, ip) significantly decreased the number of 22kHz vocalization, avoidance conditioning-induced hyperthermia and amount of defecations, and increased time spent on the open arms, but did not decrease avoidance responses or startle reactivity. Haloperidol and citalopram did not display any anxiolytic-like property in these tests. The results highlight the importance of using multiple measures of fear-related responses to delineate behavioral profiles of psychotherapeutic drugs. PMID- 20167233 TI - Screening practices of Israeli doctors' and their patients. AB - OBJECTIVE: Doctors' health matters because healthy physicians are more productive and because physicians' health practices affects their patient counseling habits, but there are few objective data on this topic. METHODS: An examination of differences in screening quality health indicators between physicians (n=429) and 1621 age, gender, and socioeconomically matched patient controls from our district Health Maintenance Organization in Israel during the first half of 2008. RESULTS: Doctors and matched patients had similar rates for low-density lipoprotein measurement (85%/84%=NS), colorectal cancer screening (23%/27%=NS), influenza vaccine among the chronically ill (23%/24%=NS), and mammography (for women, 55%/57%=NS). Doctors with hypertension had blood pressures clinically recorded considerably less frequently than matched patients do (56%/77%, p<0.001), and their smoking habits were recorded less often, but their recorded tobacco habits were significantly better. Physician-patient contrasts were also minimal (again except for clinician-recorded blood pressure and smoking) among the chronically ill. CONCLUSIONS: These are the first objective data of which we know that test (and confirm) prior self-reported data that physicians' screening experiences are similar to patients'. Improving physicians' personal screening could also improve patient screening: physicians' self-reported primary prevention habits are considerably better than patients' and have been shown repeatedly to strongly and consistently positively influence patient counseling practices, and hence the health of the public. PMID- 20167234 TI - Phenotype markers and cytokine intracellular production by CD8+ gammadelta T lymphocytes do not support a regulatory T profile in Behcet's disease patients and healthy controls. AB - gammadelta T lymphocytes (GD) have been suggested as one of the causes of cytokine dysregulation that results in neutrophils hyperactivation in Behcet's disease (BD) patients. In addition, GD can provoke cytotoxic lesions in autoimmune diseases by interaction with MICA (MHC class I chain-related A) molecules, through NKG2D receptor on its surface. In contrast, the CD8+ subset of gammadelta T lymphocytes (GDCD8+) has been related to regulatory T activity. The aim of this study was to determine the phenotype and the intracellular cytokine profile in GD from peripheral blood, to discern if they were skewed to an effector or regulatory pattern in BD. We performed phenotype analysis, by three colour flow cytometry, in 28 BD, 15 healthy controls (HC) and 14 patients with recurrent bucal ulcers (RBU). We studied intracellular cytokine production in 10 BD and 14 HC, after polyclonal stimulation. In addition, we analysed serum IL-15 and soluble MICA, by ELISA, in 27 BD, 21 HC and 40 rheumatoid arthritis patients. The hallmark in BD was a specific increase in CD8 expression by GD, and in GDCD8+ absolute numbers. Most of GDCD8+ presented CD8 alphaalpha homodimers and were negative for CD103, Foxp3 and CTLA-4. GDCD8+ and GDCD8- were high IFNgamma-, but poor IL-2, IL-10, TGFbeta and IL-4-producing cells, with no differences between BD and HC. NKG2D expression on CD8+ T cells, serum IL-15 and soluble MICA were not significantly increased in BD. Our results do not suggest a T regulatory profile for GDCD8+ neither in HC, nor in BD. We cannot rule out other suppression mechanisms or some heterogeneity within this subset that could contribute to regulatory function. PMID- 20167235 TI - Differential expression of the EGF-TM7 family members CD97 and EMR2 in lipid laden macrophages in atherosclerosis, multiple sclerosis and Gaucher disease. AB - The members of the epidermal growth factor (EGF)-transmembrane (TM)7 family of adhesion class G-protein coupled receptors are abundantly expressed by cells of the myeloid lineage. A detailed investigation of their expression by functional subsets of activated macrophages is still lacking. Therefore, we determined the expression of CD97, EGF module-containing mucin-like receptor (EMR)2 and EMR3 by monocyte-derived macrophages experimentally polarized in vitro. This was compared to three types of disease-associated lipid-laden macrophages displaying an alternatively activated phenotype in situ. Polarization in vitro towards classically activated M1 versus alternatively activated M2 extremes of macrophage activation did not result in a congruent regulation of EGF-TM7 receptor mRNA and protein except for a down-regulation of CD97 by IL-10. In contrast, macrophages handling lipid overload in vivo displayed differences in the expression of CD97 and EMR2. While foamy macrophages in atherosclerotic vessels expressed both CD97 and EMR2, foam cells in multiple sclerosis brain expressed CD97, but only little EMR2. Foam cell formation in vitro by oxidized LDL and myelin did not affect CD97 or EMR2 expression. Gaucher spleen cells accumulating glucosylceramide expressed very high levels of CD97 and EMR2. These findings indicate that complex cellular expression programmes rather than activation modes regulate the expression of EGF TM7 receptors in macrophages. PMID- 20167236 TI - Recurrent vaginal shedding of herpes simplex type 2 virus in the mouse and effects of antiviral therapy. AB - A mouse model of recurrent herpes simplex type 2 (HSV-2) would improve our understanding of the immunobiology of recurrent disease and provide a useful model for evaluating antiviral treatments. We developed a model to evaluate recurrent vaginal HSV-2 shedding using high-dose acyclovir (ACV) therapy beginning at 3 days post infection (dpi). Treatment with 150mg/kg of ACV for 10 days increased survival to 80% following vaginal challenge with HSV-2 strain 186 and to 100% after challenge with strain MS. We then evaluated recurrent vaginal HSV-2 shedding in surviving mice. Although infectious virus was not detected in vaginal samples after 21dpi, viral DNA was detectable by PCR in 80% of mice (47/59) on at least 1 day, while no animal was positive for virus on every day. ACV therapy administered from day 21 to 31 significantly reduced recurrent virus shedding during this period from 7.3% (8/109 swabs) to 0.8% (1/126 swabs) (p=0.013). Lastly, ACV-rescued HSV-2-infected mice treated with cyclophosphamide at 35 and 38dpi rapidly succumbed, indicating that this model can be used to study immune control of the persistent infection. Thus, this model provides an inexpensive model for evaluating therapeutic strategies and immune control of persistent HSV. PMID- 20167237 TI - Identification and characterization of proteins that selectively interact with the LHR mRNA binding protein (LRBP) in rat ovaries. AB - Luteinizing hormone receptor (LHR) mRNA binding protein (LRBP), identified as mevalonate kinase, has been shown to be a trans factor mediating the post transcriptional regulation of LHR mRNA expression in ovaries. LRBP binds to the coding region of LHR mRNA and accelerates its degradation. Our previous studies in an in vitro system showed that LRBP represses the translation of LHR mRNA by forming an untranslatable ribonucleoprotein (mRNP) complex, further suggesting that the untranslatable mRNP complex is directed to the mRNA repression/decay machinery for subsequent mRNA turnover. In the present studies, we used yeast two hybrid system to screen a cDNA library which was constructed from LHR down regulated ovaries. Two proteins were identified interacting with LRBP: ribosomal protein S20 (RP S20) and ubiquitin conjugating enzyme 2i (UBCE2i). Their interactions with LRBP were confirmed by the mating assay, co-immunoprecipitation analyses and in vitro sumoylation assays. Furthermore, we show that LRBP is a target for modification by SUMO2/3 but not by SUMO1, at K256 and/or K345. Mutation of both lysine residues is sufficient to abrogate the sumoylation of LRBP. These findings suggest that the direct interaction of LRBP with the translation machinery, through RP S20, may be responsible for the transition of LHR mRNA to an untranslatable complex, and that sumoylation of LRBP may play a role in targeting the untranslatable mRNP complex to the mRNA decay machinery in specific cytoplasmic foci. PMID- 20167238 TI - Energy and macronutrient composition of breakfast affect gastric emptying of lunch and subsequent food intake, satiety and satiation. AB - Satiety and food intake are closely related to gastrointestinal transit and specifically gastric emptying. High-fat (HF) meals empty more slowly from the stomach yet are less satiating than isoenergetic low-fat (LF) meals. The current study examines how gastric emptying and satiety at lunch are affected by energy and macronutrient content of breakfast. Nine male volunteers consumed either (1) a HF breakfast, (2) a LF breakfast isoenergetic to HF (LFE) or (3) a LF breakfast of equal mass to HF (LFM). Gastric emptying half time measured using the sodium [(13)C] acetate breath test was delayed after HF compared to LF meals (HF: 102 + or - 11, LFE: 96 + or - 13, LFM: 95 + or - 13 min, mean + or - SD). Fullness increased and desire to eat decreased following the LFE breakfast measured using visual analogue scales. Eating a HF breakfast increased the energy, fat and protein from an ad libitum buffet meal given 4h after lunch. In conclusion, eating a HF breakfast delayed gastric emptying of lunch and increased food intake 7 h later compared to a LFM breakfast. These data suggest both mass and energy content of food regulate subsequent appetite and feeding and demonstrate the hyperphagic effect of a single HF meal. PMID- 20167239 TI - A thermally targeted peptide inhibitor of symmetrical dimethylation inhibits cancer-cell proliferation. AB - Targeting splicing machinery components is an underdeveloped strategy for cancer therapy. Uridine-rich small nuclear ribonucleoproteins (UsnRNPs) are essential spliceosome components that recognize splice sites in newly transcribed RNA. The major spliceosomal snRNPs are comprised of UsnRNA bound by a ring of Sm proteins. The survival of motor neuron (SMN) complex provides specificity for binding of Sm proteins to UsnRNAs. Three of the seven proteins that comprise the Sm core possess post-translationally modified C-terminal symmetric dimethylarginine (sDMA) residues which promote binding of these proteins to SMN. Here we describe a peptide inhibitor of sDMA that is capable of interfering with SMN/SmB interaction. The inhibitory peptide was attached to elastin-like polypeptide, a thermally responsive macromolecular carrier, in order to increase its stability and allow enhancement of its cellular uptake by thermal targeting. The fusion polypeptide inhibited the interaction of SMN/SmB, inhibited proliferation, and induced apoptosis in HeLa cells. PMID- 20167240 TI - Evaluation of metal concentration and antioxidant activity of three edible mushrooms from Mugla, Turkey. AB - This study is designed for the determination of metal concentrations, antioxidant activity potentials and total phenolics of Amanita caesarea, Clitocybe geotropa and Leucoagaricus pudicus. Concentrations of four heavy metals (Pb, Cd, Cr, Ni) and five minor elements (Zn, Fe, Mn, Cu, Co) are determined. In the case of A. caesarea, Cr and Ni concentrations are found in a high level. Concentrations of the metals are found to be within safe limits for C. geotropa. In beta carotene/linoleic acid test, L. pudicus showed the highest activity potential. In DPPH system, A. caesarea showed 79.4% scavenging ability. Additionally, reducing power and chelating capacity of the mushrooms increased with concentration. The strongest super-oxide anion scavenger was A. caesarea. In the case of total phenolics, L. pudicus found to have the highest content. PMID- 20167241 TI - The platelet activating factor (PAF) signaling cascade in systemic inflammatory responses. AB - The platelet-activating factor (PAF) signaling cascade evolved as a component of the repertoire of innate host defenses, but is also an effector pathway in inflammatory and thrombotic diseases. This review focuses on the PAF signaling cascade in systemic inflammatory responses and, specifically, explores its activities in experimental and clinical sepsis and anaphylaxis in the context of the basic biochemistry and biology of signaling via this lipid mediator system. PMID- 20167242 TI - Efficient use and recycling of the micronutrient iodide in mammals. AB - Daily ingestion of iodide alone is not adequate to sustain production of the thyroid hormones, tri- and tetraiodothyronine. Proper maintenance of iodide in vivo also requires its active transport into the thyroid and its salvage from mono- and diiodotyrosine that are formed in excess during hormone biosynthesis. The enzyme iodotyrosine deiodinase responsible for this salvage is unusual in its ability to catalyze a reductive dehalogenation reaction dependent on a flavin cofactor, FMN. Initial characterization of this enzyme was limited by its membrane association, difficult purification and poor stability. The deiodinase became amenable to detailed analysis only after identification and heterologous expression of its gene. Site-directed mutagenesis recently demonstrated that cysteine residues are not necessary for enzymatic activity in contrast to precedence set by other reductive dehalogenases. Truncation of the N-terminal membrane anchor of the deiodinase has provided a soluble and stable source of enzyme sufficient for crystallographic studies. The structure of an enzyme.substrate co-crystal has become invaluable for understanding the origins of substrate selectivity and the mutations causing thyroid disease in humans. PMID- 20167243 TI - Calorimetric and spectroscopic studies of aminoglycoside binding to AT-rich DNA triple helices. AB - Calorimetric and fluorescence techniques were used to characterize the binding of aminoglycosides-neomycin, paromomycin, and ribostamycin, with 5'-dA(12)-x-dT(12) x-dT(12)-3' intramolecular DNA triplex (x = hexaethylene glycol) and poly(dA).2poly(dT) triplex. Our results demonstrate the following features: (1) UV thermal analysis reveals that the T(m) for triplex decreases with increasing pH value in the presence of neomycin, while the T(m) for the duplex remains unchanged. (2) The binding affinity of neomycin decreases with increased pH, although there is an increase in observed binding enthalpy. (3) ITC studies conducted in two buffers (sodium cacodylate and MOPS) yield the number of protonated drug amino groups (Deltan) as 0.29 and 0.40 for neomycin and paromomycin interaction with 5'-dA(12)-x-dT(12)-x-dT(12)-3', respectively. (4) The specific heat capacity change (DeltaC(p)) determined by ITC studies is negative, with more negative values at lower salt concentrations. From 100 mM to 250 mM KCl, the DeltaC(p) ranges from -402 to -60 cal/(mol K) for neomycin. At pH 5.5, a more positive DeltaC(p) is observed, with a value of -98 cal/(mol K) at 100 mM KCl. DeltaC(p) is not significantly affected by ionic strength. (5) Salt dependence studies reveal that there are at least three amino groups of neomycin participating in the electrostatic interactions with the triplex. (6) FID studies using thiazole orange were used to derive the AC(50) (aminoglycoside concentration needed to displace 50% of the dye from the triplex) values. Neomycin shows a seven fold higher affinity than paromomycin and eleven fold higher affinity than ribostamycin at pH 6.8. (7) Modeling studies, consistent with UV and ITC results, show the importance of an additional positive charge in triplex recognition by neomycin. The modeling and thermodynamic studies indicate that neomycin binding to the DNA triplex depends upon significant contributions from charge as well as shape complementarity of the drug to the DNA triplex Watson-Hoogsteen groove. PMID- 20167245 TI - Beneficial effects of omega-3 long-chain fatty acids in breast cancer and cardiovascular diseases: voltage-gated sodium channels as a common feature? AB - Cancers are among the leading causes of death worldwide. Voltage-gated sodium channels, among other ion channels, appear as new molecular players in epithelial cancers. Highly metastatic breast cancer cells express Na(V)1.5, the main isoform expressed in cardiac cells, where the current generated by the flux of sodium ions is responsible for the excitability. Breast cancer cells are not excitable and the protein activity regulates cell invasiveness, through the modulation of activity of acidic cathepsins, a characteristic involved in the metastatic phenotype. Interestingly, it is known that omega-3 LC-PUFA can exert beneficial effects by preventing post-myocardial infarction arrhythmias and by reducing the incidence of metastatic breast cancer. In this review, we compare the effects of some omega-3 LC-PUFA on Na(V)1.5 expressed in both cardiac and MDA-MB-231 breast cancer cells. We propose that some of the effects of omega-3 LC-PUFA act through common mechanisms involved in both diseases. PMID- 20167246 TI - Confrontation with blood and disgust stimuli precipitates respiratory dysregulation in blood-injection-injury phobia. AB - Blood-injection-injury (BII) phobia patients sometimes faint during exposure to relevant stimuli. However, mechanisms and timing of physiological adjustments in BII phobia remain poorly understood. In a larger sample of 60 patients and 20 controls, we sought to replicate findings of a prior study demonstrating the role of hyperventilation in the phobic response. We also investigated the timing of respiratory adjustment across an extended exposure recovery period. In addition, because intense disgust is commonly reported by patients, responses to surgery films were compared to a pure disgust film. End-tidal PCO(2) dropped significantly while volume and flow increased during the surgery film in patients compared to controls and to other emotional films except disgust. Patients recovered quickly following the disgust film but not the surgery film. PCO(2), volume, and flow parameters showed robust associations with anxiety, disgust, and physical symptoms. Findings suggest that respiratory adjustments during and after phobic exposure may provide a critical missing link in the understanding of the psychophysiology of this singular disorder, including why fainting often occurs after the stimulus is removed. PMID- 20167244 TI - S1P metabolism in cancer and other pathological conditions. AB - Nearly two decades ago, the sphingolipid metabolite sphingosine 1-phosphate was discovered to function as a lipid mediator and regulator of cell proliferation. Since that time, sphingosine 1-phosphate has been shown to mediate a diverse array of fundamental biological processes including cell proliferation, migration, invasion, angiogenesis, vascular maturation and lymphocyte trafficking. Sphingosine 1-phosphate acts primarily via signaling through five ubiquitously expressed G protein-coupled receptors. Intracellular sphingosine 1 phosphate molecules are transported extracellularly and gain access to cognate receptors for autocrine and paracrine signaling and for signaling at distant sites reached through blood and lymphatic circulation systems. Intracellular pools of sphingosine 1-phosphate available for signaling are tightly regulated primarily by three enzymes: sphinosine kinase, S1P lyase and S1P phosphatase. Alterations in sphingosine 1-phosphate as well as the enzymes involved in its synthesis and catabolism have been observed in many types of malignancy. These enzymes are being evaluated for their role in mediating cancer formation and progression, as well as their potential to serve as targets of anti-cancer therapeutics. In this review, the impact of sphingosine 1-phosphate, its cognate receptors, and the enzymes of sphingosine 1-phosphate metabolism on cell survival, apoptosis, autophagy, cellular transformation, invasion, angiogenesis and hypoxia in relation to cancer biology and treatment are discussed. PMID- 20167247 TI - Persistence of donor-derived protein in host myeloid cells after induced rejection of engrafted allogeneic bone marrow cells. AB - OBJECTIVE: In recipients of allogeneic hematopoietic stem cell transplantation to treat hematologic malignancies, we have unexpectedly observed anti-tumor effects in association with donor cell rejection in both mice and humans. Host-type CD8 T cells were shown to be required for these anti-tumor effects in the murine model. Because sustained host CD8 T-cell activation was observed in the murine bone marrow following the disappearance of donor chimerism in the peripheral blood, we hypothesized that donor antigen presentation in the bone marrow might be prolonged. MATERIALS AND METHODS: To assess this hypothesis, we established mixed chimerism with green fluorescent protein (GFP)-positive allogeneic bone marrow cells, induced rejection of the donor cells by giving recipient leukocyte infusions, and utilized in vivo microscopy to follow GFP-positive cells. RESULTS: After peripheral donor leukocytes disappeared, GFP persisted within host myeloid cells surrounding the blood vessels in the bone marrow, suggesting that the host myeloid cells captured donor-derived GFP protein. CONCLUSIONS: Because the host vs-graft reaction promotes induction of anti-tumor responses in this model, this retention of donor-derived protein may play a role in the efficacy of recipient leukocyte infusions as an anti-tumor therapy. PMID- 20167248 TI - Therapeutic efficacy of the pan-cdk inhibitor PHA-793887 in vitro and in vivo in engraftment and high-burden leukemia models. AB - OBJECTIVE: The aim of the work was to determine and characterize, in vitro and in vivo, the therapeutic activity of PHA-793887, a new potent pan-cdk inhibitor, in the context of hematopoietic neoplasms. MATERIALS AND METHODS: Thirteen leukemic cell lines bearing different cytogenetic abnormalities and normal hematopoietic cells were used in cytotoxicity and colony assays. The drug activity at the molecular level was analyzed by Western blotting. PHA-793887 was also tested in vivo in several leukemia xenograft models. RESULTS: PHA-793887 was cytotoxic for leukemic cell lines in vitro, with IC(50) ranging from 0.3 to 7 microM (mean: 2.9 microM), regardless of any specific chromosomal aberration. At these doses, the drug was not cytotoxic for normal unstimulated peripheral blood mononuclear cells or CD34(+) hematopoietic stem cells. Interestingly, in colony assays PHA-793887 showed very high activity against leukemia cell lines, with an IC(50) <0.1 microM (mean: 0.08 microM), indicating that it has efficient and prolonged antiproliferative activity. PHA-793887 induced cell-cycle arrest, inhibited Rb and nucleophosmin phosphorylation, and modulated cyclin E and cdc6 expression at low doses (0.2-1 microM) and induced apoptosis at the highest dose (5 microM). It was also effective in vivo in both subcutaneous xenograft and primary leukemic disseminated models that better mimic naturally occurring human disease. Interestingly, in one disseminated model derived from a relapsed Philadelphia positive acute lymphoid leukemia patient, PHA-793887 showed strong therapeutic activity also when treatment was started after establishment of high disease burden. CONCLUSIONS: We conclude that PHA-793887 has promising therapeutic activity against acute leukemias in vitro and in vivo. PMID- 20167249 TI - Identification of multiple vasotocin receptor cDNAs in teleost fish: sequences, phylogenetic analysis, sites of expression, and regulation in the hypothalamus and gill in response to hyperosmotic challenge. AB - Vasopressin and its homolog vasotocin regulate hydromineral balance, stress responses, and social behaviors in vertebrates. In mammals, the functions of vasopressin are mediated via three classes of membrane-bound receptors: V1a-type, V1b-type and V2-type. To date, however, only a single class of vasotocin receptor has been identified in teleost fish. Here, cDNAs encoding three putative vasotocin receptors - two distinct V1a-type receptor paralogs (V1a1 and V1a2) and a previously undescribed V2-type receptor (V2) - and a single isotocin receptor were isolated and sequenced from the Amargosa pupfish (Cyprinodon nevadensis amargosae). RT-PCR revealed that mRNAs for these receptors differed in expression patterns with V1a1 mRNAs abundant in the brain, pituitary and testis, V1a2 transcripts at greatest levels in brain, heart and muscle, V2 transcripts most common in the gills, heart and kidney, and isotocin receptor mRNAs abundant in the midbrain, pituitary and gonads. In response to an acute hyperosmotic challenge, pro-vasotocin and V2 mRNA levels in the hypothalamus decreased, while transcripts of V1a1 in the hypothalamus and V1a2 in the gills increased. Partial transcripts for structurally related V2-type, as well as multiple V1a-type, receptors were also identified in other teleosts, suggesting that multiple vasotocin receptors may be present in many Actinopterygii fishes. PMID- 20167250 TI - Small-angle X-ray scattering studies of the intact eye lens: effect of crystallin composition and concentration on microstructure. AB - BACKGROUND: The cortex and nucleus of eye lenses are differentiated by both crystallin protein concentration and relative distribution of three major crystallins (alpha, beta, and gamma). Here, we explore the effects of composition and concentration of crystallins on the microstructure of the intact bovine lens (37 degrees C) along with several lenses from Antarctic fish (-2 degrees C) and subtropical bigeye tuna (18 degrees C). METHODS: Our studies are based on small angle X-ray scattering (SAXS) investigations of the intact lens slices where we study the effect of crystallin composition and concentration on microstructure. RESULTS: We are able to distinguish the nuclear and cortical regions by the development of a characteristic peak in the intensity of scattered X-rays. For both the bovine and fish lenses, the peak corresponds to that expected for dense suspensions of alpha-crystallins. CONCLUSIONS: The absence of the scattering peak in the nucleus indicates that there is no characteristic wavelength for density fluctuations in the nucleus although there is liquid-like order in the packing of the different crystallins. The loss in peak is due to increased polydispersity in the sizes of the crystallins and due to the packing of the smaller gamma crystallins in the void space of alpha-crystallins. GENERAL SIGNIFICANCE: Our results provide an understanding for the low turbidity of the eye lens that is a mixture of different proteins. This will inform design of optically transparent suspensions that can be used in a number of applications (e.g., artificial liquid lenses) or to better understand human diseases pathologies such as cataract. PMID- 20167251 TI - Depolarization induces acetylation of histone H2B in the hippocampus. AB - Phosphorylation is critically involved in synaptic plasticity and memory. Recent studies have shown that another posttranslational modification, acetylation, particularly of histone H3, also plays important roles in long-term potentiation and memory. However, activity-dependent modification of different histones of the nucleosome is not clearly understood. Here we show that depolarization enhances acetylation of histone H2B in the CA1 region of the hippocampus. Depolarization induced H2B acetylation is dependent on calcium/calmodulin-dependent kinase and extracellular signal-regulated kinase activity. In addition, inhibition of DNA methyltransferase activity also abolishes depolarization-induced increase in H2B acetylation. These results show that acetylation of histone H2B is regulated in an activity-dependent manner by the molecular events important for synaptic plasticity and memory. PMID- 20167252 TI - Effects of intracerebroventricular application of the delta opioid receptor agonist [D-Ala2, D-Leu5] enkephalin on neurological recovery following asphyxial cardiac arrest in rats. AB - The delta opioid receptor (DOR) agonist [D-Ala2, D-Leu5] enkephalin (DADLE) has been implicated as a novel neuroprotective agent in the CNS. The current study was designed to evaluate the effects of intracerebroventricular (ICV) application of DADLE on neurological outcomes following asphyxial cardiac arrest (CA) in rats. Male Sprague-Dawley rats were randomly assigned to four groups: Sham group, CA group, DADLE group (DADLE+CA), and Naltrindole group (Naltrindole and DADLE+CA). All drugs were administered into the left cerebroventricle 30 min before CA. CA was induced by 8-min asphyxiation and the animals were resuscitated with a standardized method. DOR protein expression in the hippocampus was significantly increased in the CA group at 1 h after restoration of spontaneous circulation (ROSC) compared with the Sham group. As time progressed, expression of DOR proteins decreased gradually in the CA group. Treatment with DADLE alone or co-administration with Naltrindole reversed the down-regulation of DOR proteins in the hippocampus induced by CA at 24 h after ROSC. Compared with the CA group, the DADLE group had persistently better neurological functional recovery, as assessed by neurological deficit score (NDS) and Morris water maze trials. The number of surviving hippocampal CA1 neurons in the DADLE group was significantly higher than those in the CA group. However, administration of Naltrindole abolished most of the neuroprotective effects of DADLE. We conclude that ICV administration of DADLE 30 min before asphyxial CA has significant protective effects in attenuating hippocampal CA1 neuronal damage and neurological impairments, and that DADLE executes its effects mainly through DOR. PMID- 20167253 TI - The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons. An anatomical and behavioral study. AB - The sigma-1 receptor regulates various ion channel activity and possesses protein chaperone function. Using an antibody against the full sequence of the sigma-1 receptor we detected immunostaining in wild type but not in knockout mice. The receptor was found primarily in motoneurons localized to the brainstem and spinal cord. At the subcellular level the receptor is restricted to large cholinergic postsynaptic densities on the soma of motoneurons and is colocalized with the Kv2.1 potassium channel and the muscarinic type 2 cholinergic receptor. Ultrastructural analysis of the neurons indicates that the immunostained receptor is located close but separate from the plasma membrane, possibly in subsurface cisternae formed from the endoplasmic reticulum (ER), which are a prominent feature of cholinergic postsynaptic densities. Behavioral testing on a rotorod revealed that Sigma-1 receptor knockout mice remained on the rotorod for significantly less time (a shorter latency period) compared to the wild type mice. Together these data indicate that the sigma-1 receptor may play a role in the regulation of motor behavior. PMID- 20167254 TI - Erythropoietin promotes spinal cord-derived neural progenitor cell proliferation by regulating cell cycle. AB - Erythropoietin (EPO) regulates the proliferation and differentiation of erythroid cells by binding to its specific transmembrane receptor (EPOR). The presence of EPO and its receptor in the CNS suggests a different function for EPO other than erythropoiesis. The purpose of the present study was to examine EPOR expression and the role of EPO in the proliferation of neonatal spinal cord-derived neural progenitor cells. The effect of EPO on cell cycle progression was also examined, as well as the signaling cascades involved in this process. Our results showed that EPOR was present in the neural progenitor cells and EPO significantly enhanced their proliferation. Cell cycle analysis of EPO-treated neural progenitor cells indicated a reduced percentage of cells in G0/G1 phase, whereas the cell proliferation index (S phase plus G2/M phase) was increased. EPO also increased the proportion of 5-bromo-2-deoxyuridine (BrdU)-positive cells. With respect to the cell cycle signaling, we examined the cyclin-dependent kinases D1, D2 and E, and cyclin-dependent kinase inhibitors, p21cip1, p27kip1 and p57kip2. No significant differences were observed in the expression of these transcripts after EPO administration. Interestingly, the anti-apoptotic factors, mcl-1 and bcl-2 were significantly increased twofold. Moreover, these specific effects of EPO were eliminated by incubation of the progenitor cells with anti-EPO neutralizing antibody. Those observations suggested that EPO may play a role in normal spinal cord development by regulating cell proliferation and apoptosis. PMID- 20167255 TI - Intra-accumbens rimonabant is rewarding but induces aversion to cocaine in cocaine-treated rats, as does in vivo accumbal cannabinoid CB1 receptor silencing: critical role for glutamate receptors. AB - Reinforcing effects mediated by accumbal CB(1) receptors (CB(1)R) are controversial, as well as their role in the rewarding effects of cocaine. Accumbal glutamate and glutamate receptors have been proposed to be involved in CB(1)R-mediated effects on cocaine reward. Rewarding effects of cocaine can be evaluated with the conditioned place preference or CPP test. Rimonabant, a cannabinoid CB(1)R ligand, lentiviruses aimed at silencing CB(1)R, and selective glutamatergic ligands are good tools for studying the function of accumbal CB(1) and glutamate receptors. The objectives of the present study were (i) to discern the CPP effects of in vivo gene silencing of accumbal CB(1) receptors by means of lentiviruses containing siRNAs; (ii) to discern the CPP effects of intra accumbens infusions of the cannabinoid CB(1)R ligand rimonabant, and to evaluate whether effects are due to receptor blockade or inverse agonism; (iii) to discern the role of CB(1)R located within the nucleus accumbens shell in the rewarding effects of cocaine, by means of local infusions of rimonabant, and (iv) to discern the role of glutamate receptors (AMPAR, NMDAR, mGluR2/3) in rimonabant induced effects on CPP in cocaine-treated rats. The findings revealed that in vivo silencing of accumbal CB(1) receptors with Lenti-CB(1)R-siRNAs induced place aversion to cocaine, but intra-accumbal rimonabant induced place preference in its own right, indicating that this compound seems to act as inverse agonist on the CPP. Glutamate receptors participate in rimonabant-mediated place preference because it was abolished after blocking AMPA glutamate receptors, but not NMDAR or mGluR2/3. Finally, in cocaine-treated rats, local rimonabant induced place aversion to the drug (not place preference), and this effect was mediated by glutamate neurotransmission because it was abolished after blockade of AMPA, NMDA or mGlu2/3 receptors, even though only the blockade of mGlu2/3 autoreceptors restored the emergence of place preference to cocaine. PMID- 20167256 TI - The immediate large-scale dendritic plasticity of cortical pyramidal neurons subjected to acute epidural compression. AB - Head trauma and acute disorders often instantly compress the cerebral cortex and lead to functional abnormalities. Here we used rat epidural bead implantation model and investigated the immediate changes following acute compression. The dendritic arbors of affected cortical pyramidal neurons were filled with intracellular dye and reconstructed 3-dimensionally for analysis. Compression was found to shorten the apical, but not basal, dendrites of underlying layer III and V cortical pyramidal neurons and reduced dendritic spines on the entire dendritic arbor immediately. Dendrogram analysis showed that in addition to distal, proximal apical dendrites also quickly reconfigured. We then focused on apical dendritic trunks and explored how proximal dendrites were rapidly altered. Compression instantly twisted the microtubules and deformed the membrane contour of dendritic trunks likely a result of the elastic nature of dendrites as immediate decompression restored it and stabilization of microtubules failed to block it. Subsequent adaptive remodeling restored plasmalemma and microtubules to normal appearance in 3 days likely via active mechanisms as taxol blocked the restoration of microtubules and in addition partly affected plasmalemmal reorganization which presumably engaged recycling of excess membrane. In short, the structural dynamics and the associated mechanisms that we revealed demonstrate how compression quickly altered the morphology of cortical output neurons and hence cortical functions consequently. PMID- 20167257 TI - Differential effects of dopamine and opioid receptor blockade on motivated Coca Cola drinking behavior and associated changes in brain, skin and muscle temperatures. AB - Although pharmacological blockade of both dopamine (DA) and opiate receptors has an inhibiting effect on appetitive motivated behaviors, it is still unclear which physiological mechanisms affected by these treatments underlie the behavioral deficit. To clarify this issue, we examined how pharmacological blockade of either DA (SCH23390+eticlopride at 0.2 mg/kg each) or opioid receptors (naloxone 1 mg/kg) affects motor activity and temperature fluctuations in the nucleus accumbens (NAcc), temporal muscle, and facial skin associated with motivated Coca Cola drinking behavior in rats. In drug-free conditions, presentation of a cup containing 5 ml of Coca-Cola induced locomotor activation and rapid NAcc temperature increases, which both transiently decreased during drinking, and phasically increased again after the cup was emptied. Muscle temperatures followed this pattern, but increases were weaker and more delayed than those in the NAcc. Skin temperature rapidly dropped after cup presentation, remained at low levels during consumption, and slowly restored during post-consumption behavioral activation. By itself, DA receptor blockade induced robust decrease in spontaneous locomotion, moderate increases in brain and muscle temperatures, and a relative increase in skin temperatures, suggesting metabolic activation coupled with adynamia. Following this treatment (approximately 180 min), motor activation to cup presentation and Coca-Cola consumption were absent, but rats showed NAcc and muscle temperature increases following cup presentation comparable to control. Therefore, DA receptor blockade does not affect significantly central and peripheral autonomic responses to appetitive stimuli, but eliminates their behavior-activating effects, thus disrupting appetitive behavior and blocking consumption. Naloxone alone slightly decreased brain and muscle temperatures and increased skin temperatures, pointing at the enhanced heat loss and possible minor inhibition of basal metabolic activity. This treatment (approximately 60 min) had minimal effects on the latencies of drinking, but increased its total duration, with licking interrupted by pauses and retreats. This behavioral attenuation was coupled with weaker than in control locomotor activation and diminished temperature fluctuations in each recording location. Therefore, attenuation of normal behavioral and physiological responses to appetitive stimuli appears to underlie modest inhibiting effects of opiate receptor blockade on motivated behavior and consumption. PMID- 20167258 TI - Neuroprotection by caffeine: time course and role of its metabolites in the MPTP model of Parkinson's disease. AB - Epidemiological studies have raised the possibility of caffeine serving as a neuroprotective agent in Parkinson's disease (PD). This possibility has gained support from findings that dopaminergic neuron toxicity induced by 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) or other neurotoxins is attenuated by co administration of caffeine in mice. Here we examined the time window of caffeine's neuroprotection as well as the effects of caffeine's metabolites (theophylline and paraxanthine) in the MPTP mouse model of PD. In the first experiment, caffeine pre-treatment (30 mg/kg ip) significantly attenuated MPTP induced striatal dopamine depletion when it was given 10 min, 30 min, 1 h, or 2 h but not 6 h before MPTP (40 mg/kg ip) treatment. Meanwhile, caffeine post treatment also significantly attenuated striatal dopamine loss when it was given 10 min, 30 min, 1 h or 2 h but not 4 h, 8 h or 24 h after MPTP injection. In the second experiment, both theophylline (10 or 20 mg/kg) and paraxanthine (10 or 30 mg/kg) administration (10 min before MPTP) significantly attenuated MPTP-induced dopamine depletion in mice, as did caffeine (10 mg/kg) treatment. Thus the metabolites of caffeine also provide neuroprotective effects in this mouse model of PD. The data suggest that if caffeine protects against putative toxin-induced dopaminergic neuron injury in humans, then precise temporal pairing between caffeine and toxin exposures may not be critical because the duration of neuroprotection by caffeine may be extended by protective effects of its major metabolites. PMID- 20167259 TI - Rapid, transient effects of the protein kinase C activator phorbol 12-myristate 13-acetate on activity and trafficking of the rat high-affinity choline transporter. AB - Cholinergic neurons rely on the sodium-dependent choline transporter CHT to provide choline for synthesis of acetylcholine. CHT cycles between cell surface and subcellular organelles, but little is known about regulation of this trafficking. We hypothesized that activation of protein kinase C with phorbol ester modulates choline uptake by altering the rate of CHT internalization from or delivery to the plasma membrane. Using SH-SY5Y cells that stably express rat CHT, we found that exposure of cells to phorbol ester for 2 or 5 min significantly increased choline uptake, whereas longer treatment had no effect. Kinetic analysis revealed that 5 min phorbol ester treatment significantly enhanced V(max) of choline uptake, but had no effect on K(m) for solute binding. Cell-surface biotinylation assays showed that plasma membrane levels of CHT protein were enhanced following 5 min phorbol ester treatment; this was blocked by protein kinase C inhibitor bisindolylmaleimide-I. Moreover, CHT internalization was decreased and delivery of CHT to plasma membrane was increased by phorbol ester. Our results suggest that treatment of neural cells with the protein kinase C activator phorbol ester rapidly and transiently increases cell surface CHT levels and this corresponds with enhanced choline uptake activity which may play an important role in replenishing acetylcholine stores following its release by depolarization. PMID- 20167260 TI - The brain mapping of the retrieval of conditioned taste aversion memory using manganese-enhanced magnetic resonance imaging in rats. AB - Manganese-enhanced MRI (MEMRI) is a newly developed noninvasive imaging technique of brain activities. The signal intensity of MEMRI reflects cumulative activities of the neurons. To validate the use of MEMRI technique to investigate the neural mechanisms of learning and memory, we tried to map brain areas involved in the retrieval of conditioned taste aversion (CTA) memory. CTAs were established to saccharin (conditioned stimulus: CS) by pairing its ingestion with an i.p. injection of LiCl (unconditioned stimulus: US). LiCl solutions (as a robust aversion chemical) of 0.15 M were injected i.p. 15 min after drinking the saccharine solution (CS). After the two times conditionings, these rats showed a robust aversion to the saccharine solution (CS). Rats of the control group were injected saline i.p. instead of LiCl solutions. The MRI signal intensities at the gustatory cortex (GC), the core subregion of the nucleus accumbens (NAcC), the shell subregion of the nucleus accumbens (NAcSh), the ventral pallidum (VP), the central nucleus of amygdala (CeA), the lateral hypothalamus (LH), and the basolateral nucleus of amygdala (BLA) of the conditioned group were higher than those of the control group. There were no significant differences between the conditioned and the control groups in the intensities for other regions, such as the striatum area, motor cortex, cingulate cortex, interstitial nucleus of the posterior limb of the anterior commissure and hippocampus. These indicate that the GC, NAcC, NAcSh, VP, CeA, LH and BLA have important roles in the memory retrieval of CTA. PMID- 20167262 TI - Facilitation of endocannabinoid effects in the ventral hippocampus modulates anxiety-like behaviors depending on previous stress experience. AB - Although several pieces of evidence indicate that the endocannabinoid system modulates anxiety-like behaviors and stress adaptation, few studies have investigated the brain sites of these effects. The ventral hippocampus (VHC) has been related to anxiety behaviors and has a high expression of cannabinoid-1 (CB1) receptors. Moreover, endocannabinoid signaling in the hippocampus is proposed to regulate stress adaptation. In the present study we investigated the role of previous stressful experience on the effects of AM404, an anandamide uptake inhibitor, microinjected into the VHC of rats submitted to the elevated plus maze (EPM), a widely used animal model of anxiety. Stressed animals were forced restrained for two h 24 h before the test. AM404 (5-50 pmol) microinjection promoted an anxiogenic-like effect in non-stressed rats but decreased anxiety in stressed animals. AM251 (0.01 to 1000 pmol), a CB1 receptor antagonist, failed to change behavior in the EPM over a wide dose range but prevented the effects of AM404. Anxiolytic-like effects of AM404 (5 pmol) intra VHC injection were also observed in the Vogel conflict test (VCT), another model of anxiety that involves previous exposure to stressful situations (48 h of water deprivation). These results suggest that facilitation of endocannabinoid system neurotransmission in the ventral hippocampus modulates anxiety-like behaviors and that this effect depends on previous stress experience. PMID- 20167261 TI - Diverse antiepileptic drugs increase the ratio of background synaptic inhibition to excitation and decrease neuronal excitability in neurones of the rat entorhinal cortex in vitro. AB - Although most anti-epileptic drugs are considered to have a primary molecular target, it is clear that their actions are unlikely to be limited to effects on a single aspect of inhibitory synaptic transmission, excitatory transmission or voltage-gated ion channels. Systemically administered drugs can obviously simultaneously access all possible targets, so we have attempted to determine the overall effect of diverse agents on the balance between GABAergic inhibition, glutamatergic excitation and cellular excitability in neurones of the rat entorhinal cortex in vitro. We used an approach developed for estimating global background synaptic excitation and inhibition from fluctuations in membrane potential obtained by intracellular recordings. We have previously validated this approach in entorhinal cortical neurones [Greenhill and Jones (2007a) Neuroscience 147:884-892]. Using this approach, we found that, despite their differing pharmacology, the drugs tested (phenytoin, lamotrigine, valproate, gabapentin, felbamate, tiagabine) were unified in their ability to increase the ratio of background GABAergic inhibition to glutamatergic excitation. This could occur as a result of decreased excitation concurrent with increased inhibition (phenytoin, lamotrigine, valproate), a decrease in excitation alone (gabapentin, felbamate), or even with a differential increase in both (tiagabine). Additionally, we found that the effects on global synaptic conductances agreed well with whole cell patch recordings of spontaneous glutamate and GABA release (our previous studies and further data presented here). The consistency with which the synaptic inhibition:excitation ratio was increased by the antiepileptic drugs tested was matched by an ability of all drugs to concurrently reduce intrinsic neuronal excitability. Thus, it seems possible that specific molecular targets among antiepileptic drugs are less important than the ability to increase the inhibition:excitation ratio and reduce overall neuronal and network excitability. PMID- 20167263 TI - New insights on the neuropeptide Y system in the larval lamprey brain: neuropeptide Y immunoreactive neurons, descending spinal projections and comparison with tyrosine hydroxylase and GABA immunoreactivities. AB - Lampreys are useful models for studying the evolution of the nervous system of vertebrates. Here we used immunofluorescence and tract-tracing methods to study new aspects of the neuropeptide Y-immunoreactive (NPY-ir) system in larval sea lampreys. NPY-ir neurons were observed in brain nuclei that contain NPY-ir cells in other lamprey species. Moreover, a group of NPY-ir cells that migrated away the periventricular layer was observed in the lateral part of the dorsal hypothalamus, which suggests a role for NPY in feeding behavior in lampreys. We also report NPY-ir cells in the dorsal column nucleus, which appears to be unique among vertebrates, and in the habenula. A combination of tract-tracing and immunohistochemical labeling demonstrated the presence of spinal projecting NPY ir reticular cells in the anterior rhombencephalic reticular formation, and the relationships between the NPY-ir system and the reticulospinal nuclei and some afferent systems. The colocalization of catecholamines and GABA in lamprey NPY-ir neurons was investigated by double immunofluorescence methods. Colocalization of tyrosine hydroxylase (TH) and NPY immunoreactivities was not observed in any brain neuron, although reported in amphibians and mammals. The frequent presence of NPY-ir terminals on TH-ir cells suggests that NPY modulates the activity of some dopaminergic nuclei in lampreys. Colocalization of NPY and GABA immunoreactivities was frequently observed in neurons of different rhombencephalic and diencephalic NPY-ir populations. These results in lampreys suggest that the coexpression of NPY and GABA in neurons appeared early on in the brains of vertebrates. PMID- 20167264 TI - Expression of the kcnk3 potassium channel gene lessens the injury from cerebral ischemia, most likely by a general influence on blood pressure. AB - We examined the possible protective effect of TASK-1 (TWIK-related acid-sensitive potassium channel-1, kcnk3) and -3 potassium channels during stroke. TASK-1 and TASK-3, members of the two pore domain (K2P or kcnk) potassium channel family, form hetero or homodimers and help set the resting membrane potential. We used male TASK-1 and TASK-3 knockout mice in a model of focal cerebral ischemia, permanent middle cerebral artery occlusion (pMCAO). Infarct volume was measured 48 h after pMCAO. The TASK-1 knockout brains had larger infarct volumes (P=0.004), and those in TASK-3 knockouts were unchanged. As the TASK-1 gene is expressed in adrenal gland, heart and possibly blood vessels, the higher infarct volumes in the TASK-1 knockout mice could be due to TASK-1 regulating blood vessel tone and hence blood pressure or influencing blood vessel microarchitecture and blood flow rate. Indeed, we found that male TASK-1 knockout mice had reduced blood pressure, likely explaining the increased brain injury seen after pMCAO. Thus to make precise conclusions about how TASK-1 protects neurons, neural- or organ-specific deletions of the gene will be needed. Nevertheless, a consequence of having TASK-1 channels expressed (in various non neuronal tissues and organs) is that neuronal damage is lessened when stroke occurs. PMID- 20167265 TI - Defects of synaptic vesicle turnover at excitatory and inhibitory synapses in Niemann-Pick C1-deficient neurons. AB - Niemann-Pick disease type C (NPC) is a progressive neurodegenerative disorder characterized by accumulation of free cholesterol in late endosomes/lysosomes. The pathological basis for the disease is poorly understood. In the present study, electrophysiological and fluorescent dye studies were applied to examine neuron-specific functions of Niemann-Pick disease type C1 (NPC1) and to determine whether excitatory and inhibitory synapses are differentially impaired by NPC1 deficiency. Densities of spines and postsynaptic receptor clusters were not affected by NPC1 deficiency over the period examined. However, drastic defects on exocytosis were found both in glutamatergic and GABAergic synapses. The defects were caused in part by a delay in the time required for replacement of excytosed vesicles with new fusion-competent ones. Moreover, we found that the delay of synaptic vesicle turnover was longer in inhibitory synapses (>3 s) than in excitatory synapses (<0.2 s). These defects may be early indicators, and could provide a potential explanation for key features of the disease, such as dystonia and seizures. PMID- 20167266 TI - A cyclic peptide targeted against PSD-95 blocks central sensitization and attenuates thermal hyperalgesia. AB - Post-synaptic density protein PSD-95 is emerging as a valid target for modulating nociception in animal studies. Based on the key role of PSD-95 in neuronal plasticity and the maintenance of pain behavior, we predicted that CN2097, a peptide-based macrocycle of nine residues that binds to the PSD-95 Discs large, Zona occludens 1 (PDZ) domains of PSD-95, would interfere with physiologic phenomena in the spinal cord related to central sensitization. Furthermore, we tested whether spinal intrathecal injection of CN2097 attenuates thermal hyperalgesia in a rat model of sciatic neuropathy. Results demonstrate that spinal CN2097 reverses hyperexcitability of wide dynamic range (WDR) neurons in the dorsal horn of neuropathic rats and decreases their evoked responses to peripheral stimuli (brush, low caliber von Frey and pressure), whereas CN5125 ("negative control") has no effect. CN2097 also blocks C-fiber long-term potentiation (LTP) in the dorsal horn, which is linked to neuronal plasticity and central sensitization. At a molecular level, CN2097 attenuates the increase in phosphorylated p38 MAPK, a key intracellular signaling pathway in neuropathic pain. Moreover, spinal injection of CN2097 blocks thermal hyperalgesia in neuropathic rats. We conclude that CN2097 is a small molecule peptide with putative anti-nociceptive effects that modulates physiologic phenomena related to central sensitization under conditions of chronic pain. PMID- 20167267 TI - Repeat-induced gene silencing of L1 transgenes is correlated with differential promoter methylation. AB - Recent transgenic studies on L1 retrotransposons have afforded exciting insights into L1 biology, and a unique opportunity to model their function and regulation in vivo. Thus far, the majority of the transgenic L1 mouse lines are constructed via pronuclear microinjection, a procedure that typically results in the integration of tandem arrayed transgenes. Transgene arrays are susceptible to repeat-induced gene silencing (RIGS) in both plants and animals. In order to examine the potential impact of RIGS on L1 retrotransposition, we derived a cohort of animals carrying reduced copies of ORFeus transgene at the same genomic locus by Cre-mediated recombination. The copy number reduction of ORFeus transgenes did not decrease the overall retrotransposition activity. Using a sensitive and reproducible quantitative PCR assay, an average frequency of 0.45 insertions per cell was observed for animals carrying the donor transgene at a single copy, representing a 9-fold increase of retrotransposition frequency on a per-copy basis. DNA methylation analyses revealed that the observed retrotransposition activity was correlated with differential CpG methylation at the heterologous promoter: the promoter region was largely methylated in animals with the high-copy array but significantly hypomethylated in animals with the single-copy counterpart. In contrast, the ORF2 region, which represents the body of the ORFeus transgene, and the 3' end of the transgene showed high level of methylation in both high-copy and single-copy samples. The observed methylation patterns were metastable across generations. In summary, our data suggest that tandem arrayed L1 transgenes are subject to RIGS, and transgenes present at a single copy in the genome are thus recommended for modeling L1 in animals. PMID- 20167268 TI - Dynamic pattern of gene expression of ZnT-1, ZnT-3 and PRG-1 in rat brain following flurothyl-induced recurrent neonatal seizures. AB - Zinc transporters (ZnTs) and plasticity-related genes (PRGs) both play the key roles in the formation of hippocampal mossy fiber sprouting, which is associated with cognitive deficits following developmental seizures. Here, for the first time, we report the timing of expression pattern of ZnT-1, ZnT-3 and PRG-1 in hippocampus and cerebral cortex following developmental seizures. A seizure was induced by inhalant flurothyl daily in neonatal Sprague-Dawley rats from postnatal day 6 (P6). Rats were assigned into the recurrent-seizure group (RS, seizures induced in 6 consecutive days) and the control group. At 1.5 h, 3 h, 6 h, 12 h, 24 h, 48 h, 7 d and 14 d after the last seizures, the mRNA level was detected using RT-PCR method; PRG-1 protein level was examined by Western blotting analysis. At an early period of 12 h and 48 h after the last seizures, both ZnT-1 and ZnT-3 showed significantly down-regulated mRNA level in the cerebral cortex of RS group than those at the corresponding time point in control group. In the long-term time point of 14 d after the last seizure, ZnT-3 mRNA and PRG-1 protein level in hippocampus were up-regulated while the mRNA level of ZnT 1 down-regulated; in addition, there were up-regulated level of both the mRNA and protein level of PRG-1 and down-regulated mRNA level of ZnT-3 in the cerebral cortex of RS group when compared to the control. Taken together, these dates are consistent with an important role for ZnT-1, ZnT-3 and PRG-1 in the pathophysiology of the long-term adverse effects of recurrent neonatal seizure induced hippocampal mossy fiber sprouting and cognitive deficit. PMID- 20167269 TI - The FMCA-GM assays, high throughput non-clonogenic alternatives to CFU-GM in preclinical hematotoxicity testing. AB - One of the most common dose limiting adverse effects in cancer treatment is myelotoxicity. The aim of this study was to develop an in vitro method for measuring potential myelotoxic properties of a drug candidate in a high throughput setting. Human CD34(+) progenitor cells from umbilical cord blood were plated in 384-well microplates with drugs in liquid culture, supplemented with specific cytokines for the granulocytopoietic-macrophage lineage. After 7 or 14 days of proliferation and differentiation the cells were analyzed using the automated non-clonogenic fluorometric microculture cytotoxicity assay (FMCA). Two types of assays setups were evaluated, the FMCA-GM7 where cells were exposed to drugs directly after thawing and cytotoxicity measured on day 7 in contrast to the FMCA-GM14 where the cells were cultured 7 days prior to plating and drug exposure, with viability analysis on day 14 of differentiation. Drug sensitivity was similar in both assays and method validation was performed using 24 drugs with known myelotoxic profile (acyclovir, bortezomib, busulfan, carboplatin, chloramphenicol, chlorpromazine, cisplatin, cytarabine, clozapine, doxorubicin, erlotinib, etoposide, 5-fluorouracil, fludarabine, gefitinib, gemcitabine, hydroxyurea, imatinib, lomustine, melphalan, sorafenib, sunitinib, taxol and 6 thioguanine). The 50% inhibitory concentrations (IC(50)) from the FMCA-GM7 and the FMCA-GM14 correlated highly (r = 0.83) and (r = 0.82), respectively, with IC(50) from the established clonogenic assay (CFU-GM), obtained from the literature. The current data suggests that the FMCA-GM could offer a simple and robust alternative to the CFU-GM assay in preclinical hematotoxicity studies. PMID- 20167270 TI - Understanding the structure and stability of paclitaxel nanocrystals. AB - Previously, PTX/Pluronic F127 nanocrystals were prepared in our laboratory using the stabilization of nanocrystals (SNC) method. For PTX nanocrystals, dosages could be increased to yield improved antitumor activity over Taxol without incidence of acute toxicity. The objectives of this current study are to further understand the structure and stability of PTX nanocrystals. More Pluronic F127 surfactant was added in the formulation to attempt to further stabilize the nanocrystals against thermal induced aggregation. However, this resulted in formation of micelles that worsened the stability of nanocrystals. The F127 desorption experiment suggested different surfactant adsorption affinity to nanocrystal surface below and above the CMC. Below the CMC monomers bound to nanocrystal surface with high affinity, but above the CMC low affinity surfactant aggregates readily left the surface upon dilution. At higher temperature the tendency of F127 micellization is enhanced due to drastically lower CMC. Consequently, at 37 degrees C there was F127 desorption even for nanocrystals prepared with low amounts of F127 (1:5 (w/w) PTX/F127). To improve the stability of nanocrystals, re-nanonization by incubation-sonication procedure was used to disrupt the preferred crystal growth pattern of PTX. Furthermore, we have demonstrated that a higher heating temperature (45 degrees C vs. 37 degrees C) used in the incubation-sonication procedure was able to provide even better nanocrystal stability for long periods of incubation time. PMID- 20167272 TI - Marinobufagenin, resibufogenin and preeclampsia. AB - The bufodienolides are cardiac glycosides which have the ability to inhibit the enzyme, Na(+)/K(+) ATPase (sodium potassium adenosine triphosphatase). They are cardiac inotropes, cause vasoconstriction (and, potentially, hypertension) and are natriuretic. Evidence has accrued over time which supports the view that they are mechanistically involved in volume expansion-mediated hypertension. In this communication, the authors summarize data which support the view that the bufodienolides and, in particular, marinobufagenin (MBG) are involved in the pathogenesis of preeclampsia. In a rat model of the syndrome, MBG causes hypertension, proteinuria, intrauterine growth restriction and increased weight gain. All of these phenotypic characteristics are prevented by an antagonist to MBG, resibufogenin (RBG). The "preeclamptic" animals also develop a vascular leak syndrome, resulting in hemoconcentration. Abnormalities in the MAPK (mitogen activated protein kinase) system play a role in the mechanism by which MBG produces the abnormalities in the pregnant rat. Studies to discover the relevance of these findings to human preeclampsia are currently underway in several laboratories and clinics. PMID- 20167271 TI - Psychological stress, telomeres, and telomerase. PMID- 20167273 TI - Fluorescence tools to measure helicase activity in real time. AB - Methods are described to show how different fluorescent labeling strategies can be used to probe various aspects of the helicase mechanism. Fluorophores on the adenine nucleotide, the DNA or the helicase can modify the activity of the system to a greater or lesser extent. Reagentless biosensors, binding proteins that are labeled with a fluorophore, target products of the helicase reaction, namely ADP, inorganic phosphate or single-stranded DNA, and can be used to measure rates of product formation with little interference to the system. Protocols are described to examine ATP usage and translocation speeds and also to investigate details of the ATP hydrolysis cycle. The methods are described in terms of PcrA, a bacterial DNA helicase that moves in single base steps along either single-stranded or double-stranded DNA, hydrolyzing one ATP per base moved. PMID- 20167274 TI - Ensemble and single-molecule fluorescence-based assays to monitor DNA binding, translocation, and unwinding by iron-sulfur cluster containing helicases. AB - Many quantitative approaches for analysis of helicase-nucleic acid interactions require a robust and specific signal, which reports on the presence of the helicase and its position on a nucleic acid lattice. Since 2006, iron-sulfur (FeS) clusters have been found in a number of helicases. They serve as endogenous quenchers of Cy3 and Cy5 fluorescence which can be exploited to characterize FeS cluster containing helicases both in ensemble-based assays and at the single molecule level. Synthetic oligonucleotides site-specifically labeled with either Cy3 or Cy5 can be used to create a variety of DNA substrates that can be used to characterized DNA binding, as well as helicase translocation and unwinding. Equilibrium binding affinities for ssDNA, duplex and branched DNA substrates can be determined using bulk assays. Identification of preferred cognate substrates, and the orientation and position of the helicase when bound to DNA can also be determined by taking advantage of the intrinsic quencher in the helicase. At the single-molecule level, real-time observation of the helicase translocating along DNA either towards the dye or away from the dye can be used to determine the rate of translocation by the helicase on ssDNA and its orientation when bound to DNA. The use of duplex substrates can reveal the rate of unwinding and processivity of the helicase. Finally, the FeS cluster can be used to visualize protein-protein interactions, and to examine the interplay between helicases and other DNA binding proteins on the same DNA substrate. PMID- 20167275 TI - Analyzing the branch migration activities of eukaryotic proteins. AB - The Holliday junction is a key intermediate of DNA repair, recombination, and replication. Branch migration of Holliday junctions is a process in which one DNA strand is progressively exchanged for another. Branch migration of Holliday junctions may serve several important functions such as affecting the length of genetic information transferred between homologous chromosomes during meiosis, restarting stalled replication forks, and ensuring the faithful repair of double strand DNA breaks by homologous recombination. Several proteins that promote branch migration of Holliday junctions have been recently identified. These proteins, which function during DNA replication and repair, possess the ability to bind Holliday junctions and other branched DNA structures and drive their branch migration by translocating along DNA in an ATPase-dependent manner. Here, we describe methods employing a wide range of DNA substrates for studying proteins that catalyze branch migration of Holliday junctions. PMID- 20167276 TI - Mesmerising mirror neurons. AB - Mirror neurons have been hailed as the key to understanding social cognition. I argue that three currents of thought-relating to evolution, atomism and telepathy have magnified the perceived importance of mirror neurons. When they are understood to be a product of associative learning, rather than an adaptation for social cognition, mirror neurons are no longer mesmerising, but they continue to raise important questions about both the psychology of science and the neural bases of social cognition. PMID- 20167277 TI - Preparing for growth: current capacity and challenges in hematopoietic stem cell transplantation programs. AB - During the past decade, the demand for hematopoietic stem cell transplantation has grown dramatically, and there are expectations that this will continue or even accelerate over the next decade. This prompts a variety of questions about the ability of the health care system to accommodate the increased demands on transplantation centers; for example, what is the current patient capacity of transplantation programs, and how much elasticity do they have to accept a larger volume of patients? An informal survey of a sample of medical directors of transplantation programs found that existing facilities might be able to increase their patient volume by about 7%. Expanding much beyond that limit will require an infusion of resources to enlarge current programs and/or establish new programs. PMID- 20167279 TI - Protective immunity transferred by infusion of cytomegalovirus-specific CD8(+) T cells within donor grafts: its associations with cytomegalovirus reactivation following unmanipulated allogeneic hematopoietic stem cell transplantation. AB - Human cytomegalovirus (CMV)-specific cytotoxic T lymphocyte (CTL) immune response must be reconstituted for long-term protection against CMV relapse and disease in hematopoietic stem cell transplantation (HSCT) recipients. We phenotypically quantitated absolute numbers of CMV-pp65 peptide-specific CTLs (CTL(CMV)) in 50 related donor unmanipulated allografts infused into HLA-matched or -mismatched recipients and examined the incidence of CMV reactivation. High CTL(CMV) with terminally differentiated effector CD45RO(-)CD62L(-) cell (T(EMRA)) phenotype in the allografts were associated with reduced risk of CMV reactivation, in the presence of sufficient CD45RO(+)CD62L(-) cell (T(EM)) infusion (>/=0.208 x 10(6)/kg). Early after transplantation, there was significant expansion of CTL(CMV) with the central memory CD45RO(+)CD62L(+) cell (T(CM)) phenotype when CMV was reactivated. The frequencies of CTL(CMV) T(Naive) (CD45RO(-)CD62L(+)), T(CM), and T(EM) at day 90 posttransplantation and of CTL(CMV) T(EMRA) at day 60 posttransplantation were greater in recipients with higher infusions of CTL(CMV) T(EMRA), suggesting protective immunity transferred by infusion of CTL(CMV) within allografts. Moreover, the majority of the CTL(CMV) identified in the recipients early after HSCT was of donor origin. Our findings support that measuring levels of CTL(CMV) and its subsets in the donor grafts and manipulating these cells early after transplantation may help control CMV reactivation, which is closely correlated with immune reconstitution and differentiation of CTL(CMV) subsets. PMID- 20167280 TI - Endothelial dysfunction after hematopoietic stem cell transplantation: role of the conditioning regimen and the type of transplantation. AB - There is endothelial activation and damage in hematopoietic stem cell transplantation (HSCT). The impact of the conditioning and type of HSCT on endothelial dysfunction in the early phases of HSCT has been evaluated. Plasma samples were obtained before and at different times after autologous and allogeneic HSCT with and without early complications. Changes in soluble markers of endothelial damage (VWF, ADAMTS-13, sVCAM-1, sICAM-1, and sTNFRI) were measured. There were changes in all markers evaluated that followed different patterns in auto and allo settings. For VWF and sTNRI, progressive increases from day Pre to day 14 and to day 21 were observed in the auto and the allo group, respectively. ADAMTS-13 activity correlated inversely with VWF levels. Levels of sVCAM-1 decreased until day 7, and raised significantly to day 14 and to day 21 in the auto and the allo HSCT, respectively. No significant changes were detected for sICAM-1. Our results confirm that there is endothelial damage at the early phases of HSCT, apparently induced by the consecutive effects of the conditioning, the proinflammatory agents used during transplantation, the translocation of endotoxins across the damaged gastrointestinal tract, and the engraftment. However, the comparative analysis between patients with and without complications suggests that none of these markers has diagnostic or prognostic value. PMID- 20167278 TI - Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial. AB - Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for > or =14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day +100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day +100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD. PMID- 20167281 TI - Immunochemical and molecular characterization of a novel cell line derived from the brain of Trachinotus blochii (Teleostei, Perciformes): A fish cell line with oligodendrocyte progenitor cell and tanycyte characteristics. AB - Ependymal radial glial cells, also called tanycytes, are the predominant glial fibrillary acidic protein (GFAP)- and vimentin (VIM)-expressing cells in fish ependyma. Radial glial cells have been proposed to be neural stem cells but their molecular expression is not well understood. Previous studies revealed that fish neural progenitor and neural stem cells have A2B5, a marker for oligodendrocyte progenitor cells (OPCs). In this study, an A2B5(+) cell line, SPB, was isolated from the brain of the teleost Trachinotus blochii and characterized. SPB cells usually grew as polygonal epithelial cells, but at high density, long processes were commonly observed. Using immunocytochemistry, SPB cells were shown to exhibit oligodendrocyte markers such as galactocerebroside and Olig2, and radial glial cell markers such as brain lipid-binding protein, GFAP, Sox2, and VIM. SPB cells were also observed to have DARPP-32, a marker for tanycytes in mammals, and primary cilia. RT-PCR additionally revealed expression of bone morphogenetic protein 4, connexin35, Noggin2, and proteolipid protein in SPB cells. Results of this study suggest that SPB cells are OPCs that can display tanycyte characteristics. Fish tanycytes can be neural stem cells suggesting that SPB cells are neural stem cells. SPB is the first fish cell line showing primary cilia and markers for both OPCs and tanycytes. PMID- 20167282 TI - Perspective--Exercise in fish: 50+years and going strong. AB - Swimming in fish has garnered the attention of researchers for more than 50years. Research has focused on the mechanisms that fish utilize during exercise, fuel use patterns, recovery dynamics and the effects of abiotic and biotic factors on fish exercise physiology. Research direction has been influenced both by technology (e.g., availability of telemetry devices and access to swim flumes) and environmental changes (e.g., global warming and pollution). In addition, researchers have begun to examine the interplay between swimming physiology and behaviour. As part of the 50th Anniversary of Comparative Physiology and Biochemistry, this perspective examines the history of fish exercise research, and some of the individuals who have made significant contributions. PMID- 20167283 TI - Respiratory and cutaneous water loss of temperate-zone passerine birds. AB - We measured respiratory water loss (RWL) and cutaneous water loss (CWL) of 12 species of passerine birds, all from a temperate environment, and related their CWL to classes of lipids within the stratum corneum (SC). We purposed to gain insight into the generality of patterns of CWL in birds that have been generated mostly from studies on species from deserts, and we addressed the hypothesis that CWL is a passive diffusion process. Despite taxonomic and ecological differences among 12 species of temperate birds, mass-specific RWL and surface-specific CWL were statistically indistinguishable across species. When the birds were dead, CWL was reduced by 16.3% suggesting that CWL is, in part, under physiological control. We found that ceramides, cerebrosides, dioscylceramides, cholesterol, cholesterol sulfate, fatty acid methyl esters, free fatty acid, sterol esters, and triacylglycerol constituted the intercellular lipids of the avian SC. CWL was positively associated with amount of ceramide 3, but this lipid class represented less than 2% of the total SC lipids. Combining direct measurements (n=24) of RWL with indirect estimates (n=25) yielded the equation log RWL (g H(2)O/d)= 0.86+0.73 (log body mass, g). PMID- 20167284 TI - Effect of seawater transfer on CYP1A gene expression in rainbow trout gills. AB - During the transfer of rainbow trout from freshwater to seawater, the gills have to switch from an ion-absorption epithelium to an ion-secretion epithelium in order to maintain equilibrium of their hydromineral balance. After a change to ambient salinity, several gill modifications have already been demonstrated, including ion transporters. In order to identify new branchial mechanisms implicated in seawater acclimation, we carried out an extensive analysis of gene expression in gills using microarray technology. This strategy allowed us to show that CYP1A gene expression was up-regulated in the gills after salinity transfer. This increase was confirmed by real-time reverse transcription PCR. Furthermore, measurements of CYP1A enzyme activity (EROD) showed a significant increase after transfer to seawater. Immunohistochemistry analysis in the gills revealed that cells with a higher expression of CYP1A protein were principally pillar cells and those in the primary lamellae not in contact with the external medium. The results of this study suggest for the first time that CYP1A may be implicated in the seawater acclimation of the gills of rainbow trout. PMID- 20167285 TI - Temperature influence on post-prandial metabolic rate of sub-Antarctic teleost fish. AB - The influence of temperature on the aerobic metabolism and the energetic cost of food intake (Specific Dynamic Action; SDA) have been investigated in four species of Sub-Antarctic teleosts. The species were the notothenioids Paranotothenia magellanica, Patagonotothen sima and Harpagifer bispinis and the zoarcid Austrolycus depressiceps. Individuals were captured in the vicinity of Ushuaia Bay. Experimental temperatures were 10, 4 and 2 degrees C, which correspond to summer, winter and extreme winter respectively. Individual respirometry chambers and calorimetric techniques were used. Different food items were provided: crustaceans (isopods and amphipods) and Argentinean hake muscle. Interspecific analysis was done on species fed with isopods. A rapid increase in oxygen consumption was registered after meals, indicating a typical SDA response. The Duration of the SDA was longer at low temperatures. The extra energy spent during the process itself, and when expressed as a percentage of consumed food energy, decreased with decreasing temperature. The SDA Coefficient was higher for H. bispinis that were fed with isopods. We suggest that decreases in temperature diminish the metabolic cost and extend SDA. Energy-saving mechanisms could be an evolutionary advantage to minimize the energetic cost of living at low sub Antarctic temperatures. A general model of exponential decay is suggested for the duration of SDA and Temperature, based on the present study and compiled from literature data. PMID- 20167286 TI - Molecular cloning, characterization and mRNA expression of two antibacterial peptides: crustin and anti-lipopolysaccharide factor in swimming crab Portunus trituberculatus. AB - In this study, the cDNAs of a crustin and an anti-lipopolysaccharide factor (ALF) were cloned from the hemocytes of swimming crab Portunus trituberculatus using rapid amplification of cDNA ends (RACE) approaches. The full-length cDNA of P. trituberculatus crustin (denoted as PtCrustin) was of 584 bp, including an open reading frame (ORF) of 333 bp encoding a 21 amino acids signal peptide and a mature polypeptide of 89 amino acids with the predicted molecular mass of 10.08 kDa. The typical conserved cysteine residues containing WAP domain at the C terminal displayed high similarity to other crustins. Moreover, the full-length cDNA of P. trituberculatus ALF (denoted as PtALF) was of 1050 bp, including an ORF of 372 bp encoding a 26 amino acids signal peptide and a mature polypeptide of 97 amino acids with the predicted molecular mass of 11.35 kDa. PtALF contained two conserved cysteine residues and showed high similarity to other crab ALFs. Using fluorescent real-time quantitative PCR, PtCrustin mRNA was expressed at the highest level in hemocytes and higher level in stomach while extremely low in hepatopancreas, muscle, gill and heart. In contrast, the PtALF mRNA expression was observed in all tissues. The relative expression levels of PtCrustin and PtALF in hemocytes of P. trituberculatus showed a clear time-dependent response after challenge with Vibrio alginolyticus. These results indicate that PtCrustin and PtALF are two acute-phase proteins involved in the immune responses of P. trituberculatus. PMID- 20167287 TI - Biogenic amines modulate pulse rate in the dorsal blood vessel of Lumbriculus variegatus. AB - The biogenic amines are widespread regulators of physiological processes, and play an important role in regulating heart rate in diverse organisms. Here, we present the first pharmacological evidence for a role of the biogenic amines in the regulation of dorsal blood vessel pulse rate in an aquatic oligochaete, Lumbriculus variegatus (Muller, 1774). Bath application of octopamine to intact worms resulted in an acceleration of pulse rate, but not when co-applied with the adenylyl cyclase inhibitor MDL-12,330a. The phosphodiesterase inhibitor theophylline mimicked the effects of OA, but the polar adenosine receptor antagonist 8(p-sulphophenyl)theophylline was significantly less potent than theophylline. Pharmacologically blocking synaptic reuptake of the biogenic amines using the selective 5-HT reuptake blocker fluoxetine or various tricyclic antidepressants also accelerated heart rate. Depletion of the biogenic amines by treatment with the monoamine vesicular transporter blocker reserpine dramatically depressed pulse rate. Pulse rate was partially restored in amine-depleted worms after treatment with octopamine or dopamine, but fully restored following treatment with serotonin. This effect of 5-HT was weakly mimicked by 5 methoxytryptamine, but not by alpha-methylserotonin; it was completely blocked by clozapine and partially blocked by cyproheptadine. Because they are known to orchestrate a variety of adaptive behaviors in invertebrates, the biogenic amines may coordinate blood flow with behavioral state in L.variegatus. PMID- 20167288 TI - Aluminum as an endocrine disruptor in female Nile tilapia (Oreochromis niloticus). AB - The effects of aluminum on plasma ion, lipid, protein and steroid hormone concentration were evaluated in Oreochromis niloticus broodstock females. Lipid and protein concentrations from the gonads and liver were also measured. Experiments were performed at neutral and acidic water pH. Four groups of fish were tested for 96h: 1) control conditions at neutral water pH; 2) control conditions at acidic water pH (CTR-Ac); 3) aluminum at neutral water pH (Al-N); and 4) aluminum at acidic water pH (Al-Ac). Aluminum and acidic water pH exposure caused no ionoregulatory disturbances. Total lipid concentration increased in the mature gonads and decreased in the liver, suggesting an acceleration of lipid mobilization to the ovaries in animals exposed to aluminum. However, a decreased protein concentration in ovaries was also observed. Exposure of control fish to acidic water pH caused an increased concentration of plasma 17alpha hydroxyprogesterone. However, females exposed to aluminum at acidic water pH showed a decreased of plasma 17alpha-hydroxyprogesterone and cortisol. No differences in plasma 17beta-estradiol were observed. The physiological mechanisms underlying the disturbances observed are discussed focusing on reproduction. We suggest that aluminum can be considered an endocrine disrupting compound in mature O. niloticus females. PMID- 20167289 TI - Safety and efficacy of a new magnetic resonance imaging-compatible pacing system: early results of a prospective comparison with conventional dual-chamber implant outcomes. AB - BACKGROUND: A new pacing system has been designed and tested preclinically for safe use in the magnetic resonance imaging (MRI) environment. Experience with this innovative system has not yet been reported. OBJECTIVE: The purpose of this study was to verify the safety and effectiveness of this newly designed system compared to conventional DDD implant outcomes. METHODS: Over an 11-month period, 107 consecutive patients (71 men and 36 women; age 72.6 +/- 8.5 years) were implanted with either the MRI system (n = 50; MRI group) or a dual-chamber, active-fixation lead (Medtronic 4076) non-MRI system (n = 57; DDD group). Data were collected at implant and during postoperative follow-up at 1, 3, 6, and 12 months. Procedural and fluoroscopic times at implant, as well as lead measurements, handling characteristics, and procedural-related complications, were prospectively analyzed. RESULTS: The implantation success rate in both groups was 100%. Cephalic access was 63% for MRI patients and 70% for DDD patients (P = NS). Follow-up was obtained for all patients (median 6.8 months, range 3-12 months). At implant and at the end of follow-up, stimulation thresholds, sensing, and impedance were acceptable. No cases of high pacing thresholds or inadequate sensing were noted. No complications occurred, and no patient experienced subsequent lead displacement. CONCLUSION: This prospective, controlled study provides strong evidence that the feasibility and safety of this novel technology compare favorably with those of the conventional technique. PMID- 20167290 TI - Mortality and safety of catheter ablation for antiarrhythmic drug-refractory ventricular tachycardia in elderly patients with coronary artery disease. AB - BACKGROUND: As the population ages, recurrent ventricular tachycardia (VT) is increasingly encountered in elderly patients with ischemic heart disease. Radiofrequency catheter ablation is useful for reducing VT therapy in patients with an implantable defibrillator. The utility of radiofrequency catheter ablation in the elderly is not well defined. OBJECTIVE: The purpose of this study was to evaluate the prognosis and safety of radiofrequency catheter ablation of postinfarct VT in elderly patients. METHODS: Radiofrequency catheter ablation was performed in 285 consecutive patients with recurrent postinfarct VT refractory to antiarrhythmic drugs. Mortality and outcomes were compared for an elderly group (age >or=75 years, n = 72) and a younger group (age <75 years, n = 213). RESULTS: The groups were similar with regard to baseline characteristics, except for a greater number of females in the elderly group (20.8% vs 10.8%, P = .03). Inducible VTs were abolished or modified in 79.2% of the elderly group and 87.8% of the younger group (P = .12). Major complications occurred in 5.6% of elderly patients and 2.3% of younger patients (P = .48). Periprocedural mortality was similar between both groups (2/72 in elderly and 9/213 in younger group, P = .74). During mean follow-up of 42 +/- 33 months, 50.0% of the elderly group and 35.2% of the younger group died (P = .08). No VT was observed in 63.9% of the elderly patients and 60.1% of the younger patients, respectively (mean follow-up 18 +/- 24 months, P = .80). CONCLUSION: Outcomes of catheter ablation are similar for selected elderly and younger patients. Advanced age should not preclude ablation when recurrent VT is adversely affecting quality of life in elderly patients who otherwise have a reasonable expectation for survival. PMID- 20167291 TI - Patterned transgene expression in multiple-channel bridges after spinal cord injury. AB - Patterning of gene delivery on sub-millimeter length scales within tissue engineering scaffolds is fundamental to recreating the complex architectures of tissues. Surface-mediated delivery of lipoplexes mixed with fibronectin was investigated to pattern vectors within 250 microm channels in poly(lactide-co glycolide) (PLG) bridges. Initial studies performed in vitro on PLG surfaces indicated that a DNA density of 0.07 microg mm(-2) inside each channel with a weight ratio of DNA to fibronectin of 1:20 maximized the number of transfected cells and the levels of transgene expression. Patterned vectors encoding for nerve growth factor (NGF) resulted in localized neurite extension within the channel. Translation to three-dimensional multiple-channel bridges enabled patterned transfection of different vectors throughout the channels for DNA:fibronectin ratios of 1:4 and multiple DNA depositions, with a large increase of neural cell bodies and neurite extension for delivery of DNA encoding for NGF. In vivo, the immobilization of non-viral vectors within the channels resulted in localized transfection within the pore structure of the bridge immediately around the channels of the bridge containing DNA. This surface immobilization strategy enables patterned gene delivery in vitro and in vivo on length scales of hundreds of microns and may find utility in strategies aimed at regenerating tissues with complex architectures. PMID- 20167292 TI - Varying the diameter of aligned electrospun fibers alters neurite outgrowth and Schwann cell migration. AB - Aligned, electrospun fibers have shown great promise in facilitating directed neurite outgrowth within cell and animal models. While electrospun fiber diameter does influence cellular behavior, it is not known how aligned, electrospun fiber scaffolds of differing diameter influence neurite outgrowth and Schwann cell (SC) migration. Thus, the goal of this study was to first create highly aligned, electrospun fiber scaffolds of varying diameter and then assess neurite and SC behavior from dorsal root ganglia (DRG) explants. Three groups of highly aligned, electrospun poly-l-lactic acid (PLLA) fibers were created (1325+383 nm, large diameter fibers; 759+179 nm, intermediate diameter fibers; and 293+65 nm, small diameter fibers). Embryonic stage nine (E9) chick DRG were cultured on fiber substrates for 5 days and then the explants were stained against neurofilament and S100. DAPI stain was used to assess SC migration. Neurite length and SC migration distance were determined. In general, the direction of neurite extension and SC migration were guided along the aligned fibers. On the small diameter fiber substrate, the neurite length was 42% and 36% shorter than those on the intermediate and large fiber substrates, respectively. Interestingly, SC migration did not correlate with that of neurite extension in all situations. SCs migrated equivalently with extending neurites in both the small and large diameter scaffolds, but lagged behind neurites on the intermediate diameter scaffolds. Thus, in some situations, topography alone is sufficient to guide neurites without the leading support of SCs. Scanning electron microscopy images show that neurites cover the fibers and do not reside exclusively between fibers. Further, at the interface between fibers and neurites, filopodial extensions grab and attach to nearby fibers as they extend down the fiber substrate. Overall, the results and observations suggest that fiber diameter is an important parameter to consider when constructing aligned, electrospun fibers for nerve regeneration applications. PMID- 20167293 TI - Crystal templating dendritic pore networks and fibrillar microstructure into hydrogels. AB - Native tissues contain space-filling dendritic pore networks, such as vasculature, for the efficient distribution of oxygen and nutrients; however, it is not yet possible to create tissue-engineered scaffolds with dendritic porosity. Fibers are also important structural features of native tissues because they provide sites for cell anchorage, promote cell guidance and contribute to mechanical stability. Here, we have developed a "crystal templating" technique, which is simple and inexpensive, for fabricating polymer scaffolds with space filling dendritic pore networks and fibrillar microtopography. To do this, we grow dendritic urea crystals in solution cast films of hyaluronic acid (HA), photocrosslink the HA around the crystal network to lock in the dendritic configuration, and dissolve the crystals to obtain empty pores. During in situ crystal growth the HA biopolymer is phase separated from the long narrow urea crystals and shaped into a fibrillar microstructure. The porous fibrillar HA scaffolds created by crystal templating may be applicable as regenerative patches for skin and other tissues. PMID- 20167294 TI - Hydroxyapatite nanorods/poly(vinyl pyrolidone) composite nanofibers, arrays and three-dimensional fabrics: electrospun preparation and transformation to hydroxyapatite nanostructures. AB - Electrospinning has been recognized as an efficient technique for fabricating polymer nanofibrous biomaterials. However, the study of electrospun inorganic biomaterials with well-designed three-dimensional (3-D) structures is still limited and little reported. In this study hydroxyapatite (HAp) nanorods with an average diameter of approximately 7 nm and length of approximately 27 nm were synthesized through a simple precipitation method and used for the fabrication of inorganic/organic [poly(vinyl pyrolidone) (PVP)] composite nanofibers by electrospinning in ethanol solution. 3-D fabrics and aligned nanofiber arrays of the HAp nanorods/PVP composite were obtained as precursors. Thereafter, 3-D single phase HAp fabrics, tubular structures and aligned nanofiber arrays were obtained after thermal treatment of the corresponding composite precursors. Cytotoxicity experiments indicated that the HAp fabric scaffold had good biocompatibility. In vitro experiments showed that mesenchymal stem cells could attach to the HAp fabric scaffold after culture for 24h. PMID- 20167295 TI - Amorphous calcium phosphates: synthesis, properties and uses in biomaterials. AB - This review paper on amorphous calcium phosphates (ACPs) provides an update on several aspects of these compounds which have led to many studies and some controversy since the 1970s, particularly because of the lack of irrefutable proof of the occurrence of an ACP phase in mineralised tissues of vertebrates. The various synthesis routes of ACPs with different compositions are reported and the techniques used to characterise this phase are reviewed. We focus on the various physico-chemical properties of ACPs, especially the reactivity in aqueous media, which have been exploited to prepare bioactive bone substitutes, particularly in the form of coatings and cements for orthopaedic applications and composites for dental applications. PMID- 20167296 TI - Femtosecond laser induced fixation of calcium alkali phosphate ceramics on titanium alloy bone implant material. AB - Femtosecond lasers provide a novel method of attaching bioceramic material to a titanium alloy, thereby improving the quality of bone implants. The ultrashort 30 fs laser pulses (790 nm wavelength) penetrate a thin dip-coated layer of fine ceramic powder, while simultaneously melting a surface layer of the underlying metal. The specific adjustment of the laser parameters (pulse energy and number of pulses per spot) avoids unnecessary melting of the bioactive calcium phosphate, and permits a defined thin surface melting of the metal, which in turn is not heated throughout, and therefore maintains its mechanical stability. It is essential to choose laser energy densities that correspond to the interval between the ablation fluences of both materials involved: about 0.1-0.4 Jcm(-2). In this work, we present the first results of this unusual technique, including laser ablation studies, scanning electron microscopy and optical microscope images, combined with EDX data. PMID- 20167297 TI - Rare asymptomatic presentations of schwannomas in early adolescence: three cases with review of literature. AB - INTRODUCTION: Schwannoma also known as Neurilemoma is a benign neoplasm of the Schwann Cells of the neural sheath. They are usually found to occur in the extremities, but can also be found in the trunk, head and neck, pelvis, and rectum. It is seldom painful and usually remains small. It has no potential for malignancy unless the patient has multi-neural tumours. It usually presents as a slowly enlarging painless nodule somewhat movable beneath the surface, rarely becomes larger than 2cm in diameter and is most frequently diagnosed in 25-55 yrs of age. PATIENTS AND METHODS: We report three rare, asymptomatic presentations of schwannomas at adolescent age, in the back, pancreas and in the cervical region with a review of the available literature. CONCLUSION: Despite the rarity of the presentations, as encountered by us, similar swellings in the adolescent age group can be schwannomas and can be adequately managed surgically alone. This is what should be borne in mind, for 'what the mind knows is what the eyes see'. PMID- 20167298 TI - An optimized data structure for high-throughput 3D proteomics data: mzRTree. AB - As an emerging field, MS-based proteomics still requires software tools for efficiently storing and accessing experimental data. In this work, we focus on the management of LC-MS data, which are typically made available in standard XML based portable formats. The structures that are currently employed to manage these data can be highly inefficient, especially when dealing with high throughput profile data. LC-MS datasets are usually accessed through 2D range queries. Optimizing this type of operation could dramatically reduce the complexity of data analysis. We propose a novel data structure for LC-MS datasets, called mzRTree, which embodies a scalable index based on the R-tree data structure. mzRTree can be efficiently created from the XML-based data formats and it is suitable for handling very large datasets. We experimentally show that, on all range queries, mzRTree outperforms other known structures used for LC-MS data, even on those queries these structures are optimized for. Besides, mzRTree is also more space efficient. As a result, mzRTree reduces data analysis computational costs for very large profile datasets. PMID- 20167299 TI - Identification of Candida albicans exposed surface proteins in vivo by a rapid proteomic approach. AB - We have set up a fast and easy methodology to identify cell-surface proteins in live yeasts. A non-gel proteomic approach was based on a short period of trypsin treatment followed by peptide separation and identification using nano-LC followed by off-line MS/MS. Candida albicans was used as a model organism and proteins involved in cell wall organization, cell rescue, defense, virulence, transport, protein fate and metabolism were identified. This strategy is a powerful tool to study host-pathogen interactions and to look for potential vaccine candidates and drug targets. PMID- 20167300 TI - Role of PI3K on the regulation of BMP2-induced beta-Catenin activation in human bone marrow stem cells. AB - Bone morphogenetic protein 2 (BMP2), a very potent bone-inducing agent, promotes the differentiation of bone marrow stem cells (BMSCs) to osteoblasts. However, the potency of BMP2 action is variable and its perturbed dynamic signaling pathways in human BMSCs has not been fully elucidated. In this study, we used a combination of stable isotope labeling by amino acids during cell culture (SILAC) and liquid-chromatography electrospray ionization mass spectrometry (LC-ESI MS/MS) technology to reveal the BMP2 action in BMSC. In this quantitative proteomic analysis, 414 of 449 proteins were successfully quantified with 79.2% peptide quantification efficiency. Interestingly, beta-Catenin was identified in BMP2-stimulated heavy isotope-labeled cells, and further analysis confirmed that BMP2 increased beta-Catenin mRNA and protein levels. The increment effects of BMP2 on the beta-Catenin expression levels and its translocation to nucleus were diminished by blocking the PI3K signal pathway. In addition, BMP2-induced beta Catenin activity and ALP activity were blocked by PI3K inhibition. Thus, our quantitative proteomics analysis and further biochemical investigations showed that BMP2 modulates beta-Catenin signaling via PI3K pathway and that this pathway plays roles in BMP2-induced osteoblast differentiation of hBMSCs. PMID- 20167301 TI - Vaccine failures after active immunisation against tick-borne encephalitis. AB - Tick-borne encephalitis (TBE) is a major disease of the central nervous system in Europe and is endemic in Sweden with about 200 notified cases annually. The far most effective protective measure against TBE is active immunisation. The vaccines available today induce a high degree of protection in field studies. However, vaccine failures have occasionally been reported and may be overlooked due to different, and sometimes confusing, antibody kinetics in vaccinees with TBEV infection. In this study, 27 patients with clinical and serological evidences of TBE despite adequate immunisation are presented. Vaccination failure is characterized by a slow, and initially non-detectable, development of the specific TBEV-IgM response, seen together with a rapid rise of IgG and neutralising antibodies in serum. The majority (70%) of the patients were more than 50 years of age, which may implicate a need for a modified immunisation strategy in the elderly. PMID- 20167302 TI - Gender inequity in the provision of care for hip disease: population-based cross sectional study. AB - OBJECTIVES: To examine gender differences along the care pathway to total hip replacement. METHODS: We conducted a population-based cross-sectional study of 26,046 individuals aged 35 years and over in Avon and Somerset. Participants completed a questionnaire asking about care provision at five milestones on the pathway to total hip replacement. Those reporting hip disease were invited to a clinical examination. We estimated odds ratios (ORs) [95% confidence intervals (CI)] for provision of care to women compared with men. RESULTS: 3169 people reported hip pain, 2018 were invited for clinical examination, and 1405 attended (69.6%). After adjustment for age and disease severity, women were less likely than men to have consulted their general practitioner (OR 0.78, 95%-CI 0.61 1.00), as likely as men to have received drug therapy for hip pain in the previous year (OR 0.96, 95%-CI 0.74-1.24), but less likely to have been referred to specialist care (OR 0.53, 95%-CI 0.40-0.70), to have consulted an orthopaedic surgeon (OR 0.50, 95%-CI 0.32-0.78), or to be on a waiting list for total hip replacement (OR 0.41, 95%-CI 0.20-0.87). Differences remained in the 746 people who had sought care from their general practitioner, and after adjustment for willingness and fitness for surgery. CONCLUSIONS: There are gender inequalities in provision of care for hip disease in England, which are not fully accounted for by gender differences in care seeking and treatment preferences. Differences in referral to specialist care by general practitioners might unwittingly contribute to this inequity. Accurate information about availability, benefits and risks of hip replacement for providers and patients, and continuing education to ensure that clinicians interpret and correct patients' assumptions could help reduce inequalities. PMID- 20167304 TI - Complexes of surfactants with oppositely charged polymers at surfaces and in bulk. AB - Addition of surfactants to aqueous solutions of polyelectrolytes carrying an opposite charge causes the spontaneous formation of complexes in the bulk phase in certain concentration ranges. Under some conditions, compact monodisperse multichain complexes are obtained in the bulk. The size of these complexes depends on the mixing procedure and it can be varied in a controlled way from nanometers up to micrometers. The complexes exhibit microstructures analogous to those of the precipitates formed at higher concentrations. In other cases, however, the bulk complexes are large, soft and polydisperse. In most cases, the dispersions are only kinetically stable and exhibit pronounced non-equilibrium features. Association at air-water interfaces readily occurs, even at very small concentrations. When the surfactant concentration is small, the surface complexes are usually made of a surfactant monolayer to which the polymer binds and adsorbs in a flat-like configuration. However, under some conditions, thicker layers can be found, with bulk complexes sticking to the surface. The association at solid water interfaces is more complex and depends on the specific interactions between surfactants, polymers and the surface. However, the behaviour can be understood if distinctions between hydrophilic surfaces and hydrophobic surfaces are made. Note that the behaviour at air-water interfaces is closer to that of hydrophobic than that of hydrophilic solid surfaces. The relation between bulk and surface complexation will be discussed in this review. The emphasis will be given to the results obtained by the teams of the EC-funded Marie Curie RTN "SOCON". PMID- 20167303 TI - Posthumous diagnosis of long QT syndrome from neonatal screening cards. AB - BACKGROUND: Molecular autopsy in sudden unexplained death in the young (SUDY) victims cannot usually be performed if tissue suitable for DNA extraction is not retained at autopsy. OBJECTIVE: The purpose of this study was to assess the feasibility and clinical value of posthumous genetic testing for long QT syndrome (LQTS) using residual material from the neonatal screening (Guthrie) card in SUDY victims. METHODS: Twenty-one cases were investigated up to 13 years after death. Deaths occurred at <1 year in one, 1-18 years in 18, and 19-35 years in two patients. Guthrie cards were 3-39 years old. DNA was extracted, and amplicons corresponding to the coding regions of the LQTS genes 1, 2, 3, 5, and 6 underwent either denaturing high-performance liquid chromatography screening or direct DNA sequencing. RESULTS: Adequate DNA was extracted in every case, although repeated purification and amplification was often required. Rare variants were detected in six of 19 cases undergoing diagnostic screening. Four (21%) are considered to be pathological and have been used for family screening: R243C and H455Y in KCNQ1 in 12-year-old and 13-year-old boys, respectively, and Q81H and S621R in KCNH2 in 21 month and 28-year-old females, respectively. Variants of uncertain significance were R1047L in KCNH2 in a 2-year-old girl and S38G in KCNE1 in a 19-month-old boy. Point mutation tests for previously identified familial LQTS mutations revealed a positive result in both cases: E146K in KCNQ1 and exon 6-4del in KCNH2. CONCLUSION: Residual material from Guthrie cards collected for newborn metabolic screening can be used as a reliable source of DNA for the posthumous diagnosis of LQTS decades after SUDY, although purification and amplification of DNA is time intensive. PMID- 20167305 TI - [Doctor Brown-Sequard's therapy]. AB - Pioneer in the field of hormone therapy, Charles-Edward Brown-Sequard (1817-1894) tried to stop the effects of aging on his contemporaries by injecting animal testicle extracts. His therapy was very popular in the last years of the 19th century. He even had followers in the following century, amongst whom Serge Voronoff (1866-1951), who grafted monkey testicles in replacement of human ones, or Paul Niehans (1882-1971) who practiced therapy using calf embryo cells in Switzerland. PMID- 20167306 TI - Metacognitive training for patients with schizophrenia (MCT): feasibility and preliminary evidence for its efficacy. AB - BACKGROUND: The treatment program "Metacognitive training for patients with schizophrenia" (MCT) addresses cognitive deficits and biases assumed to play a crucial role in the pathogenesis of delusions (e.g. jumping to conclusions, theory of mind deficits, bias against disconfirmatory evidence). The feasibility of this approach and its effects on positive symptoms and cognitive biases were investigated in this pilot study. METHODS: Thirty inpatients of the Department of Psychiatry of the University Hospital Heidelberg with a schizophrenia spectrum diagnosis were randomly assigned to either MCT or an active control intervention. Both training programs were carried out over a time period of four weeks. Psychopathological, cognitive and metacognitive measures were collected at baseline and after completion of the training. Schizophrenia symptoms were determined blind to group allocation with the Positive and Negative Syndrome Scale (PANSS). RESULTS: No adverse reactions were noted in the MCT group and patients expressed a greater subjective training success relative to the control condition (d = .57). A stronger improvement on all PANSS subscales was found at a descriptive level; positive symptoms attenuated under MCT with a medium effect size of d = .43. In addition, results showed a reduced jumping to conclusions bias for MCT patients (d = .31). However, none of the effects reached statistical significance. Optimal sample size was calculated for future studies. CONCLUSION: The present study confirms the feasibility of MCT and provides preliminary evidence for its efficacy ameliorating positive symptoms and the jumping to conclusions bias. PMID- 20167307 TI - The Dutch version of the Behavioral Activation for Depression Scale (BADS): psychometric properties and factor structure. AB - In a community sample of 402 respondents, the authors examined the psychometric properties of the Dutch version of the Behavioral Activation for Depression Scale (BADS; Kanter, Mulick, Busch, Berlin, & Martell, 2006). Results of confirmatory factor analysis supported the original 4-factor structure, providing the following subscales: Activation, Avoidance/Rumination, Work/School Impairment, and Social Impairment. All subscales showed adequate internal consistency, evidence of convergent validity with concurrent measures of depressive symptoms, rumination, psychological flexibility, and avoidance behavior, and evidence of differential validity between currently, formerly, and never depressed respondents. PMID- 20167308 TI - Chitosan-based microcapsules containing grapefruit seed extract grafted onto cellulose fibers by a non-toxic procedure. AB - A novel non-toxic procedure is described for the grafting of chitosan-based microcapsules containing grapefruit seed oil extract onto cellulose. The cellulose was previously UV-irradiated and then functionalized from an aqueous emulsion of the chitosan with the essential oil. The novel materials are readily attained with durable fragrance and enhanced antimicrobial properties. The incorporation of chitosan as determined from the elemental analyses data was 16.08+/-0.29 mg/g of sample. Scanning electron microscopy (SEM) and gas chromatography-mass spectroscopy (GC-MS) provided further evidence for the successful attachment of chitosan microcapsules containing the essential oil to the treated cellulose fibers. The materials thus produced displayed 100% inhibition of Escherichia coli and Staphylococcus epidermidis up to 48 h of incubation. Inhibition of bacteria by the essential oil was also evaluated at several concentrations. PMID- 20167309 TI - Synthesis and antitubercular evaluation of new fluoroquinolone derivatives coupled with carbohydrates. AB - We describe in this work the synthesis of nine new fluoroquinolone derivatives based on modifications at the C-7 position of the known fluoroquinolones cipro-, gati-, and moxifloxacin, as well as their antitubercular evaluation. The synthesis of these new analogues was improved using microwave irradiation, providing several advantages such as better yields and shorter reaction times, in comparison with classical reaction conditions. Derivatives 4, 5, and 7 exhibited promising antitubercular activities. PMID- 20167311 TI - Role of spiral wave pinning in inhomogeneous active media in the termination of atrial fibrillation by electrical cardioversion. AB - Atrial fibrillation is the most common type of arrhythmia to affect humans. One of the treatment modalities for atrial fibrillation is an electrical cardioversion. Electrical cardioversion can result in one of three outcomes: an immediate termination of arrhythmic activity, a delayed termination or unsuccessful termination. The mechanism of delayed termination is unknown. Here we present a model of an atrial fibrillation as a coexistence of several spiral waves pinned to the inhomogeneities in active media. We show that in inhomogeneous system delayed termination can be explained as the unpinning of a spiral wave from inhomogeneities and its termination after collision with the edge of the system. PMID- 20167310 TI - Anti-tumor effects of fusion vaccine prepared by renal cell carcinoma 786-O cell line and peripheral blood dendritic cells of healthy volunteers in vitro and in human immune reconstituted SCID mice. AB - Dendritic cells (DC), as professional antigen presenting cells, play the central role in the process of body initiating the anti-tumor immunity, and the study on DC anti-tumor vaccine has become heated in recent years. In this study, we used polyethylene glycol (PEG) to induce renal cell carcinoma (RCC) 786-O cell line fused with peripheral blood DC of healthy volunteers, and discuss the biological characteristics of fusion vaccine and its anti-tumor effects in vitro and in human immune reconstituted SCID mice model of RCC. The study found that PEG could effectively induce cell fusion, and the expressions of CD86 and HLA-DR in fusion vaccine group were significantly up-regulated compared with the DC control group; the secretion of IL-12 was much higher and longer than that of the control; the functions of dendritic cell-tumor fusion vaccine to stimulate the proliferation of allogenic T lymphocytes and to kill RCC786-O cells in vitro were significantly higher than those of the control group, and after the killing, apoptosis body was observed in the target cells; after the injection of fusion vaccine into human immune reconstituted SCID mice model of RCC786-O via vena caudalis, the volume of mice tumor was reduced significantly, proliferation index of tumor cells decreased obviously compared with that of the control group, and more hemorrhage and putrescence focuses presented, accompanying large quantity of lymphocytes soakage. The results of this experimental study shows that fusion vaccine of RCC786-O cell line and DC can significantly stimulate the proliferation of allogenic T cells and specifically inhibit and kill RCC cells in vitro and in vivo, which makes the DC-RCC786-O fusion vaccine a possible new way of effective RCC immunotherapy. PMID- 20167312 TI - Cerebellar brain volume accounts for variance in cognitive performance in older adults. AB - INTRODUCTION: Frontal lobe atrophy is implicated in patterns of age-related cognitive decline. However, other brain areas, including the cerebellum, support the work of the frontal lobes and are also sensitive to the effects of ageing. A relationship between cerebellar brain volume and cognitive function in older adults is reported, but no study has separated variance associated with cerebellar gray matter volume and cerebellar white matter volume; and no study has examined whether or not brain volume in the cerebellum is related to cognitive function in older adults after statistical control for frontal lobe volume of gray and white matter. METHOD: We used voxel based morphometry (VBM) and structural equation modelling (SEM) to analyse relations between general cognitive ability (G) and volume of GM and WM in frontal areas and cerebellum in a sample of 228 older adults (121 males and 107 females). RESULTS: Results indicate that GM volume in the cerebellum predicts G, even when total intracranial volume (TICV) and GM gray and WM volumes in frontal lobes are statistically controlled. However, results differ for males and females, with males showing a stronger relationship between brain volume in the cerebellum and G. CONCLUSIONS: Results are discussed in light of neurological models of cognitive ageing and the significance of the cerebellum in models of cognitive functioning. PMID- 20167313 TI - [Efficacy and tolerability of linezolid therapy in the treatment of orthopedic implant infections caused by gram-positive multiresistant cocci]. PMID- 20167314 TI - [Cardioembolic stroke]. AB - A 77-year old man who consulted due to left arm weakness and dysarthria. He reported having been diagnosed of high blood pressure and that he was taking enalapril/hydrochlorothiazide without adequate blood pressure control. He had smoked 2 packs of cigarettes a day and continues to smoke at present. He was admitted to the emergency service about 90 min after the onset of his symptoms. He did not report headache, nausea or vomiting. His BP was 182/104 mmHg, with irregular pulse at 88 beats per minute. The neurological examination revealed dysarthria, left homonymous hemianopsia, muscle weakness and hypoesthesia of the left limbs. How should this patient be evaluated and treated? PMID- 20167316 TI - Access to fertility treatment. PMID- 20167317 TI - Choosing a culture medium: making informed choices. PMID- 20167320 TI - Contemporary issues in women's health. PMID- 20167319 TI - Tooth wear and dental pathology of the Bronze-Iron Age people in Xinjiang, Northwest China: Implications for their diet and lifestyle. AB - Tooth wear and dental pathology related to diet and lifestyle were investigated in the human dental remains unearthed from three archaeological sites of Bronze Age and Iron Age in Xinjiang of northwest China, and in comparative samples from two Neolithic sites in Henan and Shanxi in central China along the Yellow River. Our results indicate that the average tooth wear on most tooth types in the three Xinjiang sites was close to those of the Neolithic samples from central China. The variation within the Xinjiang samples was also explored. Some special wear patterns such as severe wear on the first molar and relatively heavy wear of anterior teeth were observed on the specimens from the Xinjiang sites. Obvious differences in caries and antemortem tooth loss were found between Xinjiang and comparative samples with higher frequencies of caries observed in samples from central China and higher antemortem tooth loss in samples from the Xinjiang sites. Strongly developed exostoses (tori) were also identified on mandibles and maxillae of the specimens from Xinjiang. The authors believe that the differences in tooth wear and dental pathology between Xinjiang and central China were caused by differences in diet and lifestyle. Food of a harder texture was consumed by the people who lived in Xinjiang than by the people in Henan and Shanxi of central China. The higher occurrence of heavily worn anterior teeth and some other special wear patterns, antemortem tooth loss and presence of exostoses on jaw bones in Xinjiang suggest that the people in Xinjiang lived in a relatively harsh environment, frequently gnawing hard objects, or using teeth as some kind of tools. All these activities put masticatory organs under a heavy load. The differences in caries frequencies between the frontier and central areas of China indicate that food richer in carbohydrates was consumed by the people in the central areas. It is proposed that about 3000-2000 years BP in many areas of frontier Xinjiang, people mainly relied on the type of hunter-gatherer economy with agriculture playing a smaller role in their lifestyle. PMID- 20167321 TI - Peritoneal VEGF burden as a predictor of cytoreductive surgery outcome in women with epithelial ovarian cancer. AB - OBJECTIVE: To determine whether peripheral plasma concentration, peritoneal fluid concentration, and/or peritoneal vascular endothelial growth factor (VEGF) burden can predict the possibility of optimal cytoreduction in women with epithelial ovarian carcinoma (EOC); and if so, to determine cutoff values below which optimal cytoreduction is likely to occur. METHODS: We measured plasma VEGF concentration, peritoneal VEGF concentration, and VEGF burden in 46 women undergoing cytoreductive surgery. Univariate analysis, bivariate analysis, correlation tests, and stepwise regression were performed with cytoreduction as the outcome. RESULTS: The VEGF burden best predicted the outcome. The area under the curve was 0.84 and the log-transformed cutoff value was 15.52 log pg. Overall, the chance of optimal cytoreduction was 11 times greater when the VEGF burden was less than 15.52 log pg. For women with advanced disease, the chance was 6 times greater below this value. CONCLUSION: The VEGF burden may quantify tumor activity, and it could be used when selecting patients likely to benefit from induction chemotherapy before undergoing cytoreductive surgery. PMID- 20167322 TI - Epidemiology of TAO--correction of an error. PMID- 20167323 TI - Analysis of cell viability in intervertebral disc: Effect of endplate permeability on cell population. AB - Responsible for making and maintaining the extracellular matrix, the cells of intervertebral discs are supplied with essential nutrients by diffusion from the blood supply through mainly the cartilaginous endplates (CEPs) and disc tissue. Decrease in transport rate and increase in cellular activity may adversely disturb the intricate supply-demand balance leading ultimately to cell death and disc degeneration. The present numerical study aimed to introduce for the first time cell viability criteria into nonlinear coupled nutrition transport equations thereby evaluating the dynamic nutritional processes governing viable cell population and concentrations of oxygen, glucose and lactic acid in the disc as CEP exchange area dropped from a fully permeable condition to an almost impermeable one. A uniaxial model of an in vitro cell culture analogue of the disc is first employed to examine and validate cell viability criteria. An axisymmetric model of the disc with four distinct regions was subsequently used to investigate the survival of cells at different CEP exchange areas. In agreement with measurements, predictions of the diffusion chamber model demonstrated substantial cell death as essential nutrient concentrations fell to levels too low to support cells. Cells died away from the nutrient supply and at higher cell densities. In the disc model, the nucleus region being farthest away from supply sources was most affected; cell death initiated first as CEP exchange area dropped below approximately 40% and continued exponentially thereafter to depletion as CEP calcified further. In cases with loss of endplate permeability and/or disruptions therein, as well as changes in geometry and fall in diffusivity associated with fluid outflow, the nutrient concentrations could fall to levels inadequate to maintain cellular activity or viability, resulting in cell death and disc degeneration. PMID- 20167324 TI - Automatic determination of anatomical coordinate systems for three-dimensional bone models of the isolated human knee. AB - The combination of three-dimensional (3-D) models with dual fluoroscopy is increasingly popular for evaluating joint function in vivo. Applying these modalities to study knee motion with high accuracy requires reliable anatomical coordinate systems (ACSs) for the femur and tibia. Therefore, a robust method for creating ACSs from 3-D models of the femur and tibia is required. We present and evaluate an automated method for constructing ACSs for the distal femur and proximal tibia based solely on 3-D bone models. The algorithm requires no observer interactions and uses model cross-sectional area, center of mass, principal axes of inertia, and cylindrical surface fitting to construct the ACSs. The algorithm was applied to the femur and tibia of 10 (unpaired) human cadaveric knees. Due to the automated nature of the algorithm, the within specimen variability is zero for a given bone model. The algorithm's repeatability was evaluated by calculating variability in ACS location and orientation across specimens. Differences in ACS location and orientation between specimens were low (<1.5mm and <2.5 degrees). Variability arose primarily from natural anatomical and morphological differences between specimens. The presented algorithm provides an alternative method for automatically determining subject-specific ACSs from the distal femur and proximal tibia. PMID- 20167325 TI - Evidence of residual force enhancement for multi-joint leg extension. AB - Force enhancement is a well accepted property of skeletal muscle and has been observed at all structural levels ranging from single myofibrils to voluntarily activated m. quadriceps femoris in vivo. However, force enhancement has not been studied for multi-joint movements like human leg extension; therefore knowledge about its relevance in daily living remains limited. The purpose of this study was to determine whether there is force enhancement during maximal voluntary multi-joint leg extension. Human leg extension was studied (n=22) on a motor driven leg press dynamometer where external reaction forces under the feet as well as activity of 8 lower extremity muscles were measured. In addition, torque in the ankle and knee joints was calculated using inverse dynamics. The steady state isometric force, joint torques, and muscle activation after active stretch (20 degrees stretch amplitude at 60 degrees/s) were compared with the corresponding values obtained during isometric reference contractions. There was consistent force enhancement during and following stretch for both forces and joint torques. Potentiation during stretch reached values between 26% and 30%, while a significant force enhancement of 10.5-12.3% and 4.3-7.4% remained 0.5-1 and 2.5-3s after stretch, respectively. During stretch, EMG signals of m. gastrocnemius medialis and lateralis were significantly increased, while following stretch all analyzed muscles showed the same activity as during the reference contractions. We conclude from these results that force enhancement exists in everyday movements and should be accounted for when analyzing or modelling human movement. PMID- 20167326 TI - Investigation of the adsorption behavior of glycine peptides on 12% cross-linked agarose gel media. AB - The highly cross-linked 12% agarose gel Superose 12 10/300 GL causes retardation of glycine peptides when mobile phases containing varying concentrations of acetonitrile in water are used. An investigation has been made into the retention mechanism behind this retardation using the glycine dipeptide (GG) and tripeptide (GGG) as models. The dependence of retention times of analytical-size peaks under different experimental conditions was interpreted such that the adsorption most probably was caused by the formation of hydrogen bonds but that electrostatic interactions cannot be ruled out. Thereafter, a nonlinear adsorption study was undertaken at different acetonitrile content in the eluent, using the elution by characteristic points (ECPs) method on strongly overloaded GG and GGG peaks. With a new evaluation tool, the adsorption energy distribution (AED) could be calculated prior to the model selection. These calculations revealed that when the acetonitrile content in the eluent was varied from 0% to 20% the interactions turned from (i) being homogenous (GG) or mildly heterogeneous (GGG), (ii) via a more or less stronger degree of heterogeneity around one site to (iii) finally a typical bimodal energy interaction comprising of two sites (GG at 20% and GGG at 10% and 20%). The Langmuir, Toth and bi-Langmuir models described these interesting adsorption trends excellently. Thus, the retardation observed for these glycine peptides is interpreted as being of mixed-mode character composed of electrostatic bonds and hydrogen bonds. PMID- 20167327 TI - Measurements of coeluting unlabeled and 13C-labeled polychlorinated biphenyl congeners with partially overlapping fragment profiles using a tandem mass spectrometry. AB - (13)C-labeled compounds are often employed as surrogate or internal standards to monitor the performance of extraction and instrumental analysis procedures for their unlabeled counterparts. However, labeled and unlabeled counterparts most often coelute chromatographically with overlapping mass ion fragments, posing a challenge to the accurate quantification of these compounds. In the present study, an analytical scheme, using coeluting unlabeled and (13)C-labeled polychlorinated biphenyl (PCB) congeners as the model compounds, was developed with a low-resolution tandem mass spectrometer (MS/MS) to determine the appropriate ranges of PCB congener concentrations that satisfy the no interference condition. Interferences from unlabeled PCBs to quantitation of labeled counterparts could be minimized when (13)C-labeled PCB congeners were quantified in the MS/MS mode within a certain concentration range. In addition, good agreements between the measured and theoretically predicted quantitation errors were observed for all labeled PCB congeners except PCB 180. The exception with labeled PCB 180 was mainly attributed to the occurrence of instrumental analytical uncertainty, as analytical error was also observed with absence of unlabeled PCB 180. These results indicate that MS/MS techniques can serve as a useful tool to minimize interferences with quantitation of isotopically labeled compounds from their unlabeled counterparts, which possess partially overlapping ion fragment profiles. PMID- 20167328 TI - The clouding behaviour of PEO-PPO based triblock copolymers in aqueous ionic surfactant solutions: a new approach for cloud point measurements. AB - The cloud points (CP) of 1 g/dl solutions of polyethylene oxide-polypropylene oxide (PEO-PPO) based triblock copolymers (Pluronics(r) P84, L64, L44 and Reverse Pluronics(r) 10R5, 25R4, 17R4) were measured as a function of their molecular weight and added ionic surfactant. For identical PEO/PPO ratios, copolymers with lower molecular weight show a larger increase in the cloud point in the presence of surfactants than polymers with higher molecular weight. The opposite trend has been observed for reverse Pluronics. The cloud points of polymers with different PEO/PPO ratios have also been reported. An increase in the size of the middle PEO block in reverse Pluronics has a more significant effect on cloud points than molecular weight increment. Ionic surfactants produced marked increases in the cloud points of copolymer solutions. The effect was much larger for surfactants with higher hydrophobicity. Cationic surfactants with different chain lengths were used to examine the surfactant-polymer interaction. A novel approach for normalising the cloud points to their relative values has been carried out to see the clear effect of ionic surfactants. Tri component systems, comprising polymers, cetyltrimethylammonium bromide (C(16)TABr) surfactant and salt (NaBr), have also been studied to see the effect of salt on the phase separation behaviour of solutions within the framework of our new cloud point approach. PMID- 20167329 TI - Preparation and capacitance property of MnO2-pillared Ni(2+)-Fe3+ layered double hydroxides nanocomposite. AB - A novel MnO(2)-pillared Ni(2+)-Fe(3+) layered double hydroxides nanocomposite has been successfully fabricated using an intercalation/reduction reaction followed by heating treatment. The structural evolution of the samples obtained at different stages has been characterized by XRD, TEM, XPS, IR and N(2) adsorption desorption. The layered structure of MnO(2)-pillared Ni(2+)-Fe(3+) layered double hydroxides nanocomposite can be maintained at 300 degrees C, and the obtained material has a large surface area of 202 m(2) g(-1). Electrochemical studies indicate that the material obtained by heating at 200 degrees C exhibits an ideal capacitive behavior and good cycling property in 1 mol L(-1) Na(2)SO(4) aqueous solution, and the specific capacitance value was 190 F g(-1) at a scan rate of 5 mV s(-1). PMID- 20167330 TI - Chemical and physical characterizations of spinel ferrite nanoparticles containing Nd and B elements. AB - We first succeeded in synthesizing ferrite nanoparticles containing Nd and B elements by a chemical route using a polyol process. The lattice constants of the ferrite nanoparticles were equivalent to 8.39A of the lattice constant for Fe(3)O(4) with the spinel structure in a bulk state independently of the size in diameter and composition (Fe:Nd:B). The size in diameter was actually dominated by the amount of ligands (oleic acid and oleylamine) coating the nanoparticles and easily tuned by changing refluxing-time under reaction. The spinel-structured ferrite nanoparticles containing Nd and B elements showed large coercivity as compared to Fe(3)O(4) nanoparticles with the spinel structure, which were prepared by the same chemical method. By doping Nd and B elements into the spinel structure of ferrite, magnetic anisotropy increased in comparison with Fe(3)O(4) nanoparticles. According to the analysis of magnetization curve using the modified Langevin function, the ferrite nanoparticles displayed the coexistence of superparamagnetic and antiferromagnetic phases. The ferrite nanoparticles containing Nd and B elements exhibited magnetic core/shell structure on the basis of various magnetic properties. The interface effect between the superparamagnetic core and antiferromagnetic shell might enhance the effective magnetic anisotropy of the ferrite nanoparticles containing Nd and B elements. PMID- 20167331 TI - Ectopic ossification with haematopoietic bone marrow in the heart valves of a crossbred heavy horse. AB - Ectopic bone formation in the left atrioventricular valves and cardiac fibroskeleton, with systemic circulatory disturbance, is reported in a 4-year-old crossbred heavy horse. Microscopically, there was fibrosis, chondral metaplasia and mature bone, with bone marrow within the left atrioventricular cusps and in the annuli of the aortic and right atrioventricular valves. PMID- 20167332 TI - Early pathogenesis in porcine proliferative enteropathy caused by Lawsonia intracellularis. AB - The intestinal bacterium Lawsonia intracellularis, the cause of proliferative enteropathy (PE) in pigs, is believed to infect mitotically active epithelial cells of the intestinal crypts and then multiply and spread in these cells as they divide. Further spread of infection is thought to occur by shedding of bacteria from infected crypts followed by infection of new crypts. The early stages of the pathogenesis of PE, from 0 to 48 hours post-infection (hpi), have not been studied in vivo. In the present study pigs were inoculated with L. intracellularis and killed from 12 hpi to 5 days post-infection (dpi). The localization of L. intracellularis was determined immunohistochemically and by fluorescence in-situ hybridization. At 12 hpi L. intracellularis was found within epithelial cells at the tips of villi, indicating infection of a range of epithelial cells including mature differentiated enterocytes. Furthermore, early invasion of the intestinal connective tissue was observed; with the presence of single bacteria in the lamina propria 12 hpi, and with a further spread of bacteria in the lamina propria observed at 5 dpi, suggesting an active role for the lamina propria in the course of infection. PMID- 20167333 TI - Comparison of fractional flow reserve of composite Y-grafts with saphenous vein or right internal thoracic arteries. AB - BACKGROUND: Composite Y-grafts, using the left internal thoracic artery as the inflow, allow a more efficient use of conduits without the need to touch a diseased ascending aorta. Among other conduits, the saphenous vein graft may be an alternative to the radial artery in elderly patients. PATIENTS AND METHODS: We evaluated the hemodynamic characteristics of 17 composite Y-grafts made with the left internal thoracic artery anastomosed to the left anterior descending coronary artery in all cases and with either the free right internal thoracic artery (RITA group, n = 10) or a saphenous vein graft (SVG group, n = 7) implanted proximally to the left internal thoracic artery and distally to the circumflex territory 6 months after the operation. RESULTS: At baseline, the pressure gradient measured with a 0.014-inch pressure wire was minimal between the aorta and the internal thoracic artery stem (2 +/- 1 mm Hg), the internal thoracic artery and left anterior descending (4 +/- 2 mm Hg), the internal thoracic artery and left circumflex (3 +/- 1 mm Hg), and the saphenous vein graft and left circumflex (2 +/- 2 mm Hg). During hyperemia induced by adenosine, the pressure gradient increased significantly to 6 +/- 2 mm Hg in the internal thoracic artery stem, 9 +/- 4 mm Hg in the internal thoracic artery and left anterior descending artery, 9 +/- 3 mm Hg in the internal thoracic artery and left circumflex, and 7 +/- 4 mm Hg in the saphenous vein graft and left circumflex. Fractional flow reserve was 0.94 +/- 0.02 in internal thoracic artery stem, 0.90 +/- 0.04 mm Hg in the internal thoracic artery and left anterior descending, 0.91 +/- 0.03 mm Hg in the internal thoracic artery and left circumflex, and 0.92 +/- 0.06 mm Hg in the saphenous vein graft and left circumflex. No difference between the two types of composite Y-grafts was observed for pressure gradients or fractional flow reserve measured in internal thoracic artery stem or in distal branches. CONCLUSIONS: Composite Y-grafts with saphenous vein or right internal thoracic arteries allow similar and adequate reperfusion of the left system with minimal resistance to maximal flow and an even distribution of flow in both distal branches. PMID- 20167334 TI - Off-pump versus on-pump coronary artery bypass grafting: a systematic review and meta-analysis of propensity score analyses. AB - OBJECTIVE: Despite numerous randomized and nonrandomized trials on off- and on pump coronary artery bypass grafting, it remains open which method is superior. Patient selection and small sample sizes limit the evidence from randomized trials; lack of randomization limits the evidence from nonrandomized trials. Propensity score analyses are expected to improve on at least some of these problems. We aimed to systematically review all propensity score analyses comparing off- and on-pump coronary artery bypass grafting. METHODS: Propensity score analyses comparing off- and on-pump surgery were identified from 8 bibliographic databases, citation tracking, and a free web search. Two independent reviewers abstracted data on 11 binary short-term outcomes. RESULTS: A total of 35 of 58 initially retrieved propensity score analyses were included, accounting for a total of 123,137 patients. The estimated overall odds ratio was less than 1 for all outcomes, favoring off-pump surgery. This benefit was statistically significant for mortality (odds ratio, 0.69; 95% confidence interval, 0.60-0.75), stroke, renal failure, red blood cell transfusion (P < .0001), wound infection (P < .001), prolonged ventilation (P < .01), inotropic support (P = .02), and intraaortic balloon pump support (P = .05). The odds ratios for myocardial infarction, atrial fibrillation, and reoperation for bleeding were not significant. CONCLUSIONS: Our systematic review and meta analysis of propensity score analyses finds off-pump surgery superior to on-pump surgery in all of the assessed short-term outcomes. This advantage was statistically significant and clinically relevant for most outcomes, especially for mortality, the most valid criterion. These results agree with previous systematic reviews of randomized and nonrandomized trials. PMID- 20167335 TI - Two cases of aneurysm of the anterior mitral valve leaflet associated with transcatheter aortic valve endocarditis: a mere coincidence? PMID- 20167336 TI - The relationship between perioperative temperature and adverse outcomes after off pump coronary artery bypass graft surgery. AB - OBJECTIVE: The study objective was to determine predictors of hypothermia and hyperthermia, and the impact of hypothermia and hyperthermia on postoperative outcomes for off-pump coronary artery bypass grafting. METHODS: We performed a retrospective study of 2294 patients who underwent off-pump coronary artery bypass grafting in New York in 2007. Patients were classified as moderately to severely hypothermic (< or = 34.5 degrees C), mildly hypothermic (34.6 degrees C 35.9 degrees C), or mildly hyperthermic (37.5 degrees C-38.8 degrees C) after leaving the operating room. Significant independent predictors of these temperature states and the independent impact of each of these states on in hospital mortality and complications were identified. RESULTS: A total of 37.7% of patients were mildly hypothermic, 9.0% of patients were moderately to severely hypothermic, and 5.6% of patients were mildly hyperthermic. Significant independent predictors for postoperative hypothermia included older age, female gender, lower body surface area, congestive heart failure, higher ventricular function, non-Hispanic ethnicity, single/double-vessel disease, low postoperative hematocrit, previous cardiac surgery, race other than white or black, and organ transplant. Patients with moderate to severe hypothermia had significantly higher risk-adjusted in-hospital mortality than patients with normothermia (adjusted odds ratio 3.00; 95% confidence interval, 1.11-8.08). Patients with mild hyperthermia also had significantly higher mortality (adjusted odds ratio 5.04; 95% confidence interval,1.18-21.55). Patients with either mild or moderate to severe hypothermia had significantly higher rates of respiratory failure and unplanned operations, and patients with mild hyperthermia had a significantly higher rate of respiratory failure than normothermic patients. CONCLUSION: It is important to maintain normal postsurgical core temperatures in patients who have undergone cardiac surgery to minimize or avoid death and complications. PMID- 20167337 TI - Center variation and outcomes associated with delayed sternal closure after stage 1 palliation for hypoplastic left heart syndrome. AB - OBJECTIVE: There is debate whether primary or delayed sternal closure is the best strategy after stage 1 palliation for hypoplastic left heart syndrome. We describe center variation in delayed sternal closure after stage 1 palliation and associated outcomes. METHODS: Society of Thoracic Surgeons Congenital Database participants performing stage 1 palliation for hypoplastic left heart syndrome from 2000 to 2007 were included. We examined center variation in delayed sternal closure and compared in-hospital mortality, prolonged length of stay (length of stay > 6 weeks), and postoperative infection in centers with low (< or = 25% of cases), middle (26%-74% of cases), and high (> or = 75% of cases) delayed sternal closure use, adjusting for patient and center factors. RESULTS: There were 1283 patients (45 centers) included. Median age at surgery was 6 days (interquartile range, 4-9 days), and median weight at surgery was 3.2 kg (interquartile range, 2.8-3.5 kg); 59% were male. Delayed sternal closure was used in 74% of cases (range, 3%-100% of cases/center). In centers with high (n = 23) and middle (n = 17) versus low (n = 5) delayed sternal closure use, there was a greater proportion of patients with prolonged length of stay and infection, and a trend toward increased in-hospital mortality in unadjusted analysis. In multivariable analysis, there was no difference in mortality. Centers with high and middle delayed sternal closure use had prolonged length of stay (odds ratio, 2.83; 95% confidence interval, 1.46-5.47; P = .002 and odds ratio, 2.23; confidence interval, 1.17-4.26; P = .02, respectively) and more infection (odds ratio, 2.34; confidence interval, 1.20-4.57; P = .01 and odds ratio, 2.37; confidence interval, 1.36-4.16; P = .003, respectively). CONCLUSION: Use of delayed sternal closure after stage 1 palliation varies widely. These observational data suggest that more frequent use of delayed sternal closure is associated with longer length of stay and higher postoperative infection rates. Further evaluation of the risks and benefits of delayed sternal closure in the management of these complex infants is necessary. PMID- 20167338 TI - In vitro functional comparison of therapeutically relevant human vasculogenic progenitor cells used for cardiac cell therapy. AB - OBJECTIVE: In cardiac cell therapy almost every cell type tested experimentally has yielded some benefit. However, there is a lack of studies directly comparing the function of various stem/progenitor cell populations. This study describes the expansion of peripheral blood CD133(+) cells and compares their functional properties with those of other commonly used human progenitor cell populations. METHODS: CD133(+) cells were generated from the CD133(-) fraction of peripheral blood, either serially (pooled-derived) or after 14 days of culture (derived). Their phenotypic, migratory, and vasculogenic properties were compared with those of 4 commonly used progenitor cell populations in vitro. RESULTS: Serial expansion resulted in an 11-fold increase in the number of CD133(+) cells. The proportion of derived CD133(+) cells collected between 0 and 8 days also expressing CD34 and vascular endothelial growth factor receptor 2 was similar (approximately 60%, P = .41). Adherent, 4-day cultured endothelial progenitor cells demonstrated enhanced migration compared with each of the other 5 cell populations (all P < or = .002). The migration of derived CD133(+) progenitors was enhanced by coculture with CD133(-) cells or their supernatant (P < .05). In vitro vasculogenesis assays revealed that derived and pooled-derived CD133(+) cells had superior vasculogenic potential compared with other progenitor populations (P < or = .03). CONCLUSIONS: A novel source of expandable CD133(+) cells can be generated from the CD133(-) fraction of peripheral blood. The CD133 phenotypic marker translates into the cell being vasculogenically more potent in vitro, which could be beneficial to inducing vasculogenesis in the ischemic heart. Furthermore, intercellular interactions appear important for improving the therapeutic efficacy of cell transplantation. PMID- 20167339 TI - Measuring the physical food environment and its relationship with obesity: evidence from California. PMID- 20167340 TI - Synthesizing diverse evidence: the use of primary qualitative data analysis methods and logic models in public health reviews. AB - OBJECTIVES: The nature of public health evidence presents challenges for conventional systematic review processes, with increasing recognition of the need to include a broader range of work including observational studies and qualitative research, yet with methods to combine diverse sources remaining underdeveloped. The objective of this paper is to report the application of a new approach for review of evidence in the public health sphere. The method enables a diverse range of evidence types to be synthesized in order to examine potential relationships between a public health environment and outcomes. STUDY DESIGN: The study drew on previous work by the National Institute for Health and Clinical Excellence on conceptual frameworks. It applied and further extended this work to the synthesis of evidence relating to one particular public health area: the enhancement of employee mental well-being in the workplace. METHODS: The approach utilized thematic analysis techniques from primary research, together with conceptual modelling, to explore potential relationships between factors and outcomes. RESULTS: The method enabled a logic framework to be built from a diverse document set that illustrates how elements and associations between elements may impact on the well-being of employees. CONCLUSIONS: Whilst recognizing potential criticisms of the approach, it is suggested that logic models can be a useful way of examining the complexity of relationships between factors and outcomes in public health, and of highlighting potential areas for interventions and further research. The use of techniques from primary qualitative research may also be helpful in synthesizing diverse document types. PMID- 20167341 TI - [Letter to the SERAM's Board of Directors]. PMID- 20167343 TI - [Congenital nasal pyriform aperture stenosis]. AB - INTRODUCTION: Congenital nasal pyriform aperture stenosis (CNPAS) is a rare and an unusual cause of airway obstruction in newborns. OBSERVATION: We report the case of a female neonate delivered by C-section at 39 weeks of amenorrhea for hydramnios and macrosomia. She presented with mandibular retrognathia, nasal saddling, submucous cleft palate, and loud mouth respiration. She presented with cyanosis every time feeding was attempted. CT revealed permeable choans with a single central incisor and nasal pyriform aperture stenosis. Nasal respiration returned to normal progressively after 56 days of hospitalization. The status was unchanged at 5 months. DISCUSSION: CNPAS is a rare cause of congenital nasal obstruction. It is sometimes associated to a median incisor syndrome. The diagnosis should be made as early as possible for an optimal management. Cyanosis and swallowing disorders may be lethal consequences. Associated abnormalities should be screened for with TDM or MRI. The treatment depends on the severity and may be surgical for a severe stenosis. The prognosis is good if no severe malformation or mental retardation is associated. PMID- 20167344 TI - Gegenbauer expansion to model the incident wave-field of a high-order Bessel vortex beam in spherical coordinates. AB - The aim of this short communication is to report that Gegenbauer's (partial-wave) expansion, that may be used (under some specific conditions) to represent the incident field of an acoustical (or optical) high-order Bessel beam (HOBB) in spherical coordinates, anticipates earlier expressions for undistorted waves. The incident wave-field is written in terms of the spherical Bessel function of the first kind, the gamma function as well as the Gegenbauer or ultraspherical functions given in terms of the associated Legendre functions when the order m of the HOBB is an integer number. Expressions for high-order and zero-order Bessel beams as well as for plane progressive waves reported in prior works can be deduced from Gegenbauer's partial-wave expansion by appropriate choice of the beams' parameters. Hence the value of this note becomes historical. In addition, Gegenbauer's expansion in spherical coordinates may be used to advantage to model the wave-field of a fractional HOBB at the origin (i.e. z=0). PMID- 20167345 TI - Viral pathogenesis in mice is similar for West Nile virus derived from mosquito and mammalian cells. AB - West Nile virus (WNV) is a mosquito-borne pathogen. During replication, WNV acquires different carbohydrates and lipid membranes, depending on its mosquito or vertebrate hosts. Consequently, WNV derived from mosquito and vertebrate cell lines differ in their infectivity for dendritic cells (DCs) and induction of type I interferon (IFN-alpha/beta) in vitro. We evaluated the pathogenesis of WNV derived from mosquito (WNV(C6/36)) and vertebrate (WNV(BHK)) cell lines in mice. The tissue tropism, infectivity, clinical disease, and mortality did not differ for mice inoculated with WNV(C6/36) or WNV(BHK), and there were only minor differences in viral load and serum levels of IFN-alpha/beta. The replication kinetics of WNV(C6/36) and WNV(BHK) were equivalent in primary DCs and skin cells although primary DCs were more susceptible to WNV(C6/36) infection than to WNV(BHK) infection, suggesting that less virus is produced per infected cell for WNV(C6/36). In conclusion, viral source has minimal effect on WNV pathogenesis in vivo. PMID- 20167346 TI - CYP1A expression in liver and gills of rainbow trout (Oncorhynchus mykiss) after short-term exposure to dibenzothiophene (DBT). AB - Dibenzothiophene (DBT), a common component of crude oil, is a widespread environmental pollutant of known adverse effects to aquatic vertebrates. However, the molecular mechanism by which DBT exerts its effects still remains unknown. Our goal for this study was to examine DBT effects on CYP1A expression in liver and gills of rainbow trout after short-term exposure. Juvenile trout individuals were injected intraperitoneally with two doses of DBT (10 or 50mgkg(-1)) and were kept in tanks for 8 and 24h (T=14 degrees C), then their gene expression levels were evaluated by Real-Time qPCR and Western-blot analysis. Treatment with DBT at either dose decreased CYP1A mRNA levels through the exposure period, which resulted in the final decrease of CYP1A protein levels in liver and gills on the end of experiment (24h). Thus, our results showing significant depletion of CYP1A molecules in metabolic tissues upon DBT treatment correlate with those previous reports that indicate a role of DBT in reducing CYP1A activity in fish. PMID- 20167347 TI - Degradation of volatile organic compounds in a non-thermal plasma air purifier. AB - The degradation of volatile organic compounds in a commercially available non thermal plasma based air purifying system was investigated. Several studies exist that interrogate the degradation of VOCs in closed air systems using a non thermal plasma combined with a heterogeneous catalyst. For the first time, however, our study was performed under realistic conditions (normal indoor air, 297.5K and 12.5 g m(-3) water content) on an open system, in the absence of an auxiliary catalyst, and using standard operating air flow rates (up to 320 L min( 1)). Cyclohexene, benzene, toluene, ethylbenzene and the xylene isomers were nebulized and guided through the plasma air purifier. The degradation products were trapped by activated charcoal tubes or silica gel tubes, and analyzed using gas chromatography mass spectrometry. Degradation efficiencies of 11+/-1.6% for cyclohexene, <2% for benzene, 11+/-2.4% for toluene, 3+/-1% for ethylbenzene, 1+/ 1% for sigma-xylene, and 3+/-0.4% for m-/rho-xylene were found. A fairly wide range of degradation products could be identified. On both trapping media, various oxidized species such as alcohols, aldehydes, ketones and one epoxide were observed. The formation of adipaldehyde from nebulized cyclohexene clearly indicates an ozonolysis reaction. Other degradation products observed suggests reactions with OH radicals. We propose that mostly ozone and OH radicals are responsible for the degradation of organic molecules in the plasma air purifier. PMID- 20167348 TI - Polychlorinated biphenyl behavior in soils amended with biosolids. AB - Assessment of the mobility of polychlorinated biphenyls (PCBs) in soils, amended with biosolids at a rate of 30Mgha(-1), was performed using an incubation process and leaching columns. The incubation process was carried out for 0, 30, and 60d under field capacity conditions at 25 degrees C. The mobility of PCBs was assessed using solutions of 0.5molL(-1) CaCl(2) and 25mgL(-1) linear alkylbenzenes sulfonate (LAS). Ultrasound-assisted pressurized solvent extraction (US-PSE) was utilized for compound separation from the solid matrix. Compounds were determined by gas chromatography coupled to mass spectrometry. The biosolids, containing a background PCB concentration about 300microgkg(-1), were spiked with the analytes at 300mgkg(-1) to obtain a clearer determination of their behavior when the biosolid was mixed with soil. In biosolid-amended soils, an increase was observed in the extractability of PCBs with increasing incubation time, which may be attributed to organic matter breakdown. The leaching column study showed that CaCl(2) was unable to mobilize the PCBs from the biosolid to the soil, whereas LAS mobilized these compounds within the time scale implicit in the experiment (30d). The most mobilized congeners in the columns corresponded to those with the greatest molecular weight (hexa- and heptachlorinated), probably due to the higher hydrophobicity of these compounds. Results indicate that the presence of important concentrations of LAS in biosolids could mobilize PCBs from soil to the freatic level. PMID- 20167349 TI - Seasonal variations of sources of polycyclic aromatic hydrocarbons (PAHs) to a northeastern urban city, China. AB - Understanding the seasonal variations of sources of polycyclic aromatic hydrocarbons (PAHs) in air in urban region is important to the effective control of air pollution in the region. Based on a year round dataset (from August 2008 to July 2009), the sources of atmospheric PAHs in Harbin, a typical Chinese northeastern urban city, were analyzed by principal component analysis (PCA) and positive matrix factorization (PMF). The average total (gas plus particulate) PAH concentration varied from 6.3 ng m(-3) to 340 ng m(-3) with a mean of 100+/-94 ng m(-3), with higher concentrations in heating season than those in non-heating season. PCA and PMF identified similar source factors to atmospheric PAHs with obvious seasonal variation. The results obtained by PMF method indicated that the main sources were coal-fired boiler (39%), diesel engine (34%) and coal average (22%) in heating season and traffic emissions (59%), ground evaporation (18%) and coal average (17%) in non-heating season. Excellent correlation coefficients between predicted and measured concentrations of PAHs indicated that PMF was a useful model for source apportionment of PAHs in atmosphere. PMID- 20167350 TI - Intense winter atmospheric pollution episodes affecting the Western Mediterranean. AB - The geographic location of the Western Mediterranean Basin and its peculiar topography, the climatic conditions and the intense anthropogenic and natural emissions of atmospheric pollutants are key factors necessary to interpret the atmospheric aerosol phenomenology over this area. During the cold season it is common to have severe atmospheric particulate matter (PM) pollution episodes (of an anthropogenic origin) affecting this region, not only in the urban and industrial areas but also in the regional and rural sites. During these episodes, the midday hourly PM(1) levels at regional background sites are in many cases higher than those at urban areas. Around 10% of the days under winter anticyclonic conditions registered similar PM(1) levels at the regional background than at the urban area and, sporadically the daily PM(1) levels at the regional background sites may exceed those at urban sites. Furthermore, the very high hourly PM(1) levels measured at regional background sites during these episodes are not regularly attained in the closest urban areas, which leads to the hypothesis that an important formation of secondary aerosols occurs during the transport of the polluted air masses towards the elevated rural sites. The interpretation of the variability of PM levels and composition (2002-2008) at one urban site (Barcelona) and at one regional background site (Montseny) allows us to illustrate the phenomenology of these scenarios, to quantify the mean annual contributions to the PM levels and to identify their main tracers. Ammonium nitrate appears to be the most abundant compound during these scenarios, although organic species and trace metals also increase markedly. Owing to the intensity, composition and recurrence of these atmospheric pollution episodes, important health, climatic and ecological implications may be derived. PMID- 20167351 TI - Deleterious effects of water-soluble fraction of petroleum, diesel and gasoline on marine pejerrey Odontesthes argentinensis larvae. AB - Accidental discharges and oil spills are frequent around the world. Petroleum derived hydrocarbons are considered one of the main pollutants of aquatic ecosystem. The importance of petroleum and refined fuels is notorious because today's society depends on them. Researches related to the toxic water-soluble fraction (WSF) of petroleum and derivatives to aquatic biota are scarce. For this reason, deleterious effects of WSF of Brazilian petroleum, automotive diesel and unleaded gasoline to marine pejerrey Odontesthes argentinensis larvae were studied employing toxicity tests and histopathological examination. Each WSF was generated in a laboratory by mixing four parts of seawater with one part of pollutant by approximately 22 h. Larvae were exposed during 96 h to different concentrations of WSF of petroleum, diesel, and gasoline, plus a control. After 96 h of exposure to the different WSFs, three larvae were sampled for histopathological studies. The median lethal concentration after 96 h (LC50) of exposure for WSF of petroleum was equal to 70.68%, it was significantly higher (P<0.05) than the values for WSF of diesel and gasoline, which were 13.46% and 5.48%, respectively. The histological examination of pejerrey larvae exposed to WSF of petroleum, diesel and gasoline after 96 h revealed a variety of lesions in the larvae. The gills, pseudobranchs and esophagus presented epithelial hyperplasia, and the liver presented dilatation of hepatic sinusoids, hepatocitomegaly, bi-nucleated and nuclear degeneration of hepatocytes, such as pyknotic nuclei. The acute toxicity of diesel and gasoline is at least fivefold higher than Brazilian petroleum. However, all toxicants induced histopathological abnormalities in pejerrey larvae. The results are of importance since much attention has been paid to large visible surfaces of petroleum spills instead of potential toxic effects of dissolved aromatic hydrocarbons, which are more available to marine biota. PMID- 20167352 TI - Comparative study of pre-treatment procedures for (3)H monitoring in water samples from environmental protection programs. AB - The determination of tritium activity in water samples is included in most environmental protection programs, and the recommended procedure consists of sample distillation and further measurement by liquid scintillation. Distillation is a simple but time consuming pre-treatment, especially in routine analysis. Here we evaluate alternative pre-treatments for tritium activity determination, such as filtration or the use of multiple selective ion exchange columns. 52 samples from different water sources (rain, surface, underground, sea and drinking water) in Spanish environmental protection programs, together with an IAEA reference material were analyzed. Results show that both pre-treatments can be applied as a preliminary tool to discriminate between tritium active and non active waters in environmental monitoring programs. In addition, filtration and multiple selective ion exchange column pre-treatments can be used as alternative procedures for tritium activity determination in the routine analyses of water samples with known and reproducible chemical and isotopic composition. Both methods are less time consuming than distillation and, in the case of filtration, extremely cheap. For waters with complex matrices, especially sea water, distillation is the recommended procedure due to the interference from salts contained in the sample. PMID- 20167353 TI - In vitro evaluation of cytotoxicity of engineered carbon nanotubes in selected human cell lines. AB - In this study, we used a systematic approach to study and compare the in vitro cytotoxicity of selected engineered carbon nanotubes (CNTs) to test cell lines including human skin keratinocytes, lung cells and lymphocytes. Results of fluorescein diacetate (FDA) uptake in T4 lymphocyte A3 cells indicated cytotoxicity caused by single-walled carbon nanotubes (SWCNTs) at concentrations of 2, 5 and 10ppm. At 2ppm, the SWCNT treatment group retained 71.3% viability compared to the PBS control group. At 10ppm, cellular viability further decreased to 56.5% of the PBS control group. In the skin keratinocyte HaCaT cells and lung MSTO-211H cells, the SWCNT did not demonstrate any cytotoxicity at concentrations of 2 and 5ppm but slightly inhibited HaCaT cells and caused significant toxicity to MSTO-211H cells at 10ppm. Multi-walled carbon nanotube (MWCNT) testing showed significant cytotoxicity to A3 cells in a dose-dependent manner. At 10ppm the viability of the cells decreased to 89.1% compared to the PBS control. In MSTO 211H cells, MWCNT caused significant toxicity at concentrations of 2ppm and higher. By comparison, HaCaT cells were inhibited significantly only at 10ppm. Overall, the test CNTs inhibited cellular viabilities in a concentration, cell type, and CNT type-dependent pattern. The viabilities of the MWCNT-impacted cells are higher than the corresponding SWCNT groups. We speculate that on a per volume basis, the greater availability of defects and contaminants for cellular interaction may contribute to the higher cytotoxicity of SWCNT in this study. The interaction between the SWCNTs and A3 lymphocytes was also observed by scanning electron microscopy. The mechanism for causing cell death in this study was attributed to apoptosis and necrosis after physical penetration by CNTs and oxidative stress via formation of reactive oxygen species. PMID- 20167354 TI - "Clinical benefit rate" in phase 2 gynecologic cancer trials: implying more than the data support? PMID- 20167355 TI - The sentinel node concept in early cervical cancer performs well in tumors smaller than 2 cm. AB - OBJECTIVE: The aim of the study was to evaluate the sentinel node (SLN) concept for lymphatic mapping in early stage cervical cancer. METHODS: 105 women with early stage (1a1-2a) cervical cancer were scheduled for the sentinel node procedure in conjunction with a complete pelvic lymphadenectomy. The day before surgery, 1-1.5 mL 120MBq Tc(99) albumin nanocolloid was injected submucosally at four points around the tumor followed by a lymphoscintigram (LSG) to achieve an overview of the radiotracer uptake. RESULTS: During surgery, the overall detection rate (gamma probe) of at least one SLN was 90% (94/105 women) whereas at least one SLN was identified in 94% (61/65 women) with a tumor 2 cm) node without radiotracer uptake. The negative predictive value for patients with cervical cancers or = 32 microm of four soil samples. These soils were obtained from four different locations within Inshas site in Egypt and three groundwater samples were obtained from the same site locations. X-ray diffraction showed that the soil samples consisted mainly of quartz mixed with the minor amounts of kaolonite and clay minerals. Sorption experiments were carried out at strontium aqueous concentrations range 10(-7) to 10(-4) mol l(-1). The CEC and Kds for cesium and strontium were measured at the same metal concentrations range. Distribution coefficients of cesium were found to be influenced by the composition of the soil, while the distribution coefficients of strontium were found to depend on calcium concentrations in the soil/groundwater system. The aim of this study was to determine the safety assessment of disposal 137Cs radionuclide and Sr(II) in the aquifer regions inside the Inshas site. Sequential extraction tests showed that, strontium was associated with the carbonate fractions and majority of cesium was sorbed on the iron oxides and the residue. PMID- 20167405 TI - Precautions required for needle cricothyroidotomy. PMID- 20167406 TI - Preferences for long-term care services: willingness to pay estimates derived from a discrete choice experiment. AB - Ageing populations increase pressure on long-term care. Optimal resource allocation requires an optimal mix of care services based on costs and benefits. Contrary to costs, benefits remain largely unknown. This study elicits preferences in the general elderly population for long-term care services for varying types of patients. A discrete choice experiment was conducted in a general population subsample aged 50-65 years (N = 1082) drawn from the Dutch Survey Sampling International panel. To ascertain relative preferences for long term care and willingness to pay for these, participants were asked to choose the best of two care scenarios for four groups of hypothetical patients: frail and demented elderly, with and without partner. The scenarios described long-term care using ten attributes based on Social Production Function theory: hours of care, organized social activities, transportation, living situation, same person delivering care, room for individual preferences, coordination of services, punctuality, time on waiting list, and co-payments. We found the greatest value was attached to same person delivering care and transportation services. Low value was attached to punctuality and room for individual preferences. Nursing homes were generally considered to be detrimental for well-being except for dementia patients without a partner. Overall, long-term care services were thought to produce greatest well-being for the patients 'without a partner' and those 'with dementia'. Individuals combining these two risk factors would benefit the most from all services except transportation which was considered more important for the frail elderly. The results support the notion that long-term care services represent different value for different types of patients and that the value of a service depends upon the social context. Examination of patient profiles confirmed the notion that physical, mental and social vulnerability affect valuation of the services. Policy-making would profit from allocation models in which budgetary requirements of different services can be balanced against the well-being they produce for individuals. PMID- 20167407 TI - Income inequality, perceived happiness, and self-rated health: evidence from nationwide surveys in Japan. AB - In this study, we examined how regional inequality is associated with perceived happiness and self-rated health at an individual level by using micro-data from nationwide surveys in Japan. We estimated the bivariate ordered probit models to explore the associations between regional inequality and two subjective outcomes, and evaluated effect modification to their sensitivities to regional inequality using the categories of key individual attributes. We found that individuals who live in areas of high inequality tend to report themselves as both unhappy and unhealthy, even after controlling for various individual and regional characteristics and taking into account the correlation between the two subjective outcomes. Gender, age, educational attainment, income, occupational status, and political views modify the associations of regional inequality with the subjective assessments of happiness and health. Notably, those with an unstable occupational status are most affected by inequality when assessing both perceived happiness and health. PMID- 20167408 TI - Pharmaceutical innovation and mortality in the United States, 1960-2000. A commentary on Schnittker and Karandinos. PMID- 20167409 TI - "My health has improved because I always have everything I need here...": A qualitative exploration of health improvement and decline among immigrants. AB - Immigrants in Canada constitute approximately 20% of the total population and will continue to account for a significant portion of the country's population in the future. Accordingly, a growing body of research has focused on examining the disparity in health status between the increasing foreign-born and the Canadian born populations. The healthy immigrant effect, in particular, acknowledges that immigrants have better health status than their Canadian-born counterparts upon arrival in the country. However, studies have shown that over time the health of immigrants declines to a level on par with the Canadian-born population. There is much speculation as to the reasons for this decline including acculturation (i.e., uptake of unhealthy lifestyles) and a lack of access to health care. Yet, there have been few studies to examine possible reasons for potential declines in health, especially from the perspective of immigrants themselves. This study is one of the first to qualitatively examine perceived changes in health status and reasons for health status change among immigrants. The paper presents the results of 23 in-depth interviews with adults with recent (less than 3 years of residency), mid-term (3-10 years), and long-term (more than 10 years) immigrants living in the Greater Toronto Area. The results reveal that the majority of the participants believed their health had remained stable or even improved over time due to improved living standards and lifestyle behaviours in Canada. Those who perceived their health to have worsened over time attributed the change to the stress associated with migration, and the aging process rather than the adoption of an unhealthy lifestyle. Additionally, while the vast majority of participants reported improved access to resources upon migration, there were mixed reviews in terms of how beneficial these resources were or could be for health. The findings highlight the need for research to incorporate mental health into studies on changing immigrant health status and to focus on those factors contributing to high levels of stress among more recent immigrants. PMID- 20167410 TI - Medicaid and racial disparities in health: the issue of causality. A commentary on Rose et al. PMID- 20167411 TI - In search of 'low health literacy': threshold vs. gradient effect of literacy on health status and mortality. AB - Studies have demonstrated significant associations between limited literacy and health outcomes. Yet differences in literacy measurement and the cutoffs used for analysis have made it difficult to fully understand the relationship between literacy and health across the entire spectrum of literacy (i.e., whether the relationship is continuous and graded or whether a threshold exists below which literacy is independently associated with health). To analyze this question, we re-examined the relationship between literacy, baseline physical functioning and mental health, and all-cause mortality for a cohort of 3260 US community-dwelling elderly who were interviewed in 1997 to determine demographics, socioeconomic status, chronic conditions, self-reported physical and mental health (SF-36 subscales), health behaviors, and literacy based upon the Short Test of Functional Health Literacy in Adults (S-TOFHLA). All-cause mortality was determined using data from the US National Death Index through 2003. Seven categories of S-TOFHLA literacy scores were created and used in this analysis instead of the existing three categories identified with the measure. In multivariate analyses, a continuous, graded relationship between literacy and baseline physical functioning was identified. However, participants scoring below the third literacy category had significantly worse mental health compared to the highest literacy category, displaying a notable threshold. Finally, all six literacy categories were significantly associated with greater all-cause mortality risk compared to the highest literacy category, but again there was a marked threshold below the third category at which the adjusted mortality rate significantly increased compared to all other categories. We conclude that the nature of the relationship between literacy and health may vary depending upon the outcome under examination. PMID- 20167412 TI - Emotion and object processing in Parkinson's disease. AB - The neuropsychological literature on the processing of emotions in Parkinson's disease (PD) reveals conflicting evidence about the role of the basal ganglia in the recognition of facial emotions. Hence, the present study had two objectives. One was to determine the extent to which the visual processing of emotions and objects differs in PD. The other was to assess the impact of cognitive load on the processing of these types of information. Thirty-one patients with idiopathic PD (IPD) under dopamine replacement therapy (DRT) were compared to 30 control subjects on emotion and object recognition tasks. Recognition of objects was more accurate and faster than recognition of facial expressions of emotion, for both groups of subjects. In a second experiment using an N-back procedure with the same stimuli-a more demanding task with a higher cognitive load-patients with IPD were as accurate as control subjects in detecting the correct sequential presentation of stimuli, but were much slower in their decision responses. This indicates that IPD patients under DRT are not impaired in encoding emotion or object information, but that they have difficulty with the processing demands of the N-back task. Thus, patients with IPD appear to be more sensitive to cognitive load than to type of information, whether facial emotions or objects. In this perspective, one must consider that a deafferented dopaminergic system has problems processing more complex information before one can posit the existence of deficits affecting a specific type of information. PMID- 20167413 TI - Deconstructing the tower: parameters and predictors of problem difficulty on the Tower of London task. AB - The Tower of London (TOL) task has been widely used in both clinical and research realms. In the current study, 104 healthy participants attempted all possible moderate- to high-difficulty TOL problems in order to determine: (1) optimal measures of problem solving performance, (2) problem characteristics, other than the minimum moves necessary to solve the problem, that determine participants' difficulty in solving problems successfully, quickly, and efficiently, and (3) effects of increased task experience on which problem characteristics determine problem difficulty. A factor analysis of six performance measures found that, regardless of task experience, problem difficulty could be captured well either by a single factor corresponding to general quality of solution or possibly by three subordinate factors corresponding to solution efficiency, solution speed, and initial planning speed. Regression analyses predicting these performance factors revealed that in addition to a problem's minimum moves three problem parameters were critical in determining the problem difficulty: goal position hierarchy, start position hierarchy, and number of solution paths available. The relative contributions of each of the characteristics strongly depended on which performance factor defined performance. We conclude that TOL problem performance is multifaceted, and that classifying problem difficulty using only the minimum moves necessary to solve the problem is inadequate. PMID- 20167414 TI - Associations and dissociations of transitive and intransitive gestures in left and right hemisphere stroke patients. AB - The study investigated performance on pantomime and imitation of transitive and intransitive gestures in 80 stroke patients, 42 with left (LHD) and 38 with right (RHD) hemisphere damage. Patients were also categorized in two groups based on the time that has elapsed between their stroke and the apraxia assessment: acute subacute (n=42) and chronic (n=38). In addition, patterns of performance in apraxia were examined. We expected that acute-subacute patients would be more impaired than chronic patients and that LHD patients would be more impaired than RHD patients, relative to controls. The hemisphere prediction was confirmed, replicating previous findings. The frequency of apraxia was also higher in all LHD time post-stroke groups. The most common impairment after LHD was impairment in both pantomime and imitation in both transitive and intransitive gestures. Selective deficits in imitation were more frequent after RHD for transitive gestures but for intransitive gestures they were more frequent after LHD. Patients were more impaired on imitation than pantomime, relative to controls. In addition, after looking at both gesture types concurrently, we have described cases of patients who suffered deficits in pantomime of intransitive gestures with preserved performance on transitive gestures. Such cases show that the right hemisphere may be in some cases critical for the successful pantomime of intransitive gestures and the neural networks subserving them may be distinct. Chronic patients were also less impaired than acute-subacute patients, even though the difference did not reach significance. A longitudinal study is needed to examine the recovery patterns in both LHD and RHD patients. PMID- 20167416 TI - Comparison of current docking tools for the simulation of inhibitor binding by the transmembrane domain of the sarco/endoplasmic reticulum calcium ATPase. AB - Inhibitors of the transmembrane protein sarco/endoplasmic reticulum calcium ATPase (SERCA) are invaluable tools for the study of the enzyme's physiological functions and they have been recognized as a promising new class of anticancer agents. For the discovery of novel enzyme inhibitors, small molecule docking for virtual screens of large compound libraries has become increasingly important. Since the performance of various docking routines varies considerably, depending on the target and the chemical nature of the ligand, we critically evaluated the performance of four frequently used programs - GOLD, AutoDock, Surflex-Dock, and FRED - for the docking of SERCA inhibitors based on the structures of thapsigargin, di-tert-butylhydroquinone, and cyclopiazonic acid. Evaluation criteria were docking accuracy using crystal structures as references, docking reproducibility, and correlation between docking scores and known bioactivities. The best overall results were obtained by GOLD and FRED. Docking runs with conformationally flexible binding sites produced no significant improvement of the results. PMID- 20167415 TI - Common neural systems associated with the recognition of famous faces and names: an event-related fMRI study. AB - Person recognition can be accomplished through several modalities (face, name, voice). Lesion, neurophysiology and neuroimaging studies have been conducted in an attempt to determine the similarities and differences in the neural networks associated with person identity via different modality inputs. The current study used event-related functional-MRI in 17 healthy participants to directly compare activation in response to randomly presented famous and non-famous names and faces (25 stimuli in each of the four categories). Findings indicated distinct areas of activation that differed for faces and names in regions typically associated with pre-semantic perceptual processes. In contrast, overlapping brain regions were activated in areas associated with the retrieval of biographical knowledge and associated social affective features. Specifically, activation for famous faces was primarily right lateralized and famous names were left lateralized. However, for both stimuli, similar areas of bilateral activity were observed in the early phases of perceptual processing. Activation for fame, irrespective of stimulus modality, activated an extensive left hemisphere network, with bilateral activity observed in the hippocampi, posterior cingulate, and middle temporal gyri. Findings are discussed within the framework of recent proposals concerning the neural network of person identification. PMID- 20167417 TI - Formation of Schiff-base for photoreaction mechanism of red shift of GFP spectra. AB - We have proposed the formation of Schiff-base between R96 and chromophore (CRO) to elucidate the reaction mechanism for the irreversible red shift of green fluorescent protein (GFP) spectra under the absence of oxygen. The difference between absorption energies of reactant and product for our GFP models with CIS(D)/6-31G* level is 0.21eV, which is in reasonable agreement with the corresponding experimental value of 0.25eV. We have suggested the irreversible photoreaction mechanism, where the CRO excited from ground (S(0)) state to first excited singlet (S(1)) state immediately turns to the first excited triplet (T(1)) state, and the nucleophilic addition reaction occurs on the T(1) state. PMID- 20167418 TI - Multiple-objective evaluation of wastewater treatment plant control alternatives. AB - Besides the evaluation of the environmental issues, the correct assessment of wastewater treatment plants (WWTP) should take into account several objectives such as: economic e.g. operation costs; technical e.g. risk of suffering microbiology-related TSS separation problems; or legal e.g. accomplishment with the effluent standards in terms of the different pollution loads. For this reason, the main objective of this paper is to show the benefits of complementing the environmental assessment carried out by life cycle assessment with economical, technical and legal criteria. Using a preliminary version of the BSM2 as a case study, different combinations of controllers are implemented, simulated and evaluated. In the following step, the resulting multi-criteria matrix is mined using multivariate statistical techniques. The results showed that the presence of an external carbon source addition, the type of aeration system and the TSS controller are the key elements creating the differences amongst the alternatives. Also, it was possible to characterize the different control strategies according to a set of aggregated criteria. Additionally, the existing synergies amongst different objectives and their consequent trade-offs were identified. Finally, it was discovered that from the initial extensive list of evaluation criteria, only a small set of five are really discriminant, being useful to differentiate within the generated alternatives. PMID- 20167419 TI - Circulating tumor cells in metastatic colorectal cancer: efficacy and feasibility of different enrichment methods. AB - Comprehensive in vitro and in vivo studies comparing EpCAM-based methods with other cytometric CTC enrichment technologies in metastatic colorectal cancer (mCRC) patients are lacking. We compare four manual cytometric methods to detect CTCs in vitro and in mCRC patients. The EpCAM-based technology, MACS HEA MicroBeads((R)), showed a significant better tumor cell recovery rate compared to other cytometric methods (p-value<0.0001). CTCs of 38 mCRC patients were enriched with MACS HEA MicroBeads(R). Progression-free survival did significantly differ between mCRC patients without detectable and with >or= 1 CTCs (p=0.007). CTC enrichment with EpCAM coupled antibodies is superior to other cytometric methods and is a feasible method for CTC detection in mCRC patients. PMID- 20167421 TI - The thermal behaviour and structural stability of nesquehonite, MgCO3.3H2O, evaluated by in situ laboratory parallel-beam X-ray powder diffraction: New constraints on CO2 sequestration within minerals. AB - In order to gauge the appropriateness of CO(2) reaction with Mg chloride solutions as a process for storing carbon dioxide, the thermal behaviour and structural stability of its solid product, nesquehonite (MgCO(3).3H(2)O), were investigated in situ using real-time laboratory parallel-beam X-ray powder diffraction. The results suggest that the nesquehonite structure remains substantially unaffected up to 373 K, with the exception of a markedly anisotropic thermal expansion acting mainly along the c axis. In the 371-390 K range, the loss of one water molecule results in the nucleation of a phase of probable composition MgCO(3).2H(2)O, which is characterized by significant structural disorder. At higher temperatures (423-483 K), both magnesite and MgO.2MgCO(3) coexist. Finally, at 603 K, periclase nucleation starts and the disappearance of carbonate phases is completed at 683 K. Consequently, the structural stability of nesquehonite at high temperatures suggests that it will remain stable under the temperature conditions that prevail at the Earth's surface. These results will help (a) to set constraints on the temperature conditions under which nesquehonite may be safely stored and (b) to develop CO(2) sequestration via the synthesis of nesquehonite for industrial application. PMID- 20167420 TI - Abrogation of Akt signaling by Isobavachalcone contributes to its anti proliferative effects towards human cancer cells. AB - Akt signaling pathway has attracted much attention as a promising target for cancer therapeutics. Herein, we report that Isobavachalcone (IBC), a natural chalcone, potently abrogates Akt signaling and exerts anti-proliferative effects on several human cancer cell lines. Modeling results from the Sybyl/FlexiDock program suggest that IBC potentially binds to the ATP-binding pocket of Akt, which is confirmed by the observations that IBC inhibits Akt1 kinase in vitro. Further studies reveal that IBC significantly abates Akt phosphorylation at Ser 473 and Akt kinase activity in cells, which subsequently leads to inhibition of Akt downstream substrates and evokes significant levels of apoptosis associated with mitochondria pathway. PMID- 20167422 TI - Factors affecting the electro-catalytic characteristics of Eu doped SnO2/Sb electrode. AB - Different compositions of Eu doped electrodes were prepared by a pyrolysis method in order to investigate the effect of Eu on the electro-catalytic behavior of Ti based SnO(2)/Sb electrodes. The electrodes were characterized by SEM, EDS, XRD and their degradation abilities were evaluated using phenol. The electro catalytic performance of prepared electrodes was strongly influenced by the heat treatment temperature and Eu doping content. A temperature of 750 degrees C and a Eu content of 2% provided optimal catalytic activity for the SnO(2)/Sb electrode. Phenol removal percentage was lowered by 13.2% compared to the control when higher Eu doping (5%) was applied due to the potential concentration of oxygen vacancies and the enrichment of Eu atoms on electrode surface. The unit cell of SnO(2) expanded by about 2% after Eu doping due to the replacement of the smaller Sn(4+) by larger Eu(3+). The average size of the SnO(2) grains on the electrode surface for the Eu doped samples ranged from 8 to 9 nm, which was smaller than that of the control, suggesting catalysis improvement since smaller grain sizes produced more active sites on the electrode surface. PMID- 20167423 TI - Simultaneous removal of sulfide, nitrate and acetate: Kinetic modeling. AB - Biological removal of sulfide, nitrate and chemical oxygen demand (COD) simultaneously from industrial wastewaters to elementary sulfur (S(0)), N(2), and CO(2), or named the denitrifying sulfide (DSR) process, is a cost effective and environmentally friendly treatment process for high strength sulfide and nitrate laden organic wastewater. Kinetic model for the DSR process was established for the first time on the basis of Activated Sludge Model No. 1 (ASM1). The DSR experiments were conducted at influent sulfide concentrations of 200-800 mg/L, whose results calibrate the model parameters. The model correlates well with the DSR process dynamics. By introducing the switch function and the inhibition function, the competition between autotrophic and heterotrophic denitrifiers is quantitatively described and the degree of inhibition of sulfide on heterotrophic denitrifiers is realized. The model output indicates that the DSR reactor can work well at 0.51000 mg/L influent sulfide, however, the DSR system will break down. PMID- 20167424 TI - Metal recovery from spent refinery catalysts by means of biotechnological strategies. AB - A bioleaching study aimed at recovering metals from hazardous spent hydroprocessing catalysts was carried out. The exhaust catalyst was rich in nickel (4.5 mg/g), vanadium (9.4 mg/g) and molybdenum (4.4 mg/g). Involved microorganisms were iron/sulphur oxidizing bacteria. Investigated factors were elemental sulphur addition, ferrous iron addition and actions contrasting a possible metal toxicity (either adding powdered activated charcoal or simulating a cross current process by means of periodical filtration). Ferrous iron resulted to be essential for metal extraction: nickel and vanadium extraction yields were 83% and 90%, respectively, while about 50% with no iron. The observed values for molybdenum extraction yields were not as high as Ni and V ones (the highest values were around 30-40%). The investigated actions aimed at contrasting a possible metal toxicity resulted not to be effective; in contrast, sequential filtration of the liquor leach had a significant negative effect on metals extraction. Nickel and vanadium dissolution kinetics resulted to be significantly faster than molybdenum dissolution ones. Furthermore, a simple first order kinetic model was successfully fitted to experimental data. All the observed results supported the important role of the indirect mechanism in bioleaching of LC-Finer catalysts. PMID- 20167425 TI - Application of AlMCM-41 for competitive adsorption of methylene blue and rhodamine B: Thermodynamic and kinetic studies. AB - AlMCM-41 was applied for adsorption of methylene blue (MB) and rhodamine B (RB) in single and binary component systems. In the single component systems, AlMCM-41 represents higher adsorption capacity for MB than RB with the maximal adsorption capacity of 2.08x10(-4) and 8.74x10(-5)mol/g at 25 degrees C for MB and RB, respectively. In the binary component system, MB and RB exhibit competitive adsorption onto the adsorbent. The adsorption is approximately reduced to 94 and 79% of single component adsorption systems for MB and RB (initial concentration of 8x10(-6)M) at 25 degrees C. In single and binary component systems, kinetic and adsorption isotherm studies demonstrate that the data are following pseudo second-order kinetic model and Langmuir isotherm. Effect of solution pH on the adsorption in single and binary component systems was studied and the results were described by electrostatic interactions. PMID- 20167426 TI - Heteronanostructure of Ag particle on titanate nanowire membrane with enhanced photocatalytic properties and bactericidal activities. AB - A novel seed induced method has been developed for syntheses of Ag particles on titanate nanowires, and then the heteronanostructured Ag/titanate nanowires were assembled into porous, flexible membranes. These titanate nanowires were about several hundreds micrometers in length and about 80 nm in diameter. The size of the Ag particle can be tuned within 300-700 nm. The pore size and thickness of the heteronanostructured membrane were easily controlled. An Ag/titanate nanowire membrane reactor has been developed to study the photocatalytic degradation of methamidophos in aqueous solution, and 87.0% of the methamidophos can be degraded in a concurrent filtration and photocatalytic oxidation process. The antibacterial activity was also investigated on the heteronanostructured membrane with UVA light (365 nm) irradiation, and a 99.99% satisfactory antibacterial effect on Escherichia coli was achieved. PMID- 20167427 TI - Pharmacological effects of nonselective and subtype-selective nicotinic acetylcholine receptor agonists in animal models of persistent pain. AB - Nicotinic acetylcholine receptors (nAChRs) are longstanding targets for a next generation of pain therapeutics, but the nAChR subtypes that govern analgesia remain unknown. We tested a series of nicotinic agonists, including many molecules used or tried clinically, on a panel of cloned neuronal nAChRs for potency and selectivity using patch-clamp electrophysiology and a live cell-based fluorescence assay. Nonselective nicotinic agonists as well as compounds selective either for alpha4beta2 or for alpha7 nAChRs were then tested in the formalin and complete Freund's adjuvant models of pain. Nonselective nAChR agonists ABT-594 and varenicline were effective analgesics. By contrast, the selective alpha4beta2 agonist ispronicline and a novel alpha4beta2-selective potentiator did not appear to produce analgesia in either model. alpha7-selective agonists reduced the pain-related endpoint, but the effect could be ascribed to nonspecific reduction of movement rather than to analgesia. Neither selective nor nonselective alpha7 nicotinic agonists affected the release of pro-inflammatory cytokines in response to antigen challenge. Electrophysiological recordings from spinal cord slice showed a strong nicotine-induced increase in inhibitory synaptic transmission that was mediated partially by alpha4beta2 and only minimally by alpha7 subtypes. Taken with previous studies, the results suggest that agonism of alpha4beta2 nAChRs is necessary but not sufficient to produce analgesia, and that the spinal cord is a key site where the molecular action of nAChRs produces analgesia. PMID- 20167428 TI - Genetic variation in the beta2-adrenergic receptor but not catecholamine-O methyltransferase predisposes to chronic pain: results from the 1958 British Birth Cohort Study. AB - More than 1 in 10 adults in the general population experience chronic widespread body pain (CWP), which lies at one end of a continuous spectrum of pain ranging in both severity and duration. Neuroendocrine factors can modify the effect of known psychological and psychosocial risk factors for progression along the spectrum of pain and development of CWP, and genetic variants that affect neuroendocrine and neural processing potentially affect susceptibility to chronic pain development. We have examined variants across genes encoding the beta2 adrenergic receptor (ADRB2) and catecholamine-O-methyltransferase (COMT) - key neuroendocrine signalling factors - in a large population-based sample to determine whether these may be involved in pain progression and CWP development. A nested association study was conducted using individuals from the 1958 British Birth Cohort Study who had been assessed for pain status. Genotypes were available for nine single nucleotide polymorphisms (SNPs) across ADRB2 and 11 SNPs across COMT. ADRB2 SNPs rs12654778 and rs1042713 were associated either with CWP alone (p=0.02 for both) or with position along pain spectrum (pain status; p=0.04). Common functional ADRB2 haplotype combinations were also associated with pain status (p(model)=0.002) and, further, with both extent and duration of pain (p(model)=0.003 and p(model)=0.002, respectively). There were no associations of either CWP or pain status with COMT genotypes or haplotypes. These results are the first to suggest that functional ADRB2 variants are involved in regulating pain status at a population level. A role for COMT in chronic pain development was not identified, though could not be excluded. PMID- 20167429 TI - In defense of science: investigation and evaluation without bias and prejudice. PMID- 20167430 TI - A randomized placebo-controlled trial of intradiscal methylene blue injection for the treatment of chronic discogenic low back pain. AB - A preliminary report of clinical study revealed that chronic discogenic low back pain could be treated by intradiscal methylene blue (MB) injection. We investigated the effect of intradiscal MB injection for the treatment of chronic discogenic low back pain in a randomized placebo-controlled trial. We recruited 136 patients who were found potentially eligible after clinical examination and 72 became eligible after discography. All the patients had discogenic low back pain lasting longer than 6 months, with no comorbidity. Thirty-six were allocated to intradiscal MB injection and 36 to placebo treatment. The principal criteria to judge the effectiveness included alleviation of pain, assessed by a 101-point numerical rating scale (NRS-101), and improvement in disability, as assessed with the Oswestry Disability Index (ODI) for functional recovery. At the 24-month follow-up, both the groups differed substantially with respect to the primary outcomes. The patients in MB injection group showed a mean reduction in pain measured by NRS of 52.50, a mean reduction in Oswestry disability scores of 35.58, and satisfaction rates of 91.6%, compared with 0.70%, 1.68%, and 14.3%, respectively, in placebo treatment group (p<0.001, p<0.001, and p<0.001, respectively). No adverse effects or complications were found in the group of patients treated with intradiscal MB injection. The current clinical trial indicates that the injection of methylene blue into the painful disc is a safe, effective and minimally invasive method for the treatment of intractable and incapacitating discogenic low back pain. PMID- 20167431 TI - A failure of the review process? Comment on Ahsin et al. Clinical and endocrinological changes after electro-acupuncture treatment in patients with osteoarthritis of the knee. Pain 2009;147:60-6. PMID- 20167433 TI - Smoking outcome expectancies: A multiple indicator and multiple cause (MIMIC) model. AB - The present study was carried out to assess the construct validity of the short form of the Smoking Consequences Questionnaire, a brief measure of smoking outcome expectancies on a large sample of adolescents (N = 953). The results of this study support a four-factor structure of smoking outcome expectancies, including expectancies of negative consequences, positive reinforcement, negative reinforcement and appetite-weight control, as well as the assertion that gender, smoking status and sensation-seeking have a distinct pattern of associations with the four outcome expectancy factors. PMID- 20167432 TI - NMDA-receptor activation and nitroxidative regulation of the glutamatergic pathway during nociceptive processing. AB - The role of peroxynitrite (PN) as a mediator of nociceptive signaling is emerging. We recently reported that the development of central sensitization that follows the intraplantar injection of carrageenan in rats is associated with spinal PN synthesis. We now demonstrate that a significant pathway through which spinal PN modulates central sensitization is post-translational tyrosine nitration of key proteins involved in the glutamatergic pathway, namely glutamate transporter GLT-1 and glutamine synthetase (GS). We also reveal that spinal activation of the N-methyl-d-aspartate (NMDA) receptor provides a source of PN in this setting. Intraplantar injection of carrageenan led to the development of thermal hyperalgesia as well as nitration of GLT-1 and GS in dorsal horn tissues. Pretreatment with the PN decomposition catalyst FeTM-4-PyP(5+) [Fe(III)5,10,15,20 tetrakis(N-methylpyridinium-4-yl)porphyrin] or the NMDA receptor antagonist MK 801 blocked the development of hyperalgesia. Carrageenan-induced hyperalgesia was also associated with nitration and inactivation of spinal mitochondrial superoxide dismutase (MnSOD) known to provide a critical source of PN during central sensitization. Nitration of GLT-1 and GS contributes to central sensitization by enhancing glutamatergic neurotransmission. Our results support the critical role of nitroxidative stress in the development of hyperalgesia and suggest that post-translational nitration of enzymes and transporters linked to glutamatergic neurotransmission represent a novel mechanism of central sensitization. PMID- 20167434 TI - Are subthreshold alcohol dependence symptoms a risk factor for developing DSM-IV alcohol use disorders? A three-year prospective study of 'diagnostic orphans' in a national sample. AB - AIMS: Research suggests that diagnostic orphans (i.e., individuals experiencing only 1-2 criteria for DSM-IV alcohol dependence) may be at increased risk for developing more severe alcohol problems. This study aimed to: (i) investigate the course of diagnostic orphans in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), and (ii) explore whether a specific symptom endorsement pattern(s) could identify diagnostic orphans at Wave 1 who remitted or progressed to alcohol dependence at Wave 2. METHODS: Current drinkers (n = 15,751) were divided into diagnostic groups at Waves 1 and 2: no-alcohol use disorder (AUD); one-criterion orphans, two-criterion orphans, alcohol abuse, or alcohol dependence. Multinomial logistic regression analysis explored the association between diagnostic status at Wave 1 and Wave 2. Chi-square tests investigated differences in the criteria endorsement patterns of diagnostic orphans. RESULTS: Compared to the no-AUD group, one-criterion orphans at Wave 1 were twice as likely to be in the abuse group and four times more likely to be dependent at Wave 2. Two-criterion orphans were three times more likely to be in the abuse group and eight times more likely to have progressed to dependence. Criterion endorsement patterns of diagnostic orphans at baseline did not significantly differentiate between those who remitted and those who progressed to dependence at follow-up. CONCLUSIONS: Like previous research, diagnostic orphans are at increased for developing to more severe alcohol problems. Relying solely on the DSM-IV AUD diagnostic criteria, however, may not be sufficient to identify those diagnostic orphans who are at risk for progressing to dependence. PMID- 20167435 TI - Effect of methamphetamine dependence on everyday functional ability. AB - BACKGROUND: Methamphetamine (METH) is an increasingly popular and highly addictive psychostimulant with a significant impact on public health. Chronic METH exposure has been associated with neurotoxic effects, profound neuropsychological deficits, and impaired quality of life, but few studies have examined the effect of the drug on the ability to carry out everyday activities. We assessed the effect of METH dependence on everyday functioning using the UCSD Performance-Based Skills Assessment (UPSA-2), a performance-based measure designed to evaluate real-life skills. METHOD: UPSA-2 performance was quantified in 15 currently abstinent individuals with a history of METH dependence and 15 drug-free comparison subjects. The Positive and Negative Syndrome Scale (PANSS) and Wisconsin Card Sorting Task (WCST) were administered to assess psychopathology and executive function. RESULTS: METH-dependent participants exhibited significant impairment on the UPSA-2 total score and several UPSA-2 subscales, including comprehension, finance, transportation, communication, and medication management compared to drug-free comparison subjects. Lower UPSA-2 scores were associated with impaired performance on the WCST, higher PANSS scores, and drug use at an earlier age. CONCLUSION: METH dependence may be associated with decreased everyday functioning ability potentially mediated by frontal cortex dysfunction or the emergence of psychopathology related to chronic drug use. PMID- 20167437 TI - Frailty and resilience from physics to medicine. PMID- 20167436 TI - Severity of withdrawal symptomatology in follicular versus luteal quitters: The combined effects of menstrual phase and withdrawal on smoking cessation outcome. AB - Women are at an increased risk of relapse after a smoking cessation attempt. While the reasons for this phenomenon are not fully understood, recent research indicates that both the menstrual cycle and negative symptomatology may play a role. The goal of this study was to describe the association between withdrawal symptoms during attempted smoking cessation, and to investigate the impact of these symptoms on smoking cessation outcomes as defined by 7-day point prevalence at 14 and 30 days. Negative symptoms associated with the premenstrual period were also assessed. Participants (n = 202) were 29.8 (SD +/- 6.6) years old and smoked 16.6 (SD +/- 5.6) cigarettes per day. They were randomly assigned to quit smoking in the follicular (n = 106) or luteal (n = 96) menstrual phase. We observed several significantly more severe premenstrual and withdrawal symptoms in the luteal phase. Regardless of quit phase, most withdrawal symptoms were associated with an increased risk of relapse at 14 and 30 days post quit date. Participants attempting to quit smoking in the follicular phase who had higher levels of Anger and Craving were more likely to relapse to smoking at 14-days (OR = 2.00, p-value = 0.026; OR = 2.63, p-value = 0.006; respectively). These data suggest that the menstrual cycle may play a role in smoking cessation outcome, as well as in the symptomatology experienced during a cessation attempt. PMID- 20167438 TI - [Spectral analysis of the microvasculature of primary cutaneous melanoma]. AB - Cutaneous malignant melanoma represents one of the most dramatic skin cancers because its incidence is steadily growing in White populations. Of note, its metastatic risk and mortality dramatically increase when the primary neoplasm reaches about one millimeter thick. It is believed that angiogenesis and lymphangiogenesis associated with cutaneous melanoma potentially influence the neoplastic progression of the primary tumor and its metastases. In some instances, both the intratumoral and peritumoral microvasculature are correlated to booming of the tumoral growth fraction. In addition, the vascular network serves as a migration path for the intravascular and perivascular neoplastic spread. Hence, the quantification of the microvasculature might help establishing a prognostic factor of evolution. Among the available methods, spectral analysis of immunohistochemical sections highlighting vessels helps defining the microvasculature distribution. The benefit of using spectral analysis is discussed and the modalities of application of this analytical method are scrutinized. PMID- 20167439 TI - [Present and future of cell therapy in burns]. AB - Severe burned patients need definitive and efficient wound coverage. Outcome of massive burns has been improved by using cultured epithelial autografts (CEA). Despite fragility, percentages of success take, cost of treatment and long-term tendency to contracture, this surgical technique has been developed in few burn centres. First improvements were to combine CEA and dermis-like substitute. Cultured skin substitutes provide earlier skin closure and satisfying functional result. These methods have been used successfully in massive burns. Second improvement was to allow skin regeneration by using epidermal stem cells. Stem cells have capacity to differentiate into keratinocytes, to promote wound repair and to regenerate skin appendages. Human mesenchymal stem cells contribute to wound healing and were evaluated in cutaneous radiation syndrome. Skin regeneration and tissue engineering methods remain a complex challenge and offer the possibility of new treatment for injured and burned patients. PMID- 20167440 TI - Recognition and management of alcohol misuse in OEF/OIF and other veterans in the VA: a cross-sectional study. AB - BACKGROUND: Mental health problems have been identified among soldiers serving in Operations Enduring Freedom and Iraqi Freedom (OEF/OIF), but little is known about the prevalence and management of alcohol misuse in OEF/OIF veterans seen in the Veterans Administration health care system (VA). METHODS: We identified 12,092 veterans (n=2009 women) 55 and younger and screened for alcohol misuse in FY2007 from a cross-sectional national sample of VA outpatients randomly selected for standardized medical record review for quality monitoring. Alcohol misuse was assessed with the Alcohol Use Disorders Identification Test Consumption questions (AUDIT-C > or =5). Based on medical record reviews, brief alcohol interventions (BI) were defined as documented (1) advice to abstain or drink within recommended limits or (2) feedback about health risks associated with drinking. RESULTS: Adjusted prevalence of alcohol misuse was higher in OEF/OIF men than non-OEF/OIF men [21.8% vs. 10.5%, adjusted odds ratio (AOR)=2.37 (95% CI: 1.88-2.99)], but did not differ reliably between OEF/OIF and non-OEF/OIF women [4.7% vs. 2.9%, AOR=1.68 (0.74-3.79)]. Adjusted rates of documented advice or feedback [31.6% vs. 34.6%, AOR=0.87 (0.58-1.21)] and referral [24.1% vs. 28.9%, AOR=0.78 (0.47-1.30)] were not significantly different between OEF/OIF and non-OEF/OIF men who screened positive for alcohol misuse. CONCLUSION: OEF/OIF men were more likely to screen positive for alcohol misuse than non-OEF/OIF men. Overall, approximately half of those with alcohol misuse had documented BI and/or referral to alcohol treatment suggesting a need for improvement in addressing alcohol misuse in OEF/OIF and other veterans. PMID- 20167441 TI - Successful treatment of chronic hepatitis C virus infection in severely opioid dependent patients under heroin maintenance. AB - BACKGROUND: Severely opioid-dependent patients are at high risk of both acquiring and spreading the hepatitis C virus (HCV). It is uncertain, however, whether these patients are possible candidates for HCV treatment. We therefore explored treatment retention and adherence as well as sustained viral response in co morbid severely opioid-dependent subjects under heroin maintenance, who previously failed in conventional substitution treatment or were not in any drug treatment. METHODS: All patients in heroin maintenance in the German heroin trial, who received standard antiviral HCV therapy with pegylated interferon and ribavirin, were included. Co-consumption of licit and illicit drugs was tolerated as long as it did not interfere with treatment. RESULTS: Twenty-six patients in heroin maintenance were treated for chronic HCV infection. Both the Global Severity Index of the Symptom Checklist 90-R (average score 65.9) and the Opiate Treatment Index (average score 16.6) indicated relevant co-morbidity. Twenty-one patients (81%) were retained in treatment; the adherence rate was 92%. Eighteen patients (69%) achieved a sustained viral response, with a 100% response rate for genotype 2, 90% for genotype 3, and 42% for genotype 1. DISCUSSION: This is the first study that investigates the feasibility of antiviral HCV treatment in a well-defined sample of co-morbid severely opioid-dependent subjects in heroin maintenance treatment. Viral response rates are comparable to non-drug-user populations. Within a need-adapted treatment setting, HCV treatment may even be extended to difficult-to-treat opioid-dependent patients. PMID- 20167442 TI - Identification of coagulase-negative staphylococci isolated from ovine milk samples by PCR-RFLP of 16S rRNA and gap genes. AB - The identification of coagulase-negative staphylococci (CNS) causing ovine infections remains problematic, although these bacteria are considered the main etiologic agents of subclinical mastitis in sheep and goats. In this study, 226 CNS isolates were collected from 2201 milking sarda sheep belonging to 15 flocks with high somatic cell count scores. All isolates were subjected to identification with the API Staph ID test, and then to the amplification of staphylococcal 16S rRNA and gap genes by PCR assays. The gap gene was subjected to restriction fragment length polymorphism analysis with the restriction endonuclease AluI, whereas the 16S rRNA gene was subjected to ribosomal fingerprinting with the restriction endonucleases RsaI, PstI and AluI. When PCR RFLP patterns of CNS isolates were different from those of their reference strains, gap gene amplicons were sequenced for definitive identification. The API Staph ID test, in alternative to the genotypic identification method, produced considerably different results in terms of species identified within each group. Using the PCR-RFLP assay, most of the isolates clustered together with the Staphylococcus epidermidis type strain (131, corresponding to 57.9%), followed by S. caprae (34, corresponding to 15%) and S. chromogenes (30, corresponding to 13.2%). In conclusion, the PCR-RFLP assay of 16S rRNA and gap genes is a more reliable and reproducible method than the API Staph ID test for the identification of CNS causing sheep mastitis. PMID- 20167443 TI - Vitamin K deficiency bleeding: early history and recent trends in the United Kingdom. AB - At the start of the 20th century the mechanisms of haemostasis were virtually unknown. Townsend had coined the term 'Haemorrhagic disease of the newborn' in 1894 but it was not until the discovery of vitamin K ('Koagulation vitamin') by Dam and others in the 1930s that the condition became understood, allowing treatment and prophylaxis. Methods of prophylaxis (preparations used, doses and routes of administration), still widely debated, have varied with time and from one country to another. The formation of the British Paediatric Surveillance Unit in the 1980s has allowed a series of prospective population studies of Vitamin K deficiency bleeding (VKDB) in the United Kingdom (UK) and Ireland which, together with contemporaneous surveys of practices of vitamin K prophylaxis, have greatly improved our understanding of the condition and informed practices of prophylaxis. In the UK prophylaxis (by injection or by mouth) is now offered to every newborn baby and VKDB is very rare, most cases occurring in breastfed babies whose parents have refused prophylaxis; by contrast, in developing countries most babies do not receive prophylaxis and VKDB is probably a common (but poorly documented) cause of death and handicap in the early months of life. Vitamin K prophylaxis should be available to all newborn babies. PMID- 20167445 TI - A middle ear implant with a titanium canal wall prosthesis for a case of an open mastoid cavity. AB - OBJECTIVE: Open mastoid cavity rehabilitation should focus on both anatomical and functional aspects. We hereby report the technique and results of a combined strategy to reconstruct the external ear canal using a titanium wall implant and the middle ear using a fully implantable active middle ear device. METHODS: A fully implantable active middle ear implant was used to rehabilitate the mixed hearing loss of a 63-year-old woman, and a titanium posterior canal wall prosthesis was used to reconstruct the external ear canal during the same procedure. The middle ear implant was placed directly on the footplate. The auditory results were compared to the preoperative unaided thresholds and to the amplification of a conventional hearing aid. RESULTS: Following the procedure, there was an anatomically normal external ear canal with a healed tympanic membrane separating the external from the middle ear spaces. The postoperative auditory gains were on average 31.8 dB on pure-tone audiometry, and 20 dB on speech reception threshold. No complications occurred. CONCLUSION: The rehabilitation of the external ear canal in an open mastoid cavity allows for clinical follow-up of the patient, and the implantation of an active middle ear implant provides appropriate auditory gains both in pure tones and in speech reception thresholds. PMID- 20167444 TI - Mind-body therapies for menopausal symptoms: a systematic review. AB - OBJECTIVE: To systematically review the peer-reviewed literature regarding the effects of self-administered mind-body therapies on menopausal symptoms. METHODS: To identify qualifying studies, we searched 10 scientific databases and scanned bibliographies of relevant review papers and all identified articles. The methodological quality of all studies was assessed systematically using predefined criteria. RESULTS: Twenty-one papers representing 18 clinical trials from 6 countries met our inclusion criteria, including 12 randomized controlled trials (N=719), 1 non-randomized controlled trial (N=58), and 5 uncontrolled trials (N=105). Interventions included yoga and/or meditation-based programs, tai chi, and other relaxation practices, including muscle relaxation and breath-based techniques, relaxation response training, and low-frequency sound-wave therapy. Eight of the nine studies of yoga, tai chi, and meditation-based programs reported improvement in overall menopausal and vasomotor symptoms; six of seven trials indicated improvement in mood and sleep with yoga-based programs, and four studies reported reduced musculoskeletal pain. Results from the remaining nine trials suggest that breath-based and other relaxation therapies also show promise for alleviating vasomotor and other menopausal symptoms, although intergroup findings were mixed. Most studies reviewed suffered methodological or other limitations, complicating interpretation of findings. CONCLUSIONS: Collectively, findings of these studies suggest that yoga-based and certain other mind-body therapies may be beneficial for alleviating specific menopausal symptoms. However, the limitations characterizing most studies hinder interpretation of findings and preclude firm conclusions regarding efficacy. Additional large, methodologically sound trials are needed to determine the effects of specific mind-body therapies on menopausal symptoms, examine long-term outcomes, and investigate underlying mechanisms. PMID- 20167446 TI - Local hypothermia in the treatment of idiopathic sudden sensorineural hearing loss. AB - OBJECTIVE: The additive effects of local hypothermia and restricted activity in the treatment of idiopathic sudden sensorineural hearing loss (ISSHL) were investigated by case-matched study as a multicenter (13 hospitals) pilot trial. PATIENTS AND METHODS: In a preliminary experiment, we evaluated the effects of cooled water pillow (15 degrees C). Cooling the neck and mastoid with the pillow decreased the tympanic membrane temperature for 1.4 degrees C in 2h without causing uncomfortable sensation or frostbite. In this study, 86 patients with ISSHL were enrolled in the hypothermic group, which received hypothermic treatment with restricted activity in addition to medication, and 86 ISSHL patients constituted the control group, which received the same medication but without cooling and rest. Control patients were selected retrospectively from case records by matching the experimental patients with respect to age, gender, days until the start of treatment, hearing loss, shape of the audiogram, and accompanying vertigo. The patients in the hypothermic group were admitted and treated with a cooled water pillow for 48h, in addition to conventional drug treatment (e.g., 60 mg of prednisone) for 7 days. The water pillow was cooled to 15 degrees C and was changed 4-5 times per day. The patients used the water pillow for the first 48 h after admission, with restricted activity. The control patients received only the medications. RESULTS: Hearing results were evaluated using criteria proposed by the Sudden Sensorineural Hearing Loss Research Group of the Japanese Ministry of Health and Welfare. The recovery rates were judged 6 months after onset. The recovery rate in the hypothermic group was significantly (p<0.05) better than that in the control group. When the comparison was limited to younger patients, the use of the cooled water pillow was effective in facilitating the recovery of hearing. CONCLUSIONS: Hearing restoration in ISSHL may be improved by adding mild hypothermia and restricted activity to the conventional treatment. PMID- 20167447 TI - [Epidemiologic monitoring of human rabies in an endemic canine rabies area in the Ivory Coast]. AB - AIM: The objective of this study was to analyze the epidemiologic monitoring of human rabies in the rabies medical center of Abidjan. PATIENT: A cross-sectional study was undertaken based on files of patients having consulted in the rabies center after exposure and suspicion of human rabies between January 2001 and June 2009. RESULTS: Twenty-six cases of human rabies were reported in 10,706,136 inhabitants (annual incidence of 0.028 cases per 100,000). The number of detected cases increased considerably after reinforcing the monitoring of the disease. Most cases occurred in an urban environment and concerned both sexes. The most concerned age range was under 31 years. The patients' were mostly school children and housewives. In all cases, the rabid animal was a dog and the type of exposure was a bite. Fifty-six percent of the victims had not received any local treatment and almost all no post-exposure prophylaxis. The mean delay before the first symptoms was 49.5 days after exposure and for death, 4 days after the onset of symptoms. Virological diagnosis was made in four cases. CONCLUSION: In spite of the increase of cases observed since 2006, certainly due to reinforcement of the monitoring network, improvement is needed to assess the real incidence of rabies in the Ivory Coast. PMID- 20167448 TI - Determination of flow properties of pharmaceutical powders by near infrared spectroscopy. AB - The physical properties of pharmaceutical powders are of upmost importance in the pharmaceutical industry. The knowledge of their flow properties is of critical significance in operations such as blending, tablet compression, capsule filling, transportation, and in scale-up operations. Powders flow properties are measured using a number of parameters such as, angle of repose, compressibility index (Carr's index) and Hausner ratio. To estimate these properties, specific and expensive equipment with time-consuming analysis is required. Near infrared spectroscopy is a fast and low-cost analytical technique thoroughly used in the pharmaceutical industry in the quantification and qualification of products. To establish the potential of this technique to determine the parameters associated with the flow properties of pharmaceutical powders, blended powders based on paracetamol as the active pharmaceutical ingredient were constructed in pilot scale. Spectra were recorded on a Fourier-transform near infrared spectrometer in reflectance mode. The parameters studied were the angle of repose, aerated and tapped bulk density. The correlation between the reference method values and the near infrared spectrum was performed by partial least squares and optimized in terms of latent variables using cross-validation. The near infrared based properties predictions were compared with the reference methods results. Prediction errors, which varied between 2.35% for the angle of repose, 2.51% for the tapped density and 3.18% for the aerated density, show the potential of NIR spectroscopy in the determination of physical properties affecting the flowability of pharmaceutical powders. PMID- 20167450 TI - Multidimensional analysis of treatment adherence in patients with multiple chronic conditions. A cross-sectional study in a tertiary hospital. AB - OBJECTIVE: Determine treatment adherence in patients with multiple chronic conditions (MCC). METHODS: A random patient sample >= 15 years, discharged from hospital with >=1 chronic conditions (CC) was interviewed after 6-12 months. Analysis included variables in 5 dimensions (WHO): socio-demographics, disease, treatment, patient and health system characteristics. Morisky-Green adherence questionnaire was used. High chronic treatment complexity was defined as: >3 pills/day, >6 inhalations/day, >1 injection/day, pharmacological treatment plus diet or self-monitoring techniques. RESULTS: 301 patients were interviewed (62 +/ 15 years, 59% males). Despite good treatment information perception (79%), only 3% followed the patient education programme. Poor adherents (82%) were older (64 +/- 14 years vs. 55 +/- 16 years), had more CC (3.25 +/- 2.02 vs. 2.62 +/- 2.72), a higher frequency of hypertension (44% vs. 15%), ischaemic heart diseases: (21% vs. 4%), hyperlipidaemia (19% vs. 6%), more pills/day (5.78 +/- 4.14 vs. 3.20 +/- 4.70) and more complex treatments (95% vs. 70%) (p<0.05). On multivariate analysis number of CC [3.68 (0.75-18.15)], pills/day [2.23 (1.02-4.84)], treatment complexity [4.00 (1.45-11.04)], and hypertension [2.57 (1.06-6.25)] were predictive of poor adherence (OR 95% CI p<0.05). CONCLUSION: The WHO conceptual framework allows the construction of poor adherence risk profiles in patients with MCC after hospital discharge. PRACTICE IMPLICATIONS: Predictive variables of poor adherence could help clinicians detect patients with MCC most likely to present poor adherence. PMID- 20167451 TI - [Oseltamivir-resistant influenza A pandemic (H1N1) 2009 virus]. PMID- 20167449 TI - Accuracy of 6 commercial systems for identifying clinical Aeromonas isolates. AB - We compared the accuracy of 6 commercial systems for Aeromonas identification by testing 87 clinical isolates in routine conditions, using partial rpoB gene sequencing as the reference standard. The systems were API-20E, API-32GN, the ID GN card with the Vitek2 system (bioMerieux, Marcy l'Etoile, France), the identification portion of the NFC47 panel (MicroScan Walk/Away system; Siemens Healthcare, Sacramento, CA), ID69 (Phoenix system; BD Diagnostic Systems, Sparks, MD), and GN2 microplates (Omnilog system; Biolog, Hayward, CA), for which 67 (77.1%), 80 (91.9%), 72 (82.7%), 70 (80.5%), 64 (73.5%), and 59 (67.8%) isolates, respectively, were correctly identified at the genus and species level. Confusion with Vibrio affected 6.9% and 16.1% of results obtained with NFC47 and API-20E, respectively. Overall, the accuracy of identification for aeromonads was hampered by outdated databases and taxonomy, weak algorithms, and impractical additional tests. Commercial identification systems should be redesigned to make Aeromonas identification algorithms more robust and to cover infrequent clinical species of this genus. PMID- 20167452 TI - [Genetic demyelinating diseases]. AB - Diagnosis of leukodystrophiesin adults is difficult. Diagnosis requires a collaborative approach including clinical,neuroradiological, biochemical, and genetic analyses. Less than thirty percent ofadult-onset leukodystrophies have a precise diagnosis. Improved neuroradiological knowledgeis making it possible to determine MRI (magnetic resonance imaging) phenotypes that point towards specific causes and specific diagnoses. The cavitary leukodystrophies includechildhood ataxia with central nervous system hypomyelination/vanishing white matter(CACH/VWM) syndromeand megalencephalic leukoencephalopathy with subcortical cysts (MLC). Damage tothe posterior spinal cord suggests leukoencephalopathy with damage to the brainstem and cord marrow and is accompanied by elevated lactate (LBSL). PMID- 20167453 TI - Prefabrication of vascularized bioartificial bone grafts in vivo for segmental mandibular reconstruction: experimental pilot study in sheep and first clinical application. AB - The key elements for bioartificial bone formation in 3D matrices are large numbers of osteogenic cells and supplies of oxygen and nutrition. Vascularization becomes more important with the increasing size and complexity of seeded scaffolds required for clinical application in reconstructive craniomaxillofacial surgery. Prefabrication of vascularized bioartificial bone grafts in vivo might be an alternative to in vitro tissue engineering techniques. Two cylindrical beta TCP-scaffolds (25 mm long) were intraoperatively filled with autogenous bone marrow from the iliac crest for cell loading and implanted into the latissimus dorsi muscle in 12 sheep. To determine the effect of axial perfusion, one scaffold in each sheep was surgically supplied with a central vascular bundle. Sheep were killed 3 months after surgery. Histomorphometric analysis showed autogenous bone marrow from the iliac crest was an effective source of osteogenic cells and growth factors, inducing considerable ectopic bone growth in all implanted scaffolds. Bone growth, ceramic resorption and angiogenesis increased significantly with axial perfusion. The results encourage the application of prefabricated bioartificial bone for segmental mandibular reconstruction in man. In clinical practice, vascularized bioartificial bone grafts could change the principles of bone transplantation with minimal donor site morbidity and no shape or volume limitations. PMID- 20167454 TI - Meta-analysis of BDNF Val66Met polymorphism association with treatment response in patients with major depressive disorder. AB - The aim of our meta-analysis was to assess the association between BDNF Val66Met polymorphism and treatment response in patients with MDD. 8 studies that included data from 1115 subjects were identified. We tested two phenotypes: response rate and remission rate. OR was used as a measure of the effect of the association in a fixed/random effect model. Meta-analysis was performed for genotypes Met/Met versus Val/Val, Val/Met versus Val/Val, Met/Met versus Val/Met, Val/Met+Met/Met versus Val/Val, Met/Met versus Val/Val+Val/Met, and Met allele versus Val allele. When all groups were pooled, a significant association of Val/Met genotype and increased response rate was found in comparison to Val/Val in overall population (OR=1.66, 95%CI=1.07-2.57, P=0.02). In the subgroup analysis, similar result was shown in Asian population (OR=1.83, 95%CI=1.03-3.26, P=0.04), but not in Caucasian population. We didn't observe a significant association of BDNF Val66Met polymorphism with remission rate. This meta-analysis demonstrates the association between BDNF Val66Met polymorphism and treatment response in patients with MDD, and Val66Met heterozygous patients have a better response rate in comparison to Val/Val homozygote patients, especially in Asian population. PMID- 20167455 TI - Cationic schiff base amphiphiles and their metal complexes: Surface and biocidal activities against bacteria and fungi. AB - A series of cationic surfactants containing schiff base groups was synthesized by condensation of four fatty amines namely: dodecyl, tetradecyl, hexadecyl and octadecyl amine and 4-diethyl aminobenzaldehyde (1-4), as well as their metal complexes with divalent transition metal ions including Co, Cu and Mn (5-16). The surface activities of the synthesized surfactants were influenced by their chemical structures and the type of the transition metals. The biological activity measurements of the parent cationic schiff bases showed high efficacy against Gram positive and Gram negative bacterial strains and fungi. While on complexation, the biocidal activity was increased remarkably. The biocidal activity of the tested compounds against sulfur reducing bacteria showed promising results in the field of biocide applications. PMID- 20167456 TI - Behavioural changes induced by the conjugation-inducing pheromones, gamone 1 and 2, in the ciliate Blepharisma japonicum. AB - Preconjugant interactions between complementary mating-type cells in ciliates occur before sexual reproduction. The interactions include retardation of swimming behaviour, courtship dancing, chemoattraction, nuclear activation, cell division, or cell agglutination, depending on ciliate species. In Blepharisma japonicum, chemoattraction of mating-type I by mating-type II has been reported previously. It has been shown that chemoattraction here is caused by a conjugation-inducing substance called gamone 2 secreted by mating-type II cells. In this study, we show that mating-type II cells accumulate near the site where gamone 1 secreted by mating-type I cells is present at a high concentration. We also show that the behaviour of individual cells changes when exposed to the complementary mating-type gamone; cells begin to rotate and swim slowly, thus shortening their minimum path length (final displacement of a cell from its origin). These results suggest that gamones 1 and 2 induce behavioural changes in type II and I cells, respectively, and that gamone-stimulated cells may accumulate at the site with the highest activity of the complementary gamone, after repetition of swimming changes in the gradient of gamone concentration. This reciprocal induction of the changes in behaviour may increase the probability of sexual encounters for conjugation. PMID- 20167457 TI - Fuzzy Arden Syntax: A fuzzy programming language for medicine. AB - OBJECTIVE: The programming language Arden Syntax has been optimised for use in clinical decision support systems. We describe an extension of this language named Fuzzy Arden Syntax, whose original version was introduced in S. Tiffe's dissertation on "Fuzzy Arden Syntax: Representation and Interpretation of Vague Medical Knowledge by Fuzzified Arden Syntax" (Vienna University of Technology, 2003). The primary aim is to provide an easy means of processing vague or uncertain data, which frequently appears in medicine. METHODS: For both propositional and number data types, fuzzy equivalents have been added to Arden Syntax. The Boolean data type was generalised to represent any truth degree between the two extremes 0 (falsity) and 1 (truth); fuzzy data types were introduced to represent fuzzy sets. The operations on truth values and real numbers were generalised accordingly. As the conditions to decide whether a certain programme unit is executed or not may be indeterminate, a Fuzzy Arden Syntax programme may split. The data in the different branches may be optionally aggregated subsequently. RESULTS: Fuzzy Arden Syntax offers the possibility to formulate conveniently Medical Logic Modules (MLMs) based on the principle of a continuously graded applicability of statements. Furthermore, ad hoc decisions about sharp value boundaries can be avoided. As an illustrative example shows, an MLM making use of the features of Fuzzy Arden Syntax is not significantly more complex than its Arden Syntax equivalent; in the ideal case, a programme handling crisp data remains practically unchanged when compared to its fuzzified version. In the latter case, the output data, which can be a set of weighted alternatives, typically depends continuously from the input data. CONCLUSION: In typical applications an Arden Syntax MLM can produce a different output after only slight changes of the input; discontinuities are in fact unavoidable when the input varies continuously but the output is taken from a discrete set of possibilities. This inconvenience can, however, be attenuated by means of certain mechanisms on which the programme flow under Fuzzy Arden Syntax is based. To write a programme making use of these possibilities is not significantly more difficult than to write a programme according to the usual practice. PMID- 20167458 TI - SLC30A8 polymorphism and type 2 diabetes risk: evidence from 27 study groups. AB - BACKGROUND AND AIMS: Intense research has been performed to identify the genetic risk factors in type 2 diabetes, and a single nucleotide polymorphism (SNP) in SLC30A8 (rs13266634) was reported to be associated with type 2 diabetes mellitus. However, published data on the association between SLC30A8 polymorphism and the risk of type 2 diabetes were inconsistent. Therefore, we conducted this meta analysis to derive a more precise estimation of the relationship. METHODS AND RESULTS: We searched PubMed through October 2009 to identify all relevant papers. Odds ratios (ORs) and 95% confidence intervals (CIs) were extracted under an additive genetic model. In the current meta-analysis, we identified a total of 27 groups including 42,609 cases and 69,564 controls. In analyses of the case control studies by ethnicity, the results indicated that SLC30A8 polymorphism was related to elevate risks of type 2 diabetes both in Europeans (OR=1.15, 95% CI 1.11-1.18, P<0.001) and Asians (OR=1.15, 95% CI 1.11-1.19, P<0.001). Next, we separated hospital-based case-control studies from population-based case-control studies, however, there was no apparent difference between population-based case control study groups (OR=1.15, 95% CI 1.12-1.17, P<0.001) and hospital-based case control study groups (OR=1.16, 95% CI 1.07-1.25, P<0.001). CONCLUSION: Our present meta-analysis provided evidence that SLC30A8 (rs13266634) C allele carriers could elevate the risk of type 2 diabetes, especially in Europeans and Asians. PMID- 20167459 TI - Influence of coffee and caffeine consumption on atrial fibrillation in hypertensive patients. AB - BACKGROUND AND AIMS: Coffee and caffeine are widely consumed in Western countries. Little information is available on the influence of coffee and caffeine consumption on atrial fibrillation (AF) in hypertensive patients. We sought to investigate the relationship between coffee consumption and atrial fibrillation with regard to spontaneous conversion of arrhythmia. METHODS AND RESULTS: A group of 600 patients presenting with a first known episode of AF was investigated, and we identified 247 hypertensive patients. The prevalence of nutritional parameters was assessed with a food frequency questionnaire. Coffee and caffeine intake were specifically estimated. Left ventricular hypertrophy was evaluated by electrocardiogram (ECG) and echocardiogram. Coffee consumption was higher in normotensive patients. High coffee consumers were more frequent in normotensive patients compared with hypertensive patients. On the other hand, the intake of caffeine was similar in hypertensive and normotensive patients, owing to a higher intake in hypertensive patients from sources other than coffee. Within normotensive patients, we report that non-habitual and low coffee consumers showed the highest probability of spontaneous conversion (OR 1.93 95%CI 0.88-3.23; p=0.001), whereas, within hypertensive patients, moderate but not high coffee consumers had the lowest probability of spontaneous conversion (OR 1.13 95%CI 0.67-1.99; p=0.05). CONCLUSION: Coffee and caffeine consumption influence spontaneous conversion of atrial fibrillation. Normotensive non-habitual coffee consumers are more likely to convert arrhythmia within 48h from the onset of symptoms. Hypertensive patients showed a U-shaped relationship between coffee consumption and spontaneous conversion of AF, moderate coffee consumers were less likely to show spontaneous conversion of arrhythmia. Patients with left ventricular hypertrophy showed a reduced rate of spontaneous conversion of arrhythmia. PMID- 20167460 TI - Total polyphenol excretion and blood pressure in subjects at high cardiovascular risk. AB - BACKGROUND AND AIMS: Dietary factors are critical for the prevention and treatment of hypertension, but data on the effects of specific nutrients on blood pressure (BP) are scarce. The aim of this study was to assess the relationship between total polyphenol excretion (TPE) in urine, as an objective measurement of total polyphenol intake and BP in an elderly population at high cardiovascular risk. METHODS AND RESULTS: Cross-sectional substudy of 589 high-risk participants entering in the PREDIMED trial. BP was measured and TPE was determined in urine by Folin-Ciocalteu assay. A significant positive association was observed between TPE in urine and daily intake of fruit and vegetables (F&V), coffee or wine after adjusting for potential confounders. The intake of 100 g of F&V (Beta=0.150;P<0.001) had a greater contribution to TPE than 100 mL of coffee (Beta=0.141;P=0.001), and the latter two foods contributed more than the consumption of 100 mL of wine (Beta=0.120;P=0.019). An inverse association was observed between urinary TPE and the prevalence of hypertension. Participants in the highest quartile of urinary TPE had a reduced prevalence of hypertension compared to those in the lowest quartile (Odds Ratio=0.64; 95% confidence interval 0.45 to 0.92; P=0.015). Systolic and diastolic BP were inversely associated with urinary TPE after adjustment for potential confounders (P=0.024 and P=0.003, respectively). CONCLUSIONS: Polyphenol intake, assessed via TPE in urine, was negatively associated with BP levels and prevalence of hypertension in an elderly Mediterranean population at high cardiovascular risk. Participants with the highest intake of polyphenol-rich foods showed the lowest BP measurements. PMID- 20167461 TI - A randomized, double-blind, placebo-controlled, cross-over pilot study on the use of a standardized hop extract to alleviate menopausal discomforts. AB - OBJECTIVES: To examine the efficacy of a hop extract (standardized at 100mug 8 prenylnaringenin per day) for relief of menopausal discomforts. METHODS: A 16 week randomized, double-blind, placebo-controlled, cross-over study was conducted with 36 menopausal women. The participants were randomly allocated to either placebo or active treatment (hop extract) for a period of eight weeks after which treatments were switched for another eight weeks. The Kupperman Index (KI), the Menopause Rating Scale (MRS) and a multifactorial Visual Analogue Scale (VAS) were assessed at baseline, and after eight and sixteen weeks. RESULTS: After 8 weeks, both active treatment and placebo significantly improved all outcome measures when compared to baseline with somewhat higher average reductions for placebo than for the active treatment. After 16 weeks only the active treatment after placebo further reduced all outcome measures, whereas placebo after active treatment resulted in an increase for all outcome measures. Although, the overall estimates of treatment efficacy (active treatment-placebo) based on linear mixed models do not show a significant effect, time-specific estimates of treatment efficacy indicate significant reductions for KI (P = 0.02) and VAS (P = 0.03) and a marginally significant reduction (P = 0.06) for MRS after 16 weeks. CONCLUSIONS: Whereas the first treatment period resulted in similar reductions in menopausal discomforts in both treatment groups, results from the second treatment period suggest superiority of the standardized hop extract over placebo. Thus, phytoestrogen preparations containing this standardized hop extract may provide an interesting alternative to women seeking relief of mild vasomotor symptoms. PMID- 20167462 TI - Innate immunity. PMID- 20167464 TI - Route transition interventions: potential public health gains from reducing or preventing injecting. AB - Multiple factors are implicated in the diffusion of injecting drug use (IDU), including individual and demographic characteristics, drug markets, economics, social networks and political and cultural environments. However, studies show that individual transitions away from injecting are possible, and that a recent diffusion of non-injecting routes of administration (NIROA) has occurred in several countries. Injecting is more risk-laden than other routes of drug administration, yet relatively little attention has been paid to reducing or preventing injecting drug use by promoting NIROA. This commentary reviews the case for, and examples of, 'route transition interventions' which seek to do this. These include: prescribing oral substitutes; providing non-injecting equipment; providing safer smoking facilities; and training individuals to prevent transitions to injecting, promote NIROA, or prevent the initiation of new injectors. These initiatives have the potential-as yet largely unrealised-to offer public health gains and empower people to control and manage their drug use. Further research is needed to secure commitments at all levels to support this approach. PMID- 20167463 TI - Physical inactivity in patients with COPD, a controlled multi-center pilot-study. AB - BACKGROUND: Physical activity (PA) has been reported to be reduced in severe chronic obstructive pulmonary disease (COPD). Studies in moderate COPD are currently scarce. The aim of the present study was to investigate physical activity in daily life in patients with COPD (n=70) and controls (n=30). METHODS: A multi-center controlled study was conducted. PA was assessed using a multisensor armband device (SenseWear, BodyMedia, Pittsburgh, PA) and is reported as the average number of steps per day, and the time spent in mild and moderate physical activity. RESULTS: Patients suffered from mild (n=9), moderate (n=28), severe (n=23) and very severe (n=10) COPD. The time spent in activities with mild (80 + or - 69 min vs 160 + or - 89 min, p<0.0001) and moderate intensity (24 + or - 29 min vs 65 + or - 70 min; p<0.0036) was reduced in patients compared to controls. The number of steps reached 87 + or - 34%, 71 + or - 32%, 49 + or - 34% and 29 + or - 20% of control values in GOLD-stages I to IV respectively. The time spent in activities at moderate intensity was 53 + or - 47%, 41 + or - 45%, 31 + or - 47% and 22 + or - 34% of the values obtained in controls respectively with increasing GOLD-stage. These differences reached statistical significance as of GOLD stage II (p<0.05). No differences were observed among centers. CONCLUSIONS: Physical activity is reduced early in the disease progression (as of GOLD-stage II). Reductions in physical activities at moderate intensity seem to precede the reduction in the amount of physical activities at lower intensity. PMID- 20167465 TI - Coal fly ash based carbons for SO2 removal from flue gases. AB - Two different coal fly ashes coming from the burning of two coals of different rank have been used as a precursor for the preparation of steam activated carbons. The performance of these activated carbons in the SO(2) removal was evaluated at flue gas conditions (100 degrees C, 1000 ppmv SO(2), 5% O(2), 6% H(2)O). Different techniques were used to determine the physical and chemical characteristics of the samples in order to explain the differences found in their behaviour. A superior SO(2) removal capacity was shown by the activated carbon obtained using the fly ash coming from a sub-bituminous-lignite blend. Experimental results indicated that the presence of higher amount of certain metallic oxides (Ca, Fe) in the carbon-rich fraction of this fly ash probably has promoted a deeper gasification in the activation with steam. A more suitable surface chemistry and textural properties have been obtained in this case which explains the higher efficiency shown by this sample in the SO(2) removal. PMID- 20167466 TI - Sub-attomolar detection of cholera toxin using a label-free capacitive immunosensor. AB - A label-free immunosensor for the direct detection of cholera toxin (CT) at sub attomolar level has been developed based on potential-step capacitance measurements. Anti-CT antibody was adsorbed on gold nanoparticles (AuNPs) incorporated on a polytyramine-modified gold electrode. The concentration of CT was determined by detecting the change of capacitance caused by the formation of antibody-antigen complexes. By using AuNPs adsorbed to the sensing surface, the signal was dramatically increased leading to a significantly more sensitive assay. In fact, under optimum conditions the immunosensor could detect CT concentration with a limit of detection of 9 x 10(-20)M or 0.09 aM, with a dynamic range between 0.1 aM and 10 pM. Good analytical reproducibility could be obtained by injecting CT up to 36 times with an RSD of 2.5%. In addition, good performance of the developed immunosensor was achieved when applied to turbid water samples collected from a local stream that were spiked with CT. PMID- 20167467 TI - Electrospun hemoglobin microbelts based biosensor for sensitive detection of hydrogen peroxide and nitrite. AB - Highly porous hemoglobin (Hb) microbelts based biosensor was developed by directly electrospinning Hb onto the glassy carbon (GC) electrode surface without using immobilization matrix, offering an excellent electrochemical sensing platform. Ultraviolet-visible spectroscopy and Fourier transform infrared spectroscopy were performed to demonstrate that Hb still kept its native structure in the as-electrospun microbelts. The electrocatalytic property of Hb microbelts modified GC electrode was investigated using hydrogen peroxide (H2O2) and nitrite as model compounds. The cyclic voltammetry results have demonstrated that the Hb microbelts modified electrode shows enhanced activity in the electrochemical reduction of H2O2 and nitrite, which offers a number of attractive features and is explored to develop an amperometric biosensor. The Hb microbelts based amperometric biosensor has fast responses to H2O2 and nitrite, good dynamic response ranges, excellent detection limits of 0.61 microM for H2O2 and 0.47 microM for nitrite (S/N=3), and superior K(M,app) values of 0.093 mM for H2O2 and 0.713 mM for nitrite, respectively. These results demonstrate that the electrospun Hb microbelts can significantly enhance the direct electrochemistry of Hb and has great potential application in mediator-free biosensor applications. PMID- 20167468 TI - A dual gold nanoparticle conjugate-based lateral flow assay (LFA) method for the analysis of troponin I. AB - For signal amplification without an additional operation step in a gold nanoparticle (AuNP)-based lateral flow assay (LFA), a new and simple method utilizing two AuNP-antibody conjugates was developed. The 1st conjugate was the AuNP immobilized with an anti-troponin I antibody and blocked with bovine serum albumin (BSA), and the 2nd conjugate was the AuNP immobilized with an anti-BSA antibody and blocked with human serum albumin. The two conjugates were encapsulated in different pads, respectively. A scheme of the LFA system is described in the part A of first figure. The size of the two conjugates was very critical in the detection sensitivity of troponin I. When 10nm for the 1st and 40 nm for the 2nd were used, the detection sensitivity increased about a 100-fold compared to the conventional LFA. We could detect as low as 0.01 ng/mL troponin I in 10 min using the dual AuNP conjugate-based LFA, which was successfully applied in the analysis of serum samples of patients with myocardial infarction. PMID- 20167469 TI - Chemical and biological single cell analysis. AB - Single cells represent the minimal functional unit of life. A major goal of biology is to understand the mechanisms operating in this minimal unit. Nowadays, analysis of the single cell can be performed at unprecedented resolution using new lab-on-a-chip devices and advanced analytical methods. While cell handling and cultivation devices can be classified into finite volume reactors and flow systems, the analytical approaches differ in respect to invasive (i.e. chemical) and noninvasive (i.e. biological/living cell) analysis. Using these new and exciting technologies cell-to-cell differences, originating from regulatory circuits and distinct microenvironments, can now be explored. For example, it could be shown that the rates of transcription and translation are stochastic. Chemical and biological single cell analyses provide an unprecedented access to the understanding of cell-to-cell differences and basic biological concepts. PMID- 20167471 TI - Preparation and storage of anaesthetic drugs for obstetric emergencies. PMID- 20167470 TI - Imaging approach for monitoring cellular metabolites and ions using genetically encoded biosensors. AB - The spatiotemporal patterns of ion and metabolite levels in living cells are important in understanding signal transduction and metabolite flux. Imaging approaches using genetically encoded sensors are ideal for detecting such molecule dynamics, which are hard to capture otherwise. Recent years have seen iterative improvements and evaluations of sensors, which in turn are starting to make applications in more challenging experimental settings possible. In this review, we will introduce recent progress made in the variety and properties of biosensors, and how biosensors are used for the measurement of metabolite and ion in live cells. The emerging field of applications, such as parallel imaging of two separate molecules, high-resolution transport studies and high-throughput screening using biosensors, will be discussed. PMID- 20167472 TI - The MSL complex: X chromosome and beyond. AB - X chromosomal regulation is a process that presents systematic problems of chromosome recognition and coordinated gene regulation. In Drosophila males, the ribonucleoprotein Male-Specific Lethal (MSL) complex plays an important role in hyperactivation of the X-linked genes to equalize gene dosage differences between the sexes. It appears that X chromosome recognition by the MSL complex may be mediated through a combination of sequence-specificity and transcriptional activities. The resulting transcriptional up-regulation also seems to involve several mechanisms, encompassing both gene-specific and chromosome-wide approaches. Interestingly the histone H4 lysine 16 specific MOF histone acetyl transferase, a key MSL member that hyper-acetylates the male X chromosome, is also involved in gene regulation beyond dosage compensation. A comparison of Drosophila and mammalian systems reveals intriguing parallels in MOF behavior, and highlights the multidisciplinary nature of this enzyme. PMID- 20167473 TI - Developmental neurobiology of cognitive control and motivational systems. AB - One form of cognitive control is the ability to resist temptation in favor of long-term goal-oriented behavior. Historically, the development of cognitive control capacity has been described by a linear function from infancy to adulthood. However, the context in which control is required impacts behavioral regulation abilities, such that emotionally charged or rewarding contexts can diminish control. More recently, studies have begun to examine the development of cognitive control in contexts that vary in motivation. These studies suggest specific windows of development in which cognitive control capacity is more vulnerable to incentive-based modulation. In this review we highlight the most recent work on neurobiological changes supporting motivational and cognitive development, underscoring the importance of functional organization and development of the underlying circuitry implicated in these processes, and provide a theoretical perspective that moves away from discussing singular functional regions toward considering functional circuitry. PMID- 20167474 TI - Learning and cognitive flexibility: frontostriatal function and monoaminergic modulation. AB - Learning in a constant environment, and adapting flexibly to a changing one, through changes in reinforcement contingencies or valence-free cues, depends on overlapping circuitry that interconnects the prefrontal cortex (PFC) with the striatum and is subject to several forms of neurochemical modulation. We present evidence from recent studies in animals employing electrophysiological, pharmacological and lesion techniques, and neuroimaging, neuropsychological and pharmacological investigations of healthy humans and clinical patients. Dopamine (DA) neurotransmission in the medial striatum and PFC is critical for basic reinforcement learning and the integration of negative feedback during reversal learning, whilst orbitofrontal 5-hydroxytryptamine (5-HT) likely mediates this type of low level flexibility, perhaps by reducing interference from salient stimuli. The role of prefrontal noradrenaline (NA) in higher order flexibility indexed through attentional set-shifting has recently received significant empirical support, and similar avenues appear promising in the field of task switching. PMID- 20167476 TI - Amplification of epidermal growth factor receptor gene in renal cell carcinoma. AB - Expression of epidermal growth factor receptor (EGFR) may be of prognostic value in renal cell cancer (RCC). Gene amplification of EGFR was investigated in a cohort of 315 patients with advanced RCC from a previously reported randomised study. Using fluorescent in situ hybridisation, only 2 patients (0.6%) had gene amplification; therefore gene amplification is of no prognostic value in RCC. PMID- 20167477 TI - Survival analysis in clinical trials: old tools or new techniques. PMID- 20167475 TI - Models of macromolecular crowding effects and the need for quantitative comparisons with experiment. AB - In recent years significant effort has been devoted to exploring the potential effects of macromolecular crowding on protein folding and association phenomena. Theoretical calculations and molecular simulations have, in particular, been exploited to describe aspects of protein behavior in crowded and confined conditions and many aspects of the simulated behavior have reflected, at least at a qualitative level, the behavior observed in experiments. One major and immediate challenge for the theorists is to now produce models capable of making quantitatively accurate predictions of in vitro behavior. A second challenge is to derive models that explain results obtained from experiments performed in vivo, the results of which appear to call into question the assumed dominance of excluded-volume effects in vivo. PMID- 20167478 TI - Colour removal from aqueous solutions of metal-complex azo dyes using bacterial cells of Shewanella strain J18 143. AB - The decoloration treatment of textile dye effluents through biodegradation, using bacterial cells, has been studied as a possible means of solving some of the problems that are associated with the pollution of water sources by colorants. In this paper, the use of whole bacterial cells of Shewanella J18 143 for the reduction of aqueous solutions of selected mono-azo, metal-complex dyes, namely Irgalan Grey GLN, Irgalan Black RBLN and Irgalan Blue 3GL, was investigated. The effects of temperature, pH and dye concentration on colour removal were also investigated and shown to be important. The operative conditions for the removal of colour were 30 degrees C, at pH 6.8, with a final dye concentration of 0.12 g/L in the colour reduction system. This study provides an extension to the application of Shewanella strain J18 143 bacterial cells in the decoloration of textile wastewaters. PMID- 20167480 TI - New adjuvants to enhance anticoagulant activity of warfarin. AB - New adjuvants of warfarin anticoagulant activity have been developed. These compounds, which are 1,4-methano-1,2,3,4-tetrahydroanthracene-9,10-diol derivatives, act synergistically with warfarin to potentiate its anticoagulant effect. None of the compounds tested is an effective oral anticoagulant in the absence of warfarin. PMID- 20167479 TI - SelSA, selenium analogs of SAHA as potent histone deacetylase inhibitors. AB - Cancer treatment and therapy has moved from conventional chemotherapeutics to more mechanism-based targeted approach. Disturbances in the balance of histone acetyltransferase (HAT) and deacetylase (HDAC) leads to a change in cell morphology, cell cycle, differentiation, and carcinogenesis. In particular, HDAC plays an important role in carcinogenesis and therefore it has been a target for cancer therapy. Structurally diverse group of HDAC inhibitors are known. The broadest class of HDAC inhibitor belongs to hydroxamic acid derivatives that have been shown to inhibit both class I and II HDACs. Suberoylanilide hydroxamic acid (SAHA) and Trichostatin A (TSA), which chelate the zinc ions, fall into this group. In particular, SAHA, second generation HDAC inhibitor, is in several cancer clinical trials including solid tumors and hematological malignancy, advanced refractory leukemia, metastatic head and neck cancers, and advanced cancers. To our knowledge, selenium-containing HDAC inhibitors are not reported in the literature. In order to find novel HDAC inhibitors, two selenium based compounds modeled after SAHA were synthesized. We have compared two selenium containing compounds; namely, SelSA-1 and SelSA-2 for their inhibitory HDAC activities against SAHA. Both, SelSA-1 and SelSA-2 were potent HDAC inhibitors; SelSA-2 having IC50 values of 8.9 nM whereas SAHA showed HDAC IC(50) values of 196 nM. These results provided novel selenium-containing potent HDAC inhibitors. PMID- 20167481 TI - Rational design of potent GSK3beta inhibitors with selectivity for Cdk1 and Cdk2. AB - From an HTS hit, a series of potent and selective inhibitors of GSK3beta have been designed based on a Cdk2-homology model and with the help of several crystal structures of the compounds within Cdk2. PMID- 20167482 TI - SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from Tripterygium regelii. AB - Quinone-methide triterpenes, celastrol (1), pristimerin (2), tingenone (3), and iguesterin (4) were isolated from Triterygium regelii and dihydrocelastrol (5) was synthesized by hydrogenation under palladium catalyst. Isolated quinone methide triterpenes (1-4) and 5 were evaluated for SARS-CoV 3CL(pro) inhibitory activities and showed potent inhibitory activities with IC(50) values of 10.3, 5.5, 9.9, and 2.6 microM, respectively, whereas the corresponding 5 having phenol moiety was observed in low activity (IC(50)=21.7 microM). As a result, quinone methide moiety in A-ring and more hydrophobic E-ring assist to exhibit potent activity. Also, all quinone-methide triterpenes 1-4 have proven to be competitive by the kinetic analysis. PMID- 20167483 TI - Discovery of substituted biphenyl imidazoles as potent, bioavailable bombesin receptor subtype-3 agonists. AB - We report SAR studies on a novel non-peptidic bombesin receptor subtype-3 (BRS-3) agonist lead series derived from high-throughput screening hit RY-337. This effort led to the discovery of compound 22e with significantly improved potency at both rodent and human BRS-3. PMID- 20167484 TI - The synthesis and angiotensin converting enzyme (ACE) inhibitory activity of chalcones and their pyrazole derivatives. AB - A series of chalcones (1-9) and pyrazoles (10-18) was prepared to investigate their potential activity as Angiotensin I-Converting Enzyme (ACE) inhibitors. Their structures were verified by elemental analysis, UV, IR, MS, (1)H NMR, (13)C NMR, and 2D NMR experiments. Among tested compounds, chalcone 7 exerted the highest activity with an IC(50) value of 0.219 mM, while the most potent pyrazole was 15 (IC(50) value of 0.213 mM). PMID- 20167485 TI - Synthesis of amino acid conjugates to 2-imino-3-methylene-5-carboxypyrrolidine and 2-imino-3-methylene-6-carboxypiperidine. AB - The four stereomers of 2-imino-3-methylene-5-L(carboxy-L-valyl)pyrrolidine, a bacterial metabolite that is inhibitory to the fire blight bacterium Erwinia amylovora, were synthesised and compared for antibacterial activity. Several alternative amino acid conjugates with L,L-stereochemistry were also prepared, and the synthesis was extended to 3-methylenepiperidine-6-L-carboxylic acid and a selection of 2-imino-3-methylenepiperidine-6-L-carboxy-L-amino acid conjugates. All synthetic amino acid conjugates (L,L-stereomers) were inhibitory to the growth of E. amylovora. The likely participation of the conjugated iminomethylene moiety as a Michael acceptor is implicated. PMID- 20167486 TI - Design and evaluation of Trypanosoma brucei metacaspase inhibitors. AB - Metacaspase (MCA) is an important enzyme in Trypanosoma brucei, absent from humans and differing significantly from the orthologous human caspases. Therefore MCA constitutes a new attractive drug target for antiparasitic chemotherapeutics, which needs further characterization to support the discovery of innovative drug candidates. A first series of inhibitors has been prepared on the basis of known substrate specificity and the predicted catalytic mechanism of the enzyme. In this Letter we present the first inhibitors of TbMCA2 with low micromolar enzymatic and antiparasitic activity in vitro combined with low cytotoxicity. PMID- 20167487 TI - Novel glitazones: design, synthesis, glucose uptake and structure-activity relationships. AB - Glitazones are known to exhibit antihyperglycemic activity by decreasing peripheral insulin resistance. In the present study, we have designed some novel glitazones based on the structure-activity relationships as possible PPAR-gamma agonists. The manually designed glitazones were synthesized by using the appropriate synthetic schemes and screened for their in vitro antihyperglycemic activity by estimating glucose uptake by rat hemi-diaphragm, both in the absence and in the presence of external insulin. Some of the glitazones exhibited good antihyperglycemic activity in presence of insulin. Illustration about their design, synthesis, evaluation, and structure-activity relationships is described. PMID- 20167488 TI - The design and development of 2-aryl-2-hydroxy ethylamine substituted 1H,7H pyrido[1,2,3-de]quinoxaline-6-carboxamides as inhibitors of human cytomegalovirus polymerase. AB - Discovery efforts were focused on identifying a non-nucleoside antiviral for treating infections caused by human cytomegalovirus (HCMV) with equal or better potency and diminished toxicity compared to current therapeutics. This Letter describes the HCMV DNA polymerase inhibition and in vitro antiviral activity of various 2-aryl-2-hydroxy ethylamine substituted 1H,7H-pyrido[1,2,3-de]quinoxaline 6-carboxamides. PMID- 20167489 TI - The development of benzimidazoles as selective rho kinase inhibitors. AB - Rho Kinase (ROCK) is a serine/threonine kinase whose inhibition could prove beneficial in numerous therapeutic areas. We have developed a promising class of ATP-competitive inhibitors based upon a benzimidazole scaffold, which show excellent potency toward ROCK (IC(50)<10nM). This report details the optimization of selectivity for ROCK over other related kinases such as Protein kinase A (PKA). PMID- 20167490 TI - Feasibility study on the treatment of small breast carcinoma using percutaneous US-guided preferential radiofrequency ablation (PRFA). AB - The purpose of this study was to determine the safety and efficacy of percutaneous ultrasound (US) guided preferential radiofrequency ablation (PRFA) of unifocal human invasive breast carcinoma with largest radiological diameters of up to 16 mm. Thirty-three patients were enrolled in a study to be treated prior to scheduled partial mastectomy. A needle-shaped treatment electrode, successively developed in two different sizes, was placed into the center of the lesions using ultrasound guidance. A temperature of 85 degrees C was maintained for 10 min. The analysis of the resected specimen was performed using conventional histopathological methods with the aim to determine the size of the lesion as well as the potential viability of tumor cells. Of the 33 patients enrolled 31 were treated. In 26 (84%) patients a complete ablation of the tumor was achieved. Ultrasound guided preferential radiofrequency ablation of small breast carcinoma is feasible and patient friendly. The success rate depends on accurate preoperative diagnostic imaging as well as an exact position of the needle electrode. PMID- 20167491 TI - Intravenous versus oral vinorelbine plus capecitabine as second-line treatment in advanced breast cancer patients. A retrospective comparison of two consecutive phase II studies. AB - Vinorelbine (i.v.) plus capecitabine (oral) combination therapy is active in anthracycline/taxane pretreated patients with metastatic breast cancer. Availability of oral vinorelbine provides this combination in an all-oral formulation. Two consecutive phase II trials differing only in vinorelbine administration routes evaluated their respective activities and tolerabilities in this population. In the i.v. group (n = 38) disease control was 61% (37% PR, 24% SD), median TTP 6.8 months and median survival 11.3 months. In the oral group (n = 38) disease control was 77% (5.4% CR, 34% PR, 38% SD), median TTP 7 months and median survival 10 months. G3-G4 neutropenia was more common in the oral group (p < 0.05); G2-G3 anaemia [5] and G3 thrombocytopenia [1] were observed only in the oral group. Although the comparison between the two regimens was not randomized, the results observed in these two consecutive phase II studies may suggest that oral and iv vinorelbine, in combination with capecitabine, can achieve similar responses in patients with metastatic breast cancer refractory to anthra-taxane combinations. PMID- 20167492 TI - Worries and concerns experienced by nurse specialists during inter-hospital transports of critically ill patients: a critical incident study. AB - OBJECTIVES: Inter-hospital patient transports are required around the clock. During these transports it is the responsibility of the accompanying nurse specialists to ensure their patient's safety, while at the same time providing optimal nursing care in an unusual and often stressful situation. The aim of this study was to explore and describe the nurse specialists' cause of worries and concerns (WaC) and how they manage these. DESIGN: An explorative and qualitative design based on the critical incident technique was used. DATA COLLECTION: Interviews were conducted with 30 nurse specialists within the fields of anaesthetic, intensive and pre-hospital care in the south of Sweden. RESULTS: WaC felt by the nurse specialists were based on being unable to influence their work situation, or carry out their tasks as expected. Their responses to these unusual situations were resolved by using internal (acquired knowledge and experience) and external resources (consulting colleagues having different competences). CONCLUSION: A safe working environment improves the possibility to deliver a satisfactory work performance. Shared experiences and communication between colleagues should be encouraged; teamwork should be enhanced by the implementation of local and national training courses, and unambiguous work guidelines should be given. PMID- 20167493 TI - There's NO stopping NsrR, a global regulator of the bacterial NO stress response. AB - Nitric oxide (NO) is a toxic, free radical gas with diverse biological roles in eukaryotes and bacteria, being involved in signalling, vasodilation, blood clotting and immunity and as an intermediate in microbial denitrification. Several bacterial transcriptional regulators sense this molecule and regulate the expression of genes involved in both NO detoxification and NO damage repair. However, a recently discovered NO sensing repressor, named NsrR, has gained attention because of its suggested role as a global regulator of the bacterial NO stress response. Recent advances in biochemical and transcriptomic studies of NsrR make it timely to review the current evidence for NsrR as a global regulator and to speculate on the recent controversy over its NO sensing mechanism. PMID- 20167494 TI - Survival comparison between glioblastoma multiforme and other incurable cancers. AB - Glioblastoma multiforme (GBM) is an incurable disease that has a reputation as having one of the worst prognoses of all cancers. Recent advances in treatment have led to significant improvements in both progression-free and overall survival. Despite this, the wider medical community continues to perceive GBM as having an incomparably poor prognosis. This perception may stem from a lack of awareness regarding the significant survival advantage through the addition of concurrent and post-radiotherapy temozolomide, as well as unfair comparisons to cancers with curable early stages. In this analysis, we compared the efficacy data reported in pivotal studies for the incurable stage of common cancers to modern efficacy data for GBM. In particular, we compared median overall survival, median progression-free survival and 12-month and 5-year survival rates. Our results demonstrate that with modern treatment, GBM survival is now comparable to, if not better than, many other incurable cancers. PMID- 20167495 TI - An anatomical and radiological study of the high jugular bulb on high-resolution CT scans and alcohol-fixed skulls of adults. AB - Although many reports mention a "high jugular bulb" (HJB), it is often not clearly defined. We examined the relationship between the jugular bulb (JB) and the internal auditory canal (IAC) in 200 temporal bones on high resolution CT scans and alcohol-fixed skull bases of adults. The average distance (+/-standard deviation) between the IAC and the JB was 7.5+/-2.3mm (range, 1-16 mm). The JB was higher on the right side than its companion in 53.3% of patients (left side only in 22%; no side dominance in 23.7% of bases). When the JB reached or exceeded the floor of the IAC (16.5%), it was defined as a HJB; 61% of HJB were found in females. Bilateral HJB was found in 0.5% of patients. The HJB was not associated with a contralateral flat JB. Preoperative multiplanar high resolution CT reconstructions make the most detailed assessment of structural topography. PMID- 20167496 TI - Modified trans-oral approach with an inferiorly based flap. AB - The trans-oral approach allows direct access to pathologies of the anterior craniocervical junction. However, the classic midline incision of the posterior pharyngeal wall can be surgically burdensome and limits lateral exposure. We reviewed the medical records of nine patients undergoing the trans-oral approach. The sites of the pathology ranged from the clivus to C2, and surgical exposure ranged from the clivus to C3. Each operation utilized an inferiorly based flap. None of the patients experienced vascular or neurologic complications, and no patient had a cerebrospinal fluid fistula, pseudomeningocele, or meningitis postoperatively. The trans-oral approach with an inferiorly based flap can therefore be safely and effectively performed with minimal oropharyngeal and neurologic morbidity. Not only does a U-shaped flap allow adequate exposure from the lower half of the clivus to C3, a flap improves lateral exposure, provides a clear operating field, and allows superficial mucosal closure not directly overlying the operative field. PMID- 20167497 TI - Comment on "Intravenous thrombolysis for acute ischemic stroke: the Malabar experience 2003 to 2008". PMID- 20167498 TI - The past, present and future of imaging in multiple sclerosis. AB - Despite technological advances in imaging, multiple sclerosis (MS) remains a clinical diagnosis that is supported, but not replaced, by laboratory or imaging findings. However, imaging is essential in the current diagnostic criteria of MS, for prediction of the likelihood of MS for patients with clinically isolated syndromes, correlation with lesion pathology and assessment of treatment outcome. This article gives an overview of imaging in MS with particular emphasis on the role of MRI in various diagnostic imaging criteria. Novel imaging for MS using 3 Tesla field strengths, magnetization transfer imaging, diffusion tensor imaging, magnetic resonance spectroscopy and cell-specific contrast will be reviewed. PMID- 20167499 TI - Posterior occipitocervical instrumented fusion for dropped head syndrome after deep brain stimulation. AB - We describe dropped head syndrome in a patient with Parkinson's disease receiving subthalamic nucleus deep brain stimulation (DBS). Posterior occipitocervical instrumented fusion after transarticular screw fixation of an odontoid fracture is shown and its rationale explained. Pedunculopontine nucleus DBS as treatment for fall-predominant Parkinson's disease, and globus pallidus interna DBS for dystonia-predominant Parkinson's disease, are discussed. PMID- 20167500 TI - A clinicopathological and immunohistochemical study of central nervous system hemangiopericytomas. AB - Hemangiopericytomas (HPC) of the central nervous system (CNS) are uncommon dural based tumors that mimic meningiomas clinically and radiologically. Because there are few reports about these tumors from India, we aimed to study the clinico pathological and immunohistochemical features of CNS HPC. During 2000 to 2008 all 23 patients diagnosed with HPC of CNS at our Institution were reviewed in the study (11 males and 12 females, mean age of 46 years). Clinical, radiological and histopathological features were reviewed. There were 14 patients with grade II and nine with grade III tumors. Immunohistochemistry with antibodies to epithelial membrane antigen (EMA), vimentin, S-100, CD34 and Ki-67 was done on routinely processed, paraffin-embedded sections of 20 tumors. All patients were EMA and S-100 negative, and vimentin positive. CD34 was positive in only five out of 20 patients. The mean Ki-67 labeling index was 4.25% in grade II tumors and 7.8% in grade III tumors. We concluded that HPC are distinct from meningiomas in morphology, immunohistochemistry and biologic behavior, although they resemble each other clinically and radiologically, HPCs need to be differentiated from meningiomas. PMID- 20167501 TI - Long-term follow up of transoral anterior decompression and posterior fusion for irreducible bony compression of the craniovertebral junction. AB - The aim of this study was to examine the long-term outcomes of treating irreducible craniovertebral junction bony compression via the transoral approach, with a minimum of 4 years of follow-up. Between 1996 and 2005, the transoral transpharyngeal approach was used for 10 patients who underwent anterior decompression and posterior fusion and two who underwent only anterior decompression. All patients were monitored intraoperatively using combined somatosensory/motor evoked potentials. All patients reported substantial or complete resolution of pain. Six out of the eight patients with preoperative myelopathy experienced an improvement of one Ranawat classification level. Solid fusion was achieved in all patients, and no patient had iatrogenic neurological deficits or cerebrospinal fluid leaks. Two patients experienced wound dehiscence requiring resuturing, one experienced velopalatine incompetence, and one experienced wound infection. There was no re-growth of the bony lesion during follow up. Transoral repair provided generally acceptable long-term results for irreducible craniovertebral junction bony compression. Intraoperative spinal cord monitoring may be useful for preventing neurological complications. PMID- 20167502 TI - An improved synthesis of dopamine D2/D3 receptor radioligands [11C]fallypride and [18F]fallypride. AB - Improved syntheses of dopamine D(2)/D(3) receptor radioligands [(11)C]Fallypride and [(18)F]Fallypride are reported. The phenolic precursor (9) for C-11 labeling and the Fallypride (10) reference standard were synthesized from the starting material 2-hydroxy-3-methoxy-5-(2-propenyl)benzoic acid methyl ester (1) in 7 and 8 steps with 16% and 5% overall chemical yields, respectively. The tosylated precursor (15) for F-18 labeling was synthesized from compound 1 in 5 steps with 32% overall chemical yield. An alternate synthetic approach for Fallypride has been developed using the same starting material 1 in 5 steps with 26% overall chemical yield. [(11)C]Fallypride ([(11)C]10) was prepared by O [(11)C]methylation of the phenolic precursor with [(11)C]methyl triflate and purified with a semi-preparative HPLC method in 50-60% radiochemical yield, decay corrected to end of bombardment (EOB), based on [(11)C]CO(2), and 370+/-185 GBq/micromol specific radioactivity at EOB. [(18)F]Fallypride ([(18)F]10) was prepared by nucleophilic substitution of the tosylated precursor with K[(18)F]F/Kryptofix 2.2.2 and HPLC combined with solid-phase extraction (SPE) purification in variable (up to 50%) decay corrected radiochemical yield from K[(18)F]F and 111-222 GBq/micromol specific activity at EOB. PMID- 20167503 TI - True coincidence-summing corrections for the coincident gamma-rays measured with coplanar grid CdZnTe detectors. AB - In this study, true coincidence-summing (TCS) correction factors have been measured for the sources (22)Na, (60)Co, (133)Ba and (152)Eu by use of three large volume coplanar grid CdZnTe (acronym: CZT) detectors. In case of a close-in detection geometry, two different TCS calculation algorithms were used to compute the required TCS correction factors. Both of the algorithms are based on the measured total-to-peak (TTP) ratio and full-energy peak (FEP) efficiency values that were obtained using almost "single" energy and coincidence-free nuclides. The results for TCS correction factors obtained by two different algorithms were agreeable to each other. The obtained TCS factors were ranged from about 7% to 30.5% in a 2250 mm(3) CZT detector when a close counting geometry was used. For other two detectors with a volume of 1000 and 1687.5mm(3), the resulted TCS correction factors were relatively smaller and varied between about 0.1% and 20% at the close counting geometry condition. Therefore, the results indicate that there is a need for the estimation of TCS corrections in CZT detectors, especially when their crystal volumes are greater than 1cm(3) and these detectors are used in the case of a close-in detection geometry. PMID- 20167504 TI - Isotopic signature of plutonium at Bikini atoll. AB - Atom ratios of the isotopes (239)Pu, (240)Pu, (241)Pu and (244)Pu were determined in sediments and soils from Bikini atoll using low energy Accelerator Mass Spectrometry. All samples had been contaminated by local fallout from nuclear weapon testing between 1946 and 1958 and show significant variations in the isotopic composition, which are ascribed to the different yields of single tests and to the mixture of material from various devices. Differences in the (244)Pu/(239)Pu ratio (2.8-5.7x10(-4)) are more pronounced than in the (240)Pu/(239)Pu ratio of the same samples and provide complementary information to distinguish the sources of contamination. PMID- 20167505 TI - Clinical update in cardiac imaging including echocardiography. AB - Volumetric determinations by cardiac magnetic resonance imaging after tetralogy of Fallot repair may more accurately assess significant right ventricular dilation and pulmonary regurgitation to guide timing of pulmonary valve replacement. Recent guidelines by the American and European Societies of Echocardiography have summarized the clinical approach to valvular stenosis. They emphasize aortic stenosis given its high incidence and assessment confounders such as left ventricular function, aortic regurgitation, systemic hypertension, and mitral regurgitation. The applications of 3-dimensional echocardiography have reached transcatheter procedures such as atrial septal closure, mitral valve repair, and aortic valve replacement. It also provides detailed assessment of the mitral valve, cardiac chambers, and can guide pediatric aortic valve repair. The timing of surgery in mitral regurgitation remains controversial, especially when it is asymptomatic with normal left ventricular function. Recent data emphasize the outcome advantage of mitral valve repair in asymptomatic mitral regurgitation when the effective regurgitant orifice area is >40 mm(2). Transesophageal echocardiography is an established gold standard in the assessment of endocarditis. Multislice computed tomographic imaging has facilitated simultaneous detailed assessment of the cardiac valves and coronary arteries. Recent comparison has shown that these 2 imaging modalities are equivalent and complementary. Tricuspid valve regurgitation associated with mitral disease is common and important. At the time of mitral surgery, moderate or greater tricuspid regurgitation should be corrected, preferably by rigid annuloplasty. Recent evidence also supports tricuspid annuloplasty for an annular diameter >35 mm regardless of regurgitation severity. Although repair is preferred, tricuspid replacement also has acceptable outcomes. PMID- 20167506 TI - Left atrial appendage thrombus and real-time 3-dimensional transesophageal echocardiography. PMID- 20167507 TI - Focused attention, open monitoring and automatic self-transcending: Categories to organize meditations from Vedic, Buddhist and Chinese traditions. AB - This paper proposes a third meditation-category--automatic self-transcending--to extend the dichotomy of focused attention and open monitoring proposed by Lutz. Automatic self-transcending includes techniques designed to transcend their own activity. This contrasts with focused attention, which keeps attention focused on an object; and open monitoring, which keeps attention involved in the monitoring process. Each category was assigned EEG bands, based on reported brain patterns during mental tasks, and meditations were categorized based on their reported EEG. Focused attention, characterized by beta/gamma activity, included meditations from Tibetan Buddhist, Buddhist, and Chinese traditions. Open monitoring, characterized by theta activity, included meditations from Buddhist, Chinese, and Vedic traditions. Automatic self-transcending, characterized by alpha1 activity, included meditations from Vedic and Chinese traditions. Between categories, the included meditations differed in focus, subject/object relation, and procedures. These findings shed light on the common mistake of averaging meditations together to determine mechanisms or clinical effects. PMID- 20167508 TI - Statin treatment of hypercholesterolemic-induced aortic valve sclerosis. AB - BACKGROUND: Aortic valve sclerosis (AVS) is a common inflammatory heart valve disease prevalent in the population over the age of 65 years. Several published clinical and animal studies have examined the ability of statin treatment to modify disease progression. Clinical trials yielded conflicting results, and animal studies examined the effects of statins prior to the onset of disease. Our study assessed the effect of dietary modification and/or statin treatment on established aortic valve disease in a rabbit model of AVS to examine the tissue response to therapy. METHODS: Aortic valve sclerosis was induced in male New Zealand White rabbits by dietary cholesterol supplementation. Rabbits were followed over 2.5 years, with the introduction of statins and/or dietary changes for the second half of the study. At end point, valve function was examined by magnetic resonance imaging. Excised aortic valve cusp tissue was surveyed for thickness, lipid accumulation, protein deposition, calcification, and cellular infiltration. RESULTS: By 15 months, cholesterol-fed valves exhibited thickening due to significant lipid content, macrophage infiltration, and osteopontin expression. By 30 months, the untreated disease had progressed to include elevated collagen deposition, lymphocyte invasion, and calcification. With treatment, however, the valve cusps exhibited significant pathological changes including diminished immune cell infiltration and osteopontin expression. Unfortunately, lipid was retained and calcification persisted in all treated valves. CONCLUSIONS: In established AVS, the cellular response to statin therapy does not result in full regression of the sclerotic process. PMID- 20167509 TI - Quantitative analysis of motor performance in epilepsy patients treated with valproate. AB - PURPOSE: The aim of our study was to detect objective signs of deterioration of motor performance in epilepsy patients treated with chronic valproate therapy. METHODS: We examined 14 controls and 15 epilepsy patients receiving chronic valproate monotherapy, who had no subjective complaints related to motor function. Regularity and maximum frequency of repetitive hand and finger movements, and simple reaction time were measured. Intensity and frequency characteristics of resting and postural tremor were assessed using accelerometry. Data were statistically evaluated. RESULTS: Repetitive hand and finger movements were significantly more irregular and the maximum frequency of repetitive movements was significantly lower in the valproate group than in controls. Resting tremor peak frequency and motor reaction time of the two cohorts did not differ. CONCLUSIONS: This is the first study, which quantitatively assesses motor performance of patients with epilepsy on chronic valproate therapy. The results suggest significant irregularity of repetitive hand movements and finger tapping even in patients with no motor complaints. Objective methods might help to recognize valproate-induced motor performance deterioration. PMID- 20167510 TI - A time-limited residential unit for young adults with epilepsy and mild cognitive impairment: results of a prospective pre-post-study. AB - INTRODUCTION: This study examined the effects of a time-limited residential unit for young adults with epilepsy and mild cognitive impairment in a German epilepsy centre. Residents spend approximately 3 years in this unit to gain more independence and better seizure control. METHODS: Fifty-two individuals were interviewed about 4 weeks after admission (T1) and again at discharge (T2) using the PESOS scales on health-related quality of life (HRQOL), the depression scale D-S', the Symptom Checklist 90-R, an item on overall quality of life (QOL), and scales on activities of daily living (ADL), life satisfaction and work related problems. Changes in these self-rating scales were computed and related to changes in seizure frequency and to later support needs following rehabilitation in the residential unit. RESULTS: The frequency of epileptic seizures had declined at the time of discharge. Twenty-nine individuals could move to supported housing, 23 moved to long-term residential units. Some self-rating scales reflected changes of seizure frequency, but a main effect was not detected. Residents assigned to supported housing and those assigned to longer residential care differed significantly in changes of HRQOL, overall QOL, ADL and clinical ratings, controlling for effects of seizure status. Improvements were only found in residents moving to supported housing. However, both groups could not be selected by available information at T1. DISCUSSION: The time-limited residential unit yields positive effects in about half of their clients with epilepsy and mild cognitive impairment. Effects have to be related to a group with well-known difficulties in many aspects of living before admission. Improvements of subjective health status do not seem to be solely attributable to reduction of seizure frequency. Other determining factors for good or poor rehabilitation outcome remain to be identified. PMID- 20167511 TI - Thalamic activation and cortical deactivation during typical absence status monitored using [18F]FDG-PET: a case report. AB - We describe the ictal [(18)F]FDG-PET study of a case of absence status showing bilateral thalamic hypermetabolism and frontal cortex hypometabolism. This is the first ictal assessment of absence status by [(18)F]FDG-PET reporting this particular cortical and subcortical involvement. Our findings support the theory of corticothalamic circuitry involvement in the pathophysiology of absence seizures and stress the similarities of the clinical and metabolic pattern observed during absences with the pattern of task-induced interruption of the default state of brain function. PMID- 20167512 TI - Long-term efficacy of valproate versus lamotrigine in treatment of idiopathic generalized epilepsies in children and adolescents. AB - PURPOSE: In order to estimate and compare the long-term effectiveness of lamotrigine (LTG) versus valproate (VPA) monotherapy in treatment of newly diagnosed idiopathic generalized epilepsies (IGE) the following study was performed. METHODS: Medical records of 214 children and adolescents suffering from IGE were analyzed. 132 of them were on VPA monotherapy, 82 on LTG. The majority of patients had juvenile myoclonic epilepsy - 98, the rest: juvenile absence epilepsy - 32, childhood absence epilepsy - 53 and epilepsy with a tonic clonic seizures on awakening - 12, others - 19. Mean age of the patients was 8.9 years (range 4-16 years). The mean time of treatment was 28 months, time of observation 40 months. In order to estimate retention rates and factors predicting successful treatment with LTG and VPA we used Kapplan-Meyer analysis and Gehan tests. RESULTS: Data analysis showed significantly longer retention rates with VPA versus LTG treatment in overall rates as well in all syndromes subgroups. After 12 months of therapy 69% stayed on LTG therapy versus 89% on VPA, after 24 months 57% versus 83% respectively. VPA showed comparable efficacy in all IGE syndromes where LTG showed better efficacy in childhood and juvenile absence epilepsy than in juvenile myoclonic epilepsy. The shorter duration of treatment with LTG was due to lack of efficacy. CONCLUSIONS: Our results show the superiority of VPA versus LTG treatment in idiopathic generalized epilepsy syndromes. PMID- 20167513 TI - Neural network ensemble-based computer-aided diagnosis for differentiation of lung nodules on CT images: clinical evaluation. AB - RATIONALE AND OBJECTIVES: To evaluate the diagnostic performance of a neural network ensemble-based computer-aided diagnosis (CAD) scheme for classifying lung nodules on thin-section computed tomography (CT). MATERIALS AND METHODS: Thirty two CT images that depicted 19 malignant nodules and 13 benign nodules were used. One of three possible classifications (probably benign, uncertain, and probably malignant) for each nodule was determined by using a neural network ensemble based CAD scheme. The images were presented to three senior radiologists (each with more than 10 years of thoracic radiology experience) who were asked to determine the classification for each nodule blindly. The radiologists made their diagnostic decisions solely based on images and excluded any external data. The performance of the CAD scheme and of the radiologists was evaluated with receiver operating characteristic (ROC) analysis and agreement analysis. RESULTS: Areas under the ROC curve (Az values) for the CAD scheme and the radiologist group were 0.79 and 0.82, respectively, and the partial areas under the ROC curves at a range of sensitivity values greater than or equal to 90% were 0.051 and 0.020 (P = .203), respectively. The weighted Kappa coefficients between the CAD scheme and each radiologist were 0.657, 0.431, and 0.606, respectively. For the diagnosis of the 11 small nodules (with diameters not greater than 10 mm), areas under the ROC curves of the CAD scheme and the radiologist group were 0.915 and 0.683 (P = .227), respectively. CONCLUSIONS: The diagnostic performance of the neural network ensemble-based CAD scheme is similar to that of senior radiologists for classifying lung nodules on thin-section CT. Furthermore, the CAD scheme has certain advantages in diagnosing small lung nodules. PMID- 20167514 TI - Comment on "patients undergoing cardiac surgery with asymptomatic unilateral carotid stenoses have a low risk of perioperative stroke". PMID- 20167515 TI - Predictive risk factors for restenosis after remote superficial femoral artery endarterectomy. AB - OBJECTIVES: Restenosis following remote superficial femoral artery endarterectomy (RSFAE) remains a challenging problem. The determinants predicting failure are lacking. This study investigated patient characteristics with predictive value for restenosis during the first year after RSFAE. DESIGN: A prospective cohort study. MATERIALS AND METHODS: A total of 90 patients post-RSFAE were studied for the occurrence of restenosis (peak systolic velocity ratio >or= 2.5) in the first 12 months postoperatively. At baseline, clinical parameters were recorded. Vessel size was measured on the basis of plaque perimeter in the culprit lesion and lumen diameter on perioperative digital subtraction angiography. RESULTS: In 57 patients (63%), a restenotic lesion was diagnosed within 12 months following surgery. Patients with longer time interval between start of ischaemic walking complaints and RSFAE revealed a significantly higher incidence of restenosis (hazard ratio (HR) = 1.3 (1.05-1.52) per 4 years). Small plaque perimeter and small superficial femoral artery (SFA) diameter on angiography were significantly associated with restenosis (HR = 0.54 (0.34-0.88) per 10 mm and HR = 0.46 (0.27 0.78) per 1.5 mm, respectively). In multivariate analysis, age, duration of ischaemic walking complaints and lumen diameter were independently associated with increased risk of restenosis after RSFAE. CONCLUSIONS: This study provides evidence that age, vessel size and duration of ischaemic walking complaints before RSFAE are predictive values for restenosis after RSFAE. PMID- 20167516 TI - Comments regarding 'duplex ultrasound and contrast-enhanced ultrasound versus computed tomography for the detection of endoleak after EVAR'. PMID- 20167519 TI - First serological investigation of peste-des-petits-ruminants and Rift Valley fever in Tunisia. AB - This study, carried out between September 2006 and January 2007, is the first cross-sectional serological investigation of peste-des-petits-ruminants (PPR) and Rift Valley fever (RVF) in Tunisia. The objective was to assess the potential need to develop a dual, recombinant PPR-RVF vaccine and how such a vaccine might be utilised in Tunisia. An overall PPR seroprevalence of 7.45% was determined, a finding supported by the high specificity (99.4%) and sensitivity (94.5%) of the ELISA used. On assessment of the diversity and density of mosquitoes in the sampling area, four species of RVF-vectors of the genus Aedes and Culex were identified. However, no serological evidence of RVF was found despite the use of a highly sensitive ELISA (99-100%). Larger scale investigations are underway to confirm these findings and the continuation of the emergency vaccination program against these two diseases remains valid. PMID- 20167518 TI - Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (second update). AB - Chronic granulomatous Disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is essential in the process of intracellular pathogen killing by phagocytic leukocytes. Four of the five genes involved in CGD are autosomal; these are CYBA, encoding p22-phox, NCF2, encoding p67-phox, NCF1, encoding p47 phox, and NCF4, encoding p40-phox. This article lists all mutations identified in these genes in the autosomal forms of CGD. Moreover, polymorphisms in these genes are also given, which should facilitate the recognition of future disease-causing mutations. PMID- 20167520 TI - Role of Arg301 in substrate orientation and catalysis in subsite 2 of D-alanine:D alanine (D-lactate) ligase from Leuconostoc mesenteroides: a molecular docking study. AB - D-alanine:D-alanine (D-lactate) ligase (ADP) from Leuconostoc mesenteroides synthesizes the depsipeptide, D-alanyl-D-lactate, in addition to D-alanyl-D alanine, when D-alanine and D-lactate are incubated simultaneously. The depsipeptide is responsible for the intrinsic resistance of this organism to vancomycin. The orientations of D-lactate and D-alanine in subsite 2 of the ligase that result in both nucleophile generation and subsequent attack on the electrophilic center of D-alanyl phosphate in subsite 1 are not known. A molecular docking study using AutoDock 4 suggests a role for Arg301 in determining these orientations of acceptor substrate in subsite 2 for both nucleophile generation and subsequent attack on the phosphate intermediate. With D-lactate a bifurcated H-bond from Arg301 to the R-OH of D-lactate may account for its orientation and nucleophile activation. This orientation is observed when the guanidino side chain of this residue is flexible. D-alanine adopts an orientation that utilizes H-bonding to water 2882 and the D-alanyl phosphate in subsite 1. Both of these orientations provide mechanisms of deprotonation and place the nucleophile within 3.2A of the electrophilic carbonyl of the D-alanyl phosphate intermediate for formation of the transition state. These results suggest that Arg301 has a dual function in a sequential reaction mechanism, i.e. substrate orientation in subsite 2 as well as stabilization of the transition state. In addition, these docking studies provide insights for inhibitor design targeted to this subsite of the ligase. PMID- 20167521 TI - Dual-subtype feline immunodeficiency virus vaccine provides 12 months of protective immunity against heterologous challenge. AB - The duration of immunity of the dual-subtype feline immunodeficiency virus (FIV) vaccine, Fel-O-Vax FIV, for protection against subtype-B FIV was assessed in this study. Vaccinated cats along with controls were challenged with FIV(FC1), a subtype-B FIV strain, 54 weeks after the final vaccination, and monitored for 46 48 weeks for provirus and viral RNA in peripheral blood, provirus in lymphoid organs, and CD4:CD8 ratios. Results of provirus detection in peripheral blood and lymphoid organs and plasma viral RNA loads showed that 10/14 vaccinated cats were fully protected for 48 weeks against infection with FIV(FC1) whereas 5/5 controls were persistently infected with FIV(FC1). CD4:CD8 inversions were noted in association with FIV infection and viral loads were not significantly different between FIV infected controls and the unprotected vaccinated animals. PMID- 20167522 TI - Extracellular DNase activity of Cryptococcus neoformans and Cryptococcus gattii. AB - Extracellular DNase activity was studied in 73 strains of Cryptococcus neoformans and 12 strains of Cryptococcus gattii. DNase activity was measured by DNase agar clearance with and without Methyl Green. All strains tested showed extracellular DNase activity and no significant difference was found betweenC. neoformans and C. gattii strains. DNase production was higher in strains from clinical origin (average radius of 6.2 mm) than among environmental strains (average radius of 2.9 mm). The extracellular enzyme may be detected by DNA substrate PAGE assays and its molecular weight was estimated at 31 kD. These results suggest that extracellular DNase could be considered as a virulence factor involved in C. neoformans-C. gattii species complex pathogenicity. PMID- 20167523 TI - [Sexuality and pathogenicity in Aspergillus fumigatus: is there any relationship?]. AB - BACKGROUND: Aspergillus fumigatus, like many other fungal species of clinical relevance, has been traditionally regarded as an asexual organism. However, in last few years several pieces of evidence question this such assumption, suggesting that the sexual state of A. fumigatus may still be undiscovered. These investigations have finally led to the recent discovery of a teleomorph stage of A. fumigatus, which has been named Neosartorya fumigata. AIMS: To review the most important findings on A. fumigatus sexuality and discuss the possible implications of such findings on its pathogenicity. METHODS: A bibliographic search was performed to find the main works that study the sexuality of fungal pathogens and, especially, of A. fumigatus. Moreover, data from our recent investigations in this field were also introduced to the discussion. RESULTS: The existence of a teleomorph for A. fumigatus could have significant clinical repercussions, as sexual reproduction might produce offspring with increased virulence and/or resistance to antifungal agents. In this sense, the results of our investigations suggest the existence of an association between the MAT1-1 mating type and the invasiveness of A. fumigatus isolates. CONCLUSIONS: The study of the sexual reproduction of the fungal pathogens and its possible relationship with virulence will continue to be a topic of interest during the next years, not only because of its basic interest, but also for the possible clinical repercussions. PMID- 20167524 TI - [Prinzmetal's angina in a patient treated with capecitabine: a case study]. PMID- 20167525 TI - [Role of the hospital pharmacist in new health care technologies]. PMID- 20167526 TI - Development and testing of a perspiration measuring system. AB - Sweating measurement is a very useful tool for the physiological health state of the human body. A sweating measuring system developed in this study was composed of several sensors. All sensors were calibrated to ensure the accuracy. Three pretreatment physiological states for test subjects before sweating measurement included sit and rest for 5 min, walking for 5 min, and running for 5 min. The whole sweating value was measured and calculated over 5-min periods. The results of sweating measurement indicated the usefulness of this device. The sweating quantity of three states did not have a significant relationship with the height, weight and body mass index (BMI) values of subjects. The first sweating index is the difference between active treatment and sitting state. The second sweating index is the ratio between active state and sitting. The relationship between two sweating index and BMI values could be found. This device could serve as a detecting tool to establish the sweating database for normal conditions and to be used for diagnosis. PMID- 20167527 TI - Fluorescent blue lights, injecting drug use and related health risk in public conveniences: findings from a qualitative study of micro-injecting environments. AB - This paper presents findings relating to injecting drug users' experiences and opinions of public toilets illuminated with fluorescent blue lights and presents an empirical assessment of the intended deterrent effect of such installations. Data analysis identified that blue lights deterred less than half the sample interviewed. Furthermore over half (18/31) of the sample were prepared to inject in conditions specifically designed to deter injecting practice. Of these, 11 respondents were completely undeterred and 7 individuals were only partially deterred by blue light environments. These findings are discussed within the interpretative frameworks of Pierre Bourdieu's theory of habitus and symbolic violence. The authors conclude that fluorescent blue lights contribute towards the development of situated resistance by injecting drug users within a public injecting habitus; a resistance that produces and reproduces drug-related harm and is a behaviour that opposes the symbolic violence of harm reduction intervention. The paper concludes with suggestions for theory-driven practical intervention that may seek to disrupt the harmful elements of the public injecting habitus. PMID- 20167528 TI - The food environment in an urban Mexican American community. AB - The objective was to determine whether ethnic composition of neighborhoods is associated with number and type of food stores in an urban, Mexican American US community. Data were from a commercial food store data source and the US Census. Multivariate count models were used to test associations with adjustment for neighborhood demographics, income, and commercialization. Neighborhoods at the 75th percentile of percent Mexican American (76%) had nearly four times the number of convenience stores (RR=3.9, 95% CI: 2.2-7.0) compared with neighborhoods at the 25th percentile (36%). Percent Mexican American in the neighborhood was not associated with the availability of other food store types (supermarkets, grocery stores, specialty stores, convenience stores with gas stations) in the adjusted model. The impact of greater access to convenience stores on Mexican American residents' diets requires exploration. PMID- 20167530 TI - Novel therapeutics in combination with radiotherapy to improve cancer treatment: rationale, mechanisms of action and clinical perspective. AB - Our increased understanding of the molecular processes underlying cellular sensitivity to ionizing radiation has led to the identification of novel targets for intervention. New agents have become available for combined use to overcome radioresistance and enhance the clinical efficacy of radiotherapy. This rational selection of potential radiosensitizers contrasts with the empirical approach that has dominated the field of chemo-radiotherapy over the last decades. It allows the identification of those patients who will benefit most from a specific combination by exploiting new predictive biomarkers of response. In this review we present several approaches of targeted radiosensitization and discuss the available in vitro and in vivo results that support their translation into clinical trials. We focus on EGFR-inhibiting, anti-angiogenic, apoptosis modulating and PARP-interfering strategies. PMID- 20167531 TI - Accessing genetic diversity for crop improvement. AB - Vast germplasm collections are accessible but their use for crop improvement is limited-efficiently accessing genetic diversity is still a challenge. Molecular markers have clarified the structure of genetic diversity in a broad range of crops. Recent developments have made whole-genome surveys and gene-targeted surveys possible, shedding light on population dynamics and on the impact of selection during domestication. Thanks to this new precision, germplasm description has gained analytical power for resolving the genetic basis of trait variation and adaptation in crops such as major cereals, chickpea, grapevine, cacao, or banana. The challenge now is to finely characterize all the facets of plant behavior in carefully chosen materials. We suggest broadening the use of 'core reference sets' so as to facilitate material sharing within the scientific community. PMID- 20167532 TI - Theoretical and vibrational studies of 4,5-diphenyl-2-2 oxazole propionic acid (oxaprozin). AB - The molecular structure, linear and nonlinear optical properties, and electronic properties of 4,5-diphenyl-2-2 oxazole propionic acid (oxaprozin) as a monomer were investigated by using Hartree-Fock (HF) and density functional theory (DFT) calculations that used 6-31G(d,p) basis set. The first-order hyperpolarizability of oxaprozin (OXA) was found to be 1.117 x 10(-30) esu. The structure of oxaprozin dimer with HF/6-31G(d) level caused by the shifts of O-H and CO bands in the vibrational spectra of oxaprozin were also studied. Moreover, these calculated frequencies of oxaprozin dimer were compared with the solid FT-IR and FT-Raman spectra. The theoretical frequencies and infrared intensities were showed a good agreement with experimental data. PMID- 20167533 TI - Human factors engineering for healthcare IT clinical applications. PMID- 20167534 TI - Pooling the wrong conclusion. PMID- 20167535 TI - Role of the adaptive immune system in hypertension. AB - Recent studies have shown that both innate and adaptive immunity contribute to hypertension. Inflammatory cells, including macrophages and T cells accumulate in the vessel wall, particularly in the perivascular fat, and in the kidney of hypertensive animals. Mice lacking lymphocytes are resistant to the development of hypertension, and adoptive transfer of T cells restores hypertensive responses to angiotensin II and DOCA-salt challenge. Immune modulating agents have variable, but often-beneficial effects in ameliorating end-organ damage and blood pressure elevation in experimental hypertension. The mechanisms by which hypertension stimulates an immune response remain unclear, but might involve the formation of neoantigens that activate adaptive immunity. Identification of these neoantigens and understanding how they form might prove useful in the prevention and treatment of this widespread and devastating disease. PMID- 20167536 TI - Ion channels and the hallmarks of cancer. AB - Plasma membrane (PM) ion channels contribute to virtually all basic cellular processes and are also involved in the malignant phenotype of cancer cells. Here, we review the role of ion channels in cancer in the context of their involvement in the defined hallmarks of cancer: 1) self-sufficiency in growth signals, 2) insensitivity to antigrowth signals, 3) evasion of programmed cell death (apoptosis), 4) limitless replicative potential, 5) sustained angiogenesis and 6) tissue invasion and metastasis. Recent studies have indicated that the contribution of specific ion channels to these hallmarks varies for different types of cancer. Therefore, to determine the importance of ion channels as targets for cancer diagnosis and treatment their expression, function and regulation must be assessed for each cancer. PMID- 20167537 TI - Acute nursing episodes which challenge graduate's competence: perceptions of registered nurses. AB - On successful completion of nurse education programmes new graduate nurses are expected to meet the requirements for registration as a professional practitioner. Nurse educators need to collaborate with clinical colleagues to be responsive to changes in health care. Identifying challenging acute nursing episodes (CANE) that nurses' encounter in clinical practice and the aspect of competence that new graduate nurses require to manage these episodes effectively can inform undergraduate nursing curricula. Thus a qualitative, descriptive design was employed when undertaking a study to identify challenging acute nursing episodes which new graduates will encounter in clinical practice. Six focus groups were conducted in three university teaching hospitals in Ireland where a total of 28 registered nurses were recruited. Thematic analysis was used to extract themes from the focus group data. The results of this study identified 41 challenging acute nursing episodes and 4 key aspects of competence namely; patient assessment, technical/clinical skills; interactions and communications and clinical decision making. Findings of this study identify both the episodes which challenge new graduates and aspects of competence required by new graduates. These findings provide evidence for nurse educators to develop and deliver curricular content which is congruent with the realities of current day nursing practice. PMID- 20167538 TI - Nijmegen breakage syndrome: Long-term monitoring of viral and immunological biomarkers in peripheral blood before development of malignancy. AB - Selected viruses and immune parameters were monitored in 57 patients with Nijmegen breakage syndrome as a proposed tool for early detection of changes preceding development of malignancy. The following parameters were analysed: (1) viral infections; (2) monoclonal proteins; and (3) B-cell and T-cell receptor gene rearrangements in peripheral blood lymphocytes. Viral infections were detected in 68.4% of patients with a predominance of EBV (63.2%), followed by HBV (19.2%) and HCV (8.8%). Monoclonal gammopathy detected in 38.6% of cases correlated with the presence of EBV DNA (p=0.002) and HCV RNA (p=0.04). Clonal Ig and/or TCR gene rearrangements occurred in 73.9% of patients. The presence of at least one of the studied parameters preceded the development of malignancy in 22 patients. Systematic PCR analysis for viral infections and Ig/TCR gene rearrangements, supplemented by detection of monoclonal proteins, is advantageous in monitoring NBS patients before severe complications of the disease, including cancer, appear. PMID- 20167539 TI - Brief dexamethasone treatment during acute infection prevents virus-induced autoimmune diabetes. AB - We used the LEW1.WR1 rat to test the hypothesis that Kilham rat virus-induced innate immune activation is involved in the mechanism of autoimmune diabetes. Animals were treated with dexamethasone, an anti-inflammatory glucocorticoid, beginning on the day of infection. Administering dexamethasone on five consecutive days completely blocked the disease. Strikingly, a single dose of dexamethasone was sufficient to prevent islet destruction. Dexamethasone downmodulated inflammation and restored normal ratios between CD8(+) and CD4(+)CD25(+)Foxp3(+) cells in the spleen. Finally, dexamethasone therapy lowered the frequency of splenic anti-virus CD8(+) T cells, but did not interfere with the ability of the host to generate anti-KRV antibodies and eliminate the virus from the spleen. Our data demonstrate a strong association between early virus induced proinflammatory responses and islet destruction and raise the possibility that targeting innate immune pathways in the early stages of diabetes may be a useful strategy for disease prevention. PMID- 20167540 TI - Immunoglobulin class switch recombination deficiencies. AB - Maturation of the secondary antibody repertoire is generated by means of class switch recombination and somatic hypermutation. The molecular mechanisms underlying these important processes have long remained obscure. Inherited defects in class switch recombination variably associated to defects in somatic hypermutation are a group of genetically heterogeneous diseases, the characterization of which has allowed recognition that T-B cell interaction (resulting in CD40-mediated signaling), intrinsic B cell mechanisms, and complex DNA repair machinery are involved in class switch recombination and somatic hypermutation. Elucidation of the molecular defects underlying these disorders has been essential to better understand the molecular basis of immunoglobulin diversification and has offered the opportunity to define the clinical spectrum of these diseases and to prompt more accurate diagnostic and therapeutic approaches. PMID- 20167541 TI - CD8+ T-cell mediated self-reactivity in HLA-B27 context as a consequence of dual peptide conformation. AB - HLA-B2709 does not predispose for Ankylosing Spondylitis although it differs from B2705, the most common and AS-associated subtype in different ethnic groups, only for the substitution His116Asp. Therefore, a productive approach to elucidate the molecular mechanisms of the disease could be the comparison of these alleles. B2705 has been shown to display certain self-peptides enriched in basic residues i.e., pVIPR and pGR, in a dual conformation and this is accompanied by the presence of specific cytotoxic T cells in patients with AS. In this study, we convalidate our previous observation that B2709 healthy subjects do not possess primary reactivity towards pVIPR while showing a prompt CD8+ T cell response driven by pGR. Notably, in the B2709 context of presentation, pVIPR assumes only a single conformation in contrast with pGR which is dimorphic. These results suggest a possible general connection between the occurrence of double peptide conformation and the property of inducing specific autoimmune responses. PMID- 20167542 TI - Family planning and adolescent pregnancy. AB - High adolescent fecundity principally affects developing countries. In spite of a decrease in the incidence of pregnancies in the developing countries over the past 13 years, the differences that exist with respect to developed countries turn adolescent fecundity into an indicator of the level of development of countries. The impact of adolescent pregnancy is evident in maternal and perinatal morbidity and mortality. Nonetheless, in addition to the age involved in precocious pregnancy, it also reflects previous conditions such as malnutrition, infectious diseases and deficiencies in the health care given to pregnant adolescents. The most important impact lies in the psychosocial area: it contributes to a loss of self-esteem, a destruction of life projects and the maintenance of the circle of poverty. This affects both adolescent mothers and fathers; the latter have been studied very little. Intervention with comprehensive health services and the maintenance of the education of adolescent mothers and fathers prevents repeat pregnancies. Evidence shows success in the prevention of the first pregnancy when the intervention includes comprehensive sexual education, the existence of preferential sexual and reproductive health services for adolescents, the handout of modern contraceptives gauged to the adolescence stage of the subjects and the existence of an information network. There is little research in contraception for adolescents, and for this reason, the indications given are projections of data obtained from adults. PMID- 20167543 TI - Quantitative and morphometric changes of subpopulations of myenteric neurons in swines with toxoplasmosis. AB - The consequences of the infection caused by Toxoplasma gondii in myenteric neurons of the jejunum of swines reactive to NADH-diaphorase and NADPH-diaphorase were evaluated in this study. Ten 88-day-old mixed-breed swines (Pietrain and Wessex) were assigned into two groups: Control (n=5) and Experimental (n=5), which orally received 5000 sporulated oocysts from a genotype III T. gondii strain. After 30days, the animals were anesthetized, having part of their jejunum removed and stained with NADPH-diaphorase and NADH-diaphorase. NADPHd-p neurons (nitrergic) presented increase of the number of cells per ganglion and hypertrophy. The number of NADHd-p neurons (metabolic more active) and their nuclear area decreased. PMID- 20167545 TI - Development and validation of a method for the determination of a therapeutic peptide with affinity for the human B1 receptor in human plasma using HPLC-MS/MS. AB - The peptide described in this report (MW 1180 Da; 10-amino acid synthetic peptide) is a potent and selective antagonist of the human B1 receptor (B1) that has been investigated for the treatment of chronic pain. A method to quantitate this peptide in human plasma has been developed to support human clinical trials designed to evaluate the safety, pharmacokinetics, and efficacy of this compound. Plasma samples (0.2 mL) were extracted using a Waters Oasis MAX (10 mg) 96-well plate and the resulting samples were analyzed using an Applied Biosystems API 5000 HPLC-MS/MS with an electrospray ionization (ESI) source. The method was validated for the determination of the B1 peptide in human plasma over the concentration range of 1-50 ng/mL. Isotopically labeled B1 peptide ((13)C6(15)N(2)-B1 peptide) was used as an internal standard. Interday precision and accuracy, determined from analysis of quality control (QC) samples, yielded coefficients of variation (CV) of less than 5.3% and accuracy within a 2.4%. Within batch precision and accuracy determinations provided CV values of less than 7.3% and accuracy within a 6.0% bias. Precautions had to be taken to prevent B1 peptide loss to container surfaces and contamination of the HPLC-MS/MS. The validated assay was used in support of human clinical trials. PMID- 20167544 TI - Postural Tachycardia Syndrome associated with peripartum cardiomyopathy. AB - Here we describe a 26-year-old woman who developed peripartum cardiomyopathy characterized by fatigue, poor exercise tolerance, and palpitations. Initial echocardiography showed global left ventricular dysfunction with an ejection fraction of 40%. Subsequently, the patient developed a resting tachycardia associated with symptomatic postural tachycardia. A diagnosis of Inappropriate Sinus Tachycardia was made based on Holter monitoring studies with an average heart rate of 121 beat per minute (bpm). Standard autonomic evaluation confirmed the diagnosis of Postural Tachycardia Syndrome. The cardiomyopathy subsequently resolved (ejection fraction 60%, normal left ventricular function). However, both the postural tachycardia and sinus tachycardia persisted. PMID- 20167546 TI - Gas chromatography-ion trap mass spectrometry method for the simultaneous measurement of MDMA (ecstasy) and its metabolites, MDA, HMA, and HMMA in plasma and urine. AB - The investigation of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) abuse requires very robust methods with high sensitivity and wide linearity ranges for the quantification of this drug of abuse and its main metabolites in body fluids. An optimized gas chromatography-ion trap mass spectrometry (GC-IT/MS) methodology with electron impact ionization addressing these issues is presented. The sample preparation involves an enzymatic hydrolysis of urine and plasma for conjugate cleavage, a SPE extraction, and a derivatization process. The method was fully validated in rat plasma and urine. Linearity for a wide concentration range was achieved for MDMA, and the metabolites 3,4-methylenedioxyamphetamine (MDA), 4 hydroxy-3-methoxyamphetamine (HMA) and 4-hydroxy-3-methoxymethamphetamine (HMMA). Limits of quantification were 2 ng/mL in plasma and 3.5 ng/mL in urine using a Selected Ion Monitoring detection mode. Selectivity, accuracy, precision, and recovery met the required criteria for the method validation. This GC-IT/MS method provides high sensitivity and adequate performance characteristics for the simultaneous quantification of MDMA, MDA, HMA and HMMA in the studied matrices. PMID- 20167547 TI - Clinical implications of novel aspects of biliary pathophysiology. AB - Cholangiocytes are the epithelial cells that line the biliary tree; they are the target of chronic diseases termed cholangiopathies, which represent a daily challenge for clinicians, since definitive medical treatments are not available yet. It is generally accepted that the progression of injury in the course of cholangiopathies, and promotion and progression of cholangiocarcinoma are at least in part due to the failure of the cholangiocytes' mechanisms of adaptation to injury. Recently, several studies on the pathophysiology of the biliary epithelium have shed some light on the mechanisms that govern cholangiocyte response to injury. These studies provide novel information to help interpret some of the clinical aspects of cholangiopathies and cholangiocarcinoma; the purpose of this review is thus to describe some of these novel findings, focusing on their significance from a clinical perspective. PMID- 20167548 TI - [Nutritional rickets in a 5 month-old child. A rare disease in Spain]. PMID- 20167549 TI - Infratemporal fossa reconstruction following total auriculectomy: an alternative flap option. AB - Reconstruction following oncologic resection in the head and neck is complex due to large surgical defects left after removal of skin, subcutaneous, and skeletal structures. It is essential to adequately fill the defect as well as provide an acceptable tissue match in terms of tone, texture, thickness and contour. A 55 year-old male presented with an advanced melanoma in the right pre-tragal area. Surgical resection was performed including a total auriculectomy. A tunnelled right supraclavicular artery island (SAI) flap was used to repair the surgical defect. A Doppler probe ensured adequate circulation within the flap, especially in the distal tip. Reconstruction using the SAI flap after oncologic ear resection reduced operating room time, required less technical expertise, and provided excellent tissue match compared to more traditional methods of surgical defect reconstruction including free flaps, local flaps, and pedicled myocutaneous flaps. Successful use of the SAI flap in this case further expands the flaps versatility. We recommend that the reconstructive surgeon consider the SAI flap when presented with challenging infratemporal fossa and lateral skull base cases. PMID- 20167550 TI - The bacteriology of children prior to 1st stage autologous ear reconstruction. AB - In virtually all surgical specialities the use of peri-operative antibiotic prophylaxis to minimise wound site infection is routine practice. Antibiotic selection is targeted towards the pathogens most commonly encountered at the surgical site. The surgical management of microtia is by autologous rib cartilage reconstruction, a process that involves at least two surgical stages. The pits and recesses of the microtia ear are difficult to clean and may shelter unusual pathogens not routinely found as skin commensals, requiring modified prophylaxis. This retrospective review of 37 patients undergoing 1st stage ear reconstruction, examines the pre-operative ear site, nose and throat swabs to determine the common pre-operative bacteria encountered in children prior to ear reconstruction, to aid in appropriate antibiotic selection. PMID- 20167551 TI - The European EUCCLID pilot study on care and complications in an unselected sample of people with type 2 diabetes in primary care. AB - BACKGROUND: European studies on quality of diabetes care in an unselected primary care diabetes population are scarce. RESEARCH QUESTION: To test the feasibility of the set-up and logistics of a cross-sectional EUropean study on Care and Complications in patients with type 2 diabetes (T2DM) in Primary Care (EUCCLID) in 12 European countries. METHOD: One rural and one urban practice from each country participated. The central coordinating centre randomly selected five patients from each practice. Patient characteristics were assessed including medical history, anthropometric measures, quality indicators, UKPDS-risk engine, psychological and general well-being. RESULTS: We included 103 participants from 22 GPs in 11 countries. Central data and laboratory samples were successfully collected. Of the participants 54% were female, mean age was 66 years and mean duration of diabetes was 9.6 years. Besides, 18% were using insulin, 31% had a history of cardiovascular disease, mean HbA1c was 7.1% (range 6.6-8.0), mean systolic blood pressure was 133.7 mmHg (range 126.1-144.4) and mean total cholesterol was 4.9 mmol/l (range 4.0-6.2). CONCLUSION: A European study on care and complications in a random selection of people with T2DM is feasible. There are large differences in indicators of metabolic control and wellbeing between countries. PMID- 20167552 TI - Environmental epigenetic modifications and reprogramming-recalcitrant genes. AB - The term "environmental epigenetic modifications" refers to alterations in phenotype triggered by environmental stimuli via epigenetic mechanisms. Epidemiologic and animal model studies show that a subset of such environmental epigenetic marks may affect susceptibility to chronic diseases. A growing body of evidence regarding incompleteness of reprogramming indicates that the potential retention of pathogenic environmental epigenetics in human induced pluripotent stem cells (iPSCs) should be seriously considered. Given this possibility, the optimization of methods for the generation of human induc pluripotent stem cells may require the identification of epigenetically appropriate somatic cell sources. Similarly, techniques for controlling epigenetic modification by environmental factors may also play a critical role in the development of epigenetically stable sources of pluripotent stem cells. PMID- 20167553 TI - New insights in the modulation of tumor angiogenesis. PMID- 20167554 TI - VEGF-A: a critical regulator of blood vessel growth. AB - Angiogenesis is required for a variety of normal and pathological, proliferative processes. Numerous regulators of angiogenesis have been identified and characterized over the last decades. Among these, vascular endothelial growth factor (VEGF)-A appears especially important in normal development and in disease processes. Several VEGF inhibitors have been approved by the FDA for the treatment of tumors or the neovascular form of age-related macular degeneration. This article examines the molecular and biological characteristics of VEGF and also discusses preclinical and clinical studies with VEGF inhibitors and the lessons learned from these studies. PMID- 20167555 TI - Molecular regulation of tumour angiogenesis by nitric oxide. AB - As tumors grow, their original vasculature can be insufficient to supply the growing tissue mass, and consequently local hypoxia develops. Thus neovascularisation is a key feature determining growth and metastasis of malignant tumors. This is, at least in part, mediated by humoral factors known to stimulate angiogenesis, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2). Among the multiple angiogenic modulators released by tumor and stromal cells, a key role is played by nitric oxide (NO). Beside its capacity to regulate permeability and blood flow, NO has been reported to exert angiogenic properties in various tumor models. The focus of this review will be the proangiogenic role of NO in the tumor microenvironment and its multiple mechanism of action on vascular endothelium. Particular attention will be devoted to the role of NO in regulating metalloproteinase activity on cultured microvascular endothelium and in the in vivo rabbit cornea assay. Finally, the potential clinical outcomes and expectations related to this topic will be discussed. PMID- 20167556 TI - Thrombin's central role in angiogenesis and pathophysiological processes. AB - A plethora of endogenous modulators of angiogenesis have been identified and their roles in the molecular and cellular events that mediate and regulate angiogenesis have been proposed. In this review, we summarize the recent findings on the role of thrombin/thrombosis on angiogenesis and other related pathophysiological processes. The mechanisms by which thrombin itself and its receptor PAR1 orchestrate many cellular events through interaction with a variety of other factors and cell types are discussed. These new data point to the complexity of the regulatory processes involved in the angiogenic cascade, which may be tissue specific, and dependent upon the pathology involved. The understanding of these events may provide targets for therapeutic intervention in disease states where angiogenesis is disturbed. PMID- 20167557 TI - Roles of pleiotrophin in tumor growth and angiogenesis. AB - Pleiotrophin (PTN) is a heparin-binding growth factor with diverse biological activities, the most studied of these being those related to the nervous system, tumor growth and angiogenesis. Although interest in the involvement of PTN in tumor growth is increasing, many questions remain unanswered, particularly concerning the receptors and the signaling pathways involved. In this review, we briefly introduce PTN, and summarize data on its involvement in tumor growth and angiogenesis, and on what is known to date concerning the receptors and pathways involved. PMID- 20167558 TI - Angiogenesis: a balancing act between integrin activation and inhibition? AB - Acquisition of new genes encoding for extracellular matrix (ECM) proteins and their cognate integrin adhesive receptors, as well as secreted pro- and anti angiogenic factors, proved to be essential for the development of functional vascular networks in the vertebrate embryo. There is now clear evidence that post natal, pathological tissue neo-vascularization is crucial for cancer growth and therapy as well. Integrins are major ECM receptors that can exist in different functional states with respect to their affinity for ECM proteins. Regulation of integrin activation is crucial for their biological functions. In the embryo, the development of a properly patterned network of blood vessels relies upon the fine modulation of integrin activation by chemoattractant and chemorepulsive cues, such as angiogenic growth factors and semaphorins. Such a fine-tuning of endothelial integrin function is likely to be disrupted in cancer. Here, the vasculature is structurally and functionally abnormal and therefore inadequate for an efficient drug and oxygen delivery, which is a mandatory pre-requisite for successful chemotherapy and radiotherapy. It is thus important to identify the molecular mechanisms that regulate integrin function in normal ECs and which are altered in tumor ECs. PMID- 20167559 TI - Mast cell contribution to tumor angiogenesis: a clinical approach. AB - Mast cells (MCs) are tissue leukocytes that are distributed throughout the major organs of the body. They are an important local source of preformed and newly synthesized angiogenic molecules. MCs have been linked both to inflammatory and tumor angiogenesis. Indeed, numerous solid tumors and hematological malignancies present MC-rich infiltrates, which are believed to contribute to the formation of a new vascular supply. In addition, angiogenesis and MC density have been shown to increase simultaneously with the pathological progression in many of such tumors. This review will focus on the angiogenic potential of MCs in human solid and hematological tumors. PMID- 20167560 TI - Proteases and receptors in the recruitment of endothelial progenitor cells in neovascularization. AB - Since the initial discovery of endothelial progenitor cells (EPC), and their promise in increasing angiogenesis and vasculogenesis, a myriad of papers have highlighted their potential application in experimental and clinical neovascularization and in tissue engineering. However, promising reports are contrasted by other studies that could not find a role for EPC in neovascularization. Presently, two types of endothelial progenitor cell populations are recognized. The first population provides early-outgrowth CD34+/VEGFR-2+ cells, or colony-forming unit endothelial cells (CFU-EC), which represent myeloid cells with some endothelial properties, but no ability to form endothelial colonies. They can stimulate neovascularization by paracrine means, but are not incorporated in the endothelial lining themselves. The second population generates the late-outgrowth endothelial colony-forming cells (ECFC) from a very scant blood-derived cell population. ECFC have a very high proliferative potential, can insert into the endothelial lining of new blood vessels, and can also form endothelial tubes by themselves after stimulation with the proper angiogenic stimulus. This review surveys the mobilization of progenitor cells from the bone marrow, the homing of EPC (CFU-EC) to areas of neovascularization, and the participation of EPC (ECFC) in the endothelial lining of newly formed blood vessels. Specific emphasis has been placed on the role of proteases, which include serine proteases, including urokinase, L-cathepsin, and several ADAM- and matrix metalloproteinases. The specific properties of ECFC make them a potential source of cells for tissue engineering applications, but much has to be learned about their nature, origin and properties. PMID- 20167561 TI - Delta-like 4 and vasohibin 1: two endothelium-produced negative regulators of angiogenesis with distinctive roles. AB - Angiogenesis is regulated by the local balance between angiogenesis stimulators and inhibitors. A number of endogenous angiogenesis inhibitors have been found in the body. The origin of these inhibitors is mostly extrinsic to the vasculature. Recently however, endothelial cells themselves have been found to produce angiogenesis inhibitors including delta-like 4 and vasohibin 1. These intrinsic factors are thought to regulate angiogenesis by an autoregulatory or negative feedback mechanism. This review focuses on such negative regulators of angiogenesis produced by endothelial cells. PMID- 20167562 TI - Anti-FGF2 approaches as a strategy to compensate resistance to anti-VEGF therapy: long-pentraxin 3 as a novel antiangiogenic FGF2-antagonist. AB - Angiogenesis, the formation of new blood vessels from the endothelium of the existing vasculature, plays a pivotal role in tumor growth, progression and metastasis. Over the last 30 years, numerous pro- and antiangiogenic molecules, their ligands, and intracellular signaling pathways have been identified, and significant efforts have been undertaken to develop antiangiogenic strategies for cancer therapy. Agents that selectively target vascular endothelial growth factor (VEGF) and its receptors have shown promising activity in clinical trials and have been approved for use in selected cancer indications. However, patients may ultimately develop resistance to these drugs. One proposed mechanism of tumor escape from anti-VEGF therapy is the up-regulation of fibroblast growth factor-2 (FGF2). FGF2 is a pleiotropic, angiogenesis inducer belonging to the family of the heparin-binding FGF growth factors. FGF2 is expressed by numerous tumor types and exerts its proangiogenic activity by interacting with tyrosine kinase receptors, heparan-sulfate proteoglycans, and integrins expressed on the endothelial cell surface. Experimental evidence suggests that targeting FGF2, in addition to VEGF, might provide synergistic effects in the treatment of angiogenesis-related diseases, including cancer. Several FGF2 inhibitors, with different chemical structure and mechanism of action, have been identified. Recent observations have shown the ability of the soluble pattern recognition receptor long-pentraxin-3 (PTX3) to bind FGF2, thus acting as a FGF2 antagonist. PTX3 binds FGF2 with high affinity and specificity. This interaction prevents the binding of FGF2 to its cognate tyrosine kinase receptors, leading to inhibition of the angiogenic activity of the growth factor. Further, preliminary observations support the hypothesis that PTX3 may inhibit FGF2-mediated tumor angiogenesis and growth. The identification of the FGF2-binding domain in the unique N-terminal extension of PTX3 has allowed the design of PTX3-derived synthetic peptides endowed with significant antiangiogenic activity in vitro and in vivo. These findings may provide the basis for the development of novel antiangiogenic FGF2 antagonists, with potential implications for cancer therapy. PMID- 20167563 TI - [Mechanisms of resistance to molecular targeted therapies in breast cancer: update and future]. AB - The importance of targeted therapies has been emphasized by clinical trials using antiangiogenic or HER2 inhibitors in breast cancer. First with trastuzumab, it was demonstrated that targeted therapies may improve outcome in patients with HER overexpressing breast cancer in metastatic or adjuvant settings. The emerging role for angiogenesis inhibitors has also been demonstrated with bevacizumab. Unfortunately, there is growing clinical and biological evidence that tumour cells may develop unexpected and complex mechanisms of resistance to those targeted therapies. This review outlines the mechanisms by which tumour cells may resist to new targeted agents. Most recent developments are also highlighted. PMID- 20167564 TI - [Hepatotoxicity of metastatic colorectal cancer chemotherapy: systematic review]. AB - AIM: Hepatic toxicity of chemotherapy for colorectal cancer and its complications after hepatic metastasis surgery are unclear. Studies reporting hepatic lesions after chemotherapy for colorectal cancer and published before July 2009 have been identified by searching the Medline database. Data concerning these hepatic lesions and outcome after surgery are resumed in this review. RESULTS: Studies concerning the link between hepatic steatosis and chemotherapy have contradictory results but steatosis is clearly associated to an increase of postoperative morbidity. Steatohepatitis, especially due to irinotecan, is associated with increased postoperative mortality. Sinusoidal obstruction syndrome, a severe form of vascular hepatic lesion, associated to oxaliplatin, seems to be linked with an increase of postoperative morbidity, but not mortality. Bevacizumab would not increase, when used in combination with oxaliplatin, the rate of postoperative complications. Some studies suggest a decrease of vascular hepatic lesions when bevacizumab is administered with chemotherapy. The literature concerning hepatic toxicity of anti-EGF-R antibody is freak. CONCLUSION: The fact that irinotecan may be linked to an increased risk of hepatic failure and postoperative death, which is not the case of oxaliplatine, must be taken in consideration in the choice of the preoperative chemotherapy before resection of hepatic metastasis of colorectal cancer. PMID- 20167565 TI - Partial seizures with affective semiology versus pavor nocturnus. AB - Sudden nocturnal events with an affective semiology may have various etiologies, such as nocturnal panic attacks, nightmares, pavor nocturnus and/or different types of focal epileptic seizures, particularly in children. We describe the case of a normally developed boy who, at the age of two years, experienced nocturnal paroxysmal events that occurred about one hour after falling asleep and lasted up to 15 minutes. The clinical picture was characterized by sudden arousal, fear, inconsolable crying and an apparently voluntary search for his mother. The state of consciousness was basically maintained, and the inter-ictal EEG pattern showed independent bilateral centro-temporal spikes and spike-and-wave complexes. The child had a family history of benign partial epilepsy of childhood with rolandic spikes, and the paroxysmal events remitted after valproic acid treatment. This case report highlights the difficulties in the differential diagnosis of panic attacks, nightmares, pavor nocturnus and focal nocturnal epileptic seizures, especially those arising from the temporal and frontal lobes. PMID- 20167566 TI - Measuring empowerment in patients with psoriasis: the Psoriasis Empowerment Enquiry in the Routine Practice (PEER) questionnaire. AB - While empowerment is an outcome pursued by advocacy groups and health care providers, no data are yet available about empowerment in patients with psoriasis in the literature. Our aim was to develop a tool for measuring levels of empowerment in psoriatic patients, and to assess its validity and reliability. A cross-sectional study among outpatients with psoriasis was carried out. Principal component analysis was performed to validate the questionnaire and to measure any associations with demographic and clinical data. The 12-item questionnaire (Psoriasis Empowerment Enquiry in the Routine practice, or PEER) showed acceptable consistency and reliability, and three distinct and interpretable factors have been identified: Knowledge, Experience, Skills. Patients older than 44 years and patients with psoriasis for more than one year showed statistically significantly higher levels of empowerment. Neither educational level nor the number of consultations influenced the global empowerment score (GES). A link between GES and prescribed therapy was found, suggesting that patients receiving systemic drugs have better knowledge, more insight and superior skills to manage their psoriasis. We conclude that PEER is an appropriate tool to assess empowerment among patients with psoriasis and may be used to evaluate the efficacy of educational interventions. Further studies are needed to assess its convergent validity and to improve its reliability. PMID- 20167567 TI - Trends in dermatologic surgery research over the past decade. AB - We aimed to study the rate of change in number and categories of publications in dermatologic surgery in dermatology versus non-dermatology journals. PubMed was searched for articles on dermatologic surgery from January 1, 1998 to December 31, 2007, using the search word "dermatology" AND "surgery". Articles were characterized by publication and journal type per year. Regression analysis was used to determine the effect of year of publication on number of publications of each type. The search yielded 7570 publications on dermatologic surgery. Seventy three percent appeared in dermatology journals. Overall, the number of publications increased linearly with time. Most of this increase was accounted for by publications in non-dermatology journals. However, there was an increase in randomized control trials over the course of the study period in dermatology journals only, while low quality-of-evidence publications accounted for most of the increase in non-dermatology journals. Over the past 10 years the field of dermatologic surgery has had a significant yearly increase in published original studies. It appears that high quality evidence on dermatologic surgery is mostly published in dermatology journals. Current trends towards evidence-based dermatology might impact future research and publications in the field of dermatologic surgery. PMID- 20167568 TI - Expanding the criteria of renal kidneys for transplantation: use of donors with acute renal failure. AB - BACKGROUND: Increased numbers of patients waiting for renal transplantation have led to widening selection criteria for grafts. Thus, we have evaluated the outcome of transplanted kidneys procured in the presence of acute renal failure (ARF). METHODS: Transplant patients (n = 52) with a kidney procured with ARF were studied. Clinical data from donors and recipients, serum creatinine (SCr), creatinine clearance [estimated glomerular filtration rate (eGFR)], cold ischaemia duration, time to urine flow recovery or renal function recovery, and the number of haemodialysis sessions, were collected retrospectively. RESULTS: Mean donor age was 45.7 +/- 12.7 years, and the mean SCr at the time of harvesting was 276.3 +/- 104.2 micromol/l. Recipients' mean age was 51.1 +/- 12.1 years. After transplantation, recovery of renal function was observed after 7.6 +/- 7.1 days, and required 1.9 +/- 3.0 haemodialysis sessions. SCr was 124.6 +/- 49.5 micromol/l, and eGFR was 56.2 +/- 19.8 ml/min at last follow-up. eGFR was significantly lower if the donor's death was due to stroke or cerebral haemorrhage (CH), or if the donors had previous cardiovascular disease (CVD) (P < 0.02). Patients with eGFR of <50 ml/min (n = 23) had donors who were older, and whose cause of death was more frequently related to CVD factors or to CH/stroke (P < 0.03). There were no significant differences between the two groups regarding age of recipient, gender of the donor or recipient, cold ischaemia time, occurrence of cardiac arrest, collapse or acute rejection. Linear regression analysis indicated that donor age and occurrence of acute rejection were independent factors associated with eGFR. CONCLUSIONS: ARF before organ procurement does not have a negative effect on subsequent renal function. However, old age, CVD risk factors or CH, and late renal function recovery after transplantation are correlated with subsequent lower renal function. Thus, renal grafts with ARF can be used for renal transplantations. PMID- 20167569 TI - ERA-EDTA Immunonephrology working group. PMID- 20167570 TI - Association between hypernatraemia acquired in the ICU and mortality: a cohort study. AB - BACKGROUND: The aim of this study is to describe the prevalence and outcomes of intensive care unit (ICU)-acquired hypernatraemia (IAH). METHODS: A retrospective analysis was performed on a prospectively collected database fed by 12 ICUs. Subjects are unselected patients with ICU stay >48 h. Mild and moderate to severe hypernatraemia were defined as serum sodium >145 and >150 mmol/L, respectively. IAH was hypernatraemia occurring >or=24 h after ICU admission in patients with normal serum sodium at ICU admission. RESULTS: Of the 8441 patients, 301 were excluded because they had hypernatraemia at ICU admission. Of the remaining 8140 patients, 901 (11.1%) experienced mild hypernatraemia, and 344 (4.2%) experienced moderate to severe hypernatraemia. Factors independently associated with IAH were male gender, severity at admission as assessed by the Simplified Acute Physiology Score version II (SAPS II), and organ failure or life-supporting treatment at ICU admission. Unadjusted hospital mortality was 15.2% in patients without hypernatraemia compared to 29.5% in patients with mild IAH and 46.2% in those with moderate to severe IAH (P < 0.0001). When any degree of IAH was handled as a time-dependent variable in a subdistribution hazard model, the subdistribution hazard ratio (SHR) for ICU mortality was 4.26 [95% confidence interval (CI), 3.74 4.84]. After stratification by centre and adjustment for confounders, both mild IAH and moderate to severe IAH were independently associated with mortality [SHR 2.03 (95% CI 1.73-2.39) and 2.67 (95% CI 2.19-3.26), respectively]. CONCLUSION: IAH is frequent and associated with mortality after adjustment on severity at ICU admission. PMID- 20167571 TI - Plasma oxalate following kidney transplantation in patients without primary hyperoxaluria. AB - BACKGROUND: Patients with primary hyperoxaluria may need repeated kidney transplants due to damage from oxalic acid (oxalate) deposits. However, oxalate may also be potentially harmful in all transplant recipients. Determinants of oxalate following transplantation have not been well studied. METHODS: Two hundred and twelve recipients admitted for transplantation were included in the study. Blood samples for measurement of oxalate and other relevant laboratory parameters were collected at baseline and subsequently 10 weeks after transplantation. For oxalate determination, samples were obtained in 99, 167 and 54 patients out of the 212 at baseline, at follow-up and at both time points, respectively. We examined the bivariate association between plasma oxalate at transplantation and preemptive transplantation, time on dialysis, recipient age, creatinine, urea, phosphate, haemoglobin, PTH, albumin and calcium. Oxalate 10 weeks after transplantation was tested likewise including also laboratory parameters at baseline, primary non-function, rejection episodes, live versus deceased donor, donor age and GFR at follow-up. RESULTS: Median plasma oxalate concentration at transplantation was 35.0 micromol/L [95% confidence interval (95% CI) = 10.4-93.9] and 98% of the values were above normal limits (2.6-11.0). Oxalate concentration after 10 weeks was 9.0 micromol/L (4.0-25.5), still 37% being above the upper normal value. Multiple regression analysis revealed established dialysis treatment (P = 0.002) and creatinine (P < 0.000001) as independent positive determinants of oxalate at transplantation. Oxalate at 10 weeks was negatively associated to (51)Cr-EDTA absolute GFR (P = 0.023) and positively associated to donor age (P = 0.027) and plasma creatinine at 10 weeks (P = 0.03). CONCLUSION: At transplantation, plasma oxalate was on average three times increased and above the upper normal limit in 98% of patients and were still above normal in 37% after 10 weeks. The reduction after 10 weeks is determined by GFR and donor age. Whether increased plasma oxalate following kidney transplantation may have long-term consequences needs further study. PMID- 20167572 TI - Kidney and brain--a renal perspective of 'Les Liaisons Dangereuses'. PMID- 20167573 TI - Delayed re-endothelialization with rapamycin-coated stents is rescued by the addition of a glycogen synthase kinase-3beta inhibitor. AB - AIMS: Drug-eluting stents (DESs) reduce neointima area and in-stent restenosis but delay re-endothelialization. Recently, we demonstrated that pharmacological expansion and functional enhancement of endothelial progenitor cells (EPCs) can be achieved by treatment with a glycogen synthase kinase-3beta inhibitor (GSKi) even for feeble cells derived from coronary artery disease patients. GSKi treatment enhanced EPC adhesion via up-regulated expression of the alpha-4 integrin, ameliorated re-endothelialization, and reduced neointima formation in denuded murine arteries. Hence, we hypothesized that GSKi-coated stents (GSs) will enhance EPC adhesion and attenuate delayed vascular healing associated with rapamycin, a key DES agent. METHODS AND RESULTS: In vitro human EPCs adhered to GS with affinities that were 2x, 14x, and 13x greater than vehicle (VSs)-, rapamycin (RSs)-, and rapamycin plus GSKi (RGSs)-coated stents, respectively. Stents were inserted in rabbit carotid arteries, and at 14 days, neointima area was 45 and 49% lower in GSs compared with bare metal stents (BMSs) and VSs. Moreover, RSs had a 47% larger neointima area than GSs, but RGSs reduced neointima area to a level comparable to GSs. Seven days after stenting, GSs displayed re-endothelialization that was 40, 33, and 42% greater than BMSs, VSs, and RSs, respectively. Moreover, RGSs had 41% more re-endothelialization than RSs. At 14 days, the 7-day re-endothelialization patterns persisted. CONCLUSION: GSKi efficiently ameliorates the vascular response to stent implantation and has an important redeeming effect on the deleterious endothelial effects of rapamycin coated stents. PMID- 20167574 TI - Cs-corrected HAADF-STEM imaging of silicate minerals. AB - Significant improvement of the resolution for electron microscopy by the development of the spherical aberration corrector (Cs-corrector) brings valuable information to understand local atomic structures in silicate minerals. Cation columns separated by ca. 1.5 A, which originate from the ionic radius of oxygen anion or half of the closest oxygen-oxygen distance, are common in silicates and they are easily resolved by a Cs-corrected transmission electron microscope (TEM) or scanning TEM (STEM) with a resolution close to 1 A. High-angle annular dark field (HAADF) imaging using Cs-corrected STEM was applied to orthopyroxene (Opx) with augite lamellae, and cronstedtite, an iron-bearing sheet silicate. Noisy contrast in the HAADF images was compensated by advanced noise filtering techniques. All cation columns in the pyroxene structure were resolved in the HAADF images from the c-axis. A sub-angstrom difference in the position of the M2 site between Opx and augite, which is caused by the occupation of the site by Fe (Opx) and Ca (augite), was clearly detected in the HAADF image as well as different contrasts of the cation columns related to occupying elements. A pair of tetrahedral cation columns separated by ca. 1.5 A in cronstedtite observed along [100] directions frequently show unequal contrast, suggesting a difference of the amounts of substituted Fe(3+) between the two columns. Comparison between the experimental contrast with a simple simulation suggests the distribution of Fe(3+) in a tetrahedral sheet avoiding linkage of Fe(3+) coordinating tetrahedrons. PMID- 20167576 TI - Ketogenic diet slows down mitochondrial myopathy progression in mice. AB - Mitochondrial dysfunction is a major cause of neurodegenerative and neuromuscular diseases of adult age and of multisystem disorders of childhood. However, no effective treatment exists for these progressive disorders. Cell culture studies suggested that ketogenic diet (KD), with low glucose and high fat content, could select against cells or mitochondria with mutant mitochondrial DNA (mtDNA), but proper patient trials are still lacking. We studied here the transgenic Deletor mouse, a disease model for progressive late-onset mitochondrial myopathy, accumulating mtDNA deletions during aging and manifesting subtle progressive respiratory chain (RC) deficiency. We found that these mice have widespread lipidomic and metabolite changes, including abnormal plasma phospholipid and free amino acid levels and ketone body production. We treated these mice with pre symptomatic long-term and post-symptomatic shorter term KD. The effects of the diet for disease progression were followed by morphological, metabolomic and lipidomic tools. We show here that the diet decreased the amount of cytochrome c oxidase negative muscle fibers, a key feature in mitochondrial RC deficiencies, and prevented completely the formation of the mitochondrial ultrastructural abnormalities in the muscle. Furthermore, most of the metabolic and lipidomic changes were cured by the diet to wild-type levels. The diet did not, however, significantly affect the mtDNA quality or quantity, but rather induced mitochondrial biogenesis and restored liver lipid levels. Our results show that mitochondrial myopathy induces widespread metabolic changes, and that KD can slow down progression of the disease in mice. These results suggest that KD may be useful for mitochondrial late-onset myopathies. PMID- 20167575 TI - Genome-wide association study identifies polymorphisms in LEPR as determinants of plasma soluble leptin receptor levels. AB - Plasma soluble leptin receptor (sOB-R) levels were inversely associated with diabetes risk factors, including adiposity and insulin resistance, and highly correlated with the expression levels of leptin receptor, which is ubiquitously expressed in most tissues. We conducted a genome-wide association study of sOB-R in 1504 women of European ancestry from the Nurses' Health Study. The initial scan yielded 26 single nucleotide polymorphisms (SNPs) significantly associated with sOB-R levels (P < 5 x 10(-8)); all mapping to the leptin receptor gene (LEPR). Analysis of imputed genotypes on autosomal chromosomes revealed an additional 106 SNPs in and adjacent to this gene that reached genome-wide significance level. Of these 132 SNPs (including two non-synonymous SNPs, rs1137100 and rs1137101), rs2767485, rs1751492 and rs4655555 remained associated with sOB-R levels at the 0.05 level (P = 9.1 x 10(-9), 0.0105 and 0.0267, respectively) after adjustment for other univariately associated SNPs in a forward selection procedure. Significant associations with these SNPs were replicated in an independent sample of young males (n = 875) residing in Cyprus (P < 1 x 10(-4)). These data provide novel evidence revealing the role of polymorphisms in LEPR in modulating plasma levels of sOB-R and may further our understanding of the complex relationships among leptin, leptin receptor and diabetes-related traits. PMID- 20167577 TI - Analysis of lipid pathway genes indicates association of sequence variation near SREBF1/TOM1L2/ATPAF2 with dementia risk. AB - We conducted dense linkage disequilibrium (LD) mapping of a series of 25 genes putatively involved in lipid metabolism in 1567 dementia cases [including 1270 with Alzheimer disease (AD)] and 2203 Swedish controls. Across a total of 448 tested genetic markers, the strongest evidence of association was as anticipated for APOE (rs429358 at P approximately 10(-72)) followed by a previously reported association of ABCA1 (rs2230805 at P approximately 10(-8)). In the present study, we report two additional markers near the SREBF1 locus on chromosome 17p that were also significant after multiple testing correction (best P = 3.1 x 10(-6) for marker rs3183702). There was no convincing evidence of association for remaining genes, including candidates highlighted from recent genome-wide association studies of plasma lipids (CELSR2/PSRC1/SORT1, MLXIPL, PCSK9, GALNT2 and GCKR). The associated markers near SREBF1 reside in a large LD block, extending more than 400 kb across seven candidate genes. Secondary analyses of gene expression levels of candidates spanning the LD region together with an investigation of gene network context highlighted two possible susceptibility genes including ATPAF2 and TOM1L2. Several markers in strong LD (r(2) > 0.7) with rs3183702 were found to be significantly associated with AD risk in recent genome wide association studies with similar effect sizes, providing independent support of the current findings. PMID- 20167579 TI - The heterogeneous nuclear ribonucleoprotein-R is necessary for axonal beta-actin mRNA translocation in spinal motor neurons. AB - Axonal transport and translation of beta-actin mRNA plays an important role for axonal growth and presynaptic differentiation in many neurons including hippocampal, cortical and spinal motor neurons. Several beta-actin mRNA-binding and transport proteins have been identified, including ZBP1, ZBP2 and hnRNP-R. hnRNP-R has been found as an interaction partner of the survival motor neuron protein that is deficient in spinal muscular atrophy. Little is known about the function of hnRNP-R in axonal beta-actin translocation. hnRNP-R and beta-actin mRNA are colocalized in axons. Recombinant hnRNP-R interacts directly with the 3' UTR of beta-actin mRNA. We studied the role of hnRNP-R in motor neurons by knockdown in zebrafish embryos and isolated mouse motor neurons. Suppression of hnRNP-R in developing zebrafish embryos results in reduced axon growth in spinal motor neurons, without any alteration in motor neuron survival. ShRNA-mediated knockdown in isolated embryonic mouse motor neurons reduces beta-actin mRNA translocation to the axonal growth cone, which is paralleled by reduced axon elongation. Dendrite growth and neuronal survival were not affected by hnRNP-R depletion in these neurons. The loss of beta-actin mRNA in axonal growth cones of hnRNP-R-depleted motor neurons resembles that observed in Smn-deficient motor neurons, a model for the human disease spinal muscular atrophy. In particular, hnRNP-R-depleted motor neurons also exhibit defects in presynaptic clustering of voltage-gated calcium channels. Our data suggest that hnRNP-R-mediated axonal beta-actin mRNA translocation plays an essential physiological role for axon growth and presynaptic differentiation. PMID- 20167580 TI - Red cell distribution width: a powerful prognostic marker in heart failure. PMID- 20167578 TI - Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels. AB - P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology. PMID- 20167581 TI - Prospective associations of insomnia markers and symptoms with depression. AB - Whether insomnia, a known correlate of depression, predicts depression longitudinally warrants elucidation. The authors examined 555 Wisconsin Sleep Cohort Study participants aged 33-71 years without baseline depression or antidepressant use who completed baseline and follow-up overnight polysomnography and had complete questionnaire-based data on insomnia and depression for 1998 2006. Using Poisson regression, they estimated relative risks for depression (Zung scale score > or =50) at 4-year (average) follow-up according to baseline insomnia symptoms and polysomnographic markers. Twenty-six participants (4.7%) developed depression by follow-up. Having 3-4 insomnia symptoms versus none predicted depression risk (age-, sex-, and comorbidity-adjusted relative risk (RR) = 3.2, 95% confidence interval: 1.1, 9.6). After multiple adjustments, frequent difficulty falling asleep (RR = 5.3, 95% confidence interval: 1.1, 27.9) and polysomnographically assessed (upper or lower quartiles) sleep latency, continuity, and duration (RRs = 2.2-4.7; P's < or = 0.05) predicted depression. Graded trends (P-trend < or = 0.05) were observed with increasing number of symptoms, difficulty falling asleep, and difficulty returning to sleep. Given the small number of events using Zung > or =50 (depression cutpoint), a limitation that may bias multivariable estimates, continuous depression scores were analyzed; mean values were largely consistent with dichotomous findings. Insomnia symptoms or markers increased depression risk 2.2- to 5.3-fold. These results support prior findings based on self-reported insomnia and may extend similar conclusions to objective markers. Heightened recognition and treatment of insomnia may prevent subsequent depression. PMID- 20167582 TI - Teaching airway management to novices: a simulator manikin study comparing the 'sniffing position' and 'win with the chin' analogies. AB - BACKGROUND: The 'sniffing position' is widely promoted for teaching airway positioning before intubation, but whether this analogy results in novices placing the head and neck appropriately has not been evaluated. We compared performance following the sniffing position instructions with an alternate analogy, 'win with the chin'. We also compared performance following simple anatomic instructions and no instructions. METHODS: A randomized controlled study of medical students and PGY1 registrars in Surgery and Internal Medicine was performed. Subjects independently positioned a simulator manikin head and neck based upon their understanding of four written instructions in random order: (i) the 'sniffing position'; (ii) the 'win with the chin' analogy, (iii) anatomic instructions; and (iv) no instructions (control). Digital photographs following each instruction were analysed by two airway experts for (i) adequacy of overall positioning and (ii) the three components of airway positioning. RESULTS: Eighty one volunteers participated. The positioning was adequate most often (43.2%) following the 'win with the chin' analogy when compared with the other instructions (37.0% anatomic instructions; 19.8% control; 14.8% 'sniffing position' analogy). Positioning following the 'sniffing position' instructions was not different from no instruction (P=0.53). The 'win with the chin' and anatomic instructions were significantly better than no instructions (P=0.002 and 0.023, respectively). CONCLUSIONS: The 'win with the chin' analogy resulted in adequate airway positioning significantly more often than the 'sniffing position' or control. It also maintained atlanto-occipital extension compared with anatomic instructions. Overall, 'win with the chin' was a superior teaching analogy and could replace the 'sniffing position' analogy. PMID- 20167583 TI - Influence of steep Trendelenburg position and CO(2) pneumoperitoneum on cardiovascular, cerebrovascular, and respiratory homeostasis during robotic prostatectomy. AB - BACKGROUND: The steep (40 degrees ) Trendelenburg position optimizes surgical exposure during robotic prostatectomy. The goal of the current study was to investigate the combined effect of this position and CO(2) pneumoperitoneum on cardiovascular, cerebrovascular, and respiratory homeostasis during these procedures. METHODS: Physiological data were recorded during the whole surgical procedure in 31 consecutive patients who underwent robotic endoscopic radical prostatectomy under general anaesthesia. Heart rate, mean arterial pressure, central venous pressure, Sp(o(2)), Pe'(co(2)), P(Plat), tidal volume, compliance, and minute ventilation were monitored and recorded. Arterial samples were obtained to determine the arterial-to-end-tidal CO(2) tension gradient. Continuous regional cerebral tissue oxygen saturation (Sct(o(2))) was determined by near-infrared spectroscopy. RESULTS: Although patients were in the Trendelenburg position, all variables investigated remained within a clinically acceptable range. Cerebral perfusion pressure (CPP) decreased from 77 mm Hg at baseline to 71 mm Hg (P=0.07), and Sct(o(2)) increased from 70% to 73% (P<0.001). Pe'(co(2)) increased from 4.12 to 4.79 kPa (P<0.001) and the arterial-to Pe'(co(2)) tension difference increased from 1.06 kPa in the normal position to a maximum of 1.41 kPa (P<0.001) after 2 h in the Trendelenburg position. CONCLUSIONS: The combination of the prolonged steep Trendelenburg position and CO(2) pneumoperitoneum was well tolerated. Haemodynamic and pulmonary variables remained within safe limits. Regional cerebral oxygenation was well preserved and CPP remained within the limits between which cerebral blood flow is usually considered to be maintained by cerebral autoregulation. PMID- 20167584 TI - Effect of body mass index on the ED50 volume of bupivacaine 0.5% for supraclavicular brachial plexus block. AB - BACKGROUND: The aim of this study was to determine whether the ED(50) dose of bupivacaine 0.5% for supraclavicular brachial plexus block increases with increasing body mass index (BMI). METHODS: This double-blind, non-randomized trial followed an up-and-down sequential allocation design. Adult patients undergoing elective upper limb surgery under ultrasound-guided supraclavicular brachial block were recruited. A preliminary study was used to guide the dosing schedule for the main study in which patients were divided into three groups according to their BMI (Group A, BMI >27 kg m(-2); Group B, BMI 24-27 kg m(-2); Group C, BMI <24 kg m(-2)). The study design and analysis followed Dixon's small sample model using a 'nominal' sample size of six per group. RESULTS: Twenty-one patients were recruited to the preliminary study. Using isotonic regression, the ED(50) for bupivacaine 0.5% was estimated to be 8.9 ml [95% confidence interval (CI) 7.8-15.9]. In comparison, the ED(50) volume was found to be 10.8 ml (95% CI 5.9-19.7) using the Dixon-Massey formula. In the main study, six patients were recruited in each group with mean (range) BMI of 31.5 (27.2-38.8) kg m(-2) in Group A, 25.6 (24.4-26.3) kg m(-2) in Group B, and 21.6 (19.7-23.8) kg m(-2) in Group C. The ED(50) (95% CI) for Groups A, B, and C were 8.9 (6.2-12.7), 10.7 (7.5-15.4), and 13.4 (9.3-19.1) ml, respectively (P=0.05 for Group A vs Group C). CONCLUSIONS: Our study demonstrates that the ED(50) of bupivacaine 0.5% does not increase with an increase in BMI. We found evidence of a possible inverse relationship between ED(50) and BMI. PMID- 20167585 TI - Suppressed induction of mycobacterial antigen-specific Th1-type CD4+ T cells in the lung after pulmonary mycobacterial infection. AB - Although the importance of T(h)1-type immune response in protection against mycobacterial infection is well recognized, its regulatory mechanism in the Mycobacterium tuberculosis (Mtb)-infected lung is not well characterized. To address this issue, we analyzed kinetics of induction of mycobacterial antigen specific CD4(+) T(h)1 T cells after mycobacterial infection in P25 TCR-transgenic (Tg) mice which express TCR alpha and beta chains from a mycobacterial Ag85B specific MHC class II A(b)-restricted CD4(+) T-cell clone. To supply normal regulatory T-cell repertoire, we transferred normal spleen T cells into the P25 TCR-Tg mice before infection. High dose subcutaneous infection with Mtb or Mycobacterium bovis bacillus Calmette-Guerin (BCG) induced P25 TCR-Tg CD4(+) T(h)1 cells within a week. In contrast, high-dose Mtb or BCG infection into the lung failed to induce P25 TCR-Tg CD4(+) T(h)1 cells at the early stage of the infection. Furthermore, low-dose Mtb infection into the lung induced P25 TCR-Tg CD4(+) T(h)1 cells on day 21 in the mediastinal lymph node but not in the lung. IL-10 was partially involved in the suppression of T(h)1 induction in the lung because pretreatment of mice with anti-IL-10 antibody resulted in increase of P25 TCR-Tg CD4(+) T(h)1 cells in the Mtb-infected lung on day 21 of the infection, whereas neutralization of transforming growth factor-beta, another important suppressive cytokine in the lung, showed no effects on the T(h)1 induction. Our data suggest that induction of anti-mycobacterial CD4(+) T(h)1 cells is suppressed in the mycobacteria-infected lung partially by IL-10. PMID- 20167586 TI - Despite being highly diverse, immunovirological status strongly correlates with clinical symptoms during primary HIV-1 infection: a cross-sectional study based on 674 patients enrolled in the ANRS CO 06 PRIMO cohort. AB - OBJECTIVES: To analyse immunovirological status during primary HIV-1 infection (PHI) according to contemporary clinical status and time since infection. METHODS: Plasma HIV-RNA and peripheral blood mononuclear cell (PBMC) HIV-DNA levels and CD4 cell counts were determined at enrolment in the ANRS PRIMO cohort. Time since infection was estimated based on both the number of antibodies on western blot at enrolment (0-1, 2-4 or > or =5 specific antibodies) and the estimated interval between infection and enrolment based on clinical and epidemiological features. Patients were classified according to the presence or absence of clinical symptoms at enrolment. RESULTS: Between 1996 and 2006, 674 patients were enrolled an estimated median of 47 days after infection. Median marker values were as follows: HIV-RNA 5.10 log(10) copies/mL (range <1.70-8.33); HIV-DNA 3.30 log(10) copies/10(6) PBMCs (<1.84-4.93); and 506 CD4 cells/mm(3) (40 1542). Median HIV-RNA and PBMC HIV-DNA levels were significantly higher in patients with 0 or 1 specific antibody (n = 71) than in patients with 2-4 (n = 228) or > or =5 antibodies (n = 375). Symptomatic patients had significantly higher HIV-RNA and PBMC HIV-DNA levels and lower CD4 cell counts. However, 10% of symptomatic patients recruited shortly after infection had favourable immunovirological status. CONCLUSIONS: Plasma HIV-RNA, PBMC HIV-DNA and CD4 cell count values were highly diverse and correlated strongly with clinical status during PHI. Early diagnosis was not always associated with severe PHI. Combining PBMC HIV-DNA with HIV-RNA, CD4 cell count and clinical symptoms would have allowed identification of 179 patients (26.5%) at high risk of rapid disease progression who did not meet current guidelines for early treatment initiation. PMID- 20167587 TI - Polymyxin B, in combination with fluconazole, exerts a potent fungicidal effect. AB - OBJECTIVES: The objective of this study was to identify existing clinical compounds that either possess a fungicidal activity alone or can act synergistically with fungistatic antifungals. METHODS: We screened a clinical compound library for drugs that exhibited anti-Aspergillus activity. Among selected compounds, the cationic peptide antibiotic polymyxin B was chosen for further characterization because it can be used parenterally and topically. The fungicidal effect of polymyxin B and its synergistic interactions with azole antifungals were tested against a variety of fungal species. The toxicity of the drug combination of polymyxin B and fluconazole was compared with that of each drug alone in mammalian cell cultures. RESULTS: We found that polymyxin B possesses a broad-spectrum antifungal activity at relatively high concentrations. However, because of its synergistic interactions with azole antifungals, polymyxin B at much lower concentrations exerts a potent fungicidal effect against Cryptococcus neoformans, Candida albicans and non-albicans Candida species and moulds when combined with azoles. The combination of polymyxin B and fluconazole at concentrations within susceptible breakpoints is particularly potent against C. neoformans isolates, including fluconazole-resistant strains. The drug combination displayed no additional toxicity compared with polymyxin B alone when tested in cell culture. CONCLUSIONS: The combination of polymyxin B and fluconazole has the potential to be used in the clinic to treat systemic cryptococcosis. Our findings suggest that combining cationic peptide antibiotics with azole antifungals could provide a new direction for developing novel antifungal therapies. PMID- 20167588 TI - Novel mixed-format real-time PCR assay to detect mutations conferring resistance to triazoles in Aspergillus fumigatus and prevalence of multi-triazole resistance among clinical isolates in the Netherlands. AB - OBJECTIVES: The aim of this study was: (i) to study the prevalence of triazole resistant Aspergillus fumigatus isolates in the Netherlands; and (ii) to design rapid real-time PCR methods to identify such isolates. METHODS: A novel mixed format real-time PCR assay is described for the detection of mutations leading to triazole resistance in A. fumigatus. One set of PCR primers and a probe carrying a single fluorescent label in combination with a double-stranded DNA fluorescent dye allow simultaneous detection of (a) specific mutation(s) as well as of the amplified product that serves as an internal amplification control. The method was applied to a random collection of 209 clinical isolates from throughout the Netherlands and was compared with phenotypic susceptibility testing. RESULTS: A total of four triazole-resistant isolates were identified, resulting in a prevalence of resistant isolates of <2%. All four isolates contained an identical combination of mutations leading to multi-triazole resistance, as reported before by others. Molecular testing results were 100% concordant with phenotypic susceptibility testing. CONCLUSIONS: Although in specific patient populations the prevalence of resistance in A. fumigatus may be an emerging problem, in the general population it is still relatively low. The novel real-time PCR format allows rapid and reliable identification of such isolates. PMID- 20167589 TI - Susceptibility of carbapenemase-producing strains of Klebsiella pneumoniae and Escherichia coli to the direct antibacterial activity of NAB739 and to the synergistic activity of NAB7061 with rifampicin and clarithromycin. AB - OBJECTIVES: To determine the susceptibility of carbapenemase-producing strains of Klebsiella pneumoniae and Escherichia coli to the direct antibacterial activity of NAB739 and to the synergistic activity of NAB7061 with rifampicin and clarithromycin. NAB739 and NAB7061 are novel polymyxin derivatives that lack the cationic charges in the linear peptide portion of polymyxin B and have pharmacokinetic properties different from those of polymyxin B. METHODS: MIC determinations were performed by the agar dilution method using CLSI guidelines. Polymyxin B was used as a comparison. Synergism studies measured fractional inhibitory concentration indices (FICIs) by using increasing concentrations of the compounds in Mueller-Hinton agar and Etests. RESULTS: The MICs of NAB739 for all nine polymyxin-susceptible, carbapenemase-producing strains were identical or very close to those determined for E. coli ATCC 25922, for K. pneumoniae ATCC 13883, as well as for 18 clinical carbapenem-susceptible isolates. At a concentration of 4 mg/L, NAB7061 decreased the MIC of rifampicin and clarithromycin for all carbapenemase strains by factors ranging from 6 to 500. The polymyxin-resistant strain K. pneumoniae CL5762B was sensitized by a factor of 24 to rifampicin (FICI, 0.167) and by a factor of 12 to clarithromycin (FICI, 0.208). CONCLUSIONS: Polymyxin-susceptible, carbapenemase-producing strains are as susceptible to NAB739 as are the carbapenem-susceptible clinical isolates. In addition, NAB7061 has notable synergism with rifampicin and clarithromycin against all the carbapenemase-producing strains tested, including the polymyxin resistant K. pneumoniae strain. PMID- 20167590 TI - Biological dose estimation of UVA laser microirradiation utilizing charged particle-induced protein foci. AB - The induction of localized DNA damage within a discrete nuclear volume is an important tool in DNA repair studies. Both charged particle irradiation and laser microirradiation (LMI) systems allow for such a localized damage induction, but the results obtained are difficult to compare, as the delivered laser dose cannot be measured directly. Therefore, we revisited the idea of a biological dosimetry based on the microscopic evaluation of irradiation-induced Replication Protein A (RPA) foci numbers. Considering that local dose deposition is characteristic for both LMI and charged particles, we took advantage of the defined dosimetry of particle irradiation to estimate the locally applied laser dose equivalent. Within the irradiated nuclear sub-volumes, the doses were in the range of several hundreds of Gray. However, local dose estimation is limited by the saturation of the RPA foci numbers with increasing particle doses. Even high-resolution 4Pi microscopy did not abrogate saturation as it was not able to resolve single lesions within individual RPA foci. Nevertheless, 4Pi microscopy revealed multiple and distinct 53BP1- and gamma H2AX-stained substructures within the lesion flanking chromatin domains. Monitoring the local recruitment of the telomere repeat-binding factors TRF1 and TRF2 showed that both proteins accumulated at damage sites after UVA-LMI but not after densely ionizing charged particle irradiation. Hence, our results indicate that the local dose delivered by UVA-LMI is extremely high and cannot be accurately translated into an equivalent ionizing radiation dose, despite the sophisticated techniques used in this study. PMID- 20167591 TI - Intramuscular interferon beta-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study. AB - Disease-modifying drugs are initiated early and continued for years in patients with multiple sclerosis. Long-term tolerability and impact are not known. The objective of this study was to evaluate long-term tolerability of intramuscular interferon beta-1a and effects on disability and quality of life. Patients were evaluated an average of 15 years after randomization into a placebo-controlled, double-blind trial of intramuscular interferon beta-1a for relapsing multiple sclerosis. Patient-reported Expanded Disability Status Scale, the Short Form-36, a visual analog scale of self-care independence, and a living situation questionnaire were administered. Status was ascertained in 79% (136/172) of eligible patients. Analysis focused on 122 living patients. Despite open-label, non-standardized treatment after the 2-year clinical trial, 46% (n= 56) of the patients remained on intramuscular interferon beta-1a. Expanded Disability Status Scale scores were correlated highly with Short Form-36 subcategories and visual analog scale scores. Patients currently using intramuscular interferon beta-1a had a significantly lower mean Expanded Disability Status Scale score (p= 0.011), less progression to Expanded Disability Status Scale milestones, significantly better scores on the physical component of the Short Form-36 (p< 0.0001), and reported better general health and greater independence. We conclude that patients continuing to use intramuscular interferon beta-1a had less disability and better quality of life compared with patients not currently using intramuscular interferon beta-1a 15 years after randomization into a clinical trial. PMID- 20167592 TI - Does MRI lesion activity regress in secondary progressive multiple sclerosis? AB - BACKGROUND: The rate of new contrast-enhancing lesions (CELs) on monthly magnetic resonance imaging (MRI) scans has been shown to decrease over a 9-month period in placebo-treated patients with relapsing-remitting (RR) multiple sclerosis (RRMS). OBJECTIVE: We examined this phenomenon in placebo-treated secondary progressive MS (SPMS) patients. METHODS: Patients were chosen from two clinical trials. Monthly scans were taken at screening, baseline and months 1-9 for Cohort-1 and months 1-6 for Cohort-2. We examined the monthly new CEL rates according to initial CEL level: 0, 1-3, >3 CELs at screening, and presence and absence of pre study relapses. RESULTS: Respectively, 59, 21 and 14 of the 94 Cohort-1 patients, and 36, 17 and 9 of the 62 Cohort-2 patients had 0, 1-3 and >3 initial CELs. For Cohort-1, the monthly new CEL rates did not change during follow-up, regardless of initial CEL level. For Cohort-2, the monthly rate was unchanged in the 0 initial CEL subgroup, but decreased 33% (95% confidence interval: 8%, 52%) from months 1-3 to months 4-6 in the other two subgroups. For the combined cohorts, a decreasing rate was observed in the 12 patients with >3 initial CELs and pre study relapses. CONCLUSIONS: The short-term trend of new CEL activity in placebo treated SPMS patients may vary across cohorts. PMID- 20167593 TI - Differences in the progression of primary progressive multiple sclerosis in Brazilians of African descent versus white Brazilian patients. AB - Recent studies have suggested faster clinical progression and greater disability in multiple sclerosis patients of African descent. This study analysed the effect of ethnicity on progression and disability. Sixty-five patients with primary progressive multiple sclerosis were selected and classified as being of African descent or white. Time from onset of the disease until reaching Expanded Disability Status Scale grades 3, 6, and 8 was assessed, as well as irreversible disability (Expanded Disability Status Scale grade maintained for >or=6 months). In the African descent group, the median time to reach Expanded Disability Status Scale 3 was 1 year shorter (1 year vs 2 years, p= 0.02), and to reach Expanded Disability Status Scale 6 was 2 years shorter (3 years vs 5 years, p= 0.01) than in the group of white patients. According to the Kaplan-Meier survival curves, patients of African descent reached every disability stage faster than white patients (p= 0.03, p = 0.04, and p = 0.03, respectively, for Expanded Disability Status Scale grades 3, 6, and 8). As in United States and European patients of African descent, the more severe and faster progression of multiple sclerosis seen in Brazilian primary progressive multiple sclerosis patients of African descent suggests a possibly greater effect of ethnicity rather than environment on the progression of multiple sclerosis. PMID- 20167594 TI - Latitudinal variation in incidence and type of first central nervous system demyelinating events. AB - Increasing prevalence and variable geographic patterns of occurrence of multiple sclerosis suggest an environmental role in causation. There are few descriptive, population-level, data on whether such variability applies to first demyelinating events (FDEs). We recruited 216 adults (18-59 years), with a FDE between 1 November 2003 and 31 December 2006 in a multi-center incident case-control study in four locations on the south-eastern and eastern seaboard of Australia, spanning latitudes 27 degrees south to 43 degrees south. Population denominators were obtained from the Australian Bureau of Statistics censuses of 2001 and 2006. Age and sex adjusted FDE incidence rates increased by 9.55% (95% confidence interval (CI) 7.37-11.78, p < 0.001) per higher degree of latitude. The incidence rate gradient per higher degree of latitude varied by gender (male: 14.69% (95% CI 9.68-19.94, p < 0.001); female 8.13% (95% CI 5.69-10.62, p < 0.001)); and also by the presenting FDE type: optic neuritis 11.39% (95% CI 7.15-15.80, p < 0.001); brainstem/cerebellar syndrome 9.47% (95% CI 5.18-13.93, p < 0.001); and spinal cord syndrome 5.36% (95% CI 1.78-9.06, p = 0.003). Differences in incidence rate gradients were statistically significant between males and females (p = 0.02) and between optic neuritis and spinal cord syndrome (p = 0.04). The male to female ratio varied from 1 : 6.7 at 27 degrees south to 1 : 2.5 at 43 degrees south. The study establishes a positive latitudinal gradient of FDE incidence in Australia. The latitude-related factor(s) influences FDE incidence variably according to subtype and gender, with the strongest influence on optic neuritis presentations and for males. These descriptive case analyses show intriguing patterns that could be important for understanding the etiology of multiple sclerosis. PMID- 20167595 TI - Clinical outcome of leiomyosarcomas of vascular origin: comparison with leiomyosarcomas of other origin. AB - BACKGROUND: There are no data about the natural history of leiomyosarcoma of vascular origin (vLMS) in comparison with leiomyosarcoma (LMS) of other origin and about the management of advanced disease. METHODS: Among 1472 patients diagnosed with sarcoma from January 1980 to December 2008 at our institution, 195 patients (13%) had LMS. LMS had a vascular origin in 14 cases (7%). RESULTS: Patients with vLMS had a significantly worse median metastasis-free survival (MFS) (0.25 versus 9.6 years, P = 0.001) and overall survival (OS; 2.1 versus 7 years, P < 0.0001) than patients with LMS of other origin. On multivariate analysis, grade and vascular origin were the sole independent adverse prognostic factors for OS. Eight metastatic patients with vLMS received a first-line anthracycline chemotherapy regimen. Two patients had partial response, four had stable disease and two had progressive disease. OS of patients with metastatic vLMS was not significantly different from that observed in patients with metastatic LMS of other origin (22.1 versus 16.5 months, P = 0.84). CONCLUSIONS: Vascular origin is an independent adverse prognostic factor for MFS and OS in patients with LMS. Patients with metastatic vLMS had a similar outcome than patients with metastatic LMS of other origin. PMID- 20167596 TI - Magnesium coordination controls the molecular switch function of DNA mismatch repair protein MutS. AB - The DNA mismatch repair protein MutS acts as a molecular switch. It toggles between ADP and ATP states and is regulated by mismatched DNA. This is analogous to G-protein switches and the regulation of their "on" and "off" states by guanine exchange factors. Although GDP release in monomeric GTPases is accelerated by guanine exchange factor-induced removal of magnesium from the catalytic site, we found that release of ADP from MutS is not influenced by the metal ion in this manner. Rather, ADP release is induced by the binding of mismatched DNA at the opposite end of the protein, a long-range allosteric response resembling the mechanism of activation of heterotrimeric GTPases. Magnesium influences switching in MutS by inducing faster and tighter ATP binding, allowing rapid downstream responses. MutS mutants with decreased affinity for the metal ion are impaired in fast switching and in vivo mismatch repair. Thus, the G-proteins and MutS conceptually employ the same efficient use of the high energy cofactor: slow hydrolysis in the absence of a signal and fast conversion to the active state when required. PMID- 20167597 TI - Nucleosome formation activity of human somatic nuclear autoantigenic sperm protein (sNASP). AB - NASP (nuclear autoantigenic sperm protein) is a member of the N1/N2 family, which is widely conserved among eukaryotes. Human NASP reportedly prefers to bind to histones H3.H4 and the linker histone H1, as compared with H2A.H2B, and is anticipated to function as an H3.H4 chaperone for nucleosome assembly. However, the direct nucleosome assembly activity of human NASP has not been reported so far. In humans, two spliced isoforms, somatic and testicular NASPs (sNASP and tNASP, respectively) were identified. In the present study we purified human sNASP and found that sNASP efficiently promoted the assembly of nucleosomes containing the conventional H3.1, H3.2, H3.3, or centromere-specific CENP-A. On the other hand, sNASP inefficiently promoted nucleosome assembly with H3T, a testis-specific H3 variant. Mutational analyses revealed that the Met-71 residue of H3T is responsible for this inefficient nucleosome formation by sNASP. Tetrasomes, composed of the H3.H4 tetramer and DNA without H2A.H2B, were efficiently formed by the sNASP-mediated nucleosome-assembly reaction. A deletion analysis of sNASP revealed that the central region, amino acid residues 26-325, of sNASP is responsible for nucleosome assembly in vitro. These experiments are the first demonstration that human NASP directly promotes nucleosome assembly and provide compelling evidence that sNASP is a bona fide histone chaperone for H3.H4. PMID- 20167598 TI - Novel insights into the cellular mechanisms of the anti-inflammatory effects of NF-kappaB essential modulator binding domain peptides. AB - The classical nuclear factor kappaB (NF-kappaB) signaling pathway is under the control of the IkappaB kinase (IKK) complex, which consists of IKK-1, IKK-2, and NF-kappaB essential modulator (NEMO). This complex is responsible for the regulation of cell proliferation, survival, and differentiation. Dysregulation of this pathway is associated with several human diseases, and as such, its inhibition offers an exciting opportunity for therapeutic intervention. NEMO binding domain (NBD) peptides inhibit the binding of recombinant NEMO to IKK-2 in vitro. However, direct evidence of disruption of this binding by NBD peptides in biological systems has not been provided. Using a cell system, we expanded on previous observations to show that NBD peptides inhibit inflammation-induced but not basal cytokine production. We report that these peptides cause the release of IKK-2 from an IKK complex and disrupt NEMO-IKK-2 interactions in cells. We demonstrate that by interfering with NEMO-IKK-2 interactions, NBD peptides inhibit IKK-2 phosphorylation, without affecting signaling intermediates upstream of the IKK complex of the NF-kappaB pathway. Furthermore, in a cell-free system of IKK complex activation by TRAF6 (TNF receptor-associated factor 6), we show that these peptides inhibit the ability of this complex to phosphorylate downstream substrates, such as p65 and inhibitor of kappaB alpha (IkappaB alpha). Thus, consistent with the notion that NEMO regulates IKK-2 catalytic activity by serving as a scaffold, appropriately positioning IKK-2 for activation by upstream kinase(s), our findings provide novel insights into the molecular mechanisms by which NBD peptides exert their anti-inflammatory effects in cells. PMID- 20167599 TI - Rational design of interleukin-21 antagonist through selective elimination of the gammaC binding epitope. AB - The cytokine interleukin (IL)-21 exerts pleiotropic effects acting through innate as well as adaptive immune responses. The activities of IL-21 are mediated through binding to its cognate receptor complex composed of the IL-21 receptor private chain (IL-21Ralpha) and the common gamma-chain (gammaC), the latter being shared by IL-2, IL-4, IL-7, IL-9, and IL-15. The binding energy of the IL-21 ternary complex is predominantly provided by the high affinity interaction between IL-21 and IL-21Ralpha, whereas the interaction between IL-21 and gammaC, albeit essential for signaling, is rather weak. The design of IL-21 analogues, which have lost most or all affinity toward the signaling gammaC chain, while simultaneously maintaining a tight interaction with the private chain, would in theory represent candidates for IL-21 antagonists. We predicted the IL-21 residues, which compose the gammaC binding epitope using homology modeling and alignment with the related cytokines, IL-2 and IL-4. Next we systematically analyzed the predicted binding epitope by a mutagenesis study. Indeed two mutants, which have significantly impaired gammaC affinity with undiminished IL 21Ralpha affinity, were successfully identified. Functional studies confirmed that these two novel hIL-21 double mutants do act as hIL-21 antagonists. PMID- 20167600 TI - Activating transcription factor 3 activates p53 by preventing E6-associated protein from binding to E6. AB - Genomic integration of human papillomavirus (HPV) DNA accounts for more than 90% of cervical cancers. High-risk genital HPVs encode E6 proteins that can interact with a cellular ubiquitin ligase E6-associated protein (E6AP) and target the tumor suppressor p53 for ubiquitin-mediated proteolysis. Currently, how this critical event is regulated is largely unknown. Here we report that activating transcription factor 3 (ATF3), a broad DNA damage sensor whose expression is frequently downregulated in cervical cancer, interacted with E6 and prevented p53 from ubiquitination and degradation mediated by the viral protein. Consistent with its role as a potent E6 antagonist, ATF3 expressed enforcedly in HPV positive SiHa cells activated p53, leading to expression of p53-target genes (e.g. p21 and PUMA), cell cycle arrest and apoptotic cell death. The leucine zipper domain of ATF3 appears indispensable for these effects as an ATF3 mutant lacking this domain failed to interact with E6 and activate p53 in the cervical cancer cells. The prevention of p53 degradation was unlikely caused by binding of ATF3 to the tumor suppressor, but rather was a consequence of disruption of the E6-E6AP interaction by ATF3. These results indicate that ATF3 plays a key role in a mechanism defending against HPV-induced carcinogenesis, and could serve as a novel therapeutic target for HPV-positive cancers. PMID- 20167601 TI - Structural basis of membrane targeting by the Dock180 family of Rho family guanine exchange factors (Rho-GEFs). AB - The Dock180 family of atypical Rho family guanine nucleotide exchange factors (Rho-GEFs) regulate a variety of processes involving cellular or subcellular polarization, including cell migration and phagocytosis. Each contains a Dock homology region-1 (DHR-1) domain that is required to localize its GEF activity to a specific membrane compartment where levels of phosphatidylinositol (3,4,5) trisphosphate (PtdIns(3,4,5)P(3)) are up-regulated by the local activity of PtdIns 3-kinase. Here we define the structural and energetic bases of phosphoinositide specificity by the DHR-1 domain of Dock1 (a GEF for Rac1), and show that DHR-1 utilizes a C2 domain scaffold and surface loops to create a basic pocket on its upper surface for recognition of the PtdIns(3,4,5)P(3) head group. The pocket has many of the characteristics of those observed in pleckstrin homology domains. We show that point mutations in the pocket that abolish phospholipid binding in vitro ablate the ability of Dock1 to induce cell polarization, and propose a model that brings together recent mechanistic and structural studies to rationalize the central role of DHR-1 in dynamic membrane targeting of the Rho-GEF activity of Dock180. PMID- 20167602 TI - The YTH domain is a novel RNA binding domain. AB - The YTH (YT521-B homology) domain was identified by sequence comparison and is found in 174 different proteins expressed in eukaryotes. It is characterized by 14 invariant residues within an alpha-helix/beta-sheet structure. Here we show that the YTH domain is a novel RNA binding domain that binds to a short, degenerated, single-stranded RNA sequence motif. The presence of the binding motif in alternative exons is necessary for YT521-B to directly influence splice site selection in vivo. Array analyses demonstrate that YT521-B predominantly regulates vertebrate-specific exons. An NMR titration experiment identified the binding surface for single-stranded RNA on the YTH domain. Structural analyses indicate that the YTH domain is related to the pseudouridine synthase and archaeosine transglycosylase (PUA) domain. Our data show that the YTH domain conveys RNA binding ability to a new class of proteins that are found in all eukaryotic organisms. PMID- 20167603 TI - DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1. AB - DYRK1A (the dual specificity tyrosine phosphorylation-regulated kinase 1A) plays an important role in body growth and brain physiology. Overexpression of this kinase has been associated with the development of Down syndrome in both human and animal models, whereas single copy loss-of-function of DYRK1A leads to increased apoptosis and decreased brain size. Although more than a dozen of DYRK1A targets have been identified, the molecular basis of its involvement in neuronal development remains unclear. Here we show that DYRK1A and another pro survival member of the DYRK family, DYRK3, promote cell survival through phosphorylation and activation of SIRT1, an NAD(+)-dependent protein deacetylase that is essential in a variety of physiological processes including stress response and energy metabolism. DYRK1A and DYRK3 directly phosphorylate SIRT1 at Thr(522), promoting deacetylation of p53. A SIRT1 phosphorylation mimetic (SIRT1 T522D) displays elevated deacetylase activity, thus inhibiting cell apoptosis. Conversely, a SIRT1 dephosphorylation mimetic (SIRT1 T522V) fails to mediate DYRK induced deacetylation of p53 and cell survival. We show that knockdown of endogenous DYRK1A and DYRK3 leads to hypophosphorylation of SIRT1, sensitizing cells to DNA damage-induced cell death. We also provide evidence that phosphorylation of Thr(522) activates SIRT1 by promoting product release, thereby increasing its enzymatic turnover. Taken together, our findings provide a novel mechanism by which two anti-apoptotic DYRK members promote cell survival through direct modification of SIRT1. These findings may have important implications in understanding the molecular mechanisms of tumorigenesis, Down syndrome, and aging. PMID- 20167604 TI - Interleukin-7 compartmentalizes its receptor signaling complex to initiate CD4 T lymphocyte response. AB - Interleukin (IL)-7 is a central cytokine that controls homeostasis of the CD4 T lymphocyte pool. Here we show on human primary cells that IL-7 binds to preassembled receptors made up of proprietary chain IL-7Ralpha and the common chain gammac shared with IL-2, -4, -9, -15, and -21 receptors. Upon IL-7 binding, both chains are driven in cholesterol- and sphingomyelin-rich rafts where associated signaling proteins Jak1, Jak3, STAT1, -3, and -5 are found to be phosphorylated. Meanwhile the IL-7.IL-7R complex interacts with the cytoskeleton that halts its diffusion as measured by single molecule fluorescence autocorrelated spectroscopy monitored by microimaging. Comparative immunoprecipitations of IL-7Ralpha signaling complex from non-stimulated and IL-7 stimulated cells confirmed recruitment of proteins such as STATs, but many others were also identified by mass spectrometry from two-dimensional gels. Among recruited proteins, two-thirds are involved in cytoskeleton and raft formation. Thus, early events leading to IL-7 signal transduction involve its receptor compartmentalization into membrane nanodomains and cytoskeleton recruitment. PMID- 20167605 TI - Modulation of myocardin function by the ubiquitin E3 ligase UBR5. AB - Fully differentiated mature smooth muscle cells (SMCs) are characterized by the presence of a unique repertoire of smooth muscle-specific proteins. Although previous studies have shown myocardin to be a critical transcription factor for stimulating expression of smooth muscle-specific genes, the mechanisms regulating myocardin activity are still poorly understood. We used a yeast two-hybrid screen with myocardin as bait to search for factors that may regulate the transcriptional activity of the myocardin. From this screen we identified a HECT domain-containing protein UBR5 (ubiquitin protein ligase E3 component n-recognin 5) as a myocardin-binding protein. Previous studies have shown that HECT domain containing proteins are ubiquitin E3 ligases that play an important role in protein degradation. UBR5 has, however, also been shown to regulate transcription independent of its E3 ligase activity. In the current study we demonstrated that UBR5 localized in the nuclei of SMCs and forms a complex with myocardin in vivo and in vitro. We also show that UBR5 specifically enhanced trans-activation of smooth muscle-specific promoters by the myocardin family of proteins. In addition, UBR5 significantly augmented the ability of myocardin to induce expression of endogenous SMC marker genes independent on its E3 ligase function. Conversely, depletion of endogenous UBR5 by small interfering RNA in fibroblast cells attenuated myocardin-induced smooth muscle-specific gene expression, and UBR5 knockdown in SMCs resulted in down-regulation of smooth muscle-specific genes. Furthermore, we found that UBR5 can attenuate myocardin protein degradation resulting in increased myocardin protein expression without affecting myocardin mRNA expression. The effects of UBR5 on myocardin requires only the HECT and UBR1 domains of UBR5. This study reveals an unexpected role for the ubiquitin E3 ligase UBR5 as an activator of smooth muscle differentiation through its ability to stabilize myocardin protein. PMID- 20167606 TI - Insulin-like growth factor-binding protein-5-induced laminin gamma1 transcription requires filamin A. AB - Insulin-like growth factor-binding protein-5 (IGFBP-5) has IGF-1-independent intranuclear effects that are poorly defined. Treatment of cells with IGFBP-5 induces migration, prevents apoptosis, and leads to increased laminin subunit transcription. Similarly, filamin A (FLNa), an actin-binding protein that participates in cell attachment, plays important additional roles in signal transduction and modulation of transcriptional responses. In this report, we show that IGFBP-5 leads to dephosphorylation of FLNa with subsequent FLNa cleavage. Following cleavage, there is enhanced recruitment of Smad3/4 to a C-terminal FLNa fragment with nuclear translocation and subsequent binding to the promoter region of the laminin gamma1 (lamc1) gene. FLNa knockdown prevents IGFBP-5-mediated increases in lamc1 transcription. These data indicate that IGFBP-5 induces formation of a FLNa-based nuclear shuttle that recruits transcription factors and regulates transcription of IGFBP-5 target genes. These studies provide new insights into the mechanisms whereby IGFBP-5 and FLNa exert intranuclear effects. PMID- 20167607 TI - A qualitative examination of perceived barriers and facilitators of physical activity for urban and rural youth. AB - Many adolescents, both rural and urban, are not meeting the recommended levels for physical activity (PA). This investigation was designed to elicit socioecologic barriers and facilitators for PA in rural and urban middle school youth and their parents. Thirteen focus groups were conducted with 41 youth and 50 parents from eastern North Carolina. Distance, cost, crime/danger and television were mentioned as the primary barriers among parents. Youth mentioned school policies related to PA and crime/danger as the main PA barriers. The most salient facilitators discussed by parents were social/peer facilitators, facilities available and parental role modeling of PA. The primary facilitators mentioned by youth were social outlets and facilities available. Results indicate that intrapersonal, interpersonal, environmental and policy factors related to PA resonated with both youth and parents. Since rural and urban residents often perceive and interact differently with PA environments, more research is needed to properly adapt interventions. PMID- 20167608 TI - Examining the relationships of depressive symptoms, stigma, social support and regimen-specific support on quality of life in adult patients with epilepsy. AB - Epilepsy research efforts have primarily focused on medical treatment and physical management of epilepsy; however, to provide comprehensive care, efforts cannot focus solely on physical manifestations of epilepsy. Research findings show that people with epilepsy face many challenges that can negatively affect quality of life (QOL). In this descriptive study, we examined the individual relationships between depressive symptoms, stigma, social support and regimen specific support and QOL in adults with epilepsy. Study data were obtained from a subset of patients (N = 147) who participated in a longitudinal study of adult patients with epilepsy. Measures of QOL, depressive symptoms, stigma, social support and regimen-specific support were analyzed to answer the research questions. The results of correlational analyses revealed statistically significant negative correlations between depressive symptoms, stigma and sometimes regimen-specific support and QOL and statistically significant positive correlations between social support and QOL. A hierarchical multiple linear regression model revealed that depressive symptoms accounted for the most variance in QOL. Psychosocial variables measured 3 months prior to QOL were entered into a hierarchical multiple linear regression model, revealing that depressive symptoms, stigma and social support can be used to predict QOL at a later time. PMID- 20167609 TI - Revisiting the insect mitochondrial molecular clock: the mid-Aegean trench calibration. AB - Phylogenetic trees in insects are frequently dated by applying a "standard" mitochondrial DNA (mtDNA) clock estimated at 2.3% My(-1), but despite its wide use reliable calibration points have been lacking. Here, we used a well established biogeographic barrier, the mid-Aegean trench separating the western and eastern Aegean archipelago, to estimate substitution rates in tenebrionid beetles. Cytochrome oxidase I (cox1) for six codistributed genera across 28 islands (444 individuals) on both sides of the mid-Aegean trench revealed 60 independently coalescing entities delimited with a mixed Yule-coalescent model. One representative per entity was used for phylogenetic analysis of mitochondrial (cox1, 16S rRNA) and nuclear (Mp20, 28S rRNA) genes. Six nodes marked geographically congruent east-west splits whose separation was largely contemporaneous and likely to reflect the formation of the mid-Aegean trench at 9 12 Mya. Based on these "known" dates, a divergence rate of 3.54% My(-1) for the cox1 gene (2.69% when combined with the 16S rRNA gene) was obtained under the preferred partitioning scheme and substitution model selected using Bayes factors. An extensive survey suggests that discrepancies in mtDNA substitution rates in the entomological literature can be attributed to the use of different substitution models, the use of different mitochondrial gene regions, mixing of intraspecific with interspecific data, and not accounting for variance in coalescent times or postseparation gene flow. Different treatments of these factors in the literature confound estimates of mtDNA substitution rates in opposing directions and obscure lineage-specific differences in rates when comparing data from various sources. PMID- 20167610 TI - Splicing and transcription differ between spore and intracellular life stages in the parasitic microsporidia. AB - Microsporidia are a diverse group of highly derived fungal relatives that are intracellular parasites of many animals. Both transcription and introns have been shown to be unusual in microsporidia: The complete genome of the human parasite Encephalitozoon cuniculi has only a few very short introns, and two distantly related microsporidian spores have been shown to harbor transcripts encoding several genes that overlap on different strands. However, microsporidia alternate between two life stages: the intracellular proliferative stage and the extracellular and largely metabolically dormant infectious spore. To date, most studies have focused on the spore. Here, we have compared transcription profiles for a number of genes from both life stages of microsporidia and found major differences in both the prevalence of overlapping transcription and splicing. Specifically, spore transcripts in E. cuniculi have longer 5' untranslated regions, overlap more frequently with upstream genes, and have a significantly higher number of transcription initiation sites compared with intracellular transcripts from the same species. In addition, we demonstrate that splicing occurs exclusively in the intracellular stage and not in spore messenger RNAs (mRNAs) in both E. cuniculi and the distantly related Antonospora locustae. These differences between the microsporidian life stages raise questions about the functional importance of transcripts in the spore. We hypothesize that at least some transcripts in spores are a product of the cell's transition into a dormant state and that these unusual mRNAs could play a structural role rather than an informational one. PMID- 20167611 TI - Identification of a Mg-protoporphyrin IX monomethyl ester cyclase homologue, EaZIP, differentially expressed in variegated Epipremnum aureum 'Golden Pothos' is achieved through a unique method of comparative study using tissue regenerated plants. AB - Variegated plants provide a valuable tool for studying chloroplast biogenesis by allowing direct comparison between green and white/yellow sectors within the same leaf. While variegated plants are abundant in nature, the mechanism of leaf variegation remains largely unknown. Current studies are limited to a few mutants in model plant species, and are complicated by the potential for cross contamination during dissection of leaf tissue into contrasting sectors. To overcome these obstacles, an alternative approach was explored using tissue culture techniques to regenerate plantlets from unique sectors. Stable green and pale yellow plants were developed from a naturally variegated Epipremnum aureum 'Golden Pothos'. By comparing the gene expression between green and pale yellow plants using suppression subtractive hybridization in conjunction with homologous sequence search, nine down-regulated and 18 up-regulated genes were identified in pale yellow plants. Transcript abundance for EaZIP (Epipremnum aureum leucine zipper), a nuclear gene homologue of tobacco NTZIP and Arabidopsis CHL27, was reduced more than 4000-fold in qRT-PCR analysis. EaZIP encodes the Mg protoporphyrin IX monomethyl ester cyclase, one of the key enzymes in the chlorophyll biosynthesis pathway. Examination of EaZIP expression in naturally variegated 'Golden Pothos' confirmed that EaZIP transcript levels were correlated with leaf chlorophyll contents, suggesting that this gene plays a major role in the loss of chlorophyll in the pale yellow sectors of E. aureum 'Golden Pothos'. This study further suggests that tissue-culture regeneration of plantlets from different coloured sectors of variegated leaves can be used to investigate the underlying mechanisms of variegation. PMID- 20167612 TI - Molecular analysis of SCARECROW genes expressed in white lupin cluster roots. AB - The Scarecrow (SCR) transcription factor plays a crucial role in root cell radial patterning and is required for maintenance of the quiescent centre and differentiation of the endodermis. In response to phosphorus (P) deficiency, white lupin (Lupinus albus L.) root surface area increases some 50-fold to 70 fold due to the development of cluster (proteoid) roots. Previously it was reported that SCR-like expressed sequence tags (ESTs) were expressed during early cluster root development. Here the cloning of two white lupin SCR genes, LaSCR1 and LaSCR2, is reported. The predicted amino acid sequences of both LaSCR gene products are highly similar to AtSCR and contain C-terminal conserved GRAS family domains. LaSCR1 and LaSCR2 transcript accumulation localized to the endodermis of both normal and cluster roots as shown by in situ hybridization and gene promoter::reporter staining. Transcript analysis as evaluated by quantitative real-time-PCR (qRT-PCR) and RNA gel hybridization indicated that the two LaSCR genes are expressed predominantly in roots. Expression of LaSCR genes was not directly responsive to the P status of the plant but was a function of cluster root development. Suppression of LaSCR1 in transformed roots of lupin and Medicago via RNAi (RNA interference) delivered through Agrobacterium rhizogenes resulted in decreased root numbers, reflecting the potential role of LaSCR1 in maintaining root growth in these species. The results suggest that the functional orthologues of AtSCR have been characterized. PMID- 20167613 TI - Termination of atrial fibrillation by flecainide: mechanistic insights from spectral analysis. PMID- 20167614 TI - Inferior myocardial infarction scars could be more arrhythmogenic than anterior ones. PMID- 20167615 TI - Characterization of bipolar electrograms during sinus rhythm for complex fractionated atrial electrograms recorded in patients with paroxysmal and persistent atrial fibrillation. AB - AIMS: Complex fractionated atrial electrogram (CFAE) has been reported to relate to maintain atrial fibrillation (AF). The aims of this study were to investigate the relationship between CFAE and background conditions during sinus rhythm (SR). METHODS AND RESULTS: Electroanatomical mapping using an EnSite Array was performed in 20 patients (paroxysmal AF:persistent AF = 16:4) who underwent pulmonary vein antrum isolation (PVAI). Contact bipolar electrograms were recorded before PVAI, during SR, and subsequently during induced AF. Peak-to-peak voltages and morphologies of the electrograms during SR were compared between sites with and without CFAE during AF. Among 1947 points obtained during SR, 974 (50%) were included in CFAE sites and 973 (50%) in non-CFAE sites. Electrogram amplitude during SR was higher at the CFAE sites than at the non-CFAE sites (2.4 +/- 1.7 vs. 1.9 +/- 1.9 mV; P < 0.0001), whereas fractionated or double electrograms were found in a similar range between the two areas (2 vs. 3%; P = 0.21). When analysed further in terms of AF termination by PVAI followed by confirmation of non-inducibility, the voltage of electrograms at the CFAE sites was lower (2.1 +/- 1.7 vs. 2.6 +/- 1.8 mV; P = 0.0001) and the morphology was more complex in patients without AF termination compared with those with AF termination. CONCLUSION: Our results suggest that in paroxysmal and persistent AF with minimally damaged LA, the CFAE sites in patients with AF termination by PVAI alone represent healthy atrial tissue with rapid electrical activity in response to an AF driver located in the pulmonary vein. However, in patients without AF termination, they represent more damaged tissue responsible for maintaining AF. PMID- 20167617 TI - Cohort profile: the study of health in Pomerania. PMID- 20167618 TI - DnaK from Bifidobacterium animalis subsp. lactis is a surface-exposed human plasminogen receptor upregulated in response to bile salts. AB - Bifidobacterium animalis subsp. lactis lives in the gastrointestinal tract of most mammals, including humans. Recently, for the probiotic strain B. animalis subsp. lactis BI07, a dose-dependent plasminogen-binding activity was demonstrated and five putative plasminogen-binding proteins were identified. Here we investigated the role of surface DnaK as a B. animalis subsp. lactis BI07 plasminogen receptor. DnaK was visualized on the bacterial cell surface by transmission electron microscopy. The His-tagged recombinant DnaK protein showed a high affinity for human plasminogen, with an equilibrium dissociation constant in the nanomolar range. The capability to tolerate physiological concentrations of bile salts is a crucial feature for an intestinal symbiont micro-organism. By proteome analysis we demonstrated that the long-term exposure of B. animalis subsp. lactis BI07 to bile salts results in the upregulation of important surface plasminogen receptors such as DnaK and enolase. Moreover, adaptation of B. animalis subsp. lactis BI07 to physiological concentrations of bile salts significantly increased its capacity to interact with the host plasminogen system. By enhancing the bacterial capacity to interact with the host plasminogen, the gut bile environment may facilitate the colonization of the human host by B. animalis subsp. lactis BI07. PMID- 20167619 TI - Metabolic flux analysis of wild-type Escherichia coli and mutants deficient in pyruvate-dissimilating enzymes during the fermentative metabolism of glucuronate. AB - The fermentative metabolism of d-glucuronic acid (glucuronate) in Escherichia coli was investigated with emphasis on the dissimilation of pyruvate via pyruvate formate-lyase (PFL) and pyruvate dehydrogenase (PDH). In silico and in vivo metabolic flux analysis (MFA) revealed that PFL and PDH share the dissimilation of pyruvate in wild-type MG1655. Surprisingly, it was found that PDH supports fermentative growth on glucuronate in the absence of PFL. The PDH-deficient strain (Pdh-) exhibited a slower transition into the exponential phase and a decrease in specific rates of growth and glucuronate utilization. Moreover, a significant redistribution of metabolic fluxes was found in PDH- and PFL deficient strains. Since no role had been proposed for PDH in the fermentative metabolism of E. coli, the metabolic differences between MG1655 and Pdh- were further investigated. An increase in the oxidative pentose phosphate pathway (ox PPP) flux was observed in response to PDH deficiency. A comparison of the ox-PPP and PDH pathways led to the hypothesis that the role of PDH is the supply of reducing equivalents. The finding that a PDH deficiency lowers the NADH : NAD(+) ratio supported the proposed role of PDH. Moreover, the NADH : NAD(+) ratio in a strain deficient in both PDH and the ox-PPP (Pdh-Zwf-) was even lower than that observed for Pdh-. Strain Pdh-Zwf- also exhibited a slower transition into the exponential phase and a lower growth rate than Pdh-. Finally, a transhydrogenase deficient strain grew more slowly than wild-type but did not show the slower transition into the exponential phase characteristic of Pdh- mutants. It is proposed that PDH fulfils two metabolic functions. First, by creating the appropriate internal redox state (i.e. appropriate NADH : NAD(+) ratio), PDH ensures the functioning of the glucuronate utilization pathway. Secondly, the NADH generated by PDH can be converted to NADPH by the action of transhydrogenases, thus serving as biosynthetic reducing power in the synthesis of building blocks and macromolecules. PMID- 20167620 TI - A new small regulatory protein, HmuP, modulates haemin acquisition in Sinorhizobium meliloti. AB - Sinorhizobium meliloti has multiple systems for iron acquisition, including the use of haem as an iron source. Haem internalization involves the ShmR haem outer membrane receptor and the hmuTUV locus, which participates in haem transport across the cytoplasmic membrane. Previous studies have demonstrated that expression of the shmR gene is negatively regulated by iron through RirA. Here, we identify hmuP in a genetic screen for mutants that displayed aberrant control of shmR. The normal induction of shmR in response to iron limitation was lost in the hmuP mutant, showing that this gene positively affects shmR expression. Moreover, the HmuP protein is not part of the haemin transporter system. Analysis of gene expression and siderophore production indicates that disruption of hmuP does not affect other genes related to the iron-restriction response. Our results strongly indicate that the main function of HmuP is the transcriptional regulation of shmR. Sequence alignment of HmuP homologues and comparison with the NMR structure of Rhodopseudomonas palustris CGA009 HmuP protein revealed that certain amino acids localized within predicted beta-sheets are well conserved. Our data indicate that at least one of the beta-sheets is important for HmuP activity. PMID- 20167621 TI - Genome-wide analysis of DNA turnover and gene expression in stationary-phase Saccharomyces cerevisiae. AB - Exponential-phase yeast cells readily enter stationary phase when transferred to fresh, carbon-deficient medium, and can remain fully viable for up to several months. It is known that stationary-phase prokaryotic cells may still synthesize substantial amounts of DNA. Although the basis of this phenomenon remains unclear, this DNA synthesis may be the result of DNA maintenance and repair, recombination, and stress-induced transposition of mobile elements, which may occur in the absence of DNA replication. To the best of our knowledge, the existence of DNA turnover in stationary-phase unicellular eukaryotes remains largely unstudied. By performing cDNA-spotted (i.e. ORF) microarray analysis of stationary cultures of a haploid Saccharomyces cerevisiae strain, we demonstrated on a genomic scale the localization of a DNA-turnover marker [5-bromo-2' deoxyuridine (BrdU); an analogue of thymidine], indicative of DNA synthesis in discrete, multiple sites across the genome. Exponential-phase cells on the other hand, exhibited a uniform, total genomic DNA synthesis pattern, possibly the result of DNA replication. Interestingly, BrdU-labelled sites exhibited a significant overlap with highly expressed features. We also found that the distribution among chromosomes of BrdU-labelled and expressed features deviates from random distribution; this was also observed for the overlapping set. Ty1 retrotransposon genes were also found to be labelled with BrdU, evidence for transposition during stationary phase; however, they were not significantly expressed. We discuss the relevance and possible connection of these results to DNA repair, mutation and related phenomena in higher eukaryotes. PMID- 20167622 TI - Amino acid identity at one position within the alpha1 helix of both the histidine kinase and the response regulator of the WalRK and PhoPR two-component systems plays a crucial role in the specificity of phosphotransfer. AB - Two-component systems usually function as cognate pairs, thereby ensuring an appropriate response to the detected signal. The ability to exclusively phosphorylate a partner protein, often in the presence of many competing homologous substrates, demonstrates a high level of specificity that must derive from the interacting surfaces of the two-component system. Here, we identify positions within the histidine kinases and response regulators of the WalRK and PhoPR two-component systems of Bacillus subtilis that make a major contribution to the specificity of phosphotransfer. Changing the identity of the amino acid at position 11 within the alpha1 helix of WalK and at position 17 within the alpha1 helix of PhoP altered discrimination and allowed phosphotransfer to occur with the non-cognate partner. Changing amino acids at additional positions of the WalK kinase increased phosphotransfer, while changes at additional positions in PhoP only had an effect in the presence of the change at position 17. The importance of amino acid identity at these two positions is supported by the fact that the amino acid combinations of Ile and Ser in WalRK, and Leu and Gly in PhoPR, are very highly conserved among orthologues, while modelling indicates that these amino acid pairs are juxtaposed in the WalRK and PhoPR complexes. PMID- 20167623 TI - cwrA, a gene that specifically responds to cell wall damage in Staphylococcus aureus. AB - Transcriptional profiling data accumulated in recent years for the clinically relevant pathogen Staphylococcus aureus have established a cell wall stress stimulon, which comprises a coordinately regulated set of genes that are upregulated in response to blockage of cell wall biogenesis. In particular, the expression of cwrA (SA2343, N315 notation), which encodes a putative 63 amino acid polypeptide of unknown biological function, increases over 100-fold in response to cell wall inhibition. Herein, we seek to understand the biological role that this gene plays in S. aureus. cwrA was found to be robustly induced by all cell wall-targeting antibiotics tested - vancomycin, oxacillin, penicillin G, phosphomycin, imipenem, hymeglusin and bacitracin - but not by antibiotics with other mechanisms of action, including ciprofloxacin, erythromycin, chloramphenicol, triclosan, rifampicin, novobiocin and carbonyl cyanide 3 chlorophenylhydrazone. Although a DeltacwrA S. aureus strain had no appreciable shift in MICs for cell wall-targeting antibiotics, the knockout was shown to have reduced cell wall integrity in a variety of other assays. Additionally, the gene was shown to be important for virulence in a mouse sepsis model of infection. PMID- 20167624 TI - Cholesterol utilization in mycobacteria is controlled by two TetR-type transcriptional regulators: kstR and kstR2. AB - Mycobacterium tuberculosis is able to use a variety of carbon sources in vivo and current knowledge suggests that cholesterol is used as a carbon source during infection. The catabolized cholesterol is used both as an energy source (ATP generation) and as a source of precursor molecules for the synthesis of complex methyl-branched fatty acids. In previous studies, we described a TetR-type transcriptional repressor, kstR, that controls the expression of a number of genes involved in cholesterol catabolism. In this study, we describe a second TetR-type repressor, which we call kstR2. We knocked this gene out in Mycobacterium smegmatis and used microarrays and quantitative RT-PCR to examine the effects on gene expression. We identified a palindromic regulatory motif for KstR2, showed that this motif is present in three promoter regions in mycobacteria and rhodococcus, and demonstrated binding of purified KstR2 to the motif. Using a combination of motif location analysis, gene expression analysis and the examination of gene conservation, we suggest that kstR2 controls the expression of a 15 gene regulon. Like kstR, kstR2 and the kstR2 regulon are highly conserved among the actinomycetes and studies in rhodococcus suggest a role for these genes in cholesterol catabolism. The functional significance of the regulon and implications for the control of cholesterol utilization are discussed. PMID- 20167625 TI - Regional variations in the population structure of Pseudomonas syringae pathovar phaseolicola from Spain are revealed by typing with PmeI pulsed-field gel electrophoresis, plasmid profiling and virulence gene complement. AB - One hundred and twenty pathogenic isolates of Pseudomonas syringae pv. phaseolicola recovered in Spain were subjected to biochemical and genomic typing, and investigated for virulence gene complement. Fifty-six were recovered from common beans (Phaseolus vulgaris) of the type Granja Asturiana, grown in a northern Spanish region (Asturias), and 64 from other common beans cultured in the neighbouring region of Castilla y Leon. Typing by PmeI digestion followed by pulsed-field gel electrophoresis revealed 27 profiles, with only three being common to both regions. Relationships between profiles distributed the isolates into two clusters: A (subdivided into subclusters A1 and A2) and B. Cluster A included all isolates from Granja Asturiana and about a quarter of the isolates from Castilla y Leon. Isolates from cluster A were negative for mannitol utilization and hybridized to probes for the argK-tox region responsible for phaseolotoxin production. Isolates that grouped in cluster B, which were only found in Castilla y Leon, were able to utilize mannitol but did not hybridize to probes for the argK-tox region. Separation of the isolates into three genomic groups, subsequently termed PphA1, PphA2 and PphB, was also supported by effector gene complement and location. In PphB, all effector genes tested (hopX1, hopF1, avrB2 and avrD1) mapped on chromosomal fragments, but faint hybridization of avrB2 with plasmids of about 40 kb was also observed. In PphA hopX1 mapped on the chromosome; in PphA1 avrB2 and avrD1 were carried on virulence plasmids (most of approx. 125 kb) and hopF1 was not detected, while in PphA2 the three genes were located on plasmids (approx. 75-160 kb). These results can be used as a framework to investigate the basis of regional variation in population structure, and for further epidemiological surveillance of P. syringae pv. phaseolicola. PMID- 20167626 TI - Chronic conditions account for rise in Medicare spending from 1987 to 2006. AB - Medicare beneficiaries' medical needs, and where beneficiaries undergo treatment, have changed dramatically over the past two decades. Twenty years ago, most spending growth was linked to intensive inpatient (hospital) services, chiefly for heart disease. Recently, much of the growth has been attributable to chronic conditions such as diabetes, arthritis, hypertension, and kidney disease. These conditions are chiefly treated not in hospitals but in outpatient settings and by patients at home with prescription drugs. Health reform must address changed health needs through evidence-based community prevention, care coordination, and support for patient self-management. PMID- 20167627 TI - SLiM on Diet: finding short linear motifs on domain interaction interfaces in Protein Data Bank. AB - MOTIVATION: An important class of protein interactions involves the binding of a protein's domain to a short linear motif (SLiM) on its interacting partner. Extracting such motifs, either experimentally or computationally, is challenging because of their weak binding and high degree of degeneracy. Recent rapid increase of available protein structures provides an excellent opportunity to study SLiMs directly from their 3D structures. RESULTS: Using domain interface extraction (Diet), we characterized 452 distinct SLiMs from the Protein Data Bank (PDB), of which 155 are validated in varying degrees-40 have literature validation, 54 are supported by at least one domain-peptide structural instance, and another 61 have overrepresentation in high-throughput PPI data. We further observed that the lacklustre coverage of existing computational SLiM detection methods could be due to the common assumption that most SLiMs occur outside globular domain regions. 198 of 452 SLiM that we reported are actually found on domain-domain interface; some of them are implicated in autoimmune and neurodegenerative diseases. We suggest that these SLiMs would be useful for designing inhibitors against the pathogenic protein complexes underlying these diseases. Our findings show that 3D structure-based SLiM detection algorithms can provide a more complete coverage of SLiM-mediated protein interactions than current sequence-based approaches. PMID- 20167628 TI - Development of a group intervention to improve school functioning in adolescents with chronic pain and depressive symptoms: a study of feasibility and preliminary efficacy. AB - OBJECTIVE: To establish feasibility and preliminary efficacy of "Coping with Pain in School" (CPS), an intervention to improve school functioning in adolescents with chronic pain and depressive symptoms. METHODS: Forty adolescents and parents participated in this uncontrolled trial. Participants completed measures of pain severity, depression, and school attendance at baseline and one month after participating in a manualized group intervention. Several other indicators of school functioning were explored. RESULTS: CPS was generally acceptable and satisfying to families and feasible to implement but participation was low. Post treatment analyses suggest that pain, some dimensions of depression, and school attendance improved after treatment. Conclusions CPS is feasible and holds promise in terms of its effects on pain and school attendance. Addressing enrollment challenges, refining the role of depression and its treatment, and further developing treatments with a school-functioning focus for adolescents with chronic pain are key areas for continued research. PMID- 20167629 TI - Experimental impact of aspirin exposure on rat intestinal bacteria, epithelial cells and cell line. AB - Aspirin, a commonly used therapeutic non-steroidal anti-inflammatory drug (NSAID) is known to cause gastric mucosal damage. Intestinal bacteria having a regulatory effect on intestinal homeostasis play significant role in NSAID-induced intestinal injury. Bacteria and specific cell lines are considered to be suitable for toxicity screening and testing of chemicals. Therefore, to evaluate and compare in vitro toxicity, cultures of rat intestinal epithelial cells (IEC), isolated bacteria and IEC-6 cell line were assessed for viability, morphometric analysis, membrane transport enzymes and structural constituents for membrane damage, dehydrogenase activity test for respiratory and energy producing processes and esterase activity test for intra- and extra-cellular degradation, following the post exposure to aspirin (0-50 ug mL(- 1)). Similar pattern of dose dependent changes in these parameters were observed in three types of cells. Similar in situ effects on IEC validated the in vitro findings. These findings indicate that higher aspirin concentrations may alter cellular functions of IEC and gut bacteria. Furthermore, results suggest that gut bacteria and IEC-6 cell line can be used for the initial screening of gastrointestinal cellular toxicity caused by NSAIDs. PMID- 20167630 TI - Sugar-free, glycine-stabilized intravenous immunoglobulin prevents skin but not renal disease in the MRL/lpr mouse model of systemic lupus. AB - Intravenous immunoglobulin (IVIG) has a therapeutic potential in many autoimmune diseases. Based on its immune modulating and complement inhibiting effects, IVIG has been tested in systemic lupus erythematosus (SLE), but due to osmotic tubular injury caused by immunoglobulin-stabilizing sugar components, lupus nephritis had been accelerated in some patients, thus IVIG use in SLE has been abandoned. The availability of non-sugar-stabilized IVIG raised the possible re-evaluation of IVIG for SLE. We investigated high-dose, long-term non-sugar-stabilized IVIG treatment on skin and renal SLE manifestations in the MRL/lpr mouse model. Animals were treated once a week with glycine-stabilized IVIG or saline (0.2 ml/ 10 g BW) from 6 weeks until they were humanely killed at 5 months of age. IVIG diminished macroscopic cutaneous lupus compared with saline treated mice. Histology and complement-3 immunostaining also demonstrated a significant reduction of skin disease after IVIG treatment. However, renal histology and function were similar in both groups. Compared with typical osmotic tubular damage induced by 5% sucrose and 10% maltose (used for IVIG stabilization), we did not observe any osmotic tubular injury in the glycine-stabilized IVIG treated mice. Our data demonstrate a beneficial effect of IVIG on skin lupus without renal side-effects. Deeper understanding of the organ-specific pathomechanism may aid an individualized SLE therapy. PMID- 20167631 TI - Retinoic acid-inducible gene-I (RIG-I) is induced by IFN-{gamma} in human mesangial cells in culture: possible involvement of RIG-I in the inflammation in lupus nephritis. AB - Interferon-gamma is a potent Th1-type cytokine and a key molecule in the pathogenesis of autoimmune diseases including lupus nephritis. Retinoic acid inducible gene-I is a putative RNA helicase that plays an important role in immune and inflammatory reactions. We previously demonstrated the increased expression of the retinoic acid-inducible gene-I protein in the kidney tissue of patients with lupus nephritis, and the presence of a significant amount of retinoic acid-inducible gene-I mRNA in the urinary sediment of patients with this inflammatory renal disease. In the present study, interferon-gamma was found to induce the expression of retinoic acid-inducible gene-I in human mesangial cells in culture. Knockdown of retinoic acid-inducible gene-I inhibited the interferon gamma-induced upregulation of interferon regulatory factor 7, a transcriptional factor involved in immune and inflammatory reactions. These findings suggest that retinoic acid-inducible gene-I produced by mesangial cells may be involved in the pathogenesis of lupus nephritis. PMID- 20167633 TI - Socio-demographic factors and appropriate health care-seeking behavior for childhood illnesses. AB - The objective of the study was to determine the influence of socio-demographic factors on healthcare-seeking behaviors for childhood illnesses. This cross sectional survey was conducted among consecutively admitted acutely ill children in the Children Emergency Room of a Nigerian tertiary care hospital. A total of 168 respondents were surveyed out of which only 12 (7.1%) performed well with regard to all the four indicators of appropriate healthcare-seeking behaviors. Bivariate analysis showed significant association between high maternal education and early care-seeking, utilization of orthodox health facilities, and drug use at home (p < 0.001 in each case). Similarly, age of child <1 year was associated with early care-seeking, care-seeking outside home, and utilization of orthodox health services (p < 0.001 in each case). Logistic regression showed that high maternal education and high family socioeconomic status were strong predictors of early care-seeking and care-seeking outside the home. It is concluded that maternal age, maternal education, and family socioeconomic status are predictors of appropriate healthcare-seeking behaviors for childhood illnesses. PMID- 20167632 TI - Overexpression of interferon-activated gene 202 (Ifi202) correlates with the progression of autoimmune glomerulonephritis associated with the MRL chromosome 1. AB - B6.MRLc1(82-100) congenic mice carrying the telomeric region of lupus-prone MRL chromosome 1 develop autoimmune glomerulonephritis (GN). The GN susceptibility locus of B6.MRLc1(82-100) contains the interferon activated gene 200 (Ifi200) family, which consists of Ifi202, 203, 204, and 205. Recently, Ifi202 was suggested as a candidate gene for murine lupus. In this study, we assessed the association between Ifi200 family and GN in several disease models. We compared the expression of Ifi200 family members in 24 organs between the C57BL/6 and B6.MRLc1(82-100). The expressions of Ifi200 family members differed between strains, and the most dramatic differences appeared in Ifi202 expression. Briefly, in the blood, immune organs, lungs, and testes mRNA expression was higher in B6.MRLc1(82-100) mice. In the kidney and immune organs, only Ifi202 expression increased with the development of GN in B6.MRLc1(82-100), and significant differences from C57BL/6 were observed even before disease onset. Ifi202 expression in the kidneys of BXSB, NZB/WF1, and MRL/lpr was also significantly high in the early- and late-disease stages. Furthermore, laser microdissection-reverse-transcriptase-polymerase chain reaction analysis confirmed the high Ifi202 expression in all areas of B6.MRLc1(82-100) kidneys. In conclusion, in the Ifi200 family, Ifi202 expressions in the kidney and immune organs significantly increased with GN progression. PMID- 20167634 TI - Long-term follow-up outcomes of perinatally HIV-infected adolescents: infection control but school failure. AB - Perinatally human immunodeficiency virus (HIV)-infected children are fighting acquired immune deficiency syndrome (AIDS) and becoming adolescents. The objective of this study was to examine long-term outcomes among perinatally HIV-1 infected adolescents. Cross-sectional clinical and laboratory data were collected for 49 perinatally HIV-infected adolescents followed at the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP's) Hospital from 1987 to 2007. The mean age of these adolescents was 12.5 years, the majority were female (73.5%) with a mean follow-up duration of 9.0 years, 71.4% of adolescents had no signs of HIV infection, 81.6% had normal CD4(+) lymphocyte count, and 53.1% had undetectable HIV viral load. HIV disclosure to the adolescent was reported in 31 (63.3%) participants. The majority were in school (89.8%) but failure and drop-out were reported by 51% and 28.6% of the subjects, respectively. All five domains of quality of life (QOL) measured revealed high scores. The majority of long-term adolescent survivors showed HIV-infection control and high scores of QOL, but with problems in schooling functioning that need early detection and intervention. PMID- 20167636 TI - Menthol and non-menthol cigarette use among Black smokers in Southern California. AB - INTRODUCTION: Menthol cigarette smoking is more prevalent among Blacks than among other groups in the United States. This study examined associations between demographic, psychological, attitudinal, social, and cultural factors and menthol smoking among Black adults. METHODS: This study recruited 720 Black smokers from community intercept locations throughout Los Angeles County, California, and surveyed them by telephone. RESULTS: Fifty-seven percent of respondents were menthol-only smokers, 15% were regular-only smokers, and 28% smoked both menthols and regular cigarettes (combined smokers). In bivariate models, menthol-only and combined smokers had stronger beliefs in the medicinal effects of menthols relative to regular-only smokers. Menthol-only smokers held stronger beliefs, relative to regular-only smokers, that menthols were less harmful than regular cigarettes. Menthol-only smokers preferred the menthol taste/sensation more than combined smokers, who preferred the menthol taste/sensation more than regular only smokers. Menthol-only and combined smokers had more menthol smokers in their current social networks compared with regular-only smokers. In multivariate analyses, preference for menthol taste/sensation, belief in medicinal effects of menthols, and menthol smokers in current social network differentiated menthol only and combined smokers from regular-only smokers, controlling for confounding variables. Correlates of menthol smoking varied across genders and age groups. DISCUSSION: Health education efforts are needed to dispel the myth that menthol cigarettes are more medicinal and less harmful than regular cigarettes. Prevention and cessation efforts in Black communities can be tailored to reflect predictors of menthol smoking to reduce tobacco-related morbidity and mortality. In the era of Food and Drug Administration regulation of cigarettes, research is needed to prevent health disparities associated with menthol cigarette smoking. PMID- 20167635 TI - Relationships of personality and psychiatric disorders to multiple domains of smoking motives and dependence in middle-aged adults. AB - INTRODUCTION: Individual differences in psychopathology and personality may associate with dependence on smoking for specific motivational reasons. However, the associations among psychopathology, personality, and smoking dependence and motives have not been examined simultaneously in studies to date, leaving it unclear whether specific patterns of affective and behavioral functioning are associated with specific aspects of smoking dependence. METHODS: The present study examined these associations in 296 current smokers aged 35-43 years. Smoking dependence and motives were assessed with structured interview, the Fagerstrom Test for Nicotine Dependence, and the Wisconsin Inventory of Smoking Dependence Motives. RESULTS: Regardless of the measure of smoking dependence tested, a lifetime history of major depression and high levels of trait stress reaction were consistently related to greater current smoking dependence severity. Substance dependence showed significant associations with some measures of smoking dependence but had relatively few effects when entered in models along with depression history and trait stress reaction. In multivariate models, alcohol dependence and conduct disorder history did not show unique significant associations with smoking dependence nor did trait aggression, alienation, control, or harm avoidance. DISCUSSION: Results indicate little specificity in the associations of particular psychiatric diagnoses or personality traits with specific self-reported facets of smoking dependence. It appears that a general vulnerability to depression and negative emotions is the most robust indicator of vulnerability to high levels of self-reported smoking dependence, regardless of which dimensions of smoking dependence are analyzed. PMID- 20167637 TI - Myocardial infarction associated with recency of immigration to Ontario. AB - BACKGROUND: New immigrants to North America exhibit lower rates of obesity and hypertension than their native-born counterparts. Whether this is reflected by a lower relative risk of acute myocardial infarction (AMI) is not known. OBJECTIVE: To determine the risk of AMI among new immigrants compared to long-term residents, and, among those who develop AMI, their short- and long-term mortality rate. DESIGN: Population-based, matched, retrospective cohort study. SETTING: Entire province of Ontario, the most populated province in Canada, from 1 April 1995 to 31 March 2007. PARTICIPANTS: A total of 965,829 new immigrants were matched to 3,272,393 long-term residents by year of birth, sex and geographic location. MEASUREMENTS: The main study outcome was hospitalization with a most responsible diagnosis of AMI. Secondary study outcomes among those who sustained an AMI were in-hospital, 30-day and 1-year mortality. RESULTS: The mean age of the participants at study entry was approximately 34 years. The incidence rate of AMI was 4.14 per 10,000 person-years among new immigrants and 6.61 per 10,000 person-years among long-term residents. After adjusting for age, income quintile, urban vs. rural residence, history of hypertension, diabetes mellitus and smoking and number of health insurance claims, the hazard ratio for AMI was 0.66 [95% confidence interval (CI): 0.63-0.69]. CONCLUSION: New immigrants appear to be at lower risk of AMI than long-term residents. This finding does not appear to be explained by the availability of health-care services or income level. PMID- 20167638 TI - Modified dsRNAs that are not processed by Dicer maintain potency and are incorporated into the RISC. AB - Chemical modification of RNA duplexes can provide practical advantages for RNA interference (RNAi) triggering molecules including increased stability, safety and specificity. The impact of nucleotide modifications on Dicer processing, RISC loading and RNAi-mediated mRNA cleavage was investigated with duplexes >or=25 bp in length. It is known that dsRNAs >or=25 bp are processed by Dicer to create classic 19-bp siRNAs with 3'-end overhangs. We demonstrate that the presence of minimal modification configurations on longer RNA duplexes can block Dicer processing and result in the loading of the full-length guide strand into RISC with resultant mRNA cleavage at a defined site. These longer, modified duplexes can be highly potent gene silencers, with EC50s in the picomolar concentration range, demonstrating that Dicer processing is not required for incorporation into RISC or potent target silencing. PMID- 20167639 TI - GenoCAD for iGEM: a grammatical approach to the design of standard-compliant constructs. AB - One of the foundations of synthetic biology is the project to develop libraries of standardized genetic parts that could be assembled quickly and cheaply into large systems. The limitations of the initial BioBrick standard have prompted the development of multiple new standards proposing different avenues to overcome these shortcomings. The lack of compatibility between standards, the compliance of parts with only some of the standards or even the type of constructs that each standard supports have significantly increased the complexity of assembling constructs from standardized parts. Here, we describe computer tools to facilitate the rigorous description of part compositions in the context of a rapidly changing landscape of physical construction methods and standards. A context-free grammar has been developed to model the structure of constructs compliant with six popular assembly standards. Its implementation in GenoCAD makes it possible for users to quickly assemble from a rich library of genetic parts, constructs compliant with any of six existing standards. PMID- 20167641 TI - Infrared thermometry in the diagnosis of hand-arm vibration syndrome. AB - BACKGROUND: Clinicians need an accurate diagnostic test for hand-arm vibration syndrome (HAVS). AIMS: To validate a simple thermometric method to diagnose HAVS related Raynaud's phenomenon. METHODS: Fifteen workers with photographically confirmed HAVS-related Raynaud's phenomenon were compared to controls without Raynaud's phenomenon and an occupational history of hand-arm vibration exposure. Digit temperatures were measured using an infrared thermometer before and after immersion in 5 degrees C water for 1 min. RESULTS: The HAVS patients differed significantly from the controls in terms of baseline temperature, rewarming time and rate. The fingertip-base temperature gradient was more commonly positive among the controls. CONCLUSIONS: The test method evaluated in this study is simple, cheap and accurate. If the pre-test probability is at least 35%, the best test variable to confirm the diagnosis of HAVS-related Raynaud's phenomenon is the time to rewarm to baseline of the first three fingertips providing the interval is > or =8-9 min. PMID- 20167640 TI - Kinetic analysis of the nucleic acid chaperone activity of the hepatitis C virus core protein. AB - The multifunctional HCV core protein consists of a hydrophilic RNA interacting D1 domain and a hydrophobic D2 domain interacting with membranes and lipid droplets. The core D1 domain was found to possess nucleic acid annealing and strand transfer properties. To further understand these chaperone properties, we investigated how the D1 domain and two peptides encompassing the D1 basic clusters chaperoned the annealing of complementary canonical nucleic acids that correspond to the DNA sequences of the HIV-1 transactivation response element TAR and its complementary cTAR. The core peptides were found to augment cTAR-dTAR annealing kinetics by at least three orders of magnitude. The annealing rate was not affected by modifications of the dTAR loop but was strongly reduced by stabilization of the cTAR stem ends, suggesting that the core-directed annealing reaction is initiated through the terminal bases of cTAR and dTAR. Two kinetic pathways were identified with a fast pre-equilibrium intermediate that then slowly converts into the final extended duplex. The fast and slow pathways differed by the number of base pairs, which should be melted to nucleate the intermediates. The three peptides operate similarly, confirming that the core chaperone properties are mostly supported by its basic clusters. PMID- 20167643 TI - Registration of observational studies. PMID- 20167644 TI - Effect of a perturbation-based balance training program on compensatory stepping and grasping reactions in older adults: a randomized controlled trial. AB - BACKGROUND: Compensatory stepping and grasping reactions are prevalent responses to sudden loss of balance and play a critical role in preventing falls. The ability to execute these reactions effectively is impaired in older adults. OBJECTIVE: The purpose of this study was to evaluate a perturbation-based balance training program designed to target specific age-related impairments in compensatory stepping and grasping balance recovery reactions. DESIGN: This was a double-blind randomized controlled trial. SETTING: The study was conducted at research laboratories in a large urban hospital. PARTICIPANTS: Thirty community dwelling older adults (aged 64-80 years) with a recent history of falls or self reported instability participated in the study. INTERVENTION: Participants were randomly assigned to receive either a 6-week perturbation-based (motion platform) balance training program or a 6-week control program involving flexibility and relaxation training. MEASUREMENTS: Features of balance reactions targeted by the perturbation-based program were: (1) multi-step reactions, (2) extra lateral steps following anteroposterior perturbations, (3) foot collisions following lateral perturbations, and (4) time to complete grasping reactions. The reactions were evoked during testing by highly unpredictable surface translation and cable pull perturbations, both of which differed from the perturbations used during training. RESULTS: /b> Compared with the control program, the perturbation-based training led to greater reductions in frequency of multi-step reactions and foot collisions that were statistically significant for surface translations but not cable pulls. The perturbation group also showed significantly greater reduction in handrail contact time compared with the control group for cable pulls and a possible trend in this direction for surface translations. LIMITATIONS: Further work is needed to determine whether a maintenance program is needed to retain the training benefits and to assess whether these benefits reduce fall risk in daily life. CONCLUSION: Perturbation-based training shows promise as an effective intervention to improve the ability of older adults to prevent themselves from falling when they lose their balance. PMID- 20167645 TI - Kinematics of rising from a chair: image-based analysis of the sagittal hip-spine movement pattern in elderly people who are healthy. AB - BACKGROUND: Rehabilitation of elderly patients with sit-to-stand (STS) dysfunction includes retraining coordinated movement among participating body segments. Although trunk position is considered important, spinal movement has not been measured. OBJECTIVE: The aim of this study was to describe the sagittal thoracolumbar kinematics and hip-lumbar interaction during the STS task in elderly people who were healthy in order to guide physical therapists in developing treatment strategies. DESIGN: This was an observational study. METHODS: Ten retroreflective markers were attached to the midline thoracolumbar spine, pelvis, and right lower limb of 41 elderly people who were healthy. A 2 dimensional video analysis system was used to measure sagittal thoracic, lumbar, hip, and knee joint angles during the STS task. Maximal available flexion extension angles in these joints and regions also were determined. RESULTS: Prior to buttocks lift-off, forward trunk lean comprised concurrent hip and lumbar flexion and thoracic extension. Hip flexion dominated, with a hip/lumbar ratio of 4.7:1 and a thoracic/lumbar ratio of 1.7:1. The hip and lumbar spine contributed 90% and 23% of their maximal available flexion angle, respectively, and the thoracic spine contributed 86% of its maximal extension range of movement. After lift-off, the hips and lumbar spine extended (ratio of 5.2:1), and the thoracic spine flexed (thoracic/lumbar ratio of 0.4:1). At lift-off, the hips and knees were similarly flexed (96 degrees ) and then locked together in a linear pattern of extension. Following lift-off, there was a brief transition phase (5% of STS duration) in which, although the hips, knees, and lumbar spine were extending, the trunk continued to flex forward a few degrees. LIMITATIONS: Results may differ in elderly people who are less active. CONCLUSIONS: The revised model for image-based analysis demonstrated concurrent hip and thoracolumbar movement during the STS task. Close to full available hip flexion and thoracic extension were needed for optimal STS performance. PMID- 20167646 TI - Doctors on the front line. PMID- 20167647 TI - Risk and equality. PMID- 20167648 TI - Long road to recovery. PMID- 20167650 TI - Cetuximab (erbitux). AB - Cetuximab, a recombinant chimeric monoclonal antibody, has been successfully used in the treatment of the head and neck and colorectal cancers. We present a review of its mechanism of action, indications, side effects and economic issues, accompanied by a clinical example from our institution. PMID- 20167651 TI - Parametric color coding of digital subtraction angiography. AB - BACKGROUND AND PURPOSE: Color has been shown to facilitate both visual search and recognition tasks. It was our purpose to examine the impact of a color-coding algorithm on the interpretation of 2D-DSA acquisitions by experienced and inexperienced observers. MATERIALS AND METHODS: Twenty-six 2D-DSA acquisitions obtained as part of routine clinical care from subjects with a variety of cerebrovascular disease processes were selected from an internal data base so as to include a variety of disease states (aneurysms, AVMs, fistulas, stenosis, occlusions, dissections, and tumors). Three experienced and 3 less experienced observers were each shown the acquisitions on a prerelease version of a commercially available double-monitor workstation (XWP, Siemens Healthcare). Acquisitions were presented first as a subtracted image series and then as a single composite color-coded image of the entire acquisition. Observers were then asked a series of questions designed to assess the value of the color-coded images for the following purposes: 1) to enhance their ability to make a diagnosis, 2) to have confidence in their diagnosis, 3) to plan a treatment, and 4) to judge the effect of a treatment. The results were analyzed by using 1 sample Wilcoxon tests. RESULTS: Color-coded images enhanced the ease of evaluating treatment success in >40% of cases (P < .0001). They also had a statistically significant impact on treatment planning, making planning easier in >20% of the cases (P = .0069). In >20% of the examples, color-coding made diagnosis and treatment planning easier for all readers (P < .0001). Color-coding also increased the confidence of diagnosis compared with the use of DSA alone (P = .056). The impact of this was greater for the naive readers than for the expert readers. CONCLUSIONS: At no additional cost in x-ray dose or contrast medium, color-coding of DSA enhanced the conspicuity of findings on DSA images. It was particularly useful in situations in which there was a complex flow pattern and in evaluation of pre- and posttreatment acquisitions. Its full potential remains to be defined. PMID- 20167652 TI - A doctor heads home to Haiti. AB - A second-year medical resident returned to Haiti, his native country, in the aftermath of the 12 January 2010 earthquake. He witnessed the total devastation of Port-au-Prince, the city of his birth, and great human suffering. He describes the emotional and logistical challenges of providing care to the wounded of this impoverished nation. PMID- 20167653 TI - Identification of dynamical hinge points of the L1 ligase molecular switch. AB - The L1 ligase is an in vitro selected ribozyme that uses a noncanonically base paired ligation site to catalyze regioselectively and regiospecifically the 5' to 3' phosphodiester bond ligation, a reaction relevant to origin of life hypotheses that invoke an RNA world scenario. The L1 ligase crystal structure revealed two different conformational states that were proposed to represent the active and inactive forms. It remains an open question as to what degree these two conformers persist as stable conformational intermediates in solution, and along what pathway are they able to interconvert. To explore these questions, we have performed a series of molecular dynamics simulations in explicit solvent of the inactive-active conformational switch in L1 ligase. Four simulations were performed departing from both conformers in both the reactant and product states, in addition to a simulation where local unfolding in the active state was induced. From these simulations, along with crystallographic data, a set of four virtual torsion angles that span two evolutionarily conserved and restricted regions were identified as dynamical hinge points in the conformational switch transition. The ligation site visits three distinct states characterized by hydrogen bond patterns that are correlated with the formation of specific contacts that may promote catalysis. The insights gained from these simulations contribute to a more detailed understanding of the coupled catalytic/conformational switch mechanism of L1 ligase that may facilitate the design and engineering of new catalytic riboswitches. PMID- 20167654 TI - Embryonic stem cell-derived endothelial cells engraft into the ischemic hindlimb and restore perfusion. AB - OBJECTIVE: We examined the effect of delivery modality on the survival, localization, and functional effects of exogenously administered embryonic stem cells (ESCs) or endothelial cells derived from them (ESC-ECs) in the ischemic hindlimb. METHODS AND RESULTS: Murine ESCs or ESC-ECs were stably transduced with a construct for bioluminescence imaging (BLI) and fluorescent detection. In a syngeneic murine model of limb ischemia, ESCs or ESC-ECs were delivered by intramuscular (IM), intrafemoral artery (IA), or intrafemoral vein injections (n=5 in each group). For 2 weeks, cell survival and localization were tracked by BLI and confirmed by immunohistochemistry, and functional improvement was assessed by laser Doppler perfusion. BLI showed that ESCs localized to the ischemic limb after IM or IA, but not after intrafemoral vein administration. Regardless of the route of administration, ESCs were detected outside the hindlimb circulation in the spleen or lungs. ESCs did not improve limb perfusion and generated teratomas. In contrast, ESC-ECs delivered by all 3 modalities localized to the ischemic limb, as assessed by BLI. Most surprisingly, ESC-EC injected intrafemoral vein eventually localized to the ischemic limb after initially lodging in the pulmonary circulation. Immunohistochemical studies confirmed the engraftment of ESC-ECs into the limb vasculature after 2 weeks. Notably, ESC-ECs were not detected in the spleen or lungs after 2 weeks, regardless of route of administration. Furthermore, ESC-ECs significantly improved limb perfusion and neovascularization compared with the parental ESCs or the vehicle control group. CONCLUSION: In contrast to parental ESCs, ESC-ECs preferentially localized in the ischemic hindlimb by IA, IM, and intrafemoral vein delivery. ESC-ECs engrafted into the ischemic microvasculature, enhanced neovascularization, and improved limb perfusion. PMID- 20167655 TI - Intranasal immunization with an apolipoprotein B-100 fusion protein induces antigen-specific regulatory T cells and reduces atherosclerosis. AB - OBJECTIVE: Atherosclerosis is an inflammatory disease. Autoimmune responses to low-density lipoproteins (LDL) contribute to its progression, whereas immunization with LDL may induce atheroprotective or proatherogenic responses. The objective of this study was to develop an atheroprotective vaccine by targeting a peptide of the LDL protein constituent apolipoprotein B-100 (apoB 100) to the nasal mucosa to induce a protective mucosal immune response. METHODS AND RESULTS: A peptide comprising amino acids 3136 to 3155 of apoB-100 (p210) was fused to the B subunit of cholera toxin (CTB), which binds to a ganglioside on mucosal epithelia. The effect of nasal administration of the p210-CTB fusion protein on atherogenesis was compared with that of an ovalbumin peptide fused to CTB and with untreated controls. Immunization with p210-CTB for 12 weeks caused a 35% reduction in aortic lesion size in Apoe(-/-) mice. This effect was accompanied by induction of regulatory T cells that markedly suppressed effector T cells rechallenged with apoB-100 and increased numbers of interleukin (IL) 10(+) CD4(+) T cells. Furthermore, a peptide-specific antibody response was observed. Atheroprotection was also documented in apoe(-/-) mice lacking functional transforming growth factor-beta receptors on T cells. CONCLUSION: Nasal administration of an apoB-100 peptide fused to CTB attenuates atherosclerosis and induces regulatory Tr1 cells that inhibit T effector responses to apoB-100. PMID- 20167656 TI - Adenosine receptor A2A deficiency in leukocytes increases arterial neointima formation in apolipoprotein E-deficient mice. AB - OBJECTIVE: To use the mice deficient in both adenosine receptor A(2A)(A(2A)R(-/ )) and apolipoprotein E (apoE(-/-)) to investigate the role of A(2A)R in mediating the interactions of leukocytes with injured arterial walls and the formation of arterial neointima induced by a guide wire. METHODS AND RESULTS: In apoE(-/-) mice, A(2A)R deficiency increased the size of the arterial neointima in injured carotid arteries by 83%. Arterial neointima formation was also enhanced in chimeric mice that underwent bone marrow transplantation (these mice lacked A(2A)R in their bone marrow-derived cells). Epifluorescence intravital microscopy showed that neutrophil rolling and adherence to the injured arterial area were enhanced by 80% and 110% in A(2A)R(-/-)/apoE(-/-) mice, respectively. This phenomenon occurred even though the protein levels of homing molecules on A(2A)R deficient neutrophils were unchanged from those of wild-type neutrophils. A(2A)R deficient neutrophils exhibited an increase in the phosphorylation of p38 mitogen activated protein kinase, P-selectin glycoprotein ligand-1 (PSGL-1) clustering, and the affinity of b(2) integrins. The inhibition of p38 phosphorylation abrogated the increased PSGL-1 clustering and beta(2) integrin affinity, thus reversing the increased homing ability of A(2A)R-deficient leukocytes. CONCLUSION: A(2A)R plays a complex role in inflammation and tissue injury. The deficiency of A(2A)R enhances the homing ability of leukocytes and increases the formation of the arterial neointima after injury. A(2A)R antagonists are being tested for the treatment of neurodegenerative and other chronic diseases. An evaluation of the effect of A(2A)R antagonists on arterial restenosis after arterial angioplasty should be conducted. PMID- 20167657 TI - Inhibition of glycosphingolipid synthesis induces a profound reduction of plasma cholesterol and inhibits atherosclerosis development in APOE*3 Leiden and low density lipoprotein receptor-/- mice. AB - OBJECTIVE: The iminosugar N-(5'-adamantane-1'-yl-methoxy)-pentyl-1 deoxynoijirimycin (AMP-DNM), an inhibitor of the enzyme glucosylceramide synthase catalyzing glycosphingolipid (GSL) biosynthesis, ameliorates diabetes and reduces liver steatosis in ob/ob mice. Because an accumulation of sphingolipids, including sphingomyelin and GSLs, has been reported in atherosclerotic lesions in animal models and in humans, the objective of this study was to determine whether AMP-DNM also exerts beneficial effects on the development of atherosclerosis. METHODS AND RESULTS: APOE*3 Leiden mice, maintained on a high-cholesterol diet, were treated for up to 18 weeks with AMP-DNM. The iminosugar prevented hyperlipidemia, generated a less atherogenic lipid profile, and induced a dramatic reduction in the development of atherosclerotic lesions. At the highest dose, no lesions were detectable. The effect of AMP-DNM was associated with a decrease in liver cholesterol, an increase in bile secretion, and enhanced excretion of cholesterol in the feces. Similar effects of AMP-DNM were observed in mice deficient for the low-density lipoprotein receptor. CONCLUSION: By lowering plasma cholesterol, the iminosugar AMP-DNM dramatically reduces the development of atherosclerosis in APOE*3 Leiden and low-density lipoprotein receptor -/- mice. Thus, targeting GSL synthesis may be a new treatment modality to prevent cardiovascular disease. PMID- 20167658 TI - Nitro-fatty acids reduce atherosclerosis in apolipoprotein E-deficient mice. AB - OBJECTIVE: Inflammatory processes and foam cell formation are key determinants in the initiation and progression of atherosclerosis. Electrophilic nitro-fatty acids, byproducts of nitric oxide- and nitrite-dependent redox reactions of unsaturated fatty acids, exhibit antiinflammatory signaling actions in inflammatory and vascular cell model systems. The in vivo action of nitro-fatty acids in chronic inflammatory processes such as atherosclerosis remains to be elucidated. METHODS AND RESULTS: Herein, we demonstrate that subcutaneously administered 9- and 10-nitro-octadecenoic acid (nitro-oleic acid) potently reduced atherosclerotic lesion formation in apolipoprotein E-deficient mice. Nitro-fatty acids did not modulate serum lipoprotein profiles. Immunostaining and gene expression analyses revealed that nitro-oleic acid attenuated lesion formation by suppressing tissue oxidant generation, inhibiting adhesion molecule expression, and decreasing vessel wall infiltration of inflammatory cells. In addition, nitro-oleic acid reduced foam cell formation by attenuating oxidized low-density lipoprotein-induced phosphorylation of signal transducer and activator of transcription-1, a transcription factor linked to foam cell formation in atherosclerotic plaques. Atherosclerotic lesions of nitro-oleic acid treated animals also showed an increased content of collagen and alpha-smooth muscle actin, suggesting conferral of higher plaque stability. CONCLUSION: These results reveal the antiatherogenic actions of electrophilic nitro-fatty acids in a murine model of atherosclerosis. PMID- 20167659 TI - DGAT1 participates in the effect of HNF4A on hepatic secretion of triglyceride rich lipoproteins. AB - OBJECTIVE: Hepatocyte nuclear factor-4alpha (HNF4A) is a transcription factor that influences plasma triglyceride metabolism via an as of yet unknown mechanism. In this study, we searched for the critical protein that mediates this effect using different human model systems. METHODS AND RESULTS: Up- and downregulation of HNF4A in human hepatoma Huh7 and HepG2 cells was associated with marked changes in the secretion of triglyceride-rich lipoproteins (TRLs). Short interfering RNA (siRNA) inhibition of HNF4A influenced the expression of several genes, including acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1). siRNA knockdown of DGAT1 reduced DGAT1 activity and decreased the secretion of TRLs. No additive effects of combined siRNA inhibition of HNF4A and DGAT1 were found on the secretion of TRLs, whereas the increase in TRL secretion induced by HNF4A overexpression was largely abolished by DGAT1 siRNA inhibition. A putative binding site for HNF4A was defined by in silico and in vitro methods. HNF4A and DGAT1 expressions were analyzed in 80 human liver samples, and significant relationships were observed between HNF4A and DGAT1 mRNA levels (r(2)=0.50, P<0.0001) and between DGAT1 mRNA levels and plasma triglyceride concentration (r(2)=0.09, P<0.01). CONCLUSION: This study identified DGAT1 as an important protein that participates in the effect of HNF4A on hepatic secretion of TRLs. PMID- 20167660 TI - Evidence that niacin inhibits acute vascular inflammation and improves endothelial dysfunction independent of changes in plasma lipids. AB - OBJECTIVE: To determine if niacin can confer cardiovascular benefit by inhibiting vascular inflammation and improving endothelial function independent of changes in plasma lipid and lipoprotein levels. METHODS AND RESULTS: New Zealand white rabbits received normal chow or chow supplemented with 0.6% or 1.2% (wt/wt) niacin. This regimen had no effect on plasma cholesterol, triglyceride, or high density lipoprotein levels. Acute vascular inflammation and endothelial dysfunction were induced in the animals with a periarterial carotid collar. At the 24-hour postcollar implantation, the endothelial expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and monocyte chemotactic protein-1 was markedly decreased in the niacin-supplemented animals compared with controls. Niacin also inhibited intima-media neutrophil recruitment and myeloperoxidase accumulation, enhanced endothelial-dependent vasorelaxation and cyclic guanosine monophosphate production, increased vascular reduced glutathione content, and protected against hypochlorous acid-induced endothelial dysfunction and tumor necrosis factor alpha-induced vascular inflammation. CONCLUSION: Previous human intervention studies have demonstrated that niacin inhibits coronary artery disease. This benefit is thought to be because of its ability to reduce low-density lipoprotein and plasma triglyceride levels and increase high density lipoprotein levels. The present study showed that niacin inhibits vascular inflammation and protects against endothelial dysfunction independent of these changes in plasma lipid levels. PMID- 20167661 TI - Identification and assessment of plasma lysozyme as a putative biomarker of atherosclerosis. AB - OBJECTIVE: To identify a plasma biomarker of atheromatous disease. METHODS AND RESULTS: Surface-enhanced laser desorption ionization-time-of-flight mass spectrometry was used to identify possible plasma protein biomarkers of atheromatous disease in patients presenting with chronic stable angina pectoris by comparing those with 3-vessel disease with those without any evidence of coronary artery disease. The level of a 14.7-kDa protein was elevated; this protein was isolated and identified as a lysozyme. Arterial plasma lysozyme levels, measured by immunoassay, confirmed this observation in separate cohorts of patients. The application of arterial plasma lysozyme levels to 197 patients with varying degrees of coronary artery disease, using a cutoff value of 1.5 microg/mL, was able to distinguish patients with 1 or more occluded coronary arteries, with 86% sensitivity and 93% specificity. Of 20 patients with carotid atheroma, 19 had increased arterial plasma levels. In contrast, C-reactive protein levels showed no association with disease severity. Venous lysozyme levels in patients with carotid atheroma were shown to decrease after intensive atorvastatin treatment. CONCLUSION: Raised plasma lysozyme levels may be a useful biomarker of atherosclerotic cardiovascular disease and response to therapy. Additional studies to investigate this are warranted. PMID- 20167663 TI - When endothelial progenitor cell says I2 shall limit neointima formation! PMID- 20167662 TI - Association of circulating matrix metalloproteinases with carotid artery characteristics: the Atherosclerosis Risk in Communities Carotid MRI Study. AB - OBJECTIVE: To examine the relationship of plasma levels of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase 1 (TIMP-1) with carotid artery characteristics measured by MRI in a cross-sectional investigation among Atherosclerosis Risk in Communities Carotid MRI Study participants. METHODS AND RESULTS: A stratified random sample was recruited based on intima-media thickness from a previous ultrasonographic examination. A high resolution gadolinium-enhanced MRI examination of the carotid artery was performed from 2004 to 2005 on 1901 Atherosclerosis Risk in Communities cohort participants. Multiple carotid wall characteristics, including wall thickness, lumen area, calcium area, lipid core, and fibrous cap measures, were evaluated for associations with plasma MMPs 1, 2, 3, 7, 8, and 9 and TIMP-1. Plasma MMPs 1, 3, and 7 were significantly higher among participants in the high intima-media thickness group compared with those in the low intima-media thickness group. The normalized wall index was independently associated with MMPs 3 and 7 and TIMP-1. MMP-7 was positively associated with carotid calcification. The mean fibrous cap thickness was significantly higher in individuals with elevated TIMP-1 levels. In addition, TIMP-1 was positively associated with measures of lipid core. CONCLUSION: Circulating levels of specific MMPs and TIMP-1 were associated with carotid wall remodeling and structural changes related to plaque burden in elderly participants. PMID- 20167664 TI - Mechanical stretch and intimal hyperplasia: the missing link? PMID- 20167665 TI - Hemostasis and vascular dementia. PMID- 20167666 TI - Laminar shear stress modulates phosphorylation and localization of RNA polymerase II on the endothelial nitric oxide synthase gene. AB - OBJECTIVE: In endothelial cells exposed to unidirectional laminar shear stress, endothelial nitric oxide synthase transcription (eNOS), mRNA stability, and protein levels are enhanced. We have previously demonstrated that these changes are associated with increased 3' polyadenylation of eNOS mRNA. Here, we investigated the effect of laminar shear stress on the phosphorylation and localization of RNA polymerase (Pol) II, the enzyme primarily responsible for coordinating transcription and posttranscriptional processing. METHODS AND RESULTS: Using Western and chromatin immunoprecipitation analyses, Pol II phosphorylation and localization on the eNOS gene were assessed in bovine aortic endothelial cells exposed to laminar shear stress. Total Pol II (phosphorylated and unphosphorylated) levels were increased 65% in response to laminar shear stress. This was associated with an increase in Pol II phosphoserine 2, but no change in levels of the unphosphorylated or phosphoserine 5 isoforms. Quantitative chromatin immunoprecipitation analysis showed that laminar shear stress enhanced binding of Pol II phosphoserine 2 to the 3' end of the eNOS gene, particularly exon 26, which encodes the 3'UTR. Treatment of cells with DRB attenuated laminar shear stress-induced Pol II phosphorylation, eNOS 3' polyadenylation, and eNOS expression. CONCLUSIONS: These data suggest that laminar shear stress enhances eNOS mRNA 3' polyadenylation by modulating phosphorylation and localization of Pol II. PMID- 20167667 TI - Depressive behavior and vascular dysfunction: a link between clinical depression and vascular disease? AB - As chronic stress and depression have become recognized as significant risk factors for peripheral vascular disease in patients with no prior history of vasculopathy, we interrogated this relationship utilizing an established mouse model of chronic stress/depressive symptoms from behavioral research. Male mice were exposed to 8 wk of unpredictable chronic mild stress (UCMS; e.g., wet bedding, predator sound/smell, random disruption of light/dark cycle), with indexes of depressive behavior (coat status, grooming, and mobility) becoming exacerbated vs. controls. In vascular rings, constrictor (phenylephrine) and endothelium-independent dilator (sodium nitroprusside) responses were not different between groups, although endothelium-dependent dilation (methacholine) was attenuated with UCMS. Nitric oxide synthase (NOS) inhibition was without effect in UCMS but nearly abolished reactivity in controls, while cyclooxygenase inhibition blunted dilation in both. Combined blockade abolished reactivity in controls, although a significant dilation remained in UCMS that was abolished by catalase. Arterial NO production was attenuated by UCMS, although H2O2 production was increased. UCMS mice demonstrated an increased, although variable, insulin resistance and inflammation. However, while UCMS-induced vascular impairments were consistent, the predictive power of aggregate plasma levels of insulin, TNF alpha, IL-1beta, and C-reactive peptide were limited. However, when separated into tertiles with regard to vascular outcomes, insulin resistance and hypertension were predictive of the most severe vascular impairments. Taken together, these data suggest that aggregate insulin resistance, inflammation, and hypertension in UCMS mice are not robust predictors of vascular dysfunction, suggesting that unidentified mechanisms may be superior predictors of poor vascular outcomes in this model. PMID- 20167669 TI - Muscle shear elastic modulus measured using supersonic shear imaging is highly related to muscle activity level. AB - This pilot study was designed to determine whether the shear elastic modulus measured using supersonic shear imaging can be used to accurately estimate muscle activity level. Using direct visual feedback of torque, six healthy subjects were asked to perform two incremental isometric elbow flexions, consisting of linear torque ramps of 30 s from 0 to 40% of maximal voluntary contraction. Both electromyographic (EMG) activity and shear elastic modulus were continuously measured in the biceps brachii during the two ramps. There was significant linear regression (P<0.001) between shear elastic modulus and EMG activity level for both ramps of all six subjects (R2=0.94+/-0.05, ranging from 0.82 to 0.98). Good repeatability was found for shear elastic modulus estimated at both 3% (trial 1: 21.7+/-6.7 kPa; trial 2: 23.2+/-7.2 kPa, intraclass correlation coefficient=0.89, standard error in measurement=2.3 kPa, coefficient of variation=12.7%) and 7% (trial 1: 42.6+/-14.1 kPa; trial 2: 44.8+/-15.8 kPa, intraclass correlation coefficient=0.94, standard error in measurement=3.7 kPa, coefficient of variation=7.1%) of maximal EMG activity. The shear elastic modulus estimated at both 3 and 7% of maximal EMG activity was not significantly different (P>0.05) between the two trials. These results confirm our hypothesis that the use of supersonic shear imaging greatly improves the correlation between muscle shear elastic modulus and EMG activity level. Due to the nonlinearity of muscle mechanical properties, the muscle elasticity should be linked to the muscle stress. Therefore, the present study represents a first step in attempting to show that supersonic shear imaging can be used to indirectly estimate muscle stress. PMID- 20167668 TI - Exercise and the metabolic syndrome with weight regain. AB - Weight loss improves metabolic syndrome (MetS) factors, but risk may return with weight regain. This study was designed to determine if exercise training can maintain improvements in MetS risk factors during weight regain. In a randomized control trial,102 overweight or obese (body mass index 25.0-39.9 kg/m(2)) men and women (age 21-52 yr), with characteristics of the MetS, lost 10% of body weight with supervised walking/jogging at 60% of maximal oxygen consumption (Vo(2 max)) (-400 kcal/session), 5 days/wk, and caloric restriction (-600 kcal/day) over a 4- to 6-mo period. After weight loss, 77 remaining subjects underwent programmed weight regain (+50% of lost weight) for 4-6 mo with random assignment to two groups: no exercise (NoEX) or continued supervised exercise (EX). Blood pressure, regional fat, glucose homeostasis, lipids, and inflammatory markers were assessed at baseline, post-weight loss, and post-weight regain. Groups were compared by two-way repeated-measures ANOVA on the 67 subjects. After weight loss (9.7 +/- 0.2% of body weight), significant (P < 0.05) improvements were observed in almost all parameters assessed. Following weight regain (54.4 +/- 1.6% of lost weight), the NoEX group exhibited deterioration in most metabolic markers, while the EX group maintained improvements in Vo(2 max), blood pressures, glucose homeostasis, high- and low-density lipoprotein cholesterol (HDL-C and LDL-C), oxidized LDL, and other markers of inflammation, but did not maintain improvements in triglyceride and cholesterol concentrations or abdominal fat. Results of this design of controlled human weight regain suggest that aerobic exercise can counter the detrimental effects of partial weight regain on many markers of disease risk. PMID- 20167670 TI - Acinar determinants of the apparent diffusion coefficient for helium-3. AB - The apparent diffusion coefficient (ADC) obtained by helium-3 magnetic resonance imaging over several seconds is thought to reflect diffusion impairment due to both intra- and interacinar structure. In this study, numerical simulations of intra-acinar gas mixing and effective diffusion were performed in a multiple branch-point model of the human acinus. Using a previously described method, we computed the instantaneous effective diffusion resulting from the diffusive impairment imposed by intra-acinar branching for varying times up to 5 s. We also tested the influence on effective diffusion of intra-acinar collateral channels in the fully alveolated intra-acinar airways to mimic the effect of emphysema. Randomly connecting two or four pairs of airways per generation (in generations 19-25) led to a 40 and 142% increase, respectively, in effective diffusion coefficient cumulated over the time interval of 0.2-5 s. Finally, we also used a system of two coupled multiple branch-point models to simulate diffusive attenuation over a 50-s interval in cases of purely acinar tagging (i.e., the initial gas concentration = 1 in one acinus and 0 in the other) and of partial tagging astride on two acini. It is shown that, in the latter case, the decay rate cannot be approximated by a mono-exponential with a several-fold faster decay for times below 10 s due to intra-acinar diffusion. We conclude that both the characteristic biphasic time dependence of simulated effective diffusion and its sensitivity to intra-acinar structural change mimic experimental ADC behavior. Additional simulations of combined inter- and intra-acinar diffusion strongly suggest that neglecting intra-acinar branching would in fact lead to considerable error of simulated ADC. PMID- 20167671 TI - Hypoxic cutaneous vasodilation is sustained during brief cold stress and is not affected by changes in CO2. AB - Hypoxia decreases core body temperature in animals and humans during cold exposure. In addition, hypoxia increases skin blood flow in thermoneutral conditions, but the impact of hypoxic vasodilation on vasoconstriction during cold exposure is unknown. In this study, skin blood flow was assessed using laser Doppler flowmetry, and cutaneous vascular conductance (CVC) was calculated as red blood cell flux/mean arterial pressure and normalized to baseline (n = 7). Subjects were exposed to four different conditions in the steady state (normoxia and poikilocapnic, isocapnic, and hypercapnic hypoxia) and were cooled for 10 min using a water-perfused suit in each condition. CVC increased during all three hypoxic exposures (all P < 0.05 vs. baseline), and the magnitude of these steady state responses was not affected by changes in end-tidal CO(2) levels. During poikilocapnic and hypercapnic hypoxia, cold exposure reduced CVC to the same levels observed during normoxic cooling (P > 0.05 vs. normoxia), whereas CVC remained elevated throughout cold exposure during isocapnic hypoxia (P < 0.05 vs. normoxia). The magnitude of vasoconstriction during cold stress was similar in all conditions (P > 0.05). Thus the magnitude of cutaneous vasodilation during steady-state hypoxia is not affected by CO(2) responses. In addition, the magnitude of reflex vasoconstriction is not altered by hypoxia, such that the upward shift in skin blood flow (hypoxic vasodilation) is maintained during whole body cooling. PMID- 20167672 TI - Central and peripheral contributions to neuromuscular fatigue induced by a 24-h treadmill run. AB - This experiment investigated the fatigue induced by a 24-h running exercise (24TR) and particularly aimed at testing the hypothesis that the central component would be the main mechanism responsible for neuromuscular fatigue. Neuromuscular function evaluation was performed before, every 4 h during, and at the end of the 24TR on 12 experienced ultramarathon runners. It consisted of a determination of the maximal voluntary contractions (MVC) of the knee extensors (KE) and plantar flexors (PF), the maximal voluntary activation (%VA) of the KE and PF, and the maximal compound muscle action potential amplitude (Mmax) on the soleus and vastus lateralis. Tetanic stimulations also were delivered to evaluate the presence of low-frequency fatigue and the KE maximal muscle force production ability. Strength loss occurred throughout the exercise, with large changes observed after 24TR in MVC for both the KE and PF muscles (-40.9+/-17.0 and 30.3+/-12.5%, respectively; P<0.001) together with marked reductions of %VA ( 33.0+/-21.8 and -14.8+/-18.9%, respectively; P<0.001). A reduction of Mmax amplitude was observed only on soleus, and no low-frequency fatigue was observed for any muscle group. Finally, KE maximal force production ability was reduced to a moderate extent at the end of the 24TR (-10.2%; P<0.001), but these alterations were highly variable (+/-15.7%). These results suggest that central factors are mainly responsible for the large maximal muscle torque reduction after ultraendurance running, especially on the KE muscles. Neural drive reduction may have contributed to the relative preservation of peripheral function and also affected the evolution of the running speed during the 24TR. PMID- 20167673 TI - High-intensity exercise training in mice with cardiomyocyte-specific disruption of Serca2. AB - Several lines of evidence indicate that the sarco(endo)plasmic reticulum ATPase type 2 (SERCA2) is essential for maintaining myocardial calcium handling and cardiac pump function. Hence, a reduction in SERCA2 abundance is expected to reduce work performance and maximal oxygen uptake (VO2max) and to limit the response to exercise training. To test this hypothesis, we compared VO2max and exercise capacity in mice with cardiac disruption of Serca2 (SERCA2 KO) with control mice (SERCA2 FF). We also determined whether the effects on VO2max and exercise capacity could be modified by high-intensity aerobic exercise training. Treadmill running at 85-90% of VO2max started 2 wk after Serca2 gene disruption and continued for 4 wk. VO2max and maximal running speed were measured weekly in a metabolic chamber. Cardiac function was assessed by echocardiography during light anesthesia. In sedentary SERCA2 KO mice, the aerobic capacity was reduced by 50% and running speed by 28%, whereas trained SERCA2 KO mice were able to maintain maximal running speed despite a 36% decrease in VO2max. In SERCA2 FF mice, both VO2max and maximal running speed increased by training, while no changes occurred in the sedentary group. Left ventricle dimensions remained unchanged by training in both genotypes. In contrast, training induced right ventricle hypertrophy in SERCA2 KO mice. In conclusion, the SERCA2 protein is essential for sustaining cardiac pump function and exercise capacity. Nevertheless, SERCA2 KO mice were able to maintain maximal running speed in response to exercise training despite a large decrease in VO2max. PMID- 20167674 TI - Reaction time to peripheral visual stimuli during exercise under hypoxia. AB - The purpose of this study was to test the hypothesis that decrease in cerebral oxygenation compromises an individual's ability to respond to peripheral visual stimuli during exercise. We measured the simple reaction time (RT) to peripheral visual stimuli at rest and during and after cycling at three different workloads [40%, 60%, and 80% peak oxygen uptake (VO2)] under either normoxia [inspired fraction of oxygen (FIO2)=0.21] or normobaric hypoxia (FIO2=0.16). Peripheral visual stimuli were presented at 10 degrees to either the right or the left of the midpoint of the eyes. Cerebral oxygenation was monitored during the RT measurement over the right frontal cortex with near-infrared spectroscopy. We used the premotor component of RT (premotor time) to assess effects of exercise on the central process. The premotor time was significantly longer during exercise at 80% peak VO2 (normoxia: 214.2+/-33.0 ms, hypoxia: 221.5+/-30.1 ms) relative to that at rest (normoxia: 201.0+/-27.2 ms, hypoxia: 202.9+/-29.7 ms) (P<0.01). Under normoxia, cerebral oxygenation gradually increased up to 60% peak VO2 and then decreased to the resting level at 80% peak VO2. Under hypoxia, cerebral oxygenation progressively decreased as exercise workload increased. We found a strong correlation between increase in premotor time and decrease in cerebral oxygenation (r2=0.89, P<0.01), suggesting that increase in premotor time during exercise is associated with decrease in cerebral oxygenation. Accordingly, exercise at high altitude may compromise visual perceptual performance. PMID- 20167675 TI - Activations of TRPA1 and P2X receptors are important in ROS-mediated stimulation of capsaicin-sensitive lung vagal afferents by cigarette smoke in rats. AB - Capsaicin-sensitive lung vagal afferents (CSLVAs) are important in detecting pulmonary reactive oxygen species (ROS). We investigated the mechanisms underlying the stimulation of CSLVAs by inhaled cigarette smoke (CS) in 216 anesthetized rats. In spontaneously breathing rats, CS evoked a CSLVA-mediated reflex bradypnea that was prevented by N-acetyl-L-cysteine (NAC; an antioxidant), HC-030031 [a transient receptor potential ankyrin 1 (TRPA1) receptor antagonist], and iso-pyridoxalphosphate-6-azophenyl-2',5'-disulfonate (iso-PPADS; a P2X receptor antagonist). In paralyzed, artificially ventilated rats, CS evoked an increase in CSLVA fiber activity (DeltaFA) that was abolished by NAC and was attenuated by HC-030031, iso-PPADS, indomethacin (Indo; a cyclooxygenase inhibitor), and a combination of apyrase and adenosine deaminase (ADA) (ATP scavengers); the response to CS was reduced to 11.7+/-4.0%, 39.5+/-10.0%, 52.9+/ 14.4%, 68.7+/-10.1%, and 47.2+/-12.9% of control, respectively. The suppressive effect on this afferent response was not improved by a combination of HC-030031 and Indo (DeltaFA=39.5+/-10.1% of control) compared with that induced by HC 030031 alone. In contrast, the suppressive effect was enhanced by a combination of HC-030031 and apyrase+ADA (DeltaFA=5.3+/-4.9% of control) or a combination of iso-PPADS and Indo (DeltaFA=23.3+/-7.7% of control) compared with that induced by HC-030031 alone or iso-PPADS alone. This afferent response was not altered by the vehicles for these drugs. These results suggest that activations of TRPA1 receptors by cyclooxygenase metabolites and P2X receptors by ATP are both necessary for the ROS-mediated stimulation of CSLVA fibers by CS in rats. PMID- 20167676 TI - Dietary inhibition of xanthine oxidase attenuates radiation-induced endothelial dysfunction in rat aorta. AB - Radiation exposure is associated with the development of various cardiovascular diseases. Although irradiation is known to cause elevated oxidant stress and chronic inflammation, both of which are detrimental to vascular function, the molecular mechanisms remain incompletely understood. We previously demonstrated that radiation causes endothelial dysfunction and increased vascular stiffness by xanthine oxidase (XO) activation. In this study, we investigated whether dietary inhibition of XO protects against radiation-induced vascular injury. We exposed 4 mo-old rats to a single dose of 0 or 5 Gy gamma radiation. These rats received normal drinking water or water containing 1 mM oxypurinol, an XO inhibitor. We measured XO activity and superoxide production in rat aorta and demonstrated that both were significantly elevated 2 wk after radiation exposure. However, oxypurinol treatment in irradiated rats prevented aortic XO activation and superoxide elevation. We next investigated endothelial function through fluorescent measurement of nitric oxide (NO) and vascular tension dose responses. Radiation reduced endothelium-dependent NO production in rat aorta. Similarly, endothelium-dependent vasorelaxation in the aorta of irradiated rats was significantly attenuated compared with the control group. Dietary XO inhibition maintained NO production at control levels and prevented the development of endothelial dysfunction. Furthermore, pulse wave velocity, a measure of vascular stiffness, increased by 1 day postirradiation and remained elevated 2 wk after irradiation, despite unchanged blood pressures. In oxypurinol-treated rats, pulse wave velocities remained unchanged from baseline throughout the experiment, signifying preserved vascular health. These findings demonstrate that XO inhibition can offer protection from radiation-induced endothelial dysfunction and cardiovascular complications. PMID- 20167677 TI - The pontine respiratory group, particularly the Kolliker-Fuse nucleus, mediates phases of the hypoxic ventilatory response in unanesthetized goats. AB - The objective of the present study was to test the hypothesis that, in the in vivo awake goat model, perturbation/lesion in the pontine respiratory group (PRG) would decrease the sensitivity to hypercapnia and hypoxia. The study reported herein was part of two larger studies in which cholinergic modulation in the PRG was attenuated by microdialysis of atropine and subsequently ibotenic acid injections neurotoxically lesioned the PRG. In 14 goats, cannula were bilaterally implanted into either the lateral (n=4) or medial (n=4) parabrachial nuclei or the Kolliker-Fuse nucleus (KFN, n=6). Before and after cannula implantation, microdialysis of atropine, and injection of ibotenic acid, hypercapnic and hypoxic ventilatory sensitivities were assessed. Hypercapnic sensitivity was assessed by three 5-min periods at 3, 5, and 7% inspired CO2. In all groups of goats, CO2 sensitivity was unaffected (P>0.05) by any PRG perturbations/lesions. Hypoxic sensitivity was assessed with a 30-min period at 10.8% inspired O2. The response to hypoxia was typically triphasic, with a phase 1 increase in pulmonary ventilation, a phase 2 roll-off, and a phase 3 prolonged increase associated with shivering and increased metabolic rate and body temperature. In all groups of goats, the phase 1 of the hypoxic ventilatory responses was unaffected by any PRG perturbations/lesions, and there were no consistent effects on the phase 2 responses. However, in the KFN group of goats, the phase 3 ventilatory, shivering, metabolic rate, and temperature responses were markedly attenuated after the atropine dialysis studies, and the attenuation persisted after the ibotenic acid studies. These findings support an integrative or modulatory role for the KFN in the phase 3 responses to hypoxia. PMID- 20167678 TI - Exercise-induced immunosuppression: roles of reactive oxygen species and 5'-AMP activated protein kinase dephosphorylation within immune cells. AB - We previously proposed 5'-AMP-activated protein kinase (AMPK) dephosphorylation within immune cells as an intracellular mechanism linking exercise and immunosuppression. In this study, AMPK phosphorylation underwent transient (<1 h) decreases (53.8+/-7.2% basal) immediately after exercise (45 min of cycling at 70% VO2max) in a cohort of 16 adult male participants. Similar effects were seen with running. However, because exercise-induced inactivation of AMPK was previously shown to occur in an AMP-independent manner, the means by which AMPK is inactivated in this context is not yet clear. To investigate the hypothesis that exercise-induced inactivation of AMPK is mediated via signaling mechanisms distinct from changes in cellular AMP-to-ATP ratios, reactive oxygen species (ROS) and intracellular Ca2+ signaling were investigated in mononuclear cells before and after exercise and in cultured monocytic MM6 cells. In in vitro studies, treatment with an antioxidant (ascorbic acid, 4 h, 50 microM) decreased MM6 cell intracellular ROS levels (88.0+/-5.2% basal) and induced dephosphorylation of AMPK (44.7+/-17.6% basal). By analogy, the fact that exercise decreased mononuclear cell ROS content (32.8+/-16.6% basal), possibly due to downregulation (43.4+/-8.0% basal) of mRNA for NOX2, the catalytic subunit of the cytoplasmic ROS-generating enzyme NADPH oxidase, may provide an explanation for the AMPK-dephosphorylating effect of exercise. In contrast, exercise-induced Ca2+ signaling events did not seem to be coupled to changes in AMPK activity. Thus we propose that the exercise-induced decreases in both intracellular ROS and AMPK phosphorylation seen in this study constitute evidence supporting a role for ROS in controlling AMPK, and hence immune function, in the context of exercise-induced immunosuppression. PMID- 20167679 TI - Insulin sensitivity in skeletal muscle: "use it or lose it, fast". PMID- 20167680 TI - Familial resemblance and shared latent familial variance in recurrent fall risk in older women. AB - BACKGROUND: A possible familial component to fracture risk may be mediated through a genetic liability to fall recurrently. METHODS: Our analysis sample included 186 female sibling-ships (n=401) of mean age 71.9 yr (SD=5.0). Using variance component models, we estimated residual upper-limit heritabilities in fall-risk mobility phenotypes (e.g., chair-stand time, rapid step-ups, and usual paced walking speed) and in recurrent falls. We also estimated familial and environmental (unmeasured) correlations between pairs of fall-risk mobility phenotypes. All models were adjusted for age, height, body mass index, and medical and environmental factors. RESULTS: Residual upper-limit heritabilities were all moderate (P<0.05), ranging from 0.27 for usual-paced walking speed to 0.58 for recurrent falls. A strong familial correlation between usual-paced walking speed and rapid step-ups of 0.65 (P<0.01) was identified. Familial correlations between usual-paced walking speed and chair-stand time (-0.02) and between chair-stand time and rapid step-ups (-0.27) were both nonsignificant (P>0.05). Environmental correlations ranged from 0.35 to 0.58 (absolute values), P<0.05 for all. CONCLUSIONS: There exists moderate familial resemblance in fall risk mobility phenotypes and recurrent falls among older female siblings, which we expect is primarily genetic given that adult siblings live separate lives. All fall-risk mobility phenotypes may be coinfluenced at least to a small degree by shared latent familial or environmental factors; however, up to approximately one half of the covariation between usual-paced walking speed and rapid step-ups may be due to a common set of genes. PMID- 20167681 TI - Application of variable number of tandem repeats typing to describe familial outbreaks of brucellosis in Argentina. AB - Consumption of inadequately pasteurized dairy products is the most common means of transmission of brucellosis. This report describes two foodborne outbreaks that occurred in families infected after consumption of fresh home-made cheese bought in different Argentine provinces. High resolution variable number of tandem repeats (VNTR)-based analysis revealed two well-defined groups comprising essentially identical profiles and corresponding to the two different outbreaks. Similar clinical findings in members of the same family could indicate that the differential virulence of different bacterial clones, as indicated by VNTR data, could have influenced the course of the disease. We observed the importance of adequate treatment in early stages of the disease; combination therapy and extended treatment for 6 weeks or longer yielded significantly better results. The risk of the foodborne transmission of this zoonotic disease and disease prevention should be considered. PMID- 20167682 TI - Macrophage inhibitory cytokine-1 is increased in individuals before type 2 diabetes diagnosis but is not an independent predictor of type 2 diabetes: the Whitehall II study. AB - OBJECTIVE: Macrophage inhibitory cytokine-1 (MIC-1) belongs to the transforming growth factor (TGF)-beta superfamily, and has been reported to be involved in energy homoeostasis and weight loss and to have anti-inflammatory properties. We hypothesized that decreased concentrations of MIC-1 would be associated with higher risk of developing type 2 diabetes. DESIGN AND METHODS: We designed a nested case-control study within the Whitehall II cohort and measured serum concentrations of MIC-1 by ELISA in 180 individuals without type 2 diabetes at baseline who developed type 2 diabetes during the follow-up period of 11.5+/-3.0 years and in 372 controls frequency-matched for age, sex, and body mass index with normal glucose tolerance throughout the study. RESULTS: MIC-1 concentrations at baseline were higher in cases (median (25/75th percentiles) 537.1 (452.7 677.4) pg/ml) than in controls (499.7 (413.8-615.4) pg/ml; P=0.0044). In the age- and sex-adjusted model, a 1-S.D. increase in MIC-1 (206.0 pg/ml) was associated with an odds ratio (95% confidence interval) of 1.21 (0.997; 1.46; P=0.054) for type 2 diabetes. Adjustment for waist circumference, cardiovascular risk factors, socioeconomic status, proinflammatory mediators, and glycemia abolished the association. CONCLUSIONS: Baseline MIC-1 concentrations were increased, not decreased, in individuals before type 2 diabetes manifestation, but not independently associated with incident type 2 diabetes in multivariable analyses. This upregulation of MIC-1 could be part of an anti-inflammatory response preceding the onset of type 2 diabetes, which has been described before for interleukin-1 receptor antagonist and TGF-beta1. PMID- 20167683 TI - Vitamins K and D status in stages 3-5 chronic kidney disease. AB - BACKGROUND AND OBJECTIVES: Vitamin K, vitamin K-dependent proteins, and vitamin D may be involved in the regulation of calcification in chronic kidney disease (CKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Vitamin K and D status was measured as dietary intake, plasma phylloquinone, serum percent uncarboxylated osteocalcin (%ucOC), proteins induced by vitamin K absence (PIVKA-II), Vitamin K Epoxide Reductase single-nucleotide polymorphism, apolipoprotein E genotype, and plasma 25-hydroxyvitamin D (25(OH)D) in 172 subjects with stage 3 to 5 CKD. Nutritional status was determined by subjective global assessment. RESULTS: Subclinical vitamin K deficiency criteria was met by 6% (phylloquinone), 60% (%ucOC), and 97% (PIVKA-II) of subjects, whereas 58.3% and 8.6% had 25(OH)D insufficiency and deficiency, respectively. Dietary vitamin K intake was associated with higher phylloquinone and lower PIVKA-II. There were positive correlations between phylloquinone and the presence of stable weight, and the absence of subcutaneous fat loss or muscle wasting. 25(OH)D levels were positively associated with stable weight and albumin (P < 0.001). PIVKA-II levels were associated with apolipoprotein E genotype. Higher %ucOC and lower 25(OH)D were similarly associated with CKD stage, parameters of mineral metabolism, and urine albumin to creatinine ratio. CONCLUSIONS: These data indicate that a suboptimal vitamin K and D status is prevalent in patients with CKD. Sufficiency of both vitamins K and D was similarly predicted by measures of overall improved nutritional status. Proteinuria was associated with both a suboptimal vitamin D status as well as worse peripheral vitamin K status. PMID- 20167684 TI - Median intradialytic blood pressure can track changes evoked by probing dry weight. AB - BACKGROUND: Median BP obtained over a single dialysis treatment can diagnose hypertension among hemodialysis patients. Whether median BP is as useful to track change in BP is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among patients participating in the dry-weight reduction in hypertensive hemodialysis patients (DRIP) trial, interdialytic ambulatory BP was recorded at baseline, 4 weeks, and 8 weeks. The mean interdialytic ambulatory BP was compared to the following recordings: predialysis on one dialysis treatment (Pre1), predialysis averaged over 2 weeks of dialysis treatment (Pre6), postdialysis on one dialysis treatment (Post1), postdialysis averaged over 2 weeks of dialysis treatment (Post6), and median intradialytic BP over one treatment. RESULTS: Pre1 was unable to detect change in ambulatory BP. Although Pre6 was able to detect change, it overestimated the ambulatory BP. On average, the magnitude of reduction in Post1 in response to probing dry-weight was nearly twice that obtained by ambulatory BP monitoring. Even Post6 overestimated the magnitude of reduction in BP at 8 weeks. Median systolic BP was responsive to probing dry-weight and neither overestimated nor underestimated the interdialytic ambulatory systolic BP at baseline or over time. However, the SD of the differences between median systolic BP and interdialytic ambulatory systolic BP varied from 16 to 20 mmHg. CONCLUSIONS: Median intradialytic BP recordings can detect change in ambulatory BP evoked by reduction in dry-weight at the population level. Because of wide agreement limits between intradialytic and interdialytic BP, the individual prediction of ambulatory BP from median intradialytic BP can be misleading. PMID- 20167685 TI - New-onset diabetes mellitus after kidney transplantation in Denmark. AB - BACKGROUND AND OBJECTIVES: This study aimed to investigate the development of new onset diabetes mellitus (NODM) in a prospective study of 97 nondiabetic uremic patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Included were 57 kidney recipients (Tx group, age 39 +/- 13 years) and 40 uremic patients remaining on the waiting list for kidney transplantation (uremic controls, age 47 +/- 11 years). All were examined at baseline before possible transplantation and after 12 months. The prevalence of diabetes, prediabetes, insulin sensitivity index (ISI), and insulin secretion index (Isecr) were estimated using an oral glucose tolerance test with measurements of plasma glucose and plasma insulin. RESULTS: One year after transplantation NODM was present in 14% (8 of 57) compared with 5% (2 of 40) in the uremic control group (P = 0.01). ISI in the Tx group deteriorated from 6.8 +/- 3.9 before transplantation to 4.9 +/- 2.8 at 12 months after transplantation (P = 0.005), and a slight increase in Isecr from 37 +/- 19 to 46 +/- 22 (P = 0.02) was seen. No significant changes occurred in the uremic controls (ISI was 7.9 +/- 5 and 8.5 +/- 5, and Isecr was 31 +/- 17 and 28 +/- 15). Using multivariate ordinal logistic regression, pre-Tx ISI and age predicted NODM (odds ratios: 0.82, P = 0.01 and 1.06, P = 0.02, respectively). CONCLUSIONS: One year after kidney transplantation, NODM was present in 14% of patients. This was mainly caused by an increase in insulin resistance and was observed despite improvement in insulin secretion. PMID- 20167686 TI - A pilot clinical study to evaluate changes in urine osmolality and urine cAMP in response to acute and chronic water loading in autosomal dominant polycystic kidney disease. AB - BACKGROUND AND OBJECTIVES: Autosomal dominant polycystic kidney disease (ADPKD) leads to kidney failure in half of those affected. Increased levels of adenosine 3':5'-cyclic monophosphate (cAMP) play a critical role in disease progression in animal models. Water loading, by suppressing arginine vasopressin (AVP) stimulated cAMP production, is a proposed therapy for ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The effects of acute and sustained water loading on levels of urine osmolality (Uosm) and cAMP in 13 subjects with ADPKD and 10 healthy controls were studied. Uosm and cAMP concentrations were measured before and after water loading. RESULTS: Urine [cAMP] indexed to Uosm significantly decreased with acute water loading in both groups (58% in controls and 35% in ADPKD). Chronic water loading resulted in a nonsignificant 13% decrease in 24 hour urine cAMP excretion in ADPKD participants, despite an increase in 24-hour urine volume by 64% to 3.14 +/- 0.32 L and decrease in mean Uosm by 46%, to below that of plasma (270 +/- 21 mOsm/L). CONCLUSIONS: Increased water intake of 3 L per day decreased Uosm in most ADPKD subjects. While urine [cAMP] accurately reflects changes in Uosm during acute water loading in ADPKD subjects, chronic water loading did not lower 24-hour urine cAMP excretion, although subjects with higher baseline [cAMP] (>2 nmol/mg Cr) responded best. Decreases in urine [cAMP] and osmolality are consistent with decreased AVP activity. These results support the need for a larger study to evaluate the effect of chronic water loading on ADPKD progression. PMID- 20167687 TI - Fluid administration in critically ill patients with acute kidney injury. AB - Physiologic end points for fluid resuscitation in septic shock patients with acute kidney injury (AKI) have been undertaken in randomized studies using the Early Goal-Directed Therapy (EGDT) approach. These studies have demonstrated a beneficial effect on in-hospital mortality with EGDT. The Saline versus Albumin Fluid Evaluation (SAFE) randomized study in critically ill patients demonstrated no difference in survival when saline versus albumin solutions were used for resuscitation. However, a benefit of albumin has been demonstrated in a randomized study on renal function and survival in cirrhotic patients with spontaneous bacterial periotonitis. On the other hand, recent observational studies have shown a correlation between fluid overload and mortality in AKI patients whether or not they necessitated dialysis. Moreover, the Adult Respiratory Distress Syndrome (ARDS) network performed a randomized study in critically ill patients to compare liberal versus conservative fluid administration. The liberal fluid administration group exhibited worse pulmonary function and no protection of renal function. Constancy of central venous pressure (CVP) measurements in the 12-mmHg range were observed in the liberal fluid group despite a mean increase in positive fluid balance of 7 L, thus suggesting increased interstitial fluid accumulation leading to pulmonary congestion. The review presented here discusses these various aspects of fluid administration in critically ill patients, particularly those with AKI, and indicates the potential deleterious effects of fluid overload on lung, heart, and kidney function that could contribute to increased mortality. PMID- 20167688 TI - Allocation of initial modality for renal replacement therapy in Brazil. AB - BACKGROUND AND OBJECTIVES: The use of dialysis modalities for ESRD varies around the world. There is no consensus in literature regarding the most appropriate choice of dialysis method. The aim of this study was to analyze the initial modality for ESRD in Brazil and evaluate the factors determining patients' allocation to either hemodialysis (HD) or peritoneal dialysis (PD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A retrospective cohort study was performed using national administrative registries of all patients financed by the public system who began renal replacement therapy in 2000 in Brazil. Logistic regression analysis was used to investigate factors associated with the probability of receiving HD or PD at the start of treatment. Independent variables tested were age, sex, presence of diabetes, geographic region of residence, and health care supply indicators. RESULTS: Of 11,563 patients analyzed, 88% started on HD and 12% started on PD. Patients were more likely to be assigned to HD if they were male (odds ratio: 1.44; 95% confidence interval: 1.23 to 1.68) and nondiabetic (odds ratio: 0.71; 95% confidence interval: 0.60 to 0.84). With regard to age, the youngest and the elderly showed lower probability of being in HD. In addition, the state of residence at the start of treatment was very important to explain initial modality allocation. CONCLUSIONS: Our findings suggest that patient allocation in Brazil is not random. The probability of allocation to HD or PD is highly associated with individual attributes and supply variables. PMID- 20167689 TI - Inappropriate use of commercial human chorionic gonadotropin assays. PMID- 20167690 TI - Early prostate cancer antigen-2: a controversial prostate cancer biomarker? PMID- 20167691 TI - Identification of pathogens by mass spectrometry. AB - BACKGROUND: Mass spectrometry (MS) is a suitable technology for microorganism identification and characterization. CONTENT: This review summarizes the MS-based methods currently used for the analyses of pathogens. Direct analysis of whole pathogenic microbial cells using MS without sample fractionation reveals specific biomarkers for taxonomy and provides rapid and high-throughput capabilities. MS coupled with various chromatography- and affinity-based techniques simplifies the complexity of the signals of the microbial biomarkers and provides more accurate results. Affinity-based methods, including those employing nanotechnology, can be used to concentrate traces of target microorganisms from sample solutions and, thereby, improve detection limits. Approaches combining amplification of nucleic acid targets from pathogens with MS-based detection are alternatives to biomarker analyses. Many data analysis methods, including multivariate analysis and bioinformatics approaches, have been developed for microbial identification. The review concludes with some current clinical applications of MS in the identification and typing of infectious microorganisms, as well as some perspectives. SUMMARY: Advances in instrumentation (separation and mass analysis), ionization techniques, and biological methodologies will all enhance the capabilities of MS for the analysis of pathogens. PMID- 20167692 TI - Microtechnology in the clinical laboratory: will it solve analytical problems, and when will it make an impact? PMID- 20167693 TI - Counterpoint: The reporting of estimated glucose with hemoglobin A1c. PMID- 20167694 TI - Point: The reporting of estimated glucose with hemoglobin A1c. PMID- 20167695 TI - Correlation between methylphenidate and ritalinic acid concentrations in oral fluid and plasma. AB - BACKGROUND: We studied the excretion profile of methylphenidate (MPH) and its metabolite ritalinic acid (RA) in oral fluid and plasma, the oral fluid-to-plasma (OF/P) drug ratio, and the variations of oral fluid pH after drug administration. METHODS: We analyzed oral fluid and plasma samples, obtained from 8 healthy volunteers after ingestion of a single dose of 20 mg fast-release or extended release MPH, for MPH and RA by LC-MS. We estimated the apparent pharmacokinetic parameters of MPH in plasma and oral fluid and calculated the OF/P ratio for each time interval. RESULTS: MPH and RA were detected in oral fluid. Whereas parent drug concentrations in oral fluid were an order of magnitude higher than those in plasma, the opposite was observed for RA. Oral fluid concentrations of MPH ranged between 0.5 and 466.7 microg/L and peaked at 0.5 h after administration of the fast-release formulation; they ranged between 0.7 and 89.5 microg/L and peaked at 2 h after administration of the extended-release formulation. Both formulations presented bimodal time-course curves for the OF/P ratio, ranging between 1.8 and 242.1 for the fast-release formulation and between 2.6 and 27.0 for extended release. Oral fluid pH did not appear to be modified by the administration of the drug, and its influence on OF/P ratio did not affect the correlation of MPH between the 2 body fluids. CONCLUSIONS: The results obtained support the measurement of MPH in oral fluid as an alternative to plasma if the extended release formulation is used. PMID- 20167696 TI - Interlaboratory diagnostic validation of conformation-sensitive capillary electrophoresis for mutation scanning. AB - BACKGROUND: Indirect alternatives to sequencing as a method for mutation scanning are of interest to diagnostic laboratories because they have the potential for considerable savings in both time and costs. Ideally, such methods should be simple, rapid, and highly sensitive, and they should be validated formally to a very high standard. Currently, most reported methods lack one or more of these characteristics. We describe the optimization and validation of conformation sensitive capillary electrophoresis (CSCE) for diagnostic mutation scanning. METHODS: We initially optimized the performance of CSCE with a systematic panel of plasmid-based controls. We then compared manual analysis by visual inspection with automated analysis by BioNumerics software (Applied Maths) in a blinded interlaboratory validation with 402 BRCA1 (breast cancer 1, early onset) and BRCA2 (breast cancer 1, early onset) variants previously characterized by Sanger sequencing. RESULTS: With automated analysis, we demonstrated a sensitivity of >99% (95% CI), which is indistinguishable from the sensitivity for conventional sequencing by capillary electrophoresis. The 95% CI for specificity was 90%-93%; thus, CSCE greatly reduces the number of fragments that need to be sequenced to fully characterize variants. By manual analysis, the 95% CIs for sensitivity and specificity were 98.3%-99.4% and 93.1%-95.5%, respectively. CONCLUSIONS: CSCE is amenable to a high degree of automation, and analyses can be multiplexed to increase both capacity and throughput. We conclude that once it is optimized, CSCE combined with analysis with BioNumerics software is a highly sensitive and cost-effective mutation-scanning technique suitable for routine genetic diagnostic analysis of heterozygous nucleotide substitutions, small insertions, and deletions. PMID- 20167697 TI - High-sensitivity cardiac troponin T for early prediction of evolving non-ST segment elevation myocardial infarction in patients with suspected acute coronary syndrome and negative troponin results on admission. AB - BACKGROUND: We sought to determine the diagnostic performance of the new high sensitivity cardiac troponin T (hs-cTnT) assay for early detection of non-ST segment myocardial infarction (NSTEMI) in patients with acute coronary syndrome. METHODS: We enrolled patients with retrospectively confirmed unstable angina or NSTEMI and an initially negative cTnT concentration and compared the performance of baseline concentrations and serial changes in concentration within 3 and 6 h. Percentage change criteria included >or=20% delta change and ROC-optimized value. RESULTS: Based on the standard fourth-generation cTnT result of >or=0.03 microg/L, an evolving NSTEMI was diagnosed in 26 patients, and 31 patients were classified as having unstable angina. With the use of the hs-cTnT assay at the 99th-percentile cutoff, the percentage of NSTEMI cases detected increased gradually from 61.5% on presentation to 100% within 6 h, and the overall number of MI diagnoses increased by 34.6% (35 vs 26 cases). A delta change >or=20% or >or=ROC-optimized value of >117% within 3 h or >or=243% within 6 h yielded a specificity of 100% at sensitivities between 69% and 76%. The standard cTnT at the 99th percentile was less sensitive than hs-cTnT for early diagnosis of MI on presentation, and follow-up samples obtained within the initial 3 h demonstrated very low specificity of cTnT compared with hs-cTnT. CONCLUSIONS: The high sensitivity cTnT assay increases the number of NSTEMI diagnoses and enables earlier detection of evolving NSTEMI. A doubling of the hs-cTnT concentration within 3 h in the presence of a second concentration >or=99th percentile is associated with a positive predictive value of 100% and a negative predictive value of 88%. PMID- 20167698 TI - Iothalamate quantification by tandem mass spectrometry to measure glomerular filtration rate. AB - BACKGROUND: Glomerular filtration rate (GFR) can be determined by measuring renal clearance of the radiocontrast agent iothalamate. Current analytic methods for quantifying iothalamate concentrations in plasma and urine using liquid chromatography or capillary electrophoresis have limitations such as long analysis times and susceptibility to interferences. We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to overcome these limitations. METHODS: Urine and plasma samples were deproteinized using acetonitrile and centrifugation. The supernatant was diluted in water and analyzed by LC-MS/MS using a water:methanol gradient. We monitored 4 multiple reaction monitoring transitions: m/z 614.8-487.0, 614.8-456.0, 614.8-361.1, and 614.8-177.1. We compared the results to those obtained via our standard capillary electrophoresis (CE-UV) on samples from 53 patients undergoing clinical GFR testing. RESULTS: Mean recovery was 90%-110% in both urine and plasma matrices. Imprecision was 3.4 muU/ml; 21/127, 16.5%), also showing a progressive increase from the lower to the upper quartile of normal range. A significantly higher proportion of L T(4)-treated patients (6650/7859, 84.6%) had serum TSH below the median (0.90 muU/ml) with respect to untreated patients (12,599/20,055, 62.8%; chi(2) P value <0.0001), with it being included in the range of TSH associated with a lower frequency of PTC. The relationship between serum TSH and frequency of PTC was unrelated to the type of nodularity (solitary versus multinodular) and was not age dependent. In conclusion, patients with nodular goiter, treatment with L-T(4) is responsible for the reduction of serum TSH and is associated with a decreased frequency of PTC. PMID- 20167723 TI - Setting new standards for targeted HIV prevention: the Avahan initiative in India. PMID- 20167724 TI - Ecological analysis of the association between high-risk population parameters and HIV prevalence among pregnant women enrolled in sentinel surveillance in four Southern India states. AB - BACKGROUND: The HIV epidemic is very heterogeneous at the district level in the four Southern states of India most affected by the epidemic and where transmission is mainly heterosexual. The authors carried out an ecological study of the relationship between high-risk population parameters and HIV prevalence among pregnant women (ANC HIV prevalence). METHODS: The data used in this study included: ANC HIV prevalence available from the National AIDS Control Organization (dependent variable); data on prevalence of HIV and other sexually transmitted infections among female sex workers (FSWs), their clients and high risk men who have sex with men (HR-MSM) from studies carried out in 24 districts under Avahan; data on clients' volume reported by FSWs and on the size estimates of FSWs and HR-MSM in each district; and census data. The latter two sets of data were used to estimate the percentage of female (male) adults who are FSWs (HR MSM). The latter was also multiplied by HIV prevalence in FSWs (HR-MSM) to obtain the percentage of HIV-positive FSWs (HR-MSM) in the adult female (male) population. Linear regression was used for statistical analyses. RESULTS: In univariate analyses, HIV (r=0.59, p=0.002) and HSV-2 (r=0.49, p=0.014) prevalence among FSWs and mean number of clients in the last week reported by FSWs (r=0.43, p=0.036) were significant predictors of ANC HIV prevalence. In multivariate analysis, only FSW HIV prevalence remained significant. CONCLUSIONS: This ecological study suggests that there is a link between HIV prevalence among FSWs and the spread of HIV to the general population in Southern India. Such an observation supports the rationale of interventions targeted at the sex industry. PMID- 20167725 TI - Changes in risk behaviours and prevalence of sexually transmitted infections following HIV preventive interventions among female sex workers in five districts in Karnataka state, south India. AB - OBJECTIVES: To examine the impact of a large-scale HIV prevention programme for female sex workers (FSW) in Karnataka state, south India, on the prevalence of HIV/sexually transmitted infections (STI), condom use and programme coverage. METHODS: Baseline and follow-up integrated biological and behavioural surveys were conducted on random samples of FSW in five districts in Karnataka between 2004 and 2009. RESULTS: 4712 FSW participated in the study (baseline 2312; follow up 2400), with follow-up surveys conducted 28-37 months after baseline. By follow up, over 85% of FSW reported contact by a peer educator and having visited a project STI clinic. Compared with baseline, there were reductions in the prevalence of HIV (19.6% vs 16.4%, adjusted odds ratio (AOR) 0.81, 95% CI 0.67 to 0.99, p=0.04); high-titre syphilis (5.9% vs 3.4%, AOR 0.53, 95% CI 0.37 to 0.77, p=0.001); and chlamydia and/or gonorrhoea (8.9% vs 7.0%, AOR 0.72, 95% CI 0.54 to 0.94, p=0.02). Reported condom use at last sex increased significantly for repeat clients (66.1% vs 84.1%, AOR 1.98, 95% CI 1.58 to 2.48, p<0.001) and marginally for occasional clients (82.9% vs 88.0%, AOR 1.22, 95% CI 0.89 to 1.66, p=0.2), but remained stable for regular partners (32%). Compared with street and home based FSW, brothel-based FSW were at highest risk of HIV and STI, despite high levels of reported condom use. CONCLUSIONS: This large-scale HIV prevention programme for FSW achieved reductions in HIV and STI prevalence, high rates of condom use with clients and high rates of programme coverage. Improved strategies to increase condom use with regular partners and reduce the vulnerability of brothel-based FSW to HIV are required. PMID- 20167726 TI - Community engagement in HIV prevention in Asia: going from 'for the community' to 'by the community'--must we wait for more evidence? PMID- 20167727 TI - Increases in self-reported consistent condom use among male clients of female sex workers following exposure to an integrated behaviour change programme in four states in southern India. AB - PURPOSE: As part of the Avahan India AIDS Initiative, a behaviour change communication programme sought to increase consistent condom use (CCU) among male clients of female sex workers (FSWs) in four Indian states through the use of outdoor static promotional materials, interpersonal communication and mid-media activities. This paper presents key findings related to programme coverage levels, trends over time in self-reported condom use, and correlations between levels of exposure to programme activities and self-reported condom use. METHODS: Five stratified two-stage cluster sample surveys were conducted between April 2006 and November 2008 (sample sizes ranged from 1741 to 2041). The independent samples were composed of clients of FSWs in selected clusters. Multivariate logistic regression was used to model whether behavioural outcomes varied between baseline and endline, and whether they varied with levels of exposure to the intervention. RESULTS: Over two-thirds of men in each survey round recalled one or two of the main intervention channels. An increase in CCU with FSWs was found between baseline and endline (63.6% vs 86.5; p<0.01). Men exposed to two intervention channels reported higher CCU than men exposed to none or only static outdoor media (89.4% vs 82.0%, p<0.05). This trend was sustained for condom use at last sex (96.2% vs 92.6%, p<0.05). CONCLUSION: Evaluation suggests that a multi-channel behavioural intervention delivered at sites where FSWs are solicited can increase CCU among male clients of FSWs. Further research is needed on the dynamics of exposure to multiple communication channels and the contributions of complementary interventions. PMID- 20167729 TI - Evaluation of HIV prevention programmes: the case of Avahan. PMID- 20167728 TI - Interim modelling analysis to validate reported increases in condom use and assess HIV infections averted among female sex workers and clients in southern India following a targeted HIV prevention programme. AB - OBJECTIVES: This study assesses whether the observed declines in HIV prevalence since the beginning of the 'Avahan' India HIV/AIDS prevention initiative are consistent with self-reported increases in condom use by female sex workers (FSWs) in two districts of southern India, and provides estimates of the fraction of new infections averted among FSWs and clients due to increases in condom use in commercial sex after 2004. METHODS: A deterministic compartmental model of HIV/sexually transmitted infection (STI) transmission incorporating heterogeneous sexual behaviour was developed, parameterised and fitted using data from two districts in Karnataka, India. Three hypotheses of condom use among FSWs were tested: (H(0)), that condom use increased in line with reported FSW survey data prior to the Avahan initiative but remained constant afterwards; (H(1)) that condom use increased following the Avahan initiative, in accordance with survey data; (H(2)) that condom use increased according to estimates derived from condom distribution data. The proportion of fits to HIV/STI prevalence data was examined to determine which hypothesis was most consistent. RESULTS: For Mysore 0/36/82.7 fits were identified per million parameter sets explored under hypothesis H(0)/H(1)/H(2), respectively, while for Belgaum 9.7/8.3/0 fits were identified. The HIV epidemics in Belgaum and Mysore are both declining. In Mysore, increases in condom use during commercial sex between 2004 and 2009 may have averted 31.2% to 47.4% of new HIV infections in FSWs, while in Belgaum it may have averted 24.8% to 43.2%, if there was an increase in condom use. DISCUSSION: Increased condom use following the Avahan intervention is likely to have played a role in curbing the HIV epidemic in Mysore. In Belgaum, given the limitations in available data, this method cannot be used alone to decide if there has been an increase in condom use. PMID- 20167730 TI - Assessing reported condom use among female sex workers in southern India through examination of condom availability. AB - OBJECTIVES: A key indicator of success of HIV prevention programmes is the number of female sex worker (FSW) sex acts protected by condoms. This measure usually relies on FSW reports, which may be biased. We examined condom availability data in five Karnataka districts to estimate the proportion of FSW sex acts potentially protected by condoms. METHODS: Financial, programme, population, condom and contraceptive data were obtained from governmental and non governmental sources, surveys and HIV prevention programmes. Sexual behaviour data were obtained from general population and FSW surveys. We examined four scenarios in a sensitivity analysis, each one assuming different proportions of available condoms that might have been used by sex workers. RESULTS: Possible condom use rates for all FSW sex acts ranged from 3%-36% in 2004 to 56%-96% in 2008. The two most realistic scenarios that discounted the number of private sector condoms that might have been bought for sex acts other than with FSWs showed that 16-24% of FSW sex acts could have been protected by condoms in 2004 rising to 77-85% in 2008. CONCLUSIONS: These data suggest that condom availability in these Karnataka districts in 2004 was low in relation to the number of FSW sex acts, but rose substantially over the ensuing 4 years. Condom availability data can be useful for triangulation with other available data, such as self-reported condom use, to provide a range of possibilities regarding the number of FSW sex acts protected by condoms. PMID- 20167731 TI - Assessment of intervention outcome in the absence of baseline data: 'reconstruction' of condom use time trends using retrospective analysis of survey data. AB - BACKGROUND: Avahan, the India AIDS Initiative, is a large-scale targeted intervention. Data on condom use prior to Avahan are unavailable. The authors used a novel method of analysing cross-sectional survey data to 'reconstruct' condom use rates in presurvey years, and to assess the relationship between Avahan and time trends in condom use among female sex workers (FSWs). METHODS: Among FSWs reporting consistent condom use (CCU) with clients in surveys from 21 districts in southern India (n=7358), data on length of time using condoms, and length of time selling sex, were converted into number of FSWs using condoms (numerator) and selling sex (denominator) by year, to give yearly rates of CCU from 2001 to year of survey. Linear regression with generalised estimating equations was used to assess time trends and to compare the rate of increase in condom use before and after Avahan initiation in 2003. RESULTS: In all 21 districts, the rate of increase in CCU from 2001 to time of the surveys was highly significant. Overall CCU increased from 27% (22%) with occasional (regular) clients in 2001, to 76% (68%) in 2006, respectively. The yearly rate of increase in CCU was significantly greater after (slope 2003-2006: 12.7% (12.0%) per year for occasional (regular) clients) than prior to Avahan (slope 2001-2003: 5.1% (5.3%) per year for occasional (regular) clients) implementation (p<0.0001). CONCLUSIONS: The findings indicate a positive relationship between implementation of the Avahan programme and rates of CCU increase among FSW. This method of analysis may be useful in other contexts where preintervention data are lacking. PMID- 20167732 TI - Lot quality assurance sampling for monitoring coverage and quality of a targeted condom social marketing programme in traditional and non-traditional outlets in India. AB - OBJECTIVES: This study reports on the results of a large-scale targeted condom social marketing campaign in and around areas where female sex workers are present. The paper also describes the method that was used for the routine monitoring of condom availability in these sites. METHODS: The lot quality assurance sampling (LQAS) method was used for the assessment of the geographical coverage and quality of coverage of condoms in target areas in four states and along selected national highways in India, as part of Avahan, the India AIDS initiative. RESULTS: A significant general increase in condom availability was observed in the intervention area between 2005 and 2008. High coverage rates were gradually achieved through an extensive network of pharmacies and particularly of non-traditional outlets, whereas traditional outlets were instrumental in providing large volumes of condoms. CONCLUSION: LQAS is seen as a valuable tool for the routine monitoring of the geographical coverage and of the quality of delivery systems of condoms and of health products and services in general. With a relatively small sample size, easy data collection procedures and simple analytical methods, it was possible to inform decision-makers regularly on progress towards coverage targets. PMID- 20167733 TI - The importance of sex-worker interventions: the case of Avahan in India. PMID- 20167734 TI - Programme coverage, condom use and STI treatment among FSWs in a large-scale HIV prevention programme: results from cross-sectional surveys in 22 districts in southern India. AB - OBJECTIVE: This paper evaluates Avahan programme's coverage of female sex workers (FSWs), focus on high-risk FSWs and intermediate outcomes. METHODS: First round of cross-sectional survey data, Integrated Behavioral and Biological Assessments (IBBA), conducted in 22 districts, were aggregated into district categories: Solo, where Avahan was the sole service provider covering all FSWs and Major or Minor where Avahan was not the sole provider, but intended coverage was >50% or or=15 clients in the past week had a higher chance of being exposed to core services (AOR=1.56; 95% CI 1.03 to 2.35). Exposure to the three services in Solo Avahan districts was significantly associated with correct knowledge on condom use (AOR=1.36; 95% CI 1.05 to 1.78), consistent condom use with occasional clients (AOR=3.17; 95% CI 2.17 to 4.63) and regular clients (AOR=2.47; 95% CI 1.86 to 3.28) and STI treatment-seeking behaviour (AOR=3.00; 95% CI 1.94 to 4.65). CONCLUSIONS: Higher coverage of FSWs was achieved in districts where Avahan was the only intervention compared with districts having multiple and longstanding non-Avahan programmes. Exposure in Solo districts was associated with intermediate outcomes; this need to be further evaluated in comparison with non Avahan areas and substantiated through data from next IBBA. PMID- 20167735 TI - Factors associated with awareness and utilisation of a community mobilisation intervention for female sex workers in Andhra Pradesh, India. AB - OBJECTIVES: Examine factors associated with awareness and active utilisation of a community mobilisation intervention (CMI) to address HIV risk in female sex workers (FSWs) in a context characterised by multiple forms of sex work. DESIGN: Data came from two rounds, conducted in Spring 2006 and Spring 2007, of a serial cross-sectional survey of FSWs (n=812 in round 1, n=673 in round 2) recruited through respondent-driven sampling in Rajahmundry, Andhra Pradesh, India. METHODS: Descriptive statistics compared characteristics of programme aware and unaware FSWs and from among the aware, to characterise active program users. Multinomial logistic regression was used to assess factors associated with programme exposure. RESULTS: Between Rounds 1 and 2, programme awareness increased from 41.8% to 69.6% of respondents, and active utilisation (among those who were aware) increased from 49.2% to 61.0%. Street-based FSWs were under represented and brothel-based FSWs overrepresented in both groups and rounds. Geographic proximity and literacy were associated with programme awareness but not utilisation. The most important factor associated with both forms of intervention exposure across rounds was willingness to be identified in public as a FSWs (OR 2.2-4.8). CONCLUSION: Public visibility is a critical component of CMIs. Such interventions should develop strategies for involving FSWs that allow them to remain invisible, while also working to reduce the threat associated with public visibility. In contexts where sex work occurs in multiple venues, it is important to develop CMIs that include and address the needs of FSWs working in them all. PMID- 20167736 TI - Avahan: the transition to a publicly funded programme as a next stage. PMID- 20167738 TI - Recreating the impact of interventions in the absence of baseline data: challenges for intervention programmes. PMID- 20167737 TI - Scale-up and coverage of Avahan: a large-scale HIV-prevention programme among female sex workers and men who have sex with men in four Indian states. AB - OBJECTIVE: Documenting the implementation of a public health programme as per its design is critical to interpretation of results from survey-led outcome and impact evaluation activities, the authors describe the scale-up and coverage of large-scale HIV-prevention services provided to female sex workers (FSWs) and high-risk men who have sex with men (HR-MSM) during the first 5 years of the Avahan programme in India. METHODS: Implementing NGO partner-generated denominator estimates from 70 districts were used to estimate the programme's intended coverage. Routine programme-monitoring data until December 2008 were used to describe the service and commodity availability, service utilisation to generate internal estimates of coverage. Coverage was validated in few districts using data from a cross-sectional survey. RESULTS: In December 2008, the estimated denominators for intended services were about 217,000 FSWs and 80,000 HR-MSM. By January 2007, 79% of eventual total clinics and 75% drop-in centres were established, and 83% of eventual peer educators were active. By month 48, sufficient condoms to cover all estimated FSW commercial sex acts were distributed free. By month 60, 75% of the estimated denominator intended to be covered was met monthly. 86% of FSWs and 67% of HR-MSM ever contacted had used sexually transmitted infections services at least once. Cross-sectional survey generated coverage results suggest that programme-monitoring data provide a proxy to coverage of services. CONCLUSION: Avahan's monitoring data show that Avahan achieved infrastructure scale by year 3 and high contact coverage through peers and with commodities by year 5 of implementation as per the design. PMID- 20167739 TI - Quality assurance and quality improvement using supportive supervision in a large scale STI intervention with sex workers, men who have sex with men/transgenders and injecting-drug users in India. AB - BACKGROUND: Documentation of the long-term impact of supportive supervision using a monitoring tool in STI intervention with sex workers, men who have sex with men and injection-drug users is limited. The authors report methods and results of continued quality monitoring in a large-scale STI services provided as a part of a broader HIV-prevention package in six Indian states under Avahan, the India AIDS Initiative. METHODOLOGY: Guidelines and standards for STI services, and a supportive supervisory tool to monitor the quality were developed for providing technical support to STI component of large-scale HIV-prevention intervention through 372 project-supported STI clinics. The tool contained 80 questions to track the quality of STI services provided on a five-point scoring scale in five performance areas: coverage, quality of clinic and services, referral networks, community involvement and technical support. RESULTS: The tool was applied to different STI clinics during supportive supervision visits conducted once in every 3 months to assess quality, give immediate feedback and develop a quality score. A total of 292 clinics managed by seven lead implementing partners in six Indian states were covered in 15 quarters over 45 months. Overall quality indicators for the five performance areas showed a three- to sevenfold improvement over the period. CONCLUSION: It was possible to improve quality over the long-term in STI interventions for sex workers, men who have sex with men and injection-drug users using an interactive and comprehensive supportive supervision tool which gives on-the-spot feedback. However, such an effort is time-consuming and resource-intensive, and needs a structured approach. PMID- 20167740 TI - The effects of scale on the costs of targeted HIV prevention interventions among female and male sex workers, men who have sex with men and transgenders in India. AB - BACKGROUND: The India AIDS Initiative (Avahan) project is involved in rapid scale up of HIV-prevention interventions in high-risk populations. This study examines the cost variation of 107 non-governmental organisations (NGOs) implementing targeted interventions, over the start up (defined as period from project inception until services to the key population commenced) and first 2 years of intervention. METHODS: The Avahan interventions for female and male sex workers and their clients, in 62 districts of four southern states were costed for the financial years 2004/2005 and 2005/2006 using standard costing techniques. Data sources include financial and economic costs from the lead implementing partners (LPs) and subcontracted local implementing NGOs retrospectively and prospectively collected from a provider perspective. Ingredients and step-down allocation processes were used. Outcomes were measured using routinely collected project data. The average costs were estimated and a regression analysis carried out to explore causes of cost variation. Costs were calculated in US$ 2006. RESULTS: The total number of registered people was 134,391 at the end of 2 years, and 124,669 had used STI services during that period. The median average cost of Avahan programme for this period was $76 per person registered with the project. Sixty one per cent of the cost variation could be explained by scale (positive association), number of NGOs per district (negative), number of LPs in the state (negative) and project maturity (positive) (p<0.0001). CONCLUSIONS: During rapid scale-up in the initial phase of the Avahan programme, a significant reduction in average costs was observed. As full scale-up had not yet been achieved, the average cost at scale is yet to be realised and the extent of the impact of scale on costs yet to be captured. Scale effects are important to quantify for planning resource requirements of large-scale interventions. The average cost after 2 years is within the range of global scale-up costs estimates and other studies in India. PMID- 20167741 TI - Coronary atherosclerosis: extending to the microcirculation? PMID- 20167742 TI - Evaluating dyspnoea in acute heart failure: progress at last! PMID- 20167744 TI - Division of cytokines into TH1/TH2: a word of caution. PMID- 20167743 TI - Early and late outcome of treated patients referred for syncope to emergency department: the EGSYS 2 follow-up study. AB - AIMS: We evaluated the early (1 month) and late (2 years) death rate and syncopal relapses of patients referred for syncope to 11 general hospitals emergency departments. Patients were enrolled in the Evaluation of Guidelines in SYncope Study 2 (EGSYS 2) study. The guidelines of the European Society of Cardiology were strictly followed in the management of patients. METHODS AND RESULTS: Out of the 465 patients enrolled in the EGSYS 2 study, 398 (86%) underwent a complete follow-up. We excluded 18 patients with non-syncopal attacks. Among the remaining 380 patients, death of any cause occurred in 35 (9.2%). The mean follow-up was 614 +/- 73 days. Six deaths (17% of total) occurred during the first month of follow-up. Patients who died were older, had a higher incidence of structural heart disease and/or abnormal ECG, had injuries related to syncope and higher EGSYS score. Syncope recurred in 63 (16.5%) patients. Syncopal relapses occurred in only one patient during the first month of follow-up. The incidence of syncopal recurrences was unrelated to the mechanism of syncope. No clinical differences were found between patients with or without syncopal recurrence and in patients with EGSYS score < or >or=3. CONCLUSION: A peak of cardiovascular mortality but not of syncopal recurrences was observed in patients attending to the emergency department for syncope within the first month. Late unfavourable outcomes were caused by associated cardiovascular diseases rather than by the mechanism of syncope. The causes of syncope did not determine the recurrence rate. PMID- 20167745 TI - A longitudinal study of oxidative stress and antioxidant status in women with uncomplicated pregnancies throughout gestation. AB - Pregnancy is associated with increased oxidative stress, and exaggeration of oxidative damage is considered important in pregnancy complications such as preeclampsia. There is, however, only scattered information regarding the longitudinal change of oxidative stress during pregnancy. We surmised that the placenta is the cause of the increased oxidative stress during pregnancy and hypothesized that the amount of placenta-derived cell-free fetal DNA in maternal plasma is correlated with maternal oxidative stress status. Blood and urine samples were collected at different stages of gestation and 6 to 8 weeks postpartum from 105 women with uncomplicated pregnancies. Additionally, 40 healthy women of reproductive age, but not pregnant, were recruited as controls. All oxidative stress markers, including urinary 8-hydroxydeoxyguanosine (8-OHdG), plasma 8-isoprostane, total antioxidant capacity (TAC), and erythrocyte glutathione peroxidase (GPX) and superoxide dismutase (SOD) activities, were increased in the third trimester, and most of them returned to nonpregnant levels postpartum. Furthermore, the DYS14 gene of the Y chromosome was quantified from plasma samples obtained at 26 to 30 weeks' gestation in 54 women who later delivered a male infant. Significant associations were noted between plasma concentrations of the DYS14 gene and the levels of urinary 8-OHdG and plasma 8 isoprostane, suggesting an association between the breakdown of syncytiotrophoblast and maternal oxidative stress during pregnancy. PMID- 20167746 TI - Design of polymethine dyes with large third-order optical nonlinearities and loss figures of merit. AB - All-optical switching applications require materials with large third-order nonlinearities and low nonlinear optical losses. We present a design approach that involves enhancing the real part of the third-order polarizability (gamma) of cyanine-like molecules through incorporation of polarizable chalcogen atoms into terminal groups, while controlling the molecular length to obtain favorable one- and two-photon absorption resonances that lead to suitably low optical loss and appreciable dispersion enhancement of the real part of gamma. We implemented this strategy in a soluble bis(selenopyrylium) heptamethine dye that exhibits a real part of gamma that is exceptionally large throughout the wavelength range used for telecommunications, and an imaginary part of gamma, a measure of nonlinear loss, that is smaller by two orders of magnitude. This combination is critical in enabling low-power, high-contrast optical switching. PMID- 20167749 TI - Brazil. Race for cellulosic fuels spurs Brazilian research program. PMID- 20167748 TI - Bridging science and society. PMID- 20167750 TI - U.S. Congress. Ehlers's retirement called 'big loss' for science. PMID- 20167752 TI - China. Fear of MRI scans trips up brain researchers. PMID- 20167753 TI - Invasive species. Biologists rush to protect Great Lakes from onslaught of carp. PMID- 20167755 TI - U.S. immigration policy. Prominent Iranian scientist blocked from attending physics meeting. PMID- 20167756 TI - Newsmaker interview. Embattled U.K. scientist defends track record of climate center. Interview by Eli Kintisch. PMID- 20167757 TI - Psychiatry. Behavioral addictions debut in proposed DSM-V. PMID- 20167758 TI - Public health. Brawling over mammography. PMID- 20167759 TI - China. Leprosy's last stand--or early days of a war of attrition? PMID- 20167760 TI - Bhutan. Improbable partners aim to bring biotechnology to a Himalayan kingdom. PMID- 20167761 TI - Joint Mathematics Meeting, 13-16 January, San Francisco, California. Perfection in a box. PMID- 20167762 TI - Joint Mathematics Meeting, 13-16 January, San Francisco, California. Politics as (un)usual. PMID- 20167763 TI - Joint Mathematics Meeting, 13-16 January, San Francisco, California. What comes next? PMID- 20167764 TI - 2009 Visualization Challenge. PMID- 20167770 TI - Responsible researchers required. PMID- 20167772 TI - Opposites attract. [corrected]. PMID- 20167771 TI - Sustainable foresting: easier said than done. PMID- 20167773 TI - Research ethics. NIH guidelines for stem cell research and gamete donors. PMID- 20167774 TI - Cell biology. Rise of the rival. PMID- 20167775 TI - Chemistry. Cooperativity tames reactive catalysts. PMID- 20167776 TI - Cell biology. When the beginning marks the end. PMID- 20167777 TI - Paleontology. On giant filter feeders. PMID- 20167778 TI - Physics. The lowdown on heavy fermions. PMID- 20167779 TI - Atmospheric science. Can we understand clouds without turbulence? PMID- 20167780 TI - Retrospective. Marshall Warren Nirenberg (1927-2010). PMID- 20167781 TI - Tuning the dimensionality of the heavy fermion compound CeIn3. AB - Condensed-matter systems that are both low-dimensional and strongly interacting often exhibit unusual electronic properties. Strongly correlated electrons with greatly enhanced effective mass are present in heavy fermion compounds, whose electronic structure is essentially three-dimensional. We realized experimentally a two-dimensional heavy fermion system, adjusting the dimensionality in a controllable fashion. Artificial superlattices of the antiferromagnetic heavy fermion compound CeIn3 and the conventional metal LaIn3 were grown epitaxially. By reducing the thickness of the CeIn3 layers, the magnetic order was suppressed and the effective electron mass was further enhanced. Heavy fermions confined to two dimensions display striking deviations from the standard Fermi liquid low temperature electronic properties, and these are associated with the dimensional tuning of quantum criticality. PMID- 20167782 TI - The silicate-mediated formose reaction: bottom-up synthesis of sugar silicates. AB - Understanding the mechanism of sugar formation and stabilization is important for constraining theories on the abiotic origin of complex biomolecules. Although previous studies have produced sugars from small molecules through the formose and related reactions, the product mixtures are complex and unstable. We have demonstrated that simple two- and three-carbon molecules (glycolaldehyde and glyceraldehyde), in the presence of aqueous sodium silicate, spontaneously form silicate complexes of four- and six-carbon sugars, respectively. Silicate selects for sugars with a specific stereochemistry and sequesters them from rapid decomposition. Given the abundance of silicate minerals, these observations suggest that formose-like reactions may provide a feasible pathway for the abiotic formation of biologically important sugars, such as ribose. PMID- 20167783 TI - Asymmetric cooperative catalysis of strong Bronsted acid-promoted reactions using chiral ureas. AB - Cationic organic intermediates participate in a wide variety of useful synthetic transformations, but their high reactivity can render selectivity in competing pathways difficult to control. Here, we describe a strategy for inducing enantioselectivity in reactions of protio-iminium ions, wherein a chiral catalyst interacts with the highly reactive intermediate through a network of noncovalent interactions. This interaction leads to an attenuation of the reactivity of the iminium ion and allows high enantioselectivity in cycloadditions with electron rich alkenes (the Povarov reaction). A detailed experimental and computational analysis of this catalyst system has revealed the precise nature of the catalyst substrate interactions and the likely basis for enantioinduction. PMID- 20167784 TI - 100-million-year dynasty of giant planktivorous bony fishes in the Mesozoic seas. AB - Large-bodied suspension feeders (planktivores), which include the most massive animals to have ever lived, are conspicuously absent from Mesozoic marine environments. The only clear representatives of this trophic guild in the Mesozoic have been an enigmatic and apparently short-lived Jurassic group of extinct pachycormid fishes. Here, we report several new examples of these giant bony fishes from Asia, Europe, and North America. These fossils provide the first detailed anatomical information on this poorly understood clade and extend its range from the lower Middle Jurassic to the end of the Cretaceous, showing that this group persisted for more than 100 million years. Modern large-bodied, planktivorous vertebrates diversified after the extinction of pachycormids at the Cretaceous-Paleogene boundary, which is consistent with an opportunistic refilling of vacated ecospace. PMID- 20167785 TI - Climate, critters, and cetaceans: Cenozoic drivers of the evolution of modern whales. AB - Modern cetaceans, a poster child of evolution, play an important role in the ocean ecosystem as apex predators and nutrient distributors, as well as evolutionary "stepping stones" for the deep sea biota. Recent discussions on the impact of climate change and marine exploitation on current cetacean populations may benefit from insights into what factors have influenced cetacean diversity in the past. Previous studies suggested that the rise of diatoms as dominant marine primary producers and global temperature change were key factors in the evolution of modern whales. Based on a comprehensive diversity data set, we show that much of observed cetacean paleodiversity can indeed be explained by diatom diversity in conjunction with variations in climate as indicated by oxygen stable isotope records (delta18O). PMID- 20167786 TI - Regulation of cellular metabolism by protein lysine acetylation. AB - Protein lysine acetylation has emerged as a key posttranslational modification in cellular regulation, in particular through the modification of histones and nuclear transcription regulators. We show that lysine acetylation is a prevalent modification in enzymes that catalyze intermediate metabolism. Virtually every enzyme in glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, the urea cycle, fatty acid metabolism, and glycogen metabolism was found to be acetylated in human liver tissue. The concentration of metabolic fuels, such as glucose, amino acids, and fatty acids, influenced the acetylation status of metabolic enzymes. Acetylation activated enoyl-coenzyme A hydratase/3-hydroxyacyl coenzyme A dehydrogenase in fatty acid oxidation and malate dehydrogenase in the TCA cycle, inhibited argininosuccinate lyase in the urea cycle, and destabilized phosphoenolpyruvate carboxykinase in gluconeogenesis. Our study reveals that acetylation plays a major role in metabolic regulation. PMID- 20167787 TI - Acetylation of metabolic enzymes coordinates carbon source utilization and metabolic flux. AB - Lysine acetylation regulates many eukaryotic cellular processes, but its function in prokaryotes is largely unknown. We demonstrated that central metabolism enzymes in Salmonella were acetylated extensively and differentially in response to different carbon sources, concomitantly with changes in cell growth and metabolic flux. The relative activities of key enzymes controlling the direction of glycolysis versus gluconeogenesis and the branching between citrate cycle and glyoxylate bypass were all regulated by acetylation. This modulation is mainly controlled by a pair of lysine acetyltransferase and deacetylase, whose expressions are coordinated with growth status. Reversible acetylation of metabolic enzymes ensure that cells respond environmental changes via promptly sensing cellular energy status and flexibly altering reaction rates or directions. It represents a metabolic regulatory mechanism conserved from bacteria to mammals. PMID- 20167788 TI - Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa. AB - Antibiotics with new mechanisms of action are urgently required to combat the growing health threat posed by resistant pathogenic microorganisms. We synthesized a family of peptidomimetic antibiotics based on the antimicrobial peptide protegrin I. Several rounds of optimization gave a lead compound that was active in the nanomolar range against Gram-negative Pseudomonas spp., but was largely inactive against other Gram-negative and Gram-positive bacteria. Biochemical and genetic studies showed that the peptidomimetics had a non membrane-lytic mechanism of action and identified a homolog of the beta-barrel protein LptD (Imp/OstA), which functions in outer-membrane biogenesis, as a cellular target. The peptidomimetic showed potent antimicrobial activity in a mouse septicemia infection model. Drug-resistant strains of Pseudomonas are a serious health problem, so this family of antibiotics may have important therapeutic applications. PMID- 20167789 TI - Limits of predictability in human mobility. AB - A range of applications, from predicting the spread of human and electronic viruses to city planning and resource management in mobile communications, depend on our ability to foresee the whereabouts and mobility of individuals, raising a fundamental question: To what degree is human behavior predictable? Here we explore the limits of predictability in human dynamics by studying the mobility patterns of anonymized mobile phone users. By measuring the entropy of each individual's trajectory, we find a 93% potential predictability in user mobility across the whole user base. Despite the significant differences in the travel patterns, we find a remarkable lack of variability in predictability, which is largely independent of the distance users cover on a regular basis. PMID- 20167791 TI - Discrepancy between absorbed dose estimated from phantom measurements and from estimates using data on individual head sizes in head CT examinations. AB - Patient doses during computed tomography (CT) scanning are relative high, as compared with doses received by patients during conventional X-ray examinations. Owing to this, every possible optimisation of CT examinations is of importance. Dose estimation in CT examinations of patients are normally based on measurements of CT dose index and dose length products in standardised CT phantoms, representing a standard person of 70 kg. Real patients may differ significantly from this standard, and hence the dose values calculated for a phantom are not relevant for the individual patient. In this investigation, the effective dose for 31 patients undergoing a CT examination of their head has been evaluated using measurements on a standard CT head phantom and the data corrected for the real size (perimeter) and exposed volume of the patient's head. It is shown that the actual doses to patients were higher in 50 % cases of all performed head CT examinations, compared with doses estimated from phantom measurements. A dose calculation model for head CT patients based on the individual patient's head size (perimeter) and exposed head volume is proposed and the possibility to optimise head CT examinations of patients is discussed. PMID- 20167792 TI - Radiation exposure of patients and personnel from a PET/CT procedure with 18F FDG. AB - The positron emission tomography (PET)/computed tomography (CT) camera is a combination of a PET camera and a CT. The image from the PET camera is based on the detection of radiation that is emitted from a radioactive tracer, which has been given to the patient as an intravenous injection. The radiation that is emitted from the radioactive tracer is more energetic than any other radiation used in medical diagnostic procedures and this requires special radiation protection routines. The CT image is based on the detection of radiation produced from an X-ray tube and transmitted through the patient. The radiation exposure of the personnel during the CT procedure is generally very low. Regarding radiation exposure of the patient, it is important to notice whether a CT scan has been performed prior to the PET/CT in order to avoid any unnecessary irradiation. The total effective dose to the patient from a PET/CT procedure is approximately 10 mSv. The major part comes from internal irradiation due to radiopharmaceuticals within the patients (e.g. (18)F-FDG: approximately 6-7 mSv), and a minor part is due to the CT scan (low-dose CT scan: approximately 2-4 mSv). If a full diagnostic CT investigation is performed, the effective dose may be considerably higher. If the patient is pregnant, a PET/CT procedure should be avoided or postponed, unless it is vital for the patient. An interruption in breastfeeding is not necessary after a PET/CT procedure of the nursing mother. Close contact between the patient and a small child should however be avoided for a couple of hours after the administration of the radiopharmaceutical. The radiation dose to the personnel arises mainly due to handling of the radiopharmaceuticals (syringe withdrawal, injection, waste handling, etc.) and from close contact to the patient. This radiation dose can be limited by using the inverse-square law, i.e. by using the fact that the absorbed dose decreases substantially with increasing distance between the radiation source and the personnel. PMID- 20167793 TI - Microdosing for early biokinetic studies in humans. AB - Microdosing is a new concept in drug development that--if implemented in the pharmaceutical industry--would mean that new drugs can be tested earlier in humans than done today. The human microdosing concept--or 'Phase 0'--may offer improved candidate selection, reduced failure rates in the drug development line and a reduction in the use of laboratory animals in early drug development, factors which will help to speed up drug development and also reduce the costs. Microdosing utilises sub-pharmacological amounts of the substance to open opportunities for early studies in man. Three technologies are used for microdosing: accelerator mass spectrometry (AMS), positron emission tomography and liquid chromatography-tandem mass spectrometry. This paper focuses on the principle of AMS and discusses the current status of microdosing with AMS. PMID- 20167794 TI - New calculations for internal dosimetry of beta-emitting radiopharmaceuticals. AB - The calculation of absorbed dose from internally incorporated radionuclides is based on the so-called specific absorbed fractions (SAFs) which represent the fraction of energy emitted in a given source region that is absorbed per unit mass in a specific target organ. Until recently, photon SAFs were calculated using MIRD-type mathematical phantoms. For electrons, the energy released was assumed to be absorbed locally ('ICRP 30 approach'). For this work, photon and electron SAFs were derived with Monte Carlo simulations in the new male voxel based reference computational phantom adopted by the ICRP and ICRU. The present results show that the assumption of electrons being locally absorbed is not always true at energies above 300-500 keV. For source/target organ pairs in close vicinity, high-energy electrons escaping from the source organ may result in cross-fire electron SAFs in the same order of magnitude as those from photons. Examples of organ absorbed doses per unit activity are given for (18)F-choline and (123)I-iodide. The impact of the new electron SAFs used for absorbed dose calculations compared with the previously used assumptions was found to be small. The organ dose coefficients for the two approaches differ by not more than 6 % for most organs. Only for irradiation of the urinary bladder wall by activity in the contents, the ICRP 30 approach presents an overestimation of approximately 40 50%. PMID- 20167795 TI - Photocathode non-uniformity contribution to the energy resolution of scintillators. AB - This paper introduces the basics of the light transport simulation in scintillators and the wavelength-dependencies in the process. The non-uniformity measurement of the photocathode surface is undertaken, showing that for the photocathode used in this study the quantum efficiency falls to about 4 % of its maximum value, especially in areas far from the centre. The wavelength- and position-dependent quantum efficiency is implemented in the Monte Carlo light transport code, showing that, the contribution of the photocathode non-uniformity to the energy resolution is estimated to be around 18 %, when all position- and wavelength-dependencies are included. PMID- 20167796 TI - A rapid bioassay method for the determination of 90Sr in human urine sample. AB - A rapid bioassay method has been developed for the determination of (90)Sr in human urine samples. The method is based on on-cartridge decolourisation of urine sample, separation of (90)Y from (90)Sr on an anion exchange resin column and by determination of (90)Sr using a liquid scintillation analyser (LSA). Separation of (90)Y from (90)Sr was achieved through selective complexation of yttrium with phosphate and subsequent retention of the anionic yttrium phosphate species on anion exchange resin. A total recovery of 97 +/- 2 % was obtained for strontium with three washes. The minimum detectable activity for the method was 0.2 Bq or 40 Bq l(-1). Measurement accuracy (relative bias, B(r)) and repeatability (relative precision, S(B)) of the method for the determination of (90)Sr were found to be -1 and 4.7 %, respectively. Excellent linearity (r(2) > 0.999) was established over an activity range from 3.25 x 10(2) to 3.25 x 10(4) Bq l(-1). The method was also found to be very robust (S(B) < 5 %) against the matrix effect from different urine samples. Performance of the rapid bioassay method for sensitivity, accuracy and repeatability evaluated against the performance criteria for radiobioassay (ANSI N13.30) was found to be in compliant. Considering the simplicity, excellent analytical figures of merit, fast sample turnaround time (<1 h) and cost efficiency (<30 USD per sample) of the developed method, it is very promising as a rapid bioassay method for supporting the medical response to an emergency where internal contamination of (90)Sr is involved. PMID- 20167797 TI - Computed tomography commissioning programmes: how to obtain a reliable MTF with an automatic approach? AB - The purpose of this study was to assess the spatial resolution of a computed tomography (CT) scanner with an automatic approach developed for routine quality controls when varying CT parameters. The methods available to assess the modulation transfer functions (MTF) with the automatic approach were Droege's and the bead point source (BPS) methods. These MTFs were compared with presampled ones obtained using Boone's method. The results show that Droege's method is not accurate in the low-frequency range, whereas the BPS method is highly sensitive to image noise. While both methods are well adapted to routine stability controls, it was shown that they are not able to provide absolute measurements. On the other hand, Boone's method, which is robust with respect to aliasing, more resilient to noise and provides absolute measurements, satisfies the commissioning requirements perfectly. Thus, Boone's method combined with a modified Catphan 600 phantom could be a good solution to assess CT spatial resolution in the different CT planes. PMID- 20167798 TI - Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents. AB - Protein tyrosine phosphatases are often exploited and subverted by pathogenic bacteria to cause human diseases. The tyrosine phosphatase mPTPB from Mycobacterium tuberculosis is an essential virulence factor that is secreted by the bacterium into the cytoplasm of macrophages, where it mediates mycobacterial survival in the host. Consequently, there is considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique antituberculosis (antiTB) agents. We uncovered that mPTPB subverts the innate immune responses by blocking the ERK1/2 and p38 mediated IL-6 production and promoting host cell survival by activating the Akt pathway. We identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity, from a combinatorial library of bidentate benzofuran salicylic acid derivatives assembled by click chemistry. We demonstrated that inhibition of mPTPB with I-A09 in macrophages reverses the altered host immune responses induced by the bacterial phosphatase and prevents TB growth in host cells. The results provide the necessary proof-of-principle data to support the notion that specific inhibitors of the mPTPB may serve as effective antiTB therapeutics. PMID- 20167800 TI - Some features of the spread of epidemics and information on a random graph. AB - Random graphs are useful models of social and technological networks. To date, most of the research in this area has concerned geometric properties of the graphs. Here we focus on processes taking place on the network. In particular we are interested in how their behavior on networks differs from that in homogeneously mixing populations or on regular lattices of the type commonly used in ecological models. PMID- 20167799 TI - DNA repair by the cryptic endonuclease activity of Mu transposase. AB - Phage Mu transposes by two distinct pathways depending on the specific stage of its life cycle. A common strand transfer intermediate is resolved differentially in the two pathways. During lytic growth, the intermediate is resolved by replication of Mu initiated within the flanking target DNA; during integration of infecting Mu, it is resolved without replication, by removal and repair of DNA from a previous host that is still attached to the ends of the incoming Mu genome. We have discovered that the cryptic endonuclease activity reported for the isolated C-terminal domain of the transposase MuA [Wu Z, Chaconas G (1995) A novel DNA binding and nuclease activity in domain III of Mu transposase: Evidence for a catalytic region involved in donor cleavage. EMBO J 14:3835-3843], which is not observed in the full-length protein or in the assembled transpososome in vitro, is required in vivo for removal of the attached host DNA or "5'flap" after the infecting Mu genome has integrated into the E. coli chromosome. Efficient flap removal also requires the host protein ClpX, which is known to interact with the C-terminus of MuA to remodel the transpososome for replication. We hypothesize that ClpX constitutes part of a highly regulated mechanism that unmasks the cryptic nuclease activity of MuA specifically in the repair pathway. PMID- 20167801 TI - Reptilian all the way? PMID- 20167802 TI - Cross-metathesis-based approaches to heteroaromatics: combining catalysts for furan formation. PMID- 20167804 TI - Viruses know more than one way to don a cap. PMID- 20167803 TI - Antitumor activity of an allosteric inhibitor of centromere-associated protein-E. AB - Centromere-associated protein-E (CENP-E) is a kinetochore-associated mitotic kinesin that is thought to function as the key receptor responsible for mitotic checkpoint signal transduction after interaction with spindle microtubules. We have identified GSK923295, an allosteric inhibitor of CENP-E kinesin motor ATPase activity, and mapped the inhibitor binding site to a region similar to that bound by loop-5 inhibitors of the kinesin KSP/Eg5. Unlike these KSP inhibitors, which block release of ADP and destabilize motor-microtubule interaction, GSK923295 inhibited release of inorganic phosphate and stabilized CENP-E motor domain interaction with microtubules. Inhibition of CENP-E motor activity in cultured cells and tumor xenografts caused failure of metaphase chromosome alignment and induced mitotic arrest, indicating that tight binding of CENP-E to microtubules is insufficient to satisfy the mitotic checkpoint. Consistent with genetic studies in mice suggesting that decreased CENP-E function can have a tumor suppressive effect, inhibition of CENP-E induced tumor cell apoptosis and tumor regression. PMID- 20167805 TI - Perceptron learning rule derived from spike-frequency adaptation and spike-time dependent plasticity. AB - It is widely believed that sensory and motor processing in the brain is based on simple computational primitives rooted in cellular and synaptic physiology. However, many gaps remain in our understanding of the connections between neural computations and biophysical properties of neurons. Here, we show that synaptic spike-time-dependent plasticity (STDP) combined with spike-frequency adaptation (SFA) in a single neuron together approximate the well-known perceptron learning rule. Our calculations and integrate-and-fire simulations reveal that delayed inputs to a neuron endowed with STDP and SFA precisely instruct neural responses to earlier arriving inputs. We demonstrate this mechanism on a developmental example of auditory map formation guided by visual inputs, as observed in the external nucleus of the inferior colliculus (ICX) of barn owls. The interplay of SFA and STDP in model ICX neurons precisely transfers the tuning curve from the visual modality onto the auditory modality, demonstrating a useful computation for multimodal and sensory-guided processing. PMID- 20167809 TI - Temozolomide and MGMT forever? PMID- 20167806 TI - mTORC1 activates SREBP-1c and uncouples lipogenesis from gluconeogenesis. PMID- 20167810 TI - Akt2 and Akt3 play a pivotal role in malignant gliomas. AB - Akt, one of the major downstream effectors of phosphatidylinositol 3-kinase, is hyper-expressed and activated in a variety of cancers including glioblastoma. However, the expression profiles of the Akt isoforms Akt1/PKBalpha, Akt2/PKBbeta, and Akt3/PKBgamma and their functional roles in malignant glioma are not well understood. Therefore, we examined the protein and mRNA expression patterns of Akt isoforms in tissues from human astrocytomas, glioblastomas, and non neoplastic regions. We also explored the biological role of each Akt isoform in malignant glioma cells using RNA interference-mediated knock-down and the over expression of plasmid DNA of each isoform. The expression of Akt1 protein and mRNA was similar in glioma and normal control tissues. Although the protein and mRNA level of Akt2 increased with the pathological grade of malignancy, the expression of Akt3 mRNA and protein decreased as the malignancy grade increased. In U87MG, T98G, and TGB cells, the down-regulation of Akt2 or Akt3 by RNA interference reduced the expression of the phosphorylated form of Bad, resulting in the induction of caspase-dependent apoptosis. Akt1 knock-down did not affect cell growth or survival. We first demonstrate that the over-expression of Akt2 or Akt3 down-regulated the expression of the other protein and that endogenous Akt3 protein showed high kinase activity in U87MG cells. Our data suggest that Akt2 and Akt3 play an important role in the viability of human malignant glioma cells. Targeting Akt2 and Akt3 may hold promise for the treatment of patients with gliomas. PMID- 20167811 TI - Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. AB - Patients with recurrent malignant glioma treated with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), alone or in combination with irinotecan have had impressive reductions in MRI contrast enhancement and vasogenic edema. Responses to this regimen, as defined by a decrease in contrast enhancement, have led to significant improvements in progression-free survival rates but not in overall survival duration. Some patients for whom this treatment regimen fails have an uncharacteristic pattern of tumor progression, which can be observed radiographically as an increase in hyperintensity on T2-weighted or fluid-attenuated inverse recovery (FLAIR) MRI. To date, there have been no reports of paired correlations between radiographic results and histopathologic findings describing the features of this aggressive tumor phenotype. In this study, we correlate such findings for 3 illustrative cases of gliomas that demonstrated an apparent phenotypic shift to a predominantly infiltrative pattern of tumor progression after treatment with bevacizumab. Pathologic examination of abnormal FLAIR areas on MRI revealed infiltrative tumor with areas of thin-walled blood vessels, suggesting vascular "normalization," which was uncharacteristically adjacent to regions of necrosis. High levels of insulin-like growth factor binding protein-2 and matrix metalloprotease-2 expression were seen within the infiltrating tumor. In an attempt to better understand this infiltrative phenotype associated with anti-VEGF therapy, we forced a highly angiogenic, noninvasive orthotopic U87 xenograft tumor to become infiltrative by treating the mice with bevacizumab. This model mimicked many of the histopathologic findings from the human cases and will augment the discovery of alternative or additive therapies to prevent this type of tumor recurrence in clinical practice. PMID- 20167812 TI - Differential proteome analysis of human gliomas stratified for loss of heterozygosity on chromosomal arms 1p and 19q. AB - Combined deletion of chromosomal arms 1p and 19q is an independent prognostic marker in patients with oligodendroglial brain tumors, including oligodendrogliomas and oligoastrocytomas. However, the relevant genes in these chromosome arms and the molecular mechanisms underlying the prognostic significance of 1p/19q deletion are yet unknown. We used two-dimensional difference gel electrophoresis followed by mass spectrometry to perform a proteome-wide profiling of low-grade oligoastrocytomas stratified for the presence or absence of 1p/19q deletions. Thereby, we identified 22 different proteins showing differential expression in tumors with or without combined deletions of 1p and 19q. Four of the differentially expressed proteins, which are vimentin, villin 2 (ezrin), annexin A1, and glial fibrillary acidic protein, were selected for further analysis. Lower relative expression levels of these proteins in 1p/19q-deleted gliomas were confirmed at the protein level by Western blot analysis and immunohistochemistry. Furthermore, sequencing of sodium bisulfite treated tumor DNA revealed more frequent methylation of 5'-CpG islands associated with the VIM and VIL2 genes in 1p/19q-deleted gliomas when compared with gliomas without these deletions. In summary, we confirm proteome-wide profiling as a powerful means to identify candidate biomarkers in gliomas. In addition, our data support the hypothesis that 1p/19q-deleted gliomas frequently show epigenetic down-regulation of multiple genes due to aberrant methylation of the 5'-CpG islands. PMID- 20167813 TI - Descriptive epidemiology of central nervous system germ cell tumors: nonpineal analysis. AB - Central nervous system (CNS) germ cell tumors (GCT) have not been epidemiologically well described. Our study describes 2 population-based series of nonpineal CNS GCT. Data on all primary (malignant and nonmalignant) CNS (ICD-O 3 sites: C70.0-C72.9, C75.1-C75.3) GCT diagnosed between 2000 and 2004 from the Central Brain Tumor Registry of the United States (CBTRUS) and on all malignant GCT diagnosed between 1992 and 2005 from the Surveillance, Epidemiology, and End Results (SEER) were analyzed. Of 234 nonpineal GCT in CBTRUS, the most common site was brain, NOS (31.6%). Males had a greater frequency (59.7%) than females (40.3%). However, by age group, the male-to-female incidence rate ratio (IRR) differed: children (0-14 years) had an IRR of 1.1, young adults (15-29 years) an IRR of 2.3, and adults (aged 30+) an IRR of 1.0. For children and young adults, most tumors were malignant (86.8% and 89.0%, respectively), whereas for adults, more than half were nonmalignant (56.8%). Germinoma was the most frequent diagnosis (61.5%). In SEER, the frequency of malignant GCT in the CNS (2.5%) was greater than that in the mediastinum (2.1%). Of 408 malignant CNS GCT, 216 (52.9%) were nonpineal. The male-to-female IRR was 1.5. Overall relative survival for nonpineal CNS malignant GCT was 85.3% at 2 years, 77.3% at 5 years, and 67.6% at 10 years. Previous studies of GCT that have not stratified by site have suggested greater gender disparity. Nonpineal CNS GCT show no significant gender preference, yet have outcomes similar to pineal GCT. PMID- 20167814 TI - Expression of synaptic vesicle protein 2A in epilepsy-associated brain tumors and in the peritumoral cortex. AB - Synaptic vesicle protein 2A (SV2A) has been identified as the binding site for the antiepileptic drug levetiracetam and is thought to decrease neuronal excitability. Since knockout of SV2A in mice leads to seizures, we hypothesized that a reduction in SV2A expression promotes seizure generation in epilepsy associated brain tumors. We compared the SV2A expression and distribution in surgically removed tumor tissue (n = 63) and peritumoral cortex (n = 31) of patients with glial and glioneuronal tumors to normal control cortex obtained at autopsy in nonbrain tumor patients (n = 6). Additionally, we compared the SV2A expression and distribution in tumor patients with epilepsy (n = 39) with SV2A expression in tumor patients without epilepsy (n = 24). Immunohistochemistry in control cortex demonstrated strong and diffuse SV2A immunoreactivity (IR) throughout all cortical layers. Similar strong SV2A IR (with the same diffuse distribution pattern) was observed in the peritumoral cortical specimens in both patients with and without epilepsy. Modest SV2A IR was observed within the tumor area. The SV2A-positive cells detected within the tumor area were mainly entrapped neurons. Oligodendrogliomas and glioneuronal tumors displayed variable SV2A neuropil staining. In ganglioglioma (GG), strong SV2A IR was present along the dysplastic neuronal cell borders and processes. In both GG and dysembryoplastic neuroepithelial tumors, SV2A IR was occasionally observed within the neuronal perikarya. We found no differences in SV2A expression in the peritumoral cortex between the patients with and without epilepsy, which suggests that the role of SV2A in epileptogenesis in patients with glial tumors is questionable. The distinct pattern of SV2A IR in glioneuronal tumors suggests a redistribution of SV2A. PMID- 20167815 TI - Six-month progression-free survival as an alternative primary efficacy endpoint to overall survival in newly diagnosed glioblastoma patients receiving temozolomide. AB - We assessed six-month progression-free survival (PFS) as an alternative primary efficacy endpoint to overall survival in newly diagnosed glioblastoma multiforme (GBM) patients receiving temozolomide (TMZ). A total of 183 patients with newly diagnosed GBM enrolled in 3 phase II protocols at the University of California San Francisco were included. Patients were treated with interventions based on the Stupp regimen, each with the added component of a second oral agent given concurrently with radiotherapy and TMZ, followed by its coadministration with adjuvant TMZ. We examined whether progression status at 2, 4, and 6 months predicted subsequent survival using the landmark analysis. The hazard ratios of death as a function of progression status were estimated based on the Cox proportional hazards model after adjustment for putative prognostic factors. Progression status at 2, 4, and 6 months were all consistently found to be strong predictors of subsequent survival in all studies. The study-specific hazard ratios associated with progression status at 6 months ranged from 2.03 to 3.39. The hazard ratios associated with the earlier time points (2- and 4-month progression) all exceeded 2 in magnitude, ranging from 2.29 to 4.73. P-values were statistically significant for all time points. In this report, we demonstrated a strong association between the endpoints of PFS at 2, 4, and 6 months and survival. Patients who showed the signs of early progression were at significantly higher risk of earlier death. Our analysis suggests that 6-month PFS may be an appropriate primary endpoint in the context of phase II upfront GBM trials in the TMZ era. PMID- 20167816 TI - O(6)-methylguanine DNA-methyltransferase methylation status can change between first surgery for newly diagnosed glioblastoma and second surgery for recurrence: clinical implications. AB - O(6)-methylguanine DNA-methyltransferase (MGMT) promoter methylation status is a prognostic factor in newly diagnosed glioblastoma patients. However, it is not yet clear whether, and if so how, MGMT methylation status may change. Moreover, it is unknown whether the prognostic role of this epigenetic feature is retained during the disease course. A retrospective analysis was made using a database of 614 glioblastoma patients treated prospectively from January 2000 to August 2008. We evaluated only patients who met the following inclusion criteria: age > or = 18 years; performance status 0-2; histological diagnosis of glioblastoma at both first and second surgery for recurrence; postoperative treatment consisting of: (i) radiotherapy (RT) followed by adjuvant temozolomide (TMZ) until 2005 and (ii) TMZ concurrent with and adjuvant to RT after 2005; a time interval > or = 3 months between first and second surgery. MGMT status was evaluated at first and second surgery in all 44 patients (M:F 32:12, median age: 49 years, range: 27-67 years). In 38 patients (86.4%), MGMT promoter status was assessable at both first and second surgery. MGMT methylation status, changed in 14 patients (37%) of second surgery samples and more frequently in methylated than in unmethylated patients (61.5% vs 24%, P = .03). The median survival was significantly influenced only by MGMT methylation status determined at first surgery (P = .04). Significant changes in MGMT methylation status during the course of GBM occur more frequently in MGMT methylated than unmethylated cases. MGMT methylation status determined at first surgery appears to be of prognostic value; however, it is not predictive of outcome following second surgery. PMID- 20167817 TI - Phase II trial of low-dose continuous (metronomic) treatment of temozolomide for recurrent glioblastoma. AB - The prognosis for patients with recurrent glioblastomas (GBMs) is dismal, with a median survival of 3-6 months. We performed a phase II trial of low-dose continuous (metronomic) treatment using temozolomide (TMZ) for recurrent GBMs. TMZ-refractory patients with GBM who experienced disease recurrence or progression during or after the cyclic treatment schedule of TMZ after surgery and standard radiotherapy were eligible. This phase II trial included 2 cohorts of patients. The initial cohort, comprising 10 patients, received TMZ at 40 mg/m(2) everyday. After this regimen seemed safe and effective, the metronomic schedule was changed to 50 mg/m(2) everyday. The second cohort, comprising 28 patients, received TMZ at 50 mg/m(2) everyday. The 6-month progression-free survival in all 38 patients was 32.5% (95% CI: 29.3%-35.8%) and the 6-month overall survival was 56.0% (95% CI: 36.2%-75.8%). One patient developed a grade III neutropenia, grade II thrombocytopenia in 3 patients, and grade II increase of liver enzyme (GOT/GPT) in 3 patients. Of all patients included in this study, 4 patients were withdrawn from this study because of side effects including sustained hematological disorders, cryptococcal infection, and cellulitis. In a response group, quality of life measured with short form-36 was well preserved, when compared with the pretreatment status. Metronomic treatment of TMZ is an effective treatment for recurrent GBM that is even refractory to conventional treatment of TMZ and has acceptable toxicity. PMID- 20167818 TI - High-dose carboplatin, thiotepa, and etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma. AB - Recurrent medulloblastoma is highly lethal in previously irradiated patients. Previously irradiated patients with M-0-M-3 recurrences who achieved a minimal disease state prior to protocol enrollment received carboplatin (Calvert formula with area under the curve = 7 mg/mL min, maximum 500 mg/m(2)/day) on days -8 to 6, and thiotepa (300 mg/m(2)/day) and etoposide (250 mg/m(2)/day) on days -5 to 3, followed by autologous stem cell rescue (ASCR) on day 0. Twenty-five patients, aged 7.6-44.7 years (median 13.8 years) at ASCR, were treated. Three (12%) died of treatment-related toxicities within 30 days of ASCR, due to multiorgan system failure (n = 2) and aspergillus infection with veno-occlusive disease (n = 1). Tumor recurred in 16 at a median of 8.5 months (range 2.3-58.5 months). Six are event-free survivors at a median of 151.2 months post-ASCR (range 127.2-201.6 months). The Kaplan-Meier estimate of median overall survival is 26.8 months (95% CI: 11.9-51.1 months) and of event-free survival (EFS) and overall survival are both 24% (95% CI: 9.8%-41.7%) at 10 years post-ASCR. M-0 (vs M-1 + ) recurrence prior to protocol, lack of tissue confirmation of relapse, and initial therapy of radiation therapy (RT) alone (vs RT + chemotherapy) were not significantly associated with better EFS (P = .33, .34, and .27, respectively). Trends toward better EFS were noted in patients (n = 5) who received additional RT as part of their retrieval therapy (P = .07) and whose recurrent disease was demonstrated to be sensitive to reinduction chemotherapy (P = .09). This retrieval strategy provides long-term EFS for some patients with previously irradiated recurrent medulloblastoma. The use of additional RT may be associated with better outcome. PMID- 20167819 TI - Small molecule kinase inhibitors in glioblastoma: a systematic review of clinical studies. AB - The efficacy of small-molecule kinase inhibitors has recently changed standard clinical practice for several solid cancers. Glioblastoma is a solid cancer that universally recurs and unrelentingly results in death despite maximal surgery and radiotherapy with concomitant and adjuvant temozolomide. Several clinical studies using kinase inhibitors in glioblastoma have been reported. The present study systematically reviews the efficacy, toxicity, and tissue analysis of small molecule kinase inhibitors in adult patients with glioblastoma as reported in published clinical studies and determines which kinases have been targeted by the inhibitors used in these studies. Publications were retrieved using a MEDLINE search and by screening meeting abstracts. A total of 60 studies qualified for inclusion, of which 25 were original reports. A total of 2385 glioblastoma patients receiving kinase inhibitors could be evaluated. The study designs included 2 phase III studies and 37 phase II studies. Extracted data included radiological response, progression-free survival, overall survival, toxicity, and biomarker analysis. The main findings were that (i) efficacy of small-molecule kinase inhibitors in clinical studies with glioblastoma patients does not yet warrant a change in standard clinical practice and (ii) 6 main kinase targets for inhibitors have been evaluated in these studies: EGFR, mTOR, KDR, FLT1, PKCbeta, and PDGFR. PMID- 20167821 TI - The Bournewood gap (as amended?). PMID- 20167822 TI - Vulnerable adults, mental capacity and social care refusal. PMID- 20167823 TI - Implementing the Nairobi Call to Action: Africa's opportunity to light the way. PMID- 20167824 TI - An ecological approach to health promotion in remote Australian Aboriginal communities. AB - Poor environmental conditions and poor child health in remote Australian Aboriginal communities are a symptom of a disjuncture in the cultures of a disadvantaged (and only relatively recently enfranchised) minority population and a proportionally large, wealthy dominant immigrant population, problematic social policies and the legacy of colonialism. Developing effective health promotion interventions in this environment is a challenge. Taking an ecological approach, the objective of this study was to identify the key social, economic, cultural and environmental factors that contribute to poor hygiene in remote Aboriginal communities, and to determine approaches that will improve hygiene and reduce the burden of infection among children. The methods included a mix of quantitative and qualitative community-based studies and literature reviews. Study findings showed that a combination of crowding, non-functioning health hardware and poor standards of personal and domestic hygiene underlie the high burden of infection experienced by children. Also, models of health promotion drawn from developed and developing countries can be adapted for use in remote Australian Aboriginal community contexts. High levels of disadvantage in relation to social determinants of health underlie the problem of poor environmental conditions and poor child health in remote Australian Aboriginal communities. Measures need to be taken to address the immediate problems that impact on children's health-for example, by ensuring the availability of functional and adequate water and sanitation facilities-but these interventions are unlikely to have a major effect unless the underlying issues are also addressed. PMID- 20167825 TI - Healthy universities--time for action: a qualitative research study exploring the potential for a national programme. AB - Despite the absence of national or international steers, there is within England growing interest in the Healthy University approach. This article introduces Healthy Universities; reports on a qualitative study exploring the potential for a national programme contributing to health, well-being and sustainable development; and concludes with reflections and recommendations. The study used questionnaires and interviews with key informants from English higher education institutions and national stakeholder organizations. The findings confirmed that higher education offers significant potential to impact positively on the health and well-being of students, staff and wider communities through education, research, knowledge exchange and institutional practice. There was strong support for extending the healthy settings approach beyond schools and further education, through a National Healthy Higher Education Programme that provides a whole system Healthy University Framework. Informants argued that although there are important public health drivers, it will also be necessary to show how a Healthy Universities can help achieve core business objectives and contribute to related agendas such as sustainability. Two models were discussed: an accreditation scheme with externally assessed standardized achievement criteria; and a flexible and light-touch framework focusing on change-related processes and utilizing self assessment. While highlighting the appeal of league tables, many informants feared that a top-down approach could backfire, generating resistance and resulting in minimal compliance. In contrast, the majority felt that a process focused aspirational model would be more likely to win hearts and minds and facilitate system-level change. Key recommendations relate to national programme development, research and evaluation and international collaboration and networking. PMID- 20167826 TI - Building capacity through the Internet: lessons learnt from the Reviews of Health Promotion & Education Online. AB - From 2000 to 2008, the International Union for Health Promotion and Health Education transformed the Internet Journal of Health Promotion it had inherited into an innovative electronic multilingual capacity building experiment, the Reviews of Health Promotion & Education Online . Using a variety of sources (content analysis of the papers, site consultation statistics, users' survey), this paper analyzes reflexively the strengths and weaknesses of this experiment that was replaced in October 2009 by an Internet forum: Views on Health Promotion Online . PMID- 20167827 TI - Prioritizing policy interventions to improve diets? Will it work, can it happen, will it do harm? AB - Policies from non-health sectors have considerable impacts on the food environment and in turn on population nutrition. Health impact assessment (HIA) methods have been developed to identify the potential health effects of non health policies; however, they are underused both within and outside the health sector. HIA and other assessment methods and tools can be used more extensively in health promotion to assist with the identification of the best policy options to pursue to improve and protect health. A participatory process is presented in this paper which combines HIAs with feasibility and effectiveness assessments. The intention is to enable health promoters to more accurately identify which policy change options would be most likely to improve diets, considering both impact and likelihood of implementation. The process was successfully used in Fiji and Tonga and provided a more systematic way of understanding which policy interventions showed the most promise. PMID- 20167828 TI - Multiple streams theory in Sweden: an error III. PMID- 20167832 TI - Psychosocial concerns in patients with advanced cancer: an observational study at regional cancer centre, India. AB - INTRODUCTION: The diagnosis and treatment of cancer is associated with substantial physical, psychological, and social morbidity. The objective of this study was to identify the prevalence of psychosocial concerns in the patients with advanced cancer admitted to our institute. MATERIALS AND METHODS: A total of 100 patients admitted to the inpatient palliative care unit of our institute were enrolled in this study. A descriptive questionnaire that dealt with the patient's psychological acceptance of the disease and emotional distress that accompanies the diagnosis was prepared. Patient's social and spiritual needs were addressed, and the future concerns that the patient is preoccupied with were discussed on a one-on-one basis with the patient himself or herself. RESULTS: It was found that a majority of patients, though aware of their diagnosis, were not aware of the disease prognosis. There was a generalized anxiety regarding the treatment of the disease and fear of suffering. Most patients preferred to keep the revelation of the diagnosis to those close to them and not reveal it publicly. Financial drain out of resources was a major concern. Future concerns about their own fitness, the settlement of their children, and the family's well-being were seen commonly in almost all the patients. CONCLUSIONS: Attention to psychosocial and spiritual health needs of patients with cancer is an integral part of an effective palliation, though they are less commonly expressed but are strongly felt by patients with cancer. It is therefore recommended that all clinicians and health care providers should address psychosocial health needs as a part of their routine practice. PMID- 20167833 TI - Reliability and validity of the Euthanasia Attitude Scale (EAS) for Hong Kong medical doctors. AB - This study aimed to examine the reliability and validity of the Euthanasia Attitude Scale (EAS) in Hong Kong medical doctors. A total of 107 medical doctors (61.7% men) participated in a survey at clinical settings in 2008. The 21-item EAS was used to assess their attitudes toward euthanasia. The mean (standard deviation) and median of the EAS were 63.60 (60.31) and 63.00. Total EAS scores correlated well with ''Ethical Considerations,'' ''Practical Considerations,'' and ''Treasuring Life'' (Spearman rho =.37-.96, P < .001) but not ''Naturalistic Beliefs.'' The construct validity of the 3-factor model was appropriate (Kaiser Meyer-Olkin [KMO] value = 0.90) and showed high internal consistency (Cronbach alpha =.79-.92). Euthanasia Attitude Scale may be a reliable and valid measure for assessing the attitudes toward euthanasia in medical professionals. PMID- 20167834 TI - Implementing evidence-based practices: considerations for the hospice setting. AB - With increased regulation and scrutiny of outcomes, hospice programs are being challenged to consider the implementation of evidence-based practices (EBPs). This study reports findings from hospice director interviews and staff focus groups, which occurred following the completion of a multifaceted translating research into practice (TRIP) intervention designed to promote evidence-based pain management practices. The purpose of this article is to provide background on the use of EBPs, to report facilitators and barriers to overall implementation of pain management EBPs in hospice, and to provide recommendations for hospices interested in increasing the use of EBPs. Three areas for evaluation prior to implementing an EBP initiative in hospices were identified: community, agency, and staff cultures. Recommendations for implementation of EBPs in hospices are provided. PMID- 20167835 TI - Dementia, goals of care, and personhood: a study of surrogate decision makers' beliefs and values. AB - Surrogate decision makers for persons with advanced dementia play a key role in making decisions about medical treatments for their loved ones. We conducted in depth interviews of 20 surrogates to examine their goals of care preferences and beliefs about personhood. All surrogates believed the goal of comfort was important, and 30.0% believed that curing physical problems was important. Significant proportions of surrogates acknowledged dementia-related changes in patients' ability to reason, communicate, and relate to others. Qualitative findings demonstrated diverse beliefs regarding the impact of dementia on factors related to personhood, for example, dignity, respect from others, and having a life worth living. In conclusion, the surrogates we interviewed expressed diverse preferences regarding goals of care and diverse assessments about the impact of dementia on personhood. PMID- 20167836 TI - A palliative care approach in treating patients with sickle cell disease using exchange transfusion. AB - The authors present a case report of an adult patient with sickle cell disease (SCD), who required frequent hospitalizations for sickle cell vaso-occlusive painful crisis as well as management of complications that resulted from treatment. The patient demonstrated clinical improvement after initiating palliative exchange transfusions of packed red blood cells (PRBCs) once every 4 weeks. They also promptly addressed their physical and psychosocial issues of care. The author described that because the patient was started on chronic exchange transfusions, there was a significant decrease in hospitalizations and emergency department (ED) visits. They saw a major improvement in the quality of life of this patient. The review of medical literature did not reveal any clear cut guidelines for palliative chronic exchange transfusion for painful vaso occlusive crisis in adult patients. This case review highlights the usefulness of this palliative model of care. The burden and benefits of chronic exchange transfusion always need to be weighed carefully. PMID- 20167837 TI - Principles of wound care in hospice and palliative medicine. AB - The author presents a case report of an elderly patient who was extremely frail and debilitated. The patient was a resident of a skilled care facility because of advanced chronic illnesses that included end-stage Alzheimer, dementia, and Parkinson disease. This patient had acquired multiple stages III to IV pressure ulcers. Aggressive wound care treatment was initiated with partial success, but the patient passed away before the wound could completely heal. Medical literature was reviewed to offer the best possible wound care approach in providing care to patients who are terminally ill without compromising the patient's dignity and comfort and at the same time delivering cost-effective quality care. PMID- 20167838 TI - Where do Egyptian palliative care patients with cancer die? AB - This report describes the death place of patients with advanced cancer referred to an Egyptian palliative care program over 1 year. Of 79 patients included, 73% died at home and 27% in hospital or ambulance. Patients who were visited by a palliative care physician at home were significantly more likely to die at home compared to those who did not (92% vs 64%, P = .008). The palliative care survival of those who died at home was significantly longer than those who died in hospital or ambulance (63 vs 39 days, P = .04). These results demonstrate the need for the integration of effective home care model in evolving Egyptian palliative care programs and suggest that physician home visits and earlier referral to palliative care help patients die at home. PMID- 20167839 TI - Prognostic factors in chemotherapy-treated patients with HIV-associated Plasmablastic lymphoma. AB - BACKGROUND: Plasmablastic lymphoma (PBL) is a variant of diffuse large B-cell lymphoma commonly seen in the oral cavity of HIV-infected individuals. PBL has a poor prognosis, but prognostic factors in patients who have received chemotherapy have not been adequately evaluated. METHODS: An extensive literature search rendered 248 cases of PBL, from which 157 were HIV(+). Seventy cases with HIV associated PBL that received chemotherapy were identified. Whenever possible, authors of the original reports were contacted to complete clinicopathological data. Univariate analyses were performed calculating Kaplan-Meier estimates and compared using the log-rank test. RESULTS: The mean age was 39 years, with a male predominance. The mean CD4(+) count was 165 cells/mm(3). Advanced clinical stage was seen in 51% and extraoral involvement was seen in 43% of the cases. The expression levels of CD20 and Epstein-Barr virus-encoded RNA were 13% and 86%, respectively. The overall survival duration was 14 months. In a univariate analysis, early clinical stage and a complete response to chemotherapy were associated with longer survival. There was no apparent difference in survival with regimens more intensive than cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). CONCLUSIONS: Patients with HIV-associated PBL have a poor prognosis. Prognosis is strongly associated with achieving a complete clinical response to CHOP or CHOP-like chemotherapy. The role of more intensive regimens is currently unclear. Further research is needed to improve responses using novel therapeutic agents and strategies. PMID- 20167840 TI - GLP-2 receptor agonism ameliorates inflammation and gastrointestinal stasis in murine postoperative ileus. AB - Glucagon-like peptide 2 (GLP-2) is a pleiotropic intestinotrophic hormone that we hypothesized could lessen gastrointestinal inflammation associated with postoperative ileus (POI). To test this idea, the prophylactic timing and dose of a long-acting variant of human GLP-2 linked to the Fc portion of murine immunoglobulin G (IgG) (GLP-2/IgG) was optimized in a murine model of POI. Surgically treated mice received a single dose of GLP-2/IgG, IgG isotype control, or phosphate-buffered saline 1 to 48 h before small bowel surgical manipulation. The distribution of orally fed fluorescein isothiocyanate-dextran and histological analyses of myeloperoxidase-positive immune cells were determined 24 and 48 h postoperatively. TaqMan quantitative polymerase chain reaction was used to determine early changes in mRNA expression in the muscularis or mucosa. In normal mice, prolonged exposure to GLP-2 increased upper gastrointestinal (GI) transit and mucosal weight. When administered 1 or 3 h before surgery, GLP-2/IgG reduced the leukocyte infiltrate 24 and 48 h postoperatively and improved GI transit 48 h postoperatively. Surgical manipulation rapidly increased gene expression of proinflammatory cytokines and enzymes for kinetically active mediators in the mucosa and muscularis. GLP-2/IgG2a affected the expression of genes associated with mucosal inflammation and barrier function. We conclude that prophylactic treatment with a long-acting GLP-2 agonist ameliorates inflammation and improves intestinal dysmotility associated with surgical manipulation of the bowel. The action of GLP-2 is consistent with a lessening of inflammation, leading to a more rapid recovery. PMID- 20167841 TI - Trimetazidine, administered at the onset of reperfusion, ameliorates myocardial dysfunction and injury by activation of p38 mitogen-activated protein kinase and Akt signaling. AB - Trimetazidine [1-(2,3,4-trimethoxybenzyl)piperazine; TMZ] is an anti-ischemic cardiac drug; however, its efficacy and mechanism of cardioprotection upon reperfusion are largely unknown. The objective of this study was to determine whether TMZ, given before reperfusion, could attenuate myocardial reperfusion injury. Ischemia/reperfusion (I/R) was induced in rat hearts by ligating the left anterior descending (LAD) coronary artery for 30 min followed by 48 h of reperfusion. TMZ (5 mg/kg b.wt.) was administered 5 min before reperfusion. The study used three experimental groups: control (-I/R; -TMZ), I/R (+I/R; -TMZ), and TMZ (+I/R; +TMZ). Echocardiography and EPR oximetry were used to assess cardiac function and oxygenation, respectively. The ejection fraction, which was significantly depressed in the I/R group (62 +/- 5 versus 84 +/- 3% in control), was restored to 72 +/- 3% in the TMZ group. Myocardial pO2 in the TMZ group returned to baseline levels (approximately 20 mm Hg) within 1 h of reperfusion, whereas the I/R group showed a significant hyperoxygenation even after 48 h of reperfusion. The infarct size was significantly reduced in the TMZ group (26 +/- 3 versus 47 +/- 5% in I/R). TMZ treatment significantly attenuated superoxide levels in the tissue. Tissue homogenates showed a significant increase in p38 and p-Akt and decrease in caspase-3 levels in the TMZ group. In summary, the results demonstrated that TMZ is cardioprotective when administered before reperfusion and that this protection appears to be mediated by activation of p38 mitogen activated protein kinase and Akt signaling. The study emphasizes the importance of administering TMZ before reflow to prevent reperfusion-mediated cardiac injury and dysfunction. PMID- 20167842 TI - Nitric-oxide synthase mediates the ability of darbepoetin alfa to attenuate pre existing spatial working memory deficits in rats subjected to transient global ischemia. AB - Erythropoietin has been reported to improve the behavioral performance of healthy mice in tests thought to depend on synaptic plasticity in the CA1 region of the hippocampus. We show here for the first time that a single injection of the erythropoietin analog darbepoetin alfa reverses pre-existing cognitive deficits in adult rats that had been subjected to transient global ischemia produced by four-vessel occlusion (4-VO). Quantification of neuronal density demonstrated that 12 min of 4-VO selectively killed more than 90% of CA1 neurons in the dorsal hippocampus. Rats that had sustained a bilateral loss of hippocampal CA1 neurons in this range (4-VO rats) displayed more errors and longer escape latencies in the Barnes maze compared with sham-operated controls. A single injection of darbepoetin alfa (5000 U/kg i.p.) 4 h before behavioral testing decreased deficits in escape latency for 4-VO rats but not sham-operated controls. This improvement in spatial working memory performance was correlated with increased levels of nitric-oxide metabolites in the ventral hippocampus. Systemic administration of the nitric-oxide synthase inhibitor N(G)-nitro-L-nitro-arginine methyl ester reversed the increase in nitric-oxide metabolites and improvements in spatial working memory produced by darbepoetin alfa (5000 U/kg, i.p.) at a dose (10 mg/kg, i.p.) that did not impair the spatial working memory performance of intact rats. Taken together, these findings suggest that darbepoetin alfa reverses pre-existing spatial working memory deficits resulting from transient global ischemia by increasing the activity of nitric-oxide synthase, an enzyme implicated in synaptic plasticity. PMID- 20167843 TI - Pharmacological targeting of the mitochondrial phosphatase PTPMT1. AB - The dual-specificity protein tyrosine phosphatases (PTPs) play integral roles in the regulation of cell signaling. There is a need for new tools to study these phosphatases, and the identification of inhibitors potentially affords not only new means for their study, but also possible therapeutics for the treatment of diseases caused by their dysregulation. However, the identification of selective inhibitors of the protein phosphatases has proven somewhat difficult. PTP localized to mitochondrion 1 (PTPMT1) is a recently discovered dual-specificity phosphatase that has been implicated in the regulation of insulin secretion. Screening of a commercially available small-molecule library yielded alexidine dihydrochloride, a dibiguanide compound, as an effective and selective inhibitor of PTPMT1 with an in vitro concentration that inhibits response by 50% of 1.08 microM. A related dibiguanide analog, chlorhexidine dihydrochloride, also significantly inhibited PTPMT1, albeit with lower potency, while a monobiguanide analog showed very weak inhibition. Treatment of isolated rat pancreatic islets with alexidine dihydrochloride resulted in a dose-dependent increase in insulin secretion, whereas treatment of a pancreatic beta-cell line with the drug affected the phosphorylation of mitochondrial proteins in a manner similar to genetic inhibition of PTPMT1. Furthermore, knockdown of PTPMT1 in rat islets rendered them insensitive to alexidine dihydrochloride treatment, providing evidence for mechanism-based activity of the inhibitor. Taken together, these studies establish alexidine dihydrochloride as an effective inhibitor of PTPMT1, both in vitro and in cells, and support the notion that PTPMT1 could serve as a pharmacological target in the treatment of type II diabetes. PMID- 20167844 TI - Venous thromboembolism and risk of idiopathic interstitial pneumonia: a nationwide study. AB - RATIONALE: Idiopathic interstitial pneumonia is characterized by pulmonary fibrosis and high mortality. OBJECTIVES: We examined the association between ever diagnosed venous thromboembolism and risk of incident idiopathic interstitial pneumonia. Venous thromboembolism was taken as a proxy for a procoagulant state in an individual. METHODS: We conducted a study of the entire Danish population from 1980 through 2007, comprising 7.4 million individuals. Incident idiopathic interstitial pneumonia, ever-diagnosed venous thromboembolism, and use of prescription anticoagulants were drawn from national Danish registries. MEASUREMENTS AND MAIN RESULTS: Age-standardized incidence rates per 10,000 person years for idiopathic interstitial pneumonia were higher among those ever diagnosed with venous thromboembolism (1.8; n = 158,676), pulmonary embolism (2.8; n = 70,586), and deep venous thrombosis only (1.2; n = 88,090), than among control subjects (0.8; n = 7,260,278). Multivariate-adjusted hazard ratios for idiopathic interstitial pneumonia were 1.8 (95% confidence interval [CI], 1.7 1.9) in those ever diagnosed with venous thromboembolism, 2.4 (95% CI, 2.3-2.6) in those ever diagnosed with pulmonary embolism, and 1.3 (95% CI, 1.2-1.4) in those ever diagnosed with deep venous thrombosis only, compared with control subjects. Corresponding hazard ratios in those ever diagnosed with venous thromboembolism stratified in those ever and never treated with anticoagulants were 1.4 (95% CI, 1.2-1.6) and 2.8 (95% CI, 2.4-3.1) (venous thromboembolism x anticoagulation use interaction on idiopathic interstitial pneumonia outcome: P = 1.5 x 10(-10)). CONCLUSIONS: In the general population, ever-diagnosed venous thromboembolism was associated with idiopathic interstitial pneumonia, particularly among those never treated with anticoagulants. PMID- 20167845 TI - Cytomegalovirus pneumonitis is a risk for bronchiolitis obliterans syndrome in lung transplantation. AB - RATIONALE: Cytomegalovirus pneumonitis is one of the most prevalent opportunistic infections after lung transplantation. Early studies reported that cytomegalovirus pneumonitis was a risk factor for chronic allograft dysfunction. More recently, in the era of routine prophylaxis and ganciclovir treatment, the adverse impact of treated cytomegalovirus pneumonitis on bronchiolitis obliterans syndrome has been challenged. OBJECTIVES: We hypothesized that cytomegalovirus pneumonitis contributes to adverse outcomes in the current antiviral era. We sought to define the impact of treated cytomegalovirus pneumonitis on bronchiolitis obliterans syndrome and survival in a large single-center cohort (n = 231) of consecutive patients undergoing lung transplantation from 2000 to 2004, all receiving short-course ganciclovir prophylaxis. METHODS: Transbronchial biopsies were performed at defined intervals with prospective cytomegalovirus immunostaining on every biopsy (n = 1,887). Cox proportional hazards models were used to assess the relationship between treated cytomegalovirus pneumonitis and clinical outcomes. MEASUREMENTS AND MAIN RESULTS: Forty-nine (21%) recipients developed cytomegalovirus pneumonitis a median of 106 days after transplantation. Treated cytomegalovirus pneumonitis within the first 6 months after transplantation significantly increased the risk for bronchiolitis obliterans syndrome (P = 0.001; hazard ratio, 2.19; 95% confidence interval, 1.36-3.51) and post-transplantation death (P = 0.02; hazard ratio, 1.89; 95% confidence interval, 1.11-3.23). This risk persisted when cytomegalovirus pneumonitis was considered as a time-dependent predictor as well as in multivariable models controlling for other risk factors. CONCLUSIONS: Cytomegalovirus pneumonitis affects more than 20% of lung transplant recipients. Despite treatment, it increases the risk for bronchiolitis obliterans syndrome and death. More effective preventive strategies for cytomegalovirus pneumonitis are needed to improve long-term outcomes after lung transplantation. PMID- 20167846 TI - Screening for lymphangioleiomyomatosis by high-resolution computed tomography in young, nonsmoking women presenting with spontaneous pneumothorax is cost effective. AB - RATIONALE: Women with pulmonary lymphangioleiomyomatosis (LAM) who present with a sentinel spontaneous pneumothorax (SPTX) will experience an average of 2.5 additional pneumothoraces. The diagnosis of LAM is typically delayed until after the second pneumothorax. OBJECTIVES: We hypothesized that targeted screening of an LAM-enriched population of nonsmoking women between the ages of 25 and 54 years, who present with a sentinel pneumothorax indicated by high-resolution computed tomography (HRCT), will facilitate early identification, definitive therapy, and improved quality of life for patients with LAM. METHODS: We constructed a Markov state-transition model to assess the cost-effectiveness of screening. Rates of SPTX and prevalence of LAM in populations stratified by age, sex, and smoking status were derived from the literature. Costs of testing and treatment were extracted from 2007 Medicare data. We compared a strategy based on HRCT screening followed by pleurodesis for patients with LAM, versus no HRCT screening. MEASUREMENTS AND MAIN RESULTS: The prevalence of LAM in nonsmoking women, between the ages of 25 and 54 years, with SPTX is estimated at 5% on the basis of the available literature. In our base case analysis, screening for LAM by HRCT is the most cost-effective strategy, with a marginal cost-effectiveness ratio of $32,980 per quality-adjusted life-year gained. Sensitivity analysis showed that HRCT screening remains cost-effective for groups in which the prevalence of LAM in the population subset screened is greater than 2.5%. CONCLUSIONS: Screening for LAM by HRCT in nonsmoking women age 25-54 that present with SPTX is cost-effective. Physicians are advised to screen for LAM by HRCT in this population. PMID- 20167848 TI - Consolidative dendritic cell-based immunotherapy elicits cytotoxicity against malignant mesothelioma. AB - RATIONALE: We previously demonstrated that dendritic cell-based immunotherapy induced protective antitumor immunity with a prolonged survival rate in mice. However, the clinical relevance is still in question. To examine this, we designed a clinical trial using chemotherapy followed by antigen-pulsed dendritic cell vaccination in mesothelioma patients. OBJECTIVES: The aim of this study was to assess the safety and immunological response induced by the administration of tumor lysate-pulsed dendritic cells in patients with mesothelioma. METHODS: Ten patients with malignant pleural mesothelioma received three vaccinations of clinical-grade autologous dendritic cells intradermally and intravenously at 2 week intervals after chemotherapy. Each vaccine was composed of 50 x 10(6) mature dendritic cells pulsed with autologous tumor lysate and keyhole limpet hemocyanin (KLH) as surrogate marker. Delayed-type hypersensitivity activity to tumor antigens and KLH was assessed, both in vivo and in vitro. Peripheral blood mononuclear cells during the treatment were analyzed for immunological responses. MEASUREMENTS AND MAIN RESULTS: Administration of dendritic cells pulsed with autologous tumor lysate in patients with mesothelioma was safe with moderate fever as the only side effect. There were no grade 3 or 4 toxicities associated with the vaccines or any evidence of autoimmunity. Local accumulations of infiltrating T cells were found at the site of vaccination. The vaccinations induced distinct immunological responses to KLH, both in vitro and in vivo. Importantly, after three vaccinations, cytotoxic activity against autologous tumor cells was detected in a subgroup of patients. CONCLUSIONS: This study demonstrated that autologous tumor lysate-pulsed dendritic cell-based therapy is feasible, well-tolerated, and capable of inducing immunological response to tumor cells in mesothelioma patients. Clinical trial registered with www.clinicaltrials.gov (NCT00280982). PMID- 20167847 TI - The novel tuberculosis vaccine, AERAS-402, induces robust and polyfunctional CD4+ and CD8+ T cells in adults. AB - RATIONALE: AERAS-402 is a novel tuberculosis vaccine designed to boost immunity primed by bacillus Calmette-Guerin (BCG), the only licensed vaccine. OBJECTIVES: We investigated the safety and immunogenicity of AERAS-402 in healthy Mycobacterium tuberculosis-uninfected BCG-vaccinated adults from a tuberculosis endemic region of South Africa. METHODS: Escalating doses of AERAS-402 vaccine were administered intramuscularly to each of three groups of healthy South African BCG-vaccinated adults, and a fourth group received two injections of the maximal dose. Participants were monitored for 6 months, with all adverse effects documented. Vaccine-induced CD4(+) and CD8(+) T-cell immunity was characterized by an intracellular cytokine staining assay of whole blood and peripheral blood mononuclear cells. MEASUREMENTS AND MAIN RESULTS: AERAS-402 was well tolerated, and no vaccine-related serious adverse events were recorded. The vaccine induced a robust CD4(+) T-cell response dominated by cells coexpressing IFN-gamma, tumor necrosis factor-alpha, and IL-2 ("polyfunctional" cells). AERAS-402 also induced a potent CD8(+) T-cell response, characterized by cells expressing IFN-gamma and/or tumor necrosis factor-alpha, which persisted for the duration of the study. CONCLUSIONS: Vaccination with AERAS-402 is safe and immunogenic in healthy adults. The immunity induced by the vaccine appears promising: polyfunctional T cells are thought to be important for protection against intracellular pathogens such as Mycobacterium tuberculosis, and evidence is accumulating that CD8(+) T cells are also important. AERAS-402 induced a robust and durable CD8(+) T-cell response, which appears extremely promising. Clinical trial registered with www.sanctr.gov.za (NHREC no. 1381). PMID- 20167849 TI - Cystic fibrosis transmembrane conductance regulator channel dysfunction in non cystic fibrosis bronchiectasis. AB - RATIONALE: Although in patients with diffuse bronchiectasis (DB) and a normal sweat test the presence of one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is frequently observed, its pathogenic role in the development of DB remains unclear. OBJECTIVES: To evaluate the association between CFTR heterozygosity and CFTR protein dysfunction in the airways of patients with DB. METHODS: Nasal potential difference was measured in 122 patients with DB of unknown origin and with a normal sweat test (Cl(-) < 60 mmol/L). They were classified according to the presence of CFTR mutations: zero (85 patients), one (22 patients), or two mutations (15 patients). Control groups comprised 26 healthy subjects, 38 obligate heterozygotes for CFTR, and 92 patients with classic cystic fibrosis (CF) with an abnormal sweat test (Cl(-) > or = 60 mmol/L). Patients classified as mild-CF were carrying at least one mild mutation and patients classified as severe-CF were homozygous for the F508del mutation. MEASUREMENTS AND MAIN RESULTS: There was a continuum of airway CFTR dysfunction in the study population as shown by nasal potential difference measurements, ranging from normal values in healthy subjects, to intermediate values in subjects with DB, to highly abnormal values in subjects classified as severe-CF. This continuum of airway CFTR dysfunction was thus strongly associated with defects in the CFTR gene. Moreover, among patients with DB, a similar continuum in intermediate nasal potential difference was identified that was associated with the bearing of zero, one, or two CFTR mutations. These electrophysiological phenotypes and CFTR genotypes were also associated with the clinical phenotype, as shown by the frequency of Staphylococcus aureus and Pseudomonas aeruginosa bronchial colonization. CONCLUSIONS: Our study supports the hypothesis that a unique CFTR mutation may have pathogenic consequences in patients with DB. PMID- 20167850 TI - Innate immune recognition in infectious and noninfectious diseases of the lung. AB - Diseases of the respiratory tract are among the leading causes of death in the world population. Increasing evidence points to a key role of the innate immune system with its pattern recognition receptors (PRRs) in both infectious and noninfectious lung diseases, which include pneumonia, chronic obstructive pulmonary disease, acute lung injury, pneumoconioses, and asthma. PRRs are capable of sensing different microbes as well as endogenous molecules that are released after cell damage. This PRR engagement is the prerequisite for the initiation of immune responses to infections and tissue injuries which can be beneficial or detrimental to the host. PRRs include the Toll-like receptors, NOD like receptors, RIG-I-like receptors, and cytosolic DNA sensors. The PRRs and their signaling pathways represent promising targets for prophylactic and therapeutic interventions in various lung diseases. PMID- 20167851 TI - Knocking down Cav1 calcium channels implicated in Th2 cell activation prevents experimental asthma. AB - RATIONALE: Th2 cells orchestrate allergic asthma and the cytokines they produce (IL-4, IL-5, and IL-13) are deleterious in allergy. Therefore, it is important to identify key signaling molecules expressed by Th2 cells that are essential for their function. We have previously shown that dihydropyridines selectively modulate Th2 cell functions. OBJECTIVES: Because dihydropyridines bind to and modulate voltage-dependent calcium (Ca(v)1) channel in excitable cells, we aimed at showing that Th2 cells selectively express functional Ca(v)1-related channels, the inhibition of which may prevent asthma. METHODS: We looked for Ca(v)1 channel expression in Th2 and Th1 cells by real-time polymerase chain reaction and Western blotting. We sequenced the isoforms expressed by Th2 cells and tested whether Ca(v)1 antisense oligodeoxynucleotides (Ca(v)1AS) affected Ca(2+) signaling and cytokine production. Finally, we tested the effect of Ca(v)1AS in the passive asthma model by injection of ovalbumin-specific Th2 cells transfected with Ca(v)1AS into BALB/c mice challenged with intranasal ovalbumin and in the active model of asthma by intranasal delivery of Ca(v)1AS together with soluble ovalbumin in BALB/c mice previously immunized with ovalbumin in alum. MEASUREMENTS AND MAIN RESULTS: We show that mouse Th2 but not Th1 cells expressed Ca(v)1.2 and Ca(v)1.3 channels. Th2 cells transfected with Ca(v)1AS had impaired Ca(2+) signaling and cytokine production, and lost their ability to induce airway inflammation on adoptive transfer. Furthermore, intranasal administration of Ca(v)1AS suppressed airway inflammation and hyperreactivity in an active model of asthma. CONCLUSIONS: These results indicate that Th2 cells selectively express Ca(v)1 channels that may be efficiently targeted in T lymphocytes to prevent experimental asthma. PMID- 20167852 TI - Beyond atopy: multiple patterns of sensitization in relation to asthma in a birth cohort study. AB - RATIONALE: The pattern of IgE response (over time or to specific allergens) may reflect different atopic vulnerabilities which are related to the presence of asthma in a fundamentally different way from current definition of atopy. OBJECTIVES: To redefine the atopic phenotype by identifying latent structure within a complex dataset, taking into account the timing and type of sensitization to specific allergens, and relating these novel phenotypes to asthma. METHODS: In a population-based birth cohort in which multiple skin and IgE tests have been taken throughout childhood, we used a machine learning approach to cluster children into multiple atopic classes in an unsupervised way. We then investigated the relation between these classes and asthma (symptoms, hospitalizations, lung function and airway reactivity). MEASUREMENTS AND MAIN RESULTS: A five-class model indicated a complex latent structure, in which children with atopic vulnerability were clustered into four distinct classes (Multiple Early [112/1053, 10.6%]; Multiple Late [171/1053, 16.2%]; Dust Mite [47/1053, 4.5%]; and Non-dust Mite [100/1053, 9.5%]), with a fifth class describing children with No Latent Vulnerability (623/1053, 59.2%). The association with asthma was considerably stronger for Multiple Early compared with other classes and conventionally defined atopy (odds ratio [95% CI]: 29.3 [11.1-77.2] versus 12.4 [4.8-32.2] versus 11.6 [4.8-27.9] for Multiple Early class versus Ever Atopic versus Atopic age 8). Lung function and airway reactivity were significantly poorer among children in Multiple Early class. Cox regression demonstrated a highly significant increase in risk of hospital admissions for wheeze/asthma after age 3 yr only among children in the Multiple Early class (HR 9.2 [3.5-24.0], P < 0.001). CONCLUSIONS: IgE antibody responses do not reflect a single phenotype of atopy, but several different atopic vulnerabilities which differ in their relation with asthma presence and severity. PMID- 20167853 TI - The role of surfactant protein A in bleomycin-induced acute lung injury. AB - RATIONALE: Surfactant protein A (SP-A) is a collectin family member that has multiple immunomodulatory roles in lung host defense. SP-A levels are altered in the bronchoalveolar lavage (BAL) fluid and serum of patients with acute lung injury and acute respiratory distress syndrome, suggesting the importance of SP-A in the pathogenesis of acute lung injury. OBJECTIVES: Investigate the role of SP A in the murine model of noninfectious lung injury induced by bleomycin treatment. METHODS: Wild-type (WT) or SP-A deficient (SP-A(-/-)) mice were challenged with bleomycin, and various indices of lung injury were analyzed. MEASUREMENTS AND MAIN RESULTS: On challenge with bleomycin, SP-A(-/-) mice had a decreased survival rate as compared with WT mice. SP-A(-/-) mice had a higher degree of neutrophil-dominant cell recruitment and the expression of the inflammatory cytokines in BAL fluid than did WT mice. In addition, SP-A(-/-) mice had increased lung edema as assessed by the increased levels of intravenously injected Evans blue dye leaking into the lungs. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling and active caspase-3 staining suggested the increased apoptosis in the lung sections from SP-A(-/-) mice challenged with bleomycin. SP-A also specifically reduced bleomycin-induced apoptosis in mouse lung epithelial 12 cells in vitro. Moreover, intratracheal administration of exogenous SP-A rescued the phenotype of SP-A(-/-) mice in vivo. CONCLUSIONS: These data suggest that SP-A plays important roles in modulating inflammation, apoptosis, and epithelial integrity in the lung in response to acute noninfectious challenges. PMID- 20167854 TI - Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis. AB - RATIONALE: Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied. OBJECTIVES: To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP. METHODS: We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a Pa(O(2)) of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar arterial oxygen difference [A-aDO(2)] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 microg Days 1-8, none Days 9-14; x six cycles; 12 wk); low-dose therapy (125 microg Days 1-4, none Days 5-14; x six cycles; 12 wk), and follow-up (52 wk). MEASUREMENTS AND MAIN RESULTS: Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A-aDO(2) of 12.3 mm Hg (95% confidence interval, 8.4-16.2; n = 35, P < 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A-aDO(2) and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year. CONCLUSIONS: Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP. Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN18931678), www.jmacct.med.or.jp/english (JMA-IIA00013). PMID- 20167855 TI - Lung function in patients with primary ciliary dyskinesia: a cross-sectional and 3-decade longitudinal study. AB - RATIONALE: Early diagnosis and treatment is considered important to prevent lung damage in primary ciliary dyskinesia (PCD). OBJECTIVES: Few studies have addressed long-term evolution of lung function after PCD diagnosis. We investigated whether long-term lung function was dependent on age or level of lung function at PCD diagnosis. METHODS: An observational, single-center, cross sectional, and three-decade longitudinal study of FEV(1) and FVC related to age at diagnosis until current age was performed. Linear regression was used to describe the relation between first measured lung function values and age at diagnosis across the cohort. Courses of lung function after diagnosis and the according slopes were used to group patients into increasing, stable, or decreasing courses. Additionally, slopes from courses of 10 years of follow-up were related to age at diagnosis and initial level of lung function, respectively, using linear regression. MEASUREMENTS AND MAIN RESULTS: Seventy four children and adults with PCD were observed for median 9.5 (range, 1.5-30.2) years during which 2,937 lung function measurements were performed. First measured FEV(1) was less than 80% of predicted in one-third of preschool diagnosed children. During observation, 34% of patients lost more than 10 percentage points, 57% were stable, and 10% improved more than 10 percentage points in FEV(1). Courses of lung function after diagnosis were related to neither age at diagnosis nor initial level. CONCLUSIONS: Our study strongly suggests that PCD is a disease of serious threat to lung function already at preschool age, and with a high degree of variation in courses of lung function after diagnosis that was not linked to either age or level of lung function at diagnosis. Early diagnosis did not protect against decline in lung function. PMID- 20167856 TI - Primary cell cultures from human renal cortex and renal-cell carcinoma evidence a differential expression of two spliced isoforms of Annexin A3. AB - Primary cell cultures from renal cell carcinoma (RCC) and normal renal cortex tissue of 60 patients have been established, with high efficiency (more than 70%) and reproducibility, and extensively characterized. These cultures composed of more than 90% of normal or tumor tubular cells have been instrumental for molecular characterization of Annexin A3 (AnxA3), never extensively studied before in RCC cells although AnxA3 has a prognostic relevance in some cancer and it has been suggested to be involved in the hypoxia-inducible factor-1 pathway. Western blot analysis of 20 matched cortex/RCC culture lysates showed two AnxA3 protein bands of 36 and 33 kDa, and two-dimensional Western blot evidenced several specific protein spots. In RCC cultures the 36-kDa isoform was significantly down-regulated and the 33-kDa isoform up-regulated. Furthermore, the inversion of the quantitative expression pattern of two AnxA3 isoforms in tumor cultures correlate with hypoxia-inducible factor-1alpha expression. The total AnxA3 protein is down-regulated in RCC cultures as confirmed also in tissues by tissue microarray. Two AnxA3 transcripts that differ for alternative splicing of exon III have been also detected. Real-time PCR quantification in 19 matched cortex/RCC cultures confirms the down-regulation of longer isoform in RCC cells. The characteristic expression pattern of AnxA3 in normal and tumor renal cells, documented in our primary cultures, may open new insight in RCC management. PMID- 20167857 TI - Transglutaminase1 preferred substrate peptide K5 is an efficient tool in diagnosis of lamellar ichthyosis. AB - Lamellar ichthyosis (LI) is a genetically heterogeneous, severe genodermatosis showing widespread hyperkeratosis of the skin. Transglutaminase 1 (TGase1) deficiency by TGase1 gene (TGM1) mutations is the most prevalent cause of LI. Screening of TGase1 deficiency in skin is essential to facilitate the molecular diagnosis of LI. However, cadaverine, the most widely used substrate for TGase activity assay, is not isozyme specific. Recently, a human TGase1-specific highly preferred substrate peptide K5 (pepK5) was generated. To evaluate its potential as a diagnostic tool for LI, we performed pepK5 labeling of TGase1 activity in normal human and LI skin. Ca(2+)-dependent labeling of FITC-pepK5 was clearly seen in the upper spinous and granular layers of normal human skin where it precisely overlapped with TGase1 immunostaining. Both specificity and sensitivity of FITC-pepK5 labeling for TGase1 activity were higher than those of FITC cadaverine labeling. FITC-pepK5 labeling colocalized with involucrin and loricrin immunostaining at cornified cell envelope forming sites. FITC-pepK5 labeling was negative in LI patients carrying TGM1 truncation mutations and partially abolished in the other LI patients harboring missense mutations. The present results clearly indicate that pepK5 is a powerful tool for screening LI patient TGase1 deficiency when we make molecular diagnosis of LI. PMID- 20167858 TI - Histidine-rich glycoprotein modulates the anti-angiogenic effects of vasculostatin. AB - Brain angiogenesis inhibitor 1 (BAI1) is a transmembrane protein expressed on glial cells within the brain. Its expression is dramatically down-regulated in many glioblastomas, consistent with its functional ability to inhibit angiogenesis and tumor growth in vivo. We have shown that the soluble anti angiogenic domain of BAI1 (termed Vstat120) requires CD36, a cell surface glycoprotein expressed on microvascular endothelial cells (MVECs), for it to elicit an anti-angiogenic response. We now report that Vstat120 binding to CD36 on MVECs activates a caspase-mediated pro-apoptotic pathway, and this effect is abrogated by histidine-rich glycoprotein (HRGP). HRGP is a circulating glycoprotein previously shown to function as a CD36 decoy to promote angiogenesis in the presence of thrombospondin-1 or -2. Data here show that Vstat120 specifically binds HRGP. Under favorable MVEC growth conditions this interaction allows chemotactic-directed migration as well as endothelial tube formation to persist in in vitro cellular systems, and increased tumor growth in vivo as demonstrated in both subcutaneous and orthotopic brain tumor models, concomitant with an increase in tumor vascularity. Finally, we show that HRGP expression is increased in human brain cancers, with the protein heavily localized to the basement membrane of the tumors. These data help define a novel angiogenic axis that could be exploited for the treatment of human cancers and other diseases where excess angiogenesis occurs. PMID- 20167859 TI - Adriamycin nephropathy: a failure of endothelial progenitor cell-induced repair. AB - Adriamycin-associated nephropathy (AAN) remains poorly understood. We hypothesized that adriamycin affects endothelial progenitor cells (EPCs), leading to impaired regeneration. We analyzed renal hematopoietic stem cells (HSCs) and EPCs in mice with AAN and examined the potential contribution of adoptive transfer of intact EPCs to the repair processes. FACS analyses revealed that populations of HSCs and EPCs were scarcely represented in control kidneys and did not change numerically in kidneys obtained from mice with AAN. The observed defect in engraftment was attributable to the decreased viability and increased senescence of EPCs. Adoptive transfer of intact EPCs improved proteinuria and renal function, with a threefold decrease in mortality. Infusion of EPCs to adriamycin-treated mice reduced plasma levels of interleukin-1alpha and -beta and granulocyte-colony stimulating factor as well as increased the level of vascular endothelial growth factor with concomitant improvement of vascular density and reduction of apoptosis. An additional mechanism of tissue repair is proposed based on tunneling nanotube formation between EPCs and endothelial cells exposed to adriamycin, leading to the multiple rounds of exchange between EPCs and mature cells. In conclusion, AAN is associated with development of EPC incompetence; adoptive transfer of intact EPCs blunts morphological and functional manifestations of AAN; and the proposed mechanisms of repair by EPCs include direct incorporation into blood vessels, paracrine signaling, and tunneling nanotube renewal of mitochondrial pool in endothelial cells. PMID- 20167860 TI - Expression of vascular notch ligand delta-like 4 and inflammatory markers in breast cancer. AB - Delta-like ligand 4 (Dll4) is a Notch ligand that is predominantly expressed in the endothelium. Evidence from xenografts suggests that inhibiting Dll4 may overcome resistance to antivascular endothelial growth factor therapy. The aims of this study were to characterize the expression of Dll4 in breast cancer and assess whether it is associated with inflammatory markers and prognosis. We examined 296 breast adenocarcinomas and 38 ductal carcinoma in situ tissues that were represented in tissue microarrays. Additional whole sections representing 10 breast adenocarcinomas, 10 normal breast tissues, and 16 angiosarcomas were included. Immunohistochemistry was then performed by using validated antibodies against Dll4, CD68, CD14, Dendritic Cell-Specific Intercellular adhesion molecule 3-Grabbing Non-integrin (DC-SIGN), CD123, neutrophil elastase, CD31, and carbonic anhydrase 9. Dll4 was selectively expressed by intratumoral endothelial cells in 73% to 100% of breast adenocarcinomas, 18% of in situ ductal carcinomas, and all lactating breast cases, but not normal nonlactating breast. High intensity of endothelial Dll4 expression was a statistically significant adverse prognostic factor in univariate (P = 0.002 and P = 0.01) and multivariate analyses (P = 0.03 and P = 0.04) of overall survival and relapse-free survival, respectively. Among the inflammatory markers, only CD68 and DC-SIGN were significant prognostic factors in univariate (but not multivariate) analyses of overall survival (P = 0.01 and 0.002, respectively). In summary, Dll4 was expressed by endothelium associated with breast cancer cells. In these retrospective subset analyses, endothelial Dll4 expression was a statistically significant multivariate prognostic factor. PMID- 20167861 TI - Establishment and genomic characterization of mouse xenografts of human primary prostate tumors. AB - Serum prostate-specific antigen screening has led to earlier detection and surgical treatment of prostate cancer, favoring an increasing incidence-to mortality ratio. However, about one third of tumors that are diagnosed when still confined to the prostate can relapse within 10 years from the first treatment. The challenge is therefore to identify prognostic markers of aggressive versus indolent tumors. Although several preclinical models of advanced prostate tumors are available, a model that recapitulates the genetic and growth behavior of primary tumors is still lacking. Here, we report a complete histopathological and genomic characterization of xenografts derived from primary localized low- and high-grade human prostate tumors that were implanted under the renal capsule of immunodeficient mice. We obtained a tumor take of 56% and show that these xenografts maintained the histological as well as most genomic features of the parental tumors. Serum prostate-specific antigen levels were measurable only in tumor xenograft-bearing mice, but not in those implanted with either normal prostate tissue or in tumors that likely regressed. Finally, we show that a high proliferation rate, but not the pathological stage or the Gleason grade of the original tumor, was a fundamental prerequisite for tumor take in mice. This mouse xenograft model represents a useful preclinical model of primary prostate tumors for their biological characterization, biomarker discovery, and drug testing. PMID- 20167862 TI - Functions of type II pneumocyte-derived vascular endothelial growth factor in alveolar structure, acute inflammation, and vascular permeability. AB - Vascular endothelial growth factor-A (VEGF) is a potent regulator of vascular permeability, inflammatory response, and cell survival in the lung. To explore the functions of VEGF produced locally in type II pneumocytes, we generated mice with a conditional deletion of VEGF-A using Cre recombinase driven by the human surfactant protein C (SPC) promoter. In 7- to 10-week-old VEGF-knockout (SPC-VEGF KO) mice, lung histology and physiology were essentially normal, except for higher dynamic lung compliance and lower pulmonary vascular permeability. Emphysema was seen in 28- to 32-week-old animals. To investigate the role of type II pneumocyte-derived VEGF in acute lung injury, we challenged 7- to 10-week-old SPC-VEGF-KO mice and their wild-type littermates with intestinal ischemia reperfusion. Bronchoalveolar lavage fluid total cell count, pulmonary permeability, and lung injury score were significantly attenuated, and total lung VEGF levels were significantly lower in SPC-VEGF-KO mice compared with wild-type controls. In SPC-VEGF-KO mice, activated caspase 3-positive type II epithelial cells were increased after intestinal ischemia-reperfusion, even though there was no significant difference in the total number of cells positive for terminal deoxynucleotidyl transferase dUTP nick-end labeling. We conclude that VEGF in type II cells helps protect alveolar epithelial cells from caspase-dependent apoptosis. However, VEGF produced from type II cells may contribute to increased vascular permeability during acute lung injury. PMID- 20167863 TI - Elusive identities and overlapping phenotypes of proangiogenic myeloid cells in tumors. AB - It is now established that bone marrow-derived myeloid cells regulate tumor angiogenesis. This was originally inferred from studies of human tumor biopsies in which a positive correlation was seen between the number of tumor-infiltrating myeloid cells, such as macrophages and neutrophils, and tumor microvessel density. However, unequivocal evidence was only provided once mouse models were used to examine the effects on tumor angiogenesis by genetically or pharmacologically targeting myeloid cells. Since then, identifying the exact myeloid cell types involved in this process has proved challenging because of myeloid cell heterogeneity and the expression of overlapping phenotypic markers in tumors. As a result, investigators often simply refer to them now as "bone marrow-derived myeloid cells." Here we review the findings of various attempts to phenotype the myeloid cells involved and discuss the therapeutic implications of correctly identifying-and thus being able to target-this proangiogenic force in tumors. PMID- 20167864 TI - Tumor suppressor function of androgen receptor coactivator ARA70alpha in prostate cancer. AB - Androgen receptor (AR), a member of the steroid receptor family, is a transcription factor that has an important role in the regulation of both prostate cell proliferation and growth suppression. AR coactivators may influence the transition between cell growth and growth suppression. We have shown previously that the internally spliced ARA70 isoform, ARA70beta, promotes prostate cancer cell growth and invasion. Here we report that the full length ARA70alpha, in contrast, represses prostate cancer cell proliferation and anchorage-independent growth in vitro and inhibits tumor growth in nude mice xenograft experiments in vivo. Further, the growth inhibition by ARA70alpha is AR dependent and mediated through induction of apoptosis rather than cell cycle arrest. Interestingly, AR with T877A mutation in LNCaP cells decreased its physical and functional interaction with ARA70alpha, facilitating the growth of LNCaP cells. The tumor suppressor function of ARA70alpha is consistent with our previous findings that ARA70alpha expression is decreased in prostate cancer cells compared with benign prostate. ARA70alpha also reduced the invasion ability of LNCaP cells. Although growth inhibition by ARA70alpha is AR-dependent, the inhibition of cell invasion is an androgen-independent process. These results strongly suggest that ARA70alpha functions as a tumor suppressor gene. PMID- 20167865 TI - Tim3 is upregulated and protective in nephrotoxic serum nephritis. AB - T cell immunoglobulin and mucin protein-3 (Tim3) is mainly expressed on the cell surface of T-helper lymphocytes (T(H)) that negatively regulates T(H)-type 1 (T(H)-1) responses. Because blockade of Tim3 aggravates disease activity in T(H) 1-dependent diseases, we investigated whether Tim3 is involved in the pathogenesis of the T(H)-1-dependent nephrotoxic nephritis (NTS). We first evaluated Tim3 expression in mice after induction of nephrotoxic serum nephritis (NTS) and then studied the effects of anti-Tim3 treatment toward the course of NTS for up to seven days. Whereas Tim3 expression was undetectable in control mice, we found significantly increased Tim3 expression in kidneys, but not in draining lymph nodes, at one, four, and eight weeks after induction of NTS. Tim3 expressing cells that infiltrated kidneys of mice subjected to NTS turned out to be CD4(+) T cells rather than CD8(+) cytotoxic T cells and dendritic cells. Administration of a blocking anti-Tim3 antibody aggravated nephritis as shown by significantly increased albuminuria, respective histological changes, and increased expression of the kidney injury molecule lipocalin-2. In parallel, an increase of infiltrating T cells, macrophages, and macrophage pro-inflammatory cytokine formation as well as increased proliferation and apoptosis in kidneys of anti-Tim3-treated mice was detected. Together, we provide the first evidence that Tim3 is up-regulated in kidneys in NTS and that Tim3 exerts protective roles in the course of disease. PMID- 20167866 TI - Cooperation of TLR2 with MyD88, PI3K, and Rac1 in lipoteichoic acid-induced cPLA2/COX-2-dependent airway inflammatory responses. AB - Lipoteichoic acid (LTA) plays a role in the pathogenesis of severe inflammatory responses induced by Gram-positive bacterial infection. Cytosolic phospholipase A(2) (cPLA(2)), cyclooxygenase-2 (COX-2), prostaglandin E(2) (PGE(2)), and interleukin (IL)-6 have been demonstrated to engage in airway inflammation. In this study, LTA-induced cPLA(2) and COX-2 expression and PGE(2) or IL-6 synthesis were attenuated by transfection with siRNAs of TLR2, MyD88, Akt, p42, p38, JNK2, and p65 or pretreatment with the inhibitors of PI3K (LY294002), p38 (SB202190), MEK1/2 (U0126), JNK1/2 (SP600125), and NF-kappaB (helenalin) in human tracheal smooth muscle cells (HTSMCs). LTA also induced cPLA(2) and COX-2 expression and leukocyte count in bronchoalveolar lavage fluid in mice. LTA-regulated PGE(2) or IL-6 production was inhibited by pretreatment with the inhibitors of cPLA(2) (AACOCF(3)) and COX-2 (NS-398) or transfection with cPLA(2) siRNA or COX-2 siRNA, respectively. LTA-stimulated NF-kappaB translocation or cPLA(2) phosphorylation was attenuated by pretreatment with LY294002, SB202190, U0126, or SP600125. Furthermore, LTA could stimulate TLR2, MyD88, PI3K, and Rac1 complex formation. We also demonstrated that Staphylococcus aureus could trigger these responses through a similar signaling cascade in HTSMCs. It was found that PGE(2) could directly stimulate IL-6 production in HTSMCs or leukocyte count in bronchoalveolar lavage fluid in mice. These results demonstrate that LTA-induced MAPKs activation is mediated through the TLR2/MyD88/PI3K/Rac1/Akt pathway, which in turn initiates the activation of NF-kappaB, and ultimately induces cPLA(2)/COX 2-dependent PGE(2) and IL-6 generation. PMID- 20167867 TI - Seasonal and pandemic human influenza viruses attach better to human upper respiratory tract epithelium than avian influenza viruses. AB - Influenza viruses vary markedly in their efficiency of human-to-human transmission. This variation has been speculated to be determined in part by the tropism of influenza virus for the human upper respiratory tract. To study this tropism, we determined the pattern of virus attachment by virus histochemistry of three human and three avian influenza viruses in human nasal septum, conchae, nasopharynx, paranasal sinuses, and larynx. We found that the human influenza viruses-two seasonal influenza viruses and pandemic H1N1 virus-attached abundantly to ciliated epithelial cells and goblet cells throughout the upper respiratory tract. In contrast, the avian influenza viruses, including the highly pathogenic H5N1 virus, attached only rarely to epithelial cells or goblet cells. Both human and avian viruses attached occasionally to cells of the submucosal glands. The pattern of virus attachment was similar among the different sites of the human upper respiratory tract for each virus tested. We conclude that influenza viruses that are transmitted efficiently among humans attach abundantly to human upper respiratory tract, whereas inefficiently transmitted influenza viruses attach rarely. These results suggest that the ability of an influenza virus to attach to human upper respiratory tract is a critical factor for efficient transmission in the human population. PMID- 20167868 TI - Transcription factor Stat3 stimulates metastatic behavior of human prostate cancer cells in vivo, whereas Stat5b has a preferential role in the promotion of prostate cancer cell viability and tumor growth. AB - Identification of the molecular changes that promote viability and metastatic behavior of prostate cancer is critical for the development of improved therapeutic interventions. Stat5a/b and Stat3 are both constitutively active in locally-confined and advanced prostate cancer, and both transcription factors have been reported to be critical for the viability of prostate cancer cells. We recently showed that Stat3 promotes metastatic behavior of human prostate cancer cells not only in vitro but also in an in vivo experimental metastases model. In this work, we compare side-by-side Stat5a/b versus Stat3 in the promotion of prostate cancer cell viability, tumor growth, and induction of metastatic colonization in vivo. Inhibition of Stat5a/b induced massive death of prostate cancer cells in culture and reduced both subcutaneous and orthotopic prostate tumor growth, whereas Stat3 had a predominant role over Stat5a/b in promoting metastases formation of prostate cancer cells in vivo in nude mice. The molecular mechanisms underlying the differential biological effects induced by these two transcription factors involve largely different sets of genes regulated by Stat5a/b versus Stat3 in human prostate cancer model systems. Of the two Stat5 homologs, Stat5b was more important for supporting growth of prostate cancer cells than Stat5a. This work provides the first mechanistic comparison of the biological effects induced by transcription factors Stat5a/b versus Stat3 in prostate cancer. PMID- 20167869 TI - MCP1 directs trafficking of hematopoietic stem cell-derived fibroblast precursors in solid tumor. AB - Our previous studies have demonstrated that hematopoietic stem cells (HSCs) are a novel source of carcinoma-associated fibroblasts. However, the mechanisms regulating recruitment and homing of HSC-derived carcinoma-associated fibroblasts or their precursors to the tumor microenvironment are unknown. Herein, we demonstrate using a single cell transplantation model that circulating fibroblast precursors (CFPs) are of HSC origin. This population increased with tumor burden in vivo and functional in vitro studies showed that CFPs preferentially migrated and differentiated into fibroblasts in response to tumor, suggesting that HSC derived CFPs serve as an intermediate between the bone marrow and tumor. Based on this chemotactic ability and our demonstration of a monocyte lineage origin for CFPs, we investigated the role of monocyte chemoattractant protein (MCP1) in mediating CFP recruitment/homing. Blocking tumor-produced MCP1 inhibited in vitro migration of CFPs in response to multiple tumor types, indicating broad biological significance for this CFP/chemokine interaction. In vivo, CCR2 expressing CFPs increased in circulation during the period of active tumor growth and stromal development. Inhibition of MCP1 during tumor development resulted in decreased tumor volume in tumor-bearing mice. Together these findings confirm an HSC origin for CFPs, demonstrate a role for MCP1 in regulating their contribution to the tumor microenvironment, and suggest a potential therapeutic target for limiting tumor growth. PMID- 20167870 TI - Toll-like receptor 3 ligand dampens liver inflammation by stimulating Valpha 14 invariant natural killer T cells to negatively regulate gammadeltaT cells. AB - Valpha14 invariant natural killer T (Valpha14iNKT) cells are at the interface between the innate and adaptive immune responses and are thus critical for providing full engagement of host defense. We investigated the role of polyriboinosinic:polycytidylic acid (poly I:C), a replication-competent viral double-stranded RNA mimic and a specific agonist that recognizes the cellular sensor Toll-like receptor 3 (TLR3), in regulating Valpha14iNKT cell activation. We established for the first time that hepatic Valpha14iNKT cells up-regulate TLR3 extracellularly after poly I:C treatment. Notably, activation of TLR3 expressing hepatic Valpha14iNKT cells by a TLR3 ligand was suppressed by TLR3 deficiency. Our studies also revealed that Valpha14iNKT cell activation in response to poly I:C administration uniquely suppressed the accumulation and activation of intrahepatic gammadeltaT cells (but not natural killer cells) by inducing apoptosis. Furthermore, we established that activated hepatic Valpha14iNKT cells (via cytokines and possibly reactive oxygen species) influenced the frequency and absolute number of intrahepatic gammadeltaT cells, as evidenced by increased hepatic gammadeltaT cell accumulation in Valpha14iNKT cell-deficient mice after poly I:C treatment relative to wild-type mice. Thus, hepatic Valpha14iNKT cells and intrahepatic gammadeltaT cells are functionally linked on application of TLR3 agonist. Overall, our results demonstrate a novel and previously unrecognized anti-inflammatory role for activated hepatic Valpha14iNKT cells in negatively regulating intrahepatic gammadeltaT cell accumulation (probably through TLR3 signaling) and thereby preventing potentially harmful activation of intrahepatic gammadeltaT cells. PMID- 20167871 TI - Amyloid-beta, the retina, and mouse models of Alzheimer disease. PMID- 20167873 TI - The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction. AB - Disruption of the intestinal barrier is a causal factor in the development of alcoholic endotoxemia and hepatitis. This study was undertaken to determine whether zinc deficiency is related to the deleterious effects of alcohol on the intestinal barrier. Mice were pair fed an alcohol or isocaloric liquid diet for 4 wk, and hepatitis was detected in association with elevated blood endotoxin level. Alcohol exposure significantly increased the permeability of the ileum but did not affect the barrier function of the duodenum or jejunum. Reduction of tight-junction proteins at the ileal epithelium was detected in alcohol-fed mice although alcohol exposure did not cause apparent histopathological changes. Alcohol exposure significantly reduced the ileal zinc concentration in association with accumulation of reactive oxygen species. Caco-2 cell culture demonstrated that alcohol exposure increases the intracellular free zinc because of oxidative stress. Zinc deprivation caused epithelial barrier disruption in association with disassembling of tight junction proteins in the Caco-2 monolayer cells. Furthermore, minor zinc deprivation exaggerated the deleterious effect of alcohol on the epithelial barrier. In conclusion, epithelial barrier dysfunction in the distal small intestine plays an important role in alcohol-induced gut leakiness, and zinc deficiency attributable to oxidative stress may interfere with the intestinal barrier function by a direct action on tight junction proteins or by sensitizing to the effects of alcohol. PMID- 20167874 TI - Upper esophageal sphincter during transient lower esophageal sphincter relaxation: effects of reflux content and posture. AB - Although some studies show that the upper esophageal sphincter (UES) contracts during transient lower esophageal sphincter relaxation (TLESR), others show that it relaxes. We hypothesized that the posture of the subject and constituents of gastroesophageal reflux (GER) may determine the type of UES response during the TLESR. High-resolution manometry and esophageal pH/impedance recording were performed in 10 healthy volunteers in the right recumbent (1 h) and upright (1 h) positions following the ingestion of a 1,000-Kcal meal. The UES pressure response during TLESR and constituents of GER (liquid, air, and pH) were determined. 109 TLESRs (58 upright and 51 recumbent) were analyzed. The majority of TLESRs were associated with GER (91% upright and 88% recumbent) events. UES relaxation was the predominant response during upright position (81% of TLESRs), and it was characteristically associated with presence of air in the reflux (92%). On the other hand, UES contraction was the predominant response during recumbent position (82% of TLESRs), and it was mainly associated with liquid reflux (71%). The rate of esophageal pressure increase (dP/dt) during the GER, but not the pH, had major influence on the type of UES response during TLESR. The dP/dt during air reflux (127 +/- 39 mmHg/s) was significantly higher than liquid reflux (31 +/ 6 mmHg/s, P < 0.0001). We concluded that the nature of UES response during TLESR, relaxation or contraction, is related to the posture and the constituents of GER. We propose that the rapid rate of esophageal pressure increase associated with air reflux determines the UES relaxation response to GER. PMID- 20167872 TI - Removal of Toxoplasma gondii cysts from the brain by perforin-mediated activity of CD8+ T cells. AB - Chronic infection with Toxoplasma gondii is one of the most common parasitic infections in humans. Formation of tissue cysts is the basis of persistence of the parasite in infected hosts, and this cyst stage has generally been regarded as untouchable. Here we provide the first evidence that the immune system can eliminate T. gondii cysts from the brains of infected hosts when immune T cells are transferred into infected immunodeficient animals that have already developed large numbers of cysts. This T cell-mediated immune process was associated with accumulation of microglia and macrophages around tissue cysts. CD8(+) immune T cells possess a potent activity to remove the cysts. The initiation of this process by CD8(+) T cells does not require their production of interferon-gamma, the major mediator to prevent proliferation of tachyzoites during acute infection, but does require perforin. These results suggest that CD8(+) T cells induce elimination of T. gondii cysts through their perforin-mediated cytotoxic activity. Our findings provide a new mechanism of the immune system to fight against chronic infection with T. gondii and suggest a possibility of developing a novel vaccine to eliminate cysts from patients with chronic infection and to prevent the establishment of chronic infection after a newly acquired infection. PMID- 20167876 TI - Properties of Rikkunshi-to (TJ-43)-induced relaxation of rat gastric fundus smooth muscles. AB - The relaxant effects of Rikkunshi-to (TJ-43), a gastroprotective herbal medicine, on rat gastric fundus were investigated. Experiments were carried out using standard tension and intracellular microelectrode recording techniques. During contraction induced by enprostil (0.5 microM), a prostaglandin E(2) analog, TJ 43, produced relaxation dose dependently (0.1-5.0 mg/ml) in the rat fundic circular smooth muscle (CSM) strips. The relaxant effects of TJ-43 were not affected by tetrodotoxin or 1 H[1, 2, 4] oxadiazolo [4, 3-a] quinoxalin-1-one (10 microM), an inhibitor of soluble guanylate cyclase. TJ-43 inhibited enprostil induced membrane depolarization. Apamin (1 microM), a blocker of small conductance Ca(2+)-activated K(+) (SK) channel, inhibited T-43-induced membrane repolarization. TJ-43-induced relaxation was biphasic, comprising of an initial fast followed by a second slow relaxation. The fast relaxation was abolished by apamin. Application of high K(+) (29.4 mM [K(+)](o)) also abolished the fast relaxation induced by TJ-43. In diabetic Goto-Kakizaki (GK) rat fundic CSM strips, the relaxant responses of TJ-43 during enprostil-induced contraction were increased compared with control rat strips. These results indicate that TJ-43 elicited fast muscle relaxation through membrane hyperpolarization induced by the activation of SK channels; the time-dependent slow relaxation reflects an additional direct of TJ-43 on CSM in the rat gastric fundus. Because TJ-43-evoked relaxation of fundic CSM strips was more potent in diabetic GK rat than in control rat, further analysis of this herb could lead to better treatments of diabetic gastroparesis. PMID- 20167875 TI - MicroRNA-21 is upregulated during the proliferative phase of liver regeneration, targets Pellino-1, and inhibits NF-kappaB signaling. AB - During liver regeneration, normally quiescent liver cells reenter the cell cycle, nonparenchymal and parenchymal cells divide, and proper liver architecture is restored. The gene expression programs regulating these transitions are not completely understood. MicroRNAs are a newly discovered class of small regulatory RNAs that silence messenger RNAs by binding to their 3'-untranslated regions (UTRs). A number of microRNAs, including miR-21, have been shown to be involved in regulation of cell proliferation. We performed partial hepatectomies on mice and allowed the liver to regenerate for 1, 6, 12, 24, and 48 h and 4 and 7 days. We compared the expression of miR-21 in the posthepatectomy liver to the prehepatectomy liver by Northern blot and found that miR-21 was upregulated during the early stages of liver regeneration. NF-kappaB signaling is also activated very early during liver regeneration. It has been previously reported that NF-kappaB upregulates the miR-21 precursor transcript. The predicted miR-21 target, Pellino (Peli1), is a ubiquitin ligase involved in activating NF-kappaB signaling. We observed an inverse correlation between miR-21 and Peli1 mRNA levels during liver regeneration. miR-21 overexpression in cultured cells inhibited a Peli1 3'-UTR luciferase reporter. Using NF-kappaB reporter assays, we determined that miR-21 overexpression inhibits NF-kappaB signaling. In conclusion, miR-21 expression was upregulated during early stages of liver regeneration. Targeting of Peli1 by miR-21 could potentially provide the basis for a negative feedback cycle regulating NF-kappaB signaling. PMID- 20167878 TI - A healthier America, a healthier world. PMID- 20167877 TI - Serum proteomic analysis of diet-induced steatohepatitis and metabolic syndrome in the Ossabaw miniature swine. AB - We recently developed a nutritional model of steatohepatitis and metabolic syndrome in Ossabaw pigs. Here we describe changes in the serum proteome of pigs fed standard chow (control group; n = 7), atherogenic diet (n = 5), or modified atherogenic diet (M-ath diet group; n = 6). Pigs fed atherogenic diet developed metabolic syndrome and mildly abnormal liver histology, whereas pigs fed M-ath diet exhibited severe metabolic syndrome and liver injury closely resembling human nonalcoholic steatohepatitis (NASH). Using a label-free mass spectrometry based proteomics approach, we identified 1,096 serum proteins, 162 of which changed significantly between any two diet groups (false discovery rate <5%). Biological classification of proteins with significant changes revealed functions previously implicated in development of NASH in humans, including immune system regulation and inflammation (orosomucoid 1, serum amyloid P component, paraoxonase 1, protein similar to alpha-2-macroglobulin precursor, beta-2 microglobulin, p101 protein, and complement components 2 and C8G), lipid metabolism (apolipoproteins C-III, E, E precursor, B, and N), structural and extracellular matrix proteins (transthyretin and endopeptidase 24.16 type M2), and coagulation [carboxypeptidase B2 (plasma)]. Several proteins with significant differential expression in pigs were also identified in our recent human proteomics study as changing significantly in serum from patients across the spectrum of nonalcoholic fatty liver disease, including apolipoproteins C-III and B, orosomucoid 1, serum amyloid P component, transthyretin, paraoxonase 1, and a protein similar to alpha-2-macroglobulin precursor. This serum proteomic analysis provides additional information about the pathogenesis of NASH and further characterizes our large animal model of diet-induced steatohepatitis and metabolic syndrome in Ossabaw pigs. PMID- 20167879 TI - Russell E. Train : a leading environmental figure of the 1970s. PMID- 20167880 TI - A framework for public health action: the health impact pyramid. AB - A 5-tier pyramid best describes the impact of different types of public health interventions and provides a framework to improve health. At the base of this pyramid, indicating interventions with the greatest potential impact, are efforts to address socioeconomic determinants of health. In ascending order are interventions that change the context to make individuals' default decisions healthy, clinical interventions that require limited contact but confer long-term protection, ongoing direct clinical care, and health education and counseling. Interventions focusing on lower levels of the pyramid tend to be more effective because they reach broader segments of society and require less individual effort. Implementing interventions at each of the levels can achieve the maximum possible sustained public health benefit. PMID- 20167881 TI - Ethical considerations in surveys employing respondent-driven sampling. PMID- 20167882 TI - Images of health. Unite to fight malaria! PMID- 20167883 TI - Negative freedom and death in the United States. AB - Personal freedoms have been characterized as "positive" (freedom to pursue opportunities) and "negative" (freedom from external constraints on decision making). An ecological analysis of US data revealed a strong positive association (r = 0.41; P = .003) between state-level negative personal freedom (defined in terms of regulation of personal behavior) and state-level age-adjusted rates of unintentional injury. A conceptual emphasis on positive freedom construed as freedom to pursue a life without risk of unintentional injury could help motivate a conversation to improve public health. PMID- 20167884 TI - Using STD electronic medical record data to drive public health program decisions in New York City. AB - Electronic medical records can house patient information gathered over time and at multiple sites, thus they have the potential to increase continuity of care and improve service delivery in a multiclinic system. The New York City Department of Health and Mental Hygiene implemented an electronic medical record system in its 10 sexually transmitted disease clinics during 2004 and 2005. We examine the use of real-time electronic medical record data analyses to evaluate clinical services or program activities and present 3 examples of such analyses that have led to program improvements. Analyses of electronic medical record data have produced changes in clinical practice that in turn have resulted in more effective staff use, increased disease detection, and increased clinic capacity. PMID- 20167885 TI - Promoters and barriers to fruit, vegetable, and fast-food consumption among urban, low-income African Americans--a qualitative approach. AB - To identify promoters of and barriers to fruit, vegetable, and fast-food consumption, we interviewed low-income African Americans in Philadelphia. Salient promoters and barriers were distinct from each other and differed by food type: taste was a promoter and cost a barrier to all foods; convenience, cravings, and preferences promoted consumption of fast foods; health concerns promoted consumption of fruits and vegetables and avoidance of fast foods. Promoters and barriers differed by gender and age. Strategies for dietary change should consider food type, gender, and age. PMID- 20167886 TI - Financial strain and smoking cessation among racially/ethnically diverse smokers. AB - OBJECTIVES: We evaluated the influence of financial strain on smoking cessation among Latino, African American, and Caucasian smokers of predominantly low socioeconomic status. METHODS: Smokers enrolled in a smoking cessation study (N = 424) were followed from 1 week prequit through 26 weeks postquit. We conducted a logistic regression analysis to evaluate the association between baseline financial strain and smoking abstinence at 26 weeks postquit after control for age, gender, race/ethnicity, educational level, annual household income, marital status, number of cigarettes smoked per day, and time to first cigarette of the day. RESULTS: Greater financial strain at baseline was significantly associated with reduced odds of abstinence at 26 weeks postquit among those who completed the study (odds ratio [OR] = 0.77; 95% confidence interval [CI] = 0.62, 0.94; P = .01). There was a significant association as well in analyses that included those who completed the study in addition to those lost to follow-up who were categorized as smokers (OR = 0.78; 95% CI = 0.64, 0.96; P = .02). CONCLUSIONS: Greater financial strain predicted lower cessation rates among racially/ethnically diverse smokers. Our findings highlight the impact of economic concerns on smoking cessation and the need to address financial strain in smoking cessation interventions. PMID- 20167887 TI - Physical activity resources and changes in walking in a cohort of older men. AB - OBJECTIVES: We evaluated the influence of physical activity resources and neighborhood-level socioeconomic status (SES) on walking among community-dwelling older men. METHODS: Participants reported time walked per day at baseline (2000 2002) and follow-up. Residential addresses were linked to a geographic information system database to assess proximity to parks, trails, and recreational facilities. Log-binomial regression analyses were conducted to test the hypothesis that men living near physical activity resources were more likely to increase or maintain time walked. RESULTS: Average time walked per day declined by 6 minutes between baseline and follow-up (P < .05). There was a significant interaction of neighborhood SES and physical activity with walking time (P < .1). Proximity to parks and proximity to trails, respectively, were associated with a 22% (95% confidence interval [CI] = 1.01, 1.47) and 34% (95% CI = 1.16, 1.55) higher likelihood of maintaining or increasing walking time in high SES neighborhoods, but there was no association in low-SES neighborhoods. Proximity to recreational facilities was not associated with walking. CONCLUSIONS: Uncovering reasons that proximity to parks and trails is not associated with maintenance of walking activity among men in low-SES neighborhoods could provide new insight into ways to promote physical activity. PMID- 20167888 TI - Marketing public health through older adult volunteering: Experience Corps as a social marketing intervention. AB - OBJECTIVES: We present a social marketing conceptual framework for Experience Corps Baltimore City (EC) in which the desired health outcome is not the promoted product or behavior. We also demonstrate the feasibility of a social marketing based recruitment campaign for the first year of the Baltimore Experience Corps Trial (BECT), a randomized, controlled trial of the health benefits of EC participation for older adults. METHODS: We recruited older adults from the Baltimore, MD, area. Participants randomized to the intervention were placed in public schools in volunteer roles designed to increase healthy behaviors. We examined the effectiveness of a recruitment message that appealed to generativity (i.e., to make a difference for the next generation), rather than potential health benefits. RESULTS: Among the 155 participants recruited in the first year of the BECT, the average age was 69 years; 87% were women and 85% were African American. Participants reported primarily generative motives as their reason for interest in the BECT. CONCLUSIONS: Public health interventions embedded in civic engagement have the potential to engage older adults who might not respond to a direct appeal to improve their health. PMID- 20167889 TI - Five steps for structural reform in clinical cancer research. AB - Despite advances in the prevention and early detection of cancer and the treatment of some malignancies, clinical research has not yet delivered treatment benefits of the magnitude anticipated after the launch of imatinib, which established highly effective new treatment standards. The primary impediments to progress are scientific, but the efficiency of research is also affected by structural deficiencies relating to where and by whom it is conducted, as well as how it is organized and regulated. To optimize the research environment and maximize the benefits of improved funding, adjustments in the roles of government, industry, the academic community, national research bodies, and regulatory authorities are needed. A patchwork of reforms that are enabling in character and build on existing expertise can deliver substantial progress without the need for radical intervention. PMID- 20167890 TI - Lifetime segmented assimilation trajectories and health outcomes in Latino and other community residents. AB - OBJECTIVES: Under an ecodevelopmental framework, we examined lifetime segmented assimilation trajectories (diverging assimilation pathways influenced by prior life conditions) and related them to quality-of-life indicators in a diverse sample of 258 men in the Phoenix, AZ, metropolitan area. METHODS: We used a growth mixture model analysis of lifetime changes in socioeconomic status, and used acculturation to identify distinct lifetime segmented assimilation trajectory groups, which we compared on life satisfaction, exercise, and dietary behaviors. We hypothesized that lifetime assimilation change toward mainstream American culture (upward assimilation) would be associated with favorable health outcomes, and downward assimilation change with unfavorable health outcomes. RESULTS: A growth mixture model latent class analysis identified 4 distinct assimilation trajectory groups. In partial support of the study hypotheses, the extreme upward assimilation trajectory group (the most successful of the assimilation pathways) exhibited the highest life satisfaction and the lowest frequency of unhealthy food consumption. CONCLUSIONS: Upward segmented assimilation is associated in adulthood with certain positive health outcomes. This may be the first study to model upward and downward lifetime segmented assimilation trajectories, and to associate these with life satisfaction, exercise, and dietary behaviors. PMID- 20167891 TI - Ethnic density effects on birth outcomes and maternal smoking during pregnancy in the US linked birth and infant death data set. AB - OBJECTIVES: We investigated whether mothers from ethnic minority groups have better pregnancy outcomes when they live in counties with higher densities of people from the same ethnic group-despite such areas tending to be more socioeconomically deprived. METHODS: In a population-based US study, we used multilevel logistic regression analysis to test whether same-ethnic density was associated with maternal smoking in pregnancy, low birthweight, preterm delivery, and infant mortality among 581 151 Black and 763 201 Hispanic mothers and their infants, with adjustment for maternal and area-level characteristics. RESULTS: Higher levels of same-ethnic density were associated with reduced odds of infant mortality among Hispanic mothers, and reduced odds of smoking during pregnancy for US-born Hispanic and Black mothers. For Black mothers, moderate levels of same-ethnic density were associated with increased risk of low birthweight and preterm delivery; high levels of same ethnic density had no additional effect. CONCLUSIONS: Our results suggest that for Hispanic mothers, in contrast to Black mothers, the advantages of shared culture, social networks, and social capital protect maternal and infant health. PMID- 20167892 TI - Effect of a two-year obesity prevention intervention on percentile changes in body mass index and academic performance in low-income elementary school children. AB - OBJECTIVES: We assessed the effects of a school-based obesity prevention intervention that included dietary, curricula, and physical activity components on body mass index (BMI) percentiles and academic performance among low-income elementary school children. METHODS: The study had a quasi-experimental design (4 intervention schools and 1 control school; 4588 schoolchildren; 48% Hispanic) and was conducted over a 2-year period. Data are presented for the subset of the cohort who qualified for free or reduced-price school lunches (68% Hispanic; n = 1197). Demographic and anthropometric data were collected in the fall and spring of each year, and academic data were collected at the end of each year. RESULTS: Significantly more intervention than control children stayed within normal BMI percentile ranges both years (P = .02). Although not significantly so, more obese children in the intervention (4.4%) than in the control (2.5%) decreased their BMI percentiles. Overall, intervention schoolchildren had significantly higher math scores both years (P < .001). Hispanic and White intervention schoolchildren were significantly more likely to have higher math scores (P < .001). Although not significantly so, intervention schoolchildren had higher reading scores both years. CONCLUSIONS: School-based interventions can improve health and academic performance among low-income schoolchildren. PMID- 20167893 TI - Avertable deaths associated with household income in Virginia. AB - OBJECTIVES: We estimated how many deaths would be averted if the entire population of Virginia experienced the mortality rates of the 5 most affluent counties or cities. METHODS: Using census data and vital statistics for the years 1990 through 2006, we applied the mortality rates of the 5 counties/cities with the highest median household income to the populations of all counties and cities in the state. RESULTS: If the mortality rates of the reference population had applied to the entire state, 24.3% of deaths in Virginia from 1990 through 2006 (range = 21.8%-28.1%) would not have occurred. An annual mean of 12 954 deaths would have been averted (range = 10 548-14 569), totaling 220 211 deaths from 1990 through 2006. In some of the most disadvantaged areas of the state, nearly half of deaths would have been averted. CONCLUSIONS: Favorable conditions that exist in areas with high household incomes exert a major influence on mortality rates. The corollary-that health suffers when society is exposed to economic stresses-is especially timely amid the current recession. Further research must clarify the extent to which individual-level factors (e.g., earnings, education, race, health insurance) and community characteristics can improve health outcomes. PMID- 20167894 TI - Trends in childhood leukemia in Basrah, Iraq, 1993-2007. AB - OBJECTIVES: Through a sister-university relationship between the University of Basrah and the University of Washington, we analyzed Ibn Ghazwan Hospital's leukemia registry data to evaluate trends in childhood leukemia since 1993. METHODS: We documented leukemia cases among children aged 0 to 14 years for each of the last 15 years. Population data were obtained from a 1997 census and various subsequent estimates to calculate rates. RESULTS: We observed 698 cases of childhood leukemia between 1993 and 2007, ranging between 15 cases (2.6 per 100 000 annual rate) in the first year and 56 cases (6.9 per 100 000 annual rate) in the final year, reaching a peak of 97 cases in 2006 (12.2 per 100 000 annual rate). CONCLUSIONS: Childhood leukemia rates in Basrah more than doubled over a 15-year period. The test for trend was significant (P = .03). Basrah's childhood leukemia rate compared unfavorably with neighboring Kuwait and nearby Oman, as well as the United States, the European Union, and other countries. PMID- 20167895 TI - Behavioral changes associated with testing HIV-positive among sexually transmitted infection clinic patients in Cape Town, South Africa. AB - OBJECTIVES: We sought to examine behavioral risks and behavior changes associated with testing HIV-positive among sexually transmitted infection (STI) patients, in order to inform HIV- and STI-prevention interventions. METHODS: We performed a cohort study of 29 STI patients who seroconverted from HIV-negative to HIV positive during 1 year of observation and 77 STI patients who persistently tested HIV-negative. Computerized behavioral interviews were collected at baseline and at 1 year, and STI clinic charts were abstracted over the same 1-year period. RESULTS: The STI patients who reported genital bleeding during sexual activity at baseline were significantly more likely to test HIV-positive. Reductions in number of sexual partners and rates of unprotected intercourse occurred for all STI clinic patients regardless of whether they tested HIV-positive. CONCLUSIONS: Although risk reductions occurred, 5% of HIV-negative STI clinic patients subsequently tested HIV-positive over 1 year. Behavioral risk-reduction interventions are urgently needed for male and female STI clinic patients. PMID- 20167896 TI - Tuberculosis transmission and use of methamphetamines in Snohomish County, WA, 1991-2006. AB - OBJECTIVES: We investigated a cluster of tuberculosis (TB) cases among persons using methamphetamines in Snohomish County, Washington, to determine the extent of the outbreak, examine whether methamphetamine use contributed to TB transmission, and implement strategies to prevent further infections. METHODS: We screened contacts to find and treat persons with TB disease or infection. We then formed a multidisciplinary team to engage substance abuse services partners and implement outreach strategies including novel methods for finding contacts and a system of incentives and enablers to promote finding, screening, and treating patients with TB and their infected contacts. RESULTS: We diagnosed and completed treatment with 10 persons with TB disease. Eight of 9 adult patients and 67% of their adult contacts reported using methamphetamines. Of the 372 contacts, 319 (85.8%) were screened, 80 (25.1%) were infected, 71 (88.8%) started treatment for latent infection, and 57 (80.3%) completed treatment for latent infection. CONCLUSIONS: Collaborative approaches integrating TB control, outreach, incentives, and enablers resulted in high rates of treatment adherence and completion among patients and infected contacts. TB control programs should collaborate with substance abuse programs to address addiction, overcome substance abuse-related barriers to treatment, treat TB, and prevent ongoing transmission. PMID- 20167897 TI - When intraclass correlation coefficients go awry: a case study from a school based smoking prevention study in South Africa. AB - OBJECTIVES: We conducted a group randomized trial of 2 South African school-based smoking prevention programs and examined possible sources and implications of why our actual intraclass correlation coefficients (ICCs) were significantly higher than the ICC of 0.02 used to compute initial sample size requirements. METHODS: Thirty-six South African high schools were randomly assigned to 1 of 3 experimental groups. On 3 occasions, students completed questionnaires on tobacco and drug use attitudes and behaviors. We used mixed-effects models to partition individual and school-level variance components, with and without covariate adjustment. RESULTS: For 30-day smoking, unadjusted ICCs ranged from 0.12 to 0.17 across the 3 time points. For lifetime smoking, ICCs ranged from 0.18 to 0.22; for other drug use variables, 0.02 to 0.10; and for psychosocial variables, 0.09 to 0.23. Covariate adjustment substantially reduced most ICCs. CONCLUSIONS: The unadjusted ICCs we observed for smoking behaviors were considerably higher than those previously reported. This effectively reduced our sample size by a factor of 17. Future studies that anticipate significant cluster-level racial homogeneity may consider using higher-value ICCs in sample-size calculations to ensure adequate statistical power. PMID- 20167898 TI - Effects of work permits on illegal employment among youth workers: findings of a school-based survey on child labor violations. AB - We compared self-reported child labor violations between teenagers with and without work permits. Data were obtained from a school-based survey of working teenagers in 16 randomly selected high schools in North Carolina. We examined associations between work hour violations, hazardous order violations (performance of illegal tasks), and possession of a work permit. Work permits appear to be protective against performance of illegal tasks but not against work hour violations, demonstrating the need for stricter enforcement policies and improvements in work permit screening processes. PMID- 20167899 TI - A system dynamics model for planning cardiovascular disease interventions. AB - Planning programs for the prevention and treatment of cardiovascular disease (CVD) is a challenge to every community that wants to make the best use of its limited resources. Selecting programs that provide the greatest impact is difficult because of the complex set of causal pathways and delays that link risk factors to CVD. We describe a system dynamics simulation model developed for a county health department that incorporates and tracks the effects of those risk factors over time on both first-time and recurrent events. We also describe how the model was used to evaluate the potential impacts of various intervention strategies for reducing the county's CVD burden and present the results of those policy tests. PMID- 20167900 TI - A randomized trial of tailored skin cancer prevention messages for adults: Project SCAPE. AB - OBJECTIVES: We evaluated the impact of a mailed, tailored intervention on skin cancer prevention and skin self-examination behaviors of adults at moderate and high risk for skin cancer. METHODS: Adults at moderate and high risk for skin cancer were recruited in primary health care settings in Honolulu, HI, and Long Island, NY. After completing a baseline survey, participants were randomized to 2 groups. The treatment group received tailored materials, including personalized risk feedback, and the control group received general educational materials. Multivariate analyses compared sun protection and skin self-examination between groups, controlling for location, risk level, gender, and age. RESULTS: A total of 596 adults completed the trial. The tailored materials had a significant effect on overall sun-protection habits, the use of hats, the use of sunglasses, and the recency of skin self-examination. Some effects were moderated by location and risk level. CONCLUSIONS: Tailored communications including personalized risk feedback can improve sun-protection behaviors and skin self-examination among adults at increased risk for skin cancer. These convenient, low-cost interventions can be implemented in a variety of settings and should be tested further to assess their long-term effectiveness. PMID- 20167901 TI - Meta-synthesis of health behavior change meta-analyses. AB - OBJECTIVES: We integrated and compared meta-analytic findings across diverse behavioral interventions to characterize how well they have achieved change in health behavior. METHODS: Outcomes from 62 meta-analyses of interventions for change in health behavior were quantitatively synthesized, including 1011 primary level investigations with 599,559 participants. Content coding suggested 6 behavioral domains: eating and physical activity, sexual behavior, addictive behaviors, stress management, female-specific screening and intervention behaviors, and behaviors involving use of health services. RESULTS: Behavior change interventions were efficacious (mean effect sizes = 0.08-0.45). Behavior change was more evident in more recent meta-analyses; those that sampled older interventions and literatures or sampled more published articles; those that included studies that relied on self-report, used briefer interventions, or sampled fewer, older, or female participants; and in some domains (e.g., stress management) more than others (e.g., sexual behaviors). CONCLUSIONS: Interventions improved health-related behaviors; however, efficacy varied as a function of participant and intervention characteristics. This meta-synthesis provides information about the efficacy of behavioral change interventions across health domains and populations; this knowledge can inform the design and development of public health interventions and future meta-analyses of these studies. PMID- 20167902 TI - Detecting selection effects in community implementations of family-based substance abuse prevention programs. AB - To calculate valid estimates of the costs and benefits of substance abuse prevention programs, selection effects must be identified and corrected. A supplemental comparison sample is typically used for this purpose, but in community-based program implementations, such a sample is often not available. We present an evaluation design and analytic approach that can be used in program evaluations of real-world implementations to identify selection effects, which in turn can help inform recruitment strategies, pinpoint possible selection influences on measured program outcomes, and refine estimates of program costs and benefits. We illustrate our approach with data from a multisite implementation of a popular substance abuse prevention program. Our results indicate that the program's participants differed significantly from the population at large. PMID- 20167903 TI - Effectiveness of an HIV/STD risk-reduction intervention for adolescents when implemented by community-based organizations: a cluster-randomized controlled trial. AB - OBJECTIVES: We evaluated the effectiveness of an HIV/STD risk-reduction intervention when implemented by community-based organizations (CBOs). METHODS: In a cluster-randomized controlled trial, 86 CBOs that served African American adolescents aged 13 to 18 years were randomized to implement either an HIV/STD risk-reduction intervention whose efficacy has been demonstrated or a health promotion control intervention. CBOs agreed to implement 6 intervention groups, a random half of which completed 3-, 6-, and 12-month follow-up assessments. The primary outcome was consistent condom use in the 3 months prior to each follow-up assessment, averaged over the follow-up assessments. RESULTS: Participants were 1707 adolescents, 863 in HIV/STD-intervention CBOs and 844 in control intervention CBOs. HIV/STD-intervention participants were more likely to report consistent condom use (odds ratio [OR] = 1.39; 95% confidence interval [CI] = 1.06, 1.84) than were control-intervention participants. HIV/STD-intervention participants also reported a greater proportion of condom-protected intercourse (beta = 0.06; 95% CI = 0.00, 0.12) than did the control group. CONCLUSIONS: This is the first large, randomized intervention trial to demonstrate that CBOs can successfully implement an HIV/STD risk-reduction intervention whose efficacy has been established. PMID- 20167904 TI - 'Al pie de la letra': crafting a report card for elderly Spanish-only-speaking patients with stroke. AB - BACKGROUND AND PURPOSE: Ethnic minorities are at higher stroke risk than non Hispanic whites yet are less likely to have optimal vascular risk factor control. There is a need to develop culturally sensitive strategies for enhancing vascular risk reduction in minority patients with stroke. This study aimed to develop a postdischarge report card to boost treatment adherence among elderly Spanish speaking patients with stroke within an urban health system. METHODS: This study included a total of 13 Spanish-only speaking participants aged > or = 60 years discharged from a local government hospital in Los Angeles within 18 months of an index ischemic stroke and 6 caregivers engaged in focus groups and interviews. Structured interviews were conducted with 11 care providers and 9 administrators at the hospital. Framework analysis examined the data and elicited themes to adapt a pre-existing patient report card tool. RESULTS: Spontaneously using the same phrase, "Al pie de la letra," several participants expressed a need to follow medical instructions accurately to prevent recurrent stroke and identified barriers/facilitators for doing so. They made comments about the pre-existing report card, advising several changes, including the clarification of phrases, and written instructions to explain the need for the card and how to fill it out. The providers and administrators recommended avenues for successfully using the card at the hospital. A new report card was created that incorporated all major perspectives. CONCLUSIONS: Crafting a culturally sensitive tool for promoting treatment adherence in elderly Spanish-only-speaking patients with stroke within an urban health system using a participatory methodology is feasible. The efficacy of this new report card should be tested in a randomized controlled trial. PMID- 20167905 TI - Urinary tract infections complicating stroke: mechanisms, consequences, and possible solutions. AB - BACKGROUND AND PURPOSE: Hospital-acquired urinary tract infection (UTI) is a common complication in hospitalized patients. Recently, catheter-associated UTI has been identified by the Centers for Medicare and Medicaid Services as a preventable condition, and additional payments to hospitals for its treatment are now declined, increasing the need for prevention of this important complication. SUMMARY OF REVIEW: This article explores in-depth the pathophysiology, risk factors for, and consequences of UTI after stroke and possible methods to reduce its incidence in the stroke population. Patients with stroke are particularly vulnerable to UTI due to increased risk from immunosuppression, bladder dysfunction, and increased Foley catheter use; and the fever and systemic inflammatory response associated with UTI may impair stroke recovery. UTI is associated with poorer neurological outcomes, longer hospital stays, and increased cost of care after stroke. Intervention strategies previously attempted in this and other populations include prophylactic antibiotics, antiseptic impregnated catheters, and quality improvement interventions to reduce inappropriate catheterization. CONCLUSION: Patients with stroke have different risks for, consequences of, and barriers to reducing UTI than other hospitalized patients. Further research is needed to develop an effective approach to decreasing this important complication in the stroke population. PMID- 20167906 TI - Alarmingly high serious complication rate of stent-assisted coiling in unruptured intracranial aneurysms: the need for reflection and reconsideration. PMID- 20167908 TI - Outcome improvement in acute stroke revascularization procedures. PMID- 20167907 TI - Augmented superoxide production by Nox2-containing NADPH oxidase causes cerebral artery dysfunction during hypercholesterolemia. AB - BACKGROUND AND PURPOSE: We tested the hypothesis that elevated superoxide production by Nox2-NADPH oxidase occurs in cerebral arteries during hypercholesterolemia and causes decreased nitric oxide function. METHODS: Wild type (WT), apolipoprotein E-deficient (ApoE(-/-)) and Nox2(-/-)/ApoE(-/-) mice were fed a high-fat diet for 7 to 14 weeks. Basal superoxide production by cerebral arteries was measured using L-012 (100 micromol/L)-enhanced chemiluminescence. Nitric oxide function was assessed in isolated middle cerebral arteries through the constrictor response to N(omega)-nitro-L-arginine methyl ester (L-NAME; 100 micromol/L). Western blotting was used to measure protein expression of Nox2, p47phox, endothelial nitric oxide synthase, and superoxide dismutases (1-3). RESULTS: Morphology of cerebral arteries was similar in WT and ApoE(-/-) mice. In ApoE(-/-), but not Nox2(-/-)/ApoE(-/-) mice, superoxide production by cerebral arteries was approximately 50% greater than in WT mice (P<0.05). Moreover, the magnitude of L-NAME-induced contractions of isolated middle cerebral arteries from ApoE(-/-) mice was <50% of that in WT mice (P<0.05), whereas in Nox2(-/-)/ApoE(-/-) mice, the contractile response was comparable to WT responses. In the presence of the superoxide scavenger, tempol (1 mmol/L), L-NAME-induced contractions of middle cerebral arteries were similar between WT and ApoE(-/-) mice. Expression of p47phox was approximately 2-fold higher in ApoE(-/-) versus WT mice, whereas Nox2, endothelial nitric oxide synthase, and superoxide dismutase isoforms were unchanged. CONCLUSIONS: Elevated superoxide production and reduced basal nitric oxide-mediated relaxation occur in cerebral arteries of hypercholesterolemic mice even in the absence of lesions. These changes appear to be exclusively due to increased activity of Nox2-NADPH oxidase, possibly through increased expression of its regulatory subunit p47phox. PMID- 20167909 TI - 'Where there's smoke ...': are premature ventricular complexes a new risk factor for stroke? PMID- 20167910 TI - Emergency physician and stroke specialist beliefs and expectations regarding telestroke. AB - BACKGROUND AND PURPOSE: Telestroke has been effective in the management of acute ischemic stroke. This study characterizes and compares stroke specialist (SS) and emergency physician (EP) perceptions of telestroke and identifies barriers preventing increased implementation. METHODS: A survey was developed and distributed nationwide to 382 SSs through an online survey system and in paper form to 226 EPs attending the 2008 American College of Emergency Physicians national conference. RESULTS: Stroke specialists perceived themselves to be more knowledgeable about telemedicine and telestroke (P<0.001 and P=0.010, respectively). A large majority of physicians in both specialties either strongly agreed or agreed that telestroke will reduce geographical differences in stroke management and that it is superior to telephone consultation. EPs perceived patient preference (P<0.001), recombinant tissue plasminogen activator side effects (P<0.001), level of technology (P=0.005), and recombinant tissue plasminogen activator not the standard of care (P<0.001) to be more significant obstacles to increased implementation of telestroke than SSs. However, SSs found increased personal work to be a greater barrier than EPs (P<0.001). CONCLUSIONS: SSs and EPs report positive beliefs regarding telestroke; however, perceived obstacles exist to implementation. Differences between barriers perceived by EPs and SSs need to be addressed to enhance acute ischemic stroke treatment. PMID- 20167911 TI - A matching algorithm to address imbalances in study populations: application to the National Institute of Neurological Diseases and Stroke Recombinant Tissue Plasminogen Activator acute stroke trial. AB - BACKGROUND AND PURPOSE: Outcome from stroke is highly dependent on baseline conditions. Patients with stroke have a wide range of severities, ages, and etiologies and it has proven difficult to achieve randomization of key variables in clinical trials. We present a new post hoc approach to achieve balance among selected variables. To illustrate the approach, we rebalanced the National Institute of Neurological Diseases and Stroke Recombinant Tissue Plasminogen Activator trial, in which the contribution of baseline imbalances continues to be debated. METHODS: We selected baseline stroke severity (National Institutes of Health Stroke Scale), age, and glucose as matching criteria. The closest matched placebo and treated subjects were identified based on nearness to each other in 3 dimensional Euclidean space. Matching was performed within the quintiles of National Institutes of Health Stroke Scale that have been previously used to assess balance. Subjects who could not be matched were eliminated. Outcomes were assessed using the original specified National Institute of Neurological Diseases and Stroke trial measures. RESULTS: We successfully matched the 2 arms resulting in nearly identical baseline characteristics and distribution among quintiles. Despite fewer subjects after outlier elimination, the primary outcome measures remained significantly improved. After rebalancing, the magnitude of benefit was reduced by 13% to 23%. Benefit was apparent mostly in the large vessel occlusion subtype. CONCLUSION: This study demonstrated the feasibility of rebalancing individual subjects within a randomized trial. After rebalancing and outlier elimination, recombinant tissue plasminogen activator continued to demonstrate improved outcome. That the apparent treatment effect was reduced suggests that imbalances contributed to the magnitude of the original National Institute of Neurological Diseases and Stroke outcomes. This method could in theory be applied to any data set to find matched subjects for outcome or other analyses. PMID- 20167912 TI - Acupuncture in poststroke rehabilitation: a systematic review and meta-analysis of randomized trials. AB - BACKGROUND AND PURPOSE: Acupuncture is a low-risk treatment with purported claims of effectiveness for poststroke rehabilitation. To comprehensively assess the efficacy of acupuncture in poststroke rehabilitation, we conducted a systematic review and meta-analysis of all randomized clinical trials of acupuncture for poststroke rehabilitation. METHODS: We searched 7 English and 2 Chinese databases from inception to September 2009. Eligible studies included randomized clinical trials that evaluated the clinical efficacy of acupuncture in adult patients with disability after stroke. We extracted data on trial quality, protocol, and outcomes assessed. A summary OR was calculated based on pooled dichotomous results. I(2) was used to infer heterogeneity and we conducted metaregression to determine if specific covariates explained heterogeneity. RESULTS: Thirty-five articles written in Chinese and 21 articles written in English were included. The overall quality of the studies was "fair" and most studies were small (median n=86; range, 16 to 241). The majority (80%) of the studies reported a significant benefit from acupuncture; however, there was some evidence of publication bias. In 38 trials, data were available for meta-analysis and metaregression, yielding an OR in favor of acupuncture compared with controls (OR=4.33, 95% CI: 3.09 to 6.08; I2=72.4%). Randomization, modes of delivery, method of control, study source country, and reporting of randomization may explain some of the heterogeneity observed between the studies. CONCLUSIONS: Randomized clinical trials demonstrate that acupuncture may be effective in the treatment of poststroke rehabilitation. Poor study quality and the possibility of publication bias hinder the strength of this recommendation and argue for a large, transparent, well-conducted randomized clinical trial to support this claim and implement changes to clinical practice. PMID- 20167913 TI - Five-year outcome of a stroke cohort in Martinique, French West Indies: Etude Realisee en Martinique et Centree sur l'Incidence des Accidents vasculaires cerebraux, Part 2. AB - BACKGROUND AND PURPOSE: Limited information exists on stroke among black populations outside the United States and United Kingdom. Part 1 of the Etude Realisee en Martinique et Centree sur l'Incidence des Accidents vasculaires cerebraux (ERMANCIA) provided strong epidemiologic data on the incidence of first ever stroke in a black Caribbean population and showed a 40% greater incidence of stroke in Martinique than in continental France. In ERMANCIA part 2, we evaluated the long-term outcomes of our cohort. METHODS: Survivors of a first stroke from this prospective, community-based, stroke incidence study were reassessed at 5 years according to standardized procedures and criteria, including the modified Rankin scale, Barthel Index, Montgomery-Asberg Depression-Rating Scale, Mini Mental State Examination, treatment compliance, and blood pressure control. RESULTS: Of the 293 survivors of the original 580 (50.5%) patients who were still alive 5 years after stroke, 262 (89.4%) were assessed. Among these survivors, 66.4% were functionally independent and 43% were completely autonomous for activities of daily living, but 25.8% were depressed and 58.9% were cognitively impaired. Only 50 of 170 (29.4%) of the hypertensive patients achieved their target blood pressure. CONCLUSIONS: These results highlight the very poor blood pressure control and the very high rate of cognitive impairment in Martinican patients after stroke. As a consequence, a poststroke prevention network was established in Martinique. PMID- 20167914 TI - Statewide hospital-based stroke services in North Carolina: changes over 10 years. AB - BACKGROUND AND PURPOSE: Statewide assessments of stroke prevention and treatment services were performed in North Carolina in 1998 and 2003. The 2003 survey found certain technologies, but not stroke-related programs, were more widely available. The survey was repeated in 2008 to determine whether there was an interval change in accessibility. METHODS: A 2-page questionnaire was sent to each North Carolina hospital. Results were compared with the 1998 and 2003 surveys. RESULTS: Complete responses were obtained from each of the state's emergent stroke care hospitals. The proportions providing CT angiography and diffusion-weighted MRI increased between each period (each P<0.05); the use of care maps and intravenous tissue plasminogen activator protocols increased between 2003 and 2008 but not between 1998 and 2003. There were no changes in availability of MRI, MR angiography, catheter angiography, carotid ultrasound, transcranial Doppler, transthoracic echocardiography, or in the proportions of hospitals having a stroke unit, having a neurologist or neurointerventionalist readily available, or providing stroke-related public education (each P>0.05). The proportions of hospitals having a group of "basic" stroke capabilities did not change (18%, 21%, and 20%, respectively, P>0.05). In 2008, 41% of North Carolina's population resided in a county with at least 1 Primary Stroke Center and an additional 40% in a county using telemedicine or having a transfer plan for patients with acute stroke. CONCLUSIONS: The availability of certain diagnostic tests, but not specialty staff or stroke units, increased in North Carolina hospitals between 1998 and 2008. Although there was no change in stroke related hospital-based organizational features between 1998 and 2003, there were improvements between 2003 and 2008, possibly reflecting programs aimed at developing stroke care systems. PMID- 20167915 TI - Radiological investigation of spontaneous intracerebral hemorrhage: systematic review and trinational survey. AB - BACKGROUND AND PURPOSE: It is not always clear whether, how, and when to undertake further radiological investigation of spontaneous (nontraumatic) intracerebral hemorrhage (ICH). METHODS: We systematically reviewed Ovid MEDLINE and EMBASE databases for studies of the diagnostic utility of radiological investigations of the cause(s) of ICH. We sent a structured survey to neurologists, stroke specialists, neurosurgeons, and neuroradiologists in the United Kingdom, the Netherlands, and France to assess whether, how, and when they would investigate supratentorial ICH. RESULTS: This systematic review detected 20 relevant studies (including 1933 patients), which either quantified the yield of a radiological investigation/imaging strategy (n=15) or compared 2 imaging techniques (n=5). Six hundred ninety-two (49%) physicians responded to the survey. Further investigation would have been undertaken by the following: 99% of respondents, for younger (38 to 43 years), normotensive adults with lobar or deep ICH; 76%, for older (age 72 to 83 years), normotensive adults with deep ICH; and 31%, for older adults with deep ICH and prestroke hypertension. Younger patient age was the strongest influence on the decision to further investigate ICH (odds ratio=16; 95% confidence interval, 13 to 20), followed by the absence of prestroke hypertension (odds ratio=5; 95% confidence interval, 4 to 6) and lobar ICH location (odds ratio=2; 95% confidence interval, 1 to 2). CONCLUSIONS: The paucity of studies on the diagnostic utility of imaging investigations of the cause(s) of ICH may contribute to the variation observed in when and how and which patients are investigated in current clinical practice. Studies comparing different types of diagnostic strategies are required. PMID- 20167916 TI - Presence of finger extension and shoulder abduction within 72 hours after stroke predicts functional recovery: early prediction of functional outcome after stroke: the EPOS cohort study. AB - BACKGROUND AND PURPOSE: The aim of the present study was to determine if outcome in terms of upper limb function at 6 months after stroke can be predicted in hospital stroke units using clinical parameters measured within 72 hours after stroke. In addition, the effect of the timing of assessment after stroke on the accuracy of prediction was investigated by measurements on days 5 and 9. METHODS: Candidate determinants were measured in 188 stroke patients within 72 hours and at 5 and 9 days after stroke. Logistic regression analysis was used for model development to predict upper limb function at 6 months measured with the action research arm test (ARAT). RESULTS: Patients with an upper limb motor deficit who exhibit some voluntary extension of the fingers and some abduction of the hemiplegic shoulder on day 2 have a probability of 0.98 to regain some dexterity at 6 months, whereas the probability was 0.25 for those without this voluntary motor activity. Sixty percent of patients with some early finger extension achieved full recovery at 6 months in terms of action research arm test score. Retesting the model on days 5 and 9 resulted in a gradual decline in probability from 0.25 to 0.14 for those without voluntary motor activity of shoulder abduction and finger extension, whereas the probability remained 0.98 for those with this motor activity. CONCLUSIONS: Based on 2 simple bedside tests, finger extension and shoulder abduction, functional recovery of the hemiplegic arm at 6 months can be predicted early in a hospital stroke unit within 72 hours after stroke onset. PMID- 20167917 TI - Ultraearly thrombolysis in acute ischemic stroke is associated with better outcome and lower mortality. AB - BACKGROUND AND PURPOSE: Pooled analysis of major placebo-controlled trials suggests that the earlier thrombolysis is given after ischemic stroke, the better the outcome. We report a single-center assessment of the effect of ultraearly thrombolysis on the outcome of our patients. METHODS: Between January 2003, and December 2008, a total of 878 patients with ischemic stroke received thrombolysis within 4.5 hours from the symptom onset at the Helsinki University Central Hospital. Using univariate methods and multivariable logistic regression, we assessed the association between onset-to-treatment time (OTT) and favorable 3 month outcome (modified Rankin Scale 0 to 2). RESULTS: Median age was 70.5 years, median OTT 115 minutes, and median National Institutes of Health Stroke Scale (NIHSS) on admission 9. After adjustment for baseline stroke severity, more patients with OTT <70 minutes had a favorable outcome than those with OTT > or = 70 minutes. Specifically, OR of 5.15 (1.50 to 27.5) was for the patients with NIHSS 7 to 12, and 2.74 (1.26 to 5.90) for those with NIHSS > or = 13. Of the patients with OTT < or = 90 minutes, those with NIHSS 7 to 12 had an OR of 1.72 (1.00 to 2.96) for a favorable outcome, and those with NIHSS > or = 13 had lower mortality than the ones with OTT >90 minutes (16.4% versus 29.5%; P=0.01). Multivariable model showed an association of better outcome with lower baseline glucose level, younger age, lower baseline NIHSS, and OTT <70 minutes. CONCLUSIONS: Ultraearly thrombolysis was associated with better outcome of our patients with stroke with moderate or severe symptoms. The earlier the treatment was given, the higher the likelihood of favorable outcome. PMID- 20167918 TI - Advances in genomic analysis of stroke: what have we learned and where are we headed? AB - As a result of technological advances, the genomic analysis of stroke has shifted from candidate gene association studies to genome-wide association studies (GWAS). Agnostic GWAS evaluate up to 90% of common genetic variation in a single experiment, creating an improved framework for identifying novel genetic leads for biochemical and cellular mechanisms underlying stroke. Given the ubiquity of the GWAS approach, it has become essential for stroke researchers and clinicians to be able to interpret GWAS results. Thus, we review the basic elements of design, methods, presentation, and interpretation of GWAS in the context of stroke research. In 8 recent stroke GWAS reports, no single locus has been identified in 2 GWAS at a genome-wide level of significance. Additionally, no significant association signal between stroke and a locus with previous evidence from candidate gene studies of stroke has been identified yet. Some caveats of the approach and future directions for stroke genomics are discussed, including the use of intermediate phenotypes, Mendelian randomization, phenomics, and deep resequencing. Intelligent, appropriately powered, multidisciplinary studies incorporating knowledge from clinical medicine, epidemiology, genetics, and molecular biology will be required to fully characterize the genomic contributors to stroke. PMID- 20167919 TI - Association of MRI markers of vascular brain injury with incident stroke, mild cognitive impairment, dementia, and mortality: the Framingham Offspring Study. AB - BACKGROUND AND PURPOSE: White matter hyperintensities and MRI-defined brain infarcts (BIs) have individually been related to stroke, dementia, and mortality in population-based studies, mainly in older people. Their significance in middle aged community-dwelling persons and the relative importance of these associations remain unclear. We simultaneously assessed the relation of white matter hyperintensities and BI with incident stroke, mild cognitive impairment, dementia, and mortality in a middle-aged community-based cohort. METHODS: A total of 2229 Framingham Offspring Study participants aged 62+/-9 years underwent volumetric brain MRI and neuropsychological testing (1999 to 2005). Incident stroke, dementia, and mortality were prospectively ascertained and for 1694 participants in whom a second neuropsychological assessment was performed (2005 to 2007), incident mild cognitive impairment was evaluated. All outcomes were related to white matter hyperintensities volume (WMHV), age-specific extensive WMHV and BI adjusting for age and gender. RESULTS: Extensive WMHV and BI were associated with an increased risk of stroke (hazard ratio [HR]=2.28, 95% CI: 1.02 to 5.13; HR=2.84, 95% CI: 1.32 to 6.10). WMHV, extensive WMHV, and BI were associated with an increased risk of dementia (HR=2.22, 95% CI: 1.32 to 3.72; HR=3.97, 95% CI: 1.10 to 14.30; HR=6.12, 95% CI: 1.82 to 20.54) independently of vascular risk factors and interim stroke. WMHV and extensive WMHV were associated with incident amnestic mild cognitive impairment in participants aged > or = 60 years only (OR=2.47, 95% CI: 1.31 to 4.66 and OR=1.49, 95% CI: 1.14 to 1.97). WMHV and extensive WMHV were associated with an increased risk of death (HR=1.38, 95% CI: 1.13 to 1.69; HR=2.27, 95% CI: 1.41 to 3.65) independent of vascular risk factors and of interim stroke and dementia. CONCLUSIONS: In a large community based sample of middle-aged adults, BI predicted an increased risk of stroke and dementia independent of vascular risk factors. White matter hyperintensities portended an increased risk of stroke, amnestic mild cognitive impairment, dementia, and death independent of vascular risk factors and interim vascular events. PMID- 20167920 TI - Retinal microvascular signs may provide clues to the underlying vasculopathy in patients with deep intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Deep intracerebral hemorrhage (ICH) and lacunar infarcts are the result of small vessel disease, whereas nonlacunar infarcts are often caused by large artery atherosclerosis or cardiac embolism. We hypothesized that patients with deep ICH and lacunar infarcts have similar retinal microvascular signs and that these differ from those seen in patients with nonlacunar infarcts. METHODS: We studied patients with acute stroke and classified their stroke as deep ICH, lacunar infarction, or nonlacunar infarction. In a masked fashion we assessed retinal photographs for quantitative and qualitative evidence of microvascular damage. RESULTS: We recruited 630 patients (51 had deep ICH, 93 had lacunar infarction, and 486 had nonlacunar infarction). Patients with deep ICH were more likely than those with nonlacunar infarcts to have severe focal narrowing of the retinal arterioles (OR, 3.7), severe arteriovenous nicking (OR, 2.6), and quantitatively narrower retinal arterioles and wider retinal venules. Retinal microvascular signs were similar in patients with deep ICH and lacunar infarction. CONCLUSIONS: Patients with deep ICH and lacunar infarcts are more likely than patients with nonlacunar infarcts to have signs indicating hypertensive damage in the retinal arteriolar wall. PMID- 20167921 TI - Clinical spectrum of CADASIL and the effect of cardiovascular risk factors on phenotype: study in 200 consecutively recruited individuals. AB - BACKGROUND AND PURPOSE: Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is an inherited arteriopathy with clinical features that include recurrent lacunar stroke, migraine, and cognitive impairment. For reasons that remain unclear, there is great variability in the clinical expression of CADASIL, both between and within families. This study examined the clinical phenotype as well as any associations with risk factors and genotype in a large, prospective cohort. METHODS: Two hundred symptomatic individuals from 124 families were recruited as part of a UK prevalence study of CADASIL and were seen subsequently in a national referral clinic. All were assessed by a standardized questionnaire and examination. RESULTS: Mean age at assessment was 47.7 years and was 33.6 years at symptom onset. Migraine, usually with aura, was the most prevalent feature, affecting 75% of individuals. More than half had a history of stroke, with a mean age at onset of 46 years. Hypertension (odds ratio=2.57, P=0.007) and pack-years of smoking (odds ratio=1.07, P=0.001) were associated with an increased risk of stroke. A history of stroke was a significant risk factor for both dementia and disability. Mutations clustered in exon 4 of the NOTCH3 gene, which contained > or = 71.4% of familial mutations. Four previously unreported mutations were found (T697C, C1279T, G1370C, and C1774T). No associations were identified between genotype and clinical phenotype. CONCLUSIONS: Our data suggest that cardiovascular risk factors may modulate the clinical expression of CADASIL. The associations with hypertension and smoking suggest that risk factors should be treated aggressively in patients with CADASIL. PMID- 20167922 TI - Premature ventricular complexes and the risk of incident stroke: the Atherosclerosis Risk In Communities (ARIC) Study. AB - BACKGROUND AND PURPOSE: Premature ventricular complexes (PVCs) on a 2-minute electrocardiogram are a common, largely asymptomatic finding associated with increased risk of coronary heart disease and death. They may reflect atherosclerosis or other pathogenic pathways that predispose to arrhythmias and stroke. METHODS: We conducted a prospective evaluation of the Atherosclerosis Risk In Communities Study cohort (n=14,783) of middle-aged men and women to assess whether the presence of PVCs at study baseline (1987 to 1989) influenced the risk of incident stroke through December 31, 2004. RESULTS: PVCs were seen in 6.1% of the participants at baseline, and 729 (4.9%) had incident stroke. The unadjusted cumulative proportion of incident stroke in individuals with any PVC was 6.6% compared with 4.1% in those without PVC. The unadjusted hazard ratio of incident stroke in individuals with any PVC compared with those without any PVCs was 1.71 (95% CI, 1.33 to 2.20). Among individuals without hypertension and diabetes at baseline, PVCs were independently associated with incident stroke (hazard ratio: 1.72; 95% CI: 1.14 to 2.59). Among those with either diabetes or hypertension, the presence of any PVCs did not increase the risk of stroke. The association was stronger for noncarotid embolic stroke than for thrombotic stroke and its magnitude increased with higher frequency of PVCs. CONCLUSIONS: Frequent PVCs are associated with risk of incident stroke in participants free of hypertension and diabetes. This suggests that PVCs may contribute to atrioventricular remodeling or may be a risk marker for incident stroke, particularly embolic stroke. PMID- 20167923 TI - Diagnostic criteria and yield of real-time transcranial Doppler monitoring of intra-arterial reperfusion procedures. AB - BACKGROUND AND PURPOSE: Intra-arterial (IA) rescue procedures are increasingly used to treat acute ischemic stroke. We implemented continuous transcranial Doppler (TCD) monitoring during these procedures to detect any potentially harmful flow changes. Here, we report diagnostic criteria and yield of TCD monitoring. METHODS: We studied consecutive acute stroke patients who underwent IA reperfusion procedures. TCD flow signatures during these procedures were analyzed and any abnormal findings were documented. RESULTS: Patients were included only if there was successful insonation through the skull; of 56 eligible patients, 51 were included. IA procedures included IA tissue plasminogen activator, use of the Merci retriever, the Penumbra system, balloon angioplasty, and stenting. On TCD monitoring, contrast injections produced high-intensity signals and increased the mean flow velocity (MFV). Deployment of the Merci device appeared as high-intensity, short-duration signals with a transient MFV decrease of 11.5%. The Penumbra system produced lower-intensity signals with a greater transient decrease in MFV during aspiration. IA tissue plasminogen activator significantly increased MFV by 7.5% over Merci and Penumbra flow velocity changes. Power motion Doppler-TCD detected reocclusion in 13 patients, artery-to-artery embolization in 2 patients, air embolism in 2 patients, and hyperperfusion in 6 patients. Overall, the yield of TCD monitoring was positive in 23 (49%) patients who received IA reperfusion procedures. CONCLUSIONS: Our velocity, intensity, and flow signatures criteria for TCD monitoring of IA reperfusion procedures detect reocclusion, hyperperfusion, or thromboembolism and air embolism in nearly half of all procedures. This hemodynamic information can be particularly helpful when neurological assessment is limited or delayed. PMID- 20167924 TI - A novel loss-of-function DDAH1 promoter polymorphism is associated with increased susceptibility to thrombosis stroke and coronary heart disease. AB - RATIONALE: Asymmetrical dimethylarginine (ADMA), an endogenous arginine analogue, inhibits nitric oxide synthases and plays an important role in endothelial dysfunction. OBJECTIVE: In the present study, we tested whether a novel genetic variant in dimethylarginine dimethylaminohydrolase 1 (DDAH1), an important ADMA hydrolyzing gene, was associated with stroke and coronary heart disease (CHD) susceptibility in the Chinese Han population. METHODS AND RESULTS: By resequencing, we identified a novel 4-nucleotide deletion/insertion variant in the DDAH1 promoter. The insertion allele disrupted binding of metal-regulatory transcription factor 1, which resulted in significant reduction of in vitro DDAH1 transcriptional activity and in vivo DDAH1 mRNA level, and in turn, increased plasma ADMA level and the ratio of ADMA to L-arginine. We initially genotyped the polymorphism in 1388 stroke patients and 1027 controls as well as 576 CHD patients and 557 controls and then replicated our study in additional independent case-control cohorts comprising 961 stroke patients and 822 controls and 482 CHD patients and 1072 controls. We identified that the -396 4N ins allele was significantly associated with increased risk of thrombosis stroke and CHD after adjusting for environmental factors in both samples for both diseases (thrombosis stroke discovery set: odds ratio [OR]=1.35, P=0.032; replication set: OR=1.51, P=0.006; CHD discovery set: OR=1.45, P=0.035; replication set: OR=1.47, P=0.003). CONCLUSIONS: Our results suggest that the DDAH1 loss-of-function polymorphism is associated with both increased risk of thrombosis stroke and CHD. PMID- 20167925 TI - Zac1 is an essential transcription factor for cardiac morphogenesis. AB - RATIONALE: The transcriptional networks guiding heart development remain poorly understood, despite the identification of several essential cardiac transcription factors. OBJECTIVE: To isolate novel cardiac transcription factors, we performed gene chip analysis and found that Zac1, a zinc finger-type transcription factor, was strongly expressed in the developing heart. This study was designed to investigate the molecular and functional role of Zac1 as a cardiac transcription factor. METHODS AND RESULTS: Zac1 was strongly expressed in the heart from cardiac crescent stages and in the looping heart showed a chamber-restricted pattern. Zac1 stimulated luciferase reporter constructs driven by ANF, BNP, or alphaMHC promoters. Strong functional synergy was seen between Zac1 and Nkx2-5 on the ANF promoter, which carries adjacent Zac1 and Nkx2-5 DNA-binding sites. Zac1 directly associated with the ANF promoter in vitro and in vivo, and Zac1 and Nkx2 5 physically associated through zinc fingers 5 and 6 in Zac1, and the homeodomain in Nkx2-5. Zac1 is a maternally imprinted gene and is the first such gene found to be involved in heart development. Homozygous and paternally derived heterozygous mice carrying an interruption in the Zac1 locus showed decreased levels of chamber and myofilament genes, increased apoptotic cells, partially penetrant lethality and morphological defects including atrial and ventricular septal defects, and thin ventricular walls. CONCLUSIONS: Zac1 plays an essential role in the cardiac gene regulatory network. Our data provide a potential mechanistic link between Zac1 in cardiogenesis and congenital heart disease manifestations associated with genetic or epigenetic defects in an imprinted gene network. PMID- 20167926 TI - Inotropic response of cardiac ventricular myocytes to beta-adrenergic stimulation with isoproterenol exhibits diurnal variation: involvement of nitric oxide. AB - RATIONALE: Although >10% of cardiac gene expression displays diurnal variations, little is known of their impact on excitation-contraction coupling. OBJECTIVE: To determine whether the time of day affects excitation-contraction coupling in rat ventricles. METHODS AND RESULTS: Left ventricular myocytes were isolated from rat hearts at 2 opposing time points, corresponding to the animals resting or active periods. Basal contraction and [Ca(2+)](i) was significantly greater in myocytes isolated during the resting versus active periods (cell shortening 12.4+/-0.3 versus 11.0+/-0.2%; P<0.05 and systolic [Ca(2+)](i) 422+/-12 versus 341+/-9 nmol/L; P<0.01. This corresponded to a greater sarcoplasmic reticulum (SR) Ca(2+) load (672+/-20 versus 551+/-13 nmol/L P<0.001). The increase in systolic [Ca(2+)](i) in response to isoproterenol (>3 nmol/L) was also significantly greater in resting versus active period myocytes, reflecting a greater SR Ca(2+) load at this time. This diurnal variation in response of Ca(2+)-homeostasis to isoproterenol translated to a greater incidence of arrhythmic activity in resting period myocytes. Inhibition of neuronal NO synthase during stimulation with isoproterenol, further increased systolic [Ca(2+)](i) and the percentage of arrhythmic myocytes, but this effect was significantly greater in active period versus resting period myocytes. Quantitative RT-PCR analysis revealed a 2.65-fold increase in neuronal NO synthase mRNA levels in active over resting period myocytes (P<0.05). CONCLUSIONS: The threshold for the development of arrhythmic activity in response to isoproterenol is higher during the active period of the rat. We suggest this reflects a reduction in SR Ca(2+) loading and a diurnal variation in neuronal NO synthase signaling. PMID- 20167927 TI - AMPKalpha2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: role of 26S proteasomes. AB - RATIONALE: AMP-activated protein kinase (AMPK) is an energy sensor and ubiquitously expressed in vascular cells. Recent studies suggest that AMPK activation improves endothelial function by counteracting oxidative stress in endothelial cells. How AMPK suppresses oxidative stress remains to be established. OBJECTIVE: The aim of this study is to examine the effects of AMPK in regulating NAD(P)H oxidase, oxidative stress, and endothelial function. METHODS AND RESULTS: The markers of oxidative stress, NAD(P)H oxidase subunit expression (gp91(phox), p47(phox), p67(phox), NOX1 to -4), NAD(P)H oxidase mediated superoxide production, 26S proteasome activity, IkappaBalpha degradation, and nuclear translocation of nuclear factor (NF)-kappaB (p50 and p65) were examined in cultured human umbilical vein endothelial cells and mouse aortas isolated from AMPKalpha2 deficient mice. Compared to the wild type, acetylcholine-induced endothelium-dependent relaxation was significantly impaired in parallel with increased production of oxidants in AMPKalpha2(-/-) mice. Further, pretreatment of aorta with either superoxide dismutase (SOD) or tempol or apocynin significantly improved acetylcholine-induced endothelium-dependent relaxation in AMPKalpha2(-/-) mice. Analysis of aortic endothelial cells from AMPKalpha2(-/-) mice and human umbilical vein endothelial cells expressing dominant negative AMPK or AMPKalpha2-specific siRNA revealed that loss of AMPK activity increased NAD(P)H oxidase subunit expression (gp91(phox), p47(phox), p67(phox), NOX1 and -4), NAD(P)H oxidase-mediated superoxide production, 26S proteasome activity, IkappaBalpha degradation, and nuclear translocation of NF kappaB (p50 and p65), whereas AMPK activation by AICAR or overexpression of constitutively active AMPK had the opposite effect. Consistently, we found that genetic deletion of AMPKalpha2 in low-density lipoprotein receptor knockout (LDLr(-/-)) strain markedly increased 26S proteasome activity, IkappaB degradation, NF-kappaB transactivation, NAD(P)H oxidase subunit overexpression, oxidative stress, and endothelial dysfunction, all of which were largely suppressed by chronic administration of MG132, a potent cell permeable proteasome inhibitor. CONCLUSIONS: We conclude that AMPKalpha2 functions as a physiological suppressor of NAD(P)H oxidase and ROS production in endothelial cells. In this way, AMPK maintains the nonatherogenic and noninflammatory phenotype of endothelial cells. PMID- 20167928 TI - Short communication: Subcellular motion compensation for minimally invasive microscopy, in vivo: evidence for oxygen gradients in resting muscle. AB - RATIONALE: In vivo microscopy seeks to observe dynamic subcellular processes in a physiologically relevant context. A primary limitation of optical microscopy in vivo is tissue motion, which prevents physiological time course observations or image averaging. OBJECTIVE: To develop and demonstrate motion compensation methods that can automatically track image planes within biological tissues, including the tissue displacements associated with large changes in blood flow, and to evaluate the effect of global hypoxia on the regional kinetics and steady state levels of mitochondrial NAD(P)H. METHODS AND RESULTS: A dynamic optical microscope, with real-time prospective tracking and retrospective image processing, was used collect high-resolution images through cellular responses to various perturbations. The subcellular metabolic response to hypoxia was examined in vivo. Mitochondria closest to the capillaries were significantly more oxidized at rest (67+/-3%) than the intrafibrillar mitochondria (83+/-3%; P<0.0001) in the same cell. CONCLUSIONS: These data are consistent with the hypothesis that a significant oxygen gradient from capillary to muscle core exists at rest, thereby reducing the oxidative load on the muscle cell. PMID- 20167929 TI - Short communication: Dating components of human atherosclerotic plaques. AB - RATIONALE: Atherosclerotic plaques that give rise to acute clinical symptoms are typically characterized by degradation of the connective tissue and plaque rupture. Experimental studies have shown that mechanisms to repair vulnerable lesions exist, but the rate of remodeling of human plaque tissue has not been studied. OBJECTIVE: In the present study, we determined the biological age of different components of advanced human atherosclerotic plaques by analyzing tissue levels of (14)C released into the atmosphere during the nuclear weapons tests in the late 1950s and early 1960s. METHODS AND RESULTS: Atherosclerotic plaques were obtained from 10 patients (age 46 to 80 years) undergoing carotid surgery. Different regions of the plaques were dissected and analyzed for (14)C content using accelerator mass spectrometry. At the time of surgery, the mean biological age of the cap region was 6.4+/-3.2 years, which was significantly lower than that of the shoulder region (12.9+/-3.0 years, P<0.01), the interface toward the media (12.4+/-3.3 years, P<0.01), and the core (9.8+/-4.5 years, P<0.05). Analysis of proliferative activity and rate of apoptosis showed no signs of increased cellular turnover in the cap, suggesting that the lower (14)C content reflected a more recent time of formation. CONCLUSIONS: These results show that the turnover time of human plaque tissue is very long and may explain why regression of atherosclerotic plaque size rarely is observed in cardiovascular intervention trials. PMID- 20167930 TI - Lung endothelial dysfunction in congestive heart failure: role of impaired Ca2+ signaling and cytoskeletal reorganization. AB - RATIONALE: Congestive heart failure (CHF) frequently results in remodeling and increased tone of pulmonary resistance vessels. This adaptive response, which aggravates pulmonary hypertension and thus, promotes right ventricular failure, has been attributed to lung endothelial dysfunction. OBJECTIVE: We applied real time fluorescence imaging to identify endothelial dysfunction and underlying molecular mechanisms in an experimental model of CHF induced by supracoronary aortic banding in rats. METHODS AND RESULTS: Endothelial dysfunction was evident in lungs of CHF rats as impaired endothelium-dependent vasodilation and lack of endothelial NO synthesis in response to mechanical stress, acetylcholine, or histamine. This effect was not attributable to downregulation of endothelial NO synthase. Imaging of the cytosolic Ca(2+) concentration ([Ca(2+)](i)) revealed a singular impairment of endothelial [Ca(2+)](i) homeostasis and signaling characterized by a lack of [Ca(2+)](i) oscillations and deficient or attenuated [Ca(2+)](i) responses to mechanical stress, histamine, acetylcholine, or thapsigargin. Reconstitution of a [Ca(2+)](i) signal by ionophore treatment restored endothelial NO production, but lack of endothelial responsiveness was not primarily attributable to downregulation of Ca(2+) influx channels in CHF. Rather, we identified a massive remodeling of the endothelial cytoskeleton in the form of an increased expression of beta-actin and F-actin formation which contributed critically to endothelial dysfunction in CHF because cytoskeletal disruption by cytochalasin D largely reconstituted endothelial [Ca(2+)](i) signaling and NO production. CONCLUSIONS: Our findings characterize a unique scenario of endothelial dysfunction in CHF that is caused by a singular impairment of [Ca(2+)](i) signaling, and identify cytoskeletal reorganization as a major regulator of endothelial signaling and function. PMID- 20167931 TI - Regulation of coronary arterial BK channels by caveolae-mediated angiotensin II signaling in diabetes mellitus. AB - RATIONALE: The large conductance Ca(2+)-activated K(+) (BK) channel, a key determinant of vascular tone, is regulated by angiotensin II (Ang II) type 1 receptor signaling. Upregulation of Ang II functions and downregulation of BK channel activities have been reported in diabetic vessels. However, the molecular mechanisms underlying Ang II-mediated BK channel modulation, especially in diabetes mellitus, have not been thoroughly examined. OBJECTIVES: The aim in this study was to determine whether caveolae-targeting facilitates BK channel dysfunction in diabetic vessels. METHODS AND RESULTS: Using patch clamp techniques and molecular biological approaches, we found that BK channels, Ang II type 1 receptor, G(alphaq/11) (G protein q/11 alpha subunit), nonphagocytic NAD(P)H oxidases (NOX-1), and c-Src kinases (c-Src) were colocalized in the caveolae of rat arterial smooth muscle cells and the integrity of caveolae in smooth muscle cells was critical for Ang II-mediated BK channel regulation. Most importantly, membrane microdomain targeting of these proteins was upregulated in the caveolae of streptozotocin-induced rat diabetic vessels, leading to enhanced Ang II-induced redox-mediated BK channel modification and causing BK channel and coronary dysfunction. The absence of caveolae abolished the effects of Ang II on vascular BK channel activity and preserved BK channel function in diabetes. CONCLUSIONS: These results identified a molecular scheme of receptor/enzyme/channel/caveolae microdomain complex that facilitates the development of vascular BK channel dysfunction in diabetes. PMID- 20167935 TI - Louis Ignarro: NO stupid questions. Interview by Ruth Williams. PMID- 20167932 TI - Ultrastructure and regulation of lateralized connexin43 in the failing heart. AB - RATIONALE: Gap junctions mediate cell-to-cell electric coupling of cardiomyocytes. The primary gap junction protein in the working myocardium, connexin43 (Cx43), exhibits increased localization at the lateral membranes of cardiomyocytes in a variety of heart diseases, although the precise location and function of this population is unknown. OBJECTIVE: To define the subcellular location of lateralized gap junctions at the light and electron microscopic level, and further characterize the biochemical regulation of gap junction turnover. METHODS AND RESULTS: By electron microscopy, we characterized gap junctions formed between cardiomyocyte lateral membranes in failing canine ventricular myocardium. These gap junctions were varied in structure and appeared to be extensively internalizing. Internalized gap junctions were incorporated into multilamellar membrane structures, with features characteristic of autophagosomes. Intracellular Cx43 extensively colocalized with the autophagosome marker GFP-LC3 when both proteins were exogenously expressed in HeLa cells, and endogenous Cx43 colocalized with GFP-LC3 in neonatal rat ventricular myocytes. Furthermore, a distinct phosphorylated form of Cx43, as well as the autophagosome targeted form of LC3 (microtubule-associated protein light chain 3) targeted to lipid rafts in cardiac tissue, and both were increased in heart failure. CONCLUSIONS: Our data demonstrate a previously unrecognized pathway of gap junction internalization and degradation in the heart and identify a cellular pathway with potential therapeutic implications. PMID- 20167933 TI - Prostaglandin E2regulation of cystic fibrosis transmembrane conductance regulator activity and airway surface liquid volume requires gap junctional communication. AB - Stimulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by protease-activated receptors (PARs) at the basolateral membranes and by adenosine receptors (ADO-Rs) at the apical membrane maintain airway surface liquid (ASL) volume, which is required to ensure hydrated and clearable mucus. Both pathways involve the release of prostaglandin E2 (PGE2) and the stimulation of their basolateral receptors (EP-Rs). We sought to determine whether gap junctions contribute to the coordination of these pathways for modulating CFTR activity and mucus hydration. We used RT-PCR and Western blotting to determine connexin (Cx), CD73, and EP-R expression in a Calu-3 airway epithelial cell line grown on Transwell (Corning Costar, Cambridge, MA) inserts. We used dye coupling to evaluate gap junctional intercellular communication (GJIC). We used Ussing chamber studies and X-Z confocal microscopy to monitor Cl(-) secretion and ASL volume regulation. We found that connexin 43 (Cx43)-mediated GJIC was increased either by endogenous ADO after the hydrolysis of purine nucleotides by CD73 or by the direct activation of ADO-Rs. Inhibition of phospholipase A2 and cyclooxygenase prevented ADO-dependent increases in GJIC, suggesting the involvement of PGE2. PGE2 was found to increase GJIC markedly by stimulating EP4 Rs. The modulation of ADO signaling also affected the PAR-dependent activation of CFTR. The reduction of GJIC by CD73 or Cx43 inhibition prevented PAR-evoked CFTR currents in Ussing chambers. The inhibition of GJIC resulted in a failure of PGE2 to increase ASL volume in Calu-3 cells and in primary cultures of well differentiated human airway epithelial cells. Thus, gap junctions coordinate a signaling network comprising CFTR, ADO-Rs, PARs, and EP-Rs, and are required for ASL volume homeostasis. PMID- 20167936 TI - MicroRNAs in angiogenesis and vascular smooth muscle cell function. PMID- 20167938 TI - Integrin alpha(7)beta(1) COMPels smooth muscle cells to maintain their quiescence. PMID- 20167939 TI - Is there a better time of day to have a heart attack? PMID- 20167940 TI - Novel imaging approaches provide new windows to view subcellular changes in the redox state of smooth muscle cells. PMID- 20167941 TI - The role of the funny current in pacemaker activity. AB - Abstract: Pacemaking is a basic physiological process, and the cellular mechanisms involved in this function have always attracted the keen attention of investigators. The "funny" (I(f)) current, originally described in sinoatrial node myocytes as an inward current activated on hyperpolarization to the diastolic range of voltages, has properties suitable for generating repetitive activity and for modulating spontaneous rate. The degree of activation of the funny current determines, at the end of an action potential, the steepness of phase 4 depolarization; hence, the frequency of action potential firing. Because I(f) is controlled by intracellular cAMP and is thus activated and inhibited by beta-adrenergic and muscarinic M2 receptor stimulation, respectively, it represents a basic physiological mechanism mediating autonomic regulation of heart rate. Given the complexity of the cellular processes involved in rhythmic activity, an exact quantification of the extent to which I(f) and other mechanisms contribute to pacemaking is still a debated issue; nonetheless, a wealth of information collected since the current was first described more than 30 years ago clearly agrees to identify I(f) as a major player in both generation of spontaneous activity and rate control. I(f)- dependent pacemaking has recently advanced from a basic, physiologically relevant concept, as originally described, to a practical concept that has several potentially useful clinical applications and can be valuable in therapeutically relevant conditions. Typically, given their exclusive role in pacemaking, f-channels are ideal targets of drugs aiming to pharmacological control of cardiac rate. Molecules able to bind specifically to and block f-channels can thus be used as pharmacological tools for heart rate reduction with little or no adverse cardiovascular side effects. Indeed a selective f-channel inhibitor, ivabradine, is today commercially available as a tool in the treatment of stable chronic angina. Also, several loss-of-function mutations of HCN4 (hyperpolarization-activated, cyclic-nucleotide gated 4), the major constitutive subunit of f-channels in pacemaker cells, are known today to cause rhythm disturbances, such as for example inherited sinus bradycardia. Finally, gene- or cell-based methods for in situ delivery of f-channels to silent or defective cardiac muscle represent novel approaches for the development of biological pacemakers eventually able to replace electronic devices. PMID- 20167943 TI - Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease. AB - The ubiquitin proteasome system (UPS) plays a crucial role in biological processes integral to the development of the cardiovascular system and cardiovascular diseases. The UPS prototypically recognizes specific protein substrates and places polyubiquitin chains on them for subsequent destruction by the proteasome. This system is in place to degrade not only misfolded and damaged proteins, but is essential also in regulating a host of cell signaling pathways involved in proliferation, adaptation to stress, regulation of cell size, and cell death. During the development of the cardiovascular system, the UPS regulates cell signaling by modifying transcription factors, receptors, and structural proteins. Later, in the event of cardiovascular diseases as diverse as atherosclerosis, cardiac hypertrophy, and ischemia/reperfusion injury, ubiquitin ligases and the proteasome are implicated in protecting and exacerbating clinical outcomes. However, when misfolded and damaged proteins are ubiquitinated by the UPS, their destruction by the proteasome is not always possible because of their aggregated confirmations. Recent studies have discovered how these ubiquitinated misfolded proteins can be destroyed by alternative "specific" mechanisms. The cytosolic receptors p62, NBR, and histone deacetylase 6 recognize aggregated ubiquitinated proteins and target them for autophagy in the process of "selective autophagy." Even the ubiquitination of multiple proteins within whole organelles that drive the more general macro-autophagy may be due, in part, to similar ubiquitin-driven mechanisms. In summary, the crosstalk between the UPS and autophagy highlight the pivotal and diverse roles the UPS plays in maintaining protein quality control and regulating cardiovascular development and disease. PMID- 20167944 TI - Assessment and optimization of cell engraftment after transplantation into the heart. AB - Myocardial regeneration using stem and progenitor cell transplantation in the injured heart has recently become a major goal in the treatment of cardiac disease. Experimental studies and clinical applications have generally been encouraging, although the functional benefits that have been attained clinically are modest and inconsistent. Low cell retention and engraftment after myocardial delivery is a key factor limiting the successful application of cell therapy, irrespective of the type of cell or the delivery method. To improve engraftment, accurate methods for tracking cell fate and quantifying cell survival need to be applied. Several laboratory techniques (histological methods, real-time quantitative polymerase chain reaction, radiolabeling) have provided invaluable information about cell engraftment. In vivo imaging (nuclear medicine modalities, bioluminescence, and MRI) has the potential to provide quantitative information noninvasively, enabling longitudinal assessment of cell fate. In the present review, we present several available methods for assessing cell engraftment, and we critically discuss their strengths and limitations. In addition to providing insights about the mechanisms mediating cell loss after transplantation, these methods can evaluate techniques for augmenting engraftment, such as tissue engineering approaches, preconditioning, and genetic modification, allowing optimization of cell therapies. PMID- 20167942 TI - Circadian rhythms and metabolic syndrome: from experimental genetics to human disease. AB - The incidence of the metabolic syndrome represents a spectrum of disorders that continue to increase across the industrialized world. Both genetic and environmental factors contribute to metabolic syndrome and recent evidence has emerged to suggest that alterations in circadian systems and sleep participate in the pathogenesis of the disease. In this review, we highlight studies at the intersection of clinical medicine and experimental genetics that pinpoint how perturbations of the internal clock system, and sleep, constitute risk factors for disorders including obesity, diabetes mellitus, cardiovascular disease, thrombosis and even inflammation. An exciting aspect of the field has been the integration of behavioral and physiological approaches, and the emerging insight into both neural and peripheral tissues in disease pathogenesis. Consideration of the cell and molecular links between disorders of circadian rhythms and sleep with metabolic syndrome has begun to open new opportunities for mechanism-based therapeutics. PMID- 20167945 TI - Regulation of protein levels in subcellular domains through mRNA transport and localized translation. AB - Localized protein synthesis is increasingly recognized as a means for polarized cells to modulate protein levels in subcellular regions and the distal reaches of their cytoplasm. The axonal and dendritic processes of neurons represent functional domains of cytoplasm that can be separated from their cell body by vast distances. This separation provides a biological setting where the cell uses locally synthesized proteins to both autonomously respond to stimuli and to retrogradely signal the cell body of events occurring is this distal environment. Other cell types undoubtedly take advantage of this localized mechanism, but these have not proven as amenable for isolation of functional subcellular domains. Consequently, neurons have provided an appealing experimental platform for study of mRNA transport and localized protein synthesis. Molecular biology approaches have shown both the population of mRNAs that can localize into axons and dendrites and an unexpectedly complex regulation of their transport into these processes. Several lines of evidence point to similar complexities and specificity for regulation of mRNA translation at subcellular sites. Proteomics studies are beginning to provide a comprehensive view of the protein constituents of subcellular domains in neurons and other cell types. However, these have currently fallen short of dissecting temporal regulation of new protein synthesis in subcellular sites and mechanisms used to ferry mRNAs to these sites. PMID- 20167948 TI - Statistical methods for the assessment of prognostic biomarkers(part II): calibration and re-classification. AB - Calibration is the ability of a prognostic model to correctly estimate the probability of a given event across the whole range of prognostic estimates (for example, 30% probability of death, 40% probability of myocardial infarction, etc.). The key difference between calibration and discrimination is that the latter reflects the ability of a given prognostic biomarker to distinguish a status (died/survived, event/non-event), while calibration measures how much the prognostic estimation of a predictive model matches the real outcome probability (that is, the observed proportion of the event). Re-classification is another measure of prognostic accuracy and it reflects how much a new prognostic biomarker increases the proportion of individuals correctly re-classified as having or not having a given event compared to a previous classification based on an existing prognostic biomarker or predictive model. PMID- 20167947 TI - Cyclic AMP- and (Rp)-cAMPS-induced conformational changes in a complex of the catalytic and regulatory (RI{alpha}) subunits of cyclic AMP-dependent protein kinase. AB - We took a discovery approach to explore the actions of cAMP and two of its analogs, one a cAMP mimic ((S(p))-adenosine cyclic 3':5'-monophosphorothioate ((S(p))-cAMPS)) and the other a diastereoisomeric antagonist ((R(p))-cAMPS), on a model system of the type Ialpha cyclic AMP-dependent protein kinase holoenzyme, RIalpha(91-244).C-subunit, by using fluorescence spectroscopy and amide H/(2)H exchange mass spectrometry. Specifically, for the fluorescence experiments, fluorescein maleimide was conjugated to three cysteine single residue substitution mutants, R92C, T104C, and R239C, of RIalpha(91-244), and the effects of cAMP, (S(p))-cAMPS, and (R(p))-cAMPS on the kinetics of R-C binding and the time-resolved anisotropy of the reporter group at each conjugation site were measured. For the amide exchange experiments, ESI-TOF mass spectrometry with pepsin proteolytic fragmentation was used to assess the effects of (R(p))-cAMPS on amide exchange of the RIalpha(91-244).C-subunit complex. We found that cAMP and its mimic perturbed at least parts of the C-subunit interaction Sites 2 and 3 but probably not Site 1 via reduced interactions of the linker region and alphaC of RIalpha(91-244). Surprisingly, (R(p))-cAMPS not only increased the affinity of RIalpha(91-244) toward the C-subunit by 5-fold but also produced long range effects that propagated through both the C- and R-subunits to produce limited unfolding and/or enhanced conformational flexibility. This combination of effects is consistent with (R(p))-cAMPS acting by enhancing the internal entropy of the R.C complex. Finally, the (R(p))-cAMPS-induced increase in affinity of RIalpha(91 244) toward the C-subunit indicates that (R(p))-cAMPS is better described as an inverse agonist because it decreases the fractional dissociation of the cyclic AMP-dependent protein kinase holoenzyme and in turn its basal activity. PMID- 20167946 TI - Liver membrane proteome glycosylation changes in mice bearing an extra-hepatic tumor. AB - Cancer is well known to be associated with alterations in membrane protein glycosylation (Bird, N. C., Mangnall, D., and Majeed, A. W. (2006) Biology of colorectal liver metastases: A review. J. Surg. Oncol. 94, 68-80; Dimitroff, C. J., Pera, P., Dall'Olio, F., Matta, K. L., Chandrasekaran, E. V., Lau, J. T., and Bernacki, R. J. (1999) Cell surface n-acetylneuraminic acid alpha2,3-galactoside dependent intercellular adhesion of human colon cancer cells. Biochem. Biophys. Res. Commun. 256, 631-636; and Arcinas, A., Yen, T. Y., Kebebew, E., and Macher, B. A. (2009) Cell surface and secreted protein profiles of human thyroid cancer cell lines reveal distinct glycoprotein patterns. J. Proteome Res. 8, 3958-3968). Equally, it has been well established that tumor-associated inflammation through the release of pro-inflammatory cytokines is a common cause of reduced hepatic drug metabolism and increased toxicity in advanced cancer patients being treated with cytotoxic chemotherapies. However, little is known about the impact of bearing a tumor (and downstream effects like inflammation) on liver membrane protein glycosylation. In this study, proteomic and glycomic analyses were used in combination to determine whether liver membrane protein glycosylation was affected in mice bearing the Engelbreth-Holm Swarm sarcoma. Peptide IPG-IEF and label-free quantitation determined that many enzymes involved in the protein glycosylation pathway specifically; mannosidases (Man1a-I, Man1b-I and Man2a-I), mannoside N-acetylglucosaminyltransferases (Mgat-I and Mgat-II), galactosyltransferases (B3GalT-VII, B4GalT-I, B4GalT-III, C1GalT-I, C1GalT-II, and GalNT-I), and sialyltransferases (ST3Gal-I, ST6Gal-I, and ST6GalNAc-VI) were up-regulated in all livers of tumor-bearing mice (n = 3) compared with nontumor bearing controls (n = 3). In addition, many cell surface lectins: Sialoadhesin-1 (Siglec-1), C-type lectin family 4f (Kupffer cell receptor), and Galactose binding lectin 9 (Galectin-9) were determined to be up-regulated in the liver of tumor-bearing compared with control mice. Global glycan analysis identified seven N-glycans and two O-glycans that had changed on the liver membrane proteins derived from tumor-bearing mice. Interestingly, alpha (2,3) sialic acid was found to be up-regulated on the liver membrane of tumor-bearing mice, which reflected the increased expression of its associated sialyltransferase and lectin receptor (siglec-1). The overall increased sialylation on the liver membrane of Engelbreth Holm Swarm bearing mice correlates with the increased expression of their associated glycosyltransferases and suggests that glycosylation of proteins in the liver plays a role in tumor-induced liver inflammation. PMID- 20167949 TI - How embodied cognitions affect judgments: height-related attribution bias in football foul calls. AB - Many fouls committed in football (called soccer in some countries) are ambiguous, and there is no objective way of determining who is the "true" perpetrator or the "true" victim. Consequently, fans as well as referees often rely on a variety of decision cues when judging such foul situations. Based on embodiment research, which links perceptions of height to concepts of strength, power, and aggression, we argue that height is going to be one of the decision cues used. As a result, people are more likely to attribute a foul in an ambiguous tackle situation to the taller of two players. We find consistent support for our hypothesis, not only in field data spanning the last seven UEFA Champions League and German Bundesliga seasons, as well as the last three FIFA World Cups, but also in two experimental studies. The resulting dilemma for refereeing in practice is discussed. PMID- 20167950 TI - Direct and buffering effects of physical activity on stress-related depression in mothers of infants. AB - This study examined the role of leisure-time physical activity in reducing the impact of high life stress and time pressure on depression, a buffer effect, for mothers of infants. A direct association between leisure-time physical activity and depression, regardless of both sources of stress, was also tested. A sample of approximately 5,000 mothers of infant children completed questionnaires that measured demographic characteristics, frequency of participation in leisure-time physical activity, life stress, time pressure, and depression (depressive symptoms). Hierarchical multiple regression incorporating an interaction component to represent the buffering effect was used to analyze the data. Frequency of leisure-time physical activity was significantly associated with lower levels of depressive symptoms for both types of stress and acted as a buffer of the association between life stress and depressive symptoms, but did not buffer the influence of time pressure on depressive symptoms. These findings indicated that leisure-time physical activity assists in maintaining the mental health of mothers of infants; however, caution is needed when promoting physical activity for mothers who feel under time pressure. PMID- 20167951 TI - Exploring the social-environmental determinants of well- and ill-being in dancers: a test of basic needs theory. AB - Grounded in the basic needs mini-theory (Deci & Ryan, 2000), this study examined the interplay among perceptions of the social environment manifested in vocational dance schools, basic need satisfaction, and indices of elite dancers' well- and ill-being. The hypothesized mediating role of need satisfaction was also tested. Dancers (N = 392) completed a questionnaire tapping the targeted variables. Structural equation modeling supported a model in which perceptions of task-involving dance environments positively predicted need satisfaction. Perceived ego-involving climates negatively corresponded with competence and relatedness. Perceptions of autonomy support were positively related to autonomy and relatedness. Need satisfaction positively predicted positive affect. Competence and relatedness satisfaction corresponded negatively to reported negative affect. Emotional and physical exhaustion was not related to need satisfaction. Partial support emerged for the assumed mediation of the needs. Results highlight the relevance of task-involving and autonomy-supportive dance climates for elite dancers' need satisfaction and healthful engagement in vocational dance. PMID- 20167952 TI - Experienced golfers' perspectives on choking under pressure. AB - Although researchers have experimentally examined the mechanisms underlying pressure-induced forms of suboptimal performance, or "choking under pressure," there is a lack of research exploring the personal experience of this phenomenon. In an attempt to fill this void in the literature, this study explored experienced golfers' perceptions of the choking experience within a personal construct psychology (Kelly, 1955/1991) framework. Both male and female golfers participated in either a focus group (n = 12; all males) or one-on-one interview (n = 10; female = 7, male = 3) using experience cycle methodology (Oades & Viney, 2000) to describe their perceptions of the choking experience. Discussions were transcribed verbatim and subsequently analyzed using grounded theory analytical techniques (Strauss & Corbin, 1998). Analyses revealed five central categories representing the personal experience of choking under pressure: antecedents, personal investment, choking event, consequences, and learning experiences. The findings reported here suggest that the choking phenomenon, which can involve acute or chronic bouts of suboptimal performance (relative to the performance expectations of the athlete), is a complex process involving the interplay of several cognitive, attentional, emotional, and situational factors. Implications of the findings for a construct definition of choking are discussed, and several applied considerations are offered. PMID- 20167953 TI - Habit in the physical activity domain: integration with intention temporal stability and action control. AB - The purpose of this study was to explore the role of habit in predicting physical activity with the theory of planned behavior (TPB). The study extended previous research by (a) including a measure of temporal intention stability in the regression equation, and (b) unpacking the intention x behavior x habit relationship. Participants were 153 undergraduate students who completed a habit measure and measures of the TPB at Time 1 followed by measures of intention and behavior 2 weeks later. Results using regression analysis demonstrated that habit explained 7% additional variance after accounting for the TPB and temporal stability of intention and its interaction with intention. Follow-up analyses showed considerable asymmetry in the three-way relationship between intention, behavior, and habit, where high habit participants were composed primarily of intenders (i.e., intended to be active >3 times/week at 30 min) who engaged in regular physical activity (70%, n = 28) and low habit participants were inactive nonintenders (i.e., did not intend to be active >3 times/week at 30 min and were subsequently not active; 69%, n = 25). The results support the notion that some properties of physical activity may have an automatic component and that habits may be important to physical activity action control. PMID- 20167954 TI - Motivational predictors of physical education students' effort, exercise intentions, and leisure-time physical activity: a multilevel linear growth analysis. AB - Grounded in self-determination theory (SDT; Deci & Ryan, 2000), the current study explored whether physical education (PE) students' psychological needs and their motivational regulations toward PE predicted mean differences and changes in effort in PE, exercise intentions, and leisure-time physical activity (LTPA) over the course of one UK school trimester. One hundred and seventy-eight students (69% male) aged between 11 and 16 years completed a multisection questionnaire at the beginning, middle, and end of a school trimester. Multilevel growth models revealed that students' perceived competence and self-determined regulations were the most consistent predictors of the outcome variables at the within- and between-person levels. The results of this work add to the extant SDT-based literature by examining change in PE students' motivational regulations and psychological needs, as well as underscoring the importance of disaggregating within- and between-student effects. PMID- 20167956 TI - Clinical implications of heart-lung interactions. AB - As opposed to spontaneous respiration wherein small cyclic changes in transpulmonary, negative pressure coincide with lung volume changes, positive pressure (mechanical) ventilation results in a simultaneous rise in transpulmonary pressure and lung volumes. The changes may affect biventricular cardiac loading and function in dissimilar ways, depending on baseline cardiopulmonary function. This review is intended to update current knowledge on the pathophysiology of these heart-lung interactions in helping to explain the common circulatory alterations occurring during airway pressure changes and to better understand mechanisms of disease and modes of action of treatments, during spontaneous and mechanical ventilation. PMID- 20167957 TI - ANCA-associated vasculitides: advances in pathophysiology and treatment. AB - Substantial progress has been made over the last two decades in our understanding of the immunopathogenesis of antineutrophil cytoplasmic antibodies (ANCA) associated vasculitides. Compelling evidence from in vitro studies and experimental models in conjunction with clinical trials has confirmed that ANCA directly contribute to the evolution and progression of the disease process. Continuous development in our understanding of the mechanisms that drive the disease may ultimately allow us to tailor the multitude of novel therapies, which are rapidly becoming available, to the requirements of individual patients. In this review we endeavour to provide a brief overview of the recent advances in ANCA-associated vasculitides and outline basic principles for diagnosis and treatment of these complex multisystem diseases. PMID- 20167958 TI - Bleeding in patients using new anticoagulants or antiplatelet agents: risk factors and management. AB - The most important adverse effect of antithrombotic treatment is the occurrence of bleeding. In case of serious or even life-threatening bleeding in a patient who uses anticoagulant agents or when patient on anticoagulants needs to undergo an urgent invasive procedure, anticoagulant treatment can be reversed by various specific strategies. Heparin and heparin derivatives can be counteracted by protamine sulphate, whereas the anticoagulant effect of vitamin K antagonists may be neutralised by administration of vitamin K or prothrombin complex concentrates. The antihaemostatic effect of aspirin and other antiplatelet strategies can be corrected by the administration of platelet concentrate and/or desmopressin, if needed. Recently, a new generation of anticoagulants with a greater specificity towards activated coagulation factors has been introduced and most of these agents are currently being evaluated in clinical studies, showing promising results. The new-generation anticoagulants include specific inhibitors of factor IIa or factor Xa (including pentasaccharides) and antiplatelet agents belonging to the class of thienopyridine derivatives. A limitation of the new class of anti-IIa and anti-Xa agents may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs, although in some cases the administration of recombinant factor VIIa may be an option. PMID- 20167959 TI - Survey into blood glucose control in critically ill adult patients in the Netherlands. AB - BACKGROUND: To study current clinical practice in blood glucose (BG) control in adult intensive care units (ICUs) in the Netherlands. METHODS: We performed a national survey focusing on blood glucose targets, insulin administration, BG control guidelines, and opinions regarding BG control aiming for normoglycaemia (known as intensive insulin therapy, IIT). RESULTS: The completed questionnaire was returned by 88/113 (78%) of the participating centres. In 98% (86/88) of the ICUs some sort of BG control was being practised. Half of the ICUs (42/86, 48%) used tight BG targets as with IIT; 28/86 (33%) and 13/86 (15%) used more liberal targets of 4.4 to 7.0 mmol/l and 4.4 to 8.0 mmol/l, respectively. Eighty-two (93%) reported having a local guideline on BG control (or IIT). The BG threshold to start insulin was 7.0+/-1.3 mmol/l vs 7.8+/-1.3 mmol/l in ICUs that practised IIT vs ICUs that practised less tight BG control, respectively (p=0.005). In 28/86 (33%) measurement of the BG values was done according to a strict time schedule (i.e., BG values were measured on predefined time points). While respondents were fairly agreed on the benefits of IIT, opinions regarding ease of implementation and time needed to apply this strategy varied. In addition, severe hypoglycaemia was considered a serious side effect of IIT. CONCLUSION: Approximately half of the ICUs in the Netherlands reported having implemented IIT. However, the full guideline as used in the original studies on IIT was hardly ever implemented. Concerns about severe hypoglycaemia, at least in part, hampers implementation of IIT. PMID- 20167960 TI - Severe non-type-1 Legionella pneumophila infection without pneumonia. AB - We present a patient with myalgia and ongoing fever without respiratory symptoms caused by a Legionella pneumophilia infection. We conclude that in patients with fever of unknown origin legionellosis should be considered, even in the absence of pulmonary symptoms. When considering legionellosis, diagnostic tests should include the urinary antigen test. PMID- 20167961 TI - Vinblastine, rituximab and HAART, treatment of an HIV -positive patient with multicentric Castleman's disease. AB - An HIV-positive man from Somalia presented with severe malaise, weight loss, relapsing fever, lymphadenopathy and splenomegaly. An FDG-PET-scan-guided lymph node biopsy revealed the characteristic histological features of the plasma cell variant of Castleman's disease. A high HHV-8 viral load was detected in the serum (7980 copies/ml). Treatment with HAART, rituximab and vinblastine resulted in a full and rapid recovery and lowered HHV-8 viral load to undetectable levels. PMID- 20167962 TI - Abnormal chest X-ray in a patient with mononeuritis multiplex. PMID- 20167963 TI - Acute abdomen after deceleration trauma. PMID- 20167964 TI - Blindness, confusion and seizures in a cancer patient. PMID- 20167965 TI - Oedema and Crohn's disease. PMID- 20167966 TI - Oral cholera vaccines--a call for action. PMID- 20167967 TI - Supercentenarians: the oldest people in the world. PMID- 20167968 TI - India, China, and the world. PMID- 20167969 TI - Metabolic syndrome in mental disorders. PMID- 20167970 TI - Prevention of non communicable diseases(NCDs): holistic approach needed. PMID- 20167971 TI - Hepatitis C virus: molecular biology & current therapeutic options. AB - Hepatitis C virus (HCV) is a small (approximately 55 to 65 nm), spherical, enveloped, hepatotropic RNA virus that causes acute and chronic hepatitis in humans. Persistent virus infection with HCV often leads to cirrhosis and hepatocellular carcinoma (HCC). At present there is neither a selective antiviral therapy nor a preventive vaccine. The only available treatment option is a long acting pegylated-interferon-alpha, given in combination with nucleoside analog ribavirin, which is not very effective. Molecular studies of HCV began with the successful cloning of its genome in 1989. For many years, research to develop therapeutics was stalled by the inability to grow virus in tissue culture. A major milestone was achieved with the recent development of a robust cell culture system for HCV propagation. HCV proteins assemble and form replication complexes on modified host membranes, called as membranous webs. Even though HCV is detected and targeted by host immune mechanisms, it establishes and maintains a life-long persistent infection. HCV has evolved multiple strategies to survive and persist in hostile cellular environments; and the viral population is known to rapidly change during the course of a natural infection thereby escaping immune surveillance. Rapid mutations also help virus to survive by selecting for the variants which are resistant to antiviral drugs. Although precise mechanisms regulating HCV entry into hepatic cells via receptors remain unknown, HCV also has the capability of direct cell-to-cell transmission. The extremely complex and incompletely understood nature of the HCV lifecycle has complicated the discovery of new therapies. A complete understanding of the functional roles played by the HCV proteins during HCV lifecycle is vital for developing a successful cure. This review deals with current status of efforts in addressing these daunting tasks and challenges in developing therapeutics against chronic and rapidly changing hepatitis C virus. PMID- 20167972 TI - Comparison of Uhl's anomaly, right ventricular outflow tract ventricular tachycardia (RVOT VT) & arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) with an insight into genetics of ARVD/C. AB - Among the right ventricular conditions, Uhl's anomaly, arrhythmogenic right ventricular dysplasia / cardiomyopathy (ARVD/C) and right ventricular outflow tract ventricular tachycardia (RVOT VT) are disorders that exhibit pathogenic changes involving the right ventricular (RV) myocardium, and are expected to be severe or milder forms of the same condition. The review focuses on the aspect whether the three RV disorders are a spectrum of the same disease. ARVD/C is the only condition among these to be genetically well characterized. Also, variations in the clinical expression of ARVD/C due to the genetic heterogeneity are examined. Based on clinical manifestations, age at onset, gender ratio and the possible molecular mechanisms implicated, Uhl's anomaly, ARVD/C and RVOT VT may be considered as separate entities. Further, to differentiate between the three RV disorders, the molecular studies on ARVD/C might be helpful. An attempt was made to differentiate between the eleven different types of ARVD/Cs based on clinical symptoms presented including the progression of the disease to the left ventricle, ventricular arrhythmias and clinical characteristics like ECG, SAECG, ECHO and histopathological studies. PMID- 20167973 TI - Prevalence of metabolic syndrome in psychiatric inpatients in a tertiary care centre in north India. AB - BACKGROUND & OBJECTIVES: Metabolic syndrome (MS) is associated with major mental illnesses. It is a major predictor of mortality and morbidity. This research was undertaken to study the prevalence and correlates of MS in psychiatric inpatients in a tertiary care hospital in north India. METHODS: Consecutive adult patients with a primary psychiatric disorder admitted to the psychiatric ward during the study period (July-December 2007) were evaluated for prevalence of MS as per the criteria of the International Diabetes Federation (IDF). RESULTS: Among the 90 patients included in the study, the prevalence of MS as per IDF was 37.8 per cent and it was significantly associated with the body mass index (BMI). INTERPRETATION & CONCLUSIONS: The present findings showed a higher prevalence of MS in psychiatric inpatients than that in the general population. Further studies on a larger sample need to be done before advising evaluation for the presence of MS in all psychiatric patients. PMID- 20167974 TI - Risk factor profile for chronic non-communicable diseases: results of a community based study in Kerala, India. AB - BACKGROUND & OBJECTIVES: Kerala State is a harbinger of what will happen in future to the rest of India in chronic non-communicable diseases (NCD). We assessed: (i) the burden of NCD risk factors; (ii) estimated the relations of behavioural risk factors to socio-demographic correlates, anthropometric risk factors with behavioural risk factors; (iii) evaluated if socio-demographic, behavioural and anthropometric risk factors predicted biochemical risk factors; and (iv) estimated awareness, treatment and adequacy of control of hypertension and diabetes, in Kerala state. METHODS: A total of 7449 individuals (51% women) stratified by age group, sex and place of residence were selected and information on behavioural risk factors; tobacco use, diet, physical activity, alcohol use, measured anthropometry, blood pressure was collected. Fasting blood samples were analysed for blood glucose, total cholesterol, high density lipoprotein cholesterol and triglycerides in a sample subset.Using multiple logistic regression models the associations between socio-demographic and anthropometric variables with biochemical risk factors were estimated. RESULTS: The burden of NCD risk factors was high in our sample. Prevalence of behavioural and each of the biochemical risk factors increased with age, adjusting for other factors including sex and the place of residence. The odds ratios relating anthropometric variables to biochemical variables were modest, suggesting that anthropometric variables may not be useful surrogates for biochemical risk factors for population screening purposes. INTERPRETATION & CONCLUSIONS: In this large study of community-based sample in Kerala, high burden of NCD risk factors was observed, comparable to that in the United States. These data may serve to propel multisectoral efforts to lower the community burden of NCD risk factors in India in general, and in Kerala, in particular. PMID- 20167975 TI - R659X mutation in the MLH1 gene in hereditary non-polyposis colorectal cancer(HNPCC) in an Indian extended family. AB - BACKGROUND & OBJECTIVE: Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome), is a genetically heterogeneous disorder that is believed to account for 2-10 per cent of all the colorectal cancer cases. The disease follows autosomal dominant inheritance pattern with high penetrance (85%) and younger age of onset when compared to patients with sporadic tumours. HNPCC is associated with germ-line mutations in the DNA mismatch repair (MMR) genes namely MLH1, MSH2, MSH6, and PMS2. The present study was aimed at analyzing mismatch repair gene(s) in an extended Indian family satisfying the Amsterdam criteria, and extending the analysis to general population to estimate frequency of the mutations/polymorphisms observed. METHODS: A total 12 members of the HNPCC family were studied for genetic investigation. Ethnically matched 250 normal individuals were also included as controls to study the observed mutations/polymorphisms at population level. RESULTS: The analysis resulted in identification of a 1975C>T mutation in exon 17, resulting in substitution of arginine residue with stop codon at codon 659. 655A>G substitution was also observed, resulting in replacement of isoleucine with valine at codon 219. Similar analysis on 250 ethnically matched control subjects revealed complete absence of R659X mutation, while I219V variant was found in 9.8 per cent of the controls. INTERPRETATION & CONCLUSION: R659X mutation correlates with disease phenotype, and 655A>G locus is highly polymorphic. Our study suggested that R659X substitution was prime cause for the disease phenotype in this family. I219V substitution is a polymorphism having no association with the disease onset or segregation. The family members harbouring this mutation were advised to be under regular medical surveillance. PMID- 20167976 TI - Distribution of XRCC1 genotypes in north Indian population. AB - BACKGROUND & OBJECTIVES: XRCC1, a major DNA repair gene, acts as a scaffold of different activities involved in repair by interacting with components of base excision repair (BER) at the site of damage. Polymorphisms in this gene are associated with variations in the repair efficiency which might predispose an individual to cancer risk. To associate a gene polymorphism with disease risk, it is imperative to have the data for its genotype distribution in normal population. The present study was therefore carried out to find distribution of XRCC1 polymorphisms (codons 194, 280 and 399) in normal north Indian population. METHODS: Healthy volunteers hailing from north India (150) were enrolled in the study. DNA was isolated from blood samples and genotyping of codons 194, 280 and 399 of XRCC1 gene was done by PCR- restriction fragment length polymorphism (RFLP), using specific primers. RESULTS: The frequencies obtained for heterozygous genotype of codons 194 and 399 were 45 and 49 per cent respectively and were higher than wild and variant genotypes. For codon 280, the highest frequency (59%) was obtained for the wild genotype. Frequencies of the variant genotypes of codons 194 and 399 were higher in males and females respectively. The allele frequencies also followed the similar trends. INTERPRETATION & CONCLUSIONS: A significant distribution of variant and heterozygous XRCC1 genotypes was noticed that warrants further studies on the association between these genotypes and disease risk in our study population. PMID- 20167977 TI - Renal functional & haemodynamic changes following acute unilateral renal denervation in Sprague Dawley rats. AB - BACKGROUND & OBJECTIVES: Regulation of renal function and haemodynamics are under a direct control from the renal sympathetic nerves and renal denervation produces overt diuresis and natriuresis in several mammalian species. However, the inter related series of changes in renal function and haemodynamics following acute renal denervation (ARD) is not fully understood. Thus, we aimed to investigate and relate the changes in renal function and haemodynamics following acute unilateral renal denervation in anaesthetized Sprague Dawley (SD) rats. METHODS: Male SD rats were fasted overnight, anaesthetized with sodium pentobarbitone (60 mg/kg ip), denervated by application of phenol to the left renal artery and maintained on an intravenous (iv) infusion of isotonic saline for 2 h. Throughout this period, six urine and plasma samples were taken at 20-min intervals to study kidney function parameters. In a different set of experiments, renal nerve stimulation (RNS) was carried out to characterize the changes in renal vasoconstrictor responses following ARD. RESULTS: Denervated animals showed significantly (P<0.05 vs. control innervated rats) higher urine flow rate (UFR), absolute sodium excretion (UNaV), fractional sodium excretion (FENa) and glomerular filtration rate (GFR). The renal vasoconstrictor responses to RNS were significantly (P<0.05) lower in denervated rats as compared to the innervated counterparts. However, no appreciable differences were seen in the mean arterial pressure (MAP), plasma sodium (PNa), basal renal blood flow (RBF) and basal renal vascular resistance (RVR) in both innervated and denervated SD rats. INTERPRETATION & CONCLUSIONS: Natriuresis, diuresis, enhanced GFR and impaired vasoconstriction in response to RNS are typical and instant responses to ARD in SD rats. Renal sympathetic nerves serve more important role in salt and water conservation than in dynamic autoregulation of RBF under normal sympathetic tone; yet, their effects on renal haemodynamics become more evident in the presence of augmented renal sympathetic nerve activity (RSNA). PMID- 20167978 TI - Aetiology & risk factors of recurrent vaginitis & its association with various contraceptive methods. AB - BACKGROUND & OBJECTIVES: Women who do not seek treatment for recurrent vaginitis have risk to acquire other sexually transmitted infections. Besides proper antibiotic treatment, male condom acts as a barrier to various infections. Present study was done to assess type of vaginitis, its association with various contraceptive methods and need of male condom in prevention of recurrent vaginitis. METHODS: Prospective hospital based cohort study with a total of 400 women with recurrent vaginitis was done. Wet mount and Gram's staining examination were done to diagnose type of vaginitis. After treatment, proper counselling about good hygiene and use of male condom for 4 months in addition to their contraceptive method was advised. Patients were called after four months or when they developed symptoms of vaginitis. RESULTS: Tubal ligation (38.8%) and non contraceptives (34.0%) were the most common methods used by recurrent vaginitis patients. Bacterial vaginosis (BV, 53.8%) and mixed infection (36.8%) were commonly seen infections. BV was not observed in OC pill users. Overall post treatment cure was 89.1 per cent. INTERPRETATION CONCLUSIONS: Our findings showed that male condom use provided protection against recurrent vaginitis and its use should be promoted with other contraceptive methods in high risk cases. Female condom may be another option. PMID- 20167979 TI - Interobserver variation in the interpretation of Nugent scoring method for diagnosis of bacterial vaginosis. AB - BACKGROUND & OBJECTIVES: Bacterial vaginosis (BV) is the most common form of vaginal infection and an important cause of morbidity in women of reproductive age. This study was carried out to examine the interobserver variation on interpretation of Nugent scoring method in the diagnosis of BV. METHODS: This prospective study was conducted in a rural primary health care center of north India from May 2003 to April 2004 and included 601 married, sexually active women between 18-49 yr of age presented with self-reported symptoms of vaginal discharge and/or genital itching and/or genital burning. Specimens collected from the lateral wall of vagina were subjected to Gram staining and the microscope slide smears were examined by 3 independent observers. Each of the three observers scored and interpreted the slides for diagnosis of bacterial vaginosis using the Nugent method. RESULTS: Complete agreement amongst the three observers was found in 76.2 per cent of cases. In 22.13 per cent cases, two observers were in agreement while interpretation of the slides were in complete disagreement only in 1.66 per cent of cases. The interrater reproducibility was found to be excellent between observers 1 and 3, while between observers 1 and 2, and 2 and 3 it was good to fair. INTERPRETATION & CONCLUSIONS: Nugent scoring system appears to be a reliable and convenient method for laboratory evaluation of cases of bacterial vaginosis. At the same time, one must be aware of the factors that might lead to discrepant results. PMID- 20167980 TI - Sero diagnosis of Legionella infection in community acquired pneumonia. AB - BACKGROUND & OBJECTIVES: Legionella pneumophila has been increasingly recognized as an emerging pathogen responsible for community acquired pneumonia (CAP) worldwide. In India, the actual burden is not known. The present study was thus undertaken to see the presence of Legionella infection in patients with community acquired pneumonia admitted in a tertiary care centre in north India. METHODS: Both children and adults (n=113) with symptoms of pneumonia were included in the study. Clinical samples (blood, urine, nasopharyngeal aspirates, bronchoalveolar lavage, sputum, etc.) were collected and subjected to culture and other tests. Enzyme linked immunosorbent assay (ELISA) was done by commercial kits for all the three classes of immunoglobulins (IgG, IgM & IgA). Urinary antigen was also detected using commercial kits. Culture was performed on 51 respiratory tract fluid samples. Serum samples of 44 healthy controls were also screened for the presence of anti-legionella antibodies (IgG, IgM & IgA). RESULTS: Thirty one of the 113 cases (27.43%) were serologically positive. Anti-legionella IgG, IgM and IgA antibodies were positive in 7.96, 15.92 and 11.50 per cent patients respectively. In controls, seropositivity was 9.09 (4/44). IgA was positive in 3 and IgM, IgG combined in one. Antigenuria detection by Microwell ELISA kit showed 17.69 per cent positivity. Four antigenuria positive patients were also serologically positive; of these two patients were positive for IgM, hence considered as confirmed cases of Legionella infection. None of the sample was culture positive. INTERPRETATION & CONCLUSIONS: Combination of serology and antigenuria detection may be a valuable tool for the diagnosis of Legionella infection in absence of culture positivity. In order to evaluate the actual burden of Legionella in community acquired pneumonia, further studies with larger samples need to be done. PMID- 20167981 TI - Effect of measles virus (MV) on mitochondrial respiration. AB - BACKGROUND & OBJECTIVES: Studies of interaction between viruses and mitochondria have shown that viruses can affect the mitochondria. Also linkage between human diseases and mitochondrial dysfunction has been revealed. We studied the effect of measles virus (MV) on cell respiration in MV infected Hela cells to see any possible changes in mitochondrial respiration. METHODS: Total cell respiration (TCR) of MV infected (10 pfu/cell) HeLa cells was measured using oxygen electrode (OE). Cell lines were grown in growth medium. Virus titration was done in VERO cell line using plaque assay method. RESULTS: TCR of HeLa cells was not significantly changed post MV infection and was similar to most infected cells. INTERPRETATION & CONCLUSION: Infection with measles virus did not reveal any significant effect on mitochondrial respiration in HeLa cells. Further studies need to be done using advanced techniques to throw more light on this aspect. PMID- 20167982 TI - Pediatric urinary tract infections in a tertiary care center from north India. AB - BACKGROUND & OBJECTIVES: Paediatric urinary tract infections (UTI) are associated with high morbidity and long term complications like renal scarring, hypertension, and chronic renal failure. A cause of occult febrile illness, they often remain undiagnosed. We studied the clinical and microbiologic profile and antibiotic resistance profile of such infections in paediatric UTI patients at our center. METHODS: Clean catch mid-stream urine samples for culture were received from 1974 children aged<12 yr over a period of 6 months.Quantitative wet mount microscopy and semiquantitative culture on cysteine lactose electrolyte deficient medium were done to diagnose UTI. Isolates were identified by standard biochemical tests and antimicrobial sensitivity was determined. Clinical details including risk factors and underlying illness were noted. RESULTS: Significant bacteriuria was found in 558 children (28.3%). Male gender (25.6%), age<1 yr (77.5%), vesicoureteric reflux disease (VUR) (19.9%) and posterior urethral valve (PUV) (27.6%) were common risk factors in children suffering from UTI.Pyuria was detected in 53.6 per cent of infections. Common uropathogens isolated were Escherichia coli (47.1%), Klebsiella spp. (15.6%), Enterococcus fecalis (8.7%), members of tribe Proteae (5.9%), Pseudomonas aeruginosa (5.9%) and Candida spp. (5.5%). Against lactose fermenting Enterobacteriaceae, in-vitro resistance was least against amikacin (32.5%), nitrofurantoin (26.7%) and imipenem (3.7%). Among enterococci, vancomycin resistant enterococci constituted 12 per cent of the strains. 93.4 per cent of the UTI detected was nosocomial. INTERPRETATION & CONCLUSION: Paediatric UTI was common in children with male gender, age<1 yr, and in children suffering from VUR and PUV. Spectrum of pathogens causing paediatric UTI in our center had a preponderance of nosocomial multi-drug resistant pathogens. PMID- 20167983 TI - Additive effects of Hyptis martiusii Benth with aminoglycosides against Escherichia coli. PMID- 20167984 TI - Extensively drug-resistant tuberculosis in India. PMID- 20167985 TI - Using surveys of Affymetrix GeneChips to study antisense expression. AB - We have used large surveys of Affymetrix GeneChip data in the public domain to conduct a study of antisense expression across diverse conditions. We derive correlations between groups of probes which map uniquely to the same exon in the antisense direction. When there are no probes assigned to an exon in the sense direction we find that many of the antisense groups fail to detect a coherent block of transcription. We find that only a minority of these groups contain coherent blocks of antisense expression suggesting transcription. We also derive correlations between groups of probes which map uniquely to the same exon in both sense and antisense direction. In some of these cases the locations of sense probes overlap with the antisense probes, and the sense and antisense probe intensities are correlated with each other. This configuration suggests the existence of a Natural Antisense Transcript (NAT) pair. We find the majority of such NAT pairs detected by GeneChips are formed by a transcript of an established gene and either an EST or an mRNA. In order to determine the exact antisense regulatory mechanism indicated by the correlation of sense probes with antisense probes, a further investigation is necessary for every particular case of interest. However, the analysis of microarray data has proved to be a good method to reconfirm known NATs, discover new ones, as well as to notice possible problems in the annotation of antisense transcripts. PMID- 20167986 TI - Liver transient elastography (Fibroscan): a place in the management algorithms of chronic viral hepatitis. AB - Treatment guidelines are continuously evolving in chronic viral hepatitis, taking into consideration our greater understanding of natural history and therapeutic efficacy and safety. Key in the decision making process is an assessment of liver injury. Traditionally, liver biopsy has provided this information; however, this is an invasive procedure and not completely reliable. Liver transient elastography (Fibroscan) is exciting new technology that allows estimation of hepatic fibrosis through measurement of liver stiffness. It is acceptably accurate, safe, cheap, quick and widely applicable, and can reduce the need for liver biopsy in chronic hepatitis. In chronic hepatitis C, it can identify those most likely to benefit from treatment, as well as those with cirrhosis who require more specific care. In chronic hepatitis B, it could screen groups previously excluded from treatment (normal alanine aminotransferase and low DNA) to identify the subgroup that would benefit from therapy. It cannot replace biopsy in all settings, but it will narrow the group who do require biopsy, and provide information on liver damage in patients for whom biopsy would probably not have been considered. PMID- 20167987 TI - Effect of newer oral antiviral agents on future therapy of chronic hepatitis B. AB - Long-term therapy with oral nucleoside/nucleotide analogues (NAs) is a favoured approach to the treatment of patients with chronic hepatitis B (CHB); however, all oral agents currently approved for the treatment of such patients are associated with some risk for drug resistance. This can lead to a rebound in HBV levels and, eventually, progressive liver disease. Combination therapy is one strategy that has the potential for enhanced antiviral effects and diminished or delayed resistance. The disadvantages of combination therapy include increased cost, the potential for drug interactions and increased toxicity. Additional therapeutic efficacy from combination therapy has not been demonstrated in clinical trials of HBV, and this approach might be less relevant now that potent NAs with excellent drug resistance profiles are available. However, it might be possible to identify subsets of patients (for example, those with extremely high viraemia or low baseline alanine aminotransferase levels) who derive added benefit from combination therapy. This review examines efficacy and resistance data for new low resistance oral NAs and clinical experience to date with de novo combination therapy in patients with CHB. The application of combination therapy in select populations of patients with CHB is also discussed. PMID- 20167988 TI - Intragraft cytomegalovirus infection: a randomized trial of valacyclovir prophylaxis versus pre-emptive therapy in renal transplant recipients. AB - BACKGROUND: In a randomized study, we observed a higher incidence of biopsy proven acute rejection with pre-emptive valganciclovir therapy as compared with valacyclovir prophylaxis for prevention of cytomegalovirus (CMV) disease after renal transplantation (RTx). Persistence of the virus within the allograft could stimulate the alloimmune response. The aim of our study was to evaluate intragraft CMV infection in patients randomized to the trial. METHODS: RTx recipients at risk of CMV were randomized to pre-emptive therapy with valganciclovir (n=36) for significant CMV viraemia (> or =2,000 copies/ml by quantitative PCR in whole blood samples) or 3-month prophylaxis with valacyclovir (n=34). Renal biopsies performed during 12 months post-RTx were analysed for the presence of CMV by real-time PCR and immunohistochemical staining. RESULTS: A total of 35 patients (59 biopsies) in the pre-emptive group and 31 patients (57 biopsies) with valacyclovir prophylaxis had > or =1 biopsy specimen with sufficient material for intragraft CMV determination. Cumulative incidence of intragraft CMV infection was 14% and 7% (P=0.315) with pre-emptive therapy and prophylaxis, respectively. Patients at risk for primary CMV infection (CMV serological donor-positive and recipient-negative) were at higher risk for intragraft CMV infection (40% versus 5%; P=0.008). CMV viraemia at the time of biopsy was associated with the presence of CMV within the allograft (P<0.001). CONCLUSIONS: During the first year after RTx, the incidence of intragraft CMV infection was relatively low with comparable rates in patients managed by pre emptive valganciclovir therapy and valacyclovir prophylaxis. PMID- 20167989 TI - Randomized trial of a computerized coronary heart disease risk assessment tool in HIV-infected patients receiving combination antiretroviral therapy. AB - BACKGROUND: Exposure to combination antiretroviral therapy (cART) can lead to important metabolic changes and increased risk of coronary heart disease (CHD). Computerized clinical decision support systems have been advocated to improve the management of patients at risk for CHD but it is unclear whether such systems reduce patients' risk for CHD. METHODS: We conducted a cluster trial within the Swiss HIV Cohort Study (SHCS) of HIV-infected patients, aged 18 years or older, not pregnant and receiving cART for >3 months. We randomized 165 physicians to either guidelines for CHD risk factor management alone or guidelines plus CHD risk profiles. Risk profiles included the Framingham risk score, CHD drug prescriptions and CHD events based on biannual assessments, and were continuously updated by the SHCS data centre and integrated into patient charts by study nurses. Outcome measures were total cholesterol, systolic and diastolic blood pressure and Framingham risk score. RESULTS: A total of 3,266 patients (80% of those eligible) had a final assessment of the primary outcome at least 12 months after the start of the trial. Mean (95% confidence interval) patient differences where physicians received CHD risk profiles and guidelines, rather than guidelines alone, were total cholesterol -0.02 mmol/l (-0.09-0.06), systolic blood pressure -0.4 mmHg (-1.6-0.8), diastolic blood pressure -0.4 mmHg (-1.5 0.7) and Framingham 10-year risk score -0.2% (-0.5-0.1). CONCLUSIONS: Systemic computerized routine provision of CHD risk profiles in addition to guidelines does not significantly improve risk factors for CHD in patients on cART. PMID- 20167990 TI - Factors associated with HIV RNA levels in pregnant women on non-suppressive highly active antiretroviral therapy at conception. AB - BACKGROUND: Little is known about pregnancy patterns and levels of HIV RNA in HIV infected women conceiving on highly active antiretroviral therapy (HAART) with non-suppressed viral load (VL), nor about their therapeutic management. METHODS: Linear mixed models were fitted to study changes in VL and potential associated factors including HAART type or duration and immune status among 127 women receiving HAART at conception with detectable VL enrolled in the prospective European Collaborative Study. RESULTS: Median duration of HAART at conception was 10 months. A total of 78 (61%) women conceived while on protease inhibitor (PI) based HAART. Overall, 72 (57%) women remained on the same HAART regimen throughout pregnancy, 24 (19%) switched regimens and 31 (24%) interrupted HAART during early pregnancy. The intention-to-treat model indicated constant VL up to 10 gestational weeks; thereafter, levels decreased significantly, by 0.06 log(10) copies/ml weekly until delivery. At baseline, immune status was significantly associated with HIV RNA levels. Excluding those with treatment interruption, there was no significant difference in VL slope between women who did and did not modify their HAART regimens (P=0.14); women conceiving on non-nucleoside reverse transcriptase inhibitor-based HAART had consistently lower VL throughout pregnancy than those on PI-based HAART (P=0.02). Most (64/103, 62%) women had detectable VL within 4 weeks of delivery (median 2.40 log(10) copies/ml). The overall mother-to-child transmission rate was 1.72% (95% confidence interval 0.21 6.1). CONCLUSIONS: Practices regarding management of women conceiving on HAART with detectable VL vary in Western Europe. The existence of this group of pregnant women highlights the need for improved monitoring of and support for treated women before they become pregnant, as well as during pregnancy. PMID- 20167991 TI - Mitochondrial changes during D-drug-containing once-daily therapy in HIV-positive treatment-naive patients. AB - BACKGROUND: Antiviral drugs of the category of nucleoside reverse transcriptase inhibitors (NRTIs), largely used for the treatment of HIV infection, can have toxic effects on mitochondria. We performed a cross-sectional study on mitochondrial toxicity in a randomized group of patients belonging to a larger randomized study on different NRTI-based once-daily regimens by quantifying mitochondrial DNA (mtDNA), three different mitochondrial RNAs (mtRNAs) and functional parameters in highly purified peripheral CD4+ and CD8+ T-cells. METHODS: A total of 49 previously treatment-naive patients treated for a mean of 15 months with efavirenz plus didanosine plus lamivudine (group 1), or tenofovir disoproxil fumarate plus lamivudine (group 2), or didanosine plus abacavir (group 3) were considered. The groups were matched for sex, age, CDC classification, risk factor for HIV, nadir CD4+ T-cell count and baseline viral load. mtDNA and mtRNA were quantified by using real-time PCR assays. RESULTS: No patient showed any clinical symptom; however, the amount of mtDNA in CD4+ and CD8+ T-cells was significantly lower in groups 1 and 3; similarly, the expression of different mtRNAs in both CD4+ and CD8+ T-cells showed significant differences that were dependent upon the drug used. No differences were found in mitochondrial membrane potential and mitochondrial mass in peripheral lymphocytes. The amount of total HIV DNA in CD4+ T-cells did not differ among the groups, who displayed a similar immune reconstitution and control of the virus. CONCLUSIONS: An efficient didanosine-containing once-daily therapy can have more mitochondrial toxicity than regimens devoid of this drug. PMID- 20167992 TI - Retrospective characterization of the S open reading frame of HBV isolated from children with membranous nephropathy treated with interferon-alpha2b. AB - BACKGROUND: A causal relationship exists between HBV infection and membranous nephropathy. The association is especially close in Black children in sub-Saharan Africa. Interferon-alpha2b is commonly used to treat this condition, but is effective in only 30-40% of patients. The reason for the poor response is unknown. The objective of this study was to determine if mutations in the surface gene of HBV isolated from Black children with HBV-associated membranous nephropathy before, during and after interferon treatment, have any effect on treatment response and vice versa. METHODS: HBV DNA was extracted from a responder, a reverter and a non-responder before and after initiation of 16 weeks of interferon-alpha2b treatment. The preS1/preS2/S region was amplified, cloned and sequenced. RESULTS: The preS2 region was the most variable in the reverter and the non-responder, and the S region was the most variable in the non responder. Phylogenetic analysis showed that the viral population dynamics between the responder and the reverter/non-responder strains differed as a result of mutations in the surface gene. CONCLUSIONS: The presence of mutations in the S region of HBV could be used as predictive markers to differentiate interferon alpha2b responders from non-responders provided that detailed analysis of further genomes confirms our findings. PMID- 20167993 TI - Efficacy of peroxisome proliferator activated receptor agonist in the treatment of virus-associated haemophagocytic syndrome in a rabbit model. AB - BACKGROUND: Virus-associated haemophagocytic syndrome (VAHS) is a fatal complication of viral infections, such as Epstein-Barr virus and H5N1 influenza, that results from macrophage activation and pro inflammatory cytokine injuries. The high comorbidity and mortality of current therapy urgently demands an ideal agent based on VAHS pathogenesis. Peroxisome proliferator activated receptor (PPAR) agonists, regulators of metabolic syndrome, can exhibit immunomodulatory effects on macrophage activation and cytokine secretion. METHODS: In this study, we adopted rosiglitazone, a PPAR-gamma agonist, for VAHS control in a Herpesvirus papio (HVP)-infected rabbit model. Various doses of rosiglitazone were orally administered to rabbits on day 7 or day 20 after intravenous challenge with 5 x 10(7) copies of HVP. RESULTS: The rabbits that received 4 mg/day rosiglitazone had significantly increased survival when treated at an early stage of infection (P<0.01), whereas a higher dose (8 mg/day) was required at the advanced stage of the disease (P<0.05). All rosiglitazone-treated rabbits had significantly improved laboratory parameters and plasma tumour necrosis factor-alpha levels. Importantly, rosiglitazone could also inhibit viral replication in vitro and in vivo. CONCLUSIONS: PPAR agonists could represent a potentially new agent for the therapy of VAHS. PMID- 20167994 TI - Pharmacokinetics of generic and trade formulations of lamivudine, stavudine and nevirapine in HIV-infected Malawian children. AB - BACKGROUND: The aim of this study was to evaluate the pharmacokinetics of lamivudine (3TC), stavudine (d4T) and nevirapine (NVP) in HIV-infected Malawian children receiving quartered tablet multiples of Triomune 40 (generic tablet [GT]) compared with individual generic liquid (GL) and trade liquid (TL). METHODS: This was a prospective randomized three-way crossover study. Patients (8 <12 kg, 18-<22 kg or 28-<32 kg body weight) taking Triomune 40 were recruited and randomized to receive GT twice daily (one-quarter, one-half or three-quarter tablets using Malawi treatment guidelines), GL twice daily (in the equivalent dose of GT) or TL twice daily (dosed using weight and age from US Department of Health and Human Services paediatric treatment guidelines). After 10 days of one formulation, 6-h pharmacokinetic sampling was performed, and patients were crossed over to subsequent formulations. Baseline concentration (C(0 h)), area under the curve (AUC)(0-6 h), maximum plasma concentration (C(max)) and time to C(max) were generated for each antiretroviral treatment. RESULTS: A total of 7 males and 11 females (6 in each GT dosing group) with a median (range) age of 7.2 years (1.3-13.6), weight of 19 kg (9.0-30.5) and height of 109 cm (75-132) were recruited. Combining all patients, no difference in pharmacokinetics was noted among the formulations for all drugs. However, patients in the one-quarter GT dosing group (8-<12 kg) had lower 3TC exposures than with the GL or TL (3TC AUC(0 6 h) 1,102, 1,720 and 2,060 h*ng/ml, respectively; P<0.005) and had more subtherapeutic NVP C(0 h) (10 of 13 occasions versus the one-half and three quarter tablet groups). Compared with Western paediatric cohorts, Malawians had concentrations 30-40% lower for 3TC and d4T and 50% higher for NVP. CONCLUSIONS: Quartered multiples of Triomune 40 are appropriate for children 18-<22 kg and 28 <32 kg in weight; however, alternative formulations are suggested in children weighing 8-<12 kg. PMID- 20167995 TI - The influence of abacavir and other antiretroviral agents on virological response to HCV therapy among antiretroviral-treated HIV-infected patients. AB - BACKGROUND: It remains unclear if certain antiretroviral medications, particularly abacavir, compromise response to HCV therapy. Such data could inform the selection of appropriate antiretrovirals in HIV/HCV-coinfected patients. The aim of this study was to determine if use of abacavir, as well as other antiretrovirals, was associated with reduced response to pegylated interferon (PEG-IFN) plus ribavirin. METHODS: A cohort study was performed among antiretroviral-treated HIV/HCV-coinfected patients initiating PEG-IFN plus ribavirin between January 2001 and June 2007 at six sites in the United States. Abacavir and other antiretrovirals represented exposures of interest. Study outcomes included an early virological response (> or =2 log IU/ml decrease in HCV viral load at 12 weeks) and sustained virological response (undetectable HCV viral load 24 weeks after treatment discontinuation). RESULTS: Among 212 patients, 74 (35%) received abacavir. For patients infected with HCV genotype 1 or 4, no differences were observed between abacavir users and non-users in early virological response (26 [40%] versus 53 [44%]; adjusted odds ratio [OR] 1.00; 95% confidence interval [CI] 0.50-2.00) or sustained virological response (8 [13%] versus 13 [12%]; adjusted OR 1.34; 95% CI 0.50-3.62). Among genotype 2 and 3 patients, rates of early virological response (7 [78%] versus 16 [89%]; OR 0.44; 95% CI 0.05-3.76) and sustained virological response (3 [33%] versus 8 [44%]; OR 0.63; 95% CI 0.12-3.32) were also similar between abacavir users and non-users. No association was found between other antiretrovirals and a lack of early or sustained response. CONCLUSIONS: Use of abacavir or other antiretroviral medications was not associated with reduced early or sustained virological response rates. PMID- 20167996 TI - Endothelial function is impaired in HIV-infected patients with lipodystrophy. AB - BACKGROUND: Data supporting a link between body-fat distribution changes and cardiovascular disease risk in HIV-infected patients are scarce and contradictory. We evaluated endothelial dysfunction, an early event in the development of atherosclerosis, and pro-atherosclerotic plasma biomarkers in HIV infected patients with lipodystrophy. METHODS: HIV-infected patients with and without lipodystrophy were prospectively enrolled. Endothelial function was measured through flow-mediated dilatation (FMD) of the brachial artery. Plasma levels of several biomarkers of inflammation, endothelial activation and coagulation associated with adipose tissue and endothelial dysfunction were determined. RESULTS: The study included 110 patients, 55 of them with lipodystrophy. FMD was significantly lower in patients with lipodystrophy than in those without lipodystrophy (median [IQR] 3.1% [0.4-8.9] versus 6.3% [3.3-10.7]; P=0.004). Patients with isolated lipoatrophy exhibited the lowest FMD (2.6% [0 6.6]; P(Kruskal-Wallis)=0.02). Lipodystrophy was associated with significantly higher plasma levels of interleukin 6 (IL-6) and plasminogen activator inhibitor 1 (PAI-1) and lower levels of adiponectin; severe lipodystrophy was associated with higher concentrations of vascular cell adhesion molecule 1 (sVCAM-1). There was an inverse correlation between FMD and IL-6 (Spearman's rho =-0.26; P=0.007). In a multivariate regression model with the lowest quartile of FMD as the dependent variable and lipodystrophy, traditional cardiovascular risk factors, 10 year Framingham risk score, pro-atherosclerotic biomarkers and HIV-related variables as predictors, the only independent predictor of endothelial dysfunction was lipodystrophy (odds ratio 5.22, 95% confidence interval 1.76 15.46; P=0.003). CONCLUSIONS: Lipodystrophy is associated with endothelial dysfunction, independently of the presence of traditional cardiovascular risk factors. This finding and the accompanying profile of pro-atherosclerotic biomarkers support an increased cardiovascular risk in HIV-infected patients with lipodystrophy. PMID- 20167997 TI - The influence of antiviral therapy on psychiatric symptoms among patients with hepatitis C and schizophrenia. AB - BACKGROUND: Antiviral therapy for chronic infection with HCV is associated with significant neuropsychiatric side effects. Research indicates that patients with mental illness are less likely to receive antiviral therapy, despite limited data regarding the influence of antiviral therapy on psychiatric symptoms in patients with specific psychiatric disorders. The aim of this study was to determine whether antiviral therapy is associated with higher rates of psychiatric symptoms in patients with schizophrenia (SCHZ). METHODS: A regional Veterans Healthcare Administration database was used to identify veterans meeting criteria for this retrospective chart review. Patients confirmed to have SCHZ and to have received antiviral therapy for HCV between 1998 and 2006 (n=30) were compared with a control group of demographically matched (age, race and gender) patients with SCHZ who did not receive antiviral therapy (n=30). Clinicians blinded to antiviral therapy status used chart notes to evaluate whether patients exhibited prominent symptoms of SCHZ, depression or mania during a 6 month pre-treatment period, the treatment period and a 6 month post-treatment period (or during equivalent periods for the control group). RESULTS: Groups did not significantly differ in rates of symptoms of SCHZ, depression or mania during any study period. During the treatment period, groups did not significantly differ in rates of emergency room visits or inpatient hospitalizations. CONCLUSIONS: Our retrospective chart review suggests that patients with SCHZ experience similar rates of psychiatric symptoms on and off antiviral therapy. Despite limitations and constraints of the methods, our data suggest that SCHZ is not a contraindication to antiviral therapy for HCV. PMID- 20167998 TI - HIV contamination of commercial PCR enzymes raises the importance of quality control of low-cost in-house genotypic HIV drug resistance tests. AB - BACKGROUND: Low-cost in-house technologies for genotypic drug resistance testing use reagents with quality labels for research only. Here, we report on the results of PCR amplifications in negative-controls that were observed in two independent laboratories. METHODS: Positive PCR amplifications of protease and reverse transcriptase fragments for genotypic drug resistance testing of HIV on dried blood and/or plasma spots were observed on negative-control samples and were analysed in detail by PCR and sequence and phylogenetic analyses to identify the origin of the PCR contamination. RESULTS: Detailed analysis revealed that the RT-PCR enzymes were contaminated with an HIV-based vector commercialized by the same company. CONCLUSIONS: These observations show the need to implement quality control steps that verify for the absence of HIV in new reagent batches because this can significantly compromise molecular diagnosis of HIV and genotypic drug resistance tests using in-house protocols. PMID- 20167999 TI - Decreased plasma levels of darunavir/ritonavir in a vertically infected pregnant woman carrying multiclass-resistant HIV type-1. AB - We report a case of a vertically infected woman treated with darunavir/ritonavir plus a standard backbone before pregnancy. The analysis of darunavir/ritonavir concentrations in peripheral maternal plasma throughout pregnancy, as well as in umbilical cord blood at delivery, showed low levels of darunavir in the mother and limited transfer across the placenta. PMID- 20168001 TI - Classification of prefrontal activity due to mental arithmetic and music imagery using hidden Markov models and frequency domain near-infrared spectroscopy. AB - Near-infrared spectroscopy (NIRS) has recently been investigated as a non invasive brain-computer interface (BCI). In particular, previous research has shown that NIRS signals recorded from the motor cortex during left- and right hand imagery can be distinguished, providing a basis for a two-choice NIRS-BCI. In this study, we investigated the feasibility of an alternative two-choice NIRS BCI paradigm based on the classification of prefrontal activity due to two cognitive tasks, specifically mental arithmetic and music imagery. Deploying a dual-wavelength frequency domain near-infrared spectrometer, we interrogated nine sites around the frontopolar locations (International 10-20 System) while ten able-bodied adults performed mental arithmetic and music imagery within a synchronous shape-matching paradigm. With the 18 filtered AC signals, we created task- and subject-specific maximum likelihood classifiers using hidden Markov models. Mental arithmetic and music imagery were classified with an average accuracy of 77.2% +/- 7.0 across participants, with all participants significantly exceeding chance accuracies. The results suggest the potential of a two-choice NIRS-BCI based on cognitive rather than motor tasks. PMID- 20168003 TI - A generative model approach for decoding in the visual event-related potential based brain-computer interface speller. AB - There is a strong tendency towards discriminative approaches in brain-computer interface (BCI) research. We argue that generative model-based approaches are worth pursuing and propose a simple generative model for the visual ERP-based BCI speller which incorporates prior knowledge about the brain signals. We show that the proposed generative method needs less training data to reach a given letter prediction performance than the state of the art discriminative approaches. PMID- 20168004 TI - Towards the next node in downsized devices. PMID- 20168002 TI - Relationship between speed and EEG activity during imagined and executed hand movements. AB - The relationship between primary motor cortex and movement kinematics has been shown in nonhuman primate studies of hand reaching or drawing tasks. Studies have demonstrated that the neural activities accompanying or immediately preceding the movement encode the direction, speed and other information. Here we investigated the relationship between the kinematics of imagined and actual hand movement, i.e. the clenching speed, and the EEG activity in ten human subjects. Study participants were asked to perform and imagine clenching of the left hand and right hand at various speeds. The EEG activity in the alpha (8-12 Hz) and beta (18-28 Hz) frequency bands were found to be linearly correlated with the speed of imagery clenching. Similar parametric modulation was also found during the execution of hand movements. A single equation relating the EEG activity to the speed and the hand (left versus right) was developed. This equation, which contained a linear independent combination of the two parameters, described the time-varying neural activity during the tasks. Based on the model, a regression approach was developed to decode the two parameters from the multiple-channel EEG signals. We demonstrated the continuous decoding of dynamic hand and speed information of the imagined clenching. In particular, the time-varying clenching speed was reconstructed in a bell-shaped profile. Our findings suggest an application to providing continuous and complex control of noninvasive brain computer interface for movement-impaired paralytics. PMID- 20168006 TI - Asking for help. PMID- 20168007 TI - The primary care crisis and health care reform. PMID- 20168008 TI - The immigration detention health plan: an acute care model for a chronic care population. AB - Immigration detention is the fastest-growing form of incarceration in the U.S. Numerous reports by advocacy groups and detainees themselves have alleged substandard medical care for detainees. We have undertaken an analysis of the health plan that regulates reimbursement of much of detainee health care. We conclude that this plan may place detainees at risk of receiving inadequate care, particularly if they have chronic medical problems or would benefit from routine health screening exams. We present several concrete measures that could immediately improve the level of medical care afforded to this vulnerable population. PMID- 20168009 TI - Charlottesville Health Access: a locality-based model of health care navigation for the homeless. AB - The authors describe Charlottesville Health Access (CHA), an initiative to get people who are homeless into the health care system. A community homeless shelter worked with faculty and students from the Univ. of Virginia Schools of Medicine and Nursing to create and run the program. PMID- 20168010 TI - Students who participate in a student-run free health clinic need education about access to care issues. AB - We surveyed first-year medical students about preparedness for work at student run clinics, and for addressing patients' access to care, and social issues. Most students did not know how to get uninsured patients ongoing care or medications outside of the student-run clinic. A large majority of students desired an orientation addressing these issues. PMID- 20168011 TI - Quality of diabetes care at a student-run free clinic. AB - Student-run clinics are emerging safety-net practices for the uninsured; despite the over 110 clinics that currently operate across the United States, however, no data exist on the quality of care being delivered at such sites. The East Harlem Health Outreach Partnership (EHHOP) of the Mount Sinai School of Medicine in New York is a medical student-run, attending-supervised free clinic that offers primary care to the uninsured of surrounding East Harlem. The aim of this study was to evaluate diabetes care quality at the EHHOP clinic. Diabetes management was assessed using common quality-of-care indicators such as glycosylated hemoglobin level and blood pressure control. Clinic rates of such diabetes quality-of-care indicators ranged from 12% to 96%, and in most areas was comparable to or better than averages previously reported for uninsured populations. PMID- 20168012 TI - Impact of race/ethnicity on survival among HIV-infected patients in care. AB - OBJECTIVE: To determine the prognostic influence of race/ethnicity on survival among patients infected with HIV infection. BACKGROUND: In the U.S., HIV infection occurs disproportionately in minority communities. Additionally, worse outcomes (including higher mortality) have been reported, particularly among African Americans. METHODS: This was a retrospective cohort study among 870 HIV infected patients attending a Midwestern academic medical center. The study determined individual characteristics that were predictive of survival by using log rank tests and multivariate analysis models, after adjusting for known predictors of outcome. RESULTS: Low CD4 cell count (<100 cells/mm3), high viral load (>250,000 copies/mL), age older than 30, and Black race were independently predictive of poorer outcomes among patients infected with HIV. CONCLUSION: We found a large disparity in survival, with African Americans with advanced disease more likely to die than whites. This finding was not explained by socioeconomic status or other confounders. Future prospective studies are warranted. PMID- 20168013 TI - The impact of acculturation on utilization of HIV prevention services and access to care among an at-risk Hispanic population. AB - INTRODUCTION: HIV/AIDS disproportionately affects Hispanics in the United States, a diverse and heterogeneous population. The purpose of this study was to evaluate the relationship of acculturation with HIV and hepatitis C testing, and access to care among Hispanics at risk for HIV. METHODS: We recruited 600 Hispanics from STD clinics, community-based organizations, and needle exchange programs in Los Angeles County. RESULTS: Low levels of acculturation were significantly associated with having fewer HIV tests (OR 1.98, 95% CI 1.24, 3.15), no hepatitis C tests (OR 2.61, 95% CI 1.77, 3.84), testing positive for HIV (OR 2.67, 95% CI 1.04, 6.83), and low levels of access to care (beta=0.06; p<.05). CONCLUSIONS: Low levels of acculturation are an important barrier to the use of HIV-related health care services. Our findings may inform the development of effective interventions that address the cultural and behavioral differences among Hispanic subgroups. PMID- 20168015 TI - Psychiatric street outreach to homeless people: fostering relationship, reconnection, and recovery. AB - Individuals who suffer from serious and persistent mental illnesses constitute nearly one-third of the homeless population in this country. Perhaps the most vulnerable people in the homeless population are those who are disabled from a mental illness and are also chronically unsheltered. Psychiatric street outreach to this particular segment of the homeless population is commonly justified based upon the need to engage the most severely impaired and most medically underserved individuals in our communities assertively. This brief paper describes the core objectives of fostering relationship, reconnection, and recovery through a transdisciplinary, psychiatric street outreach initiative in Jacksonville, Florida. PMID- 20168014 TI - Sources and types of social support that influence engagement in HIV care among Latinos and African Americans. AB - The change in HIV from acute to chronic disease due to the introduction of HAART in the mid-1990s increased the importance of its successful management and imposed substantial lifestyle adjustments on HIV-positive people and their support networks. Few studies have examined the sources and types of social support and the areas of care relevant for engagement in HIV treatment among HIV positive Latinos and African Americans. This paper reports the results of 24 semi structured in-depth interviews that were conducted with HIV-positive African American and Latino women and men who have sex with men. Formal networks were found to be more critical for engagement in HIV-specific medical care; specifically, study participants relied primarily on health care providers for support in accessing and maintaining illness-specific care. In contrast, informal networks (family and friends) were crucial for other general subsistence care, such as emotional, household-related, and financial support. PMID- 20168016 TI - Development of a flexible sigmoidoscopy training program for rural nurse practitioners and physician assistants to increase colorectal cancer screening among Alaska Native people. AB - At the Alaska Native Medical Center in Anchorage, colorectal cancer screening rates improved dramatically with the initiation of a dedicated flexible sigmoidoscopy screening program staffed by mid-level providers. We describe the development and implementation of a program to train rural nurse practitioners and physician assistants in flexible sigmoidoscopy. PMID- 20168017 TI - The impact of mass incarceration on outpatients in the Bronx: a card study. AB - OBJECTIVE: We examined the impact of arrest and incarceration on primary care patients in the Bronx, New York. METHODS: Patients at three clinics were asked eight questions concerning current and past involvement in criminal proceedings, arrest, and incarceration. RESULTS: One hundred eighteen patients were surveyed. Eleven (9%) patients were currently involved in criminal proceedings. Twenty-one (18%) currently had a family member in jail or prison. Twenty-nine (25%) reported ever being arrested; 65 (55%) reported that they or a family member had been arrested. Twenty-one (18%) had been incarcerated; 60 (51%) reported they or a family member had spent time in jail or prison. For most variables, rates were higher for men and the adults accompanying children at pediatric visits. Clinicians reported positive experiences discussing incarceration. CONCLUSIONS: Involvement with the criminal justice system was common among our patients. Discussion of incarceration did not appear to have a negative impact on the clinical relationship. PMID- 20168018 TI - Assessment of clients health needs of two urban Native American health centers in the San Francisco Bay Area. AB - A needs assessment was compiled from self-administered questionnaires completed by 796 clients at the Urban Indian Health Service clinics in San Francisco and Oakland, California. Data on the health disparities between Native Americans and Alaskan Natives and the rest of the U.S. population are limited. The data that exist, however, indicate that Native Americans continue to fare worse than the general population. This needs assessment reveals the same trend among a sample of clients of two Native American Health Centers in the San Francisco Bay Area and provides further information about the health needs and interests of the population currently attending these centers. PMID- 20168019 TI - Hepatitis C in an urban cohort: who's not being treated? AB - Hepatitis C virus (HCV) remains widely prevalent in the U.S. Treatment has improved, but rates of treatment initiation remain low. We sought to identify clinical and sociodemographic characteristics of patients that are associated with failure to initiate treatment of HCV infection. We conducted a retrospective cohort study in our primary care hepatitis C treatment clinic, affiliated with an urban academic hospital. Our population was multi-ethnic, HIV-, HCV+, treatment naive patients. We measured rates of HCV treatment initiation and sociodemographic, viral, and patient-related variables associated with non initiation of treatment. The total number of treatment-eligible patients was 168, of whom 41 began treatment and 127 did not. In multivariate analysis, individuals with HCV genotypes 1 and 4 were less likely than others to initiate treatment, as were patients with more medical comorbidities. Further research is needed to understand how factors around initiation interact and how interventions can overcome them. PMID- 20168020 TI - A randomized community intervention to improve hypertension control among Mexican Americans: using the promotoras de salud community outreach model. AB - The objectives of this study were: 1) to evaluate the acceptance, effectiveness, and sustainability of a promotora (community health worker) pilot program to improve hypertension control among medically underserved Mexican Americans of the El Paso, Texas area, and 2) to demonstrate improvements in clinical measures of blood pressure, BMI and waist circumference, self-reported behaviors and changes in attitudes and beliefs about blood pressure among Mexican American hypertensives. Participants were eligible if they had been diagnosed with hypertension and if they were willing to be randomized as either participants in the intervention or as controls. A total of 58 participants enrolled in the intervention group and 40 participants served as controls. This was a 9-week promotora intervention. Health behavior constructs and clinical data were measured pre-post intervention. Perceived benefits, and two heart-healthy behaviors (salt and sodium, and cholesterol and fat) were shown to be statistically significantly different between the intervention and control groups. PMID- 20168021 TI - Alcohol use, comorbidities, and receptivity to treatment in Hispanic farmworkers in primary care. AB - Primary care is a promising setting for alcohol screening and intervention with low-income Hispanic farmworkers, yet no research has been conducted that estimates the prevalence of harmful and hazardous drinking, psychiatric comorbidities, or receptivity to treatment in this population. This study investigates rates of alcohol misuse, depression, anxiety, somatization, and cigarette use in a convenience sample of low-income Hispanic farmworkers and farmworker spouses in Florida making walk-in visits to a rural community health center. Results indicated a high prevalence of alcohol use but also a strong willingness to receive treatment. Forty-four percent (44%) screened positive for harmful and hazardous alcohol use; over half (58%) screened positive for one or more comorbidity risks. Receptivity to alcohol treatment was high (75%). These results strongly support the need for and potential utility of alcohol intervention in primary care for this population. PMID- 20168022 TI - Stirring up the mud: using a community-based participatory approach to address health disparities through a faith-based initiative. AB - This case study provides a mid-course assessment of the Bronx Health REACH faith based initiative four years into its implementation. The study uses qualitative methods to identify lessons learned and to reflect on the benefits and challenges of using a community-based participatory approach for the development and evaluation of a faith-based program designed to address health disparities. Key findings concern the role of pastoral leadership, the importance of providing a religious context for health promotion and health equality messages, the challenges of creating a bilingual/bi-cultural program, and the need to provide management support to the lay program coordinators. The study also identifies lessons learned about community-based evaluation and the importance of addressing community concern about the balance between evaluation and program. Finally, the study identifies the challenges that lie ahead, including issues of program institutionalization and sustainability. PMID- 20168027 TI - Addressing the social determinants of children's health: a cliff analogy. AB - This paper presents a "Cliff Analogy" illustrating three dimensions of health intervention to help people who are falling off of the cliff of good health: providing health services, addressing the social determinants of health, and addressing the social determinants of equity. In the terms of the analogy, health services include an ambulance at the bottom of the cliff, a net or trampoline halfway down, and a fence at the top of the cliff. Addressing the social determinants of health involves the deliberate movement of the population away from the edge of the cliff. Addressing the social determinants of equity acknowledges that the cliff is three-dimensional and involves interventions on the structures, policies, practices, norms, and values that differentially distribute resources and risks along the cliff face. The authors affirm that we need to address both the social determinants of health, including poverty, and the social determinants of equity, including racism, if we are to improve health outcomes and eliminate health disparities. PMID- 20168023 TI - Multiple switching in Medicaid managed care: a proportional hazards model. AB - This case study (n=41,969) aims to discover managerially useful predictors of multiple switching among HMOs in a Medicaid managed care population observed over 33 months. Cox's proportional hazards model was used to analyze eligibility data for the entire population, claims data for Medicaid services received during six months prior to HMO enrollment (sample n=2,474) and telephone interviews (sample n=656). Each analytic stage involved four comparisons: (1) enrollees with one switch compared with enrollees with no switches; (2) enrollees with multiple switches compared with those having no switches; (3) in relation to making the first switch, enrollees with multiple switches compared with those having one switch; and (4) in relation to making the second switch, multiple compared with those having one switch. Interruptions (which were independent of switches) predicted switching versus non-switching. Medical claims and, weakly, greater age were associated with multiple switching. Managers can use these three predictors to reduce switching and multiple switching. The finding that switching was associated with greater utilization before HMO enrollment contradicts findings for employer-sponsored insurance, but a possible explanation is offered. PMID- 20168028 TI - Care for the most vulnerable children in Tanzania: a faith-based model of care and support for children affected by HIV. AB - In the fight against HIV and AIDS in sub-Saharan Africa, the plight of orphaned and vulnerable children was long overlooked. The first United Nations report on orphans and vulnerable children did not emerge until 2002 after more than two generations of children and youth had struggled to survive with limited family, institutional, or government support. The major social determinants of health for infants and children with one or more parents dying or dead from HIV include pervasive poverty, weak community social support systems, lack of policy commitment by governments or foreign donors, lack of access to anti-retroviral drugs, limited access to schools, and gender. In this paper, we present a model of care and support to the most vulnerable children (MVC) affected by HIV that brings together faith-based institutions in partnership with the government and community volunteers in 13 rural districts of Tanzania. Although still being implemented, the project has a number of valuable lessons learned for program managers, donors, and researchers working with faith-based organizations in the development and delivery of services to the most vulnerable children in a resource-limited setting. PMID- 20168029 TI - No family left behind: the example of community-based pneumonia care in Haiti. AB - The Haitian Health Foundation (HHF) in Jeremie, Haiti conducted an intervention combating childhood bacterial pneumonia. HHF treated 60,000 episodes of respiratory illness in 15 years. The same care model is used for vaccinations, exclusive breastfeeding, diarrheal disease, congenital syphilis, and newborn care. PMID- 20168030 TI - Fostering resilience in children at risk through a cultural therapy intervention in Kingston, Jamaica. AB - This report explores an initiative in Kingston, Jamaica to foster resilience in children in an inner-city community plagued by violence and other social problems. This initiative was undertaken by CARIMENSA, the Caribbean Institute for Mental Health and Substance Abuse. PMID- 20168031 TI - An alternative model for the provision of services to HIV-positive orphans in Haiti. PMID- 20168032 TI - Promoting better oral health practices among aboriginal Taiwanese adolescents: a school based oral health education intervention program. AB - The purpose of this study was to test the efficacy of an educational program aimed at improving oral health knowledge and behaviors in junior high school students in indigenous communities in Taiwan. Two junior high schools were randomly selected. Students in the intervention school received an oral health education program. Both groups received structured questionnaires to assess their oral health practices and risk behaviors at baseline and after the intervention. The intervention group had statistically significant positive changes in their oral health knowledge (p<.001), an increase in tooth-brushing frequency (p<.001), and a decrease in tobacco use (p=.01). Most (87%) students considered the educational program excellent or good. Carefully designed health education programs delivered within schools in areas with limited access to health care can improve the students' knowledge and reduce their risk behaviors which may prove to be a mechanism that ultimately reduces health disparities. PMID- 20168033 TI - Unintentional childhood injuries in sub-Saharan Africa: an overview of risk and protective factors. AB - The rate of unintentional injuries for children in sub-Saharan Africa has reached 53.1 per 100,000, the highest for regions across all income levels. This paper reviews the relevant literature on the epidemiology of unintentional childhood injuries in the region, with an emphasis on the risk factors associated with it. Several demographic, socioeconomic, and environmental factors contributing to injuries in children have been documented for the main causes of injury. Despite the high burden, child injury prevention and control programs and policies are limited or non-existent in many countries in the region. Accurate data regarding these injuries across and within countries is incomplete. Population-based estimates and investigations into context-specific risk factors, safety attitudes, and behaviours are needed to inform the development of effective interventions. PMID- 20168034 TI - Social determinants of children's health in urban areas in India. AB - Children of the urban poor in India suffer a much poorer health status than the urban non-poor, influenced to a large extent by social determinants. In this paper, National Family Health Survey-3 (2005-06) data were analyzed to assess the health status of urban poor children vis-a-vis the non-poor, and to identify the social determinants precipitating disparities. The analysis shows sharp disparity between child health indicators between urban poor and non-poor. Key findings include under-five mortality per thousand (urban poor 72.7 and non-poor 41.8) and children under-five underweight for age (urban poor 47% and non-poor 26.2%). Significant demographic and social correlates of child health in urban areas included poverty, gender, caste status, religion, mother's educational attainment, occupational status of parents, and women's autonomy in the household. They influenced different facets of child health, such as nutritional status and access to immunization. PMID- 20168035 TI - Urban and rural differences across countries in child mortality in sub-Saharan Africa. AB - The purpose of this study is to investigate and document the differences between urban and rural areas across countries in sub-Saharan Africa (SSA) with respect to child mortality. We use recent data from Demographic and Health Surveys on 11 selected countries in SSA. Socioeconomic variables of household wealth, level of education of the mother, access to clinics, and other environmental variables are used as control variables in measuring the differences. The study employs logit regression to enable the use of the odds ratio to interpret differences across the urban and rural areas in SSA. PMID- 20168036 TI - Community case management of childhood illness in Nicaragua: transforming health systems in underserved rural areas. AB - While social factors broadly determine health outcomes, strategic health workforce innovations such as community case management (CCM) can redress social inequalities in access to health care. Community case management enables trained health workers to assess children, diagnose common childhood infections, administer medicines, and monitor life-saving treatment in the poor, remote communities where they reside. This article reports on research that combined focus group discussions and key informant interviews to examine the perceptions of multiple stakeholders, with monitoring data, in order to assess programmatic results, limitations, and lessons learned in implementing CCM in Nicaragua. We found that CCM increases the use of curative services by poor children with pneumonia, diarrhea, or dysentery by five to six-fold over facility-based services. Apart from dramatically increasing geographic access to treatment for underserved groups, our qualitative research suggests that Nicaragua's CCM model also addresses the managerial challenges and social relations that underpin good quality of care, care-giver knowledge and awareness, and community mobilization, all health system-strengthening factors that are central to equitably and effectively improving child health. While our findings are promising, we suggest areas for further operational research to strengthen CCM program learning and functioning. PMID- 20168037 TI - Reducing inequities among children with asthma in the island of Puerto Rico: experiences of a community-based, trans-sectoral effort. AB - Children living in the Commonwealth of Puerto Rico have the highest poverty and asthma prevalence rates of all U.S. children. Since 2000, a group of community, health care, education, housing, and academic representatives have been collaborating in a project to improve quality of life and reduce disparities among children with asthma in very poor communities in Puerto Rico. To date the project has implemented a successful intervention in the Luis Llorens Torres Housing Project, aimed at adapting evidence-based interventions to improve the social and physical environment of children with asthma. The program has recently been extended to another San Juan housing area, the Manuel A. Perez Housing Project. Using implementation theory, the authors report and reflect on the project's experience to date, provide recommendations, and discuss implications of lessons learned to address inequities in asthma care throughout other underserved areas in the U.S., Latin America, and the Caribbean. PMID- 20168038 TI - Social, economic, and political factors in progress towards improving child survival in developing nations. AB - Child mortality is a persistent health problem faced by developing nations. In 2000 the United Nations (UN) established a set of high priority goals to address global problems of poverty and health, the Millennium Development Goals, which address extreme poverty, hunger, primary education, child mortality, maternal health, infectious diseases, environmental sustainability, and partnerships for development. Goal 4 aims to reduce by two thirds, between 2000 and 2015, the under-five mortality rate in developing countries. In sub-Saharan Africa from 2000 to 2006 these rates have only been reduced from 167 per 1,000 live births to 157, and 27 nations in this region have made no progress towards the goal. A country-specific database was developed from the UN Millennium Development Goal tracking project and other international sources which include age distribution, under-nutrition, per capita income, government expenditures on health, external resources for health, civil liberties, and political rights. A multiple regression analysis examined the extent to which these factors explain the variance in child mortality rates in developing countries. Nutrition, external resources, and per capita income were shown to be significant factors in child survivability. Policy options include developed countries' renewed commitment of resources, and developing nations' commitments towards governance, development, equity, and transparency. PMID- 20168039 TI - Reduction in maternal and child mortality in sub-Saharan Africa: the yo-yo effect in delivering on the promises. AB - Trends in maternal and child mortality (MCM) in sub-Saharan Africa do not follow the patterns seen in developed nations or match the funds and effort invested so far. This paper critically explores trends in MCM, global efforts to reduce MCM, and some of the underlying policies and programmatic issues that have shaped the slow progress or failure in reducing MCM in sub-Saharan Africa. We describe a "yo yo" effect in policies and funding of Maternal and Child Health, Family Planning, and HIV/AIDS/STI programs in the region, and how this yo-yo effect may limit sustained community level reductions in MCM. We conclude by highlighting how renewed interest in the Alma-Ata declaration, particularly its primary health care concepts with their strong emphasis on horizontally integrated linkage of programs and resources, greater community involvement in program design and implementation, and economic development can contribute to sustainable reductions in MCM in the region. PMID- 20168040 TI - Learning how to measure the well-being of OVC in a maturing HIV/AIDS crisis. AB - The HIV/AIDS epidemic in Africa is frequently referred to as a crisis while the principal U.S. program to address it is labeled emergency relief. These terms trigger specific policy responses and corresponding evaluation activities. In this article, three stages in the response to HIV/AIDS are distinguished: awareness, emergency, and structural integration. In the awareness phase, emphasis is on defining and then estimating the affected population. In the emergency phase, evaluation activity is focused on demonstrating accountability for the assistance provided; and finally, in the structural integration phase, concern shifts to demonstrating the impact of assistance on improving the recipients' well-being. The shifting focus of evaluation is discussed in terms of how to measure the impact of aid on the well-being of orphaned and vulnerable children. A case study based on work in rural Tanzania is presented and then discussed in term of its broader implications for evaluating future aid. PMID- 20168042 TI - Methylglyoxal enhances sodium nitroprusside-induced relaxation in rat aorta. AB - The concentration of methylglyoxal (MGO), a metabolite of glucose, increases in plasma of type II diabetic patients as well as in tissues of hypertensive rats. We have previously shown that MGO inhibited noradrenaline (NA)-induced smooth muscle contraction in rat aorta. However, the effect of MGO on relaxing responses in isolated blood vessel remains to be clarified. Thus, we examined if MGO affects acetylcholine (ACh)- or sodium nitroprusside (SNP)-induced vasodilation on NA (100 nM)-induced pre-contraction in rat thoracic aorta. Treatment of endothelium-intact aorta with MGO (420 microM, 30 min) did not change ACh (1 nM - 3 microM)-induced endothelium-dependent relaxation. In contrast, treatment of endothelium-denuded aorta with MGO shifted the concentration-response curve for SNP (0.1 - 300 nM) to the left. MGO increased reactive oxygen species (ROS) production in smooth muscle on analysis of protein carbonylation. Anti-oxidant agents such as tempol (10 microM), catalase (5000 U/mL), and nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methylester (100 microM) had no effect on MGO-induced enhancement of SNP-induced relaxation. However, iberiotoxin (100 nM), a large-conductance Ca(2+)-activated K(+) (BK(Ca))-channel inhibitor, significantly prevented the effect. The present study revealed that MGO enhanced SNP-induced relaxation in a ROS-independent manner via in part opening smooth muscle BK(Ca) channels. PMID- 20168043 TI - Ginsenoside-Rb1 attenuates dilated cardiomyopathy in cTnT(R141W) transgenic mouse. AB - Familial dilated cardiomyopathy (FDCM) is caused by defective genes and specific medicines are not currently available to treat this. Ginsenoside-Rb1 provides cardioprotection in the experimental models of myocardial ischemia-reperfusion injury. Here we investigate Rb1's effect on DCM in cTnT(R141W) transgenic mouse. The transgene-positive mice aged 2 months were randomized into the model group and Rb1 [70 mg/(kg.day)] group; transgene-negative mice were used as a control. After 4-month treatment, cardiac function was assessed by echocardiography; cardiac tissues were prepared for histology and electron microscopy. Expression levels of molecular markers of cardiac hypertrophy, fibrosis, and intercalated disc proteins were detected by RT-PCR. Rb1 significantly decreased mortality, chamber dilation, and contractile dysfunction in cTnT(R141W) mice. Rb1 attenuated cardiac hypertrophy, interstitial fibrosis, ultrastructural degeneration, and intercalated disc remodeling in DCM hearts. Western blotting showed that Rb1 significantly decreased heparin-binding epidermal growth factor-like growth factor (HB-EGF) expression and signal transduction and activators of transcription 3 (STAT3) activation, which were gradually increased in DCM hearts. Our results showed that Rb1 clearly alleviated cardiac dysfunction and remodeling in the cTnT(R141W) transgenic mouse, indicating its potential utility in the treatment of FDCM. PMID- 20168045 TI - Comparison of endothelium-related responses to nucleotides of dog and monkey cerebral arteries. AB - We compared mechanical responses to uridine-5'triphosphate (UTP) and 2 (methylthio)adenosine-5'diphosphate (2MeSADP) of cerebral arteries isolated from dogs and monkeys. In the dog, UTP induced endothelium-independent contraction, whereas 2MeSADP induced endothelium-dependent relaxation that was abolished by N(G)-nitro-L-arginine (L-NA). In the monkey, both UTP and 2MeSADP induced endothelium-dependent relaxation. L-NA largely inhibited the UTP-induced relaxation whereas it partially inhibited the 2MeSADP-induced relaxation, and both remaining relaxations were abolished by charybdotoxin plus apamin. In conclusion, dog and monkey cerebral arteries respond differentially to UTP and similarly to 2MeSADP; however, involvement of endothelium-derived relaxing factor in the endothelium-dependent relaxation by 2MeSADP is quite different between the two species. PMID- 20168044 TI - The cannabinoid 1-receptor silent antagonist O-2050 attenuates preference for high-fat diet and activated astrocytes in mice. AB - Endocannabinoids have been shown to activate reward-related feeding and to promote astrocytic differentiation. We investigated whether high-fat diet (HFD) intake produced a preference for HFD via an endocannabinoid-dependent mechanism. In the conditioned place preference test, the 2-week HFD-intake group showed preference for HFD and had increased expression of a marker for reactive astrocytes, glial fibrillary acid protein (GFAP), in the hypothalamus. The cannabinoid CB(1)-receptor antagonist O-2050 reduced the preference for HFD and expression of GFAP in the hypothalamus. These results suggested that HFD intake led to the development of a preference for HFD via astrocytic CB(1) receptors in the hypothalamus. PMID- 20168046 TI - Losartan normalizes endothelium-derived hyperpolarizing factor-mediated relaxation by activating Ca2+-activated K+ channels in mesenteric artery from type 2 diabetic GK rat. AB - Ca(2+)-activated K(+) (K(Ca)) channels are important for endothelium-derived hyperpolarizing factor (EDHF) signaling. Since treatment with angiotensin II receptor blockers (ARBs) improves vasculopathies in type 2 diabetic patients, we asked whether the EDHF-type relaxation and its associated K(Ca) channels [small (SK(Ca))-, intermediate (IK(Ca))-, and large (BK(Ca))-conductance channels] are abnormal in mesenteric arteries isolated from Goto-Kakizaki (GK) rats at the chronic stage of type 2 diabetes (34 - 38 weeks) and whether an ARBs (losartan, 25 mg . kg(-1) . day(-1) for 2 weeks) might correct these abnormalities. Although the acetylcholine chloride-induced EDHF-type relaxation in mesenteric arteries from GK rats was reduced versus the Wistar controls, it was significantly restored by losartan treatment. The SK(Ca)-blocker apamin or the IK(Ca)-blocker 1 [(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) inhibited such relaxations in the losartan-treated or -untreated Wistar groups and in the losartan-treated GK group, but not in the losartan-untreated GK group. The BK(Ca)-blocker iberiotoxin had a significant inhibitory effect in only one of these groups, the losartan-treated GK. The relaxations induced by the SK(Ca)/IK(Ca) activator NS309 and the BK(Ca) activator NS1619, which were impaired in GK rats, were normalized by losartan treatment. We conclude that losartan improves EDHF-type relaxation in GK rats at least partly by normalizing SK(Ca)/IK(Ca) activities and increasing BK(Ca) activity. PMID- 20168047 TI - Inhibition by 2-methoxy-4-ethylphenol of Ca2+ influx through acquired and native N-methyl-D-aspartate-receptor channels. AB - Pharmacological properties were evaluated for the antidiarrheic wood creosote ingredient 2-methoxy-4-ethylphenol (2M4EP), which was shown to be protective against neurotoxicity of N-methyl-D-aspartate (NMDA), to modulate Ca(2+) influx across acquired and native NMDA receptor (NMDAR) channels. NMDA markedly increased intracellular free Ca(2+) levels in HEK293 cells transfected with the expression vector of either NR2A or NR2B subunit together with the essential NR1 subunit vector. Further addition of dizocilpine inhibited the increase by NMDA in intracellular Ca(2+) levels in both types of acquired NMDAR channels, while 2M4EP and the NR2B-subunit-selective antagonist ifenprodil were more effective in inhibiting the increase by NMDA in HEK293 cells expressing NR1/NR2B subunits than in those with NR1/NR2A subunits. 2M4EP significantly prevented the increased intracellular Ca(2+) levels by NMDA in cultured rat hippocampal neurons. Brief exposure to NMDA led to a drastic decrease in cellular viability 24 h later in cultured hippocampal neurons, while 2M4EP significantly prevented the loss of cellular vitality by NMDA. Similarly, 2M4EP more efficiently protected HEK293 cells with NR1/NR2B subunits than those with NR1/NR2A subunits. These results suggest that 2M4EP may protect neurons from excitotoxicity through inhibition of Ca(2+) influx across NMDAR channels composed of NR1/NR2B, rather than NR1/NR2A, subunits. PMID- 20168048 TI - Effects of antiepileptics on behavioral and electroencephalographic seizure induced by pentetrazol in mice. AB - The present study was undertaken to investigate changes of the electroencephalogram (EEG) induced by pentetrazol (PTZ) in comparison with behavioral seizures in mice. Under pentobarbital anesthesia, mice were fixed to a stereotaxic apparatus, and electrodes were implanted into the frontal and occipital cortex. Behavioral and EEG changes were observed for 30 min following PTZ administration. After PTZ administration, mice showed myoclonic seizure (MCL) and clonic seizure (CL) in order. At the same time, spiking activity and spike wave discharge in the cortex were observed. Phenobarbital, sodium valproate, diazepam, ethosuximide, and gabapentin caused a dose-dependent shortening of the duration of MCL and CL. In addition, they shortened the duration of spiking activity and spike-wave discharge dose-dependently. Moreover, phenytoin significantly inhibited the duration of spiking activity. It can be concluded that PTZ-induced spiking activity and spike-wave discharge serve as useful indices to assess the potential of antiepileptic activity in absence and MCLs in humans. Moreover, it is supposed that employing an index of EEG activity in addition to that of behavioral activity is desirable for objectivity. PMID- 20168049 TI - Progesterone is essential for maintenance of Tace/Adam17 mRNA expression, but not EGF-like factor, in cumulus cells, which enhances the EGF receptor signaling pathway during in vitro maturation of porcine COCs. AB - During in vitro maturation of porcine cumulus-oocyte complexes (COCs), progesterone was secreted from cumulus cells and acted on the cumulus cells themselves, which required for cumulus expansion and oocyte maturation. EGF-like factor (amphiregulin, AREG; epiregulin, EREG) and its protease, TACE/ADAM17, are also expressed in cumulus cells, and thereby, soluble EGF domain was acted on the EGF receptor expressed on cumulus cells. In this study, we examined the relationship between progesterone function and EGF-like factor stimuli in cumulus cells of porcine COCs. When COCs were cultured with FSH and LH, Areg, Ereg and Tace/Adam17 were expressed in cumulus cells. Treatment with a progesterone receptor (PGR) antagonist, RU486, did not affect the Areg and Ereg mRNA expression levels at any culture time points. However, the Tace/Adam17 mRNA level, protein level and its activity were significantly suppressed by RU486 at the 30 or 40 h time point. At 20 h of culture, phosphorylation of ERK1/2 and the expressions of target genes (Has2, Tnfaip6 and Ptgs2) were not suppressed by RU486; however, at 40 h, ERK1/2 phosphorylation and the target gene expression levels were significantly downregulated by RU486 in cumulus cells. Furthermore, the negative effects of RU486 at 40 h were overcome by the addition of EGF. These results indicated that the level of TACE/ADAM17 in cumulus cells was regulated by the progesterone-PGR pathway during in vitro maturation of porcine COCs. Therefore, we concluded that the progesterone-induced TACE/ADAM17 leads to production of soluble EGF domain from cumulus cells, which enhances functional changes of cumulus cells and progresses meiotic maturation of oocytes during in vitro maturation of porcine COCs. PMID- 20168050 TI - Effect of resveratrol on the development of porcine embryos produced in vitro. AB - The effects of resveratrol (a phytoalexin with a wide variety of pharmacological activities) on pig embryos produced by parthenogenesis and/or in vitro fertilization have been investigated. First, parthenogenetic embryos were generated and cultured in PZM-3 medium supplemented with various amounts of resveratrol (0, 0.05, 0.1, 0.5, 1.0 and 25 microM final concentrations). In the presence of 0.5 microM resveratrol a significantly higher percentage of parthenogenetic embryos reached the blastocyst stage by day 7 compared to non treated control (43.5+/-6.3% vs. 33.0+/-5.4%; P<0.05). The total cell number of blastocysts also increased as a result of incubation with 0.5 microM resveratrol; the difference was statistically significant between treated and non-treated embryos on day 5 of culture (35.8+/-0.9 vs. 32.1+/-1.1; P<0.05). Resveratrol incubation affected the expression levels of apoptosis-related genes in parthenogenetic blastocysts: the level of Bax transcripts was similar but lower expression of Bcl-2 and Caspase-3 was observed in embryos treated with 0.5 microM resveratrol when compared to control blastocysts (P<0.05). The results of the TUNEL assay were similar in blastocysts developing with or without resveratrol supplementation. In addition, when embryos produced by in vitro fertilization were incubated with 0.5 microM resveratrol, the treatment led to higher frequencies of blastocyst formation (8.6% vs. 13.3%) and elevated total cell numbers (37.1+/-2.4 vs. 43.2+/-1.7) by the end of the 7-day culture period (P<0.05). The results indicate that 0.5 microM resveratrol during culture has a positive effect on early embryonic development of porcine embryos. PMID- 20168051 TI - The effect of short-time active listening training. AB - OBJECTIVES: We conducted mental health training incorporating active listening for managers at a site of a general chemical company with 1,400 employees. Our purpose was to clarify the effect of active listening training of 2.5h. METHODS: All subjects were managers. The mental health training was given to 229 managers, 21 times from May 2007 until March 2008. Surveys were conducted from May 2007 to September 2008. The training sessions were conducted in a company meeting room, starting at 2:00 p.m. The importance and significance of listening as a mental health measure and methods of active listening were explained in the training. Afterward, role-playing and follow-up discussions were done twice each. In summaries, participants wrote down what they noticed about listening and gave group presentations. The instructor commented on the presentations, and ended the session by passing out and explaining a paper summarizing what is important in listening. The training was evaluated with a questionnaire distributed at the completion of training, and questionnaires on implementation of what was learned were distributed 1, 3, and 6 mo later. The Active Listening Attitude Scale (ALAS; composed of two scales for method of listening and listening attitude) developed by Mishima et al. was also used before and 1, 3, and 6 mo after the training. RESULTS AND CONCLUSIONS: In questionnaires distributed on the same day after training, 60% of the 212 respondents said the training time was just right, and 30.1% felt it was too short. The difficulty level of the training was considered appropriate by 77.8%, and 79.7% intended to implement what they had learned. Overall satisfaction was high at 85.9%. In the questionnaire 6 mo after training, 81.4% of the 145 respondents remembered the content of the training and 49.7% said they were practicing what they had learned. They responded that their conversations with subordinates about non-work topics had increased, and communication and support at work had become smoother. ALAS was administered 4 times, from before training to 6 mo afterward, and analysis was conducted for 84 respondents. No significant difference was seen in attitude to listening, but the score increased compared with before the training. The score for method of listening increased significantly. The same results were seen when the analysis was expanded to 125 respondents before and 6 mo after the training. These results are similar to those reported previously for ALAS. The findings suggest that even short listening training of 2 h and 30 min has a positive lasting effect. PMID- 20168052 TI - Assessment of dental fluorosis prevalence in Swiss populations. AB - In 1996 and 2006, recruits of the Swiss army participated in a dental survey. Similarly in 1995/96 and 2004/05, randomly selected schoolchildren from 16 rural communities of the Canton of Zurich participated in a dental survey. As part of these surveys, color slides were taken of the incisor teeth of all recruits, as well as of third and fourth grade schoolchildren. The slides (N = 2049) were examined for the presence of fluoride-associated enamel opacities (FOP), using the Thyl-strup-Fejerskov (TF) index. Two examiners (A and B) assessed all slides. The examiners were blind as to the year of survey. Examiner A recorded prevalences of FOP between 18% and 27% depending on population; examiner B recorded prevalences between 7% and 12%. The examiners' influence on the estimation of the prevalence was obvious. The prevalences reported should, therefore, be considered as rough estimates. FOP of TF score 2 were only observed in approximately 1% of the participants. One examiner recorded a TF score 3 in a single individual. FOP therefore are not a cosmetic problem and certainly not a public health concern. The prevalence of FOP decreased slightly during observation period I (recruits born 1975-77 vs 1985-87) and period II (school children born 1985-87 vs 1994-96). However, the decline was statistically supported in only one instance (Period I, Examiner B). PMID- 20168053 TI - [A Case of Hyperplastic Polyp at Distal Common Bile Duct.] AB - No abstract availble. PMID- 20168054 TI - [Health-related quality of life issues in gastroesophageal reflux disease]. AB - Several studies have reported significant Health-Related Quality of life (HRQOL) impairment in gastroesophageal reflux disease (GERD) patients compared with the general population. The evaluation of quality of life is important as a parameter for the treatment. Because GERD has diverse symptoms such as esophageal and extraesophageal syndromes, HRQOL of GERD should be determined by both disease and non-disease related factors. The purpose is to overview the HRQOL instruments used in the evaluation of GERD, published reports regarding HRQOL in GERD, and the effects of medical treatments on GERD. PMID- 20168055 TI - [Helicobacter pylori eradication for stage I(E1) gastric mucosa-associated lymphoid tissue lymphoma: predictive factors of complete remission]. AB - BACKGROUND/AIMS: Eradication of Helicobacter pylori (H. pylori) is accepted as initial treatment of stage I(E1) gastric mucosa associated lymphoid tissue (MALT) lymphoma. However, 10-20% of gastric low grade MALT lymphomas are unresponsive to H. pylori eradication treatment. The aim of this study was to find out the predictive factors of complete remission of gastric MALT lymphoma after H. pylori eradication. METHODS: From 1995 to 2006, consecutive 95 patients with modified Ann Arbor stage I(E1) gastric MALT lymphoma were enrolled, and their medical records were reviewed. The patients were initially treated by H. pylori eradication. The complete remission was determined by endoscopic and histologic finding. RESULTS: Eighty eight patients (92.6%) achieved complete remission after H. pylori eradication therapy. Mean follow up time for these patients was 40+/-25 months. Seven patients (7.4%) failed to achieve complete remission. There was no significant difference in the age, sex, endoscopic appearance, and large cell component between the remission group and failure group. Among 66 patients with distal tumor, 65 patients (98.5%) achieved complete remission. On the other hand, among 13 patient with proximal tumor, 9 patients (69.2%) achieved complete remission (p=0.001). The odds ratio of proximal tumor for H. pylori eradication failure was 28.9 (95% CI=2.9-288.0). CONCLUSIONS: The proximally location of MALT lymphoma is a risk factor of the H. pylori eradication treatment failure. Therefore, the proximally located gastric MALT lymphoma should be carefully treated and followed. PMID- 20168056 TI - [Clinical analysis of recurrence rate and symptom improvement in gastro esophageal reflux disease patients]. AB - BACKGROUND/AIMS: Gastro-esophageal reflux disease (GERD) is a chronic condition, with 50-80% of patients experiencing recurrence within one year following completion of initial treatment. The present study aimed to estimate recurrence rate and treatment response in GERD patients treated with proton pump inhibitor. METHODS: A total of 207 symptomatic GERD patients, which were confirmed by endoscopy from July 2008 till January 2009, were enrolled. They were divided into non-erosive reflux disease (NERD) group and erosive reflux disease (ERD) group by endoscopic findings. Patients were treated with lansoprazole 15 mg (NERD group) or 30 mg (ERD group) once daily for 8 weeks. The presence of symptoms was assessed in each patient at baseline and post-treatment using a questionnaire. Subsequent symptomatic recurrence on the cessation of therapy in each improved patients was checked by telephone survey or outpatient interview. RESULTS: Ninety four patients and 113 patients were first diagnosed with NERD and ERD, respectively. The mean post-treatment follow-up period was 24.4+/-8.5 weeks. Recurrence rate was 40.0% (NERD, 43.8%; ERD, 37.1% (p=0.224)). Recurrence time was 10.1+/-5.8 weeks (NERD 9.6 weeks; ERD, 10.6 weeks (p=0.444)). Regarding the symptom improvement after 8 week therapy with lansoprazole, 89.4% (NERD, 85.1%; ERD, 92.9% (p=0.056)) of total patients were symptomatically improved. CONCLUSIONS: Forty percentage of GERD patients recurred within 6 months following the completion of 8 week therapy with lansoprazole. Recurrence rate, recurrence time, and rate of symptom improvement were not significantly different between NERD group treated with half dose and ERD group treated with full dose lansoprazole. PMID- 20168057 TI - [The relationship between the popular beverages in Korea and reported postprandial heartburn]. AB - BACKGROUND/AIMS: The aim of this study was to investigate the frequency of heartburn produced by beverages available in Korea and to clarify the mechanism causing heartburn. METHODS: We measured pH, titratable acidity, and osmolality of 35 beverages in vitro and correlated them with the severity of heartburn reported by questionnaire in 382 patients from November 2004 to June 2005. RESULTS: Coffee (1.15) and soju (1.12) showed the highest heartburn score, while oolong tea (0.17) and carrot juice (0.18) showed the lowest heartburn score among all beverages. Titratable acidity of citrus juices correlated with heartburn (r=0.78; p=0.023). Soft drinks had the lowest pH, which was unrelated with heartburn scores (r=-0.54; p=0.460). Increasing pH among alcoholic beverages was correlated with heartburn scores (r=0.84; p=0.037), and osmolality was inversely associated with heartburn scores (r=-0.86; p=0.028). The heartburn score of decaffeinated coffee was significantly lower than that of regular coffee (p<0.001). Regular milk caused more heartburn than low-fat milk (p=0.008). CONCLUSIONS: Our findings provide dietary information that helps to select appropriate beverages to the patients with heartburn. PMID- 20168058 TI - [Histopathologic analysis of adenoma and adenoma-related lesions of the gallbladder]. AB - BACKGROUND/AIMS: In order to determine the malignant potential of gallbladder adenoma for progression to carcinoma, we evaluated the histopathologic features of adenoma and adenoma-related lesions on cholecystectomized specimens. METHODS: Among 1,847 cholecystectomized specimens, 63 specimens from 26 benign adenomas, 9 carcinomas in situ (CIS), and 28 invasive carcinomas were selected. A pathologist reviewed all specimens and selected benign adenomas, CIS in the adenoma, and adenoma residue in invasive carcinomas. Adenomas and adenoma-related lesions were classified according to morphology (tubular, tubulopapillary, and papillary) and the consisting epithelium (biliary, pyloric metaplasia, and intestinal metaplasia). The age and the size of the benign adenomas and carcinomas in the adenoma were also compared. RESULTS: Adenoma and adenoma-related lesions were found in 34 out (1.8%) of all resected gallbladder. Among 9 CIS and 28 invasive carcinomas, adenoma-related lesions were detected in 7 and 1 case, respectively. All eight carcinomas arising in the adenoma were well-differentiated solitary tumors. The diameters of the carcinomas in the adenoma were, on average, larger than that of the benign adenomas (1.8 cm vs. 0.9 cm, p=0.01). The patients with carcinomas in the adenoma were, on average, older than those with benign adenomas, although the difference was insignificant (57 years vs. 47 years, p=0.09). The morphology and consisting epithelium did not differ between the benign adenomas and carcinomas in the adenoma. The malignant transformation occurred in 23.5% of adenomas. CONCLUSIONS: Gallbladder adenoma is a rare disease, although malignant transformation occurs frequently. Adenoma is a precancerous lesion and the adenoma-carcinoma sequence is one of the gallbladder cancer carcinogenesis. PMID- 20168059 TI - [A case of extranodal histiocytic sarcoma of stomach mimicking gastric adenocarcinoma]. AB - Histiocytic sarcoma is a rare malignant neoplasm that originates from a histiocytic hematopoietic lineage characterized by histiocytic differentiation and its corresponding immunophenotypic features. Patients with histiocytic sarcoma usually have a poor prognosis due to its aggressive clinical behavior. Here we report a rare case of extranodal histiocytic sarcoma of the stomach which was confirmed through immunohistochemical staining. A 71-year- old man was presented with epigastric pain. Gastroscopy, abdominal CT, and EUS revealed a mass located on the posterior wall of upper body and fundus of the stomach. Grossly, grayish white solid masses were seen extending down to the submucosal layer. Microscopically, the tumor cells had eosinophilic cytoplasm, abundant vacuole, and mitosis. Immunohistochemical staining revealed that the tumor cells were positive for LCA, CD68, and lysozyme. Early detection and accurate diagnosis of this rare neoplasm is important because it can make a great difference in prognostic outcomes. To make an accurate and definitive diagnosis, immunohistochemical staining is essential in the confirmation of histiocytic origin. PMID- 20168060 TI - [A case of spontaneous regression of hepatocellular carcinoma with multiple lung metastases]. AB - Spontaneous regression of hepatocellular carcinoma (HCC) is extremely rare. We report a case of 67-year-old man having HBV-associated HCC with multiple lung metastases which regressed spontaneously. The patient had single liver mass and received surgical resection. The mass was confirmed as HCC histopathologically. Nine years after surgical resection, a 3.3 cm sized recurred HCC was detected on the resection margin in CT scan. Transarterial chemoembolization (TACE) was performed 3 times, and lung metastases developed thereafter. The patient received 2 more sessions of TACE, however, metastatic lung nodules were in progress very rapidly. We decided to stop TACE and followed the patient regularly without any anti-cancer treatment. Nine months after development of lung metastasis, the size and number of metastatic lung nodules decreased and were not detected anymore after 14 months. Serum alpha-fetoprotein levels also decreased to normal range and no viable tumor was noted in the liver. The patient is still alive 12 years after the first diagnosis of HCC and 16 months after lung metastasis developed. PMID- 20168061 TI - [A case of acinar cell carcinoma of pancreas, manifested by subcutaneous nodule as initial clinical symptom]. AB - Pancreas acinar cell carcinoma (ACC) accounts for only 1-2% of pancreatic exocrine malignant tumor. The symptoms of patients with ACC are usually non specific, for example the anorexia and weight loss. Patients may develop Schmid's triad including subcutaneous fat necrosis, polyarthritis, and eosinophilia. We reported a case of ACC which was manifested by subcutaneous nodule as initial clinical symptom. To our knowledge, this is the first reported case of ACC presenting as subcutaneous fat necrosis in Korea. PMID- 20168062 TI - [A case of undifferentiated (embryonal) liver sarcoma mimicking klatskin tumor in an adult]. AB - Undifferentiated sarcoma is an uncommon primary malignant tumor of the liver typically occurring in older children. It is also referred to as malignant mesenchymoma, fibromyxosarcoma, or mesenchymal sarcoma. We experienced a case of undifferentiated sarcoma in 72-year-old male. Contrast enhanced liver CT scan revealed a 3.4 cm heterogeneously enhancing, ill-defined, and low attenuated mass in the left liver and subtle intrahepatic duct dilatation. And, in tubogram, there were segmental stenosis and occlusion from the hilum to the proximal common bile duct. We did ultrasonography guided liver biopsy. The pathologic finding revealed infiltrative growth of atypical cells with rhabdoid features. Some atypical cells showed clear cytoplasm, but no organoid pattern was identified. The stroma around atypical cells was filled with eosinophilic hyaline material. These tumor cells were positive for vimentin only, and the tumor was consistent with undifferentiated sarcoma of the liver. PMID- 20168063 TI - [Therapeutic endopoints in allergic rhinitis]. PMID- 20168064 TI - [Allergic conjunctivitis]. PMID- 20168065 TI - [One point message of PG-MARJ 2009 (allergic rhinitis)--the clinical points and issues in the revision]. PMID- 20168066 TI - [Practical management of patients with food allergy]. PMID- 20168067 TI - [Aiming to overcome asthma]. PMID- 20168068 TI - [Diagnostic approach for the autoinflammatory syndromes based on the molecular mechanism of innate immunity]. PMID- 20168069 TI - [Factors related to recurrent wheezing after hospitalization with RSV infection with the children who were aged three years old or younger: a questionnaire survey]. AB - Respiratory syncytial virus (RSV) infections in infancy have been related to the subsequent recurrent wheezing and asthma. However, there are a few reports about the relationship between RSV infection and subsequent wheezing in Japan. We sought to determine the contributing factors for wheezing illness after RSV infection in 99 Japanese patients with RSV-associated hospitalizations by questionnaire and follow up survey. Fifty eight patients, who were aged three years old or younger on admission and could be followed up more than one year, were analyzed. The mean duration from discharge to last survey were 703.6+/-105.5 days (432-950 days), the mean age on admission were 9.4+/-8.8 months (0-30 months). Wheezing episodes after discharge were reported in 29 of the subjects (50.0%). Univariable and multivariable analysis identified that the subsequent wheezing after RSV infection were related with the history of wheezing before admission and attending a daycare. The patient's age on admission, the patient's atopic profile, history of continuous nocturnal cough before admission, gestational ages, birth weight, length of hospital stay, perinatal abnormality, environmental tobacco smoke, parental history of allergy and asthma, presence of sibling and sibling history of allergy and asthma were not associated with subsequent wheezing. These results suggest that some host factors susceptible to wheezing and chance of infection due to attending a daycare may be related to recurrent wheezing possibly onset of bronchial asthma, after RSV infection. PMID- 20168070 TI - [Individualized inhalation instruction using check sheets by a pharmacist in community pharmacy improves inhalation techniques in asthmatic patients]. AB - BACKGROUND: Many types of inhaled medications are used for the treatment of asthma; however, inadequate inhalation techniques and poor adherence cause exacerbations of asthma symptoms. It is necessary to therefore provide adequate instruction to acquire correct inhalation techniques. This study aimed to evaluate the usefulness of individualized inhalation instruction in asthmatic outpatients by a community pharmacist for an improvement of the inhalation techniques and asthma control. METHODS: Twenty-eight asthmatic outpatients who have developed asthma over a long period and received prescriptions from Kumamoto Chuo Hospital from April to August 2008 were instructed by a pharmacist on inhalation techniques at Shimokawa Hamasen Pharmacy. Individual instruction by the pharmacist consisted of a skill-check with inhalers, followed by the use of a checklist of inhalation technique, a self-evaluation checklist, and visual information for the patients. Outcomes were evaluated based on changes in inhalation technique mastery between their first visit and the subsequent visit. Nineteen of the 28 patients who completed the Asthma Control Test (ACT) were also evaluated for asthma control according to changes in their ACT scores. RESULTS: Twenty patients showed inadequate inhalation techniques. The individualized instruction resulted in significant improvement in the inhalation techniques. Moreover, there were significant improvement in the ACT scores (from 19.1 to 21.4) of 19 patients who received the individualized instruction. CONCLUSION: The individualized instruction to the asthmatic outpatients enables them to improve the inhalation techniques to mend their asthmatic symptoms. We suggest that coordination with hospital and community pharmacy improves therapeutic outcomes in inhaled medication for the asthmatic outpatients. PMID- 20168071 TI - [A case of MPO-ANCA positive vasculitis associated with alveolar hemorrhage and progressive glomerulonephritis following propylthiouracil treatment, the interval was 6 years and 4 months]. AB - The patient was a 62-year-old female. In June 1999, thiamazole (MMI) was orally administered under a diagnosis of hyperthyroidism. However, drug exanthema developed. In July, oral administration of propylthiouracil (PTU) was started. On October 20, 2005, palpitation and exertional dyspnea occurred. On November 1, bloody sputum was noted, and the patient consulted our hospital on November 8. In addition to severe anemia, chest X-ray and CT revealed diffuse infiltration in the bilateral lungs. The patient was admitted for detailed examination and treatment. After admission, the myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA) level was 390 EU, suggesting ANCA-associated angitis. PTU was discontinued, and steroid pulse therapy resulted in the disappearance of alveolar hemorrhage and hematuria. Transbronchial lung biopsy suggested alveolar hemorrhage, and kidney biopsy showed glomerular necrosis and interstitial infiltration of inflammatory cells, suggesting PTU-induced ANCA-associated angitis. Posttreatment with prednisolone at 30 mg/day gradually decreased the MPO ANCA level. There has been no relapse during the 2-years follow-up. PMID- 20168072 TI - [Cryptococcemia with a severe bronchial asthma: case report and review of the literature]. AB - A 64-year old hospitalized male for severe bronchial asthma began to complain fatigue and appetite loss. His asthma had been treated with oral bethamethasone. The Chest CT at this time revealed a bilateral consolidation of the lower lung. Despite a week of treatment with antibiotics and anti-fungals, the patient expired from DIC progression. His premortem sputum and blood culture grew Cryptococcus Neoformans. We concluded his diagnosis as cryptococcal pneumonia and sepsis. Sepsis by Cryptococcus neoformans is a rare clinical event, and only 20 cases have been reported in Japan. Although 16 of the 20 had preexisting medical conditions, a case with underlying bronchial asthma has never been reported. A comparison of the reported cases of the US and Europe to that of Japan revealed differences in the patients' underlying conditions. We report a case with a brief review of the literature and summarize the 20 cases that have been reported in Japan. PMID- 20168073 TI - [Improved capability of a revised test kit, FASTKIT ELISA version II (Egg), to detect heated proteins of egg white but not egg yolk]. AB - BACKGROUND: A kit, FASTKIT ELISA version II (Egg) (Nippon Meat Packers) is an enzyme-linked immunosorbent assay kit for detecting hen's egg proteins in foodstuffs. This kit is an enhanced version of FASTKIT ELISA (Egg) with a greater efficiency in terms of extraction of egg proteins from heated foodstuffs. However, the property of this kit remains to be fully elucidated. METHODS: Using this new kit, we measured the amount of egg proteins in unheated or heated (140 degrees C or 180 degrees C, 20 min) homemade cookies containing whole egg, egg white or egg yolk. RESULTS: The capability for detection of unheated or heated (140 degrees C or 180 degrees C) whole egg proteins was similar. In addition, there was no significant difference in the detectability between heated (140 degrees C) whole egg and egg white proteins. However, unheated or heated (140 degrees C or 180 degrees C) egg yolk proteins were not sufficiently measured by this kit. CONCLUSION: Our data suggest that this new kit is significantly improved for detection of heated egg white proteins as compared to that of old version, but not sufficient for detection of egg yolk proteins. PMID- 20168074 TI - Can indole-based extracts prevent colorectal cancer via early apoptotic pathways? PMID- 20168075 TI - Accessing the human repertoire for broadly neutralizing HIV antibodies. AB - The human antibody response has special significance in the ongoing efforts to develop a protective HIV vaccine. The observation that a subset of HIV infected individuals, who do not develop AIDS, have a broadly neutralizing antibody response has drawn attention to deciphering the nature of this response. It is hoped that an understanding of these protective antibodies, developed over time in response to the ongoing accumulation of mutations in the infecting virus, will facilitate the development of a vaccine that can elicit a similar response. This strategy will be greatly aided by the identification of broadly neutralizing monoclonal HIV antibodies from infected individuals. Several methods have been utilized to isolate and characterize individual antibodies from the human repertoire and each of these methods has been applied to the generation of broadly neutralizing HIV antibodies, albeit with differing rates of success. This review describes several of these methods including human hybridoma; EBV transformation; non-immortalized B cell culture; clonal sorting; and combinatorial display. Key considerations used in the comparison of different methods includes: efficiency of interrogation of an individual's entire repertoire; assay formats that can be used to screen for antibodies of interest (i.e., binding versus biological assays); and the ability to recover native antibody heavy and light chain pairs. PMID- 20168076 TI - AQP1 is not only a water channel: It contributes to cell migration through Lin7/beta-catenin. AB - AQPs are water channel proteins. In particular, AQP1 was demonstrated to be involved in cell migration. According to the model proposed by Verkman and collaborators, AQP drives water influx, facilitating lamellipodia extension and cell migration. Investigating the possible connection between AQP1 and cytoskeleton, our group showed that such a water channel through Lin7/beta catenin affects the organization of the cytoskeleton and proposed a model. All together, these data appear particularly intriguing since the use of AQP1 as target might be useful to modulate angiogenesis/vasculogenic mimicry. PMID- 20168077 TI - Receptor tyrosine kinase transmembrane domains: Function, dimer structure and dimerization energetics. AB - The transmembrane (TM) domains of receptor tyrosine kinases (RTKs) play an active role in signaling. They contribute to the stability of full-length receptor dimers and to maintaining a signaling-competent dimeric receptor conformation. In an exciting new development, two structures of RTK TM domains have been solved, a break-through achievement in the field. Here we review these structures, and we discuss recent studies of RTK TM domain dimerization energetics, possible synergies between domains, and the effects of pathogenic RTK TM mutations on structure and dimerization. PMID- 20168079 TI - Numb: A new player in EMT. AB - Epithelial to mesenchymal transition (EMT) is a critical event in embryogenesis and plays a fundamental role in cancer progression and metastasis. Numb has been shown to play an important role in the proper functions of Par protein complex and in cell-cell junctions, both of which are associated with EMT. However, the role of Numb in EMT has not been fully elucidated. Recently, we showed that Numb is capable of binding to both Par3 and E-cadherin. Intriguingly, the interaction of Numb with E-cadherin or the Par protein complex is dynamically regulated by tyrosine phosphorylation induced by HGF or Src. Knockdown of Numb by shRNA in MDCK cells led to a lateral to apical translocation of E-cadherin and beta catenin, active F-actin polymerization, mis-localization of Par3 and aPKC, a decrease in cell-cell adhesion and an increase in cell migration and proliferation. These data suggest a diverse role for Numb in regulating cell-cell adhesion, polarity and migration during EMT. PMID- 20168078 TI - Snail: More than EMT. AB - Snail has moved into the fast lane of development and cancer biology with the epithelial-mesenchymal transition (EMT) emerging as one of the hottest topics in medical science within the past few years. Snail not only acts primarily as a key inducer of EMT but also plays an important role in cell survival, immune regulation and stem cell biology. This review focuses on the regulation of Snail and discusses the EMT-dependent and -independent functions of Snail in development and disease. Understanding the regulation and functional roles of Snail will shed new light on the mechanism of tumor progression and the development of novel cancer therapies. PMID- 20168080 TI - Structural basis of transmembrane domain interactions in integrin signaling. AB - Cell surface receptors of the integrin family are pivotal to cell adhesion and migration. The activation state of heterodimeric alphabeta integrins is correlated to the association state of the single-pass alpha and beta transmembrane domains. The association of integrin alphaIIbbeta3 transmembrane domains, resulting in an inactive receptor, is characterized by the asymmetric arrangement of a straight (alphaIIb) and tilted (beta3) helix relative to the membrane in congruence to the dissociated structures. This allows for a continuous association interface centered on helix-helix glycine-packing and an unusual alphaIIb(GFF) structural motif that packs the conserved Phe-Phe residues against the beta3 transmembrane helix, enabling alphaIIb(D723)beta3(R995) electrostatic interactions. The transmembrane complex is further stabilized by the inactive ectodomain, thereby coupling its association state to the ectodomain conformation. In combination with recently determined structures of an inactive integrin ectodomain and an activating talin/beta complex that overlap with the alphabeta transmembrane complex, a comprehensive picture of integrin bi directional transmembrane signaling has emerged. PMID- 20168081 TI - MicroRNAs and cancer: a meeting summary of the eponymous Keystone Conference. AB - This report summarizes the information presented at the 2009 Keystone Conference on MicroRNAs and Cancer, held in Keystone, Colorado, USA, June 10th to 15th 2009. Soon after microRNAs (miRNAs) emerged as an abundant new class of non-coding RNAs (ncRNAs), evidence started to mount supporting important roles for these regulatory RNAs in human health and disease. Mis-regulation of specific miRNA pathways has been linked to diverse cancers. The recent Keystone meeting highlighted progress in understanding the role of miRNAs in normal development and oncogenesis. Recurring themes included the complexities associated with miRNA biogenesis, target recognition, elucidation of genetic networks where miRNAs play pivotal roles often within feedback loops, and the promise of small RNAs as diagnostics and therapeutics in combating cancer. PMID- 20168082 TI - Nitric oxide modulates sensitivity to ABA. AB - Nitric oxide (NO) is a gas with crucial signaling functions in plant defense and development. As demonstrated by generating a triple nia1nia2noa1-2 mutant with extremely low levels of NO (February 2010 issue of Plant Physiology), NO is synthesized in plants through mainly two different pathways involving nitrate reductase (NR/NIA) and NO Associated 1 (AtNOA1) proteins. Depletion of basal NO levels leads to a priming of ABA-triggered responses that causes hypersensitivity to this hormone and results in enhanced seed dormancy and decreased seed germination and seedling establishment in the triple mutant. NO produced under non-stressed conditions represses inhibition of seed developmental transitions by ABA. Moreover, NO plays a positive role in post-germinative vegetative development and also exerts a critical control of ABA-related functions on stomata closure. The triple nia1nia2noa1-2 mutant is hypersensitive to ABA in stomatal closure thus resulting in a extreme phenotype of resistance to drought. In the light of the recent discovery of PYR/PYL/RCAR as a family of potential ABA receptors, regulation of ABA sensitivity by NO may be exerted either directly on ABA receptors or on downstream signaling components; both two aspects that deserve our present and future attention. PMID- 20168083 TI - miRNAs and cancer: New research developments and potential clinical applications. AB - miRNAs are small non-protein coding transcripts that regulate gene expression post-transcriptionally by binding to the 3' UTRs (untranslated regions) of messenger RNAs (mRNAs). The number of newly discovered miRNAs and our understanding of their biological roles continue to grow. In addition to their roles in important biological processes such as development, differentiation, proliferation and cell death, deregulated expression of miRNAs has been implicated in a wide range of pathologies, especially in cancer. We now understand that miRNA expression is often deregulated in cancer cells and that a vast number of genes, including tumor suppressor genes and oncogenes, are regulated by these small RNAs. The small size of miRNAs and sequence similarity of miRNA family members pose some challenges in routine molecular detection and quantification techniques. Therefore, methods are being modified to specifically and sensitively detect miRNAs in cancer cells. Our current knowledge and the ever increasing pace of new discoveries clearly show that miRNAs are quite important in normal and in cancer cells in surprisingly diverse aspects. The better we understand how miRNAs contribute to cancer, the more likely we will be able to exploit them as tumor classifiers, biomarkers and, potentially, as unique targets for therapeutic applications. PMID- 20168085 TI - Filopodial focal complexes direct adhesion and force generation towards filopodia outgrowth. AB - Filopodia are key structures within many cells that serve as sensors constantly probing the local environment. Although filopodia are involved in a number of different cellular processes, their function in migration is often analyzed with special focus on early processes of filopodia formation and the elucidation of filopodia molecular architecture. An increasing number of publications now describe the entire life cycle of filopodia, with analyses from the initial establishment of stable filopodium-substrate adhesion to their final integration into the approaching lamellipodium. We and others can now show the structural and functional dependence of lamellipodial focal adhesions as well as of force generation and transmission on filopodial focal complexes and filopodial actin bundles. These results were made possible by new high resolution imaging techniques as well as by recently developed elastomeric substrates and theoretical models. The data additionally provide strong evidence that formation of new filopodia depends on previously existing filopodia through a repetitive filopodial elongation of the stably adhered filopodial tips. In this commentary we therefore hypothesize a highly coordinated mechanism that regulates filopodia formation, adhesion, protein composition and force generation in a filopodia dependent step by step process. PMID- 20168084 TI - The essential role of LIS1, NDEL1 and Aurora-A in polarity formation and microtubule organization during neurogensis. AB - Lissencephaly is a devastating neurological disorder caused by to defective neuronal migration. LIS1 (or PAFAH1B1), the gene mutated in lissencephaly patients and its binding protein NDEL1 were found to regulate cytoplasmic dynein function and localization. LIS1 and NDEL1 also play a pivotal role on a microtubule regulation and determination of cell polarity. For example, LIS1 is required for the precise control of mitotic spindle orientation in both neuroepithelial stem cells and radial glial progenitor cells. On the other hand, NDEL1 is essential for mitotic entry as an effector molecule of Aurora-A kinase. In addition, an atypical protein kinase C (aPKC)-Aurora-A-NDEL1 pathway is critical for the regulation of microtubule organization during neurite extension. These findings suggest that physiological functions of LIS1 and NDEL1 in neurons have been ascribed for proteins fundamentally required for cell cycle progression and control. In turn, cell cycle regulators may exert other functions during neurogenesis in a direct or an indirect fashion. Thus far, only a handful of cell cycle regulators have been shown to play physiological cell cycle-independent roles in neurons. Further identification of such proteins and elucidation of their underlying mechanisms of action will likely reveal novel concepts and/or patterns that provide a clear link between their seemingly distinct cell cycle and neuronal functions. PMID- 20168087 TI - Updates from the 19(th) National Immunisation Conference for Health Care Workers: Manchester conference centre, December 2008. PMID- 20168086 TI - tRNA insulator function: insight into inheritance of transcription states? AB - DNA in eukaryotes is invariably present as a complex with histone and non-histone proteins called chromatin. These proteins play an important role in the proper regulation of genes during development and differentiation. Transcription factors and the covalent modifications of DNA, histone and non-histone proteins establish an epigenetic state that is heritable and which does not involve a change in genotype. The heritability of transcription states through cell division brings up specific questions: How are epigenetic marks established and re-established in the daughter cells following DNA replication and mitosis? In this article we explore what is known of the cell cycle dependence of epigenetic inheritance with particular emphasis on yeast loci and discuss the role of specific proteins responsible for the establishment and maintenance of these states. PMID- 20168088 TI - Activation of autophagy and Akt/CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia-ischemia. AB - We have previously shown that in neonatal rats subjected to hypoxia-ischemia (HI) rapamycin administration increases autophagy, decreases apoptosis and significantly reduces brain damage. After HI, when autophagy is blocked neuronal cells rapidly progress toward necrotic cell death. The present study was undertaken to assess the potential role of activation of autophagic and phosphatidylinositol 3-kinase (PI3K)/Akt kinase pathways in the neuroprotective effect of rapamycin. Rapamycin administration caused a significant reduction of 70 kDa S6 kinase (p70S6K) phosphorylation and a significant increase of the autophagic proteins Beclin 1 and microtubule-associated protein 1 light chain 3 (LC3), as of monodansylcadaverine (MDC) labeling in the lesioned side. The phosphorylation of Akt and cAMP response element binding protein (CREB) was increased in neuronal cells, and both p-Akt and p-CREB colocalized with Beclin 1. Wortmannin (WM) administration significantly reduced Akt and CREB phosphorylation as well as the neuroprotective effect of rapamycin but did not affect the phosphorylation of p70S6K, the expression of Beclin 1 and LC3, and MDC labeling. In contrast, 3-methyladenine (3MA) reduced the increased Beclin 1 expression, the MDC labeling and the neuroprotective effect of rapamycin without affecting Akt phosphorylation. However, both compounds significantly increased necrotic cell death. Taken together, these data indicate that in neonatal HI autophagy can be part of an integrated prosurvival signaling which includes the PI3K-Akt-mammalian target of rapamycin (mTOR) axis. When the autophagic or the PI3K-Akt-mTOR pathways are interrupted cells undergo necrotic cell death. PMID- 20168089 TI - Upregulation of imprinted genes in mice: an insight into the intensity of gene expression and the evolution of genomic imprinting. AB - Imprinted genes are expressed monoallelically because one of the two copies is silenced epigentically in a parent-of-origin pattern. This pattern of expression is controlled by differential marking of parental alleles by DNA methylation and chromatin modifications, including both suppressive and permissive histone acetylation and methylation. Suppressive histone modifications mark silenced alleles of imprinted genes, while permissive histone modifications mark the active alleles, suggesting the possibility that imprinted genes would show upregulation in gene expression. However, it is currently unknown whether imprinted genes show such upregulation. To address this question in mice, we estimated the intensity of expression of 59 genes relative to the rest of the genome by analyzing microarray data. Expression levels of 24 genes were validated using quantitative real-time PCR (qPCR). Expression of imprinted genes was found to be upreguled in various adult and embryonic mouse tissues. Consistent with their functions in growth and development, imprinted genes were found to be highly expressed in extraembryonic tissues and progressively upregulated during early embryonic development. In conclusion, upregulation of imprinted genes found in this study is similar to the dosage compensation (twofold upregulation) recently reported for X-linked genes. It has been proposed that the twofold upregulation of X-linked genes has been coupled with low transcriptional variation (noise) which could lead to deleterious effects on the organism. Results of this study suggest a general need for imprinted genes in the mouse to be upregulated to certain levels in order to avoid deleterious effects of variation in gene expression. PMID- 20168090 TI - Neutralizing epitopes of the SARS-CoV S-protein cluster independent of repertoire, antigen structure or mAb technology. AB - Neutralizing antibody responses to the surface glycoproteins of enveloped viruses play an important role in immunity. Many of these glycoproteins, including the severe acute respiratory syndrome-coronavirus (SARS-CoV) spike (S) protein form trimeric units in the membrane of the native virion. There is substantial experimental and pre-clinical evidence showing that the S protein is a promising lead for vaccines and therapeutics. Previously we generated a panel of monoclonal antibodies (mAbs) to whole inactivated SARS-CoV which neutralize the virus in vitro. Here, we define their specificity and affinity, map several of their epitopes and lastly characterise chimeric versions of them. Our data show that the neutralizing mAbs bind to the angiotensin-converting enzyme 2 (ACE2) receptor binding domain (RBD) of the SARS S protein. Three of the chimeric mAbs retain their binding specificity while one conformational mAb, F26G19, lost its ability to bind the S protein despite high level expression. The affinity for recombinant S is maintained in all of the functional chimeric versions of the parental mAbs. Both parental mAb F26G18 and the chimeric version neutralize the TO R2 strain of SARS-CoV with essentially identical titres (2.07 and 2.47 nM, respectively). Lastly, a comparison with other neutralizing mAbs to SARS-CoV clearly shows that the dominance of a 33 amino acid residue loop of the SARS-CoV RBD is independent of repertoire, species, quaternary structure, and importantly, the technology used to derive the mAbs. In cases like this, the dominance of a compact RBD antigenic domain and the central role of the S protein in pathogenesis may inherently create immunoselection pressure on viruses to evolve more complex evasion strategies or die out of a host species. The apparent simplicity of the mechanism of SARS-CoV neutralization is in stark contrast to the complexity shown by other enveloped viruses. PMID- 20168091 TI - Autophagy impairment stimulates PS1 expression and gamma-secretase activity. AB - Gamma-secretase plays an important role in the development of Alzheimer disease (AD). Gamma-secretase activity is enriched in autophagic vacuoles and it augments amyloid-beta (Abeta) synthesis. Autophagy-lysosomal dysfunction has been implicated in AD, but whether gamma-secretase activity is affected by autophagy remains unclear. Here we report that gamma-secretase activity is enhanced in basal autophagy-disturbed cells through the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) kinase, general control nonderepressible 2 (GCN2). Presenilin-1 (PS1) expression was increased even in the presence of nutrients in autophagy-related 5 knockdown (Atg5KD) human embryonic kidney (HE K293) cells expressing a short hairpin RNA as well as in chloroquine-treated HE K293 cells. However, PS1 expression induction was prevented in GCN2KD and ATF4KD cells. Furthermore, Atg5KD cells showed an increase in Abeta production and Notch1 cleavage. These were reduced by an autophagy inducer, resveratrol. Thus, we conclude that the autophagy-lysosomal system regulates gamma-secretase activity through GCN2. PMID- 20168092 TI - p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy. AB - Accumulation of ubiquitinated proteins in cytoplasmic and/or nuclear inclusions is a hallmark of several diseases associated with premature cell death. SQSTM1/p62 is known to bind ubiquitinated substrates and aid their aggregation and degradation by macroautophagy. We show here that p62 is required to recruit the large phosphoinositide-binding protein ALFY to cytoplasmic p62 bodies generated upon amino acid starvation or puromycin-treatment. ALFY, as well as p62, is required for formation and autophagic degradation of cytoplasmic ubiquitin-positive inclusions. Moreover, both p62 and ALFY localize to nuclear promyleocytic leukemia (PML) bodies. The Drosophila p62 homologue Ref(2) P accumulates in ubiquitinated inclusions in the brain of flies carrying mutations in the ALFY homologue Blue cheese, demonstrating that ALFY is required for autophagic degradation of p62-associated ubiquitinated proteins in vivo. We conclude that p62 and ALFY interact to organize misfolded, ubiquitinated proteins into protein bodies that become degraded by autophagy. PMID- 20168094 TI - Pregnancy as a window to future health. PMID- 20168095 TI - Hypertensive disorders in pregnancy and subsequently measured cardiovascular risk factors. AB - OBJECTIVE: To study the association of hypertensive pregnancy disorders with modifiable risk factors for cardiovascular and metabolic diseases and to estimate the feasibility for early detection and prevention. METHODS: This was a prospective study of 15,065 women with a first singleton birth between 1967 and 1995, who later participated in a population study that included standardized measurements of blood pressure, serum lipids, and body mass index (BMI). RESULTS: Women with a history of hypertensive disorders in pregnancy (preeclampsia or gestational hypertension) had higher BMI, higher blood pressure, and unfavorable levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides. Preeclampsia was associated with substantially higher risk of developing diabetes (odds ratio 3.8, 95% confidence interval [CI] 2.1-6.6), and if the hypertensive disorder occurred in more than one pregnancy, or in a relatively late pregnancy, the associations with later cardiovascular risk factors were substantially stronger. Thus, women with two episodes of preeclampsia were approximately 10 times more likely to use blood pressure medication at follow-up (adjusted odds ratio, 11.6, 95% CI 7.1-26.3), and in women with gestational hypertension in three consecutive pregnancies, systolic pressure was on average 27 mm Hg (95% CI 18-37 mm Hg) higher, and diastolic pressure was 12 mm Hg (95% CI 5-19 mm Hg) higher, compared with women without a history of hypertensive disorders. Adjustment for current body mass index partly attenuated these associations, suggesting that BMI may play an important mediating role. CONCLUSION: Women with a history of hypertensive disorders in pregnancy, and particularly women with recurrent pregnancy disorders, should be candidates for intervention intended to prevent premature cardiovascular disease. LEVEL OF EVIDENCE: II. PMID- 20168096 TI - Antiviral medications for pregnant women for pandemic and seasonal influenza: an economic computer model. AB - OBJECTIVE: To estimate the economic value of administering antiviral medications to pregnant women who have come in contact with an infectious individual with influenza. METHODS: A computer-simulation model was developed to predict the potential economic effect of antiviral use for postexposure prophylaxis among pregnant women in both seasonal influenza and pandemic influenza scenarios. The model allowed us to examine the effects of varying influenza exposure risk, antiviral efficacy, antiviral cost, and the probability of different influenza outcomes such as hospitalization, preterm delivery, and mortality. RESULTS: For a variety of pandemic influenza scenarios (attack rate 20% or more, probability of preterm birth for women with influenza 12% or more, mortality for a preterm neonate 2% or more, and probability of influenza-attributable hospitalization 4.8% or more), the postexposure prophylactic use of antiviral medications was strongly cost-effective, with incremental cost-effectiveness ratio values below $50,000 per quality-adjusted life-year. Antiviral prophylaxis became an economically dominant strategy (that is, less costly and more effective) when the influenza attack rate is 20% or more and preterm birth rate is 36% or more, and when attack rate is 30% or more and preterm birth rate is 24% or more. Antiviral prophylaxis was not cost-effective under seasonal influenza conditions. CONCLUSION: These findings support the use of antiviral medications for postexposure prophylaxis among pregnant women in a pandemic influenza scenario but not in a seasonal influenza setting. PMID- 20168097 TI - Obstetric health care workers' attitudes and beliefs regarding influenza vaccination in pregnancy. AB - OBJECTIVE: To explore obstetric health care workers' attitudes and beliefs regarding influenza vaccination in pregnancy. METHODS: A survey consisting of 16 multiple-choice questions was administered to nurses, medical and nursing assistants, receptionists, and clinical administrators in obstetric settings. Survey questions addressed general knowledge of influenza and recommendations for vaccination during pregnancy, as well as personal beliefs about the acceptability of the vaccine in the pregnant population. The study was conducted at two sites, Women & Infants Hospital in Providence, RI, and Magee-Women's Hospital in Pittsburgh, PA. Variables were compared by Fisher exact test. RESULTS: Two hundred sixty-seven completed surveys were available for analysis, with a completion rate of 85%. Almost one third of health care workers surveyed do not believe that vaccines are a safe and effective way to decrease infections (31%) and a minority believe that vaccines are safe in pregnancy (36%). Just over half of health care workers know that pregnant women are at increased risk of complications from the flu (56.6%). Only 46% were able to correctly identify influenza symptoms, and only 65% would recommend influenza vaccination to a pregnant woman if indicated. A small percentage would be willing to give an avian influenza vaccine to pregnant women during a pandemic if it had not been tested in pregnancy (12.3%). CONCLUSION: Many obstetric health care workers lack knowledge regarding the safety and importance of influenza vaccination during pregnancy. Misinformed or inadequately informed health care workers may represent a barrier to influenza vaccine coverage of pregnant women. This lack of knowledge among the health care workforce takes on added importance in the setting of the H1N1 2009 swine-origin influenza pandemic. LEVEL OF EVIDENCE: III. PMID- 20168098 TI - Association between menopausal transition stages and developing urinary incontinence. AB - OBJECTIVE: To estimate whether menopause transition stage is independently associated with the development of incontinence symptoms. METHODS: We conducted a longitudinal analysis, using discrete proportional hazards models, of women who were continent at baseline in the Study of Women's Health Across the Nation (SWAN), a multicenter, multiracial, multiethnic prospective cohort study of community-dwelling midlife women transitioning through menopause. At baseline and each of the six annual visits, SWAN elicited frequency and type of incontinence in a self- administered questionnaire and classified menopausal stage from menstrual bleeding patterns. RESULTS: Compared with premenopause, being in the early perimenopause (incidence 17.8 per 100 woman years) made it 1.34 times and in the late perimenopause (incidence 14.5 per 100 woman years) made it 1.52 times more likely for women to develop monthly or more frequent incontinence. In contrast, women in postmenopause (incidence 8.2 per 100 woman years) were approximately one half as likely to develop this degree of incontinence. This pattern of association across the menopausal transition was similar for stress and urge incontinence. However, menopausal stage was not associated with developing more frequent incontinence (leaking several times per week or more). Worsening anxiety symptoms, a high baseline body mass index, weight gain, and new onset diabetes were associated with developing more frequent incontinence. CONCLUSION: Menopausal transition stage was associated with developing monthly or more frequent but not weekly or more frequent incontinence, suggesting that only infrequent incontinence symptoms were attributable to the perimenopause. Because modifiable factors such as anxiety, weight gain, and diabetes were associated with developing more frequent incontinence, determining whether healthy life changes and treating medical problems can prevent incontinence is a priority. LEVEL OF EVIDENCE: II. PMID- 20168099 TI - Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy of zoledronic acid in the prevention of bone loss in postmenopausal women with low bone mass. METHODS: In this 2-year, randomized, multicenter, double-blind, placebo-controlled study, postmenopausal women with low bone mass were selected randomly to receive either zoledronic acid 5 mg intravenously at randomization and at month 12 (zoledronic acid 2 x 5 mg), zoledronic acid 5 mg intravenously only at randomization and placebo at month 12 (zoledronic acid 1 x 5 mg), or placebo at randomization and at month 12 (placebo). The primary efficacy endpoint was the percentage change in lumbar spine bone mineral density (BMD) (lumbar spine BMD) at month 24 relative to baseline. RESULTS: Both zoledronic acid 2 x 5 mg and zoledronic acid 1 x 5 mg regimens significantly increased mean lumbar spine BMD compared with placebo at month 24 (5.18% and 4.42% compared with -1.32%, respectively, both P<.001). Similarly, significantly greater increases for both zoledronic acid regimens relative to placebo were observed for lumbar spine BMD at month 12 and for BMD at the proximal femur sites (total hip, femoral neck, trochanter) at month 12 and 24 (all P<.001). Both zoledronic acid regimens significantly reduced bone turnover markers over time relative to placebo (all P<.001), although changes with zoledronic acid 2 x 5 mg regimen were sustained greater during the second year relative to zoledronic acid 1 x 5 mg. The overall incidence of adverse events and serious adverse events were similar across all treatment groups. CONCLUSION: Both once-yearly dosing and a single dose of intravenous zoledronic acid 5 mg prevented bone loss for 2 years and were well-tolerated in postmenopausal women with low bone mass. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00132808. LEVEL OF EVIDENCE: I. PMID- 20168100 TI - Botulinum neurotoxin type A injections for vaginismus secondary to vulvar vestibulitis syndrome. AB - OBJECTIVE: To investigate whether botulinum neurotoxin type A improves vaginismus and study its efficacy with repeated treatments. METHODS: Outpatients were referred because standard cognitive-behavioral and medical treatment for vaginismus and vulvar vestibular syndrome failed. From this group, we prospectively recruited consecutive women (n=39) whose diagnostic electromyogram (EMG) recordings from the levator ani muscle showed hyperactivity at rest and reduced inhibition during straining. These women were followed for a mean (+/ standard deviation) of 105 (+/-50) weeks. Recruited patients underwent repeated cycles of botulinum neurotoxin type A injected into the levator ani under EMG guidance and EMG monitoring thereafter. At enrollment and 4 weeks after each cycle, women were asked about sexual intercourse; underwent EMG evaluation and examinations to grade vaginal resistance according to Lamont; and completed a visual analog scale (VAS) for pain, the Female Sexual Function Index Scale, a quality-of-life questionnaire (Short-Form 12 Health Survey), and bowel and bladder symptom assessment. RESULTS: At 4 weeks after the first botulinum neurotoxin type A cycle, the primary outcome measures (the possibility of having sexual intercourse, and levator ani EMG hyperactivity) both improved, as did the secondary outcomes, Lamont scores, VAS, Female Sexual Function Index Scales, Short-Form 12 Health Survey, and bowel-bladder symptoms. These benefits persisted through later cycles. When follow-up ended, 63.2% of the patients completely recovered from vaginismus and vulvar vestibular syndrome, 15.4% still needed reinjections (censored), and 15.4% had dropped out. CONCLUSION: Botulinum neurotoxin type A is an effective treatment option for vaginismus secondary to vulvar vestibular syndrome refractory to standard cognitive-behavioral and medical management. After patients received botulinum neurotoxin type A, their sexual activity improved and reinjections provided sustained benefits. LEVEL OF EVIDENCE: III. PMID- 20168102 TI - Urgent cesarean delivery for fetal bradycardia. AB - OBJECTIVE: To estimate whether fetal bradycardia-to-delivery interval or decision to-delivery interval was related to cord arterial pH according to different causes of fetal distress. METHODS: Women who delivered singleton neonates by urgent cesarean delivery because of intrapartum fetal bradycardia were retrospectively categorized into three groups according to the cause of fetal bradycardia: 1) Irreversible; 2) Potentially Reversible; and 3) Unknown (no identifiable cause). Comparisons were made between groups in regard to pH, bradycardia-to-delivery interval, and decision-to-delivery interval. Correlation analyses between pH and both intervals were then performed for different groups. RESULTS: Of 235 cases, 39, 22, and 174 were respectively categorized into the Irreversible group, Potentially Reversible group, and Unknown group. The median pH was lower in the Irreversible group (7.094; interquartile range [IQR] 6.991 7.216) than in Potentially Reversible group (7.162; IQR 7.064-7.251) or Unknown group (7.210; IQR 7.161-7.255) (P<.001). The Irreversible group's median bradycardia-to-delivery interval was 5 minutes shorter than those of the other two groups (11 compared with 16.5 and 16 minutes, respectively; P<.001), whereas its median decision-to-delivery interval was 1 minute shorter (10 compared with 11.5 and 11 minutes, respectively; P=.001). In the Irreversible group, pH decreased with the bradycardia-to-delivery interval (Spearman's rho=-0.354; P=.027) at a rate of 0.011 per minute. Cord arterial pH did not correlate with the bradycardia-to-delivery interval in the Potentially Reversible and Unknown groups. In neither group did pH correlate with decision-to-delivery interval. CONCLUSION: Cord arterial pH deteriorates with bradycardia-to-delivery interval when the underlying cause of fetal distress is irreversible, but not so otherwise. LEVEL OF EVIDENCE: II. PMID- 20168101 TI - Failed operative vaginal delivery. AB - OBJECTIVE: To compare maternal and neonatal outcomes in women undergoing second stage cesarean delivery after a trial of operative vaginal delivery with those in women undergoing second-stage cesarean delivery without such an attempt. METHODS: This study is a secondary analysis of the women who underwent second-stage cesarean delivery. The maternal outcomes examined included blood transfusion, endometritis, wound complication, anesthesia use, and maternal death. Neonatal outcomes examined included umbilical artery pH less than 7.0, Apgar score of 3 or less at 5 minutes, seizures within 24 hours of birth, hypoxic ischemic encephalopathy, stillbirth, skull fracture, and neonatal death. RESULTS: Of 3,189 women who underwent second-stage cesarean delivery, operative vaginal delivery was attempted in 640. Labor characteristics were similar in the two groups, with the exception of the admission-to-delivery time and cesarean indication. Those with an attempted operative vaginal delivery were more likely to undergo cesarean delivery for a nonreassuring fetal heart rate tracing (18.0% compared with 13.9%, P=.01), have a wound complication (2.7% compared with 1.0%, odds ratio [OR] 2.65, 95% confidence interval [CI] 1.43-4.91), and require general anesthesia (8.0% compared with 4.1%, OR 2.05, 95% CI 1.44-2.91). Neonatal outcomes, including umbilical artery pH less than 7.0, Apgar score of 3 or less at 5 minutes, and hypoxic ischemic encephalopathy, were more common for those with an attempted operative vaginal delivery. This was not significant when cases with a nonreassuring fetal heart rate tracing were removed. CONCLUSION: Cesarean delivery after an attempt at operative vaginal delivery was not associated with adverse neonatal outcomes in the absence of a nonreassuring fetal heart rate tracing. LEVEL OF EVIDENCE: II. PMID- 20168103 TI - Validation of the prediction model for success of vaginal birth after cesarean delivery. AB - OBJECTIVE: To validate a previously developed vaginal birth after cesarean (VBAC) prediction model using a patient cohort different than that from which it was derived. METHODS: We performed a cohort study of all term pregnant women (January 2002-August 2007) with one prior low transverse cesarean delivery attempting a trial of labor. Variables used in the final prediction model (maternal age, prepregnancy body mass index, ethnicity, prior vaginal delivery, prior VBAC, and indication for prior cesarean delivery) were extracted from medical records and used to calculate an individual woman's predicted VBAC success rate. These rates at the level of the study population then were partitioned into deciles and compared with the actual VBAC rates. RESULTS: Of 545 women who fit the inclusion criteria, 502 had complete data available. A total of 262 (52.2%) had VBAC. The predicted probability of VBAC, as calculated by the regression equation, was significantly higher in those who had a successful trial of labor (median 78.4%, interquartile range 62.1-88.2) than in those who did not (median 59.7%, interquartile range 50.8-75.3, P<.001). The predictive model had an area under the receiver operating characteristic of 0.70 (95% confidence interval 0.65-0.74, P<.001), which was similar to that originally described. The actual VBAC rates did not differ from the predicted rates when the predicted chance of success was less than 50%. Above a 50% predicted success, the achieved success rates were consistently 10-20% lower. CONCLUSION: The published nomogram is predictive of VBAC success. It may help pregnant women contemplating a trial of labor reach a more informed decision. LEVEL OF EVIDENCE: II. PMID- 20168104 TI - Moxibustion for breech version: a randomized controlled trial. AB - OBJECTIVE: To estimate the efficacy of moxibustion between 34 and 38 weeks of gestation to facilitate the cephalic version of fetuses in breech presentation and the acceptability of this method by women. METHODS: We conducted a randomized controlled trial in a Swiss university hospital maternity unit. We proposed to stimulate the acupoint BL 67 by moxibustion daily for 2 weeks for 212 consenting women between 34 and 36 weeks of gestation with a single fetus in breech presentation. We did the intervention three times weekly in the hospital and a teaching session and information leaflet on the technique for additional daily therapy at home. The control group received expectant management care. The availability of external cephalic version was maintained for both groups. The main outcome measure was the comparison of the proportion of women with cephalic presentation at delivery. RESULTS: Baseline characteristics were similar between groups, except more nulliparous women were randomized to moxibustion. The percentage of versions was similar between groups: 18% in the moxibustion group compared with 16% in the control group (relative risk 1.12, 95% confidence interval 0.62 to 2.03). Adjustment for the imbalance in parity did not change these results. The frequency of cesarean delivery was similar (64% compared with 58% in the moxibustion group and the control group, respectively). Acceptability of the intervention and women's perceptions of moxibustion were favorable. CONCLUSION: We observed no beneficial effect of moxibustion to facilitate the cephalic version of fetuses in breech presentation. Despite this lack of proven effectiveness, women had positive opinions on the intervention. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov,NCT00890474. LEVEL OF EVIDENCE: I. PMID- 20168105 TI - Nationwide use of laparoscopic hysterectomy compared with abdominal and vaginal approaches. AB - OBJECTIVE: To examine factors associated with undergoing laparoscopic hysterectomy compared with abdominal hysterectomy or vaginal hysterectomy. METHODS: This is a cross-sectional analysis of the 2005 Nationwide Inpatient Sample. All women aged 18 years or older who underwent hysterectomy for a benign condition were included. Multivariable analyses were used to examine demographic, clinical, and health-system factors associated with each hysterectomy route. RESULTS: Among 518,828 hysterectomies, 14% were laparoscopic, 64% abdominal, and 22% vaginal. Women older than 35 years had lower rates of laparoscopic than abdominal (odds ratio [OR] 0.85, 95% confidence interval [CI] 0.77-0.94 for age 45-49 years) or vaginal hysterectomy (OR 0.61, 95% CI 0.540.69 for age 45-49 years). The odds of laparoscopic compared with abdominal hysterectomy were higher in the West than in the Northeast (OR 1.77, 95% CI 1.2-2.62). African-American, Latina, and Asian women had 40-50% lower odds of laparoscopic compared with abdominal hysterectomy (P<.001). Women with low income, Medicare, Medicaid, or no health insurance were less likely to undergo laparoscopic than either vaginal or abdominal hysterectomy (P<.001). Women with leiomyomas (P<.001) and pelvic infections (P<.001) were less likely to undergo laparoscopic than abdominal hysterectomy. Women with leiomyomas (P<.001), endometriosis (P<.001), or pelvic infections (P<.001) were more likely to have laparoscopic than vaginal hysterectomy. Laparoscopic hysterectomy had the highest mean hospital charges ($18,821, P<.001) and shortest length of stay (1.65 days, P<.001). CONCLUSION: In addition to age and clinical diagnosis, nonclinical factors such as race/ethnicity, insurance status, income, and region appear to affect use of laparoscopic hysterectomy compared with abdominal hysterectomy and vaginal hysterectomy. LEVEL OF EVIDENCE: III. PMID- 20168106 TI - Repeat pap testing and colposcopic biopsies in the underserved. AB - OBJECTIVE: To quantify repeat Pap testing and colposcopic biopsies among women in the National Breast and Cervical Cancer Early Detection Program between 2003 and 2006 (N=955,494). METHODS: Rates of repeat Pap testing (two tests within 9 months) and colposcopic biopsies were estimated along with 95% confidence intervals (CIs). Odds ratios and 95% CIs for receipt of colposcopic biopsy compared with repeat Pap testing were estimated from multivariable logistic regression models. Finally, we estimated positive predictive values and 95% CIs of cervical intraepithelial neoplasia (CIN) 2 or worse (CIN 3, carcinoma in situ, invasive cancer) for two strategies: 1) repeat Pap testing followed by colposcopic biopsy and 2) colposcopic biopsy alone. RESULTS: There were 39,583 and 53,880 women with repeat Pap testing and colposcopic biopsy, respectively, from 2003 to 2006. Overall, age-standardized rates of repeat Pap testing and colposcopic biopsies were 37.2 per 1,000 women and 39.3 per 1,000 women, respectively. Younger women, Hispanic women, and African-American women were more likely to receive colposcopic biopsies compared with repeat Pap tests. Positive predictive values of colposcopic biopsy were highest after abnormal Pap test results (27% after a result of atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion, 70% after a result of high-grade squamous intraepithelial lesion/squamous cell cancer). CONCLUSION: Colposcopic biopsies are common among young women after being screened for cervical cancer and, except among those with the most severe Pap test results, may not be efficient in detecting serious disease. These results conflict with current recommendations for less aggressive follow-up for most young women. LEVEL OF EVIDENCE: II. PMID- 20168107 TI - Effect of the number of biopsies on the subsequent acquisition of new human papillomavirus infections. AB - OBJECTIVE: To analyze the effect of number of biopsies taken at enrollment with incident human papillomavirus (HPV) infections detected at the next 6-month visit. METHODS: Using data from the Atypical Squamous Cells of Undetermined Significance (ASCUS) and Low-Grade Squamous Intraepithelial Lesion (LSIL) Triage Study (ALTS), we compared the 6-month acquisition of new HPV infections among 988 women who underwent colposcopy, were not diagnosed and treated for cervical intraepithelial neoplasia grade 2 or more severe lesions, and had polymerase chain reaction results for 38 HPV genotypes at enrollment and follow-up. Our analysis considered each woman's possible acquisition of each of these HPV genotypes. RESULTS: The average 6-month acquisition of any HPV genotype for women with zero, one, and two or more biopsies was 1.82%, 1.74%, and 1.97%, respectively (Ptrend=.7). In a logistic regression model that controlled for age, baseline HPV status, and having a new sexual partner during the 6-month follow up, two or more biopsies (compared with one biopsy) was not associated with acquiring HPV (odds ratio 1.0, 95% confidence interval 0.75-1.3). CONCLUSION: Multiple biopsies compared with a single biopsy did not increase the likelihood of acquiring new HPV infections. LEVEL OF EVIDENCE: II. PMID- 20168108 TI - Histologic correlates of glandular abnormalities in cervical cytology among women with human immunodeficiency virus. AB - OBJECTIVE: To estimate the frequency and histologic correlates of glandular abnormalities in cervical cytology among women with the human immunodeficiency virus (HIV) and to compare findings with those of women without HIV. METHODS: In a cohort study of HIV-infected and uninfected women followed between 1994 and 2007, Pap tests were obtained every 6 months. Glandular abnormalities, including atypical glandular cells (AGC), adenocarcinoma in situ (AIS), and adenocarcinoma, were identified and correlated with biopsy histology. Multivariate models to summarize data across visits used generalized estimating equations. The association of Pap and histology results was assessed using chi tests. RESULTS: Of 48,362 Pap tests from 3,766 women, glandular abnormalities were found in 341 (0.7%) tests from 244 (6%) women, including 93 (1.0%) of 9,564 Pap tests among HIV-seropositive women with CD4 lymphocyte counts less than 250/mm, 103 (0.8%) of 13,023 tests among those with counts 250-500/mm, 68 (0.6%) of 12,470 tests among women with counts greater than 500/mm, and 70 (0.6%) of 11,769 tests among HIV seronegative women (P for trend=.006). Colposcopy was documented for only 148 (61%) of 244 index Pap tests in women with glandular abnormalities. After index abnormal tests, endocervical curettings were obtained from 106 (43%) women, cervical biopsies from 76 (38%), and endometrial biopsies from 19 (8%). Squamous lesions predominated among histologic findings and histology results did not differ by HIV serostatus (P=.16). CONCLUSION: Although immunosuppression increased the risk of glandular Pap test abnormalities in women with HIV, these remained uncommon. Compliance with management guidelines can improved. LEVEL OF EVIDENCE: II. PMID- 20168109 TI - Excessive gestational weight gain and postpartum weight retention among obese women. AB - OBJECTIVE: To evaluate the incremental effect of weight gain above that recommended for term pregnancy (15 pounds) on postpartum weight retention at 1 year among obese women. METHODS: In a retrospective cohort study, we identified 1,656 singleton gestations resulting in live births among obese women (body mass index at or above 30 kg/m) between January 2000 and December 2005 in Kaiser Permanente Northwest. Pregnancy weight change (last available predelivery weight minus weight at pregnancy onset) was categorized as less than 0, 0-15, greater than 15 to 25, greater than 25 to 35, and greater than 35 pounds. Postpartum weight change (weight at 1 year postpartum minus weight at pregnancy onset) was defined as less than 0, 0-10, and greater than 10 pounds. RESULTS: Total gestational weight gain was -33.2 (weight loss) to +98.0 pounds (weight gain). Nearly three fourths gained greater than 15 pounds, and they were younger and weighed less at baseline than women who gained 15 pounds or less. Pregnancy related weight change showed a significant relationship with postpartum weight change. For each pound gained during pregnancy, there was a 0.4-pound increase above baseline weight at 1 year postpartum. In adjusted logistic regression models, the risk of a postpartum weight greater than 10 pounds over baseline was twofold higher for women gaining greater than 15 to 25 pounds compared with women gaining 0-15 pounds (odds ratio [OR] 2.18, 95% confidence interval [CI] 1.54 3.10), fourfold higher for women gaining greater than 25 to 35 pounds (OR 3.91, 95% CI 2.75-5.56), and almost eightfold higher for women gaining greater than 35 pounds (OR 7.66, 95% CI 5.36-10.97). CONCLUSION: Incremental increases in gestational weight gain beyond the current recommendation for obese women substantially increase the risk of weight retention at 1 year postpartum. LEVEL OF EVIDENCE: II. PMID- 20168110 TI - Early-onset preeclampsia and the prevalence of postpartum metabolic syndrome. AB - OBJECTIVE: To determine the prevalence of the metabolic syndrome postpartum in women with a history of pregnancy complicated by early-onset vascular disorders compared with women with late-onset disorders. METHODS: In this retrospective cohort study 849 women with a history of pregnancy complicated by vascular disorders (preeclampsia; gestational hypertension; hemolysis, elevated liver enzymes, low platelets syndrome; eclampsia; placental abruption; fetal growth restriction; and stillbirth as a result of placental insufficiency) were divided into early-onset (delivery before 32 weeks of gestation, n=376) and late-onset (delivery at or beyond 32 weeks, n=473). By use of four internationally accepted criteria to diagnose metabolic syndrome, we compared its prevalence in both groups using odds ratios (ORs), adjusted for maternal age, smoking, alcohol and coffee consumption, birth weight centile, stillbirth, and interval between delivery and measurements. RESULTS: The metabolic syndrome was present in 15-25% of women after early-onset vascular-complicated pregnancy and in 10-14% of women after late-onset disease, depending on the criteria set used; adjusted OR 2.51 (95% confidence interval [CI] 1.66-3.80) using World Health Organization criteria; adjusted OR 2.01 (95% CI 1.37-2.96) using International Diabetes Federation criteria; adjusted OR 2.16 (95% CI 1.31-3.55) using Third Adult Treatment Panel (ATPIII) criteria; and adjusted OR 2.02 (95% CI 1.28-3.17) using Third Adult Treatment Panel updated criteria. CONCLUSION: The prevalence of the metabolic syndrome postpartum is twice as high in women with a history of early onset (delivery before 32 weeks) compared to late-onset vascular-complicated pregnancy (delivery at or beyond 32 weeks). LEVEL OF EVIDENCE: II. PMID- 20168111 TI - Effect of fetal sex on pregnancy outcome in twin pregnancies. AB - OBJECTIVE: To estimate the association between fetal sex and pregnancy outcome in dichorionic twin pregnancies and the effect of male and female fetuses on their opposite-sex co-twin. METHODS: This was a retrospective study of all dichorionic twin pregnancies at a tertiary hospital from 1995 to 2006. Pregnancies were classified into three groups according to fetal sex: female-female, male-female, and male-male. Pregnancy outcome was compared for the three groups. Neonatal outcome of female neonates from female-female pregnancies was compared with that of female neonates from male-female pregnancies. Similarly, the outcome of male neonates from male-female pregnancies was compared with that of male neonates from male-male pregnancies. RESULTS: Two thousand seven hundred four twin pregnancies were included in the study, of which there were 436 (16.1%) female female pregnancies, 1,878 (69.5%) male-female pregnancies, and 390 (14.4%) male male pregnancies. The risk of preterm delivery at less than 31 and 28 weeks of gestation was highest in the male-male group (9.2%, odds ratio [OR] 1.7, 95% confidence interval [CI] 1.2-2.6 and 4.1%, OR 2.3, 95% CI 1.3-4.2, respectively) and intermediate in the male-female group (7.5%, OR 1.4, 95% CI 1.1-1.9 and 3.2%, OR 1.8, 95% CI 1.2-3.0, respectively) using the female-female group as reference (5.5% and 1.8%, respectively). Male neonates in male-male twin pairs were characterized by a lower mean birth weight and a lower growth rate when compared with male neonates in male-female pairs. Female neonates from male-female pregnancies had a rate of respiratory and neurologic morbidity similar to that of male neonates and significantly higher than that of female neonates from female female pregnancies. CONCLUSION: In twins, pregnancy outcome is enhanced when the fetus (male or female) shares the womb with a female rather than with a male co twin. Analysis of neonatal outcome for preterm twin neonates identifies a male offending factor. LEVEL OF EVIDENCE: II. PMID- 20168112 TI - Array comparative genomic hybridization for genetic evaluation of fetal loss between 10 and 20 weeks of gestation. AB - OBJECTIVE: To estimate genomic copy number changes in fetal loss between 10 and 20 weeks of gestation using array comparative genomic hybridization. METHODS: This was a prospective series of 35 women who experienced pregnancy loss between 10-20 weeks of gestation with either normal karyotype (n=9) or no conventional cytogenetic testing (n=26). DNA was isolated from fetal tissue and parental blood. Array comparative genomic hybridization was performed on DNA from fetal tissue using a whole genome BAC array chip. Copy number changes in fetal tissue were then compared against databases of benign copy number changes. Parental DNA was analyzed using the same BAC array in cases that contained suspected pathogenic copy number changes. In cases where de novo copy number changes were detected in fetal DNA, further characterization was performed using a 244K oligonucleotide microarray. RESULTS: DNA was successfully isolated in 30 of 35 (86%) of cases. Array comparative genomic hybridization was performed in all of these. De novo copy number changes were detected in six (20%) cases using the Spectral chip and confirmed in four (13%) cases using the Agilent chip. These ranged in size from 93-289 Kb and mapped on 5p, 13q and Xq22. In the cases with de novo copy number changes, the higher-density Agilent array detected additional changes (20-1,310 Kb). CONCLUSION: Array comparative genomic hybridization detected de novo copy number changes in 13% of cases where routine cytogenetic testing was normal or not performed. These involved large regions of DNA and may provide novel explanations for some cases of otherwise unexplained pregnancy loss. LEVEL OF EVIDENCE: III. PMID- 20168113 TI - Genetic analysis of the cause of endometrial osseous metaplasia. AB - OBJECTIVE: To analyze solitary bone fragments from the uterine cavity through DNA genotyping, thus elucidating whether they originate from metaplasia, from previous abortion, or both. METHODS: We conducted a case series study on 14 patients, of whom eight yielded bone DNA. The patients selected had histopathologic diagnoses of bone fragments inside the uterine cavity or previously removed samples available for analysis. We extracted DNA from blood and bone fragments. To identify the bone tissue origin, these materials were genotyped using polymerase chain reactions for DNA loci. Six mini short tandem repeat loci frequently used for human tissue identification were analyzed using automated sequencing. RESULTS: Among these eight patients, blood and tissue samples from the same individual produced exactly the same pair of alleles for all six loci. This indicated that the DNA profile was completely the same for the bone samples and the mother's blood (95% confidence interval 63-100%), thus confirming that the DNA had the same origin and that these were cases of metaplasia. CONCLUSION: In all of the eight cases, bone formation was caused by osseous metaplasia, because the DNA in the bone fragment and in the patient's blood was identical. Although all of the women had histories of previous abortion, no difference in DNA was detected in the bone tissue in any of the cases, as would be expected if abortion had occurred. This result was completely unexpected, differing greatly from what the literature suggests. LEVEL OF EVIDENCE: III. PMID- 20168114 TI - Aortic intima media thickness in fetuses and children with intrauterine growth restriction. AB - OBJECTIVE: To measure aortic intima media thickness and diameter by ultrasonography in fetuses with intrauterine growth restriction (IUGR) and in appropriate for gestational age (AGA) fetuses and in the same children after a mean follow-up of 18 months. METHODS: This was a prospective study performed between January 2006 and August 2008. Fetuses were classified as having IUGR if the estimated fetal weight was below the 10th percentile and umbilical artery pulsatility index was greater than 2 standard deviations; they were classified as AGA if the estimated fetal weight was between the 10th and 90th percentiles. Abdominal aortic intima media thickness and diameter were measured in each fetus with IUGR and in each AGA fetus at a mean gestational age of 32 weeks. The same measurements were taken in the children after a mean follow-up of 18 months. RESULTS: Thirty-eight fetuses with IUGR and 32 AGA fetuses were enrolled in the study. Aortic intima media thickness median values were significantly higher in IUGR than in AGA both in utero (1.9 mm compared with 1.15 mm; P<.001) and after birth (2.4 mm compared with 1.03 mm; P<.001) and were significantly correlated (P=.018, r=0.48). At 32 weeks of gestation, aortic intima media thickness in fetuses with IUGR was inversely correlated with estimated fetal weight (P<.003; r=-0.58). Median diameter of the abdominal aorta and blood-flow velocity at 32 weeks of gestation were significantly higher in fetuses with IUGR compared with AGA fetuses (median diameter 4.5 mm compared with 3.6 mm, P<.001, blood-flow velocity 42.5 cm/s compared with 23.3 cm/s, P<.001). At follow-up, in 25 children who had had IUGR and 25 children who had been AGA, there was no significant difference in median diameter of the abdominal aorta (6.8 mm compared with 7.5 mm, P=.21). CONCLUSION: Aortic wall thickening in fetuses and children with IUGR shows differences with respect to those who were AGA. This may reflect a correlation between impaired growth in utero, Doppler abnormalities, low birth weight, and early signs of vascular dysfunction. LEVEL OF EVIDENCE: II. PMID- 20168115 TI - Periventricular leukomalacia and placental histopathologic abnormalities. AB - OBJECTIVE: To estimate whether there are placental histopathologic abnormalities associated with neonatal periventricular leukomalacia (PVL), a major precursor of cerebral palsy. METHODS: This is a case-control study of 167 neonates born between 23 and 34 weeks of gestation diagnosed with PVL by head ultrasonography within 6 weeks of birth, and 167 control neonates without neurologic morbidity matched by gestational age. Placentas for both case neonates and control neonates were reviewed by two perinatal pathologists who were blinded to neonatal course. RESULTS: Neonates with PVL were significantly more likely to have positive neonatal blood (28.7%, 16.8%, P=.001) and cerebrospinal fluid (14.4%, 4.8%, P=.007) cultures. The ratio of placental weight to birth weight did not differ between groups, but neonates with PVL had significantly more chronic diffuse capsular deciduitis (20.4%, 10.8%, P=.02) and capsular decidual plasma cells (8.4%, 2.4%, P=.02). Conditional logistic regression adjusting for birth weight and the presence of multiple gestation in the identification of PVL showed a significant increase for diffuse capsular deciduitis (P=.02) and capsular decidual plasma cells (P=.03). CONCLUSION: Periventricular leukomalacia has a significant but weak association with chronic diffuse capsular deciduitis and the presence of capsular decidual plasma cells, evidence of chronic infection but not histologic acute chorioamnionitis. LEVEL OF EVIDENCE: II. PMID- 20168116 TI - Optimal nutrition for improved twin pregnancy outcome. AB - Twin pregnancies contribute a disproportionate degree to perinatal morbidity, partly because of increased risks of low birth weight and prematurity. Although the cause of the morbidity is multifactorial, attention to twin-specific maternal nutrition may be beneficial in achieving optimal fetal growth and birth weight. Achievement of body mass index (BMI)-specific weight gain goals, micronutrient and macronutrient supplementation specific to the physiology of twin gestations, and carbohydrate-controlled diets are recommended for optimal twin growth and pregnancy outcomes. The daily recommended caloric intake for normal-BMI women with twins is 40-45 kcal/kg each day, and iron, folate, calcium, magnesium, and zinc supplementation is recommended beyond a usual prenatal vitamin. Daily supplementation of docosahexaenoic acid and vitamin D should also be considered. Multiple gestation-specific prenatal care settings with a focus on nutritional interventions improve birth weight and length of gestation and should be considered for the care of women carrying multiples. Antepartum lactation consultation can also improve the rate of postpartum breastfeeding in twin pregnancies. Twin gestation-specific nutritional interventions seem effective in improving the outcome of these pregnancies and should be emphasized in the antepartum care of multiple gestations. This review examines the available evidence and offers recommendations for twin pregnancy-specific nutritional interventions. PMID- 20168117 TI - Requiring human papillomavirus vaccine for immigrant women. AB - The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommends human papillomavirus (HPV) vaccination of 11- to 12-year-old girls, with catch-up vaccination for girls and women aged 13 to 26 years. Although compulsory HPV vaccination is not currently mandated for any U.S. population, immigrant women aged 11-26 years are now required to receive the first injection of the vaccine (the full series consists of three doses) as a result of the 1996 Illegal Immigration Reform and Immigrant Responsibility Act. According to this law, immigrants applying for visas to enter the United States or to adjust their immigration status must receive the inoculations that the Advisory Committee on Immunization Practices recommends for U.S. residents. In the case of HPV, this law represents not only an undue burden on immigrant women, but also raises scientific and ethical questions regarding the benefit of vaccination in this population. Given these issues, immigrant women should not be required to provide documentation of HPV vaccination at the time of visa application or adjustment of immigration status. PMID- 20168118 TI - Cervical assessment by ultrasound for preventing preterm delivery. AB - BACKGROUND: Measurement of cervical length (CL) by transvaginal ultrasound (TVU) is predictive of preterm birth (PTB). It is unclear if this screening test is effective for prevention of PTB. OBJECTIVES: To assess the effectiveness of antenatal management based on TVU CL screening for preventing PTB. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Child birth Group's Trials Register (September 2008), MEDLINE (1966 to September 2008), and reviewed the reference list of all articles. SELECTION CRITERIA: : Published and unpublished randomized controlled trials including pregnant women between the gestational ages of 14 to 32 weeks screened with TVU CL for risk of PTB. This review focuses exclusively on studies based on knowledge versus no knowledge of TVU CL results. DATA COLLECTION AND ANALYSIS: All potential studies identified as in the search were assessed for inclusion by three independent review authors. We also analyzed studies for quality measures and extracted data. MAIN RESULTS: Of 12 trials identified, five were eligible for inclusion (n=507). Three included singleton gestations with preterm labor (PTL); one included singleton gestations with preterm prelabour rupture of membranes (PPROM); and one included twin gestations without or with PTL.In the three trials of singleton gestations with PTL, 290 women were randomized; 147 to knowledge and 143 to no knowledge of TVU CL. Knowledge of TVU CL results was associated with a non-significant decrease in PTB at less than 37 weeks (22.3% versus 34.7%, respectively; risk ratio 0.59, 95% (CI) 0.26 to 1.32). Delivery occurred at a later gestational age in the knowledge versus no knowlege groups (mean difference 0.64 weeks (CI 0.03 to 1.25)). All other outcomes for which there were available data (PTB at less than 34 or 28 weeks; birthweight less than 2500 grams; perinatal death; maternal hospitalization; tocolysis; and steroids for fetal lung maturity) were similar in the two groups.The trial of singleton gestations with PPROM (n=92) evaluated as its primary outcome safety of TVU CL in this population, and not its effect on management. The incidence of maternal and neonatal infections was similar in the TVU CL and no TVU CL groups.In the trial of twin gestations with or without PTL (n=125), PTB at less than 36, 34, or 30 weeks, gestational age at delivery, and other perinatal and maternal outcomes were similar in the TVU CL and the no TVU CL groups. Life table analysis revealed significantly less preterm birth at less than 35 weeks in the TVU CL group compared to the no TVU CL group (P=.02). AUTHORS' CONCLUSION: Currently there is insufficient evidence to recommend routine screening of asymptomatic or symptomatic pregnant women with TVU CL. Since there is a non-significant association between knowledge of TVU CL results and a lower incidence of PTB at less than 37 weeks in symptomatic women, we encourage further research. Future studies should look at specific populations separately (eg singleton versus twins; symptoms of PTL or no such symptoms), report on all pertinent maternal and perinatal outcomes, and include cost effectiveness analyses. Most importantly, future studies should include a clear protocol for management of women based on TVU CL results, so that it can be easily evaluated and replicated. PMID- 20168120 TI - Appearance of the levator ani muscle subdivisions in endovaginal three dimensional ultrasonography. PMID- 20168122 TI - Evaluation of two management strategies for preoperative grade I endometrial cancer. PMID- 20168124 TI - Triple-marker prenatal screening program for chromosomal defects. PMID- 20168126 TI - ACOG Technology Assessment in Obstetrics and Gynecology No. 6: Robot-assisted surgery. AB - The field of robotic surgery is developing rapidly, but experience with this technology is currently limited. In response to increasing interest in robotics technology, the Committee on Gynecologic Practice's Technology Assessment was developed to describe the robotic surgical system,potential advantages and disadvantages, gynecologic applications, and the current state of the evidence. Randomized trials comparing robot-assisted surgery with traditional laparoscopic, vaginal, or abdominal surgery are needed to evaluate long-term clinical outcomes and cost-effectiveness, as well as to identify the best applications of this technology. PMID- 20168127 TI - ACOG Committee Opinion No. 444: choosing the route of hysterectomy for benign disease. AB - Hysterectomies are performed vaginally, abdominally, or with laparoscopic or robotic assistance. When choosing the route and method of hysterectomy, the physicians should take into consideration how the procedure may be performed most safely and cost-effectively to fulfill the medical needs of the patient. Evidence demonstrates that, in general, vaginal hysterectomy is associated with better outcomes and fewer complications than laparoscopic or abdominal hysterectomy. When it is not feasible to perform a vaginal hysterectomy, the surgeon must choose between laparoscopic hysterectomy,robot-assisted hysterectomy, or abdominal hysterectomy. Experience with robot-assisted hysterectomy is limited at this time; more data are necessary to determine its role in the performance of hysterectomy. The decision to electively perform a salpingoophorectomy should not be influenced by the chosen route of hysterectomy and is not a contraindication to performing a vaginal hysterectomy. PMID- 20168128 TI - ACOG Committee Opinion No. 445: antibiotics for preterm labor. AB - The utility of antibiotics to prolong pregnancy and reduce neonatal morbidities in women with preterm labor and intact membranes has been evaluated in numerous randomized clinical trials. Antibiotic use intended only for pregnancy prolongation in women with preterm labor with intact membranes does not have short-term neonatal benefits and may be associated with long-term harm. Thus, antibiotics should not be used for this indication in women with preterm labor and intact membranes. PMID- 20168129 TI - ACOG Committee Opinion No. 446: array comparative genomic hybridization in prenatal diagnosis. AB - The widespread use of array comparative genomic hybridization (CGH)for the diagnosis of genomic rearrangements in children with idiopathic mental retardation,developmental delay, and multiple congenital anomalies has spurred interest in applying array CGH technology to prenatal diagnosis. The use of array CGH technology in prenatal diagnosis is currently limited by several factors, including the inability to detect balanced chromosomal rearrangements, the detection of copy number variations of uncertain clinical significance, and significantly higher costs than conventional karyotype analysis. Although array CGH has distinct advantages over classic cytogenetics in certain applications, the technology is not currently a replacement for classic cytogenetics in prenatal diagnosis. PMID- 20168130 TI - Respiratory physiology of seizures. AB - Comonitoring of seizures and respiratory function with pulse oximetry has shown that ictal respiratory changes (IRCs) accompany tonic-clonic convulsions and even partial seizures, especially those of temporal lobe origin. IRCs occur in children and adults, and diminished central drive is frequent, although peripheral obstruction is observed occasionally. Case reports of sudden unexplained death in epilepsy (SUDEP) have suggested IRC as a mechanism. In a series of 15 witnessed SUDEP cases, overt convulsions with marked respiratory difficulty were observed in 12. For two cases, obstructive mechanisms may have predominated. One near-SUDEP case implicated central apnea, but another case implicated postictal laryngospasm. Inhibition of brainstem respiratory control circuits likely subserves IRCs. The pre-Botzinger complex in the rostral ventrolateral medulla is a key locus for respiratory rhythm generation, with expiratory control neurons near the nucleus ambiguous. Inputs to these neurons descend from the insula, hypothalamus, and reticular formation. Direct stimulation of limbic targets in humans causes apnea. Animal models of focal seizures with IRCs and SUDEP have produced inconsistent results: some support central mechanisms, whereas others implicate peripheral obstruction. Serotonin seems relevant in a mouse model of SUDEP. These models may elucidate how seizures embarrass respiration and possibly predispose patients to SUDEP. PMID- 20168131 TI - Noninvasive correlates of subdural grid electrographic outcome. AB - PURPOSE: To investigate reasons for patients not proceeding to resective epilepsy surgery after subdural grid evaluation (SDE). To correlate noninvasive investigation results with invasive EEG observations in a set of patients with nonlesional brain MRIs. METHODS: Retrospective study of adult epilepsy patients undergoing SDE during an 8-year period at Cleveland Clinic. Construction of semiquantitative "scores" and Bayesian predictors summarizing the localizing value and concordance between noninvasive parameters in a subset with nonlesional MRIs. RESULTS: One hundred forty patients underwent SDE, 25 of whom were subsequently denied resective surgery. In 10 of 25, this was caused by a nonlocalizing subdural ictal EEG onset. Eight of 10 such patients were nonlesional on MRI. Among all nonlesional patients (n = 34 of 140), n1 = 10 of 34 patients had nonlocalizing and n2 = 24 of 34 had localizing, subdural ictal onsets. As groups, n1 and n2 were statistically disjoint relative to their noninvasive scores. Bayesian measures predictive of focal invasive ictal EEG were highest for complete concordance of noninvasive parameters, decreasing with lesser degrees of concordance. A localizing scalp interictal EEG was a particularly good Bayesian prognosticator. CONCLUSIONS: A small but significant proportion of SDE patients are denied subsequent therapeutic resective surgery. This is due to several reasons, including a nonlocalizing intracranial ictal EEG. The majority of such patients have nonlesional MRIs. The noninvasive data may be summarized by a semiquantitative score, as well as Bayesian likelihood ratios, which correlate with subsequent invasive outcome. This approach may find use in the selection and counseling of potential surgical candidates offered SDE. PMID- 20168132 TI - Intracortical excitability after repetitive hand movements is differentially affected in cortical versus subcortical strokes. AB - Repetitive training of isolated movements induces reorganization of motor cortical representations. To elucidate the mechanisms of practice-dependent cortical plasticity within the lesioned central motor system at the time of the application of a therapeutic intervention, we examined the effect of repetitive movements on intracortical facilitation (ICF) and inhibition of agonist (extensor carpi radialis [ECR]) and antagonist (flexor carpi ulnaris) muscles of the hand shortly after the movements, by the paired-pulse technique in patients with cortical (n = 9) and subcortical strokes (n = 11). Short intracortical inhibition and ICF were studied by using interstimulus intervals of 2 and 8 milliseconds, respectively, and their interaction with active or passive movement. The active movement produced significantly larger motor-evoked potentials in the ECR muscle in both patient groups. Short intracortical inhibition was particularly decreased after cortical stroke, whereas it was still significant after subcortical stroke. ICF increased significantly after movements compared with rest in the ECR for subcortical stroke patients only. We conclude that repetitive active movements increase the excitability of the motor cortex representing the agonist muscle and interact with intracortical facilitatory circuits in the subcortical stroke group but not in the cortical stroke group. This interaction of circuitry has been reported previously in control subjects and seems to still operate after subcortical stroke during active movement. Alternative networks may be recruited for active movement after cortical stroke. This finding proposes lesion-specific mechanisms of reorganization during the same rehabilitative intervention. Distinct rehabilitative strategies may be required to optimize the activation of the physiologic motor network for different lesions. PMID- 20168133 TI - Motor imagery facilitates the spinal motor neurons without hemispheric asymmetry. AB - PURPOSE: To determine possible hemispheric differences of motor imagery in facilitating the anterior horn cells. METHODS: We conducted a side-to-side comparison of motor imagery to counter rest-induced suppression of spinal motor neurons in 10 right-handed healthy adults using the F wave as a measure of excitability. Studies consisted of sequential recording of F waves from the abductor pollicis brevis with 100 supramaximal stimuli applied to the median nerve on three consecutive sessions: (1) after standardized hand exercise to establish the baseline; (2) after immobilizing abductor pollicis brevis bilaterally for 3 hours, with one side assigned to relaxation task and the other side to motor imagery task; and (3) after standardized hand exercise to assess a recovery. The same sequence was repeated, switching the side of relaxation and motor imagery tasks. RESULTS: F-wave persistence and average amplitude showed a significant decrease (P < 0.01) from baseline after relaxation task, recovering quickly after exercise, but no change (P > 0.05) after motor imagery task. The results showed no significant differences (P > 0.05) between dominant and nondominant hands. CONCLUSION: Motor imagery facilitates the spinal motor neurons without hemispheric asymmetry. PMID- 20168135 TI - Notes from the Board: President's message. PMID- 20168134 TI - Electrodiagnosis of carpal tunnel syndrome: which transcarpal conduction technique is best? AB - Transcarpal conduction techniques are commonly used to be supplementary techniques to distal sensory and motor latencies (DSL and DML) in the electrodiagnosis of carpal tunnel syndrome (CTS). However, which transcarpal conduction techniques, or combination of techniques, are the most sensitive for the electrodiagnosis of CTS is unknown. To determine which transcarpal conduction technique is the most sensitive for the electrodiagnosis of CTS, we prospectively conduct this study. Study subjects were 100 patients with CTS and 50 controls. In addition to DSL and DML determinations, all subjects were evaluated using four transcarpal conduction techniques. These were (1) median wrist-palm sensory conduction time (W-Psen CT); (2) median wrist-palm mixed nerve conduction time (W Pmix CT); (3) the difference of conduction time across wrist between median and ulnar nerves (W-Pmix M-U CT); and (4) median wrist-palm motor conduction velocity (W-Pmot CV). The sensitivities and specificities of these tests were compared. Ninety patients had one or more electrophysiologic abnormalities. The DSL and DML diagnostic sensitivities were 74% and 72%, respectively. Better sensitivities were obtained with W-Psen CT (82%), W-Pmot CV (81%), W-Pmix CT (78%), and W-Pmix M-U CT (79%). Compared between four transcarpal conduction techniques, there was no significant difference in sensitivity. Of 26 patients with CTS with normal DSL, additional electrophysiologic abnormalities were revealed with W-Psen CT (30.7%), W-Pmot CV (53.8%), W-Pmix CT (30.7%), or W-Pmix M-U CT (38.5%). When W Pmot CV was compared with W-Psen CT and W-Pmot CV versus W-Pmix CT, calculated probabilities (P = 0.07) showed a clear trend toward statistical significance. Furthermore, of 20 patients with normal DSL and DML, five patients had abnormality for W-Psen CT, eight for W-Pmot CV, four for W-Pmix CT, and six for W Pmix M-U CT. On the basis of the results, we concluded that the most simple and reliable transcarpal conduction for electrodiagnosis of CTS was W-Psen CT. The most sensitive technique was W-Pmot CV in subjects with normal DSL or with normal DSL and DML. Evaluation of transcarpal motor conduction affords a useful supplementary technique to W-Psen CT. PMID- 20168136 TI - Aligning with the future. PMID- 20168137 TI - Thinking about the Braden Scale. PMID- 20168138 TI - Intravenous peramivir emergency use authorization 2009: update for the clinical nurse specialist. PMID- 20168139 TI - A unique collaborative nursing evidence-based practice initiative using the Iowa model: a clinical nurse specialist, a health science librarian, and a staff nurse's success story. AB - PURPOSE/OBJECTIVES: The purpose of this article was to share how the collaboration of a clinical nurse specialist (CNS), a health science librarian, and a staff nurse can heighten staff nurses' awareness of the evidence-based practice (EBP) process. BACKGROUND/RATIONALE: The staff nurse is expected to incorporate EBP into daily patient care. This expectation is fueled by the guidelines established by professional, accrediting, and regulatory bodies. Barriers to incorporating EBP into practice have been well documented in the literature. DESCRIPTION OF THE PROJECT/INNOVATION: A CNS, a health science librarian, and a staff nurse collaborated to develop an EBP educational program for staff nurses. The staff nurse provides the real-time practice issues, the CNS gives extensive knowledge of translating research into practice, and the health science librarian is an expert at retrieving the information from the literature. INTERPRETATION/CONCLUSION: The resulting collaboration at this academic medical center has increased staff nurse exposure to and knowledge about EBP principles and techniques. The collaborative relationship among the CNS, health science librarian, and staff nurse effectively addresses a variety of barriers to EBP. IMPLICATIONS: This successful collaborative approach can be utilized by other medical centers seeking to educate staff nurses about the EBP process. PMID- 20168140 TI - Clinical nurse specialist practice patterns. AB - PURPOSE: The study purpose was to describe clinical nurse specialist (CNS) practice patterns (activities, outcomes, and practice barriers). DESIGN: A cross sectional survey design was used for this research study. SETTING AND SAMPLE: California Board of Registered Nursing certified CNSs (N = 1,523). METHOD: Surveys were mailed to CNSs and included the CNS Activity Questionnaire, the Clinical Nurse Specialist Outcomes and Barriers Analysis Survey, and a demographic survey. Descriptive (means, percentages) and inferential (t tests and one-way analyses of variance) statistics were used to analyze the data. CONCLUSIONS: Practicing CNSs (n = 947) demonstrated a role preference for expert clinical practice. Practice patterns (activities, outcomes, and barriers) differed in terms of CNS specialty, years of experience, number of units covered, and CNS reporting structure. Clinical nurse specialists are spending time in the 5 broad role components expert (clinical practice, consultation, education, clinical leadership, and research) utilized by the California Board of Registered Nursing as an organizing framework for practice; however, CNS practice patterns from this study reflect more discrete and functional activities that may be better encompassed under the CNS spheres of influence practice model. A number of barriers to practice exist, the most commonly reported being reporting structure. Years of experience in the role result in differences in both practice patterns and perceptions of barriers. Recommendations for CNSs and organizations include evaluating CNS reporting structures, developing advanced practice outcome-based job descriptions and competencies, and designing performance evaluations that recognize differences between inexperienced and experienced CNSs. PMID- 20168141 TI - A clinical nurse specialist-led intervention to enhance medication adherence using the plan-do-check-act cycle for continuous self-improvement. AB - PURPOSE: A clinical nurse specialist-led intervention to improve medication adherence in chronically ill adults using renal transplant recipients as an exemplar population is proposed. BACKGROUND/RATIONALE: Meta-analyses and systematic reviews of chronically ill and transplant patients indicate that patient-specific characteristics not only are poor and inconsistent predictors for medication nonadherence but also are not amenable to intervention. Adherence has not meaningfully improved, despite meta-analyses and systematic narrative reviews of randomized controlled trials (RCTs) dealing with medication nonadherence in acutely and chronically ill persons and RCTs dealing with transplant patients. Interventions with a superior potential to enhance medication adherence must be developed. DESCRIPTION OF THE INTERVENTION: Use of a clinical nurse specialist-led continuous self-improvement intervention with adult renal transplant recipients is proposed. Continuous self-improvement focuses on improving personal systems thinking and behavior using the plan-do-check-act process. Electronic medication monitoring reports, one of several objective measures of medication adherence, are used by the clinician to provide patient feedback during the check process on medication-taking patterns. CONCLUSION: Continuous self-improvement as an intervention holds promise in supporting patient self-management and diminishing the blame that clinicians place on patients for medication nonadherence. Using an objective measure of medication adherence such as an electronic monitoring report fosters collaborative patient clinician discussions of daily medication-taking patterns. Through collaboration, ideas for improving medication taking can be explored. Changes can be followed and evaluated for effectiveness through the continuous self-improvement process. IMPLICATIONS: Future studies should include RCTs comparing educational and/or behavioral interventions to improve medication adherence. PMID- 20168142 TI - Clinical nurse specialist practice in evidence-informed multidisciplinary cardiac care. AB - Care gaps exist in the management of cardiac patients throughout the care continuum. The clinical nurse specialist (CNS) is paramount in the development, implementation, and evaluation of tools to assist care providers in the use of evidence-informed therapies to maximize patient outcomes. The purpose of this article was to describe the CNS practice in terms of these evidence-informed initiatives for defined cardiac populations. Putting evidence into practice is one of the primary responsibilities for the CNS practice. Evidence-informed tools such as clinical pathways have been implemented throughout the healthcare region to reduce care gaps for the acute myocardial infarction and cardiac surgery populations. These tools equip care providers with a standards document, physician order sets, cardiac rehabilitation referral process, care guide, depression screening tool, and patient education material. By incorporating interventions known to reduce avoidable adverse events in the cardiac population into the clinical pathways, patient outcomes have been impacted. Ongoing evaluation of the evidence-informed tools through regular tracking of key indicators has enabled refinement of existing processes and care. It is the CNS practice that ensures not only patient care standards, but also daily routine care are underpinned by scientific evidence. Bridging research with clinical practice remains the stronghold for CNS practice. PMID- 20168143 TI - A literature review of intensive insulin therapy and mortality in critically ill patients. AB - BACKGROUND: Since Van den Berghe et al published their study on tight glucose control in 2001, intensive insulin therapy (IIT) has been increasingly used for critically ill patients worldwide. However, recent studies reported a significantly increased risk of hypoglycemia without a significant reduction in mortality. OBJECTIVE: The purpose of this article was to evaluate the effect of IIT with a target glucose of 110 mg/dL or less on mortality in adult critically ill patients and to determine whether it is appropriate to generalize IIT for all critically ill patients. METHODS: Ovid, MEDLINE, and PubMed databases were searched for studies that compared "conventional" vs "intensive" insulin therapy in adult critically ill patients. RESULTS: Eleven articles were included for this review. There was no significant difference in intensive care unit mortality between tight glucose control group and conventional glucose control group in 5 of 6 studies. Only 1 study showed a significant difference in hospital mortality between the 2 groups. Seven studies showed a significant increase in the incidence of hypoglycemia. CONCLUSIONS: Intensive insulin therapy was not associated with significant reduction in mortality in adult critically ill patients but was related to a significant increase in the incidence of hypoglycemia. Therefore, it is inappropriate to generalize IIT for all critically ill patients, even though it significantly improved blood glucose control. PMID- 20168144 TI - Designing podcasts for clinical nurse specialist education. PMID- 20168145 TI - Clinical nurse specialist profile. Interview by Jo Ellen Rust. PMID- 20168146 TI - Update: music and dance bring hope to those with Parkinson disease. PMID- 20168148 TI - Nuclear factor-kappaB activation by edema inhibits intestinal contractile activity. AB - OBJECTIVE: To investigate the molecular mechanisms leading to edema-induced decreases in intestinal smooth muscle myosin light-chain phosphorylation. Intestinal interstitial edema often develops during abdominal surgery and after fluid resuscitation in trauma patients. Intestinal edema causes decreased intestinal contractile activity via decreased intestinal smooth muscle myosin light-chain phosphorylation, leading to slower intestinal transit. Interstitial edema development is a complex phenomenon, resulting in many changes to the interstitial environment surrounding intestinal smooth muscle cells. Thus, the mechanism(s) by which intestinal edema development causes intestinal dysfunction are likely to be multifactorial. DESIGN: Randomized animal study. SETTING: University laboratory. SUBJECTS: Male Sprague-Dawley rats, weighing 250-350 g. INTERVENTION: Studies were performed in a rat model in which a combination of mesenteric venous hypertension and administration of resuscitative fluids induces intestinal edema, mimicking the clinical setting of damage control resuscitation. MEASUREMENTS AND MAIN RESULTS: Microarray analysis of edematous intestinal smooth muscle combined with an in silico search for overrepresented transcription factor binding sites revealed the involvement of nuclear factor-kappaB in edema-induced intestinal dysfunction. Nuclear factor-kappaB deoxyribonucleic acid binding activity was significantly increased in edematous intestinal smooth muscle compared with controls. Inhibition of nuclear factor-kappaB activation blocked edema-induced decreases in basal intestinal contractile activity. Inhibition of nuclear factor-kappaB activation also attenuated edema-induced decreases in myosin light-chain phosphorylation. CONCLUSIONS: We conclude that intestinal edema activates nuclear factor-kappaB, which, in turn, triggers a gene regulation program that eventually leads to decreased myosin light-chain phosphorylation and, thus, decreased intestinal contractile activity. PMID- 20168149 TI - Translating research on communication in the intensive care unit into effective educational strategies. PMID- 20168150 TI - Endotoxin desynchronizes biological clocks. PMID- 20168151 TI - Deconstructing racial and ethnic disparities in critical care. PMID- 20168152 TI - Resident sleep deprivation and critical care: the unintended consequences of inaction. PMID- 20168153 TI - TRALI, transfusion, and acute lung injury: synergy in action? PMID- 20168154 TI - Reducing ventilator-associated pneumonia: when process control allows outcome improvement and even benchmarking. PMID- 20168155 TI - The bridle: path to improved enteral nutrition efficiency. PMID- 20168156 TI - High positive end-expiratory pressure and low tidal volume in acute respiratory distress syndrome: all right for the right ventricle? PMID- 20168157 TI - Qualitative research: the chicken or the egg. PMID- 20168158 TI - Passive leg raising: good for everyone? PMID- 20168159 TI - Changing trends in the epidemiology of Candida blood stream infections: a matter for concern? PMID- 20168160 TI - Making medics smarter. PMID- 20168161 TI - Blood glucose control in 2010: 110 to 150 mg/dL and minimal variability. PMID- 20168162 TI - Surgeons and their patients near the end of life. PMID- 20168163 TI - How "sweet" complexity is and how "bitter" variability can be; the new aspect of intensive care unit hyperglycemia. PMID- 20168164 TI - Dr. Jekyll and Mr. Hyde saga of a cytokine: the devil in the details. PMID- 20168165 TI - DAMPen danger signals: novel therapeutic strategies against postischemic inflammation. PMID- 20168166 TI - Altered immune surveillance: a common link between cancer and sepsis? PMID- 20168167 TI - Sepsis-induced myocardial dysfunction: linking physiology and genomics. PMID- 20168168 TI - Cardiac preconditioning by specific ligands of Toll-like receptors: is it wither or whither? PMID- 20168169 TI - The ups and downs of cardiac defibrillation: integrating the shock with cardiopulmonary resuscitation for success. PMID- 20168170 TI - Can an ice cream headache save your life? PMID- 20168171 TI - Is cerebral microcirculation really preserved in shock states? PMID- 20168172 TI - Anti-, pre-, or . . . probiotics to prevent ventilator-associated pneumonia in the intensive care unit? PMID- 20168173 TI - Organ donors after circulatory determination of death: not necessarily dead, and it does not necessarily matter. PMID- 20168175 TI - Who says bedside glucose measurement is simple (or always accurate)? PMID- 20168176 TI - Denounce demagoguery on directives! PMID- 20168178 TI - Pay for performance strategy. PMID- 20168180 TI - The use of adenosine in patients with wide complex supraventricular tachycardias. PMID- 20168181 TI - Preclinical credentialing of internal medicine residents for central line placement. PMID- 20168183 TI - Continuous lateral rotation therapy to prevent ventilator-associated pneumonia: the neglected effects of gravity on pathogenesis of ventilator-associated pneumonia. PMID- 20168186 TI - Illness perceptions after myocardial infarction: relations to fatigue, emotional distress, and health-related quality of life. AB - BACKGROUND AND RESEARCH OBJECTIVE: : Health-related quality of life (HRQoL) is impaired in patients after a myocardial infarction (MI), and fatigue and depression are common health complaints among these patients. Patients' own beliefs about their illness (illness perceptions) influence health behavior and health outcomes. The aim of the present study was to examine illness perception and its association with self-reported HRQoL, fatigue, and emotional distress among patients with MI. SUBJECTS AND METHODS: : The sample consisted of 204 patients who had had MI and who completed the questionnaires during the first week in the hospital and 4 months after the MI. The questionnaires used were the Illness Perception Questionnaire, Multidimensional Fatigue Inventory, Hospital Anxiety and Depression Scale, and the Short Form Health Survey (SF-36). RESULTS: : Patient's illness perception changed over time from a more acute to a more chronic perception of illness, and beliefs in personal and treatment control of MI had decreased. Furthermore, these negative beliefs were associated with worse experiences of fatigue and lowered HRQoL. CONCLUSIONS: : Patients' illness perceptions influence health outcomes after an MI. Supporting MI patients in increasing their perception of personal control could be a primary nursing strategy in rehabilitation programs aimed at facilitating health behavior, decreasing experiences of fatigue, and increasing HRQoL. PMID- 20168188 TI - Diabetes mellitus and the importance of self-care. AB - Self-care is believed to play an important role in diabetes mellitus (DM) management, and the relationship between DM self-care and glycemic control has been extensively examined in the literature. However, most existing DM self-care literature focuses on patients' routine health behaviors. The literature has not examined in detail the relationship between health outcomes and patient decision making/nonroutine responses to signs and symptoms of DM. This article adopted Riegel and Dickson's situation-specific theory of heart failure self-care [J Cardiovasc Nurs. 2008;23(3):190-196], which incorporates an examination of patient decision making and nonroutine behaviors in their working concept of self care, and used it as a framework for reviewing the research literature relevant to how DM self-care influences health outcomes. PMID- 20168189 TI - High school body mass index and body mass index at entry to a cardiac disease risk prevention clinic and the association to all-cause mortality and coronary heart disease: a PreCIS database study. AB - OBJECTIVE: : To investigate overweight/obese patients (body mass index [BMI], > or =25 kg/m) at entry to a preventive cardiology clinic who had a high school (HS) BMI of 25 kg/m or greater versus those with a BMI of less than 25 kg/m to determine coronary heart disease (CHD) prevalence, all-cause mortality. METHODS: : Patients (n = 4,597) who had a BMI of 25 kg/m or greater at the time of initial visit to the prevention clinic were asked to report their weight at graduation from HS. Patients with BMI of 25 kg/m or greater in HS (n = 1,285) were compared with patients (n = 3,312) with a BMI of less than 25 kg/m in HS. Prevalent CHD was assessed at entry. Patient mortality was assessed using the Social Security Death Index for a maximum of 7 years after the initial visit. RESULTS: : Mean/median values for most CHD risk factors were higher in the group with an HS BMI of 25 kg/m or greater, with the exception of low-density lipoprotein level (120 vs 132 mg/dL; P < .001), Lipoprotein (a) level (16 vs 19 mg/dL; P = .003), and systolic blood pressure (126 vs 128. 3 mm Hg; P < .001). Patients with an HS BMI of 25 kg/m or greater had a higher mean BMI at initial visit (33.9 vs 30.1; P < .001) and hemoglobin A1c (6.8% vs 6.3%; P < .001) and glucose concentrations (93 vs 91 mg/dL; P = .004), with a lower mean high-density lipoprotein level (43.2 vs 46.5 mg/dL; P < .001) as well as greater prevalence of smoking (16.2% vs 11.4%; P < .001), diabetes mellitus (32.4% vs 21.8%; P < .001), CHD (47.1% vs 43%; P = .01), and specifically myocardial infarction (25.8% vs 21.1%; P = .001). Fibrinogen and urine albumin-to-creatinine levels were elevated. After adjusting for risk factors, an HS BMI of 25 kg/m or greater was associated with a 21% higher prevalence of CHD (odds ratio, 1.20; P = .027). However, an HS BMI of 25 kg/m or greater was not a significant predictor of 7-year mortality (hazard ratio, 1.03; P = .84). CONCLUSION: : Patients with an HS BMI of 25 kg/m or greater had more CHD risk factors compared with those with an HS BMI of less than 25 kg/m. Prevalence of CHD was also significantly higher in this group. However, an HS BMI of 25 kg/m or greater was not a significant predictor of mortality. PMID- 20168190 TI - Commentary: time to treatment for acute coronary syndromes: the cost of indecision. PMID- 20168191 TI - Evidence that the brief symptom inventory can be used to measure anxiety quickly and reliably in patients hospitalized for acute myocardial infarction. AB - BACKGROUND: : Anxiety is not routinely assessed in patients hospitalized for acute myocardial infarction (AMI). Failure to identify and treat patients who are anxious after AMI makes them more vulnerable to the adverse effects of anxiety, including higher complication rates. The anxiety subscale of the Brief Symptom Inventory (BSI) is a simple, reliable measure of anxiety with minimal patient burden. However, there is limited evidence of reliability and validity of the BSI as a measure of anxiety in patients hospitalized for AMI. OBJECTIVE: : The aim of this study was to provide evidence for the reliability and validity of the BSI in hospitalized AMI patients. METHOD: : A total of 536 patients admitted for AMI (62 +/- 14 years of age, 66% men, 85% white, 27% with previous myocardial infarction) completed the BSI and the state portion of the State Anxiety Inventory (SAI) within 72 hours of admission. Internal consistency reliability, criterion-related validity, and construct validity of the BSI were tested. RESULTS: : There was sufficient evidence of internal consistency (Cronbach alpha = .87), which supported the reliability of the BSI. There was evidence of criterion-related validity based on the Spearman rho correlation coefficient of 0.70 (P < .001) between BSI and SAI scores. Anxious patients had higher complication rates than did nonanxious patients (BSI, 1.31 +/- 0.13 vs 0.82 +/- 0.08, respectively, P < .001; SAI, 1.34 +/- 0.13 vs 0.80 +/- 0.07, respectively, P < .001), demonstrating adequate construct validity. In a logistic regression, BSI scores were independent predictors of in-hospital complications after controlling for sociodemographic and clinical variables, which further supported construct validity. CONCLUSION: : These results provide support for the BSI as a reliable, valid instrument for measuring anxiety in patients hospitalized for AMI. PMID- 20168192 TI - Shared medical appointments after cardiac surgery-the process of implementing a novel pilot paradigm to enhance comprehensive postdischarge care. AB - To facilitate the physical and emotional needs of patients undergoing cardiac surgery and their families, our Cardiac Surgery Outpatient Clinic at Cleveland Clinic, a nonprofit multispecialty academic medical center in Cleveland, Ohio, decided to implement a trial of a novel care delivery paradigm called Shared Medical Appointments (SMAs). The purpose of this venture was to facilitate timely access to care 3 to 5 days after hospital discharge, include family members in the education process and the care of the patient, and provide a forum for support and shared learning among patients who have been through like surgical experiences. The clinic system, which performed 3,597 open heart surgeries and 213 robotically assisted cardiac surgeries in 2008, already used family education classes to provide instruction to the patients and family prior to surgery. Because this medium was an effective way to disseminate knowledge, we theorized that using an SMA would be an effective strategy to provide timely medical care after discharge and garner support, education, and increased access to timely medical care after discharge. Although there were many physicians in subspecialties performing these types of clinic visits at our institution since 2002, by the spring of 2007, a group of cardiothoracic nurses decided to perform a trial on this model in this cohort of patients and be a fully nurse-led SMA to provide comprehensive care after discharge. Preliminary patient satisfaction surveys have revealed that 92% of post-cardiac surgery patients rated the experience as good or excellent, and 82% would prefer an SMA for their next clinic visit rather than an individual visit. These data are consistent with physician-led SMA satisfaction surveys in our organization to date. Although still in its relative infancy, an SMA for this cohort appears to have merit in enhancing the support and education as well as providing for the complex medical needs of these patients. PMID- 20168193 TI - The efficacy of a motivational nursing intervention based on the stages of change on self-care in heart failure patients. AB - BACKGROUND AND RESEARCH OBJECTIVE: : Heart failure (HF) patients experience frequent episodes of decompensation. While medication and behavior change play a major role in maintaining physiological stability, patient adherence to self-care recommendations is not optimal. The Theory of Heart Failure Self-care helped to understand the concepts of self-care and chose a model of intervention. Conviction and confidence are central factors in facilitating self-care. Motivational interviewing (MI), which aims to strengthen conviction and confidence, has been shown to improve self-care. In addition, the Transtheoretical Model, based on patients' readiness to change, also has proven efficacy. The MI based on the stages of change (MISC), a combination of MI and Transtheoretical Model, offers promise for improving self-care. The goal of this pilot study was to evaluate the preliminary effect of an MISC intervention on HF patients' self-care behaviors. SUBJECTS AND METHOD: : Thirty patients were recruited from an HF clinic and randomly assigned to an experimental (EG) or control group (n = 15/group). Patients from the EG received 3 interventions (1 in person, 2 on the phone). Data were collected at baseline and at 1 month after randomization. The effect of the intervention was assessed on 5 self-care outcomes using analysis-of-covariance models. RESULTS AND CONCLUSION: : Significant results were obtained regarding the confidence in performing self care behaviors specific to HF (P =.005). Although the results of the other hypotheses were not statistically significant, for the majority, trends were in the expected direction in favor of the EG. The study suggests that an MISC intervention is useful to increase patients' confidence in HF self-care and has potential to improve self-care. Further research is needed. PMID- 20168194 TI - Heart failure symptom assessment and management: can caregivers serve as proxy? AB - BACKGROUND: : Caregivers (CGs) of heart failure (HF) patients are increasingly assuming greater responsibilities in symptom assessment, evaluation, and decision making and may be asked to serve as proxies. The purpose of this study was to examine the degree of congruence between HF patients and their primary CG on symptom assessment and self-care management behaviors. METHODS: : The sample consisted of 70 HF patients receiving home healthcare and their designated CG. Patients were primarily between 40 and 85 years of age and female (60%). Caregivers were predominately female (76%) and spouses (43%). Congruence in symptom assessment and management between HF patients and their designated CGs was measured in this descriptive cross-sectional study using the Heart Failure Symptom Survey and Self-care of Heart Failure Index. RESULTS: : The Spearman correlation coefficient and concordance correlation coefficient were used to assess the degree of congruence on symptom evaluation scores from the Heart Failure Symptom Survey. Dyads had the strongest correlations on ratings of the HF patients' symptoms of extremity edema, difficulty concentrating, and dizziness. Lower congruence (Spearman correlation <0.40) was found on feeling depressed, shortness of breath at night, and shortness of breath when lying down. Scores on the Self-care of Heart Failure Index self-care management and self-care confidence scales were not significantly different within the HF dyads. CONCLUSIONS: : Based on moderate levels of correlations on most HF symptoms in this study, the CG as proxy appears to be a reasonable substitute for patient responses in a community setting. However, greater family preparation for symptom assessment is warranted to improve congruence for future symptom assessment. PMID- 20168195 TI - Foreword:addressing sexual function in cardiac patients: do we need guidelines? PMID- 20168196 TI - Sexual problems in cardiac patients: how to assess, when to refer. AB - It is increasingly realized that discussing sexuality is an important issue in the holistic care for cardiac patients. In this review article, the conditions of a good assessment of sexual problems are identified such as creating an appropriate environment, ensuring confidentiality, and using appropriate language. Second, we present different styles and approaches that can be used to start the assessment, differing between settings, persons, or disciplines. The PLISSIT (permission, limited information, specific suggestion, and intensive therapy) model can be helpful to initiate discussion about sexuality with the cardiac patient and his/her partner. This model is a stepwise approach using various levels of discussion or treatment. Open-ended question can facilitate discussion about sexual concerns, and validated questionnaires or diaries can be used to assess sexual problems. Patients with sexual concerns and problems should be counseled and/or treated appropriately, and adequate follow-up is needed. Additional training and research are needed to further improve the quality of sexual assessment and counseling in cardiac patients. PMID- 20168197 TI - Recognizing myocardial infarction in women. PMID- 20168198 TI - Brugada syndrome: unmasking a silent killer. PMID- 20168199 TI - Using continuous ST-segment monitoring. PMID- 20168200 TI - High prevalence of severe vitamin D deficiency in combined antiretroviral therapy naive and successfully treated Swiss HIV patients. AB - OBJECTIVES: To evaluate the prevalence of 25-hydroxyvitamin D [25(OH)D] deficiency in HIV-positive patients, a population at risk for osteoporosis. DESIGN: Retrospective assessment of vitamin D levels by season and initiation of combined antiretroviral therapy (cART). METHODS: 25(OH)D was measured in 211 HIV positive patients: samples were taken before initiation of cART from February to April or from August to October as well as 12 (same season) and 18 months (alternate season) after starting cART. 1,25-Dihydroxyvitamin D [1,25(OH)2D] was measured in a subset of 74 patients. Multivariable analyses included season, sex, age, ethnicity, BMI, intravenous drug use (IDU), renal function, time since HIV diagnosis, previous AIDS, CD4 cell count and cART, in particular nonnucleoside reverse transcriptase inhibitor (NNRTI) and tenofovir (TDF) use. RESULTS: At baseline, median 25(OH)D levels were 37 (interquartile range 20-49) nmol/l in spring and 57 (39-74) nmol/l in the fall; 25(OH)D deficiency less than 30 nmol/l was more prevalent in spring (42%) than in fall (14%), but remained unchanged regardless of cART exposure. In multivariable analysis, 25(OH)D levels were higher in white patients and those with a longer time since HIV diagnosis and lower in springtime measurements and in those with active IDU and NNRTI use. 1 Hydroxylation rates were significantly higher in patients with low 25(OH)D. Hepatitis C seropositivity, previous AIDS and higher CD4 cell counts correlated with lower 1,25(OH)2D levels, whereas BMI and TDF use were associated with higher levels. In TDF-treated patients, higher 1,25(OH)2D correlated with increases in serum alkaline phosphatase. CONCLUSION: Based on the high rate of vitamin D deficiency in HIV-positive patients, systematic screening with consideration of seasonality is warranted. The impact of NNRTIs on 25(OH)D and TDF on 1,25(OH)2D needs further attention. PMID- 20168201 TI - Safety and efficacy of tenofovir/emtricitabine plus nevirapine in HIV-infected patients. AB - All 178 HIV-infected individuals who had initiated tenofovir-emtricitabine nevirapine (TDF/FTC/NVP) at our institution and were adherent to their medication were retrospectively examined. Only 22% were antiretroviral naive. After a median follow-up of 16 months, only five (2.8%) individuals (all with prior exposure to other antiretroviral regimens) experienced virological failure. In all instances, viral rebound occurred after 12 weeks of therapy. These results do not support an increased risk of early virological failure using TDF/FTC/NVP. PMID- 20168203 TI - Adenovirus 5 serotype vector-specific immunity and HIV-1 infection: a tale of T cells and antibodies. PMID- 20168202 TI - HIV RNA level in early infection is predicted by viral load in the transmission source. AB - OBJECTIVE: HIV-1 viral load in early infection predicts the risk of subsequent disease progression but the factors responsible for the differences between individuals in viral load during this period have not been fully identified. We sought to determine the relationship between HIV-1 RNA levels in the source partner and recently infected recipient partners within transmission pairs. METHODS: We recruited donor partners of persons who presented with acute or recent (<6 months) HIV infection. Transmission was confirmed by phylogenetic comparison of virus sequence in the donor and recipient partners. We compared viral load in the donor partner and the recipient in the first 6 months of HIV infection. RESULTS: We identified 24 transmission pairs. The median estimated time from infection to evaluation in acutely/recently infected recipient individuals was 72 days. The viral load in the donor was closely associated with viral load at presentation in the recipient case (r = 0.55, P = 0.006). CONCLUSION: The strong correlation between HIV-1 RNA levels within HIV transmission pairs indicates that virus characteristics are an important determinant of viral load in early HIV infection. PMID- 20168205 TI - HIV is associated with thrombophilia and high D-dimer in children and adolescents. AB - BACKGROUND AND OBJECTIVE: Atherosclerosis and other cardiovascular diseases associated with thrombosis appear more relevant and anticipated in HIV-infected patients after combination antiretroviral therapy (cART) has reduced AIDS-related diseases and has improved survival. The association between viral replication and coagulation abnormalities in a cohort of HIV-infected children and adolescents was investigated here. METHODS: Protein S, protein C anticoagulant and antithrombin activity, together with fibrinogen, D-dimer, high-sensitive C reactive protein and homocysteine were assayed in a cross-sectional study among a cohort of HIV-infected children and adolescents. Results in patients with high viral load (HVL, HIV-RNA > 1000 copies/ml) were compared with those in patients with a lower replication (LVL), adjusting for other demographic, clinical and therapeutic covariates. RESULTS: Eighty-eight patients (mean age 13.5 years, CD4 30%, 72% with LVL) were enrolled. A prevalence of protein S and protein C deficiency of 51 and 8% was, respectively, found. HVL group compared to LVL showed a significant reduction of protein S, protein C and antithrombin activities, and an increase of D-dimer levels. The independent association of HVL with decreased protein S activity (-11.2%, P = 0.04) and increased D-dimer levels (+0.13 microg/ml, P = 0.004) was confirmed in the multivariate model. CONCLUSIONS: HIV-infected children and adolescents present high prevalence of thrombophilic abnormalities. The multivariate model confirmed that high viral replication is independently associated with decrease of protein S and increase of D-dimer, suggesting the advantage of suppressive therapy on coagulation homeostasis and the opportunity of an active control of cardiovascular risk factors starting at a younger age. PMID- 20168206 TI - Circumcision status and HIV infection among MSM: reanalysis of a Phase III HIV vaccine clinical trial. AB - OBJECTIVE: Determine whether male circumcision would be effective in reducing HIV transmission among men who have sex with men (MSM). DESIGN: Retrospective analysis of the VAXGen VAX004 HIV vaccine clinical trial data. METHODS: Survival analysis was used to associate time to HIV infection with multiple predictors. Unprotected insertive and receptive anal sex predictors were highly correlated, thus separate models were run. RESULTS: Four thousand eight hundred and eighty nine participants were included in this reanalysis; 86.1% were circumcised. Three hundred and forty-two (7.0%) men became infected during the study; 87.4% were circumcised. Controlling for demographic characteristics and risk behaviors, in the model that included unprotected insertive anal sex, being uncircumcised was not associated with incident HIV infection [adjusted hazards ratio (AHR) = 0.97, confidence interval (CI) = 0.56-1.68]. Furthermore, while having unprotected insertive (AHR = 2.25, CI = 1.72-2.93) or receptive (AHR = 3.45, CI = 2.58-4.61) anal sex with an HIV-positive partner were associated with HIV infection, the associations between HIV incidence and the interaction between being uncircumcised and reporting unprotected insertive (AHR = 1.78, CI = 0.90-3.53) or receptive (AHR = 1.26, CI = 0.62-2.57) anal sex with an HIV-positive partner were not statistically significant. Of the study visits when a participant reported unprotected insertive anal sex with an HIV-positive partner, HIV infection among circumcised men was reported in 3.16% of the visits (80/2532) and among uncircumcised men in 3.93% of the visits (14/356) [relative risk (RR) = 0.80, CI = 0.46-1.39]. CONCLUSIONS: Among men who reported unprotected insertive anal sex with HIV-positive partners, being uncircumcised did not confer a statistically significant increase in HIV infection risk. Additional studies with more incident HIV infections or that include a larger proportion of uncircumcised men may provide a more definitive result. PMID- 20168204 TI - Total body and spinal bone mineral density across Tanner stage in perinatally HIV infected and uninfected children and youth in PACTG 1045. AB - OBJECTIVE: To characterize total body bone mineral content (BMC) and total body and spinal bone mineral density (BMD) in perinatally HIV-infected and uninfected children/youth across puberty. DESIGN: HIV-infected (7-24 years) were randomly selected from six strata based on Tanner stage/protease inhibitor use. HIV uninfected were frequency-matched by Tanner group and sociodemographic background to the HIV-infected. METHODS: Dual-energy X-ray absorptiometry (DXA) measured BMC and BMD. Linear regression models tested differences in bone outcomes by HIV and the interaction of HIV by Tanner group (1-2, 3-4, 5). Models were performed separately by sex and adjusted for DXA scanner, race/ethnicity, height, age and lean body mass. RESULTS: HIV-infected (N = 236) and uninfected (N = 143) were comparable on sex and race/ethnicity. HIV-infected were slightly older (median 12.6 versus 11.9 years). In adjusted models, HIV-infected males had significantly lower total body BMC and total body and spinal BMD at Tanner 5, lower BMC at Tanner 3-4 and similar BMC and BMD at Tanner 1-2, compared to HIV-uninfected males. HIV-infected and uninfected girls did not differ significantly on any bone outcome, but there was a marginally significant interaction of HIV and Tanner group for spinal BMD. Kaletra/ritonavir was associated with lower BMC and total body BMD and nevirapine was associated with higher spinal BMD in a model with all HIV-infected. CONCLUSIONS: Perinatally HIV-infected males showed more evidence of lower bone density especially in the final stage of pubertal development than HIV infected girls and they may be at increased risk for bone disease during adulthood. PMID- 20168207 TI - Upregulation of nuclear-encoded mitochondrial LON protease in HAART-treated HIV positive patients with lipodystrophy: implications for the pathogenesis of the disease. AB - BACKGROUND: HAART can provoke metabolic changes and body fat redistribution, resulting in lipodystrophy, a side effect significantly involving mitochondrial function. Mitochondrial DNA (mtDNA) depletion caused by nucleosidic reverse transcription inhibitors is supposed to be a crucial mechanism in the pathogenesis of mitochondrial damages. METHODS: In adipose tissue from 22 HIV positive patients with lipodystrophy and 20 healthy controls, we analyzed gene expression by microarray analysis and real-time PCR. The most upregulated gene was further studied in the human adipocytic cell line SW872 by real-time PCR, western blot, transient transfection assays and flow cytometry. RESULTS: We identified 18 genes differently expressed between lipodystrophy patients and controls, and focused our attention on the nuclear-encoded mitochondrial protease LON, essential in mtDNA maintenance. In SW872 cells, treatment with stavudine (d4T) doubled LON levels, in parallel with mtDNA depletion. As d4T increased reactive oxygen species (ROS) intracellular content, we measured LON in presence of deoxyribose, which causes oxidative stress but not mtDNA depletion, and observed LON upregulation. Ethidium bromide, which markedly depletes mtDNA, did not alter LON levels. The antioxidant glutathione inhibited the increase of intracellular ROS and the increase in LON caused by d4T or deoxyribose. CONCLUSION: LON upregulation was due to d4T-induced ROS production, rather than due to mtDNA depletion, and represents a response to an oxidative stress. Other mechanisms than mtDNA depletion thus exist that explain nucleosidic reverse transcription inhibitors toxicity. This observation provides a rationale for possible therapeutic interventions aimed at reducing intracellular ROS content in patients assuming HAART. PMID- 20168208 TI - Reduced drug accumulation is more important in acquired resistance against oxaliplatin than against cisplatin in isogenic colon cancer cells. AB - Preclinical studies have indicated that there is only partial cross-resistance between cisplatin and oxaliplatin. The molecular background for this is incompletely known. To investigate the differences in resistance, we rendered a colon cancer cell line (S1) resistant against cisplatin and oxaliplatin and characterized the subclones with regard to cross-resistance, platinum uptake, and gene expression profiles. Four oxaliplatin and four cisplatin-resistant cell lines were produced from S1 by step-wise increasing the concentrations of the drugs in the growth medium. Cytotoxicity was determined by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and platinum accumulation in cell lysates and DNA preparations by inductively coupled plasma mass spectroscopy. Gene expression was investigated by cDNA microarrays. The protein expression of the ATP-binding cassette B1 (ABCB1) was measured by immunohistochemistry. The cisplatin-resistant cell lines were 1.5-6.2-fold resistant against cisplatin and the oxaliplatin-resistant sublines 2.6-17-fold resistant against oxaliplatin. There was a limited degree of cross-resistance. Oxaliplatin resistance could be explained to a larger degree by reduced drug accumulation whereas mechanisms for increased tolerance against platinum incorporation in DNA seemed to be of higher importance for resistance against cisplatin. A greater number of ABC transporters were upregulated in the oxaliplatin-resistant cell lines compared with those selected for cisplatin resistance. ABCB1 was highly overexpressed in the three most oxaliplatin resistant sublines, but significantly underexpressed in the two most cisplatin resistant cell lines. This was also confirmed by immunohistochemistry. However, functional tests did not show any increase in ABCB1 transport activity in the oxaliplatin-resistant sub-lines compared with S1. PMID- 20168209 TI - Application of Individualized Bayesian Urea Kinetic Modeling to pediatric hemodialysis. AB - Incorporating urea rebound using equilibrated urea concentration (Ceq) after hemodialysis (HD) is essential for accurate assessment of HD efficiency. It is impractical to measure Ceq in clinical settings, and there are no recommended methodologies to predict Ceq in children. The objective of this work is to assess the ability of an Individualized Bayesian Urea Kinetic Model (IBKM) for predicting Ceq in children receiving HD. Developed based on adult HD data, the IBKM is a two-pool urea kinetic model that calculates Bayesian estimates of individual Ceq. Blood urea nitrogen (BUN) samples from 30 HD sessions in 13 children (age 12-18 years) were taken at pre-HD, immediately post-HD, and 60 minutes post-HD (Ceq). The IBKM and estimated population parameters from adult data were fitted to the observed data from children to predict individual Ceq using NONMEM VI software in comparison with observed Ceq (9.5 +/- 3.8 mmol/L), the average individual predicted Ceq was 9.4 +/- 3.8 mmol/L, with absolute individual prediction error of 6.2% +/- 4.4%. For a given dialysis goal and desired dialysis duration, the required blood flow rate and dialyzer size are predicted by IBKM and confirmed by the analysis data. This study suggests that the IBKM can be used in a pediatric HD setting and accurately predict Ceq in children using only pre-HD and immediately post-HD BUN. PMID- 20168210 TI - Intracorporeal glucose disposal during hemodialysis after a standardized glucose load. AB - The aim of this study was to quantify intracorporeal clearance and disposal of glucose after the administration of a standardized glucose load during regular hemodialysis done in stable and non-diabetic patients and to account for effects of extracorporeal clearance. A standardized load of glucose was administered approximately 30 min after starting hemodialysis with a constant dialysate glucose of 5.0 +/- 0.2 mmol/L. Glucose in the arterial line blood and in dialysate outflow was measured at baseline and in short intervals for a period of 1 h after the infusion. Tests were repeated within 1 week. Nine patients completed the study. Extracorporeal blood and dialysate flows were 304 +/- 34 and 500 mL/min, respectively. The intracorporeal clearance of glucose was 327 +/- 137 mL/min and 69.1 +/- 9.4% of total glucose clearance. Mass balance assessed from dialysate samples showed that 60.1 +/- 10.5% of glucose injected was disposed intracorporeally. The fraction of intracorporeal clearance and the fraction of intracorporeal glucose disposal were highly correlated (r = 0.94, p < 0.0001). The fraction of glucose disposed in hemodialysis patients can be determined from the amount of glucose injected and from the amount of glucose removed extracorporeally during hemodialysis without blood sampling. This measure could be of interest in surveillance of glucose control in hemodialysis patients. PMID- 20168212 TI - Estradiol valerate elicits antidepressant-like effects in middle-aged female rats under chronic mild stress. AB - The purpose of this study was to analyze the antidepressant-like actions of estradiol valerate (1 or 2 mg/rat, single injection) or citalopram (5 or 10 mg/kg, chronically administered for 21 days) given independently or combined at low doses, to middle-aged ovariectomized female rats, as a model of human menopause. Animals were exposed to chronic mild stress, a model of depression that mimics anhedonia as revealed by diminished sucrose solution intake. Stressed rats decreased their sucrose preference 1 week after chronic stress and treatment with vehicle did not reverse this reduction. A single injection of estradiol valerate (2 mg/rat) produced an antidepressant-like action, evidenced as an increase in sucrose preference specific to stressed rats. Chronic citalopram (10 mg/kg) produced an antidepressant-like effect after 1 week. A single low-dose of estradiol valerate (1 mg/rat) did not potentiate or shorten the latency of action of chronic citalopram (5 mg/kg). These results reveal the antidepressant-like action of estrogens in middle-aged rats exposed to chronic stress. These data may be of importance for clinical depression in menopausal women. PMID- 20168211 TI - Effects of dopamine antagonists on drug cue-induced reinstatement of nicotine seeking behavior in rats. AB - Dopaminergic neurotransmission has been implicated in associative learning processes related to drugs of abuse. However, it is not clear whether blockade of activation of dopamine receptors alters conditioned incentive properties of nicotine-associated cues. Using a response-reinstatement procedure, this study examined the effects of antagonists selective for the D1 and the D2 subtypes of dopamine receptors on cue-induced reinstatement of nicotine-seeking behavior. Male Sprague-Dawley rats were trained in 30 daily 1 h sessions to intravenously self-administer nicotine (0.03 mg/kg/infusion) on a fixed ratio 5 schedule and associate a conditioned stimulus (cue) with each nicotine delivery. After extinction of responding by withholding nicotine (saline substitution) and its cue, the reinstatement tests were conducted following subcutaneous administration of a D1 antagonist SCH23390 (0, 5, 10, 30 microg/kg) or a D2 antagonist eticlopride (0, 5, 10, 30 microg/kg) in different groups of animals. Both SCH23390 and eticlopride significantly attenuated the magnitude of cue-elicited reinstatement of nicotine-seeking responding. These results indicate that activation of dopaminergic D1 and D2 receptors may play a role in mediating the conditioned motivational effects of nicotine-associated cues as measured in the response-reinstatement procedure. These findings suggest that manipulation of dopaminergic neurotransmission at D1 and/or D2 receptors may prove to be a potential target for the development of pharmacotherapy for prevention of environmental nicotine cue-triggered smoking relapse. PMID- 20168213 TI - The effects of nicotine, denicotinized tobacco, and nicotine-containing tobacco on cigarette craving, withdrawal, and self-administration in male and female smokers. AB - The effects of the acute administration of nicotine [through nicotine inhalers (NI) and placebo inhalers (PI)], nicotine-containing tobacco (NT), and denicotinized tobacco (DT), on smokers' subjective responses and motivation to smoke were examined in 22 smokers (12 male, 10 female; 11 low dependent, 11 high dependent). During four randomized blinded sessions, participants self administered NI, PI, NT, or DT, and assessed their effects using Visual Analogue Scales and the Brief Questionnaire of Smoking Urges. They could then self administer their preferred brand of cigarettes using a progressive ratio task. NT and DT were each associated with increased satisfaction and relaxation as well as decreased craving relative to the inhalers and NT increased ratings of stimulation relative to each of the other products. Both NT and DT delayed the onset of preferred tobacco self-administration relative to NI and PI but only NT reduced the total amount self-administered. Sex differences were evident in the effects of DT on withdrawal-related cravings with women experiencing greater DT induced craving relief than men. Findings suggest that DT is effective in acutely reducing many smoking abstinence symptoms, especially in women, but a combination of nicotine and non-nicotine tobacco ingredients may be necessary to suppress smoking behavior. PMID- 20168214 TI - Inhibitory influence of mecamylamine on ethanol withdrawal-induced symptoms in C57BL/6J mice. AB - Several reports show the involvement of neuronal nicotinic acetylcholine receptors (nAChRs) in the behavioral effects of ethanol, including ethanol drinking and relapse. Therefore, this study evaluated the effects of mecamylamine, a nAChR antagonist, on ethanol withdrawal signs. Ethanol dependence was induced in C57BL/6J mice by ethanol liquid diet administration. Animals were provided with nutritionally balanced control liquid diet (600 kcal/l) as their sole nutrient source on day 0; from days 1 to 4, 3% v/v of ethanol, followed by 6% v/v of ethanol (from days 5 to 7), and 10% v/v of ethanol (from days 8 to 10) were incorporated into the liquid diet. On day 11, ethanol liquid diet was replaced with nutritionally balanced control liquid diet, and ethanol withdrawal induced physical signs were recorded. Results showed that acute administration of mecamylamine (1-4 mg/kg, intraperitoneally) dose-dependently attenuated ethanol withdrawal-induced signs, and these effects were comparable with those of diazepam (1-2 mg/kg, intraperitoneally). In addition, chronic administration of mecamylamine into ethanol diet-fed mice markedly attenuated the ethanol withdrawal sign scores, thus supporting the contention that nAChR is involved in ethanol dependence. In conclusion, our results suggest that mecamylamine exhibited inhibitory effects on ethanol withdrawal signs which could be mediated through nAChR. PMID- 20168215 TI - Cosmetic product migration onto the ocular surface: exacerbation of migration after eyedrop instillation. AB - PURPOSE: Cosmetic product application may be an etiologic risk factor for dry eye syndrome. This study aimed to investigate whether a cosmetic product material (CPM) could migrate onto the ocular surface and whether eyedrop instillation might exacerbate this migration. METHODS: CPM was prepared by mixing equal volumes of hydroxyethyl cellulose gel (Scopisol; Senju Pharmaceutical Co. Ltd., Osaka, Japan) and a 10% fluorescein solution. Seventy-five female volunteers were randomly separated into three groups: the outer eyelash line group, in which CPM was applied on the upper and lower eyelids approximately 2 mm from the eyelash line; the eyelash line (EL) group, in which CPM was applied close to the eyelash line but without touching it; and the inner eyelash line group, in which CPM was applied on the eyelash line extending to the margin of the eyelids. The right eye was used for this study. At 5 and 30 minutes after CPM application, slit-lamp examination was carried out to detect fluorescence, an indication of CPM migration and contamination of the ocular surface. A strip of Schirmer test paper was used to collect tears, and the color of the paper was scored (contamination score: 0-5) to determine the relative quantity of CPM contamination on the ocular surface. In another set of experiments, 5 minutes after CPM application, one drop of balanced saline solution was instilled into the eye. Thirty seconds later, eyes were examined by slit-lamp microscopy and tears were collected to determine the migration percentage (eyes with CPM migration/total eyes) and contamination score. RESULTS: At 5 minutes after CPM application, the inner eyelash line group displayed a significantly higher migration percentage (96%) and average contamination score (3.35 +/- 0.77) compared with the outer eyelash line (12%; 0.15 +/- 0.34) and EL (20%; 0.35 +/- 0.32) groups. At 30 minutes, both the migration percentage and the average contamination score increased remarkably in the EL group (60% and 2.71 +/- 1.01). The migration percentage and average contamination score in the outer eyelash line group (P = 0.005 and P = 0.003, respectively) and EL group (P = 0.009 and P = 0.006, respectively) were significantly higher after eyedrop instillation compared with values before eyedrop instillation. CONCLUSION: CPM can migrate onto the ocular surface when applied close to the eyelid margin. This migration increases with time and can be exacerbated by eyedrop instillation. PMID- 20168216 TI - Prevalence of lid wiper epitheliopathy in subjects with dry eye signs and symptoms. AB - PURPOSE: The purpose of this study was to investigate the prevalence of lid wiper epitheliopathy (LWE) in patients diagnosed with dry eye disease (DED). METHODS: Patients were recruited for two groups. Inclusion criteria for the DED group (n = 50) was: a score greater than 10 with the Standard Patient Evaluation of Eye Dryness questionnaire, fluorescein break-up time 5 seconds or less, corneal and conjunctival staining with fluorescein, lissamine green Grade 1 or greater (scale 0-3), and Schirmer test with anesthesia 5 mm or less. For the asymptomatic group (n = 50), inclusion criteria were: no dry eye symptoms, fluorescein break-up time 10 seconds or greater, no corneal or conjunctival staining, and Schirmer test 10 mm or greater. Sequential instillations (n = 2, 5 minutes apart) of a mixture of 2% fluorescein and 1% lissamine green solution were used to stain the lid wipers of all patients. LWE was graded (scale 0-3) using the horizontal lid length and the average sagittal lid widths of the stained wiper. RESULTS: In symptomatic patients, 88% had LWE, of which 22% was Grade 1, 46% Grade 2, and 20% Grade 3. In asymptomatic patients, 16% had LWE, of which 14% was Grade 1, 2% was Grade 2, and 0% Grade 3. The difference in prevalence of lid wiper staining between groups was significant (P < 0.0001). CONCLUSIONS: The prevalence of LWE was six times greater for the DED group and the prevalence of LWE Grade 2 or greater was 16 times greater for the DED group than for the control group. These data further establish LWE as a diagnostic sign of dry eye disease. PMID- 20168217 TI - Deep anterior lamellar keratoplasty versus penetrating keratoplasty for keratoconus: a clinical trial. AB - PURPOSE: To compare deep anterior lamellar keratoplasty (DALK) using the big bubble technique to penetrating keratoplasty (PK) in patients with keratoconus. MATERIALS AND METHODS: In this clinical trial, patients with moderate to advanced keratoconus with poor spectacle-corrected visual acuity and intolerant to contact lens wear were enrolled. DALK was performed using the big-bubble technique, and a full-thickness donor cornea without Descemet membrane was sutured to the recipient bed. PK was performed conventionally with a Hessburg-Barron suction trephine. Three types of suturing were used for both groups. Postoperative refractive errors, best-corrected visual acuity (BCVA), contrast sensitivity function (CSF), and higher order aberrations (HOAs) were compared between the study groups. RESULTS: The study included 81 eyes of 81 patients. Forty-six eyes underwent DALK from which 4 were excluded because of failure to achieve bared Descemet membrane. Thirty-five eyes received PK. Mean patient age was 26.91 +/- 7.9 versus 30.89 +/- 10.3 years in the DALK and PK groups, respectively (P = 0.06). Mean follow-up period was 22.0 +/- 7.9 months in the DALK group and 24.6 +/- 3.5 months in the PK group (P = 0.32). Mean postoperative spherical equivalent refractive error was -3.23 +/- 3.4 diopters in the DALK group versus 2.22 +/- 4.6 diopters in the PK group (P = 0.28), and mean postoperative BCVA was 0.18 +/- 0.08 and 0.15 +/- 0.10 logarithm of the minimum angle of resolution, respectively (P = 0.12). CSF and total aberrations and HOAs were comparable in the study groups. CONCLUSIONS: DALK is an effective alternative surgical procedure for patients with keratoconus; the outcomes are comparable to PK in terms of refractive errors, BCVA, CSF, and HOAs. PMID- 20168218 TI - Presumed corneal copper deposition and oral contraceptive use. AB - PURPOSE: To report a case of presumed bilateral corneal copper deposition secondary to oral contraceptive use. METHODS: A 23-year-old woman was referred for evaluation of bilateral corneal opacities. The location of the deposits deep in Descemet's membrane and appearance made copper deposition a likely consideration. RESULTS: Subsequent laboratory results revealed an elevated serum copper level (189 MUg/dL). Other causes of cupremia were subsequently ruled out, and the patient's corneal copper deposition was attributed to her oral contraceptive use. With cessation of the oral contraceptive, her serum copper levels normalized, but the corneal deposits remained after 5 months of follow up. CONCLUSION: To our knowledge, we report the first case in the ophthalmic literature of presumed corneal copper deposition in the setting of oral contraceptive use. It is important to recognize the corneal findings associated with copper deposition, because it may lead to the diagnosis and treatment of other serious systemic conditions causing elevated serum copper levels. PMID- 20168219 TI - Laser scanning in vivo confocal microscopy in a case of Terrien marginal degeneration. AB - PURPOSE: To describe corneal microstructural modifications in an early case of Terrien marginal degeneration by means of laser scanning in vivo corneal confocal microscopy. METHODS: A 20-year-old man affected by Terrien marginal degeneration in his right eye was examined with the Heidelberg Retina Tomograph 2 with a Rostock Cornea Module. The patient presented a corneal lesion with marked superior thinning and no clinical signs of inflammation. The left eye showed no clinical signs of degeneration. RESULTS: The right eye showed irregular Bowman's membrane, amorphous-appearing substance co-localizing with lipid exudation, and needle-like hyperreflective material in the affected peripheral corneal region. Abnormally scarce and branched sub-basal plexus nerves as well as numerous activated keratocytes, sometimes organized in hyperreflective nests, were observed in the central cornea of the same eye. Although the left eye was clinically unaffected, activated keratocytes were detected in its anterior central stroma. CONCLUSIONS: In vivo confocal microscopy supports the hypothesis of a mild inflammatory state with an atypical sub-basal nerve pattern in a patient affected by Terrien marginal degeneration. This new technique shows promise in studying this still elusive pathology. PMID- 20168220 TI - Post-traumatic fungal keratitis caused by Carpoligna sp. AB - PURPOSE: To report the first case of fungal keratitis caused by presumed Carpoligna species. METHODS: A 37-year-old gardener sustained a full-thickness, stellate corneal laceration while cutting wood outdoors with a circular saw. Two months after surgical repair, he developed a severe infectious keratitis with descemetocoele at the apex of the original stellate laceration. RESULTS: Culture results confirmed fungal elements without evidence of bacteria. Oral and topical voriconazole were initiated. Due to compliance and cost issues, voriconazole was replaced with natamycin 5% prior to discharge from hospital. The patient improved and healed without perforation. The patient was left with a central stromal scar. DNA extraction from the fungal colony allowed PCR amplification of the 28s ribosomal RNA region of the fungus that led to the diagnosis of Carpoligna pleurothecii. Corticosteroids were never used during the patient's treatment. CONCLUSION: This is the first reported case of infectious keratitis caused by presumed Carpoligna species. The treatment for Carpoligna pleurothecii keratitis includes voriconazole, natamycin, and possibly amphotericin B. PMID- 20168221 TI - Impact of the attainment of current recommended low-density lipoprotein cholesterol goal of less than 70 mg/dl on clinical outcomes in very high-risk patients treated with drug-eluting stents. AB - OBJECTIVE: We sought to evaluate whether the attainment of low-density lipoprotein cholesterol (LDL-C) goal of less than 70 mg/dl would affect clinical outcomes in Korean patients treated with drug-eluting stents (DES). BACKGROUND: The current cholesterol guideline has strongly recommended reducing LDL-C to less than 70 mg/dl as the goal of therapy for very high-risk patients. METHODS: From 2003 to 2006, a total of 1347 very high-risk patients were treated with DES. Among them, we identified 578 eligible patients with follow-up LDL-C within 6-8 months after DES and divided these patients into two groups based on the level of follow-up LDL-C: group A, follow-up LDL less than 70 mg/dl (n=234) and group B, LDL of at least 70 mg/dl (n=344). Then we analyzed the incidence of major adverse cardiac and cerebrovascular events [MACCE: death, myocardial infarction, target vessel revascularization (TVR), non-TVR, cerebrovascular accidents] of both the groups. RESULTS: During the follow-up (mean duration=30+/-10 months), group A showed a significantly lower TVR (6%) and MACCE rate (14%), compared with group B (TVR: 12%, P=0.032; MACCE: 24%, P=0.002). However, there was no difference in the rate of death, myocardial infarction, or cerebrovascular accidents between the two groups. By multivariate analysis, follow-up LDL-C level of less than 70 mg/dl was one of the significant predictors for the occurrence of MACCE (odds ratio=0.39, 95% confidence interval: 0.21-0.72, P=0.003) or TVR (odds ratio=0.39, 95% confidence interval: 0.20-0.76, P=0.005). CONCLUSION: This study showed that the attainment of LDL-C goal of less than 70 mg/dl was significantly associated with a lower MACCE or TVR rate in very high-risk Korean patients treated with DES. PMID- 20168222 TI - Airway pressure and flow monitoring. AB - PURPOSE OF REVIEW: We report on the evolution of airway pressure and flow monitoring from a pathophysiological tool to the cornerstone of ventilator induced lung injury (VILI) prevention. RECENT FINDINGS: Protective ventilatory strategies are based on reduction of volume and pressures delivered to the lungs. New evidence, which will need confirmation in further studies, suggests that transpulmonary pressure (alveolar pressure minus pleural pressure), could be used to titrate both the positive end-expiratory pressure (PEEP) level and the inspiratory pressure applied by the ventilator. A limited number of animal studies are strongly supporting a role for inspiratory flow on the development of VILI.Moreover, different airway flow patterns may affect secretion movement, both global, to the alveoli or the glottis, and regional, from lower to higher compliance regions. This intra-lung transfer may be a primary mechanism for the propagation of infections and inflammatory mediators.Alternative monitoring techniques (among others) are the rapid interrupter technique, which can be used to measure airway resistance and patients' inspiratory effort and the forced oscillation technique which could become a bedside technique to estimate recruitment/derecruitment and titrate PEEP. SUMMARY: Airway pressure and flow monitoring is essential for VILI prevention and for an appropriate setting of mechanical ventilation. PMID- 20168223 TI - Bedside assessment of mean systemic filling pressure. AB - PURPOSE OF REVIEW: The physiology of the venous part of the human circulation seems to be a forgotten component of the circulation in critical care medicine. One of the main reasons, probably, is that measures of right atrial pressure (Pra) do not seem to be directly linked to blood flow. This perception is primarily due to an inability to measure the pressure gradient for venous return. The upstream pressure for venous return is mean systemic filling pressure (Pmsf) and it does not lend itself easily to be measured. Recent clinical studies now demonstrate the basic principles underpinning the measure of Pmsf at the bedside. RECENT FINDINGS: Using routinely available minimally invasive monitoring of continuous cardiac output and Pra, one can accurately construct venous return curves by performing a series of end-inspiratory hold maneuvers, in ventilator dependent patients. From these venous return curves, the clinician can now finally obtain at the bedside not only Pmsf but also the derived parameters: resistance to venous return, systemic compliance and stressed volume. SUMMARY: Measurement of Pmsf is essential to describe the control of vascular capacitance. It is the key to distinguish between passive and active mechanisms of blood volume redistribution and partitioning total blood volume in stressed and unstressed volume. PMID- 20168224 TI - Neurophysiological testing in neurocritical care. AB - PURPOSE OF REVIEW: To summarize a consensus of European authorities about the applications of clinical neurophysiology in the ICU and, particularly, for a clinically useful management of individual patients. RECENT FINDINGS: Clinical neurophysiology is useful for diagnosis (epilepsy, brain death, and neuromuscular disorders), prognosis (anoxic ischemic encephalopathy, head trauma, and neurological disturbances of metabolic and toxic origin), and follow-up. The prognostic significance of each test varies as a function of coma etiology. A distinction should be made between tests whose abnormalities are indicative of a poor prognosis (bilateral absence of N20 in anoxic coma, abnormalities suggesting pontine involvement in head trauma) and those whose relative normalcy constitutes an argument for a good prognosis (integrity of brainstem conductions in head trauma, presence of cognitive evoked potentials - mismatch negativity, P300 - irrespective of coma etiology).The highlights of the recent literature mainly concern continuous neuromonitoring for early detection of nonconvulsive seizures, both in adult and neonatal ICU, brain entry into the ischemic penumbra zone, and neuronal functional consequences of intracranial hypertension. SUMMARY: The domain of clinical neurophysiology is similar to that of clinical examination and complementary to that of imaging techniques. It substantially improves the individual management of ICU patients. PMID- 20168225 TI - Therapeutic drug monitoring in the neurocritical care unit. AB - PURPOSE OF REVIEW: Various antiepileptics, sedative and anesthetic agents are used in the neurocritical care setting and therapeutic drug monitoring (TDM) has been proposed as a means to individualize dosing to ensure efficacy, avoid toxicity, and to account for drug-drug interactions. The purpose of this review is to highlight key articles relating to TDM published in the last 5 years with a focus on drug therapy for seizures, status epilepticus, and traumatic brain injury. RECENT FINDINGS: Current evidence supports TDM of first-generation antiepileptics, and free-level monitoring for phenytoin and valproic acid is recommended in the neurocritical care population. There are insufficient data to recommend routine TDM of second-generation antiepileptics at this time. In traumatic brain injury, routine TDM of barbiturate infusions appears to be of little value in guiding or evaluating patient response to therapy except to differentiate between drug-induced coma and brain death. Although TDM of sedative agents has been studied, the use of clinical sedation scales is preferred over TDM in evaluating a patient's level of sedation. SUMMARY: Therapeutic drug monitoring plays an important role in the care of patients in the neurocritical care setting but is applicable only to a limited number of drugs. PMID- 20168226 TI - Recent advances in nonalcoholic fatty liver disease. AB - PURPOSE OF REVIEW: This review focuses on recent advances in the study of the epidemiology, pathogenesis, natural history and treatment of nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS: Study of hepatic lipid metabolism, insulin resistance, mitochondrial dysfunction and oxidative stress, genetic variants and predisposition to altered metabolism and cell injury have contributed to our current understanding of NAFLD. Differential expression of microRNA in fatty liver and its implication in disease pathogenesis and therapeutic potential have continued to advance over the year. The pathogenesis of hepatocellular carcinoma in steatohepatitis continues to be explored. The diagnostic utility of imaging and noninvasive markers seems promising in estimating the severity of steatosis and fibrosis. Liver biopsy remains the gold standard for accurately assessing NAFLD and steatohepatitis. Lifestyle modification and weight loss improve both metabolic profile and liver histology. Pharmacotherapy for the treatment of NAFLD remains lacking. SUMMARY: The underlying mechanism and pathogenesis of NAFLD remain elusive despite ongoing researches to make significant advances in the understanding of its natural history, pathogenesis and management. Pharmacotherapy has yet to indicate a promising therapeutic intervention. Current treatment focuses on managing underlying cardio-metabolic risks. PMID- 20168227 TI - Ampullary cancer. AB - PURPOSE OF REVIEW: This manuscript reviews the recent literature on ampullary cancer, including new staging definitions, histological characteristics and treatment options. RECENT FINDINGS: Recent publications emphasize the importance of the histological differentiation (intestinal vs. pancreatobiliary), which is one of the most important prognostic factors for ampullary cancer. These histological subtypes can be differentiated by immunohistochemistry: while positivity for mucin-2 (MUC2) and caudal homeobox gene transcription factor-2 (CDX2) excludes the pancreatobiliary subtype, positivity for MUC1 and cytokeratin 17 (CK17) excludes the intestinal subtype. Also, different mechanisms of cancer development have been described, which might be related to the type of differentiation. Due to the very low risk of lymphatic spread, local resections appear sufficient for well differentiated T1 cancer smaller than 1 cm, whereas larger, less differentiated or more invasive cancer requires a radical resection. As cancer with intestinal differentiation shares a similar biology with colon cancer, and the pancreatobiliary differentiation is close to ductal adenocarcinoma of the pancreas, adjuvant chemotherapy should probably be given according to colon cancer (intestinal) and pancreatic cancer (pancreatobiliary), respectively. However, randomized trials are lacking. SUMMARY: The recent research suggests that the histological differentiation of periampullary cancer is more important than the anatomical location (ampulla). Future studies are required to take this emerging issue into account. PMID- 20168228 TI - New approaches to neuroimaging of central nervous system inflammation. AB - PURPOSE OF REVIEW: Inflammation is an important component not only in autoimmune but also in ischemic/degenerative disorders of the central nervous system (CNS). We here review magnetic resonance imaging (MRI)-based techniques to visualize neuroinflammation in vivo. RECENT FINDINGS: Iron oxide particles such as superparamagnetic iron oxide (SPIO) and ultrasmall SPIO (USPIO) are phagocytosed by hematogeneous macrophages upon systemic application into the circulation and allow in-vivo tracking of infiltration to the CNS due to their paramagnetic effect by MRI in experimental CNS disorders, and also in multiple sclerosis and stroke. Thereby, the size and application scheme of the iron particles is critical for interpretation of the MRI data which in addition to neuroinflammation involves passive diffusion and intravascular trapping. Targeting of inflammatory, activation-dependent enzymes such as myeloperoxidase or immune function molecules by MR contrast agents represents a molecular approach to visualize critical steps of lesion development caused by neuroinflammation. Clinical studies with Gd-DTPA in conjunction with experimental investigations employing more sensitive MR contrast agents such as gadofluorine revealed that breakdown of the blood-brain barrier and SPIO/USPIO-related macrophage infiltration occur mostly independently. SUMMARY: Cellular and targeted molecular MRI provides important insights into the dynamics of neuroinflammation. PMID- 20168229 TI - Mechanisms of cerebral edema in traumatic brain injury: therapeutic developments. AB - PURPOSE OF REVIEW: Although a number of factors contribute to the high mortality and morbidity associated with traumatic brain injury (TBI), the development of cerebral edema with brain swelling remains the most significant predictor of outcome. The present review summarizes the most recent advances in the understanding of mechanisms associated with development of posttraumatic cerebral edema, and highlights areas of therapeutic promise. RECENT FINDINGS: Despite the predominance of cytotoxic (or cellular) edema in the first week after traumatic brain injury, brain swelling can only occur with addition of water to the cranial vault from the vasculature. As such, regulation of blood-brain barrier permeability has become a focus of recent research seeking to manage brain edema. Aquaporins, matrix metalloproteinases and vasoactive inflammatory agents have emerged as potential mediators of cerebral edema following traumatic brain injury. In particular, kinins (bradykinins) and tachykinins (substance P) seem to play an active physiological role in modulating blood-brain barrier permeability after trauma. Substance P neurokinin-1 receptor antagonists show particular promise as novel therapeutic agents. SUMMARY: Attenuating blood-brain barrier permeability has become a promising approach to managing brain edema and associated swelling given that increases in cranial water content can only be derived from the vasculature. Inflammation, both classical and neurogenic, offers a number of attractive targets. PMID- 20168230 TI - Pediatric genitourinary tumors. AB - PURPOSE OF REVIEW: To review the 2008-2009 literature on pediatric genitourinary tumors and highlight the most significant publications. RECENT FINDINGS: New techniques such as gene expression profiling, PET, nephron-sparing surgery, and stem cell transplantation are being incorporated into contemporary treatments for pediatric patients with genitourinary tumors. The WTX gene is the most commonly mutated gene in Wilms tumor, and its product enhances Wilms tumor gene 1-mediated transcription. Germline WTX mutations cause an X-linked sclerosing bone dysplasia but do not appear to predispose to Wilms tumor formation. Protocadherin gene clusters on chromosome 5q31 may act as tumor suppressors. In rhabdomyosarcoma, ILK and platelet-derived growth factor receptor-A join the paired box gene 7 and 3-forkhead box O1 fusions as potential therapeutic targets, and muscle-specific microRNAs offer promise as adjuvant therapy. Despite the high cure rate of Wilms tumor, long-term survivors remain at risk of death from various causes. SUMMARY: In general, the prognosis for patients with pediatric genitourinary tumors is favorable. The elucidation of the molecular abnormalities in these tumors is determining risk stratification, treatment strategies, and candidates for new drug development. PMID- 20168231 TI - New developments in sentinel node staging in melanoma: controversies and alternatives. AB - PURPOSE OF REVIEW: Melanoma incidence is increasing worldwide. Elective lymph node dissections (ELNDs) could not improve survival. The sentinel node is a targeted approach to occult lymph node metastases. There are controversies regarding the sentinel node procedure for melanoma, with regard to false-negative rates, therapeutic benefit and alternatives, such as ultrasound. The clinical relevance of minimal sentinel node tumor burden is unclear. This review analyzes these issues. RECENT FINDINGS: Through the pathological work-up of the sentinel node, the sentinel node has become an independent prognostic factor for survival in melanoma. False-negative rates of the sentinel node procedure are generally an underestimation, due to incorrect calculations. A subgroup analysis of the Multicenter Selective Lymphadenectomy Trial (MSLT)-1 seemed to demonstrate a survival benefit, but is criticized for a number of reasons. Potentially, a subgroup of sentinel node-positive patients is prognostically false-positive, with dormant metastases, which might not become viable disease. SUMMARY: Sentinel node tumor burden is an extra dimension to predict prognosis, although we have not yet identified the correct group to undergo a completion lymph node dissection. The MSLT-2 and MINITUB studies are analyzing this issue. The EORTC recommends the Rotterdam criteria as the most reproducible and accurate measure of sentinel node tumor burden. Ultrasound-guided fine needle aspiration cytology is emerging as a potential cost-effective alternative. PMID- 20168232 TI - The role of food allergy in otolaryngology disorders. AB - PURPOSE OF REVIEW: Food allergy is often an unrecognized clinical entity that has been implicated as a cause in many types of chronic inflammatory conditions. This review serves to provide an update on how food allergy plays a role in otolaryngology disorders. RECENT FINDINGS: The incidence of food allergy has been on the rise over the last decade. Currently, about 6% of children and 3-4% of adults are thought to be affected by food allergy. The middle and inner ear are immunologically responsive and this includes responsiveness to food hypersenstivities. Both chronic otitis media with effusion and Meniere's disease can improve with treatment of food allergies. Some evidence supports a link between rhinitis and nasal polyps and food allergies. Finally, there is increasing literature about eosinophilic esophagitis, which is a relatively newly recognized disease with many otolaryngologic associations. Many of these patients may have food allergy, and treatment of their food allergy may be effective in treating the disease. SUMMARY: In chronic inflammatory disorders of the head and neck, especially those involving the upper aerodigestive tract, food allergy must be considered in the differential. Patients with food allergy often do not respond to conventional treatments, and it can often be a challenge to arrive at the proper diagnosis. Further research is warranted to improve our understanding of the role of food allergy in otolaryngology disorders, as well as our diagnostic and treatment methods. PMID- 20168233 TI - The role of the head and neck surgeon in contemporary multidisciplinary treatment programs for advanced head and neck cancer. AB - PURPOSE OF REVIEW: The advent of contemporary multidisciplinary treatment programs for head and neck cancer has led to a shift away from primary surgery for advanced pharyngeal and laryngeal carcinomas, in favor of concurrent chemoradiation therapy. Although primary surgical resection may no longer be the most commonly selected initial therapy for these patients, the head and neck surgeon should remain a key participant in their multidisciplinary care. We review the various ways in which the head and neck surgeon contributes to the care of these patients. RECENT FINDINGS: The surgeon fills many critical roles throughout chemoradiation therapy of advanced head and neck cancer, including initial diagnosis and staging, selection of initial therapy, pretreatment airway and nutritional support, patient assessment during and following therapy, evaluation of tumor response, salvage surgery, and management of late effects following chemoradiation therapy. SUMMARY: Continued involvement by a head and neck surgeon throughout all of the phases of chemoradiation therapy of patients with advanced head and neck cancer should be maintained by the multidisciplinary team. PMID- 20168234 TI - Current cardiovascular risk management patterns with special focus on lipid lowering in daily practice in Switzerland. AB - BACKGROUND: There may be a considerable gap between LDL cholesterol (LDL-C) and blood pressure (BP) goal values recommended by the guidelines and results achieved in daily practice. DESIGN: Prospective cross-sectional survey of cardiovascular disease risk profiles and management with focus on lipid lowering and BP lowering in clinical practice. METHODS: In phase 1, the cardiovascular risk of patients with known lipid profile visiting their general practitioner was anonymously assessed in accordance to the PROCAM-score. In phase 2, high-risk patients who did not achieve LDL-C goal less than 2.6 mmol/l in phase 1 could be further documented. RESULTS: Six hundred thirty-five general practitioners collected the data of 23 892 patients with known lipid profile. Forty percent were high-risk patients (diabetes mellitus or coronary heart disease or PROCAM score >20%), compared with 27% estimated by the physicians. Goal attainment rate was almost double for BP than for LDL-C in high-risk patients (62 vs. 37%). Both goals were attained by 25%. LDL-C values in phase 1 and 2 were available for 3097 high-risk patients not at LDL-C goal in phase 1; 32% of patients achieved LDL-C goal of less than 2.6 mmol/l after a mean of 17 weeks. The most successful strategies for LDL-C reduction were implemented in only 22% of the high-risk patients. CONCLUSION: Although patients at high cardiovascular risk were treated more intensively than low or medium risk patients, the majority remained insufficiently controlled, which is an incentive for intensified medical education. Adequate implementation of Swiss and International guidelines would expectedly contribute to improved achievement of LDL-C and BP goal values in daily practice. PMID- 20168235 TI - Methicillin-resistant Staphylococcus aureus in skin and soft tissue infections presenting to the Emergency Department of a Canadian Academic Health Care Center. AB - OBJECTIVES: This study aimed to estimate the city-wide prevalence of methicillin resistant Staphylococcus aureus (MRSA) in patients (>=18 years old) presenting with skin and soft tissue infections (SSTIs) to the emergency departments (EDs) of a Canadian Academic Health Care Center. Secondary objectives were to identify demographic and clinical variables associated with MRSA, and determine MRSA antimicrobial susceptibilities and genotypes. METHODS: This prospective observational study was conducted over 2 months. Participants completed a Health and Lifestyle Questionnaire. Cultures of the infection site, nares, and throat were obtained and MRSA isolates were confirmed by polymerase chain reaction. Patient characteristics were summarized using descriptive statistics and MRSA prevalence and 95% confidence intervals were estimated using standard equations. Backwards stepwise multivariate logistic regression models determined predictor variables independently associated with MRSA colonization or infection. RESULTS: Of 205 patients, 35 (17.1%) were infected or colonized with MRSA. Seventy-eight (38.0%) of the infection site cultures grew S. aureus of which 27 (34.6%) were MRSA. Incarceration, known exposure to MRSA and involvement in competitive sports were significant predictors of MRSA SSTIs. Antimicrobial susceptibility among MRSA isolates was trimethoprim/sulfamethoxazole, vancomycin, gentamicin, and linezolid 100%, clindamycin 75%, ciprofloxacin 59.3%, and erythromycin 7.4%. Sixty-nine percent of MRSA cases fit the clinical definition of community associated; subsequently 77% were confirmed as CMRSA 10, a recognized community acquired MRSA. CONCLUSION: Community-acquired -MRSA is a significant pathogen of SSTIs in EDs of a Canadian teaching center. MRSA should be considered when initiating empiric antibiotic therapy, particularly in patients with risk factors. PMID- 20168236 TI - Trends of acute hepatitis B hospitalizations, comorbidities, fatality rate, and costs associated with the hospitalization in Spain (2001-2006). AB - INTRODUCTION: The objective of this study is to analyze data related to hospitalization, comorbidities, fatality rate, average stays, and costs associated with hospitalized cases of acute hepatitis B in Spain, during 2001 2006. METHODS: A retrospective study to analyze the characteristics of acute hepatitis B patients admitted to Spanish hospitals was performed using the minimum basic data set. Costs were calculated using the diagnosis-related groups for the disease. RESULTS: The total number of hospitalized patients diagnosed with acute hepatitis B was 2160, of which 73.8% were diagnosed in men. The highest rate corresponds to the group aged 20-39 years (2.33/100 000 inhabitants). Ninety deaths (4.2%) were reported out of the total hospitalized patients. The average hospital stay was 10 days. The trends in the rate of hospitalized acute hepatitis B cases were not statistically significant. There were no differences found in the average length of stay or in the cost during the study period. The estimated total cost was 7 451 098 euros. CONCLUSION: The rate of hospitalized acute hepatitis B patients in Spain did not change during the 2001-2006 period. Having an adequate surveillance system and continuing with the universal immunization and risk group programs, and health education, remain a high priority. PMID- 20168239 TI - Double right coronary artery or split right coronary artery: the same anomaly? PMID- 20168238 TI - Qualitative assessment of FMR1 (CGG)n triplet repeat status in normal, intermediate, premutation, full mutation, and mosaic carriers in both sexes: implications for fragile X syndrome carrier and newborn screening. AB - PURPOSE: Fragile X syndrome is caused by expansion and subsequent methylation of a CGG trinucleotide repeat in the FMR1 5'-untranslated region. Southern blot analysis is typically required to determine expansion size for triplet repeat lengths >200. We describe a triplet-primed polymerase chain reaction-based method using automated capillary electrophoresis detection for qualitative assessment of expanded CGG repeats. METHODS: The assay uses triplet-primed polymerase chain reaction in combination with GC-melting reagents and substitution of 7-deaza-2 deoxyGTP for dGTP. Amplicons are resolved by capillary electrophoresis. RESULTS: A distinctive pattern of tapering or "stutter" polymerase chain reaction amplification was evident on capillary electrophoresis in male and female patients harboring all expanded allele lengths examined (up to 2000 CGG repeats) and could be used to differentiate normal, intermediate, premutation, and full mutation alleles. Full mutation alleles exhibited an additional late-migrating amplicon on capillary electrophoresis. Mixing experiments demonstrated sensitivity as low as 1% for detection of the full mutation allele. In a 1275 sample concordance study against our existing polymerase chain reaction platform (with Southern blot analysis for repeat lengths >=55), the triplet-primed polymerase chain reaction method exhibited 100% concordance for normal, intermediate, expanded, and full mutation alleles. This method also detected the full mutation alleles in DNA isolated from blood spots. CONCLUSION: This assay provides an accurate assessment of FMR1 repeat status and holds promise for use in carrier and newborn screening. The method distinguishes normal homozygous females from full mutation carrying females. Although the method is not useful for accurate sizing, it supplements the classic polymerase chain reaction method and results in significant reduction in the number of Southern blot analyses required to be performed in the laboratory to accurately assess the FMR1 genotype in all individuals. PMID- 20168237 TI - Microbial contamination of contact lenses, lens care solutions, and their accessories: a literature review. AB - PURPOSE: A contact lens (CL) can act as a vector for microorganisms to adhere to and transfer to the ocular surface. Commensal microorganisms that uneventfully cohabitate on lid margins and conjunctivae and potential pathogens that are found transiently on the ocular surface can inoculate CLs in vivo. In the presence of reduced tissue resistance, these resident microorganisms or transient pathogens can invade and colonize the cornea or conjunctiva to produce inflammation or infection. METHODS: The literature was reviewed and used to summarize the findings over the last 30 years on the identification, enumeration, and classification of microorganisms adherent to CLs and their accessories during the course of normal wear and to hypothesize the role that these microorganisms play in CL infection and inflammation. RESULTS: Lens handling greatly increases the incidence of lens contamination, and the ocular surface has a tremendous ability to destroy organisms. However, even when removed aseptically from the eye, more than half of lenses are found to harbor microorganisms, almost exclusively bacteria. Coagulase-negative Staphylococci are most commonly cultured from worn lenses; however, approximately 10% of lenses harbor Gram-negative and highly pathogenic species, even in asymptomatic subjects. In storage cases, the incidence of positive microbial bioburden is also typically greater than 50%. All types of care solutions can become contaminated, including up to 30% of preserved products. CONCLUSIONS: The process of CL-related microbial keratitis and inflammation is thought to be preceded by the presence or transfer or both of microorganisms from the lens to the ocular surface. Thus, this detailed understanding of lens-related bioburden is important in the understanding of factors associated with infectious and inflammatory complications. Promising mechanisms to prevent bacterial colonization on lenses and lens cases are forthcoming, which may decrease the incidence of microbially driven CL complications. PMID- 20168240 TI - Case series of resection of pelvic leiomyoma extending into the right heart: surgical safeguards and clinical follow-up. AB - OBJECTIVE: To analyze the clinical features, surgical management and oncologic results of a series of six patients undergoing seven operations for resection of uterine leiomyoma extending into the right cardiac chambers. METHODS: A retrospective review of patients operated on for surgical resection of a pelvic leiomyomatous mass originating from the uterus and extending into the right cardiac chambers was performed. The most common symptoms at presentation were syncope and dyspnea; two patients were asymptomatic. Four patients had been misdiagnosed as having intracardiac thrombus or primary cardiac tumor. The intracardiac and upper intracaval portion was removed under circulatory arrest in moderate hypothermia; the remaining portion was removed by caval incision. In one patient with cardiogenic shock, the sole intracardiac portion of the mass was removed at primary surgery. A mean of 2.8 +/- 1.5 years of follow-up was available, consisting of clinical and radiological tests (computed tomography scan, echocardiography). RESULTS: There were no cases of operative mortality in the present series. No recurrence was observed at the end of the follow-up in all cases of complete resection of the mass from its intracardiac to its pelvic end. Conversely, in the only case in which partial resection was performed due to the patient's clinical condition, recurrence of the intracardiac involvement was observed 6 months after primary surgery. CONCLUSION: Radical resection is curative for uterine leiomyomatosis extending into the right cardiac chambers. Surgery can be afforded with acceptable risks. A high level of suspicion for intracardiac extension of pelvic leiomyomatosis should be retained in the presence of a floating mass within the right cardiac chambers. Such a finding should prompt radiographic evaluation of the abdomen and the pelvis. PMID- 20168241 TI - Treatment and outcome of nonmetastatic extraocular retinoblastoma with a uniform chemotherapy protocol. AB - Nonmetastatic extraocular retinoblastoma is a common entity in South-East Asia. We did a retrospective study of patients treated for isolated extraocular retinoblastoma, that is, International retinoblastoma staging system stages II and III, using a uniform chemotherapy protocol at our oncology center, between June 2003 and June 2008. Out of the 25 patients having nonmetastatic extraocular retinoblastoma, 6 were in stage II, and 19 in stage III. The probability of event free survival was 0.54 at 18 months of follow-up with no significant difference between the 2 stages and the presence of optic nerve involvement; 11 out of 13 relapses were systemic. This is the largest case series of nonmetastatic extraocular retinoblastoma from South-East Asia. PMID- 20168242 TI - Pediatric renal non-hodgkin lymphoma with inferior vena cava thrombosis. AB - Involvement of kidneys in disseminated lymphoma is common. Primary lymphoma of the kidney is rare and has varied imaging characteristics. Abdominal lymphadenopathy can result in encasement and narrowing of the retroperitoneal vessels occasionally causing thrombosis. We present a 12-year-old boy with renal lymphoma and inferior vena caval thrombus; discuss the rarity of this presentation as well as other differential diagnosis and the need for confirmation of histopathologic diagnosis before instituting therapy in pediatric renal tumors. PMID- 20168243 TI - Juvenile myelomonocytic leukemia presenting with features of neonatal hemophagocytic lymphohistiocytosis and cutaneous juvenile xanthogranulomata and successfully treated with allogeneic hemopoietic stem cell transplant. AB - Juvenile xanthogranuloma (JXG) is rarely associated with either hemophagocytic lymphohistiocytosis (HLH) or juvenile myelomonocytic leukemia (JMML) and when in association with the latter there is usually neurofibromatosis type 1. We report a child who presented with JXG and HLH during the neonatal period and who subsequently developed JMML during early infancy in whom there is no evidence of neurofibromatosis type 1. The patient was refractory to standard HLH therapy but he is well and is now 42 months after mismatched unrelated donor hemopoietic stem cell transplant without evidence of HLH or JMML. His JXG lesions show involution, in keeping with the expected natural history of this disorder. PMID- 20168244 TI - Esophageal strictures during treatment for acute lymphoblastic leukemia. AB - Esophageal stricture is a rare complication of paediatric cancer treatment that usually occurs after esophageal exposure to radiotherapy. We describe 4 cases of esophageal stricture during chemotherapy for acute lymphoblastic leukemia. All patients presented with refractory vomiting and were diagnosed with radiologic contrast studies. None of the patients had received radiotherapy. Esophageal candidiasis was seen in 2 patients but the remaining 2 patients had earlier systemic candidiasis. High-dose dexamethasone may predispose these children to both esophageal candidiasis and peptic esophagitis. The etiology of esophageal strictures during treatment for acute leukemia is likely to be multifactorial but systemic candidiasis may play a significant role. PMID- 20168245 TI - Clinical presentation and outcome of pediatric ovarian germ cell tumor: a study of 40 patients. AB - BACKGROUND: Germ cell tumor is a rare malignancy accounting for 3% of all pediatric tumors. They are highly curable malignancies. The aim of this study was to evaluate the clinical presentation, management, and outcome in this subset. METHODOLOGY: The study population included 40 patients with age less than 18 years at diagnosis. They were treated in Cancer Institute Chennai, India from 1990 to 2002. They were analyzed for the various clinical, pathologic presentations, and survival outcomes. Actuarial method was used to estimate the overall survival and relapse-free survival. RESULTS: The mean age of the study group was 14+2.7 years with most of the patients being postpubertal. The common histologies being mixed germ cell tumor (32%) and dysgerminoma (27%). Ten percent of patients presented with ovarian torsion. Sixty-two percent of patients presented in advanced stage. Fertility preservation surgery was possible in 70% of the patients. Relapses were seen in 25% of the patients. The median duration of follow-up was 7.5 years with a 5 years disease-free survival of 72.8% and overall survival of 94.9%. Most of the patients achieved a good quality of life with normal menstrual cycles. CONCLUSIONS: This study confirms an excellent outcome for girls with ovarian germ cell tumor, although majority of the patients presented in advanced stage. Patients with initial histology of Teratoma and Mixed germ cell tumor relapsed frequently. The mainstay of treatment being fertility preservation and cisplatin-based chemotherapy. PMID- 20168246 TI - Graft-versus-leukemia effect on infant lymphoblastic leukemia relapsed after sibling hematopoietic stem cell transplantation. AB - INTRODUCTION: Infant acute lymphoblastic leukemia (ALL) is considered a high-risk entity. Patients diagnosed in the first 3 months of life have especially high mortality. By morphology, infant ALL is classified as a lymphoid lineage leukemia; however, its physiologic behavior has brought many to consider it a pathologic hybrid between lymphoid leukemia and myeloid leukemias. As such, standard of care currently employs the use of chemotherapeutic agents used commonly in ALL protocols and agents typically reserved for the treatment of myelogenous lineage leukemias. The role of hematopoietic stem cell transplantation and graft-versus-leukemia effect in these patients has not been well studied. CASE PRESENTATION: An earlier healthy 9-week-old Hispanic male diagnosed with precursor B-cell lymphoblastic leukemia was treated with protocol P9407 and matched sibling hematopoietic stem cell transplantation. Relapse was noted on posttransplant day +114 with blasts on peripheral blood smear. The sole antigraft-versus-host disease (GVHD) agent, cyclosporine, was discontinued. Blast clearance from the peripheral blood was obtained by posttransplant day +128 with the appearance of skin and liver GVHD at posttransplant day +181. Bone marrow examination on posttransplant day +205 revealed normal marrow with no evidence of leukemic cells. He remains disease free more than 2 years posttransplant. CONCLUSION: Traditionally, graft-versus-leukemia effect was thought to contribute therapeutically little to the treatment of ALL by hematopoietic stem cell transplantation (HSCT). The effects of graft-versus-leukemia immunologic phenomenon in our patient with infant acute lymphoblastic leukemia underscore the potential that infant ALL may not be entirely the same biologic entity as standard pediatric ALL and may be more responsive than understood earlier. Therapeutic response and appearance of GVHD after the withdrawal of immunosuppression in this patient provides evidence that graft-versus-leukemia effect may play a role in disease control in infant ALL after HSCT. Patients who relapse after the HSCT may be salvaged with the withdrawal of immunosuppression. This suggests that other immunotherapeutic interventions in the context of relapse may offer potential clinical benefit in this disease. PMID- 20168247 TI - Serum carnitine levels in childhood leukemia. AB - In patients with malignancies, the system of carnitine seems abnormally expressed. The serum total, free, and acyl carnitine levels in 40 children and adolescents with acute leukemia were determined using electrospray tandem mass spectrometry in 4 different phases of the disease: at the diagnosis, 1 year after the initiation of chemotherapy, at the end of treatment, and 2.4+/-1.668 years after the completion of chemotherapy. The age, sex, hemoglobin values, serum biochemistry, somatometric features of the patients, and the risk group of the disease were examined. Although the carnitine levels were found higher in patients compared with the control group from diagnosis to treatment completion, statistically significant decrease in carnitine levels was observed in patients within different phases of the disease especially during induction and consolidation treatment (phase A to B) for both free and total (P=0.023) carnitine. In addition, a statistically significant recovery in carnitine levels was observed between phase B (end of intensive chemotherapy) and D (some years after the completion of treatment) for free and total carnitine (P=0.054 and 0.035, respectively). No statistical correlation was documented between the carnitine levels and somatometric parameters or other variables studied. In conclusion, a significant transient decrease in the levels of carnitine during the treatment was observed in children with acute leukemia. Further studies are required to clarify the role of carnitine status in patients with malignancies and possibly the necessity of carnitine supplementation during chemotherapy administration. PMID- 20168248 TI - Double high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation for primary disseminated medulloblastoma: a report of 3 cases. AB - We performed double high-dose chemotherapy followed by peripheral blood stem cell transplantation (PBSCT) in 3 children with medulloblastoma and primary leptomeningial dissemination, including spinal metastasis. After resection of the main tumor mass, 30.6 Gy whole craniospinal radiation therapy and 4 or 5 courses of conventional chemotherapy with vincristine (1.5 mg/m), carboplatin (560 mg/m), ifosfamide (9000 mg/m), and etoposide (500 mg/m), and 2 courses of high-dose thiotepa (680 mg/m) and melphalan (240 mg/m) therapy with PBSCT were administered. Two patients with low erythroblastic leukemia viral oncogene homolog 2 (ERBB2) gene expression achieved long-term survival (41 mo and 40 mo) but the patient with high ERBB2 expression relapsed 9 months after the second PBSCT. PMID- 20168250 TI - L-2-hydroxyglutaric aciduria and multiple acyl-coenzyme A dehydrogenase deficiency are distinct metabolic disorders. PMID- 20168249 TI - Primary ALK-positive anaplastic large cell lymphoma of the breast: a case report and review of the literature. AB - BACKGROUND: Non-Hodgkin lymphomas of the breast are uncommon, which represent less than 1% of all breast malignancies and predominantly are of B-cell origin. OBSERVATION: In this report, a rare case of anaplastic lymphoma kinase (ALK) positive anaplastic large T-cell lymphoma in the breast of a 16-year-old female without breast implant is described. The patient presented with a 3-month history of progressive right breast swelling and erythema. Clinically, inflammatory breast carcinoma was highly suspected. A tru-cut needle biopsy of the right breast demonstrated infiltration of tumoral cells around the breast lobules and soft tissue and also in angiolymphatic spaces. The immunohistochemical profile showed positivity for CD30 and ALK and confirmed the diagnosis of ALK-positive anaplastic large T-cell lymphoma of the breast. CONCLUSION: Anaplastic large T cell lymphoma of the breast is rare, and can clinically mimic inflammatory breast carcinoma in adolescence. PMID- 20168251 TI - Osteogenic sarcoma in a child with familial expansile osteolysis syndrome: an accidental association? AB - We present the first reported case of a child with familial expansile osteolysis syndrome (FEO) who developed osteogenic sarcoma (OS) of the iliac bone. A 17-year old adolescent presented with pain and a mass on the left pelvis. He was from a family with several members who had been diagnosed with FEO, from which he also suffered. The median life expectancy of affected members of the family was reported as 25 to 30 years, with death ensuing as a result of various respiratory and cardiac complications of severe skeletal deformations, characteristic of increased bone turnover as seen in FEO. Biopsy of the patient's mass revealed chondroblastic OS. He was treated according to the P9754 protocol for patients with newly diagnosed nonmetastatic OS. Chemotherapy consisted of HD-MTX, ifosfomide, doxorubicin, and cisplatin. Complete resection of the tumor was carried out, but the patient subsequently developed metastatic disease and died (histologic response to neoadjuvant chemotherapy-85%). The patient's alkaline phosphatase level that was highly elevated before the start of chemotherapy, dropped significantly during treatment, with repeated elevation soon after definitive surgery, while he was recuperating and not on treatment. We speculate that chemotherapy affected not only the malignant cells of OS but normal osteoblasts as well, with a decreasing level of alkaline phosphatase even in the absence of any clinical and radiographic signs of OS. We also think that increased bone turnover, characteristic of a condition such as FEO, may facilitate de novo development of OS. PMID- 20168252 TI - 99mTc-sestamibi scan differentiates tumor from other contrast enhancing tissue in choroid plexus tumors. AB - Choroid plexus tumors are rare brain tumors which account for 0.4% to 0.6% among brain tumors. Tumor resection is known to be of large prognostic impact, and re resection of residual tumors is a part of standard care. However, after multiple resections it can become difficult to differentiate tumor from reactive tissue. 99mTC-sestamibi scans may assist in differentiating neoplastic (99mTC-sestamibi positive) from non-neoplastic tissue (99mTC-sestamibi negative). Previous literature showed sestamibi to be helpful in detecting residual choroid plexus tumors resulting in further resection. Here, we report the first case to show that sestamibi scans can also help with the opposite decision. PMID- 20168253 TI - Influence of commonly employed resistance exercise protocols on circulating IL-6 and indices of insulin sensitivity. AB - The purpose of this project was to examine the influence of resistance exercise (RE) intensities, resulting in different total volume loads on circulating interleukin-6 (IL-6), insulin and glucose response (IGR) to a carbohydrate feeding (CHO), and whether RE-induced IL-6 was associated with postexercise IGR. Fourteen men (21.7 +/- 1.7 years, 83 +/- 14.2 kg), performed 2 RE sessions (low intensity resulting in high volume [65% 1-repetition maximum (1RM)], LO; high intensity resulting in low volume [85% 1RM], HI); and a nonexercise control trial (CON). Resistance exercise included 3 sets (LO = 12 reps, 12 reps, and failure; HI = 8 reps, 8 reps, and failure) of 8 exercises. Blood was obtained pre- (PR) and post (PO) exercise, and 6 hours postexercise (6H). Twenty-three hours after RE or CON, participants consumed 100 g dextrose (CHO) beverage. Blood was collected before (0 minutes) and 60 minutes after CHO (n = 6, phase 1) or every 30 minutes for a 2-hour oral glucose tolerance test (n = 8; phase 2). Circulating IL-6, insulin, and glucose were analyzed via enzyme-linked immunosorbent assay, radioimmunoassay, and enzymatic methods, respectively. Total volume load was higher in LO (17,729 +/- 1,466 kg) compared with HI (13,160 +/- 1,097 kg; p < 0.001). Postexercise IL-6 was elevated (p = 0.003) in LO and HI compared with CON (7.4 +/- 1.3, 5.2 +/- 0.7, and 2.5 +/- 0.7 pg.mL, respectively), with LO IL-6 greater than HI. Areas under the curve for glucose (p = 0.081; CON: 741 +/- 46, LO: 690 +/- 28, and HI: 660 +/- 21 mM.min) and insulin (p = 0.075; CON: 6,818 +/- 1,018, LO: 5,056 +/- 869, and HI: 5,405 +/- 1,076 microIU.mL) were not different among trials (n = 8). When 0- and 60-minute values were compared (n = 14), insulin was lower at 60 minutes in LO and HI compared with CON (55 + 9.1, 83 +/- 13, 105 +/- 13 microIU.mL, respectively) with LO insulin being lower than HI (p < 0.001). No relationship was observed between PO IL-6 and IGR, but PR IL-6 was negatively related to both PR (r = -0.043, p < 0.05) and 60 minutes (r = -0.59, p < 0.01) glucose (n = 14). These results indicate that TVL contributes to RE induced IL-6 release and that TVL may be more important than RE intensity when improvements in glucose tolerance or IS are the goal. PMID- 20168254 TI - Determinants of a simulated cross-country skiing sprint competition using V2 skating technique on roller skis. AB - The present study investigated the performance-predicting factors of a simulated cross-country (XC) skiing sprint competition on roller skis, on a slow surface. Sixteen elite male XC skiers performed a simulated sprint competition (4 x 850 m heat with a 20-minute recovery) using V2 skating technique on an indoor tartan track. Heat velocities, oxygen consumption, and peak lactate were measured during or after the heats. Maximal skiing velocity was measured by performing a 30-m speed test. Explosive and maximal force production in the upper body was determined by bench press (BP). Subjects also performed maximal anaerobic skiing test (MAST) and the 2 x 2-km double poling (DP) test. The maximal velocity of MAST (VMAST) and velocities at 3 (V3), 5 (V5), 7 (V7) mmol.L lactate levels in MAST were determined. In the 2 x 2-km test, DP economy (VO2SUBDP) and maximal 2 km DP velocity (VDP2KM) were determined. The best single performance-predicting factors for the sprint performance were VDP2KM (r = 0.73, p < 0.01), V7 (r = 0.70, p < 0.01), and VO2SUBDP (r = -0.70, p < 0.01). Faster skiers in sprint simulation had a higher absolute VO2 (L.min) (p < 0.05-0.01) during sprint heats, and higher anaerobic skiing power (VMAST, p < 0.05) and better anaerobic skiing economy (V3, V5, V7, p < 0.05-0.001) than slower skiers. Faster skiers were also stronger in BP, with regard to both absolute (p < 0.01) and relative (p < 0.05) values. In addition, anaerobic characteristics seem to be of importance at the beginning of the XC skiing sprint competition, whereas the aerobic characteristics become more important as the XC skiing sprint competition progressed. This study indicates that sprint skiers should emphasize sport specific upper body training, and training skiing economy at high speeds. PMID- 20168255 TI - Acute effect of different stretching methods on Illinois agility test in soccer players. AB - The purpose of this study was to examine the effects of static, dynamic, and the combination of static and dynamic stretching within a pre-exercise warm-up on the Illinois agility test (IAT) in soccer players. Nineteen professional soccer players (age = 22.5 +/- 2.5 years, height = 1.79 +/- 0.003 m, body mass = 74.8 +/ 10.9 kg) were tested for agility performance using the IAT after different warm up protocols consisting of static, dynamic, combined stretching, and no stretching. The players were subgrouped into less and more experienced players (5.12 +/- 0.83 and 8.18 +/- 1.16 years, respectively). There were significant decreases in agility time after no stretching, among no stretching vs. static stretching; after dynamic stretching, among static vs. dynamic stretching; and after dynamic stretching, among dynamic vs. combined stretching during warm-ups for the agility: mean +/- SD data were 14.18 +/- 0.66 seconds (no stretch), 14.90 +/- 0.38 seconds (static), 13.95 +/- 0.32 seconds (dynamic), and 14.50 +/- 0.35 seconds (combined). There was significant difference between less and more experienced players after no stretching and dynamic stretching. There was significant decrease in agility time following dynamic stretching vs. static stretching in both less and more experienced players. Static stretching does not appear to be detrimental to agility performance when combined with dynamic warm up for professional soccer players. However, dynamic stretching during the warm up was most effective as preparation for agility performance. The data from this study suggest that more experienced players demonstrate better agility skills due to years of training and playing soccer. PMID- 20168256 TI - Comparison of two different resistance training intensities on excess post exercise oxygen consumption in African American women who are overweight. AB - The purpose of this study was to compare a low- and high-intensity resistance exercise session of equal work on excess post-exercise oxygen consumption (EPOC). Ten African American (AA) overweight women performed a no-exercise control (CN) session, 3 sets of 9 resistance training exercises, for 15 repetitions (reps) at 45% of their 8-repetition maximum (RM) during 1 session (LO) and for 8 reps at 85% of their 8-RM during another session (HI). For each session heart rate (HR), ventilation volume (VE), oxygen consumption (VO2), and respiratory exchange ratio, were collected continuously from 15 minutes pre exercise until 30 minutes post exercise. Blood lactate ([Lac]b) was collected pre, immediately post, 15 and 30 minutes post exercise. No significant differences were found between sessions for any pre-exercise measurements (p > 0.05). During exercise, there was no significant difference between the HI and LO sessions, as expected. The [Lac]b immediately post and 15-minute post were significantly higher in both HI and LO sessions compared with the CN session, however; no significant differences were found between the HI and LO sessions. Post-exercise HR for the HI session was significantly greater than the CN session (p = 0.006) but not different from the LO session. There were no significant differences in post-exercise VO2 between the HI and LO sessions. A trend was observed between exercise sessions with EPOC for HI (1.26 +/- 0.567 L.O2) vs. LO (0.870 +/- 0.394 L.O2) sessions. These data suggest that resistance training at either a low or high intensity with an equated work volume will produce similar exercise and post-exercise oxygen consumption for AA overweight women. Both of these resistance training programs were well tolerated and could be used for sedentary populations without a preconditioning program. PMID- 20168257 TI - Data reproducibility from an inertial kinetic exercise machine. AB - An inertial kinetic exercise (IKE, Oconomowoc, WI, USA) machine was created that permits high-velocity workouts suited for injury rehabilitation and speed development in athletes. In addition, its design does not entail the movement of resistance against Earth's gravitational pull. Thus, the design and operation associated with the IKE may be incorporated into novel environments such as space flight. Yet before it can be used for such reasons, IKE data reproducibility must first be ascertained, which serves as the present study's purpose. Methods to assess data reproducibility required subjects (n = 42) to perform 2 IKE elbow flexor trials, each comprising two 60-second sets separated by a 90-second rest. Preceded by a familiarization session on the IKE, subjects were instructed to perform high-speed elbow flexor trial repetitions in good form. Instrumentation entailed an accelerometer and a computer interfaced with software. Maximum and average forces (MF, AF), as well as work (W), were examined for reproducibility with several test-retest measures. Results showed high reproducibility, yet intertrial variability was greater due in part to the length of time between exercise sessions. It was concluded that MF reproducibility was inherently less partly due to the nature of the variable, which entailed a single instantaneous expression over each 60-second set. In contrast, AF and W denoted a cumulative, and thus better overall, representation of total exercise performance. Based on our high reproducibility values, present IKE instrumentation methods appear to be appropriate. Practical applications suggest that coaches and therapists may want to employ an IKE as instrumented in the present study to derive reproducible performance data on people who may use the device under their supervision. PMID- 20168258 TI - Influence of individualized training on psychomotor performance of young soccer players. AB - The aim of this study was to analyze the influence of individualized training (IT) on psychomotor performance of young soccer players. Psychomotor performance was measured by means of differential response time and number of correct responses to audio and visual stimuli. Kinematic analysis allowing assessment of both the distances and the average speeds of young players during consecutive matches was also performed. For the data analysis, one-way analysis of variance, Friedman test, and t-test for dependent samples were used. The obtained results clearly indicate that IT during the preparation period increases specific psychomotor performance among young soccer players. PMID- 20168259 TI - Oxygen consumption, heart rate, and blood lactate responses to an acute bout of plyometric depth jumps in college-aged men and women. AB - Although plyometrics are widely used in athletic conditioning, the acute physiologic responses to plyometrics have not been described. The purpose of this study was to investigate the oxygen consumption, heart rate, and blood lactate responses to a single session of plyometric depth jumps. Twenty recreationally trained college-aged subjects (10 men, 10 women) participated in a single session of 8 sets of 10 box depth jumps from a height of 0.8 m with 3 minutes of passive recovery between each set. Plyometric depth jumping elicited 82.5 +/- 3.1% and 77.8 +/- 3.1% of the measured maximal oxygen consumption (O2max) for women and men, respectively, with no difference in oxygen consumption in ml/kg/min or percent O2max between sexes or sets. Heart rate significantly increased (p < 0.05) from 68.1 +/- 2.9 beatsxmin-1 at rest to 169.6 +/- 1.2 beatsxmin-1 during depth jumping. Sets 5 to 8 elicited a higher (p < 0.05) heart rate (173.3 +/- 1.3 beatsxmin-1) than sets 1 to 4 (164.6 +/- 1.8 beatsxmin-1). Women exhibited a higher heart rate (p < 0.05) during sets 1 and 2 (169.9 +/- 2.8 beatsxmin-1) than men (150.7 +/- 4.4 beatsxmin-1). The blood lactate concentrations were significantly (p < 0.05) increased above resting throughout all sets (1.0 +/- 0.2 mmolxL-1 compared with 2.9 +/- 0.1 mmolxL-1), with no differences between sexes or sets. Plyometric depth jumping significantly increased oxygen consumption, heart rate, and blood lactate in both men and women, but no significant difference was found between the sexes. Plyometric depth jumping from a height of 0.8 m has similar energy system requirements to what Wilmore and Costill termed "Aerobic Power" training, which should enhance O2max, lactate tolerance, oxidative enzymes, and lactate threshold. PMID- 20168260 TI - A comparison of in-hospital mortality risk conferred by high hospital occupancy, differences in nurse staffing levels, weekend admission, and seasonal influenza. AB - BACKGROUND: Hospital occupancy, nurse staffing levels, weekend admission, and seasonal influenza have all been shown to be associated with in-hospital mortality. Yet, no study has simultaneously compared the strength of associations of these 4 factors with in-hospital mortality. OBJECTIVE: To compare the risk of in-hospital mortality conferred by high hospital occupancy on admission, increased nurse staffing levels, weekend admission, and seasonal influenza. STUDY DESIGN: Retrospective cohort study of 166,920 patients admitted to 39 Michigan hospitals between 2003 and 2006. Participants were adults, age > or = 65 years, admitted through the emergency department with 6 common discharge diagnoses (acute myocardial infarction, congestive heart failure, stroke, pneumonia, hip fracture, gastrointestinal bleeding). We used logistic regression to compare the differences in the predicted probability of death conferred by each of the 4 factors, controlling for patient age, gender, discharge diagnosis, and comorbid conditions. RESULTS: Each of the 4 factors had a statistically significant, independent association with in-hospital mortality. Seasonal influenza conferred the greatest increase in absolute risk of in-hospital mortality (0.5 percentage points; 95% CI, 0.23-0.76), followed by weekend admission (0.32, 0.11-0.54), and high hospital occupancy on admission (0.24, 0.06-0.43). Increased nurse staffing levels decreased the absolute risk of mortality by 0.25 percentage points (0.04 0.48) for each additional full-time equivalent nurse per patient-day. CONCLUSION: Hospital occupancy, nurse staffing levels, weekend admission, and seasonal influenza all appear to be independently associated with in-hospital mortality, but to varying degrees in the current sample. These findings may guide hospital administrators as they consider factors that influence weekly and seasonal patient flow and capacity, as well as staffing. PMID- 20168261 TI - Trees over forest: unpleasant stimuli compete for attention with global features. AB - Whether emotional distracters call for attentional resources has been discussed in several studies. We have earlier shown that brief unpleasant distracters captured right hemisphere (RH) attentional resources as evidenced with reduced event-related potential responses and increased reaction times to nonemotional left visual field/RH targets. The aim of this study was to investigate whether emotional distracters selectively interfere with processes predominantly relying on the RH such as processing global visual features. Evoked potentials were recorded from 18 participants carrying out a visual discrimination task engaging global RH and local left hemisphere-dependent processes. Unpleasant distracters reduced global target detection-related right parietal activity. We conclude that brief unpleasant distracters compete for RH attentional resources with global level processing. PMID- 20168262 TI - High-grade endometrial cancer: value of [(18)F]FDG PET/CT in preoperative staging. AB - OBJECTIVE: The purpose of this study was to assess the value of 2-[F]fluoro-2 deoxy-D-glucose positron emission tomography/computed tomography ([F]FDG PET/CT) in the primary staging of high-risk endometrial cancer patients. METHODS: This retrospective study was conducted on 32 consecutive patients with histological diagnosis of primary high-risk endometrial cancer, who underwent PET/CT with [F]FDG in addition to conventional clinical and instrumental staging procedures. After surgery, [F]FDG PET/CT findings were correlated with pathological findings on a patient-by-patient basis. The diagnostic accuracy of [F]FDG PET/CT for primary cancer detection, lymph nodal involvement and distant metastases was assessed. RESULTS: [F]FDG PET/CT could correctly detect primary tumor in 29 of the 32 high-risk patients, with a sensitivity of 90.6%. The overall [F]FDG PET/CT patient-based sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 57.1, 100.0, 100.0, 86.4, and 88.5%, respectively, for revealing lymph nodal neoplastic involvement, and 100.0, 96.0, 87.5, 100.0, 96.9%, respectively, for detecting distant metastases. In particular, while the suspicion of distant metastases was documented by conventional imaging in only two patients, [F]FDG PET/CT correctly identified metastatic lesions in seven patients (21.9% of cases). CONCLUSION: The major benefit provided in high-grade tumor patients by the use of [F]FDG PET/CT in the primary staging of endometrial cancer is its ability to accurately detect distant metastases in the abdomen and extra-abdominal regions. [F]FDG PET/CT adds relevant information that may influence patient management. PMID- 20168263 TI - Association of meningococcal phenotypes and genotypes with clinical characteristics and mortality of meningitis in children. AB - BACKGROUND: Neisseria meningitidis meningitis represents approximately one-half of the meningococcal cases in French children. To explore the contribution of bacterial typing in improving the management of cases, we aimed to describe clinical characteristics and mortality of meningococcal meningitis in children reported to the multicenter survey system, GPIP/ACTIV, in association with phenotypes/genotypes of bacterial isolates. METHODS: From 2001 to 2005, 259 pediatric wards and 168 microbiology laboratories enrolled all children with bacterial meningitis. Risk factors, vaccination status, signs and symptoms, cerebrospinal fluid analysis, treatments and case fatality rate were recorded. RESULTS: A total of 962 cases of Neisseria meningitidis meningitis among a total of 2131 bacterial meningitis (45%) were recorded (mean age, 4.5 +/- 4.7 years). Serogroup distribution of the isolates was 62.3%, 33.7%, 2.9%, 0.6%, and 0.6% for serogroups B, C, W135, A and Y, respectively. The major clonal complexes were ST 41/44 (32.2%), ST-11 (21.9%), ST-32 (20.8%), ST-8 (8.2%), and ST-269 (4.9%). Despite global heterogeneity of the isolates, 2 phenotypes/genotypes were of interest. Isolates of the phenotype/genotype B:14:P1.7,16/ST-32 (56% clustered in the region of Haute Normandie) were observed in older children (8.6 years) and were associated with a higher case fatality rate (12%) than were other phenotypes of serogroup B. The phenotype/genotype C:2a:P1.5/ST-11 was found in 26.3% of serogroup C cases and was possibly associated with a higher mortality among serogroup C (9.9% for C and 5.9% for B, P = 0.04). CONCLUSIONS: This large survey provides data that could be important for implementation of future vaccines. Typing of meningococcal isolates could contribute to an understanding of prognosis in meningococcal meningitis. PMID- 20168264 TI - A systematic review and critical evaluation of invasive Haemophilus influenzae type B disease burden studies in Asia from the last decade: lessons learned for invasive bacterial disease surveillance. AB - In Asia, questions regarding the burden of Haemophilus influenzae type b (Hib) disease have delayed decision-making on introduction of Hib vaccine. However, over the past decade many studies have been published regarding Hib disease burden in Asia. We conducted a systematic literature review of all reports of Hib disease burden in Asia between 1998 and 2009, and critically reviewed their methods and data quality. We identified 94 studies from 28 countries in Asia presenting data on Hib disease burden. Of the 94 studies reviewed, 49 (52%) used a case definition consistent with World Health Organization standards, and 47 (50%) described laboratory methodology used. Twenty-seven surveillance studies presented data on incidence of Hib disease, with 8 (30%) accounting for missed cases, 6 (15%) accounting for cases with missed diagnostic tests, and 2 (7%) that considered prior antibiotic use. Of the 21 studies that provided incidence data for Hib meningitis, 10 (48%) used active, prospective, population-based surveillance, and found unadjusted incidence rates of Hib meningitis ranging from a low of 0.98 per 100,000 child-years in children aged less than 5 years in China to a high of 28 per 100,000 child-years in children less than 5 years in Mongolia. Of 49 studies that reported the etiology of bacterial meningitis, 30 (60%) identified Hib as the most common cause. This review highlights the importance of using rigorous methodologies, including standardized surveillance methods and appropriate laboratory diagnostic tests, when conducting studies measuring the burden of invasive bacterial diseases including those caused by Hib. When poorly conducted, studies can underestimate disease burden and lead to inappropriate decisions about vaccine introduction. PMID- 20168265 TI - Influence of serotonin 3A and 3B receptor genes on clozapine treatment response in schizophrenia. AB - Earlier results suggest a minor role of variants in the serotonin 3 receptor (HTR3) subunit genes on antipsychotic treatment outcome of schizophrenia patients. In this study, we further investigated the role of the subunits A and B of the HTR3 receptor using 140 schizophrenia patients taking clozapine for 6 months. We have found significant allelic association of clozapine response with three variants in the HTR3A receptor (rs2276302, rs1062613, rs1150226) although only rs1062613 association remained significant after permutations (permutated P=0.041). Moreover, rs2276302 and rs1062613 have shown nominally significant genotypic association. The two haplotypes composed of rs2276302-rs1062613 rs1150226 were also nominally significant. Taken together, our results suggest that variants in the HTR3A receptor gene can play a role in the treatment outcome of clozapine in schizophrenia patients that are refractory or intolerant of typical antipsychotic therapy. Further studies are necessary to confirm the reported associations. PMID- 20168266 TI - Regression of retinal neovascularization after laser photocoagulation in incontinentia pigmenti. PMID- 20168267 TI - Secondary macular hole formation after vitrectomy. AB - PURPOSE: The purpose of this study was to report the incidence and the underlying ocular pathology of a macular hole (MH) that develops in vitrectomized eyes and to evaluate its prognosis. METHODS: A retrospective chart review was performed in patients who underwent vitrectomy between March 2004 and June 2009. Cases that developed an MH in vitrectomized eyes were identified, and the data from all ophthalmology examinations were collected. Patients with recurrent MHs after the initial MH surgery were excluded. RESULTS: We identified 10 cases of secondary MH during a period of 64 months (incidence, 8 of 3,279 [0.24%]). Two cases of secondary MHs were not included in the calculations because the initial vitrectomies were performed before March 2004. The initial vitrectomy was performed on four eyes with vitreous hemorrhage caused by proliferative diabetic retinopathy, three eyes with retinal detachment from high myopia, one eye with combined retinal detachment with uveitis, one eye with rhegmatogenous retinal detachment, and one eye with an epiretinal membrane. The macular pathology identified before MH formation included cystoid macular edema in two eyes, epiretinal membrane in four eyes, and no specific lesion in another four eyes. The secondary MHs were managed by additional vitrectomy, peeling of the internal limiting membrane, and intravitreal gas tamponade. Nine of 10 eyes achieved hole closure after the secondary surgery, and 8 eyes recovered their previous visual acuity; the other 2 eyes had visual loss within 2 Snellen chart lines, and none of the 9 patients had a recurrence during a mean follow-up of 20.7 months (range, 4-31 months). CONCLUSION: The development of secondary MHs after vitrectomy is rare. Pathogenic mechanisms other than idiopathic MH may be involved in these cases. The anatomical and functional outcome of the secondary MHs that developed after vitrectomy was good, although the final visual acuity was dependent on the underlying ocular pathology. PMID- 20168268 TI - Compliance with the American Academy of Ophthalmology Preferred Practice Pattern for Diabetic Retinopathy in a resident ophthalmology clinic. AB - PURPOSE: The purpose of this study was to evaluate compliance with the American Academy of Ophthalmology Diabetic Retinopathy (DR) Preferred Practice Pattern for an initial DR examination in a resident ophthalmology clinic. METHODS: Adult patients with diabetes were included if seen in the resident ophthalmology clinic at a Veterans Affairs Medical Center for an initial DR examination between July 2006 and June 2007. Medical records were reviewed for compliance with the 29 applicable elements from the American Academy of Ophthalmology DR Preferred Practice Pattern. RESULTS: Of 451 diabetic patient visits in the ophthalmology clinic in the study period, 70 met inclusion criteria. The overall mean compliance rate was 52%. Compliance was best in the categories of examination (mean = 87%), diagnosis (mean = 82%), and treatment (mean = 74%). Compliance was lowest in the categories of medical history (mean = 11%) and counseling/referral (mean = 34%). CONCLUSION: Compliance with both practice and documentation of American Academy of Ophthalmology DR Preferred Practice Pattern guidelines at a resident ophthalmology clinic should be monitored, especially in the areas of medical history, patient education, and referrals. A target level of compliance should be set and maintained in all the DR Preferred Practice Pattern categories, especially in a teaching hospital where residents are developing their approach to quality care. PMID- 20168269 TI - Diagnostic and therapeutic challenges. PMID- 20168270 TI - Cystoid macular edema without macular thickening: a retrospective optical coherence tomographic study. AB - BACKGROUND: This is a retrospective observational case series of 37 eyes of 32 patients meeting the inclusion criteria intended to describe the appearance, prevalence, and associated risk factors for cystoid macular edema in eyes with normal foveal thickness and contour as determined by optical coherence tomography (OCT). METHODS: A retrospective review of all patients with macular disease who underwent OCT evaluation at the New England Eye Center from January to March 2007 and met the study inclusion criteria was performed. Optical coherence tomography scans were evaluated for the presence of intraretinal cystic fluid or cystoid macular edema but with normal retinal thickness and foveal contour. Retinal thickness and contour were evaluated using OCT mapping software. The main outcome measures were as follows: OCT-defined entity based on the presence of cystoid spaces within the fovea, "normal" foveal thickness (<252 microm), normal foveal contour, and best-corrected visual acuity on the date of examination. RESULTS: Thirty-seven eyes of 32 patients were determined to have cystoid macular edema with normal foveal thickness and contour on OCT. The overall prevalence within our patient population was 4.9%. Mean foveal thickness (standard deviation) for these patients was 201.4 microm (28.9) compared with normal mean foveal thickness (standard deviation) of 212 microm (20.0). Of the 32 patients, 17 (53.1%) had a primary diagnosis of age-related macular degeneration. The mean visual acuity (Snellen; logarithm of the minimum angle of resolution) was 20/80 (0.60). CONCLUSION: Cystoid macular edema in the setting of normal foveal thickness and contour as determined by OCT has not been extensively described. This entity is not pathognomonic of a single diagnosis and can occur in the setting of several disparate diagnoses as seen in our cohort. Chief among these were age-related macular degeneration and diabetic retinopathy. Acute postcataract cystoid macular edema was absent. PMID- 20168271 TI - Results of 1-year follow-up examinations after intravitreal bevacizumab administration for idiopathic choroidal neovascularization. AB - PURPOSE: The purpose of this study was to report the results of 1-year follow-up examinations after intravitreal bevacizumab injection for the treatment of idiopathic choroidal neovascularization. METHODS: Seven eyes in 7 patients with idiopathic choroidal neovascularization were intravitreally injected with 1.25 mg/0.05 mL of bevacizumab. The need for retreatment was evaluated if spectral domain optical coherence tomography showed intraretinal edema or subretinal fluid at the time of a 1-month follow-up examination. Fluorescein angiography was performed 1 year after the first injection. The primary outcome measures were best-corrected visual acuity and central foveal thickness using spectral-domain optical coherence tomography. RESULTS: All 7 eyes were assessed at a 1-year follow-up examination. The mean number of injections per eye was 2.7. The mean logarithm of the minimum angle of resolution best-corrected visual acuity improved significantly from 0.31 +/- 0.29 to 0.15 +/- 0.38 (P < 0.05). The mean central foveal thickness decreased from 332 +/- 83 microm to 261 +/- 66 microm (P < 0.01). Fluorescein angiography showed no leakage at 1 year in all eyes. All patients whose best-corrected visual acuity improved by > or =0.2 logarithm of the minimum angle of resolution had a visual acuity of > or =20/40 when first injected at baseline. CONCLUSION: The intravitreal injection of bevacizumab is effective for stabilizing or improving vision in patients with idiopathic choroidal neovascularization, as evaluated at a 1-year follow-up examination. In particular, this treatment may be well tolerated in patients with a visual acuity of > or =20/40 at baseline. Additional investigations are needed to assess the long-term safety and the optimal protocol for intravitreal bevacizumab administration. PMID- 20168272 TI - Microperimetry and fundus autofluorescence in diabetic macular edema: subthreshold micropulse diode laser versus modified early treatment diabetic retinopathy study laser photocoagulation. AB - PURPOSE: The purpose of this study was to evaluate and compare microperimetry and fundus autofluorescence (FAF) after subthreshold micropulse diode laser versus modified Early Treatment Diabetic Retinopathy Study photocoagulation for clinically significant diabetic macular edema. METHODS: A prospective randomized clinical trial including 62 eyes (50 patients) with untreated, center-involving, clinically significant diabetic macular edema was performed. All patients underwent best-corrected visual acuity determination (logarithm of the minimum angle of resolution), slit-lamp biomicroscopy, FAF, optical coherence tomography, microperimetry (macular sensitivity), and fluorescein angiography before and after treatment. Best-corrected visual acuity, optical coherence tomography, microperimetry, and FAF were repeated at 1-, 3-, 6-, 9-, and 12-month follow-up examinations. Fluorescein angiography was performed at baseline and at 6 and 12 months. RESULTS: Before treatment, demographic and macular parameters were not different between the two treatment groups. At 12 months, best-corrected visual acuity remained stable in both groups (P = 0.41 and P = 0.82), mean central retinal thickness decreased in both groups (P = 0.0002 and P < 0.0001), and mean central 4 degrees and 12 degrees retinal sensitivity increased in the micropulse diode laser group (P = 0.02 and P = 0.0075) and decreased in the Early Treatment Diabetic Retinopathy Study group (P = 0.2 and P = 0.0026). There was no significant difference in either best-corrected visual acuity or central retinal thickness between the 2 treatment groups (P = 0.48 and P = 0.29), whereas there was a significant difference in 4 degrees and 12 degrees retinal sensitivity (P = 0.04 and P < 0.0001). Fundus autofluorescence never changed in the micropulse diode laser group even after retreatment. In the Early Treatment Diabetic Retinopathy Study group, FAF increased up to 9 months and decreased in 6 eyes (20%) at 12 months. DISCUSSION: Micropulse diode laser seems to be as effective as modified Early Treatment Diabetic Retinopathy Study laser photocoagulation in the treatment of clinically significant diabetic macular edema. Micropulse diode laser treatment does not determine any change on FAF showing (at least) nonclinically visible damage of the retinal pigment epithelium. Microperimetry data encourage the use of a new, less aggressive laser therapeutic approach in the treatment of clinically significant diabetic macular edema. PMID- 20168273 TI - Bevacizumab for choroidal neovascularization related to inflammatory diseases. AB - PURPOSE: The purpose of this study was to report our experience with intravitreal bevacizumab for inflammation-related choroidal neovascularization in two tertiary centers. METHODS: This study was a retrospective analysis of patients with choroidal neovascularization related to inflammatory diseases, treated with intravitreal bevacizumab injections (1.25 mg/0.05 mL). RESULTS: Ten eyes of 10 patients (range, 14-78 years; mean age, 44 years) with underlying uveitis were treated with intravitreal bevacizumab for inflammation-related choroidal neovascularization from 2006 to 2008. Mean follow-up time was 13 +/- 8 months, and the mean number of injections was 2.7 +/- 2. Resolved leakage on fluorescein angiography and resolution of subretinal fluid on optical coherence tomography occurred in all patients, with improvement in visual acuity in 9 of 10 eyes and no change in visual acuity in 1 of 10 eyes. Seven patients received additional treatment based on the underlying condition. Mean macular thickness on optical coherence tomography decreased from 394 +/- 116 microm to 254 +/- 52 microm (P < 0.01). Mean visual acuity improved from 0.87 +/- 0.74 logarithm of the minimum angle of resolution to 0.38 +/- 0.63 (P = 0.005). Seven patients reached a visual acuity of 0.2 logarithm of the minimum angle of resolution (Snellen 6/9) or better. CONCLUSION: Intravitreal bevacizumab is an effective treatment for choroidal neovascularization related to inflammatory diseases when inflammation is controlled. PMID- 20168274 TI - Accuracy of retinopathy of prematurity diagnosis by retinal fellows. AB - PURPOSE: The purpose of this study was to measure the accuracy of retinopathy of prematurity (ROP) diagnosis by retinal fellows. METHODS: An atlas of 804 retinal images was captured from 248 eyes of 67 premature infants with a wide-angle camera (RetCam-II, Clarity Medical Systems, Pleasanton, CA). Images were uploaded to a study Web site, from which an expert pediatric retinal specialist and 7 retinal fellows independently provided a diagnosis (no ROP, mild ROP, type 2 ROP, or treatment-requiring ROP) for each eye. The sensitivity and specificity of each retinal fellow were calculated and subsequently compared with a reference standard of diagnosis by an expert pediatric retinal specialist. RESULTS: For detection of type 2 or worse ROP by fellows, mean (range) sensitivity was 0.751 (0.512-0.953), and specificity was 0.841 (0.707-0.976). For detection of treatment-requiring ROP, mean (range) sensitivity was 0.914 (0.667-1.000), and specificity was 0.871 (0.678-0.987). CONCLUSION: In general, fellows showed high accuracy for detecting ROP. However, 3 of 7 fellows achieved <80% sensitivity for diagnosis of type 2 or worse ROP, and 2 of 7 achieved <90% sensitivity for diagnosis of treatment-requiring ROP. This could lead to undermanagement and undertreatment of clinically significant disease and raises potential concerns about the quality of ROP screening examinations performed by less-experienced examiners. PMID- 20168275 TI - Prevalence, clinical characteristics, and causes of vision loss in children with Vogt-Koyanagi-Harada disease in South India. AB - PURPOSE: The purpose of this study was to describe the prevalence, clinical characteristics, and causes of vision loss in children with Vogt-Koyanagi-Harada disease seen at a uveitis referral center in South India. METHODS: Charts of patients with Vogt-Koyanagi-Harada disease examined in the uveitis referral clinic of Aravind Eye Hospital between January 1998 and December 2007 were reviewed. A subset of patients or=20/40, whereas 13.6% had a final visual acuity of or=18 years had been prescribed an opioid pain medication during the preceding 12 months. Of those prescribed an opioid pain medication, 3.2% reported using their medication more frequently or in higher doses than had been directed by their doctor; 72.0% reported having leftover medication, and 71.0% of those with leftover medication reported that they had kept the medication. Approximately 1.8% of all adults reported using prescription opioids that had not been prescribed to them. In 2009, the Utah Department of Health published a set of guidelines to reduce morbidity, mortality, and disability associated with misuse or abuse of prescription drugs, especially narcotics. The guidelines include recommendations that providers 1) counsel patients to dispose of unused medication properly once the pain has resolved and 2) prescribe no more than the number of doses needed based on the usual duration of pain severe enough to require opioids for that condition. PMID- 20168294 TI - Syphilis outbreak among American Indians - Arizona, 2007-2009. AB - On January 25, 2007, an Indian Health Service (IHS) unit notified the Arizona Department of Health Services (ADHS) of five symptomatic syphilis cases (i.e., primary or secondary syphilis) that had occurred in members of a Southwest Indian Nation during the previous 6 months. By mid-April, three more cases had been identified. On April 18, 2007, the tribe declared an outbreak of syphilis and subsequently requested public health assistance from county, state, and federal agencies. On July 10, an enhanced, coordinated multiagency response to the outbreak began, involving tribal and Pima County health departments, IHS, ADHS, and CDC. This report summarizes the enhanced outbreak response, which identified a total of 106 cases of syphilis with onset from January 2007 to June 2009, including six congenital cases (two of them stillbirths). Initial communication gaps led to delays in response to this outbreak, but communication was improved through the formation of an outbreak response group that included members from county, state, and tribal health departments and IHS. For similar outbreaks in American Indian tribes, where various public health jurisdictions exist and often have concurrent responsibilities, formation of an outbreak response group can improve control efforts. PMID- 20168295 TI - Outbreak of 2009 pandemic influenza A (H1N1) on a Peruvian Navy ship - June-July 2009. AB - On June 25, 2009, a naval cadet reported to the infirmary of a 355-crewman Peruvian Navy ship with a febrile acute respiratory infection (FARI) 5 days after the ship docked in San Francisco, California. Pandemic 2009 influenza A (H1N1) virus was suspected as the cause because it was circulating in the city at that time. A test for pandemic H1N1 by real-time reverse transcription--polymerase chain reaction (rRT-PCR) was positive. During the subsequent 3 weeks, as the ship continued its cruise, 77 additional crew members developed confirmed pandemic H1N1 influenza. The U.S. Naval Medical Research Center Detachment (NMRCD), in collaboration with the Peruvian Navy, conducted an investigation to describe the outbreak and determine the attack rate for pandemic H1N1 influenza on the ship. This report summarizes the results of that investigation, which indicated that, of the 85 patients with FARI, 78 (92%) tested positive for pandemic H1N1 by rRT PCR. The attack rate for confirmed pandemic H1N1 influenza was 22.0%. The most frequent symptoms, other than fever, were cough, headache, nasal congestion, and malaise. No complications or deaths occurred. Patients were treated according to World Health Organization (WHO) influenza treatment guidelines; six patients received antiviral medication because of preexisting comorbidities. A shipboard respiratory surveillance program, which had been implemented aboard the ship before its departure from Peru, permitted the early detection of the outbreak. Subsequent implementation of control measures might have slowed the outbreak. Laboratory disease surveillance and adequate outbreak control procedures might reduce transmission of pandemic H1N1 influenza aboard ships. PMID- 20168296 TI - Fluorescence activated cell sorting of plant protoplasts. AB - High-resolution, cell type-specific analysis of gene expression greatly enhances understanding of developmental regulation and responses to environmental stimuli in any multicellular organism. In situ hybridization and reporter gene visualization can to a limited extent be used to this end but for high resolution quantitative RT-PCR or high-throughput transcriptome-wide analysis the isolation of RNA from particular cell types is requisite. Cellular dissociation of tissue expressing a fluorescent protein marker in a specific cell type and subsequent Fluorescence Activated Cell Sorting (FACS) makes it possible to collect sufficient amounts of material for RNA extraction, cDNA synthesis/amplification and microarray analysis. An extensive set of cell type-specific fluorescent reporter lines is available to the plant research community. In this case, two marker lines of the Arabidopsis thaliana root are used: P(SCR;)::GFP (endodermis and quiescent center) and P(WOX5;)::GFP (quiescent center). Large numbers (thousands) of seedlings are grown hydroponically or on agar plates and harvested to obtain enough root material for further analysis. Cellular dissociation of plant material is achieved by enzymatic digestion of the cell wall. This procedure makes use of high osmolarity-induced plasmolysis and commercially available cellulases, pectinases and hemicellulases to release protoplasts into solution. FACS of GFP-positive cells makes use of the visualization of the green versus the red emission spectra of protoplasts excited by a 488 nm laser. GFP positive protoplasts can be distinguished by their increased ratio of green to red emission. Protoplasts are typically sorted directly into RNA extraction buffer and stored for further processing at a later time. This technique is revealed to be straightforward and practicable. Furthermore, it is shown that it can be used without difficulty to isolate sufficient numbers of cells for transcriptome analysis, even for very scarce cell types (e.g. quiescent center cells). Lastly, a growth setup for Arabidopsis seedlings is demonstrated that enables uncomplicated treatment of the plants prior to cell sorting (e.g. for the cell type-specific analysis of biotic or abiotic stress responses). Potential supplementary uses for FACS of plant protoplasts are discussed. PMID- 20168297 TI - Mammalian recombination hot spots: properties, control and evolution. AB - Recombination, together with mutation, generates the raw material of evolution, is essential for reproduction and lies at the heart of all genetic analysis. Recent advances in our ability to construct genome-scale, high-resolution recombination maps and new molecular techniques for analysing recombination products have substantially furthered our understanding of this important biological phenomenon in humans and mice: from describing the properties of recombination hot spots in male and female meiosis to the recombination landscape along chromosomes. This progress has been accompanied by the identification of trans-acting systems that regulate the location and relative activity of individual hot spots. PMID- 20168298 TI - A polycystin-2 (TRPP2) dimerization domain essential for the function of heteromeric polycystin complexes. AB - Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in two genes, PKD1 and PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Earlier work has shown that PC1 and PC2 assemble into a polycystin complex implicated in kidney morphogenesis. PC2 also assembles into homomers of uncertain functional significance. However, little is known about the molecular mechanisms that direct polycystin complex assembly and specify its functions. We have identified a coiled coil in the C-terminus of PC2 that functions as a homodimerization domain essential for PC1 binding but not for its self oligomerization. Dimerization-defective PC2 mutants were unable to reconstitute PC1/PC2 complexes either at the plasma membrane (PM) or at PM-endoplasmic reticulum (ER) junctions but could still function as ER Ca(2+)-release channels. Expression of dimerization-defective PC2 mutants in zebrafish resulted in a cystic phenotype but had lesser effects on organ laterality. We conclude that C terminal dimerization of PC2 specifies the formation of polycystin complexes but not formation of ER-localized PC2 channels. Mutations that affect PC2 C-terminal homo- and heteromerization are the likely molecular basis of cyst formation in ADPKD. PMID- 20168299 TI - The NoRC complex mediates the heterochromatin formation and stability of silent rRNA genes and centromeric repeats. AB - Maintenance of specific heterochromatic domains is crucial for genome stability. In eukaryotic cells, a fraction of the tandem-repeated ribosomal RNA (rRNA) genes is organized in the heterochromatic structures. The principal determinant of rDNA silencing is the nucleolar remodelling complex, NoRC, that consists of TIP5 (TTF 1-interacting protein-5) and the ATPase SNF2h. Here we showed that TIP5 not only mediates the establishment of rDNA silencing but also the formation of perinucleolar heterochromatin that contains centric and pericentric repeats. Our data indicated that the TIP5-mediated heterochromatin is indispensable for stability of silent rRNA genes and of major and minor satellite repeats. Moreover, depletion of TIP5 impairs rDNA silencing, upregulates rDNA transcription levels and induces cell transformation. These findings point to a role of TIP5 in protecting genome stability and suggest that it can play a role in the cellular transformation process. PMID- 20168300 TI - Bacterial actin MreB assembles in complex with cell shape protein RodZ. AB - Bacterial actin homologue MreB is required for cell shape maintenance in most non spherical bacteria, where it assembles into helical structures just underneath the cytoplasmic membrane. Proper assembly of the actin cytoskeleton requires RodZ, a conserved, bitopic membrane protein that colocalises to MreB and is essential for cell shape determination. Here, we present the first crystal structure of bacterial actin engaged with a natural partner and provide a clear functional significance of the interaction. We show that the cytoplasmic helix turn-helix motif of Thermotoga maritima RodZ directly interacts with monomeric as well as filamentous MreB and present the crystal structure of the complex. In vitro and in vivo analyses of mutant T. maritima and Escherichia coli RodZ validate the structure and reveal the importance of the MreB-RodZ interaction in the ability of cells to propagate as rods. Furthermore, the results elucidate how the bacterial actin cytoskeleton might be anchored to the membrane to help constrain peptidoglycan synthesis in the periplasm. PMID- 20168301 TI - Chromatin association and regulation of rDNA transcription by the Ras-family protein RasL11a. AB - RasL11a and RasL11b are Ras super-family proteins of unknown function. Here, we show that RasL11a is a chromatin-associated modulator of pre-ribosomal RNA (pre rRNA) synthesis. RasL11a was found in the nucleolus of interphase mouse fibroblasts, where it co-localized with the RNA polymerase I-specific transcription factor UBF. Similar to UBF, RasL11a also marked the active subset of rDNA repeats (also called nucleolar organizers, or NORs) on mitotic chromosomes. In cells, RasL11a existed in stable complexes with UBF and, as shown by chromatin immunoprecipitation, distributed along the rDNA transcription unit. Upon treatment of cells with actinomycin D, RasL11a and UBF persisted on the transcription unit beyond the release of RNA polymerase I, and remained co localized in peri-nucleolar cap structures. Ectopic expression of RasL11a enhanced pre-rRNA levels in cells, whereas RasL11a knockdown had the opposite effect. In transient transfection experiments, RasL11a enhanced the transcriptional activity of an RNA polymerase I-specific reporter controlled by the rDNA enhancer/promoter region. We speculate that RasL11a acts in concert with UBF to facilitate initiation and/or elongation by RNA polymerase I in response to specific upstream stimuli. PMID- 20168303 TI - Controlling evening BP as well as morning BP is important in hypertensive patients with prediabetes/diabetes: the JMS-1 study. AB - BACKGROUND: The significance of home blood pressure (BP) measurement in type 2 diabetes (T2DM) has not been well investigated. We aimed to test the hypotheses that home BP is more closely associated with target-organ damage than clinic BP, and that the presence of prediabetes/T2DM enhances the impact of home BP measurement. METHODS: We studied 551 hypertensives (99 diabetics and 452 nondiabetics) whose self-measured systolic BP (SBP) was >135 mm Hg while on medication. The subjects were followed for 6 months after allocation to either a control group or an active treatment group. The changes in clinic BP and home BP were analyzed in relation to the changes in the spot urine albumin-creatinine ratio (UAR). RESULTS: The extent of clinic and home BP reduction was similar between the diabetic and nondiabetic groups. The change in UAR in nondiabetics was significantly associated with the extent of SBP reduction in the clinic (r = 0.19), morning (r = 0.33), and evening (r = 0.22, all P < 0.01). In contrast, in the diabetic group, the change in UAR was significantly associated with the changes in morning SBP (r = 0.23, P = 0.02) and evening SBP (r = 0.39, P < 0.001), but not with clinic BP. The correlation with evening SBP in the diabetic group tended to be stronger than the nondiabetic group. CONCLUSIONS: In hypertensives with prediabetes/T2DM, changes in home BP were better than changes in clinic BP to predict changes in UAR. In particular, this suggests the hypothesis that aggressive control of evening home BP might be equally or more important to morning BP in hypertensives with prediabetes/T2DM. PMID- 20168302 TI - Architecture of a nascent viral fusion pore. AB - Enveloped viruses use specialized protein machinery to fuse the viral membrane with that of the host cell during cell invasion. In influenza virus, hundreds of copies of the haemagglutinin (HA) fusion glycoprotein project from the virus surface. Despite intensive study of HA and its fusion activity, the protein's modus operandi in manipulating viral and target membranes to catalyse their fusion is poorly understood. Here, the three-dimensional architecture of influenza virus-liposome complexes at pH 5.5 was investigated by electron cryo tomography. Tomographic reconstructions show that early stages of membrane remodeling take place in a target membrane-centric manner, progressing from punctate dimples, to the formation of a pinched liposomal funnel that may impinge on the apparently unperturbed viral envelope. The results suggest that the M1 matrix layer serves as an endoskeleton for the virus and a foundation for HA during membrane fusion. Fluorescence spectroscopy monitoring fusion between liposomes and virions shows that leakage of liposome contents takes place more rapidly than lipid mixing at pH 5.5. The relation of 'leaky' fusion to the observed prefusion structures is discussed. PMID- 20168304 TI - The day-night difference of blood pressure is increased in AT(1A)-receptor knockout mice on a high-sodium diet. AB - BACKGROUND: Abnormal circadian variation of blood pressure (BP) increases cardiovascular risk. In this study, we examined the influence of angiotensin AT(1A) receptors on circadian BP variation, and specifically on its behavioral activity-related and -unrelated components. METHODS: BP and locomotor activity were recorded by radiotelemetry in AT(1A)-receptor knockout mice (AT(1A)(-/-)) and their wild-type controls (AT(1A)(+/+)) placed on a normal-salt diet (NSD) or high-salt diet (HSD, 3.1% Na). RESULTS: The 24-h BP was lower in AT(1A)(-/-) than AT(1A)(+/+) mice on a NSD (92 +/- 2 and 118 +/- 2 mm Hg, respectively), whereas the day-night BP difference (DeltaDNBP) was similar between groups (11 +/- 2 and 12 +/- 1 mm Hg, respectively). HSD increased BP by 20 +/- 2 mm Hg and DeltaDNBP by 7 +/- 1 mm Hg in AT(1A)(-/-) mice, without affecting these parameters much in AT(1A)(+/+) mice. The DeltaDNBP increase in AT(1A)(-/-) mice was caused by nondipping BP during the inactive late-dark period. Conversely, BP rise associated with circadian behavioral activation during the early dark period was not altered by HSD in AT(1A)(-/-) mice. The BP change associated with spontaneous ultradian activity-inactivity bouts was also similar between strains on HSD as was the BP rise associated with induced (cage-switch) behavioral activity. Ganglionic or alpha(1)-adrenergic blockade decreased BP in both strains; HSD did not affect this response in AT(1A)(-/-), but abolished it in AT(1A)(+/+) mice. CONCLUSIONS: AT(1A)-receptor deficiency, when combined with HSD, can increase circadian BP difference in mice. This increase is mediated principally by activity-unrelated factors, such as the nonsuppressibility of basal resting sympathetic tone by HSD, thus suggesting a form of salt-/volume-dependent hypertension. PMID- 20168305 TI - Noninvasive assessment of endothelial function in the skin microcirculation. AB - BACKGROUND: The structure and function of blood vessels varies along the vascular tree. Endothelial dysfunction is a hallmark of increased cardiovascular (CV) risk that can be assessed by several methods, some of which are invasive and of restricted application. The aim of this study was to determine whether the laser Doppler response of skin microcirculation to acetylcholine, reflects that of conduit artery assessed by brachial artery flow-mediated dilation (FMD). METHODS: Noninvasive measurement of endothelium-dependent vasodilation in the skin microcirculation by laser Doppler flowmetry (LDF) in response to a local transdermal iontophoretic application of acetylcholine (Ach-SkBF) is an operator independent method. Ach-SkBF and FMD were measured in the nondominant upper limb of 55 unselected consecutive patients admitted in our department for evaluation of CV risk factors. RESULTS: Ach-SkBF was (mean +/- s.d. (min-max)) 490 +/- 414%, (10-1667%) and FMD was 3.77 +/- 3.01% (0.91-10.91). A strong linear relationship was found between Ach-SkBF and FMD: Ach-SkBF = 122.7 FMD + 25.8 (r = 0.92, P < 0.0001). CONCLUSIONS: Endothelial dilatory response to increased blood flow and to acetylcholine are similar in large arteries and in the skin microvasculature. Thus, measurement of blood flow changes in the skin microcirculation using LDF coupled with acetylcholine iontophoresis represents a technically challenging and reliable noninvasive method for the assessment of endothelial function within a large range of normal and altered endothelium responses. PMID- 20168307 TI - The impact of exposure misclassification on associations between prepregnancy BMI and adverse pregnancy outcomes. AB - Prepregnancy BMI is a widely used marker of maternal nutritional status that relies on maternal self-report of prepregnancy weight and height. Pregravid BMI has been associated with adverse health outcomes for the mother and infant, but the impact of BMI misclassification on measures of effect has not been quantified. The authors applied published probabilistic bias analysis methods to quantify the impact of exposure misclassification bias on well-established associations between self-reported prepregnancy BMI category and five pregnancy outcomes (small for gestational age (SGA) and large for gestational age (LGA) birth, spontaneous preterm birth (sPTB), gestational diabetes mellitus (GDM), and preeclampsia) derived from a hospital-based delivery database in Pittsburgh, PA (2003-2005; n = 18,362). The bias analysis method recreates the data that would have been observed had BMI been correctly classified, assuming given classification parameters. The point estimates derived from the bias analysis account for random error as well as systematic error caused by exposure misclassification bias and additional uncertainty contributed by classification errors. In conventional multivariable logistic regression models, underweight women were at increased risk of SGA and sPTB, and reduced risk of LGA, whereas overweight, obese, and severely obese women had elevated risks of LGA, GDM, and preeclampsia compared with normal-weight women. After applying the probabilistic bias analysis method, adjusted point estimates were attenuated, indicating the conventional estimates were biased away from the null. However, the majority of relations remained readily apparent. This analysis suggests that in this population, associations between self-reported prepregnancy BMI and pregnancy outcomes are slightly overestimated. PMID- 20168306 TI - Effect of Ginkgo biloba on blood pressure and incidence of hypertension in elderly men and women. AB - BACKGROUND: Accumulating evidence suggests that Ginkgo biloba is cardioprotective, in part, through its vasodilatory and antihypertensive properties. However, definitive data on its blood pressure (BP)-lowering effects in humans is lacking. METHODS: We determined the effects of G. biloba extract (240 mg/day) on BP and incident hypertension in 3,069 participants (mean age, 79 years; 46% female; 96% white) from the Ginkgo Evaluation of Memory (GEM) study. We also examined whether the treatment effects are modified by baseline hypertension status. RESULTS: At baseline, 54% of the study participants were hypertensive, 28% were prehypertensive, and 17% were normotensive. Over a median follow-up of 6.1 years, there were similar changes in BP and pulse pressure (PP) in the G. biloba and placebo groups. Although baseline hypertension status did not modify the antihypertensive effects of G. biloba, it did influence the changes in BP variables observed during follow-up, with decreases in hypertensives, increases in normotensives, and no changes in prehypertensives. Among participants who were not on antihypertensive medications at baseline, there was no difference between treatment groups in medication use over time, as the odds ratio (95% confidence interval (CI)) for being a never-user in the G. biloba group was 0.75 (0.48-1.16). The rate of incident hypertension also did not differ between participants assigned to G. biloba vs. placebo (hazard ratio (HR), 0.99, 95% CI, 0.84-1.15). CONCLUSIONS: Our data indicate that G. biloba does not reduce BP or the incidence of hypertension in elderly men and women. PMID- 20168308 TI - Removal of melatonin receptor type 1 induces insulin resistance in the mouse. AB - The incidence of obesity, insulin resistance, and type 2 diabetes (T2D) is increasing at an alarming rate worldwide. Emerging experimental evidence suggests that the hormone melatonin plays an important role in the regulation of glucose metabolisms. In this study, we report that removal of melatonin receptor type 1 (MT1) significantly impairs the ability of mice to metabolize glucose and such inability is probably due to an increased insulin resistance in these mice. Our data suggest that MT1 receptors are implicated in the pathogenesis of T2D and open the door for a detailed exploration on the mechanisms by which MT1 receptors signaling may affect glucose metabolism. PMID- 20168309 TI - Maladaptive eating patterns, quality of life, and weight outcomes following gastric bypass: results of an Internet survey. AB - Bariatric surgery is the most effective treatment for severe obesity. However, evidence suggests that maladaptive eating behaviors such as binge eating, grazing, and a loss of control when eating may impact postsurgical weight outcomes. The current study sought to characterize the weight outcomes, eating patterns, and perceived health-related quality of life of individuals 3-10 years following gastric bypass (GBP) surgery and to assess the relationships between eating behaviors, weight outcomes, and quality of life. Eligible participants (N = 497) completed an Internet survey of their eating behaviors, health-related quality of life, and weight history. Participants self-reported a mean maximum postsurgical loss of 81% of their excess weight and maintained a mean weight loss of 70% 3-10 years following surgery (mean 4.2 years). Eighty-seven percent reported weight regain ranging from 1 to 124 lb (mean 22.6 lb). Frequency of binge eating, a loss of control when eating, and grazing were all significantly correlated with greater weight regain (binge eating r = 0.24, P = 0.006; loss of control r = 0.36, P < 0.01; grazing r = 0.39, P < 0.001) and lesser excess weight loss (EWL) (binge eating r = -0.21, P = 0.013; loss of control r = -0.41, P < 0.001; grazing r = -0.27, P < 0.001). Poorer health-related quality of life was associated with binge eating disorder (BED) (t[463] = 9.7, P < 0.001) and grazing two or more times per week (t[361] = 9.0, P < 0.001). These findings suggest that eating disturbances and a loss of control when eating are significant following GBP and are risk factors for diminished weight outcomes. PMID- 20168310 TI - Insulin and hippocampus activation in response to images of high-calorie food in normal weight and obese adolescents. AB - Responsiveness to food cues, especially those associated with high-calorie nutrients may be a factor underlying obesity. An increased motivational potency of foods appears to be mediated in part by the hippocampus. To clarify this, we investigated by means of 3-T magnetic resonance imaging (MRI) the activation of the hippocampus and associated brain structures in response to pictures of high calorie and low-calorie foods in 12 obese and 12 normal-weight adolescents. To investigate the relationship between neuronal activation patterns (e.g., hippocampus) to the caloric content of food images and plasma insulin levels, we performed a multiple regression analysis. Interestingly, a significant positive correlation between fasting plasma levels of insulin, waist circumference, and right hippocampal activation was seen after stimulation with high-caloric food images. BMI values did not correlate significantly with the hippocampal activation. On the other hand, we found a significant negative correlation in response to high-caloric food images and the plasma levels of insulin in the medial right gyrus frontalis superior and in the left thalamus. In summary, our data show that insulin is importantly involved in the central regulation of food intake. The significant positive relationship between hippocampal activation after stimulation with high-caloric food images, plasma insulin levels, and waist circumference suggests a permissive role of insulin signaling pathways in the hippocampal control of eating behavior. Interestingly, only the waist circumference, as a main indicator of abdominal obesity, correlated significantly with the hippocampal activation patterns, and not the BMI. PMID- 20168311 TI - Profiling of energy metabolism in olanzapine-induced weight gain in rats and its prevention by the CB1-antagonist AVE1625. AB - This is the first study to examine the effect of subchronic olanzapine (OLZ) on energy homeostasis in rats, covering all aspects of energy balance, including energy intake as metabolizable energy, storage, and expenditure. We further analyzed whether, and by which mechanism, the CB1-antagonist AVE1625 might attenuate OLZ-induced body weight gain. For this purpose, we selected juvenile female Hanover Wistar rats that robustly and reproducibly demonstrated weight gain on OLZ treatment, accepting limitations to model the aberrations on lipid and carbohydrate metabolism. Rats received 2 mg/kg OLZ orally twice daily for 12 days. Body weight and body composition were analyzed. Moreover daily food intake, energy expenditure, and substrate oxidation were determined in parallel to motility and body core temperature. OLZ treatment resulted in substantial body weight gain, in which lean and fat mass increased significantly. OLZ-treated rats showed hyperphagia that manifested in increased carbohydrate oxidation and lowered fat oxidation (FO). Energy expenditure was increased, motility decreased, but there was no indication for hypothermia in OLZ-treated rats. Coadministration of OLZ and AVE1625 (10 mg/kg orally once daily) attenuated body weight gain, diminishing the enhanced food intake while maintaining increased energy expenditure and decreased motility. Our data reveal that energy expenditure was enhanced in OLZ-treated rats, an effect not critically influenced by motility. Energy uptake, however, exceeded energy expenditure and led to a positive energy balance, confirming hyperphagia as the major driving factor for OLZ-induced weight gain. Combination of OLZ treatment with the CB1-antagonist AVE1625 attenuated body weight gain in rats. PMID- 20168312 TI - Downregulation of ADIPOQ and PPARgamma2 gene expression in subcutaneous adipose tissue of obese adolescents with hepatic steatosis. AB - Hepatic steatosis is associated with hypoadiponectinemia. The mechanism(s) resulting in lower serum adiponectin levels in obese adolescents with fatty liver is unknown. In two groups of equally obese adolescents, but discordant for hepatic fat content, we measured adiponectin, leptin, peroxisome proliferator activated receptor gamma 2 (PPARgamma2) and tumor necrosis factor-alpha (TNFalpha) gene expression in the abdominal subcutaneous adipose tissue (SAT). Twenty six adolescents with similar degrees of obesity underwent a subcutaneous periumbilical adipose tissue biopsy, in addition to metabolic (oral glucose tolerance test, and hyperinsulinemic--euglycemic clamp), and imaging studies (magnetic resonance imaging (MRI), DEXA). Using quantitative real-time-PCR; adiponectin, PPARgamma2, TNFalpha, and leptin mRNA were measured. Based on a hepatic fat content (hepatic fat fraction, HFF) >5.5%, measured by fast MRI, the subjects were divided into low and high HFF group. In addition to the hypoadiponectinemia in the high HFF group, we found that the expression of adiponectin as well as PPARgamma2 in the SAT was significantly decreased in this group. No differences were noted for TNFalpha and leptin plasma or mRNA levels between the groups. An inverse relationship was observed between adiponectin or PPARgamma2 expression and hepatic fat content, whereas, adiponectin expression was positively related to PPARgamma2 expression. Independent of overall obesity, a reduced expression of adiponectin and PPARgamma2 in the abdominal SAT is associated with high liver fat content, as well as with insulin resistance in obese adolescents. PMID- 20168313 TI - Glucagon treatment for post-gastric bypass hypoglycemia. AB - Hyperinsulinemic hypoglycemia is a recently described complication of Roux-en-Y gastric bypass (RYGB). We hypothesized that glucagon administration would help maintain normal postprandial plasma glucose concentrations by stimulating hepatic glucose output, and if so, represent a new therapeutic option for postbypass hypoglycemia. In this study, we compared the insulin and glycemic response to a mixed meal with and without concomitant glucagon infusion in a patient with severe recurrent hypoglycemia after RYGB. Although effective in transiently raising postprandial plasma glucose values, glucagon infusion was also associated with higher insulin concentrations, and failed to prevent symptomatic hypoglycemia. This case demonstrates that glucagon may have limited clinical utility in the treatment of post-RYGB hyperinsulinemic hypoglycemia. PMID- 20168314 TI - Protein palmitoylation in neuronal development and synaptic plasticity. AB - Protein palmitoylation, a classical and common lipid modification, regulates diverse aspects of neuronal protein trafficking and function. The reversible nature of palmitoylation provides a potential general mechanism for protein shuttling between intracellular compartments. The recent discovery of palmitoylating enzymes--a large DHHC (Asp-His-His-Cys) protein family--and the development of new proteomic and imaging methods have accelerated palmitoylation analysis. It is becoming clear that individual DHHC enzymes generate and maintain the specialized compartmentalization of substrates in polarized neurons. Here, we discuss the regulatory mechanisms for dynamic protein palmitoylation and the emerging roles of protein palmitoylation in various aspects of pathophysiology, including neuronal development and synaptic plasticity. PMID- 20168316 TI - Overnight alchemy: sleep-dependent memory evolution. PMID- 20168317 TI - How to improve R&D productivity: the pharmaceutical industry's grand challenge. AB - The pharmaceutical industry is under growing pressure from a range of environmental issues, including major losses of revenue owing to patent expirations, increasingly cost-constrained healthcare systems and more demanding regulatory requirements. In our view, the key to tackling the challenges such issues pose to both the future viability of the pharmaceutical industry and advances in healthcare is to substantially increase the number and quality of innovative, cost-effective new medicines, without incurring unsustainable R&D costs. However, it is widely acknowledged that trends in industry R&D productivity have been moving in the opposite direction for a number of years. Here, we present a detailed analysis based on comprehensive, recent, industry wide data to identify the relative contributions of each of the steps in the drug discovery and development process to overall R&D productivity. We then propose specific strategies that could have the most substantial impact in improving R&D productivity. PMID- 20168318 TI - NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? AB - The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that activates caspase 1, leading to the processing and secretion of the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and IL-18. The NLRP3 inflammasome is activated by a wide range of danger signals that derive not only from microorganisms but also from metabolic dysregulation. It is unclear how these highly varied stress signals can be detected by a single inflammasome. In this Opinion article, we review the different signalling pathways that have been proposed to engage the NLRP3 inflammasome and suggest a model in which one of the crucial elements for NLRP3 activation is the generation of reactive oxygen species (ROS). PMID- 20168321 TI - Brain-derived neurotrophic factor in depression: a male problem? PMID- 20168319 TI - Eicosanoids and cancer. AB - Eicosanoids, including prostaglandins and leukotrienes, are biologically active lipids that have been implicated in various pathological processes, such as inflammation and cancer. This Review highlights our understanding of the intricate roles of eicosanoids in epithelial-derived tumours and their microenvironment. The knowledge of how these lipids orchestrate the complex interactions between transformed epithelial cells and the surrounding stromal cells is crucial for understanding tumour evolution, progression and metastasis. Understanding the molecular mechanisms underlying the role of prostaglandins and other eicosanoids in cancer progression will help to develop more effective cancer chemopreventive and/or therapeutic agents. PMID- 20168323 TI - Neuronal biomarkers from patients with mental illnesses: a novel method through nasal biopsy combined with laser-captured microdissection. PMID- 20168320 TI - Allogeneic haematopoietic stem cell transplantation: individualized stem cell and immune therapy of cancer. AB - The year 2009 marked the fiftieth anniversary of the first successful allogeneic haematopoietic stem cell transplant (HSCT). The field of HSCT has pioneered some of the most exciting areas of research today. HSCT was the original stem cell therapy, the first cancer immune therapy and the earliest example of individualized cancer therapy. In this Timeline article we review the history of the development of HSCT and major advances made in the past 50 years. We highlight accomplishments made by researchers who continue to strive to improve outcomes for patients and increase the availability of this potentially life saving therapy for patients with otherwise incurable malignancies. PMID- 20168324 TI - Variation in DISC1 is associated with anxiety, depression and emotional stability in elderly women. PMID- 20168325 TI - Renalase, a novel soluble FAD-dependent protein, is synthesized in the brain and peripheral nerves. PMID- 20168326 TI - Evolution and regulation of cellular periodic processes: a role for paralogues. AB - Several cyclic processes take place within a single organism. For example, the cell cycle is coordinated with the 24 h diurnal rhythm in animals and plants, and with the 40 min ultradian rhythm in budding yeast. To examine the evolution of periodic gene expression during these processes, we performed the first systematic comparison in three organisms (Homo sapiens, Arabidopsis thaliana and Saccharomyces cerevisiae) by using public microarray data. We observed that although diurnal-regulated and ultradian-regulated genes are not generally cell cycle-regulated, they tend to have cell-cycle-regulated paralogues. Thus, diverged temporal expression of paralogues seems to facilitate cellular orchestration under different periodic stimuli. Lineage-specific functional repertoires of periodic-associated paralogues imply that this mode of regulation might have evolved independently in several organisms. PMID- 20168327 TI - TBCCD1, a new centrosomal protein, is required for centrosome and Golgi apparatus positioning. AB - In animal cells the centrosome is positioned at the cell centre in close association with the nucleus. The mechanisms responsible for this are not completely understood. Here, we report the first characterization of human TBCC domain containing 1 (TBCCD1), a protein related to tubulin cofactor C. TBCCD1 localizes at the centrosome and at the spindle midzone, midbody and basal bodies of primary and motile cilia. Knockdown of TBCCD1 in RPE-1 cells caused the dissociation of the centrosome from the nucleus and disorganization of the Golgi apparatus. TBCCD1-depleted cells are larger, less efficient in primary cilia assembly and their migration is slower in wound-healing assays. However, the major microtubule-nucleating activity of the centrosome is not affected by TBCCD1 silencing. We propose that TBCCD1 is a key regulator of centrosome positioning and consequently of internal cell organization. PMID- 20168328 TI - Induced pluripotent stem cells: paths to new medicines. A catalyst for disease modelling, drug discovery and regenerative therapy. PMID- 20168329 TI - From discovering to understanding. Friedrich Miescher's attempts to uncover the function of DNA. PMID- 20168330 TI - Transcriptional targets of Drosophila JAK/STAT pathway signalling as effectors of haematopoietic tumour formation. AB - Although many signal transduction pathways have been implicated in the development of human disease, the identification of pathway targets and the biological processes that mediate disease progression remains challenging. One such disease-related pathway is the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) cascade whose constitutive misactivation by the JAK2 V617F mutation underlies most human myeloproliferative disorders. Here, we use transcript profiling of Drosophila haemocyte-like cells to identify JAK/STAT target genes, combined with an in vivo model for JAK-induced blood cell overproliferation, to identify the main effectors required for haematopoietic tumour development. The identified human homologues of the Drosophila effectors were tested for potential V617F-mediated transcriptional regulation in human HeLa cells and compared with small interfering RNA-derived data, quantify their role in regulating the proliferation of cancer-derived cell lines. Such an inter species approach is an effective way to identify factors with conserved functions that might be central to human disease. PMID- 20168332 TI - Cell reprogramming: expectations and challenges for chemistry in stem cell biology and regenerative medicine. AB - The possibility of reprogramming adult somatic cells into pluripotent stem cells (iPSCs) has generated a renewed interest into stem cell research and promises to overcome several key issues, including the ethical concerns of using human embryonic stem cells and the difficulty of obtaining large numbers of adult stem cells (Belmonte et al., Nat Rev Genet, 2009). This approach is also not free from challenges like the mechanism of the reprogramming process, which has yet to be elucidated, and the warranties for safety of generated pluripotent cells, especially in view of their possible therapeutic use. Very recently, several new reprogramming methods have surfaced, which seem to be more appropriate than genetic reprogramming. Particularly, chemically induced pluripotent cells (CiPSs), obtained with recombinant proteins or small synthetic molecules, may represent a valid approach, simpler and possibly safer than the other ones. PMID- 20168331 TI - Structural basis for the function of DEAH helicases. AB - DEAH helicases participate in pre-messenger RNA splicing and ribosome biogenesis. The structure of yeast Prp43p-ADP reveals the homology of DEAH helicases to DNA helicases and the presence of an oligonucleotide-binding motif. A beta-hairpin from the second RecA domain is wedged between two carboxy-terminal domains and blocks access to the occluded RNA binding site formed by the RecA domains and a C terminal domain. ATP binding and hydrolysis are likely to induce conformational changes in the hairpin that are important for RNA unwinding or ribonucleoprotein remodelling. The structure of Prp43p provides the framework for functional and genetic analysis of all DEAH helicases. PMID- 20168334 TI - Selective neutrality analysis of 17 STRs in Mediterranean populations. AB - Detection of genes that have been targeted by natural selection is a powerful tool for predicting regions of the genome potentially linked with diseases and of interest in the field of genetic epidemiology. In recent years, several methods to detect patterns of natural selection have been developed. In general, these tests are based on different assumptions and parameters; hence, the detection of outlier loci with more than one statistical approach simultaneously will support the candidate status of a particular locus. In this study, we evaluated the presence of patterns of positive selection in 17 short tandem repeat loci genotyped in six different human populations from the Mediterranean area, for a total of 429 individuals. To identify patterns of selective pressure, we applied three different neutrality tests on the basis of different models, performing pairwise comparisons between populations. Results show the presence of one marker, a (CA)n repeat located in exon 29 of the NOS1 gene, which seems significant in the three different tests in two pairwise comparisons: Sicily vs Morocco and Balearic Islands vs Morocco. This suggests that this locus and its genome localization are candidates for further studies to investigate selective pressure, as well as for association studies. PMID- 20168333 TI - TRAIL-activated stress kinases suppress apoptosis through transcriptional upregulation of MCL-1. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potentially useful anticancer agent with exquisite selectivity for cancer cells. Unfortunately, many cancers show or acquire resistance to TRAIL. In this study we report that TRAIL activates a TGF-beta-activated kinase 1 --> mitogen-activated protein kinase (MAPK) kinase 3 (MKK3)/MKK6 --> p38 pathway in prostate cancer cells that transcriptionally upregulates expression of the antiapoptotic BCL-2 family member MCL-1. TRAIL alone triggered robust formation of the 'death inducing signaling complex' (DISC), activation of the initiator caspase-8, and truncation of the BH3-only protein BID (tBID). Nevertheless, simultaneous disruption of the p38 MAPK pathway was required to suppress MCL-1 expression, thereby allowing tBID to activate the proapoptotic BCL-2 family member BAK and stimulate mitochondrial outer membrane permeabilization (MOMP). Release of the inhibitor-of-apoptosis (IAP) antagonist, Smac/DIABLO, from the intermembrane space was sufficient to promote TRAIL-induced apoptosis, whereas release of cytochrome c and activation of the apoptosome was dispensable. Even after MOMP, however, mitochondrial-generated reactive oxygen species (ROS) activated a secondary signaling pathway, involving c-Jun N-terminal kinases (JNKs), that similarly upregulated MCL-1 expression and partially rescued some cells from death. Thus, stress kinases activated at distinct steps, before and after mitochondrial injury, mediate TRAIL resistance through maintenance of MCL-1 expression. PMID- 20168335 TI - Relationship between growth hormone 1 genetic polymorphism and susceptibility to colorectal cancer. AB - The aim of this study was to evaluate the relationship between smoking, alcohol drinking and genetic polymorphism of the growth hormone 1 gene (GH1) T1663A with reference to colorectal cancer. We conducted a case-control study with 315 cases of colorectal cancer and 438 population-based controls in the Jiangsu Province, China. GH1 T1663A genotypes were identified using PCR-RFLP (restriction fragment length polymorphism) methods. Information on smoking and drinking was collected using a questionnaire. Odds ratios (ORs) were estimated with an unconditional logistic model. The distribution of T/T and A/A genotypes was significantly different between controls and cases (chi(2)(MH)=3.877, P=0.049). Compared with the GH1 T/T genotype, the A/A genotype was at a decreased risk of developing colorectal cancer (sex-, age-, body mass index-, smoking- and alcohol drinking adjusted OR=0.56, 95% confidence interval: 0.34-0.90). Smoking was not associated with the risk of colorectal cancer, whereas alcohol drinking was associated with an increased risk of colorectal cancer. Among nonsmokers or nondrinkers, individuals who had the GH1 A/A genotype were at a decreased risk of developing colorectal cancer compared with individuals who had the GH1 T allele. These results show that the GH1 T1663A A/A genotype can decrease the risk for colorectal cancer. PMID- 20168336 TI - A small world full of opportunities. PMID- 20168338 TI - Photovoltaics: More solar cells for less. PMID- 20168339 TI - Magnetization dynamics: Ferromagnets stirred up. PMID- 20168340 TI - Oxide surfaces: Surface science goes inorganic. PMID- 20168341 TI - Topological insulators: Oscillations in the ribbons. PMID- 20168342 TI - Material witness: Web designers. PMID- 20168343 TI - Plasmonics for extreme light concentration and manipulation. AB - The unprecedented ability of nanometallic (that is, plasmonic) structures to concentrate light into deep-subwavelength volumes has propelled their use in a vast array of nanophotonics technologies and research endeavours. Plasmonic light concentrators can elegantly interface diffraction-limited dielectric optical components with nanophotonic structures. Passive and active plasmonic devices provide new pathways to generate, guide, modulate and detect light with structures that are similar in size to state-of-the-art electronic devices. With the ability to produce highly confined optical fields, the conventional rules for light-matter interactions need to be re-examined, and researchers are venturing into new regimes of optical physics. In this review we will discuss the basic concepts behind plasmonics-enabled light concentration and manipulation, make an attempt to capture the wide range of activities and excitement in this area, and speculate on possible future directions. PMID- 20168344 TI - Plasmonics for improved photovoltaic devices. AB - The emerging field of plasmonics has yielded methods for guiding and localizing light at the nanoscale, well below the scale of the wavelength of light in free space. Now plasmonics researchers are turning their attention to photovoltaics, where design approaches based on plasmonics can be used to improve absorption in photovoltaic devices, permitting a considerable reduction in the physical thickness of solar photovoltaic absorber layers, and yielding new options for solar-cell design. In this review, we survey recent advances at the intersection of plasmonics and photovoltaics and offer an outlook on the future of solar cells based on these principles. PMID- 20168346 TI - Changes in intraocular pressure and anterior segment morphometry after uneventful phacoemulsification cataract surgery. AB - PURPOSE: To study changes in anterior segment morphometry after uneventful phacoemulsification cataract surgery, and to investigate whether there is a relationship between any observed changes and intraocular pressure (IOP) reduction after the procedure. METHODS: The anterior chamber depth (ACD), anterior chamber volume (ACV), anterior chamber angle (ACA), central corneal thickness (CCT), and IOP were measured in 101 non-glaucomatous eyes before and after uneventful phacoemulsification cataract surgery. RESULTS: After cataract surgery, the mean ACD, ACV, and ACA values increased by 1.08 mm, 54.4 mm(3), and 13.1 degrees , respectively, and the mean IOP (corrected for CCT) decreased by 3.2 mm Hg. The predictive value of a previously described index (preoperative ACD/preoperative IOP (corrected for CCT) or CPD ratio) for IOP (corrected for CCT) reduction after cataract surgery was confirmed, reflected in an r(2) value of 23.3% between these two parameters (P<0.001). Other indices predictive of IOP reduction after cataract surgery were also identified, including preoperative IOP/preoperative ACV and preoperative IOP/preoperative ACA, reflected in r(2) values of 13.7 and 13.7%, respectively (P<0.001 and P<0.001, respectively). CONCLUSIONS: Our study confirms the predictive value of the CPD ratio for IOP reduction after cataract surgery, and may contribute to the decision-making process in patients with glaucoma or ocular hypertension. Furthermore, two novel indices of preoperative parameters that are predictive for IOP reduction after cataract surgery were identified, and enhance our understanding of the mechanisms underlying IOP changes after this procedure. PMID- 20168347 TI - Spontaneous dislocation of an Artisan phakic IOL causing corneal decompensation requiring an endothelial graft. PMID- 20168349 TI - Re: The report 'irrigation of the capsular bag using a sealed-capsule irrigation device and 5-fluorouracil' by Milverton. PMID- 20168350 TI - Treatment of metastatic neuroblastoma with systemic oncolytic virotherapy delivered by autologous mesenchymal stem cells: an exploratory study. AB - Treatment of metastatic tumors with engineered adenoviruses that replicate selectively in tumor cells is a new therapeutic approach in cancer. Systemic administration of these oncolytic adenoviruses lack metastatic targeting ability. The tumor stroma engrafting property of intravenously injected mesenchymal stem cells (MSCs) may allow the use of MSCs as cellular vehicles for targeted delivery. In this work, we study the safety and the efficacy of infusing autologous MSCs infected with ICOVIR-5, a new oncolytic adenovirus, for treating metastatic neuroblastoma. Four children with metastatic neuroblastoma refractory to front-line therapies received several doses of autologous MSCs carrying ICOVIR 5, under an approved preliminary study. The tolerance to the treatment was excellent. A complete clinical response was documented in one case, and the child is in complete remission 3 years after this therapy. We postulate that MSCs can deliver oncolytic adenoviruses to metastatic tumors with very low systemic toxicity and with beneficial antitumor effects. PMID- 20168351 TI - Potent antitumor effects of combined therapy with a telomerase-specific, replication-competent adenovirus (OBP-301) and IL-2 in a mouse model of renal cell carcinoma. AB - OBP-301 (a telomerase-specific, replication-competent adenovirus with hTERT promoter) was constructed in a previous study and it showed a strong anticancer effect by inducing cell lysis in human lung and prostate cancer cells. This study investigated the effectiveness of a combination therapy of OBP-301 and interleukin-2 (IL-2) in a mouse model of renal cell carcinoma (RCC). The cell killing effect of OBP-301 was confirmed in vitro in the RENCA cancer cells. In in vivo experiment, luciferase-expressing RENCA cells were implanted in the left kidney and lung of BALB/c mice to prepare the RCC metastatic model. The animals were randomly divided into four treatment groups: PBS, IL-2 alone, OBP-301 alone and the combination. The analyses of orthotopic tumor weight, lung metastasis and luciferin-stained tumor images 14 days after each treatment showed significant tumor growth inhibition in the combination group in comparison with that in the OBP-301- or IL-2-treated groups. In addition, the percentage of regulatory T cells (Tregs) in the combination group was significantly suppressed in comparison with that in the PBS and single-agent treatment groups. The outcomes of this study suggest that tumor-specific oncolytic immunovirotherapy may become an attractive strategy for the treatment of human RCC. PMID- 20168353 TI - Capacitor modification to the Schenck and Metcalf N(2) laser. PMID- 20168352 TI - Gene-modified tumor vaccine secreting a designer cytokine Hyper-Interleukin-6 is an effective therapy in mice bearing orthotopic renal cell cancer. AB - Although renal cell cancer (RCC) is known to be immunogenic, clinical efficacy of various immunotherapeutic approaches remains unsatisfactory. Novel targeted therapies showing cytostatic rather than cytotoxic activity are unable to cure RCC patients. In our studies, we evaluated the therapeutic efficacy of whole-cell vaccine based on irradiated murine RENCA cells genetically modified to secrete designer cytokine--Hyper-IL6 (H6)--comprising IL-6 and soluble IL-6 receptor. An orthotopic RCC model based on a subcapsular implantation of RENCA cells into kidneys of Balb/C mice was employed. The efficacy of RENCA-H6 vaccine was compared with control vaccine (RENCA-wt) in relation to naive (non-immunized) animals. Three sets of vaccination experiments were carried out in a (i) protective, (ii) palliative and (iii) adjuvant (following nephrectomy) setting. The influence of vaccination on survival of RCC-bearing animals was analyzed. Specificity of vaccine-induced immune response was studied using model antigen GFP. RCC-bearing animals immunized with RENCA-H6 vaccine showed prolonged survival compared with other groups. In palliative and adjuvant settings the survival RENCA-H6-immunized animals exceeded 75%. Administration of RENCA-H6 inhibited formation and recruitment of Treg cells (CD4+CD25+Foxp3+) and increased maturation of DCs. RENCA tumors in RENCA-H6- vaccinated animals contained large populations of NK cells and activated CD4+, CD8+ T cells. In addition, in mice vaccinated with RENCA-H6 cells large population of CD4+ and CD8+ memory cells (CD62Llow) were detected. In the orthotopic RCC model, RENCA-H6 vaccine showed high therapeutic potential, which resulted from modulation of numerous immunological mechanisms. PMID- 20168354 TI - Scattered light effects in photoacoustic spectroscopy. PMID- 20168355 TI - Optimal design for beam sampling mirror gratings. PMID- 20168356 TI - Applied optics. AB - 3,843,835; 3,858,979; 3,858,981; 3,862,423; 3,884,552; 3,885,143; 3,890,034; 3,891,303; 3,934,153; 3,935,493; 3,937,942; 3,938,881; 3,939,347; 3,940,201; 3,941,923; 3,942,891; 3,944,323; 3,944,324; 3,944,337; 3,944,339; 3,944,341; 3,944,347; 3,944,730; 3,945,023; 3,945,025; 3,946,264; 3,947,094; 3,947,128; 3,947,717; 3,948,584; 3,949,223; 3,949,315; 3,949,318; 3,949,323; 3,950,082; 3,951,523; 3,952,311; 3,952,321; 3,952,323; 3,953,111; 3,953,112; 3,957,340; 3,958,864; 3,958,866; 3,960,442; 3,961,844; 3,961,845. PMID- 20168357 TI - Elementary derivation of the phase shift at a caustic. PMID- 20168358 TI - Properties of the terminated optical crossbar matrix. PMID- 20168359 TI - Light scattering by particles in laser Doppler velocimeters using Mie theory. PMID- 20168360 TI - Leaky modes on a dielectric waveguide: orthogonality and excitation; erratum. PMID- 20168361 TI - Nature of transient light signals diffracted from optically etched gratings. PMID- 20168362 TI - Mode-locked and frequency-doubled laser efficiencies. PMID- 20168363 TI - Tunable linearly polarized TEM(00) operation of CO(2) laser with a concave diffraction grating. PMID- 20168364 TI - Expected lidar return from tornado clouds. PMID- 20168366 TI - Simultaneous detection of direction of motion and fringe order determination in holographic displacement measurement. PMID- 20168365 TI - CO(2) laser beam shaping with computer generated holograms. PMID- 20168367 TI - Long path Fabry-Perot interferometers for condensed phases: a note on their design. PMID- 20168368 TI - Photokeratography using moire techniques. PMID- 20168369 TI - Optical microscopic observation of single small molecules. PMID- 20168370 TI - Doppler-shifted reflections of x rays in beam foil spectroscopy: comments. PMID- 20168371 TI - Improved miniature long-lived uv light source. PMID- 20168372 TI - Luminescence rejection in Raman spectroscopy. PMID- 20168373 TI - Application of pulsed-source spectrophone to absorption by methane at DF laser wavelengths. PMID- 20168375 TI - Subtle source of contamination in spectrophones. PMID- 20168374 TI - Calibration of the absorption spectra at 14-15 microm obtained with a tunable diode laser. PMID- 20168376 TI - Temperature dependence of the absorption edge of vitreous silica. PMID- 20168377 TI - Optics in liechtenstein. AB - In the late nineteen forties, a company was founded in the Principality of Liechtenstein, a tiny country located on the right bank of the upper Rhine. The development of this Balzers Company, which took its name from the village where it was and still is located, is briefly reviewed, and its uniqueness is discussed. PMID- 20168378 TI - Nonpolarizing interference films inside a glass cube. AB - The reflectance and transmittance of dielectric films at nonzero angle of incidence show strong polarization effects, and for many applications these effects are not wanted. Costich has recently published on the reduction of these effects in interference films. The extension of his theory to the case of a multilayer inside a glass cube is possible, but an efficient design does not result. In this paper another method using quarter-wave layers only is developed. PMID- 20168379 TI - Refractive indices of TiO(2) films produced by reactive evaporation of various titanium-oxygen phases. AB - In this paper experiments with reactive evaporation of the starting materials Ti, TiO, Ti(2)O(3), Ti(3)O(5), and TiO(2) to obtain nonabsorbing TiO(2) films are under discussion. For the starting materials TiO and Ti(3)O(5) the dependence of the TiO(2) film refractive index on the substrate temperature, oxygen pressure, and deposition rate was measured. For TiO dispersion curves of the resulting TiO(2) films as a function of the substrate temperature during film formation were determined. The successive evaporation of the different starting materials resulted in the formation of lambda/4 TiO(2) films with different refractive indices. This phenomenon was most obvious during the first evaporation. It disappeared after several evaporations in two groups of TiO2 films with different refractive indices. From the beginning only the starting materials Ti and Ti(3)O(5) resulted in TiO(2) films with constant refractive indices. The first material produced a high, the latter a lower film index. Depending on the number of evaporations performed, both types of TiO(2) films can be obtained with TiO. The films and residues in the crucibles were also subjected to chemical analyses. An attempt was made to explain the optical properties of the resulting TiO(2) films with regard to crystal structure, chemical composition, packing density influenced by the molecular composition of the vapor beam, chemical reaction with the crucible, substrate temperature, O(2) pressure, and deposition rate. PMID- 20168380 TI - Electron microscopic investigations of cross sections of optical thin films. AB - In this paper results are given of an electron optical investigation of the cross section of optical single films and multilayers obtained by fracture. Direct observation techniques with scanning microscopy and the surface replica technique with transmission microscopy were used. Scanning microscopy is simple in sample preparation but has relatively low resolution. The highest resolution of microstructural details can be obtained only with the replica technique in the transmission microscope. Photographs of ZnS-, MgF(2)-, ThF(4)-, TiO(2), and SiO(2)-films mainly in the form of multilayers and of a cermet-type sun protection film are shown. Some optical film properties, such as refractive index and light scattering, are strongly influenced by film microstructure. PMID- 20168381 TI - Broadband dielectric mirror coatings for Fabry-Perot spectroscopy. AB - A general approach to the design of broadband dielectric multilayer coatings for Fabry-Perot spectroscopy is described, with specific application to the design of coatings for the PEPSIOS spectrometer. Designs are presented for reflectivities of 91.5 +/- 1.0% over spectral ranges (lambda(max)/lambda(min)) from 1.3 to 2.0. PMID- 20168382 TI - Recording the parallelism of optically contacted Fabry-Perots. AB - A simple device has been constructed to record accurately the parallelism of optically contacted Fabry-Perots immediately after their manufacture. In this a Fabry-Perot fringe is tuned to be a maximum on-axis by varying the pressure of the gas in which the etalon is emersed. An insect-eye lens is then used to photograph the different fringe patterns from a large number of separate small areas of the Fabry-Perot simultaneously. PMID- 20168383 TI - Fringe formation in two-wavelength contour holography. AB - This paper presents a description of fringe formation in two-wavelength contour holography. Approximations are introduced primarily by restricting the recording wavelength difference with the aid of a tunable dye laser and by observing the contour fringes through a controlled viewing system aperture. Several holographic recording and readout arrangements are presented for which explicit and conveniently interpretable contour fringe formulations are derived. Finally, the results from a set of experiments performed with each of the arrangements are offered as experimental evidence supporting the analysis. PMID- 20168384 TI - Dynamically produced refractive-index variations with thickness of volume holograms in electrooptic crystals. AB - Dynamic theory of volume holography is used to calculate the variations in the thickness direction of the hologram-constituting refractive-index modulation and the externally observable effects of these variations in electrooptic materials. It is shown that thick holographic gratings may exhibit significant amplitude and grating phase variations with thickness including amplitude sign reversal. These nonuniformities strongly affect holographic grating recording and readout characteristics such as maximum possible diffraction efficiency and angular selectivity. Thus a variety of grating applications will be affected by these nonuniformities. PMID- 20168385 TI - Isopachics measurement using immersion method polarization holography. AB - This paper describes a new method of separating only the isopachics of a birefringent object, the present eliminating the photoelastic effect of the object by using immersion method polarization holography. Further, the isochromatics can be also obtained from the isochromatic-isopachic fringe pattern without mutual interaction. Experimental results are given for a photoelastic model using air and water as the immersion media. PMID- 20168386 TI - Binary silica optical fibers: refractive index and profile dispersion measurements. AB - The variation of the core-cladding refractive index difference Deltan(lambda) is determined as a function of wavelength for GeO(2)-SiO(2), B(2)O(3)-SiO(2), TiO(2) SiO(2), P(2)O(5)-SiO(2), Al(2)O(3)-SiO(2), and Cs(2)O-SiO(2) optical fibers. The measurements are obtained by electronically processing the output of an interference microscope illuminated by a monochromatic light source variable over the 0.5-1.1-microm range. The Deltan(lambda) results are utilized to calculate the precise grading of the refractive index profile characterized by an exponent alpha(lambda) required to achieve a minimum modal dispersion. The material dispersion for these compositions is also calculated with the aid of available n(lambda) data for SiO(2). PMID- 20168387 TI - Propagation of ir light in flexible hollow waveguides: further discussion. AB - A refinement of theoretical optical loss estimates is given for 10.6-microm radiation propagating in hollow metal waveguides. PMID- 20168388 TI - Propagation model for long step-index optical fibers. AB - This paper reports some theoretical and experimental investigations on the propagation of a pulse in long step-index optical fibers where mode conversion is present. We derive simple analytical expressions for the frequency response and the radiation pattern as a function of the fiber's length provided the launching conditions are known. A comparison with experimental observations made on a 3-km long Corning fiber shows reasonable agreement. We conclude that the approximations used to obtain the simple analytical solutions are satisfactory for predicting the transmission characteristics of the fiber. PMID- 20168389 TI - Scaling laws for cw 337-microm HCN waveguide lasers. AB - The gain and the saturation intensity of optimized cw 337-microm lasers are shown empirically to vary inversely as tube diameter. An expression is then derived for the power of a waveguide laser as a function of geometrical parameters, losses, and coupling. For optimized coupling the power is a strong function of tube diameter with a well defined maximum. Optimum diameter depends on tube length and losses only. The results agree well with the measured powers of three waveguide lasers delivering 30 mW, 100 mW, and 170 mW from discharges of 1-m, 2-m, and 3-m lengths. Such lasers are competitive with optically pumped submillimeter lasers. PMID- 20168390 TI - Interpulse interference and passive laser pulse shapers. AB - Passive pulse shapers including Fabry-Perot etalons, double-etalons, and classical beam splitters are examined both theoretically and experimentally for their temporal behavior. For temporally and spatially overlapped pulses, interpulse interference effects determine the resulting pulse shapes. The output pulses from such devices are expected to be of great importance for laser fusion pulse shaping. PMID- 20168391 TI - Laser-induced surface damage of infrared nonlinear materials. AB - The thresholds for surface damage due to pulsed laser irradiation at 10.6 microm have been measured for CdGeAs(2), AgGaSe(2), AgGaS(2), and Tl(3)AsSe(3). In each case the threshold for pit formation is significantly lower than the threshold for visible plasma formation. PMID- 20168392 TI - Surface electromagnetic wave coupling efficiencies for several excitation techniques. AB - The excitation efficiencies for coupling surface electromagnetic waves onto aluminum at a microwave frequency (f = 8.445 GHz, lambda = 3.55 cm) were studied experimentally for several different standard microwave techniques as well as two optical techniques (prism and grating) applied to the microwave frequency region and two new techniques (hump and valley). The peak measured efficiencies found were: for the standard rectangular waveguide, 92%; for the horn antenna, 73%; for the right angle prism properly gapped above the metal, 60%; for the hump of 10 wavelength radius of curvature, 35%; for the thin grating strips on polystyrene coated metal, 30%; for the grating bars gapped (1/2) wavelength above the metal, 26%; and, for the valley of 10-wavelength radius, 12%. The measurement of the excitation efficiencies for prism and grating coupling techniques sometimes required that the prism or grating be in the near field of the antenna. In addition to measuring peak efficiencies, the efficiencies were measured as functions of the gap heights, the angular orientations, the different diffraction modes, the shapes, and the materials of the grating bars. The coupling efficiencies for both prism and grating couplers show a strong dependence on gap height above the metal. Dielectric grating bars were found to be inefficient compared to solid or hollow metallic bars, or thin metallic strips. The distance between the target point of the center line of the microwave horn antenna and the corner of the prism was found to be about 1 wavelength for maximum prism coupling efficiency. PMID- 20168393 TI - Frequency variant optical signal analysis. AB - A class of coherent optical spectrum analyzers for one-dimensional signals is described that is characterized by a frequency variant response to the spectral components of the input signal. Operations performed exploit the second degree of freedom inherent in the optical systems. One example considered is a constant proportional bandwidth, log-frequency spectrum analyzer. Experimental and analytical results are presented. PMID- 20168394 TI - Refractive null correctors for aspheric surfaces. AB - The usefulness of a refractive null corrector is limited by how closely its aberrated wavefront can match the aspheric surface that requires testing. Guidance in both the design of the asphere to insure its nullability and the design of the null corrector is presented. A functional and constructional compendium of null corrector designs is proffered. PMID- 20168396 TI - Pupil filters for moderate superresolution. AB - Some superresolving pupils, featuring a central maximum narrower than Airy's core and a first secondary maximum of a few percent, have been computed, following Frieden's formula and his criterion of maximum superresolution for circular symmetry. A superresolution factor of about 28% may be achieved without much sacrifice of illumination. Other pupils have been investigated where the SF reaches 35%. The behavior of the sidelobes in the point impulse image is examined. The corresponding encircled energy and point impulse response are given. PMID- 20168397 TI - Aplanatic grazing incidence x-ray microscopes: design and performance. AB - A slightly modified version of the Head equations are used to describe an aplanatic grazing incidence microscope with possible application in the field of controlled fusion research. The improved theoretical blur circle radius of the aplanatic microscope is presented and compared to the theoretical blur circle radius of the corresponding ellipsoid-hyperboloid microscope. The results show that the improvement is important for high resolution instruments having grazing angles greater than about 2 degrees . PMID- 20168395 TI - Focus path of a laser beam deflected by a prismatic polygon mirror: its calculation and optimization. AB - The focus path of a laser beam deflected by a prismatic polygon mirror was calculated. It is shown that the larger the focal distance of the objective or the polygon radius, the closer the focus path approaches a straight scanning line. Especially in the case of small pattern scanning, a remarkably small deviation between actual focus path and straight scanning line can be achieved by suitable sizing and arrangement of the optical elements. PMID- 20168398 TI - Characterization of the imaging properties of x-ray focal spots. PMID- 20168399 TI - Performance of a silicon vidicon at low signal levels. AB - An integrating camera based on a cooled silicon vidicon detector is briefly described. A treatment is given of the capacitive lag which limits the performance for small signals. The remedy is to alter the cathode voltage after erase to place a pedestal of about 10(5) electrons/pixel under the signal. Test results indicate that the background noise level cannot be reduced below 600 electrons/pixel in a processed frame, and values may approach 1000. Despite these limitations, the vidicon is found to be a useful and sensitive detector. PMID- 20168400 TI - Photoelectron counting with an image intensifier tube and a self-scanned photodiode array. AB - A self-scanned photodiode array was fiber-optically coupled to an ITT proximity focused image intensifier tube. It was determined that a single photoelectron event produces 3.4 x 10(4) charge carriers in a photodiode. This charge is only a factor of 2.8 above the rms noise level of the preamplifier used in the tests, but standard charge-sensitive techniques are at least a factor of 12 better. The image tube and photodiode array combination can be packaged in a disk 5.1 cm in diameter and 2.6 cm thick. PMID- 20168401 TI - Absolute reference calorimeter for measuring high power laser pulses. AB - A calorimeter for making absolute energy measurements of high power laser pulses is described. The calorimeter, based on volume absorption in a solid, is calibrated electrically and requires no window or vacuum environment. An error analysis is included giving the systematic and random errors of the instrument for a laser measurement. Briefly, the following performance is typical of the 32 mm x 32-mm aperture calorimeter: range 0.4-15-J; random error +/-0.2% (one standard deviation); systematic error +/-2.3%; and an upper operational limit of 3 J/cm(2). Most of the volume absorber documentation is applicable for 1.06 microm; however, the calorimeter should be useful from the near ir through the visible. Absorbers for use with CO(2) lasers in the 9-11-microm range are also discussed. PMID- 20168402 TI - Sensitive far uv spectrograph with a multispectral element microchannel plate detector for rocket-borne astronomy. AB - An evacuated high transmission prism spectrograph using a microchannel plate detection system with resistive strip readout was flown behind a precision pointing telescope on a sounding rocket. The construction, preparation, flight performance, and calibration stability of the system are discussed. Despite the adverse environmental conditions associated with sounding rocket flights, the microchannel detector system performed well. Far uv spectra (1160-1750 A) of stellar and planetary objects were obtained; spectral features with fluxes as low as 0.06 photons cm(-2) sec(-1) were detectable. This was achieved by operating the plates at lower than normal gains, using sensitive pulse counting electronics with both upper and lower limit discriminators, and maintaining the spectrograph and detector at a pressure of ~10(-6) Torr until reaching altitude. PMID- 20168403 TI - Sum frequency mixing in potassium pentaborate as a source of tunable coherent radiation at wavelengths below 217 nm. AB - The generation of tunable coherent uv radiation by sum frequency mixing, in potassium pentaborate, the outputs of two tunable N(2) pumped dye lasers has been investigated. Tunable radiation extending from 217 nm to 208 nm has been generated in this manner. A conversion efficiency of 2.5 x 10(-4) is observed at input powers of ~2 kW in each laser beam. Improved refractive index data for potassium pentaborate are also presented. PMID- 20168404 TI - Quantum efficiency independence of the time integrated emission from a fluorescent molecule. AB - The sensitivity of chemical or biological analyses using fluorescent tagged reagents is limited by concentration quenching of the fluorescence at high tag concentrations and by photochemical bleaching if high illumination intensities are used. This paper shows by theoretical analysis and experimental verification that concentration quenching lengthens bleaching lifetimes, and the integrated fluorescent emission obtained on complete bleaching is invariant with fluorescent quantum efficiency, absorption cross section, and the illumination's intensity and duration. This can be used to produce extremely sensitive fluorescent tagging procedes. The procedure also improves photometric reproducibility, allows a fluorescent stain to act as a probe of several properties in its microenvironment, and allows sample background differentiation even when the free stain background is more fluorescent than the bound one. PMID- 20168405 TI - Remote measurement of HCI, CH(4), and N(2)O using a single-ended chemical-laser lidar system. AB - The applicability of the high energy discretely tuned DF laser for remote measurement of HCl, CH(4), and N(2)O has been investigated. A single-ended or monostatic lidar system using radiation backscattered from topographical targets was tested. Selective absorption of the backscattered signal was used to infer concentration of gaseous species. Good agreement was obtained between the lidar measurements and the concentrations determined by in situ measurements in the remotely positioned sample chamber. The lowest measurable material concentration for each gas was inferred from random fluctuations in the measured concentration. Sensitivity of the existing system to HCl, CH(4), and N(2)O was found to be 0.05 ppm-km, 6.0 ppm-km, and 0.24 ppm-km, respectively. An N(2)O plume was also measured in the open atmosphere between the lidar system and a foliage target to demonstrate system capabilities under typical field conditions. Performance predictions indicate that total burden and range-resolved species concentration measurements are feasible to a range of 10 km or more with commercially available components. PMID- 20168406 TI - Anomalous light scattering in liquid sulfur at the polymerization transition. AB - An anomalous increase of the forward light scattering in liquid sulfur is reported to occur in the 158-169 degrees C in which other physical properties of the liquid also show an anomalous behavior. The light scattering increases abruptly between 158 degrees C and 161 degrees C and then decreases and disappears at 169 degrees C, paralleling the behavior of the viscosity and the specific heat. The anomalous scattering effect is explained in terms of composition fluctuations generated at the onset of the ring-chain equilibrium transition which produce dielectric constant fluctuations. Following the theoretical model of polymerization developed by Tobolsky, it is proposed that these composition fluctuations may be produced by the peculiar dependence of the polymerization process on the temperature. The effect of thermal gradients is taken into account to explain the spatial distribution of the observed light scattering. It is shown how the anomalous light scattering can apparently increase the measured value of the absorption coefficient of the liquid. It is also discussed how it can be used to measure the polymerization temperature of liquid sulfur or similar systems. PMID- 20168407 TI - Six-beam models in radiative transfer theory. AB - A critical analysis is given of the applicability of six-beam models to radiative transfer in particulate materials. The method of introducing transverse scattering in these models is shown to cause fundamental difficulties in the case of physically plausible phase functions; in particular, the effective absorptivity is abnormally large and thus results in incorrect reflectances and transmittances. Six-beam calculations for several media are compared with accurate solutions, with Chu-Churchill two-beam results, and with a simple modification to the Eddington approximation, the last being generally superior over a wide range of conditions. PMID- 20168408 TI - Radiance distribution over a ruffled sea: contributions from glitter, sky, and ocean. AB - The upward radiance just above the ocean surface and at the top of the atmosphere is calculated for a realistic model including an ocean surface with waves. The separate contributions of the sun glitter, the reflected sky radiance, and the upwelling photons from the ocean are calculated. The Monte Carlo method takes account of both Rayleigh scattering by the molecules and Mie scattering by the aerosols as well as molecular and aerosol absorption in the atmosphere. Similarly, in the ocean, both Rayleigh scattering by the water molecules and Mie scattering by the hydrosols as well as absorption by the water molecules and hydrosols are considered. Separate single-scattering functions are used for the aerosols and hydrosols calculated from the Mie theory. Both the reflected and refracted rays, as well as the rays that undergo total internal reflection, are followed at the ocean surface. The wave slope is chosen from the Cox-Munk distribution. The upward radiance just above the ocean surface outside of the sun glitter region is dominated by the reflected sky radiation from the horizon to a nadir angle of observation of from 68 degrees to 23 degrees depending on the azimuthal angle and the solar zenith angle; the upwelling photons from the ocean dominate over the remainder of the hemisphere, except in the region of the sun glitter which centers around the mirror image of the sun on a calm ocean. It is possible to answer various questions about the interaction of light with the ocean from the quantitative results presented here. PMID- 20168409 TI - Asymptotic radiance and polarization in optically thick media: ocean and clouds. AB - Deep in a homogeneous medium that both scatters and absorbs photons, such as a cloud, the ocean, or a thick planetary atmosphere, the radiance decreases exponentially with depth, while the angular dependence of the radiance and polarization is independent of depth. In this diffusion region, the asymptotic radiance and polarization are also independent of the incident distribution of radiation at the upper surface of the medium. An exact expression is derived for the asymptotic radiance and polarization for Rayleigh scattering. The approximate expression for the asymptotic radiance derived from the scalar theory is shown to be in error by as much as 16.4%. An exact expression is also derived for the relation between the diffusion exponent k and the single scattering albedo. A method is developed for the numerical calculation of the asymptotic radiance and polarization for any scattering matrix. Results are given for scattering from the haze L and cloud C3 distributions for a wide range of single scattering albedos. When the absorption is large, the polarization in the diffusion region approaches the values obtained for single scattered photons, while the radiance approaches the value calculated from the expression: phase function divided by (1 + kmicro), where micro is the cosine of the zenith angle. The asymptotic distribution of the radiation is of interest since it depends only on the inherent optical properties of the medium. It is, however, difficult to observe when the absorption is large because of the very low radiance values in the diffusion region. PMID- 20168410 TI - In process ellipsometer azimuth angle calibration. AB - Two methods are described which provide in-process calibration of ellipsometer divided circles. Both methods (a residual method and a nonlinear least-squares estimation procedure) utilize multiple measurements on any arbitrary specimen to compute the azimuth angle corrections for the polarizer, compensator, and analyzer divided circles. The results of an experimental comparison of the two methods show (1) the confidence limits on the calibration constants are greater than is generally assumed, (2) that within experimental uncertainties both methods yield the same set of calibration constants, but one method may be more appropriate than the other for a given set of data, (3) the calibration constants can be a function of the wavelength of the light used for measurements, (4) other factors being equal, the maximum accuracy in a conventional ellipsometer system would be obtained by using a fixed-polarizer nulling scheme with the compensator set after reflection. PMID- 20168411 TI - Absorption measurements of 1-1 difluoroethylene (C(2)H(2)F(2)) at 10.6-microm wavelength. PMID- 20168412 TI - From the editor. PMID- 20168413 TI - Applied optics of optics and opticists. PMID- 20168414 TI - Patents. AB - 3,888,569; 3,889,226; 3,914,544; 3,915,548; 3,915,549; 3,915,551; 3,917,378; 3,917,379; 3,917,380; 3,936,138; 3,936,139; 3,938,896; 3,942,008; 3,942,861; 3,947,084; 3,947,086; 3,951,524; 3,953,106; 3,953,667; 3,953,863; 3,958,104; 3,958,865; 3,961,838; 3,961,846. PMID- 20168415 TI - Vacuum uv performance of silicon detectors. PMID- 20168416 TI - Solar concentrators with maximal concentration for cylindrical absorbers: erratum. PMID- 20168417 TI - Optical pulsed ranging: method for improving measurement accuracy: comment. PMID- 20168419 TI - High-precision reflectivity measurement technique for low-loss laser mirrors. PMID- 20168418 TI - Transmittance model for absorbing gases with variable mixing ratios in inhomogeneous atmospheres. PMID- 20168420 TI - Precision interferometer for measuring photoelastic constants. PMID- 20168421 TI - Transmission of Gaussian pulses through monomode dielectric optical waveguides. PMID- 20168423 TI - Inverse sampling spatial filtering as a method of image multiplication. PMID- 20168422 TI - Photo-induced stopping of guided light in dye doped polyurethane films. PMID- 20168424 TI - Real-time optical signal processors employing optical feedback amplitude and phase control: comment. PMID- 20168425 TI - Laser applications in medicine and biology: a bibliography. AB - This bibliography covers the period from 1963 through 1974; 916 references are classified under 23 subject headings. The references are arranged chronologically. PMID- 20168426 TI - Airborne bathymetric charting using pulsed blue-green lasers. AB - Laboratory and airborne experiments have proven the feasibility and demonstrated the techniques of an airborne pulsed laser system for rapidly mapping coastal water bathymetry. Water depths of 10 +/- 0.25 m were recorded in waters having an effective attenuation coefficient of 0.175 m(-1). A2-MW peak power Nd:YAG pulsed laser was flown at an altitude of 600 m. An advanced system, incorporating a mirror scanner, a high pulsed rate laser, and a good signal processor, could survey coastal zones at the rate of several square miles per hour. PMID- 20168427 TI - Axial mode structure of a copper vapor pumped dye laser. AB - A search for lasers to be employed in the development of uranium isotope separation techniques led to the investigation of a copper vapor pumped tunable dye laser patterned after the concept developed by Hansch. This investigation revealed that although the time integrated spectral output covered approximately 1.3 GHz, which was the desired bandwidth, the time resolved spectral output included high visibility mode structure which fluctuated randomly from pulse to pulse. These fluctuations could significantly reduce the throughput efficiency of multiphoton photoionization isotope separation processes involving strongly inhomogeneously broadened transitions. PMID- 20168428 TI - Electrochemical pumping of laser dyes. AB - Calculations are made of the electrochemical pumping rates needed to reach known optical lasing thresholds in a dye laser. Rates and yields have been measured.or checked as needed. An optimum cavity is used for the calculations, but the best pumping rate is still more than 2 orders of magnitude below threshold. These calculations help explain the many failures to make an EGCL laser. PMID- 20168429 TI - HF laser spectral analysis using near-field holography. AB - Spatially resolved holographic spectral analysis has been applied to the 10-cm diam near-field beam of a pulsed HF laser. The hologram recording procedure is described, and the spatial relief fringes of the resulting phase hologram are discussed. PMID- 20168430 TI - High-energy short-pulse flashlamps: operating characteristics. AB - A study of high-current short-pulse flashtubes operating in (or near) the ablation regime is presented. It is shown that the behavior of such tubes is well represented by an analysis in which the discharge plasma is supposed to radiate as a blackbody. In particular, the analysis accounts for the fact that the light output from the flashtube tends to saturate as a function of the input energy, whereas the discharge current does not. This approach allows the development of a useful representation of the operating characteristics of this type of flashtube in terms of the energy input to unit volume of the plasma. Design criteria are developed for the diameter and radius of such flashtubes to ensure high light output without causing excessive ablation of the capillary wall material. PMID- 20168431 TI - Photoabsorption and ionization cross sections in a seeded CO(2) laser mixture. AB - Photon absorption and photoionization spectra in a CO(2) laser mixture seeded with selected low ionization threshold additives are presented. Such data are used to determine total absorption and ionization cross sections for some gases and vapors of interest. The results identify tripropylamine as an interesting seedent material, as it exhibits a longer wavelength photoionization effect essentially independent of the primary host laser gases. PMID- 20168432 TI - Soft x-ray gain in the alkali earths. AB - An unsuccessful attempt was made to observe gain in low pressure sodium vapor at 372 A at an x-ray pumping power level of 0.1 GW/cm(2) . As a result we suggest that high density alkali-earth vapors be used instead. With a system of tunable dye lasers of moderate power, it should be possible to reduce substantially the lower laser level population and achieve gains on the order of 1-3 cm(-1). The calculations reported verify this. The additional outer electron in the alkali earths is necessary to use the dye laser scheme. The tradeoff is that the upper laser level can Auger decay. Our calculations indicate that this is not too severe a limitation in Ca. Since the calculations may be in error, we further suggest that the dye laser scheme is applicable to alkali-earths which have been preexcited to levels for which Auger decay is forbidden in LS coupling. PMID- 20168433 TI - X-ray and far uv multilayer mirrors: principles and possibilities. AB - The possibility of making multilayer reflecting coatings by using materials whose dielectric susceptibility is very near to unity at the frequency under consideration is discussed. For the pair of substances with a given Ree and Ime the explicit expressions are obtained for the value of reflection coefficient and for the optimum thickness of layers. The published data on Re and Im allowed us to choose the pairs of substances for which one may hope to create (in principle) the mirrors for normal incidence with R ~ 50% at lambda greater, similar 30 A. PMID- 20168434 TI - Sub-keV x-ray imaging using a low-cost ellipsoidal lens. AB - An ellipsoidal lens has been evaluated using the sub-keV x radiation from a laser produced plasma. The measured collection efficiency is ~0.3%. Inexpensive fabrication and alignment techniques are discussed, and imaging measurements using visible and x-ray sources are presented. PMID- 20168435 TI - Measurement of HCI absorption coefficients with a DF laser. AB - Absorption coefficients in the fundamental P-branch of HCl at several DF laser transitions from 2439.02 cm(-1) to 2862.87 cm(-1) have been measured experimentally. The 2-1 P(3) DF laser transition has been shown to overlap the P(6) HCl(37) absorption line within the halfwidth of an atmospherically broadened line. The absorption coefficient k was measured to be 5.64 +/- 0.28 (atm-cm)cm( 1) for a 0.27% mixture of HCl in N(2) at a total pressure of 760 Torr. A theoretical and experimental comparison of the pressure dependence of k showed that the 2-1 P(3) DF transition lies 1.32 +/- 0.15 GHz from the center of the P(6) HCl absorption line. This line separation is in good agreement with published positions for this DF laser transition and the HCl absorption line. At least four other DF laser transitions in the spectral interval measured are reported showing measurable absorption (>/=10%) for a 10.2% mixture of HCl in N(2) across a 1-m pathlength. Applications of these results to differential absorption lidar (DIAL) and to heterodyne detection are also discussed. PMID- 20168436 TI - Photoacoustic technique for determining optical absorption coefficients in solids. AB - An investigation was made of a photoacoustic technique for determining the optical absorption coefficient in solids. A train of laser pulses was passed through the solid, and a piezoelectric transducer attached directly to the sample measured the amplitude of the elastic wave generated by the absorbed radiation. Calibration was performed at a wavelength of known absorption. The sensitivity of the technique was found to be limited to about 1 x 10(-5) cm(-1) in our samples due to radiation scattered onto the transducer, but the technique is capable of measuring absorption coefficients in the 10(-6)-cm(-1) range using laser powers of about 1 W. PMID- 20168437 TI - Profile synthesis in multicomponent glass optical fibers. AB - It is proposed that the concentration profiles of the components of a multicomponent glass be specified independently in order to synthesize an optical fiber having several optimized transmission characteristics. Assuming a linear relationship between concentration and refractive index, we show how the synthesis procedure operates for ternary glasses and illustrate the method by computing the concentration profiles required to realize a SiO(2)-GeO(2)-P(2)O(5) fiber with minimum modal dispersion over a wide range of wavelengths ( partial differentialalpha/ partial differentiallambda = 0). PMID- 20168438 TI - Mode dispersion in diffused channel waveguides by the effective index method. AB - The effective index method for calculating waveguide mode dispersion is reviewed and applied to uniform rectangular optical waveguides with both small and large index differences. The results are shown to be at least as accurate as other approximate techniques. The effective index method is then applied to channel waveguides assuming 1-D and 2-D diffusion. Channel waveguides without sideways diffusion are shown to be described by the method using a normalized notation and previously published universal dispersion curves. Two-dimensional diffusion theory is applied to treat the case of isotropic sideways diffusion. A new, normalized, 1-D universal chart is obtained which in conjunction with previous results defines waveguide mode dispersion in isotropically diffused 2-D channels. PMID- 20168439 TI - Electrooptic polarization switch for multimode fibers. AB - An extensive theoretical analysis of an electrooptic polarization switch has been carried out. The main objective of the study is to ascertain whether it is possible to design such a switch with acceptable levels of optical crosstalk and control voltage if the device is used in conjunction with a multirmode optical fiber transmission system. The results of the study show that about 30-dB signal to-crosstalk ratio can be obtained when an isotropic cubic material such as CdTe is used, and the fibers do not have an excessively large numerical aperture. Less isolation (~7 dB) can be obtained when using an anisotropic material with a small birefringence such as LiTaO(3). Drive voltages in either case range from 10 V to 50 V. PMID- 20168441 TI - Optimum imaging method for optical data processors. AB - Several two-lens systems are considered for imaging an input record with specified magnification and focal lengths. Under certain conditions the total length of each setup from input record to image can be minimized (absolute). Alternately, limiting values of minimum length configurations are determined in the neighborhood of the open endpoints of a range of operation. PMID- 20168440 TI - Dry processing of high resolution and high aspect ratio structures in GaAs Al(x)Ga(1-x) As for integrated optics. AB - The properties of ion-beam milling, rf-sputter etching, and plasma etching for the fabrication of high resolution integrated optical structures in GaAs and Al(x)Ga(l-x)As were investigated. The ion-beam milling rates for a 500-eV Ar beam were measured as a function of the angle of incidence for A2-1350 photoresist, GaAs, Al, Ti, and Ta in vacuum. For Ti and Ta, the ion-beam milling rates were measured for various O(2) partial pressures in the target chamber. For the fabrication of high-resolution patterns, a technique was developed in which a very thin resist pattern is transferred by plasma etching into a layer of Ta prior to ion-beam milling. Both ion-beam milling and rf-sputter etching through the Ta metal mask were used for the fabrication of gratings in GaAs. From measurements made in this study, it was found that rf-sputter etching in an Ar atmosphere results in a resolution comparable to ion-beam milling at normal incidence, but the material removal efficiency is somewhat lower. Third-order Bragg diffraction gratings (period = 0.36-0.37 microm) for GaAs-Al(x)Gal(1-x) As heterostructure lasers and ridged stripes 10 microm wide and 1.5-2.0 microm deep have been prepared by these techniques. High-aspect ratio or skewed-profile gratings were obtained by selection of the ion-beam milling or rf-sputter etching conditions. As previously reported, these structures have been overgrown by MBE A(x)Gal(1-x) As layers to form distributed feedback lasers. PMID- 20168442 TI - Optimum edge detection filter. AB - Edge detection and enhancement are required in a number of important image processing applications. In this paper we consider the problem of optimizing spatial frequency domain filters for detecting a class of edges in images. The filter is optimum in that it produces maximum energy in the vicinity of the location of the edge for a given spatial resolution I and the bandwidth ?. We show that the filter transfer function can be specified in terms of the prolate spheroidal wavefunctions for a given space-bandwidth product I?. Further we show that for values of I? less than 2, the optimal filter represents the Laplacian operator in image space followed by a low pass filter with a cutoff frequency ?. PMID- 20168443 TI - Real-time optical correlation of 3-D scenes. AB - A real-time correlation operation is performed on a 3-D object with a liquid crystal incoherent-to-coherent image transducer. The character of the autocorrelation peak as a function of scene translation and rotation is described and an example presented of cross correlation with a second similar object. PMID- 20168444 TI - MTF evaluation with optical matched filters. AB - A modulation transfer function (MTF) measuring technique is described that employs the optical matched filter (OMF). It is shown that this technique is mathematically equivalent to the multiple-sine-slit microdensitometer (MSSM) MTF measurement approach. Similarities and differences in the implementation of the two methods are discussed. Both theoretical and experimental matched filter results are investigated. A method for extending the OMF to high spatial frequencies is discussed. PMID- 20168445 TI - Solutions of the refraction and extinction integrals for use in inversions and image formation. AB - Analytic solutions to the refraction and extinction integrals are presented for the case of a horizontally or spherically stratified medium. These solutions are not only useful for the calculation of the images that would be seen through a lens with a continuously varying index of refraction, such as the atmosphere, they also provide a solution to the inverse problem of determining the refractive structure from measurements of the image. A remarkably simple inversion scheme is presented for determining the refractive (temperature) structure of the earth's atmosphere by observations of the setting sun. The same scheme works for determination of vertical profiles of the extinction coefficient. PMID- 20168446 TI - Geometrical optics of inhomogeneous particles: glory ray and the rainbow revisited. AB - The glory ray and the rainbow are analyzed by considering the scattering of light from inhomogeneous particles. It is shown that melting ice crystals may be strong contributors to the glory ray. Geometrical optics is used to investigate and catalog a wide variety of particle inhomogeneities which support rainbow and glory rays. PMID- 20168447 TI - Postprocessing of imagery from active optics: some pitfalls. AB - There may be pitfalls to watch for when recording imagery from active phase compensation devices located in the exit pupil of the system. At least three of these pitfalls are identified, and each is manifested as a degradation in the imagery. Both nearby and high altitude atmospheric disturbances contribute to the degradation. The first pitfall is identified as residual phase errors caused by measurement and hardware limitations. The second pitfall is identified as nonisoplanatism, and it occurs because wavefronts from different source points experience different high altitude disturbances. The third pitfall is identified as amplitude fluctuations in the exit pupil of the system, and it is also caused by the high altitude atmospheric disturbances. The two pitfalls caused by the high altitude disturbances are reduced by applying additional phase compensation in a plane that is the image of the high altitude disturbances. But even this may not be sufficient to eliminate the need for postprocessing of the image ry of extended sources. PMID- 20168448 TI - Development of laser speckle and its application to surface inspections. AB - The growth of granularity in partially developed speckle patterns produced in the near field of wave object surfaces under illumination of laser light has been experimentally investigated. The average contrast of intensity variations in near field speckle patterns due to three kinds of objects having different surface qualities has been measured as a function of the receiving distance from the object surface. It is found that a variation of the speckle contrast against the receiving distance is closely related to the surface waviness of objects. On the basis of this relation, a new and simple method is proposed to inspect the surface quality of objects. PMID- 20168449 TI - Maximum likelihood estimate of target angles for a conical scan tracking system in the presence of speckle. AB - The equation for the maximum likelihood estimate of target angle is derived for a conical scan tracking system when the target produces speckle and Gaussian noise is present. Operation with a direct detection receiver is assumed with the average photon flux large enough so that the discrete nature of photoelectric events may be ignored. For large average SNRs, the estimate is shown to be unbiased and the variance of the estimate limited by both the average SNR and the number of degrees of freedom of the detected field. PMID- 20168450 TI - Quasi-elastic light scattering from structured particles. AB - We present a formulation by which the scattered field correlation function of a nonstationary structured particle can be calculated. Specifically, we consider the case of micron-size bacteria, where the Rayleigh- Gans-Debye approximation may be used to evaluate the correlation function. We show that the width of the intensity correlation spectrum (as measured, for example, by the photon correlation technique) exhibits I an oscillatory behavior which is characteristic of the interference pattern produced by the internal structure. Two cases are of interest: diffusion and motility are considered in detail, and some evidence of the predicted behavior is shown from the photon correlation measurement of E. coli bacteria. PMID- 20168451 TI - Shearing interferometer as an interferometric filter for the reduction of scattered light. AB - The background radiation problem encountered in astronomical observations is reviewed, and it is observed that a considerable reduction of the background radiation can be achieved by using interferometric techniques. A longitudinal radial shearing interferometer is described which meets the requirements of this application. The formal development of its properties as well as the results of preliminary tests are presented. It is shown that for a small region of the telescope field, this interferometer can be expected to reduce the background radiation originating in the telescope by a factor of 50 to 500, to reduce the background radiation produced by Mie type scattering external to the telescope to a level below that produced by Rayleigh scattering, and to reduce the background radiation from Rayleigh scattering by a factor of two. These properties can be extended to broadband spectral operation and can be achieved without degrading the astrometric qualities of the telescope. The size of the interferometer is quite small making it easy to add to an existing telescope. PMID- 20168452 TI - Algebraic expression for the diffuse irradiance reflectivity of water from the two-flow model. AB - A simple expression is obtained for the irradiance reflectance of the ocean based on a two-flow radiative transfer model. This expression is found to reproduce the Monte Carlo calculations to within 7% for scattering albedo values less than 0.8. On the basis of this expression, it is shown that the remotely sensed water color data can be interpreted with the help of iterative optimization techniques, provided that the variations of backscattering coefficient and absorption coefficient with wavelength can be modeled. PMID- 20168453 TI - Zernike test. 1: Analytical aspects. AB - The Zernike test is extensively interpreted from an interferometric point of view. The discussion includes the optimization of the Zernike disk parameters (radius, phase, and transmittance) for low-order aberrations, and a method is provided for choosing the disk parameters so as to optimize test performance for maximum sensitivity and linear range. A signal-to-noise analysis predicts test sensitivity to be better than lambda/100. PMID- 20168454 TI - Zernike test. 2: Experimental aspects. AB - A step-by-step procedure for the manufacture of Zernike disks and the design and fabrication of a laboratory Zernike test instrument are described. A laboratory wavefront error simulator is used to evaluate the loworder aberration measurement sensitivity of the Zernike test instrument. Measurement sensitivities were found to be better than lambda/100 for all the low-order aberration types. PMID- 20168455 TI - Optimization of computer controlled polishing. AB - The computer controlled polisher uses a small, rotating tool which travels over the workpiece surface. By accurately controlling the velocity of the tool, a prescribed amount of material may be removed at each point on the surface. The use of a small tool permits rapid figuring of aspheric surfaces for lightweighted workpieces. The computer controlled polisher was optimized with regard to tool configurations, dwell times, scanning paths, and operating parameters. The unit has successfully fabricated several different workpieces including a mirror with a 1/80-wave rms departure, where a wave is 0.6328 microm. PMID- 20168456 TI - Coherence-length adapted hologram-interferometer. AB - The design of a diffraction shearing hologram interferometer is analyzed. It is used for temporal coherence measurements of thermal and laser sources. Formulas, geometries, experimental setup, and correction factors for spatial coherence and for the finite dimension of the detector surface are given. Models of holograms, adapted to coherence lengths in the submillimeter, millimeter, and centimeter range are proposed. The inapplicability in the cw gas laser range is stressed. Experimental results are compared with those of a Michelson interferometer and with another holographic technique. PMID- 20168457 TI - Double-pulsed time differential holographic interferometry. AB - A unique method for double-pulsed holographic interferometry has been developed and employed in a meter-long theta-pinch experiment. Q-switching of two orthogonally polarized ruby laser beams, using the same lasing medium but different laser cavities, allows pulse separations of 0.2-100 microsec. The double-pulse operation with short pulse separation avoids many temporal aberrations seen in single-pulse systems and allows time differential interferograms of transient phenomena such as seen in theta-pinch plasmas. Orthogonal polarization of the two beams permits background fringe construction without the need for a mechanically introduced planar phase shift. PMID- 20168458 TI - Spherical lamellar grating interferometer for airborne astronomical observations of far infrared objects. AB - A lamellar grating has been developed to be used for very far ir observations on the Gerard P. Kuiper Airborne Observatory. The design characteristics and performance during laboratory testing and initial observations of Jupiter at wavelengths between 50 microm and 500 microm are presented. PMID- 20168459 TI - Slow scan SEC vidicon system. AB - A slow scan SEC vidicon system is described here. This system is coupled to the 152.4-cm (60-in) McMath telescope at Kitt Peak National Observatory. An anamorphic lens system is used to couple optically the vertical spectrograph to the vidicon system. The resolution of the over-all system is 55 mA, while the resolution of the spectrograph alone is 50 mA. mance. PMID- 20168460 TI - Infrared-XUV telescope for multipurpose applications. AB - A nonfocusing, collimating telescope is described to be used for spectral regions from x-rays to the ir. In combination with optical components such as spectrometers, there is a wide range of applications in space research, earth sciences, and related fields. PMID- 20168461 TI - Optical properties of the leaves of some African crop plants. AB - The fate of radiation incident on the leaves of some African crop plants is examined. Transmission coefficients for photosynthetically active radiation are 0.05-0.10 for mature leaves and 0.09-0.39 for young leaves. Increasing the angle of incidence of radiation results in a rise in reflectivity and a fall in absorptivity. Transmissivity rises to angles of incidence of 60 degrees and then falls sharply. Absorptivity and reflectivity are cubic functions of the angle of incidence of radiation. Consequences of these findings for photosynthesis are discussed. PMID- 20168462 TI - Continuously tunable optical filter for use in resonance Raman spectroscopy. AB - A tunable optical filter is described for removing undesired emissions from laser beams for use in resonance Raman and fluorescence spectroscopy. The bandpass is 1 nm, and the filter is tunable from 400 nm to 750 nm. The degree of polarization of the dye laser beam is improved by the filter. Two independent controls tune the filter to the selected frequency, while the input and output beam directions remain fixed. PMID- 20168463 TI - Relative spectral sensitivity distribution measurements of photoreceivers. AB - Problems related to the measurement of spectral sensitivity distribution are discussed. Special systems, an electromechanical one with servo-control and an all-electronic one using an instantaneous value measuring ratiometer, have been built and their performance tested. A number of problems generally encountered in such measurements can be eliminated by using the ratiometric system. PMID- 20168464 TI - Filter plane resolution requirements for coherent optical correlators. PMID- 20168465 TI - From the editor. PMID- 20168466 TI - Incoherent optical processing of complex data. PMID- 20168467 TI - Generation of coherent optical pulses. PMID- 20168468 TI - Bipolar pointspread function synthesis by phase switching. PMID- 20168469 TI - Optical activitles in industry. PMID- 20168470 TI - Applied optics of optics and opticists. PMID- 20168471 TI - Patents. AB - 3,912,374; 3,926,506; 3,926,507; 3,927,931; 3,927,932; 3,930,713; 3,932,025; 3,932,027; 3,932,040; 3,932,041; 3,932,699; 3,932,702; PMID- 20168472 TI - Ripple structure of the extinction coefficient. PMID- 20168473 TI - Reflectance of a flat ocean in the limit of zero water depth. PMID- 20168475 TI - Infrared spectral radiance of a hot source through an atmospheric path: errata. PMID- 20168474 TI - Error probability deterioration causes: effect on, the confidence level of atmospheric laser links; entropy of an atmospheric path. PMID- 20168476 TI - Deconvolution of ir spectra in real time. PMID- 20168477 TI - Off-plane stigmatic imaging with spherical concave gratings: experimental verification. PMID- 20168478 TI - Properties of some infrared filters. PMID- 20168479 TI - Ring interferometer 950 m long. PMID- 20168480 TI - Hologram fringe stabilization method. PMID- 20168481 TI - Room temperature vulcanizing silicone rubber as an optical element. PMID- 20168482 TI - Injection tuning of a pulsed TEA CO(2) laser. PMID- 20168483 TI - Calibration of satellite radiation instruments. AB - In 1973 COSPAR and the Radiation Commission set up an ad hoc committee to consider problems of calibration and intercomparison of radiation measuring instruments mounted on rockets or satellites. This committee organized the Grenoble symposium in 1975. This short paper introduces some of the papers presented there and summarizes certain recommendations made at Grenoble. PMID- 20168484 TI - Measurement of the earth radiation balance as an instrument design problem. AB - The net radiation balance of the earth is important globally for synoptic scale models and long-term climatic trends. It is important at the mesoscale level because it is a strong driving force on local meteorological phenomena. Both synoptic and mesoscale measurements are possible only from earth orbiting spacecraft, and serious efforts have been made to implement them. They have not achieved sufficient accuracy, precision, and stability to be really meaningful meteorologically. Measuring a small difference between two large numbers-the input to the earth and the earth radiation to space-is quite difficult and compounded by the spectral differences between the two. The instrumental considerations to achieving improvements in net radiation balance are discussed. The ratio of input to outflow, like albedo, is a dimensionless number which is amenable to measurement without recourse to calibrated instruments. If the solar constant is indeed reasonably constant, this ratio, which is more easily measured than an absolute value of either quantity, will be acceptable. Instrument stability, both spectral and absolute, as well as calibration methods and accuracy will be discussed with specific emphasis on estimating how and to what degree they can be improved. PMID- 20168485 TI - Radiation standards. AB - The NPL maintains standards and provides calibrations for measuring the spectral emission of sources and the spectral sensitivity of detectors in the uv, visible, and near ir range. A brief account is given of the way these standards are established, the use of different types of calibration, and the accuracy attainable. PMID- 20168486 TI - Calibration of radiation instruments for the measurement of the radiant flux of an arbitrary source. AB - The relation between the incident radiative signal and the electrical output of a radiometric sensor system is analyzed. It is shown that the determination and use of the calibration factor depend on the knowledge of the spatiotemporal and spectral relative distribution functions of the incident source. Three fundamental rules are stated, and the easiest to use particular radiometric system is considered. PMID- 20168487 TI - Nimbus-6 earth radiation budget experiment. AB - This paper describes the Nimbus-6 earth radiation budget experiment including its prelaunch calibration and in-flight performance. A preliminary assessment of the data shows the ERB measurement of the solar constant to be 1392 W/m(2) which is 1.6% higher than the expected value of 1370 W/m(2). Both values are traceable to the cavity radiometer scale. There is a disagreement between the fixed wide-angle and scanning narrow-angle measurements of planetary outgoing longwave radiation flux. Since the scanning channels are calibrated in-flight and show good agreement with previous observations of the Nimbus-3 satellite, the discrepancy is believed to be due to erroneous wide-angle flux estimates. The erroneous estimates may be caused by the misinterpretation of the transfer function for the wide-angle-earth-flux sensing thermopile detectors when viewing the earth which, unlike the prelaunch calibration source, does not fill the field of view of the detector and is not an isotropic radiation source. A field of view factor for the wide-angle channels is determined using an in-flight calibration procedure using the night-time scanning channel longwave radiation flux measurements as the absolute standard. The planetary global albedoes, longwave radiation fluxes, and net radiation are about 30%, 240 W/m(2), and -4 W/m(2) for the months of July and August 1975, which is in good agreement with previous Nimbus-3 estimates. PMID- 20168488 TI - Calibration of infrared instruments for the remote sounding of atmospheric temperature. AB - For ir radiometers making remote observations of atmospheric temperature structure, an absolute accuracy of ~(1/2)% in radiance measurement is required and a relative accuracy between measurements of ~0.1%. Such accuracies can be achieved. The present theoretical models of the 15-microm carbon-dioxide band are inadequate for interpretation of remote sounding observations and careful measurements of atmospheric transmission in this region are required. PMID- 20168489 TI - Spectral band passes for a high precision satellite sounder. AB - Atmospheric temperature soundings with significantly improved vertical resolution can be obtained from carefully chosen narrow band-pass measurements in the 4.3 microm band of CO(2) by taking advantage of the variation of the absorption coefficients, and thereby the weighting functions, with pressure and temperature. A set of channels has been found in the 4.2-microm region that is capable of yielding about 2-km vertical resolution in the troposphere. The concept of a complete system is presented for obtaining high resolution retrievals of temperature and water vapor distribution, as well as surface and cloud top temperatures, even in the presence of broken clouds. PMID- 20168490 TI - Temperature soundings with partially scanned interferograms. AB - The information contained in a complete interferogram and in a spectra are equivalent, but within a portion of an interferogram the two contain different information and cannot be directly compared. The partial interferogram provides information about particular types of structure within the spectra and may be better suited to a particular task than the spectra which contains much information of no value to the particular task. The advantages of partially scanned interferograms for remote soundings of atmospheric temperature are discussed, and several examples are given. These suggest that partially scanned interferograms can provide more detailed and versatile information than the presently used techniques. In particular, they seem able to cope with the temperatures near the ground and temperature inversions. PMID- 20168491 TI - Estimation of the refractive-index temperature structure parameter over the ocean. AB - The semiempirical equation of Wyngaard, Izumi, and Collins is combined with the bulk aerodynamic formulas to provide equations for the estimation of C(T)(2) (the refractive-index temperature structure parameter) in the atmospheric boundary layer above the sea. The equations relate C(T)(2) to easily measured quantities of average wind speed and air-sea temperature and moisture differences. Comparison with limited C(T)(2) data obtained in the marine boundary layer suggests that the estimation equations are satisfactory. PMID- 20168492 TI - Atmospheric turbidity and the circumsolar radiation. AB - We investigate the possibility of determining the turbidity from the intensity of the circumsolar radiation and find that such a connection can be made only when the size distribution of the aerosol particles is known. However, measurements of both the turbidity and the aureole intensity can give useful information about the size distribution. PMID- 20168493 TI - Transient thermal blooming of a slewed laser beam containing a region of stagnant absorber. AB - The transient thermal blooming of a slewed laser beam containing a stagnation point is studied experimentally with pivoted absorption cells and analytically with a 4-D computer code. Natural convection is included in the code to model the experimental situation. Substantial agreement is found between the predictions of the code and the experimental data for a variety of pivot positions and slew rates. The experimental and calculated results show that after an initial transient decay the intensity at the receiver tends toward a steady-state value. The origin of this quasi-steady state is explained in terms of a shrinking stagnation zone in the slewed beam. PMID- 20168494 TI - Stagnation and transonic effects in thermal blooming. AB - The effects of slewed high-energy beams on an absorbing medium are considered near regions where the relative air velocity is (a) zero and (b) transonic. Limiting effects on the density changes are buoyancy and sound speed changes, respectively. In both cases, the immediate environs of the singular point are greater contributors to phase changes in the beam than are the singularities themselves. Detailed hydrodynamic calculations are carried out for the stagnation region and the steady near-sonic region and compared (in the case of the stagnation region) with a perturbation calculation. Moment methods are used to estimate stagnation-region effects on the subsequent development of the beam. PMID- 20168495 TI - Vacuum ultraviolet radiometry. 3: The argon mini-arc as a new secondary standard of spectral radiance. AB - A miniature argon arc has been designed and tested as a new transfer standard of spectral radiance for the wavelength range from 114 nm to 330 nm. Calibration has been performed using two primary standard sources: the hydrogen arc from 130 nm to 330 nm and the blackbody line radiator from 114 nm to 130 nm. The mini-arc provides an intense, stable, and reproducible uv continuum with dc power requirements of less than 1.5 kW. The arc characteristics have been investigated, and the sensitivity of the radiant power output to various operating parameters has been measured. The rms uncertainty in the spectral radiance is estimated to be 5.3% above 140 nm and 10.1% between 114 nm and 140 nm, due primarily to uncertainties in the primary standard sources. PMID- 20168496 TI - Radiometric errors caused by diffraction from circular apertures: edge effects. AB - The diffraction corrections associated with a circular aperture are calculated for the case of a point source and a detector aperture having a diameter approximately equal to that of the illuminated region. This investigation is made for monochromatic and complex (tungsten) radiation; two types of detectors are considered: a typical silicon diode and a neutral detector. The intensity distribution near the edge is calculated for the same cases. Some experimental results are also presented to corroborate the calculations and to suggest the behavior with extended sources. We show that strong diffraction effects are present close to the shadow edge even with a source-detector combination having a very extended wavelength band. In radiometric measurements, a suitable compromise between diffraction effects, stray light, and vignetting effects can be achieved by having the detector aperture diameter approximately half that of the illuminated region. An extended source will reduce diffraction effects. Finally, some suggestions are made with respect to making diffraction corrections for a series of apertures. PMID- 20168497 TI - Photodiode preamplifier systems: low-noise positive-feedback. AB - Positive feedback circuits have been developed that allow an NEP (1.42, 500, 1) of 10(-14) W Hz(-(1/2)) or better to be achieved for cooled intrinsic germanium photodiodes of up to 6-mm diam. These circuits have also been tested at room temperature with silicon photodiodes and with test capacitors; it is reasonable to suppose that they may be used with other transducers that have a capacitance as their dominant circuit component. Circuits that had one-half-power frequencies of 2-3 Hz with no feedback have routinely achieved bandwidth enhancement factors larger than 400 without degrading the original NEP. The technique is not limited to low frequency. PMID- 20168498 TI - X-ray calibration of RAR 2490 film for application to laser plasma experiments. AB - An x-ray sensitometric calibration of Kodak RAR 2490 film has been performed over the 0.28-8.04-keV range of photon energies. The characteristic curves (optical density D vs exposure H) are fit well over the entire range by a two-parameter, analytic function, loglo(1O(D) - 1) = A log(10)H + B. Solarization is found to occur at an exposure of 2 x 10(3) photons/(microm)(2) for 1.49-keV photons. Comparison with other films is made. PMID- 20168499 TI - Resonance absorption measurements of NO with a line-tunable CO laser: spectroscopic data for pollution monitoring. AB - Experimental coincidences between CO laser lines and seventeen NO lines have been observed. Three important parameters, the separation between each laser line and the nearest NO line (Deltanu), the pressure broadening parameter (gammaL degrees ), and the line strength ((Supsilon,J)), have been determined for each laser wavelength using the best match between experimental absorption data and theoretical calculations. These parameters are compared, where possible, with previously published results. The measured data are important for pollution monitoring systems employing tunable lasers in a direct absorption approach. PMID- 20168500 TI - Quantitative detection of atomic absorption by intracavity dye-laser quenching. AB - A new technique for quantitative detection of atomic absorption by intracavity dye-laser quenching is studied. For the sodium D(2) line, a sensitivity of 7 x 10(4) atoms/cm(3) x 1% quenching is obtained; and the sensitivity in single-pass detection is 4 x 10(8) atoms/cm(3) x 1% absorption for a 15-cm cell. Use of a cw dye laser improves the sensitivity and the stability. The dependence of the sensitivity on the bandwidth of laser action is measured, and a simple theoretical consideration is given for single-pass absorption. PMID- 20168501 TI - Suits reflectance models for wheat and cotton: theoretical and experimental tests. AB - Plant canopy reflectance models developed by Suits are tested for cotton and Penjamo winter wheat. Properties of the models are discussed, and the concept of model depth is developed. The models' predicted exchange symmetry for specular irradiance with respect to sun polar angle and observer polar angle agreed with field data for cotton and wheat. Model calculations and experimental data for wheat reflectance vs sun angle disagreed. Specular reflectance from 0.50micro to 1.10 microm shows fair agreement between the model and wheat measurements. An Appendix includes the physical and optical parameters for wheat necessary to apply Suits' models. PMID- 20168502 TI - Binary phase digital reflection holograms: fabrication and potential applications. AB - A novel technique for the fabrication of binary-phase computer-generated reflection holograms is described. By use of integrated circuit technology, the holographic pattern is etched into a silicon wafer and then aluminum coated to make a reflection hologram. Because these holograms reflect virtually all the incident radiation, they may find application in machining with high-power lasers. A number of possible modifications of the hologram fabrication procedure are discussed. PMID- 20168503 TI - Moire microwave holography. AB - A new method for the recording of a microwave field using a moire interference pattern is presented. The moire interference pattern was used to map the thermal expansion of a microwave absorbing slab when irradiated by a microwave field. The technique was evaluated by applying it to the recording of a number of different microwave holograms. The moire recording method is found to be relatively sensitive and usable to produce holographic images of good quality. PMID- 20168504 TI - Photodielectric polymer for holographic recording. AB - A novel photodielectric polymer system suitable for recording high resolution volume phase holograms is described. Highly reactive monomers that polymerize rapidly when inserted between two substrates allow for simple and convenient preparation of recording layers ranging from 10microm to 3 mm. The materials have superior chemical and dimensional stability and have in situ self-developing capabilities. During recording the polymer cross-links in the irradiated regions causing changes in index of refraction. Experimental measurements reveal that the diffraction efficiencies may exceed 90%, that the resolution is in excess of 2000 lines/mm, that the angular selectivity may be as high as several minutes of arc, and that the noise characteristics are comparable to those of high quality photographic emulsions. The hologram formation mechanism along with experimental results of exposure sensitivities, diffraction efficiencies, SNRs, and angular discrimination are presented. PMID- 20168505 TI - Variation in optical transmission and electrical resistance in a single sulfur liquid droplet during polymerization. AB - Electrical resistance and optical transmission anomalies are observed in a single droplet of liquid sulfur during polymerization and depolymerization from 155 degrees C to 190 degrees C. Correspondence is found with some of the effects observed in electrooptic studies on bulk samples. Unlike the bulk studies, however, the single droplet shows an optical transmission of laser light that appears to follow the viscosity curve in thermal dependence. This divergence between the two studies is interpreted in terms of scattering effects at the droplet surface. PMID- 20168506 TI - Infrared thermooptic coefficient measurement of polycrystalline ZnSe, ZnS, CdTe, CaF(2), and BaF(2), single crystal KCI, and TI-20 glass. AB - An interferometric technique has been used to determine the thermooptic coefficient (dn/dT) of polycrystalline ZnSe and ZnS at 0.6328 microm, 1.15 microm, 3.39 microm, and 10.6 microm; polycrystalline CdTe and TI-20 glass at 1.15 microm, 3.39 microm, and 10.6 microm; polycrystalline CaF(2) and BaF(2) at 0.6328 microm, 1.15 microm, and 3.39 microm, and pure and europium-doped single crystal KCl at 0.6328 microm, 1.15microm, 3.39 microm, and 10.6 microm. The values were obtained over the temperature range of 25-65 degrees C and were calculated using the observed change in optical path of the samples as they were heated. Some difficulties in thermometry were encountered in the standard configuration of sample and thermocouple probe, so measurements were made in an oil bath at the shortest wavelength at which the sample was transparent to provide temperature correction factors for each sample. An empirical dispersion relation for dn/dT has also been found for the semiconductor materials. This dispersion relation is of the form dn/dT = aR(b), where R is defined as lambda(2)/(lambda(2) - lambda(g)(2)), lambda(g) is the short wavelength cutoff associated with the energy gap, and a and b are constants which are different for each material. PMID- 20168507 TI - Use of hafnium dioxide in multilayer dielectric reflectors for the near uv. AB - We measured the refractive index of layers of hafnium dioxide that were prepared by evaporation in a vacuum. It is transparent to wavelengths as short as 230 nm. Its refractive index at 300 nm was as high as 2.10 or as low as 1.90, depending upon the conditions of evaporation. Tests at Los Alamos Scientific Laboratory indicate that its laser damage threshold is approximately 2 J/cm(2) at a wavelength of 355 nm. Multilayer dielectric mirrors were prepared using hafnium dioxide and silicon dioxide. The radiant reflectance exceeded 99% at a wavelength of 320 nm. PMID- 20168508 TI - Compact optical data processor employing holographic reflective lenses. AB - A compact optical data processor is described that employs holographic reflective lenses. The processor is inexpensive and requires one-half of the length of the optical bench as that required for using glass lenses. The fabrication of the holographic lenses is described, and the results of optical processing reported. The results show that an inexpensive data processor employing holographic lenses is a feasible project. The processor may find use for onboard optical processing on spacecrafts and satellites. The most distinguishing characteristic of such a processor is its extreme light weight. The angular alignment tolerances for holographic lenses are very low. The processor must, therefore, be made rugged, designed, and mounted to withstand vibrations, shocks, and other environmental problems associated with spacecrafts and satellites. PMID- 20168509 TI - Space and time variables in optics and holography: recent experimental aspects. AB - Assuming some parallelism between space and time variables, namely, in the frequency domain, that occurs in the description of optical signals as functions of space or/and space and time, the Abbe theory applies to temporal distributions. The concept of temporal response of any optical system, space invariant, working at the time frequency nu = c/lambda, is then brought out. A method of temporal encoding of optical information is also reported, leading to a consideration of the output of spectroscopic devices as a Temporal Fourier Hologram (TFH). This applies to metrology (interferometry in white light, surface testing, roughness measurements) and image processing by temporal holography. Holograms of extended self-luminous objects have been recorded in white light, and reconstructed images are presented. PMID- 20168510 TI - On-line digital image restoration and manipulation using a minicomputer. AB - A digital image processing system using a minicomputer that has the capability to make on-line digital image processing has been developed. By use of this system image restoration of motion blurred images due to uniform linear and rotating motion has been carried out in the space domain with the aid of the idea of manmachine feedback. To restrain extreme noise amplification during the restoration process, the technique of smoothing and differentiation of the data based on a method of least squares has been applied. A new technique to manipulate the low contrast image is also demonstrated by which the processed image is observable with better appearance than that of the unprocessed one. In this manipulation, the human visual system has played an important part in complementing discarded image information. PMID- 20168511 TI - Interferometry with schlieren microscopy. AB - It is demonstrated theoretically that if the stop in a schlieren system is no larger than the central maximum of the empty field Airy disk at the stop location, the system will behave as an interferometer for objects much smaller than the empty field. Interferograms produced by such a system are shown. PMID- 20168513 TI - Computing the propagation characteristics of radially stratified fibers: an efficient method. AB - An efficient method is introduced in this paper to compute the dispersion characteristics as well as the Poynting flux distribution of radially stratified fibers. Only 4 x 4 matrix operations were needed. Detailed results are given for several representative radially inhomogeneous fibers of practical interest. PMID- 20168512 TI - High spatial resolution schlieren photography. AB - Some geometrical optical considerations for attaining spatial resolution of about 100 microM in a photographic schlieren experiment are presented. The topics of astigmatism, coma, and spherical aberration are considered briefly. Special emphasis is directed to diffraction effects in a single-mirror schlieren instrument. A method for estimating the size of limiting apertures in the knife edge plane to allow a particular spatial resolution, compromised vs photographic sensitivity, is reported. A sample application for photographing the schlieren effects in a small spark discharge is included. PMID- 20168514 TI - Visibility of interference fringes: effect of the optical guide length in coherent light. AB - The visibility of the interference fringes produced by a wavefront of coherent light passing through an optical guide, divided, and recombined is studied. A cladding fiber and a light-focusing fiber are used as the optical guide. The relationship of the visibility of the interference fringes to the length of these fibers is determined. The visibility of the interference fringes produced through the light-focusing fiber and those produced through the cladding fiber are almost independent of the length of the fiber despite random internal reflection. PMID- 20168515 TI - Delay distortion characteristics of optical fiber splices. AB - The delay distortion characteristics of optical fiber splices are evaluated. Two 1.35-km graded index fibers with different transmission characteristics were each bisected and spliced together to determine how longitudinal and transverse displacement of fibers in a splice affect the delay distortion characteristics of a transmission path. The transmission characteristics of both the optical source and the fibers used play an important role in determining how delay distortion is affected by splice misalignment. The first fiber exhibited a great deal of mode mixing and a very small increase in delay distortion as the fibers were offset in the splice. In contrast, the second fiber exhibited very little mode mixing, but increased markedly in delay distortion as the fibers in the splice were displaced. PMID- 20168516 TI - Star repeaters for fiber optic links. AB - A star repeater combines the functions of a passive star coupler and a signal regenerating amplifier. By more effectively utilizing the light power radiated by a light emitting diode, the star repeater can, when used with small diameter channels, couple as much power to all receivers of a multiterminal link as would be coupled to the single receiver of a simple point-to-point link. PMID- 20168517 TI - Measuring the complete surface strain field on rubber structures using an optical method. AB - A method for determining the complete surface strain field on rubber structures is described. The technique consists of photographically depositing a set of grid lines on the surface of a photoelastic birefringent coating. The coating is bonded to the surface of the object of interest. Photoelastic data together with grid photographs provide sufficient information for determining the complete surface strain state at all points on the coating. An experimental example demonstrating the technique is presented. The technique is especially well suited for strain measurements in the range from 1% to 10%-a range commonly encountered with pneumatic tires. PMID- 20168518 TI - Temporal response of the acoustooptic modulator: geometrical optics model in the low scattering efficiency limit. AB - A phenomenological model of the acoustooptic modulator is proposed. The temporal response of the deflected light power is a quadratic invariant function of the video signal amplitude. The two-dimensional response kernel is defined by an overlap integral of the incident light and sound field profiles, similar to a convolution operator. When the incident light is focused to reduce risetime, the light throughput efficiency and the deflected light profile degrade because the modulator is a linear filter with limited angular passband operating on the propagation angle spectrum of the incident light. PMID- 20168519 TI - Ultraviolet windows in commercial sunglasses. AB - The optical transmission of a random selection of nonprescription sunglasses was measured from 0.3-microm to 0.85-microm wavelength. Several models were found with uv windows that may increase the probability of cataract formation on the eye lens. More than half of the twenty-five models tested had ir windows that may cause eye discomfort with prolonged usage. In the tested glasses, there appears to be no correlation between lens color or cost and the amount of shielding given to the eyes from the radiation not contributing to the visual response. PMID- 20168520 TI - John Dalton's discovery of his colour blindness. PMID- 20168521 TI - Simple bifocus element for microscope objectives. PMID- 20168522 TI - Electromagnetic radiation, relativity, and anomalous red shifts: author's reply to comments. PMID- 20168523 TI - From the editor. PMID- 20168524 TI - Likely effects of solar elevation on the quantification of changes in vegetation with maturity using sequential Landsat imagery. PMID- 20168525 TI - Measurement of the fundamental vibrationrotation spectrum of CIO. PMID- 20168526 TI - Intensity requirements in X-ray holography at 1 A. PMID- 20168527 TI - Infrared heterodyne spectroscopy of atmospheric ozone. PMID- 20168528 TI - Applied optics of optics and opticists. PMID- 20168531 TI - Patents. AB - 3,949,224; 3,950,073; 3,951,548; 3,952,263; 3,955,152; 3,955,153; 3,959,738; 3,959,739; 3,959,741; 3,961,283; 3,962,655; PMID- 20168529 TI - Meeting reports. PMID- 20168532 TI - Relativistic phase invariance: comments on a recent effort to reinvoke the ether. PMID- 20168534 TI - On Silvertooth's discussion of special relativity. PMID- 20168533 TI - Electromagnetic radiation, relativity, and anomalous red-shifts: a critique. PMID- 20168535 TI - Deterioration in optical materials as a result of ultrasonic cleaning. PMID- 20168536 TI - Interferometer for optical testing with computergenerated holograms. PMID- 20168537 TI - Cell-type optical circuitry fabrication. PMID- 20168538 TI - Evaluation of r(o) for propagation down through the atmosphere: correction 2. PMID- 20168539 TI - Electronic imaging and scanning system. PMID- 20168540 TI - Piecewise interferometric generation of precision gratings. AB - A simple interferometer and associated technique, allowing for sequential exposure of small segments in the writing of a large grating, is described. The increased intensity thus afforded greatly aids in overcoming nonlinear and reciprocity effects in the recording medium. Furthermore, the technique eliminates the need for a large collimator and errors introduced by imperfect collimation. Demonstration gratings written with this technique have shown maximum registration errors of +/-35 nm. PMID- 20168541 TI - Measurement of second-order coherence in a light beam using a microscope and a grating. AB - The measurement of the complex cross-spectral density function of a light beam is discussed using a new type of shearing interferometer. This interferometer is composed principally of only an imaging lens system such as a microscope and an ordinary transparent diffraction grating replica. This interferometer is selfaligning, inexpensive, and able to introduce precise wavefront shears of the order of a few light wavelengths. A theoretical analysis of the instrument is developed giving expressions for calculating the magnitude and phase of the cross spectral density function using observable properties of the interference pattern formed by the instrument. A simple experiment is described which demonstrates the operation of the instrument. PMID- 20168542 TI - Fluorescence polarization microscope for automatic screening of membrane fluidity of individual cells. AB - A fluorescence polarization instrument, in which a heterogeneous population of biological cells can be characterized according to the fluidity of their plasma membranes, is described. The analyzed cells are first labeled with a fluorescent dye specific to the lipid bilayer of the cell membrane, after which the fluidity of each cell membrane is determined separately by recording the degree of fluorescence polarization. The measurements are automatically controlled, and the fluorescence signal is detected when a cell is passing in front of a microscope objective. The distribution of the cell population as a function of the fluorescence polarization is computed and can be stored or displayed at will. PMID- 20168543 TI - Saturation effects in laser induced fluorescence spectroscopy. AB - Laser based spectroscopic diagnostic tools offer the possibility of spatially and temporally resolved measurements of species concentrations in complex reacting gas flows of engineering interest. The major problem associated with such measurements is the effect of quenching reactions on the fluorescence signal. To overcome this difficulty operating in the saturation mode is proposed. For suitable systems the fluorescence signal is then no longer a function of quenching rates or laser power. Very low detectability limits appear possible. PMID- 20168544 TI - X-ray applications of self-scanning silicon diode arrays. AB - A linear diode array consisting of 512 elements was used to measure soft x rays from laser-produced plasmas. Three modes of operation were tested, with the array behind (a) low-resolution filters, (b) a high-resolution spectrograph, and (c) a collimation device. The diode array used in this work has a higher fluence threshold, less dynamic range, and poorer spatial resolution at 2 ke V than Kodak No-Screen x-ray film. However, the immediate electronic readout characteristics of diode arrays make them attractive for some applications. PMID- 20168545 TI - Diffraction properties of hydrogen-phthalate-crystals in the 0.1-2-nm region. AB - By means of single- and double-crystal spectrometers, the integrated and the percent reflectivities and the halfwidth of the KAP, NaAP, RbAP, and NH(4)AP crystals have been measured in several orders within the (0.147-1.76-nm) spectral range. The reflection plane for all crystals is the 001 plane, which is also the cleavage plane. Among the selected crystals RbAP shows the highest reflectivity. Comparison with the theory leads in a first approximation to the conclusion that all these crystals are of nearly perfect and not of a mosaiclike structure. PMID- 20168546 TI - Spectral resolution of a zoneplate with circular sensor. AB - The energy intercepted by a circular sensor exposed to panchromatic light from a point source transmitted by a zoneplate lens is expressed as the convolution of the spectral source distribution with a wavenumber spread function. This wavenumber spread function, which represents the monochromatic energy encircled by the sensor as a function of wavenumber, depends on the product of the number of zones and the distance between sensor and focal plane and is invariant for a constant ratio of sensor radius to Airy radius. Results obtained by the diffraction integral for sensor radii larger than or comparable with the Airy radius are compared with approximate expressions based on geometrical optics and with the analytical expression for the limiting case of sensor small compared with Airy radius. The dependence of the energy intercepted by the sensor on the halfwidth of a Lorentzian source distribution is described. Applications of the sensor-zone-plate lens combination to a scanning spectrometer and monochromator are discussed. PMID- 20168547 TI - Triple grating polychromator for Thomson scattering. AB - A high rejection, high transmission, triple grating polychromator with crossed dispersion has been designed and constructed for Thomson scattering plasma diagnostics. Identical gratings, collimating, and field lenses were used for all three stages. A mechanically convenient arrangement was made possible by using the field lenses to adjust the dispersion of the second stage to the required design value. The transmission in the passband for light polarized perpendicular to the rulings of the grating was measured at 33% for the instrument itself, and at 15% through the instrument and 1.8 m of attached fiber optics. With the 30-nm passband set 4-34-nm wavelengths away from the ruby laser line, the order of 10( 11) of 694-nm light incident in the input slit was present in each 3-nm wide output channel, giving a relative rejection factor of 10(-10). PMID- 20168548 TI - Compact far ultraviolet emission source with rich spectral emission 1150-3100 A. AB - A new compact far uv emission source suitable for laboratory or space applications is described. The source is small, rugged, lightweight, spectrally rich, and bright in the 1150-3200-A region. It has met rigid spacecraft environmental tests and also is a very useful transfer standard for absolute sensitivity calibrations of spectrometric instruments. PMID- 20168549 TI - Fast-moving suspended particles: measurements of their size and velocity. AB - A simple optical instrument is developed to measure remotely the size as well as the velocity of individual particles suspended in a fast-moving stream. The instrument consists of dual laser beams, each directed toward one phototransistor. The size and velocity are determined from the signals produced by particles passing through the laser beams. The measuring range of the particle size of the present unit is between 30 microm and 800 microm; both the upper and the lower ranges, however, are adjustable. PMID- 20168550 TI - Field-averaging spectrograph camera for remote sensing applications and its characteristics. AB - A field-averaging spectrograph camera utilizing a continuous interference filter and a step tablet has been investigated and its characteristics measured. Using color patches, the values obtained with the camera are compared with those obtained by a spectroradiometer and a self-spectrophotometer. The results obtained with the photographic method show slightly higher values than those of the other methods in the measured wavelength region. In the measurement of spectral reflectances of two-color patches with different ratios of area within a field of view angle, the same reversal point of the relative reflectance curves is observed with this camera as the spectroradiometer. Therefore, the function of a field-averaging spectrograph camera is the same as a spectroradiometer, which is widely used for remote sensing applications at the present time. Moreover, it is more compact, portable, and lower priced than conventional instruments. The spectral reflectances of scenes were measured by photographic and spectroradiometer methods in field experiments. The spectral image of soil photographed by a beam split camera used with the field-averaging spectrograph camera is displayed in false color. PMID- 20168551 TI - Global monitoring of stratospheric halogen compounds from a satellite using gas filter spectroscopy in the solar occultation mode. AB - We have analyzed the gas filter radiometer approach for long-term monitoring of stratospheric HCl, HF, CH(4), and H2O using solar occultation at selected intervals in the 2-6 microm range. Our analysis shows that this instrument technique is feasible. This conclusion is based on a simulation study in which we evaluated the effect of various experiment errors on retrieval accuracy. The instrument errors used were based on measurements made on a breadboard model gas filter radiometer. The results show that HCl and HF can be measured with an rms error of 10% and CH(4), and H2O with an error of 15% over the 10-30-km range. PMID- 20168552 TI - Ozone estimates derived from Dobson direct sun measurements: effect of atmospheric temperature variations and scattering. AB - We have performed an analysis of the impact of the temperature sensitivity of the ozone absorption coefficients on estimates of total atmospheric ozone obtained by the Dobson spectrophotometer operating in direct sun mode. In general, the higher the mean ozone temperature the greater will be the tendency to overestimate the ozone amount. The spreads in ozone residuals over the temperature models we investigated were 3%, 4%, and 6% for the A, C, and D line pairs, respectively, whereas for coupled line pairs the spread was only about 2%. The A-C-D triplet showed a very small temperature effect, the spread being probably less than 2%. For the A-D system, currently recommended by the WMO, the computed spread was 2.4 +/- 0.5%. A Monte Carlo model was applied to investigate the potential impact of scattered radiation entering the system. The effect has been computed for various conical fields of view. For clear sky conditions with no aerosols present, the error introduced appears to be less than 1%. When a tropospheric aerosol model was inserted, however, significant errors were observed. For the models we studied aerosol attenuation resulted in overestimates of total ozone up to 8%, but the impact of scattered radiation was to reduce the overestimate, and, in some cases, the scattering and attenuation effects may balance for a realistic Dobson system. Both effects increased from the A to the C to the D line pairs. The results indicate that line pair coupling reduces the combined error due to both sources to less than 1%. PMID- 20168553 TI - Scattering from a moving spherical particle by two crossed coherent plane waves. AB - The Mie scattering properties of a homogeneous, isotropic spherical particle, moving at a constant velocity and illuminated by two intersecting coherent plane waves having the same polarization direction, have been analyzed based upon an exact solution to Maxwell's equations. The solutions are in a form suitable for the calculation of the time varying scattered signal integrated across a detector aperture of variable size that is centered on either the forward or backward scattering direction. This problem is of importance in defining the scattered signal in a cross beam laser Doppler velocimeter (LDV). Results obtained from calculating the integrated scattered signal indicate a strong dependence upon the following physical parameters: particle size, index of refraction, cross beam angle, and collection solid angle. PMID- 20168554 TI - Passive optical diagnostics of combustion flows. AB - A passive ir detection method based on the monochromatic radiative transfer equation is proposed to probe both a homogeneous and a nonhomogeneous medium for the simultaneous determination of temperature and species concentrations. The problem of determining these thermodynamic variables and their sensitivities is solved by a ratio technique for a homogeneous medium. The solution requires inversion of a linear matrix equation when there are more than one absorbing species at the observing frequencies. A generalized Abel inversion method utilizing multifrequency multiangle scannings is developed to solve for the nonhomogeneous 2-D distribution of these parameters. Two special cases which assume combinations of axisymmetric and asymmetric distributions of the unknown parameters are also treated. PMID- 20168555 TI - Leaf optical system modeled as a stochastic process. AB - A stochastic leaf radiation model based upon physical and physiological properties of dicot leaves has been developed. The model accurately predicts the absorbed, reflected, and transmitted radiation of normal incidence as a function of wavelength resulting from the leaf-irradiance interaction over the spectral interval of 0.40-2.50 microm. The leaf optical system has been represented as Markov process with a unique transition matrix at each 0.01-microm increment between 0.40 microm and 2.50 microm. Probabilities are calculated at every wavelength interval from leaf thickness, structure, pigment composition, and water content. Simulation results indicate that this approach gives accurate estimations of actual measured values for dicot leaf absorption, reflection, and transmission as a function of wavelength. PMID- 20168556 TI - Isophotes of sunlight glitter on a wind-ruffled sea. AB - Time-averaged intensities are computed for the glitter pattern of sunlight on a wind-ruffled sea. Isopleths are drawn from these on graphs which simulate glitter pattern photographs through projections of sea-surface grid points on an inclined plane assumed to be in front of the observer. The intensity computed for each grid point is based on a calculation of the wave-surface orientation required for direct reflection from source to observer at that point; the probability of occurrence of this orientation, determined from the Cox-Munk distribution, is the principal factor in the computed intensity. The curvature of the earth is taken into account, and calculations are made for various cases of source elevation angle, observer altitude, and wind speed (the controlling parameter for the distribution of wave inclinations). Percent polarization is computed for the glitter patterns, and projected isopleths of this quantity are plotted. The effects of variations in wind speed, source elevation angle, and observer height on the morphology of the glitter pattern are shown, and such phenomena as the shifting of a reflected image toward the horizon are clearly demonstrated. It is suggested that the technique developed here could be useful in evaluating models of ocean wave structure and in making remote determinations of the sea state in the region of the glitter pattern. PMID- 20168557 TI - Aerosol distributions in maritime air and predicted scattering coefficients in the infrared. AB - An empirical model has been developed which describes maritime aerosol distributions as a function of several parameters. A number distribution was empirically derived as a function of altitude (0-5 km), wind velocity (0-16 m sec(-1)), relative humidity, visibility, and aerosol radius. Predictions of the model are found to agree reasonably well with available experimental data. Infrared scattering coefficients calculated from the aerosol model are also presented. PMID- 20168558 TI - Statistical measurements of 6328-A atmospheric attenuation. AB - The results of 1.75 x 10(3) h of 6328-A attenuation measurements made in Rome in the period 20 September 1973-19 September 1974 from 7 a.m. to 2:30 p.m. are presented. The quantities that are reported are the frequency distribution F(A) of attenuations greater than A, the frequency distribution of the attenuation in given intervals, and the frequency distribution of the daily maximum of attenuation. The results are discussed. PMID- 20168559 TI - Turbulence-degraded beam quality: improvement obtained with a tilt-correcting aperture. AB - In this paper, we have calculated the degradation in the focal-plane irradiance distribution due to atmospheric turbulence and the potential improvement realizable by employing a wavefront filt-correcting aperture. It has been shown that, when the aperture diameter is of the order of the outer scale of turbulence, virtually no improvement is realized relative to the uncompensated case. For the case when the long-term coherence length is small compared with the diameter, there is a several-decibel improvement over the longterm case; however, for a full phase-compensating aperture (e.g., COAT), peak intensity can be increased an additional several decibels. When the coherence length is not much smaller than the diameter, close to diffraction- limited performance can be expected. Comparisons are also made of the reduction of on-axis intensity with no compensation, tilt-correction, and a full phase-compensating aperture. It is shown that the effective coherence length of the compensated aperture due to the residual amplitude fluctuations is greater than the long-term coherence length by a factor proportional to the square root of the Fresnel number of the aperture. Approximate formulas are also presented for the tilt-corrected MTF for arbitrary aperture irradiance distributions. PMID- 20168560 TI - SNR in optical velocimeters: effect of detection angle. AB - Measurements of scattering power and SNR as a function of detection angle were carried out employing a differential heterodyne laser Doppler velocimeter (DLDV) and a white light fringe image velocimeter (WFIV). Particle diameters of 0.481 microm and 5.7 microm were employed for the DLDV and WFIV, respectively. In general, the measurements are in excellent agreement with calculations based on Mie theory. PMID- 20168561 TI - Laser anemometer signals: visibility characteristics and application to particle sizing. AB - The signal visibility characteristics of a dual beam laser anemometer operated in a backscatter mode have been investigated both experimentally and analytically. The analysis is based on Mie's electromagnetic scattering theory for spherical particles and is exact within the limitations of the scattering theory. It is shown that the signal visibility is a function of the ratio of the particle diameter to the fringe spacing in a certain, restricted case; but more generally it also depends on the Mie scattering size parameter, refractive index, the illuminating beam polarization, and the size, shape, and location of the light collecting aperture. The character of backscatter signal visibility differs significantly from the forward scatter case, and it is concluded that backscatter measurements of particle diameters using the visibility sizing technique may not always be possible. Restrictions on the forward scatter application of the visibility sizing method are also discussed. PMID- 20168562 TI - Laser speckle reduction: equivalence of the moving aperture method and incoherent spatial filtering. AB - The moving aperture and the moving random mask are two methods suggested for speckle reduction in recording images of diffuse objects with coherent light. An analysis is given that shows that these methods are equivalent to a two-step recording process: (1) recording the image with the full pupil in coherent light and (2) reimaging and recording this speckled image in incoherent light with the aperture or random mask in a fixed position. The two-step process makes it easy to understand the filtering effect and can be physically implemented to offer short exposure time in the coherent step and a wider choice of filtering functions in the speckle reduction step. Experimental results to support the analysis are presented. PMID- 20168563 TI - Electronically tuned pulsed dye laser. AB - The development of an electronically tuned pulsed nitrogen laser pumped dye laser is described. Tuning of the laser is achieved by electronic coupling of a piezo ("inchworm") driven grating with a piezo driven etalon. Tuning over a range of 180 GHz has been obtained with a laser line width of 250 MHz. A description of the apparatus and representative spectra obtained with the laser are given. PMID- 20168564 TI - Detection of geometric perturbations in optical fibers. AB - A sensitive, quick, and nondestructive method to assess the short range geometrical uniformity of optical fibers is presented. The technique is based on an analysis of the backscattered light arising from a beam that is incident at right angles to the fibers axis and is capable of measuring diameter variations on the order of 0.1 microm. Geometric perturbations arising in selected fibers pulled with oxy-hydrogen torch, electric furnace, and CO(2)-laser techniques are shown in an almost instantly read snapshotlike form. The production and detection of intentionally introduced short range diameter variations are also demonstrated. PMID- 20168565 TI - Contamination of furnace-drawn silica fibers. AB - Contamination originating in an electric resistance furnace was found to increase substantially the losses of unclad and plastic-clad silica fibers. In contrast, the losses of doped silica fibers with sufficient cladding thickness were unaffected by impure drawing conditions. Operating the furnace without muffle tube and protecting the preform with a pure, inert gas injected via a counter flow resulted in practically contamination-free operation and unclad-fiber losses as low as 3 dB/km. The removal of the muffle tube significantly simplified the furnace operation and reduced the cycling time from many hours to a few minutes. PMID- 20168566 TI - Impulse response of a self-focusing optical fiber. AB - By using wave optics method, analytical expressions are derived for the impulse response of a self-focusing optical fiber with a core whose index profile is described by the second- and the fourth-order terms of the radial distance. Two cases are considered: (1) where all the possible propagating modes are equally excited; (2) where only the modes with no azimuthal variations are equally or unequally excited. It is shown that the shape and the rms width of the impulse response depend strongly on the fourth-order coefficient of the index distribution and on the excitation conditions. Comparison is also made between the results obtained from the wave optics method and those obtained from the ray optics method, and both results are found to be identical. PMID- 20168567 TI - Losses at corner bends in dielectric waveguides. AB - An approximate technique based on a sum rule is used to treat mode conversion at corner bends in dielectric waveguides. Matrix elements which describe the mode coupling are expressed as spatial integrals over electromagnetic field distributions for the guided modes. These matrix elements provide information on the magnitude, average propagation constant, and coherence of power propagating in radiation modes. Numerical results are obtained for single mode and multimode slab waveguides, and implications for the design of low-loss interconnections and mode converters for integrated optics are discussed. PMID- 20168568 TI - Plasma polymerized coating for polycarbonate: single layer, abrasion resistant, and antireflection. AB - Plasma polymerized vinyltrimethoxy silane films were deposited on transparent polycarbonate substrates. The adherent, clear films protected the substrates from abrasion and also served as antireflection coatings. Posttreatment of the vinyltrimethoxy silane films in an oxygen glow discharge further improved the abrasion resistance. ESCA (electron spectroscopy for chemical analysis) and ir transmission spectra of some films were recorded, and an elemental analysis of the films was obtained. PMID- 20168569 TI - Distance measuring based on caustics. AB - A distance measuring technique based on caustics formed by illuminating an ellipsoid reflector with a point light source was developed. A study of the influence of the ellipticity of the mirror and the relative positions of the screen where the caustic is formed, the point source, and the mirror on the limits and accuracy of the range measured was undertaken. It was found that the accuracy in measuring a distance may be greater than the accuracy obtained by a direct measurement of the same distance by any conventional method used in measuring the diameter of the caustic on the screen. PMID- 20168570 TI - Kubelka-Munk optical properties of a barium sulfate white reflectance standard. AB - We have measured the Kubelka-Munk scattering and absorption coefficients for a barium sulfate white reflectance standard. These measurements have been based on measurements of the absolute reflectance for the particular barium sulfate samples whose scattering and absorption coefficients were measured. This method gives results that are different from earlier measurements; the differences are significant for measurements of the optical properties of atmospheric aerosols. PMID- 20168572 TI - Space-variant processing of 1-D signals. AB - Two general schemes for 1-D space-variant processing are proposed. The direct output display scheme gives the space-variant system output along a line in the processor's output plane. The output spectrum display scheme directly computes the space-variant system's output spectrum. Both of these schemes utilize a 1-D input and a line spread function mask. Example applications and experimental results are also presented. PMID- 20168571 TI - Linear space-variant optical processing of 1-D signals. AB - In the past, most optical data processing systems have been restricted to performing linear space-invariant operations. However, a wide class of interesting data processing operations require linear space-variant filtering. Three methods for performing linear space-variant processing of 1-D inputs are described. Experimental results obtained with all three systems are presented, and their relative advantages and disadvantages are discussed. PMID- 20168573 TI - Ambiguity function display: an improved coherent processor. AB - A coherent optical processor for displaying a signal's ambiguity function is described. The required time delay is realized by 45 degrees rotations of two identical input transparencies and the Doppler shift by a 1-D Fourier transformation. The entire ambiguity function is displayed in the output (Doppler shift-time delay) plane. Examples of the optically computed ambiguity function for single and double pulse signals are shown to be in excellent agreement with theory. Advantages of this approach over other schemes and possible extension to real time processing are also discussed. PMID- 20168574 TI - Enhanced Faraday effect and its application to optical communication. AB - This paper shows that the enhanced Faraday effect of optical resonance lines can be applied to optical communication. A secure optical communication system was designed and successfully tested. It used the integrated enhanced Faraday effect at low fields to produce polarization modulation and the high dispersion of the enhanced effect at high fields to scramble and unscramble the transmitted messages. PMID- 20168575 TI - Extreme ultraviolet photometer for observations of helium in interplanetary space. AB - A four-channel photometer sensitive to two solar EUV lines which are resonantly scattered by helium gas was developed for flight on the Apollo-Soyuz Test Project. Two channels observed the 58.4-nm line of He I and used helium gas resonant absorption cells to determine the intensities of the center and wings of that line. The other two channels observed the 30.4-nm line of He II. The instrument surveyed much of the celestial sphere during a series of slow rolling maneuvers by the Apollo spacecraft. The experiment operated properly, and usable data were obtained. Study of the distributions of flux seen, and of the ratio of 58.4-nm fluxes seen with gas cells full and empty, will refine current understanding of several poorly known properties of the local interstellar medium. Study of the 30.4-nm flux distribution will refine present knowledge of the structure of the earth's plasmasphere. PMID- 20168576 TI - Imaging properties of Wolter I type x-ray telescopes. AB - By ray-tracing methods we have investigated various configurations of Wolter I type x-ray telescopes. For the criterion of image quality the shape of the line spread function has been chosen. The angular resolution we find herewith in a large region of the basic parameters appears to be more than three times higher than results from the rms blur circle criterion. We have concluded that in most cases of practical interest the paraboloid-hyperboloid combination has to be preferred to the Schwarzschild system. In all cases it is possible to find a solution giving an extra improvement of the angular resolution with a factor between,2 and 4 when we describe the mirror shapes with polynomials. PMID- 20168577 TI - Three-dimensional imager. AB - A mode-locked laser, a rotating beam splitter, and a streak camera are the primary components of an imager with the ability to record three-dimensional images of remote (up to several kilometers) objects in real time in broad daylight. Immediate and future applications are noted. PMID- 20168578 TI - Variation of energy throughput with off-axis angle for the S056 x-ray telescope. PMID- 20168579 TI - Fabrication and performance of intrinsic germanium photodiodes. PMID- 20168580 TI - Scattering functions of nonspherical dielectric and absorbing particles vs Mie theory. PMID- 20168581 TI - Measuring the radius of curvature of soft corneal lenses. PMID- 20168582 TI - Improved performance of fusion lasers using the imaging properties of multiple spatial filters. PMID- 20168583 TI - Applied optics of optics and opticists. PMID- 20168584 TI - Meeting reports. PMID- 20168586 TI - Patents. AB - 3,767,285; 3,770,966; 3,792,924; 3,834,808; 3,888,568; 3,920,326; 3,920,330; 3,920,331; 3,922,061; 3,924,924; 3,927,934; 3,928,764; 3,935,382; 3,936,153; 3,938,882; 3,938,884; 3,941,457; 3,944,321; 3,944,322; 3,947,085. PMID- 20168587 TI - Ultraviolet response of InGaAsP photocathodes. PMID- 20168589 TI - Spatial resolution enhancement in coaxial light scattering geometries. PMID- 20168588 TI - Sinusoidal radiation chopper for modulation of the maximum available ight intensity. PMID- 20168590 TI - Assessment of the ultraviolet range of artificial light sources for the best fit to standard illuminant D65. PMID- 20168591 TI - Temperature dependence of the 10.6-microm reflectivity of ITO-coated silicon. PMID- 20168592 TI - Parametric oscillator: a grating-coupled CdSe OPO. PMID- 20168593 TI - Short exposure and biasing holography. PMID- 20168594 TI - Wide-angle Mach-Zehnder interferometer for monochromatically selective photography. PMID- 20168595 TI - Measuring the displacement field inside a stressed sample. PMID- 20168596 TI - Measurements on four-layer isotropic waveguides. PMID- 20168597 TI - Simple interconnections in thin-film guided-wave optics. PMID- 20168598 TI - Fiber-break testing by interferometry: a comparison of two breaking methods. PMID- 20168599 TI - Acoustical resonances in modulated compact arc lamps. PMID- 20168600 TI - Skylab optics: an introduction. PMID- 20168601 TI - Apollo Telescope Mount of Skylab: an overview. AB - This introductory paper describes Skylab and the course of events that led to this complex space project. In particular it covers the Apollo Telescope Mount and its instruments and the method of operation of the ATM mission. PMID- 20168602 TI - Extreme uv spectroheliometer on the Apollo Telescope Mount. AB - The Harvard College Observatory instrument on the Skylab was a seven-channel spectrometer-spectroheliometer operating in the 280-1340-A wavelength range and capable of a variety of observing modes encompassing both spatial and spectral scans of a wide range of solar features. The instrument design and operational performance are described in detail. PMID- 20168603 TI - Photometric calibration of the EUV spectroheliometer on ATM. AB - This paper describes the derivation of the preflight photometric calibration of the uv spectrometer on Skylab. The calibration of the orbiting instrument through cross-comparison with two rocket instruments is discussed in assessing the observed changes in response to quiet solar regions during the mission. Formulas are presented for the determination of the instrument sensitivity, and an uncertainty of +/-35% is assigned over most of the 296-1340-A wavelength range. PMID- 20168604 TI - S056 x-ray telescope experiment on the Skylab Apollo Telescope Mount. AB - This paper describes the S056 x-ray instrument which was carried aboard the Skylab Apollo Telescope Mount as part of the solar instrument cluster. The instrument, which was built at the NASA Marshall Space Flight Center, consisted of a glancing incidence x-ray telescope to record solar images in the 6-40-A region, together with an x-ray event analyzer to monitor the total solar soft x ray flux in several wavelength bands. The x-ray telescope used film as a recording medium and thin foil filters to isolate specific wavelength bands. The instrument subsystems are described in detail and typical results presented. PMID- 20168605 TI - Extreme ultraviolet spectroheliograph ATM experiment S082A. AB - The XUV spectroheliograph, Apollo Telescope Mount experiment S082A, is described. The instrument was a slitless Wadsworth grating spectrograph that employed photographic recording. The grating was of 4-m radius, ruled with 3600 grooves/mm. By rotating the grating to positions where the normal was at 255 A or 400 A, the spectral ranges 175-335 A and 320-480 A, respectively, were covered with 2-sec of arc spatial resolution. Close to the normal the resolution reached 2 sec of arc, but at the extreme limit, 630 A, it was 10 sec of arc or worse. The aberrations of the instrument are discussed in detail as are the provisions necessary to maintain optimum imagery and reliability in a space environment. During the mission about 1020 exposures were made covering 171-335 A or 320-630 A. PMID- 20168606 TI - Extreme ultraviolet spectrograph ATM experiment S082B. AB - The extreme ultraviolet, double-dispersion, photographic spectrograph, Apollo Telescope Mount (ATM) Experiment S082B on Skylab is described. Novel features were the use of a predisperser grating with a ruling whose spacing varied approximately linearly with distance for the purpose of increasing the instrument speed by reducing the astigmatism and a photoelectric servo-system to stabilize to 1 sec of arc the solar image at various near-limb positions. The 970-3940-A range was covered in two sections with effective lambda/Deltalambda congruent with 30,000 from 1100 A to 1970 A. The spatial resolution was 2 x 60 solar sec of arc. During the Skylab mission 6400 exposures were made with the instrument pointed by an astronaut at selected and recorded'solar positions. PMID- 20168607 TI - Experience with Schumann-type XUV film on Skylab. AB - The Naval Research Laboratory XUV solar spectrograph (S082A) and spectroheliograph (S082B) in the Apollo Telescope Mount of Skylabrequired Schumann-type photographic film in quantities greater than had ever before been needed. The procurement, testing, handling, and processing of this film are described. Eastman Kodak type 104 and a small quantity of type 101 were used. All problems that were anticipated were met satisfactorily, and excellent results were obtained. Two new problems arose; fog associated with the stainless steel carriers and a large reduction of contrast and maximum density for the flight film that was exposed to the space vacuum. PMID- 20168608 TI - NRL-ATM extreme ultraviolet solar image TV monitor flown on Skylab. AB - An instrument for recording extreme ultraviolet television images of the sun was flown in the Apollo Telescope Mount on Skylab. Solar radiation in the 171-630 A wavelength range, defined by the transmission band of three thin-film aluminum filters, was focused onto a p-quaterphenyl photon conversion layer by a platinum coated mirror at normal incidence. The conversion layer was attached to the faceplate of a low light level SEC vidicon. An onboard video monitor enabled the Skylab crews to observe the images in realtime and to identify and follow the development of solar features. Images were also transmitted to the mission control center, where they were used in planning the ATM observing schedule. PMID- 20168609 TI - Solar XUV grazing incidence spectrograph on Skylab. AB - The objective of Skylab corollary experiment S020 was to obtain through the availability of long exposure times more complete information than was then available on the extreme ultraviolet (XUV) and soft x-ray spectrum of the sun in the 10-200-A range. The instrument was a small grazing incidence spectrograph with photographic recording. Use was made of a novel split-ruled grating that combined 1200- and 2400-1/mm rulings to double the spectral coverage of the instrument and to aid in the measurement of wavelengths and order sorting. As it happened, there were many difficulties resulting from the major problems encountered by the Apollo and Skylab missions. Useful spectra were obtained, but the sensitivity of the instrument was greatly reduced, probably because of contamination resulting from leakage of the fluid used in the spacecraft cooling system. PMID- 20168610 TI - Thin aluminum filters for use on the Apollo Telescope Mount XUV spectrographs. AB - Thin, unbacked, aluminum film filters were used on two extreme ultraviolet (XUV) instruments flown on the Apollo Telescope Mount of Skylab by the Naval Research Laboratory to transmit the XUV radiation while blocking the longer wavelength radiation that would saturate the detector. The requirements placed on these filters-large size, resistance to degradation by high acoustic and vibration fields, and low pinhole transmittances-were far more severe than those placed on any filters previously flown. Special techniques were developed for vacuum evaporation of the aluminum, removal of the films from the substrates, supporting the films and mounting them to obtain finished filters, and storing them so that no degradation took place. A description of these techniques will be given. PMID- 20168611 TI - Optical contamination: its prevention in the XUV spectrographs flown by the U.S. Naval Research Laboratory in the Apollo Telescope Mount. AB - During construction and testing of the XUV spectrographs flown in the ATM by the Naval Research Laboratory, many problems associated with optical contamination were encountered. Solving these problems required setting up a contamination prevention program to select the materials used in constructing the instruments and to delineate procedures in assembling, testing, and storing the instruments. A brief description is given of methods of assessing the effects of contamination and of the procedures used to prevent contamination. PMID- 20168612 TI - High resolution solar observations: the hydrogen-alpha telescopes on Skylab. AB - Two hydrogen-alpha telescopes were flown as part of the solar astronomy instruments on Skylab. These telescopes provided high resolution video imagery to the crew for both solar surveillance and the pointing of the entire instrument cluster. A film camera on one telescope provided photographs for a postmission pointing record. This paper details the design of the telescopes and their operating characteristics and presents an evaluation of their performance during the mission. PMID- 20168613 TI - Observing and recording instantaneous images on ATM television monitors. AB - A persistent image-converter device was utilized to make visible to the astronaut solar images that were isolated, instantaneous flashes on the ATM TV monitors. In addition, these instantaneous images, as well as normal TV images, were recorded with a Polaroid SX-70 camera for study by the astronauts. PMID- 20168614 TI - Radiance calibration of the High Altitude Observatory white-light coronagraph on Skylab. AB - The High Altitude Observatory coronagraph produced over 35,000 photographs of the solar corona over 9 mo. Images were obtained on Kodak special film type 026-02, a 3400 (Pan-X) emulsion modified by Kodak for minimal reciprocity losses at the exposure times (3 sec, 9 sec, 27 sec) used on the coronagraph. The film was processed in a specially developed chemistry to obtain the best compromise between speed, low fog, and modulation transfer function. The calibration of a nineteen-step wedge within the coronagraph is based on previously calibrated glass opal filters. The step wedge, illuminated by attenuated sunlight, is imaged on each photograph made by the instrument. Data reduction procedures employ average characteristic curves for each data set (approximately 4000 frames). It is found that the effects of radiation fog and latent image loss are negligible within these sets. The relative coronal radiance error, determined by measuring the coronal plus stray light radiance over the solar pole, is found to be le s than 8%. Based on an estimated error of 15% in the absolute calibration of the step wedge, the net absolute accuracy of a given radiance measurement is estimated to be 20%. PMID- 20168615 TI - Measurement of stray radiance in the High Altitude Observatory's Skylab coronagraph. AB - The stray radiance present in the field of view of the High Altitude Observatory's Skylab coronagraph has been measured from results obtained in orbit with two techniques. First, employing images of the lunar disk made near the time of solar eclipse, a comparison of the apparent contrasts recorded by the coronagraph of maria and highlands with those of previous studies, allows the determination of the magnitude of the stray radiance and its variation along a radius. Next, the azimuthal (position angle) variation was found through measurement of the change in the net radiance of a point in the coronal image, as the image (coronagraph) was rotated. From these measurements the stray radiance was found to be a maximum near the inner limit of the instrument field of view, variable in azimuth from 1.4 to 5.6 10(-9)B(O), where B(O) is the mean solar disk radiance. Further, the stray radiance was found to be a steep, decreasing function of distance along a radius, falling to a nearly uniform, azimuthally independent va ue of ~3.5 x 10(-10)B(O) in the outer field. In this latter region, the coronagraph stray radiance is well below a typical midtotality eclipse sky radiance of ~1.8 x 10(-9)B(O). Finally, the radiance of lunar maria and highlands (in units of 10(-10)B(O)) was determined to be 2.2 and 4.5, respectively, for the 30 June 1973 eclipse and 1.4 and 3.0, respectively, for the 24 December 1973 eclipse, in agreement with other observers. PMID- 20168616 TI - Numerical image manipulation and display in solar astronomy. AB - A scientist-oriented image processing facility at the Harvard College Observatory is described. The significanceof the system as a research tool at all post data collection states of an experiment is emphasized. Examplesare shown of various analyses of EUV observations of the sun from Skylab that are only possible withsuch a facility. PMID- 20168617 TI - Image data-processing system for solar astronomy. AB - Image processing has become an invaluable tool in the analysis of solar astronomy and other scientific data. In particular, a number of powerful and intricate image-processing systems have been developed. One such system is the MSFC/S-056 Image Data Processing System (IDAPS), especially designed for the analysis of the Skylab/ATM S-056 X-Ray Telescope experiment data. This paper describes the IDAPS, discusses its unique interactive capabilities, and shows some recent results obtained using the IDAPS. PMID- 20168618 TI - Skylab simulator visual displays and training for joint observing programs. AB - The complexity of the Skylab Apollo Telescope Mount (ATM) experiment operations necessitated the use of high fidelity simulations of the onboard visual displays and pointing system for crew training. The displays which were simulated included the H-alpha displays, XUV monitor display, XUV/slit/white light display, x-ray image display, and the white light coronagraph display. The pointing simulation was achieved by projecting film sequences which were subsequently viewed by TV cameras. An optical system in front of the vidicons simulated the pointing, roll, and zoom capabilities of the ATM and sensing systems. The simulation enabled the Skylab crewmen to obtain valuable integrated training combining such tasks as target recognition and status assessment, complex and the time dependent pointing operations, malfunction analyses, and rapid responses to flare and other transient events. PMID- 20168619 TI - Ultraviolet three-channel photographic photometer: the S183 experiment. AB - An uv three-channel photographic photometer designed for broadband photometry of uv-rich stars is described. The optical design consists of two instruments. First, an off-axis telescope, imaging a 7 degrees x 9 degrees field of view, simultaneously records two channels centered at 1878 A and 2970 A (636-A FWHM). The second is a Schmidt-Cassegrainian telescope imaging a 5 degrees x 7 degrees field of view at lambda(eff) = 2574 A (358-A FWHM). Thirty-four star fields have been observed including the Large and Small Magellanic clouds, the nucleus of the Andromeda galaxy, and galactic nebulae in the Carina, Orion, and Taurus regions. More than 3000 stars have been recorded at 2574 A with a limiting visual magnitude approaching 12. A short discussion concerning the behavior of the emulsions is given. PMID- 20168620 TI - Skylab S191 visible-infrared spectrometer. AB - The Skylab Earth Resources Experiment Package included a manually pointed spectrometer (S191), which provided reflective (0.4-2.5-microm) and thermal emissive (6-15-microm) spectra of areas 500 m in diameter on the earth below Skylab. The instrument is described, and the quality of data obtained in the Skylab mission is discussed in detail. PMID- 20168621 TI - Skylab ultraviolet stellar astronomy experiment S019. AB - An objective-prism stellar spectrograph of 15-cm aperture was flown on all three Skylab missions. The wavelength region from 1300 A to 5000 A was covered by a special optical system containing a combination of reflecting telescope optics, a CaF(2) objective prism, and an achromatized field corrector lens system of CaF(2) and LiF. Observations of 188 star fields, each covering 4.0 degrees 5.0 degrees , were conducted at the Skylab antisolar airlock with the aid of an articulated mirror system (AMS) which allowed acquisition within 30 degrees degrees 360 degrees band of the sky. PMID- 20168622 TI - Ten-color Gegenschein-zodiacal light photometer. AB - A ten-color Fabry photometer was used during Skylab missions SL-2 and SL-3 to measure sky brightness and polarization associated with zodiacal light, background starlight, F region airglow, and spacecraft corona. A brief description is given of the design, calibration, and performance of the instrument. PMID- 20168623 TI - Exploring the earth's atmosphere by photography from Skylab. AB - Availability of a 35-mm camera equipped with interference filters, together with an 8-inch-square uv-transmitting window for the Skylab scientific airlocks, revived long-standing interests at the U.S. Naval Research Laboratory in the study of the earth's upper atmosphere. The present paper details the design of several simple experiments to photograph the twilight and night airglow and the daytime ozone from an average 435-km altitude. Other phenomena of the atmosphere, including the polar aurora and noctilucent clouds, were sought, some with success. The versatile system also obtained some photographs of Comet Kohoutek. The experiment, by design, was dependent on man in space to select suitable targets and to optimize the data return from available equipment. PMID- 20168624 TI - Photographic coronagraph, Skylab particulate experiment T025. AB - A photographic coronagraph, built to monitor Skylab's extravehicular contamination, is described. This versatile instrument was used to observe the earth's vertical aerosol distribution and Comet Kohoutek (1973f) near perihelion. Although originally designed for deployment from the solar airlock, the instrument was modified for EVA operation when the airlock was rendered unusable. The results of the observations made in four EVA's were almost completely ruined by the failure of a Skylab operational camera used with the coronagraph. Nevertheless, an aerosol layer at 48 km was discovered in the southern hemisphere from the few useful photographs. PMID- 20168625 TI - Use of TV in space science activities: some considerations. AB - This paper discusses the merits of using on-board TV as the primary data recording system for certain type experiments in a manned space laboratory. Experiments of interest include fluid dynamics experiments. TV was used extensively on Skylab as the primary data system for such experiments. The results indicated a high potential for the use of TV as a data system for experiments. Contrasts with conventional photography, used on Apollo for similar experiments, are also given. PMID- 20168626 TI - Photographic film and the Skylab environment. AB - Photographic films used in the Skylab orbiting laboratory experienced changes in their response to radiant energy due to storage and use in the Skylab environment. All available data from flight film and premission tests were compiled and analyzed to quantify this environmental impact. This paper gives an overview of that evaluation, provides examples of flight film performance data, and summarizes the conclusions and recommendations derived. PMID- 20168627 TI - Nonlinear optical processing: analysis and synthesis. AB - Coherent optical systems are of interest in image or data processing because of their ability to handle rapidly large bandwidth data in parallel. They have been restricted to performing linear operations such as Fourier transformation and convolution due to the inherent linear nature of an optical system at low power levels. In this paper, the combination of a nonlinear halftoning step followed by bandpass spatial filtering to yield a specific nonlinear intensity transfer function is explored. A general analysis of the problem assuming infinite copy film gamma and saturation density is made. A constructive algorithm for designing a halftone cell shape and selecting the diffraction order to yield very general types of nonmonotonic nonlinearities is presented. Numerous examples of the synthesis procedure are given. Experimental results with general halftone screens made on a plotting flatbed microdensitometer are presented. Logarithmic, exponential, and level slice characteristics are achieved with monotonic cells. PMID- 20168628 TI - Parallel end-butt coupling for optical integrated circuits. AB - The method of parallel end-butt coupling has been used to couple GaAs laser diodes to Ta (2)O(5) thin film waveguides. Theoretical caluclations predict that a coupling efficiency into the lowest order waveguide mode of 90% is achievable if the thicknesses of the waveguide (t(g)) and the laser light emitting layer (t(L)) are equal. Experimentally, efficiencies as high as 45.1% have been measured for laser and waveguide combinations with t(g)/t(L) = 0.34. The tolerance to misalignment of the laser and waveguide has been theoretically and experimentally evaluated. PMID- 20168629 TI - Optical waveguide intersections without light leak. AB - An optical waveguide intersection on the same level, inducing no light leak, with higher refractive index in the intersecting point than in the guides, is proposed. This intersection is formed easily by the photopolymerization method, introducing double exposure at the intersecting point (typical guide width, ~0.1 mm; Deltan ~0.5% in the guide; and ~1% in the intersection). Very low losses were observed in the intersections, while large leak losses were observed in ordinary intersections, where the refractive index was equal to that of the guides. Observed losses were in good agreement with calculated ones. PMID- 20168630 TI - Excess loss caused by a lossy outer layer in multimode optical fibers. AB - Theoretical and experimental investigations are made on an excess loss arising due to a lossy outer layer attached around a cladding in multimode step-index fibers. Equations for evaluating the excess loss are derived using the electromagnetic theory for LP modes. Experiments are made on fibers with a pure fused silica jacket around a cladding, focusing on the wavelength dependence of the excess loss. It is found that the loss increases as the wavelength becomes long and that the measured values are in good agreement with the calculated ones. PMID- 20168631 TI - Efficient white laser illuminators for plastic optical fibers. AB - Multiwavelength lasers are used to compensate for color distortion in transmission of light through plastic optical fibers. Efficient methods to eliminate the speckle effect and to generate multicolor laser light are described. PMID- 20168632 TI - Mode scrambler for optical fibers. AB - Mode conversion at a splice was measured. Even the best splice, whose transmission loss was less than 0.01 dB, caused a mode conversion equaling about 11% of the total power. Spliced fiber transmission characteristics were influenced by the splicing conditions. To avoid deviations in characteristics due to splices a simple and effective mode scrambler was fabricated. Its insertion loss was less than 0.3 dB for a laser diode. Each mode's output waveform was found to be the same as the total output waveform. PMID- 20168633 TI - Radial distribution of the refractive index in light-focusing rods: determination using Interphako interference microscopy. AB - An interferometric technique for the determination of the radial distribution of the refractive index in lightfocusing plastic rods (LFR) has been developed using the shearing method of Interphako interference microscopy. We have derived mathematical expressions for the shape of interference fringes across the rod assuming the index distribution of LFR is described by n(r) n(=) (1 - ar(2) + br(4) + cr(6) + dr(2)) in which a, b, c, and d are distribution constants. The dsitribution constants were determined using a least-squares technique on a computer from the actual shape of fringes. Results for the representative cases are shown. PMID- 20168634 TI - Holographic interferometry with increased sensitivity for diffusely reflecting objects. AB - The reconstructed image of a double exposure hologram, made by deforming the object and slightly tilting the signal beam at the same time, consists of modulated Young's fringes. It would be possible to presume the plate, which is used for taking a photograph of the reconstructed image and is processed in a nonlinear way, to be equivalent to a nonlinear hologram. Therefore the principle of phase difference amplification applies. Thus the interferogram with increased sensitivity of lambda/16 per fringe was experimentally obtained with a diffusely reflecting object. Discussions of the system error are presented. PMID- 20168635 TI - Effects of medium and gain inhomogeneities in unstable optical resonators. AB - A previously formulated waveguide analysis of empty unstable optical resonators with finite mirrors is generalized to accommodate active media with transverse variations of refractive index and gain. The theory is developed for parallel plane mirrors and arbitrary medium inhomogeneities and is then applied to special profiles for which explicit analytical solutions can be obtained. Emphasis is placed on modifications, due to the active medium, of the edge-diffraction dominated resonant mode behavior. It is found that even slight variations in refractive index can exert a marked influence on the resonant mode characteristics. These conclusions remain applicable also for curved mirror geometries. PMID- 20168636 TI - Resonant-mode analysis of single-mode face pumped lasers. AB - The theoretical investigations and experimental verifications of resonant modes of optically pumped solid host face-pumped lasers (FPL) are discussed. The conditions for a single transverse-mode operation for electrooptically Q-switched neodymium glass and YAG lasers are examined in both stable and stable/unstable resonator configurations. Resonant mode computations were made, based on a Gaussian quadrature and a complex non-Hermitian matrix program. PMID- 20168637 TI - Use of a Fresnel zone plate for optical image formation with short wavelength radiations. AB - The feasibility of optical systems for short wavelength radiations ranging from the near uv to soft x rays is supported by theoretical and experimental arguments. The major problem of absorption of these radiations by materials has been overcome in the near and middle uv by using the lens properties of a Fresnel zone plate generated on a thin self-supporting film. In typical experiments with narrow field objects, it is shown that the zone plate behaves like a diffraction limited lens, the gain in resolution is noticeable as the wavelength decreases, the use of the third-order focus improves the resolution of the system, and under certain conditions the depth of field can be increased without loss of resolution. The chromatic aberrations of the zone plate are not restrictive for a large number of applications. PMID- 20168638 TI - Laser probe for measuring 2-D wave slope spectra of ocean capillary waves. AB - A laser-optical instrument for use in determining the 2-D wave slope spectrum of ocean capillary waves is described. The instrument measures up to a 35 degrees tip angle of the surface normal by measuring the position of a refracted laser beam directed vertically upward through a water surface. A telescope, a continuous 2-D Schottky barrier photodiode, and a pair of analog dividers render the signals independent of water height and insensitive to laser beam intensity fluctuations. Calibration is performed entirely in the laboratory before field use. Sample records and wave slope spectra are shown for 1-D wave tank tests and for 2-D ocean tests. These are presented along with comparison spectra for calm and choppy water conditions. A mechanical wave follower was used to adjust the instrument position in the presence of large ocean swell and tides. PMID- 20168639 TI - Broadband polarization rotator for the infrared. AB - A three-mirror system is described which is capable of rotating the polarization angle of a beam through any angle from 0 degrees to 360 degrees , with the output beam line coaxial with the input beam. Calculations are made of metallic reflective phase shifts, from the midvisible through ir, showing that this rotator would introduce negligible elliptical polarization for wavelengths longer than about 5 microm. PMID- 20168640 TI - Premonochromator for stray light rejection in Raman spectroscopy. AB - A new apparatus for attenuating the Rayleigh light is described. The main components are two concave gratings mounted in a special nondispersive way. By means of the first grating the entrance slit of the apparatus is focused as an intermediate spectrum upon a sharp-edged movable mirror. This mirror reflects all the spectrum except the Rayleigh light to the second grating, which collects the light to an image of the entrance slit. The result is a sharp cutting of the spectrum at any desired position. The rejection of the Rayleigh line has been measured to less than 10(-5) (optimally 10(-6)). Raman lines can be.measured about 10 cm(-1) from the exciting line. The instrument has been used as a preeliminating unit coupled to a conventional double monochromator. It is expected that a system consisting of the instrument and a good single monochromator can be used for Raman studies. PMID- 20168641 TI - Diffraction grating transmission efficiencies for XUV and soft x rays. AB - Efficiencies for diffraction of 45-275-eV x rays into orders by interferometrically formed, electrodeposited, gold transmission gratings have been measured on the 4 degrees beam line at the Stanford Synchrotron Radiation Project (SSRP). Anomalous dispersion affects the observed efficiency since the gold is partially transmitting to x rays. Model calculations which include anomalous dispersion are in good agreement with observations. With a suitable choice of material and thickness, a grating can be optimized for a given wavelength range by reducing the zero order transmission and enhancing the higher orders. Even orders are suppressed for a grating with equal slit and wire sizes. PMID- 20168642 TI - Lidar equation analysis allowing for target lifetime, laser pulse duration, and detector integration period. AB - A detailed study of the lidar equation has been made for both scattering and fluorescent targets. Allowance has been made for the effects of finite excited state lifetime, optical depth, laser pulse duration, detector integration period, and laser pulse shape. Analytical solutions have been obtained, and graphical solutions are also presented to aid in evaluating the magnitude of the correction factor appropriate to several cases of interest. PMID- 20168643 TI - Single particle scattering with focused laser beams. AB - A scattering technique is described in which the incident laser beam is tightly focused to isolate the effects of a single particle. In this way the individual particles may be studied in their natural environment, and experiments with latex spheres are in agreement with the theory. PMID- 20168644 TI - Computer-generated polarization hologram. 2: Experimental verification. PMID- 20168645 TI - Ultrasonic cleaning and laser surface damage threshold. PMID- 20168646 TI - Intensity fluctuations of an atmospherically degraded beam at the focus of a large collecting lens. PMID- 20168647 TI - Atmospheric visibility measurement by a modulated cw lidar: author's reply to comments. PMID- 20168648 TI - Total integrated optical scattering in the vacuum ultraviolet: polished CVD SiC. PMID- 20168649 TI - Digital hologram reconstruction of radio telescope data. PMID- 20168652 TI - Meeting reports. PMID- 20168650 TI - Of optics and opticists. PMID- 20168653 TI - Optical activities in industry. PMID- 20168654 TI - Patents. AB - 3,912,377; 3,912,379; 3,915,547; 3,915,558; 3,915,559; PMID- 20168655 TI - Atmospheric visibility measurement by a modulated cw lidar: comments. PMID- 20168656 TI - Asymptotic radiance and polarization in optically thick media: ocean and clouds; erratum. PMID- 20168657 TI - Pulsed dye laser densitometry using an optical delay. PMID- 20168659 TI - Spatial variation in the response of laser calorimeters. PMID- 20168658 TI - Variable frequency sweeping of a dye laser. PMID- 20168660 TI - Spectral output of a helical TEA C0(2) laser and its dependence on charging voltage. PMID- 20168661 TI - Plasma polymerized coating for polycarbonate: single layer, abrasion resistant, and antireflection: erratum. PMID- 20168662 TI - Mechanical vibrations: mapping their phase with hologram interferometry. PMID- 20168663 TI - Interferometre a reflexion totale frustree. PMID- 20168664 TI - Lensless matched filter: operating principle, sensitivity to spectrum shift, and third-order holographic aberrations; erratum. PMID- 20168665 TI - Coherent differential Doppler measurements of transverse velocity at a remote point. AB - We consider the analysis and results of a laser remote velocity sensing experiment in which both the longitudinal and transverse velocity components at one location were simultaneously measured from a range of 33 m. Fully coherent homodyne detection was used with a test target that simulates many aspects of distributed atmospheric aerosol targets. PMID- 20168666 TI - Asymptotic nature of grass canopy spectral reflectance. AB - The asymptotic nature of grass canopy spectral reflectance has been evaluated from field experimental data collected over the wavelength region of 0.500-1.000 microm at 0.005-microm intervals. The spectral reflectance of green vegetation against a soil background decreases in regions of absorption and increases in regions of minimal or no absorption as the vegetational density increases until a stable or unchanging spectral reflectance, called the asymptotic spectral reflectance, is reached. Results indicated spectral reflectance asymptotes occurred at significantly lower levels of total wet biomass, total dry biomass, dry green biomass, chlorophyll content, and leaf water content in regions of strong pigment absorption (low detectability threshold) than in the photographic ir region where absorption was at a minimum (high detectability threshold). These findings suggested that photographic ir sensors were more suited to remote sensing of moderate to high biomass levels or vegetational density in a grass canopy than were sensors operating in regions of the spectrum where strong absorption occurred. PMID- 20168667 TI - Photon counting processor for laser velocimetry. AB - In some of the more difficult applications of laser Doppler velocimetry such as in combustion research, transonic flow, transverse wind, and others, the optical signals are too small for classical detection methods. This paper summarizes the theory, experimental prototype hardware, and test results for a new type of highspeed photon-correlation signal processor which is being developed for weak laser velocimeter signals and other photon-resolved signals. The new system may also be considered to be a statistical digital frequency discriminator. It uses full multiplication with 10-nsec delay time and has the potential for extension to the measurement of the velocity correlations and spectra. PMID- 20168668 TI - Fast low-cost digital lock-in. AB - A fast low-cost digital lock-in has been developed for photon counting systems. Rates up to 5 MHz will be accepted by the input. The number of counts for positive and negative modulation are subtracted, and the result is emitted as a constant chain of pulses with a frequency of 5 MHz. The modulation frequency for gating the countup-countdown function is limited only by the TTL devices. For the developer's purpose 36 Hz has been used. PMID- 20168669 TI - Nonlinearly recorded matched filter: a technique to reduce the false alarm rate. AB - The effect of film nonlinearity in recording a spatial matched filter for optical signal detection is to record a distorted signal rather than the original target signal. This distorted signal could cause a large false alarm rate if it is severely distorted. We propose a method that requires an additional mask immediately before the holographic matched filter to convert the original signal to the distorted signal before processing the signal through the nonlinear matched filter. This process will, in theory, eliminate all the false alarm signal caused by film nonlinearity. The transmittance function of the mask is calculated for a given target signal and given matched filter recording parameters. For a particular choice of recording parameter, the mask can be fabricated by directly exposing the Fourier spectrum of the target signal. A computer simulation using a square function as target signal proves the validity of this technique. PMID- 20168670 TI - Dewar design for temperature tuned SHG. AB - We report a design for a wide temperature range dewar for SHG applications. This Dewar has been used for ADP, ADA, and RDP crystals. We include a schematic for a simple proportional temperature controller. PMID- 20168671 TI - Well baffled two-mirror corrector for a parabola. AB - The two-mirror Baker corrector for a parabolic telescope mirror is a well-known, very elegant design. In some variations, both corrector mirrors are spherical. The only thing marring the beauty of this solution to providing anastigmatic performance for large parabolic telescope mirrors is that the system is difficult to baffle. An alternate two-mirror corrector is presented here-based on a different design principle-that is easy to baffle. One of the two corrector mirrors is spherical, and there is a field stop to further aid in baffling. The penalty paid is that the signs. PMID- 20168672 TI - Anastigmatic two-mirror telescopes: some new types. AB - A type of two-mirror telescope is described in which light leaving the secondary mirror is allowed to reflect off the primary mirror again before coming to the final focus. It is shown that this double bounce off the primary mirror results in a telescope that may be configured to be corrected for spherical aberration, coma, and astigmatism. In fact, there are four distinct families of designs that are anastigmatic, encompassing a wide variety of optical forms. The more interesting designs are described in detail, and some performance numbers are given. PMID- 20168673 TI - Propagation of ultrashort pulses through lenses. AB - Ordinary optical components may behave in extraordinary ways when illuminated with ultrashort optical pulses. In the cases of lenses, only the flat lenses such as Fresnel lenses, Fresnel zone plates, and holographic lenses display such anomalies. For them, the pulse may be both elongated temporally and spread spatially unless very high focal number lenses are used. PMID- 20168674 TI - Optical communication at the source bandwidth limit. AB - The possible limiting components on optical communication bandwidth are the source, the modulator, the propagation medium, and the detector. It is easy to show that the source bandwidth is the fundamental limit. The possibility of source bandwidth limited communication is demonstrated theoretically and experimentally. The basic principles involved are readily extendable to more practical partial approaches to this limit. PMID- 20168675 TI - Nonlinear absorption of SF(6) at high infrared intensities and high pressures. AB - An experimental study of the saturable absorption of SF(6) at high pressure (up to 500 Torr) with high laser irradiance is presented. Experiments carried out at the P(28) line of the CO(2) laser show a decrease of transmittance with increasing laser irradiance before bleaching sets in. This is explained by a theoretical model using a single rate equation. The decrease of transmittance is shown to be due to vibrational excitation, whereas bleaching is caused by rotational hole burning. Previous results on saturation behavior of SF(6) at the P(16) line of CO(2) reported by Armstrong and Gaddy are given a new interpretation using the present model. PMID- 20168676 TI - Split-mode unstable resonator. AB - A novel class of unstable resonators is described in which the mode spatial distribution is altered within the resonator by a prism or axicon. In the particular configuration studied in this work, the resonator beam is separated into two halves by an intracavity reflecting prism. The conditions under which the two halves of the resonator become phase locked to form a coherent mode are studied experimentally and discussed in terms of laser injection locking. PMID- 20168677 TI - Plasma effects in the HCN laser. AB - The radial gain and refractive properties of an HCN amplifier using high current, short pulse excitation have been measured at 337 microm. The amplifier exhibits gain only after the electrons, which are produced at the wall, reach the amplifier axis, thus accounting for the delay normally observed between excitation and laser emission. Strong electron refractive effects, due to radial density gradients, are present that are associated with the gain and dynamics of the discharge. Weak magnetic fields can enhance or modulate the laser output. Strong fields, however, produce a current instability that destroys the symmetry of the gain profile and reduces the laser output. PMID- 20168678 TI - Laser-induced damage at 1064 nm, 125 psec. AB - A general review of extensive damage measurements using linearly polarized 1064 nm pulses with durations of 125 +/- 25 psec is presented. Samples tested included bare polished glass surfaces, several types of dielectric thin films, plastics, diamond-turned and polished metal surfaces, and evaporated metal films. A multiple- beam apparatus which allows rapid measurements of laser-damage thresholds is also described. PMID- 20168680 TI - Optical suitability of window materials for CO(2) lasers. AB - An experimental technique is reported for the measurements of the absorption coefficients of the candidate window materials for the CO(2) lasers. This technique is capable of measuring optical losses ~0.05% per transit. The optical suitability of Ge, GaAs, CdTe, ZnSe, NaCl, and KCI for the windows of the CO(2) lasers is investigated. Since these materials have varying mechanical properties, the thickness of a window is so chosen that it does not fracture or introduce significant optical distortion in the laser beam when subjected to a pressure of 1 atm across it. Surprisingly, from optical considerations, the ZnSe emerges as the best window material, although KCl has lower absorption coefficient, and Ge and GaAs are mechanically stronger. PMID- 20168679 TI - Laser induced damage in optical materials: 8th ASTM symposium. AB - The Eighth Annual Symposium on Optical Materials for High Power Lasers (Boulder Damage Symposium) was hosted by the National Bureau of Standards in Boulder, Colorado, from 13 to 15 July 1976. The Symposium was held under the auspices of ASTM Committee F-1, Subcommittee on Laser Standards, with the joint sponsorship of NBS, the Defense Advanced Research Project Agency, the Energy Research and Development Administration, and the Office of Naval Research. About 160 scientists attended the Symposium, including representatives of the United Kingdom, France, Canada, and Brazil. The Symposium was divided into five half-day sessions concerning Bulk Material Properties and Thermal Behavior, Mirrors and Surfaces, Thin Film Properties, Thin Film Damage, and Scaling Laws and Fundamental Mechanisms. As in previous years, the emphasis of the papers presented at the Symposium was directed toward new frontiers and new developments. Particular emphasis was given to new materials for use at 10.6 microm in mirror substrates, windo s, and coatings. New techniques in film deposition and advances in diamond-turning of optics were described. The scaling of damage thresholds with pulse duration, focal area, and wavelength were discussed. Alexander J. Glass of Lawrence Livermore Laboratory and Arthur H. Guenther of the Air Force Weapons Laboratory were co-chairpersons of the Symposium. The Ninth Annual Symposium is scheduled for 4-6 October 1977 at the National Bureau of Standards, Boulder, Colorado. PMID- 20168681 TI - Refractive index of GaSe between 0.45 microm and 330 microm. AB - Using the natural properties of the lamellar compounds, the ordinary refractive index of GaSe has been induced from interferential patterns of transmission and reflection spectra in the low absorption range and from reflectivity spectra in the polar modes range. An analytic development of the refractive index vs energy can reproduce the measured values of this index and provides the energy gap in the visible range, and values for omega(LO) and omega(TO) in the ir range infinity have been used as a parameter to get this fitting. PMID- 20168682 TI - Characteristics of a fiber-optic Raman laser. AB - The frequency spectrum of a continuous wave fiber-optic Raman laser is measured and observed to consist of several discrete lines covering a 3-nm spectral range. The output of the laser also contains damped transients which are attributed to strong pump-depletion effects in the fiber. Previously observed degradation of the fiber has been reduced in the later devices. PMID- 20168683 TI - Laser start-up system for magnetic mirror fusion. AB - A CO(2) laser system has been developed at the Lawrence Livermore Laboratory to provide hot start-up plasmas for magnetic mirror fusion experiments. It can irradiate a frozen ammonia pellet with a laser power density in excess of 10(13) W/cm(2) in a 50-nsec pulse. The system uses commercially available lasers. Optical components were fabricated both by direct machining and by standard techniques. The technologies used are directly applicable to reactor-scale systems. PMID- 20168684 TI - Composite x-ray pinholes for time-resolved microphotography of laser compressed targets. AB - Composite x-ray pinholes having dichroic properties are presented. These pinholes permit both x-ray imaging and visible alignment with micron accuracy by presenting different apparent apertures in these widely disparate regions of the spectrum. Their use is mandatory in certain applications in which the x-ray detection consists of a limited number of resolvable elements whose use one wishes to maximize. Mating the pinhole camera with an x-ray streaking camera is described, along with experiments which spatially and temporally resolve the implosion of laser irradiated targets. PMID- 20168685 TI - Digital deconvolution of a coded image obtained with a nonredundant pinhole array. AB - A coded image or pseudohologram, obtained optically with a nonredundant pinhole array imaging aperture, was digitized in a 512 x 512 format. Images were reconstructed digitally. The reconstruction scheme, a deconvolution in the Fourier domain, is presented. The applicability of this technique to a real-time imaging system is discussed. PMID- 20168686 TI - Real time Doppler imaging system using forced vibration of the object. AB - Forced vibration of objects is used to transform physical quantities into the amount of the Doppler shift. By combining this with a real time Doppler imaging system, a method of real time imaging of classified objects is proposed. As an example, particles are vibrated through the vibration of a water cell, which includes the particles in it. The possibility of real time display of these particles classified according to size or weight is discussed. The display of particles of different size or weight by distinct color on a TV monitor in real time seems most interesting. PMID- 20168687 TI - Constant variance enhancement: a digital processing technique. AB - An image enhancement process is one in which the image is manipulated for the purpose of increasing the information extractable by the human visual system. Constant variance enhancement is a technique which employs a high pass filtering to reduce the local average to zero for all regions of the picture and then applies a gain factor equal to the reciprocal of the local standard deviation to produce an output picture in which all local regions have equal variance. An example of a constant variance enhancement is presented with pictures illustrating the various mathematical stages of the processing operations. The concept of differential luminance gain is introduced as a crude measure of enhancement effectiveness and is numerically evaluated for the illustrative processing. The significance of negative differential luminance gain is considered, and ways of dealing with these spurious results are considered. PMID- 20168688 TI - Image emission platelet laser for optical information processing. AB - A laser light image corresponding to an image of an input transparency projected by a Rhodamine-6G dye laser has been emitted from an ultrathin GaAs crystal wafer. The image emission laser can be used as a new active device for optical parallel processings. Experimental results of image thresholding and wavelength converting are presented. PMID- 20168689 TI - Neutron diffraction on a vertical axis goniometer; high temperature diffraction furnace for all atmospheres. AB - A diffraction cell diffractofurnace for a vertical axis goniometer, permitting the recording of the diffraction patterns of neutrons of polycrystalline solids from 0 degrees to 120 degrees (2theta), was designed for the study of oxides at high temperature under their equilibrium atmosphere. An example is given of the diffraction pattern of cubic iron (II) oxide or wiustite. PMID- 20168690 TI - Reflection-type electrically controllable diffraction grating and its application to intracavity laser modulation. AB - Using the reflection of linearly polarized light from electrooptic material with an interdigital arrangement of electrodes, an electrically controllable diffraction (ECD) grating has been constructed for a He-Ne 3.39-microm laser. An intracavity modulation of 30% was obtained for a He-Ne 3.39-microm laser by setting the ECD grating inside the resonator with an applied voltage of 50 V. PMID- 20168691 TI - Planar optical waveguides achieved by ion implantation in zinc telluride: general characteristics. AB - The optical properties of ZnTe in the visible and the ir and the possibilities of realizing waveguides by ion implantation were investigated in this semiconductor. The main characteristics of the refractive index profiles obtained by implantation of light ions (proton, helium, boron) vs dose, energy, thermal annealing, and wavelength are presented. It is shown that these waveguides are the result of both the macroscopic implantation and the microscopic properties of ZnTe where the damages induced by this implantation extend deep into the substrate. This explains the low losses (1-4 dB/cm) measured in these waveguides. A first physical interpretation of the results is proposed, and some assumptions are discussed. PMID- 20168692 TI - Efficient wideband guided-wave acoustooptic Bragg diffraction using phased surface acoustic wave array in LiNbO(3) waveguides. AB - Efficient wideband guided-wave acoustooptic Bragg diffraction has been demonstrated using a phased surface acoustic wave array in Y-cut LiNbO(3) waveguides. The results of measurement made on the devices which employ the first order acoustic beam steering from six-element phased-SAWs of relatively small total acoustic aperture, at the center frequency of 325 MHz, have shown that accurate tracking of the Bragg condition is achievable for a frequency band of more than 250 MHz. In one of the deflectors that employ a larger total acoustic aperture, only 68 mW of electric drive power or 3.5 mW of acoustic power was required to diffract 50% of the light over a bandwidth of 112 MHz. This bandwidth is a nearly sixfold increase over that of the deflector that employs a single SAW of identical aperture. The quality of both deflected and undeflected light beams was very good. PMID- 20168693 TI - Plastic focusing fiber for imaging applications. AB - This paper presents a fabrication method and image transmission characteristics of a plastic focusing fiber which is flexible and has a nearly parabolic refractive index distribution. A new fabrication method is given, and the optimum control of index profile has been attained in order to reduce the aberration for imaging. A prototype fiber scope with TV monitor using the plastic fiber was made. Resolving power of 5-6 l/mm was shown to be attainable for fibers 3 mm in diameter and 150 mm in length. PMID- 20168694 TI - Impulse response of a step index optical fiber excited by a Lambertian source. AB - The impulse response of a step index multimode optical fiber excited by a Lambertian source is presented using the power flow equation. The dependence of the response on both the coupling coefficient and the attenuation coefficient is illustrated. It is shown that the width of the impulse response is proportional to the square root of the fiber length. PMID- 20168695 TI - Polarization optics of liquid-core optical fibers. AB - Whereas straight liquid-core optical fibers have the capability of transporting linearly polarized light with any incident polarization angle,bent fibers exhibit form birefringence with the principal axes fixed to the plane of curvature. The effect of this curvature-dependent birefringence can be compensated by either periodically altering the plane of curvature by 90 degrees or winding the fiber into a helix. PMID- 20168696 TI - Excess loss caused by an outer layer in multimode step-index fibers: experiment. AB - Experiments have been performed to evaluate the increase in loss due to an outer layer around the cladding in a multimode step-index fiber composed of core and cladding. Liquid has been used to simulate the outer layer. Measured excess loss for each mode group is in agreement with our previously developed electromagnetic theory. Total excess loss for all guided modes existing in the fiber has also been measured by varying the mode power distribution, the refractive index of the outer layer, the cladding thickness, and the wavelength. Results are found to be in good agreement with the theory, and it is concluded that the theory is correct. PMID- 20168697 TI - Double eccentric connectors for optical fibers. AB - An optical fiber connector with an adjusting mechanism using double eccentric tubes is reported. Tolerable impairment values of possible factors affecting connection loss are evaluated. The main factors of the connection loss are mutual core displacement and fiber axis tilt. By using a double eccentric adjusting mechanism, a 0.57-dB average connecting loss between step index multimode fibers is obtained without matching material. The connection loss can be attributed quantitatively to several impairment factors. Using a transparent thin film in the connecting section, the reflection can be reduced as low as about -25 dB, and the average connecting loss was improved to about 0.20 dB. PMID- 20168698 TI - Optical backscattering from near-spherical water, ice, and mixed phase drops. AB - An experimental assessment of the scattering behavior of freely falling artificial raindrops and mechanically suspended drops in the ice and mixed phase has been undertaken with a device which simultaneously measures the parallel and cross polarized components of backscattered linearly polarized laser light (6328 A). Among the findings are that linear depolarization ratios (delta) are generally <0.01 for raindrops up to nearly 6-mm diam, near 0.5 for regularly shaped frozen drops, and between 0.35 and 1.0 for more irregular ice particles. Anomalous scattering behavior has been observed during the liquid to solid drop phase transition (delta > 1.0) and in the relatively great amounts of parallel polarized energy returned from raindrops >~4 mm. Backscattered signal variations produced during drop melting reveal that delta values tend to remain near the initial ice value until most of the ice has changed phase. The details of the variations aid in the determination of the dominant scattering mechanisms responsible for the b ckscatter from large, near-spherical particles. The results are shown to have some bearing on measurements of atmospheric hydrometeors obtained by lidar. PMID- 20168699 TI - Kinetic cooling observation with a cw CO(2) laser. AB - An experiment permitting direct observation of kinetic cooling of a slewed 6-kW cw 10.6-microm CO(2) laser beam is described. The experimental results obtained are compared with a theoretical code, and good agreement is noted. PMID- 20168700 TI - Turbulence effects on target illumination by laser sources: phenomenological analysis and experimental results. AB - A phenomenological and analytical description is given of atmospheric turbulence effects oh laser beam waves, including the improved target irradiance characteristics resulting from cancellation of turbulenceinduced beam wander through reciprocity tracking. The mechanisms related to the mean irradiance include diffraction, wander, and wavefront distortion (beamspread), while irradiance-fading is caused by wander, first-order scintillation, and coherent fading. The phenomenological description unifies the often fragmentary and inconsistent treatment of beam wave phenomena found in the literature and is sufficiently accurate for engineering purposes. It will be shown that wander cancellation and control of the transmitter beam diameter can result in substantial improvements in target illumination. The analyses are compared with experimental data for the detailed statistical and spectral characteristics of on axis target irradiance. PMID- 20168701 TI - Fluorescence ambient NO(2) monitor with flashlamp pumping. AB - A pulsed xenon flashlamp unit was developed to provide a sensitive, economical, and compact device for determination of ambient NO(2) concentrations. The basic principles of operation are similar to a laser fluorescence monitor previously developed at the Aerospace Corporation that detects the atmospheric NO(2) by the fluorescence resulting from absorption of laser radiation. The prototype flashlamp unit has a sensitivity of 5 ppb for a 1.3-min integration time, a linear response, and provides a direct digital readout in real time. Results obtained in monitoring ambient NO(2) levels in the vicinity of the Aerospace Corporation are presented. PMID- 20168702 TI - Atmospheric transmittance of an absorbing gas. 2: A computationally fast and accurate transmittance model for slant paths at different zenith angles. AB - Models exist which allow the calculation of atmospheric transmittance at a given zenith angle for an absorbing gas with a constant mixing ratio. However, many applications require transmittances at several zenith angles. A simple, fast, and accurate model for calculating the angular dependence is given. This model is computationally fast because only the four arithmetic operations are used. Details for calculating the expansion coefficients are provided. When this technique is combined with a procedure for calculating transmittances at a fixed angle, it is possible to calculate transmittances for slant paths at arbitrary zenith angles and temperature profiles, provided the mixing ratio is constant. This technique was evaluated with a method capable of calculating transmittances at zero zenith angle with an accuracy of 0.0031. For zenith angles ranging from 0 degrees to 40 degrees , transmittances agree with line-by-line calculations to within 0.0038. PMID- 20168703 TI - Holographic speckle reduction by complementary spatial sampling. AB - A technique using complementary sampling in the reconstruction process is proposed for speckle reduction in holographic imaging. This method would not suffer the resolution reduction experienced with the simple random sampling method that has been proposed [F. T. S. Yu and E. Wang, Appl. Opt. 12, 1656 (1973)]. Experimental results and a theoretical explanation are presented. PMID- 20168704 TI - Spatially resolved excitation temperature measurements in a hypersonic flow using the hook method. AB - The extension of the hook method to include spatial resolution of nonuniformities in the test plane as suggested by Huber (1971) and Sandeman (1971) is demonstrated experimentally by measurements of the variation of the integrated line density of ground state sodium in a flame. Experiments are also described in which the variations in the flow of CO(2) in a hypersonic shock tunnel are spatially resolved along the spectrometer slit. The variations in the hook separations of the 425.4-nm Cr1 resonance and the 434.4-nm CrI 1-eV lower state line are simultaneously measured. The chromium exists as an impurity in the hypersonic flow of CO(2) over a cylinder in a shock tunnel. The populations of the levels so obtained have enabled the comparison of the excitation temperature of the Cr 1-eV level with the calculated gas temperature. PMID- 20168705 TI - Modulated-grating hologram. AB - By means of a multiple-exposure holographic recording method, a phase-and amplitude, off-axis hologram, which we call a modulated-grating hologram, has been synthesized from three computer-generated transmission masks. Each mask controls one fixed-phase component of the complex hologram transmittance. The basic grating is generated optically, relieving the computer of the burden of drawing details the size of each fringe. The maximum information capacity of the computer plotting device can thus be applied to the generation of the grating modulation function. Large digital holograms (25 mm x 25 mm) have been synthesized by this method in dichromated gelatin. The method can be used with virtually any holographic recording medium. It was designed primarily for spatial filtering applications, in which a hologram with large dynamic range and large free-spectral-range is needed. PMID- 20168706 TI - Achromatic triplet using holographic optical elements. AB - An achromatic optical system can be made using three holographic optical elements. A very simple design scheme is presented, and the properties of the system are discussed. PMID- 20168707 TI - Holographic grating scanners with aberration corrections. AB - Optically recorded Fresnel zone plates have proper spatial frequency characteristics for use as a laser scanner. Such grating scanners can easily be made and can scan over large cone angles with, however, severe aberrations of the diffracted laser beam at large deflection angles. Optically recorded Fresnel zone plates for laser beam scanning are investigated, and their aberration properties are analyzed. A method for removing the wavefront error caused by this type of zone plate is discussed, and the feasibility of the method is demonstrated. PMID- 20168708 TI - Unconventional interferometric realizations based on holographic nonlinear effects. AB - Nonlinear effects in holographic recordings can be utilized for realizations of unconventional interferometric setups, enabling extraction of additional information from a given setup. Real-time holographic interferometry without a reference beam is also conceptually feasible. PMID- 20168709 TI - Correction of Brillouin linewidths measured by multipass Fabry-Perot spectroscopy. AB - The sharper instrumental profile of the multipassed Fabry-Perot etalon introduces distortions to Brillouin spectra which may differ considerably from those introduced by the single-pass etalon. The half-width at half-height of the observed profile is calculated for five-pass and three-pass spectrometers. Phonon spectral widths may be extracted from the graphs and appropriate relationships are presented. These calculations are valid for well aligned etalons when the phonon lineshape is Lorentzian and cover a wide range of instrumental and phonon spectral widths. PMID- 20168710 TI - Performance of single photon decay spectrometers with pile-up correction. AB - The distortion and the statistical accuracy of single photon decay spectrometers with and without pile-up correction are determined. The effect of the statistical properties of the radiation is discussed. PMID- 20168711 TI - Drive nonlinearities: their effects in Fourier spectroscopy. AB - Presented is a comprehensive analysis of spectrum errors due to drive nonlinearities in a Michelson interferometer. The fringe-reference sampling case is treated for both repeatable and random nonlinearities. Partial results are given for the equal-time sampling case. The derived equations for the actual (or meansquare) spectrum error can be evaluated numerically for any choice of drive speed variation (or its power spectrum), input radiation spectrum, apodizing function, and filter response characteristic. Closed form solutions are obtained for special cases to show qualitative features of the spectrum error and to establish bounds on its magnitude. It is shown that when fringe-reference sampling is used with a filter having minimal distortion, the relative rms random error in the measured intensity of spectrum lines is typically of the same order as the rms, relative error in drive speed if the resolving power is about five times greater than needed to just resolve the lines and that this error varies as the square root of the resolved spectral interval. PMID- 20168712 TI - Properties of a transmission grating behind a grazing incidence telescope for cosmic x-ray spectroscopy. AB - Third-order aberrations are discussed of a transmission grating positioned behind a Wolter type I telescope, using Fermat's principle. We describe the conditions required to obtain a coma-free grating. The performance of a grating spectrometer for cosmic x-ray spectroscopy is discussed in some detail. PMID- 20168713 TI - Nanosecond time-resolved spectroscopy with a pulsed tunable dye laser and single photon time correlation. AB - A technique is described for performing nanosecond time-resolved spectroscopy for situations of extremely low emission rates. The system utilizes a N(2) laser pumped tunable dye laser and single photon time correlation techniques. It is applicable where there is need for nanosecond time resolution on emission which is either long-lived or has extremely low quantum efficiency and especially where monochromatic excitation is required. The technique is applied to the relaxation between a pair of excited states of Tb(3+):Y(OH):(3), where 5-nsec temporal resolution with 2- cm(-1) spectral resolution is easily obtained. PMID- 20168714 TI - Microchannel plate life tests. AB - We have investigated the manner in which the gain of a microchannel plate (MCP) changes as the plate is operated at moderate output currents. We find that the total charge per unit area Q (C-cm(-2)) extracted from the MCP is the relevant quantity for evaluating the performance of the MCP. The shape of the gain vs Q curve may contain important information on the gain decay process. The MCP's showed no long periods of stable gain similar to those frequently exhibited by channeltrons. PMID- 20168715 TI - Applications of thin graded-index films to solar absorbers. AB - The solar absorptance of a single ideal film on an idealized metallic substrate has been calculated as a function of its optical constants to determine the optimum parameters for selective absorber applications. High normal solar absorptances (>0.9) are possible for single uniform interference films if n < 1.5 and 0.2 < k < 0.8, values that are achievable using cermet materials. Grading the refractive index of single interference films improves the absorptance, with optimum results given by a uniformly increasing dielectric constant through the layer. With such a linear grading to air, normal solar absorptances of greater than 0.9 can be achieved for n < 1.5 and 0.1 < k < 5. Grading an absorbing material with a dielectric also improves the performance of the absorbing material. For bulk films, the optimum profile with minimum material is one where the dielectric constant increases slowly at the surface of the film. PMID- 20168716 TI - Lighting with sunlight using sun tracking concentrators. AB - The use of controlled beams of sunlight for lighting interior parts of a building is proposed as an economically attractive and practical option in a solar energy context. Sun tracking concentrators introduce beams of sunlight through holes in the roof. Inside, the beams can be relayed throughout the building by means of mirrors and lenses. Ideally cool lighting is obtained by using dielectric mirrors to separate the visible and ir parts of the solar spectrum. The ir can be used to generate electricity and usable heat in solar cells. Results of a preliminary experiment are given. PMID- 20168717 TI - Calorimetric measurements of stimulated emission cross sections and absorption coefficients at 1.06 microm. PMID- 20168719 TI - Piezoelectric stack for beam control. PMID- 20168718 TI - Shock tube spectroscopy: advanced instrumentation with a tunable diode laser. PMID- 20168720 TI - Vacuum-assisted silicon-chip multifiber chuck. PMID- 20168721 TI - Plasma spatial filter. PMID- 20168722 TI - Edge enhancement with incoherent optics. PMID- 20168723 TI - Isotopic chemical vapor deposition of fused silica and high-silica-content glasses for the production of low-loss optical waveguides. PMID- 20168725 TI - Applied optics of optics and opticists. PMID- 20168724 TI - Optical activities in industry. PMID- 20168726 TI - Meeting reports. PMID- 20168728 TI - Monomode fiber design: power containment. PMID- 20168727 TI - Electrostatic fiber holder. PMID- 20168729 TI - Simple method for permanently connecting single-mode fibers. PMID- 20168730 TI - Optical waveguide cable connection: erratum. PMID- 20168732 TI - Space-bandwidth product and accuracy of the optical Mellin transform. PMID- 20168731 TI - Radiation from dielectric optical waveguides: a comparison of techniques. PMID- 20168733 TI - Speckle elimination using random spatial phase modulation. PMID- 20168734 TI - Holographic simulation of ellipsoid and hyperboloid mirrors. PMID- 20168735 TI - Pumping frequency for the 17-microm ir emission from the cabbage looper moth sex scent (pheromone). PMID- 20168736 TI - Long path air spectra. PMID- 20168737 TI - Global monitoring of stratospheric halogen compounds from a satellite using gas filter spectroscopy in the solar occultation mode: correction. PMID- 20168738 TI - Measurement of the Gaussian laser beam divergence. PMID- 20168739 TI - Annular lens soft aperture for high power laser systems: comments. PMID- 20168740 TI - Annular lens soft aperture for high power laser systems: authors' reply to comments. PMID- 20168741 TI - Efficacy of ion polishing optical surfaces. PMID- 20168742 TI - SiO(2)-Si film-substrate reflection polarizers for different mercury spectral lines. PMID- 20168743 TI - Polarization flipper for infrared laser beams: comment. PMID- 20168744 TI - Colored filter glasses: an intercomparison of glasses made by different manufacturers. AB - Specifications of about eight-hundred colored glasses made by thirteen manufacturers are examined and intercompared. The internal spectral transmittances of typical glasses are plotted in a series of forty-four diagrams. A log (internal density) vs wavelength representation is used. Curves with similar characteristics are grouped together in the same diagram. The internal spectral transmittances for a number of different thicknesses of each glass type can be read directly from the diagram. The curves are identified in a table, which lists the equivalent thicknesses of glasses yielding approximately the same transmittance. Such information facilitates the choice of filter components of reasonable thickness. PMID- 20168745 TI - Noise-free contrast improvement with a low frequency polarizing filter: a practical evaluation. AB - Contrast improvement in a coherent image enhancement system by very low spatial frequency attenuation is shown, demonstrating possible errors incurred by incorrect attenuation. A novel way to achieve a continuous range of low frequency attenuation is introduced. The variable attenuation is produced by constructing the spatial filter from polarizing material and altering the relative polarization between the object transparency illumination and the spatial filter. This technique gives the observer control over a continuous change in contrast enhancement and greatly increases the versatility of low frequency spatial filtering. Coherent imaging systems are usually contaminated by noise, and a simple way to reduce the noise content in the image is shown. PMID- 20168746 TI - Transmittance ratio of a compensator: influence of detector sensitivity. AB - A scheme for the measurement of the transmittance ratio of a compensator was presented by Kothiyal [Appl. Opt. 14, 2935 (1975)]. For such a scheme we present in this paper theoretical and experimental investigations on the setting uncertainty of the compensator and analyzer considering the limited sensitivity of the detector. Information on the expected uncertainty of the measured values of the compensator amplitude transmittance ratio rho and the compensator retardation Delta is also given. PMID- 20168747 TI - Silicon monolithic infrared detector array. AB - Impurity doped silicon detector arrays sensitive to long ir wavelengths, based on monolithic processing, were designed and developed. These arrays provide optimized performance utilizing ir transparent detector contacts and reflecting counterelectrodes while minimizing electrical and optical cross talk and providing precise optical definition for the detectors. The microelectronic batch processing procedures are discussed, and the array performance obtained using these procedures is presented. This includes spectral response, the dependence of detectivity on temperature and frequency, the electrical and optical cross talk, and the optical definition obtained. The development is expected to serve as a processing guide for future arrays which will include on-chip signal processing. PMID- 20168748 TI - Self-scanned anode array with a microchannel plate electron multiplier: the SSANACON. AB - A unique type of photoelectron counting detector utilizes a 128-element linear self-scanned anode array to collect the output of a dual microchannel plate (MCP) electron multiplier. This detector, developed for the Mariner Jupiter/Saturn Ultraviolet Spectrometer, offers low noise and large dynamic range; having a dark count rate of about 3 x 10(-3) (anode-sec)(-1), it could simultaneously measure two spatially separated signals differing in count rate by more than 6 orders of magnitude. The design of the anode array drew heavily on existing self-scanned photodiode array technology. The 128 narrow aluminum anodes, each 3 mm long, were deposited on 0.1-mm centers for a total collecting area length of 13 mm. The specially designed MCP's had a rectangular active area corresponding to the collecting area of the anode array. Proximity focusing was employed. Spatial resolution was dependent on the separation and potential difference between the MCP and the anode array. The location of a spectral line could be determined to a fraction of one anode width after a few events had been recorded. Investigations of microchannel plates included measurements of the log-term gain degradation; the MCP gain was found to decrease in relation to the total charge extracted from the plate. PMID- 20168749 TI - Ultraviolet enhanced responsivity of silicon photodiodes: an investigation. AB - An enhancement of the responsivity of certain types of silicon photodetectors after exposure to uv radiation has been recently reported. Several possible mechanisms were investigated experimentally and ruled out on the basis of the results. PMID- 20168750 TI - Scattering of optical surface waves by a covered groove. AB - The reflectionjand modeconversionbehavior is considered for both TE(0) and TM(0) modes at a covered groove, which is cut in the substrate surface and covered by a thin film. With a numerical example, the scattering behavior of covered and surface grooves is presented here. It is found that a covered groove produces much less radiation loss than a surface groove of the same shape. Therefore, it is preferable as a reflector element in applications which require minimum mode conversion loss. On the other hand, surface grooves are preferable for grating couplers as they provide stronger coupling from surface to space waves as observed in this study. PMID- 20168751 TI - Optimization of prism coupling efficiency for surface electromagnetic wave excitation in the infrared. AB - The ir SEW coupling efficiency of a BaF(2) prism has been determined for various gap heights and internal angle configurations, utilizing the two prism coupling technique and a CO(2) laser. Samples consisted of W foil and Ni, Pt, and Cu films deposited on glass substrates by electron beam deposition and vacuum evaporation. Optimum prism coupling gap heights were found to occur for each metal. It was determined that selection of the proper internal prism angle increases coupling efficiency by a factor of 3 over the coupling efficiency of the right angle prism. PMID- 20168752 TI - Two-wavelength operation of a double-pass planar dye laser amplifier. AB - The simultaneous multiple line operation of a double pass dye laser amplifier is reported. Standard schemes have been used to generate two independently tunable lines and to scan one narrow line linearly around a fixed one. A simple, new scheme is illustrated, which allows symmetric splitting of narrow laser lines. PMID- 20168753 TI - Solid state organic (pheromone-beeswax) far infrared maser. AB - A low energy solid state organic maser was constructed from beeswax doped with 100 microg of cabbage looper, Trichoplusia ni (Hubner), pheromone (sex scent). Maserlike wavelengths were emitted in the 17-microm region. The wavelength fits the 1-2-wavelengths criterion for open dielectric waveguides of the same range as the type 1 (30-57-microm) cabbage looper sensilla trichodea. The wavelength shifted from 16.81 microm to 17.39 microm over a half-hour time period. The log periodic shift of wavelengths is temperature dependent and not concentration dependent, since the concentration of pheromone is fixed within the beeswax. PMID- 20168754 TI - Statistical analysis of defect-caused laser damage in thin films. AB - An analysis of the statistics of laser-induced damage to thin films is carried out for the commonly assumed single-defect model, in which damage is caused by irradiation of identical, randomly distributed defects in the film. The probability for damage due to a single irradiation with a beam of Gaussian spatial profile is calculated, and it is shown that observed variations with beam size of the intensity required to maintain a constant high probability for damage are accounted for by this expression. The multiple-shot damage probability is then calculated, assuming that irradiation is started at a low value of energy and increased stepwise, for two cases, an N-on-1 experiment where the beam irradiates the same site each time and a 1-on-1 experiment where the beam is moved to a new site with each shot. The damage thresholds, defined to be the median values of the distribution functions for these two cases, are compared to one another and to the thresholdfor a single-shot experiment. Moreover, the dependence of the threshold on the size of the pulse-to-pulse energy increment is determined. Finally, the effect of a second damage mechanism involving damage to the host material is determined by calculating the mean and variance of the probability density function. These results are shown to be in good agreement with prior measurements of the beam-size dependence of threshold. PMID- 20168755 TI - Ultraviolet spectral efficiencies of surface-spark discharges with emphasis on the iodine photodissociation laser pumpband. AB - Spectroscopic studies of the uv emission from surface-discharge sparks across Al(2)O(3), BN, ZnO, ZrO(2), BaTiO(3), ZnO-Al(2)O(3), and Cr(2)O(3).Al(2)O(3) substrates have been performed in He, N(2), CO(2), Ar, SF(6), and Ar + i C(3)F(7)I gases at pressures of 1-10 atm. Considerable differences were found in the performance of the various substrates; based on absolute measurements which are believed to be conservative, an electrical-to-optical conversion efficiency of 9.4 +/- 1.1% for uv emission in the 2500-2900-A iodine-laser pumpband was obtained from discharges across a Cr(2)O(3).Al(2)O(3) substrate in Ar gas. Pumpband energy densities of several J/cm(2) are readily attainable. PMID- 20168756 TI - Flashlamp drive circuit optimization for lasers. AB - The recently published three-parameter theory (alpha,betaEpsilon (in)) for calculating flashlamp performance is used here to derive a simple Q-switched laser pumping optimization procedure. For a single LC driving circuit, it minimizes the energy stored in C at the start of pumping needed to produce the required E(s), the energy stored in the laser rod just before Q-switching. In addition to specifying the values of L, C, and the initial voltage V(0), the process indicates the maximum current i(m), the half peak current pulse width tau(i), and the negative overshoot current i(min), if present. PMID- 20168757 TI - Visible optical isolator using ZnSe. AB - A compact Faraday effect optical isolator was constructed for visible wavelengths and tested at 5145 A. The nonreciprocal element of the isolator was polycrystalline zinc selenide placed in the magnetic field of a permanent magnet. For 5145 A the isolator had a 2.06-dB insertion loss and a 25.5-dB isolation. Indices of refraction and Verdet constants were measured for zinc selenide in the wavelengthregion from 4700 to 6300 A. PMID- 20168758 TI - Proposed multipass Thomson scattering system for tokamaks. AB - A multipass laser system is proposed for extending the period over which Thomson scattering measurements can be made with tokamaks. A Pockels cell and polarizer are used to reroute the pulse, which is reflected back through the plasma, away from the main amplifier, and onto a mirror, thus forming a closed system. A number of lenses and apertures are included in the system to maintain beam quality, with low gain amplifiers being used to maintain pulse energy. PMID- 20168759 TI - Coronagraphic technique to infer the nature of the Skylab particulate environment. AB - Photographs taken with the High Altitude Observatory's White Light Coronagraph (Skylab experiment SO52) are shown to contain information on the sizes and velocities of contaminant particulates around Skylab. Sizes as small as 5 microm (radius) are derived for particles as far away as 200 m from the spacecraft. The random error in the size derivation is about 30%, and no particle larger than 120 microm was observed. Transverse velocities are determined to within 0.08 m sec( 1) and radial velocities to within 9 m sec(-1). The S052 data bank contains about 3500 contaminated frames from which the nature of the Skylab environment can be inferred. PMID- 20168760 TI - Infrared extinction spectra of some common liquid aerosols. AB - Infrared extinction spectra in the 3-5-microm and 7-13-microm atmospheric window regions have been obtained for smokes of petroleum oil, sulfuric acid, and phosphoric acid of varying droplet concentration and for water fogs. Spectra were also obtained at 0.36-2.35microm for petroleum oil and sulfuric acid smokes. Experimental results were compared, for sulfuric acid and water aerosols, to calculated values obtained from the Mie theory. Agreement was as good as +/-10%. When absorbing smoke droplets are small compared to wavelength, very useful approximations apply, and droplet clouds may be spectrally simulated by thin liquid films. In such cases, the imaginary component of refractive index may be approximated directly from aerosol spectra. At 12.5-microm wavelength, water fog extinction is nearly independent of droplet size distribution, suggesting a simple scheme for measurement of total liquid water content of an optical path. PMID- 20168761 TI - Isoline approach to portraying atmospheric turbulence induced laser beam spread. AB - A method of portraying the effects of atmospheric turbulence induced laser beam spread on a laser beam emanating from an airborne transmitter is discussed. Application of this method yields a set of contours, called isodivs, which are loci of all points in space, relative to the transmitter, at which the atmospheric turbulence has induced a given l/e down from the axial intensity peak power level long term illumination beam spread or divergence half-angle. PMID- 20168762 TI - Dispersive correlation spectroscopy: a study of mask optimization procedures. AB - A procedure has been established to obtain the design parameters of the masks used in dispersive correlation spectrometers. The SNR equations are used to derive the mask equations. These are later solved for some simplified band models, and the obtained parameters are used as the initial values in an iterative program which determines the final design parameters. The calculations can be performed for various backgrounds and instrumental line profiles in order to achieve the best compromise for the detection of pollutants, and other trace gases, in the atmosphere. PMID- 20168763 TI - Ground mapping resolution accuracy of a scanning radiometer from a geostationary satellite. AB - Measures of the spatial and spatial rate (frequency) mapping of scanned visual imagery from an earth reference system to a spin-scan geostationary satellite are examined. Mapping distortions and coordinate inversions to correct for these distortions are formulated in terms of geometric transformations between earth and satellite frames of reference. Probabilistic methods are used to develop relations for obtainable mapping resolution when coordinate inversions are employed. PMID- 20168764 TI - Solar constants and radiometric scales. AB - The basic requirement for any type of measurement in which comparisons are made in a scale, relative or absolute. The values used by the Committee on Solar Electromagnetic Radiation to derive the solar constant were in different radiometric scales. Assuming that only difference in radiometric references produced the wide scatter of individual values, an attempt was made to convert all values to one radiometric reference. A radiometric scale based on electrical power equivalence was used as the reference. The resulting value was 137.5 mW cm( 2), as compared to the CSER derived value of 135.3 mW cm(-2) . This revised value lies within the error bounds of all the values used in the analysis. The revised estimate was then compared to values derived from more recent experiments. out of the atmosphere. There appears to be a discrepancy between values derived in and. PMID- 20168765 TI - Linearity and enhanced sensitivity of the Shipley AZ-1350B photoresist. AB - The properties of the Shipley AZ-1350B positive photoresist used with the Shipley AZ-303A developer were investigated. It was found that the use of AZ-303A developer results in a significant improvement of the sensitivity and the linearity of the photoresist. The unexposed etch rate of the photoresist was 35 A +/- 5 A/sec. Gratings of high efficiency have been successfully fabricated using the above combination of photoresist and developer. PMID- 20168766 TI - Optical fiber splicing with a low-power CO(2) laser. AB - Low loss splicing of silica fibers by means of a 5-W CO(2) laser has been demonstrated. Step-index fibers with a core diameter of 56 microm and an outer diameter of 154 microm were fused together. The chopped laser beam, effectively 2.3 W and about 1.0 mm in beam-spot diameter, was moved across the fiber ends at a speed of 10 microm/sec. Ninety percent of twenty-one splices had losses less than 0.12 dB with a minimum loss of 0.02 dB. Good reproducibility of the low loss splice was achieved by contacting the fibers tightly before fusing them together. PMID- 20168767 TI - Mode dependent attenuation in parabolic optical fibers. AB - A previous study of excess attenuation caused by slowly varying perturbations is extended to optical fibers with parabolic index profiles. For random diameter variations, total losses are found to be essentially the same in step and parabolic fibers. PMID- 20168768 TI - Transparent electrophotographic films for optical data storage applications. AB - The experimental evaluation of a transparent electrophotographic (TEP) film is reported. The objective of the evaluation was to determine the suitability of TEP films for optical data storage applications, especially those using holography. The characteristics of TEP films that motivated the evaluation are good sensitometric and holographic recording responses, relatively high resolution, and a number of attractive applications properties, e.g., long shelf life, good environmental integrity, and exceptional image permanence. In addition, TEP films have an add-on capability. A general description of TEP films is given, and sensitometric and holographic data are summarized for an experimental TEP film. PMID- 20168769 TI - Sources of correlation degradation. AB - Various sources of degradation of the peak intensity and SNR of an output optical correlation are considered both theoretically and experimentally. Several methods for limiting the effect of these sources of degradation are also advanced, and experimental and theoretical data are presented. PMID- 20168770 TI - Optimization of parameters in matched spatial filter synthesis. AB - Criteria are provided for the selection of various matched spatial filter (MSF) synthesis parameters: the bias exposure (E(B)); beam balance ratio (K); and spatial frequency band (f*) in which K is set. The signal-to-noise ratio (SNR) and peak intensity (I(p)) of the output correlation are used as measures of optimum correlation and a diffraction pattern sampling unit is used to insure reliable and reproducible data. PMID- 20168771 TI - Design considerations in counting particles by size with an optical-digital training method. AB - We discuss a technique whereby an optical-digital computer is trained to do particle-size analysis by sampling the light diffracted from a collection of particles in a coherent optical system. The computer learns the signatures of different particle classes by analyzing the light diffracted from mixed slides, i.e., slides containing more than one class of particles. Two alternative algorithms for particle-size estimation are given. Some important design considerations are discussed. PMID- 20168772 TI - Real-time transmission of a 3-D image using volume scanning and spatial modulation. AB - Theoretical and experimental investigations on real time transmission of a 3-D image using volume scanning and spatial modulation are described. By using a phase stabilized spatial modulation, a 3-D image is transmitted in real time at the rate of fifteen 3-D images per second. The signal and noise, the effect of continuous illumination, and the conditions for distortion-free imaging are shown with experimental verifications. The present system can be realized with presently available optical and electronic components. PMID- 20168773 TI - Fast 3-D scanning systems using a limited tilting angle. AB - A cone-beam scanning geometry is proposed with a linear array of x-ray sources and a flat 2-D detector array. A simple method is given for the reconstruction of the 3-D object. PMID- 20168774 TI - Instrument for the monochromatic observation of all sky auroral images. AB - To investigate the dynamics of auroras and faint upper atmospheric emissions, a new type of imaging instrument was developed. The instrument is a wide field of view, narrow-spectral-band imaging system using an intensified S.E.C. TV camera in a time exposure mode. Pictures were taken at very low light levels of a few photons per exposure per resolution element. These pictures are displayed in the form of a pseudocolor presentation in which the color represents spectral ratios of two of the observed auroral spectral emission features. The spectral ratios play an important part in the interpretation of auroral particle dynamics. A digital picture processing facility is also part of the system which enables the digital manppulation of the pictures at standard TV rates. As an example, hydrogen auroras can be displayed having been corrected for nonspectral background by subtracting a picture obtained by a suitable background filter. The instrumentation was calibrated in the laboratory and was used in several field xperiments. Elaborate exposure sequences were developed to extend the dynamic range and to cover the large range of auroral brightnesses in a fairly linear manner. PMID- 20168775 TI - Aberrations of curved zone plates and Fresnel lenses. AB - The generalization of zone plates and Fresnel lenses from the usual flat surfaces to curved surfaces is discussed. It is shown that, although Abbe's sine law applies to zone plates but not to Fresnel lenses, both can yield single-element aplanats if formed on a curved surface. Third-order aberration formulas are given. PMID- 20168776 TI - Properties of caustics from conic reflectors. 1: Meridional rays. AB - General relations for the caustic surfaces obtained by illuminating an ellipsoid, paraboloid, or hyperboloid reflector by a point-light source, lying along the principal axis of the reflector, were derived. A thorough study of the evolution of caustics with the particular type of reflector, as well as with the relative position of the point-light source and the reflector, was undertaken. Interesting laws for the shape, position, and properties of the caustics were derived, depending on the shape of the particular reflector used, its aperture, and the relative position of the light source and the reflector. These properties may be useful for the creation of wide angle all-reflective multimirror systems designed for definite limits of distances and which, by adjacent pairs of reflectors, present only a limited and reduced amount of third-order aberrations. PMID- 20168777 TI - Time-averaged shadow-moire method for studying vibrations. AB - A time-averaged shadow-moire method is presented which permits the determination of the amplitude distribution of the deflection of a plate in steady state vibration. No stroboscope is required, and the recording is done statically. The method is less sensitive than holographic methods and is therefore suitable for studying relatively large amplitudes. PMID- 20168778 TI - Errors associated with interferometric measurement of convective heat transfer coefficients. AB - Errors caused by refraction and end effects in interferometric systems are studied analytically. Both errors are estimated for Mach-Zehnder and differential interferometers when these instruments were used to measure convective heat transfer coefficients in air and water. Both errors were found to be larger for the Mach- Zehnder interferometer than for the differential interferometer. This result suggests that the differential interferometer is potentially a more suitable and accurate device than the Mach-Zehnder interferometer, if one wishes to measure heat transfer coefficients. Convective heat transfer coefficients measured with a differential interferometer are presented. The experimental study used a specially designed test section, which was inserted into the interferometer. The test involved heat dissipated from a vertical plate by free convection to water. The measured results were found to compare satisfactorily with published results at Rayleigh numbers less than 10(4). At higher Rayleigh numbers, refraction caused sufficient bending of the light rays that a zone of no information next to the heated surface resulted in significant errors. PMID- 20168779 TI - Pulsed sandwich holography. AB - A new method is introduced which utilizes sandwich holography combined with a pulsed laser. In a special rotating hologram holder two plates sandwiched together are exposed through a slit during the double pulse operation of a laser. The two pulses are separated by less than 1 msec. Afterward, in an evaluating holder, one plate is rotated in relation to the other so that the images from the two pulses are overlapped. Then the two plates are glued together. If the emulsions are separated, fringes caused by object tilt between the two pulses can be eliminated by an analogous, but much larger, tilt of the sandwich hologram during reconstruction. Even the direction of tilt, forward or backward, is found this way. PMID- 20168781 TI - Double-exposure holographic interferometry using commonpath reference waves. AB - A variation of double-exposure holographic interferometry is presented that permits accurate analysis of the interferogram. This is accomplished by the use of two unique optical components: a reference wave generator that produces two common-path, orthogonally polarized, diffuse reference waves and an optical phase shifter that varies the relative phase of the reconstructed images in small, equal increments. The incorporation of these components into a typical holographic arrangement is described both experimentally and analytically. Analysis of the interferogram, including data acquisition, computation, and graphic display, is given. This technique is demonstrated for optical and nondestructive testing. Determination of the accuracy is also presented. PMID- 20168780 TI - Galatry profile convolved with the Fabry-Perot instrument function. AB - The physical conditions in laboratory gases and in the upper atmosphere of the planets, including earth, can be deduced from a measurement of the intensity and line profile of different radiating molecules. Because of the low pressures in the upper atmospheres, many molecular lines with small pressure-broadening coefficients are collisionally narrowed. These lines are resolvable with a Fabry Perot interferometer. Analytical expressions are given relating the measured line intensity and profile to the true line intensity and profile. A deconvolution of the measured profile gives the parameters A, beta, and K characterizing the collisionally narrowed Galatry profile. General expressions for the nonideal interferometer are discussed, and, specifically, mirror defects and a limited detector aperture are treated. PMID- 20168782 TI - Statistical properties of laser speckle produced in the diffraction field. AB - The statistical properties (i.e., the probability density function and the average contrast) of laser speckle produced by a weak diffuse object in the diffraction field have been theoretically and experimentally studied with the assumption of the Gaussian statistics for the formation of speckles. The general formulas for the probability density function and the average contrast, which are valid for an entire range of object surface and for the whole diffraction field, are introduced, and their special cases, which have been studied in the past, are derived and discussed. These formulas for the probability density function and the averagae contrast are actually evaluated in the diffraction field of a weak diffuse object illuminated by the Gaussian laser beam. The experimental study has been conducted to verify the above theoretical study, and its results are in good agreement with the theoretical ones. The circularity and noncircularity of the speckle statistics in the diffraction field are discussed on the basis of the theoretical study. PMID- 20168783 TI - Procede de mesure interferometrique utilisant le speckle et son application a l'instrumentation petroliere. AB - A speckle technique recently developed for transient phenomena analysis is applied to the study of dynamic properties of petroleum wells. It is shown that the samples (proceeding from the Orinoco Belt, Venezuela) actually give rise to random speckle patterns when illuminated with a laser beam. Transverse displacements of the sample's surface can then be measured by classical speckle photography. When the root mean square of the phase and intensity variations in the scattered light are small with respect to the corresponding mean values, line of sight displacements of the surface can also be measured by means of a simple modification of the original technique. PMID- 20168784 TI - Patents. AB - 3,963,325; 3,963,328; 3,969,019; 3,969,020; 3,969,023; 3,973,832; 3,976,366; 3,976,367; 3,976,973; 3,980,398; 3,980,399; 3,981,563; 3,981,589; 3,984,802. PMID- 20168785 TI - Real-time optical sectioning having high SNR by using frequency interleaving. PMID- 20168786 TI - Holographic interferometry: identification of hot spots in a high density circuit board. PMID- 20168787 TI - Cone-shaped cover for 360 degrees holography. PMID- 20168788 TI - Optical fiber acoustic sensor. PMID- 20168791 TI - Applied optics of optis and opticists. PMID- 20168790 TI - Compact interference-filter polychromator and narrow band rejection filter. PMID- 20168789 TI - In-situ measurements of aerosol absorption with a resonant cw laser spectrophone. PMID- 20168792 TI - Optical activites in industry. PMID- 20168793 TI - Characteristics of reflection, transmission, scattering, and emission. PMID- 20168795 TI - Ambiguity function display: an improved coherent processor; addendum. PMID- 20168796 TI - Variable threshold zonal filtering. PMID- 20168798 TI - Interface model for frustrated total reflectance measurements of particulates. PMID- 20168797 TI - Diffraction in the zonal Foucault test. PMID- 20168799 TI - Surface plasma oscillations at sinusoidal silver surfaces. PMID- 20168800 TI - Absolute radiometric measurements of the emission from a BRV source at 34 nm. PMID- 20168801 TI - Spectral radiance calibrations between 165-300 nm: an interlaboratory comparison. PMID- 20168803 TI - High-order circular-mode selection in a conical resonator. PMID- 20168802 TI - Far-field energy, in the geometric mode limit, of loaded unstable resonators with centered or corner obscurations. PMID- 20168804 TI - Improved beam quality in double discharge excimer lasers. PMID- 20168805 TI - Asymptotic expression for the far field distribution of step-index single-mode fibers. PMID- 20168807 TI - Tapered gap prism couplers for high index materials. PMID- 20168806 TI - Low-loss access coupler for multimode optical fiber distribution networks. PMID- 20168808 TI - Wavelength dependence of dn/dT in infrared-transmitting semiconductor materials. PMID- 20168809 TI - KDP and ADP transmission in the vacuum ultraviolet. PMID- 20168811 TI - Phase holograms and the action of bleaching: comments. PMID- 20168810 TI - Phase holograms and the action of bleaching. PMID- 20168812 TI - Thermal expansion ultraprecise measurements. PMID- 20168813 TI - Balanced interferometers with simply adjustable interference angle. PMID- 20168814 TI - Real-time double-exposure interferometry with Bi(12)SiO(20) crystals in transverse electrooptic configuration. PMID- 20168815 TI - Interferograms of holographic optical elements. PMID- 20168816 TI - Evaluation of optical heterodyne detectors at 5145 A. PMID- 20168817 TI - Patents. AB - 3,889,207; 3,934,212; 3,937,554; 3,937,555; 3,938,058; 3,941,450; 3,946,332; 3,952,264; 3,957,339; 3,958,188; 3,958,881; 3,976,365; 3,977,772; 3,982,204; 3,982,817; 3,982,821; 3,982,822; 3,982,823; 3,982,824; 3,983,509; 3,983,510; 3,983,511; 3,984,155; 3,989,317; 3,990,785; PMID- 20168818 TI - Near infrared astronomical light collector. AB - A 4-m aperture light collector has been built using the mosaic principle specifically for high resolution stellar spectroscopy in the near infrared by the Fourier multiplex technique. The most novel feature is complete servo control of all optical elements to bring individual images to a common point. Initial goals were a spectral survey of ir objects, and the testing of techniques for a larger future collector. However, the project has been stopped by lack of interest and support; the finished collector will not be used. PMID- 20168819 TI - High resolution Michelson interferometer for airborne infrared astronomical observations. 1: Concept and performance. AB - A Michelson interferometer has been built for use with the 91-cm telescope on NASA's Gerard P. Kuiper Airborne Observatory primarily to measure ir line emission from H 11 regions. Operation is in the rapid scan mode, and the achievable resolution is 0.02 cm(-1) in the wavelength range from 10 micro to around 300 micro. A minicomputer is used to provide on-line spectrum displays and to control and monitor the instrument performance. The design and use of the instrument is discussed, and a comparison is made between the theoretical performance and that actually achieved on the first flights when measurements of line emission from the Orion nebula and from the atmosphere were made. PMID- 20168820 TI - High resolution Michelson interferometer for airborne infrared astronomical observations. 2: System design. AB - A Michelson interferometer for high resolution (lambda/Deltalambda approximately 10(4)) spectroscopic observations of astronomical ir ionic line emission has been built and flown on the NASA 91-cm airborne ir telescope facility (G. P. Kuiper Airborne Observatory). In Part 1 of this paper the requirements for such a system were outlined, and the scientific basis for the choice of instrumental parameters and the rapid scan mode of operation were discussed. In this paper design details of the instrument are presented. These include the optics, control He-Ne laser interferometer, helium-cooled bolometer detector, and cooled passband filters. In addition, the on-line computer software which enables the operator to interact rapidly with the system to produce inflight spectra and control accordingly the observational parameters is described, as are elements of the electronics hardware developed specially for airborne observations. PMID- 20168821 TI - Ultrasonic wave measurement by differential interferometry. AB - The theory and performance of a two beam differential interferometer for measurement of both surface and bulk waves are described. The system is insensitive to small errors (<1 mm) in focus or in specimen flatness. Both amplitude and phase measurements are demonstrated. The system has been absolutely calibrated and can detect 6 x 10(-4)-A surface wave displacements on glass. PMID- 20168822 TI - Analytical procedure for determining lengths from fractional fringes. AB - The development of stabilized multifrequency lasers makes fractional fringes an increasingly attractive technique for length measurement. Determination of an unknown length from the measured fractional fringes is aided by the development of analytical equations for the length and its uncertainty, and criteria are given for selecting the wavelengths. PMID- 20168823 TI - Particle sizing using laser interferometry. AB - The theory and conditions are summarized under which single spherical particles in the size range of a few micrometers and larger may be sized using the observed fringe visibility in a cross-beam laser velocimeter. Scalar diffraction theory and experimental data are presented to show how the size information in the forward- scattered light is dependent on the collection optics geometry, including the size and shape of source beam stops, which have been neglected in previous analyses. Experimental data are also presented to show that backscattered light may not be usable for this method of sizing in the range of sizes examined. PMID- 20168824 TI - Detection and measurement of small vibrations using electronic speckle pattern interferometry. AB - We describe a new method for real-time detection and measurement of small vibrations, based on phase modulation in time-average electronic speckle pattern interferometry. The modulation frequency is shifted relative to the vibration frequency, which makes the intensity of the reconstructed image vary at the difference frequency. The amplitude detection limits are about 20 A by visual observation and 0.1 A by photoelectric measurement using a lockin technique. No auxiliary system for fringe stabilization is required. At higher amplitude levels we can study the deformation of the object in slow motion. Measurements on different objects, including human ear preparation, are presented. PMID- 20168825 TI - Plastic recording media for holography at 10.6 microm. AB - A search for recording media suitable for holography at wavelengths comparable to the 10.6 microm of a CO(2) laser has led to the successful use of Saran Wrap plastic films and of thick acrylic plates. Holographic phase recording has been made with a 1-W single mode cw CO(2) laser yielding incident intensities up to 3.5 W/cm(2). Holographic reconstruction at a wavelength of 632.8 nm has given a diffraction efficiency up to 20%. At a wavelength of 10.6 microm, reconstruction by reflection on the silver-coated surface of an acrylic plate had a diffraction efficiency of 0.5%. It was observed that the recording is less linear on acrylic plates than on Saran Wrap films. PMID- 20168826 TI - Optical coating design with reduced electric field intensity. AB - Equations and tables are provided for designing high reflectors with reduced peak electric field intensity. This approach should enhance the laser damage threshold for reflectors in which the damage is correlated with peak electric field intensity in one of the two coating materials. PMID- 20168827 TI - Auger spectroscopic examination of MgF(2)-coated Al mirrors before and after uv irradiation. AB - Freshly prepared samples of evaporated Al + 250 A of MgF(2) on glass were subjected to analysis by Auger electron spectroscopy coupled with surface erosion by Ar+ ion bombardment before and after uv irradiation. The analysis identified C and 0 on the mirror surfaces prior to irradiation and the addition of Si after uv irradiation in vacuum. The relative amounts of photolyzed surface contaminants were proportional to the observed decrease in mirror reflectance at 1216 A. The Auger analysis confirmed that a very thin layer of surface contamination and not bulk photolysis in the MgF(2) film was responsible for the irradiation induced reflectance loss. PMID- 20168828 TI - Fabrication of metal-dielectric interference filters: a simple method. AB - A simple and direct method for the fabrication of metal-dielectric Fabry-Perot interference filters is proposed. This phase-correction method does not require any complex calculations, and the monitoring is done directly on the system in formation. Experimental filters have been realized and are compared with the theory. PMID- 20168829 TI - High speed frequency modulation of far infrared lasers using the Stark effect. AB - Electronic frequency tuning of an optically pumped far infrared waveguide laser has been achieved by using the Stark effect. Frequency modulation with a 50-kHz modulation frequency and an index greater than 1 has been observed as well as a maximum modulation frequency of 300 kHz. PMID- 20168830 TI - Application of saturation spectroscopy to the measurement of C(2), (3)II(u) concentrations in oxy-acetylene flames. AB - The technique of saturation spectroscopy is applied to measure the concentration of C(2) in the (3)II(u) state in oxyacetylene flames. The two level model is further developed and extended for use in intensity regions slightly lower than that required to saturate the resonances completely. As a result, it has proved feasible to measure both the C(2) number density in the (3)II(u) state of ~10(16)/cm(3) and an excited electronic state lifetime of ~10(-12) sec, both of which depend only on the Einstein A coefficient. The experimental setup is described in detail, and possible extensions of the technique to other atomic and molecular systems are discussed. PMID- 20168831 TI - Penning discharge as a photoelectric EUV spectroscopy source. AB - A Penning discharge was investigated photoelectrically as a light source from 100 A to 300 A. The source showed reasonable stability-10% over an hour's operation. Bright spectral lines observed were a mixture of lines from the filling gas (Ne) and from sputtered cathode material (Al). The discharge was found to be an intense line source; an estimate of the brightness of the 160 A Al IV lines shows them to be comparable with the highly ionized metal lines appearing in a pulsed tokamak discharge. Satellites of the Al IV resonance lines at 160 A appear clearly in the spectra. PMID- 20168832 TI - Multiple order spectra in Fourier transform infrared spectroscopy. AB - A phenomenon akin to higher order spectra in grating spectroscopy has been found in Fourier transform spectroscopy. While its relative intensity is orders of magnitude down from similar effects in gratings, the high sensitivity of Fourier transform ir allows this perturbation to be detected. PMID- 20168834 TI - Photographic shutters: better pictures with a reconsideration of shutter efficiency. AB - An efficient photographic shutter is one which can open and close in small fractions of the exposure time, and this property is generally thought desirable. But no one combination of f/stop and time in an efficient shutter can match the subjective quality, depth of field, and motion stopping ability of certain deliberately inefficient shutters used on automatic cameras. These advantages are derived from a simple optical model by MTF techniques and are confirmed experimentally. PMID- 20168833 TI - Bandpass filters for use in the visible region. AB - A series of new filter glasses showing fairly symmetrical bandpass shapes has been developed. The transmittance curves with half-widths ranging between 58 nm and 168 nm cover the whole visible region. It seems that almost any desired peak transmittance wavelength can be obtained by compositional shifting. These new filters should find useful application in optics and filter radiometry. PMID- 20168835 TI - Theoretical modeling of the simultaneous exposure and development (SED) process of a positive photoresist. AB - The simultaneous exposure and development (SED) process for a positive photoresist, when exposed to a uniform incident flux and to a real image with a nonuniform transverse intensity distribution, is mathematically simulated. The calculation is done for photoresist on optically matched and unmatched substrates while varying the incident radiation intensity, the initial resist thickness, and developer concentration. The results of the calculation and several experiments with SED produced gratings suggest that SED will yieldhigher contrast than the usual expose-and-then-develop (E-D) process. Furthermore, the standing wave effect in the photoresist films coated on reflective substrates is minimized and decreases with depth into the films when the SED process is used. PMID- 20168836 TI - Time-resolved molecular excitation and heat effects induced by infrared radiation. AB - A saturable absorber (SF(6)) is irradiated by a step of radiation from a CO(2) laser, and the step response of the medium is observed. Since the characteristic times of rotational, vibrational, and thermal excitation are different, it is possible to observe each process separately. A set of rate equations is developed for a simplified model of two energy levels. This set includes only one differential equation and qualitatively describes the effects of rotational hole burning and vibrational relaxation. Heat effects are accounted for separately. PMID- 20168837 TI - Nonlinear optical processing: nonmonotonic halftone cells and phase halftones. AB - The halftone screen process has proven to be a useful, flexible technique for achieving general nonlinear functions in coherent optical systems. The two steps to the process involve making a binary pulse-width modulated copy of the continuous-level input using a halftone screen and spatial filtering of single diffraction orders of the image to produce the nonlinearly transformed output. The halftone screens are usually monotonic nondecreasing functions; thus the fundamental sampling periodicity of the screen is maintained. This paper describes some generalizations of the process using nonmonotonic periodic halftone screens. With this new type of screen, functions with an arbitrary number of slope changes can be obtained in the first diffraction order. A detailed synthesis algorithm for specifying the screen shape is given, along with examples and experimental realization of irradiance notch filter and quantization functions. A technique for making the halftone process more resistant to line blooming is descr bed, and a binary phase system made by bleaching ordinary halftoned input is analyzed. PMID- 20168838 TI - Application of optical processing techniques to the quality control of micromechanics. AB - An optical correlator combining most of the features required by a practical automatic control system has been built and used to control small series of work pieces. The functional properties of such an apparatus have been studied, especially its reliability, its sensitivity to mechanical vibrations and misalignment, and the effect of input position on the maximum control rate. In order to obtain a precisely defined response curve, the filters may be computed using the technique of synthetic holography. Computer holograms were used for the control of elementary objects. The accuracy of their transfer function was verified experimentally, and the influence of their bandwidth on the shape of the response curve was studied. PMID- 20168839 TI - Production of color coded equidensities using nonlinear filtering. AB - An optical method to generate a family of color coded equidensities from a continuous tone input is presented. A halftone screen technique is used together with the method of theta modulation to encode each density slice independently. The resulting coded image is demodulated in a spatial filtering system using a polychromatic extended source. With a simple screen, the method allows the number of slices and their density levels to be adapted to the input to be processed while a color code can easily be added to the processed output. PMID- 20168840 TI - Optical pattern recognition on nonvertical imagery. AB - An optical matched spatial filtering system is described that is capable of correlating nonvertical imagery with no loss in the peak intensity and SNR of the output correlation. From the coordinates of the correlation peak, the tilt angle of one camera (or angle of approach of the object being photographed) and the scale of the image (distance from the object) can be determined. Experimental demonstrations of the principle(combined geometrical and optical transformations) on actual imagery are included. PMID- 20168841 TI - Bragg electrostriction in optical waveguides. AB - A reverse process of acoustooptic diffraction in thin films is studied. The high optical field concentration in thin films is utilized by mixing two optical guided modes electrostrictively to generate an acoustic surface wave. A theoretical analysis analogous to acoustooptic diffraction is presented by taking the power balance approach. The nonuniform electric and acoustic field distributions are fully taken into account. A relation between electrostriction and diffraction is established, and the published results on Bragg diffraction are applied directly to Bragg electrostriction. Bragg electrostriction is film thickness dependent, and cw operation of acoustic wave generation is possible. PMID- 20168842 TI - Hybrid laser-to-fiber coupler with a cylindrical lens. AB - Several laser-to-fiber coupling schemes have been compared with regard to coupling efficiency. A coupling scheme with a cylindrical lens is simple and effective for enhancing coupling efficiency. As a mounting and aligning structure for the laser-to-fiber coupling with a cylindrical lens, a hybrid structure has been proposed using a copper mount on which two vee grooves are produced for aligning all optical elements without adjustment. Even though the mounting structures have been produced by machining, the average coupling efficiency of about 50% has been achieved when using a multimode optical fiber with a half acceptance angle of 3-4 degrees . The couplers have been successfully mounted in hermetically sealed laser packages, indicating feasibility and usefulness for practical applications. PMID- 20168843 TI - Knife-edge scanning measurements of subwavelength focused light beams. AB - This note describes a convenient working technique for measuring the minimum size focused spot formed by a lens system. The technique is routinely capable of measurement precision of better than ?lambda. The theory of knife-edge scanning is presented, and the relationship of the measured spot profile to the actual spot profile is shown to be relatively insensitive to the acceptance solid angle of the photodetector. Finally, some typical results of high resolution microscope objectives are presented. PMID- 20168844 TI - Numerical study of a CO(2) laser beam focused on a theta-pinch plasma in the axial direction. AB - Using two different empirical density profiles for the end region of a theta pinch plasma, one with a maximum density on the axis (radiation-dispersing profile) the other with a pronounced axial minimum (radiation- trapping profile), the trajectory of the CO(2) laser beam (10.6 microm) focused axially on such a plasma was studied numerically. This calculation is used to evaluate the optical influence of the plasma, since the maximum power density in the focal plane can be reduced by several orders of magnitude owing to the presence of the plasma. This influence can be substantial even for very subcritical electron densities (n(e) << 10(19) cm(-3)). In cases of large dispersion, the characteristics of a multifocal lens capable of producing perfect focusing are found, and it is shown that the solution is not unique. The radial distribution of the laser beam power density is also calculated and shows numerous irregularities and discontinuities due to the nonuniform beam dispersion. PMID- 20168845 TI - Maximum angular accuracy of pulsed laser radar in photocounting limit. AB - To estimate the angular position of targets with pulsed laser radars, their images may be sensed with a fourquadrant noncoherent detector and the image photocounting distribution processed to obtain the angular estimates. The limits imposed on the accuracy of angular estimation by signal and background radiation shot noise, dark current noise, and target cross-section fluctuations are calculated. Maximum likelihood estimates of angular positions are derived for optically rough and specular targets and their performances compared with theoretical lower bounds. PMID- 20168846 TI - Capacity of polarization and amplitude modulated links in the presence of atomospheric scintillation. AB - A transmission channel may be characterized by its capacity, i.e., the largest quantity of mean mutual information transmitted between the emitter and the receiver. The channel we have studied is a light beam traveling in the low atmosphere, and the capacity has been calculated for polarization (PCM/PL) and intensity (IM) modulation, assuming a Poisson detection process and log-normal fluctuations for scintillation. The depolarization of light has been neglected, and the polarizers have been considered perfect. The appended graphs show that PCM/PL modulation has a greater capacity in all investigated cases. PMID- 20168847 TI - Corrections for atmospheric refractivity in satellite laser ranging. AB - The range correction calculated from ground-level meteorological measurements is shown to consist of a series of terms. The zeroth order term of this series corresponds to the correction obtained under the assumption of a spherically symmetric refractivity profile. The higher order terms arise due to departures from the spherical-symmetry assumption. The range correction is also shown to have residual errors, and an analytic expression for these errors is derived. Pertinent surface data are analyzed to obtain the magnitudes of the higher order corrections and the residual errors. PMID- 20168849 TI - Optical properties of turbid media with specularly reflecting boundaries: applications to biological problems. AB - The optical properties of turbid media are formulated in terms of the diffusion equation approximation to linear transport theory. In particular the important effects of specular reflection at bounding surfaces are accurately accounted for by means of explicit boundary conditions at these surfaces. Applications of these results to two problems of biological interest are made. In one a simple multiple scattering model of a leaf is shown to account well for its measured optical properties. In another a method is proposed for finding accurate absorption spectra of pigment-containing cells. PMID- 20168848 TI - Retroreflecting multipass cell for Raman scattering. AB - A retroreflecting multipass cell consisting of two lenses and both on-axis and off-axis retroreflecting mirror assemblies has been constructed and tested. A gain in Raman scattered signal intensity of 20 has been attained in a focal volume 1.1 mm x 0.3 mm x 0.3 mm. A system employing off-axis paraboloids should provide somewhat higher gain and a diffraction limited focal volume. These systems are applicable to Raman diagnostics of various gas dynamic processes, including flame gases, or the characterization of the gas mixing process in gas dynamic or chemical laser nozzle arrays. PMID- 20168850 TI - Effect of refractive index discontinuity on the reconstruction of the refractive index field. PMID- 20168851 TI - Silicon-carbide diffraction grating for the vacuum ultraviolet: feasibility. PMID- 20168853 TI - Off beam axis scattering by spherical particles. PMID- 20168852 TI - Large-size distortion-free computer-generated holograms in photoresist. PMID- 20168855 TI - Applied optics of optics and opticists. PMID- 20168854 TI - Optical activities in Industry. PMID- 20168856 TI - Meeting reports. PMID- 20168858 TI - Patents. AB - 3,947,630; 3,974,383; 3,976,380; 3,976,882: 3,977,773; 3,978,281; 3,978,334; 3,980,403; 3,983,529; 3,983,573; 3,984,171; 3,985,419; 3,989,348; 3,989,355; 3,989,946; 3,990,771; 3,990,773. PMID- 20168859 TI - Film calibration method for analysis of laser light energy distributions. PMID- 20168860 TI - Randomly spaced phased arrays with large interelement spacing. PMID- 20168861 TI - Isolator in integrated optics using Faraday and Cotton-Mouton effects. PMID- 20168862 TI - Electromagnetic analysis of a laser resonator filled with a flowing medium. PMID- 20168863 TI - Stereoscopic approach to 3-D display using computer-generated holograms: comment. PMID- 20168864 TI - Aging of optical properties of polished copper mirrors. PMID- 20168865 TI - Light scattering from red blood cell ghosts: sensitivity of angular dependent structure to membrane thickness and refractive index. PMID- 20168866 TI - Radiation pattern for a diffuse wall cavity, nonuniform in temperature and emissivity. PMID- 20168867 TI - Simultaneous optical and x-ray imaging telescopes. PMID- 20168868 TI - Image quality and alignment tolerances of IAC 80-cm telescope. PMID- 20168869 TI - Atmospheric water vapor at South Pole. PMID- 20168870 TI - Picture tube for real-time monochrome stereo TV. PMID- 20168871 TI - Double-beam Raman difference spectroscopy. PMID- 20168872 TI - High-resolution spectroscopy of combustion gases using a tunable ir diode laser. PMID- 20168873 TI - End fire coupling between optical fibers and diffused channel waveguides. PMID- 20168874 TI - Effect of the Shuttle contaminant environment on a sensitive infrared telescope. AB - A sensitive ir telescope on the Space Shuttle Orbiter will be limited in its performance by fluctuations in the ir radiation from the natural environment and the contaminant atmosphere. Models of the Orbiter's contaminant atmosphere were used to predict its spectral radiance from 3 microm to 300 microm. At 350 km, statistical fluctuations in the radiation from a water vapor column density of 10(12) cm(-2) produce a noise equivalent power of about 2 x 10(-17) W/Hz(1/2) in a 1 min of arc field of view of a 1-m diameter telescope with a 10-microm spectral bandwidth. This noise is somewhat smaller than the expected contribution from zodiacal light from 5 microm to 30 microm. The column density of all ir emitting molecules can be kept as low as 10(12) cm(-2) only if restrictions on rocket firings and liquid vents are maintained. The relatively low frequency of particle sightings from Skylab, coupled with improvements in Orbiter venting techniques, indicates that sightings of particles 2 microm and larger in radius will not seriously hamper tele cope performance provided that liquid vents and rocket firings are properly restricted. PMID- 20168875 TI - Anastigmatic three-mirror telescope. AB - A new configuration of a three-mirror telescope is introduced that combines high performance with practicality. A geometric spot size of less than 0.1 sec of arc in an easily accessible flat field of 1.5 degrees and excellent stray light suppression are the outstanding features. PMID- 20168876 TI - X-ray efficiencies of blazed gratings in extreme off-plane mountings. AB - The measured first order diffraction efficiencies in the X-ray wavelength region of a blazed grating ruled with 3600 grooves/mm are reported. The grating is used in an extreme off-plane configuration which means that the incident beam is nearly parallel to the grooves. It appeared that in this configuration the efficiencies are between 40% and 70% of the reflection coefficient of the selected grating material. PMID- 20168877 TI - Doubly curved crystal point-focusing x-ray monochromators: geometrical and practical optics. AB - The geometrical optics of symmetrical point-focusing x-ray monochromators made with elastically bent ideal monocrystalline wafers in the geometry employed by Despujols and Berreman are reinvestigated. Sharpness of focus is limited mainly by accuracy of curvature of the crystal wafer and by thermal diffuse scattering. Monochromaticity is limited by these factors and by source and crystal dimensions in the plane of reflection and rarely by the inherent width of the reflection band of the curved crystal. Two existing monochromators reflect about 2-3% of the incident CuKalpha(1) radiation. PMID- 20168878 TI - Groove depth determination using a laser for sinusoidal groove gratings. AB - We describe a technique for determining the groove depth of gratings having sinusoidal grooves. Absolute efficiencies measured using a laser are compared with numerical results to give an indication of groove depth. PMID- 20168879 TI - Poincare sphere analysis of liquid crystal optics. AB - The Poincare sphere representation, a geometrical method for solving problems involving the propagation of polarized light through birefringent and optically active media, is applied to several electrooptic liquid crystal problems. The emphasis is on the twisted nematic case, for which the quiescent state solution was given by Mauguin in 1911. The Poincare construction shows that the normal modes for the undeformed twisted nematic layer are slightly ellipticity. polarized and suggests convenient experiments for measuring the ellipticity. For the field-activated state, a construction is indicated as an alternative to matrix-multiplication methods. PMID- 20168880 TI - Near infrared wide-band spectroscopy with 27-MHz resolution. AB - For the first time, the resolution of a spectrometer capable of recording very wide spectral ranges is better than 10(-3) cm(-1). This performance, obtained by multipassing an existing Fourier interferometer, is initially intended to get Doppler-limited spectra around 20 microm. The halfwidth of the actual unapodized apparatus function can now be meaningfully expressed in frequency units and is found to be 27 MHz. With such an apparatus it becomes possible to record, from adequate sources, sub-Doppler spectra within wide spectral ranges in the visible and the near ir where the resolution can be easily of the order of 20 times less than the width of the Doppler profiles. The tilt-compensated multipass system which may be used to increase by 3 the resolution of already built Fourier interferometers is described together with the first results obtained on our instrument. PMID- 20168881 TI - Intracavity dye laser spectroscopy studies of the Ba + N(2)O, Ca + N(2)O + CO, and Sr + N(2)O + CO reactions. AB - A search for gain or absorption on several candidate visible chemical laser transitions has been carried out using the intracavity dye laser probe technique. Absorption was found on the following v'' ? v' bands of the BaO(A(1)Sigma ? X(1)Sigma) bands in the Ba + N(2)O reaction: 0 ? 1; 0 ? 4; 1 ? 1; 1 ? 2, and 5 ? 1. No gain or absorption could be detected on the 7 ? 1, 6 ? 0, and 4 ? 0 bands (sensitivity ~10(-4)/cm). In Ca, Sr + N(2)O + CO flames, absorption was found in the green arc bands of CaO and the red arc bands of SrO. Several new bandhead wavelengths are reported. Our results support assignment of the arc bands to the diatomic metal oxides. Absorptions and enhancements were found on various Sr, Ba, and Ba(+) transitions. PMID- 20168882 TI - Modulated transmission spectroscopy of gaseous chemi-excited Ca and Sr monoxides. AB - Low pressure dilute diffusion flames of the metal-oxidation (M + N(2)O) and chain reaction (M + N(2)O + CO) types have been studied in absorption by means of modulated intracavity resonance spectroscopy. The measurements obtained were comparable in sensitivity to the intracavity dye laser technique but were of lower spectral resolution. The modulation experiment which is described herein has the advantage of measuring linearly and in real time the transmission factor gamma free from adverse anomalous dispersion effects. It is therefore well suited to the determination of electronic state densities. In these measurements, theground states of CaO and SrO were not detected, but the excited (1)pi and (3)pi states absorbed measurably and as a function of CO content in the flames. PMID- 20168883 TI - Use of the AFCRL line parameters compilation to test the performance of an infrared spectrometer system. AB - The resolution and the frequency accuracy of a spectrum and the abundance of an absorbing gas can be obtained by ratioing observed and calculated spectra. Line positions (to +/-0.002 cm(-1)), spectral resolution (0.075 +/- 0.003 cm(-1)), and a CO abundance [(2.35 +/- 0.23) x 10(-2)atm-cm (STP)] have been found by comparing an observed CO spectrum with a spectrum calculated from the AFCRL line parameter listing. PMID- 20168884 TI - Conditions of pressure scanning of a Fabry-Perot interferometer over a wide spectrum range. AB - The association of a Michelson interferometer and a Fabry-Perot etalon enables the control of the displacement of the peaks of Fabry-Perot transmittance by pressure scanning through Michelson fringes counting. Assuming the variations of the refractive index of gas as a function of wavenumber, pressure, and temperature are known, we show that it is perfectly possible to compute the number of fringes to shift in order to position a chosen peak of Fabry-Perot transmittance for any point in the spectrum. These possibilities enable us to build a real spectrometer whose accuracy is better than 0.05 cm(-1) in the whole visible range. PMID- 20168885 TI - Image transfer properties of proximity focused image tubes. AB - Experimental measurements of the lateral (i.e., radial) spreading of photoelectrons from a multialkali photocathode in an unfocused image dissector tube have shown that (a) the distribution of the radial emission energies is approximately Maxwellian and (b) the radial emission energies are smaller than expected based on the difference between the input photon energies and the long wavelength threshold energy of the multialkali photocathode ( congruent with1.4 eV). Both results are favorable with respect to the predicted electron optical image transfer properties of proximity focused image tubes. The observed data indicate that at least a 40-lp/mm or a 1600-lp/40-mm image field diameter should be resolvable for white light input to commercially available tubes-and that this resolving power should increase to at least 60 lp/mm for input wavelengths longer than approximately 600 nm and decrease to 30 lp/mm or less for input wavelengths shorter than approximately 400 nm. PMID- 20168886 TI - Optical window interferograms: a simple method for their evaluation. AB - A simple procedure for evaluating interferograms based on the calculation of wavefront deviation is demonstrated in the context of image analysis, specifically as applied to optical windows. PMID- 20168887 TI - Holographic laser beam scanners utilizing an auxiliary reflector. AB - Holographic laser beam scanners utilizing a main substrate of simple geometry and an auxiliary reflector are described. The design parameters have been defined and the resolution capabilities analyzed. An experimental scanner using a flat main substrate and a convex auxiliary reflector has been constructed. Diffraction limited reconstructions have been obtained throughout the entire scanning range. A method for dynamically stabilizing the scanning beam is described. Since the main substrate on which the holograms are recorded is either flat or slightly concave, they lend themselves to low cost replication. PMID- 20168888 TI - Loss mechanisms in dielectric optical interference devices. AB - Residual absorption and scattering are loss mechanisms that degrade the performance of all thin films optical devices. By analogy to residual absorption, expressions are derived to evaluate losses due to surface and bulk scattering in dielectric multilayers. Based on these, proposals are made to improve the traditional performances of some basic filters. It is shown how, by means of index inhomogeneity, surface scattering is expected to be reduced considerably. PMID- 20168889 TI - Scanning moire method and automatic measurement of 3-D shapes. AB - A new type of moire and its application to topography are discussed. moire fringes are generated by observing a grating projected on an object under test with a scanning imaging device. The general equations of the projection-type moire topography are given. By controlling the phase, the pitch, or the direction of the virtual grating corresponding to the scanning lines of the imaging device, the automatic sign determination of the contour lines is accomplished. By the use of a high precision flying spot scanner with CRT(DD-tube) and a minicomputer system, an experimental measurement system is developed. Very significant is the fact that a contour line system and a sectional shape of the object are automatically reconstructed and displayed on a color TV monitor. PMID- 20168890 TI - Propagation of modes in curved hollow metallic waveguides for the infrared. AB - Field configurations and attenuation constants of TE-modes in curved parallel plate metallic waveguides are calculated numerically. It is assumed that the distance between the plates is much larger than the freespace wavelength and that the radius of curvature is much larger than the distance between the plates. For curvatures not too small the attenuation constant is shown to be inversely proportional to the radius of curvature, but independent of the plate distance. The discrepancy between theory and experimental observations existing so far is hereby resolved. PMID- 20168891 TI - Polarization-insensitive integrated-optical switches: na new electrode design. AB - The combination of two different types of electrodes in integrated optical switches is shown to permit polarization- insensitive operation. The ability to process arbitrarily polarized light is critical to the use of integrated optical devices with glass fiber transmission lines, due to the rapid changes in polarization state of light propagating in the fibers. We examine the performance of a Deltabeta reversal switch which uses two different types of electrodes and show that polarization-insensitive operation is readily achievable. PMID- 20168892 TI - Effect of the cladding on pulse broadening in graded-index optical waveguides. AB - The WKB analysis is extended to take into account the discontinuity in index profile shape that occurs at the core-cladding boundary of graded-index optical waveguides. The presence of the cladding introduces a large correction to the delay times of the highest 5% of the guided modes and greatly increases the predicted rms pulse broadening of a parabolic profile fiber. Using a model of differential mode attenuation, it is shown that these highest order modes are very susceptible to attenuation. A small degree of waveguide irregularity restores the low pulse broadening originally predicted for a parabolic fiber. PMID- 20168893 TI - Pulse circulation measurement of transmission characteristics in long optical fibers. AB - A pulse circulation method to measure the length dependence of transmission characteristics in optical fibers is described. In principle, the method has the advantage that no unnecessary power is branched off in the loop. Using this method, the length dependence of transmission characteristics of step and graded index fibers has been measured and found to be different in both cases. It is concluded that the difference is due to the material dispersion effect, which significantly influences pulse spreading in long length graded index fibers. PMID- 20168894 TI - Wavelength multiplexing in multimode optical fibers. AB - The capacity of optical fiber transmission systems could be increased by multiplexing several signals at different wavelengths on each fiber. This paper considers various multiplex system designs that might be used with multimode fiber transmission systems. In each case, the required multiplexer size and material properties are calculated as functions of the basic parameters of the fiber system. For fiber systems of the type currently being tested, a compact (~2 mm in diameter x 1 cm long), rugged, three-channel multiplexer could be constructed using a blazed plane reflection grating and graded-refractive-index (GRIN) optics; and it appears that such devices could be produced using available materials and technology. Multiplexers using thick gratings or multilayer dielectric filters are larger, more complicated, and require materials at the very edge of available technology. Multiplexers using a multiple thick grating or hologram could be even smaller than the blazed-grating devices, but materials having the quired characteristics have not been demonstrated. PMID- 20168895 TI - New planar optical coupler for a data bus system with single multimode fibers. AB - We report an optical coupler suitable for use as an access coupler in a data bus T-system with single multimode fibers as transmission lines. The in- and out coupling factors are determined by a lateral displacement of the main trunk fibers which are butt joined. The fabrication of the coupler takes advantage of a simple, sufficiently reproducible, and cheap planar photolithographic process. Using fibers with 100-microm o.d. and 90-microm core diam a total insertion loss of about 1.5 dB and an out-coupling of about -14 dB was measured with a lateral displacement of 20 microm. PMID- 20168896 TI - Leaky modes on W-fibers: mode structure and attenuation. AB - The mode structure of a W-fiber has been discussed in conjunction with that of an SC-fiber using the WKB approximation, and the leaky mode attenuation coefficient has been derived using Poynting's vector theorem. Furthermore, a simplified expression for the attenuation coefficient of the W-fiber has been obtained and compared with that of the SC-fiber. Comparisons between the calculated and measured spatial transient responses have also been carried out and shown to agree well with each other. The results are useful in the study of W-fiber properties. PMID- 20168897 TI - Propagation in a weakly anisotropic waveguide. AB - In this communication we have considered propagation in a weakly anisotropic dielectric waveguide. It is shown that for a positive anisotropy the fractional power carried by the guide core increases over the isotropic case and that the anisotropy has an increasing effect as cutoff is approached. For negative anisotropy the effect is reversed. The increase in the fractional power varies linearly with the value of anisotropy with slope increasing as cutoff is approached. The degeneracy between the HE(n+1,m) and EH(n+1,m) modes present in the isotropic weakly guiding approximation is broken, and it is physically significant to distinguish between EH and HE modes. The anisotropy in retinal receptors (considered as dielectric waveguides) increases the stability of modal power with variation of the wavelength, although the effect is too small to explain the observation. PMID- 20168898 TI - Optical constants of crystalline and fused quartz in the far ultraviolet. AB - Near-normal incidence reflectance measurements of crystal and fused quartz are reported in the 1026-1640-A interval. The reflectance spectra are extended either with known data or with extrapolations to allow a Kramers-Kronig analysis. The calculated complex index of refraction is in good agreement with the results obtained by other methods. This agreement even extends to the ir. PMID- 20168899 TI - Microscope adapted for the generation of various contrast types: theory and experiment. AB - With the aid of a polarizer, an analyzer, and two birefringent double plates placed in conjugate positions at the front focal plane of the condenser and the rear focal plane of the objective, respectively, a microscope is adapted to generate in a pure form one of four contrast types, i.e., either phase or amplitude differential or nondifferential. The theory of such an arrangement is discussed, and some practical results are shown. PMID- 20168900 TI - Linewidth measurement with an optical microscope: the effect of operating conditions on the image profile. AB - A theoretical model of the optical microscope based on the theory of partial coherence is used to predict the image profiles of lines on IC photomasks and assess factors contributing to measurement errors for different conditions of microscope operation. A comparison of experimental and theoretical image profiles is given, showing good agreement with theory for a 0.9 N.A. and linewidths as small as 0.5 microm. The primary sources of differences appear to be edge quality and accuracy of focus. The theory indicates that for well-corrected microscope optical systems, spectrally filtered to eliminate longitudinal chromatic aberration and chromatic difference of magnification, accurate determinations of linewidth may be made from the image profile using a threshold of 25% of maximum intensity (corrected for finite background transmittance in the opaque region). The correspondence between the edge location and the 25% threshold appears to be nearly invariant with small amounts of defocus and spherical aberration as well as variation in the numerical aperture of the condenser. PMID- 20168901 TI - Investigation of structure and dynamics of aerosol inhomogeneities in the ground layer of the atmosphere. AB - The development of methods for active optical sounding of the wind velocity vector on the basis of scattered signal correlation requires a detailed study of the inhomogeneity parameters of the scattering properties of the atmosphere. However, at present the information on inhomogeneity parameters is mainly limited by stating the fact of their presence and reporting on the contrast value of atmospheric scattering irregularities under definite atmospheric conditions. The knowledge of inhomogeneity sales and their lifetimes is also extremely important for correlation sounding of wind velocity. The present paper gives the results of experimental investigations of inhomogeneity parameters in the ground layer of the atmosphere. PMID- 20168902 TI - Measurement of rain parameters by optical scintillation. AB - We describe a technique for measuring path-averaged rain parameters by analyzing the rainfall-induced scintillations of a laser beam. From the time-lagged covariance function of two vertically spaced line detectors, we determine the average rainfall rate and drop-size distribution along the optical path. This technique requires no prior assumption of the form of the drop-size distribution. Sample measurements on a 140-m path confirm that the path-averaged drop-size distribution of a steady rain follows a Marshall-Palmer distribution. The optically measured path-averaged rain rate also shows good agreement with conventional tipping-bucket rain-gauge data. PMID- 20168903 TI - Atmospheric scintillation of optical and infrared waves: a laboratory simulation. AB - Accurate simulation, on a laboratory scale, of atmospherically induced scintillation phenomena is achieved by creating an unstable vertical temperature gradient in a 1.5-m long, 40-cm wide, and 60-cm deep water tank. The turbulent index of refraction has a statistical structure similar to that of the atmosphere, in particular, Kolmogorov's inertial subrange model is verified. The measured saturation and supersaturation of the irradiance variance agree very well with theory and atmospheric data. The simulation results are properly scaled by the first-order expression for the log-amplitude variance, and the saturation distance is typically reduced by a factor of 300-400. PMID- 20168904 TI - Relative contribution of upper and lower atmosphere to integrated refractive index profiles. AB - We measure the wavefront coherence and the irradiance fluctuations of stellar sources to obtain integrated refractive-turbulence profiles of two regions of the atmosphere. Comparison of experimental data during our measurement program shows an equal contribution of upper and lower layers to the limitation of the optical seeing. We also note the great variability of turbulence located above 3 km up to the stratosphere, from night to night. When simultaneously operated, these two methods are suitable for astronomical site testing. PMID- 20168905 TI - Albedo of the ocean-atmosphere system: influence of sea foam. AB - The influence of the ocean's optical properties and wind induced sea surface foam (white caps) on the shortwave albedo of the ocean-atmosphere system is studied by solving the radiative transfer equation using a Monte Carlo method. It is found that for a foam free ocean, the planetary albedo of a very clear ocean is at most 10% greater than that for a totally absorbing ocean. However, the introduction of a relatively small amount of sea foam on the surface can produce a considerable increase in the albedo, especially if the foam is highly reflecting. For example, it is shown that for foam which is totally reflecting (the foam albedo is 1), an increase in the wind speed from 6 to 14 m/sec would double the planetary albedo for small solar zenith angles. PMID- 20168906 TI - Spatial frequency sampling by phase modulation as a method of generating multiple images. AB - A technique of forming multiple images by an object with phase only periodic transmittance, which acts as a spatial filter, is described. Preliminary experimental results are presented to confirm some of the theoretical predictions. PMID- 20168907 TI - Spatial frequency filtering and its application to microscopy. AB - Application of spatial frequency filtering techniques gives powerful tools for the automation of screening ofbiomedical microsamples. Band-pass filtering provides a size selection of objects, whereas high-pass filtering combined with a subsequent reduction of the field size enables the separation of the superposition of thefield and the object spectrum. Besides the theoretical background and numerical evaluations, experimental applications to cytological and cytogenetical samples are shown. PMID- 20168908 TI - Depth of convergence of a sharpness index autofocus system. AB - The critical parameters in the selection of an autofocus cost functional are that it must have a high sensitivity and selectivity at and near the correct focus point and that it must be capable of converging to the correct focus from a large initial or preclosed loop defocus state. The largest initial focal range error an autofocus system is capable of correcting in closed loop is referred to as the depth of convergence. It is shown theoretically and also verified experimentally that the depth of convergence is a sensitive function of the object range, the initial focal range of the imaging system, and, more remarkably, the spatial spectrum of the object. PMID- 20168909 TI - Nonlinear optical processing: effects of input medium and precompensation. AB - The halftone screen process for obtaining nonlinear functions with coherent optical systems utilizes a preiprocessing step with an ideally hard-clipping binaryinput recording medium. This paper analyzes in detail the effects of using film or other media with finite gamma and saturation density. A mathematical model to predict the system performance for both one-step and two-step copying procedures is developed, and numerous computer results of parameter variation are given. It is found that nonlinear functions with threshold or jump characteristics are the most sensitive to the nonideal effects. A precompensation technique allowingnonideal copy film to be used with minimum degradation of the transfer characteristic is presented, and an algorithm for calculating compensated halftone cell shapes is given, with examples. PMID- 20168910 TI - Deformation invariant optical processors using coordinate transformations. AB - A general formulation of the properties, optical synthesis, and existence of space variant optical processors using coordinate transformations is provided. General expressions that the coordinate transformations must satisfy are described. Specific examples of the use of the methodology to determine the existence of and methods for the realization of space variant optical processors are included for various specific data deformations and applications. PMID- 20168911 TI - Ablative flashlamps for high peak power dye lasers. AB - An experimental investigation of ablative wall flashlamps used to pump high peak power dye laser is presented. The duration of the flashes was about 2 microsec. Three tubes with diameters 1.6 mm, 4.4 mm, and 8 mm were used. We have measured the emission spectrum, the brightness, and the efficiency between 250 nm and 580 nm for electrical energy input densities up to 560 J/cm(3). The performance of the flashlamps with xenon and air is shown. The experiments demonstrate that above an energy density of about 150 J/cm(3) the gas type and pressure are unimportant but that xenon is always superior. PMID- 20168912 TI - Lorentz broadening in the modeling of the HF chemical laser. AB - The results of a survey of pressure-broadening data in the literature pertaining to species present in H(2) - F(2) chemical lasers are described. Pressure broadened linewidths of the HF vibration-rotation transitions were found to depend strongly on the vibrational and rotational quantum numbers, as well as on the perturbing species. The experimental data were incorporated into a rate equation model of the pulsed H(2) - F(2) laser; where experimental data were unavailable, theoretical values were used. The calculations made from this model demonstrate the importance of including such detailed pressure-broadening information. Recent experimental results of Kwok and Cohen for HF V ? R,T deactivation were also included in the model and were taken to be a multiquantum process. Comparisons of model predictions for pulse energy and pulse duration with several atmospheric-pressure laser measurements showed good agreement. PMID- 20168913 TI - Integrated construction of low-cost gas lasers. AB - Helium-neon lasers have been fabricated using methods and materials particularly suited to high-volume in-line production. Pilot-project results suggest that satisfactory life and performance can probably be achieved in production lasers incorporating pressed or ground soft-glass parts, extensive solder-glass seals, and thin-film-metallization cathodes. The new construction methods suggested should lead to other innovative laser products. PMID- 20168914 TI - Evaluating the inequivalence and a computational simplification for the NBS laser energy standards. AB - A model with two time constants is used to estimate the inequivalence in response between a laser energy pulse and an electrical energy pulse put into a calorimeter of the C series type. The results are as follows: the calorimeter labeled C41 showed a 0.15% inequivalence and the calorimeter labeled C46 showed none. We also find that the complicated model currently used to get the corrected temperature rise of a measurement can be replaced by a simpler four-data-point method with no significant loss in accuracy. This simplification means we can substitute a microprocessor for a large computer to get the corrected temperature rise in an electrical calibration or laser energy measurement. PMID- 20168915 TI - Use of rate equations to describe laser excitation in flames. AB - In describing the excitation of atomic and molecular species with lasers in spectroscopic applications, only the density matrix formulation is exactly correct. Many workers, however, have used the conventional rate equation formulation. The range of application of the conventional rate equations is examined and, for flames, shown to be valid for sufficiently slow laser pulse rise times under single-mode excitation and for certain special cases of multimode excitation. PMID- 20168916 TI - Closure of pinholes under intense laser radiation. AB - The closure of pinholes due to plasma created by intense laser radiation interacting with the pinhole perimeter is studied. Pinholes with 100-300-microm initial diam close in 3-14 nsec, respectively, for a 10-nsec FWHA, 10-J incident laser pulse. For a constant focal spot size and pulse duration, the closure time and rate are found to be a function of laser energy; however, the energy transmitted through the pinhole is independent of the incident energy for the pulse duration, pinhole diameters, and focal spot size used in these experiments. PMID- 20168917 TI - Silicon carbide infrared cavity radiator. PMID- 20168919 TI - Study of flow pattern in a fluid by scattered laser light. PMID- 20168918 TI - Optical detection of acoustic emission waves. PMID- 20168920 TI - Patents. AB - 3,963,347; 3,963,995; 3,964,003; 3,965,439; 3,965,440; 3,967,211; 3,967,212; 3,968,456; 3,969,687; 3,969,688; 3,992,085; 3,992,086; 3,994,574; 3,994,575; 3,997,247; 3,998,527; 3,999,840; 4,009,943; 4,009,944; 4,012,126; 4,013,349; 4,013,350; 4,018,511. PMID- 20168922 TI - Applied optics of optics and opticists. PMID- 20168921 TI - Optical activities in industry. PMID- 20168923 TI - Tunable diode laser spectroscopy of (14)CO(2): absorption coefficients and analytical applications. PMID- 20168924 TI - Brewster angle light trap. PMID- 20168925 TI - Effect of Goos-Hanchen shifts on pulse widths in optical waveguides. PMID- 20168926 TI - Fiber optic data distribution systems utilizing variable tap ratio optical couplers. PMID- 20168927 TI - Generation of coherent radiation tunable from 201 nm to 212 nm. PMID- 20168929 TI - Scan-playback corrections. PMID- 20168928 TI - Laser anemometer signals: visibility characteristics and application to particle sizing; errata. PMID- 20168930 TI - Holographic scan aberration correction: a clarification. PMID- 20168931 TI - Spatial multiplex tomography. AB - We present a new method for the synthesis of sections of a 3-D object from an encoded record of its projections. This record is prepared by spatially multiplexing selected projections of the original object onto a photographic film. The film is then inserted into a coherent optical analyzing system, where an image of one planar section is generated; only a single plane of object is in sharp focus, while the rest of the object is blurred. The location of the sharp plane may be chosen arbitrarily with no need to recall the original object. Analysis, supported with experimental verification, is presented. PMID- 20168932 TI - Nondestructive interferometric measurement of the delta and alpha of clad optical fibers. AB - It is shown that interferograms generated by passing light perpendicular to the axis of a fiber can be used to obtain the maximum refractive index difference and the index profile shape to better than +/-10% accuracy in regions of the core where alpha is constant. This technique avoids the time consuming sample preparation required for the slab method, the propagation problems associated with the near-field technique, and the surface quality problem associated with the reflection technique. PMID- 20168933 TI - Splice losses in step-index fibers: dependency on fiber-break angle. AB - Coupling has been measured for dry-spliced fibers as a function of break angle. The angles were measured interferometrically to about 0.1 degrees accuracy. An analysis is performed, and the measurements are found to be within 1.0% RMS of the calculation. PMID- 20168934 TI - Optical time domain reflectometer. AB - By using an optical time domain reflectometer a new measurement technique which allows displaying the length dependence of the fiber attenuation by analyzing backscattered light has been developed. This paper compares the backscatter and insertion-loss techniques. In addition, results of several experiments which illustrate the versatility of an optical time domain reflectometer are described. PMID- 20168935 TI - Handling optical cables: safety aspects. AB - We found that it is very dangerous to stare directly at thQ free end of an optical cable excited by a GaAlAs laser or by a high radiance LED. We determined the minimum tolerable distance between the human eye and the cable end. In the case of a cable with one multimode fiber, the typical safety zone should be 1 m when using a laser light source and 15 cm when using an LED. In the case of a single mode fiber the critical distance is approximately two to four times as large as in the multimode case; however, when taking into account typical values of the power level in single mode fibers, the critical distance is approximately 1 m as well. For N fibers within the cable the critical distance agrees with that of the single fiber, provided that the fibers are not too closely packaged. PMID- 20168936 TI - Optical fiber coating concentricity: measurement and analysis. AB - Backscattering of laser light that is incident at right angles to the axis of an optical fiber is utilized to evaluate the degree of eccentricity of a plastic jacket on the fiber. An analytical treatment of the problem based on ray optics is shown to be in excellent agreement with experiments, which are capable of detecting coreto- jacket offsets on the order of 1 microm. PMID- 20168937 TI - Microbending losses of doubly clad (W-type) optical fibers. AB - The microbending of optical fibers causes some additional transmission losses. In this paper, the theoretical and experimental results on the microbending characteristics for doubly clad (W-type) fibers are described. A simple approximation in which W-type fibers are considered as equivalent singly clad fibers is employed to calculate the additional losses due to microbending. It is shown that the additional losses of W-type fibers depend on the optical wavelength. Further, it is shown that the structural imperfections of the guide can be also considered a kind of microbending which affects the spectral loss characteristics of W-type fibers. PMID- 20168938 TI - High-speed noncontact fiber-diameter measurement using forward light scattering. AB - The forward scattering of light by an optical fiber produces an interference fringe pattern, and the fringe period is inversely proportional to the fiber diameter. An electrooptic system has been developed to produce and detect this scattering pattern to provide an instrument which will measure fiber diameter during the drawing operation. The system measures the fiber diameter at a 1-kHz rate with a precision of 0.25 microm and an accuracy of +/-0.25 microm over a range of 50-150-microm diams. The instrument allows the fiber to move laterally in a 1-cm diam window maintaining the above accuracy. The system can be calibrated optically and does not need a standard fiber for this procedure. The instrument has been used for months without the need for recalibration. In addition to the digital diameter output, the system employs a microprocessor to compute mean and standard deviation values for various sample lengths and provides suitable signals for feedback control of fiber diameter. PMID- 20168939 TI - Electrooptically switched multipass system for laser scattering diagnostics. AB - A multiple pass technique for use in laser scattering experiments is accomplished by trapping a pulse in a resonatorlike geometry. The construction, test, and operation of the multipass system are described. The gain is measured by Rayleigh scattering from a gas filled experimental chamber. Consequences for plasma diagnostics are discussed. PMID- 20168940 TI - Scintillation statistics caused by atmospheric turbulence and speckle in satellite laser ranging. AB - We study the statistics of scintillation at the ground-based receiver for the earth-space-earth retroreflector configuration of satellite laser ranging. These statistics are governed by the joint effects of atmospheric turbulence and speckle produced by the retroreflector array. An expression for the probability density function of scintillation is obtained and evaluated numerically. Comparison of the normalized variance of scintillation calculated by using this function shows good agreement with results obtained by other methods. PMID- 20168941 TI - Atmospheric extinction between 0.55 microm and 10.6 microm due to soil-derived aerosols. AB - We have calculated the extinction expected for soil-derived aerosols for several laser wavelengths and have shown that these aerosols result in approximately neutral extinction between 0.55 microm and 10.6 microm. This result is valid whenever the extinction is due primarily to soil-derived aerosols, and it appears to be independent of whether the aerosols are of local origin. Comparison with visibility data shows that visibility reductions due to these aerosols are of relatively greater importance in arid or semiarid areas. Lower bounds on the frequency of occurrence of such visibility reductions may also be determined from analysis of visibility data. PMID- 20168942 TI - Daytime r(0) evaluated from vertical microthermal measurements. AB - The usefulness of parameter r(0) for describing the effect of atmospheric turbulence on wavefront distortion sensitive optical systems has been widely discussed. In this paper we present in situ daytime r(0) measurements (5500 A, Zenith propagation) obtained from balloon-borne microthermal radiosondes. We find that the parameter r(0) is log normal distributed at various levels aloft and that r(0) follows a power law in the 100-10,000-m range. Comparing our results with nighttime ground based observations we conclude that local turbulence prevails in determining image quality. PMID- 20168943 TI - Spectral characteristics of image quality for imaging horizontally through the atmosphere. AB - Spectral effects of visible and near ir imaging for horizontal paths through the atmosphere are considered. For high glare and long range imaging situations, image resolution and quality in the near ir are significantly improved over that in the visible spectrum in clear weather, primarily as a result of less atmospheric scattering of radiation at longer wavelengths. PMID- 20168944 TI - Correction of laser tracking data for the effects of horizontal refractivity gradients. AB - Pulsed laser ranging systems are being used to measure accurately the distance from the earth to retroreflector equipped satellites. At the lower elevation angles horizontal refractivity gradients can introduce centimeter level errors into the range measurements. A correction formula which compensates for the gradient effects is developed and evaluated using typical meteorological data obtained from weather stations located near Washington, D.C. PMID- 20168945 TI - Estimation of image centroid, size, and orientation with laser radar. AB - Angular tracking of targets with monopulse laser radar can be performed by tracking the centroid of the image. The image irradiance distribution is sensed with an array of noncoherent photocounting detectors and the counts processed to provide estimates of the image centroid, size, and orientation. The mean and variance of the centroid and second moment are obtained for optically rough and smooth extended targets, as functions of coherence, target extent, resolution, and integration time. The limits on accuracy imposed by shot noise from the image and background irradiances and by laser speckle are discussed. PMID- 20168946 TI - Annular apertures for angular tracking. AB - The estimation of the angular position of a target based on its image is considered when the image is formed with a telescope possessing an annular pupil and is sensed with a four-quadrant noncoherent detector. The Cramer-Rao lower bound on the estimation error is calculated as a function of the linear obscuration ratio for unresolved targets in the shot-noise limit. The ratio influences the error both via the shape of the telescope point spread function (PSF) and via the SNR. The error increase associated with the PSF becomes significant for greater, similar 0.5. PMID- 20168947 TI - Synthetic modal interferometric laser imaging. AB - Objects can be imaged if passed through a field formed by the interference of a Hermite-Gaussian (modal) laser beam with a spatial offset reference beam. The light intensity scattered by the object is electronically detected and spatially recorded onto film moving synchronously with the object. The recording is a hologram. In the reconstruction of the hologram, each object point produces a modal beam, and this collection of modal beams is matched filtered to yield an image characterized by a point spread function of Laguerre- Gaussian form. The resolution is dependent upon the waist size and order of the modal beam and is invariant with respect to object/source/detector distances. Theoretical and experimental results are given. PMID- 20168949 TI - Null curves in diffraction patterns. AB - We show that there is a large class of plane curves which never appear in partial form, as curves along which destructive interference takes place. These curves have an analytic property which, when combined with an analytic property of the free light field, gives rise to patterns of interference that are commonly observed. PMID- 20168948 TI - Varifocal moire zone plates for straightness measurement. AB - A Fresnel zone plate of variable size can be formed as a moire pattern between a suitable pair of identical grids. The focusing power may be varied over a considerable range by relative translation of the grids if their line sbapejs are determined by a combination of cubic and linear functions. Elliptical and hyperbolic patterns are also obtainable. If both grids ae constructed in phase reversal form, the irradiance in the diffraction image due to the zone plate is enhanced substantially. The device may then be used with photoelectric detection to monitor the straightness of a continuous linear motion. A possible application to field widening in interference spectroscopy is also suggested. PMID- 20168950 TI - Quasi-microscope concept for planetary missions. AB - Viking lander cameras have returned stereo and multispectral views of the Martian surface with a resolution that approaches 2 mm/lp in the near field. A two-orders of-magnitude increase in resolution could be obtained for collected surface samples by augmenting these cameras with auxiliary optics that would neither impose special camera design requirements nor limit the cameras field of view of the terrain. Quasi-microscope images would provide valuable data on the physical and chemical characteristics of planetary regoliths. PMID- 20168951 TI - Two-point resolution of a microscope: effect of nonuniform and nonsymmetric illumination using a semitransparent pi-phase annular aperture. AB - This paper presents a theoretical study of the effects of partial coherence (via the effect of condenser aperture) on the resolution of two pinholes by a semitransparent and pi-phase annular aperture microscope. The illumination used is nonuniform and nonsymmetric. The response of the resolution has been studied in three discrete planes of illumination. It has been seen that by making the central region of the pi-phase annular aperture completely transparent, best resolution is obtained in the plane of illumination o = pi/2. The oscillatory behavior of the limiting resolution has also been displayed graphically. PMID- 20168952 TI - Primary aberrations for grazing incidence. AB - Beginning with exact relations between-object and image coordinates for a single reflective surface, a systematic analysis of general grazing incidence systems is presented. A complete set of primary aberrations for single-element and two element systems is developed. The importance of a judicious choice for a coordinate system in showing field curvature to be clearly the predominant aberration for a two-element system is discussed. The validity of the theory is verified through comparisons with the exact ray-trace results for the case of a telescope. PMID- 20168953 TI - Improved detection of ultraviolet radiation with gas-filled phototubes through photoionization of excited atoms. AB - Using dc biases higher than those recommended by manufacturers, it is possible to exploit photoionization of excited atoms to obtain high sensitivities to uv radiation using gas-filled phototubes. Spectral response, nonlinearity of response, and dc bias effects are discussed. Comparisons are made with uv semiconductor detectors, and suggestions for future research are made. If a photocathode is used in a gas tube such devices are quite sensitive to both visible and uv radiation. PMID- 20168954 TI - Vacuum ultraviolet radiation scales: an accurate comparison between plasma blackbody lines and synchrotron radiation. AB - Blackbody limited lines of C and N from an argon wali-stabilized arc have been used to determine the spectral radiance of specially developed deuterium discharge lamps at 165.7 nm, 167.0 nm, 174.3 nm, and 193.1 nm, following the attainment of significantly increased accuracy in plasma temperature determination. Comparison with calibrations based on the use of synchrotron radiation has shown agreement to within typically 1.5%, as the result of extensive studies of sources of systematic error. The agreement is well within the estimated uncertainties, which range from +/-3.7% at 165.7 nm to +/-2.7% at 193.1 nm for both techniques. PMID- 20168955 TI - Thin film optical coatings. 1. Optical coating stabilities. AB - Following a short mathematical recapitulation of thin film theory, the stability of a coating is defined with respect to the optical thickness of each layer or with respect to wavelength. The first and second derivatives of the reflection factor are calculated, and these results are applied to practical examples. PMID- 20168956 TI - Liquid surface coating for optical components used in high power laser applications. AB - Measured absorption coefficients of paraffin oil in the ir, visible, and uv spectral regions indicate that paraffin oil is potentially useful in these spectral regions as a protective and index-matching surface coating material for high power laser applications. Liquid coatings are unique because of their self healing, index matching, nonporous, hydrophobic properties. PMID- 20168957 TI - Absorptance of thin films. AB - This paper describes a study of the absorptance of thin films with the aim of elucidating the region of validity for a direct relationship between the absorptance and the absorption coefficient. The calculations are performed for an unsupported film, a film on a transparent or metallic substrate, and for the absorptance as a function of polarization. PMID- 20168958 TI - Determination of axially symmetrical refractive index distribution from directions of emerging rays. AB - A successful verification of a method for numerical reconstruction of axially symmetric refractive index distribution is reported. Directions of rays emerging from a test object are used as input data for reconstruction. They are obtained by numerically calculating the spatial frequency of the fringes in an interferogram. It is also shown that the same data can be obtained directly by counting moire fringes arising from two slightly displaced interferograms. An acrylic resin immersed in liquid is used as a test object. The reconstruction is carried out with errors of a few percent. PMID- 20168959 TI - Recording slope and curvature contours of flexed plates using a grating shearing interferometer. AB - A diffraction grating shearing interferometer is presented which, depending on the recording procedure, can be used to measure directly the slopes and curvatures of specularly reflecting flexed plates. Three system arrangements are described: two for slope measurement and one for curvature. One slope arrangement yields results in real time but, in general, does not compensate for initial model curvature. The second requires an additional spatial filtering step but does compensate for the initial curvature. A diffraction theory approach is used to arrive at expressions for the complex field amplitude of the light at the output plane. This leads to expressions for the fringe values. Experimental results for three types of model are also presented. Errors of 2-4% were found for the various system arrangements. In addition, an analytical expression is derived and verified experimentally, which shows that when the system is used for measuring slope, the curvature of the model limits the measuring sensitivity. The theoretical analysis shows that this is a fundamental property of grating interferometers in general. This property is then exploited as the basis of the curvature measuring technique. PMID- 20168960 TI - Stable multipass Fabry-Perot interferometer: design and analysis. AB - A multipass plane parallel Fabry-Perot interferometer (FPP-M) can give extremely high contrast (in excess of 10(6)) over a wide range of finesse values without reducing the transmission significantly. Curves and tables are provided along with a brief outline of Chabbal's analysis for the residual defects of the Fabry Perot mirrors to aid a quick assessment of the optimum parameters for a desired spectrometric work. The exploitation of the advantages of an FPP-M depends upon the maintenance of its stability. So, we have constructed a passive interferometer of low thermal expansion material, Cer-Vit, along with nonkinematic design and thermally compensated mirror mounts to achieve long term stability without the use of a servo control device. PMID- 20168961 TI - Sandwich hologram interferometry. 4: Holographic studies of two milling machines. AB - The deformation of two milling machines was studied using real time holography, double exposure holography, and sandwich holography. The about 2-m high machines had a weight of about 2 tons each, and the experiments were made directly on the floor of ordinary machine laboratories using continuous lasers. The machines were deformed by static forces of the same magnitude and direction as ordinary cutting forces. The main advantages of sandwich holography were that it made possible detection of the signs of displacement, measurement of small deformations without influence of large rigid body motions, measurement of larger displacements than possible with ordinary holography, and study of local deformations of details down to fractions of a fringe. Some vibration measurements were also made using the conventional time average method. PMID- 20168962 TI - Electrically accessible Lippmann hologram memory. AB - Using Fe-doped LiNbO(3) crystals we have constructed Lippmann-type holograms where access both in writing and in reading is performed electrically. Discussions are given for the interlayer cross talks in a stacked structure. Device operations are demonstrated with a double-layered memory. PMID- 20168963 TI - Analysis of a system for hologram interferometry with a continuously scanning reconstruction beam. AB - A detailed analysis is made of a system for fringe evaluation in hologram interferometry in which a conjugate reconstruction beam scans the hologram, and the resulting fringe motion is observed in the real image of the object. The factors decisive for best use of the system are studied, especially the sensitivity and accuracy of the measurements and their dependence upon the geometry of the setup. For the relation between the geometry and the sensitivity, the concept of the K sphere is introduced. The effect of speckle noise due to the limited apertures of the system is also discussed. It is shown that the speckles determine the displacement measuring range together with suitable aperture sizes of the system. PMID- 20168964 TI - Strain components obtained from contrast measurement of holographic fringe patterns. AB - In the study of the deformation of objects by holographical interferometry, it is possible to determine directly strain components by measurement of the contrast of the fringes. With adequate geometry and a zero method, contrast measurements give accurate values of the strain components. PMID- 20168965 TI - Mode control of Ti-diffused LiNbO(3) slab optical waveguide. AB - The investigations were carried out on optical waveguides obtained by thermal diffusion of Ti into LiNbO(3) single crystals. In the Ti-diffused LiNbO(3) slab waveguides, the relationships of the refractive index profile (index change at the surface, diffusion depth) to various diffusion conditions were examined. Conditions were found to fabricate the waveguides of the required number of modes (TE modes) and effective indices for the wavelength of a He-Ne laser (0.6328 microm) and a GaAs-GaAIAs double heterostructure laser (DH laser) (0.8730 microm). The slab waveguides of the required number of modes and effective indices could be obtained by adjusting only the thickness of evaporated Ti film. PMID- 20168966 TI - Space-bandwidth product of some deblurring filters. AB - We present an estimate of the space-bandwidth product of a filter of the form W(f) = [H(f)]/[H(2)(f) + C(f)], which is often encountered in image processing. The estimate applies to blur functions H(f) which are similar to the linear motion blur in that they oscillate smoothly under a decreasing envelope. PMID- 20168967 TI - Image restoration by Wiener filtering in the presence of signal-dependent noise. AB - An optimum filter to restore the degraded image due to blurring and the signal dependent noise is obtained on the basis of the theory of Wiener filtering. Computer simulations of image restoration using signal-dependent noise models are carried out. It becomes clear that the optimum filter, which makes use of a priori information on the signal-dependent nature of the noise and the spectral density of the signal and the noise showing significant spatial correlation, is potentially advantageous. PMID- 20168968 TI - Optical logarithmic filtering using inherent film nonlinearity. AB - Linear optical spatial filtering cannot be effectively applied to multiplied and convolved signals. One approach is to first perform a logarithmic transformation to produce a signal in additive form suitable for linear filtering processes [A. V. Oppenheim et al., Proc. IEEE 56, 1264 (1968)]. It was first suggested that a halftone screen be used to perform such a transformation [H. Kato and J. W. Goodman, Appl. Opt. 14, 1813 (1975)]. However, the maximum spatial resolution of this halftone screen technique is limited by the resolution of the screen. In this paper, we shall propose a different technique using the inherent film nonlinearity for the logarithmic transformation. Such a technique would enable the transformation of signals of very high spatial resolution, limited only by the resolution limit of the photographic film. This technique is applied to the spatial filtering and detection of signals in multiplicative noise. Experimental comparisons between linear and logarithmic filtering are presented. PMID- 20168969 TI - White light optical processing and holography. AB - A method is described wherein optical processing and holography using transparencies are performed using point source white light. The method is coherent, in that the optical systems are linear in amplitude rather than intensity. Perfect wavelength compensation is achieved, with no restriction on the source spectral width. PMID- 20168970 TI - Unit magnification optical system. AB - A simple self-conjugate optical arrangement, originally proposed by Dyson, consists of a spherical mirror and a plano-convex lens. Despite the fact that all the Seidel aberrations are corrected, the field coverage is severely limited by higher order tangential astigmatism. This paper discusses modifications to improve the field coverage. It also treats the creation of internal reflecting surfaces to separate the object and image planes. Finally a few possible applications are discussed, including one to the creation of a high speed spectrograph. PMID- 20168971 TI - Spectroscopy at very high pressures. 14: Laser Raman scattering in ultrasmall samples in a diamond anvil cell. AB - The problem of obtaining Raman spectra at high pressures with a diamond anvil cell is analyzed, and the successful use of a 90 degrees off-axis ellipsoidal mirror for collection in both 0 degrees and 180 degrees scattering modes is demonstrated with nu(OH) spectra of ice VI, VII, and vIII. PMID- 20168972 TI - Measurement of reflectance by gas ionization. AB - In an attempt to improve the accuracy of reflectance determinations, particularly from high vapor pressure samples, we have built and tested a double ionization chamebr which measures the ionization from a photon beam in the vapor or added gas before and after reflection. The photon beam strikes the sample at nearnormal incidence after passing through an oblong ionization chamber containing two collector wires. These are connected to one side of an electrometer-ratiometer of new design. A similar geometry is used for the specularly reflected beam, with the wires here connected to the other side of the ratiometer. A potential of 20 V on the sample is found to be sufficient to prevent the large photoelectric current from the sample from entering the chambers for photon energies to 26 eV. A sitnple calculation shows that the current ratio should decline exponentially with pressure in the operating pressure range from 100 microm to 5000 microm. Extrapolation of the data to zero pressure yields the sample reflectance. In testing, we found the reflectance to be 12.47% at 841 A for an evaporated gold film using a filling gas of air. PMID- 20168973 TI - Does gender predict medical students' stress in mansoura, egypt? AB - BACKGROUND: Medical education is perceived as being stressful with negative effects on students' mental health. However, few studies have addressed the influence of gender on stress in medical students. AIM: To compare male and female medical students in Egypt on sources of stress, perception of stress, anxiety, depression, physical symptomatology, and personality profile. METHODS: Data were collected through an anonymous self-administered questionnaire covering socio-demographic data, stressors, perceived stress scale, physical wellbeing factors, the Hospital Anxiety and Depression scale as well as neuroticism and extraversion subscales of the Eysenck Personality Questionnaire. RESULTS: Stressors were reported by 94.5% of the total sample with equal gender proportions. Univariate analysis indicated that female students scored higher than males on depression and neuroticism scales while male and female medical students were similar on level of perceived stress, number of stressors, clinical anxiety, physical well-being factors and the extraversion scale. Multivariate logistic regression revealed that the independent predictors of a high stress level were the presence of more than five stressors, clinical anxiety and depression, and increased scores on the global sickness index and on the extraversion and neuroticism sub-scales. CONCLUSION: Despite there being no significant difference in perceived stress according to gender, females were less likely to cite relationship problems with teachers and substance abuse as sources of stress. Moreover, females scored significantly higher than males on depression and neuroticism scales. PMID- 20168974 TI - The Psychometric Properties of the Older People's Quality of Life Questionnaire, Compared with the CASP-19 and the WHOQOL-OLD. AB - Purpose. To present the psychometric properties of a new measure of quality of life in older age, the Older People's Quality of Life (OPQOL) Questionnaire, compared with the CAPSE-19 and the WHOQOL-OLD. Design and Methods. The vehicle was three national population surveys of older people living at home in Britain, including a survey of ethnically diverse older people. Results. The OPQOL had acceptable levels of reliability and validity in British population samples of older people, but more modest in the ethnically diverse population sample. The CASP-19 and WHOQOL-OLD had acceptable levels of reliability and validity in the British population sample, but not in the ethnically diverse sample. Implications. The OPQOL has potential for use as a multidimensional population surveillance instrument for use with older populations, or as an outcome measure of multisector policy. Its strengths are that its development was embedded firmly in the perspectives of older people, integrated with theory. PMID- 20168975 TI - Systemic lymphadenectomy cannot be recommended for low-risk corpus cancer. AB - Objective. The objective of this study is to ascertain whether omission of lymphadenectomy could be possible when uterine corpus cancer is considered low risk based on intraoperative pathologic indicators. Patient and Methods. Between 1998 and 2007, a total of 83 patients with low risk corpus cancer (endometrioid type, grade 1 or 2, myometrial invasion <==50%, and no intraoperative evidence of macroscopic extrauterine spread, including pelvic and paraaortic lymph node swelling and adnexal metastasis) underwent the total abdominal hysterectomy and bilateral salpingo-oophorectomy without lymphadenectomy. A retrospective review of the medical records was performed, and the disease-free survival (DFS), overall survival (OS), peri- and postoperative morbidities and complications were evaluated. Results. The 5-year DFS rates and the 5-year OS rates were 97.6% and 98.8%, respectively. No patient presented postoperative leg lymphedema and deep venous thrombosis. Conclusion. Omission of lymphadenectomy did not worsen the DFS or OS. The present findings suggest that systemic lymphadenectomy could be omitted in low-risk endometrial carcinoma. PMID- 20168976 TI - Determining the levels of volatile organic pollutants in urban air using a gas chromatography-mass spectrometry method. AB - The paper presents the application of a method based on coupled gas chromatography-mass spectrometry, using an isotopically labelled internal standard for the quantitative analysis of benzene (B), toluene (T), ethyl benzene (E), and o-, m-, p-xylenes (X). Their atmospheric concentrations were determined based on short-term sampling, in different sites of Cluj-Napoca, a highly populated urban centre in N-W Romania, with numerous and diversified road vehicles with internal combustion engines. The method is relatively inexpensive and simple and shows good precision and linearity in the ranges of 7-60 mug/m(3) (B), 13-90 mug/m(3) (T), 7-50 mug/m(3) (E), 10-70 mug/m(3) (X-m,p), and 20-130 mug/m(3) (X-o). The limits of quantitation/detection of the method LOQ/LOD are of 10/5 mug/m(3) (Xo), 5/3 mug/m(3) (B, E, X-m,p), and of 3/1 mug/m(3) (T), respectively. PMID- 20168977 TI - Cloning, purification, and partial characterization of Bacillus subtilis urate oxidase expressed in Escherichia coli. AB - Urate oxidase (EC 1.7.3.3) is an enzyme involved in purine metabolism which is used in the treatment of gout and as diagnostic reagent for detection of uric acid. In order to produce this enzyme in large quantities for biotechnological purposes, the gene coding for the Bacillus subtilis urate oxidase was cloned and heterologously expressed in Escherichia coli. Time course induction in E. coli showed an induced protein with an apparent molecular mass of approximately 60 kDa. Soluble recombinant enzyme was purified in a single-step procedure using Ni NTA column. The enzyme was purified 2.1-fold with a yield of 56% compared to the crude extract. MALDI-TOF analysis revealed an ion with a mass of 58675 Da which is in agreement with the expected mass of the recombinant protein. The purified enzyme showed an optimal pH and temperature of 8.0 and 37 degrees C, respectively, and retained 90% of its activity after 72 hours of incubation at 20 degrees C and 4 degrees C. PMID- 20168978 TI - Review of Two Siblings with Werner's Syndrome: A Case Report. AB - We report the clinical course of two siblings with Werner's syndrome (WS) who were diagnosed and followed at our clinics for 12 years. Initial diagnosis of the first sibling (sister) was at age 20, the second (brother) at 16. At the initial diagnosis, the sister had amenorrhea, muscle atrophy at arms and legs, diabetes mellitus (DM), short stature, bilateral cataracts, genital hypoplasia, osteoporosis, and gray hair. During 12 years follow-up period, high-pitched voice, hepatosteatosis, renal parenchymal disease, and urethral obstruction developed. Regarding the brother, DM, cataracts and genital hypoplasia were observed at the initial diagnosis. During the 12 years follow-up period, gray hair, high-pitched voice, steatohepatosis, and osteoporosis developed. PMID- 20168979 TI - A multisampling reporter system for monitoring microRNA activity in the same population of cells. AB - MicroRNAs (miRNAs) downregulate gene expression by binding to the partially complementary sites in the 3' untranslated region (UTR) of target mRNAs. Several methods, such as Northern blot analysis, quantitative real-time RT-PCR, microarray, and the luciferase reporter system, are commonly used to quantify the relative level or activity of miRNAs. The disadvantage of these methods is the requirement for cell lysis, which means that several sets of wells/dishes of cells must be prepared to monitor changes in miRNA activity in time-course studies. In this study, we developed a multisampling reporter system in which two secretable bioluminescence-generating enzymes are employed, one as a reporter and the other as an internal control. The reporters consist of a pair of vectors containing the Metridia luciferase gene, one with and one without a duplicated miRNA targeting sequence at their 3'UTR, while the other vector coding for the secreted alkaline phosphatase gene is used as an internal control. This method allows miRNA activity to be monitored within the same population of cells over time by withdrawing aliquots of the culture medium. The practicability and benefits of this system are addressed in this report. PMID- 20168980 TI - Inhalation exposure of organophosphate pesticides by vegetable growers in the Bang-Rieng subdistrict in Thailand. AB - This study investigated inhalation exposure to organophosphate pesticides (OPPs) and evaluated the associated health risks to vegetable growers living in the Bang Rieng agricultural community. Air samples were collected by using personal sampling pumps with sorbent tubes placed in the vegetable growers' breathing zone. Samples were collected during both wet and dry seasons. Residues of organophosphate pesticides, that is, chlorpyrifos, dicrotofos, and profenofos, were analyzed from 33 vegetable growers and 17 reference subjects. Results showed that median concentrations of OPPs in air in farm areas were in the range of 0.022-0.056 mg/m(3) and air in nonfarm areas in the range of <0.0016-<0.005 mg/m(3). The concentration of the three pesticides in the vegetable growers was significantly higher than that of the references during both seasons. The results also indicate that the vegetable growers may be at risk for acute adverse effects via the inhalation of chlorpyrifos and dicrotofos during pesticide application, mixing, loading, and spraying. It is suggested that authorities and the community should implement appropriate strategies concerning risk reduction and risk management. PMID- 20168982 TI - Wegener granulomatosis revealed by pleural effusion. AB - Pulmonary signs are common in Wegener's granulomatosis (WG). However, an initial presentation including pleural effusion has not been described. We describe a case of WG in which pleural effusion was the first clinical manifestation. A 45 year-old man with dorsal pain presented with pleural thickening and effusion, and a visible nodule on a thoracic scan. A dense chronic inflammatory infiltrate was obtained by pleural biopsy and an open lung biopsy revealed necrotizing granulomatous vasculitis. Serologies were positive for antineutrophil cytoplasmic antibodies and antiproteinase 3 antibodies. A diagnosis of WG was conducted and the patient was started on cyclophosphamide and methylprednisolone as an initial treatment, with a favorable evolution. Although pleural effusion is rarely described in WG, this pathology must be considered in the presence of this clinical manifestation. PMID- 20168981 TI - Receptor-mediated and fluid-phase transcytosis of horseradish peroxidase across rat hepatocytes. AB - Horseradish peroxidase (HRP) is often used as a fluid-phase marker to characterize endocytic and transcytotic processes. Likewise, it has been applied to investigate the mechanisms of biliary secretion of fluid in rat liver hepatocytes. However, HRP contains mannose residues and thus binds to mannose receptors (MRs) on liver cells, including hepatocytes. To study the role of MR mediated endocytosis of HRP transport in hepatocytes, we determined the influence of the oligosaccharid mannan on HRP biliary secretion in the isolated perfused rat liver. A 1-minute pulse of HRP was applied followed by marker-free perfusion. HRP appeared in bile with biphasic kinetics: a first peak at 7 minutes and a second peak at 15 minutes after labeling. Perfusion with 0.8 mg/mL HRP in the presence of a twofold excess of mannan reduced the first peak by 41% without effect on the second one. Together with recently published data on MR expression in rat hepatocytes this demonstrates two different mechanisms for HRP transcytosis: a rapid, receptor-mediated transport and a slower fluid-phase transport. PMID- 20168983 TI - Rottlerin inhibits ROS formation and prevents NFkappaB activation in MCF-7 and HT 29 cells. AB - Rottlerin, a polyphenol isolated from Mallotus Philippinensis, has been recently used as a selective inhibitor of PKC delta, although it can inhibit many kinases and has several biological effects. Among them, we recently found that Rottlerin inhibits the Nuclear Factor kappaB (NFkappaB), activated by either phorbol esters or H(2)O(2). Because of the redox sensitivity of NFkappaB and on the basis of Rottlerin antioxidant property, we hypothesized that Rottlerin could prevent NFkappaB activation acting as a free radicals scavenger, as other natural polyphenols. The current study confirms the antioxidant property of Rottlerin against the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) in vitro and against oxidative stress induced by H(2)O(2) and by menadione in culture cells. We also demonstrate that Rottlerin prevents TNFalpha-dependent NFkappaB activation in MCF 7 cells and in HT-29 cells transfected with the NFkappaB-driven plasmid pBIIX LUC, suggesting that Rottlerin can inhibit NFkappaB via several pathways and in several cell types. PMID- 20168984 TI - Sources of indoor air pollution and respiratory health in preschool children. AB - We carried out bibliographic searches in PubMed and Embase.com for the period from 1996 to 2008 with the aim of reviewing the scientific literature on the relationship between various sources of indoor air pollution and the respiratory health of children under the age of five. Those studies that included adjusted correlation measurements for the most important confounding variables and which had an adequate population size were considered to be more relevant. The results concerning the relationship between gas energy sources and children's respiratory health were heterogeneous. Indoor air pollution from biomass combustion in the poorest countries was found to be an important risk factor for lower respiratory tract infections. Solvents involved in redecorating, DYI work, painting, and so forth, were found to be related to an increased risk for general respiratory problems. The distribution of papers depending on the pollution source showed a clear relationship with life-style and the level of development. PMID- 20168985 TI - Anterior hip dislocation in a football player: a case report. AB - Hip dislocations during sporting activities represent only 2%-5% of all hip dislocations. Most hip dislocations in sports can be categorised as "less complicated traumatic hip dislocations" by the Stewart-Milford classification due to the fact that minimal force is involved. The incidence of avascular necrosis of the femoral head greatly increases if the time to reduction is more than six hours. We report the case of a 38-year-old football player who suffered hip dislocation while kicking the ball with the medial aspect of the right foot in an external rotated manner of the right hip. Closed reduction was performed within 2 hours; postoperative follow-up was uneventful. Six months later the patient is out of any complaints; there is no sign of AVN of the femoral head. PMID- 20168986 TI - Tuberculous infection of thyroid gland: a case report. AB - Introduction. Tuberculosis is one of the leading causes of morbidity and mortality and almost one-third of the world is infected with this disease. Tuberculosis has been reported in many parts of the human body. But thyroid gland involvement is extremely rare and its true incidence is unknown. Case Presentation. We present the case of a 26-year-old woman who presented with a thyroid cyst which turned out to be a primary mycobacterium tuberculosis infection. Conclusion. The correct diagnosis of thyroid tuberculosis is important because of the availability of medical treatment and the limited role of surgery. PMID- 20168987 TI - A patient with an unusual cause right lower quadrant pain and vomiting: pyelonephritis of an ectopic right kidney masquerading as acute appendicitis. AB - An adolescent female presented with one day of abdominal pain and clinical findings of acute appendicitis. CT scan revealed an ectopic right kidney with changes of acute pyelonephritis. This paper underscores the importance of imaging the right pelvis prior to surgical intervention in suspected cases of acute appendicitis in children. PMID- 20168988 TI - Ovarian Fibrosarcoma: Clinicopathologic Considerations about the Intraoperative and Post-Surgical Procedures. AB - Primary ovarian fibrosarcomas are very uncommon neoplasms. Since the diagnostic criteria were established in 1981, less than one hundred cases have been reported. This diagnosis can be difficult to establish and other similar appearing mesenchymal processes must be ruled out. In every case this diagnosis is under consideration. Multiple sections of the specimen and immunohistochemical stains will be necessary to support this diagnosis. The difficulty of recognition in frozen section in the majority of the situations implies that the diagnosis should be deferred to the definitive study of the permanent sections with immunohistochemical studies. There exists a histological resemblance between a primary ovarian fibrosarcoma and actively mitotic fibroma. In some cases, it can be impossible to separate exactly these two entities. We report a well differentiated ovarian fibrosarcoma, with less than 1-2 mitosis x10 HPF and low grade cytological atypia, similar to active mitotic fibromas, developing liver metastasis one year later. Despite having distant metastasis, some cases with long survival rates have been reported in patients who received chemotherapy after surgery; so that the adjuvant chemotherapy should be considered, especially in young females. PMID- 20168989 TI - Lethal antibody enhancement of dengue disease in mice is prevented by Fc modification. AB - Immunity to one of the four dengue virus (DV) serotypes can increase disease severity in humans upon subsequent infection with another DV serotype. Serotype cross-reactive antibodies facilitate DV infection of myeloid cells in vitro by promoting virus entry via Fcgamma receptors (FcgammaR), a process known as antibody-dependent enhancement (ADE). However, despite decades of investigation, no in vivo model for antibody enhancement of dengue disease severity has been described. Analogous to human infants who receive anti-DV antibodies by transplacental transfer and develop severe dengue disease during primary infection, we show here that passive administration of anti-DV antibodies is sufficient to enhance DV infection and disease in mice using both mouse-adapted and clinical DV isolates. Antibody-enhanced lethal disease featured many of the hallmarks of severe dengue disease in humans, including thrombocytopenia, vascular leakage, elevated serum cytokine levels, and increased systemic viral burden in serum and tissue phagocytes. Passive transfer of a high dose of serotype-specific antibodies eliminated viremia, but lower doses of these antibodies or cross-reactive polyclonal or monoclonal antibodies all enhanced disease in vivo even when antibody levels were neutralizing in vitro. In contrast, a genetically engineered antibody variant (E60-N297Q) that cannot bind FcgammaR exhibited prophylactic and therapeutic efficacy against ADE-induced lethal challenge. These observations provide insight into the pathogenesis of antibody-enhanced dengue disease and identify a novel strategy for the design of therapeutic antibodies against dengue. PMID- 20168990 TI - A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes. AB - It has been suggested that genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy. A large-scale genotyping analysis of gene based single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes identified the gene encoding acetyl-coenzyme A carboxylase beta (ACACB) as a candidate for a susceptibility to diabetic nephropathy; the landmark SNP was found in the intron 18 of ACACB (rs2268388: intron 18 +4139 C > T, p = 1.4x10( 6), odds ratio = 1.61, 95% confidence interval [CI]: 1.33-1.96). The association of this SNP with diabetic nephropathy was examined in 9 independent studies (4 from Japan including the original study, one Singaporean, one Korean, and two European) with type 2 diabetes. One case-control study involving European patients with type 1 diabetes was included. The frequency of the T allele for SNP rs2268388 was consistently higher among patients with type 2 diabetes and proteinuria. A meta-analysis revealed that rs2268388 was significantly associated with proteinuria in Japanese patients with type 2 diabetes (p = 5.35 x 10(-8), odds ratio = 1.61, 95% Cl: 1.35-1.91). Rs2268388 was also associated with type 2 diabetes-associated end-stage renal disease (ESRD) in European Americans (p = 6 x 10(-4), odds ratio = 1.61, 95% Cl: 1.22-2.13). Significant association was not detected between this SNP and nephropathy in those with type 1 diabetes. A subsequent in vitro functional analysis revealed that a 29-bp DNA fragment, including rs2268388, had significant enhancer activity in cultured human renal proximal tubular epithelial cells. Fragments corresponding to the disease susceptibility allele (T) had higher enhancer activity than those of the major allele. These results suggest that ACACB is a strong candidate for conferring susceptibility for proteinuria in patients with type 2 diabetes. PMID- 20168991 TI - A dynamic model of interactions of Ca2+, calmodulin, and catalytic subunits of Ca2+/calmodulin-dependent protein kinase II. AB - During the acquisition of memories, influx of Ca2+ into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca2+influx during the first few seconds of activity is interpreted within the Ca2+-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity,including Ca2+/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bindup to 4 Ca2+ ions. As a first step toward clarifying how the Ca2+-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca2+, calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca2+ play a significant role in activation of CaMKII in the physiological regime,supporting the notion that processing of Ca2+ signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca2+ is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca2+ transients arises from the kinetics of interaction of fluctuating Ca2+with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning. PMID- 20168992 TI - Conditions for the evolution of gene clusters in bacterial genomes. AB - Genes encoding proteins in a common pathway are often found near each other along bacterial chromosomes. Several explanations have been proposed to account for the evolution of these structures. For instance, natural selection may directly favour gene clusters through a variety of mechanisms, such as increased efficiency of coregulation. An alternative and controversial hypothesis is the selfish operon model, which asserts that clustered arrangements of genes are more easily transferred to other species, thus improving the prospects for survival of the cluster. According to another hypothesis (the persistence model), genes that are in close proximity are less likely to be disrupted by deletions. Here we develop computational models to study the conditions under which gene clusters can evolve and persist. First, we examine the selfish operon model by re implementing the simulation and running it under a wide range of conditions. Second, we introduce and study a Moran process in which there is natural selection for gene clustering and rearrangement occurs by genome inversion events. Finally, we develop and study a model that includes selection and inversion, which tracks the occurrence and fixation of rearrangements. Surprisingly, gene clusters fail to evolve under a wide range of conditions. Factors that promote the evolution of gene clusters include a low number of genes in the pathway, a high population size, and in the case of the selfish operon model, a high horizontal transfer rate. The computational analysis here has shown that the evolution of gene clusters can occur under both direct and indirect selection as long as certain conditions hold. Under these conditions the selfish operon model is still viable as an explanation for the evolution of gene clusters. PMID- 20168993 TI - Minimization of biosynthetic costs in adaptive gene expression responses of yeast to environmental changes. AB - Yeast successfully adapts to an environmental stress by altering physiology and fine-tuning metabolism. This fine-tuning is achieved through regulation of both gene expression and protein activity, and it is shaped by various physiological requirements. Such requirements impose a sustained evolutionary pressure that ultimately selects a specific gene expression profile, generating a suitable adaptive response to each environmental change. Although some of the requirements are stress specific, it is likely that others are common to various situations. We hypothesize that an evolutionary pressure for minimizing biosynthetic costs might have left signatures in the physicochemical properties of proteins whose gene expression is fine-tuned during adaptive responses. To test this hypothesis we analyze existing yeast transcriptomic data for such responses and investigate how several properties of proteins correlate to changes in gene expression. Our results reveal signatures that are consistent with a selective pressure for economy in protein synthesis during adaptive response of yeast to various types of stress. These signatures differentiate two groups of adaptive responses with respect to how cells manage expenditure in protein biosynthesis. In one group, significant trends towards downregulation of large proteins and upregulation of small ones are observed. In the other group we find no such trends. These results are consistent with resource limitation being important in the evolution of the first group of stress responses. PMID- 20168994 TI - Characterizing dynamic changes in the human blood transcriptional network. AB - Gene expression data generated systematically in a given system over multiple time points provides a source of perturbation that can be leveraged to infer causal relationships among genes explaining network changes. Previously, we showed that food intake has a large impact on blood gene expression patterns and that these responses, either in terms of gene expression level or gene-gene connectivity, are strongly associated with metabolic diseases. In this study, we explored which genes drive the changes of gene expression patterns in response to time and food intake. We applied the Granger causality test and the dynamic Bayesian network to gene expression data generated from blood samples collected at multiple time points during the course of a day. The simulation result shows that combining many short time series together is as powerful to infer Granger causality as using a single long time series. Using the Granger causality test, we identified genes that were supported as the most likely causal candidates for the coordinated temporal changes in the network. These results show that PER1 is a key regulator of the blood transcriptional network, in which multiple biological processes are under circadian rhythm regulation. The fasted and fed dynamic Bayesian networks showed that over 72% of dynamic connections are self links. Finally, we show that different processes such as inflammation and lipid metabolism, which are disconnected in the static network, become dynamically linked in response to food intake, which would suggest that increasing nutritional load leads to coordinate regulation of these biological processes. In conclusion, our results suggest that food intake has a profound impact on the dynamic co-regulation of multiple biological processes, such as metabolism, immune response, apoptosis and circadian rhythm. The results could have broader implications for the design of studies of disease association and drug response in clinical trials. PMID- 20168996 TI - Design of a trichromatic cone array. AB - Cones with peak sensitivity to light at long (L), medium (M) and short (S) wavelengths are unequal in number on the human retina: S cones are rare (<10%) while increasing in fraction from center to periphery, and the L/M cone proportions are highly variable between individuals. What optical properties of the eye, and statistical properties of natural scenes, might drive this organization? We found that the spatial-chromatic structure of natural scenes was largely symmetric between the L, M and S sensitivity bands. Given this symmetry, short wavelength attenuation by ocular media gave L/M cones a modest signal-to noise advantage, which was amplified, especially in the denser central retina, by long-wavelength accommodation of the lens. Meanwhile, total information represented by the cone mosaic remained relatively insensitive to L/M proportions. Thus, the observed cone array design along with a long-wavelength accommodated lens provides a selective advantage: it is maximally informative. PMID- 20168995 TI - Molecular poltergeists: mitochondrial DNA copies (numts) in sequenced nuclear genomes. AB - The natural transfer of DNA from mitochondria to the nucleus generates nuclear copies of mitochondrial DNA (numts) and is an ongoing evolutionary process, as genome sequences attest. In humans, five different numts cause genetic disease and a dozen human loci are polymorphic for the presence of numts, underscoring the rapid rate at which mitochondrial sequences reach the nucleus over evolutionary time. In the laboratory and in nature, numts enter the nuclear DNA via non-homolgous end joining (NHEJ) at double-strand breaks (DSBs). The frequency of numt insertions among 85 sequenced eukaryotic genomes reveal that numt content is strongly correlated with genome size, suggesting that the numt insertion rate might be limited by DSB frequency. Polymorphic numts in humans link maternally inherited mitochondrial genotypes to nuclear DNA haplotypes during the past, offering new opportunities to associate nuclear markers with mitochondrial markers back in time. PMID- 20168997 TI - Adaptable functionality of transcriptional feedback in bacterial two-component systems. AB - A widespread mechanism of bacterial signaling occurs through two-component systems, comprised of a sensor histidine kinase (SHK) and a transcriptional response regulator (RR). The SHK activates RR by phosphorylation. The most common two-component system structure involves expression from a single operon, the transcription of which is activated by its own phosphorylated RR. The role of this feedback is poorly understood, but it has been associated with an overshooting kinetic response and with fast recovery of previous interrupted signaling events in different systems. Mathematical models show that overshoot is only attainable with negative feedback that also improves response time. Our models also predict that fast recovery of previous interrupted signaling depends on high accumulation of SHK and RR, which is more likely in a positive feedback regime. We use Monte Carlo sampling of the parameter space to explore the range of attainable model behaviors. The model predicts that the effective feedback sign can change from negative to positive depending on the signal level. Variations in two-component system architectures and parameters may therefore have evolved to optimize responses in different bacterial lifestyles. We propose a conceptual model where low signal conditions result in a responsive system with effectively negative feedback while high signal conditions with positive feedback favor persistence of system output. PMID- 20168998 TI - Invasive salmonellosis among children admitted to a rural Tanzanian hospital and a comparison with previous studies. AB - BACKGROUND: The importance of invasive salmonellosis in African children is well recognized but there is inadequate information on these infections. We conducted a fever surveillance study in a Tanzanian rural hospital to estimate the case fraction of invasive salmonellosis among pediatric admissions, examine associations with common co-morbidities and describe its clinical features. We compared our main findings with those from previous studies among children in sub Saharan Africa. METHODOLOGY/PRINCIPAL FINDINGS: From 1 March 2008 to 28 Feb 2009, 1,502 children were enrolled into the study. We collected clinical information and blood for point of care tests, culture, and diagnosis of malaria and HIV. We analyzed the clinical features on admission and outcome by laboratory-confirmed diagnosis. Pathogenic bacteria were isolated from the blood of 156 (10%) children, of which 14 (9%) were S. typhi, 45 (29%) were NTS and 97 (62%) were other pathogenic bacteria. Invasive salmonellosis accounted for 59/156 (38%) bacteremic children. Children with typhoid fever were significantly older and presented with a longer duration of fever. NTS infections were significantly associated with prior antimalarial treatment, malarial complications and with a high risk for death. CONCLUSIONS/SIGNIFICANCE: Invasive salmonellosis, particularly NTS infection, is an important cause of febrile disease among hospitalized children in our rural Tanzanian setting. Previous studies showed considerable variation in the case fraction of S. typhi and NTS infections. Certain suggestive clinical features (such as older age and long duration of fever for typhoid whereas concomitant malaria, anemia, jaundice and hypoglycemia for NTS infection) may be used to distinguish invasive salmonellosis from other severe febrile illness. PMID- 20168999 TI - Budding of Taenia crassiceps cysticerci in vitro is promoted by crowding in addition to hormonal, stress, and energy-related signals. AB - Taenia crassiceps cysticerci (cysts) reproduce by budding. The cysts' production of buds was measured in vitro to explore parasite and environmental-related factors involved in the extreme individual variation in parasite loads of inbred mice. Cysts were placed in in vitro culture for 10 days at initial parasite densities of 1, 5, 10 cysts/well in 1 ml of RPMI Medium 1640 without serum. Results showed that there is considerable intrinsic initial variation among inoculated cysts in their production of buds and that increasing parasite density (crowding) stimulates the overall production of buds and recruit into budding most of the cysts. Identical cultures were then subjected to various treatments such as heating and exposure to peroxide to induce stress, or to 17beta estradiol, insulin, glucose, or insulin+glucose to supplement putatively limiting hormonal and energy resources. All treatments increased budding but the parasites' strong budding response to crowding alone overshadows the other treatments. PMID- 20169000 TI - MIClique: An algorithm to identify differentially coexpressed disease gene subset from microarray data. AB - Computational analysis of microarray data has provided an effective way to identify disease-related genes. Traditional disease gene selection methods from microarray data such as statistical test always focus on differentially expressed genes in different samples by individual gene prioritization. These traditional methods might miss differentially coexpressed (DCE) gene subsets because they ignore the interaction between genes. In this paper, MIClique algorithm is proposed to identify DEC gene subsets based on mutual information and clique analysis. Mutual information is used to measure the coexpression relationship between each pair of genes in two different kinds of samples. Clique analysis is a commonly used method in biological network, which generally represents biological module of similar function. By applying the MIClique algorithm to real gene expression data, some DEC gene subsets which correlated under one experimental condition but uncorrelated under another condition are detected from the graph of colon dataset and leukemia dataset. PMID- 20169001 TI - Interaction of botulinum toxin with the epithelial barrier. AB - Botulinum neurotoxin (BoNT) is a protein toxin (approximately 150 kDa), which possesses a metalloprotease activity. Food-borne botulism is manifested when BoNT is absorbed from the digestive tract to the blood stream and enters the peripheral nerves, where the toxin cleaves core proteins of the neuroexocytosis apparatus and elicits the inhibition of neurotransmitter release. The initial obstacle to orally ingested BoNT entering the body is the epithelial barrier of the digestive tract. Recent cell biology and molecular biology studies are beginning to elucidate the mechanism by which this large protein toxin crosses the epithelial barrier. In this review, we provide an overview of the structural features of botulinum toxins (BoNT and BoNT complex) and the interaction of these toxins with the epithelial barrier. PMID- 20169003 TI - Association of TLR4-T399I polymorphism with chronic obstructive pulmonary disease in smokers. AB - Tobacco smoking has been considered the most important risk factor for chronic obstructive pulmonary disease (COPD) development. However, not all smokers develop COPD and other environmental and genetic susceptibility factors underlie disease pathogenesis. Recent studies have indicated that the impairment of TLR signaling might play a crucial role in the development of emphysema. For this purpose we investigated the prevalence and any possible associations of common TLR polymorphisms (TLR2-R753Q, TLR4-D299G, and TLR4-T399I) in a group of 240 heavy smokers (>20 pack years), without overt atherosclerosis disease, of whom 136 had developed COPD and 104 had not. The presence of TLR4-T399I polymorphism was associated with a 2.4-fold increased risk for COPD development (P = .044), but not with disease stage or frequency of exacerbations. Considering that infections contribute to COPD and emphysema pathogenesis, our findings possibly indicate that dysfunctional polymorphisms of innate immune genes can affect the development of COPD in smokers. Although this finding warrants further investigation, it highlights the importance of impaired innate immunity towards COPD development. PMID- 20169005 TI - Text processing variables predict the readability of everyday documents read by older adults. AB - A model is presented to predict the readability of documents encountered by older adults. The documents studied are contained in the Educational Testing Service's Test of Basic Skills (1977 edition) and require readers to answer questions about charts (e.g., bus schedules), labels (e.g., plant spray labels and prescriptions), and forms (e.g., tax forms). The components of the model came from theoretical and empirical work on discourse processing and include such factors as discourse structure, emphasis, and position of an answer in a linguistic analysis of the everyday document.A sample of 482 adults from 52 to 93 years of age took the everyday problems test as well as a psychometric ability battery. The correlation was .54 (p < .01) between the readability scores for test items predicted by the model and the percentage of older adults correctly answering those items. In addition, the more difficult test items as identified by the model were correlated more highly with fluid intelligence abilities (figural relations and induction), crystallized intelligence abilities (vocabulary, experiential evaluation), and with memory span. PMID- 20169006 TI - Response to Intervention: Ready or Not? Or, From Wait-to-Fail to Watch-Them-Fail. AB - Response to Intervention (RTI) models of diagnosis and intervention are being implemented rapidly throughout the schools. The purposes of invoking an RTI model for disabilities in the schools clearly are laudable, yet close examination reveals an unappreciated paucity of empirical support for RTI and an overly optimistic view of its practical, problematic issues. Models are being put into practice without adequate research and logistical support and neglect the potential negative long-term impact on students with disabilities. Many implementation problems exist: (a) the vagaries of critical details of the model in practice; (b) the lack of consideration of bright struggling readers; (c) the relativeness, contextual, situation dependent nature of who is identified; (d) the worrisome shortcomings of the RTI process as a means of diagnosis or determination of a disability; and (e) the apparent lack of student-based data to guide effective choice of approaches and components of intervention. Practiced as a model of prevention, the authors agree with the concept of RTI. As the authors witness its application to disability determination sans the benefit of a reliable and valid empirical basis, the potential benefits to some children with disabilities remain an unproven hypothesis while the potential detriment to some children with disabilities remains a very real possibility. PMID- 20169004 TI - Influence of Salvia miltiorrhizae on the mesenteric lymph node of rats with severe acute pancreatitis or obstructive jaundice. AB - OBJECTIVE: To observe the effect of salvia miltiorrhizae injection on inflammatory mediator levels and mesenteric lymph nodes in severe acute pancreatitis (SAP) and obstructive jaundice (OJ) rats and explore the protective mechanism of salvia miltiorrhizae on the lymph nodes of these rats. METHODS: A total of 288 rats were used in SAP-associated and OJ-associated experiments. The rats were randomly divided into sham-operated group, model control group, and treated group. At various time points after operation, the pathological changes in mesenteric lymph nodes of rats in each group were observed, respectively. RESULTS: The pathological severity scores in lymph nodes of SAP rats in treated group were significantly lower than those in model control group (P < .05) while the pathological changes in lymph nodes of OJ rats in treated group also showed varying degrees of mitigation. CONCLUSION: Salvia miltiorrhizae can exert protective effects on the lymph nodes of SAP or OJ rats via a mechanism that is associated with reducing the contents of inflammatory mediators in blood. PMID- 20169002 TI - Towards an understanding of the herpes simplex virus type 1 latency-reactivation cycle. AB - Infection by herpes simplex virus type 1 (HSV-1) can cause clinical symptoms in the peripheral and central nervous system. Recurrent ocular shedding can lead to corneal scarring and vision loss making HSV-1 a leading cause of corneal blindness due to an infectious agent. The primary site of HSV-1 latency is sensory neurons within trigeminal ganglia. Periodically, reactivation from latency occurs resulting in virus transmission and recurrent disease. During latency, the latency-associated transcript (LAT) is abundantly expressed. LAT expression is important for the latency-reactivation cycle in animal models, in part, because it inhibits apoptosis, viral gene expression, and productive infection. A novel transcript within LAT coding sequences (AL3) and small nonprotein coding RNAs are also expressed in trigeminal ganglia of latently infected mice. In this review, an update of viral factors that are expressed during latency and their potential roles in regulating the latency-reactivation cycle is discussed. PMID- 20169007 TI - Polymerization shrinkage and stress development in amorphous calcium phosphate/urethane dimethacrylate polymeric composites. AB - This study explores how substituting a new high molecular mass oligomeric poly(ethylene glycol) extended urethane dimethacrylate (PEG-U) for 2-hydroxyethyl methacrylate (HEMA) in photo-activated urethane dimethacrylate (UDMA) resins affects degree of vinyl conversion (DC), polymerization shrinkage (PS), stress development (PSSD) and biaxial flexure strength (BFS) of their amorphous calcium phosphate (ACP) composites. The composites were prepared from four types of resins (UDMA, PEG-U, UDMA/HEMA and UDMA/PEG-U) and zirconia-hybridized ACP. Introducing PEG-U improved DC while not adversely affecting PS, PSSD and the BFS of composites. This improvement in DC is attributed to the long, more flexible structure between the vinyl groups of PEG-U and its higher molecular mass compared to poly(HEMA). The results imply that PEG-U has the potential to serve as an alternative to HEMA in dental and other biomedical applications. PMID- 20169008 TI - The Effects of Problem Drinking and Sexual Risk Among Mexican Migrant Workers on Their Community of Origin. AB - Although the financial remittances sent by male Mexican migrant workers residing in the United States can result in higher standards of living for their families and home communities, out-migration may lead to increased migrant problem drinking and sexual risk behaviors, which may in turn impact these same communities of origin. Based on semi-structured interviewing (n=60) and participant observation in a migrant sending community in central Mexico and a receiving community in the Northeastern United States, this paper explores the effects of out-migration on HIV risk and problem drinking among United States based migrants from a small agricultural community in the Mexican state of Puebla. We argue that problem drinking and risky sexual behaviors among these migrant workers have had significant consequences for their home community in terms of diminished remittances, the introduction of HIV and other sexually transmitted infections, and loss of husbands or kinsmen to automobile accidents. Moreover, although rumor and gossip between the two communities serve as a form of social control, they may also contribute to increased problem drinking and sexual risk. PMID- 20169010 TI - Both the peroxisome proliferator-activated receptor delta agonist, GW0742, and ezetimibe promote reverse cholesterol transport in mice by reducing intestinal reabsorption of HDL-derived cholesterol. AB - Peroxisome proliferator-activated receptor delta (PPARdelta) agonism increases HDL cholesterol and has therefore the potential to stimulate macrophage-to-feces reverse cholesterol transport (RCT). To test whether PPARdelta activation promotes RCT in mice, in vivo macrophage RCT was assessed using cholesterol loaded/3H-cholesterol-labeled macrophages injected intraperitoneally. PPARdelta agonist GW0742 (10 mg/kg per day) did not change 3H-tracer plasma appearance, but increased fecal 3H-free sterols excretion by 103% ( p < 0.005) over 48 hours. Total free cholesterol efflux from macrophages to serum (collected from both control and GW0742 groups) was not different, although ABCA1-mediated efflux was significantly higher with GW0742. The metabolic fate of HDL labeled with 3H- cholesteryl ether or 3H-cholesteryl oleate was also measured. While 3H cholesteryl ether tissue uptake was unchanged, the 3H-tracer recovered in fecal free sterol fraction after 3H-cholesteryl oleate injection increased by 88% with GW0742 ( p < 0.0005). This was associated with a lower Niemann-Pick C1 like 1 (NPC1L1) mRNA expression in the small intestine ( p < 0.05). The same experiments in mice treated with ezetimibe, which blocks NPC1L1, showed a similar 2-fold increase in fecal free sterol excretion after labeled macrophages orHDL injection. In conclusion, PPARdelta activation enhances excretion of macrophage or HDL-derived cholesterol in feces through reduced NPC1L1 expression in mice, comparable to the effect of ezetimibe. PMID- 20169011 TI - New Horizons for the Next Era of Human Brain Imaging, Cognitive, and Behavioral Research: Pacific Rim Interactivity. AB - Beginning in the 1990's, substantial advances have been made in the ability to image the living human brain. Functional MRI, PET, and other modalities have been developed to provide a rich means for assessing brain function and structure across spatial and temporal dimensions. Such methods are now the preferred means to examine the brain in vivo, with several thousand articles now appearing in the literature each year. The next era of human brain imaging is upon us now as technological developments reach a level where data can be processed quickly and combined with other biological information to provide fundamentally new applications and insights. This new era will involve and require the collaborative participation of leading research groups from around the world to share information and expertise for understanding observed effects and synthesizing these into new knowledge. One particular community that is gaining in its prominence in the field is that of the Pacific Rim, whose collective research efforts present an important corpus of research effort into brain structure and function. The Pacific Rim represents an important collection of researchers interested in the greater sharing of ideas. In this special issue of Brain Imaging and Behavior, we focus on emerging areas of research that utilize brain imaging methodology, and discuss how current developments are driving the expansion of functional imaging research. Moreover, we focus on the robust interaction of researchers from around the Pacific Rim whose collaborations are significantly shaping the future of brain imaging. PMID- 20169012 TI - Corneal epithelial cell biocompatibility to silicone hydrogel and conventional hydrogel contact lens packaging solutions. AB - PURPOSE: Although all contact lenses (CLs) are applied initially to the eye directly from a packaging solution, little is known about the effects of these solutions on human corneal epithelial cells (HCECs). Due to the porous nature of CL materials, they have the potential to sorb components of the packaging solution during storage, which could then be subsequently released upon insertion of the CL on the eye. The purpose of this study was to investigate the effect of various packaging solutions on HCECs, using an in vitro model. METHODS: An in vitro assay was developed whereby various silicone hydrogels and conventional, poly-2-hydroxyethylmethacrylate (polyHEMA)-based lens materials were removed directly from their packaging and then incubated for up to 24 h with HCECs. The effect of the retained and released packaging solution components on HCECs was assessed by measuring cell viability, adhesion phenotype, and apoptosis. RESULTS: Incubation of HCECs with CLs stored in borate-buffered packaging solutions resulted in a significant reduction in cell viability. Adherent cells incubated with these CLs also exhibited reduced levels of beta(1) and alpha(3) integrin. Soaking borate-buffered packaged CLs in PBS before cell incubation resolved viability and integrin expression in all cases, with the exception of galyfilcon A and balafilcon A, from which a 20% reduction in cell viability was still observed. In comparison, CLs stored in phosphate-buffered packaging solutions had cellular viability and expression of integrins similar to control cells (cells incubated in the absence of a lens). When incubated with cells at a 10% concentration in serum-free medium, borate-buffered packaging solutions and borate-containing saline (Unisol 4) significantly reduced cell viability and integrin expression. Neither caspase activation nor annexin V binding was observed on cells following exposure to borate buffer solution. However, a significant decrease in reactive oxygen species was observed at 24 h. These latter results suggest that in vitro exposure to low concentration of borate/boric acid results in cell dysfunction, leading to necrosis rather than apoptosis. CONCLUSIONS: Borate-buffered packaging solutions were shown to adversely affect the viability and integrin expression of HCECs in vitro. When used in ophthalmic packaging solutions, the antimicrobial properties of borate buffer may be outweighed by its relatively cytotoxic effects on cells. PMID- 20169013 TI - A framework for predicting EHR adoption attitudes: a physician survey. AB - With a focus on improving the quality of patient care, the President George W. Bush called for electronic health records (EHRs) for all Americans by the year 2014; however, recent estimates for EHR adoption in the ambulatory care environment are just over 10 percent. The objective of this study was to determine the individual characteristics and the social and technical factors that may contribute to physician acceptance of EHRs. This first paper of a two part study presents a framework grounded in Diffusion of Innovations theory and the Technology Acceptance Model, which was developed using case study and survey methods, and tested using structural equation modeling (SEM). Model variables explained over 73 percent of the variance in attitude toward EHRs, and acceptable model fit was achieved. Lack of user acceptance continues to impede diffusion of EHRs, and this analysis supports the impact that leadership and other organizational changes have on user adoption. PMID- 20169014 TI - Application of multivariate probabilistic (Bayesian) networks to substance use disorder risk stratification and cost estimation. AB - INTRODUCTION: This paper explores the use of machine learning and Bayesian classification models to develop broadly applicable risk stratification models to guide disease management of health plan enrollees with substance use disorder (SUD). While the high costs and morbidities associated with SUD are understood by payers, who manage it through utilization review, acute interventions, coverage and cost limitations, and disease management, the literature shows mixed results for these modalities in improving patient outcomes and controlling cost. Our objective is to evaluate the potential of data mining methods to identify novel risk factors for chronic disease and stratification of enrollee utilization, which can be used to develop new methods for targeting disease management services to maximize benefits to both enrollees and payers. METHODS: For our evaluation, we used DecisionQ machine learning algorithms to build Bayesian network models of a representative sample of data licensed from Thomson-Reuters' MarketScan consisting of 185,322 enrollees with three full-year claim records. Data sets were prepared, and a stepwise learning process was used to train a series of Bayesian belief networks (BBNs). The BBNs were validated using a 10 percent holdout set. RESULTS: The networks were highly predictive, with the risk stratification BBNs producing area under the curve (AUC) for SUD positive of 0.948 (95 percent confidence interval [CI], 0.944-0.951) and 0.736 (95 percent CI, 0.721-0.752), respectively, and SUD negative of 0.951 (95 percent CI, 0.947 0.954) and 0.738 (95 percent CI, 0.727-0.750), respectively. The cost estimation models produced area under the curve ranging from 0.72 (95 percent CI, 0.708 0.731) to 0.961 (95 percent CI, 0.95-0.971). CONCLUSION: We were able to successfully model a large, heterogeneous population of commercial enrollees, applying state-of-the-art machine learning technology to develop complex and accurate multivariate models that support near-real-time scoring of novel payer populations based on historic claims and diagnostic data. Initial validation results indicate that we can stratify enrollees with SUD diagnoses into different cost categories with a high degree of sensitivity and specificity, and the most challenging issue becomes one of policy. Due to the social stigma associated with the disease and ethical issues pertaining to access to care and individual versus societal benefit, a thoughtful dialogue needs to occur about the appropriate way to implement these technologies. PMID- 20169016 TI - Exploratory study of radiology coding in health information management practice. AB - An exploratory study was undertaken to determine the role and practice issues of radiology coding in health information management (HIM) practice. The study sought to identify the challenges of radiology coding and the solutions implemented to address these challenges. A self-report survey was sent to 828 American Health Information Management Association (AHIMA) members identified as directors, managers, or supervisors of HIM departments and/or coding. Two hundred seventy-eight surveys were used for data analysis purposes. Sites reported that on average they have 3.4 coders devoted to radiology coding who code an average of 4,245 reports per month. Productivity standards varied by exam type ranging from 7 (interventional radiology) to 31 (diagnostic) exams coded per hour. Diagnosis codes were assigned most frequently for diagnostic, ultrasound/nuclear, MRI/CT, and mammography exams, while diagnosis and procedural codes were assigned more frequently for interventional radiology exams. The need for education specifically focused on interventional radiology coding was identified along with other issues affecting the quality of radiology coding. Suggested solutions to challenges of radiology coding such as establishing a good working relationship with physicians, radiology, and charge description master (CDM) departments were suggested. PMID- 20169015 TI - Policy agenda for the next decade: creating a path for graceful evolution and harmonized classifications and terminologies used for encoding health information in electronic environments. PMID- 20169017 TI - Exploring medical identity theft. AB - The crime of medical identity theft is a growing concern in healthcare institutions. A mixed-method study design including a two-stage electronic survey, telephone survey follow-up, and on-site observations was used to evaluate current practices in admitting and registration departments to reduce the occurrence of medical identity theft. Survey participants were chief compliance officers in acute healthcare organizations and members of the Health Care Compliance Association. Study results indicate variance in whether or how patient identity is confirmed in healthcare settings. The findings of this study suggest that information systems need to be designed for more efficient identity management. Admitting and registration staff must be trained, and compliance with medical identity theft policies and procedures must be monitored. Finally, biometric identity management solutions should be considered for stronger patient identification verification. PMID- 20169018 TI - Factors influencing acceptance of electronic health records in hospitals. AB - The study's aim was to examine factors that may influence health information managers in the adoption of electronic health records. The Technology Acceptance Model (TAM) served as theoretical foundation for this quantitative study. Hospital health information managers in Arkansas were queried as to the constructs of perceived usefulness, perceived ease of use, and behavior intention. The study population comprised 94 health information managers with a return rate of 74.5 percent. One manager was identified to represent each hospital. In each of the construct areas, the results showed a difference between health information managers that had adopted components of EHRs versus those that had not. This study may serve to guide the educational process of both health information managers that have yet to implement EHRs as well as the EHR vendor community. PMID- 20169019 TI - Healthcare fraud and abuse. PMID- 20169020 TI - Translational bioinformatics and healthcare informatics: computational and ethical challenges. AB - Exponentially growing biological and bioinformatics data sets present a challenge and an opportunity for researchers to contribute to the understanding of the genetic basis of phenotypes. Due to breakthroughs in microarray technology, it is possible to simultaneously monitor the expressions of thousands of genes, and it is imperative that researchers have access to the clinical data to understand the genetics and proteomics of the diseased tissue. This technology could be a landmark in personalized medicine, which will provide storage for clinical and genetic data in electronic health records (EHRs). In this paper, we explore the computational and ethical challenges that emanate from the intersection of bioinformatics and healthcare informatics research. We describe the current situation of the EHR and its capabilities to store clinical and genetic data and then discuss the Genetic Information Nondiscrimination Act. Finally, we posit that the synergy obtained from the collaborative efforts between the genomics, clinical, and healthcare disciplines has potential to enhance and promote faster and more advanced breakthroughs in healthcare. PMID- 20169021 TI - A class-wide phylogenetic assessment of Dothideomycetes. AB - We present a comprehensive phylogeny derived from 5 genes, nucSSU, nucLSU rDNA, TEF1, RPB1 and RPB2, for 356 isolates and 41 families (six newly described in this volume) in Dothideomycetes. All currently accepted orders in the class are represented for the first time in addition to numerous previously unplaced lineages. Subclass Pleosporomycetidae is expanded to include the aquatic order Jahnulales. An ancestral reconstruction of basic nutritional modes supports numerous transitions from saprobic life histories to plant associated and lichenised modes and a transition from terrestrial to aquatic habitats are confirmed. Finally, a genomic comparison of 6 dothideomycete genomes with other fungi finds a high level of unique protein associated with the class, supporting its delineation as a separate taxon. PMID- 20169022 TI - Phylogenetic lineages in the Capnodiales. AB - The Capnodiales incorporates plant and human pathogens, endophytes, saprobes and epiphytes, with a wide range of nutritional modes. Several species are lichenised, or occur as parasites on fungi, or animals. The aim of the present study was to use DNA sequence data of the nuclear ribosomal small and large subunit RNA genes to test the monophyly of the Capnodiales, and resolve families within the order. We designed primers to allow the amplification and sequencing of almost the complete nuclear ribosomal small and large subunit RNA genes. Other than the Capnodiaceae (sooty moulds), and the Davidiellaceae, which contains saprobes and plant pathogens, the order presently incorporates families of major plant pathological importance such as the Mycosphaerellaceae, Teratosphaeriaceae and Schizothyriaceae. The Piedraiaceae was not supported, but resolves in the Teratosphaeriaceae. The Dissoconiaceae is introduced as a new family to accommodate Dissoconium and Ramichloridium. Lichenisation, as well as the ability to be saprobic or plant pathogenic evolved more than once in several families, though the taxa in the upper clades of the tree lead us to conclude that the strictly plant pathogenic, nectrotrophic families evolved from saprobic ancestors (Capnodiaceae), which is the more primitive state. PMID- 20169023 TI - A molecular phylogenetic reappraisal of the Hysteriaceae, Mytilinidiaceae and Gloniaceae (Pleosporomycetidae, Dothideomycetes) with keys to world species. AB - A reappraisal of the phylogenetic integrity of bitunicate ascomycete fungi belonging to or previously affiliated with the Hysteriaceae, Mytilinidiaceae, Gloniaceae and Patellariaceae is presented, based on an analysis of 121 isolates and four nuclear genes, the ribosomal large and small subunits, transcription elongation factor 1 and the second largest RNA polymerase II subunit. A geographically diverse and high density taxon sampling strategy was employed, including multiple isolates/species from the following genera: Anteaglonium (6/4), Encephalographa (1/1), Farlowiella (3/1), Gloniopsis (8/4), Glonium (4/2), Hysterium (12/5), Hysterobrevium (14/3), Hysterographium (2/1), Hysteropatella (2/2), Lophium (4/2), Mytilinidion (13/10), Oedohysterium (5/3), Ostreichnion (2/2), Patellaria (1/1), Psiloglonium (11/3), Quasiconcha (1/1), Rhytidhysteron (8/3), and 24 outgroup taxa. Sequence data indicate that although the Hysteriales are closely related to the Pleosporales, sufficient branch support exists for their separation into separate orders within the Pleosporomycetidae. The Mytilinidiales are more distantly related within the subclass and show a close association with the Gloniaceae. Although there are examples of concordance between morphological and molecular data, these are few. Molecular data instead support the premise of a large number of convergent evolutionary lineages, which do not correspond to previously held assumptions of synapomorphy relating to spore morphology. Thus, within the Hysteriaceae, the genera Gloniopsis, Glonium, Hysterium and Hysterographium are highly polyphyletic. This necessitated the transfer of two species of Hysterium to Oedohysteriumgen. nov. (Od. insidenscomb. nov. and Od. sinense comb. nov.), the description of a new species, Hysterium barrianumsp. nov., and the transfer of two species of Gloniopsis to Hysterobreviumgen. nov. (Hb. smilaciscomb. nov. and Hb. constrictumcomb. nov.). While Hysterographium, with the type Hg. fraxini, is removed from the Hysteriaceae, some of its species remain within the family, transferred here to Oedohysterium (Od. pulchrumcomb. nov.), Hysterobrevium (Hb. moricomb. nov.) and Gloniopsis (Gp. subrugosacomb. nov.); the latter genus, in addition to the type, Gp. praelonga, with two new species, Gp. arciformissp. nov. and Gp. kenyensis sp. nov. The genus Glonium is now divided into Anteaglonium (Pleosporales), Glonium (Gloniaceae), and Psiloglonium (Hysteriaceae). The hysterothecium has evolved convergently no less than five times within the Pleosporomycetidae (e.g., Anteaglonium, Farlowiella, Glonium, Hysterographium and the Hysteriaceae). Similarly, thin-walled mytilinidioid (e.g., Ostreichnion) and patellarioid (e.g., Rhytidhysteron) genera, previously in the Mytilinidiaceae and Patellariaceae, respectively, transferred here to the Hysteriaceae, have also evolved at least twice within the subclass. As such, character states traditionally considered to represent synapomorphies among these fungi, whether they relate to spore septation or the ascomata, in fact, represent symplesiomorphies, and most likely have arisen multiple times through convergent evolutionary processes in response to common selective pressures. PMID- 20169024 TI - Multi-locus phylogeny of Pleosporales: a taxonomic, ecological and evolutionary re-evaluation. AB - Five loci, nucSSU, nucLSU rDNA, TEF1, RPB1 and RPB2, are used for analysing 129 pleosporalean taxa representing 59 genera and 15 families in the current classification of Pleosporales. The suborder Pleosporineae is emended to include four families, viz.Didymellaceae, Leptosphaeriaceae, Phaeosphaeriaceae and Pleosporaceae. In addition, two new families are introduced, i.e. Amniculicolaceae and Lentitheciaceae. Pleomassariaceae is treated as a synonym of Melanommataceae, and new circumscriptions of Lophiostomataceaes. str., Massarinaceae and Lophiotrema are proposed. Familial positions of Entodesmium and Setomelanomma in Phaeosphaeriaceae, Neophaeosphaeria in Leptosphaeriaceae, Leptosphaerulina, Macroventuria and Platychora in Didymellaceae, Pleomassaria in Melanommataceae and Bimuria, Didymocrea, Karstenula and Paraphaeosphaeria in Montagnulaceae are clarified. Both ecological and morphological characters show varying degrees of phylogenetic significance. Pleosporales is most likely derived from a saprobic ancestor with fissitunicate asci containing conspicuous ocular chambers and apical rings. Nutritional shifts in Pleosporales likely occured from saprotrophic to hemibiotrophic or biotrophic. PMID- 20169025 TI - Molecular phylogenetics of Pleosporales: Melanommataceae and Lophiostomataceae re circumscribed (Pleosporomycetidae, Dothideomycetes, Ascomycota). AB - The classification of Pleosporales has posed major challenges due to the lack of clear understanding of the importance of the morphological characters used to distinguish between different groups in the order. This has resulted in varied taxonomic treatments of many families in the group including Melanommataceae and Lophiostomataceae. In this study we employ two nuclear DNA gene markers, nuclear ribosomal large subunit DNA and translation elongation factor 1-alpha in order to examine the molecular phylogenetics of Pleosporales with strong emphasis on the families Melanommataceae and Lophiostomataceae. Phylogenetic analyses recovered Melanommataceae, Lophiostomataceae, Hypsostromataceae, and a few others as strongly supported clades within the Pleosporales. Melanommataceae as currently circumscribed was found to be polyphyletic. The genera Byssosphaeria, Melanomma, and Pseudotrichia were recovered within the family, while others such as Ostropella and Xenolophium nested outside in a weakly supported group along with Platystomum compressum and Pseudotrichia guatopoensis that may correspond to the family Platystomaceae. The genus Byssosphaeria was recovered as a strongly supported group within the Melanommataceae while Melanomma was weakly supported with unclear relationships among the species. The genera Herpotrichia and Bertiella were also found to belong in the Melanommataceae. Lophiostomataceae occurs as a strongly supported group but its concept is here expanded to include a new genus Misturatosphaeria that bears morphology traditionally not known to occur in the family. The strongly supported clade of Misturatosphaeria contains nine species that have gregarious, papillate ascomata with lighter coloured apices and plugged ostioles and that vary in ascospore morphology from 1- to 3 septate to muriform. Along with a strongly supported Lophiostoma clade, also within the family are Thyridaria macrostomoides based on new sequences from Kenyan collections and Massariosphaeria triseptata, M. grandispora, Westerdykella cylindrica and Preussia terricola based on GenBank sequences. The family Hypsostromataceae was recovered as a strongly supported monophyletic group nested within the Pleosporales. PMID- 20169027 TI - Unravelling the phylogenetic relationships of lichenised fungi in Dothideomyceta. AB - We present a revised phylogeny of lichenised Dothideomyceta (Arthoniomycetes and Dothideomycetes) based on a combined data set of nuclear large subunit (nuLSU) and mitochondrial small subunit (mtSSU) rDNA data. Dothideomyceta is supported as monophyletic with monophyletic classes Arthoniomycetes and Dothideomycetes; the latter, however, lacking support in this study. The phylogeny of lichenised Arthoniomycetes supports the current division into three families: Chrysothrichaceae (Chrysothrix), Arthoniaceae (Arthonia s. l., Cryptothecia, Herpothallon), and Roccellaceae (Chiodecton, Combea, Dendrographa, Dichosporidium, Enterographa, Erythrodecton, Lecanactis, Opegrapha, Roccella, Roccellographa, Schismatomma, Simonyella). The widespread and common Arthonia caesia is strongly supported as a (non-pigmented) member of Chrysothrix. Monoblastiaceae, Strigulaceae, and Trypetheliaceae are recovered as unrelated, monophyletic clades within Dothideomycetes. Also, the genera Arthopyrenia (Arthopyreniaceae) and Cystocoleus and Racodium (Capnodiales) are confirmed as Dothideomycetes but unrelated to each other. Mycomicrothelia is shown to be unrelated to Arthopyrenia s.str., but is supported as a monophyletic clade sister to Trypetheliaceae, which is supported by hamathecium characters. The generic concept in several groups is in need of revision, as indicated by non-monophyly of genera, such as Arthonia, Astrothelium, Cryptothecia, Cryptothelium, Enterographa, Opegrapha, and Trypethelium in our analyses. PMID- 20169026 TI - Phylogeny of rock-inhabiting fungi related to Dothideomycetes. AB - The class Dothideomycetes (along with Eurotiomycetes) includes numerous rock inhabiting fungi (RIF), a group of ascomycetes that tolerates surprisingly well harsh conditions prevailing on rock surfaces. Despite their convergent morphology and physiology, RIF are phylogenetically highly diverse in Dothideomycetes. However, the positions of main groups of RIF in this class remain unclear due to the lack of a strong phylogenetic framework. Moreover, connections between rock dwelling habit and other lifestyles found in Dothideomycetes such as plant pathogens, saprobes and lichen-forming fungi are still unexplored. Based on multigene phylogenetic analyses, we report that RIF belong to Capnodiales (particularly to the family Teratosphaeriaceae s.l.), Dothideales, Pleosporales, and Myriangiales, as well as some uncharacterised groups with affinities to Dothideomycetes. Moreover, one lineage consisting exclusively of RIF proved to be closely related to Arthoniomycetes, the sister class of Dothideomycetes. The broad phylogenetic amplitude of RIF in Dothideomycetes suggests that total species richness in this class remains underestimated. Composition of some RIF rich lineages suggests that rock surfaces are reservoirs for plant-associated fungi or saprobes, although other data also agree with rocks as a primary substrate for ancient fungal lineages. According to the current sampling, long distance dispersal seems to be common for RIF. Dothideomycetes lineages comprising lichens also include RIF, suggesting a possible link between rock dwelling habit and lichenisation. PMID- 20169028 TI - The molecular phylogeny of freshwater Dothideomycetes. AB - The freshwater Dothideomycetes species are an ecological rather than taxonomic group and comprise approximately 178 meiosporic and mitosporic species. Due to convergent or parallel morphological adaptations to aquatic habitats, it is difficult to determine phylogenetic relationships among freshwater taxa and among freshwater, marine and terrestrial taxa based solely on morphology. We conducted molecular sequence-based phylogenetic analyses using nuclear ribosomal sequences (SSU and/or LSU) for 84 isolates of described and undescribed freshwater Dothideomycetes and 85 additional taxa representative of the major orders and families of Dothideomycetes. Results indicated that this ecological group is not monophyletic and all the freshwater taxa, except three aeroaquatic Tubeufiaceae, occur in Pleosporomycetidae as opposed to Dothideomycetidae. Four clades comprised of only freshwater taxa were recovered. The largest of these is the Jahnulales clade consisting of 13 species, two of which are the anamorphs Brachiosphaera tropicalis and Xylomyces chlamydosporus. The second most speciose clade is the Lindgomycetaceae clade consisting of nine taxa including the anamorph Taeniolella typhoides. The Lindgomycetaceae clade consists of taxa formerly described in Massarina, Lophiostoma, and Massariosphaeriae.g.,Massarina ingoldiana, Lophiostoma breviappendiculatum, and Massariosphaeria typhicola and several newly described and undescribed taxa. The aquatic family Amniculicolaceae, including three species of Amniculicola, Semimassariosphaeria typhicola and the anamorph, Anguillospora longissima, was well supported. A fourth clade of freshwater species consisting of Tingoldiago graminicola,Lentithecium aquaticum,L. arundinaceum and undescribed taxon A-369-2b was not well supported with maximum likelihood bootstrap and Bayesian posterior probability. Eight freshwater taxa occurred along with terrestrial species in the Lophiostoma clades 1 and 2. Two taxa lacking statistical support for their placement with any taxa included in this study are considered singletons within Pleosporomycetidae. These singletons, Ocala scalariformis, and Lepidopterella palustris, are morphologically distinct from other taxa in Pleosporomycetidae. This study suggests that freshwater Dothideomycetes are related to terrestrial taxa and have adapted to freshwater habitats numerous times. In some cases (Jahnulales and Lindgomycetaceae), species radiation appears to have occurred. Additional collections and molecular study are required to further clarify the phylogeny of this interesting ecological group. PMID- 20169029 TI - Molecular systematics of the marine Dothideomycetes. AB - Phylogenetic analyses of four nuclear genes, namely the large and small subunits of the nuclear ribosomal RNA, transcription elongation factor 1-alpha and the second largest RNA polymerase II subunit, established that the ecological group of marine bitunicate ascomycetes has representatives in the orders Capnodiales, Hysteriales, Jahnulales, Mytilinidiales, Patellariales and Pleosporales. Most of the fungi sequenced were intertidal mangrove taxa and belong to members of 12 families in the Pleosporales: Aigialaceae, Didymellaceae,Leptosphaeriaceae, Lenthitheciaceae, Lophiostomataceae, Massarinaceae,Montagnulaceae, Morosphaeriaceae, Phaeosphaeriaceae, Pleosporaceae, Testudinaceae and Trematosphaeriaceae. Two new families are described: Aigialaceae and Morosphaeriaceae, and three new genera proposed: Halomassarina, Morosphaeria and Rimora. Few marine species are reported from the Dothideomycetidae (e.g. Mycosphaerellaceae, Capnodiales), a group poorly studied at the molecular level. New marine lineages include the Testudinaceae and Manglicolaguatemalensis in the Jahnulales. Significantly, most marine Dothideomycetes are intertidal tropical species with only a few from temperate regions on salt marsh plants (Spartina species and Juncus roemerianus), and rarely totally submerged (e.g. Halotthia posidoniae and Pontoporeia biturbinata on the seagrasses Posidonia oceanica and Cymodocea nodosum). Specific attention is given to the adaptation of the Dothideomycetes to the marine milieu, new lineages of marine fungi and their host specificity. PMID- 20169030 TI - Molecular taxonomy of bambusicolous fungi: Tetraplosphaeriaceae, a new pleosporalean family with Tetraploa-like anamorphs. AB - A new pleosporalean family Tetraplosphaeriaceae is established to accommodate five new genera; 1) Tetraplosphaeria with small ascomata and anamorphs belonging to Tetraploa s. str., 2) Triplosphaeria characterised by hemispherical ascomata with rim-like side walls and anamorphs similar to Tetraploa but with three conidial setose appendages, 3) Polyplosphaeria with large ascomata surrounded by brown hyphae and anamorphs producing globose conidia with several setose appendages, 4) Pseudotetraploa, an anamorphic genus, having obpyriform conidia with pseudosepta and four to eight setose appendages, and 5) Quadricrura, an anamorphic genus, having globose conidia with one or two long setose appendages at the apex and four to five short setose appendages at the base. Fifteen new taxa in these genera mostly collected from bamboo are described and illustrated. They are linked by their Tetraploa s. l. anamorphs. To infer phylogenetic placement in the Pleosporales, analyses based on a combined dataset of small- and large-subunit nuclear ribosomal DNA (SSU+LSU nrDNA) was carried out. Tetraplosphaeriaceae, however, is basal to the main pleosporalean clade and therefore its relationship with other existing families was not completely resolved. To evaluate the validity of each taxon and to clarify the phylogenetic relationships within this family, further analyses using sequences from ITS-5.8S nrDNA (ITS), transcription elongation factor 1-alpha (TEF), and beta-tubulin (BT), were also conducted. Monophyly of the family and that of each genus were strongly supported by analyses based on a combined dataset of the three regions (ITS+TEF+BT). Our results also suggest that Tetraplosphaeria (anamorph: Tetraploa s. str.) is an ancestral lineage within this family. Taxonomic placement of the bambusicolous fungi in Astrosphaeriella, Kalmusia, Katumotoa, Massarina, Ophiosphaerella, Phaeosphaeria, Roussoella, Roussoellopsis, and Versicolorisporium, are also discussed based on the SSU+LSU phylogeny. PMID- 20169031 TI - Subcutaneous immunoglobulin replacement therapy in the treatment of patients with primary immunodeficiency disease. AB - Antibody deficiency is the most frequently encountered primary immunodeficiency disease (PIDD) and patients who lack the ability to make functional immunoglobulin require life-long replacement therapy to prevent serious bacterial infections. Human serum immunoglobulin manufactured from pools of donated plasma can be administered intramuscularly, intravenously or subcutaneously. With the advent of well-tolerated preparations of intravenous immunoglobulin (IVIg) in the 1980s, the suboptimal painful intramuscular route of administration is no longer used. However, some patients continued to experience unacceptable adverse reactions to the intravenous preparations, and for others, vascular access remained problematic. Subcutaneously administered immunoglobulin (SCIg) provided an alternative delivery method to patients experiencing difficulties with IVIg. By 2006, immunoglobulin preparations designed exclusively for subcutaneous administration became available. They are therapeutically equivalent to intravenous preparations and offer patients the additional flexibility for the self-administration of their product at home. SCIg as replacement therapy for patients with primary antibody deficiencies is a safe and efficacious method to prevent serious bacterial infections, while maximizing patient satisfaction and improving quality of life. PMID- 20169033 TI - A review of the applications of the hydrofiber dressing with silver (Aquacel Ag) in wound care. AB - Aquacel Ag((R)) (ConvaTec, Princeton, NJ, USA) is a new hydrofiber wound dressing consisting of soft non-woven sodium carboxymethylcellulose fibers integrated with ionic silver. It is a moisture-retention dressing, which forms a gel on contact with wound fluid and has antimicrobial properties of ionic silver. We present a current literature review on Aquacel Ag((R)), of both in vitro and in vivo efficacy and clinical applications. In vitro and in vivo studies have demonstrated the wide antimicrobial properties of Aquacel Ag((R)), and additionally demonstrated the cytotoxicity of ionic silver to keratinocytes and fibroblasts that cause delay in wound re-epithelialization. Clinical studies confirmed that Aquacel Ag((R)) is an effective and safe dressing for a variety of wound types, both acute and chronic. Incorporation of ionic silver into the hydrofibers does not cause undue alteration in the performance properties of the base dressing, which continues to provide favorable wound moisture and exudate management. The addition of ionic silver reduces local pain and dressing changes, and provides significant broad-spectrum antimicrobial properties, with no delay in wound healing. PMID- 20169032 TI - Update on the efficacy, effectiveness and safety of artemether-lumefantrine combination therapy for treatment of uncomplicated malaria. AB - Artemether-lumefantrine is one of the artemisisnin-based combination therapies recommended for treatment of uncomplicated falciparum malaria. The drug combination is highly efficacious against sensitive and multidrug resistant falciparum malaria. It offers the advantage of rapid clearance of parasites by artemether and the slower elimination of residual parasites by lumefantrine. The combination can be used in all populations except pregnant mothers in the first trimester where safety is still uncertain. There are still concerns about safety and pharmacokinetics of the drug combination in children, especially infants, pregnant mothers and drug interactions with mainly non-nucleoside reverse transcriptase inhibitors and protease inhibitors used for HIV therapy. PMID- 20169036 TI - Profile of etravirine for the treatment of HIV infection. AB - Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with the advantages of in vitro potency against many strains of virus resistant to efavirenz and nevirapine, as well as a higher genetic barrier to resistance. Etravirine is indicated for use in treatment-experienced patients, and the approved dose in adults is 200 mg twice daily. Etravirine should be administered after a meal as bioavailability is significantly reduced when taken in the fasting state. Etravirine is a substrate of CYP3A4, CYP2C9, CYP2C19, and uridine diphosphate glucuronyltransferase, and induces CYP3A4, weakly inhibits CYP2C9 and moderately inhibits CYP2C19. Etravirine may be coadministered with nucleoside/tide reverse transcriptase inhibitors, raltegravir and boosted darunavir, lopinavir, and saquinavir without dosage adjustment. Etravirine should not be given with other NNRTIs, unboosted protease inhibitors, and atazanavir/ritonavir, tipranavir/ritonavir, and fosamprenavir/ritonavir due to unfavorable drug interactions. In randomized, controlled trials, twice daily etravirine combined with darunavir/ritonavir plus optimized background therapy demonstrated better efficacy compared to darunavir/ritonavir plus optimized background therapy alone in treatment-experienced populations out to 96 weeks follow-up. The main etravirine-associated toxicity is mild to moderate self limiting rash, although severe and sometimes fatal hypersensitivity reactions have been reported. Etravirine offers a potent sequencing option after the development of resistance to first-line NNRTIs, and is a welcome addition to this established drug class. PMID- 20169035 TI - Tenofovir-associated bone density loss. AB - Clinical observations have revealed a strong correlation between loss of bone density in HIV-infected individuals, particularly in conjunction with the antiretroviral drug tenofovir, a nucleotide analog that inhibits HIV reverse transcriptase. The most compelling correlations have been observed in clinical studies involving young children and adolescents. These observations strongly suggest that bone density is being affected during active bone growth and development, implicating a role for tenofovir in bone loss. Here we discuss the literature and potential mechanisms for how tenofovir-associated bone loss may arise, which likely involves perturbation of cellular DNA synthesis and gene expression. Elucidation of the mechanism(s) involved in tenofovir-mediated bone loss will help in developing adjuvant therapies to reduce tenofovir-associated bone density loss. PMID- 20169034 TI - Current and emerging treatment options for Graves' hyperthyroidism. AB - Radioiodine, antithyroid drugs and surgery have been well established therapies for Graves' hyperthyroidism for several decades. However there remain large variations in practice among physicians in the preferred modality and the method of administration. Patient choice and perceptions also play a big role in the choice of treatment. Radioiodine may be given using fixed high doses or by calculated doses following uptake studies. The risks of radioiodine including eye disease and the role of prophylactic steroid therapy are discussed. The commonly used antithyroid drugs include carbimazole, methimazole and propylthiouracil; however a number of other agents have been tried in special situations or in combination with these drugs. The antithyroid drugs may be given in high (using additional levothyroxine in a block-replace regimen) or low doses (in a titration regimen). This review examines the current evidence and relative benefits for these options as well as looking at emerging therapies including immunomodulatory treatments such as rituximab which have come into early clinical trials. The use of antithyroid therapies in special situations is also discussed as well as clinical practice issues which may influence the choices. PMID- 20169037 TI - Galantamine-ER for the treatment of mild-to-moderate Alzheimer's disease. AB - An extended release form of the cholinesterase inhibitor (ChEI) drug galantamine (galantamine-ER) was developed, chiefly to increase adherence to medication regimes in patients with mild-to-moderate Alzheimer's disease (AD). Except for predicted differences in (C(max)) and t(max), comparable doses of once daily galantamine-ER and regular, immediate release galantamine, (galantamine-IR), are pharmacologically equivalent. A 24-week randomized, double-blind, placebo-and active-controlled, multicenter phase III trial, which compared galantamine-IR, galantamine-ER and placebo in subjects with mild to moderate AD (mini-mental state examination [MMSE] score range, 10 to 24) showed that both formulations of galantamine were significantly better than placebo in terms of cognition, although not with regard to global change. There was no difference in drug related adverse events between galantamine-ER and galantamine-IR. Since its release onto the market galantamine-ER has enjoyed wide popularity and a recent surveillance study suggests that it has the highest 1-year persistence rate of all the ChEIs. PMID- 20169038 TI - Management of hyperuricemia in gout: focus on febuxostat. AB - Gout is the most common inflammatory arthritis in an elderly population, and can be diagnosed with absolute certainty by polarization microscopy. However, diagnosis may be challenging because atypical presentations are more common in the elderly. Management of hyperuricemia in the elderly with gout requires special consideration because of co-medication, contra-indications, and risk of adverse reactions. Urate-lowering agents include allopurinol and uricosuric agents. These also must be used sensibly in the elderly, especially when renal function impairment is present. However, if used at the lowest dose that maintains the serum urate level below 5.0 to 6.0 mg/dL (0.30 to 0.36 mmol/L), the excess urate in the body will eventually be eliminated, acute flares will no longer occur, and tophi will resolve. Febuxostat, a new xanthine oxidase inhibitor, is welcomed, as few alternatives for allopurinol are available. Its pharmacokinetics and pharmacodynamics are not significantly altered in patients with moderate renal function or hepatic impairment. Its antihyperuricemic efficacy at 80 to 120 mg/day is better than "standard dosage" allopurinol (300 mg/day). Long-term safety data and efficacy data on tophus diminishment and reduction of gout flares have recently become available. Febuxostat may provide an important option in patients unable to use allopurinol, or refractory to allopurinol. PMID- 20169039 TI - Selective estrogen receptor modulator (SERM) for the treatment of osteoporosis in postmenopausal women: focus on lasofoxifene. AB - Selective estrogen receptor modulators (SERMs) represent a class with a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissue-specific manner. This article reviews lasofoxifene, a new-generation SERM that has completed phase III development for the prevention and treatment of osteoporosis in postmenopausal women. Consistent with preclinical observations, this new SERM demonstrated improved skeletal efficacy over raloxifene and at an oral dose of 0.5 mg/day was effective in the prevention of both vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. At the same dosage, lasofoxifene treatment also reduced estrogen receptor-positive breast cancer risk and the occurrence of vaginal atrophy, but, like the other SERMs, was associated with hot flushes and an increased risk of venous thromboembolic events. With its increased efficacy on the prevention of nonvertebral fractures than current available SERMs and its positive effects on the vagina, this new compound may represent an alternative and cost-effective therapy for osteoporosis in postmenopausal women. PMID- 20169040 TI - Measuring cortisol and DHEA in fingernails: a pilot study. AB - PURPOSE: Abnormalities in both cortisol and dehydroepiandrosterone (DHEA) have been reported in psychiatric disorders. Analysis of saliva, urine and blood cortisol and DHEA levels provides an index of hormone levels over a short time period. Unlike such conventional measures, fingernails incorporate endogenous hormones that passively diffuse to the nail matrix from capillaries during keratinization. This study piloted the measurement of cortisol and DHEA levels in fingernails as a potential measure of their accumulated secretion of steroid hormones over a prolonged time period. METHOD: Thirty-three university students (18-24 years) provided fingernail samples on two occasions over a school semester. The visits were scheduled so nail cortisol and DHEA levels were collected from periods when students might be under different levels of stress. RESULTS: DURING THE PUTATIVELY STRESSFUL PERIOD, THE NAIL SAMPLES SHOWED A SIGNIFICANT INCREASE IN THE CORTISOL: DHEA ratio (P = 0.0002) due to a significant decrease in the DHEA levels (P = 0.004) and a numerical but not statistically significant increase in the cortisol levels (P = 0.256). DISCUSSION: This pilot study showed that nails can be used to measure cortisol and DHEA, a measure which may reflect environmental stress. More work is required to further validate this technique which may prove useful in studies of both healthy individuals and patient groups. PMID- 20169041 TI - Impulsivity, gender, and the platelet serotonin transporter in healthy subjects. AB - The present study explored the possible relationships between impulsivity, gender, and a peripheral serotonergic marker, the platelet serotonin (5-HT) transporter (SERT), in a group of 32 healthy subjects. The impulsivity was measured by means of the Barratt Impulsivity Scale, version 11 (BIS-11), a widely used self-report questionnaire, and the platelet SERT was evaluated by means of the specific binding of (3)H-paroxetine ((3)H-Par) to platelet membranes, according to standardized protocols. The results showed that women had a higher BIS-11 total score than men, and also higher scores of two factors of the same scale: the motor impulsivity and the cognitive complexity. The analysis of the correlations revealed that the density of the SERT proteins, as measured by the maximum binding capacity (B(max)) of (3)H-Par, was significantly and positively related to the cognitive complexity factor, but only in men. Men showed also a significant and negative correlation with the dissociation constant, Kd, of ((3)H Par) binding, and the motor impulsivity factor. These findings suggest that women are generally more impulsive than men, but that the 5-HT system is more involved in the impulsivity of men than in that of women. PMID- 20169042 TI - Topiramate in the prevention and treatment of migraine: efficacy, safety and patient preference. AB - Migraine is a very common disorder characterized by the combination of typical headache with associated autonomic symptoms and/or the presence of aura. Considerable advances have been made in recent years to understand the pathophysiology of migraine, which has led to improved treatment options for the acute migraine attack as well as migraine prophylaxis. Unfortunately, preventive treatment is often insufficient to decrease migraine frequency substantially or is not well tolerated. Topiramate is an antipileptic drug with a complex mode of action which has proven its efficacy and safety in the prophylactic treatment of episodic migraine in a number of randomized controlled clinical trials. Topiramate is also effective in treating patients with chronic migraine. It has little pharmacological interaction with other drugs and is generally well tolerated by patients. PMID- 20169043 TI - Considerations in glaucoma therapy: fixed combinations versus their component medications. AB - Fixed combinations of medications that lower intraocular pressure (IOP) are increasingly used in the treatment of glaucoma and ocular hypertension and offer several potential advantages over combined use of the separate component medications including enhanced convenience, improved adherence, reduced exposure to preservatives, and possible cost savings. This review aims to examine the current role of IOP-lowering fixed combinations in disease management. The results of studies that compared the efficacy and safety of IOP-lowering fixed combinations with their component medications are summarized, including those fixed combinations that consist of a prostaglandin analog and timolol. The fixed combinations currently available for use in the United States are fixed combination dorzolamide/timolol (FCDT) and fixed-combination brimonidine/timolol (FCBT). Both of these fixed combinations reduce IOP more effectively than their component medications used separately as monotherapy. FCBT therapy also demonstrates a more favorable safety profile and reduced ocular allergy compared to monotherapy with brimonidine, a component medication. Few studies have directly compared the efficacy and safety of FCDT and FCBT, but available evidence suggests that FCBT is at least as effective as FCDT in lowering IOP and is more comfortable and better tolerated. Additional studies are needed to further evaluate the comparative efficacy and tolerability of FCDT and FCBT in the management of glaucoma and ocular hypertension. PMID- 20169044 TI - Antiviral selection in the management of acute retinal necrosis. AB - There is no consensus on the optimal antiviral regimen in the management of acute retinal necrosis, a disease caused by herpetic viruses with devastating consequences for the eye. The current gold standard is based on retrospective case series. Because the incidence of disease is low, few well-designed, randomized trials have evaluated treatment dosage and duration. Newer oral antiviral agents are emerging as alternatives to high-dose intravenous acyclovir, avoiding the need for inpatient intravenous treatment. Drug resistance is uncommon but may also be difficult to identify. Antiviral drugs have few side effects, but special attention needs to be paid to patients who have underlying renal disease, are pregnant or are immunocompromised. PMID- 20169045 TI - Trimetazidine for prevention of induced ischemia and reperfusion of guinea pig retina. AB - OBJECTIVE: Trimetazidine (TMZ) has been used to protect against ischemia/reperfusion (I/R) injury of many tissues. We aimed to evaluate the effect of TMZ during retinal I/R in a guinea pig model. STUDY DESIGN/PATIENTS AND METHODS: An experimental study in retinal I/R. Three groups of five guinea pigs were studied to include a control, placebo, and drug test groups. Prior to the application of 90 minutes of high intraocular pressure (IOP) to induce retinal ischemia followed by 24 hours of reperfusion, we applied intraperitoneal saline to the placebo group and 3 mg/kg of TMZ for the drug test group and repeated the injections at intervals of six hours for four cycles. Both eyes of the animals were enucleated at the end of the reperfusion period. Biochemical assay and histopathologic evaluation was performed on one randomly selected eye of each animal. The level of retinal-free malondialdehyde (MDA) and retinal layer thicknesses were determined and comparisons were then made with the control group. RESULTS: The mean free MDA level increased in the placebo group (P = 0.006) but not in the drug group (P > 0.05). We observed polymorphonucleated leukocyte infiltration, retinal edema and hydropic degeneration in the retina of the placebo group. However, significant histopathologic change was not observed in specimens of the drug group. CONCLUSIONS: This study suggests TMZ has a beneficial effect on retinal lipid peroxidation and histopathologic changes due to I/R injury. PMID- 20169046 TI - A two-week clinical evaluation of the safety of Systane Ultra in contact lens wearing patients. AB - OBJECTIVE: To evaluate the safety of Systane((R)) Ultra Lubricant Eye Drops (test solution) in contact lens wearers. A currently marketed contact lens rewetting drop was the control solution. PARTICIPANTS: This investigator- and patient masked, single-site, randomized, and prospective study involved 45 successful contact lens wearers. METHODS: Eligible subjects' baseline biomicroscopy findings, visual acuity, and corneal staining score were recorded. Subjects received either the test or control solution with masked labeling. Subjects were instructed to instill their assigned solution in both eyes: 15 minutes prior to lens insertion, at least one drop during lens wear and another drop immediately following lens removal. After 14 days, biomicroscopy results, visual acuity, and corneal staining score were recorded. RESULTS: No adverse events were documented for either the test or the control solution. For subjects using Systane((R)) Ultra, no statistically significant change was detected in visual acuity (= 0.7667) or corneal staining score (P = 1.000). For subjects using the control solution, the change in visual acuity (P = 0.0011, mean difference = 1.70 +/- 3.22 standard deviation) was not clinically relevant and there was no significant change in corneal staining score (P = 0.5413). CONCLUSIONS: This clinical study provided evidence of safety and compatibility of Systane Ultra Lubricant Eye Drops in contact lens wearers. PMID- 20169047 TI - Evaluation of ultraviolet light toxicity on cultured retinal pigment epithelial and retinal ganglion cells. AB - PURPOSE: Our study is aimed at evaluating the role of UVB light in inducing cytotoxicity in an in vitro model. METHODS: RGC-5 and ARPE-19 cells were exposed to different time periods of UVB light: 0, 15, 30, and 45 min. They were subsequently examined for changes in cell morphology, cell viability (neutral red uptake assay), generation of reactive oxygen species (ROS), expression of bax, bcl-2 and cytochome C by reverse transcriptase polymerase chain reaction and western blot, respectively. RESULTS: Dose-dependent reduction in cell viability to UVB light was demonstrated with parallel increase in ROS. Increased duration of exposure (>15 minutes), was associated with increased expression of bax and cytochrome C, and absence of bcl-2 expression. CONCLUSION: UVB light exposure results in cell cytotoxicity. The concomitant generation of ROS and expression of apoptotic markers suggests the role of oxidative stress in UVB-mediated apoptosis in an in vitro model of retinal ganglion and pigment epithelial cells. PMID- 20169048 TI - Kinetics of kill of bacterial conjunctivitis isolates with moxifloxacin, a fluoroquinolone, compared with the aminoglycosides tobramycin and gentamicin. AB - PURPOSE: To compare the kinetics and speed of kill of Streptococcus pneumoniae and Haemophilus influenzae on exposure to three topical ophthalmic antibiotic solutions. MATERIALS AND METHODS: Bacterial conjunctivitis isolates of S. pneumoniae and H. influenzae were exposed to 1:1000 dilutions of moxifloxacin 0.5%, tobramycin 0.3%, gentamicin 0.3%, and water (control). At 15, 30, 60, 120, and 180 minutes after exposure, aliquots were collected, cells were cultured, and viable cell counts were determined using standard microbiological methods. RESULTS: Moxifloxacin achieved 99.9% kill (3-log reduction) at approximately 2 hours for S. pneumoniae and at 15 minutes for H. influenzae. Tobramycin and gentamicin did not achieve 3-log reduction of S. pneumoniae during the 180-minute study period. An increase in bacterial growth was noted for these isolates. Gentamicin took more than 120 minutes to achieve the 3-log reduction of H. influenzae and tobramycin did not reach the 3-log reduction of this pathogen during the 180-minute study period. CONCLUSION: Moxifloxacin killed S. pneumoniae and H. influenzae in vitro faster than tobramycin and gentamicin, suggesting its potential clinical benefit as a first-line treatment for bacterial conjunctivitis to minimize patient symptoms and to limit the contagiousness of the disease. PMID- 20169049 TI - A multicenter investigation of OPTI-FREE RepleniSH multi-purpose disinfecting solution impact on soft contact lens patient comfort. AB - OBJECTIVE: Demonstrate that successful soft contact lens wearers using competitive multipurpose solutions report improvement in comfort with OPTI FREE((R)) RepleniSH((R)) Multi-Purpose Disinfecting Solution (MPDS). METHODS: This 30-day, multicentered, open-label study enrolled 109 eligible soft contact lens wearers using COMPLETE((R)) Multi-Purpose Solution (MPS) Easy Rub((R)) or ReNu MultiPlus((R)) MPS. The test solution (OPTI-FREE((R)) RepleniSH((R)) MPDS) was dispensed for use in place of habitual care solutions. Subjects assessed their experience with their habitual solution (baseline) and the test solution (Day 30) using Likert-style questions. Contact lens acuity and biomicroscopy findings were recorded at each visit. RESULTS: The test solution was associated with a statistically significant improvement in instillation comfort (P = 0.02), end of day comfort (P < 0.0001), clear vision (P < 0.0001) and overall satisfaction (P < 0.001). Subjects reported the test solution enhanced their overall lens-wearing experience more effectively than their previous solution (P < 0.0001) and that they would continue test solution use after the study (P < 0.0001). CONCLUSIONS: The test solution was effective at improving comfort and overall contact lens experience compared to COMPLETE((R)) MPS Easy Rub((R)) or ReNu MultiPlus((R)) MPS in successful contact lens wearers. These results indicate that changing contact lens care solutions, even in successful lens wearers, may improve comfort and overall lens-wearing experience. PMID- 20169050 TI - Exoresection via partial lamellar sclerouvectomy approach for uveal tumors: A successful performance by a novice surgeon. AB - PURPOSE: To evaluate the results and complications of exoresection via a partial lamellar sclerouvectomy (PLSU) procedure for uveal tumors performed by a novice surgeon without help from an experienced surgeon. METHODS: Medical records of 22 patients who underwent exoresection for uveal tumors between February 1999 and January 2009 were evaluated retrospectively. Exoresection was considered for tumors with their epicenter in the iris or in the ciliary body. RESULTS: Twenty two patients with a mean age of 45.9 years (range: 19-72 years) were included in this study. The histopathologic diagnosis was uveal malignant melanoma in 16 patients, iridociliary nevus in 2 patients, iris nevus in 2 patients, and iridociliary melanocytoma in 2 patients. Postoperative complications included cataract in 11 patients (50%), scleral thinning in 4 patients (18%), vitreous hemorrhage in 2 patients (9%), hyphema in 2 patients (9%), secondary glaucoma in 2 patients (9%), iridodialysis in 1 patient (4.5%), bullous keratopathy in 1 patient (4.5%), and posterior synechiae in 1 patient (4.5%). At a mean follow-up of 40.1 months (range: 1-98 months), there were no recurrences or metastatic events. CONCLUSIONS: Exoresection seems to be an effective treatment option in selected cases of iridociliary and ciliary body tumors. Novice surgeons with limited training in PLSU should not discourage themselves from doing this type of surgery. Several postoperative complications inevitably occur and require frequent patient monitoring. PMID- 20169051 TI - Laparoendoscopic single-site surgery for the treatment of benign adnexal disease: a prospective trial. AB - Background. To validate feasibility, efficacy, and safeness of laparoscopic treatment of benign adnexal diseases through a single transumbilical access (LESS) in a prospective series of patients. Methods. A prospective clinical trial including 30 women has been conducted at the Division of Gynecology of Catholic University of Sacred Hearth of Rome. Patients underwent different laparoscopic procedures by LESS utilizing a multiport trocar and conventional straight laparoscopic instrumentation. Intra and perioperative outcome has been reported. Results. Ten mono/bilateral adnexectomies and 20 cystectomies have been performed by LESS approach. Laparoscopic procedures were completed through a single access in 28 cases (93.4%). No major intra- or postoperative complications were observed. Mean hospital stay was 1.3 days. Conclusions. LESS approach is feasible to treat benign adnexal disease with a very low conversion rate and no early or late complications. More clinical data are needed to confirm these advantages compared to standard laparoscopic technique. PMID- 20169052 TI - Single incision laparoscopic surgery for acute appendicitis: feasibility in pediatric patients. AB - Background. Laparoscopic appendicectomy is accepted by many as the gold standard approach for the treatment of acute appendicitis. The use of Single Incision Laparoscopic Surgery (SILS) has the potential of further reducing postoperative port site complications as well as improving cosmesis and patient satisfaction. Method. In this paper we report our experience and assess the feasibility of SILS appendicectomy in the pediatric setting. Results. Five pediatric patients with uncomplicated appendicitis underwent SILS appendicectomy. There were no significant intraoperative or postoperative complications. All patients were discharged within 24 hours. Conclusions. The use of Single Incision Laparoscopic Surgery appears to be a feasible and safe technique for the treatment of uncomplicated appendicitis in the pediatric setting. Further studies are warranted to fully investigate the potential advantages of this new technique. PMID- 20169053 TI - Update on Instrumentations for Cholecystectomies Performed via Transvaginal Route: State of the Art and Future Prospectives. AB - Natural Orifice Transluminal Endoscopic Surgery (NOTES) is an innovative approach in which a flexible endoscope enters the abdominal cavity via the transesophageal, transgastric, transcolonic, transvaginal or transvescical route, combining the technique of minimally invasive surgery with flexible endoscopy. Several groups have described different modifications by using flexible endoscopes with different levels of laparoscopic assistance. Transvaginal cholecystectomy (TVC) consists in accessing the abdominal cavity through a posterior colpotomy and using the vaginal incision as a visual or operative port. An increasing interest has arisen around the TVC; nevertheless, the most common and highlighted concern is about the lack of specific instruments dedicated to the vaginal access route. TVC should be distinguished between "pure", in which the entire operation is performed through the transvaginal route, and "hybrid", in which the colpotomy represents only a support to introduce instruments and the operation is performed mainly by the classic transabdominal-introduced instruments. Although this new technique seems very appealing for patients, on the other hand it is very challenging for the surgeon because of the difficulties related to the mode of access, the limited technology currently available and the risk of complications related to the organ utilized for access. In this brief review all the most recent advancements in the field of TVC's techniques and instrumentations are listed and discussed. PMID- 20169054 TI - Current Limitations and Perspectives in Single Port Surgery: Pros and Cons Laparo Endoscopic Single-Site Surgery (LESS) for Renal Surgery. AB - Laparo-Endoscopic Single-Site surgery (LESS) for kidney diseases is quickly evolving and has a tendency to expand the urological armory of surgical techniques. However, we should not be overwhelmed by the surgical skills only and weight it against the basic clinical and oncological principles when compared to standard laparoscopy. The initial goal is to define the ideal candidates and ideal centers for LESS in the future. Modification of basic instruments in laparoscopy presumably cannot result in better functional and oncological outcomes, especially when the optimal working space is limited with the same arm movements. Single port surgery is considered minimally invasive laparoscopy; on the other hand, when using additional ports, it is no more single port, but hybrid traditional laparoscopy. Whether LESS is a superior or equally technique compared to traditional laparoscopy has to be proven by future prospective randomized trials. PMID- 20169055 TI - Transvesicoscopic repair of vesicovaginal fistula. AB - Introduction. Vesicovaginal fistula has been a social and surgical problem for centuries. Many surgical techniques have been developed to correct this abnormality, including transabdominal, transvaginal, and endoscopic approaches. The best approach is probably the one with which the surgeon feels most experienced and comfortable. Laparoscopy has become increasingly popular in urology, reducing the invasiveness of treatment and shortening the period of convalescence. We report our results of transvesicoscopic approach for VVF repair. Materials and Methods. Patients with VVF were offered repair using the transvesicoscopic route. With the patient under general anaesthesia and in modified lithotomy position cystoscopy was performed with gas insufflation. Under cystoscopic guidance the bladder was fixed to anterior abdominal wall and ports inserted into the bladder. The fistula was repaired under endoscopic vision. Results. Four women, who had VVF following abdominal hysterectomy, underwent this procedure. The operating time ranged from 175 to 235 minutes. There was minimal bleeding. Post operative complications included ileus in one and fever in another. No recurrence of VVF was noted in any patient. Conclusions. Transvesicoscopic repair of VVF is feasible, safe, and results in lower morbidity and quicker recovery time. PMID- 20169056 TI - Glucocorticoid effects on the programming of AT1b angiotensin receptor gene methylation and expression in the rat. AB - Adverse events in pregnancy may 'programme' offspring for the later development of cardiovascular disease and hypertension. Previously, using a rodent model of programmed hypertension we have demonstrated the role of the renin-angiotensin system in this process. More recently we showed that a maternal low protein diet resulted in undermethylation of the At1b angiotensin receptor promoter and the early overexpression of this gene in the adrenal of offspring. Here, we investigate the hypothesis that maternal glucocorticoid modulates this effect on fetal DNA methylation and gene expression. We investigated whether treatment of rat dams with the 11beta-hydroxylase inhibitor metyrapone, could prevent the epigenetic and gene expression changes we observed. Offspring of mothers subjected to a low protein diet in pregnancy showed reduced adrenal Agtr1b methylation and increased adrenal gene expression as we observed previously. Treatment of mothers with metyrapone for the first 14 days of pregnancy reversed these changes and prevented the appearance of hypertension in the offspring at 4 weeks of age. As a control for non-specific effects of programmed hypertension we studied offspring of mothers treated with dexamethasone from day 15 of pregnancy and showed that, whilst they had raised blood pressure, they failed to show any evidence of Agtr1b methylation or increase in gene expression. We conclude that maternal glucocorticoid in early pregnancy may induce changes in methylation and expression of the Agtr1b gene as these are clearly reversed by an 11 beta hydroxylase inhibitor. However in later pregnancy a converse effect with dexamethasone could not be demonstrated and this may reflect either an alternative mechanism of this glucocorticoid or a stage-specific influence. PMID- 20169057 TI - Cerebral and peripheral changes occurring in nitric oxide (NO) synthesis in a rat model of sleeping sickness: identification of brain iNOS expressing cells. AB - BACKGROUND: The implication of nitric oxide (NO) in the development of human African trypanosomiasis (HAT) using an animal model, was examined. The manner by which the trypanocidal activity of NO is impaired in the periphery and in the brain of rats infected with Trypanosoma brucei brucei (T. b. brucei) was analyzed through: (i) the changes occurring in NO concentration in both peripheral (blood) and cerebral compartments; (ii) the activity of nNOS and iNOS enzymes; (iii) identification of the brain cell types in which the NO-pathways are particularly active during the time-course of the infection. METHODOLOGY/PRINCIPAL FINDINGS: NO concentration (direct measures by voltammetry) was determined in central (brain) and peripheral (blood) compartments in healthy and infected animals at various days post-infection: D5, D10, D16 and D22. Opposite changes were observed in the two compartments. NO production increased in the brain (hypothalamus) from D10 (+32%) to D16 (+71%), but decreased in the blood from D10 (-22%) to D16 ( 46%) and D22 (-60%). In parallel with NO measures, cerebral iNOS activity increased and peaked significantly at D16 (up to +700%). However, nNOS activity did not vary. Immunohistochemical staining confirmed iNOS activation in several brain regions, particularly in the hypothalamus. In peritoneal macrophages, iNOS activity decreased from D10 (-83%) to D16 (-65%) and D22 (-74%) similarly to circulating NO. CONCLUSION/SIGNIFICANCE: The NO changes observed in our rat model were dependent on iNOS activity in both peripheral and central compartments. In the periphery, the NO production decrease may reflect an arginase-mediated synthesis of polyamines necessary to trypanosome growth. In the brain, the increased NO concentration may result from an enhanced activity of iNOS present in neurons and glial cells. It may be regarded as a marker of deleterious inflammatory reactions. PMID- 20169058 TI - IL-17 produced during Trypanosoma cruzi infection plays a central role in regulating parasite-induced myocarditis. AB - BACKGROUND: Chagas disease is a neglected disease caused by the intracellular parasite Trypanosoma cruzi. Around 30% of the infected patients develop chronic cardiomyopathy or megasyndromes, which are high-cost morbid conditions. Immune response against myocardial self-antigens and exacerbated Th1 cytokine production has been associated with the pathogenesis of the disease. As IL-17 is involved in the pathogenesis of several autoimmune, inflammatory and infectious diseases, we investigated its role during the infection with T. cruzi. METHODOLOGY/PRINCIPAL FINDINGS: First, we detected significant amounts of CD4, CD8 and NK cells producing IL-17 after incubating live parasites with spleen cells from normal BALB/c mice. IL-17 is also produced in vivo by CD4(+), CD8(+) and NK cells from BALB/c mice on the early acute phase of infection. Treatment of infected mice with anti-mouse IL-17 mAb resulted in increased myocarditis, premature mortality, and decreased parasite load in the heart. IL-17 neutralization resulted in increased production of IL-12, IFN-gamma and TNF-alpha and enhanced specific type 1 chemokine and chemokine receptors expression. Moreover, the results showed that IL-17 regulates T-bet, RORgammat and STAT-3 expression in the heart, showing that IL-17 controls the differentiation of Th1 cells in infected mice. CONCLUSION/SIGNIFICANCE: These results show that IL-17 controls the resistance to T. cruzi infection in mice regulating the Th1 cells differentiation, cytokine and chemokine production and control parasite-induced myocarditis, regulating the influx of inflammatory cells to the heart tissue. Correlations between the levels of IL-17, the extent of myocardial destruction, and the evolution of cardiac disease could identify a clinical marker of disease progression and may help in the design of alternative therapies for the control of chronic morbidity of chagasic patients. PMID- 20169060 TI - Prolonged graft survival in older recipient mice is determined by impaired effector T-cell but intact regulatory T-cell responses. AB - Elderly organ transplant recipients represent a fast growing segment of patients on the waiting list. We examined age-dependent CD4(+) T-cell functions in a wild type (WT) and a transgenic mouse transplant model and analyzed the suppressive function of old regulatory T-cells. We found that splenocytes of naive old B6 mice contained significantly higher frequencies of T-cells with an effector/memory phenotype (CD4(+)CD44(high)CD62L(low)). However, in-vitro proliferation (MLR) and IFNgamma-production (ELISPOT) were markedly reduced with increasing age. Likewise, skin graft rejection was significantly delayed in older recipients and fewer graft infiltrating CD4(+)T-cells were observed. Old CD4(+) T cells demonstrated a significant impaired responsiveness as indicated by diminished proliferation and activation. In contrast, old alloantigen-specific CD4(+)CD25(+)FoxP3(+) T-cells demonstrated a dose-dependent well-preserved suppressor function. Next, we examined characteristics of 18-month old alloreactive T-cells in a transgenic adoptive transfer model. Adoptively transferred old T-cells proliferated significantly less in response to antigen. Skin graft rejection was significantly delayed in older recipients, and graft infiltrating cells were reduced. In summary, advanced recipient age was associated with delayed acute rejection and impaired CD4(+) T-cell function and proliferation while CD4(+)CD25(+)FoxP3(+) T-cells (Tregs) showed a well-preserved function. PMID- 20169059 TI - Vacuolar ATPase regulates surfactant secretion in rat alveolar type II cells by modulating lamellar body calcium. AB - Lung surfactant reduces surface tension and maintains the stability of alveoli. How surfactant is released from alveolar epithelial type II cells is not fully understood. Vacuolar ATPase (V-ATPase) is the enzyme responsible for pumping H(+) into lamellar bodies and is required for the processing of surfactant proteins and the packaging of surfactant lipids. However, its role in lung surfactant secretion is unknown. Proteomic analysis revealed that vacuolar ATPase (V-ATPase) dominated the alveolar type II cell lipid raft proteome. Western blotting confirmed the association of V-ATPase a1 and B1/2 subunits with lipid rafts and their enrichment in lamellar bodies. The dissipation of lamellar body pH gradient by Bafilomycin A1 (Baf A1), an inhibitor of V-ATPase, increased surfactant secretion. Baf A1-stimulated secretion was blocked by the intracellular Ca(2+) chelator, BAPTA-AM, the protein kinase C (PKC) inhibitor, staurosporine, and the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), KN-62. Baf A1 induced Ca(2+) release from isolated lamellar bodies. Thapsigargin reduced the Baf A1 induced secretion, indicating cross-talk between lamellar body and endoplasmic reticulum Ca(2+) pools. Stimulation of type II cells with surfactant secretagogues dissipated the pH gradient across lamellar bodies and disassembled the V-ATPase complex, indicating the physiological relevance of the V-ATPase mediated surfactant secretion. Finally, silencing of V-ATPase a1 and B2 subunits decreased stimulated surfactant secretion, indicating that these subunits were crucial for surfactant secretion. We conclude that V-ATPase regulates surfactant secretion via an increased Ca(2+) mobilization from lamellar bodies and endoplasmic reticulum, and the activation of PKC and CaMKII. Our finding revealed a previously unrealized role of V-ATPase in surfactant secretion. PMID- 20169061 TI - Effect of control strategies on prevalence, incidence and re-infection of clonorchiasis in endemic areas of China. AB - BACKGROUND: A pilot clonorchiasis control project was implemented to evaluate the efficacies of various chemotherapy strategies on prevalence, incidence and re infection in Heilongjiang Province, China. METHODS AND FINDINGS: Seven intervention groups (14,139 residents, about 2000 in each group) in heavily or moderately endemic areas were subjected to repeated praziquantel administration from 2001 to 2004. In the selective chemotherapy groups, residents were examined for fecal eggs, and those who tested positive were treated with three doses of 25 mg/kg praziquantel at 5-hour-intervals in one day. However, all residents were treated in the mass chemotherapy groups. In heavily endemic areas, two mass treatments of all residents in 2001 and 2003 reduced the prevalence from 69.5% to 18.8%, while four annual mass treatments reduced the prevalence from 48.0% in 2001 to 8.4% in 2004. Selective annual treatments for egg-positive subjects reduced the egg-positive rates from 54.9% in 2001 to 15.0% in 2004 or from 73.2% in 2001 to 12.3% in 2004. Selective treatments every 6 months significantly reduced the prevalence from 59.5% in 2001 to 7.5% in 2004. All of the repeated treatments reduced EPG (eggs per gram of feces) significantly. The annual mass treatment and selective treatment every 6 months produced lower prevalence and re infection rates and higher egg reduction rate than annual selective treatments did. In the moderate endemic areas, egg positive rates were 24.8% and 29.7% in 2001 but were 1.9% and 1.3% after 2 or 3 selective treatments. The prevalence, incidence, re-infection rates in a moderately endemic area were significantly lower than those of heavy endemic areas. CONCLUSIONS: Repeated mass treatment or selective treatment with praziquantel every 6 to 12 months is highly effective for clonorchiasis control in heavily endemic areas. In contrast, one or two selective treatments with health education is effective in moderately endemic areas. PMID- 20169062 TI - Expression and function of macrophage migration inhibitory factor (MIF) in melioidosis. AB - BACKGROUND: Macrophage migration inhibitory factor (MIF) has emerged as a pivotal mediator of innate immunity and has been shown to be an important effector molecule in severe sepsis. Melioidosis, caused by Burkholderia pseudomallei, is an important cause of community-acquired sepsis in Southeast-Asia. We aimed to characterize the expression and function of MIF in melioidosis. METHODOLOGY AND PRINCIPAL FINDINGS: MIF expression was determined in leukocytes and plasma from 34 melioidosis patients and 32 controls, and in mice infected with B. pseudomallei. MIF function was investigated in experimental murine melioidosis using anti-MIF antibodies and recombinant MIF. Patients demonstrated markedly increased MIF mRNA leukocyte and MIF plasma concentrations. Elevated MIF concentrations were associated with mortality. Mice inoculated intranasally with B. pseudomallei displayed a robust increase in pulmonary and systemic MIF expression. Anti-MIF treated mice showed lower bacterial loads in their lungs upon infection with a low inoculum. Conversely, mice treated with recombinant MIF displayed a modestly impaired clearance of B. pseudomallei. MIF exerted no direct effects on bacterial outgrowth or phagocytosis of B. pseudomallei. CONCLUSIONS: MIF concentrations are markedly elevated during clinical melioidosis and correlate with patients' outcomes. In experimental melioidosis MIF impaired antibacterial defense. PMID- 20169064 TI - Differential recognition of P. falciparum VAR2CSA domains by naturally acquired antibodies in pregnant women from a malaria endemic area. AB - BACKGROUND: Plasmodium falciparum infected red blood cells (iRBC) express variant surface antigens (VSA) of which VAR2CSA is involved in placental sequestration and causes pregnancy-associated malaria (PAM). Primigravidae are most susceptible to PAM whereas antibodies associated with protection are often present at higher levels in multigravid women. However, HIV co-infection with malaria has been shown to alter this parity-dependent acquisition of immunity, with more severe symptoms as well as more malaria episodes in HIV positive women versus HIV negative women of a similar parity. METHODS: Using VAR2CSA DBL-domains expressed on the surface of CHO-745 cells we quantified levels of DBL-domain specific IgG in sera from pregnant Malawian women by flow cytometry. Dissociations constants of DBL5epsilon specific antibodies were determined using a surface plasmon resonance technique, as an indication of antibody affinities. RESULTS: VAR2CSA DBL5epsilon was recognized in a gender and parity-dependent manner with anti DBL5epsilon IgG correlating significantly with IgG levels to VSA-PAM on the iRBC surface. HIV positive women had lower levels of anti-DBL5epsilon IgG than HIV negative women of similar parity. In primigravidae, antibodies in HIV positive women also showed significantly lower affinity to VAR2CSA DBL5epsilon. CONCLUSIONS: Pregnant women from a malaria-endemic area had increased levels of anti-DBL5epsilon IgG by parity, indicating this domain of VAR2CSA to be a promising vaccine candidate against PAM. However, it is important to consider co infection with HIV, as this seems to change the properties of antibody response against malaria. Understanding the characteristics of antibody response against VAR2CSA is undoubtedly imperative in order to design a functional and efficient vaccine against PAM. PMID- 20169063 TI - The impact of vitamin D on dendritic cell function in patients with systemic lupus erythematosus. AB - BACKGROUND: Excessive activity of dendritic cells (DCs) is postulated as a central disease mechanism in Systemic Lupus Erythematosus (SLE). Vitamin D is known to reduce responsiveness of healthy donor DCs to the stimulatory effects of Type I IFN. As vitamin D deficiency is reportedly common in SLE, we hypothesized that vitamin D might play a regulatory role in the IFNalpha amplification loop in SLE. Our goals were to investigate the relationship between vitamin D levels and disease activity in SLE patients and to investigate the effects of vitamin D on DC activation and expression of IFNalpha-regulated genes in vitro. METHODOLOGY/PRINCIPAL FINDINGS: In this study, 25-OH vitamin D (25-D) levels were measured in 198 consecutively recruited SLE patients. Respectively, 29.3% and 11.8% of African American and Hispanic SLE patient had 25-D levels <10 ng/ml. The degree of vitamin D deficiency correlated inversely with disease activity; R = .234, p = .002. In 19 SLE patients stratified by 25-D levels, there were no differences between circulating DC number and phenotype. Monocyte-derived DCs (MDDCs) of SLE patients were normally responsive to the regulatory effects of vitamin D in vitro as evidenced by decreased activation in response to LPS stimulation in the presence of 1,25-D. Additionally, vitamin D conditioning reduced expression of IFNalpha-regulated genes by healthy donor and SLE MDDCs in response to factors in activating SLE plasma. CONCLUSIONS/SIGNIFICANCE: We report on severe 25-D deficiency in a substantial percentage of SLE patients tested and demonstrate an inverse correlation with disease activity. Our results suggest that vitamin D supplementation will contribute to restoring immune homeostasis in SLE patients through its inhibitory effects on DC maturation and activation. We are encouraged to support the importance of adequate vitamin D supplementation and the need for a clinical trial to assess whether vitamin D supplementation affects IFNalpha activity in vivo and, most importantly, improves clinical outcome. PMID- 20169065 TI - In situ hybridization analysis of the expression of futsch, tau, and MESK2 homologues in the brain of the European honeybee (Apis mellifera L.). AB - BACKGROUND: The importance of visual sense in Hymenopteran social behavior is suggested by the existence of a Hymenopteran insect-specific neural circuit related to visual processing and the fact that worker honeybee brain changes morphologically according to its foraging experience. To analyze molecular and neural bases that underlie the visual abilities of the honeybees, we used a cDNA microarray to search for gene(s) expressed in a neural cell-type preferential manner in a visual center of the honeybee brain, the optic lobes (OLs). METHODOLOGY/PRINCIPAL FINDINGS: Expression analysis of candidate genes using in situ hybridization revealed two genes expressed in a neural cell-type preferential manner in the OLs. One is a homologue of Drosophila futsch, which encodes a microtubule-associated protein and is preferentially expressed in the monopolar cells in the lamina of the OLs. The gene for another microtubule associated protein, tau, which functionally overlaps with futsch, was also preferentially expressed in the monopolar cells, strongly suggesting the functional importance of these two microtubule-associated proteins in monopolar cells. The other gene encoded a homologue of Misexpression Suppressor of Dominant negative Kinase Suppressor of Ras 2 (MESK2), which might activate Ras/MAPK signaling in Drosophila. MESK2 was expressed preferentially in a subclass of neurons located in the ventral region between the lamina and medulla neuropil in the OLs, suggesting that this subclass is a novel OL neuron type characterized by MESK2-expression. These three genes exhibited similar expression patterns in the worker, drone, and queen brains, suggesting that they function similarly irrespective of the honeybee sex or caste. CONCLUSIONS: Here we identified genes that are expressed in a monopolar cell (Amfutsch and Amtau) or ventral medulla preferential manner (AmMESK2) in insect OLs. These genes may aid in visualizing neurites of monopolar cells and ventral medulla cells, as well as in analyzing the function of these neurons. PMID- 20169066 TI - Modulation of alpha-synuclein aggregation by dopamine analogs. AB - The action of dopamine on the aggregation of the unstructured alpha-synuclein (alpha-syn) protein may be linked to the pathogenesis of Parkinson's disease. Dopamine and its oxidation derivatives may inhibit alpha-syn aggregation by non covalent binding. Exploiting this fact, we applied an integrated computational and experimental approach to find alternative ligands that might modulate the fibrillization of alpha-syn. Ligands structurally and electrostatically similar to dopamine were screened from an established library. Five analogs were selected for in vitro experimentation from the similarity ranked list of analogs. Molecular dynamics simulations showed they were, like dopamine, binding non covalently to alpha-syn and, although much weaker than dopamine, they shared some of its binding properties. In vitro fibrillization assays were performed on these five dopamine analogs. Consistent with our predictions, analyses by atomic force and transmission electron microscopy revealed that all of the selected ligands affected the aggregation process, albeit to a varying and lesser extent than dopamine, used as the control ligand. The in silico/in vitro approach presented here emerges as a possible strategy for identifying ligands interfering with such a complex process as the fibrillization of an unstructured protein. PMID- 20169067 TI - In vitro induction of Entamoeba histolytica cyst-like structures from trophozoites. AB - Inhibition of encystment can be conceived as a potentially useful mechanism to block the transmission of Entamoeba histolytica under natural conditions. Unfortunately, amoeba encystment has not been achieved in vitro and drugs inhibiting the formation of cysts are not available. Luminal conditions inducing encystment in vivo are also unknown, but cellular stress such as exposure to reactive oxygen species from immune cells or intestinal microbiota could be involved. A role for certain divalent cations as cofactors of enzymes involved in excystment has also been described. In this study, we show that trophozoite cultures, treated with hydrogen peroxide in the presence of trace amounts of several cations, transform into small-sized spherical and refringent structures that exhibit resistance to different detergents. Ultrastructural analysis under scanning and transmission electron microscopy revealed multinucleated structures (some with four nuclei) with smooth, thick membranes and multiple vacuoles. Staining with calcofluor white, as well as an ELISA binding assay using wheat germ agglutinin, demonstrated the presence of polymers of N-acetylglucosamine (chitin), which is the primary component of the natural cyst walls. Over expression of glucosamine 6-phosphate isomerase, likely to be the rate-limiting enzyme in the chitin synthesis pathway, was also confirmed by RT-PCR. These results suggest that E. histolytica trophozoites activated encystment pathways when exposed to our treatment. PMID- 20169068 TI - Delayed onset of positive feedback activation of Rab5 by Rabex-5 and Rabaptin-5 in endocytosis. AB - BACKGROUND: Rabex-5 is a guanine nucleotide exchange factor (GEF) that specifically activates Rab5, i.e., converting Rab5-GDP to Rab5-GTP, through two distinct pathways to promote endosome fusion and endocytosis. The direct pathway involves a pool of membrane-associated Rabex-5 that targets to the membrane via an early endosomal targeting (EET) domain. The indirect pathway, on the other hand, involves a cytosolic pool of Rabex-5/Rabaptin-5 complex. The complex is recruited to the membrane via Rabaptin-5 binding to Rab5-GTP, suggesting a positive feedback mechanism. The relationship of these two pathways for Rab5 activation in the cell is unclear. METHODOLOGY/PRINCIPAL FINDINGS: We dissect the relative contribution of each pathway to Rab5 activation via mathematical modeling and kinetic analysis in the cell. These studies show that the indirect pathway constitutes a positive feedback loop for converting Rab5-GDP to Rab5-GTP on the endosomal membrane and allows sensitive regulation of endosome fusion activity by the levels of Rab5 and Rabex-5 in the cell. The onset of this positive feedback effect, however, contains a threshold, which requires above endogenous levels of Rab5 or Rabex-5 in the cell. We term this novel phenomenon "delayed response". The presence of the direct pathway reduces the delay by increasing the basal level of Rab5-GTP, thus facilitates the function of the Rabex-5/Rabaptin-5-mediated positive feedback loop. CONCLUSION: Our data support the mathematical model. With the model's guidance, the data reveal the affinity of Rabex-5/Rabaptin-5/Rab5-GTP interaction in the cell, which is quantitatively related to the Rabex-5 concentration for the onset of the indirect positive feedback pathway. The presence of the direct pathway and increased Rab5 concentration can reduce the Rabex-5 concentration required for the onset of the positive feedback loop. Thus the direct and indirect pathways cooperate in the regulation of early endosome fusion. PMID- 20169069 TI - Gene expression prediction by soft integration and the elastic net-best performance of the DREAM3 gene expression challenge. AB - BACKGROUND: To predict gene expressions is an important endeavour within computational systems biology. It can both be a way to explore how drugs affect the system, as well as providing a framework for finding which genes are interrelated in a certain process. A practical problem, however, is how to assess and discriminate among the various algorithms which have been developed for this purpose. Therefore, the DREAM project invited the year 2008 to a challenge for predicting gene expression values, and here we present the algorithm with best performance. METHODOLOGY/PRINCIPAL FINDINGS: We develop an algorithm by exploring various regression schemes with different model selection procedures. It turns out that the most effective scheme is based on least squares, with a penalty term of a recently developed form called the "elastic net". Key components in the algorithm are the integration of expression data from other experimental conditions than those presented for the challenge and the utilization of transcription factor binding data for guiding the inference process towards known interactions. Of importance is also a cross-validation procedure where each form of external data is used only to the extent it increases the expected performance. CONCLUSIONS/SIGNIFICANCE: Our algorithm proves both the possibility to extract information from large-scale expression data concerning prediction of gene levels, as well as the benefits of integrating different data sources for improving the inference. We believe the former is an important message to those still hesitating on the possibilities for computational approaches, while the latter is part of an important way forward for the future development of the field of computational systems biology. PMID- 20169070 TI - The dynamics of transmission and spatial distribution of malaria in riverside areas of Porto Velho, Rondonia, in the Amazon region of Brazil. AB - The study area in Rondonia was the site of extensive malaria epidemic outbreaks in the 19(th) and 20(th) centuries related to environmental impacts, with large immigration flows. The present work analyzes the transmission dynamics of malaria in these areas to propose measures for avoiding epidemic outbreaks due to the construction of two Hydroelectric Power Plants. A population based baseline demographic census and a malaria prevalence follow up were performed in two river side localities in the suburbs of Porto Velho city and in its rural vicinity. The quantification and nature of malaria parasites in clinical patients and asymptomatic parasite carriers were performed using microscopic and Real Time PCR methodologies. Anopheles densities and their seasonal variation were done by monthly captures for defining HBR (hourly biting rate) values. MAIN RESULTS: (i) malaria among residents show the riverside profile, with population at risk represented by children and young adults; (ii) asymptomatic vivax and falciparum malaria parasite carriers correspond to around 15% of adults living in the area; (iii) vivax malaria relapses were responsible for 30% of clinical cases; (iv) malaria risk for the residents was evaluated as 20-25% for vivax and 5-7% for falciparum malaria; (v) anopheline densities shown outdoors HBR values 5 to 10 fold higher than indoors and reach 10.000 bites/person/year; (vi) very high incidence observed in one of the surveyed localities was explained by a micro epidemic outbreak affecting visitors and temporary residents. Temporary residents living in tents or shacks are accessible to outdoors transmission. Seasonal fishermen were the main group at risk in the study and were responsible for a 2.6 fold increase in the malaria incidence in the locality. This situation illustrates the danger of extensive epidemic outbreaks when thousands of workers and secondary immigrant population will arrive attracted by opportunities opened by the Hydroelectric Power Plants constructions. PMID- 20169071 TI - The smallest known genomes of multicellular and toxic cyanobacteria: comparison, minimal gene sets for linked traits and the evolutionary implications. AB - Cyanobacterial morphology is diverse, ranging from unicellular spheres or rods to multicellular structures such as colonies and filaments. Multicellular species represent an evolutionary strategy to differentiate and compartmentalize certain metabolic functions for reproduction and nitrogen (N(2)) fixation into specialized cell types (e.g. akinetes, heterocysts and diazocytes). Only a few filamentous, differentiated cyanobacterial species, with genome sizes over 5 Mb, have been sequenced. We sequenced the genomes of two strains of closely related filamentous cyanobacterial species to yield further insights into the molecular basis of the traits of N(2) fixation, filament formation and cell differentiation. Cylindrospermopsis raciborskii CS-505 is a cylindrospermopsin producing strain from Australia, whereas Raphidiopsis brookii D9 from Brazil synthesizes neurotoxins associated with paralytic shellfish poisoning (PSP). Despite their different morphology, toxin composition and disjunct geographical distribution, these strains form a monophyletic group. With genome sizes of approximately 3.9 (CS-505) and 3.2 (D9) Mb, these are the smallest genomes described for free-living filamentous cyanobacteria. We observed remarkable gene order conservation (synteny) between these genomes despite the difference in repetitive element content, which accounts for most of the genome size difference between them. We show here that the strains share a specific set of 2539 genes with >90% average nucleotide identity. The fact that the CS-505 and D9 genomes are small and streamlined compared to those of other filamentous cyanobacterial species and the lack of the ability for heterocyst formation in strain D9 allowed us to define a core set of genes responsible for each trait in filamentous species. We presume that in strain D9 the ability to form proper heterocysts was secondarily lost together with N(2) fixation capacity. Further comparisons to all available cyanobacterial genomes covering almost the entire evolutionary branch revealed a common minimal gene set for each of these cyanobacterial traits. PMID- 20169072 TI - Soluble erythropoietin receptor contributes to erythropoietin resistance in end stage renal disease. AB - BACKGROUND: Erythropoietin is a growth factor commonly used to manage anemia in patients with chronic kidney disease. A significant clinical challenge is relative resistance to erythropoietin, which leads to use of successively higher erythropoietin doses, failure to achieve target hemoglobin levels, and increased risk of adverse outcomes. Erythropoietin acts through the erythropoietin receptor (EpoR) present in erythroblasts. Alternative mRNA splicing produces a soluble form of EpoR (sEpoR) found in human blood, however its role in anemia is not known. METHODS AND FINDINGS: Using archived serum samples obtained from subjects with end stage kidney disease we show that sEpoR is detectable as a 27kDa protein in the serum of dialysis patients, and that higher serum sEpoR levels correlate with increased erythropoietin requirements. Soluble EpoR inhibits erythropoietin mediated signal transducer and activator of transcription 5 (Stat5) phosphorylation in cell lines expressing EpoR. Importantly, we demonstrate that serum from patients with elevated sEpoR levels blocks this phosphorylation in ex vivo studies. Finally, we show that sEpoR is increased in the supernatant of a human erythroleukaemia cell line when stimulated by inflammatory mediators such as interleukin-6 and tumor necrosis factor alpha implying a link between inflammation and erythropoietin resistance. CONCLUSIONS: These observations suggest that sEpoR levels may contribute to erythropoietin resistance in end stage renal disease, and that sEpoR production may be mediated by pro inflammatory cytokines. PMID- 20169073 TI - Alterations in adenosine metabolism and signaling in patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. AB - BACKGROUND: Adenosine is generated in response to cellular stress and damage and is elevated in the lungs of patients with chronic lung disease. Adenosine signaling through its cell surface receptors serves as an amplifier of chronic lung disorders, suggesting adenosine-based therapeutics may be beneficial in the treatment of lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Previous studies in mouse models of chronic lung disease demonstrate that the key components of adenosine metabolism and signaling are altered. Changes include an up-regulation of CD73, the major enzyme of adenosine production and down-regulation of adenosine deaminase (ADA), the major enzyme for adenosine metabolism. In addition, adenosine receptors are elevated. METHODOLOGY/PRINCIPAL FINDINGS: The focus of this study was to utilize tissues from patients with COPD or IPF to examine whether changes in purinergic metabolism and signaling occur in human disease. Results demonstrate that the levels of CD73 and A(2B)R are elevated in surgical lung biopsies from severe COPD and IPF patients. Immunolocalization assays revealed abundant expression of CD73 and the A(2B)R in alternatively activated macrophages in both COPD and IPF samples. In addition, mediators that are regulated by the A(2B)R, such as IL-6, IL-8 and osteopontin were elevated in these samples and activation of the A(2B)R on cells isolated from the airways of COPD and IPF patients was shown to directly induce the production of these mediators. CONCLUSIONS/SIGNIFICANCE: These findings suggest that components of adenosine metabolism and signaling are altered in a manner that promotes adenosine production and signaling in the lungs of patients with COPD and IPF, and provide proof of concept information that these disorders may benefit from adenosine-based therapeutics. Furthermore, this study provides the first evidence that A(2B)R signaling can promote the production of inflammatory and fibrotic mediators in patients with these disorders. PMID- 20169074 TI - Hsp60 is actively secreted by human tumor cells. AB - BACKGROUND: Hsp60, a Group I mitochondrial chaperonin, is classically considered an intracellular chaperone with residence in the mitochondria; nonetheless, in the last few years it has been found extracellularly as well as in the cell membrane. Important questions remain pertaining to extracellular Hsp60 such as how generalized is its occurrence outside cells, what are its extracellular functions and the translocation mechanisms that transport the chaperone outside of the cell. These questions are particularly relevant for cancer biology since it is believed that extracellular chaperones, like Hsp70, may play an active role in tumor growth and dissemination. METHODOLOGY/PRINCIPAL FINDINGS: Since cancer cells may undergo necrosis and apoptosis, it could be possible that extracellular Hsps are chiefly the result of cell destruction but not the product of an active, physiological process. In this work, we studied three tumor cells lines and found that they all release Hsp60 into the culture media by an active mechanism independently of cell death. Biochemical analyses of one of the cell lines revealed that Hsp60 secretion was significantly reduced, by inhibitors of exosomes and lipid rafts. CONCLUSIONS/SIGNIFICANCE: Our data suggest that Hsp60 release is the result of an active secretion mechanism and, since extracellular release of the chaperone was demonstrated in all tumor cell lines investigated, our observations most likely reflect a general physiological phenomenon, occurring in many tumors. PMID- 20169075 TI - Visualizing interactions along the Escherichia coli twin-arginine translocation pathway using protein fragment complementation. AB - The twin-arginine translocation (Tat) pathway is well known for its ability to export fully folded substrate proteins out of the cytoplasm of gram-negative and gram-positive bacteria. Studies of this mechanism in Escherichia coli have identified numerous transient protein-protein interactions that guide export competent proteins through the Tat pathway. To visualize these interactions, we have adapted bimolecular fluorescence complementation (BiFC) to detect protein protein interactions along the Tat pathway of living cells. Fragments of the yellow fluorescent protein (YFP) were fused to soluble and transmembrane factors that participate in the translocation process including Tat substrates, Tat specific proofreading chaperones and the integral membrane proteins TatABC that form the translocase. Fluorescence analysis of these YFP chimeras revealed a wide range of interactions such as the one between the Tat substrate dimethyl sulfoxide reductase (DmsA) and its dedicated proofreading chaperone DmsD. In addition, BiFC analysis illuminated homo- and hetero-oligomeric complexes of the TatA, TatB and TatC integral membrane proteins that were consistent with the current model of translocase assembly. In the case of TatBC assemblies, we provide the first evidence that these complexes are co-localized at the cell poles. Finally, we used this BiFC approach to capture interactions between the putative Tat receptor complex formed by TatBC and the DmsA substrate or its dedicated chaperone DmsD. Our results demonstrate that BiFC is a powerful approach for studying cytoplasmic and inner membrane interactions underlying bacterial secretory pathways. PMID- 20169076 TI - Increased phosphorylation of vimentin in noninfiltrative meningiomas. AB - BACKGROUND: Tissue invasion or tissue infiltration are clinical behaviors of a poor-prognosis subset of meningiomas. We carried out proteomic analyses of tissue extracts to discover new markers to accurately distinguish between infiltrative and noninfiltrative meningiomas. METHODOLOGY/PRINCIPAL FINDINGS: Protein lysates of 64 different tissue samples (including two brain-invasive and 32 infiltrative tumors) were submitted to SELDI-TOF mass spectrometric analysis. Mass profiles were used to build up both unsupervised and supervised hierarchical clustering. One marker was found at high levels in noninvasive and noninfiltrative tumors and appeared to be a discriminative marker for clustering infiltrative and/or invasive meningiomas versus noninvasive meningiomas in two distinct subsets. Sensitivity and specificity were 86.7% and 100%, respectively. This marker was purified and identified as a multiphosphorylated form of vimentin, a cytoskeletal protein expressed in meningiomas. CONCLUSIONS/SIGNIFICANCE: Specific forms of vimentin can be surrogate molecular indicators of the invasive/infiltrative phenotype in tumors. PMID- 20169077 TI - Explicit logic circuits predict local properties of the neocortex's physiology and anatomy. AB - BACKGROUND: Two previous articles proposed an explicit model of how the brain processes information by its organization of synaptic connections. The family of logic circuits was shown to generate neural correlates of complex psychophysical phenomena in different sensory systems. METHODOLOGY/PRINCIPAL FINDINGS: Here it is shown that the most cost-effective architectures for these networks produce correlates of electrophysiological brain phenomena and predict major aspects of the anatomical structure and physiological organization of the neocortex. The logic circuits are markedly efficient in several respects and provide the foundation for all of the brain's combinational processing of information. CONCLUSIONS/SIGNIFICANCE: At the local level, these networks account for much of the physical structure of the neocortex as well its organization of synaptic connections. Electronic implementations of the logic circuits may be more efficient than current electronic logic arrays in generating both Boolean and fuzzy logic. PMID- 20169078 TI - Carboxy terminal tail of polycystin-1 regulates localization of TSC2 to repress mTOR. AB - Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited renal disorder caused by defects in the PKD1 or PKD2 genes. ADPKD is associated with significant morbidity, and is a major underlying cause of end-stage renal failure (ESRF). Commonly, treatment options are limited to the management of hypertension, cardiovascular risk factors, dialysis, and transplantation when ESRF develops, although several new pharmacotherapies, including rapamycin, have shown early promise in animal and human studies. Evidence implicates polycystin-1 (PC-1), the gene product of the PKD1 gene, in regulation of the mTOR pathway. Here we demonstrate a mechanism by which the intracellular, carboxy-terminal tail of polycystin-1 (CP1) regulates mTOR signaling by altering the subcellular localization of the tuberous sclerosis complex 2 (TSC2) tumor suppressor, a gatekeeper for mTOR activity. Phosphorylation of TSC2 at S939 by AKT causes partitioning of TSC2 away from the membrane, its GAP target Rheb, and its activating partner TSC1 to the cytosol via 14-3-3 protein binding. We found that TSC2 and a C-terminal polycystin-1 peptide (CP1) directly interact and that a membrane-tethered CP1 protects TSC2 from AKT phosphorylation at S939, retaining TSC2 at the membrane to inhibit the mTOR pathway. CP1 decreased binding of 14-3-3 proteins to TSC2 and increased the interaction between TSC2 and its activating partner TSC1. Interestingly, while membrane tethering of CP1 was required to activate TSC2 and repress mTOR, the ability of CP1 to inhibit mTOR signaling did not require primary cilia and was independent of AMPK activation. These data identify a unique mechanism for modulation of TSC2 repression of mTOR signaling via membrane retention of this tumor suppressor, and identify PC-1 as a regulator of this downstream component of the PI3K signaling cascade. PMID- 20169079 TI - FoxM1, a forkhead transcription factor is a master cell cycle regulator for mouse mature T cells but not double positive thymocytes. AB - FoxM1 is a forkhead box transcription factor and a known master regulator required for different phases of the cell cycle. In cell lines, FoxM1 deficient cells exhibit delayed S phase entry, aneuploidy, polyploidy and can't complete mitosis. In vivo, FoxM1 is expressed mostly in proliferating cells but is surprisingly also found in non-proliferating CD4(+)CD8(+) double positive thymocytes. Here, we addressed the role of FoxM1 in T cell development by generating and analyzing two different lines of T-cell specific FoxM1 deficient mice. As expected, FoxM1 is required for proliferation of early thymocytes and activated mature T cells. Defective expression of many cell cycle proteins was detected, including cyclin A, cyclin B1, cdc2, cdk2, p27 and the Rb family members p107 and p130 but surprisingly not survivin. Unexpectedly, loss of FoxM1 only affects a few cell cycle proteins in CD4(+)CD8(+) thymocytes and has little effect on their sensitivity to apoptosis and the subsequent steps of T cell differentiation. Thus, regulation of cell cycle genes by FoxM1 is stage- and context-dependent. PMID- 20169080 TI - Primary and secondary rewards differentially modulate neural activity dynamics during working memory. AB - BACKGROUND: Cognitive control and working memory processes have been found to be influenced by changes in motivational state. Nevertheless, the impact of different motivational variables on behavior and brain activity remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: The current study examined the impact of incentive category by varying on a within-subjects basis whether performance during a working memory task was reinforced with either secondary (monetary) or primary (liquid) rewards. The temporal dynamics of motivation-cognition interactions were investigated by employing an experimental design that enabled isolation of sustained and transient effects. Performance was dramatically and equivalently enhanced in each incentive condition, whereas neural activity dynamics differed between incentive categories. The monetary reward condition was associated with a tonic activation increase in primarily right-lateralized cognitive control regions including anterior prefrontal cortex (PFC), dorsolateral PFC, and parietal cortex. In the liquid condition, the identical regions instead showed a shift in transient activation from a reactive control pattern (primary probe-based activation) during no-incentive trials to proactive control (primary cue-based activation) during rewarded trials. Additionally, liquid-specific tonic activation increases were found in subcortical regions (amygdala, dorsal striatum, nucleus accumbens), indicating an anatomical double dissociation in the locus of sustained activation. CONCLUSIONS/SIGNIFICANCE: These different activation patterns suggest that primary and secondary rewards may produce similar behavioral changes through distinct neural mechanisms of reinforcement. Further, our results provide new evidence for the flexibility of cognitive control, in terms of the temporal dynamics of activation. PMID- 20169081 TI - Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile. AB - In recent years it has become clear that the therapeutic properties of bone marrow-derived mesenchymal stromal cells (MSC) are related not only to their ability to differentiate into different lineages but also to their capacity to suppress the immune response. We here studied the influence of MSC on macrophage function. Using mouse thioglycolate-elicited peritoneal macrophages (M) stimulated with LPS, we found that MSC markedly suppressed the production of the inflammatory cytokines TNF-alpha, IL-6, IL-12p70 and interferon-gamma while increased the production of IL-10 and IL-12p40. Similar results were observed using supernatants from MSC suggesting that factor(s) constitutively released by MSC are involved. Supporting a role for PGE(2) we observed that acetylsalicylic acid impaired the ability of MSC to inhibit the production of inflammatory cytokines and to stimulate the production of IL-10 by LPS-stimulated M. Moreover, we found that MSC constitutively produce PGE2 at levels able to inhibit the production of TNF-alpha and IL-6 by activated M. MSC also inhibited the up regulation of CD86 and MHC class II in LPS-stimulated M impairing their ability to activate antigen-specific T CD4+ cells. On the other hand, they stimulated the uptake of apoptotic thymocytes by M. Of note, MSC turned M into cells highly susceptible to infection with the parasite Trypanosoma cruzi increasing more than 5-fold the rate of M infection. Using a model of inflammation triggered by s.c. implantation of glass cylinders, we found that MSC stimulated the recruitment of macrophages which showed a low expression of CD86 and the MHC class II molecule Ia(b) and a high ability to produce IL-10 and IL-12p40, but not IL-12 p70. In summary, our results suggest that MSC switch M into a regulatory profile characterized by a low ability to produce inflammatory cytokines, a high ability to phagocyte apoptotic cells, and a marked increase in their susceptibility to infection by intracellular pathogens. PMID- 20169082 TI - Establishment of a mouse model with misregulated chromosome condensation due to defective Mcph1 function. AB - Mutations in the human gene MCPH1 cause primary microcephaly associated with a unique cellular phenotype with premature chromosome condensation (PCC) in early G2 phase and delayed decondensation post-mitosis (PCC syndrome). The gene encodes the BRCT-domain containing protein microcephalin/BRIT1. Apart from its role in the regulation of chromosome condensation, the protein is involved in the cellular response to DNA damage. We report here on the first mouse model of impaired Mcph1-function. The model was established based on an embryonic stem cell line from BayGenomics (RR0608) containing a gene trap in intron 12 of the Mcph1 gene deleting the C-terminal BRCT-domain of the protein. Although residual wild type allele can be detected by quantitative real-time PCR cell cultures generated from mouse tissues bearing the homozygous gene trap mutation display the cellular phenotype of misregulated chromosome condensation that is characteristic for the human disorder, confirming defective Mcph1 function due to the gene trap mutation. While surprisingly the DNA damage response (formation of repair foci, chromosomal breakage, and G2/M checkpoint function after irradiation) appears to be largely normal in cell cultures derived from Mcph1(gt/gt) mice, the overall survival rates of the Mcph1(gt/gt) animals are significantly reduced compared to wild type and heterozygous mice. However, we could not detect clear signs of premature malignant disease development due to the perturbed Mcph1 function. Moreover, the animals show no obvious physical phenotype and no reduced fertility. Body and brain size are within the range of wild type controls. Gene expression on RNA and protein level did not reveal any specific pattern of differentially regulated genes. To the best of our knowledge this represents the first mammalian transgenic model displaying a defect in mitotic chromosome condensation and is also the first mouse model for impaired Mcph1-function. PMID- 20169083 TI - Avian magnetoreception: elaborate iron mineral containing dendrites in the upper beak seem to be a common feature of birds. AB - The magnetic field sensors enabling birds to extract orientational information from the Earth's magnetic field have remained enigmatic. Our previously published results from homing pigeons have made us suggest that the iron containing sensory dendrites in the inner dermal lining of the upper beak are a candidate structure for such an avian magnetometer system. Here we show that similar structures occur in two species of migratory birds (garden warbler, Sylvia borin and European robin, Erithacus rubecula) and a non-migratory bird, the domestic chicken (Gallus gallus). In all these bird species, histological data have revealed dendrites of similar shape and size, all containing iron minerals within distinct subcellular compartments of nervous terminals of the median branch of the Nervus ophthalmicus. We also used microscopic X-ray absorption spectroscopy analyses to identify the involved iron minerals to be almost completely Fe III-oxides. Magnetite (Fe II/III) may also occur in these structures, but not as a major Fe constituent. Our data suggest that this complex dendritic system in the beak is a common feature of birds, and that it may form an essential sensory basis for the evolution of at least certain types of magnetic field guided behavior. PMID- 20169086 TI - DSC Study of Collagen in Disc Disease. AB - Differential scanning calorimetry (DSC) has been used to estimate the effect of disc disease on the collagen helix-coil transition and morphology for tissue extracted from patients during surgical operation. Forty discs were obtained from patients with degenerative disc disease undergoing surgery for low back pain. The patients were in the age between 20 and 70 years old. The specimens were kept wet during DSC experiment. The data allow the comparison between thermal stability of collagen tissue from healthy patients and from patients suffering from disc disease. In the paper the comparison between thermal helix-coil transition for collagen fibers from patients suffering from disc disease and collagen fibers from healthy organisms has been discussed. The heating rate has an influence on the position on denaturation temperatures of collagen in disc tissues. Higher helix-coil transition temperature of collagen in degenerated disc suggests that additional intermolecular cross linking of collagen fibers occurs. Denaturation temperatures of collagen in degenerated male disc possess smaller values than in female ones. Disc disease induces changes in collagen structure and leads to formation of additional crosslinks between collagen fibers. PMID- 20169084 TI - Selective serotonin reuptake inhibitors potentiate the rapid antidepressant-like effects of serotonin4 receptor agonists in the rat. AB - BACKGROUND: We have recently reported that serotonin(4) (5-HT(4)) receptor agonists have a promising potential as fast-acting antidepressants. Here, we assess the extent to which this property may be optimized by the concomitant use of conventional antidepressants. METHODOLOGY/PRINCIPAL FINDINGS: We found that, in acute conditions, the 5-HT(4) agonist prucalopride was able to counteract the inhibitory effect of the selective serotonin reuptake inhibitors (SSRI) fluvoxamine and citalopram on 5-HT neuron impulse flow, in Dorsal Raphe Nucleus (DRN) cells selected for their high (>1.8 Hz) basal discharge. The co administration of both prucalopride and RS 67333 with citalopram for 3 days elicited an enhancement of DRN 5-HT neuron average firing rate, very similar to what was observed with either 5-HT(4) agonist alone. At the postsynaptic level, this translated into the manifestation of a tonus on hippocampal postsynaptic 5 HT(1A) receptors, that was two to three times stronger when the 5-HT(4) agonist was combined with citalopram. Similarly, co-administration of citalopram synergistically potentiated the enhancing effect of RS 67333 on CREB protein phosphorylation within the hippocampus. Finally, in the Forced Swimming Test, the combination of RS 67333 with various SSRIs (fluvoxamine, citalopram and fluoxetine) was more effective to reduce time of immobility than the separate administration of each compound. CONCLUSIONS/SIGNIFICANCE: These findings strongly suggest that the adjunction of an SSRI to a 5-HT(4) agonist may help to optimize the fast-acting antidepressant efficacy of the latter. PMID- 20169085 TI - Molecular characterisation of trimethoprim resistance in Escherichia coli and Klebsiella pneumoniae during a two year intervention on trimethoprim use. AB - BACKGROUND: Trimethoprim resistance is increasing in Enterobacteriaceae. In 2004 2006 an intervention on trimethoprim use was conducted in Kronoberg County, Sweden, resulting in 85% reduction in trimethoprim prescriptions. We investigated the distribution of dihydrofolate reductase (dfr)-genes and integrons in Escherichia coli and Klebsiella pneumoniae and the effect of the intervention on this distribution. METHODOLOGY/PRINCIPAL FINDINGS: Consecutively isolated E. coli (n = 320) and K. pneumoniae (n = 54) isolates phenotypically resistant to trimethoprim were studied. All were investigated for the presence of dfrA1, dfrA5, dfrA7, dfrA8, dfrA12, dfrA14, dfrA17 and integrons class I and II. Isolates negative for the seven dfr-genes (n = 12) were also screened for dfr2d, dfrA3, dfrA9, dfrA10, dfrA24 and dfrA26. These genes accounted for 96% of trimethoprim resistance in E. coli and 69% in K. pneumoniae. The most prevalent was dfrA1 in both species. This was followed by dfrA17 in E. coli which was only found in one K. pneumoniae isolate. Class I and II Integrons were more common in E. coli (85%) than in K. pneumoniae (57%). The distribution of dfr-genes did not change during the course of the 2-year intervention. CONCLUSIONS/SIGNIFICANCE: The differences observed between the studied species in terms of dfr-gene and integron prevalence indicated a low rate of dfr-gene transfer between these two species and highlighted the possible role of narrow host range plasmids in the spread of trimethoprim resistance. The stability of dfr-genes, despite large changes in the selective pressure, indirectly suggests a low fitness cost of dfr gene carriage. PMID- 20169087 TI - Central venous catheter-associated pericardial tamponade in a 6-day old: a case report. AB - Introduction. Pericardial effusion (PCE) and tamponade can cause significant morbidity and mortality in neonates. Such cases have been reported in the literature in various contexts. Case Presentation. A 6-day old neonate with meconium aspiration syndrome and persistent pulmonary hypertension of newborn on high frequency oscillator ventilation and inhaled nitric oxide was referred to our hospital with a large pericardial effusion causing hemodynamic compromise. Prompt pericardiocentesis led to significant improvement in the cardio respiratory status and removal of the central line prevented the fluid from reaccumulating. Cellular and biochemical analysis aided in the diagnosis of catheter related etiology with possibility of infusate diffusion into the pericardial space. Conclusion. We present this paper to emphasize the importance of recognizing this uncommon but serious complication of central venous catheters in intensive care units. We also discuss the proposed hypothesis for the mechanism of production of PCE. PMID- 20169089 TI - Ileocecal intussusception with histomorphological features of inflammatory neuropathy in adenovirus infection. AB - The pathophysiological mechanisms for ileocecal intussusception in children with adenovirus infection are not well characterized. Here we demonstrate coincidence of adenovirus infection and inflammatory neuropathy of myenteric plexus in two children with ileocecal intussusception. Inflammatory neuropathy, an unspecific morphological feature which is found in peristalsis disorders, was morphologically characterized by the influx of CD3 positive lymphocytes in nervous plexus. To our knowledge, this is the first report suggesting peristalsis disorders from inflammatory neuropathy as additional mechanism in the pathophysiological concept of adenovirus-associated ileocecal intussusception. PMID- 20169090 TI - Congenital circumferential constriction band of the abdomen: a case report. AB - We report a case of congenital constriction band of abdomen associated with limb pseudarthrosis. The constriction band around the abdomen, though may cause initial difficulty with ventilation and parental distress, does not interfere with feeding, bowel movements, and growth. It heals spontaneously with supportive treatment though surgery may be needed in some cases. PMID- 20169088 TI - Three-dimensional culture of human embryonic stem cell derived hepatic endoderm and its role in bioartificial liver construction. AB - The liver carries out a range of functions essential for bodily homeostasis. The impairment of liver functions has serious implications and is responsible for high rates of patient morbidity and mortality. Presently, liver transplantation remains the only effective treatment, but donor availability is a major limitation. Therefore, artificial and bioartificial liver devices have been developed to bridge patients to liver transplantation. Existing support devices improve hepatic encephalopathy to a certain extent; however their usage is associated with side effects. The major hindrance in the development of bioartificial liver devices and cellular therapies is the limited availability of human hepatocytes. Moreover, primary hepatocytes are difficult to maintain and lose hepatic identity and function over time even with sophisticated tissue culture media. To overcome this limitation, renewable cell sources are being explored. Human embryonic stem cells are one such cellular resource and have been shown to generate a reliable and reproducible supply of human hepatic endoderm. Therefore, the use of human embryonic stem cell-derived hepatic endoderm in combination with tissue engineering has the potential to pave the way for the development of novel bioartificial liver devices and predictive drug toxicity assays. PMID- 20169091 TI - Single Balloon Enteroscopy-Assisted ERCP Using Rendezvous Technique for Sharp Angulation of Roux-en-Y Limb in a Patient with Bile Duct Stones. AB - The acute angulation of Roux-en-Y (R-Y) limb precludes endoscopic access for endoscopic retrograde cholangiopancreatography (ERCP) even using a balloon enteroscopy. Here, we describe a case of successful single balloon enteroscopy (SBE)-assisted ERCP using a rendezvous technique in a patient with sharply angulated R-Y limb in a 79-year-old woman who had bile duct stones. Method. At first, a guidewire was passed antegradely through the major papilla after the needle puncture using percutaneous transhepatic biliary drainage technique. A hydrophilic guidewire with an ERCP catheter was antegradely advanced beyond the Roux limb. After a guidewire was firmly grasped by a snare forceps, it was pulled out of the body, resulting that the enteroscope could advance to the papilla. After papillary dilation, complete removal of bile duct stones was achieved without any procedure-related complication. In conclusion, although further study is needed, SBE-assisted ERCP using a rendezvous technique may have a potential for selected patients. PMID- 20169092 TI - ATP-Binding Cassette Systems of Brucella. AB - Brucellosis is a prevalent zoonotic disease and is endemic in the Middle East, South America, and other areas of the world. In this study, complete inventories of putative functional ABC systems of five Brucella species have been compiled and compared. ABC systems of Brucella melitensis 16M, Brucella abortus 9-941, Brucella canis RM6/66, Brucella suis 1330, and Brucella ovis 63/290 were identified and aligned. High numbers of ABC systems, particularly nutrient importers, were found in all Brucella species. However, differences in the total numbers of ABC systems were identified (B. melitensis, 79; B. suis, 72; B. abortus 64; B. canis, 74; B. ovis, 59) as well as specific differences in the functional ABC systems of the Brucella species. Since B. ovis is not known to cause human brucellosis, functional ABC systems absent in the B. ovis genome may represent virulence factors in human brucellosis. PMID- 20169093 TI - Influence of melatonin on cerebrovascular proinflammatory mediators expression and oxidative stress following subarachnoid hemorrhage in rabbits. AB - The aim of this study is to analyze whether melatonin administration influenced the nuclear factor-kappa B (NF-kappaB) activity, proinflammatory cytokines expression, and oxidative response in the basilar artery after SAH. A total of 48 rabbits were randomly divided into four groups: control group, SAH group, SAH + vehicle group, and SAH + melatonin group. All SAH animals were subjected to injection of autologous blood into cisterna magna twice on day 0 and day 2. The melatonin was administered intraperitoneally at a dose of 5 mg/kg/12 h simultaneously with SAH from day 0 to day 5. The basilar arteries were extracted on day 5 after SAH. As a result, we found that vascular inflammation and oxidative stress were induced in all SAH animals. In animals given melatonin, basilar arterial NF-kappaB and pro-inflammatory cytokines were decreased in comparison to vehicle-treated animals. Measures of oxidative stress also showed significant downregulation after melatonin treatment. Furthermore, administration of melatonin prevented vasospasm on day 5 following SAH. In conclusion, post-SAH melatonin administration may attenuate inflammatory response and oxidative stress in the spasmodic artery, and this may be one mechanism involved in the therapeutic effect of melatonin on the subsequent vasospasm after SAH. PMID- 20169095 TI - Duplication cyst of the sigmoid colon. AB - A 21-year-old male with developmental delay presented with abdominal pain of two days' duration. He was afebrile and his abdomen was soft with mild diffuse tenderness. There were no peritoneal signs. Plain x-ray demonstrated a large air filled structure in the right upper quadrant. Computed tomography of the abdomen revealed a 9 x 8 cm structure adjacent to the hepatic flexure containing an air fluid level. It did not contain oral contrast and had no apparent communication with the colon. At operation, the cystic lesion was identified as a duplication cyst of the sigmoid colon that was adherent to the right upper quadrant. The cyst was excised with a segment of the sigmoid colon and a stapled colo-colostomy was performed. Recovery was uneventful. Final pathology was consistent with a duplication cyst of the sigmoid colon. The cyst was attached to the colon but did not communicate with the lumen. PMID- 20169094 TI - Epidemiology of HPV in HIV-positive and HIV-negative fertile women in Cameroon, West Africa. AB - BACKGROUND: HPV types vary by country and HIV status. There are no data on the prevalent HPV genotypes from Cameroon. METHODS: We conducted a cross-sectional, observational study on 65 Cameroonian women. Samples were sent for HPV genotyping and Thin Prep analyses. RESULTS: 41 out of 61 samples tested (67.2%) had HPV subtypes detected. The most common high risk types encountered were: 45 (24.6%) and 58 (21.5%). HIV-positive women were more likely to test positive for any HPV (P = .014), have more than one HPV subtype (P = .003), and to test positive for the high risk subtypes (P = .007). Of those with high risk HPV, HIV-positive women were more likely to have Thin Prep abnormalities than HIV-negative women (P = .013). CONCLUSIONS: Oncogenic HPV subtypes 45 and 58 were more prevalent than those subtypes carried in the quadrivalent vaccine. Further studies are needed to assess whether the current vaccine will be effective in this region. PMID- 20169096 TI - Decoupling action potential bias from cortical local field potentials. AB - Neurophysiologists have recently become interested in studying neuronal population activity through local field potential (LFP) recordings during experiments that also record the activity of single neurons. This experimental approach differs from early LFP studies because it uses high impedence electrodes that can also isolate single neuron activity. A possible complication for such studies is that the synaptic potentials and action potentials of the small subset of isolated neurons may contribute disproportionately to the LFP signal, biasing activity in the larger nearby neuronal population to appear synchronous and cotuned with these neurons. To address this problem, we used linear filtering techniques to remove features correlated with spike events from LFP recordings. This filtering procedure can be applied for well-isolated single units or multiunit activity. We illustrate the effects of this correction in simulation and on spike data recorded from primary auditory cortex. We find that local spiking activity can explain a significant portion of LFP power at most recording sites and demonstrate that removing the spike-correlated component can affect measurements of auditory tuning of the LFP. PMID- 20169097 TI - Biochanin A Modulates Cell Viability, Invasion, and Growth Promoting Signaling Pathways in HER-2-Positive Breast Cancer Cells. AB - Overexpression of HER-2 receptor is associated with poor prognosis and aggressive forms of breast cancer. Scientific literature indicates a preventive role of isoflavones in cancer. Since activation of HER-2 receptor initiates growth promoting events in cancer cells, we studied the effect of biochanin A (an isoflavone) on associated signaling events like receptor activation, downstream signaling, and invasive pathways. HER-2-positive SK-BR-3 breast cancer cells, MCF 10A normal breast epithelial cells, and NIH-3T3 normal fibroblast cells were treated with biochanin A (2-100 muM) for 72 hours. Subsequently cell viability assay, western blotting and zymography were carried out. The data indicate that biochanin A inhibits cell viability, signaling pathways, and invasive enzyme expression and activity in SK-BR-3 cancer cells. Biochanin A did not inhibit MCF 10A and NIH-3T3 cell viability. Therefore, biochanin A could be a unique natural anticancer agent which can selectively target cancer cells and inhibit multiple signaling pathways in HER-2-positive breast cancer cells. PMID- 20169098 TI - Hypoxia-inducible factor-1 as a therapeutic target in endometrial cancer management. AB - In the Western world, endometrial cancer (EC) is the most common malignant tumor of the female genital tract. Solid tumors like EC outgrow their vasculature resulting in hypoxia. Tumor hypoxia is important because it renders an aggressive phenotype and leads to radio- and chemo-therapy resistance. Hypoxia-inducible factor-1alpha (HIF-1alpha) plays an essential role in the adaptive cellular response to hypoxia and is associated with poor clinical outcome in EC. Therefore, HIF-1 could be an attractive therapeutic target. Selective HIF-1 inhibitors have not been identified. A number of nonselective inhibitors which target signaling pathways upstream or downstream HIF-1 are known to decrease HIF 1alpha protein levels. In clinical trials for the treatment of advanced and/or recurrent EC are the topoisomerase I inhibitor Topotecan, mTOR-inhibitor Rapamycin, and angiogenesis inhibitor Bevacizumab. Preliminary data shows encouraging results for these agents. Further work is needed to identify selective HIF-1 inhibitors and to translate these into clinical trials. PMID- 20169099 TI - Granular cell tumours: a rare entity in the musculoskeletal system. AB - Granular Cell Tumours are rare mesenchymal soft tissue tumours that arise throughout the body and are believed to be of neural origin. They often present as asymptomatic, slow-growing, benign, solitary lesions but may be multifocal. 1 2% of cases are malignant and can metastasise. Described series in the literature are sparse. We identified eleven cases in ten patients treated surgically and followed-up for a period of over 6 years in our regional bone and soft tissue tumour centre. Five tumours were located in the lower limb, four in the upper limb, and two in the trunk. Mean patient age was 31.2 years (range 8-55 years). Excision was complete in one case, marginal in five cases and intralesional in five cases. No patients required postoperative adjuvant treatment. Mean follow-up was 19.3 months (range 1-37 months). One case was multifocal, but there were no cases of local recurrence or malignancy. Histopathological and immunohistochemical analysis revealed the classical granular cell tumour features in all cases. We believe this case series to be the largest of its type in patients presenting to an orthopaedic soft tissue tumour unit. We present our findings and correlate them with findings of other series in the literature. PMID- 20169101 TI - Long-term follow-up of flexible bronchoscopic treatment for bronchial carcinoids with curative intent. AB - Background. Typical pulmonary carcinoids represent less than 5% of primary lung tumors. In patients with typical bronchial carcinoid, formal surgical resection still remains the gold-standard treatment. Data regarding long-term outcome in using flexible bronchoscope-based modalities under conscious sedation is very limited. Objectives. We sought to investigate, over extended follow-up period, the effectiveness of endobronchial resection for carcinoid tumors with curative intent using flexible bronchoscopy. Methods. Nd:YAG laser photoresection using flexible bronchoscope under conscious sedation. Follow-up included repeat bronchoscopy every 6 months and chest CT every year. Results. Ten patients aged 24 to 70 years with endobronchial carcinoid were treated. The tumor location was variable: 2 left Main bronchus, 1 left upper lobe bronchus, 2 right main bronchus, 2 right middle lobe bronchus and 3 right lower lobe bronchus. No major complications were observed. The patients required between 2 and 4 procedures. Patients were followed for a median period of 29 months with no evidence of tumor recurrence. Conclusions. Endobronchial laser photoresection of typical bronchial carcinoids using flexible bronchsocopy under conscious sedation is an effective treatment modality for a subgroup of patients that provides excellent long-term results that are similar to outcome obtained by more invasive procedures. PMID- 20169100 TI - Parasitic helminths: new weapons against immunological disorders. AB - The prevalence of allergic and autoimmune diseases is increasing in developed countries, possibly due to reduced exposure to microorganisms in childhood (hygiene hypothesis). Epidemiological and experimental evidence in support of this hypothesis is accumulating. In this context, parasitic helminths are now important candidates for antiallergic/anti-inflammatory agents. Here we summarize antiallergic/anti-inflammatory effects of helminths together along with our own study of the effects of Schistosoma mansoni on Th17-dependent experimental arthritis. We also discuss possible mechanisms of helminth-induced suppression according to the recent advances of immunology. PMID- 20169102 TI - Directed fiber outgrowth from transplanted embryonic cortex-derived neurospheres in the adult mouse brain. AB - Neural transplantation has emerged as an attractive strategy for the replacement of neurons that have been lost in the central nervous system. Multipotent neural progenitor cells are potentially useful as donor cells to repopulate the degenerated regions. One important aspect of a transplantation strategy is whether transplanted cells are capable of fiber outgrowth with the aim of rebuilding axonal connections within the host brain. To address this issue, we expanded neuronal progenitor from the cortex of embryonic day 15 ubiquitously green fluorescent protein-expressing transgenic mice as neurospheres in vitro and grafted them into the entorhinal cortex of 8-week-old mice immediately after a perforant pathway lesion. After transplantation into a host brain with a lesion of the entorhino-hippocampal projection, the neurosphere-derived cells extended long fiber projections directed towards the dentate gyrus. Our results indicate that transplantation of neurosphere-derived cells might be a promising strategy to replace lost or damaged axonal projections. PMID- 20169103 TI - Ensemble fractional sensitivity: a quantitative approach to neuron selection for decoding motor tasks. AB - A robust method to help identify the population of neurons used for decoding motor tasks is developed. We use sensitivity analysis to develop a new metric for quantifying the relative contribution of a neuron towards the decoded output, called "fractional sensitivity." Previous model-based approaches for neuron ranking have been shown to largely depend on the collection of training data. We suggest the use of an ensemble of models that are trained on random subsets of trials to rank neurons. For this work, we tested a decoding algorithm on neuronal data recorded from two male rhesus monkeys while they performed a reach to grasp a bar at three orientations (45 degrees, 90 degrees, or 135 degrees). An ensemble approach led to a statistically significant increase of 5% in decoding accuracy and 25% increase in identification accuracy of simulated noisy neurons, when compared to a single model. Furthermore, ranking neurons based on the ensemble fractional sensitivities resulted in decoding accuracies 10%-20% greater than when randomly selecting neurons or ranking based on firing rates alone. By systematically reducing the size of the input space, we determine the optimal number of neurons needed for decoding the motor output. This selection approach has practical benefits for other BMI applications where limited number of electrodes and training datasets are available, but high decoding accuracies are desirable. PMID- 20169104 TI - Prevalence of joint hypermobility and patterns of articular manifestations in patients with inflammatory bowel disease. AB - OBJECTIVE: The objective is the investigation of Joint Hypermobility (JH) and the Hypermobility Syndrome (HMS) in patients with inflammatory bowel disease (IBD). METHODS: We examined 83 patients with IBD and 67 healthy individuals for the presence of JH. Patients were excluded if they were under 18 or over 50 years of age and if they had other conditions which affect joint mobility. The x(2) and the Fisher exact test were used appropriately between study groups. Odds ratios (ORs) for the risk of JH and HMS in IBD groups were calculated. RESULTS: A total of 150 individuals (83 IBD patients and 67 healthy controls) participated in the study. 69 IBD patients, 41 with Crohn's Disease (CD) and 28 with ulcerative colitis (UC), were finally eligible. JH was detected in 29 CD patients (70.7%), in 10 UC patients (35.7%), and in 17 healthy control subjects (25.4%). Significant difference was detected on JH in CD patients as compared to UC patients (P = .0063) and controls (P < .0001). The estimated OR for JH was 7.108 (95% CI: 2.98-16.95) in CD and 1.634 (95% CI: 0.63-4.22) in UC patients. HMS was detected in 5 (12.2%) CD and in 1 (3.57%) UC patients. The OR for HMS in CD was 3.75 (95% CI: 0.41-34.007), while 7 (17.1%) CD patients had overlapping symptoms for both HMS and early spondylarthropathy. CONCLUSIONS: JH and the HMS are common in CD patients, thus articular manifestations should be carefully interpreted. This implies an involvement of collagen varieties in the pathogenesis of IBD. PMID- 20169105 TI - Tumour cell lines HT-29 and FaDu produce proinflammatory cytokines and activate neutrophils in vitro: possible applications for neutrophil-based antitumour treatment. AB - There is evidence that polymorphonuclear neutrophils (PMNs) can exert severe antineoplastic effects. Cross-talk between tumour cells and endothelial cells (ECs) is necessary for the accumulation of PMN around a tumour. This work reports the ability of two PMN-sensitive, human, permanent cell lines-colorectal adenocarcinoma (HT-29) and pharyngeal squamous-cell carcinoma (FaDu) cells-to act as inflammatory foci. PMNs were cytotoxic to both lines, the adhesion of the PMNs to the tumour cells being important in this effect. The tumour cells released appreciable amounts of IL-8 and GROalpha, and induced the transmigration of PMN through human microvascular-EC monolayers. Conditioning media associated with both lines induced the adhesion of PMN and the surface expression of ICAM-1 in microvascular-EC. In addition, FaDu-conditioning-medium strongly induced the production of proinflammatory cytokines by microvascular-EC. These results support the idea that tumour cells might normally induce a potent acute inflammatory response, leading to their own destruction. PMID- 20169106 TI - Peroxisome proliferator-activated receptor (PPAR): balance for survival in parasitic infections. AB - Parasitic infections induce a magnitude of host responses. At the opposite ends of the spectrum are those that ensure the host's needs to eliminate the invaders and to minimize damage to its own tissues. This review analyzes how parasites would manipulate immunity by activating the immunosuppressive nuclear factor, peroxisome proliferator-activated receptors (PPARs) with type 2 cytokines and free fatty acids from arachidonic acid metabolism. PPARs limit the action of type 1 immunity, in which classically activated macrophages act through the production of proinflammatory signals, to spare the parasites. They also favor the development of alternately activated macrophages which control inflammation so the host would not be destroyed. Possibly, the nuclear factors hold a pivotal role in the establishment of chronic infection by delicately balancing the pro- and anti-inflammatory signaling mechanisms and their ligands may be used as combination therapeutics to limit host pathology. PMID- 20169107 TI - Realistic and spherical head modeling for EEG forward problem solution: a comparative cortex-based analysis. AB - The accuracy of forward models for electroencephalography (EEG) partly depends on head tissues geometry and strongly affects the reliability of the source reconstruction process, but it is not yet clear which brain regions are more sensitive to the choice of different model geometry. In this paper we compare different spherical and realistic head modeling techniques in estimating EEG forward solutions from current dipole sources distributed on a standard cortical space reconstructed from Montreal Neurological Institute (MNI) MRI data. Computer simulations are presented for three different four-shell head models, two with realistic geometry, either surface-based (BEM) or volume-based (FDM), and the corresponding sensor-fitted spherical-shaped model. Point Spread Function (PSF) and Lead Field (LF) cross-correlation analyses were performed for 26 symmetric dipole sources to quantitatively assess models' accuracy in EEG source reconstruction. Realistic geometry turns out to be a relevant factor of improvement, particularly important when considering sources placed in the temporal or in the occipital cortex. PMID- 20169108 TI - Analysis of the putative remains of a European patron saint--St. Birgitta. AB - Saint Birgitta (Saint Bridget of Sweden) lived between 1303 and 1373 and was designated one of Europe's six patron saints by the Pope in 1999. According to legend, the skulls of St. Birgitta and her daughter Katarina are maintained in a relic shrine in Vadstena abbey, mid Sweden. The origin of the two skulls was assessed first by analysis of mitochondrial DNA (mtDNA) to confirm a maternal relationship. The results of this analysis displayed several differences between the two individuals, thus supporting an interpretation of the two skulls not being individuals that are maternally related. Because the efficiency of PCR amplification and quantity of DNA suggested a different amount of degradation and possibly a very different age for each of the skulls, an orthogonal procedure, radiocarbon dating, was performed. The radiocarbon dating results suggest an age difference of at least 200 years and neither of the dating results coincides with the period St. Birgitta or her daughter Katarina lived. The relic, thought to originate from St. Birgitta, has an age corresponding to the 13(th) century (1215 1270 cal AD, 2sigma confidence), which is older than expected. Thus, the two different analyses are consistent in questioning the authenticity of either of the human skulls maintained in the Vadstena relic shrine being that of St. Birgitta. Of course there are limitations when interpreting the data of any ancient biological materials and these must be considered for a final decision on the authenticity of the remains. PMID- 20169109 TI - VertNet: a new model for biodiversity data sharing. PMID- 20169110 TI - Synopsis. BIN1: a protein with great heart. PMID- 20169111 TI - BIN1 localizes the L-type calcium channel to cardiac T-tubules. AB - The BAR domain protein superfamily is involved in membrane invagination and endocytosis, but its role in organizing membrane proteins has not been explored. In particular, the membrane scaffolding protein BIN1 functions to initiate T tubule genesis in skeletal muscle cells. Constitutive knockdown of BIN1 in mice is perinatal lethal, which is associated with an induced dilated hypertrophic cardiomyopathy. However, the functional role of BIN1 in cardiomyocytes is not known. An important function of cardiac T-tubules is to allow L-type calcium channels (Cav1.2) to be in close proximity to sarcoplasmic reticulum-based ryanodine receptors to initiate the intracellular calcium transient. Efficient excitation-contraction (EC) coupling and normal cardiac contractility depend upon Cav1.2 localization to T-tubules. We hypothesized that BIN1 not only exists at cardiac T-tubules, but it also localizes Cav1.2 to these membrane structures. We report that BIN1 localizes to cardiac T-tubules and clusters there with Cav1.2. Studies involve freshly acquired human and mouse adult cardiomyocytes using complementary immunocytochemistry, electron microscopy with dual immunogold labeling, and co-immunoprecipitation. Furthermore, we use surface biotinylation and live cell confocal and total internal fluorescence microscopy imaging in cardiomyocytes and cell lines to explore delivery of Cav1.2 to BIN1 structures. We find visually and quantitatively that dynamic microtubules are tethered to membrane scaffolded by BIN1, allowing targeted delivery of Cav1.2 from the microtubules to the associated membrane. Since Cav1.2 delivery to BIN1 occurs in reductionist non-myocyte cell lines, we find that other myocyte-specific structures are not essential and there is an intrinsic relationship between microtubule-based Cav1.2 delivery and its BIN1 scaffold. In differentiated mouse cardiomyocytes, knockdown of BIN1 reduces surface Cav1.2 and delays development of the calcium transient, indicating that Cav1.2 targeting to BIN1 is functionally important to cardiac calcium signaling. We have identified that membrane-associated BIN1 not only induces membrane curvature but can direct specific antegrade delivery of microtubule-transported membrane proteins. Furthermore, this paradigm provides a microtubule and BIN1-dependent mechanism of Cav1.2 delivery to T-tubules. This novel Cav1.2 trafficking pathway should serve as an important regulatory aspect of EC coupling, affecting cardiac contractility in mammalian hearts. PMID- 20169112 TI - Guidance for developers of health research reporting guidelines. AB - David Moher and colleagues from the EQUATOR network offer guidance and recommended steps for developing health research reporting guidelines. PMID- 20169113 TI - Effectiveness of non-nucleoside reverse-transcriptase inhibitor-based antiretroviral therapy in women previously exposed to a single intrapartum dose of nevirapine: a multi-country, prospective cohort study. AB - BACKGROUND: Intrapartum and neonatal single-dose nevirapine (NVP) reduces the risk of mother-to-child HIV transmission but also induces viral resistance to non nucleoside reverse transcriptase inhibitor (NNRTI) drugs. This drug resistance largely fades over time. We hypothesized that women with a prior single-dose NVP exposure would have no more than a 10% higher cumulative prevalence of failure of their NNRTI-containing antiretroviral therapy (ART) over the first 48 wk of therapy than would women without a prior exposure. METHODS AND FINDINGS: We enrolled 355 NVP-exposed and 523 NVP-unexposed women at two sites in Zambia, one site in Kenya, and two sites in Thailand into a prospective, non-inferiority cohort study and followed them for 48 wk on ART. Those who died, discontinued NNRTI-containing ART, or had a plasma viral load >or=400 copies/ml at either the 24 wk or 48 wk study visits and confirmed on repeat testing were characterized as having failed therapy. Overall, 114 of 355 NVP-exposed women (32.1%) and 132 of 523 NVP-unexposed women (25.2%) met criteria for treatment failure. The difference in failure rates between the exposure groups was 6.9% (95% confidence interval [CI] 0.8%-13.0%). The failure rates of women stratified by our predefined exposure interval categories were as follows: 47 of 116 women in whom less than 6 mo elapsed between exposure and starting ART failed therapy (40%; p<0.001 compared to unexposed women); 25 of 67 women in whom 7-12 mo elapsed between exposure and starting ART failed therapy (37%; p = 0.04 compared to unexposed women); and 42 of 172 women in whom more than 12 mo elapsed between exposure and starting ART failed therapy (24%; p = 0.82 compared to unexposed women). Locally weighted regression analysis also indicated a clear inverse relationship between virologic failure and the exposure interval. CONCLUSIONS: Prior exposure to single-dose NVP was associated with an increased risk of treatment failure; however, this risk seems largely confined to women with a more recent exposure. Women requiring ART within 12 mo of NVP exposure should not be prescribed an NNRTI-containing regimen as first-line therapy. PMID- 20169114 TI - Can broader diffusion of value-based insurance design increase benefits from US health care without increasing costs? Evidence from a computer simulation model. AB - BACKGROUND: Evidence suggests that cost sharing (i.e.,copayments and deductibles) decreases health expenditures but also reduces essential care. Value-based insurance design (VBID) has been proposed to encourage essential care while controlling health expenditures. Our objective was to estimate the impact of broader diffusion of VBID on US health care benefits and costs. METHODS AND FINDINGS: We used a published computer simulation of costs and life expectancy gains from US health care to estimate the impact of broader diffusion of VBID. Two scenarios were analyzed: (1) applying VBID solely to pharmacy benefits and (2) applying VBID to both pharmacy benefits and other health care services (e.g., devices). We assumed that cost sharing would be eliminated for high-value services (<$100,000 per life-year), would remain unchanged for intermediate- or unknown-value services ($100,000-$300,000 per life-year or unknown), and would be increased for low-value services (>$300,000 per life-year). All costs are provided in 2003 US dollars. Our simulation estimated that approximately 60% of health expenditures in the US are spent on low-value services, 20% are spent on intermediate-value services, and 20% are spent on high-value services. Correspondingly, the vast majority (80%) of health expenditures would have cost sharing that is impacted by VBID. With prevailing patterns of cost sharing, health care conferred 4.70 life-years at a per-capita annual expenditure of US$5,688. Broader diffusion of VBID to pharmaceuticals increased the benefit conferred by health care by 0.03 to 0.05 additional life-years, without increasing costs and without increasing out-of-pocket payments. Broader diffusion of VBID to other health care services could increase the benefit conferred by health care by 0.24 to 0.44 additional life-years, also without increasing costs and without increasing overall out-of-pocket payments. Among those without health insurance, using cost saving from VBID to subsidize insurance coverage would increase the benefit conferred by health care by 1.21 life-years, a 31% increase. CONCLUSION: Broader diffusion of VBID may amplify benefits from US health care without increasing health expenditures. PMID- 20169116 TI - T-lymphocyte subsets in apparently healthy nigerian children. AB - Population studies showed that there are differences in T-lymphocytes subpopulation of normal children in different regions, and reference values in an area might be different from another. This study compared the values in our population with CDC and WHO reference values. Blood samples from 279 healthy, HIV negative children <12 years of age were analysed for complete blood count, CD3+, CD4+, CD8+ counts and percentages. Except for CD8%, mean values for all parameters measured significantly decreased with age. CD4+ counts were higher in females than males, P < .05. Using the WHO criteria, 15.9% of subjects had low total lymphocyte count and 20.6% had low CD4 count. Children <3 years had median CD4% lower than WHO normal values. Our median CD4+ counts correlated with CDC values. Values used by WHO in infants are higher than ours. We suggest that our children be assessed using CDC reference values which correlate with ours. PMID- 20169115 TI - Detection of Wuchereria bancrofti L3 larvae in mosquitoes: a reverse transcriptase PCR assay evaluating infection and infectivity. AB - BACKGROUND: Detection of filarial DNA in mosquitoes by PCR cannot differentiate infective mosquitoes from infected mosquitoes. In order to evaluate transmission risk an assay is needed that can specifically detect infective L3 stage parasites. We now report the development of an assay that specifically detects the infective stage of Wuchereria bancrofti in mosquitoes. The assay detects an L3-activated mRNA transcript by reverse-transcriptase PCR (RT-PCR). METHODOLOGY/PRINCIPAL FINDINGS: W. bancrofti cuticle-related genes were selected using bioinformatics and screened as potential diagnostic target genes for L3 detection in mosquitoes. Expression profiles were determined using RT-PCR on RNA isolated from mosquitoes collected daily across a two-week period after feeding on infected blood. Conventional multiplex RT-PCR and real-time multiplex RT-PCR assays were developed using an L3-activated cuticlin transcript for L3 detection and a constitutively expressed transcript, tph-1, for 'any-stage' detection. CONCLUSIONS/SIGNIFICANCE: This assay can be used to simultaneously detect W. bancrofti infective stage larvae and 'any-stage' larvae in pooled vector mosquitoes. This test may be useful as a tool for assessing changes in transmission potential in the context of filariasis elimination programs. PMID- 20169117 TI - Mechanisms of ER Stress-Mediated Mitochondrial Membrane Permeabilization. AB - During apoptosis, the process of mitochondrial outer membrane permeabilization (MOMP) represents a point-of-no-return as it commits the cell to death. Here we have assessed the role of caspases, Bcl-2 family members and the mitochondrial permeability transition pore on ER stress-induced MOMP and subsequent cell death. Induction of ER stress leads to upregulation of several genes such as Grp78, Edem1, Erp72, Atf4, Wars, Herp, p58ipk, and ERdj4 and leads to caspase activation, release of mitochondrial intermembrane proteins and dissipation of mitochondrial transmembrane potential (DeltaPsim). Mouse embryonic fibroblasts (MEFs) from caspase-9, -2 and, -3 knock-out mice were resistant to ER stress induced apoptosis which correlated with decreased processing of pro-caspase-3 and -9. Furthermore, pretreatment of cells with caspase inhibitors (Boc-D.fmk and DEVD.fmk) attenuated ER stress-induced loss of DeltaPsim. However, only deficiency of caspase-9 and -2 could prevent ER stress-mediated loss of DeltaPsim. Bcl-2 overexpression or pretreatment of cells with the cell permeable BH4 domain (BH4-Tat) or the mitochondrial permeability transition pore inhibitors, bongkrekic acid or cyclosporine A, attenuated the ER stress-induced loss of DeltaPsim. These data suggest a role for caspase-9 and -2, Bcl-2 family members and the mitochondrial permeability transition pore in loss of mitochondrial membrane potential during ER stress-induced apoptosis. PMID- 20169119 TI - Vitamin d receptor activation mitigates the impact of uremia on endothelial function in the 5/6 nephrectomized rats. AB - Endothelial dysfunction increases cardiovascular disease risk in chronic kidney disease (CKD). This study investigates whether VDR activation affects endothelial function in CKD. The 5/6 nephrectomized (NX) rats with experimental chronic renal insufficiency were treated with or without paricalcitol, a VDR activator. Thoracic aortic rings were precontracted with phenylephrine and then treated with acetylcholine or sodium nitroprusside. Uremia significantly affected aortic relaxation (-50.0 +/- 7.4% in NX rats versus -96.2 +/- 5.3% in SHAM at 30 muM acetylcholine). The endothelial-dependent relaxation was improved to -58.2 +/- 6.0%, -77.5 +/- 7.3%, and -90.5 +/- 4.0% in NX rats treated with paricalcitol at 0.021, 0.042, and 0.083 mug/kg for two weeks, respectively, while paricalcitol at 0.042 mug/kg did not affect blood pressure and heart rate. Parathyroid hormone (PTH) suppression alone did not improve endothelial function since cinacalcet suppressed PTH without affecting endothelial-dependent vasorelaxation. N-omega nitro-L-arginine methyl ester completely abolished the effect of paricalcitol on improving endothelial function. These results demonstrate that VDR activation improves endothelial function in CKD. PMID- 20169118 TI - One year sustainability of risk factor change from a 9-week workplace intervention. AB - We examined the effect of a 9-week diet and physical activity intervention provided in the workplace by a group education session where personal dietary and physical activity goals were proposed. Measurements of anthropometry, fasting blood lipids, glucose and insulin, assays for antioxidant activity (AOA) and questionnaires were completed at 0, 3, 6, 9, and 12 weeks in 50 healthy workers (50% male, mean age 46y). Followup measurements in 39 (56% male) were possible at 52 weeks. At week 3 a group dietary and physical activity "motivational seminar" was held. At week 6, half the group were supplied daily kiwifruit for 3 weeks with cross over at week 9 until week 12. Compared to baseline, lipid, glucose, insulin and AOA measurements were improved at 12 and 52 weeks. Body measurements did not change. Group diet and physical activity advice reinforced over 9 weeks is associated with a sustained improvement in cardiovascular risk factors at 52 weeks. PMID- 20169120 TI - Recent bioinformatics advances in the analysis of high throughput flow cytometry data. PMID- 20169121 TI - Quality, stability, and safety data of packed red cells and plasma processed by gravity separation using a new fully integrated hollow-fibre filter device. AB - Background. We developed a completely closed system based on gravity separation without centrifugation steps for separation of whole blood. With this new system we compared quality and stability of the processed blood components (PRC and plasma) with respect to classical preparation. Furthermore the cost-effectiveness of this hollow fibre system was evaluated. Study Design and Methods. Whole blood collections of 15 regular blood donors were used for component preparation using the U shaped hollow fibre filter device. Results were compared to 15 whole blood preparations using centrifugation. The following parameters were evaluated: total hemoglobin, leukocyte counts, the serum concentration of total protein, lactate dehydrogenase (LDH) and potassium. Furthermore ATIII, vWF and F VIII were analyzed at different timepoints. Results. packed red cells: the data directly after separation and after 42 days of storage are in line with the guidelines of the council of Europe. Plasma. all plasma quality data are in line with the guidelines of the council of Europe for quality assurance of plasma, except for a low protein amount (factor 0.75). Conclusion. Separation of whole blood on a clinical scale in this new closed system is feasible, however the plasma protein content must be optimized. PMID- 20169122 TI - Immunogenetics and the Pathological Mechanisms of Human T-Cell Leukemia VirusType 1- (HTLV-1-)Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). AB - Human T-cell leukemia virus type 1 (HTLV-1) is a replication-competent human retrovirus associated with two distinct types of disease only in a minority of infected individuals: the malignancy known as adult T-cell leukemia (ATL) and a chronic inflammatory central nervous system disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the factors that cause these different manifestations of HTLV-1 infection are not fully understood, accumulating evidence suggests that complex virus-host interactions play an important role in determining the risk of HAM/TSP. This review focuses on the role of the immune response in controlling or limiting viral persistence in HAM/TSP patients, and the reason why some HTLV-1-infected people develop HAM/TSP whereas the majority remains asymptomatic carriers of the virus. PMID- 20169123 TI - An overview of the importance of conformational flexibility in gene regulation by the transcription factors. AB - A number of proteins with intrinsically disordered (ID) regions/domains are reported to be found disproportionately higher in transcription factors. Available evidences suggest that presence of ID region/domain within a transcription factor plays an important role in its biological functions. These ID sequences provide large flexible surfaces that can allow them to make more efficient physical and functional interactions with their target partners. Since transcription factors regulate expression of target genes by interacting with specific coregulatory proteins, these ID regions/domains can be used as a platform for such large macromolecular interactions, and may represent a mechanism for regulation of cellular processes. The precise structural basis for the function of these ID regions/domains of the transcription factors remains to be determined. In the recent years there has been growing evidence suggesting that an induced fit-like process leads to imposition of folded functional structure in these ID domains on which large multiprotein complexes are built. These multiprotein complexes may eventually dictate the final outcome of the gene regulation by the transcription factors. PMID- 20169124 TI - Blood Pressure and Left Ventricular Characteristics in Young Patients with Classical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency. AB - High steroid doses are often necessary in congenital adrenal hyperplasia (CAH) to suppress androgens and may increase blood pressure (BP). We evaluated 24-hour BP profile (ambBP), BP during exercise (excBP), and echocardiography in 20 young CAH patients. Systolic and diastolic BP during ambBP and excBP was normal in all patients. None presented myocardial hypertrophy. Nocturnal diastolic BP was affected by testosterone (P: .016, 95% CI: 0.002 to 0.021, beta = 0.01). Left ventricular mass (LVM ) was affected by height SDS (P: .007, 95% CI: 2.67 to 14.17, beta = 8.42), age (P: < .0001, 95% CI: 2.12 to 5.82, beta = 3.97), and testosterone (P: .008, 95% CI: 0.01 to 0.09, beta = 0.053). Left ventricular mass index (LVMI) correlated with BMI SDS (P: .044, 95% CI: 0.09 to 6.17, beta = 3.13) and testosterone (P: .031, 95% CI: 0.002 to 0.035, beta = 0.018). Hydrocortisone dose did not influence ambBP, excBP, or myocardial hypertrophy. PMID- 20169126 TI - Head and neck cancer. PMID- 20169125 TI - Cellular mediators of inflammation: tregs and TH17 cells in gastrointestinal diseases. AB - Human lymphocyte subpopulations were originally classified as T- and B-cells in the 70s. Later, with the development of monoclonal antibodies, it became possible to recognize, within the T-cells, functional populations: CD4(+) and CD8(+). These populations were usually referred to as "helper" and "suppressor" cells, respectively. However several investigations within the CD8 cells failed to detect a true suppressor activity. Therefore the term suppressor was neglected because it generated confusion. Much later, true suppressor activity was recognized in a subpopulation of CD4 cells characterized by high levels of CD25. The novel population is usually referred to as T regulatory cells (Tregs) and it is characterized by the expression of FoxP3. The heterogeneity of CD4 cells was further expanded by the recent description of a novel subpopulation characterized by production of IL-17. These cells are generally referred to as T(H)17. They contribute to regulate the overall immune response together with other cytokine producing populations. Treg and T(H)17 cells are related because they could derive from a common progenitor, depending on the presence of certain cytokines. The purpose of this review is to summarize recent findings of the role of these novel populations in the field of human gastroenterological disease. PMID- 20169128 TI - Plemorphic adenoma of the infratemporal space: a new case report. AB - Plemorphic adenoma is a frequent benign tumor of the major salivary glands. It could also develop from accessory salivary glands. We are reporting an extremely rare case of pleomorphic adenoma developing from the infratemporal space. The final diagnosis was based on histological confirmation. The treatment was mainly a complete resection via an anterior transmaxillary approach. Diagnosis, clinical behaviour, and treatment of pleomorphic adenoma of the infra-temporal space are reviewed from the literature. PMID- 20169127 TI - Telomeric heterochromatin in Plasmodium falciparum. AB - Until very recently, little was known about the chromatin structure of the telomeres and subtelomeric regions in Plasmodium falciparum. In yeast and Drosophila melanogaster, chromatin structure has long been known to be an important aspect in the regulation and functioning of these regions. Telomeres and subtelomeric regions are enriched in epigenetic marks that are specific to heterochromatin, such as methylation of lysine 9 of histone H3 and lysine 20 of histone H4. In P. falciparum, histone modifications and the presence of both the heterochromatin "writing" (PfSir2, PKMT) and "reading" (PfHP1) machinery at telomeric and subtelomeric regions indicate that these regions are likely to have heterochromatic structure that is epigenetically regulated. This structure may be important for telomere functions such as the silencing of the var gene family implicated in the cytoadherence and antigenic variation of these parasites. PMID- 20169129 TI - Statistical evaluations of the reproducibility and reliability of 3-tesla high resolution magnetization transfer brain images: a pilot study on healthy subjects. AB - Magnetization transfer imaging (MT) may have considerable promise for early detection and monitoring of subtle brain changes before they are apparent on conventional magnetic resonance images. At 3 Tesla (T), MT affords higher resolution and increased tissue contrast associated with macromolecules. The reliability and reproducibility of a new high-resolution MT strategy were assessed in brain images acquired from 9 healthy subjects. Repeated measures were taken for 12 brain regions of interest (ROIs): genu, splenium, and the left and right hemispheres of the hippocampus, caudate, putamen, thalamus, and cerebral white matter. Spearman's correlation coefficient, coefficient of variation, and intraclass correlation coefficient (ICC) were computed. Multivariate mixed effects regression models were used to fit the mean ROI values and to test the significance of the effects due to region, subject, observer, time, and manual repetition. A sensitivity analysis of various model specifications and the corresponding ICCs was conducted. Our statistical methods may be generalized to many similar evaluative studies of the reliability and reproducibility of various imaging modalities. PMID- 20169130 TI - Aggressive Trimodality Therapy for T1N2M1 Nonsmall Cell Lung Cancer with Synchronous Solitary Brain Metastasis: Case Report and Rationale. AB - Aggressive treatment, including resection of both metastasis and primary tumor, has been studied for non-small cell lung cancer patients with synchronous solitary brain metastasis. Involvement of mediastinal lymph nodes is considered a poor prognostic factor and a contraindication to surgical resection of the primary lung tumor after treatment for brain metastasis. Here we present the case of a patient who presented with a Stage IV T1N2M1 non-small cell lung cancer with synchronous solitary brain metastasis. He is alive and without evidence of disease two years after aggressive, multimodality treatment that included craniotomy, whole-brain radiation therapy, thoracic surgery, chemotherapy, and mediastinal radiation therapy. PMID- 20169131 TI - Recombinant Human Insulin-Like Growth Factor-1 Treatment: Prime Time or Timeout? [Commentary on "Recombinant Human Insulin Like Growth Factor-1 Treatment: Ready for Prime Time" by Bright GM, Mendoza JR, Rosenfeld RG, Endocrinol Metab Clin N Am 2009; 38:625-38]. PMID- 20169132 TI - Analyzing adherence to prenatal supplement: does pill count measure up? AB - Objective. To determine if adherence as measured by pill count would show a significant association with serum-based measures of adherence. Methods. Data were obtained from a prenatal vitamin D supplementation trial where subjects were stratified by race and randomized into three dosing groups: 400 (control), 2000, or 4000 IU vitamin D(3)/day. One measurement of adherence was obtained via pill counts remaining compared to a novel definition for adherence using serum 25 hydroxy-vitamin D (25-OH-D) levels (absolute change in 25(OH)D over the study period and the subject's steady-state variation in their 25(OH)D levels). A multivariate logistic regression model examined whether mean percent adherence by pill count was significantly associated with the adherence measure by serum metabolite levels. Results. Subjects' mean percentage of adherence by pill count was not a significant predictor of adherence by serum metabolite levels. This finding was robust across a series of sensitivity analyses. Conclusions. Based on our novel definition of adherence, pill count was not a reliable predictor of adherence to protocol, and calls into question how adherence is measured in clinical research. Our findings have implications regarding the determination of efficacy of medications under study and offer an alternative approach to measuring adherence of long half-life supplements/medications. PMID- 20169134 TI - Minimally invasive video-assisted thyroidectomy and parathyroidectomy with intraoperative recurrent laryngeal nerve monitoring. AB - Objective. Our goal is to study the feasibility of using intraoperative neuromonitoring (IONM) in minimally invasive video-assisted thyroidectomy and parathyroidectomy (MIVAT/P) with emphasis given to the identification of recurrent laryngeal nerve (RLN). Methods. Consecutive series of forty-seven patients with seventy-seven recurrent laryngeal nerves at risk undergoing both MIVAT/P and IONM were enrolled in this retrospective, nonrandomized analysis study. All operations were performed by the same surgeon within an academic institution setting. All patients underwent vocal cord evaluation postoperatively. Demographics and intraoperative and postoperative complications following surgery were collected. Results. Out of seventy-seven RLNs, there was one permanent unilateral RLN injury (1.29%) in a patient with advanced papillary thyroid cancer, managed by cord injection. There was another transient RLN paresis that resolved spontaneously (1.29%). There were no instances of equipment malfunction or interference. Conclusions. To our knowledge, this is the first reported MIVAT/P series from the United States of America with a standardized IONM technique. The technical feasibility of IONM seems acceptable and may serve as a meaningful adjunct to the visual identification of nerves. Neuromonitoring during MIVAT/P is effective in providing identification of laryngeal nerves and enables surgeons to feel more comfortable with MIVAT/P. Comparative series are needed for further evaluation. PMID- 20169135 TI - Delayed Presentation of a Giant Ascending Aortic Aneurysm following Aortic Valve Replacement. AB - Giant ascending aortic aneurysm formation following aortic valve replacement is rare. A 28-year-old man who underwent aortic valve replacement with a prosthetic valve for aortic regurgitation secondary to congenital bicuspid aortic valve about 10 years ago was diagnosed with a giant ascending aortic aneurysm about 16 cm in diameter in follow-up. The aneurysm was resected leaving the functional old mechanical prosthesis in place and implanted a 34-mm Hemashield woven graft, associated with the left and right coronary artery button implantation. Histological findings of the aortic aneurysm wall showed cystic medial necrosis. The postoperative course was uneventful and postoperative examination demonstrated good surgical results. PMID- 20169133 TI - Gene expression in trypanosomatid parasites. AB - The parasites Leishmania spp., Trypanosoma brucei, and Trypanosoma cruzi are the trypanosomatid protozoa that cause the deadly human diseases leishmaniasis, African sleeping sickness, and Chagas disease, respectively. These organisms possess unique mechanisms for gene expression such as constitutive polycistronic transcription of protein-coding genes and trans-splicing. Little is known about either the DNA sequences or the proteins that are involved in the initiation and termination of transcription in trypanosomatids. In silico analyses of the genome databases of these parasites led to the identification of a small number of proteins involved in gene expression. However, functional studies have revealed that trypanosomatids have more general transcription factors than originally estimated. Many posttranslational histone modifications, histone variants, and chromatin modifying enzymes have been identified in trypanosomatids, and recent genome-wide studies showed that epigenetic regulation might play a very important role in gene expression in this group of parasites. Here, we review and comment on the most recent findings related to transcription initiation and termination in trypanosomatid protozoa. PMID- 20169136 TI - Methods for monitoring endoplasmic reticulum stress and the unfolded protein response. AB - The endoplasmic reticulum (ER) is the site of folding of membrane and secreted proteins in the cell. Physiological or pathological processes that disturb protein folding in the endoplasmic reticulum cause ER stress and activate a set of signaling pathways termed the Unfolded Protein Response (UPR). The UPR can promote cellular repair and sustained survival by reducing the load of unfolded proteins through upregulation of chaperones and global attenuation of protein synthesis. Research into ER stress and the UPR continues to grow at a rapid rate as many new investigators are entering the field. There are also many researchers not working directly on ER stress, but who wish to determine whether this response is activated in the system they are studying: thus, it is important to list a standard set of criteria for monitoring UPR in different model systems. Here, we discuss approaches that can be used by researchers to plan and interpret experiments aimed at evaluating whether the UPR and related processes are activated. We would like to emphasize that no individual assay is guaranteed to be the most appropriate one in every situation and strongly recommend the use of multiple assays to verify UPR activation. PMID- 20169137 TI - Association between residential proximity to PERC dry cleaning establishments and kidney cancer in New York City. AB - Perchloroethylene (PERC) is commonly used as a dry cleaning solvent and is believed to be a human carcinogen, with occupational exposure resulting in elevated rates of kidney cancer. Living near a dry cleaning facility using PERC has been demonstrated to increase the risk of PERC exposure throughout the building where the dry cleaning is conducted, and in nearby buildings. We designed this study to test the hypothesis that living in an area where there are many PERC dry cleaners increases PERC exposure and the risk of kidney cancer. We matched the diagnosis of kidney cancer from hospitalization discharge data in New York City for the years 1994-2004 by zip code of patient residence to the zip code density of dry cleaners using PERC, as a surrogate for residential exposure. We controlled for age, race, gender, and median household income. We found a significant association between the density of PERC dry cleaning establishments and the rate of hospital discharges that include a diagnosis of kidney cancer among persons 45 years of age and older living in New York City. The rate ratio increased by 10 to 27% for the populations in zip codes with higher density of PERC dry cleaners. Because our exposure assessment is inexact, we are likely underestimating the real association between exposure to PERC and rates of kidney cancer. Our results support the hypothesis that living near a dry cleaning facility using PERC increases the risk of PERC exposure and of developing kidney cancer. To our knowledge, this study is the first to demonstrate an association between residential PERC exposure and cancer risk. PMID- 20169139 TI - Life-threatening cardiac manifestations of pheochromocytoma. AB - Pheochromocytoma is a catecholamine-secreting tumor of the adrenal glands, usually with benign manifestations, whose typical clinical presentation includes the triad of headache, palpitations and diaphoresis. However, a wide range of signs and symptoms may be present. In the cardiovascular system, the most common signs are labile hypertension and sinus tachycardia. Systolic heart failure and ST-segment deviations mimicking myocardial infarction have also been reported, as well as QT interval prolongation and, rarely, ventricular tachycardia. We describe a challenging diagnosis of pheochromocytoma with many cardiovascular manifestations, which could have been missed due to the absence of typical symptoms. PMID- 20169138 TI - Angiogenesis inhibition in prostate cancer: current uses and future promises. AB - Angiogenesis has been well recognized as a fundamental part of a multistep process in the evolution of cancer progression, invasion, and metastasis. Strategies for inhibiting angiogenesis have been one of the most robust fields of cancer investigation, focusing on the vascular endothelial growth factor (VEGF) family and its receptors. There are numerous regulatory drug approvals to date for the use of these agents in treating a variety of solid tumors. While therapeutic efficacy has been established, challenges remain with regards to overcoming resistance and assessing response to antiangiogenic therapies. Prostate cancer is the most common noncutaneous malignancy among American men and angiogenesis plays a role in disease progression. The use of antiangiogenesis agents in prostate cancer has been promising and is hereby explored. PMID- 20169141 TI - Antidepressant drugs for chronic urological pelvic pain: an evidence-based review. AB - The use of antidepressant drugs for the management of chronic pelvic pain has been supported in the past. This study aimed to evaluate the available evidence for the efficacy and acceptability of antidepressant drugs in the management of urological chronic pelvic pain. Studies were selected through a comprehensive literature search. We included all types of study designs due to the limited evidence. Studies were classified into levels of evidence according to their design. Ten studies were included with a total of 360 patients. Amitriptyline, sertraline, duloxetine, nortriptyline, and citalopram are the antidepressants that have been reported in the literature. Only four randomized controlled trials (RCTs) were identified (two for amitriptyline and two for sertraline) with mixed results. We conclude that the use of antidepressants for the management of chronic urological pelvic pain is not adequately supported by methodologically sound RCTs. From the existing studies amitriptyline may be effective in interstitial cystitis but publication bias should be considered as an alternative explanation. All drugs were generally well tolerated with no serious events reported. PMID- 20169140 TI - Circulating levels of interleukin-1 family cytokines in overweight adolescents. AB - OBJECTIVES: Obesity and related diseases are dramatically increasing problems, particularly in children and adolescents. We determined circulating levels of different interleukin (IL)-1 family members in normal weight and overweight adolescents. METHODS: Seventy male, Caucasian adolescents (13-17 years) were recruited. Thirty-five had a body-mass index (BMI) above the 90th age-specific percentile. IL-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1ra), and IL-18 were determined using multiplex-technology. RESULTS: IL-18 concentrations were higher in the overweight group compared to normal weight (161.6 +/- 40.7 pg/ml versus 134.7 +/- 43.4 pg/ml, P = .009). Concentrations of circulating IL-1beta levels were below the detection threshold. IL-18 (R2:0.355, P < .01) and IL-1ra (R2:0.287, P < .05) correlated with BMI, whereas IL-1alpha did not. CONCLUSIONS: Accumulating data indicate the importance of the endocrine function of adipose tissue for the pathophysiological consequences of obesity-related co-morbidities. Since IL-18 is involved in the pathogenesis of different cardiovascular diseases, we conclude that IL-18 may represent a link between obesity and related co morbidities in children and adolescents. PMID- 20169142 TI - Online detection of P300 and error potentials in a BCI speller. AB - Error potentials (ErrPs), that is, alterations of the EEG traces related to the subject perception of erroneous responses, have been suggested to be an elegant way to recognize misinterpreted commands in brain-computer interface (BCI) systems. We implemented a P300-based BCI speller that uses a genetic algorithm (GA) to detect P300s, and added an automatic error-correction system (ECS) based on the single-sweep detection of ErrPs. The developed system was tested on-line on three subjects and here we report preliminary results. In two out of three subjects, the GA provided a good performance in detecting P300 (90% and 60% accuracy with 5 repetitions), and it was possible to detect ErrP with an accuracy (roughly 60%) well above the chance level. In our knowledge, this is the first time that ErrP detection is performed on-line in a P300-based BCI. Preliminary results are encouraging, but further refinements are needed to improve performances. PMID- 20169143 TI - A note on "Malaria at parturition in Nigeria: current status and delivery outcome". PMID- 20169144 TI - Different activity of the biological axis VEGF-Flt-1 (fms-like tyrosine kinase 1) and CXC chemokines between pulmonary sarcoidosis and idiopathic pulmonary fibrosis: a bronchoalveolar lavage study. AB - BACKGROUND: We have previously shown a different local and systemic angiogenic profile of CXC chemokines in Idiopathic Pulmonary Fibrosis (IPF) patients compared to sarcoidosis. In particular, sarcoidosis showed an angiostatic microenvironment, as compared with the angiogenic cytokine milieu seen in IPF. Purpose of the Study. Our aim was to further investigate the aforementioned finding by measuring the expression of different chemokines in granulomatous and fibrotic diseases. We estimated the levels of vascular endothelial growth factor (VEGF) and its high-affinity receptor, Flt-1 (fms-like tyrosine kinase 1), in bronchoalveolar lavage fluid (BALF) of patients with IPF and pulmonary sarcoidosis. We have also investigated the mRNA expression of angiogenetic chemokines' receptors such as CXCR2 and CXCR3 and the biological axis of stromal derived factor-1 alpha (SDF-1 alpha or CXCL12 alpha/CXCL12 beta) and receptor, CXCR4. METHODS: We studied prospectively three groups of patients: (i) one group of 18 patients with IPF, (ii) one group of 16 patients with sarcoidosis, and (iii) 10 normal subjects. RESULTS: A statistically significant increase has been detected in VEGF mRNA expression in IPF in comparison with pulmonary sarcoidosis (P = .03). In addition, a significant increase has been measured in CXCL12 alpha in sarcoidosis in comparison to IPF (P = .02). Moreover, a statistically significant decrease has been found in Flt-1 protein levels in pulmonary sarcoidosis in comparison with IPF (P = .03). A significant increase in VEGF (P = .03) and CXCR4 (P = .03) mRNA levels has been also detected in sarcoidosis' patients when compared with healthy controls. CONCLUSIONS: Our data suggest that increased expression of Flt-1 and downregulation of CXCL12 alpha in IPF may further support the hypothesis of a different angiogenetic profile between fibrotic and granulomatous diseases. However, further studies are needed in order to better investigate these enigmatic diseases. PMID- 20169145 TI - Constructing Physical and Genomic Maps for Puccinia striiformis f. sp. tritici, the Wheat Stripe Rust Pathogen, by Comparing Its EST Sequences to the Genomic Sequence of P. graminis f. sp. tritici, the Wheat Stem Rust Pathogen. AB - The wheat stripe rust fungus, Puccinia striiformis f. sp. tritici (Pst), does not have a known alternate host for sexual reproduction, which makes it impossible to study gene linkages through classic genetic and molecular mapping approaches. In this study, we compared 4,219 Pst expression sequence tags (ESTs) to the genomic sequence of P. graminis f. sp. tritici (Pgt), the wheat stem rust fungus, using BLAST searches. The percentages of homologous genes varied greatly among different Pst libraries with 54.51%, 51.21%, and 13.61% for the urediniospore, germinated urediniospore, and haustorial libraries, respectively, with an average of 33.92%. The 1,432 Pst genes with significant homology with Pgt sequences were grouped into physical groups corresponding to 237 Pgt supercontigs. The physical relationship was demonstrated by 12 pairs (57%), out of 21 selected Pst gene pairs, through PCR screening of a Pst BAC library. The results indicate that the Pgt genome sequence is useful in constructing Pst physical maps. PMID- 20169146 TI - Identification of novel glial genes by single-cell transcriptional profiling of Bergmann glial cells from mouse cerebellum. AB - Bergmann glial cells play critical roles in the structure and function of the cerebellum. During development, their radial processes serve as guides for migrating granule neurons and their terminal endfeet tile to form the glia limitans. As the cerebellum matures, Bergmann glia perform important roles in synaptic transmission and synapse maintenance, while continuing to serve as essential structural elements. Despite growing evidence of the diverse functions of Bergmann glia, the molecular mechanisms that mediate these functions have remained largely unknown. As a step toward identifying the molecular repertoire underlying Bergmann glial function, here we examine global gene expression in individual Bergmann glia from developing (P6) and mature (P30) mouse cerebellum. When we select for developmentally regulated genes, we find that transcription factors and ribosomal genes are particularly enriched at P6 relative to P30; whereas synapse associated molecules are enriched at P30 relative to P6. We also analyze genes expressed at high levels at both ages. In all these categories, we find genes that were not previously known to be expressed in glial cells, and discuss novel functions some of these genes may potentially play in Bergmann glia. We also show that Bergmann glia, even in the adult, express a large set of genes thought to be specific to stem cells, suggesting that Bergmann glia may retain neural precursor potential as has been proposed. Finally, we highlight several genes that in the cerebellum are expressed in Bergmann glia but not astrocytes, and may therefore serve as new, specific markers for Bergmann glia. PMID- 20169147 TI - Rho kinases regulate the renewal and neural differentiation of embryonic stem cells in a cell plating density-dependent manner. AB - BACKGROUND: Rho kinases (ROCKs) mediate cell contraction, local adhesion, and cell motility, which are considered to be important in cell differentiation. We postulated that ROCKs are involved in controlling embryonic stem (ES) cell renewal and differentiation. METHODOLOGY/PRINCIPAL FINDINGS: CCE, a murine ES cell, was treated with Y-27632 for 48 to 96 hours and colony formation was evaluated. Y-27632 blocked CCE colony formation and induced CCE to grow as individual cells, regardless of the initial seeding cell density either at 10(4)/cm(2) ("high" seeding density) or 2x10(3)/cm(2) ("low" density). However, at high seeding density, Y-27632-treated cells exhibited reduction of alkaline phosphatase (AP) staining and Oct3/4 expression. They expressed SOX-1, nestin, and MAP2c, but not betaIII-tubulin or NG-2. They did not express endoderm or mesoderm lineage markers. After removal of Y-27632, the cells failed to form colonies or regain undifferentiated state. Silencing of ROCK-1 or ROCK-2 with selective small interference RNA induced CCE morphological changes similar to Y 27632. Silencing of ROCK-1 or ROCK-2 individually was sufficient to cause reduction of AP and Oct3/4, and expression of SOX-1, nestin, and MAP2c; and combined silencing of both ROCKs did not augment the effects exerted by individual ROCK siRNA. Y-27632-treated CCE cells seeded at 2x10(3) or 6.6x10(3) cells/cm(2) did not lose renewal factors or express differentiation markers. Furthermore, they were able to form AP-positive colonies after removal of Y-27632 and reseeding. Similar to ROCK inhibition by Y-27632, silencing of ROCK-1 or ROCK 2 in cells seeded at 2x10(3)/cm(2) did not change renewal factors. CONCLUSIONS/SIGNIFICANCE: We conclude that ROCKs promote ES cell colony formation, maintain them at undifferentiated state, and prevent them from neural differentiation at high seeding density. ROCK inhibition represents a new strategy for preparing large numbers of neural progenitor cells. PMID- 20169148 TI - A dynamic model for stem cell homeostasis and patterning in Arabidopsis meristems. AB - Plants maintain stem cells in their meristems as a source for new undifferentiated cells throughout their life. Meristems are small groups of cells that provide the microenvironment that allows stem cells to prosper. Homeostasis of a stem cell domain within a growing meristem is achieved by signalling between stem cells and surrounding cells. We have here simulated the origin and maintenance of a defined stem cell domain at the tip of Arabidopsis shoot meristems, based on the assumption that meristems are self-organizing systems. The model comprises two coupled feedback regulated genetic systems that control stem cell behaviour. Using a minimal set of spatial parameters, the mathematical model allows to predict the generation, shape and size of the stem cell domain, and the underlying organizing centre. We use the model to explore the parameter space that allows stem cell maintenance, and to simulate the consequences of mutations, gene misexpression and cell ablations. PMID- 20169152 TI - Overexpression of microRNA miR-30a or miR-191 in A549 lung cancer or BEAS-2B normal lung cell lines does not alter phenotype. AB - BACKGROUND: MicroRNAs (miRNAs) are small, noncoding RNAs (ribonucleic acids) that regulate translation. Several miRNAs have been shown to be altered in whole cancer tissue compared to normal tissue when quantified by microarray. Based on previous such evidence of differential expression, we chose to study the functional significance of miRNAs miR-30a and -191 alterations in human lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: The functional significance of miRNAs miR 30a and -191 was studied by creating stable transfectants of the lung adenocarcinoma cell line A549 and the immortalized bronchial epithelial cell line BEAS-2B with modest overexpression of miR-30a or -191 using a lentiviral system. When compared to the corresponding controls, both cell lines overexpressing miR 30a or -191 do not demonstrate any significant changes in cell cycle distribution, cell proliferation, adherent colony formation, soft agar colony formation, xenograft formation in a subcutaneous SCID mouse model, and drug sensitivity to doxorubicin and cisplatin. There is a modest increase in cell migration in cell lines overexpressing miR-30a compared to their controls. CONCLUSIONS/SIGNIFICANCE: Overexpression of miR-30a or -191 does not lead to an alteration in cell cycle, proliferation, xenograft formation, and chemosensitivity of A549 and BEAS-2B cell lines. Using microarray data from whole tumors to select specific miRNAs for functional study may be a suboptimal strategy. PMID- 20169153 TI - The extent of the preserved feathers on the four-winged dinosaur Microraptor gui under ultraviolet light. AB - BACKGROUND: The holotype of the theropod non-avian dinosaur Microraptor gui from the Early Cretaceous of China shows extensive preservation of feathers in a halo around the body and with flight feathers associated with both the fore and hindlimbs. It has been questioned as to whether or not the feathers did extend into the halo to reach the body, or had disassociated and moved before preservation. This taxon has important implications for the origin of flight in birds and the possibility of a four-winged gliding phase. METHODOLOGY/PRINCIPAL FINDINGS: Examination of the specimen under ultraviolet light reveals that these feathers actually reach the body of the animal and were not disassociated from the bones. Instead they may have been chemically altered by the body tissues of the animal meaning that they did not carbonise close into the animal or more likely were covered by other decaying tissue, though evidence of their presence remains. CONCLUSIONS/SIGNIFICANCE: These UV images show that the feathers preserved on the slab are genuinely associated with the skeleton and that their arrangement and orientation is likely correct. The methods used here to reveal hidden features of the specimen may be applicable to other specimens from the fossil beds of Liaoning that produced Microraptor. PMID- 20169154 TI - Mark my words: tone of voice changes affective word representations in memory. AB - The present study explored the effect of speaker prosody on the representation of words in memory. To this end, participants were presented with a series of words and asked to remember the words for a subsequent recognition test. During study, words were presented auditorily with an emotional or neutral prosody, whereas during test, words were presented visually. Recognition performance was comparable for words studied with emotional and neutral prosody. However, subsequent valence ratings indicated that study prosody changed the affective representation of words in memory. Compared to words with neutral prosody, words with sad prosody were later rated as more negative and words with happy prosody were later rated as more positive. Interestingly, the participants' ability to remember study prosody failed to predict this effect, suggesting that changes in word valence were implicit and associated with initial word processing rather than word retrieval. Taken together these results identify a mechanism by which speakers can have sustained effects on listener attitudes towards word referents. PMID- 20169155 TI - Quantitative kinetic study of the actin-bundling protein L-plastin and of its impact on actin turn-over. AB - BACKGROUND: Initially detected in leukocytes and cancer cells derived from solid tissues, L-plastin/fimbrin belongs to a large family of actin crosslinkers and is considered as a marker for many cancers. Phosphorylation of L-plastin on residue Ser5 increases its F-actin binding activity and is required for L-plastin mediated cell invasion. METHODOLOGY/PRINCIPAL FINDINGS: To study the kinetics of L-plastin and the impact of L-plastin Ser5 phosphorylation on L-plastin dynamics and actin turn-over in live cells, simian Vero cells were transfected with GFP coupled WT-L-plastin, Ser5 substitution variants (S5/A, S5/E) or actin and analyzed by fluorescence recovery after photobleaching (FRAP). FRAP data were explored by mathematical modeling to estimate steady-state reaction parameters. We demonstrate that in Vero cell focal adhesions L-plastin undergoes rapid cycles of association/dissociation following a two-binding-state model. Phosphorylation of L-plastin increased its association rates by two-fold, whereas dissociation rates were unaffected. Importantly, L-plastin affected actin turn-over by decreasing the actin dissociation rate by four-fold, increasing thereby the amount of F-actin in the focal adhesions, all these effects being promoted by Ser5 phosphorylation. In MCF-7 breast carcinoma cells, phorbol 12-myristate 13 acetate (PMA) treatment induced L-plastin translocation to de novo actin polymerization sites in ruffling membranes and spike-like structures and highly increased its Ser5 phosphorylation. Both inhibition studies and siRNA knock-down of PKC isozymes pointed to the involvement of the novel PKC-delta isozyme in the PMA-elicited signaling pathway leading to L-plastin Ser5 phosphorylation. Furthermore, the L-plastin contribution to actin dynamics regulation was substantiated by its association with a protein complex comprising cortactin, which is known to be involved in this process. CONCLUSIONS/SIGNIFICANCE: Altogether these findings quantitatively demonstrate for the first time that L plastin contributes to the fine-tuning of actin turn-over, an activity which is regulated by Ser5 phosphorylation promoting its high affinity binding to the cytoskeleton. In carcinoma cells, PKC-delta signaling pathways appear to link L plastin phosphorylation to actin polymerization and invasion. PMID- 20169156 TI - The transcriptional repressor Kaiso localizes at the mitotic spindle and is a constituent of the pericentriolar material. AB - Kaiso is a BTB/POZ zinc finger protein known as a transcriptional repressor. It was originally identified through its in vitro association with the Armadillo protein p120ctn. Subcellular localization of Kaiso in cell lines and in normal and cancerous human tissues revealed that its expression is not restricted to the nucleus. In the present study we monitored Kaiso's subcellular localization during the cell cycle and found the following: (1) during interphase, Kaiso is located not only in the nucleus, but also on microtubular structures, including the centrosome; (2) at metaphase, it is present at the centrosomes and on the spindle microtubules; (3) during telophase, it accumulates at the midbody. We found that Kaiso is a genuine PCM component that belongs to a pericentrin molecular complex. We analyzed the functions of different domains of Kaiso by visualizing the subcellular distribution of GFP-tagged Kaiso fragments throughout the cell cycle. Our results indicate that two domains are responsible for targeting Kaiso to the centrosomes and microtubules. The first domain, designated SA1 for spindle-associated domain 1, is located in the center of the Kaiso protein and localizes at the spindle microtubules and centrosomes; the second domain, SA2, is an evolutionarily conserved domain situated just before the zinc finger domain and might be responsible for localizing Kaiso towards the centrosomal region. Constructs containing both SA domains and Kaiso's aminoterminal BTB/POZ domain triggered the formation of abnormal centrosomes. We also observed that overexpression of longer or full-length Kaiso constructs led to mitotic cell arrest and frequent cell death. Knockdown of Kaiso accelerated cell proliferation. Our data reveal a new target for Kaiso at the centrosomes and spindle microtubules during mitosis. They also strongly imply that Kaiso's function as a transcriptional regulator might be linked to the control of the cell cycle and to cell proliferation in cancer. PMID- 20169157 TI - Regulation of CCR5 expression in human placenta: insights from a study of mother to-child transmission of HIV in Malawi. AB - BACKGROUND: Human promoter polymorphisms in the chemokine co-receptor 5 gene (CCR5) have been noted for association with mother-to-child transmission of HIV (HIV MTCT) as well as reduced receptor expression in vitro, but have not been clearly associated with CCR5 expression in vivo. Placental expression of CCR5 may be influenced by such polymorphisms as well as other in vivo regulatory factors. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the associations between infant CCR5 polymorphisms, measures of maternal infection, and placental expression of CCR5 among mother-infant pairs in Blantyre, Malawi. RNA was extracted from placental tissue and used in multiplex real-time PCR to quantify gene expression. Through linear regression, we observed that CCR5-2554T (beta = -0.67, 95% CI = -1.23, 0.11) and -2132T (beta = -0.75, 95% CI = -0.131, -0.18) were significantly associated with reduced placental expression of CCR5. An incremental increase in CCR5 expression was observed for incremental increases in expression of two heparan sulfate genes involved in viral infection, HS3ST3A1 (beta = 0.27, 95% CI = 0.18, 0.35) and HS3ST3B1 (beta = 0.11, 95% CI = 0.06, 0.18). Among HIV infected mothers, an incremental increase in maternal HIV viral load was also associated with higher CCR5 expression (beta = 0.76, 95% CI = 0.12, 1.39). Maternal HIV status had no overall effect (beta = 0.072, 95% CI = -0.57, -0.72). Higher CCR5 expression was observed for mothers with malaria but was not statistically significant (beta = 0.37, 95% CI = -0.43, 1.18). CONCLUSIONS/SIGNIFICANCE: These results provide in vivo evidence for genetic and environmental factors involved in the regulation of CCR5 expression in the placenta. Our findings also suggest that the measurement of placental expression of CCR5 alone is not an adequate indicator of the risk of mother-to-child transmission of HIV. PMID- 20169158 TI - Circadian plasticity in photoreceptor cells controls visual coding efficiency in Drosophila melanogaster. AB - In the fly Drosophila melanogaster, neuronal plasticity of synaptic terminals in the first optic neuropil, or lamina, depends on early visual experience within a critical period after eclosion. The current study revealed two additional and parallel mechanisms involved in this type of synaptic terminal plasticity. First, an endogenous circadian rhythm causes daily oscillations in the volume of photoreceptor cell terminals. Second, daily visual experience precisely modulates the circadian time course and amplitude of the volume oscillations that the photoreceptor-cell terminals undergo. Both mechanisms are separable in their molecular basis. We suggest that the described neuronal plasticity in Drosophila ensures continuous optimal performance of the visual system over the course of a 24 h-day. Moreover, the sensory system of Drosophila cannot only account for predictable, but also for acute, environmental changes. The volumetric changes in the synaptic terminals of photoreceptor cells are accompanied by circadian and light-induced changes of presynaptic ribbons as well as extensions of epithelial glial cells into the photoreceptor terminals, suggesting that the architecture of the lamina is altered by both visual exposure and the circadian clock. Clock mutant analysis and the rescue of PER protein rhythmicity exclusively in all R1-6 cells revealed that photoreceptor-cell plasticity is autonomous and sufficient to control visual behavior. The strength of a visually guided behavior, the optomotor turning response, co-varies with synaptic-terminal volume oscillations of photoreceptor cells when elicited at low light levels. Our results show that behaviorally relevant adaptive processing of visual information is performed, in part, at the level of visual input level. PMID- 20169159 TI - When the sun prickles your nose: an EEG study identifying neural bases of photic sneezing. AB - BACKGROUND: Exposure to bright light such as sunlight elicits a sneeze or prickling sensation in about one of every four individuals. This study presents the first scientific examination of this phenomenon, called 'the photic sneeze reflex'. METHODOLOGY AND PRINCIPAL FINDINGS: In the present experiment, 'photic sneezers' and controls were exposed to a standard checkerboard stimulus (block 1) and bright flashing lights (block 2) while their EEG (electro-encephalogram) was recorded. Remarkably, we found a generally enhanced excitability of the visual cortex (mainly in the cuneus) to visual stimuli in 'photic sneezers' compared with control subjects. In addition, a stronger prickling sensation in the nose of photic sneezers was found to be associated with activation in the insula and stronger activation in the secondary somatosensory cortex. CONCLUSION: We propose that the photic sneeze phenomenon might be the consequence of higher sensitivity to visual stimuli in the visual cortex and of co-activation of somatosensory areas. The 'photic sneeze reflex' is therefore not a classical reflex that occurs only at a brainstem or spinal cord level but, in stark contrast to many theories, involves also specific cortical areas. PMID- 20169160 TI - High log-scale expansion of functional human natural killer cells from umbilical cord blood CD34-positive cells for adoptive cancer immunotherapy. AB - Immunotherapy based on natural killer (NK) cell infusions is a potential adjuvant treatment for many cancers. Such therapeutic application in humans requires large numbers of functional NK cells that have been selected and expanded using clinical grade protocols. We established an extremely efficient cytokine-based culture system for ex vivo expansion of NK cells from hematopoietic stem and progenitor cells from umbilical cord blood (UCB). Systematic refinement of this two-step system using a novel clinical grade medium resulted in a therapeutically applicable cell culture protocol. CD56(+)CD3(-) NK cell products could be routinely generated from freshly selected CD34(+) UCB cells with a mean expansion of >15,000 fold and a nearly 100% purity. Moreover, our protocol has the capacity to produce more than 3-log NK cell expansion from frozen CD34(+) UCB cells. These ex vivo-generated cell products contain NK cell subsets differentially expressing NKG2A and killer immunoglobulin-like receptors. Furthermore, UCB-derived CD56(+) NK cells generated by our protocol uniformly express high levels of activating NKG2D and natural cytotoxicity receptors. Functional analysis showed that these ex vivo-generated NK cells efficiently target myeloid leukemia and melanoma tumor cell lines, and mediate cytolysis of primary leukemia cells at low NK-target ratios. Our culture system exemplifies a major breakthrough in producing pure NK cell products from limited numbers of CD34(+) cells for cancer immunotherapy. PMID- 20169161 TI - Specific involvement of pilus type 2a in biofilm formation in group B Streptococcus. AB - Streptococcus agalactiae is the primary colonizer of the anogenital mucosa of up to 30% of healthy women and can infect newborns during delivery and cause severe sepsis and meningitis. Persistent colonization usually involves the formation of biofilm and increasing evidences indicate that in pathogenic streptococci biofilm formation is mediated by pili. Recently, we have characterized pili distribution and conservation in 289 GBS clinical isolates and we have shown that GBS has three pilus types, 1, 2a and 2b encoded by three corresponding pilus islands, and that each strain carries one or two islands. Here we have investigated the capacity of these strains to form biofilms. We have found that most of the biofilm-formers carry pilus 2a, and using insertion and deletion mutants we have confirmed that pilus type 2a, but not pilus types 1 and 2b, confers biofilm forming phenotype. We also show that deletion of the major ancillary protein of type 2a did not impair biofilm formation while the inactivation of the other ancillary protein and of the backbone protein completely abolished this phenotype. Furthermore, antibodies raised against pilus components inhibited bacterial adherence to solid surfaces, offering new strategies to prevent GBS infection by targeting bacteria during their initial attachment to host epithelial cells. PMID- 20169162 TI - Delineating genetic alterations for tumor progression in the MCF10A series of breast cancer cell lines. AB - To gain insight into the role of genomic alterations in breast cancer progression, we conducted a comprehensive genetic characterization of a series of four cell lines derived from MCF10A. MCF10A is an immortalized mammary epithelial cell line (MEC); MCF10AT is a premalignant cell line generated from MCF10A by transformation with an activated HRAS gene; MCF10CA1h and MCF10CA1a, both derived from MCF10AT xenografts, form well-differentiated and poorly-differentiated malignant tumors in the xenograft models, respectively. We analyzed DNA copy number variation using the Affymetrix 500 K SNP arrays with the goal of identifying gene-specific amplification and deletion events. In addition to a previously noted deletion in the CDKN2A locus, our studies identified MYC amplification in all four cell lines. Additionally, we found intragenic deletions in several genes, including LRP1B in MCF10CA1h and MCF10CA1a, FHIT and CDH13 in MCF10CA1h, and RUNX1 in MCF10CA1a. We confirmed the deletion of RUNX1 in MCF10CA1a by DNA and RNA analyses, as well as the absence of the RUNX1 protein in that cell line. Furthermore, we found that RUNX1 expression was reduced in high grade primary breast tumors compared to low/mid-grade tumors. Mutational analysis identified an activating PIK3CA mutation, H1047R, in MCF10CA1h and MCF10CA1a, which correlates with an increase of AKT1 phosphorylation at Ser473 and Thr308. Furthermore, we showed increased expression levels for genes located in the genomic regions with copy number gain. Thus, our genetic analyses have uncovered sequential molecular events that delineate breast tumor progression. These events include CDKN2A deletion and MYC amplification in immortalization, HRAS activation in transformation, PIK3CA activation in the formation of malignant tumors, and RUNX1 deletion associated with poorly-differentiated malignant tumors. PMID- 20169163 TI - In vitro fertilization and embryo culture strongly impact the placental transcriptome in the mouse model. AB - BACKGROUND: Assisted Reproductive Technologies (ART) are increasingly used in humans; however, their impact is now questioned. At blastocyst stage, the trophectoderm is directly in contact with an artificial medium environment, which can impact placental development. This study was designed to carry out an in depth analysis of the placental transcriptome after ART in mice. METHODOLOGY/PRINCIPAL FINDINGS: Blastocysts were transferred either (1) after in vivo fertilization and development (control group) or (2) after in vitro fertilization and embryo culture. Placentas were then analyzed at E10.5. Six percent of transcripts were altered at the two-fold threshold in placentas of manipulated embryos, 2/3 of transcripts being down-regulated. Strikingly, the X chromosome harbors 11% of altered genes, 2/3 being induced. Imprinted genes were modified similarly to the X. Promoter composition analysis indicates that FOXA transcription factors may be involved in the transcriptional deregulations. CONCLUSIONS: For the first time, our study shows that in vitro fertilization associated with embryo culture strongly modify the placental expression profile, long after embryo manipulations, meaning that the stress of artificial environment is memorized after implantation. Expression of X and imprinted genes is also greatly modulated probably to adapt to adverse conditions. Our results highlight the importance of studying human placentas from ART. PMID- 20169164 TI - Two years after molecular diagnosis of familial hypercholesterolemia: majority on cholesterol-lowering treatment but a minority reaches treatment goal. AB - BACKGROUND: The risk of premature cardiovascular disease in patients with familial hypercholesterolemia (FH) can be profoundly reduced by cholesterol lowering therapy, and current guidelines for FH advocate ambitious low-density lipoprotein cholesterol (LDL-C) goals. In the present study, we determined whether these goals are reflected in current clinical practice once FH has been diagnosed. METHODOLOGY/PRINCIPAL FINDINGS: In 2008, we sent questionnaires to all subjects (aged 18-65 years) who were molecularly diagnosed with FH in the year 2006 through the screening program in The Netherlands. Of these 1062 subjects, 781 completed the questionnaire (46% males; mean age: 42+/-12 years; mean LDL-C at molecular diagnosis (baseline): 4.1+/-1.3 mmol/L). The number of persons that used cholesterol-lowering therapy increased from 397 (51%) at baseline to 636 (81%) after diagnosis. Mean treated LDL-C levels decreased significantly to 3.2+/ 1.1 mmol/L two years after diagnosis. Only 22% achieved the LDL-C target level of < or = 2.5 mmol/L. CONCLUSIONS/SIGNIFICANCE: The proportion of patients using cholesterol-lowering medication was significantly increased after FH diagnosis through genetic cascade screening. The attained LDL-C levels were lower than those reported in previous surveys on medication use in FH, which could reflect the effect of more stringent lipid target levels. However, only a minority of the medication users reached the LDL-C target. PMID- 20169165 TI - SIRT1 negatively regulates the mammalian target of rapamycin. AB - The IGF/mTOR pathway, which is modulated by nutrients, growth factors, energy status and cellular stress regulates aging in various organisms. SIRT1 is a NAD+ dependent deacetylase that is known to regulate caloric restriction mediated longevity in model organisms, and has also been linked to the insulin/IGF signaling pathway. Here we investigated the potential regulation of mTOR signaling by SIRT1 in response to nutrients and cellular stress. We demonstrate that SIRT1 deficiency results in elevated mTOR signaling, which is not abolished by stress conditions. The SIRT1 activator resveratrol reduces, whereas SIRT1 inhibitor nicotinamide enhances mTOR activity in a SIRT1 dependent manner. Furthermore, we demonstrate that SIRT1 interacts with TSC2, a component of the mTOR inhibitory-complex upstream to mTORC1, and regulates mTOR signaling in a TSC2 dependent manner. These results demonstrate that SIRT1 negatively regulates mTOR signaling potentially through the TSC1/2 complex. PMID- 20169166 TI - Non-invasive stem cell therapy in a rat model for retinal degeneration and vascular pathology. AB - BACKGROUND: Retinitis pigmentosa (RP) is characterized by progressive night blindness, visual field loss, altered vascular permeability and loss of central vision. Currently there is no effective treatment available except gene replacement therapy has shown promise in a few patients with specific gene defects. There is an urgent need to develop therapies that offer generic neuro and vascular-protective effects with non-invasive intervention. Here we explored the potential of systemic administration of pluripotent bone marrow-derived mesenchymal stem cells (MSCs) to rescue vision and associated vascular pathology in the Royal College Surgeons (RCS) rat, a well-established animal model for RP. METHODOLOGY/PRINCIPAL FINDINGS: Animals received syngeneic MSCs (1x10(6) cells) by tail vein at an age before major photoreceptor loss. PRINCIPAL RESULTS: both rod and cone photoreceptors were preserved (5-6 cells thick) at the time when control animal has a single layer of photoreceptors remained; Visual function was significantly preserved compared with controls as determined by visual acuity and luminance threshold recording from the superior colliculus; The number of pathological vascular complexes (abnormal vessels associated with migrating pigment epithelium cells) and area of vascular leakage that would ordinarily develop were dramatically reduced; Semi-quantitative RT-PCR analysis indicated there was upregulation of growth factors and immunohistochemistry revealed that there was an increase in neurotrophic factors within eyes of animals that received MSCs. CONCLUSIONS/SIGNIFICANCE: These results underscore the potential application of MSCs in treating retinal degeneration. The advantages of this non invasive cell-based therapy are: cells are easily isolated and can be expanded in large quantity for autologous graft; hypoimmunogenic nature as allogeneic donors; less controversial in nature than other stem cells; can be readministered with minor discomfort. Therefore, MSCs may prove to be the ideal cell source for auto cell therapy for retinal degeneration and other ocular vascular diseases. PMID- 20169167 TI - A Boolean model of the Pseudomonas syringae hrp regulon predicts a tightly regulated system. AB - The Type III secretion system (TTSS) is a protein secretion machinery used by certain gram-negative bacterial pathogens of plants and animals to deliver effector molecules to the host and is at the core of the ability to cause disease. Extensive molecular and biochemical study has revealed the components and their interactions within this system but reductive approaches do not consider the dynamical properties of the system as a whole. In order to gain a better understanding of these dynamical behaviours and to create a basis for the refinement of the experimentally derived knowledge we created a Boolean model of the regulatory interactions within the hrp regulon of Pseudomonas syringae pathovar tomato strain DC3000 Pseudomonas syringae. We compared simulations of the model with experimental data and found them to be largely in accordance, though the hrpV node shows some differences in state changes to that expected. Our simulations also revealed interesting dynamical properties not previously predicted. The model predicts that the hrp regulon is a biologically stable two state system, with each of the stable states being strongly attractive, a feature indicative of selection for a tightly regulated and responsive system. The model predicts that the state of the GacS/GacA node confers control, a prediction that is consistent with experimental observations that the protein has a role as master regulator. Simulated gene "knock out" experiments with the model predict that HrpL is a central information processing point within the network. PMID- 20169168 TI - Structural ordering of disordered ligand-binding loops of biotin protein ligase into active conformations as a consequence of dehydration. AB - Mycobacterium tuberculosis (Mtb), a dreaded pathogen, has a unique cell envelope composed of high fatty acid content that plays a crucial role in its pathogenesis. Acetyl Coenzyme A Carboxylase (ACC), an important enzyme that catalyzes the first reaction of fatty acid biosynthesis, is biotinylated by biotin acetyl-CoA carboxylase ligase (BirA). The ligand-binding loops in all known apo BirAs to date are disordered and attain an ordered structure only after undergoing a conformational change upon ligand-binding. Here, we report that dehydration of Mtb-BirA crystals traps both the apo and active conformations in its asymmetric unit, and for the first time provides structural evidence of such transformation. Recombinant Mtb-BirA was crystallized at room temperature, and diffraction data was collected at 295 K as well as at 120 K. Transfer of crystals to paraffin and paratone-N oil (cryoprotectants) prior to flash-freezing induced lattice shrinkage and enhancement in the resolution of the X-ray diffraction data. Intriguingly, the crystal lattice rearrangement due to shrinkage in the dehydrated Mtb-BirA crystals ensued structural order of otherwise flexible ligand binding loops L4 and L8 in apo BirA. In addition, crystal dehydration resulted in a shift of approximately 3.5 A in the flexible loop L6, a proline-rich loop unique to Mtb complex as well as around the L11 region. The shift in loop L11 in the C-terminal domain on dehydration emulates the action responsible for the complex formation with its protein ligand biotin carboxyl carrier protein (BCCP) domain of ACCA3. This is contrary to the involvement of loop L14 observed in Pyrococcus horikoshii BirA-BCCP complex. Another interesting feature that emerges from this dehydrated structure is that the two subunits A and B, though related by a noncrystallographic twofold symmetry, assemble into an asymmetric dimer representing the ligand-bound and ligand-free states of the protein, respectively. In-depth analyses of the sequence and the structure also provide answers to the reported lower affinities of Mtb-BirA toward ATP and biotin substrates. This dehydrated crystal structure not only provides key leads to the understanding of the structure/function relationships in the protein in the absence of any ligand-bound structure, but also demonstrates the merit of dehydration of crystals as an inimitable technique to have a glance at proteins in action. PMID- 20169169 TI - Diagnostic strategies for postmenopausal bleeding. AB - Postmenopausal bleeding (PMB) is a common clinical problem. Patients with PMB have 10%-15% chance of having endometrial carcinoma and therefore the diagnostic workup is aimed at excluding malignancy. Patient characteristics can alter the probability of having endometrial carcinoma in patients with PMB; in certain groups of patients the incidence has been reported to be as high as 29%. Transvaginal sonography (TVS) is used as a first step in the diagnostic workup, but different authors have come to different conclusions assessing the accuracy of TVS for excluding endometrial carcinoma. Diagnostic procedures obtaining material for histological assessment (e.g., dilatation and curettage, hysteroscopy, and endometrial biopsy) can be more accurate but are also more invasive. The best diagnostic strategy for diagnosing endometrial carcinoma in patients with PMB still remains controversial. Future research should be focussed on achieving a higher accuracy of different diagnostic strategies. PMID- 20169170 TI - Nitric oxide and respiratory helminthic diseases. AB - Nitric oxide (NO) is a very simple molecule that displays very important functions both in helminths (mainly those involved in respiratory pathology) and in mammalian hosts. In this paper we review four issues related to interaction of NO and lung helminthic diseases. Firstly, we evaluated data available on the NO synthesis and release by helminths and their biological role. Next, we summarized the effect of antigens obtained from different phases of the biological cycle on NO production by host mammalian cells (mainly from human sources). Thirdly, we revised the evaluation of NO on the biological activities and/or the viability of respiratory helminths. Lastly, the deleterious consequences of increased production of NO during helminthic human infection are detailed. PMID- 20169171 TI - Preclinical studies of chemotherapy using histone deacetylase inhibitors in endometrial cancer. AB - Because epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and promotion of tumorigenesis in endometrial cancers, novel compounds endowed with a histone deacetylase (HDAC) inhibitory activity are an attractive therapeutic approach. In this review, we discuss the biologic and therapeutic effects of HDAC inhibitors (HDACIs) in treating endometrial cancer. HDACIs were able to mediate inhibition of cell growth, cell cycle arrest, apoptosis, and the expression of genes related to the malignant phenotype in a variety of endometrial cancer cell lines. Furthermore, HDACIs were able to induce the accumulation of acetylated histones in the chromatin of the p21(WAF1) gene in human endometrial carcinoma cells. In xenograft models, some HDACIs have demonstrated antitumor activity with only few side effects. In this review, we discuss the biologic and therapeutic effects of HDACIs in treating endometrial cancer, with a special focus on preclinical studies. PMID- 20169172 TI - Liver development, regeneration, and carcinogenesis. AB - The identification of putative liver stem cells has brought closer the previously separate fields of liver development, regeneration, and carcinogenesis. Significant overlaps in the regulation of these processes are now being described. For example, studies in embryonic liver development have already provided the basis for directed differentiation of human embryonic stem cells and induced pluripotent stem cells into hepatocyte-like cells. As a result, the understanding of the cell biology of proliferation and differentiation in the liver has been improved. This knowledge can be used to improve the function of hepatocyte-like cells for drug testing, bioartificial livers, and transplantation. In parallel, the mechanisms regulating cancer cell biology are now clearer, providing fertile soil for novel therapeutic approaches. Recognition of the relationships between development, regeneration, and carcinogenesis, and the increasing evidence for the role of stem cells in all of these areas, has sparked fresh enthusiasm in understanding the underlying molecular mechanisms and has led to new targeted therapies for liver cirrhosis and primary liver cancers. PMID- 20169174 TI - Simultaneous Distillation Extraction of Some Volatile Flavor Components from Pu erh Tea Samples-Comparison with Steam Distillation-Liquid/Liquid Extraction and Soxhlet Extraction. AB - A simutaneous distillation extraction (SDE) combined GC method was constructed for determination of volatile flavor components in Pu-erh tea samples. Dichloromethane and ethyl decylate was employed as organic phase in SDE and internal standard in determination, respectively. Weakly polar DB-5 column was used to separate the volatile flavor components in GC, 10 of the components were quantitatively analyzed, and further confirmed by GC-MS. The recovery covered from 66.4%-109%, and repeatability expressed as RSD was in range of 1.44%-12.6%. SDE was most suitable for the extraction of the anlytes by comparing with steam distillation-liquid/liquid extraction and Soxhlet extraction. Commercially available Pu-erh tea samples, including Pu-erh raw tea and ripe tea, were analyzed by the constructed method. the high-volatile components, such as benzyl alcohol, linalool oxide, and linalool, were greatly rich in Pu-erh raw teas, while the contents of 1,2,3-Trimethoxylbenzene and 1,2,4-Trimethoxylbenzene were much high in Pu-erh ripe teas. PMID- 20169173 TI - Macrophage migration inhibitory factor: critical role in obesity, insulin resistance, and associated comorbidities. AB - Obesity is associated with insulin resistance, disturbed glucose homeostasis, low grade inflammation, and comorbidities such as type 2 diabetes and cardiovascular disease. The cytokine macrophage migration inhibitory factor (MIF) is an ubiquitously expressed protein that plays a crucial role in many inflammatory and autoimmune disorders. Increasing evidence suggests that MIF also controls metabolic and inflammatory processes underlying the development of metabolic pathologies associated with obesity. This is a comprehensive summary of our current knowledge on the role of MIF in obesity and obesity-associated comorbidities, based on human clinical data as well as animal models of disease. PMID- 20169175 TI - Contributions of matrix metalloproteinases to neural plasticity, habituation, associative learning and drug addiction. AB - The premise of this paper is that increased expression of matrix metalloproteinases (MMPs) permits the reconfiguration of synaptic connections (i.e., neural plasticity) by degrading cell adhesion molecules (CAMs) designed to provide stability to those extracellular matrix (ECM) proteins that form scaffolding supporting neurons and glia. It is presumed that while these ECM proteins are weakened, and/or detached, synaptic connections can form resulting in new neural pathways. Tissue inhibitors of metalloproteinases (TIMPs) are designed to deactivate MMPs permitting the reestablishment of CAMs, thus returning the system to a reasonably fixed state. This review considers available findings concerning the roles of MMPs and TIMPs in reorganizing ECM proteins thus facilitating the neural plasticity underlying long-term potentiation (LTP), habituation, and associative learning. We conclude with a consideration of the influence of these phenomena on drug addiction, given that these same processes may be instrumental in the formation of addiction and subsequent relapse. However, our knowledge concerning the precise spatial and temporal relationships among the mechanisms of neural plasticity, habituation, associative learning, and memory consolidation is far from complete and the possibility that these phenomena mediate drug addiction is a new direction of research. PMID- 20169176 TI - A kinetic model of dopamine- and calcium-dependent striatal synaptic plasticity. AB - Corticostriatal synapse plasticity of medium spiny neurons is regulated by glutamate input from the cortex and dopamine input from the substantia nigra. While cortical stimulation alone results in long-term depression (LTD), the combination with dopamine switches LTD to long-term potentiation (LTP), which is known as dopamine-dependent plasticity. LTP is also induced by cortical stimulation in magnesium-free solution, which leads to massive calcium influx through NMDA-type receptors and is regarded as calcium-dependent plasticity. Signaling cascades in the corticostriatal spines are currently under investigation. However, because of the existence of multiple excitatory and inhibitory pathways with loops, the mechanisms regulating the two types of plasticity remain poorly understood. A signaling pathway model of spines that express D1-type dopamine receptors was constructed to analyze the dynamic mechanisms of dopamine- and calcium-dependent plasticity. The model incorporated all major signaling molecules, including dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP32), as well as AMPA receptor trafficking in the post-synaptic membrane. Simulations with dopamine and calcium inputs reproduced dopamine- and calcium-dependent plasticity. Further in silico experiments revealed that the positive feedback loop consisted of protein kinase A (PKA), protein phosphatase 2A (PP2A), and the phosphorylation site at threonine 75 of DARPP-32 (Thr75) served as the major switch for inducing LTD and LTP. Calcium input modulated this loop through the PP2B (phosphatase 2B)-CK1 (casein kinase 1)-Cdk5 (cyclin-dependent kinase 5)-Thr75 pathway and PP2A, whereas calcium and dopamine input activated the loop via PKA activation by cyclic AMP (cAMP). The positive feedback loop displayed robust bi-stable responses following changes in the reaction parameters. Increased basal dopamine levels disrupted this dopamine-dependent plasticity. The present model elucidated the mechanisms involved in bidirectional regulation of corticostriatal synapses and will allow for further exploration into causes and therapies for dysfunctions such as drug addiction. PMID- 20169177 TI - Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. AB - Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33x10(-11), OR = 1.29; WDFY4: rs7097397, P = 8.15x10(-12), OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3'-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved. PMID- 20169178 TI - The scale of population structure in Arabidopsis thaliana. AB - The population structure of an organism reflects its evolutionary history and influences its evolutionary trajectory. It constrains the combination of genetic diversity and reveals patterns of past gene flow. Understanding it is a prerequisite for detecting genomic regions under selection, predicting the effect of population disturbances, or modeling gene flow. This paper examines the detailed global population structure of Arabidopsis thaliana. Using a set of 5,707 plants collected from around the globe and genotyped at 149 SNPs, we show that while A. thaliana as a species self-fertilizes 97% of the time, there is considerable variation among local groups. This level of outcrossing greatly limits observed heterozygosity but is sufficient to generate considerable local haplotypic diversity. We also find that in its native Eurasian range A. thaliana exhibits continuous isolation by distance at every geographic scale without natural breaks corresponding to classical notions of populations. By contrast, in North America, where it exists as an exotic species, A. thaliana exhibits little or no population structure at a continental scale but local isolation by distance that extends hundreds of km. This suggests a pattern for the development of isolation by distance that can establish itself shortly after an organism fills a new habitat range. It also raises questions about the general applicability of many standard population genetics models. Any model based on discrete clusters of interchangeable individuals will be an uneasy fit to organisms like A. thaliana which exhibit continuous isolation by distance on many scales. PMID- 20169179 TI - Transcriptional rewiring of the sex determining dmrt1 gene duplicate by transposable elements. AB - Control and coordination of eukaryotic gene expression rely on transcriptional and posttranscriptional regulatory networks. Evolutionary innovations and adaptations often require rapid changes of such networks. It has long been hypothesized that transposable elements (TE) might contribute to the rewiring of regulatory interactions. More recently it emerged that TEs might bring in ready to-use transcription factor binding sites to create alterations to the promoters by which they were captured. A process where the gene regulatory architecture is of remarkable plasticity is sex determination. While the more downstream components of the sex determination cascades are evolutionary conserved, the master regulators can switch between groups of organisms even on the interspecies level or between populations. In the medaka fish (Oryzias latipes) a duplicated copy of dmrt1, designated dmrt1bY or DMY, on the Y chromosome was shown to be the master regulator of male development, similar to Sry in mammals. We found that the dmrt1bY gene has acquired a new feedback downregulation of its expression. Additionally, the autosomal dmrt1a gene is also able to regulate transcription of its duplicated paralog by binding to a unique target Dmrt1 site nested within the dmrt1bY proximal promoter region. We could trace back this novel regulatory element to a highly conserved sequence within a new type of TE that inserted into the upstream region of dmrt1bY shortly after the duplication event. Our data provide functional evidence for a role of TEs in transcriptional network rewiring for sub- and/or neo-functionalization of duplicated genes. In the particular case of dmrt1bY, this contributed to create new hierarchies of sex-determining genes. PMID- 20169180 TI - Uncoupling of satellite DNA and centromeric function in the genus Equus. AB - In a previous study, we showed that centromere repositioning, that is the shift along the chromosome of the centromeric function without DNA sequence rearrangement, has occurred frequently during the evolution of the genus Equus. In this work, the analysis of the chromosomal distribution of satellite tandem repeats in Equus caballus, E. asinus, E. grevyi, and E. burchelli highlighted two atypical features: 1) several centromeres, including the previously described evolutionary new centromeres (ENCs), seem to be devoid of satellite DNA, and 2) satellite repeats are often present at non-centromeric termini, probably corresponding to relics of ancestral now inactive centromeres. Immuno-FISH experiments using satellite DNA and antibodies against the kinetochore protein CENP-A demonstrated that satellite-less primary constrictions are actually endowed with centromeric function. The phylogenetic reconstruction of centromere repositioning events demonstrates that the acquisition of satellite DNA occurs after the formation of the centromere during evolution and that centromeres can function over millions of years and many generations without detectable satellite DNA. The rapidly evolving Equus species gave us the opportunity to identify different intermediate steps along the full maturation of ENCs. PMID- 20169181 TI - Spatial and topological organization of DNA chains induced by gene co localization. AB - Transcriptional activity has been shown to relate to the organization of chromosomes in the eukaryotic nucleus and in the bacterial nucleoid. In particular, highly transcribed genes, RNA polymerases and transcription factors gather into discrete spatial foci called transcription factories. However, the mechanisms underlying the formation of these foci and the resulting topological order of the chromosome remain to be elucidated. Here we consider a thermodynamic framework based on a worm-like chain model of chromosomes where sparse designated sites along the DNA are able to interact whenever they are spatially close by. This is motivated by recurrent evidence that there exist physical interactions between genes that operate together. Three important results come out of this simple framework. First, the resulting formation of transcription foci can be viewed as a micro-phase separation of the interacting sites from the rest of the DNA. In this respect, a thermodynamic analysis suggests transcription factors to be appropriate candidates for mediating the physical interactions between genes. Next, numerical simulations of the polymer reveal a rich variety of phases that are associated with different topological orderings, each providing a way to increase the local concentrations of the interacting sites. Finally, the numerical results show that both one-dimensional clustering and periodic location of the binding sites along the DNA, which have been observed in several organisms, make the spatial co-localization of multiple families of genes particularly efficient. PMID- 20169182 TI - The Syk kinase SmTK4 of Schistosoma mansoni is involved in the regulation of spermatogenesis and oogenesis. AB - The signal transduction protein SmTK4 from Schistosoma mansoni belongs to the family of Syk kinases. In vertebrates, Syk kinases are known to play specialized roles in signaling pathways in cells of the hematopoietic system. Although Syk kinases were identified in some invertebrates, their role in this group of animals has not yet been elucidated. Since SmTK4 is the first Syk kinase from a parasitic helminth, shown to be predominantly expressed in the testes and ovary of adult worms, we investigated its function. To unravel signaling cascades in which SmTK4 is involved, yeast two-/three-hybrid library screenings were performed with either the tandem SH2-domain, or with the linker region including the tyrosine kinase domain of SmTK4. Besides the Src kinase SmTK3 we identified a new Src kinase (SmTK6) acting upstream of SmTK4 and a MAPK-activating protein, as well as mapmodulin acting downstream. Their identities and colocalization studies pointed to a role of SmTK4 in a signaling cascade regulating the proliferation and/or differentiation of cells in the gonads of schistosomes. To confirm this decisive role we performed biochemical and molecular approaches to knock down SmTK4 combined with a novel protocol for confocal laser scanning microscopy for morphological analyses. Using the Syk kinase-specific inhibitor Piceatannol or by RNAi treatment of adult schistosomes in vitro, corresponding phenotypes were detected in the testes and ovary. In the Xenopus oocyte system it was finally confirmed that Piceatannol suppressed the activity of the catalytic kinase domain of SmTK4. Our findings demonstrate a pivotal role of SmTK4 in gametogenesis, a new function for Syk kinases in eukaryotes. PMID- 20169183 TI - A novel pseudopodial component of the dendritic cell anti-fungal response: the fungipod. AB - Fungal pathologies are seen in immunocompromised and healthy humans. C-type lectins expressed on immature dendritic cells (DC) recognize fungi. We report a novel dorsal pseudopodial protrusion, the "fungipod", formed by DC after contact with yeast cell walls. These structures have a convoluted cell-proximal end and a smooth distal end. They persist for hours, exhibit noticeable growth and total 13.7+/-5.6 microm long and 1.8+/-0.67 microm wide at the contact. Fungipods contain clathrin and an actin core surrounded by a sheath of cortactin. The actin cytoskeleton, but not microtubules, is required for fungipod integrity and growth. An apparent rearward flow (225+/-55 nm/second) exists from the zymosan contact site into the distal fungipod. The phagocytic receptor Dectin-1 is not required for fungipod formation, but CD206 (Mannose Receptor) is the generative receptor for these protrusions. The human pathogen Candida parapsilosis induces DC fungipod formation strongly, but the response is species specific since the related fungal pathogens Candida tropicalis and Candida albicans induce very few and no fungipods, respectively. Our findings show that fungipods are dynamic actin-driven cellular structures involved in fungal recognition by DC. They may promote yeast particle phagocytosis by DC and are a specific response to large (i.e., 5 microm) particulate ligands. Our work also highlights the importance of this novel protrusive structure to innate immune recognition of medically significant Candida yeasts in a species specific fashion. PMID- 20169184 TI - A broad distribution of the alternative oxidase in microsporidian parasites. AB - Microsporidia are a group of obligate intracellular parasitic eukaryotes that were considered to be amitochondriate until the recent discovery of highly reduced mitochondrial organelles called mitosomes. Analysis of the complete genome of Encephalitozoon cuniculi revealed a highly reduced set of proteins in the organelle, mostly related to the assembly of iron-sulphur clusters. Oxidative phosphorylation and the Krebs cycle proteins were absent, in keeping with the notion that the microsporidia and their mitosomes are anaerobic, as is the case for other mitosome bearing eukaryotes, such as Giardia. Here we provide evidence opening the possibility that mitosomes in a number of microsporidian lineages are not completely anaerobic. Specifically, we have identified and characterized a gene encoding the alternative oxidase (AOX), a typically mitochondrial terminal oxidase in eukaryotes, in the genomes of several distantly related microsporidian species, even though this gene is absent from the complete genome of E. cuniculi. In order to confirm that these genes encode functional proteins, AOX genes from both A. locustae and T. hominis were over-expressed in E. coli and AOX activity measured spectrophotometrically using ubiquinol-1 (UQ-1) as substrate. Both A. locustae and T. hominis AOX proteins reduced UQ-1 in a cyanide and antimycin resistant manner that was sensitive to ascofuranone, a potent inhibitor of the trypanosomal AOX. The physiological role of AOX microsporidia may be to reoxidise reducing equivalents produced by glycolysis, in a manner comparable to that observed in trypanosomes. PMID- 20169185 TI - Pathogen entrapment by transglutaminase--a conserved early innate immune mechanism. AB - Clotting systems are required in almost all animals to prevent loss of body fluids after injury. Here, we show that despite the risks associated with its systemic activation, clotting is a hitherto little appreciated branch of the immune system. We compared clotting of human blood and insect hemolymph to study the best-conserved component of clotting systems, namely the Drosophila enzyme transglutaminase and its vertebrate homologue Factor XIIIa. Using labelled artificial substrates we observe that transglutaminase activity from both Drosophila hemolymph and human blood accumulates on microbial surfaces, leading to their sequestration into the clot. Using both a human and a natural insect pathogen we provide functional proof for an immune function for transglutaminase (TG). Drosophila larvae with reduced TG levels show increased mortality after septic injury. The same larvae are also more susceptible to a natural infection involving entomopathogenic nematodes and their symbiotic bacteria while neither phagocytosis, phenoloxidase or-as previously shown-the Toll or imd pathway contribute to immunity. These results firmly establish the hemolymph/blood clot as an important effector of early innate immunity, which helps to prevent septic infections. These findings will help to guide further strategies to reduce the damaging effects of clotting and enhance its beneficial contribution to immune reactions. PMID- 20169187 TI - On the diversity of malaria parasites in African apes and the origin of Plasmodium falciparum from Bonobos. AB - The origin of Plasmodium falciparum, the etiological agent of the most dangerous forms of human malaria, remains controversial. Although investigations of homologous parasites in African Apes are crucial to resolve this issue, studies have been restricted to a chimpanzee parasite related to P. falciparum, P. reichenowi, for which a single isolate was available until very recently. Using PCR amplification, we detected Plasmodium parasites in blood samples from 18 of 91 individuals of the genus Pan, including six chimpanzees (three Pan troglodytes troglodytes, three Pan t. schweinfurthii) and twelve bonobos (Pan paniscus). We obtained sequences of the parasites' mitochondrial genomes and/or from two nuclear genes from 14 samples. In addition to P. reichenowi, three other hitherto unknown lineages were found in the chimpanzees. One is related to P. vivax and two to P. falciparum that are likely to belong to distinct species. In the bonobos we found P. falciparum parasites whose mitochondrial genomes indicated that they were distinct from those present in humans, and another parasite lineage related to P. malariae. Phylogenetic analyses based on this diverse set of Plasmodium parasites in African Apes shed new light on the evolutionary history of P. falciparum. The data suggested that P. falciparum did not originate from P. reichenowi of chimpanzees (Pan troglodytes), but rather evolved in bonobos (Pan paniscus), from which it subsequently colonized humans by a host switch. Finally, our data and that of others indicated that chimpanzees and bonobos maintain malaria parasites, to which humans are susceptible, a factor of some relevance to the renewed efforts to eradicate malaria. PMID- 20169186 TI - Six RNA viruses and forty-one hosts: viral small RNAs and modulation of small RNA repertoires in vertebrate and invertebrate systems. AB - We have used multiplexed high-throughput sequencing to characterize changes in small RNA populations that occur during viral infection in animal cells. Small RNA-based mechanisms such as RNA interference (RNAi) have been shown in plant and invertebrate systems to play a key role in host responses to viral infection. Although homologs of the key RNAi effector pathways are present in mammalian cells, and can launch an RNAi-mediated degradation of experimentally targeted mRNAs, any role for such responses in mammalian host-virus interactions remains to be characterized. Six different viruses were examined in 41 experimentally susceptible and resistant host systems. We identified virus-derived small RNAs (vsRNAs) from all six viruses, with total abundance varying from "vanishingly rare" (less than 0.1% of cellular small RNA) to highly abundant (comparable to abundant micro-RNAs "miRNAs"). In addition to the appearance of vsRNAs during infection, we saw a number of specific changes in host miRNA profiles. For several infection models investigated in more detail, the RNAi and Interferon pathways modulated the abundance of vsRNAs. We also found evidence for populations of vsRNAs that exist as duplexed siRNAs with zero to three nucleotide 3' overhangs. Using populations of cells carrying a Hepatitis C replicon, we observed strand-selective loading of siRNAs onto Argonaute complexes. These experiments define vsRNAs as one possible component of the interplay between animal viruses and their hosts. PMID- 20169188 TI - Universal features of post-transcriptional gene regulation are critical for Plasmodium zygote development. AB - A universal feature of metazoan sexual development is the generation of oocyte P granules that withhold certain mRNA species from translation to provide coding potential for proteins during early post-fertilization development. Stabilisation of translationally quiescent mRNA pools in female Plasmodium gametocytes depends on the RNA helicase DOZI, but the molecular machinery involved in the silencing of transcripts in these protozoans is unknown. Using affinity purification coupled with mass-spectrometric analysis we identify a messenger ribonucleoprotein (mRNP) from Plasmodium berghei gametocytes defined by DOZI and the Sm-like factor CITH (homolog of worm CAR-I and fly Trailer Hitch). This mRNP includes 16 major factors, including proteins with homologies to components of metazoan P granules and archaeal proteins. Containing translationally silent transcripts, this mRNP integrates eIF4E and poly(A)-binding protein but excludes P body RNA degradation factors and translation-initiation promoting eIF4G. Gene deletion mutants of 2 core components of this mRNP (DOZI and CITH) are fertilization-competent, but zygotes fail to develop into ookinetes in a female gametocyte-mutant fashion. Through RNA-immunoprecipitation and global expression profiling of CITH-KO mutants we highlight CITH as a crucial repressor of maternally supplied mRNAs. Our data define Plasmodium P granules as an ancient mRNP whose protein core has remained evolutionarily conserved from single-cell organisms to germ cells of multi-cellular animals and stores translationally silent mRNAs that are critical for early post-fertilization development during the initial stages of mosquito infection. Therefore, translational repression may offer avenues as a target for the generation of transmission blocking strategies and contribute to limiting the spread of malaria. PMID- 20169189 TI - Direct presentation is sufficient for an efficient anti-viral CD8+ T cell response. AB - The extent to which direct- and cross-presentation (DP and CP) contribute to the priming of CD8(+) T cell (T(CD8+)) responses to viruses is unclear mainly because of the difficulty in separating the two processes. Hence, while CP in the absence of DP has been clearly demonstrated, induction of an anti-viral T(CD8+) response that excludes CP has never been purposely shown. Using vaccinia virus (VACV), which has been used as the vaccine to rid the world of smallpox and is proposed as a vector for many other vaccines, we show that DP is the main mechanism for the priming of an anti-viral T(CD8+) response. These findings provide important insights to our understanding of how one of the most effective anti-viral vaccines induces immunity and should contribute to the development of novel vaccines. PMID- 20169191 TI - Decrease of plasma platelet-activating factor acetylhydrolase activity in lipopolysaccharide induced mongolian gerbil sepsis model. AB - Platelet-activating factor (PAF) plays an important role in the pathogenesis of sepsis, and the level of plasma PAF acetylhydrolase (pPAF-AH), which inactivates PAF, decreases in sepsis patients except for the sepsis caused by severe leptospirosis. Usually, increase of pPAF-AH activity was observed in lipopolysaccharide (LPS)-induced Syrian hamster and rat sepsis models, while contradictory effects were reported for mouse model in different studies. Here, we demonstrated the in vivo effects of LPS upon the change of pPAF-AH activity in C57BL/6 mice and Mongolian gerbils. After LPS-treatment, the clinical manifestations of Mongolian gerbil model were apparently similar to that of C57BL/6 mouse sepsis model. The pPAF-AH activity increased in C57BL/6 mice after LPS induction, but decreased in Mongolian gerbils, which was similar to that of the human sepsis. It thus suggests that among the LPS-induced rodent sepsis models, only Mongolian gerbil could be used for the study of pPAF-AH related to the pathogenesis of human sepsis. Proper application of this model might enable people to clarify the underline mechanism accounted for the contradictory results between the phase II and phase III clinical trials for the administration of recombinant human pPAF-AH in the sepsis therapy. PMID- 20169190 TI - Kaposi's sarcoma associated herpes virus (KSHV) induced COX-2: a key factor in latency, inflammation, angiogenesis, cell survival and invasion. AB - Kaposi's sarcoma (KS), an enigmatic endothelial cell vascular neoplasm, is characterized by the proliferation of spindle shaped endothelial cells, inflammatory cytokines (ICs), growth factors (GFs) and angiogenic factors. KSHV is etiologically linked to KS and expresses its latent genes in KS lesion endothelial cells. Primary infection of human micro vascular endothelial cells (HMVEC-d) results in the establishment of latent infection and reprogramming of host genes, and cyclooxygenase-2 (COX-2) is one of the highly up-regulated genes. Our previous study suggested a role for COX-2 in the establishment and maintenance of KSHV latency. Here, we examined the role of COX-2 in the induction of ICs, GFs, angiogenesis and invasive events occurring during KSHV de novo infection of endothelial cells. A significant amount of COX-2 was detected in KS tissue sections. Telomerase-immortalized human umbilical vein endothelial cells supporting KSHV stable latency (TIVE-LTC) expressed elevated levels of functional COX-2 and microsomal PGE2 synthase (m-PGES), and secreted the predominant eicosanoid inflammatory metabolite PGE2. Infected HMVEC-d and TIVE-LTC cells secreted a variety of ICs, GFs, angiogenic factors and matrix metalloproteinases (MMPs), which were significantly abrogated by COX-2 inhibition either by chemical inhibitors or by siRNA. The ability of these factors to induce tube formation of uninfected endothelial cells was also inhibited. PGE2, secreted early during KSHV infection, profoundly increased the adhesion of uninfected endothelial cells to fibronectin by activating the small G protein Rac1. COX-2 inhibition considerably reduced KSHV latent ORF73 gene expression and survival of TIVE-LTC cells. Collectively, these studies underscore the pivotal role of KSHV induced COX 2/PGE2 in creating KS lesion like microenvironment during de novo infection. Since COX-2 plays multiple roles in KSHV latent gene expression, which themselves are powerful mediators of cytokine induction, anti-apoptosis, cell survival and viral genome maintainence, effective inhibition of COX-2 via well-characterized clinically approved COX-2 inhibitors could potentially be used in treatment to control latent KSHV infection and ameliorate KS. PMID- 20169192 TI - A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen. AB - Cellular senescence irreversibly arrests cell proliferation in response to oncogenic stimuli. Human cells develop a senescence-associated secretory phenotype (SASP), which increases the secretion of cytokines and other factors that alter the behavior of neighboring cells. We show here that "senescent" mouse fibroblasts, which arrested growth after repeated passage under standard culture conditions (20% oxygen), do not express a human-like SASP, and differ from similarly cultured human cells in other respects. However, when cultured in physiological (3%) oxygen and induced to senesce by radiation, mouse cells more closely resemble human cells, including expression of a robust SASP. We describe two new aspects of the human and mouse SASPs. First, cells from both species upregulated the expression and secretion of several matrix metalloproteinases, which comprise a conserved genomic cluster. Second, for both species, the ability to promote the growth of premalignant epithelial cells was due primarily to the conserved SASP factor CXCL-1/KC/GRO-alpha. Further, mouse fibroblasts made senescent in 3%, but not 20%, oxygen promoted epithelial tumorigenesis in mouse xenographs. Our findings underscore critical mouse-human differences in oxygen sensitivity, identify conditions to use mouse cells to model human cellular senescence, and reveal novel conserved features of the SASP. PMID- 20169193 TI - Inheritance of DNA transferred from American trypanosomes to human hosts. AB - Interspecies DNA transfer is a major biological process leading to the accumulation of mutations inherited by sexual reproduction among eukaryotes. Lateral DNA transfer events and their inheritance has been challenging to document. In this study we modified a thermal asymmetric interlaced PCR by using additional targeted primers, along with Southern blots, fluorescence techniques, and bioinformatics, to identify lateral DNA transfer events from parasite to host. Instances of naturally occurring human infections by Trypanosoma cruzi are documented, where mitochondrial minicircles integrated mainly into retrotransposable LINE-1 of various chromosomes. The founders of five families show minicircle integrations that were transferred vertically to their progeny. Microhomology end-joining of 6 to 22 AC-rich nucleotide repeats in the minicircles and host DNA mediates foreign DNA integration. Heterogeneous minicircle sequences were distributed randomly among families, with diversity increasing due to subsequent rearrangement of inserted fragments. Mosaic recombination and hitchhiking on retrotransposition events to different loci were more prevalent in germ line as compared to somatic cells. Potential new genes, pseudogenes, and knockouts were identified. A pathway of minicircle integration and maintenance in the host genome is suggested. Thus, infection by T. cruzi has the unexpected consequence of increasing human genetic diversity, and Chagas disease may be a fortuitous share of negative selection. This demonstration of contemporary transfer of eukaryotic DNA to the human genome and its subsequent inheritance by descendants introduces a significant change in the scientific concept of evolutionary biology and medicine. PMID- 20169194 TI - Structural and functional restraints on the occurrence of single amino acid variations in human proteins. AB - Human genetic variation is the incarnation of diverse evolutionary history, which reflects both selectively advantageous and selectively neutral change. In this study, we catalogue structural and functional features of proteins that restrain genetic variation leading to single amino acid substitutions. Our variation dataset is divided into three categories: i) Mendelian disease-related variants, ii) neutral polymorphisms and iii) cancer somatic mutations. We characterize structural environments of the amino acid variants by the following properties: i) side-chain solvent accessibility, ii) main-chain secondary structure, and iii) hydrogen bonds from a side chain to a main chain or other side chains. To address functional restraints, amino acid substitutions in proteins are examined to see whether they are located at functionally important sites involved in protein protein interactions, protein-ligand interactions or catalytic activity of enzymes. We also measure the likelihood of amino acid substitutions and the degree of residue conservation where variants occur. We show that various types of variants are under different degrees of structural and functional restraints, which affect their occurrence in human proteome. PMID- 20169195 TI - Automated network analysis identifies core pathways in glioblastoma. AB - BACKGROUND: Glioblastoma multiforme (GBM) is the most common and aggressive type of brain tumor in humans and the first cancer with comprehensive genomic profiles mapped by The Cancer Genome Atlas (TCGA) project. A central challenge in large scale genome projects, such as the TCGA GBM project, is the ability to distinguish cancer-causing "driver" mutations from passively selected "passenger" mutations. PRINCIPAL FINDINGS: In contrast to a purely frequency based approach to identifying driver mutations in cancer, we propose an automated network-based approach for identifying candidate oncogenic processes and driver genes. The approach is based on the hypothesis that cellular networks contain functional modules, and that tumors target specific modules critical to their growth. Key elements in the approach include combined analysis of sequence mutations and DNA copy number alterations; use of a unified molecular interaction network consisting of both protein-protein interactions and signaling pathways; and identification and statistical assessment of network modules, i.e. cohesive groups of genes of interest with a higher density of interactions within groups than between groups. CONCLUSIONS: We confirm and extend the observation that GBM alterations tend to occur within specific functional modules, in spite of considerable patient-to-patient variation, and that two of the largest modules involve signaling via p53, Rb, PI3K and receptor protein kinases. We also identify new candidate drivers in GBM, including AGAP2/CENTG1, a putative oncogene and an activator of the PI3K pathway; and, three additional significantly altered modules, including one involved in microtubule organization. To facilitate the application of our network-based approach to additional cancer types, we make the method freely available as part of a software tool called NetBox. PMID- 20169196 TI - Anticipatory modulation of digit placement for grasp control is affected by Parkinson's disease. AB - BACKGROUND: Successful object manipulation relies on the ability to form and retrieve sensorimotor memories of digit forces and positions used in previous object lifts. Past studies of patients affected by Parkinson's disease (PD) have revealed that the basal ganglia play a crucial role in the acquisition and/or retrieval of sensorimotor memories for grasp control. Whereas it is known that PD impairs anticipatory control of digit forces during grasp, learning deficits associated with the planning of digit placement have yet to be explored. This question is motivated by recent work in healthy subjects revealing that anticipatory control of digit placement plays a crucial role for successful manipulation. METHODOLOGY/PRINCIPAL FINDINGS: We asked ten PD patients off medication and ten age-matched controls to reach, grasp and lift an object whose center of mass (CM) was on the left, right or center. The only task requirement was to minimize object roll during lift. The CM remained the same across consecutive trials (blocked condition) or was altered from trial to trial (random condition). We hypothesized that impairment of the basal ganglia-thalamo-cortical circuits in PD patients would reduce their ability to anticipate digit placement appropriate to the CM location. Consequently, we predicted that PD patients would exhibit similar digit placement in the blocked vs. random conditions and produce larger peak object rolls than that of control subjects. In the blocked condition, PD patients exhibited significantly weaker modulation of fingertip contact points to CM location and larger object roll than controls (p<0.05 and p<0.01, respectively). Nevertheless, both controls and PD patients minimized object roll more in the blocked than in the random condition (p<0.01). CONCLUSIONS/SIGNIFICANCE: Our findings indicate that, even though PD patients may have a residual ability of anticipatory control of digit contact points and forces, they fail to implement a motor plan with the same degree of effectiveness as controls. We conclude that intact basal ganglia-thalamo-cortical circuits are necessary for successful sensorimotor learning of both grasp kinematics and kinetics required for dexterous hand-object interactions. PMID- 20169197 TI - IL-9 induces CCL11 expression via STAT3 signalling in human airway smooth muscle cells. AB - BACKGROUND: Previous findings support the concept that IL-9 may play a significant role in mediating both pro-inflammatory and changes in airway responsiveness that characterizes the atopic asthmatic state. We previously demonstrated that human airway smooth muscle (ASM) cells express a functional IL 9R that mediate CCL11 expression. However, the signaling pathway governing this effect is not well understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we showed that IL-9 mediated CCL11 expression in ASM cells does not rely on STAT6 or STAT5 but on STAT3 pathway. IL-9 induced rapid STAT3 activation in primary ASM cells that was not observed in case of STAT6 or STAT5. STAT3 binding to CCL11 promoter was also observed in vivo upon IL-9 stimulation of ASM cells. Disruption of STAT3 activity with SH2 domain binding inhibitory peptide results in significant reduction of IL-9 mediated CCL11 promoter activity. DN STAT3beta over expression in ASM cells, but not Ser 727 STAT3 or STAT6 DN, abolishes IL-9 mediated CCL11 promoter activity. Finally, STAT3 but not STAT6 silenced ASM cells showed significant reduction in IL-9 mediated CCL11 promoter activity and mRNA expression. CONCLUSION/SIGNIFICANCE: Taken together, our results indicate that IL 9 mediated CCL11 via STAT3 signalling pathway may play a crucial role in airway inflammatory responses. PMID- 20169198 TI - Mechanistic characterization and molecular modeling of hepatitis B virus polymerase resistance to entecavir. AB - BACKGROUND: Entecavir (ETV) is a deoxyguanosine analog competitive inhibitor of hepatitis B virus (HBV) polymerase that exhibits delayed chain termination of HBV DNA. A high barrier to entecavir-resistance (ETVr) is observed clinically, likely due to its potency and a requirement for multiple resistance changes to overcome suppression. Changes in the HBV polymerase reverse-transcriptase (RT) domain involve lamivudine-resistance (LVDr) substitutions in the conserved YMDD motif (M204V/I +/- L180M), plus an additional ETV-specific change at residues T184, S202 or M250. These substitutions surround the putative dNTP binding site or primer grip regions of the HBV RT. METHODS/PRINCIPAL FINDINGS: To determine the mechanistic basis for ETVr, wildtype, lamivudine-resistant (M204V, L180M) and ETVr HBVs were studied using in vitro RT enzyme and cell culture assays, as well as molecular modeling. Resistance substitutions significantly reduced ETV incorporation and chain termination in HBV DNA and increased the ETV-TP inhibition constant (K(i)) for HBV RT. Resistant HBVs exhibited impaired replication in culture and reduced enzyme activity (k(cat)) in vitro. Molecular modeling of the HBV RT suggested that ETVr residue T184 was adjacent to and stabilized S202 within the LVDr YMDD loop. ETVr arose through steric changes at T184 or S202 or by disruption of hydrogen-bonding between the two, both of which repositioned the loop and reduced the ETV-triphosphate (ETV-TP) binding pocket. In contrast to T184 and S202 changes, ETVr at primer grip residue M250 was observed during RNA-directed DNA synthesis only. Experimentally, M250 changes also impacted the dNTP-binding site. Modeling suggested a novel mechanism for M250 resistance, whereby repositioning of the primer-template component of the dNTP-binding site shifted the ETV-TP binding pocket. No structural data are available to confirm the HBV RT modeling, however, results were consistent with phenotypic analysis of comprehensive substitutions of each ETVr position. CONCLUSIONS: Altogether, ETVr occurred through exclusion of ETV-TP from the dNTP binding site, through different, novel mechanisms that involved lamivudine resistance, ETV-specific substitutions, and the primer-template. PMID- 20169199 TI - Growing Burkholderia pseudomallei in biofilm stimulating conditions significantly induces antimicrobial resistance. AB - BACKGROUND: Burkholderia pseudomallei, a gram-negative bacterium that causes melioidosis, was reported to produce biofilm. As the disease causes high relapse rate when compared to other bacterial infections, it therefore might be due to the reactivation of the biofilm forming bacteria which also provided resistance to antimicrobial agents. However, the mechanism on how biofilm can provide tolerance to antimicrobials is still unclear. METHODOLOGY/PRINCIPAL FINDINGS: The change in resistance of B. pseudomallei to doxycycline, ceftazidime, imipenem, and trimethoprim/sulfamethoxazole during biofilm formation were measured as minimum biofilm elimination concentration (MBEC) in 50 soil and clinical isolates and also in capsule, flagellin, LPS and biofilm mutants. Almost all planktonic isolates were susceptible to all agents studied. In contrast, when they were grown in the condition that induced biofilm formation, they were markedly resistant to all antimicrobial agents even though the amount of biofilm production was not the same. The capsule and O-side chains of LPS mutants had no effect on biofilm formation whereas the flagellin-defective mutant markedly reduced in biofilm production. No alteration of LPS profiles was observed when susceptible form was changed to resistance. The higher amount of N-acyl homoserine lactones (AHLs) was detected in the high biofilm-producing isolates. Interestingly, the biofilm mutant which produced a very low amount of biofilm and was sensitive to antimicrobial agents significantly resisted those agents when grown in biofilm inducing condition. CONCLUSIONS/SIGNIFICANCE: The possible drug resistance mechanism of biofilm mutants and other isolates is not by having biofilm but rather from some factors that up-regulated when biofilm formation genes were stimulated. The understanding of genes related to this situation may lead us to prevent B. pseudomallei biofilms leading to the relapse of melioidosis. PMID- 20169200 TI - Evolution and ecophysiology of the industrial producer Hypocrea jecorina (Anamorph Trichoderma reesei) and a new sympatric agamospecies related to it. AB - BACKGROUND: Trichoderma reesei, a mitosporic green mould, was recognized during the WW II based on a single isolate from the Solomon Islands and since then used in industry for production of cellulases. It is believed to be an anamorph (asexual stage) of the common pantropical ascomycete Hypocrea jecorina. METHODOLOGY/PRINCIPAL FINDINGS: We combined molecular evolutionary analysis and multiple methods of phenotype profiling in order to reveal the genetic relationship of T. reesei to H. jecorina. The resulting data show that the isolates which were previously identified as H. jecorina by means of morphophysiology and ITS1 and 2 (rRNA gene cluster) barcode in fact comprise several species: i) H. jecorina/T. reesei sensu stricto which contains most of the teleomorphs (sexual stages) found on dead wood and the wild-type strain of T. reesei QM 6a; ii) T. parareesei nom. prov., which contains all strains isolated as anamorphs from soil; iii) and two other hypothetical new species for which only one or two isolates are available. In silico tests for recombination and in vitro mating experiments revealed a history of sexual reproduction for H. jecorina and confirmed clonality for T. parareesei nom. prov. Isolates of both species were consistently found worldwide in pantropical climatic zone. Ecophysiological comparison of H. jecorina and T. parareesei nom. prov. revealed striking differences in carbon source utilization, conidiation intensity, photosensitivity and mycoparasitism, thus suggesting adaptation to different ecological niches with the high opportunistic potential for T. parareesei nom. prov. CONCLUSIONS: Our data prove that T. reesei belongs to a holomorph H. jecorina and displays a history of worldwide gene flow. We also show that its nearest genetic neighbour--T. parareesei nom. prov., is a cryptic phylogenetic agamospecies which inhabits the same biogeographic zone. These two species thus provide a so far rare example of sympatric speciation within saprotrophic fungi, with divergent ecophysiological adaptations and reproductive strategies. PMID- 20169201 TI - Enhancing survival of mouse oocytes following chemotherapy or aging by targeting Bax and Rad51. AB - BACKGROUND: Therapeutic approaches to preserve fertility in females undergoing cancer treatments are currently ineffective. This is partly due to limited knowledge of the molecular mechanisms that injured germ cells elicit to repair damage and survive or to abort repair and activate biochemical pathways leading to death. So far, we know that following spontaneously occurring or drug-induced DNA damage, the efficiency of DNA repair is a critical determinant of the cell's fate. The protein encoded by the Rad51 gene is one of several components recruited for homologous recombination-dependent DNA double-strand break repair in both somatic cells and germ cells. Recently, we showed that microinjection of recombinant Rad51 into AKR/J mouse oocytes decreased the extent of spontaneous DNA double-strand breaks, suppressed apoptosis, and restored the developmental competence in AKR/J embryos. Herein we characterized the nature of chemotherapy induced lesions in oocytes, and the associated individual components of the DNA damage sensor and repair apparatus. For comparison, we also assessed parallel spontaneous changes in aging oocytes. METHODS: Data collected were derived from: analysis of apoptosis; immunodepletion; oocyte microinjections; immunocytochemistry; immunofluorescence; and CHIP-like assays. RESULTS: Our data show that: (i) DNA damage in oocytes can be induced by both chemotherapy and spontaneously by the aging process; (ii) oocytes possess the machinery and capability for repairing such DNA damage; (iii) Rad51 is a critical player in the repair of both chemotherapy-induced and spontaneously-sustained DNA damage; and (iv) in response to damage, oocytes exhibit an inverse functional relationship between presence of Bax and activity of Rad51. CONCLUSION/SIGNIFICANCE: Our results establish Rad51 and/or Bax as potential candidates that can be targeted for development of individualized chemotherapeutic interventions that are effective, but minimal in toxicity. The use of Rad51 and Bax modulating compounds could offer women the opportunity to maintain fully functional germ cells despite cancer treatments or aging. PMID- 20169202 TI - Phenotypic variance predicts symbiont population densities in corals: a modeling approach. AB - BACKGROUND: We test whether the phenotypic variance of symbionts (Symbiodinium) in corals is closely related with the capacity of corals to acclimatize to increasing seawater temperatures. Moreover, we assess whether more specialist symbionts will increase within coral hosts under ocean warming. The present study is only applicable to those corals that naturally have the capacity to support more than one type of Symbiodinium within the lifetime of a colony; for example, Montastraea annularis and Montastraea faveolata. METHODOLOGY/PRINCIPAL FINDINGS: The population dynamics of competing Symbiodinium symbiont populations were projected through time in coral hosts using a novel, discrete time optimal resource model. Models were run for two Atlantic Ocean localities. Four symbiont populations, with different environmental optima and phenotypic variances, were modeled to grow, divide, and compete in the corals under seasonal fluctuations in solar insolation and seawater temperature. Elevated seawater temperatures were input into the model 1.5 degrees C above the seasonal summer average, and the symbiont population response was observed for each location. The models showed dynamic fluctuations in Symbiodinium populations densities within corals. Population density predictions for Lee Stocking Island, the Bahamas, where temperatures were relatively homogenous throughout the year, showed a dominance of both type 2, with high phenotypic variance, and type 1, a high-temperature and high-insolation specialist. Whereas the densities of Symbiodinium types 3 and 4, a high-temperature, low-insolation specialist, and a high-temperature, low insolation generalist, remained consistently low. Predictions for Key Largo, Florida, where environmental conditions were more seasonally variable, showed the coexistence of generalists (types 2 and 4) and low densities of specialists (types 1 and 3). When elevated temperatures were input into the model, population densities in corals at Lee Stocking Island showed an emergence of high temperature specialists. However, even under high temperatures, corals in the Florida Keys were dominated by generalists. CONCLUSIONS/SIGNIFICANCE: Predictions at higher seawater temperatures showed endogenous shuffling and an emergence of the high-temperature Symbiodinium specialists, even though their phenotypic variance was low. The model shows that sustaining these "hidden" specialists becomes advantageous under thermal stress conditions, and shuffling symbionts may increase the corals' capacity to acclimatize but not adapt to climatechange induced ocean warming. PMID- 20169203 TI - Specific strains of Escherichia coli are pathogenic for the endometrium of cattle and cause pelvic inflammatory disease in cattle and mice. AB - BACKGROUND: Escherichia coli are widespread in the environment and pathogenic strains cause diseases of mucosal surfaces including the female genital tract. Pelvic inflammatory disease (PID; metritis) or endometritis affects approximately 40% of cattle after parturition. We tested the expectation that multiple genetically diverse E. coli from the environment opportunistically contaminate the uterine lumen after parturition to establish PID. METHODOLOGY/PRINCIPAL FINDINGS: Distinct clonal groups of E. coli were identified by Random Amplification of Polymorphic DNA (RAPD) and Multilocus sequence typing (MLST) from animals with uterine disease and these differed from known diarrhoeic or extra-intestinal pathogenic E. coli. The endometrial pathogenic E. coli (EnPEC) were more adherent and invasive for endometrial epithelial and stromal cells, compared with E. coli isolated from the uterus of clinically unaffected animals. The endometrial epithelial and stromal cells produced more prostaglandin E(2) and interleukin-8 in response to lipopolysaccharide (LPS) purified from EnPEC compared with non-pathogenic E. coli. The EnPEC or their LPS also caused PID when infused into the uterus of mice with accumulation of neutrophils and macrophages in the endometrium. Infusion of EnPEC was only associated with bacterial invasion of the endometrium and myometrium. Despite their ability to invade cultured cells, elicit host cell responses and establish PID, EnPEC lacked sixteen genes commonly associated with adhesion and invasion by enteric or extraintestinal pathogenic E. coli, though the ferric yersiniabactin uptake gene (fyuA) was present in PID-associated EnPEC. Endometrial epithelial or stromal cells from wild type but not Toll-like receptor 4 (TLR4) null mice secreted prostaglandin E(2) and chemokine (C-X-C motif) ligand 1 (CXCL1) in response to LPS from EnPEC, highlighting the key role of LPS in PID. CONCLUSIONS/SIGNIFICANCE: The implication arising from the discovery of EnPEC is that development of treatments or vaccines for PID should focus specifically on EnPEC and not other strains of E. coli. PMID- 20169204 TI - Is it easy to be urban? Convergent success in urban habitats among lineages of a widespread native ant. AB - The most rapidly expanding habitat globally is the urban habitat, yet the origin and life histories of the populations of native species that inhabit this habitat remain poorly understood. We use DNA barcoding of the COI gene in the widespread native pest ant Tapinoma sessile to test two hypotheses regarding the origin of urban populations and traits associated with their success. First, we determine if urban samples of T. sessile have a single origin from natural populations by looking at patterns of haplotype clustering from across their range. Second, we examine whether polygynous colony structure--a trait associated with invasion success--is correlated with urban environments, by studying the lineage dependence of colony structure. Our phylogenetic analysis of 49 samples identified four well supported geographic clades. Within clades, Kimura-2 parameter pairwise genetic distances revealed <2.3% variation; however, between clade genetic distances were 7.5-10.0%, suggesting the possibility of the presence of cryptic species. Our results indicate that T. sessile has successfully colonized urban environments multiple times. Additionally, polygynous colony structure is a highly plastic trait across habitat, clade, and haplotype. In short, T. sessile has colonized urban habitats repeatedly and appears to do so using life history strategies already present in more natural populations. Whether similar results hold for other species found in urban habitats has scarcely begun to be considered. PMID- 20169205 TI - Raptor is phosphorylated by cdc2 during mitosis. AB - BACKGROUND: The appropriate control of mitotic entry and exit is reliant on a series of interlocking signaling events that coordinately drive the biological processes required for accurate cell division. Overlaid onto these signals that promote orchestrated cell division are checkpoints that ensure appropriate mitotic spindle formation, a lack of DNA damage, kinetochore attachment, and that each daughter cell has the appropriate complement of DNA. We recently discovered that AMP-activated protein kinase (AMPK) modulates the G2/M phase of cell cycle progression in part through its suppression of mammalian target of rapamycin (mTOR) signaling. AMPK directly phosphorylates the critical mTOR binding partner raptor inhibiting mTORC1 (mTOR-raptor rapamycin sensitive mTOR kinase complex 1). As mTOR has been previously tied to mitotic control, we examined further how raptor may contribute to this process. METHODOLOGY/PRINCIPAL FINDINGS: We have discovered that raptor becomes highly phosphorylated in cells in mitosis. Utilizing tandem mass spectrometry, we identified a number of novel phosphorylation sites in raptor, and using phospho-specific antibodies demonstrated that raptor becomes phosphorylated on phospho-serine/threonine proline sites in mitosis. A combination of site-directed mutagenesis in a tagged raptor cDNA and analysis with a series of new phospho-specific antibodies generated against different sites in raptor revealed that Serine 696 and Threonine 706 represent two key sites in raptor phosphorylated in mitosis. We demonstrate that the mitotic cyclin-dependent kinase cdc2/CDK1 is the kinase responsible for phosphorylating these sites, and its mitotic partner Cyclin B efficiently coimmunoprecipitates with raptor in mitotic cells. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that the key mTOR binding partner raptor is directly phosphorylated during mitosis by cdc2. This reinforces previous studies suggesting that mTOR activity is highly regulated and important for mitotic progression, and points to a direct modulation of the mTORC1 complex during mitosis. PMID- 20169206 TI - How far away from the society of knowledge are we? PMID- 20169207 TI - [The parliamentary debate on immigration and health in Spain]. AB - OBJECTIVE: Describing and analysing the Spanish Parliamentary debate on immigration and health. METHODS: A systematic search regarding parliamentary initiatives (PI) on immigration and immigration and health was conducted from the beginning of the Spanish democratic period (1979 to 2007). A protocol for collecting information was used to identify the parliamentary debate's main characteristics and the main topics related to PI concerning immigration and health. The PI immigration rate was calculated regarding the total rate of PI about the immigrant population based on the Spanish population per year. RESULTS: 4,022 PI concerning "immigration" were identified. The main content concerned statistical information about the immigrant population (57.2 %). 116 PI about "immigration and health" were analysed. The most frequently recurring topics were health-care strategies (25 %), health-service access (24.1 %) and epidemiological information (19.8 %). Most PI concerned questions related to the function of government control (94 %). No decisions were taken in 113 PI (97.4 %). Immigrant population rates increased per year; however, notable changes in PI regarding immigration were not observed until 1996 and PI about immigration and health until 1999. CONCLUSION: The immigration and health debate on the parliamentary agenda is heterogeneous. It would seem necessary to increase parliamentary debate about strategies and action for promoting immigrant-based needs in health. PMID- 20169208 TI - [Persistence of social representation regarding breast cancer]. AB - OBJECTIVE: Understanding the social representation of breast cancer and how it has influenced breast cancer prevention and self-care practice in a group of women from the city of Medellin. METHODS: This was a qualitative study using 19 semi-structured interviews with adult females who had not had breast cancer, using maximum variation criterion as sampling technique. The analysis was orientated by grounded theory. RESULTS: Some women physiologically represented breast cancer while others represented it by its social and psychological effects. They identified its causes with personal and emotional problems and certain daily habits such as inadequate food ("a bodily payback for the abuses which we subject ourselves to"). DISCUSSION: The word "breast cancer" was associated with inevitable death, terror, suffering, incurability, devastation, powerlessness and pain. This cancer has strong social representation due to its severe implications for females, their attractiveness and self-image. CONCLUSIONS: The persistence of breast cancer's negative image is associated with "the life-style myth" (1) for which people tend to blame the patient. Our biological reductionism hides environmental, social and political factors. We are obsessed by the dangers and their control (2) and powerful images are added to these messages such as those in which "one out of nine women will develop breast cancer" to foster self-responsibility (2). However, the ghost of cancer in developing societies in which many people are still trapped is magnified and has also yet to be overcome. PMID- 20169209 TI - [Inequalities in oral health services in Cali, Colombia]. AB - OBJECTIVE: Assessing the presence of inequity in access to dental care in a health network in the city of Cali in Colombia. METHODS: This was a descriptive, retrospective study. The study area was located in the area of influence of Cali's largest health-service provider's network (accounting for 70 % of the city's geographical extension). The study population dealt with the poor and vulnerable, consisting of both the insured and uninsured population. A survival rate analysis was carried for determining the likelihood of each population finishing treatment or abandoning it during treatment. RESULTS: The subsidised population had an 11.12 Decayed, Missing, and Filled Teeth (DMFT) index while that of the subsidised population was 9.41. In the area of dental operation, 63.7 % treatments were completed in the subsidised population and 33.3 % in the unsubsidised population; 63.3 % of the population in area of oral surgery were subsidised and 36.6 % were people without subsidy. It was noted that the likelihood of the subsidised population completing the first 30 days treatment was 85.5 % (0.8-0.9, 80 % CI) and 78 % (0.4-0.8, 80 % CI) for the population lacking insurance. CONCLUSIONS: Inequities were found in both populations' oral health status. Inequity were also shown in oral health care, in the percentage of patients being likely to finish treatment or being likely to abandon it, this being higher in the subsidised population (emphasis being placed on the first month of attention). PMID- 20169210 TI - [Self-care agency and adherence to treatment in people having cardiovascular risk]. AB - OBJECTIVE: Determining the relationship between self-care agency and adherence to pharmacological and non-pharmacological treatment in patients having cardiovascular risk factors at the Tunjuelito hospital in Bogota. METHODOLOGY: This study involved a descriptive and correlational design which evaluated self care agency ability and adherence to treatment in a random sample of 201 people having the following cardiovascular risk factors: being obese, having a sedentary lifestyle, arterial hypertension and diabetes mellitus. The patients being studied were attending Tunjuelito hospital's chronic-patient programme. Appraisal of self-care agency (ASA) scale and a questionnaire for evaluating behaviour regarding adherence to pharmacological and non-pharmacological treatment from the NOC taxonomy were carried out in the research. RESULTS: 62.6 % of the people having cardiovascular risk factors had regular self-care agency ability, whilst 77 % presented good adherence to pharmacological and nonpharmacological treatment. Spearman's coefficient revealed a 0.413 correlation between self-care agency ability and adherence to pharmacological and non-pharmacological treatment, indicating moderate and positive correlation. CONCLUSIONS: Self-care agency involves an individual's active and tacit participation in discerning, decision-making and taking self-care action for maintaining and improving her/his health (i.e. adhering to prescribed treatment). PMID- 20169211 TI - [Impact perception on health, social and physical environments of the municipal solid waste disposal site in Cali]. AB - OBJECTIVE: Describing the self-perceived impact on health of people living near to a solid waste disposal site in Cali and on their physical and social environments. METHODS: In addition to a cohort study, qualitative research was carried out to explore experiences amongst 16 residents in leadership positions in their communities. Seven semi-structured interviews and one focus group were conducted. Thematic analysis was developed using thematic networks to identify recurrent patterns related to theexperience of living in proximity to the solid waste disposal dump. RESULTS: Participants perceived respiratory health problems as mainly arising from the sickening odours emanating form the Navarro dump. The area has also developed a bad reputation ("stigma") because of the exasperating odours, flies and the close view of waste disposal. CONCLUSIONS: Participants perceived the Navarro dump had a negative impact on their physical health and also that its bad reputation in the neighbourhood had effects on the social and physical environment of people living close to the solid waste disposal dump. PMID- 20169212 TI - [Evaluating HIV pre-test counseling in people attending a national hospital in Lima, Peru]. AB - OBJECTIVE: Evaluating the knowledge acquired by the pre-test counselling programme in a national hospital in Lima Peru. METHOD: A cross-sectional descriptive observational study was carried out on 499 patients attending the National STI/HIV Prevention and Control Sanitary Strategy service after they had been counselled. The patients were intentionally selected by probabilistic means. A questionnaire having direct questions was applied; it had been previously validated by experts. > or = 75 % of correct answers was defined as being a variable of correct knowledge and <75 % of correct answers as incorrect knowledge. RESULTS: 64.1 % (n=320) of the patients were female. The age group having a better level of knowledge after counselling was the 22-28 year old group, 40.3 % (n=201) (p<0.05). People having a partner diagnosed as having HIV/AIDS answered more questions correctly (12.3 on average). Men showed higher correct knowledge (63.6 %) related to women (36.4 %) (p<0.05). Only 4.4 % (n=22) of the patients had a correct level of knowledge. CONCLUSION: The pre-test counselling programme did not improve knowledge regarding HIV/AIDS. It is thus suggested that the approach and method should be changed so that patients become well-informed, thereby reducing STI and HIV/AIDS-related morbidity and mortality. PMID- 20169213 TI - [Body image and eating disorders]. AB - OBJECTIVE: Assessing the association of age and weight with internalisation of the ideal of being thin, bodily dissatisfaction and eating disorder symptoms amongst three groups of females: teenage, young and adult women. MATERIAL AND METHODS: 145 females participated, ranging in age from 12 to 46, who answered four self-reporting questionnaires aimed at measuring symptoms of anorexia nervosa, bulimia nervosa, the ideal of being thin and bodily dissatisfaction. The participants' weight and height were also recorded for calculating their body mass index. Data analysis included descriptive and inferential statistics, specifically Spearman correlation and Kruskal-Wallis test. RESULTS: Being an older woman was associated with high internalisation of ideally being thin and bodily dissatisfaction; however, it was not correlated with eating disorder symptoms. Comparisons between groups showed that adult females were more dissatisfied with their bodies and their attitudes towards being thin; however, their attitudes and behaviour concerning abnormal eating were just as inappropriate as that amongst teenagers. CONCLUSIONS: These findings show the need for research into attitudes towards eating amongst adult women because they use extreme methods for controlling weight which may result in higher health risks. PMID- 20169214 TI - [Detecting antibiotics in milk: a public health problem]. AB - OBJECTIVE: Determining the presence of antibiotics in raw and processed milk in the city of Monteria. MATERIALS AND METHODS: Three samplings were three samples were taken in a dairy company in the city of Monteria at two-month intervals. Pasteurised milk samples were taken from six trademarks. All milk samples were tested for acidity by alcoholometry; the presence of antiseptic H2O2 was determined by using 35 % KI and 1 % V2O5 diluted in H2SO4. The incidence of antibiotics (Total antibiotic Bio K 331 (Diagnostic Jemelle dioxide, Belgique) was then determined. The test's sensitivity limit was determined by using 0.004 UI/ml penicillin, 0.100 mg/ml oxytetracycline and 5,000 mg/ml chloramphenicol as positive controls in two-fold serial dilutions. Aliquots of milk were used as positive and negative controls for each sample. The first sampling evaluated 212 samples of milk, the second 167 and the third 66, for a total of 445 samples. RESULTS: All samples were negative for alcoholometry acidity. Antibiotics were detected in 111 (25 %) samples of raw milk; however, no antibiotics were detected in the pasteurised milk. The test's sensitivity revealed that penicillin was detectable in a maximum 0.002UI/ml dilution, oxytetracycline in 0.005ig/ml and chloramphenicol in 1.25 mg/ml. CONCLUSIONS: Traces of antibiotics being found in 25 % of milk samples revealed a lack of public health controls, as well as evidence of the indiscriminate use of antibiotics in the livestock industry and a risk to public health. PMID- 20169215 TI - [Myocarditis in children affected by dengue hemorrhagic fever in a teaching hospital in Colombia]. AB - OBJECTIVE: To determining myocarditis frequency in children suffering from DHF in the Huila region of Colombia. METHODS: This was a descriptive and prospective study which was carried out between March 2005 and October 2005 involving 102 patients suffering from DHF, based on WHO criteria. These children were followed up to identify signs of myocarditis. RESULTS: 10.7 % of the children had signs of myocarditis; one of them was classified as having dengue II and the other ten were classified as suffering form dengue III and IV. This difference was statistically significant (p=0.0004). 10 patients had fulminant myocarditis and required early inotropic support. Two patients had tachyarrythmias in the EKG (one SV and one ventricular); the others had sinusal bradichardia and low voltages. Echocardiograms were perfomed on 50 % of the children, revealing pericardial leakage grade I and II in two patients, one with very diminished EF and AF. Average hospital stay was 7 days. 10 had satisfactory outcome whereas one died. CONCLUSION: This series of cases in children reinforces the association between myocarditis and dengue viral infection. PMID- 20169216 TI - [Cigarette-smoking amongst students in a Colombian city: gender-associated factors]. AB - OBJECTIVE: Establishing gender-related factors associated with cigarette-smoking amongst adolescent students in Santa Marta, Colombia. METHOD: A cross-sectional study was designed to ascertain factors associated with lastmonth (occasional) cigarette-smoking. Logistic regression was used for independently adjusting factors associated with girls' and boys' last-month occasional cigarette-smoking. RESULTS: A total of 2,039 girls and 1,536 boys participated in the research. It was observed that 12.0 % of boys and 8.3 % of girls reported occasional cigarette smoking during the last-month (OR=1.5). Cigarette-smoking in girls was strongly associated with drinking alcohol (OR=20.4), cannabis use (OR=9.3), inhalant use (OR=2.5), being older than fifteen (OR=2.5), having poor or mediocre last month academic achievement (OR=1.9) and attending private schools (OR=1.6). Cigarette smoking in boys was related to drinking alcohol (OR=30.1), cannabis use (OR=13.0), cocaine use (OR=6.4), having poor or mediocre last month academic achievement (OR=2.7), having heterosexual orientation (OR=2.4) and having low socioeconomic status (OR=2.0). CONCLUSIONS: Cigarette-smoking is differentially associated in boys and girls. Cigarettesmoking in girls was related to inhalant consumption, being older than 15 and attending a private school; in boys, it was associated with cocaine use, having heterosexual orientation and low socioeconomic status. PMID- 20169217 TI - [HIV infection prevalence in patients having cutaneous pathology in a National Reference Center (2005-2006)]. AB - OBJECTIVE: Determining the prevalence of HIV infection in patients suffering from cutaneous disease in a national reference center in Colombia. METHODS: This was a cross-sectional study of patients aged 18 or older, having cutaneous pathology and no previous HIV diagnosis. The calculated sample size was 1,537 patients. A confirmed case was defined as being that of a patient having positive results in the ELISA and Western blot tests. Prevalence was the number of confirmed cases divided by the total population. The associations were measured by using prevalence ratio. RESULTS: 1,649 patients were enrolled in the study. Our center's prevalence was 1.21 % (20 cases). Molluscum contagiosum and seborrheic dermatitis were the diseases having the highest prevalence of HIV infection which had not been previously diagnosed (3.91 % and 2.05 %, respectively). Molluscum contagiosum and HIV infection prevalence ratio was 3.96 (p: 0.01562). CONCLUSIONS: The risk of HIV infection in patients aged 18 or older suffering from Molluscum contagiosum was nearly 4 times higher than the risk in patients having other cutaneous pathologies. PMID- 20169218 TI - [Risk indicators for dental caries in preschool children from La Boquilla, Cartagena]. AB - OBJECTIVE: Describing the occurrence of dental caries in preschool children from the Boquilla neighbourhood in Cartagena and relating it to risk factors reported in the medical literature. METHODS: The sample consisted of 238 preschool children aged 3 to 5. Average age was 4.1. Regarding gender, there were 116 boys and 122 girls. The children were individually selected in a probabilistic way, bearing in mind the size of the population from the chosen educational institution; a questionnaire and clinical instrument were used. The data was analysed according to outcome using Odd ratios for bivariate analysis and logistical regression for multivariable analysis. RESULTS: Caries prevalence was 60 %, mainly occurring amongst 5 year old children. The major risk factors observed were parents having not progressed to more than secondary level studies and a background of caries. A 26.6 OR was obtained at the moment of adjusting the logistical regression estimators for having a background of caries, 3.37 OR for daily candy consumption and 2.17 OR for non-exposure to fluorides. CONCLUSIONS: The presence of caries in this population could be explained by means of the three associated risk factors mentioned above. This evidence may become changed when other circumstances, moments and places are involved in children having the same characteristics. PMID- 20169219 TI - [Dental fluorosis in 6-13-year-old children attending public schools in Medellin, Colombia]. AB - OBJECTIVE: This study was aimed at determining dental fluorosis prevalence and severity amongst 6-13-year-old students residing in Medellin, Colombia. METHODS: A descriptive study was carried out on 1,330 students attending 34 public schools in the city of Medellin. Two dentists trained in dental fluorosis diagnosis performed the examinations were after the teeth had been brushed. Teeth were dried with gauze, isolated with cotton pellets and visually examined in natural light. The Thylstrup and Fejerskov index (TFI) was used for rating fluorosis. RESULTS: Dental fluorosis prevalence was 81 % (TFI>1); 46.4 % was related to mild dental fluorosis (TFI1 and TFI2) and 8.8% to severe dental fluorosis (TFI >5). TFI > or = 1 was found in 21 % of the children being examined in at least 50 % of their teeth. CONCLUSION: Dental fluorosis prevalence level was found to be high in Medellin, Colombia; health authorities should thus focus their attention on preventing this problem. PMID- 20169220 TI - [Western blot, ELISA and indirect immunofluorescence test evaluation of Leishmania (Leishmania) infantum-infected dogs]. AB - OBJECTIVE: Evaluating canine visceral leishmaniasis diagnostic test performance in Colombia and adapting the Western blot test in naturally and experimentally infected dogs. METHODS: Sera were obtained from 10 experimentally L. Infantum infected dogs, 5 naturally infected dogs, 16 healthy dogs, 26 Babesia canis, Erhlichia canis, Dirofilaria immitis, Trypanosoma cruzi and Leishmania (Viannia) spp infected dogs, 40 dogs from non-endemic areas and 150 from endemic areas. Sera were tested for L. infantum infection using immunofluorescent antibody (IFAT), ELISA and Western blot (WB) tests. RESULTS: Positives results were obtained for 73 % of known infected dogs by the IFAT test and false positives were obtained for 2.5 % of non-infected dogs using WB. ELISA was not efficient for diagnosis. 24 antigenic fractions were recognised in tested sera using WB; however, 29, 34, 50, 69, 75, 86, 99 and 123 kDa bands were recognised in sera from dogs from non-endemic areas, healthy dogs and Trypanosoma cruzi, Erhlichia canis, Dirofilaria immitis and Babesia canis infected dogs. The 13 kDa fraction proved potentially useful for diagnosing canine visceral leishmaniasis. CONCLUSIONS: The separate use of parasitological and serological test could lead to misdiagnosis of Leishmania infection; using both kinds of technique simultaneously is thus highly recommended. PMID- 20169221 TI - [A comparative study of maintenance services using the data-mining technique]. AB - OBJECTIVES: The main goal in this research was comparing two hospitals' maintenance service quality. One of them had a contract service; the other one had an in-house maintenance service. MATERIALS AND METHODS: The authors followed the next stages when conducting this research: domain understanding, data characterisation and sample reduction, insight characterisation and building the TAT predictor. Multiple linear regression and clustering techniques were used for improving the efficiency of corrective maintenance tasks in a clinical engineering department (CED). The indicator being studied was turnaround time (TAT). RESULTS: The institution having an in-house maintenance service had better quality indicators than the contract maintenance service. CONCLUSIONS: There was lineal dependence between availability and service productivity. PMID- 20169222 TI - [Understanding fibromyalgia]. AB - OBJECTIVE: This study was aimed at describing the main features of articles published in scientific journals between 1992 and 2007 addressing the analysis of the etiological factors associated with this condition. MATERIALS AND METHODS: This consisted of a systematic review of scientific articles regarding this association using the following health and social science databases: Medline, Cinhal, Web of Science, Lilacs, Sociological Abstracts, Embase, Psycoinfo and ISI web of Knowledge. RESULTS: 21 articles were obtained during the study period, distributed as follows: 7 theoretical reviews (33.3 %), 6 cross-sectional studies (28.5 %), 4 cohort studies, (19.0 %) 2 case-control studies (9.5 %) and 1 systematic review (4.7 %). Of these, 7 (33.3 %) considered the following to risk factors to be associated with the emergence of other factors such as silicone implants, socio-demographic and hormonal factors: 3 on stress (14.3 %), 4 on hepatitis C (19.0 %), 3 on traumatic antecedents (14.3 %) and 4 on occupation (19.0 %). The most productive time was 2000-2004. There was broad thematic dispersion in the published journals. DISCUSSION: Available empirical evidence about risk factors related to fibromyalgia is still scarce and scattered. Future studies should focus on generating more knowledge about the risk factors studied so as to help improve fibromyalgia care, diagnosis and treatment. PMID- 20169223 TI - [Research on food and nutritional security in Brazil from 2000 to 2005: trends and challenges]. AB - Discussion of Research on Food and Nutritional Security (FNS) in Brazil started with the Directory of Brazilian Research Groups from the National Council for Scientific and Technological Development (CNPq). Searches using the expression 'food security' allowed the identification of 72 groups in 2005. Proportions between researchers and students suggest little dynamism and consolidation of such research. Groups in the area of Food Science and Technology, and those concerned with food quality are predominant; then there is the Nutrition area, mainly discussing the nutritional state of population groups; in the field of Humanities there is a small number of groups discussing political, economic and social aspects within FNS's national and regional scopes. It seems that investments in the integration between food and nutrition components of research on FNS are necessary, in order to attenuate differences between the economic (food security) and the social focus (human rights to a healthy nutrition). PMID- 20169224 TI - [Nutritional knowledge production and public policy development in the area of food and nutrition security in Brazil]. PMID- 20169225 TI - [Challenges in the research-construction interface of the human right to feeding: reflections in the scope of food security and nutrition]. PMID- 20169226 TI - [From research on food security and nutrition in Brazil to the challenge of creating committees on feeding and nutrition]. PMID- 20169227 TI - [Researching about food security and nutrition in Brazil: what is the purpose?]. PMID- 20169229 TI - [Nutritional status and perceived body image of elderly women in the Northeast of Brazil]. AB - This paper aims to investigate the association between perceived body image and nutritional status in elderly women. The methodology used was a cross-sectional cohort study of a sample of 265 elderly women aged 60 to 96 and selected by randomized proportional stratification by groups of convenience in the town of Jequie, Bahia, Brazil. Each subject was interviewed in order to obtain information on sociodemographic characteristics (age, marital status, educational level and economic class) and perceived body image (on a nine-silhouette scale) and their body mass and height were measured in order to calculate their Body Mass Index as a parameter of nutritional status. Data analysis employed descriptive statistics, measures of association and non-parametric analysis. A total of 43.8% of the elderly women interviewed were well-nourished, 3.4% were underweight and 52.8% were overweight. With reference to perceived body image, 54% of the women were unsatisfied, primarily due to excess body mass (35.1%), and this was associated with nutritional status, in that increases in BMI raised the percentage of unsatisfied women. The elderly from Bahia were unsatisfied with their body images, and this dissatisfaction was associated with the prevalence of obesity. PMID- 20169230 TI - [Organic food and educational actions in schools: diagnosis for health and nutrition education]. AB - This research involved a diagnosis of the educational actions and organic food of the Taste and Awareness Project (Projeto Sabor e Saber, PSS) in a state school in Florianopolis, Brazil. Based on a qualitative approach, a semi-structured interview, documentation analysis and focal groups were used for data collection. The participants were managers of School Meals; a school head and a group of students and teachers representing the school. The results indicated that the PSS has advanced in its objectives, combining the introduction of organic foods with educational actions involving food, health, nutrition and the environment but with no evaluations of this process; organic food is present in school meals, although there is no record of educational actions; food is a subject on the Science course; the themes of food, health and nutrition in the school environment come up without planning; the evaluation of students regarding the food is positive, but no reference was made to organic foods. It was concluded that the use of organic food, is still not an element of the pedagogical project. However, the research contributed to the teachers, on the need to develop educational actions in health, organic foods and nutrition, within the school community. PMID- 20169231 TI - [Vitamin C loss in vegetables during storage, preparation and distribution in restaurants]. AB - The main objective of this study was to evaluate vitamin c loss following vegetable manipulation stages, reception, storage, preparation, and distribution, in commercial and institutional restaurants. Seven vegetables were used: lettuce, carrots, chicory, collard greens, cauliflower, cabbage and tomatoes. Vitamin c analysis was made by high-performance liquid chromatography (hplc). After all manipulation stages, cumulative vitamin c loss was high in vegetables prepared in institutional restaurants and commercial restaurants corresponding to 44.38% 67.03% and 32.90%-71.32%, respectively. In both restaurants, storage accounted for the most expressive loss of vitamin c in the majority of the vegetables. The adoption of measurements to control vitamin c loss in vegetables is suggested, such as purchase and reception according to demand, storage at refrigerated temperatures, monitoring of hygiene and sanitation times, slicing near serving time, cooking preferably steamed, by pressure or stewed, monitoring of cooking time and temperature, and control of the exposure time between preparation and distribution. The results obtained for vitamin c content contribute to the nutritional characterization of vegetables, since studies related to this area are scarce in brazil and in the world. PMID- 20169232 TI - [Microbiological evaluation of drinking water used in feeding units]. AB - The water for human consumption is the main vehicle for the transmission of pathogens that are capable of causing enteric parasitic diseases; therefore, its microbiological control is vital. This work had the purpose of evaluating the bacteriological quality of drinking water, in terms of the presence of total and thermotolerant coliforms, in different Feeding Units in the city of Recife, Pernambuco State, according to the potableness standards established by Ordinance No. 518 of 2004 of the Brazilian Ministry of Health/ANVISA. Forty water samples were collected in the Feeding Units located near the UFPE and UFRPE. The bacteriological tests for research on total and thermotolerant coliforms were carried out in accordance with the protocol of APHA (1995). Of the analyzed samples, 62.5% presented total coliforms and 42.5% thermotolerant coliforms. According to the results obtained, 62.5% of the samples are not in compliance with the law in force. PMID- 20169233 TI - [Some considerations about aesthetic medicine]. AB - In this article, we will discuss some aspects of the construction of the meanings concerning the body from the scientific speech which was modeled based on modern thinking and became the hegemonic thinking of some sectors of the medical field. Meanings attributed to the body bring questions that come from other areas of the social life and those questions will build the aesthetic parameters which will be part of the identity construction, in the relation with the body itself, subjectivity and healthcare. We will describe some moments of the construction of the modern scientific thought and how this thought became hegemonic, influences the common sense, naturalizes identity construction and how dealing with the body, interferes in the healthcare, show a division among some sectors of the biomedicine, reinforce an specific type of medical rationality and makes an epistemic base and principle (theoretical and discursive) to some sectors connected to aesthetic medicine and aesthetic surgeries. PMID- 20169234 TI - [Body, aesthetic surgery and public health: a case study]. AB - The body, in the occidental culture, was for many centuries rejected, feared and devaluated; today, differently, it is super valued and became a precious good, for this reason it is well-taken care of and shaped, due to successes and virtues of the individual contemporary being attributed to it. In the search for an ideal body, many people look for aesthetic surgeries as solution for their problems and improvement of their self-esteem. This article aims to understand the relation of the aesthetic surgery with the Public Health and the promotion of health. We carried out a qualitative study, using the case study method, with the objective of understanding the underlying beliefs, attitudes, perceptions and cultural processes to the narratives of the college's students submitted to aesthetic surgery and of the plastic surgeons. The results demonstrate that the body must be understood as something more complex than the physical and visible body, because many of those who look for aesthetic surgery continue unsatisfied, seeing that their dissatisfactions attributed to their body are also a matter of them being attributed to their soul. We conclude that aesthetic beauty is becoming a medical subject and that aesthetic surgery is a question of public health, as the results depend on the motivations and expectations of who searches for this procedure. PMID- 20169235 TI - [Representations of the body: with the word one group of adolescents from popular classes]. AB - In view of the great body aesthetic concern demonstrated by a group of adolescents from popular classes, this study had the purpose of getting to know and analyze the social representations of the body. It investigated the qualitative approach carried out with adolescent workers from the Centro Salesiano do Menor, in Vitoria, Espirito Santo State. A random sample was selected from a group of 334 individuals. Eight girls and seven boys were approached by means of non-structured interview. From the analysis of their speeches, a categorization was performed and the theory of the Social Representations was used for discussion. The results pointed out that body perception, for boys as well as for girls, are focused on the ideas of proportionality, normality and perfection. Regarding the consequences of not having an ideal body, both stated situations such as: exclusion, illnesses, unhappiness and even death. In-depth knowledge on opinion, thoughts and feelings of the adolescents relative to the body, may contribute to subside interventions in this group, extending significantly the scope of professional performance in the health sector. PMID- 20169236 TI - [Prevalence of hypertension among obese children and adolescents]. AB - There has been an increase in chronic diseases affecting the population not only in the world but also in Brazil. Hypertension and obesity fit this context, including among early age individuals. This paper aims at investigating the prevalence of hypertension among obese children and adolescents, checking its manifestation in compliance with gender and age. The study involved 129 obese individuals, ages ranging from 7 to 14 years, both sexes. The evaluation consisted of anthropometric measures and blood pressure measurements. The data were then analysed statistically through BioEstat 3.0 program, which indicated the prevalence of hypertension in both sexes (male = 15.8% and female = 26.4%), with no significant differences between each other. The disease was also present in the different age groups, especially among those aged 13 to 14 (52.4%), who were statistically different from other age groups, which, in turn, were not different from each other. This led to the conclusion that hypertension was remarkably present in the investigated population, indicating that the obesity can interfere in the elevation of the children's blood pressure and adolescents. PMID- 20169237 TI - [Obesity in adults: a population based study in a small town in South of Brazil, 2005]. AB - Changes in nutritional pattern in Brazilian population have been observed mainly in relation to obesity increase. This study aims to estimate the prevalence of obesity and associated factors in adult population in Santo Angelo, Rio Grande do Sul State, 2005. A cross sectional study was carried out involving adult subjects from 20 to 59 years old (n=434), of both sexes. People with Body Mass Index equal to or higher than 30 kg/m(2) were considered obese. A questionnaire was applied to collect data related to socioeconomic, demographic, and behavioral conditions. The multiple logistic regression analysis was performed to identify the associated factors. The response rate was 95.0% and the prevalence of obesity was equal to 16.6% (CI 95% 13.120.1). Presence of obesity was positively associated with lack of physical activity, none feeding habits care, and some individuals that mentioned current health problems regardless of sex. The prevalence of obesity found was similar to other Brazilian population based studies. The results may support planning and implementing prevention actions as well as obesity control in adult population taking into account the relevant details of a small size town. PMID- 20169238 TI - [Physical activity and quality of life]. AB - Physical activity is believed to be a form to restore the health of the harmful effects caused by a stressful work/study routine. The study comprises a transversal research which aims at analyzing the associations of the practice of sports activities in the quality of life of individuals. The sample was comprised 107 professors, 111 employees and 638 students of the Universidade Catolica de Pelotas UCPEL-RS, totalizing 863 participants. WHOQOL-brief/OMS were used as a tool to evaluate quality of life as well as the Questionnaire of habitual physical activities translated and modified by Nahas-NuPAF/UFSC, 2001. Of the total, 394 are males and 469 are females. Of these, 313 are moderately active, 210 inactive, 207 active and 136 are very active. We can observe that, on average, the more active the person is, the better their quality of life is. Moreover, amongst the differences in the quality of life of people who practice physical activities compared with those who do not practice any activity, are not only the aspects of physical health, but also psychological and cognitive aspects. These results serve as a motivation to professionals of different areas to encourage and support the definition of physical activities routine for their patients. PMID- 20169239 TI - [Transforming the hunger problem into food and nutritional approach: a continuous social inequality]. AB - The origin of the social (public) politics related to food and nutrition in Brazil has a discontinuous and neglected course by the Brazilian State throughout its history. The objective of this article is to rescue this process and to identify elements that interfere in the insertion of the food and nutrition question in the Brazilian politics agenda. Thus, it reviews the politics and social programs formulated since the decade of 40s aimed to solve the problem of hunger in Brazil, identifying the changes of an epidemiological and nutritional transition of the local population. It is necessary to progress in the agreement of the biological manifestations of the hunger: malnutrition or obesity (bad nutrition) is reflected on a social development model that privileges the capital in detriment of the welfare state. Also it reflects the alimentary and nutritional context, therefore the submission of the society to the capital reflecting in the ways of eating, living, falling ill and dying. PMID- 20169240 TI - [Lifestyle and risk factors associated to body fat increase in women]. AB - The objectives were to describe the association between body mass index (BMI, kg/m(2)), body composition and risk factors to metabolic diseases; observe the prevalence of metabolic syndrome and list the characteristics of overweight and obese women. Voluntaries (n=50; BMI=31+/-6; age=36+/-11 years old), were evaluated regarding clinical examination, anthropometrics measurements, samples of blood and urine, resting energy expenditure and food register. Phases in which they become obese in descending order: adulthood, pregnancy, adolescence, over 40 years old and after marriage. The odds to have one or more obese family members were 316%. They were anxious (60%), depressives (12%), compulsives (34%) and had sleep disturbance (32%). The odds to dyslipidemia was 28%, to hypertension was 25% and to glucose over 100 mg/dL 35%. They were in caloric deficit, but, nitrogen balance was positive. The metabolic syndrome was present in 25% of these women and was positively correlated with body fat indicators and age. The obesity of these women seems to be multifactorial with a family influence that could be caused by genetics and environment contributions. The emotional/physical balance should be influenced on this process. PMID- 20169241 TI - [Determining of body mass index in adolescents from public schools in Piracicaba, Sao Paulo State]. AB - The objective of this study was to assess determining factors of body mass index (BMI) in adolescents enrolled in public schools in Piracicaba, Sao Paulo. The sample had 328 adolescents from both genders; minimum age was 10 years old. We have assessed weight, height, sexual maturity, physical activity, and diet. A multiple linear regression model was used to assess the association between independent variables and BMI. While girls considered physically active presented greater mean BMI than those insufficiently active, boys did not present statistical difference between mean BMI among those active and those insufficiently active. Sexual maturity was a determinant for BMI, for both genders, reinforcing the idea that it is essential to take this variable into account in studies that assess the nutritional situation in adolescents. We believe that the methods used in the present study, which are normally used in similar surveys, have important limitations to assess the influence of variables such as the level of physical activity and food intake on the BMI of adolescents. Thus, it is important to improve these methods and adopt them in further studies. PMID- 20169242 TI - [Beliefs of diabetic patients about nutritional therapy and its influence on their compliance with treatment]. AB - The system of health beliefs influences the process of compliance with diabetes treatment. Compliance with nutritional therapy is one of the greatest challenges found. The purpose of this qualitative approach study was to analyze the beliefs of type 2 diabetic patients regarding nutritional therapy and its influence on the compliance with it. The participants of the study were nine patients being treated in a reference unit for diabetic patients' treatment. The procedures involved were blood exam to check the glycated hemoglobin, a questionnaire, semi structured recorded interview and patient report checking. The analysis of the speeches was made using the thematic categories of Bardin (2000), and the models of Rokeach (1981) and Rosenstock (1974). All participants showed glycated hemoglobin levels higher than 7%, what shows that is difficult for them to control their glicemic levels and possible non compliance. After the analysis of the speeches, two thematic categories were identified: 'Recommendations received about feeding' and 'Nutritional therapy compliance'. Both categories showed authority beliefs and consensus zero, and barriers to nutritional therapy, which the participants see as a restrictive imposition. Those beliefs have negative influence on the compliance, and so, they have to be considered when providing health assistance to the population. PMID- 20169243 TI - [Systematic review about the concept of access to health services: planning contributions]. AB - This article aims to discuss the category access to health services and the Planning contributions to building it on SUS. The central discourse axis refers to the connection between theoretic and practice planning on the Collective Health field related to different analysis dimensions of access: economic, technical-assistential, political and symbolic, described theorists in the field. The dimensions evidence contributions of subjects/authors for greatest approximation to the health reality of country; regarding the understanding of symbolic elements that determinate intervention in health-disease process, as well as regarding the different ways of organization of the Health System and policies, observed in its political, economic, technical-assistential components. PMID- 20169244 TI - [Democracy without equity: analysis of health reform and nineteen years of National Health System in Brazil]. AB - This paper aims to evaluate the nineteen years of the National Health System in Brazil, under the prism of equity. It takes into account the current political context in Brazil in the 80s, that the democratization of the country and the health sector could, per se, lead to a more equitable situation regarding the access to health services. Democracy and equity concepts are here discussed; analyzing which situations may facilitate or make it difficult its association in a theoretical plan, applying them to the Brazilian context in a more general form and, to emphasizing practical implications to the National Health System and to groups of activism related to health reforms. It also seeks to show the limits and possibilities of these groups with regards to the reduction of inequality, in relation to the access to health services, which still remain. To conclude, the author points out the need for other movements to be established which seek the reduction of such and other inequalities, such as access to education, housing, etc, drawing special attention to the role played by the State, which is questioned regarding its incapacity of promoting equity, once it presents itself as being powerful when approaching other matters. PMID- 20169245 TI - [Obesity: a plural perspective]. AB - Obesity is a disease characterized by the excessive accumulation of corporal fat, which produces deleterious effects to the health. There is consent in the literature that its etiology is multi-factorial, involving biological, historical, ecological, political, social-economical, psychosocial and cultural aspects. In that sense, this article's objective is to talk about the multi factorial character of obesity, involving the wide variety of environmental and genetic factors implicated in its etiology, starting from secondary studies of literature revision in the main bases of data and specialized libraries. Nowadays, obesity has been considered the most important nutritional disorder in the developed countries and the ones in development, due to the increase of its incidence. The approach of the genetic, metabolic, psychosocial, symbolic, and cultural aspects in addition to the lifestyle allowed to base obesity as a plural illness, and showed the necessity to create public politics with multidiscipline and inter-sectorial actions, that value the partnership between government and civil society, in the prevention and combat of obesity and the promotion of health, making possible the community's participation in that process, through responsibility and self care. PMID- 20169247 TI - [From legitimation to (re-)signification: the therapeutic itinerary of workers with RSIs/WMSDs]. AB - Repetitive Strain Injuries (RSIs)/Work-Related Musculoskeletal Disorders (WMSDs) are a major issue in Brazilian public health. The way such sickness is produced, its multidetermined origin and the troubled care provided to sufferers point to the very contradictions of the capitalist production system. This work aims at understanding the macrosocial processes surfaced in the workers' search for cure of RSIs/WMSDs, paying close attention to the negotiation and (re-)signification processes present in those trajectories. By drawing on 'explanatory models' and the concept of 'therapeutic itinerary', 'thematic analysis' of in-depth interviews with Brazilian workers receiving Social Security compensation was used to approach the socioeconomic and political realms. Culpability and excess were reported in connection with etiology whereas pain, tiredness and stress were shown to be related to symptom initiation. Legal medical assessment, rehabilitation programs and prognosis were all along (re-) signified by the interviewees in an attempt to create an 'ideal type' of productive worker despite the injury. It is then urged that public health policies responsive to the wider organization and processes of power and class related to the care of RSIs/WMSDs are devised. PMID- 20169248 TI - [Not everything is supervised training: contributions for the debate]. AB - This paper discusses supervised training as a fundamental opportunity for the consolidation of the teaching space and also as means of facing the challenges posed by the guidelines for dental courses. It is not a new proposal. It is in fact a fight for changes in dental practicing which began in the 70s with the movement for the integration between dental teaching and dental services. It approaches public health services spaces and the world of work as central for a new teaching strategy. That would generate the opportunity to graduate professionals with a more critical profile, also capable of understanding reality and intervening on it. The paper points the risks of understanding and misunderstanding - supervised training with practicing inside the dental school, under the label of curricular supervised training. In that perspective traditional practices, with emphasis on technical and biological aspects would not have the potential to achieve the changes proposed by the curricular guidelines. While highlighting the relevance of curricular supervised training in professional education, the paper sets a dialogue with ABENO, contesting some of its positions. In that sense, the paper shows the need for a deeper and more participative discussion, that joins as many dental schools as possible. PMID- 20169246 TI - Environment and obesity in the National Children's Study. AB - We describe the approach taken by the National Children's Study (NCS) to understanding the role of environmental factors in the development of obesity. We review the literature with regard to the two core hypotheses in the NCS that relate to environmental origins of obesity and describe strategies that will be used to test each hypothesis. Although it is clear that obesity in an individual results from an imbalance between energy intake and expenditure, control of the obesity epidemic will require understanding of factors in the modern built environment and chemical exposures that may have the capacity to disrupt the link between energy intake and expenditure. Through its embrace of the life-course approach to epidemiology, the NCS will be able to study the origins of obesity from preconception through late adolescence, including factors ranging from genetic inheritance to individual behaviors to the social, built, and natural environment and chemical exposures. It will have sufficient statistical power to examine interactions among these multiple influences, including gene-environment and gene-obesity interactions. A major secondary benefit will derive from the banking of specimens for future analysis. PMID- 20169249 TI - [Temporal evolution of dengue fever in Ribeirao Preto, Sao Paulo State, 1994 2003]. AB - This epidemiological-descriptive study aimed to describe the temporal evolution of dengue cases in Ribeirao Preto, Sao Paulo State, between 1994 and 2003, according to month of occurrence and gender. Data were obtained from the compulsory notification forms provided by the Epidemiological Surveillance service of the Ribeirao Preto Municipal Health Secretary. We obtained incidence coefficients per 100,000 inhabitants, according to population estimates by the Brazilian Institute of Geography and Statistics. The city experienced a dengue epidemic in 2001, when the incidence coefficient reached 619.65 cases/100,000 inhabitants. We found 5553 cases during the study period, 0.07% of which occurred in 1994, 3.68% in 1995, 4.52% in 1996, 2.40% in 1997, 1.82% in 1998, 5.73% in 1999, 3.75% in 2000, 57.37% in 2001, 6.25% in 2002 and 14.39% in 2003. January to May were the months with the highest occurrence levels. As to the gender variable, we found a proportion of approximately 1:1, showing small fluctuations between men and women for dengue cases during the entire study period. Results indicate the need to study the theme and reinforce the role of teaching institutions to tackle dengue in Brazil. PMID- 20169250 TI - [Intra-urban differentials of the mortality situation in the municipality of Camaragibe: 1999 to 2003]. AB - The epidemiological profile of the populations has changed throughout history and populace spaces. Throughout the years, epidemiologists have studied the changes in the epidemiological profiles of the populations, employing, according to the given health figures, the health of the populations, using specially the mortality data of the information systems in the entire country. Aiming to identify the mortality situation as per sex, age, cause groups and specific death causes in the municipality of Camaragibe, from 1999 to 2003, a descriptive study has been used taking into account the variables presented at SIM (Sistema de Mortalidade). Moreover, using the RPA's as analysis units, a description of the mortality situation was performed taking into consideration the intra-urban differentials. The mortality behavior presented variations in relation to RPA of residence, albeit, for some indicators, these differentials were not so clear. The findings suggest that the mortality differentials were polarized in the municipality regions, and a further analysis using a more spaced out unit may be needed. PMID- 20169251 TI - [Use of telemedicine technology as a strategy to promote health care of riverside communities in the Amazon: experience with interdisciplinary work, integrating NHS guidelines]. AB - This article aims at presenting an experience of professional and medical assistance education using telemedicine as a technology for the promotion and prevention in health care as well as professional qualification of the riverside population living in the margins of Madeira river, in the State of Rondonia. This project comprised a small pole of the telemedicine in the community of Santa Catarina, located by Madeira river, 200 km from the city of Porto Velho, Rondonia State. Field experience was performed between July 17 and 31, 2006, promoting the inclusion of inhabitants of nine riverside communities. The system allowed simultaneous, real time audio and video exchange providing the riverside communities with unique access to information, medical assistance, and lectures on prevention in basic health to the population in general. This project showed that the implantation of telemedicine is an alternative for a better distribution of health services. In addition to bringing assistance to people less favoured, it allows social reintegralization of people excluded due to geographic isolation, assists in information diffusion, proves education to the population and future system users, promotes prevention in health, developing responsibility of the population for a better quality of life of the region. PMID- 20169252 TI - [Thinking about health related professions humanized practice]. AB - This article intends to contribute with some reflections about contemporary clinical approach concerning humanized health assistance based on the review of literature indexed and published in Brazil at BVS and Scielo between 1987 and 2007, including some authors referred in these studies and published in the same period, when considered essential to consubstantiate the discussions presented. Matters are also discussed regarding humanized health care based on public policies and health related professional practices, as well as the possibilities for extending discussions related to the need of inclusion of theses principles in various stages of the health professional background, from undergraduate studies. In addition, some propositions are presented to contribute with the education of the healthcare professional, as well as subsidies for the reflection related to curricular proposals and opportunities offered by university professors, who may strongly influence the professional education and, further, with the health assistance and health services practices. PMID- 20169253 TI - [Health education as a strategy for the promotion of oral health in the pregnancy period]. AB - This literature revision is intended to discuss the importance of health education as a strategy to oral health promotion in the pregnancy period. The most common mouth manifestations during pregnancy have been studied, and the conclusion is that, although pregnancy itself is not responsible for such manifestations in the mouth, e.g. dental decay and periodontal diseases, a dentistry follow-up during prenatal care is necessary, considering that hormonal alterations in pregnancy may aggravate the diseases contracted. The oral health promotion for pregnant women has been focused on mouth health education, considering it an important part of the Program of Attention to Women's Health, as recommended by the current National Politics' Mouth Health Policy. It is considered that, by means of mouth health education activities, implemented during prenatal care by a multiprofessional team, under an oral surgeon, women may be aware of the importance of their role in the attainment and maintenance of positive mouth health habits in family environment and act as an agent to multiply preventive and mouth-health-promotion information. PMID- 20169254 TI - [Is there an association between cancer mortality and agrotoxics use? A contribution to the debate]. AB - The chronic use of agrotoxics in rural regions of Rio Grande do Sul State (RS) has been tentatively associated to a possible increase in the incidence of cancer in rural areas. A time-trend ecological study was performed in the micro region of Ijui County (MI), in RS and Brazil, with data of the 1979 to 2003 period. Data was collected from the Mortality Information System, Brazilian Ministry of Health (DATASUS), to evaluate the cancer mortality rate, standardized by gender and age corrected mortality ratios. Linear regression for mortality time-trend analysis and multiple regressions for mortality differences among three regions were calculated. The highest average mortality rate in men and also women were observed in RS and MI and they were significantly higher (p<0,001) than the one for Brazil. When the model was adjusted for three regions the upward trend on mortality remained the same. This data suggests that the relation between chronic use of agrotoxics and cancer cannot be denied and should be further investigated. PMID- 20169255 TI - [Epidemiologic aspects of dental fluorosis in Brazil: research in the period 1993 2006]. AB - The epidemiology of dental fluorosis derives from surveys carried out in recent years, as a result of a better comprehension of metabolic aspects of fluoride in the human organism and oral health concerns. This reflection aims at presenting studies carried out on fluorosis between 1993 and 2006. The period of 1993-2004 delimits the interval between the 2nd and the 3rd National Conferences on Oral Health, and, in the period of 2005-2006, the search of primary data presented in scientific meetings confirmed the findings in the literature, showing that the Brazilian scientific agenda was not substantially influenced by the discussions engaged during the 3rd National Conference on Oral Health. Most studies concentrate on urban areas and the predominance, in Brazil, of 'very mild' and 'mild' levels of fluorosis shows that there is no compromising in terms of functional order. The low perception of fluorosis by the population, along with its low prevalence, evokes the necessary debate on public health issues, in the country. Since the national scientific production constitutes an important source of knowledge to subsidize the elaboration of public policies for the health sector, the successive and punctual studies analyzed show that, as far as fluorosis is concerned, the epidemiological diagnosis reaffirms the need, importance and safety of the fluoridation of public water supplies, as a public health measure. PMID- 20169256 TI - [Mother Kangaroo Method: an investigation about the domestic practice]. AB - This is a descriptive study, within uantitative approach, aiming at acquiring knowledge regarding the domestic practice of Mother Kangaroo Method. Data were collected from a survey for the parents of prematures hospitalized in a University Hospital in Sao Luis, Maranhao State, from May to August, 2005. According to the findings, 100% of the families received training and guidance in the hospital and only in 53.3% of the cases the mothers were guided. The benefits of the education works developed by the team were confirmed by domestic practice with 93.3% of the mothers performing the kangaroo position correctly, where 86.7% of the babies were slightly dressed, 86.7% of the mothers were breast feeding technically in a correct manner and 86.7% without any other items being used. 46.7% of the mothers stay 5 to 8 hours/day with their babies in this position and 66.7% identified house tasks as the principal obstacle of the practice. Regarding neonatal walk-in unit follow-up 63.3% of the mothers identified the lack of financial recourses to pay for transportation as the main difficulty factor. The data obtained show that the support from the family network and the health team seem to be the best way to guarantee the extension of domestic care. PMID- 20169258 TI - Analgesic efficacy of the intra-articular administration of high doses of morphine in patients undergoing total knee arthroplasty. AB - BACKGROUND AND OBJECTIVES: Although the efficacy of intraarticular (IA) morphine is still controversial, it has been shown that higher doses promote better results and consequently decrease postoperative analgesic consumption, characterizing a dose-dependent peripheral action. A controlled, randomized, double-blind study was undertaken to evaluate the efficacy of the intra-articular administration of 10 mg of morphine in patients undergoing total knee arthroplasty. METHODS: Fifty patients undergoing total knee arthroplasty were randomly divided into two groups: the treatment group received 10 mg (1 mL) of intra-articular morphine diluted in 19 mL of NS, while the control group received the intra-articular administration of 20 mL of NS, both after closure of the capsule at the end of the surgery. On demand subcutaneous morphine was available for residual pain. The following parameters were evaluated: pain severity according to the numeric scale (NS), 2 h (M1), 6 h (M2), 12 h (M3), and 24 h (M4) after the IA injection; time until the first request of analgesic; analgesic consumption, and side effects. CONCLUSIONS: The treatment group had lower NS than the control group in M1 and M2, while significant differences were not observed in the other moments. The time until the first request of analgesics was significantly higher in the treatment group, and analgesic consumption in the first 24 hours was also lower in this group. The incidence of side effects did not differ between both groups. We concluded that the postoperative IA administration of 10 mg of morphine promoted a longer period without rescue analgesics and reduced their consumption in the first 24 hours. PMID- 20169259 TI - Use of the ultrasound to determine the level of lumbar puncture in pregnant women. AB - BACKGROUND AND OBJECTIVES: An imaginary line connecting both iliac crests is used to determine the vertebral level for lumbar puncture. This line crosses the spine at the level of L4 or the L4-L5 space. This anatomical reference can be inaccurate in a large proportion of patients. The objective of the present study was to determine whether the identification of the L3-L4 space by the physical exam differs from that of the ultrasound in obese and non-obese pregnant women. METHODS: Adult patients undergoing elective cesarean sections under spinal block participated in this study. Patients were divided in two groups: obese and non obese. The L3-L4 space was determined by physical exam with the patient in the sitting position. This was followed by a lumbar ultrasound. After the sacrum was identified, the transducer was directed in the cephalad direction to identify the spinous processes of the lumbar vertebrae. The clinically estimated L3-L4 level was recorded. RESULTS: Ninety patients, 43 obese and 47 non-obese, were included in this study. Lumbar intervertebral spaces were identified by ultrasound in all patients. The L3-L4 space clinically identified corresponded to the ultrasound identification in 53% and 49% of the cases in the non-obese and obese groups, respectively. There was no significant difference between groups. CONCLUSIONS: The L3-L4 space is correctly identified in a low percentage of obese and non obese pregnant women. Spinal ultrasound can reduce the incidence of mistaken identification of the L3-L4 space in obese and non-obese pregnant women. PMID- 20169260 TI - Applicability of the simplified acute physiology score (SAPS 3) in Brazilian hospitals. AB - BACKGROUND AND OBJECTIVES: The SAPS 3 (Simplified Acute Physiology Score 3) prognostic system is composed of 20 parameters, represented by an acute physiology score and assessment of the previous status, aimed at establishing a predictive mortality index for patients admitted to intensive care units (ICU). The objective of this study was to validate this system and determine its discriminatory power in surgical patients in Brazil. METHODS: This is a prospective study undertaken in two surgical ICUs of two different hospitals over a one-year period; patients younger than 16 years, who stay at the ICU for less than 24 hours, readmitted to the unit, and those admitted for dialysis were excluded from the study. The predictive ability of the SAPS 3 index to differentiate survivors and non-survivors was determined by the ROC curve and calibration by the Hosmer-Lemeshow goodness-of-fit test. RESULTS: One thousand three-hundred and ten patients were included in the study. Gastrointestinal surgeries predominated (34.9%). Eighteen was the lower SAPS 3 index and the highest was 154, with a mean of 48.5 +/- 18.1. The predicted and real hospital mortality was 10.3% and 10.8%, respectively; the standardized mortality ratio (SMR) was 1.04 (95%CI = 1.03-1.07). Calibration by the Hosmer and Lemeshow method showed X(2) = 10.47 p = 0.234. The SAPS 3 score that better discriminated survivors and non-survivors was 57, with sensitivity of 75.8% and specificity 86%. Among the patients with SAPS 3 index higher than 57, 73.5% did not survive versus 26.5% who survived (OR= 1.32, 95%CI 1.23-1.42, p < 0.0001). CONCLUSIONS: The SAPS 3 system is valid for the Brazilian population of surgical patients, being a useful indicator of critical patients and to determine greater care in this group. PMID- 20169261 TI - Disposable versus reusable laryngeal tube suction for ventilation in patients undergoing laparoscopic cholecystectomy. AB - BACKGROUND AND OBJECTIVE: The laryngeal tube suction II (LTS-II) is a recent version of reusable supraglottic airway devices allowing gastric drainage. In this prospective, randomized study we compared insertion and ventilation of disposable LTS-II (LTS-D) with reusable type (LTS-II) for airway management under conditions with elevated intra abdominal pressure induced by capnoperitoneum. METHODS: 60 ASA I and II patients undergoing elective laparoscopic cholecystectomy were randomized to receive either a LTS-D (n=30) or LTS-II (n=30) for airway management. After induction of general anaesthesia the devices were inserted, their correct placement was verified and airway leak pressure was measured. Ease of insertion, quality of airway seal, fiberoptic view, risk of gastric insufflation, insertion of nasogastric tube and postoperative pharyngeal morbidity were examined. RESULTS: First time and second time success rates were comparable for both groups (86% vs. 93% and 96% vs. 96% in LTS-D and LTS-II groups, respectively). One patient in each group could not be intubated after three attempts. After gas insufflation, ventilation of one patient in LTS-D and 2 patients in LTS-II groups was faulty and the patients were intubated with endotracheal tube. Time until delivery of first tidal volume for LTS-D and LTS-II was 20.8 +/- 11.6 s, and 18.2 +/- 4.8 seconds respectively (p = 0.27), fixation and manipulation time was 73.3 +/- 18.5 and 65.5 +/- 16.2 seconds, respectively (p = 0.096). Nasogastric tube insertion was successful in all patients. There were no significant differences in postoperative complaints. CONCLUSIONS: Both devices provide a secure airway under conditions of elevated intra abdominal pressure. PMID- 20169262 TI - Evaluation of the quality of life of anesthesiologists in the city of Recife. AB - BACKGROUND AND OBJECTIVES: The practice of Anesthesiology is exhausting and stressful. The present study evaluated the quality of life of anesthesiologists working in the city of Recife, correlating the profile of the quality of life with the degree of satisfaction with their health, number of working days and weekly shifts, gender, and age group. METHODS: The WHOQOL-BREF questionnaire was used. Spearman's correlation and Student t test, ANOVA, and Scheffe test for variance were used, considering a p < 0.05 significant. RESULTS: Subjective analysis demonstrated that 44.6% of anesthesiologists have a negative or undefined perception about their quality of life. The degree of satisfaction with their health (r = 0.525; p = 0.01) and the excess of weekly working shifts (p = 0.03) had a significant influence on the results. Female anesthesiologists had significantly lower scores than males in the subjective evaluation of quality of life and in the psychological and social relationships domains. A significant difference was not observed among different age groups. The environmental domain had lower scores than the others in all parameters analyzed. CONCLUSIONS: Long working hours represented a negative factor in quality of life of all anesthesiologists in the city of Recife, and that of female anesthesiologists was significantly worse than males. Therefore, we concluded that reflection and actions are required to influence positively the health and quality of life of those professionals. Besides individual actions, institutional support is fundamentally important for the practice of anesthesiology and, to achieve positive changes, decisions should be based on scientific evidence. PMID- 20169263 TI - Hemodynamic effects of atracurium and cisatracurium and the use of diphenhydramine and cimetidine. AB - BACKGROUND AND OBJECTIVES: Since atracurium can cause hypotension in humans, the hemodynamic effects of atracurium and cisatracurium as well as the hemodynamic protection of diphenhydramine and cimetidine were investigated in rats. METHODS: 1) Wistar rats were anesthetized with sodium pentobarbital and prepared according to Brown et al. to evaluate different doses of atracurium and cisatracurium in the reduction of T4/T1 equal or greater than 95%. 2) Assessment of the hemodynamic changes caused by the intravenous administration of atracurium and cisatracurium by monitoring the blood pressure in the carotid artery and the electrocardiogram of rats. 3) Observation of the hemodynamic protection of prior treatment with the intravenous administration of diphenhydramine (2 mg.kg(-1)) and/or cimetidine (4 mg.kg(-1)). STATISTICAL ANALYSIS: Student t test and ANOVA. RESULTS: Doses of 1 mg.kg(-1) and 0.25 mg.kg(-1) of atracurium and cisatracurium respectively did not change the mean arterial pressure (MAP). Doses of 4 mg.kg( 1) of atracurium and cisatracurium decreased MAP to 62.8 +/- 4.5% and 82.5 +/- 2.3% respectively when compared to control levels. When the rats were pre-treated with diphenhydramine and cimetidine, diastolic pressure was reduced to 95.4% +/- 2.5%. With cimetidine, diastolic pressure was reduced to 82.7 +/- 8.4% when compared to the control group. The effects on systolic and diastolic blood pressure were reflected in the levels of MAP. CONCLUSIONS: The isolated administration of diphenhydramine and cimetidine did not prevent the reduction in mean arterial pressure induced by atracurium. However, the association of both drugs was able to prevent the hemodynamic effects of atracurium. The doses of cisatracurium used in this study did not cause a reduction in blood pressure significant enough to justify the use of the preventive measures used in the atracurium groups. PMID- 20169264 TI - Anesthesia for partial bilateral salpingectomy in a patient with idiopathic hypertrophic cardiomyopathy: case report and review of the literature. AB - BACKGROUND AND OBJECTIVES: Hypertrophic cardiomyopathy is a rare, autosomal dominant cardiac disorder characterized by hypertrophy of the interventricular septum and mitral valve abnormalities. CASE REPORT: A 25-year old female, second gestation, with a diagnosis of hypertrophic cardiomyopathy for four years and history of mild intermittent asthma controlled with sporadical use of corticosteroids. On physical exam, the patient had a IV/VI systolic and plurifocal heart murmur and accentuated scoliosis with palpable intervertebral spaces. She complained of occasional palpitations during pregnancy, and was treated with 100 mg of atenolol a day. Complete blood count, creatinine, and electrolytes were within normal limits; echocardiogram showed hypertrophic cardiomyopathy predominantly septal and ejection fraction of 0.76%. The patient underwent emergency labor giving birth to a live female fetus, Apgar 9/9, without maternal and fetal hemodynamic complications. The patient was scheduled for bilateral partial salpingectomy. During the interview, the patient refused general anesthesia for the procedure. A decision was made for combined regional blockade. The surgical procedure lasted 20 minutes during which changes in blood pressure and heart rate were up to 10% lower than baseline levels without immediate hemodynamic or surgical complications. CONCLUSIONS: Absolute maternal mortality in hypertrophic cardiomyopathy (HC) is very low and it is usually seen in patients with high risk factors. Evidence does not show an increased risk of regional blocks in females with HC when it is used for vaginal delivery. Both general anesthesia and regional blocks were successfully used without complication for cesarean sections in patients with HC. PMID- 20169265 TI - Drugs errors in anaesthesia practice: four cases of non-fatal morbidity. AB - BACKGROUND AND OBJECTIVES: Anesthesiologists became more concerned about ensuring patient safety by a greater emphasis on outcome, quality patient care both in operation theatre and elsewhere in hospital. In the clinical practice, there is no aspect of Anesthesia that occupies a more important place in the safe management of the patients than the accurate drug administration. Medication errors represent a small part of anesthesia problems but still have potential for serious morbidity and legal consequences. The objective of this report was to describe four cases of unusual medical errors (ME) in the operation theatre, without harm to the patient, and how their analysis and identification had prevented more serious damage occurrence. CASE REPORTS: Four cases of inadvertent overdose in operation theatre previous to induction anesthesia. The same syringe was used to prepare and dilute two different drugs. This error was therefore caused by the presence of the second drug. Toxicity was manifested as brief respiratory depression and sedation, and assisted ventilation was required but no adverse outcomes happened. CONCLUSIONS: We explain how we identified the drug involved, the point at which the error occurred in order to improve clinical practice reducing medication errors. We focus on providing more information and education to each health care professional about new drugs and their preparation process, because this is should not be an acceptable practice in 2009. PMID- 20169266 TI - Anesthesia in patients with positive direct coombs test: report of three cases. AB - BACKGROUND AND OBJECTIVES: Neoplasias can be associated with autoimmune hemolytic anemia (AHA) with the consequent blood incompatibility that hinders blood transfusion. The authors describe and discuss the conduct in three patients undergoing surgical intervention for neoplastic disease with positive Coombs Test (CT), and the impossibility to determine the blood type. CASE REPORT: 1st case: 87-year old male patient, ASA III, scheduled for surgery for colon neoplasia. The patient had positive CT, being treated with corticosteroids, immunoglobulin (Ig), and erythropoietin, after which it was possible to determine his blood type. One unit of packed-red blood cells (PRBC) was transfused intraoperatively without intercurrences. Twenty four hours after the transfusion, the patient died due to an ischemic stroke. 2nd case: 77-year old male patient, ASA III, scheduled for surgery for a gastric carcinoma. The patient had a positive CT, being treated with corticosteroids and Ig, but we were unable to determine his blood type. The surgery was performed without intercurrences. The patient died on the 18th postoperative day after a cardiorespiratory arrest. 3rd case: 80-year old female patient, ASA IV, undergoing emergency exploratory laparotomy. She also had a positive CT. The surgery (hemicolectomy) was performed without intercurrences. The patient died 48 hours after the surgery from an ischemic stroke. CONCLUSIONS: Circulating autoantibodies in AHA can make it impossible to determine the blood type to transfuse compatible blood. Proper treatment of AHA is aimed at remission of autoantibodies and anemia. When it is not possible to determine the blood type, the procedure should be a life-saving blood transfusion. PMID- 20169267 TI - Uncommon causes of hemodynamic instability during myocardial revascularization without cardiopulmonary bypass. AB - BACKGROUND AND OBJECTIVES: Myocardial revascularization (MR) in patients with ventricular hypertrophy and/or dysfunction is frequently performed without cardiopulmonary bypass (CB), since it can be difficult to wean those patients off CB. Intraoperative control demands strict hemodynamic adjustment, as well as partial clamping of the aorta to minimize hemodynamic changes. The objective of this study was to report two cases of hemodynamic instability during MR without CB after partial clamping of the aorta. CASE REPORT: The first case is a female patient, whose aortic diameter was slightly reduced (2.8 cm); the second case refers to a patient with left ventricular ejection fraction (LVEF) of 24% on the echocardiogram. In both cases, significant hypotension and increase in pulmonary blood pressure were observed immediately after clamping of the aorta. The surgical teams were informed of the problem, and in both cases the hemodynamic instability was reverted after unclamping of the aorta. Afterwards, smaller areas of the aorta were clamped and proximal anastomoses were performed without intercurrence. CONCLUSIONS: Although cardiac manipulation and changes in ventricular preload represent the most common causes of hemodynamic instability during MR without CB, in the cases presented here, hypotension and pulmonary hypertension were most likely secondary to a reduction in cardiac output due to the increase in afterload in patients with a relatively small aortic diameter or ventricular dysfunction even with partial clamping. Adequate intraoperative monitoring and immediate correction of the hemodynamic changes can minimize surgical morbidity and mortality. PMID- 20169268 TI - Failure of subarachnoid blocks. AB - BACKGROUND AND OBJECTIVES: Due to the discomfort caused to patients, failure of subarachnoid blocks that happen occasionally even when properly conducted be the most capable professionals have been described since Bier. However, the concept of failure and especially identification of the causes vary. The objective of this report was to identify the causes of this discomfort through a systematic review of publications with a significant number of patients. CONTENTS: The analysis was divided in three topics: anatomy and its variations; anesthetic agent, focusing on drug selection, its solutions, and additions to achieve the most appropriate result of the proposed surgery; and the dose, discussing concentration, volume, or gravimetric dose, to obtain the most adequate result regarding the intensity of the blockade and its duration. CONCLUSIONS: Failures are more commonly secondary to technical factors: adequate anatomic assessment, judicious choice of the needle and puncture site, care when storing the drugs, dose adequacy, and baricity, besides proper patient positioning during and after the puncture, and they all should be adequate for the surgical objective. PMID- 20169269 TI - The airways and gastric contents in obese patients. AB - BACKGROUND AND OBJECTIVES: The objective of this study was to review the literature and to question the concept that obese patients should be considered as having a potential full stomach and, therefore, question how the airways, considered as of difficult access due to obesity, should be approached during anesthetic induction. CONTENTS: Classically, obese patients are viewed as having a potential full stomach, leading to conducts to protect the airways during anesthetic induction. Frequently, awake intubation or rapid sequence intubation is performed. However, this concept is based on a single study, which has been cited by other authors. Obese patients are also considered difficult to intubate, raising the concern on the successful approach of the airways. However, studies in the literature question this concept, leading to questioning of the techniques used to access the airways. CONCLUSIONS: Studies in the literature demonstrate that gastric emptying is not slowed in obese patients as previously believed, and gastric contents are not greater in this patient population; intubation can, therefore, be safely done after anesthesia. Although obesity alone does not lead to failure to intubate, other signs can be used to predict difficult intubations. PMID- 20169271 TI - Tracheal transplantation: is there lumen at the end of the tunnel? PMID- 20169270 TI - Applications of magnesium sulfate in obstetrics and anesthesia. AB - BACKGROUND AND OBJECTIVES: Magnesium is predominantly an intracellular ion. Its blocking effects on NMDA receptors are responsible for the analgesic and sedative characteristics of this ion. The objective of this study was to review the physiology, pharmacology, and decreased plasma levels of magnesium, as well as its applications in obstetrics and anesthesia. CONTENTS: Magnesium is an intracellular cation with multiple functions: it is a cofactor for enzymes of the glucose metabolism and those that participate in the degradation of nucleic acids, proteins, and fatty acids; it regulates the movements of transmembrane ions; and it intervenes in the activity of several enzymes. Critical patients have a tendency to develop hypomagnesemia, and the treatment consists in correcting the cause, whenever possible, and replacement of magnesium. A reduction in the minimum alveolar concentration (MAC) of inhalational agents in animals and the use of opioids in humans under anesthesia has been demonstrated. CONCLUSIONS: Magnesium sulfate has been used in obstetrics with good results, inhibiting premature labor and in the treatment of eclampsia-associated seizures. It is potentially analgesic and sedative, and could be used as adjuvant during general anesthesia, attenuating the blood pressure response to tracheal intubation and decreasing the need of anesthetics. PMID- 20169272 TI - Prevalence of chimerism after non-myeloablative hematopoietic stem cell transplantation. AB - CONTEXT AND OBJECTIVE: Non-myeloablative hematopoietic stem cell transplantation (NMA-HSCT) is performed in onco-hematological patients who cannot tolerate ablative conditioning because of older age or comorbidities. This approach does not completely eliminate host cells and initially results in mixed chimerism. Long-term persistence of mixed chimerism results in graft rejection and relapse. Involvement of graft-versus-host disease is concomitant with complete chimerism and graft-versus-tumor effect. The aim of this study was to evaluate the prevalence of chimerism in onco-hematological patients who underwent NMA-HSCT. DESIGN AND SETTING: Observational clinical study on chimerism status after human leukocyte antigen-identical NMA-HSCT at the Discipline of Hematology and Hemotherapy of Universidade Federal de Sao Paulo. METHODS: We sequentially analyzed the amplification of APO-B, D1S80, DxS52, FVW, 33.6, YNZ-2 and H-ras primers using variable number of tandem repeats (VNTR) on 17 pairs and fluorescent in situ hybridization (FISH) with the XY probe and SRY primer on 13 sex-unmatched pairs. RESULTS: The informativeness of the primers using VNTR was 60% for APO-B, 75% D1S80, 36% DxS52, 14% FVW, 40% YNZ-22 and 16% H-ras. The SRY primer was informative in female receptors with male donors. The XY-FISH method was informative in 100% of the sex-unmatched pairs. CONCLUSION: These methods were sensitive and informative. In VNTR, the association of APO-B with D1S80 showed 88% informativeness. The quantitative FISH method was more sensitive, but had the disadvantage of only being used for sex-unmatched pairs. PMID- 20169273 TI - Accuracy of different methods for blood glucose measurement in critically ill patients. AB - CONTEXT AND OBJECTIVE: Although glucometers have not been validated for intensive care units, they are regularly used. The aim of this study was to compare and assess the accuracy and clinical agreement of arterial glucose concentration obtained using colorimetry (Agluc-lab), capillary (Cgluc-strip) and arterial (Agluc-strip) glucose concentration obtained using glucometry and central venous glucose concentration obtained using colorimetry (Vgluc-lab). DESIGN AND SETTING: Cross-sectional study in a university hospital. METHOD: Forty patients with septic shock and stable individuals without infection were included. The correlations between measurements were assessed both in the full sample and in subgroups using noradrenalin and presenting signs of tissue hypoperfusion. RESULTS: Cgluc-strip showed the poorest correlation (r = 0.8289) and agreement ( 9.87 +/- 31.76). It exceeded the limits of acceptable variation of the Clinical and Laboratory Standards Institute in 23.7% of the cases, and was higher than Agluc-lab in 90% of the measurements. Agluc-strip showed the best correlation (r = 0.9406), with agreement of -6.75 +/- 19.07 and significant variation in 7.9%. For Vgluc-lab, r = 0.8549, with agreement of -4.20 +/- 28.37 and significant variation in 15.7%. Significant variation was more frequent in patients on noradrenalin (36.4% versus 6.3%; P = 0.03) but not in the subgroup with hypoperfusion. There was discordance regarding clinical management in 25%, 22% and 15% of the cases for Cgluc-strip, Vgluc-lab and Agluc-strip, respectively. CONCLUSION: Cgluc-strip should be avoided, particularly if noradrenalin is being used. This method usually overestimates the true glucose levels and gives rise to management errors. CLINICAL TRIAL REGISTRATION: ACTRN12608000513314 (registered as an observational, cross-sectional study). PMID- 20169274 TI - Prevalence of high-grade squamous intraepithelial lesions and cervical cancer among patients with unsatisfactory colposcopic examination, without visible lesion. AB - CONTEXT AND OBJECTIVE: Cervical cancer is a serious public health problem in Brazil. For patients with unsatisfactory colposcopic examinations without visible lesions, but with cervical cytological tests suggesting high-grade squamous intraepithelial lesion (HSIL), the national recommendation is to repeat cervical cytological tests after three months. Our aim was to assess the prevalence of HSIL and cancer among patients with initial cervical cytological tests suggestive of HSIL but with unsatisfactory colposcopic examinations without visible lesions, in order to contribute towards the discussion regarding a more effective clinical approach that might diminish the likelihood of patient abandonment of follow-up before appropriate diagnosis and treatment. DESIGN AND SETTING: Cross-sectional study in Colposcopy Clinic of IFF/Fiocruz. METHOD: Patients admitted between December 1989 and April 2007 with cytological diagnoses of HSIL but with unsatisfactory colposcopic examinations without visible lesions underwent cervical cone biopsy. RESULTS: Sixty-five such patients were included, comprising 33.8% with HSIL and 4.6% with cancer, confirmed histologically. The other patients presented low-grade squamous intraepithelial lesion (26.1%), glandular dysplasia (1.5%) and absence of disease (33.8%). CONCLUSION: The observed prevalence of cancer and HSIL does not seem to be enough to justify immediate referral for cone biopsies to investigate the cervical canal in these cases. The findings suggest that the recommendation of repeated cytological tests following an initial one with HSIL, among patients with unsatisfactory colposcopic examinations without visible lesions, is appropriate in our setting. Efforts are needed to ensure adherence to follow-up protocols in order to reduce the chances of losses. PMID- 20169275 TI - Scar endometrioma following obstetric surgical incisions: retrospective study on 33 cases and review of the literature. AB - CONTEXT AND OBJECTIVE: The incidence of scar endometrioma ranges from 0.03 to 3.5%. Certain factors relating to knowledge of the clinical history of the disease make correct diagnosis and treatment difficult. The aim here was to identify the clinical pattern of the disease and show surgical results. The literature on this topic was reviewed. DESIGN AND SETTING: Retrospective descriptive study at Hospital Municipal Maternidade - Escola Dr. Mario de Moraes Altenfelder Silva. METHODS: Data from the medical records of patients with preoperative diagnoses of scar endometrioma who underwent operations between 2001 and 2007 were surveyed and reviewed. The postoperative diagnosis came from histopathological analysis. The main information surveyed was age, obstetric antecedents, symptoms, tumor location, size and palpation, duration of complaint, diagnosis and treatment. All patients underwent tumor excision with a safety margin. RESULTS: There were 33 patients, of mean age 30.1 +/- 5.0 years (range: 18-41 years). The total incidence was 0.11%: 0.29% in cesarean sections and 0.01% in vaginal deliveries. Twenty-nine tumors (87.9%) were located in cesarean scars, two (6.0%) in episiotomy scars and two (6.0%) in the umbilical region. The main symptom was localized cyclical pain (66.7%), of mean duration 30.5 months (+/- 23). Surgical treatment was successful in all cases. CONCLUSION: This is an uncommon disease. The most important diagnostic characteristic is coincidence of painful symptoms with menstruation. Patients undergoing cesarean section are at greatest risk: relative risk of 27.37 (P < 0.01). The surgical treatment of choice is excision of the endometrioma with a safety margin. PMID- 20169276 TI - Prevalence of low bone mineral density in children and adolescents with celiac disease under treatment. AB - CONTEXT AND OBJECTIVE: Low bone mineral density may be a finding among children and adolescents with celiac disease, including those undergoing treatment with a gluten-free diet, but the data are contradictory. The aim of this study was to determine the frequency of bone mineral density abnormalities in patients on a gluten-free diet, considering age at diagnosis and duration of dietary treatment. DESIGN AND SETTING: Cross-sectional prevalence study at the Pediatric Gastroenterology Outpatient Clinic of Instituto Materno Infantil Professor Fernando Figueira. METHODS: Thirty-one patients over five years of age with celiac disease and on a gluten-free diet were enrolled. Bone mineral density (in g/cm(2)) was measured in the lumbar spine and whole body using bone densitometry and categorized using the criteria of the International Society for Clinical Densitometry, i.e. low bone mineral density for chronological age < -2.0 Z scores. Age at diagnosis and duration of dietary treatment were confirmed according to the date of starting the gluten-free diet. RESULTS: Low bone density for chronological age was present in 3/31 patients in the lumbar spine and 1/31 in the whole body (also with lumbar spine abnormality). At diagnosis, three patients with low bone mineral density for the chronological age were more than 7.6 years old. These patients had been on a gluten-free diet for six and seven months and 3.4 years. CONCLUSION: Pediatric patients with celiac disease on long term treatment are at risk of low bone mineral density. Early diagnosis and long periods of gluten-free diet are directly implicated in bone density normalization. PMID- 20169277 TI - Prevalence of cervical intraepithelial neoplasia grades II/III and cervical cancer in patients with cytological diagnosis of atypical squamous cells when high-grade intraepithelial lesions (ASC-H) cannot be ruled out. AB - CONTEXT AND OBJECTIVE: The latest update of the Bethesda System divided the category of atypical squamous cells of undetermined significance (ASCUS) into ASC US (undetermined significance) and ASC-H (high-grade intraepithelial lesion cannot be ruled out). The aims here were to measure the prevalence of pre invasive lesions (cervical intraepithelial neoplasia, CIN II/III) and cervical cancer among patients referred to Instituto Fernandes Figueira (IFF) with ASC-H cytology, and compare them with ASC-US cases. DESIGN AND SETTING: Cross-sectional study with retrospective data collection, at the IFF Cervical Pathology outpatient clinic. METHODS: ASCUS cases referred to IFF from November 1997 to September 2007 were reviewed according to the 2001 Bethesda System to reach cytological consensus. The resulting ASC-H and ASC-US cases, along with new cases, were analyzed relative to the outcome of interest. The histological diagnosis (or cytocolposcopic follow-up in cases without such diagnosis) was taken as the gold standard. RESULTS: The prevalence of CIN II/III in cases with ASC-H cytology was 19.29% (95% confidence interval, CI, 9.05-29.55%) and the risk of these lesions was greater among patients with ASC-H than with ASC-US cytology (prevalence ratio, PR, 10.42; 95% CI, 2.39-45.47; P = 0.0000764). Pre-invasive lesions were more frequently found in patients under 50 years of age with ASC-H cytology (PR, 2.67; 95% CI, 0.38-18.83); P = 0.2786998). There were no uterine cervical cancer cases. CONCLUSION: The prevalence of CIN II/III in patients with ASC-H cytology was significantly higher than with ASC-US, and division into ASC diagnostic subcategories had good capacity for discriminating the presence of pre invasive lesions. PMID- 20169278 TI - Frequency of polymorphisms and protein expression of cyclin-dependent kinase inhibitor 1A (CDKN1A) in central nervous system tumors. AB - CONTEXT AND OBJECTIVE: Genetic investigation of central nervous system (CNS) tumors provides valuable information about the genes regulating proliferation, differentiation, angiogenesis, migration and apoptosis in the CNS. The aim of our study was to determine the prevalence of genetic polymorphisms (codon 31 and 3' untranslated region, 3'UTR) and protein expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A) gene in patients with and without CNS tumors. DESIGN AND SETTING: Analytical cross-sectional study with a control group, at the Molecular Biology Laboratory, Pediatric Oncology Department, Hospital das Clinicas de Ribeirao Preto. METHODS: 41 patients with CNS tumors and a control group of 161 subjects without cancer and paires for sex, age and ethnicity were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP). Protein analysis was performed on 36 patients with CNS tumors, using the Western Blotting technique. RESULTS: The frequencies of the heterozygote (Ser/Arg) and polymorphic homozygote (Arg/Arg) genotypes of codon 31 in the control subjects were 28.0% and 1.2%, respectively. However, the 3'UTR site presented frequencies of 24.2% (C/T) and 0.6% (T/T). These frequencies were not statistically different (P > 0.05) from those seen in the patients with CNS tumors (19.4% and 0.0%, codon 31; 15.8% and 2.6%, 3'UTR site). Regarding the protein expression in ependymomas, 66.67% did not express the protein CDKN1A. The results for medulloblastomas and astrocytomas were similar: neither of them expressed the protein (57.14% and 61.54%, respectively). CONCLUSION: No significant differences in protein expression patterns or polymorphisms of CDKN1A in relation to the three types of CNS tumors were observed among Brazilian subjects. PMID- 20169279 TI - Lapatinib for treatment of advanced or metastasized breast cancer: systematic review. AB - CONTEXT AND OBJECTIVE: Around 16% to 20% of women with breast cancer have advanced, metastasized breast cancer. At this stage, the disease is treatable, but not curable. The objective here was to assess the effectiveness of lapatinib for treating patients with advanced or metastasized breast cancer. DESIGN AND SETTING: Systematic review of the literature, developed at Centro Paulista de Economia da Saude (CPES), Universidade Federal de Sao Paulo (Unifesp). METHOD: Systematic review with searches in virtual databases (PubMed, Lilacs [Literatura Latino-Americana e do Caribe em Ciencias da Saude], Cochrane Library, Scirus and Web of Science) and manual search. RESULTS: Only one clinical trial that met the selection criteria was found. This study showed that lapatinib in association with capecitabine reduced the risk of cancer progression by 51% (95% confidence interval, CI: 0.34-0.71; P < 0.001), compared with capecitabine alone, without any increase in severe adverse effects. CONCLUSION: The combination of lapatinib plus capecitabine was more effective than capecitabine alone for reducing the risk of cancer progression. Further randomized clinical trials need to be carried out with the aim of assessing the effectiveness of lapatinib as monotherapy or in association for first-line or second-line treatment of advanced breast cancer. PMID- 20169280 TI - Biomechanical parameters of gait among transtibial amputees: a review. AB - Rehabilitation for lower-limb amputees needs to focus on restoration of daily functions and independent locomotion. As gait is reestablished, reorganization of the motor pattern takes place in order to optimize the functions of the locomotor system. Biomechanics is a field of study that enables understanding of this reorganization. From such knowledge, appropriate strategies for recovering the autonomy of the means of locomotion can be established. Thus, this paper had the aim of reviewing the current status of the biomechanics of locomotion among unilateral transtibial amputees. To achieve this aim, papers written in English or Portuguese and published up to 2005 were selected from the Cochrane Library, PubMed, Scientific Electronic Library Online (SciELO), Literatura Latino Americana e do Caribe em Ciencias da Saude (Lilacs) and Dedalus databases. In cases of transtibial amputation, the absence of plantar flexors negatively affects locomotion. Increased absorption and energy generation by the muscles that control the hip joint of the amputated leg can be considered to be the main compensatory strategy developed by unilateral transtibial amputees during gait. Factors associated with the characteristics of the amputation, prosthesis and experimental protocol used directly influence the results. PMID- 20169281 TI - Primary malignancy in giant cell tumor: a case report. AB - CONTEXT: Primary malignancy in giant cell tumor (PMGCT) is rare. It is defined as a high-grade sarcoma originating in a giant cell tumor (GCT) and seems to behave less aggressively than its secondary counterpart does. CASE REPORT: This report presents the case of a 39-year-old female with pain in her left shoulder for one month. Radiography showed a pathological fracture of the proximal humerus associated with an osteolytic lesion. Histopathological analysis showed typical areas of GCT juxtaposed with a sarcomatous component. CONCLUSIONS: PMGCT seems to behave less aggressively than secondary malignancy in GCT, and it may simulate its more common benign counterpart clinically and radiographically. However, it requires a more aggressive type of treatment. PMID- 20169282 TI - Autoinflammatory syndromes: report on three cases. AB - CONTEXT: Autoinflammatory syndromes are diseases manifested by recurrent episodes of fever and inflammation in multiple organs. There is no production of autoantibodies, but interleukins play an important role and acute-phase reactants show abnormalities. Our aim was to report on three cases of autoinflammatory syndromes that are considered to be rare entities. CASE REPORTS: The authors describe the clinical features of three patients whose diagnosis were the following: tumor necrosis factor receptor-associated periodic syndrome (TRAPS), chronic infantile neurological cutaneous articular (CINCA) syndrome and familial Mediterranean fever (FMF). All of the patients presented fever, joint or bone involvement and increased acute phase reactants. The genetic analysis confirmed the diagnoses of two patients. The great diversity of manifestations and the difficulties in genetic analyses make the diagnosing of these diseases a challenge. PMID- 20169283 TI - Levothyroxine, mental confusion and suicide attempt. PMID- 20169284 TI - Improvement course on evidence-based healthcare via teleconference. PMID- 20169290 TI - Set-up and pilot of a population cohort for the study of the natural history of COPD and OSA: the PULSAIB study. AB - AIMS: We describe the set-up of a population-based study focussed on respiratory conditions, and describe a pilot study - the PULmons SAns Illes Balears (PULSAIB) study - aimed at investigating the natural history of COPD, obstructive sleep apnoea (OSA), and other common chronic diseases. METHODS: A cross-sectional study was designed to survey two fieldwork areas, one rural and one urban, in the Balearic Islands, Spain. Tests conducted included a questionnaire, spirometry with post-bronchodilator (PBD) test, and portable respiratory polygraphy. RESULTS: We assessed all processes and tools to be used, and piloted them in 175 participants from Bunyola (rural) and 130 participants from the Son Piza area (urban). Within this first cross-sectional assessment of the Balearic population aged 30 to 80 years, we report the prevalence of airflow limitation defined as a PBD FEV1/FVC ratio <0.7 and the prevalence of OSA defined as an apnoea-hypopnoea index (AHI) >10/hour. CONCLUSION: A cohort study in the Balearic population to investigate the natural history of COPD and OSA is feasible. PMID- 20169292 TI - Exposure to mercury among Norwegian dentists and dental healthcare personnel. PMID- 20169291 TI - Onset of depressive symptoms among adults with asthma: results from a longitudinal observational cohort. AB - AIMS: Individuals with asthma may be at increased risk of depression, but few studies have identified precursors to the onset of depression. The study goal was to identify risk factors for depression onset among a community-based sample of adults with asthma. METHODS: Data were obtained from three telephone interviews conducted at 2-yearly intervals on a longitudinal cohort of adults with asthma (n=439). The Center for Epidemiologic Studies Depression scale (CESD) was used to measure depressive symptoms. Multiple regression analyses tested associations of sociodemographic and health-related variables with depression prevalence (cross sectional analyses) and incident depression (longitudinal analyses). RESULTS: 15% of subjects were classified as "depressed" (CESD> or =23) at each interview. Individuals depressed at baseline were more likely to drop out (OR=1.76 [95% CI 1.05, 2.96]). Low perceived control of asthma (measured with the Perceived Control of Asthma Questionnaire [PCAQ]) exhibited the most consistent association with depression. Lower PCAQ was cross-sectionally associated with depression (OR=0.51 per 0.5 SD difference in PCAQ [0.35, 0.75]). Onset of depression was noted in 38 individuals. Decrease in perceived control at follow-up was associated with depression onset (OR=7.47 [2.15, 26.01]). CONCLUSIONS: Low perceived control of asthma predicted depression onset among adults with asthma. This risk factor may respond to self-management education. PMID- 20169293 TI - Serological studies in bullous pemphigoid: a literature review of antibody titers at presentation and in clinical remission. AB - Bullous pemphigoid is associated with antibodies to a 230 kDa and a 180 kDa protein. In a literature review we investigated the role of auto-antibodies as detected by different serological assays. Nine reports containing data on 143 patients were analyzed. Pre-treatment data showed that indirect immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and immunoblotting offer an 82.2% or greater probability of being positive. At the end of the study period, all patients had clinically improved, whether or not they were on therapy. Auto-antibodies were present in 29% of patients evaluated by monkey esophagus immunofluorescence and 75% of those evaluated by human skin immunofluorescence. Positive titers were also reported in 67.6% of patients evaluated by ELISA. In 100% of patients in whom immunoblotting was performed the titers became negative. In 3 patients (5.3%) using human skin immunofluorescence and in one patient (1.4%) using ELISA the titers were increased at the end of the study period. The correlation between anti-basement membrane zone antibodies and the clinical course of bullous pemphigoid requires further and long-term studies. PMID- 20169294 TI - Prevention of ulcerative lesions by episodic treatment of recurrent herpes labialis: A literature review. AB - There are substantial difficulties involved in carrying out clinical studies of recurrent herpes labialis, since the disease has a rapid onset, short-lasting viral shedding period and is rapidly self-healing. The aim of this paper was to critically assess published reports of episodic treatment of herpes labialis and to review biological and methodological problems involved in such studies. Limited, but statistically significant, results have been shown with topical antivirals, such as acyclovir and penciclovir, improving healing times by approximately 10%. Orally administrated antivirals, such as valaciclovir and famciclovir, have subsequently found clinical use. However, these two oral medications have different profiles in phase 3 studies. Famciclovir showed additional improvement of efficacy in terms of lesion healing time, but no effect on prevention of ulcerative lesions, while valaciclovir appeared to have similar efficacy to that of acyclovir cream on lesion healing, but some additional efficacy with respect to prevention of ulcerative lesions. A formulation of acyclovir/hydrocortisone showed further improvement in prevention of ulcerative lesions, while retaining efficacy with respect to lesion healing. PMID- 20169295 TI - Platelet-derived growth factor receptor alpha gene mutations in vitiligo vulgaris. AB - Vitiligo vulgaris is an acquired depigmenting disorder resulting from the loss of melanocytes in the skin. Though several putative susceptibility loci of vitiligo have been identified in different populations, the pathogenesis of the disease remains poorly understood. Through genetic linkage analysis of a large Chinese family cohort of vitiligo, we identified a vitiligo linkage locus AIS4 within chromosome 4q12-q21, a region containing several possible candidate genes, including the platelet-derived growth factor receptor alpha (PDGFRA) gene. We postulated that PDGFR mutations may be linked with vitiligo. To test this hypothesis, we performed DNA sequencing on this gene in 143 multiplex families with familial vitiligo vulgaris, 480 patients with sporadic vitiligo vulgaris, and 480 healthy subjects. Mutations were found in 3.5% of familial vitiligo cases, which is significantly higher than for the general population (0.42%, p = 0.008, Fisher's exact test), and possibly higher than in sporadic vitiligo patients (1.0%, p = 0.053). To our knowledge, this is the first observation that PDGFRA mutations are linked with familial vitiligo vulgaris. PMID- 20169296 TI - Increased skin cancer mortality in Chile beyond the effect of ageing: Temporal analysis 1990 to 2005. AB - Chile has a medium-to-high skin cancer mortality rate. Previous studies have shown an increasing rate of skin cancer mortality. We evaluated skin cancer mortality characteristics and their temporal evolution in Chile from 1990 to 2005 in a mixed ecological study using death certificate databases. Age, sex, year and region of residence were obtained for melanoma and non-melanoma deaths. Crude and age-sex-adjusted rates were calculated using the national projections and WHO 2000 standard population data. Descriptive and temporal analyses, using a Prais Winsten regression, were computed. A total of 3588 deaths were registered, of which 55% were melanoma and 54% occurred in men (median age 71 years; women were older). The adjusted rate was 1.75 deaths per 100,000 inhabitants (2.22 in men vs. 1.39 in women). Melanoma skin cancer and non-melanoma skin cancer mortality had a tendency to increase. In conclusion, skin cancer mortality is rising beyond the rate predicted by ageing. An increased incidence due to changes in modifiable factors, such as exposure to ultraviolet radiation and arsenic, might explain the increase in skin cancer mortality. PMID- 20169297 TI - Co-morbidity and age-related prevalence of psoriasis: Analysis of health insurance data in Germany. AB - Epidemiological studies indicate an increased risk of co-morbidities and an association with other inflammatory diseases in psoriasis. However, most analyses have been performed on small samples of patients. The aim of this study was to evaluate the prevalence of co-morbidities in psoriasis based on a large set of health insurance data. The database of 1.3 million patients in a German nationwide statutory health insurance scheme was analysed. Data-sets of patients with confirmed psoriasis were extracted and analysed for co-morbidities. Of 1,344,071 subjects, 33,981 had a diagnosis of psoriasis (prevalence 2.5%). Metabolic syndrome was 2.9-fold more frequent among these patients. The most common diagnoses were arterial hypertension (35.6% in psoriasis vs. 20.6% in controls) and hyperlipidaemia (29.9% vs. 17.1%). The frequencies of rheumatoid arthritis (prevalence ratio (PR) 3.8), Crohn's disease (PR 2.1) and ulcerative colitis (PR 2.0) were also increased among patients with psoriasis. In conclusion, psoriasis is associated with significant co-morbidities that imply an elevated risk of severe complications. PMID- 20169298 TI - Is story-based blended learning a promising avenue for skin and sexual health education? Results from the PAEDIMED project. AB - The PAEDIMED study group developed a learning and teaching scenario for school health education in the area of skin and sexual health in Italy, Romania and Germany, combining web-based and traditional learning ("blended learning"). A questionnaire-based needs assessment and context analysis were conducted, based on which an education scenario was designed. Particular emphasis was put on emotional and motivational aspects, using narrative components in the didactic concept. The design process occupied a central role in the project (design-based research). Evaluation was both formative and summative. Continuous feedback was obtained from relevant stakeholders. Following a prototypical implementation, the scenario was evaluated using questionnaires. The results revealed a high level of acceptance of the education scenario as well as an increase in students' knowledge concerning skin and sexual health. Evaluation also suggested that health education is highly influenced by cultural background and habits as well as diverse contextual and personal conditions. PMID- 20169299 TI - Long-term follow-up of in situ extramammary Paget's disease in Asian skin types IV/V treated with photodynamic therapy. AB - Photodynamic therapy is a potentially advantageous treatment for non-melanoma skin cancers. We evaluated the clinical response, recurrence and adverse events of photodynamic therapy for in situ extramammary Paget's disease in 14 male and 3 female Chinese patients with 21 lesions. Topical 20% 5-aminolevulinic acid was applied for 6 h. Each lesion was irradiated with 633 nm red light three times, 1 week apart, at a total dose of 339 J/cm2, followed by three assessments at 6, 12 and 24 months. Overall complete response (CR) rates were 52.4%, 42.9%, and 33.3% at 6, 12 and 24 months, respectively. The CR rate was significantly higher in scrotal lesions (66.6%) than in non-scrotal lesions (8.3%). The overall recurrence rate was 50%. The highest CR rate was for the lesions < 4 cm in diameter (62.5%), followed by those 4-8 cm (33.3%) and > 8 cm (0%). Most adverse events were well tolerated. In conclusion, photodynamic therapy for extramammary Paget's disease is not recommended as the first option except for scrotal cases or lesions < 4 cm in diameter. PMID- 20169300 TI - Response of intractable skin ulcers in recessive dystrophic epidermolysis bullosa patients to an allogeneic cultured dermal substitute. AB - Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited skin disorder caused by mutations in the COL7A1 gene, which encodes collagen VII (COL7). Skin ulcers in RDEB patients are sometimes slow to heal. We describe here the therapeutic response of intractable skin ulcers in two patients with generalized RDEB to treatment with an allogeneic cultured dermal substitute (CDS). Skin ulcers in both patients epithelialized by 3-4 weeks after this treatment. Immunohistochemical studies demonstrated that the COL7 expression level remained reduced with respect to the control skin and that it did not differ significantly between graft-treated and untreated areas. Electron microscopy showed aberrant anchoring fibrils beneath the lamina densa of both specimens. In conclusion, CDS is a promising modality for treatment of intractable skin ulcers in patients with RDEB, even though it does not appear to increase COL7 expression. PMID- 20169301 TI - One-year treatment with 0.1% tacrolimus ointment versus a corticosteroid regimen in adults with moderate to severe atopic dermatitis: A randomized, double-blind, comparative trial. AB - A one-year, randomized, double-blind study was conducted in 80 patients with atopic dermatitis treated with tacrolimus ointment or a corticosteroid regimen (hydrocortisone acetate 1% ointment for head and neck, hydrocortisone butyrate 0.1% ointment for trunk and limbs) to compare efficacy and safety, and effects on Th2-reactivity. The study was completed by 36/40 patients in the tacrolimus group, and 31/40 patients in the corticosteroid group. In both groups affected body surface area, eczema area and severity index, and transepidermal water loss decreased at months 6 and 12. Tacrolimus was superior for all efficacy scores at month 6, and in the head and neck area at month 12. Recall antigen reactivity increased at month 12 in both groups. Adverse events were reported by 40/40 patients in the tacrolimus, and by 34/40 patients in the corticosteroid group. Long-term treatment with topical tacrolimus or a corticosteroid regimen improves atopic dermatitis and recall antigen reactivity, suggesting an improvement in the Th1/Th2-balance. PMID- 20169302 TI - Toxic epidermal necrolysis-like cutaneous lupus erythematosus: A series of three patients. AB - Toxic epidermal necrolysis-like lesions have been described in the setting of lupus erythematosus, and have been considered as a specific hyperacute variant of cutaneous lupus erythematosus, with features different from classical drug related toxic epidermal necrolysis. We report here a series of three patients with lupus erythematosus who presented with severe worsening of their cutaneous disease in a toxic epidermal necrolysis-like fashion. We compared these cases with cases reported previously. Based on this discussion, we speculate that some of these patients may have classical drug-related toxic epidermal necrolysis rather than lupus erythematosus-related toxic epidermal necrolysis. PMID- 20169303 TI - Persistent improvement of previously recalcitrant Hailey-Hailey disease with electron beam radiotherapy. AB - Hailey-Hailey disease, or familial benign chronic pemphigus, is an autosomal dominant genodermatosis. Disease symptoms may contribute to an adverse impact on quality of life and functional limitation and disability. As Hailey-Hailey disease is chronic and frequently recalcitrant to treatment, multiple therapeutic approaches, including surgical options, have been attempted. We describe here three cases of recalcitrant Hailey-Hailey disease that showed long-term improvement with radiotherapy. Axillary lesions were treated with electron beam at an anti-inflammatory dose (energy 6-8 MeV). Patients received 20 Gy in 10 fractions to 90% isodose, at each axilla. No disease recurrence was observed during a 38 months follow-up of the treated sites. The effect of radiotherapy was thus considered to be locally beneficial, but without any positive influence on the general course of the disease. PMID- 20169304 TI - Paradoxical reactions to targeted biological treatments: A way to treat and trigger? PMID- 20169305 TI - Erosive lichen planus on an atypical site mimicking a factitial dermatitis. PMID- 20169307 TI - Repeated anaphylactic responses induced by oral challenge with ranitidine. PMID- 20169306 TI - Allergic contact dermatitis due to cinnamon oil in galenic vaginal suppositories. PMID- 20169308 TI - Development of a prominent granulomatous eruption after interferon-gamma therapy in a patient with mycosis fungoides. PMID- 20169309 TI - A myopericytoma of the nose. PMID- 20169310 TI - A case of sebaceous naevus of the leg with secondarily developed trichoblastoma. PMID- 20169311 TI - Sebaceous carcinoma with actinic keratosis. PMID- 20169312 TI - ALK-positive primary systemic anaplastic large cell lymphoma with extensive cutaneous manifestation. PMID- 20169313 TI - Infantile erosive pustular dermatosis of the scalp associated with Klippel-Feil syndrome. PMID- 20169314 TI - Perifollicular xanthomas associated with epidermal growth factor receptor inhibitor therapy. PMID- 20169315 TI - Generalized eruptive histiocytosis in an infant. PMID- 20169316 TI - Clarithromycin treatment failure due to macrolide resistance in Treponema pallidum in a patient with primary syphilis. PMID- 20169317 TI - Is recurrent pseudoepitheliomatous keratotic balanitis related to human papillomavirus infection? PMID- 20169318 TI - Naevus lentiginosus linearis: A distinct skin disorder. PMID- 20169319 TI - Development of segmental superficial actinic porokeratosis during immunosuppressive therapy for pemphigus vulgaris. PMID- 20169320 TI - Dermacentor-borne Necrosis Erythema and Lymphadenopathy (DEBONEL): A case associated with Rickettsia rioja. PMID- 20169321 TI - Photodynamic therapy for distal and lateral subungual toenail onychomycosis caused by Trichophyton rubrum: Preliminary results of a single-centre open trial. PMID- 20169322 TI - Successful treatment of nail lichen planus with topical tacrolimus. PMID- 20169323 TI - Intravascular papillary endothelial hyperplasia simulating malignant melanoma. PMID- 20169324 TI - Unusual features of peristomal erosion: a quiz. Intestinal epithelium on a peristomal erosion. PMID- 20169325 TI - Papular skin lesions in the retroauricular area: a quiz. Premature sebaceous hyperplasia en plaque. PMID- 20169326 TI - [Incisional hernia: an unpleasant complication in surgery]. PMID- 20169327 TI - [Chances and limitations of chemotherapy in elderly patients]. AB - The chronological age of a patient should not be a barrier to apply chemotherapy. Elderly patients can benefit from chemotherapy. Chronological age should not be a reason for diagnostic or therapeutic nihilism, as the age of a patient poorly characterizes their health situation. Data with high level of evidence on treatment of elderly patients with cancer are limited. A comprehensive geriatric assessment (CGA) describes the individual deficits and resources of a patient much better. Limitations in CGA are risk factors for increased toxicity and decreased treatment benefit. The currently available data demonstrate under- and over-treatment in elderly patients with cancer. PMID- 20169329 TI - [Seizure and non-cardiogenic pulmonary edema after intoxication]. AB - We report a case of severe intoxication with extended-release verapamil. In addition to cardiovascular toxicities with hypotension, atrioventricular block and bradycardia, the patient suffered from grand-mal seizure and pulmonary edema 13 and 48 hours respectively, after ingestion of 4.8 g of extended-release verapamil. Adverse reactions after intoxications with extended-release tablets appear delayed with prolonged manifestation of symptoms. Early and repetitive administration of activated charcoal and antegrade whole bowel lavage are crucial, even in primary asymptomatic patients. PMID- 20169330 TI - [Treatment of primary varicosis]. AB - While the treatment of varicose veins has remained unchanged over the past 100 years based on the three principles of compression, sclerotherapy, and classic varicose vein surgery, alternative approaches and advancements in treatment have developed in the last 10 years such as foam sclerotherapy, endovenous laser therapy, and radiofrequency obliteration. In contrast to classic varicose vein surgery, prospective, randomized, comparative studies are available with respect to the modern treatment procedures. They clearly show that endovenous thermal techniques are not inferior to the classic operation regarding the perioperative complication rate. There appears to be a tendency toward considerably fewer perioperative complaints with endovenous laser therapy and in particular with radiofrequency obliteration. Foam sclerotherapy represents a minimally invasive alternative that is markedly cost-effective. Even though the occlusion rate of the root veins after foam sclerotherapy is not as good as after endovenous therapy, the method is initially very effective. Especially in cases of recurrent varicose veins from the saphenofemoral or popliteal junction, foam sclerotherapy should be considered as the ideal method. All procedures significantly improve the patients' quality of life and the symptom complaints related to varicose veins. They are not in competition, but rather partially complement each other so that a combination of several approaches is quite judicious. PMID- 20169332 TI - Chinese validation of Urogenital Distress Inventory and Incontinence Impact Questionnaire short form. AB - INTRODUCTION AND HYPOTHESIS: UDI-6 and IIQ-7 are useful disease-specific questionnaires evaluating the impact of urinary incontinence on the QOL of women. We aim at validating them in Chinese language. METHODS: Both instruments were translated; 207 urinary incontinent women completed UDI-6 and IIQ-7, SF-36, bladder diary and urodynamic evaluation. The reliability and validity were assessed. RESULTS: There were high internal consistency (Cronbach's alpha for UDI 6 and IIQ-7 was 0.80 and 0.93) and test-retest reliability (Intraclass correlation coefficient was 0.72 and 0.75, P < 0.001). Scoring of UDI-6 and IIQ-7 was negatively correlated with SF-36 (P < 0.001); positively correlated with daytime urinary frequency and incontinent episodes (P < 0.001), and women's VAS (P < 0.001). Subscales of UDI-6 and IIQ-7 could discriminate women with different urodynamic diagnoses. CONCLUSIONS: The Chinese UDI-6 and IIQ-7 is reliable and valid. Study on the responsiveness to treatment is in progress. They are useful in assessing impact of the urinary incontinence in Chinese women. PMID- 20169333 TI - Validated quantification for selective cellular uptake of ginsenosides on MCF-7 human breast cancer cells by liquid chromatography-mass spectrometry. AB - The cellular behavior of ginsenosides on cancer cells has not been measured directly despite their potent anticancer activities and biological actions. A liquid chromatography-mass spectrometry (LC-MS) method was developed to measure the selective cellular uptake of ginsenosides in both cell lysates and culture media. Fifteen ginsenosides were separated within 17 min with good peak shapes using a 2-microm sub-particle size C18 column. Quantification was performed by triple-quadrupole MS with electrospray ionization in negative ion mode. The sample preparation containing the solid-phase extraction was linear (correlation coefficient, r(2) > 0.992) for all analytes, while the limit of quantification ranged from 0.5 to 2.0 ng/mL in both matrices. The assay precision (%CV) and accuracy (%bias) at three different concentrations (5, 20, and 100 ng/mL) were 1.4% to 11.6% and 94.9% to 106.4%, respectively. When this method was used to examine the selective cellular uptake of ginsenosides, the relative non-polar and protopanaxadiol class ginsenosides, such as Rg3, Rk1, Rg5, Rh2, compound-K, and protopanaxadiol (PPD), showed cellular uptake in the MCF-7 cells, but the relative polar and protopanaxatriol class of ginsenosides did not accumulate in the cells. The most non-polar ginsenoside PPD, which is an aglycone of the protopanaxadiol type, resulted in the highest uptake rate. These results show that the different anticancer activities are due to the selective uptake of ginsenosides based on their chemical structures. This LC-MS-based method can be used to estimate the biological activity of ginsenosides on cells from their structural diversity. PMID- 20169331 TI - Natural and synthetic STAT3 inhibitors reduce hepcidin expression in differentiated mouse hepatocytes expressing the active phosphorylated STAT3 form. AB - During the inflammatory process, hepcidin overexpression favours the development of anaemia of chronic diseases which represents the second most common form of anaemia worldwide. The identification of therapeutic agents decreasing hepcidin expression is therefore an important goal. The aim of this study was to target the STAT3 signalling involved in the development of increased hepcidin expression related to chronic inflammation. In a co-culture model associating mouse hepatocytes and rat liver epithelial cells, the mRNA levels of hepcidin1, albumin, aldolase B, Cyp3a4, Stat3, Smad4 and iron regulatory genes were measured by real-time PCR. STAT3 and phosphorylated SMAD1/5/8 proteins were analysed by Western blot. At variance of hepatocyte pure culture, co-culture provided high levels of hepcidin1 mRNA, reaching 400% of the freshly isolated hepatocyte values after 6 days of culture. Hepcidin expression was associated with the maintenance of hepatocyte phenotype, STAT3 phosphorylation and functional BMP/SMAD pathway. Stat3 siRNAs inhibited the hepcidin1 mRNA expression. STAT3 inhibitors, including curcumin, AG490 and a peptide (PpYLKTK), reduced hepcidin1 mRNA expression even when cells were additionally exposed to IL-6. Hepcidin1 mRNA was expressed at high levels by hepatocytes in the co-culture model, and STAT3 pathway activation was controlled through STAT3 inhibitors. Such inhibitors could be useful to prevent anaemia related to hepcidin overexpression during chronic inflammation. PMID- 20169334 TI - Isolation of N-linked glycopeptides by hydrazine-functionalized magnetic particles. AB - We introduce a novel combination of magnetic particles with hydrazine chemistry, dubbed as hydrazine-functionalized magnetic particles (HFMP) for isolation of glycopeptides. Four methods have been developed and compared for the production of HFMP by hydrazine modification of the surface of the carboxyl and epoxy silanized magnetic particles, respectively. The evaluation of the capability and specificity of HFMP as well as the optimization of the coupling condition for capturing of glycoproteins were systematically investigated. The results showed that HFMP prepared by adipic dihydrazide functionalization from carboxyl silanized magnetic particles (HFCA) displayed the maximum capture capacity and isolated efficiency for glycoprotein. When measured with glycoproteins, the capacity of the HFCA (1 g) for coupling bovine fetuin was 130 +/- 5.3 mg. The capability of this method was also confirmed by successful isolation of all formerly glycosylated peptides from standard glycoproteins and identification of their glycosylation sites, which demonstrated the feasibility of the HFCA as an alternative solid support for isolation of glycoproteins/glycopeptides. PMID- 20169335 TI - Application of the novel 5-chloro-2,2,3,3,4,4,5,5-octafluoro-1-pentyl chloroformate derivatizing agent for the direct determination of highly polar water disinfection byproducts. AB - A novel derivatizing agent, 5-chloro-2,2,3,3,4,4,5,5-octafluoropentyl chloroformate (ClOFPCF), was synthesized and tested as a reagent for direct water derivatization of highly polar and hydrophilic analytes. Its analytical performance satisfactorily compared to a perfluorinated chloroformate previously described, namely 2,2,3,3,4,4,5,5-octafluoropentyl chloroformate (OFPCF). The chemical properties (reactivity, selectivity, derivatization products, and their chromatographic and spectral features) for ClOFPCF were investigated using a set of 39 highly polar standard analytes, including, among others, hydroxylamine, malic and succinic acids, resorcinol, hydroxybenzaldehyde, and dihydroxybenzoic acid. Upon derivatization, the analytes were extracted from the aqueous solvent and analyzed by gas chromatography (GC)-mass spectrometry (MS) in the electron capture negative ionization (ECNI) mode. Positive chemical ionization (PCI)-MS was used for confirming the molecular ions, which were virtually absent in the ECNI mass spectra. ClOFPCF showed good reaction efficiency, good chromatographic and spectroscopic properties (better than with OFPCF), good linearity in calibration curves, and low detection limits (0.3-1 microg/L). A unique feature of the derivatizations with ClOFPCF, and, in general, highly fluorinated chloroformates, is their effectiveness in reacting with carboxylic, hydroxylic, and aminic groups at once, forming multiply-substituted non-polar derivatives that can be easily extracted from the aqueous phase and determined by GC-ECNI-MS. The entire procedure from raw aqueous sample to ready-to-inject hexane solution of the derivatives requires less than 10 min. Another benefit of this procedure is that it produced stable derivatives, with optimal volatility for GC separation, and high electron affinity, which allows their detection as negative ions at trace level. In addition, their mass spectra exhibits chlorine isotopic patterns that clearly indicate how many polar hydrogens of the analyte undergo derivatization. Finally, derivatization with ClOFPCF was used successfully to identify 13 unknown highly polar disinfection byproducts (DBPs) in ozonated fulvic and humic acid aqueous solutions and in real ozonated drinking water. PMID- 20169336 TI - Spectrophotometric analysis of nucleic acids: oxygenation-dependent hyperchromism of DNA. AB - The absorbance at 260 nm (A(260)) is ubiquitously used for nucleic acid quantification. We show that following oxygenation, DNA solutions experience alterations in both spectral properties (hyperchromism in the UV region, lambda(max) 260 nm) and DNA conformation. The spectral changes caused by oxygen DNA complexation are stable for at least several weeks at room temperature or several hours at 37 degrees C, but are also reversible by purging with nitrogen. Our data indicate that DNA in working solutions might already exist in the oxygen complexed state, potentially confounding spectrophotometric analyses. Further, the presence of these complexes does not appear to impart cell toxicity in vitro or affect the biophysical functional behaviour (e.g. hybridisation) of DNA. Interestingly, our work also suggests that hybridisation could determine a release of bound oxygen, a phenomenon that could open the way to the use of such systems as oxygen carriers. PMID- 20169337 TI - Panel of synaptic protein ELISAs for evaluating neurological phenotype. AB - The purpose of this study was to develop ELISAs for key neural proteins, three synaptic and one glial, that exist in different intracellular compartments, which would be used as a measure of synaptic phenotype. These assays would be valuable to neurologically phenotype transgenic mouse models of human disease and also human disease itself using minimal amounts of post-mortem tissue. We showed that supernatant from crude brain tissue homogenates extracted in RIPA buffer containing 0.1% SDS bind to synaptophysin, synaptosome-associated protein of 25 kDa (SNAP-25), post-synaptic density-95 (PSD-95), and glial fibrillary acidic protein (GFAP) antibody pairs with high affinity and selectivity. Overall, RIPA + 0.1% SDS were more efficient than RIPA + 2% SDS or a buffer containing only 1% Triton-X-100. Diluting the brain extracts resulted in dose-dependent binding to the antibody pairs for each neural protein, with EC50s that varied from 8.6 microg protein for PSD-95 to 0.23 microg for GFAP. The assays were used to measure synaptic marker protein levels at various times during mouse development and GFAP in a model of disease accompanied by neuroinflammation. Comparison of ELISAs with Western blots by measuring marker levels in brain extract from developing mice showed a greater relative difference in values derived from ELISA. These ELISAs should be valuable to phenotype the synapse in neurological disease and their rodent models. PMID- 20169338 TI - Non-monotonicity on a spatio-temporally defined cyclic task: evidence of two movement types? AB - We tested 23 healthy participants who performed rhythmic horizontal movements of the elbow. The required amplitude and frequency ranges of the movements were specified to the participants using a closed shape on a phase-plane display, showing angular velocity versus angular position, such that participants had to continuously control both the speed and the displacement of their forearm. We found that the combined accuracy in velocity and position throughout the movement was not a monotonic function of movement speed. Our findings suggest that specific combinations of required movement frequency and amplitude give rise to two distinct types of movements: one of a more rhythmic nature, and the other of a more discrete nature. PMID- 20169339 TI - Effect of selective and distributed training on visual identification of orientation. AB - An experiment contrasted the effect of four training schedules in a visual orientation reproduction task. Two selective schedules involved repeated presentation of a single target orientation. Two non-selective schedules involved targets covering the first quadrant either at fixed, equispaced orientations, or distributed randomly. In pre-training sessions, we observed the classical oblique effect (precision for vertical and horizontal stimuli higher than for oblique ones). Practice improved precision with both distributed schedules, but was ineffectual for non-selective schedules. However, a significant oblique effect persisted under all conditions. We argue that the pattern of results is compatible with the hypothesis that the oblique effect reflects both the intrinsic neuronal properties of the primary visual system, and the structure of the visual space imposed by higher, more cognitive processes. The results challenge the thesis that only attentional and post-perceptual factors are able to affect the working of the early visual system. PMID- 20169340 TI - Effects of long-term addition of Cu(II) and Ni(II) on the biochemical properties of aerobic granules in sequencing batch reactors. AB - Copper (Cu(II)) and nickel (Ni(II)) are often encountered in wastewaters. This study investigated the individual toxic effects of long-term addition of Cu(II) and Ni(II) on the biochemical properties of aerobic granules in sequencing batch reactors (SBRs). The biochemical properties of aerobic granules were characterized by extracellular polymeric substances (EPS) content, dehydrogenase activity, microbial community biodiversity, and SBR performance. One SBR was used as a control system, while another two received respective concentration of Cu(II) and Ni(II) equal to 5 mg/L initially and increased to 15 mg/L on day 27. Results showed that the addition of Cu(II) drastically reduced the biomass concentration, bioactivity, and biodiversity of aerobic granules, and certainly deteriorated the treatment performance. The toxic effect of Ni(II) on the biodiversity of aerobic granules was milder and the aerobic granular system elevated the level of Ni(II) toxicity tolerance. Even at a concentration of 15 mg/L, Ni(II) still stimulated the biomass yield and bioactivity of aerobic granules to some extent. The elevated tolerance seemed to be owed to the concentration gradient developed within granules, increased biomass concentration, and promoted EPS production in aerobic granular systems. PMID- 20169341 TI - Biological control of microbial attachment: a promising alternative for mitigating membrane biofouling. AB - Microbial attachment to a solid surface is a universal phenomenon occurring in both natural and engineering systems and is responsible for various types of biofouling. Membrane systems have been widely applied in drinking water production, wastewater reuse, and seawater desalination. However, membrane biofouling is the bottleneck that limits the development of membrane systems. In this review, some biological control strategies of microbial attachment which would have great potential in alleviating membrane biofouling are discussed, including inhibition of quorum sensing system, nitric oxide-induced biofilm dispersal, enzymatic disruption of extracellular polysaccharides, proteins, and DNA, inhibition of microbial attachment by energy uncoupling, use of cell wall hydrolases, and disruption of biofilm by bacteriophage. It appears that biological control of microbial attachment would be a novel and promising alternative for mitigating membrane biofouling and would be a new research niche that deserves further study. PMID- 20169342 TI - Mineralization of s-triazine herbicides by a newly isolated Nocardioides species strain DN36. AB - A novel s-triazine-mineralizing bacterium-Nocardioides sp. strain DN36-was isolated from paddy field soil treated with ring-U-(14)C-labeled simetryn ([(14)C]simetryn) in a model paddy ecosystem (microcosm). In a tenfold-diluted R2A medium, strain DN36 liberated (14)CO(2) from not only [(14)C]simetryn but also three ring-U-(14)C-labeled s-triazines: atrazine, simazine, and propazine. We found that DN36 mineralized ring-U-(14)C-cyanuric acid added as an initial substrate, indicating that the bacterium mineralized s-triazine herbicides via a common metabolite, namely, cyanuric acid. Strain DN36 harbored a set of genes encoding previously reported s-triazine-degrading enzymes (TrzN-AtzB-AtzC), and it also transformed ametryn, prometryn, dimethametryn, atraton, simeton, and prometon. The findings suggest that strain DN36 can mineralize a diverse range of s-triazine herbicides. To our knowledge, strain DN36 is the first Nocardioides strain that can individually mineralize s-triazine herbicides via the ring cleavage of cyanuric acid. Further, DN36 could not grow on cyanuric acid, and the degradation seemed to occur cometabolically. PMID- 20169343 TI - A novel family 9 beta-1,3(4)-glucanase from thermoacidophilic Alicyclobacillus sp. A4 with potential applications in the brewing industry. AB - An endo-beta-1,3(4)-glucanase gene, Agl9A, was cloned from Alicyclobacillus sp. A4 and expressed in Pichia pastoris. Its deduced amino acid sequence shared the highest identity (48%) with an endo-beta-1,4-glucansae from Alicyclobacillus acidocaldarius that belongs to family 9 of the glycoside hydrolases. The purified recombinant Agl9A exhibited relatively wide substrate specificity, including lichenan (109%), barley beta-glucan (100%), CMC-Na (15.02%), and laminarin (6.19%). The optimal conditions for Agl9A activity were pH 5.8 and 55 degrees C. The enzyme was stable over a broad pH range (>60% activity retained after 1-h incubation at pH 3.8-11.2) and at 60 degrees C (>70% activity retained after 1-h incubation). Agl9A was highly resistant to various neutral proteases (e.g., trypsin, alpha-chymotrypsin, and collagenase) and Neutrase 0.8L (Novozymes), a protease widely added to the mash. Under simulated mashing conditions, addition of Agl9A (20 U/ml) or a commercial xylanase (200 U/ml) reduced the filtration rate (26.71% and 20.21%, respectively) and viscosity (6.12% and 4.78%, respectively); furthermore, combined use of Agl9A (10 U/ml) and the xylanase (100 U/ml) even more effectively reduced the filtration rate (31.73%) and viscosity (8.79%). These characteristics indicate that Agl9A is a good candidate to improve glucan degradation in the malting and brewing industry. PMID- 20169344 TI - Acute retropharyngeal calcific tendinitis: a case report with unusual location of calcification. AB - Retropharyngeal calcific tendinitis is an inflammatory process caused by calcium hydroxyapatite crystal deposition in the longus colli tendon of the prevertebral space, and it may mimic a retropharyngeal infection or abscess. The diagnosis of retropharyngeal calcific tendinitis will be made radiologically by the detection of calcifications anterior to C1-C3 and prevertebral soft tissue swelling. We present a case of acute retropharyngeal calcific tendinitis with an unusual location of calcification anterior to the C5-C6 disc. PMID- 20169345 TI - Study on the effect of T-2 toxin combined with low nutrition diet on rat epiphyseal plate growth and development. AB - The purpose of this study was to observe early lesions of rat epiphyseal plates and metaphysis caused by T-2 toxin and T-2 toxin combined with a low nutrition diet to determine possible pathogenic factors of Kashin-Beck disease (KBD). Ninety Wistar rats were divided into three groups. Group A was fed with a normal diet as control; group B was fed with a normal diet and T-2 toxin; and group C was fed with a low nutrition diet and T-2 toxin. The left knee specimens were collected, fixed in formaldehyde solution, stained by hematoxylin and eosin and Masson. After two weeks, the epiphyseal plate showed necrosis of chondrocytes in groups B and C. After four weeks, more obvious chondrocyte necrosis appeared. The positive rate of Lamellar necrosis in group C was significantly higher than that in groups B and A (P < 0.01). Metaphyseal trabecular bone showed sparse disorder and disruption in group C. T-2 toxin combined with a low nutrition diet could lead to more serious chondrocyte necrosis in the epiphyseal plate and disturb metaphyseal trabecular bone formation. PMID- 20169346 TI - Planning for the human dimensions of oil spills and spill response. AB - Oil spill contingency planners need an improved approach to understanding and planning for the human dimensions of oil spills. Drawing on existing literature in social impact assessment, natural hazards, human ecology, adaptive management, global change and sustainability, we develop an integrative approach to understanding and portraying the human dimensions impacts of stressors associated with oil spill events. Our approach is based on three fundamental conclusions that are drawn from this literature review. First, it is productive to acknowledge that, while stressors can produce human impacts directly, they mainly affect intermediary processes and changes to these processes produce human impacts. Second, causal chain modeling taken from hazard management literature provides a means to document how oil spill stressors change processes and produce human impacts. Third, concepts from the global change literature on vulnerability enrich causal models in ways that make more obvious how management interventions lessen hazards and mitigate associated harm. Using examples from recent spill events, we illustrate how these conclusions can be used to diagrammatically portray the human dimensions of oil spills. PMID- 20169347 TI - Population pharmacokinetic study of a test dose oral busulfan in Japanese adult patients undergoing hematopoietic stem cell transplantation. AB - PURPOSE: The aim of this study is to determine the population pharmacokinetics of oral busulfan in Japanese adults. METHODS: We previously underwent a clinical trial involving the dose adjustment of oral busulfan depending on the individual pharmacokinetics using a test dose in hematopoietic stem cell transplantation recipients. Seventy-one Japanese patients aged from 16 to 67 years were enrolled. After taking oral busulfan 0.5 mg/kg as a test dose, blood samples were collected at five time points from each patient. Busulfan concentrations were measured by high-performance liquid chromatography, and the individual parameters were estimated by using the nonlinear mixed effects model computer program. A one compartment model with first-order absorption was sufficient to describe the concentration-time profile. RESULTS: The final pharmacokinetic parameter were the clearance (CL/F) = 0.153 L/h/kg, distribution volume (Vd/F) = 0.695 L/kg, and absorption rate constant (ka) = 2.39 h(-1). The inter-individual variabilities in CL/F, Vd/F and ka were 25.9, 26.2, and 111.8%, respectively, and the residual variability was 12.1% as the coefficient of variation. CONCLUSION: We developed a population pharmacokinetic model of oral busulfan in Japanese adults. The final population model was implemented into the program excel, leading to an easy and proper therapeutic monitoring of oral BU by using small number of samples. PMID- 20169348 TI - Single center prospective study of tacrolimus efficacy and safety in the treatment of various manifestations in systemic lupus erythematosus. AB - The aim of this study was to prospectively evaluate the efficacy and safety of tacrolimus (TAC) in various manifestations of systemic lupus erythematosus (SLE) patients in daily clinical practice. Each of the 21 TAC-treated patients with SLE in our care over 2 years was enrolled in this open-label trial. Patients were administered TAC at a dosage of 1-6 mg once daily, followed up for 24 weeks. Efficacy and safety were evaluated utilizing clinical and laboratory findings. As treatment targets, TAC was preferentially used with oral corticosteroid administration for mild active manifestations such as arthritis, skin eruptions, or asymptomatic nephritis. In efficacy, the mean value of the SLE disease activity index was significantly reduced to 4.1, 2.7, 1.8, and 1.2 (N=21, 20, 16 and 13) at 0, 4, 12, and 24 weeks, respectively. In eight cases, treatment was discontinued within 24 weeks due to insufficient effects (6 cases) and side effects (2 cases). Non-serious side effects were observed in only five cases (23.8%) over 24 weeks. TAC can be considered both effective and safe for the treatment of various manifestations of SLE. PMID- 20169349 TI - Simultaneous suppression of three genes related to brassinosteroid (BR) biosynthesis altered campesterol and BR contents, and led to a dwarf phenotype in Arabidopsis thaliana. AB - We generated transgenic lines of Arabidopsis thaliana with an RNA interference construct that expressed hairpin double-stranded RNA for DET2:DWF4:SMT2 to induce sequence-specific RNA silencing. In transgenic plants, expressions of DET2, DWF4, and SMT2 were simultaneously reduced, and the campesterol content was increased by up to 420% compared to the level in the wild-type plant. Triple knock-down of the DET2, DWF4, and SMT2 enzymes also resulted in reduction of brassinosteroid (BR)-specific biosynthesis intermediates. Transgenic plants harboring the RNA interference construct displayed a semi-dwarf phenotype due to altered development. Our findings indicate that redesigning of plant architecture is possible through simultaneous suppression of multiple genes involved in BR biosynthesis. PMID- 20169350 TI - Comparison of the erectile function in male patients with rectal cancer treated by preoperative radiotherapy followed by surgery and surgery alone. AB - PURPOSE: This study evaluates the erectile function of male patients treated by preoperative radiotherapy followed by surgery and surgery alone for locally advanced rectal cancer. METHODS: A total of 112 men treated by total mesorectal excision with autonomic nerve preservation were included. Seventy-three patients were treated by preoperative radiotherapy followed by surgery (RTS group), and 39 were treated by surgery alone (surgery group). Patients filled out the five-item version of the international index of erectile function (IIEF-5) questionnaire at least 6 months after initial erectile function assessment. We analyzed the impact of age, surgery type, location, and size of tumor on erectile function. RESULTS: Total score was decreased significantly at follow-up compared to initial assessment in both RTS and surgery group (20.31 +/- 4.39 vs. 11.52 +/- 4.83, P = 0.012; 19.86 +/- 4.61 vs. 14.07 +/- 6.37, P = 0.031, respectively). Score difference was statistically higher in RTS group compared with surgery group (P = 0.028). In terms of surgery type for RTS group, score difference was statistically higher in the patients with abdominoperineal resection (APR) compared with those with lower anterior resection (P = 0.023). In comparison of score difference according to tumor location, difference was statistically higher in the patients with lower rectal cancer compared with those with upper rectal cancer (P = 0.017). CONCLUSION: The erectile functions of patients treated by preoperative radiotherapy followed by surgery are more affected than that of patients treated by surgery alone in locally advanced rectal cancer. Also APR and lower rectal cancer were significantly associated with erectile dysfunction in the patients treated by preoperative radiotherapy followed by surgery. PMID- 20169352 TI - The "Innsbruck Emergency Algorithm" avoids the underdiagnosis of blunt cervical vascular injuries. AB - OBJECTIVES: Blunt cervical vascular injuries (BCVI) from alpine sports accidents bear an increased risk for being underdiagnosed during initial radiological evaluation. At our hospital, the "Innsbruck Emergency Algorithm", which includes assessment of the neck as a computed tomography (CT) angiography during initial whole-body CT, has been introduced to avoid misdiagnoses and optimizes emergency radiology management. METHODS: Critically injured patients who were admitted for emergency CT after trauma from alpine skiing and mountain-biking accidents and who were reported with BCVI were included in this retrospective study. RESULTS: During 2003-2009, 36 victims were eligible for inclusion. They presented with a mean (SD) of 4.6 (2.1) diagnoses per patient, of which 3.5 (2.3) were perceptible on radiology examinations only. The "Innsbruck Emergency Algorithm" was performed in 15 individuals while 21 underwent another CT protocol including a native scan of the neck or during a parenchymatous contrast-medium phase only. In addition to BCVI, most patients (71%) were diagnosed with fractures followed by unspecific contusion/s (54%), head injuries (43%), and injuries of parenchymatous organs (19%). In five (14%), BCVI was underdiagnosed during the initial radiological examination. All of the latter had CT during a parenchymatous contrast-medium phase and not according to the "Innsbruck Emergency Algorithm". Four of those patients died during their hospital stay. In 11, cerebral follow-up examinations showed cerebral pathologies considered as results from BCVI. CONCLUSIONS: The "Innsbruck Emergency Algorithm" in patients with clinically unapparent BCVI after skiing and mountain-biking accidents avoided overlooking vascular injuries, which significantly improved their long-term outcome. PMID- 20169351 TI - Is daily 400 IU of vitamin D supplementation appropriate for every country: a cross-sectional study. AB - BACKGROUND: Vitamin D deficiency in childhood is a significant problem worldwide. Religious, social customs, and lack of food fortification were significant hurdles in the way of the rickets scourge. Recent data support a serum level of 25(OH)D level > 40 ng/mL as the appropriate standard to achieve to prevent rickets. Herein, the current approaches of preventing rickets and optimal level of different vitamin D intakes were evaluated. METHODS: A total of 148 fully breastfed, healthy children between age of 2-24 months were investigated by screening serum 25(OH)D from April 1 to May 31, 2006. Three groups were composed according to ages (2-6, 6-12, 12-24 months), and those groups were paired with three subgroups established according to vitamin D intake of <=300, 400, and 600 IU/day. Vitamin D status was evaluated with regard to cut-off value of 15 ng/mL and 40 mg/dL. The clothing types and vitamin D supplementation of mothers were recorded. RESULTS: We found that 27.3% of cases in 2-6 months, 8.3% in 6-12 months and 30% in 12-24 months had 25(OH)D <15 ng/mL and 54.5, 33.3, and 50% of cases were <40 ng/dL with 400 IU/day vitamin D intake. With 600 IU/day supplementation, 14.3, 10.3, and 4.8% of cases had 25(OH)D <15 ng/mL, respectively. CONCLUSION: Vitamin D intake of 400 IU/day seems to be favorable at the first year in breastfed children but vitamin D deficiency was still evident after prophylaxis. Vitamin D supplementation should be at least 600 IU/day in Turkey, and nutrition policy should focus on the food fortification with vitamin D. PMID- 20169353 TI - Time-dependent changes in nasal ciliary beat frequency. AB - As the ex vivo lifetime of nasal ciliary cells is limited, these cells have to be transferred to a culture medium for analysis with vital cytology immediately. Although the ciliary beat frequency (CBF) is likely to change over time, sufficient data regarding changes in the ex vivo CBF has not been published to date. In the present study, nasal epithelial cells were harvested from the mucosa of the inferior turbinate of 19 healthy volunteers with a cytology brush. Beating cilia were visualized with phase-contrast microscopy. Over a 12-h timeframe, 2 s epochs of video were captured every 5 min from the identical group of cells using a high-speed digital camera with a sampling rate of 100 fps. Temperature was maintained at about 22 degrees C and controlled by an infrared pyrometer. The CBF rapidly increased by 47 +/- 53% during the first 3 h of measurement. A relative plateau followed this increase from 3 to 9 h. After 9 h, CBF reduced linearly. After 12 h, the mean frequency reduced to 20 +/- 69% of baseline. However, there was considerable variance between the samples. The initial increase in CBF has not been reported previously. This interval seems to be unsuitable for meaningful measurements. Measurements of CBF are most reliable during the plateau phase between 3 and 9 h. After 9 h, there is clearly a significant decrease in CBF, together with a considerable interindividual variance. PMID- 20169354 TI - Patients with schizophrenia show deficits of working memory maintenance components in circuit-specific tasks. AB - Working memory (WM) deficits are a neuropsychological core finding in patients with schizophrenia and also supposed to be a potential endophenotype of schizophrenia. Yet, there is a large heterogeneity between different WM tasks which is partly due to the lack of process specificity of the tasks applied. Therefore, we investigated WM functioning in patients with schizophrenia using process- and circuit-specific tasks. Thirty-one patients with schizophrenia and 47 controls were tested with respect to different aspects of verbal and visuospatial working memory using modified Sternberg paradigms in a computer based behavioural experiment. Total group analysis revealed significant impairment of patients with schizophrenia in each of the tested WM components. Furthermore, we were able to identify subgroups of patients showing different patterns of selective deficits. Patients with schizophrenia exhibit specific and, in part, selective WM deficits with indirect but conclusive evidence of dysfunctions of the underlying neural networks. These deficits are present in tasks requiring only maintenance of verbal or visuospatial information. In contrast to a seemingly global working memory deficit, individual analysis revealed differential patterns of working memory impairments in patients with schizophrenia. PMID- 20169355 TI - Impact of sociodemographic and health variables on mini-mental state examination in a community-based sample of older people. AB - The mini-mental state examination (MMSE) has been widely used as a screening instrument for cognitive disorders. Age, schooling and many other sociodemographic and health variables may be associated with a worse performance on the MMSE. The objectives of this study were to investigate the distribution of MMSE percentiles in a large Brazilian community-based elderly sample, divided according to age and schooling, and to evaluate the impact of sociodemographic and health variables on groups of elderly people with lower cognitive performance. The MMSE was applied to a sample of 2,708 adults, aged 60 years and older. Of this population, 1,563 individuals were living in the city of Sao Paulo, while 1,145 were living in the city of Ribeirao Preto. The subjects were divided into six groups according to the amount of schooling that they had received (no formal education, 1-4 and >=5 years) and age (<75 and >=75 years old). To each one of the subgroups a stepwise logistic regression was applied, considering the following dependent variable: subjects who scored under or above the 15th percentile on MMSE. High scores on a depression scale, high scores on a memory complaints scale and low socio-economic levels were associated with poorer performance on the MMSE. Being currently employed and being married were related to higher scores on the test. Many sociodemographic and health variables can influence MMSE performance, with impacts depending on age and schooling. Clinicians and primary care physicians should pay attention to variables that may be associated with worse cognitive performance. PMID- 20169356 TI - Intracellular bevacizumab reduces phagocytotic uptake in RPE cells. AB - BACKGROUND: We have previously shown that bevacizumab, but not ranibizumab, is taken up by porcine RPE cells. In this study, the effects of bevacizumab and ranibizumab on proliferation, wound healing and phagocytosis of the RPE were investigated. METHODS: Primary porcine RPE cell culture were prepared from fresh eyes, cultivated and treated with clinically relevant concentrations of bevacizumab or ranibizumab respectively. Proliferation was investigated in a proliferation assay, wound healing in a wound scratch assay and phagocytosis was investigated by feeding RPE cells photoreceptor outer segment-opsonized FITC labeled latex beads. RESULTS: Bevacizumab, and to a lesser extend ranibizumab, impair the proliferation of RPE cells but do not affect wound healing. Bevacizumab, but not ranibizumab, reduces the phagocytotic function of RPE cells. CONCLUSIONS: The uptake of bevacizumab reduces phagocytosis in RPE cells, which indicates possible long-term effects of repeated bevacizumab treatment. PMID- 20169357 TI - Intravitreal injection of triamcinolone combined with bevacizumab for choroidal neovascularization associated with large retinal pigment epithelial detachment in age-related macular degeneration. AB - PURPOSE: To discuss the effect and outcome of a combined intravitreal triamcinolone acetonide (IVTA) injection with intravitreal bevacizumab (IVB) in treating choroidal neovascularization (CNV) associated with large retinal pigment epithelial detachment (PED) in age-related macular degeneration (AMD). DESIGN: Prospective, consecutive, observational case series. METHODS: Seven eyes (five patients) with CNV associated with large PED in AMD were treated by IVTA (4 mg/ 0.1 ml), followed by a IVB (1.25 mg/0.05 ml) 1 week later. Patients were evaluated for best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) at baseline, at 1 week and every 6 weeks. Fluorescein angiography (FA) and indocyanine green angiography (ICG) were performed at baseline and every 3 months afterwards. Indications for retreatment by combined injection were defined as persistent PED with subretinal and/or intraretinal fluid on OCT. Patients with flattening of the PED and activity leakage demonstrated by OCT underwent subsequent IVB. RESULTS: The mean duration of follow-up was 11 months (range 9-14 months). BCVA at baseline averaged 20/125, and 20/80 at the end of follow-up. FA showed no leakage from the lesion in four eyes at the end of follow-up, and three eyes showed a decrease in leakage. Average central foveal thickness was (CFT) 325.7 microns at baseline and 209.2 microns at the end. The average size of the PED was 2.34 disk diameters (range 1.33-3.25) at baseline, and the PED disappeared in four eyes, while it decreased in size at the end in the remaining three. The subretinal fluid disappeared in all patients at the end. The combined treatment (IVTA with IVB 1 week later) was repeated in four eyes, and the number of IVB after combined injection ranged from one to three. No RPE tear appeared during follow-up. Two eyes developed glaucoma controlled by topical medication. There were no other ocular or systemic complications CONCLUSION: Combined IVB and IVTA therapy seems to be an effective and safe procedure to treat CNV associated with large PED in AMD. PMID- 20169359 TI - Effects of carbohydrate supplementation on competitive runners undergoing overload training followed by a session of intermittent exercise. AB - This study evaluated the effects of a micro cycle of overload training (1st-8th day) on metabolic and hormonal responses in male runners with or without carbohydrate supplementation and investigated the cumulative effects of this period on a session of intermittent high-intensity running and maximum performance-test (9th day). The participants were 24 male runners divided into two groups, receiving 61% of their energy intake as CHO (carbohydrate-group) and 54% in the control-group (CON). The testosterone was higher for the CHO than the CON group after the overload training (694.0 +/- 54.6 vs. CON 610.8 +/- 47.9 pmol/l). On the ninth day participants performed 10 x 800 m at mean 3 km velocity. An all-out 1000 m running was performed before and after the 10 x 800 m. Before, during, and after this protocol, the runners received solution containing CHO or the CON equivalent. The performance on 800 m series did not differ in either group between the first and last series of 800 m, but for the all-out 1000 m test the performance decrement was lower for CHO group (5.3 +/- 1.0 vs. 10.6 +/- 1.3%). The cortisol concentrations were lower in the CHO group in relation to CON group (22.4 +/- 0.9 vs. 27.6 +/- 1.4 pmol/l) and the IGF1/IGFBP3 ratio increased 12.7% in the CHO group. During recovery, blood glucose concentrations remained higher in the CHO group in comparison with the CON group. It was concluded that CHO supplementation possibly attenuated the suppression of the hypothalamic-pituitary-gonadal axis and resulted in less catabolic stress, and thus improved running performance. PMID- 20169358 TI - A tissue-engineered approach towards retinal repair: scaffolds for cell transplantation to the subretinal space. AB - BACKGROUND: Several mechanisms of retina degeneration result in the deterioration of the outer retina and can lead to blindness. Currently, with the exception of anti-angiogenic treatments for wet age-related macular degeneration, there are no treatments that can restore lost vision. There is evidence that photoreceptors and embryonic retinal tissue, transplanted to the subretinal space, can form new synapses with surviving host neurons. However, these transplants have yet to result in a clinical treatment for retinal degeneration. METHODS: This article reviews the current literature on the transplantation of scaffolds with retinal and retinal pigmented epithelial (RPE) cells to the subretinal space. We discuss the types of cells and materials that have been investigated for transplantation to the subretinal space, summarize the current findings, and present opportunities for future research and the next generation of scaffolds for retinal repair. RESULTS: Challenges to cell transplantation include limited survival upon implantation and the formation of abnormal cell architectures in vivo. Scaffolds have been shown to enhance cell survival and direct cell differentiation and organization in a number of models of retinal degeneration. CONCLUSIONS: The transplantation of cells within a scaffold represents a possible treatment to repair retinal degeneration and restore vision in effected patients. Materials have been developed for the delivery of retinal and RPE cells separately however, the development of a combined tissue-engineered scaffold targeting both cell populations represents a promising direction for retinal repair. PMID- 20169361 TI - Introduction to the special issue of brain structure and function on transgenic modeling of neurodegenerative disorders. PMID- 20169360 TI - Effect of moderate intensity resistance training during weight loss on body composition and physical performance in overweight older adults. AB - The impact of resistance training has not been thoroughly examined in overweight older adults undergoing weight loss. Subjects (n = 27) were overweight and obese (BMI 31.7 +/- 3.6 kg/m(2)) older (age 67 +/- 4 years) adults and were randomized into either a 10-week Dietary Approaches to Stop Hypertension for weight loss diet (DASH, n = 12) or DASH plus moderate intensity resistance training (DASH-RT, n = 15). Outcomes included weight loss, total body and mid-thigh composition, muscle and physical function. There were no significant weight loss differences between the DASH-RT and DASH groups (-3.6 +/- 0.8 vs. -2.0 +/- 0.9%, p = 0.137). The DASH-RT group had a greater reduction in body fat than the DASH group (-4.1 +/- 0.9 vs. -0.2 +/- 1.0 kg, p = 0.005). The DASH-RT group had greater changes in lean mass (+0.8 +/- 0.4 vs. -1.4 +/- 0.4 kg, p = 0.002) and strength (+60 +/- 18 vs. -5 +/- 9 N, p = 0.008) than the DASH group. There were favorable changes in mid-thigh composition variables in the DASH-RT group that were different than the lack of changes observed in the DASH group, except for intermuscular adipose tissue. Both groups experienced decreases in 400-m walk times showed (DASH -36 +/ 11 s, DASH-RT -40 +/- 7 s) with no differences between groups. Moderate intensity resistance training during weight loss appears to improve fat mass and thigh composition, but weight loss only does not. However, global measures of physical functioning may improve with a weight loss-only program. PMID- 20169362 TI - Perineural invasion in carcinoma of the cervix uteri--prognostic impact. AB - PURPOSE: Limited information exists about the occurrence and the impact of perineural invasion (PNI) in patients with cervical carcinoma (CX). METHODS: The original histologic slides from patients primarily treated by radical hysterectomy and systematic pelvic lymphadenectomy were re-examined regarding the occurrence of PNI. PNI was correlated to recurrence free (RFS) and overall survival (OS). RESULTS: 35.1% of all patients (68/194) represented perineural invasion (=PNI). The 5-year-overall-survival-rate was significantly decreased in patients representing PNI, when they were compared with those without PNI (51.1% [95% CI 38.0-64.2] vs. 75.6% [95% CI 67.8-83.4]; p = 0.001). In a separate analysis the prognostic impact persisted in the node negative, but disappeared in the node-positive cases. In multivariate analysis, pelvic lymph node involvement and PNI were independent prognostic factors for overall survival. CONCLUSIONS: Perineural invasion is seen in about one-third of patients with cervical carcinoma. Patients affected by PNI represented a decreased overall survival. Further studies are required to get a deeper insight into the clinical impact and the pathogenetic mechanisms of PNI in CX. PMID- 20169363 TI - Redescription of Syphacia venteli Travassos 1937 (Nematoda: Oxyuridae) from Nectomys squamipes in Argentina and Brazil and description of a new species of Syphacia from Melanomys caliginosus in Colombia. AB - Syphacia venteli Travassos, Mem Inst Oswaldo Cruz 32:607-613, 1937 is redescribed on the basis of specimens recovered from the type host, Nectomys squamipes (Brants 1827), from Brazil and Argentina. Specimens determined by Quentin (Bull Mus Natl Hist Nat 2:909-925, 1969) as S. venteli from Melanomys caliginosus (Tomes 1860) in Colombia were re-studied and assigned to a new species. In both species, structures such as the shape of the cephalic plate, details and distribution of the submedian papillae and amphids, presence and absence of the lateral and cervical alae, and shape and structure of the accessory hook of the gubernaculum were studied with the light microscope and scanning electron microscope. The present survey is the first detailed study of the species S. venteli since the original description, and the first record of this species from Argentina. Moreover, the present study suggests that the validity of some host species of Syphacia should be questioned and that through of the study of deposited specimens, a more exact number of parasitized host species can be confirmed, contributing to a better understanding of host specificity in this genus. PMID- 20169364 TI - Differential identification of Entamoeba spp. based on the analysis of 18S rRNA. AB - Entamoeba histolytica is known to cause intestinal and extra-intestinal disease while the other Entamoeba species are not considered to be pathogenic. However, all Entamoeba spp. should be reported when identified in clinical samples. Entamoeba polecki, Entamoeba coli, and Entamoeba hartmanii can be differentiated morphologically from E. histolytica, but some of their diagnostic morphologic features overlap. E. histolytica, Entamoeba dispar, and Entamoeba moshkovskii are morphologically identical but can be differentiated using molecular tools. We developed a polymerase chain reaction (PCR) procedure followed by DNA sequencing of specific regions of 18S rRNA gene to differentiate the Entamoeba spp. commonly found in human stools. This approach was used to analyze 45 samples from cases evaluated for the presence of Entamoeba spp. by microscopy and a real-time PCR method capable of differential detection of E. histolytica and E. dispar. Our results demonstrated an agreement of approximately 98% (45/44) between the real time PCR for E. histolytica and E. dispar and the 18S rRNA analysis described here. Five previously negative samples by microscopy revealed the presence of E. dispar, E. hartmanii, or E. coli DNA. In addition, we were able to detect E. hartmanii in a stool sample that had been previously reported as negative for Entamoeba spp. by microscopy. Further microscopic evaluation of this sample revealed the presence of E. hartmanii cysts, which went undetected during the first microscopic evaluation. This PCR followed by DNA sequencing will be useful to refine the diagnostic detection of Entamoeba spp. in stool and other clinical specimens. PMID- 20169365 TI - Endoscopic submucosal dissection with a combination of small-caliber-tip transparent hood and flex knife for superficial esophageal neoplasia. Is it safe for elderly patients? AB - BACKGROUND: Safety and efficacy of endoscopic submucosal dissection (ESD) for esophageal neoplasias have not been adequately investigated in elderly patients. This study was designed to evaluate the safety and efficacy of ESD for esophageal neoplasias in elderly patients. METHODS: Fifty-three superficial esophageal neoplasias treated with ESD using a combination of small-caliber-tip transparent hood and flex knife from May 2006 to June 2009 were divided into elderly group (aged 70 years or older: 25 lesions in 23 patients) and nonelderly group (younger than aged 70 years: 28 lesions in 25 patients). Therapeutic efficacy, complications, and follow-up results were evaluated retrospectively. RESULTS: The history of cerebral infarction or cardiopulmonary disease and the usage of antiplatelet agents or anticoagulants were significantly higher in elderly group (p 0.0050 and p 0.0013, respectively). Median procedural times in the elderly group and the nonelderly group were 93 +/- 53 (range, 42-235) min and 95 +/- 55 (range, 40-230) min (p 0.73), respectively. Median sizes of the neoplasias and the resected specimens were 14 +/- 11 (range, 5-45) mm and 15 +/- 17 (range, 5 83) mm (p 0.56), and 35 +/- 12 (range, 18-60) mm and 38 +/- 17 (range, 18-90) mm (p 0.38), respectively. En bloc resection rate was 100% in each group. Body temperature and white blood cell counts of the next day after ESD were significantly higher in the nonelderly group than in the elderly group (p 0.0087 and p 0.0043, respectively). There were no complications, such as postoperative bleeding or perforation, in each group. The median follow-up period of 23 +/- 10 (range, 4-35) months in the elderly group revealed no local or distant metastasis. CONCLUSIONS: ESD with a combination of small-caliber-tip transparent hood and flex knife is a safe and effective treatment for superficial esophageal neoplasia in elderly and nonelderly patients. PMID- 20169366 TI - Oxidative stress in erythrocytes: a study on the effect of antioxidant mixtures during intermittent exposures to high altitude. AB - The aim of our study was to compare and assess the effectiveness of antioxidant mixtures on the erythrocytes (RBC) of adult male albino rats (Wister) subjected to simulated intermittent high altitudes--5,100 m (AL(1)) and 6,700 m (AL(2))--to induce oxidative stress (OS). To achieve our objective, we pre-supplemented four sets of animals with different antioxidant mixtures [vitamin E (vit.E; 50 IU/kg BW), vitamin C (vit.C; 400 mg/kg) and L: -carnitine (400 mg/kg)] in different combinations [M1 (vit.E+vit.C), M2 (vit.C+carnitine), M3 (vit.E+carnitine) and M4 (vit.C+vit.E+carnitine)] for 30 days prior to as well during exposure to intermittent hypobaric hypoxia (IHH). Membrane instability, in terms of osmotic fragility and hemolysis, decreased in RBCs of supplemented animals. There was a significant increase in the activity of glutathione peroxidase in the RBCs of supplemented animals. We confirmed OS imposed by IHH with assays relating to lipid [thiobarbituric acid reactive substances (TBARS) and lipofuscin (LF)] and protein (carbonyl, PrC) oxidation, and found a positive correlation between PrC and hemolysis, with a decrease in both upon supplementation with M3 and M4 mixtures. Fluorescence microscopic observation showed a maximum decrease in the LF content in rats administered M4 and M1 compared to those on M2 and M3 mixtures at both altitudes. We suggest that multiple antioxidant fortifications are effective in overcoming increased OS experienced by RBCs at high altitudes. PMID- 20169367 TI - Relationships between sudden weather changes in summer and mortality in the Czech Republic, 1986-2005. AB - The study examines the relationship between sudden changes in weather conditions in summer, represented by (1) sudden air temperature changes, (2) sudden atmospheric pressure changes, and (3) passages of strong atmospheric fronts; and variations in daily mortality in the population of the Czech Republic. The events are selected from data covering 1986-2005 and compared with the database of daily excess all-cause mortality for the whole population and persons aged 70 years and above. Relative deviations of mortality, i.e., ratios of the excess mortality to the expected number of deaths, were averaged over the selected events for days D 2 (2 days before a change) up to D+7 (7 days after), and their statistical significance was tested by means of the Monte Carlo method. We find that the periods around weather changes are associated with pronounced patterns in mortality: a significant increase in mortality is found after large temperature increases and on days of large pressure drops; a decrease in mortality (partly due to a harvesting effect) occurs after large temperature drops, pressure increases, and passages of strong cold fronts. The relationship to variations in excess mortality is better expressed for sudden air temperature/pressure changes than for passages of atmospheric fronts. The mortality effects are usually more pronounced in the age group 70 years and above. The impacts associated with large negative changes of pressure are statistically independent of the effects of temperature; the corresponding dummy variable is found to be a significant predictor in the ARIMA model for relative deviations of mortality. This suggests that sudden weather changes should be tested also in time series models for predicting excess mortality as they may enhance their performance. PMID- 20169368 TI - Patients' views about causes and preferences for the management of cancer-related fatigue-a case for non-congruence with the physicians? AB - PURPOSE: Cancer-related fatigue (CRF) is frequently overlooked. Adherence to treatment guidelines may be related to the patient's views about illness. This study aimed at exploring patients' views about CRF and determining whether they are congruent with best practice treatments. METHODS: Data were collected in 160 consecutive patients hospitalized in a supportive care setting. Biological, clinical, and psychological variables were assessed using validated questionnaires. Patients were also asked to complete the Brief Fatigue Inventory (BFI) and a questionnaire investigating their main symptoms and views about CRF and its management. RESULTS: Patients were mainly men (60%); median age was 66 years. Various cancer diagnoses were represented; 17.5% had primary local diseases, 40% local recurrences, and 42.5% metastatic diseases. The majority of the patients experienced moderate or severe CRF (76.3%) on the BFI. Fatigue was the most frequently reported symptom (87.5%). Only anxiety, depression, and dimensions of quality of life were significantly related with CRF. Two thirds of the patients associated CRF with cancer-related morbidities. As for the best treatments, patients first stressed control of adverse effects. Over half of the patients were reluctant to report fatigue, mainly because they considered fatigue as an unavoidable side effect, but also because they feared a change towards less active/aggressive treatments. CONCLUSION: Patients mostly consider that CRF must be tolerated. Guidelines emphasize activity enhancement strategies as beneficial. The patients' preferences for rest rather than activity may be related to their high level of fatigue, which leads them to disregard activity as a possible treatment. PMID- 20169369 TI - From inside the bubble: migrants' perceptions of communication with the cancer team. AB - PURPOSE: Migrants with cancer struggle to communicate with their health care team. This study aimed to identify health-care related unmet needs and communication issues for migrants who develop cancer and factors associated with these challenges. In this paper, the findings related to communication issues are presented. PATIENTS AND METHODS: Seventy-three cancer patients diagnosed within the previous 3 years and 18 carers, who had migrated to Australia and spoke the designated languages, participated in focus groups or structured interviews. Participants were recruited from ethnic community support organisations, support groups and Oncology clinics within three metropolitan hospitals in two states of Australia. Focus groups and semi-structured interviews were conducted in participants' own language or English as preferred, audio-taped, transcribed and translated into English and analysed using qualitative methods. RESULTS: Four themes emerged: (1) cultural isolation, alienation and identification; (2) language and communication difficulties; (3) interpreter issues; and (4) advice for health professionals. Participants, especially those less acculturated, described feeling alone and misunderstood, failing to comprehend medical instructions, being unable to communicate questions and concerns and a lack of consistency in interpreters and interpretation. CONCLUSIONS: Migrants with cancer experience additional challenges to those of native-born patients. Participants provided cogent advice regarding optimal communication with people from their culture. There is clearly a need to develop strategies to increase the cultural competence of care to people from different countries. PMID- 20169370 TI - The combination of semi-sitting position and intraoperative MRI--first report on feasibility. AB - INTRODUCTION: Intraoperative MRI (iMRI) has been established as a routine imaging modality with a remarkable impact on specific neurosurgical procedures. The technological advancement continuously extends the spectrum of iMRI, leading to an increasing number of installations. Yet, procedures in which a semi-sitting position would be advantageous were beyond the reach of iMRI. MATERIALS AND METHODS: We performed an iMRI-guided surgical procedure in a patient with a cystic lesion of the inferior parieto-occipital lobe while the patient was placed in a semi-sitting position, employing a mobile 0.15-T intraoperative MRI system. For that purpose, we adapted a standard OR table according to the needs of iMRI. FINDINGS: Patient positioning could be accomplished easily. For intraoperative scanning, the OR table was tilted backwards so as to position the patient's head in the magnet's aperture. Obtained images were used for neuronavigated cyst evacuation via burr hole trephination after repositioning the OR table. Subsequent intraoperative imaging documented collapse of the cyst at the end of the procedure. There were no adverse effects resulting from the combination of semi-sitting position and iMRI guidance. CONCLUSION: This report demonstrates for the first time that the combination of iMRI and the semi-sitting position is feasible and that this procedure bears specific benefits. Issues such as brain shift due to table tilting warrant further investigations in order to expand this technique to posterior fossa craniotomies. PMID- 20169371 TI - Decision-making of vestibular schwannoma patients. AB - BACKGROUND: Patients suffering from vestibular schwannoma can choose between four modalities of management: (1) wait-and-scan, (2) tumour resection, (3) radiosurgery and (4) fractionated radiotherapy. METHOD: This study is based on postal questionnaire survey of 739 vestibular schwannoma patients (survey response rate, 78%). It not only investigates the decision-making of patients, especially the medical consultation, but also further influences on the therapy decision and the patients' evaluation of possible side-effects of the treatment. RESULTS: Only a minority of the patients was informed about radiosurgery and radiotherapy at all. CONCLUSION: The praxis of patient counselling of acoustic neuroma patients in Germany is far from the ideal condition of medical consultation: The most important shortcoming is that it is unilateral: About 69% of the patients are informed about only one treatment option, generally surgery. Furthermore, information about side effects is usually insufficient. We recommend to advice all patients on all treatment options by an interdisciplinary team. The counselling should firstly be based on evidence-based medicine and secondly respond to the patients' individual life situation and preferences. PMID- 20169372 TI - Phylogenetic analysis of bovine leukemia viruses isolated in South America reveals diversification in seven distinct genotypes. AB - Bovine leukaemia virus (BLV) is an oncogenic member of the genus Deltaretrovirus of the family Retroviridae. Recent studies revealed that BLV strains can be classified into six different genotypes and raised the possibility that another genotype may exist. In order to gain insight into the degree of genetic variability of BLV strains circulating in the South American region, a phylogenetic analysis was performed using gp51 env gene sequences. The results of these studies revealed the presence of seven BLV genotypes in this geographic region and the suitability of partial gp51 env gene sequences for phylogenetic inference. A significant number of amino acid substitutions found in BLV strains isolated in South America map to the second neutralization domain of gp51. A 3D molecular model of BLV gp51 revealed that these substitutions are located on the surface of the molecule. This may provide a selective advantage to overcome immune host neutralization. PMID- 20169373 TI - The interaction of zinc with membrane-associated 18.5 kDa myelin basic protein: an attenuated total reflectance-Fourier transform infrared spectroscopic study. AB - Myelin basic protein (MBP) is an essential structural protein required for tight compaction of the myelin sheath of the central nervous system, and belongs to the family of intrinsically disordered proteins. It contains a high proportion of polar and charged amino acids, and has an adaptive conformation depending on its environment and binding surfaces (membranes) or partners (other proteins or small ligands including divalent cations). Zinc is an important stabilizing component of myelin and its concentration is substantially higher than that of any other trace element in the brain. In this study, we investigate the effect of zinc on different variants of 18.5 kDa MBP, including new recombinant forms lacking hexahistidine tags which would interfere with the binding of the cation. Isothermal titration calorimetry showed the dissociation constant to be in the micromolar range for all variants. Circular dichroism spectroscopy showed that there was minimal effect of zinc on the secondary structure on MBP in aqueous solution. When MBP was reconstituted with myelin-mimetic membranes, attenuated total reflectance-Fourier transform infrared spectroscopy revealed that there was a rearrangement of secondary structure components upon addition of zinc that was subtly different for each variant, indicative of a synergistic protein-membrane cation interaction. PMID- 20169374 TI - Peptide-based molecular beacons for cancer imaging and therapy. AB - Peptide-based molecular beacons are Forster resonance energy transfer-based target-activatable probes. They offer control of fluorescence emission in response to specific cancer targets and thus are useful tools for in vivo cancer imaging. With our increasing knowledge about human genome in health and disease, peptide-based "smart" probes are continually developed for in vivo optical imaging of specific molecular targets, biological pathways and cancer progression and diagnosis. A class of fluorescent photosensitizers further extends the application of peptide beacons to cancer therapeutics. This review highlights the applications of peptide beacons in cancer imaging, the simultaneous treatment and response monitoring and smart therapeutics with a focus on recent improvements in the design of these probes. PMID- 20169375 TI - Metabolic correlations of glucocorticoids and polyamines in inflammation and apoptosis. AB - Glucocorticoid hormones (GC) are essential in all aspects of human health and disease. Their anti-inflammatory and immunosuppressive properties are reasons for therapeutic application in several diseases. GC suppress immune activation and uncontrolled overproduction and release of cytokines. GC inhibit the release of pro-inflammatory cytokines and stimulate the production of anti-inflammatory cytokines. Investigation of GC's mechanism of action, suggested that polyamines (PA) may act as mediators or messengers of their effects. Beside glucocorticoids, spermine (Spm) is one of endogenous inhibitors of cytokine production. There are many similarities in the metabolic actions of GC and PA. The major mechanism of GC effects involves the regulation of gene expression. PA are essential for maintaining higher order organization of chromatin in vivo. Spermidine and Spm stabilize chromatin and nuclear enzymes, due to their ability to form complexes with negatively charged groups on DNA, RNA and proteins. Also, there is an increasing body of evidence that GC and PA change the chromatin structure especially through acetylation and deacetylation of histones. GC display potent immunomodulatory activities, including the ability to induce T and B lymphocyte apoptosis, mediated via production of reactive oxygen species (ROS) in the mitochondrial pathway. The by-products of PA catabolic pathways (hydrogen peroxide, amino aldehydes, acrolein) produce ROS, well-known cytotoxic agents involved in programmed cell death (PCD) or apoptosis. This review is an attempt in the better understanding of relation between GC and PA, naturally occurring compounds of all eukaryotic cells, anti-inflammatory and apoptotic agents in physiological and pathological conditions connected to oxidative stress or PCD. PMID- 20169376 TI - Synthetic study on cystinyl peptides using solution and solid phase methodology: human IgG1 hinge region. AB - Synthetic study on cystinyl peptides using solution and solid phase methodology was carried out with the central hinge region of immunoglobulin IgG1. In the solid phase synthesis of hexadecapeptide 1c, the time necessary for the formation of disulfide bonds between linear precursors was shortened four times by the action of pure oxygen in buffered solution, in comparison with air oxidation. The product was thus obtained devoid of impurities from side reactions. In the preparation of the shortened bis-cystinyl analogs 2k and 3d of the natural hexadecapeptide 1c, both the classical and polyethylene glycol (PEG6000) solution methods were utilized using a disulfide synthon (Boc-Cys-OPfp)2 to obtain peptide chains in a natural parallel alignment. In the PEG6000 strategy, lysine as a linker on both sides of the polymer was attached to enhance the loading capacity. The leucine residue, instead of proline one, was introduced to the carboxy terminus to facilitate a specific enzymatic cleavage of the peptides from PEG6000 by thermolysine. PMID- 20169377 TI - An association study between the Val66Met polymorphism of the BDNF gene and postpartum depression. AB - Postpartum depression disorder (PPD) is a severe illness affecting around 15% of deliveries. Several evidences suggest that PPD is, at least, partially genetic determined. The gene encoding BDNF is a strong candidate for pathogenesis of PPD since that it has been observed decrease of serum BDNF in patients suffering from PPD. The gene encoding BDNF has a polymorphism (Val66Met) that alters the regulated protein secretion; the methionine variant being associated with insufficient secretion compared with the Valine variant. We hypothesized that BDNF gene Val66Met polymorphism could be associated with PPD. We assessed 227 subjects randomly selected who had delivery at a maternity hospital using EPDS. Differences in genotype frequency were calculated by chi (2) test. Logistic Regression Analyses was performed to verify the existence of interaction between biological, psychiatric and environmental variables and PPD. Difference between groups was tested with Student's t test. Tests were two-tailed and results significant when p < or = 0.05. No difference in BDNF genotype distribution was observed between the depressed and non-depressed women. Educational level, stress during pregnancy, bipolar disorder and anxiety was strongly associated with PPD. We were not able to show an association between BDNF polymorphisms and PPD. Further studies are necessary to both of confirm our results and improve validity of PPD diagnosis. PMID- 20169378 TI - The efficacy of classical massage on stress perception and cortisol following primary treatment of breast cancer. AB - To investigate the efficacy of classical massage on stress perception and mood disturbances, 34 women diagnosed with primary breast cancer were randomized into an intervention or control group. For a period of 5 weeks, the intervention group (n = 17) received biweekly 30-min classical massages. The control group (n = 17) received no additional treatment to their routine health care. The Perceived Stress Questionnaire (PSQ) and the Berlin Mood Questionnaire (BSF) were used and the patients' blood was collected at baseline (T1), at the end of the intervention period (T2), and 6 weeks after T2 (T3). Compared with control group, women in the intervention group reported significantly lower mood disturbances, especially for anger (p = 0.048), anxious depression (p = 0.03) at T2, and tiredness at T3 (p = 0.01). No group differences were found in PSQ scales, cortisol and serotonin concentrations at T2 and T3. However, perceived stress and cortisol serum levels (p = 0.03) were significantly reduced after massage therapy (T2) compared with baseline in the intervention group. Further research is needed to validate our findings. PMID- 20169379 TI - Cu(A) centers and their biosynthetic models in azurin. AB - Cu(A) is a binuclear copper center that functions as an electron transfer agent, cycling between a reduced Cu(I)Cu(I) state and an oxidized mixed-valence Cu(+1.5)...Cu(+1.5) state. The copper ions are bridged by two cysteine thiolate ligands and form a copper-copper bond, the first reported of its kind in Nature. Such a "diamond-core" Cu(2)S(Cys)(2) structure allows an unpaired electron to be completely delocalized over the two copper ions and contributes to its highly efficient electron transfer properties. This review provides accounts of how the Cu(A) center was structurally characterized and highlights its salient spectroscopic properties. In the process, it introduces the Cu(A) center in four different systems-native protein systems, soluble protein truncates of native proteins, synthetic models using organic molecules, and biosynthetic models using proteins as ligands-with a greater emphasis on biosynthetic models of Cu(A), especially on new, deeper insights gained from their studies. PMID- 20169380 TI - Dissemination of an evidence-based intervention to parents of children with behavioral problems in a developing country. AB - This project describes the dissemination of an evidence-based parenting skills intervention by training social and health workers with little or no mental health background so that they themselves train mothers of children with behavioral problems in impoverished communities in a developing country. The Strengths and Difficulties Questionnaire was completed by mothers to screen for children with behavioral problems and was repeated at the end of the intervention. Pre- and post-tests of knowledge and parenting attitudes were administered to mothers. Mental health workers trained social and health workers in social development centers and dispensaries. Each social and health worker trained mothers of children with behavioral problems under supervision utilizing an Arabic adaptation of the treatment manual for externalizing disorders "Helping Challenging Children" developed by the Integrated Services Taskforce of the World Psychiatric Association Child Mental Health Presidential Programme. A total of 20 workers and 87 mothers participated in the training. The proportion of children who obtained an SDQ total difficulties score in the abnormal range decreased from 54.4 to 19.7% after the training. Whereas 40.2% of mothers used severe corporal punishment with their children before the intervention, this decreased to 6.1% post-intervention. Three-fourths of mothers related that the program helped them develop new parenting skills. This pilot project demonstrated the feasibility of dissemination of a manual-based intervention and training of workers who have little background in mental health to offer effective services to families in impoverished communities who otherwise would have not received them. Successful replication in other developing countries would pave the way to incorporating such programs in national policies given their potential sustainability and cost effectiveness. PMID- 20169381 TI - Ab initio studies on the reactivity of the CF3OCH 2O radical: thermal decomposition vs. reaction with O2. AB - Hydrofluoroethers are being considered as potential candidates for third generation refrigerants. The present investigation involves the ab initio quantum mechanical study of the decomposition mechanism of CF(3)OCH(2)O radical formed from a hydrofluoroether, CF(3)OCH(3) (HFE-143a) in the atmosphere. The geometries of the reactant, products and transition states involved in the decomposition pathways are optimized and characterized at the DFT (B3LYP) level of theory using 6-311G(d,p) basis set. Energy calculations have been performed at the G2(MP2) and G2M(CC,MP2) level of theory. Two prominent decomposition channels, C-O bond scission and reaction with atmospheric O(2) have been considered for detailed investigation. Studies performed at the G2(MP2) level reveals that the decomposition channel involving C-O bond scission occurs with a barrier height of 23.8 kcal mol(-1) whereas the oxidative pathway occurring with O(2) proceeds with an energy barrier of 7.2 kcal mol(-1). On the other hand the corresponding values at G2M(CC,MP2) are 24.5 and 5.9 kcal mol(-1) respectively. Using canonical transition state theory (CTST) rate constants for the two pathways considered are calculated at 298 K and 1 atm pressure and found to be 5.9 x 10(-6) s(-1) and 2.3 x 10(-5) s(-1) respectively. The present study concludes that reaction with O(2) is the dominant path for the consumption of CF(3)OCH(2)O in the atmosphere. Transition states are searched and characterized on the potential energy surfaces involved in both of the reaction channels. The existence of transition state on the corresponding potential energy surface is ascertained by performing intrinsic reaction coordinate (IRC) calculation. PMID- 20169382 TI - Pharmacophore modeling and 3D-QSAR analysis of phosphoinositide 3-kinase p110alpha inhibitors. AB - Pharmacophore modeling studies were undertaken for a series of compounds belonging several groups of phosphoinositide 3-kinase (PI3K) p110alpha inhibitors: 4-morpholino-2-phenylquinazolines derivatives, pyrido[3',2':4,5]furo [3,2-d]pyrimidine derivatives, imidazo[1,2-a]pyridine derivatives, sulfonylhydrazone substituted imidazo[1,2-a]pyridines, and LY294002. A five-point pharmacophore with three hydrogen bond acceptors (A), one hydrophobic group (H), and one aromatic ring (R) as pharmacophore features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of R (2) = 0.95 for training set compounds. The model generated showed excellent predictive power, with a correlation coefficient of Q (2) = 0.88 and r (pret) (2) = 0.95 for a test set of 14 compounds. Furthermore, the structure-activity relationships of PI3K p110alpha inhibitors were elucidated and the activity differences between them discussed. Docking studies were also carried out wherein active and inactive compounds were docked into the active site of the PI3K p110alpha crystal structure to analyze PI3K p110alpha-inhibitor interactions. The results provide insights that will aid optimization of these classes of PI3K p110alpha inhibitors for better activity, and may prove helpful for further lead optimization and virtual screening. PMID- 20169383 TI - Sequence analysis, in silico modeling and docking studies of caffeoyl CoA-O methyltransferase of Populus trichopora. AB - Caffeoyl coenzyme A-O-methyltransferases (CCoAOMTs) which are characterized under class I plant OMTs, methylates CoA thioesters, with an in vitro kinetic preference for caffeoyl CoA. CCoAOMTs exhibit association with lignin biosynthesis by showing a prime role in the synthesis of guaiacyl lignin and providing the substrates for synthesis of syringyl lignin. The sequence analysis of CCoAOMT from Populus trichopora exhibits 58 nucleotide substitutions, where transitions overcome transversions. Validation of homology models of both CCoAOMT1 and 2 isoforms reveals that 92.4% and 96% residues are falling in the most favorable region respectively in the Ramachandran plot, indicating CCoAOMT2 as the more satisfactory model, and the overall quality factor of both isoforms is 98.174. The structural architecture analysis is showing very good packing of residues similar to protein crystal structures data. The active site residues and substrate-product interactions showed that CCoAOMT2 possesses more affinity toward caffeoyl CoA, feruloyl CoA, 5-hydroxy feruloyl CoA and sinapoyl CoA than CCoAOMT1, therefore it exist in a more active conformation. The affinity of CCoAOMT2 with feruloyl CoA is highest among all the affinities of both CCoAOMT isoforms with their substrates and products. This information has potential implications to understand the mechanism of CCoAOMT related enzymatic reactions in Populus trichopora, however the approach will be applicable in prediction of substrates and engineering 3D structures of other enzymes as well. PMID- 20169384 TI - Hemoglobin and hematocrit at the end of hemodialysis: a better way to adjust erythropoietin dose? AB - A severe disadvantage of administration of recombinant human erythropoietin to hemodialysis patients has been reported. A significant correlation has been shown with hemoglobin values determined online by use of the blood volume monitor (BVM) and by laboratory measurement. Online hemoglobin and hematocrit were measured by use of the BVM during hemodialysis session. Data were analyzed by t test and statistical significance was defined as a P of <0.05. Increases in the mean values of hemoglobin and hematocrit from 11.6 +/- 1.9 to 13.9 +/- 2.4 g/dL (17.4 +/- 7.1%, P = 0.02) and from 34.4 +/- 6.8 to 42 +/- 8.3% (20.6 +/- 8.8%, P = 0.022), respectively, were observed from the beginning to the end of dialysis. We hypothesize that a new strategy for adjusting erythropoietin dose may be based on hemoglobin and hematocrit values evaluated at the end of hemodialysis, when patients are no longer hypervolemic. Inadvertent high levels of hemoglobin could be one explanation why patients present higher rates of cardiovascular and access related events, especially when monitored online by use of the BVM to achieve the dry weight. PMID- 20169385 TI - Development of a device for chemiluminescence determination of superoxide generated inside a dialysis hollow-fiber membrane. AB - Reactive oxygen species (ROS) generated during hemodialysis treatment cause dialysis complications because of the high reactivity of ROS. To prevent dialysis complications caused by oxidative stress, it is important to evaluate the generation and dismutation of ROS during hemodialysis treatment. In this study, our aim was to develop a device to determine superoxide (O(2)(-)) generated inside a dialysis hollow fiber, and also to examine whether this device could detect O(2)(-) separated from plasma using hollow fibers. Experimental apparatus was set up so that hypoxanthine (HX) solution flowed inside the hollow fibers and 2-methyl-6-p-methoxyphenylethynyl-imidazopyrazinone (MPEC) solution flowed outside the hollow fibers. Then, xanthine oxidase (XOD) solution was added to the HX solution to generate O(2)(-), and chemiluminescence resulting from the reaction of O(2)(-) with MPEC was measured with an optical fiber. Chemiluminescence intensity was measured at different HX concentrations, and the peak area of relative luminescence intensity yielded a first-order correlation with the HX concentration. Based on the relationship between HX and O(2)(-) concentrations determined by the cytochrome c reduction method, the relative luminescence intensity measured by this device was linearly dependent on the O(2)(-) concentration inside the hollow fibers. After modifications were made to the device, XOD solution injection into plasma including HX resulted in an increase in the relative luminescence intensity. We concluded that this novel device based on chemiluminescence is capable of determining aqueous O(2)(-) generated inside a hollow fiber and also of detecting O(2)(-) in plasma. PMID- 20169387 TI - Cryptococcus neoformans as a cause of bronchiolitis obliterans organizing pneumonia. AB - The most frequent manifestations of Cryptococcus neoformans (CN) disease are systemic infections in immunocompromised patients and localized pulmonary disease in immunocompetent individuals. Such pulmonary cryptococcosis can range from asymptomatic infection to frank pneumonia that can be severe. Bronchiolitis obliterans organizing pneumonia (BOOP) is a rare severe form of pneumonitis caused by a variety of infectious and toxic agents or connective tissue diseases. BOOP due to Cryptococcus neoformans has very rarely been reported; there have been only five such case reports, mostly in immunocompromised patients. We report herein on a case of CN-associated BOOP in an immunocompetent individual and discuss the diagnosis and treatment of this entity. PMID- 20169386 TI - Aspartic cathepsin D endopeptidase contributes to extracellular digestion in clawed lobsters Homarus americanus and Homarus gammarus. AB - Acid digestive proteinases were studied in the gastric fluids of two species of clawed lobster (Homarus americanus and Homarus gammarus). An active protein was identified in both species as aspartic proteinase by specific inhibition with pepstatin A. It was confirmed as cathepsin D by mass mapping, N-terminal, and full-length cDNA sequencing. Both lobster species transcribed two cathepsin D mRNAs: cathepsin D1 and cathepsin D2. Cathepsin D1 mRNA was detected only in the midgut gland, suggesting its function as a digestive enzyme. Cathepsin D2 mRNA was found in the midgut gland, gonads, and muscle. The deduced amino acid sequence of cathepsin D1 and cathepsin D2 possesses two catalytic DTG active-site motifs, the hallmark of aspartic proteinases. The putatively active cathepsin D1 has a molecular mass of 36.4 kDa and a calculated pI of 4.14 and possesses three potential glycosylation sites. The sequences showed highest similarities with cathepsin D from insects but also with another crustacean cathepsin D. Cathepsin D1 transcripts were quantified during a starvation period using real-time qPCR. In H. americanus, 15 days of starvation did not cause significant changes, but subsequent feeding caused a 2.5-fold increase. In H. gammarus, starvation caused a 40% reduction in cathepsin D1 mRNA, and no effect was observed with subsequent feeding. PMID- 20169388 TI - Radiographic progression of cervical lesions in patients with rheumatoid arthritis receiving infliximab treatment. AB - We evaluated radiographic change in the cervical lesions of 47 RA patients receiving continuous infliximab therapy for at least 1 year. Infliximab treatment had been initiated between November 2003 and December 2007. Patients who were progressive and non-progressive in terms of RA cervical lesions were compared. Matrix metalloproteinase 3 (MMP3) values improved significantly only in non progressive patients within the 1-year treatment window. Cervical lesion progression was suppressed in 19 of the 23 patients (83%) showing a good response to infliximab treatment and occurred in 16 of the 24 patients (67%) showing a moderate response. This difference was shown to be significant by the Fisher's exact test (p = 0.002). In the well-responding patients (n = 23) and moderately responding patients (n = 24), the respective changes in the cervical lesion parameters within 1 year were: atlanto-dental interval, 0.17 +/- 0.49 and 0.54 +/ 0.58 mm (p = 0.013); spinal cord, -0.17 +/- 0.49 and -0.54 +/- 0.59 mm (p = 0.025); Ranawat value, -0.09 +/- 0.29 and -0.42 +/- 0.65 mm (p = 0.032). Based on these results, we conclude that infliximab treatment can be used to suppress the progression of rheumatoid arthritis (RA) cervical lesions. It is possible that response to infliximab and MMP3 values can be used to predict the progression of these cervical lesions. PMID- 20169389 TI - A meta-analysis of the association of STAT4 polymorphism with systemic lupus erythematosus. AB - STAT4 has been newly identified as a susceptibility gene for systemic lupus erythematosus (SLE) in recent reports. To more precisely estimate the association between STAT4 polymorphism and SLE risk, a meta-analysis was performed. Studies on the association of STAT4 rs7574865 or rs7601754 with SLE were fully considered and carefully selected using three electronic databases (PubMed, Embase, and Web of Science). A total of 17 comparisons from 8 relevant studies involving 7,381 patients and 11,431 controls were included to analyze the association between STAT4 rs7574865 and SLE risk. The pooled OR for the minor T allele of STAT4 rs7574865 was 1.65 (95% CI 1.56-1.75, P < 0.001) in SLE. In a subgroup analysis by ethnicity, the degree of risk of STAT4 rs7574865 with SLE susceptibility was similar in populations of European or Asian origin, although significant differences in the minor T allele frequencies were observed in the two population controls. As for rs7601754, there were five comparisons from four relevant studies involving 2,498 patients and 4,825 controls in this meta-analysis. The pooled OR for the minor C allele of STAT4 rs7601754 was 0.67 (95% CI 0.59-0.75, P < 0.001) in SLE. Conversely, the major T allele of STAT4 rs7601754 might be a risk factor for SLE risk. In conclusion, our results do support STAT4 rs7574865 polymorphism as a susceptibility factor for SLE in populations of European and Asian origin. Our results also suggest that STAT4 rs7601754 polymorphism might be associated with SLE risk. PMID- 20169390 TI - Therapeutic angiogenesis in patients with systemic sclerosis by autologous transplantation of bone-marrow-derived cells. AB - We examined the efficacy and safety of autologous transplantation of bone-marrow derived cells in patients with intractable ulcers caused by systemic sclerosis. Eight patients with ulcers resistant to treatment were enrolled. Bone marrow cells were gathered from the bilateral iliac crests with multiple repositioning bone marrow needles, and bone-marrow-derived mononuclear cells were isolated and injected into skeletal muscles of the ischemic limb. Visual analog scale (VAS), Sclerosis Health Assessment Questionnaire (SHAQ), modified Rodnan total skin score (mTSS), and the size and depth of the ulcer were examined. Thermography, capillaroscopy, intra-arterial digital subtraction angiography (IA-DSA), and laser Doppler flowmetry were also examined before and after transplantation. In all patients, reduction of ulcer size and improvement of VAS were observed after treatment. Elevation of surface temperature, increase of blood flow volume, and new capillaries of the nail bed were also found after our treatment. There were no major adverse effects of this treatment. Autologous transplantation of bone marrow-derived cells was shown to be a novel and useful approach to intractable ulcers in systemic sclerosis. PMID- 20169391 TI - Variable intrafamilial expressivity of the rare tumor necrosis factor-receptor associated periodic syndrome-associated mutation I170N that affects the TNFR1A cleavage site. AB - We report on a 33-year-old female patient with a relatively mild clinical case of TNF-receptor associated periodic syndrome (TRAPS) and her 58-year-old father in whom end-stage renal disease due to TRAPS-related AA-amyloidosis has already developed. TRAPS was caused by a I170N mutation that has previously not been associated with amyloidosis. It remains unclear if an only mildly affected patient such as ours would benefit from treatment considering her father's severe course of disease. The relevant literature on this problem is reviewed. PMID- 20169392 TI - Key factors in determining surgical timing of total knee arthroplasty in osteoarthritic patients: age, radiographic severity, and symptomatic severity. AB - BACKGROUND: Patient age, radiographic severity of osteoarthritis (OA), and severity of symptoms are typically considered as the three key factors in selecting the osteoarthritic patients for total knee arthroplasty (TKA). The purpose of this study was to evaluate the associations between the three selection criteria and the postoperative outcomes including patient satisfaction. We also attempted to determine whether the patients not fully satisfying the criteria are different from the typical candidates in postoperative outcomes. MATERIALS AND METHODS: Three hundred and eighty-three uncomplicated TKAs with 1 year follow-up data were included in this study. We evaluated three preoperative factors including age, radiographic severity of OA, and WOMAC pain and function scores as proxies of preoperative level of symptoms. Evaluation of the postoperative outcomes included WOMAC pain and function scores and the level of patient satisfaction. Regression analyses were used to investigate the associations between the preoperative factors and the postoperative outcomes. Comparative analyses of the postoperative outcomes were made between the typical candidates with all selection criteria and the groups of patients who did not meet one of the selection criteria. RESULTS: Increasing age was associated with worse postoperative functional outcomes. Worse preoperative WOMAC pain and function scores were associated with worse postoperative WOMAC pain and function scores, and had a statistical tendency toward higher patient dissatisfaction. Compared to the typical candidates, the groups of patients who did not meet one of the selection criteria did not have worse postoperative outcomes. On the contrary, the group of younger age and the group with less severe preoperative symptoms were more likely to have better postoperative outcomes. The radiographic severity of OA had no significant associations with any of postoperative outcomes. CONCLUSION: This study indicates that, when considering TKA as a treatment option, orthopedic surgeons need to comprehend the selection criteria in an overall view to offer the best timing for optimal postoperative outcomes. PMID- 20169393 TI - The effect of zoledronate during bone healing. AB - BACKGROUND: Bisphosphonates have become the treatment of choice for a variety of bone diseases in which excessive osteoclastic activity is an important pathologic feature. However, inhibition of osteoclastic activity could lead to inhibition of remodeling during bone healing or repair. The objective of this study is to investigate the effect of zoledronate (the most potent bisphosphonate) in the biological process of bone healing. METHODS: Thirty immature male rabbits were divided into two groups (control and experimental) of 15 animals each. Both groups were submitted to fibular osteotomy. Only in the experimental group a single dose of zoledronate was administered. After 1, 2, and 4 weeks, animals of both groups were euthanized and the osteotomy site was histomorphometrically evaluated. The associated parameters analyzed were tissue volume (TV), fractional trabecular bone volume (BV/TV), fractional woven bone volume (WoV/TV), fractional periosteal fibrous volume (FbV/TV), and medullary fibrous volume (MaV/TV). RESULTS: The first week of healing was characterized by small callus area (experimental group) and less periosteal fibrosis. The second week was characterized by a large quantity of woven bone and marked decrease in periosteal fibrosis in the two groups. In the control group there was also a significant increase in trabecular bone. The fourth week was characterized by increased amount of woven bone and trabecular bone in the experimental group; there was increased medullary fibrosis in the two groups, while there continued to be significantly less periosteal fibrosis in the experimental group. CONCLUSIONS: Zoledronate does not prevent bone healing. However, the effect of zoledronate was characterized by accentuated stimulation of primary bone production and probably inhibition of remodeling, leading to retention of trabecular bone. PMID- 20169395 TI - Applying controlled non-uniform deformation for in vitro studies of cell mechanobiology. AB - Cells within connective tissues routinely experience a wide range of non-uniform mechanical loads that regulate many cell behaviors. In this study, we developed an experimental system to produce complex strain patterns for the study of strain magnitude, anisotropy, and gradient effects on cells in culture. A standard equibiaxial cell stretching system was modified by affixing glass coverslips (5, 10, or 15 mm diameter) to the center of 35 mm diameter flexible-bottomed culture wells. Ring inserts were utilized to limit applied strain to different levels in each individual well at a given vacuum pressure thus enabling parallel experiments at different strain levels. Deformation fields were measured using high-density mapping for up to 6% applied strain. The addition of the rigid inclusion creates strong circumferential and radial strain gradients, with a continuous range of stretch anisotropy ranging from strip biaxial to equibiaxial strain and radial strains up to 24% near the inclusion. Dermal fibroblasts seeded within our 2D system (5 mm inclusions; 2% applied strain for 2 days at 0.2 Hz) demonstrated the characteristic orientation perpendicular to the direction of principal strain. Dermal fibroblasts seeded within fibrin gels (5 mm inclusions; 6% applied strain for 8 days at 0.2 Hz) oriented themselves similarly and compacted their surrounding matrix to an increasing extent with local strain magnitude. This study verifies how inhomogeneous strain fields can be produced in a tunable and simply constructed system and demonstrates the potential utility for studying gradients with a continuous spectrum of strain magnitudes and anisotropies. PMID- 20169394 TI - Biomimetic bone mechanotransduction modeling in neonatal rat femur organ cultures: structural verification of proof of concept. AB - The goal of this work was to develop and validate a whole bone organ culture model to be utilized in biomimetic mechanotransduction research. Femurs harvested from 2-day-old neonatal rat pups were maintained in culture for 1 week post harvest and assessed for growth and viability. For stimulation studies, femurs were physiologically stimulated for 350 cycles 24 h post-harvest then maintained in culture for 1 week at which time structural tests were conducted. Comparing 1 and 8 days in culture, bones grew significantly in size over the 7-day culture period. In addition, histology supported adequate diffusion and organ viability at 2 weeks in culture. For stimulation studies, 350 cycles of physiologic loading 24 h post-harvest resulted in increased bone strength over the 7-day culture period. In this work, structural proof of concept was established for the use of whole bone organ cultures as mechanotransduction models. Specifically, this work established that these cultures grow and remain viable in culture, are adequately nourished via diffusion and are capable of responding to a brief bout of mechanical stimulation with an increase in strength. PMID- 20169396 TI - Monitoring tobacco use and implementation of prevention policies is vital for strengthening tobacco control: an Indian perspective. PMID- 20169398 TI - Peloruside A inhibits microtubule dynamics in a breast cancer cell line MCF7. AB - Peloruside A (PelA), a novel microtubule-stabilizing agent and potential anti cancer drug, isolated from the marine sponge Mycale hentscheli, binds to a distinct, non-taxoid binding site on tubulin. Using live-cell confocal microscopy, the effects of PelA on microtubule dynamics were quantified in a human breast adenocarcinoma cell line (MCF7) stably expressing GFP-alpha-tubulin. Changes in microtubule length were tracked over time in cells treated with PelA concentrations ranging from 3.8-100 nM. As with other microtubule-targeting drugs like paclitaxel and epothilone B, microtubule dynamics were suppressed in a concentration-dependent manner. At the PelA IC50 concentrations for cell proliferation (3.8 nM) and G2/M block (25 nM), PelA inhibited dynamicity by 23% and 45%, respectively. At 25 nM PelA, effects included a 24% and 41% reduction in average growth rate and growth length, respectively. Additionally, the total time spent in pause increased by 53% and coincided with a 36% reduction in the average amount of time spent growing. Rescue and catastrophe frequencies were not significantly affected by PelA, except for length-based catastrophe (67% increase). The results provide further insight into PelA's unique mode of stabilization and contribute to our understanding of how microtubule-targeting agents exert their anti-mitotic effects. PMID- 20169397 TI - Non-caspase proteases: triggers or amplifiers of apoptosis? AB - Caspases are the most important effectors of apoptosis, the major form of programmed cell death (PCD) in multicellular organisms. This is best reflected by the appearance of serious development defects in mice deficient for caspase-8, 9, and -3. Meanwhile, caspase-independent PCD, mediated by other proteases or signaling components has been described in numerous publications. Although we do not doubt that such cell death exists, we propose that it has evolved later during evolution and is most likely not designed to execute, but to amplify and speed-up caspase-dependent cell death. This review shall provide evidence for such a concept. PMID- 20169399 TI - A natural compound, methyl angolensate, induces mitochondrial pathway of apoptosis in Daudi cells. AB - Natural products discovered from medicinal plants have played an important role in the treatment of cancer. In an effort to identify novel small molecules which can affect the proliferation of lymphoma cells, we tested methyl angolensate (MA), a plant derived tetranortriterpenoid, purified from the crude extract of the root callus of Soymida febrifuga commonly known as Indian red wood tree. We have tested MA for its cytotoxic properties on Burkitt's lymphoma cell lines, using various cellular assays. We observed that MA induces cytotoxicity in Daudi cells in a dose-dependent manner using trypan blue, MTT and LDH assays. We find that the treatment with MA led to activation of DNA double-strand break repair proteins including KU70 and KU80, suggesting the activation of nonhomologous DNA end joining pathway in surviving cells. Further, we find that methyl angolensate could induce apoptosis by cell cycle analysis, annexin V-FITC staining, DNA fragmentation and PARP cleavage. Besides, MA treatment led to reactive oxygen species generation and loss of mitochondrial transmembrane potential. These results suggest the activation of mitochondrial pathway of apoptosis. Hence, we identify MA as a potential chemotherapeutic agent against Daudi cells. PMID- 20169400 TI - Cribrostatin 6 induces death in cancer cells through a reactive oxygen species (ROS)-mediated mechanism. AB - Cribrostatin 6 is a quinone-containing natural product that induces the death of cancer cell lines in culture, and its mechanism of action and scope of activity are unknown. Here we show that cribrostatin 6 has broad anticancer activity, potently inducing apoptotic cell death that is not preceded by any defined cell cycle arrest. Consistent with this data, we find that cribrostatin 6 treated cells have large amounts of reactive oxygen species (ROS) and, based on transcript profiling experiments and other data, this ROS generation is likely the primary mechanism by which cribrostatin 6 induces apoptosis. Given the success of certain ROS producers as anticancer agents, cribrostatin 6 has potential as a novel chemotherapeutic agent. PMID- 20169401 TI - Negative regulation of the RTBV promoter by designed zinc finger proteins. AB - The symptoms of rice tungro disease are caused by infection by a DNA-containing virus, rice tungro bacilliform virus (RTBV). To reduce expression of the RTBV promoter, and to ultimately reduce virus replication, we tested three synthetic zinc finger protein transcription factors (ZF-TFs), each comprised of six finger domains, designed to bind to sequences between -58 and +50 of the promoter. Two of these ZF-TFs reduced expression from the promoter in transient assays and in transgenic Arabidopsis thaliana plants. One of the ZF-TFs had significant effects on plant regeneration, apparently as a consequence of binding to multiple sites in the A. thaliana genome. Expression from the RTBV promoter was reduced by approximately 45% in transient assays and was reduced by up to 80% in transgenic plants. Co-expression of two different ZF-TFs did not further reduce expression of the promoter. These experiments suggest that ZF-TFs may be used to reduce replication of RTBV and thereby offer a potential method for control of an important crop disease. PMID- 20169402 TI - Children's perceived social support after a parent is diagnosed with cancer. AB - This study examined perceived social support among children of parents diagnosed with cancer. Twenty-nine participants, ages 18-38, who had been children when one of their parents was diagnosed with cancer provided demographic information and participated in an interview about the impact of their parent's illness on their lives. Five common themes characterized participants' perceived social support received during their parent's illness: (a) listening and understanding; (b) encouragement and reassurance; (c) tangible assistance; (d) communication about cancer and treatment; and (e) engaging in normal life experiences. Depending on the circumstances, however, a given type of social support was perceived to be helpful to some, while perceived by others as ineffective or detrimental. Differences in respondents' perceptions of the effects of specific forms of received social support speak to the need for individualized support for children of cancer patients based upon each child's specific needs and circumstances. PMID- 20169403 TI - Overexpression of cold shock protein A of Psychromonas arctica KOPRI 22215 confers cold-resistance. AB - A polar bacterium was isolated from Arctic sea sediments and identified as Psychromonas artica, based on 16S rDNA sequence. Psychromonas artica KOPRI 22215 has an optimal growth temperature of 10 degrees C and a maximum growth temperature of 25 degrees C, suggesting this bacterium is a psychrophile. Cold shock proteins (Csps) are induced upon temperature downshift by more than 10 degrees C. Functional studies have researched mostly Csps of a mesophilic bacterium Escherichia coli, but not on those of psychrophilic bacteria. In an effort to understand the molecular mechanisms of psychrophilic bacteria that allow it withstand freezing environments, we cloned a gene encoding a cold shock protein from P. artica KOPRI 22215 (CspA(Pa)) using the conserved sequences in csp genes. The 204 bp-long ORF encoded a protein of 68 amino acids, sharing 56% homology to previously reported E. coli CspA protein. When CspA(Pa) was overexpressed in E. coli, it caused cell growth-retardation and morphological elongation. Interestingly, overexpression of CspA(Pa) drastically increased the host's cold-resistance by more than ten times, suggesting the protein aids survival in polar environments. PMID- 20169404 TI - The epidemiology of acute poisonings in women of reproductive age and during pregnancy, California, 2000-2004. AB - The aims of this study were to describe and compare the epidemiology of acute poisoning hospital discharges in women of reproductive age and during pregnancy (aged between 15 and 44) to include the incidence rate, risk factors, substances involved, rates of intentional versus unintentional poisonings, and in pregnant women, distribution over trimesters. Through a cohort study design, the California patient discharge dataset and linked vital statistics-patient discharge database were used to identify cases of acute poisoning hospital discharges from 2000 to 2004 among women of reproductive age and among pregnant women. Odds ratios (OR) were calculated to identify risk factors using logistic regression. Of 4,436,019 hospital discharges in women of reproductive age, 1% were for an acute poisoning (115.3/100,000 person-years). There were 2,285,540 deliveries and 833 hospital discharges for an acute poisoning during pregnancy (48.6/100,000 person-years). Pregnancy was associated with a lower risk of acute poisoning (OR = 0.89, P = 0.0007). Poisonings were greatest among young black women regardless of pregnancy status and among those with substance abuse or mental health problems. Analgesic and psychiatric medications were most commonly implicated. The majority of poisonings among women of reproductive age (69.6%) and among pregnant women (61.6%) were self-inflicted. Efforts to reduce acute poisonings among women of reproductive age should include education regarding the use of over-the-counter medications and interventions to reduce self-inflicted harm. PMID- 20169405 TI - Non-cancer mortality among long-term survivors of adult cancer in Korea: national cancer registry study. AB - OBJECTIVES: To investigate the pattern of non-cancer deaths and to determine whether there is excess mortality from non-cancer causes among Korean long-term survivors of adult cancer. METHODS: We merged national cancer registry data and national death registration data to determine non-cancer death patterns of 243,713 people who were diagnosed with cancer from 1993 to 2000 and who survived > or =5 years. We calculated standardized mortality ratios (SMRs) by an indirect standardization method. RESULTS: Of the patient population, 26,498 (10.9%) had died as of December 2005; the cause of death for 6,364 (24.0%) of those was not cancer. The proportion of non-cancer mortality increased with age at diagnosis and correlated with the 5-year survival rate (r = 0.336 for women, 0.571 for men). Although the risk for non-cancer death was lower among long-term survivors in general (SMR, 0.78; 95% CI, 0.76-0.80), it was higher among younger survivors (SMR, 1.23-2.50, for those who died before 50) than the general population. Survivors had an elevated suicide rate (SMR, 1.28; 95% CI, 1.15-1.42), especially male (SMR, 1.35; 95% CI, 1.19-1.53) and stomach cancer survivors (SMR, 1.38; 95% CI, 1.14-1.66). CONCLUSIONS: Appropriate medical attention for long-term adult cancer survivors, especially younger survivors, is warranted to prevent premature deaths from non-cancer causes. PMID- 20169406 TI - Suitability of village pond waters for irrigation-a case study from district Ludhiana, India. AB - The village ponds were used for storing rainwater for animals and recharging of underground water. Recent developments like public water supply for household purpose, provision of household wastewater concrete channels, and toilet septic tanks have polluted the village ponds. The infiltration of water has decreased due to non-cleaning of silt from the pond beds. Increased discharge of wastewater from households, coupled with a low infiltration rate, has inundated these ponds. People have abandoned the use of this water for animals. An effort has been made to assess the suitability of this water for irrigation in the vicinity so as to clean these ponds. Seventy-eight water samples were collected from the village ponds in the Ludhiana district of Punjab. The samples were analyzed for total solids (TS), total dissolved solids (TDS), total suspended solids (TSS), biological oxygen demand (BOD), chemical oxygen demand (COD), electrical conductivity (EC), residual sodium carbonate (RSC), nitrogen, water soluble P and K, as well as micronutrients and pollutant elements. The total solids content of these waters were on the higher side. Considering TSS, BOD, and COD, some of these waters are unsafe for their disposal in river or water bodies. Electrical conductivity ranged from 693 to 5050 MUmhos/cm, and RSC varied between -1.9 and 22.8 meq/l. The inorganic N (NH+4+ NO-3-N) and total Kjeldahl N ranged from 3 to 30 and 8 to 41 mg/l, respectively. The amount of micronutrients (Zn, Cu, Fe, and Mn) present in pond water indicated its high nutrient value. The content of the pollutant elements such as nickel, cadmium, and lead was below the maximum permissible limits, thereby indicating its suitability for irrigation. According to the EC and RSC criteria, 18% of the samples were fit, 31% were marginal, and 51% were unfit for irrigation. The data indicate that these waters are a good source of nutrients for agriculture. PMID- 20169407 TI - Assessment of acetylcholinesterase activity in Clarias gariepinus as a biomarker of organophosphate and carbamate exposure. AB - The objective of this study was to investigate the response of acetylcholinesterase (AChE) activities in Clarias gariepinus in response to Organophosphates (Ops) and carbamate exposure. The AChE activities were determined in plasma, and eye and brain homogenates of unexposed and exposed fish using Ellman's method and 5,5'-dithiobis-2-nitrobenzoic acid (DTNB) chromophore. The baseline AChE activities in plasma, eyes and brain tissues in unexposed fish were comparable between males and females (P > 0.05). Concentrations of pesticides that inhibited 50% (IC(50)) of AChE activities in brain homogenates following in vitro exposures were 0.003, 0.03, 0.15, 190, 0.2, 0.003 and 0.002 microM for carbaryl, chlorfenvinphos, diazinon, dimethoate, fenitrothion, pirimiphosmethyl and profenofos, respectively. The in vivo dose-effect relationships were assessed using chlorfenvinphos and carbaryl at different concentrations that ranged from 0.0003 to 0.06 microM and 0.0005 to 0.05 microM, respectively. Acetylcholinesterase activities were comparable in plasma, and eye and brain homogenates from control and carbaryl-exposed fish. Following exposure of fish to chlorfenvinphos at concentrations above 0.03 microM, a significant inhibition of AChE activities in plasma (84%) and eye homogenate (50%) was observed. The AChE activities in brain homogenate were comparable between chlorfenvinphos-exposed fish and controls. Because carbaryl cause reversible inhibition of AChE activities was found to be more potent than chlorfenvinphos that cause irreversible inhibition following in vitro exposure. Contrary, carbaryl was less potent than chlorfenvinphos after in vivo exposure possibly due to more rapid biotransformation of carbaryl than chlorfenvinphos. Findings from this study have demonstrated that inhibition of AChE activity in C. gariepinus is a useful biomarker in assessing aquatic environment contaminated by anticholinesterases. PMID- 20169408 TI - New-onset diabetes after transplantation in tacrolimus-treated, living kidney transplantation: long-term impact and utility of the pre-transplant OGTT. AB - BACKGROUND: To evaluate the role of the oral glucose tolerance test (OGTT) before transplantation and to examine the risk factors for new-onset diabetes after transplantation (NODAT) during long-term follow-up of renal transplant recipients receiving FK-based therapy. METHODS: The study evaluated 378 patients pre transplantation using the OGTT and assigned them to one of three groups: Group 1, normal pattern; Group 2, impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) pattern (IFG/IGT); and Group 3, DM pattern. RESULTS: Although the incidence of NODAT was higher in Group 3 than in groups 1 and 2, no significant difference was found between the three groups with regard to graft survival during long-term follow-up. Multivariate analysis showed that only a family history of diabetes was a significant factor determining NODAT progression. CONCLUSIONS: Impaired glucose tolerance appears to be a threshold influencing NODAT; however, it was not a significant factor in graft survival. Careful monitoring and management based on the result of the pre-transplantation OGTT appear to prevent the deterioration of impaired glucose tolerance in renal transplant recipients receiving FK-based therapy, even when a pre-operative OGTT shows impaired glycemic control. PMID- 20169409 TI - Comparative analysis of upper ureteral stones (> 15 mm) treated with retroperitoneoscopic ureterolithotomy and ureteroscopic pneumatic lithotripsy. AB - OBJECTIVE: To investigate an appropriate treatment for patients with upper ureteral stones, > 15 mm in size, by comparing the therapeutic outcomes for those undergoing retroperitoneoscopic ureterolithotomy (RPUL) and rigid ureteroscopic pneumatic lithotripsy (URSPL) retrospectively. PATIENTS AND METHODS: During the study period, 81 patients with a large upper ureteral stone (> 15 mm) were divided into two groups. RPUL was performed with retroperitoneal approach, and the stone was removed in group A. URSPL was conducted using a rigid ureteroscope, and pneumatic probe was used for lithotripsy in group B. The patient characteristics, success rate, stone-free rate, operation time, and complications were analyzed prospectively in the two groups. RESULTS: The success rates of operation were 94.5% (34/36) in group A and 88.8% (40/45) in group B, but there were no significant differences between two groups (P > 0.05). After 4 weeks of follow-up, the stone-free rate after RPUL (100%, 34/34) and URSPL (77.5%, 31/40) groups were statistically different (P = 0.006). Furthermore, simultaneous ureterolithotomy and ureteroplasty by retroperitoneal laparoscopic surgery were performed on four patients combined with ureteral stricture. However, the mean operation time and hospital staying time after surgery in group A were longer than that in group B, and the differences were statistically significant (P < 0.05). The complication rate after RPUL (17.6%, 6/34) was lower than that after URSPL (20%, 8/40), but the differences were not statistically significant (P > 0.05). CONCLUSION: RPUL is a safe and effective treatment technique for large, impacted, upper ureteral stones >15 mm in size when first-line treatments have failed or are unlikely to be effective. It can handle with combined pathologies simultaneously. PMID- 20169410 TI - Preventing college women's sexual victimization through parent based intervention: a randomized controlled trial. AB - A randomized controlled trial, using parent-based intervention (PBI) was designed to reduce the incidence of alcohol-involved sexual victimization among first-year college students. The PBI, adapted from Turrisi et al. (2001), was designed to increase alcohol-specific and general communication between mother and daughter. Female graduating high school seniors and their mothers were recruited from the community and randomly assigned to one of four conditions: Alcohol PBI (n = 305), Enhanced Alcohol + Sex PBI (n = 218), Control (n = 288) or Unmeasured Control (n = 167). Mothers in the intervention conditions were provided an informational handbook and encouraged to discuss its contents with their daughters prior to college matriculation. Consistent with hypotheses, PBI, either standard or enhanced, was associated with lower incidence of incapacitated rape in the first year of college relative to controls. Path analysis revealed support for a hypothesized indirect effects model, by which intervention increased mother daughter communication, which predicted lower frequency of first semester heavy episodic drinking, resulting in lower rates of alcohol-involved sexual victimization in the first year of college. PMID- 20169411 TI - Changing ecophysiological processes and carbon budget in East Asian ecosystems under near-future changes in climate: implications for long-term monitoring from a process-based model. AB - Using a process-based model, I assessed how ecophysiological processes would respond to near-future global changes predicted by coupled atmosphere-ocean climate models. An ecosystem model, Vegetation Integrative SImulator for Trace gases (VISIT), was applied to four sites in East Asia (different types of forest in Takayama, Tomakomai, and Fujiyoshida, Japan, and an Alpine grassland in Qinghai, China) where observational flux data are available for model calibration. The climate models predicted +1-3 degrees C warming and slight change in annual precipitation by 2050 as a result of an increase in atmospheric CO2. Gross primary production (GPP) was estimated to increase substantially at each site because of improved efficiency in the use of water and radiation. Although increased respiration partly offset the GPP increase, the simulation showed that these ecosystems would act as net carbon sinks independent of disturbance-induced uptake for recovery. However, the carbon budget response relied strongly on nitrogen availability, such that photosynthetic down regulation resulting from leaf nitrogen dilution largely decreased GPP. In relation to long-term monitoring, these results indicate that the impacts of global warming may be more evident in gross fluxes (e.g., photosynthesis and respiration) than in the net CO2 budget, because changes in these fluxes offset each other. PMID- 20169412 TI - What is life? Defining life in the context of emergent complexity. AB - Erwin Schrodinger defined life not only as a "self-reproducing" aperiodic crystal of DNA coding for proteins but within the context of living entities increasing their order by dissipating matter/energy gradients to maintain themselves away from equilibirium. Since then most definitions of life have focused on the former. But living cells do more than replicate their DNA. Cells also have membrane barriers across which metabolites must move, via which energy transduction as well as information processing occurs, and within which metabolic transformation occurs. An approach of complex systems dynamics, including nonequilibrium thermodynamics, may provide a more robust approach for defining life than a "naked replicator" at the origin of life. The crucial issue becomes the process of emergence of life from pre-biotic chemistry, concomitant with the emergence of function, information, and semiosis. Living entities can be viewed as bounded, informed autocatalytic cycles feeding off matter/energy gradients, exhibiting agency, capable of growth, reproduction, and evolution. Understanding how life might have emerged should sharpen our definition of what life is. PMID- 20169413 TI - Micropatterned assembly of silica nanoparticles for a protein microarray with enhanced detection sensitivity. AB - We used an assembly of silica nanoparticles (SNPs) as a three-dimensional template for protein immobilization to prepare a protein microarray with enhanced protein loading capacity and detection sensitivity. SNPs were first modified with 3-aminopropyltriethoxysilane (APTES) for covalent immobilization of protein and micropatterned on poly(ethylene glycol)(PEG)-coated glass slides using elastomeric membranes with an array of holes. Proteins were selectively immobilized only on the SNP region, while the PEG regions served as an effective barrier to protein adsorption. Because of multi-layered SNPs that had curved surface, protein loading in the SNP micropattern was about six times greater than on a planar surface, as observed by fluorescence microscopy, which consequently improved the protein activity and reaction rate. GOX-catalyzed glucose oxidation and the molecular recognition mediated, specific binding between biotin and streptavidin were both successfully assayed using SNP microarrays, with better fluorescence signal and sensitivity than corresponding planar microarrays. PMID- 20169415 TI - Detection and quantitative analysis of organochlorine compounds (PCBs and DDTs) in deep sea fish liver from Mediterranean Sea. AB - BACKGROUND, AIM AND SCOPE: Polychlorinated biphenyls (PCB) and dichlorodiphenyltrichloroethane (DDT) concentrations were determined in the liver of two deep sea fish species, Mediterranean slimehead and blackfin sorcerer, from the Adriatic Sea (southeastern Mediterranean Sea). RESULTS AND DISCUSSION: The examination of congener profiles showed that hexachlorinated molecules were dominant (hexa-CBs, 55.3-56.2%), followed by penta-CBs (21.5-21.8%) and hepta-PCB 180 (14.9-16.0%). PCB 138, 153 and 180 were the prominent congeners accounting for 69.3% of the total PCBs. Among the compounds of DDT, p,p'-DDE was the most dominant molecule (Mediterranean slimehead, 86.6%; blackfin sorcerer, 92.8%), demonstrating the old age of these compounds in the environment. In both species, PCB contents were higher than those of DDTs. Contaminant load was higher in Mediterranean slimehead (PCBs, 1,086 ng g(-1) lipid weight; DDTs, 799 ng g(-1) lipid weight) than in blackfin sorcerer (PCBs, 561 ng g(-1) lipid weight; DDTs, 224 ng g(-1) lipid weight). CONCLUSION: The high ratios SigmaPCBs/SigmaDDTs indicated predominantly industrial versus agrarian activities in the area. Dioxins toxic equivalent (TEQ) concentrations (8.1-18.7 pg TEQ per gram wet weight) reached those encountered in marine organisms at higher levels in the trophic chain, revealing the onerous status of contamination by PCBs in Mediterranean deep sea biota. PMID- 20169414 TI - Effects of mercury on the activity and community composition of soil ammonia oxidizers. AB - PURPOSE: Experiments were conducted to examine the effects of mercury (Hg) on soil nitrification activities and the microbial communities of ammonia-oxidizing bacteria (AOB) and ammonia-oxidizing archaea (AOA). METHODS: The soil samples spiked with different Hg concentrations were incubated for a period of 1, 2, 4, and 8 weeks in triplicate and the potential nitrification rate (PNR) of the samples was determined. The abundance of AOB and AOA was measured after an 8-week incubation by real-time polymerase chain reaction (PCR) assay of the amoA genes, while the community compositions by cloning and sequencing approaches. RESULTS: The soil PNR differed with different incubation periods. It tended to decrease with increasing soil Hg concentrations at week 1, basing on which the half maximal effective concentration (EC50) was 1.59 mg kg(-1). There was no significant difference in the abundance of AOB or AOA among the treatments. The AOB community was dominated by Nitrosospira-like sequences and more than 70% of the obtained clones were affiliated with the cluster 3a.2. The percentage of cluster 3a.1 in AOB community appeared to a consistent trend of decreasing with ascending soil Hg concentrations. While all the AOA sequences in the clone libraries were grouped into cluster S (soil and sediment origin). CONCLUSIONS: This study revealed that Hg could inhibit soil potential nitrification and the extent varied with incubation periods. Soil Hg pollution changed the composition of soil AOB to some extent. These findings will be helpful to recognize the effects of Hg on the activity and community composition of soil ammonia oxidizers. PMID- 20169416 TI - A model of CatSper channel mediated calcium dynamics in mammalian spermatozoa. AB - CatSpers are calcium (Ca(2+)) channels that are located along the principal piece of mammalian sperm flagella and are directly linked to sperm motility and hyperactivation. It has been observed that Ca(2+) entry through CatSper channels triggers a tail to head Ca(2+) propagation in mouse sperm, as well as a sustained increase of Ca(2+) in the head. Here, we develop a mathematical model to investigate this propagation and sustained increase in the head. A 1-d reaction diffusion model tracking intracellular Ca(2+) with flux terms for the CatSper channels, a leak flux, and plasma membrane Ca(2+) clearance mechanism is studied. Results of this simple model exhibit tail to head Ca(2+) propagation, but no sustained increase in the head. Therefore, in this model, a simple plasma membrane pump-leak system with diffusion in the cytosol cannot account for these experimentally observed results. It has been proposed that Ca(2+) influx from the CatSper channels induce additional Ca(2+) release from an internal store. We test this hypothesis by examining the possible role of Ca(2+) release from the redundant nuclear envelope (RNE), an inositol 1,4,5-trisphosphate (IP(3)) gated Ca(2+) store in the neck. The simple model is extended to include an equation for IP(3) synthesis, degradation, and diffusion, as well as flux terms for Ca(2+) in the RNE. When IP(3) and the RNE are accounted for, the results of the model exhibit a tail to head Ca(2+) propagation as well as a sustained increase of Ca(2+) in the head. PMID- 20169417 TI - Quasi-steady state reduction of molecular motor-based models of directed intermittent search. AB - We present a quasi-steady state reduction of a linear reaction-hyperbolic master equation describing the directed intermittent search for a hidden target by a motor-driven particle moving on a one-dimensional filament track. The particle is injected at one end of the track and randomly switches between stationary search phases and mobile nonsearch phases that are biased in the anterograde direction. There is a finite possibility that the particle fails to find the target due to an absorbing boundary at the other end of the track. Such a scenario is exemplified by the motor-driven transport of vesicular cargo to synaptic targets located on the axon or dendrites of a neuron. The reduced model is described by a scalar Fokker-Planck (FP) equation, which has an additional inhomogeneous decay term that takes into account absorption by the target. The FP equation is used to compute the probability of finding the hidden target (hitting probability) and the corresponding conditional mean first passage time (MFPT) in terms of the effective drift velocity V, diffusivity D, and target absorption rate lambda of the random search. The quasi-steady state reduction determines V, D, and lambda in terms of the various biophysical parameters of the underlying motor transport model. We first apply our analysis to a simple 3-state model and show that our quasi-steady state reduction yields results that are in excellent agreement with Monte Carlo simulations of the full system under physiologically reasonable conditions. We then consider a more complex multiple motor model of bidirectional transport, in which opposing motors compete in a "tug-of-war", and use this to explore how ATP concentration might regulate the delivery of cargo to synaptic targets. PMID- 20169418 TI - Differential geometry based multiscale models. AB - Large chemical and biological systems such as fuel cells, ion channels, molecular motors, and viruses are of great importance to the scientific community and public health. Typically, these complex systems in conjunction with their aquatic environment pose a fabulous challenge to theoretical description, simulation, and prediction. In this work, we propose a differential geometry based multiscale paradigm to model complex macromolecular systems, and to put macroscopic and microscopic descriptions on an equal footing. In our approach, the differential geometry theory of surfaces and geometric measure theory are employed as a natural means to couple the macroscopic continuum mechanical description of the aquatic environment with the microscopic discrete atomistic description of the macromolecule. Multiscale free energy functionals, or multiscale action functionals are constructed as a unified framework to derive the governing equations for the dynamics of different scales and different descriptions. Two types of aqueous macromolecular complexes, ones that are near equilibrium and others that are far from equilibrium, are considered in our formulations. We show that generalized Navier-Stokes equations for the fluid dynamics, generalized Poisson equations or generalized Poisson-Boltzmann equations for electrostatic interactions, and Newton's equation for the molecular dynamics can be derived by the least action principle. These equations are coupled through the continuum discrete interface whose dynamics is governed by potential driven geometric flows. Comparison is given to classical descriptions of the fluid and electrostatic interactions without geometric flow based micro-macro interfaces. The detailed balance of forces is emphasized in the present work. We further extend the proposed multiscale paradigm to micro-macro analysis of electrohydrodynamics, electrophoresis, fuel cells, and ion channels. We derive generalized Poisson-Nernst-Planck equations that are coupled to generalized Navier-Stokes equations for fluid dynamics, Newton's equation for molecular dynamics, and potential and surface driving geometric flows for the micro-macro interface. For excessively large aqueous macromolecular complexes in chemistry and biology, we further develop differential geometry based multiscale fluid electro-elastic models to replace the expensive molecular dynamics description with an alternative elasticity formulation. PMID- 20169419 TI - The effect of pH on continuous biohydrogen production from swine wastewater supplemented with glucose. AB - The effect of pH on hydrogen production from liquid swine manure supplemented with glucose by a mixed culture of fermentative bacteria in an anaerobic sequencing batch reactor was evaluated in this study. At 37 +/- 1 degrees C, five pH values ranging from 4.7 to 5.9 at an increment of 0.3 were tested at a hydraulic retention time (HRT) of 16 h. The results showed that at this HRT, the optimal pH for hydrogen production was 5.0, under which the biogas comprised 33.57 +/- 5.65% of hydrogen with a production rate of 8.88 +/- 2.94 L-H(2)/day and a yield of 1.48 +/- 0.49 L-H(2)/L liquid swine manure. The highest biomass concentration, highest butyric acid to acetic acid ratio, lowest propionic acid concentration, and the best stability were all found at pH 5.0, while the highest CH(4) productivity was found at pH 5.9. For efficient hydrogen production, oxygen content should be controlled under 2%, beyond which an inverse linear relationship (R(2) = 0.986) was observed. PMID- 20169420 TI - Triage in public health emergencies: ethical issues. AB - General concepts about medical disasters, public health and triage are outlined. Triage is described in the context of public health emergencies and disaster settings, and the main ethical values at stake in triage are discussed. Possible conflicts between competing values are outlined. Special attention is given to possible conflicts between the protection of individual interests (typical of clinical ethics), and the pursuit of collective interests (typical of public health and triage). Hippocratic ethics is compared to utilitarian ethics and to perspectives that emphasize the principle of justice. Three ethical attitudes are suggested that may contribute to a resolution of competing values: protection of human dignity, precaution and, especially, solidarity. Personalism promotes the collective good by safeguarding and giving value to the well-being of each individual. A personalistic perspective is suggested as a way to deepen the concept of solidarity as a pillar both of clinical and public health ethics. PMID- 20169421 TI - ECG signs of biatrial enlargement in a young adult. PMID- 20169422 TI - The uncontrolled clinical trial: scientific, ethical, and practical reasons for being. AB - According to principles of clinical trial design, the demonstration of efficacy of a new treatment is based on comparing the response in the treated group with that of a control group receiving placebo or another active treatment. The need for a control group is also recommended by the major international institutions that govern the ethics and the practice of clinical research. Despite these principles and recommendations, inspection of a purposive sample of ongoing clinical trials listed in the NIH registry ( http://ClinicalTrials.gov ) reveals that as many as one-third of trials are uncontrolled. Since these trials were approved through a formal evaluation by ethics committees, the lack of adequate control was not perceived as a major deficiency in the study design. Most uncontrolled trials belong to the oncology/hematology area. If two extreme disease conditions for nature and progression are analyzed, such as acute myeloid leukemia (AML) and chronic heart failure (CHF), the difference in the prevalence of uncontrolled trials is very striking. The number of uncontrolled trials is only 13% in CHF, whereas it reaches 66% in the AML group. I believe that the underlying disease condition plays a primary role in orienting the design of the study: oncology and hematology may be fields in which uncontrolled studies are common, whereas in other fields, e.g., cardiology, this phenomenon can be reduced. Within the limitations of the selection process of the examined trials, the current analysis indicates that the clinical trial reality does not strictly follow experimental design theory and official recommendations. PMID- 20169423 TI - Bicarbonate therapy in the treatment of septic shock: a second look. AB - The use of supplemental sodium bicarbonate for the treatment of patients with septic shock and elevated blood lactate levels remains a controversial therapy. We conducted a retrospective study between March 2004 and February 2009 of 36 consecutive patients diagnosed with septic shock who received continuous infusion of bicarbonate therapy. A control group was matched 1:1 for age, site of infection, and predicted mortality by APACHE II. All patients were managed according to standard protocols. The median time until reversal of shock did not achieve statistical significance between the bicarbonate group (44.5 h [95% confidence interval [CI] 34-54] and the control group (55.0 h [95% CI 39-60] (p = 0.09). The median time to liberation of mechanical ventilation was significantly reduced in the bicarbonate group (10 days [95% CI 5.0-13.0] compared to the control group (14 days [95% CI 9.0-19.0], p = 0.02). The length of intensive care unit (ICU) stay was also shorter in the surviving patients who received bicarbonate compared to controls (median 11.5 days (95% CI 6.0-16.0) vs. 16.0 days (95% CI 13.5-19.0), respectively; p = 0.01). However, there was no difference in 28-day mortality between the two study groups (28%; 95% CI 14-45% vs. 33%; 95% CI 19-51%, respectively; p = 0.79). Infusion of sodium bicarbonate in septic patients with arterial hyperlactatemia may facilitate weaning from mechanical ventilation and reduce length of ICU stay. PMID- 20169425 TI - The evolution and impact of therapy in multiple myeloma. AB - Multiple myeloma is a clonal B-cell malignancy characterized by aberrant expression of plasma cells within the bone marrow, and is associated with the well known clinical manifestations anemia, bone disease, renal dysfunction, hypercalcemia, and recurrent infections. For many years, melphalan and prednisone represented the standard of care in multiple myeloma therapy, with stem cell transplantation reserved for selected patients. Treatment of the disease has evolved rapidly over the past decade, however, with the development and utilization of thalidomide, lenalidomide, and bortezomib. As a result of these developments, clinical outcomes have improved significantly. This review highlights important historic landmarks as well as more recent events that have played an important role in the evolution of myeloma therapy. PMID- 20169424 TI - Acute infection-inflammation and coronary stent thrombosis: an observational study. AB - Coronary stent thrombosis (CST) is a major concern of interventional cardiology. Several risk factors for CST have been identified, but as a whole they do not explain the pathophysiology of CST. This study was designed to investigate whether acute infection-inflammation could facilitate the occurrence of CST. Forty-one patients, aged 66.6 +/- 11 years, consecutively admitted to our catheterization laboratory for acute, subacute or late CST, were retrospectively analysed. Transient acute infection-inflammation on admission for CST was diagnosed by predefined criteria. Prevalence of known risk factors for CST was also investigated. Twenty-one patients (51%) met predefined criteria for the occurrence of acute infection-inflammation. On admission, in these patients, levels of systemic humoral and cellular inflammatory markers were significantly higher than those of patients without recent or ongoing acute infection inflammation (p < 0.05 for all). 62% of patients with acute infection inflammation had less than two known risk factors for CST whereas only 37% patients without infection-inflammation showed less than two risk factors (p = 0.03) and showed more frequent interruption of antiplatelet treatment (17 vs. 2.4%, p = 0.02), mean longer stent length (20.5 +/- 4.8 vs. 16.5 +/- 5.1 mm, p = 0.02) and lower left ventricular ejection fraction before CST (42.9 +/- 14 vs. 47.3 +/- 11%, p = 0.02). In conclusion, acute infection-inflammation could play a role in facilitating the occurrence of CST in a subgroup with low risk profile for known risk factors. Our findings, if confirmed, could suggest new opportunities for prevention and treatment of CST. PMID- 20169426 TI - Brucellosis: a rare cause of febrile neutropenia in acute myeloblastic leukemia. AB - Brucellosis is a zoonotic disease and endemically seen in the Middle East, Eastern Europe and continental America. Febrile neutropenia related to Brucellosis has been reported only in a few cases. Brucella was cultured from the bone marrow of a 42-year-old woman who was admitted to hospital with symptoms of fever and fatigue and later diagnosed as acute myeloblastic leukemia (AML). The patient was treated for both AML and Brucellosis without any problems and discharged from the hospital after scheduling her follow-up visits. Brucellosis might be considered in the etiology of febrile neutropenia in endemic regions and must be treated effectively to prevent possible morbidity and mortality during or after chemotherapy. PMID- 20169428 TI - Motivation and physiologic responses of playing a physically interactive video game relative to a sedentary alternative in children. AB - BACKGROUND: While there is emerging research outlining the physiologic cost of the physically interactive Nintendo Wii, there are no evaluations of the relative reinforcing value (RRV) of the Wii versus a sedentary alternative. PURPOSE: The purpose of this study is to evaluate the physiologic cost, RRV, and liking of playing Wii Sports Boxing (Wii) versus a traditional sedentary video game (SVG) in 11 lean and 13 overweight/obese 8- to 12-year-old children. METHODS: Heart rate (HR) and VO(2) were assessed during rest, treadmill walking, and playing an SVG and Wii using a counterbalance design. Liking was assessed during treadmill walking and video game play. RRV was assessed for Wii versus SVG. RESULTS: Average HR, VO(2), and liking were significantly greater for Nintendo Wii (p < or = 0.001 for all) than all other conditions. Lean children displayed a greater (p < 0.001) peak responding for access to Wii relative to the SVG while overweight/obese children did not (p > or = 0.16). CONCLUSION: Wii was a well liked activity of greater physiologic intensity than both the SVG and treadmill walking. Lean children were more motivated while overweight/obese children were equally as motivated to play Wii relative to the SVG. PMID- 20169427 TI - Hematopoiesis from pluripotent stem cell lines. AB - Embryonic stem cells (ESCs) can differentiate into various types of hematopoietic cells (HPCs) when placed in an appropriate environment. Various methods for the differentiation of ESCs into specific HPC lineages have been developed using mouse ESCs. These ESC-differentiation methods have been utilized also as an in vitro model to investigate hematopoiesis in embryos and they provided critical perceptions into it. These methods have been adapted for use with human ESCs, which have the possibility of being employed in regenerative medicine; further improvement of these methods may lead to the efficient production of HPCs for use in transfusions. The generation of transplantable hematopoietic stem cells is a medical goal that is still difficult to achieve. Recently, induced pluripotent stem (iPS) cells have been established from differentiated cells. Thereby, iPS cells have expanded further possibilities of the use of pluripotent stem cell lines in clinical application. Indeed, iPS cells have been established from cells with disease genes and those which have undergone reprogramming and targeting have generated phenotypically normal HPCs. Here, we mainly summarize the recent progress in research on hematopoiesis conducted with ESCs and iPS cells. PMID- 20169429 TI - Facilitating interventions and/or relationships in malignant brain tumors. AB - Brain tumors have special oncological significance. The prognosis of brain tumors is mostly poor, and they are also connected to functional and cognitive deficiencies, as well as possible personality changes. Therefore, the social impact of the disease has special significance as it also affects family and friends of patients with brain tumors. This review focuses on different professional arenas that can psychologically facilitate for the patient and/or for their next of kin. The different arenas discussed are: the patient-physician relationship, the specialist nurse function, functional and cognitive rehabilitative efforts, and support groups. The patient-physician relationship is important, but there is a lack of knowledge of its psychological impact outside of information giving. The few studies conducted on the specialist nurse function are quite unanimous about its facilitating value and this mainly seems to pertain to the next of kin. Functional rehabilitative efforts seem to be worthy, but even if there are promising results, there is still lack of knowledge of the potential of cognitive rehabilitation. Although there is a long history of peer support groups for patients with brain tumors, we do not know enough about the potential in professionally initiated supportive groups or different Internet forums. When initiating further studies within the different arenas for the purpose of understanding how to facilitate for patients with brain tumors and their families, we should also consider the psychological meaning of the activity/intervention. PMID- 20169430 TI - Treatment of acute scapholunate ligament injuries with bone anchor. AB - Scapholunate instability is the most common form of carpal instability. Repair or reconstruction of the scapholunate interosseus ligament is advocated to reduce symptoms, stabilize the scapholunate joint and avoid the progression of carpal degeneration. Aim of this study is to evaluate the results (clinical and radiographic) obtained in 18 patients treated in our department for acute lesions SLIL from 2003 to 2008. Patients were 16 males and 2 females with an average age at the time of the trauma of 33.8 years old (min 17 and max 68 years). The diagnosis of scapholunate dissociation relies on a through history and physical examination and imaging studies. Early surgical repair of the torn schapolunate ligament was performed in all the patients. The method used for the treatment of these lesions was open reduction and direct ligament reinsertion through a minianchor MITEK. In our surgical experience in 3 cases we have found a combination between an isolated scaphoid fractures and a scapholunate ligament rupture without carpal dislocation. We reviewed all patients treated with an average follow-up of 32 months (range 9-68 months). The review was carried out both clinically and radiographically (static and dynamic). We achieved 13 excellent results (Mayo score average 94,77), 3 good results (Mayo score average 84), 1 sufficient results (Wrist score 72) and 1 bad result (Wrist score 35). From the radiographic evaluation we found a loss of reduction in the two cases identified clinically as sufficient and bad. One patient after an optimal ligament healing, underwent to a recurrence of the lesion SLIL 2 years from surgery. Open reduction and direct bony fixation of the torn scapholunate ligament using a suture anchor is generally successful in restoring scapholunate stability and has produced good functional mid-term results. At an average follow up of 32 months excellent or good functional outcomes were reported in 88% of the patients despite a large number of cases with a high energy trauma and other associated injury. The association between an isolated scaphoid fracture and a SLIL lesion is rare but not impossible in presence of a scapholunate instability we recommend the immediate reconstruction of the torn ligament. PMID- 20169431 TI - Representation of movement velocity in the rat's interpositus nucleus during passive forelimb movements. AB - The interpositus nucleus (IN) receives a large amount of sensory information from the limbs and, in turn, elaborates signals for movement control. In this paper, we tried to gather evidence on the possibility that neurons in the IN may elaborate sensory representations of the forelimb kinematics and, particularly, of the movement velocity vector. For this purpose, the forepaw of anesthetized rats was attached to a computer-controlled robot arm displaced passively along two types of trajectories (circular and figure eight), with the limb joints unconstrained. The firing activity of single cells was recorded and related to limb position and the two components of the movement velocity vector, namely, movement speed and direction. By using multiple regression analysis, we found that 12 out of 85 (14%) neurons were modulated by position, 18 out of 85 (21%) neurons were modulated by direction, 24 out of 85 (28%) neurons were modulated by movement speed, and 31 out of 85 (37%) neurons were sensitive to the full movement velocity vector. Most of the neurons modulated only by the speed component of the velocity vector (19 out of 24) were located in the posterior portion of the IN, whereas neurons in the anterior portion were mostly related to both components of the velocity vector. These results suggest that sensory information related to whole-limb movement velocity may be encoded by the IN, indicating also that the posterior interpositus may preferentially represent movement speed. PMID- 20169432 TI - Fetal response to induced maternal emotions. AB - This study investigated the relationship between fetal movements and acute maternal emotional changes during pregnancy. Two empirically validated feature film clips were used for the external generation of two subjectively and facially well-characterized target emotions: happiness and sadness. We simultaneously monitored separate fetal arm, leg, and trunk movements by means of two ultrasound apparatuses while maternal emotions were manipulated by film clip presentation. The number of fetal arm movements, but not the duration, was increased when pregnant women were being shown a happy film. Both the number and the duration of fetal arm movements decreased with the sad film presentation. Neither the presentation of happiness nor the presentation of sadness affected fetal leg or trunk movements. These findings suggest that induced emotions in pregnant women primarily affect arm movements of their fetuses, and that positive and negative emotions have the opposite effects on fetus movement. PMID- 20169433 TI - How does workaholism affect worker health and performance? The mediating role of coping. AB - BACKGROUND: The underlying mechanisms connecting workaholism on the one hand and ill-health and performance on the other hand have to date hardly been examined empirically. PURPOSE: The aim was to study the mediating role of coping (i.e., active coping and emotional discharge) in the relationship between workaholism, ill-health (i.e., psychological distress and physical complaints), and job performance. METHOD: A theory-based model was tested among 757 employees of a Japanese construction machinery company. RESULTS: Workaholism was positively related to active coping, which was, in its turn, negatively associated with ill health and positively with job performance. Workaholism was also positively related to emotional discharge, which was positively associated with ill-health. In addition, workaholism was positively and directly related to ill-health, whereas it was not significantly related to job performance. CONCLUSION: Workaholism is associated with both active coping and emotional discharge. Active coping leads to better health and performance, whereas emotional discharge leads to poor health. In addition, workaholism coincides with poor health. Since the costs for workaholics themselves (in terms of ill-health) are high, workaholism has on average adverse effects on health and performance. PMID- 20169434 TI - Therapeutic effect of the combined use of growth hormone releasing peptide-6 and epidermal growth factor in an axonopathy model. AB - Amyotrophic lateral sclerosis (ALS) is a disease of the central nervous system characterized by loss of spinal motor neurons, for which no effective treatment exists. Epidermal growth factor (EGF) and growth hormone releasing peptide-6 (GHRP-6) have been considered as good candidates for the treatment of this disease, due to their well documented effects in eliciting pleiotrophic and cell survival mechanisms. The aim of the present work was to evaluate the separate and combined effects of both peptides in an experimental animal model of ALS, the proximal axonopathy induced by 1,2 diacetylbenzene (1,2 DAB) in mice. The evaluations were conducted by means of behavioral tests (trapeze, tail suspension, gait pattern, and open field) and by recording the complex muscle action potential (CMAP) in three different hind limb segments: proximal S1, medial S2, and distal S3. Intraperitoneal daily administration of 1,2 DAB produced significant reduction in body weight, muscle strength, extensor reflex, spontaneous activity, and changes in gait pattern parameters. In parallel 1,2 DAB produced significant prolongation of onset latency and decrease in amplitude of CMAP and in the integrated complex action potential index. Daily administration of the separate compounds did not accelerate the recovery of the affected parameters, except for the gait pattern. The combined treatment produced significant improvement in behavioral parameters, as well as in electrophysiological recovery, particularly in the proximal segment of CMAP. The latter results confirm the proximal character of 1,2 DAB neuropathy, and suggest that combined therapy with EGF and GHRP-6 might be a good therapeutic strategy for the treatment of ALS. PMID- 20169435 TI - Hippocampal neurons exposed to the environmental contaminants methylmercury and polychlorinated biphenyls undergo cell death via parallel activation of calpains and lysosomal proteases. AB - Methylmercury (MeHg) and polychlorinated biphenyls (PCBs) are widespread environmental pollutants commonly found as contaminants in the same food sources. Even though their neurotoxic effects are established, the mechanisms of action are not fully understood. In the present study, we have used the mouse hippocampal neuronal cell line HT22 to investigate the mechanisms of neuronal death induced by MeHg, PCB 153, and PCB 126, alone or in combination. All chemicals induced cell death with morphological changes compatible with either apoptosis or necrosis. Mitochondrial functions were impaired as shown by the significant decrease in mitochondrial Ca2+ uptake capacity and ATP levels. MeHg, but not the PCBs, induced loss of mitochondrial membrane potential and release of cytochrome c into the cytosol. Also, pre-treatment with the antioxidant MnTBAP was protective only against cell death induced by MeHg. While caspase activation was absent, the Ca2+-dependent proteases calpains were activated after exposure to MeHg or the selected PCBs. Furthermore, lysosomal disruption was observed in the exposed cells. Accordingly, pre-treatment with the calpain specific inhibitor PD150606 and/or the cathepsin D inhibitor Pepstatin protected against the cytotoxicity of MeHg and PCBs, and the protection was significantly enhanced when the two inhibitors were combined. Simultaneous exposures to lower doses of MeHg and PCBs suggested mostly antagonistic interactions. Taken together, these data indicate that MeHg and PCBs induce caspase-independent cell death via parallel activation of calpains and lysosomal proteases, and that in this model oxidative stress does not play a major role in PCB toxicity. PMID- 20169436 TI - [The relevance of magnetic resonance imaging (MRI) for the detection and exclusion of prostate cancer]. AB - This review illustrates the relevance of magnetic resonance imaging (MRI) for the detection or exclusion of prostate cancer. The functional MR methods dynamic contrast-enhanced MRI (DCE-MRI), MR spectroscopy, and diffusion-weighted imaging (DWI) helped in recent years to establish MRI as the imaging method of choice for prostate cancer. Indications for MRI of the prostate regarding recent guidelines and new concepts of cancer therapy are introduced. PMID- 20169439 TI - Anterior pelvic endometriosis: MRI features. AB - Many atypical locations for deep endometriosis exist that are not well known to both the radiologist and gynecologist. This work explores these unusual localizations, which we have arbitrarily grouped under the term "anterior endometriosis" in contrast to the more common posterior presentation of deep endometriosis that has been so well described in the literature. Parietal and inguinal involvement is first detailed, followed by a description of deep endometriosis involving the urinary system and anterior supporting ligaments of the uterus. A necessary adaptation to the MRI protocol in order to accurately diagnosis deep anterior endometriosis as well as specific diagnostic criteria for each type of lesion is reviewed. PMID- 20169438 TI - The pharmacological treatment of opioid addiction--a clinical perspective. AB - This article reviews the main pharmacotherapies that are currently being used to treat opioid addiction. Treatments include detoxification using tapered methadone, buprenorphine, adrenergic agonists such as clonidine and lofexidine, and forms of rapid detoxification. In opioid maintenance treatment (OMT), methadone is most widely used. OMT with buprenorphine, buprenorphine-naloxone combination, or other opioid agonists is also discussed. The use of the opioid antagonists naloxone (for the treatment of intoxication and overdose) and oral and sustained-release formulations of naltrexone (for relapse prevention) is also considered. Although recent advances in the neurobiology of addictions may lead to the development of new pharmacotherapies for the treatment of addictive disorders, a major challenge lies in delivering existing treatments more effectively. Pharmacotherapy of opioid addiction alone is usually insufficient, and a complete treatment should also include effective psychosocial support or other interventions. Combining pharmacotherapies with psychosocial support strategies that are tailored to meet the patients' needs represents the best way to treat opioid addiction effectively. PMID- 20169440 TI - RNA editing in six mitochondrial ribosomal protein genes of Didymium iridis. AB - Similarity searches with Didymium iridis mitochondrial genomic DNA identified six possible ribosomal protein-coding regions, however, each region contained stop codons that would need to be removed by RNA editing to produce functional transcripts. RT-PCR was used to amplify these regions from total RNA for cloning and sequencing. Six functional transcripts were verified for the following ribosomal protein genes: rpS12, rpS7, rpL2, rpS19, rpS3, and rpL16. The editing events observed, such as single C and U nucleotide insertions and a dinucleotide insertion, were consistent with previously observed editing patterns seen in D. iridis. Additionally, a new form of insertional editing, a single A insertion, was observed in a conserved region of the rpL16 gene. While the majority of codons created by editing specify hydrophobic amino acids, a greater proportion of the codons created in these hydrophilic ribosomal proteins called for positively charged amino acids in comparison to the previously characterized hydrophobic respiratory protein genes. This first report of edited soluble mitochondrial ribosomal proteins in myxomycetes expands upon the RNA editing patterns previously seen; there was: a greater proportion of created codons specifying positively charged amino acids, a shift in the codon position edited, and the insertion of single A nucleotides. PMID- 20169441 TI - Optimal timing for repair of an inguinal hernia in premature infants. AB - PURPOSE: The aim of this study was to determine the optimal timing for inguinal herniotomy in premature infants treated in the neonatal intensive care unit. METHODS: A two-institutional-center retrospective study was performed including 41 prematures at gestational age 28-35 weeks who underwent herniotomy within 1 week of diagnosis [short-waiting group (SWG), median 5 days, n = 25] or more than 1 week after diagnosis [long-waiting group (LWG), median 30.55 days, n = 16]. Gestational age, birthweight, post-conceptional age at diagnosis, age at diagnosis, post-conceptional age at surgery, age at surgery, weight at surgery, timing of surgery, operative time, and occurrence of incarceration, postoperative apnea, hernia recurrence, testicular atrophy, and hospital stay were compared between the two groups. Statistical analysis was performed using one-way ANOVA. RESULTS: Twelve preoperative episodes of incarceration occurred: three in the SWG and nine in the LWG (P < 0.05). Six infants had apnea postoperatively: four in the SWG and two in the LWG (P > 0.05). Follow-up revealed five hernia recurrences, one in the SWG and four in the LWG (P < 0.05); four testicular atrophies were found, one in the SWG and three in the LWG (P > 0.05). CONCLUSION: Early elective herniotomy should be considered in prematures in order to avoid perioperative morbidity and to reduce the risk of incarceration and subsequent testicular ischemia, and hernia recurrence. PMID- 20169442 TI - Factors affecting the outcome of ureteroscopy in the management of ureteral stones in children. AB - PURPOSE: To identify the factors involved in failure and post-operative complications of retrograde rigid ureteroscopy (URS) in the treatment of ureteric stones in children. METHODS: This is a retrospective study, including 33 children who underwent 34 rigid URS (one case bilateral) for obstructive ureteric stones over a period of 10 years. Patient age, sex, presenting symptoms, stone size and location, operative technique, surgical outcomes and complications were recorded. Ureteroscopy was done in a manner similar to that in adults. Statistical analysis was performed using the Mann-Whitney U, the Chi-square or Fisher's exact test. RESULTS: There were 33 children (22 girls and 11 boys) with a mean age of 10.8 years (range 4-16 years) presenting 34 stones. The site of stones was pelvic in 24 cases (70.5%), iliac in 2 cases (6%) and lumbar in 8 cases (23.5%). The mean size of stones was 10.9 mm (5-22 mm). The success rate was 91%. There were no intraoperative complications. Post-operative complications rate was 21%. Factors associated with failure were size, localization of the stone, and delay of surgery. Factors associated with post-operative complications were size of the stone and operative time. CONCLUSION: The rigid URS in children is a reliable and effective treatment option in the management of ureteric stones. Favorable factors for success of the procedure are pelvic stone and stone size <10 mm. PMID- 20169443 TI - Urinary function after Snodgrass repair of distal hypospadias: comparison with the Mathieu repair. AB - PURPOSE: To evaluate urinary function in patients with distal hypospadias undergoing repair by the tubularized incised-plate urethroplasty (TIP or Snodgrass), compare the results with those in patients treated by the Mathieu technique, and show the potential issues inherent to the evaluation of such results. PATIENTS AND METHODS: A cross-sectional assessment was performed of uncomplicated distal hypospadias operated on during a 3-year period, already toilet trained, and able to void volitionally. Evaluation included clinical assessment urinary symptoms and urinary stream, and uroflowmetry. RESULTS: Out of 83 patients operated on during the study period, 10 (12%) developed complication and 32 were not toilet trained or refused to participate in the study. Median follow-up in the remaining 41 patients included in the study was 20 (3-36) months. None of these patients presented voiding symptoms or urinary stream abnormalities. Uroflowmetry was normal in 30 cases and obstructive in 11 (27%). An obstructive flow pattern was more common in patients undergoing TIP versus Mathieu repair, 8 of 19 (42%) versus 3 of 22 (14%), respectively (P = 0.07). Four TIP cases with an obstructive uroflow pattern were managed conservatively. CONCLUSIONS: Although both the TIP and the Mathieu repair allow good results in terms of urinary function after distal hypospadias repairs, the TIP technique seems more likely to be associated with urine flow pattern abnormalities. The actual clinical relevance of this finding remains ill defined. PMID- 20169444 TI - A missense mutation c.G2747A (p.R916Q) of ADAR1 gene in dyschromatosis symmetrica hereditaria is not a novel mutation. PMID- 20169445 TI - Hydatid cyst of urinary bladder associated with pregnancy:a case report. AB - Echinococcosis or hydatid disease which is caused by Echinococcus group of cestodes is very rare in pregnancy. While liver and lungs are commonly involved, other sites can be rarely affected. The management of hydatid disease in pregnancy is challenging in view of varied presentation and manifestation. We report a case of hydatid cyst arising from the bladder associated with pregnancy and presenting with abdominal pain. The cyst was surgically removed and the bladder wash was given with povidone-iodine. The postoperative recovery was uneventful with ongoing pregnancy. This is to our knowledge, the first case of hydatid cyst arising from the bladder associated with pregnancy to be reported. PMID- 20169446 TI - Charcot-Marie-Tooth disease type 2D with a novel glycyl-tRNA synthetase gene (GARS) mutation. PMID- 20169447 TI - High frequency of exon 10 mutations in the NOTCH3 gene in Italian CADASIL families: phenotypic peculiarities. PMID- 20169448 TI - Increased plasma isoprostane is associated with visceral fat, high molecular weight adiponectin, and metabolic complications in obese children. AB - Oxidative stress is considered to be increased in obese subjects. However, the association of oxidative stress with visceral adiposity and adiponectin level is not fully understood in children. Forty-four obese Japanese children and adolescents, 28 boys and 16 girls, with median age of 9.9 years [5.2-13.8 years], and the 28 age-matched non-obese healthy controls, 15 boys and 13 girls, were enrolled in this study. The median BMI Z scores were +2.21 [1.31-4.38] for the obese subjects and -0.72 [-2.11-1.31] for the control. Plasma concentrations of 8 epi-prostaglandin F2alpha (isoprostane), a marker of oxidative stress, and adiponectin fractions were assayed using ELISA. 8-epi-PGF2alpha levels were significantly higher in the obese group (37.1 [4.7-112.7], median and the range) than in the control (11.5 [4.5-27.3]). In a univariate analysis, concentrations of 8-epi-PGF2alpha positively correlated with visceral adipose tissue area measured by computed tomography, waist circumference, serum triglycerides, alanine aminotransferase, insulin levels, and the homeostasis of minimal assessment of insulin resistance and inversely correlated with high-density lipoprotein cholesterol and high-molecular weight (HMW) adiponectin. Total-, medium-, or low-molecular weight adiponectin fraction did not show a significant correlation with 8-epi-PGF2alpha Forty of 44 obese children had one or more metabolic complications. The 8-epi-PGF[Formula: see text] levels also elevated with increasing numbers of obesity-related complications. These results suggest that oxidative stress is enhanced in relation to visceral fat accumulation and decreasing HMW adiponectin level in childhood obesity. Oxidative stress may be associated with the development of obesity-related complications. PMID- 20169449 TI - Glycemic control in diabetic children: role of mother's knowledge and socioeconomic status. AB - The aim of this study is to investigate the role of mother's knowledge and socioeconomic status (SES) of the family on glycemic control in diabetic children. Our sample was taken from successive admissions to the outpatient's diabetes clinics in Tuzla, Bosnia and Herzegovina. Diabetes knowledge was assessed using the Michigan Diabetes Research and Training Center Diabetes Knowledge Test. Glycemic control was assessed by glycosylated hemoglobin (HbA(1C)). The mother's demographics were obtained by self-report. To categorize families' SES, parents' level of education, and current employment were recorded and analyzed using the Hollingshed two-factor index of social position. As expected, higher mother's knowledge was significantly associated with lower HbA(1C) (r = -0.2861705, p = 0.0442). Also, a significant correlation was found between the families' SES and HbA(1C) levels (r = 0.4401921; p = 0.0015). Mothers with more knowledge have children with better metabolic control, and low SES is significantly associated with higher levels of HbA1c. Improvement of mothers' knowledge and family SES may improve glycemic control and ultimately decrease acute and chronic complications of diabetes in children. PMID- 20169450 TI - Leukocyte DNA damage in children with iron deficiency anemia: effect of iron supplementation. AB - Iron deficiency is frequently associated with anemia. Iron is a transition-metal ion, and it can induce free radical formation, which leads to formation of various lesions in DNA, proteins, and lipids. The aim of this study was to investigate baseline oxidative DNA damage and to clarify the role of the administration of a therapeutic dose of iron on DNA oxidation in children with iron deficiency anemia (IDA). Twenty-seven children with IDA and 20 healthy children were enrolled in the study. Leukocyte DNA damage (strand breaks and Fpg sensitive sites) was assessed using comet assay before and after 12 weeks of daily iron administration. Before the iron administration, the frequency of DNA strand breaks in the children with IDA was found to be lower than those in the control group (P < 0.05), but there was not a significant difference for frequency of Fpg-sensitive sites. After 12 weeks of iron administration, the frequency of both DNA strand breaks and Fpg-sensitive sites were found to be increased (P < 0.01). No significant association was determined between DNA damage parameters and hemoglobin, hematocrit, serum iron, total iron binding capacity, and ferritin. In conclusion, basal level of DNA strand breaks is at a low level in children with IDA. After iron administration, DNA strand breaks and Fpg-sensitive sites, which represent oxidatively damaged DNA, increased. However, this increase was unrelated to serum level of iron and ferritin. PMID- 20169451 TI - Individual variability in tree allometry determines light resource allocation in forest ecosystems: a hierarchical Bayesian approach. AB - Tree species differences in crown size and shape are often highlighted as key characteristics determining light interception strategies and successional dynamics. The phenotypic plasticity of species in response to light and space availability suggests that intraspecific variability can have potential consequences on light interception and community dynamics. Species crown size varies depending on site characteristics and other factors at the individual level which differ from competition for light and space. These factors, such as individual genetic characteristics, past disturbances or environmental micro-site effects, combine with competition-related phenotypic plasticity to determine the individual variability in crown size. Site and individual variability are typically ignored when considering crown size and light interception by trees, and residual variability is relegated to a residual error term, which is then ignored when studying ecological processes. In the present study, we structured and quantified variability at the species, site, and individual levels for three frequently used tree allometric relations using fixed and random effects in a hierarchical Bayesian framework. We focused on two species: Abies alba (silver fir) and Picea abies (Norway spruce) in nine forest stands of the western Alps. We demonstrated that species had different allometric relations from site to site and that individual variability accounted for a large part of the variation in allometric relations. Using a spatially explicit radiation transmission model on real stands, we showed that individual variability in tree allometry had a substantial impact on light resource allocation in the forest. Individual variability in tree allometry modulates species' light-intercepting ability. It generates heterogeneous light conditions under the canopy, with high light micro habitats that may promote the regeneration of light-demanding species and slow down successional dynamics. PMID- 20169452 TI - Habitat selection, facilitation, and biotic settlement cues affect distribution and performance of coral recruits in French Polynesia. AB - Habitat selection can determine the distribution and performance of individuals if the precision with which sites are chosen corresponds with exposure to risks or resources. Contrastingly, facilitation can allow persistence of individuals arriving by chance and potentially maladapted to local abiotic conditions. For marine organisms, selection of a permanent attachment site at the end of their larval stage or the presence of a facilitator can be a critical determinant of recruitment success. In coral reef ecosystems, it is well known that settling planula larvae of reef-building corals use coarse environmental cues (i.e., light) for habitat selection. Although laboratory studies suggest that larvae can also use precise biotic cues produced by crustose coralline algae (CCA) to select attachment sites, the ecological consequences of biotic cues for corals are poorly understood in situ. In a field experiment exploring the relative importance of biotic cues and variability in habitat quality to recruitment of hard corals, pocilloporid and acroporid corals recruited more frequently to one species of CCA, Titanoderma prototypum, and significantly less so to other species of CCA; these results are consistent with laboratory assays from other studies. The provision of the biotic cue accurately predicted coral recruitment rates across habitats of varying quality. At the scale of CCA, corals attached to the "preferred" CCA experienced increased survivorship while recruits attached elsewhere had lower colony growth and survivorship. For reef-building corals, the behavioral selection of habitat using chemical cues both reduces the risk of incidental mortality and indicates the presence of a facilitator. PMID- 20169453 TI - Order of invasion affects the spatial distribution of a reciprocal intraguild predator. AB - When intraguild predation is reciprocal, i.e. two predator species kill and feed on each other, theory predicts that well-mixed populations of the two species cannot coexist. At low levels of the shared resource, only the best competitor exists, whereas if the level of the common resource is high, the first species to arrive on a patch can reach high numbers, which prevents the invasion of the second species through intraguild predation. The order of invasion may therefore be of high importance in systems with reciprocal intraguild predation with high levels of productivity, with the species arriving first excluding the other species. However, natural systems are not well mixed and usually have a patchy structure, which gives individuals the possibility to choose patches without the other predator, thus reducing opportunities for intraguild predation. Such avoidance behaviour can cause spatial segregation between predator species, which, in turn, may weaken the intraguild interaction strength and facilitate their co-occurrence in patchy systems. Using a simple set-up, we studied the spatial distribution of two reciprocal intraguild predators when either of them was given priority on a patch with food. We released females of two predatory mite species sequentially and found that both species avoided patches on which the other species was resident. This resulted in partial spatial segregation of the species and thus a lower chance for the two species to encounter each other. Such behaviour reinforces segregation, because heterospecifics avoid patches with established populations of the other species. This may facilitate coexistence of two intraguild predators that would exclude each other in well-mixed populations. PMID- 20169454 TI - Plant species richness regulates soil respiration through changes in productivity. AB - Soil respiration is an important pathway of the C cycle. However, it is still poorly understood how changes in plant community diversity can affect this ecosystem process. Here we used a long-term experiment consisting of a gradient of grassland plant species richness to test for effects of diversity on soil respiration. We hypothesized that plant diversity could affect soil respiration in two ways. On the one hand, more diverse plant communities have been shown to promote plant productivity, which could increase soil respiration. On the other hand, the nutrient concentration in the biomass produced has been shown to decrease with diversity, which could counteract the production-induced increase in soil respiration. Our results clearly show that soil respiration increased with species richness. Detailed analysis revealed that this effect was not due to differences in species composition. In general, soil respiration in mixtures was higher than would be expected from the monocultures. Path analysis revealed that species richness predominantly regulates soil respiration through changes in productivity. No evidence supporting the hypothesized negative effect of lower N concentration on soil respiration was found. We conclude that shifts in productivity are the main mechanism by which changes in plant diversity may affect soil respiration. PMID- 20169456 TI - Focused ion beam (FIB)/scanning electron microscopy (SEM) in tissue structural research. AB - The focused ion beam (FIB) and scanning electron microscope (SEM) are commonly used in material sciences for imaging and analysis of materials. Over the last decade, the combined FIB/SEM system has proven to be also applicable in the life sciences. We have examined the potential of the focused ion beam/scanning electron microscope system for the investigation of biological tissues of the model organism Porcellio scaber (Crustacea: Isopoda). Tissue from digestive glands was prepared as for conventional SEM or as for transmission electron microscopy (TEM). The samples were transferred into FIB/SEM for FIB milling and an imaging operation. FIB-milled regions were secondary electron imaged, back scattered electron imaged, or energy dispersive X-ray (EDX) analyzed. Our results demonstrated that FIB/SEM enables simultaneous investigation of sample gross morphology, cell surface characteristics, and subsurface structures. The same FIB exposed regions were analyzed by EDX to provide basic compositional data. When samples were prepared as for TEM, the information obtained with FIB/SEM is comparable, though at limited magnification, to that obtained from TEM. A combination of imaging, micro-manipulation, and compositional analysis appears of particular interest in the investigation of epithelial tissues, which are subjected to various endogenous and exogenous conditions affecting their structure and function. The FIB/SEM is a promising tool for an overall examination of epithelial tissue under normal, stressed, or pathological conditions. PMID- 20169455 TI - Early-stage blocking of Notch signaling inhibits the depletion of goblet cells in dextran sodium sulfate-induced colitis in mice. AB - BACKGROUND: Goblet cells, which contribute to mucosal defense and repair in the intestinal epithelium, are depleted in human and rodent colitis. The Notch signal pathway regulates the differentiation of intestinal stem cells into epithelial cells and inhibits the differentiation of secretory lineages, including goblet cells. The aim of our study was to clarify whether the blocking of the Notch pathway at an early stage of colitis would preserve goblet cells and facilitate the healing process in dextran sulfate sodium (DSS)-induced colitis in mice. METHODS: DSS was orally administered to C57/BL6 mice for 7 days, and dibenzazepine (DBZ), a Notch pathway blocker, was administered for 5 consecutive days, beginning on the first day of DSS treatment. Colonic mucosal inflammation was evaluated clinically, biochemically, and histologically. The expression of the goblet cell-associated genes Math1 and MUC2 and proinflammatory cytokines was evaluated by real-time reverse-transcriptase-PCR, with the expression of Math1 and MUC2 also visualized by immunohistochemical examination. RESULTS: The administration of DBZ at 4 mumol/kg significantly reduced the severity of the colitis. Compared with the DSS only-treated intestine, the number of goblet cells was relatively sustained, and the expression of Math1 and MUC2 was also elevated in the DSS/DBZ-treated intestine. DBZ treatment suppressed the mRNA levels for interleukin-1beta and -6, and matrix metalloproteinases-3 and -9 in the DSS treated intestine. CONCLUSIONS: Early-stage blocking of Notch signaling may ameliorate acute DSS colitis by preventing reduction in the number of goblet cells. PMID- 20169457 TI - Drought tolerance of juvenile and mature leaves of a deciduous dwarf shrub Vaccinium myrtillus L. in a boreal environment. AB - The difference between drought tolerance of juvenile and mature leaves of the winter-deciduous dwarf shrub bilberry (Vaccinium myrtillus L.) from a northern boreal environment was investigated. It was hypothesised that mature leaves are more drought sensitive than juvenile leaves. Bilberry plants were allowed to dry out by excluding irrigation when leaves were at juvenile and mature stages. Tissue water content decreased at both phenological stages, but the response was more pronounced in the mature leaves. Anthocyanin concentrations increased as the tissue water content decreased, and again this occurred to a greater extent in the mature leaves. Chlorophyll concentrations decreased only marginally at the juvenile stage, while the decrease was significant in the mature leaves. Chlorophyll degradation was enhanced by drought stress. Soluble proteins decreased and protein oxidation increased in the mature leaves, and degradation of oxidised proteins increased in the drought-stressed plants. The results suggest that leaves of bilberry are more sensitive to drought stress at the mature stage, and that drought stress accelerates senescence at the mature stage. The significance of the results is that dry periods during the juvenility of leaves are not as detrimental as they may be later in summer. In addition, the strategy of a winter-deciduous plant is obviously to protect its perennial parts from severe drought by accelerated leaf senescence at the mature stage. Therefore, the deciduous life form may provide an excellent adaptation against drought also in northern ecosystems. The role of anthocyanins in photoprotection under drought stress is also discussed. PMID- 20169458 TI - Efficacy of tin-containing solutions on erosive mineral loss in enamel and dentine in situ. AB - The addition of tin to mouth rinses is, at least in vitro, a promising strategy for symptomatic therapy of dental erosion. The aim of this study was to evaluate the in situ efficacy of an experimental tin-containing fluoride solution on erosive tissue loss in human enamel and dentine. The study was a three-cell (7 days each) crossover design involving eight healthy participants. Samples were mounted on buccal shields of mandibular mouth appliances, which were worn for 24 h except during meals and drinks. Specimens were demineralised extraorally with 0.05 M citric acid (pH 2.3) for 6 * 5 min daily and were treated with test solutions intraorally once per day for 30 s after the first demineralisation. Three solutions were used: placebo (negative control), a commercially available tin- and fluoride-containing (SnF(2)) mouth rinse (positive control, 409 ppm Sn(2+), 250 ppm F(-), pH 4.2) and an experimental solution (pH 4.5) containing 1,900 ppm Sn(2+) (SnCl(2)) and 1,000 ppm F(-) (AmF/NaF). Tissue loss (micrometre) was determined profilometrically. In enamel, tissue loss was 54.8 +/- 8.6 in the placebo, 24.5 +/- 14.4 in the positive control and 9.7 +/- 4.1 in the experimental solution group. The respective values for dentine were 48.5 +/- 13.0 in the placebo, 32.8 +/- 9.6 in the positive control and 26.2 +/- 6.7 in the experimental solution group. The experimental solution was notably effective for enamel but was less effective for dentine. The positive control solution was less effective than the experimental solution; its effects for enamel and dentine were similar. PMID- 20169459 TI - Validity, reliability, and comparison of the WOMAC osteoarthritis index and Lequesne algofunctional index in Turkish patients with hip or knee osteoarthritis. AB - To assess validity and reliability of the Western Ontario and McMaster Universities (WOMAC) osteoarthritis (OA) index and Lequesne algofunctional index in Turkish patients with hip or knee OA and to compare the results of the instruments for these two particular sites of involvement. Two disease-specific instruments: WOMAC LK 3.1 and Lequesne indices were administered to 117 outpatients with OA (44 hip and 73 knee) living in Turkey. These indices were administered twice 7-10 days apart to ensure the test-retest reliability. All patients were asked to reply a generic health-related quality-of-life instrument (Short Form-36, SF-36) and a structured interview assessing demographic and other characteristics. Internal consistency and reliability was evaluated by Cronbach's alpha and intra-class correlation coefficients (ICC). Construct validity was tested by correlating the WOMAC or Lequesne with each other, and also with SF-36 and visual analog scale (VAS). The Cronbach's alphas of the WOMAC and Lequesne subscales were ranged 0.78-0.95 and 0.51-0.85 for hip and 0.78-0.94 and 0.61-0.71 for knee OA, respectively. Test-retest reliability of the WOMAC and Lequesne subscales yielded ICCs of 0.77-0.94 and 0.51-0.85 for hip and 0.80-0.98 and 0.61 0.71 for knee OA, respectively. WOMAC and Lequesne showed moderate-good correlations between comparable subscales of SF-36 (physical functioning and bodily pain) and weak-moderate correlations between VAS. All subscales and total WOMAC had better internal consistency and more satisfactory concurrent validity compared with Lequesne. Our results indicated that WOMAC is a more reliable index for use in Turkish patients with hip or knee OA than Lequesne. PMID- 20169460 TI - Renal cortical necrosis at presentation in a patient with systemic lupus erythematosus: an autopsy case report. AB - Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disorder. Renal involvement has the worst prognosis. However, renal cortical necrosis is extremely unusual in SLE. In this case report, we describe the autopsy findings in a young female patient with SLE presenting with renal failure. At autopsy, there was Libmann-Sacks endocarditis with multiorgan infarcts and renal cortical necrosis. Secondary antiphospholipid antibodies contribute to the cardiac and renal manifestations in SLE. We discuss the incidence and pathogenesis of endocarditis with differential diagnosis for cortical necrosis in a patient of SLE. PMID- 20169461 TI - Is mycophenolate mofetil superior to pulse intravenous cyclophosphamide for induction therapy of proliferative lupus nephritis in Egyptian patients? AB - BACKGROUND: Recent studies have suggested that mycophenolate mofetil (MMF) may offer advantages over intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis. The aim of this study was to evaluate the efficacy of MMF compared with IVC in the induction therapy of proliferative lupus nephritis. METHODS: We randomly assigned 47 patients with newly diagnosed active proliferative lupus nephritis class III or IV to open-label oral MMF 2 g/day for 6 months or intravenous cyclophosphamide 0.5-1 g/m(2) monthly for 6 months in addition to corticosteroids. RESULTS: In the intention-to-treat analysis, 14 of the 24 patients (58.33%) receiving MMF and 12 of the 23 patients receiving cyclophosphamide (52.17%) had remission (P = 0.48); complete remission occurred in 6 of the 24 patients (25%) and 5 of the 23 patients (21.74%), respectively (P = 0.53). Improvements in packed cell volume, the erythrocyte sedimentation rate, anti-double-stranded DNA antibodies titer (anti-dsDNA), serum complement, proteinuria, urinary activity, renal function, serum soluble interleukin-2 receptor alpha concentration and the systemic lupus activity measure score were similar in both groups. Two patients assigned to MMF and another patient assigned to IVC developed end-stage renal failure with commencement of dialysis. Adverse events were similar. Major infections occurred in two patients in each group. There was no difference in gastrointestinal side effects, but more diarrhea occurred in those receiving MMF. CONCLUSION: In this 24-week trial, MMF or IVC combined with corticosteroids demonstrated equal efficacy in inducing remission of proliferative lupus nephritis. PMID- 20169463 TI - Lossy JPEG compression in quantitative angiography: the role of X-ray quantum noise. AB - In medical imaging, contrary to applications in the consumer market, the use of irreversible or lossy compression is still in its beginnings. This is due to the suspected risk of compromising the diagnostic content. Many studies have been performed, but it was not until 2008 that national activities in different countries resulted in recommendations for the safe use of irreversible image compression in clinical practice. Quantitative coronary angiography (QCA), however, poses a special problem, since here a large variation in published maximum compression factors has strengthened the general concerns about the use of lossy techniques. Up to now, the reason for the variation has not been thoroughly investigated. Reasons for the discrepancies in published compression factors are determined in this study. Since JPEG compression reduces the quantum noise of the X-ray images, the impact of compression is overestimated when interpreting any change in local diameter as an error. By taking into consideration the quantitative effect of quantum noise in QCA, it is shown that the influence of JPEG compression can be neglected for compression factors up to ten at clinically applicable X-ray doses. This limit is comparable to that found by visual analysis for aesthetic image quality. Future studies on image compression effects should take the interaction with quantum noise explicitly into consideration. PMID- 20169462 TI - Renal infiltration of immunocompetent cells: cause and effect of sodium-sensitive hypertension. AB - This review examines the participation of immunocompetent cells that accumulate in tubulointerstitial areas of the kidney in the pathogenesis of sodium-sensitive hypertension. Tubulointerstitial inflammation is a universal feature in experimental models of sodium-sensitive hypertension, and the suppression of inflammation and its constant companions, oxidative stress and renal angiotensin II activity, ameliorates or prevents hypertension. Human studies also support the association between renal inflammation and hypertension. The proinflammatory effects of a high sodium diet and the mechanisms by which renal inflammation induces sodium retention are discussed. It is suggested that autoimmune reactivity may play a role in the development and maintenance of renal inflammation in hypertensive states. PMID- 20169464 TI - Is sedation-induced BOLD fMRI low-frequency fluctuation increase mediated by increased motion? AB - OBJECT: Increases in low-frequency fluctuations (LFF, 0.01-0.1 Hz) of BOLD fMRI signal were observed during sedation and sleep. We tested the hypothesis that sedation-induced LFF increases may be mediated by increased head motion likely associated with these brain states. MATERIALS AND METHODS: Twenty healthy volunteers were scanned in resting-state baseline and (15 thereof) in midazolam sedation condition. After standard preprocessing, LFF power was computed from average time series from 14 ROIs representing 5 functional networks (visual, motor, auditory, default mode, dorsal attentional). We assessed the effects of sedation on LFF and indirect effects of head motion (mean relative displacement) using mediation analysis. RESULTS: Sedation increased LFF power with the indirect effect of motion on sedation-induced LFF significant for all networks. Global mean corrected data showed similar but weaker results: significant total effect for auditory, motor and visual; significant mediation for auditory and motor networks. Motion was strongly correlated with LFF even at baseline. Reported results were significant at p < 0.05. CONCLUSION: The study confirms that conscious sedation induces LFF increase, but demonstrates that this effect is mediated by increased head motion. Hence, caution in design and interpretation is recommended for studies comparing subjects or conditions differently predisposing to head motion. PMID- 20169467 TI - Hypersexual disorder: a more cautious approach. PMID- 20169465 TI - Morphologic and functional changes in the unilateral 6-hydroxydopamine lesion rat model for Parkinson's disease discerned with microSPECT and quantitative MRI. AB - OBJECT: In the present study, we aimed to evaluate the impact of neurodegeneration of the nigrostriatal tract in a rodent model of Parkinson's disease on the different MR contrasts (T(2), T(1), CBF and CBV) measured in the striatum. MATERIAL AND METHODS: Animals were injected with 6-hydroxydopamine (6OHDA) in the substantia nigra resulting in massive loss of nigrostriatal neurons and hence dopamine depletion in the ipsilateral striatum. Using 7T MRI imaging, we have quantified T(2), T(1), CBF and CBV in the striata of 6OHDA and control rats. To validate the lesion size, behavioral testing, dopamine transporter muSPECT and tyrosine hydroxylase staining were performed. RESULTS: No significant differences were demonstrated in the absolute MRI values between 6OHDA animals and controls; however, 6OHDA animals showed significant striatal asymmetry for all MRI parameters in contrast to controls. CONCLUSIONS: These PD related asymmetry ratios might be the result of counteracting changes in both intact and affected striatum and allowed us to diagnose PD lesions. As lateralization is known to occur also in PD patients and might be expected in transgenic PD models as well, we propose that MR-derived asymmetry ratios in the striatum might be a useful tool for in vivo phenotyping of animal models of PD. PMID- 20169466 TI - Differences in cognitive distortions between pathological and non-pathological gamblers with preferences for chance or skill games. AB - Cognitive distortions have been thought to play an important role in the development and maintenance of pathological gambling. The present study investigated whether severity of gambling problems and gamblers' preference for chance or skill games were related to two sub-factors of cognitive distortions as measured by the Gamblers Belief Questionnaire: Luck/Perseverance, which reflects an individual's perception that chance is favorable to him/her, and Illusion of Control, which reflects an individual's perception that his/her behavior influences chance occurrences. Participants (N = 166) were recruited from a race track (n = 79), off-course betting facilities (n = 50) and from an online treatment program for problem gamblers (n = 49). Gambling severity was measured by the South Oaks Gambling Screen, and 73 were classified as pathological gamblers whereas 93 were classified as non-pathological gamblers. The present study supports previous proposals that cognitive distortions are core processes related to gambling behavior as pathological gamblers reported more cognitive distortions than did non-pathological gamblers. A preference for skill games was also associated with greater Illusion of Control compared to a preference for chance games. For gamblers preferring skill games there were no differences in Luck/Perseverance or Illusion of Control between pathological and non pathological gamblers. PMID- 20169468 TI - Eye tracking of men's preferences for female breast size and areola pigmentation. AB - Sexual selection via male mate choice has often been implicated in the evolution of permanently enlarged breasts in women. While questionnaire studies have shown that men find female breasts visually attractive, there is very little information about how they make such visual judgments. In this study, we used eye tracking technology to test two hypotheses: (1) that larger breasts should receive the greatest number of visual fixations and longest dwell times, as well as being rated as most attractive; (2) that lightly pigmented areolae, indicative of youth and nubility, should receive most visual attention and be rated as most attractive. Results showed that men rated images with medium-sized or large breasts as significantly more attractive than small breasts. Images with dark and medium areolar pigmentation were rated as more attractive than images with light areolae. However, variations in breast size had no significant effect on eye tracking measures (initial visual fixations, number of fixations, and dwell times). The majority of initial fixations during eye-tracking tests were on the areolae. However, areolar pigmentation did not affect measures of visual attention. While these results demonstrate that cues indicative of female sexual maturity (large breasts and dark areolae) are more attractive to men, patterns of eye movements did not differ based on breast size or areolar pigmentation. We conclude that areolar pigmentation, as well as breast size, plays a significant role in men's judgments of female attractiveness. However, fine-grained measures of men's visual attention to these morphological traits do not correlate, in a simplistic way, with their attractiveness judgments. PMID- 20169469 TI - Sexual dysfunctions and difficulties in denmark: prevalence and associated sociodemographic factors. AB - Sexual dysfunctions and difficulties are common experiences that may impact importantly on the perceived quality of life, but prevalence estimates are highly sensitive to the definitions used. We used questionnaire data for 4415 sexually active Danes aged 16-95 years who participated in a national health and morbidity survey in 2005 to estimate the prevalence of sexual dysfunctions and difficulties and to identify associated sociodemographic factors. Overall, 11% (95% CI, 10 13%) of men and 11% (10-13%) of women reported at least one sexual dysfunction (i.e., a frequent sexual difficulty that was perceived as a problem) in the last year, while another 68% (66-70%) of men and 69% (67-71%) of women reported infrequent or less severe sexual difficulties. Estimated overall frequencies of sexual dysfunctions among men were: premature ejaculation (7%), erectile dysfunction (5%), anorgasmia (2%), and dyspareunia (0.1%); among women: lubrication insufficiency (7%), anorgasmia (6%), dyspareunia (3%), and vaginismus (0.4%). Highest frequencies of sexual dysfunction were seen in men above age 60 years and women below age 30 years or above age 50 years. In logistic regression analysis, indicators of economic hardship in the family were positively associated with sexual dysfunctions, notably among women. In conclusion, while a majority of sexually active adults in Denmark experience sexual difficulties with their partner once in a while, approximately one in nine suffer from frequent sexual difficulties that constitute a threat to their well-being. Sexual dysfunctions seem to be more common among persons who experience economic hardship in the family. PMID- 20169470 TI - Molecular profiling of a 6-hydroxydopamine model of Parkinson's disease. AB - Convection enhanced delivery of 6-hydroxydopamine (6-OHDA) to the rat striatum results in a model of Parkinson's disease. An important feature of this unilateral model is the progressive loss of dopaminergic (DA) neurons over the course of several weeks. To improve the understanding of this model, gene expression changes in the substantia nigra, which contains the DA neuron cell bodies, and the striatum, which contains the DA neuron synaptic terminals, were examined using DNA microarrays. Samples were collected and behavior was analyzed from vehicle and toxin treated animals at 3 days, 1 week, 2 weeks and 4 weeks following 6-OHDA treatment. Tissue DA content was determined and samples from animals which exhibited a substantial depletion of striatal DA were included in the subsequent gene expression analysis. The results of the gene expression analysis indicated that 6-OHDA elicits a vigorous inflammatory response, comprised of several distinct pathways, in the striatum at the earliest time point tested. In contrast, relatively few gene expression changes were observed in the SN at the 3-day time point. In both tissues examined there was evidence for a vigorous inflammatory response at the 1- and 2-week time points, which was substantially diminished by the 4-week time point. Inflammation plays a prominent role in the 6-OHDA model of Parkinson's disease. PMID- 20169471 TI - Proximal and distal determinants of access to health care among Hispanics in El Paso County, Texas. AB - In the United States, having health insurance is an important determinant of health care access and individual health outcomes. Nationwide, a significant proportion of the population does not have health insurance. Hispanics, in particular, are less likely than non-Hispanics to have insurance. A framework was established to examine the relationships between the determinants of insurance coverage and health care affordability in El Paso County, Texas. Data from the 2005 Behavioral Risk Factor Surveillance System were used to examine the relationships described by this framework. The sample included 653 adults, of those 477 self-identified as Hispanic or Latino. In El Paso County, almost half of adult Hispanics lack any type of health insurance coverage, three times the rate of non-Hispanics. Among Hispanics, the lack of health insurance was strongly associated with reduced affordability of health care. Employment status, income, and age were found to have significant associations with insurance coverage and health care affordability. Sex and education level were relevant, yet distal determinants of these outcomes. Ongoing conversations about health care reform should take into account the patterns of coverage within the Hispanic population. Knowing how economic and social factors affect coverage is necessary to inform policy that can effectively alleviate disparities experienced by Hispanics. PMID- 20169472 TI - The COSMIN checklist for assessing the methodological quality of studies on measurement properties of health status measurement instruments: an international Delphi study. AB - BACKGROUND: Aim of the COSMIN study (COnsensus-based Standards for the selection of health status Measurement INstruments) was to develop a consensus-based checklist to evaluate the methodological quality of studies on measurement properties. We present the COSMIN checklist and the agreement of the panel on the items of the checklist. METHODS: A four-round Delphi study was performed with international experts (psychologists, epidemiologists, statisticians and clinicians). Of the 91 invited experts, 57 agreed to participate (63%). Panel members were asked to rate their (dis)agreement with each proposal on a five point scale. Consensus was considered to be reached when at least 67% of the panel members indicated 'agree' or 'strongly agree'. RESULTS: Consensus was reached on the inclusion of the following measurement properties: internal consistency, reliability, measurement error, content validity (including face validity), construct validity (including structural validity, hypotheses testing and cross-cultural validity), criterion validity, responsiveness, and interpretability. The latter was not considered a measurement property. The panel also reached consensus on how these properties should be assessed. CONCLUSIONS: The resulting COSMIN checklist could be useful when selecting a measurement instrument, peer-reviewing a manuscript, designing or reporting a study on measurement properties, or for educational purposes. PMID- 20169473 TI - Intracranial hemorrhage following neuroendovascular procedures with abciximab is associated with high mortality: a multicenter series. AB - BACKGROUND: Abciximab is being used as an adjunct to neuroendovascular procedures both to prevent and treat ischemic sequelae. Experience with abciximab in this setting is limited; major bleeding complications, including fatal intracranial hemorrhage (ICH), are of particular concern. We report our multicenter experience with ICH following the administration of abciximab during neuroendovascular procedures. METHODS: We identified neuroendovascular procedures (including cerebral angiograms, aneurysm coiling procedures, angioplasty/vascular stenting procedures, and emergent revascularization procedures) that used abciximab at Mayo Clinic Hospitals in Rochester, Jacksonville, and Phoenix between November 2000 and April 2009. Cases of periprocedural ICH were identified and pertinent demographic, historical, procedural, radiographic, and laboratory data were collected. Clinical outcome was measured either at death or discharge by the Glasgow Outcome Scale (GOS). RESULTS: Abciximab was used in 51 neuroendovascular procedures; 9 cases of ICH were identified. Procedures performed and indications for abciximab use varied. Route of abciximab administration included IV bolus only (n = 4), IA bolus followed by IV infusion (n = 3), IV bolus followed by IV infusion (n = 1), and IV infusion without preceding bolus (n = 1). All but 1 of the patients received concomitant periprocedural antiplatelet, anticoagulant, or thrombolytic agents. Eight of the 9 cases of ICH were detected within 7 h of abciximab administration. ICH pattern varied. Four patients died following ICH. CONCLUSIONS: Adjunctive use of abciximab to prevent or treat ischemic sequelae during neuroendovascular procedures is associated with a high risk of ICH (18%). We report 9 cases of ICH associated with abciximab administration during neuroendovascular procedures with 44% mortality. PMID- 20169474 TI - Homicidal firearm injuries: a study from Sri Lanka. AB - Stabbing, mechanical asphyxia, blunt head injury and shooting are the most common methods of homicides, with firearm homicides on the increase throughout the world. This study was a retrospective study carried out by the Department of Forensic Medicine, University of Kelaniya, Sri Lanka over a 1 year period on firearm homicides examined at two principal forensic institutions in the western province (Office of the Judicial Medical Officer Colombo and Ragama) of Sri Lanka. During the period of the study (June 2005 to July 2006) 3100 medicolegal autopsies were carried out at these two institutions with 265 representing alleged homicides. Eighty-three cases (31%) were identified as homicides due to fatal firearm injuries. The majority of the victims (N = 76) were young adult males (aged 18-40 years). Almost half of the firearm homicides (47%; N = 39) were associated with previous enmity, while 33% (N = 27) were due to ethnic rebel killings in the North and East. Daylight hours (6.00 a.m. to 6.00 p.m.) were preferred by rebels, while there was no relation to the time of day in the other firearm deaths. The weapon of choice was a rifled firearm (98%). While 70% of war related deaths had one or two fatal shots, either to the head or chest, homicides motivated by personal enmity had multiple wounds, with an average of 5.7 fatal shots per victim. This study demonstrates that firearm homicides in Sri Lanka mainly involve young men, and that when related to armed conflict the fatal injury usually consists of a single shot to the head or chest. PMID- 20169476 TI - Phantom evaluation of a cardiac SPECT/VCT system that uses a common set of solid state detectors for both emission and transmission scans. AB - BACKGROUND: We developed a cardiac SPECT system (X-ACT) with low dose volume CT transmission-based attenuation correction (AC). Three solid-state detectors are configured to form a triple-head system for emission scans and reconfigured to form a 69-cm field-of-view detector arc for transmission scans. A near mono energetic transmission line source is produced from the collimated fluorescence x ray emitted from a lead target when the target is illuminated by a narrow polychromatic x-ray beam from an x-ray tube. Transmission scans can be completed in 1 min with insignificant patient dose (deep dose equivalent <5 muSv). METHODS: We used phantom studies to evaluate (1) the accuracy of the reconstructed attenuation maps, (2) the effect of AC on image uniformity, and (3) the effect of AC on defect contrast (DC). The phantoms we used included an ACR phantom, an anthropomorphic phantom with a uniform cardiac insert, and an anthropomorphic phantom with two defects in the cardiac insert. RESULTS: The reconstructed attenuation coefficient of water at 140 keV was .150 +/- .003/cm in the uniform region of the ACR phantom, .151 +/- .003/cm and .151 +/- .002/cm in the liver and cardiac regions of the anthropomorphic phantom. The ACR phantom images with AC showed correction of the bowing effect due to attenuation in the images without AC (NC). The 17-segment scores of the images of the uniform cardiac insert were 78.3 +/- 6.5 before and 87.9 +/- 3.3 after AC (average +/- standard deviation). The inferior-to-anterior wall ratio and the septal-to-lateral wall ratio were .99 and 1.16 before and 1.02 and 1.00 after AC. The DC of the two defects was .528 and .156 before and .628 and .173 after AC. CONCLUSION: The X-ACT system generated accurate attenuation maps with 1-minute transmission scans. AC improved image quality and uniformity over NC. PMID- 20169475 TI - The early-onset torsion dystonia-associated protein, torsinA, displays molecular chaperone activity in vitro. AB - TorsinA is a member of the AAA+ ATPase family of proteins and, notably, is the only known ATPase localized to the ER lumen. It has been suggested to act as a molecular chaperone, while a mutant form associated with early-onset torsion dystonia, a dominantly inherited movement disorder, appears to result in a net loss of function in vivo. Thus far, no studies have examined the chaperone activity of torsinA in vitro. Here we expressed and purified both wild-type (WT) and mutant torsinA fusion proteins in bacteria and examined their ability to function as molecular chaperones by monitoring suppression of luciferase and citrate synthase (CS) aggregation. We also assessed their ability to hold proteins in an intermediate state for refolding. As measured by light scattering and SDS-PAGE, both WT and mutant torsinA effectively, and similarly, suppressed protein aggregation compared to controls. This function was not further enhanced by the presence of ATP. Further, we found that while neither form of torsinA could protect CS from heat-induced inactivation, they were both able to reactivate luciferase when ATP and rabbit reticulocyte lysate were added. This suggests that torsinA holds luciferase in an intermediate state, which can then be refolded in the presence of other chaperones. These data provide conclusive evidence that torsinA acts as a molecular chaperone in vitro and suggests that early-onset torsion dystonia is likely not a consequence of a loss in torsinA chaperone activity but might be an outcome of insufficient torsinA localization at the ER to manage protein folding or trafficking. PMID- 20169477 TI - Relevance of mytilid shell microtopographies for fouling defence--a global comparison. AB - Prevention of epibiosis is of vital importance for most aquatic organisms, which can have consequences for their ability to invade new areas. Surface microtopography of the shell periostracum has been shown to have antifouling properties for mytilid mussels, and the topography shows regional differences. This article examines whether an optimal shell design exists and evaluates the degree to which shell microstructure is matched with the properties of the local fouling community. Biomimics of four mytilid species from different regional provenances were exposed at eight different sites in both northern and southern hemispheres. Tendencies of the microtopography to both inhibit and facilitate fouling were detected after 3 and 6 weeks of immersion. However, on a global scale, all microtopographies failed to prevent fouling in a consistent manner when exposed to various fouling communities and when decoupled from other shell properties. It is therefore suggested that the recently discovered chemical anti microfouling properties of the periostracum complement the anti-macrofouling defence offered by shell microtopography. PMID- 20169478 TI - Sexuality, gendered identities and exclusion: the deployment of proper (hetero)sexuality within an HIV-prevention text from South Africa. AB - HIV prevention discourses concern lives, the protection of bodily rights and people's active involvement in the policies and programmes that affect them. HIV prevention discourses also create lives, relying upon the deployment of normative sexual identities at the same time as they invite complex and fluid youth identities to embody the norms of prevention. This paper examines a particular HIV prevention text that is available to teachers in the Western Cape province of South Africa to support the implementation of the national Life Orientation programme. Rather than considering this text as a neutral 'scaffold' upon which teachers and students add cultural meanings, it is important to interrogate the ways in which texts rely upon and reiterate particular discursive constructions of the youth sexual subject. This paper argues that the text deploys a particular discursive framework in order to construct a 'normal' (and hetero) sexuality that validates, rather than questions, social constructions of masculine privilege within heterosexuality. This is achieved through the deployment of a scientific expertise of sexuality; the mobilisation of a valued hetero/homosexual binary to create a 'safe' heterosexuality; the normalisation of bourgeois sexuality through the ideology of marriage; and the naturalisation of heterosexual masculine and feminine identities. PMID- 20169479 TI - Contraceptive decision-making in sexual relationships: young men's experiences, attitudes and values. AB - Much attention has been focused on efforts to reduce unintended pregnancy by improving contraceptive use among high-risk women; however, there is limited information to guide interventions to engage young men in contraceptive decision making. We conducted focus groups of young men, aged 19-26, from diverse racial backgrounds from low-income communities in the San Francisco Bay Area to examine social norms about sexual relationships and how they impact on contraceptive use. The data were analysed using content analysis. A range of relationships were described, however casual relationships predominated. While young men expressed strong desires to avoid pregnancy in casual relationships, the unpredictable nature of relationships, together with low communication and regard for the women involved, made stressing consistent contraceptive use among partners unlikely. The themes expressed by these young men about sex and behaviour in different relationships illustrate a spectrum of decision-making dilemmas and illustrate the inherent difficulty in fully engaging young men in contraceptive decision making. A strategy is needed to address relationship values, dynamics and condom use beyond STI-prevention frameworks and young women's ability to make appropriate contraceptive choices in light of the inherent difficulties and uncertainty associated with casual relationships. PMID- 20169480 TI - 'Love of the heart': romantic love among young mothers in Mali. AB - This paper calls attention to an ideal of romantic love among young unmarried mothers in Mali. It demonstrates that romantic love constitutes a motivating force for the agency of young Malian mothers who invest themselves in hopes of romantic outcomes from their relationships. Like the majority of people in Mali, the young mothers in this study dedicated a considerable time each weekday to watching a Venezuelan soap opera, which could be regarded as offering a modern version of Romeo and Juliet. Yet, romance is not the only thing that matters in young mothers' ideals of love. Materiality plays an important role as well. Thus, young mothers have multiple motives for engaging in relationships with men: they seek both romance and material stability, which is why an either love or exchange perspective is insufficient when examining the topic of romantic love in a Malian context. PMID- 20169481 TI - Barriers to post exposure prophylaxis (PEP) completion after rape: a South African qualitative study. AB - Sexual violence and HIV are two serious public health problems in South Africa. Post exposure prophylaxis (PEP) to prevent HIV after rape was introduced into the South African public health services in 2002 but many questions on the completion of PEP medication remain. A qualitative study involving in-depth interviews was conducted with 29 women attending sexual assault services in an urban and a rural site to explore PEP use after rape. It showed how PEP adherence was a complex and challenging experience, with survivors experiencing disruptions in their lives and unable to adhere to the medication adequately. Only nine completed their prescribed drug regimes. Rape stigma and perceptions of rape impacted on adherence, which became a lesser priority if the rape was contested by important others. Being blamed and not receiving social support had profound psychological impact. Stigma of rape and fear of HIV played very powerful roles in debilitating women's ability to take medication to prevent HIV infection. Further research is needed to support the development of interventions that acknowledge the complex barriers to adherence of PEP after rape. PMID- 20169482 TI - Acidic pH as a determinant of TRI gene expression and trichothecene B biosynthesis in Fusarium graminearum. AB - Reducing production of type B trichothecenes by Fusarium graminearum on cereals is necessary to control contamination, prevent yield reduction and protect human and animal health. Thus, an understanding of how trichothecene biosynthesis is induced is essential. The effect of ambient pH on fungal growth, toxin biosynthesis and expression of TRI genes was studied during in vitro liquid culture of F. graminearum on minimal medium. Fungal development stopped at day 3 after a sharp pH drop in the medium. At the same time, induction of TRI gene expression was observed and toxin began accumulating 1 day later. Acidification seems a determinant of induction, as neither the toxin nor the TRI genes were detected when the pH was maintained neutral. Shifting from neutral to acidic pH by mycelium transfer induced TRI gene expression and toxin accumulation. The regulation of toxin production by ambient pH appears to be specific to some TRI genes since TRI5, located in the core FgTRI5 cluster, showed an immediate induction while TRI101, located elsewhere in the genome, showed a more progressive response. The regulation of trichothecene biosynthesis by the ambient pH appears to be a general mechanism, independent of strain or chemotype, as all tested strains, including F. graminearum and F. culmorum species, showed a regulation of toxin production in response to the ambient pH. We conclude that, in vitro, external acidification is required for induction of TRI gene expression. PMID- 20169483 TI - Novel TaqMan real-time polymerase chain reaction assay for verifying the authenticity of meat and commercial meat products from game birds. AB - Species-specific real-time polymerase chain reaction (PCR) assays using TaqMan probes have been developed for verifying the labeling of meat and commercial meat products from game birds, including quail, pheasant, partridge, guinea fowl, pigeon, Eurasian woodcock and song thrush. The method combines the use of species specific primers and TaqMan probes that amplify small fragments (amplicons <150 base pairs) of the mitochondrial 12S rRNA gene, and an endogenous control primer pair that amplifies a 141-bp fragment of the nuclear 18S rRNA gene from eukaryotic DNA. Analysis of experimental raw and heat-treated binary mixtures as well as of commercial meat products from the target species demonstrated the suitability of the assay for the detection of the target DNAs. PMID- 20169484 TI - Validation of an analytical method for the determination of glyceroltriheptanoate (GTH) in processed animal by-products: results of a collaborative study. AB - The performance characteristics of a method for the determination of the marker substance glycerol triheptanoate (GTH) in processed animal by-products (ABPs) based on gas chromatography (GC) coupled to mass spectrometry (MS) were determined via a collaborative study. Within the European Union, GTH needs to be added to the portion of processed ABPs that must not enter the feed and food chain (Categories 1 and 2) at a minimum concentration of 250 mg kg(-1) related to the fat fraction of the test samples analysed. The test materials included in the validation study consisted of three meat and bone meal (MBM) and three fat samples that contained GTH at different concentrations ranging from 61 to 455 mg kg(-1). The relative standard deviation of repeatability (RSD(r)) varied from 3.4 to 7.8% and the relative standard deviation of reproducibility (RSD(R)) varied from 9.0 to 16.5%, corresponding to HORRAT values that were, in all cases, equal or below the critical value of 2.0. The estimated trueness expressed in terms of average concentration compared to the target concentrations of GTH in all test materials varied from 95 to 107%, confirming acceptable values for the trueness of the method. Based on the acceptable values for precision and trueness, the method is fit for the intended purpose and can be used for official control purposes to determine GTH in processed animal by-products from Category 1 and Category 2. PMID- 20169485 TI - Short-term effect of PM(2.5) on daily hospital admissions in Madrid (2003-2005). AB - The aim of this paper was to analyse the effect of particulate matter PM(2.5), a recent air quality guideline value for the protection of health, on hospital admissions in Madrid, Spain. This dependent variable was used as a measure against the daily number of emergency hospital admissions from 2003-2005. The causes analysed were: all causes, respiratory and circulatory. The independent variables were daily records of PM(2.5), PM(10), NO(2), NO(x), SO(2) and O(3). Seasonalities, trend, flu epidemics, noise and pollen were used as control variables. Poisson Regression Models were performed to calculate the Relative Risk (RR) and the Attributable Risk (AR). The function relationship with hospital admissions was linear and without threshold. The RR for an increase of 25 microg/m(3) in PM(2.5) concentrations was 1.07 IC 95% (1.05 1.09) for all causes; for circulatory was 1.08 IC 95%: (1.03 1.13) and for respiratory was 1.07 IC 95% (1.02 1.11). PM(2.5) concentrations were the only primary pollutant that showed a statistical association with hospital admissions in Madrid. PMID- 20169486 TI - Improvement of the air quality in student health centers with chlorine dioxide. AB - This study aims to monitor bioaerosol levels of a local campus of a student health center in Taiwan and then to perform disinfection by applying chlorine dioxide. First, air samples were taken and evaluated in the six areas of the center. The average background bioaerosol levels were 714 +/- 1706 CFU/m(3) for bacterium and 802 +/- 633 CFU/m(3) for fungi. Then, chlorine dioxide was applied through three different procedures: single, multiple and regular disinfections. The results indicated that both multiple and regular disinfections can achieve efficiency levels higher than 59.0%. The regression analysis on bioaerosol levels showed that the number of people present correlating to the number of persons entering the room per door-opening, had a correlation of p < 0.05. Utilizing this analysis result, an empirical model was developed to predict indoor bioaerosol concentrations. It can be inferred that for indoor human activity of health centers, regular disinfection is a very effective process. PMID- 20169487 TI - Seven challenges for the future of occupational safety and health. PMID- 20169489 TI - An accurate substitution method for analyzing censored data. AB - When analyzing censored datasets, where one or more measurements are below the limit of detection (LOD), the maximum likelihood estimation (MLE) method is often considered the gold standard for estimating the GM and GSD of the underlying exposure profile. A new and relatively simple substitution method, called beta substitution, is presented and compared with the MLE method and the common substitution methods (LOD/2 and LOD/square root(2) substitution) when analyzing a left-censored dataset with either single or multiple censoring points. A computer program was used to generate censored exposure datasets for various combinations of true geometric standard deviation (1.2 to 4), percent censoring (1% to 50%), and sample size (5 to 19 and 20 to 100). Each method was used to estimate four parameters of the lognormal distribution: (1) the geometric mean, GM; (2) geometric standard deviation, GSD; (3) 95th percentile, and (4) Mean for the censored datasets. When estimating the GM and GSD, the bias and root mean square error (rMSE) for the beta-substitution method closely matched those for the MLE method, differing by only a small amount, which decreased with increasing sample size. When estimating the Mean and 95th percentile the beta-substitution method bias results closely matched or bettered those for the MLE method. In addition, the overall imprecision, as indicated by the rMSE, was similar to that of the MLE method when estimating the GM, GSD, 95th percentile, and Mean. The bias for the common substitution methods was highly variable, depending strongly on the range of GSD values. The beta-substitution method produced results comparable to the MLE method and is considerably easier to calculate, making it an attractive alternative. In terms of bias it is clearly superior to the commonly used LOD/2 and LOD/square root(2) substitution methods. The rMSE results for the two substitution methods were often comparable to rMSE results for the MLE method, but the substitution methods were often considerably biased. PMID- 20169491 TI - 18-year experience in the management of men with a complaint of a small penis. AB - In many cultures, the erect penis has been a symbol of masculine qualities. Because of this symbolism, a penis that is less than average size can cause insecurity or embarrassment. This series reports the authors' 18-year experience in the management of 60 men with a complaint of a small penis. For 44 of these 60 men, counseling was sufficient; the other 16 had surgery, and of these, 9 were satisfied with the result. Despite limitations, the authors conclude that those men who already achieve a penis length of no less than 7.5 cm (2.95 in) in erection, have only limited benefit from penis-enhancing surgery. This particular patient category should therefore be dissuaded from surgery. PMID- 20169490 TI - Laboratory evaluation to reduce respirable crystalline silica dust when cutting concrete roofing tiles using a masonry saw. AB - Respirable crystalline silica dust exposure in residential roofers is a recognized hazard resulting from cutting concrete roofing tiles. Roofers cutting tiles using masonry saws can be exposed to high concentrations of respirable dust. Silica exposures remain a serious threat for nearly two million U.S. construction workers. Although it is well established that respiratory diseases associated with exposure to silica dust are preventable, they continue to occur and cause disability or death. The effectiveness of both a commercially available local exhaust ventilation (LEV) system and a water suppression system in reducing silica dust was evaluated separately. The LEV system exhausted 0.24, 0.13, or 0.12 m(3)/sec of dust laden air, while the water suppression system supplied 0.13, 0.06, 0.03, or 0.02 L/sec of water to the saw blade. Using a randomized block design, implemented under laboratory conditions, the aforementioned conditions were evaluated independently on two types of concrete roofing tiles (s shape and flat) using the same saw and blade. Each engineering control (LEV or water suppression) was replicated eight times, or four times for each type of tile. Analysis of variance was performed by comparing the mean airborne respirable dust concentrations generated during each run and engineering control treatment. The use of water controls and ventilation controls compared with the "no control" treatment resulted in a statistically significant (p < 0.05) reduction of mean respirable dust concentrations generated per tile cut. The percent reduction for respirable dust concentrations was 99% for the water control and 91% for the LEV. Results suggest that water is an effective method for reducing crystalline silica exposures. However, water damage potential, surface discolorations, cleanup, slip hazards, and other requirements may make the use of water problematic in many situations. Concerns with implementing an LEV system to control silica dust exposures include sufficient capture velocity, additional weight of the saw with the LEV system, electricity connections, and cost of air handling unit. PMID- 20169492 TI - Penile enlargement: from medication to surgery. AB - Penis lengthening pills, stretch apparatus, vacuum pumps, silicone injections, and lengthening and thickening operations are available for men who worry about their penis size. Surgery is thus far the only proven scientific method for penile enlargement. In this article, we consider patient selection, outcome evaluation, and techniques applied. In our view, sexological counseling and detailed explanation of risks and complications are mandatory before any operative intervention. PMID- 20169493 TI - Sexual initiative and intercourse behavior during pregnancy among brazilian women: a retrospective study. AB - Sexual behavior may be altered during pregnancy. The authors aimed to investigate the behavior of pregnant women in terms of level of sexual initiative and change in sexual positions for intercourse. The authors conducted a retrospective research with 156 pregnant Brazilian women who completed a questionnaire. Before pregnancy, both partners usually initiated sex, whereas during pregnancy, the male partner generally did. In general, women who took the sexual initiative showed better scores in the sexuality variables. During pregnancy, the use of each sexual position reduced significantly. Couples in which both partners take the sexual initiative tend to accept a wider variety of sexual positions. PMID- 20169494 TI - Emotional dysregulation: concurrent relation to sexual problems among trauma exposed adult cigarette smokers. AB - Despite the documented association between trauma exposure and sexual problems (sexual dissatisfaction and sexual functioning), only a paucity of studies have investigated possible mechanisms underlying this association. The present study tested the role of emotion dysregulation in regard to levels of sexual dissatisfaction and functioning among a sample of 43 trauma-exposed cigarette smokers (17 women; M(age) = 20.20, SD = 10.87). When controlling for negative affectivity, type of trauma (sexual vs. nonsexual), daily smoking rate, posttraumatic stress symptoms, and anxiety sensitivity, emotion dysregulation provided an independent and unique contribution to sexual dissatisfaction but not to sexual function. These preliminary findings suggest that emotion dysregulation may be more important to understanding certain sexual problems (dissatisfaction) among cigarette-smoking trauma survivors than previously recognized, and this topic is, therefore, worthy of further investigation. PMID- 20169495 TI - The unique needs of couples experiencing androgen deprivation therapy for prostate cancer. AB - Androgen deprivation therapy (ADT) is being increasingly used to treat men with prostate cancer. ADT has been associated with many side effects that may persist for the lifetime of the patient and can have potentially devastating effects on the quality of life of both men and their intimate relationships. Despite U.S. estimates that more than 40,000 men begin ADT each year and live on average for 10 years, there have been few studies examining the effect of ADT on couples. This article reviews the emerging literature on the challenges faced by men and their partners while undergoing ADT. Loss of libido, erectile dysfunction, genital shrinkage, low self-esteem, and diminished masculinity are commonly associated with undergoing ADT. These losses frequently lead to changes in the marital relationship in areas such as roles and responsibilities, communication, and intimacy. Intervention strategies for helping couples maintain a strong relational bond need to be selected carefully for this population because of these unique and profound changes. Couples who succeed in maintaining sexuality and intimacy have been shown to have higher quality of life and more satisfying relationships. PMID- 20169496 TI - Sexual dysfunction treatment in a patient with mullerian agenesy submitted to neovaginoplasty: a case report. AB - Vagina agenesis is a rare entity. Mayer-Rokitansky-Kuster-Hauser syndrome is the most significant cause of vagina agenesis, whereas the second most common cause is complete androgen syndrome. Surgical treatment can propitiate a vaginal reconstruction, but sexual function depends on several factors that affect sexual performance. Many reports focus on the intraoperative and postoperative results and only describe the global approach to these patients, but reports focusing on the management of these patients to enable them to have a normal sexual life are lacking. This case report highlights a multidisciplinary treatment for this kind of morbidity and emphasizes the necessity of incorporating careful attention to sexual health in the treatment of these patients so that they may achieve a good therapeutic response, resulting in a pleasurable sexual life and a good quality of living. PMID- 20169500 TI - The effect of investigator gender on lateral tympanic membrane temperature. AB - The measurement of tympanic membrane temperature (TMT) using hand-held infrared devices is common in both clinical and experimental research. However, the role that measurement context has on TMT has been overlooked. In the present investigation 94 women and men had their right and left TMT measured by either a male or female investigator. Regardless of participant's gender, when measured by a female investigator the right TMT was significantly lower than the left TMT. When measured by a male investigator, both male and female participants had similar right and left TMT. These lateral TMT results correspond with neuropsychological theories regarding threat appraisal. PMID- 20169501 TI - Grapheme-colour synaesthesia yields an ordinary rather than extraordinary memory advantage: evidence from a group study. AB - In synaesthesia, the input of one sensory modality automatically triggers an additional experience, not normally triggered by the input of that modality. Therefore, compared to non-synaesthetes, additional experiences exist and these may be used as retrieval cues when memory is tested. Previous case studies have suggested that synaesthesia may yield even extraordinary memory abilities. However, group studies found either a task-specific memory advantage or no performance advantage at all. The aim of the present study was to test whether grapheme-colour synaesthesia gives rise to a general memory benefit using a standardised memory test (Wechsler Memory Scale). The synaesthetes showed a performance advantage in episodic memory tests, but not in short-term memory tests. However, performance was still within the ordinary range. The results support the hypothesis that synaesthesia provides for a richer world of experience and as a consequence additional retrieval cues may be available and beneficial but not to the point of extraordinary memory ability. PMID- 20169502 TI - Pregnane glycoside from Hemidesmus indicus as a potential anti-oxidant and anti dyslipidemic agent. AB - A new pregnane glycoside hindicusine (1) was isolated from the CHCl(3)-EtOH (3 : 2) extract of Hemidesmus indicus, whose structure was established on the basis of spectroscopic studies. The glycoside (1) and its acetylated derivative (5) were evaluated for their anti-oxidant and anti-dyslipidemic activities. PMID- 20169503 TI - Effects of naturalistic stressors on cognitive flexibility and working memory task performance. AB - Experimental stressors impair performance on tasks requiring certain types of cognitive flexibility, an effect that may be mediated by the noradrenergic system. The goal of this experiment was to examine the effects of psychological stress on cognitive flexibility in problem solving and immediate memory with a more naturalistic psychological stressor, and examine the interaction between subject ability and the cognitive effects of psychological stress. Twenty subjects performed the compound remote associates task (CRA) and a number series recall task after watching the first 30 minutes of 'Saving Private Ryan' and after the first 30 minutes of 'Shrek', with condition order and test version order counterbalanced. An interaction effect was observed between stress and subject ability for the CRA, with performance on the CRA significantly worse after the stress film among those performing well on the task. No effects were found on the memory task. Therefore, the naturalistic stressor impairs cognitive flexibility in a manner dependent upon how much difficulty the subject has with these types of tasks. Further work will be necessary to better understand the pharmacological mechanism of the effects of these types of stressors, and the clinical implications of this effect. PMID- 20169504 TI - Exploring motor system contributions to the perception of social information: Evidence from EEG activity in the mu/alpha frequency range. AB - Putative contributions of a human mirror neuron system (hMNS) to the perception of social information have been assessed by measuring the suppression of EEG oscillations in the mu/alpha (8-12 Hz), beta (15-25 Hz) and low-gamma (25-25 Hz) ranges while participants processed social information revealed by point-light displays of human motion. Identical dynamic displays were presented and participants were instructed to distinguish the intention, the emotion, or the gender of a moving image of a person, while they performed an adapted odd-ball task. Relative to a baseline presenting a nonbiological but meaningful motion display, all three biological motion conditions reduced the EEG amplitude in the mu/alpha and beta ranges, but not in the low-gamma range. Suppression was larger in the intention than in the emotion and gender conditions, with no difference between the latter two. Moreover, the suppression in the intention condition was negatively correlated with an accepted measure of empathy (EQ), revealing that participants high in empathy scores manifested less suppression. For intention and emotion the suppression was larger at occipital than at central sites, suggesting that factors other than motor system were in play while processing social information embedded in the motion of point-light displays. PMID- 20169505 TI - Trial after trial: general processing consequences as a function of repetition and change in multidimensional sound. AB - While there are pointers relating to the consequences of repetition, a general framework regarding the cognitive implications of processing multidimensional stimuli as a function of previous stimulus history is currently lacking. Three experiments using sounds varying in location and pitch were carried out, in which the immediate consequences of repeating or changing task-relevant and task irrelevant attributes were orthogonally examined. A consistent pattern of data was shown, in that the magnitude of selective attention failure was larger when the task-relevant value repeated across trials, while differences between dimensions were larger when the task-relevant value changed across trials. These effects of irrelevance and dimension as a function of intertrial contingency are summarized in a model depicting the dynamic allocation of processing resource. PMID- 20169507 TI - Farewell to 2009! PMID- 20169508 TI - Identification, pathogenesis, and treatment of factor inhibitors. PMID- 20169509 TI - The multifactorial etiology of inhibitor development in hemophilia: genetics and environment. AB - The most important complication in the treatment of hemophilia A patients today is the development of inhibitory antibodies against infused factor VIII (FVIII). Inhibitor development is caused by a complex interplay between both genetic and environmental factors. The risk of developing inhibitors is greatest in previously untreated patients with severe hemophilia A. Several genetic factors, such as a positive family history of inhibitors, ethnicity, FVIII genotype, and certain polymorphisms in immune modulatory genes, are associated with the risk of inhibitor development. Treatment-related factors, such as intensive treatment with FVIII for bleeds or surgery, are associated with a higher inhibitor risk. However, regular prophylaxis seems to have a protective effect on inhibitor development. Knowledge about the risk factors of inhibitor development is a condition for predicting and in the future possibly even preventing the development of inhibitors in patients with severe hemophilia A. This review summarizes the current knowledge on the potential risk factors of inhibitor development. At present, many uncertainties still remain that will require collaborative investigation. PMID- 20169510 TI - Inhibitors in hemophilia A: advances in elucidation of inhibitory mechanisms and in inhibitor management with bypassing agents. AB - Development of inhibitory antibodies (inhibitors) to factor VIII (FVIII) is the most serious adverse event in replacement therapy of hemophilia A patients. The etiology and management of this condition remain major challenges for both researchers and clinicians. In the present review, we discuss recent advances in understanding the molecular mechanisms by which inhibitors inactivate FVIII and experimental approaches used for the mapping of inhibitor epitopes. We also present a comparative analysis of treatment of hemophilia A patients with inhibitors with currently available bypassing agents-activated prothrombin complex concentrate (FEIBA VH; Baxter Healthcare Corp., Westlake Village, CA) and recombinant activated factor VII (NovoSeven; Novo Nordisk, Princeton, NJ)-and describe some ongoing research programs aimed at developing new treatment options for these patients. Availability of sensitive and standardized laboratory assays that would assist in monitoring the effectiveness of bypass therapies is essential for designing customized treatment regimens and improvement in the management of health conditions of hemophilia patients with inhibitors. PMID- 20169511 TI - Improvements in factor VIII inhibitor detection: From Bethesda to Nijmegen. AB - All methods for the detection of factor VIII (FVIII) inhibitors are based on the measurement of inactivation of FVIII in a mixture of the test plasma containing the putative inhibitor and an exogenous source of FVIII. Various types of assays have been developed since the first inhibitor was described in 1941. Nowadays, two methods are preferably used, the Bethesda assay and the Nijmegen assay. Although the Nijmegen assay shows a better specificity and intra- and interlaboratory variation, it is still hampered by several limitations related to assay characteristics (pH, temperature, and time of incubation), type of control sample, and the von Willebrand factor content of the assay mixture. Epitope specificity plays an important role in the reliability of functional assays because inhibitors against the C2 domain are more difficult to quantify compared with inhibitors against the A2 domain. Finally, lupus anticoagulants can interfere with inhibitor assays, resulting in aberrant results. This report describes in detail the various problems encountered with the assays used in the quantification of functional FVIII inhibitors. PMID- 20169512 TI - Laboratory identification of factor inhibitors: the perspective of a large tertiary hemophilia center. AB - Coagulation factor inhibitors are antibodies that bind and neutralize specific procoagulant plasma proteins. The identification of coagulation factor inhibitors by the hemostasis laboratory requires a careful and systematic approach that excludes other possible causes of prolonged screening tests such as the activated partial thromboplastin time and prothrombin time. Once the laboratory is confident that a specific coagulation factor inhibitor is present in a sample, its strength or titer must be measured. The clinician will use this information as a treatment guide. The most frequently occurring factor inhibitors encountered in the hemostasis laboratory are those directed against factor VIII (FVIII), which can arise in individuals with inherited hemophilia A as an immune response to factor replacement therapy or as an autoantibody leading to the condition of acquired hemophilia A. The Bethesda assay is the most widely used test for measuring the FVIII inhibitor titer. The Bethesda assay has several components that must be carefully controlled to achieve consistent results. This overview examines the behavior of various coagulation inhibitors and laboratory tests with an emphasis on the Bethesda assay for factor inhibitors. PMID- 20169513 TI - Twelve years of experience of acquired hemophilia A: trials and tribulations in South Australia. AB - Acquired hemophilia A (AH) is a rare and serious acquired bleeding disorder where prompt and correct diagnosis is crucial, and immune suppression is often required for factor VIII (FVIII) autoantibody eradication. The acquired FVIII deficiency usually manifests as bruises and bleeding, and treatment such as FVIII has limited efficacy because of the neutralizing FVIII inhibitor. Expensive bypassing agents such as recombinant activated factor VII (rFVIIa) may be required to treat clinically significant bleeding. This report summarizes the experience related to AH from a large Australian hemophilia center based in South Australia. We identified 25 patients retrospectively over 12 years (1997 to 2008) and reviewed diagnostic features, treatment for bleeds and to eradicate the autoantibody, treatment response, and survival outcomes. The incidence in South Australia was 1.20 cases per million/year with a median age of 78 years with an approximately equivalent sex ratio (12 males versus 13 females); median FVIII and inhibitor titer were 2.5 IU/dL and 11.0 BU/mL, respectively. Twenty-four patients were evaluated further. Thirteen patients (54%) required hemostatic agents, and rFVIIa was used in seven for major bleeds, of which four were limb or life threatening. Eighteen patients were treated by hematologists with immune suppression, and combination steroid and azathioprine was used most commonly to eradicate autoantibody; 15 of these 18 achieved remission (i.e., 83% response rate). Two patients had persistent low-titer inhibitor when treatments were withdrawn, and one died of a fatal bleed shortly after starting treatment. One had spontaneous remission. Five patients (33%) relapsed, three in less than 6 months after starting treatment; all were retreated successfully. Rituximab was used in six patients for high-titer inhibitor, second relapse, two life-threatening bleeds, underlying lymphoma, and steroid intolerance, respectively. Overall mortality was 25% ( N = 6), five of whom were not treated. Advanced age and lack of treatment were predictive of poor survival outcomes. The very elderly (>75 years of age) may warrant a different treatment modality such as rituximab, which is potentially more tolerable and efficacious. PMID- 20169514 TI - Interlaboratory variation in factor VIII:C inhibitor assay results is sufficient to influence patient management: data from the UK national quality external assessment scheme for blood coagulation. AB - We report the results of external quality assessment exercises in which 60 to 120 centers performed factor VIII (FVIII) inhibitor testing on a series of samples over a 13-year period. Samples from seven different subjects were distributed for analysis comprising the following: four different subjects with severe hemophilia A with antibodies following replacement therapy, one subject with acquired hemophilia A and antibodies to FVIII, one subject with normal FVIII and an easily detected lupus anticoagulant, and one subject with mild hemophilia A and a difficult-to-detect lupus anticoagulant but without antibodies to FVIII. In all of the surveys the results obtained in different centers analyzing the same sample varied to an extent that would influence patient management decisions. In the UK National External Quality Assessment Scheme surveys reported here, there was considerable interlaboratory variation in the results of FVIII inhibitor testing that did not improve over the survey period. The coefficient of variation of results in different centers was between 33% and 106% in samples from patients with severe congenital hemophilia A. In some cases, results were affected by assay components. For one plasma, the mean FVIII inhibitor results in centers using one source of normal plasma was 3.9 Bethesda unit (BU)/mL compared with a mean of 5.7 BU/mL in centers using a different normal plasma source ( P = 0.04). Our data indicate that the detection of FVIII inhibitors is not the same in different centers, and the degree of variability noted makes it likely that assay variability has contributed to the lack of international consensus in relation to the real incidence of FVIII inhibitors in different clinical settings. Improvements in assay standardization are urgently needed. PMID- 20169515 TI - The between-laboratory variation of factor VIII inhibitor testing: the experience of the external quality assessment program of the ECAT foundation. AB - The detection and quantification of factor VIII (FVIII) inhibitors is clinically important both for the identification of hemophilia A patients with inhibitors and for the management of immune tolerance treatment. Only limited data are available on the between-laboratory variation of FVIII inhibitor testing. This report describes the evaluation of the results of the large-scale external quality assessment program of the European Concerted Action on Thrombosis Foundation. This study includes the results of six different surveys for the period 2006 to 2008 with 100 to 170 participating laboratories. The overall between-laboratory variation ranged from 28% to 52% with a slightly lower variation for the Nijmegen assay (approximately 39%) on average than for the Bethesda assay (approximately 45%). The use of buffered normal pooled plasma as FVIII source showed better performance compared with the use of nonbuffered pooled plasma; likewise the use of FVIII-deficient plasma compared with the use of imidazole buffer. However, the combination of both was essential for lowest between-laboratory variation. The Nijmegen assay also showed better performance with respect to specificity and sensitivity than the Bethesda assay, although the results for neither were entirely satisfactory. In general, it can be concluded that the measurement of FVIII inhibitory antibodies with the Nijmegen assay should be favored over the use of the Bethesda assay. However, further improvement of the laboratory test for FVIII inhibitors is urgently needed. PMID- 20169516 TI - Investigations from external quality assurance programs reveal a high degree of variation in the laboratory identification of coagulation factor inhibitors. AB - The laboratory has a key role in the initial detection of factor inhibitors and an ongoing role in the measurement of inhibitor titers during the course of inhibitor eradication therapy. The most commonly seen factor inhibitors are those directed against factor VIII (FVIII), usually detected either with the original or the Nijmegen-modified Bethesda assay. In addition, several circumstances can arise in which the laboratory may test samples that potentially reflect false identification of factor inhibitors. These include lupus anticoagulants and other events generally related to preanalytical variables, including incorrect sample presentations. This article reviews each of these elements, largely from the perspective of cross-laboratory studies undertaken within the framework of external quality assurance (EQA), a peer-laboratory process that aims to assess the ongoing performance of groups of similar laboratories. This review details the experience of the Royal College of Pathologists of Australasia Haematology Quality Assurance Program, and it also reflects on the experience of other EQA organizations. Our analysis reveals a wide variety of test practice among inhibitor testing laboratories, a wide variation in detected inhibitor levels in cross-tested samples, and substantial evidence of false-positive and false negative detection of factor inhibitors. These findings hold some significance for the clinical management of patients affected by these inhibitors. There is still much need for standardization and improvement in factor inhibitor detection, and we hope that this report provides a basis for future improvements in this area. PMID- 20169518 TI - Prophylaxis in congenital hemophilia with inhibitors: the role of recombinant activated factor VII. AB - The development of inhibitors against therapeutically administered factors VIII or IX is actually the most challenging complication of hemophilia patients with inhibitors. The introduction of bypassing agents (i.e., activated prothrombin complex concentrates and recombinant activated factor VII [rFVIIa]) has dramatically improved the management of bleeding episodes in such patients. Over the last decade, there have been increasing reports on the ability of bypassing agents to prevent surgical, joint, or other bleeds in inhibitor patients. The published data on the use of rFVIIa as a prophylactic treatment in hemophilia patients with inhibitors are reviewed in this article. PMID- 20169517 TI - Recent improvements in the clinical treatment of coagulation factor inhibitors. AB - The mainstay of therapy in patients with congenital hemophilia is factor replacement. However, the development of inhibitors in these patients is a major complication that represents an important challenge in hemophilia care. Development of inhibitors complicates the clinical course of severe hemophilia in up to 30% of patients with hemophilia A and up to 5% of patients with hemophilia B. Although the main short-term objective of the treatment of alloantibodies against factors VIIII and IX is to control the bleeding diathesis, the eradication of the inhibitor is the leading long-term goal. The management of severe bleeding episodes and the definitive eradication of the autoantibody are also the two main options of the clinical management of patients with acquired hemophilia, a rare but life-threatening hemorrhagic condition. The most recent options available for treating patients with acquired hemophilia and congenital hemophilia with inhibitors are addressed in this review. PMID- 20169519 TI - Management of hemophilia in patients with inhibitors: the perspective from developing countries. AB - Data are limited on inhibitors in people with hemophilia (PWH) in developing countries. There is a perception that the overall prevalence of inhibitors, ranging from 7 to 19% in different reports, may be lower in these countries as compared with that reported from developed countries. This is possible given the fact that most patients are treated after 2 years of age with plasma-derived clotting factor concentrates. Whether genetic or other environmental factors also contribute to this needs further evaluation. There is a need to develop laboratory infrastructure and establish quality control programs for laboratory tests for inhibitors in developing countries. Management options vary widely given the socioeconomic diversity among these countries. Significant individualization of approach to management is therefore required depending on the available resources, particularly with regard to the use of bypassing agents. The limited data on immune tolerance induction with some low-dose regimens deserve further evaluation. Even in resource-constrained environments, education and a policy of systematic screening of patients associated with judicious use of bypassing agents can significantly improve the care of PWH who develop inhibitors. PMID- 20169520 TI - [Europe]. PMID- 20169521 TI - [An adult diagnosed situs anomaly--a (not so rare?) surprise finding]. PMID- 20169522 TI - [Interventional management of a rare complication in radiofrequency ablation of an osteosclerotic bone metastasis]. PMID- 20169523 TI - Pseudoaneurysm of splenic artery ruptured in pancreatic pseudocyst and complicated by wirsungorrhagia: the role of the ultrasound techniques and contrast substances. PMID- 20169524 TI - Effect of low-dose FK506 after contralateral C7 transfer to the musculocutaneous nerve: a study in rats. AB - The purpose of this study in rats was to identify whether a minimal dose of FK506 could enhance nerve regeneration along a 4-cm cross-chest saphenous nerve graft. Our center established a cross-chest nerve regeneration model previously using the contralateral C7 root transfer to the musculocutaneous nerve. Using this model, 10 adult male Sprague-Dawley rats were divided into two groups: group 1 (N = 5) consisted of animals that did not receive any further treatment, and group 2 (N = 5) consisted of animals that received a daily subcutaneous dose of 0.7 mg/kg FK506 for a period of 4 weeks. Evaluation methods of the study groups consisted of behavioral assessment, needle electromyography studies, and qualitative and quantitative morphometry. In the FK506 group, the middle of the graft and the musculocutaneous nerve contained larger axons and thicker myelin, bicep muscle weight recovered to an average of 68% of the normal (right) side, and overall behavioral results were better (P = 0.03175) than for untreated controls. Although the FK506 group achieved higher average myelinated fiber counts in all histologic sections, higher amplitude, and shorter latency results, there was no statistically significant difference between the two groups. Contralateral C7 transfer in the rat brachial plexus is a good experimental model to assess nerve regeneration and test treatments designed to enhance recovery in lesions with long nerve gaps (40 mm). FK506-treated animals demonstrated more advanced axonal regeneration, myelinated fiber maturation, and bicep muscle reinnervation. These results suggest a potential clinical use of low-dose FK506 in patients with severe nerve injuries. PMID- 20169525 TI - Various modifications to internal mammary vessel anastomosis in breast reconstruction with deep inferior epigastric perforator flap. AB - Free autologous tissue transfer has been used in mastectomized patients for high quality reconstruction. Since the deep inferior epigastric perforator flap was developed, it has been considered preferable owing to reduced donor site morbidity. At our institution, anastomosis of internal mammary vessels has been top priority because of better positioning and shorter pedicle length. We publish our experiences with various technical modifications that assure internal mammary vessel anastomosis. From 2003 to 2008, 35 patients received free deep inferior epigastric perforator flap for breast reconstruction by anastomosis with internal mammary vessels. Twenty-nine reconstructions were done immediately upon mastectomy whereas six were delayed. The patterns of anastomosis between the flap pedicle and internal mammary vessel were categorized and the results were followed by flap survival and complications. These deep inferior epigastric perforator flaps were all supplied by a single pedicle artery. Twenty-five of them were drained by a single pedicle vein, and the venous anastomosis pattern was end to end to the single internal mammary vein (IMV) (type I, N = 25). However, the other nine flaps were drained by one pedicle vein anastomosed end to end to double IMV (type II, N = 2), end to end to both proximal and distal ends of single IMV (type III, N = 5), end to end and end to side to single IMV (type IV, N = 2), and end to end to single IMV without anastomosing the other (type V, N = 1). All flaps were successful, except in one patient with type I anastomosis who received vascular reexploration due to pedicle twisting. Another patient with type I anastomosis needed revision due to partial fat necrosis of the flap. No other complications were found. Various modifications of internal mammary vessel anastomosis can be used to ensure the safety of deep inferior epigastric perforator flap in breast reconstruction. PMID- 20169526 TI - Reconstruction of an external hemipelvectomy defect with a two-stage fillet of leg-free flap. AB - The defect created by external hemipelvectomy for bone and soft tissue tumor resection is a challenge to reconstruct because of the exposure of bone, neurovascular structures, and peritoneal contents, particularly in the setting of previous radiotherapy. In a nonsalvageable limb with extensive tumor involvement and radiation damage, a free fillet of leg flap can be used to provide the necessary large volume of tissue for reconstruction without donor site morbidity. Because of the lengthy operative time for the hemipelvectomy procedure, the fillet of leg flap may be subject to long ischemia time and a subsequently compromised outcome. A two-stage fillet of leg flap for a hemipelvectomy defect was performed with two goals: to decrease ischemia time and to allow the necessary resuscitation of the patient between operative stages. Stage one was dissection of a lower fillet of leg flap, transfer and anastomosis to the contralateral femoral vessels, and temporary inset in the groin. The patient and flap were observed in the intensive care unit for several days. The patient returned to the operating room 3 days later for staged external hemipelvectomy and inset of the viable fillet of leg flap. Throughout follow-up, the reconstructive results and functional outcome were excellent. PMID- 20169527 TI - The sGAP flap: rare exception or second choice in autologous breast reconstruction? AB - Various flaps are available for autologous breast reconstruction. However, there is no accepted standard. The superior gluteal artery perforator (sGAP) flap is one possible option for autologous breast reconstruction. Eighty-one sGAP flaps were performed for breast reconstruction. Patient data regarding age, body mass index, medical history, timing of reconstruction, operating time, success of the operation, and complications were retrospectively analyzed. The success rate was 93% ( N = 75). Thrombosis occurred in nine flaps, and three revisions were successful. There was no partial necrosis. All but one bilateral breast reconstruction was performed in two stages. The average time between the reconstructions was 3 and 5 months (2 to 6). The average operating time was 7 hours 36 minutes (5'45 to 9'33). For autologous breast reconstruction, there is no universally accepted standard and no flap meets all the requirements. The deep inferior epigastric perforator flap is our first choice. We favor the sGAP as a second choice particularly for larger breast sizes. For a staged bilateral reconstruction, the sGAP flap advances to be our first choice. The sGAP flap is a safe and reliable perforator flap providing a good breast projection, cosmetically pleasing outcome on the breast, and an acceptable outcome on the buttock with the disadvantage of a demanding dissection. PMID- 20169528 TI - [Introduction of the electronic health card in Germany: influence of interest positions and sector membership on the establishment of an implementation network]. AB - This article raises the question as to which mode of governance has been established for the implementation of the electronic health card (eHC) in Germany and which coordination problems have emerged. It will be shown that the amalgamation of two different policy domains - namely health-care and innovation policy - leads to a novel governance configuration in which information exchange (hence governance) is affected by sector membership and interest similarity as opposed to anticipated financial burdens or influence reputation in the newly established policy domain. The study is based on a standardised survey of 29 organisations that are involved in the implementation of the eHC. The analysis is carried out using quantitative methods such as social network analysis. PMID- 20169529 TI - Changes in plasma membrane structure and electromotile properties in prestin deficient outer hair cells. AB - Cochlear outer hair cells (OHCs) rapidly change their length and stiffness when their membrane potential is altered. Prestin, the motor protein for this electromotility, is present along the OHC lateral plasma membrane where there is a high density of intra-membrane protein particles (IMPs). However, it is not known to what extent prestin contributes to this unusual dense population of proteins and overall organization of the membrane to generate the unique electromechanical response of OHCs. We investigated the relationship of prestin with the IMPs, the underlying cortical cytoskeletal lattice, and electromotility in prestin-deficient mice. Using freeze-fracture, we observed a reduction in density and size of the IMPs that correlates with the reduction and absence of prestin in the heterozygous and homozygous mice, respectively. We also observed a reduction or absence of electromotility-related charge density, axial stiffness, and piezoelectric properties of the OHC. A comparison of the charge density with the number of IMPs suggests that prestin forms tetramers in the wild type but is likely to form lower number oligomers in the prestin-deficient OHCs from the heterozygous mice. Interestingly, the characteristic actin-based cortical cytoskeletal lattice that underlies the membrane is absent in the prestin-null OHCs, suggesting that prestin is also required for recruiting or maintaining the cortical cytoskeletal lattice. These results suggest that the majority of the IMPs are indeed prestin and that electrically evoked length and stiffness changes are interrelated and dependent on both prestin and on the cortical actin cytoskeletal lattice of the OHC lateral membrane. PMID- 20169530 TI - Efficient spatiotemporal analysis of the flagellar waveform of Chlamydomonas reinhardtii. AB - The 9 + 2 axoneme is a microtubule-based machine that powers the oscillatory beating of cilia and flagella. Its highly regulated movement is essential for the normal function of many organs; ciliopathies cause congenital defects, chronic respiratory tract infections and infertility. We present an efficient method to obtain a quantitative description of flagellar motion, with high spatial and temporal resolution, from high speed video recording of bright field images. This highly automated technique provides the shape, shear angle, curvature, and bend propagation speeds along the length of the flagellum, with approximately 200 temporal samples per beat. We compared the waveforms of uniflagellated wild-type and ida3 mutant cells, which lack the I1 inner dynein complex. Video images were captured at 350 fps. Rigid-body motion was eliminated by fast Fourier transform (FFT)-based registration, and the Cartesian (x-y) coordinates of points on the flagellum were identified. These x-y "point clouds" were embedded in two data dimensions using Isomap, a nonlinear dimension reduction method, and sorted by phase in the flagellar cycle. A smooth surface was fitted to the sorted point clouds, which provides high-resolution estimates of shear angle and curvature. Wild-type and ida3 cells exhibit large differences in shear amplitude, but similar maximum and minimum curvature values. In ida3 cells, the reverse bend begins earlier and travels more slowly relative to the principal bend, than in wild-type cells. The regulation of flagellar movement must involve I1 dynein in a manner consistent with these results. PMID- 20169532 TI - Susceptibility of isolated myofibrils to in vitro glutathionylation: Potential relevance to muscle functions. AB - In this study we investigated the molecular mechanism of glutathionylation on isolated human cardiac myofibrils using several pro-glutathionylating agents. Total glutathionylated proteins appeared significantly enhanced with all the pro oxidants used. The increase was completely reversed by the addition of a reducing agent, demonstrating that glutathione binding occurs by a disulfide and that the process is reversible. A sensitive target of glutathionylation was alpha-actin, showing a different reactivity to the several pro-glutathionylating agents by ELISA. Noteworthy, myosin although highly sensitive to the in vitro glutathionylation does not represent the primary glutathionylation target in isolated myofibrils. Light scattering measurements of the glutathionylated alpha actin showed a slower polymerisation compared to the non-glutathionylated protein and force development was depressed after glutathionylation, when the myofibrils were mounted in a force recording apparatus. Interestingly, confocal laser scanning microscopy of cardiac cryosections indicated, for the first time, the constitutive glutathionylation of alpha-cardiac actin in human heart. Due to the critical location of alpha-actin in the contractile machinery and to its susceptibility to the oxidative modifications, glutathionylation may represent a mechanism for modulating sarcomere assembly and muscle functionality under patho physiological conditions in vivo. PMID- 20169531 TI - Chlamydomonas mutants display reversible deficiencies in flagellar beating and axonemal assembly. AB - Axonemal complexes in flagella are largely prepackaged in the cell body. As such, one mutation often results in the absence of the co-assembled components and permanent motility deficiencies. For example, a Chlamydomonas mutant defective in RSP4 in the radial spoke (RS), which is critical for bend propagation, has paralyzed flagella that also lack the paralogue RSP6 and three additional RS proteins. Intriguingly, recent studies showed that several mutant strains contain a mixed population of swimmers and paralyzed cells despite their identical genetic background. Here we report a cause underlying these variations. Two new mutants lacking RSP6 swim processively and other components appear normally assembled in early log phase indicating that, unlike RSP4, this paralogue is dispensable. However, swimmers cannot maintain the typical helical trajectory and reactivated cell models tend to spin. Interestingly the motile fraction and the spokehead content dwindle during stationary phase. These results suggest that (1) intact RS is critical for maintaining the rhythm of oscillatory beating and thus the helical trajectory; (2) assembly of the axonemal complex with subtle defects is less efficient and the inefficiency is accentuated in compromised conditions, leading to reversible dyskinesia. Consistently, several organisms only possess one RSP4/6 gene. Gene duplication in Chlamydomonas enhances RS assembly to maintain optimal motility in various environments. PMID- 20169533 TI - A FERM domain in a class XIV myosin interacts with actin and tubulin and localizes to the cytoskeleton, phagosomes, and nucleus in Tetrahymena thermophila. AB - Previous studies have shown that Myo1(myosin class XIV) localizes to the cytoskeleton and is involved in amitosis of the macronucleus and trafficking of phagosomes. Myo1 contains a FERM domain that could be a site for interaction between Myo1 and the cytoskeleton. Here, we explore the function of FERM by investigating its cytoskeleton binding partners and involvement in localization of Myo1. Alignment of Myo1 FERM with a talin actin-binding sequence, a MAP-2 tubulin-binding sequence, the radixin FERM dimerization motif, and the SV40 nuclear localization sequence (NLS) revealed putative actin- and tubulin-binding sequences, a putative FERM dimerization motif, and NLS-like sequences in both the N-terminal and C-terminal regions of Myo1 FERM. Alignment of Myo1 with an ERM C terminal motif revealed a similar sequence in the Myo1 motor domain. GFP-FERM and two truncated FERM domains were separately expressed in Tetrahymena. GFP-FERM contained the entire Myo1 FERM. Truncated Myo1 FERM domains contained either the N-terminal or the C-terminal region of FERM and one putative sequence for actin binding, one for tubulin-binding, a putative dimerization motif, and a NLS-like sequence. Actin antibody coprecipitated GFP-fusion polypeptides and tubulin from lysate of cells expressing GFP-fusions. Cosedimentation assays performed with either whole cell extracts or anti-actin immunoprecipitation pellets revealed that F-actin (independent of ATP) and microtubules cosedimented with GFP-fusion polypeptides. GFP-FERM localized to the cytoskeleton, phagosomes, and nucleus. Truncated GFP-FERM domains localized to phagosomes but not to the cytoskeleton or nucleus. PMID- 20169534 TI - Asymmetric microtubule arrays organize the endoplasmic reticulum during polarity establishment in the brown alga Silvetia compressa. AB - Polarity is a fundamental characteristic of most cell types, and is crucial to early development of the brown alga Silvetia compressa. In eukaryotes the cytoskeleton plays an important role in generating cellular asymmetries. While it is known that F-actin is required for polarization and growth in most tip-growing cells, the roles of microtubules are less clear. We examined the distribution and function of microtubules in S. compressa zygotes as they polarized and initiated tip growth. Microtubules formed asymmetric arrays oriented toward the rhizoid hemisphere early in the polarization process. These arrays were spatially coupled with polar adhesive deposition, a marker of the rhizoid pole. Reorientation of the light vector during polarization led to sequential redistribution of polar axis components, with the microtubules and the polar axis reorienting nearly simultaneously, followed by cell wall loosening and then deposition of new polar adhesive. These findings suggested that microtubules may organize and target endomembrane arrays. We therefore examined the distribution of the endoplasmic reticulum during polarization and found it colocalized with microtubules and became targeted toward the rhizoid pole as microtubule asymmetry was generated. Endoplasmic reticulum association with microtubules remained fully intact following pharmacological disruption of F-actin, whereas microtubule disruption led to aggregation of the endoplasmic reticulum around the nucleus. We propose that brown algae utilize microtubules for organization of the endoplasmic reticulum and migration of exocytotic components to the rhizoid cortex, and present a model for polarity establishment to account for these new findings. PMID- 20169535 TI - Inv acts as a molecular anchor for Nphp3 and Nek8 in the proximal segment of primary cilia. AB - A primary cilium is an antenna-like structure extending from the surface of most vertebrate cells. It is structurally divided along its vertical axis into sub compartments that include the ciliary tip, the shaft, the ciliary necklace segment, the transitional zone and the basal body. We recently discovered that the shaft of the primary cilia has a distinct molecular compartment, termed the "Inv compartment", which is characterized by the accumulation of Inv at the base of primary cilia. Inv was discovered as a causative gene in inv mutant mice. It was later found to be responsible for the infantile type of nephronophthisis (NPHP2). Nephronophthisis (NPHP) is an autosomal recessive kidney disease. Nine causative genes have been identified, with all examined products thought to function in cilia, basal body and/or centrioles. However, their exact intra ciliary localization and relationship have not been clear. Here, we report that products of Nphp3 and Nek8 (the mouse orthologs of the causative genes for NPHP3 and NPHP9, respectively) localize to the Inv compartment. We also show that Inv is essential for the compartmental localization of Nphp3 and Nek8, whereas localization of Inv does not require Nphp3 or Nek8. Nphp1 and Nphp4 also localize at the proximal region of the cilium, but not in Inv compartment. Our results indicate that Inv acts as an anchor for Nphp3 and Nek8 in the Inv compartment, and suggest that Inv compartment is a candidate site for intra-ciliary interaction of Inv, Nphp3 and Nek8. PMID- 20169537 TI - In vivo modulation of nitric oxide concentration dynamics upon glutamatergic neuronal activation in the hippocampus. AB - Nitric oxide ((*)NO) is a labile endogenous free radical produced upon glutamatergic neuronal activity in hippocampus by neuronal nitric oxide synthase (nNOS), where it acts as a modulator of both synaptic plasticity and cell death associated with neurodegeneration. The low CNS levels and fast time dynamics of this molecule require the use of rapid analytical methods that can more accurately describe its signaling in vivo. This is critical for understanding how the kinetics of (*)NO-dependent signaling pathways is translated into physiological or pathological functions. In these studies, we used (*)NO selective microelectrodes coupled with rapid electrochemical recording techniques to characterize for the first time the concentration dynamics of (*)NO endogenously produced in hippocampus in vivo following activation of ionotropic glutamate receptors. Both L-glutamate (1-100 mM) and N-methyl-D-aspartate (NMDA; 0.01-5 mM) produced transient, dose-dependent increases in extracellular (*)NO concentration. The production of (*)NO in the hippocampus by glutamate was decreased by the nNOS inhibitor 7-NI. Intraperitoneal administration of the NMDA receptor blocker, MK-801, and the inhibitor of alpha-amino-3-hydroxy-5-methyl-4 isoazolepropionic acid (AMPA) receptor, NBQX, applied locally greatly attenuated glutamate-evoked overflow of (*)NO. Thus, (*)NO overflow elicited by activation of glutamate receptors appeared to result from an integrated activation of ionotropic glutamate receptors, both of the NMDA and AMPA receptors subtypes. Additionally, distinct concentration dynamics was observed in the trisynaptic loop with stronger and longer lasting effects of glutamate activation on (*)NO overflow seen in the CA1 region as compared with the dentate gyrus. Overall, the results provide a quantitative and temporal basis for a better understanding of (*)NO activity in the rat hippocampus. PMID- 20169536 TI - A central role for the WH2 domain of Srv2/CAP in recharging actin monomers to drive actin turnover in vitro and in vivo. AB - Cellular processes propelled by actin polymerization require rapid disassembly of filaments, and then efficient recycling of ADF/cofilin-bound ADP-actin monomers back to an assembly-competent ATP-bound state. How monomer recharging is regulated in vivo is still not well understood, but recent work suggests the involvement of the ubiquitous actin-monomer binding protein Srv2/CAP. To better understand Srv2/CAP mechanism, we explored the contribution of its WH2 domain, the function of which has remained highly elusive. We found that the WH2 domain binds to actin monomers and, unlike most other WH2 domains, exhibits similar binding affinity for ATP-actin and ADP-actin (K(d) approximately 1.5 microM). Mutations in the WH2 domain that impair actin binding disrupt the ability of purified full-length Srv2/CAP to catalyze nucleotide exchange on ADF/cofilin bound actin monomers and accelerate actin turnover in vitro. The same mutations impair Srv2/CAP function in vivo in regulating actin organization, cell growth, and cell morphogenesis. Thus, normal cell growth and organization depend on the ability of Srv2/CAP to recharge actin monomers, and the WH2 domain plays a central role in this process. Our data also reveal that while most isolated WH2 domains inhibit nucleotide exchange on actin, WH2 domains in the context of intact proteins can help promote nucleotide exchange. PMID- 20169538 TI - A method for recording evoked local field potentials in the primate dentate gyrus in vivo. AB - Recording evoked local field potentials (LFPs) in the hippocampus in vivo has yielded us useful information about the neural mechanisms of learning and memory. Although this technique has been used in studies of the hippocampus of rodents, lagomorphs, and felines, it has not yet been applied to the primate hippocampus. Here, we report a method for recording evoked LFPs in the hippocampus of monkeys. A stimulation electrode and a recording electrode were implanted in the perforant pathway and dentate gyrus, respectively, under the guidance of electrophysiological recording. With a low stimulus intensity just above the threshold, the potential appeared as a slow positive-wave component, which was regarded as field excitatory postsynaptic potential (putative fEPSP); as stimulation intensity increased, the fEPSP amplitude increased, followed by a sharp negative component which was regarded as putative population spike. When the coordinates of the recording or stimulation electrode were moved stepwise, we observed a systematic change in the waveforms of evoked LFPs; this change corresponded to the structural arrangement through which the electrode passed. In a test for short-term synaptic plasticity by paired-pulse stimulation, potentials evoked by the second pulse were influenced by the first one in a manner dependent on interpulse intervals. In a test for long-term synaptic plasticity by high frequency stimulation, the slopes of the fEPSPs and the area of population spikes were increased for more than 1 h. These results indicate that the method developed in the present study is useful for testing theories of hippocampal functions in primates. PMID- 20169539 TI - Impact of hepatitis B virus infection on outcome following resection for intrahepatic cholangiocarcinoma. AB - BACKGROUND: Little is known about the prognosis of intrahepatic cholangiocarcinoma (ICC) patients with hepatitis B virus (HBV) infection following surgical resection. METHODS: The clinico-pathological data of 40 consecutive ICC patients including 29 patients with HBV infection were analyzed after surgical resection. RESULTS: Of all 40 ICC patients, the overall 1-, 3-, 5 year survival rates and a median survival for 29 (74.4%) patients with current or previous HBV infection were 78.9%, 42.8%, 35.7%, and 32.0 months, respectively. Twenty-nine (74.4%) patients with HBV infection, represented by HBsAg(+) or anti HBc(+), had a better prognosis than 10(25%) patients without HBV infection represented by all markers-negative. Compared with 10 (25%) patients without HBV infection, 11 (27.5%) ICC patients with HBsAg(+) had a better prognosis as well. Additionally, lymph node metastasis were identified as an independent predictors of poor overall survival on multivariate analysis in the study of all the 40 patients and 29 patients with HBV infection. CONCLUSIONS: Patients with current or previous HBV infection, represented by HBsAg+ or anti-HBc+, had significantly better prognosis than patients without HBV infection. Patients with HBV infection should be distinguished from other ICC patients, because of their favorable outcome after surgery. PMID- 20169541 TI - PROTEOMICS reviews 2010. PMID- 20169542 TI - Development of Loffler's endocarditis in FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome despite continuous imatinib mesylate therapy and continuous complete remission. PMID- 20169543 TI - Cardiac tamponade or hemopericardium are not associated with bleeding risk factors in consecutive patients hospitalized with noniatrogenic, pericardial effusions. PMID- 20169545 TI - Acute chest syndrome in sickle cell disease due to the new influenza A (H1N1) virus infection. PMID- 20169546 TI - TTP disease course is independent of myeloma treatment and response. PMID- 20169549 TI - The celebrated ecorches of honore Fragonard, part 2: The details of the technique used by Fragonard. AB - It is remarkable that the famous ecorches of Honore Fragonard have survived the centuries to reach us today. Studies carried out by several teams have established details of the technique used by Fragonard that help to explain their longevity. The injection of the vessels was achieved by means of a mixture of mutton tallow and pine resin diluted in essence of turpentine and essential oils. This gave Fragonard a very high success rate. Above all, he did not add pigments to his mixture while injecting the veins, and this facilitated the procedure. The vessels were painted after preservation to give them the vivid colors that we can still see today. Another detail that explains their exceptional conservation is that the varnish used by Fragonard was composed of Venice turpentine, made from larch resin and known to repel insects. PMID- 20169550 TI - Editor Vaclav Kasicka and Carl-Henrik Brogren speak with Dr. Gabriel Peltre. PMID- 20169551 TI - Monolithic chiral stationary phases for liquid-phase enantioseparation techniques. AB - This short overview summarizes the development in the field of enantioselective monolithic chromatographic media and their application for pressure-driven and electrokinetic separations. The major emphasis is put on the currently existing problems and the author's vision for their solution is provided. Due to the author's personal experience silica-based monoliths are discussed in more detail although the key developments in the field of organic monolithic materials for separation of enantiomers are also discussed. PMID- 20169552 TI - Strategies of solvent system selection for the isolation of flavonoids by countercurrent chromatography. AB - Flavonoids form a large class of important naturally occurring bioactive compounds. Their isolation and purification from natural sources can sometimes be very difficult and time-consuming when traditional phytochemical techniques are used. Countercurrent chromatography (CCC), a support-free liquid-liquid partition chromatography technique, is very useful for the isolation of polar compounds and its use is increasing in the natural products field. In this paper, we propose strategies of solvent system selection for the isolation of flavonoids by CCC, based on data from the literature, plus incorporation of own practical experiences. The selected references report the isolation of over 300 different flavonoid compounds from more than 100 plant species, using 40 different solvent systems, showing the versatility of this technique. The solvent system hexane ethylacetate-methanol-water is proposed as a starting point for the separation of samples containing free flavonoids, as it was cited in more than 60% of the papers. A "fine tuning" step is proposed at each level of this solvent family. Other modifications include exchanging the alcohol in the system as well as introducing a fifth solvent. The solvent system ethyl-acetate-butanol-water is proposed as the starting point for glycosylated flavonoids. Other solvent systems are also discussed. The use of gradients is proposed for samples containing both free and glycosylated flavonoids, as the polarity window is larger in these cases. High-speed countercurrent chromatography was used in 89% of the reviewed data. PMID- 20169553 TI - Test compounds for detecting the silanol effect on the elution of ionized amines in reversed-phase LC. AB - The effectiveness of several basic compounds for testing silica-based stationary phases was reviewed by applying them to recent columns for reversed-phase HPLC. Most octadecylsilylated (C18) stationary phases, prepared as a base-deactivated material from high-purity silica gel with endcapping, provided excellent peak shape and column efficiency for the bases including benzylamine and amitriptyline that once caused problems and were subsequently employed for testing silanol activities. However, a cyclic tertiary amine, dextrometorphan, was eluted as an acceptable peak from only a few columns at neutral pH. Such a more sensitive probe is expected to contribute to further improvement of the stationary phase for reversed-phase HPLC. PMID- 20169554 TI - Chromatographic and capillary electrophoretic determination of microcystins. AB - Microcystins are cyclic peptide hepatotoxins that are produced during blooming of cyanobacteria. In recent two decades they gained a great interest because of the related ecological and public health risks. Over 70 different analogs of microcystins have been isolated from natural blooms and laboratory cultures of cyanobacteria. Because they are inhibitors of protein phosphatases they act as tumor promoters, but on the other hand, inhibitive enzymatic and ELISA methods may be employed for their screening or quantitative determination. Much larger analytical potential for this purpose have, however high-performance separation chromatographic and electromigration techniques. Based on about 70 references from original journal papers these methods are reviewed together with presentation of their preconcentration methods and clean-up procedures for analyzing environmental samples. Some attention is also focused on increasing application of LC/MS methods, and comparison of separation techniques with immunochemical or enzymatic methods. PMID- 20169555 TI - Calibration of delta(17)O and delta(18)O of international measurement standards - VSMOW, VSMOW2, SLAP, and SLAP2. AB - Due to exhaustion of the two primary calibration materials, Vienna Standard Mean Ocean Water (VSMOW) and Standard Light Antarctic Precipitation (SLAP), two replacement materials, VSMOW2 and SLAP2, were created with isotopic compositions as close as possible to the original standards in their D/H and (18)O/(16)O ratios. Measurements of the delta(17)O composition constitute therefore an appropriate independent check of the achieved isotopic adjustment. Aliquots from ampoules of VSMOW, VSMOW2, SLAP, and SLAP2 were fluorinated by BrF(5) and analyzed using a dual-inlet Delta E mass spectrometer. VSMOW2 and SLAP2 were found to be indistinguishable from VSMOW and SLAP, respectively, in their delta(17)O and delta(18)O values within measurement uncertainties. This result is a confirmation of the successful isotopic matching of VSMOW2 and SLAP2 to their predecessors. Further checks of the delta(17)O value of SLAP2 seem desirable. PMID- 20169557 TI - Development of a graphite low-temperature plasma source with dual-mode in-source fragmentation for ambient mass spectrometry. AB - A new low-temperature plasma (LTP), based on dielectric barrier discharge (DBD), has been developed as an alternative ionization source for ambient mass spectrometry. For organic samples, the source is able to produce two different fragmentation patterns which are selectable by an electrical switch. The two source modes are different only in the second electrodes: in configuration (A), bar-plate and in configuration (B), coaxial bar-cylinder shapes are used. A disposable graphite probe is used as the first electrode, the same in both configurations, and a copper foil is used as the second electrode. The ionization source is applicable to gas and liquid samples, without any change being necessary in its design. Under optimal conditions, to take ethylbenzene as an example, a detection limit of less than 25 ng was obtained and a relative standard deviation (RSD) of 13.36% has been demonstrated for 50 ng of ethylbenzene (n = 11). We have found several interesting differences in the mass spectra of the tested volatile organic compounds (VOCs) in the two modes, which might be applicable in identification studies. We have investigated the effect of variation of the first electrode material and the second electrode length in mode B. Moreover, in this design the graphite electrode is capable of acting as a sample adsorbent, which is a new sampling method for LTP mass spectrometry (MS). This capability was investigated by adsorption of the selected VOCs onto the surface of the graphite electrode in a headspace solid-phase microextraction (SPME) system, and direct desorption and ionization of the samples by LTPMS. PMID- 20169556 TI - Conversion of methionine into homocysteic acid in heavily oxidized proteomics samples. AB - Analysis of protein oxidation is necessary in numerous areas of biochemistry, including hydroxyl radical surface mapping, oxidative stress assays, and pharmaceutical stability testing. Mass spectrometry is one of the tools most often used to identify protein oxidation products, and previous studies have attempted to identify and characterize all of the major oxidation products detected by mass spectrometry for each amino acid residue. In this note, we present evidence that in heavily oxidized protein samples, such as those produced by hydroxyl radical surface mapping, a major oxidation product of methionine is homocysteic acid. The formation of homocysteic acid from methionine was previously unrecognized in other mass spectrometric analyses, and has important implications for the analysis of oxidized samples, as well as potential implications as to the functional consequences of methionine oxidation. PMID- 20169558 TI - A comparison of nano-electrospray gas-phase electrophoretic mobility macromolecular analysis and matrix-assisted laser desorption/ionization linear time-of-flight mass spectrometry for the characterization of the recombinant coagulation glycoprotein von Willebrand factor. AB - Von Willebrand factor (VWF), an adhesive glycoprotein with an approximate molecular weight (MW) of the monomer of 260 kDa, circulates in human blood plasma as a series of multimers ranging in size up to 20.000 kDa; thus the determination of the accurate MW of the monomer is of great importance and due to its high MW quite challenging. In this study accurate MW determination of intact recombinant VWF monomer (rVWF) was performed with GEMMA (gas-phase electrophoretic mobility macromolecular analysis) and MALDI TOF MS (matrix-assisted laser desorption/ionization linear time-of-flight mass spectrometry). Three rVWF preparations with differing buffer systems and glycoprotein concentrations were analyzed. First investigations directed towards heterogeneity determination by means of capillary gel electrophoresis (CGE)-on-the-chip with a laser-induced fluorescence detector revealed two compounds (MW of 277 kDa (migration time 44.3 s) and 341 kDa (migration time 49.5 s)) present in each sample to varying extents, namely mature and pro-rVWF. MALDI MS analysis in the linear positive ion mode allowed the detection of mature rVWF with an exact MW of 256.1 kDa (+/-0.8%) and pro-rVWF with a MW of 349.8 kDa (+/-0.8%). Two samples containing pro-rVWF in very minor concentration resulted in GEMMA detection of the mature rVWF with a MW of 227.4 kDa (+/-2.5%), derived from the measured globular size of 10.9 nm. For one sample containing both rVWF species in almost equal concentrations no differentiation of the two species was possible with GEMMA. Due to its lower resolution only a peak representing a mixture of both species at 11.8 nm could be observed, yielding a MW of 298.8 kDa (+/-1.6%). PMID- 20169559 TI - Detection of alpha(2u)-globulin and its bound putative pheromones in the preputial gland of the Indian commensal rat (Rattus rattus) using mass spectrometry. AB - The role of pheromones and pheromone-binding proteins in the laboratory rat has been extensively investigated. However, we have previously reported that the preputial gland of the Indian commensal rat produces a variety of pheromonal molecules and preputial glands would seem to be the predominant source for pheromonal communication. The presence of pheromone-binding proteins has not yet been identified in the preputial gland of the Indian commensal rat; therefore, the experiments were designed to unravel the alpha(2u)-globulin (alpha2u) and its bound volatiles in the commensal rat. Total preputial glandular proteins were first fractionated by sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS-PAGE) and subsequently analyzed by mass spectrometry. Further, we purified alpha2u and screened for the presence of bound pheromonal molecules with the aid of gas chromatography/mass spectrometry (GC/MS). A novel alpha2u was identified with a high score and this protein has not been previously described as present in the preputial gland of Indian commensal rats. This novel alpha2u was then characterized by tandem mass spectrometry (MS/MS). Peptides with m/z values of 969, 1192, 1303 and 1876 were further fragmented with the aid of MS/MS and generated de novo sequences which provided additional evidence for the presence of alpha2u in the preputial gland. Finally, we identified the presence of farnesol 1 and 2 bound to alpha2u. The present investigation confirms the presence of alpha2u (18.54 kDa) in the preputial gland of the Indian commensal rat and identifies farnesol 1 and 2 as probably involved in chemo-communication by the Indian commensal rat. PMID- 20169560 TI - Identification of circulatory and excretory metabolites of meisoindigo in rat plasma, urine and feces by high-performance liquid chromatography coupled with positive electrospray ionization tandem mass spectrometry. AB - Meisoindigo has been a routine therapeutic agent in the clinical treatment of chronic myelogenous leukemia in China since the 1980s. However, information relevant to in vivo metabolism of meisoindigo is absent so far. In this study, in vivo circulatory metabolites of meisoindigo in rat plasma, as well as excretory metabolites in rat urine and feces, were identified by liquid chromatography/tandem mass spectrometry (LC/MS/MS). Integration of multiple reaction monitoring with conventional metabolic profiling methodology was adopted to enable a more sensitive detection of in vivo metabolites. By comparing with the MS/MS spectra and retention times of the in vitro reduced metabolites, the major metabolites in rat plasma were proposed to form from 3,3' double bond reduction, whereas the minor metabolites were formed from reduction followed by N demethylation, and reduction followed by phenyl mono-oxidation. The major metabolites in the rat urine were proposed to form from reduction followed by phenyl mono-oxidation, and its glucuronide conjugation and sulfate conjugation, whereas the minor metabolites were formed from 3,3' double bond reduction, N demethylation, reduction followed by N-demethylation, phenyl di-oxidation, phenyl mono-oxidation and its glucuronide conjugation and sulfate conjugation. The major metabolites in the rat feces were proposed to form from reduction followed by phenyl mono-oxidation, whereas the minor metabolites were formed from reduction followed by N-demethylation, and reduction followed by phenyl di-oxidation. The phase I metabolic pathways showed a significant in vitro-in vivo correlation in rat. PMID- 20169561 TI - Peptidomic approach, based on liquid chromatography/electrospray ionization tandem mass spectrometry, for detecting sheep's milk in goat's and cow's cheeses. AB - A common fraud in the dairy field is the addition of sheep's milk to goat's cheeses, because it has a very similar taste to goat's milk, but is more available, and is commonly considered to have a better capacity to curdle. For similar reasons, and due to economic convenience, sheep's cheeses may also contain fraudulent cow's milk. In order to detect this fraud, an EU official method may be used, but it is only a qualitative method (presence/absence of cow's milk). A method able to quantify the presence of sheep's milk during cheese production in goat's and cow's cheeses was developed. The method is based on liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI MS/MS) analysis of peptides of a casein extract from the cheese. By a simple procedure, caseins are extracted from cheeses, solubilized, digested with plasmin, and subsequently analyzed by LC/ESI-MS/MS. A typical sheep's peptide produced by plasmin hydrolysis (m/z = 860) was accurately selected and analyzed to understand if, and by how much, a declared pure goat's cheese contains sheep's milk. By analyzing the same peptide it is also possible to detect if, and by how much, a declared pure sheep's milk contains, or not, cow's milk. The method was applied to several goat's and cow's cheese samples. Quantitation was performed with a calibration curve obtained by analyzing curd cheeses containing different percentages of sheep's milk. The method detection limit and method quantitation limit were evaluated. This method appears accurate and suitable for detecting up to 2% of sheep's milk in cheeses. PMID- 20169562 TI - Fetal anatomy of the human carotid sheath and structures in and around it. AB - The aim of this study was to find basic rules governing the morphological development of the typical neurovascular sheath. We carried out histological examination of 15 paraffin-embedded mid-term fetuses at 9-25 weeks of gestation (three fetuses each at 9, 12, 15, 20, and 25 weeks). As the result, the vagus nerve showed a high propensity to change its topographical relationship with the common carotid artery (CCA) during 9-20 weeks of gestation: that is, from a primitive ventral course to a final dorsal course. The adventitia of the great arteries, which was distinct from other fascial structures, became evident by 15 weeks. The carotid sheath appeared at and after 20 weeks: it was clearly separated from the prevertebral lamina of the deep cervical fasciae, but fused with the pretracheal lamina covering the strap muscles. Thus the carotid sheath, as well as the topographical relationships of structures within it, seems to become established much later than the prevertebral and pretracheal laminae of the deep cervical fasciae. However, the adventitia of the cervical great arteries consistently becomes evident much earlier than the sheath, and it seems to be regarded as one of the basic components of the fetal deep cervical fasciae. PMID- 20169563 TI - Hypoxia stabilizes microtubule networks and decreases tumor cell chemosensitivity to anticancer drugs through Egr-1. AB - The hypoxic environment of solid tumor causes the tumor cells survive and which could protect them from death by facilitating resistance to therapy. Here, we provide evidence that hypoxia can increase tumor cell viability and proliferation through an Egr-1-dependant pathway. Hypoxia protected the microtubules from disassembly, and Egr-1 was colocalized with microtubules in different cell cycle stages. Knockdown of Egr-1 with its siRNA overcame the protection effect of hypoxia and increased the sensitivity of tumor cells to vinblastine under hypoxic conditions. Our results suggest a novel approach for increasing the sensitivity of tumor cells to chemotherapeutics that target microtubule assembly. PMID- 20169564 TI - Desmosomes in the uterine epithelium of noninvasive skink placentae. AB - Australian species of viviparous skinks have noninvasive epitheliochorial placentation where there is no breeching or interruption of the uterine epithelial cell barrier. This is contrary to some African and South American species of skinks which exhibit invading chorionic cells and a localized endotheliochorial placenta. The desmosomes, which maintain the adhesive properties of the junctional complex between uterine epithelial cells, were found to decrease as gestation progressed in the uterus of two highly placentotrophic Australian skinks, but no changes in desmosomal numbers were present in the uterus of two Australian oviparous skinks or viviparous skinks with a simple placenta. In mammals, desmosomes decrease in the uterine epithelium of species with invasive hemochorial placentation, where less chemical and mechanical adhesion between cells assists the invading trophoblast at the time of implantation. However, Australian viviparous skinks do not have an invasive trophoblast; yet, similarities in decreasing lateral cellular adhesion exist in the uterus of both invasive and noninvasive placental types. This similarity in cellular mechanisms suggests a conservation of plasma membrane changes across placentation irrespective of reptilian or mammalian origin. PMID- 20169565 TI - Optimal treatment of cervical necrotizing fasciitis associated with descending necrotizing mediastinitis. AB - BACKGROUND: Cervical necrotizing fasciitis (CNF) associated with descending necrotizing mediastinitis (DNM) is a rapidly evolving and life-threatening condition. The aim of this retrospective study was to describe a treatment strategy for CNF with DNM and present a management algorithm for mediastinal extensions of CNF. METHODS: Patients diagnosed and treated for CNF with DNM over 14 years in a tertiary referral centre were included. RESULTS: Seventeen adult patients were included. The origin of infection was mainly oropharyngeal. The diagnosis of CNF/DNM was based on clinical and computed tomography findings. All patients underwent cervicotomy for CNF. In ten patients, DNM was located above the carina and could be accessed by a cervical approach. In seven patients, DNM was below the carina, and necessitated sternotomy for anteroinferior mediastinal involvement and posterolateral thoracotomy for posteroinferior mediastinal involvement. All patients received broad-spectrum antibiotics. One patient died 3 days after surgery. The median hospital stay was 30 days. There was no recurrence during long-term follow-up. CONCLUSION: Prompt diagnosis and early surgical treatment are essential for reducing mortality in CNF/DNM. All patients should undergo extensive cervicotomy. The surgical approach to the mediastinum depends on the supracarinal or infracarinal location of the disease. PMID- 20169566 TI - Distribution pattern of muscle fiber types in the perivertebral musculature of two different sized species of mice. AB - Many physiological parameters scale with body size. Regarding limb muscles, it has been shown that the demands for relatively faster muscles, less postural work, and greater heat production in small mammals are met by lower proportions of Type I and conversely higher proportions of Type II fibers. To investigate possible adaptations of the perivertebral musculature, we investigated the proportion, spatial distribution, and cross-sectional area (csa) of the different muscle fiber types in the laboratory and harvest mouse. Serial cross sections from the posterior thoracic to the lumbo-sacral region were prepared and Type I, IIA, and IIB fibers identified using enzymehistochemistry. The general distribution of Type I and IIB fibers, as well as the more or less equal distribution of IIA fibers, resembles the pattern found in other mammals. However, the overall proportion of Type I fibers was very low in the laboratory mouse and particularly low in the harvest mouse. Muscular adaptations to a small body size were met primarily by increased Type IIA fiber proportions. Thereby, not all muscles or muscle regions similarly reflected the expected scaling effects. However, our results clearly show that body size is a critical factor when fiber-type proportions are compared among different sized mammals. PMID- 20169567 TI - Immunohistochemical localization of substance P And cholecystokinin in the dorsal root ganglia and spinal cord of the bottlenose dolphin (Tursiops truncatus). AB - The presence of substance P (SP) and cholecystokinin (CCK) immunoreactive neurons was examined in the bottlenose dolphin dorsal root ganglia (DRGs) and spinal cord by immunohistochemical techniques. SP-positive and CCK-immunoreactive neurons were respectively approximately 50% and 1% of the total number of ganglion cells examined and especially belonged to small and medium-sized cell populations. Using double labeling techniques we observed that SP- and CCK-immunoreactivity coexisted in a very low number of primary afferent neurons (2.7%). Few SP immunoreactive (IR) neurons (2.7%) were also CCK-positive. On the contrary, 65% of CCK-immunoreactive neurons contained SP. Interestingly, we observed CCK immunoreactive satellite glial cells located around large cell class somata. Virtually no SP-IR and CCK-positive neurons were surrounded by peripheral CCK immunoreactive satellite glial cells. The SP-IR and CCK-positive nerve fibers were particularly conspicuous in the superficial layers of the spinal cord. The present study indicates that SP and CCK only partially overlap in the thoracic, lumbar, and caudal DRGs of the bottlenose dolphin, suggesting that the majority of SP-IR ganglion neurons are lacking in CCK-immunoreactivity. The role of SP containing DRG neurons is discussed also in relation to the huge vascular spinal retia mirabilia typical of cetaceans. PMID- 20169569 TI - Long-term outcome after proximal gastrectomy with jejunal interposition for suspected early cancer in the upper third of the stomach. AB - BACKGROUND: Proximal gastrectomy was introduced as a function-preserving operation for early gastric cancer (EGC). The aim of this study was to investigate long-term outcomes after this procedure. METHODS: Between 1993 and 2005, patients with suspected EGC in the upper third of the stomach underwent proximal gastrectomy. The long-term oncological and surgical outcomes were assessed. RESULTS: Of 128 patients thought to have EGC, 14 had advanced disease. Nodal involvement was seen in 13 patients (10.2 per cent). Postoperative complications developed in 20 (15.6 per cent). Anastomotic stricture was the most frequent complication, occurring in 13 patients (10.2 per cent). There were no postoperative deaths. During follow-up, nine patients (7.0 per cent) were hospitalized owing to bowel obstruction. Eight (6.3 per cent) developed a second primary gastric carcinoma. The overall 5-year survival rate was 90.5 per cent. CONCLUSION: Proximal gastrectomy is well tolerated, with excellent outcomes in patients with suspected EGC. It is recommended as a standard procedure for the treatment of EGC in the upper third of the stomach. PMID- 20169570 TI - Value of specimen radiographs in diagnosing multifocality of thyroid cancer. AB - BACKGROUND: Specimen radiography has been used widely to evaluate the complete excision of calcified breast lesions but has not been evaluated for thyroid cancer. METHODS: Specimen radiographs were evaluated retrospectively to identify additional cancers that were demonstrated only as calcifications. Receiver operating characteristic curve analysis was performed to compare the combination of specimen radiography and ultrasonography versus ultrasonography alone for detecting multifocality. RESULTS: Some 122 thyroid cancer specimens were obtained from 122 patients between January and April 2008. Specimen radiography detected 27 cancers (18.5 per cent) not detected by ultrasonography. Diagnoses were changed after evaluation of specimen radiographs in three of these patients. The area under the curve of the combination of specimen radiography and ultrasonography was significantly higher than that of ultrasonography alone (P = 0.005). CONCLUSION: Specimen radiography is a potentially useful tool for diagnosing cancer type and predicting the extent of thyroid cancer. PMID- 20169571 TI - Detection of bacterial DNA in acute and chronic cholecystitis. AB - BACKGROUND: The incidence of bacterbilia in cholelithiasis remains controversial. The positivity of cultures ranges from 0 to 73 per cent. The aim of this study was to employ the polymerase chain reaction (PCR) to detect bacterial DNA in gallbladder bile extracted during elective laparoscopic cholecystectomy, and to compare PCR findings with those of bile culture. METHODS: Bile samples from 84 laparoscopic cholecystectomies were collected for culture and PCR analysis. RESULTS: Positive results for bacterbilia were found in 42 (50 per cent) of 84 patients by PCR but in only 16 patients (19 per cent) by culture (P < 0.001). Agreement between the two methods was seen in 44 samples (52 per cent), which were negative in 35 cases. Pathological examination showed chronic cholecystitis in 69 cases (82 per cent) and acute cholecystitis in 15 (18 per cent). Thirty three (48 per cent) of the patients with chronic cholecystitis were PCR positive but only ten (14 per cent) were culture positive (P < 0.001). Only culture results correlated with findings on pathological examination (P = 0.033). CONCLUSION: PCR is more sensitive in detecting bacterial contamination of gallbladder bile in cholecystitis than conventional culture. The clinical relevance of this high sensitivity remains unclear. PMID- 20169572 TI - Malignant risk and surgical outcomes of presacral tailgut cysts. AB - BACKGROUND: Presacral tailgut cysts are uncommon and few data exist on the outcomes following surgery. METHODS: Patients undergoing tailgut cyst resection at the Mayo Clinic between 1985 and 2008 were analysed retrospectively. Demographic data, clinicopathological features, operative details, postoperative complications and recurrence were reviewed. RESULTS: Thirty-one patients were identified (28 women), with a median age of 52 years. Seventeen patients were symptomatic and 28 had a palpable mass on digital rectal examination. Median cyst diameter was 4.4 cm. Four patients had a fistula to the rectum. Complete cyst excision was achieved in all patients; eight underwent distal sacral resection or coccygectomy. Postoperative complications occurred in eight patients but without 30-day mortality. Malignant transformation was present in four patients: adenocarcinoma in three and carcinoid in one. The cyst recurred in one patient after surgery for a benign lesion. CONCLUSION: Presacral tailgut cysts should be removed due to the risk of malignant transformation. PMID- 20169573 TI - Screened individuals' preferences in the delivery of abdominal aortic aneurysm repair. AB - BACKGROUND: This study aimed to determine preferences for service attributes in a population screened for abdominal aortic aneurysm. METHODS: A questionnaire was designed to encompass various aspects of service provision. Questions were calibrated against the time an individual was willing to travel to access specific attributes. Subjects attending an aneurysm screening programme were asked to complete a questionnaire before their screening ultrasound scan. Statistical analysis was through pairwise analysis of the median travel times with the signed rank test. The Wilcoxon rank sum, analysed by the Kruskal-Wallis test, was used to compare preference ratings. RESULTS: A total of 262 individuals were asked to complete the questionnaire; the response rate was 98.5 per cent. Approximately 92 per cent of individuals stated a willingness to travel for at least 1 h beyond their nearest hospital in order to access services with a 5 per cent lower perioperative mortality rate, a 2 per cent lower amputation or stroke rate, a high annual caseload of aneurysm repairs, and routine availability of endovascular repair. CONCLUSION: Patients attending aneurysm screening were willing to travel beyond their nearest hospital to access a service with better outcomes, higher surgical volumes and endovascular surgery. PMID- 20169574 TI - Repeated intermittent methylenedioxymethamphetamine exposure protects against the behavioral and neurotoxic, but not hyperthermic, effects of an MDMA binge in adult rats. AB - We have recently shown that chronic intermittent exposure of adolescent rats to 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy) completely blocks the reduction in serotonin transporter (SERT) binding and the hypoactivity seen following a subsequent MDMA binge treatment. The present study determined whether a similar neuroprotective effect also occurs in rats given the same intermittent MDMA exposure in adulthood. Adult male Sprague-Dawley rats were given either MDMA (10 mg/kg x 2) or saline, every fifth day, from postnatal day (PD) 60 to PD 85. The MDMA-induced latency until seminal plug production was reduced over the course of intermittent treatments. After a 1-week wash-out period, animals received either a low- or high-dose MDMA binge (2.5 or 5.0 mg/kg x 4). Core body temperature was measured during and after the binge to determine the effects of MDMA pretreatment on MDMA-induced hyperthermia. Spontaneous motor activity was determined the next day, and cortical and hippocampal samples were collected at 1 week postbinge to measure serotonin (5-HT) and 5-hydroxyindoleacetic acid (5 HIAA) concentrations as well as [3H]citalopram binding to SERT. Hyperthermia occurred more rapidly and seminal discharge was more common in the MDMA pretreated group compared to the MDMA-naive group in animals given the low-dose binge. MDMA preexposure protected animals from the reductions in cortical 5-HT levels and SERT binding produced by the high-dose binge and blocked the postbinge hypoactivity. These findings indicate that chronic, intermittent MDMA exposure in adulthood induces neuroprotective effects similar to those seen with adolescent treatment. However, there was also evidence for drug-induced sensitization in adults that was not observed in adolescents. Thus, altered drug sensitivity in chronic Ecstasy users may depend not only on the frequency and pattern of use but also on the age of the user. PMID- 20169575 TI - Upregulation of L-type Ca(v)1 channels in the development of psychological dependence. AB - Although L-type voltage-dependent Ca2+ channels regulate activity-dependent processes including synaptic plasticity and synapse formation, there are few data on the changes of Ca(v)1 channel expression in psychological dependence. This study investigated the role of L-type Ca(v)1 channel expression in the brain of mouse that was psychologically dependent on methamphetamine (2 mg/kg, subcutaneous injection [s.c.]), cocaine (10 mg/kg, s.c.), and morphine (5 mg/kg, s.c.) with the conditioned place preference paradigm. Intracerebroventricular administration of nifedipine (3, 10, and 30 nmol/mouse) dose-dependently reduced the development of methamphetamine-, cocaine-, and morphine-induced rewarding effect. Under such conditions, protein levels of both Ca(v)1.2 and Ca(v)1.3 in the frontal cortex and the limbic forebrain were significantly increased on methamphetamine-, cocaine-, and morphine-induced psychologically dependent mice. These findings suggest that the upregulation of Ca(v)1.2 and Ca(v)1.3 participated in the development of psychological dependence. PMID- 20169576 TI - Prenatal and postnatal exposure to bisphenol a induces anxiolytic behaviors and cognitive deficits in mice. AB - Bisphenol A (BPA), an environmental endocrine-disrupting chemical, has been extensively evaluated for reproductive toxicity and carcinogenicity. However, little is known about the behavioral and neurochemical effects of BPA exposure. This study examined whether chronic daily exposure to an environmental endocrine disrupting chemical, bisphenol A [(BPA); 100 microg/kg/day or 500 microg/kg/day, p.o.], from prenatal Day 7 to postnatal Day 36 would lead to changes in anxiety and memory in mice. First, we observed the behavioral alterations of BPA-treated mice using two anxiety-related models, the open field test and elevated plus maze (EPM) test. In the open field test, BPA treatment (100 microg/kg/day) increased movement in the central zone. BPA treatment (500 microg/kg/day) also increased the time spent in the open arms in the EPM test. Second, we measured cognitive ability in the Y-maze test and novel object test. BPA-treated mice showed decreased alternation behavior in the Y-maze at both of doses, indicating working memory impairment. BPA-treated mice (100 microg/kg/day) also showed decreased novel object recognition as expressed by central locomotion and frequency in the central zone, showing recognition memory impairment. Finally, to measure changes in the dopaminergic and NMDAergic systems in the brain, we performed autoradiographic receptor binding assays for dopamine D(1) and D(2) receptors, the NMDA receptor, and the dopamine transporter. BPA treatment increased D(2) receptor binding in the caudate putamen (CPu) but decreased DAT binding. BPA treatment also decreased NMDA receptor binding in the frontal cortex and CA1, CA3, and DG of the hippocampus. Taken together, our results suggest that long term BPA exposure in mice can induce anxiolytic behaviors, cognitive deficits and changes in the dopaminergic and NMDAergic systems. PMID- 20169577 TI - Lesion of the ventromedial nucleus of the thalamus blocks acute cocaine-induced changes in striatal glutamate. AB - A single injection of cocaine increases extracellular glutamate in the rat dorsolateral striatum 1 day after the acute cocaine was administered (McKee and Meshul, 2005). However, the nuclei that facilitate this increase in striatal glutamate remain unknown. We hypothesized that the cocaine-induced increase in striatal glutamate was produced by activation of the ventromedial (VM) nucleus of the thalamus via the thalamo-corticostriatal or thalamostriatal pathways. First, rats received an electrolytic lesion of the VM. One day after a single cocaine or vehicle injection, extracellular glutamate was measured in the dorsolateral striatum using in vivo microdialysis. The motor thalamus lesion blocked the cocaine-induced increase in striatal glutamate and reduced extracellular glutamate to the level of the vehicle-treated group. This study shows a critical role for the VM nucleus of the thalamus in mediating the effects of cocaine on extracellular glutamate levels in the rat dorsolateral striatum. PMID- 20169578 TI - Influence of a low dose of amphetamine on vesicular monoamine transporter binding: a PET (+)[11C]DTBZ study in humans. AB - We previously reported increased binding of (+)[11C]DTBZ (dihydrotetrabenazine), the vesicular monoamine transporter (VMAT2) positron emission tomography (PET) radioligand, in striatum of some methamphetamine users. This finding might be explained by stimulant-induced vesicular DA depletion resulting in decreased DA (+)[11C]DTBZ competition at VMAT2. In a prospective PET study, we now find that administration of an acute oral dose of amphetamine (0.4 mg/kg) to humans does not cause increased striatal (+)[11C]DTBZ binding but a slight 5% decrease. Our data suggest that a low amphetamine dose is unlikely to cause sufficient DA depletion to detect increased (+)[11C]DTBZ binding and that a higher dose might be required. PMID- 20169579 TI - Tautomerism and isotopic multiplets in the 13C NMR spectra of partially deuterated 3-arylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones and their sulfur analogs--evidence for elucidation of the structure backbone and tautomeric forms. AB - The tautomerism of the synthesized 3-arylpyrimido[4,5-c]pyridazine-5,7(6H,8H) diones (1a-d) and 3-aryl-7-thioxo-7,8-dihydro-6H-pyrimido[4,5-c]pyridazine-5-ones (2a-d) was studied in dimethyl sulfoxide (DMSO)-d(6). (1)H NMR spectra of 1a-d showed a clustered water molecule in the structure backbone that is attached by strong intermolecular H bonding. The relation between the temperature and H bonding of the clustered water molecule with 1a was also studied as representative. The relation between the electronegativity (chi) of the substituent on phenyl ring and the chemical shifts of clustered water protons in 1a-d was also studied. All of 1a-d and also 2d compounds existed in lactam (I) form, whereas 2a-c compounds have two distinguished tautomers in DMSO-d(6) [lactam (I) and lactim (II) forms]. The solvent-substrate proton exchange was examined in compounds 1a-d and 2a-d by adding one drop of D(2)O. All compounds (except 1d) showed proton/deuterium exchange of the clustered water protons in DMSO by adding one drop of D(2)O. Some compounds (but not all of them) that are easily soluble in DMSO-d(6) containing D(2)O showed isotopic splitting (beta isotope effect) in their (13)C NMR spectra. Among them, compound 1a was the best evidence to help the spectral assignments and structure determination of predominant tautomer by carbon-13 splitting (beta-isotope effect). PMID- 20169581 TI - A novel method for the direct measurement of urinary conjugated metabolites of alpha-tocopherol and its use in diabetes. PMID- 20169580 TI - Chrysophanol induces necrosis through the production of ROS and alteration of ATP levels in J5 human liver cancer cells. AB - Anthraquinone compounds have been shown to induce apoptosis in different cancer cell types. Effects of chrysophanol, an anthraquinone compound, on cancer cell death have not been well studied. The goal of this study was to examine if chrysophanol had cytotoxic effects and if such effects involved apoptosis or necrosis in J5 human liver cancer cells. Chrysophanol induced necrosis in J5 cells in a dose- and time-dependent manner. Non-apoptotic cell death was induced by chrysophanol in J5 cells and was characterized by caspase independence, delayed externalization of phosphatidylserine and plasma membrane disruption. Blockage of apoptotic induction by a general caspase inhibitor (z-VAD-fmk) failed to protect cells against chrysophanol-induced cell death. The levels of reactive oxygen species production and loss of mitochondrial membrane potential (DeltaPsi(m)) were also determined to assess the effects of chrysophanol. However, reductions in adenosine triphosphate levels and increases in lactate dehydrogenase activity indicated that chrysophanol stimulated necrotic cell death. In summary, human liver cancer cells treated with chrysophanol exhibited a cellular pattern associated with necrosis and not apoptosis. PMID- 20169583 TI - alpha-Tocopheryl phosphate--an active lipid mediator? AB - The vitamin E (alpha-tocopherol, alphaT) derivative, alpha-tocopheryl phosphate (alphaTP), is detectable in small amounts in plasma, tissues, and cultured cells. Studies done in vitro and in vivo suggest that alphaT can become phosphorylated and alphaTP dephosphorylated, suggesting the existence of enzyme(s) with alphaT kinase or alphaTP phosphatase activity, respectively. As a supplement in animal studies, alphaTP can reach plasma concentrations similar to alphaT and only a part is dephosphorylated; thus, alphaTP may act both as pro-vitamin E, but also as phosphorylated form of vitamin E with possibly novel regulatory activities. Many effects of alphaTP have been described: in the test tube alphaTP modulates the activity of several enzymes; in cell culture alphaTP affects proliferation, apoptosis, signal transduction, and gene expression; in animal studies alphaTP prevents atherosclerosis, ischemia/reperfusion injury, and induces hippocampal long-term potentiation. At the molecular level, alphaTP may act as a cofactor for enzymes, as an active lipid mediator similar to other phosphorylated lipids, or indirectly by altering membrane characteristics such as lipid rafts, fluidity, and curvature. In this review, the molecular and cellular activities of alphaTP are examined and the possible functions of alphaTP as a natural compound, cofactor and active lipid mediator involved in signal transduction and gene expression discussed. PMID- 20169582 TI - Tocopheryl quinones and mitochondria. AB - In the past, the role of tocopherols and tocopheryl hydroquinones as antioxidants in mitochondria has been examined. However, structural properties of tocopherols and tocopheryl quinones (arrangement of polar/apolar moieties) have also been recognized as being crucial for the selective transport of RRR-alpha-congeners compared with other tocopherols in the cell, suggesting that these properties might be generally important for the binding of vitamin E-related compounds to proteins and enzymes in mitochondria. Therefore, direct modulation of mitochondrial activities, such as bioenergetics, production of reactive oxygen species and apoptosis, not exclusively related to the redox activity of these compounds is increasingly studied. This overview focuses on the influence of alpha-/gamma-tocopheryl quinones and their parent alpha-/gamma-tocopherols on mitochondrial functions, including formation of tocopheryl quinones, their analytical aspects, their potential as alternative substrates and their inhibitory activity for some mitochondrial functions. It is shown that the understanding of how tocopheryl quinones and tocopherols interfere with mitochondrial functions on the molecular level is still incomplete and that a better comprehension requires further research activities. PMID- 20169584 TI - Regulation of xenobiotic metabolism, the only signaling function of alpha tocopherol? AB - There is growing concern based on meta-analyses of clinical trials using vitamin E supplements that these supplements increase the risk of all-cause mortality in humans. My laboratory has been investigating the metabolism and disposition of "excess" vitamin E. This review focuses on the various mechanisms that prevent vitamin E intoxication. Non-alpha-tocopherols are aggressively metabolized thereby preventing their tissue accumulation and limiting increases in their plasma concentrations. Moreover, "excess" alpha-tocopherol is also metabolized and its concentrations are limited. The mechanisms for this limitation do not seem to be specific for vitamin E, but rather are general xenobiotic pathways. We suggest that the most relevant cytochrome P450-mediated pathway is the one that is most important for the regulation and activation of vitamin K, specifically the one dependent on CYP4F2. PMID- 20169585 TI - Analysis of vitamin E metabolites in biological specimen. AB - Vitamin E is known as the most important lipid antioxidant and is widely used to prevent age-associated diseases. Despite increasing knowledge about human vitamin E metabolism, little is known to justify its widespread use. As meta-analyses revealed even harmful effects of high vitamin E doses, a profound understanding of vitamin E metabolism is mandatory. By recent advances in analytical methodology, new metabolites with distinct physicochemical and biological properties were discovered. This review covers current methods to analyze vitamin E metabolites in biological samples. Special emphasis is laid on analytical applications for the identification and quantification of metabolites with a modified hydroxychromanol ring or a truncated side chain. PMID- 20169586 TI - alpha-Tocopherol enhances degranulation in RBL-2H3 mast cells. AB - Based on the observation that 3 months alpha-tocopherol supplementation caused an up-regulation of the mRNA of vesicular transport proteins in livers of mice, the functional relevance was investigated in RBL-2H3 cells, a model for mast cell degranulation. In total, 24 h incubation with 100 muM alpha-tocopherol enhanced the basal and phorbol-12-myristyl-13-acetate/ionomycin-stimulated release of beta hexosaminidase and cathepsin D as measured by enzymatic analysis as well as Western blotting and immunocytochemistry, respectively. beta-Tocopherol exerted the same effect, whereas alpha-tocopheryl phosphate and trolox were inactive, indicating that both the side chain and the 6-OH group at the chroman ring are essential for activation of degranulation. alpha-Tocopherol did not induce mRNA expression of soluble NSF-attachment protein receptor (soluble N-ethylmaleimide sensitive factor-attachment protein receptor) proteins, such as N-ethylmaleimide sensitive fusion protein, complexin-2, SNAP23 or syntaxin-3, in the RBL-2H3 cell model. In view of the well known alpha-tocopherol-mediated activation of protein phosphatases, which regulate soluble NSF-attachment protein receptor activities by dephosphorylation, underlying mechanisms are discussed in terms of preventing oxidative inactivation of protein phosphatases and so far unknown functions in certain membrane domains. PMID- 20169587 TI - Importance of health system context for evaluating utilization patterns across systems. AB - Measuring health services provided to patients can be difficult when patients see providers across multiple health systems and all visits are rarely captured in a single data source covering all systems where patients receive care. Studies that account for only one system will omit the out-of-system health-care use at the patient level. Combining data across systems and comparing utilization patterns across health systems creates complications for both aggregation and accuracy because data-generating processes (DGPs) tend to vary across systems. We develop a hybrid methodology for aggregation across systems, drawing on the strengths of the DGP in each system, and demonstrate its validity for answering research questions requiring cross-system assessments of health-care utilization. Positive and negative predictive probabilities can be useful to assess the impact of the hybrid methodology. We illustrate these issues comparing public sector (administrative records from the US Department of Veterans Affairs system) and private sector (billing records from the US Medicare system) patient level data to identify primary-care utilization. Understanding the context of a particular health system and its effect on the DGP is important in conducting effective valid evaluations. PMID- 20169588 TI - Evolving generalized Voronoi diagrams for accurate cellular image segmentation. AB - Analyzing cellular morphologies on a cell-by-cell basis is vital for drug discovery, cell biology, and many other biological studies. Interactions between cells in their culture environments cause cells to touch each other in acquired microscopy images. Because of this phenomenon, cell segmentation is a challenging task, especially when the cells are of similar brightness and of highly variable shapes. The concept of topological dependence and the maximum common boundary (MCB) algorithm are presented in our previous work (Yu et al., Cytometry Part A 2009;75A:289-297). However, the MCB algorithm suffers a few shortcomings, such as low computational efficiency and difficulties in generalizing to higher dimensions. To overcome these limitations, we present the evolving generalized Voronoi diagram (EGVD) algorithm. Utilizing image intensity and geometric information, EGVD preserves topological dependence easily in both 2D and 3D images, such that touching cells can be segmented satisfactorily. A systematic comparison with other methods demonstrates that EGVD is accurate and much more efficient. PMID- 20169589 TI - Validation of an incremental motor unit number estimation technique in rabbits. AB - Motor unit number estimation (MUNE) allows for quantitative assessment of functional motor units in a nerve. Several techniques have been applied to human studies. Although MUNE has been performed in animals to study neurological disorders, reproducibility has not been addressed. We analyzed the test-retest reproducibility of an incremental MUNE technique in rabbits and performed histological correlation. A peroneal MUNE was performed in 9 rabbits on two occasions separated by 30 days. MUNE was then performed on 18 rabbits prior to euthanize. A count of total fibers and a second count of large myelinated fibers were performed on nerve cross-sections. Test-retest reproducibility revealed an intraclass correlation coefficient (ICC) of 0.75. The average test-retest relative difference was 26.6%. Comparison of MUNE and histomorphometrical counts revealed a correlation coefficient (r) of 0.21 (total fiber counts) and 0.27 (large fibers). Although incremental MUNE has a high degree of reproducibility in rabbits, there is poor correlation with histological fiber counts. PMID- 20169590 TI - Effects of prolonged repetitive stimulation of median, ulnar and peroneal nerves. AB - It is important to know the effects of prolonged repetitive nerve stimulation (RNS) when it is used in neurophysiological studies. RNS with up to 100 supramaximal stimuli was given to the median, ulnar, and peroneal nerves of normal subjects and the ulnar nerves of subjects with early amyotrophic lateral sclerosis (ALS), recording evoked compound muscle action potentials (CMAPs). In all nerves, there was a decline in the CMAP area and a decrease in CMAP duration. For the peroneal nerve there was a decline in the CMAP amplitude, but a similar decline was not seen in the median or ulnar nerves. Cooling of the muscles resulted in decrement of both the amplitude and area with RNS. In ALS subjects, CMAP amplitude and area both declined after RNS of the ulnar nerve. In this study we describe the changes in CMAP with prolonged RNS among commonly tested normal nerves. Our findings have important implications with regard to RNS. PMID- 20169591 TI - Branched-chain amino acids protect against dexamethasone-induced soleus muscle atrophy in rats. AB - We investigated the utility of branched-chain amino acids (BCAA) in dexamethasone induced muscle atrophy. Dexamethasone (600 microg/kg, intraperitoneally) and/or BCAA (600 mg/kg, orally) were administered for 5 days in rats, and the effect of BCAA on dexamethasone-induced muscle atrophy was evaluated. Dexamethasone decreased total protein concentration of rat soleus muscles. Concomitant administration of BCAA reversed the decrease. Dexamethasone decreased mean cross sectional area of soleus muscle fibers, which was reversed by BCAA. Dexamethasone increased atrogin-1 expression, which has been reported to play a pivotal role in muscle atrophy. The increased expression of atrogin-1 mRNA was significantly attenuated by BCAA. Furthermore, dexamethasone-induced conversion from microtubule-associated protein 1 light chain 3 (LC3)-I to LC3-II, which is an indicator of autophagy, was blocked by BCAA. These findings suggest that BCAA decreased protein breakdown to prevent muscle atrophy. BCAA administration appears to be useful for prevention of steroid myopathy. PMID- 20169592 TI - CER in 2010. PMID- 20169594 TI - Detection of circulating tumor cells in breast cancer patients utilizing multiparameter flow cytometry and assessment of the prognosis of patients in different CTCs levels. AB - We wanted to demonstrate the value of multiparameter flow cytometry in detecting human tumor cells of breast cancer (BC) (SKBR-3) in normal peripheral blood. In addition, we investigated a cluster of patients to compare the overall survival (OS) between advanced BC patients [circulating tumor cells (CTCs) >or=5 group] and limited BC patients (CTCs <5 group). SKBR-3 human BC cells were serially diluted in normal whole blood to demonstrate the sensitivity of multiparameter flow cytometry for detecting CTCs, and we also compared the specificity with reverse transcriptase polymerase chain reaction (RT-PCR) method. On the other hand, we detected CTCs among 45 patients by multiparameter flow cytometry. OS was calculated by the Kaplan-Meier product limit method, and compared it between CTCs <5 and CTCs >or=5 groups with the log-rank test. Cox regression models were fitted to determine the associated factors on survival. Human BC cells (SKBR-3) could be differentiated from normal blood based on the multiple light scatter and cell surface marker expression by multiparameter flow cytometry. The method was found to have a sensitivity limit of 10(-5) and was effective for detecting human BC cells in vivo. It also found that this method had a higher specificity compared with RT-PCR. For the retrospective study, the median OS was 95 weeks and 65.5 weeks (P < 0.05, 2-tailed) for patients with CTCs <5 and CTCs >or=5, respectively. Kaplan-Meier was used to analyze the patients' survival with Log Rank P = 0.004 and Breslow P = 0.003, which showed that these two groups had statistically significant difference. Cox regression analysis was performed, and we found CTCslevels, metastasis and age (P < 0.05) were three relative factors for patients' survival. Multiparameter flow cytometry can detect CTCs effectively and has the potential to be a valuable tool for prognosis assessment among BC patients in clinical situations in China. PMID- 20169598 TI - Medicaments: gifts from the jungle. PMID- 20169599 TI - A highly charged Ag(6)(4+) core in a DNA-encapsulated silver nanocluster. PMID- 20169600 TI - Synthesis, structure and light-harvesting properties of some new transition-metal dithiocarbamates involving ferrocene. AB - Nine new transition-metal dithiocarbamates involving ferrocene (Fc), namely, [M(FcCH(2)Bzdtc)(2)] (M=Ni(II) (1), Cu(II) (2), Cd(II) (3), Hg(II) (4), Pd(II) (5), Pt(II) (6) and Pb(II) (7); Bzdtc=N-benzyl dithiocarbamate) and [M(FcCH(2)Bzdtc)(3)] (M=Co(II) (8) and UO(2) (VI) (9)), have been synthesised and characterised by micro analyses, IR spectroscopy, (1)H and (13)C NMR spectroscopy, and in three cases by single-crystal X-ray analysis. The peak broadening in the (1)H spectrum of the copper complex indicates the paramagnetic behaviour of this compound. A square-planar geometry around the nickel and copper complexes and distorted linear geometry around the mercury complex have been found. The latter geometry is attributed to the bulkiness of the methylferrocenyl and benzyl groups. The observed single quasi-reversible cyclic voltammograms for complexes 2, 8 and 9 indicate the stabilisation of a metal centre other than Fe in their characteristic oxidation state. These complexes have been used as a photosensitiser in dye-sensitised solar cells. PMID- 20169601 TI - Kumada-Corriu cross-couplings with 2-pyridyl Grignard reagents. PMID- 20169603 TI - Gold nanoparticle ensembles allow mechanistic insights into electrochemical processes. AB - Gold-nanoparticle-modified electrodes find wide and diverse applications in the area of electrochemistry. We demonstrate for the first time that gold nanoparticle-modified electrodes can provide mechanistic information and we exemplify this with the electrochemical deposition of arsenic(III). Our approach of using nanoparticle ensembles is a facile and economical methodology that provides an alternative to using expensive gold single-crystal electrodes that require careful surface preparation before each measurement. PMID- 20169604 TI - In situ high-field dynamic nuclear polarization--direct and indirect polarization of 13C nuclei. PMID- 20169606 TI - Smoothing the ripples. PMID- 20169605 TI - Fluorescent copper(II) bis(thiosemicarbazonates): synthesis, structures, electron paramagnetic resonance, radiolabeling, in vitro cytotoxicity and confocal fluorescence microscopy studies. AB - Copper bis(4-ethyl-3-thiosemicarbazonato) acenaphthenequinone (1) and copper bis(4-methyl-3-thiosemicarbazonato) acenaphthenequinone (2) are synthesized and characterized in solution, in the solid state, and radiolabeled. Serum-protein binding radioassays show good stability in solution and about 25 % binding to protein over 1 h, which is comparable with the hypoxia selective tracer [(64)Cu(ATSM)]. Cyclic voltammetry shows fast and reversible reduction at redox potentials similar to the values known for hypoxia-selective copper compounds. However, despite this, complex 1 does not show any hypoxic-selective uptake in HeLa cells over 1-h standard assays. Possible reasons for this are studied by using the intrinsic fluorescence of the Cu(II) complexes to determine the cellular distributions and uptake mechanism by confocal microscopy. The complexes are found to bind to the external cell membrane and disperse evenly in the cytoplasm only after a very slow cell internalization (>1 h). No significant changes in distribution are observed by fluorescence imaging under hypoxic conditions. The rate of localization in the cytoplasm contrasts with their Zn(II) analogues, which are known to have fast cell uptake (up to 20 min) and a clear localization in lysosomes and mitochondria. The cytotoxicity mechanism of 1 over 24 h against a number of adherent cell lines is seen to be by membrane disruption and is of a comparable magnitude to that of [Cu(ATSM)], as demonstrated by methyl tetrazolium (MTT) and lactate dehydrogenase (LDH) assays. PMID- 20169607 TI - Jan Drukker (1936-2009). PMID- 20169608 TI - A case of persistent left and absent right superior caval vein: An anatomical and embryological perspective. AB - The relatively common persistent left superior caval vein (LSCV) is in most cases associated with doubling of the superior caval vein. A persistent LSCV with absent right superior caval vein (RSCV)-a rather rare event-was found during our course of gross anatomy. The LSCV drained into an enlarged coronary sinus, which was partly accompanied by an apparent "double" sinus of normal size draining into this enlarged coronary sinus. Histological and immunofluorescence studies using antibodies against smooth and cardiac muscle actins were performed. The terminal part of the LSCV near the opening into the right atrium contained cardiac actin as expected for a normal derivative of the left sinus horn. Previously only one case of doubled coronary sinus with LSCV has been reported and this abnormality was explained by splitting of the sinus. In our case, the partly doubled coronary sinus had the structure of coronary veins. Mechanical forces have been invoked for the obliteration of the LSCV. Therefore, we examined thirteen human embryos from 15 mm to 32 mm crown-rump length. In one embryo, we found a persistent LSCV together with an enormously enlarged left atrium. Contrary to previous suggestions our data indicate that during normal development a compression of the left anterior cardinal vein does not sufficiently explain the obliteration of the left and the persistence of the right vein. We therefore believe that beside a left dominated blood flow of head and arm, genes for left-right signaling may have to be taken into consideration. PMID- 20169610 TI - Dynamic imaging in patients with carpal tunnel syndrome. PMID- 20169611 TI - Variability of the lateral femoral cutaneous nerve: An anatomic basis for planning safe surgical approaches. AB - Current surgical assumptions identify the lateral femoral cutaneous nerve (LFCN) running just under the inguinal ligament two fingerbreadths medial to the anterior superior iliac spine (ASIS). On the basis of the increasing incidence of Meralgia Paresthetica associated with various surgical procedures, it is clear that surgeons are relying on an inadequate description of the nerve's course. This study provides a better understanding of the variability of the LFCN with regards to its relationship to the ASIS and the depth at which it passes deep to the inguinal ligament. A total of 35 bodies were examined yielding 65 sets of data. Dissections were performed on 26 formalin fixed cadavers and 9 fresh morgue specimens. Measurements and calculations were made with regard to the distance from the LFCN to the ASIS along the inguinal ligament, the depth of the LFCN as it crossed the inguinal ligament, and the length of the inguinal ligament. The LFCN was observed to cross the inguinal ligament 1.4 +/- 0.4 cm medial to the ASIS with a standard deviation of 1.5 cm. The LFCN traversed the inguinal ligament 1.0 +/- 0.1 cm deep to the ligament with a standard deviation of 0.6 cm. The LFCN runs approximately one fingerbreadth medial to the ASIS. The nerve may be found far more medial or lateral than expected with several distinct branching patterns. In addition, the LFCN crosses deeper to the inguinal ligament than previously described in the literature, with a high variability of depth between specimens. PMID- 20169612 TI - Three-dimensional high-resolution reconstruction of the human gastro-oesophageal junction. AB - The aim of this study was to obtain detailed information regarding the three dimensional structure of the gastro-oesophageal region, and, in particular, the fiber orientation of the different muscle layers of the junction. This was achieved by a study of an en bloc resection of the gastro-oesophageal junction (GOJ) harvested from a human cadaver. The excised tissue block was suspended in a cage to preserve anatomical relationships, fixed in formalin and embedded in wax. The tissue block was then processed by a custom-built extended-volume imaging system to obtain the microstructural information using a digital camera which acquires images at a resolution of 8.2 microm/pixel. The top surface of the tissue block was sequentially stained and imaged. At each step, the imaged surface was milled off at a depth of 50 microm. The processing of the tissue block resulted in 650 images covering a length of 32.25 mm of the GOJ. Structures, including the different muscle and fascial layers, were then traced out from the cross-sectional images using color thresholding. The traced regions were then aligned and assembled to provide a three-dimensional representation of the GOJ. The result is the detailed three-dimensional microstructural anatomy of the GOJ represented in a new way. The next stage will be to integrate key physiological events, including peristalsis and relaxation, into this model using mathematical modeling to allow accurate visual tools for training health professionals and patients. PMID- 20169613 TI - Letter in response to Winkelmann and Schagen and Hildebrandt regarding: Hermann Stieve's clinical anatomical research and the history of anatomy in the Third Reich. PMID- 20169614 TI - The celebrated ecorches of Honore Fragonard, part 1: The classical techniques of preparation of dry anatomical specimens in the 18th century. AB - The ecorches that Honore Fragonard created between 1766 and 1771 have miraculously survived the ravages of time due to a technique of preparation which Fragonard never revealed. The present paper and a subsequent article aim to explain the classical methods used by anatomists of the 18th century (Part 1) and to throw light on the details of Fragonard's method (Part 2). Anatomists of the 18th century who wished to preserve their dissections used a method of mummification, which has now fallen into disuse: drying after immersion in alcohol. This article explains the stages of the classical method utilized by French anatomists of the Age of Enlightenment. The cadaver was selected with care before the vascular system was injected with a colored mixture of wax, animal fat, and plant resins. The body was then dehydrated by immersion in a bath of alcohol, after which it was removed and positioned by means of a wooden framework, which held the body in the desired pose while the alcohol evaporated. The vessels were painted, and finally the body was varnished. PMID- 20169615 TI - Clinical significance of the sphenoidal process of the cartilaginous nasal septum: A preliminary morphological evaluation. AB - The bony septum ossifies from cranial to caudal and from ventral to dorsal, thereby forming the perpendicular plate of ethmoid bone and vomer. A small strip of cartilage from the cartilaginous septum remains between these parts, the so called sphenoidal process of the cartilaginous septum. This sphenoidal process is usually seen at the top of a deviated nasal septum during septoplasty. This study evaluated the clinical significance of the sphenoidal process of the cartilaginous septum as a cause of nasal septal deviation. We studied 37 patients with septal deviation who underwent septoplasty. The complex consisting of the sphenoidal process of the cartilaginous septum, perpendicular plate of the ethmoid bone (PPE), and vomer was removed at surgery. The sphenoidal process was measured and the surgical specimen were evaluated histologically and compared to controls. The mean length of the sphenoidal process in patients with a deviated nasal septum was 26.05 +/- 5.32 mm versus 11.95 +/- 2.38 mm in controls. The sphenoidal process was significantly longer in the patients with a deviated nasal septum (P < 0.05). The sphenoidal process of the cartilaginous septum was connected to the PPE and vomer in the patients with a deviated nasal septum and differed histologically from that of the controls. The sphenoidal process of the cartilaginous septum was long and prominent in the patients with septal deviation, implying that delayed nasal septal ossification may be one cause of nasal septal deviation. PMID- 20169616 TI - Two different pathways for the transport of primitive and definitive blood cells from the yolk sac to the embryo in humans. AB - During the early human embryonic period nutrients and blood cells are temporarily provided by the extraembryonic yolk sac (YS). The YS before week six is involved not only in primitive but also in definitive erythropoiesis. While the destiny of primitive erythroid cells that fill the blood vessels of the YS is well known, the final destination of erythrocytes present in the endodermal vesicular system is unknown. In the present study we have investigated, step by step, the destiny of the erythrocytes present in the endodermal vesicles during the embryonic period. Twelve human YSs and their corresponding yolk stalks were analyzed between weeks 4 and 7 of embryonic age by light and scanning electron microscopy. It is shown that erythrocytes (according to their size and morphological features) located within the endodermal vesicles of the YS wall are pulled out through endodermal pits into the YS cavity, from where they reach the lumen of the primitive gut of the embryo through the vitelline duct, a temporary pathway communicating both compartments. During the study period no erythrocytes were seen within the embryo's vascular network where only primitive erythroblasts were identified. Our results indicate that the vitelline duct plays an important transient role as a pathway for the transport of nutrients and blood cells between the YS and the embryo before week five of embryonic development that ends just at the time when YS-embryo circulation becomes established. PMID- 20169617 TI - Histological analysis of the alterations on cortical bone channels network after radiotherapy: A rabbit study. AB - The aim of this study was to evaluate the effects of radiotherapy in cortical bone channels network. Fourteen rabbits were divided in two groups and test group received single dose of 15 Gy cobalt-60 radiation in tibia, bilaterally. The animals were sacrificed and a segment of tibia was removed and histologically processed. Histological images were taken and had their bone channels segmented and called regions of interest (ROI). Images were analyzed through developed algorithms using the SCILAB mathematical environment, getting percentage of bone matrix, ROI areas, ROI perimeters, their standard deviations and Lacunarity. The osteocytes and empty lacunae were also counted. Data were evaluated using Kolmogorov-Smirnov, Mann Whitney, and Student's t test (P < 0.05). Significant differences in bone matrix percentage, area and perimeters of the channels, their respective standard deviations and lacunarity were found between groups. In conclusion, the radiotherapy causes reduction of bone matrix and modifies the morphology of bone channels network. PMID- 20169618 TI - Early history, discovery, and expression of Aequorea green fluorescent protein, with a note on an unfinished experiment. AB - The bioluminescent hydromedusan jellyfish, Aequorea victoria, emits a greenish light (lambda(max) = 508 nm) when stimulated electrically or mechanically. The light comes from photocytes located along the margin of its umbrella. The greenish light depends on two intracellular proteins working in consort: aequorin (21.4 kDa) and a green fluorescent protein (27 kDa). An excited state green fluorescent protein molecule results, which, on returning to the ground state, emits a greenish light. Similarly, a green light emission may be induced in the green fluorescent protein by exposing it to ultraviolet or blue light. Because the green light can be readily detected under a fluorescence microscope, the green fluorescent protein, tagged to a protein of interest, has been used widely as a marker to locate proteins in cells and to monitoring gene expression. This article reviews the work that took place leading to the discovery, cloning, and expression of the green fluorescent protein, with a note on an unfinished experiment. PMID- 20169619 TI - Localization of the supraorbital, infraorbital, and mental foramina using palpable, bony landmarks. AB - The purpose of this study was to locate the infraorbital, supraorbital, and mental foramina by using palpable anatomical landmarks that are conducive to surgical use. Fourteen embalmed cadavers (27 sides) were dissected to expose the supraorbital, infraorbital, and mental foramina. Measurements were made from the lateral orbital rim at the zygomaticofrontal (ZF) suture to both the supraorbital and infraorbital foramina. The distance from the inferior orbital rim at the zygomaticomaxillary (ZM) suture to both foramina was also measured. The distance to the mental foramen was measured from the angle and the inferior border of the mandible. The supraorbital foramen was located 26.2 +/- 2.8 mm medial and 13.5 +/ 3.7 mm superior to the ZF suture. The infraorbital foramen was located 23.8 +/- 3.1 mm medial and 30.9 +/- 3.8 mm inferior to the ZF suture, on average. Vertical measurements made from the ZM suture to the supraorbital foramen averaged 34.4 +/ 3.6 mm and from the ZM suture to the infraorbital foramina averaged 7.6 +/- 2.2 mm. The mental foramen was 64.2 +/- 6.4 mm medial to the angle of the mandible and 12.9 +/- 1.6 mm superior to the inferior border of the mandible. This study provides data that may be useful in predicting the location of the supraorbital, infraorbital, and mental foramina using palpable landmarks. These data may be particularly helpful for surgery in patients with missing teeth or fractures of the maxillary bone. Clin. Anat., 2010. (c) 2009 Wiley-Liss, Inc. PMID- 20169620 TI - Effect of indirubin-3-monoxime against lung cancer as evaluated by histological and transmission electron microscopic studies. AB - The aim of this study is to evaluate the antitumor effect of indirubin-3-monoxime and its mode of action in benzo(alpha)pyrene [B(alpha)P] induced lung cancer in A/J mice. Light microscopic examination of lung sections of [B(alpha)P] induced lung cancer mice revealed the presence of adenocarcinoma characterized by extensive proliferation of alveolar epithelium and loss of alveolar spaces. The control lung tissue showed a normal architecture with clear alveolar spaces. Interestingly the indirubin-3-monoxime treated groups showed the reduced adenocarcinoma with appearance of alveolar spaces. Transmission Electron Microscopic (TEM) studies of lung sections of [B(alpha)P] induced lung cancer mice showed the presence of phaemorphic cells with dense granules and increased mitochondria. The lung sections of mice treated with indirubin-3-monoxime showed the presence of shrunken, fragmented, and condensed nuclei implying apoptosis. The effects were dose dependent and prominent in 10 mg/kg/5 d/week groups suggesting the therapeutic role of indirubin analogue against this deadly human malignancy. Here, our results indicate that indirubin-3-monoxime brings antitumor effect against [B(alpha)P] induced lung cancer by its apoptotic action in A/J mice. PMID- 20169621 TI - TGFbeta1 induces Jagged1 expression in astrocytes via ALK5 and Smad3 and regulates the balance between oligodendrocyte progenitor proliferation and differentiation. AB - Notch1 receptor signaling regulates oligodendrocyte progenitor differentiation and myelin formation in development, and during remyelination in the adult CNS. In active multiple sclerosis lesions, Notch1 localizes to oligodendrocyte lineage cells, and its ligand Jagged1 is expressed by reactive astrocytes. Here, we examined induction of Jagged1 in human astrocytes, and its impact on oligodendrocyte differentiation. In human astrocyte cultures, the cytokine TGFbeta1 induced Jagged1 expression and blockade of the TGFbeta1 receptor kinase ALK5 abrogated Jagged1 induction. TGFbeta2 and beta3 had similar effects, but induction was not observed in response to the TGFbeta family member activin A or other cytokines. Downstream, TGFbeta1 activated Smad-dependent signaling, and Smad-independent pathways that included PI3 kinase, p38, and JNK MAP kinase, but only inhibition of the Smad-dependent pathway blocked Jagged1 expression. SiRNA inhibition of Smad3 downregulated induction of Jagged1, and this was potentiated by Smad2 siRNA. Purified oligodendrocyte progenitor cells (OPCs) nucleofected with Notch1 intracellular signaling domain displayed a shift towards proliferation at the expense of differentiation, demonstrating functional relevance of Notch1 signaling in OPCs. Furthermore, human OPCs plated onto Jagged1-expressing astrocytes exhibited restricted differentiation. Collectively, these data illustrate the mechanisms underlying Jagged1 induction in human astrocytes, and suggest that TGFbeta1-induced activation of Jagged1-Notch1 signaling may impact the size and differentiation of the OPC pool in the human CNS. PMID- 20169622 TI - Endogenous glucocorticoids improve myelination via Schwann cells after peripheral nerve injury: An in vivo study using a crush injury model. AB - Glucocorticoids improve the symptoms of peripheral nerve disorders, such as carpal tunnel syndrome and peripheral neuropathy. The effects of glucocorticoids are mainly anti-inflammatory, but the mechanisms of their effects in peripheral nerve disorders remain unclear. Schwann cells of the peripheral nerves express glucocorticoid receptors (GR), and glucocorticoids enhance the rate of myelin formation in vitro. Therefore, it is possible that the clinical improvement of peripheral nerve disorders by glucocorticoids is due, at least in part, to the modulation of myelination. In this study, an adrenalectomy (ADX) was performed, and followed by a daily injection of either low dose (1 mg/kg) or high dose (10 mg/kg) corticosterone (CORT). We then simulated a crush injury of the sciatic nerves. A sham ADX operation, followed by a simulated crush injury, was conducted as a control. Immunohistochemistry showed that the nuclei of in vivo Schwann cells expressed GR and that glucocorticoids impacted the GR immunoreactivity of the Schwann cells. The mRNA and protein expression of myelin basic protein was significantly lower in the animals given ADX with vehicle than in the sham operation group. However, the expression was restored in the low-dose CORT replacement group. Morphological analyses showed that the ADX with vehicle group had a significantly lower myelin thickness than did the low-dose CORT replacement group and the sham operation group. These results suggest that endogenous glucocorticoids have an important role in myelination through the GR in Schwann cells after an in vivo peripheral nerve injury. PMID- 20169623 TI - Biomedical application of MALDI mass spectrometry for small-molecule analysis. AB - Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) is an emerging analytical tool for the analysis of molecules with molar masses below 1,000 Da; that is, small molecules. This technique offers rapid analysis, high sensitivity, low sample consumption, a relative high tolerance towards salts and buffers, and the possibility to store sample on the target plate. The successful application of the technique is, however, hampered by low molecular weight (LMW) matrix-derived interference signals and by poor reproducibility of signal intensities during quantitative analyses. In this review, we focus on the biomedical application of MALDI-MS for the analysis of small molecules and discuss its favorable properties and its challenges as well as strategies to improve the performance of the technique. Furthermore, practical aspects and applications are presented. PMID- 20169625 TI - Transgenic solutions for the germline. PMID- 20169626 TI - Effect of cyclic bis(3'-5')diguanylic acid and its analogs on bacterial biofilm formation. AB - Cyclic bis(3'-5')diguanylic acid (cyclic-di-GMP) functions as a second messenger in diverse species of bacteria to trigger wide-ranging physiological changes. We measured cyclic-di-GMP and its structural analogs such as cyclic bis(3' 5')guanylic/adenylic acid (cyclic-GpAp), cyclic bis(3'-5')guanylic/inosinic acid (cyclic-GpIp) and monophosphorothioic acid of cyclic-di-GMP (cyclic-GpGps) for effects on the biofilm formation of Staphylococcus aureus and Pseudomonas aeruginosa. We constructed a knockout mutant of SA0701, which is a GGDEF motif protein relevant to diguanylate cyclase from S. aureus 2507. We confirmed that the biofilm formation of this mutant (MS2507 Delta SA0701) was reduced. Cyclic-di GMP corresponding to physiological intracellular levels given in the culture recovered the biofilm formation of MS2507 Delta SA0701, whereas its analogs did not, indicating that unlike a previous suggestion, cyclic-di-GMP was involved in the positive regulation of the biofilm formation of S. aureus and its action was structurally specific. At a high concentration (200 microM), cyclic-di-GMP and its analogs showed suppression effects on the biofilm formation of S. aureus and P. aeruginosa, and according to the quantification study using costat analysis, the suppression potential was in the order of cyclic-di-GMP, cyclic-GpGps, cyclic GpAp and cyclic-GpIp, suggesting that the suppression effect was not strictly specific and the change of base structure quantitatively affected the suppression activity. PMID- 20169627 TI - PD growth in the developing world. PMID- 20169628 TI - Iliac artery aneurysm mistaken for distended bladder. PMID- 20169624 TI - Specific human leukocyte antigen class I and II alleles associated with hepatitis C virus viremia. AB - Studies of human leukocyte antigen (HLA) alleles and their relation with hepatitis C virus (HCV) viremia have had conflicting results. However, these studies have varied in size and methods, and few large studies assessed HLA class I alleles. Only one study conducted high-resolution class I genotyping. The current investigation therefore involved high-resolution HLA class I and II genotyping of a large multiracial cohort of U.S. women with a high prevalence of HCV and HIV. Our primary analyses evaluated associations between 12 HLA alleles identified through a critical review of the literature and HCV viremia in 758 HCV seropositive women. Other alleles with >5% prevalence were also assessed; previously unreported associations were corrected for multiple comparisons. DRB1*0101 (prevalence ratio [PR] = 1.7; 95% confidence interval [CI] = 1.1-2.6), B*5701 (PR=2.0; 95% CI = 1.0-3.1), B*5703 (PR = 1.7; 95% CI = 1.0-2.5), and Cw*0102 (PR = 1.9; 95% CI = 1.0-3.0) were associated with the absence of HCV RNA (i.e., HCV clearance), whereas DRB1*0301 (PR = 0.4; 95% CI = 0.2-0.7) was associated with HCV RNA positivity. DQB1*0301 was also associated with the absence of HCV RNA but only among HIV-seronegative women (PR = 3.4; 95% CI = 1.2 11.8). Each of these associations was among those predicted. We additionally studied the relation of HLA alleles with HCV infection (serostatus) in women at high risk of HCV from injection drug use (N = 838), but no significant relationships were observed. CONCLUSION: HLA genotype influences the host capacity to clear HCV viremia. The specific HLA associations observed in the current study are unlikely to be due to chance because they were a priori hypothesized. PMID- 20169629 TI - Bisphosphonates in renal insufficiency: comparison of estimated glomerular filtration rate methods. PMID- 20169630 TI - Clinical observation: hyponatremia associated with diuretic use and urinary retention in an older man. PMID- 20169631 TI - Cholinesterase inhibitors and peripheral neuromuscular function in dementia. PMID- 20169632 TI - The challenges of accurate measurement of health-related quality of life in frail elderly people and dementia. PMID- 20169633 TI - Delirium-depression overlap. PMID- 20169634 TI - Education of lifestyle risk factors associated with dementia likely to help primary care physicians to improve consultation for elderly people with dementia. PMID- 20169635 TI - Facilitating clinical trials of anemia in older adults: a point-of-care system to measure hemoglobin in the home and its agreement with a hospital core laboratory. PMID- 20169636 TI - An unusual case of asthenia and anorexia in an elderly chinese man. PMID- 20169637 TI - Effect of vitamin D3 on quality of life. PMID- 20169638 TI - Heart attack warning issued. PMID- 20169639 TI - Barriers prevent HPV vaccination in low-income populations. PMID- 20169640 TI - The course of adverse effects of nortriptyline and venlafaxine in elderly patients with major depression. PMID- 20169641 TI - "Swine abattoir workers exposed to aerosolized porcine brains": will we ever learn? PMID- 20169642 TI - Aspects of human disease. 43. Lichen planus. PMID- 20169643 TI - ED manager salaries remain stagnant--experts say doctors faring better than nurses. PMID- 20169644 TI - Following the death TRAIL to hunt down tumor cells: translating programmed cell death signaling mechanisms into clinical practice. PMID- 20169645 TI - Compare cost, too. PMID- 20169646 TI - Governance. Can you avert disaster after the abrupt departure of a CEO? PMID- 20169647 TI - Rural IT + quality. PMID- 20169648 TI - An unbearable task. PMID- 20169649 TI - When you least expect it. PMID- 20169650 TI - Just another test? PMID- 20169651 TI - Case study. Just another test? Commentary. PMID- 20169652 TI - GINA and preemployment criminal background checks. PMID- 20169653 TI - How should the benefits of bioprospecting be shared? AB - The search for valuable new products from among the world's stock of natural biological resources is mostly carried out by people from wealthy countries, and mostly takes place in developing countries that lack the research capacity to profit from it. Surely, the indigenous people should receive some compensation from it. But we must build a robust defense for this intuition, rooted in the Western moral traditions that are widely accepted in wealthy countries, if we are to put it into practice and enforce it. PMID- 20169654 TI - Leukoagglutination. PMID- 20169655 TI - Predictors of persistent gastrointestinal symptoms among new presenters to primary care. AB - BACKGROUND AND AIMS: To quantify the relative contribution of environmental, clinical, infection and psychosocial factors in the persistence of gastrointestinal (GI) symptoms among new patients presenting to primary care. METHODS: We conducted a population-based prospective cohort study of 4986 adults aged 25-65 years. The study team obtained permission from the participants to monitor their general practice records for consultation with GI symptoms and to contact them at that time. Group 1 (n = 177) patients completed a postal questionnaire, whereas those in group 2 (n = 191) completed an identical questionnaire and provided a blood and stool sample. The participants were followed up for 1 and 6 months postconsultation. RESULTS: Of 610 (12.2%) participants who consulted, 368 (60.3%) agreed to participate. Two hundred and eighty participants (76.1%) completed 1 and 6-month follow-up questionnaires and 106 (37.9%) had persistent (present 1 and 6 months postconsultation) GI symptoms. After adjusting for age, sex, area of residence and duration of symptoms before consultation, symptom persistence was independently predicted by high levels of psychological distress [odds ratio (OR): 2.5, 95% confidence interval (CI): (1.1 5.3)], symptom episode duration of more than 2 h [OR: 3.1, 95% CI: (1.3-7.1)] and symptom interference with daily activities [OR: 2.3, 95% CI: (1.1-4.8)]. Changing diet [OR: 0.2, 95% CI: (0.1-0.9)] and recent gastroenteritis or food poisoning [OR: 0.2, 95% CI: (0.1-0.98)] were associated with protective effects. Infection was not associated. Exposure to three or more of these factors identified 87.3% (n = 92) of the participants with persistent symptoms. CONCLUSION: The factors measured at the time of consultation with GI symptoms can accurately predict those patients at increased risk of persistent symptoms up to 6 months later. PMID- 20169657 TI - Ileal intubation with a transnasal endoscope. AB - Transnasal upper endoscopy has been implemented in the last decade as it is perceived as less fastidious than peroral endoscopy, and small-caliber gastroscopes are widely available in the endoscopic centres. We report the feasibility of performing a full colonic study with ileal intubation, using a small-caliber endoscope commonly used for transanal endoscopy, after failing with a standard gastroscope. PMID- 20169656 TI - The prognosis of patients having received optimal therapy for nonvariceal upper gastrointestinal bleeding might be worse in daily practice than in randomized clinical trials. AB - BACKGROUND: Combination of endoscopic haemostatic and high-dose intravenous proton-pump inhibitors is considered to be the standard care for patients with acute peptic ulcer bleeding. AIM: This study assessed predictive factors of rebleeding and death in unselected patients presented to our hospital. METHODS: Consecutive patients with nonmalignant bleeding ulcers and stigmata of recent haemorrhage who received optimal treatment, between 22 August 2003 and 15 October 2007, were studied retrospectively. RESULTS: Among 140 included patients, 45 (32%) rebled and 30 received another haemostatic endoscopy, which was successful in 20 cases. In multivariate analysis, the only significant predictive factor of rebleeding was duodenal site of the ulcer [adjusted odds ratio (OR): 2.75; 95% confidence interval (CI): 1.28-6.19]. In-hospital death occurred in 27 (19%) patients; with five deaths related to uncontrolled or recurrent bleeding. In multivariate analysis, predictors of in-hospital mortality were rebleeding (adjusted OR: 3.28; 95% CI: 1.17-9.16), a Rockall score higher than 6 (adjusted OR: 9.12; 95% CI: 2.57-44.29) and bleeding occurring in the intensive care unit (adjusted OR: 15.68; 95% CI: 4.41-55.82). CONCLUSION: In unselected patients, rebleeding and mortality rates are substantially higher than those found in prospective randomized clinical trials. Intensive care unit stay is an important predictive factor of hospital mortality and should be considered in further therapeutic trials in ulcer bleeding. PMID- 20169658 TI - Reducing interruptions. PMID- 20169659 TI - EMS & the DEA. AB - It's clear that EMS medical directors and management staff must be vigilant in their oversight of implementation, administration and monitoring of controlled substances within their agencies to best serve the public and avoid running afoul of investigation and incurring significant penalties. Those potentially affected by the need for individual registrations of both emergency vehicles and central inventory systems should carefully monitor upcoming developments in the interpretation od DEA regulations. PMID- 20169660 TI - Sex, drugs and R&R (resuscitation & reanimation). PMID- 20169661 TI - TP53 mutations in endometrial cancers: relation to PTEN gene defects. AB - OBJECTIVE: The PTEN and TP53 genes participate in the carcinogenesis of many malignancies, but the role of both genes in endometrial carcinogenesis is not fully elucidated. The aim of the study was to determine the quality and the frequency of incidence of TP53 and PTEN gene mutations and to assess their coexistence in endometrial cancers. Besides that, the correlation was studied between the detected defects and clinicohistopathological characteristics of the studied endometrial cancers. METHODS: The study material included DNA isolated from 81 endometrial cancers. The incidence of TP53 and PTEN gene mutations was assessed using polymerase chain reaction-single-strand conformation polymorphism and sequencing techniques. The statistical analysis of the results was performed using [chi]2 test. RESULTS: In 64.2% of the 81 endometrial cancers, mutations occurred in TP53 and/or PTEN genes: in 16.1%, mutations occurred only in TP53; in 33.3%, only in PTEN gene; and in 14.8%, in both TP53 and PTEN genes. In 35.8% of cases, no mutations were found in these genes. No statistically significant relationship was found between the incidence of mutations in TP53 gene and that in PTEN gene (P = 0.986). The incidence of mutations in PTEN gene was higher in medium and poorly differentiated endometrial cancers than in well-differentiated ones and was statistically significant (G2 + G3 vs G1; P = 0.049). Besides that, mutations in PTEN gene occurred significantly more frequently in patients younger than 55 years than in older women (> or =55 years; P = 0.027). No similar differences were found in TP53 gene. CONCLUSIONS: The results of the study demonstrate that TP53 gene mutations occur in some of endometrioid endometrial cancers in the presence of PTEN gene mutations, suggesting that both these genes participate in the development of these tumors. PMID- 20169663 TI - p38alpha is required for ovarian cancer cell metabolism and survival. AB - INTRODUCTION: Ovarian cancer is highly sensitive to chemotherapy but also shows a high rate of recurrence and drug resistance. These negative outcomes mostly depend on altered apoptotic pathways, making the design of new therapeutic strategies based on the induction of other types of cell death highly desirable. Several lines of research are now addressing cancer-specific features to specifically target tumor cells, thus reducing adverse effects. In this light, a great deal of attention has been devoted to the metabolic reprogramming occurring in cancer cells, which display increased levels of glycolysis compared with their normal counterparts. We recently showed that inhibition of p38alpha impairs key metabolic functions of colorectal cancer cells, inducing growth arrest, autophagy, and cell death both in vivo and in vitro. These effects are mediated by a switch from hypoxia-inducible factor 1alpha (HIF1alpha) to forkhead transcription factor O (FoxO)-dependent transcription. METHODS: We first characterized p38 expression in OVCAR-3, A2780, and SKOV-3 ovarian cancer cell lines. Then, we treated these cells with the p38alpha/p38beta-specific inhibitor SB202190 and performed a morphological, proliferation, and survival analyses. Finally, we studied HIF1alpha and FoxO3A expressions and signaling pathways to evaluate their role in SB202190-induced effects. RESULTS: p38alpha blockade induces the formation of intracellular autophagic vacuoles and reduces growth and viability of ovarian cancer cells. As in colorectal cancer, the underlying molecular mechanism seems to rely on a shift from HIF1alpha- to FoxO3A-dependent transcription, which is promoted by the activation of the adenosine monophosphate activated protein kinase pathway. CONCLUSIONS: These data corroborate the hypothesis that pharmacological modulation of genes involved in cancer-specific homeostasis, such as p38alpha, might be exploited to design new therapeutic approaches to cancer treatment. PMID- 20169665 TI - Coronary heart disease risk profile in women who underwent salpingo-oophorectomy to prevent hereditary breast ovarian cancer. AB - INTRODUCTION: We examined coronary heart disease risk profile in women from hereditary breast ovarian cancer families who had undergone risk-reducing salpingo-oophorectomy and compared the results to that of controls from the general population. METHODS: A sample of 326 (65% of invited) women with previous risk-reducing salpingo-oophorectomy after genetic counseling provided data and blood samples (cases). Controls were 1630 age-matched women from a Norwegian population-based health study. We examined the coronary heart disease risk profile and the Framingham risk score in both groups. RESULTS: The cases had a lower mean (SD) Framingham total score compared to the controls (12.9 [5.1] vs 14.5 [5.2]; P = 0.02). Except for a wider waist circumference, the cases had a more favorable coronary heart disease risk profile including more physical activity, lower levels of total cholesterol, higher levels of high-density lipoprotein cholesterol, lower systolic blood pressure, and lower body mass index compared with the controls. In multivariate logistic regression analyses, the risk-reducing salpingo-oophorectomy group was inversely associated with a Framingham 10-year risk score of 5% or higher (odds ratio, 0.49; 95% confidence interval, 0.34-0.71; P < 0.001). Lower levels of education, not having paid work, a history of stroke, and a wider waist circumference were significantly associated with a Framingham risk score higher than 10% in the total sample. CONCLUSIONS: Self-selection of women seeking risk-reducing salpingo-oophorectomy, changes in lifestyle after surgery, and survival bias may explain that the women who underwent risk-reducing salpingo-oophorectomy had a more favorable coronary heart disease risk profile compared with the controls. Longitudinal studies are needed to further clarify the associations observed in this cross-sectional study. PMID- 20169666 TI - Defining womanhood: Irish women and the Catholic Church in Victorian Liverpool. PMID- 20169667 TI - Randomized phase II trial of paclitaxel plus carboplatin therapy versus irinotecan plus cisplatin therapy as first-line chemotherapy for clear cell adenocarcinoma of the ovary: a JGOG study. AB - INTRODUCTION: Paclitaxel plus carboplatin (TC) is generally considered to be the "gold standard" regimen for treatment of epithelial ovarian carcinomas. Little data are available, however, on the use of this regimen in patients with clear cell adenocarcinoma of the ovary (CCC). Combination chemotherapy with irinotecan hydrochloride plus cisplatin has been reported to be effective for primary and recurrent or resistant CCC. We compared these 2 combinations in patients with CCC. METHODS: Patients (n = 99) with CCC were randomly assigned to receive either 180 mg/m2 paclitaxel on day 1 plus AUC 6 mg/mL x minute carboplatin on day 1 every 21 days (TC arm) or 60 mg/m2 irinotecan hydrochloride on days 1, 8, 15 plus 60 mg/m2 cisplatin on day 1 every 28 days (CPT-P arm). RESULTS: Percentages of patients receiving the scheduled 6 cycles of chemotherapy in the TC and CPT-P arms were 70.8% and 72.0%, respectively. Although toxicity was well tolerated in both arms, the toxicity profile of each arm differed. Progression-free survival (PFS) showed no significant difference between the 2 treatment groups. Because there were more patients with large residual disease in the CPT-P arm, we performed a subset analysis by removing those patients, and then compared the PFS with that of patients without residual disease or with residual disease less than 2 cm. The PFS tended to be longer in the CPT-P group, although the difference was not statistically significant. CONCLUSIONS: A phase III randomized trial is required to elucidate the effectiveness of CPT-P combination chemotherapy for CCC. PMID- 20169668 TI - From Londonderry to London: identity and sense of place for a Protestant Northern Irish woman in the 1930s. PMID- 20169669 TI - Intraperitoneal dissemination of endometrial cancer cells after hysteroscopy: a systematic review and meta-analysis. AB - INTRODUCTION: Hysteroscopy is a diagnostic procedure with a high accuracy in diagnosing endometrial cancer. Because of the increase of intrauterine pressure during distention media inflation, several retrospective studies postulated that it may result in cancer cell dissemination within the peritoneal cavity through the fallopian tubes. We therefore set to estimate whether hysteroscopy increases the risk for intraperitoneal cancer cell dissemination in patients with endometrial cancer and the risk of disease upstaging in patients with clinically early-stage disease. METHODS: We searched the PubMed, the ISI Web of Science, and the Cochrane Library through July 2009. Eligible trials were all controlled clinical trials in which patients were allocated to hysteroscopy (alone or after other diagnostic procedure, eg, dilation and curettage and biopsy) versus any other diagnostic procedure except hysteroscopy or no procedure before surgery for endometrial carcinoma. RESULTS: Nine trials were included in our analysis. One thousand fifteen patients with histologically proven endometrial carcinoma were allocated to hysteroscopy or no hysteroscopy before surgery. Hysteroscopy resulted in a significantly higher rate of malignant peritoneal cytology (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.13-2.79; P = 0.013) and significantly higher disease upstaging owing solely to the presence of malignant cells in the peritoneal cavity (OR, 2.61; 95% CI, 1.47-4.63; P = 0.001) compared with no hysteroscopy. When isotonic sodium chloride was used as distention medium, hysteroscopy resulted in a statistically significant higher rate of malignant peritoneal cytology (OR, 2.89; 95% CI, 1.48-5.64; P = 0.002), whereas a nonsignificant trend for higher malignant cells was observed in patients allocated to the hysteroscopy group (OR, 3.23; 95% CI, 0.94-11.09; P = 0.062) when inflated media pressure reached or exceeded 100 mm Hg. CONCLUSIONS: Hysteroscopy in patients with endometrial cancer hints a risk for cancer cell dissemination within the peritoneal cavity. Prospective and sufficiently powered trials are needed to clarify whether the risk of cancer cell spreading is correlated with worse prognosis. PMID- 20169670 TI - Results of surgery after concurrent chemoradiotherapy in advanced cervical cancer: comparison of extended hysterectomy and extrafascial hysterectomy. AB - OBJECTIVES: The primary objective of this study was to compare disease-free survival (DFS) and overall survival (OS) of patients with and without completion surgery. The secondary objective was to compare DFS and OS of patients who had had systematic simple extrafascial hysterectomy or extended hysterectomy. The other objectives were to compare early and late complications with and without completion surgery and between the various surgical techniques. METHODS: One hundred seventy-one patients with advanced cervical cancer were included in a retrospective, multicenter series. RESULTS: The rate of pelvic control was 81.29% in our study after chemoradiotherapy, but histological residual cervical tumor persisted in nearly half of cases (49.71%). After a mean follow-up of 33 months, OS and DFS were not significantly higher in surgically treated patients, nor was the complication rate higher. Overall survival and DFS were not better after radical hysterectomy than after extrafascial hysterectomy. Statistically significant predictors of survival were clinical stage, tumor size, node extension, and residual tumor after chemoradiotherapy. CONCLUSION: There is no consensus regarding the maximal residual tumor volume after chemoradiotherapy suitable for surgery as there is no reliable imaging yet. Therefore, extrafascial hysterectomy with bilateral pelvic lymphadenectomy seems as a reasonable option if there are histological factors suggesting poor prognosis. PMID- 20169671 TI - Neoadjuvant chemotherapy in advanced vulvar cancer. AB - INTRODUCTION: Locally advanced tumors of the vulva represent approximately one third of all vulvar cancers. Therapeutic options include chemoradiation, radiotherapy, and neoadjuvant chemotherapy (NACT). MATERIALS AND METHODS: Analysis of 3 NACT schemes, bleomicine, paclitaxel, and 5-fluorouracil/cisplatin, used in patients with locally advanced vulvar tumors in a 12-year period. The following parameters were evaluated and compared between regimens: age, initial tumor size, inguinal involvement, histological type, toxicities, response to treatment, surgery performed after NACT, and overall survival. RESULTS: Of the 25 patients included, 10 underwent an NACT regimen with bleomicine (Group A); 5, with paclitaxel (Group B); and 10, with a combination of 5-fluorouracil/cisplatin (Group C). In Group A, there was a 60% response rate. Mortality was 70%, with an overall survival rate of 70%, 40%, and 30% at 12, 24, and 60 months, respectively. The mean (SD) survival was 46.7 (15.4) months. In Group B, the response rate was 40%, with an 80% mortality rate and a survival rate of 60% and 20% at 12 and 24 months, respectively. The mean (SD) survival was 17.0 (3.8) months. In Group C, 20% of the responses were observed and the mortality was 90%, with an overall survival rate of 10% at 12 and 24 months and a mean (SD) survival of 7.6 (2.0) months. CONCLUSION: The best response and overall survival rates were achieved in Group A with the NACT scheme of bleomicine. PMID- 20169672 TI - Medicare program; payment policies under the physician fee schedule and other revisions to Part B for CY 2010. Final rule with comment period. AB - This final rule with comment period implements changes to the physician fee schedule and other Medicare Part B payment policies to ensure that our payment systems are updated to reflect changes in medical practice and the relative value of services. It also implements or discusses certain provisions of the Medicare Improvements for Patients and Providers Act of 2008. (See the Table of Contents for a listing of the specific issues addressed in this rule.) This final rule with comment period also finalizes the calendar year (CY) 2009 interim relative value units (RVUs) and issues interim RVUs for new and revised codes for CY 2010. In addition, in accordance with the statute, it announces that the update to the physician fee schedule conversion factor is -21.2 percent for CY 2010, the preliminary estimate for the sustainable growth rate for CY 2010 is -8.8 percent, and the conversion factor (CF) for CY 2010 is $28.4061. PMID- 20169673 TI - Medicaid program: state flexibility for Medicaid benefit packages and premiums and cost sharing. Final rule. AB - This final rule temporarily delays the effective date of the November 25, 2008 final rule entitled, "Medicaid Program; Premiums and Cost Sharing'' and the December 3, 2008 final rule entitled, "Medicaid Program; State Flexibility for Medicaid Benefit Packages" until July 1, 2010. PMID- 20169674 TI - Community residential care program. Final rule. AB - This document amends the Department of Veterans Affairs (VA) Community Residential Care regulations to update the standards for VA approval of facilities, including standards for fire safety and heating and cooling systems. This rule also establishes a 12-month duration for VA approvals and would authorize provisional approval of certain facilities. Finally, this rule eliminates the statement of needed care requirement and clarifies that it is the care providers at the facility that determine the services needed by a particular veteran. PMID- 20169675 TI - Classification of three steroids as schedule III anabolic steroids under the Controlled Substances Act. Final rule. AB - With the issuance of this final rule, the Deputy Administrator of the Drug Enforcement Administration (DEA) classifies the following three steroids as "anabolic steroids" under the Controlled Substances Act (CSA): Boldione, desoxymethyltestosterone, and 19-nor-4,9(10)-androstadienedione. These steroids and their salts, esters, and ethers are schedule III controlled substances subject to the regulatory control provisions of the CSA. PMID- 20169676 TI - Medicare program: changes to the Medicare claims appeal procedures. Final rule. AB - Under the procedures in this final rule, Medicare beneficiaries and, under certain circumstances, providers and suppliers of health care services can appeal adverse determinations regarding claims for benefits under Medicare Part A and Part B pursuant to sections 1869 and 1879 of the Social Security Act (the Act). Section 521 of the Medicare, Medicaid, and SCHIP Benefits Improvement and Protection Act of 2000 (BIPA) amended section 1869 of the Act to provide for significant changes to the Medicare claims appeal procedures. After publication of a proposed rule implementing the section 521 changes, additional new statutory requirements for the appeals process were enacted in Title IX of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA). In March 2005, we published an interim final rule with comment period to implement these statutory changes. This final rule responds to comments on the interim final rule regarding changes to these appeal procedures, makes revisions where warranted, establishes the final implementing regulations, and explains how the new procedures will be put into practice. PMID- 20169677 TI - Medicare program; application of certain appeals provisions to the Medicare prescription drug appeals process. Final rule. AB - This final rule will implement the procedures that the Department of Health and Human Services will follow at the Administrative Law Judge and Medicare Appeals Council levels in deciding appeals brought by individuals who have enrolled in the Medicare prescription drug benefit program. In addition, it will implement the reopening procedures that will be followed at all levels of appeal. PMID- 20169678 TI - Current good manufacturing practice for positron emission tomography drugs. AB - The Food and Drug Administration (FDA) is issuing regulations on current good manufacturing practice (CGMP) for positron emission tomography (PET) drugs. The regulations are intended to ensure that PET drugs meet the requirements of the Federal Food, Drug, and Cosmetic Act (the act) regarding safety, identity, strength, quality, and purity. In this final rule, we are establishing CGMP regulations for approved PET drugs. For investigational and research PET drugs, the final rule states that the requirement to follow CGMP may be met by complying with these regulations or by producing PET drugs in accordance with the United States Pharmacopeia (USP) general chapter on compounding PET radiopharmaceuticals. We are establishing these CGMP requirements for PET drugs under the provisions of the Food and Drug Administration Modernization Act of 1997 (the Modernization Act). Elsewhere in this issue of the Federal Register, we are announcing the availability of a guidance entitled "PET Drugs--Current Good Manufacturing Practice (CGMP)." PMID- 20169679 TI - School food safety program based on hazard analysis and critical control point principles. Final rule. AB - This final rule implements a legislative provision which requires school food authorities participating in the National School Lunch Program (NSLP) or the School Breakfast Program (SBP) to develop a school food safety program for the preparation and service of school meals served to children. The school food safety program must be based on the hazard analysis and critical control point (HACCP) system established by the Secretary of Agriculture. The food safety program will enable schools to take systematic action to prevent or minimize the risk of foodborne illness among children participating in the NSLP and SBP. PMID- 20169680 TI - Beyond "plastic Paddy": a re-examination of the second-generation Irish in England. PMID- 20169681 TI - Copayments for medications. Interim final rule. AB - The Department of Veterans Affairs (VA) is taking action to amend its medical regulations concerning the copayment required for certain medications. Under current regulations, the copayment amount must be increased based on the prescription drug component of the Medical Consumer Price Index, and the maximum annual copayment amount must be increased when the copayment is increased. Under the amendments in this document, we will freeze copayments at the current rate for the next 6 months, and thereafter resume increasing copayments in accordance with any change in the prescription drug component of the Medical Consumer Price Index. PMID- 20169682 TI - Local heroes: Belgian refugees in Britain during the First World War. AB - The Belgians during the First World War represented the largest refugee movement in British history. Despite the size of this influx - at its peak some 250,000 were present in Britain - there has been an almost total absence of reference to them. This article suggests that this neglect is unfortunate both with regard to our understanding of the First World War and the history of refugees during the twentieth century. In particular, this article stresses the importance of local responses and reactions to the refugees and the significance of place in the process of rebuilding lives and identities in Britain. PMID- 20169683 TI - Kamal A. Chunchie of the Coloured Men's Institute: the man and the legend. AB - The lives of black communities in Britain in the inter-war period, the racial hostility faced by them, the discriminatory Coloured Alien Seamen's Order (1925), have all been documented by historians of black history. The lives of the black communities of the East End of London, and the work of organizations, notably, Harold Moody's League of Coloured Peoples, among them has also been touched on by historians. The work of other individuals and organizations among the black communities in the East End are less well known. This piece rescues and documents the work of one such individual, Pastor Kamal A Chunchie, and his organization, the Coloured Men's Institute. Kamal A. Chunchie, arriving in Britain from the trenches of the First World War, struggled for upwards of 30 years to improve the lives of the black communities in London's docklands, through social welfare and Christian fellowship, working first with the Methodists, and later as a freelance. It also examines the relationship between Chunchie and Methodism. PMID- 20169685 TI - [Translational research on early screening of colorectal cancer]. PMID- 20169684 TI - [Inspiration of the third scientific and technical revolution to gastrointestinal surgeon in China]. PMID- 20169686 TI - [Strategy to cope with local recurrence of rectal cancer]. PMID- 20169687 TI - [To improve the diagnosis and management of gastric cancer in China]. PMID- 20169689 TI - [Integration and application of new concept in peri-gastrointestinal surgery]. PMID- 20169688 TI - Lesion of the will: medical resolve and criminal responsibility in Victorian insanity trials. PMID- 20169690 TI - [Trend of minimally invasive treatment in gastrointestinal surgery and its standard implementation]. PMID- 20169691 TI - [Progression of comprehensive diagnosis and treatment in gastrointestinal tumors and change of surgeon's idea]. PMID- 20169692 TI - Vice into virtue? Progressive politics and welfare reform in continental Europe. PMID- 20169694 TI - The gendering of history in "she". PMID- 20169695 TI - William Hogarth and the tradition of sexual scissors. PMID- 20169696 TI - The dental implant patient on anticoagulant therapy. PMID- 20169698 TI - Focal nodular hyperplasia. PMID- 20169697 TI - Dental implant of a different flavor: tooth restores eyesight. PMID- 20169699 TI - What surgeons know: a note on clinical working knowledge. PMID- 20169700 TI - Breast carcinoma in situ. PMID- 20169701 TI - A comparison of open versus needle biopsy (Tru-cut R) of the testis. AB - Testicular biopsy is an important investigation in the management of an infertile patient with azoospermia. The study is aimed at defining the role of needle biopsy (Tru-cut R) of the testes as an alternative to conventional open testicular biopsy in a prospective controlled trial of 45 consecutive patients. Our study shows that needle biospy of the testis is safe and effective, making it a reliable alternative to open biopsy of the testes. PMID- 20169702 TI - Extradural malignant lymphoma associated with spinal cord compression. AB - Cord compression was noted in 26 patients with extradural malignant lymphoma. There were 19 cases of nonHodgkin's lymphoma and seven cases of Hodgkin's disease. Eighteen cases of non-Hodgkin's lymphoma had intermediate or high grade malignancy types according to the Working Formulation Lymphoma Classification. These patients represented 28% of all extradural malignant tumours seen at the Royal Adelaide Hospital (RAH) and 2.5% of all patients with malignant lymphoma, during an 11 year period. The patients were classified in three presenting groups: Group A, six patients with primary extranodal extradural lymphoma; Group B, nine patients with both extradural lymphoma and disseminated disease at initial presentation; and Group C, 11 patients who developed extradural lymphoma during the course of established disease. Only classification by groups appeared to affect survival time. Group A had the most favourable prognosis, with a 5 year survival of 83%. Five of the Group A patients had a relapse of lymphoma; four at distant sites and one in the retroperitoneum. Laminectomy was essential to provide a diagnosis in Group A patients. The most useful warning symptom of impending spinal cord compression was back and/or radicular pain, which preceded neurological deficit either by days or by up to 5 years. Plain spinal X-rays were abnormal in 64% of cases, emphasizing the value of this simple procedure. PMID- 20169703 TI - Screening for abdominal aortic aneurysms in Western Australia. AB - A study of ultrasound screening for abdominal aortic aneurysms (AAA) was performed. During a 6 month period, 1225 men and women aged 60-80 years were screen at a variety of community venues. Screening was well received by the public and logistically simple to perform. Thirty-three AAA were detected with sizes between 30 and 81 mm. In the 60-80 year age group, the prevalence of AAA > 30 mm in diameter was 4.7% in men and 0.35% in women, and the prevalence of AAA > 50 mm was 0.6% in men and 0.17% in women. Cigarette smoking, but not hypertension or diabetes, was found to be a significant risk factor for AAA. This study confirms that screening for AAA is feasible and yields high prevalence rates in major population centres. PMID- 20169704 TI - Ultrasound screening of the abdominal aorta in Malaysians. AB - Ultrasound examination of the abdominal aorta was performed on 100 patients with cardiovascular disease and a control group of 100 subjects. The objectives were to define the normal aortic size of Malaysians, to screen for aneurysms and to compare the aorta size of the different population groups. In the study group the mean anteroposterior (AP) diameter of the non-aneurysmal aortas at the level of the renal arteries was 1.82 cm (range 0.9-2.6 cm) in men and 1.83 cm (range 1.5 2.3 cm) in women. This compares with 1.61 cm (range 1.1-2.2 cm) in men and 1.50 cm (range 0.8-2.4 cm) in women in the control group. The dimensions of the infrarenal aorta show a similar relationship between the two groups. These AP diameters were significantly smaller than the published figures from studies done on Western populations and are consistent with the smaller stature of Malaysians. Five aneurysms and one ectasia were found (mean size 5 cm, range 3.5-6.0 cm), all in men aged 50-75 years in the study group, and none in the control group. All the aneurysms were easily palpable in these patients who were thinner than the average Caucasian. Given the lower incidence of aortic aneurysms in Malaysians there is no role for routine ultrasound screening of the population. High risk groups can be adequately screened by clinical examination alone. PMID- 20169705 TI - Day case anorectal surgery. AB - All patients referred to the University Department of Surgery, Wellington Hospital, Wellington, New Zealand, with minor anorectal conditions requiring surgery were considered for day case surgery. Eighty-three per cent of the patients were found suitable for day surgery. One hundred patients underwent 103 procedures under general anaesthesia. Admission to hospital from the day care facility was required for four patients; two for bleeding, one for pain and one for drowsiness. One patient required readmission due to inability to cope at home. Twenty-six per cent reported severe pain. Eighty-nine per cent found day surgery to be convenient and preferable to inpatient surgery. Eleven per cent found day surgery inconvenient and would prefer inpatient surgery in future. It is suggested that many anorectal procedures can be performed on a day case basis in selected patients, with safety and convenience. It is well tolerated and accepted. PMID- 20169706 TI - The treatment of disseminated prostate cancer with estramustine. AB - Forty-three patients with disseminated prostate cancer, resistant to orchidectomy or hormone therapy with estramustine were treated. Of the 33 evaluable patients, three patients had stable disease and two had a partial tumour response according to National Prostatic Cancer Project criteria. Twenty-five patients (58%) showed improvement in pain and urinary symptoms. Ten patients (23%) had side effects requiring cessation of therapy. These results show that estramustine has a limited role in the treatment of advanced prostate cancer and that therapy is frequently associated with intolerable side effects. PMID- 20169707 TI - The fasciocutaneous island flap: an extension of the angiotome concept. AB - The concept of the fasciocutaneous island flap (FCIF) has been established as a result of clinical experience in which over 180 cases have been compiled. It is a reconstructive design principle based on vascular and neural anatomy. Even though the flap pattern varies from region to region, it is the trilaminate composition of skin, fat and fascia supplied by fasciocutaneous, musculocutaneous and septocutaneous vessels, which is the basis for its success. Sometimes regional variations in this arrangement occur, for example: there is no deep fascia evident in the trigeminal nerve (CN-V); and in the hand and the foot, the local vascular anatomy still supports this island flap idea without any defined fascial lining. Following their use in the head and neck region, and as more successful ones were designed, the flaps seemed to follow the circumferential layout on the trunk and the longitudinal distribution in the limbs, similar to the dermatomal markouts. Such dermatomal charts thus became the basis of unexplored flap potentials with or without axial vessels. In the past, the clinical word 'angiotome' (which means a vascularized segment) has been used in world literature to describe flap vasculature with axial input. Thus flaps with a fasciocutaneous basis may well be described as a fasciocutaneous angiotome. PMID- 20169708 TI - Continent ileal neobladder urinary diversion: as an alternative to ileal conduit diversion. AB - Total bladder replacement with an ileal neobladder was performed in five male patients undergoing cystoprostatectomy. The surgical technique and short-term results are reported. Four of these patients exhibited total urinary continence day and night. One patient was totally continent during the day but had difficulty with continence at night due to mucus leakage. All patients demonstrated satisfactory bladder emptying (average post-micturition residual < 40 mL) with a flow rate of 4-15 mL/s. Until 1989 the ileal conduit, first described by Bricker in 1950, was used as the preferred method of urinary diversion. We believe that the ileal neobladder in male patients is an excellent bladder substitute with an associated low operative and peri-operative morbidity and a high long-term continence rate, allowing the patient to be free from urostomy. PMID- 20169709 TI - Elevated plasma calcitonin gene-related peptide and the symptoms associated with medullary thyroid cancer. AB - Calcitonin gene-related peptide (CGRP) is a potent vaso-active peptide. Typically, it is elevated in the plasma of patients with medullary thyroid cancer (MTC), but is undetectable in the plasma of healthy individuals. Some symptoms associated with MTC could be caused by elevated CGRP. The plasma level of CGRP was measured in patients with recurrent MTC at rest and again after intravenous pentagastrin to further elevate the CGRP. When normal subjects received pentagastrin the CGRP level still remained below the detectable threshold (< 4 pmol/L). The CGRP levels did not correlate with the patients' blood pressure but a rise in CGRP was associated with a rise in heart rate. As not all patients showed symptoms, further investigation examined the possibility of plasma elevation of somatostatin, a known inhibitor, preventing responses but no change was found. Similarly, examination of the patient plasma for CGRP fractions did not reveal any increased breakdown. PMID- 20169710 TI - Endosurgical treatment for spontaneous pneumothorax. AB - When spontaneous pneumothorax is recurrent or persistent, an open pleurodesis with excision or ligation of the bullae is the procedure of choice but can lead to significant morbidity. Thorascopic surgery for the management of spontaneous pneumothorax was first introduced in 1937 but this has become a useful technique only since the introduction of video-controlled thorascopic surgery and the availability of suitable endothoracic instrumentation. A review was made of nine patients having endosurgery for recurrent (six) or persistent (three) pneumothorax. At surgery the bullae were ligated with an endoloop (four) or excluded with an endostapler (five). Pleurodesis was obtained by a combination of strip pleurectomy, diathermy and installation of an alcohol iodine solution. The early results are similar to those following an open operation with considerably reduced hospital stay and morbidity. PMID- 20169711 TI - The common bilio-pancreatic channel syndrome in childhood. PMID- 20169712 TI - Recurrent traumatic splenic rupture two years after non-operative treatment of splenic trauma. AB - Non-operative and conservative surgical management are now the preferred methods of treatment for blunt splenic trauma in children and adults. These conservative strategies evolved as the risk of late septic complications following splenectomy for trauma became apparent. Although recurrent splenic trauma following conservative management of the ruptured spleen is rare, its surgical management may pose some difficult problems. We present a case in which a second episode of splenic trauma required surgery, two years after the successful non-operative management of the first splenic injury. PMID- 20169713 TI - An infected abdominal aortic aneurysm and hepatic abscesses due to streptococcus milleri. AB - The case of a 78 year old man who presented with fever and hepatic abscesses is reported. He was found to have an infected abdominal aortic aneurysm and the organism cultured was Streptococcus milleri. He was treated with an in situ Dacron graft and high-dose intravenous penicillin. This may be suitable treatment when Gram-positive organisms are involved and there is no gross peritoneal soiling. PMID- 20169714 TI - Endo-anal approaches to adult sigmoido-rectal intussusception. AB - Intussusception of intestinal lesions in the adult is an infrequent event, indeed, those occurring in the distal large bowel are quite rare. Popular management options centre on laparotomy with resection of involved bowel. Two recent cases of intussuscepting polypoid lesions of the rectosigmoid that were successfully managed using an endo-anal approach are presented. PMID- 20169715 TI - Incidental bilateral Morgagni hernia in a traumatized child. AB - The case of a 9 year old male child with Down syndrome and multiple injuries including splenic injury, who was incidentally found to have bilateral Morgagni hernia is presented. Aspects of pre-operative diagnosis and management are discussed. PMID- 20169716 TI - [Nonfarmacological treatment of erectile dysfunction in obese patients]. AB - An original combined treatment of obese patients with erectile dysfunction including transcranial magnetotherapy and transabdominal electrostimulation in the region of fat deposit for 6 months reduces body weight by up to 17% and elevates testosterone by up to 29%. Erectile function improved to normal in 31.8% patients. This method is pathogenetically sound in minimal use of medicines and low risk of cardiovascular disorders. PMID- 20169717 TI - [Advanced microwave thermotherapy (PLFT) as a method of choice in the treatment of complicated, inoperable prostatic adenoma]. AB - The aim of our study was assessment of efficacy of PLFT technique on ProstaLund CoreTHerm unit in nanagement of acute urine retention in patients with prostatic adenoma. We treated 31 patients with prostatic adenoma (age 58-97, mean age 74 years, volume of the prostatic gland from 32 to 188 ml); 11 patients had suprapubic fistula, 8 carried urethral catheter for acute urinary retention. All the patients were inoperable because of a high surgical-anasthetic risk. All of them were exposed to PLFT for 9-15 min. Efficacy of the treatment was assessed by recovery of physiological urination, by IPSS tests and quality of life (QoL). PLFT destroyed 15 +/- 5% prostatic tissue in each of the treated patients. The procedure was well tolerated. Physiological voiding was achieved in all the cases. Such complications typical for TUR as urethral stricture, vesical stenosis, urinary incontinence were not registered. On month 6 after the treatment QoL was assessed by the patients as 1-2 points, Qmax exceeded 15.2 +/- 1.9 ml/s. Thus, PLFT is a highly effective and save treatment of prostatic adenoma and can be recommended as a standard management of patients with acute urinary retention at high surgical risk. PMID- 20169718 TI - [Efficacy and safety of combined treatment of prostatic adenoma with 5-alpha reductase and alpha-adrenoblockers]. AB - Pharmacotherapy of prostatic adenoma is based in present-day practice primarily on two basic groups of medicines--inhibitors of 5alpha-reductase and blockers of alphal-adrenoreceptors. Our trial included 98 patients with prostatic adenoma aged 59-79 years given combined treatment with finasteride (inhibitor of 5alpha reductase) made in Hungary (prosteride, Gedeon Richter) and an uroselective blocker of alpha1-adrenoreceptors sonisin (Gedeon Richter, Hungary). Prosteride was given for 12 months, sonisine--for the first 6 months of combined treatment. Positive results were achieved in 97 (99%) of 98 patients. After 12-month combined treatment symptoms of the disease reduced by IPSS from 17.9 +/- 1.8 to 3.9 +/- 0.9 points, Qmax rose from 8.8 +/- 0.3 to 14.6 +/- 0.3, residual urine volume diminished from 91.7 +/- 8.5 to 31.7 +/- 4.4, the size of the prostate reduced from 72.4 +/- 2.9 to 50.6 +/- 3.7, quality of life improved 2-fold. Combined administration of finasteride (prosteride) and alpha1-adrenoblocker tamsulosine (sonisine) meet three principles of pharmacotherapy of prostatic adenoma: prevents progression of the disease and surgical treatment, relieves symptoms and improves quality of life. PMID- 20169719 TI - [Efficacy of vitaprost forte in the treatment of prostatic adenoma]. AB - Thirty patients with a documented diagnosis of prostatic adenoma were treated with vitaprost forte (100 mg rectal suppositoria) for 60 days. Treatment efficacy was assessed after therapy and for two months with a 30-day interval. It is shown that the drug can be used as monotherapy. Its efficacy was proved by improved urodynamics of the lower urinary tract, reduction of prostatic size. A therapeutic effect after the drug discontinuation points to a complex organotropic action of the drug. Side effects were not registered. Vitaprost forte is recommended for treatment of patients suffering from prostatic adenoma with mild and moderate symptoms. PMID- 20169720 TI - [Administration of two uroselective alpha-adrenoblockers in pharmacological treatment of acute urinary retention in patients with prostatic adenoma]. AB - Acute urinary retention in males is often caused by infravesical obstruction due to enlargement of the prostatic gland. Recently it was found that alpha adrenoblockers promote recovery of physiological voiding in patients with benign prostatic hyperplasia. In our study urinary bladder draining with urethral catheter in 136 patients with acute urinary retention was immediately followed by simultaneous administration of two alpha1-adrenoblockers--alfuzosine (10 mg once a day) (dalfaz CP) and tamsulosine (0.4 mg once a day) (omnik okas). The control group of 96 patients received monotherapy with alfuzosine. Physiological voiding recovered in 42.7% patients on alfuzosine monotherapy and in 64% patients on alfuzosine+tamsulosine. PMID- 20169721 TI - [Local anesthesia with block of the sexual nerve in conduction of transperineal biopsy of the prostate]. AB - We studied 137 males (mean age 68 +/- 8.6 years) with suspected prostatic cancer who had undergone transperineal biopsy of the prostate (12 tissue samples). The biopsy was made under local anesthesia either as paraprostatic block (n=76, group 1) or paraprostatic block in combination with block of the sexual nerve (n=61, group 2). Pain intensity was evaluated with visual analogue scales. Induction of anesthesia was more painful in group 2, three other stages--in group 1. Mean pain at biopsy was significantly (p < 0.001) lower in group 2. Thus, addition of sexual nerve blockade to standard paraprostatic block increases efficacy of anesthesia in conduction of transperitoneal biopsy of the prostate. PMID- 20169722 TI - [The role of combined treatment of prostatic gland after biopsy of the prostate for an elevated PSA level]. AB - Benign prostatic hyperplasia and prostatic cancer have a significant effect of men's health, quality of life and death rate. Recent researches propose algorithms for treatment of benign prostatic hyperplasia which help determine optimal management of the disease using either alpha-adrenoblocker or combined therapy basing on factors of progression risk. Molecular-genetic, biological investigations reveal pathological prosesses leading to onset of the above pathological conditions thus opening prospects for prophylaxis of both benign and malignant prostatic hyperplasia. Further studies will specify efficacy and safety of 5-alpha reductase inhibitors in prevention of prostatic cancer. PMID- 20169723 TI - [Overweight and secretory male infertility]. AB - We have performed a trial with participation of 60 males aged 23-52. Of them, 30 had secretory male iufertility (SMI) and obesity. The control 30 patients were healthy volunteers. The protocol was performed by two stages. Stage 1 included: investigation of a clinico-laboratory status, of correlation between a sorption function of erythrocytes, endogenic metabolic intoxication (EMI) and spermogram parameters, concentration of serum testosterone in SMI patients. Stage 2 consisted in treatment of the intoxication by reducing body mass. All the infertile men were obese; 30% of them had low glucose tolerance, 46.7% had stage 2 hypertension, 23.3%--seasonal allergic symptoms. The level of organic substances on the surface of erythrocytes in infertile men was higher than in the controls (p < 0.01). A negative correlation was seen between spermogram parameters and organic substances content on erythrocytic surface (p < 0/05), concentration of serum testosterone and the above substances (p < 0.01). The loss of fat tissue by 7-14 kg by infertile men resulted in a positive trend in spermogram parameters and the level of serum testosterone (p < 0.01). PMID- 20169724 TI - [Pilot experience with application of a novel pneumatic lithotripter LMA StonrBreaker in the treatment of urolithiasis]. AB - The pneumatic lithotripter LMA StoneBreaker has been tested and proved effective in removal of uroliths of different location. It is a reliable and comfortable in use modality of contact destruction of the stones of the upper and lower urinary tracts. This lithotripter is perspective for wide urological practice. PMID- 20169725 TI - [Clinical efficacy and safety of the drug "Likoprofit potential-formula"]. PMID- 20169726 TI - [The role of selenium and zinc in development of male infertility]. PMID- 20169727 TI - [Coral nephrolithiasis: surgical treatment, complications and prevention of complications]. PMID- 20169728 TI - [Varicocele: contradictions and problems]. PMID- 20169729 TI - [Pelvic lymphadenectomy in prostatic cancer]. PMID- 20169730 TI - [Spasmex in the treatment of overactive bladder. Russian experience]. PMID- 20169731 TI - [Potentiality of building-up the medical operations system for long-duration space missions by noncontact physiological functions recording during sleep time]. AB - Methods of investigating the physiological functions in space crews on extended missions during night sleep are of much fundamental and practical substance. The design of experiment "Sonocard" utilizes the method of seismocardiography. Purpose of the experiment is to validate the procedures of noncontact in-sleep physiological data recoding which are potent to enhance the space crew medical operations system. The experiment was performed systematically by ISS Russian crew members starting from mission-16. The experimental procedure is easy and does not cause discomfort to human subjects. Results of the initial experimental sessions demonstrated that, as on Earth, sleep in microgravity is crucial for the recovery of body functional reserves and that the innovative technology is instrumental in studying the recovery processes as well as person unique patterns of adaptation to extended space mission. It also allows conclusions about sleep quality, mechanisms of recreation, and body functionality. These data may enrich substantially the information used by medical operators of the space missions control centers. PMID- 20169732 TI - [Histogeny of the visceral organs of embryonic Japanese quails developed in the micro-g environment]. AB - The paper reports the results of organogenic and histogenic investigations of the visceral organs of embryonic Japanese quails incubated in the microgravity aboard orbital complex Mir. Investigations of the gastrointestinal tract failed to reveal macrodeviations in the organs' structure, differentiation of layers or cells along the full length of the entodermal canal. However, comparison with the ground controls exhibited poor development of stromal connective tissues in the flight embryos evidencing loose arrangement and small number of fibers. Local hyperplasia in the duodenal epithelium was due to the proliferation rather than differentiation processes; it could affect food intake and parietal digestion in the flight chicks. Though the Japanese quail embryos developed in space microgravity had some deviations, their digestic apparatus was mature to uptake and assimilate food. PMID- 20169733 TI - [Perinatal model of human transition from hypogravity to the earth's gravity based on the electromyogram nonlinear characteristics]. AB - Interferential electromyogram (iEMG) was analyzed in healthy newborn infants (n=29) during the first 24 hours of life as a model of transition from hypogravity (intrauterine immersion) to the Earth's gravity (postnatal period). Nonlinear instruments of iEMG analysis (correlation dimension, entropy and fractal dimension) reflected the complexity, chaotic character and predictability of signals from the leg and arm antagonistic muscles. Except for m. gastrocnemius, in all other musles iEMG fractal dimension was shown to grow as the postnatal period extended. Low fractal and correlation dimensions and entropy marked flexor muscles, particularly against low iEMG amplitude suggesting a better congenital programming for the flexors as compared to the extensors. It is concluded that the early ontogenesis model can be practicable in studying the evolution and states of antigravity functions. PMID- 20169734 TI - [Effects of dehydration and infusion of blood substitutes on the hemostasis system in an experiment with 21-hour bed rest]. AB - Eight volunteered male test-subjects (20-40 y.o.) took part in an experiment with 21-hr bed rest aimed to investigate trends in the hemostasis parameters (activated partial thromboplastin time, prothrombin time, thrombin time, fibrinogen, plasminogen, D-dimers, soluble fibrin-monomer complexes (SFMC), as well as antithrombin III (ATIII) and protein C (antiplasmin) activities) after diuretics-induced dehydration followed by intravenous infusion of colloid and crystalloid solutions. It was shown that noncompensible dehydration during bed rest does not lead to noteworthy alterations in the procoagulating component of hemostasis. Intravenous infusion of blood substituting sterofundin (crystalloid) and venofundin (colloid) to the bedrested human subjects accelerated coagulation within the physiological norm. In all series of the experiment ATIII was suppressed and plasminogen content went down causing growth in SFMC. Fibrinogen concentration remained essentially unchanged pointing to the absence of acute reaction of organism to the experimental conditions. PMID- 20169735 TI - [Manifestation of the adaptive response and bystander-effect of C3H10T1/2 fibroblasts irradiated by protons and gamma-rays]. AB - Adaptive response and bystander-effect were studied in mice fibroblasts irradiated by gamma-rays and protons with the energy of 150 MeV Monolayer of fibroblasts cultivated on the wall of a plastic vial first were exposed to 2 and 4 cGy of ionizing radiation (presumably adaptive doses) and later, after 40-min. or 16-hr. period at 37 degrees C, to damaging 4 Gy. To study the bystander effect, either the whole vial surface (25 cm2) or central area (1 cm2) were irradiated by a beam of protons. The results showed that the preliminary gamma irradiation 40-min. or 16-hr. before exposure to the damaging dose equally alleviates the harmful effect of protons on fibroblasts. The adaptive response was observed as in the cells subjected to the direct irradiation by protons at 4 Gy, so in bystander-cells. When protons were used for adaptive irradiation, the response was visible only to the dose of 4 cGy in fibroblasts exposed to gamma radiation 16 hrs. later. In all the rest cases, proton- and gamma-induced damages added together. Besides, the experiments showed that the adaptive effect of protons is passed on to bystander-cells. Adaptive and damaging gamma-irradiation evoked the response invariably. PMID- 20169736 TI - [On pseudomonas aerugenosa immunity to microwave energies]. AB - Experiments were performed to investigate immunity of a variety of water suspended Pseudomonas aerugenosa to microwave energies. The objectives were to determine lethal temperatures for different Pseudomonas aerugenosa strains in water stream and to test whether Pseudomonas aerugenosa are adaptable to repeated microwave exposure.In the experiments, Pseudomonas aerugenosa died when water temperature was in the interval from 60 to 65 degrees C. It was also shown that Pseudomonas aerugenosa do not adapt to microwave energies. Therefore, we obtained evidence that microwave energies can be effectively used for water decontamination and heating in advanced life support systems. PMID- 20169737 TI - [Evaluation of antihypoxic and antiamnemonic effects of mexicor in animals]. AB - In experiments with mice closed in airtight and altitude chambers mexicor effectiveness against hypoxia was evident only at the dose of 100 mg/kg; effect was nil against acute hemic and histotoxic hypoxia. The reference antihypoxic substance (amtisol succinate, 25-100 mg/kg) excelled mexicor in all models of acute hypoxia. In the model of cerebral infarct in rats, the mexicor neuroprotective effect at the doses from 12.5 to 100 mg/kg was dose-dependent with a nearly linear trend and significantly stronger as compared to amtisol succinate. In amnesia models in mice the antimnemonic effect of the drug at the dose of 50-100 mg/kg was much stronger than of amtisol succinate and comparable to commonly used pyracetam and oxiracetam. Mexicor (5 mM per 53 +/- 4%, 10 mM per 94 +/- 6%) inhibited the orthodromic population response in survival sections of hippocampal CA1 in rats. Stimulation of respiration of isolated mitochondria from rat's cerebral cells showed linear dose dependence in the range from 1 mM to 5 mM. It can be concluded that the antihypoxic, neuroprotective and antiamnemonic action is achievable with high mexicor dosage. PMID- 20169738 TI - Sympathetic B antagonist prevents bone mineral density decrease induced by labyrinthectomy. AB - We previously showed that bilateral vestibular lesion in rats induces a bone loss in weight bearing bones. To determine whether this effect is mediated by the sympathetic nervous system (SNS), bone mineral density (BMD) was measured in 4 groups of 10 female Wistar rats: bilateral labyrinthectomy (Bilab), Bilab with propranolol treatment, sham operated with or withoutpropranolol. In untreated rats, 30 days after lesion Bilab animals showed a reduced BMD in distal femoral metaphysis comparatively to intact rats (p < 0.001). In treated rats, there was no difference in BMD 30 days after lesion. This protective effect of propranolol against bone loss suggests that the vestibular system influence on bone remodeling is mediated by SNS. If this hypothesis is correct, this could have important consequences in devising countermeasures to spaceflight induced bone loss. PMID- 20169739 TI - [Human walk in spacesuit as a self-oscillating process]. AB - A series of 40 biomechanic and physiological tests of semi-rigid and flexible spacesuits as possible candidates for Moon explorations purposes were conducted with involvement of 20 volunteered subjects. Ability to walk in the spacesuits with the internal positive pressure of 0.4 kg/cm2 in the normal gravity was assessed simultaneously with energy expenditure for moving over preset distances. Also, mating of the leg movements with the spacesuit shell was investigated The longest distance test elicited the fact of acquisition of stable motor skills in the unusual circumstances. The acquired motor skills bring about restructuring of step kinematics and make equal knee flexures during leg transfer and stepping on platform (matching the angular movement of the spacesuit knee joint) to an accuracy of tenths of degree. This phenomenon is used by the authors as the ground for proposing a reasoned optimization of the walk pattern in spacesuits as a self-oscillating process. PMID- 20169740 TI - [Microcirculation stream modeling: hydromechanic and acoustic models]. AB - The objective was to attempt mathematical modeling of ultrasonic scanning tissue section in order to discern signals from erythrocytes and leucocytes that is displayed as Doppler images. Hydromechanic and acoustic microcirculation models have been constructed for a 20 MHz ultrasonic sensor. Results of the modeling showed that ultrasonic blood cells differentiation will require complex analysis of amplitude and frequency parameters of echoed signal. PMID- 20169741 TI - [Effect of cryopowder Rhodiola rosae L. on cardiorespiratory parameters and physical performance of humans]. AB - Seven-hour continuous physical loading test (bicycle ergometry) was used to assess effects of Rhodiola rosae L. (cryopowder) on the human cardiorespiratory system. Comparing with the control, the preparation facilitated activation of the energy-supplying mechanisms in human organism during physical work. In addition, it increased efficiency of the cardiovascular and respiration systems and prevented fatigue growth. The medical herb powder demonstrated explicitly the protective action and can be recommended for use in extreme conditions. PMID- 20169742 TI - [Investigations of the morphofunctional properties of red blood in human subjects during 9-day exposure in oxyargon medium with various oxygen content]. AB - Biochemical investigations of red blood and oxygen transportation by erythrocyte hemoglobin were performed in volunteered for chamber experiments (0.14 MPa) with normal and hypoxic oxyargon medium (O2-Ar). Erythrocyte metabolism, lipid and phospholipids spectra, and effectiveness of oxygen release and retention by hemoglobin were studied in the baseline data collection period, on day 6 in hyperbaric and normoxic O2-Ar medium (13.7% O2), on day 3 in hyperbaric and hypoxic O2-Ar (9.9% O2) and on day 1 and 10 during the post-experiment rehab. Elevated pressure, hypoxia and ensuing decompression revealed an ATP reduction that could be a result of shifts on the membrane level and increased G6PD activity associated with cell reparation processes. Changes in membrane lipid and phospholipids composition point to an altered phase state of plasmatic membrane, i.e., increased viscosity which is indicative of possible impairment of membrane permeability As a rule, hyperbaria impacted oxygen transportation in blood of the subjects; effect of hypoxia combined with hyperbaria was not uniform ranging from none to decreasing or increasing oxygen transportation that can be extenuated by selectivity and individual sensitivity to the factors in the experiment Loss of O2 transportation efficiency by hemoglobin is most likely connected with the increase of plasmatic membrane viscosity that could affect hemoporphyrin conformation of membrane-bound hemoglobin and obstruct oxygen transport though membrane. PMID- 20169743 TI - [Cytogenetic characteristics of human blood lymphocytes in vivo in a 120-day bedrest study]. AB - Effects of 120-d bed rest on chromosomal aberration rate were studied in lymphocytes of human peripheral blood in vivo. Chromosomal analysis revealed statistically significant increases in dicentrics and paired acentric fragments in blood lymphocytes of human test-subjects. PMID- 20169744 TI - [Innovative accounting for human psychophysiological capability in aviation and cosmonautics (conference data overview)]. PMID- 20169745 TI - Cooking and drying as effective mechanisms in limiting the zoonotic effect of Mycobacterium bovis in beef. AB - For this study 48 non-infected muscle, lymphatic and visceral bovine tissue samples were collected from an approved red meat abattoir and spiked with 8 x 10(7) cfu/ml of M. bovis. The different spiked samples were subjected to cooking and drying (drying through the process of biltong-making) processes in a controlled laboratory environment. Mycobacterial isolates confirmed as M. bovis by means of polymerase chain reaction (PCR) were observed in 17 of a total of 576 samples that were exposed to the secondary processing method of cooking. The study showed that not only can M. bovis survive the cooking process but the survival of the bacterium will be determined by its unique adaptive changes to the surrounding composition of the environment. The results for the samples exposed to the drying process (n = 96) did not show any growth, suggesting that the process of biltong production as used in this study is likely to render infected meat safe for human consumption. PMID- 20169746 TI - Assessment of viability and acrosomal status of Asian elephant (Elephas maximus) sperm after treatment with calcium ionophore and heparin. AB - Knowledge about the acrosomal status of Asian elephant (Elephas maximus) sperm is extremely limited. The objective of this study was to evaluate the viability and acrosomal status of Asian elephant sperm following induction by calcium ionophore and heparin using propidium iodide (PI) and fluorescein isothiocyanate conjugated peanut agglutinin (FITC-PNA). Semen samples were collected from elephant bulls by manual stimulation. Semen was diluted with extender, cooled to 4 degrees C and transported to a laboratory for the experiment. Sperm cells were incubated in modified Tyrode's medium containing either 1 mM calcium ionophore or 10 mg/ml heparin for 5 h at 39 degrees C. Sperm recovered at the onset (0 h), 1, 2, 3, 4 and 5 h of incubation were simultaneously assessed for the viability and acrosomal status using dual staining of FITC-PNA and PI. Results were confirmed by transmission electron microscopy. A progressive increase in the proportion of live-acrosome reacted sperm was observed within 3 h of incubation in both treatment groups which slightly decreased at 4 to 5 h of incubation. At 1 to 3 h of incubation, the percentage of live-acrosome reacted sperm induced by calcium ionophore was higher (P < 0.05) than those induced by heparin and the control. However, there were no statistical differences at 4 to 5 h of incubation. A progressive reduction of the percentage of motile sperm was observed in the control as well as both treatment groups. Sperm motility decreased sharply when they were incubated in calcium ionophore compared with incubation in heparin and control groups. These results indicate that the occurrence of live-acrosome reacted sperm in the Asian elephant was induced by calcium ionophore at a rate higher than that induced by heparin. PMID- 20169747 TI - The epidemiology of lion lentivirus infection among a population of free-ranging lions (Panthera leo) in the Kruger National Park, South Africa. AB - Feline immunodeficiency virus is a lentivirus of domestic cats that causes significant lifelong infection. Infection with this or similar lentiviruses has been detected in several nondomestic feline species, including African lions (Panthera leo). Although lion lentivirus (FIVple) infection is endemic in certain lion populations in eastern and southern Africa, little is known about its pathogenic effects or its epidemiological impact in free-ranging lions. This report describes the epidemiological investigation of lentivirus positivity of free-ranging lions in the Kruger National Park, South Africa. A nested polymerase chain reaction assay for virus detection was performed on all whole blood samples collected. In addition, serum samples were tested for cross-reactive antibodies to domestic feline lentivirus antigens and to puma lentivirus synthetic envelope peptide antigen. The results were analysed in conjunction with epidemiological data to provide a descriptive epidemiological study on lion lentivirus infection in a free-ranging population of lions. The overall prevalence of lentivirus infection was 69%, with a prevalence of 41% in the north of the park, and 80% in the south. Adult males had the highest prevalence when combining the factors of sex and age: 94%. The lowest prevalences were found among juveniles, with male juveniles at 29%. Adults were 5.58 times more likely to test positive for FIVple than juveniles, with adult males being 35 times more likely to be test positive for FIVple compared with juvenile males. This research represents the 1st epidemiological study of the lion lentivirus among free-ranging lions in the Kruger National Park. PMID- 20169748 TI - Economic assessment of the performance of trypanotolerant cattle breeds in a pastoral production system in Kenya. AB - Cattle are the major source of food security and income for pastoral farmers in sub-Saharan Africa. However, infectious and parasitic diseases remain a major constraint to improved cattle productivity in the region. The use of animal health economics to support decision-making on cost-effective disease control options is increasingly becoming important in the developing world. Trypanotolerant indigenous Orma/zebu cattle in a trypanosomosis-endemic area of Kenya were evaluated for economic performance using gross-margin analysis and partial-farm budgeting. Orma/zebu and Sahiwal/zebu cross-bred cattle were exposed to similar husbandry practices and monitored for growth rate, incidence of common infections (trypanosomosis, anaplasmosis, babesiosis, East Coast Fever and helminthosis) and the cost of treatment assessed. Interview questionnaires were also used to assess the preference rating of the 2 breeds. Results indicated that incidence of infection was trypanosomosis 3%, anaplasmosis 58%, babesiosis 11%, East Coast Fever 22% and helminthosis 28%, with no significant difference between breeds. The Orma/zebu and Sahiwal/zebu breeds had comparable economic benefits, hence a pastoralist in Magadi division is likely to get similar returns from both breeds. This study therefore recommends adoption of not only the Sahiwal/zebu but also the Orma/zebu breed for cattle improvement in trypanosomosis endemic areas and conservation of indigenous genetic resources. PMID- 20169749 TI - Prevalence of clinical and subclinical mastitis and quality of milk on smallholder dairy farms in Tanzania. AB - A cross sectional study was conducted during October and November 2006 on 69 smallholder dairy farms with lactating cows in Mvomero and Njombe districts Tanzania, to determine the prevalence of mastitis and to assess the milk quality on the study farms. Clinical mastitis was investigated using clinical changes of udder and milk at animal level. Cow-side California Mastitis Test (CMT) and microbiological cultures were used to assess subclinical mastitis at quarter level. Milk quality was determined on bulk milk samples at herd level using alcohol and acidity tests, butter fat content, total solids, ash content as well as Delvotest for antimicrobial residues. Overall prevalence of clinical mastitis at herd level in both districts was 21.7% (n = 69). Based on CMT, prevalence of subclinical mastitis at animal level was 51.6% (n = 91). Prevalence of bacterial isolates at animal level was 35.2% (n = 91) while for fungal it was 16.7% (n = 90). Based on CMT results, prevalence of subclinical mastitis at quarter level was 30% (n = 353), while for bacteria and fungi it was 16% and 6% respectively. Contamination of milk with antimicrobial residues was 4.5% (n = 67). The milk quality parameters for most of the milk samples were within acceptable levels. Findings in this study have demonstrated high prevalence of subclinical mastitis that may contribute to low productivity of dairy cattle in both districts. About 20% of CMT subclinical cases had no involvement of microbial pathogens that suggested the need for minimal interventions with antimicrobial agents. These findings call for use of udder disinfectants and improved milking hygiene as intervention strategies to control mastitis on the smallholder dairy farms in Tanzania. PMID- 20169750 TI - After-hours equine emergency admissions at a university referral hospital (1998 2007): causes and interventions. AB - Medical records of equine after-hours admissions from 1998 to 2007 are reviewed. Data extracted from the medical records included signalment, reason for admission, pre-admission treatment, clinical presentation, procedures performed, final diagnoses, complications occurring in hospital, length of stay and outcome. Eight hundred and twenty after-hours admissions were available of which 75% were classified as emergencies. Most horses originated from Gauteng province (82%), with Thoroughbred, Arabian, and Warmbloods representing 46%, 10% and 7% of horses. Horses had a median age of 7 years and were predominantly male (60%). Gastrointestinal (64%) and musculoskeletal (19%) disorders were the primary reasons for admission. Anti-inflammatories, sedation and antibiotics were given in 51%, 20% and 15% of cases respectively prior to referral. On admission, 23% of horses had surgical intervention. Intravenous catheterisation (64%), rectal examination (61%), nasogastric intubation (56%), abdominocentesis (33%) and ultrasonography (19%) were the procedures performed most frequently. Surgical and medical colics constituted 28% and 27% respectively of the overall diagnoses, while piroplasmosis was diagnosed in 5% of horses. Post-admission complications occurred in <2% of horses. The median length of stay was 4 days (95% CI: 1 to 21 days). Overall survival to discharge was 74%. This study demonstrates that the majority of after-hours equine admissions to a university referral hospital required medical intervention and were mostly due to gastrointestinal disorders. Information obtained from this study can be used in emergency referral planning. PMID- 20169751 TI - Efficacy of a genotype 2 Newcastle disease vaccine (Avinew) against challenge with highly virulent genotypes 5d and 3d. AB - Since 2002, following its introduction, the lineage 5d Newcastle disease virus (so-called Goose paramyxovirus - GPMV) strain has caused numerous disease outbreaks among commercial and backyard poultry in South Africa, raising questions about the ability of commercially available Newcastle disease vaccines to fully protect poultry against the strain. This study aimed to determine whether there are differences in the level of protection offered by Avinew Newcastle disease vaccine against GPMV virus as compared with a 3d Newcastle disease virus isolated in South Africa in 1993 (Rainbow challenge virus - RCV) strain. Six groups of 10-day-old, specific pathogen-free chickens were vaccinated with doses of 10(3.0), 10(4.5) and 10(6.0) EID50 of Avinew vaccine and challenged at 4 weeks of age intramuscularly at a dose of 10(5.3) EID50/0.2 ml/bird of GPMV and RCV. No statistically significant difference could be found in the protection offered by Avinew vaccine against GPMV as compared to RCV challenge. The protection offered against the ND challenge was found to be dose dependent. At the recommended field dose of 10(6.0) EID50 the vaccine gave 100% protection from mortality against both the challenge viruses, but not against infection and replication of the viruses, as gross lesions were evident even in apparently healthy birds that survived the challenge. The protective dose (PD90) of the Avinew vaccine against GPMV challenge was calculated at 10(4.38) and against that of RCV at 10(4.43). PMID- 20169752 TI - The effects of firocoxib (Previcox) in geriatric dogs over a period of 90 days. AB - The long-term use of non-steroidal anti-inflammatory agents in geriatric dogs with osteoarthritis has not been well studied in veterinary medicine. This study evaluated the effects of firocoxib administered to dogs over 7 years of age for 90 days. Pain and lameness scores were evaluated by the owner weekly for the 1st month and then biweekly through to the end of the study, the veterinarian evaluated the dogs monthly. Serum chemistry, including urea, creatinine, alanine transferase, aspartate transaminase, bile acids and bilirubin, urine specific gravity and a urine dipstick, were performed at monthly intervals. Forty-five dogs were enrolled into the treatment group and 9 into the control group. A total of 33 dogs completed the trial in the treatment group and 8 in the control group. Lameness and pain scores were found to be significantly lower in the treated group from day 30 for most parameters evaluated. Bile acids (although not comparable to controls, with higher mean value and a high standard deviation in the control group; in addition the control group had increased bile acids at day 0) and urea (within normal reference range provided (WNL)) were significantly different in the treatment group between days 0 and 90. Urea (WNL) on days 30 and 90 and creatinine (WNL) on day 90 were significantly different between the control group and the treatment group. The most common adverse events reported were diarrhoea, vomition, dark faeces and anorexia. This study showed that firocoxib was effective in managing pain associated with osteoarthritis for 90 days. Despite the geriatric high-risk population used for this study, minimal biochemical changes were seen and adverse drug events seen were in agreement with those previously reported. PMID- 20169753 TI - Preliminary assessment of the AAI Index during isoflurane anaesthesia in dogs undergoing clinical procedures. AB - The auditory evoked potential (AEP) is correlated to anaesthetic depth. The AEP has been used in rats, pigs, dogs and humans to assess anaesthetic depth. This study was undertaken to determine whether the AAI Index derived from the AEP correlated with changes in end tidal isoflurane concentration in dogs. The average AAI Index was 21.8 +/- 10.5 and isoflurane concentration was 1.7 +/- 0.4%. Data were divided into 0.5% intervals of end tidal anaesthetic agent concentration (ETAA). When ETAA values were higher than 2.5% the AAI values were 2.1-2.5%, 1.6-2.0% and 1.1-1.5% higher than AAI values although not statistically different. The 2.1-2.5 % interval was statistically different from the 1.1-1.5% and <1.1% interval. The 1.6-2.0% interval was statistically different from the 1.1-1.5% and the <1.1% intervals. The 1.1-1.5% interval was statistically different from the <1.1% interval. The correlation between the AAI Index and isoflurane was -0.176 and was statistically significant (P = 0.0009). A linear regression between the AAI Index and isoflurane revealed the following relationship: AAI = 29.074 - (4.2755 x isoflurane) with a power of 0.913. The polynomial regression relationship was AAI = 53.334 - (35.715 x isoflurane) + (10.322 x isoflurane2) - (0.43646 x isoflurane3) with a power of 0.999. The AAI Index was found to correlate with changes in isoflurane concentration. PMID- 20169754 TI - A survey of ectoparasites, cestodes and management of free-range indigenous chickens in rural Zimbabwe. AB - A survey of ectoparasites, cestodes and husbandry aspects of indigenous free range chickens was carried out in selected districts from the highveld and lowveld of rural Zimbabwe. The survey recorded infection with 4 species from the order Phthiraptera (lice), 1 species from the order Siphonaptera (fleas), 6 species from the order Acarina (ticks and mites) and 9 species of cestodes. Among the ectoparasites, the most prevalent was Menacanthus stramineus (87.7%) followed by Echidinophaga gallinacea (71.9%). Chickens in the Mazowe district had the highest number of ectoparasites species (10 of 11) followed by Goromonzi district (9 of 11) both these districts are situated in the highveld of Zimbabwe. The most prevalent cestode species was Raillietina tetragona (84.4%), followed by Raillietina echinobothrida (32.2%). Chickens in the Goromonzi district had the highest number of cestode species (7 of 9), followed by Mazowe district (one subgenus and 5 of 9). In all the districts sampled the main purpose of keeping free-range chickens was for meat for the household, with few households using the birds as a source of income. The majority of households kept their birds extensively with barely any appropriate housing, and supplementary feeding was only occasionally practised. PMID- 20169755 TI - Causes of gastrointestinal colic at an equine referral hospital in South Africa (1998-2007). AB - The most common causes of gastrointestinal colic at an equine referral hospital in South Africa were determined following retrieval of the medical records of horses admitted during a 10-year study period. The study included 935 horses of which 28% were admitted after hours. Most horses were Thoroughbreds (54%), male (57%), with a mean age of 8.2 years and originated from the Gauteng Province (81%). Heart rate (98%), mucous membrane colour (95%) and auscultation of the abdomen (91%) were the clinical data commonly obtained at admission. Packed cell volume, total serum protein and white cell count were recorded in 78%, 75% and 44% of horses respectively. Transrectal palpation (93%), nasogastric intubation (84%), intravenous catheterisation (74%) and abdominocentesis (53%) were the most frequently performed procedures. Medical intervention was performed in 558 horses (60%). The common causes of medical colic were impactions (39%), tympany (7%) and displacement of the large colon (6%). An exploratory laparotomy was performed in 331 horses (36%). The common causes of surgical colic were displacement (29%), impaction (22%) and small intestinal strangulating lesions (18%). Death occurred in 3% of horses, while euthanasia before medical intervention was performed in 4%. Overall, medical intervention was successful in 93% of horses and 67% in horses managed surgically. In conclusion, 55% of all the equine admissions responded to medical intervention and the recovery rate for horses receiving both medical and surgical intervention was comparable to that reported in other studies. PMID- 20169756 TI - Urinary bladder botryoid rhabdomyosarcoma with widespread metastases in an 8 month-old Labrador cross dog. AB - An 8-month-old crossbred Labrador retriever was presented with a history and clinical signs suggestive of lower urinary tract obstruction. Laboratory results revealed azotaemia and hyperphosphataemia. Ultrasonographic evaluation of the urinary tract showed a mass at the bladder trigone, hydronephrosis, hyrodureter, and suspected metastases to lymph nodes and the liver. Pulmonary metastasis was identified on thoracic radiographs. A post mortem confirmed metastases to the liver, lungs and regional lymph nodes, as well as to the mesenteric lymph nodes, mediastinum, heart, subcutaneous tissue and several muscle groups. A histopathological diagnosis of metastatic botryoid rhabdomyosarcoma (sarcoma botryoides) was made. A review of the literature shows that, although the bladder trigone is a well documented location for this tumour, this case was unique with its widespread metastases to previously undocumented organs. The incidence, embryology, ultrasonographic appearance and treatment of this tumour are discussed. PMID- 20169757 TI - The effect of coaching intervention on elite fast bowling technique over a two year period. AB - Fast bowling in cricket is an activity that is well recognised as having high injury prevalence and there has been debate regarding the most effective fast bowling technique. The aim of this study was to determine whether two-year coaching interventions conducted in a group of elite young fast bowlers resulted in fast bowling technique alteration. Selected kinematics of the bowling action of 14 elite young fast bowlers were measured using an 18 camera Vicon Motion Analysis system before and after two-year coaching interventions that addressed specific elements of fast bowling technique. Mann-Whitney tests were used to determine whether any changes in kinematic variables occurred pre- and post intervention between those who had the coaching interventions and those who didn't. The coaching interventions, when applied, resulted in a more side-on shoulder alignment at back foot contact (BFC) (p = 0.002) and decreased shoulder counter-rotation (p = 0.001) however, there was no difference in the degree of change in back and front knee flexion angles or lower trunk side-flexion. This study has clearly shown that specific aspects of fast bowling technique are changeable over a two-year period in elite level fast bowlers and this may be attributed to coaching intervention. PMID- 20169758 TI - Cycling with noncircular chainring system changes the three-dimensional kinematics of the lower limbs. AB - This study investigated the three-dimensional (3-D) pedaling kinematics using a noncircular chainring system and a conventional system. Five cyclists pedaled at their preferred cadence at a workload of 300 W using two crank systems. Flexion/extension of the hip, knee and ankle as well as shank rotation, foot adduction/abduction, and pedal angle were measured. Joint range of motion (ROM) and angular displacements were compared between the systems. Sagittal plane ROM was significantly greater (P < 0.05) at the hip (noncircular system = 39 +/- 3 degrees; conventional system = 34 +/- 4 degrees) the knee (noncircular system = 69 +/- 4 degrees; conventional system = 57 +/- 10 degrees), and ankle (noncircular system = 21 +/- 2 degrees; conventional system = 19 +/- 4 degrees) resulting in greater pedal ROM (noncircular system = 43 +/- 3 degrees; conventional system = 37 +/- 5 degrees) while using the noncircular system. Shank rotation ROM was significantly lower (P < 0.05) while using the noncircular chainring (noncircular system = 10 +/- 1 degree; conventional system = 14 +/- 1 degree). These results support a significant effect of the noncircular chainring system on pedaling kinematics during submaximal exercise. PMID- 20169759 TI - Application of functional principal component analysis in race walking: an emerging methodology. AB - This study considered the problem of identifying and evaluating the factors of individual performance during race walking. In particular, the study explored the use of functional principal component analysis (f-PCA), a multivariate data analysis, for assessing and classifying the kinematics and kinetics of the knee joint in competitive race walkers. Seven race walkers of international and national level participated to the study. An optoelectronic system and a force platform were used to capture three-dimensional kinematics and kinetics of lower limbs during the race walking cycle. Functional principal component analysis was applied bilaterally to the sagittal knee angle and net moment data, because knee joint motion is fundamental to race walking technique. Scatterplots of principal component scores provided evidence of athletes' technical differences and asymmetries even when traditional analysis (mean +/- s curves) was not effective. Principal components provided indications for race walkers' classification and identified potentially important technical differences between higher and lower skilled athletes. Therefore, f-PCA might represent a future aid for the fine analysis of sports movements, if consistently applied to performance monitoring. PMID- 20169760 TI - Relative shank to thigh length is associated with different mechanisms of power production during elite male ergometer rowing. AB - The effect of anthropometric differences in shank to thigh length ratio upon timing and magnitude of joint power production during the drive phase of the rowing stroke was investigated in 14 elite male rowers. Rowers were tested on the RowPerfect ergometer which was instrumented at the handle and foot stretcher to measure force generation, and a nine segment inverse dynamics model used to calculate the rower's joint and overall power production. Rowers were divided into two groups according to relative shank thigh ratio. Time to half lumbar power generation was significantly earlier in shorter shank rowers (p = 0.028) compared to longer shank rowers, who showed no lumbar power generation during the same period of the drive phase. Rowers with a relatively shorter shank demonstrated earlier lumbar power generation during the drive phase resulting from restricted rotation of the pelvic segment requiring increased lumbar extension in these rowers. Earlier lumbar power generation and extension did not appear to directly affect performance measures of the short shank group, and so can be attributed to a technical adaptation developed to maximise rowing performance. PMID- 20169761 TI - Biomechanical pole and leg characteristics during uphill diagonal roller skiing. AB - Diagonal skiing as a major classical technique has hardly been investigated over the last two decades, although technique and racing velocities have developed substantially. The aims of the present study were to 1) analyse pole and leg kinetics and kinematics during submaximal uphill diagonal roller skiing and 2) identify biomechanical factors related to performance. Twelve elite skiers performed a time to exhaustion (performance) test on a treadmill. Joint kinematics and pole/plantar forces were recorded separately during diagonal roller skiing (9 degrees; 11 km/h). Performance was correlated to cycle length (r = 0.77; P < 0.05), relative leg swing (r = 0.71), and gliding time (r = 0.74), hip flexion range of motion (ROM) during swing (r = 0.73) and knee extension ROM during gliding (r = 0.71). Push-off demonstrated performance correlations for impulse of leg force (r = 0.84), relative duration (r= -0.76) and knee flexion (r = 0.73) and extension ROM (r = 0.74). Relative time to peak pole force was associated with performance (r = 0.73). In summary, diagonal roller skiing performance was linked to 1) longer cycle length, 2) greater impulse of force during a shorter push-off with larger flexion/extension ROMs in leg joints, 3) longer leg swing, and 4) later peak pole force, demonstrating the major key characteristics to be emphasised in training. PMID- 20169762 TI - Effects of a power-focussed resistance training intervention on backward grinding performance in America's Cup sailing. AB - This study determined whether backward grinding performance in America's Cup sailing could be improved using a training intervention to increase power capability in the upper-body pull movement. Fourteen elite male sailors (34.9 +/- 5.9 years; 98.1 +/- 14.4 kg; 186.6 +/- 7.7 cm) were allocated into experimental (speed-focussed) and control groups. Grinding performance was assessed using a grinding ergometer and an instrumented Smith machine measured force, velocity and power during the bench pull exercise. Conventional training produced significant improvements in bench pull 1 RM (5.2 +/- 4.0%; p = 0.016) and maximum force production (5.4 +/- 4.0%; p = 0.014). Speed-focussed training improved maximum power (7.8 +/- 4.9%; p = 0.009), power at 1 RM (10.3 +/- 8.9%; p = 0.019) and maximum velocity (8.4 +/- 2.6%; p = 0.0002). Backward grinding performance showed greater improvements in the experimental group than the control group for moderate (+1.8%) and heavy load (+6.0%) grinding. Changes in maximum power output and power at 1 RM had large correlations (r = 0.56-0.61) with changes in both moderate and heavy load grinding performance. Time to peak force had the strongest relationship, explaining 70% of the change in heavy load grinding performance. Although the performance benefit was not entirely clear the likelihood of a detrimental effect was low (< 5%) and therefore implementation could be recommended. PMID- 20169763 TI - A toy model that predicts the qualitative role of bar bend in a push jerk. AB - In this work, we describe a simple coarse-grained model of a barbell that can be used to determine the qualitative role of bar bend during a jerk. In simulations of this model, we observed a narrow time window during which the lifter can leverage the elasticity of the bar in order to lift the weight to a maximal height. This time window shifted to later times as the weight was increased. In addition, we found that the optimal time to initiate the drive was strongly correlated with the time at which the bar had reached a maximum upward velocity after recoiling. By isolating the effect of the bar, we obtained a generalized strategy for lifting heavy weight in the jerk. PMID- 20169764 TI - Hydrodynamics of undulatory underwater swimming: a review. AB - Undulatory underwater swimming (UUS) occurs in the starts and turns of three of the four competitive swimming strokes and plays a significant role in overall swimming performance. The majority of research examining UUS is comparative in nature, dominated by studies comparing aquatic animals' undulatory locomotion with the UUS performance of humans. More recently, research directly examining human forms of UUS have been undertaken, providing further insight into the factors which influence swimming velocity and efficiency. This paper reviews studies which have examined the hydromechanical, biomechanical, and coordination aspects of UUS performance in both animals and humans. The present work provides a comprehensive evaluation of the key factors which combine to influence UUS performance examining (1) the role of end-effector frequency and body amplitudes in the production of a propulsive waveform, (2) the effects of morphology on the wavelength of the propulsive waveform and its subsequent impact on the mode of UUS adopted, and (3) the interactions of the undulatory movements to simultaneously optimise propulsive impulse whilst minimising the active drag experienced. In conclusion, the review recommends that further research is required to fully appreciate the complexity of UUS and examine how humans can further optimise performance. PMID- 20169765 TI - Admission and acute complication rate for outpatient lumbar microdiscectomy. PMID- 20169766 TI - Diagnosis of prodromal Alzheimer's disease: do you really want to know? PMID- 20169767 TI - Non-invasive ventilation for Canadian patients with ALS: do we have consensus? PMID- 20169768 TI - Acute stroke imaging. Part I: Fundamentals. AB - Neuroimaging is essential to stroke diagnosis and management. To date, the non contrast CT has served as our main diagnostic tool. Although brain parenchymal changes visible on CT do provide valuable prognostic information, they provide limited insight into the potential for tissue salvage in response to reperfusion therapy, such as thrombolysis. Newer advanced CT and MRI based imaging techniques have increased the detection sensitivity for hyperacute and chronic parenchymal changes, including ischemia and hemorrhage, permit visualization of blood vessels and cerebral blood flow. This review outlines the basic principles underlying acquisition and interpretation of these newer imaging modalities in the setting of acute stroke. The utility of advanced brain parenchymal and blood flow imaging in the context of acute stroke patient management is also discussed. Part II in this series is a discussion of how these techniques can be used to rationally select appropriate patients for thrombolysis based on pathophysiological data. PMID- 20169769 TI - Acute stroke imaging. Part II: The ischemic penumbra. AB - In acute ischemic stroke, the volume of threatened but potentially salvageable tissue, i.e. the ischemic penumbra, is critical to the success of all acute therapeutic interventions, most notably thrombolysis. Despite the availability of both CT and MRI based techniques to detect and assess the penumbra, advanced imaging of this type remains under-utilized. Although the optimal selection criteria are still being refined and technical improvements are ongoing, rapid imaging of the penumbra appears to be the most promising approach to expanding the acute thrombolysis population, as well as tailoring treatment based on specific pathophysiological findings. This second article in a two-part series reviews current evidence for penumbral-based treatment selection and discusses the barriers to implementation of these advanced imaging techniques in acute stroke management protocols. PMID- 20169770 TI - Disability and survival of multiple sclerosis in Saskatoon, Saskatchewan. AB - BACKGROUND: A population-based prevalent group of 150 clinical definite patients ascertained on 1 January 1977, in Saskatoon, Saskatchewan, was followed for 30 years. OBJECTIVES: To outline the clinical characteristics, determine the levels of disability at 15, 25, 35, 40, and 45 years after onset, to estimate the survival after onset and life expectancy. METHODS: Clinical records were maintained, and the cohort reviewed each decade for 30 years. The disability levels according to the Kurtzke Extended Disability Status Scale were recorded and survival times were estimated. SPSS and Kaplan-Meier methods were used for analysis. RESULTS: On prevalence day, 1 January 1977, there were 48 (32%) men and 102 (68%) women, with an average age of onset of 32.2 +/- 10 years and 28.4 +/- 8.6 years. The average duration of disease was 15.7 years. On 1 January 2007, 39 (26%) patients were living, 105 (70%) deceased, and 6 (4%) were missing The disability levels recorded in 1977 and 2007, at 15 and 45 years after onset, were mild (EDSS < or = 2.5), 33.3% and 8.0%; moderate (EDSS3-5.5), 17.3% and 2.7%; severe (EDSS6-7.5), 6.6% and 4.7%; maximum (EDSS8-9.5), 22.7% and 10.7%. The median survival time after onset was 33 (95% CI: 27.3-38.6) years for men and 38 (95% CI: 34.1-41.9) years for women. The median duration of life was 68.9 years for men and 69.5 years for women, and a decreased life expectancy of 7.7 and 12.8 years. CONCLUSIONS: Multiple sclerosis is a progressive neurological disorder and long-term survival is associated with moderate to severe disability and decreased life expectancy. PMID- 20169771 TI - Pseudoprogression following chemoradiotherapy for glioblastoma multiforme. AB - PURPOSE: Pseudoprogression (psPD) is now recognised following radiotherapy with concurrent temozolomide (RT/TMZ) for glioblastoma multiforme (GBM). The aim of this study was to determine the incidence of psPD following RT/TMZ and the effect of psPD on prognosis. MATERIALS/METHODS: All patients receiving RT/TMZ for newly diagnosed GBM were identified from a prospective database. Clinical and radiographic data were retrospectively reviewed. Early progression was defined as radiological progression (RECIST criteria) during or within eight weeks of completing RT/TMZ. Pseudoprogression was defined as early progression with subsequent disease stabilization, without salvage therapy, for at least six months from completion of RT/TMZ. The primary outcome was overall survival (Kaplan-Meier) and log rank analysis was used to compare groups. RESULTS: Out of 111 patients analyzed, 104 were evaluable for radiological response. Median age was 58 years and median follow-up 55 weeks. Early progression was confirmed in 26% and within this group 32% had psPD. Median survival for the whole cohort was 56.7 weeks [95% CI (51.0, 71.3)]. Median survival for patients with psPD was significantly higher than for patients with true early progression (124.9 weeks versus 36.0 weeks, p = 0.0286). CONCLUSIONS: Approximately one third of patients with early progression were found to have psPD which was associated with a favourable prognosis. Maintenance TMZ should not be abandoned on the basis of seemingly discouraging imaging features identified within the first three months after RT/TMZ. PMID- 20169772 TI - External ventricular drains and mortality in patients with severe traumatic brain injury. AB - PURPOSE: To determine our institutional adherence to the Brain Trauma Foundation guidelines with respect to intracranial pressure (ICP) monitoring, and examine the relationship between external ventricular drain (EVD) use and mortality. MATERIALS & METHODS: Retrospective cohort study of 171 patients with severe traumatic brain injury (TBI). Propensity score adjusted logistic regression was used to model the association between EVD use and mortality. RESULTS: EVDs were inserted in 98 of 171 patients. Of the 73 patients without an EVD, 63 (86%) would have qualified for ICP monitoring under the current guidelines. EVDs were in situ for a median of 8 days (SD 6). In adjusted analyses, EVD use was associated with hospital mortality (OR 2.8, 95% CI: 1.1 - 7.1, p = 0.04) and 28-day mortality (OR 2.1, 95% CI: 0.80 - 5.6, p = 0.13). We observed significant modification of the association between EVD and 28-day mortality by GCS within 12 hours (p interaction = 0.04), indicating strong association only among those patients with GCS score of at least 6 (OR 5.0, 95% CI: 1.5 - 16.7, p < 0.01). CONCLUSIONS: The association of EVD with 28-day mortality was only apparent among patients with GCS score of > or = 6. Further research is warranted to further refine which patients may benefit from ICP monitoring. PMID- 20169773 TI - Admission and acute complication rate for outpatient lumbar microdiscectomy. AB - OBJECTIVE: Specialization is generally independently associated with improved outcomes for most types of surgery. This is the first study comparing the immediate success of outpatient lumbar microdiscectomy with respect to acute complication and conversion to inpatient rate. Long-term pain relief is not examined in this study. METHODS: Two separate prospective databases (one belonging to a neurosurgeon and brain tumor specialist, not specializing in spine (NS) and one belonging to four spine surgeons (SS)) were retrospectively reviewed. All acute complications as well as admission data of patients scheduled for outpatient lumbar microdiscectomy were extracted. RESULTS: In total, 269 patients were in the NS group and 137 patients were in the SS group. The NS group averaged 24 cases per year while the SS group averaged 50 cases per year. Chi square tests revealed no difference in acute complication rate [NS (6.7%), SS (7.3%)] (p > 0.5) and admission rate [NS (4.1%), SS (5.8%)] (p = 0.4) while the SS group had a significantly higher proportion of patients undergoing repeat microdiscectomy [NS (4.1%), SS (37.2%)] (p < 0.0001). Excluding revision operations, there was no statistically significant difference in acute complication [NS (5.4%), SS (1.2%)] (p = 0.09) and conversion to inpatient [NS (4.3%), SS (4.6%)] (p > 0.5) rate. The combined acute complication and conversion to inpatient rate was 6.9% and 4.7% respectively. CONCLUSION: Based on this limited study, outpatient lumbar microdiscectomy can be apparently performed safely with similar immediate complication rates by both non-spine specialized neurosurgeons and spine surgeons, even though the trend favored the latter group for both outcome measures. PMID- 20169774 TI - NIPPV: prevalence, approach and barriers to use at Canadian ALS centres. AB - OBJECTIVE: The purpose of this study was to evaluate Canadian amyotrophic lateral sclerosis (ALS) centres with respect to: 1) the prevalence of Non-invasive positive pressure ventilation (NIPPV) and invasive mechanical ventilation via tracheostomy (TV) utilization, 2) the approach to NIPPV use, focusing upon the currently employed initiation criteria and 3) the barriers influencing NIPPV administration. METHODS: A descriptive survey research design aimed to obtain quantitative data and open-ended responses from an active physician at each of the 15 multidisciplinary Canadian ALS centres. RESULTS: The principal findings of this study were: 1) NIPPV and TV are used in 18.3% and 1.5% of patients at Canadian ALS centres, respectively, 2) symptoms of respiratory insufficiency, namely orthopnea (clinical significance rated at 9.00/10 +/- 1.48), dyspnea (8.27 +/- 1.95) and morning headache (7.55 +/- 1.21) are the most significant indicators for NIPPV initiation, 3) the primary barriers to NIPPV utilization are patient intolerance (70% of centres) and inaccessibility of respirologists and ventilation technologists (50% of centres). CONCLUSIONS: Variability in NIPPV use has an impact upon the management of Canadian ALS patients. The establishment of more definitive NIPPV initiation criteria, emphasizing respiratory symptoms, and the attenuation of barriers to NIPPV use should be targeted so as to ensure optimal care for all ALS patients. PMID- 20169776 TI - Diagnosis disclosure of prodromal Alzheimer disease-ethical analysis of two cases. AB - BACKGROUND: According to a recent proposal for revised diagnostic criteria for Alzheimer disease, the diagnosis could be made even in the absence of impairment of social function or daily life activities, provided positivity of one or more abnormal biomarkers. The use of the new proposed diagnostic criteria raises ethical issues and needs to be carefully evaluated. METHOD: We describe two clinical cases of prodromal Alzheimer's disease and discuss the diagnosis disclosure, taking into consideration several issues: (i) the issue of the boundary between well founded research procedures and clinical practice, (ii) the issue of the fuzziness of the concepts of scientific evidence and scientific uncertainty, (iii) the issue of patient's autonomy and patient's best interest, and (iv) the issue of the patients' specific personal and social context. RESULTS: The degree of informativeness of the proposed diagnostic criteria for the single patient is already such as to deserve high regard in making the diagnosis and in the diagnosis disclosure process. During the disclosure process, the physician needs to take into account both what is known and what it is not sufficiently known. The patient's personal and environmental conditions should drive the physician to partial or full diagnostic disclosure, or delay communication. CONCLUSION: We proposed two different diagnosis disclosure processes, on the basis of the common neurological features and of the different global clinical situations, socio-personal contexts and attitudes towards the communication of the diagnosis. PMID- 20169777 TI - Predictors of unfavourable seizure outcome in patients with epilepsy in Nepal. AB - BACKGROUND: Despite optimal medical therapy, a sizeable number of patients continue to have persistent seizures. We evaluated the association of pretreatment and treatment variables with unfavorable seizure outcome. METHODS: Patients with follow-up over 12 years in the Nepal Epilepsy Association were evaluated. Patients having seizures for at least a year and already on polytherapy after failure of two monotherapy trials were considered having unfavourable outcome. Variables under study were: age, sex, duration and frequency of seizures prior to treatment, type of seizure, neurological status, Computed Tomography (CT) finding, and failure of first anti-epileptic drug (AED). Bivariate analysis was done with Chi-square and Fisher exact tests. Potential interaction between variables was studied with a logistic regression analysis. RESULTS: Out of a total 529 consecutive patients, 490 were included in the study. Unfavorable seizure outcome was seen in 26.8% of patients. Among 284 patients who remained viable for analysis, bivariate analysis showed significant association of unfavorable outcome with frequency of seizure (p 0.01), abnormal neurological status (p 0.01) and failure of first AED (p 0.00), while no significant association was seen with age at onset (p 0.45), sex (p 0.47), duration of seizure (p 0.43), type of seizure (p 0.12), and presence of CT abnormality (p 0.46). The fitted regression model portended an unfavorable prognosis with failure of first AED and abnormal neurological status, however, failed to show significant association with frequency of seizure. CONCLUSIONS: Failure of first AED trial and associated neurological deficits are significant predictors of unfavorable seizure outcome. PMID- 20169775 TI - Depression in Parkinson's disease. AB - OBJECTIVE: To examine predictive factors associated with onset of depression among individuals diagnosed with Parkinson's disease (PD). BACKGROUND: Depression may precede or follow symptomatic parkinsonism in PD. It is frequently treatable but often overlooked. METHODS: The clinical series comprised 685 individuals who were diagnosed with PD and followed by one neurologist (RJU) from 1994 to 2007. The primary outcome was time to depression following the onset of PD. Diagnosis of depression was based on clinical assessment of depressive symptoms from patients (and spouse/family/caregiver) and antidepressant usage. A number of demographic, historical and clinical predictive factors were examined, including gender, age at symptomatic onset, disease duration, onset characteristics, clinical ratings, antiparkinsonian medications, cognitive status, depression history, and familial history of PD and other neurodegenerative disorders. RESULTS: Seventy-two percent of patients developed depression within ten years of symptomatic PD onset, and the mean time to depression was 7.9 years (median: 5.7 years). Factors associated with depression included longer PD duration, greater impairment in activities of daily living, and positive family history of motor neuron disease (MND). CONCLUSIONS: A high rate of individuals with PD develop depressive symptoms during the course of the disease. Based on first clinic visit characteristics, most factors examined were not helpful in identifying individuals with an increased risk of depression. However, disease duration, functional limitations and family history of MND should lead clinicians to an increased vigilance for identifying depression. PMID- 20169778 TI - Minocycline protects dopaminergic neurons against long-term rotenone toxicity. AB - BACKGROUND: In Parkinson's disease, most of current therapies only provide symptomatic treatment and so far there is no drug which directly affects the disease process. OBJECTIVES: To investigate the neuroprotective effects of minocycline against long-term rotenone toxicity in primary dopaminergic cell cultures. METHODS: Embryonic mice of 14-days-old were used for preparation of primary dopaminergic cell cultures. On the 6th day in vitro, prepared cultures were treated both with minocycline alone (1, 5, 10 and 20 microM) and concomitantly with rotenone (5 and 20 nM) and minocycline. Cultures were incubated at 37 degrees C for six consecutive days. On Day in vitro culture medium was aspirated and used for measuring lactate dehydrogenase. Cultured cells were fixed in 4% paraformaldhyde and stained immunohistochemically against tyrosine hydroxylase. RESULTS: Treatment of cultures with 5 and 20 nM of rotenone significantly decreased the survival of tyrosine hydroxylase immunoreactive neurons by 27 and 31% and increased the release of lactate dehydrogenase into the culture medium by 31 and 236%, respectively compared to untreated controls. Minocycline (1, 5, 10 microM) significantly protected tyrosine hydroxylase immunoreactive neurons by 17, 15 and 19% and 13, 22 and 23% against 5 and 20 nM of rotenone, respectively compared to rotenone-treated cultures. Minocycline (only at 10 microM) significantly decreased the release of lactate dehydrogenase by 79% and 133% against 5 and 20 nM of rotenone, respectively. CONCLUSION: Minocycline has neuroprotective potential against the progressive loss of tyrosine hydroxylase immunoreactive neurons induced by long-term rotenone toxicity in primary dopaminergic cultures. PMID- 20169779 TI - Neuropsychiatric behaviors in the MPTP marmoset model of Parkinson's disease. AB - OBJECTIVES: Neuropsychiatric symptoms are increasingly recognised as a significant problem in patients with Parkinson's disease (PD). These symptoms may be due to 'sensitisation' following repeated levodopa treatment or a direct effect of dopamine on the disease state. The levodopa-treated MPTP-lesioned marmoset was used as a model of neuropsychiatric symptoms in PD patients. Here we compare the time course of levodopa-induced motor fluctuations and neuropsychiatric-like behaviors to determine the relationship between duration of treatment and onset of symptoms. METHODS: Marmosets were administered 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (2.0 mg/kg s.c.) for five days, resulting in stable parkinsonism. Levodopa (15 mg/kg and benserazide, 3.75 mg/kg) p.o. b.i.d, was administered for 30 days. Animals were evaluated for parkinsonian disability, dyskinesia and on-time (motor fluctuations) and neuropsychiatric-like behaviors on Day 0 (prior to levodopa) and on Days 1, 7, 13, 27 and 30 of treatment using post hoc DVD analysis by a trained rater, blind to the treatment day. RESULTS: The neuropsychiatric-like behavior rating scale demonstrated high interrater reliability between three trained raters of differing professional backgrounds. As anticipated, animals exhibited a progressive increase in levodopa-induced motor fluctuations, dyskinesia and wearing-off, that correlated with the duration of levodopa therapy. In contrast, levodopa-induced neuropsychiatric-like behaviors were present on Day 1 of levodopa treatment and their severity did not correlate with duration of treatment. CONCLUSIONS: The data suggest that neuropsychiatric disorders in PD are more likely an interaction between levodopa and the disease state than a consequence of sensitisation to repeated dopaminergic therapy. PMID- 20169780 TI - Acquired monocular nystagmus as the initial presenting sign of a chiasmal glioma. PMID- 20169781 TI - Use of natalizumab in multiple sclerosis patients. PMID- 20169782 TI - Neuroembryology education for paediatric neurology and neuropathology trainees in Canada. PMID- 20169783 TI - Genome-wide TDT analysis in French-Canadian families with Tourette syndrome. PMID- 20169784 TI - Damage of white matter in the parietal lobe results in anomic alexia of kana. PMID- 20169785 TI - Frontal variant of Alzheimer's disease: clinico-CSF-pathological correlation. PMID- 20169786 TI - Systemic sclerosis, transient neurological symptoms, and macrovascular disease. PMID- 20169787 TI - Delayed neurologic complications of vertebral bone cement injections. PMID- 20169788 TI - Restricted diffusion and poor clinical outcome in cerebral fat embolism syndrome. PMID- 20169789 TI - Skull base hemangiopericytoma: treatment options. PMID- 20169790 TI - Vessel reconstruction in acute basilar artery occlusion. PMID- 20169791 TI - Marchiafava-Bignami disease (MBD) in a nonalcoholic patient: a case report. PMID- 20169792 TI - Seizure recurrence 29 years after hemispherectomy for Sturge Weber syndrome. PMID- 20169793 TI - Doctor-patient privilege. AB - Doctor-patient privilege, while it does not exist at common law, has a significant and lengthy history under Australian law. It currently exists under differing statutory formulations in Victoria, Tasmania and the Northern Territory. Whether it should continue to have a place in Australia's evidence law was a significant issue canvassed by the Australian Law Reform Commission's reports on Evidence during the 1980s. The privilege is controversial but, for pragmatic, strategic reasons, relatively rarely availed of--for fear of adverse inferences being drawn from its invocation. In addition, there are many circumstances in which it has been found to have been waived by necessary disclosure by plaintiffs in both personal injury and medical negligence litigation. This editorial examines a recent decision of Judd J of the Victorian Supreme Court in Elliott v Tippett (2008) 20 VR 195; [2008] VSC 175 in which the plaintiff was not permitted to invoke the privilege. It argues that, although the aspiration of protecting the confidentiality of doctor-patient communications deserves support, there is little to be said in favour of retention of the statutory forms of the privilege currently in force in Australia. PMID- 20169794 TI - Review of New Zealand's Health and Disability Commissioner Act and Code of Rights. AB - This column discusses some key issues considered in the third review of New Zealand's Code of Patients' Rights and its complaints regime, a system which is generally working well. The review considered whether a broad access right should included in the Code, and supported a narrower right in the disability area. In a notable omission the Code has never included a right to the confidentiality of health information. The review would remedy this gap. An intriguing submission sought the inclusion in the Code of a right to be treated with compassion. Legislative amendment of a narrow definition of "aggrieved person", which has the effect of restricting access to the tribunal with a damages jurisdiction, was recommended. A recommendation to allow research on incompetent patients to proceed if "not known to be contrary to the best interests" of the consumer warrants consideration of further options before implementation. PMID- 20169795 TI - Ecstasy: as harmful as heroin? AB - There is evidence that the use of MDMA (methylenedioxymethamphetamine), colloquially known as "ecstasy" particularly among late adolescents and young adults is increasing in Australia. Despite recent government-sponsored public education programs, there is a perception that recreational use of MDMA is much less harmful than other illicit substances like heroin. Recent seizures by police in Australia underline the extent of the demand for MDMA and how lucrative trafficking in MDMA has become. In two recent Australian cases, appellate courts considered the legislative intent of both State and Commonwealth legislation and held that a quantity-based penalty regime applied which distinguished between "traffickable" and "commercial" quantities of illicit drugs and that no distinction turned on the relative "harmfulness" of MDMA. In examining the question of harmfulness, this column summarises the pharmacology and morbidity of MDMA and considers the links between MDMA and other substances of abuse and the implications for further prevention programs. PMID- 20169796 TI - Withdrawing treatment at the direct or indirect request of patients or in their best interests: HNEAHS v A; Brightwater CG v Rossiter; and Australian Capital Territory v JT. AB - In Hunter and New England Area Health Service v A [2009] NSWSC 761; Brightwater Care Group (Inc) v Rossiter [2009] WASC 229; and Australian Capital Territory v JT [2009] ACTSC 105 Australian courts have recently considered the circumstances in which technically futile treatment may be withdrawn from patients at their direct or indirect request or purportedly in their best interests. The cases provide many valuable lessons about how norms of ethics, law and international human rights shape the regulatory framework of this area of health care in Australia. PMID- 20169797 TI - Sovereignty and international politics in the negotiation of the avian influenza Material Transfer Agreement. AB - Indonesia's action in 2007 to withhold samples of avian influenza viruses was a declaration of sovereignty over biological resources. This assertion of sovereign rights resulted in conflicting international views which can be broadly characterised as a demonstration of the diverse perspectives between the developed and developing countries about the fair and equitable use of biological resources and the acknowledgment of sovereignty within that context. The relevant international agreements were drafted with the use of acceptable diplomatic language that hides the varied political views of the participants. The use of neutral language results in different interpretations of the final text; this is particularly relevant to the application of the Convention on Biological Diversity and the International Health Regulations to the sharing of virus samples. Within this political context the intended interpretation of the text becomes difficult to determine. This article illustrates the political conflicts in the context of the sharing of virus samples and benefits and determines that the likely resolution will be through political compromise. PMID- 20169798 TI - Making public health policy: what place for the alcohol-dependent? AB - Although public policy in general, and health policy in particular, can be powerful and effective tools in shaping a "healthy" environment for citizens, the influences and agendas that underpin them are often lacking in transparency. In the case of the alcohol-dependent, the critical importance of identifying strategies appropriate to their specific needs is often sidelined. This, it is argued, results in part from the influence of the alcohol industry on governments and on social conditions and in part from the ethical underpinnings of public health policy, which depends on maximising social benefits even at the expense of "hard to reach" groups. In addition, much of alcohol policy rests on the kind of' "healthy living" message that appeals to the otherwise healthy While not infantilising people who are dependent on alcohol, consideration must be given to the extent to which their ability to choose health is compromised by the nature of dependence itself. PMID- 20169799 TI - Public policy on alcohol in the United Kingdom: towards a safety net for the alcohol-dependent. AB - Public policy on alcohol in the United Kingdom fails to support, and may even undermine, the wellbeing of those with the worst alcohol misuse problems, the alcohol-dependent. This is partly because it evades the thorny issue of impaired control that characterises dependence. In addition, until recently, all United Kingdom alcohol policy focused on improving individualised treatment for the dependent, rather than attending to the wider social and environmental factors that influence the condition. The efforts of policy to normalise "sensible" drinking, while stigmatising drunkenness, also risk exacerbating the social vulnerability of the alcohol-dependent. The article examines these issues and concludes by pointing to a number of developments that are required to help ensure that the dependent do not continue to fall through policy that claims to be inclusive. PMID- 20169800 TI - Drugs, discrimination and disability. AB - Whether addiction to prohibited drugs should be classified as a disability for the purposes of disability discrimination is a controversial question in Australia. The leading Australian case of Marsden v Human Rights Equal Opportunity Commission & Coffs Harbour & District Ex-Servicemen & Women's Memorial Club Ltd (HREOC, No H98/51, 30 August 1999); [2000] FCA 1619 concerned a disability discrimination complaint brought by Mr Marsden as a result of his treatment by the club. The case was brought as a public interest test case by the New South Wales Legal Aid Commission. Mr Marsden was on a methadone program at the time. The reasoning of the decision at the Federal Court opened the way for a finding that dependence on illegal drugs constituted a disability under disability discrimination legislation. The media reaction to the court's decision led to State and federal governments proposing legislation limiting legal protection from discrimination for people addicted to illegal drugs on the basis of their drug use. While the proposed federal legislation lapsed after objections from a coalition of medical, legal and other advocacy groups, the New South Wales legislation still provides that, in employment matters, it is not unlawful to discriminate against a person on the ground of disability if the disability relates to the person's addiction to a prohibited drug and the person is actually addicted to a prohibited drug at the time of the discrimination. The article details the sequence of events in the Marsden case, reflects on the role of public interest litigation in achieving social justice outcomes and suggests that Australia's recent ratification of the Convention on the Rights of Persons with Disabilities on 17 July 2008 should encourage legislators to review legislation which may have a discriminatory effect on people suffering from addictions. PMID- 20169801 TI - Developing an equivalent to the National Medicines Policy for medical devices. AB - While Australia has enjoyed the benefits of a National Medicines Policy (NMP) for many years, there is no equivalent national policy for medical devices. This is despite an established medical device legal framework that spans multiple departments across the Australian Government. The existing NMP offers an effective and proven benchmark for the development of a national medical devices policy. The four NMP principles of industry, standards, access and use are applicable to all phases of the medical device life-cycle and align with existing medical devices policy. This article proposes that Australia's approach to medical devices stands to benefit from an equivalent whole-of-government policy. PMID- 20169802 TI - Can we prevent doctors being complicit in torture? Breaking the serpent's egg. AB - A significant minority of the tortured prisoners who survive report that a doctor was present during their torture. Yet few medical practitioners are ever criminally prosecuted or even disciplined by their regulatory bodies. Can such gross violations of the Hippocratic Code be so easily ignored or are these doctors carefully shielded from detection and prosecution by a grateful state? Mostly doctors act to vet prisoners for their capacity to withstand the torture or resuscitate them to allow torture and interrogation to continue. However, on occasion, the "healers" may be the actual torturers as happened in Russian psychoprisons in the latter part of the 20th century. This article argues that the de facto immunity which complicit doctors currently appear to enjoy must be stripped away and replaced by effective processes to detect and then prosecute criminal behaviour. This will require widespread reporting of cases and action by international bodies, including non-government organisations. Prevention is clearly preferable and this will require improvements in undergraduate and graduate medical education about international humanitarian and human rights law. There is evidence that many medical faculties pay scant attention to this education and their students graduate with serious flaws in their understanding and attitudes towards human rights. Education should target "doctors at risk" in prisons, armed forces and the police. It should address professional behaviour which tolerates or even protects cultures of abuse. A code of professional conduct would assist "doctors at risk" to resist overtures for them to become complicit in torture, Medical Practice Acts should include statements on respecting human rights when defining good professional conduct. Doctors who become complicit in torture betray their profession. Swift action should be taken to stop such abuses and perpetrators should receive strong disciplinary action from regulatory bodies. PMID- 20169803 TI - Necessity to palliate pain and suffering as a defence to medical homicide. AB - The courts, in applying the criminal law in relation to homicide, rely heavily on determining the cause of death, and the existence of intention to cause death. The inadequacy of such processes in relation to prosecutions for medical actions at the end of life is discussed. The principle that there is no "special defence" for doctors is refuted. The legal and ethical obligation of doctors to respect their patients' autonomy, and maximally relieve their pain and suffering, creates a special and exposed position for doctors treating patients near life's end. The result is a quasi-legal practice in which doctors achieve such relief, even though it may commonly hasten death. This medical and legal position has its basis in hypocrisy and obfuscation. The astonishing rarity of prosecution of doctors indicates a "benign conspiracy" on the part of prosecutorial authorities in this regard. It is argued that a transparent and objectively sustainable defence to medical homicide would be a defence based on the necessity to palliate pain and suffering, combined with documented consent by the sufferer to the provision of such palliation. PMID- 20169804 TI - Regulating preimplantation genetic diagnosis: a criminal model versus a professional model. AB - This article examines a criminal and professional approach to the regulation of preimplantation diagnosis (PGD) in the two Australian States of Victoria and New South Wales. Under the Assisted Reproductive Treatment Act 2008 (Vic), Victorian medical practitioners face criminal sanctions if they ignore legal requirements. The criminal sanctions do not apply directly to patients, but those seeking PGD treatment have to satisfy guiding legislative principles, statutory rules and the controversial new "presumption against treatment" hurdle. On the other hand, the Assisted Reproductive Technology Act 2008 (NSW) does not specifically address PGD and medical practitioners in New South Wales are not subject to criminal sanctions but must follow the National Health and Medical Research Council Guidelines. As far as patients in New South Wales are concerned, PGD is essentially a medical procedure. In both Victoria and New South Wales, PGD practice is relatively liberal compared to that in many other countries, although the Victorian approach is clearly the more restrictive model of regulation with the threat of criminal sanctions overriding the medical practitioner's ethical duty to act in the best interests of a patient. PMID- 20169805 TI - Presenting testimony before the Institution of Medicine. PMID- 20169806 TI - Designing and pilot-testing a church-based community program to reduce obesity among African Americans. AB - Obesity raises the risk for many chronic diseases and poor health outcomes. African Americans have the highest rates of excess weight in the nation, and standard weight management programs have not worked well with this population. The Genesis Health Project, a community-designed, culturally competent intervention to reduce obesity and promote healthy lifestyles, represents a successful partnership among Syracuse University, local Black churches, and several sponsors to empower families of color to adopt and sustain positive health practices across the lifespan. This article describes the Phase I design and pilot-testing of this demonstration project, and reports the results of the first-year nutrition education/exercise-fitness program. Participant feedback indicates notable shifts toward healthier food choices, cooking methods, and exercise habits, as well as increased motivation, improved health indicators, and revamped church menus. Lessons learned from this project can be helpful in developing other community/faith-based health promotion programs for African Americans. PMID- 20169807 TI - The Coppin Academy for Pre-Nursing Success: a model for the recruitment and retention of minority students. AB - There is a clearly documented need for greater minority representation in professional nursing as the nation grows more diversified. Increasing the ranks of minority nurses will assist both in alleviating the nursing shortage and in addressing the health care disparities that plague our healthcare systems. One barrier has been the recruitment and retention of underserved minority nursing students. To address this, the Coppin State University Helene Fuld School of Nursing (HFSON) in Baltimore, Maryland developed and implemented the "Coppin Academy for Pre-Nursing Success" (CAPS), a comprehensive year-round pre-entry baccalaureate preparation program, targeting high school students from disadvantaged backgrounds who are interested in a nursing career. CAPS graduates have met or exceeded goals in retention, passing rate on the nursing licensure exam, and service to the community. As a result, the program is growing, and the School plans to replicate the CAPS model, not only in surrounding communities, but in other vulnerable and under-served urban settings in the nation. PMID- 20169808 TI - Tales from the "hood:" placing reproductive health communication between African American fathers and children in context. AB - OBJECTIVE: To evaluate reproductive health communication between African American fathers and their children. DESIGN: In this qualitative ethnographic study, data were collected through tape-recorded individual interviews about the content and timing of reproductive health communication, the reproductive health values fathers intended to impart to their children, and their comfort level in doing so. SAMPLE: A total sample of 19 African-American fathers participated. MEASUREMENTS: Data were coded according to the qualitative analytic principles established by Miles and Huberman (1994), and analyzed using manifest and latent content analysis approaches. RESULTS: Although 10 fathers reported feeling uncomfortable having these conversations, 18 reported having reproductive health communication with their children, and most encouraged their sons and daughters to delay sex until adulthood. These conversations were primarily driven by the fear of HIV/AIDS and the negative consequences of sex; however, some conversations were inappropriate for developmental age. CONCLUSIONS: African American fathers may benefit from education to help them have age appropriate reproductive health communication with their children. Registered Nurses and Nurse Practitioners are well positioned to educate African American adolescents and their fathers on reproductive health. Future dyadic African American father child studies are needed to explore more fully African-American children's perceptions of reproductive health communication and the effect on delaying sex. PMID- 20169809 TI - Race, stability of health insurance coverage, and prescription medication use. AB - OBJECTIVE: To determine the effects of health insurance and race on prescription medication use and expense. METHODS: An observational, non-experimental design was used. Multivariable regression analyses were conducted to evaluate the independent effects of health insurance status and race on prescription medication use and expense while controlling for sociodemographic, geographic, and health status characteristics. The sample consisted of 19,035 participants in the 1996 through 2003 Medical Expenditure Panel Survey. FINDINGS: European Americans spent about $300 to $400 more and used three to four more prescriptions annually compared to other racial groups. Prescription medication expenses increased as time spent uninsured increased. Participants with part-year coverage filled four fewer prescriptions than those with full-year health insurance coverage. Participants with private coverage spent less on prescription medications compared to those with public and those with dual public and private coverage ($1,194 vs. $1,931 and $2,076, respectively; p < or = 0.001). CONCLUSIONS: Significant racial and health insurance status disparities in prescription medication use and expenses exist after controlling for sociodemographic, geographic, and health status characteristics. PMID- 20169811 TI - [Violence against aged people. "We must deal with violence"]. PMID- 20169810 TI - [2010, a year of bridge building]. PMID- 20169812 TI - [Interview with Elsbeth Luginbuhl. "The culture of failure is decided in industry"]. PMID- 20169813 TI - [Twelve dead, because they were not on nurses' watch]. PMID- 20169815 TI - [Disorderly delegate meeting. Compromises with moderate gaps]. PMID- 20169814 TI - [Pregnancy in advanced age. Information and counsel are essential]. PMID- 20169817 TI - [Stressful situations. From the emergency station to accusation]. PMID- 20169816 TI - [Career model for nurses. From the specialist to the expert]. PMID- 20169818 TI - [Equal problems, distinctive consequences]. PMID- 20169819 TI - [Visionary personalities at the beginning: Anna Heer and Walter Sahli]. PMID- 20169820 TI - [Prevention under the magnifying glass. Between liberty and responsibility]. PMID- 20169821 TI - [Developmental disabilities. A helpful environment for little children]. PMID- 20169822 TI - [Project moulding in palliative nursing. Better response to moral suffering]. PMID- 20169823 TI - [Project of Swiss diagnostic related groups and nurses. Taking into account the welfare of nurses]. PMID- 20169824 TI - ["Dependencies." Peculiar trajectories]. PMID- 20169825 TI - [Analysis of the active components of a complex intervention for the care]. PMID- 20169826 TI - [Quality of the clinical reports: observational study in Sassari]. AB - Within the program of clinical risk management, and in particular in the phase of the "knowledge" of company reality, the work deals with the topic of the case history in Sassari' local health authority. A study is treated where, on a sample of about 400 cases history, four definite aspects are considered, in particular those that are regarded as the most important in the risk management and about medical responsability: 1) formal consent; 2) daily clinical allowance; 3) therapeutic card; 4) operating card. The results we got show the presence of a formal consent filled in correctly in 36 cases (9%), completed a daily allowance in 36 cases (9%), therapeutic card in 14 (3.5%) cases, operation card in 21 cases (19% su 116 surgical cases). These data, that have permitted to estimate the specific company reality as from pointed out critical states, show the necessity of working, with involvement of professional doctors, to build a history case model with clear and shared rules where you can clearly find the clinical path of a patient, where everything made is quoted and easily readable when necessary. PMID- 20169827 TI - [Managing the hospitalizations for older patients in University Hospital of Pisa]. AB - We have analyzed hospitalizations of older people (> 64) from 2002 to 2005. Patients, discharges and stay in hospital have increased, the variation has been statistically significant. We have noticed the same trend about the rehospitalizations. Patients and discharges coming from ASL 5 and zone 4 have decreased in relation with all the elderly people. The reduction of stay in hospital and the decrease of rehospitalizations have been statistically significant. PMID- 20169828 TI - Mediterranean lifestyle: nutritional education on-line. AB - Our goal is to spread on-line the Italian Weekly Pyramid, a tool designed to convey both portion size and frequency of food intake. The Pyramid is referring to the "Well-being Index" (WI) as a unit for an adequate lifestyle. The user can verify his weekly lifestyle by participating to a "game" based on food/beverages consumption and time assigned to physical activity. The site has been visited by 15920 individuals, of whom 4033 completed the game. Self-selected sample, not representative of the Italian population. The data collected included WI consumption by gender for each food group compared to WI suggested. Statistical data evaluation has been performed with the SPSS inc.13 program, without applying any statistical significance to the results. The sample showed a varied eating pattern; all the food groups were consumed almost daily, albeit in much lower quantities with regards to the suggested WI. Fruit and vegetable consumption was higher in women, while men showed a higher intake of meat and cut meats. The percentage of the participants consuming more WI with respect to the recommended amounts was very low for fruit, vegetable, pasta and bread, while was much higher as regards energy dense food. PMID- 20169829 TI - [A survey on diet manuals in Italian hospitals]. AB - Hospital catering is very important to counteract the onset of malnutrition due to either undernutrition or overnutrition and for dietetic treatment. The aim of the study was to evaluate nutritional quality of the hospital dietetic manual used in some Italian hospitals and to analyze the role of the institutional Catering Service and of the Department of Clinical Nutrition. A survey has been carried out, in some Italian hospitals, using a questionnaire to point out the characteristics of hospitals, the typology of catering service, of the diets and of the staff of the Department of Clinical Nutrition. Only 22% of the hospitals has answered; three Italian regions (Umbria, Molise, Basilicata) are completely missing; -each hospital has a specific dietetic manual in most cases completely different from structure and nutritional quality point of view; the staff acting in this field is absolutely insufficient in term of numerousness and of professional typologies. Hospital in-patients are not homogeneous as for age, dietary needs and diseases, so it's necessary to treat them with an ad hoc nutritional intervention not established in advance in a dietetic manual; if from an organisation point of view it is necessary to have such a dietetic manual, it has to be based on nutritional guidelines and recommended dietary allowances. PMID- 20169830 TI - [Tour operator liability in health protection for not informing travellers about health risks they could be exposed]. AB - Consumer-tourist is considered the weaker bargaining party in an "all included" travel contract, compared with tour organizer and tour vendor. That's why Statute Act protecting consumer's rights provides a specific discipline concerning this particular sector In front of widening of warrants for travellers, obligations for organizer and seller of the travel have been increased, and include now specific duty to inform travellers as well. According to the law such duties of information are consistent with travel contract performance itself. In such way, failing to inform client constitutes a breach of contract liable not only in the field of civil responsibility; the subject liable with such an omission may face criminal prosecution as well. More specifically we are in front of a breach of contract by the tour organizer who will respond of all damages concerned with such a breach. Damages will concern not only the price of the travel package, but also other damages connected with the illness suffered by traveller: compensation for spoiled holidays, biological damages, patrimonial damages (these last ones could include for instance expenses for medical treatments, just to quote the more likely one). In other words, tour organizer has to grant general organization of the tour which has to take place as specified on travel brochure, but traveller have to be provided also with any information, concerning documents necessary for the travel, whether passport or visa are needed or not, vaccinations peremptory or optional. It will be very difficult for tour operator be exempted from liability for damages if traveller hasn't been informed of health risks; the only possibility consists in managing to demonstrate that the obligation hasn't been compelled due to reason for which the operator couldn't be held responsible. Besides as we have already mentioned before, criminal relevance of such omission of information couldn't be excluded. In fact, it's true that such omission, notwithstanding its preventive nature, needs a specific statute provision to be criminally sanctioned. Anyhow a criminal court can consider such omission in a more articulated landscape, as one of highly symptomatic elements in a criminal behaviour within criminal offence of injuries, consumed or attempted, that could be performed through further actions or omissions. PMID- 20169831 TI - [Specific antisepsis and environmental disinfection in preventing "Clostridium difficile associated diarrhea"]. AB - In the last years, Clostridium difficile acquired great interest for public health because of constant increase of Clostridium difficile associated diarrhea (CDAD), especially in nosocomial field and as a consequences of its pathogenicity and virulence. Oro-faecal transmission and great environmental persistence of Clostridium difficile indicate hand hygiene of health care workers and environmental disinfection practices as key interventions for prevention and control of nosocomial CDAD. The current indications relative to the hand hygiene suggest the use of soap and water for hand washing and, to achieve a better compliance of health care workers to this treatment, the alternative use of sodium dichloroisocyanurate or alcohol-based solution or gel waterless. Regard to environmental disinfection, to avoid high concentrations of sodium hypochlorite (in the magnitude of 5.000-6.000 ppm), necessary to reduce microbic load of dirty environment, the most appropriate treatment should consist of 2 phases: preliminary cleaning with water and detergents or polyphenol, followed by treatment with solution containing 1.000 ppm available chlorine, obtained from sodium hypochlorite or sodium dichloroisocyanurate. PMID- 20169832 TI - [Effects of different chicken breeding on microbiological characteristics of fresh eggs]. AB - The influence of three different systems of chicken breeding (battery, outdoor and free-range type) on contamination of the shell, yolk and albumen on category A eggs was evaluated. The eggs collected from free-range type did not resulted in conforming according to Italian legislation (5%) that foresees total absence of Salmonella spp. both on shells that yolk and albumen. Moreover the handled eggs can transmit microorganisms present on the shell because non-hygienic operator's hands favour horizontal bacterial transmission. In conclusion, this survey revealed that the breeding type as well as storing time and handling quality influence the product quality. PMID- 20169834 TI - Medical devices: partnering for success. PMID- 20169833 TI - Invasive pneumococcal infections in infants up to three years of age: results of a longitudinal surveillance in North-East Italy. AB - Pneumococcus is considered one of the main causes of the infections acquired in the community setting and also seems to be the most frequent cause of community acquired pneumonia in children under 5 years of age. To establish suitable preventive measures as vaccination policy, it would be important to document the incidence of IPD. The main feature of this study was that it demanded a cooperative effort between family pediatricians and those working in the hospitals to estimate the real burden of IPD in children aged 0-36. From 1 January 2003 to 31 December 2003, a prospective active surveillance of clinical cases due to S. pneumoniae was conducted by 87 specifically-trained sentinel pediatricians [all family pediatricians] randomly selected from among those working in North-East Italy. Suspected pneumococcal infections were confirmed by blood cultures at the laboratories of the hospitals involved in the study. 32 cases were suspected, 12 of those proved positive on blood culture and 6 of these 12 confirmed cases were hospitalized. 2 were cases of meningitis, 1 of pneumonia and 9 of bacteremia. The cumulative annual incidence was 58.9 cases/100,000 infants aged 0-36 months (95% CI 30.38-102.71), meaning that North-East Italy can be classified as a mesoendemic area. This study demonstrated that the incidence of IPD in infants aged (0-36 months) is often under-estimated, documenting the importance of prospective active surveillance for assisting rational choices for public health issues. PMID- 20169835 TI - The role, responsibilities and status of the clinical medical physicist in AFOMP. AB - This document is the first of a series of policy statements being issued by the Asia-Oceania Federation of Organizations for Medical Physics (AFOMP). The document was developed by the AFOMP Professional Development Committee (PDC) and was endorsed for official release by AFOMP Council in 2006. The main purpose of the document was to give guidance to AFOMP member organizations on the role and responsibilities of clinical medical physicists. A definition of clinical medical physicist has also been provided. This document discusses the following topics: professional aspects of education and training; responsibilities of the clinical medical physicist; status and organization of the clinical medical physics service and the need for clinical medical physics service. PMID- 20169836 TI - A brief review of radiation hormesis. AB - This paper reviews physical, experimental and epidemiological evidence for and against radiation hormesis and discusses implications with regards to radiation protection. The scientific community is still divided on the premise of radiation hormesis, with new literature published on a regular basis. The International Commission on Radiological Protection (ICRP) recommends the use of the Linear No Threshold (LNT) model, for planning radiation protection. This model states that the probability of induced cancer and hereditary effects increases with dose in a linear fashion. As a consequence, all radiation exposures must be justified and have a sufficient protection standard in place so that exposures are kept below certain dose limitations. The LNT model has sufficient evidence at high doses but has been extrapolated in a linear fashion to low dose regions with much less scientific evidence. Much experimentation has suggested discrepancies of this extrapolation at low doses. The hypothesis of radiation hormesis suggests low dose radiation is beneficial to the irradiated cell and organism. There is definite standing ground for the hormesis hypothesis both evolutionarily and biophysically, but experimental evidence is yet to change official policies on this matter. Application of the LNT model has important radiation protection and general human health ramifications, and thus it is important that the matter be resolved. PMID- 20169837 TI - Fractal-feature distance analysis of contrast-detail phantom image and meaning of pseudo fractal dimension and complexity. AB - The purposes of our studies are to examine whether or not fractal-feature distance deduced from virtual volume method can simulate observer performance indices and to investigate the physical meaning of pseudo fractal dimension and complexity. Contrast-detail (C-D) phantom radiographs were obtained at various mAs values (0.5 - 4.0 mAs) and 140 kVp with a computed radiography system, and the reference image was acquired at 13 mAs. For all C-D images, fractal analysis was conducted using the virtual volume method that was devised with a fractional Brownian motion model. The fractal-feature distances between the considered and reference images were calculated using pseudo fractal dimension and complexity. Further, we have performed the C-D analysis in which ten radiologists participated, and compared the fractal-feature distances with the image quality figures (IQF). To clarify the physical meaning of the pseudo fractal dimension and complexity, contrast-to-noise ratio (CNR) and standard deviation (SD) of images noise were calculated for each mAs and compared with the pseudo fractal dimension and complexity, respectively. A strong linear correlation was found between the fractal-feature distance and IQF. The pseudo fractal dimensions became large as CNR increased. Further, a linear correlation was found between the exponential complexity and image noise SD. PMID- 20169838 TI - Dose and absorption spectra response of EBT2 Gafchromic film to high energy x rays. AB - With new advancements in radiochromic film designs and sensitivity to suit different niche applications, EBT2 is the latest offering for the megavoltage radiotherapy market. New construction specifications including different physical construction and the use of a yellow coloured dye has provided the next generation radiochromic film for therapy applications. The film utilises the same active chemical for radiation measurement as its predecessor, EBT Gafchromic. Measurements have been performed using photo spectrometers to analyse the absorption spectra properties of this new EBT2 Gafchromic, radiochromic film. Results have shown that whilst the physical coloration or absorption spectra of the film, which turns yellow to green as compared to EBT film, (clear to blue) is significantly different due to the added yellow dye, the net change in absorption spectra properties for EBT2 are similar to the original EBT film. Absorption peaks are still located at 636nm and 585nm positions. A net optical density change of 0.590 +/- 0.020 (2SD) for a 1 Gy radiation absorbed dose using 6 MV x rays when measured at the 636nm absorption peak was found. This is compared to 0.602 +/- 0.025 (2SD) for the original EBT film (2005 Batch) and 0.557 +/- 0.027 (2009 Batch) at the same absorption peak. The yellow dye and the new coating material produce a significantly different visible absorption spectra results for the EBT2 film compared to EBT at wavelengths especially below approximately 550nm. At wavelengths above 550nm differences in absolute OD are seen however, when dose analysis is performed at wavelengths above 550nm using net optical density changes, no significant variations are seen. If comparing results of the late production EBT to new production EBT2 film, net optical density variations of approximately 10 % to 15 % are seen. As all new film batches should be calibrated for sensitivity upon arrival this should not be of concern. PMID- 20169839 TI - A method for patient set-up guidance in radiotherapy using augmented reality. AB - A system for patient set-up in external beam radiotherapy was developed using Augmented Reality (AR). Live images of the linac treatment couch and patient were obtained with video cameras and displayed on a nearby monitor. A 3D model of the patient's external contour was obtained from planning CT data, and AR tracking software was used to superimpose the model onto the video images in the correct position for treatment. Throughout set-up and treatment, the user can view the monitor and visually confirm that the patient is positioned correctly. To ensure that the virtual contour was displayed in the correct position, a process was devised to register the coordinates of the linac with the camera images. A cube with AR tracking markers attached to its faces was constructed for alignment with the isocentre using room lasers or cone-beam CT. The performance of the system was investigated in a clinical environment by using it to position an anthropomorphic phantom without the aid of additional set-up methods. The positioning errors were determined by means of CBCT and image registration. The translational set-up errors were found to be less than 2.4 mm and the rotational errors less than 0.3 degrees. This proof-of-principle study has demonstrated the feasibility of using AR for patient position and pose guidance. PMID- 20169840 TI - Lead attenuation characteristics models. AB - Lead attenuation characteristic curves are often consulted in premises radiation shielding assessments employing the non-destructive testing (NDT) method. This study developed lead attenuation characteristics mathematical models for the radionuclide Co-57. These models take into account the statistical variation of the attenuation characteristics. The results are a set of equations that a NDT assessor can use to predict the range of transmission factors for the NDT measurement or, using the inverse functions, to gauge the lead equivalence (with the associated uncertainty) of a radiation barrier. This study showed that the combined effect of types of statistical variations can form an uncertainty region on the transmission characteristics such that the relative uncertainty decreases for values of lead mass per unit area up to approximately 20 kg/m2 and 15 kg/m2 for the Ludlum 18 and Ludlum 2241-2 survey meters respectively but thereafter increases. PMID- 20169841 TI - Simulation of corneal tissue mechanical deformation due to laser thermokeratoplasty: a finite element methods study. AB - Laser thermokeratoplasty (LTK) is the ophthalmologic procedure used for the correction of hyperopia. In this paper, the grid compartmentalization, loading and restriction of cornea model were reported based on the principle and process of LTK. The corneal deformation and the change of curvature radius were analyzed with different operation parameters. The effects of different parameters on the corneal curvature were obtained and consequently the effects on the diopter correction were determined. It was found that eye pressure only had a small effect on the changes of cornea diopter. Under the same eye pressure, the greater the diameter of operation area changed, the greater the corneal curvature changed with a more obvious operation efficacy. To obtain a significant operation efficacy, the diameter of operation area should not be less than 4.5 mm. PMID- 20169842 TI - Performance of Al2O3:C optically stimulated luminescence dosimeters for clinical radiation therapy applications. AB - A commercial Optical Stimulated Luminescence (OSL) dosimetry system developed by Landauer was tested to analyse the possibility of using OSL dosimetry for external beam radiotherapy planning checks. Experiments were performed to determine signal sensitivity, dose response range, beam type/energy dependency, reproducibility and linearity. Optical annealing processes to test OSL material reusability were also studied. In each case the measurements were converted into absorbed dose. The experimental results show that OSL dosimetry provides a wide dose response range, good linearity and reproducibility for the doses up to 800cGy. The OSL output is linear with dose up to 600cGy range showing a maximum deviation from linearity of 2.0% for the doses above 600cGy. The standard deviation in response of 20 dosimeters was 3.0%. After optical annealing using incandescent light, the readout intensity decreased by approximately 98% in the first 30 minutes. The readout intensity, I, decreased after repeated optical annealing as a power law, given by I infinity t (-1.3). This study concludes that OSL dosimetry can provide an alternative dosimetry technique for use in in-vivo dosimetry if rigorous measurement protocols are established. PMID- 20169843 TI - Slice-based plan evaluation methods for three dimensional conformal radiotherapy treatment planning. AB - Dose volume histograms (DVHs) play a vital role in determining the optimal plan for radiotherapy treatment delivery. The current concepts of conformality index (CI), equivalent uniform dose (EUD) derived from dose volume histogram (DVH) does not provide any spatial information. In this study, slice-based evaluation methods have been proposed for spatially analyzing the radiotherapy treatment plans. A case of prostate cancer has been selected for demonstrating the proposed tools for evaluating the dose distribution. Three dimensional conformal radiotherapy treatment planning (3D-CRT) was performed to a dose of 27 Gy/15# with three fields (6 MV anteroposterior and two 15 MV lateral fields) employing multileaf collimator after delivering 45 Gy/25#. The dose was normalized to isocenter and the treatment plan was evaluated with DVH. The dose maximum point, conformality index, planning target volume coverage index (PCI), planning target volume overdose index (POI) and equivalent uniform dose (EUD) were evaluated for every single slice along the cranio-caudal direction for all the planning target volume (PTV) contours and plotted against the slice location. The dose maximum point plotted against the slice position helps in identifying the slices where the dose maximum point is outside the target volume. The plot of conformality index gives the information about the location of those slices where excess of surrounding normal tissues is encompassed inside the prescription isodose. POI quantifies the high dose regions inside the PTV slices that receive doses above 107% of the prescription dose. Similarly, the plot of PCI and EUD with slice position gives the information about those slices where the tumor is not covered adequately. The proposed methods in this study forms as a simpler way to assess the spatial distribution of the dose inside the target volume. It could be used in combination with the current plan evaluation tools and will be very helpful in analyzing the treatment plans. PMID- 20169844 TI - Autonomous detection of heart sound abnormalities using an auscultation jacket. AB - This paper presents a study using an auscultation jacket with embedded electronic stethoscopes, and a software classification system capable of differentiating between normal and certain auscultatory abnormalities. The aim of the study is to demonstrate the potential of such a system for semi-automated diagnosis for underserved locations, for instance in rural areas or in developing countries where patients far outnumber the available medical personnel. Using an "auscultation jacket", synchronous data was recorded at multiple chest locations on 31 healthy volunteers and 21 patients with heart pathologies. Electrocardiograms (ECGs) were also recorded simultaneously with phonocardiographic data. Features related to heart pathologies were extracted from the signals and used as input to a feed-forward artificial neural network. The system is able to classify between normal and certain abnormal heart sounds with a sensitivity of 84% and a specificity of 86%. Though the number of training and testing samples presented are limited, the system performed well in differentiating between normal and abnormal heart sounds in the given database of available recordings. The results of this study demonstrate the potential of such a system to be used as a fast and cost-effective screening tool for heart pathologies. PMID- 20169845 TI - A comparison of medical physics training and education programs--Canada and Australia. AB - An overview and comparison of medical physics clinical training, academic education, and national certification/accreditation of individual professionals in Canada and Australia is presented. Topics discussed include program organization, funding, fees, administration, time requirements, content, program accreditation, and levels of certification/accreditation of individual Medical Physicists. Differences in the training, education, and certification/accreditation approaches between the two countries are highlighted. The possibility of mutual recognition of certified/accredited Medical Physicists is examined. PMID- 20169846 TI - NMC chief pledges tough approach to poor practice. Interview by Dave West. PMID- 20169847 TI - Health promotion could help us all grow old gracefully. PMID- 20169848 TI - A Slovenian model of integrated care for older people can offer solutions for NHS services. AB - The population in Britain is ageing and creating a burden on healthcare that will require the NHS and social care to deliver innovative strategies. This article outlines a visit to Slovenia to view a model of care that fits in well with the Department of Health's integrated care approach to the care of older people and those with long term conditions. PMID- 20169849 TI - What quality healthcare means to older people: exploring and meeting their needs. AB - BACKGROUND: The over 85s is the fastest growing age group in England and a major user of healthcare services. It is vital to understand what quality healthcare means to this group. AIM: To investigate qualitatively what vulnerable older people value in the NHS and whether these aspirations are being met by policy and practice. METHOD: Face to face interviews were conducted with 20 vulnerable older adults, most of whom were aged over 80, and the findings matched with current policy and practice. RESULTS: Nine aspirations were identified: face to face, personalised and flexible appointments; to retain control in their home; respect for property and belongings; company and the opportunity to be listened to; proactive healthcare and support; choice and control over daily routines; a connected relationship between staff and patients; maintenance of privacy in hospital; and joined-up care. DISCUSSION: Gaps can be identified in each of these areas and the government, healthcare providers and professionals, as well as regulators and professional bodies, need to take steps to ensure policy and practice meet the needs of vulnerable older people. CONCLUSION: There are two main conclusions from this work: older people are more concerned about their needs being met than about who meets them; and if the NHS is serious about delivering quality it needs to listen to patients about what they want rather than making assumptions about this. PMID- 20169850 TI - Depression in adults with long term conditions 2: antidepressant and psychological treatments. AB - The second in this two part unit on depression in people with long term conditions examines the range of treatment options for moderate to severe depression, and for persistent subthreshold/mild to moderate illness that does not respond to treatment. Part 1 discussed the prevalence and causes of depression in this group, identification and assessment, and also outlined initial treatment for mild illness. PMID- 20169851 TI - Using screening tools to identify the risk or presence of depression in older people. AB - Depression is a common mood disorder affecting at least 20% of older people and has been predicted to become one of the world's most disabling illnesses. Perhaps due to its wide range of signs and symptoms, the condition remains notoriously complex to diagnose. Management is typically inadequate and prognosis is bleak. This article examines the use of screening tools for mild depression in those over 65 in primary care, to help determine whether screening would aid recognition and improve patient outcomes. PMID- 20169852 TI - Does oxygen need humidification? PMID- 20169853 TI - Principles to effectively manage people with interstitial lung disease in the community. AB - This article examines the problems of caring for people with interstitial lung disease in primary care. It describes simple strategies that can support people to remain at home during the end stage of their illness. The diagnosis and investigations of ILD have been covered in previous Nursing Times articles (Duck, 2007a; 2007b). PMID- 20169854 TI - We are taking great strides to strengthen nursing roles. PMID- 20169855 TI - Nurses must not aim their frustrations at students. PMID- 20169856 TI - Formulation and characterization of nanoemulsion of olanzapine for intranasal delivery. AB - The objective was to formulate an olanzapine nanoemulsion that could potentially deliver the drug directly to the brain following intranasal administration. The nanoemulsions were prepared using the water titration method. The mucoadhesive character was imparted by the addition of 0.5%w/w chitosan and 0.5%w/w polycarbophil and was characterized for drug content, pH, percentage transmittance, globule size, zeta potential, and PDI. The composition (%w/w) of the optimized olanzapine nanoemulsion was capmul MCM, tween 80, and a mixture of 1:1 ratio of polyethylene glycol 400 and ethanol, and aqueous phase in a ratio of 15:35:17.5:32.5. The optimized olanzapine nanoemulsion exhibited a high diffusion coefficient and no nasal cilio-toxicity. The drug release followed the Higuchi model. The optimized nanoemulsions were found to be stable for 3 months. PMID- 20169857 TI - Preparation and characterization of poly lactide-co-glycolide nanoparticles of SN 38. AB - SN-38 (7-ethyl-10-hydroxycamptothecin) is the active metabolite of irinotecan (CPT-11), which is 100-1000-fold more cytotoxic than irinotecan. Nonetheless, the extreme hydrophobicity of SN-38 has prevented its clinical use. SN-38 is poorly soluble in aqueous solutions, and it is practically insoluble in most physiologically compatible and pharmaceutically acceptable solvents. One way of improving the solubility and stability of SN-38 is to formulate the drug into nanoparticles. Incorporation of cytotoxic agents into nanoparticles has also shown increased toxicity. In this study, poly lactide-co-glycolide was used for the preparation of nanoparticles of SN-38. The nanoparticles were fabricated by an emulsification/solvent evaporation method. The effect of several variables on nanoparticle characteristics was evaluated, including the ratio of drug-polymer, the amount of the poly vinyl alcohol as surfactant, and the internal phase volume/composition. The SN-38 encapsulation efficiency and the particle size distribution were optimized by varying these parameters. Nanoparticles were spherical with a relatively mono-dispersed size distribution. As the ratio of acetone to dichloromethane increased, a considerable decrease in the particle size of nanoparticles was achieved. The encapsulation efficiency of all samples was more than 80%. Changing the poly vinyl alcohol concentration in the external phase had some effects on size and morphology and encapsulation efficiency. It was shown that SN-38 nanoparticles are considerably stable in a long-term stability study. PMID- 20169858 TI - Formulation and evaluation of taste-masked levocetirizine dihydrochloride orally disintegrating tablets. AB - Orally disintegrating tablets of levocetirizine dihydrochloride were formulated with different superdisintegrants (sodium starch glycollate, croscarmellose sodium, and crospovidone) using mannitol as a diluent. Tulsion-335, Indion-204, and poly kyron T-134 cation exchange resins were used as taste-masking agents. The drug and resin complex was prepared by the kneading method. Ten formulations were prepared with varying combinations of superdisintegrants and ion-exchange resins by the wet granulation technique, using polyvinylpyrrolidone K-30 as the binder. The prepared tablets were evaluated for degree of taste masking, weight variation, hardness, friability, in vitro and in vivo disintegration time, content uniformity, and water absorption ratio. Dissolution studies were performed in two dissolution media: 0.1N HCl and distilled water. The corresponding dissolution rates were compared with the marketed formulation. Differential scanning calorimetry studies were carried out on the drug-resin complexes. Prepared tablets were good in appearance and showed acceptable results for hardness and friability. In vitro and in vivo disintegration times for the optimum formulation (F-1) were found to be 22 and 55 s, respectively. Relatively acceptable taste was achieved with both Indion-204 and Tulsion-335. Rapid disintegration time was achieved in tablets containing crosspovidone as the superdisintegrant. Dissolution studies indicated the formation of the complex of drug and resin. Differential scanning calorimetry studies indicated the formation of drug-resin complex. PMID- 20169859 TI - Comprehensive determination of extractables from five different brands of stoppers used for injectable products. AB - Five commonly used stopper formulations were tested for extractables using three different vehicles (pH 3 citrate buffer with 20% w/v sulfobutylether-beta cyclodextrin, pH 8 phosphate buffer and 50/50 v/v polyoxyethylated castor oil/dehydrated alcohol). The stoppers, made from butyl and halobutyl rubbers, coated and uncoated with proprietary films, were stored in contact with each vehicle for up to 6 months at 40 degrees C/75% relative humidity (RH) or for up to 24 months at 25 degrees C/60% RH. Samples were analyzed for the presence of extractables using inductively coupled plasma-atomic emission spectroscopy, ion chromatography, high-performance liquid chromatography, and gas chromatography. Extractables were observed at greater than 10 ppm for only one of the five stoppers that were tested. Based on these results, a standardized protocol for stopper extractable testing was developed. This protocol has been used to satisfy stopper extractable testing regulatory requirements for a number of different new injectable products. PMID- 20169860 TI - Development and evaluation of nefopam transdermal matrix patch system in human volunteers. AB - Nefopam hydrochloride, a nonsteroidal anti-inflammatory drug, is administered in tablet form three times daily or as intramuscular injection at 6-h intervals to treat disorders such as acute or constant pain. It is also used for a prolonged treatment of severe pain, when morphine therapy has to be withdrawn for morphine related dependence. To achieve a constant drug-plasma level of nefopam for a prolonged period, a transdermal drug delivery system was fabricated in our present study by employing suitable experimental hydrophilic and lipophilic polymeric combinations of polyvinyl pyrrolidone (PVP) and ethyl cellulose (EC). Physical studies including weight variation, moisture content, moisture uptake, flatness, external morphology of the formulations, and in vitro drug release were performed. Drug-excipient interaction studies were carried out using Fourier transform infrared spectroscopy. In vitro skin permeation study with cadaver skin was conducted using modified Keshary-Chein diffusion cells. Interactions between nefopam and PVP seem to contribute to the slow and controlled release pattern of nefopam. The scanning electron microscopy evaluation of prepared matrix patches revealed that drug was dispersed uniformly in polymeric matrix. In vitro drug release study showed that an increase in concentration of hydrophilic polymer, PVP, enhanced drug release substantially. In vitro skin permeation study showed variable permeation profiles of nefopam from the experimental patches. Among the formulations, PVP:EC (1:3) was found to provide slowest release and maximum sustained skin permeation of drug in vitro. Application of those patches, PVP:EC (1:3), on human volunteers was found to provide systemic availability of the drug till 48 h. PMID- 20169861 TI - RUNspike, a complementary virus filter spiking method: a solution to the problem of reduced throughput due to the addition of the virus spike. AB - The traditional approach to virus filter spiking studies (virus added to the feed solution before the start of filtration) can lead to oversized viral filtration systems because of the non-representative volumetric throughputs (L/m2) that can be seen with the addition of the virus spike. The reduction in throughput is thought to be caused by interactions that take place between the species in the virus stock solution alone, or in conjunction with the species in the drug product. The traditional approach assumes that virus filter log reduction value (LRV) is directly related to volumetric throughput and limits manufacturing scale designs to the volumetric throughput achieved in the spiking study. This article references previous work that shows that % flow decay is a more relevant critical parameter than volumetric throughput for a poly(vinylidene diflouride) (PVDF) parvovirus filter. Based on this work, one could design the manufacturing-scale viral filtration system to the representative volumetric throughput achieved without the virus spike and implement a flow decay limit in manufacturing to ensure virus LRV. RUNspike is a complementary method that can be easily implemented today and that goes one step further. The RUNspike method challenges the same total virus as the traditional method, but the virus is added at the end of the filtration, after the representative volumetric throughput has been demonstrated. Comparable RUNspike and traditional LRV data, at the same flow decay, bridges the gap and strengthens the case for the flow decay-based design approach. PMID- 20169862 TI - Cleanroom airborne particulate limits and 70% isopropyl alcohol: a lingering problem for pharmaceutical manufacturing? AB - Seventy percent isopropyl alcohol (70% IPA) in water for injection is extensively utilised within pharmaceutical cleanrooms for glove and surface disinfection. When supplied in pressurised containers and delivered as an aerosol, it has been demonstrated that large quantities of 70% IPA particles are generated that remain airborne for substantial periods of time. Within non-unidirectional airflow cleanroom areas, such particles are likely to be recorded by the particle monitoring system. Consequently, the derived operational limits for particles will almost certainly be at "artificially high" levels and any particle generating activities with contamination potential may be masked. These high particle levels may not comply with the requirements of Annex 1 of the European Unions Guide to Good Manufacturing Practices (EU GGMP) and the United States Food and Drug Administration (FDA) Aseptic Processing Guideline. This is the case predominantly for the larger particles (> or =5 microm), the monitoring of which is exclusively required by the Annex 1 guide. However, by using canisters that deliver the 70% IPA as a stream, large quantities of particles are not generated and more meaningful and compliant operational levels can be obtained. Additionally, the EU GGMP's Annex 1 continuing requirement to monitor particles > or =5 microm appears to have little value or scientific justification and restricts further harmonisation of the European guide with the US FDA Aseptic Processing Guideline. PMID- 20169863 TI - Application of surface-enhanced Raman spectroscopy (SERS) for cleaning verification in pharmaceutical manufacture. AB - Cleaning verification is the process by which pharmaceutical manufacturing equipment is determined as sufficiently clean to allow manufacture to continue. Surface-enhanced Raman spectroscopy (SERS) is a very sensitive spectroscopic technique capable of detection at levels appropriate for cleaning verification. In this paper, commercially available Klarite SERS substrates were employed in order to obtain the necessary enhancement of signal for the identification of chemical species at concentrations of 1 to 10 ng/cm2, which are relevant to cleaning verification. The SERS approach was combined with principal component analysis in the identification of drug compounds recovered from a contaminated steel surface. PMID- 20169864 TI - A risk-based approach to scheduling audits. AB - The manufacture and supply of pharmaceutical products can be a very complex operation. Companies may purchase a wide variety of materials, from active pharmaceutical ingredients to packaging materials, from "in company" suppliers or from third parties. They may also purchase or contract a number of services such as analysis, data management, audit, among others. It is very important that these materials and services are of the requisite quality in order that patient safety and company reputation are adequately protected. Such quality requirements are ongoing throughout the product life cycle. In recent years, assurance of quality has been derived via audit of the supplier or service provider and by using periodic audits, for example, annually or at least once every 5 years. In the past, companies may have used an audit only for what they considered to be "key" materials or services and used testing on receipt, for example, as their quality assurance measure for "less important" supplies. Such approaches changed as a result of pressure from both internal sources and regulators to the time driven audit for all suppliers and service providers. Companies recognised that eventually they would be responsible for the quality of the supplied product or service and audit, although providing only a "snapshot in time" seemed a convenient way of demonstrating that they were meeting their obligations. Problems, however, still occur with the supplied product or service and will usually be more frequent from certain suppliers. Additionally, some third-party suppliers will no longer accept routine audits from individual companies, as the overall audit load can exceed one external audit per working day. Consequently a different model is needed for assessing supplier quality. This paper presents a risk-based approach to creating an audit plan and for scheduling the frequency and depth of such audits. The approach is based on the principles and process of the Quality Risk Management guideline (ICH Q9) of the International Conference on Harmonisation (ICH). It proposes that if regulatory conditions allow, it may be possible to remove the need to conduct audits on the sole basis of time elapsed since the last audit, or at least to increase the time interval between such audits without compromising either patient safety or company reputation. The proposal is equally applicable to both large and small companies. Small companies may find it particularly useful in cases where they use a supplier that may have a monopoly position or that serves many other pharmaceutical companies. In such circumstances the supplier may be reluctant or even refuse to accept audits from some individual companies because of their low purchasing levels. A similar approach could be proposed for regulatory authorities for the scheduling of regulatory inspections. PMID- 20169865 TI - [Investigation of biologically active compounds at the Department of Organic Chemistry of University of Debrecen between 1992-2009 I]. AB - The author briefly reviews the history of the Department of Organic Chemistry of University of Debrecen and summarizes the most important synthetic and pharmacological results achieved in the field of poppy alkaloids in the institute between 1992-2008, Part I. PMID- 20169866 TI - [Application possibilities of chemical imaging in pharmaceutical technology]. AB - Chemical imaging is a novel analytical method that simultaneously delivers spatial, chemical, structural, and functional information on the dosage forms. Both infrared and Raman spectroscopic imaging may serve as useful nondestructive analytical techniques in the pharmaceutical product development and quality control. Most important application possibilities are reviewed and some studies demonstrate the advantages of the structure exploration. Raman imaging is suitable to understand and control the quality attributes of different dosage forms. PMID- 20169867 TI - [Thermoanalytical investigation of rat myometrium during gestation]. AB - The aim of our present study was the investigation of rat myometrium by means of differential scanning calorimetry as a function of gestational age. Some additional groups of animals were exposed to adjuvant arthritis as a model for generalized inflammation. In order to find a connection between calorimetrically determined parameters and motor activity isolated organ experiments were performed and spontaneous as well as KCl-stimulated contractility were recorded. Uterine rings from the 5th day of early pregnancy (days 3-6) exhibited a maximum motor activity. A close correlation was revealed between calorimetric enthalpy (deltaH value) and basal and stimulated contractility. The generalized inflammation increased the maximal contractions at all tested stages (non pregnant, days 14 and 21). As gestation progressed deltaH value increased in control rats but not in animals exposed to inflammation. Our results indicate that calorimetric technique is suitable for functional investigation of pregnancy induced or disease-related changes of myometrial samples. PMID- 20169868 TI - [Solubility enhancement with extrusion technology]. AB - The transformation of the stable crystalline form can enhance the bioavailability of poorly water soluble drugs. The molecular dispersion, or solid solution, can be formed by various methods. The thermodynamic and kinetic properties of such compounds are very similar to the amorphous state. Twin-screw melt-extrusion, with controlled pressure, heat and shear stress, is a powerful way for separating the molecules of the active ingredient from each other and distributing them in the matrix homogenously. The extrudate can be processed onward immediately after a required cooling phase. The dependence of the possible effect of extrusion on the process parameters was investigated by Raman-microscopy and X-ray powder diffraction in course of the preparation of solid solution of spironolactone. PMID- 20169869 TI - Lactoferrin--a promising bone-growth promoting milk-derived glycoprotein. AB - Lactoferrin, an iron-chelating protein present in the granules of polymorphonuclear leukocytes and in the milk whey is having powerful osteogenic activity, as demonstrated by experiments performed in vitro on osteoblast cell cultures and in vivo on mice. It seems to be a promising factor to be applied in osteoporosis treatment. PMID- 20169870 TI - [Results of the treatment of chronic complex regional pain syndrome type 1 of the lower limb by continuous epidural anaesthesia with bupivacaine]. AB - The results of the treatment of 9 patients, exclusively women, suffering from chronic CRPS Type 1 involving lower limb and lasting a mean of 13 months are reported. Foot and ankle was involved in 5 cases and knee in four. The treatment consisted in 7 days course of epidural anaesthesia with 0.25% bupivacaine. Continuos epidural infusion was performed by a pump, with flow in average 4 ml per hour, and intensity of the flow was matched to achieve sufficient anaesthesia, but none, or minimal muscle paralysis, in order to allow patients to bear their legs or to walk on crutches. The results were assessed twice: immediately after the treatment was completed and at a mean of 20 months later. Pain at rest and at loading of the extremity, CRPS score and ability of walking were considered. Results. Of the 9 patients, three can be considered recovered, self-walking, although still complaining of residual, intermittent pain. Next three patients had moderate symptoms and were able to walk only on crutch or crutches, and next in one the disease recurred and was the same severe as before treatment. In two other patients treatment was temporarily effective for a mean of 2.5 months and then symptoms and signs recurred. These patients over a three years period underwent 7 and 8 treatments, respectively. CONCLUSION: Continuos epidural anaesthesia with bupivacaine for 7 days is a moderately effective treatment for chronic CRPS Type 1 of the lower limb, recommended particularly when long-lasting therapy fails to improve and patient is unable to walk on the involved extremity. PMID- 20169871 TI - [Early result of femur neck fracture treated with modular hemiarthroplasty fenix]. AB - The aim of the study is clinical assessment of modular arthroplasty Fenix and early assessment of 77 patient with femoral neck fracture treated with Fenix hemiarthroplasty. The mean age of the group was 77 years. There were 51 woman and 16 men in the group. Size of the used steam and head, the way of steam implantation, time of the operation and early complication was assessed. Operated patients were evaluated with Harris Hip Score, Larson I and Larson II score. The most common used steams were number 3 and 4, and the most common used head was number 44 with -4 mm offset. Mean operation time was 68.9 minute. The following early complication occurs: superficial wound infection treated with antibiotics- 8 cases, pneumonia--8 cases, urinary tract infection--6 cases, intra operative femur shaft fracture during steam implantation, treated with plate osetosynthesis -1 cases. There were 14 cases of death in the group. 22 patients were evaluated with HHS and Larson. Mean score in HHS was 71 point, in Larson I--76 point, in Larson II--72 point. There was found that operating technique is similar like in the others hemiarthroplasty system and system is easy to use. Most of the stems were cemented. There was found that there are a high percent of death in femur neck fracture patient group during the first year after the operation and this kind of fractures handicap patient locomotion in spite of good hip joint function. PMID- 20169872 TI - Custom made total hip replacement--necessary or not? AB - Indication and technical requirements analyses for custom made THR have been made. Indications for the use of custom made THR and the results achieved have been assessed according to the available literature and compared to the results of standard THR. There is a significant divergence in indications, late results and production costs. Clinical reports focus mostly on individual project metric data preparation method, technical aspects (such as shape or used material) or implantation method. Biomechanical analysis of achievable range of motion, ways of load transportation and equalization of frequently substantial discrepancy in leg length, is more hypothetical. The difficulty stems from the soft tissue quality which cannot be determined precisely, the cause of contracture or dynamic dysfunction triggered by the change of muscle action axis and muscle force over the joint, after changes of offset and joint axis of motion. In complicated cases, preoperative planning of a single approach/solution strategy can pose severe difficulties which would be hard to overcome during operation. Analysis was based on 2 cases. PMID- 20169873 TI - [Surgical treatment of perinatal brachial plexus palsy in children--late surgical technique]. AB - Apart from the possibilities to predict and eliminate the risk factors (especially in highly developed countries) the perinatal brachial plexus palsy (PBPP) still constitutes severe labor complications. PBPP treatment may be divided into conservative and operative categories. It is considered that the time necessary to regain functioning of brachial and ulnar articulations in children with BPPP (treated conservatively and surgically) amounts to 2 years approximately. Therefore, second late surgical technique of muscles and tendons of paralysed limb is performed in children at this age and older. It is accompanied by orthopaedic treatment and therapeutic rehabilitation, the aim of which is the improvement of its efficiency. The choice of proper treatment method (especially when chronic paralysis is observed) is conditioned by disorders of functioning in particular parts of a limb. Most frequently detected impairments resulting from BPPP which are treated surgically are disorders of shoulder functioning which occurs in 50% of plexus palsies. Ulnar dysfunctions constitute 15%, forearm dysfunctions amount to 15% and finally hand dysfunction is equal to 10%. Dysfunctioning of the upper limb constitutes 10%. Its reconstruction procedure is not necessary. The positive aspect of surgical reconstruction in patients with PBPP is not only improvement of paralysed limb functioning but also of patient's self-evaluation. PMID- 20169874 TI - [Hand deformity in adult rheumatoid arthritis and juvenile chronic arthritis]. AB - Adult rheumatoid arthritis (RA) is the most common of rheumatoid diseases, that may cause hand dysfunction in some patients. Its equivalent in children is juvenile chronic arthritis (JCA). The aim of our study was to evaluate differences in hand deformity between children with JCA and adults with RA. The prospective study was performed on two groups of patients: 15 with JCA (average age 13.1 years, range from 9 to 18 years) and 15 with RA (average age 53.6 years, range from 42 to 60 years). Both groups were similar in terms of Seyfried classification system and duration of the disease--7.9 years for children and 8.6 for adults. Clinical assessment was performed according to Swanson and Seyfrieda classification system. Patients with RA had only radial wrist "deviation" and those with JCA had both radial and ulnar wrist deviation. In MCP joints in adult's group fingers were always in ulnar position and in children's group finder position was opposite to wrist position. "Swan neck" deformity of fingers from II to V was found in both groups. "Buttonhole deformity" was more often seen in older group. Pain of wrist and in IP joints was more often found and was more severe in RA group. Hypertrophy of synovium and subluxation of IP and wrist joust were found with similar frequency in both groups. In other joints subluxation was rare. Concluding, radial wrist deviation is typical for RA patients. Children with JCA had both radial and ulnar wrist deviation. In MCP joints deformity is always opposite to wrist deviation. PMID- 20169875 TI - [The Polish model of physiotherapeutic conduct in rheumatoid arthritis and recommendation of Ottawa Panel]. AB - THE AIM: The aim of the research was to evaluate how the suggestions of the Ottawa Panel are implemented with regard to the patents suffering from rheumatoid arthritis in Poland. MATERIAL AND METHOD: in the research there was a test group of 41 people (33 women and 8 men) with rheumatoid arthritis. The criterion that was decisive in this study was the phase of reemission of the illness and whether the patient was taking part in physiotherapeutic treatment. The age of the subjects varied from 25 and 79 (the average age was 53.11). The average duration of the illness was 12.17 years. The research was conducted from November 2006 until September 2007 in Wiktor Dega Orthopedic-Rehabilitation Clinical Hospital (O-RSK4) in Poznan and in 22nd Military Rehabilitation Hospital in Ciechocinek. RESULTS: It was shown in the tested group there was a deep correlation between the joints with movement restrictions and the ones that caused most pain (r = 0.6086 for sum of painful joints with those with movement restrictions). Any link between the presence of deformation within the lower limb and exercising the suggested elements of gait during rehabilitation has not been found. Similarly, there was no dependence between the presence of deformations in the upper limb and the appropriate physiotherapeutic treatment. However, only in one patient the physical treatment recommended by the Panel was not used at all. CONCLUSIONS: The majority of the Ottawa Panel recommendations is implemented in the Polish model. A big part of patients has access to rehabilitation and usually the physical treatment techniques that proved to be the most beneficial are used. However, certain changes should be introduced to kinesis therapy, which tends to be focused more on joint deformation than on global work on the improvement of functionality and thus--the quality of patient's life. PMID- 20169876 TI - [Modification of finger replantation after ring avulsion injury--a case raport]. AB - Modification of replantation after total amputation of the fourth finger caused by ring avulsion injury was presented. It can be applied in finger amputations with bone or joint injury at the level or close to DIP joint. In proposed modification distal phalanx is removed from amputated part and remaining pulp tissues are transferred to middle phalanx. It enables primary vessel anastomoses after excision of their damaged ends. Moreover, it eliminates necessity of bone stabilization and tendon repair, shortens operation time, rehabilitation period and allows for earlier return to professional activity. This unique solution is particularly indicated in physical workers. Presented modification of finger replantation was successfully used in 44-year old female farmer. Despite 2 cm shortening of the fourth finger, vein grafts were used in restoration of blood outflow. Due to prolonged ischemia time significant edema of the dorsal aspect of the finger was present. Primary venous anastomoses were not possible due to resultant increased tension. All replanted tissues survived with good functional result. One year after the replantation and 2 months after the FDS tenolysis TAM was 180. Hand was aesthetically accepted by the patient. PMID- 20169877 TI - [Radial artery perforator flaps in posttraumatic thumb reconstructions]. AB - Between 2002 and 2008 author treated 6 patients aged 15-40 (mean 24 years), after severe hand injuries reconstructing soft tissues of the first ray with various flaps based on perforators of distal part of radial artery. All patients requested secondary thumb reconstruction due to its amputation and disfigurement of the hand (particularly tissues of the first ray). Following three different forearm flaps based on radial artery perforators were used: adipo-cutaneous, fascio-cutaneous and island fascio-cutaneous. Primary closure of the donor site was possible in 4 cases. In remaining two patients split thickness skin grafts were used. All flaps survived. Minor partial necrosis did not impaired reconstruction of the first ray soft tissues. In two patients thumb reconstruction by the second toe transfer and rebuilt first ray soft tissues were performed in one procedure. Author suggests broader application of distal radial artery perforator flaps in soft tissues reconstruction of the first ray of the hand. PMID- 20169878 TI - [Finger transfer from contra lateral hand on metacarpal hand--case illustration]. AB - A case of reconstruction of metacarpal hand by means of ring finger transfer from contra lateral hand is presented. The patient did not accept the option of a toe transfer. The finger was implanted on the third ray. The unification of bones was done by headless AO screw resulting in an excellent bony union. The result was assessed after 11 months. Sensitivity of the transferred finger is excellent; 2 points discrimination test: 8 mm, range of motion is small--65. The cosmesis of the recipient and donor hands are excellent. No diminishing of grasp strength or of the range of finger motion of the donor hand was observed. As the result of the transfer the patient is able to perform many activities which he was unable to do preoperatively. PMID- 20169879 TI - [Triple arthrodesis of the foot after treated talar fracture--report of 3 cases]. AB - Fracture of the talus, especially talar neck associated with talar dome necrosis, due to serious disorders of the ankle and subtalar joints. Disorders are so great that they often suggest to perform arthrodesis of the ankle joint. Disorders of subtalar joint are not so much visible on standard X-rays. Results of triple arthodesis performed in 3 patients (3 feet) because of talar fracture sequele were reported. In 1 femal talar fracture was combined with calcaneal fracture in the same foot. Age at trauma ranged from 22 do 31 years (mean 27). Indications for secondary operative treatment were mainly clinical criterias as subtalar pain and in 1 male additionaly varus deformity of the foot. Feet were stabilized by K wires going both through Chopart and ankle joints. Follow-up ranged from 35 to 50 months. Functional results in modyfied AOFAS scale ranged from 43 to 81 points (mean 65) of 94. Subjective results ranged from 7 to 10 points (mean 8) of 10. At follow-up examination no one reported restricted range of motion in the ankle joint in comparison to pre operation as well no any progression of osteoarthritis was visible on x-rays. PMID- 20169882 TI - [Results of anterior lamellar keratoplasty performed with "big bubble" technique]. AB - PURPOSE: To present the results of deep anterior lamellar keratoplasty (DALK) using "big bubble" technique, performed from 2006 to 2008 in Ophthalmology Department, District Railway Hospital in Katowice. MATERIAL AND METHODS: 53 patients (53 eyes) underwent DALK using "big bubble" technique due to keratoconus, corneal dystrophies and postinflammatory corneal opacification with continue Descemet's membrane and healthy endothelium. Best corrected visual acuity, main astigmatism, central corneal thickness, endothelium cell density, intra- and postoperative complications were assessed. RESULTS: Mean follow up 15.4 months ranged from 11 to 24 months. Averaged best corrected visual acuity averaged equaled 0.6 and ranged from 0.1 to 4.0, mean astigmatism 2.6 D, ranged from 1.0 D to 2.6 D. Mean central corneal thickness was 503.4 microm and ranged from 379 microm to 694 microm, mean endothelium cell density before surgery equaled 2895/ mm2 and postoperatively 2398/ mm2. Incomplete Descemet's membrane detachment was diagnosed in 3 cases, intraoperative microperforations in 5 eyes and conversion to penetrating keratoplasty was needed in 4 patients. Postoperative disc opacity in 3 cases, increase of intraocular preassures in 1 case and early postoperative Descemet's membrane detachment in 1 eye. Posterior cataract formation in 4 eyes and in 1 case permanent mydriasis (Urrets-Zavalia Syndrome), was observed. There was no graft rejection observed. CONCLUSIONS: Although technically more demanding lamellar keratoplasty, could be considered as an alternative "gold standard" penetrating keratoplasty. PMID- 20169883 TI - [Evaluation of VEGF and IGF-1 plasma levels in preterm infants--potential correlation with retinopathy of prematurity, clinical implications]. AB - PURPOSE: Insulin-like growth factor-1 plays an important role in fetal growth and development, and its level increases with gestational age. The latest reports show that IGF-1 can directly influence the production of VEGF and regulate the development of blood vessels. Thus, the aim of the study was to evaluate the plasma concentrations of IGF-1 and VEGF as well as analyze their mutual correlation in preterm infants with retinopathy of prematurity (ROP), compared with preterm infants without ROP and full-term babies. MATERIAL AND METHODS: To address this issue, peripheral blood samples (PB) were analyzed and collected 10 weeks after delivery from: 25 preterm infants with proliferative stage of retinopathy of prematurity (ROP) and neovascularization (stage 3 or more advanced), 25 preterm infants without ROP, and 25 healthy full-term control infants. Plasma concentrations of VEGF and IGF-1 were measured using high sensitivity enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: Increased concentrations of VEGF (p < 0.05), were found in the PB of the preterm infants with ROP compared with the preterm babies without retinopathy as well as with the full-term control infants, in whom the lowest levels of the growth factor were observed. The plasma concentrations of IGF-1 in the preterm infants were significantly lower than those of the full-term babies (p < 0.001). After adjustment for gestational age as a independent variable, a tendency to higher concentrations of IGF-1 was observed in the preterm infants with ROP. CONCLUSIONS: Disturbances in the interactions of VEGF and IGF-1 at early stages of ROP, leading to uncontrolled increases in their levels in the proliferative phase of disease, can play an important role in the pathogenesis of retinopathy of prematurity. PMID- 20169884 TI - [Intraocular and intraorbital foreign bodies characteristics in patients with penetrating ocular injury]. AB - PURPOSE: To determine clinical features of intraocular and intraorbital foreign body (IOFB) injuries. MATERIAL AND METHODS: 62 patients with IOFB injury were retrospectively reviewed. Data on age, sex, activity at the time of injury, initial visual acuity and presenting clinical features were recorded. Special attention was paid on foreign bodies characteristics. Factors analyzed included: material, quantity and size of IOFB, site of entrance wound and final IOFB location. RESULTS: The mean patient age was 38.1 years. All but one patient were male. Hammering and chiselling were the most common activities at the time of injury. 93.5% of patients had single IOFB. Metallic foreign body comprised 85.5% of all cases. The average IOFB size was 3.9 x 15.1 mm. 83.9% of IOFBs were located inside the globe, among them: 46.1% in the anterior segment; 44.2% in the vitreous and the rest in the posterior part of globe. The most frequent entrance wound site was cornea (59.7%). Initial visual acuity was worse or equal 5/50 in 50% of the cases. Patients with greater size of IOFB had worse initial visual acuity. The most common clinical features, presenting at the time of injury, were corneal wound (64.5%), lens lesion (33.9%), endophthalmitis (29%) and vitreous hemorrhage (25.8%). CONCLUSIONS: The majority of patients with IOFB injury were young male. Tool-related activities, particularly hammering, were more likely to cause of IOFB injuries. Single metallic foreign body occurred much more frequently. Cornea was the most frequent site of entrance wound. The vitreous and the anterior segment were the most common final location of IOFB. Increasing IOFB size was associated with worse initial visual acuity. IOFB injury has been found to be associated with a lot number of the ocular tissues lesions. PMID- 20169885 TI - [Late complications after penetrating ocular injuries caused by intraocular and intraorbital foreign bodies]. AB - PURPOSE: To evaluate late complications in patients with penetrating ocular injuries caused by intraocular or intraorbital foreign bodies (IOFBs). MATERIAL AND METHODS: We reviewed 58 posttraumatic patients with IOFBs removed by external electromagnet or intraocular forceps. The patients underwent a follow-up examinations at 1 to 7 years after trauma. We noted final visual acuity, frequency and type of complications and following surgical treatment. RESULTS: Final visual acuity of 5/50 or more was obtained in 65.5% of patients. Ocular complications were found in 50 patients (86.2%). The most frequent consequence of past trauma was corneal scar (58.6%), cataract (44.8%), and retinal detachment (20.7%). 37 patients (63.7%), required the next surgical interventions. 23 patients 139.6%), underwent posttraumatic cataract extraction, 9 (15.5%)--pars plana vitrectomy for retinal detachment or vitreoretinal proliferations, 5 (8.6%) -scleral buckling procedure, 3 (5.2%)--antiglaucoma surgery, and 2 (3.4%)- enucleation. CONCLUSIONS: Penetrating ocular injuries caused by IOFBs were often complicated with corneal scar, cataract and retinal detachment. More than 2/3rd of patients required subsequent surgical interventions. PMID- 20169886 TI - [Causes of epiphora in diagnosed and treated patients in Department of Ophthalmology in Military Institute of Health Service]. AB - PURPOSE: Analysis of causes of epiphora in patients which have been examined in Department of Ophthalmology in Military Institute of Health Service from 2004 to 2007. MATERIAL AND METHODS: The study has comprised 330 subjects: 241 women and 89 men (mean age 58.85 +/- 19.93 years). All patients have been examined because of epiphora (eyelid and lacrimal punctum position, medial canthal tendon laxity- horizontal resting position, lateral distraction test, fluorescein dye disappearance test, syringing of the upper and lower canaliculus, dacryocystography and/or lacrimal scintigraphy). RESULTS: There have been 3% patients with epiphora who have been examined in our clinic. Duration of epiphora has been mean 39.24 months. The main causes of epiphora have been: primary acquired nasolacrimal duct obstruction, idiopathic acquired dacryostenosis, punctal stenosis (22.42%, 19.7%, 19.09%), and rare: diverticulum, punctal papilloma, stenosis after radiotheraphy, Recklinghausen's disease. CONCLUSIONS: The correct diagnosis is the condition for the proper planning of the therapy schedule. Epiphora is frequent and annoying symptom. PMID- 20169887 TI - The impact of common classes of topical antiglaucoma medications on central corneal thickness--own observations. AB - PURPOSE: To investigate the influence of common classes of topical antiglaucoma medications used either in monotherapy or combined therapy on CCT. MATERIAL AND METHODS: In a retrospective study 487 eyes from consecutive 260 patients (148 F/112 M) with open angle glaucoma were examined. Depending on the topical treatment they were classified into 7 groups: A/PGA (n=212), B/BB (n= 54), C/CAI (n=36), D/PGA + CAI (n=25) E/PGA + BB (n=23) F/BB + CAI (n=54), G/ non-treated (n=83). The CCT was measured using ultrasound pachymetry Tomey AL-2000. The central corneal power was measured with the Topcon keratometer. ANOVA analyses were used for statistical analysis. RESULTS: There were no statistically significant differences between CCT of all groups (F = 1.06, p = 0.3931); the lowest values were in the eyes treated with PGA + BB (535.9 microm SD 31.4) and the highest in the eyes treated with PGA + CAI (571.3 microm SD 46.3). The Mean CCT in group A was 550.4 microm (SD 40.8), group B 552.5 microm (SD 34.7), group C 562.6 microm (SD 40.2), group D 571.3 microm (SD 46.3), group E 535.9 microm (SD 31.4), group F 559.5 microm (SD 32.5), group F 557.5 microm (SD 42.2). There were no statistically significant differences between CCT of eyes treated with different PGA. The highest CCT was found in the eyes treated with bimatoprost (554.4 microm SD 46.0) and the lowest in the eyes treated with latanoprost (546.4 microm SD 37.7). CONCLUSIONS: In this study CCT appears not to differ in eyes treated with different classes of antiglaucoma medications either in monotherapy or combined therapy. CCT appears not to differ in eyes treated with different prostaglandin and prostamide anal logs. CCT of treated glaucoma eyes does not differ from CCT of untreated glaucoma eyes. PMID- 20169888 TI - Cataract surgery with bilateral multifocal ReZoom intraocular lens implantation- comparison of 3 and 12 month follow-up. AB - PURPOSE: To evaluate the visual outcome, spectacles independence, contrast sensitivity (CS), subjective symptoms, patient satisfaction and complications three and 12 months after cataract surgery with bilateral ReZoom multifocal refractive intraocular lens (IOL) implantation. PATIENTS AND METHODS: This study comprised 40 eyes of selected 20 patients who had uneventful cataract surgery with bilateral implantation of ReZoom (AMO) multifocal IOL. Three and 12 months after bilateral surgery binocular uncorrected, the best corrected distance, near and uncorrected intermediate visual acuities (VA), spectacle independence, the best corrected binocular distance (with and without glare), near photopic CS, subjective symptoms, patient satisfaction and complications were evaluated. RESULTS: Three and 12 months after surgery all patients had binocular uncorrected distance visual acuity (VA) of 0.5 or better; the best corrected distance VA was 1.0 in all cases. Three months after surgery, the mean binocular uncorrected intermediate VA was J4.10. The mean binocular uncorrected and the best corrected near VA were J3.10 and J1.70 respectively. Total spectacle independence and independence for distance, intermediate and near vision were achieved in 65%, 100%, 95% and 70% of patients respectively. The best corrected binocular distance and near CS were within normal limits. The most frequent subjective symptoms were mild glare and halo (65%--13/20 of patients).Total vision satisfaction was very high (9.6/ 10). There were no postoperative complications. One year after surgery, statistically significant improvement occurred in the best distance corrected near VA (p < 0.04), photopic distance best corrected CS without glare for 12 cycl/deg (p < 0.03) and in the level perception of glare/halo (p < 0.02) in comparison to the results from 3 months follow-up. The rest of analyzed parameters was unchanged. No complications were noticed except posterior capsule opacification in four patients one year after surgery who needed YAG laser treatment. CONCLUSION: Bilateral ReZoom multifocal IOL implantation was effective in selected cataract patients, providing very good uncorrected distance, intermediate, and near visual acuities as well as very high level of patient satisfaction. Longer than three months of the neuroadaptation time after bilateral surgery is necessary to obtain significantly better visual function results. PMID- 20169889 TI - Surgical treatment of cataract and glaucoma in nanophthalmic eye--case report. AB - Work presents surgical strategy in case of cataract and glaucoma in patient with simple nanophthalmus. Moreover optimal manner of calculation of the IOL and treatment in case of occurrence of complication from disturbed structure of eyeball. Surgical procedure included removal of cataract by using phacoemulsification, implantation of artificial Acri.Lyc Extreme lens, account from Haigis rule. Because of high intraocular pressure in early postoperative period we decided to implant Ahmed devices--children's type with drain placed in posterior chamber combined with posterior vitrectomy. We obtained stabilization of intraocular pressure and effective visual acuity. PMID- 20169890 TI - [Glaucoma in patient with pituitary tumor--case report]. AB - Ocular hypertension and visual field loss would usually be thought sufficient to suspect glaucoma. A case is presented which illustrates the continuing need for vigilance in circumstance of an apparently straightforward diagnosis has been made. PMID- 20169891 TI - [Impairment of optic nerves as the result of cerebral sinus venous thrombosis]. AB - Cerebral venous sinus thrombosis is a disease with potentially serious consequences and usually affecting young to middle aged people. Headache was the most frequent symptom. Diagnosis is based on clinical signs, radiological imaging (CT scan, MRI), bacteriological examinations and laboratory biochemical tests. Mastoidectomy and tympanic cavity drainage is performed in cases with lateral sinus thrombosis in acute mastoiditis. Intravenous antibiotics therapy should be continued for 2 weeks. Anticoagulants should be given, taking into consideration parameters of coagulation system and the type of thrombus. Because of moderate to high mortality rate, patients should be closely monitored. PURPOSE: Presentation of the case of bilateral optic nerve atrophy after extensive thrombus of sigmoid and right transverse sinuses. MATERIAL AND METHODS: We present the case of a boy, who suffered inflammation of venous sinuses of cranial basis, when he was 6 years old. It happened 1 month after right mastoid bone injury. In the course of this disease, intracranial hypertension with bilateral optic disc swelling appeared. RESULTS: 5 years after thrombosinusitis, the child has pale optic discs, changes in the peripheral visual field, abnormal VEP and incorrect contrast sensitivity. CONCLUSIONS: Trauma in the region of the temporal bone may cause hard complications from thrombosinusitis, and lead to bilateral optic damage. PMID- 20169892 TI - [A severe case of sympathetic ophthalmia--case report]. AB - PURPOSE: The aim of our work is to present clinical and histological data of the case of severe sympathetic ophthalmia (SO). Sympathetic ophthalmia is a rare, bilateral, non-necrotizing granulomatous panuveitis that follows penetrating injury to one eye. SO is a potentially blinding condition. MATERIAL AND METHODS: A 40-year-old man sustained a penetrating injury to his right eye. He refused to be treated surgically. A few days later, he developed bacterial endophthalmitis. After 5 months the patient came to our hospital with clinical manifestations suggesting SO. His right eye was removed. Unfortunately, despite the intensive pharmacological treatment the uveitis of the left eye intensified. RESULTS: Generalized uveitis with optic nerve oedema, secondary cataract and glaucoma resulted in total blindness. CONCLUSIONS: Although, SO is a rare disease, ophthalmologists should be aware of its devastating effect on vision. PMID- 20169893 TI - [Goldmann-Favre syndrome--case report]. AB - Goldmann-Favre syndrome is a very rare vitreoretinal degeneration with typical changes (like retinoschisis, bone corpuscle like pigmentations, dendritic vessels of peripheral retina). We presented a case of Goldmann-Favre vitreoretinal degeneration in 53 years old man, which is observed in our department due to macular changes in the left eye. PMID- 20169894 TI - [Ophthalmologic findings in child in the Cornelia de Lange syndrome]. AB - PURPOSE: Cornelia de Lange syndrome is a rare disease showing characteristic facial appearance, development delay, low birth weight, skeletal anomaly, hirsutism and various ophthalmologic and hearing findings. MATERIAL AND METHODS: We described ophthalmologic problems in 2-year-old girl. RESULTS: We have find arched eyebrows, long lashes, epiphora, ptosis, nystagmus, myopia, and fundus eye changes. CONCLUSIONS: We recommend early ophthalmologic examination in patients with Cornelia de Lange syndrome. PMID- 20169895 TI - [Mesectodermal leiomyoma of the ciliary body--case report]. AB - PURPOSE: The aim of this report is to present a case of mesectodermal leiomyoma of the ciliary body. MATERIAL AND METHODS: In the left eye of the 15 years old female patient presenting 2 months history of deterioration of visual acuity a medium-pigmented, dome-shaped tumor at the inferotemporal side was detected. It measured 21.6 mm in base diameter 11.2 mm in thickness and was revealed with imaging techniques such as ultrasound, MRI and orbital radiography. Taking into consideration all clinical features, despite patients' young age, malignant melanoma of the ciliary body was suspected. Due to the size of the tumor and the impossibility of conducting conservative treatment the globe was eventually enucleated. RESULTS: The final diagnosis was established on the basis of histopathological microscopic examination and immunohistochemical stains. The co expression of muscular (SMA, caldesmon, desmin), as well as neural markers (S-100 protein and synaptophysin), has been proved. CONCLUSIONS: Mesectodermal leiomyoma of the ciliary body is an extremely rare benign tumor, which originates from neural crests. It exhibits features of both muscular and neural differentiation. PMID- 20169896 TI - [Estimation of the quality of life 8-year-old child with bilateral anophthalmia]. AB - PURPOSE: The main aim of our work was to estimate the physical and psychomotor development and the arrangement to the daily life for a 8-year-old girl with inborn bilateral anophthalmia. MATERIAL AND METHODS: The basic ophthalmic, pediatric and neurological examinations were performed with additional genetic and radiological examinations. RESULTS: The ophthalmic and MRI examination find out the absence of the eyeballs, optic nerves, optic chiasm, optic tracts and optic radiation. CONCLUSIONS: Anophthalmia limits in a big grade an independent life of the child. However, currently the girl's development indicates for good intellectual abilities what is promising for future independent life and professional work. PMID- 20169897 TI - [Systemic blood pressure in oculist practice--chosen aspects]. AB - Blood pressure have the dual importance in eye-doctor practice. Its high values, leading to injury of vascular wall, cause its stiffness, narrowing and eye-ball perfusion disturbance. On the other hand, in case of impaired eye-ball circulation autoregulation, recurrent episodes of low blood pressure may lead to processes of ischemia-reperfusion with oxygen free radicals overproduction and retinal ganglion cells apoptosis. It seems, that complex control of the atherosclerosis risk factors level as well as use of drugs favourable affecting endothelial function (angiotensin-converting enzyme inhibitor, statins), may decrease an eye-ball vasculature injury and make it less susceptible to blood pressure variation. This suggests acceptance of atherosclerosis risk factors, especially hypertension, as a predictor of early glaucomatous optic neuropathy on the "pre-perimetric" stage of disease. PMID- 20169898 TI - [The use of autologous serum in the treatment of the ocular surface diseases]. AB - In the literature, there is evidence suggesting that autologous serum eyedrops can be helpful in the treating various ocular conditions. Using eyedrops containing the 20-100% solution of patient's own serum, centrifuged 3000-4000 rpm, diluted in either saline, BSS or chloramphenicol solution, is a relatively new therapeutic strategy. Nevertheless, in some publications, a positive influence of using autologous serum topically has been proven in numerous ocular diseases. It has been found, that using autologous serum eyedrops is safe, such eyedrops can be stored in temperature ranging from -30 degrees C to +4 degrees C. Moreover, effectiveness of this treatment has been proven for many diseases, e.g.: keratoconjunctivitis sicca, superior limbal keratoconjunctivitis, recurrent erosion syndrome and persistent epithelial defects. Although, complications of the treatment are possible, according to available data from the literature, they are not frequent. A unified standard of preparing the autologous serum eyedrops has not been elaborated and in various publications different modes of preparation of the solution have been used. It is important to document indications for this treatment appropriately, as well as to be cautious while preparing and using the solution. PMID- 20169899 TI - [Pathogenesis of posterior capsule opacification in pseudophakia]. AB - The lens epithelial cells of A and E type are involved in pathogenesis of posterior capsule opacification (PCO). They undergo metaplasia into microfibroblasts, then migrate towards posterior capsule where they proliferate and form opacification. These processes are stimulated by cytokines and interleukines. The extracellular matrix which constitutes a scaffold for migration and attachment of epithelial cells plays an important role in PCO formation. Integrines intercede in this process. PMID- 20169900 TI - [Perioperative posterior ischemic optic neuropathy--pathogenesis and clinical characteristics]. AB - Posterior ischemic optic neuropathy (PION) is an uncommon cause of perioperative visual loss. It has been most frequently reported after spinal surgery and radical neck dissection. This type of PION occurs in the setting of profound hypotension and severe anemia during the perioperative period. The visual loss, which typically presents immediately after surgery, is often bilateral and profound with count fingers vision or worse. The examination findings are consistent with an optic neuropathy, however the optic disc is normal. Diagnosis of PION can be made only after other causes of the optic neuropathy have been excluded. The prognosis for visual recovery is generally poor. Although correction of hemodynamic derangements may be beneficial, no treatment has proven to be effective. PMID- 20169901 TI - [Pathogenesis and the most frequent symptoms of neurofibromatosis type 1]. AB - PURPOSE: This study was to evaluate pathogenesis, symptoms, clinical course and possible treatment of neurofibromatosis type 1. Neurofibromatosis type 1, von Recklinghausen's disease, is one of the phacomatoses. It belongs to the most frequent inherited diseases in human population. This disease is autosomal dominant, but new spontaneous mutation are also common. The symptoms are caused by disorders in the melanocytes and gliocytes. In ophthalmological examination Lisch nodules, cafe-au lait spots, neurofibromas of the lids, optic pathway gliomas and deformation of the orbit bones, can be observed. The symptoms are different, depend upon the age and demonstrate charateristic evolution through the lifetime. PMID- 20169902 TI - [Role of complement system in the pathogenesis of AMD]. AB - Age related macular degeneration (AMD), is the leading cause of blindness in individuals over age 50 years old. The pathogenesis of AMD is still not well understood with both genetic and environmental factors known to influence susceptibility to this condition. Data accumulated in the last decade implicate the chronic inflammatory processes as playing an important role in the progression of AMD. According to the recent findings, complement system is suggested to be a triggering point of the initiation of pathologic inflammatory response in the development and clinical course of AMD. PMID- 20169903 TI - Anatomic logic of the foramen Luschka in neurootologic surgery. AB - The authors emphasise the key role of the state of the foramen Luschka in indication of neurootologic surgical approaches. Blockage of the foramen of Luschka with a medium or big tumour may impaire the CSF circulation. In such case the lateral transtemporal approaches--translabyrinthine and transotic are the best options. In all other situations where there is no blockage of the CSF circulation in the affected pontocerebellar angle the choice of a surgical approach is determined by the state of hearing and character of disease. Surgical indications schould be elective and individually considered. PMID- 20169904 TI - [Magnetic resonance tractography in neuroradiological diagnostic aspects]. AB - Diffusion tensor imaging is unique in its ability to non-invasively visualize white matter fiber tracts in the human brain in vivo. White matter fiber bundles of the human brain form a spatial defined by the anatomical and functional architecture. Determination of axonal pathways provides an invaluable means to study the connectivity of human brain and its functional network. Comparison of fiber tract properties across subjects requires comparison at corresponding anatomical locations. In this paper, we present application of white matter tractography method based on incoherent motion of water molecules in fiber tissue, mainly in central nervous system. This motion is itself dependent on the micro-structural environment that restricts the movement of the water molecules. In white matter fibers there is a pronounced directional dependence on diffusion. With white matter fiber tracking or tractography, projections among brain regions can be detected in the three-dimentional diffusion tensor dataset according to the directionality of the fibers. The authors indicate diagnostic possibilities of MR tractography in otolaryngology for imaging the nervous tracts of sense of hearing, smell and taste with particular consideration of otoneurological evaluation of patients with cochlear implants and bone anchored hearing aid (BAHA). White matter tracts can be evaluated independently by using diffusion tensor tractography, which appears to be a promising technique for determining changes in white matter in degenerative disease. The authors also indicate that method as a beneficial in the surgical planning for patients with intrinsic brain tumors. PMID- 20169905 TI - [Metastases to the parotid gland and parotid region]. AB - INTRODUCTION: Among the malignant tumors found within the parotid gland, the primary tumors, as well as a metastatic tumors may be found. AIM: Epidemiological and clinical characteristic, and preliminary assessment of treatment results of metastatic tumors to the parotid gland and the parotid region. MATERIAL AND METHODS: The retrospective analysis of 60 cases with metastatic tumors to the parotid gland and parotid region, selected from the material of Dept. ORL H&N Surg. Holy Cross Cancer Center in Kielce - Poland (2001-2008), with the analysis of age, sex, localization and histopathology of primary tumor, stage according to O'Brien classification, diagnostic methods and treatment modalities, and analysis of 3 and 5 years survival. RESULTS: In the analyzed group of 60 patients (35M + 25F), in the age ranging from 31 to 92 years (mean age 73,5), the most common primary localization of metastatic tumor was skin of the head and neck (Squamous Cell Ca - 41,6%; Malignant Melanoma 25,0%). The therapy with radical intention was applied in 75,0% of patients treated, mostly combined surgery and radiotherapy. 25,0% of patients received symptomatic and palliative treatment only. In the group with 3 (17 cases) and 5 years (6 cases) of observation accordingly, 53,1% and 33,3% total survival was achieved. CONCLUSIONS: The most common primary localization of metastases to the parotid region are Squamous Cell Carcinoma and Malignant Melanoma of the head and neck skin. Metastases to the parotid gland and region are usually diagnosed in the advanced local stage of the disease. The treatment of choice in mentioned above metastases are surgery followed by radiotherapy. The unfavorable prognosis of metastatic tumors to the parotid gland and parotid region may be improved, with systematic follow up of the patients with the skin cancer. PMID- 20169906 TI - [Differential diagnosis and treatment of neck masses. A study based on observation in Otolaryngology Department of Miedzyleski Specialistic Hospital in Warsaw]. AB - In otolaryngology practice we quite often encounter neck masses in all age group patients. The differential diagnosis is extensive and represents a variety of pathologic conditions of various origins, especially in relation to patient age. The authors present a retrospective analysis of patients with a neck mass treated in Otolaryngology Department of Miedzyleski Specialistic Hospital in Warsaw over the period of two years. Patients were divided into groups according to their age. Within each group the incidence of congenital, inflammatory and neoplastic disease was assessed. The most numerous was the group of adults older than 40 years of age with the highest incidence of malignant neoplasms. The location of metastatic lymph nodes in relation to primary site was described. Finally, methods of management for each tumour type were presented. Then we discuss a work up of a neck mass with regard to literature data. PMID- 20169907 TI - [Recurrence in operated patients with laryngeal squamous cell carcinoma]. AB - PURPOSE: The aim of the present study was to investigate the recurrence prevalence in patients with laryngeal squamous cell carcinoma (LSCC) underwent surgery as primary treatment. MATERIAL: The assessed group consisted of 148 patients with operable LSCC underwent surgery as primary treatment between 1999 2002. Surgery was performed in all cases. Total laryngectomy was performed in 107 (72.3%) patients and laser endoscopic tumor resection was performed in 41 (27.7%) patients. RESULTS: Local recurrence occurred in 18 (12.2%) patients, nodal recurrence in 12 (8.1%) and both and/or remote metastases in 6 (4%) patients. Altogether, recurrence was present in 36 (24.3%) patients and 111 (75.7%) patients had no symptoms of recurrence. Recurrence prevalence in 3-year follow-up -prevalence of recurrence significantly increased with tumor's T feature (p=0.04), N feature (p=0.03), progression of clinical stage (p=0.008) and histological malignancy G stage (p=0.01). Recurrence prevalence in 5-year follow up--prevalence of recurrence significantly increased with tumor's T feature (p=0.02), N feature (p=0.01), progression of clinical stage (p=0.003) and histological malignancy G stage (p=0.002). Tumors localized in glottic area had less recurrences than those localized in supraglottic area (p=0.05). There were no significant dependence between recurrence type (local or nodal) and tumor's clinicopathological features. Multiple factor analysis with logistic regression model did not revealed simultaneous influence of many variables on recurrence's presence and type. Using multiple factor analysis with Cox's regression model it was proved that recurrence presence (p<0.00001) is a significant independent prognostic factor in the analyzed group of patients with laryngeal carcinoma in 3 year follow-up. CONCLUSIONS: Recurrence prevalence depends on localization, systemic progression stage, clinical progression stage, cervical lymph nodes state and histological malignancy stage of tumor. Patients with local recurrence have statistically significantly worse prognosis than patients with no recurrence. Recurrence presence is significant independent prognostic factor in 3 year follow-up. PMID- 20169908 TI - [The cysts and fistulas of the neck in material of Otolaryngology Department of Rydygier District Hospital in Cracow]. AB - The retrospective study describes 118 patients treated for congenital cysts and fistulas of the neck between 1997 and 2007 in ORL Department of Rydygier District Hospital in Cracow. Malformation was divided into midline and laterocervical region anomalies. Malformation of midline included thyreoglossal duct and dermoid cyst. The most common malformation of laterocervical were cysts followed by fistulas. The theory of development, method of diagnosis and operative management were presented. Complication and recurrences were rare. Proper differential diagnosis and radical operation led to successful cure. PMID- 20169909 TI - [Method of ossicular chain valuation. Experimental measurement and clinical application]. AB - AIM OF STUDY: Evaluation of usefulness new non-contact method--Laser Doppler vibrometry (LDV) in measurements of movability of ossicular chain during second look operation was aim of the study. We would like answer to questions: 1. Is LDV helpful in intraoperative conditions? 2. Which measurements points have the largest practical value? 3. Which measured parameters could be used to determination of effectiveness ossicular chain reconstruction? METHODS AND MATERIALS: In experiment there were taken 3 fresh temporal bones kept in 0,9% NaCl. In first stage were executed: antromastoidectomy with wide tympanotomy. The ossicular chain movability investigation was conducted on: back branch of stapes, front branch of stapes, round window, umbo of eardrum. Laser Doppler Vibrometer was used to measurement ossicular chain's movability. ER-2 loudspeakers were generated wave: 1000 Hz, 2000 Hz, 4000Hz. In second stage were executed: Malleus Stapes Assembly (MSA) ossicular chain's reconstruction and repeated investigation in measured points. RESULTS: The most convenient points to measurement were respectively: back branch of stapes, front branch of stapes, umbo of eardrum. In two cases round window was placed in deep niche and was partly covered by facial nerve. MSA performance didn't influence accessibility of measuring points. Theresholds of measured point's movability was useful to evaluation of reconstruction. CONCLUSIONS: Back branch of stapes, front branch of stapes and umbo of eardrum are useful to intraoperatve measurements ossicular chain movability. Delimitation thresholds of ossicular chain movability can help in reconstruction's evaluation. After next experiments LDV can be use in practice intraoperative. PMID- 20169910 TI - [Intralabyrinthine schwannoma of the vestibulocochlear nerve]. AB - AIM: Presenting and discussing the patient with intravestibular schwannoma of the vestibulocochlear nerve, the course of disease, audiologic and radiologic examination and treatment possibilities. METHODS: Analysis of clinical presentation and treatment of the patient with intravestibular schwannoma and review of available literature on intralabyrinthine schwannomas. RESULTS: A 34 year-old male was diagnosed with a tumor localized in the left vestibule and semicircular canals without accompanying vertigo at any time of the disease but with tinnitus and total deafness of the left ear. Preoperative diagnosis was established on the basis of MRI with contrast. Localization of the tumor laterally to the fundus of internal auditory canal was essential for the diagnosis. Surgical treatment was chosen via translabyrinthine approach. Postoperative course was uneventful. DISCUSSION: Intralabyrinthine schwannoma are rare pathology. Their occurrence implies that schwannomas can originate at any segment of vestibulocochlear nerve. Most commonly intralabyrinthine schwannomas are observed at intracochlear or intravestibular localization. Present trials of these tumors classification were presented. The symptoms emerging in the course of disease are hearing loss, tinnitus, and vertigo, thus there were described patients with intralabyrinthine schwannomas diagnosed and treated as Meniere disease. Treatment depends on the intensity of symptoms and tumor expansion, while approach is dependant on its localization. CONCLUSION: Elaborate radiologic examination including MRI with contrast is essential in case of atypical course of disease with hearing loss, tinnitus and vertigo, or with early diagnosis of Meniere disease. PMID- 20169911 TI - [Acinic cell carcinoma of glandule parotidea presenting untypical clinical symptoms and their bad prognosis]. AB - Differential diagnosis of neck tumours puts precedence on diagnosing neoplastic lesions. In the case of neck tumours, these are unfortunately late signs, but in patients with a primary neoplastic focus within the head and neck, neck tumour is often the first sign of the disease. The authors describe a clinical case of neck tumour with initially unclear etiology. The preoperative diagnostics including ultrasonography, thin-needle puncture, MRI, carotid angiography and videostroboscopy was significant for surgical treatment planning; yet it was the intraoperative clinical picture which indicated that the tumour derived from the inferior parotid pole. The preoperative histopathological diagnosis using thin needle biopsy: cellulae carcinomatosae and the clinical picture resulted in block operation with neck lymphatic system removal and tissue defect reconstruction by means of a pectoral flap. The histopathological examination confirmed non cornifying basal cell epithelioma only in the essential lesion with no metastases to lymph nodes and surrounding tissue margins free of infiltrates. Two and a half years after the procedure, the patient presented with a tumour localized on the front thoracic wall and two rapidly enlarging tumours in the nape of the neck. In the collected specimen of the tumour on the front thoracic wall, a diagnosis of acinic cell carcinoma was made. The deteriorating general condition of the patient, his cancer emaciation, problems with movement and suspected liver metastases confirmed by abdominal USG as well as radiological bone lesions resulted in the abandonment of surgical treatment due to disseminated neoplastic process and the patient was referred for palliative care. PMID- 20169912 TI - [The surgical achievements of Jan Kwasnicki (1838-1883) for Polish rhinolaryngology were important?]. AB - The professional and scientific activities of Jan Kwasnicki (1838-1883), a Varsovian surgeon, his medical education in various medical institutions is shortly outlined. He was the head of surgical ward at the Evangelical Hospital in Warsaw. He was an author of two-volume book "The operating surgery" (along with Wladyslaw Stankiewicz and Jozef Wszebor) (Warsaw 1868, 1874). Kwasnicki's successful surgical treatment of rhinolaryngological diseases (such as perforation of hard palate, carcinomas of tongue and lower lip) are described in some more detail. PMID- 20169913 TI - [Assesment of haemostatic dressings in endoscopic sinus surgery]. PMID- 20169914 TI - Distribution and chemical coding of calretinin- and calbindin-expressing enteric neurons in the duodenum of the sheep. AB - Recent decades has brought significant advances in our knowledge of the chemical coding and function of enteric neurons. Calcium ions are important second messenger involved in many aspects of neuron physiology. In the present study, we analyzed immunohistochemically the presence of calcium binding proteins (calretinin and calbindin) in various subpopulations of enteric neurons from the ovine duodenum. Ten percent of submucous neurons were immunoreactive (IR) to calretinin. The presence of calretinin was not detected in myenteric neurons. Calretinin-expressing nerve fibres were found in both myenteric and submucous ganglia, between the circular and longitudinal smooth muscle layers and in the lamina muscularis mucosae. Calretinin-IR submucous neurons did not exhibit the presence of SP, NPY and VIP. Co-localization of calretinin and serotonin was found only in a small number of submucous neurons. Calbindin was expressed in 35% of myenteric neurons and in 60% of submucous neurons. Nerve fibres containing calbindin were localized in myenteric and submucous ganglia where they frequently formed basket-like formations. Calbindin-positive nerve fibres emerging from myenteric ganglia ran between the circular and longitudinal smooth muscle layers. Immunoreactivity to calbindin was also visualized in the lamina muscularis mucosae, around mucosal glands and blood vessels. None of calbindin-IR myenteric neurons revealed immunoreactivity to SP, NPY, VIP and serotonin. Virtually all calbindin-expressing submucous neurons were SP-positive. In moderate numbers of submucous perikarya, co-incidence of calbindin and NPY, calbindin and VIP or calbindin and serotonin was observed. We conclude that in the ovine duodenum, the expression of calretinin and calbindin is species specific. Co-localization studies and distribution patterns indicate that in the duodenum of the sheep, calretinin and calbindin may be present in several functional subclasses of enteric neurons. PMID- 20169915 TI - Molecular analysis of the nucleoprotein gene of canine distemper virus isolated from clinical cases of the disease in foxes, minks and dogs. AB - In this study, we used RT-PCR to detect and characterize canine distemper virus isolated from 9 naturally infected foxes, 3 minks and 3 dogs in Poland by amplifying and sequencing a portion of the NP gene. A 293-bp fragment of the CDV NP gene was amplified by RT-PCR. Sequencing of the PCR products from the isolates led to the identification of 3 sequence variants. The mostly representative polymorphic variant No. 1 showed high homology with Chinese isolate of CDV with a accession number EF 375619. The sequences of all isolates from this polymorphic variants compared with the sequences of other polymorphic variants obtained in the study and with European and American isolates sequences from GenBank showed the conservative nucleotides changes in positions 57, 132, 143, 159 and 237. These mutations can indicate that in this part of Europe there are new variants of CDV. PMID- 20169916 TI - The effect of chemically and hydrothermally treated rapeseed on the performance and thyroid parameters of layers. AB - A feeding trial with brown laying hens was carried out in order to examine the effects of chemical and hydrothermal treatment of rapeseeds on the performance and thyroid parameters of birds during a long-term experiment. Untreated and treated rapeseeds were included in layer diets at a level of 7.5, 15.0, 22.5 and 30.0%, and the results obtained were compared with a control group fed a diet containing no rapeseed. Rapeseed treatment involved a combination of chemical and hydrothermal processing with subsequent expansion and drying. This treatment decreased sinapine content, from 6152 mg rapeseed/kg to less than 50 mg/kg, and glucosinolate concentration, from 13.8 mmol per kg to 1.4 mmol per kg (basis - 91% dry matter). The inclusion of 22.5% and 30.0% of both untreated and treated rapeseeds significantly impaired egg-laying rate and feed conversion. Egg weight was significantly affected by rapeseed feeding, with a significant decline at the 30.0% vs. the 7.5% rapeseed level. Rapeseed inclusion in the diet had a negative influence on weight gain. An increase in the dietary levels of untreated rapeseeds caused a greater decrease in egg mass, hen weight and feed conversion ratio, compared with the respective levels of treated rapeseeds. Untreated rapeseeds at the lowest level of 7.5% in the diet caused an increase in thyroid weight, epithelial cell height and changes in other histomorphometric thyroid parameters, as well as a decrease in the serum concentrations of thyroid hormones. Treated rapeseeds at a dietary level of 22.5% evoked a dose response, which shows that the chemical and hydrothermal treatment of rapeseed considerably reduced the anti-thyroid effects. PMID- 20169917 TI - The influence of dietary vitamin A supplementation on vitamin A and insulin levels in sedentary or physically trained rats. AB - Male rats of Wistar strain (n = 48) were fed a vitamin A deficient diet for 3 days of adaptation period and then a 10 day experimental period to reduce slightly the body stores of this vitamin. Half of the animals were subjected to physical training and/or oral vitamin A supplementation. Four different doses of supplementation were used--0, 7.5, 15 and 60 microg/d/rat, which is equivalent to 0, 25, 50 and 200 IU of vitamin A, respectively. Animals from the defined groups ran on a treadmill with a rate of 2.0 m/s for 15 minutes per day for 10 days. After overnight fasting, the rats were sacrificed, and insulin in blood serum and hepatic retinol concentrations were estimated. Daily feed intake and daily body gains were similar in groups of sedentary and physically trained rats. A moderate level of oral vitamin A supplementation (the highest supplemented dose was about 6 x the above recommended NRC level) did not cause any changes in these zootechnical parameters. Oral Vitamin A supplementation resulted in an increase in retinol concentration in the liver (F = 15.2, p < 0.001), but without significant difference between trained and untrained animals. Physical training of rats caused a statistically significant decrease of insulin concentration in blood serum (1.53 +/- 0.18 vs. 1.73 +/- 0.20). This difference was highly significant (F = 11.1, p < 0.001). Vitamin A supplementation was found not to influence the concentration of this hormone, which is responsible for energy metabolism regulation in the body. Based on estimated parameters, the necessity of vitamin A excessive use in physically trained subjects was not proven. PMID- 20169918 TI - Effect of diets with different contents of soybean alpha-galactosides and crude fibre on modification of duodenal microstructure and selected parameters of nutrient utilization in young turkeys. AB - The aim of the present study was to assess the physiological response of growing turkeys' duodenal surface to dietary replacement of a common dietary component- soybean meal (SBM) with a soy protein isolate (SPI), as this treatment was associated with almost complete removal of alpha-galactosides from the diet (from 2.44 to 0.15%). Additionally, the utilization of selected dietary ingredients upon dietary treatments was recorded. Effects of raffinose-family oligosaccharides were assessed as well in low- and high-fibre dietary environment (3.5 and 5.3% of crude fibre, respectively). This study revealed that the duodenal morphological parameters were differently affected by dietary treatments at different production stages, i.e. at 4 and 8 weeks of life. Although villus height/crypt depth ratio (VCR) was insignificantly decreased by high-alpha galactoside treatment in younger 4-week birds, the presence of these oligosaccharides in the diet positively influenced the VCR index in 8-week turkeys. A similar tendency was observed when calcium retention was considered. Different contents of dietary crude fibre affected the physiological action of alpha-galactosides, including duodenal crypts depth and phosphorus retention in the 4-week birds, as well as duodenal goblet cells number and nitrogen utilization in the older turkeys. A high content of alpha-galactosides in the diet resulted in increased hydration of intestinal contents, but without a significant decline in the dry matter digestibility and utilization of nitrogen, calcium and phosphorus. Having in mind the development and physiology of the GIT, it may preliminary be concluded that in later production stages, total withdrawal of soybean alpha-galactosides from turkeys' diets does not seem to be nutritionally advisable. PMID- 20169919 TI - Resistance to antimicrobial agents of Campylobacter spp. strains isolated from animals in Poland. AB - A total of 69 Campylobacter jejuni and 16 Campylobacter coli strains isolated from chicken, dog and pig stool samples were characterized based on their resistance to five antimicrobial agents and on plasmid pTet profiles. Antimicrobials used in this study were: amoxicillin/clavulanic acid, ciprofloxacin, erythromycin, tetracycline and trimethoprim/sulfamethoxazole. Among the isolates studied, 91.7% were resistant to one or more antimicrobial agent. The highest level of resistance for the whole test group was to trimethoprim/sulfamethoxazole (57.6%), followed by ciprofloxacin (44.2%) and tetracycline (20%). All isolates were susceptible to amoxicillin/clavulanic acid. Strains isolated from chickens were susceptible to erythromycin. Few erythromycin resistant strains were isolated from dogs and pigs (5.8%). C. coli strains exhibited a higher antibiotic resistance than C. jejuni strains, excluding resistance to trimethoprim/sulfamethoxazole. The pTet plasmid harboring the tet(O) gene was detected in 14 Campylobacter spp. strains. Our studies demonstrate that the majority (71.4%) of tetracycline-resistant isolates carry a plasmid-borne tet(O) gene, particularly strains for which the minimum inhibitory concentration (MIC) are > or = 256 microg/ml. In conclusion, we have found high level trimethoprim/sulfamethoxazole, ciprofloxacin and tetracycline resistance in Polish strains isolated from different sources. This study has demonstrated that resistance of Campylobacter species differs depending on both the bacterial species and animal origins. All strains that displayed resistance to four antimicrobial agents were isolated from pigs. Localization of the tet(O) gene on either plasmid or chromosome was not found to be correlated with tetracycline resistance. PMID- 20169920 TI - Abnormal morphology of skeletal muscles in meat-type chickens--ultrastructural observations. AB - In order to determine the effect of different production systems on muscle ultrastructure in meat-type chickens, we examined m. gastrocnemius and m. pectoralis superficialis in two lines of chickens (Anak Titan and Isa 215) raised in three different technological systems (indoors in a conventional facility, indoors with limited outdoor access and outdoors with an umbrella roof). Our previous study showed some abnormalities in the histological structure of these muscles. We hypothesized that electron microscopy, having a strategic position in muscle examination, would provide insight into changes in muscle tissue revealed by light microscopy. The results of the study indicate that the muscles examined undergo ultrastructural alterations regardless of the muscle type, chicken line and production system. The abnormalities observed in the present study were found to affect many aspects of fiber ultrastructure impairing function of the myofibrillar apparatus--the structure of mitochondria and sarcoplasmic reticulum, defects of the sarcolemma as well as the appearance of remnants resulting from fiber disintegration. Abnormal responses were found primarily in myofibrils and mitochondria, and--to a lesser extent--in other structures of muscle fibers. We suggest that the majority of the changes observed may lead to muscle damage followed by pathology. The severity of these changes was particularly evident in the muscles of chickens of the Isa 215 line (highly selected) kept outdoors with an umbrella roof. The observations point to a dependence of the above changes on the line of chickens and rearing conditions. Therefore, the limited potential of highly selected broilers to adapt to different environmental conditions should be taken into account while selecting a new production technology. PMID- 20169921 TI - Occurrence of bacteria of the genus Staphylococcus in table eggs descended from different sources. AB - This paper presents the degree of contamination of table eggs with bacteria of the genus Staphylococcus, taking into account the source of the eggs. The results of the study indicate a relatively high degree of contamination of table eggs with Staphylococcus bacteria. In 1125 bacteriological tests conducted on whites, yolks and shells of eggs from three sources, staphylococci were found in 514 cases. Thirteen strains were isolated from the whites, but Staphylococcus bacteria were found more often in yolks--199 strains. The highest percentage of staphylococci were found on the surface of the egg shell--302 strains. Twelve species of staphylococci were isolated from the eggs tested, including both coagulase-positive strains (Staphylococcus aureus, S. hyicus) and coagulase negative strains, particularly Staphylococcus lentus, S. warneri, S. epidermidis and S. xylosus. This study determined that regardless of the source of the eggs, egg yolks were more often contaminated with Staphylococcus aureus than with coagulase-negative Stapphylococci. It was also demonstrated that S. aureus dominated in the yolks and on the shells of eggs from the small-scale poultry farm. PMID- 20169922 TI - Analysis of the correlation between the level of anti-Salmonella antibodies in egg yolks and the presence of these microorganisms in egg contents following experimental infection of hens with Salmonella Enteritidis and after treatment with selected antibiotics. AB - Serological tests applied in poultry flocks can be a valuable tool in assessing health of hens. One obstacle in making this assessment is that results of serological tests in a given flock are not always correlated with results of bacteriological tests. The aim of this study was to determine dependencies between the level of antibodies in egg yolk and the contamination of egg contents (whites and yolks) with Salmonella Enteritidis bacilli. Infected birds were also treated with selected antibiotics. It was determined that Salmonella Enteritidis was not found in experimentally infected laying hens until day 12 post inoculation. The results of the study also suggest the existence of relation between the level of anti-Salmonella antibodies in egg yolks and the frequency of isolation of Salmonella from eggs. It was also found that the lowest level of yolk antibodies was found in the group of birds treated with enrofloxacin. PMID- 20169923 TI - The influence of experimental Yersinia enterocolitica infection on the pregnancy course in sows--preliminary studies. II. Antibodies, C-reactive proteins and haptoglobin as an immunological response. AB - The aim of the study was to determine the time of emergence and level of Y. enterocolitica antibodies in pregnant sows challenged orally with Y. enterocolitica in particular trimesters of pregnancy (groups I, II and III, respectively) and also the assignation of its influence on the CRP and Hp concentration in sera of pigs. Levels of antibodies measured by tube agglutination test increased slowly from 2 weeks post infection (wpi) and positive results were obtained not in all animals. In ELISA, in 2 weeks in all groups of infected animals high levels of antibodies against Y. enterocolitica were formed and lasted up to the end of the experiment. In newborn piglets in all groups, a significant decrease in antibody levels 6 weeks after birth was observed in both agglutination and ELISA tests. Concentrations of CRP as Hp in all groups of infected animals increased in 1 week post infection. Statistically significant differences (P < or = 0.05) between CRP levels in groups I and II (46 fold and 44-fold) as well as III (29-fold) were revealed. In case of Hp, statistically significant differences between groups of animals in the first week post infection were not observed. Our findings indicate that Y. enterocolitica infection evoked strong and long-lasting immunological reaction in the form of specific antibodies production in all inoculated animals. The significant increase in CRP and moderate increase in Hp concentrations in the sera of pregnant sows also occurred. However, relationships between colostrums antibody levels in piglets' sera and phase of pregnancy when the Y. enterocolitica infection happened in sows were not observed. PMID- 20169924 TI - The relationship between concentrations of vitamin D-binding protein (DBP) in serum and colostrum of mares and in serum of their foals in the neonatal period. AB - Vitamin D-binding protein (DBP) participates in the actin scavenger system, it is a carrier of vitamin D and its derivatives, it manifests the capacity to bind mainly monounsaturated and saturated fatty acids, it binds to the surface of several cells and enhances chemotactic activity of C5a of the complement. The present study was aimed at answering the question whether serum DBP level in mares is related to levels of this protein in colostrum and in serum of its progeny. For this purpose, sera from 77 mares, colostra from 72 mares and sera from 69 Thoroughbred foals were collected. Mother's age, number of deliveries experienced in the past, month of delivery, feeding of foals with colostra were recorded. Blood of the foals was sampled from the umbilical vein during delivery (0h) and 36-48 h after delivery from the external jugular vein, colostra of the mares were obtained after delivery and blood of the mares was sampled 36-48 h after delivery. Concentration of DBP was estimated by a self-designed ELISA. In the present study, DBP concentrations in newborn's serum were found independent of their concentrations in mother's serum, her age and number of parities experienced in the past. Colostrum DBP level was found to be lower than that in the mare's serum and was not correlated to the concentration of this protein in mare's serum. There was no effect of colostrum feeding on DBP level in the foal serum. These results indicate that serum DBP concentration in newborn foals depends on factors which act directly on the foal. Because of the lack of correlation between plasma and colostrum concentrations of DBP, it can be assumed that DBP is synthesised in the mammary gland and/or specific transport mechanisms exist in the mammary gland. PMID- 20169925 TI - Influence of Bi 58 Nowy (38% dimethoate) on pyrantel embonate concentration in the liver of rats. AB - The aim of the study was to determine the concentration of pyrantel residues in the liver of rats in different time points after oral administration of pyrantel embonate as well as combined administration of the Bi 58 Nowy preparation (38% of dimethoate) and pyrantel embonate. The experiment was conducted in two stages involving different doses of compounds and modes of exposure. At the first stage, the animals were administered pyrantel embonate with a stomach tube at a dose of 1000 mg/kg b.w. twice in a two-week interval, i.e. on day 14 and 28, and the Bi 58 Nowy preparation with drinking water at a dose of 15.48 mg/kg b.w. for 28 days. At the second stage, the rats received pyrantel embonate at a dose of 400 mg/kg b.w. with a stomach tube for 3 consecutive days, whereas the Bi 58 Nowy preparation was administered at a dose of 38.7 mg/kg b.w. also with a stomach tube for 5 consecutive days. In the rats doubly administered with pyrantel embonate, its residues were present until day 14, whereas when the drug was administered for 3 consecutive days they were present until day 7 of the experiment. The maximum concentration of pyrantel embonate was found in the liver after the 3rd hour, whereas a considerable decrease occurred between the 3rd and the 12th hour. The combined administration of pyrantel embonate and the Bi 58 Nowy preparation caused a significant decrease in the concentration of pyrantel residues in the liver 3 and 6 hours after exposure, as compared to the rats receiving the drug alone. PMID- 20169926 TI - Selected biochemical blood compounds in cows with abomasum displacement. AB - The aim of this study was to compare some blood biochemical indicators in cows with displacement of abomasum (DA) which recovered or died after treatment. Examinations were performed on 60 multiparous cows with left (L) or right (R) displacement and on 15 healthy herdmates. Diagnosis was made by experienced practitioners on the basis of clinical examination. Surgical treatment was undertaken during the first 24 hours after diagnosis. Almost all animals (55 = 91.5%) became sick in the post parturient period (21 days p.p. on average) with the exception of 5 (8.3%) that became sick later. Blood samples were taken from each cow immediately before surgical procedure. Serum nonesterified fatty acid (NEFA), glucose (Glu), cholesterol (Chol), aspartate aminotransferase (AST), total bilirubin (Bil) and blood urea nitrogen (BUN) were measured. Sick animals were characterized by low mean values of Chol (< or = 2 mmol/l) and normal level of BUN (12-15 mg/dl), higher levels of NEFA (> 600 micromol/l) and Bil (> 22 micromol/l), higher activity of AST (> 100 U/l). Seven cows (11.67%) died after surgical correction and all others recovered. No significant differences in NEFA, Chol, AST, Bil and BUN levels were observed as dependent on the efficacy of treatment (survival, deaths). It was found that cows which died after surgical treatment were characterized by significant higher levels of glucose (5.05 mmol/l) compared to surviving cows (2.93 mmol/l). PMID- 20169927 TI - The influence of administering "effective microorganisms" to pullets on chosen haematological and biochemical blood indexes. AB - "Effective Microorganisms" (EM)--a mixture of lactic acid bacteria, photosynthetic bacteria, yeasts and fungi are used mainly in agriculture and organic waste treatment. Recently, they have also been added to water and feed for animals, as well as to processing their excrements into compost and to eliminate the stench. The objective of the present study was to assess the influence of a 14-day administration of an EM solution in drinking water to layer hens on chosen haematological and biochemical indexes. The research was carried out on 120 hens divided into two equal groups. The birds in the experimental group were given drinking water with dissolved EM (5% solution), and those in the control group--water without the preparation. On the 64th day of the aviculture, the hens were weighted and their blood was taken from the wing vein for haematological and biochemical examinations. Administering EM with water to hens did not influence significantly their body weight nor chosen haematological and biochemical indexes. A significant increase was found only in the number of platelets, the level of albumins, the content of total cholesterol and the LDH activity, however, a decrease in the ALT activity was observed. PMID- 20169928 TI - Thrombocytopenia as a characteristic trait in the Polish ogar dog. AB - The study was undertaken to ascertain if the normal thrombocyte count in Polish ogar dog differs from normal values in other dog breeds. The reason for this study was constatation that during routine blood analysis in healthy Polish ogar dogs, thrombocytopenia, not related to the clinical state of the animals, was frequently encountered. The study was carried out on 38 Polish ogar dogs. The control group consisted of 80 dogs of various breeds. All the animals were clinically healthy. A full hematological analysis was performed. The mean platelet value in all dog breeds without the Polish ogar dogs was 344.4 +/- 6.85, while the mean number of platelets in the Polish ogar dogs amounted to 167 +/- 11.6 G/l. The limited genetic material used to rebuild the Polish ogar breed after its drastic decline during the Second World War could be the reason for various, including hematological, abnormalities that with time became a normal characteristic traits for this breed. PMID- 20169929 TI - Influence of green muscle disease on quality of meat subjected to thermal treatment. AB - As a result of continuous increase in poultry production and poultry breeding selection numerous forms of diseases appeared including the green muscle disease. The goal of the study was to determine the influence of the green muscle disease on quality of meat subjected to thermal processing. The material for the study consisted of 55 samples of the major pectoral muscles originating from female post-production turkeys and turkey broilers. The samples were subjected to organoleptic evaluation and tests aimed at determining the meat tenderness. On the basis of the results obtained it is concluded that the meat originating from turkeys suffering from the green muscle disease, subjected to thermal processing, shows significant differences in cross-section color, juiciness and taste. PMID- 20169930 TI - Some physicochemical bone parameters of sows fed microbial phytase-supplemented diet. AB - The aim of the present study was to determine the effect of microbial phytase addition to sow diets on a mineral content, mineralization level and geometric parameters of femoral and humeral bone. The studies were done on 75 sows assigned to 3 feeding groups. The animals from group I (positive control) were fed a diet of standard calcium and phosphorus dietary contents which complied with the requirements of the Polish Norms for Pig Nutrition (1993). The sows from group II (negative control) received a diet without an inorganic phosphorus content and finally, group III was provided with a diet without an inorganic phosphorus additive, but supplemented with microbial phytase (500 PU kg(-1)) and formic acid. After lactation completion and piglet weaning, 4 sows were selected from each group for slaughter and laboratory evaluation of femoral and humeral bone samples. The bone samples were examined for a content of dry matter, crude ash and minerals (phosphorus, Ca+2, Mg+2, Mn+2, Zn+2, Cu+2). The isolated femurs were analyzed for a mineralization degree and geometric parameters. A combined microbial phytase with formic acid supplementation significantly increased manganese and zinc concentration in femoral bone and a level of phosphorus, calcium, zinc and iron in humeral bone of sows. There was also observed significantly higher trabecular bone mineral density (Td) in the femoral bone as well as the bone volume. The evaluation of geometric parameters and bone cortical indices showed a significant influence of the sow feedstuff supplementation with microbial phytase and formic acid on the parameters studied. PMID- 20169931 TI - Evaluation of the degree of pancreas activity in piglets from sows fed enzymatic stimulating complex. AB - One of the possibilities for estimating pancreas activity is the estimation of zymogene granule content in pancreatic follicular cells. In the present study, the degree of pancreatic activity was measured in piglets from sows receiving enzymatic stimulating complex throughout pregnancy and during the lactation period. The pancreas was collected for ultrastructural examination from 1-day-old and 21-day-old piglets. The enzyme preparation influenced the ultrastructural structure of the piglet pancreas, but the secretory cells in these animals did not confirm a more intensive course of creation and maturation processes. The accumulation of granules in extra-secretory pancreatic cells was observed, with a large volume of these granules and granular crinophagy observed in older piglets. The findings indicate a slow process of granule release, which may be the result of overproduction, lower requirements for enzymes contained in the granules, or both. PMID- 20169932 TI - New localities of Dermacentor reticulatus tick (vector of Babesia canis canis) in central and eastern Poland. AB - Dermacentor reticulatus tick is a vector and final host of Babesia canis canis, protozoan parasite of the dog. In Poland and other European countries, endemic regions for canine babesiosis caused by B. canis canis are the same as endemic regions for D. reticulatus. In many of these regions, canine babesiosis is the most prevalent tick-borne disease in dogs. In Europe, increasing range of geographical distribution of D. reticulatus is observed. A consequence of this fact may be increasing range of canine babesiosis. D. reticulatus is one of the most common ticks occurring in Poland, however, it occurs mainly in the north eastern and eastern part of the country, and there are many areas in which this species has not been reported yet. In this study, D. reticulatus ticks were collected from March 2007 to November 2008 in central and eastern Mazowsze region, and in some localities in Bialystok and Lublin regions. Twenty four new sites for D. reticulatus, mainly in central and eastern regions of Mazowsze Province have been found. 18 localities are placed on banks of the fishing ponds or in river valleys and 6 are forests borders or barren lands and meadows, not situated near rivers or other water reservoirs. All tick-rich sites are localized in river valleys or on pond banks. However, statistical analysis showed that there were no differences in the density of ticks between groups of areas. These results show that the occurrence of D. reticulatus in newly detected areas has became endemic. Probably woodless, unregulated river valleys are important migration tracts for this species of tick and enable them to penetrate new territories. It seems likely that geographical range of D. reticulatus is widening from east to west of Poland what can induce an increase in the number of canine babesiosis cases in areas non-endemic for B. canis canis and its vector. Climate change may be also partially responsible for earlier beginning of tick's seasonal activity as well as for bigger faunal diversity (more potential host species both for adults and immature stages). PMID- 20169933 TI - Blood haematological profile and meat colour of calves slaughtered in summer and autumn season. AB - The purpose of this study was to compare the haematological profile and meat colour of calves slaughtered in summer and autumn. The material covered 42 calves chosen randomly i.e. 22 slaughtered in summer (June-August) and 20 in autumn (October-December). Haematological analyses included haematocrit (HCT), haemoglobin level (HGB), red blood cells (RBC), white blood cells (WBC) and platelets (PLT). The morphology of the erythrocytes and platelets, and differentiation of leucocytes were examined. The colour of meat was evaluated instrumentally by Minolta CIE L*a*b* and haematin pigment content was determined. The blood haemoglobin content in calves in the compared seasons was similar (11.3 g/L) and found within a normal range. Blood of calves from the autumn season showed higher HCT, RBC, and MCV values with concurrent lower MCH and MCHC values in comparison to the summer season. Blood of calves slaughtered in summer showed a higher content of WBC and a significantly higher percentage of lymphocytes as against blood of calves from the autumn. Meat of calves from the summer season was paler (higher L* value), and had a significantly (p < or = 0.05) higher proportion of yellowness (b*). A brighter colour of meat from calves presented for slaughter in the summer season was noted along with a lower content of haematin pigments. Significant correlations were found between haematological variables (HGB, HCT and RBC, particularly) and haematin pigment content and meat lightness (L*) and redness (a*). PMID- 20169934 TI - Measurement of milk D-3-hydroxybutyrate with a simple UV spectrophotometer method: an alternative assay method. AB - The measurement of D-3-hydroxybutyrate (D-BHBA) in milk samples is an important tool for diagnosis of subclinical/clinical ketosis in dairy cows. We describe a simple UV spectrophotometric method for measuring the concentration of D-BHBA in milk of dairy cows. From two herds, 119 milk samples were taken from dairy cows. The standard-curve equation was y = 0.2582x + 0.0269 (R2 = 0.9967). The assay was highly specific with a minimum detection limit of 0.01 mmol/L and measuring range of up to 5 mmol/L. The recovery was between 99.35% and 100.22% and repeatability was 99.8%. The comparison between the spectrophotometric method and the fluorometric method revealed a close correlation (r = 0.9939). These results show that the spectrophotometric method can be successfully used as an alternative method to measure D-BHBA content in milk. PMID- 20169935 TI - Morphological examination of the proximal ganglion of the vagus nerve in the pig. AB - This is the first report dealing with the localisation and morphology of the proximal (jugular) ganglion in the pig. Six 3-months-old pigs of both sexes were used in this study. Tissues were stained with three histological methods: Kluver Barer counterstained with Cresyl violet, Haematoxylin-eosin and Mayer's haematoxylin. The localisation and morphological features of the ganglion and ganglionic neurones were described and discussed. PMID- 20169936 TI - Changes in the prevalence of parasitic nematode infections in dogs from animal asylums in Warsaw and sourroundings. AB - The distribution of parasitic nematodes of dogs from three shelters for homeless animals in the Warsaw region (Celestynow and Milanowek near Warsaw, Paluch in Warsaw) was investigated. It was found that since our previous investigations (1993-1995) the prevalence of nematode infections had increased in Celestynow and Milanowek and decreased in the municipal shelter in Warsaw (Paluch). The highest percentage of infected animals was found in Celestynow (as in 1993-1995). What can be the importance of local environmental conditions for the prevalence of nematode infections. PMID- 20169937 TI - The impact of environmental stress on Listeria monocytogenes virulence. AB - Listeria monocytogenes, a significant food-borne pathogen, must defy a variety of conditions encountered in the food environment and during the infection process. In reaction to adverse conditions, the bacteria significantly change their metabolism, inducing a stress response which is mediated by a range of alternative sigma factors. The extent of the response to stress was shown to vary in the L. monocytogenes population. According to recent evidence a major L. monocytogenes alternative sigma factor, designated sigma B (sigma B), regulates some virulence genes in response to stress, which supports an older hypothesis that stress-resistant strains should be more pathogenic. The induction of sigma B dependent genes may also be important from the point of view of food hygiene. It seems that stress response activation can paradoxically enhance resistance to agents used in food preservation. Therefore, monitoring the expression of sigma B dependent genes can serve as a useful marker to assess the innate resistance of L. monocytogenes strains. This knowledge will allow the design of new methods with sequential preservation steps that could inactivate the bacteria without inducing their stress response. PMID- 20169938 TI - Mycotoxins and mycotoxicoses under climatic conditions of Poland. AB - Ochratoxin A (OA), zearalenone (ZON), moniliformin (MON) as well as trichotecenes and fumonisines (FUM) are naturally occurring contaminants of cereals and animal feed. They pose a health risk not only to humans but also to livestock and, as a consequence, may cause economical losses either due to unfavorable effects on domestic animals themselves or to an increased potential for health effects in human beings consuming mycotoxin-contaminated edible animal products. At present, large-scale studies are carried out in EU countries to determine a safe, admissible concentration of these toxins in cereals and their processed products. The aim of this review is to collect and summarize information concerning the properties, occurrence and toxicity of these mycotoxins. PMID- 20169939 TI - [Multisite-based approach to assure inter-assay system compatibility among different exclusive-typed immunoassay systems through determining exchanged calibrators]. AB - It is well known that most exclusive-typed immunoassay systems are highly precise but are poor in compatibility of their determinations. Thus, it is difficult to compare the determinations among different systems, posing problems when a patient is transferred to different hospitals or when a laboratory intends to change the system currently used. In the study, we tried to approach how to assure inter-immunoassay compatibility among four different systems through determination of the exchanged calibrators. First, determinations of total protein and albumin, and electrophoretic fractionation demonstrated marked differences among calibrators in their protein constituent. Some calibrators were prepared with human sera, but others were with inorganic or non-human albumin based solution. Regression analysis of calibrators between the indicated concentrations by manufacturers and those actually determined by the different immunoassay systems revealed that; most slopes were closed to 1.0 for alpha fetoprotein and prostate-specific antigen, but widely dissociated from 0.28 to 4.71 for CA19-9. In evaluation of clinical serum samples, determinations by one immunoassay system were compared with those converted based on a linear regression equation that was obtained by determination of the exchanged calibrators. However, this procedure could not improve compatibility, and positive effects of conversion varied by immunoassay systems combined, and also by test parameters. With these, we concluded that simple conversion of determinations by using the exchanged calibrators and a statistical linear regression could not provide us with the expected compatibility. Thus, standardization of target molecules or probes, and of calibrator constituent were urgent issue to assure inter-immunoassay compatibility. PMID- 20169940 TI - [Comparison of two HER-2 FISH kits on formalin-fixed paraffin-embedded tissues: signal detection and simple procedure]. AB - The gene amplification of human epidermal growth factor receptor (HER-2) detected by fluorescence in situ hybridization (FISH) help to select breast cancer patients who could benefit from therapeutic strategies targeting HER-2, trastuzumab. For formalin-fixed paraffin-embedded tissue specimens, the preprocessing procedure, which is consisted of heat-treatment and protease digestion, is necessary to detect probe specific signal by FISH. We compared the findings of two commercial kits for HER-2 (Histra HER2 FISH Kit [JOKOH CO.LTD] and Pathvysion HER-2 DNA Probe Kit [Abbot Molecular CO. LTD]) using 9 breast cancer specimens, which were fixed in formalin for various durations after the surgical extirpation or biopsy. The two kits showed the same results that HER 2/17 centromere (17cen) signal ratio was within normal rage (< 2.0) in 7 cases among 9 and was over 2.0 in remaining 2. Histra could obtain sufficient signals on both surgical and needle biopsy speciments after the same pretreatments. PathVysion, on the other hand, require a different protease or modification of protease digestion time. Furthermore, the specific signals for HER-2 and 17cen could be observed more clearly by Histra than PathVysion under fluorescensce microscope. Histra is more suitable for routine examination because of its simple and constant-processing procedure. PMID- 20169941 TI - [Case of spuriously high level of squamous cell carcinoma antigen in patient without carcinoma--HPLC and ultrafiltration are useful to analyze the true value]. AB - Squamous cell carcinoma antigen (SCCA) is a diagnostic tumor marker for the advanced uterine, cervix and lung tumor. Although SCCA is a prognostic indicator for some tumors, recent progress of this marker has shown that the SCCA could also be found in the serum of nonmalignant disease such as renal failure and others. Here, we report a case of spuriously high level of SCCA in patient without carcinoma, renal failure, head-and-neck disease and lung disease. An early fifties female who had been undergone the diagnostic conization for high grade cervical intraepithelial neoplasia ten years ago and observed without special treatment with around 20ng/ml level of SCCA. She has no signs of tumor, renal failure, head-and-neck disease or lung disease until now. The high performance liquid chromatography with Superdex 200 showed the molecular weight of the major part of SCCA of the patient is more than 160 kDa and the part of 45 kDa, the same molecular weight as lung tumor, is trace amount. Moreover, the ultrafiltration analysis showed the SCCA of the present case did not penetrate the 100 kDa cut-filter, but SCCAs with other patients with uterine, cervix, lung tumor and renal failure did penetrate the filter. In this case, the analysis of molecular weight of SCCA using HPLC gel filtration and ultrafiltration is useful to rule out spuriously elevated SCCA. PMID- 20169942 TI - [Rare case report of solitary ganglioneuroma of the transverse colon]. AB - We report herein a rare case of solitary ganglioneuroma occurring in the transverse colon with a brief literature review. A 45-year-old man was diagnosed as having hemorrhoids by a local medical practitioner and referred to our hospital for further examination. He showed neither signs nor symptoms of neurofibromatosis and multiple endocrine neoplasia. Colonic endoscopic examination demonstrated that a pedunculated polyp with a size of 11 mm in the diameter in the transverse colon. Histopathologic and immunohistochemical examination demonstrated that the endoscopic mucosal resection specimen of the polyp had abundant ganglionic cells, Schwann cells, and nerve fibers in the mucosa and submucosa. PMID- 20169943 TI - [Therapeutic application of diacylglycerol oil for the metabolic syndrome]. AB - Excess adiposity has been shown to play a crucial role in the development of the metabolic syndrome. Characteristics for dyslipidemia in the metabolic syndrome are elevated fasting and postprandial triglyceride (TG) and decreased high density lipoprotein-cholesterol (HDL-C). Diacylglycerol(DAG) has been suggested to suppress postprandial hyperlipidemia and promote negative caloric balance by increasing energy expenditure, due to intestinal physiochemical dynamics that differ from triacylglycerol (TAG). Our study (Study 1) demonstrated that DAG suppressed postprandial increase in TG-rich lipoprotein, very low density lipoprotein (VLDL), and insulin as compared with TAG in young male individuals. Further, our another study using the apolipoprotein C-II deficient subject demonstrated that DAG suppressed postprandial increase in VLDL-cholesterol and remnant-like particle-cholesterol compared with TAG, suggesting that DAG suppress postprandial TG-rich lipoprotein independent of lipoprotein lipase. Study 1 also showed that DAG significantly increased plasma serotonin, which is mostly present in intestine and mediates thermogenesis, proposing a possible mechanism for a postprandial increase in energy expenditure by DAG. Our studies presented DAG mediated amelioration in postprandial TG-rich lipoprotein, insulin, and energy metabolism, indicating the therapeutic application of DAG for the metabolic syndrome. PMID- 20169944 TI - [Analyses on activation and regulation of blood coagulation]. AB - We have been investigating the mechanism of blood coagulation and anticoagulation related to pathogenesis and the regulation of thrombosis and bleeding disorders. Since our focus is basically internal medicine and hematology, the contribution to this field is clinically based and aimed to help patients and maintain public health. In this review some of our achievements associated with the activation and regulation of blood coagulation are introduced, mainly based on our research with post-graduate medical technologists. The main topics are the structural and functional relationship of thrombomodulin (TM), the regulation of tissue factor (TF) and TM expression, TM gene therapy, activation of the extrinsic coagulation system due to increased TF-bearing leukocytes during and after cardiac surgery, endoplasmic reticulum-associated degradation of protein C and plasmin inhibitor mutants leading to protein deficiency, activation of blood coagulation with exposure of cellular or viral RNA, and the detection of novel bioactive peptides salusin-alpha and -beta. PMID- 20169945 TI - [Standardization of measurement of catalytic activity concentration of enzymes- current situation regarding the external quality assessment program provided by the Japan Medical Association]. AB - Measurement of the catalytic activity concentration of enzymes has been standardized using a traceability chain, consisting a reference measurement system for enzyme catalytic activity and reference standard-JSCC enzyme. The Japan Medical Association (JMA) has provided an external quality assessment (EQA) survey program for clinical laboratory testing. More than 3,100 clinical laboratories participated in 2008. The EQA program indicated that standardization of the measurement of the catalytic activity concentration of enzymes has been completed for AST, ALT, LD, ALP, gammaGT, and CK in more than 90% laboratories, and for Amy and ChE in nearly 80% of laboratories. Because such a large survey program must use artificial specimens, a matrix effect cannot be avoided, especially in dry chemistry. However, the bias produced by a matrix effect usually has a predictable tendency: it can be corrected. Next, after standardization of the measurement of the catalytic activity concentration of enzymes, we should develop and use common reference intervals. On completing the standardization, we can make standard medical decisions using reference measurement systems and rules. PMID- 20169946 TI - [History of ISO 15189 and its future perspective]. AB - ISO 15189, Medical laboratories--Particular requirements for quality and competence was prepared by ISO/TC212, Clinical laboratory testing and in vitro diagnostic test systems, and its first edition published in 2003 and the second edition in 2007. Its purpose is to be used by medical laboratories in developing their quality management systems and assessing their own competence, also for use by accreditation bodies in confirming or recognizing the competence of medical laboratories. Since its publication, it has been recognized officially by the International Laboratory Accreditation Cooperation (ILAC) to be used as the international standard for the accreditation of medical laboratories worldwide. In Japan, the Japanese Committee for Clinical Laboratory Standards (JCCLS) and the Japan Accreditation Board for Conformity Assessment (JAB) cojointly started the accreditation program in August, 2005, and a total of 46 medical laboratories had been accredited by April 2009. In ISO/TC212/WG1 is working on the preparation of its third edition. PMID- 20169947 TI - [Significance and future prospects of the ISO15189 accreditation topics on systems of operation in preparation for accreditation]. AB - ISO 15189 is a standard for systems of operation to provide medical laboratory services. It is essential that daily operations be performed in accordance with ISO 15189, but acquisition of accreditation under ISO 15189 should not be the goal. Furthermore, since ISO 15189 does not stipulate operational procedures, the optimal method for the individual laboratory should be used. After obtaining ISO 15189 accreditation, the laboratory only has to manage and perform daily operations in accordance with ISO 15189 on the basis of the quality management system that has been established, and the quality of service that the medical laboratory provides will improve accordingly. PMID- 20169948 TI - [Merits of acquiring ISO15189 accreditation]. AB - In Japan, an ISO15189 accreditation system was started in 2005. To date, 47 hospitals have been accredited. In this session, I will present the merits of acquiring accreditation regarding ISO15189 based on our experience. Our hospital has 263 beds. The Clinical Examination Section consists of 12 staff (including 5 part-time workers): 7 in change of sample examination and 5 in charge of physiological examination. The annual number of samples is approximately 150,000. Samples collected on health checkups account for 90%. To improve the quality and service, assessment by third persons has been positively utilized in our hospital. Accreditation regarding ISO9001, ISO14001, ISO27001, privacy mark, hospital function assessment, the functional assessment of "ningen-dock"/health checkup hospitals, labor/hygiene service function assessment, and ISO15189 has been acquired. Patients may not recognize ISO. So, it must be utilized, considering that the acquisition of accreditation is not a goal but a starting point. Furthermore, cost-performance should be improved to achieve utilization related merits. It is important to not only acquire accreditation but also help clinical staff and patients become aware of some changes/merits. Patients may consult a hospital for the following reasons: confidence in the hospital, and the staffs kind/polite attitudes. Long-term management strategies should be established without pursuing only short-term profits. I will introduce several merits of acquiring accreditation regarding ISO15189. Initially, incidental conditions for bids and appeal points include accreditation regarding ISO15189. Our corporation has participated in some competitive bids regarding health checkup business. In some companies, the bid conditions included ISO acquisition. In our hospital, clinical trials have been positively carried out. For participation in trials, hospitals must pass an institutional examination. However, ISO acquisition facilitates the preparation of documents, leading to successful results. The staffs consciousness has also change. I feel that they try to manage samples from blood collection until reporting laboratory data and interpret laboratory findings strictly. With ISO9001 and ISO14001 activities in our corporation, improvements in consciousness and service have increased the number of patients. Although items other than ISO also improved, ISO played an important role. We could participate in an international collaborative study, "Regional Difference in Laboratory Data and Establishment of Common Reference Ranges", which was mainly designed by Prof. Ichihara, Medical Research Department, Yamaguchi University Graduate School. This also resulted from ISO15189 acquisition. Furthermore, the Japanese Society of "Ningen-Dock" selected Dr. Yoshida, the chairman of the board of directors in our corporation, as a chairman of a meeting that will be held by this society in Asahikawa in 2010 as a result of ISO15189 acquisition by the Clinical Examination Section of our hospital, that is, high-level consciousness. It may be the first case for a middle-/small-scale general hospital to lead a meeting held by such a prestigious society. Thus, I have introduced the merits of ISO15189 acquisition. I hope that our experience will contribute to future ISO activities. PMID- 20169949 TI - [Effectiveness of incorporating a quality management system]. AB - In 2003, the ISO 15189 international standardization program on the quality and competence of the clinical reference laboratory was introduced. To date, 46 facilities have committed themselves to providing a higher level of medical service by incorporating a quality management system (QMS) and acquiring accreditation. QMS is defined as "setting up a policy and goals pertaining to quality, and adopting an appropriate system," and is a scheme that includes all managerial and technical factors that can affect test results. Regarding the Health Sciences Research Institute Group, 4 facilities have previously received the accreditation described above, but in the process of implementing the QMS, a number of problems have been identified. Here, we report on the effectiveness of adopting such a QMS based on the results of employee questionnaires, internal audits, customer complaint analyses, and external audits by the Japan Accreditation Board for Conformity Assessment (JAB), the official inspection body for accreditation. PMID- 20169950 TI - [Optimum intubating dose of rocuronium for short duration surgery in adult patients]. AB - BACKGROUND: The aim of this study was to examine optimum intubating dose of rocuronium in adult patients who had been scheduled for short duration surgery. METHODS: Thirty patients were randomly assigned to receive rocuronium 0.4 mg x kg(-1), 0.5 mg x kg(-1) or 0.6 mg x kg(-1) during induction with propofol and fentanyl. Immediately after the adduction of thumb to the ulnar nerve stimulation could not be visually observed, the patients were intubated tracheally and the intubating conditions were evaluated. Thereafter, time to recover to train-of four (TOF) counts of 4 was recorded during sevoflurane and nitrous oxide anesthesia. RESULTS: Intubating conditions after rocuronium 0.5 and 0.6 mg x kg( 1) were all graded either excellent or good. In contrast, inadequate conditions for safe and easy tracheal intubation were observed in 60% of the patients receiving 0.4 mg x kg(-1). Time to spontaneous recover to the TOF counts of 4 correlated with the intubating doses of rocuronium. CONCLUSIONS: For short duration surgeries, rocuronium 0.5 mg x kg(-1) was appropriate to perform safe tracheal intubation and minimize duration of action of rocuronium. PMID- 20169951 TI - [Efficacy of acetated-Ringer containing 10% dextran: evaluation in a rat model of acute normovolemic hemodilution]. AB - BACKGROUND: In this study, we prepared acetated-Ringer containing 10% dextran, and evaluated its efficacy in a rat model of acute normovolemic hemodilution (ANH). METHODS: Under sevoflurane anesthesia, 21 rats (350-400 g) underwent ANH. In all rats 10 ml of blood was withdrawn, and they were infused with 10 ml of acetated-Ringer containing 10% dextran (Group-A, n = 11) or lactated-Ringer containing 10% dextran (Group-L, n = 10). For each rat, ANH procedure took 20 minutes. Hemodynamics and arterial blood gas data before and after ANH were compared. RESULTS: All results but for blood lactate level after ANH were comparable between the 2 groups. Blood lactate level was elevated in both groups after ANH; however, the elevation was significantly higher in Group-L. CONCLUSIONS: No differences in hemodynamics after ANH reveal that 2 plasma substitutes used in this study have almost the same quality in maintaining intravascular volume. Blood lactate level is generally recognized as an indicator of tissue hypoxia. A possible explanation for the significantly higher blood lactate level in Group-L after ANH is that exogenous overload of lactate as well as tissue hypoxia might have elevated blood lactate levels after ANH in this study. These results suggest the efficacy of acetated-Ringer containing 10% dextran. PMID- 20169952 TI - [Preoperative lung function tests using impulse oscillometry]. AB - BACKGROUND: Preoperative lung function tests are useful to evaluate the preoperative pulmonary condition and to detect a high risk of postoperative pulmonary complications. However, maximum expiratory effort by patients is necessary to determine lung function using spirometry and flow-volume curve measurements. When patients are not able to expire completely during the measurement, incorrect data regarding their respiratory system is obtained. On the other hand, respiratory system impedance using an impulse oscillatory system (IOS) can evaluate total airway resistance (R5), large airway resistance (R20), small airway resistance (R5-20) and reactance (X5) under breathing at rest within a few minutes. There are few reports that indicate the standard values for IOS. In addition, the effects of age on IOS value are not clear. In this study preoperative lung functions using IOS were studied to examine the standard value and effect of aging. METHODS: Subjects were 420 patients aged from 20 to 89 years with normal pulmonary function (%VC > or = 80%, %FEV(1.0) > or = 70%), and scheduled for an elective surgery. Lung function measurements such as IOS, spirometry, maximum expiratory flow-volume curve and single N2 washout were done preoperatively. Subjects were divided into seven groups in decades from 20 to 80. RESULTS: Although there was no statistical change in R5, R20, R5-R20, Z5 and X5 in the decades from 20 to 60, there were statistically significant changes during the 70s and 80s. There were significant differences in IOS parameters between the adult group and the aged group. Changes due to aging were stronger on V25/Ht than those of IOS. CONCLUSIONS: This study indicates that there are differences between V25/Ht and IOS values because of the difference in breathing conditions during measurements. PMID- 20169953 TI - [Comparison of urinary output during general anesthesia, between patients administered with remifentanil and those without remifentanil administration]. AB - BACKGROUND: Transient renal failure during surgery is caused by increasing secretion of stress hormone such as ADH and renin. We suspected that urinary output varies according to administration of remifentanil with potent analgesic effects. Consequently, we studied intraoperative urinary output of two groups, patients administered with remifentanil and those without remifentanil administration. METHODS: We compared urinary output during general anesthesia, of 327 patients administered with remifentanil (Group R) and 314 patients without remifentanil administration (Group NR) retrospectively. Patients were excluded if they were under the age of eighteen, receiving epidural anesthesia, or having medicine with diuretic effect. RESULTS: There were no significant difference in background of the patients in each group, in particular, age, sex, body weight, and ASA grade. We found no significant difference in intraoperative factors; operation time, total blood loss, volume of infusion, anesthesia time, and given dose of fentanyl. Urinary output of Group R was estimated as 512 +/- 435 ml, and that of Group NR was 409 +/- 405 ml (P value was 0.02). CONCLUSIONS: We found a significance difference in urinary output during anesthesia, between patients administered with remifentanil and those without remifentanil administration. We suspect that remifentanil decreases urinary output in the perioperative period. PMID- 20169954 TI - [Anesthetic management with remifentanil for tracheobronchial stent insertion]. AB - BACKGROUND: Although remifentanil produces respiratory depression, its very short duration of action provides a great advantage for the control of hemodynamics during anesthesia for tracheobronchial stent insertion. We compared remifentanil with fentanyl during propofol-based anesthesea for anesthetic management for tracheobronchial stent insertion. METHODS: Seventy-eight patients were analyzed retrospectively by anesthetic chart review. Thirty-nine patients were anesthetized with bolus infusion of fentanyl with propofol (group PF). The remaining 39 patients were anesthetized with continuous infusion of remifentanil with propofol (group PR). Demographic data, duration of anesthesia and operative procedure, airway management, duration of emergence, dose of propofol, fentanyl and remifentanil, and use of cardiovascular drug were analyzed for the 2 groups. Chi-square tests and Student-t test were used for statistical analysis. Differences were considered significant when P was below 0.05. RESULTS: The dose of propofol was less in the PR group than in the PF group (0.10 +/- 0.04 mg x kg( 1) x min(-1) vs. 0.14 +/- 0.04 mg x kg(-1) x min(-1), P = 0.025). The duration of emergence was shorter in the PR group than in the PF group (9.0 +/- 6.8 min vs. 12.5 +/- 6.2 min). CONCLUSIONS: We conclude that the continuous infusion of low dose remifentanil with propofol produce more efficient respiratory and hemodynamic stability than the bolus infusion of fentanyl with propofol during anesthesia for tracheobronchial stent insertion. PMID- 20169955 TI - [Effect of remifentanil on intraoperative ECoG--a comparison with sevoflurane]. AB - BACKGROUND: In surgeries for epilepsy, electrocorticography (ECoG) enables tailored resection of the epileptogenic brain and pharmacological stimulation should be employed in surgeries under general anesthesia. To identify the efficacy of continuous remifentanil in surgeries for epilepsy, ECoG findings with remifentanil and those with sevoflurane were compared. METHODS: Sixteen patients with intractable epilepsy were included with institutional ethics committee approval and informed consent. General anesthesia was induced and maintained with sevoflurane, remifentanil and rocuronium. After dural opening, ECoG recordings were obtained before stimulation, with sevoflurane-stimulation (ET-sevoflurane 2.5%) and with remifentanil-stimulation (0.7 microg x kg(-1) x min(-1) for 2 min followed by 0.35 microg x kg(-1) x min(-1)). RESULTS: In 11 of the 16 cases, activation was confirmed with remifentanil and numbers of spikes with remifentanil- and sevoflurane-stimulation were larger than those before stimulation. CONCLUSIONS: There have been some reports on bolus remifentanil on ECoG but not on its continuous infusion. This is the first report of the effect of remifentanil on ECoG as compared to sevoflurane. In this study, continuous infusion of remifentanil showed a stimulating effect on ECoG with the same potency as sevoflurane. Remifentanil may be used as an alternative to sevoflurane. PMID- 20169956 TI - [Anesthetic management for robot assisted off-pump construction of composite graft using the da Vinci surgical system]. AB - Robot-assisted minimally invasive surgery has become common in recent years. We used the da Vinci surgical system and managed anesthesia in 6 cases of bilateral internal mammary artery dissection and construction of a composite graft using the radial artery. To ensure vision inside the thoracic cavity, endoscopic robotic surgery employs the inflation of the thoracic cavity with carbon dioxide, producing a pneumothorax and turning the thoracic cavity into a positive pressure chamber. Thus, marked acidosis and circulatory changes manifest during anesthetic management. Although robotic surgery is considered "minimally invasive, such surgery involves a number of problems in terms of anesthetic management, and these problems must be examined. PMID- 20169957 TI - [Utility of SVV (stroke volume variation) during abdominal aortic surgery]. AB - BACKGROUND: Stroke volume variation (SVV) has been shown to be a reliable predictor of fluid responsiveness. It has been reported that SVV is useful for perioperative fluid management. We evaluated SVV and hemodynamics after aortic declamping during abdominal aortic surgery. METHODS: Patients scheduled to undergo abdominal aortic surgery were selected for this study. A FloTrac sensor was fitted to a 20 G cannula indwelled in the radial artery, and cardiac output (CO), central venous pressure (CVP) and SVV were continuously monitored. Patients were divided into two groups depending on pressure decrease after aortic declamping: above 50 mmHg (F group) and below 50 mmHg (N group). CO, CVP and SVV before and after the aortic declamping in the two groups were compared. RESULTS: Thirty patients were included in this study (15 in the F group and 15 in the N group). Measurement points were 26 points in the F group and 28 points in the N group. SVV before aortic declamping in the F group was significantly higher than that in the N group. Rate of decrease in CO after aortic declamping in the F group was significantly higher than that in the N group. There was no difference in CVP between the two groups. CONCLUSIONS: The results of this study suggest that monitoring SVV during abdominal aortic surgery is useful. PMID- 20169958 TI - [Anesthetic management of craniotomy for a young adult patient with congenital cyanotic heart disease]. AB - We present an emergency anesthetic management of craniotomy for a 22-year-old man with congenital cyanotic heart disease due to brain abscess. Pulmonary blood flow was completely supplied via major arteriopulmonay collatelal artery (MAPCA). This patient complicated with Eisenmenger syndrome, has no history of cardiac surgery but several times of craniotomy due to repeated brain abscess. Total intravenous anesthesia with propofol and remifentanil was induced and maintained. SpO2 and PaO2 were elevated after oxygen administration via mask. Although systemic blood pressure level was decreased by anesthesia and continuous infusion of vasopressors was required. Oxygenation parameters were unchanged. This indicates that blood flow through MAPCA did not respond to changes in of respiratory and circulatory circumstances during anesthesia. PMID- 20169959 TI - [Case of chronic trifascicular block resulting in cardiac arrest during operation]. AB - An 82-year-old man underwent thoracoscopic upper lobectomy of the left lung for the treatment of the lung cancer. The major complication was asymptomatic chronic trifascicular block. During the surgery, after the upper lobe had been resected, second degree atrioventricular block (Morbitz type II) occurred unexpectedly, soon evolving in complete AV block, with pulse wave disappearing, indicating pulseless electrical activity. Immediately, we used an epicardial pacing wire, and spontaneous circulation returned. Postoperatively, a permanent pacemaker was implanted. Asymptomatic chronic bifascicular block and trifascicular block rarely progress into complete AV block during operation, which we should be prepared in advance. Accordingly in some cases, preoperative insertion of a temporary pacemaker should be considered as a preventive measure. PMID- 20169960 TI - [Patient who developed acute myocardial infarction after total-gastrectomy]. AB - We report a case of a man who underwent coronary artery stent placement, and developed acute myocardial infarction immediately after total-gastrectomy. Thirty seven days before surgery, he developed an AMI due to 90% stenosis of #1 of the right coronary artery, for which a bare-metal stent was inserted. After the procedure, the patient took aspirin and ticlopidine, which were discontinued preoperatively. Even though the surgery progressed uneventfully, the patient developed ST-T segment elevation in II, III, aVF and complete A-V block soon after surgery. Emergency coronary angiography demonstrated 100% stenosis and clotting of the stent part, for which emergency thrombectomy was required. In conclusion, the risk is very high in the operation early after the insertion of BMS. Therefore, it is better to wait as long as possible and to avoid the easy stopping of the anticoagulant-drugs. It may be also better to give epidural anesthesia. PMID- 20169961 TI - [Intrathoracic blood volume during laparoscopic adrenectomy for primary aldosteronism under general anesthesia]. AB - We used PiCCO (Pulsion Ltd) device to measure the intrathoracic blood volume by transpulmonary thermodilution method in order to estimate infusion rate in patients undergoing laparoscopic adrenectomy for primary aldosteronism. A systemic blood volume in patients with primary aldosteronism might increase by an oversecreted aldosteron and the patients usually suffer from hypertension, because of increasing systemic blood volume. During anesthesia, we should carefully perform fluid therapy in order not to cause pulmonary edema. After anesthesia induction, the intrathoracic blood volume increased. And, during surgery, the blood epinephrine concentration increased due to direct tumor manupulation by surgeon, leading to induced hypertension. Because of induced hypertension, it was difficult to estimate the systemic blood volume. Under these conditions, PiCCO device was a useful monitor to estimate the systemic blood volume during surgery in patients with primary aldosteronism. PMID- 20169962 TI - [Respiratory management for a patient with a giant bulla and pulmonary dysfunction during off-pump coronary artery bypass grafting]. AB - This case report describes a successful anesthetic management of a 74-year-old patient with a giant bulla and pulmonary dysfunction during off-pump coronary artery bypass grafting (OPCAB). BiPAP Vision with a laryngeal mask airway (LMA) was used for intraoperative respiratory management. General anesthesia was induced with propofol. After insertion of a LMA anesthesia was maintained with propofol and dexmedetomidine under spontaneous breathing with bilevel positive airway pressure. Epidural analgesia was used in combination with general anesthesia. The LMA was removed without coughing and bucking soon after the end of the surgery. There was no complication during and after anesthesia. This respiratory management may be beneficial for patients with a giant bulla and pulmonary dysfunction during OPCAB. PMID- 20169963 TI - [Right heart failure during modified ultrafiltration in pediatric living donor lobar lung transplantation]. AB - A six-year-old girl with bronchiolitis obliterans was scheduled for living donor lobar lung transplantation from her mother. Under cardiopulmonary bypass (CPB), she underwent right pneumonectomy and her mother's right lower lobe was transplanted. Weaning from CPB was smooth, by the use of olprinone as an inotrope, nitric oxide (NO) and alprostadil as pulmonary vasodilators. Immediately after weaning from CPB, modified ultrafiltration (MUF) was started, in which blood was drained from the aorta, concentrated, filtered and returned to the right atrium. During MUF, systolic arterial blood pressure (sABP) declined and systolic pulmonary arterial pressure (sPAP) increased gradually. Although administration of dopamine and noradrenaline was started and the inhaled concentration of NO was increased, sPAP overwhelmed sABP after all. Transesophageal echocardiography showed that the left ventricular wall contracted well but its lumen was small, and that both right atrial and ventricular lumen enlarged. After starting administration of adrenaline, under the diagnosis of right heart failure, both sABP and sPAP were normalized and circulatory status got stable until the end of operation. We considered that pulmonary vasoconstriction due to ischemic reperfusion injury might cause right heart failure, which might be exacerbated by MUF, because MUF produces artificial left to-right shunt and can increase right heart volume load. PMID- 20169964 TI - [Perioperative management of a patient with deep vein thrombosis caused by estrogen producing granulosa cell tumor of the ovary]. AB - We experienced perioperative management of a woman with large thrombi in femoral veins caused by estrogen producing ovarian tumor. At presentation, serum estradiol level was extremely high. Time constraint due to rapid expansion of the tumor did not allow us a trial of preoperative anti-coagulation. We placed a temporary IVC filter and proceeded with operation. As catastrophic pulmonary embolism could occur even with the presence of a filter, we prepared for institution of cardiopulmonary bypsss and pulmonary embolectomy via full sternotomy. We monitored arterial pressure based-cardiac output for immediate detection of pulmonary embolism. Postoperatively, serum estradiol level declined to normal range by postoperative day 7, and thrombi dissolved with anticoagulation therapy with warfarin and heparin without recurrence. In this case, surgery without preoperative anticoagulation was considered to pose extreme risk of perioperative pulmonary embolism. However, we considered that the thrombi would disolve by the removal of the tumor because estradiol production was the primary cause of thrombi. With above mentioned perioperative approach, the patient was managed uneventfully. PMID- 20169965 TI - [Case of a schizophrenic patient refusing emergent operation for ovarian torsion]. AB - We report a case of a schizophrenic patient who rejected an emergent operation for ovarian torsion. A 48-year-old woman with ovarian torsion strictly turned down emergent surgery against the recommendation of her gynecologist, who could not communicate with her. In response to his request, a psychiatrist examined and diagnosed her as schizophrenia. Therefore, she was transferred to our hospital for management in closed wards. She was so paranoiac and self-defensive that we, the psychiatrist, the gynecologist, and the anesthesiologist, could not obtain informed consent for the operation from her. Because this was an emergent and life-threatening case, we attempted anesthesia and surgery with the consent of her mother and uncle. First, we took her not directly to the operating room but to ICU to relieve her anxiety and fear. Then, we intubated her under sedation and analgesia. Finally, we took her to the operating room and started the operation. Anesthesia was maintained with 1.5-2.0% sevoflurane and fentanyl (total 9 microg x kg(-1)). The operation was uneventful and she was retransferred to ICU with the tracheal tube in place. Next day she was extubated and left ICU. She was informed by her psychiatrist of the fact that the operation had been performed. Fortunately, her mental status and postoperative course was generally stable. PMID- 20169966 TI - [Case of ischemic heart disease resulting from persistent diuresis after giant ovarian tumor resection]. AB - A patient with a giant ovarian tumor weighing about 7 kg was successfully removed by operation. However, her ECG demonstrated ischemic changes after the operation. We report a case of ischemic heart disease due to persistent diuresis after giant ovarian tumor resection. A 75-year-old, 56.5 kg, 143.5 cm woman was admitted to our hospital for ovarian tumor resection. The preoperative ECG showed normal sinus rhythm and no ischemic changes. Both general anesthesia and epidural anesthesia were planed. An epidural catheter was inserted at T12-L1. Anesthesia was induced with propofol 100 mg, fentanyl 100 microg and vecuronium 8 mg under 100% oxygen inhalation. General anesthesia was maintained with sevoflurane while epidural anesthesia was achieved using 0.375% ropivacaine 6 ml. During the operation, blood pressure was 90-110/70-80 mmHg, with SaO2, 100% and heart rate, 70-80 beats x min(-1). The content of tumor was suctioned for 30 minutes. Surgery was successfully finished without any other incidence. After extubation, her ECG changed to atrial fibrillation from normal sinus rhythm and showed ST-T depression. And then her systolic blood pressure became 80 mmHg or below, but we found continued diuresis at about 10 ml x kg(-1) x hr(-1) for over 2 hr. The total of 7 unit vasopressin was intermittently given for vasoconstriction and antidiuresis. Her hemodynamic was immediately restored, and ECG turned to normal ST-T. The patient had uneventful postoperative recovery. PMID- 20169967 TI - [Case with difficulty in differentiating between transient neuroleptic malignant syndrome and catatonia after neuroleptic analgesia]. AB - An 18-year-old woman was treated with neuroleptic analgesia using fentanyl, morphine, droperidol and haloperidol for general anesthesia and pain control for her knee operation. Postoperatively, she showed emotional unstableness, following dyspnea, tachycardia, fever, hyperhydrosis, muscle rigidity and myoclonus like involuntary movement. She received infusion of 140 mg dantrolene in total under suspicion of having neuroleptic malignant syndrome, but her symptoms improved slightly. After being transferred to our hospital, she exhibited immobility, mutism, rigidity, and catalepsy, and she was suspected of having lethal catatonia. Infusion of diazepam 10 mg resulted in dramatical improvement of her symptoms. Differential diagnosis between neuroleptic malignant syndrome and catatonia is difficult; however, a first line therapy is differential diagnosis. Thus, physician should consider catatonia when treating neuroleptic malignant like syndrome. PMID- 20169968 TI - [Case of acute dystonia during epidural droperidol infusion to prevent postoperative nausea and vomiting]. AB - We report a case of bilateral ocular deviation due to droperidol-induced acute dystonia that was initially undiagnosed. A 22-year-old, 72 kg, parturient at 42 weeks' gestation underwent emergency cesarean section for pregnancy-induced hypertension under combined spinal-epidural analgesia. The epidural catheter was inserted through the T11-12 interspace, followed by intrathecal hyperbaric bupivacaine with adjunctive fentanyl. The patient complained of nausea shortly after delivery, which subsided with intravenous droperidol 1.25 mg and metoclopramide 10 mg. After surgery, epidural infusion with a mixture of ropivacaine, fentanyl, and droperidol was started. Around 25 hours postoperatively, both of the patient's eyes rotated upwards, although she was fully conscious. Brain CT/MRI did not show any abnormalities. An ophthalmologist and a neurosurgeon were consulted but there was no definitive diagnosis. On subsequent consultation with anesthesiologists, it was assumed that the symptom was related to external ophthalmoplegia secondary to spinal anesthesia. Thereafter, a "wait and see" approach was adopted. After 8 hours, she gradually developed torticollis and increased muscle tone of the lower extremities, which facilitated a diagnosis based on extrapyramidal signs. Epidural infusion was discontinued without further treatment. Her symptoms completely disappeared within 5 hours. The estimated cumulative dose of intravenous and epidural droperidol was 4.6 mg over 34 hours. PMID- 20169969 TI - [Effectiveness of continuous central venous oxymetry in living-donor liver transplantation with massive bleeding]. AB - In living relative liver transplantation, patients are exposed to enormous stress and multifaced monitors are required to evaluate physiologic status of the patient such as blood volume, electrolytes balance, clotting ability and metabolic status including oxygen consumption. To maintain transplanted liver graft function, an adequate oxygen supply to the graft is one of the most important factors. Central venous oxygen saturation is minimally invasive and one of the most useful monitor to evaluate the oxygen demand and supply balance in the graft. A continuous central venous oximetry (PreSep, Edwards Lifesciences, Tokyo, JAPAN) was used. The use of the oxymetry to evaluate oxygen demand and supply balance in a living relative liver transplantation especially in a case of massive bleeding was very effective. PMID- 20169970 TI - [Anesthetic management of a child with Lennox-Gastaut syndrome]. AB - General anesthesia was given twice to a 9-year-old girl with Lennox-Gastaut syndrome (LGS). LGS is one of the catastrophic forms of childhood epilepsy, and very few reports describe its anesthetic management. The anesthetic concern in LGS patients is a possibility of perioperative epilepsy due to proconvulsive effects of anesthesia-related drugs and due to the interaction between anesthetics and therapeutic drugs. Fortunately, her perioperative course was uneventful. The patients having LGS should be placed under careful observation postoperatively. PMID- 20169971 TI - [Case of hyperkalemia possibly caused by gabexate mesilate]. AB - We report a case of hyperkalemia in a recipient of living-related liver transplantation. The patient received a continuous infusion of gabexate mesilate at 60 mg x hr(-1) starting about 1 hr after the induction of anesthesia. The serum potassium concentration (K+) was increased from 4.53 mEq x l-(1) to 5.08 mEq x l(-1) within about 1 hr. Thereafter, a massive blood loss caused by an accidental damage of the portal vein necessitated rapid fluid therapy to maintain blood pressure. We observed an abnormal ECG recording including a wide QRS complex and a high T wave when about 30 units of leukocytes-reduced red cell concentrates had been transfused. Blood gas analysis showed high K+ (7.52 mEq x l(-1)) and metabolic acidosis (pH 7.167, base excess-12.5 mmol x l(-1)). We successfully controlled K+ with combination of therapies before causing any cardiac events to the patient. Gabexate mesilate is one possible cause of hyperkalemia in the present case because an increase in K+ was observed before transfusion, and transfusion might have augmented the effect. Gabexate mesilate is one of the protease inhibitors. Naphamostat mesilate, another protease inhibitor, is known to cause hyperkalemia by limiting potassium excretion from the kidney through an inhibition of Na/K-ATPase at the cortical collecting ducts. Although the mechanism by which gabexate mesilate causes hyperkalemia is unclear, it would be of benefit to use this drug cautiously, as it may cause hyperkalemia. PMID- 20169972 TI - [Incidence and clinical features of anaphylaxis during general anesthesia]. AB - BACKGROUND: Anaphylaxis is an acute life-threatening systematic reaction, and it requires early diagnosis and correct management to save the patients. The true incidence of anaphylaxis during general anesthesia is unknown. Although anaphylaxis is a rare intraoperative complication, most drugs used in the perioperative period can lead to anaphylaxis. METHODS: All patients who had received operations under general anesthesia in our hospital were covered in this study during the 5-year period. We searched for the incidence and clinical features of anaphylaxis retrospectively. RESULTS: Seven cases in 9,844 patients were recognized. Various drugs were suspected as causal agents, but they were all nonanesthesia related drugs. The diagnosis of anaphylaxis relied on the history and clinical course of each patient. There was no reliable diagnostic testing such as serum tryptase and skin test. So we could not determine whether the reaction was IgE-mediated or not. CONCLUSIONS: Immediate discontinuation of causal drugs and early administration of epinephrine are cornerstones of treatment. More specific diagnostic tests are required for correct identification of causal drugs. To reduce the risk of anaphylaxis during anesthesia, we hope practical data bases and guidelines for anaphylaxis related to anesthesia will be published in the future. PMID- 20169973 TI - [Anesthetic management using esmolol for arthroscopic synovectomy in a patient with thyroid storm]. AB - We report a case of a 47-year-old woman with past medical history of Graves disease who presented with thyroid storm, a state of physiologic decompensation due to severe thyrotoxicosis, and arthritis purulenta. Antithyroid therapy ameliorated thyrotoxicosis in 4 days, and arthroscopic synovectomy of the right knee was performed. Anesthesia was induced with intravenous propofol. Esmolol, an ultra-short-acting beta blocker listed in national drug tariff of Japan for intraoperative continuous iv infusion in March 2008, was also administered to control heart rate. Then, laryngeal mask airway was inserted and echo-guided femoral nerve block was done with ropivacaine. Anesthesia was maintained with i.v. infusion of propofol and fentanyl. Short episode of supraventricular tachycardia occurred twice, but each tachycardia disappered in about a half minute. The postoperative course was uneventful. Esmolol probably acted to prevent intraoperative tachycardia due to increased beta-adrenergic tone. PMID- 20169974 TI - [Anesthetic management of a child with moyamoya disease combined with von Gierke's disease]. AB - We report on a child with moyamoya disease combined with von Gierke's disease. A 7-year-old girl with von Gierke's disease had a stroke associated with moyamoya disease. She had had many episodes of hypoglycemia and severe metabolic acidosis before surgery. General anesthesia was induced with midazolam 3 mg and fentanyl 100 microg followed by rocuronium 12 mg. After tracheal intubation, anesthesia was maintained with sevoflurane 2.5% in 33% oxygen and 66% nitrous oxide. We used mainly mixture of saline and glucose as intraoperative fluid instead of acetated Ringer solution, and controlled administration of glucose according to blood glucose levels. The patient's plasma lactate levels and base excess during operation showed changes compared with those before operation, because sodium bicarbonate was used during the surgery. The duration of anesthesia was 374 minutes. The patient woke up and spontaneous respiration returned, and the trachea was extubated in the operating room. We were able to manage this case safely without any complications. PMID- 20169975 TI - [Application of continuous controlled administration of three agents for total intravenous anesthesia]. AB - General anesthesia was maintained by continuous administration of propofol, rocuronium and remifentanil. The dose of the medicine was determined by the effect site concentration calculated on a pharmacokinetics simulator respectively. Furthermore, a pharmacokinetics simulator enabled us to predict duration before the appearance of awareness. PMID- 20169976 TI - [Use of the Airway Scope for awake intubation in five cases]. AB - Several case reports have shown that the Airway Scope is useful in patients with difficult airways. We experienced five patients with known or predicted difficult airways who underwent awake intubation using the Airway Scope. The patients were known or predicted as having a difficult airway due to the following factors: limited head and neck movement (2 cases), risk for aspiration of gastric contents (1 case), and the thyroid tumor causing displacement of the trachea (2 cases). After the desired sedation with fentanyl and topical anesthesia of the airway, awake intubation was performed using the Airway Scope. All patients were successfully intubated without any complications. This experience suggests that the technique has the following advantages. First, the Airway Scope allows detection of regurgitation and vomiting during intubation and avoids accidental esophageal intubation. Second, the Airway Scope provides a useful means of teaching and supervising tracheal intubation compared with the conventional Macintosh laryngoscope. We believe that this method can achieve effective, safe and successful awake intubation in patients with known or predicted difficult airways. PMID- 20169977 TI - [Work load of anesthesiologists at the Central Surgical Unit of the Jichi Medical University Hospital]. AB - BACKGROUND: Since the diagnosis procedure combination (DPC) for health insurance plans in Japan was started in medical practice, the number of surgical procedures is increasing at teaching hospitals. METHODS: We retrospectively surveyed 8,672 surgical procedures performed at the central surgical unit of the Jichi Medical University Hospital from April 1, 2007 to March 31, 2008. RESULTS: Of the 8,672 surgical procedures, 6,922 operations were performed under the management of anesthesia staffs, and 1,904 procedures (27.5%) were done in emergency situation. Central surgical unit has 14 operating rooms and an estimated maximum number of surgical procedures is 7,700. CONCLUSIONS: This survey revealed that the present status of manpower of anesthesiologists at our hospital was insufficient for the work. In particular, the demands for anesthesiologists have increased in emergency operations including major cardiovascular surgery, neurosurgery and liver transplantations. PMID- 20169978 TI - [Two cases of leprosy related conditions and relevant issues on medical services for ex-leprosy patients who live in communities in Japan]. AB - In Japan people affected by leprosy who were forced to admit to national leprosy sanatoria under leprosy prevention/segregation law (1953) have ever been promoted to return to live in community, after destruction of the law in 1996. In this paper two cases are shown with some comments who had already been discharged from leprosy sanatoria and came late to OPD of National Suruga Sanatorium for consultations of their leprosy related conditions. One case is a 60 year-old male who developed squamous cell carcinoma (SCC) from chronic planter ulcer. The other is a 69 year-old female who developed relapse after more than 20 years BI negativity. In these cases, periods until consultation to our clinic were one year and five months, and five years and five months respectively. One reason is that there is no follow-up system of leprosy related conditions for ex-patients in current medical service of Japan. Another reason may be that patients hesitated to consult local doctors for their leprosy related conditions. Since national leprosy sanatoria will come to be closed in near future, services should be available for leprosy related conditions, such as prevention of disability (POD), prevention of worsening disability (POWD), early detection of relapse and leprosy reaction, in general medical service of Japan. PMID- 20169979 TI - [100 years of the National Sanatoriums in Japan]. PMID- 20169980 TI - [On the occasion of the centenary of the National Sanatorium Tamazenshoen]. PMID- 20169981 TI - [Reflections at the centennial of a leprosy sanatorium]. PMID- 20169982 TI - [Learning from the history of leprosy--looking back at one hundred years of medicine at the leprosaria]. AB - This year is the centennial anniversary of the five national leprosaria in Japan. It means that the official accommodation of leprosy patients who were wandering on the streets started in 1909. At that time, the existence of these leprosy patients on the streets was considered as a national shame and also an evidence of falling behind the Western cultured countries. Japanese people and the government were hypersensitive of such notoriety, especially from the Western countries. Some doctors, politicians and bureaucrats were really concerned about the situation and made great efforts to establish the leprosy separation law. It was implemented in 1907, but it took two more years for the preparation of the sanatoria for accommodation. The leprosy separation law has persisted until 1996. It has been revised to the leprosy segregation law in 1931, and to the leprosy isolation law in 1953. Although the law underwent two revisions, the main ideology of isolation has been abundant for almost ninety years. This law has been infamous for its misery and pointed out to be abolished by the WHO. This paper will focus attention on the doctors, politicians and bureaucrats who have worked for the institution of this cruel law, and also discuss the reason why this law had prevailed. PMID- 20169983 TI - [Report of the tenth meeting of the WHO Technical Advisory Group on Leprosy Control]. AB - The tenth meeting of the WHO Technical Advisory Group (TAG) on Leprosy Control was held in New Delhi, India on 23rd April 2009. The meeting was chaired by Professor WCS Smith and attended by TAG members, several experts, WHO secretariat, and members of the technical bodies of International Leprosy Association (ILA) and the International Federation of Anti-Leprosy Associations (ILEP) also attended the meeting. PMID- 20169984 TI - [Leprosy situation in the world in 2009]. AB - The epidemiological situation of leprosy is reported by the health division of each country to WHO. The reported data is collected by WHO and is immediately run on the Weekly Epidemiological Record. On this latest edition, data from the beginning of 2009 was reported. In almost all of the highly endemic countries, control activities have been integrated within the general healthcare system. However, early case detection and prompt treatment with MDT remain the cornerstone of leprosy. In order to reduce the physical, mental and socioeconomic burded of leprosy, much remains to be done. PMID- 20169985 TI - [Future strategies for global leprosy control, 2011-2015]. AB - The main principles of leprosy control, based on timely detection of new cases and their treatment with effective chemotherapy in the form of multidrug therapy, will not change over the coming years. The emphasis will remain on sustaining the provisions for quality patient care that are equitably distributed, affordable and easily accessible. The Enhanced Global Strategy for Further Reducing the Disease Burden due to Leprosy: 2011-2015 together with the updated Operational Guidelines of the Enhanced Global Strategy. The Strategy will require endorsement and commitment from everyone working towards the common goal of reducing the disease burden due to leprosy and its detrimental physical, social and economic consequences in order to move closer to achieving the common dream of "world without leprosy". PMID- 20169986 TI - [The impact of sedentary lifestyle on risk factors for cardiovascular disease among Japanese young women]. AB - OBJECTIVE: The purpose of this study was to examine body composition, blood biochemical markers, and dietary intake in 2 groups of young women engaged in different physical activities and to assess the impact of sedentary lifestyle on risk factors for diabetes and cardiovascular disease. METHODS: The subjects were 208 students of a women's university. Of these, 108 majored in nutrition (physically sedentary group, SG) and 100 majored in sports (physically active group, AG). We conducted a survey from mid-June to mid-July in 2004, during which physical examinations, including measurements of body weight and height, evaluation of body composition using dual energy X-ray absorptiometry (DXA), determination of the ankle brachial index (ABI) by measuring the brachial and ankle systolic and assessment of diastolic blood pressure, blood biochemical tests, and examination of 7-day weighted diet records (DRs) were all conducted. The physical and blood biochemical values and the food and nutrient intakes calculated from the DRs were then compared between the groups. RESULTS: We analyzed a total 133 subjects who had completed all the DRs (78 SG subjects and 55 AG subjects). A comparison between the 2 groups revealed mean body mass indices (BMIs) of 20.5 and 21.4 kg/m2 and mean body fat percentages of 29.4% and 22.6% in the SG and AG subjects, respectively. Even though the SG subjects had lower BMIs, they had significantly higher body fat percentages. The ankle systolic blood pressure and ABI were significantly higher in the AG subjects. With regard to blood biochemistry, the HOMA-beta, leptin, and apoprotein-B levels were significantly higher in the SG subjects. The mean energy intakes (kcal/day) of the SG and AG subjects was 1550 and 1853, respectively. The intakes of most nutrients were significantly higher in the AG subjects, and the amount of food consumed by the SG subjects was low. CONCLUSION: The levels of blood biochemical markers such as leptin and apoprotein-B were higher and the ABI was lower in the SG subjects than in the AG subjects. We think that these results are attributable to the accumulation of body fat, including visceral fat. Therefore, it is important for SG subjects to increase their energy expenditure by regular exercise and consume a diet that corresponds to their dietary requirements. PMID- 20169987 TI - [Family support and quality of life of pregnant women during pregnancy and after birth]. AB - PURPOSE: The primary purpose of this study was to measure family support for pregnant women after birth (PWAB) and to examine its relationships with quality of life (QOL), child care, and health conditions. METHOD: A self-administered questionnaire was distributed three times by mail to the women attending a maternity class in an urban hospital, during late pregnancy and one month and six months after birth (n=151). The objective was to assess family support (from husbands and parents), child care, health conditions, and QOL. An original QOL scale was developed using twelve items, revealing three factors: "Positive feeling", "contentment with the physical environment and financial situation (Surrounding factors)", and "satisfaction with lifestyle and relationships (Daily life)". We conducted path analysis to examine the correlates of the QOL scale. RESULTS: (1) The support score of husbands increased gradually over the period of the study, while parents were found to be most supportive one month after birth. Additionally, husbands and parents were found to compensate for each other in their support. (2) The more support the PWAB received in a given period, the higher the mean scores for child care, health conditions, and QOL. (3) "Positive feeling" was influenced by the husband's support during the whole study period (i.e., during pregnancy and one month and six months after birth). "Surrounding factors" correlated with the husband's support during pregnancy and at one month after birth. "Daily life" correlated with the support most strongly at six months after birth. CONCLUSION: Family support was shown to be a strong correlate for the QOL of PWAB. Providing family support could improve mothers' child care, health conditions, and QOL. PMID- 20169988 TI - [Determinant factors encouraging work motivation: a study of care staff working in health services facilities for elderly people]. AB - PURPOSE: Work motivation among care workers influences the quality of care for facility residents. The purpose of this study was to identify related factors in care staff. METHOD: Sixty hundred and seven care staff working at 25 health services facilities for elderly people participated in this study. We applied a theoretically derived model of specific relationships among work motivation, jobsatisfaction, profession identity, job competence, interprofessional working and profession image. These factor relationships were then tested using a structural equation modeling technique. RESULTS: Profession identity, job competence and the profession image of caring were shown to have direct influences on work motivation. In addition, job satisfaction, inter professional working, profession images of nursing and rehabilitation responsibilities were shown to have indirect influences. CONCLUSION: These data suggest that improving profession identity, job competence and the profession image of caring are important to enhance work motivation of care staff. PMID- 20169989 TI - [Factors impacting on daily self-monitoring of blood glucose (SMBG) by patients with impaired glucose tolerance results of a qualitative analysis using focus group interviews]. PMID- 20169990 TI - [Development and evaluation of an educational program for promotion of healthy nutrition and physical activity by health volunteers]. AB - OBJECTIVES: The purpose of the present trial was to develop and evaluate an educational program for promotion of healthy nutrition and physical activity by health volunteers. The educational program consisted of the following four phases: preliminary self-learning by mail (3 weeks), basic learning (3 sessions of 3 hours), practice of planned activities (2 months), and a report session (1 session of 3 hours). METHODS: Beginner volunteers (n=18, mean age 63.3 +/- 6.4) were recruited from two volunteer health organizations in Kurume city. They then participated in a program that taught basic health knowledge regarding nutrition and physical activity, how to plan effective support activities, and methods for self-evaluation. In the preliminary self-learning phase, an assessment sheet, health information, and homework (goal setting, etc.) were delivered to the volunteers by mail. In the basic learning phase, volunteers attended a 3 day seminar on essential principles for behavioral change and assessment methods for volunteer activity. In addition, effective support activities were planned through group discussion. After a 2-month practice of support activities, each group reported and discussed the results of their activity in a 3-hour report session. Main outcome measures were health knowledge (15 items, 0-1 points), self efficacy for life style support (5 items, 0-100%), and evaluation of the educational program (9 items, 1-5 points). All measures were self-administered. RESULTS: Significant increases in rate of true answers for health knowledge were observed during the preliminary self-learning and before basic learning phases (54.8% --> 67.1%, P < 0.05), and before and after basic learning phases (67.1% - > 87.6%, P < 0.05). Self-efficacy for life style support were significantly higher after the report session than before the preliminary self-learning phase (35.1% --> 53.1%, P < 0.05). In the two-month practice, all groups received feedback through questionnaires completed by participants who took part in their planned activity. The mean scores for the overall evaluation of the program, the effectiveness of the course materials and group-work, the staff, and the course contents were all higher than 4.0 points. CONCLUSION: These findings indicate that this program is structured effectively and is appropriate for educating beginner health volunteers regarding promotion of healthy nutrition and physical activity. PMID- 20169991 TI - [Bioenergetics of obligate alkaliphic Bacillus]. PMID- 20169992 TI - [Structures and functions of NLRs, intracellular pattern recognition receptors]. PMID- 20169993 TI - [Design, synthesis and biological application of chemical probes for imaging protein functions]. PMID- 20169994 TI - [Mechanism of zinc transport by zinc transporters, ZnT and ZIP]. PMID- 20169995 TI - [Novel mechanisms of drug resistance in cancer]. PMID- 20169997 TI - [Emerging world of nuclear long noncoding RNAs]. PMID- 20169996 TI - [Regulation and physiological roles of mitochondrial dynamics]. PMID- 20169998 TI - [Novel metabolic pathway of glucosylceramide that involves Klotho-related protein KLrP]. PMID- 20169999 TI - [New physiological function of neutral cysteine protease bleomycin hydrolase]. PMID- 20170001 TI - [Current issues of medical care in Japan--shortage and unbalanced distribution of medical doctors]. PMID- 20170000 TI - [Tel2, a common partner of PIKK family proteins]. PMID- 20170002 TI - [Dispatch and the prospects of the disaster medical care from Hokkaido]. PMID- 20170003 TI - [Molecular mechanisms underlying synaptic circuit development]. PMID- 20170004 TI - [Update on congenital adrenal disorders--heterogeneity of pathogenesis and pathophysiology]. PMID- 20170005 TI - [Today's occupational respiratory disease--from our recent investigations]. PMID- 20170007 TI - [Efficacy of intradermal regimen using Japanese rabies vaccine for pre-exposure prophylaxis]. AB - In Japan, only one vaccine is commercially available for rabies (Chemo-Sero Therapeutic Institute (Kaketsuken), Kumamoto, Japan). It is a tissue-cultured inactivated vaccine made using purified chick embryo cells (PCEC-K) and administered subcutaneously using a schedule differing from that recommended by the World Health Organization (WHO). The current regimen of pre-exposure prophylaxis for rabies in Japan consists of three subcutaneous administrations of PCEC-K vaccine at 0, 28, and 180 days, requiring 6 months to complete. With the exception of a few imported cases, Japan is rabies-free and rabies vaccine production is small. Globalization should trigger rabies re-emergence in Japan, however, we would have to determine whether PCEC-K vaccine is effective through intradermal administration following the WHO-recommended regimen. In a study of 50 healthy volunteers without a history of rabies vaccination and all of whom provided, PCEC-K vaccine (0.1 mL, 2 sites) was administered intradermal by on days 0, 7, and 28, and the viral neutralizing antibody level (VNA) against rabies virus was tested using the rapid fluorescent focus-inhibiting test (RFFIT) on days 0, 14, 28, 42, 56, 84, and 208. On day 42, all individuals showed adequate VNA (GMT: 3.21 IU /mL), maintained for 84 days. VNA acquisition differed slightly with the PCEC-K vaccine lot and local adverse effects were minor. The intradermal PCEC-K regimen was found to be safe and effective in inducing adequate VNA using a smaller amount of vaccine within a shorter period. PMID- 20170006 TI - [Helicobacter pylori infection and autoimmune disease such as immune thrombocytopenic purpura]. AB - Helicobacter pylori infection is implicated in the pathogenesis of extradigestive diseases such as acne rosacea and idiopathic chronic urticaria and autoimmune diseases such as autoimmune gastric atrophy, rheumatoid arthritis, anti phospholipid antibody syndrome, autoimmune thyroiditis, Sjoegren syndrome, Henoch Schoenlein purpura, and Type B insulin resistance syndrome. H. pylori eradication ameliorated the condition in some, but not all, of those with these autoimmune diseases. Recent studies primarily in Italy and Japan found that H. pylori eradication in those infected with chronic immune thrombocytopenic purpura (ITP) results in a persistent platelet count increase in over half of those treated, suggesting that although pathogenetic mechanisms underlying the relationship between H. pylori infection and autoimmune disease remain unclear, yet-unknown immunological events induced by H. pylori infection almost certainly occur in the development of autoimmune response. A majority of isolated H. pylori strains express human Lewis (Le(x) and/or Le(y) determinants and in some strains, Le(a), Le(b), sialyl-Le(x)), and H determinants in the O-chain of the surface lipopolysaccharide. Previous studies showed that this molecular mimicry helps the bacterium evade host responses while evoking autoantibody responses to Le antigens. The anti-Le(y) autoantibody is also reported to promote H. pylori adhesion to gastric epithelial cells, leading to development of gastric atrophy. Moreover, one can hypothesize that anti-Le autoreactive antibodies induced by H. pylori infection are involved in the development of autoimmune diseases, although no clinical studies showing that anti-Le immune responses are involved in the etiology of these autoimmune diseases have been conducted. Proving this hypothesis would require quantitative and qualitative analysis of autoantibodies and T cell functions to Le antigens. High frequent phase variation of Le structures in the O-polysaccharide of H. pylori may influence the immune response of patients to Le antigens. PMID- 20170008 TI - [Inpatient and personnel vaccination influence on influenza outbreaks in long term medical and care hospital]. AB - The influence of the vaccination rate among inpatients and hospital personnel on the risk of influenza outbreaks in long-term medical and care hospital was investigated. Vaccination rates and the annual number of influenza cases were analyzed from 2003/2004 to 2008/ 2009. During the first three influenza seasons, vaccination among inpatients was low-45.4% in 2003/4, 49.7% in 2004/5, and 57.5% in 2005/6. Minor influenza outbreaks accounted for 22 patients in 2003/4, 10 in 2004/5, and 10 in 2005/6. During the next three seasons, vaccination was higher than in the previous years, at follows: 65.8% in 2006/7, 65.6% in 2007/8, and 72.0% in 2008/9. This improvement apparently accounted for the absence of outbreaks during these seasons, with patients numbering 0 in 2006/7 and 2 each in 2007/8 and 2008/9. A strong negative correlation thus exist between inpatient vaccination rates and the number of influenza patients (r = -0.903, p = 0.014). The vaccination rate among hospital personnel was high at 79.3%-91.2% throughout the study, and no correlation was seen between hospital personnel vaccination and the number of influenza patients (r = 0.379, p = 0.459). No correlation was seen, either, between the number of influenza patients and national influenza occurrence (r = - 0.146, p = 0.783). This results thus indicate that a high vaccination rate among hospital personnel is not enough to prevent influenza outbreaks, making it important to raise vaccination rates among both inpatients and hospital personnel if influenza outbreaks are to be controlled and prevented. PMID- 20170009 TI - [The prevalence of Enterobius vermicularis among Japanese expatriates living in developing countries]. AB - Parasitic infections are widespread in developing countries. Enterobiasis, caused by the Enterobius vermicularis nematode, is probably the most common helminth infecting the humanrace. We studied fecal specimens from Japanese residents in developing countries to determine the prevalence of E. vermicularis infection in this population. Individual specimens were collected using the cellophane tape method from Japanese residents in Asia, the Middle East, East Europe, Africa, and Central and South America in 2004. The specimens were examined in Japan. Subjects surveyed numbered 2247. The E. vermicularis infection rate was 0.62%. The most children infected with E. vermicularis ranged between 5 and 8 years of age. The prevalence of infection among Japanese children living in developing countries was 1.82%, higher than that in those living in Japan. Our results underscore the need to continue preventive measures such as health education to eradicate E. vermicularis infection in this group. PMID- 20170010 TI - [Antimicrobial susceptibility and resistance genes among Salmonella enterica Serovar Weltevreden isolates from humans, farm animals, and the environment in Okinawa Prefecture between 1992 and 2007]. AB - Between 1992 and 2007, a total of 86 isolates of Salmonella enterica Weltevreden were obtained from clinical human samples (n = 41), 45 farm animals and their environment on 20 farms, including poultry (n = 25), beef cattle (n = 5), swine (n = 5), dairy cattle (n = 3), mice (n = 2), pony (n = 1), fly (n = 1) and feed samples (n = 3), in Okinawa Prefecture, Japan. Only seven isolates (8.1%) of the isolates were resistance to one or more antimicrobial agents tested; six streptomycin (7.0%), six oxytetracycline (7.0%), two ampicillin (2.3%), two kanamycin, (2.3%), two chloramphenicol (2.3%), two suffamethoxazole/trimethoprim (2.3%), whereas all isolates were susceptible to gentamicin, sefuroxime, colistin, nalidixic acid, fosfomycin and ofloxacin. Drug resistance patterns showed six patterns; ABPC-SM-KM-OTC-CP-ST, ABPC-SM-ST, SM-KM-OTC, SM-OTC-CP, SM OTC, OTC. Two ampicillin-resistant isolates harbored the blaTEM genes, streptomycin-resistant isolates (four aadA, two strA), tetracycline-resistant isolates (two tetA, three tetB), chloramphenicol-resistant isolates (two catA1), respectively. PMID- 20170011 TI - [Prevalence of kidney disease in HIV-infected patients in Japan--A single center study]. AB - BACKGROUND: Kidney disease is a significant cause of morbidity and mortality among persons infected with the human immunodeficiency virus (HIV). However, epidemiologic and clinical variables regarding kidney disease have not been determined among HIV-infected patients in Japan. PATIENTS AND METHODS: A cross sectional study of 788 HIV-infected outpatients including 706 men was conducted in 2009. The patient's mean age and CD4+ T cell count were 46.2 +/-11.8 years and 418 +/- 202/microL, respectively. Of them, 677 patients (86%) had an undetectable HIV-RNA level (<50 copies/mL). Random urine and blood samples were collected to study the coexistence of chronic kidney disease (CKD). In addition, serum cystatin C was measured since it is considered to be an alternative marker of early kidney dysfunction in the HIV population. The estimated glomerular filtration rate (eGFR) based on serum creatinine was calculated using the 3 variable equation, proposed by the Japanese Society of Nephrology [eGFR (mL/ min/1.73m2) = 194 x Serum creatinine (-1.094) x Age (-0.287 x 0.739 (if female)]. CKD stages were classified based on the National Kidney Foundation guidelines. RESULTS: The prevalence of CKD and that of CKD > or = stage 3 was 14.9% and 9.4%, respectively. The pro-portion of each stage was as follows: stage 1, 15 patients (1.9%); stage 2, 28 patients (3.6%); stage 3, 66 patients (8.4%); stage 4, 1 patient (0.1%); stage 5, 1 patient (0.1%); and stage 5D, 6 patients (0.8%). Elevation of serum cystatin C (> or = 0.9 mg/L) was found in 23.3%. Comorbidities such as hypertension and diabetes were found in 55.4% and 27.0% in patients with CKD > or = stage 3, respectively. Urinalysis showed 71 patients (9.1%) with proteinuria and 44 patients (5.6%) with hematuria. CONCLUSION: CKD has become an important comorbidity for HIV-infected patients in Japan, a point that should be given more emphasis from public health perspective. PMID- 20170012 TI - [Childhood bacterial meningitis trends in Japan from 2007 to 2008]. AB - We surveyed pediatrics bacterial meningitis epidemiology from January 2007 to December 2008 in Japan, with the following results: Cases numbered 287-160 male and 127 female-equivalent to 1.54-1.62 of 1,000 pediatric hospitalization per year. Children under 1-year-old accounted for the highest number of cases, which decreased with increasing age. Haemophilus influenzae was the most common cause of infection, followed by Streptococcus pneumoniae, group B streptococcus (GBS), and Escherichia coli. GBS and E. coli were major pathogens in children under 4 months of age, while H. influenzae and S. pneumoniae mainly accounted for those over 4 months of age. Susceptibility tests showed that 51% of H. influenzae isolates and 56.5% of S. pneumoniae isolates in 2008 were drug-resistant. Ampicillin combined with cephem antibiotics effective against GBS, E. coli, and Listeria, were mainly used to initially treat those under 4 months of age. In those over 4 months of age, carbapenem antibiotics are effective against PRSP and cephem antibiotics against H. influenza. PMID- 20170013 TI - [Analysis of clinical features of community-acquired pneumonia caused by pediatric respiratory syncytial virus and human metapneumovirus]. AB - We retrospectively reviewed the background, clinical features, blood tests, and complications in the 720 children seen for acute respiratory tract infection from July 2004 to December 2005. Of these, 75 (10.5%) were diagnosed with pneumonia due to respiratory syncytial virus (RSV) and 19 (2.6%) with pneumonia due to human metapneumovirus (hMPV) based on multiplex PCR analysis of nasopharyngeal samples. RSV was PCR-positive mostly in winter, -from November to January-, and hMPV mostly in spring, -from March to June. The mean RSV pneumonia group age was 1.3 +/- 1.4 years and in the hMPV pneumonia group 3.0 +/- 3.1 years, showing a statistically significant differences in the age of virus onset. Clinically the RSV group showed more rhinorrhea and wheezing (p < 0.05) and the hMPV group a higher maximum body temperature and a longer wheezing duration (p < 0.05). Fever, cough, vomiting, diarrhea, fever frequency, and C-reactive protein level were similar in both groups (p > 0.05). Complication prevalence was 49.3% in the RSV group and 42.1% in the hMPV group. Acute otitis media was seen more often in the RSV group (32.0%) and febrile convulsion more often in the hMPV group (15.8%) (p > 0.05). These findings may be helpful in clinically diagnosing community acquired pneumonia due to RSV or hMPV. PMID- 20170014 TI - [Tsutsugamushi disease and Japanese spotted fever recognition among medical seminar participants for the general public in epidemic and non-epidemic areas]. AB - Questionnaires on Tsutsugamushi disease (TD) and Japanese spotted fever (JSF) recognition, were distributed at lectures to the general public held in Sakai, Osaka (Lecture A), and Sumoto, Hyogo (Lecture B). Questions included knowledge of transmission routes, symptoms, and seeing physicians after having suspected symptoms. Hyogo had more reported cases of both diseases than Osaka. The response was 57.9% (113/195) to Lecture A, and 87.2% (61/70) to Lecture B. Analysis covered 89 Lecture A and 53 Lecture B respondents after excluding medical and public health specialists and those with unknown occupations. Disease recognition for JSF, knowledge of TD transmission routes, and symptoms of both diseases were better among Lecture B respondents -a statistically significant finding. The two groups saw physicians after having suspected symptoms at roughly the same rate. When these two groups were combined, those with knowledge of transmission routes or symptoms were significantly more likely to see physicians (p<0.05). PMID- 20170015 TI - [Epidemiological study of health impact on influenza outpatients during 2008-2009 influenza season, Shonai, Yamagata]. AB - To make up for the lack of data on influenza-like illness (ILI), we studied patterns among 6,828 ILI patients seen at 34 healthcare facilities during the 2008-2009 influenza season in Shonai, Yamagata, Japan. Healthcare facilities were classified into 1) hospitals, 2) pediatric clinics, 3) internal medicine and pediatric clinics, 4) internal medicine clinics, and 5) others. The majority went to hospitals, but the highest percentage in all outpatient visits was 13.7% seen at pediatric clinics during the peak epidemiological week. Based on estimated incidence and hospitalization data for pandemic (H1N1) 2009 from Ministry of Health, Labour and Welfare, Japan, we estimated the number of ILI patients at 59,600-89,400 and the number hospitalized for pandemic (H1N1) 2009 at 895-2,240 in Shonai. If those with ILI follow the same consultation patterns as outpatients in the 2008/09 influenza season, this indicates an estimated 23,800-35,700 with ILI will go to hospitals and 20,040-30,060 to pediatric clinics during the H1N1 pandemic. This in turns means that an urgent need will arise for appropriate measures reducing this potentially huge burden during pandemic (H1N1) 2009 outbreak in Japan. PMID- 20170016 TI - [A case of severe leptospirosis infection (Weil's disease) in Tokyo]. AB - We report a case of severe leptospirosis infection (Weil's disease) in Tokyo. A 54-year-old man admitted on September 14, 2006, for a 5-day inability to walk due to severe progressive bilateral leg pain, shoulder pain, and fever exhibited jaundice, conjunctival suffusion, hypoxia, and grasping pain in the bilateral leg muscles. Laboratory findings showed severe liver damage, renal failure, leukocytosis, anemia, thrombocytopenia, elevated CRP, hyponatremia, and hypokalemia. Chest X-ray imaging showed interstitial infiltrates in the bilateral lung fields. After cefepime was initiated, he developed chills, fever, and hypotension due to Jarisch-Herxheimer reaction, necessitating respiratory support. Pulmonary hemorrhaging was also found. On hospital day 2, a urine polymerase chain reaction test for leptospira proved positive for the same base sequence as part of the leptospira gene. A microscopic agglutination test showed elevated antibody titers against Leptospira interrogans. Based on a diagnosis of leptospirosis, the man was treated with 2g per day of ceftriaxione for 2 weeks and recovered fully. The leptospira strain was isolated from rodents captured at his home, and we identified the same base sequence as from his urine sample. Reports shows, leptospirosis in Japan have decreased recently, but, as this case can still be seen even in Tokyo, and diagnosticians should maintain an awareness of possible significance in patients with typical findings for this disease. PMID- 20170017 TI - [Two cases of Corynebacterium pseudodiphtheriticum respiratory tract infection]. AB - Corynebacterium pseudodiphtheriticum, one cause of respiratory tract infection, is rarely considered as a pathogen because it is among normal bacterial flora colonizing the oral cavity. We report two cases of C. pseudodiphtheriticum causing respiratory tract infection--an exacerbation of chronic obstructive pulmonary disease and pneumonia--, both in the presence of underlying respiratory disease. Both required antibiotics after first-line chemotherapy failed. Isolates were susceptible to beta-lactams. Gram-staining of respiratory tract specimens is important in diagnosing this infection and determining appropriate antimicrobial use. PMID- 20170018 TI - [A 14-year-old healthy boy with splenic abscess due to Salmonella enterica serovar Senftenberg]. AB - Salmonella enterica serovar Senftenberg may very rarely cause splenic abscess, which can be diagnosed using gallium scintigraphy and drained. A 14-year-old boy admitted for stomachache, diarrhea and fever and diagnosed from his symptoms as having enteritis did not respond when treated with fosfomycin, meropenem, and clindamycin. A low-density splenic area seen in abdominal computed tomography on admission did not show contrast medium enhancement. Gallium scintigraphy on hospital day 10, however, showed abnormal splenic accumulation confirming the splenic abscess diagnosis, after which we punctured and drained the abscessout. S. Senftenberg was isolated from pus aspirated pus from the abscess, after which responded well to ceftriaxone and levofloxacin. Follow-up gallium scintigraphy on hospital day 24 showed that the abnormal splenic accumulation had disappeared, after which he has been followed up with abdominal ultrasonography and blood tests as an outpatient. He has experienced no relapse of splenic abscess. PMID- 20170019 TI - Characterization of phosphobacteria isolated from eutrophic aquatic ecosystems. AB - Phosphobacteria are able to enhance phosphorus availability in soil and improve crop yields. To develop such biofertilizers, 14 predominant phosphobacteria were isolated from eutrophic aquatic ecosystems. Molecular identification and phylogenetic analysis revealed three groups among the nine isolates of inorganic phosphate-solubilizing bacteria (IPSB): IPSB1 and IPSB2 belonged to the actinobacteria and flavobacteria, respectively, and the other seven belonged to the gamma-proteobacteria. Among five isolates of organic phosphorus-mineralizing bacteria (OPMB), two groups were present: OPMB1 and OPMB3 belonged to the beta proteobacteria, while the other three belonged to the gamma-proteobacteria. The IPSB isolates released 62.8-66.7 mg P 1(-1) from tricalcium phosphate under shaking conditions, and 26.8 to 43.7 mg P 1(-1) under static conditions; the OPMB strains released 23.5-30.2 mg P 1(-1) from lecithin under shaking conditions, and 16.7-27.6 mg P 1(-1) under static conditions. To the best of our knowledge, this is the first report indicating that IPSBI (designated Aureobacterium resistents) as a tricalcium phosphate-solubilizing bacterium and OPMB1 and OPMB3 (designated Acidovorax temperans and Achromobacter xylosoxidans, respectively) are lecithin mineralizing bacteria. This investigation demonstrated that a eutrophic aquatic ecosystem is a selective source of phosphobacteria and the screened phosphobacteria are a potential alternative to the development of biofertilizers. PMID- 20170020 TI - Collaboration: why it matters. PMID- 20170021 TI - Preview: Nursing practice environment legislative package 2009. PMID- 20170022 TI - [Alain Pecoud: "the increase in costs threaten the solidarity"]. PMID- 20170023 TI - [Progress in allergy/immunology in 2009]. AB - Progresses in allergy in 2009 were particularly noticeable in the field of diagnosis with an increased use of recombinant food allergens; tolerance induction protocols, in particular for egg and milk allergy show promising results for the future; and interesting new possibilities for treatment of mastocytosis with anti-IgE antibodies are reported. Clinical immunology has witnessed advances along two main axes. The first aiming at defining new efficacious therapeutic strategies less toxic compared to those currently in use to control SLE and ANCA-related vasculitis. The second highlights a novel response index appears to be a major advancement toward our understanding of SLE. PMID- 20170024 TI - [Cardiology 2009: what is new?]. AB - The present review provides a selected choice of clinical research in the field of heart failure, electrophysiology, cardiac imaging and interventional cardiology. PMID- 20170025 TI - [Diabetes]. AB - In 2009 a novel screening strategy for diabetes based on the level of glycated hemoglobin has been proposed by the main international organizations, with a diagnostic threshold of 6.5%. The preventive efficacy of multiple risk factor control in type 2 diabetes reflected by the low rate of cardiac events in the DIAD 2 study calls for a revision of the current recommendations for coronary disease screening. In gestational diabetes, the linear correlation between degree of hyperglycemia and risk of associated complications in the HAPO study strenghtens the therapeutic targets for this frequent condition, which identifies women at high future risk of diabetes. No conclusive evidence for an increased risk of cancer associated with insulin glargin remains when taking into account all the data currently available on this topic. PMID- 20170026 TI - [Gynecology]. AB - Widespread use of the Pap test for cervical cancer screening has dramatically reduced cervical cancer incidence and mortality rates. The knowledge about optimal use of cervical cancer screening has evolved these last year and conducted to improve new cervical prevention. The American College of Obstetricians and Gynecologists (ACOG) recommend that cervical cancer screening should not begin before the age 21 years and that screening tests should be performed at less frequent intervals. CA 125 is considered to be the best test to detect relapse among women previously treated for ovarian cancer. However, a recent randomized trial has reported that there is no benefice to initiate the therapy before presence of symptoms. In 2009, the FIGO published a revised staging for cervical, endometrial and vulvar cancer to improve prognostic disease and therapy decision. PMID- 20170027 TI - [Update on new antithrombotic treatments]. AB - Update on new antithrombotic treatments Antithrombotic treatments are frequently prescribed in different clinical situations. Classical anticoagulants have some disadvantages. New anticoagulants have emerged recently. Fondaparinux is now prescribed for both prophylaxis and treatment of venous thromboembolism. Two drugs are particularly interesting: rivaroxaban and dabigatran. Concerning the new antiplatelet agents, many molecules such as prasugrel, ticagrelor, cangrelor, SCH530348 or terutroban have appeared recently. They are directed either to the P2Y12 receptor or to other original targets. Studies have shown an increased bleeding risk for some of them as well as unexpected side effects. In the next future, these new molecules could allow a more individualised prescription of antithrombotic agents. PMID- 20170028 TI - [Influenza A (H1N1) and antibiotic resistance in constant progress]. AB - The epidemics of Influenza A(H1N1) started at the end of march 2009. Since then there was an exponential growth of knowledge in this area. This review deals with information of this disease in November 2009 (epidemiology, prophylaxis, vaccination and therapy) in our region. Highlights of ICAAC 2009 dealing with antibiotic resistance are also reviewed. PMID- 20170029 TI - [Adolescent medicine in Guglera: a novel approach for unemployed, severely obese adolescents]. AB - The Center "la Guglera", located in the canton of Fribourg (Switzerland) provides a novel approach to the care of severely obese adolescents who are currently unemployed. These young people, whose BMI is usually higher than 35 to 40 kg/m2 spend a 6 to 12 months long stay in an in-patient institution which also takes care of other unemployed non obese adolescents on an outpatient basis. Besides a nutritional education which is part of the everyday life of the institution, the program includes a generous amount of hours of physical activities and sports. The adolescents also participate in a rehabilitation training program which fosters the future integration in a professional milieu, such as an apprenticeship. The short term results of la Guglera seem very promising. The program is financially co-supported by the Swiss and cantonal administrations, the insurance companies and the parents. PMID- 20170030 TI - [Emergency medicine: update 2009]. AB - Emergency medicine is a cross-discipline characterized by its ability to identify critical threats, as well as its ability to prioritize investigations and identify appropriate treatments. Recent publications have been published on upper gastrointestinal haemorrhage, elbow fracture or brain haemorrhage, to optimize and standardize the investigations. In parallel, conditions such as cardiopulmonary arrest, spontaneous pneumothorax or stroke, benefit from recent therapeutic advances. However, emergency physicians and primary care physicians must remain critical of the numerous medical publications, as evidenced by the contradictory results concerning the interaction between proton pump inhibitors and clopidogrel. PMID- 20170031 TI - [Pharmacovigilance update]. AB - Main pharmacovigilance signals and alerts issued in 2009 are reviewed. Efalizumab was withdrawn from the market due to increased risks, including progressive multifocal leukoencephalopathy (PML) and questionable efficacy. New cases of PML are still being reported with rituximab and natalizumab. Rare cases of pure red cell aplasia have been observed with mycophenate. Gastrointestinal perforation, severe skin rashes and various ocular disorders have been reported during erlotinib use. Severe skin rashes have been related to etravirine. Acute renal failure and pancreatitis can occur with exenatide. A link between sitagliptin and pancreatitis is suspected. Raised concerns of causality between insuline glargine and malignant tumors are not supported by strong evidence. Proton pump inhibitors seem to blunt clopidogrel benefit. Aliskiren can cause angioedema. PMID- 20170032 TI - [Pneumology. Treatment of obstructive sleep apnea by continuous positive airway pressure: new options]. AB - Continuous Positive Airway Pressure (CPAP) is accepted as first line therapy for Sleep Obstructive Apnea-Hypopnea Syndrome. Over the past few years, several new devices have been made available, aiming to improve patient comfort and compliance. In 25 years, major changes in technology have occurred, and CPAP has evolved from fixed pressure devices to auto-adjusting bi-level positive airway pressure. The algorithms and software of the newly commercialized devices are sometimes difficult to apprehend. In spite of impressive changes in technology, an obvious benefit in terms of compliance or comfort is yet to be demonstrated, and independent validations of these new devices are necessary. PMID- 20170033 TI - [Psychiatry]. AB - Methods of brain stimulation such as transcranial magnetic stimulation, deep brain stimulation and vagus nerve stimulation may have a place in the treatment of depression or severe anxiety disorders resistant to conventional treatments. Several advances in chronotherapy as well as developments in treatment protocols have helped to prolong the antidepressant effect of sleep deprivation. The clinical applications of these methods in depressive episodes and especially in bipolar depression are discussed. The complete remission of a depressive episode and the maintenance of therapeutic benefit beyond the mere reduction of symptoms, have become important issues. The persistence of residual depressive symptoms is associated with increased risk of relapse: their recognition and treatment are illustrated in this article. PMID- 20170034 TI - [Rheumatoid arthritis and ankylosing spondylitis-rheumatologic highlights 2009]. AB - In this year rheumatology highlights, we will especially note a new treatment, the tocilizumab, an interleukin-6 targeting therapy, effective and adequately safe for the treatment of rheumatoid arthritis. New classification criteria for axial spondylarthropathy have also been published, criteria that should facilitate earlier diagnosis, a diagnosis that should be pursue like a diagnosis of rheumatoid arthritis even in the absence of an inflammatory biological syndrome. PMID- 20170035 TI - [Urology]. AB - Two important expanded studies about the early detection of prostate cancer were made and give contradictory results. The American study didn't demonstrate any benefit on rate of survival, whereas the European one demonstrated 20% lower mortality, however with a non-negligible morbidity, and indubitable necessity of additional treatment. The PCA3 genetic test, praticed on urine after rectal touch, will allow in the future improving selection of patients with a pathological PSA for whom the first series of biopsies are negative, and where the question of further biopsies is still opened. The active observation of some prostate cancers (latent cancer) is a valuable therapeutic option, which, when done in an adequate manner, does not question the long term vital prognostic. The vitamines E and C as well the Selenium have no effect in preventing prostate cancer. PMID- 20170036 TI - [New frontiers on the relationship between death and money (1)]. PMID- 20170037 TI - [Organ donation: clear lessons from Finland]. PMID- 20170038 TI - [Ginkgo biloba has no effect on memory]. PMID- 20170039 TI - [Fate vs responsibility]. PMID- 20170040 TI - Childhood trauma and psychotic disorders: evidence, theoretical perspectives, and implication for interventions. PMID- 20170041 TI - Childhood sexual abuse and psychosis: aetiology and mechanism. AB - The aim of this Editorial is to describe the association between child sexual abuse and psychosis, and to consider potential mechanisms for the association. The association is strongly supported by the literature. Evidence from a variety of sources is triangulated in order to create a plausible model of the link, which can then be used to direct future research. The mechanisms are certainly complex, and there is evidence of interacting contributions at genetic, neurophysiological, behavioural, cognitive and emotional levels. Child sexual abuse is an important antecedent in psychosis, both theoretically and clinically. At the theoretical level, it potentially illuminates mechanisms by which psychotic symptoms are generated, at the clinical level it opens possibilities for improving cognitive-behavioural approaches to treatment. PMID- 20170042 TI - A cognitive behavioural perspective on the relationship between childhood trauma and psychosis. AB - This editorial reviews the relationship between childhood trauma and the development of psychosis in adulthood. There are numerous studies, including large, prospective studies, which clearly support a link between childhood adversity and experience of psychosis later in life. There is also evidence that there is a dose response relationship, and that childhood trauma is particularly associated with the experience of hallucinations and delusional ideas. It is possible that psychosis is a relatively understandable response to the experience of severe trauma, and recent cognitive models of psychosis can help to explain the underlying mechanisms in such a causal relationship. There are obvious treatment implications, which include the need to assess histories of childhood trauma in people with psychosis, the incorporation of trauma in shared understandings of psychosis with service users, the incorporation of change strategies in cognitive behaviour therapy for psychosis that are derived from evidence-based approaches to the treatment of trauma and PTSD, and the prevention of traumatisation by mental health services. PMID- 20170043 TI - Time to abandon the bio-bio-bio model of psychosis: Exploring the epigenetic and psychological mechanisms by which adverse life events lead to psychotic symptoms. AB - Mental health services and research have been dominated for several decades by a rather simplistic, reductionistic focus on biological phenomena, with minimal consideration of the social context within which genes and brains inevitably operate. This 'medical model' ideology, enthusiastically supported by the pharmaceutical industry, has been particularly powerful in the field of psychosis, where it has led to unjustified and damaging pessimism about recovery. The failure to find robust evidence of a genetic predisposition for psychosis in general, or 'schizophrenia' in particular, can be understood in terms of recently developed knowledge about how epigenetic processes turn gene transcription on and off through mechanisms that are highly influenced by the individual's socio environmental experiences. To understand the emerging evidence of the relationship between adverse childhood events and subsequent psychosis, it is necessary to integrate these epigenetic processes, especially those involving the stress regulating functions of the HPA axis, with research about the psychological mechanisms by which specific types of childhood trauma can lead to specific types of psychotic experiences. The implications, for research, mental health services and primary prevention, are profound. PMID- 20170044 TI - Superiority, equivalence or non-inferiority? AB - One of the most important critical decision to be taken when designing a randomized controlled trial (RCT) in clinical psychopharmacology is the choice of the comparator. This choice is crucial because it affects many issues related to both internal and external validity. The aim of a RCT may be to establish efficacy in absolute terms, against an inert treatment (usually a placebo), or to establish efficacy with respect to another treatment (also known as comparator), a trial may be designed to demonstrate that the new drug is superior to the control intervention or, by contrast, that the new drug is similar to the control intervention in terms of, say, symptoms' reduction. Three kinds of RCTs may be designed: Superiority trials, Equivalence studies, Non-inferiority studies. PMID- 20170045 TI - Language disturbances in schizophrenia. AB - Language disturbances represent a core feature of schizophrenia, affecting social interactions and quality of life. Here we summarize linguistic and pragmatic deficits and illustrate the role of brain imaging studies in delineating the neural substrates of language deficits in patients with schizophrenia. PMID- 20170046 TI - Antidepressants and the placebo response. AB - AIMS: To evaluate new generation antidepressants in relation to the placebo response. METHODS: I review meta-analyses in which response to antidepressant medication and response to placebo were calculated. RESULTS: All but one of these meta-analyses included unpublished as well as published trials. Most trials failed to show a significant advantage of SSRIs over inert placebo, and the differences between drug and placebo are not clinically significant for most depressed patients. Documents obtained from the U.S. Food and Drug Administration (FDA) revealed an explicit decision to keep this information from the public and from prescribing physicians. CONCLUSIONS: Because they do not incur drug risks, exercise and psychotherapy, which show at benefits at least equal to those of antidepressants, may be a better treatment choice for depressed individuals. PMID- 20170047 TI - Problems in psychiatric care of 'difficult patients': a Delphi-study. AB - AIMS: 'difficult patients' may evoke strong feelings in health professionals. The ambivalent attitude of, especially, non-psychotic chronic patients towards psychiatric care may be frustrating and burdensome to professionals. Many of these patients are cared for in non-specialized services, where professionals are often more used to working with psychotic patients. Specific problems with 'difficult' non-psychotic patients may occur, and hamper the quality of care offered. The aim of this research is to determine precisely what problems psychiatric professionals perceive in contact with non-psychotic chronic patients in order to identify starting points for alternative or improved care in non specialized services. METHODS: a modified five-phase Delphi study with three groups of eight participants from was used to identify and prioritize experts' judgments. RESULTS: 46 problems were identified of which some were relevant to one or two subgroups and some were relevant to the entire group. CONCLUSIONS: a program that combines a coherent view at services level, with support and increased communication at the interprofessional level (e.g. through regular supervision, sharing of case-loads) may be highly beneficial to non-specialized services. PMID- 20170048 TI - Does sport have a protective effect against suicide? AB - AIM: The association between sporting activities, or lack there of, and suicidal behaviour has not yet been clarified. The objective of this study was to determine, if sports participation has an impact on risk for completed suicide. METHODS: Axis I and Axis II disorders, sociodemographic factors, and current and former sports activities, including various sports disciplines, were assessed by a semi-structured interview by psychological autopsy method in 163 suicides and by personal interview in 396 living population-based control persons. RESULTS: Current sports activities (OR = 0.24, 95%CI, 0.15 to 0.39; OR = 0.27, 95%CI, 0.16 to 0.45) and sports activities at some point in life (OR = 0.33, 95%CI, 0.18 to 0.62; OR = 0.40, 95%CI, 0.23 to 0.68, after adjustment for axis I and II disorders or educational level, each) were associated with decreased suicide risk. CONCLUSIONS: Current sports activities and sports activities at some point in life may reduce suicide risk. PMID- 20170049 TI - Seasonal affective disorder and latitude of living. AB - AIM: Since the importance of latitude of living for the prevalence of Seasonal Affective Disorder (SAD) is unclear, the study aims to test the latitude hypothesis by comparing SAD in two rather similar groups of students living at latitudes far apart. METHODS: Two groups of students, 199 in Tromso, Norway (690 N) and 188 in Ferrara, Italy (440 N) were asked to fill in the Seasonal Pattern Assessment Questionnaire. RESULTS: Global Seasonality score (GS-score) was significantly higher in Italian than in Norwegian students, in females and in students with sleeping-problems. Norwegian students had significantly higher SAD prevalence in winter and in spring. Most people in both countries felt worst in October and November, and the prevalence of Autumn SAD was not significantly different between the two countries. CONCLUSIONS: The hypothesis that SAD is linked to amount of environmental light and latitude of living was not supported. PMID- 20170050 TI - Predictors of employment status change over 2 years in people with schizophrenia living in Europe. AB - AIM: To examine the associations of job acquisition and loss in a representative, prospective community sample of people with schizophrenia living in the UK, France and Germany. METHOD: A representative sample of twelve hundred and eight people with schizophrenia were recruited from selected secondary mental health services in the U.K, France and Germany and followed up for 2 years. Information on demographic details, psychotic symptoms and work status was collected. RESULTS: The odds of getting jobs were increased by being resident in Marseille, Leipzig, Hemer and Heilbronn and by a higher regional general population employment rate. The odds were reduced by living in Lyon, a later illness onset, a longer length of illness, a continuous illness course and more severe negative psychotic symptoms. Previous vocational training reduced the odds of losing employment, whilst living in Lyon or Leipzig, harmful use of alcohol and more positive psychotic symptoms at baseline all increased the odds. CONCLUSIONS: In addition to illness related factors, area of residence and local labour market conditions appear to be important in explaining employment status change in people with schizophrenia. PMID- 20170051 TI - Attitudes to depression among community health workers in Kenya. PMID- 20170052 TI - Perceptive significance of frequency and amplitude characteristics of vowels with difference fundamental frequency. PMID- 20170053 TI - Irregularity of entropy processes in the body as an indicator of functional stability. PMID- 20170054 TI - (4S,5R,6R)-para-mentha-1,8-dien-5,6-diol is a new highly effective anticonvulsant agent. PMID- 20170055 TI - The influence of agonists of GABA(A) and GABA(B) receptors on the formation of the defensive and inhibitory conditioned reflexes. PMID- 20170056 TI - Influence of seasonal fluctuations, sex, and age on epoxide synthetase and epoxide hydrolase activities of the xenobiotic-metabolizing enzyme system. PMID- 20170057 TI - Polyoxidonium induces adrenocorticotropic hormone secretion by peripheral blood mononuclear cells. PMID- 20170058 TI - The use of phospholipid nanoparticles for increasing Semax resistance in various proteolytic biological media. PMID- 20170059 TI - Interleukin-2 modulatory effects on the functional activity of human mononuclear cells in vitro. PMID- 20170060 TI - Location of the decision-making centre during image shape perception. PMID- 20170061 TI - Estimation of spatiotemporal transformations of lake ecosystems by the method of diatom analysis. PMID- 20170062 TI - Noninvasive individual identification of the Amur tiger (Panthera tigris altaica) by molecular-genetic methods. PMID- 20170063 TI - High genetic diversity in the long-tailed ground squirrel (Spermophilus undulatus) population on Olkhon Island: a natural gene bank or the consequences of long-term isolation? PMID- 20170064 TI - The current level of dioxin pollution in the area of large-scale spraying of Agent Orange in Vietnam. PMID- 20170065 TI - Hybrid origin of karyotypic variation in the common shrew, Sorex araneus (Mammalia), from the Dnieper River basin. PMID- 20170067 TI - Composition of the essential oil of introduced mint forms of Mentha piperita and Mentha arvensis species. PMID- 20170066 TI - Antiinflammatory activity of proanthocyanidins of rhizomes with roots of Comarum palustre L. PMID- 20170068 TI - Ecology of the harp seal feeding in spring in the White Sea. PMID- 20170069 TI - Introduction of sibling species to the ecosystem of the Baltic Sea. PMID- 20170070 TI - Histochemical analysis of nickel distribution in the hyperaccumulator and excluder in the genus Alyssum L. PMID- 20170071 TI - Limb autotomy in red king crab in the coastal waters of the Barents Sea. PMID- 20170072 TI - Electrical activity of Asian catfish Clarias macrocephalus (Claridae, Siluriformes) during spawning behavior. PMID- 20170073 TI - Effects of sex and gene order on the recombination frequency and distribution in the chromosome 1 of the house mouse. PMID- 20170074 TI - Polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls in the serum of firefighters who participated in extinguishing the 1992 fire at a cable manufacturing plant in Irkutsk oblast. PMID- 20170075 TI - Influence of unrhythmical stepwise changes in temperature on the dynamics of abundance of Simocephalus vetulus (O.F. Muller, 1776). PMID- 20170076 TI - Response of taiga ecosystems to extreme weather conditions and climate anomalies. PMID- 20170077 TI - Localization of the highest retinal resolution area in the retinal ganglion cell layer of the Caspian seal Phoca caspica: a topographic study. PMID- 20170078 TI - Orto-aminoazotoluen induces the expression of the p53 gene in inbred strains of mice susceptible and resistant to hepatocarcinogenesis. PMID- 20170079 TI - Secreted growth factors from stromal fibroblasts of the human lung and pancreatic carcinomas. PMID- 20170080 TI - The possibilities of optical laser technologies in cell engineering. PMID- 20170082 TI - Automated needle trap heart-cut GC/MS and needle trap comprehensive two dimensional GC/TOF-MS for breath gas analysis in the clinical environment. AB - This study was intended to evaluate low-volume (20 mL) multibed needle trap (NTD) sampling combined with heart-cut gas chromatography/mass spectrometry (GC/MS) and comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry (GC x GC/TOF-MS) for trace gas analysis under clinical conditions. NTDs, high throughput automatic desorption and separation systems, were tested in vitro and within a study in 11 patients undergoing cardiac surgery with respect to reproducibility, reliability, and clinical applicability. NTD-heart-cut GC/MS analysis of standard mixtures containing different volatile organic compounds (VOCs) yielded relative standard deviations (RSDs) from 4.0% to 18.5%. Substance adsorption was stable for 1 day if NTDs were closed on both ends and was stable for approximately 7.8 h when NTD tip ends had to be left open during autosampler storage. Even in the presence of high concentrations of contaminants linearity of heart-cut GC/MS was conserved. In patients' breath potential biomarkers could be determined even in the presence of very high concentrations of sevoflurane. Profiles of blood-borne biomarkers, intravenous drugs, and clinical contaminants were characterized. Comprehensive GC x GC/TOF-MS may be used as a screening tool for new biomarkers, if patterns are generated from deconvoluted normalized areas. Needle trap sampling in combination with hyphenated chromatographic techniques can thus be used to provide well-tailored solutions for complex problems occurring in clinical breath analysis. PMID- 20170081 TI - Pyrophosphate activation in hypoxanthine--guanine phosphoribosyltransferase with transition state analogue. AB - Isotope-edited difference Raman and FTIR studies complemented by ab initio calculations have been applied to the transition state analogue complex of HGPRT.ImmHP.MgPP(i) to determine the ionic states of the 5'-phosphate moiety of ImmHP and of PP(i). These measurements characterize electrostatic interactions within the enzyme active site as deduced from frequency shifts of the phosphate groups. The bound 5'-phosphate moiety of ImmHP is dianionic, and this phosphate group exists in two different conformations within the protein complex. In one conformation, a hydrogen bond between the 5'-phosphate of ImmHP and the OH group of Tyr104 in the catalytic loop appears to be stronger. With the stronger H-bond, the OH of Tyr104 approaches one of the P..O bonds from the bridging oxygen side to cause distortion of the PO(3) moiety, as indicated by a lowered symmetric P..O stretch frequency. The asymmetric stretch frequencies are similar in both phosphate conformations. Bound PP(i) in this complex is fully ionized to P(2)O(7)(4-). Bond frequency changes for bound PP(i) indicate coordination to Mg(2+) ions but show no indication of significant P..O bond polarization. Extrapolation of these results to reaction coordinate motion for HGPRT suggests that bond formation between C1' of the nucleotide ribose and the oxygen of PP(i) is accomplished by migration of the ribocation toward immobilized pyrophosphate. PMID- 20170083 TI - Simultaneous measurement of [15N]nitrate and [15N]nitrite enrichment and concentration in urine by gas chromatography mass spectrometry as pentafluorobenzyl derivatives. AB - Quantification of (15)N-labeled nitrate and determination of the (15)N-enrichment in urine upon administration of (15)N-labeled precursors such as L-[guanidino (15)N(2)]arginine is a suitable approach to study formation and metabolism of nitric oxide (NO) and its metabolites in vivo. Previously, we have reported on the simultaneous derivatization and accurate quantification of nitrite and nitrate in various biological fluids using pentafluorobenzyl bromide and GC/MS. We report here on a modification of this method that allows for the simultaneous determination of (15)N-enrichment of [(15)N]nitrate and [(15)N]nitrite and the simultaneous quantification of [(15)N]nitrate, [(14)N]nitrate, [(15)N]nitrite, and [(14)N]nitrite in human urine. In a pilot study, using the carbonic anhydrase inhibitor drug acetazolamide at therapeutical oral doses (5.4 and 5 mg per kg bodyweight) and by oral intake of [(15)N]nitrite (0.31 and 0.5 micromol per kg bodyweight) by two healthy volunteers, we demonstrate for the first time that renal carbonic anhydrase activity is mainly responsible for the reabsorption of nitrite from the primary urine and confirm previous findings on nitrate. PMID- 20170084 TI - Nanoassembled thin film gas sensors. III. Sensitive detection of amine odors using TiO2/poly(acrylic acid) ultrathin film quartz crystal microbalance sensors. AB - Quartz crystal microbalance (QCM) gas sensors based on the alternate adsorption of TiO(2) and polyacrilic acid (PAA) were developed for the sensitive detection of amine odors. Individual TiO(2) gel layers could be regularly assembled with a thickness of approximately 0.3 nm by the gas-phase surface sol-gel process (GSSG). The thickness of the poly(acrylic acid) (PAA) layer is dependent on its molecular weight, showing different thicknesses of approximately 0.4 nm for PAA(25) (Mw 250,000) and 0.6-0.8 nm for PAA(400) (Mw 4,000,000). The QCM sensors showed a linear response to ammonia in the concentration range 0.3-15 ppm, depending on the deposition cycle of the alternate TiO(2)/PAA layer. The ammonia binding is based on the acid-base interaction to the free carboxylic acid groups of PAA and the limit of detection (LOD) of the 20-cycle TiO(2)/PAA(400) film was estimated to be 0.1 ppm when exposed to ammonia. The sensor response was very fast and stable in a wide relative humidity (rH) range of 30-70%, showing almost the same frequency changes at a given concentration of ammonia. Sensitivity to n butylamine and ammonia was higher than to pyridine, which is owing to the difference of molecular weight and basicity of the amine analytes. The alternate TiO(2)/PAA(400) films have a highly effective ability to capture amine odors, and the ambient ammonia concentration of 15 ppm could be condensed up to approximately 20,000 ppm inside the films. PMID- 20170086 TI - Parallel synthesis of an oligomeric imidazole-4,5-dicarboxamide library. AB - A library of oligomeric compounds was synthesized based on the imidazole-4,5 dicarboxylic acid scaffold along with amino acid esters and chiral diamines derived from amino acids. The final compounds incorporate nonpolar amino acids (Leu, Phe, Trp), polar amino acids (Ser, Asp, Arg), and neutral amino acids (Gly, Ala), and were designed to be useful in screening for inhibitors of protein protein interactions. Many of the protected and deprotected oligomers show evidence of conformational isomers persistent at room temperature in aqueous solution. A total of 317 final oligomers, out of 441 targeted compounds, were obtained in high analytical purity and of sufficient quantity to submit them for high-throughput screening as part of the NIH Roadmap. PMID- 20170087 TI - Revisiting the thermal decomposition of layered gamma-titanium phosphate and structural elucidation of its intermediate phases. AB - The thermal transformations of gamma-titanium phosphate, Ti(PO(4))(H(2)PO(4)) x 2 H(2)O, have been studied by thermal analyses (thermogravimetry (TG) and differential thermal analysis (DTA)) and variable-temperature (31)P magic-angle spinning (MAS)/CPMAS and 2D (31)P-(31)P spin-exchange NMR. The structure of this material has been refined from synchrotron powder X-ray diffraction data (monoclinic, P2(1), a = 5.1811(2) A, b = 6.3479(2) A, c = 23.725(2) A, beta = 102.57(1) degrees). Vyazovkin's model-free kinetic algorithms have been applied to determine the apparent activation energy to both dehydration and dehydroxylation of gamma-titanium phosphate. In these processes, several overlapped steps have been detected. Structural models for Ti(PO(4))(H(2)PO(4)) x H(2)O and Ti(PO(4))(H(2)P(2)O(7))(0.5) intermediate layered phases have been proposed. PMID- 20170088 TI - Fluorous mixture synthesis of asymmetric dendrimers. AB - A divergent fluorous mixture synthesis (FMS) of asymmetric fluorinated dendrimers has been developed. Four generations of fluorinated dendrimers with the same fluorinated moiety were prepared with high efficiency, yield, and purity. Comparison of the physicochemical properties of these dendrimers provided valuable information for their application and future optimization. This strategy has not only provided a practical method for the synthesis and purification of dendrimers, but also established the possibility of utilizing the same fluorinated moiety for FMS. PMID- 20170089 TI - Diastereoselective synthesis of hexahydro-3H-pyrrolyzin-3-ones through Pd catalyzed carboamination. AB - The reaction of readily available (5R)-5-but-3-en-1-ylpyrrolidin-2-one with aryl bromides, chlorides, or triflates in the presence of Pd(2)(dba)(3), Xphos, and Cs(2)CO(3) in 1,4-dioxane at 120 degrees C affords (5R,7aR)-5-aryl hexahydropyrrolizidin-3-ones in good to high yields through a diastereoselective carboamination reaction. Aryl iodides are less successful substrates than bromides and chlorides. PMID- 20170091 TI - pH-Controllable bioelectrocatalysis based on "on-off" switching redox property of electroactive probes for spin-assembled layer-by-layer films containing branched poly(ethyleneimine). AB - Weak polybase branched poly(ethyleneimine) (BPEI) and strong polyacid poly(styrenesulfonate) (PSS) were assembled into BPEI/{PSS/BPEI}(n) layer-by layer (LBL) films on electrodes by electrostatic interaction between them with spin-coating approach. The cyclic voltammetric (CV) response of ferrocenedicarboxylic acid (Fc(COOH)(2)) at BPEI/{PSS/BPEI}(n) film electrodes was very sensitive to the pH of the testing solutions. At pH 4.0, the probe showed a well-defined CV peak pair with relatively large peak currents for the films, while, at pH 7.0, the CV response was significantly depressed. By switching the film electrodes in buffers between pH 4.0 and 7.0, the CV peak currents changed periodically between a relatively high value at the "on" state and a very low value at the "off" state, indicating that the pH-sensitive "on off" switching function of the films toward the probe is reversible. A series of comparative experiments indicates that the electrostatic interaction between the films and the probe plays a predominant role in deciding the pH-sensitive behavior of the films. This pH-dependent property of the films could be used to control or modulate the bioelectrocatalysis of glucose by glucose oxidase (GOD) with Fc(COOH)(2) as the mediator by changing the surrounding pH. This "smart" bioelectrocatalytic film system may establish a foundation for fabricating novel pH-controllable electrochemical biosensors. PMID- 20170090 TI - K3PO4-catalyzed regiospecific aminobromination of beta-nitrostyrene derivatives with N-bromoacetamide as aminobrominating agent. AB - A very simple, efficient, and regiospecific protocol for aminobromination of a wide scope of beta-nitrostyrene derivatives with N-bromoacetamide (NBA) as nitrogen/bromine sources has been developed by using K(3)PO(4) as catalyst. The reaction proceeded smoothly and cleanly to give the bromoamines in good to excellent yields (78-99%) within 24 h in CH(2)Cl(2) at room temperature without protection of inert gases. A possible mechanism involving a nucleophilic conjugate addition was proposed. PMID- 20170092 TI - Variation of the lateral mobility of transmembrane peptides with hydrophobic mismatch. AB - A hydrophobic mismatch between protein length and membrane thickness can lead to a modification of protein conformation, function, and oligomerization. To study the role of hydrophobic mismatch, we have measured the change in mobility of transmembrane peptides possessing a hydrophobic helix of various length d(pi) in lipid membranes of giant vesicles. We also used a model system where the hydrophobic thickness of the bilayers, h, can be tuned at will. We precisely measured the diffusion coefficient of the embedded peptides and gained access to the apparent size of diffusing objects. For bilayers thinner than d(pi), the diffusion coefficient decreases, and the derived characteristic sizes are larger than the peptide radii. Previous studies suggest that peptides accommodate by tilting. This scenario was confirmed by ATR-FTIR spectroscopy. As the membrane thickness increases, the value of the diffusion coefficient increases to reach a maximum at h approximately = d(pi). We show that this variation in diffusion coefficient is consistent with a decrease in peptide tilt. To do so, we have derived a relation between the diffusion coefficient and the tilt angle, and we used this relation to derive the peptide tilt from our diffusion measurements. As the membrane thickness increases, the peptides raise (i.e., their tilt is reduced) and reach an upright position and a maximal mobility for h approximately = d(pi). Using accessibility measurements, we show that when the membrane becomes too thick, the peptide polar heads sink into the interfacial region. Surprisingly, this "pinching" behavior does not hinder the lateral diffusion of the transmembrane peptides. Ultimately, a break in the peptide transmembrane anchorage is observed and is revealed by a "jump" in the D values. PMID- 20170093 TI - Cytocompatibility and uptake of halloysite clay nanotubes. AB - Halloysite is aluminosilicate clay with hollow tubular structure of 50 nm external diameter and 15 nm diameter lumen. Halloysite biocompatibility study is important for its potential applications in polymer composites, bone implants, controlled drug delivery, and for protective coating (e.g., anticorrosion or antimolding). Halloysite nanotubes were added to different cell cultures for toxicity tests. Its fluorescence functionalization by aminopropyltriethosilane (APTES) and with fluorescently labeled polyelectrolyte layers allowed following halloysite uptake by the cells with confocal laser scanning microscopy (CLSM). Quantitative Trypan blue and MTT measurements performed with two neoplastic cell lines model systems as a function of the nanotubes concentration and incubation time indicate that halloysite exhibits a high level of biocompatibility and very low cytotoxicity, rendering it a good candidate for household materials and medicine. A combination of transmission electron microscopy (TEM), scanning electron microscopy (SEM), and scanning force microscopy (SFM) imaging techniques have been employed to elucidate the structure of halloysite nanotubes. PMID- 20170094 TI - Lipid peroxyl radicals mediate tyrosine dimerization and nitration in membranes. AB - Protein tyrosine dimerization and nitration by biologically relevant oxidants usually depend on the intermediate formation of tyrosyl radical ((*)Tyr). In the case of tyrosine oxidation in proteins associated with hydrophobic biocompartments, the participation of unsaturated fatty acids in the process must be considered since they typically constitute preferential targets for the initial oxidative attack. Thus, we postulate that lipid-derived radicals mediate the one-electron oxidation of tyrosine to (*)Tyr, which can afterward react with another (*)Tyr or with nitrogen dioxide ((*)NO(2)) to yield 3,3'-dityrosine or 3 nitrotyrosine within the hydrophobic structure, respectively. To test this hypothesis, we have studied tyrosine oxidation in saturated and unsaturated fatty acid-containing phosphatidylcholine (PC) liposomes with an incorporated hydrophobic tyrosine analogue BTBE (N-t-BOC l-tyrosine tert-butyl ester) and its relationship with lipid peroxidation promoted by three oxidation systems, namely, peroxynitrite, hemin, and 2,2'-azobis (2-amidinopropane) hydrochloride. In all cases, significant tyrosine (BTBE) oxidation was seen in unsaturated PC liposomes, in a way that was largely decreased at low oxygen concentrations. Tyrosine oxidation levels paralleled those of lipid peroxidation (i.e., malondialdehyde and lipid hydroperoxides), lipid-derived radicals and BTBE phenoxyl radicals were simultaneously detected by electron spin resonance spin trapping, supporting an association between the two processes. Indeed, alpha tocopherol, a known reactant with lipid peroxyl radicals (LOO(*)), inhibited both tyrosine oxidation and lipid peroxidation induced by all three oxidation systems. Moreover, oxidant-stimulated liposomal oxygen consumption was dose dependently inhibited by BTBE but not by its phenylalanine analogue, BPBE (N-t-BOC l phenylalanine tert-butyl ester), providing direct evidence for the reaction between LOO(*) and the phenol moiety in BTBE, with an estimated second-order rate constant of 4.8 x 10(3) M(-1) s(-1). In summary, the data presented herein demonstrate that LOO(*) mediates tyrosine oxidation processes in hydrophobic biocompartments and provide a new mechanistic insight to understand protein oxidation and nitration in lipoproteins and biomembranes. PMID- 20170095 TI - Identification of 3,4-Dihydroisoquinoline-2(1H)-sulfonamides as potent carbonic anhydrase inhibitors: synthesis, biological evaluation, and enzyme--ligand X-ray studies. AB - Following previous studies we herein report the exploration of the carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects and enzyme selectivity of a small class of 1-(cyclo)alkylisoquinolines containing a sulfonamide function considered a key feature for inhibiting CA. The results of enzymatic assays against human (h) CA isoforms, hCA I and hCA II (cytosolic, ubiquitous enzymes), hCA IX (transmembrane, tumor-associated), and hCA XIV (transmembrane), suggested that the presence of C-1 small substituents on isoquinoline scaffold controls both inhibitory potency and selectivity. Some derivatives showed potent hCA IX and hCA XIV inhibitory effects at nanomolar concentrations as well as low affinity for the ubiquitous hCA II. Moreover, we report the X-ray crystal structure of one of these derivatives in complex with dominant human isoform II, thus confirming the sulfonamide--zinc interactions. Finally, the results of docking experiments suggested the hypothetic interactions in the catalytic binding site for the most active and selective hCA IX and hCA XIV inhibitor. PMID- 20170096 TI - Novel diamidino-substituted derivatives of phenyl benzothiazolyl and dibenzothiazolyl furans and thiophenes: synthesis, antiproliferative and DNA binding properties. AB - A series of new diamidino-, diisopropylamidino-, and diimidazolinyl-substituted derivatives of phenyl benzothiazolyl and dibenzothiazolyl furans and thiophenes were successfully prepared and evaluated for their antiproliferative activity on tumor cell lines in vitro, DNA binding propensity, and sequence selectivity as well as cellular distribution. A strong antiproliferative effect of the tested compounds was observed on all tested cell lines in a concentration-dependent response pattern. In general, imidazolinyl-substituted derivatives and/or the thiophene core were in correlation with increased antiproliferative activity. Two compounds (2b and 3b) were chosen for biological studies due to their differential antiproliferative properties. The DNA binding properties of this new series of compounds were assessed and evidenced their efficient minor groove binding properties with preferential interaction at AT-rich sites. Both compounds also present nuclear subcellular localization, suggesting that their cellular mode of action implies localization in the DNA compartment and direct inhibition of DNA replication and induction of apoptosis. PMID- 20170097 TI - Synthesis and biological activities of 2-amino-1-arylidenamino imidazoles as orally active anticancer agents. AB - 2-Amino-1-arylidenaminoimidazoles, a novel class of orally (po) active microtubule-destabilizing anticancer agents, were synthesized. The compounds were designed from a hit compound identified in a drug discovery platform by using cancer cell-based high throughput screening assay. Selective synthesized compounds exerted cell cytotoxicity against human cancer cells. The underlying mechanisms for the anticancer activity were demonstrated as interacting with the tubulins and inhibiting microtubule assembly, leading to proliferation inhibition and apoptosis induction in the human tumor cells. Furthermore, two compounds showed in vivo anticancer activities in both po and intravenously (iv) administered routes and prolonged the life spans of murine leukemic P388 cells inoculated mice. These new po active antimitotic anticancer agents are to be further examined in preclinical studies and developed for clinical uses. PMID- 20170099 TI - 5-Cyclic amine-3-arylsulfonylindazoles as novel 5-HT6 receptor antagonists. AB - Novel 5-cyclic amine-3-arylsulfonylindazoles were prepared, and several analogues within this class have been identified as high-affinity 5-HT(6) receptor ligands with improved pharmacokinetic and pharmacological properties. One selected example, 18b, showed good brain penetrability and a generally favorable pharmacokinetic profile with procognitive efficacy in the rat novel object recognition assay. The synthesis and structure-activity relationship of this potent class are discussed. PMID- 20170098 TI - Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2). AB - The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) plays a pivotal role in growth factor and cytokine signaling. Gain-of-function SHP2 mutations are associated with Noonan syndrome, various kinds of leukemias, and solid tumors. Thus, there is considerable interest in SHP2 as a potential target for anticancer and antileukemia therapy. We report a salicylic acid based combinatorial library approach aimed at binding both active site and unique nearby subpockets for enhanced affinity and selectivity. Screening of the library led to the identification of a SHP2 inhibitor II-B08 (compound 9) with highly efficacious cellular activity. Compound 9 blocks growth factor stimulated ERK1/2 activation and hematopoietic progenitor proliferation, providing supporting evidence that chemical inhibition of SHP2 may be therapeutically useful for anticancer and antileukemia treatment. X-ray crystallographic analysis of the structure of SHP2 in complex with 9 reveals molecular determinants that can be exploited for the acquisition of more potent and selective SHP2 inhibitors. PMID- 20170100 TI - Suppressed blinking dynamics of single QDs on ITO. AB - The exciton quenching dynamics of single CdSe/CdS(3ML)ZnCdS(2ML)ZnS(2ML) core/multishell QDs adsorbed on glass, In2O3, and ITO have been compared. Single QDs on In2O3 show shorter fluorescence lifetimes and higher blinking frequencies than those on glass because of interfacial electron transfer from QDs to In2O3. Compared to glass and In2O3, single QDs on ITO show suppressed blinking activity as well as reduced fluorescence lifetimes. For QDs in contact with the n-doped ITO, the equilibration of their Fermi levels leads to the formation of negatively charged QDs. In these negatively charged QDs, the off states are suppressed because of the effective removal of the valence band holes, and their fluorescence lifetimes are shortened because of exciton Auger recombination and hole transfer processes involving the additional electrons. This study shows that the blinking of single QDs can be effectively suppressed on the surface of ITO. This phenomenon may also be observable for other QDs and on different n-doped semiconductors. PMID- 20170101 TI - A computational approach to the study of the binding mode of dual ACE/NEP inhibitors. AB - Combined blockade of the renin-angiotensin-aldosterone system (RAAS) is an attractive therapeutic strategy for the treatment of cardiovascular diseases. Vasopeptidase inhibitors are a group of compounds capable of inhibiting more than one enzyme, which leads to potentiation of natriuretic peptide actions and suppression of the RAAS. In this study, molecular modeling has been used to elucidate key structural features that govern the binding and/or selectivity of a single compound toward the zinc catalytic sites of the N- and C-domains of the angiotensin-converting enzyme (ACE) and the neutral endopeptidase (NEP). Eleven dual inhibitors were categorized in three classes, according to their zinc binding groups. Analysis of their docked conformers revealed the molecular environment of the catalytic sites and the specific interactions between the inhibitors and amino acid residues that are important for selectivity and cooperativity. In addition, inhibitors were predicted to bind to the C-domain of the ACE with greater affinity than the N-domain, with an average difference in the free energy of binding approximately 2-3 kcal mol(-1). Residues that were identified to actively participate in the binding and stabilizing of the enzyme inhibitor complexes were analyzed in a consensus way for both the ACE and the NEP. These atomic-level insights into enzyme-ligand binding can be used to drive new structure-based drug design processes in the quest for more selective and effective vasopeptidase inhibitors. PMID- 20170102 TI - Enhanced tetrahedral ordering of water molecules in minor grooves of DNA: relative role of DNA rigidity, nanoconfinement, and surface specific interactions. AB - Confinement and surface specific interactions can induce structures otherwise unstable at that temperature and pressure. Here we study the groove specific water dynamics in the nucleic acid sequences, poly-AT and poly-GC, in long B-DNA duplex chains by large scale atomistic molecular dynamics simulations, accompanied by thermodynamic analysis. While water dynamics in the major groove remains insensitive to the sequence differences, exactly the opposite is true for the minor groove water. Much slower water dynamics observed in the minor grooves (especially in the AT minor) can be attributed to an enhanced tetrahedral ordering () of water. The largest value of in the AT minor groove is related to the spine of hydration found in X-ray structure. The calculated configurational entropy (S(C)) of the water molecules is found to be correlated with the self-diffusion coefficient of water in different region via Adam-Gibbs relation D = A exp(-B/TS(C)), and also with . PMID- 20170103 TI - Copper-catalyzed guanidinylation of aryl iodides: the formation of N,N' disubstituted guanidines. AB - A copper-catalyzed cross-coupling reaction of guanidine nitrate with aryl iodides was used for the formation of N,N'-disubstituted guanidines to be used as potential therapeutics for strokes. A relatively inexpensive commercially available guanidine salt and a series of aryl iodides together with copper iodide and N,N-diethylsalicylamide as an efficient catalyst/ligand system provided a simple diarylation procedure. PMID- 20170104 TI - Molecular geometry of vanadium dichloride and vanadium trichloride: a gas-phase electron diffraction and computational study. AB - The molecular geometries of VCl2 and VCl3 have been determined by computations and gas-phase electron diffraction (ED). The ED study is a reinvestigation of the previously published analysis for VCl2. The structure of the vanadium dichloride dimer has also been calculated. According to our joint ED and computational study, the evaporation of a solid sample of VCl2 resulted in about 66% vanadium trichloride and 34% vanadium dichloride in the vapor. Vanadium dichloride is unambiguously linear in its 4Sigma(g)+ ground electronic state. For VCl3, all computations yielded a Jahn-Teller-distorted ground-state structure of C(2v) symmetry. However, it lies merely less than 3 kJ/mol lower than the 3E'' state (D(3h) symmetry). Due to the dynamic nature of the Jahn-Teller effect in this case, rigorous distinction cannot be made between the planar models of either D(3h) symmetry or C(2v) symmetry for the equilibrium structure of VCl3. Furthermore, the presence of several low-lying excited electronic states of VCl3 is expected in the high-temperature vapor. To our knowledge, this is the first experimental and computational study of the VCl3 molecule. PMID- 20170105 TI - Superaromatic terpyridines: hexa-peri-hexabenzocoronenes with tridentate functionality. AB - Two superaromatic terpyridine ligands (1 and 2) incorporating a hexa-peri hexabenzocoronene (HBC) unit at the 4'-position have been prepared. In 1, the terpyridine and the HBC domains are directly fused, while in 2, they are separated by an acetylene linker. Also presented is the synthesis and characterization of several novel HBC derivatives, including 2-iodo-5,8,11,14,17 penta-tert-butylhexa-peri-hexabenzocoronene (7), a valuable synthetic intermediate. Different synthetic routes to 1 and 2 are employed, and two alternative methods resulted in excellent yields of 2. The optical properties of both novel terpyridines are examined using UV-visible absorption and emission spectroscopy. The single-crystal X-ray structures of 7 and a precursor, 4-iodo-4' tert-butylphenylacetylene (5), are discussed. PMID- 20170106 TI - Extended surfaces nanopatterned with functionalized cavities for positioning nanoparticles. AB - This contribution reports a method delivering inorganic nanopatterned and functional surfaces from the ion beam etching of mesoporous thin films. The nanoscaled patterns are spherical or cylindrical cavities that are arranged on a macroscale. A variety of chemical functions can be grafted selectively in the cavities to add specific interactions with functional nanoparticles to be positioned. The process opens a simple route to localize and organize functional spherical or linear nanoparticles on extended surfaces. PMID- 20170107 TI - Influence of anthocyanins, derivative pigments and other catechol and pyrogallol type phenolics on breast cancer cell proliferation. AB - Anthocyanins (cyanidin-3-glucoside (Cy-3-gluc) and delphinidin-3-glucoside (Dp-3 gluc)) and their respective vinylpyranoanthocyanin-catechins (portisins) were studied in order to evaluate the cytotoxicity effect on the estrogen responsive human breast cancer cell line (ER+) MCF-7 and their effect on estrogen receptor (ER-alpha and ER-beta) expression. Other flavonoid classes and phenolic molecules were also tested, aiming to study possible structural features related with these effects. Also, the antiproliferative effect of Cy-3-gluc and Dp-3-gluc was studied by an immunofluorescence assay. Generally, all the anthocyanin pigments studied inhibited, in a dose-dependent manner, the growth of the (ER+) MCF-7. The cytotoxicity effect was higher when cells were treated with Dp-3-gluc and its respective portisin. Altogether, the results point to the ortho trihydroxylated moiety in the phenolic ring as an important structural feature for more potent cytotoxicity effect on MCF-7 cells comparatively to the effect observed with the similar dihydroxylated compounds. In order to elucidate the molecular mechanism involved, expression of estrogen receptor was assayed by RT-PCR and real time RT PCR. The higher antiproliferative effect observed after cell treatment with Dp-3 gluc was not followed by modification on ER expression. However, the anthocyanin Cy-3-gluc was able to induce a downregulation of ER levels although with no significant effect on MCF-7 proliferation. PMID- 20170108 TI - Investigating the origin of tomatoes and triple concentrated tomato pastes through multielement determination by inductively coupled plasma mass spectrometry and statistical analysis. AB - The concentration of 32 elements (Al, As, Ba, Be, Ca, Cd, Ce, Cu, Dy, Fe, K, La, Lu, Mg, Mn, Na, Nd, Pb, Rb, Sm, Sr, Th, U, V, Zn) was determined in tomatoes harvested in different four Italian regions and in triple concentrated tomato paste samples coming from Italy, China, Greece and California. The resulting multielement profiles were processed using three chemometric techniques to evaluate the possibility of discrimination between different cultivation areas. The closed-vessel microwave digested samples were diluted and analyzed by DRC-ICP MS with CH(4) as reaction gas. The accuracy of the proposed method was considered acceptable (values in the range 75-120%) for 25 out of the 35 elements of the reference material NCS ZC85006 Tomato. The origin of tomato fruits and the areas of production as "Italy" and "non-Italy" of the triple concentrated pastes were evaluated by three supervised pattern recognition procedures, linear discriminant analysis (LDA), soft independent modeling of class analogy (SIMCA) and K-nearest neighbors (KNN). PMID- 20170109 TI - Tryptophan depletion and formation of alpha-aminoadipic and gamma-glutamic semialdehydes in porcine burger patties with added phenolic-rich fruit extracts. AB - The effect of added fruit extracts on the oxidation of muscle proteins in porcine burger patties subjected to cooking and chill storage was studied. Extracts from arbutus berries (Arbutus unedo L., AU), common hawthorns (Crataegus monogyna L., CM), dog roses (Rosa canina L., RC), and elm-leaf blackberries (Rubus ulmifolius Schott, RU) were prepared, characterized, added to burger patties (3% of total weight), and evaluated as inhibitors of protein oxidation. Negative (no added extract, C) and positive control (added quercetin, 230 mg/kg, Q) groups were also included in the design. Protein oxidation was assessed by means of tryptophan loss using fluorescence spectroscopy (FS) and formation of the specific protein carbonyls alpha-aminoadipic (AAS) and gamma-glutamic semialdehyde (GGS) using liquid chromatography and mass spectroscopy (LC-MS). Both advanced methodologies (FS and LC-MS) were found to be reliable and specific protein oxidation measurements that allow us to gain chemical insight into protein oxidation. The mechanisms likely involved in the oxidative reactions affecting proteins during cooking and storage of burger patties are profusely discussed. Phenolic-rich fruit extracts protected tryptophan residues against oxidation and inhibited the formation of both semialdehydes in burger patties during cooking and subsequent chill storage. In general, RC, RU, and AU were the most effective inhibitors of protein oxidation, with this effect being more intense than that of pure polyphenols like quercetin. These fruit extracts could be considered functional ingredients as their antioxidant actions contribute to the enhancement of the nutritional value of the meat products. PMID- 20170110 TI - Development of a dielectric spectroscopy technique for determining key chemical components of apple maturity. AB - Dielectric measurements (from 500 MHz to 20 GHz) on different standard solutions (K(+), malic acid) with different sugar contents were assayed simulating concentrations of these substances during apple ripening. These assays were performed for considering the potential use of dielectric spectra (500 MHz to 20 GHz) to determine the optimal time for eating the fruit. Good correlations between a newly defined dielectric maturity index and the Thiault index were found. This work presents prospective data of dielectric spectra for certain apple key chemical components in order to consider its potential application as a nondestructive control sensor for the prediction of climacteric fruit maturity. PMID- 20170111 TI - Compositional analysis of water-soluble materials in switchgrass. AB - Any valuation of a potential feedstock for bioprocessing is inherently dependent upon detailed knowledge of its chemical composition. Accepted analytical procedures for compositional analysis of biomass water-soluble extracts currently enable near-quantitative mass closure on a dry weight basis. Techniques developed in conjunction with a previous analytical assessment of corn stover have been applied to assess the composition of water-soluble materials in four representative switchgrass samples. To date, analytical characterization of water soluble material in switchgrass has resulted in >78% mass closures for all four switchgrass samples, three of which have a mass closure of >85%. Over 30 previously unknown constituents in aqueous extracts of switchgrass were identified and quantified using a variety of chromatographic techniques. Carbohydrates (primarily sucrose, glucose, and fructose) were found to be the predominant water-soluble components of switchgrass, accounting for 18-27% of the dry weight of extractives. Total glycans (monomeric and oligomeric sugars) contributed 25-32% to the dry weight of extractives. Additional constituents contributing to the mass balance for extractives included various alditols (2 3%), organic acids (10-13%), inorganic ions (11-13%), and a distribution of oligomers presumed to represent a diverse mixture of lignin-carbohydrate complexes (30-35%). Switchgrass results are compared with previous analyses of corn stover extracts and presented in the context of their potential impact on biomass processing, feedstock storage, and future analyses of feedstock composition. PMID- 20170112 TI - Chemical evaluation and sensory quality of sauerkrauts obtained by natural and induced fermentations at different NaCl levels from Brassica oleracea Var. capitata Cv. Bronco grown in eastern Spain. Effect of storage. AB - The aim of the present work was to optimize fermentation conditions of white cabbage ( Brassica oleracea L. var. capitata cv. Bronco) grown in winter in eastern Spain. The influence of two salt concentrations (0.5 and 1.5% NaCl) in combination with spontaneous or induced cabbage fermentation on the content of ascorbigen (ABG) and vitamin C as well as on the sensory quality of sauerkraut was investigated. The effect of storage at 4 degrees C for 1-3 months was also studied. ABG content increased from 14 micromol/100 g of dm in raw cabbage to 63 137 micromol/100 g of dm during fermentation, whereas vitamin C decreased from 354 to 236-277 mg/100 g of dm, and the variations depended on the fermentation conditions. Sauerkrauts obtained by Leuconostoc mesenteroides at 0.5% NaCl showed the highest ABG content and a large amount of vitamin C. Refrigeration for 1-3 months led to a reduction of ABG and vitamin C levels, but L. mesenteroides sauerkrauts presented considerable amounts of both compounds at the end of the storage period (74-82 micromol/100 g of dm and 33-44 mg/100 g of dm, respectively), higher than those found with Lactobacillus plantarum and the mixed starter culture before storage. Experimental sauerkrauts presented better organoleptic properties than the commercial products, and no differences in overall acceptability were found among natural fermentations and those performed with starter cultures. These results suggest than low-salted sauerkraut produced with L. mesenteroides provided highly beneficial antioxidant and anticarcinogenic compounds and low sodium content, which is in accordance with the general trend in industrialized countries of reducing the salt level of foods to prevent cardiovascular diseases. PMID- 20170113 TI - Quantification of immunoglobulin g in bovine and caprine milk using a surface plasmon resonance-based immunosensor. AB - Detection of colostrum in bovine and caprine milks is essential for dairy industries to avoid negative economical and technological consequences. One of the best markers of the presence of colostrum is immunoglobulin G (IgG). Two quantification methods have been evaluated for IgG in bovine or caprine milk, based on the real-time immunodetection of IgG by surface plasmon resonance (SPR) spectroscopy. Calibration curves were established by extracting affinity data from the sensorgrams, either using the residual bound IgG level after the association and dissociation phases or using the IgG binding rate during the association phase. The binding rate method allows for substantially reduced analysis times of below 4 min, which make it compatible with the milking time of small ruminants. Moreover, the binding rate method showed a better analytical performance, with lower detection limit and higher precision and accuracy than the residual binding method. PMID- 20170114 TI - Characterization of the adhesive plaque of the barnacle Balanus amphitrite: amyloid-like nanofibrils are a major component. AB - The nanoscale morphology and protein secondary structure of barnacle adhesive plaques were characterized using atomic force microscopy (AFM), far-UV circular dichroism (CD) spectroscopy, transmission Fourier transform infrared (FTIR) spectroscopy, and Thioflavin T (ThT) staining. Both primary cement (original cement laid down by the barnacle) and secondary cement (cement used for reattachment) from the barnacle Balanus amphitrite (= Amphibalanus amphitrite) were analyzed. Results showed that both cements consisted largely of nanofibrillar matrices having similar composition. Of particular significance, the combined results indicate that the nanofibrillar structures are consistent with amyloid, with globular protein components also identified in the cement. Potential properties, functions, and formation mechanisms of the amyloid-like nanofibrils within the adhesive interface are discussed. Our results highlight an emerging trend in structural biology showing that amyloid, historically associated with disease, also has functional roles. PMID- 20170115 TI - Controlling factors for C-H functionalization versus cyclopropanation of dihydronaphthalenes. AB - Rhodium(II)-catalyzed reactions of vinyldiazoacetates with dihydronaphthalenes were systematically studied. These substrates underwent cyclopropanantion and/or the combined C-H activation/Cope rearrangement in good overall yield and with good diastereo- and enantiocontrol. The selectivity of these reactions was profoundly influenced by the nature of the chiral catalyst, the vinyldiazoacetate, and the dihydronaphthalene. The best combinations for achieving the highest selectivity in the cyclopropanation and the combined C-H activation/Cope rearrangement of 1,2-dihydronaphthalenes are methyl 2-diazopent-3 enoate (2a)/Rh(2)(S-DOSP)(4) and methyl 3-(tert-butyldimethylsilyloxy)-2 diazopent-3-enoate (2b)/Rh(2)(S-PTAD)(4). These combinations are very effective at enantiodivergent reactions of 1-methyl-1,2-dihydronaphthalenes. PMID- 20170116 TI - A phospholipid-PEG2000 conjugate of a vascular endothelial growth factor receptor 2 (VEGFR2)-targeting heterodimer peptide for contrast-enhanced ultrasound imaging of angiogenesis. AB - The transition of a targeted ultrasound contrast agent from animal imaging to testing in clinical studies requires considerable chemical development. The nature of the construct changes from an agent that is chemically attached to microbubbles to one where the targeting group is coupled to a phospholipid, for direct incorporation to the bubble surface. We provide an efficient method to attach a heterodimeric peptide to a pegylated phospholipid and show that the resulting construct retains nanomolar affinity for its target, vascular endothelial growth factor receptor 2 (VEGFR2), for both the human (kinase insert domain-containing receptor - KDR) and the mouse (fetal liver kinase 1 - Flk-1) receptors. The purified phospholipid-PEG-peptide isolated from TFA-based eluents is not stable with respect to hydrolysis of the fatty ester moieties. This leads to the time-dependent formation of the lysophospholipid and the phosphoglycerylamide derived from the degradation of the product. Purification of the product using neutral eluent systems provides a stable product. Methods to prepare the lysophospholipid (hydrolysis product) are also included. Biacore binding data demonstrated the retention of binding of the lipopeptide to the KDR receptor. The phospholipid-PEG2000-peptide is smoothly incorporated into gas filled microbubbles and provides imaging of angiogenesis in a rat tumor model. PMID- 20170117 TI - N-methyl phenylalanine-rich peptides as highly versatile blood-brain barrier shuttles. AB - Here we studied the capacity of N-MePhe-(N-MePhe)(3)-CONH(2), Cha-(N-MePhe)(3) CONH(2), and 2Nal-(N-MePhe)(3)-CONH(2) to carry various drugs (cargos) in in vitro blood-brain barrier (BBB) models in order to determine the versatility of these peptides as BBB-shuttles for drug delivery to the brain. Using SPPS, the peptides were coupled to GABA, Nip, and ALA to examine their passive BBB permeation by means of PAMPA and their lipophilicity by IAMC. Unaided, these nonpermeating drugs alone did not cross the PAMPA barrier and the BBB passively; however, the peptides tested as potential BBB shuttles transferred them by passive transfer through the PAMPA phospholipid. The permeability of peptides that showed the highest permeability in PAMPA, and Ac-N-MePhe-(N-MePhe)(3) CONH(2) as the parent peptide was also examined in bovine brain microvessel endothelial cells (BBMECs). These peptide-based BBB shuttles open up the possibility to overcome the formidable obstacle of the BBB, thereby achieving drug delivery to the brain. PMID- 20170118 TI - An organocatalytic asymmetric chlorolactonization. AB - A reagent controlled organocatalytic enantioselective chlorolactonization reaction has been developed. Several 4-aryl pentenoic acids were cyclized in the presence of 0.1 equiv of (DHQD)(2)PHAL, employing various N-chlorinated hydantoins as the terminal chlorenium source. Ten examples are presented with selectivities ranging from 43 to 90% ee. This work represents the first example of an enantioselective reagent-controlled chlorolactonization that approaches synthetically useful enantioselectivities. PMID- 20170119 TI - Low-temperature rapid synthesis and superconductivity of Fe-based oxypnictide superconductors. AB - Fe-based oxypnictide superconductors were successfully synthesized at lower reaction temperatures and with shorter reaction times made possible by starting with less stable compounds, which provide a larger driving force for reactions. Using ball-milled powders of intermediate compounds, phase-pure superconductors with T(c) above 50 K were synthesized at 1173 K in 20 min. This method is particularly advantageous for retaining F, a volatile dopant that enhances superconductivity. Bulk superconductivity and high upper critical fields up to 392 T in Sm(0.85)Nd(0.15)FeAsO(0.85)F(0.15) were demonstrated. PMID- 20170120 TI - CO2 binding by dynamic combinatorial chemistry: an environmental selection. AB - We now report that a dynamic combinatorial selection approach can quantitatively provide, from trivial building blocks, an architecturally complex organic material, in which carbon dioxide is reversibly but covalently incorporated as a guest with a mass content of 20%. Solid-state analyses combined with covalent disconnection and quantization of the liberated components allowed identification of a three-component monomeric unit repeated within a range of assembled oligomeric adducts whose repartition and binding capacity can be finely tuned through the starting stoichiometries. The self-assembly of these architectures occurs through the simultaneous creation of more than 25 covalent bonds per molecular entity. It appears that the thermodynamic selection is directed by the packing efficiency of these adducts, explaining the spectacular building block discrimination between homologues differing by one carbon unit. This selectivity, combined with the reversible nature of the system, provided pure molecular building blocks after a simple chemical disconnection, promoting CO(2) as a green auxiliary to purify polyaldehyde or polyamine from mixtures of homologous structures. Moreover, the gas template could be expelled as a pure compound under thermodynamic control. This cooperative desorption process yielded back the initial libraries of high molecular diversity with a promising reduction of the energetic costs of capture and recycling. PMID- 20170121 TI - Radical cation of helical, cross-conjugated beta-oligothiophene. AB - The radical cation of carbon-sulfur [7]helicene is configurationally stable in solution at room temperature. In contrast to the radical cations of alpha oligothiophenes, which form diamagnetic pi-dimers at low temperature, the radical cation of this helical, cross-conjugated beta-oligothiophene shows a low propensity toward dimerization. PMID- 20170122 TI - Crossbyanols A-D, toxic brominated polyphenyl ethers from the Hawai'ian bloom forming Cyanobacterium Leptolyngbya crossbyana. AB - Periodically, the marine cyanobacterium Leptolyngbya crossbyana forms extensive blooms on Hawai'ian coral reefs and results in significant damage to the subtending corals. Additionally, corals near mats of this cyanobacterium, but not directly overgrown, have been observed to undergo bleaching. Therefore, samples of this cyanobacterium were chemically investigated for bioactive secondary metabolites that might underlie this toxicity phenomenon. (1)H NMR spectroscopy guided fractionation led to the isolation of four heptabrominated polyphenolic ethers, crossbyanols A-D (1-4). Structure elucidation of these compounds was made challenging by their very low proton to carbon (H/C) ratio, but was completed by combining standard NMR and MS data with 2 Hz-optimized HMBC data. Derivatization of crossbyanol A as the diacetate assisted in the assignment of its structure. Crossbyanol B (2) showed antibiotic activity with an MIC value of 2.0-3.9 microg/mL against methicillin-resistant Staphylococcus aureus (MRSA) and relatively potent brine shrimp toxicity (IC(50) 2.8 ppm). PMID- 20170123 TI - Unraveling mechanistic events in solids-stabilized emulsion polymerization by monitoring the concentration of nanoparticles in the water phase. AB - The fate of nanoparticles used as stabilizers in solids-stabilized, or Pickering, emulsion polymerization for the formation of armored hybrid polymer latexes was studied. We showed that disk centrifugation can be used as a powerful quantitative tool to analyze and determine the concentration of nanoparticles in the water phase throughout solids-stabilized emulsion polymerizations. We performed a series of emulsion polymerizations using vinyl acetate, vinyl pivalate, methyl methacrylate, or butyl acrylate in presence of silica nanoparticles (Ludox TM-40, ca. 25 nm in diameter). The developed method to quantify the number of silica nanoparticles in the water phase proved to be an invaluable tool for determining key features of the polymerization process. The obtained concentration profiles versus monomer conversion explained the existence of limited coalescence of armored particles in the later stages of the solids stabilized emulsion polymerization process of vinyl acetate, leading to nonspherical structures. Moreover, we demonstrated that the correlation of the measured number of silica nanoparticles present in the water phase with the average particle sizes of the latex particles provided excellent predictions for the coverage of the armored layer of nanoparticles on the surfaces of the polymer particles, corresponding to observed packing patterns. PMID- 20170124 TI - Stress-transfer in anisotropic and environmentally adaptive cellulose whisker nanocomposites. AB - Quantitative insights into the stress-transfer mechanisms that determine the mechanical properties of tunicate cellulose whisker/poly(vinyl acetate) nanocomposites were gained by Raman spectroscopy. The extent of stress-transfer is influenced by local orientation (or anisotropy) of the whiskers, which in turn is governed by the processing conditions used to fabricate the nanocomposites. Solution-cast materials display no microscopic anisotropy, while samples that were cast and subsequently compression molded contain both isotropic regions as well as domains of locally oriented whiskers. Polarized optical microscopy showed these regions to have dimensions in the hundreds of mum. Polarized Raman spectroscopy of the 1095 cm(-1) Raman band, associated with C-O ring stretching of the cellulose backbone, was used to quantify the local orientation of the cellulose whiskers. Clear and discernible shifts of this Raman band upon uniaxial deformation of nanocomposite films were further used to determine the level of stress experienced by the cellulose whiskers, ultimately reflecting the levels of stress-transfer predominantly between the poly(vinyl acetate) matrix and the tunicate whiskers, but also between the whiskers within the network. In the isotropic regions, where whiskers form a percolating network, the observed Raman shift rate with respect to strain is smaller than in the regions where the whiskers are uniaxially orientated. The Raman shift is strongly affected by the presence of water, leading to a lack of stress-transfer when the samples are fully hydrated, which is clearly detected by the Raman technique. Heating of the nanocomposites above the glass transition temperature of the poly(vinyl acetate) matrix also reduces the stress experienced by the individual whiskers. PMID- 20170125 TI - Importance of alanine at position 178 in proteorhodopsin for absorption of prevalent ambient light in the marine environment. AB - It is usually assumed that only amino acids located near the retinal chromophore are responsible for color tuning of rhodopsins. However, we recently found that replacement of Ala178 with Arg in the E-F loop of proteorhodopsin (PR), an archaeal-type rhodopsin in marine bacteria, shifts the lambda(max) from 525 to 545 nm at neutral pH [Yoshitsugu, M., Shibata, M., Ikeda, D., Furutani, Y., and Kandori, H. (2008) Angew. Chem., Int. Ed. 47, 3923-3926]. Since the location of Ala178 is distant from the retinal chromophore (approximately 25 A), the molecular mechanism of the unusual mutation effect on color tuning is intriguing. A recent mutation study revealed that the observed color change was highly specific to position 178 [Yoshitsugu, M., Yamada, J., and Kandori, H. (2009) Biochemistry 48, 4324-4330]. Thus, in the study presented here, we replaced Ala178 with 19 different amino acids and measured the absorption spectra and the pK(a) of the Schiff base counterion, Asp97. Most of the mutants exhibited a spectral red shift and increased pK(a) of Asp97. None of charged amino acids at position 178 influences color tuning of PR specifically, being similar to the Arg replacement studied earlier. Only Cys and Thr replacements exhibited color and a pK(a) similar to that of the wild type. Ser, Val, and Gly mutants behave like the wild type only with respect to the lambda(max) of the species with deprotonated Asp97. We conclude that the E-F loop region contains a unique structure in PR, disruption of which causes large-scale rearrangement of alpha-helices. Ala178 in PR contributes to the blue-shifted absorption (525 nm at neutral pH) and lowering of the counterion pK(a), which is important for proton-pump function in the marine environment, even though its position is far removed from the chromophore binding domain. PMID- 20170126 TI - Nucleophile specificity in anthranilate synthase, aminodeoxychorismate synthase, isochorismate synthase, and salicylate synthase. AB - Anthranilate synthase (AS), aminodeoxychorismate synthase (ADCS), isochorismate synthase (IS), and salicylate synthase (SS) are structurally homologous chorismate-utilizing enzymes that carry out the first committed step in the formation of tryptophan, folate, and the siderophores enterobactin and mycobactin, respectively. Each enzyme catalyzes a nucleophilic substitution reaction, but IS and SS are uniquely able to employ water as a nucleophile. Lys147 has been proposed to be the catalytic base that activates water for nucleophilic attack in IS and SS reactions; in AS and ADCS, glutamine occupies the analogous position. To probe the role of Lys147 as a catalytic base, the K147Q IS, K147Q SS, Q147K AS, and Q147K ADCS mutants were prepared and enzyme reactions were analyzed by high-performance liquid chromatography. Q147K AS employs water as a nucleophile to a small extent, and the cognate activities of K147Q IS and K147Q SS were reduced approximately 25- and approximately 50-fold, respectively. Therefore, Lys147 is not solely responsible for activation of water as a nucleophile. Additional factors that contribute to water activation are proposed. A change in substrate preference for K147Q SS pyruvate lyase activity indicates Lys147 partially controls SS reaction specificity. Finally, we demonstrate that AS, ADCS, IS, and SS do not possess chorismate mutase promiscuous activity, contrary to several previous reports. PMID- 20170127 TI - Platinum-based nanostructured materials: synthesis, properties, and applications. PMID- 20170130 TI - A temperature-induced narrow DNA curvature range sustains the maximum activity of a bacterial promoter in vitro. AB - Among the molecular strategies bacteria have set up to quickly match their transcriptional program to new environments, changes in sequence-mediated DNA curvature play a crucial role. Bacterial promoters, especially those of mesophilic bacteria, are in general preceded by a curved region. The marked thermosensitivity of curved DNA stretches allows bacteria to rapidly sense outer temperature variations and affects transcription by favoring the binding of activators or repressors. Curved DNA is also able to influence the transcriptional activity of a bacterial promoter directly, without the involvement of trans-acting regulators. This study attempts to quantitatively analyze the role of DNA curvature in thermoregulated gene expression using a real time in vitro transcription model system based on a specific fluorescence molecular beacon. By analyzing the temperature-dependent expression of a reporter gene in a construct carrying a progressively decreasing bent sequence upstream from the promoter, we show that with a decrease in temperature a narrow curvature range accounts for a significant enhancement of promoter activity. This strengthens the view that DNA curvature-mediated regulation of gene expression is likely a strategy offering fine-tuning control possibilities and that, considering the widespread presence of curved sequences upstream from bacterial promoters, it may represent one of the most primitive forms of gene regulation. PMID- 20170128 TI - Molecular gastronomy: a new emerging scientific discipline. PMID- 20170131 TI - Detergent effects on membranes at subsolubilizing concentrations: transmembrane lipid motion, bilayer permeabilization, and vesicle lysis/reassembly are independent phenomena. AB - Soluble amphiphiles, or detergents, are known to produce a number of structural and dynamic effects on membranes, even at concentrations below those causing membrane solubilization (i.e. in the so-called stage I of detergent-membrane interaction). The main subsolubilizing detergent effects on membranes are transmembrane lipid motion (flip-flop), breakdown of the membrane permeability barrier (leakage), and vesicle lysis/reassembly. For a proper understanding of membrane solubilization by detergents, it is important to assess whether the various effects seen at subsolubilizing surfactant concentrations occur independently from each other or are interconnected by cause-effect relationships so that they can be interpreted as necessary steps in the overall process of solubilization. To answer this question, we have explored the three above mentioned effects (i.e., flip-flop, leakage, and lysis/reassembly) apart from solubilization in model (large unilamellar vesicles) and cell (erythrocyte) membranes. Five structurally different surfactants, namely, chlorpromazine, imipramine, Triton X-100, sodium dodecylsulfate, and sodium deoxycholate have been used. Each of them behaves in a unique way. Our results reveal that lipid flip-flop, vesicle leakage, and vesicle lysis/reassembly occur independently between them and with respect to bilayer solubilization so that they cannot be considered to be necessary parts of a higher-order unified process of membrane solubilization by detergents. PMID- 20170129 TI - Phage display in molecular imaging and diagnosis of cancer. PMID- 20170132 TI - Visualizing materials chemistry at atomic resolution. AB - Analytical electron microscopy--empowered by advances in electron optics and detectors--is poised to radically transform our understanding of the complex phenomena arising from atomic and electronic structure in materials chemistry. (To listen to a podcast about this article, please go to the Analytical Chemistry multimedia page at pubs.acs.org/page/ancham/audio/index.html.). PMID- 20170133 TI - Exfoliation of graphene from graphite and their self-assembly at the oil-water interface. AB - High-quality graphene flakes have been exfoliated directly from graphite by solvothermal treatment. By introducing the oil/water interface, graphene can be easily and quickly separated from the graphene/NMP solution, which overcomes shortcomings of the time-consuming method of filtration. At the same time, the graphene film can be fabricated at the oil/water interface by controlling the volume of graphene/NMP solution. Furthermore, carbon nanotube/carbon nanospheres films can also be prepared successfully through the same separation method. PMID- 20170135 TI - Predicting oral druglikeness by iterative stochastic elimination. AB - Integration of computational methods in the early stages of drug discovery has been one of the key trends in the pharmaceutical industry. Starting with high quality drug candidates should ultimately minimize clinical attrition rates and give rise to higher success rates. In this paper, we present a novel approach for indexing oral druglikeness of compounds. With the Iterative Stochastic Elimination (ISE) Algorithm, we distinguish between orally available drugs and nondrugs by generating sets of optimized descriptors' ranges, each set constituting a "filter". We delineate in this paper how to produce an ensemble of best k-descriptor sets out of the huge number of possibilities, and how to construct a "filter bank" that retains diverse filters by clustering. Finally, we define the "orally bioavailable drug-like" character of individual molecules by combining the filters into an "Orally Bioavailable Druglike Index" (OB-DLI) which may be used to prioritize molecules in databases and discuss its uses in several potential applications. The predictive power with sets of 4-6 descriptors is high (i.e., one filter of 5 descriptors retrieved 81% true positives and >77% true negatives). Thus, OB-DLI has advantages over binary decisions (that use only one filter) not only in raising discriminative power but also in ranking drug candidates according to their chance to be successful oral drugs. We demonstrate the ability of our approach to discover molecular entities with the required property, orally bioavailable drug likeness, that are structurally dissimilar to those of the training set. Comparison of this ISE application to some of the current main methods for classification reveals that our approach has >13% improvement in the Matthews Correlation Coefficient, which measures the success of identifying true and false positives and negatives. PMID- 20170134 TI - Surface plasmon resonance analysis of antibiotics using imprinted boronic acid functionalized Au nanoparticle composites. AB - Au nanoparticles (NPs) are functionalized with thioaniline electropolymerizable groups and (mercaptophenyl)boronic acid. The antibiotic substrates neomycin (NE), kanamycin (KA), and streptomycin (ST) include vicinal diol functionalities and, thus, bind to the boronic acid ligands. The electropolymerization of the functionalized Au NPs in the presence of NE, KA, or ST onto Au surfaces yields bisaniline-cross-linked Au NP composites that, after removal of the ligated antibiotics, provide molecularly imprinted matrixes which reveal high sensitivities toward the sensing of the imprinted antibiotic analytes (detection limits for analyzing NE, KA, and ST correspond to 2.00 +/- 0.21 pM, 1.00 +/- 0.10 pM, and 200 +/- 30 fM, respectively). The antibiotics are sensed by surface plasmon resonance (SPR) spectroscopy, where the coupling between the localized plasmon of the NPs and the surface plasmon wave associated with the Au surface is implemented to amplify the SPR responses. The imprinted Au NP composites are, then, used to analyze the antibiotics in milk samples. PMID- 20170136 TI - Redox induced electron transfer in doublet azo-anion diradical rhenium(II) complexes. Characterization of complete electron transfer series. AB - Reactions of dirhenium decacarbonyl with the two azoaromatic ligands, L(a) = (2 phenylazo)pyridine and L(b) = (4-chloro-2-phenylazo)pyridine (general abbreviation of the ligands is L) afford paramagnetic rhenium(II) complexes, [Re(II)(L(*-))(2)(CO)(2)] (1) (S = 1/2 ground state) with two one-electron reduced azo-anion radical ligands in an octahedral geometrical arrangement. At room temperature (300 K) the complexes 1a-b, showed magnetic moments (mu(eff)) close to 1.94 mu(B), which is suggestive of the existence of strong antiferromagnetic interactions in the complexes. The results of magnetic measurements on one of the complexes, 1b, in the temperature range 2-300 K are reported. The above complexes showed two cathodic and two anodic responses in cyclic voltammetry where one-electron oxidation leads to an unusual redox event involving simultaneous reduction of the rhenium(II) and oxidation of the second ligand via intramolecular electron transfer. The oxidized complexes 1a(+) and 1b(+) are air stable and were isolated as crystalline solids as their tri-iodide (I(3)(-)) salts. The structures of the two representative complexes, 1b and [1b]I(3), as determined by X-ray crystallography, are compared. The anionic complexes, [1](-) and [1](2-) were characterized in solution by their spectral properties. PMID- 20170137 TI - Crossed-beam investigation of O(3P) + C2H5 --> C2H4 + OH. AB - The reaction dynamics of ground-state atomic oxygen [O((3)P)] with an ethyl radical (C(2)H(5)) in the gas phase was investigated using high-resolution laser spectroscopy in a crossed-beam configuration. An exothermic channel of O((3)P) + C(2)H(5) --> C(2)H(4) + OH was identified, and the nascent distributions of OH (X (2)Pi: upsilon'' = 0, 1) showed significant internal excitations with an unusual bimodal feature of low and high rotational N''-components with neither spin-orbit nor Lambda-doublet propensities. On the basis of the ab initio and statistical calculations, the reaction mechanism can be rationalized by two competing mechanisms: abstraction vs addition. The low N''-components with significant vibrational excitation can be described in terms of the direct abstraction process as a major channel. The extraordinarily hot rotational distribution of high N''-components implies that a portion of the fraction proceeds through the indirect short-lived addition-complex forming process. From the comparative analysis of the reactions of O((3)P) + several hydrocarbon molecules and radicals, the reactivity and mechanistic characteristics of the title reaction are discussed. PMID- 20170138 TI - Electronic energy migration on different time scales: concentration dependence of the time-resolved anisotropy and fluorescence quenching of Lumogen Red in poly(methyl methacrylate). AB - Electronic energy transfer plays an important role in many types of organic electronic devices. Forster-type theories of exciton diffusion provide a way to calculate diffusion constants and lengths, but their applicability to amorphous polymer systems must be evaluated. In this paper, the perylenediimide dye Lumogen Red in a poly(methyl methacrylate) host matrix is used to test theories of exciton motion over Lumogen Red concentrations (C(LR)'s) ranging from 1 x 10(-4) to 5 x 10(-2) M. Two experimental quantities are measured. First, time-resolved anisotropy decays in films containing only Lumogen Red provide an estimate of the initial energy transfer rate from the photoexcited molecule. Second, the Lumogen Red lifetime decays in mixed systems where the dyes Malachite Green and Rhodamine 700 act as energy acceptors are measured to estimate the diffusive quenching of the exciton. From the anisotropy measurements, it is found that theory accurately predicts both the C(LR)(-2) concentration dependence of the polarization decay time tau(pol), as well as its magnitude to within 30%. The theory also predicts that the diffusive quenching rate is proportional to C(LR)(alpha), where alpha ranges between 1.00 and 1.33. Experimentally, it is found that alpha = 1.1 +/- 0.2 when Malachite Green is used as an acceptor, and alpha = 1.2 +/- 0.2 when Rhodamine 700 is the acceptor. On the basis of the theory that correctly describes the anisotropy data, the exciton diffusion constant is projected to be 4-9 nm(2)/ns. By use of several different analysis methods for the quenching data, the experimental diffusion constant is found to be in the range of 0.32 1.20 nm(2)/ns. Thus the theory successfully describes the early time anisotropy data but fails to quantitatively describe the quenching experiments which are sensitive to motion on longer time scales. The data are consistent with the idea that orientational and energetic disorder leads to a time-dependent exciton migration rate, suggesting that simple diffusion models cannot accurately describe exciton motion within this system. PMID- 20170139 TI - Desorption of polycyclic aromatic hydrocarbons from soot surface: five- and six ring (C22, C24) PAHs. AB - The kinetics of thermal desorption of five soot-bound nonvolatile (C(22), C(24)) polycyclic aromatic hydrocarbons (benzo(ghi)perylene (BghiP), indeno(1,2,3 cd)pyrene (IdP), anthanthrene (Antha), dibenz(ah)anthracene (DBahA), dibenzo(ae)pyrene (DBaeP)) identified in laboratory-generated kerosene soot were studied over the temperature range 335-370 K in a low pressure flow reactor. The PAH desorption rate constants were measured using off-line HPLC monitoring of their concentrations in soot samples as a function of desorption time. The following Arrhenius expressions were determined for the desorption rate constants of the soot-bound PAHs studied: k(des) = 8.4 x 10(15) exp[-(129.7 +/- 4.4)/RT], 1.0 x 10(16) exp[-(130.6 +/- 6.1)/RT], 1.1 x 10(16) exp[-(131.6 +/- 3.2)/RT], 1.0 x 10(16) exp[-(128.0 +/- 3.9)/RT], and 1.4 x 10(16) exp[-(134.2 +/- 10.7)/RT] (k(des) are in s(-1) and activation energies in kJ mol(-1)) for BghiP, IdP, Antha, DBahA, and DBaeP, respectively. Analysis of the present and previous experimental data showed that PAH-soot binding energies linearly correlate with the number of PAH carbon atoms. The present data and those from previous studies are discussed in the frame of the existing theoretical gas-to-particle partitioning model. PMID- 20170140 TI - Nanoparticles from lipid-based liquid crystals: emulsifier influence on morphology and cytotoxicity. AB - Here, monoolein-based nanoparticles (NPs), obtained through fragmentation of bulk liquid crystalline phases, and stabilized by two different emulsifiers, namely, Pluronic F127 (PF127) and lauroylcholine chloride (LCh), are investigated for structural features and for short-term in vitro cytotoxicity. Depending on the emulsifiers, different morphologies of the lipid NPs (cubosomes and liposomes) are obtained, as demonstrated by cryo-TEM images. Although NPs offer many advantages in medical applications and various chemicals used for their preparation are under investigation, so far there are no standardized procedures to evaluate cell biocompatibility. Two different protocols to evaluate the impact of these lipid NPs on biological systems are presented. Results show that nanoparticles stabilized by PF127 (cubosomes) display a relevant toxicity toward different cell lines, whereas those stabilized by LCh (liposomes) affect cell viability at a much lesser extent. PMID- 20170141 TI - Photophysical properties of coordination-driven self-assembled metallosupramolecular rhomboids: experimental and theoretical investigations. AB - In this work, the photophysical properties of coordination-driven self-assembled metallosupramolecular rhomboids with the donor ligands 1,2-bis(3-pyridyl)ethyne (3a) and 1,4-bis(3-pyridyl)-1,3-butadiyne (3b) are investigated by use of both spectroscopic experiments and quantum chemistry calculations. All the geometric conformations of the chair and boat conformers of 3a and 3b are fully optimized using density functional theory. The time-dependent density functional theory method was also used to study the excited-state properties of these self assembled metallosupramolecular rhomboids. At the same time, steady-state absorption and fluorescence as well as the time-correlated single photon counting techniques are used to measure their various spectral properties. The fluorescence spectra of these self-assembled metallosupramolecular rhomboids are very wide and show an evident two-peak feature, which can be tuned by different excitation wavelengths. It has been demonstrated that the chair conformers of both 3a and 3b are formed preferentially over their boat conformers due to the close proximity of the chelated bisphosphine platinum groups. Moreover, an additional shoulder observed at 416 nm in the fluorescence spectra of 3b indicates the presence of minor amounts of the boat conformer of 3b. In addition, we have also demonstrated that lengthening the acetylene chain of the donor ligand component of these rhomboids results in a red-shifted and broadened absorption band for these metallosupramolecular rhomboids. Furthermore, the nature of the excited states for these metallosupramolecular rhomboids varies with the acetylene chain length of the donor ligands and with the different conformers. PMID- 20170142 TI - Analysis of ion transport in nanofiltration using phenomenological coefficients and structural characteristics. AB - The analysis of salt transport in nanofiltration using extended Nernst-Planck equations or similar models often suffers from the difficulties to establish and independently and transparently verify the consistency between the filtration results, assumed mechanism, and fitted values of parameters. As a general alternative, we propose here a procedure that reduces filtration data to two general phenomenological coefficients, concentration-dependent salt permeability omega(s) and Peclet coefficient A, which does not require that a specific exclusion mechanism be assumed and thus allows a transparent test on consistency with commonly used models. This approach was demonstrated using concentration polarization-corrected filtration data for NF-200 membrane and four monovalent salts, NaCl, NaBr, KBr, and KCl. The coefficient A was found to be very small, which points to the negligible contribution of convection to salt transport. The smallness of A was verified through estimates of the effective pore radius of the membrane, found to be between 0.2 and 0.3 nm, and comparing them with similar independent estimates from the hydraulic permeability L(p) using the data on the thickness and swelling of the selective polyamide layer obtained by AFM. The concentration dependence of omega(s) and its variation for different salts suggested that in the concentration range above 0.01 M the salt exclusion may be dominated by a combination of Donnan and dielectric mechanisms. The values of omega(s) obtained for single salts were also consistent with the selectivity observed for equimolar feed mixtures of NaCl and NaBr. However, the observed variation of omega(s) with concentrations of single salts below 0.01 M reveals a new regime that is inconsistent with all commonly used models of NF based on a Donnan mechanism modified with dielectric and steric effects. In particular, omega(s) appeared to approach a constant value at low salt concentrations, whereas the standard mechanisms predict a linear or even steeper decrease as concentration decreases. This puzzling discrepancy could have passed unnoticed in the standard multiparameter fitting extended Nernst-Planck equations and demonstrates the benefits of the present phenomenological analysis. PMID- 20170143 TI - Sums and densities of fully coupled anharmonic vibrational states: a comparison of three practical methods. AB - Three practical methods for computing sums and densities of states of fully coupled anharmonic vibrations are compared. All three methods are based on the standard perturbation theory expansion for the vibrational energy. The accuracy of the perturbation theory expansion is tested by comparisons with computed eigenvalues and/or experimental vibrational constants taken from the literature for three- and four-atom molecules. For a number of examples, it is shown that the X(ij) terms in the perturbation theory expansion account for most of the anharmonicity, and the Y(ijk) terms also make a small contribution; contributions from the Z(ijkl) terms are insignificant. For molecules containing up to approximately 4 atoms, the sums and densities of states can be computed by using nested DO-loops, but this method becomes impractical for larger species. An efficient Monte Carlo method published previously is both accurate and practical for molecules containing 3-6 atoms but becomes too slow for larger species. The Wang-Landau algorithm is shown to be practical and reasonably accurate for molecules containing approximately 4 or more atoms, where the practical size limit (with a single computer processor) is currently on the order of perhaps 50 atoms. It is shown that the errors depend mostly on the average number of stochastic samples per energy bin. An automated version of the Wang-Landau algorithm is described. Also described are the effects of Fermi resonances and procedures for deperturbation of the anharmonicity coefficients. Computer codes based on all three algorithms are available from the authors and can also be downloaded freely from the Internet (http://aoss.engin.umich.edu/multiwell/). PMID- 20170144 TI - Selective deprotection of methanesulfonamides to amines. AB - Methanesulfonamides were deprotected to their parent amines via deprotonation and oxygenation with O(2) (g), even in the presence of other traditional sulfonamides. PMID- 20170145 TI - Two new quinochalcones from the florets of Carthamus tinctorius. AB - Two new quinochalcone compounds, named saffloquinoside A (1) and saffloquinoside B (2), were isolated from the florets of Carthamus tinctorius. Their unusual structures including their absolute stereochemistry were elucidated based on UV, IR, HRESIMS, 1D and 2D NMR data, and CD spectrum. Saffloquinoside A has an uncommon six-five member dioxaspirocycle and saffloquinoside B has a cyclohexatrione skeleton with a benzyl group and two C-glycosyl units. Saffloquinoside A exhibited middling anti-inflammatory activity. PMID- 20170146 TI - Highly diastereoselective Pd-catalyzed carboetherification reactions of acyclic internal alkenes. Stereoselective synthesis of polysubstituted tetrahydrofurans. AB - A highly diastereoselective synthesis of substituted tetrahydrofurans bearing stereocenters at C2 and C1' via Pd-catalyzed carboetherification reactions of acyclic internal alkenes is described. Use of an improved catalyst composed of Pd(2)(dba)(3)/S-Phos provides products with up to >20:1 dr. The stereoselective preparation of tetrahydrofurans containing three stereocenters, including a molecule structurally related to simplakidine A, is also reported. PMID- 20170147 TI - Heavyweight "R-SMS-Phos" ligands in the olefins' hydrogenation arena. AB - A series of enantiopure P-stereogenic 1,2-bis[(o-RO phenyl)(phenyl)phosphino]ethane (R-SMS-Phos) ligands wherein R = i-Pr, i-Bu, t Bu, 3-Pen, and CH(2)TMS was assessed in the Rh(I)-catalyzed hydrogenation of an indicative set of olefins. The best performing t-Bu-SMS-Phos ligand was screened against a wide range of representative classes of standard and new olefinic substrates such as dehydroamido esters, dehydro-alpha-amido-phosphonates, enamides, itaconates, acrylates, enol acetates, alpha-phosphonovinyl benzoates, alpha-(2-pyridyl N-oxide)styrenes, and alpha-(1-hydroxyliminoethyl)styrenes. Excellent enantioselectivities and high TOFs were attained under mild conditions. PMID- 20170148 TI - Contrasting solvent polarity effect on the photophysical properties of two newly synthesized aminostyryl dyes in the lower and in the higher solvent polarity regions. AB - Solvent polarity effect on the photophysical properties of two newly synthesized aminostyryl-thiazoloquinoxaline dyes, one with a flexible diphenylamino group, namely, N,N-diphenyl-4-[2-(thiazolo[4,5-b]quinoxalin-2-yl)vinyl]aniline (TQ1), and the other with a rigid julolidinylamino group, namely, (9-[2-(thiazolo[4,5 b]quinoxalin-2-yl)vinyl]julolidine) (TQ2), have been investigated in different aprotic solvents and solvent mixtures. From the polarity dependent changes in the absorption and fluorescence spectral properties, it is indicated that the fluorescent states of the dyes are of intramolecular charge transfer (ICT) character. For both the dyes, the photophysical properties like fluorescence quantum yields (Phi(f)), fluorescence lifetimes (tau(f)), radiative rate constants (k(f) = Phi(f)/tau(f)), and nonradiative rate constants (k(nr) = 1/tau(f) - Phi(f)/tau(f)) show clearly contrasting solvent polarity effects in the lower and in the higher solvent polarity region, causing an interesting reversal in the properties below and above an intermediate solvent polarity. It is inferred that the domination of the cis-trans isomerization in the lower solvent polarity region and that of the twisted intramolecular charge transfer (TICT) state formation in the higher solvent polarity region are responsible for the observed contrasting solvent polarity effects on the photophysical properties of the two dyes. As both isomerization and TICT state formation causes an enhancement in the nonradiative decay rate of the excited dyes and both the processes become less significant at the intermediate solvent polarity region, the two dyes show their largest Phi(f) and tau(f) values at intermediate solvent polarities. Suitable mechanistic schemes have been proposed and qualitative potential energy diagrams have been presented to explain the observed results with the changes in the polarity of the solvents used. PMID- 20170150 TI - Triphenylamine-based dyes bearing functionalized 3,4-propylenedioxythiophene linkers with enhanced performance for dye-sensitized solar cells. AB - Introduction of modified 3,4-propylenedioxythiophene units into triphenylamine based dyes is found to enhance light capturing, suppress dye aggregation, and remarkably retard charge recombination in dye-sensitized solar cells. Open circuit voltages of the as-synthesized dyes (approximately 800 mV) are much higher than that with a thiophene congener (720 mV) under similar conditions as a result of self-passivation benefiting from their three-dimensional branched structures. PMID- 20170149 TI - Torquoselective ring closures of chiral amido trienes derived from allenamides. A tandem allene isomerization-pericyclic ring-closure-intramolecular Diels-Alder cycloaddition. AB - A new torquoselective ring-closure of chiral amide-substituted 1,3,5-hexatrienes and its application in tandem with [4 + 2] cycloaddition are described. The trienes were derived via either a 1,3-H or 1,3-H-1,7-H shift of alpha-substituted allenamides, and the entire sequence through the [4 + 2] cycloaddition could be in tandem from allenamides. PMID- 20170151 TI - From poly(3,4-ethylenedioxythiophene) to poly(3,4-phenylenedioxythiophene): impact of the substitution of the ethylene bridge by the phenyl ring on the molecular properties. AB - The structural and electronic properties of poly(3,4-phenylenedioxythiophene) and poly(3,4-ethylenedioxythiophene) have been studied using quantum mechanical methods. Calculations have been performed considering a series of oligomers up to 12 repeating units in the neutral and cation states, results being used to extrapolate the properties of the two polymers in the undoped and doped states. Moreover, the electronic properties were estimated in the gas phase and acetonitrile solution, the latter solvent being used in the electrogeneration of the two conducting polymers. A detailed analysis of the results indicates that, although the pi-pi* transition energy of poly(3,4-ethylenedioxythiophene) is lower than that of poly(3,4-phenylenedioxythiophene) in the neutral state, the latter behaves as excellent electronic conductor upon p-doping. Accordingly, the oxidized poly(3,4-phenylenedioxythiophene) shows the lowest pi-pi* electron transition energy. PMID- 20170152 TI - Distinguishing ovarian maturity of farmed white sturgeon (Acipenser transmontanus) by Fourier transform infrared spectroscopy: a potential tool for caviar production management. AB - Fourier transform infrared spectroscopy (FT-IR, 4000-400 cm(-1)) was applied to blood plasma of farmed white sturgeon (N = 40) to differentiate and predict the stages of ovarian maturity. Spectral features of sex steroids (approximately 3000 cm(-1)) and vitellogenin (approximately 1080 cm(-1)) were identified. Clear segregation of maturity stages (previtellogenesis, vitellogenesis, postvitellogenesis, and follicular atresia) was achieved using principal component analysis (PCA). Progression of oocyte development in the late phase of vitellogenesis was also monitored using PCA based on changes in plasma concentrations of sex steroid and lipid content. The observed oocyte polarization index (PI, a measure of nuclear migration) was correlated with changes in plasma sex steroid levels revealed by FT-IR PCA results. A partial least squares (PLS) model predicted PI values within the range 0.12-0.40 (R = 0.95, SEP = 2.18%) from differences in spectral features. These results suggest that FT-IR may be a good tool for assessing ovarian maturity in farmed sturgeon and will reduce the need for the invasive ovarian biopsy required for PI determination. PMID- 20170153 TI - Hesperidin upregulates heme oxygenase-1 to attenuate hydrogen peroxide-induced cell damage in hepatic L02 cells. AB - Hesperidin, a naturally occurring flavonoid presents in fruits and vegetables, has been reported to exert a wide range of pharmacological effects that include antioxidant, anti-inflammatory, antihypercholesterolemic, and anticarcinogenic actions. However, the cytoprotection and mechanism of hesperidin to neutralize oxidative stress in human hepatic L02 cells remain unclear. In this work, we assessed the capability of hesperidin to attenuate hydrogen peroxide (H(2)O(2)) induced cell damage by augmenting the cellular antioxidant defense. Real-time quantitative polymerase chain reaction, Western blot, and enzyme activity assay demonstrated that hesperidin upregulated heme oxygenase-1 (HO-1) expression to protect hepatocytes against oxidative stress. In addition, hesperidin also promoted nuclear translocation of nuclear factor erythroid 2-related factor (Nrf2). What's more, hesperidin exhibited activation of extracellular signal regulated protein kinase 1/2 (ERK1/2). Besides, ERK1/2 inhibitor significantly inhibited hesperidin-mediated HO-1 upregulation and Nrf2 nuclear translocation. Taken together, the above findings suggested that hesperidin augmented cellular antioxidant defense capacity through the induction of HO-1 via ERK/Nrf2 signaling. Therefore, hesperidin has potential as a therapeutic agent in the treatment of oxidative stress-related hepatocyte injury and liver dysfunctions. PMID- 20170154 TI - P4 activation by late-transition metal complexes. PMID- 20170155 TI - Synthesis of odd generation triazine dendrimers using a divergent, macromonomer approach. AB - Using a macromonomer, first, third, and fifth generation triazine dendrimers can be prepared using a divergent approach. The nine-step process to the fifth generation target relies on an iterative two-reactions-per-generation strategy to yield the desired material in approximately 48% overall yield. This target displays 96 surface groups. NMR spectroscopy and mass spectrometry show that exceptionally narrow polydispersity is achieved using this strategy. PMID- 20170156 TI - Tailoring the pore alignment for rapid ion transport in microporous carbons. AB - The power density and charge-discharge time of electrical double layer capacitors are largely determined by how fast the electrolyte ions can travel within the carbon electrode particles. Our systematic studies using zeolite-templated carbons show that an enhancement in ion transport rate by more than 2 orders of magnitude is possible by minimizing the micropore tortuosity. Very uniform carbon deposition was achieved using a well-controlled process involving the decomposition of acetylene precursor at a reduced pressure of 10 Torr and under a constant flow rate of 100 sccm. Selected carbon samples with well-aligned, straight micropores demonstrate high specific capacitance of up to 300 F/g and outstanding frequency response of up to 10 Hz for 250 microm thick electrodes, indicating an attractive combination of high specific energy and high specific power in electrical double layer capacitors. Such properties are critical for many peak-power hungry applications, such as the leveling of subsecond disturbances in power lines. Our findings provide guidance for the optimal design of porous carbons with greatly improved power storage characteristics. PMID- 20170157 TI - In situ single-crystal diffraction studies of the structural transition of metal organic framework copper 5-sulfoisophthalate, Cu-SIP-3. AB - The flexibility of the metal-organic framework Cu(2)(OH)(C(8)H(3)O(7)S)(H(2)O) x 2 H(2)O (Cu-SIP-3) toward reversible single-crystal to single-crystal transformations is demonstrated using in situ diffraction methods at variable temperature. At temperatures below a dehydration-induced phase transition (T < 370 K) the structure is confirmed as being hydrated. In the temperature range where the transition takes place (370 K < T < 405 K) no discrete, sharp Bragg peaks can be seen in the single-crystal X-ray diffraction pattern, indicating significant loss of long-range order. At temperatures higher than 405 K, the Bragg peaks return and the structure can be refined as dehydrated Cu-SIP-3. The loss of guest water molecules can be followed at temperatures below the phase transition giving insight into the mechanism of the dehydration. Addition of nitric oxide gas to the material above the gating opening pressure of 275 mbar also leads to loss of Bragg scattering in the diffraction pattern. PMID- 20170158 TI - Silver ion incorporation and nanoparticle formation inside the cavity of Pyrococcus furiosus ferritin: structural and size-distribution analyses. AB - Highly symmetrical protein cage architectures from three different iron storage proteins, heavy and light human ferritin chains (HuHFt and HuLFt) and ferritin from the hyperthemophilic bacterium Pyrococcus furiosus (PfFt), have been used as models for understanding the molecular basis of silver ion deposition and metal core formation inside the protein cavity. Biomineralization using protein cavities is an important issue for the fabrication of biometamaterials under mild synthetic conditions. Silver nanoparticles (AgNPs) were produced with high yields within PfFt but not within HuHFt and HuLFt. To explain the molecular basis of silver incorporation, the X-ray crystal structure of Ag-containing PfFt has been solved. This is the first structure of a silver containing ferritin reported to date, and it revealed the presence of specific binding and nucleation sites of Ag(I) that are not conserved in other ferritin templates. The AgNP encapsulated by PfFt were further characterized by the combined use of different physical chemical techniques. These showed that the AgNPs are endowed with a narrow size distribution (2.1 +/- 0.4 nm), high stability in water solution at millimolar concentration, and high thermal stability. These properties make the AgNP obtained within PftFt exploitable for a range of applications, in fields as diverse as catalysis in water, preparation of metamaterials, and in vivo diagnosis and antibacterial or tumor therapy. PMID- 20170159 TI - Redox transformations and transport of cesium and iodine (-1, 0, +5) in oxidizing and reducing zones of a sand and gravel aquifer. AB - Tracer tests were performed in distinct biogeochemical zones of a sand and gravel aquifer in Cape Cod, MA, to study the redox chemistry (I) and transport (Cs, I) of cesium and iodine in a field setting. Injection of iodide (I(-)) into an oxic zone of the aquifer resulted in oxidation of I(-) to molecular iodine (I(2)) and iodate (10(3)(-)) over transport distances of several meters. Oxidation is attributed to Mn-oxides present in the sediment Transport of injected 10(3)(-) and Cs(+) was retarded in the mildly acidic oxic zone, with retardation factors of 1.6-1.8 for 10(3)(-) and 2.3-4.4 for Cs. Cs retardation was likely due to cation exchange reactions. Injection of 10(3)(-) into a Fe-reducing zone of the aquifer resulted in rapid and complete reduction to I(-) within 3 m of transport. Then on conservative behavior of Cs and I observed during the tracer tests underscores the necessity of taking the redox chemistry of I as well as sorption properties of I species and Cs into account when predicting transport of radionuclides (e.g., (129)I and (137)Cs) in the environment. PMID- 20170160 TI - Economic sources and spatial distribution of airborne chromium risks in the U.S. AB - We present a model that integrates the economic input-output approach of life cycle assessment with environmental fate, exposure, and risk assessment to estimate the spatial distribution of air toxic health risks due to sector specific economic activity in the U.S. The model is used to relate the economic activity and exposure potential (population density and meteorology) associated with point source emissions of the heavy metal and carcinogen, hexavalent chromium, or Cr(VI), on a county basis. Total direct annual airborne emissions of Cr(VI) in the U.S. were 44 tonnes in 2002, with 97% from facilities in four major sectors: power generation, wood, plastics, and chemicals, metals, and scientific services. These include 6 tonnes of Cr(VI) emitted in the supply chains of these sectors. A highly variable national distribution of lifetime cancer risk is predicted, with a population-weighted mean of 2.7 x 10(-7), but with hot-spot counties with lifetime risks as high as 6 x 10(-6). Furthermore, high exposures and risks tend to occur in more highly populated counties. In particular, the population of Los Angeles County is exposed to the highest level of risk in the country and almost three-quarters of the total predicted cancer incidence due to inhalation of airborne Cr(VI) emissions. This finding can be attributed largely to the use of Cr(VI) as a corrosion inhibitor by the scientific services sector facilities in the county, the use of shorter facility stacks, and their sitting within a highly populated area. These results indicate that linking economic activity, emission estimates, and fate and transport models for air toxics can inform both life cycle impact and comparative health risk assessments, allowing us to better target emission reductions to minimize hot-spots of risk. PMID- 20170161 TI - Chlorinated aromatic compounds in a thermal process promoted by oxychlorination of ferric chloride. AB - The relationship between the formation of chlorinated aromatic (aromatic-Cl) compounds and ferric chloride in the solid phase during a thermal process motivated us to study the chemical characteristics of iron in a model solid sample, a mixture of FeCl(3) x 6H(2)O, activated carbon, and boron nitride, with increasing temperature. Fe K-edge extended X-ray absorption fine structure (EXAFS) spectroscopy revealed drastic changes in the chemical form of amorphous iron, consistent with other analytical methods, such as X-ray diffraction using synchrotron radiation (SR-XRD) and Fourier-transform infrared (FT-IR) spectroscopy. Atomic-scale evidence of the chlorination of aromatic carbon was detected by Cl-K X-ray absorption near edge structure (XANES) spectroscopy. These results showed the thermal formation mechanism of aromatic-Cl compounds in the solid phase with ferric chloride. We attribute the formation of aromatic-Cl compounds to the chlorination of carbon, based on the oxychlorination reaction of FeCl(3) at temperatures in excess of ca. 300 degrees C, when the carbon matrix is activated by carbon gasification, catalyzed by Fe(2)O(3), and surface oxygen complexes (SOC) generated by a catalytic cycle of FeCl(2) and FeOCl. Chemical changes of trace iron in a thermal process may offer the potential to generate aromatic-Cl compounds in the solid phase. PMID- 20170162 TI - Estimation of PCB stocks, emissions, and urban fate: will our policies reduce concentrations and exposure? AB - PCBs, used to manage risks from the flammability of dielectric fluids and to increase the durability of elastic sealants, had declining environmental concentrations after legislation banning new production was passed during the 1970s and 1980s in Europe and North America. To answer why PCB temporal trends are now nearly stable and if current policies will further reduce concentrations and our exposure, we estimated PCB stocks in Toronto, Canada (population of approximately 2.5 million) of 437 (282-796) tonnes, of which 97 and 3% are in closed sources and building sealants, respectively. The greatest geographic density of PCBs is downtown, specifically in commercial, electricity-intensive skyscrapers. An unknown stock is within now-buried landfills and other waste handling facilities as well as diffuse sources such as electrical wiring and paints. Using the Multimedia Urban Model, we estimated city-wide emissions of approximately 0.14-1.4 mg m(-2) y(-1) or 35-350 mg capita(-1) y(-1) of SigmaPCB(70), which is approximately 0.01-0.3% annually of total documented stocks. Canada, as one of 159 signatories of the Stockholm Convention and the 35 parties that have reported progress toward environmentally sound management of their PCB inventories by 2028, has passed national legislation with a timetable of inventory reductions. It is unclear whether this legislation will successfully reduce concentrations and exposures, however the analysis should inform our management of other contaminants. PMID- 20170163 TI - Identification of 2-anilino-9-methoxy-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin 6-ones as dual PLK1/VEGF-R2 kinase inhibitor chemotypes by structure-based lead generation. AB - To develop multikinase inhibitors with dual PLK1/VEGF-R2 inhibitory activity, the d-annulated 1-benzazepin-2-one scaffold present in the paullone family of kinase inhibitors was investigated as a general structure template suitable for anchoring annulated heterocycles at the hinge region of the ATP binding site. For this purpose, the indole substructure of the paullones was replaced by other nitrogen containing heteroaromatics. The designed scaffolds were synthesized and tested on the indicated kinases. The 2-anilino-5,7-dihydro-6H-pyrimido[5,4 d][1]benzazepin-6-ones were found to be VEGF-R2 inhibitors with selectivity against the insulin receptor kinase. The attachment of a methoxy group to the 9 position of the scaffold led to additional PLK1 inhibitory activity, which was explained by an alternative binding mode of the 9-methoxy derivatives. Selected members of the compound class inhibited the VEGF-R2 autophosphorylation in human umbilical vein endothelial cells, the sprouting of human umbilical vein endothelial cell speroids, and the proliferation of diverse cancer cell lines. PMID- 20170164 TI - A new class of naphthalimide-based antitumor agents that inhibit topoisomerase II and induce lysosomal membrane permeabilization and apoptosis. AB - Based on the advantages of multitarget drugs for cancer treatment, a new class of naphthalimides was designed, synthesized, and proved to inhibit topoisomerase II (topo II), induced lysosomal membrane permeabilization (LMP), and ultimately caused apoptosis and cell death. The majority of compounds 7a-d and 8a-d potently inhibited the growth of the five tested cancer cell lines with IC(50) values ranging from 2 to 10 microM and are more active than amonafide, a naphthalimide that was in phase III clinical trials. These compounds were tested for their interactions with DNA and their cell-free topo II inhibition activities, which demonstrated these compounds were weak DNA binders but modest topo II inhibitors. Furthermore, compounds 7b-d were found to notably induce LMP and exhibited better antiproliferative activity compared with their single-target analogues. All of the newly synthesized compounds were demonstrated to efficiently induce apoptosis via a mitochondrial pathway. Accordingly, a new paradigm was suggested for the design of novel multitarget anticancer drugs. PMID- 20170165 TI - Noncovalent tripeptidyl benzyl- and cyclohexyl-amine inhibitors of the cysteine protease caspase-1. AB - Potent and noncovalent inhibitors of caspase-1 were produced by incorporating a secondary amine (reduced amide) isostere in place of the conventional electrophile (e.g., aldehyde) that normally confers high potency to cysteine protease inhibitors. Benzyl- or cyclohexylamines produced potent, reversible, and competitive inhibitors that were selective for caspase-1 (e.g., K(i) = 47 nM) over caspases 3 and 8 with minimal cytotoxicity. Unlike most cysteine protease inhibitors, these compounds do not react covalently and indiscriminately with thiols. PMID- 20170166 TI - Classification of HER2 receptor status in breast cancer tissues by MALDI imaging mass spectrometry. AB - Clinical laboratory testing for HER2 status in breast cancer tissues is critically important for therapeutic decision making. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is a powerful tool for investigating proteins through the direct and morphology-driven analysis of tissue sections. We hypothesized that MALDI-IMS may determine HER2 status directly from breast cancer tissues. Breast cancer tissues (n = 48) predefined for HER2 status were subjected to MALDI-IMS, and protein profiles were obtained through direct analysis of tissue sections. Protein identification was performed by tissue microextraction and fractionation followed by top-down tandem mass spectrometry. A discovery and an independent validation set were used to predict HER2 status by applying proteomic classification algorithms. We found that specific protein/peptide expression changes strongly correlated with the HER2 overexpression. Among these, we identified m/z 8404 as cysteine-rich intestinal protein 1. The proteomic signature was able to accurately define HER2-positive from HER2-negative tissues, achieving high values for sensitivity of 83%, for specificity of 92%, and an overall accuracy of 89%. Our results underscore the potential of MALDI-IMS proteomic algorithms for morphology-driven tissue diagnostics such as HER2 testing and show that MALDI-IMS can reveal biologically significant molecular details from tissues which are not limited to traditional high-abundance proteins. PMID- 20170167 TI - Metabolic depletion of sphingolipids impairs ligand binding and signaling of human serotonin1A receptors. AB - Sphingolipids are essential components of eukaryotic cell membranes and are thought to be involved in a variety of cellular functions. Mycotoxins such as fumonisins can disrupt sphingolipid metabolism, and treatment with fumonisins represents an efficient approach to modulate cellular sphingolipid levels. In this work, we modulated sphingolipid levels in CHO cells stably expressing the human serotonin(1A) receptor by metabolically inhibiting the biosynthesis of sphingolipids using fumonisin B(1). Serotonin(1A) receptors belong to the family of seven-transmembrane domain receptors that couple to G-proteins and are implicated in the generation and modulation of various cognitive, behavioral, and developmental functions. We explored the function of serotonin(1A) receptors under sphingolipid-depleted conditions by monitoring ligand binding, G-protein coupling, and downstream signaling of the receptor. Importantly, our results show that the function of the serotonin(1A) receptor is impaired upon metabolic depletion of sphingolipids, although the membrane receptor level does not exhibit any reduction. Interestingly, we find that the replenishment of sphingolipids using sphingosine results in restoration of ligand binding of serotonin(1A) receptors, demonstrating that the loss of ligand binding due to metabolic depletion of sphingolipids is reversible. These novel results demonstrate that sphingolipids are necessary for ligand binding and downstream signaling of the human serotonin(1A) receptor. We discuss possible mechanisms of specific interaction of sphingolipids with the serotonin(1A) receptor that could involve the proposed "sphingolipid-binding domain" (SBD). PMID- 20170168 TI - Application of supercritical CO(2) extraction for the elimination of odorant volatile compounds from winemaking inactive dry yeast preparation. AB - A procedure based on the application of supercritical CO(2) extraction to reduce and/or to remove odorant volatile compounds from a winemaking inactive dry yeast (IDY) preparation has been set up. By applying a factorial design, a screening of different temperatures and pressure conditions was assayed in order to determine the optimal deodorization conditions, and afterward the effect of several sample pretreatments was investigated. The best extraction conditions were achieved at 200 atm and 60 degrees C, applying the cryogenic grinding of the sample and using 40% (w/w) ethanol as cosolvent. By using these conditions, it was possible to reduce to approximately 70% of the volatile compounds present in the samples that may be released into the wines and therefore affecting their sensory characteristics. Odorant volatile compounds such as 2-methylhydroxypyrrole, 2 ethyl-6-methylpyrazine, and 2,3,5-trimethylpyrazine completely disappeared from the deodorized sample as verified by GC-O analysis. Additional experiments in model wines confirmed the low release of volatile compounds from the deodorized samples, without provoking any change to their nonvolatile composition (nitrogen compounds and neutral polysaccharides) that is related to the technological properties of these preparations. PMID- 20170169 TI - Analysis of perchlorate in milk powder and milk by hydrophilic interaction chromatography combined with tandem mass spectrometry. AB - A simple, selective, and sensitive method using hydrophilic interaction chromatography combined with tandem mass spectrometry (HILIC-MS/MS) for quantifying perchlorate in milk powder and milk was developed. The analysis was conducted on an Inertsil HILIC column (150 mm x 3.0 mm, 3.5 mum) using a mobile phase consisting of methanol and 0.1% formic acid (60:40, v/v). The detection was performed by MS/MS via electrospray ionization. Linear calibration curves were obtained in the concentration range of 2.00 x 10(-2) to 8.00 microg/g and 4.00 x 10(-1) to 20.0 microg/L for perchlorate in milk powder and milk, respectively. The method detection limit was 4.00 x 10(-3) microg/g for milk powder and 8.00 x 10(-2) microg/L for milk. The recoveries of perchlorate in milk powder and milk were all >90%. This method was successfully applied to the quantitative determination of perchlorate in milk powder and milk. PMID- 20170170 TI - Use of attenuated total reflectance midinfrared for rapid and real-time analysis of compositional parameters in commercial white grape juice. AB - A simple and fast midinfrared (MIR) spectroscopy method was developed for simultaneously determining total soluble solids (TSS, degrees Brix), pH, total phenolics, ammonia, free amino nitrogen (FAN), and yeast assimilable nitrogen (YAN) contents in grape juice samples using attenuated total reflectance (ATR). Results from this study demonstrated the capability of ATR-MIR coupled with partial least-squares regression to measure TSS and pH and to monitor FAN, ammonia, and YAN in a wide range of grape juice samples. The standard error in cross-validation and the residual predictive deviation obtained were 0.20 degrees Brix and 9 for TSS, 0.07 and 3.3 for pH, 14.8 mg/L and 2 for ammonia, 28.3 mg/L and 2 for FAN, and 36.9 mg/L and 2 for YAN, respectively. Both the time of analysis and the volume of sample required were considerably reduced as compared to the transmission MIR measurements currently used by the wine industry. PMID- 20170171 TI - Development of a modified Caco-2 cell model system for studying iron availability in eggs. AB - A modified Caco-2 cell model system was developed for studying iron availability in mixtures of fresh and/or cooked foods subjected to a simulated gastrointestinal digestion. The effect of combining foods containing high levels of ascorbic acid with cooked eggs on ferritin expression in the cells was measured. There was no detectable increase in ferritin with eggs alone, indicating that none of the iron was available for uptake into the cells, but when mixed with orange juice or salad (lettuce, tomatoes, and red pepper) in ratios similar to those found in meals, there was a significant increase in ferritin concentration (p = 0.0012 and p = 9.2 x 10(-10), respectively); the enhancing effect of salad was greater than orange juice (p = 0.028). These results suggest that the iron in eggs will be more readily absorbed when consumed with foods high in ascorbic acid. PMID- 20170172 TI - Protein adsorption and cell adhesion/detachment behavior on dual-responsive silicon surfaces modified with poly(N-isopropylacrylamide)-block-polystyrene copolymer. AB - Diblock copolymer grafts covalently attached to surfaces have attracted considerable attention because of their special structure and novel properties. In this work, poly(N-isopropylacrylamide)-block-polystyrene (PNIPAAm-b-PS) brushes were prepared via surface-initiated consecutive atom-transfer radical polymerization on initiator-immobilized silicon. Because of the inherent thermosensitivity of PNIPAAm and the hydrophobicity difference between the two blocks, the modified surfaces were responsive to both temperature and solvent. Moreover, the diblock copolymer brushes exhibited both resistance to nonspecific protein adsorption and unique cell interaction properties. They showed strong protein resistance in both phosphate-buffered saline and blood plasma. In particular, fibrinogen adsorption from plasma at either room temperature or body temperature was less than 8 ng/cm(2), suggesting that the surfaces might possess good blood compatibility. In addition, the adhesion and detachment of L929 cells could be "tuned", and the ability to control the detachment of cells thermally was restored by block polymerization of hydrophobic, cell-adhesive PS onto a thicker PNIPAAm layer. In addition to providing a simple and effective design for advanced cell-culture surfaces, these results suggest new biomedical applications for PNIPAAm. PMID- 20170173 TI - Plasma oxidized polyhydroxymethylsiloxane--a new smooth surface for supported lipid bilayer formation. AB - A novel substrate for preparation of supported lipid bilayers (SLBs), smooth at the subnanometer scale and of variable thickness from ten to several hundred nanometers, was developed by surface oxidation of spin-coated poly(hydroxymethylsiloxane) (PHMS) films. The deposited polymeric thin films were modified by a combination of oxygen plasma and thermal treatment (PHMS(ox)), in order to convert the outermost surface layer of the polymer film to a stable SiO(2) film, suitable for SLB formation. The hydrophilic, SiO(2)-like surfaces were characterized by XPS, wetting angle, ellipsometry, and AFM. Lipid bilayers were formed on this surface using the well-known vesicle adsorption-rupture fusion process, usually performed on glass or vapor-deposited SiO(2). Reproducible formation of homogeneous SLBs of different compositions (POPC, DOEPC, and POPC/DOPS) was demonstrated on the new SiO(2) surface by quartz crystal microbalance with dissipation (QCM-D), surface plasmon resonance (SPR), and optical reflectometry measurements. The SLB formation kinetics on the PHMS(ox)-coated sensors showed very similar characteristics, for all investigated PHMS thicknesses, as on reference sensors coated with vapor-deposited SiO(2). The good adhesive properties of the PHMS to gold allows for the preparation of thin PHMS(ox) layers compatible with SPR. The much smaller roughness at the nanometer scale of the PHMS(ox) surfaces, compared to standard vapor-deposited SiO(2) coated sensors, makes them advantageous for AFM and optical experiments and promising for patterning. To benefit optical experiments with the PHMS(ox) surfaces, it was also investigated how the PHMS film thickness influences the SPR and reflectometry responses upon SLB formation. PMID- 20170174 TI - Direct visualization of the enzymatic digestion of a single fiber of native cellulose in an aqueous environment by atomic force microscopy. AB - Atomic force microscopy (AFM) was used to study native cellulose films prepared from a bacterial cellulose source, Acetobacter xylinum, using a novel application of the Langmuir-Blodgett technique. These films allowed high-resolution AFM images of single fibers and their microfibril structure to be obtained. Two types of experiments were performed. First, the fibers were characterized using samples that were dried after LB deposition. Next, novel protocols that allowed us to image single fibers of cellulose in films that were never dried were developed. This procedure allowed us to perform in situ AFM imaging studies of the enzymatic hydrolysis of single cellulose fibers in solution using cellulolytic enzymes. The in situ degradation of cellulose fibers was monitored over a 9 h period using AFM. These studies provided the first direct, real-time images of the enzymatic degradation of a single cellulose fiber. We have demonstrated the tremendous potential of AFM to study the mechanism of the enzymatic digestion of cellulose and to identify the most effective enzymes for the digestion of various cellulose structures or isomorphs. PMID- 20170175 TI - Sustainable polymerizations in recoverable microemulsions. AB - Free radical and atom-transfer radical polymerizations were conducted in monomer/ionic liquid microemulsions. After the polymerization and isolation of the resultant polymers, the mixture of the catalyst and ionic liquids (surfactant and continuous phase) can be recovered and reused, thereby dramatically improving the environmental sustainability of such chemical processing. The addition of monomer to recovered ionic liquid mixtures regenerates transparent, stable microemulsions that are ready for the next polymerization cycle upon addition of initiator. The method combines the advantages of IL recycling and microemulsion polymerization and minimizes environmental disposable effects from surfactants and heavy metal ions. PMID- 20170176 TI - N-heterocyclic carbene-ruthenium complexes for the racemization of chiral alcohols. AB - The activity of well-defined 16-electron ruthenium complexes bearing an N heterocyclic carbene ligand in the racemization of chiral alcohols is reported. Mechanistic considerations are also presented. PMID- 20170177 TI - Synthesis of a solid solution series of layered Eu(x)Gd(1-x)(OH)2.5Cl0.5 x 0.9 H2O and its transformation into (Eu(x)Gd(1-x))2O3 with enhanced photoluminescence properties. AB - The synthesis of a series of new layered rare-earth hydroxide solid solutions and their transformation into (Eu(x)Gd(1-x))(2)O(3) crystallites are described. Highly crystalline platelets of Eu(x)Gd(1-x)(OH)(2.5)Cl(0.5) x 0.9 H(2)O solid solutions with various Eu(3+)/Gd(3+) ratios were prepared through a homogeneous precipitation method. The hydroxide solid-solution samples exhibited characteristic Eu(3+) photoluminescence properties through the energy transfer from Gd(3+) to Eu(3+) and the self-excitation of Eu(3+). Cubic (Eu(x)Gd(1 x))(2)O(3) crystallites were obtained via quasi-topotactic transformation of Eu(x)Gd(1-x)(OH)(2.5)Cl(0.5) x 0.9 H(2)O solid solutions above 800 degrees C. The as-transformed cubic (Eu(x)Gd(1-x))(2)O(3) crystallites well retained the original platelet morphology and single crystalline nature, and exhibited greatly enhanced photoluminescence properties with respect to the precursor hydroxides. The Eu(3+) content of 0.05 in the cubic (Eu(x)Gd(1-x))(2)O(3) gave a maximum luminescence intensity, which is comparable with that of a commercial Y(2)O(3):Eu phosphor. PMID- 20170178 TI - Partially fluorinated butatrienes: a coupled cluster study. AB - The geometries of 19 different partially fluorinated butatrienes and their related butenyne isomers have been calculated at the Moller-Plesset second order perturbation theory level with Dunning's valence triple-zeta basis set. Final energies were determined at the CCSD(T)/cc-pVQZ level of theory. Increasing fluorine substitution has only a limited effect on the bond lengths but a substantial effect on the angles. The CCC bond angles of 4 of the 5 partially fluorinated butatrienes show a deviation of more than 2 degrees from collinearity, therefore representing angle-strained butatrienes. Increasing degree of fluorination has a substantial effect on the isomerization energies. The energy difference between the least stable enyne nonfluorinated at the acetylenic center and the most stable enyne fluorinated at the acetylenic center decreases from 66.8 kJ/mol, in case of the monofluorinated system, to 29.7 kJ/mol in the triple fluorinated system. The acetylenic F substitution is crucial in raising the energies of fluorinated but-1-en-3-yne relative to their butatriene isomers. Within the triple fluorinated system and unprecedented for all discussed molecules, 1,1,4-trifluoro-but-1-en-3-yne represents the only molecule fluorinated at the acetylenic center that is more stable than its triene isomer. PMID- 20170179 TI - Rapid release of N-linked glycans from glycoproteins by pressure-cycling technology. AB - The standard, well-established sample preparation protocol to release N-linked glycans from glycoproteins for downstream analysis requires relatively long deglycosylation times (from several hours to overnight) and relatively high endoglycosidase concentration (from 1:250 to 1:500 enzyme:substrate molar ratio). In this paper, we significantly improve this standard protocol by the use of pressure-cycling technology (PCT) to increase the speed and decrease the relative amount of PNGase F during the release of N-linked glycans from denatured glycoproteins. With the application of pressure cycling from atmospheric to as high as 30 kpsi, >95% release of the asparagine-linked glycans from bovine ribonuclease B, human transferrin, and polyclonal human immunoglobulin was rapidly achieved in a few minutes using as low as 1:2500 enzyme:substrate molar ratio. The deglycosylation rate was first examined by SDS-PAGE at the protein level. The released glycans were then quantitated by capillary electrophoresis with laser induced fluorescence detection (CE-LIF). This new sample preparation protocol readily supports large-scale glycan analysis of biopharmaceuticals with rapid deglycosylation times. PMID- 20170180 TI - Altering amine basicities in biodegradable branched polycationic polymers for nonviral gene delivery. AB - In this work, biodegradable branched polycationic polymers were synthesized by Michael addition polymerization from different amine monomers and the triacrylate monomer trimethylolpropane triacrylate. The polymers varied in the number of amines that dissociate in different pH ranges, which are considered to be beneficial to different parts of the gene delivery process. P-DED, a polymer synthesized from trimethylolpropane triacrylate and dimethylethylenediamine, had the highest number of protonated amines that are available for plasmid DNA (pDNA) complexation at pH 7.4 of all polymers synthesized. P-DED formed a positive polyplex (13.9 +/- 0.5 mV) at a polymer/pDNA weight ratio of 10:1 in contrast with the other polymers synthesized, which formed positive polyplexes only at higher weight ratios. Polyplexes formed with the synthesized polymers at the highest polymer/pDNA weight ratio tested (300:1) resulted in higher transfection with enhanced green fluorescent protein reporter gene (5.3 +/- 1.0 to 30.6 +/- 6.6%) compared with naked pDNA (0.8 +/- 0.4%), as quantified by flow cytometry. Polyplexes formed with P-DED (weight ratio of 300:1) also showed higher transfection (30.6 +/- 6.6%) as compared with polyplexes formed with branched polyethylenimine (weight ratio of 2:1, 25.5 +/- 2.7%). The results from this study demonstrated that polymers with amines that dissociate above pH 7.4, which are available as positively charged groups for pDNA complexation at pH 7.4, can be synthesized to produce stable polyplexes with increased zeta potential and decreased hydrodynamic size that efficiently transfect cells. This work indicated that polymers containing varying amine functionalities with different buffering capabilities can be synthesized by using different amine monomers and used as effective gene delivery vectors. PMID- 20170181 TI - Lead contamination of subarctic lakes and its response to reduced atmospheric fallout: can the recovery process be counteracted by the ongoing climate change? AB - Can a climate-triggered export of old contaminants from the soil alter the lead (Pb) contaminant burden of subarctic lakes? To address this question, we reconstructed the pollution history of three high latitude lakes situated in a region where a recent climatic shift has occurred. Dated sediment records were used as archives of past Pb inputs to the lakes, where the difference in the (206)Pb/(207)Pb ratio between atmospheric contaminants ((206)Pb/(207)Pb ratio <1.16) and geogenic Pb in the catchment soil ((206)Pb/(207)Pb ratio >1.22) were used to trace fluxes of Pb contaminants. Lead contaminants were found in sediments deposited since Roman times. A significant export of Pb from the soil contaminant pool is indicated in two of the lakes surrounded by near-shore permafrost soils. Here, levels of Pb contaminants and (206)Pb/(207)Pb ratios of sediments deposited after the 1970s appear not to have been strongly affected by the >or=90% reduction in atmospheric deposition rates and increasing (206)Pb/(207)Pb ratios of atmospheric Pb since the 1990s. We concluded that soil processes stimulated by the ongoing climate change at high latitudes might work counteractive to efforts to reduce contaminant levels in subarctic lakes. PMID- 20170182 TI - Small molecule colorimetric probes for specific detection of human arylamine N acetyltransferase 1, a potential breast cancer biomarker. AB - The identification, synthesis, and evaluation of a series of naphthoquinone derivatives as selective inhibitors of human arylamine N-acetyltransferase 1 and mouse arylamine N-acetyltransferase 2 are described. The compounds undergo a distinctive color change (red --> blue) upon binding to these human and mouse NAT isoenzymes driven by a proton transfer event. No color change is observed in the presence of functionally distinct but highly similar isoenzymes which are >70% identical. These molecules may be used as sensors to detect the presence of human NAT1 in cell lysates. PMID- 20170183 TI - Purification of plant-derived antibodies through direct immobilization of affinity ligands on cellulose. AB - Plants possess enormous potential as factories for the large scale production of therapeutic reagents such as recombinant proteins and antibodies. A major factor limiting commercial advances of plant-derived pharmaceuticals is the cost and inefficiency of purification. As a model system, we have developed a simple yet robust method for immobilizing affinity capture ligands onto solid supports by interfacing the secreted expression and coupling of a chimeric fusion protein in Pichia pastoris to microcrystalline cellulose in a single step. The fusion protein, which consisted of antibody-binding proteins L and G fused to a cellulose-binding domain (LG-CBD), was tethered directly onto cellulose resins added to P. pastoris cultures and subsequently used for antibody purification. Both the antibody-binding protein L and protein G domains were functional, as demonstrated by the ability of cellulose-immobilized LG-CBD to purify both a scFv antibody fragment from yeast and a human IgG1 monoclonal antibody from transgenic tobacco. Furthermore, combining two P. pastoris strains expressing LG-CBD and scFv with CP-102 cellulose in a single culture allowed for easy recovery of biologically active scFv. Direct immobilization of affinity purification ligands, such as LG-CBD, onto inexpensive support matrices such as cellulose is an effective method for the generation of functional, single-use antibody purification reagents. Straightforward preparation of purification reagents will help make antibody purification from genetically modified crop plants feasible and address one of the major bottlenecks facing commercialization of plant derived pharmaceuticals. PMID- 20170184 TI - Soluble semiconductors AAsSe2 (A = Li, Na) with a direct-band-gap and strong second harmonic generation: a combined experimental and theoretical study. AB - AAsSe(2) (A = Li, Na) have been identified as a new class of polar direct-band gap semiconductors. These I-V-VI(2) ternary alkali-metal chalcoarsenates have infinite single chains of (1/infinity)[AsQ(2)(-)] derived from corner-sharing pyramidal AsQ(3) units with stereochemically active lone pairs of electrons on arsenic. The conformations and packing of the chains depend on the structure directing alkali metals. This results in at least four different structural types for the Li(1-x)Na(x)AsSe(2) stoichiometry (alpha-LiAsSe(2), beta-LiAsSe(2), gamma NaAsSe(2), and delta-NaAsSe(2)). Single-crystal X-ray diffraction studies showed an average cubic NaCl-type structure for alpha-LiAsSe(2), which was further demonstrated to be locally distorted by pair distribution function (PDF) analysis. The beta and gamma forms have polar structures built of different (1/infinity)[AsSe(2)(-)] chain conformations, whereas the delta form has nonpolar packing. A wide range of direct band gaps are observed, depending on composition: namely, 1.11 eV for alpha-LiAsSe(2), 1.60 eV for LiAsS(2), 1.75 eV for gamma NaAsSe(2), 2.23 eV for NaAsS(2). The AAsQ(2) materials are soluble in common solvents such as methanol, which makes them promising candidates for solution processing. Band structure calculations performed with the highly precise screened-exchange sX-LDA FLAPW method confirm the direct-gap nature and agree well with experiment. The polar gamma-NaAsSe(2) shows very large nonlinear optical (NLO) second harmonic generation (SHG) response in the wavelength range of 600-950 nm. The theoretical studies confirm the experimental results and show that gamma-NaAsSe(2) has the highest static SHG coefficient known to date, 337.9 pm/V, among materials with band gaps larger than 1.0 eV. PMID- 20170186 TI - 1-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl] 3-azabicyclo[3.1.0]hexanes: a new series of potent and selective triple reuptake inhibitors. AB - The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SAR. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability (>30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression. PMID- 20170187 TI - Sn(IV) porphyrin based axial-bonding type porphyrin triads containing heteroporphyrins as axial ligands. AB - The thiaporphyrin building blocks with N(3)S and N(2)S(2) cores containing one hydroxyphenyl functional group at the meso position were synthesized by adopting the unsymmetrical thiophene diol method. These monohydroxy thiaporphyrins were used to construct the first examples of axial bonding type Sn(IV) porphyrin triads in which Sn(IV) porphyrin acts as basal unit and the two thiaporphyrin units as axial ligands by treating with SnTTP(OH)(2) in benzene at refluxing temperature. The axial bonding type triads were confirmed by mass, 1D and 2D NMR studies. The absorption and electrochemical studies support weak ground state interaction among the porphyrin subunits within the porphyrin triads. The fluorescence studies indicate there is a possibility of energy transfer at the singlet state from basal Sn(IV) porphyrin unit to axial thiaporphyrin units. PMID- 20170185 TI - Development of novel adenosine monophosphate-activated protein kinase activators. AB - In light of the unique ability of thiazolidinediones to mediate peroxisome proliferator-activated receptor (PPAR)gamma-independent activation of adenosine monophosphate-activated protein kinase (AMPK) and suppression of interleukin (IL) 6 production, we conducted a screening of an in-house, thiazolidinedione-based focused compound library to identify novel agents with these dual pharmacological activities. Cell-based assays pertinent to the activation status of AMPK and mammalian homologue of target of rapamycin (i.e., phosphorylation of AMPK and p70 ribosomal protein S6 kinase, respectively) and IL-6/IL-6 receptor signaling (i.e., IL-6 production and signal transducer and activator of transcription 3 phosphorylation, respectively) in lipopolysaccharide (LPS)-stimulated THP-1 human macrophages were used to screen this compound library, which led to the identification of compound 53 (N-{4-[3-(1-methyl-cyclohexylmethyl)-2,4-dioxo thiazolidin-5-ylidene-methyl]-phenyl}-4-nitro-3-trifluoro-methyl benzenesulfonamide) as the lead agent. Evidence indicates that this drug-induced suppression of LPS-stimulated IL-6 production was attributable to AMPK activation. Furthermore, compound 53-mediated AMPK activation was demonstrated in C-26 colon adenocarcinoma cells, indicating that it is not a cell line-specific event. PMID- 20170188 TI - Synthesis, structure, and phosphatase-like activity of a new trinuclear Gd complex with the unsymmetrical ligand H3L as a model for nucleases. AB - The new trinuclear gadolinium complex [Gd(3)L(2)(NO(3))(2)(H(2)O)(4)]NO(3).8H(2)O (1) with the unsymmetrical ligand 2-[N-bis-(2-pyridylmethyl)aminomethyl]-4-methyl 6-[N-bis(2-hydroxy-2-oxoethyl)aminomethyl] phenol (H(3)L) was synthesized and characterized. The new ligand H(3)L was obtained in good yield. Complex 1 crystallizes in an orthorhombic cell, space group Pcab. Kinetic studies show that complex 1 is highly active in the hydrolysis of the substrate 2,4 bis(dinitrophenyl)phosphate (K(m) = 4.09 mM, V(max) = 2.68 x 10(-2) mM s(-1), and k(cat) = V(max)/[1] = 0.67 s(-1)). Through a potentiometric study and determination of the kinetic behavior of 1 in acetonitrile/water solution, the species present in solution could be identified, and a trinuclear monohydroxo species appears to be the most prominent catalyst under mild conditions. Complex 1 displays high efficiency in DNA hydrolytic cleavage, and complete kinetic studies were carried out (K(m) = 4.57 x 10(-4) M, k'(cat) = 3.42 h(-1), and k'(cat)/K(m) = 7.48 x 10(3) M(-1) h(-1)). Studies with a radical scavenger (dimethyl sulfoxide, DMSO) showed that it did not inhibit the activity, indicating the hydrolytic action of 1 in the cleavage of DNA, and studies on the incubation of distamycin with plasmid DNA suggest that 1 is regio-specific, interacting with the minor groove of DNA. PMID- 20170189 TI - Swift and efficient synthesis of 4-phenylquinazolines: involvement of N heterocyclic carbene in the key cyclization step. AB - An original route to 2-alkyamino-4-phenylquinazolines in three steps from simple (hetero)aromatic amines is reported here. The key step involves the intramolecular cyclization of benzoyl arylguanidines performed in [OMIm]Cl ionic liquid. The basic (hetero)aromatic guanidines deprotonate the imidazolium-based ionic liquid, thus triggering the cascade process ultimately leading to the intramolecular cyclization. This reaction is the first example of a Friedel Crafts-type reaction in which an N-heterocyclic carbene is involved in the formation of the electrophilic intermediate. PMID- 20170190 TI - Synthesis, biological activity, and molecular modeling studies of 1H-1,2,3 triazole derivatives of carbohydrates as alpha-glucosidases inhibitors. AB - A class of drugs in use for treating type II diabetes mellitus (T2D), typified by the pseudotetrasaccharide acarbose, act by inhibiting the alpha-glucosidase activity present in pancreatic secretions and in the brush border of the small intestine. Herein, we report the synthesis of a series of 4-substituted 1,2,3 triazoles conjugated with sugars, including D-xylose, D-galactose, D-allose, and D-ribose. Compounds were screened for alpha-glucosidase inhibitory activity using yeast maltase (MAL12) as a model enzyme. Methyl-2,3-O-isopropylidene-beta-D ribofuranosides, such as the 4-(1-cyclohexenyl)-1,2,3-triazole derivative, were among the most active compounds, showing up to 25-fold higher inhibitory potency than the complex oligosaccharide acarbose. Docking studies on a MAL12 homology model disclosed a binding mode consistent with a transition-state-mimicking mechanism. Finally, the actual pharmacological potential of this triazole series was demonstrated by the reduction of postprandial blood glucose levels in normal rats. These compounds could represent new chemical scaffolds for developing novel drugs against T2D. PMID- 20170191 TI - Short and straightforward synthesis of (-)-1-deoxygalactonojirimycin. AB - The mildness and low basicity of vinylzinc species functioning as a nucleophile in addition to alpha-chiral aldehydes is characterized by lack of epimerization of the vulnerable stereogenic center. This is demonstrated by a highly diastereoselective synthesis of 1-deoxygalactonojirimycin in eight steps from commercial starting materials with overall yield of 35%. PMID- 20170192 TI - Annulation of tetrathiafulvalene to the bay region of perylenediimide. AB - A tetrathiafulvalene donor has been annulated to the bay region of perylenediimide affording a new pi-conjugated molecular dyad. Various electronic excited charge-transfer states are generated in different oxidation states, leading to almost full absorption in the visible to near-IR region with a high extinction coefficient. PMID- 20170193 TI - Harvesting waste thermal energy using a carbon-nanotube-based thermo electrochemical cell. AB - Low efficiencies and costly electrode materials have limited harvesting of thermal energy as electrical energy using thermo-electrochemical cells (or "thermocells"). We demonstrate thermocells, in practical configurations (from coin cells to cells that can be wrapped around exhaust pipes), that harvest low grade thermal energy using relatively inexpensive carbon multiwalled nanotube (MWNT) electrodes. These electrodes provide high electrochemically accessible surface areas and fast redox-mediated electron transfer, which significantly enhances thermocell current generation capacity and overall efficiency. Thermocell efficiency is further improved by directly synthesizing MWNTs as vertical forests that reduce electrical and thermal resistance at electrode/substrate junctions. The efficiency of thermocells with MWNT electrodes is shown to be as high as 1.4% of Carnot efficiency, which is 3-fold higher than for previously demonstrated thermocells. With the cost of MWNTs decreasing, MWNT based thermocells may become commercially viable for harvesting low-grade thermal energy. PMID- 20170195 TI - Temperature dependence of the structure of bound water in dried glassy poly-N,N, dimethylacrylamide. AB - Raman spectroscopy was used to investigate the temperature dependence of structural changes of bound water in dried glassy poly-N,N,-dimethylacrylamide in the temperature range 286.1-329.7 K. The results show that the frequency of the O H stretching mode of the bound water that is present in the dried glassy polymer shifts to the higher side with increasing temperature. The rate changes at around 310 K, while that for the bulk water is constant in the temperature range studied. The rates of change of the frequencies for the C=O stretching mode and CH(3) rocking mode also change at around 310 K. These results indicate a significant change in the interaction between the bound water and polymer chains at 310 K. Temperature dependence of the local structure of the bound water was analyzed by applying a structural model of bulk water to the spectra of the O-H stretching region. The result shows that the density of a tetragonal water structure consisting of four hydrogen bonds increases with increasing temperature below 310 K and begins to decrease at temperatures above 310 K. Further, estimates of the water content indicate that the evaporation rate of the bound water significantly changes at around 310 K. These results suggest that the bound water present in the dried glassy polymer can be classified as being in two states. At temperatures below 310 K, the water that forms a shell layer around the polymer chains evaporates, while at temperatures above 310 K the water that is bound to polar groups of polymer chains begins to evaporate. The structural changes of bound water might have important implications for the interpretation of properties of hydrated polymer systems, including both biological and synthetic polymers. PMID- 20170194 TI - Kinetic analysis of the interaction of b/HLH/Z transcription factors Myc, Max, and Mad with cognate DNA. AB - Myc, Mad, and Max proteins belong to the basic helix-loop-helix leucine zipper family of transcription factors. They bind to a specific hexanucleotide element of DNA, the E-box (CACGTG). To be biologically active, Myc and Mad require dimerization with Max. For the route of complex assembly of these dimers, there are two proposed pathways. In the monomer pathway, two monomers bind DNA sequentially and assemble their dimerization interface while bound to DNA. In the dimer pathway, two monomers form a dimer first prior to association with DNA. The monomer pathway is kinetically favored. In this report, stopped-flow polarization was utilized to determine the rates and temperature dependence of all of the individual steps for both assembly pathways. Myc.Max dimerization had a rate constant approximately 5- and approximately 2-fold higher than those of Max.Max and Mad.Max dimerization, respectively. The protein dimerization rates as well as the dimer-DNA rates were found to be independent of concentration, suggesting conformational changes were rate-limiting. The Arrhenius activation energies for the dimerization of Myc, Mad, and Max with Max were 20.4 +/- 0.8, 29 +/- 0.6, and 40 +/- 0.2 kJ/mol, respectively. Further, rate constants for Max.Max homodimer DNA binding are significantly higher than for Myc.Max and Mad.Max heterodimers binding to DNA. Monomer-DNA binding showed a faster rate than dimer-DNA binding. These studies show the rate-limiting step for the dimer pathway is the formation of protein dimers, and this reaction is slower than formation of protein dimers on the DNA interface, kinetically favoring the monomer pathway. PMID- 20170196 TI - Flow-induced dynamic surface tension effects at nanoscale. AB - The aim of this study is to investigate flow-induced dynamic surface tension effects, similar to the well-known Marangoni phenomena, but solely generated by the nanoscale topography of the substrates. The flow-induced surface tension effects are examined on the basis of a sharp interface theory. It is demonstrated how nanoscale objects placed at the boundary of the flow domain result in the generation of substantial surface forces acting on the bulk flow. PMID- 20170197 TI - De novo self-assembling collagen heterotrimers using explicit positive and negative design. AB - We sought to computationally design model collagen peptides that specifically associate as heterotrimers. Computational design has been successfully applied to the creation of new protein folds and functions. Despite the high abundance of collagen and its key role in numerous biological processes, fibrous proteins have received little attention as computational design targets. Collagens are composed of three polypeptide chains that wind into triple helices. We developed a discrete computational model to design heterotrimer-forming collagen-like peptides. Stability and specificity of oligomerization were concurrently targeted using a combined positive and negative design approach. The sequences of three 30 residue peptides, A, B, and C, were optimized to favor charge-pair interactions in an ABC heterotrimer, while disfavoring the 26 competing oligomers (i.e., AAA, ABB, BCA). Peptides were synthesized and characterized for thermal stability and triple-helical structure by circular dichroism and NMR. A unique A:B:C-type species was not achieved. Negative design was partially successful, with only A + B and B + C competing mixtures formed. Analysis of computed versus experimental stabilities helps to clarify the role of electrostatics and secondary-structure propensities determining collagen stability and to provide important insight into how subsequent designs can be improved. PMID- 20170198 TI - Substrate specificity determinants of the methanogen homoaconitase enzyme: structure and function of the small subunit. AB - The aconitase family of hydro-lyase enzymes includes three classes of proteins that catalyze the isomerization of alpha-hydroxy acids to beta-hydroxy acids. Besides aconitase, isopropylmalate isomerase (IPMI) proteins specifically catalyze the isomerization of alpha,beta-dicarboxylates with hydrophobic gamma chain groups, and homoaconitase (HACN) proteins catalyze the isomerization of tricarboxylates with variable chain length gamma-carboxylate groups. These enzymes' stereospecific hydro-lyase activities make them attractive catalysts to produce diastereomers from unsaturated precursors. However, sequence similarity and convergent evolution among these proteins lead to widespread misannotation and uncertainty about gene function. To find the substrate specificity determinants of homologous IPMI and HACN proteins from Methanocaldococcus jannaschii, the small-subunit HACN protein (MJ1271) was crystallized for X-ray diffraction. The structural model showed characteristic residues in a flexible loop region between alpha2 and alpha3 that distinguish HACN from IPMI and aconitase proteins. Site-directed mutagenesis of MJ1271 produced loop-region variant proteins that were reconstituted with wild-type MJ1003 large-subunit protein. The heteromers formed promiscuous hydro-lyases with reduced activity but broader substrate specificity. Both R26K and R26V variants formed relatively efficient IPMI enzymes, while the T27A variant had uniformly lower specificity constants for both IPMI and HACN substrates. The R26V T27Y variant resembles the MJ1277 IPMI small subunit in its flexible loop sequence but demonstrated the broad substrate specificity of the R26V variant. These mutations may reverse the evolution of HACN activity from an ancestral IPMI gene, demonstrating the evolutionary potential for promiscuity in hydro-lyase enzymes. Understanding these specificity determinants enables the functional reannotation of paralogous HACN and IPMI genes in numerous genome sequences. These structural and kinetic results will help to engineer new stereospecific hydro-lyase enzymes for chemoenzymatic syntheses. PMID- 20170200 TI - Steric control of coordination geometry in titanium-imido complexes of N,N' bis(arylimino)acenaphthylene ligands. AB - Titanium complexes of N,N'-bis(arylimino)acenaphthylene (BIAN) alpha-diimine ligands with varied steric profiles have been prepared. Coordination of the BIAN ligand derivatives to TiCl(4) afforded the adducts (dpp-BIAN)TiCl(4) (1a), (tmp BIAN)TiCl(4) (1b), and (dmp-BIAN)TiCl(4) (1c) (dpp = 2,6-diisopropylphenyl; tmp = 2,4,6-trimethylphenyl; dmp = 3,5-dimethylphenyl). While the least sterically crowded complex 1c is robust toward loss of the diimine ligand, the dpp-BIAN and tmp-BIAN ligands are readily displaced by pyridine from the more crowded derivatives 1a and 1b, respectively. The crowded profiles engendered by the tmp BIAN and dpp-BIAN ligands result in the formation of five-coordinate titanium imide complexes, (dpp-BIAN)TiCl(2)(=N(t)Bu) (2a) and (tmp-BIAN)TiCl(2)(=N(t)Bu) (2b), upon addition of (t)BuNH(2) to solutions of 1a or 1b, respectively. Single crystal X-ray diffraction studies reveal a square pyramidal coordination environment with an apical imide ligand and a short Ti-N distance, consistent with a Ti-N triple bond. Conversely, the less crowded dmp-BIAN ligand affords a six-coordinate titanium imido complex, (dmp-BIAN)TiCl(2)(=N(t)Bu)(NH(2)(t)Bu) (4), upon treatment of 1c with (t)BuNH(2). Surprisingly the imido ligand is coordinated trans to one arm of the diimine. This six coordinate species is fluxional in solution, and exchange and variable temperature (1)H NMR experiments suggest dissociation of the coordinated (t)BuNH(2) ligand to generate a five coordinate imido intermediate analogous to 2a and 2b. PMID- 20170201 TI - Monometallic and bimetallic ruthenium(II) complexes derived from 4,5 bis(benzimidazol-2-yl)imidazole (H3Imbzim) and 2,2'-bipyridine as colorimetric sensors for anions: synthesis, characterization, and binding studies. AB - Mixed-ligand monometallic and bimetallic ruthenium(II) complexes of compositions [(bpy)(2)Ru(H(3)Imbzim)](ClO(4))(2) x 2 H(2)O (1) and [(bpy)(2)Ru(H(2)Imbzim)Ru(bpy)(2)](ClO(4))(3) x CH(2)Cl(2) (2), where H(3)Imbzim = 4,5-bis(benzimidazol-2-yl)imidazole and bpy = 2,2'-bipyridine, have been synthesized and characterized using standard analytical and spectroscopic techniques. The X-ray crystal structures of both compounds have been determined and showed that 1 crystallized in the triclinic form with space group P1 and 2 is in the monoclinic form with space group P2(1)/m. The anion binding properties of complexes 1 and 2, as well as those of the parent H(3)Imbzim, were thoroughly investigated in an acetonitrile solution using absorption, emission, and (1)H NMR spectral studies, which revealed that both of the metalloreceptors act as sensors for F(-), for AcO(-), and, to some extent, for H(2)PO(4)(-). At a relatively lower concentration of anions, a 1:1 hydrogen-bonded adduct was formed; however, in the presence of an excess of anions, stepwise deprotonation of the two benzimidazole NH fragments occurred, an event that was signaled by the development of vivid colors visible with the naked eye. Double deprotonation was also observed in the presence of hydroxide. Less basic anions (AcO(-) and H(2)PO(4)(-)) induce deprotonation of only one NH. The effect of solvents on the absorption and emission spectral behavior has also been studied in detail. The binding affinities of different anions toward the receptors were evaluated and showed that the binding constants of 1 and 2 are substantially enhanced relative to free H(3)Imbzim because upon coordination to the Ru(II) center(s), H(3)Imbzim/H(2)Imbzim(-) becomes electron-deficient, thereby rendering the imidazole NH protons more available for hydrogen bonding to the anions. Cyclic voltammetry studies carried out in acetonitrile provided evidence of an anion dependent electrochemical response with F(-) and AcO(-). Anion-induced lifetime shortening makes complex 2 a suitable lifetime-based sensor for anions. PMID- 20170202 TI - Contaminant desorption during long-term leaching of hydroxide-weathered Hanford sediments. AB - Mineral sorption/coprecipitation is thought to be a principal sequestration mechanism for radioactive (90)Sr and (137)Cs in sediments impacted by hyperalkaline, high-level radioactive waste (HLRW) at the DOE's Hanford site. However, the long-term persistence of neo-formed, contaminant bearing phases after removal of the HLRW source is unknown. We subjected pristine Hanford sediments to hyperalkaline Na-AI-NO(3)-OH solutions containing Sr, Cs, and I at 10(-5), 10(-5), and 10(-7) molal, respectively, for 182 days with either <10 ppmv or 385 ppmv pCO(2). This resulted in the formation of feldspathoid minerals. We leached these weathered sediments with dilute, neutral-pH solutions. After 500 pore volumes (PVs), effluent Sr, Cs, NO(3), Al, Si, and pH reached a steady-state with concentrations elevated above those of feedwater. Reactive transport modeling suggests that even after 500 PV, Cs desorption can be explained by ion exchange reactions, whereas Sr desorption is best described by dissolution of Sr substituted, neo-formed minerals. While, pCO(2) had no effect on Sr or Cs sorption, sediments weathered at <10 ppmv pCO(2) did desorb more Sr (66% vs 28%) and Cs (13% vs 8%) during leaching than those weathered at 385 ppmv pCO(2). Thus, the dissolution of neo-formed aluminosilicates may represent a long-term, low level supply of (90)Sr at the Hanford site. PMID- 20170203 TI - Aqueous basic solutions: hydroxide solvation, structural diffusion, and comparison to the hydrated proton. PMID- 20170199 TI - Characterization of cell cycle specific protein interaction networks of the yeast 26S proteasome complex by the QTAX strategy. AB - Ubiquitin-proteasome dependent protein degradation plays a fundamental role in the regulation of the eukaryotic cell cycle. Cell cycle transitions between different phases are tightly regulated to prevent uncontrolled cell proliferation, which is characteristic of cancer cells. To understand cell cycle phase specific regulation of the 26S proteasome and reveal the molecular mechanisms underlying the ubiquitin-proteasome degradation pathway during cell cycle progression, we have carried out comprehensive characterization of cell cycle phase specific proteasome interacting proteins (PIPs) by QTAX analysis of synchronized yeast cells. Our efforts have generated specific proteasome interaction networks for the G1, S, and M phases of the cell cycle and identified a total of 677 PIPs, 266 of which were not previously identified from unsynchronized cells. On the basis of the dynamic changes of their SILAC ratios across the three cell cycle phases, we have employed a profile vector-based clustering approach and identified 20 functionally significant groups of PIPs, 3 of which are enriched with cell cycle related functions. This work presents the first step toward understanding how dynamic proteasome interactions are involved in various cellular pathways during the cell cycle. PMID- 20170204 TI - A rare example of a krypton difluoride coordination compound: [BrOF2][AsF6] x 2 KrF2. AB - The synthesis of [BrOF(2)][AsF(6)] x 2 KrF(2), its structural characterization, and bonding are described in this study. Although several KrF(2) adducts with transition metal centers have been previously reported, none have been crystallographically characterized. The solid-state Raman spectrum of [BrOF(2)][AsF(6)] x 2 KrF(2) has been assigned with the aid of quantum-chemical calculations. The low-temperature (-173 degrees C) X-ray crystal structure of [BrOF(2)][AsF(6)] x 2 KrF(2) consists of isolated molecular units and represents an example of KrF(2) coordinated to a main-group atom. The coordination geometry around the BrOF(2)(+) cation renders the free valence electron lone pair more compact than in free BrOF(2)(+). The KrF(2) ligands are coordinated trans to the fluorine atoms of BrOF(2)(+) with the AsF(6)(-) anion coordinated trans to oxygen. The quantum theory of atoms in molecules (QTAIM) and electron localization function (ELF) analyses have been carried out in order to define the nature of the bonding in the complex. A significant amount of charge (0.25 e) is transferred to BrOF(2)(+) from the two KrF(2) ligands (0.10 e each) and from the AsF(6)(-) anion (0.05 e). Significant polarization also occurs within the KrF(2) ligands, which enhances the anionic characters of the fluorine bridges. The interaction energy is mostly governed by the electrostatic interaction of the positively charged bromine atom with the surrounding fluorine atoms. PMID- 20170206 TI - Pharmacokinetics and pharmacodynamics of tamsulosin in its modified-release and oral controlled absorption system formulations. AB - Tamsulosin is an alpha(1)-adrenoceptor antagonist used for the treatment of lower urinary tract symptoms that are suggestive of benign prostatic hyperplasia. It is mostly used in a modified-release (MR) formulation, but an oral controlled absorption system (OCAS) and a 'without-water' tablet formulation are also available in some countries. The oral bioavailability of the MR formulation in the fasted state is close to 100%. Whereas absorption from the MR formulation is affected by concomitant food intake, that of the OCAS formulation is food independent. Tamsulosin exhibits high plasma-protein binding, largely to alpha(1) acid glycoprotein. It is metabolized, mainly by cytochrome P450 (CYP) 3A4 and CYP2D6 to compounds with low abundance, and 8.7-15% of an oral dose is excreted renally as the parent compound. The pharmacokinetics of tamsulosin are not affected to a major extent by age, and pharmacokinetic alterations in renally impaired patients relate largely to an increased concentration of alpha(1)-acid glycoprotein. Pharmacokinetic alterations with hepatic impairment are also only moderate, thus neither renal nor mild to moderate hepatic impairment necessitates dose adjustment. Concomitant exposure to potent CYP3A4 inhibitors can more than double the exposure of tamsulosin. Clinical studies have indicated that despite its lower bioavailability, the OCAS formulation has the same treatment efficacy as the MR formulation but causes somewhat fewer cardiovascular adverse effects. PMID- 20170205 TI - Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I. AB - The calcineurin inhibitors ciclosporin (cyclosporine) and tacrolimus are immunosuppressant drugs used for the prevention of organ rejection following transplantation. Both agents are metabolic substrates for cytochrome P450 (CYP) 3A enzymes--in particular, CYP3A4 and CYP3A5--and are transported out of cells via P-glycoprotein (ABCB1). Several single nucleotide polymorphisms (SNPs) have been identified in the genes encoding for CYP3A4, CYP3A5 and P-glycoprotein, including CYP3A4 -392A>G (rs2740574), CYP3A5 6986A>G (rs776746), ABCB1 3435C>T (rs1045642), ABCB1 1236C>T (rs1128503) and ABCB1 2677G>T/A (rs2032582). The aim of this review is to provide the clinician with an extensive overview of the recent literature on the known effects of these SNPs on the pharmacokinetics of ciclosporin and tacrolimus in solid-organ transplant recipients. Literature searches were performed, and all relevant primary research articles were critiqued and summarized. Influence of the CYP3A4 -392A>G SNP on the pharmacokinetics of either ciclosporin or tacrolimus appears limited. Variability in CYP3A4 expression due to environmental factors is likely to be more important than patient genotype. Influence of the CYP3A5 6986A>G SNP on the pharmacokinetics of ciclosporin is also uncertain and likely to be small. CYP3A4 may play a more dominant role than CYP3A5 in the metabolism of ciclosporin. The CYP3A5 6986A>G SNP has a well established influence on the pharmacokinetics of tacrolimus. Several studies in kidney, heart and liver transplant recipients have reported an approximate halving of tacrolimus dose-adjusted trough concentrations and doubling of tacrolimus dose requirements in heterozygous or homozygous carriers of a CYP3A5*1 wild-type allele compared with homozygous carriers of a CYP3A5*3 variant allele. Carriers of a CYP3A5*1 allele take a longer time to reach target blood tacrolimus concentrations. Influence of ABCB1 3435C>T, 1236C>T and 2677G>T/A SNPs on the pharmacokinetics of ciclosporin and tacrolimus remains uncertain, with inconsistent results. Genetic linkage between the three variant genotypes suggests that the pharmacokinetic effects are complex and not related to any one ABCB1 SNP. It is likely that these polymorphisms exert a small but combined effect, which is additive to the effects of the CYP3A5 6986A>G SNP. In liver transplant patients, recipient and donor liver genotypes may act together in determining overall drug disposition, hence the importance of assessing both. Studies with low patient numbers may account for many inconsistent results to date. Meta-analyses of the current data should help resolve some discrepancies. The majority of studies have only evaluated the effects of individual SNPs; however, multiple polymorphisms may interact to produce a combined effect. Further haplotype analyses are likely to be useful. It is not yet clear whether pharmacogenetic profiling of calcineurin inhibitors will be a useful clinical tool for personalizing immunosuppressant therapy. PMID- 20170208 TI - Communications: Elementary oxygen electrode reactions in the aprotic Li-air battery. AB - We discuss the electrochemical reactions at the oxygen electrode of an aprotic Li air battery. Using density functional theory to estimate the free energy of intermediates during the discharge and charge of the battery, we introduce a reaction free energy diagram and identify possible origins of the overpotential for both processes. We also address the question of electron conductivity through the Li(2)O(2) electrode and show that in the presence of Li vacancies Li(2)O(2) becomes a conductor. PMID- 20170207 TI - A semi-mechanistic model to predict the effects of liver cirrhosis on drug clearance. AB - BACKGROUND AND OBJECTIVE: Liver cirrhosis is characterized by a decrease in functional hepatocytes, lowered circulating levels of plasma proteins and alterations in blood flow due to the development of portacaval shunts. Depending on the interplay between these parameters and the characteristics of an administered drug, varying degrees of impaired systemic clearance and first-pass metabolism are anticipated. The Simcyp Population-based ADME Simulator has already been used successfully to incorporate genetic, physiological and demographic attributes of certain subgroups within healthy populations into in vitro-in vivo extrapolation (IVIVE) of xenobiotic clearance. The objective of this study was to extend population models to predict systemic and oral drug clearance in relation to the severity of liver cirrhosis. METHODS: Information on demographics, changes in hepatic blood flow, cytochrome P450 enzymes, liver size, plasma protein binding and renal function was incorporated into three separate population libraries. The latter corresponded to Child-Pugh scores A (mild), B (moderate) and C (severe) liver cirrhosis. These libraries, together with mechanistic IVIVE within the Simcyp Simulator, were used to predict the clearance of intravenous and oral midazolam, oral caffeine, intravenous and oral theophylline, intravenous and oral metoprolol, oral nifedipine, oral quinidine, oral diclofenac, oral sildenafil, and intravenous and oral omeprazole. The simulated patients matched the clinical studies as closely as possible with regard to demographics and Child-Pugh scores. Predicted clearance values in both healthy control and liver cirrhosis populations were compared with observed values, as were the fold increases in clearance values between these populations. RESULTS: There was good agreement (lack of statistically significant difference, two-tailed paired t-test) between observed and predicted clearance ratios, with the exception of those for two studies of intravenous omeprazole. Predicted clearance ratios were within 0.8- to 1.25-fold of observed ratios in 65% of cases (range 0.34- to 2.5-fold). CONCLUSION: The various drugs that were studied showed different changes in clearance in relation to disease severity, and a 'one size fits all' solution does not exist without considering the multiple sources of the changes. Predictions of the effects of liver cirrhosis on drug clearance are of potential value in the design of clinical studies during drug development and, clinically, in the assessment of likely dosage adjustment. PMID- 20170209 TI - The diffusive finite state projection algorithm for efficient simulation of the stochastic reaction-diffusion master equation. AB - We have developed a computational framework for accurate and efficient simulation of stochastic spatially inhomogeneous biochemical systems. The new computational method employs a fractional step hybrid strategy. A novel formulation of the finite state projection (FSP) method, called the diffusive FSP method, is introduced for the efficient and accurate simulation of diffusive transport. Reactions are handled by the stochastic simulation algorithm. PMID- 20170210 TI - Multireference study of spin-orbit coupling in the hydrides of the 6p-block elements using the model core potential method. AB - Careful spin-orbit multireference studies were carried out for the late p-block elements Tl, Pb, Bi, Po, At, and Rn and their hydrides using the model core potentials developed in the present work. The model core potentials were designed to treat the scalar-relativistic and spin-orbit coupling effects at the Douglas Kroll level. The variational stability of the spin-orbit coupling operator was discussed in terms of the relativistic kinematic operators and depicted graphically. A detailed analysis of the spin-orbit multireference dissociation curves of the 6p element hydrides as well as of their atomic spectra allowed to establish the accuracy of the model core potentials with respect to all-electron calculations to be within several mA for r(e), meV (ceV) for D(e) at the correlation level of configuration interaction (multireference perturbation theory), 30 cm(-1) for omega(e), and about 350 cm(-1) for the low-lying atomic and molecular term and level energies. These values are expected to be the maximum error limits for the model core potentials of all the np-block elements (n=2-6). Furthermore, a good agreement with experiment requires that many terms be coupled in the spin-orbit coupling calculations. A timing study of Tl and TlH computations indicates that the model core potentials lead to 20-fold (6-fold) speedup at the level of configuration interaction (multireference perturbation theory) calculations. PMID- 20170211 TI - Full implementation and benchmark studies of Mukherjee's state-specific multireference coupled-cluster ansatz. AB - The state-specific multireference coupled-cluster (SS-MRCC) ansatz developed by Mukherjee and co-workers [J. Chem. Phys. 110, 6171 (1999)] has been implemented by means of string-based techniques. The implementation is general and allows for using arbitrary complete active spaces of any spin multiplicity and arbitrarily high excitations in the cluster operators. Several test calculations have been performed for single- and multiple-bond dissociations of molecular systems. Our experience shows that convergence problems are encountered when solving the working equations of the SS-MRCC in the case the weight of one or more reference functions tends to take on very small values. This is system specific and cannot yet be handled in a black-box fashion. The problem can be obviated by either dropping all the cluster amplitudes from the corresponding model functions with coefficients below a threshold or by a regularization procedure suggested by Tikhonov or a combination of both. In the current formulation the SS-MRCC is not invariant with respect to transformation of active orbitals among themselves. This feature has been extensively explored to test the degree of accuracy of the computed energies with both pseudocanonical and localized active orbitals. The performance of the method is assessed by comparing the results with the corresponding full configuration interaction (CI) values with the same set of orbitals (correlated and frozen). Relative efficacies of CI methods such as MRCI singles and doubles with the same active space and size-extensivity corrected ones such as MR averaged coupled pair functional and MR averaged quadratic CC have also been studied. Allied full-fledged CC methods have also been employed to see their relative performance vis-a-vis the SS-MRCC. These latter methods are the complete-active-space-inspired single-reference (SR) CC based SS theory and the single-root MR Brillouin-Wigner CC. Our benchmark results indicate that the performance of the SS-MRCC is generally quite good for localized active orbitals. The performance with the pseudocanonical orbitals, however, is sometimes not as satisfactory as for the localized orbitals. PMID- 20170212 TI - Cholesky decomposition within local multireference singles and doubles configuration interaction. AB - A local multireference singles and doubles configuration interaction method in which Cholesky vectors are used in place of conventional two-electron integrals has been developed (CD-LMRSDCI). To reduce the overall cost associated with our linear scaling LMRSDCI method presented earlier [T. S. Chwee et al., J. Chem. Phys. 128, 224106 (2008)], we adopt a two-pronged approach. First, localized orthogonal virtual orbitals, introduced by Subotnik et al. [J. Chem. Phys. 123, 114108 (2005)], are substituted for nonorthogonal projected atomic orbitals. This obviates the need for contraction with overlap matrices and simplifies our working formalism. In addition, we restructure the rate-limiting step of our LMRSDCI algorithm to be driven by the search for two-electron integrals instead of configuration state functions. The shift necessitates a flexible way of processing the four-indexed two-electron integrals, which is facilitated by use of two-indexed Cholesky vectors. Our restructured LMRSDCI method is an order of magnitude faster and has greatly reduced storage requirements so that we are able to apply it to molecules containing up to 50 heavy atoms. However, generation of the Cholesky vectors and their subsequent transformation to the molecular orbital (MO) basis is not linear scaling. Together with assembling the MO integrals from the Cholesky vectors, these now constitute the rate-limiting steps in our method. PMID- 20170213 TI - Long-lasting molecular alignment: fact or fiction? AB - It has been suggested that appropriate periodic sequences of laser pulses can maintain molecular alignment for arbitrarily long times [J. Ortigoso, Phys. Rev. Lett. 93, 073001 (2004)]. These aligned states are found among the cyclic eigenstates of truncated matrix representations of the one-period time propagator U(T,0). However, long time localization of periodic driven systems depends on the nature of the spectrum of their exact propagator; if it is continuous, eigenstates of finite-basis propagators cease to be cyclic, in the long time limit, under the exact time evolution. We show that, for very weak laser intensities, the evolution operator of the system has a point spectrum for most laser frequencies, but for the laser powers needed to create aligned wave packets it is unknown if U(T,0) has a point spectrum or a singular continuous spectrum. For this regime, we obtain error bounds on the exact time evolution of rotational wave packets that allow us to determine that truncated aligned cyclic states do not lose their alignment for millions of rotational periods when they evolve under the action of the exact time propagator. PMID- 20170214 TI - Decoherence and quantum-classical dynamics in a dissipative bath. AB - The dynamics of a mixed quantum-classical system, in which the classical subsystem interacts with a dissipative bath, is investigated. This description of the dynamics will be appropriate if the details of the bath dynamics are unimportant but its presence plays an important role in the dissipation of energy to the environment. In this dynamical description, which can be simulated employing an ensemble of stochastic surface-hopping trajectories, the strength of the dissipation is controlled by a friction coefficient. We show that if decoherence, whose effects are controlled by the bath friction, is sufficiently rapid, the equation of motion can be reduced to a master equation. Thus, decoherence and the validity of master equation models may be explored as a function of bath friction. We use this framework to study the mechanism of decoherence in a simple model nonadiabatic chemical reaction. PMID- 20170215 TI - Perturbative triples corrections in state-specific multireference coupled cluster theory. AB - We formulated and implemented a perturbative triples correction for the state specific multireference coupled cluster approach with singles and doubles suggested by Mukherjee and co-workers, Mk-MRCCSD [Mol. Phys. 94, 157 (1998)]. Our derivation of the energy correction [Mk-MRCCSD(T)] is based on a constrained search for stationary points of the Mk-MRCC energy functional together with a perturbative expansion with respect to the appearing triples cluster operator. The Lambda-Mk-MRCCSD(T) approach derived in this way consists in (1) a correction to the off-diagonal matrix elements of the effective Hamiltonian which is unique to coupled cluster methods based on the Jeziorski-Monkhorst ansatz, and (2) an asymmetric energy correction to the diagonal elements of the effective Hamiltonian. The Mk-MRCCSD(T) correction is obtained from the Lambda-Mk-MRCCSD(T) method by approximating the singles and doubles Lagrange multipliers with the corresponding cluster amplitudes. We investigate the performance of the Mk MRCCSD(T) method by applying it to the potential energy curve of the BeH(2) model and F(2) and the geometry and harmonic vibrational frequencies of ozone. Computation of the energy difference between the mono- and bicyclic forms of the 2,6-pyridyne diradical illustrates the potential of Mk-MRCCSD(T) as a tool for the study of realistic chemical problems requiring multireference zeroth-order wave functions. PMID- 20170216 TI - A new analytical potential energy surface for the adsorption system CO/Cu(100). AB - Electronic structure data and analytical representations of the potential energy surface for the adsorption of carbon monoxide on a crystalline copper Cu(100) substrate are reviewed. It is found that a previously published and widely used analytical hypersurface for this process [J. C. Tully, M. Gomez, and M. Head Gordon, J. Vac. Sci. Technol. A 11, 1914 (1993)] represents rather poorly the data obtained from a slab type calculation of the electronic structure. A new, global analytical representation of the potential energy surface for this process is derived via a nonlinear adjustment of parameters. It is more general and fits qualitatively better the electronic structure data. Key characteristic elements of the new surface are the "top" equilibrium adsorption site in the perpendicular arrangement Cu-C-O with Cu-C and C-O distances of 184 and 115 pm, the desorption energy of 0.76 eV and the barrier for lateral diffusion of 33 meV, including approximative corrections for the variation of zero point energy. Anharmonic vibrational fundamentals and overtones are also calculated from six dimensional variational calculations. All these values agree equally well or better with experimental data than previous published theoretical data within estimated uncertainties. The analytical representation is compact and robust, and may be used to describe other adsorption processes of diatomic molecules, including dissociative chemisorption. PMID- 20170217 TI - Accurate ab initio potential energy curve of O2. I. Nonrelativistic full configuration interaction valence correlation by the correlation energy extrapolation by intrinsic scaling method. AB - The recently introduced method of correlation energy extrapolation by intrinsic scaling is used to calculate the nonrelativistic electron correlations in the valence shell of the O(2) molecule at 24 internuclear distances along the ground state (3)Sigma(g)(-) potential energy curve from 0.9 to 6 A, the equilibrium distance being 1.207 52 A. Using Dunning's correlation-consistent triple- and quadruple-zeta basis sets, the full configuration interaction energies are determined, with an accuracy of about 0.3 mhartree, by successively generating up to sextuple excitations with respect to multiconfigurational reference functions that strongly change along the reaction path. The energies of the reference functions and those of the correlation energies with respect to these reference functions are then extrapolated to their complete basis set limits. PMID- 20170218 TI - Comparing geometric and kinetic cluster algorithms for molecular simulation data. AB - The identification of metastable states of a molecule plays an important role in the interpretation of molecular simulation data because the free-energy surface, the relative populations in this landscape, and ultimately also the dynamics of the molecule under study can be described in terms of these states. We compare the results of three different geometric cluster algorithms (neighbor algorithm, K-medoids algorithm, and common-nearest-neighbor algorithm) among each other and to the results of a kinetic cluster algorithm. First, we demonstrate the characteristics of each of the geometric cluster algorithms using five two dimensional data sets. Second, we analyze the molecular dynamics data of a beta heptapeptide in methanol--a molecule that exhibits a distinct folded state, a structurally diverse unfolded state, and a fast folding/unfolding equilibrium- using both geometric and kinetic cluster algorithms. We find that geometric clustering strongly depends on the algorithm used and that the density based common-nearest-neighbor algorithm is the most robust of the three geometric cluster algorithms with respect to variations in the input parameters and the distance metric. When comparing the geometric cluster results to the metastable states of the beta-heptapeptide as identified by kinetic clustering, we find that in most cases the folded state is identified correctly but the overlap of geometric clusters with further metastable states is often at best approximate. PMID- 20170219 TI - Fluid phase coexistence and critical behavior from simulations in the restricted Gibbs ensemble. AB - The symmetrical restricted Gibbs ensemble (RGE) is a version of the Gibbs ensemble in which particles are exchanged between two boxes of fixed equal volumes. It has recently come to prominence because--when combined with specialized algorithms--it provides for the study of near-coexistence density fluctuations in highly size-asymmetric binary mixtures. Hitherto, however, a detailed framework for extracting accurate estimates of critical point and coexistence curve parameters from RGE density fluctuations has been lacking. Here we address this problem by exploiting an exact link between the RGE density fluctuations and those of the grand canonical ensemble. In the subcritical region we propose and test a simple method for obtaining accurate estimates of coexistence densities. In the critical region we identify an observable that serves as a finite system size estimator for the critical point parameters, and present a finite-size scaling theory that allows extrapolation to the thermodynamic limit. PMID- 20170220 TI - Combining ab initio quantum mechanics with a dipole-field model to describe acid dissociation reactions in water: first-principles free energy and entropy calculations. AB - We introduce a novel approach to compute dissociation free energy and entropy values in simulations that employ a density functional theory description of the acidic moiety and of the solvent. The approach consists of utilizing an alchemical transformation of a weak acid A-COOH into the strong acid B-COOH, which makes it practical to employ alchemical free energy perturbation methods in the context of ab initio molecular dynamics simulations. The present alchemical transformation circumvents the need to tackle changes in the total number of electrons and atoms by replacing the chemical residue responsible for the change in acidity with an easily tunable external effective potential. Our investigation demonstrates that (1) a simple but effective class of external potentials that control acidity changes in the acetic/trifluoroacetic acid series can be achieved by replacing the methyl and trifluoromethyl substituents by screened dipoles. Using this dipole-field/quantum-mechanics (DF/QM) approach one can predict gas phase geometries, proton dissociation energies, total dipole moments, and water binding energies in good agreement with full-QM values. (2) The resulting alchemical perturbation calculations are stable and well converged and allow one to compute absolute pK(a) values whose accuracy is limited primarily by the exchange-correlation functional employed: H-COOH=2.5+/-0.6 (full-QM calculation), 3.7 (exp); F(3)C-COOH=0.4+/-0.6 (DF/QM calculation), 0.5 (exp); H(3)C-COOH=3.1+/ 0.7 (DF/QM calculation), 4.7 (exp); 3) Our DF/QM model predicts that the difference in acidity between H-COOH and H(3)C-COOH is dominated by solvent entropy effects, in excellent agreement with experimental observations. The calculated difference between the dissociation energies of these acids is DeltaDelta(d)U=0.0+/-0.26 kcal/mol while the experimental value is 0.0+/-0.1 kcal/mol. PMID- 20170221 TI - Dipole oscillator strength distributions with improved high-energy behavior: dipole sum rules and dispersion coefficients for Ne, Ar, Kr, and Xe revisited. AB - The construction of the dipole oscillator strength distribution (DOSD) from theoretical and experimental photoabsorption cross sections combined with constraints provided by the Kuhn-Reiche-Thomas sum rule and molar refractivity data is a well-established technique that has been successfully applied to more than 50 species. Such DOSDs are insufficiently accurate at large photon energies. A novel iterative procedure is developed that rectifies this deficiency by using the high-energy asymptotic behavior of the dipole oscillator strength density as an additional constraint. Pilot applications are made for the neon, argon, krypton, and xenon atoms. The resulting DOSDs improve the agreement of the predicted S(2) and S(1) sum rules with ab initio calculations while preserving the accuracy of the remainder of the moments. Our DOSDs exploit new and more accurate experimental data. Improved estimates of dipole properties for these four atoms and of dipole-dipole C(6) and triple-dipole C(9) dispersion coefficients for the interactions among them are reported. PMID- 20170222 TI - Rotation of methane and silane molecules in He droplets. AB - This work studies the renormalization of the molecular moments of inertia I(G) in liquid helium. For this purpose we have measured the rotational-vibrational spectra of the nu(3) modes of a series of homologous light spherical top molecules such as CH(4), CD(4), SiH(4), and SiD(4) in He droplets. The spectra were fitted to an empirical gas phase Hamiltonian, yielding a set of spectroscopic constants. We found that the additional moment of inertia, DeltaI(He), scales approximately as square of I(G). This is in agreement with the theoretical model which assigns DeltaI(He) to coupling of molecular rotation with vibration of He in the molecular vicinity. Our results also indicate a large increase in the effective centrifugal distortion constants, which is another manifestation of the interaction of the molecular rotors with the He environment. Finally, the mechanism of the relaxation of rotational energy in liquid helium is discussed. PMID- 20170223 TI - The ground state van der Waals potentials of the strontium dimer and strontium rare-gas complexes. AB - The entire ground state potential energy curve of the strontium dimer is accurately described by the Tang-Toennies potential model defined by the three dispersion coefficients and two well parameters. The predicted vibrational frequency, anharmonicity, and vibration-rotation coupling constant are in excellent agreement with experiment. The Sr(2) reduced potential is almost identical to that of Ca(2) and Hg(2), providing further evidence to the conjecture that the van der Waals dimer potentials of group IIA and group IIB elements have the same shape, which is different from that of rare-gas dimers. The potentials of Sr-RG complexes (RG=He,Ne,Ar,Kr,Xe) are generated by the same potential model with its parameters calculated with combining rules. These potentials are shown to have the same shape which is between that of the strontium and rare-gas dimers. PMID- 20170224 TI - Modeling disequilibrium in gas ensembles: how quantum state populations evolve under multicollision conditions; CO*+Ar, CO, O2, and N2. AB - The method of Marsh and McCaffery [J. Chem. Phys. 117, 503 (2002)] is used to quantify how rovibrational populations and mode temperatures change as an ensemble of CO molecules, initially excited to (v;j)=(8;12), evolves to thermal equilibrium in a bath gas. The bath gases considered are Ar, N(2), O(2), and CO all at 300 K with the diatomics in their (0;8) rovibrational states. Ensembles generally contain 1000 molecules, 10% of which are excited CO (CO( *)) molecules. State (v;j) populations and mode temperatures of CO* and bath molecules are calculated for successive collisions to 1000 or more. We find that relaxation to local thermodynamic equilibrium occurs in distinct phases that vary widely in rate of cooling. There is especially fast vibration-vibration (VV) exchange in CO*-CO mixtures that is largely decoupled from rotation and translation. Several aspects of ensemble behavior may be rationalized using concepts established in quantum state resolved single collision studies. We demonstrate the existence of a simultaneous energy quasiresonant, angular momentum conserving, low Deltaj VV process that can cause either ultrafast relaxation or up pumping of the kind seen in a number of experiments. PMID- 20170225 TI - Intensity-resolved IR multiple photon ionization and fragmentation of C60. AB - The sequential absorption of multiple infrared (IR) photons by isolated gas-phase species can lead to their dissociation and/or ionization. Using the newly constructed "Free-Electron Laser for IntraCavity Experiments" (FELICE) beam line at the FELIX facility, neutral C(60) molecules have been exposed to an extremely high number (approximately 10(23)) of photons/cm(2) for a total time duration of up to 5 micros. At wavelengths around 20 microm, resonant with allowed IR transitions of C(60), ionization and extensive fragmentation of the fullerenes are observed. The resulting photofragment distributions are attributed to absorption in fragmentation products formed once C(60) is excited to internal energies at which fragmentation or ionization takes place within the duration of the laser pulse. The high IR intensities available combined with the large interaction volume permit spatially resolved detection of the ions inside the laser beam, thereby disentangling the contributions from different IR intensities. The use of spatial imaging reveals intensity dependent mass distributions that are substantially narrower than what has been observed previously, indicating rather narrow energy distributions. A simple rate-equation modeling of the excitation process supports the experimental observations. PMID- 20170226 TI - Electron scattering at high momentum transfer from methane: analysis of line shapes. AB - The measurement of the energy distribution of keV electrons backscattered elastically from molecules reveals one or more peaks. These peaks are at nonzero energy loss and have an intrinsic width. The usual interpretation of these measurements is attractively simple and assumes billiard-ball-type collisions between the electron and a specific atom in the molecule, and the scattering atom is assumed to behave as a free particle. The peak position is then related to the mass of the scattering atom, and its width is a Compton profile of the momentum distribution of this atom in the molecule. Here we explore the limits of the validity of this picture for the case of electrons scattering from methane. The biggest discrepancy is found for electrons scattering from carbon. For electrons scattering from hydrogen the effects are substantial at relatively low incoming energies and appear to decrease with increasing momentum transfer. The discrepancy is analyzed in terms of the force the atom experiences near the equilibrium position. PMID- 20170227 TI - Accurate ab initio potential energy curve of O2. II. Core-valence correlations, relativistic contributions, and vibration-rotation spectrum. AB - In the first paper of this series, a very accurate ab initio potential energy curve of the (3)Sigma(g)(-) ground state of O(2) has been determined in the approximation that all valence shell electron correlations were calculated at the complete basis set limit. In the present study, the corrections arising from core electron correlations and relativity effects, viz., spin-orbit coupling and scalar relativity, are determined and added to the potential energy curve. From the 24 points calculated on this curve, an analytical expression in terms of even tempered Gaussian functions is determined and, from it, the vibrational and rotational energy levels are calculated by means of the discrete variable representation. We find 42 vibrational levels. Experimental data (from the Schumann-Runge band system) only yield the lowest 36 levels due to significant reduction in the transition intensities of higher levels. For the 35 term values G(v), the mean absolute deviation between theoretical and experimental data is 12.8 cm(-1). The dissociation energy with respect to the lowest vibrational energy is calculated within 25 cm(-1) of the experimental value of 41,268.2+/-3 cm(-1). The theoretical crossing between the (3)Sigma(g)(-) state and the (1)Sigma(g)(+) state is found to occur at 2.22 A and the spin-orbit coupling in this region is analyzed. PMID- 20170228 TI - Photoelectron spectroscopy and density functional calculations of Fe(n)BO2- clusters. AB - We conducted a study of Fe(n)BO(2)(-) clusters by mass spectrometry and photoelectron spectroscopy. The vertical detachment energies and adiabatic detachment energies of these clusters were evaluated from their photoelectron spectra. We have also performed density-functional calculations of Fe(n)BO(2)(-) (n=1-5) clusters and determined their structures by comparison of theoretical calculations to experimental results. The studies show that BO(2) moiety still maintains its linear structure as the bare BO(2) cluster. BO(2) behaves as a superhalogen. Analysis of molecular orbitals reveals that the highest occupied molecular orbitals of Fe(n)BO(2)(-) clusters are mainly localized on the Fe(n) units. PMID- 20170229 TI - Substitution effects in elastic electron collisions with CH3X (X=F, Cl, Br, I) molecules. AB - We report absolute elastic differential, integral, and momentum transfer cross sections for electron interactions with the series of molecules CH(3)X (X=F, Cl, Br, I). The incident electron energy range is 50-200 eV, while the scattered electron angular range for the differential measurements is 15 degrees-150 degrees. In all cases the absolute scale of the differential cross sections was set using the relative flow method with helium as the reference species. Substitution effects on these cross sections, as we progress along the halomethane series CH(3)F, CH(3)Cl, CH(3)Br, and CH(3)I, are investigated as a part of this study. In addition, atomic-like behavior in these scattering systems is also considered by comparing these halomethane elastic cross sections to results from other workers for the corresponding noble gases Ne, Ar, Kr, and Xe, respectively. Finally we report results for calculations of elastic differential and integral cross sections for electrons scattering from each of the CH(3)X species, within an optical potential method and assuming a screened corrected independent atom representation. The level of agreement between these calculations and our measurements was found to be quite remarkable in each case. PMID- 20170230 TI - Determination of the v-j vector correlation in the photodissociation of nitrosobenzene at 305 nm. AB - The 305 nm photofragmentation dynamics of nitrosobenzene was measured using velocity-mapped ion imaging with polarized 1+1' resonance-enhanced multiphoton ionization probing of the NO (X, v"=0) fragment. The product recoil energy and angular distributions of selected rotational states of NO (X (2)Pi(1/2,3/2)) products have been measured. The recoil anisotropy of the NO photofragment is very small with beta(0)(2)(20)=0.03. The v-j vector correlation of NO shows a preference for v//j with an average value of beta(0)(0)(22)=+0.15 over the transitions studied. A mechanism involving dissociation from the ground state is used to explain the unusual propellerlike trajectory of the nascent NO. PMID- 20170231 TI - Light scattering and sum rules of three coexisting phases for quasiternary solutions near the tricritical point. AB - The upper critical temperatures (T(U)) and the lower critical temperatures (T(L)) were precisely determined for 11 quasiternary solutions of water +n-decane and +n undecane +tert-butanol with various mass ratios of n-decane to n-undecane. Measurements of angular dependence of the scattered light intensity for each of the three liquid coexisting phases and each of the 11 solutions at the middle temperatures T(m)=(T(U)+T(L))/2 are reported. From the light scatting data, the zero-angle scattering intensities I(0) and the correlation lengths xi at T(m) in each of the phases were calculated and used to test the Griffiths sum rules. It was found that (DeltaT)(2/3) (where DeltaT=T(U)-T(L)) is a good thermodynamic field to measure the distance from the tricritical point, and the second sum is converged to zero with a proportionality to (DeltaT)(2/3) as the system approaches the tricritical point, which is in agreement with what the classical asymptotic theory predicted. However the first sums are neither zero nor constant, they are significantly curved and unambiguously diverged as strongly as does an individual susceptibility, which evidences that the amplitude ratios are nonclassical. PMID- 20170232 TI - Effect of the local hydrogen bonding network on the reorientational and translational dynamics in supercritical water. AB - Molecular dynamics simulations have been performed in a wide range of densities along a near critical isotherm of supercritical water in order to reveal the interconnection between the local hydrogen bonding (HB) network and several related dynamic properties. The results obtained have revealed a significant slowing down of reorientational dynamics of the water molecules as the value of the number of hydrogen bond per molecule increases and this is reflected on the increase in the reorientational correlation times. The calculated reorientational times exhibit also an increasing trend by increasing the bulk density, and this effect is more pronounced in the case of the first-order Legendre reorientational correlation functions. A clear nonlinear dependence of the librational mode frequencies of the water molecules on the augmented local density around them has also been revealed. This result could be regarded as an additional support of experimental observations suggesting the use of a nonlinear relation when analyzing the density dependence of spectroscopic peak frequencies in order to extract information about local density augmentation in supercritical fluids. The HB dynamics have been also investigated, revealing a plateau in the calculated HB lifetimes at intermediate and higher liquidlike densities and a small increase at low, gaslike densities. PMID- 20170233 TI - Excess entropy and structural transitions in a two-dimensional square-shoulder fluid. AB - Metropolis Monte Carlo simulations on the square-shoulder fluid of Malescio and Pellicane are used to trace the temperature dependent excess entropy, the heat capacity, and configurational energy along several isochores, including those for which mechanically stable zero-temperature structures have been predicted. Thermodynamic signatures of structural phase transitions are identified along several isochores, in addition to the low-density triangular solid and stripe phase transitions identified earlier. The finite temperature phases illustrate the competition between cluster formation and stripe formation as competing mechanisms for generating minimum free energy configurations as a function of density, consistent with earlier results at zero temperature. We also critically examine the usefulness of a phase-ordering rule based on the residual multiparticle entropy (RMPE) in predicting the formation of this diverse set of ordered structures from a disordered fluid phase. For the majority of the isochores studied, the RMPE prediction and the thermodynamic evidence for a phase transition were consistent. However, this criterion fails along isochores that are in regions of coexistence. Thus, the zero-RMPE rule is only likely to be approximately predictive in systems with small phase coexistence regimes, e.g., in the case of liquid crystal forming systems. PMID- 20170234 TI - Collective dynamics in a liquid polyvalent metal: liquid thallium at the melting point. AB - Collective dynamics in liquid thallium at the melting point in a wide range of wave numbers and frequencies is studied by molecular dynamics simulations and a theoretical analysis of time correlation functions within the approach of generalized collective modes. The heat fluctuations were explicitly treated in the theoretical scheme within the thermoviscoelastic dynamic model. We report dispersion and damping of generalized longitudinal sound excitations, nonhydrodynamic shear and heat waves, as well as wave number dependence of main relaxation processes. Generalized wave number-dependent thermodynamic quantities and transport coefficients in liquid Tl are discussed. PMID- 20170235 TI - Crystallization limits of the two-term Yukawa potentials based on the entropy criterion. AB - We examine the fluid-solid transition for the potential with two Yukawa terms (one attractive and the other repulsive) and a hard core by exploration of the parameter space of (K(1), Z(1), and Z(2)), i.e., the parameters of interaction strength and interaction ranges, respectively. We apply the single-phase crystallization rule of Giaquinta and Giunta (1992) by searching for the conditions where the residual entropy reaches zero. To obtain accurate entropy properties, we adopt the self-consistent closure theory of the zero-separation genre. This closure gives accurate thermodynamic properties. The Ornstein-Zernike equation is solved to obtain the correlation functions. The structure factor S(q) is examined with respect to its cluster-cluster peak, whose value is another indication of phase transition according to Hansen and Verlet (1969). We discover that the parameter Z(1) (which determines the range of attractive forces) is important in crystal formation, so long as sufficient attraction (parameter K(1)) is present. If the range of attraction is too narrow, strength alone is not adequate to satisfy the Giaquinta rule or to solidify at given concentration and temperature. The control of the range of repulsion rests with the Z(2)-parameter. Its variations can bring about a high peak in S(q) at zero wave number (i.e., at q=0). Implications for the crystallization of protein and colloidal solutions are discussed. PMID- 20170236 TI - Calculations of vibrationally resonant sum- and difference-frequency-generation spectra of chiral molecules in solutions: three-wave-mixing vibrational optical activity. AB - Determining absolute configuration of chiral molecule can be achieved by using vibrational optical activity (VOA) measurement methods, such as vibrational circular dichroism and Raman optical activity (ROA). Recently, vibrationally resonant sum frequency generation and difference frequency generation utilizing circularly polarized beams were theoretically studied and shown that they can be alternative and complementary VOA measurement techniques [S. Cheon and M. Cho, Phys. Rev. A 71, 013808 (2005); J. Phys. Chem. A 113, 2438 (2009)]. Even for randomly oriented chiral molecules in solutions, the sum- and difference frequency-generation signals induced by linearly polarized incident beams with mutually perpendicular polarization directions can be nonzero and are determined by the optical activity hyperpolarizability given by a product of antisymmetric Raman tensor and vibrational transition dipole. If one of the beams involved in the three-wave-mixing processes is circularly polarized and if the difference signal is measured, not only the same optical activity hyperpolarizability but also that including electric quadrupole-ROA tensor are required to determine the signals. Here, we carried out quantum chemistry calculations to obtain these quantities for a representative chiral molecule, (S)-methyl lactate, and numerically simulated the corresponding spectra. It is shown that the circular polarization three-wave-mixing signal intensities are quantitatively similar to those of the linear polarization three-wave-mixing signals, respectively, and that they are sensitive to the absolute configuration of chiral molecule. The calculation results thus suggest that these two novel techniques will be of use in studying molecular chirality even in time domain, once polarization-modulated ultrashort pulses are used to carry out circular polarization three-wave-mixing experiments. PMID- 20170237 TI - Calculation of proper energy barriers for atomistic kinetic Monte Carlo simulations on rigid lattice with chemical and strain field long-range effects using artificial neural networks. AB - In this paper we take a few steps further in the development of an approach based on the use of an artificial neural network (ANN) to introduce long-range chemical effects and zero temperature relaxation (elastic strain) effects in a rigid lattice atomistic kinetic Monte Carlo (AKMC) model. The ANN is trained to predict the vacancy migration energies as calculated given an interatomic potential with the nudged elastic band method, as functions of the local atomic environment. The kinetics of a single-vacancy migration is thus predicted as accurately as possible, within the limits of the given interatomic potential. The detailed procedure to apply this method is described and analyzed in detail. A novel ANN training algorithm is proposed to deal with the necessarily large number of input variables to be taken into account in the mathematical regression of the migration energies. The application of the ANN-based AKMC method to the simulation of a thermal annealing experiment in Fe-20%Cr alloy is reported. The results obtained are found to be in better agreement with experiments, as compared to already published simulations, where no atomic relaxation was taken into account and chemical effects were only heuristically allowed for. PMID- 20170238 TI - The observation of formation and annihilation of solitons and standing strain wave superstructures in a two-dimensional colloidal crystal. AB - Confining a colloidal crystal within a long narrow channel produced by two parallel walls can be used to impose a mesoscale superstructure of a predominantly mechanical elastic character [Chui et al., EPL 83, 58004 (2008)]. When the crystal is compressed in the direction perpendicular to the walls, we obtain a structural transition when the number of rows of particles parallel to the walls decreases by one. All the particles of this vanishing row are distributed throughout the crystal. If the confining walls are structured (say with a corrugation along the length of the walls), then these extra particles are distributed neither uniformly nor randomly; rather, defect structures are created along the boundaries resembling "soliton staircases," inducing a nonuniform strain pattern within the crystal. Here, we study the conditions of stability, formation, and annihilation of these solitons using a coarse grained description of the dynamics. The processes are shown by comparing superimposed configurations as well as molecular animations obtained from our simulations. Also, the corresponding normal and shear stresses during the transformation are calculated. A study of these dynamical processes should be useful for controlling strain wave superstructures in the self-assembly of various nano- and mesoscaled particles. PMID- 20170239 TI - First-principles calculations of Fe-doped monolayer C60 on h-BN/Ni(111) surface. AB - We have used large-scale first-principles calculations based on density functional theory to investigate the structure, energetics, electronic, and magnetic structures of Fe(n)-doped C(60) monolayers supported by h-BN monolayer covered Ni(111) surfaces. A systematic study of n-dependent physical properties has been performed (n=1-4,15). Binding energies on Fe atoms to the Fe(n-1)-C(60) complex have been calculated for n=1-4 after a thorough configuration search and structural optimization. The binding energy, electron charge transfer (from Fe(n) to C(60)), and magnetic moment all increase monotonically as functions of n. The electron charge transfer, ranging from approximately 1e(-) to 5e(-), is from the spin minority population. This leads to a situation in which the net spin of the C(60) molecule aligns with the spin minority and the magnetic moment in C(60) is opposite to the total magnetic moment of the system. For n=2, a competing antiferromagnetic state has been found. In this state, the net spin of the system as well as the C(60) is zero. Density of states and projected density of states analysis indicate that the system becomes metallic upon metal doping regardless its magnetic state. In addition, we have also performed calculations with the Hubbard U term (DFT+U) for two systems, n=4 and 15, to investigate possible gap opening near the Fermi surface. PMID- 20170240 TI - Bond order effects in electromechanical actuation of armchair single-walled carbon nanotubes. AB - In this paper we first use ab initio simulations to study the strains induced by charging an armchair (5,5) carbon nanotube (CNT) segment. The observed behavior is far from a monotonic expansion that one might have expected from a classical point of view. Subsequently a new method is proposed to predict the nonelectrostatic part of the electromechanical actuation response of the nanotube based on the spatial distribution of its molecular orbitals. Locally bonding and locally antibonding molecular orbitals are defined for the CNT segment structure based on analogy with bonding and antibonding orbitals in diatomic molecules. The nonmonotonic overall actuation is explained based on the above proposition and the general alignment of the expanding and contracting bonds with respect to the axis or circumference of the CNT segment. Using the well-known concept of bond order, the actuation of this complex system of many atoms is predicted with close quantitative agreement with the ab initio simulations. PMID- 20170241 TI - The intensity correlation function in evanescent wave scattering. AB - As a first step toward the interpretation of dynamic light scattering with evanescent illumination from suspensions of interacting spheres, in order to probe their near wall dynamics, we develop a theory for the initial slope of the intensity autocorrelation function. An expression for the first cumulant is derived that is valid for arbitrary concentrations, which generalizes a well known expression for the short-time, wave-vector dependent collective diffusion coefficient in bulk to the case where a wall is present. Explicit expressions and numerical results for the various contributions to the initial slope are obtained within a leading order virial expansion. The dependence of the initial slope on the components of the wave vector parallel and perpendicular to the wall, as well as the dependence on the evanescent-light penetration depth are discussed. For the hydrodynamic interactions between colloids and between the wall, which are essential for a correct description of the near-interface dynamics, we include both far-field and lubrication contributions. Lubrication contributions are essential to capture the dynamics as probed in experiments with small penetration depths. Simulations have been performed to verify the theory and to estimate the extent of the concentration range where the virial expansion is valid. The computer algorithm developed for this purpose will also be of future importance for the interpretation of experiments and to develop an understanding of near interface dynamics, at high colloid concentrations. PMID- 20170242 TI - Self-assembly of enantiopure domains: the case of indigo on Cu(111). AB - The adsorption of indigo molecules on Cu(111) was investigated by low temperature (5 K) scanning tunneling microscopy from the isolated single molecule regime to one monolayer. Structural optimization and image calculations demonstrate that the molecules are in a physisorbed state. Because of the reduced symmetry at the surface, single molecules acquire a chiral character upon adsorption leading to a two-dimensional (2D) chirality. They adopt two adsorption configurations, related by a mirror symmetry of the substrate, each with a distinct molecular orientation. Consequently, the 2D chirality is expressed by the orientation of the molecule. For higher coverage, molecules self-assemble by hydrogen bonding in nearly homochiral molecular chains, whose orientation is determined by the orientation taken by the isolated molecules. When the coverage approaches one monolayer, these chains pack into domains. Finally, the completion of the monolayer induces the expulsion of the molecules of the wrong chirality that are still in these domains, leading to perfect resolution in enantiopure domains. PMID- 20170243 TI - Structure and infrared absorption of the first layer C2H2 on the NaCl(100) single crystal surface. AB - The adsorbate structure of the first layer acetylene on the NaCl(100) single crystal surface is investigated using polarization infrared spectroscopy in combination with low-energy electron diffraction (LEED) experiments, and potential calculations on the basis of pair potentials. In agreement with a previous study, a triplet of infrared absorptions in the region of the asymmetric stretch vibration of C(2)H(2) was observed and assigned to an adsorbate phase with (3 square root 2 x square root 2)R45 degrees translational symmetry determined in the LEED experiment. The polarization dependence of the infrared spectra is consistent with a parallel orientation of the molecules with respect to the surface. The number of molecules per unit cell is four to six as determined by photometric considerations. Total energy minimizations support a new structure model which contains five inequivalent molecules per unit cell in a herringbone arrangement. The application of a vibrational exciton approach demonstrates that this new structure model can reproduce the triplet spectrum observed in the infrared experiments. PMID- 20170244 TI - Photodissociation of CH3Cl, C2H5Cl, and C6H5Cl on the Ag(111) surface: ab initio embedded cluster and configuration interaction study. AB - We report a comparative study of the photoinduced C-Cl bond cleavage in three Rd Cl molecules (Rd=CH(3), C(2)H(5), and C(6)H(5) radicals) on the Ag(111) surface. The ground, lowest excited states as well as anion states of adsorbed molecules have been computed at their equilibrium geometry and along the C-Cl dissociation pathway using the ab initio embedded cluster and multireference configuration interaction methods. The anion state can be formed by photoinduced electron transfer from the substrate to an adsorbate and is strongly bound to the surface in contrast with the electronic states of the adsorbate itself, which are only weakly perturbed by the silver surface. The excitation energy of the anion state lies lower in the Franck-Condon region than that of the lowest singlet excited state for all adsorbates and correlates directly with the dissociation products: adsorbed chlorine atom and the gas phase or adsorbed radical for Rd=CH(3), C(2)H(5), and C(6)H(5), respectively. The computed redshift of the photodissociation spectrum for the substrate-mediated photodissociation process relative to the corresponding gas-phase reaction is approximately 2 eV for CH(3)Cl and C(2)H(5)Cl, and approximately 1 eV for C(6)H(5)Cl, which result is in good agreement with experimental data. PMID- 20170245 TI - Self-assembly of amphiphilic peanut-shaped nanoparticles. AB - We use computer simulation to investigate the self-assembly of Janus-like amphiphilic peanut-shaped nanoparticles, finding phases of clusters, bilayers, and micelles in accord with ideas of packing familiar from the study of molecular surfactants. However, packing arguments do not explain the hierarchical self assembly dynamics that we observe, nor the coexistence of bilayers and faceted polyhedra. This coexistence suggests that experimental realizations of our model can achieve multipotent assembly of either of two competing ordered structures. PMID- 20170246 TI - The stress tensor in thermodynamics and statistical mechanics. AB - We prove that the stress tensor, tau(ab), of a molecular system with arbitrary, short-range interactions can be point-wisely expressed as the functional derivative of the partition function with respect to the local deformation tensor. In this approach, the set of components of tau(ab) has a simple interpretation as the set of Lagrangian multipliers which one needs to introduce to enforce the conditions relating point particle displacements to the body local deformation tensor. The question of the possible nonuniqueness of the formula for tau(ab) is discussed. PMID- 20170247 TI - Solvent effects in polyelectrolyte adsorption: computer simulations with explicit and implicit solvent. AB - The adsorption of strongly charged polyelectrolyte chains to an oppositely charged planar surface is studied using computer simulation. In addition to an explicit solvent model, two implicit solvent models are considered: one where the solvent induces an implicit Lennard-Jones (ILJ) interaction between polymer sites and one where the solvent induces a many body interaction that depends on the solvent accessible surface area (SASA) of the monomers. Molecular and Brownian dynamics simulations are reported for the explicit and implicit solvent models, respectively. All three models give similar results for the adsorption of the chains in good solvent. The electrostatic attraction between the surface and the polymers is not sufficient to drive the strong adsorption that is seen in experiments. In poor solvents, the models give different results for the adsorption excess and the mechanism for polyelectrolyte adsorption. With explicit solvent, thick adsorbed layers are formed at both charged and neutral surfaces. With the SASA model, adsorbed layers are formed on the charged but not on the neutral surface. With the ILJ model, adsorbed layers are not formed on any surfaces. The results show that the solvent plays a dominant role in the adsorption of polyelectrolytes under poor solvent conditions and that many-body solvent effects have a qualitative effect on the adsorption characteristics and mechanism. In particular, SASA and depletion effects could possibly play an important role; the former can be incorporated in the SASA model, but the latter cannot. The results suggest that accurate computational models for polymer adsorption under poor solvent conditions must incorporate the solvent explicitly. PMID- 20170248 TI - The finite size effect of monomer units on the electrostatics of polyelectrolyte solutions. AB - The effective interactions between two test counterions and two test solvent dipoles in a semidilute/concentrated weakly charged polyelectrolyte solution are studied using the field-theoretical approach on the mean-field level. From the effective Hamiltonians in terms of the two test counterions and the two test solvent dipoles, respectively, analytical expressions for the effective interactions in the real space are derived. It is unambiguously demonstrated that, at a Theta solvent condition, both the effective interactions between two counterions and two parallel-oriented solvent dipoles consist of an attractive part at intermediate distances of separation. As the electrostatic screening effect from counterions and salt ions quantified by the Debye-Huckel screening parameter becomes stronger, the magnitude of the attraction decreases and the minimum of the attractive profile shift to a shorter distance of separation. On the other hand, when the excluded volume effect is dominant, the effective interactions are purely repulsive. This nontrivial and seemingly counterintuitive result originates from the finite size effect of the monomer units of the polymer chains on the electrostatics of the polyelectrolyte solution. As the size of the monomer units goes to zero, at the Theta solvent condition, the effective interactions between two counterions and two parallel-oriented solvent dipoles are purely repulsive. PMID- 20170249 TI - Fluctuation in entanglement positions via elastic slip-links. AB - We consider the spatiotemporal fluctuation of slip-link positions via the implementation of elastic slip-links. The level of description is similar to our previously proposed slip-link model, wherein we use the entanglement position in space as dynamic variables, and the number of Kuhn steps between entanglements. However, since it is a mean-field, single-chain description it has some relevance to the slip-spring simulations of Likhtman, and the phantom chain model for cross linked networks. It might also provide a connection between slip-links and tubes. Two implementations are possible, depending on whether or not the slip-links are allowed to pass through one another. If a boundary condition on the dynamics preventing such passage is imposed, then the plateau modulus is unchanged from perfectly rigid slip-links. Only the dynamics is changed. On the other hand, for phantom slip-links the distribution of the number of entanglements changes from Poisson. Furthermore, requiring normalization of the distribution function sets a constraint on how loose the virtual springs for the elastic slip-link are. These restrictions appear to be in agreement with parameter values used for the slip spring simulations, although nonphantom slip-links were used there. The results are completely analogous to what was found by James and Guth for ideal elastic networks, whose derivation is repeated here. Our earlier rigid slip-link model is recovered as a limiting case. PMID- 20170250 TI - Does Brillouin light scattering probe the primary glass transition process at temperatures well above glass transition? AB - The primary alpha-relaxation time (tau(alpha)) for molecular and polymeric glass formers probed by dielectric spectroscopy and two light scattering techniques (depolarized light scattering and photon correlation spectroscopy) relates to the decay of the torsional autocorrelation function computed by molecular dynamics simulation. It is well known that Brillouin light scattering spectroscopy (BLS) operating in gigahertz frequencies probes a fast (10-100 ps) relaxation of the longitudinal modulus M*. The characteristic relaxation time, irrespective of the fitting procedure, is faster than the alpha-relaxation which obeys the non Arrhenius Vogel-Fulcher-Tammann equation. Albeit, this has been noticed, it remains a puzzling finding in glass forming systems. The available knowledge is based only on temperature dependent BLS experiments performed, however, at a single wave vector (frequency). Using a new BLS spectrometer, we studied the phonon dispersion at gigahertz frequencies in molecular [o-terphenyl (OTP)] and polymeric [polyisoprene (PI) and polypropylene (PP)] glass formers. We found that the hypersonic dispersion does relate to the glass transition dynamics but the disparity between the BLS-relaxation times and tau(alpha) is system dependent. In PI and PP, the former is more than one order of magnitude faster than tau(alpha), whereas the two relaxation times become comparable in the case of OTP. The difference between the two relaxation times appears to relate to the "breadth" of the relaxation time distribution function. In OTP the alpha-relaxation process assumes a virtually single exponential decay at high temperatures well above the glass transition temperature, in clear contrast with the case of the amorphous bulk polymers. PMID- 20170251 TI - Correlated dynamics of water and amphiphilic molecules in thin Newton black films. AB - The dynamical properties of amphiphilics in Newton black films, as well as those of the water confined between the two charged hydrophilic surfaces, have been calculated via a series of molecular dynamic calculations in several films with different water contents. A charged semiflexible amphiphilic model and the TIP5P model of water are used in our simulations [Z. Gamba, J. Chem. Phys. 129, 164901 (2008)]. We calculate the diffusion coefficients, reorientational dynamics, and the atomic density profile of water molecules as a function of the number of water molecules per amphiphilic (n(w)). We also analyze the reorientational motion of the amphiphilics and determine a strong correlation between the dynamics of water molecules and the translational and reorientational dynamics of the amphiphilics, as well as a correlation between the reorientational dynamics of the amphiphilics belonging to the upper and lower halves of the studied thin films. PMID- 20170253 TI - Characterisation of protein adsorption on different liquid crystal phthalocyaninethin films. AB - Bovine serum albumin (BSA) protein adsorption on thin spun films of different metal octakishexylthiophthalocyanine [(C(6)S)(8)PcM, M=Cu, Ni] derivatives is investigated by using three independent spectroscopic measurements namely Raman spectroscopy, ellipsometry and surface plasmon resonance imaging. Thermally induced molecular self-reorganisations in the phthalocyanine films are found to have produced the changes in the surface energy which, in turn, control protein adsorption. The amount of BSA adsorption on [(C(6)S)(8)PcNi] is more limited than that on [(C(6)S)(8)PcCu] and this observation is consistent with the results on the surface wettability obtained from the contact angle measurements. The shift from the plasmonic resonance wavelength because of the BSA adsorption was significantly larger for the heat-treated [(C(6)S)(8)PcCu] than as-deposited film. Similar measurements on the [(C(6)S)(8)PcNi] films showed a limited BSA adsorption. The results of surface plasmon resonance experiments are consistent with those obtained from Raman spectroscopic and ellipsometric techniques. PMID- 20170252 TI - Thermal nanostructure: an order parameter multiscale ensemble approach. AB - Deductive all-atom multiscale techniques imply that many nanosystems can be understood in terms of the slow dynamics of order parameters that coevolve with the quasiequilibrium probability density for rapidly fluctuating atomic configurations. The result of this multiscale analysis is a set of stochastic equations for the order parameters whose dynamics is driven by thermal-average forces. We present an efficient algorithm for sampling atomistic configurations in viruses and other supramillion atom nanosystems. This algorithm allows for sampling of a wide range of configurations without creating an excess of high energy, improbable ones. It is implemented and used to calculate thermal-average forces. These forces are then used to search the free-energy landscape of a nanosystem for deep minima. The methodology is applied to thermal structures of Cowpea chlorotic mottle virus capsid. The method has wide applicability to other nanosystems whose properties are described by the CHARMM or other interatomic force field. Our implementation, denoted SIMNANOWORLD, achieves calibration-free nanosystem modeling. Essential atomic-scale detail is preserved via a quasiequilibrium probability density while overall character is provided via predicted values of order parameters. Applications from virology to the computer aided design of nanocapsules for delivery of therapeutic agents and of vaccines for nonenveloped viruses are envisioned. PMID- 20170254 TI - Coupled model analysis of the structure and nano-mechanical properties of dragonfly wings. AB - To establish the quantitative model of the dragonfly wing the reconfiguration and nanoindentation technique were used. The mechanical properties of wings were measured by nanoindentre. Generally, the costa undertake is mainly pressure, and its mechanical properties should be the largest. However, in the nanoindentation test, the largest value of the reduced modulus (E(r)) and hardness (H) mainly appear in the radius, except the value at 0.7L (L is the wing length). The E(r) and H of the forewing were larger than that of the hindwing, except the value at 0.7L. The reversing engineering (3-D scanner) and AutoCAD were cooperated to reconfigure the dragonfly wing. Then the material parameters and skeleton transforms to a finite element analysis. The quantitative models were discussed in static range. PMID- 20170256 TI - An evaluation study on the relevance and effectiveness of training activities in Northern Uganda. AB - INTRODUCTION: In-service training is required for quality health service delivery, particularly in a human resource constrained setting. However, detailed evaluation of training effectiveness is rarely conducted because the improved theoretical knowledge demonstrated by trainees during training is commonly used as a proxy indicator of effectiveness. This study focused on a trained health workforce in Northern Uganda. The retention of specifically-trained staff 12-15 months after attending training was examined, as was the relevance and usefulness of the training as perceived by the health workers. METHODS: This cross-sectional descriptive study used a structured questionnaire to interview 104 health workers (mainly paramedics) who received training in the Northern Uganda Malaria, AIDS & HIV and TB Program in the period July 2007 to February 2008. RESULTS: Of the 104 interviewed health workers, 71% were still deployed at the original work site at the time of the interview and 87% reported they found the training event attended to be useful. However, any form of follow up was provided to only 40% of respondents, and 25% reported having attended another similar training event on the same topic at some point in time. CONCLUSION: All programs with a substantial training component should conduct a periodic methodical evaluation of the training. PMID- 20170255 TI - Parallel growth and healing of DNA self-assembly for interconnects. AB - Self-assembly has been employed in nano-technology to build crystals using individual components (commonly referred to as tiles) with limited control. Templates of regular lattice structures for two-dimensional scaffolds and interconnects have been recently implemented by self-assembly. This study proposes a diagonally based growth scheme that is applicable to these templates of interconnects (as an example). Differently from previous techniques (mostly sequential in execution), growth is allowed along two different directions in the aggregate, thus permitting a parallel mode of operation. This is made possible by utilising a tile set and binding scheme to allow multiple seed tiles to grow along the main diagonal of the pattern. The conditions by which this type of new growth is possible at a reduced error occurrence in mismatched tiles, are presented; error tolerance is achieved by employing healing and so-called robust generation of the seed tiles, thus ensuring that pattern growth is controlled along both directions. Simulation results are presented under different scenarios of growth direction (inclusive of backward growth for healing). PMID- 20170257 TI - The evolution of epidemic suicide on Guam: context and contagion. AB - Thirty years of suicide rates for Guam were analyzed by age, sex, period, and cohort. Youth suicide increased rapidly in the 1990s; certain cohorts have higher rates. Four explanatory factors are discussed, including ecological factors and migration from the Federated States of Micronesia. Direct and indirect suicide contagion followed the death by suicide of a respected politician, strongly influencing period and cohort patterns. Suicide pacts inflated suicide among young people. These factors acted in combination to produce epidemic levels of suicide in the 1990s. PMID- 20170258 TI - Suicide attempts within 12 months of treatment for substance use disorders. AB - There are limited prospective data on suicide attempts (SA) during the months following treatment for substance use disorders (SUD), a period of high risk. In an analysis of the Drug Abuse Treatment Outcomes Study, a longitudinal naturalistic multisite study of treated SUDs, variables associated with SA in the 12 months following SUD treatment were examined. Participants included 2,966 patients with one or more SUDs. By 12 months, 77 (2.6%) subjects had attempted suicide. Multivariate logistic regression analyses were used to identify variables associated with SA. Variables collected at baseline that were associated with SA included lifetime histories of SA, suicidal ideation (SI), depression, cocaine as primary substance of use, outpatient methadone treatment, and short-term inpatient treatment. Male sex, older age, and minority race or ethnicity were associated with lower likelihood of SA. After controlling for baseline predictors, variables assessed at 12 months associated with SA included SI during follow-up and daily or more use of cocaine. The data contribute to a small but growing literature of prospective studies of SA among treated SUDs, and suggest that SUDs with cocaine use disorders in particular should be a focus of prevention efforts. PMID- 20170259 TI - Method of suicide in the mentally ill: a national clinical survey. AB - Comparisons of psychiatric patients who die by suicide using different methods are scarce. We aimed to establish the methods of suicide used by those who are currently or have recently been in contact with mental health services in England and Wales (N = 6,203), and describe the social and clinical characteristics of suicides by different methods. We found that hanging, self-poisoning, and jumping (from a height or in front of a moving vehicle) were the most common methods of suicide, accounting for 79% of all deaths. The implications of these and other findings are discussed. PMID- 20170260 TI - Negative intrusive thoughts and dissociation as risk factors for self-harm. AB - Relationships between self-harm and vulnerability factors were studied in a general population of 432 participants, of whom 30% reported some experience of self-harm. This group scored higher on dissociation and childhood trauma, had lower self-worth, and reported more negative intrusive thoughts. Among the non harming group, 10% scored similarly to the self-harmers on the dissociation and self-worth scales, and engaged in potentially maladaptive behaviors that are not defined as indicating clinical self-harm, but experienced fewer negative intrusive thoughts. This group may be at risk of future self-harm if they begin to experience negative intrusive thoughts. If negative intrusive thoughts are playing a causal role, then therapeutic approaches tackling them may help those who are currently self-harming. PMID- 20170261 TI - Investigating the co-occurrence of self-mutilation and suicide attempts among opioid-dependent individuals. AB - The prevalence and risk factors associated with self-mutilation among opioid dependent cases and controls were determined, and the co-occurrence of self mutilation and attempted suicide was examined. The prevalence of self-mutilation among cases and controls did not differ significantly (25% vs. 23%, respectively), with gender differences identified among cases only. A number of risk factors were found to be associated with self-mutilation, including borderline personality disorder, alcohol dependence, childhood sexual abuse, and multiple suicide attempts. Not only is self-mutilation a clinically significant problem, but when combined with a history of attempted suicide, the psychological dysfunction observed is markedly high. PMID- 20170262 TI - Suicide and firearm means restriction: can training make a difference? AB - Along with physician education in depression recognition and treatment, restricting lethal methods is an effective suicide prevention strategy. The present study surveyed a random sample (N = 697) of Ohio licensed social workers regarding client firearm assessment and safety counseling. Analyses sought to determine what independent factors would predict the probability that a social worker would hold positive attitudes regarding firearm risk assessment and counseling. Findings indicated that prior training and reporting from an urban area significantly increased the odds (p < .05) of registering more positive attitudes toward firearm assessment and safety counseling by 91.1% and 44.7%, respectively. Training mental health professionals in firearm assessment and safety counseling is an important aspect in addressing the reduction of suicide by this means. PMID- 20170263 TI - Why we need qualitative research in suicidology. AB - Using the differentiation between explanations and understanding from philosophy of science as the point of departure, a critical look at the current mainstream suicidological research was launched. An almost exclusive use of quantitative methodology focusing on explanations is demonstrated. This bias in scope and methodology has to a large extent taken the suicidological field into a dead-end of repetitious research. It is argued that an increased focus on understanding and thus extended use of qualitative methodology is essential in bringing the suicidological field forward. PMID- 20170264 TI - The media and suicide: evidence based on population data over 9 years in Taiwan. AB - The relationship between the regional distribution densities of different media and the suicide death rate was explored by analyzing the annual total, male, and female suicide rates and media densities from 23 cities/counties in Taiwan during 1998-2006 by univariate and multivariate regression adjusted for five socioeconomic factors. The regional density of newspapers was significantly inversely related to the total, male, and female suicide rates, while that of television sets was not. The density of in-home personal computers was significantly positively related to the total and male suicide rates, but not the female suicide rate. The results indicate that media reporting on suicide can be beneficial, instead of harmful, depending on the content. PMID- 20170265 TI - The associations between infant homicide, homicide, and suicide rates: an analysis of world health organization and centers for disease control statistics. AB - Previous studies have found that rates of homicide of children aged under one (infant homicide) are associated with rates of suicide, but not with rates of homicide. Linear regression was used to examine associations among infant homicide, homicide, and suicide in samples of regions in the United States and other countries. Infant homicide rates were significantly and independently associated in all analyses with both total homicide and total suicide rates. The epidemiological evidence supports the clinical observation that infant homicides are due to a range of causes, including maternal mental illness, but are also related to the level of serious violence within a community. PMID- 20170266 TI - Our sexy brain; our compelling environment: interactionism in female development. PMID- 20170267 TI - Womb speak. PMID- 20170268 TI - The "undifferentiated selfobject"--a contribution to understanding symptomatic behavior and fixation: the suicidal patient. PMID- 20170269 TI - Toward new metapsychologies. PMID- 20170270 TI - Mind, meaning, and quantum physics: models for understanding the dynamic unconscious. PMID- 20170271 TI - A holistic framework for psychoanalysis. PMID- 20170272 TI - Desdemona's inner conflicts. PMID- 20170273 TI - The resurgence of the repressed in John Updike's homecoming stories "The Sandstone Farmhouse" and "The Cats". PMID- 20170276 TI - Sudden unexpected death in infancy associated with an epithelial-type hepatoblastoma in a 6-month-old infant. AB - Sudden unexpected death in infancy and childhood attributable to undiagnosed neoplasia is rare. Malignant neoplasms are very uncommon in infancy, with an age standardized incidence rate of 118.3 per million. Primary malignant liver tumors are rare, with hepatoblastoma accounting for up to two thirds of cases. Although hepatoblastoma is the most common malignant neoplasm of the liver in childhood, it only accounts for 3.1% of childhood cancers for infants less than 12 months of age. We describe the first case of sudden death in an apparently healthy 6-month old infant whose autopsy revealed an epithelial type hepatoblastoma with mixed fetal and embryonal patterns. PMID- 20170277 TI - 'Could I be imagining this?' - the dialectic struggles of people with persistent unexplained back pain. AB - PURPOSE: To explore how patients with persistent unexplained pain interpret and utilise the biopsychosocial model. This might have an impact on the outcome from treatment programmes that adopts a biopsychosocial approach. METHOD: We conducted three interviews with 20 patients attending a pain management programme for persistent unexplained back pain; prior to attending the course, immediately following the course and at 1 year. We used the methods of grounded theory. RESULTS: Patients battled through several dialectic tensions in an attempt to legitimise their pain: First, patients wanted a medical diagnosis but also recognised that psychosocial factors contributed to their pain. Second, although the outward appearance of pain was important to legitimacy, it was also important not to appear 'too ill'. Third, meeting others with unexplained pain reinforced credibility, but patients also described how they were not 'like the others'. Finally, although holding on to one's self was important, patients also described an acceptance of loss. CONCLUSIONS: These dialectic tensions are likely to have an impact on a person's decision to embrace the biopsychosocial model, and might therefore effect their outcome. Health care professionals should be sensitive to the cultural ambiguity of patients with persistent unexplained pain. PMID- 20170278 TI - Musculo-skeletal pain, quality of life and depression in mothers of children with cerebral palsy. AB - OBJECTIVE: To evaluate musculoskeletal pain (MSP) in mothers of children with cerebral palsy (CP), and to determine the effects of zone of pain on health related quality of life (QoL) and symptoms of depression. PATIENTS AND METHODS: The study included a total of 81 children with CP, together with their mothers (group 1), and a total of 60 healthy children, together with their mothers (group 2). Presence of MSP, and the zone of pain in mothers were evaluated [lower back pain (LBP), pain in other zones, without pain]. Mothers' QoL was assessed with Short Form-36 (SF-36) scale, and presence of symptoms of depression was assessed with Beck Depression Inventory (BDI). Multivariate analysis of variance test analysis was performed to see the main effects of the factors mother having a child with CP (group 1, group 2) and zone of pain (LBP, other, no pain) on the BDI scores and SF-36 QoL sub parameters of mothers. Logistic regression analysis was performed to determine the parameters predicting the presence of LBP in mothers in group 1. RESULTS: MSP and LBP were found to be significantly higher in group 1. Main effect of the mother having a child with CP on BDI score and physical role (PR) and mental health (MH) parameters was found to be significant. Mean BDI scores of mothers in group 1 was found to be significantly higher as compared to the other group, and mean PR parameter and MH values were found to be significantly lower. Main effect of the zone of pain (arising from the group of mothers with LBP) was found to be significant on physical functioning, bodily pain, general health perception, MH parameters and BDI. Logistic regression analysis showed that MH and bodily pain parameters significantly predicted the presence of LBP. CONCLUSION: Deterioration of MH in mothers with cerebral palsied child may be causing them to experience more LBP. Experience of increased LBP causes deterioration of health-related QoL. PMID- 20170279 TI - Factors contributing to work-ability for injured workers: literature review and comparison with available measures. AB - PURPOSE: Despite a range of factors being proposed in research literature to be key to 'work-ability', agreed definitions and boundaries of this concept are lacking. This review sought to identify and clarify key factors thought to contribute to individual work-ability, then compare these against existing measures of work-ability for people with injury. METHOD: A literature search was undertaken based on principles of systematic review. MEDLINE, AMED, Scopus and Web of Science databases were searched. All potentially relevant articles were obtained and, if they met inclusion criteria, evaluated for quality. The search was expanded and repeated to identify currently available measures of work ability for people with injury. These measures were then compared against components from the first search. RESULTS: Thirty-four articles were obtained from the first search, and 23 provided information about factors that contribute to work-ability. Six broad categories were identified: physical, psychological, cognitive, social/behavioural, workplace factors, and factors outside the workplace. The follow-up search identified 10 measures. No one measure captured all six identified categories. CONCLUSIONS: Components contributing to work ability go beyond the ability to perform particular work tasks. Measures intended to be used to inform vocational rehabilitation arguably need to consider all these factors to maximise likelihood of a sustainable return to work. PMID- 20170280 TI - Comparative renal excretion of VX-702, a novel p38 MAPK inhibitor, and methotrexate in the perfused rat kidney model. AB - CONTEXT: VX-702 is a novel p38 mitogen-activated protein kinase inhibitor being developed to treat rheumatoid arthritis. OBJECTIVE: To characterize the renal excretion profile of VX-702 using the isolated perfused rat kidney (IPRK) model. METHODS: Studies were performed to assess the dose linearity of VX-702 excretion and to evaluate the effect of inhibitors of organic anion (probenecid) and organic cation (cimetidine) transport systems on VX-702 disposition. VX-702 excretion was studied over a range of doses targeting concentrations between 100 and 600 ng/mL. VX-702 (600 ng/mL) was also co-perfused with probenecid (1 mM) and cimetidine (2 mM). The results were compared to parallel experiments performed with methotrexate (MTX). RESULTS: VX-702 excretion was linear over the range of doses studied, and clearance data were consistent with net reabsorption by the kidney. Transport inhibition studies indicate that VX-702 is not a substrate for renal organic anion and organic cation transport systems. MTX (500 ng/mL) also displayed net reabsorption in the IPRK, but secretory transport was inhibited upon co-administration with probenecid. This finding is consistent with previous IPRK studies that demonstrated inhibitory effects of NSAIDS on MTX excretion. CONCLUSION: Overall, this study suggests that a renal drug-drug interaction between VX-702 and MTX would be unlikely if these medications were co administered. PMID- 20170281 TI - Effects of cryopreservation on sperm DNA integrity in normospermic and four categories of infertile males. AB - This study examined the effects of cryopreservation on DNA integrity of spermatozoa from 34 fertile subjects and 166 infertile subjects comprised of 80 teratospermic, 32 normospermic, 30 astheno-teratospermic, and 24 oligo-astheno teratospermic individuals. Semen samples were prepared by swim-up and the Percoll density gradient centrifugation method (Pdgc) prior to freezing in liquid nitrogen. Neat and prepared samples were supplemented with cryoprotectant (SpermFreez) in cryoampoules and were frozen using the static phase vapor cooling procedure. Sperm DNA integrity of all thawed samples was determined using the alkaline comet assay. It was noticed that the sperm DNA integrity of frozen samples of fertile subjects was considerably higher than that of infertile subjects with greater catch-up integrity similar to the fresh samples. Freezing caused less chromatin damage to sperm of Pdgc samples from both fertile and infertile subjects as was compared to the neat and swim-up samples. It is concluded that the increase in comet frequency of frozen-thawed samples from infertile subjects was more prominent (8.25-22.78%; P<0.01) than in the fresh samples. Frozen-thawed samples from Ts (Teratospermic individuals) and ATs (Astheno-teratozoosspermic) showed higher level of OTM (Olive tail moment) indicating a higher level of chromatin fragmentation than fertile, Ns (Normospermics), and OATs (Oligo-astheno-teratozoospermics). PMID- 20170282 TI - Improving efficiencies of locus-specific DNA methylation assessment for bovine in vitro produced embryos. AB - Characterization of DNA methylation is one assessment of chromatin remodeling in early embryos. Unfortunately, evaluation at specific loci is hindered by their small cell numbers. Our objective was to determine if bisulfite sequencing could be optimized for preimplantation embryos, comparing conversion times, primer design, and DNA amplification methods. Methylation at three loci, SATI, OCT4, and IGF2, was investigated in bovine in vitro produced (IVP) embryos, somatic cells, and no template controls. Bisulfite treatment for 15-16 h gave higher quality DNA than treatment for 18 h. Three step primer design improved bisulfite primer specificity, yielding more PCR product than primers previously reported. Following optimization, methylation data were obtained from as few as 4 cell equivalents. Finally, DNA amplification efficiencies were evaluated using miniprep, TempliPhi, or 96-well glycerol stocks with automated TempliPhi. While TempliPhi was better than standard minipreps, the 96-well format proved most efficient. Preliminary methylation profiles of bovine IVP 2-cell, 8-cell, blastocyst stage embryos and somatic cells were 25, 10, 22, and 74% for SATI and 88, 88, 79, and 88% for OCT4, respectively, suggesting that SATI is demethylated during early embryonic reprogramming, while OCT4 remains hypermethylated. IGF2 methylation was 84, 28, and 84% for bovine IVP 8-cell, blastocyst stage embryos and somatic cells; blastocyst stage embryos exhibited more variability, ranging from 0 to 80%. This new assay will enhance assessment of chromatin remodeling in embryos, and be especially useful for evaluating those produced by assisted reproductive technologies. PMID- 20170284 TI - DNA fragmentation dynamics in fresh versus frozen thawed plus gradient-isolated human spermatozoa. AB - The aim of this study was to compare the rate of sperm DNA fragmentation (rSDF; increase of SDF over time) in fresh and gradient isolated frozen-thawed semen samples from male sperm donors of proven fertility. SDF was assessed in the two samples obtained from the same fifteen male donors after 0.5, 1.5, 4.5, 6, 24, 48, and 72 h of incubation in a humidified atmosphere of 5% CO(2) in air at 37 degrees C. Analysis was performed based on chromatin dispersion patterns evaluated using the Halosperm kit. No significant differences in SDF were obtained when fresh and gradient-isolated frozen-thawed spermatozoa were compared at baseline. However, the rSDF shown by the two samples differed and gradient isolation selected for sperm subpopulations showing a lower variance for SDF. At the individual level, sperm selection by density gradient purification in frozen thawed samples did not improve the levels of SDF when compared with the values obtained in fresh samples at baseline. PMID- 20170285 TI - Tetraethylammonium-sensitive K(+) current in the bovine spermatozoa and its blocking by the venom of the Chilean Latrodectus mactans. AB - The morphology and size of spermatozoa hinder the study of the functional properties of the spermatozoa plasma membrane. However, some studies have revealed the presence of a number of ion channels in this cell. We set out to measure the endogenous currents and to study the effect of the venom of the Chilean black widow spider (Latrodectus mactans). By patch-clamping bovine spermatozoa our results indicate the presence of an outwardly rectifying current, sensitive to changes in K(+) concentration (30-140 mM) and to tetraethylammonium (TEA, 10-100 mM). The application of the venom (7.5 microg/ml) blocks these K+ currents and then alters the passive properties of the plasma membrane. This leads to the entry of Ca(++), reflected by a change in basal fluorescent units (5+/-2 at 35+/-10 FAU). The Ca(++) influx follows a reduction in the membrane conductance (control 22+/-2; venom 10+/-1 pS), as calcium channels open in accord with voltage dependence. PMID- 20170286 TI - Histone H4 acetylation is essential to proceed from a histone- to a protamine based chromatin structure in spermatid nuclei of Drosophila melanogaster. AB - In humans, other mammals, and also in Drosophila, the paternal genome in the sperm is highly condensed and organized mainly in a protamine-based chromatin structure. However, the timing and mechanism of the switch from a histone- to the protamine-based chromatin configuration is still poorly understood. We therefore established Drosophila in vitro cultures of cysts with 64 synchronously developing spermatids genetically marked with histone H2AvD-RFP and ProtamineB eGFP. Live cell imaging showed that the switch from H2AvD-RFP to Protamine-eGFP chromatin takes approximately five hours, with a short but clear overlap of the presence of both histones and protamines. Moreover, cultured pupal testes showed H4 hyperacetylation at the canoe stage shortly before histone removal; a feature previously observed in the intact animal. We then used TSA to inhibit histone deacetylation and found that premature hyperacetylation was already induced at the round nuclei stage of spermatids. However, this premature hyperacetylation did not lead to a premature switch to the protamine-based chromatin structure, showing that histone hyperacetylation is not the sole inducer of the histone to protamine switch. Importantly, we observed that inactivation of histone acetyltransferases by anacardic acid blocks further differentiation and thus prevents the degradation of histones and the switch to a protamine-based chromatin. Thus, we conclude that H4 hyperacetylation is an essential feature but not the sole inducer of the histone to protamine switch during spermiogenesis. PMID- 20170287 TI - eNOS, NO, and the activation of ERK and AKT signaling at mid-gestation and near term in an ovine model of intrauterine growth restriction. AB - Intrauterine growth restriction (IUGR) is a disease responsible for neonatal morbidity and mortality and perinatal death affecting 8% of all pregnancies. In sheep, IUGR that mimics the human IUGR disease closely can be brought on by environmental hyperthermia. Endothelial nitric oxidase synthase (eNOS) and nitric oxide (NO) are important in the regulation of blood flow in the fetal-placental circulation and are modulated by several factors including hypoxia. eNOS activity is also regulated by the phosphorylation of ERK1/2 and AKT proteins in various tissues. In a hyperthermic (HT) ovine model of IUGR with systemic hypertension and increased blood flow resistance, our objective was to determine the relationship between p-ERK, p-AKT, eNOS, and NO concentrations in the placenta, uterine, and umbilical vessels at mid-gestation and near-term. Eight pregnant ewes were exposed to hyperthermic conditions for either 55 or 80 days to induce IUGR. Sheep necropsies were performed at mid-gestation and near-term for collection of placentomes, umbilical vessels, and the uterine artery. Tissues were assessed for eNOS mRNA and protein, and p-ERK and p-AKT protein. Blood was collected for NO determination at the time of necropsy. Placental insufficiency and IUGR (PI-IUGR) pregnancies demonstrated: 1) reduced placental weight at mid gestation and reduced placental and fetal weight near-term, 2) no changes in eNOS protein concentration in the uterine artery and umbilical vessels, but an increase in NO in umbilical vein blood at both time points, 3) no significant changes in signal transduction makers (ERK/AKT) in placental tissue at mid gestation but a significant increase near-term in cotyledon tissues, and 4) an increase in p-AKT in the uterine vessels at term. The near-term findings of increased placental p-ERK and p-AKT proteins and umbilical vein NO concentration suggest one mechanism responsible for the increase in placental eNOS previously described in this PI-IUGR model characterized by fetal systemic hypertension and abnormal umbilical artery Doppler velocimetry. PMID- 20170288 TI - Follicle-stimulating hormone receptor gene haplotypes and male infertility in estonian population and meta-analysis. AB - Follicle-stimulating hormone (FSH) is crucial for male fertility and it exerts its effects via a gonad-specific receptor (FSHR). In the present study, the common G-29A, A919G, and A2039G polymorphisms in the FSHR gene were analysed in 150 (36 non-obstructive azoospermia and 114 individuals with oligozoospermia) patients and 208 normozoospermic men. The results showed that the FSHR polymorphisms were not associated with either azoo- or oligozoospermia as the distributions of alleles, genotypes, and haplotypes among patients and controls were similar. Amongst normozoospermic men, those carrying at least one minor A allele (GA and AA genotypes) of the G-29A polymorphism had a smaller mean testicular volume compared to men with GG homozygosity (25.8 ml vs. 27.4 ml, respectively; P=0.013). In a subsequent meta-analysis combining our data with previous studies, the G-29-A919-A2039 haplotype was shown to be more prevalent in normozoospermic men than in azoospermic patients (38.4% vs. 33.9%, respectively; chi(2)test, P=0.045), indicating that this haplotype may be a protective factor against male sterility. In conclusion, we suggest that FSHR haplotypes are not considerable risk factors for spermatogenic failure. The protective nature of G 29-A919-A2039 haplotype cannot be concluded without additional studies. PMID- 20170289 TI - The effects of severity of oligozoospermia on Intracytoplasmic Sperm Injection (ICSI) cycle outcome. AB - The objective of this study was to explore the relationship between the severity of oligozoospermia and the development of embryos and clinical outcome in patients undergoing ICSI. A total of 908 intracytoplasmic sperm injection cycles involving women of < or =37 years of age were included in this study. The patients were divided into four treatment groups according to the results of an analysis of their husbands' semen: (A) mild oligozoospermia that ranged from 10 x 10(6)/ml to <20 x 10(6)/ml (n=283), (B) mild to severe oligozoospermia that ranged from 5 x 10(6)/ml to <10 x 10(6)/ml (n=192), (C) severe oligospermia that ranged from 1 x10(6)/ml to <5 x 10(6)/ml (n=259), and (D) very severe oligozoospermia that ranged from 0 to <1 x10(6)/ml (n=174). Two pronuclei (PN) oocytes at MII were injected and the development of high quality embryos on day 2, as well blastocyst formation rate on day 5, the implantation rate, clinical pregnancies, and fetal loss, were examined. A lower percentage of two pronuclei (2PN) oocytes in the very severe oligozoospermia group was observed, however, there was no difference in clinical outcome when the oligozoospermic patients were divided by sperm concentration. In addition, no significant difference was detected in zygote production or clinical outcome between spermatozoa with a motility of <40% and spermatozoa with a motility of > or =40%. The results of this study emphasize the importance of selecting good quality sperm for oocyte injection, especially in cases involving very severe oligozoospermia. PMID- 20170291 TI - The relationships between high-sensitivity C-reactive protein and incident depressed mood among older adults. AB - Abstract Background. High levels of high-sensitivity C-reactive protein (hs-CRP) are associated with depressed mood, but the causal relationships are not known. Therefore, we examined the relationships between hs-CRP and incident depressed mood among the elderly. Methods. Altogether 764 (69%) individuals out of a representative sample of subjects aged 70 years or older (N = 1113) were screened with the Short Zung Self Rating Depression Scale (SZSRDS), and serum hs-CRP determinations were done at the same time. After a two-and-a-half-year follow-up, the SZSRDS examinations were repeated among those who were free of depressed mood (SZSRDS score >or=28 or use of an anti-depressant drug) at the baseline (N = 404). Analysis of covariance (ANCOVA) and logistic regression were used to analyse the relationship between the baseline hs-CRP (<1, 1 < 3, 3 <10 mg/L) and the follow-up SZSRDS scores (10-40) and depressed mood. Results. Baseline hs-CRP was not associated with an increasing trend in SZSRDS scores and depressed mood in the total study population, but there was a significant gender interaction. Among the men, elevated hs-CRP was associated with an increasing trend in the SZSRDS score and depressed mood. Conclusions. High hs-CRP predicts a higher incident SZSRDS score and depressed mood among older men, suggesting a possible inflammatory etiology for depression. PMID- 20170292 TI - Trends in the survival of patients diagnosed with cancers in the respiratory system in the Nordic countries 1964-2003 followed up to the end of 2006. AB - BACKGROUND: Previous studies have shown that there have been systematic differences between the Nordic countries in population-based relative survival of patients with respiratory cancer (lung, pleura, larynx, nose and sinuses). MATERIAL AND METHODS: Relative survival of patients with respiratory cancer diagnosed in the Nordic countries in 1964-2003 and followed up to the end of 2006 was studied and contrasted with developments in incidence and mortality. RESULTS: For cancer of the lung, relative survival is lower in Danish patients than in the other countries during the first months of follow-up after diagnosis. For cancer of pleura, the relative survival ratios indicate that there may be problems in the official coding of the causes of death in Denmark, Norway and Sweden. There has been little improvement in survival of patients with cancer of the respiratory organs in the Nordic countries over time. CONCLUSIONS: The slightly lower survival of Danish lung cancer patients may be related to a less favourable stage distribution and to an increased prevalence of causal factors, affecting the mortality due to competing risks of death. A reclassification of official causes of death at the cancer registry may be needed for cancer of the pleura in order to make the corresponding mortality rates comparable between countries. PMID- 20170293 TI - Trends in the survival of patients diagnosed with cancers of the lip, oral cavity, and pharynx in the Nordic countries 1964-2003 followed up to the end of 2006. AB - BACKGROUND: This is the first comprehensive population-based study on relative survival of lip, oral cavity and pharyngeal cancer in the Nordic countries. MATERIAL AND METHODS: Relative survival of patients with cancers of the lip, oral cavity, and pharynx diagnosed in the Nordic countries in 1964-2003 and followed up to the end of 2006 was studied and contrasted with trends in incidence and mortality. RESULTS: There are marked differences in incidence between countries and over time. The stability of the relative survival ratios gives support to the hypothesis that the incidence differences are more likely to be real and not materially affected by differences in definitions and coding. Of particular note are the steep rises in pharyngeal cancer incidence in Denmark in both sexes. Survival has only moderately improved over time and has tended to be slightly higher in females than males. CONCLUSIONS: Co-morbidity caused by smoking and high alcohol consumption are likely to be partially responsible for differences between countries. Advances in therapy and standards of care are also likely to have played a role in the increasing survival trends. PMID- 20170294 TI - Comparison of T1-weighted fast spin-echo and T1-weighted fluid-attenuated inversion recovery images of the lumbar spine at 3.0 Tesla. AB - BACKGROUND: T1-weighted fluid-attenuated inversion recovery (FLAIR) sequence has been reported to provide improved contrast between lesions and normal anatomical structures compared to T1-weighted fast spin-echo (FSE) imaging at 1.5T regarding imaging of the lumbar spine. PURPOSE: To compare T1-weighted FSE and fast T1 weighted FLAIR imaging in normal anatomic structures and degenerative and metastatic lesions of the lumbar spine at 3.0T. MATERIAL AND METHODS: Thirty-two consecutive patients (19 females, 13 males; mean age 44 years, range 30-67 years) with lesions of the lumbar spine were prospectively evaluated. Sagittal images of the lumbar spine were obtained using T1-weighted FSE and fast T1-weighted FLAIR sequences. Both qualitative and quantitative analyses measuring the signal-to noise ratio (SNR), contrast-to-noise ratio (CNR), and relative contrast (ReCon) between degenerative and metastatic lesions and normal anatomic structures were conducted, comparing these sequences. RESULTS: On quantitative evaluation, SNRs of cerebrospinal fluid (CSF), nerve root, and fat around the root of fast T1 weighted FLAIR imaging were significantly lower than those of T1-weighted FSE images (P<0.001). CNRs of normal spinal cord/CSF and disc herniation/ CSF for fast T1-weighted FLAIR images were significantly higher than those for T1 weighted FSE images (P<0.001). ReCon of normal spinal cord/CSF, disc herniation/CSF, and vertebral lesions/CSF for fast T1-weighted FLAIR images were significantly higher than those for T1-weighted FSE images (P<0.001). On qualitative evaluation, it was found that CSF nulling and contrast at the spinal cord (cauda equina)/CSF interface for T1-weighted FLAIR images were significantly superior compared to those for T1-weighted FSE images (P<0.001), and the disc/spinal cord (cauda equina) interface was better for T1-weighted FLAIR images (P<0.05). CONCLUSION: The T1-weighted FLAIR sequence may be considered as the preferred lumbar spine imaging sequence compared to T1-weighted FSE, as it has demonstrated superior CSF nulling, better conspicuousness of normal anatomic structures and degenerative and metastatic lesions, and improved image contrast. PMID- 20170295 TI - Metabolite concentrations in supraventricular white matter from teenage to early old age: A short echo time 1H magnetic resonance spectroscopy (MRS) study. AB - BACKGROUND: Age- and sex-related changes of metabolites in healthy adult brains have been examined with different (1)H magnetic resonance spectroscopy (MRS) methods in varying populations, and with differing results. A long repetition time and short echo time technique reduces quantification errors due to T(1) and T(2) relaxation effects and makes it possible to measure metabolites with short T(2) relaxation times. PURPOSE: To examine the effect of age on the metabolite concentrations measured by (1)H MRS in normal supraventricular white matter using a long repetition time (TR) and a short echo time (TE). MATERIAL AND METHODS: Supraventricular white matter of 57 healthy subjects (25 women, 32 men), aged 13 to 72 years, was examined with a single-voxel MRS at 1.5T using a TR of 6000 ms and a TE of 22 ms. Tissue water was used as a reference in quantification. RESULTS: Myoinositol increased slightly and total N-acetyl aspartate (NAA) decreased slightly with increasing age. Glutamine/glutamate complex (Glx) showed U-shaped age dependence, with highest concentrations in the youngest and oldest subjects. No significant age dependence was found in total choline and total creatine. No gender differences were found. Macromolecule/ lipid (ML) fractions were reliably measurable only in 36/57 or even fewer subjects and showed very large deviations. CONCLUSION: The concentrations of several metabolites in cerebral supraventricular white matter are age dependent on (1)H MRS, even in young and middle-aged people, and age dependency can be nonlinear. Each (1)H MRS study of the brain should therefore take age into account, whereas sex does not appear to be so important. The use of macromolecule and lipid evaluations is compromised by less successful quantification and large variations in healthy people. PMID- 20170296 TI - Depth electrodes and outcome. PMID- 20170297 TI - Stereotactic radiosurgery coding and reimbursement. PMID- 20170298 TI - Successful bilateral deep brain stimulation of the globus pallidus internus for persistent status dystonicus and generalized chorea. AB - The authors report the cases of 2 young male patients (aged 16 and 26 years) with dystonic cerebral palsy of unknown origin, who developed status dystonicus, an acute and persistent combination of generalized dystonia and chorea. Both patients developed status dystonicus after undergoing general anesthesia, and in 1 case, after administration of metoclopramide. In attempting to control this acute hyperkinetic movement disorder, multiple medication trials failed in both cases and patients required prolonged intubation and sedation with propofol. Bilateral deep brain stimulation of the globus pallidus internus (4 and 2 months after the onset of symptoms in the first and second case, respectively) produced immediate resolution of the hyperkinetic movement disorder in each case. Deep brain stimulation provided persistent suppression of the dystonic movement potential after a follow-up of 30 and 34 months, respectively, as demonstrated by the reemergence of severe dystonia during the end of battery life of the implantable pulse generators that was readily controlled by exchange of the generators in each case. PMID- 20170299 TI - Stereotactic radiosurgery for symptomatic solitary cerebral cavernous malformations considered high risk for resection. AB - OBJECT: A retrospective study was conducted to reassess the benefit and safety of stereotactic radiosurgery (SRS) in patients with solitary cerebral cavernous malformations (CCMs) that bleed repeatedly and are poor candidates for surgical removal. METHODS: Between 1988 and 2005 at the University of Pittsburgh, the authors performed SRS in 103 evaluable patients (57 males and 46 females) with solitary symptomatic CCMs. The mean patient age was 39.3 years. Ninety-eight percent of these patients had experienced 2 or more hemorrhages associated with new neurological deficits. Seventeen patients (16.5%) had undergone attempted resection before radiosurgery. Ninety-three CCMs were located in deep brain structures and 10 were in subcortical lobar areas of functional brain importance. The median malformation volume was 1.31 ml, and the median tumor margin dose was 16 Gy. RESULTS: The follow-up ranged from 2 to 20 years. The annual hemorrhage rate--that is, a new neurological deficit associated with imaging evidence of a new hemorrhage--before SRS was 32.5%. After SRS 22 hemorrhages were observed within 2 years (10.8% annual hemorrhage rate) and 4 hemorrhages were observed after 2 years (1.06% annual hemorrhage rate). The risk of hemorrhage from a CCM was significantly reduced after radiosurgery (p < 0.0001). Overall, new neurological deficits due to adverse radiation effects following SRS developed in 14 patients (13.5%), with most occurring early in our experience. Modifications in technique (treatment volume within the T2-weighted MR imaging-defined margin, use of MR imaging, and dose reduction for CCM in critical brainstem locations) further reduced risks after SRS. CONCLUSIONS: Data in this study provide further evidence that SRS is a relatively safe procedure that reduces the rebleeding rate for CCMs located in high-surgical-risk areas of the brain. PMID- 20170300 TI - Clinical use of supinator motor branch transfer to the posterior interosseous nerve in C7-T1 brachial plexus palsies. AB - OBJECT: In C7-T1 brachial plexus palsies, finger extension and flexion are absent. At the authors' institution, finger flexion has been successfully reconstructed by transferring the brachialis motor branch to the anterior interosseous nerve. However, there is no reliable method for restoring finger extension. In the present study, the authors examined the surgical results of transferring the supinator motor branch to the posterior interosseous nerve. METHODS: Since October 2007, the authors have performed a supinator motor branch transfer to the posterior interosseous nerve in 4 patients. The patients underwent follow-up every 3-4 months postoperatively. RESULTS: Finger extension appeared between 5 and 9 months in the first 3 cases and demonstrated promising improvement over time. One recent case remains under follow-up. CONCLUSIONS: A supinator motor branch to posterior interosseous nerve transfer leads to reliable recovery of thumb and finger extension. Therefore, it is a viable option for C7 T1 brachial plexus palsies. PMID- 20170301 TI - Radiosurgery in cavernous malformations: anatomy of a controversy. PMID- 20170303 TI - The 2009 devaluation of radiosurgery and its impact on the neurosurgery-radiation oncology partnership. AB - Neurosurgeons, radiation oncologists, and, increasingly, other surgical specialists recognize that radiosurgery is an important tool for managing selected disorders throughout the body. The partnership between neurosurgeons and radiation oncologists has resulted in collaborative studies that have established the clinical benefits of radiosurgery. Today, however, a range of political and financial issues is straining this relationship and thereby undermining the practice of radiosurgery. Neurosurgeons and radiation oncologists recently restricted the definition of radiosurgery to include only cranial- and spine focused radiation treatments. Meanwhile, organized radiation oncology decided unilaterally that radiosurgery administered to other parts of the body would be termed stereotactic body radiation therapy. Finally, neurosurgical and radiation oncology coding experts developed new Current Procedural Terminology codes for cranial vault and spine radiosurgery, which were approved for use by the Relative Value Scale Update Committee as of 2009. The authors suggest that the neurosurgery strategy-which included 1) reasserting that all of the tasks of a radiosurgery procedure remain bundled, and 2) agreeing to limit the definition of radiosurgery to cranial vault and spine-has failed neurosurgeons who perform radiosurgery, and it may jeopardize patient access to this procedure in the future. The authors propose that all of the involved medical specialties recognize that the application of image-guided, focused radiation therapy throughout the body requires a partnership between radiation and surgical disciplines. They also urge surgeons to reexamine their coding methods, and they maintain that Current Procedural Terminology codes should be consistent across all of the different specialties involved in these procedures. Finally, surgeons should consider appropriate training in medical physics and radiobiology to perform the tasks involved in these specific procedures; ultimately all parties should receive equivalent reimbursement for similar assigned tasks, whether performed individually or jointly. PMID- 20170304 TI - Gamma Knife irradiation-induced histopathological changes in the trigeminal nerves of rhesus monkeys. AB - OBJECT: The authors' goal was to observe histopathological changes in the trigeminal nerve after Gamma Knife surgery (GKS) in rhesus monkeys, and to investigate the radiobiological mechanism of GKS for primary trigeminal neuralgia. The nerve length-dosage effect of irradiation is also discussed. METHODS: One of 5 rhesus monkeys randomly served as a control, and the other 4 monkeys were randomly administered a target radiation dose of 60, 70, 80, or 100 Gy (a different dose in each animal). The size of the collimator was 4 mm, and the target point was the trigeminal nerve root. In each experimental monkey, one side was exposed to single-target-point irradiation, and the contralateral side was exposed to double-target-point irradiation. After 6 months, the trigeminal nerve root was examined using light microscopy, transmission electron microscopy, and immunohistochemistry. RESULTS: At each radiation dose, the damage to the nerve tissue by single-target-point irradiation was identical to that caused by double-target-point irradiation. In the trigeminal nerve tissues of the monkeys irradiated with 60 and 70 Gy, there was limited nerve demyelination and degeneration, fragmentation, or loss of axons. In the trigeminal nerve tissue of the monkey irradiated with 80 Gy, the nerve tissue showed a disordered structure. In the trigeminal nerve tissue of the monkey irradiated with 100 Gy, there was severe derangement in the structure of the nerve tissue, and extensive demyelination, fragmentation, and loss of axons. CONCLUSIONS: The target doses of 60 and 70 Gy have very little impact on the structure of the trigeminal nerve. Irradiation at 80 Gy can cause partial degeneration and loss of axons and demyelination. A 100-Gy dose can cause some necrosis of neurons. Comparing the single-target-point with the double-target-point irradiation, the extent of damage to the nerve tissue is identical, and no difference in the nerve length dosage effect was found. PMID- 20170305 TI - Cause-specific mortality among neurosurgeons. AB - OBJECT: The authors sought to determine a cause-specific mortality profile for US neurosurgeons during the period 1979-2005. METHODS: Neurosurgeons who died during the study period were identified from the Physician Master File database. Using the National Death Index, the reported cause of death was identified for 93.7% of decedents. Standardized mortality ratios were used to compare mortality risk in the study cohort to that of the US population. RESULTS: There was a marked reduction in mortality from virtually all causes in comparison with the control population. This finding is consistent with prior studies of mortality in physicians. The small number of deaths among female neurosurgeons precluded meaningful analysis for this group. Increased mortality risk for male neurosurgeons was seen from leukemia, nervous system disease (particularly Alzheimer disease), and aircraft accidents. Deaths from viral hepatitis and HIV infection, considered to be occupational hazards for surgeons, were less frequent than in the general population. Suicide, drug-related deaths, and alcohol-related deaths were less frequent than in the general population. CONCLUSIONS: Neurosurgeons may be at higher risk for death from leukemia, aircraft accidents, and diseases of the nervous system, particularly Alzheimer disease; however, the mortality profile of neurosurgeons is favorable when compared with the general population. PMID- 20170306 TI - Preoperative or preembolization lesion targeting using rotational angiographic fiducial marking in the neuroendovascular suite. AB - Three-dimensional rotational digital subtraction (DS) angiography and DynaCT allow precise localization of intracranial arteriovenous fistulas (AVFs) with fiducial markers that have helped in surgical planning. These techniques are particularly useful when the AVF is not evident on cross-sectional imaging. The authors demonstrate the utility of 3D DS angiography and DynaCT in the localization of intracranial AVFs in 3 cases. Their first case was a dural AVF with multiple arterial feeders from the left occipital artery that drained into the left transverse sinus. Blood flow to the left transverse sinus was first decreased by embolizing the branch arterial feeders with polyvinyl alcohol particles. Thereafter, 3D DS angiography enabled precise localization of the site for the bur hole creation with a fiducial to allow access for the transverse sinus in the second part of the procedure where definitive transvenous sinus embolization of the dural AVF with coils was performed. They also used 3D DS angiography and DynaCT with fiducials for precise localization of a superficial pial AVF (Case 2) and a tentorial AVF (Case 3) not visible on cross-sectional angiography. With the precise localization of the target lesion, the neurosurgeons were able to perform relatively small craniotomies, minimizing the cranial opening yet allowing the opening for full access to the lesion. By correlating 3D DS angiography/DynaCT with CT images, the neurosurgeon could use neuronavigation in cases of AVF not appreciated on cross-sectional imaging. PMID- 20170307 TI - Resident perceptions of radiosurgical training and the effect of a focused resident training seminar. AB - OBJECT: Neurosurgical training is critical in providing residents with the skill set, knowledge, and confidence to perform challenging neurosurgical procedures. Radiosurgery, which neurosurgeons helped define and refine, differs from more traditional, open neurosurgical approaches. This study evaluates the opinions of residents on current radiosurgical training and the effect of a focused educational course on those residents. METHODS: The American Association of Neurological Surgeons sponsored a 3-day course focused on intracranial and spinal radiosurgery. Senior-level residents were nominated by US program directors to participate in the course. Twenty-eight residents from distinct training programs were surveyed before and after the course to discern current training practices in radiosurgery and the effect of the focused educational program. The median training level of the participants was postgraduate Year 5 (mean 5.3 years, range 3-7 years). RESULTS: Two-thirds of residents reported that their training institutions had no formal radiosurgery rotation. Twenty-five percent planned to obtain postresidency fellowship training that would include radiosurgery. Before the course, 79% of the residents expected to include radiosurgery in their practice. However, prior to the course, those describing themselves as "very uncomfortable" with performing intracranial or spinal radiosurgery were 33.3 and 45.8%, respectively. After the course, mean self-assessment scores for understanding the indications and performing intracranial radiosurgery increased by 43 and 89%, respectively. The mean scores for understanding the indications and comfort with performing spinal radiosurgery increased by 79 and 200%, respectively. Following the course, there was a 12.3% increase in the number of residents planning to perform radiosurgery following residency. CONCLUSIONS: Current neurosurgical residents appear uneasy about their grasp of radiosurgical indications and their ability to perform the procedure. Focused training courses sponsored by professional societies may improve resident education and training in this area of neurosurgery, which has a skill set and basis of knowledge different from traditional open neurosurgical procedures. Further evaluation of the radiosurgical training process for residents must be performed so as to ensure competency and sufficient workforce to meet expanding demands for neurosurgeons performing radiosurgery in a multidisciplinary climate. PMID- 20170308 TI - Stereotactic radiosurgery. PMID- 20170309 TI - Toward the revaluation of radiosurgery. PMID- 20170310 TI - Radiation oncology partnership and its impact on neurosurgery. PMID- 20170311 TI - Stereotactic electroencephalography with temporal grid and mesial temporal depth electrode coverage: does technique of depth electrode placement affect outcome? AB - OBJECT: Intracranial monitoring for temporal lobe seizure localization to differentiate neocortical from mesial temporal onset seizures requires both neocortical subdural grids and hippocampal depth electrode implantation. There are 2 basic techniques for hippocampal depth electrode implantation. This first technique uses a stereotactically guided 8-contact depth electrode directed along the long axis of the hippocampus to the amygdala via an occipital bur hole. The second technique involves direct placement of 2 or 3 4-contact depth electrodes perpendicular to the temporal lobe through the middle temporal gyrus and overlying subdural grid. The purpose of this study was to determine whether one technique was superior to the other by examining monitoring success and complications. METHODS: Between 1997 and 2005, 41 patients underwent invasive seizure monitoring with both temporal subdural grids and depth electrodes placed in 2 ways. Patients in Group A underwent the first technique, and patients in Group B underwent the second technique. RESULTS: Group A consisted of 26 patients and Group B 15 patients. There were no statistically significant differences between Groups A and B regarding demographics, monitoring duration, seizure localization, or outcome (Engel classification). There was a statistically significant difference at the point in time at which these techniques were used: Group A represented more patients earlier in the series than Group B (p < 0.05). The complication rate attributable to the grids and depth electrodes was 0% in each group. It was more likely that the depth electrodes were placed through the grid if there was a prior resection and the patient was undergoing a new evaluation (p < 0.05). Furthermore, Group A procedures took significantly longer than Group B procedures. CONCLUSIONS: In this patient series, there was no difference in efficacy of monitoring, complications, or outcome between hippocampal depth electrodes placed laterally through temporal grids or using an occipital bur hole stereotactic approach. Placement of the depth electrodes perpendicularly through the grids and middle temporal gyrus is technically more practical because multiple head positions and redraping are unnecessary, resulting in shorter operative times with comparable results. PMID- 20170312 TI - International classification of functioning, disability, and health core sets for hearing loss: a discussion paper and invitation. AB - The World Health Organization's International Classification of Functioning, Disability and Health (ICF) has adopted a multifactorial understanding of functioning and disability, merging a biomedical paradigm with a social paradigm into a wider understanding of human functioning. Altogether there are more than 1400 ICF-categories describing different aspects of human functioning and there is a need to developing short lists of ICF categories to facilitate use of the classification scheme in clinical practice. To our knowledge, there is currently no such standard measuring instrument to facilitate a common validated way of assessing the effects of hearing loss on the lives of adults. The aim of the project is the development of an internationally accepted, evidence-based, reliable, comprehensive and valid ICF Core Sets for Hearing Loss. The processes involved in this project are described in detail and the authors invite stakeholders, clinical experts and persons with hearing loss to actively participate in the development process. PMID- 20170313 TI - Adrenomedullin prevents sex-dependent impairment of autoregulation during hypotension after piglet brain injury through inhibition of ERK MAPK upregulation. AB - Cerebrospinal fluid (CSF) adrenomedullin (ADM) levels are increased in female, but remain unchanged in male, piglets after fluid percussion injury (FPI) of the brain. Subthreshold vascular concentrations of ADM restore impaired hypotensive pial artery dilation after FPI more in males than females. Extracellular signal related kinase (ERK) mitogen-activated protein kinase (MAPK) is upregulated and contributes to reductions in cerebral blood flow (CBF) after FPI. We hypothesized that ADM prevents sex-dependent impairment of autoregulation during hypotension after FPI through inhibition of ERK MAPK upregulation. FPI increased ERK MAPK more in males than in females. CBF was unchanged during hypotension in sham animals, was reduced more in males than in females after FPI during normotension, and was further reduced in males than in females during hypotension and after FPI. ADM and the ERK MAPK antagonist U 0126 prevented reductions in CBF during hypotension and FPI more in males than in females. Transcranial Doppler (TCD) blood flow velocity was unchanged during hypotension in sham animals, was decreased during hypotension and FPI in male but not in female pigs, and was ameliorated by ADM. Intracranial pressure (ICP) was increased after FPI more in male than in female animals. ADM blunted elevated ICP during FPI and hypotension in males, but not in females. ADM prevented reductions in cerebral perfusion pressure (CPP) during FPI and hypotension in males but not in females. The calculated autoregulatory index was unchanged during hypotension in sham animals, but was reduced more in males than females during hypotension and FPI. ADM prevented reductions in autoregulation during hypotension and FPI more in males than females. These data indicate that ADM prevented loss of cerebral autoregulation after FPI in a sex-dependent and ERK MAPK-dependent manner. PMID- 20170315 TI - New insight into the genes susceptible to asthma. AB - There is considerable worldwide interest in identifying genes related to susceptibility to asthma. Progress has been slow in part because of the complexity and heterogeneity of the disease. Although at least 170 genes located on 10 chromosomes have been associated with or in linkage with asthma and asthma related phenotypes, the majority of the reports have either been preliminary or the results have been controversial. In order to overcome the problems with the inherent complexity of asthma and methodological issues, the authors propose a strategy for identification of asthma susceptibility genes based on theories of systems biology and bioinformatics and candidate gene approach. PMID- 20170316 TI - Thymic stromal lymphopoietin promotes lung inflammation through activation of dendritic cells. AB - Asthma is an epithelial disorder in which T helper 2 (Th2)-type inflammation has a prominent role. Recent studies indicated that a cytokine, thymic stromal lymphopoietin (TSLP), is essential for the development of antigen-induced asthma. The authors used ovalbumin (OVA) sensitization and challenge to induce a murine asthmatic model. The model was confirmed by airway hyperresponsiveness, serum levels of total and OVA-specific immunoglobulin (IgE), histological analysis of lung tissues. The authors found that expression of TSLP was significantly increased in both mRNA and protein levels in mice lungs treated with OVA. The expression of CD40, CD80, and CD86 in bronchoalveolar lavage fluid (BALF) was increased in mice with OVA. Tight correlation between TSLP mRNA and interleukin (IL)-4, IL-5, and IL-13 in BALF was identified. Furthermore, treating mice with TSLP-neutralizing antibody reduced the expression of TSLP mRNA of lungs, CD40, CD80, and CD86 on dendritic cells, and IL-4, IL-5, and IL-13 in the OVA group. This study indicates that TSLP is increased in the airway epithelium in mice treated with OVA. In the lung inflammation model, TSLP activates dendritic cells (DCs) via up-regulation of CD40, CD80, and CD86, then induces the differentiation of prime naive CD4(+) T cells to become proinflammatory Th2 cells. Blocking TSLP is capable of inhibiting the production of Th2 cytokines, thus presents a promising strategy for the treatment of asthma. PMID- 20170317 TI - Factors associated with the control of severe asthma. AB - INTRODUCTION: Control is a priority treatment objective in asthma, and classification based on control is recommended in the follow-up of asthmatic patients. Different factors affect this control, and there are several regional differences, both in terms of prevalence and in terms of management and degree of control. OBJECTIVE: To evaluate the factors associated with control of severe asthma in routine clinical practice. MATERIAL AND METHODS: This was a prospective, cross-sectional, observational study of patients with severe asthma who were receiving treatment with a fixed combination of a corticosteroid (at least 800 microg/day of budesonide or equivalent) and an inhaled beta(2) adrenergic agonist in respiratory medicine and allergology clinics throughout Spain. The authors collected demographic and socioeconomic data, as well as clinical data on asthma. The patients also completed a self-administered validated questionnaire-the Asthma Control Questionnaire (ACQ)-about the control of their asthma. RESULTS: The authors included 1471 patients, of whom 1224 (83%) were valid for the final analysis. Women accounted for 61%. Mean age was 51 +/- 16 years. The mean number of exacerbations during the previous year was 2.0 +/- 2.0. The global score on the ACQ was 1.8 +/- 1.1 (0 = no symptoms; 6 = maximum number of symptoms). Only 20.4% of patients were well controlled (ACQ < 0.75), and 55.7% of patients were poorly controlled (ACQ > 1.5). The multivariate analysis revealed that the variable with the greatest effect on control of asthma was the number of exacerbations during the previous year: when the number of exacerbations increased from 0 to 1 or more, the ACQ score increased by 0.56 points. Employed patients had a mean of 0.23 points less (better control) than unemployed and retired patients. Control of asthma was also significantly affected by adherence to treatment, patient knowledge of the disease, body mass index, gender, and number of visits to a physician in the previous 3 months. CONCLUSIONS: Many patients with severe asthma have poor control of their disease. The number of exacerbations is the variable with the greatest effect on control of asthma. Knowledge of the disease and adherence to treatment are associated with better control. PMID- 20170318 TI - Serum eosinophilic cationic protein: is there a role in respiratory disorders? AB - BACKGROUND: Eosinophilic cationic protein (ECP) has been widely investigated in the clinical practice as a potential biomarker for asthma. However, there are conflicting data concerning its validity in other respiratory disorders. METHODS: Serum ECP levels were retrospectively analyzed in 441 patients (227 males and 214 females) suffering from respiratory disease and visited for the first time, and in 33 healthy subjects (17 males and 16 females). RESULTS: The mean of ECP was significantly higher (p = .0001) in patients compared with healthy volunteers. No correlation was found between serum ECP value and peripheral eosinophil absolute number (p = .881; r = .007). The predictive model was significant only for asthma, with a sensitivity of 70% and a specificity of 74% (efficiency 73%). CONCLUSIONS: This study demonstrates that serum ECP may be considered a marker for identifying only asthmatic patients with an efficiency of 73% and is not useful for the differentiation of other respiratory disorders. PMID- 20170319 TI - Nitric oxide in both bronchoalveolar lavage fluid and serum is associated with pathogenesis and severity of antigen-induced pulmonary inflammation in rats. AB - BACKGROUND: Nitric oxide (NO) is considered as a hallmark for allergic airway inflammation in asthmatics and animal models. But the correlation between NO and antigen-induced pulmonary inflammation (AIPI), a rat model for asthma, in varying genetic background population has not been completely understood. OBJECTIVE: The objective in this study is to observe the different responsiveness to AIPI in two commonly used inbred rat strains and verify the correlation between NO from different sources and pathological parameters of AIPI by using Dark Agouti (DA), E3, F1 (E3 x DA), and F2 rat populations. METHODS: AIPI was induced by systemically immunizing and intranasally challenging E3, DA, F1 (DA x E3), and F2 rats with ovalbumin (OVA). Pathological changes and mucus secretion in lungs were observed after hematoxylin and eosin (HE) and periodic acid Schiff (PAS) staining, whereas eosinophils in bronchoalveolar lavage fluid (BALF) were counted after Giemsa staining. Delayed-type hyperresponsiveness was determined by subcutaneous injection of OVA in ear. Total immunoglobulin E (IgE) and OVA specific IgG1 were detected with enzyme-linked immunosorbent assay (ELISA). NO concentration was measured by the Griess method. RESULTS: DA rats were unresponsive to OVA treatment, whereas E3 rats were susceptible to AIPI. F1 rats manifested the same responsiveness to OVA treatment as DA rats, and individual F2 rats showed the variable severity of AIPI. NO concentration in BALF and serum was significantly elevated in E3 rats but not in DA and F1 rats after OVA treatment. In F2 rats, NO concentration in serum was positively correlated with eosinophils in BALF, total IgE, and pathological scores, whereas NO concentration in BALF correlated only with eosinophils in BALF and total IgE. CONCLUSION: DA and F1 rats are resistant, whereas E3 rats are sensitive, to AIPI. NO in serum can represent the severity of allergic inflammation and pathological changes in lungs in F2 population. PMID- 20170321 TI - A current picture of asthma diagnosis, severity, and control in a low-income minority preteen population. AB - BACKGROUND: Asthma severity, control, type of medical regimen provided, and compliance with it are not well understood in minority patients at the transition stage from childhood to adolescence. OBJECTIVE: Describe the level of asthma severity and control and the clinical regimens provided to a large population of low-income, African American children at this developmentally significant period. METHODS: Parents of 1292 children with asthma among 6827 preteens in 19 middle schools in predominantly African American (94%), low-income neighborhoods in Detroit, Michigan, were enrolled in the study. Data were collected through self administered survey and telephone interviews and were useable for 936 participants. Study queries related to demographics, asthma symptoms, and medication use. Mixed effects models with a random intercept for school were used to determine severity and control and the association of medical regimens to these. RESULTS: Sixty-seven percent of children with probable asthma had received a physician's diagnosis. Being female was associated with being undiagnosed (p = .02). Forty-seven with no diagnosis had persistent asthma and 10% of these were classified as severe. Sixty-eight percent with a diagnosis and asthma medicine prescriptions were not controlled. Compliant use of controller medicine was associated with poorer asthma control compared to noncompliant controller users (p = .04) and reliever-only users (p < .001). Thirty-nine percent of children had controller medicine; of those 40% were not compliant with controller use; 9% nebulized their controller medicine. CONCLUSIONS: Care provided low-income minority children at an important stage in their development was not consistent with guidelines for asthma control. Therapy choices for treatment did not account for the actual level of their symptoms. Lack of an asthma diagnosis was significant in the population. Adolescent girls were at risk for not receiving a diagnosis. Patient compliance with asthma regimens was limited. Both clinician and patient education regarding effective asthma management appears needed regarding preteens in low-income minority communities. PMID- 20170320 TI - Influence of maternal asthma and asthma severity on newborn morphometry. AB - OBJECTIVE: To determine if maternal asthma or asthma severity affects newborn morphometry. STUDY DESIGN: A secondary analysis was performed on data collected in a multicenter prospective observational cohort study of asthma in pregnancy. Patients enrolled included women with asthma stratified by severity of disease and controls. Asthma severity was defined according to the classification proposed by the National Asthma Education Program (NAEP) Report of the Working Group on Asthma and Pregnancy, modified to include medication requirements. Newborn morphometry measurements included birth weight (BW) and multiples of the median birth weight (BW-MOM), head circumference (HC), length (L), HC:BW ratio, and ponderal index (PI). RESULTS: Of 2480 patients there were 828 nonasthmatic controls, 828 with mild, 775 with moderate, and 49 with severe disease. Comparing all groups, there were statistically significant differences in maternal age (p < .001), race (p = .005), parity (p = .006), prepregnancy weight (p = .028), and medical care source (p = .001), with the severe asthma group having the highest mean maternal age (25.7 years), and proportion of African Americans (71.4%), proportion of multiparous patients (63.3%), and proportion of patients receiving government assistance (85.7%). When the control group was excluded from the comparisons, differences in prepregnancy weight and medical care source were no longer significant. BW-MOM and L did not differ between groups. The HC:BW ratio increased with asthma severity (p = .029) and was increased compared to controls (p = .010). This remained significant after controlling for confounding variables (both p <.001). HC was statistically significantly different between all groups (p = .032), as well as among women with varying degrees of asthma severity (p = .013), which was not clinically significant. After covariates adjustment, HC was not significantly different among all groups (p = .228), nor the asthma groups (p = .144). CONCLUSION: Asthma severity is associated with an increased HC:BW ratio. Severity was not found to impact HC, BW-MOM, L, or PI independently. However, the magnitudes of the effects were too small to suggest a clinically significant effect of asthma on neonatal morphometry in this large prospectively studied sample. PMID- 20170322 TI - Prevalence of work-related asthma in Michigan, Minnesota, and Oregon. AB - INTRODUCTION: Adults who have asthma that is caused or aggravated by triggers at work experience a reduced quality of life. In this study, the authors sought to estimate the proportion of asthma that is associated with work using a state based survey of adults with asthma. METHODS: In 2005, Michigan, Minnesota, and Oregon piloted the Behavioral Risk Factor Surveillance System Adult Asthma Call Back Survey, with sample sizes of 867, 469, and 1072, respectively. Six questions addressing work-related asthma (WRA) were analyzed to generate estimates of the proportion of adult asthma that is work-related and compare those with and without WRA. RESULTS: Over half of all adults with asthma (53%) reported that their asthma was caused or made worse by any job they ever had, and among these respondents reporting WRA, only 21.5% to 25.1% reported ever telling or being told by a health professional that their asthma was work-related. Additionally, adults with WRA consistently reported poorer asthma control and higher health care utilization than adults with non-WRA. CONCLUSIONS: WRA is a common but frequently unrecognized health problem, and this lack of recognition might contribute to poorer asthma control among adults with WRA. Because early recognition, treatment, and management of WRA are crucial for improving long-term prognosis, clinicians need to include assessment of workplace triggers in both their diagnostic and treatment plans for adult patients with asthma. PMID- 20170323 TI - Adherence to asthma therapy in elderly patients. AB - OBJECTIVES: To assess the adherence to antiasthmatic therapy by the use of questionnaire and objective methods in elderly people, as well as to evaluate the association between cognition, depressive symptoms, functional status, and compliance. METHODS: Patients aged 65 to 102 with chronic asthma under therapy were analyzed retrospectively to evaluate adherence using the Modified Morisky (MM) scale and a visual analog scale (VAS). In the second part of the study, a 1 year monitoring of asthma based on electronic diary and assessment of drug usage was performed. The MM scale and VAS as well as the estimation of cognition, depression symptoms, and functional status were carried out at the beginning and at the end of the observations. RESULTS: Among 117 participants at the beginning of the study, only 9% and 21% had high adherence to therapy according to the MM scale and VAS, respectively. After 1 year of monitoring, the compliance assessed by the MM scale increased from 3.08 +/- 0.97 to 3.85 +/- 1.01 and by the VAS from 44% +/- 7.8% to 90% +/- 5.9%. Adherence by electronic diary and drug packages was lower than in both MM scale and VAS. Cognition status correlated with the results of MM and VAS tests but did not influence other methods of assessment. There was a statistical correlation between depression symptoms, cognition, and adherence (p >.01) in contrast to functional status. Compliance correlated with asthma control tests and PEFR. CONCLUSION: Low adherence to antiasthmatic treatment is common in elderly people. Proper monitoring of asthma by the use of diary or assessment of drugs packages with estimation of depression symptoms and cognition status could increase the compliance and asthma control in this group of patients. PMID- 20170324 TI - Performance of the ISAAC questionnaire to establish the prevalence of asthma in adolescents: a population-based study. AB - BACKGROUND: The epidemiology of asthma has been investigated with questionnaires, such as the International Study of Asthma and Allergies in Childhood protocol. AIM: To investigate the performance of the questions of the International Study of Asthma and Allergies in Childhood questionnaire to diagnose asthma in adolescents. METHODS: This is a population-based cross-sectional study of adolescents in the Syndrome of Obesity and Risk Factors for Cardiovascular Disease study. The validity of the asthma symptoms of the International Study of Asthma and Allergies in Childhood protocol was assessed by calculating sensitivity, specificity, positive and negative posttest probabilities, and Youden's Index, taking as a gold standard the history of a medical diagnosis of asthma. Risk ratios (RRs) and 95% confidence intervals (CIs), adjusting for sex and age, were calculated using Cox regression model. RESULTS: In total, 575 adolescents were investigated. Overall, 28.7% reported a lifetime medical diagnosis of asthma, and 40.0% reported at least one episode of wheezing. Ever wheezing had the highest sensitivity (80.6%) for the diagnosis of asthma, compared with the other ISAAC questions. Adolescents who reported ever wheezing were about 8 times more likely (adjusted RR: 8.3; 95% CI: 4.9-14.2) to have ever had asthma, independent of age and sex. Symptoms within the last 12 months (wheezing, cough without cold or respiratory infection, sleep disturbed due to wheezing, wheezing due to exercise, speech limited due to wheezing) had specificity of 92.0% or higher. Dry cough at night without cold or respiratory infection was the strongest independent predictor of asthma (adjusted RR: 8.8; 95% CI: 6.1-12.7). CONCLUSIONS: Ever wheezing is the most sensitive indicator of the diagnosis of asthma but falsely identifies a portion of adolescents as asthmatic. Symptoms of asthma in the last 12 months, such as cough without cold or respiratory infection, are rarely positive in the absence of a lifetime asthma diagnosis. The combination of ever wheezing for screening and the presence of other symptoms within the past 12 months to confirm the diagnosis could be an effective strategy to identify the prevalence of asthma in communities. PMID- 20170325 TI - Reliability, validity, and responsiveness of the pediatric quality of life inventory (PedsQL) generic core scales and asthma symptoms scale in vulnerable children with asthma. AB - BACKGROUND: Patient-reported outcomes such as health-related quality of life (HRQOL) are increasingly used as primary endpoints in clinical trials. The Pediatric Quality of Life Inventory (PedsQL) is widely used as a measure of HRQOL and may be a particularly suitable primary outcome in pediatric asthma clinical trials. OBJECTIVES: To examine the reliability, validity, and responsiveness to clinical change of the PedsQL 4.0 Generic Core Scales and PedsQL Asthma Module Asthma Symptoms Scale in a sample of vulnerable children with persistent asthma recruited from Federally Qualified Health Centers. METHODS: Children (N = 252; ages 3 to 14 years) with persistent asthma (27% mild, 40.9% moderate, 32.1% severe) and their parents (93.7% mother, 83.3% Hispanic, 76.9% Spanish-speaking, 72.6% less than a high school diploma) enrolled in a clinical trial completed the PedsQL 4.0 Generic Core Scales, the PedsQL 3.0 Asthma Module Asthma Symptoms Scale, and a measure of asthma symptom frequency (used as an indicator of clinical change) at baseline and 3-month follow-up. RESULTS: The PedsQL demonstrated adequate internal consistency reliability and convergent and discriminative validity. Based on intra- and intersubject change, effect sizes, and standard errors of measurement, the PedsQL demonstrated responsiveness to clinical change. Conclusions. For both child self-report and parent proxy-report, the PedsQL Generic Core Scales Total Scale score and the PedsQL Asthma Symptoms Scale are suitable for use as primary asthma clinical trial outcomes. PMID- 20170326 TI - Evaluation of fitness to utilize Self-Contained Breathing Apparatus (SCBA). AB - BACKGROUND: Breathing dry, cold air may cause bronchoconstriction in asthmatics working with self-contained breathing apparatus (SCBA). Air delivered by SCBA is cooler than ambient air. It is unclear whether a bronchial challenge test using mannitol (BCTM) can predict a fall in forced expiratory volume in one second (FEV(1)) during exercise with SCBA. METHODS: A prospective study of army recruits assigned to work with SCBA was carried out. Participants completed self administered questionnaires on respiratory symptoms, BCTM, and measurement of exhaled nitric oxide. A subgroup of participants with a positive BCTM (BTCM+) and with negative BCTM underwent exercise test on bicycle ergometer (ET) while using SCBA. RESULTS: One hundred and six recruits participated in this study. One hundred and two underwent BCTM and 28 ET. Nineteen out of 97 participants had a positive BCTM and 6 out of 27 had a positive ET. Seventeen out of 19 participants with a positive BCTM had current respiratory symptoms such as wheeze, cough, chest tightness, or dyspnea. Sensitivity, specificity, positive predictive value, and negative predictive value for a positive ET under SCBA were 100%, 64%, 43%, and 100% for the BCTM, respectively. BCTM-positive participants with respiratory symptoms had more physician consultations during MBT compared to BCTM-negative participants. CONCLUSION: Despite medical evaluation and exclusion of asthmatics by a physician during conscription, a high proportion of recruits assigned to work with SCBA smoke, have respiratory symptoms, and have a positive BCTM suggesting current asthma. BCTM has a high sensitivity to predict a significant fall in FEV(1) after exercise with SCBA and participants with a positive BCTM tend to use more health care resources during basic military training. Recruits should be counseled about smoking cessation prior and during basic military training. PMID- 20170327 TI - Asthma knowledge and asthma management behavior in urban elementary school teachers. AB - BACKGROUND: Although schools are an important setting for asthma care in youth, teachers' asthma knowledge and symptom management is poor. This study investigated the knowledge, prevention and management behaviors, and communication regarding asthma of teachers of low-income, ethnic minority students. It was hypothesized that relative to colleagues whose students did not have active asthma (i.e., did not have symptoms during the day), teachers of students with active asthma would have better asthma knowledge and that more would take asthma prevention steps and communicate with parents and school nurses. METHODS: Drawing from 25 elementary schools in New York City, 320 pre Kindergarten through 5th grade classroom teachers with at least one student with asthma completed measures assessing their asthma knowledge, steps taken to manage asthma, communication with the school nurse or parents, information they received about asthma, and whether or not they had at least one student in their class experience asthma symptoms. t test and chi-square were used to test hypotheses. RESULTS: Asthma knowledge varied among teachers. Most could identify potential triggers, yet few knew that medication taken prior to exercise could prevent symptoms and that students with asthma need not avoid exercise. Communication between teachers and school nurses and between teachers and parents was lacking. Relative to colleagues whose students did not have active asthma, teachers whose students had active asthma had better asthma knowledge, more took steps to prevent students from having asthma symptoms, communicated with parents, and more initiated communication with the nurse. CONCLUSIONS: Teachers' knowledge about asthma and asthma management is limited, especially among those whose students did not have active asthma. Teachers respond reactively to students who have symptoms in class by increasing prevention steps and communications with parents and the school nurse. A more proactive approach to managing asthma in schools is warranted. PMID- 20170328 TI - Barriers to patient-clinician collaboration in asthma management: the patient experience. AB - OBJECTIVE: To describe what adult patients with asthma report about their experiences with their own self-management behavior and working with their clinicians to control asthma. METHODS: The study sample consisted of 104 patients with persistent asthma participating in a clinical trial on asthma monitoring. All subjects were seen by primary care clinicians of a large, academic medical center. This qualitative post hoc analysis examined the views of adults with asthma about their asthma-related health care. Patients attended monthly visits as part of their study participation, during which data were derived from semistructured interviews. All patients included in this analysis participated in the study for 1 year. At the end of study participation, patients were asked to complete an evaluation of their clinician's communication behavior. All study clinicians were also asked to complete a self-evaluation of their own communication behavior. RESULTS: Five major themes of barriers to successful self management were identified, including personal constraints, social constraints, communication failures, medication issues, and health care system barriers to collaboration with their clinicians. Patients most frequently reported lack of communication surrounding issues relating to day-to-day management of asthma (31%) and home management of asthma (24%). Clinicians generally rated themselves well for consistency in showing nonverbal attentiveness (89%) and maintaining interactive conversations (93%). However, only 30% of clinicians reported consistency in helping patients make decisions about asthma management and only 33% of clinicians reported consistency in tailoring medication schedules to the patient's routines. CONCLUSION: These findings emphasize the difficulties of establishing and maintaining a therapeutic partnership between patients and clinicians. The results underscore the need for system-wide interventions that promote the success of a therapeutic patient-clinician relationship in order to achieve long-term success in chronic disease management. PMID- 20170329 TI - Providing feedback on adherence increases use of preventive medication by asthmatic children. AB - This study investigates the impact of measuring adherence and providing feedback on medication usage by children with unstable asthma. Adherence was measured using an electronic monitoring device. Subjects were randomized to either being told of their adherence during review consultations or for their adherence to remain undisclosed to their parents and treating physician. Subjects were reviewed monthly for 4 months. Twenty-six children aged between 6 and 14 years were recruited. Adherence was significantly higher in the intervention group (79% versus 58%, p <.01). There were significant improvements in clinical measures of disease control compared with baseline in both groups. The change in forced expiratory volume in 1 s (FEV(1)) (% predicted) was greater in those subjects receiving feedback (13.8% versus 9.8%). However, lung function values were lower in the intervention group at baseline and the relative improvement failed to reach statistical significance. Measuring adherence and providing feedback increases the use of preventive medication. A larger study is required to explore implications for disease control. PMID- 20170330 TI - Repeated instruction on inhalation technique improves adherence to the therapeutic regimen in asthma. AB - BACKGROUND: Adherence to inhalation therapy is a critical determinant of the success of asthma management. Reasons for nonadherence have been well studied, but reasons for good adherence are poorly understood. Understanding the mechanisms of adherence to inhalation therapy is important in developing strategies to promote adherence. The objective of this study was to assess the factors and mechanisms that contribute to and the clinical outcomes relating to adherence to inhalation therapy. METHODS: The factors and outcomes related to adherence to inhalation therapy were examined cross-sectionally in 176 adults with asthma using a self-reported adherence questionnaire that consisted of four items dealing with the use of inhaled controller medications. A 5-point Likert scale was used for the responses to each item. Adherence was assessed based on the overall mean adherence score. RESULTS: Of the 176 patients who were potential participants, 146 (83%) responded with usable information. Significant factors associated with the overall mean adherence score were older age (r = .18, p = .032) and receiving repeated instruction on inhalation techniques (p = .0016). Of the 146 respondents, 25 (17.1%) patients were given repeated verbal instruction or demonstrations of inhalation technique by a respiratory physician. On logistic regression analysis, good adherence to inhalation therapy was significantly related to the receiving of repeated instruction on inhalation technique, with an odds ratio of 2.90 (95% confidence interval 1.07-7.88; p = .037). Furthermore, less intentional nonadherent behavior was reported in patients with repeated instruction on inhalation technique compared to those without it. A significant correlation was found between the overall mean adherence score and the frequency of asthma exacerbations (r = -.19, p = .021), emergency room visits (r = -.19, p = .042), and the health-related quality of life score (St. George's Respiratory Questionnaire: Total, r = -.22, p = .024; Symptoms, r = -.21, p = .022; Impacts, r = -.20, p = .035). CONCLUSIONS: Repeated instruction on inhalation techniques may contribute to adherence to inhalation therapy through decreasing intentional nonadherence. Furthermore, good adherence to the therapeutic regimen may offer good asthma-related outcomes. PMID- 20170331 TI - Asthma therapy during the first 8 years of life: a PIAMA cohort study. AB - OBJECTIVE: Many studies evaluated asthma medication use in children in a cross sectional manner, yet little is known about longitudinal use patterns. This study describes the formation of a longitudinal data set on asthma medication use and shows first results regarding the prevalence and incidence of medication use. METHODS: The PIAMA (Prevention and Incidence of Asthma and Mite Allergy) study is a prospective birth cohort study among 3963 Dutch children. Recruitment took place in 1996-1997. The data of the PIAMA birth cohort study were complemented with pharmacy data. Prescription information of family members was used to determine whether medication histories were complete from birth until age 8. The prevalence and incidence of asthma medication use was studied in children for whom complete medication histories were available. RESULTS: A first prescription for asthma medication was filled before age 8 by 280 (36%) children, with 88% starting therapy before age 5. Of all children who started therapy, 91.1% received short-acting beta(2)-agonists and 61.1% inhaled corticosteroids. CONCLUSION: The applied method of data collection rendered a data set including 777 children with complete medication histories for their first 8 years of life. This data set provides the opportunity to study longitudinal medication use patterns. First analyses show that asthma medication is initiated in a rather high percentage of children in this cohort and mainly at an age at which an asthma diagnosis cannot yet be firmly established. PMID- 20170332 TI - Does low-dose seretide reverse chronic obstructive pulmonary disease and are the benefits sustained over time? An open-label Swedish crossover cohort study between 1999 and 2005. AB - Chronic obstructive pulmonary disease (COPD) still poses a formidable challenge to patients and clinicians alike. A fixed-dose dry powder combination inhaler, Seretide/Advair, containing salmeterol and fluticasone, is licensed in the European Community for the treatment of moderate to severe COPD in the strength of 50/500 microg twice daily (BID). Several studies have investigated the effects of this combination and show improved forced expiratory volume in 1 s (FEV(1)), quality of life, and a decrease of exacerbations. Most of the studies have run for less than 1 year. The aim of this investigator-initiated, independent study was to elucidate if the combination containing 50 microg of salmeterol and 250 microg of fluticasone BID could be shown to have the same beneficial effect as the higher dosage, and if the effect could be sustained over time. PMID- 20170333 TI - Comparison of patient-reported outcomes during treatment with adjustable- and fixed-dose budesonide/formoterol pressurized metered-dose inhaler versus fixed dose fluticasone propionate/salmeterol dry powder inhaler in patients with asthma. AB - OBJECTIVE: Assessment of patient-reported outcomes is important in evaluating the impact of asthma treatment. This study was conducted to compare effects of adjustable- and fixed-dose budesonide/formoterol pressurized metered-dose inhaler with fixed-dose fluticasone propionate/salmeterol dry powder inhaler regimens on patient-reported outcomes in patients aged > or =18 years with moderate to severe asthma. METHODS: In this phase III, randomized, open-label study, 1225 patients were randomized 2:1 to fixed-dose budesonide/formoterol 160/4.5 microg x 2 inhalations (320/9 mug) twice daily or fixed-dose fluticasone propionate/salmeterol 250/50 microg twice daily for 1 month. In the subsequent 6 months, patients receiving fixed-dose fluticasone propionate/salmeterol continued therapy, whereas those receiving fixed-dose budesonide/formoterol were randomized 1:1 to fixed-dose or adjustable-dose budesonide/formoterol (adjustable from 320/9 microg twice daily to 320/9 microg once daily or 640/18 microg twice daily). RESULTS: Mean improvements from baseline to end of treatment in the Asthma Quality of Life Questionnaire (standardized) overall and individual domain scores and the Asthma Control Questionnaire score were clinically important (> or =0.5 points) for all treatments. Patients in both budesonide/formoterol groups reported greater treatment satisfaction on the Asthma Treatment Satisfaction Measure questionnaire than patients in the fluticasone propionate/salmeterol dry powder inhaler group for the attributes of timely relief of symptoms (p < or = .037) and feel medication working (p < or = .020). Onset of Effect Questionnaire scores showed a greater percentage of patients perceiving onset of effect with budesonide/formoterol regimens versus fixed-dose fluticasone propionate/salmeterol (p < or = .002). CONCLUSIONS: Treatment regimens did not differ regarding improvements in asthma-specific quality of life and asthma control. Questions related to perceived rate of onset and feeling medication working in the Asthma Treatment Satisfaction Measure and Onset of Effect Questionnaire generally elicited somewhat more favorable responses with budesonide/formoterol pressurized metered-dose inhaler regimens versus fixed-dose fluticasone propionate/salmeterol dry powder inhaler. PMID- 20170334 TI - Acute exacerbation of asthma complicated by hyperventilation in emergency department. AB - Acute asthmatic attack is an important emergency medical condition. The author hereby reports a case in the emergency department of an acute exacerbation of asthma, complicated by hyperventilation. In this case, the patient had underlying needle phobia, which suddenly occurred during the salbutamol injection. Nevertheless, both physical and psychological approaches led to the successful control of the condition. This report addresses a situation, which, although rare, should not be overlooked. PMID- 20170335 TI - Chronic inhalation exposures of Fischer 344 rats to 1,6-hexamethylene diisocyanate did not reveal a carcinogenic potential. AB - The polyisocyanates of 1,6-hexamethylene diisocyanate (HDI) find widespread commercial use as components of paints and in the formulation of light-stable polyurethane coating materials. This 2-year study assessed the oncogenicity of the diisocyanate monomer HDI in male and female Fischer-344 rats exposed 6 h/day, 5 days/week to mean analytical air concentrations of 0, 0.005, 0.025, and 0.164 ppm HDI. During the in-life phase, transient eye irritation was observed in 0.164 ppm males, and a slight body weight decrease (5%) in the 0.164 ppm females during the second year of exposure. There were no exposure-related effects on mortality. Compound-related, non-neoplastic histopathologic changes were limited to the respiratory tract and changes were characterized by epithelial tissue reaction to the acute irritant properties of HDI vapor. For tissues of the nasal cavity, the major histopathologic findings were degeneration of the olfactory epithelium characterized by destruction of the epithelial architecture often with narrowing or atrophy and occasional focal erosion or ulceration. In addition, there was variable degeneration of the respiratory epithelium with hyperkeratosis of the epithelium, epithelial and mucus secretory cell hyperplasia, squamous metaplasia, chronic-active inflammation, and errosive or ulcerative changes. These tissue effects along with a statistically significant decrease in body weight of female rats demonstrated attainment of a maximum tolerated dose. There was no evidence of progression of these changes in the nasal epithelium to neoplasia nor evidence of any compound-related neoplastic lesions for any of the other tissues examined. Therefore, it is concluded that HDI did not show a carcinogenic potential in this study. PMID- 20170336 TI - Safety and toxicological evaluation of undenatured type II collagen. AB - Previous research has shown that undenatured type II collagen is effective in the treatment of arthritis. The present study evaluated the broad-spectrum safety of UC-II by a variety of toxicological assays including acute oral, acute dermal, primary dermal irritation, and primary eye irritation toxicity. In addition, genotoxicity studies such as Ames bacterial reverse mutation assay and mouse lymphoma tests, as well as a dose-dependent 90-day sub-chronic toxicity study were conducted. Safety studies indicated that acute oral LD(50) of UC-II was greater than 5000 mg/kg in female Sprague-Dawley rats. No changes in body weight or adverse effects were observed following necropsy. Acute dermal LD(50) of UC-II was determined to be greater than 2000 mg/kg. Primary skin irritation tests conducted on New Zealand Albino rabbits classified UC-II as slightly irritating. Primary eye irritation tests conducted on rabbits indicated that UC-II was moderately irritating to the eye. UC-II did not induce mutagenicity in the bacterial reverse mutation test in five Salmonella typhimurium strains either with or without metabolic activation. Similarly, UC-II did not induce a mutagenic effect in the gene mutation test in mouse lymphoma cells either with or without metabolic activation. A dose-dependent 90-day sub-chronic toxicity study revealed no pathologically significant changes in selected organ weights individually or as percentages of body or brain weights. No significant changes were observed in hematology and clinical chemistry. Therefore, the results from the current study show a broad-spectrum safety profile of UC-II. PMID- 20170337 TI - Description and assessment of a model for GSK-3beta database virtual screening. AB - Molecular docking was used in order to prioritize organic syntheses or experimental evaluations. Different GSK-3beta protein models were generated in silico from a known X-ray structure. A set of 42 known inhibitors were then flexibly docked into each rigid model and re-scored with various functions, which led to different rankings. The biological activities of the chemicals were then compared to each set of results and one of the rigid models emerged in combination with two scoring functions as giving the best correlation. This methodology constitutes an easy and accurate way to generate reliable models for virtual database screening. PMID- 20170339 TI - An experimental test of Darwin's naturalization hypothesis. AB - One of the oldest ideas in invasion biology, known as Darwin's naturalization hypothesis, suggests that introduced species are more successful in communities in which their close relatives are absent. We conducted the first experimental test of this hypothesis in laboratory bacterial communities varying in phylogenetic relatedness between resident and invading species with and without a protist bacterivore. As predicted, invasion success increased with phylogenetic distance between the invading and the resident bacterial species in both the presence and the absence of protistan bacterivory. The frequency of successful invader establishment was best explained by average phylogenetic distance between the invader and all resident species, possibly indicating limitation by the availability of the unexploited niche (i.e., organic substances in the medium capable of supporting the invader growth); invader abundance was best explained by phylogenetic distance between the invader and its nearest resident relative, possibly indicating limitation by the availability of the unexploited optimal niche (i.e., the subset of organic substances supporting the best invader growth). These results were largely driven by one resident bacterium (a subspecies of Serratia marcescens) posting the strongest resistance to the alien bacterium (another subspecies of S. marcescens). Overall, our findings support phylogenetic relatedness as a useful predictor of species invasion success. PMID- 20170338 TI - Angiotensin I converting enzyme inhibitory peptide extracted from freshwater zooplankton. AB - In this study, hydrolysates obtained from the freshwater rotifer Brachionus calyciflonus were investigated for angiotensin I converting enzyme (ACE) inhibitory peptides. Freshwater rotifer protein was hydrolyzed using six separate enzymes in a batch reactor. The peptic hydrolysate had the highest ACE inhibitory activity compared to the other hydrolysates. The highest ACE inhibitory peptide was separated using Sephadex G-25 column chromatography and high-performance liquid chromatography on a C18 column. The 50% inhibitory concentration (IC(50)) value of purified ACE inhibitory peptide was 40.01 microg/mL. ACE inhibitory peptide was identified as being seven amino acid residues of Ala-Gln-Gly-Glu-Arg His-Arg by N-terminal amino acid sequence analysis. The IC(50) value of purified ACE inhibitory peptide was 47.1 microM, and Lineweaver-Burk plots suggested that the peptide purified from rotifer protein acts as a competitive inhibitor against ACE. The results of this study suggest that peptides derived from freshwater rotifers may be beneficial as antihypertension compounds in functional foods or as pharmaceuticals. PMID- 20170340 TI - The natural flavonoid apigenin suppresses Th1- and Th2-related chemokine production by human monocyte THP-1 cells through mitogen-activated protein kinase pathways. AB - Dietary flavonoids have various biological functions, and there is increasing evidence that reduced prevalence and severity of allergic reactions are associated with the intake of flavonoids. Among natural flavonoids, apigenin is a potent anti-inflammatory agent. However, the mechanisms of apigenin's effect remain uncertain. Monocyte-derived chemokine (MDC) plays a pivotal role in recruiting T-helper (Th) 2 cells in the allergic inflammation process. In the late phase of allergic inflammation, the Th1 chemokine interferon-inducible protein 10 (IP-10) has also been found in elevated levels in the bronchial alveolar fluid of asthmatic children. We used human THP-1 monocyte cells, pretreated with or without apigenin, prior to lipopolysaccharide stimulation. By means of enzyme-linked immunosorbent assay, we found that apigenin inhibited production of both MDC and IP-10 by THP-1 cells and that the suppressive effect of apigenin was not reversed by the estrogen receptor antagonist ICI182780. The p65 phosphorylation of nuclear factor kappaB remained unaffected, but the phosphorylation of p38, c-Jun N-terminal kinase, and extracellular signal regulated kinase mitogen-activated protein kinase pathways were all blocked. We found that inhibition of c-raf phosphorylation might be the target of apigenin's anti-inflammation property. PMID- 20170341 TI - Angiotensin converting enzyme gene insertion/deletion polymorphism in patients with polycystic ovary syndrome. AB - OBJECTIVE: The aim of this study is to investigate the relevance of polymorphism in angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism to the pathophysiology of polycystic ovary syndrome (PCOS). SUBJECTS AND METHODS: Thirty patients with PCOS by Rotterdam consensus criteria and 33 control subjects were prospectively investigated. ACE gene amplification of DNA was performed by polymerase chain reaction. Homeostatic model assessment (HOMA-IR) was applied. RESULTS: Compared to controls, ACE gene DD genotype and D allele were observed more frequently in PCOS (63% vs. 46% for DD genotype and 75% vs. 67% for D allele) (p > 0.05). Body mass index, fasting glucose and insulin levels, HOMA-IR index and total testosterone levels were higher in PCOS group (p < 0.05). The frequencies of D and I alleles were 45 (75%) and 15 (25%) for PCOS group and 44 (67%) and 22 (33%) for control group (p > 0.05). No significant differences were observed in the genotype and allele distributions between cases and control groups. HOMA-IR index was significantly higher in patients with PCOS with DD genotype than those with II genotype (p < 0.05). CONCLUSION: The ACE gene polymorphism was not associated with PCOS. However, the presence of D allele was associated with higher rate of insulin resistance in patients with PCOS. PMID- 20170342 TI - Skewed X chromosome inactivation may be not associated with premature ovarian failure. AB - BACKGROUND: In view of the controversies about the skewed X chromosome inactivation (XCI) and premature ovarian failure (POF) association, a meta analysis of the published data was performed to evaluate the relationship between XCI skewing and POF. METHODS: We searched for all published articles indexed in MEDLINE (1950 approximately 2009) and CNKI (1994 approximately 2009). Any case control or cohort study that tested the association between skewed XCI and POF was included and data were extracted independently by two reviewers. We performed this meta-analysis involving 325 cases and 403 controls with Review Manager 4.2 software. RESULTS: Four eligible studies were selected for meta-analysis. It suggested that there was no significant difference between the incidence of skewed XCI (XCI >or=70% skewing) in POF cases comparing to healthy controls, odds ratio (OR) = 1.13 [95% confidence interval (CI): 0.84 approximately 1.53, P = 0.42]. The link between extremely skewed XCI (XCI >or=90% skewing) and POF was also analysed, and no significant difference was found, either, OR = 1.46 (95% CI: 0.79 approximately 2.69, P = 0.22). CONCLUSIONS: Skewed XCI had no association with POF. However, more case-control and cohort studies are needed in the future. PMID- 20170343 TI - A 46, XX SRY - negative man with infertility, and co-existing with chronic autoimmune thyroiditis. AB - 46, XX male (de la Chapelle syndrome) is a rare syndrome with a frequency of 1 in 20,000-25,000 males. 46, XX males exist in different clinical categories with ambiguous genitalia or partially to fully mature male genitalia, in combination with complete or incomplete masculinisation. We herein report a case of SRY negative XX male with complete masculinisation but with infertility, and co existing with autoimmune thyroiditis. The patient had fully mature male genitalia with descended but small testes and no signs of undervirilisation. Peripheral blood culture for chromosome studies revealed 46 chromosomes with XX constitution. Repeat polymerase chain reaction analysis, using Y-specific sequence tagged sites analysing about 40 metaphases of genomic DNA, confirmed the absence of the Y chromosome, including any detectable SRY gene. We herein report a case of a man 46, XX male SRY with normal male phenotype and infertility. This case is the first reported case, co-existing with chronic autoimmune thyroiditis. PMID- 20170344 TI - 17-alpha-hydroxylase deficiency: a case report with clinical and molecular analysis. AB - BACKGROUND: 17alpha-Hydroxylase deficiency (17OHD) is a rare disease of congenital adrenal hyperplasia. It is characterised by hypertension, hypokalaemia, primary amenorrhoea. Deficiency of P450c17 enzyme is caused by mutation of the CYP17 gene. CASE: A 16-year-old female with genotypic 46, XY suffered from 17OHD. She presented with primary amenorrhoea, lack of secondary sexual characteristics, and hypertension. Laboratory tests showed hypokalaemia, low levels of androgens (testosterone and dehydroepiandrosterone), corticosteroid, and high levels of adrenocorticotropic hormone and progesterone. A P409R mutation was found in exon7 of CYP17 gene, revealing homozygosis and confirming diagnosis of 17OHD. CONCLUSION: 17OHD is a rare disease associated with primary amenorrhoea and hypertension. Identification of mutation in CYP17 gene can help to a better understanding of this enzyme deficiency. PMID- 20170345 TI - Antimullerian hormone levels after laparoscopic endometrioma stripping surgery. AB - OBJECTIVE: To evaluate whether a change takes place in antimullerian hormone (AMH) levels reflecting the ovarian reserve after laparoscopic endometrioma stripping surgery and to demonstrate if there is any correlation between AMH levels and the sizes of endometriomas. METHOD: Fourty-seven women participated as the study group in this prospective controlled trial, 33 of whom (70.2%) had unilateral and 14 (29.7%) of whom had bilateral endometriomas. Pre- and post operative serum AMH levels were measured and compared with 17 normo-ovulatory control cases and also correlated with endometrioma sizes. RESULT(S): Mean pre operative AMH levels of the study group and the normo-ovulatory control cases did not reveal a statistically significant difference (1.62 +/- 1.09 ng/ml and 2.06 +/- 0.51 ng/ml, P > 0.05). Mean level of post-operative serum AMH of the study group decreased from 1.62 +/- 1.09 to 1.39 +/- 1.16. However, this reduction was not statistically significant. (P > 0.05). Pre- and post-operative AMH levels do not reveal a correlation with the size of endometrioma in both group of patients with either unilateral or bilateral endometrioma. CONCLUSION(S): The presence of the endometrioma does not impair the AMH levels. Laparoscopic endometrioma stripping surgery do not appear to cause a damage in the AMH secreting healthy ovarian tissue, in the short-term follow-up. Laparoscopic stripping surgery of endometriomas in experienced hands is currently a valid approach. PMID- 20170346 TI - Longitudinal changes of adiponectin, carbohydrate and lipid metabolism in pregnant women at high risk for gestational diabetes. AB - To evaluate, in pregnant women at high risk for gestational diabetes (GDM), the longitudinal changes of adiponectin, carbohydrate and lipid metabolism, and to assess their independent value as risk factors for the development of GDM. Fifty women at beginning of pregnancy were studied. Adiponectin, insulin sensitivity (homeostasis model assessment, HOMA) and lipid panel were measured at 1st, 2nd and 3rd trimesters of pregnancy. Twelve patients developed GDM. In both groups, GDM and normal glucose tolerance (NGT), adiponectin decreased from 1st to 2nd and 3rd trimesters by about 5 and 20% (GDM, p < 0.05), and of about 17 and 25% in NGT (p < 0.05), respectively. Values observed in NGT were similar to those of GDM (F = 9.401; p = 0.238). The Cox regression model identified as the strongest independent risk factor for GDM HOMA over 1.24 (RR = 14.12) at 1st trimester, fasting glycaemia over 87 mg/dl (RR = 42.68) triglycerides over 158 mg/dl (RR = 5.87) and body mass index (BMI) over 27 kg/m(2) (RR = 4.38) at 2nd trimester. Adiponectin in high-risk women is characterised by a constant reduction throughout gestation, irrespective of the development of GDM. HOMA, fasting glycaemia, triglycerides and BMI, but not adiponectin are independent predictors of GDM. PMID- 20170347 TI - Micronucleus frequency in lymphocytes and 8-hydroxydeoxyguanosine level in plasma of women with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) has recently been linked with genomic instability and DNA damage. The aim of this study was to test genomic damage in women PCOS, using two different methods for assessing damage in both chromosome and base level. The study was performed on 36 newly diagnosed women with PCOS and 29 healthy women as controls. The micronucleus (MN) analysis used as a biomarker of chromosomal/DNA damage was performed in peripheral lymphocytes by cytokinesis block method. 8-hydroxydeoxyguanosine (8-OHdG) levels used as a reliable marker of oxidative DNA damage were measured in plasma using an ELISA kit. We found that MN frequencies obtained from lymphocytes of the women with PCOS were significantly higher than those of controls (4.1 +/- 1.0 vs. 2.1 +/- 0.6, P = 0.001), whereas, no differences in 8-OHdG level were found between the patients with PCOS and controls (0.5 +/- 0.3 vs. 0.5 +/- 0.2, P = 0.858). These findings indicate that women with PCOS seem to have increased genomic instability, but do not appear to have oxidative DNA damage despite the increased oxidative stress associated with PCOS. PMID- 20170348 TI - C-reactive protein as the indicator of severity in ovarian hyperstimulation syndrome. AB - BACKGROUND: To establish correlations between laboratory findings and clinical symptoms of moderate and severe ovarian hyperstimulation syndrome (OHSS). DESIGN: A retrospective study. SETTING: Department of obstetrics and gynecology, public clinical hospital. PATIENTS: Nineteen women admitted to the public hospital with a diagnosis of OHSS. The procedure of controlled ovarian stimulation (COH) was performed in the private assisted reproductive technology centre. METHODS: Blood samples were collected, ultrasound examination of ovaries, abdominal circumference measurement were performed, intravenous crystalloids, plasma expanders such colloids and albumin were given. Correlations between mean laboratory results (haematocrit, c-reactive protein (CRP), white blood count, serum protein, serum albumin), ovarian size in ultrasound examination, abdominal circumference, and amount of albumin and hydroxyethyl starch transfused to the patient were assessed. RESULTS: Significant correlation was observed between CRP concentration and abdominal circumference measured when the patient was admitted to the department, between CRP concentration and ovarian size measured during ultrasound examination at admission and between CRP concentration and body weight. CONCLUSIONS: CRP can be a potential candidate to an indicator of OHSS severity. PMID- 20170349 TI - Assessment of the predictive value of follicular fluid insulin, leptin and adiponectin in assisted reproductive cycles. AB - PURPOSE: To assess the correlation of intrafollicular insulin, leptin and adiponectin levels with assisted reproductive technologies (ART) outcome. METHODS: This was a retrospective study of 46 patients undergoing in vitro fertilisation/intracytoplasmic sperm injection. Follicular fluid (FF) samples collected at oocyte retrieval were assayed for insulin, leptin and adiponectin levels using enzyme-linked immunosorbent assay, and correlations with ART outcome were analysed. RESULTS: There was no significant correlation between intrafollicular insulin, leptin and adiponectin levels. There was a significant difference in the concentration of insulin (P = 0.007), but not leptin or adiponectin, between pregnant (n = 20) and non-pregnant (n = 26) cycles. Only two pregnancies was observed in the 12 cycles in which the concentration of insulin was greater than 7 mU/l in FF, while 18 pregnancies was observed in the 34 cycles in which the concentration of insulin was less than 7 mU/l (P = 0.043). The significantly high concentration of insulin in FF was observed in non-pregnant cycles of patients with polycystic ovary syndrome (PCOS). CONCLUSIONS: Our results suggest the possible involvement of intrafollicular insulin in folliculogenesis. Insulin resistance-related substances may affect the reproductive process in patients with PCOS. PMID- 20170350 TI - Intrafollicular concentration of adrenomedullin is associated with IVF outcome. AB - OBJECTIVE: To test the hypothesis that serum or intrafollicular concentrations of adrenomedullin (AM) would correlate with reproductive outcomes in in vitro fertilisation (IVF) cycles. DESIGN: Serum and follicular fluid samples were collected during transvaginal oocyte retrieval. The follicular fluid was individually aspirated, and the presence of oocyte was recorded. AM concentrations were measured using an enzyme-linked immunosorbent assay. SETTING: Department of Gynaecology, Perinatology and Child Health, 'Sapienza' University of Rome, Italy. PATIENTS: Eighty women undergoing IVF for primary infertility aged 18-45 years. MAIN OUTCOME MEASURES: AM concentrations in plasma and follicular fluid were correlated to follicular fluid volume, presence of oocyte, oocyte maturation, embryo grading, fertilisation and pregnancy rates, live-birth rate and plasma estrogen concentration. RESULTS: Monofollicular fluid AM concentrations did not differ between follicles containing oocyte and those without oocyte; however, AM concentrations were lower in follicles that resulted in pregnancy than in those that failed. Serum but not follicular fluid AM concentrations correlated with serum estrogen levels. Follicular fluid AM correlated with plasma AM levels. CONCLUSION: We conclude that higher level of AM in the follicular fluid appears to be associated with a negative outcome in IVF treatment. PMID- 20170351 TI - Impact of overweight and underweight on IVF treatment in Chinese women. AB - OBJECTIVE: To investigate the effects of body mass index (BMI) on ovarian stimulation and the outcome of IVF or ICSI treatment in Asian population who have different characteristics of BMI from white people. DESIGN: In this retrospective study, the first fresh cycles of 1107 Chinese women were classified by BMI: underweight (BMI <18.5 kg/m(2)), normal weight (BMI: 18.5-23.9 kg/m(2)) and overweight (BMI >or= 24 kg/m(2)). Dose and days of ovarian simulation, cancelled cycles and number of oocytes collected, fertilisation and embryo utilisation rates and pregnancy outcome were compared among BMI groups. RESULTS: It showed that overweight women required more ampoules of gonadotrophin (P = 0.002) and had lower peak oestradiol concentration (P = 0.001), increased cycle cancellation due to insufficient follicle development (P = 0.018) and a higher miscarriage rate (10.5 vs. 5.4%, P = 0.018, OR = 2.006 (95% CI: 1.09-3.69, P = 0.025)) compared with normal weight women. However, no differences were found in clinical pregnancy and live-birth rates. Underweight compared with normal weight women showed no differences in ovarian stimulation and IVF outcome although the clinical pregnancy rate was lower (31.1 vs. 37.3%). CONCLUSION: At a lower cutoff point of BMI in Chinese women, overweight is associated with increased miscarriage risks and impaired response to ovarian stimulation after IVF and ICSI. PMID- 20170352 TI - The prevalence of Gly972Arg and C825T polymorphisms in Slovak women with polycystic ovary syndrome and their relation to the metabolic syndrome. AB - AIM: To assess the prevalence of IRS-1 Gly972Arg and GNB3 C825T polymorphisms in women with polycystic ovary syndrome (PCOS) and their relation to the metabolic syndrome and hyperandrogenaemia. METHODS: Fifty-three female patients with diagnosis of PCOS and 21 healthy women were genotyped for the commom Gly972Arg and C825T polymorphisms. Body mass index, serum glucose, insulin, insulin sensitivity index HOMA (homeostasis model assessment) and serum lipoproteins were estimated. RESULTS: The prevalence of Gly972Arg genotype in PCOS women was 22.64% and was not significantly higher than in control group with the prevalence 9.52%. The frequency of T alleles was 28% in PCOS group that was similar to control group (29%). We did not find the significant differences in the frequency of TC + TT genotypes between patients and controls. There were no significant differences in serum glucose, insulin, lipoproteins, index HOMA, as well as BMI and waist circumference between patients with GlyArg and GlyGly. Both CC and TC/TT genotype patients had similar values of BMI, waist and measured biochemical variables. Moreover, Gly972Arg and C825T polymorphisms were not related to hormonal status of PCOS women. CONCLUSION: The Gly972Arg and C825T polymorphisms are associated neither with PCOS nor with metabolic syndrome in the Slovak female population. PMID- 20170353 TI - Menstrual abnormalities and predisposition to pregnancy-related hypertensive disorders: a retrospective study. AB - OBJECTIVE: Pregnancy-related hypertensive disorders (PRHDs) are a leading cause of maternal and perinatal morbidity and mortality in developed countries. This study investigated a possible association of PRHDs with menstrual abnormalities. MATERIALS AND METHODS: We contacted all women with PRHDs who delivered in our clinic between 2004 and 2007 as well as a random control cohort without pregnancy complications and asked them about their menstrual cycle characteristics. Statistical analyses were performed using R, with significance set at p < 0.05. RESULTS: We collected data for 237 women with normal pregnancies and 255 women with PRHDs, among whom 143 had gestational hypertension and 70 had mild and 41 severe preeclampsia. By monovariate analysis, PRHDs correlated with dysmenorrhoea, hypermenorrhoea and menstrual irregularity (p < 0.05). By multivariate analysis, the occurrence of PRHDs was influenced by dysmenorrhoea and menstrual irregularity (p < 0.05). CONCLUSIONS: PRHDs usually affect women with painful or irregular menstrual cycles, perhaps due to metabolic syndrome or molecular pathways involving vasoactive substances, with clear vascular implications. PMID- 20170354 TI - Design of a programmable multi-pattern FES system for restoring foot drop in stroke rehabilitation. AB - A programmable and portable multi-pattern transcutaneous neuromuscular stimulator was developed and evaluated for correction of foot drop in stroke subjects. The stimulator unit was designed to optimize functionality while keeping its size and power consumption to a minimum. It had two channels of biphasic stimulation (charge-balanced and constant current), and all parameters were programmable to accommodate a range of stimulation profiles. The 'natural' electromyographic (EMG) pattern of tibialis anterior (TA) muscle stimulation envelope algorithms and constant amplitude stimulation envelope was provided for foot drop corrections in stroke patients. A foot-switch sensor was used to trigger the device in the swing phase of gait cycle. Various tests on prototype units were performed, including output power characteristics with a skin model, and tested with a stroke subject to validate the results. This paper provides a detailed description of the hardware and block-level functional electrical stimulation (FES) system design for applications in stroke rehabilitation. PMID- 20170355 TI - Activation of lower back muscles via FES for pressure sores prevention in paraplegia: a case study. AB - The aim of this paper is to show the feasibility of the use of functional electrical stimulation (FES) applied to the lower back muscles for pressure sores prevention in paraplegia. The hypothesis under study is that FES induces a change in the pressure distribution on the contact area during sitting. Tests were conducted on a paraplegic subject (T5), sitting on a standard wheelchair and cushion. Trunk extensors (mainly the erector spinae) were stimulated using surface electrodes placed on the skin. A pressure mapping system was used to measure the pressure on the sitting surface in four situations: (a) no stimulation; (b) stimulation on one side of the spine only; (c) stimulation on both sides, at different levels; and (d) stimulation at the same level on both sides, during pressure-relief manoeuvres. A session of prolonged stimulation was also conducted. The experimental results show that the stimulation of the erector spinae on one side of the spine can induce a trunk rotation on the sagittal plane, which causes a change in the pressure distribution. A decrease of pressure on the side opposite to the stimulation was recorded. The phenomenon is intensified when different levels of stimulation are applied to the two sides, and such change can be sustained for a considerable time (around 5 minutes). The stimulation did not induce changes during pressure-relief manoeuvres. Finally, from this research we can conclude that the stimulation of the trunk extensors can be a useful tool for pressure sores prevention, and can potentially be used in a routine for pressure sores prevention based on periodical weight shifts. PMID- 20170356 TI - Berries from South America: a comprehensive review on chemistry, health potential, and commercialization. AB - Dietary intake of berry fruits has been demonstrated to positively impact human health. Interest in exploring new and exotic types of berries has grown in recent years. This article provides botanical descriptions and reviews the chemistry, biological activities, and commercialization of berry-producing plants from South America, specifically Aristotelia chilensis, Euterpe oleracea, Malpighia emarginata, Ugni molinae, Fragaria chiloensis, Rubus glaucus, Rubus adenotrichus, and Vaccinium floribundum. These species possess a rich and diversified composition of bioactive compounds with health-promoting properties. The most significant health benefits have been attributed to phenolic compounds and vitamin C, potentially protective against cardiovascular disease and cancer. Although both traditional folk medicine and composition of these berries suggest significant health benefits, few studies to date have investigated these potentials. PMID- 20170357 TI - The carcinogenicity of dietary acrylamide intake: a comparative discussion of epidemiological and experimental animal research. AB - Since 2002, it is known that the probable human carcinogen acrylamide is present in commonly consumed carbohydrate-rich foods, such as French fries and potato chips. In this review, the authors discuss the body of evidence on acrylamide carcinogenicity from both epidemiological and rodent studies, including variability, strengths and weaknesses, how both types of evidence relate, and possible reasons for discrepancies. In both rats and humans, increased incidences of various cancer types were observed. In rats, increased incidences of mammary gland, thyroid tumors and scrotal mesothelioma were observed in both studies that were performed. In humans, increased risks of ovarian and endometrial cancers, renal cell cancer, estrogen (and progesterone) receptor-positive breast cancer, and oral cavity cancer (the latter in non-smoking women) were observed. Some cancer types were found in both rats and humans, e.g., endometrial cancer (observed in one of the two rat studies), but there are also some inconsistencies. Interestingly, in humans, some indications for inverse associations were observed for lung and bladder cancers in women, and prostate and oro- and hypopharynx cancers in men. These latter observations indicate that genotoxicity may not be the only mechanism by which acrylamide causes cancer. The estimated risks based on the epidemiological studies for the sites for which a positive association was observed were considerably higher than those based on extrapolations from the rat studies. The observed pattern of increased risks in the rat and epidemiological studies and the decreased risks in the epidemiological studies suggests that acrylamide might influence hormonal systems, for which rodents may not be good models. PMID- 20170359 TI - Aronia plants: a review of traditional use, biological activities, and perspectives for modern medicine. AB - The Aronia genus (Rosaceae family, Maloideae subfamily) includes two species of native North American shrubs: Aronia melanocarpa (Michx.) Ell. (black chokeberry) and Aronia arbutifolia (L.) Pers. (red chokeberry). The fruits of A. melanocarpa have been traditionally used by Potawatomi Native Americans to cure colds. In the first half of the 20(th) century, cultivars of black chokeberry were introduced to the Soviet Union and other European countries, providing fruits used by food industry. At present, it is used mainly for juice, jam, and wine production, as well as an ornamental plant. Among other substances, the berries of A. melanocarpa contain anthocyanins and procyanidins, possessing strong antioxidative potential. Numerous health-promoting activities-namely, antioxidative, antimutagenic, anticancer, cardioprotective, hepatoprotective, gastroprotective, antidiabetic, anti-inflammatory, antibacterial, antiviral, radioprotective, and immunomodulatory-have been demonstrated for black chokeberry extracts by both in vitro and in in vivo studies. The presented review summarizes the information concerning botany, cultivation, chemical composition, and pharmacological activities of Aronia plants. PMID- 20170358 TI - Preliminary studies on the antinociceptive activity of Vaccinium ashei berry in experimental animal models. AB - The aim of this study was to carry out pharmacological screening in order to evaluate the potential effects of lyophilized fruits of different cultivars of Vaccinium ashei Reade (Family Ericaceae) berries, commonly known as rabbiteye blueberries, on nociception. This was achieved using the formalin, hot plate, tail-flick, and writhing tests in mice. During this experiment the mice consumed approximately 3.2-6.4 mg/kg/day (p.o.) of the anthocyanins. The extract was administered for 21 days or 60 minutes before test. Morphine and diclofenac (10 mg/kg, p.o.) as the standard drug (positive control) and water (via oral gavage) as the negative control were administered before all tests. The blueberry extract produced a significant decrease in constrictions induced by acetic acid and caused graded inhibition of the second phase of formalin-induced pain. Moreover, in both the hot plate and tail-flick tests, it significantly increased the threshold. These data suggest that the extract from V. ashei produced antinociceptive effects, as demonstrated in the experimental models of nociception in mice. Additional experiments are necessary in order to clarify the true target for the antinociceptive effects of rabbiteye blueberry extract. PMID- 20170360 TI - Quantification of saponins in extractive solution of mate leaves (Ilex paraguariensis A. St. Hil.). AB - Mate (Ilex paraguariensis A. St. Hil.) is a raw material used to prepare popular beverages in South America, whose healthy effects have been pointed out. The leaves and stems of mate contain a complex assemblage of saponins, mainly ursolic acid and oleanolic acid glycosides, and their quantification presents difficulties such as weak cromophorous sites and interference of other compounds. On the other hand, the sugar moieties are a chief character that distinguishes them. We developed and validated a high-performance liquid chromatography method using a refractometer detector for quantifying the major saponins in extractive solution of mate leaves. The validation indicates the suitability of the method, presenting linearity in the concentration range between 102.5 to 854.0 microg/mL to matesaponin 1 and between 103.0 to 515.0 microg/mL to matesaponin 3. The repeatability coefficient of variation was 4.70% and 6.61% for matesaponin 1 and matesaponin 3, respectively. The inter-day coefficient of variation was 6.77% and 7.79% for matesaponin 1 and matesaponin 3, respectively. The analysis of plants from Brazilian States Mato Grosso do Sul and Rio Grande do Sul showed the predominance of matesaponins 1, 2, and 3 in the corresponding extractive solution. The sum of these three saponins ranged between 3 and 10 mg/g for mature leaves in the majority of sampled plants. PMID- 20170362 TI - Utility of functional imaging in prediction or assessment of treatment response and prognosis following thermotherapy. AB - The purpose of this review is to examine the roles that functional imaging may play in prediction of treatment response and determination of overall prognosis in patients who are enrolled in thermotherapy trials, either in combination with radiotherapy, chemotherapy or both. Most of the historical work that has been done in this field has focused on magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS) methods, so the emphasis will be there, although some discussion of the role that positron emission tomography (PET) might play will also be examined. New optical technologies also hold promise for obtaining low cost, yet valuable physiological data from optically accessible sites. The review is organised by traditional outcome parameters: local response, local control and progression-free or overall survival. Included in the review is a discussion of future directions for this type of translational work. PMID- 20170363 TI - Umbilical cord-derived mesenchymal stem cells isolated by a novel explantation technique can differentiate into functional endothelial cells and promote revascularization. AB - Stem cells transplantation holds great promise for the treatment of ischemic diseases through functional revascularization. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) are also an ideal candidate for cell-based bioengineering. Herein, we report on the development of a simple and effective protocol to isolate UC-MSCs, and confirm their endothelial potential both in vitro and in vivo. UC-MSCs were isolated by a novel explantation technique and induced to differentiate into endothelial-like cells. Then UC-MSCs were transplanted into ischemic mouse model and cultured on 3D gel/MMT-CS composite scaffolds. Morphological and proliferation assessments show that sufficient UC-MSCs can be generated during a relatively short culture period with explantation technique. Increased expression of endothelial-specific markers (KDR and vWF), and functional markers (ac-LDL uptake and UEA-1 binding), indicate that functional endothelial progenitor cells are induced after 9 days of in vitro culture. In an ischemic hindlimb mouse model, the ratio of ischemic/nonischemic limb perfusion 4 weeks after MSCs transplantation reached 0.84 +/- 0.09. The capillary density of this group was 2.57-fold greater than that of sham-injected mice (P < 0.05). Immunofluorescence and immunohistological analyses indicate that MSCs may act to salvage the ischemic tissue by incorporating into the local vasculature. In vitro, UC-MSCs were observed to incorporate into 3D gel/MMT-CS composite scaffolds, to secrete extracellular matrix, to remain viable, and to retain their proliferation capacity. In conclusion, UC-MSCs isolated by novel yet simple explantation technique are well suited for application in the development of novel stem cell-based revascularization therapies. PMID- 20170364 TI - Multinucleate spores contribute to evolutionary longevity of asexual glomeromycota. AB - Arbuscular mycorrhizal fungi (Glomeromycota) are the dominant symbionts of land plants and one of the oldest multicellular lineages that exist without evidence of sexual reproduction. The mechanisms that protect these organisms from extinction due to accumulation of deleterious mutations in the absence of sexual recombination are unclear. Glomeromycota reproduce by spores containing hundreds of nuclei, which represents a departure from the typical eukaryotic developmental pattern, where a multicellular organism is re-created from a uninucleate propagule. To understand whether the multinucleate spore makeup may have contributed to the evolutionary success of Glomeromycota, we examined the dynamics of spore nuclei in Glomus etunicatum using live three-dimensional imaging and mathematical models. We show that the spores are populated by an influx of a stream of nuclei from the surrounding mycelium rather than by divisions of a single founder nucleus. We present evidence that mechanisms of selection are likely to operate at the level of individual nuclei. On the basis of mathematical analyses of the effects that these nuclear dynamics have on the population mutation load, we postulate that the developmental patterns of sporogenesis have adaptive significance for moderating the accumulation of deleterious mutations and may have contributed to the evolutionary longevity of Glomeromycota. PMID- 20170365 TI - Analgesic and anti-inflammatory effects of aqueous extract of Zea mays husk in male Wistar rats. AB - The analgesic and anti-inflammatory activities of Zea mays husk extract (25, 50, 100, and 200 mg/kg of body weight) were investigated in rats. The hot plate and formalin-induced paw licking models were used to assess analgesic effects of the extract, whereas the carrageenan and cotton pellet models were used for the evaluation of anti-inflammatory activity. The extract at 25, 50, 100, and 200 mg/kg body weight significantly (P < .05) reduced pain stimuli and inflammatory activity when compared with the control group. The reductions in paw licking time and granuloma weight in the formalin and cotton pellet models were both dose dependent. Also, the 200 mg/kg doses of the extract produced higher effects compared with indomethacin (5 mg/kg body of weight) in all the tests. These observations suggest that Z. mays husk extract may have analgesic and anti inflammatory effects that may be due to its tannins and polyphenolic constituents. These results provide scientific validation for the use of Z. mays husk decoction for the treatment of pain and inflammatory conditions in Nigerian folk medicine. PMID- 20170367 TI - The Panton-Valentine leukocidin is a virulence factor in a murine model of necrotizing pneumonia. PMID- 20170369 TI - Further analysis of correlates of protection from a phase 2a trial of the falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults. PMID- 20170366 TI - Functional characterization of core genes from patients with acute hepatitis C virus infection. AB - BACKGROUND: The hepatitis C virus (HCV) core protein is implicated in diverse aspects of HCV-induced pathogenesis. There is a paucity of information on core in acute hepatitis C infection. METHODS: We analyzed core gene sequences and protein functions from 13 patients acutely infected with HCV genotype 1. RESULTS: Although core isolates differed slightly between patients, core quasispecies were relatively homogeneous within each patient. In 2 of 4 patients studied temporally, core quasispecies did not change over time. Comparison with more than 2700 published core isolates indicated that amino acid changes from a prototype reference strain found in acute core isolates were present in chronically infected persons at low frequency (6.4%; range, 0%-32%). Core isolates associated with lipid droplets to similar degrees in Huh7 cells. Core diffusion in cells was not affected by nonconservative changes F130L and G161S in the lipid targeting domain of core. Core isolates inhibited interferon-stimulated response element- and nuclear factor kappaB-dependent transcription and tumor necrosis factor alpha induced nuclear translocation of nuclear factor kappaB and were also secreted from Huh7 cells. CONCLUSIONS: The data suggest that upon transmission, core quasispecies undergo genetic homogenization associated with amino acid changes that are rarely found in chronic infection and that, despite genetic variation, acute core isolates retain similar functions in vitro. PMID- 20170370 TI - The ontogeny of plant defense and herbivory: characterizing general patterns using meta-analysis. AB - Defense against herbivores often changes dramatically as plants develop. Hypotheses based on allocation theory and herbivore selection patterns predict that defense should increase or decrease, respectively, across ontogeny, and previous research partly supports both predictions. Thus, it remains unclear which pattern is more common and what factors contribute to variability among studies. We conducted a meta-analysis of 116 published studies reporting ontogenetic patterns in plant defense traits and herbivory. Patterns varied depending on plant life form (woody, herbaceous, grass), type of herbivore (insect, mollusk, mammal), and type of defense trait (secondary chemistry, physical defense, tolerance). In woody plants, chemical defense increased during the seedling stage, followed by an increase in physical defenses during the vegetative juvenile stage. Mammalian herbivores showed a strong preference for mature compared to juvenile tissues in woody plants. Herbs experienced a significant increase in secondary chemistry across the entire ontogenetic trajectory, although the magnitude of increase was greatest during the seedling stage. Correspondingly, mollusks preferred young compared to older herbs. Future research investigating growth/defense trade-offs, allometry, herbivore selection patterns, and ecological costs would shed light on the mechanisms driving the ontogenetic patterns observed. PMID- 20170371 TI - Cross-reactive neutralizing humoral immunity does not protect from HIV type 1 disease progression. AB - Broadly reactive neutralizing antibodies are the focus of human immunodeficiency virus (HIV) type 1 vaccine design. However, only little is known about their role in acquired immunodeficiency syndrome (AIDS) pathogenesis and the factors associated with their development. Here we used a multisubtype panel of 23 HIV-1 variants to determine the prevalence of cross-reactive neutralizing activity in serum samples obtained approximately 35 months after seroconversion from 82 HIV-1 subtype B-infected participants from the Amsterdam Cohort Studies on HIV Infection and AIDS. Of these patients, 33%, 48%, and 20%, respectively, had strong, moderate, or absent cross-reactive neutralizing activity in serum. Viral RNA load at set point and AIDS-free survival were similar for the 3 patient groups. However, higher cross-reactive neutralizing activity was significantly associated with lower CD4(+) T cell counts before and soon after infection. Our findings underscore the importance of vaccine-elicited immunity in protecting from infection. The association between CD4(+) T cell counts and neutralizing humoral immunity may provide new clues as to how to achieve this goal. PMID- 20170372 TI - HIV neutralizing antibodies: clinical correlates and implications for vaccines. PMID- 20170374 TI - Assessment of the efficacy of commercially available and candidate vaccines against a pandemic H1N1 2009 virus. AB - BACKGROUND: The emergence and global spread of the pandemic H1N1 2009 influenza virus have raised questions regarding the protective effect of available seasonal vaccines and the efficacy of a newly produced matched vaccine. METHODS: Ferrets were immunized with the 2008-2009 formulations of commercially available live attenuated (FluMist; MedImmune) or split-inactivated (Fluviral; GlaxoSmithKline) vaccines, a commercial swine vaccine (FluSure; Pfizer), or a laboratory-produced matched inactivated whole-virus vaccine (A/Mexico/InDRE4487/2009). Adaptive immune responses were monitored, and the animals were challenged with A/Mexico/InDRE4487/2009 after 5 weeks. RESULTS: Only animals that received the swine or matched vaccines developed detectable hemagglutination-inhibiting antibodies against the challenge virus, whereas a T cell response was exclusively detected in animals vaccinated with FluMist. After challenge, all animals had high levels of virus replication in the upper respiratory tract. However, preexisting anti-pandemic H1N1 2009 antibodies resulted in reduced clinical signs and improved survival. Surprisingly, FluMist was associated with a slight increase in mortality and greater lung damage, which correlated with early up regulation of interleukin-10. CONCLUSIONS: The present study demonstrates that a single dose of matched inactivated vaccine confers partial protection against a pandemic H1N1 2009 virus, and it suggests that a higher dose or prime-boost regimen may be required. The consequences of mismatched immunity to influenza merit further investigation. PMID- 20170373 TI - Epidemiological and biological evidence for a compensatory effect of connection domain mutation N348I on M184V in HIV-1 reverse transcriptase. AB - BACKGROUND: The connection domain mutation N348I confers resistance to zidovudine (AZT) and is associated with the lamivudine (3TC) mutation M184V. We explored the biochemical and virological influence of N348I in the context of M184V. METHODS: Genotypic resistance data for patients receiving monotherapy or dual therapy with AZT, lamivudine (3TC), or AZT/3TC were analyzed. Rates of N348I emergence were compared between treatment groups. Mutant reverse transcriptases (RTs) containing M184V and/or N348I were generated to study enzymatic and virological properties. RESULTS: We included 50 AZT-treated, 11 3TC-treated, and 10 AZT/3TC-treated patients. N348I was observed in 3 (6%), 0, and 4 (40%) of these patients, respectively. The rate of N348I emergence was increased by 5-fold in the AZT/3TC group (11.7 instances [95% confidence interval {CI}, 3.2-30.1 instances] per 100 person-years of receipt of AZT), compared with the rate noted for the AZT group (2.3 instances [95% CI, 0.4-6.8 instances] per 100 person-years of receipt of AZT; P = .04). Biochemical data show that N348I can partially compensate for the diminution in processive DNA synthesis and the reduction in AZT excision associated with M184V. Furthermore, virological analyses demonstrate that N348I confers low-level resistance to AZT and partly restores the reduced RT activity of the M184V variant. CONCLUSION: In vivo selection of N348I is driven by AZT and is further facilitated when 3TC is coadministered. Compensatory interactions between N348I and M184V help to explain these findings. PMID- 20170375 TI - Synthetic human chorionic gonadotropin-related oligopeptides impair early innate immune responses to Listeria monocytogenes in Mice. AB - Background. Synthetic human chorionic gonadotropin (hCG)-related oligopeptides are potent inhibitors of pathogenic inflammatory responses induced by in vivo lipopolysaccharide exposure or hemorrhagic shock-induced injury. In this study, we tested whether hCG-related oligopeptide treatment similarly altered inflammatory responses and innate host defenses in mice during experimental Listeria monocytogenes infection. Methods. Mice were infected with L. monocytogenes and treated with hCG-related oligopeptides (LQGV, VLPALP, or AQGV) or phosphate-buffered saline. Subsequently, mice were analyzed for bacterial loads, cytokine and chemokine responses, and inflammatory cell infiltrates in target organs. Results. Oligopeptide administration increased bacterial numbers in the spleen and liver at 6 h after infection. Simultaneously, CXCL1/KC and CCL2/MCP-1 plasma levels as well as neutrophil numbers in the spleen, blood, and peritoneal cavity decreased. In contrast, at 18 h after infection, systemic tumor necrosis factor alpha, interleukin 12 p70, interleukin 6, and interferon gamma levels increased statistically significantly in oligopeptide-treated mice compared with controls, which correlated with increased bacterial numbers. Conclusion. These data show that treatment with hCG-related oligopeptides (LQGV, VLPALP, and AQGV) inhibits early innate immune activation by reducing initial chemokine secretion following infection. This leads to bacterial overgrowth with subsequent enhanced systemic inflammation. Our data underscore the importance of early innate immune activation and suggest a role for hCG-derived oligopeptides at the placenta that increases the risk of L. monocytogenes infections. PMID- 20170376 TI - Influence of age and nature of primary infection on varicella-zoster virus specific cell-mediated immune responses. AB - BACKGROUND: Varicella-zoster virus (VZV)-specific cell-mediated immunity is important for protection against VZV disease. We studied the relationship between VZV cell-mediated immunity and age after varicella or VZV vaccination in healthy and human immunodeficiency virus (HIV)-infected individuals. METHODS: VZV responder cell frequency (RCF) determinations from 752 healthy and 200 HIV infected subjects were used to identify group-specific regression curves on age. RESULTS: In healthy individuals with past varicella, VZV RCF peaked at 34 years of age. Similarly, VZV-RCF after varicella vaccine increased with age in subjects aged <1 to 43 years. In subjects aged 61-90 years, VZV RCF after zoster vaccine decreased with age. HIV-infected children had lower VZV RCF estimates than HIV infected adults. In both groups, VZV RCF results were low and constant over age. Varicella vaccination of HIV-infected children with CD4 levels 20% generated VZV RCF values higher than wild-type infection and comparable to vaccine-induced responses of healthy children. CONCLUSIONS: In immunocompetent individuals with prior varicella, VZV RCF peaked in early adulthood. Administration of varicella vaccine to HIV-infected or uninfected individuals aged >5 years generated VZV RCF values similar to those of immunocompetent individuals with immunity induced by wild-type infection. A zoster vaccine increased the VZV RCF of elderly adults aged <75 years to values higher than peak values induced by wild-type infection. PMID- 20170377 TI - BBA52 facilitates Borrelia burgdorferi transmission from feeding ticks to murine hosts. AB - Borrelia burgdorferi, the pathogen of Lyme borreliosis, persists in nature through a tick-rodent transmission cycle. A selective assessment of the microbial transcriptome, limited to gene-encoding putative membrane proteins, reveals that bba52 transcription in vivo is strictly confined to the vector-specific portion of the microbial life cycle, with the highest levels of expression noted in feeding ticks and with swift down-regulation noted in mice. bba52 deletion did not affect murine disease as assessed by the genesis of arthritis and carditis or long-term persistence of pathogens in mice or ticks. However, bba52 deficiency did impair microbial transitions between hosts and vector, defects that could be fully rescued when bba52 expression was genetically restored to the original genomic locus. These studies establish that BBA52 facilitates vector-host transitions by the pathogen and therefore is a potential antigenic target for interference with transmission of B. burgdorferi from ticks to mammalian hosts. PMID- 20170378 TI - Sialidase-based anti-influenza virus therapy protects against secondary pneumococcal infection. AB - BACKGROUND: DAS181 (Fludase) is a sialidase fusion protein in clinical development as a broad-spectrum anti-influenza virus (IFV) therapeutic agent. Previous reports by other investigators have raised the concern that desialylation of airway epithelium might increase susceptibility to Streptococcus pneumoniae infection. METHODS: To address whether DAS181 would lead to an increased risk of pneumococcal infection, we tested S. pneumoniae colonization after DAS181 treatment of human A549 cells, healthy mice, and mice challenged with a lethal dose of IFV A/PR/8/34 (H1N1) or A/Victoria/3/75 (H3N2), followed by 10(4) cfu of S. pneumoniae (D39) on day 3 or day 7. DAS181 treatment was given 24 48 h after IFV challenge. RESULTS: DAS181 treatment did not increase S. pneumoniae colonization in vitro or in vivo in healthy animals. In IFV-infected mice, DAS181 prevented pneumonia and significantly prolonged survival and inhibited the IFV titer by > or = 3 logs. None of the treated animals showed enhanced S. pneumoniae colonization of the lung. In addition, opportunistic infections with Citrobacter species or Klebsiella species occurred only in mice receiving vehicle, not in animals treated with DAS181. CONCLUSIONS: These data indicate that DAS181 treatment does not exacerbate secondary bacterial infection in mice. DAS181 may reduce the risk of secondary bacterial infection by inhibiting IFV. PMID- 20170379 TI - Antioxidative and antiproliferative activities of different horsetail (Equisetum arvense L.) extracts. AB - In this study we investigated antioxidative and antiproliferative activity of different horsetail (Equisetum arvense L.) extracts. The antioxidative activity was measured by the electron spin resonance (ESR) spectroscopy-spin trapping method. The influence of different horsetail extracts during lipid peroxidation of (1) sunflower oil induced by the lipophilic azo-initiator 4,4'-azobis(4 cyanovaleric acid) and (2) soybean phosphatidylcholine liposomes induced by the hydrophilic azo-initiator 2,2'-azobis(2-amidinopropane) dihydrochloride was studied. Antiproliferative activity was measured using the sulforhodamine B colorimetric assay on the human cancer cell lines HeLa, HT-29, and MCF7. The results of ESR analysis confirmed that the extracts investigated suppressed the formation of lipid peroxyl radicals in both systems investigated in a dose dependent manner. The results indicate that n-butanol, methanol, ethyl acetate, and water extracts had significant peroxyl radical scavenging activity. Extracts inhibited cell growth that was dependent on cell line, type of extract, and extract concentration. Ethyl acetate extract exhibited the most prominent antiproliferative effect, without inducing any cell growth stimulation on human tumor cell lines. The results obtained suggest that the horsetail extracts could be used as an easily accessible source of natural antioxidants and as potential phytochemicals. PMID- 20170380 TI - Essential oil terpenes: adjunctive role in the management of childhood urolithiasis. AB - Essential oil preparation of the terpenic type was introduced for the first time in the 1930s for the management of urolithiasis. Although essential oil preparations are registered in 50 countries, including some developed countries such as the United Kingdom, Italy, and Japan, for use in urolithiasis, no literature has been published in a peer-reviewed English (Anglo-American) medical journal. Recently the use of these terpenes has been investigated in children with urolithiasis and underlying metabolic abnormalities. The aim of this article is to extract the useful and worthy information about the use of these terpenes in urolithiasis from the previous literature as many of these articles are now considered of poor quality for a thorough systematic scientific review. The main disadvantages of most of the old literature about terpenes are the treatment was not followed radiologically and most of these articles represent anecdotal reports of spontaneous passage of calculi and symptomatic improvement of colic in association with the use of terpenes. The other aim is to discuss the possible role of essential oil terpenes in the management of childhood urolithiasis. PMID- 20170381 TI - Chicken collagen hydrolysate protects rats from hypertension and cardiovascular damage. AB - We previously reported that chicken collagen hydrolysate (CCH) has strong angiotensin I converting enzyme (ACE) inhibitory activity and antihypertensive effects on spontaneously hypertensive rats. Here, we investigated the chronic therapy effects of CCH on blood pressure and vascular relaxation in a cardiovascular damage model of Wistar-Kyoto rats induced by N-nitro-l-arginine methyl ester (L-NAME). Following co-treatment with CCH for 4 weeks, the increment of systolic blood pressure was suppressed significantly. At 8 weeks, the vasorelaxation of thoracic aorta increased significantly, and cardiovascular damage was ameliorated. The concentration of soluble intercellular adhesion molecule-1 (ICAM-1) in blood was reduced significantly by long-term administration of CCH, whereas the nitric oxide concentration was increased significantly at 1 hour post-treatment. The results suggest that beneficial effects of CCH result from antihypertensive function, but also from inhibition of cardiovascular damage to the endothelial cells via its ACE inhibitory activity and regulation of nitric oxide and ICAM-1, which suggests that CCH may be useful as a medicinal food for patients with cardiovascular disease. PMID- 20170382 TI - Cytotoxic and cell cycle effects induced by two herbal extracts on human cervix carcinoma and human breast cancer cell lines. AB - In recent times interest has increased in the complementary medicine of cancer patients. Two herbal mixtures were prepared from 17 and 12 plants, respectively. The goal of this study was to examine the in vitro cytotoxic and cell cycle effects of the aqueous-ethanol extracts (Extract 1 and Extract 2) obtained by maceration of the mixtures. The two extracts investigated exhibited significant antiproliferative activity toward two human breast cancer cell lines (MDA-MB-361 and MDA-MB-453) and a human cervix carcinoma cell line (HeLa) with 50% inhibitory concentration (IC(50)) values ranging from 9.92 to 17.38 microL/mL. The extracts did not exert any significant cytotoxicity toward healthy human peripheral blood mononuclear cells. In vitro antitumor activities were accompanied by an important apoptotic fraction of all cell lines after treatment with the extracts. The amount of total phenols was similar in both extracts, whereas the concentration of total tannins was significantly higher in Extract 1. Extract 1 was also found to be a stronger free radical scavenger, with an IC(50) value of 13.4 microg/mL. Both extracts contained rosmarinic acid, while ursolic acid was identified in Extract 2. PMID- 20170383 TI - Antinociceptive activity of aqueous extract of Bowdichia virgilioides in mice. AB - Bowdichia virgilioides Kunth (Family Fabaceae) is a plant that is distributed widely in the tropical and subtropical regions of the world. In the northeast region of Brazil, where B. virgilioides is called "sucupira-preta," the stem bark is used in folk medicine to treatment of inflammatory and painful diseases. This study aimed to evaluate the antinociceptive activity of the aqueous extract of the dried stem bark of B. virgilioides. The aqueous extract of B. virgilioides in doses of 50, 100, 200, and 400 mg/kg was administered orally 1 hour prior to pain induction. Only the doses of 200 and 400 mg/kg produced an inhibition by 61% and 74%, respectively, in the number of abdominal writhings induced by acetic acid. This antinociceptive effect was not reversed by pretreatment with naloxone, indicating that the effect is not associated with the activation of opioid receptors. In the formalin test, using the two highest doses, the extract had no effect in the first phase but produced an analgesic effect on the second phase with the inhibition of licking time (P < .001). In the hot plate test, no effect was seen at the dose of 400 mg/kg p.o. Our findings show that B. virgilioides contains pharmacologically active constituents that possess antinociceptive activity justifying its popular therapeutic use in treating conditions associated with the painful conditions. PMID- 20170384 TI - Musculoskeletal pain and treatment choice: an exploration of illness perceptions and choices of conventional or complementary therapies. AB - PURPOSE: This study explored experiences of receiving treatment for musculoskeletal pain (MSKP), particularly choices of complementary and alternative medicine (CAM) and/or conventional treatment, using the illness perception dimension of Leventhal's Self-Regulatory Model as the underpinning model within the broader biopsychosocial framework of the International Classification of Functioning, Disability and Health. METHOD: A mixed-method study was conducted involving 17 people with MSKP. Data were collected in semi structured interviews, using a phased approach that included the Brief Illness Perception Questionnaire and open-ended questions about experiences of managing and seeking treatment for MSKP. Questionnaire data were analysed descriptively; interview data were transcribed verbatim and analysed using the principles of Interpretative Phenomenological Analysis. RESULTS: Analysis points to health professionals and participants as gatekeepers to treatment, with gatekeeping based on matters of power, searching for solutions, and managing day to day. The themes Role of the Gatekeeper, Swing of the Interminable Pendulum, and Solution of Soldiering On are discussed in relation to literature about health beliefs and choices of CAM or conventional treatments. CONCLUSIONS: Future research could include mixed-method designs to further explore issues of knowledge, beliefs, and control that feed into the role of gatekeepers to treatment, as well as comparing CAM choices between public and privately-funded healthcare. PMID- 20170385 TI - Relationship between quality of life and functional status of young adults and adults with cerebral palsy. AB - PURPOSE: The aim of this study was investigate the relation between health related quality of life (HRQoL) and functional status in young adult or adult cerebral palsied individuals. METHODS: The study included 45 cerebral palsied subjects who were divided into two groups as young adults (n = 21, group 1) and adults (n = 24, group 2), over the age 15 years. Gross Motor Function Classification System (GMFCS), Functional Independence Measurement (FIM), Physical Mobility Scale (PMS), Nottingham Health Profile (NHP), Visual Analogue Scale (VAS) were used as outcome measures. RESULTS: In group 1, GMFCS and PMS scores were significantly correlated with total the total score of FIM (p < 0.05). Although total FIM, PMS, LS and GMFCS scores were not correlated with the total NHP score (p > 0.05), pain subscale of NHP was significantly correlated with self care and mobility subscales of FIM (p < 0.05). Also, self care, mobility, locomotion subscales and total score of FIM were highly correlated with the physical activity subscale of NHP (p < 0.05). In group 2, our findings were also similar to those of young adults when the relations between total NHP score and total FIM, PMS, LS and GMFCS were investigated (p > 0.05) and also some subscales of FIM and NHP presented high correlations in between. In addition, there were significant differences between the groups in GMFCS, LS and locomotion and self care subscales of FIM (p < 0.05). CONCLUSION: Although HRQoL in young cerebral palsied individuals seems to be more effected by parameters related to physical condition, in cerebral palsied adults psychological and emotional aspects may be more important indicators related to HRQoL. For that reasons, more population specific measures have to be developed for in-depth analysis of these factors. PMID- 20170387 TI - Orthodontic treatment with tooth transplantation for patients with cleft lip and palate. AB - This article describes the use of tooth transplantation and orthodontic tooth alignment in patients with cleft lip and palate. Due to bone defects in the maxilla, the congenital absence of teeth, especially lateral incisors, is frequently observed in patients with cleft lip and palate. As compared with orthodontic space closure or prosthodontic treatment, tooth transplantation has several advantages, including induction of alveolar growth potential during adolescence. In this study, two cleft lip and palate patients with congenitally missing teeth were treated successfully by tooth transplantation followed by orthodontic treatment. Our results show that tooth transplantation is a viable alternative to other treatments for patients with cleft lip and palate accompanied by congenitally missing teeth. PMID- 20170386 TI - Association between TGFB3 and nonsyndromic cleft lip with or without cleft palate in a Chilean population. AB - OBJECTIVE: To assess the possible association between TGFB3 allele variants and nonsyndromic cleft lip with or without cleft palate in a Chilean population. DESIGN: In our study we used a case-parents trios design. The sample consisted of 150 unrelated trios ascertained through probands affected with nonsyndromic cleft lip with or without cleft palate. Three TGFB3 polymorphisms were analyzed (rs2268626, rs2268625, and rs3917201). An allele/haplotype transmission disequilibrium test was used to evaluate the possible genotype-phenotype association. RESULTS: An overtransmission from parents to affected progeny was observed for the A allele of rs3917201 (p = .03) and for the rs2268625-rs3917201 A-A haplotype (p = .022). A defect of transmission of rs2268625-rs3917201 G-G haplotype (p = .022) was observed also. CONCLUSIONS: Allelic and haplotypic associations implicate a possible role of TGFB3 in nonsyndromic cleft lip with or without cleft palate in the Chilean population. Additional studies are needed in order to elucidate the possible mechanisms that can explain the role of TGFB3 genetic variants in the condition. PMID- 20170388 TI - Effect of alveolar bone grafting on nasal morphology, symmetry, and nostril shape of patients with unilateral cleft lip and palate. AB - OBJECTIVE: To evaluate nasal morphology, symmetry, and nostril shape in patients with unilateral cleft lip and palate following mixed-dentition alveolar bone grafting. DESIGN: Prospective stereophotogrammetric study. SETTING: Hospital based. PATIENTS: Thirty-nine patients with a history of repaired unilateral cleft lip and palate who received an iliac crest alveolar bone graft were recruited prospectively to participate in the study. Each patient served as his/her own control. INTERVENTIONS: Partial facial impressions of all patients were acquired before and a minimum of 6 months after the alveolar bone grafting procedure. Image acquisition and analysis of the casts constructed from these models were carried out using three-dimensional stereophotogrammetry. MAIN OUTCOME MEASURES: Surface-based registrations and linear measurements were performed to assess nasal morphology and nostril shape. A modified Procrustes technique was used to determine the change in nasal symmetry. A two-tailed, paired t test and an analysis of covariance were used to assess statistical significance. RESULTS: Significant side-to-side asymmetry exists in the nasal region of patients with unilateral cleft lip and palate, both before and after alveolar bone grafting. No significant changes were observed between pre-alveolar bone graft and post alveolar bone graft images based on linear measurements, asymmetry scores, and registrations. Gender and surgeon were not significant factors. CONCLUSION: Under the conditions of this study, mixed-dentition alveolar bone grafting appears to have no significant long-term effect on nasal morphology, symmetry, or nostril shape. PMID- 20170389 TI - Chromosome 4q deletion syndrome: craniofacial characteristics associated with monosomy of the long arm of chromosome 4q. AB - Chromosome 4q deletion syndrome is a monosomy that comprises all interstitial and terminal deletions of the long arm of chromosome 4. It results in a variety of phenotypes characterized by various craniofacial and bodily abnormalities. The purpose of this study is to report a case of 4q deletion syndrome and describe its clinical manifestations, with particular attention to the craniofacial presentation and subsequent management of the syndrome, as well as its associated micrognathia and airway complications. Among treatment options, the investigators chose bilateral distraction osteogenesis of the mandible in order to increase the subject's posterior airway space. At follow-up, the subject was able to ventilate without any adjuncts or mechanical ventilation assistance. PMID- 20170390 TI - Escitalopram causes fewer seizures in human overdose than citalopram. AB - CONTEXT: Seizures are a recognized complication of acute overdose with the racemic (1:1 ratio of R- and S-enantiomers) selective serotonin reuptake inhibitor antidepressant citalopram. OBJECTIVE: We tested the hypothesis that escitalopram (the therapeutically active S-enantiomer of citalopram) causes fewer seizures in overdose than citalopram at comparable doses of the S-enantiomer. METHODS: Multicenter retrospective review of cases with citalopram and escitalopram overdose reported to German, Austrian, and Swiss Poisons Centers between 1997 and 2006. RESULTS: 316 citalopram and 63 escitalopram cases were analyzed. Somnolence, nausea, vomiting, tachycardia, QT prolongation, and tremor occurred with similar frequency in both groups. There was a striking difference in the frequency of single and multiple seizures: 43 cases (13.5%) in the citalopram group and 1 case (1.6%) with a single seizure in the escitalopram group (p=0.0065). DISCUSSION AND CONCLUSIONS: At comparable ingested doses of the S-enantiomer, the symptom profile for citalopram and escitalopram intoxications is similar except for seizures that occur more frequently in citalopram than in escitalopram poisoning. PMID- 20170391 TI - Low-dose exposure to Veratrum album in children causes mild effects--a case series. AB - INTRODUCTION: White or false hellebore (Veratrum album) has a toxicological relevance because of the potential for misidentification of this plant as yellow gentian (Gentiana lutea). CASE SERIES: We report a retrospective case series of 11 children (8-12 years) with accidental intake of V. album at a youth camp where they had collected herbs for preparing fresh herb tea. Two children (18%) remained asymptomatic. Nine (82%) developed mild gastrointestinal symptoms, six (55%) presented neurological symptoms, and three (27%) showed bradycardia. All children recovered completely within 10 h of ingestion. The plant was identified at the emergency department; however, detection of veratridine and cevadine by means of high-performance liquid chromatography-Mass spectrometry from the blood of the child with the most severe symptoms was negative (limit 0.01 ng/mL). DISCUSSION: Veratrum species contain more than 200 different alkaloids, which are the principal toxins and are responsible for most clinical symptoms. There are likely multiple mechanisms of toxicity and some of them are only partially understood. The opening of voltage-gated sodium channels is probably one of the most relevant pathophysiological mechanisms. CONCLUSIONS: Veratrum album intoxication in children demonstrated the same clinical course as observed in adults. Accidental ingestion of a low dose of the plant had a favorable outcome with supportive care. PMID- 20170392 TI - Peyote and mescaline exposures: a 12-year review of a statewide poison center database. AB - BACKGROUND: Peyote, a cactus containing the hallucinogen mescaline, has been used by Native Americans for thousands of years. Illicit use is also known to occur, but reports in the medical literature consist only of isolated case reports. OBJECTIVES: We sought to identify characteristics of patients with reported exposure to peyote or mescaline. METHODS: We performed a retrospective review of the California Poison Control System database for the years 1997-2008 for all cases of single-substance human exposure using the search terms "peyote" and "mescaline." RESULTS: There were a total of 31 single-substance exposures to peyote or mescaline. Thirty (97%) exposures were intentional; 30 (97%) exposures were through the oral route, whereas one patient (3%) insufflated mescaline powder. Five patients (16%) were managed at home, whereas the remainder patients were managed in a healthcare facility. Commonly reported effects included hallucinations, tachycardia, agitation, and mydriasis. Vomiting was reported in only one case. CONCLUSIONS: Although uncommonly encountered, use of peyote and mescaline was associated with clinically significant effects requiring treatment in a substantial number of patients. Clinical effects were usually mild or moderate, and life-threatening toxicity was not reported in this case series. PMID- 20170393 TI - Caffeine fatalities--do sales restrictions prevent intentional intoxications? AB - OBJECTIVE: Caffeine is widely available in beverages and in different over-the counter products, including tablets containing 100 mg caffeine. Because intentional fatal intoxications with caffeine occur, the maximum quantity of caffeine tablets that can be bought over the counter in a single purchase was restricted from 250 to 30 in Sweden in the year 2004. The objective of this article was to study the effect of this decision on the number of fatal caffeine intoxications. METHOD: In Sweden 95% of all cases undergoing forensic autopsy are screened for a number of drugs including caffeine. All cases during January 1993 September 2009 with a caffeine concentration above 80 microg/g blood were recorded. RESULTS: During the study period toxicological investigations were performed in 83,580 forensic autopsies. Caffeine contributed to the fatal outcome in 20 cases (0.02%). Thirteen (65%) of these fatalities occurred before the introduction of the sales restriction. However, no fatal intoxications where caffeine contributed to the cause of death was recorded between May 2007 and September 2009. CONCLUSION: Overdoses of tablets containing caffeine can be fatal, suicides as well as accidents occur. Restricting the maximum quantity of caffeine tablets available over the counter seemed to be effective in preventing suicides because of caffeine although some time elapsed until the effect was noted. Further monitoring is required to ensure that the observed lower caffeine mortality is a sustained effect. PMID- 20170394 TI - The underestimated problem of using serum magnesium measurements to exclude magnesium deficiency in adults; a health warning is needed for "normal" results. AB - BACKGROUND: A major use of serum magnesium measurements in clinical practice is to identify patients with deficiency. However, numerous studies have shown that magnesium deficiency is common and may be present in over 10% of hospitalized patients, as well as in the general population. An important cause for under diagnosis of deficiency is that serum magnesium, the most commonly used test, can be normal despite negative body stores. This article focuses on the limitations of "normal" magnesium results and highlights the importance of lifestyle or "modus vivendi" as a pragmatic means of identifying those individuals potentially at risk for negative body magnesium stores. METHODS: Researched peer reviewed articles on magnesium published between 1990 and 2008 in MEDLINE and EMBASE, using database keywords "magnesium, deficiency, diagnosis, treatment and hypomagnesaemia". Bibliographies of retrieved articles have been searched and followed. We have also performed a manual search of each individual issue in which most of these reports have appeared. RESULTS: In 183 peer reviewed studies published from 1990 to 2008, magnesium deficiency was associated with increased prevalence and risk in 11 major conditions. Similarly, in 68 studies performed over the same period, magnesium deficiency was found to predict adverse events and a decreased risk of pathology was noted when supplementation or treatment was instituted. CONCLUSIONS: The perception that "normal" serum magnesium excludes deficiency is common among clinicians. This perception is probably enforced by the common laboratory practice of highlighting only abnormal results. A health warning is therefore warranted regarding potential misuse of "normal" serum magnesium because restoration of magnesium stores in deficient patients is simple, tolerable, inexpensive and can be clinically beneficial. PMID- 20170395 TI - Lack of association between DAZ gene methylation patterns and spermatogenic failure. AB - BACKGROUND: Abnormal DNA methylation of the male germ line is proposed as a possible mechanism causing compromised spermatogenesis in some men diagnosed with idiopathic infertility. Previous studies suggested that aberrant DNA methylation of several genes is associated with disruptions in spermatogenesis. However, little information is available on DNA methylation patterns of testis-specific genes in idiopathic male infertility. METHODS: To investigate the association between DAZ gene methylation patterns and spermatogenic failure, we performed an analysis of methylation patterns in 174 idiopathic infertile patients and 58 fertile controls using bisulfite-modified sequencing. RESULTS: We found that the methylation patterns of CpG island (CGI) in the DAZ gene promoter region were different between somatic cells and spermatic cells in the control group. DAZ gene methylation patterns among groups with different spermatogenic status were the same in somatic cells, completely methylated, and in spermatic cells. The results were concordant, except for the group with azoospermia (AZ) which were completely unmethylated. CONCLUSIONS: Our data indicate that the methylation patterns of the DAZ gene are not associated with spermatogenic failure. This suggests that epigenetic modification of DAZ is unlikely to be involved in the etiology of spermatogenic failure. PMID- 20170396 TI - Evaluation of five routine glucose methods on an Olympus AU5400 analyzer using the CDC hexokinase reference method. AB - BACKGROUND: In China, two common methods are used to detect serum glucose, glucose oxidase (GOD) and hexokinase (HK) methods. We evaluated five commercially available glucose reagent kits with the Center of Disease Control (CDC) HK reference method. METHODS: Five routine methods were compared with the HK reference method according to Clinical and Laboratory Standards Institute (CLSI) guideline (EP9-A2). These five routine methods were performed on an "open channel" Olympus 5400 analyzer. RESULTS: All five evaluated methods were closely correlated to the reference method (r > 0.9998). Compared to the HK reference method, the Olympus-HK method and Roche-GOD method showed a very small positive bias (mean +/- SD: 0.08 +/- 0.09 mmol/L and 0.03 +/- 0.08 mmol/L); while the Biosino-HK method, Osborne-GOD method and Baiding-GOD method showed a very small negative bias (mean +/- SD: -0.07 +/- 0.06 mmol/L, -0.09 +/- 0.07 mmol/L and 0.01 +/- 0.04 mmol/L). CONCLUSIONS: All five reagents we evaluated using matching calibrators showed good correlation to the reference method and small bias. These five glucose reagents are acceptable for use in clinical laboratories. PMID- 20170397 TI - The polymorphisms -1131T>C and the S19W of the APOA5 gene are not associated with coronary artery disease in a Brazilian population. PMID- 20170398 TI - Ability of deferasirox to bind iron during measurement of iron. PMID- 20170399 TI - On algebraic properties of extreme pathways in metabolic networks. AB - We give a concise development of some of the major algebraic properties of extreme pathways (pathways that cannot be the result of combining other pathways) of metabolic networks, contrasting them to those of elementary flux modes (pathways involving a minimal set of reactions). In particular, we show that an extreme pathway can be recognized by a rank test as simple as the existing rank test for elementary flux modes, without computing all the modes. We make the observation that, unlike elementary flux modes, the property of being an extreme pathway depends on the presence or absence of reactions beyond those involved in the pathway itself. Hence, the property of being an extreme pathway is not a local property. As a consequence, we find that the set of all elementary flux modes for a network includes all the elementary flux modes for all its subnetworks, but that this property does not hold for the set of all extreme pathways. PMID- 20170400 TI - A double-layered mixture model for the joint analysis of DNA copy number and gene expression data. AB - Copy number aberration is a common form of genomic instability in cancer. Gene expression is closely tied to cytogenetic events by the central dogma of molecular biology, and serves as a mediator of copy number changes in disease phenotypes. Accordingly, it is of interest to develop proper statistical methods for jointly analyzing copy number and gene expression data. This work describes a novel Bayesian inferential approach for a double-layered mixture model (DLMM) which directly models the stochastic nature of copy number data and identifies abnormally expressed genes due to aberrant copy number. Simulation studies were conducted to illustrate the robustness of DLMM under various settings of copy number aberration frequency, confounding effects, and signal-to-noise ratio in gene expression data. Analysis of a real breast cancer data shows that DLMM is able to identify expression changes specifically attributable to copy number aberration in tumors and that a sample-specific index built based on the selected genes is correlated with relevant clinical information. PMID- 20170401 TI - Computing the stochastic dynamics of phosphorylation networks. AB - Cells of all organisms share the ability to respond to various extracellular signals. Depending on the cell type and the organism, these signals may include hormones secreted by other cells or changes in nutrient concentrations. The signals are processed by an intricate network of protein-protein interactions, including phosphorylation and de-phosphorylation events. As some signaling proteins are only present in low concentrations, random fluctuations may affect the dynamics of the network. The mathematical modeling of networks with significant random fluctuations requires the use of stochastic methods. The stochastic dynamics of a chemical reaction system are described by the Chemical Master Equation. Often the numerical evaluation of this equation is problematic. The first problem is that many systems have an infinite number of possible states; leaving simulations of individual trajectories as the only alternative. To circumvent this problem, we focus on a class of systems that have a finite state space. More specifically, we focus on networks of phosphorylation cycles without taking into account the synthesis and degradation of proteins. The second problem is that memory requirements cause a practical limit to the size of systems that can be evaluated. In this paper, we discuss how these limitations can be overcome using parallel computation and methods dealing efficiently with the available memory. These methods were implemented in a parallel C++ program. We discuss two networks for which the stochastic dynamics were evaluated using this program: a single phosphorylation cycle and an oscillating MAP-kinase cascade. PMID- 20170402 TI - The redox activity of hemoglobins: from physiologic functions to pathologic mechanisms. AB - Pentacoordinate respiratory hemoproteins such as hemoglobin and myoglobin have evolved to supply cells with oxygen. However, these respiratory heme proteins are also known to function as redox enzymes, reacting with compounds such as nitric oxide and peroxides. The recent discoveries of hexacoordinate hemoglobins in vertebrates and nonsymbiotic plants suggest that the redox activity of globins is inherent to the molecule. The uncontrolled formation of radical species resulting from such redox chemistry on respiratory hemoproteins can lead to oxidative damage and cellular toxicity. In this review, we examine the functions of various globins and the mechanisms by which these globins act as redox enzymes under physiologic conditions. Evidence that redox reactions also occur under disease conditions, leading to pathologic complications, also is examined, focusing on recent discoveries showing that the ferryl oxidation state of these hemoproteins is present in these disease states in vivo. In addition, we review the latest advances in the understanding of globin redox mechanisms and how they might affect cellular signaling pathways and how they might be controlled therapeutically or, in the case of hemoglobin-based blood substitutes, through rational design. PMID- 20170404 TI - Bioelectrochemistry, reactive oxygen species, receptors, and cell signaling: how interrelated? AB - Electrochemistry and cell signaling are widely involved in the operation of biochemical systems. This article discusses the relationship of the two, as well as interconnection with a variety of other aspects, such as free radicals, receptors, and stereochemistry. Both endogenous and exogenous agents are involved. The electrochemistry deals with electrostatics, electron transfer, reduction potentials, as well as involvement in membranes, proteins, and neurotransmission. Application of electrostatics is made to cell signaling involving receptor-ligand action, phosphates, sulfates, metal cations, and miscellaneous others. Apparently, energetics play a significant part. Practical and experimental aspects are also addressed. PMID- 20170403 TI - Annatto constituent cis-bixin has selective antimyeloma effects mediated by oxidative stress and associated with inhibition of thioredoxin and thioredoxin reductase. AB - In pursuit of the anticancer effects of seeds of the rain forest plant Bixa orellana (annatto), we found that its constituent cis-bixin induced cytotoxicity in a wide variety of tumor cell lines (IC(50) values from 10 to 50 microM, 24-h exposures) and, importantly, also selectively killed freshly collected patient multiple myeloma cells and highly drug-resistant multiple myeloma cell lines. Mechanistic studies indicated that cis-bixin-induced cytotoxicity was greatly attenuated by co-treatment with glutathione or N-acetylcysteine (NAC); whereas fluorescence-activated cell sorting (FACS) assays using the cell-permeable dyes 5 (and-6) chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester (CM H(2)DCFDA), or dihydroethidium demonstrated that cis-bixin rapidly induced cellular reactive oxygen species (ROS) in dose- and time-dependent fashions, collectively implicating ROS as contributory to cis-bixin-induced cytotoxicity. In pursuit of potential contributors to ROS imposition by cis-bixin, we found that cis-bixin inhibited both thioredoxin (Trx) and thioredoxin reductase (TrxR1) activities at concentrations comparable to those required for cytotoxicity, implicating the inhibition of these redox enzymes as potentially contributing to its ability to impose cellular ROS and to kill cancer cells. Collectively, our studies indicate that the annatto constituent cis-bixin has intriguing selective antimyeloma activity that appears to be mediated through effects on redox signaling. PMID- 20170405 TI - Promoter-proximal pausing of RNA polymerase II: an opportunity to regulate gene transcription. AB - Transcription of eukaryotic genes by RNA polymerase II (pol II) is a complex, highly regulated multiphasic process. Pol II pauses in the proximity of the promoter on a large fraction of transcribed genes. Transcription initiation and elongation of transcripts are under distinct control. Induced gene expression can thus be due to enhanced initiation and/or stimulated elongation. Pausing and resumption of the elongation of transcripts is under the control of transcription elongation factors. Three of them, P-TEFb, DSIF, and NELF have been well characterized as protein complexes with multiple general but also gene specific functions. Elongation factors execute checkpoint functions but serve also as targets for signaling processes which regulate gene expression. Due to the general importance of transcription elongation factors, it is difficult to delineate the mechanisms by which elongation of specific genes is regulated by specific intracellular signals. However, it is clear that the controlled pausing of pol II provides an opportunity to finely control timing and quantity of transcriptional output. PMID- 20170406 TI - Hodgkin's lymphoma cells exhibit high expression levels of the PICOT protein. AB - PICOT was originally discovered as a protein kinase C (PKC) binding protein in human Jurkat T-lymphocytes in which it was found to modulate PKCtheta-dependent functions. In addition, RT-PCR analysis suggested the expression of PICOT in a wide range of organs and cell types, including cells that are devoid of PKCtheta. We aimed at analyzing the expression of the PICOT protein in mouse lymphoid organs, and to compare them with those of Jurkat T-lymphocytes and other cell lines. We also analyzed whether PICOT expression in T-lymphocytes is dependent on the presence of PKCtheta, and whether it correlates with cell growth rate. Western blot analyses demonstrated PICOT expression in all lymphoid organs and cell lines tested. In addition, similar expression levels were observed in lymphoid organs of wild-type and PKCtheta-null mice, suggesting that PICOT expression in T-lymphocytes is independent of PKCtheta. However, PICOT expression levels were higher in Jurkat T-lymphocytes and other lymphoma cell lines compared to freshly isolated lymphocytes, while T-lymphocyte mitogens, such as concanavalin A, increased PICOT expression concomitantly with the induction of a faster T-lymphocyte growth rate. Finally, immunohistochemistry of freshly isolated lymph nodes from Hodgkin's lymphoma patients revealed significantly higher levels of PICOT in Hodgkin's cells, compared to the normal surrounding lymphocytes. The present results show a direct correlation between PICOT expression levels and increased cell growth, both in vitro and in vivo, and suggest that immunostaining of PICOT might be useful for in situ identification of transformed cells, such as those of Hodgkin's lymphoma. PMID- 20170407 TI - Using 17 alpha-hydroxyprogesterone caproate to impact rates of recurrent preterm delivery in clinical practice. AB - OBJECTIVE: Evaluation of an outpatient 17 alpha-hydroxyprogesterone caproate (17P) administration programme. METHODS: A retrospective analysis of data collected from patients with a history of preterm birth (PTB) and current singleton gestation enrolled between 16.0 and 20.9 weeks' gestational age (GA) for weekly outpatient 17P administration and nursing assessment between 7/2004 and 12/2007 was conducted (n=3139). RESULTS: The population was mostly white (50.3%), 18-35 years old (77.7%), and married (67.0%). Median GA at 17P initiation and stop was 17.4 (16.0, 20.9) weeks and 35.1 (18.6, 37.4) weeks. Mean injections per patient were 16.5+/-4.9, at an interval of 7.2 days. Median GA at delivery was 37.3 (18.6, 44.0) weeks. Rate of recurrent spontaneous PTB was 29.8%, with 15.5% and 7.0% with PTB at <35 and <32 weeks. CONCLUSIONS: This represents the largest cohort reported to date of patients prescribed 17P therapy in clinical practice to prevent recurrent spontaneous PTB. PMID- 20170409 TI - Being a close relative of a person with aphasia. AB - The aim was to investigate close relatives' experiences of the influences of aphasia on their own life situation, as well as their perceptions of everyday activity for the person with aphasia and support for the family in daily life. Fourteen close relatives of people with aphasia were interviewed on one occasion each. The interview text was analysed using qualitative content analysis, and sorted into three themes: "The influence of aphasia in the family", "Everyday life", and "The meaning of support". The aspect most apparent from the interviews was the great changes in the interviewees' lives after their relatives had been stricken with aphasia, particularly the loss of friends. There were also communication problems in the beginning. While many said that their aphasic relative always used to be active, only a few described the resumption of previous activities. Having an aphasic family member in need of support created a sense of emotional loneliness, and of being the one who does the majority of the practical chores. The results accentuate the importance of close relatives, and their essential function for support and motivation. The close relatives must be given support from rehabilitation and community staff, to make it easier for them to communicate with and cope with the aphasic person in everyday activities. PMID- 20170410 TI - Innovation or advances in four areas of research or practice: planning, implementing, documenting, and measuring occupation-based programs. PMID- 20170411 TI - Using the evaluation of social interaction in a community-based program for persons with traumatic brain injury. AB - The purpose of this study was to examine the utility of the Evaluation of Social Interaction (ESI) in a community-based program for persons with traumatic brain injury (TBI), as well as its effectiveness in measuring occupational therapy intervention. Ten people who experienced a TBI and were participating in a community-based program were a convenience sample for this study. The Occupational Therapy Intervention Process Model (OTIPM) provided the theoretical framework. The ESI provided a pre-test performance measure and also served as a guide for an eight-week occupational therapy intervention program, and as a post test to measure intervention effectiveness. This study showed that the ESI was effective in guiding therapist intervention related to social skill performance of participants during their participation in a community-based program. As a group, the difference between pre and post ESI logit measures was also significant (t=4.977, p=0.001). The study provides initial considerations for the utility of the ESI to guide intervention related to social skill performance during daily occupations. It further documents the effectiveness of the ESI in measuring occupational therapy intervention, based on OTIPM, and supports occupational therapy services provided in a community-based program context for those living with TBI. PMID- 20170412 TI - Occupational justice-bridging theory and practice. AB - The evolving theory of occupational justice links the concept to social justice and to concerns for a justice of difference: a justice that recognizes occupational rights to inclusive participation in everyday occupations for all persons in society, regardless of age, ability, gender, social class, or other differences. The purpose of this descriptive paper is to inspire and empower health professionals to build a theoretical bridge to practice with an occupational justice lens. Using illustrations from a study of leisure and the use of everyday technology in the lives of very old people in Northern Sweden, the authors argue that an occupational justice lens may inspire and empower health professionals to engage in critical dialogue on occupational justice; use global thinking about occupation, health, justice, and the environment; and combine population and individualized approaches. The authors propose that taking these initiatives to bridge theory and practice will energize health professionals to enable inclusive participation in everyday occupations in diverse contexts. PMID- 20170413 TI - Critical reflections on school-based occupational therapy. AB - This article describes the process of facilitating change to practice that is more client-centered and occupation-based in a diverse suburban public school district in the USA from 2001 to 2006. The author sets the context, describes the process that included the use of the School AMPS, and considers factors that facilitated and constrained change. PMID- 20170414 TI - ADL skill profiles across three psychiatric diagnoses. AB - BACKGROUND: Occupational therapists' ability to develop diagnostic-specific ADL intervention strategies is facilitated by an understanding of the ADL abilities of diagnostic groups. AIM: To determine whether there are significant differences in ADL ability and ADL skill profiles between samples of persons with bipolar disorder depression (n=158), bipolar disorder mania (n=200), and schizophrenia (n=200). Methods. All participants were assessed using the Assessment of Motor and Process Skills (AMPS). Mean ADL ability and skill item calibrations were compared between the three diagnostic samples. FINDINGS: No clinically significant differences were found in mean ADL ability. The ADL process skill item "Attends" was more difficult for those with bipolar disorder mania than for those with bipolar disorder depression. This difference did not disrupt the measurement model. IMPLICATIONS: The findings fail to support the idea that valid predictions of skill performance can be made on the basis of psychiatric diagnosis. Thus, occupational performance must be assessed individually. The findings also provide solid evidence that valid measures of ADL ability are generated when persons with bipolar disorder and schizophrenia complete the AMPS. Intervention strategies are recommended to address limitations in the skill Attends among persons with bipolar disorder manic episode. PMID- 20170415 TI - Non-invasive estimation of glomerular filtration rate (GFR). The Lund model: Simultaneous use of cystatin C- and creatinine-based GFR-prediction equations, clinical data and an internal quality check. AB - Knowledge of glomerular filtration rate (GFR) is required to detect and follow impairment of renal function, to allow correct dosage of drugs cleared by the kidneys, and for the use of nephrotoxic contrast media. Correct determination of GFR requires invasive techniques, which are expensive, slow and not risk-free. Therefore, GFR-prediction equations based solely upon cystatin C or creatinine and anthropometric data or upon cystatin C, creatinine and anthropometric data have been developed. The combined prediction equations display the best diagnostic performance, but in several easily identifiable clinical situations (e.g. abnormal muscle mass, treatment with large doses of glucocorticoids) prediction equations based upon either cystatin C or creatinine are better than the combined equations. In Lund, where cystatin C has been used as a GFR-marker in the clinical routine since 1994, a strategy based upon this knowledge has therefore been developed. This comprises simultaneous use of a cystatin C-based and a creatinine-based GFR-prediction equation. If the GFRs predicted agree, the mean value is used as a reliable GFR-estimate. If the GFRs predicted do not agree, clinical data is evaluated to identify reasons for not using one of the two prediction equations and the GFR predicted by the other one is used. If no reasons for the difference in predicted GFRs are found, an invasive gold standard determination of GFR is performed. If the GFRs predicted agree for a patient, the creatinine value is reliably connected to a specific GFR and can be used to follow changes in GFR of that patient. PMID- 20170416 TI - Poor outcome of revised resurfacing hip arthroplasty. AB - BACKGROUND AND PURPOSE: Recent years have seen a rapid increase in the use of resurfacing hip arthroplasty despite the lack of literature on the long-term outcome. In particular, there is little evidence regarding the outcome of revisions of primary resurfacing. The purpose of this analysis was to examine the survivorship of primary resurfacing hip arthroplasties that have been revised. PATIENTS AND METHODS: Over 12,000 primary resurfacing hip arthroplasties were recorded by the Australian Orthopaedic Association National Joint Replacement Registry between September 1, 1999 and December 31, 2008. During this time, 397 revisions for reasons other than infection were reported for these primary resurfacings and classified as acetabular, femoral, or both acetabular and femoral revisions. The survivorship of the different types of revisions was estimated using the Kaplan-Meier method and compared using proportional hazard models. Additionally, the outcome of a femoral-only revision was compared to that of primary conventional total hip arthroplasty. RESULTS: Acetabular-only revision had a high risk of re-revision compared to femoral-only and both acetabular and femoral revision (5-year cumulative per cent revision of 20%, 7%, and 5% respectively). Femoral-only revision had a risk of re-revision similar to that of revision of both the acetabular and femoral components. Femoral-only revision had over twice the risk of revision of primary conventional total hip arthroplasty. INTERPRETATION: Revision of a primary resurfacing arthroplasty is associated with a major risk of re-revision. The best outcome is achieved when either the femoral only or both the acetabular and femoral components are revised. Technically straightforward femoral-only revisions generally have a worse outcome than a primary conventional total hip arthroplasty. PMID- 20170417 TI - Borggreve-Van Nes rotationplasty for infected knee arthroplasty - a case report. PMID- 20170418 TI - The classic. PMID- 20170420 TI - The Swedish Knee Arthroplasty Register (www.knee.se). PMID- 20170419 TI - Treatment of the displaced femoral neck fracture, as reflected in Acta Orthopaedica Scandinavica. PMID- 20170422 TI - The value of arthroplasty registry data. PMID- 20170421 TI - Translational systems approaches to the biology of inflammation and healing. AB - Inflammation is a complex, non-linear process central to many of the diseases that affect both developed and emerging nations. A systems-based understanding of inflammation, coupled to translational applications, is therefore necessary for efficient development of drugs and devices, for streamlining analyses at the level of populations, and for the implementation of personalized medicine. We have carried out an iterative and ongoing program of literature analysis, generation of prospective data, data analysis, and computational modeling in various experimental and clinical inflammatory disease settings. These simulations have been used to gain basic insights into the inflammatory response under baseline, gene-knockout, and drug-treated experimental animals for in silico studies associated with the clinical settings of sepsis, trauma, acute liver failure, and wound healing to create patient-specific simulations in polytrauma, traumatic brain injury, and vocal fold inflammation; and to gain insight into host-pathogen interactions in malaria, necrotizing enterocolitis, and sepsis. These simulations have converged with other systems biology approaches (e.g., functional genomics) to aid in the design of new drugs or devices geared towards modulating inflammation. Since they include both circulating and tissue-level inflammatory mediators, these simulations transcend typical cytokine networks by associating inflammatory processes with tissue/organ impacts via tissue damage/dysfunction. This framework has now allowed us to suggest how to modulate acute inflammation in a rational, individually optimized fashion. This plethora of computational and intertwined experimental/engineering approaches is the cornerstone of Translational Systems Biology approaches for inflammatory diseases. PMID- 20170423 TI - A novel flow bioreactor for in vitro microvascularization. AB - Although the importance of fluid flow for proper vascular development and function in vivo is well recognized, microvascular formation in response to flow has not been well evaluated in a three-dimensional (3D) environment in vitro. In this study, we developed a novel 3D in vitro perfusion system that allows direct investigation of the effects of shear stress on the development of microvasculature in vitro. This system utilizes a 3D collagen gel for suspension of vascular cells and mesenchymal stem cells, through which flow is directly perfused. We characterized the flow conditions and demonstrate the impact of flow on the development of microvasculature using a coculture of endothelial cells and mesenchymal stem cells. With the unique ability to apply bulk flow through the collagen gels, and to estimate shear stress within the constructs, this perfusion system provides a flexible platform for developing a controllable biomimetic environment that can be adapted for a variety of investigations of microvascularization. PMID- 20170425 TI - Development of a porcine bladder acellular matrix with well-preserved extracellular bioactive factors for tissue engineering. AB - In this study, we compared four decellularization protocols and finally developed an optimized one through which a porcine bladder acellular matrix (BAM) with well preserved extracellular bioactive factors had been prepared. In this protocol, the intact bladder was treated with trypsin/ethylenediaminetetraacetic acid to remove the urothelium, then with hypotonic buffer and Triton X-100 in hypertonic buffer to remove the membranous and cytoplasmic materials, and finally with nuclease to degrade the cellular nuclear components. Bladder distention and mechanical agitation were simultaneously used to facilitate cell removal. Meanwhile, several preservative techniques, including limitation of wash time, supplement with inhibitors of proteinase, control of the pH value and temperature of the wash buffer, ethylene oxide sterilization, and lyophilization of the scaffold for storage, were used to protect the extracellular bioactive factors. This decellularization protocol had completely removed the cellular materials and well preserved the extracellular collagen, sulfated glycosaminoglycan (GAG), and bioactive factors. The preserved bioactive factors had a great potential of promoting the proliferation and migration of both human bladder smooth muscle cell and human umbilical vein endothelial cell. It was also found that the amount of two representative bioactive factors, platelet-derived growth factor BB and vascular endothelial growth factor, was positively correlated with the sulfated GAG content in the porcine BAM, implying that the amount of sulfated GAG might be a determinant for preservation of bioactive factors in the decellularized tissues. In conclusion, the porcine BAM with well-preserved extracellular bioactive factors might be a favorable scaffold for tissue engineering applications. PMID- 20170424 TI - Plate fixation or intramedullary fixation of humeral shaft fractures. AB - BACKGROUND: The optimal approach to operative treatment of humeral shaft fractures remains debatable. Previously published trials have been limited in size and have been inconclusive regarding important patient outcome variables following treatment with either intramedullary nails or plates. We conducted a meta-analysis of available trials comparing treatment of humeral shaft fractures. METHODS: We performed a literature search from 1967 to November 2007 in the main medical search engines and selected 4 randomized trials that compared nails and plates in patients with humeral shaft fractures and that reported on complications due to surgery. We statistically pooled patient data using standard meta-analytic approaches. Our primary outcome was the total complication rate, comprised of all complications listed in the articles included. Secondary outcomes included non-union, infection, nerve palsy, and reoperation rate. Methodology was assessed using the CLEAR NPT. RESULTS: When pooling the data of the 4 trials (n = 203 patients), we did not find a statistically significant difference between implants in the rate of total complications, non-union, infection, nerve-palsy, or the need for reoperation. The studies included were small and had methodological limitations. CONCLUSIONS: Our meta-analysis suggests stastistically insignificant differences between plates and nails in the treatment of humeral shaft fractures. Small sample sizes, study heterogeneity, and methodological limitations argue strongly for a definitive, large trial. We recommend that this trial should be a randomized controlled trial with appropriate allocation of patients and blinding of patients and care providers and outcome assessors, and that it should include patient-important outcomes. PMID- 20170427 TI - Virtual reality: we are virtually there. PMID- 20170428 TI - Enabling occupational performance of children through coaching parents: three case reports. AB - This study explores the use of occupational performance coaching (OPC) with three parent-child dyads using descriptive case study methodology. OPC is a parent directed intervention in which parents are coached to improve their own or their children's performance in home and community contexts. In this study, parent and child performance was examined using a pre-post intervention design with the key outcome measures being the Canadian Occupational Performance Measure (COPM) and goal attainment scaling (GAS). Parent experiences of engaging with a therapist using OPC were explored through thematic analysis of interviews with parents after completing intervention. Themes relating to learning, changes at home, and the challenges and rewards of OPC emerged from interviews with parents. Results indicate that OPC may be a useful intervention for therapists seeking to achieve occupational performance outcomes with children and parents. Further research avenues are described. PMID- 20170429 TI - Ever vigilant: maternal support of participation in daily life for boys with autism. AB - This study presents emergent findings from a qualitative study of caregivers' well-being that illuminates why caregivers of children with autism are often found to be more stressed by their caregiving than caregivers of children with other disabilities. Nine mothers with diverse backgrounds whose sons had autism spectrum disorders participated. Data were gathered through intensive interviewing and analyzed using a deductive interpretive approach. Mothers characterized their caregiving as vigilance rather than burden. Yet, this vigilance was highly fatiguing. Mothers intensely attended to their children's activities. This intense focus promoted participation in self-care, leisure, and social activities, and prevented frustration and behavioral meltdowns. Mothers also performed "forensic analyses" to understand the root cause of participation problems. This parenting was intensive because mothers oversaw the children's activities at all times even during periods when mothers of typical children could take breaks. The children's continuing participation problems included limited self-care skills, difficulties in problem solving in novel situations, and lack of leisure skills. This intense vigilance may be a key factor in maternal health issues, such as anxiety and depression. While these problems fall within the scope of occupational therapy's expertise, it appears that many of these issues were not addressed by the current service-delivery models, leaving families to continue to struggle and the children to lack the skills for independent living as adults. PMID- 20170430 TI - Perspectives of therapist's role in care coordination between medical and early intervention services. AB - This study explored perspectives of therapist's role in care coordination between early intervention (EI) and medical services, and identified strategies for improving service delivery. Fifty adults participated in one of six focus groups. Participants included parents, pediatricians, and therapists working in hospital and EI programs. Structured guiding questions were used to obtain participants' perceptions. Transcript analysis included open code identification, axial code grouping, and constant comparative methods. The researchers established inter rater reliability (kappa = 0.85) in the coding scheme before data analysis. The themes identified included information exchange, communication among parents and therapists, approaches toward child and family care, supporting social and emotional needs, perceptions of therapists' roles, and understanding service delivery systems to improve care coordination. Participants recommended training for therapy service providers and pediatricians in the areas of child development, team building, and service systems. Family-centered strategies emphasizing systems of care are recommended to improve therapists' role in care coordination. PMID- 20170426 TI - Cardiac specific deletion of N-methyl-d-aspartate receptor 1 ameliorates mtMMP-9 mediated autophagy/mitophagy in hyperhomocysteinemia. AB - Autophagy is an important process in the pathogenesis of cardiovascular diseases; however, the proximal triggers for mitochondrial autophagy were unknown. The N methyl-d-aspartate receptor 1 (NMDA-R1) is a receptor for homocysteine (Hcy) and plays a key role in cardiac dysfunction. Cardiac-specific deletion of NMDA-R1 has been shown to ameliorate Hcy-induced myocyte contractility. Hcy activates mitochondrial matrix metalloproteinase-9 (mtMMP-9) and induces translocation of connexin-43 (Cxn-43) to the mitochondria (mtCxn-43). We sought to show cardiac specific deletion of NMDA-R1 mitigates Hcy-induced mtCxn-43 translocation, mtMMP 9-mediated mtCxn-43 degradation, leading to mitophagy, in part, by decreasing mitochondrial permeability (MPT). Cardiac-specific knockout (KO) of NAMDA-R1 was generated using the cre/lox approach. The myocyte mitochondria were isolated from wild type (WT), WT + Hcy (1.8 g of DL-Hcy/L in the drinking water for 6 weeks), NMDA-R1 KO + Hcy, and NR1(fl/fl)/Cre (NR1(fl/fl)) genetic control mice. Mitochondrial respiratory capacity and MPT were measured by fluorescence-dye methods. The mitochondrial superoxide and peroxinitrite levels were detected by confocal microscopy using Mito-SOX and dihydrorhodamine-123. The mtMMP-9 activity and expression were detected by zymography and RT-PCR analyses. The mtCxn-43 translocation was detected by confocal microscopy. The degradation of mtCxn-43 and LC3-I/II (a marker of autophagy) were detected by Western blot. These results suggested that Hcy enhanced intramitochondrial nitrosative stress in myocytes. There was a robust increase in mtMMP-9 activity. An increase in translocation and degradation of mtCxn-43 was also noted. These increases led to mitophagy. The effects were ameliorated by cardiac-specific deletion of NMDA-R1. We concluded that HHcy increased mitochondrial nitrosative stress, thereby activating mtMMP-9 and inciting the degradation of mtCxn-43. This led to mitophagy, in part, by activating NMDA-R1. The findings of this study will lead to therapeutic ramifications for mitigating cardiovascular diseases by inhibiting the mitochondrial mitophagy and NMDA-R1 receptor. PMID- 20170432 TI - Effects of prolonged standing on gait in children with spastic cerebral palsy. AB - The purpose of this study was to determine the effects of prolonged standing on gait characteristics in children with spastic cerebral palsy. Six children with spastic cerebral palsy participated in this study with an average age of 6.5 years (SD = 2.5, range = 4.0-9.8 years). A reverse baseline design (A-B-A) was used over a 9-week period. During phase A, the children received their usual physical therapy treatment. During phase B, children received the prolonged standing program three times per week, in addition to their usual physical therapy treatment. During phase A2, children received their usual physical therapy treatment. Gait analysis and clinical assessment of spasticity were performed before and after each phase. Analysis of variance (ANOVA) for repeated measurements was used to test for changes in gait measures across the four measurement sessions. Friedman's was used to test for changes in muscle tone (Modified Ashworth Scale) across the four measurement sessions. Stride length (p <.001), gait speed (p <.001), stride time (p <.001), stance phase time (p <.001), double support time (p <.003), muscle tone (p <.02), and peak dorsiflexion angle during midstance (p <.004) improved significantly following the intervention phase. The results of this study demonstrate that the gait pattern of children with cerebral palsy classified as level II or III on the Gross Motor Functional Classification System (GMFCS) improved by a prolonged standing program. However, these improvements were not maintained at 3 weeks. Further research is necessary with larger sample sizes to replicate these findings and determine specific "dosing" for standing programs to create long-lasting functional effects on gait. PMID- 20170431 TI - Feasibility of a computerized method to measure quality of "everyday" life in children with neuromuscular disorders. AB - Measurement of quality of life is becoming increasingly important in health care. Self-reported quality of life is the preferred method of gathering this information, but children are often excluded from this process, their input being replaced by parent-proxy report. This feasibility study tested assessment of "daily" quality-of-life by a self-reported computerized method in boys with neuromuscular disorders. To establish feasibility, the method was required to be engaging, consistent, and convenient. Ten boys, aged 9-16 years, were given a personal digital assistant (PDA) and prompted randomly, eight times/day for 1 week, to answer 19 questions about their daily experiences (including happiness, mood, self-esteem, location, and activity). Subjects completed sampling with an acceptable response rate (79%). Split-week reliability analysis for participant variability (r = 0.45-0.88) indicated acceptable consistency. Participants reported that the method was easy and convenient, and analysis of standardized mean scores supported internal validity. The computerized method to assess "daily" quality of life, from the child's perspective, was feasible and may be useful to understand the impact of disease progression and interventions on day to-day function. PMID- 20170433 TI - Responses to a modified visual cliff by pre-walking infants born preterm and at term. AB - The purpose of this study was to examine, using a modified visual cliff apparatus, possible perceptual differences at crawling age between infants born preterm and infants born at term without documented visual or motor impairments. Sixteen infants born at term and 16 born preterm were encouraged to crawl to their caregivers on a modified visual cliff. Successful trials, crossing time, duration of visual attention, duration of tactile exploration, motor strategies, and avoidance behaviors were analyzed. A significant surface effect was found, with longer crossing times and longer durations of visual attention and tactile exploration in the condition with the visual appearance of a deep cliff. Although the two groups of infants did not differ on any of the timed measures, infants born at term demonstrated a larger number of motor strategies and avoidance behaviors by simple tally. This study indicates that infants born at term and those born preterm can perceive a visual cliff and adapt their responses accordingly. PMID- 20170434 TI - The Canadian Joint Replacement Registry-what have we learned? AB - The Canadian Joint Replacement Registry (CJRR) was launched in 2000 through the collaborative efforts of the Canadian Orthopedic Association and the Canadian Institutes for Health Information. Participation is voluntary, and data collected by participating surgeons in the operating room is linked to hospital stay information from administrative databases to compile yearly reports. In the fiscal year 2006-2007, there were 62,196 hospitalizations for hip and knee replacements in Canada, excluding Quebec. This represents a 10-year increase of 101% and a 1-year increase of 6%. Compared to men, Canadian women have higher age adjusted rates per 105 for both TKA (148 vs. 110) and THA (86 vs. 76). There also exist substantial inter-provincial variations in both age-adjusted rates of arthroplasty and implant utilization that cannot be explained entirely on the basis of differing patient demographics. The reasons for these variations are unclear, but probably represent such factors as differences in provincial health expenditure, efforts to reduce waiting lists, and surgeon preference. The main challenge currently facing the CJRR is to increase procedure capture to > 90%. This is being pursued through a combination of efforts including simplification of the consent process, streamlining of the data collection form, and the production of customized reports with information that has direct clinical relevance for surgeons and administrators. As the CJRR continues to mature, we are optimistic that it will provide clinically important information on the wide range of factors that affect arthroplasty outcome. PMID- 20170435 TI - The Swedish Hip Arthroplasty Register (www.shpr.se). PMID- 20170436 TI - Vitamin E prevents steroid-induced osteonecrosis in rabbits. AB - BACKGROUND AND PURPOSE: Prevention of osteonecrosis after corticosteroid administration would be important. We examined the potential of vitamin E (alpha tocopherol) to reduce the incidence of corticosteroid-induced osteonecrosis in an animal model. METHODS: Japanese white rabbits were divided into 2 groups; the control group was fed a normal diet and the experimental group was fed alpha tocopherol-supplemented diet in which alpha-tocopherol (600 mg/kg diet) was added to the normal diet. To induce osteonecrosis, high-dose methylprednisolone acetate (MPSL) (20 mg/kg body weight) was injected once into the right gluteus medius muscle of all rabbits. 4 weeks after the injection of MPSL, the presence or absence of osteonecrosis of bilateral femurs was examined histopathologically. The tocopherol/cholesterol ratios were calculated. The plasma levels of thiobarbituric acid-reactive substances (TBARS) were measured. RESULTS: Alpha tocopherol-supplemented diet reduced the incidence of osteonecrosis, which developed in 14 of 20 rabbits in the control group and 5 of 21 rabbits in the experimental group (p = 0.004). The tocopherol/cholesterol ratio was higher in the experimental group than in the control group after the alpha-tocopherol administration. The plasma TBARS level was lower in the experimental group than in the control group at 4 weeks after the MPSL administration. INTERPRETATION: Our findings may offer a new approach for the prevention of corticosteroid induced osteonecrosis. PMID- 20170451 TI - Improving use of medicines with clinician-led use of validated clinical indicators. PMID- 20170452 TI - Identifying the pathways to suicide in child sexual abuse victims. PMID- 20170453 TI - Suicide and fatal drug overdose in child sexual abuse victims: a historical cohort study. AB - OBJECTIVE: To determine the rate and risk of suicide and accidental fatal drug overdose (ie, overdose deemed not to have been suicide) in individuals who had been medically ascertained as having been sexually abused during childhood. DESIGN: A historical cohort linkage study of suicide and accidental drug-induced death among victims of child sexual abuse (CSA). SETTING AND PATIENTS: Forensic medical records of 2759 victims of CSA who were assessed between 1964 and 1995 were obtained from the Victorian Institute of Forensic Medicine and linked with coronial data representing a follow-up period of up to 44 years. MAIN OUTCOME MEASURES: Rates of suicide and accidental fatal drug overdose recorded in coronial databases between 1991 and 2008, and rates of psychiatric disorders and substance use recorded in public mental health databases. RESULTS: Twenty-one cases of fatal self-harm were recorded. Relative risks for suicide and accidental fatal overdose among CSA victims, compared with age-limited national data for the general population, were 18.09 (95% CI, 10.96-29.85; population-attributable risk, 0.37%), and 49.22 (95% CI, 36.11-67.09; population-attributable risk, 0.01%) respectively. Relative risks were higher for female victims. Similar to the general population, CSA victims who died as a result of self-harm were predominantly aged in their 30s at time of death. Most had contact with the public mental health system and half were recorded as being diagnosed with an anxiety disorder. CONCLUSION: Our data highlight that CSA victims are at increased risk of suicide and accidental fatal drug overdose. CSA is a risk factor that mediates suicide and fatal overdose. PMID- 20170454 TI - Painting the picture: Australasian medical student views on wellbeing teaching and support services. AB - OBJECTIVE: To explore medical students' views on support services, stigma, and teaching of wellbeing in light of their experiences of stress and distress. DESIGN, PARTICIPANTS AND SETTING: Quantitative survey of medical students at five universities in Australia and New Zealand in November 2007. MAIN OUTCOME MEASURES: Medical students' experiences of support services, stigma attached to undergoing stress and distress, and teaching of wellbeing. RESULTS: 1328 students completed the survey (26% response rate). Seventy-one per cent of students were aware of support services at their university. Of these, 46% believed the services were adequately promoted, and 49% had either used the services themselves or knew someone who had. Overall, 70% of students had their own general practitioner, but this fell to 45% for international students (P < 0.001). Fifty-five per cent of students believed there was a stigma associated with being a medical student undergoing stress and distress. Fifty-six per cent of students believed they had formal teaching on stress and distress. Students most wanted to learn methods to help somebody else cope and preferred to be taught through formal lectures. CONCLUSION: Medical curricula on wellbeing should include strategies for self-help and giving assistance to others, and aim to decrease stigma. Adequate and well-promoted support services are required to complement this teaching, in particular for international students. PMID- 20170455 TI - Computerised prescribing: assessing the impact on prescription repeats and on generic substitution of some commonly used antibiotics. AB - OBJECTIVES: To assess the impact of two interventions on computer-generated prescriptions for antibiotics--(i) an educational intervention to reduce automatic computerised ordering of repeat antibiotic prescriptions, and (ii) a legislative change prohibiting the "no brand substitution" box being checked as a default setting in prescribing software--and to compare these findings with those of a similar survey we conducted in 2000. DESIGN AND SETTING: Prospective audit of consecutive prescriptions for four antibiotics (amoxycillin, amoxycillin/clavulanate, roxithromycin, and cefaclor) commonly prescribed for upper respiratory tract infections in community pharmacies in New South Wales and Queensland between 1 November 2008 and 31 January 2009. MAIN OUTCOME MEASURES: PRIMARY OUTCOME: rate of repeat prescription ordering on computer-generated versus handwritten prescriptions. Secondary outcome: rate of checking of the "no brand substitution" box on computer-generated versus handwritten prescriptions. RESULTS: Data were collected on 2807 prescriptions presented to 51 pharmacies (50 in NSW, one in Queensland), of which 2354 were computer-generated. Repeats were ordered on 1633 computer-generated prescriptions (69%) compared with 183 handwritten prescriptions (40%). These proportions were identical to those found in 2000, although the rates of computer prescribing were much higher in this study (84% v 54%). This difference in repeat prescribing was statistically significant (odds ratio adjusted for clustering at pharmacy level, 2.87; 95% CI, 2.32-3.55). Twenty-three (1%) of the computer-generated prescriptions had the "no brand substitution" box checked compared with 3 (0.7%) of the handwritten prescriptions (27% and 1%, respectively, in our previous survey). CONCLUSIONS: The legislative change which disallowed having the "no brand substitution" box checked as a default setting in prescribing software had a dramatic impact on the checking of the "no brand substitution" box. In contrast, there was no sustained effect of educating prescribers about software default settings relating to repeat prescribing of antibiotics. Other actions are required if unnecessary repeat prescriptions for some medicines, such as antibiotics, are to be reduced. PMID- 20170456 TI - AUSDRISK: an Australian Type 2 Diabetes Risk Assessment Tool based on demographic, lifestyle and simple anthropometric measures. AB - OBJECTIVE: To develop and validate a diabetes risk assessment tool for Australia based on demographic, lifestyle and simple anthropometric measures. DESIGN AND SETTING: 5-year follow-up (2004-2005) of the Australian Diabetes, Obesity and Lifestyle study (AusDiab, 1999-2000). PARTICIPANTS: 6060 AusDiab participants aged 25 years or older who did not have diagnosed diabetes at baseline. MAIN OUTCOME MEASURES: Incident diabetes at follow-up was defined by treatment with insulin or oral hypoglycaemic agents or by fasting plasma glucose level > or = 7.0 mmol/L or 2-hour plasma glucose level in an oral glucose tolerance test > or = 11.1 mmol/L. The risk prediction model was developed using logistic regression and converted to a simple score, which was then validated in two independent Australian cohorts (the Blue Mountains Eye Study and the North West Adelaide Health Study) using the area under the receiver operating characteristic curve (AROC) and the Hosmer-Lemeshow (HL) chi(2) statistic. RESULTS: 362 people developed diabetes. Age, sex, ethnicity, parental history of diabetes, history of high blood glucose level, use of antihypertensive medications, smoking, physical inactivity and waist circumference were included in the final prediction model. The AROC of the diabetes risk tool was 0.78 (95% CI, 0.76-0.81) and HL chi(2) statistic was 4.1 (P = 0.85). Using a score > or = 12 (maximum, 35), the sensitivity, specificity and positive predictive value for identifying incident diabetes were 74.0%, 67.7% and 12.7%, respectively. The AROC and HL chi(2) statistic in the two independent validation cohorts were 0.66 (95% CI, 0.60-0.71) and 9.2 (P = 0.32), and 0.79 (95% CI, 0.72-0.86) and 29.4 (P < 0.001), respectively. CONCLUSIONS: This diabetes risk assessment tool provides a simple, non-invasive method to identify Australian adults at high risk of type 2 diabetes who might benefit from interventions to prevent or delay its onset. PMID- 20170457 TI - Australian experience with frozen blood products on military operations. AB - Historically, the Australian Defence Force (ADF) has sourced all its blood supplies from the Australian Red Cross Blood Service. Recent ADF operations in the Middle East have highlighted a need to rely on other nations' blood supply systems. In 2008, the ADF embedded a surgical and intensive care team into the Netherlands-led forward health facility at the Uruzgan Medical Centre at Tarin Kowt in Afghanistan. To date, three teams have provided 2-month rotations as part of the North Atlantic Treaty Organization International Security Assistance Force in Afghanistan. The Netherlands armed forces use a sophisticated system for supply of liquid and frozen blood products (frozen red cells, plasma and platelets). We review Australian experience with the Dutch system of supplying blood products for major trauma resuscitation in Afghanistan. PMID- 20170458 TI - The Healthy Kids Check - is it evidence-based? AB - OBJECTIVE: To assess whether the components of the Healthy Kids Check (HKC), a preschool screening check recently added to the Australian Government's Enhanced Primary Care Program, are supported by evidence-based guidelines or reviews. DATA SOURCES: Guideline and MEDLINE databases were searched for guidelines and systematic reviews published between 2000 and 2008 that were relevant to screening, prevention or well-child care in primary health care, and including children of preschool age. Search subjects reflected the HKC components: growth, weight, obesity, vision, hearing, oral health, enuresis, encopresis, allergic disease and food allergies. STUDY SELECTION: 34 relevant guidelines or reviews were retrieved. DATA EXTRACTION: For each component of the HKC, guidelines addressing the presumed rationale for screening, or the test or tool required to implement it, were reviewed. Relevant evidence-based and consensus-based guideline recommendations were assessed as either supporting or opposing components of the HKC, or stating that the evidence was insufficient to recommend screening of preschool children. DATA SYNTHESIS: Guidelines were often inconsistent in their recommendations. Most of the components of the HKC (eg, screening for chronic otitis media and questioning about toilet habits) are not supported by evidence-based guidelines relevant to the primary care setting, though a number of consensus-based guidelines are supportive. CONCLUSIONS: There is currently a dearth of evidence relevant to child health surveillance in primary care. The components of the HKC could be refined to better reflect evidence-based guidelines that target health monitoring of preschool children. PMID- 20170459 TI - Applicant characteristics and their influence on success: results from an analysis of applicants to the University of Adelaide Medical School, 2004-2007. AB - OBJECTIVE: To determine the applicant characteristics that influence success at each application stage for entry to the University of Adelaide Medical School. DESIGN, SETTING AND PARTICIPANTS: Retrospective analysis of characteristics associated with a successful outcome to an undergraduate-entry medical school for 6699 applicants from four cohorts (2004-2007). MAIN OUTCOME MEASURES: Offer of an interview, offer of a place, and acceptance of a place in the medical school. RESULTS: Female applicants were less likely to gain an interview (odds ratio [OR], 0.88; 95% CI, 0.78-0.99) but more likely to receive an offer of a place (OR, 1.33; 95% CI, 1.07-1.66). Older applicants were less likely than younger applicants (OR, 0.78; 95% CI, 0.71-0.86) and non-school leavers (applying after leaving school) were more likely than school leavers (applying while at school) (OR, 9.54; 95% CI, 6.16-14.78) to receive an offer of an interview. Applicants from areas of high socioeconomic status were more likely to gain an interview (quartile 1 v 4: OR, 0.55; 95% CI, 0.45-0.68). The more interviews an applicant had, the more likely he or she was to be offered a place (OR, 1.49; 95% CI, 1.34 1.66). CONCLUSION: This study indicates that some applicant characteristics have a significant influence on the success of an application at particular stages, but overall there does not appear to be a large or inherent systematic bias in the selection process at the University of Adelaide Medical School. PMID- 20170460 TI - Waiting lists and elective surgery: ordering the queue. AB - In the Australian public health system, access to elective surgery is rationed through the use of waiting lists in which patients are assigned to broad urgency categories. Surgeons are principally responsible for referring patients to waiting lists, deciding on the appropriate urgency category, and selecting patients from the waiting list to receive surgery. There are few agreed-upon criteria to help surgeons make these decisions, leading to striking differences between institutions in proportions of patients allocated to urgency categories. In other countries with publicly funded health systems, programs have been developed that aim to make prioritisation more consistent and access to surgery more equitable. As demand for health care increases, similar programs should be established in Australia using relevant clinical and psychosocial factors. Prioritisation methodology adapted for elective surgery may have a role in prioritising high-demand procedures in other areas of health care. PMID- 20170461 TI - Performance-based hospital funding: a reform tool or an incentive for fraud? AB - Hospital funding based on achieving targets for numerical key performance indicators was implicated in Queensland's Bundaberg Base Hospital scandal and has driven hospital data fraud in Victoria and New South Wales. Nationally uniform legislation is required to make health service reporting standards consistent and to criminalise public sector data fraud. Urgent action is needed to develop realistic outcome measures that base hospital funding more on the quality and safety of patient care and less on patient throughput numbers. PMID- 20170462 TI - Giant villous adenoma presenting as McKittrick-Wheelock syndrome and pseudo obstruction. AB - McKittrick-Wheelock syndrome is a rare but recognised complication of hypersecretory rectosigmoid villous adenoma. Fluid and electrolyte imbalances require close monitoring because of large-volume losses of water, sodium and potassium. We report an unusual presentation of the syndrome associated with the development of acute pseudo-obstruction of the colon, presumably due to electrolyte dysfunction and acute renal failure. PMID- 20170463 TI - Anticoagulation and intraocular haemorrhage in age-related macular degeneration: a probable link? PMID- 20170464 TI - Autonomic neuropathy - an uncommon variant of Guillain-Barre syndrome. PMID- 20170465 TI - Microbiological diagnostic tests for community-acquired pneumonia are useful. PMID- 20170466 TI - The growing popularity of "low-carb" beers: good marketing or community health risk? PMID- 20170467 TI - Encysted seizures: status epilepticus in a recently resettled refugee child. PMID- 20170468 TI - Outcomes of a cystic fibrosis carrier testing clinic for couples. PMID- 20170469 TI - Timing of transfer for pregnant women from Queensland Cape York communities to Cairns for birthing. PMID- 20170470 TI - The role of general practitioners in managing and treating hepatitis C. PMID- 20170471 TI - General Practice Super Clinics - how will they meet their educational objectives? PMID- 20170472 TI - Metabotropic glutamate receptors as therapeutic targets for cognitive disorders. AB - Since more than one decade, metabotropic glutamate receptors have been under investigation as targets for various CNS disorders such as anxiety, pain, depression, schizpohrenia, Alzheimer's disease and Parkinson's disease. It has been shown that some mGluRs play a crucial role in cognitive processes such as learning and memory, which was initially, demonstrated using knockout mice for each receptor subtype. Later, selective pharmacological tools were developed allowing more specific examinations of the involvement of mGluR1-8 in various forms of learning and memory. Ligands for group I and II mGluRs have been proposed as promising candidates for the treatment of cognitive disorders such as schizophrenia, Fragile X syndrome, Alzheimer's and Parkinson's disease and post traumatic stress disorder, of which some have made it to clinical testing. The present paper reviews relevant data on the role of mGluRs in learning and cognition processes focusing on their utility as targets for cognition enhancement in several CNS diseases. PMID- 20170473 TI - Heat shock proteins as suppressors of accumulation of toxic prefibrillar intermediates and misfolded proteins in neurodegenerative diseases. AB - The most characteristic feature of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease, is the occurrence of extra- or intracellular fibrillar aggregates containing misfolded proteins with beta-sheet conformation. These aggregates are composed of distinct proteins in each neurodegenerative disease. However, mutations in genes encoding major constituents of aggregates, such as Abeta, tau, alpha-synuclein, SOD1 and huntingtin, have been identified to causally associate with familial forms of the diseases. Biochemical studies demonstrate that these mutant and some wild-type proteins tend to be misfolded or form aggregates. It has been proposed that these diseases are caused by a common mechanism involving misfolded proteins that trigger a toxic cascade leading to neuronal degeneration. This hypothesis is the basis of the therapeutic potential of heat shock proteins (HSPs), which prevent protein misfolding and aggregation. Transgenic animal models of the diseases have demonstrated that induction or overexpression of HSPs can suppress neuronal dysfunction and degeneration. Do the results promise clinical success for HSP-based therapy in neurodegenerative diseases? Recent findings regarding the pathogenic species generated during fibril formation have highlighted some of the beneficial and problematic aspects of HSP-based therapy. In this review, we focus on the pathogenic role of prefibrillar intermediates, including soluble oligomers and protofibrils, on neurodegeneration, and the relationship between prefibrillar intermediates and the proteins targeted by HSPs. We discuss in vitro and in vivo experimental data showing that HSPs counteract disease progression by acting as suppressors of toxic prefibrillar intermediates and toxic misfolded proteins in neurodegenerative diseases. PMID- 20170474 TI - Heat shock proteins; an overview. AB - Heat shock proteins (Hsps) protect protein substrates against conformational damage to promote the function of the proteins, prevent aggregation and prevent formation of toxic inclusion bodies. Protein aggregates and fibrils have been associated with neurodegenerative diseases and with inclusion bodies. High-level expression of recombinant protein for biotechnological purposes often leads to insoluble inclusion bodies. Therefore, misfolded proteins must be properly folded or must be degraded through heat shock protein action. This function protects cells against cytotoxic outcomes. In addition to their cytoprotective roles, Hsps are involved in other functions since Hsps exist in all types of cells and tissues. Therefore, several diseases are associated with alterations of these biochemical functions. This first review of the theme issue will discuss general properties of Hsps concisely along with their potential use in pharmaceutical and biotechnological applications. PMID- 20170475 TI - Influence of MT7 toxin on the oligomerization state of the M1 muscarinic receptor. AB - BACKGROUND INFORMATION: The idea that GPCRs (G-protein-coupled receptors) may exist as homo- or hetero-oligomers, although still controversial, is now widely accepted. Nevertheless, the functional roles of oligomerization are still unclear and gaining greater insight into the mechanisms underlying the dynamics of GPCR assembly and, in particular, assessing the effect of ligands on this process seems important. We chose to focus our present study on the effect of MT7 (muscarinic toxin 7), a highly selective allosteric peptide ligand, on the oligomerization state of the hM1 (human M1 muscarinic acetylcholine receptor subtype). RESULTS: We analysed the hM1 oligomerization state in membrane preparations or in live cells and observed the effect of MT7 via four complementary techniques: native-PAGE electrophoresis analysed by both Western blotting and autoradiography on solubilized membrane preparations of CHO-M1 cells (Chinese-hamster ovary cells expressing muscarinic M1 receptors); FRET (fluorescence resonance energy transfer) experiments on cells expressing differently tagged M1 receptors using either an acceptor photobleaching approach or a novel fluorescence emission anisotropy technique; and, finally, by BRET (bioluminescence resonance energy transfer) assays. Our results reveal that MT7 seems to protect the M1 receptor from the dissociating effect of the detergent and induces an increase in the FRET and BRET signals, highlighting its ability to affect the dimeric form of the receptor. CONCLUSIONS: Our results suggest that MT7 binds to a dimeric form of hM1 receptor, favouring the stability of this receptor state at the cellular level, probably by inducing some conformational rearrangements of the pre-existing muscarinic receptor homodimers. PMID- 20170476 TI - The effect of a controlled manipulation of maternal dietary fat intake on medium and long chain fatty acids in human breast milk in Saskatoon, Canada. AB - BACKGROUND: Few studies in recent years have demonstrated the effect of maternal diet on fatty acid composition of human milk. METHODS: Fourteen free-living lactating women participated in a cross-over dietary intervention study, consuming a low fat diet (17.6% of energy as fat, 14.4% of energy as protein, 68.0% of energy as carbohydrate) and a high fat diet (40.3% of energy as fat, 14.4% of energy as protein, 45.3% of energy as carbohydrate) each for periods of 4 days, in randomised order. Each mother was her own control. Mature milk samples were collected during each period and analysed for medium and long chain fatty acids. RESULTS: The concentration of medium chain fatty acids (MCFA), was 13.6% in breast milk for the low fat diet compared to 11.4% for the high fat (p < 0.05). Arachidonic acid (C20:4n-6) levels were significantly higher in breast milk when women consumed the low fat diet. Increased dietary intake of stearic acid (C18:0) and alpha-linolenic acid (C18:3n-3) on the high fat diet significantly increased proportions of these fatty acids in breast milk (p < 0.05) in 4 days. CONCLUSIONS: Changing maternal dietary fat intake has a rapid response in terms of changes to fatty acids in breast milk. PMID- 20170477 TI - Efficacy of non-artemisinin- and artemisinin-based combination therapies for uncomplicated falciparum malaria in Cameroon. AB - BACKGROUND: The use of drug combinations, including non-artemisinin-based and artemisinin-based combination therapy (ACT), is a novel strategy that enhances therapeutic efficacy and delays the emergence of multidrug-resistant Plasmodium falciparum. Its use is strongly recommended in most sub-Saharan African countries, namely Cameroon, where resistance to chloroquine is widespread and antifolate resistance is emerging. METHODS: Studies were conducted in Cameroonian children with acute uncomplicated P. falciparum malaria according to the standard World Health Organization protocol at four sentinel sites between 2003 and 2007. A total of 1,401 children were enrolled, of whom 1,337 were assigned to randomized studies and 64 were included in a single non-randomized study. The proportions of adequate clinical and parasitological response (PCR-uncorrected on day 14 and PCR-corrected on day 28) were the primary endpoints to evaluate treatment efficacy on day 14 and day 28. The relative effectiveness of drug combinations was compared by a multi-treatment Bayesian random-effect meta analysis. FINDINGS: The results based on the meta-analysis suggested that artesunate-amodiaquine (AS-AQ) is as effective as other drugs (artesunate sulphadoxine-pyrimethamine [AS-SP], artesunate-chlorproguanil-dapsone [AS-CD], artesunate-mefloquine [AS-MQ], dihydroartemisinin-piperaquine [DH-PP], artemether lumefantrine [AM-LM], amodiaquine, and amodiaquine-sulphadoxine-pyrimethamine [AQ SP]). AM-LM appeared to be the most effective with no treatment failure due to recrudescence, closely followed by DH-PP. CONCLUSION: Although AM-LM requires six doses, rather than three doses for other artemisinin-based combinations, it has potential advantages over other forms of ACT. Further studies are needed to evaluate the clinical efficacy and tolerance of these combinations in different epidemiological context. PMID- 20170478 TI - Measuring adherence to antiretroviral treatment in resource-poor settings: the clinical validity of key indicators. AB - BACKGROUND: Access to antiretroviral therapy has dramatically expanded in Africa in recent years, but there are no validated approaches to measure treatment adherence in these settings. METHODS: In 16 health facilities, we observed a retrospective cohort of patients initiating antiretroviral therapy. We constructed eight indicators of adherence and visit attendance during the first 18 months of treatment from data in clinic and pharmacy records and attendance logs. We measured the correlation among these measures and assessed how well each predicted changes in weight and CD4 count. RESULTS: We followed 488 patients; 63.5% had 100% coverage of medicines during follow-up; 2.7% experienced a 30-day gap in treatment; 72.6% self-reported perfect adherence in all clinic visits; and 19.9% missed multiple clinic visits. After six months of treatment, mean weight gain was 3.9 kg and mean increase in CD4 count was 138.1 cells/mm3.Dispensing based adherence, self-reported adherence, and consistent visit attendance were highly correlated. The first two types of adherence measure predicted gains in weight and CD4 count; consistent visit attendance was associated only with weight gain. CONCLUSIONS: This study demonstrates that routine data in African health facilities can be used to monitor antiretroviral adherence at the patient and system level. PMID- 20170479 TI - Measuring adherence to antiretroviral treatment in resource-poor settings: the feasibility of collecting routine data for key indicators. AB - BACKGROUND: An East African survey showed that among the few health facilities that measured adherence to antiretroviral therapy, practices and definitions varied widely. We evaluated the feasibility of collecting routine data to standardize adherence measurement using a draft set of indicators. METHODS: Targeting 20 facilities each in Ethiopia, Kenya, Rwanda, and Uganda, in each facility we interviewed up to 30 patients, examined 100 patient records, and interviewed staff. RESULTS: In 78 facilities, we interviewed a total of 1,631 patients and reviewed 8,282 records. Difficulties in retrieving records prevented data collection in two facilities. Overall, 94.2% of patients reported perfect adherence; dispensed medicine covered 91.1% of days in a six month retrospective period; 13.7% of patients had a gap of more than 30 days in their dispensed medication; 75.8% of patients attended clinic on or before the date of their next appointment; and 87.1% of patients attended within 3 days.In each of the four countries, the facility-specific median indicators ranged from: 97%-100% for perfect self-reported adherence, 90%-95% of days covered by dispensed medicines, 2%-19% of patients with treatment gaps of 30 days or more, and 72%-91% of appointments attended on time. Individual facilities varied considerably.The percentages of days covered by dispensed medicine, patients with more than 95% of days covered, and patients with a gap of 30 days or more were all significantly correlated with the percentages of patients who attended their appointments on time, within 3 days, or within 30 days of their appointment. Self reported recent adherence in exit interviews was significantly correlated only with the percentage of patients who attended within 3 days of their appointment. CONCLUSIONS: Field tests showed that data to measure adherence can be collected systematically from health facilities in resource-poor settings. The clinical validity of these indicators is assessed in a companion article. Most patients and facilities showed high levels of adherence; however, poor levels of performance in some facilities provide a target for quality improvement efforts. PMID- 20170480 TI - Current themes in molecular pediatrics: molecular medicine and its applications. AB - We focus on themes that are derived from clinical practice and research in the field of genetic diseases of bone and inborn errors of metabolism but may be of more general interest as they indicate some trends in molecular medicine as related to pediatrics. Identifying the disease-causing mechanism brings about efficient therapeutic strategies and discovering the mutant genotype in the near future may become helpful for devising custom-built molecular responses. At the same time, the transition of therapy from the experimental phase to industrial application is difficult as there may be novel roles (and potentially conflicting interests) between physicians, patient organisations, governmental agencies and the pharmaceutical industry. Awareness of these potential conflicts may help in recognizing and dealing with these issues. PMID- 20170481 TI - The Randomized Shortened Dental Arch study (RaSDA): design and protocol. AB - BACKGROUND: Various treatment options for the prosthetic treatment of jaws where all molars are lost are under discussion. Besides the placement of implants, two main treatment types can be distinguished: replacement of the missing molars with removable dental prostheses and non-replacement of the molars, i.e. preservation of the shortened dental arch. Evidence is lacking regarding the long-term outcome and the clinical performance of these approaches. High treatment costs and the long time required for the treatment impede respective clinical trials. METHODS/DESIGN: This 14-center randomized controlled investigator-initiated trial is ongoing. Last patient out will be in 2010. Patients over 35 years of age with all molars missing in one jaw and with at least both canines and one premolar left on each side were eligible. One group received a treatment with removable dental prostheses for molar replacement (treatment A). The other group received a treatment limited to the replacement of all missing anterior and premolar teeth using fixed bridges (treatment B). A pilot trial with 32 patients was carried out. Two hundred and fifteen patients were enrolled in the main trial where 109 patients were randomized for treatment A and 106 for treatment B. The primary outcome measure is further tooth loss during the 5-year follow-up. The secondary outcome measures encompassed clinical, technical and subjective variables. The study is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG WA 831/2-1, 2-2, 2-3, 2-4, 2-5). DISCUSSION: The particular value of this trial is the adaptation of common design components to the very specific features of complex dental prosthetic treatments. The pilot trial proved to be indispensable because it led to a number of adjustments in the study protocol that considerably improved the practicability. The expected results are of high clinical relevance and will show the efficacy of two common treatment approaches in terms of oral health. An array of secondary outcome measures will deliver valuable supplementary information. If the results can be implemented in the clinical practice, the daily dental care should strongly profit thereof. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov under ISRCTN68590603 (pilot trial) and ISRCTN97265367 (main trial). PMID- 20170482 TI - Rationale and design of the ADDITION-Leicester study, a systematic screening programme and randomised controlled trial of multi-factorial cardiovascular risk intervention in people with type 2 diabetes mellitus detected by screening. AB - BACKGROUND: Earlier diagnosis followed by multi-factorial cardiovascular risk intervention may improve outcomes in type 2 diabetes mellitus (T2DM). Latent phase identification through screening requires structured, appropriately targeted population-based approaches. Providers responsible for implementing screening policy await evidence of clinical and cost effectiveness from randomised intervention trials in screen-detected T2DM cases. UK South Asians are at particularly high risk of abnormal glucose tolerance and T2DM. To be effective national screening programmes must achieve good coverage across the population by identifying barriers to the detection of disease and adapting to the delivery of earlier care. Here we describe the rationale and methods of a systematic community screening programme and randomised controlled trial of cardiovascular risk management within a UK multiethnic setting (ADDITION-Leicester). DESIGN: A single-blind cluster randomised, parallel group trial among people with screen detected T2DM comparing a protocol driven intensive multi-factorial treatment with conventional care. METHODS: ADDITION-Leicester consists of community-based screening and intervention phases within 20 general practices coordinated from a single academic research centre. Screening adopts a universal diagnostic approach via repeated 75g-oral glucose tolerance tests within an eligible non-diabetic population of 66,320 individuals aged 40-75 years (25-75 years South Asian). Volunteers also provide detailed medical and family histories; complete health questionnaires, undergo anthropometric measures, lipid profiling and a proteinuria assessment. Primary outcome is reduction in modelled Coronary Heart Disease (UKPDS CHD) risk at five years. Seven thousand (30% of South Asian ethnic origin) volunteers over three years will be recruited to identify a screen detected T2DM cohort (n = 285) powered to detected a 6% relative difference (80% power, alpha 0.05) between treatment groups at one year. Randomisation will occur at practice-level with newly diagnosed T2DM cases receiving either conventional (according to current national guidelines) or intensive (algorithmic target driven multi-factorial cardiovascular risk intervention) treatments. DISCUSSION: ADDITION-Leicester is the largest multiethnic (targeting >30% South Asian recruitment) community T2DM and vascular risk screening programme in the UK. By assessing feasibility and efficacy of T2DM screening, it will inform national disease prevention policy and contribute significantly to our understanding of the health care needs of UK South Asians. TRIAL REGISTRATION: Clinicaltrial.gov (NCT00318032). PMID- 20170483 TI - Keratoconus associated with choroidal neovascularization: a case report. AB - INTRODUCTION: Keratoconus and choroidal neovascularization can occur as a result of dysfunction of the epithelium and its basement membrane. CASE PRESENTATION: A 17-year-old Asian man, who was diagnosed with myopic choroidal neovascularization in both eyes and who subsequently underwent intravitreal injection of ranibizumab (Lucentis(R)) five times over six months, presented with further vision decrease and pain in his right eye. Examination showed corneal steepening and stromal edema in the inferocentral cornea of his right eye, both of which were indicative of advanced keratoconus with acute hydrops. Corneal topography also showed features consistent with keratoconus in his left eye. Fluorescein angiography and optical coherence tomography revealed choroidal neovascularization-associated subretinal hemorrhages and lacquer cracks in both eyes. CONCLUSION: Keratoconus and choroidal neovascularization, possibly resulting from dysfunction of the epithelium and its basement membrane, can occur together in the same individual. This would suggest a possible connection in pathogenesis between these two conditions. PMID- 20170484 TI - Bacterial diversity and reductive dehalogenase redundancy in a 1,2-dichloroethane degrading bacterial consortium enriched from a contaminated aquifer. AB - BACKGROUND: Bacteria possess a reservoir of metabolic functionalities ready to be exploited for multiple purposes. The use of microorganisms to clean up xenobiotics from polluted ecosystems (e.g. soil and water) represents an eco sustainable and powerful alternative to traditional remediation processes. Recent developments in molecular-biology-based techniques have led to rapid and accurate strategies for monitoring and identification of bacteria and catabolic genes involved in the degradation of xenobiotics, key processes to follow up the activities in situ. RESULTS: We report the characterization of the response of an enriched bacterial community of a 1,2-dichloroethane (1,2-DCA) contaminated aquifer to the spiking with 5 mM lactate as electron donor in microcosm studies. After 15 days of incubation, the microbial community structure was analyzed. The bacterial 16S rRNA gene clone library showed that the most represented phylogenetic group within the consortium was affiliated with the phylum Firmicutes. Among them, known degraders of chlorinated compounds were identified. A reductive dehalogenase genes clone library showed that the community held four phylogenetically-distinct catalytic enzymes, all conserving signature residues previously shown to be linked to 1,2-DCA dehalogenation. CONCLUSIONS: The overall data indicate that the enriched bacterial consortium shares the metabolic functionality between different members of the microbial community and is characterized by a high functional redundancy. These are fundamental features for the maintenance of the community's functionality, especially under stress conditions and suggest the feasibility of a bioremediation treatment with a potential prompt dehalogenation and a process stability over time. PMID- 20170485 TI - Different fetal-neonatal outcomes in siblings born to a mother with Graves Basedow disease after total thyroidectomy: a case series. AB - INTRODUCTION: We describe three different fetal or neonatal outcomes in the offspring of a mother who had persistent circulating thyrotropin receptor antibodies despite having undergone a total thyroidectomy several years before. CASE PRESENTATION: The three different outcomes were an intrauterine death, a mild and transient fetal and neonatal hyperthyroidism and a severe fetal and neonatal hyperthyroidism that required specific therapy. CONCLUSIONS: The three cases are interesting because of the different outcomes, the absence of a direct correlation between thyrotropin receptor antibody levels and clinical signs, and the persistence of thyrotropin receptor antibodies several years after a total thyroidectomy. PMID- 20170486 TI - Novel induced mlo mutant alleles in combination with site-directed mutagenesis reveal functionally important domains in the heptahelical barley Mlo protein. AB - BACKGROUND: Recessively inherited natural and induced mutations in the barley Mlo gene confer durable broad-spectrum resistance against the powdery mildew pathogen, Blumeria graminis f.sp. hordei. Mlo codes for a member of a plant specific family of polytopic integral membrane proteins with unknown biochemical activity. Resistant barley mlo mutant alleles identify amino acid residues that are critical for Mlo function in the context of powdery mildew susceptibility. RESULTS: We molecularly analyzed a novel set of induced barley mlo mutants and used site-directed mutagenesis in combination with transient gene expression to unravel novel amino acid residues of functional significance. We integrate these results with previous findings to map functionally important regions of the heptahelical Mlo protein. Our data reveal the second and third cytoplasmic loop as being particularly sensitive to functional impediment by mutational perturbation, suggesting that these regions are critical for the susceptibility conferring activity of the Mlo protein. In contrast, only mutations in the second but not the third cytoplasmic loop appear to trigger the Endoplasmic Reticulum localized quality control machinery that ensures the biogenesis of properly folded membrane proteins. CONCLUSION: Our findings identify functionally important regions of the polytopic barley Mlo protein and reveal the differential sensitivity of individual protein domains to cellular quality control. PMID- 20170487 TI - Resource utilization and outcome at a university versus a community teaching hospital in tPA treated stroke patients: a retrospective cohort study. AB - BACKGROUND: Comparing patterns of resource utilization between hospitals is often complicated by biases in community and patient populations. Stroke patients treated with tissue plasminogen activator (tPA) provide a particularly homogenous population for comparison because of strict eligibility criteria for treatment. We tested whether resource utilization would be similar in this homogenous population between two hospitals located in a single Midwestern US community by comparing use of diagnostic testing and associated outcomes following treatment with t-PA. METHODS: Medical records from 206 consecutive intravenous t-PA-treated stroke patients from two teaching hospitals (one university, one community-based) were reviewed. Patient demographics, clinical characteristics and outcome were analyzed, as were the frequency of use of CT, MRI, MRA, echocardiography, angiography, and EEG. RESULTS: Seventy-nine and 127 stroke patients received t-PA at the university and community hospitals, respectively. The two patient populations were demographically similar. There were no differences in stroke severity. All outcomes were similar at both hospitals. Utilization of CT scans, and non-invasive carotid and cardiac imaging studies were similar at both hospitals; however, brain MR, TEE, and catheter angiography were used more frequently at the university hospital. EEG was obtained more often at the community hospital. CONCLUSIONS: Utilization of advanced brain imaging and invasive diagnostic testing was greater at the university hospital, but was not associated with improved clinical outcomes. This could not be explained on the basis of stroke severity or patient characteristics. This variation of practice suggests substantial opportunities exist to reduce costs and improve efficiency of diagnostic resource use as well as reduce patient exposure to risk from diagnostic procedures. PMID- 20170488 TI - Two frequenins in Drosophila: unveiling the evolutionary history of an unusual neuronal calcium sensor (NCS) duplication. AB - BACKGROUND: Drosophila frequenin (Frq), the homolog of the mammalian neuronal calcium sensor-1 (NCS-1), is a high affinity calcium-binding protein with ubiquitous expression in the nervous system. This protein has an important role in the regulation of neurotransmitter release per synapse, axonal growth and bouton formation. In D. melanogaster, frequenin is encoded by two genes (frq1 and frq2), a very unexpected feature in the Frq/NCS-1 subfamily. These genes are located in tandem in the same genomic region, and their products are 95% identical in their amino acid sequence, clearly indicating their recent origin by gene duplication. Here, we have investigated the factors involved in this unusual feature by examining the molecular evolution of the two frq genes in Drosophila and the evolutionary dynamics of NCS family in a large set of bilaterian species. RESULTS: Surprisingly, we have found no amino acid replacements fixed across the twelve Drosophila species surveyed. In contrast, synonymous substitutions have been prevalent in the evolution of the coding region of frq1 and frq2, indicating the presence of strong functional constraints following gene duplication. Despite that, we have detected that significant evolutionary rate acceleration had occurred in Frq1 in early times from the duplication, in which positive selection (likely promoting functional diversification) had probably an important role. The analysis of sequence conservation and DNA topology at the non-coding regions of both genes has allowed the identification of DNA regions candidates to be cis regulatory elements. The results reveal a possible mechanism of regulatory diversification between frq1 and frq2. CONCLUSIONS: The presence of two frequenins in Drosophila and the rapid accumulation of amino acid substitutions after gene duplication are very unusual features in the evolution of the Frq/NCS 1 subfamily. Here we show that the action of positive selection in concordance with some extent of regulatory diversification might explain these findings. Selected amino acid substitutions in Frq1 likely contributed to the functional divergence between the two duplicates, which, in turn, should have diverged in their regulation by ecdysone-induced early genes. PMID- 20170489 TI - Oxygen consumption is depressed in patients with lactic acidosis due to biguanide intoxication. AB - INTRODUCTION: Lactic acidosis can develop during biguanide (metformin and phenformin) intoxication, possibly as a consequence of mitochondrial dysfunction. To verify this hypothesis, we investigated whether body oxygen consumption (VO2), that primarily depends on mitochondrial respiration, is depressed in patients with biguanide intoxication. METHODS: Multicentre retrospective analysis of data collected from 24 patients with lactic acidosis (pH 6.93 +/- 0.20; lactate 18 +/- 6 mM at hospital admission) due to metformin (n = 23) or phenformin (n = 1) intoxication. In 11 patients, VO2 was computed as the product of simultaneously recorded arterio-venous difference in O2 content [C(a-v)O2] and cardiac index (CI). In 13 additional cases, C(a-v)O2, but not CI, was available. RESULTS: On day 1, VO2 was markedly depressed (67 +/- 28 ml/min/m2) despite a normal CI (3.4 +/- 1.2 L/min/m2). C(a-v)O2 was abnormally low in both patients either with (2.0 +/- 1.0 ml O2/100 ml) or without (2.5 +/- 1.1 ml O2/100 ml) CI (and VO2) monitoring. Clearance of the accumulated drug was associated with the resolution of lactic acidosis and a parallel increase in VO2 (P < 0.001) and C(a-v)O2 (P < 0.05). Plasma lactate and VO2 were inversely correlated (R2 0.43; P < 0.001, n = 32). CONCLUSIONS: VO2 is abnormally low in patients with lactic acidosis due to biguanide intoxication. This finding is in line with the hypothesis of inhibited mitochondrial respiration and consequent hyperlactatemia. PMID- 20170490 TI - Neo-adjuvant chemo-radiation of rectal cancer with volumetric modulated arc therapy: summary of technical and dosimetric features and early clinical experience. AB - BACKGROUND: To report about initial technical and clinical experience in preoperative radiation treatment of rectal cancer with volumetric modulated arcs with the RapidArc (RA) technology. METHODS: Twenty-five consecutive patients (pts) were treated with RA. All showed locally advanced rectal adenocarcinoma with stage T2-T4, N0-1. Dose prescription was 44 Gy in 22 fractions (or 45 Gy in 25 fractions). Delivery was performed with single arc with a 6 MV photon beam. Twenty patients were treated preoperatively, five did not receive surgery. Twenty three patients received concomitant chemotherapy with oral capecitabine. A comparison with a cohort of twenty patients with similar characteristics treated with conformal therapy (3DC) is presented as well. RESULTS: From a dosimetric point of view, RA improved conformality of doses (CI95% = 1.1 vs. 1.4 for RA and 3DC), presented similar target coverage with lower maximum doses, significant sparing of femurs and significant reduction of integral and mean dose to healthy tissue. From the clinical point of view, surgical reports resulted in a down staging in 41% of cases. Acute toxicity was limited to Grade 1-2 diarrhoea in 40% and Grade 3 in 8% of RA pts, 45% and 5% of 3DC pts, compatible with known effects of concomitant chemotherapy. RA treatments were performed with an average of 2.0 vs. 3.4 min of 3DC. CONCLUSION: RA proved to be a safe, qualitatively advantageous treatment modality for rectal cancer, showing some improved results in dosimetric aspects. PMID- 20170491 TI - Immune signatures in human PBMCs of idiotypic vaccine for HCV-related lymphoproliferative disorders. AB - Hepatitis C virus (HCV) is one of the major risk factors for chronic hepatitis, which may progress to cirrhosis and hepatocellular carcinoma, as well as for type II mixed cryoglobulinemia (MC), which may further evolve into an overt B-cell non Hodgkin's lymphoma (NHL). It has been previously shown that B-cell receptor (BCR) repertoire, expressed by clonal B-cells involved in type II MC as well as in HCV associated NHL, is constrained to a limited number of variable heavy (VH)- and light (VL)-chain genes. Among these, the VK3-20 light chain idiotype has been selected as a possible target for passive as well as active immunization strategy. In the present study, we describe the results of a multiparametric analysis of the innate and early adaptive immune response after ex vivo stimulation of human immune cells with the VK3-20 protein. This objective has been pursued by implementing high-throughput technologies such as multiparameter flow cytometry and multiplex analysis of cytokines and chemokines. PMID- 20170492 TI - Chronic pain associated with the Chikungunya Fever: long lasting burden of an acute illness. AB - BACKGROUND: Chikungunya virus (CHIKV) is responsible for major epidemics worldwide. Autochthonous cases were recently reported in several European countries. Acute infection is thought to be monophasic. However reports on chronic pain related to CHIKV infection have been made. In particular, the fact that many of these patients do not respond well to usual analgesics suggests that the nature of chronic pain may be not only nociceptive but also neuropathic. Neuropathic pain syndromes require specific treatment and the identification of neuropathic characteristics (NC) in a pain syndrome is a major step towards pain control. METHODS: We carried out a cross-sectional study at the end of the major two-wave outbreak lasting 17 months in Reunion Island. We assessed pain in 106 patients seeking general practitioners with confirmed infection with the CHIK virus, and evaluated its impact on quality of life (QoL). RESULTS: The mean intensity of pain on the visual-analogical scale (VAS) was 5.8 +/- 2.1, and its mean duration was 89 +/- 2 days. Fifty-six patients fulfilled the definition of chronic pain. Pain had NC in 18.9% according to the DN4 questionnaire. Conversely, about two thirds (65%) of patients with NC had chronic pain. The average pain intensity was similar between patients with or without NC (6.0 +/- 1.7 vs 6.1 +/- 2.0). However, the total score of the Short Form-McGill Pain Questionnaire (SF-MPQ)(15.5 +/- 5.2 vs 11.6 +/- 5.2; p < 0.01) and both the affective (18.8 +/- 6.2 vs 13.4 +/- 6.7; p < 0.01) and sensory subscores (34.3 +/ 10.7 vs 25.0 +/- 9.9; p < 0.01) were significantly higher in patients with NC. The mean pain interference in life activities calculated from the Brief Pain Inventory (BPI) was significantly higher in patients with chronic pain than in patients without it (6.8 +/- 1.9 vs 5.9 +/- 1.9, p < 0.05). This score was also significantly higher in patients with NC than in those without such a feature (7.2 +/- 1.5 vs 6.1 +/- 1.9, p < 0.05). CONCLUSIONS: There exists a specific chronic pain condition associated to CHIKV. Pain with NC seems to be associated with more aggressive clinical picture, more intense impact in QoL and more challenging pharmacological treatment. PMID- 20170493 TI - A statistical framework for differential network analysis from microarray data. AB - BACKGROUND: It has been long well known that genes do not act alone; rather groups of genes act in consort during a biological process. Consequently, the expression levels of genes are dependent on each other. Experimental techniques to detect such interacting pairs of genes have been in place for quite some time. With the advent of microarray technology, newer computational techniques to detect such interaction or association between gene expressions are being proposed which lead to an association network. While most microarray analyses look for genes that are differentially expressed, it is of potentially greater significance to identify how entire association network structures change between two or more biological settings, say normal versus diseased cell types. RESULTS: We provide a recipe for conducting a differential analysis of networks constructed from microarray data under two experimental settings. At the core of our approach lies a connectivity score that represents the strength of genetic association or interaction between two genes. We use this score to propose formal statistical tests for each of following queries: (i) whether the overall modular structures of the two networks are different, (ii) whether the connectivity of a particular set of "interesting genes" has changed between the two networks, and (iii) whether the connectivity of a given single gene has changed between the two networks. A number of examples of this score is provided. We carried out our method on two types of simulated data: Gaussian networks and networks based on differential equations. We show that, for appropriate choices of the connectivity scores and tuning parameters, our method works well on simulated data. We also analyze a real data set involving normal versus heavy mice and identify an interesting set of genes that may play key roles in obesity. CONCLUSIONS: Examining changes in network structure can provide valuable information about the underlying biochemical pathways. Differential network analysis with appropriate connectivity scores is a useful tool in exploring changes in network structures under different biological conditions. An R package of our tests can be downloaded from the supplementary website http://www.somnathdatta.org/Supp/DNA. PMID- 20170494 TI - Subolesin expression in response to pathogen infection in ticks. AB - BACKGROUND: Ticks (Acari: Ixodidae) are vectors of pathogens worldwide that cause diseases in humans and animals. Ticks and pathogens have co-evolved molecular mechanisms that contribute to their mutual development and survival. Subolesin was discovered as a tick protective antigen and was subsequently shown to be similar in structure and function to akirins, an evolutionarily conserved group of proteins in insects and vertebrates that controls NF-kB-dependent and independent expression of innate immune response genes. The objective of this study was to investigate subolesin expression in several tick species infected with a variety of pathogens and to determine the effect of subolesin gene knockdown on pathogen infection. In the first experiment, subolesin expression was characterized in ticks experimentally infected with the cattle pathogen, Anaplasma marginale. Subolesin expression was then characterized in questing or feeding adult ticks confirmed to be infected with Anaplasma, Ehrlichia, Rickettsia, Babesia or Theileria spp. Finally, the effect of subolesin knockdown by RNA interference (RNAi) on tick infection was analyzed in Dermacentor variabilis males exposed to various pathogens by capillary feeding (CF). RESULTS: Subolesin expression increased with pathogen infection in the salivary glands but not in the guts of tick vector species infected with A. marginale. When analyzed in whole ticks, subolesin expression varied between tick species and in response to different pathogens. As reported previously, subolesin knockdown in D. variabilis infected with A. marginale and other tick-borne pathogens resulted in lower infection levels, while infection with Francisella tularensis increased in ticks after RNAi. When non-tick-borne pathogens were fed to ticks by CF, subolesin RNAi did not affect or resulted in lower infection levels in ticks. However, subolesin expression was upregulated in D. variabilis exposed to Escherichia coli, suggesting that although this pathogen may induce subolesin expression in ticks, silencing of this molecule reduced bacterial multiplication by a presently unknown mechanism. CONCLUSIONS: Subolesin expression in infected ticks suggested that subolesin may be functionally important for tick innate immunity to pathogens, as has been reported for the akirins. However, subolesin expression and consequently subolesin-mediated innate immunity varied with the pathogen and tick tissue. Subolesin may plays a role in tick innate immunity in the salivary glands by limiting pathogen infection levels, but activates innate immunity only for some pathogen in the guts and other tissues. In addition, these results provided additional support for the role of subolesin in other molecular pathways including those required for tissue development and function and for pathogen infection and multiplication in ticks. Consequently, RNAi experiments demonstrated that subolesin knockdown in ticks may affect pathogen infection directly by reducing tick innate immunity that results in higher infection levels and indirectly by affecting tissue structure and function and the expression of genes that interfere with pathogen infection and multiplication. The impact of the direct or indirect effects of subolesin knockdown on pathogen infection may depend on several factors including specific tick-pathogen molecular interactions, pathogen life cycle in the tick and unknown mechanisms affected by subolesin function in the control of global gene expression in ticks. PMID- 20170495 TI - Increased susceptibility of Huh7 cells to HCV replication does not require mutations in RIG-I. AB - BACKGROUND: The cytosolic retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor that senses HCV double-stranded RNA and triggers type I interferon pathways. The clone Huh7.5 of human hepatoma Huh7 cells contains a mutation in RIG-I that is believed to be responsible for the improved replication of HCV in these cells relative to the parental strain. We hypothesized that, in addition to RIG-I, other determinant(s) outside the RIG-I coding sequence are involved in limiting HCV replication in cell culture. To test our hypothesis, we analyzed Huh7 cell clones that support the efficient replication of HCV and analyzed the RIG-I gene. RESULTS: One clone, termed Huh7D, was more permissive for HCV replication and more efficient for HCV-neomycin and HCV-hygromycin based replicon colony formation than parental Huh7 cells. Nucleotide sequence analysis of the RIG-I mRNA coding region from Huh7D cells showed no mutations relative to Huh7 parental cells. CONCLUSIONS: We derived a new Huh7 cell line, Huh7D, which is more permissive for HCV replication than parental Huh7 cells. The higher permissiveness of Huh7D cells is not due to mutations in the RIG-I protein, indicating that cellular determinants other than the RIG-I amino-acid sequence are responsible for controlling HCV replication. In addition, we have selected Huh7 cells resistant to hygromycin via newly generated HCV-replicons carrying the hygromycin resistant gene. Further studies on Huh7D cells will allow the identification of cellular factors that increased the susceptibility to HCV infection, which could be targeted for anti-HCV therapies. PMID- 20170496 TI - Treatment of menopausal symptoms by an extract from the roots of rhapontic rhubarb: the role of estrogen receptors. AB - A dry extract from the roots of rhapontic rhubarb (extract Rheum rhaponticum (L.); ERr) has been commercially available in Germany for over two decades to treat menopausal symptoms. However, the molecular basis of its clinical effectiveness remains obscure. This article reviews the in vitro and in vivo data of its estrogenic actions, particularly those mediated by estrogen receptor-beta (ERbeta). PMID- 20170497 TI - Anti-inflammatory activity of nanocrystalline silver-derived solutions in porcine contact dermatitis. AB - BACKGROUND: Nanocrystalline silver dressings have anti-inflammatory activity, unlike solutions containing Ag+ only, which may be due to dissolution of multiple silver species. These dressings can only be used to treat surfaces. Thus, silver containing solutions with nanocrystalline silver properties could be valuable for treating hard-to-dress surfaces and inflammatory conditions of the lungs and bowels. This study tested nanocrystalline silver-derived solutions for anti inflammatory activity. METHODS: Inflammation was induced on porcine backs using dinitrochlorobenzene. Negative and positive controls were treated with distilled water. Experimental groups were treated with solutions generated by dissolving nanocrystalline silver in distilled water adjusted to starting pHs of 4 (using CO2), 5.6 (as is), 7, and 9 (using Ca(OH)2). Solution samples were analyzed for total silver. Daily imaging, biopsying, erythema and oedema scoring, and treatments were performed for three days. Biopsies were processed for histology, immunohistochemistry (for IL-4, IL-8, IL-10, TNF-alpha, EGF, KGF, KGF-2, and apoptotic cells), and zymography (MMP-2 and -9). One-way ANOVAs with Tukey-Kramer post tests were used for statistical analyses. RESULTS: Animals treated with pH 7 and 9 solutions showed clear visual improvements. pH 9 solutions resulted in the most significant reductions in erythema and oedema scores. pH 4 and 7 solutions also reduced oedema scores. Histologically, all treatment groups demonstrated enhanced re-epithelialisation, with decreased inflammation. At 24 h, pMMP-2 expression was significantly lowered with pH 5.6 and 9 treatments, as was aMMP-2 expression with pH 9 treatments. In general, treatment with silver-containing solutions resulted in decreased TNF-alpha and IL-8 expression, with increased IL 4, EGF, KGF, and KGF-2 expression. At 24 h, apoptotic cells were detected mostly in the dermis with pH 4 and 9 treatments, nowhere with pH 5.6, and in both the epidermis and dermis with pH 7. Solution anti-inflammatory activity did not correlate with total silver content, as pH 4 solutions contained significantly more silver than all others. CONCLUSIONS: Nanocrystalline silver-derived solutions appear to have anti-inflammatory/pro-healing activity, particularly with a starting pH of 9. Solutions generated differently may have varying concentrations of different silver species, only some of which are anti inflammatory. Nanocrystalline silver-derived solutions show promise for a variety of anti-inflammatory treatment applications. PMID- 20170498 TI - An interprofessional approach to improving paediatric medication safety. AB - BACKGROUND: Safe drug prescribing and administration are essential elements within undergraduate healthcare curricula, but medication errors, especially in paediatric practice, continue to compromise patient safety. In this area of clinical care, collective responsibility, team working and communication between health professionals have been identified as key elements in safe clinical practice. To date, there is limited research evidence as to how best to deliver teaching and learning of these competencies to practitioners of the future. METHODS: An interprofessional workshop to facilitate learning of knowledge, core competencies, communication and team working skills in paediatric drug prescribing and administration at undergraduate level was developed and evaluated. The practical, ward-based workshop was delivered to 4th year medical and 3rd year nursing students and evaluated using a pre and post workshop questionnaire with open-ended response questions. RESULTS: Following the workshop, students reported an increase in their knowledge and awareness of paediatric medication safety and the causes of medication errors (p < 0.001), with the greatest increase noted among medical students. Highly significant changes in students' attitudes to shared learning were observed, indicating that safe medication practice is learnt more effectively with students from other healthcare disciplines. Qualitative data revealed that students' participation in the workshop improved communication and teamworking skills, and led to greater awareness of the role of other healthcare professionals. CONCLUSION: This study has helped bridge the knowledge-skills gap, demonstrating how an interprofessional approach to drug prescribing and administration has the potential to improve quality and safety within healthcare. PMID- 20170499 TI - Characterization of Phi2954, a newly isolated bacteriophage containing three dsRNA genomic segments. AB - BACKGROUND: Bacteriophage Phi12 is a member of the Cystoviridae and is distinct from Phi6, the first member of that family. We have recently isolated a number of related phages and five showed high similarity to Phi12 in the amino acid sequences of several proteins. Bacteriophage Phi2954 is a member of this group. RESULTS: Phi2954 was isolated from radish leaves and was found to have a genome of three segments of double-stranded RNA (dsRNA), placing it in the Cystoviridae. The base sequences for many of the genes and for the segment termini were similar but not identical to those of bacteriophage Phi12. However, the host specificity was for the type IV pili of Pseudomonas syringae HB10Y rather than for the rough LPS to which Phi12 attaches. Reverse genetics techniques enabled the production of infectious phage from cDNA copies of the genome. Phage were constructed with one, two or three genomic segments. Phage were also produced with altered transcriptional regulation. Although the pac sequences of Phi2954 show no similarity to those of Phi12, segment M of Phi2954 could be acquired by Phi12 resulting in a change of host specificity. CONCLUSIONS: We have isolated a new member of the bacteriophage family Cystoviridae and find that although it shows similarity to other members of the family, it has unique properties that help to elucidate viral strategies for genomic packaging and gene expression. PMID- 20170500 TI - The impact of genetic relationship information on genomic breeding values in German Holstein cattle. AB - BACKGROUND: The impact of additive-genetic relationships captured by single nucleotide polymorphisms (SNPs) on the accuracy of genomic breeding values (GEBVs) has been demonstrated, but recent studies on data obtained from Holstein populations have ignored this fact. However, this impact and the accuracy of GEBVs due to linkage disequilibrium (LD), which is fairly persistent over generations, must be known to implement future breeding programs. MATERIALS AND METHODS: The data set used to investigate these questions consisted of 3,863 German Holstein bulls genotyped for 54,001 SNPs, their pedigree and daughter yield deviations for milk yield, fat yield, protein yield and somatic cell score. A cross-validation methodology was applied, where the maximum additive-genetic relationship (amax) between bulls in training and validation was controlled. GEBVs were estimated by a Bayesian model averaging approach (BayesB) and an animal model using the genomic relationship matrix (G-BLUP). The accuracy of GEBVs due to LD was estimated by a regression approach using accuracy of GEBVs and accuracy of pedigree-based BLUP-EBVs. RESULTS: Accuracy of GEBVs obtained by both BayesB and G-BLUP decreased with decreasing amax for all traits analyzed. The decay of accuracy tended to be larger for G-BLUP and with smaller training size. Differences between BayesB and G-BLUP became evident for the accuracy due to LD, where BayesB clearly outperformed G-BLUP with increasing training size. CONCLUSIONS: GEBV accuracy of current selection candidates varies due to different additive-genetic relationships relative to the training data. Accuracy of future candidates can be lower than reported in previous studies because information from close relatives will not be available when selection on GEBVs is applied. A Bayesian model averaging approach exploits LD information considerably better than G-BLUP and thus is the most promising method. Cross-validations should account for family structure in the data to allow for long-lasting genomic based breeding plans in animal and plant breeding. PMID- 20170501 TI - An optimal control theory approach to non-pharmaceutical interventions. AB - BACKGROUND: Non-pharmaceutical interventions (NPI) are the first line of defense against pandemic influenza. These interventions dampen virus spread by reducing contact between infected and susceptible persons. Because they curtail essential societal activities, they must be applied judiciously. Optimal control theory is an approach for modeling and balancing competing objectives such as epidemic spread and NPI cost. METHODS: We apply optimal control on an epidemiologic compartmental model to develop triggers for NPI implementation. The objective is to minimize expected person-days lost from influenza related deaths and NPI implementations for the model. We perform a multivariate sensitivity analysis based on Latin Hypercube Sampling to study the effects of input parameters on the optimal control policy. Additional studies investigated the effects of departures from the modeling assumptions, including exponential terminal time and linear NPI implementation cost. RESULTS: An optimal policy is derived for the control model using a linear NPI implementation cost. Linear cost leads to a "bang-bang" policy in which NPIs are applied at maximum strength when certain state criteria are met. Multivariate sensitivity analyses are presented which indicate that NPI cost, death rate, and recovery rate are influential in determining the policy structure. Further death rate, basic reproductive number and recovery rate are the most influential in determining the expected cumulative death. When applying the NPI policy, the cumulative deaths under exponential and gamma terminal times are close, which implies that the outcome of applying the "bang-bang" policy is insensitive to the exponential assumption. Quadratic cost leads to a multi-level policy in which NPIs are applied at varying strength levels, again based on certain state criteria. Results indicate that linear cost leads to more costly implementation resulting in fewer deaths. CONCLUSIONS: The application of optimal control theory can provide valuable insight to developing effective control strategies for pandemic. Our findings highlight the importance of establishing a sensitive and timely surveillance system for pandemic preparedness. PMID- 20170502 TI - A group-randomized controlled trial for health promotion in Girl Scouts: healthier troops in a SNAP (Scouting Nutrition & Activity Program). AB - BACKGROUND: Girl Scouting may offer a viable channel for health promotion and obesity prevention programs. This study evaluated the effectiveness of an intervention program delivered through Girl Scout Junior troops that was designed to foster healthful troop meeting environments and increase obesity prevention behaviors at home. METHODS: Seven Girl Scout troops were randomized to intervention (n = 3, with 34 girls) or standard-care control (n = 4, with 42 girls) conditions. Girls ranged in age from 9 to 13 years (mean 10.5 years). Intervention troop leaders were trained to implement policies promoting physical activity (PA) and healthful eating opportunities at troop meetings, and to implement a curriculum promoting obesity-prevention behaviors at home. The primary outcome variable was child body mass index (BMI) z-score. Secondary outcomes included accelerometer-assessed PA levels in troop meetings, direct observations of snack offerings, time spent in physically active meeting content, and leader encouragement of PA and healthful eating. RESULTS: The intervention was delivered with good fidelity, and intervention troops provided greater opportunities for healthful eating and PA (x2 = 210.8, p < .001), relative to control troops. In troop meetings, intervention troop leaders promoted PA (x2 = 23.46, p < .001) and healthful eating (x2 = 18.14, p < .001) more frequently, and discouraged healthful eating and PA less frequently (x2 = 9.63, p = .002) compared to control troop leaders. Most effects of the intervention on individual level variables of girls and parents were not significantly different from the control condition, including the primary outcome of child BMI z-score (F1, 5 = 0.42, p = .544), parent BMI (F1, 5 = 1.58, p = .264), and related behavioral variables. The notable exception was for objectively assessed troop PA, wherein girls in intervention troops accumulated significantly less sedentary (x2 = 6.3, p = .011), significantly more moderate (x2 = 8.2, p = .004), and more moderate-to vigorous physical activity, (x2 = 18.4, p < .001), than girls in control troops. CONCLUSIONS: Implementing a health promotion curriculum and supporting policies to provide more healthful environments in Girl Scout troop meetings appears feasible on a broader scale. Additional work is needed to bridge health promotion from such settings to other environments if lasting individual-level behavior change and obesity prevention remain targeted outcomes. TRIAL REGISTRATION NUMBER: NCT00949637. PMID- 20170503 TI - Performance of mixed effects models in the analysis of mediated longitudinal data. AB - BACKGROUND: Linear mixed effects models (LMMs) are a common approach for analyzing longitudinal data in a variety of settings. Although LMMs may be applied to complex data structures, such as settings where mediators are present, it is unclear whether they perform well relative to methods for mediational analyses such as structural equation models (SEMs), which have obvious appeal in such settings. For some researchers, SEMs may be more difficult than LMMs to implement, e.g. due to lack of training in the methodology or the need for specialized SEM software. It therefore is of interest to evaluate whether the LMM performs sufficiently in a scenario particularly suitable for SEMs. We focus on evaluation of the total effect (i.e. direct and indirect) of an exposure on an outcome of interest when a mediating factor is present. Our aim is to explore whether the LMM performs as well as the SEM in a setting that is conducive to using the SEM. METHODS: We simulated mediated longitudinal data from an SEM where a binary, main independent variable has both direct and indirect effects on a continuous outcome. We conducted analyses with both the LMM and SEM to evaluate the performance of the LMM in a setting where the SEM is expected to be preferable. Models were evaluated with respect to bias, coverage probability and power. Sample size, effect size and error distribution of the simulated data were varied. RESULTS: Both models performed well in a range of settings. Marginal increases in power estimates were observed for the SEM, although generally there were no major differences in performance. Power for both models was good with a sample of size of 250 and a small to medium effect size. Bias did not substantially increase for either model when data were generated from distributions that were both skewed and kurtotic. CONCLUSIONS: In settings where the goal is to evaluate the overall effects, the LMM excluding mediating variables appears to have good performance with respect to power, bias and coverage probability relative to the SEM. The major benefit of SEMs is that it simultaneously and efficiently models both the direct and indirect effects of the mediation process. PMID- 20170504 TI - Independent mobility, perceptions of the built environment and children's participation in play, active travel and structured exercise and sport: the PEACH Project. AB - BACKGROUND: Independent mobility (IM) and perceptions of the built environment may relate differentially to children's participation in various physical activity contexts. This cross-sectional study investigated whether independent mobility and perceptions of the built environment in boys and girls were related to physical activity in three different contexts (outdoor play, structured exercise/sport, active commuting). METHODS: Thirteen hundred and seven 10-11 year old boys and girls from 23 schools in a large UK city completed a computerised questionnaire. Independent variables in logistic regression analyses were weekly self-reported frequency of participation in outdoor play, structured exercise/sport and mode of travel home from school. Dependent variables were perceptions of the environment (aesthetics, nuisance, safety, social norm, constraint, play space, accessibility), local and area independent mobility and linear distance from home to school. Analyses were adjusted for body mass index, minutes of daylight after school, level of neighbourhood deprivation and pubertal status. RESULTS: For boys, local independent mobility (Local-IM) was related to an increased likelihood of everyday participation in play (OR 1.58: 95% CI 1.19 2.10), structured exercise/sport (OR 1.42: 1.06-1.89) and active commuting (OR 1.40: 1.07-1.87) but was only related to active commuting for girls (OR1.49: 1.07 2.07). Boys and girls were more likely to report playing out every day if they had higher scores for Social Norm (Boys: OR 1.63 (1.12-2.37); Girls: OR 1.53 (1.01-2.31)) and, for girls only, more positive perceptions of traffic safety (OR 1.63: 1.14-2.34). Easy access to a range of destinations was the dominant predictor for taking part in structured exercise/sport everyday (Boys: OR 1.62 (1.01-2.66); Girls: OR 1.65 (1.07-2.53)). Shorter distance from home to school (OR 0.99: 0.98-0.99) and, for boys only, greater perceived accessibility (OR 1.87: 1.04-3.36) were significantly related to active commuting to school. CONCLUSIONS: Perceptions of the physical environment relate differently to different physical activity contexts and by gender. The only consistent correlate for outdoor play, structured ex/sport and active commuting was higher independent mobility to visit local destinations (Local-IM) for boys. Considering both the physical activity context and its independent correlates should improve the specificity of physical activity interventions in children. PMID- 20170506 TI - External costs of atmospheric Pb emissions: valuation of neurotoxic impacts due to inhalation. AB - BACKGROUND: The Impact Pathway Approach (IPA) is an innovative methodology to establish links between emissions, related impacts and monetary estimates. Only few attempts have so far been presented regarding emissions of metals; in this study the external costs of airborne lead (Pb) emissions are assessed using the IPA. Exposure to Pb is known to provoke impacts especially on children's cognition. As cognitive abilities (measured as IQ, intelligence quotient) are known to have implications for lifetime income, a pathway can be established leading from figures for Pb emissions to the implied loss in earnings, and on this basis damage costs per unit of Pb emission can be assessed. METHODS: Different types of models are here linked. It is relatively straightforward to establish the relationship between Pb emissions and consequent increase in air-Pb concentration, by means of a Gaussian plume dispersion model (OML). The exposed population can then be modelled by linking the OML-output to population data nested in geo-referenced grid cells. Less straightforward is to establish the relationship between exposure to air-Pb concentrations and the resulting blood-Pb concentration. Here an Age-Dependent Biokinetic Model (ADBM) for Pb is applied. On basis of previous research which established links between increases in blood Pb concentrations during childhood and resulting IQ-loss we arrive at our results. RESULTS: External costs of Pb airborne emissions, even at low doses, in our site are in the range of 41-83 euro/kg emitted Pb, depending on the considered meteorological year. This estimate applies only to the initial effects of air-Pb, as our study does not address the effects due to the Pb environmental accumulation and to the subsequent Pb re-exposure. These are likely to be between one and two orders of magnitude higher. CONCLUSIONS: Biokinetic modelling is a novel tool not previously included when applying the IPA to explore impacts of Pb emissions and related external costs; it allows for more fine-tuned, age dependent figures for the external costs from low-dose exposure. Valuation of additional health effects and impacts e.g. due to exposure via ingestion appear to be feasible when extending the insights from the present pilot study. PMID- 20170505 TI - Bisphosphonates and risk of atrial fibrillation: a meta-analysis. AB - INTRODUCTION: Bisphosphonates are the most commonly used drugs for the prevention and treatment of osteoporosis. Although a recent FDA review of the results of clinical trials reported no clear link between bisphosphonates and serious or non serious atrial fibrillation (AF), some epidemiologic studies have suggested an association between AF and bisphosphonates. METHODS: We conducted a meta-analysis of non-experimental studies to evaluate the risk of AF associated with bisphosphonates. Studies were identified by searching MEDLINE and EMBASE using a combination of the Medical Subject Headings and keywords. Our search was limited to English language articles. The pooled estimates of odds ratios (OR) as a measure of effect size were calculated using a random effects model. RESULTS: Seven eligible studies with 266,761 patients were identified: three cohort, three case-control, and one self-controlled case series. Bisphosphonate exposure was not associated with an increased risk of AF [pooled multivariate OR 1.04, 95% confidence interval (CI) 0.92-1.16] after adjusting for known risk factors. Moderate heterogeneity was noted (I-squared score = 62.8%). Stratified analyses by study design, cohort versus case-control studies, yielded similar results. Egger's and Begg's tests did not suggest an evidence of publication bias (P = 0.90, 1.00 respectively). No clear asymmetry was observed in the funnel plot analysis. Few studies compared risk between bisphosphonates or by dosing. CONCLUSIONS: Our study did not find an association between bisphosphonate exposure and AF. This finding is consistent with the FDA's statement. PMID- 20170507 TI - Neighbourhood physical activity environments and adiposity in children and mothers: a three-year longitudinal study. AB - BACKGROUND: Although neighbourhood environments are often blamed for contributing to rising levels of obesity, current evidence is based predominantly on cross sectional samples. This study examined associations between objectively-measured environmental characteristics of neighbourhoods and adiposity cross-sectionally and longitudinally over three years in children and their female carers. METHODS: Longitudinal study of 140 5-6 year-old and 269 10-12 year-old children and their female carers (n = 369). At baseline (2001) and follow-up (2004), height and weight were measured among children and self-reported among female carers, and were used to compute BMI z-scores and BMI, respectively. A Geographic Information System determined access to destinations (public open spaces, sports options, walking/cycling tracks), road connectivity (density of cul-de-sacs and intersections, proportion of 4-way intersections, length of 'access' paths (overpasses, access lanes, throughways between buildings)) and traffic exposure (length of 'busy' and 'local' roads) within 800 m and 2 km of home. Univariate and multivariable linear regression analyses examined associations between environmental characteristics and BMI/BMI z-scores at baseline and change in BMI/BMI z-scores over the three years. RESULTS: Cross-sectionally, BMI z-score was inversely associated with length (km) of access paths within 800 m (b = 0.50) and 2 km (b = -0.16) among younger and number of sport/recreation public open spaces (b = -0.14) and length (km) of 'access' paths (b = -0.94) within 800 m and length of local roads within 2 km (b = -0.01) among older children. Among female carers, BMI was associated with length (km) of walking/cycling tracks (b = 0.17) and busy roads (b = -0.34) within 800 m. Longitudinally, the proportion of intersections that were 4-way (b = -0.01) within 800 m of home was negatively associated with change in BMI z-score among younger children, while length (km) of access paths (b = 0.18) within 800 m was significant among older children. Among female carers, options for aerobics/fitness and swimming within 2 km were associated with change in BMI (B = -0.42). CONCLUSION: A small number of neighbourhood environment features were associated with adiposity outcomes. These differed by age group and neighbourhood scale (800 m and 2 km) and were inconsistent between cross-sectional and longitudinal findings. However, the results suggest that improvements to road connectivity and slowing traffic and provision of facilities for leisure activities popular among women may support obesity prevention efforts. PMID- 20170508 TI - Retrotransposition and mutation events yield Rap1 GTPases with differential signalling capacity. AB - BACKGROUND: Retrotransposition of mRNA transcripts gives occasionally rise to functional retrogenes. Through acquiring tempero-spatial expression patterns distinct from their parental genes and/or functional mutations in their coding sequences, such retrogenes may in principle reshape signalling networks. RESULTS: Here we present evidence for such a scenario, involving retrogenes of Rap1 belonging to the Ras family of small GTPases. We identified two murine and one human-specific retrogene of Rap1A and Rap1B, which encode proteins that differ by only a few amino acids from their parental Rap1 proteins. Markedly, human hRap1B retro and mouse mRap1A-retro1 acquired mutations in the 12th and 59th amino acids, respectively, corresponding to residues mutated in constitutively active oncogenic Ras proteins. Statistical and structural analyses support a functional evolution scenario, where Rap1 isoforms of retrogenic origin are functionally distinct from their parental proteins. Indeed, all retrogene-encoded GTPases have an increased GTP/GDP binding ratio in vivo, indicating that their conformations resemble that of active GTP-bound Rap1. We furthermore demonstrate that these three Rap1 isoforms exhibit distinct affinities for the Ras-binding domain of RalGDS. Finally, when tested for their capacity to induce key cellular processes like integrin-mediated cell adhesion or cell spreading, marked differences are seen. CONCLUSIONS: Together, these data lend strong support for an evolution scenario, where retrotransposition and subsequent mutation events generated species-specific Rap1 isoforms with differential signaling potential. Expression of the constitutively active human Rap1B-retro in cells like those derived from Ramos Burkitt's lymphoma and bone marrow from a patient with myelodysplastic syndrome (MDS) warrants further investigation into its role in disease development. PMID- 20170509 TI - Characterization of rubber particles and rubber chain elongation in Taraxacum koksaghyz. AB - BACKGROUND: Natural rubber is a biopolymer with exceptional qualities that cannot be completely replaced using synthetic alternatives. Although several key enzymes in the rubber biosynthetic pathway have been isolated, mainly from plants such as Hevea brasiliensis, Ficus spec. and the desert shrub Parthenium argentatum, there have been no in planta functional studies, e.g. by RNA interference, due to the absence of efficient and reproducible protocols for genetic engineering. In contrast, the Russian dandelion Taraxacum koksaghyz, which has long been considered as a potential alternative source of low-cost natural rubber, has a rapid life cycle and can be genetically transformed using a simple and reliable procedure. However, there is very little molecular data available for either the rubber polymer itself or its biosynthesis in T. koksaghyz. RESULTS: We established a method for the purification of rubber particles--the active sites of rubber biosynthesis--from T. koksaghyz latex. Photon correlation spectroscopy and transmission electron microscopy revealed an average particle size of 320 nm, and 13C nuclear magnetic resonance (NMR) spectroscopy confirmed that isolated rubber particles contain poly(cis-1,4-isoprene) with a purity > 95%. Size exclusion chromatography indicated that the weight average molecular mass (Mw) of T. koksaghyz natural rubber is 4,000-5,000 kDa. Rubber particles showed rubber transferase activity of 0.2 pmol min(-1) mg(-1). Ex vivo rubber biosynthesis experiments resulted in a skewed unimodal distribution of [1-14C]isopentenyl pyrophosphate (IPP) incorporation at a M of 2,500 kDa. Characterization of recently isolated cis-prenyltransferases (CPTs) from T. koksaghyz revealed that these enzymes are associated with rubber particles and are able to produce long chain polyprenols in yeast. CONCLUSIONS: T. koksaghyz rubber particles are similar to those described for H. brasiliensis. They contain very pure, high molecular mass poly(cis-1,4-isoprene) and the chain elongation process can be studied ex vivo. Because of their localization on rubber particles and their activity in yeast, we propose that the recently described T. koksaghyz CPTs are the major rubber chain elongating enzymes in this species. T. koksaghyz is amenable to genetic analysis and modification, and therefore could be used as a model species for the investigation and comparison of rubber biosynthesis. PMID- 20170510 TI - Waist circumference cut-off values for the prediction of cardiovascular risk factors clustering in Chinese school-aged children: a cross-sectional study. AB - BACKGROUND: Waist circumference has been identified as a valuable predictor of cardiovascular risk in children. The development of waist circumference percentiles and cut-offs for various ethnic groups are necessary because of differences in body composition. The purpose of this study was to develop waist circumference percentiles for Chinese children and to explore optimal waist circumference cut-off values for predicting cardiovascular risk factors clustering in this population. METHODS: Height, weight, and waist circumference were measured in 5529 children (2830 boys and 2699 girls) aged 6-12 years randomly selected from southern and northern China. Blood pressure, fasting triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and glucose were obtained in a subsample (n = 1845). Smoothed percentile curves were produced using the LMS method. Receiver-operating characteristic analysis was used to derive the optimal age- and gender-specific waist circumference thresholds for predicting the clustering of cardiovascular risk factors. RESULTS: Gender-specific waist circumference percentiles were constructed. The waist circumference thresholds were at the 90th and 84th percentiles for Chinese boys and girls respectively, with sensitivity and specificity ranging from 67% to 83%. The odds ratio of a clustering of cardiovascular risk factors among boys and girls with a higher value than cut-off points was 10.349 (95% confidence interval 4.466 to 23.979) and 8.084 (95% confidence interval 3.147 to 20.767) compared with their counterparts. CONCLUSIONS: Percentile curves for waist circumference of Chinese children are provided. The cut-off point for waist circumference to predict cardiovascular risk factors clustering is at the 90th and 84th percentiles for Chinese boys and girls, respectively. PMID- 20170511 TI - Feasibility of physical map construction from fingerprinted bacterial artificial chromosome libraries of polyploid plant species. AB - BACKGROUND: The presence of closely related genomes in polyploid species makes the assembly of total genomic sequence from shotgun sequence reads produced by the current sequencing platforms exceedingly difficult, if not impossible. Genomes of polyploid species could be sequenced following the ordered-clone sequencing approach employing contigs of bacterial artificial chromosome (BAC) clones and BAC-based physical maps. Although BAC contigs can currently be constructed for virtually any diploid organism with the SNaPshot high-information content-fingerprinting (HICF) technology, it is currently unknown if this is also true for polyploid species. It is possible that BAC clones from orthologous regions of homoeologous chromosomes would share numerous restriction fragments and be therefore included into common contigs. Because of this and other concerns, physical mapping utilizing the SNaPshot HICF of BAC libraries of polyploid species has not been pursued and the possibility of doing so has not been assessed. The sole exception has been in common wheat, an allohexaploid in which it is possible to construct single-chromosome or single-chromosome-arm BAC libraries from DNA of flow-sorted chromosomes and bypass the obstacles created by polyploidy. RESULTS: The potential of the SNaPshot HICF technology for physical mapping of polyploid plants utilizing global BAC libraries was evaluated by assembling contigs of fingerprinted clones in an in silico merged BAC library composed of single-chromosome libraries of two wheat homoeologous chromosome arms, 3AS and 3DS, and complete chromosome 3B. Because the chromosome arm origin of each clone was known, it was possible to estimate the fidelity of contig assembly. On average 97.78% or more clones, depending on the library, were from a single chromosome arm. A large portion of the remaining clones was shown to be library contamination from other chromosomes, a feature that is unavoidable during the construction of single-chromosome BAC libraries. CONCLUSIONS: The negligibly low level of incorporation of clones from homoeologous chromosome arms into a contig during contig assembly suggested that it is feasible to construct contigs and physical maps using global BAC libraries of wheat and almost certainly also of other plant polyploid species with genome sizes comparable to that of wheat. Because of the high purity of the resulting assembled contigs, they can be directly used for genome sequencing. It is currently unknown but possible that equally good BAC contigs can be also constructed for polyploid species containing smaller, more gene-rich genomes. PMID- 20170512 TI - Upstream molecular signaling pathways of p27(Kip1) expression: effects of 4 hydroxytamoxifen, dexamethasone, and retinoic acids. AB - BACKGROUND: p27(Kip1) is a cyclin-dependent kinase inhibitor that inhibits G1-to S phase transition of the cell cycle. It is known that a relatively large number of nutritional and chemopreventive anti-cancer agents specifically up-regulate expression of p27 without directly affecting the expression of other G1-to-S phase cell cycle regulatory proteins including p21(Cip1Waf1). However, the upstream molecular signaling pathways of how these agents up-regulate the expression of p27 have not been well characterized. The objective of this study was to identify such pathways in human breast cancer cells in vitro using 4 hydroxytamoxifen, dexamethasone, and various retinoic acids as examples of such anti-cancer agents. RESULTS: Experimental evidence presented in the first half of this report was obtained by transfecting human breast cancer cells in vitro with proximal upstream region of p27 gene-luciferase reporter plasmids. 1) The evidence indicated that 4-hydroxytamoxifen, dexamethasone, and various retinoic acids up-regulated expression of p27 in both estrogen receptor-positive and negative human breast cancer cells in vitro. 2) The degree of up-regulation of p27 expression by these anti-cancer agents in human breast cancer cells in vitro linearly correlated with the degree of inhibition of methylnitrosourea (MNU) induced rat mammary adenocarcinoma in vivo. 3) Lastly, up-regulation of the expression of p27 was likely due to the activation of translation initiation rather than transcription of p27 gene. The experimental evidence presented in the second half of this report was obtained by a combination of Western immunoblot analysis and transfection analysis. It indicated that 4-hydroxytamoxifen and dexamethasone up-regulated expression of p27 by down-regulating phosphorylation of eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) at Ser65 and this phosphorylation was likely to be mediated by upstream receptor tyrosine kinases/phosphoinositide-3-kinase/Akt/5'-AMP-activated protein kinase/mammalian target of rapamycin (RTKs/PI3K/Akt/AMPK/mTOR) protein kinase signaling pathways. Retinoic acids up-regulated expression of p27 without using either 4E-BP1 or RTKs/PI3K/Akt/AMPK/mTOR protein kinase signaling pathways. CONCLUSIONS: 4-Hydroxytamoxifen and dexamethasone up-regulated translation initiation of p27 by down-regulating 4E-BP1 phosphorylated at Ser65 and this down regulation seemed to be mediated by upstream RTKs/PI3K/Akt/AMPK/mTOR protein kinase signaling pathways. Retinoic acids also up-regulated translation initiation of p27, but without using any of these pathways. PMID- 20170513 TI - Structural classification by the Lipase Engineering Database: a case study of Candida antarctica lipase A. AB - BACKGROUND: The Lipase Engineering Database (LED) integrates information on sequence, structure and function of lipases, esterases and related proteins with the alpha/beta hydrolase fold. A new superfamily for Candida antarctica lipase A (CALA) was introduced including the recently published crystal structure of CALA. Since CALA has a highly divergent sequence in comparison to other alpha/beta hydrolases, the Lipase Engineering Database was used to classify CALA in the frame of the already established classification system. This involved the comparison of CALA to similar structures as well as sequence-based comparisons against the content of the LED. RESULTS: The new release 3.0 (December 2009) of the Lipase Engineering Database contains 24783 sequence entries for 18585 proteins as well as 656 experimentally determined protein structures, including the structure of CALA. In comparison to the previous release 1 with 4322 protein and 167 structure entries this update represents a significant increase in data volume. By comparing CALA to representative structures from all superfamilies, a structure from the deacetylase superfamily was found to be most similar to the structure of CALA. While the alpha/beta hydrolase fold is conserved in both proteins, the major difference is found in the cap region. Sequence alignments between both proteins show a sequence similarity of only 15%. A multisequence alignment of both protein families was used to create hidden Markov models for the cap region of CALA and showed that the cap region of CALA is unique among all other proteins of the alpha/beta hydrolase fold. By specifically comparing the substrate binding pocket of CALA to other binding pockets of alpha/beta hydrolases, the binding pocket of Candida rugosa lipase was identified as being highly similar. This similarity also applied to the lid of Candida rugosa lipase in comparison to the potential lid of CALA. CONCLUSION: The LED serves as a valuable tool for the systematic analysis of single proteins or protein families. The updated release 3.0 was used for the evaluation of alpha/beta hydrolases. The HTML version of the database with new features is available at http://www.led.uni stuttgart.de and provides sequences, structures and a set of analysis tools including phylogenetic trees and HMM profiles. PMID- 20170514 TI - Short versus standard treatment with pegylated interferon alfa-2A plus ribavirin in patients with hepatitis C virus genotype 2 or 3: the cleo trial. AB - BACKGROUND: In patients with chronic hepatitis C virus (HCV) genotype 2 or 3, 24 weeks' treatment with pegylated interferon alfa (PEG-IFN-alpha) and ribavirin induces a sustained virological response (SVR) in almost 80% of cases. Evidence suggests that a similar response rate may be obtained with shorter treatment periods, especially in patients with a rapid virological response (RVR). The aim of this study was to compare the efficacy of 12 or 24 weeks of treatment in patients with chronic HCV genotype 2 or 3 and to identify patients suitable for 12 weeks treatment. METHODS: Two hundred and ten patients received PEG-IFN-alpha 2a (180 ug/week) and ribavirin (800-1200 mg/day) for 4 weeks. Patients with a RVR (HCV RNA not detectable) were randomized (1:1) to either 12 (group A1) or 24 (group A2) weeks of combination therapy. Patients without a RVR continued with 24 weeks' combination therapy (group B). HCV RNA was monitored at weeks 4, 8, 12, and 24, and at week 24 post-treatment. RESULTS: At study end, end of treatment response (ETR) was observed in 62 (86%) patients of group A1 and in 55 (77%) patients of group A2 (p < 0.05) Relapse rate was 3% each in groups A1 and A2, and 6% in group B. Among patients with a HCVRNA test 24 weeks after the end of treatment, SVR was observed in 60 (83%) of group A1 patients and in 53 (75%) of group A2 patients. Rapid virological response, low baseline HCV RNA levels, elevated alanine aminotransferase levels and low fibrosis score, were the strongest covariates associated with SVR, independent of HCV genotype. No baseline characteristic was associated with relapse. CONCLUSION: In HCV patients with genotype 2 or 3, 12-week combination therapy is as efficacious as 24-week therapy and several independent covariates were predictive of SVR. TRIAL REGISTRATION: Trial number ISRCTN29259563. PMID- 20170515 TI - Can primary optimal cytoreduction be predicted in advanced epithelial ovarian cancer preoperatively? AB - INTRODUCTION: Prediction of optimal cytoreduction in patients with advanced epithelial ovarian caner preoperatively. METHODS: Patients with advanced epithelial ovarian cancer who underwent surgery for the first time from Jan. to June 2008 at gynecologic oncology ward of TUMS (Tehran University of Medical Sciences) were eligible for this study. The possibility of predicting primary optimal cytoreduction considering multiple variables was evaluated. Variables were peritoneal carcinomatosis, serum CA125, ascites, pleural effusion, physical status and imaging findings.Univariate comparisons of patients underwent suboptimal cytoreduction carried out using Fisher's exact test for each of the potential predictors. The wilcoxon rank sum test was used to compare variables between patients with optimal versus suboptimal cytoreduction. RESULTS: 41 patients met study inclusion criteria. Statistically significant association was noted between peritoneal carcinomatosis and suboptimal cytoreduction. There were no statistically significant differences between physical status, pleural effusion, imaging findings, serum CA125 and ascites of individuals with optimal cytoreduction compared to those with suboptimal cytoreduction. CONCLUSIONS: Because of small populations in our study the results are not reproducible in alternate populations. Only the patient who is most unlikely to undergo optimal cytoreduction should be offered neoadjuvant chemotherapy, unless her medical condition renders her unsuitable for primary surgery. PMID- 20170516 TI - SING: subgraph search in non-homogeneous graphs. AB - BACKGROUND: Finding the subgraphs of a graph database that are isomorphic to a given query graph has practical applications in several fields, from cheminformatics to image understanding. Since subgraph isomorphism is a computationally hard problem, indexing techniques have been intensively exploited to speed up the process. Such systems filter out those graphs which cannot contain the query, and apply a subgraph isomorphism algorithm to each residual candidate graph. The applicability of such systems is limited to databases of small graphs, because their filtering power degrades on large graphs. RESULTS: In this paper, SING (Subgraph search In Non-homogeneous Graphs), a novel indexing system able to cope with large graphs, is presented. The method uses the notion of feature, which can be a small subgraph, subtree or path. Each graph in the database is annotated with the set of all its features. The key point is to make use of feature locality information. This idea is used to both improve the filtering performance and speed up the subgraph isomorphism task. CONCLUSIONS: Extensive tests on chemical compounds, biological networks and synthetic graphs show that the proposed system outperforms the most popular systems in query time over databases of medium and large graphs. Other specific tests show that the proposed system is effective for single large graphs. PMID- 20170517 TI - "The non-ischemic repair" as a safe alternative method for repair of anterior post-infarction VSD. AB - Patient's myocardium with post-infarction ventricular septum defect (VSD) is characterized by severe dysfunction. The "additive ischemia" caused by the operating process of cross-clamp ischemia and reperfusion injury, has a significant aggravation to the myocardium and overall negative impact to patient's outcome. We present a useful, safe and advantageous methodology in order to abolish "the toxic phase" of ischemia-reperfusion which is adopted by most as the "classic repair method" of myocardial protection. This abolition is in our opinion, particularly beneficial in order to reverse postoperatively the Low Cardiac Output Syndrome (LOS) and achieve better short and long term results. By using this method we avoid the aortic occlusion, the use of systematic hypothermia and any cardioplegic arrest. Furthermore, the total cardio-pulmonary bypass (CPB) time is significantly reduced, tissue debridement and stitching is much easier and safer. We think the method is applicable for every anterior and apical case of post-infarction septum rupture. After application of method in 3 patients with anterior post-myocardial infarction VSD, we are convinced that the patient will have a better postoperative haemodynamic condition and therefore a better outcome. PMID- 20170518 TI - SEL1L deficiency impairs growth and differentiation of pancreatic epithelial cells. AB - BACKGROUND: The vertebrate pancreas contains islet, acinar and ductal cells. These cells derive from a transient pool of multipotent pancreatic progenitors during embryonic development. Insight into the genetic determinants regulating pancreatic organogenesis will help the development of cell-based therapies for the treatment of diabetes mellitus. Suppressor enhancer lin12/Notch 1 like (Sel1l) encodes a cytoplasmic protein that is highly expressed in the developing mouse pancreas. However, the morphological and molecular events regulated by Sel1l remain elusive. RESULTS: We have characterized the pancreatic phenotype of mice carrying a gene trap mutation in Sel1l. We show that Sel1l expression in the developing pancreas coincides with differentiation of the endocrine and exocrine lineages. Mice homozygous for the gene trap mutation die prenatally and display an impaired pancreatic epithelial morphology and cell differentiation. The pancreatic epithelial cells of Sel1l mutant embryos are confined to the progenitor cell state throughout the secondary transition. Pharmacological inhibition of Notch signaling partially rescues the pancreatic phenotype of Sel1l mutant embryos. CONCLUSIONS: Together, these data suggest that Sel1l is essential for the growth and differentiation of endoderm-derived pancreatic epithelial cells during mouse embryonic development. PMID- 20170519 TI - User-centered virtual environment design for virtual rehabilitation. AB - BACKGROUND: As physical and cognitive rehabilitation protocols utilizing virtual environments transition from single applications to comprehensive rehabilitation programs there is a need for a new design cycle methodology. Current human computer interaction designs focus on usability without benchmarking technology within a user-in-the-loop design cycle. The field of virtual rehabilitation is unique in that determining the efficacy of this genre of computer-aided therapies requires prior knowledge of technology issues that may confound patient outcome measures. Benchmarking the technology (e.g., displays or data gloves) using healthy controls may provide a means of characterizing the "normal" performance range of the virtual rehabilitation system. This standard not only allows therapists to select appropriate technology for use with their patient populations, it also allows them to account for technology limitations when assessing treatment efficacy. METHODS: An overview of the proposed user-centered design cycle is given. Comparisons of two optical see-through head-worn displays provide an example of benchmarking techniques. Benchmarks were obtained using a novel vision test capable of measuring a user's stereoacuity while wearing different types of head-worn displays. Results from healthy participants who performed both virtual and real-world versions of the stereoacuity test are discussed with respect to virtual rehabilitation design. RESULTS: The user centered design cycle argues for benchmarking to precede virtual environment construction, especially for therapeutic applications. Results from real-world testing illustrate the general limitations in stereoacuity attained when viewing content using a head-worn display. Further, the stereoacuity vision benchmark test highlights differences in user performance when utilizing a similar style of head-worn display. These results support the need for including benchmarks as a means of better understanding user outcomes, especially for patient populations. CONCLUSIONS: The stereoacuity testing confirms that without benchmarking in the design cycle poor user performance could be misconstrued as resulting from the participant's injury state. Thus, a user-centered design cycle that includes benchmarking for the different sensory modalities is recommended for accurate interpretation of the efficacy of the virtual environment based rehabilitation programs. PMID- 20170520 TI - Maternal characteristics associated with the dietary intake of nitrates, nitrites, and nitrosamines in women of child-bearing age: a cross-sectional study. AB - BACKGROUND: Multiple N-nitroso compounds have been observed in animal studies to be both mutagenic and teratogenic. Human exposure to N-nitroso compounds and their precursors, nitrates and nitrites, can occur through exogenous sources, such as diet, drinking water, occupation, or environmental exposures, and through endogenous exposures resulting from the formation of N-nitroso compounds in the body. Very little information is available on intake of nitrates, nitrites, and nitrosamines and factors related to increased consumption of these compounds. METHODS: Using survey and dietary intake information from control women (with deliveries of live births without major congenital malformations during 1997 2004) who participated in the National Birth Defects Prevention Study (NBDPS), we examined the relation between various maternal characteristics and intake of nitrates, nitrites, and nitrosamines from dietary sources. Estimated intake of these compounds was obtained from the Willet Food Frequency Questionnaire as adapted for the NBDPS. Multinomial logistic regression models were used to estimate odds ratios and 95% confidence intervals for the consumption of these compounds by self-reported race/ethnicity and other maternal characteristics. RESULTS: Median intake per day for nitrates, nitrites, total nitrites (nitrites + 5% nitrates), and nitrosamines was estimated at 40.48 mg, 1.53 mg, 3.69 mg, and 0.472 microg respectively. With the lowest quartile of intake as the referent category and controlling for daily caloric intake, factors predicting intake of these compounds included maternal race/ethnicity, education, body mass index, household income, area of residence, folate intake, and percent of daily calories from dietary fat. Non-Hispanic White participants were less likely to consume nitrates, nitrites, and total nitrites per day, but more likely to consume dietary nitrosamines than other participants that participated in the NBDPS. Primary food sources of these compounds also varied by maternal race/ethnicity. CONCLUSIONS: Results of this study indicate that intake of nitrates, nitrites, and nitrosamines vary considerably by race/ethnicity, education, body mass index, and other characteristics. Further research is needed regarding how consumption of foods high in nitrosamines and N-nitroso precursors might relate to risk of adverse pregnancy outcomes and chronic diseases. PMID- 20170521 TI - Replacing the wild type loxP site in BACs from the public domain with lox66 using a lox66 transposon. AB - BACKGROUND: Chromatin adjoining the site of integration of a transgene affects expression and renders comparisons of closely related transgenes, such as those derived from a BAC deletion series retrofitted with enhancer-traps, unreliable. Gene targeting to a pre-determined site on the chromosome is likely to alleviate the problem. FINDINGS: A general procedure to replace the loxP site located at one end of genomic DNA inserts in BACs with lox66 is described. Truncating insert DNA from the loxP end with a Tn10 transposon carrying a lox66 site simultaneously substitutes the loxP with a lox66 sequence. The replacement occurs with high stringency, and the procedure should be applicable to all BACs in the public domain. Cre recombination of loxP with lox66 or lox71 was found to be as efficient as another loxP site during phage P1 transduction of small plasmids containing those sites. However the end-deletion of insert DNA in BACs using a lox66 transposon occurred at no more than 20% the efficiency observed with a loxP transposon. Differences in the ability of Cre protein available at different stages of the P1 life cycle to recombine identical versus non-identical lox-sites is likely responsible for this discrepancy. A possible mechanism to explain these findings is discussed. CONCLUSIONS: The loxP/lox66 replacement procedure should allow targeting BACs to a pre-positioned lox71 site in zebrafish chromosomes; a system where homologous recombination-mediated "knock-in" technology is unavailable. PMID- 20170522 TI - The use of LeptiCore in reducing fat gain and managing weight loss in patients with metabolic syndrome. AB - BACKGROUND: LeptiCore is a proprietary combination of various ingredients which have been shown to have properties which could be beneficial to weight loss in obese and overweight human subjects. This study evaluates the effect of Lepticore on bodyweight as well as parameters associated with obesity and metabolic syndrome. METHODS: The study was an 8 week randomized, double-blind, placebo controlled design involving 92 obese (mean BMI > 30 kg/m2) participants (37 males; 55 females; ages 19-52; mean age = 30.7). The participants were randomly divided into three groups: placebo (n = 30), LeptiCore formula A (low dose) (n = 31) and LeptiCore formula B (high dose) (n = 31). Capsules containing the placebo or active formulations were administered twice daily before meals with 300 ml of water. None of the participants followed any specific diet nor took any weight reducing medications for the duration of the study. A total of 12 anthropomorphic and serological measurements were taken at the beginning of the study and after 2, 4, 6, and 8 weeks of treatment. RESULTS: Compared to the placebo group, the two active groups showed statistically significant differences on all 12 variables by week 8. These included four anthropomorphic variables (body weight, body fat, waist and hip size) and eight measures of serological levels (plasma total cholesterol, LDL, HDL, triglycerides, blood glucose, serotonin, leptin, C reactive protein). The two active groups also showed significant intra-group differences on all 12 variables between study onset and week 8. CONCLUSION: The LeptiCore formulation at both the low and high dosages appears to be helpful in the management of fat gain and its related complications. The higher dosage resulted in significantly greater reductions in body weight and triglyceride, blood glucose, and C-reactive protein levels, as well as increased serotonin levels. PMID- 20170523 TI - Addison's disease presenting with idiopathic intracranial hypertension in 24-year old woman: a case report. AB - INTRODUCTION: Idiopathic intracranial hypertension can rarely be associated with an underlying endocrine disorder such as Cushing's syndrome, hyperthyroidism, or with administration of thyroxine or growth hormone. Though cases of idiopathic intracranial hypertension associated with Addison's disease in children have been reported, there is only one documented case report of this association in adults. We describe a case of an acute adrenal insufficiency precipitated by idiopathic intracranial hypertension in a Caucasian female. CASE PRESENTATION: A 24-year-old Caucasian woman was acutely unwell with a background of several months of generalised fatigue and intermittent headaches. She had unremarkable neurological and systemic examination with a normal computerised tomography and magnetic resonance imaging of the brain. Normal cerebrospinal fluid but increased opening pressure at lumbar puncture suggested intracranial hypertension. A flat short synacthen test and raised level of adrenocorticotrophic hormone were consistent with primary adrenal failure. CONCLUSION: Addison's disease can remain unrecognised until precipitated by acute stress. This case suggests that idiopathic intracranial hypertension can rarely be associated with Addison's disease and present as an acute illness. Idiopathic intracranial hypertension is possibly related to an increase in the levels of arginine vasopressin peptide in serum and cerebrospinal fluid secondary to a glucocorticoid deficient state. PMID- 20170524 TI - Frequency and diversity of small cryptic plasmids in the genus Rahnella. AB - BACKGROUND: Rahnella is a widely distributed genus belonging to the Enterobacteriaceae and frequently present on vegetables. Although Rahnella has interesting agro-economical and industrial properties and several strains possess antibiotic resistances and toxin genes which might spread within microbial communities, little is known about plasmids of this genus. Thus, we isolated a number of Rahnella strains and investigated their complements of small plasmids. RESULTS: In total 53 strains were investigated and 11 plasmids observed. Seven belonged to the ColE1 family; one was ColE2-like and three shared homology to rolling circle plasmids. One of them belonged to the pC194/pUB110 family and two showed similarity to poorly characterised plasmid groups. The G+C content of two rolling circle plasmids deviated considerably from that of Rahnella, indicating that their usual hosts might belong to other genera. Most ColE1-like plasmids formed a subgroup within the ColE1 family that seems to be fairly specific for Rahnella. Intriguingly, the multimer resolution sites of all ColE1-like plasmids had the same orientation with respect to the origin of replication. This arrangement might be necessary to prevent inappropriate synthesis of a small regulatory RNA that regulates cell division. Although the ColE1-like plasmids did not possess any mobilisation system, they shared large parts with high sequence identity in coding and non-coding regions. In addition, highly homologous regions of plasmids isolated from Rahnella and the chromosomes of Erwinia tasmaniensis and Photorhabdus luminescens could be identified. CONCLUSIONS: For the genus Rahnella we observed plasmid-containing isolates at a frequency of 19%, which is in the average range for Enterobacteriaceae. These plasmids belonged to different groups with members of the ColE1-family most frequently found. Regions of striking sequence homology of plasmids and bacterial chromosomes highlight the importance of plasmids for lateral gene transfer (including chromosomal sequences) to distinct genera. PMID- 20170525 TI - Statin-associated weakness in myasthenia gravis: a case report. AB - INTRODUCTION: Myasthenia gravis is a commonly undiagnosed condition in the elderly. Statin medications can cause weakness and are linked to the development and deterioration of several autoimmune conditions, including myasthenia gravis. CASE PRESENTATION: We report the case of a 60-year-old Caucasian man who presented with acute onset of dysarthria and dysphagia initially attributed to a brain stem stroke. Oculobulbar and limb weakness progressed until myasthenia gravis was diagnosed and treated, and until statin therapy was finally withdrawn. CONCLUSION: Myasthenia gravis may be underappreciated as a cause of acute bulbar weakness among the elderly. Statin therapy appeared to have contributed to the weakness in our patient who was diagnosed with myasthenia gravis. PMID- 20170526 TI - Apolipoprotein-E forms dimers in human frontal cortex and hippocampus. AB - BACKGROUND: Apolipoprotein-E (apoE) plays important roles in neurobiology and the apoE4 isoform increases risk for Alzheimer's disease (AD). ApoE3 and apoE2 are known to form disulphide-linked dimers in plasma and cerebrospinal fluid whereas apoE4 cannot form these dimers as it lacks a cysteine residue. Previous in vitro research indicates dimerisation of apoE3 has a significant impact on its functions related to cholesterol homeostasis and amyloid-beta peptide degradation. The possible occurrence of apoE dimers in cortical tissues has not been examined and was therefore assessed. Human frontal cortex and hippocampus from control and AD post-mortem samples were homogenised and analysed for apoE by western blotting under both reducing and non-reducing conditions. RESULTS: In apoE3 homozygous samples, approximately 12% of apoE was present as a homodimer and approximately 2% was detected as a 43 kDa heterodimer. The level of dimerisation was not significantly different when control and AD samples were compared. As expected, these dimerised forms of apoE were not detected in apoE4 homozygous samples but were detected in apoE3/4 heterozygotes at a level approximately 60% lower than seen in the apoE3 homozygous samples. Similar apoE3 dimers were also detected in lysates of SK-N-SH neuroblastoma cells and in freshly prepared rabbit brain homogenates. The addition of the thiol trapping agent, iodoacetamide, to block reactive thiols during both human and rabbit brain sample homogenisation and processing did not reduce the amount of apoE homodimer recovered. These data indicate that the apoE dimers we detected in the human brain are not likely to be post-mortem artefacts. CONCLUSION: The identification of disulphide-linked apoE dimers in human cortical and hippocampal tissues represents a distinct structural difference between the apoE3 and apoE4 isoforms that may have functional consequences. PMID- 20170528 TI - Using breath carbon monoxide to validate self-reported tobacco smoking in remote Australian Indigenous communities. AB - BACKGROUND: This paper examines the specificity and sensitivity of a breath carbon monoxide (BCO) test and optimum BCO cutoff level for validating self reported tobacco smoking in Indigenous Australians in Arnhem Land, Northern Territory (NT). METHODS: In a sample of 400 people (>/=16 years) interviewed about tobacco use in three communities, both self-reported smoking and BCO data were recorded for 309 study participants. Of these, 249 reported smoking tobacco within the preceding 24 hours, and 60 reported they had never smoked or had not smoked tobacco for >/=6 months. The sample was opportunistically recruited using quotas to reflect age and gender balances in the communities where the combined Indigenous populations comprised 1,104 males and 1,215 females (>/=16 years). Local Indigenous research workers assisted researchers in interviewing participants and facilitating BCO tests using a portable hand-held analyzer. RESULTS: A BCO cutoff of >/=7 parts per million (ppm) provided good agreement between self-report and BCO (96.0% sensitivity, 93.3% specificity). An alternative cutoff of >/=5 ppm increased sensitivity from 96.0% to 99.6% with no change in specificity (93.3%). With data for two self-reported nonsmokers who also reported that they smoked cannabis removed from the analysis, specificity increased to 96.6%. CONCLUSION: In these disadvantaged Indigenous populations, where data describing smoking are few, testing for BCO provides a practical, noninvasive, and immediate method to validate self-reported smoking. In further studies of tobacco smoking in these populations, cannabis use should be considered where self-reported nonsmokers show high BCO. PMID- 20170527 TI - Epidemiology of burn injuries in the East Mediterranean Region: a systematic review. AB - BACKGROUND: Burn injuries remain one of the leading causes of injury morbidity and mortality in the World Health Organization's East Mediterranean Region. To provide an overview on the epidemiology of burn injuries in this region, a systematic review was undertaken. METHODS: Medline, Embase and CINAHL were searched for publications on burns in this region published between 01/01/1997 and 16/4/2007. Data were extracted to a standard spreadsheet and synthesised using a narrative synthesis. No attempt has been made to quantitatively synthesise the data due to the large degree of clinical heterogeneity between study populations. RESULTS: Seventy one studies were included in the review, from 12 countries. Burn injuries were found to be one of the leading causes of injury morbidity and mortality. The reported incidence of burns ranged from 112 to 518 per 100,000 per year. Burn victims were more frequently young and approximately one third of the victims were children aged 0-5 years. Hospital mortality ranged from 5 to 37%, but was commonly above 20%. Intentional self-harm burns particularly involving women were common in some countries of the region and were associated with a very high mortality of up to 79%. CONCLUSION: Burn injuries remain an important public health issue in the East Mediterranean Region therefore further research is required to investigate the problem and assess the effectiveness of intervention programmes. PMID- 20170529 TI - Surveillance of febrile patients in a district and evaluation of their spatiotemporal associations: a pilot study. AB - BACKGROUND: Fever is an undifferentiated clinical feature that may enhance the sensitivity of syndromic surveillance systems. By studying the spatiotemporal associations of febrile patients, it may allow early detection of case clustering that indicates imminent threat of infectious disease outbreaks in the community. METHODS: We captured consecutive emergency department visits that led to hospitalization in a district hospital in Hong Kong during the period of 12 Sep 2005 to 14 Oct 2005. We recorded demographic data, provisional diagnoses, temperature on presentation and residential location for each patient-episode, and geocoded the residential addresses. We applied Geographical Information System technology to study the geographical distribution these cases, and their associations within a 50-m buffer zone spatially. A case cluster was defined by three or more spatially associated febrile patients within each three consecutive days. RESULTS: One thousand and sixty six patient-episodes were eligible for analysis; 42% of them had fever (>37 degrees C; oral temperature) on presentation. Two hundred and four patient-episodes (19.1%) came from residential care homes for elderly (RCHE). We detected a total of 40 case clusters during the study period. Clustered cases were of older age; 57 (33.3%) were residents of RCHE. We found a median of 3 patients (range: 3 - 8) and time span of 3 days (range: 2 - 8 days) in each cluster. Twenty five clusters had 2 or more patients living in the same building block; 18 of them were from RCHE. CONCLUSIONS: It is technically feasible to perform surveillance on febrile patients and studying their spatiotemporal associations. The information is potentially useful for early detection of impending infectious disease threats. PMID- 20170530 TI - Hepatitis B virus X protein upregulates HSP90alpha expression via activation of c Myc in human hepatocarcinoma cell line, HepG2. AB - BACKGROUND: The Hepatitis B Virus X protein (HBx) plays a major role in hepatocellular carcinoma (HCC) development, however, its contribution to tumor invasion and metastasis has not been established so far. Heat shock protein 90 alpha (HSP90alpha) isoform is an ATP-dependent molecular chaperone that maintains the active conformation of client oncoproteins in cancer cells, which is abundantly expressed in HCC, especially in hepatitis B virus (HBV)-related tumors, might be involved in tumor progression. METHODS: The levels of HSP90alpha, extracellular signal-regulated kinase 1/2 (ERK1/2), phosphorylated ERK1/2 (p-ERK1/2) and c-Myc in HBx-transfected HepG2 cells were determined by western blots analysis. The endogenous ERKs activity was demonstrated by ELISA assay. The regulation of c-Myc-mediated HSP90 alpha promoter transactivation by HBx was evaluated through electrophoretic mobility shift analysis (EMSA). The c Myc-mediated HSP90alpha transcription was analysed by promoter assay. The HBx expressing cells were transfected with specific small interference RNA (siRNA) against c-Myc. The in vitro invasion potentials of cells were evaluated by Transwell cell invasion assay. RESULTS: HBx induces HSP90alpha expression at the transcription level. The induction effect of HBx was inhibited after treatment with c-Myc inhibitor, 10058-F4. In addition, the luciferase activity of the HSP90alpha promoter analysis revealed that the HBx is directly involved in the c Myc-mediated transcriptional activation of HSP90alpha. Furthermore, HBx induces c Myc expression by activation of Ras/Raf/ERK1/2 cascades, which in turn results in activation of the c-Myc-mediated HSP90alpha promoter and subsequently up regulation of the HSP90alpha expression. Overexpression of HSP90alpha in HBx transfected cells enhances tumor cells invasion. siRNA-mediated c-Myc knockdown in HBx-transfected cells significantly suppressed HSP90alpha expression and cells invasion in vitro. CONCLUSION: These results demonstrate the ability of HBx to promote tumor cells invasion by a mechanism involving the up-regulation of HSP90alpha and provide new insights into the mechanism of action of HBx and its involvement in tumor metastasis and recurrence of HCC. PMID- 20170532 TI - A case of pulmonary tuberculosis presenting as diffuse alveolar haemorrhage: is there a role for anticardiolipin antibodies? AB - BACKGROUND: Diffuse alveolar haemorrhage (DAH) has been rarely reported in association with pulmonary infections. CASE PRESENTATION: We report the case of a 43 year old immunocompetent man presenting with dyspnoea, fever and haemoptysis. Chest imaging showed bilateral ground glass opacities. Microbiological and molecular tests were positive for Mycobacterium tuberculosis and treatment with isoniazid, rifampicin, ethambutol and pyrazinamide was successful. In this case the diagnosis of DAH relies on clinical, radiological and endoscopic findings. Routine blood tests documented the presence of anticardiolipin antibodies. In the reported case the diagnostic criteria of antiphospholipid syndrome were not fulfilled. CONCLUSIONS: The transient presence of anticardiolipin antibodies in association with an unusual clinical presentation of pulmonary tuberculosis is intriguing although a causal relationship cannot be established. PMID- 20170531 TI - Could giardiasis be a risk factor for low zinc status in schoolchildren from northwestern Mexico? A cross-sectional study with longitudinal follow-up. AB - BACKGROUND: Both giardiasis and zinc deficiency are serious health problems worldwide. In Mexico, the prevalence of G. intestinalis was estimated at 32% in 1994. It remains a health problem in northwestern Mexico. Recent surveys (1987, 1995, and 1999) reported zinc deficiency in the Mexican population. The association of giardiasis and malabsorption of micronutrients has been well documented, although the association with zinc remains controversial. This study investigated the association between giardiasis and zinc deficiency in schoolchildren from northwestern Mexico. METHODS: We combined a cross-sectional design with a longitudinal follow-up six months after parasite treatment. The baseline sample consisted of 114 schoolchildren (mean age 8.8 yr) from seven suburban public schools, grouped as Giardia-free (n = 65, 57%) and Giardia infected (n = 49, 43%). Three stool analyses per child were done using Faust's method. Children with giardiasis received secnidazole. Serum zinc was determined by atomic absorption spectrophotometry. Height and weight were measured. Socioeconomic information was obtained in an oral questionnaire, and daily zinc intake was assessed using 24 hour-recalls. Pearson's correlation and ANCOVA and paired t-test analyses were used to determine the association between giardiasis and zinc status. RESULTS: Longitudinal analysis demonstrated a significant increase of the mean serum zinc levels in the Giardia-infected group six months after treatment (13.78 vs. 19.24 mumol/L mumol/L; p = 0.001), although no difference was found between the Giardia-free and the Giardia-infected groups (p = 0.86) in the baseline analysis. Z scores for W/A and H/A were lower in the Giardia-infected than in the Giardia-free group (p < 0.05). No difference was observed in the socioeconomic characteristics and mean daily intakes of zinc between the groups (p > 0.05). CONCLUSIONS: Giardiasis may be a risk factor for zinc deficiency in schoolchildren from northwestern Mexico. PMID- 20170533 TI - Prevalence of genetic polymorphisms in the promoter region of the alpha-1 antitrypsin (SERPINA1) gene in chronic liver disease: a case control study. AB - BACKGROUND: Alpha-1 antitrypsin (A1AT) deficiency, caused by the Z allele (p.E342K) and S allele (p.E264V) in the SERPINA1 gene, can induce liver and pulmonary disease. Different mechanisms appear to be responsible for the pathogenesis of these divergent disease expressions. The c.-1973T >C polymorphism located in the SERPINA1 promoter region is found more frequent in A1AT deficiency patients with liver disease compared to patients with pulmonary disease, but data are lacking regarding contribution to the development of liver diseases caused by other aetiologies. AIM: To study the prevalence of c.-1973T >C, Z allele and S allele in a cohort of patients with liver disease of various aetiologies compared with healthy controls and to evaluate its effect on disease progression. METHODS: A total of 297 patients with liver disease from various aetiologies and 297 age and gender matched healthy controls were included. The c.-1973T >C polymorphism and Z and S alleles of the SERPINA1 gene were analyzed by real-time PCR. RESULTS: c.-1973T >C was similarly distributed between patients with liver disease of various origins and healthy controls. Furthermore, the distribution of c.-1973T >C was independent from aetiology subgroup. In patients with liver disease mean ages at of onset of liver disease were 44.4, 42.3 and 40.7 years for the c.-1973 T/T, T/C and C/C genotype respectively (NS). S allele heterozygosity was increased in patients with drug induced liver injury (DILI), (OR 4.3; 95%CI 1.1 17.2). CONCLUSION: In our study, c.-1973T >C polymorphism was not a risk factor for liver disease of various aetiologies. In addition, S allele heterozygosity might contribute to the development of DILI. PMID- 20170534 TI - Structural alphabets derived from attractors in conformational space. AB - BACKGROUND: The hierarchical and partially redundant nature of protein structures justifies the definition of frequently occurring conformations of short fragments as 'states'. Collections of selected representatives for these states define Structural Alphabets, describing the most typical local conformations within protein structures. These alphabets form a bridge between the string-oriented methods of sequence analysis and the coordinate-oriented methods of protein structure analysis. RESULTS: A Structural Alphabet has been derived by clustering all four-residue fragments of a high-resolution subset of the protein data bank and extracting the high-density states as representative conformational states. Each fragment is uniquely defined by a set of three independent angles corresponding to its degrees of freedom, capturing in simple and intuitive terms the properties of the conformational space. The fragments of the Structural Alphabet are equivalent to the conformational attractors and therefore yield a most informative encoding of proteins. Proteins can be reconstructed within the experimental uncertainty in structure determination and ensembles of structures can be encoded with accuracy and robustness. CONCLUSIONS: The density-based Structural Alphabet provides a novel tool to describe local conformations and it is specifically suitable for application in studies of protein dynamics. PMID- 20170535 TI - Validation of Doloplus-2 among nonverbal nursing home patients--an evaluation of Doloplus-2 in a clinical setting. AB - BACKGROUND: Pain measurement in nonverbal older adults is best based on behavioural observation, e.g. using an observational measurement tool such as Doloplus-2. The purposes of this study were to examine the use of Doloplus-2 in a nonverbal nursing home population, and to evaluate its reliability and validity by comparing registered nurses' estimation of pain with Doloplus-2 scores. METHOD: In this cross-sectional study, Doloplus-2 was used to observe the pain behaviour of patients aged above 65 years who were unable to self-report their pain. Nurses also recorded their perceptions of patient pain (yes, no, don't know) before they used Doloplus-2. Data on demographics, medical diagnoses, and prescribed pain treatment were collected from patient records. Daily life functioning was measured and participants were screened using the Mini Mental State Examination. RESULTS: In total, 77 nursing home patients were included, 75% were women and the mean age was 86 years (SD 6.6, range 68-100). Over 50% were dependent on nursing care to a high or a medium degree, and all were severely cognitively impaired. The percentage of zero scores on Doloplus-2 ranged from 17% (somatic reactions) to 40% (psychosocial reactions). Cronbach's alpha was 0.71 for the total scale. In total, 52% of the patients were judged by nurses to be experiencing pain, compared with 68% when using Doloplus-2 (p = 0.01). For 29% of the sample, nurses were unable to report if the patients were in pain. CONCLUSIONS: In the present study, more patients were categorized as having pain while using Doloplus-2 compared with nurses' estimation of pain without using any tools. The fact that nurses could not report if the patients were in pain in one third of the patients supports the claim that Doloplus-2 is a useful supplement for estimating pain in this population. However, nurses must use their clinical experience in addition to the use of Doloplus-2, as behaviour can have different meaning for different patients. Further research is still needed about the use of Doloplus-2 in patients not able to self-report their pain. PMID- 20170536 TI - Breast cancer incidence and mortality in Tyrol/Austria after fifteen years of opportunistic mammography screening. AB - BACKGROUND: The aim of this study was to analyse breast cancer incidence and mortality in Tyrol from 1970 to 2006, namely after performing more than a decade of opportunistic mammography screening and just before piloting an organised screening programme. Our investigation was conducted on a population level. METHODS: To study time trends in breast cancer incidence and mortality, we applied the age-period-cohort model by Poisson regression to the official mortality data covering more than three decades from 1970 to 2006 and to the incidence data ranging from 1988 to 2006. In addition, for incidence data we analysed data on breast cancer staging and compared these with EU guidelines. RESULTS: For the analysis of time trend in breast cancer mortality in age groups 40-79, an age-period-cohort model fits well and shows for years 2002-2006 a statistically significant reduction of 26% (95% CI 13%-36%) in breast cancer mortality as compared to 1992-1996. We see only slight non-significant increases in breast cancer incidence. For the past five years, incidence data show a 10% proportion of in situ cases, and of 50% for cases in stages II+. CONCLUSIONS: The opportunistic breast cancer screening programme in Tyrol has only in part exploited the mortality reduction known for organised screening programmes. There seems to be potential for further improvement, and we recommend that an organised screening programme and a detailed screening database be introduced to collect all information needed to analyse the quality indicators suggested by the EU guidelines. PMID- 20170537 TI - Destructive effects of smoking on molecular and genetic factors of periodontal disease. AB - Many epidemiological evidences have proven the association between smoking and periodontal disease. The causality can be further established by linking findings of traditional epidemiological studies with the developments in molecular techniques that occurred in the last decade. The present article reviews recent studies that address the effect of smoking on molecular and genetic factors in periodontal disease. Most findings support the fact that tobacco smoking modulates destruction of the periodontium through different pathways: microcirculatory and host immune systems, connective tissue, and bone metabolism. Although smokers experience an increased burden of inflammatory responses to microbial challenges compared to non-smokers, understanding the association between smoking and periodontal diseases involves substantial problems with respect to accuracy of measurements, and particularly, sampling of many subjects. It remains unclear whether genetic susceptibility to periodontal disease is influenced by exposure to smoking or the effect of smoking on periodontal disease is influenced by genetic susceptibility. Employment of molecular techniques may play a key role in further elucidation of mechanisms linking smoking and periodontal destruction, the direct relationship as environmental factors and indirect relationship through genetic factors. PMID- 20170538 TI - Transmembrane potential induced on the internal organelle by a time-varying magnetic field: a model study. AB - BACKGROUND: When a cell is exposed to a time-varying magnetic field, this leads to an induced voltage on the cytoplasmic membrane, as well as on the membranes of the internal organelles, such as mitochondria. These potential changes in the organelles could have a significant impact on their functionality. However, a quantitative analysis on the magnetically-induced membrane potential on the internal organelles has not been performed. METHODS: Using a two-shell model, we provided the first analytical solution for the transmembrane potential in the organelle membrane induced by a time-varying magnetic field. We then analyzed factors that impact on the polarization of the organelle, including the frequency of the magnetic field, the presence of the outer cytoplasmic membrane, and electrical and geometrical parameters of the cytoplasmic membrane and the organelle membrane. RESULTS: The amount of polarization in the organelle was less than its counterpart in the cytoplasmic membrane. This was largely due to the presence of the cell membrane, which "shielded" the internal organelle from excessive polarization by the field. Organelle polarization was largely dependent on the frequency of the magnetic field, and its polarization was not significant under the low frequency band used for transcranial magnetic stimulation (TMS). Both the properties of the cytoplasmic and the organelle membranes affect the polarization of the internal organelle in a frequency-dependent manner. CONCLUSIONS: The work provided a theoretical framework and insights into factors affecting mitochondrial function under time-varying magnetic stimulation, and provided evidence that TMS does not affect normal mitochondrial functionality by altering its membrane potential. PMID- 20170539 TI - A case of Poland Syndrome associated with dextroposition. AB - Classical Poland Syndrome (PS) is characterized by unilateral, partial or complete absence of the sternocostal head of the major pectoral muscle and brachysyndactyly of fingers on the same side. We report the case of a newborn infant with dextrocardia and PS located on the left side. This association is very rare: to date only 19 cases have been described in scientific literature. In all reported cases, as in the present, the Poland defect involved the left side and was associated to rib defects, whereas most cases of PS are on the right side and few have rib defects. This case supports the view that dextrocardia follows the loss of volume of the left hemithorax caused by Poland sequence and that the combination of PS and dextrocardia is not coincidental. PMID- 20170540 TI - Psychosocial impact of sickle cell disorder: perspectives from a Nigerian setting. AB - Sickle Cell Disorder is a global health problem with psychosocial implications. Nigeria has the largest population of people with sickle cell disorder, with about 150,000 births annually. This study explored the psychosocial impact of sickle cell disorder in 408 adolescents and adults attending three hospitals in Lagos, Nigeria. A questionnaire was designed for the study, with some of commonly described areas of psychosocial impact including general public perceptions and attitudes, education, employment, and healthcare issues, and emotional responses.The majority of participants thought that society in general had a negative image of SCD, and reported negative perceptions and attitudes. Some issues in education, employment, and healthcare were expressed, however these were in the minority of cases. The results also showed that depressive feelings were experienced in almost half the study population, even though feelings of anxiety or self-hate were uncommon. Clinical implications of these findings are considered. PMID- 20170541 TI - BMI1 and Mel-18 oppositely regulate carcinogenesis and progression of gastric cancer. AB - BACKGROUND: The BMI1 oncogene is overexpressed in several human malignancies including gastric cancer. In addition to BMI1, mammalian cells also express Mel 18, which is closely related to BMI1. We have reported that Mel-18 functions as a potential tumor suppressor by repressing the expression of BMI1 and consequent downregulation of activated AKT in breast cancer cells. However, the mechanisms of BMI1 overexpression and the role of Mel-18 in other cancers are still not clear. The purpose of this study is to investigate the role of BMI1 and Mel-18 in gastric cancer. RESULTS: BMI1 was found to be overexpressed in gastric cancer cell lines and gastric tumors. Overexpression of BMI1 correlated with advanced clinical stage and lymph node metastasis; while the expression of Mel-18 negatively correlated with BMI1. BMI1 but not Mel-18 was found to be an independent prognostic factor. Downregulation of BMI1 by Mel-18 overexpression or knockdown of BMI1 expression in gastric cancer cell lines led to upregulation of p16 (p16INK4a or CDKN2A) in p16 positive cell lines and reduction of phospho-AKT in both p16-positive and p16-negative cell lines. Downregulation of BMI1 was also accompanied by decreased transformed phenotype and migration in both p16- positive and p16-negative gastric cancer cell lines. CONCLUSIONS: In the context of gastric cancer, BMI1 acts as an oncogene and Mel-18 functions as a tumor suppressor via downregulation of BMI1. Mel-18 and BMI1 may regulate tumorigenesis, cell migration and cancer metastasis via both p16- and AKT dependent growth regulatory pathways. PMID- 20170542 TI - Knowledge, attitudes and practices (KAP) relating to avian influenza in urban and rural areas of China. AB - BACKGROUND: Studies have revealed that visiting poultry markets and direct contact with sick or dead poultry are significant risk factors for H5N1 infection, the practices of which could possibly be influenced by people's knowledge, attitudes and practices (KAPs) associated with avian influenza (AI). To determine the KAPs associated with AI among the Chinese general population, a cross-sectional survey was conducted in China. METHODS: We used standardized, structured questionnaires distributed in both an urban area (Shenzhen, Guangdong Province; n = 1,826) and a rural area (Xiuning, Anhui Province; n = 2,572) using the probability proportional to size (PPS) sampling technique. RESULTS: Approximately three-quarters of participants in both groups requested more information about AI. The preferred source of information for both groups was television. Almost three-quarters of all participants were aware of AI as an infectious disease; the urban group was more aware that it could be transmitted through poultry, that it could be prevented, and was more familiar with the relationship between AI and human infection. The villagers in Xiuning were more concerned than Shenzhen residents about human AI viral infection. Regarding preventative measures, a higher percentage of the urban group used soap for hand washing whereas the rural group preferred water only. Almost half of the participants in both groups had continued to eat poultry after being informed about the disease. CONCLUSIONS: Our study shows a high degree of awareness of human AI in both urban and rural populations, and could provide scientific support to assist the Chinese government in developing strategies and health education campaigns to prevent AI infection among the general population. PMID- 20170543 TI - Hemorrhage of brain metastasis from non-small cell lung cancer post gefitinib therapy: two case reports and review of the literature. AB - BACKGROUND: Gefitinib is one of the small molecule inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR TKIs). Clinical trials have demonstrated it is effective for treatment of a subset of patients with advanced non-small cell lung cancer (NSCLC). Gefitinib has been generally considered to be a relatively safe agent. Besides a small proportion of fatal interstitial pneumonia, the common adverse drug reactions of gefitinib include diarrhea and skin rash, which are generally mild and reversible. Herein, we report the first two cases of brain metastasis hemorrhage that might be involved with the use of gefitinib. CASE PRESENTATION: Two patients with brain metastasis from NSCLC developed brain hemorrhage after gefitinib therapy. The hemorrhage in one case occurred one month after gefitinib combined with whole brain radiation therapy (WBRT), and in the another case hemorrhage developed slowly within brain metastases eight months post gefitinib monotherapy for diffuse pulmonary metastasis from a lung cancer undergone surgical removal previously. CONCLUSION: We speculate brain hemorrhage could be one of the adverse drug reactions of gefitinib treatment for NSCLC and suggest clinicians be aware of this possible rare entity. More data are needed to confirm our findings, especially when gefitinib is used in the settings of brain metastases from NSCLC or other origins. PMID- 20170544 TI - Predictive ability of an early diagnostic guess in patients presenting with chest pain; a longitudinal descriptive study. AB - BACKGROUND: The intuitive early diagnostic guess could play an important role in reaching a final diagnosis. However, no study to date has attempted to quantify the importance of general practitioners' (GPs) ability to correctly appraise the origin of chest pain within the first minutes of an encounter. METHODS: The validation study was nested in a multicentre cohort study with a one year follow up and included 626 successive patients who presented with chest pain and were attended by 58 GPs in Western Switzerland. The early diagnostic guess was assessed prior to a patient's history being taken by a GP and was then compared to a diagnosis of chest pain observed over the next year. RESULTS: Using summary measures clustered at the GP's level, the early diagnostic guess was confirmed by further investigation in 51.0% (CI 95%; 49.4% to 52.5%) of patients presenting with chest pain. The early diagnostic guess was more accurate in patients with a life threatening illness (65.4%; CI 95% 64.5% to 66.3%) and in patients who did not feel anxious (62.9%; CI 95% 62.5% to 63.3%). The predictive abilities of an early diagnostic guess were consistent among GPs. CONCLUSIONS: The GPs early diagnostic guess was correct in one out of two patients presenting with chest pain. The probability of a correct guess was higher in patients with a life threatening illness and in patients not feeling anxious about their pain. PMID- 20170545 TI - Teratogen-induced alterations in microRNA-34, microRNA-125b and microRNA-155 expression: correlation with embryonic p53 genotype and limb phenotype. AB - BACKGROUND: In a large number of studies, members of the microRNA (miRNA)-34 family such as miRNA-34a, miRNA-34b, miRNA-34c, as well as miRNA-125b and miRNA 155, have been shown to be regulators of apoptosis. The ability of these miRNAs to perform this function is mainly attributed to their ability to interact with the p53 tumor suppressor, which is a powerful regulator of the teratologic susceptibility of embryos. We chose to explore whether miRNA-34a/b/c, miRNA-125b and miRNA-155 may play a role in teratogenesis by using p53+/- pregnant mice treated with cyclophosphamide (CP) as a model. We evaluated how CP-induced alterations in the expression of these miRNAs in the embryonic limbs correlate with embryonic p53 genotype and CP-induced limb phenotypes. RESULTS: The limbs of p53 positive embryos were more sensitive to CP-induced teratogenic insult than the limbs of p53 negative embryos. The hindlimbs were more severely affected than the forelimbs. Robust miRNA-34a expression was observed in the fore- and hindlimbs of p53+/+ embryos exposed to 12.5 mg/kg CP. The dose of 20 mg/kg CP induced almost a two-fold increase in the level of miRNA-34a expression as compared to that exhibited by p53+/+ embryos exposed to a lower dose. Increased miRNA-34b and miRNA-34c expression was also observed. Of note, this dose activated miRNA-34a and miRNA-34c in the forelimbs of p53-/- embryos. When embryos were exposed to 40 mg/kg CP, the expression pattern of the miRNA-34a/b/c was identical to that registered in the limbs of embryos exposed to 20 mg/kg CP. However, this dose suppressed miRNA-125b and miRNA-155 expression in the fore- and hindlimbs of p53+/+ embryos. CONCLUSION: This study demonstrates that teratogen-induced limb dysmorphogenesis may be associated with alterations in miRNA-34, miRNA-125b and miRNA-155 expression. It also suggests for the first time that p53-independent mechanisms exist contributing to teratogen-induced activation of miRNA-34a and miRNA-34c. At the same time, teratogen-induced suppression of miRNA-125b and miRNA-155 expression may be p53 dependent. The analysis of correlations between the expression pattern of the tested miRNAs and CP induced limb phenotypes implies that miRNAs regulating apoptosis may differ from each other with respect to their functional role in teratogenesis: some miRNAs act to protect embryos, whereas other miRNAs boost a teratogen-induced process of maldevelopment to induce embryonic death. PMID- 20170546 TI - Dimensional structure of the oral health-related quality of life in healthy Spanish workers. AB - BACKGROUND: Oral health-related quality of life (OHQoL) is conceived as a multidimensional construct. Here our aim was to investigate the dimensional structure of OHQoL as measured by the Spanish versions of the Oral Impacts on Daily Performance (OIDP) and the Oral Health Impact Profile (OHIP-14) questionnaires applied simultaneously. METHODS: We recruited a consecutive sample of 270 healthy Spanish workers visiting the Employment Risk Prevention Centre for a routine medical check-up. OHIP-14 was self-completed by participants but the OIDP was completed in face-to-face interviews. An Exploratory Factor Analysis (EFA) was performed to identify the underlying dimensions of the OHQoL construct assessed by both instruments. This factorial structure was later confirmed by Confirmatory Factor Analysis (CFA) using several estimators of goodness of fit indices. RESULTS: EFA and the CFA identified and respectively confirmed a set of 3 underlying factors in both questionnaires that could be interpreted as functional limitation, pain-discomfort, and psychosocial impacts. The model achieved was seen to fit properly for both instruments, but the factorial structure was clearer for the OIDP. CONCLUSIONS: The results provide evidence for construct equivalence in the latent factors assessed by both OIDP and OHIP-14, suggesting that OHQoL is a three-dimensional construct. The prevalence of impact on these three factors was coherent between both indicators, pain-discomfort having the highest prevalence, followed by psycho-social impact, and functional limitation. PMID- 20170547 TI - Association of nutritional status and serum albumin levels with development of toxicity in patients with advanced non-small cell lung cancer treated with paclitaxel-cisplatin chemotherapy: a prospective study. AB - BACKGROUND: A frequent manifestation of advanced NSCLC is malnutrition, even though there are many studies which relate it with a poor survival, its relation with toxicity has not yet been consistently reported. The aim of this study was to associate malnutrition and albumin serum levels with the occurrence of chemotherapy-induced toxicity in cisplatin plus paclitaxel chemotherapy-treated NSCLC. METHODS: We prospectively evaluated 100 stage IV NSCLC patients treated with paclitaxel (175 mg/m2) and cisplatin (80 mg/m2). Malnutrition was assessed using SGA prior treatment. Neutrophil Lymphocyte Ratio (NLR) and the Platelet Lymphocyte Ratio (PLR) were used to determine the presence of systemic inflammatory response (SIR) and were related to the development of toxicity. Toxicity was graded according to NCI CTCAE version 3.0 after two chemotherapy cycles. RESULTS: Median age was 58 +/- 10 years, 51% of patients were malnourished, 50% had albumin < or =3.0 mg/mL. NLR > or = 5 was associated with basal hypoalbuminemia (mean ranks, 55.7 vs. 39 p = 0.006), ECOG = 2 (47.2 vs. 55.4 p = 0.026) and PLR > or = 150 were significantly related with a basal body mass index < or =20 (56.6 vs. 43.5; p = 0.02) and hypoalbuminemia (58.9 vs. 41.3; p = 0.02). Main toxicities observed after 2 cycles of chemotherapy were alopecia (84%), nausea (49%), neuropathy (46%), anemia (33%), lymphopenia (31%), and leukopenia (30%). Patients malnourished and with hypoalbuminemia developed more chemotherapy-induced toxicity overall when compared with those without malnutrition (31 vs 22; p = 0.02) and normal albumin (mean ranks, 62 vs 43; p = 0.002), respectively. Hypoalbuminemia was associated with anemia (56 vs 47; p = 0.05), fatigue (58 vs 46; p = 0.01), and appetite loss (57.1 vs 46.7; p = 0.004) compared with normal albumin. PLR > or = 150 was related with the development of toxicity grade III/IV (59.27 vs. 47.03 p = 0.008) and anemia (37.9 vs 53.8 p = 0.004). CONCLUSION: SIR parameters were associated with malnutrition, weight loss and hypoalbuminemia. Chemotherapy-induced toxicity in NSCLC patients treated with paclitaxel and cisplatin was associated with malnutrition and hypoalbuminemia. Early nutritional assessment and support might confer beneficial effects. PMID- 20170548 TI - Effect of troglitazone on tumor growth and pulmonary metastasis development of the mouse osteosarcoma cell line LM8. AB - BACKGROUND: Osteosarcoma often develops micrometastases in the lung prior to diagnosis, causing a fatal outcome. Therefore, the prevention of pulmonary metastases is critical for the improvement of the prognosis of patients with osteosarcoma. The purpose of this study was to investigate whether troglitazone (TGZ) is considered as possible therapeutics in the treatment of growth and metastasis of osteosarcoma. METHODS: LM8 cells were treated for 3 days with various concentrations of TGZ. The effect of TGZ on cell proliferation was determined by DNA measurement in the cultures and 5-bromo-2'-deoxyuridine incorporation study. The assay of cell invasion and motility was performed using either the Matrigel-coated cell culture inserts or the uncoated cell culture inserts in the invasion chambers. The effect of TGZ on Akt signaling was assessed by Western blot analysis of Akt and p-Akt. The effects of oral administration of either TGZ (TGZ group) or ethanol (control group) on the growth of primary tumor and the development of pulmonary metastasis were examined in nude mice implanted with LM8 cells on their backs. The expression and activity of matrix metalloproteinase 2 (MMP-2) within the tumor were determined by immunohistochemistry and zymography. The microvessel density (MVD) within the tumor was determined by immunohistochemistry for CD34. RESULTS: TGZ dose dependently inhibits cell proliferation. TGZ-treated cells were less invasive and less motile than untreated cells. The activity of MMP-2 secreted by TGZ-treated cells was lower than that secreted by untreated cells. TGZ decreased the level of p-Akt. The primary tumor mass was smaller in the TGZ group than in the control group. The TGZ group had less metastatic tumors in the lung compared with the control group. The expression and activity of MMP-2 within the tumor of the TGZ group were lower than those of the control group. The MVD within the tumor of the TGZ group was lower than that of the control group. CONCLUSIONS: Inhibition of Akt signaling by TGZ may decrease the secretion of MMP-2, resulting in the decrease of invasiveness and motility in LM8 cells. Treatment of tumor-bearing mice with TGZ decreases the expression and activity of MMP-2 within the tumor, and inhibits primary tumor growth and pulmonary metastasis development. TGZ may offer a new approach in chemotherapy for osteosarcoma. PMID- 20170549 TI - A real-time RT-PCR for detection of clade 1 and 2 H5N1 influenza A virus using locked nucleic acid (LNA) TaqMan probes. AB - BACKGROUND: The emergence and co-circulation of two different clades (clade 1 and 2) of H5N1 influenza viruses in Vietnam necessitates the availability of a diagnostic assay that can detect both variants. RESULTS: We developed a single real-time RT-PCR assay for detection of both clades of H5N1 viruses, directly from clinical specimens, using locked nucleic acid TaqMan probes. Primers and probe used in this assay were designed based on a highly conserved region in the HA gene of H5N1 viruses. The analytical sensitivity of the assay was < 0.5 PFU and 10-100 ssDNA plasmid copies. A total of 106 clinical samples (58 from patients infected with clade 1, 2.1 or 2.3 H5N1 viruses and 48 from uninfected or seasonal influenza A virus-infected individuals) were tested by the assay. The assay showed 97% concordance with initial diagnostics for H5 influenza virus infection with a specificity of 100%. CONCLUSIONS: This assay is a useful tool for diagnosis of H5N1 virus infections in regions where different genetic clades are co-circulating. PMID- 20170550 TI - Mechanistic insights from a quantitative analysis of pollen tube guidance. AB - BACKGROUND: Plant biologists have long speculated about the mechanisms that guide pollen tubes to ovules. Although there is now evidence that ovules emit a diffusible attractant, little is known about how this attractant mediates interactions between the pollen tube and the ovules. RESULTS: We employ a semi-in vitro assay, in which ovules dissected from Arabidopsis thaliana are arranged around a cut style on artificial medium, to elucidate how ovules release the attractant and how pollen tubes respond to it. Analysis of microscopy images of the semi-in vitro system shows that pollen tubes are more attracted to ovules that are incubated on the medium for longer times before pollen tubes emerge from the cut style. The responses of tubes are consistent with their sensing a gradient of an attractant at 100-150 mum, farther than previously reported. Our microscopy images also show that pollen tubes slow their growth near the micropyles of functional ovules with a spatial range that depends on ovule incubation time. CONCLUSIONS: We propose a stochastic model that captures these dynamics. In the model, a pollen tube senses a difference in the fraction of receptors bound to an attractant and changes its direction of growth in response; the attractant is continuously released from ovules and spreads isotropically on the medium. The model suggests that the observed slowing greatly enhances the ability of pollen tubes to successfully target ovules. The relation of the results to guidance in vivo is discussed. PMID- 20170551 TI - The cross-reactivity of the enterovirus 71 to human brain tissue and identification of the cross-reactivity related fragments. AB - BACKGROUND: EV71 occasionally cause a series of severe neurological symptoms, including aseptic meningitis, encephalitis, and poliomyelitis-like paralysis. However, the neurological destruction mechanism was remained to be clarified. This study described the cross reaction between EV71 induced IgG and human brain tissue. RESULTS: Cross reaction of the IgG from 30 EV71 infected patients' sera to human tissues of cerebra was observed, which suggested that some EV71 antigens could induce IgG cross-reactivity to human cerebra. To identify the regions of EV71 virus that containing above antigens, the polypeptide of virus was divided into 19 peptides by expression in prokaryotes cell. Mouse anti-sera of these peptides was prepared and applied in immunohistochemical staining with human adult and fetus brain tissue, respectively. The result indicated the 19 peptides can be classified into three groups: strong cross-reactivity, weak cross reactivity and no cross-reactivity with human brain tissue according the cross reaction activity. Then, the increased Blood Brain Barrier (BBB) permeability and permits IgG entry in neonatal mice after EV71 infection was determined. CONCLUSION: EV71 induced IgG could enter BBB and cross-reacted with brain tissue in EV71 infected neonatal mice, and then the peptides of EV71 that could induce cross-reactivity with brain tissue were identified, which should be avoided in future vaccine designing. PMID- 20170552 TI - Recurrent hemorrhagic pericardial effusion in a child due to diffuse lymphangiohemangiomatosis: a case report. AB - INTRODUCTION: Recurrent hemorrhagic pericardial effusion in children with no identifiable cause is a rare presentation. CASE PRESENTATION: We report the case of a 4-year-old Indian girl who presented with recurrent hemorrhagic pericardial effusion. Diffuse lymphangiomatosis was suspected when associated pulmonary involvement, soft tissue mediastinal mass, and lytic bone lesions were found. Pericardiectomy and lung biopsy confirmed the diagnosis of diffuse lymphangiohemangiomatosis. Partial clinical improvement occurred with thalidomide and low-dose radiotherapy, but our patient died from progressive respiratory failure. CONCLUSION: Diffuse lymphangiohemangiomatosis should be considered in the differential diagnosis of hemorrhagic pericardial effusion of unclear cause. PMID- 20170553 TI - Hemodynamics in pulmonary arterial hypertension (PAH): do they explain long-term clinical outcomes with PAH-specific therapy? AB - BACKGROUND: Pulmonary arterial hypertension (PAH) has witnessed dramatic treatment advances over the past decade. However, with the exception of epoprostenol, data from short-term randomized controlled trials (RCTs) have not shown a benefit of these drugs on survival. There remains a need to differentiate between available therapies and current endpoint responses which in turn, could be used to guide treatment selection and provide long-term prognostic information for patients. METHODS: We performed a systematic literature search of MEDLINE and EMBASE databases for RCTs of PAH-specific therapy published between January 1980 and May 2009. Articles were selected if they contained a placebo comparator and described hemodynamic changes from baseline. We applied the weighted mean change in hemodynamic variables to the equation developed by the National Institutes of Health (NIH) Registry to estimate long-term survival with each therapy. RESULTS: Ten RCTs involving 1,635 patients met the inclusion criteria. Suitable hemodynamic data were identified for bosentan, sitaxentan, sildenafil, epoprostenol, beraprost and treprostinil. 77.6% of patients were female and the mean (SD) age was 46.5 +/- 4.9 years. 55.5% of patients had idiopathic PAH (iPAH), 23.9% PAH related to connective tissue disease, and 18.2% PAH related to congenital heart disease. Based on the effects observed in short-term trials and, relative to placebo, all analyzed therapies improved survival. The estimated 1 year survival was 78.4%, 77.8%, 76.1%, 75.8%, 75.2%, and 74.1% for epoprostenol, bosentan, treprostinil, sitaxentan, sildenafil, and beraprost, respectively. These estimates are considerably lower than the 1-year observed survival reported in several open-label and registry studies with PAH-specific therapies: 88% - 97%. CONCLUSION: When applied to the NIH Registry equation, hemodynamic changes from baseline appear to underestimate the survival benefits observed with long term PAH therapy. PMID- 20170554 TI - Changes of overweight and obesity in the adult Swiss population according to educational level, from 1992 to 2007. AB - BACKGROUND: In many high income developed countries, obesity is inversely associated with educational level. In some countries, a widening gap of obesity between educational groups has been reported. The aim of this study was to assess trends in body mass index (BMI) and in prevalence of overweight and obesity and their association with educational level in the adult Swiss population. METHODS: Four cross-sectional National health interview surveys conducted in 1992/93 (n = 14,521), 1997 (n = 12,474), 2002 (n = 18,908) and 2007 (n = 17,879) using representative samples of the Swiss population (age range 18-102 years). BMI was derived from self-reported data. Overweight was defined as BMI > or = 25 and <30 kg/m(2), and obesity as BMI > or = 30 kg/m(2). RESULTS: Mean (+/- standard deviation) BMI increased from 24.7 +/- 3.6 in 1992/3 to 25.4 +/- 3.6 kg/m2 in 2007 in men and 22.8 +/- 3.8 to 23.7 +/- 4.3 kg/m(2) in women. Between 1992/3 and 2007, the prevalence of overweight + obesity increased from 40.4% to 49.5% in men and from 22.3% to 31.3% in women, while the prevalence of obesity increased from 6.3% to 9.4% in men and from 4.9% to 8.5% in women. The rate of increase in the prevalence of obesity was greater between 1992/3 and 2002 (men: +0.26%/year; women: +0.31%/year) than between 2002 and 2007 (men: +0.10%/year; women: +0.10%/year). A sizable fraction (approximately 25%) of the increasing mean BMI was due to increasing age of the participants over time. The increase was larger in low than high education strata of the population. BMI was strongly associated with low educational level among women and this gradient remained fairly constant over time. A weaker similar gradient by educational level was apparent in men, but it tended to increase over time. CONCLUSION: In Switzerland, overweight and obesity increased between 1992 and 2007 and was associated with low education status in both men and women. A trend towards a stabilization of mean BMI levels was noted in most age categories since 2002. The increase in the prevalence of obesity was larger in low education strata of the population. These findings suggest that obesity preventive measures should be targeted according to educational level in Switzerland. PMID- 20170555 TI - Different screening strategies (single or dual) for the diagnosis of suspected latent tuberculosis: a cost effectiveness analysis. AB - BACKGROUND: Previous health economic studies recommend either a dual screening strategy [tuberculin skin test (TST) followed by interferon-gamma-release assay (IGRA)] or a single one [IGRA only] for latent tuberculosis infection (LTBI), the former largely based on claims that it is more cost-effective. We sought to examine that conclusion through the use of a model that accounts for the additional costs of adverse drug reactions and directly compares two commercially available versions of the IGRA: the Quantiferon-TB-Gold-In-Tube (QFT-GIT) and T SPOT.TB. METHODS: A LTBI screening model directed at screening contacts was used to perform a cost-effectiveness analysis, from a UK healthcare perspective, taking into account the risk of isoniazid-related hepatotoxicity and post exposure TB (2 years post contact) using the TST, QFT-GIT and T-SPOT.TB IGRAs. RESULTS: Examining costs alone, the TST/IGRA dual screening strategies (TST/T SPOT.TB and TST/QFT-GIT; 162,387 pounds and 157,048 pounds per 1000 contacts, respectively) cost less than their single strategy counterparts (T-SPOT.TB and QFT-GIT; 203,983 pounds and 202,921 pounds per 1000 contacts) which have higher IGRA test costs and greater numbers of persons undergoing LTBI treatment. However, IGRA alone strategies direct healthcare interventions and costs more accurately to those that are truly infected.Subsequently, less contacts need to be treated to prevent an active case of TB (T-SPOT.TB and QFT-GIT; 61.7 and 69.7 contacts) in IGRA alone strategies. IGRA single strategies also prevent more cases of post-exposure TB. However, this greater effectiveness does not outweigh the lower incremental costs associated with the dual strategies. Consequently, when these costs are combined with effectiveness, the IGRA dual strategies are more cost-effective than their single strategy counterparts. Comparing between the IGRAs, T-SPOT.TB-based strategies (single and dual; 39,712 pounds and 37,206 pounds per active TB case prevented, respectively) were more cost-effective than the QFT-GIT-based strategies (single and dual; 42,051 pounds and 37,699 pounds per active TB case prevented, respectively). Using the TST alone was the least cost-effective (47,840 pounds per active TB case prevented). Cost effectiveness values were sensitive to changes in LTBI prevalence, IGRA test sensitivities/specificities and IGRA test costs. CONCLUSION: A dual strategy is more cost effective than a single strategy but this conclusion is sensitive to screening test assumptions and LTBI prevalence. PMID- 20170557 TI - Patient organisations and the reimbursement process for medicines: an exploratory study in eight European countries. AB - BACKGROUND: Little is known about the role European patient organisations play in the process of deciding on reimbursement for medicines. Therefore we explore the current role of patient organisations in the process of reimbursement for medicines in Western Europe. We focus in particular on collaboration between patient organisations and the pharmaceutical industry in this respect. METHODS: Sixty-eight patient organisations representing seven medical conditions, from ten Western European countries, were asked to participate in the study. The participating organisations reported their experiences in a web-based questionnaire. RESULTS: Twenty-one patient organisations completed the questionnaire (response rate: 31%), of which ten (47.6%) demanded reimbursement for medicines. Organisations demanding reimbursement were larger than those not demanding reimbursement. The main aim of these organisations was to create better accessibility of medicines for patients. Most organisations limited themselves to single actions. Only two engaged in multiple actions. Almost all organisations had general policies on cooperation with the pharmaceutical industry, with autonomy as the key feature. The patient organisations said they were reasonably successful and almost always satisfied with their own role in the reimbursement process. CONCLUSION: Our study has found that the role of European patient organisations in the reimbursement process still seems limited, especially for small patient organisations. PMID- 20170556 TI - Computational analysis and determination of a highly conserved surface exposed segment in H5N1 avian flu and H1N1 swine flu neuraminidase. AB - BACKGROUND: Catalytic activity of influenza neuraminidase (NA) facilitates elution of progeny virions from infected cells and prevents their self aggregation mediated by the catalytic site located in the body region. Research on the active site of the molecule has led to development of effective inhibitors like oseltamivir, zanamivir etc, but the high rate of mutation and interspecies reassortment in viral sequences and the recent reports of oseltamivir resistant strains underlines the importance of determining additional target sites for developing future antiviral compounds. In a recent computational study of 173 H5N1 NA gene sequences we had identified a 50-base highly conserved region in 3' terminal end of the NA gene. RESULTS: We extend the graphical and numerical analyses to a larger number of H5N1 NA sequences (514) and H1N1 swine flu sequences (425) accessed from GenBank. We use a 2D graphical representation model for the gene sequences and a Graphical Sliding Window Method (GSWM) for protein sequences scanning the sequences as a block of 16 amino acids at a time. Using a protein sequence descriptor defined in our model, the protein sliding scan method allowed us to compare the different strains for block level variability, which showed significant statistical correlation to average solvent accessibility of the residue blocks; single amino acid position variability results in no correlation, indicating the impact of stretch variability in chemical environment. Close to the C-terminal end the GSWM showed less descriptor variability with increased average solvent accessibility (ASA) that is also supported by conserved predicted secondary structure of 3' terminal RNA and visual evidence from 3D crystallographic structure. CONCLUSION: The identified terminal segment, strongly conserved in both RNA and protein sequences, is especially significant as it is surface exposed and structural chemistry reveals the probable role of this stretch in tetrameric stabilization. It could also participate in other biological processes associated with conserved surface residues. A RNA double hairpin secondary structure found in this segment in a majority of the H5N1 strains also supports this observation. In this paper we propose this conserved region as a probable site for designing inhibitors for broad-spectrum pandemic control of flu viruses with similar NA structure. PMID- 20170558 TI - [Crisis in human resources for health: millennium development goals for maternal and child health threatened]. AB - International migration of health care workers from low-income countries to the West has increased considerably in recent years, thereby jeopardizing the achievements of The Millennium Development Goals, especially number 4 (reduction of child mortality) and 5 (improvement of maternal health).This migration, as well as the HIV/AIDS epidemic, lack of training of health care personnel and poverty, are mainly responsible for this health care personnel deficit. It is essential that awareness be raised amongst donors and local governments so that staffing increases, and that infection prevention measures be in place for their health care personnel. Western countries should conduct a more ethical recruitment of health care workers, otherwise a new millennium development goal will have to be created: to reduce the human resources for health crisis. PMID- 20170559 TI - [Nocardiosis, an important opportunistic infection]. AB - In three patients, a 69-year-old woman, a 52-year-old woman and a 35-year-old man, nocardiosis was diagnosed. The first woman had chronic B-cell leukaemia and mucosal pemphigoid; she was on immunosuppressive medication, and had fever and a suppurative arthritis of the knee. The second woman was on immunosuppressive medication following a kidney transplantation and had fever and a pulmonary infiltrate. The male patient had hereditary cystic kidneys and a soft tissue infection of the left leg. He was not immunologically compromised. Nocardiosis is mainly an opportunistic bacterial infection but can also affect immune competent patients. The disease manifestations are protean, ranging from localised skin infections to severe systemic diseases, quite often with central nervous system involvement. Identifying the organism can be challenging, and notifying the laboratory when nocardiosis is suspected can help to optimise the diagnostic yield. Nocardiosis requires a long duration of medical therapy, trimethoprim sulfonamide being the most frequently used antibiotic combination. PMID- 20170560 TI - [Course of disease and treatment policy in suspected low-grade glioma]. AB - Watchful waiting has long been justified in the Netherlands for patients in whom a low-grade glioma is suspected. According to recent advances in knowledge it is clear that the course of a suspected low-grade glioma cannot be reliably determined by clinical characteristics, imaging or biopsy. Early resection of the tumour provides a histological diagnosis, the possibility of removing a source of epilepsy and postponement of tumour growth and progression. Alleviation of symptoms, sustained quality of life and cognition are at least as important an aim of treatment as survival and postponement of tumour progression. In our opinion, early resection should be strongly considered in every patient with a suspected low-grade glioma. However, radiotherapy or chemotherapy should only be considered early in the presence of unfavourable prognostic factors or persistent epilepsy. Each patient in whom a low-grade glioma is suspected should receive specific treatment advice from a neuro-oncological team. PMID- 20170562 TI - [Risk of infection due to contamination of medicines]. AB - After minor surgery in a hospital, 7 patients suffered serious infectious complications. Microbiological analysis revealed an infection caused by contamination of the intravenous anaesthetic propofol. Several studies have shown that the administration of intravenous medication is a risky process that is prone to errors; these errors can result in harm to the patient. Within the Dutch project 'Safe medical care', the intravenous administration of medication has been chosen as one of the ten most important areas in which to patient safety can be improved. To enhance patient safety it is important to identify the separate steps that are the most prone to error, based on a good risk analysis. A systematic and coordinated approach is crucial for success in this process. PMID- 20170563 TI - [A girl with a swelling on her head]. AB - A 6-year-old girl had an eosinophilic granuloma on the parietal skull due to Langerhans cell histiocytosis. PMID- 20170564 TI - [Postoperative infection due to contaminated propofol]. AB - Seven patients operated on in a period of two consecutive days in the Havenziekenhuis, Rotterdam, the Netherlands developed symptoms of sepsis following a relatively minor procedure. One patient developed fever and hypotension a few hours after surgery, and developed thrombocytopenia and leucopenia. Postoperative bleeding occurred as a result of the thrombocytopenia, necessitating further surgery. This patient developed serious multi-organ failure, and required prolonged intensive care treatment. The other six patients developed less serious infections, the main symptoms of which were fever, leucopenia, thrombocytopenia and impairment of liver- and kidney function. They recovered quickly. Bacteriological investigation revealed that the infection was caused by extrinsic contamination of the intravenous anaesthetic propofol with Klebsiella pneumoniae and Serratia marcescens. Due to the high risk of contamination of the lipid formulation of this preparation, the use of propofol requires the following measures: syringes should be used just once; vials should be punctured just once; and administration should take place within 12 h after opening the vial or the ampoule. Hygienic working methods are also of crucial importance. PMID- 20170565 TI - [High quality of research supported by the Netherlands Heart Foundation ('Nederlandse Hartstichting')]. AB - OBJECTIVE: To assess the quality of scientific research funded by the Netherlands Heart Foundation (NHF), using bibliometrical analysis of published research results, in order to determine whether the resources of the NHF for research were being invested wisely. DESIGN: Retrospective, descriptive. METHOD: The publication data concerning research projects supported by the NHF are digitally archived in a research information system. These data were used for a bibliometric analysis by the Centre for Science and Technology Studies (CWTS), using the international publication and citation database 'Web of Science', which contains around 10,000 internationally oriented periodicals. The analysis involved calculating various indicators, such as publication and citation figures, which were used to measure scientific output and impact. RESULTS: 1,353 scientific publications were produced from NHF-supported research that commenced in the period 1999-2007 (reference date 1 Jan 2008). In this period the NHF invested between 10 and 15 million Euros each year in scientific cardiovascular research. The quality of this research is reflected in the citation score of 1.65. This means that these publications were cited 65% more often than the global average. These publications also appeared in renowned periodicals, as is evident from the average journal citation score of 1.50. There were differences in the quality of NHF supported research at the individual universities, but all universities published NHF financed research results with a high impact within the field. The citation score achieved by the Radboud University Nijmegen was outstanding high. CONCLUSION: The NHF has invested in high quality scientific research. PMID- 20170566 TI - [Sepsis: new insights into its pathogenesis and treatment]. AB - The incidence of sepsis is increasing worldwide, yet the mortality rate has barely decreased during the past decades and remains unacceptably high at between 20% - 40%. New knowledge on host-pathogen interactions has greatly increased our insights in the pathogenesis of sepsis. It is now clear that sepsis is not only characterized by proinflammation but also by immunosuppression. Here we give an overview of the functional interactions between bacteria and our immune system. Microbial virulence factors, pathogen recognition receptors, activation of coagulation, apoptosis and a wide range of new mediators of sepsis play a role in these interactions. Implementation of evidence-based guidelines for the rapid diagnosis and adequate treatment of sepsis has been shown to be instrumental in improving survival in sepsis. The increasing insights into the pathogenesis of sepsis have identified a whole new range of potential drugs which are currently being tested in clinical trials. PMID- 20170567 TI - [Transverse testicular ectopia confirmed by ultrasonography]. AB - Two newborn boys aged 2 and 3 months with unilateral inguinal hernia and a contralateral impalpable, non-scrotal testis, and a third boy aged 2.5 years with an impalpable non-scrotal testis were found to have transverse testicular ectopia. This is an uncommon abnormality in which both gonads migrate toward the same hemiscrotum. We illustrate that unilateral cryptorchidism and a contralateral inguinal hernia may indicate the presence of a rare type of male pseudohermaphroditism: persistent mullerian duct syndrome (PMDS). This syndrome is characterized by the presence of a uterus and fallopian tubes associated with abdominal testes and frequently inguinal hernia in a phenotypically and genotypically normal male. This syndrome is often discovered during repair of inguinal hernia or non-descended testes (cryptorchidism). Pre-operative ultrasonography in children with impalpable non-scrotal testis and a contralateral inguinal hernia (patent processus vaginalis) may enable an early diagnosis of transverse testicular ectopia and proper surgical planning. Surgical orchidopexy was carried out and in the first two patients resection of the mullerian duct remnant (utriculus masculinus). PMID- 20170568 TI - [More breast cancer death in 2008: stepping up prevention]. AB - According to data of Statistics Netherlands the number of women dying from breast cancer has risen from 3180 in 2007 to 3327 in 2008 (+5%). The increase was largest for women aged 60-69 years (+16%) and was rather unexpected, as breast cancer mortality had decreased by 25-30% in the Netherlands since 1995, despite the rapid increase in breast cancer incidence during the same period. Does this mean that the limits of earlier diagnosis by screening and more effective treatment have now been reached? Specific action to increase the quality and breast cancer detection rate of the current breast cancer screening program and wider use of chemotherapy, hormonal treatment, targeted therapy and their combinations will probably not be enough to compensate for the continuing increase in breast cancer incidence. Unquestionably, lowering the exposure to modifiable risk factors is the most effective strategy to reduce breast cancer mortality in the long run. These risk factors are the relatively old age when having a first child, a short period of breast feeding or absence of breast feeding, being overweight, little physical exercise and increased alcohol consumption. PMID- 20170569 TI - [Diagnostic image A woman with a painful wrist]. AB - A 70-year-old woman had a painful wrist after a fall from her bike, due to a carpometacarpal luxation. PMID- 20170570 TI - [Improved compliance with the 'Melanoma' treatment guideline]. AB - OBJECTIVE: To evaluate the level of compliance with the revised treatment guideline for melanoma (2005) and the extent to which the points of concern from the previous guideline evaluation in 2001 had been implemented. DESIGN: Retrospective observational cohort study. METHOD: The evaluation was performed using data from the pathology reports of patients diagnosed with melanoma of the skin between 1 April and 30 September 2007 at hospitals that fall under the Comprehensive Cancer Centres for the South and West of the Netherlands. RESULTS: In 85% of the patients the melanoma was treated according to the guideline in two sessions: a diagnostic excision followed by a therapeutic re-excision. These figures were 69% for melanoma in situ, and 87% for invasive melanoma. The other patients were treated in one session. In the pathology reports of the patients with an invasive melanoma the rates of pathological documentation were: margin of the diagnostic excision: 64%, Breslow thickness: 97%, presence or absence of ulceration: 77%. In the Comprehensive Cancer Care Centre West Netherlands region, the margin of re-excision was determined: this margin satisfied the guideline in 86% of patients with an invasive melanoma. CONCLUSION: Compared to the previous guideline evaluation in 2001, the excision policy had improved. In the pathology report, the excision margin and the presence or absence of ulceration should be better documented. PMID- 20170571 TI - [Problematic breastfeeding due to a short frenulum]. AB - Ankyloglossia (tongue tie) in the neonate can be a cause of breastfeeding problems. Frenotomy (cutting of the frenulum linguae) had fallen into disrepute, but has regained its place as a standard medical procedure in Anglo-Saxon countries, though not in the Netherlands. We present two neonates, both boys, presenting with breastfeeding problems caused by ankyloglossia. The first baby described did not drink enough and hence did not gain any weight. The mother of the second patient experienced a great deal of pain and had cracked nipples, caused by an abnormal suckling action. Both boys underwent frenotomy with good result. Recent ultrasound studies reveal that frenotomy immediately normalizes the suckling action in babies with ankyloglossia. Randomized controlled trials show that 95% of breastfeeding problems disappear. There is sufficient evidence to state that frenotomy is a very safe and useful procedure in neonates. PMID- 20170572 TI - [Waiting times in breast disease clinics and psychological well-being: speedy care is better care]. AB - OBJECTIVE: To examine the effect of diagnostic speed and the waiting time before surgery on the psychological well-being of patients in breast disease clinics. DESIGN: Prospective cohort study METHOD: Women with suspected breast cancer completed questionnaires about their psychological well-being before the first outpatient clinic visit (time T1: with malignancy (n = 149); without malignancy (n = 515)), shortly after diagnosis (T2: n = 96 and n = 432, respectively) and 2 3 months later (T3: with malignancy (n = 139)). Two months after the end of treatment (T4: with malignancy (n = 202)), women with breast cancer indicated which period they considered most stressful in retrospect. Diagnostic speed and the waiting time before surgery were categorized and the relation with well-being was examined. Analyses were controlled for age and cancer stage. RESULTS: Although the period before diagnosis was experienced as stressful, diagnostic speed did not affect emotional well-being after a breast cancer diagnosis. However, a diagnosis that took a long time (> 2 weeks) did affect the emotional well-being of women who were not diagnosed with breast cancer. These women were worried and distressed for a longer period of time after diagnosis than women who received the favourable news sooner. The length of the waiting time before surgery did not affect the emotional well-being of patients thereafter: women who had surgery within two weeks were not worse or better off than women who had to wait longer. Yet, patients' emotional well-being did improve considerably after surgery, which indicates that short waiting times might shorten a period of psychological distress. CONCLUSION: The results support a speedy diagnosis and surgery. There was no support for short waiting times having a negative psychological effect. PMID- 20170573 TI - [Mortality and morbidity among full-term neonates in a neonatal intensive care unit in the Utrecht region, the Netherlands]. AB - OBJECTIVE: To gain an insight into perinatal mortality and morbidity in full-term infants without congenital abnormalities admitted to a neonatal intensive care unit (NICU). DESIGN: Retrospective analysis. METHOD: In this study, all full-term infants, who were born in the period 1997-2003 without congenital disorders and admitted to the NICU at the Wilhelmina Children's Hospital in Utrecht, the Netherlands were included. Information about the delivery, NICU-admission and follow-up until the age of 18 months was obtained from the hospital charts. RESULTS: In total 597 full-term neonates were admitted to the NICU during the study period; this is equivalent to 3-4 per 1,000 full-term neonates in the Utrecht region. Of these, 47% were admitted on account of asphyxia, 17% with respiratory problems and 12% with infections. In 79% of all NICU admissions the delivery had taken place under secondary care; in 29% labour had started under exclusive care of a primary level midwife, because the pregnancy had been defined as low-risk. 21% of the neonates were admitted to the NICU following delivery under exclusive primary care. Almost 15% of the infants died in the NICU, in 89% due to asphyxia. Of the surviving infants following perinatal asphyxia, 15% had a permanent disability at the age of 18 months. CONCLUSION: Post-partum admission of a fundamentally healthy full-term neonate to the NICU is a serious adverse perinatal outcome, and warrants further investigation. The various factors that influence these admissions should be analysed in more detail, for instance by means of perinatal audits. PMID- 20170574 TI - [Using the SETQ system to evaluate and improve teaching qualities of clinical teachers]. AB - OBJECTIVE: To determine (a) the feasibility of implementing a system for the evaluation of teaching qualities (SETQ) of faculty in an academic medical centre, (b) the psychometric qualities of the questionnaires that are used for the generation of feedback and (c) how residents evaluate the teaching qualities of faculty members and how faculty rated themselves. DESIGN: Questionnaire study. METHODS: Residents evaluated the teaching qualities of faculty members and faculty also evaluated themselves. Specialty specific questionnaires were developed for both evaluations. The psychometric qualities of the questionnaires were determined by using exploratory factor analysis and by calculating the reliability coefficients of scale constructs and item-total correlation. Mean, median and range were calculated for all teaching aspects per training programme. RESULTS: In the course of one year, 16 residency programmes in our academic medical centre implemented the SETQ system for the evaluation of teaching faculty. 398 faculty members and 314 residents were invited to (self-) evaluate; the response rates were 80.9% and 73.6% respectively. Residents conducted 2,520 evaluations in total. Factor analysis resulted in the definition of 5 teaching domains: 'learning climate', 'professional attitude towards residents', 'communication of learning goals', 'evaluation of residents' and 'feedback to residents'. Item-total correlation and reliability were high for both the residents' questionnaire and the self-evaluation questionnaire (Cronbach's alpha: > 0.70), except for the educational aspect 'learning climate' on the self evaluation questionnaire (alpha: 0.67) Faculty members were rated positively, but the self-evaluation of faculty members was slightly less positive. For both groups 'professional attitude towards residents' was the highest scoring teaching domain and 'communication of learning goals' the lowest one. CONCLUSION: Implementing a system for the evaluation of teaching qualities (SETQ) of faculty in an academic hospital was proven feasible. The psychometric qualities of the underlying instruments was sufficient to good. Teaching faculty were evaluated positively, although interdepartmental variations existed. PMID- 20170575 TI - [Pertussis in the Netherlands]. AB - Despite high vaccination coverage, an increasing incidence of pertussis has been observed in recent years, especially among adults. Particularly in children less than three months of age, pertussis can lead to severe complications or even death. The increasing incidence of pertussis has been attributed to various factors, including increased awareness and waning vaccine-induced immunity in combination with pathogen adaptation. Changes in the vaccination schedule, the addition of a booster vaccination and an adjustment of the vaccine itself play an important part in handling this problem. A timely diagnosis of pertussis by a GP followed by antibiotic therapy can prevent potentially severe pertussis in young infants and avoid the spread of the bacteria. Targeting vaccination at adults and health care workers who are in close contact with infants may prevent transmission of pertussis to infants. PMID- 20170576 TI - [Trainee feedback: trainer assessment]. AB - The quality of medical specialty education depends highly on the trainers, i.e. the specialists. Trainees are very important in the assessment of their trainers because they continuously undergo all the important aspects of the training. Currently, periodical announced visits take place, creating a formal atmosphere. A regular, semi-structured questionnaire for the trainees would be a better way of evaluating the program. Additionally there should be a thorough follow-up leading to a system with a process of continuous quality improvement. PMID- 20170577 TI - [A man with acute scrotal swelling]. AB - A 33-year-old man had scrotal pruritus followed by an acute scrotal and proximal penile shaft swelling, due to adult acute idiopathic scrotal edema. PMID- 20170578 TI - [Evaluation of students and teachers]. AB - With respect to evaluating students' and teachers' performance, a distinction is made between assessment for learning and assessment of learning. The former aims at determining how the student can improve to the best extent and the latter at determining how good the student is. These different aspects have considerable implications for the approach to the evaluation of the validity of an instrument. The 'Systematic evaluation of teaching qualities' (SETQ) instrument may be seen either as assessment of performance (learning) or assessment for performance. In a recent study Lombarts et al. focused the validation procedures more on the assessment of performance (of teachers). It is notable that the other approach (assessment for learning) is becoming more popular in the assessment area. If the SETQ is viewed as an instrument for performance improvement, one wonders whether a factor analysis as carried out by Lombarts et al. is the best validation approach or whether possible judgment biases should in fact be the subject of research. In addition, the qualitative comments are more relevant than the numerical outcomes. PMID- 20170579 TI - [A premature with nail defects]. AB - A premature neonate had hypoplastic thumbnails with triangular lunulae and an aplastic left patella, due tot nail-patella-syndrome. PMID- 20170580 TI - [Infectious endophthalmitis after cataract extraction, a serious complication]. AB - Cataract extraction with lens implantation is the most used surgical procedure worldwide and is relatively safe. Nevertheless, this procedure carries the risk for infectious complications, since a foreign body is implanted in the eye to which bacteria that may cause endophthalmitis can adhere. Acute postoperative endophthalmitis is a potentially devastating disease that prompts immediate recognition and therapy, whereas chronic postoperative endophthalmitis is a low virulent, long-lasting infection that is hard to diagnose and for which the choice of treatment should be weighed carefully. We present 2 cases that illustrate both types of endophthalmitis. Before the decision to perform a cataract extraction is taken, the risk of infectious complications has to be considered in the light of the expected visual acuity gained by the procedure. PMID- 20170581 TI - [Abdominal pain caused by mobile caecum with strangulation]. AB - An 84-year-old woman was admitted to the emergency department of the St. Elisabeth Hospital in Curacao for acute diffuse abdominal pain. Her medical history revealed an 'irritable bowel syndrome' with symptoms of chronic progressive abdominal pain. Plain abdominal radiography and computed tomography showed a substantially dilated bowel with torsion of the organ structures and suspected strangulation of the colon. Perioperative examination revealed a distended mobile caecum and right hemicolon. There was also strangulation and herniation of both structures through the foramen of Winslow around the hepatoduodenal ligament, protruding through the minor omentum. After destrangulation and closure of the herniation a caecopexy with an additional appendectomy was performed. Mobile caecum is defined as a failure of the right colon to fuse to the posterior parietal peritoneum. The symptoms of chronic abdominal pain may have been the result of the pre-existing mobile caecum. PMID- 20170582 TI - Seroprevalence of Cysticercus cellulosae and associated risk factors in free range pigs in Kenya. AB - Porcine cysticercosis is an emerging zoonosis with public health and economic importance. A cross-sectional study was undertaken to investigate the disease in free-range pigs on 182 smallholder farms in Busia District, Kenya. The survey households were selected using a snowballing technique. Serum samples were obtained from 284 pigs of all ages at farm level and 37 pigs from slaughter slabs in the study area. The samples were analysed for the presence of cysticercus antigen using an antigen enzyme-linked immunosorbent assay (ELISA). A structured questionnaire was administered to determine the risk factors for porcine cysticercosis on the study farms. At pig level, the total number of pigs testing positive were 11, resulting in a seroprevalence of 4% (95% confidence interval (CI): 1.9-6.2%), while the farms with a positive pig were 9% (95% CI: 3.9-14.1%). All pigs examined in the slaughter slab survey were seronegative. The distribution of possible risk factors for porcine cysticercosis that were observed at farm level was as follows: free-range pig keeping (100%), history of human taeniosis infection in a family (51%), slaughtering of pigs at home (20%), lack of meat inspection (15%) and absence of latrines (15%). The only significant (chi2 = 4.4, P = 0.034, odds ratio (OR) = 3.8) risk factor associated with the occurrence of cysticercosis was lack of latrines at household level. The study shows that porcine cysticercosis is prevalent in free-range pigs in Busia District, Kenya and thus control measures need to be instituted. PMID- 20170583 TI - Vestibular evoked myogenic potentials in patients with fibromyalgia syndrome. AB - OBJECTIVE: To assess vestibular evoked myogenic potentials in patients with fibromyalgia syndrome. METHODS: Twenty-four patients with fibromyalgia syndrome (two men and 22 women) and 21 female controls were included in the study. All patients underwent vestibular evoked myogenic potential testing. RESULTS: Statistical comparison of fibromyalgia patients with control subjects showed a significant difference with respect to n23 latencies and interpeak latencies (p < 0.05). There was no significant difference in p13 latencies, nor in p13 amplitudes, n23 amplitudes or interpeak amplitudes (p > 0.05). CONCLUSIONS: Although patients with fibromyalgia syndrome generally have subjective neurotological symptoms, clinical and laboratory assessments usually fail to detect any objective abnormality. However, it is possible to detect abnormalities on vestibular evoked myogenic potential testing in such patients, indicating dysfunction in the vestibulospinal pathway, possibly in the saccule. Elongation of the n23 latency and of the interpeak latency of waves p13-n23, during vestibular evoked myogenic potential testing, may be a useful, objective indicator demonstrating neurotological involvement in fibromyalgia syndrome patients. Future research investigating the mechanisms of this latency elongation may help increase understanding of the pathogenesis of fibromyalgia syndrome. PMID- 20170584 TI - Bilateral hearing results of 751 unilateral stapedotomies evaluated with the Glasgow benefit plot. AB - AIMS: We aimed to evaluate bilateral hearing function in patients undergoing primary unilateral stapedotomy, according to the 1995 American Academy of Otolaryngology, Head and Neck Surgery guidelines and the Glasgow benefit plot. We also aimed to analyse the effect of pre-operative hearing impairment type on post stapedotomy hearing. STUDY DESIGN: Retrospective chart review. METHODS: Medical records relating to 1369 stapedotomies performed by the senior author (JJH) from 1991 to 2006 were reviewed. Seven hundred and fifty-one patients undergoing primary unilateral stapedotomy were included. Hearing results for these patients were evaluated according to the criteria of the 1995 American Academy of Otolaryngology, Head and Neck Surgery Committee on Hearing and Equilibrium guidelines, and the Glasgow benefit plot. Subgroups of patients with pre operative unilateral, bilateral symmetrical and bilateral asymmetrical hearing loss were separately analysed. RESULTS: The most successful results, as regards the achievement of bilateral, socially serviceable hearing, were demonstrated in patients with unilateral hearing loss; 78 per cent of these patients had normal hearing post-operatively. Overall, patients' achievement of bilateral, socially serviceable hearing correlated highly with their type of pre-operative hearing impairment (r = 0.74). Normal post-operative hearing levels also correlated with pre-operative bone conduction (r = 0.61). CONCLUSION: This study represents the largest reported series of primary stapedotomy cases evaluated with the Glasgow benefit plot. Patients' bilateral post-operative hearing function depended on their type of pre-operative hearing impairment. Pre-operative bone conduction thresholds, corrected for Carhart's effect, were useful in predicting achievable post-operative air conduction. PMID- 20170585 TI - Early intervention for cognitive decline: can cognitive training be used as a selective prevention technique? AB - BACKGROUND: Cognitive training (CT) may be effective as a therapeutic strategy to prevent cognitive decline in older adults. This review evaluates CT as a preventive tool at various stages of a prevention hierarchy with specific reference to healthy older adults, "at risk" and clinical populations. It also considers the underlying mechanism of CT, namely that which suggests that CT acts via promoting neuroplasticity. METHODS: Evidence for CT in healthy, "at risk" and clinical populations has been systematically reviewed elsewhere. This review re examines several studies in each group to clarify the potential of CT as a preventive technique, with a key focus on the secondary level of prevention. RESULTS: Studies in healthy older adults and those with mild cognitive impairment are largely positive and suggest that CT has the potential to improve cognition. However, findings in relation to Alzheimer's disease are mixed. Limitations of existing research include diverse methodologies and CT programs, small samples, insufficient focus on functional outcomes, sustainability and generalization of effects and the need for imaging data to delineate mechanisms of change. Additionally, there is limited data on those with late-life depression, despite this being an independent risk factor for dementia. CONCLUSIONS: CT offers promise as a preventive therapeutic technique in healthy older adults and particularly as a secondary prevention method for "at risk" groups. Future investigations need to focus on methodological constraints and delineating possible neuroplastic mechanisms of action. Nonetheless, CT programs may represent a viable, non-pharmacological early intervention strategy, as they are easily-implemented, engaging and promote social interaction in group settings. PMID- 20170586 TI - Adjunct treatment with levodopa in a patient with dementia with Lewy bodies, delusions and severe neuroleptic hypersensitivity syndrome: some comments. PMID- 20170587 TI - Development and validation of the Caregiver Guilt Questionnaire. AB - BACKGROUND: Family care of frail elderly people has been linked to significant negative consequences for caregivers' mental health. Although outcome variables such as burden and depression have been widely analyzed in this population, guilt, an emotion frequently observed in caregivers, has not received sufficient attention in the research literature. METHODS: Face-to-face interviews were carried out with 288 dementia caregivers. Guilt was measured using the Caregiver Guilt Questionnaire (CGQ). RESULTS: Using principal components analysis, 22 items were retained and five factors were obtained which explained 59.25% of the variance. These factors were labeled: guilt about doing wrong by the care recipient, guilt about not rising to the occasion as caregivers, guilt about self care, guilt about neglecting other relatives, and guilt about having negative feelings towards other people. Acceptable reliability indexes were found, and significant associations between the CGQ and its factors and the Zarit Burden Interview guilt factor were also found. Caregivers with higher scores on the CGQ also scored higher in depression, anxiety, frequency and appraisal of behavioral problems. Negative associations between the CGQ and its factors and frequency of/and satisfaction with leisure and social support were also found. Being female and caring for a parent were associated with higher scores on the CGQ. CONCLUSIONS: Feelings of guilt are significantly related to caregiver distress. The CGQ may be a useful measure for acknowledging feelings of guilt in caregivers; moreover, it can be used as an outcome variable for psychoeducational interventions aimed at reducing caregiver distress. PMID- 20170588 TI - Wandering and fecal smearing in people with dementia. AB - BACKGROUND: Wandering and fecal smearing (scatolia) are among the problematic behaviors in dementia, and many caregivers are troubled by these behaviors. The purpose of this study was to clarify the clinical characteristics of patients with these symptoms. METHODS: We performed a questionnaire survey. The questionnaire items were the age, sex, living environment, diagnosis, cognitive function, and activities of daily living. Other clinical characteristics were evaluated using the quality of life (QOL) questionnaire for dementia. RESULTS: A total of 246 patients with dementia were rated. Wandering was observed frequently in 23%, sometimes in 12%, rarely in 14%, and never in 51% of the patients; scatolia was observed frequently in 2%, sometimes in 8%, rarely in 15%, and never in 75%. Wanderers were more frequent among those with severe dementia. They displayed more restlessness, positive affect and attachment to others with respect to QOL. The patients with scatolia tended to get lower scores in tests of cognitive function and displayed more negative affect/actions with respect to QOL. Both wanderers and patients with scatolia suffered from insomnia more frequently. CONCLUSIONS: These results suggest that both wandering and scatolia are behavioral symptoms intimately associated with cognitive dysfunction and insomnia. PMID- 20170589 TI - Behavioral variant of frontotemporal dementia mimicking Huntington's disease. AB - Behavioral changes and cognitive decline are the core clinical manifestations in the behavioral variant of frontotemporal dementia (bv-FTD). The behavioral changes may include characteristic stereotypic movements. These movements, although without clear purpose, are not involuntary. Involuntary movements are usually not seen in FTD.Two patients with involuntary choreoathetoid movements but otherwise presenting a bv-FTD-phenotype were referred and Huntington's disease (HD) was suspected. The diagnoses of bv-FTD were made after comprehensive assessment and exclusion of other diagnoses, including HD and Huntington's disease-like (HDL) phenotypes. Although a definite diagnosis will require neuropathological confirmation, we conclude that a HDL phenotype may be part of the clinical spectrum of the bv-FTD phenotype. PMID- 20170590 TI - Eating disorders in the elderly. AB - BACKGROUND: Eating disorders in the elderly are often overlooked. When they occur, significant morbidity and mortality result. In this study we review all existing literature on eating disorders in the elderly and provide practical guidelines for clinicians in recognizing and managing eating disorders in the elderly. METHODS: A literature search using Medline, PubMed, Web of Knowledge, and PsychINFO revealed 48 published cases of eating disorders in people over the age of 50 years. RESULTS: The mean age was 68.6 years (range 50-94), and the majority (88%) of cases were females. The majority (81%) of cases had anorexia nervosa, and 10% had bulimia nervosa. Late onset eating disorders were more common (69%) than early onset. Comorbid psychiatric conditions existed in 60%, most commonly major depression. Management with a combination of behavioral and pharmacologic interventions was most successful, although only 42% were treated successfully. Mortality was high (21%) secondary to the eating disorder and its complications. CONCLUSION: Eating disorders do occur in the elderly and should be included in the differential diagnosis of unexplained weight loss in the elderly. PMID- 20170591 TI - Acute and long-term effects of grape and pomegranate juice consumption on vascular reactivity in paediatric metabolic syndrome. AB - OBJECTIVES: This study, which to the best of our knowledge is the first of its kind, aimed to determine the acute and long-term effects of the consumption of grape and pomegranate juices on endothelium function in adolescents with metabolic syndrome, and to compare the effects of these two kinds of juices. METHODS: This randomised controlled clinical trial was conducted in 2008 among 30 adolescents, aged 12-15 years, with metabolic syndrome. Participants were randomly assigned to two groups of equal number; one group was asked to drink 18 millilitre per kilogram per day of natural grape juice and the other group was asked to drink 240 millilitre per day of natural pomegranate juice once daily for 1 month. Juices were homemade without any added sweetener. Basal brachial artery dimension and flow-mediated dilation as an index of endothelial function and endothelial-dependent dilation after receiving nitoglycerin spray were evaluated by high-resolution B mode ultrasonography before juice consumption, 4 hours and 30 days after regular daily consumption. RESULTS: Flow-mediated dilation at 90 seconds and after nitoglycerin significantly improved at 4 hours and at 1 month after drinking both kinds of juices, without significant difference between the two groups. The change at 1 month versus 4 hours was significant only in the grape juice group. CONCLUSION: Daily consumption of diets rich in antioxidants might improve endothelial function in adolescents with metabolic syndrome. These effects began as soon as 4 hours after juice consumption. Such beneficial effects should be considered in dietary recommendations for the paediatric age group, notably in obese individuals. PMID- 20170592 TI - Mosquito density forecast from flooding: population dynamics model for Aedes caspius (Pallas). AB - Insect population dynamics depend strongly on environmental factors. For floodwater mosquitoes, meteorological conditions are crucial in the rhythm of mosquito abundances. Indeed, rainfall triggers the egg hatching after flooding breeding sites, and temperature controls the duration of the aquatic immature development up to adult emergence. According to this, we have developed a simple mechanistic and tractable model that describes the population dynamics of floodwater mosquitoes as a function only of the most accessible meteorological variables, rainfall and temperature. The model involves three parameters: development duration tdev of the immature aquatic stages, the adult emergence rate function f(t) (characterized by the emergence time scale tau and shaping the profile of adult population abundance), and the depletion rate, alpha, of adult disappearance. The developed model was subsequently applied to fit experimental field data of the dynamics of Aedes caspius (Pallas), the main pest mosquito in southern France. First, it was found that the emergence rate function of adult mosquitoes very well reproduce experimental data of the dynamics of immature development for all sampled temperatures. The estimated values of tdev and tau both exhibit Arrhenius behaviour as a function of temperature. Second, using the meteorological records of rainfall and temperature as inputs, the model correctly fit data from a two-site CO2 trapping survey conducted in 2004 and 2005. The estimated depletion rates (summation of the mortality and the emigration rates) were found to be a concave quadratic function of temperature with a maximum of 0.5 per days at about 22 degrees C. PMID- 20170594 TI - A new update: Urology best practices for the primary care physician (PCP). PMID- 20170593 TI - Lung abscess in adults with tetralogy of fallot and pulmonary atresia. AB - We describe 5 adults with tetralogy of Fallot and pulmonary atresia who developed lung abscesses, including some infected with atypical microbial pathogens, with important morbidity. We hypothesize that patients with such anatomy are at risk for chronic pulmonary infection due to hypo-perfusion of the pulmonary parenchyma. This previously unreported clinical association should be considered in the differential diagnosis of patients with tetralogy of Fallot and pulmonary atresia who alter their respiratory state. PMID- 20170595 TI - Erectile dysfunction and low testosterone: cause or an effect? AB - Studies have repeatedly confirmed that about 52% of men between the ages of 40 and 70 years have some degree of erectile dysfunction (ED). Other studies have shown that as a man ages, his testosterone level will naturally decrease. Over the last number of years, we have also seen that ED may be one of the earliest signs and markers of endothelial dysfunction. There appears to be an overlap between ED, metabolic syndrome, and symptomatic late onset hypogonadism (SLOH). It is very important for the primary care physician to identify patients who are suffering from ED and/or hypogonadism, and to also identify any other existing comorbidities. This article discusses the suggested work up, diagnosis, and management of men who present with either ED or symptoms and signs suggestive of hypogonadism (low testosterone). It also discusses the potential relationship between these conditions and metabolic syndrome. PMID- 20170596 TI - Overactive bladder symptoms in women: current concepts in patient management. AB - The symptoms of overactive bladder (OAB) -- urinary urgency, frequency, and urge incontinence -- can cause significant lifestyle limitations. Social isolation, depression, employment difficulties, and relationship stress are common findings in patients with this condition. This article focuses on women with OAB who are seen in primary care. Occasionally, OAB (or detrusor overactivity) may be the result of neurological disease, metabolic disease, or urinary tract abnormalities. Primary care practitioners can play a key role in identifying affected individuals by including a focused question in every annual patient physical assessment. Investigation and treatment can then be initiated, beginning with behavioral modification strategies (such as modifying fluid intake) and adding antimuscarinic pharmacotherapy or possibly local estrogen therapy where needed. Only patients with certain concurrent diseases or those who are refractory to conventional management will require referral to a specialist. PMID- 20170597 TI - Prostate-specific antigen tests and prostate cancer screening: an update for primary care physicians. AB - Prostate cancer is a highly prevalent malignancy. Using serum prostatic-specific antigen (PSA) levels to screen for prostate cancer has led to a greater detection of this cancer, at earlier stages. However, screening for prostate cancer by determining PSA levels remains controversial. Concerns include the risk of overdiagnosis and conversely, the failure to detect all prostate cancers. This article, aimed at primary care practitioners, reviews the characteristics of an ideal screening test, in relation to the characteristics of the PSA test. It then discusses the implications of recent findings from two large, randomized, prospective screening trials: the American Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) screening trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial. The latter trial demonstrated a modest survival benefit from PSA screening. Lastly, the article summarizes recommendations from recently updated guidelines about PSA testing from the American Urological Association (AUA), and it discusses when a primary care practitioner might refer a patient to a urologist. PMID- 20170598 TI - Management of benign prostatic hyperplasia by family physicians. AB - The past decade has profoundly changed how physicians manage patients with benign prostatic hyperplasia (BPH). The concepts of symptom indices, symptom complexes, flow rates, prostate-specific antigen (PSA), prostate size and new medical approaches supported by new clinical studies, have provided family practitioners as well as specialists with evidence-based management algorithms to treat BPH. Men with BPH most often visit a physician due to their partner's urging because of the many symptoms, with the most bothersome being nocturia. Today, primary care physicians are the gatekeepers for diagnosing and managing lower urinary tract symptoms (LUTS) in men. They need to be aware of long term negative consequences if these major symptoms are not treated early. PMID- 20170599 TI - Uropharmacology in primary care: 2010 update. AB - Many disorders such as erectile dysfunction, overactive bladder, hypogonadism and benign prostatic hypertrophy have traditionally been managed primarily by urologists. The development of newer agents to treat many of these conditions has allowed the primary care provider to manage many of these common conditions. The use of these newer medications has become commonplace in the primary care setting. This article will update some of the most commonly used urologic medications to optimize patient management strategies by the primary care provider or in coordination with the urologist. PMID- 20170600 TI - Coping with potentially incompatible identities: accounts of religious, ethnic, and sexual identities from British Pakistani men who identify as Muslim and gay. AB - This study explores how a group of young British Muslim gay men (BMGM) of Pakistani background in non-gay affirmative religious contexts understood and defined their sexual, religious, and ethnic identities, focusing upon the negotiation and construction of these identities and particularly upon strategies employed for coping with identity threat. A total of 12 BMGM were interviewed using a semi-structured interview schedule. Transcripts were subjected to qualitative thematic analysis as described by Braun and Clarke. The aim was to explore participants' lived experiences through the interpretive lens of identity process theory. Four superordinate themes are reported, entitled 'I'm gay because ... ': making sense of gay identity, 'It's all about temptation': invoking religious discourses to explain sexual identity, 'Going against God': fear of divine retribution, 'It's easier to be gay here': external attributions and British national identity. The data suggest the existence of an additional identity principle, which is referred to as the psychological coherence principle. This motive represents the need to ensure a sense of coherence between existing identities, and we discuss how individuals may adopt strategies to deal with threats to the principle. PMID- 20170601 TI - Longitudinal modelling of academic buoyancy and motivation: do the '5Cs' hold up over time? AB - BACKGROUND: Academic buoyancy is students' ability to successfully deal with setbacks and challenges that are typical of academic life. The present study extends previous preliminary cross-sectional work that tentatively identified five motivational predictors of academic buoyancy - referred to as the '5Cs' of academic buoyancy: confidence (self-efficacy), coordination (planning), commitment (persistence), composure (low anxiety), and control (low uncertain control). AIMS: The study seeks to more clearly ascertain the effects of motivation (and its mediating role) on academic buoyancy over and above prior academic buoyancy. SAMPLE: The study comprised N=1,866 high school students from six schools. METHOD: Longitudinal data were collected (1 year apart) and the hypothesized model exploring longitudinal effects was tested using structural equation modelling. RESULTS: After controlling for prior variance in academic buoyancy, the 5Cs were significant predictors of subsequent academic buoyancy. Furthermore, over and above the direct effects of prior academic buoyancy on subsequent academic buoyancy, the 5Cs significantly mediated this relationship. CONCLUSIONS: The study concludes with a discussion of the substantive, applied, and methodological implications for researchers and practitioners seeking to investigate and address the academic buoyancy of students who require the capacity to effectively function in an ever-challenging school environment. PMID- 20170602 TI - Assessing metacognition in schizophrenia with the Metacognition Assessment Scale: associations with the Social Cognition and Object Relations Scale. AB - OBJECTIVES: Impairments in metacognition are believed to be closely linked with functional impairments among persons with schizophrenia. Recently, we proposed a method for assessing multiple domains of metacognition by rating a narrative generated by a semi-structured interview with an abbreviated form of the Metacognition Assessment Scale (MAS). Less is known about how this measure is linked to social cognition. DESIGN: The current study sought to compare, in a cross-sectional design, assessments of metacognition using the MAS and social cognition measured using the Social Cognition and Object Relations Scale (SCORS). METHODS: Participants were 37 adults with schizophrenia spectrum disorders who completed an assessment battery that included the Hopkins Verbal Learning Test, Wisconsin Card Sorting Test, the Positive and Negative Syndrome Scale, and the procedures needed to derive the MAS and SCORS indices. RESULTS: Univariate correlations and multiple regressions revealed that mastery, a domain of metacognition measuring thinking about oneself and coping with psychological challenges, was linked to SCORS indices which assess awareness of interpersonal relationships as the result of complex psychological forces and the recognition that relationships involve people with independent needs. This relationship persisted when the effects of symptoms and neurocognitive deficits were statistically controlled. CONCLUSIONS: Mastery, one domain of metacognition, is linked to social cognition independent of neurocognitive function and symptoms. PMID- 20170603 TI - Psychosomatic symptoms and the 'group mind'. AB - OBJECTIVES: In this work, we propose a model, designed to understand mental symptoms and adapted for the analysis of psychosomatic symptoms, to be used as a tool to represent group phenomena, named the 'group mind'. DESIGN: A revision of the relevant literature on the concept of 'group mind' and psychosomatics, and the presentation of the Cambridge model. METHODS: We describe how unformatted experiences can appear as somatization, and how this process can be corrected via mental representations. Group dynamics can function creating these representations and thus contribute to solving psychosomatic symptoms. We refer to W. R. Bion's concepts, mainly the ones on proto-thoughts and the proto-mental system, comparing them to the proposed model and giving a foundation to this conceptual representation. We illustrate with four cases of clinical interaction. CONCLUSIONS: Psychotherapeutic groups are privileged places to comprehend and transform psychosomatic symptoms. The Cambridge model allows a representation of these processes. Further studies are necessary to assess its validity, test its adequacy, and expand its possibilities. PMID- 20170604 TI - [Hemodynamic monitoring from macrocirculation to microcirculation]. PMID- 20170605 TI - [Pay emphasis to problems in cardiopulmonary resuscitation]. PMID- 20170606 TI - [Early goal rescue therapy in cardiovascular emergency]. PMID- 20170607 TI - [Cardiopulmonary resuscitation by squeezing heart against diaphragm through laparotomy]. PMID- 20170608 TI - [Message measurement and feedback cardiopulmonary resuscitation board: a monitor for standard cardiopulmonary resuscitation]. AB - OBJECTIVE: To invest a message measurement and feedback cardiopulmonary resuscitation (CPR) board which could guide the first aid to perform standard CPR. METHODS: The multifunctional and intelligent CPR board which could not only support but also provide standard parameters and frequency of compression for first aid was placed underneath the patient's back, with his head in the concave headrest at the top of the board. The operator exerted chest compression with his hands according to the 2005 American heart association (AHA) guidelines for CPR, and adjusted the pressure and rate according to that showed on the board to achieve the force and frequency of chest compression according to the standard. RESULTS: The operation of the chest compression which was carried out on the message measurement and feedback CPR board was significantly better than that carried out on the ordinary board because that the former could show the pressure and rate of chest compression, so it could guide the first aid to attain an optimal CPR according to the standard. Furthermore, as the force of chest compression exerted was optimized, adverse effects of forcible chest compression such as fracture of sternum or ribs could be avoided. CONCLUSION: The message measurement and feedback CPR board is able to feed back the pressure and rate of the process of chest compression in CPR. Therefore, it can help monitor the CPR manipulation, thus improves its quality and also avoids unfavorable side effects. PMID- 20170609 TI - [The clinical application of the emergency remedial transthoracic cardiac pacing used by a steel wire loop electrode]. AB - OBJECTIVE: To explore an effective method of emergency remedial cardiac pacing and evaluate its clinical application. METHODS: The transthoracic cardiac pacing was used by a steel wire loop electrode to 18 patients with cardiac arrest or serious bradycardia, after a routine cardiac pacing was failed by way of jugular or subclavian vein. RESULTS: It is a simple procedure used by steel wire loop. All the pacing had been successfully captured the hearts except 5 cases without capturing. There were 3 cases of cardiac arrest, 2 cases of cardiac arrest after electric defibrillation, 1 case of cardiac arrest after electric shock because of ventricular running and all the 5 cases of severe cardiac bradycardia due to serious atrioventricular block caused by high blood potassium were survived. Eight cases of cardiac arrest were successful capture, that was due to the short period of time from cardiac arrest to ventricle puncture than that of 5 cases of ventricular pacing which was not successful [(17.6+/-4.6) minutes vs. (26.4+/ 5.4) minutes, P<0.05]. CONCLUSION: The steel wire loop electrode is a safe and reliable emergency cardiac pacing method, which contribute to the rapid establishment of an effective emergency cardiac pacing. When the conventional intravenous cardiac pacing was not successful, the method of emergency transthoracic cardiac pacing used by steel wire loop electrode should be bold and use to improve the successful rate of resuscitation. PMID- 20170610 TI - [Extracorporeal cardiopulmonary resuscitation in adult patients with cardiac arrest]. AB - OBJECTIVE: To review the experience of extracorporeal cardiopulmonary resuscitation (E-CPR) for cardiac arrest in adults. METHODS: From July 2005 to July 2009, extracorporeal life-support (ECLS) was performed for 10-15 minutes failed in CPR in 11 patients (male 7, female 4, age 24-71 years) with cardiac arrest. In 7 patients after cardiac operation, regular cardiopulmonary bypass was urgently established through re-opening of sternotomy incision, followed by extracorporeal membrane oxygenation (ECMO) for continuous support. In other 4 patients, ECMO implantation was directly performed through the femoral vessels during the CPR. RESULTS: With E-CPR support, although the average CPR duration prolonged to (51+/-14) minutes (30-90 minutes), successful resuscitation was achieved in 10 patients with restoration of spontaneous heart beat. Median support duration of ECMO was 126 hours, ranged from 2 to 223 hours. Six patients could be successfully weaned from ECMO. However, the final discharge rate was 36.4% (4/11). Additional intra-aortic balloon pump was used in 2 patients, with 1 patient survived. Continuous renal replacement therapy (CRRT) was necessary in 3 patients because of acute renal failure. CONCLUSION: The use of E-CPR can rescue some adult patients who fail to survive with conventional in-hospital CPR. Further studies are warranted to evaluate in order to better define patients who may benefit from E-CPR. PMID- 20170611 TI - [The influence of hypothermia therapy on enzymology and pathology of lung after cardiac arrest]. AB - OBJECTIVE: To study the effect of hypothermia on pro-inflammatory mediators in serum, the enzymology and pathology of lung tissue. METHODS: Ventricular fibrillation for 4 minutes was induced in 10 domestic pigs. Standard cardiopulmonary resuscitation was given to them. They were then divided into two groups according to the random table after restoration of spontaneous circulation (ROSC): low temperature group (n=5): pigs were given an infusion 30 ml/kg of 4 centigrade normal saline (NS) at an infusion rate of 1.33 ml * kg(-1) * min(-1), started after ROSC for 22 minutes, then 10 ml * kg(-1) * h(-1) for 4 hours; ambient temperature group (n=5) received the same infusion of NS in room temperature. Hemodynamic parameters were observed, blood samples were collected to measure tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in serum before ventricular fibrillation and 10 minutes, 2 hours, 4 hours after ROSC. Na(+)-K(+)-ATPase of lung tissue was determined 24 hours after ROSC, and the pathology and ultrastructure of the lung were studied. RESULTS: There was no significant difference in the hemodynamic parameters, except the temperature, between low temperature and ambient temperature groups. TNF-alpha contents at 10 minutes, 2 hours, 4 hours after ROSC in low temperature group were (15.55+/ 1.65), (17.06+/-0.86), (12.52+/-1.82) ng/L, and the IL-6 contents were (173.80+/ 15.01), (184.09+/-13.44), (73.17+/-6.95) ng/L, while the TNF-alpha contents at 10 minutes, 2 hours, 4 hours after ROSC in ambient temperature group were (20.09+/ 1.32), (26.18+/-1.16), (29.18+/-1.20) ng/L, and the IL-6 contents were (176.92+/ 16.68), (239.17+/-13.18), (405.48+/-55.49) ng/L. The pro-inflammatory mediators in low temperature group were reduced significantly (P<0.05 or P<0.01). Low temperature could significantly reduce the activity of Na(+)-K(+)-ATPase [(3.78+/ 1.14) U/L vs. (6.22+/-1.23) U/L, P<0.01]. The pathology of lung was milder in low temperature group compared with that of ambient temperature group. CONCLUSION: Hypothermia therapy with infusion of 4 centigrade NS can reduce the release of pro-inflammatory mediators, inhibit the ATPase activity of alveolar membrane, and shows a protective effect on lung tissue against low perfusion. PMID- 20170612 TI - [Effects of hypertension state induced by norepinephrine on liver in a swine model of cardiopulmonary resuscitation]. AB - OBJECTIVE: To study the effects of norepinephrine (NE)-induced hypertension (HT) on hepatic function and pathology after restoration of spontaneous circulation (ROSC) by cardiopulmonary resuscitation (CPR) in swine. METHODS: After 4 minutes of induced ventricular fibrillation (VF), standard CPR was carried out, and then the NE was pumped after ROSC. The survivors were then divided into two groups by the random digits table. In the HT group (n=5) the mean arterial pressure (MAP) was maintained at 130% of the baseline (MAP before VF), and in the normal pressure (NP) group (n=5) the MAP was maintained at the baseline level. At the same time, the animals of two groups received normal saline at the speed of 10 ml * kg(-1) * h(-1). Hemodynamic status was monitored and aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) were measured in blood samples obtained at baseline and at 10 minutes, 2 hours and 4 hours after ROSC. At 24 hours after ROSC, the animals were killed and the liver was removed to determine Na(+)-K(+)-ATPase and Ca(2+)-ATPase activities and pathological changes under light and electron microscopy. RESULTS: The heart rate (HR), MAP, cardiac output (CO) and coronary perfusion pressure (CPP) were obviously higher, while the oxygen extraction ratio was lower in the HT group than in the NP group. Compared with NP group, AST in the HT group was lower at ROSC 2 hours, 4 hours [ROSC 2 hours: (110.5+/-12.1) U/L vs. (141.8+/-8.1) U/L; ROSC 4 hours: (118.2+/-14.1) U/L vs. (175.0+/-14.3) U/L, both P<0.05], LDH was lower at ROSC 4 hours [(18.1+/-1.9) micromol * s(-1) * L(-1) vs. (20.7+/-1.9) micromol * s(-1) * L(-1), P<0.05], but ALT showed no significant difference between two groups after ROSC. ATPase activity in the HT group [Na(+)-K(+) ATPase: (2.054+/-0.716) U, Ca(2+)-ATPase: (1.889+/-0.450) U] was a little lower than that of the NP group [Na(+)-K(+)-ATPase: (3.274+/-0.710) U, Ca(2+)-ATPase: (2.746+/-0.778) U], but without statistical significance (both P>0.05). Compared with the NP group, there was less cellular edema, necrosis or inflammatory cells infiltration, and less damaged mitochondria in HT group. CONCLUSION: These data suggest that HT induced by NE helps to maintain stable hemodynamic status and oxygen metabolism, and may protect the liver in terms of function and cellular injury after CPR. PMID- 20170613 TI - [The significance of the changes in expressions of heat shock protein 70 and heme oxygenase-1 in the myocardium in patients died suddenly due to acute myocardial infarction]. AB - OBJECTIVE: To investigate the changes and its clinical significance of the expressions of the mRNA and protein of heat shock protein 70 (HSP70) and heme oxygenase-1 (HO-1) genes in the myocardium of acute myocardial infarction (AMI) areas in patients who died suddenly due to AMI. METHODS: Specimens of myocardial tissue at infarct site was obtained during autopsy from 18 patients who died suddenly due to AMI, and they were enlisted as study group, and that of myocardial tissue from 17 normal hearts of patients died rapidly after accidents were as control group. The levels of mRNA expression of HSP70 and HO-1 genes were measured in all the specimens by reverse transcription-polymerase chain reaction (RT-PCR) using cDNA samples, and the levels and locations of HSP70 and HO-1 protein expressions in myocardial cells of all specimens were examined by immunohistochemistry (IHC), and the pathological changes in the myocardial tissue were observed. RESULTS: The expressions of HSP70 mRNA (0.841+/-0.058), HO-1 mRNA (0.918+/-0.161) and HSP70 protein (3 556.68+/-574.19), HO-1 protein (4 336.68+/ 865.30) in the myocardium of the AMI areas in the study group were significantly higher than those in control group (the expressions of HSP70 mRNA: 0.105+/-0.034, HO-1 mRNA: 0.086+/-0.053, HSP70 protein: 289.21+/-68.51, HO-1 protein: 1 556.78+/ 506.26, all P<0.01), and a weak expression of HSP70 and HO-1 protein was found in the cardiocytes of the AMI area in study group. In the control group, HSP70 protein expression was negative in the cardiocytes, and there was a weak expression of HO-1 protein in the cardiocytes. There was a significant positive correlation between the expressions of mRNA and protein of HSP70 and HO-1 genes at the cardiocytes of patients died suddenly of AMI in study group (r(1)=0.865, r(2)=0.816, both P<0.01). CONCLUSION: HSP70 and HO-1 probably were both involved in the pathological and physiological processes of AMI, while HO-1 may express in cardiocytes, but it is more abundant in the cardiocytes in the AMI area. PMID- 20170614 TI - [Role of intestinal lymphatic in myocardial injury in rats receiving hemorrhage and lipopolysaccharide challenge]. AB - OBJECTIVE: To explore the effect of mesenteric lymph duct ligation in protecting myocardial injury in rats after hemorrhage and lipopolysaccharide (LPS) challenge. METHODS: Wistar rats were randomly divided into the sham group, non ligation group and ligation group, and the "two-hit" injury model was reproduced by hemorrhage and LPS administration. Mesenteric lymph was blocked by ligating mesenteric lymph duct in ligation group after hemorrhage. After 24 hours of the assault, myocardial tissue was harvested and homogenized. The activity of myeloperoxidase (MPO) and ATPase and the contents of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were determined in myocardial homogenate. At the same time, myocardium was pathologically studied. Apoptosis cell rate of myocardium was determined by method of terminal-deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL), the expression of bcl-2 and bax protein was determined by immunohistochemical method. RESULTS: After hemorrhage and LPS challenge, the level of MPO [(0.23+/-0.08) U/g], TNF-alpha [(9.99+/-2.74) microg/g] and IL-6 [(31.57+/-12.71) microg/g] in myocardial homogenate of non ligation group were significantly higher than those of sham group [MPO: (0.12+/ 0.03) U/g, TNF-alpha: (4.17+/-1.35) microg/g, IL-6: (17.86+/-5.17) microg/g, respectively, all P<0.01], and the activity of ATPase was significantly lower. MPO [(0.13+/-0.03) U/g], TNF-alpha [(5.57+/-1.65) microg/g] and IL-6 [(23.24+/ 5.95) microg/g] in myocardial homogenate of ligation group were significantly lower (P<0.05 or P<0.01), and the ATPase activity was significantly higher compared with non-ligation group. The apoptosis rate [(22.7+/-6.9)%] and expression of bax protein (104.5+/-11.4) of myocardial cells in non-ligation group were significantly higher compared with sham group [apoptosis rate: (3.8+/ 1.2)%, bax protein: 142.1+/-10.9] and ligation group [apoptosis rate: (8.4+/ 2.8)%, bax protein: 128.4+/-9.6], and expression of bcl-2 protein of non-ligation group (196.4+/-19.3) was significantly lower than that of sham group (132.2+/ 12.3) and ligation group (165.1+/-11.6, all P<0.01). CONCLUSION: The results demonstrate that the mesenteric lymph duct ligation ameliorate the myocardial injury in rats subjected to hemorrhage and LPS by reducing the inflammatory mediators of TNF-alpha and IL-6 levels, upregulating the bcl-2 protein expression and improving membrane ATPase activity of myocardium. PMID- 20170615 TI - [Protective effects of hypoxia-inducible factor-1 alpha on myocardial ischemia/reperfusion injury in rat and the role of protein kinase C in signal pathway]. AB - OBJECTIVE: To study the expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in a rat model of myocardial ischemia/reperfusion injury (IRI) and the role of protein kinase C (PKC) in signal pathway. METHODS: A rat model of myocardial IRI was reproduced by 30 minutes of left anterior descending coronary artery (LCA) occlusion followed by 180 minutes of reperfusion. Thirty-two healthy male Wistar rats were randomly divided into four groups. The first group was ischemic preconditioning (IPC) group; the second group was simple IRI group; the third group was IPC plus PKC inhibitor group (IPC+I group); the fourth group was the sham-operation group without ligation of LCA. Eight rats were used in each group. The heart was harvested 180 minutes post-reperfusion, the mRNA and protein expression of HIF-1 alpha and heme oxygenase-1 (HO-1) were assessed. Meanwhile, the protein expression of caspase-3 was assayed. Blood samples were obtained from heart to determine the levels of interleukin-8 (IL-8) and myeloperoxidase (MPO). RESULTS: The mRNA and protein expression of HIF-1 alpha and HO-1 increased significantly in the IRI group compared with the sham-operation group, while the protein expression of caspase-3 increased significantly in the IRI group (HIF-1 alpha mRNA: 0.849+/-0.032 vs. 0.356+/-0.022, HIF-1 alpha protein: 0.762+/-0.042 vs. 0.324+/-0.016, HO-1 mRNA: 0.862+/-0.045 vs. 0.332+/-0.012, HO-1 protein: 0.792+/-0.044 vs. 0.335+/-0.031, caspase-3 protein: 0.371+/-0.015 vs. 0.061+/ 0.012, respectively, all P<0.01). The levels of IL-8 and MPO increased significantly in the IRI group [IL-8: (812+/-26) ng/L vs. (72+/-13) ng/L, MPO: (78.7+/-2.9) kU/L vs. (13.3+/-1.5) kU/L, both P<0.01]. The protein and mRNA expression of HIF-1 alpha and HO-1 increased significantly in the IPC group compared with IRI group (HIF-1 alpha mRNA: 1.412+/-0.039, HIF-1 alpha protein: 1.362+/-0.045, HO-1 mRNA: 1.523+/-0.038, HO-1 protein: 1.420+/-0.041, respectively), meanwhile the protein expression of caspase-3 (0.129+/-0.019) decreased significantly in the IPC group (all P<0.01). The levels of IL-8 [(432+/ 59) ng/L] and MPO [(43.2+/-5.9) kU/L] decreased significantly in the IPC group compared with IRI group (both P<0.01). All above parameters showed no significant change between IPC+I group and IRI group. CONCLUSION: HIF-1 alpha plays a protective role in myocardial IRI, PKC is an important signal pathway of HIF-1 alpha gene expression in IRI. PMID- 20170616 TI - [Amelioration of myocardial ischemia/reperfusion injury by leptin pretreatment and ischemic preconditioning in mouse]. AB - OBJECTIVE: To study the effects and role of leptin pretreatment and ischemic preconditioning (IPC) on the reduction of myocardial ischemia/reperfusion injury (MIRI) in mouse. METHODS: Thirty-six male C57BL/6 mice were randomized into five groups: (1)sham operation group (n=12); (2) brief ischemia/reperfusion (I/R) treatment group (n=6), in which the mice were subjected to three cycles of a 3 minute regional ischemia followed by a 5-minute reperfusion (I/R cycle); (3) MIRI group (n=6), in which MIRI was established in the mice by blocking anterior descending branch of left coronary artery for 30 minutes, followed by 120 minutes reperfusion; (4) IPC group (n=6), in which three I/R cycles were performed on the mice followed by the MIRI protocol; (5) leptin pretreatment group (leptin group, n=6), in which 50 microg/kg of leptin was injected intraperitoneally to the mice 30 minutes before myocardial ischemia. From 6 mice of the sham operation group and from the mice of brief I/R group, serum samples were collected at different time points (0, 5, 30 and 120 minutes) after reperfusion to measure changes in serum leptin level. From the rest of the mice, blood and heart samples were harvested at 120 minutes after reperfusion to analyze the myocardial function and infarct size, leptin, myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF alpha), and interleukin-6 (IL-6) levels. RESULTS: IPC procedure resulted in an increase in serum leptin level shortly after reperfusion. The leptin level increased significantly than that of sham operation group [(6.24+/-2.34) microg/L vs. (1.35+/-0.45) microg/L] at 5 minutes after I/R, and reached the peak value of (12.36+/-1.33) microg/L at 30 minutes after I/R. Then it gradually decreased to its original (0 minute after reperfusion) value [(1.96+/-1.33) microg/L] at 120 minutes after I/R. There was no difference compared with sham operation group [(1.16+/-0.25) microg/L, P>0.05]. Administration of leptin or IPC before MIRI significantly reduced infarct size [(11.50+/-2.26)%, (9.00+/-1.90)% vs. (37.00+/ 2.53)%], the myocardial leptin levels [(8.36+/-3.42) microg/g, (6.71+/-2.03) microg/g vs. (15.51+/-3.92) microg/g], MPO [(17.10+/-3.95) microg/g, (13.33+/ 2.88) microg/g vs. (30.83+/-4.06) microg/g], serum leptin levels [(15.03+/-1.87) microg/L, (11.85+/-0.72) microg/L vs. (29.55+/-2.31) microg/L], serum TNF-alpha [(35.10+/-10.12) ng/L, (27.04+/-5.18) ng/L vs. (81.34+/-14.20) ng/L], and IL-6 levels [(167.39+/-72.83) ng/L, (149.13+/-37.69) ng/L vs. (477.30+/-29.09) ng/L, all P<0.01]. CONCLUSION: Pretreatment using leptin results in preconditioning like tolerance against infarction dysfunction. This cardiac protection effect is mediated, in part, via suppression of inflammation in preconditioned myocardium. PMID- 20170617 TI - [Effects of effective components compatibility of aqueous extracts of Salviae Miltiorrhizae and Rhizoma Chuanxiong on rat myocardial ischemia/reperfusion injury]. AB - OBJECTIVE: To observe effects of effective components compatibility of aqueous extracts of Salviae Miltiorrhizae and Rhizoma Chuanxiong on myocardial ischemia/reperfusion (I/R) injury in rat. METHODS: Sprague-Dawley (SD) rats were randomly divided into sham group, model group, Guanxinning injection group and effective components of aqueous extracts from Salviae Miltiorrhizae and Rhizoma Chuanxiong salvianolic low dose group and high dose group, with 10 rats in each group. The myocardial I/R injury model was reproduced by ligation of the left anterior descending artery, and the experimental drugs were injected intravenously via femoral vein at 10 minutes after ligation. 2.88 g/kg Guanxinning injection was given in Guanxinning group, and 2.43 g/kg or 4.86 g/kg effective components of aqueous extracts of Salviae Miltiorrhizae and Rhizoma Chuanxiong salvianolic was given in low dose group and high dose group, respectively, and equal volume of normal saline was given in sham group and model group. The anesthetic rats were sacrificed 40 minutes after ischemia and 120 minutes of reperfusion. Blood samples were collected before rats were sacrificed. The contents of serum troponin T (cTnT) and MB isoenzyme of creatine kinase (CK MB) were determined, 6-keto-prostaglandin F(1 alpha) (6-keto-PGF(1 alpha)), thromboxane B(2) (TXB(2)) and platelet aggregation rate in blood plasma were assessed, and the degree of myocardial infarction in rats was determined. RESULTS: The myocardial infarction size in combined Salviae Miltiorrhizae and Rhizoma Chuanxiong low dose group and high dose group [(23.0+/-3.8)%, (20.8+/ 4.7)%] were lower significantly than that in model group [(29.1+/-3.2)%, P<0.05 and P<0.01], the contents of serum cTnT [(0.78+/-0.29) mg/L, (0.76+/-0.29) mg/L] and CK-MB [(891.5+/-252.5) U/L, (759.5+/-191.3) U/L] were lower significantly than those in model group [(1.04+/-0.14) mg/L, (1 268.2+/-256.5) U/L, all P<0.05]. The level of 6-keto-PGF(1 alpha) was higher significantly in high dose of the combination group than that in model group [(206.7+/-35.6) ng/L vs. (138.6+/-28.9) ng/L, P<0.05], and platelet aggregation rate was inhibited significantly [(49.4+/-9.3)% vs. (77.1+/-16.7)%, P<0.05]. CONCLUSION: Effective components compatibility of aqueous extracts from Salviae Miltiorrhizae and Rhizoma Chuanxiong may reduce significantly the size of myocardial infarct and blood content of myocardial enzyme CK-MB and cTnT, and increase the ratio of 6 keto-PGF(1 alpha)/TXB(2), thus reducing myocardial I/R injury. PMID- 20170618 TI - [The effect of different methods of counting of rescue crew on the quality of cardiopulmonary resuscitation]. AB - OBJECTIVE: To compare the effective power of external chest compression and degree of exhaustion of rescue crew using different methods of counting, in order to establish a more appropriate and standard method of counting. METHODS: Forty eight subjects who had received formal training in basic life support (BLS) and advanced life support (ALS) were recruited randomly from doctors and nurses working in the emergency departments. The methods of counting were randomly selected which was performed first, and then they performed continuous chest compressions for 3 minutes using two different methods of counting with 30 minutes apart on the manikin, which was used in the hospital for cardiopulmonary resuscitation (CPR) training. The total number of compressions was recorded, and the number of those which were considered satisfactory, the peak heart rate of the performer and the time to reach peak heart were all recorded. Feeling of fatigue and discomfort was evaluated by self-reported survey results with the use of a visual analogue scale (VAS). RESULTS: The total number of compressions attempted, the effective power of external chest compression and the mean compression depth when rescuers counted form 1 to 10, which were repeated for 3 times, were greater than those when rescuers counted from 1 to 30 during 3 minutes of CPR [(202.40+/-6.52) times vs. (173.50+/-5.68) times, (67.48+/-2.00)% vs. (57.81+/-2.00)%, (4.45+/-0/.34) cm vs. (4.05+/0.21) cm, all P<0.01]. The VAS scores (22.15+/-3.09) was lower than that when rescuers counted them from 1 to 30 (31.10+/-4.09, P<0.01). The time to reach peak heart rate [(124.88+/-5.40) s] was longer than that when rescuers counted them from 1 to 30 [(106.15+/-6.80) s, P<0.01]. There was no difference in peak heart rate between two methods of counting. CONCLUSION: The effective power of external chest compression is greater when rescuers counted from 1 to 10 with repetition for 3 times than that when rescuers counted continuously from 1 to 30 during CPR. The method of counting from 1 to 10 with repetition for 3 times can save physical energy of rescue crew, so it can improve the quality of CPR to some extent. PMID- 20170623 TI - A case of 26-year-old woman with ST elevation myocardial infarction and literature review. PMID- 20170624 TI - What are the sources of hydrogen peroxide production by heart mitochondria? AB - Coupled rat heart mitochondria produce externally hydrogen peroxide at the rates which correspond to about 0.8 and 0.3% of the total oxygen consumption at State 4 with succinate and glutamate plus malate as the respiratory substrates, respectively. Stimulation of the respiratory activities by ADP (State 4-State 3 transition) decreases the succinate- and glutamate plus malate-supported H2O2 production 8- and 1.3-times, respectively. NH4+ strongly stimulates hydrogen peroxide formation with either substrate without any effect on State 4 and/or State 3 respiration. Rotenone-treated, alamethicin-permeabilized mitochondria catalyze NADH-supported H2O2 production at a rate about 10-fold higher than that seen in intact mitochondria under optimal (State 4 succinate-supported respiration in the presence of ammonium chloride) conditions. NADH-supported hydrogen peroxide production by the rotenone-treated mitochondria devoid of a permeability barrier for H2O2 diffusion by alamethicin treatment are only partially (approximately 50%) sensitive to the Complex I NADH binding site specific inhibitor, NADH-OH. The residual activity is strongly (approximately 6 fold) stimulated by ammonium chloride. NAD+ inhibits both Complex I-mediated and ammonium-stimulated H2O2 production. In the absence of stimulatory ammonium about half of the total NADH-supported hydrogen peroxide production is catalyzed by Complex I. In the presence of ammonium about 90% of the total hydrogen peroxide production is catalyzed by matrix located, ammonium-dependent enzyme(s). PMID- 20170625 TI - The mechanism of rotating proton pumping ATPases. AB - Two proton pumps, the F-ATPase (ATP synthase, FoF1) and the V-ATPase (endomembrane proton pump), have different physiological functions, but are similar in subunit structure and mechanism. They are composed of a membrane extrinsic (F1 or V1) and a membrane intrinsic (Fo or Vo) sector, and couple catalysis of ATP synthesis or hydrolysis to proton transport by a rotational mechanism. The mechanism of rotation has been extensively studied by kinetic, thermodynamic and physiological approaches. Techniques for observing subunit rotation have been developed. Observations of micron-length actin filaments, or polystyrene or gold beads attached to rotor subunits have been highly informative of the rotational behavior of ATP hydrolysis-driven rotation. Single molecule FRET experiments between fluorescent probes attached to rotor and stator subunits have been used effectively in monitoring proton motive force-driven rotation in the ATP synthesis reaction. By using small gold beads with diameters of 40-60 nm, the E. coli F1 sector was found to rotate at surprisingly high speeds (>400 rps). This experimental system was used to assess the kinetics and thermodynamics of mutant enzymes. The results revealed that the enzymatic reaction steps and the timing of the domain interactions among the beta subunits, or between the beta and gamma subunits, are coordinated in a manner that lowers the activation energy for all steps and avoids deep energy wells through the rotationally-coupled steady-state reaction. In this review, we focus on the mechanism of steady-state F1-ATPase rotation, which maximizes the coupling efficiency between catalysis and rotation. PMID- 20170626 TI - The liquid-ordered state comes of age. AB - Biomembranes are unique states of soft matter that share some of their materials properties with the mesophases of liquid crystals. Although of genuinely fluid character, membranes can display ordered states under physiological conditions, and it appears that their lateral organization and the related functional properties are intimately coupled to states in-between order and disorder. Hence, the liquid-ordered state of membranes, which owes its existence to the unique ability of cholesterol to mediate between order and disorder, has moved center stage in the characterization of membranes in terms of domains or rafts. PMID- 20170627 TI - Peptide-mediated protein delivery-which pathways are penetrable? AB - The growing number of reports on the effective cargo delivery by cell-penetrating peptides (CPPs) has extensively widened our knowledge about the mechanisms involved in CPP-mediated delivery. However, the data available on the internalization mode of CPP-cargo complexes are often conflicting and/or equivocal. Moreover, the intracellular trafficking of CPP-cargo complexes is, to date, relatively unexplored resulting in only minimal information about what is really happening to the complexes inside the cell. This review focuses on defining the endocytic pathways engaged in the transduction of CPP-cargo complexes and seeks to determine the extent of different endocytic routes required for effective uptake. In addition, the intracellular pathways utilized during the trafficking and sorting of CPP-cargo complexes as well as the ultimate fate of the complexes inside cells will be discussed. PMID- 20170628 TI - Morpholinos and their peptide conjugates: therapeutic promise and challenge for Duchenne muscular dystrophy. AB - Exon-skipping efficacies of phosphodiamidate morpholino oligomers (PMOs) or the conjugates of PMOs with cell-penetrating peptides (PPMOs) have been tested in various animal models of Duchenne muscular dystrophy (DMD), including mdx mice, utrophin-dystrophin double-knockout mice, and CXMD dogs, as well as in DMD patients in clinical trials. The studies have shown that PMOs can diffuse into leaky muscle cells, modify splicing of DMD transcripts, induce expression of partially functional dystrophin, and improve function of some skeletal muscles. PMOs are non-toxic, with a report of mdx mice tolerating a 3g/kg dose, and no drug-related safety issue in human has been reported. However, because of their poor cell uptake and rapid renal clearance, large and frequently repeated doses of PMOs are likely required for functional benefit in some skeletal muscles of DMD patients. In addition, PMOs do not enter cardiomyocytes sufficiently to relieve heart pathology, the efficacy of delivery to various muscles varies greatly, and delivery across the tissue of each skeletal muscle tissue is patchy. PPMOs enter cells at far lower doses, enter cardiomyocytes in useful quantities, and deliver more evenly to myocytes both when different muscles are compared and when assessed at the level of single muscle tissue sections. Compared to PMOs, far lower doses of PPMOs can restore dystrophin sufficiently to reduce disease pathology, increase skeletal and cardiac muscle functions, and prolong survival of animals. The biggest challenge for PPMO is determining safe and effective doses. The toxicity of PPMOs will require caution when moving into the clinic. The first PPMO-based DMD drug is currently in preclinical development for DMD patients who can benefit from skipping exon 50. PMID- 20170629 TI - Expressed protein ligation for the preparation of fusion proteins with cell penetrating peptides for endotoxin removal and intracellular delivery. AB - Expressed protein ligation (EPL) is a useful method for the native chemical ligation of proteins with other proteins or peptides. This study assessed the practicability of EPL in the preparation of fusion proteins of enhanced green fluorescent protein (EGFP) with chemically synthesized cell-penetrating peptides (CPPs) for intracellular delivery. Using intein-mediated purification with an affinity chitin-binding tag (IMPACT) system, the thioester of EGFP (EGFP-SR) was prepared. Optimization of the ligation of EGFP-SR with arginine 12-mer (R12) produced the fusion protein in high yield. The EPL procedure also allows the preparation of EGFP-R12 containing a low level of endotoxin (ET), via the satisfactory ET removal of EGFP-SR prior to ligation with the R12 peptide. Fusion proteins of EGFP with R12 and the d-isomer of R12 prepared by EPL showed similar levels of cellular uptake compared to the fusion protein directly expressed in Escherichiacoli. PMID- 20170630 TI - The influence of Pyk2 on the mechanical properties in fibroblasts. AB - The cell surface receptor integrin is involved in signaling mechanical stresses via the focal adhesion complex (FAC) into the cell. Within FAC, the focal adhesion kinase (FAK) and Pyk2 are believed to act as important scaffolding proteins. Based on the knowledge that many signal transducing molecules are transiently immobilized within FAC connecting the cytoskeleton with integrins, we applied magnetic tweezer and atomic force microscopic measurements to determine the influence of FAK and Pyk2 in cells mechanically. Using mouse embryonic fibroblasts (MEF; FAK(+/+), FAK(-/-), and siRNA-Pyk2 treated FAK(-/-) cells) provided a unique opportunity to describe the function of FAK and Pyk2 in more detail and to define their influence on FAC and actin distribution. PMID- 20170631 TI - Histone deacetylase inhibitors de-repress tyrosine hydroxylase expression in the olfactory bulb and rostral migratory stream. AB - Most olfactory bulb (OB) interneurons are derived from neural stem cells in the subventricular zone (SVZ) and migrate to the OB via the rostral migratory stream (RMS). Mature dopaminergic interneurons in the OB glomerular layer are readily identified by their synaptic activity-dependent expression of tyrosine hydroxylase (TH). Paradoxically, TH is not expressed in neural progenitors migrating in the RMS, even though ambient GABA and glutamate depolarize these progenitors. In forebrain slice cultures prepared from transgenic mice containing a GFP reporter gene under the control of the Th 9kb upstream regulatory region, treatment with histone deacetylase (HDAC) inhibitors (either sodium butyrate, Trichostatin A or Scriptaid) induced Th-GFP expression specifically in the RMS independently of depolarizing conditions in the culture media. Th-GFP expression in the glomerular layer was also increased in slices treated with Trichostatin A, but this increased expression was dependent on depolarizing concentrations of KCl in the culture media. Th-GFP expression was also induced in the RMS in vivo by intra-peritoneal injections with either sodium butyrate or valproic acid. Quantitative RT-PCR analysis of neurosphere cultures confirmed that HDAC inhibitors de-repressed Th expression in SVZ-derived neural progenitors. Together, these findings suggest that HDAC function is critical for regulating Th expression levels in both neural progenitors and mature OB dopaminergic neurons. However, the differential responses to the combinatorial exposure of HDAC inhibitors and depolarizing culture conditions indicate that Th expression in mature OB neurons and neural progenitors in the RMS are regulated by distinct HDAC-mediated mechanisms. PMID- 20170632 TI - Omentin, a novel adipokine, induces vasodilation in rat isolated blood vessels. AB - Omentin is a recently identified adipose tissue-derived cytokine and is implicated in obesity-related cardiovascular disorders. In the present study, we tested the hypothesis that omentin could directly affect vascular reactivity of isolated blood vessels. In endothelium-intact rat isolated aorta, pretreatment with omentin (300 ng/ml, 30 min) inhibited noradrenaline (NA; 1 nM-1 microM) induced concentration-dependent contraction. In NA (100 nM)-pre-contracted aorta, omentin (1-300 ng/ml) directly induced an endothelium-dependent relaxation. While a nitric oxide (NO) synthase (NOS) inhibitor, N(G)-nitro-l-arginine methyl ester (100 microM, 30 min) inhibited the relaxation, a PI3K/Akt inhibitor, LY294002 (10 microM, 30 min) or a tyrosine kinase inhibitor, genistein (30 microM, 30 min) was ineffective. Omentin (300 ng/ml, 5 min) induced a phosphorylation of endothelial NOS at serine 1177 but not a phosphorylation of Akt at serine 473. Omentin (1-300 ng/ml) also relaxed NA pre-contracted mesenteric artery. Present study for the first time demonstrated that omentin has a vasodilating effect on isolated blood vessels, which is mediated through endothelium-derived NO. PMID- 20170633 TI - Delta-like 1 expression promotes goblet cell differentiation in Notch-inactivated human colonic epithelial cells. AB - Notch signaling has previously been implicated in the regulation of the cell fate of intestinal epithelial cells. However, the expression and function of Notch ligands in the human intestine remain largely unknown. In the present study, we showed that Notch ligands Delta-like 1 (Dll1) and Delta-like 4 (Dll4) are expressed in a goblet cell-specific manner in human colonic tissue. Additionally, we found that Dll1 and Dll4 expression was regulated in-parallel with Atoh1 and MUC2, which are both under the control of the Notch-Hes1 signaling pathway. Because knockdown of Dll1 expression completely abrogated the acquisition of the goblet cell phenotype in Notch-inactivated colonic epithelial cells, we postulate that Dll1 might function as a cis-acting regulatory element that induces undifferentiated cells to become goblet cells. Our results suggest a link between Dll1 expression and human goblet cell differentiation that might be mediated by a function that is distinct from its role as a Notch receptor ligand. PMID- 20170634 TI - Maternal obesity programmes offspring development of non-alcoholic fatty pancreas disease. AB - BACKGROUND AND AIMS: The prevalence of pancreatic adenocarcinoma (PAC) parallels rising rates of obesity and dysmetabolism, a possible link being non-alcoholic fatty pancreas disease (NAFPD). We have recently shown that maternal obesity programmes the development of a dysmetabolic and fatty liver (non-alcoholic fatty liver disease, NAFLD) phenotype in adult offspring. Since the pancreas and liver originate from the same embryonic bud, it is plausible that maternal obesity may similarly programme the development of NAFPD. Our objective was to determine the effect of maternal obesity on development of NAFPD in offspring and ascertain contributions of the intra/extra-uterine periods. METHODS: Female C57BL/6J mice were fed either a standard chow (3% fat, 7% sugar) or a hypercalorific diet (16% fat, 33% sugar) for six weeks prior to mating and throughout pregnancy and lactation. Female offspring were cross-fostered for suckling to dams on the same or opposite diet to yield four groups: offspring of lean suckled by lean dams (n=6), offspring of obese suckled by obese dams (n=6), offspring of lean suckled by obese dams (n=5) and offspring of obese suckled by lean dams (n=6). All offspring were weaned onto a standard chow diet at 21 days and sacrificed at 3 months post-partum for tissue collection. RESULTS: Offspring subjected to an adverse suckling environment showed significant increases in body weight, pancreatic triglyceride content, TGF-beta, collagen gene expression and SBP at rest along with an enhanced restraint stress response, indicating a dysmetabolic and NAFPD phenotype. CONCLUSIONS: Developmental programming is involved in the pathogenesis of NAFPD and appears to be largely dependent on an adverse extra uterine environment. PMID- 20170635 TI - PPARgamma regulates the expression of cholesterol metabolism genes in alveolar macrophages. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear transcription factor involved in lipid metabolism that is constitutively expressed in the alveolar macrophages of healthy individuals. PPARgamma has recently been implicated in the catabolism of surfactant by alveolar macrophages, specifically the cholesterol component of surfactant while the mechanism remains unclear. Studies from other tissue macrophages have shown that PPARgamma regulates cholesterol influx, efflux, and metabolism. PPARgamma promotes cholesterol efflux through the liver X receptor-alpha (LXRalpha) and ATP-binding cassette G1 (ABCG1). We have recently shown that macrophage-specific PPARgamma knockout (PPARgamma KO) mice accumulate cholesterol-laden alveolar macrophages that exhibit decreased expression of LXRalpha and ABCG1 and reduced cholesterol efflux. We hypothesized that in addition to the dysregulation of these cholesterol efflux genes, the expression of genes involved in cholesterol synthesis and influx was also dysregulated and that replacement of PPARgamma would restore regulation of these genes. To investigate this hypothesis, we have utilized a Lentivirus expression system (Lenti-PPARgamma) to restore PPARgamma expression in the alveolar macrophages of PPARgamma KO mice. Our results show that the alveolar macrophages of PPARgamma KO mice have decreased expression of key cholesterol synthesis genes and increased expression of cholesterol receptors CD36 and scavenger receptor A-I (SRA-I). The replacement of PPARgamma (1) induced transcription of LXRalpha and ABCG1; (2) corrected suppressed expression of cholesterol synthesis genes; and (3) enhanced the expression of scavenger receptors CD36. These results suggest that PPARgamma regulates cholesterol metabolism in alveolar macrophages. PMID- 20170636 TI - UDP-GlcNAc:Glycoprotein N-acetylglucosamine-1-phosphotransferase mediates the initial step in the formation of the methylphosphomannosyl residues on the high mannose oligosaccharides of Dictyostelium discoideum glycoproteins. AB - The Dictyostelium discoideum gene gpt1 encodes a protein XP_638036 with sequence similarity to the alpha/beta subunits of mammalian UDP-GlcNAc:Glycoprotein N acetylglucosamine-1-phosphotransferase. We now demonstrate that extracts of D. discoideum clones with mutations in this gene transfer GlcNAc-P from UDP-GlcNAc to mannose residues at less than 5% the wild type value. Further, the lysosomal hydrolases of these mutant clones fail to bind to a cation-independent mannose 6 phosphate receptor affinity column, indicating a lack of methylphosphomannosyl residues on the high mannose oligosaccharides of these proteins. We conclude that the gpt1 gene product catalyzes the initial step in the formation of methylphosphomannosyl residues on D. discoideum lysosomal hydrolases. PMID- 20170637 TI - Post-translational modification of glutamine and lysine residues of HIV-1 aspartyl protease by transglutaminase increases its catalytic activity. AB - The human immunodeficiency virus type 1 aspartyl protease (HIV-1 PR) is a homodimeric aspartyl endopeptidase that is required for virus replication. HIV-1 PR was shown to act invitro as acyl-donor and -acceptor for both guinea pig liver transglutaminase (TG, EC 2.3.2.13) and human Factor XIIIa. These preliminary evidences suggested that the HIV-1 PR contains at least three TG-reactive glutaminyl and one lysyl residues. We report here that the incubation of HIV-1 PR with TG increases its catalytic activity. This increase is dependent upon the time of incubation, the concentration of TG and the presence of Ca2+. Identification of epsilon-(gamma-glutamyl)lysine in the proteolytic digest of the TG-modified HIV-1 PR suggested intramolecular covalent cross-linking of this protease which may promote a non-covalent dimerization and subsequent activation of this enzyme via a conformational change. This hypothesis is supported by the observation that the TG-catalyzed activation of HIV-1 PR was completely abolished by spermidine (SPD) which acts as a competitive inhibitor of epsilon-(gamma glutamyl)lysine formation. Indeed, in the presence of 1mM SPD the formation of the isopeptide was decreased of about 80%. The main products of the TG-catalyzed modification of HIV-1 PR in the presence of SPD were N(1)-mono(gamma-glutamyl)SPD and N(8)-mono(gamma-glutamyl)SPD. Negligible amount of N(1),N(8)-bis(gamma glutamyl)SPD were found. The significance of these results is discussed with respect to the activation of the protease by post-translational modification and design of potential inhibitors. PMID- 20170638 TI - Molecular cloning of a novel nuclear factor, TDRP1, in spermatogenic cells of testis and its relationship with spermatogenesis. AB - We reported the identification of a novel gene termed TDRP (encoding testis development-related protein) that might be involved in spermatogenesis. The human TDRP gene had two distinct transcripts, TDRP1 and TDRP2, which encoded proteins of 183 aa and 198 aa respectively. Tdrp mRNA was predominantly expressed in testis tissue. We generated rabbit polyclonal antibodies specific against human TDRP1. Immunohistochemistry analysis showed TDRP1 was expressed in spermatogenic cells, especially with high expression in spermatocytes. We provided evidence that TDRP1 distributed in both cytoplasm and nuclei of spermatogenic cells. Expression patterns of Tdrp1 mRNA and its protein were investigated in the rat testis tissues of different developmental stages. Both Tdrp1 mRNA and its protein were barely detected in the testis of neonatal rats, increased remarkably at 3weeks postpartum, and peaked at 2months postpartum. We also investigated TDRP1 expressions in testis tissues of azoospermic men with defective spermatogenesis. Western blot analysis showed that TDRP1 expressions were significantly lower in the testis tissues of azoospermic men compared with normal controls. These current data demonstrated that as a nuclear factor, TDRP1 might play an important role in spermatogenesis. PMID- 20170639 TI - Construction, screening and identification of a phage display antibody library against the Eimeria acervulina merozoite. AB - A single-chain antibody library against Eimeria acervulina merozoites was constructed by phage display approach. Antibody-displaying phage was selected in four panning rounds against cryopreserved E. acervulina merozoites. Five clones were randomly selected from the fourth panning round, and their nucleotide sequences were aligned and compared to mouse germ-line sequences. Soluble antibody was produced in a non-suppressor Escherichia coli strain, purified by protein A affinity chromatography, and characterized by Western-blotting. Immunofluorescence assay showed localization of the produced recombinant antibody fragment on the surface E. acervulina merozoites. These resultant antibody fragments showed high specificity and binding capacity for soluble antigens and intact fixed merozoites which seems promising as diagnostic, therapeutic and/or vaccine tools against coccidiosis. PMID- 20170640 TI - The structure of SecB/OmpA as visualized by electron microscopy: The mature region of the precursor protein binds asymmetrically to SecB. AB - SecB, a molecular chaperone in Escherichia coli, binds a subset of precursor proteins that are exported across the plasma membrane via the Sec pathway. Previous studies showed that SecB bound directly to the mature region rather than to the signal sequence of the precursor protein. To determine the binding pattern of SecB and the mature region of the preprotein, here, we visualized the structure of the SecB/OmpA complex by electron microscopy. This complex is composed by two parts: the main density represents one SecB tetramer and the unfolded part of OmpA wrapping round it; the elongated smaller density represents the rest of OmpA. Each SecB protomer makes a different contribution to the binding of SecB with OmpA. The binding pattern between SecB tetramer and OmpA is asymmetric. PMID- 20170641 TI - RNF220, an E3 ubiquitin ligase that targets Sin3B for ubiquitination. AB - Modification of proteins by ubiquitination plays important roles in various cellular processes. During this process, the target specificity is determined by ubiquitin ligases. Here we identify RNF220 (RING finger protein 220) as a novel ubiquitin ligase for Sin3B. As a conserved RING protein, RNF220 can bind E2 and mediate auto-ubiquitination of itself. Through a yeast two-hybrid screen, we isolated Sin3B as one of its targets, which is a scaffold protein of the Sin3/HDAC (histone deacetylase) corepressor complex. RNF220 specifically interacts with Sin3B both in vitro and in vivo. Sin3B can be regulated by the ubiquitin-proteasome system. Co-expression of RNF220 promotes the ubiquitination and proteasomal degradation of Sin3B. Taken together, these results reveal a new mechanism for regulating the Sin3/HDAC complex. PMID- 20170642 TI - Multiple gamma-glutamylation: a novel type of post-translational modification in a diapausing Artemia cyst protein. AB - A highly hydrophilic, glutamate-rich protein was identified in the aqueous phenol extract from the cytosolic fraction of brine shrimp (Artemia franciscana) diapausing cysts and termed Artemia phenol soluble protein (PSP). Mass spectrometric analysis revealed the presence of many protein peaks around m/z 11,000, separated by 129 atomic mass units; this value corresponds to that of glutamate, which is strongly suggestive of heterogeneous polyglutamylation. Polyglutamylation has long been known as the functionally important post translational modification of tubulins, which carry poly(L-glutamic acid) chains of heterogeneous length branching off from the main chain at the gamma-carboxy groups of a few specific glutamate residues. In Artemia PSP, however, Edman degradation of enzymatic peptides revealed that at least 13, and presumably 16, glutamate residues were modified by the attachment of a single L-glutamate, representing a hitherto undescribed type of post-translational modification: namely, multiple gamma-glutamylation or the addition of a large number of glutamate residues along the polypeptide chain. Although biological significance of PSP and its modification is yet to be established, suppression of in vitro thermal aggregation of lactate dehydrogenase by glutamylated PSP was observed. PMID- 20170643 TI - d-Serine modulates neurogenic relaxation in rat corpus cavernosum. AB - d-Serine, an endogenous co-agonist for the N-methyl-d-aspartate (NMDA) receptor in mammals, is synthesized from l-serine by serine racemase. Although much attention has been focused on the role of d-serine within the central nervous system, the physiological role of d-serine in peripheral nerves such as corpus cavernosal nerves has not been investigated. The present study was aimed to study the expression, cellular localization and function of serine racemase/d-serine system in isolated rat corpus cavernosum. Reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis showed the expression of serine racemase in rat corpus cavernosum. Immunogold electron microscopy demonstrated the cellular localization of serine racemase in the cavernosal nerves' membrane of the tissue. The organ bath studies on isolated rat corpus cavernosum showed that d-serine increases the non-adrenergic non-cholinergic neurogenic relaxation of isolated rat corpus cavernosum in vitro. This effect of d-serine was inhibited by a variety of NMDA receptor antagonists (ketamine, MK 801 and ifenprodil), suggesting that NMDA receptors are involved in the effects of d-serine on the neurogenic relaxation of corporal tissue strips. These observations provide the first evidence for the role of d-serine in modulating the neurogenic relaxation of rat corpus cavernosum, and may open new therapeutic avenues for the treatment of impotence. PMID- 20170644 TI - Altered occludin expression in brain capillaries induced by obstructive jaundice in rats. AB - The development of increased oxidative stress in the context of obstructive cholestasis has been proven in various rats' organs including the brain. The present study aimed to detect alterations of tight junction-associated occludin in rat brain capillaries after bile duct ligation (BDL). In experiment 1, occludin expression was evaluated by Western blot analysis in 5 animals 10 days after BDL and compared with 5 sham-operated ones. In experiment 2, groups of 9 animals each were used to assess occludin levels on the 1st, 5th, and 10th days after BDL and to associate these measurements with the in vivo superoxide radical production measured by means of an ultrasensitive fluorescent assay. The results indicated that occludin expression in BDL animals, as opposed to sham-operated, was significantly reduced at every time point studied, being lowest in the rats remaining on BDL condition for 10 days. Moreover, it was demonstrated that the time-dependent downregulation of occludin expression in the brain endothelial was significantly correlated with the time-dependent increase of brain superoxide radical level, implying a relationship between these two abnormalities. In conclusion, the evidence presented herein suggests the implication of occludin and, therefore, of blood-brain barrier in the pathophysiology of extrahepatic cholestasis. PMID- 20170645 TI - Invitro application of gold nanoprobes in live neurons for phenotypical classification, connectivity assessment, and electrophysiological recording. AB - Thermoregulatory neurons in the preoptic area of the anterior hypothalamus (POA) form synaptic networks, which affect responses that regulate body temperature. To characterize these pathways of activation, projections to effector control areas, like the dorsomedial hypothalamus (DMH), require labeling in live tissue slices. Traditional fluorescent dyes label axon terminals near an injection site, but unfortunately, also that of nearby fibers of passage. Here, we describe a novel methodology for retrograde labeling of neurons in vitro, which will allow for further electrophysiological recording. To determine if POA neurons project to the DMH, we have used nanometer-sized, gold nanoprobes, which provide for specific neuronal entry, via synapses in close proximity to the injection site. Upon neuronal entry, these nanoprobe complexes diffuse to the soma, where they are readily visualized and quantified. We found that conjugation of these gold nanoprobes with VGLUT-2 antibodies and polyethyleneimine (PEI) facilitates neuronal entry and a high level of labeling efficacy. This novel method, adapted from emerging cancer therapy technologies, is highly specific for determining axon terminal projections within particular neuronal populations, while maintaining neuronal viability for targeted live cell electrophysiological recording. PMID- 20170647 TI - Differences in the neural basis of automatic auditory and visual time perception: ERP evidence from an across-modal delayed response oddball task. AB - In our everyday lives, we need to process auditory and visual temporal information as efficiently as possible. Although automatic auditory time perception has been widely investigated using an index of the mismatch negativity (MMN), the neural basis of automatic visual time perception has been largely ignored. The present study investigated the automatic processing of auditory and visual time perception employing the cross-modal delayed response oddball paradigm. In the experimental condition, the standard stimulus was 200 ms and the deviant stimulus was 120 ms, which were exchanged in the control condition. Reaction time, accuracy, and event-related potential (ERP) data were measured when participants performed the duration discrimination task. The ERP results showed that the MMN, N2b, and P3 were elicited by an auditory deviant stimulus under the attention condition, while only the MMN was elicited under the inattention condition. The MMN was largest over the frontal and central sites, while the difference in MMN amplitude was not significant between under the attention and inattention condition. In contrast, the change-related positivity (CRP) and the visual mismatch negativity (vMMN) were elicited by the visual deviant stimulus under both the attention and inattention conditions. The CRP was largest over the occipito-temporal sites under the attention condition and over the fronto-central sites under the inattention condition. The difference in CRP amplitude was significant between the attention and inattention condition. The vMMN was largest over the parieto-occipital sites under the attention condition, and largest over the fronto-central sites under the inattention condition. The difference in vMMN amplitude was significant between the attention and inattention condition. Auditory MMN does not appear to be modulated by attention, whereas the visual CRP and the vMMN are modulated by attention. Therefore, the present study provides electrophysiological evidence for the existence of automatic visual time perception and supports an "attentional switch" hypothesis for a modality effect on duration judgments, such that auditory temporal information is processed relatively automatically, whereas visual temporal information processing requires controlled attention. PMID- 20170646 TI - Rat brain endothelial cells are a target of manganese toxicity. AB - Manganese (Mn) is an essential trace metal; however, exposure to high Mn levels can result in neurodegenerative changes resembling Parkinson's disease (PD). Information on Mn's effects on endothelial cells of the blood-brain barrier (BBB) is lacking. Accordingly, we tested the hypothesis that BBB endothelial cells are a primary target for Mn-induced neurotoxicity. The studies were conducted in an in vitro BBB model of immortalized rat brain endothelial (RBE4) cells. ROS production was determined by F(2)-isoprostane (F(2)-IsoPs) measurement. The relationship between Mn toxicity and redox status was investigated upon intracellular glutathione (GSH) depletion with diethylmaleate (DEM) or L buthionine sulfoximine (BSO). Mn exposure (200 or 800 microM MnCl(2) or MnSO(4)) for 4 or 24h led to significant decrease in cell viability vs. controls. DEM or BSO pre-treatment led to further enhancement in cytotoxicity vs. exposure to Mn alone, with more pronounced cell death after 24-h DEM pre-treatment. F(2)-IsoPs levels in cells exposed to MnCl(2) (200 or 800 microM) were significantly increased after 4h and remained elevated 24h after exposure compared with controls. Consistent with the effects on cell viability and F(2)-IsoPs, treatment with MnCl(2) (200 or 800 microM) was also associated with a significant decrease in membrane potential. This effect was more pronounced in cells exposed to DEM plus MnCl(2) vs. cells exposed to Mn alone. We conclude that Mn induces direct injury to mitochondria in RBE4 cells. The ensuing impairment in energy metabolism and redox status may modify the restrictive properties of the BBB compromising its function. PMID- 20170648 TI - Genetic heterogeneity of skin microvasculature. AB - Angiogenesis, the formation of new blood vessels from existing vasculature, is a complex process that is essential for normal embryonic development. Current models for experimental evaluation of angiogenesis often use tissue from large vessels like the aorta and umbilical vein, which are phenotypically distinct from microvasculature. We demonstrate that the utilization of skin to measure microvascular angiogenesis in embryonic and adult tissues is an efficient way to quantify microvasculature angiogenesis. We validate this approach and demonstrate its added value by showing significant differences in angiogenesis in monogenic and polygenic mouse models. We discovered that the pattern of angiogenic response among inbred mouse strains in this ex vivo assay differs from the strain distributions of previous in vivo angiogenesis assays. The difference between the ex vivo and in vivo assays may be related to systemic factors present in whole animals. Expression analysis of cultured skin biopsies from strains of mice with opposing angiogenic response was performed to identify pathways that contribute to differential angiogenic response. Increased expression of negative regulators of angiogenesis in C57Bl/6J mice was associated with lower growth rates. PMID- 20170649 TI - Inhibitory and facilitory actions of isocyanine derivatives at human and rat organic cation transporters 1, 2 and 3: a comparison to human alpha 1- and alpha 2-adrenoceptor subtypes. AB - Organic cation transporters (OCTs), comprising OCT1, OCT2 and OCT3 subtypes, control absorption and elimination of xenobiotics and endogenous compounds in kidney, liver and placenta. In addition, they ensure "uptake2", low-affinity catecholamine clearance in sympathetically-innervated tissue and the CNS. The prototypical OCT ligand, disprocynium24 (D24), recognises OCT3, but its actions at OCT1 and OCT2 remain unknown. Herein, together with two other isocyanine derivatives (AAC291 and AAC301) and chemically-related adrenergic agents, we evaluated actions of D24 at OCTs, monoamine transporters and alpha(1)- and alpha(2)-adrenoceptors. D24 concentration-dependently suppressed [3H]-1-methyl-4 phenylpyridinium (MPP+) transport at human (h) and rat (r) OCT1, OCT2 and OCT3 in stably transfected HEK293 cells. Interestingly, low concentrations of D24 enhanced transport by h/rOCT2, a substrate-dependent effect suppressed by inhibition of protein kinase C. AAC291 and AAC301 likewise inhibited transport by all classes of h/r OCT and at low concentrations induced even more marked increases in transport by h/rOCT2. Further, by analogy to D24, they displayed antagonist properties at halpha(1A/B/D)-adrenoceptors (Ca2+-flux) and halpha(2A/B/C)-adrenoceptors ([35S]GTPgammaS binding). They were, however, less potent than D24 at serotonin transporters ([3H]citalopram binding) and AAC291 did not bind to dopamine and norepinephrine transporters. The preferential alpha(1B) adrenoceptor antagonist, AH11110A, the alpha2-adrenoceptor agonist, RWJ52353, and the adrenergic neurotoxin DSP-4 likewise affected [3H]MPP+ transport, in an OCT subtype and species-dependent manner. In conclusion, D24, other isocyanine congeners and chemically-related adrenergic agents inhibit OCT-mediated [3H]MPP+ transport, and all drugs display significant activity at alpha1- and alpha2 adrenoceptor subtypes, expanding previous reports of promiscuity between pharmacophores recognising alpha-adrenoceptors and OCTs. PMID- 20170650 TI - Metabolic memory and diabetic retinopathy: role of inflammatory mediators in retinal pericytes. AB - Diabetic retinopathy shares many characteristics features of a low grade chronic inflammatory disease. Its progression resists arrest when good metabolic control is re-established after a period of poor metabolic control, suggesting a 'metabolic memory' phenomenon. The aim of this study is to investigate the effect of reversal of high glucose to normal glucose on the inflammatory mediators in pericytes, the site of histopathology in diabetic retinopathy. Bovine retinal pericytes were incubated in high glucose (20 mM) for 2 days followed by normal glucose (5 mM) for 4 days (2 --> 4), or in high glucose for 4 days followed by normal glucose for 4 days (4 --> 4) or 8 days (4 --> 8). Pericytes incubated in continuous normal or high glucose for 2-12 days served as controls. Continuous high glucose exposure for 2-12 days significantly elevated gene expressions and protein concentrations of IL-1 beta, NF-kB, VEGF, TNF-alpha, TGF-beta and ICAM-1 in retinal pericytes. Four days of normal glucose that followed 2 days of high glucose (2 --> 4) had marginal, but significant, beneficial effect on the increases in these inflammatory mediators. Four days of normal glucose in 4 --> 4 group failed to reverse increases in inflammatory mediators and cell apoptosis remained elevated, but addition of dexamethasone during normal glucose exposure ameliorated such increases. However, when normal glucose exposure, after 4 days of high glucose was extended to 8 days (4 --> 8), increases in these mediators were significantly decreased. Hyperglycemia-induced elevations in inflammatory mediators in retinal microvascular cells resist reversal after re-institution of normal glucose conditions. Both, the duration of the initial exposure to high glucose, and normal glucose that follows high glucose, are critical in determining the outcome of the alterations in the inflammatory mediators. PMID- 20170651 TI - EphA4 deficient mice maintain astroglial-fibrotic scar formation after spinal cord injury. AB - One important aspect of recovery and repair after spinal cord injury (SCI) lies in the complex cellular interactions at the injury site that leads to the formation of a lesion scar. EphA4, a promiscuous member of the EphA family of repulsive axon guidance receptors, is expressed by multiple cell types in the injured spinal cord, including astrocytes and neurons. We hypothesized that EphA4 contributes to aspects of cell-cell interactions at the injury site after SCI, thus modulating the formation of the astroglial-fibrotic scar. To test this hypothesis, we studied tissue responses to a thoracic dorsal hemisection SCI in an EphA4 mutant mouse line. We found that EphA4 expression, as assessed by beta galactosidase reporter gene activity, is associated primarily with astrocytes in the spinal cord, neurons in the cerebral cortex and, to a lesser extent, spinal neurons, before and after SCI. However, we did not observe any overt reduction of glial fibrillary acidic protein (GFAP) expression in the injured area of EphA4 mutants in comparison with controls following SCI. Furthermore, there was no evident disruption of the fibrotic scar, and the boundary between reactive astrocytes and meningeal fibroblasts appeared unaltered in the mutants, as were lesion size, neuronal survival and inflammation marker expression. Thus, genetic deletion of EphA4 does not significantly alter the astroglial response or the formation of the astroglial-fibrotic scar following a dorsal hemisection SCI in mice. In contrast to what has been proposed, these data do not support a major role for EphA4 in reactive astrogliosis following SCI. PMID- 20170652 TI - Lifelong protection from global cerebral ischemia and reperfusion in long-lived Mclk1(+/)(-) mutants. AB - To achieve a long life span, animals must be resistant to various injuries as well as avoid or delay lethality from age-dependent diseases. Reduced expression of the mitochondrial enzyme CLK-1/MCLK1 (a.k.a. Coq7), a mitochondrial hydroxylase that is necessary for the biosynthesis of ubiquinone (UQ), extends lifespan in Caenorhabditiselegans and in mice. Here, we show that long-lived Mclk1(+/)(-) mutants have enhanced resistance to neurological damage following global cerebral ischemia-reperfusion (I/R) injury induced by transient bilateral common carotid artery occlusion (BCCAO). Both young ( approximately 100days old) and relatively aged ( approximately 450days old) mutants display increased resistance as indicated by a significant decrease in the amount of degenerating cells observed in forebrain cortex and in hippocampal areas after ischemia and reperfusion. Furthermore, less oxidative damage resulting from the procedure was measured in the brain of young Mclk1(+/)(-) animals. The finding that both young and old mutants are protected indicates that this is a basic phenotype of these mutants and not a secondary consequence of their slow rate of aging. Thus, the partial resistance to I/R injury suggests that Mclk1(+/)(-) mutants have an enhanced recovery potential following age-dependant vascular accidents, which correlates well with their longer survival. By relating this neuroprotective effect to previously reported characteristics of the Mclk1(+/)(-) phenotype, including altered mitochondrial metabolism and increased HIF-1alpha expression, this study establishes these mutants as useful models to analyze the mechanisms underlying tolerance to ischemia, particularly those associated with ischemic preconditioning, as well as to clarify the relation between aging and age dependent diseases. PMID- 20170653 TI - Prenatal exposure to ethanol affects postnatal neurogenesis in thalamus. AB - The number of neurons in the ventrobasal thalamus (VB) in the adolescent rat is unaffected by prenatal exposure to ethanol. This is in sharp contrast to other parts of the trigeminal-somatosensory system, which exhibit 30-35% fewer neurons after prenatal ethanol exposure. The present study tested the hypothesis that prenatal ethanol exposure affects dynamic changes in the numbers of VB neurons; such changes reflect the sum of cell proliferation and death. Neuronal number in the VB was determined during the first postnatal month in the offspring of pregnant Long-Evans rats fed an ethanol-containing diet or pair-fed an isocaloric non-alcoholic liquid diet. Offspring were examined between postnatal day (P) 1 and P30. The size of the VB and neuronal number were determined stereologically. Prenatal exposure to ethanol did not significantly alter neuronal number on any individual day, nor was the prenatal generation of VB neurons affected. Interestingly, prenatal ethanol exposure did affect the pattern of the change in neuronal number over time; total neuronal number was stable in the ethanol treated pups after P12, but it continued to rise in the controls until P21. In addition, the rate of cell proliferation during the postnatal period was greater in ethanol-treated animals. Thus, the rate of neuronal acquisition is altered by ethanol, and by deduction, there appears to be less ethanol-induced neuronal loss in the VB. A contributor to these changes is a latent effect of ethanol on postnatal neurogenesis in the VB and the apparent survival of new neurons. PMID- 20170654 TI - Effects of human T-cell leukemia virus type 1 (HTLV-1) p13 on mitochondrial K+ permeability: A new member of the viroporin family? AB - Human T-cell leukemia virus type-1 (HTLV-1) encodes a mitochondrial protein named p13. p13 mediates an inward K(+) current in isolated mitochondria that leads to mitochondrial swelling, depolarization, increased respiratory chain activity and reactive oxygen species (ROS) production. These effects trigger the opening of the permeability transition pore and are dependent on the presence of K(+) and on the amphipathic alpha helical domain of p13. In the context of cells, p13 acts as a sensitizer to selected apoptotic stimuli. Although it is not known whether p13 influences the activity of endogenous K(+) channels or forms a channel itself, it shares some structural and functional analogies with viroporins, a class of small integral membrane proteins that form pores and alter membrane permeability. PMID- 20170655 TI - Effect of estrogen and tamoxifen on the shell gland AVT and VT3R of scotosensitive and scotorefractory Japanese quail. AB - The neurohypophyseal hormone arginine vasotocin (AVT) found in most vertebrate species is known to modulate different aspects of reproduction in quail. AVT system is sensitive to gonadal steroids. Previous studies have shown that estradiol benzoate stimulates the proliferation of shell gland and increases the AVT and the vasotocin 3 receptor (VT3R) in long day length. This study was undertaken to investigate the effect of estrogen and tamoxifen on AVT as well as its receptor VT3 under the short day condition (6L:18D). Estradiol benzoate (EB) was administered daily in sexually quiescent (scotosensitive) condition for 15days. After the initial period of sexual quiescence, the quail of control group exhibited sexual development (scotorefractory condition). Thereafter, scotorefractory quail were administered with anti-estrogen tamoxifen, which eliminated the reoccurrence of scotosensitivity. Immunohistochemical and in-situ hybridization studies indicate the expression of AVT and VT3R transcripts in both scotosensitive as well as scotorefractory conditions. Administration of EB to scotosensitive female quail produced an increase in AVT and VT3 while tamoxifen suppressed them in scotorefractory quail. The results indicate that in quail myometrium the expression of VT3R is upregulated by estrogen when kept under short day condition. PMID- 20170656 TI - Protein export in Plasmodium parasites: from the endoplasmic reticulum to the vacuolar export machine. AB - It is somewhat paradoxical that the malaria parasite's survival strategy involves spending almost all of its blood-stage existence residing behind a two-membrane barrier in a host red blood cell, yet giving considerable attention to exporting parasite-encoded proteins back across these membranes. These exported proteins are thought to play diverse roles and are crucial in pathogenic processes, such as re-modelling of the erythrocyte cytoskeleton and mediating the export of a major virulence protein known as Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), and in metabolic processes such as nutrient uptake and solute exchange. Despite these varied roles most exported proteins have at least one common link; they share a trafficking pathway that begins with entry into the endoplasmic reticulum and concludes with passage across the vacuole membrane via a proteinaceous translocon known as the Plasmodium translocon of exported proteins (PTEX). In this commentary we review recent advances in our understanding of this export pathway and suggest several models by which different aspects of the process may be interconnected. PMID- 20170657 TI - The cuticular hydrocarbons profiles in the stingless bee Melipona marginata reflect task-related differences. AB - Members of social insect colonies employ a large variety of chemical signals during their life. Of these, cuticular hydrocarbons are of primary importance for social insects since they allow for the recognition of conspecifics, nestmates and even members of different castes. The objectives of this study were (1) to characterize the variation of the chemical profiles among workers of the stingless bee Melipona marginata, and (2) to investigate the dependence of the chemical profiles on the age and on the behavior of the studied individuals. The results showed that cuticular hydrocarbon profiles of workers were composed of alkanes, alkenes and alkadienes that varied quantitatively and qualitatively according to function of workers in the colony. PMID- 20170658 TI - Characterization of a Cry1Ac toxin-binding alkaline phosphatase in the midgut from Helicoverpa armigera (Hubner) larvae. AB - Midgut membrane-bound alkaline phosphatases (mALP) tethered to the brush border membrane surface by a glycosylphosphatidylinositol (GPI) anchor have been proposed as crucial for Cry1Ac intoxication. In the present work, two full-length cDNAs-encoding alkaline phosphatases in the midgut of Helicoverpa armigera larvae were cloned and named HaALP1 (GenBank accession no. EU729322) and HaALP2 (GenBank accession no. EU729323), respectively. These two clones displayed high identity (above 94%) at the amino acid sequence, indicating that they may represent allelic variants, and were predicted to contain a GPI anchor. Protein sequence alignment revealed that HaALPs were grouped with mALP from the Heliothis virescens midgut. The HaALP1 and HaALP2 ( approximately 68kDa) proteins were heterologously expressed in Sf9 cells using a baculovirus expression system and purified to homogeneity. Ligand blot and dot blot analysis revealed that the Cry1Ac bound to both denatured and native purified HaALPs. Data from lectin blots, competition assays with soybean agglutinin (SBA) lectin and GalNAc binding inhibition assays were indicative of the presence of GalNAc on HaALPs and binding of Cry1Ac toxin to this residue. This observation was further confirmed through N glycosidase digestion of HaALPs, which resulted in reduced Cry1Ac binding. Our data represent the first report on HaALPs and their putative role as receptors for Cry1Ac toxin in H. armigera. PMID- 20170659 TI - X-box binding protein 1 regulates brain natriuretic peptide through a novel AP1/CRE-like element in cardiomyocytes. AB - The unfolded protein response (UPR) is triggered to assist protein folding when endoplasmic reticulum (ER) function is impaired. Recent studies demonstrated that ER stress can also induce cell-specific genes. In this study, we examined whether X-box binding protein 1 (XBP1), a major UPR-linked transcriptional factor, regulates the expression of brain natriuretic peptide (BNP) in cardiomyocytes. In samples from failing human hearts, extensive splicing of XBP1 was observed along with increased expression of glucose-regulated protein of 78 kDa (GRP78), a target of spliced XBP1 (sXBP1), suggesting that the UPR was induced in heart failure in humans. Interestingly, quantitative real-time PCR revealed a positive correlation between cardiac expression of GRP78 and BNP, leading us to test the hypothesis that sXBP1 regulates BNP as well as GRP78 in cardiomyocytes. A pharmacological ER stressor caused a dose-dependent increase in the expression of sXBP1 and BNP by cultured cardiomyocytes. Short interfering RNA targeting XBP1 suppressed the induction of BNP expression by a pharmacological ER stressor or norepinephrine, which was rescued by the adenovirus-mediated overexpression of sXBP1. The promoter assay with overexpression of sXBP1 or norepinephrine showed that the proximal AP1/CRE-like element in the promoter region of BNP was critical for transcriptional regulation of BNP by sXBP1. Direct binding of sXBP1 to this element was confirmed by the chromatin immunoprecipitation assay. These findings suggest that ER stress observed in failing hearts regulates cardiac BNP expression through a novel promoter region of the AP1/CRE-like element. PMID- 20170660 TI - Post-translational regulation of calsarcin-1 during pressure overload-induced cardiac hypertrophy. AB - Chronic pressure overload to the heart leads to cardiac hypertrophy and failure through processes that involve reorganization of subcellular compartments and alteration of established signaling mechanisms. To identify proteins contributing to this process, we examined changes in nuclear-associated myofilament proteins as the murine heart undergoes progressive hypertrophy following pressure overload. Calsarcin-1, a negative regulator of calcineurin signaling in the heart, was found to be enriched in cardiac nuclei and displays increased abundance following pressure overload through a mechanism that is decoupled from transcriptional regulation. Using proteomics, we identified novel processing of this protein in the setting of cardiac injury and identified four residues subject to modification by phosphorylation. These studies are the first to determine mechanisms regulating calsarcin abundance during hypertrophy and failure and reveal the first evidence of post-translational modifications of calsarcin-1 in the myocardium. Overall, the findings expand the roles of calsarcins to include nuclear tasks during cardiac growth. PMID- 20170661 TI - Enhanced length-dependent Ca2+ activation in fish cardiomyocytes permits a large operating range of sarcomere lengths. AB - Fish myocytes continue to develop active tension when stretched to sarcomere lengths (SLs) on the descending limb of the mammalian length-tension relationship. A greater length-dependent activation in fish than mammals could account for this because the increase in Ca(2+) sensitivity may overcome the tendency for force to fall due to reduced cross-bridge availability at SLs above optimal myofilament overlap. We stretched skinned fish and rat ventricular myocytes over a wide range of SLs, including those on the descending limb of the mammalian length-tension relationship. We found that fish myocytes developed greater active tension than rat myocytes at physiological Ca(2+) concentrations at long SLs as a result of a higher Ca(2+) sensitivity and a steeper relationship between Ca(2+) sensitivity and SL. We also investigated the diastolic properties of fish and rat myocytes at long SLs by measuring titin-based passive tension, titin isoform expression and titin phosphorylation. Fish myocytes produced higher titin-based passive tension despite expressing a higher proportion of a long N2BA like isoform (38.0+/-2% of total vs 0% in rat). However, titin phosphorylation in fish myocytes was lower than in rat, which may explain some of the difference in passive tension between species. The high level of titin-based passive tension and the differential phosphorylation of sarcomeric proteins in fish myocytes may contribute to the enhanced length-dependent activation and underlie the extended range of in vivo stroke volumes found in fish compared with mammals. PMID- 20170662 TI - Therapy with granulocyte colony-stimulating factor in the chronic stage, but not in the acute stage, improves experimental autoimmune myocarditis in rats via nitric oxide. AB - We systematically investigated serial efficacy of granulocyte colony-stimulating factor (G-CSF) therapy upon experimental autoimmune myocarditis (EAM) in rats treated with and without the inhibition of nitric oxide (NO) with the analyses of tissue regeneration. G-CSF could mobilize multipotent progenitor cells of bone marrow into the peripheral blood and may improve ventricular function. A rat model of porcine myosin-induced EAM was used. After the immunization of myosin, G CSF (10 microg/kg/day) or saline was injected intraperitoneally on days 0-21 in experiment 1 and on days 21-42 in experiment 2. Additional myosin-immunized rats were orally given 25 mg/kg/day of N(G)-nitro-L-arginine methylester (L-NAME), an inhibitor of nitric oxide synthase (NOS), in each experiment (each group; n=8 21). Serum cytokines and peripheral blood cell counts were measured in each group. In experiment 1, G-CSF treatment aggravated cardiac pathology associated with increased macrophage inflammatory protein-2 (MIP-2) and interleukin-6 (IL-6) levels and enhanced superoxide production. In experiment 2, G-CSF treatment reduced the severity of myocarditis with increased capillary density and improved left ventricular ejection fraction. In the rats with EAM treated with G-CSF associated with oral L-NAME treatment in experiment 2, the severity of myocarditis was not reduced. Myocardial c-kit(+) cells were demonstrated only in G-CSF-treated group in experiment 2 but not in other groups. G-CSF has differential effects on EAM in rats associated with the modulation of cytokine network. The overwhelming superoxide production by G-CSF administration in the acute stage may worsen the disease. G-CSF therapy improved cardiac function via NO system in a rat model of myocarditis in the chronic stage, but not in the acute stage, possibly through the myocardial regeneration and acceleration of healing process. PMID- 20170663 TI - Compensatory hypertrophy induced by ventricular cardiomyocyte-specific COX-2 expression in mice. AB - Cyclooxygenase-2 (COX-2) is an important mediator of inflammation in stress and disease states. Recent attention has focused on the role of COX-2 in human heart failure and diseases owing to the finding that highly specific COX-2 inhibitors (i.e., Vioxx) increased the risk of myocardial infarction and stroke in chronic users. However, the specific impact of COX-2 expression in the intact heart remains to be determined. We report here the development of a transgenic mouse model, using a loxP-Cre approach, which displays robust COX-2 overexpression and subsequent prostaglandin synthesis specifically in ventricular myocytes. Histological, functional, and molecular analyses showed that ventricular myocyte specific COX-2 overexpression led to cardiac hypertrophy and fetal gene marker activation, but with preserved cardiac function. Therefore, specific induction of COX-2 and prostaglandin in vivo is sufficient to induce compensated hypertrophy and molecular remodeling. PMID- 20170664 TI - Dipteran insect flight dynamics. Part 1 Longitudinal motion about hover. AB - This paper presents a reduced-order model of longitudinal hovering flight dynamics for dipteran insects. The quasi-steady wing aerodynamics model is extended by including perturbation states from equilibrium and paired with rigid body equations of motion to create a nonlinear simulation of a Drosophila-like insect. Frequency-based system identification tools are used to identify the transfer functions from biologically inspired control inputs to rigid body states. Stability derivatives and a state space linear system describing the dynamics are also identified. The vehicle control requirements are quantified with respect to traditional human pilot handling qualities specification. The heave dynamics are found to be decoupled from the pitch/fore/aft dynamics. The haltere-on system revealed a stabilized system with a slow (heave) and fast subsidence mode, and a stable oscillatory mode. The haltere-off (bare airframe) system revealed a slow (heave) and fast subsidence mode and an unstable oscillatory mode, a modal structure in agreement with CFD studies. The analysis indicates that passive aerodynamic mechanisms contribute to stability, which may help explain how insects are able to achieve stable locomotion on a very small computational budget. PMID- 20170665 TI - A probabilistic framework for microarray data analysis: fundamental probability models and statistical inference. AB - Gene expression studies generate large quantities of data with the defining characteristic that the number of genes (whose expression profiles are to be determined) exceed the number of available replicates by several orders of magnitude. Standard spot-by-spot analysis still seeks to extract useful information for each gene on the basis of the number of available replicates, and thus plays to the weakness of microarrays. On the other hand, because of the data volume, treating the entire data set as an ensemble, and developing theoretical distributions for these ensembles provides a framework that plays instead to the strength of microarrays. We present theoretical results that under reasonable assumptions, the distribution of microarray intensities follows the Gamma model, with the biological interpretations of the model parameters emerging naturally. We subsequently establish that for each microarray data set, the fractional intensities can be represented as a mixture of Beta densities, and develop a procedure for using these results to draw statistical inference regarding differential gene expression. We illustrate the results with experimental data from gene expression studies on Deinococcus radiodurans following DNA damage using cDNA microarrays. PMID- 20170666 TI - Exposure of the amygdala to elevated levels of corticosterone alters colonic motility in response to acute psychological stress. AB - The amygdala is important for integrating the emotional, endocrine and autonomic responses to stress. Exposure of the amygdala to elevated levels of corticosterone (CORT) induces anxiety-like behavior and a hypersensitive colon in rodents; however, effects on colonic transit are unknown. Micropellets releasing CORT alone or combined with a selective glucocorticoid (GR) or mineralocorticoid (MR) receptor antagonist were implanted bilaterally at the dorsal boundary of the central amygdala in male rats. Inactive cholesterol implants served as controls. Seven days later, rats received water avoidance stress (WAS) for 1 h and the fecal pellet output was measured. Colorectal transit was also evaluated following the stressor by recording the time for expulsion of a glass bead placed into the colorectum. Plasma CORT levels were evaluated before WAS, after 60 min of WAS and 90 min post-WAS. Exposure of the amygdala to elevated CORT did not alter daily fecal pellet production or the number of fecal pellets released in response to WAS. However, following WAS, rats with CORT implants on the amygdala showed a delay in colorectal transit compared to cholesterol-implanted controls. Plasma CORT measurements showed that basal and WAS-induced increases in plasma CORT were similar in all groups but a prolonged increase in plasma CORT was observed 90 after cessation of WAS in rats with CORT implants. The post-WAS changes in colonic motility and plasma CORT were prevented by antagonism of GR or MR in the amygdala, suggesting their importance in driving stress-associated changes in colonic motility. PMID- 20170667 TI - Retinal versus physical stimulus size as determinants of visual perception in simultanagnosia. AB - Patients with simultanagnosia following bilateral parieto-temporo-occipital brain damage show a characteristic impairment of global gestalt perception, while their perception of individual objects or elements remains intact. For instance, when shown 'hierarchical' stimuli comprising a larger global object (e.g. a large letter) made up from smaller components (e.g. multiple small letters), they typically report seeing one of the smaller components but not the global figure. Recent work on simultanagnosia revealed that global perception can be improved if local element spacing is reduced. However, it is still unclear whether the retinal separation or the physical (post-size-constancy) spatial separation is critical. Here, we presented various hierarchical global/local letter stimuli at different viewing distances and sizes to separate the impacts of retinal versus physical size. Our findings indicate a key role for visual angle in determining simultanagnosic perception. We observed that not only retinal spacing (in terms of visual angle) between local elements had a major impact on global perception in simultanagnosia, but also the physical size of the separation between local elements, provided that binocular cues to viewing distance were available. The results indicate both pre-size-constancy retinal influences and binocular-post constancy influences upon conscious perception in simultanagnosia. PMID- 20170668 TI - Self-organizing molecular field analysis on pregnane derivatives as human steroidal 5alpha-reductase inhibitors. AB - Normal growth and development of human prostate is regulated by the androgens which balances cell proliferation and apoptosis. Testosterone (T) and dihydrotestosterone (DHT) are the two key androgens that stimulate most of the androgen action in prostate. Testosterone is converted to DHT by the membrane bound NADPH-dependent 5alpha-reductase enzyme. As a consequence of the important observation that progesterone and deoxycortisone inhibits the synthesis of DHT by competing with 4-en-3-one function of the testosterone for the 5alpha-reductase enzyme a number of pregnane derivatives were synthesized and have been reported as inhibitors of human 5alpha-reductase enzyme. Due to lack of information on the crystal structure of human 5alpha-reductase, ligand-based 3D-QSAR study has been performed on pregnane derivatives using self-organizing molecular field analysis (SOMFA) for rationalizing the molecular properties and human 5alpha-reductase inhibitory activities. The statistical results having good cross-validated r(cv)(2) (0.881), non-cross-validated r(2) (0.893) and F-test value (175.527), showed satisfied predictive ability r(pred)(2) (0.777). Analysis of SOMFA models through electrostatic and shape grids provide useful information for the design and optimization of steroidal structure as novel human 5alpha-reductase inhibitors. PMID- 20170669 TI - A study on the venom of Bothrops alternatus Dumeril, Bibron and Dumeril, from different regions of Argentina. AB - We report a comparison of toxic and enzymatic activities of Bothrops alternatus venoms collected from specimens of different regions of Argentina with a pool of these same venoms. We determined lethal, hemorrhagic and pro-coagulant (plasma and fibrinogen) doses, as well as indirect hemolysis, hydrolysis of gelatin and fibrinogen. The electrophoretic pattern of the venoms and that of fibrinogen incubated with each of the venoms was studied by SDS-PAGE. The toxic activities were consistent with those reported for these venoms but with noticeable differences between samples which do not seem related to geographical or climatic characteristics. In some cases the pooled venom showed values close to the individual samples, but it was not representative since at least the half of the venoms (4/9) exhibited very different patterns of toxicity. The potency of some activities in the individual venoms ranged from much higher to much lower than those determined in the pooled venom (0.1 to 3 fold). Not all venoms exhibited thrombin-like activity but all hydrolyzed alpha and beta chains of fibrinogen; however, degradation patterns were not always similar. Variation in activities and toxicities do not seem to be related to geographical or climatic characteristics. PMID- 20170670 TI - Acute lecozotan administration increases learning and memory in rats without affecting anxiety or behavioral depression. AB - Lecozotan is a selective serotonergic 5-HT(1A) receptor antagonist previously shown to enhance task performance efficiency in aged rhesus monkeys. In the present report we tested the ability of this drug to modify memory and learning in rats during a modified passive avoidance response test, and also tested its effect on anxiety with the elevated plus maze, and behavioral depression in the inescapable swim test. Lecozotan enhanced memory in a dose-dependent manner (0, 0.3, 0.5, 1 and 2mg/kg; s.c.), or prevented memory impairment previously induced with scopolamine-HCl. No significant changes in anxiety and behavioral depression were detected in animals treated with different doses of lecozotan (0, 0.3, 1 and 2mg/kg; s.c.) compared to control animals. These results suggest that lecozotan could enhance learning and memory in animals without affecting anxiety or behavioral depression scores and that it could be a viable alternative in the treatment of patients with cognitive deficits such as the Alzheimer's disease. PMID- 20170671 TI - Phosphatidylinositol 3-kinase mediates pain behaviors induced by activation of peripheral ephrinBs/EphBs signaling in mice. AB - EphBs receptors and their ephrinBs ligands are present in the adult brain and peripheral tissue and play a critical role in modulating multiple aspects of physiology and pathophysiology. Our recent evidence has shown that ephrinBs acted as a sensitizer to participate in peripheral sensitization and hyperalgesia induced by activation of peripheral ephrinBs/EphBs signaling. In the present study, we explored the role of phosphatidylinositol 3-kinase (PI3K) in ephrinB1 Fc-induced pain behaviors. Intraplantar injection of ephrinB1-Fc produced a time- and dose-dependent increase of PI3K-p110gamma expression and of phosphorylation of AKT in skin of injection site. Pre-treatment with PI3K inhibitor wortmannin or LY294002 prevented activation of peripheral AKT by ephrinB1-Fc. The activated AKT expressed in peripheral nerve terminals and DRG peptide-containing and small non peptide-containing neurons. Inhibition of peripheral PI3K signaling dose dependently prevented and reversed pain behaviors and spinal Fos protein expression induced by intraplantar injection of ephrinB1-Fc. Furthermore, pre treatment with PI3K inhibitor wortmannin or LY294002 prevented ephrinB1-Fc induced ERK activation in a dose-dependent manner. These data demonstrated that PI3K and PI3K crosstalk to ERK signaling mediated pain behaviors induced by activation of peripheral ephrinBs/EphBs signaling in mice. PMID- 20170673 TI - Shuttleworthia satelles endocarditis: evidence of non-dental human disease. PMID- 20170672 TI - Neurobiological mechanisms involved in nicotine dependence and reward: participation of the endogenous opioid system. AB - Nicotine is the primary component of tobacco that maintains the smoking habit and develops addiction. The adaptive changes of nicotinic acetylcholine receptors produced by repeated exposure to nicotine play a crucial role in the establishment of dependence. However, other neurochemical systems also participate in the addictive effects of nicotine including glutamate, cannabinoids, GABA and opioids. This review will cover the involvement of these neurotransmitters in nicotine addictive properties, with a special emphasis on the endogenous opioid system. Thus, endogenous enkephalins and beta-endorphins acting on mu-opioid receptors are involved in nicotine-rewarding effects, whereas opioid peptides derived from prodynorphin participate in nicotine aversive responses. An up-regulation of mu-opioid receptors has been reported after chronic nicotine treatment that could counteract the development of nicotine tolerance, whereas the down-regulation induced on kappa-opioid receptors seems to facilitate nicotine tolerance. Endogenous enkephalins acting on mu-opioid receptors also play a role in the development of physical dependence to nicotine. In agreement with these actions of the endogenous opioid system, the opioid antagonist naltrexone has shown to be effective for smoking cessation in certain sub-populations of smokers. PMID- 20170675 TI - Multiple ERbeta antisera label in ERbeta knockout and null mouse tissues. AB - In the process of characterizing a custom-made affinity-purified antiserum for estrogen receptor beta (ERbeta), ck5912, we used a number of common tests for specificity of ck5912 along with that of 8 commercially available ERbeta antisera: Affinity Bioreagents PA1-310B, Invitrogen D7N, Upstate 06-629, Santa Cruz H150, Y19, L20, 1531, and Abcam 9.88. We tested their recognition of recombinant ERbeta (rERbeta) versus rERalpha, ERbeta versus ERalpha transfected into cell lines, as well as labeling in wildtype (WT) versus estrogen receptor beta knockout (betaERKO) and null (ERbeta(ST)(L-/L-)) mouse ovary, hypothalamus, and hippocampus. To our surprise, we found that while most of these antisera passed some tests, giving the initial impression of specificity, western blot analysis showed that all of them recognized apparently identical protein bands in WT, betaERKO and ERbeta(ST)(L-/L-) tissues. We share these results with the goal of helping other researchers avoid pitfalls in interpretation that could come from use of these ERbeta antisera. PMID- 20170676 TI - Performance of juvenile baboons on neuropsychological tests assessing associative learning, motivation and attention. AB - The CANTAB (Cambridge Neuropsychological Test Automated Battery), a system developed for human neuropsychological testing, has previously been used to assess cognitive function in two species of nonhuman primates, common marmoset monkeys and rhesus macaques. We describe the application of the system to the juvenile baboon, a nonhuman primate species offering specific investigative advantages. Juvenile baboons were trained and tested on a progressive ratio task to assess motivation, simple discrimination and simple reversal tasks to assess associative learning, and intra- and extra-dimensional set-shifting tasks to assess selective attention and attentional set-shifting, respectively. Study subjects were 8 juvenile baboons (Papio sp.), 4 females and 4 males aged 3.0+/ 0.1 (mean+SEM) years and weight 8.2+/-0.4 kg. All baboons were easily trained, readily learned the neuropsychological tests and exhibited a stable performance. Applying a method such as the CANTAB has significant implications for expanding on the translational utility of the baboon in studies of neurodevelopment. PMID- 20170677 TI - Intracellular location of syntaxin 7 in human neutrophils. AB - Neutrophils are the first line of defense in the innate immune system. Neutrophils neutralize invading microorganisms mainly by phagocytosis, but the mechanism and molecules involved in this process are not well characterized. Because the endosomal soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin 7 regulates vesicle trafficking events in phagocytosis, we investigated the expression and subcellular localization of syntaxin 7 in human neutrophils. Here we have found that human peripheral blood neutrophils and neutrophil-differentiated HL-60 cells express syntaxin 7 at both mRNA and protein levels. Using biochemical and ultrastructural approaches, we found that syntaxin 7 was broadly located in the membranes of the three major cytoplasmic granules of human neutrophils, with a major location in azurophilic granules, which are mainly involved in phagocytosis. A secondary, but extensive, location of syntaxin 7 was in specific and tertiary granules, which resulted translocated to the plasma membrane upon cell activation that promoted mobilization of these organelles. These data reveal the presence of syntaxin 7 in the membranes of exocytosis-prone granules (specific and tertiary granules) and phagocytosis-related granules (azurophilic granules) in human neutrophils, and therefore it might play a role in both exocytosis and phagocytosis in human neutrophils. PMID- 20170678 TI - Long-term "in vitro" proliferating mouse hematopoietic progenitor cell lines. AB - Long-term proliferating hematopoietic progenitor cell lines have been established from mouse bone marrow in tissue cultures on the M-CSF-deficient stromal cell line OP9. In the presence of stem cell factor (SCF), thrombopoietin, IL-3 and IL 6 pluripotent hematopoietic stem cells (pHSC) initiate proliferation. For 2-3 weeks they maintain long-term reconstitution capacity, as tested in adoptive transfer experiments into sublethally irradiated hosts, but later loose this capacity. Transfection with HOXB4 stabilises the pluripotency and long-term reconstitution capacity of these pHSC-like cell lines. Transfer into media containing SCF and FLT3L, the ligand for flt3, develops cell lines with myelopoietic and lymphopoietic potencies, reconstituting hosts with a wave of short-term reconstitutions of these cell lineages. Subsequent transfer into cultures containing SCF, FLT3L and IL-7 generates lines with lymphoid reconstitution capacities, i.e. able to develop T-lineage, B-lineage and NK lineage cells. Again, this multi-lymphoid lineage developmental capacity is lost within 2 weeks, so that the remaining, proliferating cells generate B-lineage cells only, when induced to differentiate. These cell lines become capable to proliferate in IL-7 alone and now resemble pre BI-Type cell lines, as those previously isolated from fetal liver. Hence such preBI cell lines can be generated by a stepwise alteration of the cytokine milieu in culture from pHSC but intermediate differentiation stages still need to be stabilized in attempts to establish long-term proliferating cell lines at different stages of hematopoietic development. PMID- 20170679 TI - Multiplex nested RT-PCR for the detection of porcine enteric viruses. AB - Porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), and porcine group A rotavirus (PRV-A) are major viruses causing enteric diseases of piglets. A multiplex nested reverse transcription polymerase chain reaction (multiplex nested RT-PCR) was developed for the detection of these viruses in field samples from piglets with diarrhea. A mixture of (1) three external pairs of primers, yielding in the amplification step two different amplicons with sizes of 950 bp and 317 bp and (2) three pairs of internal primers in a second round of PCR (nested PCR), yielding two different amplicons with sizes of 792 bp and 208 bp for TGEV and porcine PRV-A, respectively. The genome of PEDV was not detected after the amplification step but it was detected in the second round of PCR, yielding amplicon with size of 291 bp. Multiplex nested RT PCR can detect TGEV, PRV-A, and PEDV up to concentration 10(2) TCID(50)/mL, 10(1) TCID(50)/mL, and 27.2 microg/microl of RNA, respectively. A total of 175 field samples were collected from swine with diarrhea from January 2005 until July 2007. The samples were tested for the presence of three viruses by a multiplex nested RT-PCR. Dual infections with PEDV and PRV-A were identified in seven specimens (4%) (n = 6). Twenty-one (25%) infections were caused by PEDV and thirty-four infections (41%) were caused by PRV-A. The genome of TGEV was not detected in any of these field samples, however TGEV was detected in piglets infected experimentally. The multiplex nested RT-PCR is rapid, sensitive, and a cost-effective detection method for the detection of porcine enteric viruses. PMID- 20170680 TI - A diagnostic method based on MGB probes for rapid detection and simultaneous differentiation between virulent and vaccine strains of avian paramyxovirus type 1. AB - Newcastle disease virus (NDV), also designated avian paramyxovirus type 1 (APMV 1), is a serious pathogen of poultry, causing highly contagious Newcastle disease (ND), with high morbidity or mortality, depending on the strain. Accordingly, rapid and reliable detection of APMV-1 and differentiation between vaccine and virulent strains is of crucial importance for ND diagnosis and plays an important role in effective control of the disease. In this study, two real-time reverse transcription polymerase chain reaction (real-time RT-PCR) assays using minor groove-binding (MGB) probes were developed for broad range detection and simultaneous pathotyping of APMV-1. The two assays were evaluated for their ability to detect in allantoic fluids viral RNA of all known APMV-1 lineages. Additionally, the applicability of the developed assays was assessed by the detection and pathotype prediction of APMV-1 in swabs and organs. The assays demonstrated high analytical specificity, sensitivity and good reproducibility, with coefficients of variation ranging from 0.2% to 3.9% and from 0.6% to 7.2% for intra-assay and inter-assay variability, respectively. The results indicated the suitability of both assays as a complementary method for rapid screening and typing of APMV-1. PMID- 20170681 TI - Evaluation of an enzyme-linked immunosorbent assay for detection of West Nile virus infection based on a recombinant envelope protein produced in Trichoplusia ni larvae. AB - West Nile virus (WNV), a Flavivirus distributed most widely, is presenting lately variable epidemiological and ecological patterns, including an increasing virulence that has already caused over 1000 human deaths in USA. Currently, diagnosis of WNV is achieved mainly by enzyme-linked immunoassays (ELISAs) based on the use of inactivated whole WNV (iWNV) as antigen, although results have to be confirmed by plaque reduction neutralization tests (PRNTs). Expression of WNV envelope recombinant E (rE) protein and its usefulness as ELISA antigen are described. Production of rE was achieved upon infection of Trichoplusia ni insect larvae with a recombinant baculovirus. Once optimized, the rE-based ELISA was validated with a battery of mouse and equine sera characterized previously. Concordance with the iWNV-based ELISA used routinely was good (95%), as it was with the reference PRNT (90%), with specificity of 94.4% and sensitivity of 88.1%. Production of rE protein in insect larvae allows for an easy, low cost and quite large-scale yield of partially purified antigen which is suitable for serological diagnosis of WNV, without the need for manipulation of large quantities of infective virus. PMID- 20170682 TI - Identification of plant viruses using one-dimensional gel electrophoresis and peptide mass fingerprints. AB - A generic assay to detect and partially characterize unknown viruses from plants was developed. Proteins extracted from virus-infected and uninfected plants were separated in one dimension by SDS polyacrylamide gel electrophoresis. Differentially expressed protein bands were eluted after trypsin digestion and resulting peptide fragments separated according to their mass by matrix-assisted laser-desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. Resulting peptide mass fingerprints (PMF) were compared with those in protein databases. The assay was used to identify three known viruses: the potyviruses Zucchini yellow mosaic virus and Turnip mosaic virus, and an alfamovirus Alfalfa mosaic virus. It was also used to identify a virus that manifested symptoms in wild Cakile maritima plants, tentatively identified as Pelargonium zonate spot virus (PZSV) (genus Anulavirus) by its PMF, and then confirmed by nucleotide sequencing. The detection of PZSV constitutes a first record of this virus in Australia and in this host. It is proposed that this rapid and simple assay is a useful approach for analysis of plant samples known to harbor viruses that could not be identified using antisera or nucleic acid-based assays. PMID- 20170683 TI - Quantitative single serum-dilution liquid phase competitive blocking ELISA for the assessment of herd immunity and expected protection against foot-and-mouth disease virus in vaccinated cattle. AB - A single serum-dilution liquid phase ELISA (slpELISA) was standardized to be used for serological evaluation of herd immunity against foot-and-mouth disease. The absorbance value at a dilution 1:64 of each serum sample was interpolated in a standard curve by plotting the antibody titers of six control sera determined by end point dilution liquid phase ELISA (lpELISA), against the absorbance values for the same control sera at 1:64 dilutions. A straight line was obtained by linear regression analysis (r>0.90) in the titer range of 1.40-2.40. The reliability of the antibody titers was confirmed by the simultaneous titration of 60 cattle sera by slpELISA and lpELISA, which showed an acceptable correlation (R(2)>0.87) for viral strains A24/Cruzeiro, A/Argentina/01, O1/Campos and C3/Indaial. Titers obtained by both methods were not significantly different (p>0.05), thus confirming that slpELISA could be used successfully to replace the conventional serial dilution ELISA for the assessment of protection status of cattle in epidemiological studies. In addition, this quantitative slpELISA provides an adequate method for monitoring the effectiveness of vaccination campaigns and is also suitable for the assessment of seroconversion of naive animals during early stages of infection. PMID- 20170684 TI - The cholinergic system, nerve growth factor and the cytoskeleton. AB - Cholinergic neurons of the basal forebrain provide the major cholinergic innervation to the cortex and hippocampus, and play a key role in memory and attentional processes. Dysfunction of basal forebrain cholinergic neurons (BFCN) is a cardinal feature of Alzheimer's disease (AD) and correlates with cognitive decline. Survival of BFCN neurons depends upon binding of nerve growth factor (NGF), which is synthesized and secreted by cells in the cortex and hippocampus, with high-affinity (TrkA) and low-affinity (p75(NTR)) neurotrophin receptors produced within BFCN neurons. NGF released from target cells activates TrkA on axon terminals and triggers activation of PI3K/Akt, MEK/ERK, and PLCgamma (phospholipase C) signaling pathways. The signal then travels retrogradely along axon to cell body to promote neuronal survival. However, the nature of the retrograde signal remains mysterious. p75(NTR) receptors could mediate a fundamentally different signaling pathway leading to apoptic cell death. Dysfunction of NGF and its receptors has been suggested to underlie the selective degeneration of the BFCN in end stage Alzheimer disease. In this regard, NGF, the founding member of the neurotrophin family, has generated great interest as a potential target for the treatment of AD. This review focuses on NGF-cholinergic dependency, NGF/receptor binding, signal transduction, retrograde transport, regulation of specific cellular endpoints, and the potential involvement of cytoskeleton dysfunction in defected NGF signaling. PMID- 20170674 TI - Distinct patterns of neuronal inputs and outputs of the juxtaparaventricular and suprafornical regions of the lateral hypothalamic area in the male rat. AB - We have analyzed at high resolution the neuroanatomical connections of the juxtaparaventricular region of the lateral hypothalamic area (LHAjp); as a control and in comparison to this, we also performed a preliminary analysis of a nearby LHA region that is dorsal to the fornix, namely the LHA suprafornical region (LHAs). The connections of these LHA regions were revealed with a coinjection tract-tracing technique involving a retrograde (cholera toxin B subunit) and anterograde (Phaseolus vulgaris leucoagglutinin) tracer. The LHAjp and LHAs together connect with almost every major division of the cerebrum and cerebrospinal trunk, but their connection profiles are markedly different and distinct. In simple terms, the connections of the LHAjp indicate a possible primary role in the modulation of defensive behavior; for the LHAs, a role in the modulation of ingestive behavior is suggested. However, the relation of the LHAjp and LHAs to potential modulation of these behaviors, as indicated by their neuroanatomical connections, appears to be highly integrative as it includes each of the major functional divisions of the nervous system that together determine behavior, i.e., cognitive, state, sensory, and motor. Furthermore, although a primary role is indicated for each region with respect to a particular mode of behavior, intermode modulation of behavior is also indicated. In summary, the extrinsic connections of the LHAjp and LHAs (so far as we have described them) suggest that these regions have a profoundly integrative role in which they may participate in the orchestrated modulation of elaborate behavioral repertoires. PMID- 20170685 TI - The cholinergic system and depression. AB - Major depressive disorder is a severe psychiatric condition which forms a substantial burden to patients and society. Despite continuous efforts to unravel its etiology and pathophysiology, many questions remain. The majority of neurobiological research and classical pharmacotherapy regimens have approached this illness as the consequence of a failing monoaminergic neurotransmitter system. In the last decades, involvement of adult hippocampal neurogenesis in the pathogenesis and treatment of depressive disorder has gained an enormous interest. Numerous neurobiological systems and circuits thus appear to underlie this complex multi-factorial disease. One of them is the cholinergic system, which plays a major role in the regulation of various CNS functions, such as arousal, attention, cognition and memory. Cognitive impairments are often observed in depression, next to low mood, anhedonia and other clinical symptoms. Cholinergic dysfunctions may account for the development of cognitive symptoms during the course of depression. Changes in hippocampal neurogenesis, often associated with chronic stress in animal models, may be in part mediated by cholinergic dysfunction, which in turn could underlie the cognitive disturbances observed in depression. Here, we discuss the involvement of the cholinergic system in depressive disorder, with particular focus on its role in associated cognitive impairment. Since such deficits are often modified by cholinergic drugs, application of these neuropharmacological findings may provide a new therapeutic niche while yielding valuable insight into the pathophysiology of this complex illness. PMID- 20170687 TI - Localisation of pre- and postsynaptic cholinergic markers in the human brain. AB - The cholinergic neurotransmission in the central nervous system plays an important role in modulating cognitive processes such as learning, memory, arousal and sleep as well as in modulating locomotor activity. Dysfunction of the central cholinergic system is involved in numerous neuropsychiatric diseases. This review will provide a synopsis on the regional localisation of cholinergic and cholinoceptive structures within the adult human brain. On the cholinergic site data based on the distribution of choline acetyltransferase-immunoreactive structures are in the focus, complemented by data from acetylcholinesterase and vesicular acetylcholine transporter studies. On the cholinoceptive site, the distribution and localisation of receptors that transduce the acetylcholine message, i.e. the muscarinic and the nicotinic acetylcholine receptors is summarized. In addition to these data obtained on post mortem brain an overview of markers which allow for the in vivo monitoring of the cholinergic system in the brain is given. The detailed knowledge on the distribution and localisation of cholinergic markers in human brain will provide further information on the cholinergic circuits of neurotransmission - a prerequisite for the interpretation of in vivo imaging data and the development of selective diagnostic and therapeutic compounds. PMID- 20170688 TI - Effects of adolescent ethanol exposure on event-related oscillations (EROs) in the hippocampus of adult rats. AB - Electrophysiological studies have shown that adolescent ethanol (EtOH) exposure can produce long-term changes in hippocampal EEG and ERP activity. Recently, evidence has emerged suggesting that event-related oscillations (EROs) may be good indices of alcoholism risk in humans, however, have not been evaluated for their ability to index the effects of EtOH exposure. The objective of the present study was to characterize EROs generated in hippocampus in adult rats exposed to EtOH during adolescence. Adolescent male Sprague-Dawley rats were exposed to EtOH vapor for 12h/d for 10 days. A time-frequency representation method was used to determine delta, theta, alpha and beta ERO energy and the degree of phase variation in the hippocampus of adult rats exposed to EtOH and age-matched controls. The present results suggest that the decrease in P3 amplitudes, previously observed in adult rats exposed to EtOH during adolescence, is associated with increases in evoked theta ERO energy. These studies suggest that EROs are suitable for characterizing the long-term effects of adolescent EtOH exposure. Further studies are needed to determine the relationship between the mechanisms that regulate these neurophysiological endophenotypes and the consequences of adolescent EtOH exposure. PMID- 20170689 TI - An EcR homolog from the filarial parasite, Dirofilaria immitis requires a ligand activated partner for transactivation. AB - Filarial parasites are responsible for several serious human diseases with symptoms such as lymphoedema, elephantiasis, and blindness. An understanding of how these parasites pass through developmental checkpoints may suggest potential targets for intervention. A useful model system for the study of the human parasites is the closely related nematode, D. immitis, the causative agent of dog heartworm disease. Ecdysteroids have been identified in filarial nematodes and have been shown to have a biological affect both on molting and microfilarial production. The ecdysteroid, 20-hydroxyecdysone and its receptor, EcR, have a well-characterized developmental role in insects, where it is involved in the control of molting and metamorphosis. We have identified a D. immitis nuclear receptor, DiEcR that shows strong sequence similarity to the insect EcR and shares many of its biochemical properties, including ligand-dependent activation of transcription. However, unlike most insect EcRs, DiEcR requires a ligand activated RXR partner to exhibit ligand-dependent transcriptional activation of a reporter gene in tissue culture. PMID- 20170686 TI - Regulation of cortical acetylcholine release: insights from in vivo microdialysis studies. AB - Acetylcholine release links the activity of presynaptic neurons with their postsynaptic targets and thus represents the intercellular correlate of cholinergic neurotransmission. Here, we review the regulation and functional significance of acetylcholine release in the mammalian cerebral cortex, with a particular emphasis on information derived from in vivo microdialysis studies over the past three decades. This information is integrated with anatomical and behavioral data to derive conclusions regarding the role of cortical cholinergic transmission in normal behavioral and how its dysregulation may contribute to cognitive correlates of several neuropsychiatric conditions. Some unresolved issues regarding the regulation and significance of cortical acetylcholine release and the promise of new methodology for advancing our knowledge in this area are also briefly discussed. PMID- 20170690 TI - Bidirectional synaptic plasticity in response to single or paired pulse activation of NMDA receptors. AB - It is still incompletely known how NMDA receptors (NMDA-R) regulate bidirectional synaptic plasticity. We examined this issue by an experimental protocol in which paired pulse stimulation (PPS) with 50ms interstimulus interval and basal frequency of 0.1Hz was applied to CA1 area of rat hippocampal slices during low Mg(2+) perfusion. Under blockade of NMDA-Rs by AP5, PPS for 12-60min led to only a minor depression. In contrast, when PPS was applied in the absence of AP5, there was a prominent short-term potentiation (STP), mainly of AMPA-R mediated responses, with peak at 1min and lasting 10-15min. The STP was followed by a slowly developing long-term depression (LTD). Applying AP5 during the STP, converted it to a stable increase relative to the control pathway. Following peak STP, plasticity was controlled in a composite manner. Whereas the initial decay was counteracted by NMDA-R activation, the following LTD was dependent on such activation. Our data suggest that synaptic changes do not only depend on the instantaneous, NMDA-dependent Ca(2+) concentration in the dendritic spine, but are also influenced by prior induction events. In addition to NMDA-R driven processes, passive relaxation contributes to the synaptic plasticity and in some cases outbalances the active control. PMID- 20170691 TI - Netrin-1 elevates the level and induces cluster formation of its receptor DCC at the surface of cortical axon shafts in an exocytosis-dependent manner. AB - During development, a diffusible axon guidance cue, netrin-1, plays a variety of important roles in the correct wiring of the nervous system by inducing axon outgrowth, attraction, repulsion and/or branching in various types of neurons. It has been reported that translocation of its receptor DCC (deleted in colorectal cancer) from an intracellular pool to the plasma membrane enhances outgrowth of rat spinal commissural axons in response to netrin-1 (Bouchard et al., 2004). To find out whether netrin-1 induces DCC translocation in cerebral cortical neurons, we examined changes in the level and distribution of DCC at the surface of hamster dissociated cortical axons in response to netrin-1. At the surface of cortical axon shafts, we observed netrin-1-evoked, exocytosis-dependent DCC clustering, which was accompanied by elevation of the DCC level. These changes in cell surface DCC occurred in axon shafts, but did not occur in growth cones. Taken together, these results indicate that cell surface DCC is modulated by netrin-1 through translocation of DCC to the plasma membrane via exocytosis in cerebral cortical neurons. PMID- 20170692 TI - Cerebral activation associated with speech sound discrimination during the diotic listening task: an fMRI study. AB - Comprehending conversation in a crowd requires appropriate orienting and sustainment of auditory attention to and discrimination of the target speaker. While a multitude of cognitive functions such as voice perception and language processing work in concert to subserve this ability, it is still unclear which cognitive components critically determine successful discrimination of speech sounds under constantly changing auditory conditions. To investigate this, we present a functional magnetic resonance imaging (fMRI) study of changes in cerebral activities associated with varying challenge levels of speech discrimination. Subjects participated in a diotic listening paradigm that presented them with two news stories read simultaneously but independently by a target speaker and a distracting speaker of incongruent or congruent sex. We found that the voice of distracter of congruent rather than incongruent sex made the listening more challenging, resulting in enhanced activities mainly in the left temporal and frontal gyri. Further, the activities at the left inferior, left anterior superior and right superior loci in the temporal gyrus were shown to be significantly correlated with accuracy of the discrimination performance. The present results suggest that the subregions of bilateral temporal gyri play a key role in the successful discrimination of speech under constantly changing auditory conditions as encountered in daily life. PMID- 20170693 TI - Bioluminescence imaging of c-fos gene expression accompanying filial imprinting in the newly hatched chick brain. AB - Bioluminescence imaging is a powerful tool for examining gene expression in living animals. Previously, we reported that exogenous DNA could be successfully delivered into neurons in the newly hatched chick brain using electroporation. Here, we show the in vivo bioluminescence imaging of c-fos promoter activity and its upregulation, which is associated with filial imprinting. The upregulation of c-fos gene expression correlated with both the strength of the chicks' approach activity to the training object and the acquisition of memory. The present technique should be a powerful tool for analyzing the time changes in neural activity of certain brain areas in real-time during memory formation, using brains of living animals. PMID- 20170694 TI - Lipophilic siRNAs mediate efficient gene silencing in oligodendrocytes with direct CNS delivery. AB - Conjugation of small interfering RNA (siRNA) with lipophilic molecules has been demonstrated to enhance cellular uptake in cell culture and to produce efficient endogenous gene silencing in the liver after systemic administration and in neurons after direct local injection. Here, we evaluated the in vivo delivery of siRNAs conjugated with different linkers to cholesterol by targeting CNPase (2' 3'-cyclic nucleotide 3'-phosphodiesterase) in oligodendrocytes. Cholesterol conjugated siRNAs administered to the rat corpus callosum by intraparenchymal central nervous system (CNS) infusion show improved silencing ability compared with unconjugated siRNA. Furthermore, conjugation of siRNA to cholesterol with a cleavable disulfide linker appears to be beneficial for improving the potency of silencing of CNPase mRNA in oligodendrocytes in vivo. Taken together, these findings indicate that cholesterol-conjugated siRNAs are effective for direct CNS delivery to oligodendrocytes, and that the biocleavable disulfide linker appears to be beneficial for improving the potency of silencing of target mRNA in vivo. PMID- 20170695 TI - I don't need anybody to tell me what I should be doing'. A discursive analysis of maternal accounts of (mis)trust of healthy eating information. AB - Healthy eating initiatives, and messages about what one should be eating, are prolific in contemporary British society. This paper examines mothers' talk around food and feeding to determine how trust or mistrust in healthy eating information is established and rationalised. Discursive analysis of interviews with mothers (N=12, aged 25-45) isolated two prominent discursive positions that mothers established with regards to healthy eating messages. First, they legitimised an extensive mistrust of healthy eating information and messages on the grounds that they are at best, inconsistent and at worst, grossly contaminated by stakeholder bias. Second, and in contrast, they established (most) mothers as having a wholesome, privileged, and entirely sufficient instinctive knowledge about how to feed their children. However, an out-group of failing mothers, deemed to have inadequate nutritional knowledge, was also formulated. Mothers talk thus established a central dilemma whereby to accept nutritional advice compromised a good mothering identity. We argue that nutritional messages and interventions should be sensitive to this dilemma so that they facilitate, rather than threaten, a good mothering identity. PMID- 20170696 TI - Impaired Na+-dependent glutamate uptake in platelets during depolarization of their plasma membrane. AB - Blood platelets contain neuronal Na(+)-dependent glutamate transporters and are able to accomplish glutamate uptake. Applying high-KCl, we have demonstrated dose dependent depolarization of the plasma membrane of rabbit platelets that was registered as an increase in the fluorescence of the potential-sensitive fluorescent dye rhodamine 6G. The initial velocity of L-[(14)C]glutamate uptake (10 microM) in platelets was decreased by 20% during 35 mM KCl-evoked depolarization and consisted of 1.2+/-0.09 pmol x min(-1) x mg(-1) protein in control and 0.96+/-0.08 pmol x min(-1) x mg(-1) protein during depolarization. Confocal laser scanning microscopy and flow cytometry revealed that these changes in glutamate uptake were not a result of platelet aggregation/activation. Also, addition of high-KCl did not change acidification of platelet secretory granules that was found with pH-sensitive fluorescent dye acridine orange, thereby showing that changes in their proton gradient could not cause glutamate uptake alteration. This malfunction of glutamate transporters has to take place under: (i) the conditions of pseudohyperkalemia or hyperkalemia, i.e. activation and clotting of platelets, haemolysis, leucocytosis, acute renal failure, hypofunction of adrenal cortex, lack of aldosterone, stroke, trauma and (ii) depolarization of the plasma membrane of platelets during their activation by ADP, thrombin, platelet-activating factor. Weak glutamate uptake might have considerable consequences for platelets per se (and thus for haemostatic system) and glutamate homeostasis in the CNS. PMID- 20170697 TI - AMPA receptors serum-dependently mediate GABAA receptor alpha1 and alpha6 subunit down-regulation in cultured mouse cerebellar granule cells. AB - Depolarization of cultured mouse cerebellar granule cells with potassium or kainate results in developmentally arrested state that includes down-regulation of GABA(A) receptor alpha1, alpha6 and beta2 subunit expression. These subunits are normally strongly expressed in cerebellar granule cells from second postnatal week throughout the adulthood. In the present study we demonstrate that selective activation of AMPA subtype of glutamate receptors down-regulates alpha1 and alpha6 subunit mRNA expression. Removal of AMPA agonist from culture medium restores expression of these subunits indicating reversibility of the down regulation. In serum-free culture medium AMPA receptor activation did not down regulate alpha1 or alpha6 subunit expression. Furthermore, the down-regulation was strongly attenuated when the cells were cultured in the presence of dialysed fetal calf serum. The results indicate that down-regulation of GABA(A) receptor alpha1 and alpha6 subunits by AMPA receptor activation is dependent on the presence of low molecular weight compounds present in fetal calf serum. In order to study mouse cerebellar granule cell maturation and/or regulation of GABA(A) receptor subunit expression in culture, the experiments should be performed in the absence of fetal calf serum. PMID- 20170698 TI - Effects of Yokukansan on behavioral and psychological symptoms of dementia in regular treatment for Alzheimer's disease. AB - Yokukansan (YKS) is used frequently against behavioral and psychological symptoms of dementia (BPSD) together with donepezil in patients with Alzheimer's disease (AD). Here, we investigated the efficacy and safety of YKS in patients with AD in a non-blinded, randomized, parallel-group comparison study. Patients who had at least one symptom score of four or more on the Neuropsychiatric Inventory (NPI) subscales were enrolled in the study. The subjects were randomly assigned to the YKS-treated group (YKS/donepezil combination therapy group) and the non-YKS treated group (donepezil monotherapy group). TSUMURA Yokukansan (TJ-54, 7.5g, t.i.d.) was administered in a four-week study treatment period. The subjects were evaluated twice at the start (Week 0) and completion (Week 4) of the study treatment in terms of NPI, Mini-Mental Status Examination (MMSE), Disability Assessment for Dementia (DAD), Zarit Burden Interview, and Self-rating Depression Scale (SDS). The efficacy analysis was performed in 29 patients (YKS-treated group) and 32 patients (non-YKS-treated group). The NPI total score improved significantly more in the YKS-treated group than in the non-YKS-treated group. In the NPI subscales of agitation/aggression and irritability/lability, the YKS treated group showed significantly greater improvement than the non-YKS-treated group, but no statistically significant improvement was seen with YKS in the other subscales. There were no significant differences between the YKS-treated group and the non-YKS-treated group in MMSE, DAD, Zarit Burden Interview and SDS. No adverse reactions were noted in either group. The results of this study showed that YKS is safe and effective in the treatment of BPSD in AD patients. PMID- 20170699 TI - Gender-specific prolactin response to antipsychotic treatments with risperidone and olanzapine and its relationship to drug concentrations in patients with acutely exacerbated schizophrenia. AB - Hyperprolactinemia is a frequent consequence of treatment with antipsychotic agents, partially because the prolactin response to antipsychotics is related to dopamine blockade. Recent studies have suggested that the prolactin response to olanzapine is weaker than that to risperidone. Thus, we studied the effects of various factors on the elevated plasma prolactin levels caused by these medications. The subjects were 94 patients with acutely exacerbated schizophrenia (46 males, 48 females). For four weeks, they received 6mg of risperidone and 20mg of olanzapine daily. Plasma samples were collected before the medications were given and 12h after the bedtime dosing each week. Treatment with either risperidone or olanzapine boosted plasma prolactin levels above baseline in both males and females. Prolactin levels were significantly higher in females than in males at all sampling points in both treatments. Risperidone increased prolactin significantly more than did olanzapine in both males and females. Delta prolactin (prolactin level at four weeks minus the baseline prolactin level) during olanzapine treatment significantly correlated with olanzapine concentration at 4th week (r=-0.518, p<0.01) only in males. Multiple regression analyses showed that delta prolactin during risperidone was significantly correlated with gender (p<0.001) and age (p<0.05) and that delta prolactin during olanzapine significantly correlated with gender (p<0.001) and drug concentration (p<0.01). The present study suggests that the predominant factors influencing hyperprolactinemia are young female for risperidone treatment, and being female and lower drug concentration as a predictor for hyperprolactinemia under olanzapine. PMID- 20170700 TI - Effects of Aspergillus niger-fermented Terminalia catappa seed meal-based diet on selected enzymes of some tissues of broiler chicks. AB - Effects of Aspergillus niger-fermented Terminalia catappa seed meal-based diet on the activities of alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamate transferase (gamma-GT) in the crop, small intestine, gizzard, heart, liver and serum of broiler chicks were investigated. Milled T. catappa seed was inoculated with spores of A.niger (2.21 x 10(4) spores per ml) for 3 weeks. Forty-five day-old broiler chicks weighing between 27.62 and 36.21 g, were divided into three groups. The first group was fed soybean-based (control) diet; the second on raw T. catappa seed meal-based diet; and the third on A. niger-fermented T. catappa seed meal-based diet for 7 weeks. The results revealed a significantly increased (p<0.05) activity of ALP in the tissues. Contrarily, there were significant reductions (p<0.05) in the activities of ALP, ALT, AST and gamma-GT in the liver and heart of the broilers fed the raw T. catappa seed meal-based diet while there were significant increase (p<0.05) in the activities of these enzymes in the serum of the broilers in this group. The data obtained showed that A. niger-fermented T. catappa seed meal reduced the toxic effects of the raw seed meal on the tissues of broiler chicks. PMID- 20170701 TI - Curcumin supplementation protects from genotoxic effects of arsenic and fluoride. AB - The present study was aimed to evaluate curcumin as a potential natural antioxidant to mitigate the genotoxic effects of arsenic (As) and fluoride (F) in human peripheral blood lymphocytes. The study was divided into nine groups consisting of negative control, positive control treated with ethyl methane sulphonate (EMS; 1.93 mM) and curcumin control with only curcumin (1.7 microM) in blood culture. As (1.4 microM) and F (34 microM) were added alone as well as in combination, to the cultures, with and without curcumin. Cultures were analysed for chromosomal aberrations (both structural and numerical) and primary DNA damage via comet assay as the genotoxic parameters after an exposure duration of 24h. Results revealed that curcumin efficiently ameliorates the toxic effect of As and F by reducing the frequency of structural aberrations (>60%), hypoploidy (>50%) and primary DNA damage. In conclusion, curcumin mitigates the genotoxic effects of the two well known water contaminants (As and F) effectively and efficiently at the given concentration in vitro. PMID- 20170702 TI - TOP1 and 2, polysaccharides from Taraxacum officinale, attenuate CCl(4)-induced hepatic damage through the modulation of NF-kappaB and its regulatory mediators. AB - In this work, we estimate the inhibitory effect of two polysaccharides from Taraxacum officinale (TOP) on CCl(4)-induced oxidative stress and inflammation in Sprague-Dawley rats. TOP1 and 2 (304, 92 mg/kg bw) were administered for 7 days via a stomach sonde, and hepatitis was induced by a single dose of CCl(4) (50% CCl(4)/olive oil; 0.5 mL/kg bw) administration. CCl(4) significantly elevated serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. Histopathological observation further revealed that CCl(4)-induced moderate levels of inflammatory cell infiltration, centrilobular fatty change, apoptosis, and necrosis. However, TOPs pretreatment markedly decreased AST and ALT activities as well as hepatic lesions. TOPs also increased free radical scavenging activity, as exhibited by a lowered TBARS concentration. TOPs pretreatment also reversed other hepatitis-associated symptoms, including GSH depletion, inhibited anti-oxidative enzyme activities, up-regulation of NF-kappaB and increased expression of its regulatory inflammatory mediators, such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta. These results suggest that TOPs have a hepatoprotective effect by modulating inflammatory responses and ameliorating oxidative stress. PMID- 20170703 TI - Assessment of genotoxic effects of benzyl derivatives by the comet assay. AB - In this study, different concentrations of four benzyl derivatives (benzyl alcohol, benzyl acetate, benzoic acid and benzaldehyde) used as flavour ingredients were investigated for genotoxicity in in vitro. By taking blood from two healthy people comet assay was carried on to investigate the potential health damages of benzyl derivatives. For the evaluation of genotoxic effects, the tail moment and % tail DNA in the treated chemicals were compared to the solvent control, which is distilled water. The alkaline comet assay showed significantly increased tail moment and % tail DNA at 25 and 50 mM concentrations of benzyl alcohol. Benzyl acetate increased both % tail DNA and tail moment at 50 mM concentrations. While % tail DNA was statistically increased at 10 mM and higher concentrations, tail moment has significant difference at 10 and 25 mM concentrations of benzaldehyde. Benzoic acid has apoptotic effects at the concentrations higher than 5 mM, for this reason we tested concentrations less than 5mM (0.05, 0.1, 0.5, 1 and 5 mM). Only the highest concentration of benzoic acid increased both tail moment and % tail DNA. PMID- 20170704 TI - Metabolic interactions between ethanol and MDMA in primary cultured rat hepatocytes. AB - 3,4-Methylenedioxymethamphetamine (MDMA; ecstasy), a drug of abuse commonly consumed at rave parties, is often taken in a polydrug abuse scenario, ethanol being one of the most associated drugs. Both MDMA and ethanol are mainly metabolized in the liver with formation of toxic metabolites. Our working hypothesis is that ethanol can modify the metabolism of MDMA through the cytochrome P450 system, and that this effect may be further potentiated by hyperthermia, a well-known consequence of MDMA abuse. To investigate these putative interactions we used primary rat hepatocyte cultures, which were exposed to 300 mM ethanol, 1.6 mM MDMA and the combination of both, at normothermic (36.5 degrees C) and hyperthermic (40.5 degrees C) conditions. After 24 h, the levels of MDA, HMA and HMMA in the cell culture medium were quantified by GC/MS. In addition, we repeated the same experimental design preceded by 1h incubation with 0.18 microM ketoconazole or 150 microM diallyl sulphide (CYP3A and CYP2E1 inhibitors, respectively), to evaluate the putative role of these isoenzymes in the observed effects. The results obtained showed that ethanol exposure increases the formation of some MDMA metabolites such as HMA (1.8 times increase) and MDA (1.5 times increase). This effect was markedly increased under hyperthermic conditions (HMA, MDA and HMMA formation increased 10, 6 and 16 times, respectively) and is mediated, at least partially, by CYP3A and CYP2E1. PMID- 20170705 TI - The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time dependent. AB - A reliable in vitro model to determine the potential estrogenic activity of chemicals of interest is still unavailable. To further investigate the usefulness of a human-derived cell line, we determined the transcriptional changes induced by bisphenol A (BPA) in Ishikawa cells at various doses (1 nM, 100 nM, 10 microM, and 100 microM) and time points (8, 24 and 48 h) by comparing the response of approximately 38,500 human genes and ESTs between treatment groups and controls (vehicle-treated). By trend analysis, we determined that the expression of 2794 genes was modified by BPA in a dose- and time-dependent manner (p< or =0.0001). However, the majority of gene expression changes induced in Ishikawa cells were elicited by the highest doses of BPA evaluated (10-100 microM), while the genomic response of the cells exposed to low doses of BPA was essentially negligible. By comparing the Ishikawa cells' response to BPA vs.17 alpha-ethynyl estradiol we determined that the change in the expression of 307 genes was identical in the direction of the change, although the magnitude of the change for some genes was different. Further, the response of Ishikawa cells to high doses of BPA shared similarities to the estrogenic response of the rat uterus, specifically, 362 genes were regulated in a similar manner in vivo as well as in vitro. Gene ontology analysis indicated that BPA results in changes to multiple molecular pathways affecting various biological processes particularly associated with cell organization and biogenesis, regulation of translation, cell proliferation, and intracellular transport; processes also affected by estrogen exposure in the uterus of the rat. These results indicate that Ishikawa cells are capable of generating a biologically relevant estrogenic response after exposure to chemicals with varied estrogenic activity, and offer an in vitro model to assess this mode of action. PMID- 20170706 TI - Quality of the interface of primary tooth dentin bonded with antibacterial fluoride-releasing adhesive. AB - OBJECTIVE: Limited information is available on the physical properties and ultrastructure of resin-dentin interfaces created in primary teeth. The interfacial quality of sound and caries-affected primary tooth dentin bonded with an antibacterial fluoride-releasing self-etch adhesive was examined in the present study. METHODS: Primary molars were bonded with Clearfil Protect Bond (Kuraray Medical). A nano-indentation tester was employed for creating indentations vertically across resin-dentin interfaces of the bonded sound and caries-affected primary dentin for determination of hardness (H) and Young's modulus (Y). Statistical analysis were performed using one-way and two-way ANOVA and Fisher's PLSD test at p<0.05. Similar resin-dentin interfaces were examined with SEM/EDX, and with TEM using ammoniacal silver nitrate tracer for nanoleakage. RESULTS: In both sound and caries-affected dentin, compared to the underlying dentin, significantly lower values were seen in the H and Y values of the interfacial dentin except for the H in caries-affected dentin. No significant difference between the interfacial dentin and the underlying dentin was observed in the H of caries-affected dentin and the Ca and P contents in both sound and caries-affected dentin. TEM revealed extensive interfacial nanoleakage in bonded sound dentin, while no silver deposit in bonded caries-affected dentin. However, silver deposits were observed in the porous caries-affected dentin beneath the interface. CONCLUSION: Within the limitation of this study, Clearfil Protect Bond cannot demonstrate evidence of remineralization, does not increase the hardness and elasticity of the interfacial dentin, and does not prevent nanoleakage along the resin-dentin interface. PMID- 20170707 TI - Mental task demands and cardiovascular response patterns. AB - Though it is well known that solving mental tasks elicits tonic increases in cardiovascular activity, a good theory explaining the specificity of this effect is lacking. It is also unclear why different kinds of mental tasks elicit different response patterns. The aim of the experiment was to compare cardiovascular response patterns during three tasks matched for their duration (8 min) and probability of success (.5): a simple RT task and two numeral tasks. One of them (a RUN task) involved program running (performing basic arithmetical operations), the other (an EDIT task) required searching for a problem solution. Seven cardiovascular variables, measured by a Portapres monitor, were analyzed. The analysis showed, among other findings, that the tonic increase in blood pressure and heart rate was greater during the RUN task than during the RT task. On the other hand, the EDIT task and the RT task produced almost identical response patterns. PMID- 20170708 TI - Persistent circulating human insulin in sheep transplanted in utero with human mesenchymal stem cells. AB - OBJECTIVE: To determine if mesenchymal stem cells (MSC) derived from human fetal pancreatic tissue (pMSC) would engraft and differentiate in sheep pancreas following transplantation in utero. MATERIALS AND METHODS: A three-step culture system was established for generating human fetal pMSC. Sheep fetuses were transplanted during the fetal transplant receptivity period with human pMSC and evaluated for in situ and functional engraftment in their pancreas, liver, and bone marrow. RESULTS: Isolation and expansion of adherent cells from the human fetal pancreas yielded a cell population with morphologic and phenotypic characteristics similar to MSC derived from bone marrow. This putative stem cell population could undergo multilineage differentiation in vitro. Three to 27 months after fetal transplantation, the pancreatic engraftment frequency (chimeric index) was 79%, while functional engraftment was noted in 50% of transplanted sheep. Hepatic and marrow engraftment and expression was noted as well. CONCLUSION: We have established a procedure for isolation of human fetal pMSC that display characteristics similar to bone marrow-derived MSC. In vivo results suggest the pMSC engraft, differentiate, and secrete human insulin from the sheep pancreas. PMID- 20170709 TI - A model of network formation by Physarum plasmodium: interplay between cell mobility and morphogenesis. AB - The plasmodium of Physarum polycephalum has attracted much attention due its intelligent adaptive behavior. In this study, we constructed a model of the organism and attempted to simulate its locomotion and morphogenetic behavior. By modifying our previous model, we were able to get closer to the actual behavior. We also compared the behavior of the model with that of the real organism, demonstrating remarkable similarity between the two. PMID- 20170710 TI - Glucocorticoid receptor knock down reveals a similar apoptotic threshold but differing gene regulation patterns in T-cell and pre-B-cell acute lymphoblastic leukemia. AB - Glucocorticoids (GCs) are used in combination therapy for treating acute lymphoblastic leukemia (ALL). In T-cell (CEM-C7) and pre-B-cell (697) ALL cell lines, dexamethasone (Dex) treatment causes an auto-upregulation of glucocorticoid receptor (GR) mRNA transcripts and protein. We hypothesized that there is a threshold level of GR transcripts/protein needed for cells to respond to the apoptosis-inducing effects of hormone. GR knock down using a doxycycline controllable shRNAmir indicated that the apoptotic response changes from sensitive to resistant with changing GR levels. Titration of the 697 cell GR to equal that of the CEM-C7 T-cell ALL line caused a shift in sensitivity to that seen in CEM-C7 cells. While the same level of GR is required to trigger apoptosis in both T-cell and pre-B-cell ALL lineages, similarities and differences were observed for the regulation of target genes in these lineages. These preliminary gene regulation patterns may lead to the development of a molecular signature for GC-sensitive and GC-resistant leukemia cells. PMID- 20170711 TI - Association analysis between polymorphisms in the dopamine D2 receptor (DRD2) and dopamine transporter (DAT1) genes with cocaine dependence. AB - Genetic research on cocaine dependence (CD) may help clarify our understanding of the disorder as well as provide novel insights for effective treatment. Since dopamine neurotransmission has been shown to be involved in drug reward, related genes are plausible candidates for susceptibility to CD. The dopamine receptor D(2) (DRD2) protein and dopamine transporter (DAT1) protein play regulatory roles in dopamine neurotransmission. The TaqI A single-nucleotide polymorphism (SNP) in the DRD2 gene and the 3' variable number tandem repeat (VNTR) polymorphism in the DAT1 gene have been implicated in psychiatric disorders and drug addictions. In this study, we hypothesize that these polymorphisms contribute to increased risk for CD. Cocaine-dependent individuals (n=347) and unaffected controls (n=257) of African descent were genotyped for the polymorphisms in the DRD2 and DAT1 genes. We observed no statistically significant differences or trends in allele or genotype frequencies between cases and controls for either of the tested polymorphisms. Our study suggests that there is no association between the DRD2 and DAT1 polymorphisms and CD. However, additional studies using larger sample sizes and clinically homogenous populations are necessary before confidently excluding these variants as contributing genetic risk factors for CD. PMID- 20170712 TI - Exposure to CSF from sporadic amyotrophic lateral sclerosis patients induces morphological transformation of astroglia and enhances GFAP and S100beta expression. AB - We have earlier shown that cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients' produces selective degeneration of motor neurons, both in vitro as well as in vivo. The present study further evaluates the effect of ALS-CSF on the astrocytes in embryonic rat spinal cord cultures. We quantified the number of flat and process-bearing astrocytes in spinal cord cultures exposed to ALS-CSF and compared them against controls. In addition, GFAP and S100beta expression were quantified by Western blot and measurement of immunofluorescence intensity respectively. We found higher number of process-bearing astrocytes in the cultures exposed to ALS-CSF. Both these proteins increased significantly in cultures exposed to ALS-CSF. Our results provide evidence that astroglia respond to toxic factor(s) present in ALS-CSF by undergoing morphological transformation from flat to process bearing which is further confirmed by elevated expression of GFAP and S100beta. The above changes could possibly alter the microenvironment hastening the motor neuron degeneration. PMID- 20170713 TI - Down regulation of cerebellar serotonergic receptors in streptozotocin induced diabetic rats: Effect of pyridoxine and Aegle marmelose. AB - Oxidative stress plays an important role in cerebellar damage caused by diabetes, leading to deterioration in glucose homeostasis causing metabolic disorders. The present study was carried out to find the effects of Aegle marmelose leaf extract and insulin alone and in combination with pyridoxine on the cerebellar 5-HT through 5-HT(2A) receptor subtype, gene expression studies on the status of antioxidants-superoxide dismutase (SOD), glutathione peroxidase (GPx), 5-HT(2A) and 5-HT transporter (5-HTT) and immunohistochemical studies in streptozotocin induced diabetic rats. 5-HT and 5-HT(2A) receptor binding parameters, B(max) and K(d), showed a significant decrease (p<0.001) in the cerebellum of diabetic rats compared to control. Gene expression studies of SOD, GPx, 5-HT(2A) and 5-HTT in cerebellum showed a significant down regulation (p<0.001) in diabetic rats compared to control. Pyridoxine treated alone and in combination with insulin, A. marmelose to diabetic rats reversed the B(max), K(d) of 5-HT, 5-HT(2A) and the gene expression of SOD, GPx, 5-HT(2A) and 5-HTT in cerebellum to near control. The gene expression of 5-HT(2A) and 5-HTT were confirmed by immunohistochemical studies. Also, the Rotarod test confirms the motor dysfunction and recovery by treatment. These data suggest the antioxidant and neuroprotective role of pyridoxine and A. marmelose through the up regulation of 5-HT through 5-HT(2A) receptor in diabetic rats. Our results suggest that pyridoxine treated alone and in combination with insulin and A. marmelose has a role in the regulation of insulin synthesis and release, normalizing diabetic related oxidative stress and neurodegeneration affecting the motor ability of an individual by serotonergic receptors through 5-HT(2A) function. This has clinical significance in the management of diabetes. PMID- 20170714 TI - Dephosphorylation/inactivation of tyrosine hydroxylase at the median eminence of the hypothalamus is required for suckling-induced prolactin and adrenocorticotrop hormone responses. AB - We have recently found that dopamine (DA) released from terminals of the hypothalamic neuroendocrine dopamine (NEDA) neurons plays a role not only in prolactin (PRL), but also in adrenocorticotrop hormone (ACTH) secretion, without having any influence on alpha-melanocyte-stimulating hormone (alpha-MSH) release in lactating dams. The aim of our present studies was to further investigate this DAerg regulation of ACTH using consecutively applied physiological stimulation (suckling) and pharmacological inhibition of the rate-limiting enzyme of DA synthesis (tyrosine hydroxylase, TH) by alpha-methyl-p-tyrosine (alpha-MpT) that acutely affect secretion of these pituitary hormones during lactation. Following 4h separation period, two experimental groups were formed. In the first group, lactating rats were assembled with their litters for 60 min prior to alpha-MpT. In the second group, the alpha-MpT was injected first and 60 min later suckling stimulus was applied. Plasma samples were taken in every 15 min during the 90 min experimental period. Concentrations of plasma PRL, ACTH and alpha-MSH were measured by specific RIAs. Both stimuli applied in the first sequence, significantly elevated plasma PRL and ACTH levels in separated lactating dams, without having any effect on alpha-MSH secretion. Suckling applied in the first sequence was able to block the alpha-MpT-induced elevation of ACTH secretion, while PRL response was also significantly attenuated. alpha-MpT pretreatment prevented both PRL and ACTH responses to suckling stimulus. Investigating the dephosphorylation/inactivation of TH in the arcuate nucleus-ME (TIDA) regions, no pTH-immunoreactive perikarya or terminals can be found in continuously suckled dams. In contrast, after 4h separation of the mothers from their litters, pTH immunoreactivity can be clearly visualized in the external zone of ME. In alpha MpT pretreated mothers following 4h separation no pTH positive terminals are visible. No changes in the TH immunostaining can be observed in any of these experimental groups. In conclusion, dephosphorylation/inactivation of TH (the rate-limiting enzyme of the DA biosynthesis) in NEDA neurons is required for suckling-induced PRL and ACTH responses. PMID- 20170715 TI - Baseline training history and effects of methamphetamine on performance of pigeons on an interval-bisection task. AB - Length of baseline training influences how methamphetamine disrupts temporal performance under a peak interval schedule. Acute methamphetamine produces overestimation of time following relatively brief training, but following extended training, methamphetamine produces more general loss of stimulus control. The current study extends the study of training length on the effects of methamphetamine to an interval-bisection procedure. Six pigeons responded under a psychophysical choice procedure in which responses to one key color were correct after presentation of four shorter sample durations and responses to another key color were correct after presentation of four longer sample durations. One group of three pigeons received briefer baseline training (45 sessions), while another group received more extended training (223 sessions) prior to methamphetamine administration. There was no evidence of overestimation of time or generalized loss of stimulus control in either group. Sensitivity (precision of timing) was higher in the group with more extensive training and was disrupted by methamphetamine. PMID- 20170716 TI - Stearic acid grafted chitosan oligosaccharide micelle as a promising vector for gene delivery system: factors affecting the complexation. AB - Stearic acid (SA) grafted chitosan oligosaccharide (CSO-SA) with different molecular weight of chitosan oligosaccharide (CSO) and graft ratio of stearic acid were synthesized by coupling reaction of SA and CSO. The cationic polymeric micelles of CSO-SA via self-assemble formed and used for gene delivery of fish sperm DNA. Factors affecting complexation and stability of the complexes of CSO SA micelles and DNA were investigated. The results indicated that pKa of CSO-SA with 3kDa of CSO decreased from 8.16 to 6.02 as the substitution degree of amino groups of CSO in CSO-SA increased from 9.79% to 63.41%, whereas the molecular weight (M(W)) of CSO less affected the pKa. As for the stability of complexes, ethidium bromide assay data demonstrated that the complexes consisting of CSO-SA with lower amino substitution degree or smaller molecular weight of CSO were more stable than that with the higher amino substitution degree or molecular weight of CSO. The results also presented that the low pH and ionic strength environment were in favor for the stability of complexes. PMID- 20170717 TI - Release modulation and cytotoxicity of hydroxycamptothecin-loaded electrospun fibers with 2-hydroxypropyl-beta-cyclodextrin inoculations. AB - Hydroxycamptothecin (HCPT) is valid to various malignant tumors, but its insoluble and unstable lactone ring in physiological environment have restricted the clinic application. This work was aimed to formulate HCPT-loaded poly(DL lactic acid)-poly(ethylene glycol) (PELA) fibrous mats through blend electrospinning with 2-hydroxypropyl-beta-cyclodextrin (HPCD) to modulate the drug release and matrix degradation, and to enhance the structural integrity and cytotoxicity of the released HCPT. The entire drug fraction retained its active lactone form within electrospun fibers, and that was maintained over 85% during incubation for over 1 month. A biphasic release pattern was determined for HCPT loaded electrospun fibers, which can be modulated by the addition of HPCD. HPCD served as solubilizer to maintain a large concentration gradient for HCPT between saturation and diffusion, and liberated HPCD created microstructure of ultrafine fibers, leading a faster release profile in the second phase. In vitro cytotoxicity test showed over 7 times higher inhibitory activity against cancer cells for HCPT-loaded electrospun fibers than free drug during 72h incubation. Higher apoptosis rates and the arrest of the cell cycle during the S and G(2)/M phases were detected through flow cytometry analysis. It indicated therapeutic potentials of HCPT-loaded electrospun fibers as implantable anti-cancer agents for local chemotherapy. PMID- 20170718 TI - Transdermal patches for site-specific delivery of anastrozole: In vitro and local tissue disposition evaluation. AB - Anastrozole is a potent aromatase inhibitor and there is a need for an alternative to the oral method of administration to target cancer tissues. The purpose of the current study was to prepare a drug-in-adhesive transdermal patch for anastrozole and evaluate this for the site-specific delivery of anastrozole. Different adhesive matrixes, permeation enhancers and amounts of anastrozole were investigated for promoting the passage of anastrozole through the skin of rats in vitro. The best in vitro skin permeation profile was obtained with the formulation containing DURO-TAK 87-4098, IPM 8% and anastrozole 8%. For local tissue disposition studies, the anastrozole patch was applied to mouse abdominal skin, and blood, skin, and muscle samples were taken at different times after removing the residual adhesive from the skin. High accumulation of the drug in the skin and muscle tissue beneath the patch application site was observed in mice compared with that after oral administration. These findings show that anastrozole transdermal patches are an appropriate delivery system for application to the breast tumor region for site-specific drug delivery to obtain a high local drug concentration. PMID- 20170719 TI - Possibility and effectiveness of drug delivery to skin by needle-free injector. AB - We evaluated a needle-free injector (NFI), which has been studied as an administration device to the subcutaneous tissue, as a device to deliver drugs into skin tissues. ShimaJet used for self-injection of insulin was selected as a spring-powered NFI in this study. Weak (NFI-w) and strong (NFI-s) injectors were evaluated. Rhodamine 6G, as a model compound, was injected onto the skin surface of hairless rats and the skin distribution and amount released from the skin of the compound were followed. A modified nozzle (able to inject at an angle of 45 degrees ) was prepared in addition to the conventional dedicated nozzle. The spring constants, nozzle shapes and penetration enhancer, 1-[2-(decylthio)ethyl] azacyclopentane-2-one (HPE-101), affected not only the skin distribution, but also the release profiles of rhodamine 6G. In addition, the release profiles of rhodamine 6G after injection using NFI-w or NFI-s obeyed diffusion-controlled or membrane-controlled kinetics, respectively. This difference was probably due to the skin site (depth) of rhodamine 6G delivered by the NFI. Furthermore, HPE-101 increased the retention time of rhodamine 6G in the epidermis. The present results suggested that an NFI can be a useful tool for enhanced drug delivery into skin. PMID- 20170720 TI - High loading fragrance encapsulation based on a polymer-blend: preparation and release behavior. AB - The six fragrances, camphor, citronellal, eucalyptol, limonene, menthol and 4 tert-butylcyclohexyl acetate, which represent different chemical functionalities, were encapsulated with a polymer-blend of ethylcellulose (EC), hydroxypropyl methylcellulose (HPMC) and poly(vinyl alcohol) (PV(OH)) using solvent displacement (ethanol displaced by water). The process gave >or=40% fragrance loading capacity with >or=80% encapsulation efficiency at the fragrance to polymer weight ratio of 1:1 and at initial polymer concentrations of 2000-16,000 ppm and the obtained fragrance-encapsulated spheres showed hydrodynamic diameters of less than 450 nm. The release profile of the encapsulated fragrances, evaluated by both thermal gravimetric and electronic nose techniques, indicated different release characteristics amongst the six encapsulated fragrances. Limonene showed the fastest release with essentially no retention by the nanoparticles, while eucalyptol and menthol showed the slowest release. PMID- 20170721 TI - Investigation of the dynamic process during spray-drying to improve aerodynamic performance of inhalation particles. AB - Particle-tailoring technique requires significant improvement for wide use of pulmonary route for systemic drug delivery. In this study, the spray-dry method was used to prepare particles using maltose as a model component, with focus on interpretation of the dynamic process during the spray-drying. High-speed camera observation proved that the time required for particle formation was assumed to be on the millisecond scale. The surface tension at 10ms was found to correlate well with both the size of the droplet produced from the spray nozzle and that of the solid particles. The surfactant molecules accumulated spontaneously on the particle surface to improve surface characteristics, including dispersity and hygroscopicity. Addition of polymer molecules made the particle surface rough, which significantly improved particle dispersity. Good correlation was found between the surface roughness and the aerodynamic performance of the particles, which was determined by a cascade impactor. The particle morphology was interpreted in terms of the mass transport of each component during the drying process. This excipient approach seems to be a promising method to prepare fine drug particles of high dispersity for achieving an efficient pulmonary drug delivery. PMID- 20170722 TI - Detour behavior changes associated with prenatal morphine exposure in 11-day-old chicks. AB - The central nervous system exhibits remarkable plasticity in early life. Prenatal morphine exposure may induce adverse behavioral effects on the neonate and the developing offspring. In the present study, we investigated the effect of prenatal morphine exposure (daily from embryonic days 12-16, 20mg/kg) on 11-day old chicks using two forms of spatial paradigms: one trial detour behavior task in which animals must bypass an obstacle to reach the desired goal without any training and detour learning task which required several trials of training to reach the detour criterion. The results showed that, on the condition that chicks could successfully detour in the first trial, morphine exposed chicks exhibited longer detour latency to finish the task, coupled by a preference for turning right versus turning left. In contrast, no significant difference in learning and memory was found in detour learning task between morphine exposed chicks and saline chicks. These findings suggest specific behavioral changes associated with prenatal exposure to opioids during mid to late gestation, also raise attention to the possible health hazard from pregnancy drug use in everyday life. PMID- 20170724 TI - miR-22 functions as a micro-oncogene in transformed human bronchial epithelial cells induced by anti-benzo[a]pyrene-7,8-diol-9,10-epoxide. AB - MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively control the expression of target genes post-transcriptionally. In this study, transformed human bronchial epithelial cells induced by anti-benzo[a]pyrene-7,8-diol-9,10 epoxide were characterized for miRNA involved in carcinogenesis. We found miR-22, which was highly expressed in transformed cells, concomitant with downregulation of the tumour suppressor gene PTEN protein. Using computer-generated and experimental analysis, PTEN was identified as one of the targets of miR-22. Over expression and inhibition studies of miRNA showed decreased and increased PTEN protein, respectively, with no alteration of PTEN mRNA levels. These findings suggest that miR-22 regulates PTEN expression through translational repression. A dual-reporter assay confirmed these findings and provided evidence to suggest that miR-22 regulates PTEN expression by binding with a target site in the PTEN 3'-untranslated region. A mutated seed sequence in the PTEN binding site can abrogate the regulatory role of miR-22 on PTEN. Moreover, we found that anti-miR 22 promoted cell apoptosis, decreased colony formation and reduced the motility of malignant cells. Together, the results indicate that miR-22 functions as a micro-oncogene that can invert the functionality of PTEN. Furthermore, the binding site for miR-22 might provide insight into a potential target for gene therapy. PMID- 20170723 TI - Effects of repeated minimal electroshock seizures on NGF, BDNF and FGF-2 protein in the rat brain during postnatal development. AB - Repeated brief seizures, such as those induced by electroconvulsive therapy (ECT), markedly elevate neurotrophic factor levels in the adult rat brain, but it is not known whether a similar response to seizures occurs in immature animals. To address this question, we evoked brief seizures with electroconvulsive shock (ECS) in rat pups at different stages of postnatal development and examined basic fibroblast growth factor (FGF-2), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) proteins in selected brain regions in which these trophic factors are known to increase in the adult rat following ECS-induced seizures. ECS treatments were administered daily (3 episodes/day) over 7 days to rat pups of three different ages: postnatal day (P)1-7, P7-13, or P14-20. Protein levels were measured 6h after the last ECS using Western blotting for FGF-2 in rhinal cortex, ELISA for BDNF and NGF in hippocampus, and NGF in frontal cortex. 7 days of repeated ECS-induced seizures during P1-7 did not alter protein levels for BDNF, FGF-2, or NGF. The repeated seizures during P7-13 affected only BDNF protein, causing a significant elevation of 40% in hippocampus over sham-treated controls. In P14-20 pups, the repeated seizures resulted in a significant increase in BDNF in hippocampus (162% over controls) and FGF-2 in rhinal cortex (34% over controls), while NGF protein did not show a significant change in either hippocampus or frontal cortex. The results suggest that during the first postnatal week there is a resistance to seizure-induced increase in neurotrophic factors, but by the third postnatal week, both BDNF and FGF-2 are elevated substantially in response to repeated seizures. This time-dependent profile suggests that synthesis of these proteins is initially activity-independent, becoming subject to activity-dependent regulation by 3 weeks of age. This maturation of seizure-evoked changes in trophic factors may be important for understanding the impact of ECT and seizures in childhood. PMID- 20170725 TI - Different in vitro toxicities of structurally similar type I ribosome inactivating proteins (RIPs). AB - This study was aimed at investigating and comparing the cytotoxicities of two structurally similar type I RIPs, namely trichosanthin (TCS) and free ricin A chain (RTA). A type II RIP, namely Ricinus communis agglutinin (RCA), was also included for comparison. The three RIPs were added separately to cultures of NIH 3T3 cells. The effective doses and time courses were analyzed using cell counts. Polyclonal antibodies against TCS and RTA were produced in rabbits and purified by a protein A-Sepharose CL-4B column. The mechanisms of cell death were determined by TUNEL, immunohistochemical staining, flow cytometry, and Western blotting. The effective doses for TCS, RTA and RCA were found to be 800, 50, and 50 nM, respectively. All three RIPs induced apoptosis. In all cases, activation of caspase-3 and caspase-8, but not caspase-9, was detected. Additionally, RTA caused in vivo tissue necrosis in rabbits after intradermal administration. Hence the mechanism of cell death due to RTA intoxication may vary depending on the experimental conditions, being necrosis in vivo and apoptosis in vitro. The present findings may shed light on the apoptotic pathway induced by RIPs. RTA may be useful for studying the shift in cell death. PMID- 20170726 TI - PP1 phosphatase-binding motif in Reg1 protein of Saccharomyces cerevisiae is required for interaction with both the PP1 phosphatase Glc7 and the Snf1 protein kinase. AB - In Saccharomyces cerevisiae, Snf1 kinase, the ortholog of the mammalian AMP activated protein kinase, is activated by an increase in the phosphorylation of the conserved threonine residue in its activation loop. The phosphorylation status of this key site is determined by changes in the rate of dephosphorylation catalyzed by the yeast PP1 phosphatase Glc7 in a complex with the Reg1 protein. Reg1 and many PP1 phosphatase regulatory subunits utilize some variation of the conserved RVxF motif for interaction with PP1. In the Snf1 pathway, the exact role of the Reg1 protein is uncertain since it binds to both the Glc7 phosphatase and to Snf1, the Glc7 substrate. In this study we sought to clarify the role of Reg1 by separating the Snf1- and Glc7-binding functions. We generated a series of Reg1 proteins, some with deletions of conserved domains and one with two amino acid changes in the RVxF motif. The ability of Reg1 to bind Snf1 and Glc7 required the same domains of Reg1. Further, the RVxF motif that is essential for Reg1 binding to Glc7 is also required for binding to Snf1. Our data suggest that the regulation of Snf1 dephosphorylation is imparted through a dynamic competition between the Glc7 phosphatase and the Snf1 kinase for binding to the PP1 regulatory subunit Reg1. PMID- 20170727 TI - Transcriptional response to fluconazole and amphotericin B in Candida albicans biofilms. AB - Biofilm formation is often associated with persistent Candida albicans infections. Treatment of these infections is difficult, since sessile C. albicans cells show increased resistance towards antifungal agents. The molecular mechanisms behind biofilm resistance in C. albicans are not yet understood. In the present study, we investigated the transcriptional response in young and mature in vitro-grown biofilms after a short and longer exposure time to high doses of fluconazole or amphotericin B. Treatment of biofilms with high doses of antifungal agents resulted in a drug-specific transcriptional response. Exposure of biofilms to fluconazole induced upregulation of genes encoding enzymes involved in ergosterol biosynthesis (ERG1, ERG3, ERG11 and ERG25). Treatment of biofilms with amphotericin B resulted in an overexpression of KRE1 and SKN1, two genes encoding proteins involved in beta-1,6-glucan biosynthesis. Our data indicate that sessile C. albicans cells show controlled regulation of gene expression, as they quickly mount a drug-specific transcriptional response in the presence of high doses of antifungal agents. These transcriptional changes suggest upregulation of ergosterol biosynthesis (fluconazole) and upregulation of beta-1,6-glucan biosynthesis (amphotericin B) in sessile C. albicans cells that might contribute to a resistant biofilm phenotype. PMID- 20170728 TI - Dermal targeting using colloidal carrier systems with linoleic acid. AB - In the basic therapy of chronic skin diseases characterized by xerosis, the local treatment is an essential strategy to reach ideal therapeutic effects. Suitable active ingredients for this aim are fatty acids, in particular linoleic acid, which is an essential component for the organization and perpetuation of the skin barrier. In the present work, the development of a well-tolerated colloidal carrier system (microemulsion) containing linoleic acid as active ingredient is described. A comprehensive physiochemical characterization of the novel microemulsion system was performed using different techniques. The potential of the developed microemulsion system compared to a cream as suitable carrier for the dermal delivery of linoleic acid was determined. Penetration studies showed higher linoleic acids concentrations after administration of the colloidal carrier system in all skin layers independent of the time of incubation. Up to 23% of applied dose reached the skin from the colloidal carrier system whereas at most 8% of the active ingredient could be detected after applying the cream. Particularly, the percentage of the linoleic acids penetrated through the microemulsion in the stratum corneum and the viable epidermis differed significantly (p<0.01) when compared to that through a standard cream. Furthermore, linoleic acids accumulated in the epidermis at longer incubation times. Using the microemulsion, the penetration of linoleic acids was enhanced significantly (p<0.01). Hence, the microemulsion might be an innovative vehicle for the delivery of linoleic acids to the epidermis improving its use as their barrier regeneration and providing possible anti-inflammatory effects. PMID- 20170729 TI - Role of glucocorticoids and the glucocorticoid receptor in metabolism: insights from genetic manipulations. AB - Since the discovery of the beneficial effects of adrenocortical extracts for treating adrenal insufficiency more than 80 years ago, glucocorticoids and their cognate, intracellular receptor, the glucocorticoid receptor have been characterized as critical checkpoints in the delicate hormonal control of energy homeostasis in mammals. Whereas physiological levels of glucocorticoids are required for proper metabolic control, aberrant glucocorticoid action has been linked to a variety of pandemic metabolic diseases, such as type II diabetes and obesity. Based on its importance for human health, studies of the molecular mechanisms of within the glucocorticoid signaling axis have become a major focus in biomedical research. In particular, the understanding of tissue-specific functions of the glucocorticoid receptor pathway has been proven to be of substantial value for the development of novel therapies in the treatment of chronic metabolic disorders. Therefore, this review focuses on the consequences of endogenous and experimental modulation of glucocorticoid receptor expression for metabolic homeostasis and dysregulation, particularly emphasizing tissue specific contributions of the glucocorticoid pathway to the control of energy metabolism. PMID- 20170730 TI - The role of REST in transcriptional and epigenetic dysregulation in Huntington's disease. AB - Huntington's disease (HD) is a devastating disorder that affects approximately 1 in 10,000 people and is accompanied by neuronal dysfunction and neurodegeneration. HD manifests as a progressive chorea, a decline in mental abilities accompanied by behavioural, emotional and psychiatric problems followed by, dementia, and ultimately, death. The molecular pathology of HD is complex but includes widespread transcriptional dysregulation. Although many transcriptional regulatory molecules have been implicated in the pathogenesis of HD, a growing body of evidence points to the pivotal role of RE1 Silencing Transcription Factor (REST). In HD, REST, translocates from the cytoplasm to the nucleus in neurons resulting in repression of key target genes such as BDNF. Since these original observations, several thousand direct target genes of REST have been identified, including numerous non-coding RNAs including both microRNAs and long non-coding RNAs, several of which are dysregulated in HD. More recently, evidence is emerging that hints at epigenetic abnormalities in HD brain. This in turn, promotes the notion that targeting the epigenetic machinery may be a useful strategy for treatment of some aspects of HD. REST also recruits a host of histone and chromatin modifying activities that can regulate the local epigenetic signature at REST target genes. Collectively, these observations present REST as a hub that coordinates transcriptional, posttranscriptional and epigenetic programmes, many of which are disrupted in HD. We identify several spokes emanating from this REST hub that may represent useful sites to redress REST dysfunction in HD. PMID- 20170731 TI - Nervous-tissue-specific elimination of microtubule-actin crosslinking factor 1a results in multiple developmental defects in the mouse brain. AB - The microtubule-actin crosslinking factor 1 (MACF1) is a ubiquitous cytoskeletal linker protein with multiple spliced isoforms expressed in different tissues. The MACF1a isoform contains microtubule and actin-binding regions and is expressed at high levels in the nervous system. Macf1-/- mice are early embryonic lethal and hence the role of MACF1 in the nervous system could not be determined. We have specifically knocked out MACF1a in the developing mouse nervous system using Cre/loxP technology. Mutant mice died within 24-36h after birth of apparent respiratory distress. Their brains displayed a disorganized cerebral cortex with a mixed layer structure, heterotopia in the pyramidal layer of the hippocampus, disorganized thalamocortical and corticofugal fibers, and aplastic anterior and hippocampal commissures. Embryonic neurons showed a defect in traversing the cortical plate. Our data suggest a critical role for MACF1 in neuronal migration that is dependent on its ability to interact with both microfilaments and microtubules. PMID- 20170733 TI - Analysis of the DNA translocation and unwinding activities of T4 phage helicases. AB - Helicases are an important class of enzymes involved in DNA and RNA metabolism that couple the energy of ATP hydrolysis to unwind duplex DNA and RNA structures. Understanding the mechanism of helicase action is vital due to their involvement in various biological processes such as DNA replication, repair and recombination. Furthermore, the duplex DNA unwinding property of this class of enzymes is closely related to their single-stranded DNA translocation. Hence the study of its translocation properties is essential to understanding helicase activity. Here we review the methods that are employed to analyze the DNA translocation and unwinding activities of the bacteriophage T4 UvsW and Dda helicases. These methods have been successfully employed to study the functions of helicases from large superfamilies. PMID- 20170732 TI - Methods to study kinase regulation of the replication fork helicase. AB - Dbf4-Cdc7 phosphorylation of the Mcm2-7 complex is required for the activation of the replication fork helicase in budding yeast cells. There is a genetic interaction between Dbf4-Cdc7 and Mcm2, and Dbf4-Cdc7 phosphorylates Mcm2 in vitro and in vivo. We initiated a focused study of how Dbf4-Cdc7 phosphorylates Mcm2 in budding yeast, and we also investigated the in vivo implications of this kinase reaction. Described herein are detailed methods for how we conducted biochemical and genetic experiments to dissect the mechanism and function of Dbf4 Cdc7 phosphorylation of Mcm2 in budding yeast cells. The methods are likely applicable to other kinase reactions and studies of replication fork helicases from other organisms. PMID- 20170734 TI - Seminal plasma of brown trout, Salmo trutta fario (L.) contains a factor able to retain iron at acid pH, typical feature of lactoferrin. AB - Blood and seminal plasma of brown trout Salmo trutta fario were analyzed for their iron binding potential adopting two different methods. Seminal plasma showed an iron binding capacity that was retained even if samples were exposed at acid pH, similarly to mammalian lactoferrin that binds ferric iron also at acid pH. This suggests that the iron binding capacity is determined by a factor having a lactoferrin-like activity. Moreover, trout seminal plasma proteins were also analyzed in their pattern by sodium dodecyl sulphate polyacrylamide gel elecrophoresis (SDS-PAGE) and electroblotted onto nitrocellulose membrane. When seminal plasma was subjected to immunoblotting using goat anti-bovine lactoferrin antibodies as a probe, only a single band having an apparent molecular weight of around 80 kDa was specifically detected, showing that this protein has homology with bovine lactoferrin. PMID- 20170735 TI - Three Kazal-type serine proteinase inhibitors from the red swamp crayfish Procambarus clarkii and the characterization, function analysis of hcPcSPI2. AB - Three Kazal-type serine proteinase inhibitors, hcPcSPI2, hpPcSPI3, and hpPcSPI4, with complete cDNA sequences, were identified from a cDNA library of the red swamp crayfish, Procambarus clarkii. Semi-quantitative RT-PCR shows that hcPcSPI2 exists mainly in hemocytes while both hpPcSPI3 and hpPcSPI4 were detected in the hepatopancreas and the heart. Homology comparison and phylogenic analysis indicate that hpPcSPI3 and hpPcSPI4 shared high identity and formed the same group, and both of them were different from other hepatopancreas type inhibitors in crustaceans forming a large group, while hcPcSPI2 as well as other hemocyte type inhibitors belonged to another cluster. In addition, the temporal expression profiles of these three inhibitors were studied with quantitative real-time PCR and the results suggest that hcPcSPI2 and hpPcSPI3 are likely to be involved in antiviral immune response, and all these three inhibitors respond to Vibrio anguillarum challenge in different degrees. Further study was done on hcPcSPI2. Western blot demonstrates that hcPcSPI2 only exists in semigranular cells. Besides, after V. anguillarum challenge, the hcPcSPI2 protein could also be detected in cell-free hemolymph. Subsequently, the biochemical characteristics and bacteriostatic activity of hcPcSPI2 were assayed. The results indicate that hcPcSPI2 shows weak inhibitory activity against subtilisin A and trypsin, and may trigger bacteriostatic activity towards Bacillus subtilis and Bacillus thuringiensis, possessing MIC(50) of 30.4 and 25.0 microM, respectively. These studies reveal that hcPcSPI2 may also play an important role in the anti bacterial immunity of the crayfish. PMID- 20170736 TI - A shared antigen among Vibrio species: outer membrane protein-OmpK as a versatile Vibriosis vaccine candidate in Orange-spotted grouper (Epinephelus coioides). AB - The outer membrane protein-OmpK has been considered as a vaccine candidate for the prevention of infections due to Vibrio harveyi, Vibrio alginolyticus and Vibrio parahaemolyticus in fish. Interestingly, the polyclonal antibody raised against the recombinant OmpK from V. harveyi strain EcGs020802 recognized the OmpK homologues from other strains of Vibrio species by immunoblotting. The ompK genes from 19 Vibrio strains including V. harveyi (11), V. alginolyticus (6) and V. parahaemolyticus (2) were then cloned and sequenced. Alignment analysis based on the amino acid sequences indicated that the OmpK from V. harveyi strain EcGs020802 had 71.7-99.2% of identities with those from V. harveyi, V. alginolyticus and V. parahaemolyticus. Western blot analysis revealed that the corresponding native proteins ranged between 28 and 31 kDa, consistent with predicated molecular weight of OmpK in Vibrio strains. Furthermore, the cross protective property of recombinant OmpK was evaluated through challenge with heterogeneous virulent Vibrio strains in Orange-spotted groupers (Epinephelus coioides). Orange-spotted groupers vaccinated with recombinant OmpK were more tolerant of the infection by virulent Vibrio strains and their relative percentage survival (RPS) was correlative with the degree of the identity of deduced amino acid sequences of their OmpK. Taken together, the OmpK is a conserved protective antigen among tested Vibrio species and might be a potentially versatile vaccine candidate for the prevention of infections due to V. harveyi, V. alginolyticus and V. parahaemolyticus. PMID- 20170737 TI - Molecular phylogeny and systematics of the genus Draba (Brassicaceae) and identification of its most closely related genera. AB - Phylogenetic analyses of sequence data from the internal transcribed spacer regions of the nuclear ribosomal DNA (ITS) and the plastid trnL-F region were conducted to reconstruct the phylogenetic history of Draba and related genera. Out of the approximately 370 Draba species, 169 geographically and morphologically representative species are sampled here, including such "controversial" segregates as Abdra, Arabis, Athysanus, Drabopsis, Erophila, Graellsia, Heterodraba, Schivereckia and Tomostima. Phylogenetic analyses of the combined ITS and trnL-F markers indicate that Draba represents a monophyletic evolutionary lineage within the tribe Arabideae, but previously proposed infrageneric classification systems are mostly artificial (i.e. do not reflect true evolutionary history). Draba muralis formed an independent genus, possibly between Draba and Arabis, whereas D. hystrix fell outside Draba and was closely associated with Arabis. The New World annual, lowland Draba, D. platycarpa, D. reptans, D. cuneifolia, D. australis, D. arabidoides, (section Abdra) and D. brachycarpa and D. aspera (section Tomostima), appear to be independent genera that fall outside Draba and are monophyletic with the endemic North American Heterodraba unilateralis and Athysanus pusillus. Graellsia hederifolia and Erophila verna appear to be earlier diverging Draba species, with weak evidence of ancient hybridization in G. hederifolia. Core Draba species were organized into three major groups that encompass the segregate genera Drabopsis and Schivereckia. The three groups have geographic significance: Group I-Europe to Iran; Group II-North and South American Cordillera; Group III-Asian, Arctic, and Beringian. These three groups also have significant petal color and base chromosome level similarities. We also found that Arabis rimarum is a synonym for Draba aucheri, and is well within Group I of Core Draba. Therefore, we propose that many of the lowland and coastal temperate species often associated with Draba should be excluded from that genus. The compilation of these data indicate that true Draba are highly migrating arctic and higher alpine species that are most often perennial with white petals and n=8 as plesiomorphic characters. PMID- 20170738 TI - An evolutionary perspective on morphological and ecological characters in the mushroom family Inocybaceae (Agaricomycotina, Fungi). AB - Inocybaceae is one of the larger families among the gilled mushrooms (Agaricales) but their morphology-based taxonomy is still not fully settled considering molecular-based phylogenetic insights. Here we investigate the evolution of five morphological and four ecological characters using ancestral state reconstruction methods. All the morphological characters are correlated with the phylogeny, but we find spore shape and presence of cortina, to have the greatest taxonomic potential, as they are the most evolutionarily conserved. None of the five characters have, however, evolved in a way that easily delimits inclusive monophyletic groups and the section level taxonomy needs revision. Host preference, preference for calcareous soil, and soil nutritional status preference are shown to be reflective of the evolutionary history of the species at the scale investigated here while soil moisture preference is not. The states of three of the four ecological characters can therefore be predicted in a phylogenetic framework for species where they are unknown. PMID- 20170739 TI - Memantine ameliorates scopolamine-induced amnesia in chicks trained on taste avoidance learning. AB - In day-old chicks trained on the one-trial taste-avoidance task, activation of NMDA receptors by glutamate is particularly important in the initial stages of memory consolidation. In addition, acetylcholine receptor activation has been shown to be a necessary component of memory formation for this task because injection of scopolamine produces amnesia. Memantine, a non-competitive NMDA receptor antagonist, improves memory formation under certain impairing circumstances, despite inhibiting the activation of NMDA receptors. The present experiments tested the hypothesis that memantine can ameliorate scopolamine induced amnesia in day-old chicks (Gallus gallus domesticus) trained on the one trial taste-avoidance task. Three experiments assessed the effects of scopolamine, memantine, and glutamate in this task. The results of Experiment 1 demonstrated that 50.0mM scopolamine produces significant amnesia. In Experiment 2, 1.0mM memantine reversed the scopolamine-induced amnesia, while other doses were ineffective. In Experiment 3, injection of 50.0mM glutamate in combination with scopolamine reversed the memantine amelioration. These results indicate a relationship between glutamate and acetylcholine in memory formation in the day old chick. PMID- 20170740 TI - A role for the lysosomal protease cathepsin B in zebrafish follicular apoptosis. AB - This study presents evidence that cathepsin B, a lysosomal protease, may be involved in the regulation of apoptosis during serum-starvation in teleost follicles. Zebrafish vitellogenic follicles were isolated, incubated under serum free conditions and homogenized. The follicle extracts demonstrated caspase-3 like activity using the fluorogenic substrate DEVD-AMC, indicating the onset of apoptosis. Cathepsin B activity as measured using the fluorogenic cathepsin B substrate, Z-Arg-Arg-AMC was elevated within the first 6h of incubation in serum free media and coincided with the onset of apoptosis. This increase in cathepsin B activity was sensitive to the cathepsin B inhibitor, CA-074-ME. Furthermore, adding CA-074-ME to the follicle incubation blocked caspase-3-like activation, suggesting that cathepsin B activity is a positive regulator of the apoptotic cascade during serum-starvation. Interestingly, the increase in cathepsin-B-like activity was not preceded by an increase in cathepsin B mRNA transcription, suggesting that regulation of this enzyme is at a level other than of the gene. These results suggest a regulatory role for cathepsin B during follicular apoptosis in zebrafish ovarian follicles. PMID- 20170741 TI - What factors allow opportunistic nocturnal activity in a primarily diurnal desert lizard (Ctenotus pantherinus)? AB - Most animals show strong 24-h patterns of activity, usually being diurnal or nocturnal. An Australian desert skink, Ctenotus pantherinus, is unusual in being active day and night when all other Ctenotus species are diurnal, making it an excellent model to explore factors that promote night-time activity. We tested whether C. pantherinus 1) selects cooler temperatures than diurnal skinks, 2) shows no difference in mean selected temperature between day and night, 3) has the same metabolic rate during the day and night, 4) selects termites over other prey types, 5) can detect prey using only auditory or olfactory senses, and 6) experiences lower predation risk at night than during the day. C.pantherinus shows many features of diurnal skink species, with a high mean selected temperature (36.1+/-1.6 degrees C) that is the same night and day, and a 32% lower metabolic rate at night than during the day. C.pantherinus selects termite prey over other insects and can detect prey using only auditory and olfactory senses; models of C. pantherinus experienced less predation at night than during the day. Preference for termites and reduced predation risk at night favour opportunistic nocturnal activity in this predominantly diurnal lizard and may contribute to its wide geographic distribution in arid Australia. PMID- 20170742 TI - Nervous and humoral catecholaminergic control of blood pressure and cardiac performance in the Antarctic fish Pagothenia borchgrevinki. AB - The role of circulating and neural catecholamines for cardiovascular control in the Antarctic fish Pagothenia borchgrevinki was studied in vivo using pharmacological tools and with immunohistochemistry on isolated tissues. Adrenergic nerve blockade with bretylium decreased dorsal aortic pressure (P(da)) and systemic vascular resistance (R(sys)), while cardiac output (Q) did not change. The blockade of alpha-adrenoceptors with phentolamine reduced P(da) and R(sys) further, revealing that vasomotor tone was influenced by circulating catecholamines in bretylium treated fish. The physiological evidence for an adrenergic nervous control of the vasculature was corroborated by the presence of tyrosine hydroxylase (TH)-immunoreactive fibres associated with blood vessels in spleen, gonads and gastrointestinal tract. TH-immunoreactive fibres were not observed in the atrium and ventricle, but a dense population of TH-immunoreactive fibres was apparent in the bulbus arteriosus. The present study suggests that an adrenergic nervous mechanism is responsible for maintaining vasomotor tone in P. borchgrevinki. While experiments failed to demonstrate a tonic adrenergic nervous influence affecting cardiac performance, an adrenergic nervous control of bulbar compliance may be essential for optimizing gill blood flow dynamics in this species, which has a high relative stroke volume and displays profound changes in stroke volume in vivo. PMID- 20170744 TI - Formation and function of apolipoprotein E-containing lipoproteins in the nervous system. AB - The strongest known genetic risk factor for the development of late-onset Alzheimer disease is inheritance of the apolipoprotein (apo) E4 (epsilon4 allele) although the mechanisms underlying this connection are still not entirely clear. In this review, we shall discuss the role of apo E in the brain, particularly in relation to Alzheimer disease. Cholesterol transport and homeostasis in the central nervous system (CNS) are separated from that in the peripheral circulation by the blood-brain barrier. However, the brain operates its own lipoprotein transport system that is mediated by high density lipoprotein-sized, apo E-containing lipoproteins that are synthesized and secreted by glial cells (primarily astrocytes). Several ATP-binding cassette (ABC) transporters are expressed in the brain, including ABCA1 and ABCG1 which play important roles in the transfer of phospholipids and cholesterol to apo E. The astrocyte-derived apo E-containing lipoproteins can bind to, and be internalized by, receptors of the low density lipoprotein receptor superfamily that are located on the surface of neurons. In addition to these receptors serving as endocytosis receptors for lipoproteins, several of these receptors also act as signaling receptors in neurons and activate pathways involved in axonal growth, as well as neuronal survival. These beneficial pathways appear to be enhanced to a greater extent by apo E3 than by apo E4. Apo E has also been implicated in the deposition of amyloid plaques since apo E3, more readily than apo E4, forms a complex with Ass peptides, and mediates the degradation of amyloid deposits. PMID- 20170743 TI - Angiotensin-converting enzymes and drug discovery in cardiovascular diseases. AB - Angiotensin-converting enzyme (ACE) is a major target in the treatment of cardiovascular diseases (CVDs). In addition to ACE, ACE2 - which is a homolog of ACE and promotes the degradation of angiotensin II (Ang II) to Ang (1-7) - has been recognized recently as a potential therapeutic target in the management of CVDs. This article reviews different metabolic pathways of ACE and ACE2 (Ang I Ang II-AT1 receptors and Ang I-Ang (1-7)-Mas receptors) in the regulation of cardiovascular function and their potential in new drug development in the therapy of CVDs. In addition, recent progress in the study of angiotensin and ACE in fetal origins of CVD, which might present an interesting field in perinatal medicine and preventive medicine, is briefly summarized. PMID- 20170745 TI - Lipid mediators in the nucleus: Their potential contribution to Alzheimer's disease. AB - Degradation of glycerophospholipids, sphingolipids and cholesterol in the nucleus modulates neural cell proliferation and differentiation, inflammation, apoptosis, migration, cell adhesion, and intracellular trafficking. Extracellular signals from agonists (neurotransmitters, cytokines, and growth factors) regulate the activity of a key set of lipid-metabolizing enzymes, such as phospholipases, sphingomyelinases, and cholesterol hydroxylases. These enzymes and their downstream targets constitute a complex lipid signaling network with multiple nodes of interaction and cross-regulation through their lipid mediators, which include eicosanoids, docosanoids, diacylglycerols, platelet activating factor, lysophosphatidic acid, ceramide and ceramide 1-phosphate, sphingosine and sphingosine 1-phosphate, and hydroxycholesterols. Receptors for above lipid mediators are localized at the neural cell nucleus. Stimulation of isolated nuclei with these lipids and agonists results in changes in transcriptional regulation of major genes, including c-fos, cylooxygenase-2, secretory phospholipase A(2) and endothelial as well as inducible nitric oxide synthases. Imbalances in signaling network involving above genes may contribute to the pathogenesis of human neurological disorders. In this review, we have attempted to integrate available information on above lipid mediators in the nucleus. In addition, attempts have been made to explain cross-talk among glycerophospholipid , sphingolipid-, and cholesterol-derived lipid mediators in neural cell death in Alzheimer's disease. PMID- 20170746 TI - The "acrostyle": a newly described anatomical structure in aphid stylets. AB - The recent demonstration that a plant virus could be retained on protein receptors located exclusively in a small area inside the common duct at the tip of aphid maxillary stylets indicated the possible existence of a distinct anatomical structure at this level. Since no distinct feature within the common duct of any aphid species has ever been reported in the literature, we first carefully re-examined the distal extremity of the maxillary stylets of Acyrthosiphon pisum using transmission- and scanning-electron microscopy. Here, we describe an area of the cuticle surface displaying a different structure that is limited to a "band" paving the bottom of the common duct in each opposing maxillary stylet. This band starts at the very distal extremity, adopts a "comma like" shape as it continues up towards the salivary canal, reducing in width and disappearing before actually reaching it. Investigations on several aphid species led to the conclusion that this anatomical feature-which we have tentatively named the "acrostyle"-is highly conserved among aphids. We then produced an antibody recognizing a consensus peptide located in the middle of the RR-2 motif of cuticular proteins from A. pisum and showed that this motif is accessible specifically within the acrostyle, indicating a higher concentration of cuticular proteins. While it is clear that at least some viruses can use the acrostyle to interact with their aphid vectors to ensure plant-to-plant transmission, the role of this new "organ" in aphid biology is unknown and calls for further investigation in the near future. PMID- 20170747 TI - Nephrotoxicity assessments of acetaminophen during zebrafish embryogenesis. AB - We used a green fluorescent kidney line, Tg(wt1b:GFP), as a model to access the acetaminophen (AAP)-induced nephrotoxicity dynamically. Zebrafish (Danio rerio) embryos at different developmental stages (12-60hpf) were treated with different dosages of AAP (0-45mM) for different time courses (12-60h). Results showed that zebrafish embryos exhibited no evident differences in survival rates and morphological changes between the mock-treated control (0mM) and 2.25mM AAP exposure (12-72hpf) groups. In contrast, after higher doses (22.5 and 45mM) of exposure, embryos displayed malformed kidney phenotypes, such as curved, cystic pronephric tube, pronephric duct, and a cystic and atrophic glomerulus. The percentages of embryos with malformed kidney phenotypes increased as the exposure dosages of AAP increased. Interestingly, under the same exposure time course (12h) and dose (22.5mM), embryos displayed higher percentages of severe defects at earlier developmental stage of exposure (12-24hpf), whereas embryos displayed higher percentages of mild defects at later exposure (60-72hpf). With an exposure time course less than 24h of 45mM AAP, no embryo survived by the developmental stage of 72hpf. These results indicated that AAP-induced nephrotoxicity depended on the exposure dose, time course and developmental stages. Immunohistochemical experiments showed that the cells' morphologies of the pronephric tube, pronephric duct and glomerulus were disrupted by AAP, and consequently caused cell death. Real-time RT-PCR revealed embryos after AAP treatment decreased the expression of cox2 and bcl2, but increased p53 expression. In conclusion, AAP induced defects on glomerulus, pronephric tube and pronephric duct could be easily and dynamically observed in vivo during kidney development in this present model. PMID- 20170748 TI - Effects of the dioxin-like PCB 126 on larval summer flounder (Paralichthys dentatus). AB - Little is known about the sensitivity of teleost post-embryonic developmental stages (larval and metamorphic) to dioxin-like compounds. Larval and metamorphosing summer flounder (Paralichthys dentatus) were exposed to the dioxin like polychlorinated biphenyl congener PCB 126, to compare their sensitivity to other fish species early life stages, and to document effects on metamorphic development, including degree of eye migration and gastric maturation. Median lethal doses (LD 50s) ranged between 30 and 220 ng/g wet mass, indicating that pre- and early-metamorphic stages of summer flounder are equally sensitive to the embryos of some of the most vulnerable fish species tested. Consistent with the presence of a functional aryl hydrocarbon receptor pathway, dose-dependent induction of cytochrome P-4501A (CYP1A) at four days post-exposure was observed in liver, stomach, intestine, and kidney of metamorphosing larvae. Stage dependent differences in the epithelial distribution of CYP1A immunoreactivity were observed in the developing stomach of fish exposed to relatively high PCB 126 doses. A single sublethal dose (15 ng/g) delayed metamorphic progress (determined by the degree of eye migration), and resulted in abnormally high levels of cell proliferation and abnormal gastric gland morphology in late metamorphic stages. These results suggest that the post-embryonic larval and metamorphic stages of summer flounder, and potentially other fish species with complex life histories, are vulnerable to the effects of dioxin-like compounds, including lethality, developmental delay, and malformations. PMID- 20170749 TI - Levels of plasma ceruloplasmin protein are markedly lower following dietary copper deficiency in rodents. AB - Ceruloplasmin (Cp) is a multicopper oxidase and the most abundant copper binding protein in vertebrate plasma. Loss of function mutations in humans or experimental deletion in mice result in iron overload consistent with a putative ferroxidase function. Prior work suggested plasma may contain multiple ferroxidases. Studies were conducted in Holtzman rats (Rattusnorvegicus), albino mice (Mus musculus), Cp-/- mice, and adult humans (Homo sapiens) to investigate the copper-iron interaction. Dietary copper-deficient (CuD) rats and mice were produced using a modified AIN-76A diet. Results confirmed that o-dianisidine is a better substrate than paraphenylene diamine (PPD) for assessing diamine oxidase activity of Cp. Plasma from CuD rat dams and pups, and CuD and Cp-/- mice contained no detectable Cp diamine oxidase activity. Importantly, no ferroxidase activity was detectable for CuD rats, mice, or Cp-/- mice compared to robust activity for copper-adequate (CuA) rodent controls using western membrane assay. Immunoblot protocols detected major reductions (60-90%) in Cp protein in plasma of CuD rodents but no alteration in liver mRNA levels by qRT-PCR. Data are consistent with apo-Cp being less stable than holo-Cp. Further research is needed to explain normal plasma iron in CuD mice. Reduction in Cp is a sensitive biomarker for copper deficiency. PMID- 20170750 TI - Important elements for the diagnosis of drug-induced liver injury. AB - BACKGROUND & AIMS: Drug-induced liver disease is the leading cause of acute liver failure in the United States. Accurate reporting of drug-induced liver injury is essential for early detection of hepatotoxicity and for developing reliable, interpretable literature. We assessed the extent to which published case reports of drug-induced liver disease include sufficient clinical data for interpreting the cause of toxicity. METHODS: We developed a list of 42 predetermined, specific minimal elements necessary in evaluating causality of drug-induced liver injury. We then analyzed 97 published case reports or series studies of hepatotoxicity from 6 drugs (from 3 classes): amoxicillin/clavulanic acid (n = 35), troglitazone (n = 32), rosiglitazone (n = 10), pioglitazone (n = 8), zafirlukast (n = 8), and montelukast (n = 4). RESULTS: Patient age, sex, primary disease, and drug name were reported in most, if not all, published case reports. However, many elements were underreported; some publications did not mention initial bilirubin levels (12%), many did not provide initial alkaline phosphatase levels (58%), and others provided vague descriptions of how certain diagnoses were excluded, that is, tests for hepatitis A, B, and C were negative. Data on abnormal results from serial liver tests frequently were absent. Exclusions of competing viral etiologies were reported in less than 50% of the studies. CONCLUSIONS: Reports of drug-induced liver diseases often do not provide the data needed to determine the causes of the adverse effects. Efforts to promote and include a list of essential diagnostic elements in research articles could increase the quality and clinical utility of published case reports of drug toxicity. PMID- 20170751 TI - Rapid response to cognitive behavior therapy predicts treatment outcome in patients with irritable bowel syndrome. AB - BACKGROUND & AIMS: Cognitive behavior therapy (CBT) is an empirically validated treatment for irritable bowel syndrome (IBS), yet it is unclear for whom and under what circumstances it is most effective. We investigated whether patients who achieved a positive response soon after CBT onset (by week 4), termed rapid responders (RRs), maintain treatment gains compared with non-rapid responders. We also characterized the psychosocial profile of RRs on clinically relevant variables (eg, health status, IBS symptom severity, distress). METHODS: The study included 71 individuals (age, 18-70 y) whose IBS symptoms were consistent with Rome II criteria and were of at least moderate severity. Patients were assigned randomly to undergo a wait list control; 10 weekly 1-hour sessions of CBT; or four 1-hour CBT sessions over 10 weeks. RRs were classified as patients who reported adequate relief of pain, adequate relief of bowel symptoms, and a decrease in total IBS severity scores of 50 or greater by week 4. RESULTS: Of patients undergoing CBT, 30% were RRs; 90% to 95% of the RRs maintained gains at the immediate and 3-month follow-up examinations. Although the RRs reported more severe IBS symptoms at baseline, they achieved more substantial, sustained IBS symptom reduction than non-rapid responders. Both dosages of CBT had comparable rates of RR. CONCLUSIONS: A significant proportion of IBS patients treated with CBT have a positive response within 4 weeks of treatment; these patients are more likely to maintain treatment gains than patients without a rapid response. A rapid response is not contingent on the amount of face-to-face contact with a clinician. PMID- 20170752 TI - Dact1-3 mRNAs exhibit distinct expression domains during tooth development. AB - Wnt signaling is essential for tooth formation and Dact proteins modulate Wnt signaling by binding to the intracellular protein Dishevelled (Dvl). Comparison of the three known mouse Dact genes, Dact1-3, from the morphological initiation of mandibular first molar development through the onset of root formation using section in situ hybridization showed distinct, complementary and overlapping expression patterns for these genes. Whereas Dact2 expression was restricted to the dental epithelium, including the enamel knot signaling centers and pre ameloblasts, Dact1 and Dact3 showed developmentally regulated expression in the dental mesenchyme. Both Dact1 and Dact3 mRNAs were first detected in the presumptive dental mesenchyme. After being downregulated from the condensing dental mesenchyme of the bud stage tooth germ, Dact1 was upregulated in the dental follicle mesenchyme at the cap stage and subsequently also in the dental papilla at the bell stage, where the expression persisted to the postnatal stages. In contrast, Dact3 transcripts persisted throughout the dental mesenchyme, including the preodontoblasts, during embryogenesis before transcripts were largely downregulated from the tooth germ postnatally. Collectively, these results suggest that Dact1 and -3 may contribute to early tooth formation by modulation of Wnt signaling pathways in the mesenchyme, including preodontoblasts, whereas Dact2 may play important signal-modulating roles in the adjacent epithelial cells including the enamel knot signaling centers and pre-ameloblasts. Future loss-of-function studies will help elucidate whether any of these functions are redundant, particularly for Dact1 and Dact3. PMID- 20170754 TI - The autoimmune lymphoproliferative syndrome: A rare disorder providing clues about normal tolerance. AB - The autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic, non-malignant lymphoproliferation, autoimmunity often manifesting as multilineage cytopenias, and an increased risk of lymphoma. While considered a rare disease, there are currently over 250 patients with ALPS being followed at the National Institutes of Health in Bethesda, Maryland. Most of these patients have a mutation in the gene for the TNF receptor-family member Fas (CD 95, Apo-1), and about one-third have an unknown defect or mutations affecting function of other signaling proteins involved in the apoptotic pathway. While ALPS is one of the few autoimmune diseases with a known genetic defect, there remain unanswered questions regarding how a defect in apoptosis results in the observed phenotype. In addition to shedding light on the pathophysiology of this rare and fascinating condition, studying ALPS may improve our understanding of normal tolerance and more common, sporadic autoimmune disorders. PMID- 20170753 TI - RNA surveillance-an emerging role for RNA regulatory networks in aging. AB - In this review, we describe recent advances in the field of RNA regulatory biology and relate these advances to aging science. We introduce a new term, RNA surveillance, an RNA regulatory process that is conserved in metazoans, and describe how RNA surveillance represents molecular cross-talk between two emerging RNA regulatory systems-RNA interference and RNA editing. We discuss how RNA surveillance mechanisms influence mRNA and microRNA expression and activity during lifespan. Additionally, we summarize recent data from our own laboratory linking the RNA editor, ADAR, with exceptional longevity in humans and lifespan in Caenorhabditis elegans. We present data showing that transcriptional knockdown of RNA interference restores lifespan losses in the context of RNA editing defects, further suggesting that interaction between these two systems influences lifespan. Finally, we discuss the implications of RNA surveillance for sarcopenia and muscle maintenance, as frailty is a universal feature of aging. We end with a discussion of RNA surveillance as a robust regulatory system that can change in response to environmental stressors and represents a novel axis in aging science. PMID- 20170755 TI - State-dependent central chemoreception: a role of orexin. AB - Sites involved in central chemoreception (CCR) are widely distributed in the brain. One possible explanation for the existence of multiple central chemoreceptor sites is the vigilance state-dependent hypothesis, that some sites are of greater importance in wakefulness others in sleep. We briefly summarize the evidence for a distributed network of central chemoreceptor sites and a vigilance state-dependent differentiation among them. We then discuss the role of orexin in vigilance state-dependent CCR based on our recent studies using orexin knockout mice and focal microdialysis of an orexin receptor antagonist at the retrotrapezoid nucleus and medullary raphe in rats. Orexin affects CCR in a vigilance state-dependent manner that varies with circadian time. Orexin also contributes to emotional stress- and other state-dependent related regulation of ventilation, e.g., the defense response. Diversity in central chemoreception including orexin neurons and the synaptic control of respiratory and cardiovascular output neurons appears to be necessary for animals to adapt themselves to constantly changing situations and behavioral states. PMID- 20170756 TI - Functional proteomics reveal the effect of Salvia miltiorrhiza aqueous extract against vascular atherosclerotic lesions. AB - Salvia miltiorrhiza is a Chinese herb widely used for cardiovascular disorder regimens, yet little is known about the cellular mechanisms that contribute to attenuated growth of smooth muscle cells (SMCs) under oxidative stress such as homocysteine (Hcy) treatment. As anticipated, a low dose (0.015 mg/mL) of S.miltiorrhiza aqueous extract (SMAE) significantly inhibited (>60%) the growth of a rat smooth muscle cell line (A10) under Hcy stimulation and the intracellular reactive oxygen species (ROS) concentration obviously decreased after SMAE treatment in terms of reducing p47(phox) translocation and increasing catalase activity. Signaling profile suggests that SMAE inhibited Hcy-induced A10 cell growth via the PKC/MAPK-dependent pathway. Two-dimensional electrophoresis (2-DE) coupled with mass spectrometry revealed statistically significant changes in the intensity of 14 proteins in response to Hcy and Hcy/SMAE. Meanwhile, SMAE attenuated carbonyl-modification of specific cytoskeleton and chaperone proteins leading to cell type transformation. Moreover, a network analysis using MetaCore shed more light on the molecular basis associated with SMAE efficacy. SMAE exerts its protective effect through the scavenging of ROS and subsequent modulation of protein carbonylation to inhibit cell proliferation. These signature networks and functional proteomics highlighted herein may facilitate the evaluation of potential therapeutic targets and elucidate novel mechanisms through which protein functions can be regulated by the redox status. PMID- 20170757 TI - Evaluation of substituted triazol-1-yl-pyrimidines as inhibitors of Bacillus anthracis acetohydroxyacid synthase. AB - Acetohydroxyacid synthase (AHAS), a potential target for antimicrobial agents, catalyzes the first common step in the biosynthesis of the branched-chain amino acids. The genes of both catalytic and regulatory subunits of AHAS from Bacillus anthracis (Bantx), a causative agent of anthrax, were cloned, overexpressed in Escherichia coli, and purified to homogeneity. To develop novel anti-anthracis drugs that inhibit AHAS, a chemical library was screened, and four chemicals, AVS2087, AVS2093, AVS2387, and AVS2236, were identified as potent inhibitors of catalytic subunit with IC(50) values of 1.0 +/- 0.02, 1.0 +/- 0.04, 2.1 +/- 0.12, and 2.0 +/- 0.08 microM, respectively. Further, these four chemicals also showed strong inhibition against reconstituted AHAS with IC(50) values of 0.05 +/- 0.002, 0.153 +/- 0.004, 1.30 +/- 0.10, and 1.29 +/- 0.40 microM, respectively. The basic scaffold of the AVS group consists of 1-pyrimidine-2-yl-1H [1,2,4]triazole-3-sulfonamide. The potent inhibitor, AVS2093 showed the lowest binding energy, -8.52 kcal/mol and formed a single hydrogen bond with a distance of 1.973 A. As the need for novel antibiotic classes to combat bacterial drug resistance increases, the screening of new compounds that act against Bantx-AHAS shows that AHAS is a good target for new anti-anthracis drugs. PMID- 20170758 TI - Controllable inhibition of cellular uptake of oxidized low-density lipoprotein: structure-function relationships for nanoscale amphiphilic polymers. AB - A family of anionic nanoscale polymers based on amphiphilic macromolecules (AMs) was developed for controlled inhibition of highly oxidized low-density lipoprotein (hoxLDL) uptake by inflammatory macrophage cells, a process that triggers the escalation of a chronic arterial disease called atherosclerosis. The basic AM structure is composed of a hydrophobic portion formed from a mucic acid sugar backbone modified at the four hydroxyls with lauroyl groups conjugated to hydrophilic poly(ethylene glycol) (PEG). The AM structure-activity relationships were probed by synthesizing AMs with six key variables: length of the PEG chain, carboxylic acid location, type of anionic charge, number of anionic charges, rotational motion of the anionic group, and PEG architecture. All AM structures were confirmed by nuclear magnetic resonance spectroscopy and their ability to inhibit hoxLDL uptake in THP-1 human macrophage cells was compared in the absence and presence of serum. We report that AMs with one, rotationally restricted carboxylic acid within the hydrophobic portion of the polymer was sufficient to yield the most effective AM for inhibiting hoxLDL internalization by THP-1 human macrophage cells under serum-containing conditions. Further, increasing the number of charges and altering the PEG architecture in an effort to increase serum stabilization did not significantly impair the ability of AMs to inhibit hoxLDL internalization, suggesting that selected modifications to the AMs could potentially promote multifunctional characteristics of these nanoscale macromolecules. PMID- 20170759 TI - Synthesis and characterization of poly(methyl methacrylate)-based experimental bone cements reinforced with TiO2-SrO nanotubes. AB - In an attempt to overcome existing limitations of experimental bone cements we here demonstrate a simple approach to synthesizing strontium-modified titania nanotubes (n-SrO-TiO(2) tubes) and functionalize them using the bifunctional monomer methacrylic acid. Then, using 'grafting from' polymerization with methyl methacrylate, experimental bone cements were produced with excellent mechanical properties, radiopacity and biocompatibility. Transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy-dispersive spectroscopy mapping and backscattered SEM micrographs revealed a uniform distribution of SrO throughout the titanium matrix, with retention of the nanotubular morphology. Nanocomposites were then reinforced with 1, 2, 4 and 6 wt.% of the functionalized metal oxide nanotubes. Under the mixing and dispersion regime employed in this study, 2 wt.% appeared optimal, exhibiting a more uniform dispersion and stronger adhesion of the nanotubes in the poly(methyl methacrylate) matrix, as shown by TEM and SEM. Moreover, this optimum loading provided a significant increase in the fracture toughness (K(IC)) (20%) and flexural strength (40%) in comparison with the control matrix (unfilled) at P<0.05. Examination of the fracture surfaces by SEM showed that toughening was provided by the nanotubes interlocking with the acrylic matrix and crack bridging during fracture. On modifying the n TiO(2) tubes with strontium oxide the nanocomposites exhibited a similar radiopacity to a commercial bone cement (CMW 1), while exhibiting a significant enhancement of osteoblast cell proliferation (242%) in vitro compared with the control at P<0.05. PMID- 20170760 TI - Influences of tensile load on in vitro degradation of an electrospun poly(L lactide-co-glycolide) scaffold. AB - Scaffolds for tissue engineering and regenerative medicine are usually subjected to different mechanical loads during in vitro and in vivo degradation. In this study, the in vitro degradation process of electrospun poly(L-lactide-co glycolide) (PLGA) scaffolds was examined under continuous tensile load and compared with that under no load. As PLGA degraded in phosphate-buffered saline solution (pH 7.4) at 37 degrees C over a 7-week period, the tensile elastic modulus and ultimate strength of the loaded specimen increased dramatically, followed by a decrease, which was much faster than that of the unloaded specimen, whereas break elongation of the loaded samples declined more quickly over the whole degradation period. Moreover, molecular weight, thermal properties and lactic acid release showed greater degradation under load. Also, a ruptured morphology was more obvious after degradation under tensile load. The results demonstrate that tensile load increased the degradation rate of electrospun PLGA and it may be necessary to consider the effects of mechanical load when designing or applying biodegradable scaffolds. Finally, some possible explanation for the faster degradation under load is given. PMID- 20170761 TI - Influence of chemical structures of benzodioxole-based coinitiators on the properties of the unfilled dental resin. AB - To investigate the influence of chemical structures of benzodioxole-based coinitiator on the initiating reactivity and the mechanical properties of cured samples for the unfilled dental resin, a mixture of 2,2-bis[4-(2-hydroxy-3 methacryloxyprop-1-oxy)phenyl]propane (bis-GMA) and triethylene glycol dimethacrylate (TEGDMA) (70/30 wt.%) was photoinduced by combinations of camphorquinone (CQ) and benzodioxole derivatives. 2-(N,N-Dimethylamino)ethyl methacrylate (DMEM) was used as control. The kinetics was monitored by a real time Fourier transformation infrared spectroscopy (FTIR) and the dynamic mechanical analysis was performed on a dynamic mechanical analyzer (DMA). The cytotoxicity property of the cured samples was evaluated by MTT assay in vitro using VERO as reference cell lines. The results indicated that the 4-position phenyl ring substituents of the benzodioxole-based coinitiator had great influence on the initiating reactivity. Incorporating substituents with pi electron acceptors in the 4-position of phenyl ring led to the decrease of the rate of polymerization (R(p)) of the CQ/benzodioxole derivatives. However, the electron-donating substituents were useful to increase the reactivity. When compared with CQ/amine initiating systems, the combination of CQ and benzodioxole compounds caused lower R(p) but the comparable final double bond conversion. All the cured films initiated by CQ/benzodioxole derivatives had almost the same glass transition temperature (T(g)) and storage modulus. Indirect cytotoxicity assessment indicated low cytotoxicity of benzodioxole derivatives. These results were very useful for the design of benzodioxole derivatives with satisfactory reactivity and biocompatibility, and are very important for clinical applications. PMID- 20170762 TI - In vitro antimicrobial activity against Pseudomonas aeruginosa and acute oral toxicity of marine algae Gracilaria changii. AB - Methanol extract of the Gracilaria changii has been screened for antimicrobial activity against Pseudomonas aeruginosa. Antimicrobial activities were carried out using disc diffusion assay and broth dilution method against P. aeruginosa. The methanol extract of G. changii showed a good antimicrobial activity against P. aeruginosa with MIC (Minimum Inhibitory Concentration) value of 6.25mg/ml. Exposure of P. aeruginosa cells to 6.25mg/ml of methanol extract of G. changii resulted in complete inhibition of the bacterial cells. The main abnormalities noted via SEM and TEM studies were the alterations in morphology and cytology of the bacterial cells. The main reason for this deterioration was discussed. The effect of the methanol extract on the growth profile for the bacteria was also done and confirmed the bactericidal effect of the G. changii methanol extract on P. aeruginosa by changing the normal growth profile of P. aeruginosa. In an acute toxicity study using mice, the median lethal dose (LD(50)) of the extract was greater than 2000 mg/kg, and we found no pathological changes in macroscopic examination by necropsy of mice treated with extract. We conclude that G. changii might be safely used as an antimicrobial agent. PMID- 20170763 TI - Systematic characterization by mass spectrometric analysis of phosphorylation sites in IRF-3 regulatory domain activated by IKK-i. AB - Interferon regulatory factor 3 (IRF-3) is a critical transcription factor that regulates innate immune responses against viral infection. Upon infection, IRF-3 is activated through phosphorylation of Ser/Thr residues in its C-terminal domain by the kinases, IKK-i and/or TBK-1. This phosphorylation triggers IRF-3 to interact with the co-activators to form a complex that activates target genes in the nucleus. However, the phosphorylation sites that determine the active/inactive status of IRF-3, estimated using biochemical methods such as mutagenesis and kinase assays, remain controversial. In the present study, phosphorylated IRF-3 189-427 (IRF-3 189C) was prepared by co-expression with IKK i and was specifically fractionated into 3 major phosphorylation forms using anion-exchange chromatography. Identification of the phosphorylation sites was performed using systematic mass spectrometry approaches as follows: intact molecular mass analysis by nanoESI-MS, MS survey of phosphopeptides, and targeted MS/MS analysis of LC-MS/MS-based proteomics using a high-resolution Orbitrap mass spectrometer. Phosphorylated IRF-3 189C was clearly identified to exist as a mono phosphoprotein (at Ser-402), and in two di-phosphoprotein forms (at Ser-386, -402 and Ser-396, -402). Thus, we demonstrated that Ser-386, -396 and -402 are directly phosphorylated by IKK-i in the co-expression system. These results will help provide new insights into the IRF-3 activation mechanism. PMID- 20170764 TI - Meta sequence analysis of human blood peptides and their parent proteins. AB - Sequence analysis of the blood peptides and their qualities will be key to understanding the mechanisms that contribute to error in LC-ESI-MS/MS. Analysis of peptides and their proteins at the level of sequences is much more direct and informative than the comparison of disparate accession numbers. A portable database of all blood peptide and protein sequences with descriptor fields and gene ontology terms might be useful for designing immunological or MRM assays from human blood. The results of twelve studies of human blood peptides and/or proteins identified by LC-MS/MS and correlated against a disparate array of genetic libraries were parsed and matched to proteins from the human ENSEMBL, SwissProt and RefSeq databases by SQL. The reported peptide and protein sequences were organized into an SQL database with full protein sequences and up to five unique peptides in order of prevalence along with the peptide count for each protein. Structured query language or BLAST was used to acquire descriptive information in current databases. Sampling error at the level of peptides is the largest source of disparity between groups. Chi Square analysis of peptide to protein distributions confirmed the significant agreement between groups on identified proteins. PMID- 20170765 TI - Immunogenic properties of a recombinant fusion protein containing the C-terminal 19 kDa of Plasmodium falciparum merozoite surface protein-1 and the innate immunity agonist FliC flagellin of Salmonella typhimurium. AB - In a recent study, we demonstrated the immunogenic properties of a new malaria vaccine polypeptide based on a 19 kDa C-terminal fragment of the merozoite surface protein-1 (MSP1(19)) from Plasmodium vivax and an innate immunity agonist, the Salmonella enterica serovar Typhimurium flagellin (FliC). Herein, we tested whether the same strategy, based on the MSP1(19) component of the deadly malaria parasite Plasmodium falciparum, could also generate a fusion polypeptide with enhanced immunogenicity. The His(6)FliC-MSP1(19) fusion protein was expressed from a recombinant Escherichia coli and showed preserved in vitro TLR5 binding activity. In contrast to animals injected with His(6)MSP1(19), mice subcutaneously immunised with the recombinant His(6)FliC-MSP1(19) developed strong MSP1(19)-specific systemic antibody responses with a prevailing IgG1 subclass. Incorporation of other adjuvants, such as CpG ODN 1826, complete and incomplete Freund's adjuvants or Quil-A, improved the IgG responses after the second, but not the third, immunising dose. It also resulted in a more balanced IgG subclass response, as evaluated by the IgG1/IgG2c ratio, and higher cell mediated immune response, as determined by the detection of antigen-specific interferon-gamma secretion by immune spleen cells. MSP1(19)-specific antibodies recognised not only the recombinant protein, but also the native protein expressed on the surface of P. falciparum parasites. Finally, sera from rabbits immunised with the fusion protein alone inhibited the in vitro growth of three different P. falciparum strains. In summary, these results extend our previous observations and further demonstrate that fusion of the innate immunity agonist FliC to Plasmodium antigens is a promising alternative to improve their immunogenicity. PMID- 20170766 TI - Oral immunization with a Lactobacillus casei vaccine expressing human papillomavirus (HPV) type 16 E7 is an effective strategy to induce mucosal cytotoxic lymphocytes against HPV16 E7. AB - Although many clinical trials on human papillomavirus (HPV) therapeutic vaccines have been performed, clinical responses have not been consistent. We have addressed mucosal cytotoxic cellular immune responses to HPV16 E7 after oral immunization of mice with recombinant Lactobacillus casei expressing HPV16 E7 (LacE7). C57BL/6 mice were orally exposed to 0.1-100mg/head of attenuated LacE7 or vehicle (Lac) vaccines at weeks 1, 2, 4, and 8. Responses to subcutaneous or intramuscular injection of an HPV16 E7 fusion protein using the same timing protocol were used for comparison. Oral immunization with LacE7 elicited E7 specific IFN gamma-producing cells (T cells with E7-type 1 immune responses) among integrin alpha 4 beta 7(+) mucosal lymphocytes collected from gut mucosa. An induction of E7-specific granzyme B-producing cells (E7-CTL) exhibiting killer responses toward HPV16 E7-positive cells was also observed. The induction of T cells with specific mucosal E7-type 1 immune responses was greater after oral immunization with LacE7 when compared to subcutaneous or intramuscular antigen delivery. Oral immunization with Lactobacillus-based vaccines was also able to induce mucosal cytotoxic cellular immune responses. This novel approach at a therapeutic HPV vaccine may achieve more effective clinical responses through its induction of mucosal E7-specific CTL. PMID- 20170767 TI - Antibody responses elicited through homologous or heterologous prime-boost DNA and protein vaccinations differ in functional activity and avidity. AB - Using a gp120 envelope glycoprotein from the JR-FL strain of human immunodeficiency virus-1 (HIV-1) as a model antigen, the goal of the current study was to evaluate the level and quality of antibody responses elicited by different prime-boost vaccination regimens (protein only, DNA only, DNA plus protein) in rabbits. Our data demonstrated that incorporating DNA immunization as a prime in a heterologous prime-boost regimen was able to elicit a more diverse and conformational epitope profile, higher antibody avidity, and improved neutralizing activity than immunization with only protein. Additionally, this improved neutralizing activity was observed in spite of similar antibody specificities and avidities seen when only DNA vaccination was used, providing additional evidence that the use of a combination immunization regimen increases the protective antibody response. Insights gained from the current study confirmed that the heterologous DNA prime-protein boost approach is effective in eliciting not only high level but also improved quality of antigen-specific antibody responses, and thus may offer a new technology platform to develop better and safer subunit vaccines. PMID- 20170768 TI - Detoxified endotoxin vaccine (J5dLPS/OMP) protects mice against lethal respiratory challenge with Francisella tularensis SchuS4. AB - Francisella tularensis is a category A select agent. J5dLPS/OMP is a novel vaccine construct consisting of detoxified, O-polysaccharide side chain deficient, lipopolysaccharide non-covalently complexed with the outer membrane protein of N. meningitidis group B. Immunization elicits high-titer polyclonal antibodies specific for the highly-conserved epitopes expressed within the glycolipid core that constitutes gram-negative bacteria (e.g., F. tularensis). Mice immunized intranasally with J5dLPS/OMP exhibited protective immunity to intratracheal challenge with the live vaccine strain, as well as the highly virulent SchuS4 strain, of F. tularensis. The efficacy of J5dLPS/OMP vaccine suggests its potential utility in immunizing the general population against several different gram-negative select agents concurrently. PMID- 20170769 TI - Assessing degeneration of human articular cartilage with ultra-short echo time (UTE) T2* mapping. AB - OBJECTIVE: To examine the sensitivity of ultra-short echo time (UTE) T(2)* mapping to collagen matrix degeneration in human articular cartilage. METHODS: Magnetic resonance imaging (MRI) UTE-T(2)* maps and standard T(2) maps were acquired on four human tibial plateau explants. Thirty-three osteochondral cores were harvested for polarized light microscopy (PLM), and composition analyses. Collagen matrix integrity was evaluated from PLM and histological images. Matrix integrity and composition was compared to standard T(2) values and UTE-T(2)* values on a spatially registered basis. RESULTS: UTE-T(2)* values varied with matrix degeneration (P=0.008) and were lower in severely degraded cartilage compared to healthy tissue (P=0.012). A trend for higher UTE-T(2)* values in healthy tissue compared to mildly degenerate tissue (P=0.051) was detected. Standard T(2) values were not found to vary with matrix degeneration (P=0.13) but tended to be higher in severely degraded cartilage compared to healthy tissue. UTE-T(2)* value variations were independent of type-II collagen and glycosaminoglycan contents. UTE-T(2)* mapping of deep cartilage, adjacent to subchondral bone, was more robust than standard T(2) mapping in this zone. CONCLUSION: UTE-T(2)* mapping of articular cartilage is sensitive to matrix degeneration and detects short-T(2) signal, particularly in deep tissue, that is not well captured by standard T(2) mapping. Correlation of UTE-T(2)* values and PLM indices supports the hypothesis that both may be sensitive to collagen microstructure. Further exploration of UTE-T(2)* mapping as a non-invasive tool to detect early articular cartilage degeneration is warranted. PMID- 20170770 TI - OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009. AB - OBJECTIVE: To update evidence for available therapies in the treatment of hip and knee osteoarthritis (OA) and to examine whether research evidence has changed from 31 January 2006 to 31 January 2009. METHODS: A systematic literature search was undertaken using MEDLINE, EMBASE, CINAHL, AMED, Science Citation Index and the Cochrane Library. The quality of studies was assessed. Effect sizes (ESs) and numbers needed to treat were calculated for efficacy. Relative risks, hazard ratios (HRs) or odds ratios were estimated for side effects. Publication bias and heterogeneity were examined. Sensitivity analysis was undertaken to compare the evidence pooled in different years and different qualities. Cumulative meta analysis was used to examine the stability of evidence. RESULTS: Sixty-four systematic reviews, 266 randomised controlled trials (RCTs) and 21 new economic evaluations (EEs) were published between 2006 and 2009. Of 51 treatment modalities, new data on efficacy have been published for more than half (26/39, 67%) of those for which research evidence was available in 2006. Among non pharmacological therapies, ES for pain relief was unchanged for self-management, education, exercise and acupuncture. However, with new evidence the ES for pain relief for weight reduction reached statistical significance, increasing from 0.13 [95% confidence interval (CI) -0.12, 0.36] in 2006 to 0.20 (95% CI 0.00, 0.39) in 2009. By contrast, the ES for electromagnetic therapy which was large in 2006 (ES=0.77, 95% CI 0.36, 1.17) was no longer significant (ES=0.16, 95% CI 0.08, 0.39). Among pharmacological therapies, the cumulative evidence for the benefits and harms of oral and topical non-steroidal anti-inflammatory drugs, diacerhein and intra-articular (IA) corticosteroid was not greatly changed. The ES for pain relief with acetaminophen diminished numerically, but not significantly, from 0.21 (0.02, 0.41) to 0.14 (0.05, 0.22) and was no longer significant when analysis was restricted to high quality trials (ES=0.10, 95% CI 0.0, 0.23). New evidence for increased risks of hospitalisation due to perforation, peptic ulceration and bleeding with acetaminophen >3g/day have been published (HR=1.20, 95% CI 1.03, 1.40). ES for pain relief from IA hyaluronic acid, glucosamine sulphate, chondroitin sulphate and avocado soybean unsponifiables also diminished and there was greater heterogeneity of outcomes and more evidence of publication bias. Among surgical treatments further negative RCTs of lavage/debridement were published and the pooled results demonstrated that benefits from this modality of therapy were no greater than those obtained from placebo. CONCLUSION: Publication of a large amount of new research evidence has resulted in changes in the calculated risk-benefit ratio for some treatments for OA. Regular updating of research evidence can help to guide best clinical practice. PMID- 20170771 TI - Measuring success in atrial fibrillation: Groping the elephant. PMID- 20170772 TI - Conflict of interest in scientific publications: a historical review and update. AB - There is a stigma surrounding the reporting of conflicts of interest (COIs) that should be overcome. This article provides a discussion about COI, a brief historical review of requirements, and an update of policy for the Journal of Manipulative and Physiological Therapeutics that includes the alignment of the International Committee of Medical Journal Editors new COI form requirement. This article reviews types of COI and suggests that professions (eg, chiropractic, physical therapy, acupuncture) not directly affiliated with pharmaceutical and device companies, though they may be faced with different circumstances, should still comply with current COI reporting standards. There should be no disgrace in properly declaring interests; instead, COI declaration should be considered an important part of publication and recognized as an honorable action. Declaration of COI helps to provide transparency and disclosure to all involved including editorial staff, peer reviewers, and the readers. PMID- 20170773 TI - Risk factors associated with back pain: a cross-sectional study of 963 college students. AB - OBJECTIVE: The purpose of this study was to evaluate standard measures of health behavior for association with back pain among college students using data from the standardized National College Health Assessment survey. This investigation evaluated potential risk factors among a population of students at a Colorado university. METHODS: This cross-sectional study included 963 survey results that were assessed using backward selection logistic regression techniques to evaluate the associations between common college-life health behaviors and back pain occurrence within the past school year. RESULTS: Thirty-eight percent of college students surveyed reported having back pain within the past school year. Investigators found that univariate associations included multiple domains, but only psychosocial factors remained statistically significant in a final regression model and were associated with back pain. Feeling chronically fatigued (odds ratio, 3.89; 95% confidence interval, 1.09-13.86) and being in an emotionally abusive relationship (odds ratio, 2.78; 95% confidence interval, 1.69 4.57) were the factors most strongly associated with back pain in the final model. CONCLUSIONS: Psychosocial factors were identified to be associated with back pain. The prevalence of back pain among this younger population is of significant concern and warrants further investigation to identify contributing factors that may help in the development of interventions to reduce the epidemic of back pain within college students and lessen the burden upon college health providers. PMID- 20170774 TI - Manipulative therapy in addition to usual care for patients with shoulder complaints: results of physical examination outcomes in a randomized controlled trial. AB - OBJECTIVE: The purpose of this study was to examine the effect of manipulative therapy on the shoulder girdle, in addition to usual care provided by the general practitioner, on the outcomes of physical examination tests for the treatment of shoulder complaints. METHODS: This was a randomized controlled trial in a primary care setting in the Netherlands. A total of 150 participants were recruited from December 2000 until December 2002. All patients received usual care by the general practitioner. Usual care included one or more of the following depending on the needs of the patient: information/advice, oral analgesics or nonsteroidal antiinflammatory drugs, corticosteroid injections, exercises, and massage. In addition to usual care, the intervention group received manipulative therapy, up to 6 treatment sessions in a 12-week period. Twenty-four physical examination tests were done at baseline and after 6, 12, and 26 weeks. Factor analysis was done to reduce the number of outcome measures. RESULTS: The factor analysis resulted in 4 factors: "shoulder pain," "neck pain," "shoulder mobility," and "neck mobility." At 6 weeks, no significant differences between groups were found. At 12 weeks, the mean changes of all 4 factors favored the intervention group; the factors "shoulder pain" and "neck pain" reached statistical significance (95% confidence interval [CI], 0.1-2.1). At 26 weeks, differences in the factors "shoulder pain" (95% CI, 0.0-2.6), "shoulder mobility" (95% CI, 0.2 1.7), and "mobility neck" (95% CI, 0.2-1.3) statistically favored the intervention group. CONCLUSION: In this pragmatic study, manipulative therapy, in addition to usual care by the general practitioner, diminished severity of shoulder pain and neck pain and improved shoulder and neck mobility. PMID- 20170775 TI - Immediate and carryover changes of C5-6 joint mobilization on shoulder external rotator muscle strength. AB - OBJECTIVE: Clinical evidence has shown that extremity dysfunction, such as muscle weakness or inhibition, is associated with spinal disorders. Spinal manual therapy is a common therapeutic approach used to address extremity muscle weakness. The purpose of the study was to assess changes in the maximal muscle strength of the shoulder external rotators immediately and at 10, 20, and 30 minutes after cervical joint mobilization at the C5-6 segment. METHODS: Eighteen participants with existing or a history of neck pain were screened by 2 investigators independently for muscle weakness of shoulder external rotators. Fifteen qualified participants underwent shoulder external rotator strength testing with a handheld dynamometer. Each participant was tested 6 times, twice before, immediately after, and at 10, 20, and 30 minutes after a C5-6 joint mobilization on the involved side. The 2 strength data collected before the mobilization were used to determine intratester reliability. RESULTS: The intratester reliability of the shoulder external rotator strength was excellent (intraclass correlation coefficient(3,2) = 0.985). One-way analysis of variance with repeated measures showed a statistical significance in strength data (P = .002). Post hoc tests revealed a significant increase between prejoint mobilization and immediately postjoint mobilization (P = .003) and between pre joint mobilization and 10-minute post joint mobilization (P < .001). CONCLUSIONS: The results of the study suggest that C5-6 joint mobilization increases muscle strength of the shoulder external rotators immediately and its effect carries over for 10 minutes but not after 20 minutes. PMID- 20170776 TI - Effects of high-velocity, low-amplitude spinal manipulation on strength and the basal tonus of female pelvic floor muscles. AB - OBJECTIVE: Spinal manipulation with high-velocity and low-amplitude (HVLA) manipulation is frequently used for the treatment of lumbopelvic pain; however, the effect on the pelvic floor has been poorly studied in the past. The objective of this study was to quantify the intravaginal pressure (IVP) and the basal perineal tonus (BPT), measured in terms of pressure, before and after the HVLA manipulation in patients without neuromuscular and skeletal dysfunctions. METHODS: In this experimental, noncontrolled, nonrandomized study, IVP was obtained through a perineometer introduced into the volunteers' vagina while in dorsal horizontal decubitus. Forty young, healthy university volunteer women with no history of vaginal delivery participated. All voluntary contractions of the perineal muscles were measured in 3 different ways: phasic perineal contraction (PPC), tonic perineal contraction, and perineal contraction associated to accessory muscles. New pressure measurements were obtained immediately after the HVLA manipulation on the volunteers' sacrum. The pressures were registered and transcribed directly to a personal computer with specific software. RESULTS: The average IVPs obtained in millimeters of mercury before and after the HVLA manipulation were 56.01 (+/-25.54) and 64.65 (+/-25.63) for PPC, 445.90 (+/ 186.84) and 483.14 (+/-175.29) for tonic perineal contraction, and 65.62 (+/ 26.56) and 69.37 (+/-25.26) for perineal contraction associated to accessory muscles, respectively. There was significant statistical variation only for PPC (P = .0020) values. The BPT increased regardless of the type of contraction (P < .05). CONCLUSION: High-velocity and low-amplitude manipulation of the sacrum was associated with an increase of PPC and of BPT in women who had no associated osteoarticular diseases. These preliminary discoveries could be helpful in the future study of the treatment of women with perineal hypotony. PMID- 20170778 TI - Variable morphology of the axis vertebrae in 100 specimens: implications for clinical palpation and diagnostic imaging. AB - OBJECTIVE: The purpose of this study was to investigate and measure the variable morphologies of axis vertebrae and explore the clinical significance of variations as it may pertain to clinical palpation and diagnostic imaging. METHODS: The common variable morphologies in 100 specimens of intact dry adult axis vertebrae (Chinese) were investigated and measured. The frequencies in deviation of odontoid processes, deviation of spinous processes, and presence of bifid spinous processes were observed. The distances between the apices of transverse processes and inferior articular facets were also measured. RESULTS: Variable morphologies of C2 that we observed were deviation of odontoid processes (14 cases, 14.0%), deviation of spinous processes (3 cases, 3.0%), and bifid spinous processes (95 cases, 95.0%). Of the bifid spinous processes, 56 had a process on the left side equal to the right side, 21 were longer on the left, and 18 were longer on the right. The distances between apices of transverse processes and inferior articular facets in the left side of C2 were 17.67 +/- 2.47 mm, and that of the right side were 17.81 +/- 2.55 mm. CONCLUSIONS: Because variable morphology of the axis is common, congenital deviation of the odontoid process, deviation of the spinous process, and asymmetrical bifid spinous processes should be taken into account during clinical palpation and diagnostic imaging. PMID- 20170777 TI - The relationship of the audible pop to hypoalgesia associated with high-velocity, low-amplitude thrust manipulation: a secondary analysis of an experimental study in pain-free participants. AB - OBJECTIVE: High-velocity, low-amplitude (HVLA) manipulation is an effective treatment of low back pain (LBP); however, the corresponding mechanisms are undetermined. Hypoalgesia is associated with HVLA manipulation and suggests specific mechanisms of action. An audible pop (AP) is also associated with HVLA manipulation; however, the influence of the AP on the hypoalgesia associated with HVLA manipulation is not established. The purpose of the current study was to observe the influence of the AP on hypoalgesia associated with HVLA manipulation. METHODS: The current study represents a secondary analysis of 40 participants. All participants underwent thermal pain sensitivity testing to their leg and low back using protocols specific to A delta fiber-mediated pain and temporal summation. Next, participants received HVLA manipulation to their low back, and the examiner recorded whether an AP was perceived. Finally, participants underwent immediate follow-up thermal pain sensitivity testing using the same protocols. Separate repeated-measure analyses of variance (ANOVAs) were used to observe changes in pain sensitivity before and immediately after HVLA manipulation. RESULTS: Hypoalgesia of A delta fiber-mediated pain was observed in the low back after HVLA (P < .05), and this was independent of whether an AP was perceived (P > .05). Hypoalgesia of temporal summation was observed in the lower extremity after HVLA (P < .05), and this was independent of whether an AP was perceived (P = .08). However, a moderate effect size for temporal summation was observed favoring participants in whom an AP was perceived. CONCLUSION: The current study suggests hypoalgesia is associated with HVLA manipulation and occurs independently of a perceived AP. Inhibition of lower extremity temporal summation may be larger in individuals in whom an AP is perceived, but further study is necessary to confirm this finding. PMID- 20170779 TI - Morphological changes of the in vitro cervical vertebral canal and its cast form during flexion, extension, and lateral bending. AB - OBJECTIVE: The purpose of this study was to investigate and measure morphological changes in the vertebral canal and its cast form at the level of the cervical spine in vitro during flexion, extension, and lateral bending in cadaver specimens. METHODS: The morphological changes of vertebral canal and its contents were investigated and measured during experimental flexion, extension, and lateral bending of the cervical spine with 10 fresh specimens (Chinese); the cross-sections and sagittal diameters were also measured by pouring liquid wax into the intervertebral canal. RESULTS: During lateral bending, the nucleus pulposus was pushed to the opposite side and the inferior cervical nerve roots of the opposite side were stretched. Cross-sectional diameter at the level of C6-7 during flexion was larger than that in lateral bending (P < .05). Comparing extension with flexion, we found that changes in all segments' areas were significant (P < .05). There was no significant difference in the sagittal diameter at any segment during all postures (P > .05). CONCLUSIONS: During lateral bending, the nucleus pulposus of neck were pushed into the opposite side, and inferior cervical nerve roots of the opposite side were stretched. The C5, C6, and C7 nerve roots appeared to undergo excessive stretch when an excessive lateral bending beyond the physiologic range was undergone. This study provides some additional evidence about the mechanics of cervical spine motion. PMID- 20170780 TI - A systematic review of reliability and validity studies of methods for measuring active and passive cervical range of motion. AB - OBJECTIVE: The purpose of this study was to systematically review the literature evaluating the reliability and validity of all available methods for measuring active and passive cervical range of motion (CROM). METHODS: Electronic databases (PubMed, MEDLINE, CINAHL, EMBASE, and AMED) were searched through OVID from their inception to January 2008. Articles were selected according to a priori defined criteria. Data were extracted regarding publication details, type of study, movements and device evaluated, subject and observer characteristics, and measurement protocol including blinding and statistical analysis methods. Quality assessment was undertaken using developed criteria to assess internal validity, external validity, and statistical methods. An estimate of the level of reliability and validity was calculated and used to categorize studies as good, moderate, or poor. RESULTS: A total of 56 articles fulfilled the selection criteria and were included in the review. Forty-six of these articles described 66 reliability studies and 21 described 21 concurrent criterion validity studies. Twelve different methods were evaluated. Although it was the intention of this review to conduct meta-analysis, this was deemed inappropriate due to studies being too heterogeneous. Most of the reliability and validity studies involved asymptomatic subjects measured by allied health professionals investigating active ROM. Devices that were deemed to have "good" reliability and validity were the CROM device, the Spin-T goniometer, and the single inclinometer. CONCLUSIONS: A considerable number of reliability and concurrent validity studies have been published for CROM. The CROM device has undergone most evaluation and has been shown to be clinimetrically sound. Further research with significantly improved methodology and reporting is warranted for all devices. PMID- 20170781 TI - Neurodynamic mobilization in the conservative treatment of cubital tunnel syndrome: long-term follow-up of 7 cases. AB - OBJECTIVE: The aim of this case series is to describe the effect of nerve mobilization techniques in the standard conservative management of cubital tunnel syndrome (CTS). METHODS: Seven patients with CTS participated in this study. Inclusion criteria were having grade 1 and grade 2 entrapment neuropathy according to the McGowan grading system and no other neuropathies. In the evaluation, gripping with grip dynamometer; palmar gripping with a pinchmeter; pain level and Tinel sign with visual analog scale; sensibility with Semmes Weinstein monofilaments; and functional status of the patients with the Turkish version of the Disability of Arm, Shoulder, and Hand Index were performed before starting a rehabilitation program, at the end of the 8-week rehabilitation program, and at 12-month follow-up. The physiotherapy program consisted of cold application, pulsed ultrasound, nerve mobilization techniques, strengthening exercises, postural adaptations, patient education, and ergonomic modifications. RESULTS: Pain; Tinel sign; and Disability of Arm, Shoulder, and Hand Index scores were decreased, whereas grip and pinch strength increased in the observation period for these 7 patients. CONCLUSION: This case series demonstrated that conservative treatment of CTS may be beneficial for selected patients with mild to moderate symptoms. The treatment included neurodynamic mobilizations, including sliding techniques and tensioning techniques, which are thought to enhance ulnar nerve gliding and restore neural tissue mobility. Conservative treatment using neurodynamic mobilization with patient education and activity modification demonstrated some long-term positive results. PMID- 20170783 TI - Cryoglobulin-induced cardiomyopathy. PMID- 20170784 TI - Long-term effectiveness and safety of sirolimus stent implantation for coronary in-stent restenosis results of the TRUE (Tuscany Registry of sirolimus for unselected in-stent restenosis) registry at 4 years. AB - OBJECTIVES: The aim of this study was to evaluate the long-term clinical outcome of the efficacy and safety of sirolimus-eluting stents (SES) for in-stent restenosis (ISR) in the TRUE (Tuscany Registry of Unselected In-Stent Restenosis) database. BACKGROUND: The TRUE registry demonstrated that SES in the treatment of bare-metal stent ISR is efficacious (5% of target lesion revascularization [TLR]) and safe (stent thrombosis <1%) at 9 months. Clinical outcome at 4 years is reported. METHODS: A total of 244 patients with ISR who were treated with SES implantation represent the study population. The incidence of major adverse cardiac events was collected at 4 years. RESULTS: At 4-year follow-up, overall mortality was 9.8% (24 patients). Cardiac death occurred in 11 (4.5%), nonfatal myocardial infarction in 8 (3.2%), and TLR in 27 (11.1%) patients for a cumulative event-free survival rate of 80.3%. Definite stent thrombosis occurred in 5 (2%) patients and possible stent thrombosis in 2 (0.8%). Diabetes remained an independent negative predictor of freedom from TLR (odds ratio [OR]: 0.38; 95% confidence interval [CI]: 0.20 to 0.71, p = 0.002) and major adverse cardiac events (OR: 0.38; 95% CI: 0.20 to 0.71, p = 0.002). CONCLUSIONS: The clinical benefit of SES implantation for bare-metal stent ISR is maintained at 4 years with a low TLR rate and an overall incidence of stent thrombosis of 0.7% per year. PMID- 20170785 TI - Enoxaparin anticoagulation monitoring in the catheterization laboratory using a new bedside test. AB - OBJECTIVES: This study evaluated the ability of the bedside test Hemochron Jr. Hemonox (International Technidyne Corporation, Edison, New Jersey) to identify patients with insufficient anti-Xa activity level in the catheterization laboratory. BACKGROUND: Inadequate anticoagulation in patients undergoing percutaneous coronary intervention (PCI) is associated with increased periprocedural ischemic events. METHODS: In 296 unselected patients undergoing catheterization and/or PCI, whole blood Hemonox clotting time (CT) and activated partial thromboplastin time (aPTT) were measured at baseline (T1) and 10 min after the intravenous administration of enoxaparin (T2) in patients receiving additional enoxaparin and compared with plasma chromogenic anti-Xa activity level. RESULTS: Median values were 0.1 IU/ml (interquartile range [IQR]: 0.1 to 0.1 IU/ml) and 0.87 IU/ml (IQR: 0.74 to 1.03 IU/ml) for anti-Xa; 74 s (IQR: 70 to 81 s) and 143 s (IQR: 114 to 206 s) for Hemonox CT; and 44 s (IQR: 39 to 50 s) and 72 s (IQR: 58 to 93 s) for aPTT at T1 and T2, respectively. When using Hemonox CT to discriminate patients with anti-Xa level <0.5 IU/ml, the area under the receiver operating characteristic curve was 0.95 +/- 0.01 (95% confidence interval [CI]: 0.93 to 0.97) versus 0.89 +/- 0.01 (95% CI: 0.86 to 0.92) for aPTT. The threshold value of 120 s was associated with a 94.9% (95% CI: 91.1% to 97.4%) sensitivity and a 73.3% (95% CI: 67.6% to 78.5%) specificity to detect patients with inadequate anti-Xa level (<0.5 IU/ml) and positive predictive and negative predictive values of 73.9% (95% CI: 68.7% to 79.0%) and 94.78% (95% CI: 91.8% to 97.8%), respectively. CONCLUSIONS: Hemonox CT appears to be a fast and reliable bedside test for detecting patients insufficiently anticoagulated and needing adjustment of anticoagulation therapy with enoxaparin before PCI. PMID- 20170787 TI - What is the prognostic value of a zero calcium score? PMID- 20170786 TI - The absence of coronary calcification does not exclude obstructive coronary artery disease or the need for revascularization in patients referred for conventional coronary angiography. AB - OBJECTIVES: This study was designed to evaluate whether the absence of coronary calcium could rule out >or=50% coronary stenosis or the need for revascularization. BACKGROUND: The latest American Heart Association guidelines suggest that a calcium score (CS) of zero might exclude the need for coronary angiography among symptomatic patients. METHODS: A substudy was made of the CORE64 (Coronary Evaluation Using Multi-Detector Spiral Computed Tomography Angiography Using 64 Detectors) multicenter trial comparing the diagnostic performance of 64-detector computed tomography to conventional angiography. Patients clinically referred for conventional angiography were asked to undergo a CS scan up to 30 days before. RESULTS: In all, 291 patients were included, of whom 214 (73%) were male, and the mean age was 59.3 +/- 10.0 years. A total of 14 (5%) patients had low, 218 (75%) had intermediate, and 59 (20%) had high pre-test probability of obstructive coronary artery disease. The overall prevalence of >or=50% stenosis was 56%. A total of 72 patients had CS = 0, among whom 14 (19%) had at least 1 >or=50% stenosis. The overall sensitivity for CS = 0 to predict the absence of >or=50% stenosis was 45%, specificity was 91%, negative predictive value was 68%, and positive predictive value was 81%. Additionally, revascularization was performed in 9 (12.5%) CS = 0 patients within 30 days of the CS. From a total of 383 vessels without any coronary calcification, 47 (12%) presented with >or=50% stenosis; and from a total of 64 totally occluded vessels, 13 (20%) had no calcium. CONCLUSIONS: The absence of coronary calcification does not exclude obstructive stenosis or the need for revascularization among patients with high enough suspicion of coronary artery disease to be referred for coronary angiography, in contrast with the published recommendations. Total coronary occlusion frequently occurs in the absence of any detectable calcification. (Coronary Evaluation Using Multi-Detector Spiral Computed Tomography Angiography Using 64 Detectors [CORE-64]; NCT00738218). PMID- 20170788 TI - Modified serum profiles of inflammatory and vasoconstrictive factors in patients with emotional stress-induced acute coronary syndrome during World Cup Soccer 2006. AB - OBJECTIVES: We sought to assess whether emotional stress-induced acute coronary syndrome (ACS) is mediated by increased inflammatory and vasoconstrictive mediators. BACKGROUND: The World Cup soccer 2006 has been shown to provoke levels of stress sufficient to increase the incidence of ACS. However, the mechanisms by which stress translates into vascular injury up to plaque rupture still remain elusive. METHODS: Serum levels of soluble CD40L (sCD40L), soluble vascular cell adhesion molecule (sVCAM)-1, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF)-alpha, high-sensitivity C-reactive protein (hsCRP), regulated on activation, normal T-cell expressed and secreted (RANTES), and endothelin (ET)-1 were determined in patients who experienced an ACS during World Cup matches, in ACS reference patients (not associated with emotional stress), and in healthy volunteers. Correlations and receiver-operating characteristic curves were calculated to develop multivariable analysis and to investigate the diagnostic value of each parameter. RESULTS: The sCD40L, sVCAM-1, MCP-1, TNF alpha, and ET-1 were significantly higher in study patients compared with the reference group. The hsCRP was similar in both groups, whereas RANTES was decreased in study patients. A positive correlation was found between ET-1 and soccer-induced enhanced levels of sCD40L, sVCAM-1, MCP-1, and TNF-alpha. Receiver operating characteristic analysis displayed high performance of both MCP-1 and ET 1 as a measure to discriminate between stress-induced ACS and ACS controls. CONCLUSIONS: Stress-induced ACS is associated with a profound increase of inflammatory and vasoconstrictive mediators. The evaluation of a targeted drug delivery, such as anti-inflammatory agents, ET-1 receptor antagonists, or inhibition of endothelin-converting enzyme is warranted to reduce stress-mediated cardiovascular morbidity. PMID- 20170789 TI - Endothelin-1 release and stimulation of the inflammatory cascade: is acute coronary syndrome triggered by watching spectator sports? PMID- 20170790 TI - N-terminal pro-B-type natriuretic peptide-guided, intensive patient management in addition to multidisciplinary care in chronic heart failure a 3-arm, prospective, randomized pilot study. AB - OBJECTIVES: This study was designed to investigate whether the addition of N terminal pro-B-type natriuretic peptide-guided, intensive patient management (BM) to multidisciplinary care (MC) improves outcome in patients following hospitalization due to heart failure (HF). BACKGROUND: Patients hospitalized due to HF experience frequent rehospitalizations and high mortality. METHODS: Patients hospitalized due to HF were randomized to BM, MC, or usual care (UC). Multidisciplinary care included 2 consultations from an HF specialist who provided therapeutic recommendations and home care by a specialized HF nurse. In addition, BM included intensified up-titration of medication by HF specialists in high-risk patients. NT-proBNP was used to define the level of risk and to monitor wall stress. This monitoring allowed for anticipation of cardiac decompensation and adjustment of medication in advance. RESULTS: A total of 278 patients were randomized in 8 Viennese hospitals. After 12 months, the BM group had the highest proportion of antineurohormonal triple-therapy (difference among all groups). Accordingly, BM reduced days of HF hospitalization (488 days) compared with the hospitalization for the MC (1,254 days) and UC (1,588 days) groups (p < 0.0001; significant differences among all groups). Using Kaplan-Meier analysis, the first HF rehospitalization (28%) was lower in the BM versus MC groups (40%; p = 0.06) and the MC versus UC groups (61%; p = 0.01). Moreover, the combined end point of death or HF rehospitalization was lower in the BM (37%) than in the MC group (50%; p < 0.05) and in the MC than in the UC group (65%; p = 0.04). Death rate was similar between the BM (22%) and MC groups (22%), but was lower compared with the UC group (39%; vs. BM: p < 0.02; vs. MC: p < 0.02). CONCLUSIONS: Compared with MC alone, additional BM improves clinical outcome in patients after HF hospitalization. (BNP Guided Care in Addition to Multidisciplinary Care; NCT00355017). PMID- 20170791 TI - African-American women have a higher risk for developing peripartum cardiomyopathy. AB - OBJECTIVES: The purpose of this study was to assess whether African-American women are at increased risk of having peripartum cardiomyopathy. BACKGROUND: Peripartum cardiomyopathy is a heart disease of unknown cause that affects young women, often with devastating consequences. The frequency of peripartum cardiomyopathy varies markedly between African and non-African regions. METHODS: A case-control study was performed at a regional center that provides medical care to a racially heterogeneous population. For each case, 3 healthy control patients were randomly selected who delivered babies within the same month. RESULTS: African-American women had a 15.7-fold higher relative risk of peripartum cardiomyopathy than non-African Americans (odds ratio [OR]: 15.7, 95% confidence interval [CI]: 3.5 to 70.6). Other significant univariate risk factors were hypertension (OR: 10.8, 95% CI: 2.6 to 44.4), being unmarried (OR: 4.2, 95% CI: 1.4 to 12.3), and having had >2 previous pregnancies (OR: 2.9, 95% CI: 1.1 to 7.4). African-American ethnicity remained a significant risk factor for peripartum cardiomyopathy when other risk factors were considered in multivariable (OR: 31.5, 95% CI: 3.6 to 277.6) and stratified analyses (OR: 12.9 to 29.1, p < 0.001). Although the frequency of peripartum cardiomyopathy (185 of 100,000 deliveries) at this center was higher than in previous U.S. reports, it was comparable to the frequency in countries with more women of African descent (100 to 980 of 100,000). Analysis of other U.S. studies confirmed that the frequency of peripartum cardiomyopathy was significantly higher among African American women. CONCLUSIONS: African-American women have significantly higher odds of having peripartum cardiomyopathy that could not be explained by several other factors. Further research will be necessary to determine the potential environmental and/or genetic factors associated with African descent that confer this risk. PMID- 20170792 TI - Endothelial function, carotid-femoral stiffness, and plasma matrix metalloproteinase-2 in men with bicuspid aortic valve and dilated aorta. AB - OBJECTIVES: This study sought to examine the relationship between proximal aortic dilation and systemic vascular function in men with bicuspid aortic valve (BAV). BACKGROUND: Proximal aortic dilation in subjects with BAV is associated with structural and functional abnormalities in the ascending aorta. METHODS: We studied 32 men (median age 31 years [range 28 to 32 years]) with nonstenotic BAV categorized into 2 subgroups according to proximal ascending aorta dimensions (nondilated or=40 mm, respectively). Sixteen healthy men were studied as control subjects. Flow-mediated dilation in response to hyperemia (a marker of endothelial dysfunction) and carotid-femoral pulse wave velocity (an index of aortic stiffness) were assessed, and peripheral blood was sampled for matrix metalloproteinases (MMP-2 and -9) and their tissue inhibitors (TIMP-1 and 2), respectively. Cardiac chamber and aortic dimensions were assessed by echocardiography and cardiac magnetic resonance imaging, respectively. RESULTS: Despite the similar severity of aortic stenosis, left ventricular mass, and function, men with dilated aortas had blunted brachial flow-mediated vasodilation to hyperemia (5% [interquartile range (IQR) 4% to 6%] vs. 8% [IQR 7% to 9%] change, p = 0.001), higher carotid-femoral pulse wave velocity (9.3 cm/s [IQR 9 to 10 cm/s] vs. 7 cm/s [IQR 6.9 to 7.4 cm/s], p = 0.001), and significantly higher plasma levels of MMP-2 (1,523 [IQR 1,460 to 1,674] vs. 1,036 [IQR 962 to 1,167], p = 0.001) compared with men with BAV and nondilated aorta. Values for MMP-9, TIMP-1 and -2 levels, and nitroglycerin-induced (endothelium-independent) vasodilation were similar in all 3 groups. CONCLUSIONS: Young men with BAV and dilated proximal aortas manifest systemic endothelial dysfunction, increased carotid-femoral pulse wave velocity, and higher plasma levels of MMP-2. These observations could introduce new targets for screening and perhaps for therapeutic intervention. PMID- 20170793 TI - Bicuspid aortic valve disease beyond the aortic root: potential prognostic implications for ascending aortic dilation. PMID- 20170795 TI - Neglected cardiovascular diseases in Africa: challenges and opportunities. PMID- 20170796 TI - The year in heart failure. PMID- 20170797 TI - Multidetector computed tomography images of right aortic arch and a left subclavian artery arising from a Kommerell diverticulum. PMID- 20170794 TI - Increased oxidative stress and cardiomyocyte myofibrillar degeneration in patients with chronic isolated mitral regurgitation and ejection fraction >60%. AB - OBJECTIVES: This study assessed myocardial damage in patients with chronic isolated mitral regurgitation (MR) and left ventricular ejection fraction (LVEF) >60%. BACKGROUND: Typically, MR patients have decreased LVEF after mitral valve (MV) repair despite normal pre-operative LVEF. METHODS: Twenty-seven patients with isolated MR had left ventricular (LV) biopsies taken at time of MV repair. Magnetic resonance imaging with tissue tagging was performed in 40 normal subjects and in MR patients before and 6 months after MV repair. RESULTS: LVEF (66 +/- 5% to 54 +/- 9%, p < 0.0001) and LV end-diastolic volume index (108 +/- 28 ml/m(2) to 78 +/- 24 ml/m(2), p < 0.0001) decreased, whereas left ventricular end-systolic (LVES) volume index was 60% above normal pre- and post-MV repair (p < 0.05). The LV circumferential and longitudinal strain rates decreased below normal following MV repair (6.38 +/- 1.38 vs. 5.11 +/- 1.28, p = 0.0009, and 7.51 +/- 2.58 vs. 5.31 +/- 1.61, percentage of R to R interval, p < 0.0001), as LVES stress/LVES volume index ratio was depressed at baseline and following MV repair versus normal subjects (0.25 +/- 0.10 and 0.28 +/- 0.05 vs. 0.33 +/- 0.12, p < 0.01). LV biopsies demonstrated cardiomyocyte myofibrillar degeneration versus normal subjects (p = 0.035). Immunostaining and immunoblotting demonstrated increased xanthine oxidase in MR versus normal subjects (p < 0.05). Lipofuscin deposition was increased in cardiomyocytes of MR versus normal subjects (0.62 +/- 0.20 vs. 0.33 +/- 0.11, percentage of area: p < 0.01). CONCLUSIONS: Decreased LV strain rates and LVES wall stress/LVES volume index following MV repair indicate contractile dysfunction, despite pre-surgical LVEF >60%. Increased oxidative stress could cause myofibrillar degeneration and lipofuscin accumulation resulting in LV contractile dysfunction in MR. PMID- 20170798 TI - Radicalized physicians. PMID- 20170799 TI - Pre-morbid psychiatric and cardiovascular diseases in apical ballooning syndrome (tako-tsubo/stress-induced cardiomyopathy): potential pre-disposing factors? PMID- 20170800 TI - Further barriers to conversations about deactivation of implantable cardioverter defibrillators. PMID- 20170802 TI - A closer look at incidental findings on cardiac computed tomography. PMID- 20170804 TI - Reversible magnetic resonance diffusion-weighted abnormalities in takotsubo cardiomyopathy. PMID- 20170805 TI - Impact of genetic discoveries on the classification of lone atrial fibrillation. AB - Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, represents a major burden to patients and health care systems through its sequelae of heart failure and stroke. Its age-dependent increase in prevalence has led to worrisome predictions of an expanding burden secondary to our aging population. This growing epidemic is further exacerbated by a current lack of highly effective therapies for the arrhythmia stemming from our incomplete understanding of its complex pathophysiology. Recent genetic studies, triggered in part by evidence of a hereditary component of AF, have begun to identify predisposing genes and offer further insights into the mechanisms of lone AF. A variety of ion channels and most recently a circulating hormone have been implicated. The apparent genetic diversity underlying the arrhythmia has served to emphasize the heterogeneity of factors that govern its initiation and maintenance. The different causative genes seem to predispose to AF through distinct putative mechanisms, including enhanced and delayed atrial action potential repolarization, cellular hyperexcitability, and conduction velocity heterogeneity. Classification of lone AF into mechanistic subgroups serves to emphasize its heterogeneity and has the potential to guide developmental and clinical treatment strategies. The frequent recalcitrant nature of the arrhythmia to contemporary pharmacological and invasive therapies may be overcome through an ability to identify, through genetics, the mechanistic subclass of AF for an individual patient. Proper identification of the culprit pathophysiology may permit administration of a targeted form of therapy that carries maximal efficacy and minimal risk in a manner consistent with the vision of pharmacogenomics. PMID- 20170806 TI - The ROSE (risk stratification of syncope in the emergency department) study. AB - OBJECTIVES: The aim of this study was to develop and validate a clinical decision rule (CDR) to predict 1-month serious outcome and all-cause death in patients presenting with syncope to the emergency department. BACKGROUND: Syncope is a common, potentially serious condition accounting for many hospital admissions. METHODS: This was a single center, prospective, observational study of adults presenting to the emergency department with syncope. A CDR was devised from 550 patients in a derivation cohort and tested in a validation cohort of a further 550 patients. RESULTS: One-month serious outcome or all-cause death occurred in 40 (7.3%) patients in the derivation cohort. Independent predictors were brain natriuretic peptide concentration > or =300 pg/ml (odds ratio [OR]: 7.3), positive fecal occult blood (OR: 13.2), hemoglobin < or =90 g/l (OR: 6.7), oxygen saturation < or =94% (OR: 3.0), and Q-wave on the presenting electrocardiogram (OR: 2.8). One-month serious outcome or all-cause death occurred in 39 (7.1%) patients in the validation cohort. The ROSE (Risk stratification Of Syncope in the Emergency department) rule had a sensitivity and specificity of 87.2% and 65.5%, respectively, and a negative predictive value of 98.5%. An elevated B-type natriuretic peptide (BNP) concentration alone was a major predictor of serious cardiovascular outcomes (8 of 22 events, 36%) and all-cause deaths (8 of 9 deaths, 89%). CONCLUSIONS: The ROSE rule has excellent sensitivity and negative predictive value in the identification of high-risk patients with syncope. As a component, BNP seems to be a major predictor of serious cardiovascular outcomes and all-cause death. The ROSE rule and BNP measurement might be valuable risk stratification tools in patients with emergency presentations of syncope and should now be subjected to external validation. PMID- 20170807 TI - Initial evaluation of "syncope and collapse" the need for a risk stratification consensus. PMID- 20170808 TI - Progression from paroxysmal to persistent atrial fibrillation clinical correlates and prognosis. AB - OBJECTIVES: We investigated clinical correlates of atrial fibrillation (AF) progression and evaluated the prognosis of patients demonstrating AF progression in a large population. BACKGROUND: Progression of paroxysmal AF to more sustained forms is frequently seen. However, not all patients will progress to persistent AF. METHODS: We included 1,219 patients with paroxysmal AF who participated in the Euro Heart Survey on AF and had a known rhythm status at follow-up. Patients who experienced AF progression after 1 year of follow-up were identified. RESULTS: Progression of AF occurred in 178 (15%) patients. Multivariate analysis showed that heart failure, age, previous transient ischemic attack or stroke, chronic obstructive pulmonary disease, and hypertension were the only independent predictors of AF progression. Using the regression coefficient as a benchmark, we calculated the HATCH score. Nearly 50% of the patients with a HATCH score >5 progressed to persistent AF compared with only 6% of the patients with a HATCH score of 0. During follow-up, patients with AF progression were more often admitted to the hospital and had more major adverse cardiovascular events. CONCLUSIONS: A substantial number of patients progress to sustained AF within 1 year. The clinical outcome of these patients regarding hospital admissions and major adverse cardiovascular events was worse compared with patients demonstrating no AF progression. Factors known to cause atrial structural remodeling (age and underlying heart disease) were independent predictors of AF progression. The HATCH score may help to identify patients who are likely to progress to sustained forms of AF in the near future. PMID- 20170809 TI - Progression of paroxysmal to persistent atrial fibrillation factors promoting the HATCH score. PMID- 20170810 TI - The risk of thromboembolism and need for oral anticoagulation after successful atrial fibrillation ablation. AB - OBJECTIVES: The aim of this multicenter study was to evaluate the safety of discontinuing oral anticoagulation therapy (OAT) after apparently successful pulmonary vein isolation. BACKGROUND: Atrial fibrillation (AF) is associated with an increased risk of thromboembolic events (TE) and often requires OAT. Pulmonary vein isolation is considered an effective treatment for AF. METHODS: We studied 3,355 patients, of whom 2,692 (79% male, mean age 57 +/- 11 years) discontinued OAT 3 to 6 months after ablation (Off-OAT group) and 663 (70% male, mean age 59 +/- 11 years) remained on OAT after this period (On-OAT group). CHADS(2) (congestive heart failure, hypertension, age [75 years and older], diabetes mellitus, and a history of stroke or transient ischemic attack) risk scores of 1 and > or =2 were recorded in 723 (27%) and 347 (13%) Off-OAT group patients and in 261 (39%) and 247 (37%) On-OAT group patients, respectively. RESULTS: During follow-up (mean 28 +/- 13 months vs. 24 +/- 15 months), 2 (0.07%) Off-OAT group patients and 3 (0.45%) On-OAT group patients had an ischemic stroke (p = 0.06). No other thromboembolic events occurred. No Off-OAT group patient with a CHADS(2) risk score of > or =2 had an ischemic stroke. A major hemorrhage was observed in 1 (0.04%) Off-OAT group patient and 13 (2%) On-OAT group patients (p < 0.0001). CONCLUSIONS: In this nonrandomized study, the risk-benefit ratio favored the suspension of OAT after successful AF ablation even in patients at moderate-high risk of TE. This conclusion needs to be confirmed by future large randomized trials. PMID- 20170811 TI - Do not stop the warfarin until ... PMID- 20170812 TI - Chromosome 4q25 variants and atrial fibrillation recurrence after catheter ablation. AB - OBJECTIVES: This study tested the hypothesis that chromosome 4q25 single nucleotide polymorphisms (SNPs) associate with atrial fibrillation (AF) recurrence after catheter ablation. BACKGROUND: Recent genome-wide association studies identified 2 SNPs on chromosome 4q25 associated with AF. Although the mechanisms underlying this increased risk are unknown, the closest gene, PITX2, is critical for myocardium development in the pulmonary veins. METHODS: A total of 195 consecutive patients (mean age 56 +/- 12 years, 73% male) with drug refractory paroxysmal (78%) or persistent (22%) AF who underwent AF catheter ablation were included. Two SNPs, rs2200733 and rs10033464, were genotyped using real-time polymerase chain reaction and fluorescence resonance energy transfer. Serial 7-day Holter electrocardiographic recordings were acquired to detect AF recurrences. RESULTS: Early recurrence of atrial fibrillation (ERAF) (within the first 7 days) was observed in 37%, whereas late recurrence of atrial fibrillation (LRAF) (between 3 and 6 months) occurred in 21% of the patients. None of the clinical or echocardiographic baseline characteristics were associated with ERAF or LRAF. In contrast, the presence of any variant allele increased the risk for both ERAF (odds ratio [OR]: 1.994, 95% confidence interval [CI]: 1.036 to 3.837, p = 0.039) and LRAF (OR: 4.182, 95% CI: 1.318 to 12.664, p = 0.011). In patients with ERAF, 45% had LRAF, as opposed to 8% in patients without ERAF (OR: 9.274, 95% CI: 3.793 to 22.678, p < 0.001). CONCLUSIONS: Polymorphisms on chromosome 4q25 modulate the risk for AF recurrence after catheter ablation. This finding points to a potential role for stratification of AF ablation therapy or peri interventional management by genotype. PMID- 20170813 TI - Genetic mutations as risk predictors of atrial fibrillation recurrence after catheter ablation? PMID- 20170814 TI - Increased expression of mineralocorticoid receptor in human atrial fibrillation and a cellular model of atrial fibrillation. AB - OBJECTIVES: This study was designed to evaluate the status of steroidogenesis proteins and de novo synthesis of aldosterone in the atrium, and relationships of these factors to atrial fibrillation (AF). BACKGROUND: The role of mineralocorticoid in the pathogenesis of AF is unknown. METHODS: We studied atrial expression of steroidogenesis proteins and aldosterone level in patients with and without AF, and in HL-1 atrial myocytes. We also investigated the electrophysiologic effects and signal transduction of aldosterone on atrial myocytes. RESULTS: We found basal expressions of mineralocorticoid receptors (MRs), glucocorticoid receptors, and 11-beta-hydroxysteroid dehydrogenase type 2 (11bHSD2) but not 11-beta-hydroxylase (CYP11B1) or aldosterone synthase (CYP11B2) in human atria and HL-1 myocytes. There was no significant difference of mean atrial aldosterone level between patients with AF and those with normal sinus rhythm. However, patients with AF had a significantly higher atrial MR expression compared with those with normal sinus rhythm (1.73 +/- 0.24-fold, p < 0.001). Using mouse HL-1 atrial myocytes as a cellular AF model, we found that rapid depolarization increased MR expression (1.97 +/- 0.72-fold, p = 0.008) through a calcium-dependent mechanism, thus augmenting the genomic effect of aldosterone signaling as evaluated by MR reporter. Aldosterone increased intracellular oxidative stress through a nongenomic pathway, which was attenuated by nicotinamide adenine dinucleotide phosphate oxidase inhibitor diphenyleneiodonium, but not by MR-blockade spironolactone. Aldosterone increased expression of the alpha-1G and -1H subunits of the T-type calcium channel and thus increased the T-type calcium current (-13.6 +/- 2.9 pA/pF vs. -4.5 +/- 1.6 pA/pF, p < 0.01) and the intracellular calcium load through a genomic pathway, which were attenuated by spironolactone, but not by diphenyleneiodonium. CONCLUSIONS: Expression of MR increased in AF, thus augmenting the genomic effects of aldosterone. Aldosterone induced atrial ionic remodeling and calcium overload through a genomic pathway, which was attenuated by spironolactone. These results suggest that aldosterone may play a role in AF electrical remodeling and provide insight into the treatment of AF with MR blockade. PMID- 20170815 TI - Aldosterone signaling in atrial fibrillation another piece in the puzzle of atrial remodeling. PMID- 20170816 TI - Evaluation of early complications related to De Novo cardioverter defibrillator implantation insights from the Ontario ICD database. AB - OBJECTIVES: This study examined the predictors of early complications after defibrillator implantation. BACKGROUND: Although implantable cardioverter defibrillators are widely used, predictors of procedural complications and the consequences of these events have not been determined. METHODS: In a prospective, multicenter, population-based clinical outcomes registry of all newly implanted defibrillator patients at 18 centers in Ontario, Canada, we examined 45-day complications and all-cause mortality from February 2007 to May 2009. Complications were determined longitudinally and were categorized as direct implant-related or indirect events. RESULTS: Among 3,340 patients (mean age 63.8 +/- 12.5 years, 78.5% men), major complications occurred in 4.1% of de novo procedures. Compared with those undergoing a single-chamber device, implantation of a cardiac resynchronization defibrillator (adjusted hazard ratio [HR]: 2.17, 95% confidence interval [CI]: 1.38 to 3.43, p < 0.001) or dual-chamber device (adjusted HR: 1.82, 95% CI: 1.19 to 2.79, p = 0.006) was associated with increased risk of major complications. Major complications were increased in women (adjusted HR: 1.49, 95% CI: 1.02 to 2.16, p = 0.037) and when left ventricular end-systolic dimension exceeded 45 mm (adjusted HR: 1.54, 95% CI: 1.08 to 2.20, p = 0.018). Major complications (excluding death) occurring early after defibrillator implantation were associated with increased adjusted risk of subsequent death up to 180 days after defibrillator implant (adjusted HR: 3.70, 95% CI: 1.64 to 8.33, p = 0.002). Direct implant-related complications were associated with increased risk of early death (adjusted HR: 24.89, p = 0.01), whereas indirect clinical complications conferred increased risk of near-term death (adjusted HR: 12.35, p < 0.001) after defibrillator implantation. CONCLUSIONS: Complications after de novo defibrillator implantation were strongly associated with device type. Major complications were associated with increased risk of mortality. PMID- 20170817 TI - Risk of fatal arrhythmic events in long QT syndrome patients after syncope. AB - OBJECTIVES: The aim of this study was to identify risk factors for fatal arrhythmias in long QT syndrome (LQTS) patients presenting with syncope. BACKGROUND: Syncope is highly predictive for future fatal arrhythmias in the LQTS. However, there are no data regarding risk stratification and management strategies in the high-risk subset of LQTS patients presenting with syncope. METHODS: A total of 1,059 LQTS patients with a corrected QT interval > or =450 ms presenting with syncope as a first symptom were drawn from the International LQTS Registry. Cox proportional hazards regression was used to identify risk factors for a severe arrhythmic events comprising aborted cardiac arrest, appropriate implantable cardioverter-defibrillator therapy, and sudden cardiac death. RESULTS: The lowest risk was found in patients with only 1 syncopal episode occurring before the start of beta-blocker therapy. In contrast, patients experiencing syncope after starting beta-blocker therapy had a 3.6-fold increase in the risk of severe arrhythmic events (p < 0.001) relative to this low-risk group and displayed a risk of severe arrhythmic events similar to that of patients not treated with beta-blockers. Multiple syncopal episodes occurring before initiation of beta-blocker therapy were associated with an intermediate risk (hazard ratio: 1.8, p < 0.001). The risk of syncope during beta-blocker therapy is high during childhood in both sexes but is higher in women than in men (hazard ratio: 2.3, p < 0.001). CONCLUSIONS: Patients with syncope during beta blocker therapy are at high risk of life-threatening events, and implantable cardioverter-defibrillator therapy should be considered in these patients. The risk of beta-blocker failure is highest in young children and in women. PMID- 20170818 TI - Local depolarization abnormalities are the dominant pathophysiologic mechanism for type 1 electrocardiogram in brugada syndrome a study of electrocardiograms, vectorcardiograms, and body surface potential maps during ajmaline provocation. AB - OBJECTIVES: We sought to obtain new insights into the pathophysiologic basis of Brugada syndrome (BrS) by studying changes in various electrocardiographic depolarization and/or repolarization variables that occurred with the development of the signature type 1 BrS electrocardiogram (ECG) during ajmaline provocation testing. BACKGROUND: BrS is associated with sudden cardiac death. Its pathophysiologic basis, although unresolved, is believed to reside in abnormal cardiac depolarization or abnormal repolarization. METHODS: Ajmaline provocation was performed in 269 patients suspected of having BrS with simultaneous recording of ECGs, vectorcardiograms, and 62-lead body surface potential maps. RESULTS: A type 1 ECG was elicited in 91 patients (BrS patients), 162 patients had a negative test result (controls), and 16 patients had an abnormal test result. Depolarization abnormalities were more prominent in BrS patients and were mapped to the right ventricle (RV) by longer right precordial filtered QRS complex durations (142 +/- 23 ms vs. 125 +/- 14 ms, p < 0.01) and right terminal conduction delay (60 +/- 11 ms vs. 53 +/- 9 ms, p < 0.01). Repolarization abnormalities remained concordant with depolarization abnormalities as indicated by steady low nondipolar content (12 +/- 8% vs. 8 +/- 4%, p = NS), lower spatial QRS-T integrals (33 +/- 12 mV.ms vs. 40 +/- 16 mV.ms, p < 0.05), similar spatial QRS-T angles (92 +/- 39 degrees vs. 87 +/- 31 degrees , p = NS), similar T(peak) T(end) interval (143 +/- 36 ms vs. 138 +/- 25 ms, p = NS), and similar T(peak) T(end) dispersion (47 +/- 37 ms vs. 45 +/- 27 ms, p = NS). CONCLUSIONS: The type 1 BrS ECG is characterized predominantly by localized depolarization abnormalities, notably (terminal) conduction delay in the RV, as assessed with complementary noninvasive electrocardiographic techniques. We could not define a separate role for repolarization abnormalities but suggest that the typical signs of repolarization derangements seen on the ECG are secondary to these depolarization abnormalities. PMID- 20170819 TI - J-wave syndromes caused by repolarization or depolarization mechanisms a debated issue among experimental and clinical electrophysiologists. PMID- 20170821 TI - Maintenance of long-term clinical benefit with sirolimus-eluting stents in patients with ST-segment elevation myocardial infarction 3-year results of the SESAMI (sirolimus-eluting stent versus bare-metal stent in acute myocardial infarction) trial. AB - OBJECTIVES: The aim of this study was to investigate whether the reported favorable 1-year outcome of the sirolimus-eluting stent (SES) versus the bare metal stent (BMS) in the SESAMI (Sirolimus-Eluting Stent Versus Bare-Metal Stent In Acute Myocardial Infarction) trial, in the setting of ST-segment elevation myocardial infarction (STEMI), is maintained at 3-year follow-up. BACKGROUND: At present, only long-term registry data, but not randomized trials, on the safety and effectiveness of SES in STEMI patients are available. METHODS: Overall, 320 STEMI patients were randomized to receive SES or BMS. The primary end point was the incidence of major adverse cardiovascular events (MACE), at 3-year follow-up. The secondary end points were the rate of target lesion revascularization (TLR) and target vessel revascularization (TVR) and target vessel failure (TVF). The incidence of late events, starting from clopidogrel withdrawal, was also investigated. RESULTS: The 3-year incidence of MACE was lower in the SES group compared with the BMS group (12.7% vs. 21%, p = 0.034), as were TLR (7% vs. 13.5%, p = 0.048), TVR (8% vs. 16%, p = 0.027), and TVF (11.5% vs. 20.5%, p = 0.028) rates. The 3-year survival rate free from MACE, TLR, and TVF was significantly higher in the SES group than in the BMS group (87%, 93%, and 89.5% vs. 79%, 86.5%, and 79.5%, respectively, p < 0.05). The lower incidence of adverse events in the SES group was driven by TLR reduction and achieved in the first year of follow-up. The cumulative incidence of death and recurrent myocardial infarction, starting from clopidogrel discontinuation, was comparable in the 2 groups. CONCLUSIONS: The clinical benefits of SES have been shown to be greater than those of BMS at 3-year follow-up. PMID- 20170820 TI - Late na(+) current inhibition by ranolazine reduces torsades de pointes in the chronic atrioventricular block dog model. AB - OBJECTIVES: This study investigated whether ranolazine reduces dofetilide-induced torsades de pointes (TdP) in a model of long QT syndrome with down-regulated K(+) currents due to hypertrophic remodeling in the dog with chronic atrioventricular block (cAVB). BACKGROUND: Ranolazine inhibits the late Na(+) current (I(NaL)) and is effective against arrhythmias in long QT3 syndromes despite its blocking properties of the rapid component of delayed rectifying potassium current. METHODS: Ranolazine was administered to cAVB dogs before or after TdP induction with dofetilide and electrophysiological parameters were determined including beat-to-beat variability of repolarization (BVR). In single ventricular myocytes, effects of ranolazine were studied on I(NaL), action potential duration, and dofetilide-induced BVR and early afterdepolarizations. RESULTS: After dofetilide, ranolazine reduced the number of TdP episodes from 10 +/- 3 to 3 +/- 1 (p < 0.05) and partially reversed the increase of BVR with no abbreviation of the dofetilide induced QT prolongation. Likewise, pre-treatment with ranolazine, or using lidocaine as a specific Na(+) channel blocker, attenuated TdP, but failed to prevent dofetilide-induced increases in QT, BVR, and ectopic activity. In cAVB myocytes, ranolazine suppressed dofetilide-induced early afterdepolarizations in 25% of cells at 5 micromol/l, in 75% at 10 micromol/l, and in 100% at 15 micromol/l. At 5 micromol/l, ranolazine blocked 26 +/- 3% of tetrodotoxin sensitive I(NaL), and 49 +/- 3% at 15 micromol/l. Despite a 54% reduction of I(NaL) amplitude in cAVB compared with control cells, I(NaL) inhibition by 5 micromol/l tetrodotoxin equally shortened relative action potential duration and completely abolished dofetilide-induced early afterdepolarizations. CONCLUSIONS: Despite down-regulation of I(NaL) in remodeled cAVB hearts, ranolazine is antiarrhythmic against drug-induced TdP. The antiarrhythmic effects are reflected in concomitant changes of BVR. PMID- 20170822 TI - Slow response to clopidogrel predicts low response. AB - OBJECTIVES: The purpose of this study was to determine whether the speed of response to clopidogrel loading predicts the final degree of response. BACKGROUND: Fast inhibition of platelet aggregation is important in the setting of acute coronary syndromes and percutaneous coronary intervention, but its association with the final degree of inhibition is not well established. METHODS: We performed a post hoc analysis of the ALBION study; early kinetic profiles of adenosine diphosphate 20 micromol/l maximal platelet aggregation (MPA) and DeltaMPA (with baseline sample as reference) were studied at 8 time points within the 24 h after clopidogrel loading (300, 600, or 900 mg) in non-ST-segment elevation acute coronary syndrome patients. Low response was defined as DeltaMPA <10% over the first 24 h, fast response as DeltaMPA > or =10% at 1 h or before loading (the others being slow responders), and high post-treatment platelet reactivity as MPA > or =56.56% (fourth quartile). Inflammatory markers (PAC-1 and P-selectin) and vasodilator-stimulated phosphoprotein (VASP) were also evaluated according to onset of action. RESULTS: Fifty-five percent of patients were slow responders. Noncurrent smoking and body mass index > or =25 kg/m(2) were associated with slower and lower responses. High post-treatment platelet reactivity was more frequent in slow responders (28% vs. 14%, p < 0.0001). There was a clopidogrel dose-effect relationship on DeltaMPA, with a trend toward faster onset of platelet inhibition in the 900-mg loading dose group. Slow responders had a slower and lower decrease in PAC-1 and P-selectin and higher VASP index at 6 h (76.5% vs. 66.4%, p = 0.019) and 24 h (70.3% vs. 61.5%, p = 0.049). CONCLUSIONS: Slow response to clopidogrel, within the first hour of administration, is a reliable marker of low response at 24 h and high post treatment platelet reactivity. PMID- 20170823 TI - Updated meta-analysis of septal alcohol ablation versus myectomy for hypertrophic cardiomyopathy. AB - OBJECTIVES: The purpose of this study was to perform a systematic review and meta analysis of comparative studies to compare outcomes of septal ablation (SA) with septal myectomy (SM) for treatment of hypertrophic obstructive cardiomyopathy (HOCM). BACKGROUND: SM is considered the gold standard for treatment of HOCM. However, SA has emerged as an attractive therapeutic alternative. METHODS: A Medline search using standard terms was conducted to determine eligible studies. Due to a lack of randomized control trials, we included observational studies for review. RESULTS: Twelve studies were found eligible for review. No significant differences between short-term (risk difference [RD]: 0.01; 95% confidence interval [CI]: -0.01 to 0.03) and long-term mortality (RD: 0.02; 95% CI: -0.05 to 0.09) were found between the SA and SM groups. In addition, no significant differences could be found in terms of post-intervention functional status as well as improvement in New York Heart Association functional class, ventricular arrhythmia occurrence, re-interventions performed, and post-procedure mitral regurgitation. However, SA was found to increase the risk of right bundle branch block (RBBB) (pooled odds ratio [OR]: 56.3; 95% CI: 11.6 to 273.9) along with need for permanent pacemaker implantation post-procedure (pooled OR: 2.6; 95% CI: 1.7 to 3.9). Although the efficacy of both SA and SM in left ventricular outflow tract gradient (LVOTG) reduction seems comparable, there is a small yet significantly higher residual LVOTG amongst the SA group patients as compared with the SM group patients. CONCLUSION: SA does seem to show promise in treatment of HOCM owing to similar mortality rates as well as functional status compared with SM; however, the caveat is increased conduction abnormalities and a higher post-intervention LVOTG. The choice of treatment strategy should be made after a thorough discussion of the procedures with the individual patient. PMID- 20170824 TI - Multimodality imaging of right atrial masses. PMID- 20170826 TI - No laughing matter. PMID- 20170827 TI - Cardiology workforce crisis shortage or surplus? PMID- 20170828 TI - Reply. PMID- 20170829 TI - [More male nurses in the health care centers]. PMID- 20170830 TI - [Care quality in intensive care evaluated by the patients using a service quality scale (SERVQUAL)]. AB - INTRODUCTION: The evaluation made by the patients on the quality of service received is important to introduce improvement strategies in the care quality. OBJECTIVES: 1. To evaluate the care quality through the analysis of the differences obtained between expectations and perceptions, that the patients have of the service received in the ICU. 2. To analyze if there is any relationship between care quality evaluated by the patients and the sociodemographic variables. METHOD: A total of 86 patients who were conscious and oriented during their stay in the ICU were studied prospectively. At 24h of the discharge from the ICU, the SERVQUAL (Service Quality) scale, adapted for the hospital setting by Babakus and Mangold (1992), was applied. This scale measures the care quality based on the difference in scores obtained between expectations and perceptions of the patients. The positive scores indicate that the perceptions of the patients exceed their expectations. The scale has 5 dimensions: Tangibility, Reliability, Responsiveness, Assurances and Empathy. It includes 15 items for perceptions and the same for expectations, with 5 grades of response (1 totally disagree - 5 totally agree). RESULTS: The mean score of perceptions 66.92) exceeded that of the expectations (62.30). The mean score of the difference between perceptions and expectations for the total of the SERVQUAL scale was 4.62. It was also positive for each one of the dimensions: Tangibility=1.44, Reliability=0.53, Responsiveness=0.95, Assurances=0.99, Empathy=0.71. No statistically significant associations were found between care quality evaluated by the patients and the sociodemographic variables. CONCLUSION: The care quality perceived by the patients in the ICU exceeds their expectations, and had no relationship with the sociodemographic characteristics. PMID- 20170831 TI - [Improving the care of critical patient family members: Agreed on strategies]. AB - INTRODUCTION: Within the context of participatory action research (PAR), a 4 stage process was established with the general aim of promoting improvements in the care offered to families of patients in the Intensive Care Unit (ICU). The 4 stages consisted of a situational diagnosis, proposals for change, the design and implementation of the proposals, and an evaluation. This paper presents the first 2 stages. OBJECTIVES: To define the attention given to families of patients in the Intensive Care Unit. To reach a consensus on areas for action/intervention in the unit. MATERIALS AND METHOD: A qualitative methodology. DESIGN: PAR. Data collection technique: 4 focus groups made up of 10 professionals, and consensus with support groups made up of 30 members. Content analysis was performed. The theoretical saturation point was reached. RESULTS: Two documents were drawn up: 1) A situational diagnosis, describing the current situation of the attention given to families and 2) 10 proposals for change, 5 of which were given priority. They were: a session to familiarize professionals with evidence concerning families of patients in the ICU and the handing out of informative leaflets, the improvement of (nurse-family and intra-team) informative procedures, more privacy for patients and a reduction in environmental noise, a training plan for professionals, and change in the visiting policy. CONCLUSION: By using consensus based methodologies, strategies for change can be prioritized and designed, adapted to the context in which they will be applied. PMID- 20170832 TI - [Development of an attention guideline for the critical patient's family]. AB - INTRODUCTION: Within the context of participatory action research (PAR) at an Intensive Care Unit (ICU), 4 proposals for change were agreed by consensus to improve the attention given to families of critical patients. One proposal was the creation of a guideline for attending to family members, inspired by the participants' desire to improve the attention given to this group of users. OBJECTIVES: 1) To design a guide that would meet the needs of professionals and users. 2) To reach an agreement on the minimum requirements for attention given to families of critical patients. MATERIALS AND METHODS: Qualitative methodology, based on PAR. For each of the initiatives, a working group was created, composed mainly of professionals from the ICU coordinated by a researcher. In the case of the guide, an online community was also created as a working tool to speed up communications among the participants, reducing the number of face-to-face sessions. Participation was voluntary. To draft the guideline, a Clinical Practice Guideline for support the family was made available, which had been translated into Spanish, together with an up-to-date bibliography. RESULTS: Twenty four professionals were involved. We developed a guide that contained the following sections: introduction, objectives, the experiences and needs of families of patients in the ICU, strategies for action, specific procedures, and hospital resources. We designed strategies for the diffusion and implementation of the guide. CONCLUSIONS: The guide is a useful tool that offers the professionals greater assurances and unifying criteria for action. During subsequent stages of the PAR project, an assessment will be made of the impact on professionals and users. PMID- 20170834 TI - Antiepileptic drugs: the drawbacks of generic substitution. PMID- 20170833 TI - [Pressure monitoring in continuous renal replacement therapy]. AB - INTRODUCTION: Continuous renal replacement therapy (CRRT) has experienced significant advances that have lead to an increase of its indications and improved the technology used in continued pressures monitoring. AIM: This study has aimed to discover if there are any associations between the increase of the circuit pressures and their duration. MATERIALS AND METHODS: A prospective, longitudinal analytic pilot study was conducted in an Intensive Care Unit of a university hospital from October 2008 to April 2009. The study analyzed the patient's information with CRRT and the hourly values of entry pressure (EP), comeback pressure (CP), transmembrane pressure (TMP) and pre-filter pressure (PFP). The Spearman correlation and the Student's T test were used. RESULTS: The study analyzed 44 sets corresponding to 11 patients (45.5% men and 54.5% women) with a life expectancy of 62 years. The same light catheter GamCath (11 French) and Continuous Venovenous Hemodiafiltration (CVVHDF) therapy were used in all patients. The mean duration of the circuits was 39 h. Mean, median, maximum and minimum values of the sample pressures were: EP:-52.17; -52.57; 160; -256 (millimeters of mercury) mmHg]; CP: (98.6; 95.3; 323; -2 mmHg); TMP: (58.57; 58.52; 245; -20 mmHg) and PFP: (161.76; 159.42; 375; -13 mmHg), respectively. CONCLUSIONS: A negative correlation was demonstrated between the duration of the sets and the mean CP and PFP. The sample obtained circuits withdrawn due to finished treatment (72 h), and by coagulation or changes in pressures. PMID- 20170835 TI - Gluten sensitivity: an emerging issue behind neurological impairment? PMID- 20170836 TI - Tarenflurbil for Alzheimer's disease: a "shot on goal" that missed. PMID- 20170838 TI - The human connectome: just another 'ome? PMID- 20170839 TI - Max Wiznitzer: ever hopeful, ever happy. PMID- 20170841 TI - Antithrombotic drugs for patients with ischaemic stroke and transient ischaemic attack to prevent recurrent major vascular events. AB - Aspirin is widely used for the prevention of recurrent stroke in patients with transient ischaemic attack (TIA) and ischaemic stroke of arterial origin, because it is effective and inexpensive. Clopidogrel and the combination of aspirin and extended-release dipyridamole are more effective than aspirin, but are also much more expensive. No other antithrombotic regimens provide significant advantages over aspirin, although cilostazol and the novel platelet protease activated receptor-1 antagonist, SCH 530348, are currently being evaluated. For patients with TIA and ischaemic stroke of cardiac origin due to atrial fibrillation, vitamin K antagonists (VKAs) are highly effective in preventing recurrent ischaemic stroke but have important limitations and are thus underused. Antiplatelet therapy is much less effective than VKAs. The direct thrombin inhibitor, dabigatran etexilate, has shown efficacy over warfarin in a recent trial. Other new anticoagulants, including the oral factor Xa inhibitors, rivaroxaban, apixaban, and edoxaban, the parenteral factor Xa inhibitor, idrabiotaparinux, and the novel VKA, tecarfarin, are currently being assessed. PMID- 20170842 TI - Current practice and future directions in the prevention and acute management of migraine. AB - Migraine is a common and disabling brain disorder with a strong inherited component. Because patients with migraine have severe and disabling attacks usually of headache with other symptoms of sensory disturbance (eg, light and sound sensitivity), medical treatment is often required. Patients can be managed by use of acute attack therapies (eg, simple analgesics or non-steroidal anti inflammatory drugs) or specific agents with vasoconstrictor properties (ie, triptans or ergot derivatives). Future non-vasoconstrictor approaches include calcitonin gene-related peptide receptor antagonists. Preventive therapy is probably indicated in about a third of patients with migraine, and a broad range of pharmaceutical and non-pharmaceutical options exist. Medication overuse is an important concern in migraine therapeutics and needs to be identified and managed. In most patients, migraine can be improved with careful attention to the details of therapy, and in those for whom it cannot, neuromodulation approaches, such as occipital nerve stimulation, are currently being actively studied and offer much promise. PMID- 20170843 TI - Combination therapy in multiple sclerosis. AB - Multiple sclerosis (MS) is an autoimmune disease of the CNS. It is the most common non-traumatic cause of neurological disability among young adults in western Europe and North America. Existing MS therapies are partly effective in halting ongoing inflammatory tissue damage and clinical progression. MS pathogenesis is complex and probably heterogeneous among patients, suggesting that combination therapy strategies that target a range of disease mechanisms might be more effective than medications used as monotherapy. Potential regimens include the combination of interferons and glatiramer acetate with each other or with approved second-line drugs such as natalizumab and mitoxantrone. Disease modifying therapies have also been used in combination with drugs approved for other indications, such as corticosteroids, methotrexate, azathioprine, and cyclophosphamide. Many preliminary studies have provided favourable results for various combination regimens. However, several subsequent large, randomised, controlled trials have had negative or conflicting results. Therefore, the usefulness of combination therapy in MS remains uncertain. PMID- 20170845 TI - Gluten sensitivity: from gut to brain. AB - Gluten sensitivity is a systemic autoimmune disease with diverse manifestations. This disorder is characterised by abnormal immunological responsiveness to ingested gluten in genetically susceptible individuals. Coeliac disease, or gluten-sensitive enteropathy, is only one aspect of a range of possible manifestations of gluten sensitivity. Although neurological manifestations in patients with established coeliac disease have been reported since 1966, it was not until 30 years later that, in some individuals, gluten sensitivity was shown to manifest solely with neurological dysfunction. Furthermore, the concept of extraintestinal presentations without enteropathy has only recently become accepted. In this Personal View, we review the range of neurological manifestations of gluten sensitivity and discuss recent advances in the diagnosis and understanding of the pathophysiological mechanisms underlying neurological dysfunction related to gluten sensitivity. PMID- 20170844 TI - Migraine aura pathophysiology: the role of blood vessels and microembolisation. AB - Migraine attacks with auras are sometimes associated with underlying hereditary or acquired cerebrovascular disorders. A unifying pathophysiological explanation linking migraine to these conditions has been difficult to identify. On the basis of genetic and epidemiological evidence, we suggest that changes in blood vessels, hypoperfusion disorders, and microembolisation can cause neurovascular dysfunction and evoke cortical spreading depression, an event that is widely thought to underlie aura symptoms. In fact, recent experimental data have indicated that focal, mild, and transient ischaemia can trigger cortical spreading depression without an enduring tissue signature. Although migraine with aura has many causes (eg, neuronal network excitability), it seems that migraine and stroke might both be triggered by hypoperfusion and could therefore exist on a continuum of vascular complications in a subset of patients who have these hereditary or acquired comorbid vascular conditions. PMID- 20170846 TI - Driving in ICD recipients - new European recommendations. PMID- 20170847 TI - Consensus statement of the European Heart Rhythm Association: updated recommendations for driving by patients with implantable cardioverter defibrillators. AB - Patients with an implantable cardioverter defibrillator (ICD) have an ongoing risk of sudden incapacitation that might cause harm to others while driving a car. Driving restrictions vary across different countries in Europe. The most recent recommendations for driving of ICD patients in Europe were published in 1997 and focused mainly on patients implanted for secondary prevention. In recent years there has been a vast increase in the number of patients with an ICD and in the percentage of patients implanted for primary prevention. The EHRA task force on ICD and driving was formed to reassess the risk of driving for ICD patients based on the literature available. The recommendations are summarized in the following table and are further explained in the document, (Table see text). Driving restrictions are perceived as difficult for patients and their families, and have an immediate consequence for their lifestyle. To increase the adherence to the driving restrictions, adequate discharge of education and follow-up of patients and family are pivotal. The task force members hope this document may serve as an instrument for European and national regulatory authorities to formulate uniform driving regulations. PMID- 20170848 TI - Reproduction after breast cancer. AB - Breast cancer is the most frequently occurring cancer in women of developed countries, and as a result of new developments in breast cancer treatment, more women are cured after being diagnosed with this disease. It is important that fertility preservation strategies are addressed before chemotherapy, because chemotherapy may induce premature ovarian failure (depending on the woman's age, the drugs used, the dosage and duration of treatment). Among possible solutions are embryos or oocytes cryopreservation, ovarian tissue cryopreservation-freezing with a subsequent orthotopic and heterotopic autotransplantation, whole ovary cryopreservation, ovarian suppression with gonadotropin-releasing hormone (GnRH) analogues, which inhibit ovarian follicular depletion induced by chemotherapeutic agents and in vitro fertilisation (IVF) after ovulation induction with aromatase inhibitors or tamoxifen. PMID- 20170849 TI - OTSR-RCOT: 1 year already! PMID- 20170850 TI - Dual mobility design use in preventing total hip replacement dislocation following tumor resection. AB - INTRODUCTION: Total hip replacement (THR) following hip tumor resection incurs a high risk of dislocation. We assessed the incidence of dislocation associated with use of a dual mobility cup,and the functional results achieved. HYPOTHESIS: Use of a dual mobility cup would reduce the risk of THR instability following hip tumor resection. MATERIAL AND METHODS: We analyzed dislocation rates in a retrospective series of 71 dual mobility cup THRs implanted following the resection of a tumor hip condition: 33 primary bone tumors and 38 bone metastases. The presenting pathology was diagnosed anatomically, and surgery classified in terms of adopted abductor system strategy. Functional results were assessed in terms of pain (analgesia on the World Health Organisation [WHO] scale), assisted walking and Musculoskeletal Tumor Society (MSTS) score. RESULTS: An overall rate of 9.8% dislocation was observed, taking into account all etiologies and contexts together. More precisely, this rate resulted from a compound figure of 5.2% in bone metastasis and 15% in primitive bone tumor. Dislocation risk depended lesson etiology than on the surgical management of the abductor system, being 3.5% in the case of abductor conservation, 9.5% in the case of abductor sectioning/reinsertion, and 18%in case of gluteus medius muscle or nerve resection. Functional improvement was consistently observed, especially in bone metastasis. At the maximal follow-up, 32 patients were not using analgesics, six were taking WHO class III analgesics, 10 class II and 23 class I. Mean MSTS score was 68.1% +/- 23.5% in bone metastasis and 59.6% +/- 17.5% in primary bone tumor.Fourteen patients could walk without assistance, 33 with a single cane, 15 with two canes and eight with a walker; one patient had not been able to resume walking. DISCUSSION: In these indications, dual mobility cups use lead to lower dislocation rates than those reported in the literature. It proved especially effective in the case of bone metastasis and consolidation surgery. In the case of primary bone tumor, it failed to prevent dislocation following acetabular resection, especially when involving the abductor muscles and/or abductor innervation, although it provided lower dislocation rates, comparable to those experienced with other techniques, when applied to limited resection. LEVEL OF EVIDENCE: IV. Retrospective therapeutic study. PMID- 20170851 TI - Acetabular revision using a press-fit dual mobility cup. AB - INTRODUCTION: Dual mobility cups are especially indicated in total hip replacement revision, the risk of recurrent instability being greater than in primary surgery. In revision, however, primary cup fixation is uncertain without routine anchoring screws. HYPOTHESIS: The stability of dual mobility cups impacted without cement, supplementary screw(s) or anchoring pegs fixation is satisfactory in total hip arthroplasty acetabular component revision, and prevents instability accidents. PATIENTS AND METHODS: Twenty three patients were operated on by the same surgeon between January 1999 and December 2006 and prospectively followed up to a mean 4 1/2 years (range,2-10 yrs). A Collegia cup (Wright Medical France, Creteil, France) was impacted in 23 total hip arthroplasty acetabular component revisions, including 17 cases of SOFCOT grade-1 bone-stock loss and six of grade 2. RESULTS: There were six clinically poor results on the Merle D'Aubigne scale. One case of early migration occurred, in a multioperated acetabulum. There was one isolated dislocation and one recurrent dislocation associated with loose greater trochanter nonunion, but tolerated as it was infrequent. DISCUSSION: This option simplifies revision surgery and limits the risk of dislocation if the abductor muscles unit is continuous. It is indicated when local bone-site compromise encompass a wall-contained cavitary defect at most. A medial wall defect, if moderate, does not in our view preclude using a primary cup, impacted with a certain degree of protrusion. Longer-term follow-up will be needed to confirm these medium-term findings. LEVEL OF EVIDENCE: Level IV. Prospective non comparative therapeutic study. PMID- 20170852 TI - Large diameter head metal-on-metal bearings total hip arthroplasty: preliminary results. AB - INTRODUCTION: Although the use of the metal-on-metal bearings has been validated over the long term in total hip arthroplasty (THA) for standard 28 and 32 mm diameters, and over the medium term in resurfacing procedures, the use of larger metal head size in conventional THA has not yet been extensively reported. HYPOTHESIS: The large-diameter metal-on-metal head is beneficial in terms of implant stability without altering the result in terms of function and bone fixation compared to the standard 28 and 32 mm diameters. OBJECTIVE: The objective was to test this hypothesis by assessing the short-term clinical and radio graphic results of a metal-on-metal large-diameter heads THA system, using cups from the resurfacing hip concept. MATERIAL AND METHODS: We conducted a retrospective study on a continuous series of 106 uncemented acetabular cups (Durom) implanted in 102 patients (mean age, 66 years): 93 cases of primary or secondary coxarthrosis, 11 cases of aseptic osteonecrosis, one fracture of the femoral neck, and one case of rheumatoid arthritis of the hip. At 30 months of follow-up,the Harris Hip Score and the Merle d'Aubigne (PMA) score were calculated. The radiological investigation included comparison of the implant head with native head diameters, variations of acetabular center of rotation, inspection for implant migration, and search for a gap or radiolucent line. RESULTS: The series included two post-traumatic dislocations as well as spontaneously receding tendinitis of the gluteus medius with no further recurrence. The mean Harris Hip Score improved from 49.3 preoperatively to 91.6 at the latest follow-up and the mean PMA score ranged from 12 to 17. The results were excellent for 70 cases, good for 31 cases, fair for three cases, and poor for two cases. In the last five cases, the overall results were undermined by low pain subscore,with no identifiable explanation. Restoration of the original head diameter was verified for 65 hips. No cup migration was observed. Measurement of the acetabular centre of rotation showed a mean lateralization of 1.1mm. Of the 67 immediate postoperative gaps, only two did no disappear at follow-up. Implant head diameter, cup position, and the existence of a gap were not correlated with the clinical results. DISCUSSION: These results are comparable to 28 mm-diameter metal-on-metal heads in uncemented cups but with improved stability but without demonstrable alteration of the quality of the bone fixation. We found no mechanical or medical cause that could explain the five cases of persistent pain leading to fair or poor results. Long-term follow-up will validate these theoretical advantages in terms of wear and implant survival. LEVEL OF EVIDENCE: IV. Retrospective series. PMID- 20170853 TI - EOS orthopaedic imaging system to study patellofemoral kinematics: assessment of uncertainty. AB - BACKGROUND: Accurate knowledge of knee joint kinematics, especially patellofemoral joint kinematics,is essential for prosthetic evaluation so as to further improve total knee arthroplasty performances. Improving the evaluation of the functioning of the extensor apparatus appears,in this respect, particularly important in this optimization effort. OBJECTIVES: The aim of this study was to propose a new experimental setup for the analysis of knee joint kinematics and to validate its relevance in terms of accuracy and uncertainty.The technique developed herein combines 3D reconstruction imaging with the use of a motion capture system. MATERIAL AND METHODS: Eight pairs of fresh-frozen cadaver specimens with no evidence of previous knee surgery were studied using a new test rig where the femur remains fixed and the tibia is free to rotate. The flexion extension cycles were executed using computer-controlled traction of the quadriceps tendon combined with an antagonist force applied to the distal part of the tibia. Knee joint kinematics were tracked using an optoelectronic motion capture system after a preliminary stage of data acquisition of bone geometry and markers position. This stage was carried out using a new digital stereophotogrammetric system, EOS, combined with specific 3D reconstruction software that also determined the coordinate system used in the kinematic analysis. The resulting uncertainty was assessed as was its impact on the estimated kinematics. RESULTS: Test results on eight knees validated the setup designed for the analysis of knee joint kinematics during the flexion-extension cycle. More specifically, the statistical results show that measurement uncertainty for rotations and translations remains below 0.4 and 1.8 mm,respectively, for the tibia and 0.4 and 1.2 mm for the patella (+/- 2 S.D. for all four measurements). DISCUSSION: The combination of 3D imaging and motion capture enables the proposed method to track the real-time motion of any bone segment during knee flexion-extension cycle. In particular,the new test rig introduced in this paper allows in vitro measurements of the patello femoral and tibiofemoral kinematics with a good level of accuracy. Moreover, this personalized experimental analysis can provide a more objective approach to the evaluation of knee implants as well as the validation of the finite-elements based models of the patellofemoral joint. PMID- 20170854 TI - Importance of screw position in intertrochanteric femoral fractures treated by dynamic hip screw. AB - BACKGROUND: Tip-apex distance greater than 25 mm is accepted as a strong predictor of screw cut-out in patients with intertrochanteric femoral fracture treated by dynamic hip screw. The aim of this retrospective study was to evaluate the position of the screw in the femoral head and its effect on cut-out failure especially in patients with inconvenient tip-apex distance. MATERIALS AND METHODS: Sixty-five patients (42 males, 23 females; mean age of 57.6 years) operated by dynamic hip screw for intertrochanteric femoral fractures were divided in two groups taking into consideration the tip-apex distance less (group A; 14 patients) or more (group B; 51 patients) than 25 mm. Patient's age and gender, follow-up period, fracture type, degree of osteoporosis, reduction quality of the fracture, position of the screw in the femoral head, number of patients with cut-out failure and Harris hip score were compared. RESULTS: The average follow-up time was 41.7 months. The mean tip-apex distance was 17.14 mm in group A and 36.67 mm in group B. One (7.1%) patient in group A and three (5.8%) patients in group B had screw cut-out. Except the screw position, no statistical differences were observed between the two groups with regards to study data. The screw was placed in femoral head more inferiorly (p=0.045) on frontal and more posteriorly (p=0.013) on sagital planes in group B, while central placement of the screw was present in group A. The common characteristics of three patients with screw cut-out in group B was the position of the screw which was located in femoral head more superiorly and anteriorly after an acceptable fracture reduction. CONCLUSIONS: Peripheral placement of the screw in femoral head increases tip-apex distance. However posterior and inferior locations may help to support posteromedial cortex and calcar femoral in unstable intertrochanteric fractures and reduce the risk of cut-out failure. LEVEL OF EVIDENCE: IV, retrospective series. PMID- 20170855 TI - Patellar height relevance in opening-wedge high tibial osteotomy. AB - INTRODUCTION: The decrease of patellar height following opening-wedge proximal tibial osteotomy can affect function, and subsequent total knee arthroplasty may be more difficult and give poorer results. HYPOTHESIS: Pre-operative patellar height is an objective predictor of functional result in opening-wedge osteotomy. PATIENTS AND METHODS: The effect of opening-wedge high tibial osteotomy (HTO) and internal fixation on patellar height and its functional outcome were assessed. Forty supra-tuberosity medial opening wedge osteotomies were performed in 36 patients presenting with medial femorotibial osteoarthritis and varus deformity. Mean age was 55 years. Mean varus was 9 degrees and mean opening 11 degrees. Minimum follow-up was 22 months, with a mean of 4.2 years. Clinical results were assessed on the International Knee Society (IKS) scale. X-ray measurements (HKA angle, tibial slope, and patellar height as per Caton-Deschamps [CD], Insall Salvati [IS] and Blackburne-Peel [BP]) were taken pre-operatively, postoperatively and on follow-up. RESULTS: Patellar height decreased by 10 to 15% (p < 0.0001), depending on the selected ratio. Mean CD index was 0.85 preoperatively (S.D. = 0.12), 0.76 postoperatively (S.D. = 0.14) and 0.75 at follow-up (S.D. = 0.14). Mean IS index was 0.95 preoperatively (S.D. = 0.11), 0.86 postoperatively (S.D. = 0.12) and 0.87 at follow-up (S.D. = 0.12). Mean BP index was 0.68 preoperatively(S.D. = 0.10) and 0.58 postoperatively and at follow up (S.D. = 0.12). Tibial slope was altered by a mean of 1.5 degrees (range: -4 to + 9 degrees). There was no correlation between opening angle and patellar lowering. Patellar height decrease did not affect functional results whether height remained normal or became low (total IKS score, 179 and 170, respectively); the poorest functional results, however, were associated with patella infera (total score, 147). DISCUSSION: Medial opening-wedge HTO is an established treatment for unicompartmental varus knee osteoarthritis. We do not, however, recommend it in case of preoperative patellar height of less than 0.6 on the CD ratio. LEVEL OF EVIDENCE: Retrospective, level IV. PMID- 20170856 TI - Type C periprosthetic fractures treated with locking plate fixation with a mean follow up of 2.5 years. AB - BACKGROUND: Type C periprosthetic femoral fractures present fixation problems related to the extent of the fracture and the quality of the bone stock. OBJECTIVES: The authors report a continuous and prospective series of type C periprosthetic femoral fractures to assess the mechanical stability of the femoral implant and the clinical outcome at the medium term. MATERIAL AND METHODS: Between April 2004 and November 2006, we treated 17 patients (15 females, two males) presenting a prosthetic hip fracture (12 cases), between the hip prosthesis and the knee (one case), and with a knee prosthesis (four cases). All the implants had no sign of loosening at the time of fracture. The patients' mean age was 76.7 years (range, 39-93 years). Internal fixation was obtained with a locking compression plate (LCP) Synthes bridging the implant in place to prevent a weak zone. The rehabilitation protocol consisted in full weight bearing as much as possible. RESULTS: The mean follow-up of the series was 31.5 months (range, 4-51 months). Four deaths were recorded during the follow-up. Minimally invasive surgery was performed in 15 patients.Total loading was possible immediately in 10 patients, partial loading at 20 kg in three patients,and no loading was possible until 6 weeks in four patients. Two infections and a bending type mechanical complication of the plate secondary to a fall were observed. Consolidation was obtained in all cases with the appearance of callus formation beginning in the 6th week. DISCUSSION: The technique used allies the principle of closed internal fixation (with preservation of the fracture hematoma) with mechanical stability. The screws locking to the plate warrant an internal fixator with increased stability that is sufficient for early loading with no risk of losing the secondary axis. Despite this increased rigidity, we did not observe any particular stress on the femoral implants. We recommend bridging the implant and spaced locking for better distribution of the stresses during loading. This hardware, with, if possible, insertion using a reduced approach, seems adapted to periprosthetic femoral fractures, particularly in the elderly. LEVEL OF EVIDENCE: Level IV, prospective therapeutic study. PMID- 20170857 TI - Infection risk prevention following total knee arthroplasty. AB - INTRODUCTION: Implant infection is serious; prevention is mandatory, and requires assessment.The present study assessed the incidence of deep surgical-site infection (SSI) at 1 year following total knee arthroplasty (TKA) and adherence to skin preparation, antibiotic prophylaxis,screening and prevention in case of methicillin-resistant S. aureus (MRSA). HYPOTHESIS: Adherence to prevention measures reduces infection risk secondary to TKA. MATERIAL AND METHODS: A prospective study of the incidence of SSI following primary TKA was run from December 1st 2005 to December 31st 2006 in a continuous series of 364 operations in 359 patients, excluding cases of septic or aseptic revision. Each implant was followed up for 12 months. Adherence to practice was assessed by independent observers. Antibiotic prophylaxis was assessed; skin preparation was scored (out of 10); MRSA was systematically screened for, and preventive measures were assessed in positive cases. Median follow-up was 12 months.Patients with less than 11 months' FU were contacted by telephone. Median age was 72 years(range, 45 92 years). Eighty-seven percent of patients had ASA scores of 2; 14% were diabetic,and 42% obese. Mean surgery time was 70 min (range, 30-164 min). Among the implants, 81.5% were cemented. Eighty-six percent of operations had NNIS scores of 0. Infection risk linked to theater environment and teams was under control. RESULTS: Fourteen patients were lost to follow-up and excluded from analysis. The incidence of infection was 1.4% (n = 5/350) (95% CI [0.41-3.22]). Three of the infections were early ( 0.05). After percutaneous coronary intervention, these percentages decreased in the placebo group (32%) and in greater measure in the vitamin C group (4%, p < 0.01). Complete microcirculatory reperfusion (TIMI myocardial perfusion grade = 3) was achieved in 79% of the vitamin C-treated group compared with 39% of the placebo group (p < 0.01); 8-hydroxy-2 deoxyguanosine (p < 0.002) and 8-iso-prostaglandin F(2alpha) (p < 0.02) plasma levels significantly increased in the placebo group while they were significantly reduced in the vitamin C-treated group (p < 0.0001). TIMI myocardial perfusion grade changes from the baseline showed significant correlation with 8-hydroxy-2 deoxyguanosine (p < 0.006) or 8-iso-prostaglandin F(2alpha) (p < 0.01) plasma levels changes. CONCLUSIONS: In patients undergoing elective percutaneous coronary intervention, impaired microcirculatory reperfusion is improved by vitamin C infusion suggesting that oxidative stress is implicated in such a phenomenon. PMID- 20170882 TI - Vitamin C and percutaneous coronary intervention. PMID- 20170883 TI - Correlation of Device landing zone calcification and acute procedural success in patients undergoing transcatheter aortic valve implantations with the self expanding CoreValve prosthesis. AB - OBJECTIVES: The aim of this study was to assess the influence of amount and distribution of calcifications of the aortic valve and the left ventricular outflow tract on the acute procedural outcome of patients undergoing transcatheter aortic valve implantation (TAVI). BACKGROUND: Transcatheter aortic valve implantation is a new percutaneous technique especially for elderly, high risk patients with significant aortic valve stenosis (AS). After TAVI, post interventional paravalvular aortic regurgitations (PAR) can occur, which is believed to be related partially to valve calcifications. METHODS: We prospectively analyzed 100 symptomatic patients with severe AS scheduled for TAVI with the CoreValve ReValving (Medtronic, Minneapolis, Minnesota) prosthesis. In all patients, a native and contrast-enhanced multislice cardiac computed tomography was performed pre-interventionally. Calcification load of the valve and the adjacent outflow tract was estimated by the Agatston Score (AgS), and the amount and distribution of calcification was semi-quantitatively assessed and graded on a 1 to 4 scale (device "landing zone" calcification score [DLZ-CS]). Aortography was performed to evaluate the PAR pre-interventionally, after initial device release (PAR0) and after termination of the procedure (PAR1). Transthoracic echocardiography was performed 2 weeks after implantation (PAR2). RESULTS: The AgS and DLZ-CS showed a significant correlation with the grade of PAR0 (AgS: r = 0.329, p = 0.001; DLZ-CS: r = 0.356, p < 0.001), PAR1 (AgS: r = 0.254, p = 0.011; DLZ-CS: r = 0.240, p = 0.016), and PAR2 (AgS: r = 0.341, p = 0.001; DLZ-CS: r = 0.300, p = 0.002). Both scores (AgS and DLZ-CS) showed a significant positive correlation (r = 0.858, p < 0.001). CONCLUSIONS: Calcification in the CoreValve device "landing zone" shows a significant positive correlation to PAR after TAVI. Furthermore, the need for "second maneuvers" (i.e., post-dilation after initial device release) can be predicted by these calcification scores (AgS and DLZ-CS). PMID- 20170884 TI - Procedural and mid-term results in patients with aortic stenosis treated with implantation of 2 (in-series) CoreValve prostheses in 1 procedure. AB - OBJECTIVES: This study sought to assess post-procedural and mid-term outcome of patients, in which a second "in-series" CoreValve prosthesis (Medtronic, Minneapolis, Minnesota) was implanted during the same procedure. BACKGROUND: Because of the increasing number of patients implanted with CoreValves, the need for management of special complications has emerged. A misplaced prosthesis can be corrected by various maneuvers. An option is to pull the valve out of the aortic annulus into the ascending aorta or beyond and position a second one (in series). METHODS: Out of 277 patients who underwent CoreValve implantation with the 18-F device in our institution, we had to implant a second prosthesis (due to severe aortic regurgitation or dislocation of the first one) in 9 (3.2%). Immediate post-procedural as well as mid-term follow-up data (5 to 20 months, mean 10.6 +/- 6 months, total 95 patient-months) were collected for analysis. RESULTS: All implantations of the second device were successful, resulting in elimination of the gradient (mean gradient 43.1+/-4.0 mm Hg before to 7.0 +/- 1.1 mm Hg after implantation). There was no final aortic regurgitation grade >or=2+. The extra-anatomically placed first prosthesis (ascending aorta, n = 8; abdominal aorta, n = 1) did not cause any clinical sequelae or gradients. During mid-term follow-up, none of the 18 prostheses showed any sign of malfunction. Specifically, there were no signs of valve migration or of worsening paravalvular regurgitation. No case of valve thrombosis was documented. CONCLUSIONS: A second CoreValve can be safely and effectively implanted in an in-series manner, without periprocedural complications. No problems arose on mid-term follow-up, ranging up to 20 months. PMID- 20170885 TI - Redo mitral valve clipping after partial clip detachment. PMID- 20170886 TI - Coronary ostia stenosis after transcatheter aortic valve implantation. PMID- 20170887 TI - 2009 Focused updates to guidelines in ST-elevation myocardial infarction and percutaneous coronary intervention: application to interventional cardiology. AB - Practice guidelines reflect a consensus of expert opinion for patient care after a thorough review of clinical trials relevant to a given patient population. However, in keeping pace with the influx of new data, these recommendations need to be revised periodically to remain current. The American College of Cardiology (ACC) and the American Heart Association (AHA) published the Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction in 2004 and the Guidelines for Percutaneous Coronary Intervention in 2005 with their respective Focused Updates in 2007. Now, 2 years later, further revision of these guidelines has been published as Focused Updates of 2009. PMID- 20170888 TI - All roads (even those less traveled) lead to rome benefits of transradial coronary interventions. PMID- 20170890 TI - Phenotypes, genotypes, and the 9p21 locus for prediction of cardiovascular events. PMID- 20170892 TI - Gold is not all that glitters. PMID- 20170893 TI - Introspective duration estimation of reactive and proactive motor responses. AB - The metajudgment of motor responses refers to our ability to evaluate the accuracy of our own actions. Can humans metajudge the duration of their Reaction Times (RTs) to a light-flash and the accuracy of their reproduction of a reference time interval bounded by two light flashes (Anticipatory Response Time, ART)? A series of four distinct experiments shows that RT_Meta and ART_Metajudgments are possible but with accuracies about x2.4 and x3 poorer than the corresponding RT and ART ones. In order to reveal the origin of this drop in performance, we ask whether a visual feedback synchronous with subjects' key presses could improve performance. We show that overall the presence of a visual feedback does not significantly improve metajudgment accuracy although such a trend is noticeable in ART_Meta. We then compare these performances with the passive perceptual estimation of the played back (Pb) RT and ART time intervals when bounded by two (RT_Pb) and three (ART_Pb) light flashes. We show that RT_Meta and RT_Pb accuracies are close to equal, but that ART_Meta is about x2 less accurate than ART_Pb which in turn is x1.5 less accurate than ART. The latter observation fails however to reach statistical significance hence not sustaining proposals that active time estimation is more reliable than passive one. The whole dataset is accounted for by a clock-type model where duration estimation performance is limited by four noise sources (visual, clock-count, motor and proprioceptive+efference copy) plus one proper to ART_Meta task. It is proposed that the latter reflects the impossibility for the time-counting system to use the same time origin more than once. PMID- 20170894 TI - Symmetry breaking in confined fluids. AB - The recent progress in the theoretical investigation of the symmetry breaking (the existence of a stable state of a system, in which the symmetry is lower than the symmetry of the system itself) for classical and quantum fluids is reviewed. The emphasis is on the conditions which cause symmetry breaking in the density distribution for one component fluids and binary mixtures confined in a closed nanoslit between identical solid walls. The existing studies have revealed that two kinds of symmetry breaking can occur in such systems. First, a one dimensional symmetry breaking occurs only in the direction normal to the walls as a fluid density profile asymmetric with respect of the middle of the slit and uniform in any direction parallel to the walls. Second, a two-dimensional symmetry breaking occurs in the fluid density distribution which is nonuniform in one of the directions parallel to the walls and asymmetrical in the direction normal to the walls. It manifests through liquid bumps and bridges in the fluid density distribution. For one component fluids, conditions of existence of symmetry breaking are provided in terms of the average fluid density, strength of fluid-solid interactions, distance at which the solid wall generates a hard core repulsion, and temperature. In the case of binary mixtures, the occurrence of symmetry breaking also depends on the composition of the confined mixtures. PMID- 20170895 TI - Capillary forces between particles at a liquid interface: general theoretical approach and interactions between capillary multipoles. AB - The liquid interface around an adsorbed colloidal particle can be undulated because of roughness or heterogeneity of the particle surface, or due to the fact that the particle has non-spherical (e.g. ellipsoidal or polyhedral) shape. In such case, the meniscus around the particle can be expanded in Fourier series, which is equivalent to a superposition of capillary multipoles, viz. capillary charges, dipoles, quadrupoles, etc. The capillary multipoles attract a growing interest because their interactions have been found to influence the self assembly of particles at liquid interfaces, as well as the interfacial rheology and the properties of particle-stabilized emulsions and foams. As a rule, the interfacial deformation in the middle between two adsorbed colloidal particles is small. This fact is utilized for derivation of accurate asymptotic expressions for calculating the capillary forces by integration in the midplane, where the Young-Laplace equation can be linearized and the superposition approximation can be applied. Thus, we derived a general integral expression for the capillary force, which was further applied to obtain convenient asymptotic formulas for the force and energy of interaction between capillary multipoles of arbitrary orders. The new analytical expressions have a wider range of validity in comparison with the previously published ones. They are applicable not only for interparticle distances that are much smaller than the capillary length, but also for distances that are comparable or greater than the capillary length. PMID- 20170896 TI - Deletion and point mutations of PTHLH cause brachydactyly type E. AB - Autosomal-dominant brachydactyly type E (BDE) is a congenital limb malformation characterized by small hands and feet predominantly as a result of shortened metacarpals and metatarsals. In a large pedigree with BDE, short stature, and learning disabilities, we detected a microdeletion of approximately 900 kb encompassing PTHLH, the gene coding for parathyroid hormone related protein (PTHRP). PTHRP is known to regulate the balance between chondrocyte proliferation and the onset of hypertrophic differentiation during endochondral bone development. Inactivation of Pthrp in mice results in short-limbed dwarfism because of premature differentiation of chondrocyte. On the basis of our initial finding, we tested further individuals with BDE and short stature for mutations in PTHLH. We identified two missense (L44P and L60P), a nonstop (X178WextX( *)54), and a nonsense (K120X) mutation. The missense mutation L60P was tested in chicken micromass culture with the replication-competent avian sarcoma leukosis virus retroviral expression system and was shown to result in a loss of function. Thus, loss-of-function mutations in PTHLH cause BDE with short stature. PMID- 20170897 TI - Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease. AB - Ubiquitin ligases play an important role in the regulation of the immune system. Absence of Itch E3 ubiquitin ligase in mice has been shown to cause severe autoimmune disease. Using autozygosity mapping in a large Amish kindred, we identified a linkage region on chromosome 20 and selected candidate genes for screening. We describe, in ten patients, identification of a mutation resulting in truncation of ITCH. These patients represent the first reported human phenotype associated with ITCH deficiency. These patients not only have multisystem autoimmune disease but also display morphologic and developmental abnormalities. This disorder underscores the importance of ITCH ubiquitin ligase in many cellular processes. PMID- 20170898 TI - Mutations in TPRN cause a progressive form of autosomal-recessive nonsyndromic hearing loss. AB - We performed genome-wide homozygosity mapping in a large consanguineous family from Morocco and mapped the autosomal-recessive nonsyndromic hearing loss (ARNSHL) in this family to the DFNB79 locus on chromosome 9q34. By sequencing of 62 positional candidate genes of the critical region, we identified a causative homozygous 11 bp deletion, c.42_52del, in the TPRN gene in all seven affected individuals. The deletion is located in exon 1 and results in a frameshift and premature protein truncation (p.Gly15AlafsX150). Interestingly, the deleted sequence is part of a repetitive and CG-rich motive predicted to be prone to structural aberrations during crossover formation. We identified another family with progressive ARNSHL linked to this locus, whose affected members were shown to carry a causative 1 bp deletion (c.1347delG) in exon 1 of TPRN. The function of the encoded protein, taperin, is unknown; yet, partial homology to the actin caping protein phostensin suggests a role in actin dynamics. PMID- 20170899 TI - Targeted capture and next-generation sequencing identifies C9orf75, encoding taperin, as the mutated gene in nonsyndromic deafness DFNB79. AB - Targeted genome capture combined with next-generation sequencing was used to analyze 2.9 Mb of the DFNB79 interval on chromosome 9q34.3, which includes 108 candidate genes. Genomic DNA from an affected member of a consanguineous family segregating recessive, nonsyndromic hearing loss was used to make a library of fragments covering the DFNB79 linkage interval defined by genetic analyses of four pedigrees. Homozygosity for eight previously unreported variants in transcribed sequences was detected by evaluating a library of 402,554 sequencing reads and was later confirmed by Sanger sequencing. Of these variants, six were determined to be polymorphisms in the Pakistani population, and one was in a noncoding gene that was subsequently excluded genetically from the DFNB79 linkage interval. The remaining variant was a nonsense mutation in a predicted gene, C9orf75, renamed TPRN. Evaluation of the other three DFNB79-linked families identified three additional frameshift mutations, for a total of four truncating alleles of this gene. Although TPRN is expressed in many tissues, immunolocalization of the protein product in the mouse cochlea shows prominent expression in the taper region of hair cell stereocilia. Consequently, we named the protein taperin. PMID- 20170900 TI - Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. AB - Distal hereditary motor neuropathies comprise a clinically and genetically heterogeneous group of disorders. We recently mapped an X-linked form of this condition to chromosome Xq13.1-q21 in two large unrelated families. The region of genetic linkage included ATP7A, which encodes a copper-transporting P-type ATPase mutated in patients with Menkes disease, a severe infantile-onset neurodegenerative condition. We identified two unique ATP7A missense mutations (p.P1386S and p.T994I) in males with distal motor neuropathy in two families. These molecular alterations impact highly conserved amino acids in the carboxyl half of ATP7A and do not directly involve the copper transporter's known critical functional domains. Studies of p.P1386S revealed normal ATP7A mRNA and protein levels, a defect in ATP7A trafficking, and partial rescue of a S. cerevisiae copper transport knockout. Although ATP7A mutations are typically associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome, we demonstrate here that certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency. This previously unrecognized genotype-phenotype correlation suggests an important role of the ATP7A copper transporter in motor neuron maintenance and function. PMID- 20170902 TI - Research in visually induced motion sickness. AB - While humans have experienced motion sickness symptoms in response to inertial motion from early history through the present day, motion sickness symptoms also occur from exposure to some types of visual displays. Even in the absence of physical motion, symptoms may result from visually perceived motion, which are often classified as effects of visually induced motion sickness (VIMS). This paper provides a brief discussion of general motion sickness and then reviews findings from three lines of recent VIMS investigations that we have conducted. PMID- 20170901 TI - Systems genetics analysis of gene-by-environment interactions in human cells. AB - Gene by environment (GxE) interactions are clearly important in many human diseases, but they have proven to be difficult to study on a molecular level. We report genetic analysis of thousands of transcript abundance traits in human primary endothelial cell (EC) lines in response to proinflammatory oxidized phospholipids implicated in cardiovascular disease. Of the 59 most regulated transcripts, approximately one-third showed evidence of GxE interactions. The interactions resulted primarily from effects of distal-, trans-acting loci, but a striking example of a local-GxE interaction was also observed for FGD6. Some of the distal interactions were validated by siRNA knockdown experiments, including a locus involved in the regulation of multiple transcripts involved in the ER stress pathway. Our findings add to the understanding of the overall architecture of complex human traits and are consistent with the possibility that GxE interactions are responsible, in part, for the failure of association studies to more fully explain common disease variation. PMID- 20170903 TI - Searching for needles in a haystack: identifying innovations to prevent MSDs in the construction sector. AB - This study identified innovations that could potentially reduce the risk of MSDs in the construction sector. The action research approach was based on a collaborative model of researchers working with workplace representatives. We searched for innovations being used by construction companies. From a potential database of 125 innovations, the study focused on 20 innovations that varied in their penetration into worksites in the geographical area, represented a variety of trades, and were a cross-section of tools and work organizational processes. It examined the attributes of the innovations, and the barriers to their adoption. The analysis was based on observations of workers, surveys of workers and construction-safety consultants, and company interviews. The study found that innovations were adopted by companies for multiple advantages including productivity and quality, but not necessarily ability to reduce MSD risks, their non-complexity, and cost. The major barriers for adoption were the traditional culture of the construction sector rather than financial ones. PMID- 20170904 TI - How to increase academic performance in children with oppositional defiant disorder? An implicit theory effect. AB - The aim of the present study was to determine whether the implicit theory effect extends to children with oppositional defiant disorder (ODD), with academic difficulties. Twenty-five male children, aged 8-11 years with ODD were randomly assigned to one of two experimental conditions (Incremental Theory highlighting the possibility of self-improvement vs. control). An increase of cognitive performance (IQ) was found for children with ODD in the incremental condition, but not in the control condition. This cognitive improvement could be viewed as a protective factor for children and adolescents with ODD on academic setting. PMID- 20170905 TI - Total synthesis of caminoside B, a novel antimicrobial glycolipid isolated from the marine sponge Caminus sphaeroconia. AB - The first total synthesis of caminoside B, a novel marine antimicrobial glycolipid isolated from the marine sponge Caminus sphaeroconia, was developed. This marine small molecule inhibitor (IC(50)=20 microM) targeting type III secretory pathway of bacterial pathogenesis was assembled in good yield via a '2+2+1' strategy based on stereocontrolled construction of the four glycosidic linkages. PMID- 20170906 TI - Synthesis, physico-chemical properties and complexing abilities of new amphiphilic ligands from D-galacturonic acid. AB - This paper describes a convenient and efficient synthesis of new complexing surfactants from d-galacturonic acid and n-octanol as renewable raw materials in a two-step sequence. In the first step, simultaneous O-glycosidation esterification under Fischer conditions was achieved. The anomeric ratio of the products was studied based on the main experimental parameters and the activation mode (thermal or microwave). In the second step, aminolysis of the n-octyl ester was achieved with various functionalized primary amines under standard thermal or microwave activation. The physico-chemical properties of these new amphiphilic ligands were measured and these compounds were found to exhibit interesting surface properties. Complexing abilities of one uronamide ligand functionalized with a pyridine moiety toward Cu(II) ions was investigated in solution by EPR titrations. A solid compound was also synthesized and characterized, its relative structure was deduced from spectroscopic data. PMID- 20170907 TI - Exogenous allogenic fragmented double-stranded DNA is internalized into human dendritic cells and enhances their allostimulatory activity. AB - Exogenous allogenic DNA as nucleosome-free fragments reaches main cellular compartments (cytoplasm, nucleus) of human dendritic cells and deposits in the nuclear interchromosomal space without visibly changing in linear size. The presence of such allogenic fragmented DNA in medium in which human dendritic cells are cultured produces an enhancement of their allostimulatory activity. This enhancement is comparable to that produced by the standard maturation stimulus lipopolysaccharide Escherichia coli. PMID- 20170908 TI - Association between As and Cu renal cortex accumulation and physiological and histological alterations after chronic arsenic intake. AB - Arsenic (As) is one of the most abundant hazards in the environment and it is a human carcinogen. Related to excretory functions, the kidneys in humans, animal models or naturally exposed fauna, are target organs for As accumulation and deleterious effects. Previous studies carried out using X-ray fluorescence spectrometry by synchrotron radiation (SR-microXRF) showed a high concentration of As in the renal cortex of chronically exposed rats, suggesting that this is a suitable model for studies on renal As accumulation. This accumulation was accompanied by a significant increase in copper (Cu) concentration. The present study focused on the localization of these elements in the renal cortex and their correlation with physiological and histological As-related renal effects. Experiments were performed on nine male Wistar rats, divided into three experimental groups. Two groups received 100 microg/ml sodium arsenite in drinking water for 60 and 120 consecutive days, respectively. The control group received water without sodium arsenite (< 50 ppb As). For histological analysis, 5-mum-thick sections of kidneys were stained with hematoxylin and eosin. Biochemical analyses were used to determine concentrations of plasma urea and creatinine. The As and Cu mapping were carried out by SR-microXRF using a collimated white synchrotron spectrum (300 microm x 300 microm) on kidney slices (2 mm thick) showing As and Cu co-distribution in the renal cortex. Then, renal cortical slices (100 microm thick) were scanned with a focused white synchrotron spectrum (30 microm x 30 microm). Peri-glomerular accumulation of As and Cu at 60 and 120 days was found. The effects of 60 days of arsenic consumption were seen in a decreased Bowman's space as well as a decreased plasma blood urea nitrogen (BUN)/creatinine ratio. Major deleterious effects; however, were seen on tubules at 120 days of exposition. This study supports the hypothesis that tubular accumulation of As-Cu may have some bearing on the arsenic-associated nephrotoxicological process. PMID- 20170909 TI - Natural orifice transluminal endoscopic surgery versus laparoscopic surgery for inadvertent colon injury repair: feasibility, risk of abdominal adhesions, and peritoneal contamination in a porcine survival model. AB - BACKGROUND: Adhesions are common after conventional surgery; natural orifice transluminal endoscopic surgery (NOTES) avoids peritoneal disruption and may reduce adhesions. OBJECTIVES: To determine whether adhesions (and peritoneal contamination) are less common with NOTES transgastric colon injury and repair (TGCR) than with laparoscopic colon repair (LCR). DESIGN/SETTING: Porcine survival study. INTERVENTIONS: After colon preparation and administration of antibiotics, forty 25-kg male pigs were randomly assigned to either TGCR or LCR. TGCR involved an endoscopic gastrotomy (needle-knife plus balloon dilation), CO(2) pneumoperitoneum, and a 2-cm needle-knife transmural incision of spiral colon. Colotomies were repaired with clips; gastrotomies were closed with clips and a detachable snare. MAIN OUTCOME MEASUREMENTS: Adhesions were assessed at necropsy at 21 days; biopsy specimens were blindly reviewed. A 9-point adhesion score (density/vascularity, width, and extent) was averaged from 3 reviewers. Peritoneal lavage was sent for cell count and culture. RESULTS: Two of 20 TGCR pigs died immediately (unrecognized preoperative autopsy-proven pneumonia). The median procedure times were 70.5 and 19.0 minutes for TGCR and LCR, respectively; weight gains were 7.1 and 8.2 kg, respectively. The median adhesion scores were 4.3 and 3.7, respectively (P = .26); subscores were similar (1.9, 1.5, 1.3 vs 1.7, 1.1, 1.0, respectively (P = .3-.6)). Peritoneal lavage bacterial growth was nonsignificantly lower after TGCR than after LCR (38.9% vs 60.0%, respectively; P = .30); administration of intragastric antibiotics did not decrease contamination. Three TGCR (vs no LCR) pigs had histologic peritonitis. LIMITATIONS: Animal model, colon prepped, injury immediately recognized. CONCLUSION: NOTES colon repair is feasible after transmural injury. Adhesions, histologic peritonitis, and contamination were similar to those with laparoscopy and were not helped by intragastric antibiotics. PMID- 20170910 TI - High diagnostic and clinical impact of small-bowel capsule endoscopy in patients with hereditary hemorrhagic telangiectasia with overt digestive bleeding and/or severe anemia. AB - BACKGROUND: Patients with hereditary hemorrhagic telangiectasia (HHT) often present with recurrent anemia because of epistaxis or GI bleeding in relation to telangiectases mostly located in the stomach or small bowel. Capsule endoscopy is considered a major diagnostic tool for small-bowel diseases, but the impact of capsule endoscopy imaging on patient management in HHT is poorly understood. OBJECTIVE: To clarify the contribution of capsule endoscopy in selected patients with HHT. DESIGN: Prospective, descriptive study. SETTING: Multicenter, two university hospital tertiary-care centers, from January 2003 to June 2007. PATIENTS: This study involved 30 patients with HHT and severe anemia (hemoglobin <9 g/dL; normal: 11-15 g/dL) and minimal epistaxis or moderate anemia but overt GI bleeding. INTERVENTION: Capsule endoscopy investigation. MAIN OUTCOME MEASUREMENTS: Clinical characteristics and capsule endoscopy results and their clinical consequences. RESULTS: Capsule endoscopy detected gastric and small bowel telangiectases in 14 (46.7%) and 26 (86.7%) cases, respectively. Active bleeding was present in 36.7% of cases. Diffuse telangiectases were detected in 42.3% without correlation with age, sex, or type of HHT mutation. Further investigations were carried out as a consequence of the capsule endoscopy results in 67% of cases. Treatment, consisting mostly of endoscopic argon plasma coagulation, was scheduled in 46.7% of patients. LIMITATIONS: Our population was essentially composed of patients with the ALK1 mutation. CONCLUSION: This study shows that there is a high diagnostic yield for capsule endoscopy in selected patients with HHT. Capsule endoscopy makes possible precise mapping of lesions and has a considerable impact on the management of these selected patients by using a predefined algorithm: a limited number of accessible lesions is suitable for endoscopic treatment, whereas innumerable diffuse lesions require a medical approach. We suggest that capsule endoscopy could be a first-line, noninvasive, digestive tract examination in selected patients with HHT. PMID- 20170911 TI - Nasoenteral feeding tube placement by nurses using an electromagnetic guidance system (with video). AB - BACKGROUND: The early institution of feeding in patients who need postpyloric feeding tubes is often hampered by a limited availability of endoscopists experienced in safe tube positioning. OBJECTIVE: To test the feasibility of having nurses place postpyloric feeding tubes by using a universal path finding system device. DESIGN: Prospective study. SETTING: Academic hospital. PATIENTS: The success rate and learning curve of a senior nurse placing postpyloric feeding tubes in 50 patients was studied, followed by a study in 160 patients on the success rates and learning curves of 4 inexperienced nurses instructed by the senior nurse. Finally, the success rate of postpyloric feeding tube placement by the senior nurse in 50 critically ill patients was investigated. INTERVENTION: Postpyloric feeding tube positioning by nurses using an electromagnetic universal path-finding system device enabling them to follow the path of the tip of the feeding tube on a monitor screen. MAIN OUTCOME MEASUREMENTS: Success was defined by postpyloric positioning of the feeding tube. The ultimate aim was to reach at least the duodenojejunal flexure. RESULTS: In the first part, the senior nurse was successful in 72% of cases. There was a clear learning curve. In the second part, the 4 newly instructed nurses had a success rate of 89.4% without an evident learning curve. In the third part, successful feeding tube positioning was achieved in 78% of critically ill patients. Of the 217 successfully positioned tubes, 74% reached at least the duodenojejunal flexure. In half of the unsuccessful cases, an explanation for the failure was found at endoscopy. No complications were seen. LIMITATIONS: The generalization to less-specialized hospitals should be investigated. CONCLUSION: Postpyloric positioning of feeding tubes by nurses at the bedside without endoscopy is feasible and safe. Nurses may take over some of the tasks of doctors in a time of high endoscopic needs. PMID- 20170912 TI - A novel double-endoloop technique for natural orifice transluminal endoscopic surgery gastric access site closure. AB - BACKGROUND: Effective and safe access site closure is critical for clinical application of natural orifice transluminal endoscopic surgery. OBJECTIVE: The current study evaluated a simple novel technique of gastrotomy closure. DESIGN: Feasibility study with a survival animal model. SETTING: Animal laboratory. SUBJECTS: Ten female domestic pigs. INTERVENTIONS: Endoscopic closure of a gastrotomy incision was evaluated in 10 pigs in a survival study. A standard double-channel endoscope was advanced into the peritoneal cavity through an incision made by a needle-knife and an 18-mm dilation balloon. After peritoneoscopy and salpingectomy, gastric closure was performed by using an endoscopic grasper and sequential application of 2 endoloops. After a follow-up period of 1 to 3 weeks, the pigs were killed for postmortem examination. MAIN OUTCOME MEASUREMENTS: Feasibility, efficiency, and safety of a novel closure technique. RESULTS: Correct positioning and delivery of endoloops was achieved in all animals in a median time of 17 minutes (range 13-25 minutes). All animals survived without complications. Postmortem examination demonstrated patent full thickness gastric closure without any evidence of infection. LIMITATIONS: Feasibility study with a small number of subjects in a porcine model. CONCLUSION: Double endoloop technique represents a novel, simple, safe, and efficient means of gastric access site closure in natural orifice transluminal endoscopic surgery. PMID- 20170913 TI - Esophageal dilation in eosinophilic esophagitis: safety and predictors of clinical response and complications. AB - BACKGROUND: Esophageal strictures resulting from eosinophilic esophagitis present management challenges, and high rates of rents and perforation have been reported. OBJECTIVE: To assess the safety of esophageal dilation in eosinophilic esophagitis and to characterize predictors of both clinical response and complications of the procedure. DESIGN: Retrospective study of the University of North Carolina eosinophilic esophagitis database. SETTING: Tertiary care referral center. PATIENTS: Cases of eosinophilic esophagitis were defined as per consensus guidelines. INTERVENTION: Dilation with either Savary or through-the-scope balloon techniques. MAIN OUTCOME MEASUREMENTS: Complications (deep mucosal rents, contained or free perforation, and chest pain requiring medical attention or hospitalization) and the global clinical symptom response. RESULTS: Of 130 eosinophilic esophagitis cases identified, 70 dilations (12 Savary, 58 balloon) were performed in 36 patients. Esophageal size improved from 12 to 16 mm (P < .001), with an overall symptom response rate of 83%. The only predictor of clinical response was final dilation diameter. There were 5 complications (7%): 2 deep mucosal rents and 3 episodes of chest pain. There were no perforations. There was one hospitalization for chest pain. All complications occurred in patients being treated with topical steroids, who underwent balloon dilation. Complications were associated with younger age (23 vs 42; P = .02) and more dilations (4 vs 1.7; P = .009). LIMITATIONS: Single center, retrospective study. CONCLUSIONS: Esophageal dilation can be performed in eosinophilic esophagitis with low rates of tears, chest pain, and hospitalization. No perforations were found in our database. The effectiveness of dilation was best when a larger esophageal caliber was achieved, but patients undergoing more procedures was associated with complications. PMID- 20170914 TI - Less invasive percutaneous wave plating of simple femur shaft fractures: A prospective series. AB - In developing nations, fixation of femoral shaft fractures with intramedullary (IM) nails can pose significant challenges. Use of IM implants is commonly limited by availability, funds or patient's physique. Conversely, traditional compression plates are usually readily available at a much lower cost, making bridge plating of femur fractures a frequently used surgical technique. We hypothesised that less invasive percutaneous plate osteosynthesis (MIPPO) of femoral shaft fractures has a similar outcome compared to IM nailing. The study is designed as a prospective case series at a Level 1 university trauma centre. Fifty-seven patients with simple femur shaft fractures (Arbeitsgemeinschaft fur Osteosynthesefragen/Orthopaedic Trauma Association (AO/OTA) type A) were enrolled between April 2001 and December 2005 and followed up for a minimum of 1 year or until fracture union. Primary outcome measures included union rate and time to union. Secondary outcome parameters were hardware failure, malalignment, infection and need for revision surgery. The mean age of the study cohort was 24.7 years. Fifty-four patients sustained associated systems injury. Primary union occurred in 54 patients in an average time of 13 weeks. Two patients presented with implant failure, and one patient displayed signs of delayed union. Six patients developed valgus deformities, whereas five patients displayed external rotation malalignment. One patient developed a superficial wound infection, and another presented with a deep infection. Bridge wave plating represents a safe and efficacious treatment alternative to IM nailing for simple femoral shaft fractures in countries where IM nails are limited by availability, costs and patient's physical characteristics. PMID- 20170915 TI - How do nurses, midwives and health visitors contribute to protocol-based care? A synthesis of the UK literature. AB - OBJECTIVES: To explore how nurses, midwives and health visitors contribute to the development, implementation and audit of protocol-based care. Protocol-based care refers to the use of documents that set standards for clinical care processes with the intent of reducing unacceptable variations in practice. Documents such as protocols, clinical guidelines and care pathways underpin evidence-based practice throughout the world. METHODS: An interpretative review using the five stage systematic literature review process. The data sources were the British Nursing Index, CINAHL, EMBASE, MEDLINE and Web of Science from onset to 2005. The Journal of Integrated Care Pathways was hand searched (1997-June 2006). Thirty three studies about protocol-based care in the United Kingdom were appraised using the Qualitative Assessment and Review Instrument (QARI version 2). The literature was synthesized inductively and deductively, using an official 12-step guide for development as a framework for the deductive synthesis. RESULTS: Most papers were descriptive, offering practitioner knowledge and positive findings about a locally developed and owned protocol-based care. The majority were instigated in response to clinical need or service re-design. Development of protocol-based care was a non-linear, idiosyncratic process, with steps omitted, repeated or completed in a different order. The context and the multiple purposes of protocol-based care influenced the development process. Implementation and sustainability were rarely mentioned, or theorised as a change. The roles and activities of nurses were so understated as to be almost invisible. There were notable gaps in the literature about the resource use costs, the engagement of patients in the decision-making process, leadership and the impact of formalisation and new roles on inter-professional relations. CONCLUSIONS: Documents that standardise clinical care are part of the history of nursing as well as contemporary evidence-based care and expanded roles. Considering the proliferation and contested nature of protocol-based care, the dearth of literature about the contribution, experience and outcomes for nurses, midwives and health visitors is noteworthy and requires further investigation. PMID- 20170916 TI - Association of selected ABC gene family single nucleotide polymorphisms with postprandial lipoproteins: results from the population-based Hortega study. AB - The aim of the study was to determine the influence of twenty single nucleotide polymorphisms (SNPs) of the ABCA1, ABCG1, ABCG5 and ABCG8 genes on the plasmatic concentrations of total cholesterol (TC), HDL and LDL cholesterol (HDLc, LDLc) in the postprandial state with a representative Spanish Caucasian population (1473 individuals, 50.0% women, ages ranging 21-85 years). In men, subjects with the AA genotype of the ABCA1 rs2230806 (R219K) polymorphism were associated with increased plasma LDLc levels, while the ABCA1 haplotype, which included the rs2230806 A allele, was associated with higher TC and LDLc plasma concentrations. In women, significant relationships were found between rs1893590 polymorphisms (ABCG1 gene) and HDLc plasma concentrations (subjects with the AA genotype had lower HDLc levels). For the ABCG8 gene, the rs4148211 polymorphism was associated with higher plasma TC and LDLc concentrations in the total population. Moreover, an ABCG5-G8 haplotype, which included the rs6544718 T allele, was associated with higher HDLc plasma concentrations in women. In conclusion, different SNPs of the ABCA1, ABCG1 and ABCG5-ABCG8 genes were associated, some under gender-specific analysis, with variations in the plasma lipid levels under postprandial conditions in a representative Spanish population. PMID- 20170917 TI - Substructuring and poroelastic modelling of the intervertebral disc. AB - We proposed a substructure technique to predict the time-dependant response of biological tissue within the framework of a finite element resolution. Theoretical considerations in poroelasticity preceded the calculation of the sub structured poroelastic matrix. The transient response was obtained using an exponential fitting method. We computed the creep response of an MRI 3D reconstructed L(5)-S(1) intervertebral disc of a scoliotic spine. The FE model was reduced from 10,000 degrees of freedom for the full 3D disc to only 40 degrees of freedom for the sub-structured model defined by 10 nodes attached to junction nodes located on both lower and upper surfaces of the disc. Comparisons of displacement fields were made between the full poroelastic FE model and the sub-structured model in three different loading conditions: compression, offset compression and torsion. Discrepancies in displacement were lower than 10% for the first time steps when time-dependant events were significant. The substructuring technique provided an exact solution in quasi-static behavior after pressure relaxation. Couplings between vertical and transversal displacements predicted by the reference FE model were well stored by the sub structured model despite the drastic reduction of degrees of freedom. Finally, we demonstrated that substructuring was very efficient to reduce the size of numerical models while respecting the time-dependant behavior of the structure. This result highlighted the potential interest of substructure techniques in large-scale models of musculoskeletal structures. PMID- 20170918 TI - Oblique abdominal muscle activity in response to external perturbations when pushing a cart. AB - Cyclic activation of the external and internal oblique muscles contributes to twisting moments during normal gait. During pushing while walking, it is not well understood how these muscles respond to presence of predictable (cyclic push-off forces) and unpredictable (external) perturbations that occur in pushing tasks. We hypothesized that the predictable perturbations due to the cyclic push-off forces would be associated with cyclic muscle activity, while external perturbations would be counteracted by cocontraction of the oblique abdominal muscles. Eight healthy male subjects pushed at two target forces and two handle heights in a static condition and while walking without and with external perturbations. For all pushing tasks, the median, the static (10th percentile) and the peak levels (90th percentile) of the electromyographic amplitudes were determined. Linear models with oblique abdominal EMGs and trunk angles as input were fit to the twisting moments, to estimate trunk stiffness. There was no significant difference between the static EMG levels in pushing while walking compared to the peak levels in pushing while standing. When pushing while walking, the additional dynamic activity was associated with the twisting moments, which were actively modulated by the pairs of oblique muscles as in normal gait. The median and static levels of trunk muscle activity and estimated trunk stiffness were significantly higher when perturbations occurred than without perturbations. The increase baseline of muscle activity indicated cocontraction of the antagonistic muscle pairs. Furthermore, this cocontraction resulted in an increased trunk stiffness around the longitudinal axis. PMID- 20170919 TI - Changes in power curve shapes as an indicator of fatigue during dynamic contractions. AB - The purpose of this study was to analyze exercise-induced leg fatigue during a dynamic fatiguing task by examining the shapes of power vs. time curves through the combined use of several statistical methods: B-spline smoothing, functional principal components and (supervised and unsupervised) classification. In addition, granulometric size distributions were also computed to allow for comparison of curves coming from different subjects. Twelve physically active men participated in one acute heavy-resistance exercise protocol which consisted of five sets of 10 repetition maximum leg press with 120 s of rest between sets. To obtain a smooth and accurate representation of the data, a basis of 180 B-splines was used. Functional principal component (FPC) analysis was used to find the dominant modes of variation in the curves. A multivariate cluster over the FPC scores and a k-nearest neighbor classification led to three interpretable groups corresponding to different levels of fatigue. Fatigue-induced changes in the shapes of the power curves were evident, in which curves progressively flatten and develop a second power peak. In a practical setting FPC analysis greatly reduces dimensionality and the use of granulometries allows for comparison of the curve shapes without distorting the time scale. In contrast to the present methodology, which considers each curve as a datum, classical statistical approaches using summary parameters of time series may lead to limited information about the impact of dynamic fatiguing protocols on kinematic and kinetic time-course changes in curve shapes. PMID- 20170920 TI - In-vitro results of rapid maxillary expansion on adults compared with finite element simulations. AB - This study was mainly performed to investigate the effects of high maxillary expansion forces on the skull with fresh and thiel-fixed human skulls. The maxillary suture was not weakened except in one experiment. This study compares the strain measured on the zygomatic process of the skull with the results of a finite element model generated for this purpose. An increasing transversal force was applied on the alveolar process (teeth) until rupture. Strain on the zygomatic process, maxilla displacement and the expanding forces were registered. The results of this study show linear material behaviour of the skull before rupture. The highest stress during the experiments and FE simulation was observed on the alveolar process. Conclusions of this study are the necessity of the existence of appropriate models and that female specimens seem to rupture at a lower force than male ones. Both male and female specimens show a similar linear behaviour in the force/strain curve within each gender group. The probability of maxillary suture opening in adults during ultra-rapid maxillary expansion with tooth anchorage is very low. Complications and unwanted rupture could occur. PMID- 20170921 TI - Trabecular bone strains around a dental implant and associated micromotions--a micro-CT-based three-dimensional finite element study. AB - The first objective of this computational study was to assess the strain magnitude and distribution within the three-dimensional (3D) trabecular bone structure around an osseointegrated dental implant loaded axially. The second objective was to investigate the relative micromotions between the implant and the surrounding bone. The work hypothesis adopted was that these virtual measurements would be a useful indicator of bone adaptation (resorption, homeostasis, formation). In order to reach these objectives, a microCT-based finite element model of an oral implant implanted into a Berkshire pig mandible was developed along with a robust software methodology. The finite element mesh of the 3D trabecular bone architecture was generated from the segmentation of microCT scans. The implant was meshed independently from its CAD file obtained from the manufacturer. The meshes of the implant and the bone sample were registered together in an integrated software environment. A series of non-linear contact finite element (FE) analyses considering an axial load applied to the top of the implant in combination with three sets of mechanical properties for the trabecular bone tissue was devised. Complex strain distribution patterns are reported and discussed. It was found that considering the Young's modulus of the trabecular bone tissue to be 5, 10 and 15GPa resulted in maximum peri-implant bone microstrains of about 3000, 2100 and 1400. These results indicate that, for the three sets of mechanical properties considered, the magnitude of maximum strain lies within an homeostatic range known to be sufficient to maintain/form bone. The corresponding micro-motions of the implant with respect to the bone microstructure were shown to be sufficiently low to prevent fibrous tissue formation and to favour long-term osseointegration. PMID- 20170922 TI - The impact of a systematic reduction in shoe-floor friction on heel contact walking kinematics-- A gait simulation approach. AB - Falls initiated by slips and trips are a serious health hazard to older adults. Experimental studies have provided important descriptions of postural responses to slipping, but it is difficult to determine why some slips result in falls from experiments alone. Computational modeling and simulation techniques can complement experimental approaches by identifying causes of failed recovery attempts. The purpose of this study was to develop a method to determine the impact of a systematic reduction in the foot-floor friction coefficient (mu) on the kinematics of walking shortly after heel contact (approximately 200 s). A walking model that included foot-floor interactions was utilized to find the set of moments that best tracked the joint angles and measured ground reaction forces obtained from a non-slipping (dry) trial. A "passive" slip was simulated by driving the model with the joint-moments from the dry simulation and by reducing mu. Slip simulations with values of mu greater than the subject-specific peak required coefficient of friction (RCOF), an experimental measure of slip resistant gait, resulted in only minor deviations in gait kinematics from the dry condition. In contrast, slip simulations run in environments characterized by mu C(16)MeImCl > C(15)AEtBzMe(2)Cl. The enthalpies of micellization, DeltaH(mic) degrees, were calculated indirectly from by use of the van't Hoff treatment; directly by isothermal titration calorimetry, ITC. Calculation of the degree of counter-ion dissociation, alpha(mic), from conductivity measurements, by use of Evans equation requires knowledge of the aggregation numbers, N(agg), at different temperatures. We have introduced a reliable method for carrying out this calculation, based on the volume and length of the monomer, and the dependence of N(agg) on temperature. The N(agg) calculated for C(16)PyCl and C(16)MeImCl were corroborated by light scattering measurements. Conductivity- and ITC-based DeltaH(mic) degrees do not agree; reasons for this discrepancy are discussed. Micelle formation is entropy driven: at all studied temperatures for C(16)MeImCl; only up to 65 degrees C for C(16)PyCl; and up to 55 degrees C for C(15)AEtBzMe(2)Cl. All these data can be rationalized by considering hydrogen-bonding between the head-ions of the monomers in the micellar aggregate. The empirical polarities and concentrations of interfacial water were found to be independent of the nature of the head group. PMID- 20170925 TI - In-vitro studies on the susceptibility of ovine strains of Anaplasma phagocytophilum to antimicrobial agents and to immune serum. AB - Five strains of Anaplasma phagocytophilum, the causative agent of tick-borne fever of sheep and cattle and human granulocytic anaplasmosis, were tested in vitro for their susceptibility to nine antibiotics using the continuous tick cell line ISE6. Minimum inhibitory concentrations (MICs) were evaluated by comparing the percentage of infection of Giemsa-stained antibiotic-treated Anaplasma phagocytophilum-infected cells with that of untreated controls after 6 days of culture. The minimum bactericidal concentrations (MBCs) were evaluated after washing infected cells with antibiotic-free medium and further incubation of 6 days before comparing the percentage of infection of Giemsa-stained antibiotic treated and untreated cells and by comparing the number of copies of the p44 gene by real-time polymerase chain reaction using p44-specific primers. The tick cell culture system was also used to assay the possible neutralizing effects of immune serum on cell-free bacteria in vitro. The neutralizing effects of immune serum were evaluated by comparing the number of copies of the p44 gene in samples inoculated with cell-free bacteria after 1h incubation with two-fold dilutions of immune sera obtained 21 days after infection with those inoculated with cell-free bacteria after incubation for 1h with two-fold dilutions of sera obtained before infection. Doxycycline, rifampin and ciprofloxacin were the most effective compounds, with MICs of 0.125 microg/ml, 0.5 mg/ml and 1 microg/ml, respectively. There was total resistance to penicillin, ampicillin, ceftriaxone and streptomycin and only very limited susceptibility to gentamycin and chloramphenicol. Both doxycycline and rifampin were also bactericidal at the same concentrations. Exposure of bacteria to immune ovine sera resulted in significant reductions of the number of copies of p44 gene. PMID- 20170926 TI - Recurrent polymorphonuclear pleocytosis with increased red blood cells caused by varicella zoster virus infection of the central nervous system: Case report and review of the literature. AB - We describe an immunocompetent 45-year-old woman who had four episodes of neurological disease (meningoencephalitis, multifocal vasculopathy, myelitis and inflammatory brain stem disease) produced by varicella zoster virus (VZV) over an 11-month period, all in the absence of rash. The cerebrospinal fluid (CSF) contained anti-VZV IgG antibody, but not VZV DNA throughout her illness, reaffirming the superiority of detection of anti-VZV IgG in CSF compared to VZV DNA in diagnosing VZV infection of the nervous system. Moreover, 3 of 7 CSF samples examined during the 11 months showed a VZV-induced pleocytosis consisting predominantly of polymorphonuclear cells (PMNs), and 4 of 7 samples also contained increased numbers of red blood cells (RBCs). Because increased PMNs and RBCs in CSF can also occur in patients with central and peripheral nervous system disease produced by cytomegalovirus (CMV), the differential diagnosis of chronic nervous system infection with increased PMNs and RBCs in CSF should include analyses for both VZV and CMV. PMID- 20170927 TI - Evaluation of a new left atrial retractor for minimally invasive mitral valve surgery. PMID- 20170928 TI - Liquiritigenin pharmacokinetics in a rat model of diabetes mellitus induced by streptozotocin: greater formation of glucuronides in the liver, especially M2, due to increased hepatic uridine 5'-diphosphoglucuronic acid level. AB - Liquiritigenin (LQ) is a candidate for the treatment of inflammatory liver disease. Many studies have confirmed that hepatic disease and diabetes mellitus are closely associated. Thus, the pharmacokinetic changes of LQ and its 2 glucuronides, M1 and M2, in a rat model of diabetes mellitus induced by streptozotocin (DMIS rats) were evaluated. Liquiritigenin was administered intravenously (20 mg/kg) or orally (50 mg/kg) in DMIS and control rats. Changes in in vitro activity and in vivo uridine 5'-diphosphoglucuronic acid level in the liver and intestine of DMIS rats compared with controls were also studied. After intravenous administration of LQ in DMIS rats, no significant changes in the pharmacokinetic parameters of LQ were observed. However, the AUC(M2)/AUC(LQ) ratio was significantly greater (by 53.0%) than that of controls. After oral administration of LQ, the AUC of LQ and metabolite ratios of M1 and M2 were comparable to controls. The increase in the formation of glucuronides of LQ, especially M2, after intravenous administration of LQ was due to the increased in vivo hepatic uridine 5'-diphosphoglucuronic acid level in DMIS rats as a result of alteration in carbohydrate metabolism in diabetes. The comparable pharmacokinetics of LQ, M1, and M2 after oral administration of LQ were mainly due to the comparable intestinal metabolism of LQ between the control and DMIS rats. PMID- 20170929 TI - Plasma interleukin-1beta concentrations are closely associated with fasting blood glucose levels in healthy and preclinical middle-aged nonoverweight and overweight Japanese men. AB - Plasma interleukin (IL)-1beta and IL-6 are markers that predict the risk of inflammation in diabetes. In the current study, we examined the relationship between fasting glucose and plasma inflammatory cytokines (IL-1beta and IL-6) concentrations in healthy and preclinical middle-aged Japanese men (mean +/- SD, 58.7 +/- 7.8 years old) divided according to body mass index (<25 kg/m(2), nonoverweight group; >=25 kg/m(2), overweight group). We conducted a cross sectional study of 413 healthy and preclinical men aged 40 to 69 years who participated in health checkups in Japan. We measured their clinical parameters, lifestyle factors, and plasma IL-1beta and IL-6 concentrations. Participants were classified according to their fasting blood glucose levels, and we compared their plasma cytokine levels. Plasma IL-1beta and IL-6 levels in nonoverweight subjects were positively and strongly associated with fasting blood glucose and hemoglobin A(1c); in contrast, these cytokines were strongly associated with homeostasis model assessment of insulin resistance and fasting glucose in overweight subjects. Significant positive associations between plasma IL-1beta and glucose concentrations were observed within the groups classified according to glucose concentrations, after adjustment for age and body mass index. The results of our current study show that plasma IL-1beta levels are strongly associated with fasting blood glucose concentrations in healthy and preclinical nonoverweight and overweight Japanese men. PMID- 20170931 TI - Consequences of antisense down-regulation of a lignification-specific peroxidase on leaf and vascular tissue in tobacco lines demonstrating enhanced enzymic saccharification. AB - Tobacco plants expressing an antisense construct for a cationic peroxidase, which down-regulated lignin content at the presumed level of polymerisation, have been further analysed. T(1) plants were derived from a large-scale screen of T(0) mutant lines, previously published, which identified lines demonstrating consistent lignin down-regulation. Of these, line 1074 which had the most robust changes in lignin distribution through several generations was shown to have accompanying down-regulation of transcription of most lignin biosynthesis genes, except cinnamoyl-CoA reductase. The consistent 20% reduction in lignin was not accompanied by significant gross changes in vascular polysaccharide content and composition, despite a modest up-regulation of transcripts of genes involved in cellulose and hemicellulose synthesis. Morphologically, 1074 plants have under developed xylem with both fibers and vessels having thin cell walls and limited secondary wall thickening with an abnormal S2 layer. However, they were not compromised in overall growth. Nevertheless, these and other lines showed improved potential industrial utility through a threefold increase in enzymic saccharification efficiency compared with wild-type (wt). Therefore, they were profiled for further un-intended effects of transgenesis that might compromise their value for industrial or biofuel processes. Other phenotypic changes included increased leaf thickness and bifurcation at the tip of the leaf. wt Plants had smaller chloroplasts and higher stomatal numbers than mutants. Transgenic lines also showed a variable leaf pigment distribution with light green areas that contained measurably less chlorophyll a, b, and carotenoids. Changes in epidermal pavement cells of mutant lines were also observed after exposure to various chemicals, while wt leaves retained their structural integrity. Despite these changes, the mutant plants grew and were viable indicating that lignification patterns can be manipulated considerably through targeting polymerisation without serious deleterious effects. PMID- 20170930 TI - Presence or absence of a known diabetic ketoacidosis precipitant defines distinct syndromes of "A-beta+" ketosis-prone diabetes based on long-term beta-cell function, human leukocyte antigen class II alleles, and sex predilection. AB - Ketosis-prone diabetes (KPD) is heterogeneous. Longitudinal follow-up revealed that patients with "A-beta+" KPD (absent autoantibodies and preserved beta-cell function) segregated into 2 subgroups with distinct evolution of beta-cell function and glycemic control. Generalized linear analysis demonstrated that the variable that most significantly differentiated them was presence of a clinically evident precipitating event for the index diabetic ketoacidosis (DKA). Hence, we performed a comprehensive analysis of A-beta+ KPD patients presenting with "provoked" compared with "unprovoked" DKA. Clinical, biochemical, and beta-cell functional characteristics were compared between provoked and unprovoked A-beta+ KPD patients followed prospectively for 1 to 8 years. Human leukocyte antigen class II allele frequencies were compared between these 2 groups and population controls. Unprovoked A-beta+ KPD patients (n = 83) had greater body mass index, male preponderance, higher frequency of women with oligo-/anovulation, more frequent African American ethnicity, and less frequent family history of diabetes than provoked A-beta+ KPD patients (n = 64). The provoked group had higher frequencies of the human leukocyte antigen class II type 1 diabetes mellitus susceptibility alleles DQB1*0302 (than the unprovoked group or population controls) and DRB1*04 (than the unprovoked group), whereas the unprovoked group had a higher frequency of the protective allele DQB1*0602. beta-Cell secretory reserve and glycemic control improved progressively in the unprovoked group but declined in the provoked group. The differences persisted in comparisons restricted to patients with new-onset diabetes. "Unprovoked" A-beta+ KPD is a distinct syndrome characterized by reversible beta-cell dysfunction with male predominance and increased frequency of DQB1*0602, whereas "provoked" A-beta+ KPD is characterized by progressive loss of beta-cell reserve and increased frequency of DQB1*0302 and DRB1*04. Unprovoked DKA predicts long-term beta-cell functional reserve, insulin independence, and glycemic control in KPD. PMID- 20170932 TI - [Primary renal carcinoid tumor]. AB - Primary renal carcinoid tumors are very rare, so their characteristic imaging findings have not been well defined. We describe the case of a man with a large right renal mass associated to a retroperitoneal lymph-node conglomerate. Increased urine concentrations of 5-hydroxy-indole-acetic acid and the histologic findings led to the diagnosis of primary renal carcinoid tumor. We review the epidemiology, clinical presentation, and findings at ultrasonography, computed tomography, and magnetic resonance image for primary renal carcinoid tumors. PMID- 20170934 TI - Activation of PI 3-kinase/Akt/NF-kappaB and Stat3 signaling by avian reovirus S1133 in the early stages of infection results in an inflammatory response and delayed apoptosis. AB - Avian reovirus (ARV) strain S1133 causes apoptosis in host cells in the middle to late stages of infection. This study investigated the early-stage biological response and intracellular signaling in ARV S1133-infected Vero and chicken cells. Treatment with conditioned medium from ARV S1133-infected cells increased the chemotactic activity of U937 cells. Neutralizing antibodies against IL-1beta and IL-6 showed that both cytokines contribute to viral-induced inflammation but neither affect cell survival. Inhibition of Akt, NF-kappaB, and Stat3 released the chemotactic activity and anti-apoptotic effect elicited by ARV S1133. ARV S1133 activated PI 3-kinase-dependent Akt/NF-kappaB and p70 S6 kinase, as well as Stat3; however, p70 S6 kinase was not involved in ARV S1133-mediated effects. DF1 cells over-expressing constitutively active PI 3-kinase and Stat3 showed association with enhancement of anti-apoptotic activity. In conclusion, in the early stages of ARV S1133 infection, activation of cell survival signals contributes to virus-induced inflammation and anti-apoptotic response. PMID- 20170933 TI - Seoul virus suppresses NF-kappaB-mediated inflammatory responses of antigen presenting cells from Norway rats. AB - Hantavirus infection reduces antiviral defenses, increases regulatory responses, and causes persistent infection in rodent hosts. To address whether hantaviruses alter the maturation and functional activity of antigen presenting cells (APCs), rat bone marrow-derived dendritic cells (BMDCs) and macrophages (BMDMs) were generated and infected with Seoul virus (SEOV) or stimulated with TLR ligands. SEOV infected both DCs and macrophages, but copies of viral RNA, viral antigen, and infectious virus titers were higher in macrophages. The expression of MHCII and CD80, production of IL-6, IL-10, and TNF-alpha, and expression of Ifnbeta were attenuated in SEOV-infected APCs. Stimulation of APCs with poly I:C prior to SEOV infection increased the expression of activation markers and production of inflammatory cytokines and suppressed SEOV replication. Infection of APCs with SEOV suppressed LPS-induced activation and innate immune responses. Hantaviruses reduce the innate immune response potential of APCs derived from a natural host, which may influence persistence of these zoonotic viruses in the environment. PMID- 20170935 TI - Mutational analysis of the putative pipo of soybean mosaic virus suggests disruption of PIPO protein impedes movement. AB - The presence of a small open reading frame embedded in the P3 cistron of potyvirus turnip mosaic virus, termed "pipo," was recently discovered. We have now studied the putative pipo of soybean mosaic virus (SMV). Introduction of single, or multiple, stop codon mutations at different locations within pipo, without substitution in polyprotein amino acids, did not abolish replication, but restricted the virus to small cluster of cells within the inoculated leaves. Furthermore, extensive mutagenesis of the conserved GA(6) motif at the 5' end of pipo also generated two out of five mutants that remained restricted to small foci of infected cells within the inoculated leaves. Long-distance movement function of the movement-defective PIPO-mutants was not restored following co inoculation with competent SMV strains. Taken together, the data suggest that the putative pipo of SMV is essential for the virus movement; however, knock out of its expression does not abolish replication. PMID- 20170937 TI - Characterization of VOC and formaldehyde emissions from a wood based panel: results from an inter-laboratory comparison. AB - Six European laboratories used the emission test chamber method (EN ISO 16000-9) for the determination of VOC and formaldehyde emissions from a wood based panel (particleboard). The tested panel was conditioned without wrapping over 28 d at 23 degrees C and 50% RH before shipping to each participating laboratory. Emission chamber testing was carried out with air sampling after 3 and 28 d. Main VOCs (alpha-pinene, beta-pinene, pentanal, hexanal) and TVOC were analysed according to ISO 16000-6 and main aldehydes (formaldehyde, acetaldehyde, pentanal, hexanal) were specifically analysed according to ISO 16000-3. Results indicated that relative standard deviations of reproducibility after 28 testing days are between 27.5% and 45.5% for VOC concentrations ranging from 5.9 to 38.6 microg m(-3) and between 17.1% and 23.8% for aldehyde concentrations ranging from 5.5 to 57.6 microg m(-3). Formaldehyde results showed standard deviation of only 17.4% for a mean concentration of 57.6 microg m(-3) after 28 testing days. In general, results are similar to recent inter-laboratory comparison studies even if wood based panels can be considered as heterogeneous materials. PMID- 20170939 TI - Preparation and photocatalytic performance of Fe (III)-amidoximated PAN fiber complex for oxidative degradation of azo dye under visible light irradiation. AB - Polyacrylonitrile (PAN) fiber was modified with hydroxylamine hydrochloride to introduce amidoxime groups onto the fiber surface. These amidoxime groups were used to react with Fe (III) ions to prepare Fe (III)-amidoximated PAN fiber complex, which was characterized using SEM, XRD, FTIR, XPS, DMA, and DRS respectively. Then the photocatalytic activity of Fe-AO-PAN was evaluated in the degradation of a typical azo dye, C. I. Reactive Red 195 in the presence of H(2)O(2) under visible light irradiation. Moreover, the effect of the Fe content of Fe-AO-PAN on dye degradation was also investigated. The results indicated that Fe (III) ions can crosslink between the modified PAN fiber chains by the coordination of Fe (III) ions with the amino nitrogen atoms and hydroxyl oxygen atoms of the amidoximation groups to form Fe (III)-amidoximated PAN fiber complex, and the Fe content of which is mainly determined by Fe (III) ions and amidoximation groups. Fe (III)-amidoximated PAN fiber complex is found to be activated in the visible light region. Moreover, Fe (III)-amidoximated PAN fiber complex shows the catalytic activity for dye degradation by H(2)O(2) at pH=6.0 in the dark, and can be significantly enhanced by increasing light irradiation and Fe content, therefore, it can be used as a new heterogeneous Fenton photocatalyst for the effective decomposition of the dye in water. In addition, ESR spectra confirm that Fe (III)-amidoximated PAN fiber complex can generate more OH radicals from H(2)O(2) under visible light irradiation, leading to dye degradation. A possible mechanism of photocatalysis is proposed. PMID- 20170940 TI - What are we monitoring and why? Using geomorphic principles to frame eco hydrological assessments of river condition. AB - Monitoring and assessment are integral components in adaptive management programmes that strive to improve the condition of river systems. Unfortunately, these procedures are generally applied with an emphasis upon biotic attributes and water quality, with limited regard for the geomorphic structure, function and evolutionary trajectory of a river system. Geomorphic principles convey an understanding of the landscape context within which ecohydrologic processes interact. Collectively, geo-eco-hydrologic understanding presents a coherent biophysical template that can be used to frame spatially and temporally rigorous approaches to monitoring that respect the inherent diversity, variability and complexity of any given river system. This understanding aids the development of management programmes that 'work with nature.' Unless an integrative perspective is used to monitor river condition, conservation and rehabilitation plans are unlikely to reach their true potential. PMID- 20170941 TI - A comparative optical aggregometry study of antiplatelet activity of taxanes from Taxus cuspidata. AB - Platelets are highly reactive components of the circulatory system. The cytoskeleton of a platelet is an important structure for platelet aggregation as stimulated by several agonists. An anticancer agent, taxol, has been suggested to exert platelet anti-aggregating activity by stabilizing microtubules during the aggregation process. An activity-guided fractionation was performed with a methanol extract of the leaves and twigs of Taxus cuspidata to isolate taxanes with platelet anti-aggregating effects. Compounds 1 to 7 - taxinine (1), taxinine A (2), taxinine B (3), 2-deacetoxytaxinine B (4), taxacin (5), taxchinin B (6), and taxol (7) - were obtained as the antiplatelet components of this plant. These taxane compounds present the possibility of securing new antiplatelet compounds which differ from currently available antiplatelet agents in chemical structure and possibly in mechanisms of action. All compounds showed stronger inhibitory effects than acetylsalicylic acid (ASA) on platelet aggregation induced by arachidonic acid (AA) (IC(50): 14.4, 64.5, 35.5, 16.0, 21.9, 28.6 and 48.2 versus 63.0microM) or U46619 (IC(50): 34.8, 24.9, 36.2, 35.0, 46.9, 71.9 and 68.7 versus 340microM). Compounds 1, 3, 4 and 5, with a cinnamoyl group at the C(5) position, showed strong inhibitory effects against AA-induced aggregation compared to compound 2 (with an -OH group at C(5)) or compounds with an oxetane ring at C(4),(5), such as compounds 6 and 7. All of the seven compounds were 5-13-fold more strongly inhibitory than ASA against U46619-induced aggregation. PMID- 20170942 TI - Wound healing in hemophilia B mice and low tissue factor mice. AB - Wound healing involves a number of physiologic mechanisms including coagulation, inflammation, formation of granulation tissue, and tissue remodeling. Coagulation with robust thrombin generation leading to fibrin formation is necessary for wound healing. It is less clear if there is a requirement for ongoing coagulation to support tissue remodeling. We have studied wound healing in mice with defects in both the initiation (low tissue factor) and propagation (hemophilia B) phases. In hemophilia B mice, dermal wound healing is delayed; this delay is associated with bleeding into the granulation tissue. Mice can be treated with replacement therapy (factor IX) or bypassing agents (factor VIIa) to restore thrombin generation. If treated just prior to wound placement, mice will have normal hemostasis in the first day of wound healing. As the therapeutic agents clear, the mice will revert to hemophilic state. If the primary role of coagulation in wound healing is to provide a stable platelet/fibrin plug that is loaded with thrombin, then treating hemophilic animals just prior to wound placement should restore normal wound healing. The results from this study did not support that hypothesis. Instead the results show that restoring thrombin generation only at the time of wound placement did not improve the delayed wound healing. In preliminary studies on low tissue factor mice, there also appears to be a delay in wound healing with evidence of bleeding into the granulation tissue. The current data suggests that ongoing coagulation function needs to be maintained to support a normal wound healing process. PMID- 20170943 TI - Mutant macaque factor IX T262A: a tool for hemophilia B gene therapy studies in macaques. AB - INTRODUCTION: Gene therapy is expected to be the next generation therapy for hemophilia, and a good animal model is required for hemophilia gene therapy preclinical studies. METHODS: Taking advantage of the human factor IX (FIX) specificity of monoclonal antibody 3A6, the epitope of which resides in the amino acid polypeptide segment including Ala 262 of human FIX, mutant macaque FIX with an amino acid substitution of Thr 262 to Ala (macaque FIX T262A) was generated and its reactivity to monoclonal antibody 3A6, biological activity and expression in vivo were studied. RESULTS: Enzyme-linked immunosorbent assays (ELISAs) and Western blot analyses showed that monoclonal antibody 3A6 bound to human FIX and macaque FIX T262A but not to wild-type macaque FIX. Recombinant macaque FIX T262A exhibited a comparable coagulation activity to wild-type macaque FIX and human FIX. High expression of macaque FIX T262A was achieved in mice by injection of AAV8 vectors carrying the macaque FIX T262A gene and reached levels of up to 31.5microg/mL (1050% of the normal human FIX concentration). Macaque FIX T262A expressed in the liver of mice was as biologically active as that expressed in vitro. In addition, the macaque FIX T262A concentrations determined by a 3A6 based ELISA were not influenced by the presence of normal macaque plasma. CONCLUSIONS: The results of the present study suggest that macaque FIX T262A may be processed appropriately in vivo and that the macaque FIX T262A concentration in the macaque circulation can be quantified precisely by a monoclonal antibody 3A6-based ELISA. PMID- 20170944 TI - Long-term cervical cancer survivors suffer from pelvic floor symptoms: a cross sectional matched cohort study. AB - OBJECTIVE: The aim of this study was to determine prevalence of and experienced distress from pelvic floor symptoms in cervical cancer survivors (CCS). METHODS: For this cross-sectional matched cohort study, we matched CCS, treated in the Academic Medical Center, Amsterdam between 1997 and 2007, to a random female population sample aged 20 to 70 years (reference group). We assessed prevalence of and distress from bladder and bowel symptoms with validated pelvic-floor related questionnaires. Severe distress was defined as values above the 90th percentile of reference group's symptom domain scores. RESULTS: One-hundred and forty-six CCS underwent radical hysterectomy and pelvic lymph node dissection (RH and LND), 49 underwent surgery and adjuvant radiotherapy (SART), and 47 underwent primary radiotherapy (PRT). Urinary incontinence and obstructive voiding were reported by each treatment group more frequently than by the reference group and caused more distress. Patients treated with RH and LND reported more distress from most uro-genital symptoms, except from overactive bladder symptoms. Patients treated with PRT reported more distress from each uro-genital symptom than matched controls. The RH and LND group reported more distress from constipation and obstructive defecation than the reference group. Patients who underwent primary or adjuvant radiotherapy reported more distress from anal incontinence than their matched controls. CONCLUSIONS: Treatment of cervical cancer impairs pelvic floor function. Patients treated with PRT report the most adverse effects on pelvic floor function. The results of our study enable physicians to counsel accurately about specific symptoms. Furthermore, to facilitate referral to pelvic floor specialists when bothersome symptoms occur, we recommend evaluating pelvic floor symptoms as a standard during follow-up. PMID- 20170946 TI - Slumping tendency and rheological properties of flowable composites. AB - OBJECTIVES: The aim of this study was to develop a method for measuring the slumping tendency of flowable resin composites and to correlate the results with those obtained from standard rheological methods. METHODS: Five commercial flowable composites (Aeliteflo: AF, Filtek flow: FF, DenFil flow: DF, Tetric flow: TF and Revolution: RV) were used. A fixed volume of each composite was extruded from a syringe onto a glass slide using a custom-made loading device. The composite was allowed to slump for 10s at 25 degrees C and light cured. The aspect ratio (height/diameter) of the cone or dome shaped specimen was measured to estimate the slumping tendency of the composites. In order to investigate the relationship between the slumping tendency and the rheological properties of the composites, the complex viscosity eta* of each composite was measured by a dynamic oscillatory shear test over a range of angular frequency omega=0.1 100rad/s using a rheometer. The aspect ratios of the composites were compared by one-way ANOVA and Tukey's post hoc test at the 5% significance level. Regression analysis was performed to investigate the relationship between the aspect ratio and the complex viscosity. RESULTS: Slumping tendency based on the aspect ratio varied among the five materials (AF0.1%) occurred in 8/26 mice transplanted with CD34+ cells from 5/13 PV patients (median: 4.26%, range: 0.3-5.56%), in contrast to 0/14 mice from 9 SP patients (P=0.017). The engrafting PV cells were of multi-lineage. JAK2V617F/total JAK2 ratios decreased after transplantation (initial: 65.9% versus 6-week: 13.0%, P=0.001). Essential thrombocythemia (ET) BM cells also exhibited a similar decrease in JAK2V617F clone. The results suggested that events in addition to JAK2V617F are involved in the pathogenesis of PV and ET. PMID- 20170960 TI - Depression and anger as risk factors underlying the relationship between maternal substance involvement and child abuse potential. AB - OBJECTIVE: This study examines how emotion regulation deficits in the area of anger arousal and reactivity are associated with child abuse potential in mothers with substance use and depressive disorders in order to identify targeted areas for prevention and treatment. METHODS: A sample of 152 urban mothers was interviewed on measures of substance use, diagnosis of depression, anger arousal and reactivity, and child abuse potential. RESULTS: Linear hierarchical regressions revealed that anger arousal and reactivity exceeded diagnostic and demographic variables in predicting maternal child abuse potential. Additionally, anger arousal and reactivity was found to be a partial mediator of the relationship between diagnostic category and child abuse potential. CONCLUSIONS: Findings are discussed in relation to a multifaceted model of child abuse potential which broadens the existing literature to include an examination of depression and emotion regulation in order to more fully understand how substance use and child abuse potential are linked. PRACTICE IMPLICATIONS: Models and approaches which help clients to manage and regulate difficult feeling states, specifically anger, could be helpful, and may be most readily applied in such populations. PMID- 20170961 TI - Bioaccumulation behavior of polybrominated diphenyl ethers (PBDEs) in the freshwater food chain of Baiyangdian lake, north China. AB - Polybrominated diphenyl ethers (PBDEs) are of great environmental concern due to bioaccumulation in different food chains. Trophodynamics of PBDEs in freshwater food chain is an important criterion for assessing their ecological risk. In the study, PBDEs were analyzed in sixteen aquatic species collected from Baiyangdian Lake, North China. The concentrations of nine PBDE congeners (BDE-28, -47, -66, 99, -100, -85, -153, -154, and -183) in aquatic organisms ranged from 3.4 to 160.2ng/g lipid weight. BDE-47 was the predominant PBDE congener in most samples except for river snails and swan mussels. BDE-209 was detected in 50% of biota samples, which indicated the bioavailability of BDE209. Correlation between lipid normalized concentrations of PBDEs and trophic levels determined by stable isotope nitrogen technologies confirmed that PBDEs were biomagnified in the freshwater food chain. The trophic magnification factors (TMFs) ranged from 1.3 to 2.1 for PBDE congeners, greater than one, indicating the biomagnification potential for the PBDE congeners in the freshwater food chain. The relationship between TMFs and Log K(ow) (octanol-water partition coefficient) indicated that the phenomenon of trophic magnification for lowly brominated congeners was obvious in the freshwater food chain. PMID- 20170962 TI - Investigation of source apportioning for alpha-HCH using enantioselective analysis. AB - Enantiomeric analysis can be used as a complementary tool for source apportionment of chiral compounds, particularly for alpha-HCH. In this study we used archived samples from studies related to the distribution of POPs in air water and air-soil-grass systems. Such approach is based on the behaviour of chiral compounds released into the atmosphere from a primary source, when they are expected to show racemic or close to racemic composition. Contrarily, when chiral compounds have been reemitted from secondary sources (e.g. water or soil), their enantiomeric signatures are frequently non-racemic and are similar to the signature of the secondary source. To show such evidence, extracts from passive air samples deployed throughout Europe were analyzed for the enantiomers of alpha HCH. The proximity to a large water body showed a high impact on the enantiomeric signatures: Baltic air had enantiomeric fractions (EFs) <0.500, while Mediterranean air had predominantly EFs >0.500. Similarly, Atlantic air showed a latitude influence: above 50 degrees N most EFs <0.500, whereas at latitudes below 50 degrees N, EFs were >0.500. A similar trend was also observed for EFs of alpha-HCH measured in air samples from a latitudinal transect during an Atlantic cruise. This transect shows that samples from higher latitudes (above 40 degrees N) have EF <0.500, whereas in the more southern samples (African coast and Southern Atlantic), there is no clear trend for EFs. Inland air samples showed a large range in EF values, with racemic signatures for samples with the highest alpha-HCH concentrations and an increasing spread in the EFs for lower alpha-HCH concentrations. As expected, the EF values of alpha-HCH in air, soils and grass were also impacted by latitude. Correlations between EFs and geographic characteristics of the sampling locations, as well as alpha-HCH concentrations, alpha-/gamma-isomer ratios, or temperature suggest that enantioselective analysis can give additional information on the distribution and sources of alpha-HCH in the environment. PMID- 20170963 TI - Novel leukocyte protein, Trojan, differentially expressed during thymocyte development. AB - "Trojan" is a novel cell surface protein, discovered from chicken embryonic thymocytes on the purpose to identify molecules involved in T cell differentiation. The molecule is predicted as a type I transmembrane protein having a Sushi and two fibronectin type III domains and a pair of intracellular phosphorylation sites. Its transcript expression is specific for lymphoid tissues and the presence of the protein on the surface of recirculating lymphocytes and macrophages was confirmed by immunofluorescence analysis. In thymus, about half of the double negative (CD4(-) CD8(-)) and CD8 single positive and the majority of CD4 single positive cells express Trojan with a relatively high intensity. However, only a minority of the double positive (CD4(+) CD8(+)) cells are positive for Trojan. This expression pattern, similar to that of some proteins with anti-apoptotic and function, like IL-7Ralpha, makes Trojan an attractive candidate of having an anti-apoptotic role. PMID- 20170948 TI - Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial. AB - BACKGROUND: The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed that initial antihypertensive therapy with benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing cardiovascular morbidity and mortality. We assessed the effects of these drug combinations on progression of chronic kidney disease. METHODS: ACCOMPLISH was a double-blind, randomised trial undertaken in five countries (USA, Sweden, Norway, Denmark, and Finland). 11 506 patients with hypertension who were at high risk for cardiovascular events were randomly assigned via a central, telephone-based interactive voice response system in a 1:1 ratio to receive benazepril (20 mg) plus amlodipine (5 mg; n=5744) or benazepril (20 mg) plus hydrochlorothiazide (12.5 mg; n=5762), orally once daily. Drug doses were force-titrated for patients to attain recommended blood pressure goals. Progression of chronic kidney disease, a prespecified endpoint, was defined as doubling of serum creatinine concentration or end-stage renal disease (estimated glomerular filtration rate <15 mL/min/1.73 m(2) or need for dialysis). Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00170950. FINDINGS: The trial was terminated early (mean follow-up 2.9 years [SD 0.4]) because of superior efficacy of benazepril plus amlodipine compared with benazepril plus hydrochlorothiazide. At trial completion, vital status was not known for 143 (1%) patients who were lost to follow-up (benazepril plus amlodipine, n=70; benazepril plus hydrochlorothiazide, n=73). All randomised patients were included in the ITT analysis. There were 113 (2.0%) events of chronic kidney disease progression in the benazepril plus amlodipine group compared with 215 (3.7%) in the benazepril plus hydrochlorothiazide group (HR 0.52, 0.41-0.65, p<0.0001). The most frequent adverse event in patients with chronic kidney disease was peripheral oedema (benazepril plus amlodipine, 189 of 561, 33.7%; benazepril plus hydrochlorothiazide, 85 of 532, 16.0%). In patients with chronic kidney disease, angio-oedema was more frequent in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group. In patients without chronic kidney disease, dizziness, hypokalaemia, and hypotension were more frequent in the benazepril plus hydrochlorothiazide group than in the benazepril plus amlodipine group. INTERPRETATION: Initial antihypertensive treatment with benazepril plus amlodipine should be considered in preference to benazepril plus hydrochlorothiazide since it slows progression of nephropathy to a greater extent. FUNDING: Novartis. PMID- 20170964 TI - Schistosoma mansoni worm glycolipids induce an inflammatory phenotype in human dendritic cells by cooperation of TLR4 and DC-SIGN. AB - In schistosomiasis, a major human parasitic disease caused by helminths, different life-stages of the parasite contribute to the developing host immune response. To increase our understanding of the mechanisms that play a role in shaping the host immune responses, we have investigated the effects of schistosome glycoconjugates on the phenotype of dendritic cells (DCs), which form a crucial link between the innate and the adaptive immunity. We show here that Schistosoma mansoni worm glycolipids induce DC activation as indicated by upregulation of the maturation markers CD80, CD86 and MHC-II, as well as the production of the cytokines interleukin-12 p40 (IL-12 p40), IL-10, IL-1beta, IL 6, IL-8 and tumor necrosis factor-alpha (TNF-alpha). Co-culture of glycolipid primed DCs with naive T cells results in skewing of the T cell response towards a Th1 profile. Remarkably, the DC activation is dependent on fucosylated glycan moieties of the glycolipids. On the DCs, the C-type lectin DC-SIGN and TLR4 are both critically involved in the induced activation, as was demonstrated by using monoclonal antibodies that block interaction of these receptors with the glycolipids. Furthermore, whereas the worm glycolipids were not able to activate HEK 293 cells expressing TLR4, they did show TLR4 activation after introduction of DC-SIGN in the HEK 293-TLR4 cells. Our data provide evidence for a novel function of DC-SIGN as an essential co-receptor for TLR4-induced activation of human DCs. This mechanism of TLR4 activation by worm glycolipids may contribute to eliciting Th1 immune responses in schistosome infection. PMID- 20170965 TI - Histamine modified 2'-deoxyriboadenosine--potential copper binding site in DNAzymes. AB - Copper(II) complexes of histamine modified 2'-deoxyriboadenosine (N-[(9-beta-D-2' deoxyribofuranosylpurin-6-yl)-carbamoyl]histamine) ligand were studied by potentiometric, UV-visible and EPR techniques. The imidazole residue of the ligand was described as the main binding site forming mono-, bis-(ligand) and dimer complexes, but the interactions between adenosine nitrogen N(1) and carbamoyl nitrogen atoms and the copper(II) ion also were detected. This is the first report evaluating the coordinating ability of such a modified adenosine ligand towards copper(II) ion. Our findings suggest that histamine modified 2' deoxyriboadenosine could chelate efficiently copper(II) ions if it were incorporated into DNAzyme sequence. PMID- 20170966 TI - Metal ion-N7 coordination in a ribozyme branch domain by NMR. AB - The N7 of purine nucleotides presents one of the most dominant metal ion binding sites in nucleic acids. However, the interactions between kinetically labile metal ions like Mg(2+) and these nitrogen atoms are inherently difficult to observe in large RNAs. Rather than using the insensitive direct (15)N detection, here we have used (2)J-[(1)H,(15)N]-HSQC (Heteronuclear Single Quantum Coherence) NMR experiments as a fast and efficient method to specifically observe and characterize such interactions within larger RNA constructs. Using the 27 nucleotides long branch domain of the yeast-mitochondrial group II intron ribozyme Sc.ai5gamma as an example, we show that direct N7 coordination of a Mg(2+) ion takes place in a tetraloop nucleotide. A second Mg(2+) ion, located in the major groove at the catalytic branch site, coordinates mainly in an outer sphere fashion to the highly conserved flanking GU wobble pairs but not to N7 of the sandwiched branch adenosine. PMID- 20170967 TI - Visual modulation of pleasure in subjects with physical and social anhedonia. AB - Anhedonia is a personality trait associated with a decrease in the ability to feel pleasure. We investigated the experience of pleasure in individuals with physical and social anhedonia for positive pictures with varying levels of luminance contrast. Photographs with either a sensory or a social content were modified with a contrast-gradation procedure. Participants had to report the intensity of the pleasure they experienced in response to these pictures. Twenty six subjects with physical anhedonia, 18 with social anhedonia and 34 control subjects completed the task. In controls, high-contrast pictures elicited an intense feeling of pleasure, whereas low contrast pictures elicited little pleasure. Although they were also sensitive to the modulation of contrast, subjects with physical and social anhedonia reported less pleasure than controls, across a larger range of contrast levels for sensory and social pictures, respectively. The findings suggest that the deficit in the experience of positive emotion in anhedonia is associated with a diminished pleasure intensity, fairly selective for the sensory or the social emotion dimension. This study encourages further investigation of the interaction between perceptual encoding and emotional processing in anhedonia. PMID- 20170968 TI - Lymphatic malformations: a proposed management algorithm. AB - OBJECTIVE: The aim of this study was to develop a management algorithm for cervicofacial lymphatic malformations, based on the authors' experience in managing these lesions as well as current literature on the subject. STUDY DESIGN AND METHODS: A retrospective medical record review of all the patients treated for lymphatic malformations at our institution during a 10-year period (1998 2008) was performed. DATA COLLECTED: age at diagnosis, location and type of lesion, radiologic investigation performed, presenting symptoms, treatment modality used, complications and results achieved. RESULTS: 14 patients were identified. Eight (57%) male and six (43%) female. There was an equal distribution between the left and right sides. The majority (71%) of cases were diagnosed within the first year of life. The majority of lesions were located in the suprahyoid region. The predominant reason for referral was an asymptomatic mass in 7 cases (50%) followed by airway compromise (36%) and dysphagia (14%). Management options employed included: observation, OK-432 injection, surgical excision and laser therapy. In 5 cases (36%) a combination of these were used. CONCLUSION: Historically surgical excision has been the management option of choice for lymphatic malformations. However due to the morbidity and high complication rate associated this is increasingly being questioned. Recent advances in sclerotherapy e.g. OK-432 injection have also shown significant promise. Based on experience in managing these lesions as well as current literature the authors of this paper have developed an algorithm for the management of cervicofacial lymphatic malformations. PMID- 20170969 TI - Bioavailability of sorbed phenanthrene and permethrin in sediments to Chironomus tentans. AB - The availability of sorbed hydrophobic organic contaminants (HOCs) to benthic organisms is important for characterizing sediment toxicity. While many studies show a correlation between the rapid desorption HOC pool and bioavailability to benthic organisms, bioavailability of the slow or very slow desorption fraction is still poorly understood. In this study, Chironomus tentans were exposed to phenanthrene (PHE) or permethrin (PM) to derive biota-sediment accumulation factors (BSAFs) in a sediment that was sequentially desorbed with Tenax extraction or amended with a charcoal to modify the distribution of PHE and PM among the rapid (f(rapid)), slow (f(slow)) and very slow (f(vslow)) desorption pools. As the desorption interval was increased, the f(rapid) quickly decreased to zero and became negligible after 12h desorption for PHE and 48h desorption for PM. However, in samples with depleted f(rapid), BSAF values were substantially greater than zero, suggesting availability of f(slow) and f(vslow). A multivariate linear regression model was further used to estimate BSAFs specific to the different desorption pools, i.e., BSAF(rapid), BSAF(slow) or BSAF(vslow). The slow desorption pool was found to be readily available to C. tentans, with BSAF(slow) values ranging from 25.3 to 73.9% of BSAF(rapid). In comparison, BSAF(vslow) ranged from 0 to 5.9% of BSAF(rapid), suggesting a lack of availability. Therefore, the kinetically slow desorption fraction is relatively bioavailable and should not be ignored in sediment toxicity assessment. PMID- 20170970 TI - Controlling and maintaining exposure of hydrophobic organic compounds in aquatic toxicity tests by passive dosing. AB - The risk assessment of hydrophobic organic compounds (HOCs) in aquatic toxicity or bioconcentration tests is a challenge due to their low aqueous solubilities, sorption and losses leading to poorly defined exposure and reduced test sensitivity. Passive dosing overcomes these problems via the continual partitioning of HOCs from a dominating reservoir loaded in a biocompatible polymer such as silicone, providing defined and constant freely dissolved concentrations and eliminating spiking with co-solvents. This study characterised the performance of a passive dosing format for aquatic tests with small organism such as invertebrates and algae, consisting of PDMS silicone cast into the base of the glass test vessel. The PDMS silicone was loaded by partitioning from a methanol solution containing PAHs (logK(OW) 3.56-6.63) as model compounds, followed by removal of the methanol with water. This resulted in highly reproducible PDMS silicone HOC concentrations. When shaking, release of PAHs into aqueous solution was rapid and reproducible, and equilibrium partitioning was reached within 5h for all compounds. The buffering capacity was sufficient to maintain stable concentrations over more than 10 weeks. This format was applied in a 48h Daphnia magna immobilisation assay to test the toxicity of a range of PAHs at their aqueous solubility. D. magna immobilisation did not show a trend with aqueous solubility or hydophobicity (K(OW)) of the PAHs. However, the immobilisation data for all compounds could be fitted with one maximum chemical activity response curve. Those PAHs with the lowest maximum chemical activities resulted in no immobilisation. Naphthalene and phenanthrene showed full toxicity at aqueous solubility, and passive dosing was also used for the concentration response testing of these compounds. The freely dissolved aqueous concentrations causing 50% immobilisation (EC-50) were 1.96 mg L(-1) for naphthalene and 0.48 mg L(-1) for phenanthrene. Therefore, passive dosing is a practical and economical means of improving the exposure of HOCs in aquatic toxicity or bioconcentration tests. PMID- 20170971 TI - Association of single nucleotide polymorphisms in ATM, GSTP1, SOD2, TGFB1, XPD and XRCC1 with clinical and cellular radiosensitivity. AB - PURPOSE: To examine the association of polymorphisms in ATM (codon 158), GSTP1 (codon 105), SOD2 (codon 16), TGFB1 (position -509), XPD (codon 751), and XRCC1 (codon 399) with fibrosis and also individual radiosensitivity. METHODS AND MATERIALS: Retrospective analysis with 69 breast cancer patients treated with breast-conserving radiotherapy; total dose delivered was restricted to vary between 54 and 55Gy. Fibrosis was evaluated according to LENT/SOMA score. DNA was extracted from blood samples; cellular radiosensitivity was measured using the G0 assay and polymorphisms by PCR-RFLP and MALDI-TOF, respectively. RESULTS: Twenty five percent of all patients developed fibrosis of grade 2 or 3. This proportion tends to be higher in patients being polymorphic in TGFB1 or XRCC1 when compared to patients with wildtype genotype, whereas for ATM, GSTP1, SOD2 and XPD the polymorphic genotype appears to be associated with a lower risk of fibrosis. However, none of these associations are significant. In contrast, when a risk score is calculated based on all risk alleles, there was significant association with an increased risk of fibrosis (per risk allele odds ratio (ORs)=2.09, 95% confidence interval (CI): 1.32-3.55, p=0.0005). All six polymorphisms were found to have no significant effect on cellular radiosensitivity. CONCLUSIONS: It is most likely that risk for radiation-induced fibrosis can be assessed by a combination of risk alleles. This finding needs to be replicated in further studies. PMID- 20170972 TI - Discontinuous induction of X-linked inhibitor of apoptosis in EA.hy.926 endothelial cells is linked to NF-kappaB activation and mediates the anti inflammatory properties of low-dose ionising-radiation. AB - BACKGROUND AND PURPOSE: This study aimed to characterize a link between X-linked inhibitor of apoptosis protein (XIAP) expression, apoptosis induction, Nuclear Factor kappa B (NF-kappaB) activity and the anti-inflammatory properties of low dose ionising-radiation (LD-RT). MATERIAL AND METHODS: EA.hy.926 endothelial cells (ECs) were irradiated with doses ranging from 0.3 to 3Gy, and subsequently stimulated by TNF-alpha, and XIAP expression was either detected by immunoblotting or TaqMan-PCR. Apoptosis was quantified by AnnexinV staining or by caspase 3/7 activity assays. NF-kappaB transcriptional activity was analysed by a luciferase reporter assay, secretion of Transforming Growth Factor beta 1 (TGF beta(1)) and adhesion of peripheral blood mononuclear cells (PBMC) to EC were quantified using ELISA and adhesion assays. RESULTS: LD-RT of the activated EA.Hy.926 EC induces XIAP expression in a discontinuous manner with a relative maximum at 0.5Gy and 3Gy which parallels a discontinuity in apoptosis induction and caspase 3/7 activity. siRNA-mediated attenuation of XIAP resulted in an increased rate of apoptosis, a hampered NF-kappaB transcriptional activity and a diminished secretion of TGF-beta(1). As compared to control-siRNA treated cells, adhesion of PBMC to EC was increased in XIAP depleted EA.Hy.926 EC. CONCLUSION: The modulation of apoptosis, NF-kappaB activity and TGF-beta(1) by XIAP in irradiated and subsequent stimulated EC contributes to an impaired PBMC/EC adhesion and to the anti-inflammatory properties of LD-RT. PMID- 20170973 TI - Vorsprung durch Technik: evolution, implementation, QA and safety of new technology in radiotherapy. PMID- 20170974 TI - Radiosurgery scope of practice in Canada: a report of the Canadian association of radiation oncology (CARO) radiosurgery advisory committee. AB - Radiosurgery has a long history in Canada. Since the treatment of the first patient at the McGill University Health Center in 1985, radiosurgery programs have been developed from coast to coast. These have included multidisciplinary teams of radiation oncologists, neurosurgeons, medical physicists, radiation technologists and other health professionals. In 2008, the CARO Board of Directors requested that a working group be formed to define the role of the radiation oncologist in the practice of radiosurgery. Taking into account evolving technology, changing clinical practice and current scope of practice literature, the working group made recommendations as to the role of the radiation oncologists. These recommendations were endorsed by the Canadian Association of Radiation Oncology board of directors in September 2009 and are present herein. It is recognized that patients benefit from a team approach to their care but it is recommended that qualified radiation oncologists be involved in radiosurgery delivery from patient consultation to follow-up. In addition, radiation oncologists should continue to be involved in the administrative aspects of radiosurgery programs, from equipment selection to ongoing quality assurance/quality improvement. PMID- 20170975 TI - Identification of a common autoantigenic epitope of protein disulfide isomerase, golgin-160 and voltage-gated potassium channel in type 1 diabetes. AB - A common epitope of proteins golgin-160, voltage-gated potassium channel and disulfide isomerase was identified by screening with autoantibodies of a type 1 diabetic (T1D) patient a lambdaUni-Zap cDNA library from human diabetic islets. The significance of the identified autoantigens to the disease pathogenesis remains to be elucidated. PMID- 20170976 TI - Evaluation of policies to support drug development in New Zealand. AB - OBJECTIVES: Changes in the traditional model of drug development are creating a potential opportunity for New Zealand's drug development industry. This research evaluates whether New Zealand could utilise some of the policies employed by countries with successful drug development industries. METHODS: A framework to support a drug development industry was developed by taking into account policies that affect the industry. The framework was then used to analyse the types of policies provided by different countries and to postulate six different models that support a pharmaceutical industry. RESULTS: Countries with a successful drug development industry have identified their strengths, analysed the opportunities in the industry, and have employed consistent and specific policies in support of their industry. New Zealand's policy in support of its drug development industry is most similar to that of the medical research-based model of the UK, Australia and Canada. CONCLUSIONS: New Zealand needs to develop a consistent policy for support of its drug development industry based on identifying and focussing on the competencies where it is internationally competitive. A strong partnership with Australia could capitalise on the strengths of both countries and linkages with other Asia-Pacific countries could further promote the region's capabilities in drug development research. PMID- 20170977 TI - Structure and management of tuberculosis control programs in fragile states- Afghanistan, DR Congo, Haiti, Somalia. AB - OBJECTIVES: Health care delivery is particularly problematic in fragile states often connected with increased incidence of communicable diseases, among them tuberculosis. This article draws upon experiences in tuberculosis control in four fragile states from which four lessons learned were derived. METHODS: A structured inventory to extract common themes specific for TB control in fragile states was conducted among twelve providers of technical assistance who have worked in fragile states. The themes were applied to the TB control programs of Afghanistan, DR Congo, Haiti and Somalia during the years 2000-2006. RESULTS: Case notifications and treatment outcomes have increased in all four countries since 2003 (treatment success rates 81-90%). Access to care and case detection however have remained insufficient (case detection rates 39-62%); There are four lessons learned: 1. TB control programs can function in fragile states. 2. National program leadership and stewardship are essential for quality and sustained TB control. 3. Partnerships with non-governmental providers are vital for continuous service delivery; 4. TB control programs in fragile states require consistent donor support. CONCLUSION: Despite challenges in management, coordination, security, logistics and funding, TB control programs can function in fragile states, but face considerable problems in access to diagnosis and treatment and therefore case detection. PMID- 20170978 TI - A bibliometric analysis of scientific production in mesothelioma research. AB - This study aims at comparing scientific production in malignant mesothelioma (MM) among countries and evaluating publication trends and impact factor (IF). The PubMed database was searched with a strategy combining keywords listed in the Medical Subject Headings and free-text search. Publications numbers and IF were evaluated both as absolute values and after standardization by population and gross domestic product (GDP). 5240 citations were retrieved from the biennium 1951-1952 (n = 22) to 2005-2006 (n = 535). The 177% increase of MM publications from 1987 to 2006 exceeded by large the corresponding value of total cancer literature (123.5%). In these two decades, 2559 articles with IF were published: 46.4% came from the European Union (EU) (the UK, Italy and France ranking at the top), and 36.2% from the US. The highest mean IF was reported for the US (3.346), followed by Australia (3.318), and EU (2.415, with the UK, Belgium and the Netherlands first). Finland, Sweden and Australia had the best ratio between IF (sum) and resident population or GDP. The number of publications correlated with GDP (p = 0.001) and national MM mortality rates (p = 0.002). An association was found between a country commitment to MM research and the burden of disease (p = 0.04). Asbestos, survival, prognosis, occupational exposure, differential diagnosis, and immunohistochemistry were the most commonly used keywords. This report represents the first effort to explore the geographical and temporal distribution of MM research and its determinants. This is an essential step in understanding science priorities and developing disease control policies. PMID- 20170979 TI - Storage lipids as a source of carbon skeletons for asparagine synthesis in germinating seeds of yellow lupine (Lupinus luteus L.). AB - The (14)C-acetate metabolism and regulatory functions of sucrose and sodium fluoride (NaF) were examined in embryo axes and cotyledons isolated from yellow lupine seeds and grown in vitro. After 15 min of incubating organs in solutions of labeled acetate, more radioactivity was found in amino acids (particularly in glutamate, asparagine and glutamine) than in sugars. After 120 min of incubation, (14)C was still localized mainly in amino acids (particularly in asparagine and glutamate). The (14)C atoms from position C-1 of acetate were mostly localized in the liberated (14)CO(2), whereas those from position C-2 were incorporated chiefly into amino acids, sugars and the insoluble fraction of the studied organs. The addition of NaF caused a decrease in the amount of (14)C incorporated into amino acids and in the insoluble fraction. The influence of NaF on incorporation of (14)C into sugars differed between organs. In embryo axes, NaF inhibited this process, but in cotyledons it stimulated (14)C incorporation into glucose. The release of (14)CO(2) with the C-1 and C-2 carbon atoms from acetate was more intensive in embryo axes and cotyledons grown on a medium without sucrose. This process was markedly limited by NaF, which inhibits glycolysis and gluconeogenesis. Alternative pathways of carbon flow from fatty acids to asparagine are discussed. PMID- 20170980 TI - Contribution of momilactone A and B to rice allelopathy. AB - Eight cultivars of rice (Oryza sativa L.) inhibited shoot and root growth of Echinochloa crus-galli when co-cultured with rice seedlings in a bioassay medium. Momilactone A and B were found in the bioassay medium of all rice cultivars, and concentrations of momilactone A and B in the medium were 0.21-1.5 and 0.66-3.8 micromol/L, respectively, indicating that all rice cultivars may secrete momilactone A and B into the medium. Exogenously applied momilactone A and B inhibited the growth of shoots and roots of E. crus-galli at concentrations greater than 30 and 1 micromol/L, respectively. The concentrations required for 50% growth inhibition of E. crus-galli shoots and roots, respectively, were 146 and 91 micromol/L for momilactone A and 6.5 and 6.9 micromol/L for momilactone B. Considering the growth inhibitory activity and concentrations found in the bioassay medium, momilactone A may have caused only 0.8-2.2% of the observed growth inhibition of E. crus-galli roots and shoots by rice. However, momilactone B in the medium was estimated to be able to cause 59-82% of the observed growth inhibition of E. crus-galli roots and shoots by the rice seedlings. In addition, the concentrations of momilactone B in the medium reflected the observed differences in the growth inhibition of E. crus-galli by the eight rice cultivars investigated. This suggests that the allelopathic activity of rice may depend primarily on the secretion level of momilactone B. Therefore, momilactone B may play a very important role in rice allelopathy. PMID- 20170981 TI - cGMP is required for seed germination in Arabidopsis thaliana. AB - Cyclic guanosine 3',5'-monophosphate (cGMP) is an important second messenger in animals, and is emerging as a player in regulatory functions in plants. In this study, we investigated the role of cGMP in seed germination in Arabidopsis thaliana (Col-0). We demonstrated that both, a membrane-permeant analogue of cGMP (8-Br-cGMP) and the cyclic nucleotide phosphodiesterase (PDE) inhibitor Tadalafil promoted A. thaliana seed germination, whereas the guanylate cyclase inhibitor LY 83583 (6-anilino-5,8-quinolinedione; LY) inhibited it. LY blocked gibberellic acid (GA)-induced seed germination, whereas GA and 8-Br-cGMP co-treatment increased the germination rate and more effectively overcame LY-inhibition than 8 Br-cGMP alone. The gibberellin biosynthesis inhibitor paclobutrazol (PAC) also blocked 8-Br-cGMP and Tadalafil promotion of seed germination. Furthermore, 8-Br cGMP and Tadalafil decreased abscisic acid (ABA) sensitivity during seed germination. These findings highlight that cGMP is a positive regulator and plays a crucial role in Arabidopsis seed germination. Furthermore, both GA and cGMP are required for seed germination. PMID- 20170982 TI - Outbreak of carbapenem-resistant Pseudomonas aeruginosa infection in a surgical intensive care unit. AB - Infection control personnel performing surveillance activities noticed a cluster of patients with isolates of carbapenem-resistant Pseudomonas aeruginosa (CRPA) in the surgical intensive care unit (SICU) of a German University Hospital. An outbreak investigation including a descriptive analysis, a case-control study comparing 15 CRPA case patients with 18 patients with carbapenem-susceptible P. aeruginosa, environmental sampling and pulsed-field gel electrophoresis (PFGE) typing of P. aeruginosa isolates was carried out. Fifteen patients acquired CRPA in the SICU during the outbreak period between 1 July 2006 and 31 October 2006 and PFGE typing of 11 available patient isolates revealed two outbreak strains as well as sporadic CRPA isolates. Both outbreak strains were resistant to penicillins, cephalosporins, carbapenems, aminoglycosides and quinolones, and remained susceptible only to colistin. The most likely mode of transmission was cross-transmission between patients during postoperative wound care with abdominal and/or thoracic drains (odds ratio: 64.33; 95% confidence interval: 5.32-999) and therapy with quinolones (48.37; 3.71-999) being independent risk factors for acquisition of CRPA. No further clusters of CRPA cases were observed after implementation of contact isolation precautions and after healthcare workers were made aware of the likely mode of transmission. This study shows the complex epidemiology of CRPA in a SICU including cross-transmission of two CRPA strains related to postoperative wound care. PMID- 20170983 TI - Nosocomial outbreak of biotype I, multidrug-resistant, serologically non-typeable Haemophilus influenzae in a respiratory care ward in Taiwan. PMID- 20170984 TI - Characterisation of vancomycin-resistant enterococci from hospitalised patients at a tertiary centre over a seven-year period. AB - Vancomycin-resistant enterococci (VRE) were isolated from 41 patients at a medical centre in southern Taiwan from 1999 to 2005. This accounted for 0.55% of 7449 patients with clinical colonisation or infection due to Enterococcus species. Nine (22%) patients had clinical infections caused by VRE. Twenty-five (61%) VRE isolates were Enterococcus faecalis with VanA phenotype and vanA gene cluster, the remaining 16 (39%) isolates were Enterococcus faecium with VanB phenotype and vanB (15 isolates) or vanA (1 isolate) gene cluster. The esp gene cluster was found in 6 (24%) E. faecalis isolates and 14 (87.5%) E. faecium isolates, and hyl in 2 (8%) E. faecalis and 6 (37.5%) E. faecium isolates. Analysis of SmaI-digested DNA by pulsed-field gel electrophoresis revealed that most isolates of E. faecalis were distinct, indicating a limited person-to-person spread or sporadic nature of spread. By contrast, 10 (67%) of 15 VanB phenotype E. faecium isolates were identical, suggesting the presence of an occult and limited clonal spread at the hospital. The presence of the esp or hyl gene was not associated with the virulence or outbreak of VRE. In summary, epidemiological data and molecular typing suggest that there was occult clonal spread of VanB phenotype-vanB genotype E. faecium in the surgical ICU, and the limited person-to person spread or sporadic nature of E. faecalis. Infection control measures are warranted due to the potential for spread of VRE. PMID- 20170985 TI - [Longitudinal studies on aging: past, present and future]. AB - Longitudinal studies on aging have played an important role in the development of gerontology and geriatrics, and have multiplied in the last 30 years. This is related to methodological advantages of this type of design and to issues closely connected to geriatrics itself. The understanding of the complex process of aging and its associated clinical and functional consequences, which are usually slow, requires a sufficiently long observation and follow-up. In this article, along with historical and methodological aspects, we examine possible future lines development for longitudinal studies on ageing. PMID- 20170987 TI - Application of PC-ANN and PC-LS-SVM in QSAR of CCR1 antagonist compounds: a comparative study. AB - Principal component regression (PCR), principal component-artificial neural network (PC-ANN), and principal component-least squares-support vector machine (PC-LS-SVM) as regression methods were investigated for building quantitative structure-activity relationships for the prediction of inhibitory activity of some CCR1 antagonists. Nonlinear methods (PC-ANN and PC-LS-SVM) were better than the PCR method considerably in the goodness of fit and predictivity parameters and other criteria for evaluation of the proposed model. These results reflect a nonlinear relationship between the principal components obtained from molecular descriptors and the inhibitory activity of this set of molecules. The maximum variance in activity of the molecules, in PCR method was 45.5%, whereas nonlinear methods, PC-ANN and PC-LS-SVM, could explain more than 93.7% and 95.6% variance in activity data respectively. PMID- 20170986 TI - Assessing the chemical diversity of an hsp90 database. AB - The 90-kDa heat shock protein (hsp90) has emerged as a new, promising target for cancer drug discovery. With the simultaneous disruption of a large range of oncogenic pathways, hsp90 inhibition results in either cytostasis or cell death. Diverse inhibitors of this molecular chaperone are currently under intensive study, and several have reached clinical trials. In the present work, patented and published structure-activity relationships on hsp90 inhibitors were organised in a database format that associates chemical structures with their biological activities. This hsp90 database contains 814 unique structures and, to our knowledge, is the most complete ever reported. With the aim to provide a general overview and evaluation of the chemical diversity of the ligands included in the dataset, a two-dimensional analysis was performed. A set of twenty-five topological molecular descriptors was calculated, allowing the emphasis of those that have higher importance for hsp90 active compounds, and for the three chemical scaffold families, geldanamycins, purines and pyrazole-isoxazoles. We have used a principal-component analysis (PCA) computational approach to analyse the 2D descriptor space of active and non-active hsp90 ligands. Furthermore, a fragment-based study highlighted the most frequently moieties represented in the active purine and pyrazole-isoxazole derivatives that are likely to be responsible for the observed biological activities. PMID- 20170988 TI - Design, synthesis and biological evaluation of new ionone derivatives as potential neuroprotective agents in cerebral ischemia. AB - A new series of ionone derived allylic alcohols have been evaluated for anti ischemic activity. Out of them, 12f and 13b decreased infarct volume to 23.98+/ 4.7 mm3 and 93.98+/-24.8 mm3 as compared to ischemic group. PMID- 20170989 TI - Novel 3-alkanoyl/aroyl/heteroaroyl-2H-chromene-2-thiones: synthesis and evaluation of their antioxidant activities. AB - A facile, convenient and high yielding synthesis of a combinatorial library of 3 alkanoyl/aroyl/heteroaroyl-2H-chromene-2-thiones has been developed by the condensation of easily accessible beta-oxodithioesters and salicylaldehyde/substituted 2-hydroxybenzaldehydes under solvent-free conditions. The assessment of radical scavenging capacity of the compounds towards the stable free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) was measured and these compounds were found to scavenge DPPH free radical efficiently. Five selected compounds were able to protect curcumin from the attack of sulfur free radical generated by radiolysis of glutathione (GSH). The newly synthesized compounds exhibited profound antioxidant activities. Five of them rendered comparatively high antioxidant capacity. PMID- 20170990 TI - [Gastrointestinal sarcoidosis]. AB - INTRODUCTION: Sarcoidosis is a granulomatous disorder of unknown cause, characterised by noncaseating granulomas affecting multiple organs. Gastrointestinal tract involvement in sarcoidosis is rare. The stomach, particularly the antrum is the most common extra-hepatic organ to be involved. We report four cases of gastro-intestinal sarcoidosis. METHODS: Retrospective study of a series of four cases. RESULTS: All patients had gastric sarcoidosis. It involved the duodenum, ileum and gall bladder in a patient with a history of an acute pancreatitis probably due to sarcoidosis. This patient presented with obstructive intestinal manifestations, weight loss and exsudative enteropathy. Two patients presented with mild abdominal pain and the last patient was admitted for upper gastrointestinal bleeding. The endoscopy was normal in one case and showed an antral congestion in another case. Gastric ulcers were found in the patient with a history of upper gastro-intestinal bleeding. A pseudo-linitic aspect was noticed in the patient with obstructive manifestations. The duodenum and the ileum were normal. This patient had an antrectomy and was treated with corticosteroids. Surgery evidenced a perforated duodenal ulcer, which was obstructed by the gall bladder. The patient with gastrointestinal bleeding received proton pump inhibitor and corticosteroids. These two patients improved gradually. The two other patients recovered spontaneously. CONCLUSION: The stomach is the most commonly affected organ in gastrointestinal sarcoidosis. Gastric sarcoidosis can mimic a malignant lesion owing to narrowing of the gastric lumen or can be revealed by upper gastrointestinal bleeding. Duodenum, small bowel and colon involvement is uncommon but may be underestimated in the absence of systematic biopsies. PMID- 20170991 TI - Do patients with lymphoedema cholestasis syndrome 1/Aagenaes syndrome need dietary counselling outside cholestatic episodes? AB - BACKGROUND & AIMS: Patients with lymphoedema cholestasis syndrome 1/Aagenaes Syndrome need a fat reduced diet when cholestatic. We wanted to assess the need for dietary counselling outside cholestatic episodes, and hypothetized that no counselling was needed. METHODS: Fifteen patients above 10 years of age without symptoms of cholestasis were compared with a sex and age matched control group. Diet from a four-day weighed record and blood samples were compared between the two groups and with general Norwegian recommendations. RESULTS: The patients had a similar diet to the healthy controls, except for statistically significant lower intake of energy from total fat (p=0.04) and saturated fat (0.02), and fish (0.05). The patients met the dietary recommendations for macronutrients, except for saturated fat, monounsaturated fat, refined sugar and fibre. Supplements were needed to meet the micronutrient recommendations. Patients had a significantly lower serum level of alpha-tocopherol (0.01) compared with the control group, and the serum 25-OH D level was below reference ranges. CONCLUSIONS: The patients would benefit from counselling on fat quality, carbohydrates including fibre intake, and individual needs for vitamins D and E. To secure serum 25-OH D and alpha-tocopherol levels within reference ranges, regular examinations to determine the need for supplementary vitamins D and E are recommended. PMID- 20170992 TI - Overview of strontium-89,90 deposition measurements in Finland 1963-2005. AB - In Finland the deposition of strontium-89 (90Sr) and strontium-90 (90Sr) has been monitored since the early 1960s. The measured cumulative 90Sr deposition in 1963 2005 is on average 1200 Bq m(-2), of which 150 Bq m(-2) originates from the Chernobyl accident. Adding to this the deposition in 1945-1962 produces a value of 2040 Bq m(-2) for the cumulative deposition in Finland. The nuclear explosion derived deposition up to 1985 obtained in this study, 1850 Bq m(-2), is in good agreement with the zonal 90Sr deposition of 1740 Bq m(-2) in the 60 degrees N-70 degrees N latitude band estimated by UNSCEAR. The regional deposition patterns of 89Sr and 90Sr following the Chernobyl accident resemble those of the refractory nuclides such as 239,240Pu and 95Zr. The total deposition of Chernobyl-derived 90Sr in Finland was about 5.3 x 10(13) Bq. This activity corresponds to 0.027% of the reactor core inventory and 0.66% of the atmospheric emissions from the accident. The corresponding figures for 89Sr are 4.5 x 10(14) Bq, 0.023% and 0.56%, respectively. PMID- 20170993 TI - Correction of skeletal Class II--anterior deep bite and prominent chin by forced surgical rotation of the mandible. AB - The purpose of this paper is to describe a technique of forced surgical rotation of the mandible used in skeletal Class II patients with deep bite and prominent chin. Posterior occlusal composite onlays combined with preoperative orthodontic treatment without anterior intrusion increase the posterior rotational component of the surgical mandibular advancement, when removed during operation. This manoeuvre allows for the surgical closure of the posterior open bite, while anteriorly the deep bite is opened. This technique avoids bimaxillary rotation surgery with dorsal impaction in mild to moderate cases. In any case, a chin setback osteotomy with compromised aesthetics can be avoided. PMID- 20170994 TI - Surgically assisted rapid palatal expansion (SARPE). PMID- 20170996 TI - The distribution characteristics of pollutants released at different cross sectional positions of a river. AB - The distribution characteristics of heavier or lighter pollutants released at different cross-sectional positions of a wide river is investigated with a well tested three-dimensional numerical model of gravity flows based on Reynolds Averaged Navier-Stokes equations and turbulence k-epsilon model. By focusing on investigating the influences of flow and buoyancy on pollutants, it is found that while carrying by the river flow downstream: i) a heavier pollutant released from the cross-sectional side position, forms transverse oscillation between two banks with decreased amplitude, i.e. forms kind of helical flow pattern along the straight part of channel bed; ii) a heavier pollutant released from the cross sectional middle position, forms collapse oscillation in the middle of the straight channel part with reduced amplitude; iii) in the downstream sinuous channel, heavier pollutant is of higher concentration on the outer side of channel bends; iv) a light pollutant released from the cross-sectional side position, slips partly to the other side of the river, resulting in higher concentrations on two sides of the channel top; v) a light pollutant released from the cross-sectional middle position, splits into two parts symmetrically along two sides of the channel top; vi) in the downstream sinuous channel, light pollutant presents higher concentration on the inner side of channel bends. These findings may assist in cost-effective scientific countermeasures to be taken for accidental or planned pollutant releases into a river. PMID- 20170995 TI - The use of transcutaneous electrical nerve stimulation (TENS) for pain relief in labour: a review of the evidence. AB - OBJECTIVE: to assess the effects of transcutaneous electrical nerve stimulation (TENS) for pain relief in labour. SEARCH METHODS: studies were identified from a search of the Cochrane Pregnancy and Childbirth Group's Trials Register (November 2008). SELECTION CRITERIA: randomised controlled trials comparing women receiving TENS for pain relief in labour vs routine care or placebo devices. All types of TENS machines were included. DATA COLLECTION AND ANALYSIS: two review authors assessed all trials identified by the search strategy, carried out data extraction and assessed risk of bias. RESULTS: 14 studies including 1256 women were included: 11 examined TENS applied to the back, two to acupuncture points and one to the cranium. Overall, there was little difference in satisfaction with pain relief or in pain ratings between TENS and control groups, although women receiving TENS to acupuncture points were less likely to report severe pain (risk ratio 0.41, 95% confidence interval 0.32-0.55). The majority of women using TENS would use it again in a future labour. There was no evidence that TENS had any impact on interventions and outcomes in labour. There was little information on outcomes for mothers and infants. No adverse events were reported. CONCLUSIONS: there is only limited evidence that TENS reduces pain in labour and it does not seem to have any impact on other outcomes for mothers or infants. The use of TENS at home in early labour has not been evaluated. Although the guidelines of the National Institute for Health and Clinical Excellence recommend that TENS should not be offered to women in labour, women appear to be choosing it and midwives are supporting them in their choice. Given the absence of adverse effects and the limited evidence base, it seems unreasonable to deny women that choice. More robust studies of effectiveness are needed. PMID- 20170997 TI - Sediment-water distribution of perfluorooctane sulfonate (PFOS) in Yangtze River Estuary. AB - Analysis of Perfluorooctane sulfonate (PFOS) distribution in water and sediment in Yangtze River Estuary showed that the estuary was a sink for PFOS. Salinity was an important parameter in controlling the sediment-water interactions and the fate or transport of PFOS in the aquatic environment. As the salinity (S per thousand) increased from 0.18 to 3.31, the distribution coefficient (K(d)) between sediment and water linearly increased from 0.76 to 4.70 L g(-1). The study suggests that PFOS may be carried with the river water and transported for long distances before it reaches to the sea and largely scavenged to the sediment in the estuaries due to the dramatic change in salinity. PMID- 20170999 TI - Spanning the know-do gap: understanding knowledge application and capacity in long-term care homes. AB - Using a multiple case study design, this article explores the translation process that emerges within Ontario long-term care (LTC) homes with the adoption and implementation of evidence-based clinical practice guidelines (CPGs). Within organization knowledge translation is referred to as knowledge application. We conducted 28 semi-structured interviews with a range of administrative and care staff within 7 homes differentiated by size, profit status, chain membership, and rural/urban location. We further undertook 7 focus groups at 5 locations, involving a total of 35 senior clinical staff representing 15 homes not involved in earlier structured interviews. The knowledge application process that emerges across our participant organizations is highly complex, iterative, and reliant upon a facility's knowledge application capacity, or absorptive capacity to effect change through learning. Knowledge application capacity underpins the emergence of the application process and the advancement of knowledge through it. We find that different elements of capacity are important to different stages of the knowledge application process. Capacity can pre-exist, or can be acquired. The majority of the capacity elements required for successful knowledge application in the LTC contexts we studied were organizational. It is essential for managers and practitioners therefore to conceptualize and orchestrate knowledge application initiatives at the organization level; organizational leaders (including clinical leaders) have a vital role to play in the success of knowledge application processes. PMID- 20170998 TI - Optimism. AB - Optimism is an individual difference variable that reflects the extent to which people hold generalized favorable expectancies for their future. Higher levels of optimism have been related prospectively to better subjective well-being in times of adversity or difficulty (i.e., controlling for previous well-being). Consistent with such findings, optimism has been linked to higher levels of engagement coping and lower levels of avoidance, or disengagement, coping. There is evidence that optimism is associated with taking proactive steps to protect one's health, whereas pessimism is associated with health-damaging behaviors. Consistent with such findings, optimism is also related to indicators of better physical health. The energetic, task-focused approach that optimists take to goals also relates to benefits in the socioeconomic world. Some evidence suggests that optimism relates to more persistence in educational efforts and to higher later income. Optimists also appear to fare better than pessimists in relationships. Although there are instances in which optimism fails to convey an advantage, and instances in which it may convey a disadvantage, those instances are relatively rare. In sum, the behavioral patterns of optimists appear to provide models of living for others to learn from. PMID- 20171000 TI - Violence victimization among Finnish university students: prevalence, symptoms and healthcare usage. AB - The present study examined the prevalence of various forms of violence victimization among university students in Finland. Violence victimization was analyzed in relation to physical and mental health symptoms, and the use of student healthcare services. A cross-sectional Student Health Survey was performed as a national postal survey for Finnish university students in 2004. In the next phase of the study, an additional postal survey regarding violence victimization was sent to those who had answered the original survey, which resulted in a sample of 905 students. It was found that violence victimization and violence-related health issues were markedly prevalent among Finnish university students. The students reported multiple forms of violence and injury demonstrating the diversity of violence victimization. Male and female victims differed both in the amount and type of symptoms, and in their relationship to the abuser/offender. Violence victimization and gender had a significant main effect on specific symptoms, while no interaction effect was found. The data also showed that violence victimization is overrepresented among frequent healthcare users. These findings have implications for clinical practice and public policy. The present findings provide useful information for policy makers and healthcare professionals concerning the health effects of violence in accordance with the use of healthcare services. More specifically, this information should be taken into consideration when planning student healthcare and could serve as a guideline for student healthcare management. PMID- 20171001 TI - Racial and social class gradients in life expectancy in contemporary California. AB - Life expectancy, or the estimated average age of death, is among the most basic measures of a population's health. However, monitoring differences in life expectancy among sociodemographically defined populations has been challenging, at least in the United States (US), because death certification does not include collection of markers of socioeconomic status (SES). In order to understand how SES and race/ethnicity independently and jointly affected overall health in a contemporary US population, we assigned a small-area-based measure of SES to all 689,036 deaths occurring in California during a three-year period (1999-2001) overlapping the most recent US census. Residence at death was geocoded to the smallest census area available (block group) and assigned to a quintile of a multifactorial SES index. We constructed life tables using mortality rates calculated by age, sex, race/ethnicity and neighborhood SES quintile, and produced corresponding life expectancy estimates. We found a 19.6 (+/-0.6) year gap in life expectancy between the sociodemographic groups with the longest life expectancy (highest SES quintile of Asian females; 84.9 years) and the shortest (lowest SES quintile of African-American males; 65.3 years). A positive SES gradient in life expectancy was observed among whites and African-Americans but not Hispanics or Asians. Age-specific mortality disparities varied among groups. Race/ethnicity and neighborhood SES had substantial and independent influences on life expectancy, underscoring the importance of monitoring health outcomes simultaneously by these factors. African-American males living in the poorest 20% of California neighborhoods had life expectancy comparable to that reported for males living in developing countries. Neighborhood SES represents a readily available metric for ongoing surveillance of health disparities in the US. PMID- 20171002 TI - Rapid sequence airway vs rapid sequence intubation in a simulated trauma airway by flight crew. AB - BACKGROUND: Rapid sequence airway (RSA) utilizes rapid sequence intubation (RSI) pharmacology followed by the placement of an extraglottic airway without direct laryngoscopy. STUDY OBJECTIVE: To evaluate the difference in time to airway placement and lowest oxygen saturations in a simulated trauma patient using RSI or RSA with a Laryngeal Mask Airway-Supreme (LMAS). METHODS: This randomized, prospective, non-blinded, IRB-approved observational study used a SimMan human simulator in an ambulance. FC were randomly assigned to initially manage the patient with RSI or RSA. They then completed the same scenario with the other modality to serve as their own control. Trained assistants performed directed tasks. SimMan had an initial grade III view and desaturated along a standardized curve until intubation, LMAS, or bag-valve-mask ventilation (BVMV) was initiated. When BVMV was used, oxygen saturation increased along a standardized curve. The simulator's airway converted to a grade II view after the first attempt if difficult airway maneuvers were applied. Time, oxygen saturation, number of attempts and back-up airway placement were recorded. RESULTS: Nineteen FC completed both paired modalities. Paired T-test was used for statistical analysis. Average time to secure the airway was 145 s shorter in the RSA group (95% CI: 100.4-189.7). Lowest oxygen saturation was 4.8% higher (95% CI: 2.8-6.8) in the RSA group. During RSI, FC placed a back-up airway 47% of the time. CONCLUSION: In a simulated moderately difficult trauma airway managed by FC, RSA results in a significantly shorter time to secure the airway and less hypoxemia compared to RSI. PMID- 20171003 TI - Macrolide antibiotics in the treatment of asthma. An update. AB - It seems clear that certain macrolide antibiotics exert anti-inflammatory and immune modulating effects beyond their purely antibacterial action, as has been demonstrated in a number of bronchial inflammatory disorders such as diffuse panbronchiolitis. Randomised, controlled clinical trials involving larger patient samples are needed to confirm whether these actions are of clinical relevance in application to asthma. On the other hand, the macrolide antibiotics have a long half-life, with a prolonged elimination interval, which appears to favour the development of resistances that persist over the long term, as in the case of azithromycin. Would the risk/benefit ratio of sustained low-dose macrolide use be justified, considering the risk of selecting resistant strains? A number of questions must be answered before these drugs can be recommended in application to asthmatic patients: In which patients should they be used? Which drug or drugs would be most appropriate? What would the recommended dose be, and for how long should treatment be administered? What adverse effects can be expected? PMID- 20171004 TI - Interfacial mechanism of lipolysis as self-regulated process. AB - Obesity is a serious public health concern with an increasing prevalence worldwide. The diet contributes strongly to this problem and high-fat food leads to unhealthy conditions. Fat digestion is an energy intensive process as it requires hydrolysis to allow the body to profit from this nutrient. This additional energy expenditure is also present in a highly redundant hormonal regulation system for fat storage which is converted in not a readily accessible form (therefore, an upstream is required in order to tackle fat-related diseases). Due to the low water solubility of oils and fats, the lipase catalyzed reactions take place at a specific locus, the oil-water interface. Despite considerable efforts in the past the effects of the interfacial composition on lipase activity have been only qualitatively understood until recently. It has recently been undertaken a detailed study of the interfacial behavior of lipases, their substrates and products which have contributed to shed light into the mechanism of lipolysis [1-4]. In addition, there are strong evidences that lipase activity is a function of interfacial composition and changes concurrently with lipolytic conversion [1]. In these cases lipase "inhibition" should be attributed to substrate depletion and not to lipase desorption or denaturation as previously hypothesized [5]. This self-limiting effect through the feedback of interfacial composition to the reaction conditions of the enzyme opens a new avenue to control lipase catalysis through the interface. A set of experiments are proposed which can be performed to further characterize and gain a deeper insight into interfacial enzymology. PMID- 20171005 TI - Anti-aggregation properties of trehalose on heat-induced secondary structure and conformation changes of bovine serum albumin. AB - During our experimental work, aggregation of bovine serum albumin was obtained incubating the protein solution at 60 degrees C to investigate temperature induced secondary structure, conformation changes and anti-aggregative activity of trehalose. IR-measurements suggested that in the presence of 1.0M of trehalose there is a little increase in short segment connecting alpha-helical and a clearly decrease in the loss of alpha-helix structure and in the formation of intermolecular and antiparellel beta-sheet up to 78 and 55%, respectively. Useful information also arose following the temperature evolution of Amide I' band profile in the range of temperature between 25 and 90 degrees C in absence or in presence of 1.0M trehalose. Complementary information is obtained by electrophoresis, circular dichroism, fluorescence spectroscopy, titration of SH groups and light scattering measurements. Results encouraged biotechnology and pharmaceutical application of the disaccharide and provided evidence for its utilization in degenerative diseases evolving via aggregation process. PMID- 20171006 TI - Low quality of evidence for robot-assisted laparoscopic prostatectomy: a problem not only in the robotic literature. PMID- 20171007 TI - The ground water ammonium sorption onto Croatian and Serbian clinoptilolite. AB - The removal of ammonium from the Valpovo region ground water (VGW) with the use of natural clinoptilolite samples from the Donje Jesenje deposit (Croatia) and the Zlatokop deposit in Vranjska Banja (Serbia) was studied. The natural Serbian (SZ) and Croatian zeolites (CZ) were transformed to the Na-form (Na-CZ and Na-SZ) in order to increase the exchange capacity of zeolite. The CZ and SZ theoretic ammonium sorption capacities were 24.24 mg NH(4)(+)/g CZ and 32.55 mg NH(4)(+)/g SZ, respectively. The application of natural and Na-form of clinoptilolite for efficient removal of ammonium ions from VGW was further investigated. For that purpose, the four "filter guard" vessels filled with zeolite samples were set in parallel in the ground water purification pilot plant. The complete ammonium removal, with the use of SZ and Na-SZ was achieved during 20 h. After having observed saturation of clinoptilolite, the samples were regenerated with the use of 2 mol/L NaCl, and reused for determination of ammonium sorption efficiency. The regenerated samples showed to be still very efficient for NH(4)(+) removal and, in addition, the SZ was shown as superior for ammonium removal in comparison to the CZ. PMID- 20171008 TI - Template-free sol-gel preparation and characterization of free-standing visible light responsive C,N-modified porous monolithic TiO2. AB - Visible light responsive C,N-modified porous monolithic titania (MT(f)) has been successfully synthesized. The template-free sol-gel synthesis method accompanied by phase separation and in situ C,N-modification has been used. The molar ratio of water to tetrabutyl titanate (f) in starting solution plays an important role in the porous structure and photoactivity of MT(f). Scanning electron microscopy (SEM) analysis and N(2) adsorption-desorption analysis show that MT(f) possess mesoporous structure as well as macroporous structure. MT(22) has been further characterized by using X-ray powder diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and UV-vis diffuse reflectance spectra (DRS). The results show that both nitrogen and carbon elements exist in MT(22) and result in the visible light photocatalytic activity of MT(22). The observed reaction rate of decolorization of methyl orange is 0.0026 min(-1). PMID- 20171009 TI - Loose ligation of the rat sciatic nerve elicits early accumulation of Shank1 protein in the post-synaptic density of spinal dorsal horn neurons. AB - Plasticity in the spinal dorsal horn may contribute to the development of pain following peripheral nerve injury. Shank proteins are a constituent family of the post-synaptic density (PSD), and they may play a role in synaptic plasticity through activity-dependent synaptic remodeling and growth. In this study we examined the early consequences of the loose ligation of the sciatic nerve on Shank1 protein and message levels in the PSD of spinal dorsal horn neurons. Four hours after sciatic ligation, the protein levels of Shank1 increased in the ipsilateral PSD of ligated animals. In contrast, no changes were detected in the contralateral PSD of these ligated animals, or either the ipsilateral or contralateral PSD of sham-operated animals. Shank1 was linked to the PSD marker protein PSD-95 and the NR2B subunit of NMDA receptors. The ligated animals also exhibited two early signs of pain behavior, a shift in weight distribution and thermal hyperalgesia. There was no overall change in Shank1 message in either ligated or sham-operated animals. The accumulation of Shank1 in the PSD was abolished by intrathecal pre-treatment with anisomycin or Shank1 siRNA, but not with non-target siRNA. The same pre-treatment prevented both the early signs of pain behavior. Intrathecal pre-treatment with either MK-801 or U0126 similarly prevented the Shank1 accumulation and alleviated both the behavioral signs of pain. The early accumulation of Shank1 in the PSD of dorsal horn neurons may be a necessary step in the injury-associated plasticity that in time leads to the development of persistent pain. PMID- 20171011 TI - Immunolocalization of multiple membrane proteins on a carbon replica with STEM and EDX. AB - We present a method for immunolabeling of multiple species of membrane proteins with high spatial resolution. It allows differentiation of equally sized very small markers with different chemical compositions, which leads to high labeling efficiency and reduces steric hindrance of closely spaced immunolabeled biomolecules. Markers such as CdSe/ZnS semiconductor quantum dots and colloidal gold particles are distinguished by differential contrast in high-angle annular detector dark-field STEM mode or by EDX microanalysis of their elemental contents. This method was tested by observation of labeled AMPA- and NMDA-type glutamate receptors on sodium-dodecyl-sulfate-digested replica prepared from rat hippocampus. To improve particle visibility and detectability, the replica films were made exclusively with carbon to avoid the high background of conventional platinum/carbon replica. Extension of the method is suggested by detection of 1.4 nm nanogold particles and its potential application in the biological imaging research. PMID- 20171010 TI - Anti-GD(2) with an FC point mutation reduces complement fixation and decreases antibody-induced allodynia. AB - Monoclonal antibodies against GD(2) ganglioside, such as ch14.18, the human-mouse chimeric antibody, have been shown to be effective for the treatment of neuroblastoma. However, treatment is associated with generalized, relatively opiate-resistant pain. We investigated if a point mutation in ch14.18 antibody (hu14.18K332A) to limit complement-dependent cytotoxicity (CDC) would ameliorate the pain behavior, while preserving antibody-dependent cellular cytotoxicity (ADCC). In vitro, CDC and ADCC were measured using europium-TDA assay. In vivo, allodynia was evaluated by measuring thresholds to von Frey filaments applied to the hindpaws after injection of either ch14.18 or hu14.18K332 into wild type rats or rats with deficient complement factor 6. Other rats were pretreated with complement factor C5a receptor antagonist and tested following ch14.18 injection. The mutation reduces the antibody's ability to activate complement, while maintaining its ADCC capabilities. Injection of hu14.18K322 (1 or 3mg/kg) produced faster resolving allodynia than that engendered by ch14.18 (1mg/kg). Injection of ch14.18 (1mg/kg) into rats with C6 complement deficiency further reduced antibody-induced allodynia, while pre-treatment with complement factor C5a receptor antagonist completely abolished ch14.18-induced allodynia. These findings showed that mutant hu14.18 K322 elicited less allodynia than ch14.18 and that ch14.18-elicited allodynia is due to activation of the complement cascade: in part, to formation of membrane attack complex, but more importantly to release of complement factor C5a. Development of immunotherapeutic agents with decreased complement-dependent lysis while maintaining cellular cytotoxicity may offer treatment options with reduced adverse side effects, thereby allowing dose escalation of therapeutic antibodies. PMID- 20171012 TI - Laser Doppler Imaging prediction of burn wound outcome in children: is it possible before 48 h? AB - BACKGROUND: Laser Doppler Imaging (LDI) assists in prediction burn wound outcome. Previous data has validated this technique in children between 48 and 72 h after burn. AIM: To evaluate the ability of Laser Doppler Imaging (LDI) to predict burn wound outcome in paediatric patients prior to and after 48 h from the time of injury. METHODS: A prospective evaluation was performed in 400 children over a 12 month period that presented to our burns clinic. Patients were divided into two groups: those that presented within 48 h of injury (n=160) and those that presented after 48 h (n=240). Patients were reviewed until healing had occurred or operative intervention was required. RESULTS: The median age of the patients was 2.4 years (range 0.1-15.9 years). For patients who presented within 48 h, the sensitivity and specificity of the LDI was 78% and 74% respectively compared to 75% and 85% for those scanned after 48 h. This difference was not statistically significant. CONCLUSIONS: LDI predicted burn wound outcome in children within 48 h of the burn wound. Moderate degrees of movement, infection, whether first aid was administered and type of dressing did not impact on the accuracy of LDI. PMID- 20171013 TI - Absence of pathological scarring in the donor site of the scalp in burns: an analysis of 295 cases. AB - AIM: This study aims to describe the incidence of complications on scalp from which a thin split-skin graft was harvested (0.005-0.007 in.) of the donor site in children and adult burn victims. METHODS: We reviewed the medical records of 295 burn patients admitted in the Burn Unit of the Clinical Hospital of the Faculty of Medicine of Ribeirao Preto, from January 1998 to December 2007, whose scalps were used as donor site for grafts. Skin-graft thickness varied from 0.005 in. to 0.007 in. The occurrence of pathological healing was evaluated clinically and the time of epithelisation by the main surgeon and a plastic surgeon or a staff nurse. RESULTS: Of the 295 patients whose scalps were used as donor site, 274 were followed from 6 months to 10 years after the procedure (median 18.2 months). Twenty-one patients were lost to follow-up in the first 6 months. No hypertrophic scarring or keloids on the donor site was observed. Five patients (1.82%) presented with folliculitis and two of them were evaluated with small areas of alopecia (0.7%), treated with resection of these areas and primary suture. The average time of epithelisation of the donor site was 7 days. CONCLUSION: The harvest of thinner split graft from the scalp is a safe procedure. PMID- 20171014 TI - Epidemiology of minor and moderate burns in rural Ardabil, Iran. AB - Epidemiology of minor burns is not well defined worldwide. The aim of this study was to examine epidemiological features of minor and moderate burn events that could be beneficial for prevention purposes. The study was conducted in Ardabil province in north-west Iran in 2005-2006. A total of 1700 minor and moderate burns were studied using a pretested questionnaire. Using the SAS 9.1 statistical program analyses were made. Females comprised the majority of cases (n=1000, 58.8%) and children, aged six and younger, made up 36.4% of burn victims. The majority of burns were caused by hot water and tea with the primary containers being kettles in 37.8%, cups or glasses in 24.2%, pots in 13.6% and samovars in 7.9%. Samovars, gas stoves, valors and picnic gas stoves were the primary heating devices involved in burns. In 56% of the cases, overturning of liquid containers was the primary injury mechanism of scalds. 43% had a second-degree burn with a mean total body surface area of 1.3%. This study provides possible beneficial information for burn prevention in the Ardabil area and other similar settings. PMID- 20171015 TI - The severe burns patient with tracheostomy: implications for management of dysphagia, dysphonia and laryngotracheal pathology. AB - INTRODUCTION: Insertion of a tracheostomy for a severe burn patient is not uncommon. The method of decannulation, effects of the tracheostomy on voice and swallowing and subsequent complications have not been described in the literature specifically for this population. The aim of this study was to investigate the risk of dysphagia, dysphonia and laryngotracheal pathology in severe burn patients with tracheostomy and following decannulation. METHOD: A retrospective chart review was conducted for severe burn patients admitted from January 2000 to December 2007 that received tracheostomy as part of their treatment. RESULTS: Two hundred and thirty patients were admitted during the study period, 26 of whom underwent tracheostomy. Significant positive correlations were identified between tracheostomy duration and %TBSA burn, days to commence oral intake and days to commence pre-morbid oral diet. Several dysphagic features were identified within the oral and pharyngeal phases of swallowing and dysphonia was frequently demonstrated on perceptual voice assessment with the tracheostomy in situ and following decannulation. Laryngotracheal pathology was diagnosed in 12 of the 26 patients (46.2%) whilst the tracheostomy was in place; 2 with laryngeal granulation tissue, 2 with tracheal granulation tissue, 2 with supraglottic oedema and erythema and 6 with reduced vocal mobility. CONCLUSION: Severe burn patients that have prolonged tracheostomy are likely to have a larger size burn, take longer to commence oral intake and achieve pre-morbid oral diet. These patients are also at risk for dysphagia, dysphonia and laryngotracheal pathology. PMID- 20171016 TI - Burns related to sunbed use. AB - The quest for a year round tan has led to an increase in the use of artificial tanning devices, namely sunbeds. There has been much debate in the press recently regarding the dangers of sunbed use and calls for tighter regulation of the industry, particularly the licensing of unmanned tanning salons. The dangers of sunbed use have long been recognised and the body of evidence linking sunbed use to skin malignancy is growing, in fact this month the Lancet published a review from the International Agency for Research on Cancer classifying UV emitting tanning devices as carcinogenic to humans. At the Welsh Centre for Burns and Plastic Surgery we noticed a rise in the number of patients presenting with burns related to sunbed use and present our data surrounding this injury over the last 6 years. PMID- 20171017 TI - Evaluation of a new type of wound dressing made from recombinant spider silk protein using rat models. AB - This study investigates the feasibility of recombinant spider silk protein as a wound-dressing material for coverage of deep second-degree burn wounds using an animal model. Sixty Sprague-Dawley (SD) rats were randomly divided into four groups (15 rats in each group). Two types of recombinant spider silk proteins, pNSR-16 and pNSR-32, as well as collagen (as a control) were applied on the wound; the fourth group was left untreated as a negative control. Each group was evaluated on the 3rd, 5th, 7th, 14th and 21st days for wound-healing rate, histological test, levels of hydroxyproline synthesis and the samples were stained for immunohistochemical detection of the basic fibroblast growth factor (bFGF). The results of implantation testing showed that wound healing in the treatment groups--recombinant spider silk protein pNSR-16 and pNSR-32--was much better than that in the control group (p<0.01). On the 7th, 14th and 21st days, higher expression of bFGF and the increase of hydroxyproline content of the skin indicated good regeneration of wound skin in the treatment groups. Preliminarily, we conclude that the recombinant spider silk protein membrane promotes the recovery of wound skin by increasing the expression and secretion of the growth factor bFGF and hydroxyproline. PMID- 20171018 TI - Identifying patterns in cortisol secretion in an older population. Findings from the Whitehall II study. AB - Alterations in the patterning of diurnal cortisol secretion are associated with poor health in clinical populations with 'flat' patterns a particular risk. Flatter patterns in cortisol secretion may reflect impaired negative feedback in the hypothalamic-pituitary-adrenal axis. The correlates of discrete clusters of patterns in the diurnal secretion of cortisol have not been well described in large community dwelling populations. We describe discrete clusters of patterns of cortisol secretion and examine the correlates of these patterns using a latent variable mixture modelling approach. Analyses use data from 2802 participants with complete information on cortisol secretion, age, walking/gait speed, stress, waking up time and sleep duration. Cortisol was assessed from six saliva samples collected at waking, waking plus 30 min, 2.5h, 8h, 12h and bedtime. We find two patterns ("curves") of diurnal cortisol secretion. These curves are described as 'normative' [prevalence 73%] and a 'raised' [27%] curve differentiated by a lower cortisol awakening response in the normative group, a higher diurnal cortisol and 'flatter' pattern of release in the raised group. Older age, being male, a smoker, stress on the day of sampling, slower walking speed and shorter sleep duration increased the odds of being in the raised curve, relative to the normative curve. In conclusion, two patterns of cortisol secretion occur in middle aged men and women. Raised pattern of secretion, which occurs in 27% of our participants is associated with demographic variables, adverse health behaviours, psychosocial environment and impaired physical functioning. PMID- 20171019 TI - The Cannabis Expectancy Questionnaire for Men who have Sex with Men (CEQ-MSM): A measure of substance-related beliefs. AB - OBJECTIVE: Substance-related expectancies are associated with substance use and post-substance use thoughts, feelings and behaviours. The expectancies held by specific cultural or sub-cultural groups have rarely been investigated. This research maps expectancies specific to gay and other men who have sex with men (MSM) and their relationship with substance patterns and behaviours following use, including sexual practices (e.g., unprotected anal intercourse). This study describes the development of a measure of such beliefs for cannabis, the Cannabis Expectancy Questionnaire for Men who have Sex with Men (CEQ-MSM). METHOD: Items selected through a focus group and interviews were piloted on 180 self-identified gay or other MSM via an online questionnaire. RESULTS: Factor analysis revealed six distinct substance reinforcement domains ("Enhanced sexual experience", "Sexual negotiation", "Cognitive impairment", "Social and emotional facilitation", "Enhanced sexual desire", and "Sexual inhibition"). The scale was associated with consumption patterns of cannabis, and in a crucial test of discriminant validity not with the consumption of alcohol or stimulants. CONCLUSIONS: The CEQ-MSM represents a reliable and valid measure of outcome expectancies, related to cannabis among MSM. Future applications of the CEQ-MSM in health promotion, clinical settings and research may contribute to reducing harm associated with substance use among MSM, including HIV transmission. PMID- 20171021 TI - The origin of pre-eclampsia: from decidual "hyperoxia" to late hypoxia. AB - Normal gestation implants on a relatively hypoxic deciduas so that trophoblast deeply invades endometrium and angiogenesis seeks for oxygen supply. If implantation occurs before those hypoxic conditions occur, trophoblast invasion is defective, due to the relatively high oxygen tension in the decidual environment, laying the foundations for subsequent pre-eclampsia. PMID- 20171020 TI - Longitudinal associations between depressive symptoms and alcohol problems: The influence of comorbid delinquent behavior. AB - OBJECTIVE: Although numerous studies have demonstrated a positive association between depressive symptoms and alcohol problems and related disorders, it remains unclear whether this link can be explained by the joint co-occurrence of these disorders with delinquent behavior. This study examined the longitudinal associations between depressive symptoms and alcohol problems from early adolescence through early adulthood, while accounting for delinquent behavior and the potential interaction effects between delinquent behavior and each of these problems. METHOD: The National Longitudinal Study of Adolescent Health sample of 20,728 adolescents, followed for 6 years, was used. Males and females were examined separately. Multilevel modeling was used to predict both initial levels and rate of change in alcohol problems based on levels of depressive symptoms and delinquent behavior (and their interaction), and initial level and rate of change in depressive symptoms based on alcohol problems and delinquent behavior (and their interaction). RESULTS: Once delinquent behavior was included in the model, the reciprocal positive associations between alcohol problems and depressive symptoms tended to remain significant. Some interactive effects between delinquent behavior and these problems were found, mainly in females. CONCLUSIONS: The reciprocal positive associations between alcohol problems and depressive symptoms over time are not fully due to their joint co-occurrence with delinquent behavior, though delinquent behavior does moderate these links in some cases. PMID- 20171022 TI - Association of polymorphism in alcohol dehydrogenase and interaction with other genetic risk factors with alcoholic liver cirrhosis. AB - The association of polymorphism of alcohol dehydrogenase (ADH) and its interaction with genes involved in the generation and detoxification of free radicals such as cytochrome P4502E1 (CYP2E1) and glutathione S-transferases M1 (GSTM1) were studied with alcoholic liver cirrhosis. The study included 175 alcoholic cirrhotic patients, 140 non-alcoholic cirrhotic patients, 255 non alcoholic controls and 140 alcoholic controls. Our data revealed that the ADH1C*1/*1 genotype exhibited significant association with alcoholic liver cirrhosis while ADH1B genotypes did not show any significant association. A much higher risk to alcoholic liver cirrhosis was observed in patients carrying a combination of wild genotypes of ADH1C (ADH1C*1/*1) and variant genotype of ADH1B (ADH1B*2/*2) or CYP2E1 (CYP2E1*5B) or null genotype of GSTM1. Our data suggest a role for the interaction amongst the genes involved in metabolizing alcohol and in generating and detoxifying free radicals with susceptibility to alcoholic liver cirrhosis. PMID- 20171023 TI - Characteristics of pregnant illicit drug users and associations between cannabis use and perinatal outcome in a population-based study. AB - BACKGROUND: According to the 2004 National Survey on Drug Use and Health, 4.6% of American women reported use of an illicit drug during pregnancy. Previous studies on illicit drug use during pregnancy and perinatal outcomes showed inconsistent results. METHODS: This population-based study included mothers who delivered live born infants without birth defects between 1997 and 2004 and completed interviews for the National Birth Defects Prevention Study (response rate 69%; n=5871). Prevalence of self-reported illicit drug use (specifically cannabis, cocaine, and stimulants) during pregnancy and its associations with demographic and social factors were assessed. We used multivariable linear and logistic regression analyses to study the associations of cannabis use with birth weight and gestational age. RESULTS: The prevalence of reported illicit drug use during pregnancy was 3.6% (standard error 0.24). Pregnant users of cannabis, cocaine, and stimulants were younger, had a lower level of education and lower household income, and were less likely to have used folic acid in the periconceptional period than nonusers. Illicit drug users were also more likely to have used alcohol and tobacco. After adjustment for confounding, cannabis use was not associated with mean birth weight or gestational age or with low birth weight or preterm delivery. CONCLUSION: Women who report use of illicit drugs during pregnancy differ in demographic and socioeconomic background from nonusers. Reported cannabis use does not seem to be associated with low birth weight or preterm birth. PMID- 20171024 TI - Identification of putative virulence-associated genes of Haemophilus parasuis through suppression subtractive hybridization. AB - Haemophilus parasuis is the causative agent of Glasser's disease. Up to now 15 serovars of H. parasuis have been identified, with significant differences existing in virulence between serovars. In this study, suppression subtractive hybridization (SSH) was used to identify the genetic difference between Nagasaki (H. parasuis serovar 5 reference strain, highly virulent) and SW114 (H. parasuis serovar 3 reference strain, non-virulent). A total of 191 clones were obtained from the SSH library. Using dot hybridization and PCR, 15 clones were identified containing fragments that were present in the Nagasaki genome while absent in the SW114 genome. Among these 15 fragments, three fragments (ssh1, ssh13, ssh15) encode cell surface-associated components; three fragments (ssh2, ssh5, ssh9) are associated with metabolism and stress response; one fragment (ssh8) is involved in assembly of fimbria and one fragment (ssh6) is a phage phi-105 ORF25-like protein. The remaining seven fragments are hypothetical proteins or unknown. Based on PCR analysis of the 15 serovar reference strains, eight fragments (ssh1, ssh2, ssh3, ssh6, ssh8, ssh10, ssh11 and ssh12) were found in three to five of most virulent serovars (1, 5, 10, 12, 13 and 14), zero to two in three moderately virulent serovars (2, 4 and 15), but absent in the low virulent serovar (8) and non-virulent serovars (3, 6, 7, 9 and 11). In vivo transcription fragments ssh1, ssh2, ssh8 and ssh12 were identified in total RNA samples extracted from experimental infected pig lung by RT-PCR. This study has provided some evidence of genetic differences between H. parasuis strains of different virulence. PMID- 20171025 TI - IL-6 and TNFalpha across the umbilical circulation in term pregnancies: relationship with labour events. AB - OBJECTIVE: We have determined venous and arterial cord blood levels for IL-6 and TNFalpha at the time of delivery to assess gestational tissue versus fetal sources in labouring and non-labouring patients at term, and the relationship to labour events. METHODS: Fifty-five patients were studied (elective cesarean section n=24, and labouring n=31) with blood sampling from a clamped segment of cord after delivery of the fetus and from the cord at its insertion into the placenta after delivery of the placenta, with subsequent measurement of blood gases, pH, IL-6 and TNFalpha. RESULTS: Umbilical cord levels for IL-6 were increased by 4 fold in low risk labouring patients, and a further 6 fold when showing histologic chorioamnionitis, but with no evident effect of nuchal cord with 'variable' fetal heart rate decelerations, fetal acidemia, nor of labour duration. IL-6 levels from the cord at its insertion into the placenta were generally higher than those from the respective umbilical levels indicating that placental release of IL-6 into cord blood must be occurring. However, a consistent venoarterial difference for IL-6 and thereby a net flux from the placenta could not be demonstrated. TNFalpha levels for both patient groups were uniformly low for all of the cord measurements with no significant differences noted. CONCLUSION: Umbilical cord levels for IL-6 are increased in low risk labouring patients at term in the absence of evident infection which likely involves both gestational tissue and fetal contributions. Cord levels for IL-6 are further increased in low risk labouring patients showing histologic chorioamnionitis which might then contribute to newborn morbidity in these pregnancies. PMID- 20171026 TI - Cytokine expression in the gilt oviduct: effects of seminal plasma, spermatozoa and extender after insemination. AB - Effects of semen components [fresh semen in extender, spermatozoa in extender (Spz), seminal plasma (SP)], or extender alone (Beltsville thawing solution, BTS) on the expression of selected cytokines [interleukin (IL)-1beta, IL-6, IL-10 and transforming growth factor (TGF)-beta1)] as well as the presence of cells positive for CD8 or CD25 were studied in the pig oviduct. In addition, cytokines in SP and oviductal flushings were analyzed. In experiment (Exp) I, groups of gilts were sampled at 5-6h after insemination with SP, Spz, fresh semen in BTS or only BTS (control). In Exp II, gilts were sampled 35-40 h after insemination with SP, Spz, BTS or only catheter insertion (control). Most oviductal flushing samples were positive (> or =detectable limits) for IL-10 and TGF-beta1 but only few for IL-6. The IHC-labelling of IL-6, IL-10 and TGF-beta1 was evident, especially in the epithelial cells of the isthmus and infundibulum as well as in the cells of the regional (mesometrial) lymph node. Cilia of the epithelium were positive for IL-6 (strongest in the infundibulum) and TGF-beta1 (strongest in the isthmus) but negative for IL-10. There were no consistent differences in IHC labelling of the cytokines in relation to different treatments, except at 35-40 h after insemination (Exp II), when IL-6 was slightly higher in epithelium of the SP group and IL-10 in the infundibular connective tissue was higher in the SP and Spz groups. In the isthmus and infundibulum, there were no differences between animals inseminated with BTS (control) and the semen components for any of the cytokine mRNAs at 5-6h after insemination (Exp I). However, later (35-40 h, Exp II), insemination with SP, Spz and BTS alone appeared to up-regulate TGF-beta1 mRNA expression compared with the control group (without any fluid infused). In all treatment groups, the mRNA level for TGF-beta1 was higher than for IL-1beta, IL-6 and IL-10. Higher mRNA levels of all cytokines were found in the isthmus compared with the infundibulum. Numbers of CD8-positive cells (both in epithelium and connective tissue) appeared higher in the infundibulum compared with the isthmus and were mostly higher shortly (Exp I) after treatment with SP, SPZ and BTS than later (Exp II) in both segments. CD25-positive cells were few and found solely in the sub-epithelial connective tissue. The results indicate that in the porcine oviduct, IL-6, IL-10 and TGF-beta1 are endogenous produced and that TGF beta1 may have a more important role for immunomodulation than the other cytokines, especially in isthmus. Differences between isthmus and infundibulum in cytokine mRNA expression and in presence of CD8-positive cells indicate different patterns of immune reactivity in the upper and lower parts of the oviduct. PMID- 20171027 TI - Antioxidant systems of brown trout (Salmo trutta f. fario) semen. AB - The present study characterizes the antioxidant systems of brown trout, Salmo trutta, semen as supplementation of semen dilution media with antioxidants can be beneficial to improve techniques for semen storage and cryopreservation. Antioxidants and oxidant defensive enzymes of spermatozoa and seminal plasma were analyzed. To determine whether antioxidants and oxidant defensive enzymes have an effect on sperm functionality, in vitro experiments were performed. Selected antioxidants and oxidant defensive enzymes were added to sperm motility inhibiting saline solution and their effects on sperm viability (motility when activated, membrane integrity, and lipid peroxidation) were measured. In seminal plasma and spermatozoa the enzymes catalase, glutathione reductase, methionine sulfoxide reductase, peroxidase, and superoxide dismutase and the metabolites ascorbic acid, glutathione, methionine, tocopherol, and uric acid were detected. Of the enzymes superoxide dismutase had the highest activity, of the metabolites uric acid occurred in highest concentrations. During in vitro incubation uric acid and catalase increased the sperm motility, sperm membrane integrity, and decreased the sperm lipid peroxidation in comparison to the control. However, catalase was effective only at an activity much higher than that occurring in seminal plasma. Reduced methionine increased the sperm motility and sperm membrane integrity and oxidized methionine the motility. However, neither reduced nor oxidized methionine decreased the sperm membrane lipid peroxidation. It is concluded, that uric acid is the main antioxidant of brown trout semen. PMID- 20171028 TI - Forensically significant scavenging guilds in the southwest of Western Australia. AB - Estimation of time since death is an important factor in forensic investigations and the state of decomposition of a body is a prime basis for such estimations. The rate of decomposition is, however, affected by many environmental factors such as temperature, rainfall, and solar radiation as well as by indoor or outdoor location, covering and the type of surface the body is resting upon. Scavenging has the potential for major impact upon the rate of decomposition of a body, but there is little direct research upon its effect. The information that is available relates almost exclusively to North American and European contexts. The Australian faunal assemblage is unique in that it includes no native large predators or large detrivorous avians. This research investigates the animals that scavenge carcasses in natural outdoor settings in southern Western Australia and the factors which can affect each scavenger's activity. The research was conducted at four locations around Perth, Western Australia with different environmental conditions. Pig carcasses, acting as models for the human body, were positioned in an outdoor environment with no protection from scavengers or other environmental conditions. Twenty-four hour continuous time-lapse video capture was used to observe the pattern of visits of all animals to the carcasses. The time of day, length of feeding, material fed upon, area of feeding, and any movement of the carcass were recorded for each feeding event. Some species were observed to scavenge almost continually throughout the day and night. Insectivores visited the carcasses mostly during bloat and putrefaction; omnivores fed during all stages of decomposition and scavenging by carnivores, rare at any time, was most likely to occur during the early stages of decomposition. Avian species, which were the most prolific visitors to the carcasses in all locations, like reptiles, fed only during daylight hours. Only mammals and amphibians, which were seldom seen during diurnal hours, were nocturnal feeders. The combined effects of the whole guild of scavengers significantly accelerated the later stages of decomposition, especially in the cooler months of the year when natural decomposition was slowest. PMID- 20171029 TI - [Locoregional polymorphous Pseudomonas aeruginosa skin infection]. AB - A 72-year-old diabetic woman was referred with a painful chronic leg ulcer associated with venous and arterial insufficiency. She then developed a polymorphous skin infection due to Pseudomonas aeruginosa, with ecthyma gangrenosum, subcutaneous abscess and panniculitis of the homolateral inferior limb, without general sepsis. Although P. aeruginosa infection may induce polymorphous skin lesions, they are most often observed in immunocompromised patients following septicaemia. PMID- 20171030 TI - [Adherence to antibiotherapy guidelines for acute community-acquired pneumonia in adults, in a teaching hospital]. AB - OBJECTIVE: The authors had for aim to assess the conformity of antibiotic prescription with guidelines, for the management of community-acquired pneumonia, in a French University Hospital. DESIGN: This prospective study included adults patients hospitalized for pneumonia over a period of six months. The attending physician estimated the severity of pneumonia. The adequacy to guidelines focused on: first antibiotic choice and prescription modality, antibiotic choice in case of treatment modification at 48 to 72 hours, and duration of antibiotherapy. RESULTS: A hundred and nine cases of pneumonia were included in 106 patients. The mean age was 66 years, the mortality rate was 17 %. Bacterial documentation was recorded in 40.4 % of cases. The first antibiotics used were in accordance with guidelines in 52.3 % of cases. The non conformity rate was minor in 55.8 % of cases. Antibiotherapies putting the patient at risk were used in less than 10 % of the cases. The rate of antibiotic modification at 48 to 72 hours was 46.8 %, primarily for bacteriological purposes (35.3 %) or initial treatment failure (27.4 %). The treatment duration was inappropriate in 52.7 % of cases and generally too long in case of non conformity. CONCLUSION: It seems important to support guideline information, training of prescribers, and to consult an antibiotic expert. PMID- 20171031 TI - [Fatal venous air embolism during biliary endoscopy]. PMID- 20171032 TI - [Cholestatic acute hepatitis induced by tadalafil (Cialis)]. PMID- 20171033 TI - [Cystic metastases of gallbladder adenocarcinoma]. PMID- 20171034 TI - Fast volumetric spatial-spectral MR imaging of hyperpolarized 13C-labeled compounds using multiple echo 3D bSSFP. AB - PURPOSE: The goal of this work was to develop a fast 3D chemical shift imaging technique for the noninvasive measurement of hyperpolarized (13)C-labeled substrates and metabolic products at low concentration. MATERIALS AND METHODS: Multiple echo 3D balanced steady state magnetic resonance imaging (ME-3DbSSFP) was performed in vitro on a syringe containing hyperpolarized [1,3,3-2H3; 1 (13)C]2-hydroxyethylpropionate (HEP) adjacent to a (13)C-enriched acetate phantom, and in vivo on a rat before and after intravenous injection of hyperpolarized HEP at 1.5 T. Chemical shift images of the hyperpolarized HEP were derived from the multiple echo data by Fourier transformation along the echoes on a voxel by voxel basis for each slice of the 3D data set. RESULTS: ME-3DbSSFP imaging was able to provide chemical shift images of hyperpolarized HEP in vitro, and in a rat with isotropic 7-mm spatial resolution, 93 Hz spectral resolution and 16-s temporal resolution for a period greater than 45 s. CONCLUSION: Multiple echo 3D bSSFP imaging can provide chemical shift images of hyperpolarized (13)C labeled compounds in vivo with relatively high spatial resolution and moderate spectral resolution. The increased signal-to-noise ratio of this 3D technique will enable the detection of hyperpolarized (13)C-labeled metabolites at lower concentrations as compared to a 2D technique. PMID- 20171035 TI - Coupling of neural activity and fMRI-BOLD in the motion area MT. AB - The fMRI-BOLD contrast is widely used to study the neural basis of sensory perception and cognition. This signal, however, reflects neural activity only indirectly, and the detailed mechanisms of neurovascular coupling and the neurophysiological correlates of the BOLD signal remain debated. Here we investigate the coupling of BOLD and electrophysiological signals in the motion area MT of the macaque monkey by simultaneously recording both signals. Our results demonstrate that a prominent neuronal response property of area MT, so called motion opponency, can be used to induce dissociations of BOLD and neuronal firing. During the presentation of a stimulus optimally driving the local neurons, both field potentials [local field potentials (LFPs)] and spiking activity [multi-unit activity (MUA)] correlated with the BOLD signal. When introducing the motion opponency stimulus, however, correlations of MUA with BOLD were much reduced, and LFPs were a much better predictor of the BOLD signal than MUA. In addition, for a subset of recording sites we found positive BOLD and LFP responses in the presence of decreases in MUA, regardless of the stimulus used. Together, these results demonstrate that correlations between BOLD and MUA are dependent on the particular site and stimulus paradigm, and foster the notion that the fMRI-BOLD signal reflects local dendrosomatic processing and synaptic activity rather than principal neuron spiking responses. PMID- 20171037 TI - Monitoring quality of care in nursing homes and making information available for the general public: state of the art. AB - OBJECTIVE: To improve quality of care, nursing homes need to assess and monitor their performance. This study aims to gain insight in the availability and contents of publicly accessible quality systems in northwestern Europe and the USA. METHODS: This study employed a systematic search consisting of searching bibliographic sources from 2005 to September 2009, personal communication with experts, a conventional internet search, and hand-searching of references. RESULTS: Ten out of the 14 included countries use a quality systems. There is a large variety in type and number of indicators assessed. In general more attention is paid to the assessment of structure and process indicators, compared to outcome indicators. The countries differ in the way the results are made available to the general public. CONCLUSION: It can be concluded that monitoring and publicizing data on quality of care in nursing homes is becoming increasingly widespread. However, the systems still need further development and refinement. PRACTICE IMPLICATIONS: The systems need to be further developed regarding validity and reliability. Furthermore, the uniformity of the systems should be increased, more attention must be paid to the assessment of patient satisfaction, and additional insight must be gained in the user-friendliness of the systems. PMID- 20171036 TI - 5-year clinical outcomes of the ARTS II (Arterial Revascularization Therapies Study II) of the sirolimus-eluting stent in the treatment of patients with multivessel de novo coronary artery lesions. AB - OBJECTIVES: The purpose of this study is to compare the 5-year clinical outcomes, safety, and efficacy of sirolimus-eluting stents (SES) in the ARTS II (Arterial Revascularization Therapies Study II) with the outcomes of coronary artery bypass graft (CABG) and bare-metal stenting (BMS) from the ARTS I. BACKGROUND: The long term outcomes after SES implantation in patients with multivessel disease remains to be established. METHODS: The ARTS I was a randomized trial of 1,205 patients with multivessel disease comparing CABG and BMS. The ARTS II study was a nonrandomized trial with the Cypher sirolimus-eluting stent (Cordis, a Johnson & Johnson Company, Warren, New Jersey), applying the same inclusion and exclusion criteria, end points, and protocol definitions. The ARTS II trial enrolled 607 patients, with an attempt to enroll at least one-third of patients with 3-vessel disease. RESULTS: At 5-year, the death/stroke/myocardial infarction event-free survival rate was 87.1% in ARTS II SES, versus 86.0% (p = 0.1) and 81.9% (p = 0.007) in ARTS I CABG and BMS cohorts, respectively. The 5-year major adverse cardiac and cerebrovascular event (MACCE) rate in ARTS II (27.5%) was significantly higher than ARTS I CABG (21.1%, p = 0.02), and lower than in ARTS I BMS (41.5%, p < 0.001). The cumulative incidence of definite stent thrombosis was 3.8%. Thirty-two percent (56 of 176) of major adverse cardiac events (MACE) at 5 years were related to possible, probable, or definite stent thrombosis. CONCLUSIONS: At 5 years, SES had a safety record comparable to CABG and superior to BMS, and a MACCE rate that was higher than in patients treated with CABG, and lower than in those treated with BMS. Approximately one-third of the events seen with SES could be prevented through the elimination of early, late, and very late stent thrombosis. PMID- 20171038 TI - HIV testing and counseling in the nation's outpatient substance abuse treatment system, 1995-2005. AB - This article examines the extent to which U.S. outpatient substance abuse treatment (OSAT) facilities provide HIV counseling and testing (C&T) to clients between 1995 and 2005. We also examine organizational and client characteristics associated with OSAT facilities' provision of HIV C&T. Data were collected from a nationally representative sample of outpatient treatment facilities in 1995 (n = 618), 2000 (n = 571), and 2005 (n = 566). Results show that in 1995, 26.8% of OSAT clients received HIV C & T; by 2005, this proportion had increased, but only to 28.8%. Further, results from random-effects interval regression analysis show that C&T is especially widespread in public and nonprofit facilities, in methadone facilities, and in units that serve injection drug users and commercial sex workers. HIV C&T was also more widespread in units that employed formal intake protocols. Despite widespread efforts to increase HIV C&T services in OSAT care, only a small and stable minority of clients receive these services. Adoption of formal intake procedures may provide one vehicle to increase provision of C&T services. PMID- 20171039 TI - [Neurosyphilis: A rare cause of myelitis]. PMID- 20171040 TI - [Pathophysiology of multiple sclerosis]. AB - Multiple sclerosis (MS) is a severe neurological disease that affects young adults. A large body of evidence suggests that MS is mediated by an immunological process in genetic susceptible individuals. This process probably varies greatly not only between individuals, but also for one patient over time. In this review, we will describe current knowledge about the pathogenesis of MS, providing special attention to the questions patients frequently ask. We also describe the immunological foundations of this disease so that we can better understand the mechanisms by which the different approved treatments act. A better understanding of the disease has led to substantial improvement in treatments that act on the immune system. By blocking immune attacks early, we can hope to avoid the secondarily progressive phase of the disease, which remains frequent. PMID- 20171041 TI - Re: Comparison of the early results of minimally invasive vs standard approaches to total knee arthroplasty: a prospective, randomized study. PMID- 20171042 TI - Are current total knee arthroplasty implants designed to restore normal trochlear groove anatomy? AB - Biomechanical studies have shown that external rotation of the femoral TKA component improves patellar tracking but does not restore it to physiologic values. We hypothesized that this could be due to differences in the trochlear groove geometry of TKA and normal knees. This was investigated via a virtual TKA procedure that mounted femoral components on to 3-dimensional models of healthy femurs, followed by measurement of the trochlear geometry before and after the simulated TKA. The results showed that (1) external rotation of the component brought the trochlear groove closer to normal anatomy than no external rotation; (2) however, even with external rotation, the trochlear anatomy was only partially restored to normal. Further work is needed to determine implications for patellofemoral complications observed with current TKA designs. PMID- 20171043 TI - Chronic expanding hematoma of the lateral thigh and massive bony destruction after a failed total hip arthroplasty. AB - Pseudotumors have been described around both stable and failed total hip arthroplasties. The causes are varied and include polyethylene debris and masses associated with metal-on-metal bearings. We present a patient with a massive tumor of the thigh that grossly and pathologically was associated with recurrent bleeding and extensive bony destruction. The characteristics of this tumor most resemble those of a chronic expanding hematoma. To our knowledge, this has not previously been reported in association with a total hip arthroplasty. PMID- 20171044 TI - Margin of error in alignment: a study undertaken when converting from conventional to computer-assisted total knee arthroplasty. AB - We analyzed alignment of 300 knees, divided equally into groups according to total knee arthroplasty technique: Conventional, CAS-Early (computer-assisted surgery during the surgeon's learning curve), and CAS-Late (after experience with CAS). With the margin of error for alignment of the mechanical axis and femoral and tibial components each within +/-3 degrees , the Conventional group's success rate was only 66%; but the rate for the CAS-Early group was 94%. The CAS-Late group's rate was 100%, with no outliers; moreover, the margin of error was reduced to within +/-2 degrees in 92% of patients and within +/-1 degrees in 52%. For the Conventional group's success rate to be 100%, the margin of error would have to be statistically relaxed to an unacceptable +/-8 degrees . Computed assisted surgery improves alignment even early in the learning curve. PMID- 20171046 TI - Re: A randomized controlled trial comparing "high-flex" vs "standard" posterior cruciate substituting polyethylene tibial inserts in total knee arthroplasty. PMID- 20171045 TI - Body mass index and the impact on hospital resource use in patients undergoing total knee arthroplasty. AB - We identified all total knee arthroplasty patients between 1996 and 2004 and classified them by preoperative body mass index (BMI) as normal (BMI, 18.5-24.9 kg/m(2)), overweight (BMI, 25.0-29.9 kg/m(2)), obese (30-34.9 kg/m(2)), or morbidly obese (>= 35.0 kg/m(2)). Of 5521 patients, 769 had a normal BMI, 1938 were overweight, 1539 were obese, and 1275 were morbidly obese. Adjusted length of stay was no different between normal (4.85 days), overweight (4.84 days), obese (4.86 days), or morbidly obese patients (4.93 days) (P = .30). Overall costs were similar among normal ($15,386), overweight ($15,430), obese ($15,646), or morbidly obese patients ($15,752) (P = .24). Postsurgical costs were no different among normal ($9860), overweight ($9889), obese ($10,063), or morbidly obese patients ($10,136) (P = .44). Our results suggest that increased BMI does not lead to increased hospital resource use for total knee arthroplasty. PMID- 20171047 TI - Modification of the explant system for the removal of well fixed hip resurfacing sockets. AB - A major concern during revision hip arthroplasty is acetabular bone loss during the extraction of well-fixed acetabular components. Despite the good early survivorship of resurfacing prostheses, revision surgery may be necessary. We recommend the use of the Explant acetabular extraction system (Zimmer, Warsaw, Ind) with a trial liner to preserve acetabular bone stock. We present 2 cases of revised resurfacings using this technique, demonstrating minimal interference to the remaining acetabular bone. PMID- 20171048 TI - Tranexamic acid to reduce blood loss after bilateral total knee arthroplasty: a prospective, randomized double blind study. AB - The effects of 2-dosage regimens of tranexamic acid (10 mg/kg and 15 mg/kg) on blood loss and transfusion requirement were compared to saline placebo in 60 patients undergoing concurrent bilateral total knee arthroplasty, with additional reinfusion autotransfusion from intraarticular drains. Mean blood loss was 462 mL in 15 mL/kg group, 678 mL in 10 mg/kg group, and 918 mL in controls (P < .01 vs 15 mg/kg). Blood available for autotransfusion was greatest in controls and least in 15 mg/kg group. Combined autologous and allogenic transfusion volumes were similar in the treatment groups and significantly less than controls (P < .01). With use of an autologous reinfusion strategy, the lower dose is sufficient to lead to a lesser allogenic transfusion requirement. PMID- 20171049 TI - Patients with bilateral procedures can be included in total hip arthroplasty research without biasing results. AB - We explored the influence of bilaterality on the results of a trial of cemented vs uncemented acetabular components. Harris hip scores after 6 months, 2 years, 5 years, and 10 years were analyzed in 240 arthroplasties in 215 patients. Thus, 190 cases in 190 patients were compared to 50 cases in 25 patients. The group of 190 patients were further split into a group of 90 patients who had contralateral hip impairment, knee or spine problems, or significant comorbidities and into a group of 100 patients who had unilateral hip arthropathy. There was no significant difference between the cemented and uncemented groups or between any of these groups and the total group on Harris hip score, indicating that the inclusion of bilateral cases did not alter the outcome. PMID- 20171050 TI - Changes in cobalt and chromium levels after metal-on-metal hip resurfacing in young, active Chinese patients. AB - Metal-on-metal resurfacing arthroplasty is increasingly being performed in young, active patients. Serum and urine metal ion levels are monitored in these patients to assess the physiologic effects of metal-on-metal wear on them. The aim of our prospective study was to evaluate the serum and urine levels of cobalt (Co) and chromium (Cr) in young (age, <=50 years), active Chinese patients who had undergone metal-on-metal hybrid resurfacing arthroplasties. Levels were measured preoperatively using atomic absorption spectrometry and then sequentially at 3, 6, 9, 12, and 24 months after surgery. For both serum and urine Co and Cr, there was an initial increase to a peak at 6 months, followed by a gradual decline after 6 months, whereas renal function was normal during the study the 2-year study period. There was no radiographic evidence of component loosening. All implants were functioning well. Further long-term studies are needed to observe clinical outcomes and to determine the physiologic effects of the wearing process. PMID- 20171051 TI - Total hip arthroplasty with an uncemented tapered femoral component in patients younger than 50 years. AB - The purpose of the present study was to evaluate the outcome of primary uncemented total hip arthroplasty in patients younger than 50 years using the Taperloc (Biomet, Warsaw, Ind) femoral component. We evaluated 94 hips in 79 patients at a mean follow-up of 16 years (range, 11-18.5 years). The average age of the patients at the time of surgery was 36 years (range, 20-49 years). Three femoral components had been revised, none for aseptic loosening. Complete clinical and radiographic follow-up was obtained on the 91 hips that had not undergone femoral component revision. The mean Harris hip score increased from 54 points (range, 20-72) before surgery to 93 points (range, 68-100) at the time of this review. Radiographically, 89 stems (98%) were determined to have fixation by bone ingrowth, 2 (2%) demonstrated stable fibrous ingrowth, and no femoral component was loose. Distal femoral osteolysis was identified in 1 hip (1%). These findings indicate that excellent clinical and radiographic results can be achieved in young patients with the Taperloc femoral component at a mean follow up of 16 years. PMID- 20171052 TI - Whole blood metal ion concentrations in correlation with activity level in three different metal-on-metal bearings. AB - Seventy consecutive osteoarthritis patients younger than 65 years undergoing a hip arthroplasty were included. Three different metal bearings were used (2 different resurfacing systems and one 28-mm metal bearing) and compared with a ceramic control group. Whole blood cobalt and chromium levels were analyzed preoperatively, at 3 months, 6 months, 1 year, and 2 years. Patients with steep cups (abduction >55 degrees ) were excluded. No significant differences in functional scores and activity level were found between either groups. Ion levels were significantly lower with one type of resurfacing. No correlation was found between ion and activity level. In conclusion, although the current second generation metal bearings may show differences in ion release, more attention should be paid to the correlation between ion release and implant positioning. PMID- 20171053 TI - Distal femoral arthroplasty for the treatment of periprosthetic fractures after total knee arthroplasty. AB - Periprosthetic fractures after total knee arthroplasty present substantial challenge if associated with poor bone stock, fracture comminution, and loose or damaged components. Revision total knee arthroplasty with distal femoral arthroplasty is often necessary in these injuries. We reviewed 20 patients (22 knees) with a mean age of 69.5 years who underwent revision with distal femoral arthroplasty fracture. Patients were followed for an average of 58.6 months. At the latest follow-up, the mean Knee Society knee and functional score were 82.8 and 40, and the Short Form 36 mean physical functioning and mental functioning scores were 55.8 and 65.6, respectively. There were 10 postoperative complications with 5 patients requiring additional surgery. Distal femoral arthroplasty seems to be a viable option for complex periprosthetic femoral fractures after total knee arthroplasty. However, considering the relatively high rate of complications, this procedure should be reserved for patients where alternative treatments are not possible. PMID- 20171054 TI - Testing a hierarchical model of anxiety and depression in adolescents: a tri level model. AB - The present study examined the structural relationships among anxiety and depressive symptoms in a sample of high school juniors. The best-fitting structural representation was a tri-level hierarchical arrangement with a broad general factor (general distress), two factors of intermediate breadth (anxious misery and fears), and five conceptually meaningful, narrow group factors. In accord with the integrative hierarchical model of anxiety and depression, the results supported a structure with a symptom factor central to major depression, and other symptom factors specific to particular anxiety disorders. These group factors displayed significant, unique associations with clinician severity ratings (CSRs) for their respective DSM diagnoses. The hierarchical arrangement demonstrated temporal invariance over a one-year period and configural and partial metric invariance in females and males. Implications for DSM classification and arrangement of anxiety and depressive disorders are discussed as is how present findings help bridge existing research conducted at symptom and diagnostic levels. PMID- 20171055 TI - A double-blind, placebo-controlled study investigating the effects of omega-3 supplementation in children aged 8-10 years from a mainstream school population. AB - Despite the increased interest in the effects of omega-3 supplementation on children's learning and behaviour, there are a lack of controlled studies of this kind that have utilised a typically developing population. This study investigated the effects of omega-3 supplementation in 450 children aged 8-10 years old from a mainstream school population, using a randomised, double-blind, placebo-controlled design. Participants were supplemented with either active supplements (containing docosahexaenoic acid, DHA and eicosapentaenoic acid, EPA) or a placebo for 16 weeks. Cheek cell fatty acid levels were recorded pre- and post-supplementation and a range of cognitive tests and parent and teacher questionnaires were used as outcome measures. After supplementation, changes in the relationship between omega-6 and omega-3 were significant in the active group. Despite the wide range of cognitive and behavioural outcome measures employed, only three significant differences between groups were found after 16 weeks, one of which was in favour of the placebo condition. Exploring the associations between changes in fatty acid levels and changes in test and questionnaire scores also produced equivocal results. These findings are discussed in relation to previous findings with clinical populations and future implications for research. PMID- 20171056 TI - The potential of multi-slice computed tomography based volumetry for demonstrating reverse remodeling induced by cardiac resynchronization therapy. AB - BACKGROUND: Multi-slice computed tomography (MSCT) was proved to provide precise cardiac volumetric assessment. Cardiac resynchronization therapy (CRT) is an effective treatment for selected patients with heart failure and reduced ejection fraction (HFREF). In HFREF patients we investigated the potential of MSCT based wall motion analysis in order to demonstrate CRT-induced reversed remodeling. METHODS: Besides six patients with normal cardiac pump function serving as control group seven HFREF patients underwent contrast enhanced MSCT before and after CRT. Short cardiac axis views of the left ventricle (LV) in end-diastole (ED) and end-systole (ES) served for planimetry. Pre- and post-CRT MSCT based volumetry was compared with 2D echo. To demonstrate CRT-induced reverse remodeling, MSCT based multi-segment color-coded polar maps were introduced. RESULTS: With regard to the HFREF patients pre-CRT MSCT based volumetry correlated with 2D echo data for LV-EDV (MSCT 278.3+/-75.0mL vs. echo 274.4+/ 85.6mL) r=0.380, p=0.401, LV-ESV (MSCT 226.7+/-75.4mL vs. echo 220.1+/-74.0mL) r=0.323, p=0.479 and LV-EF (MSCT 20.2+/-8.8% vs. echo 20.0+/-11.9%) r=0.617, p=0.143. Post-CRT MSCT correlated well with 2D echo: LV-EDV (MSCT 218.9+/-106.4mL vs. echo 188.7+/-93.1mL) r=0.87, p=0.011, LV-ESV (MSCT 145+/-71.5mL vs. echo 125.6+/-78mL) r=0.84, p=0.018 and LV-EF (MSCT 29.6+/-11.3mL vs. echo 38.6+/ 14.6mL) r=0.89, p=0.007. There was a significant increase of the mid-ventricular septum in terms of absolute LV wall thickening of the responders (pre 0.9+/-2.1mm vs. post 3.3+/-2.2mm; p<0.0005). CONCLUSION: MSCT based volumetry involving multi segment color-coded polar maps offers wall motion analysis to demonstrate CRT induced reverse remodeling which needs to be further validated. PMID- 20171057 TI - Rehabilitation of totally atrophied maxilla by means of four zygomatic implants and fixed prosthesis: a 6-40-month follow-up. AB - The zygomatic implant is an alternative to bone grafting in extremely resorbed maxilla. This study evaluates the results of a consecutive cohort of 20 patients (mean age 56 years) with extremely resorbed maxillas provided with four zygomatic implants. The first 10 patients had a two-stage procedure, the next 10 next patients benefited from a one-stage surgical procedure and one of them had flapless guided surgery with Nobelguide in development and immediate function. The same surgical drilling protocol, according to Branemark's procedure, was applied to all the patients. Except for one patient who lost three implants, 18 patients received a fixed Procera implant bridge and another an overdenture retained by a screwed bar fixed on the four zygomatic implants. The cumulative survival rate after 40 months is 96%. Although bone augmenting procedures such as onlay grafts and sinus grafts are popular and well-documented, the four zygomatic implants procedure results in less morbidity, shorter delays between anatomical reconstruction and functional rehabilitation and can provide immediate or early loading with immediate function. Four zygomatic implants and a fixed bridge seem to be a valuable technique for the rehabilitation of extremely resorbed maxillas. PMID- 20171058 TI - Formal thought disorder in non-clinical individuals with auditory verbal hallucinations. AB - BACKGROUND: Auditory verbal hallucinations (AVH) and formal thought disorder (FTD) may originate from the same aberration in the language system. The hypothesis of a shared neurobiological basis would be strengthened by the presence of FTD in individuals who frequently experience AVH, but do not meet DSM IV criteria for a psychotic disorder. METHODS: In this study, FTD was quantified in 40 non-clinical subjects with AVH, in 50 healthy subjects without AVH and in 40 schizophrenia patients with AVH. Recorded speech samples were analysed by one rater who was blind to the presence/absence of AVH and to diagnosis, using the Thought and Language Index. RESULTS: Negative FTD was barely present in non clinical subjects with AVH and in healthy controls without AVH. Positive FTD, however, was significantly higher in both groups experiencing AVH than in controls without AVH. Severity of positive FTD did not differ significantly between non-clinical subjects with AVH and schizophrenia patients with AVH. CONCLUSION: Negative FTD (alogia) appears not to be associated with AVH. However, the fact that positive FTD (disorganised speech) in schizophrenia patients with AVH is equally high in non-clinical subjects with AVH indicates that these two symptoms tend to co-occur, which may be suggestive of a shared neurobiological substrate. PMID- 20171059 TI - Reply to drs. R. Glaser and ch. Bornkessel. PMID- 20171060 TI - [Liaison pediatric psychiatry: a position in between?]. PMID- 20171061 TI - Skull base meningioma - comparison of intensity-modulated radiotherapy planning techniques using the moduleaf micro-multileaf collimator and helical tomotherapy. AB - AIMS: Therapeutic radiotherapy to lesions of the skull base is limited by complex target shapes and their proximity to organs at risk. Intensity-modulated radiotherapy (IMRT) using helical tomotherapy may result in improved dose distributions and safer dose escalation. The aim of this study was to compare plan efficacy and efficiency using, linac-based micro-multileaf collimator (mMLC) IMRT and helical tomotherapy. MATERIALS AND METHODS: Five cases of skull base meningioma, previously treated with three-dimensional conformal radiotherapy (50 Gy/30 fractions) were identified. They were re-planned to a dose of 60 Gy/30 fractions using IMRT with Moduleaf mMLC (2.5 mm) and helical tomotherapy. Plan efficacy was compared using measures of PTV(60) coverage (D(min), D(max), V(90%), V(95%) and V(100%)). Plan efficiency was assessed by comparing estimated beam-on times. RESULTS: The critical structure dose was limited to below predetermined tolerance levels in all cases, with similar doses obtained between techniques. The average PTV(60)D(max), D(min), D(med), D(mean), V(90%), V(95%) and V(100%) across the five cases achieved were as follows: mMLC IMRT: 64.9 Gy, 40.1 Gy, 60 Gy, 59.6 Gy, 95.4%, 88.8% and 69.2%, respectively; helical tomotherapy: 67.2 Gy, 50.3 Gy, 60 Gy, 59.9 Gy, 95.8%, 83.5% and 51.9%, respectively. The average treatment time per fraction was 18.4 min for IMRT with mMLC and 6.7 min for helical tomotherapy. DISCUSSION: This study shows that safe dose escalation to a dose of 60G y to skull base lesions can be achieved; using either mMLC- or helical tomotherapy-based IMRT. A plan comparison between the two solutions is difficult, but they seem to be similar in efficacy with any small differences being difficult to interpret and of questionable clinical significance. Helical tomotherapy has the advantage of a significantly decreased beam-on time. PMID- 20171062 TI - Coffee consumption and the incidence of type 2 diabetes in men and women with normal glucose tolerance: the Strong Heart Study. AB - BACKGROUND AND AIMS: It was reported that high coffee consumption was related to decreased diabetes risk. The aim of this study is to examine the association between coffee consumption and the incidence of type 2 diabetes in persons with normal glucose tolerance in a population with a high incidence and prevalence of diabetes. METHODS AND RESULTS: In a prospective cohort study, information about daily coffee consumption was collected at the baseline examination (1989-1992) in a population-based sample of American Indian men and women 45-74 years of age. Participants with normal glucose tolerance (N = 1141) at the baseline examination were followed for an average of 7.6 years. The incidence of diabetes was compared across the categories of daily coffee consumption. The hazard ratios of diabetes related to coffee consumption were calculated using Cox proportional hazards models, adjusted for potential confounders. Levels of coffee consumption were positively related to levels of current smoking and inversely related to body mass index, waist circumference, female gender, and hypertension. Compared to those who did not drink coffee, participants who drank 12 or more cups of coffee daily had 67% less risk of developing diabetes during the follow-up (hazard ratio: 0.33, 95% confidence interval: 0.13, 0.81). CONCLUSION: In this population, a high level of coffee consumption was associated with a reduced risk of deterioration of glucose metabolism over an average 7.6 years of follow-up. More work is needed to understand whether there is a plausible biological mechanism for this observation. PMID- 20171063 TI - The role of HDL cholesterol in metabolic syndrome predicting cardiovascular events. The Gubbio population study. AB - BACKGROUND AND AIMS: Metabolic syndrome (MS) has recently been claimed to be an important new risk factor for the occurrence of coronary heart disease (CHD) and cardiovascular disease (CVD) events, although it is simply a combination of known risk factors used in a dichotomized fashion. The aims of this analysis were to explore the predictive role of MS for CHD and CVD events in a population study, in comparison with using the same factors in a continuous fashion, with special emphasis on HDL cholesterol. METHODS AND RESULTS: In the second examination of the Gubbio population study from central Italy, 2650 cardiovascular disease-free men and women, aged 35-74 years around 1990, were examined and followed-up for 12 years. The classic risk factors (sex, age, systolic blood pressure, serum cholesterol and smoking habits) were studied as predictors of CHD and CVD events, alone and with the contribution of other factors (HDL cholesterol, blood glucose, serum triglycerides and waist circumference) included in the so-called MS, based on several multivariate models. MS was also tested after adjustment for other risk factors. MS produced a predictive significant relative risk of 1.67 for CHD events and 1.82 for CVD events, but considering its single risk factors, the only ones contributing to prediction were HDL cholesterol and systolic blood pressure. Dedicated analyses showed that MS does not add anything to the power of prediction beyond the role of the single risk factors treated in a continuous fashion, while the best predictive power is obtained using classic risk factors (sex, age, smoking habits, total cholesterol, systolic blood pressure) with the addition of HDL cholesterol. CONCLUSIONS: The predictive power of MS is bound only to the presence of HDL cholesterol and blood pressure and does not add anything to using the same risk factor treated in a continuous fashion. PMID- 20171065 TI - Bacterial protein complexes investigation using blue native PAGE. AB - Investigation of protein-protein interactions has arisen as a comprehensive approach for understanding bacterial physiology as well as pathogenesis. From this point of view, bacterial membrane as a place of contact with outer milieu seems to be crucial compartment and therefore, investigation of lipophilic proteins and their interactions is inevitable. Unfortunately, several methods developed for the analysis of protein interaction suffer from their labour intensiveness and underrepresent integral membrane proteins. Therefore, blue native polyacrylamide gel electrophoresis (BN-PAGE) with its simplicity and suitability for lipophilic entities has been widely employed in microbiological research. For investigation of membrane proteins interactions BN-PAGE became a method of choice. The efficacy in this area was proven by the elucidation not only of the stoichiometry, but also dynamic changes of several complexes involved in energetic metabolism, secretion and transport systems, localized both in inner as well as in outer membrane. Moreover, BN-PAGE was also successfully applied on peripheral membrane and cytoplasmic proteins and enabled complex analysis of interactomes of several microorganisms. This review shows BN-PAGE as a potent tool in microbiological fundamental research ranging from Archaea, through Gram positive and Gram-negative bacteria to Chlamydia. PMID- 20171064 TI - Characterization of a broad-range aldehyde dehydrogenase involved in alkane degradation in Geobacillus thermodenitrificans NG80-2. AB - An aldehyde dehydrogenase (ALDH) involved in alkane degradation in crude oil degrading Geobacillus thermodenitrificans NG80-2 was characterized in vitro. The ALDH was expressed heterologously in Escherichia coli and purified as a His tagged homotetrameric protein with a subunit of 57 kDa based on SDS-PAGE and Native-PAGE analysis. The purified ALDH-oxidized alkyl aldehydes ranging from formaldehyde (C1) to eicosanoic aldehyde (C20) with the highest activity on C1. It also oxidized several aromatic aldehydes including benzaldehyde, phenylacetaldehyde, o-chloro-benzaldehyde and o-phthalaldehyde. The ALDH uses only NAD(+) as the cofactor, and has no reductive activity on acetate or hexadecanoic acid. Therefore, it is an irreversible NAD(+)-dependent aldehyde dehydrogenase. Kinetic parameters, temperature and pH optimum of the enzyme, and effects of metal ions, EDTA and Triton X-100 on the enzyme activity were investigated. Physiological roles of the ALDH for the survival of NG80-2 in oil reservoirs are discussed. PMID- 20171066 TI - Thymoquinone, a potential therapeutic agent of Nigella sativa, binds to site I of human serum albumin. AB - Thymoquinone (TQ) is the main constituent of Nigella sativa essential oil which shows promising in vitro and in vivo antineoplastic growth inhibition against various tumor cell lines. Because of the increasing interest to test it in pre clinical and clinical researches for assessing its health benefits, we here evaluate the interactions between TQ and human serum albumin (HSA), a possible carrier of this drug in vivo. Binding to HSA was studied using different spectroscopic techniques. Fourier transform infrared (FT-IR) and circular dichroism (CD) spectroscopies suggest that the association between TQ and HSA does not affect the secondary structure of HSA. Using fluorescence spectroscopy, one mole of TQ was found to bind one mole of HSA with a binding constant of 2.39 +/- 0.2 10(4)M(-1). At 25 degrees C (pH 7.4), van't Hoff's enthalpy and entropy that accompany the binding were found to be -10.24 kJ/mol(-1) and 45 J/mol(-1)K( 1) respectively. The thermodynamic analysis of the TQ-HSA complex formation shows that the binding process is enthalpy driven and spontaneous, and that hydrophobic interactions are the predominant intermolecular forces stabilizing the complex. Furthermore, displacement experiments using warfarin and ibuprofen indicate that TQ could bind to site I of HSA, which is also in agreement with the results of the molecular modeling study. PMID- 20171067 TI - Antistaphylococcal activity of Zataria multiflora essential oil and its synergy with vancomycin. AB - Staphylococcus aureus is recognized as one of the major cause of infections in communities and hospitals. In this study, the chemical composition and antistaphylococcal activity of Zataria multiflora Boiss essential oil were evaluated, along with its synergistic activity with vancomycin. The essential oil was obtained by hydrodistillation from aerial parts of the plant and analyzed using GC and GC-MS. Thymol (38.7%), carvacrol (15.3%) and rho-cymene (10.2%) were the main components of the oil. Antibacterial activity of the oil was evaluated by microbroth dilution assay against clinical isolates of methicillin -resistant (MR) and methicillin-sensitive (MS) strains of S. aureus. The oil showed high antibacterial activity against MRSA and MSSA with minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values in the range of 0.25-1 and 0.5-2microl/ml, respectively. The synergistic action was evaluated by microtiter assay. The essential oil exhibited synergism with vancomycin and displayed the ability to enhance the activity of vancomycin. This study showed that Z. multiflora oil has significant antimicrobial activity against clinical isolates of S. aureus, especially MRSA, and might be useful in controlling MRSA infections. PMID- 20171068 TI - Cardioprotective properties of Crataegus oxycantha extract against ischemia reperfusion injury. AB - The aim of the study was to investigate the cardioprotective effect and mechanism of Crataegus oxycantha (COC) extract, a well-known natural antioxidant-based cardiotonic, against ischemia/reperfusion (I/R) injury. Electron paramagnetic resonance studies showed that COC extract was capable of scavenging superoxide, hydroxyl, and peroxyl radicals, in vitro. The cardioprotective efficacy of the extract was studied in a crystalloid perfused heart model of I/R injury. Hearts were subjected to 30min of global ischemia followed by 45min of reperfusion. During reperfusion, COC extract was infused at a dose rate of 1mg/ml/min for 10min. Hearts treated with COC extract showed a significant recovery in cardiac contractile function, reduction in infarct size, and decrease in creatine kinase and lactate dehydrogenase activities. The expressions of xanthine oxidase and NADPH oxidase were significantly reduced in the treated group. A significant upregulation of the anti-apoptotic proteins Bcl-2 and Hsp70 with simultaneous downregulation of the pro-apoptotic proteins cytochrome c and cleaved caspase-3 was observed. The molecular signaling cascade including phospho-Akt (ser-473) and HIF-1alpha that lead to the activation or suppression of apoptotic pathway also showed a significant protective role in the treatment group. No significant change in phospho-p38 levels was observed. The results suggested that the COC extract may reduce the oxidative stress in the reperfused myocardium, and play a significant role in the inhibition of apoptotic pathways leading to cardioprotection. PMID- 20171069 TI - Effects of chronic administration of Melissa officinalis L. extract on anxiety like reactivity and on circadian and exploratory activities in mice. AB - This study aimed to determine the effects of chronic (15 consecutive days of treatment) per os administration of Melissa officinalis L. extract (Cyracos, Naturex) on anxiety-like reactivity in mice. As measured by HPLC, Cyracos contains significant amounts of rosmarinic acid and the triterpenoids oleanolic acid and ursolic acid, which inhibit gamma-aminobutyric acid transaminase (GABA T) activity and increase GABA levels in the brain (Awad et al., 2007; Awad et al., 2009). Thus, we evaluated Cyracos use in independent groups of C57BL/6 mice with regard to anxiety-like reactivity in an elevated plus maze and an open field task. We found that Cyracos significantly reduced anxiety-like reactivity in the elevated plus maze dose-dependently, but no significant effect was observed in the open field task. Parallel experiments in independent groups of mice showed that the Cyracosdose at which it exerted anxiolytic-like effects in the elevated plus maze did not alter exploratory or circadian activities. Therefore, our results demonstrate that Cyracos has anxiolytic-like effects under moderate stress conditions and does not alter activity levels. PMID- 20171070 TI - Baicalin, a flavonoid from Scutellaria baicalensis Georgi, activates large conductance Ca2+-activated K+ channels via cyclic nucleotide-dependent protein kinases in mesenteric artery. AB - Baicalin isolated from Scutellaria baicalensis is a traditional Chinese herbal medicine used for cardiovascular dysfunction. The ionic mechanism of the vasorelaxant effects of baicalin remains unclear. We investigated whether baicalin relaxes mesenteric arteries (MAs) via large-conductance Ca2+-activated K+ (BK(Ca)) channel activation and voltage-dependent Ca2+ channel (VDCC) inhibition. The contractility of MA was determined by dual wire myograph. BK(Ca) channels and VDCCs were measured using whole-cell recordings in single myocytes, enzymatically dispersed from rat MAs. Baicalin (10-100 microM) attenuated 80 mM KCl-contracted MA in a concentration-related manner. L-NAME (30 microM) and indomethacin (10 microM) little affected baicalin (100 microM)-induced vasorelaxations. Contractions induced by iberiotoxin (IbTX, 0.1 microM), Bay K8644 (0.1 microM) or PMA (10 microM) were abolished by baicalin 100 microM. In MA myocytes, baicalin (0.3-30 microM) enhanced BK(Ca) channel activity in a concentration-dependent manner. Increased BK(Ca) currents were abolished by IbTX (0.1 microM). Baicalin-mediated (30 microM) BK(Ca) current activation was significantly attenuated by an adenylate cyclase inhibitor (SQ 22536, 10 microM), a soluble guanylate cyclase inhibitor (ODQ, 10 microM), competitive antagonists of cAMP and cGMP (Rp-cAMP, 100 microM and Rp-cGMP, 100 microM), and cAMP- and cGMP-dependent protein kinase inhibitors (KT5720, 0.3 microM and KT5823, 0.3 microM). Perfusate with PMA (0.1 microM) abolished baicalin-enhanced BK(Ca) currents. Additionally, baicalin (0.3-30 microM) reduced the amplitude of VDCC currents in a concentration-dependent manner and abolished VDCC activator Bay K8644-enhanced (0.1 microM) currents. Baicalin produced MA relaxation by activating BK(Ca) and inhibiting VDCC channels by endothelium-independent mechanisms and by stimulating the cGMP/PKG and cAMP/PKA pathways. PMID- 20171071 TI - Protective effects of Asiaticoside on acute liver injury induced by lipopolysaccharide/D-galactosamine in mice. AB - Asiaticoside (AS), a triterpenoid product isolated from Centella asiatica, has been described to exhibit anti-in fl ammatory activities in several inflammatory models. However, the effects of AS on liver injury are poorly understood. The present study was undertaken to investigate whether AS is efficacious against Lipopolysaccharide (LPS) /D-galactosamine (D-GalN)-induced acute liver injury in mice and its potential mechanisms. AS (5, 10 and 20 mg/kg/d) was pretreated orally once daily for 3 days before LPS/D-GalN injected in mice. The mortality, hepatic tissue histology, plasma levels of Tumor necrosis factor-alpha (TNF alpha) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST), hepatic tissue TNF-alpha and caspase-3 activity were measured. Besides, western blotting analysis of phospho-p38 mitogen-activated protein kinase (phospho-p38 MAPK), phospho-c-jun N-terminal kinase (phospho-JNK) and phospho-extracellular signal regulated kinase (phospho-ERK) were determined. As a result, AS showed significant protection as evidenced by the decrease of elevated aminotransferases, hepatocytes apoptosis and caspase-3, alleviation of mortality and improvement of liver pathological injury in a dose-dependent manner. Further, we found that AS dose-dependently reduced the elevation of phospho-p38 MAPK, phospho-JNK, phospho-ERK protein and TNF-alpha mRNA expression in liver tissues and plasma TNF-alpha. These results suggest that AS has remarkable hepatoprotective effects on LPS/D-GalN-induced liver injury and the possible mechanism is related to inhibition of TNF-alpha and MAPKs. PMID- 20171072 TI - Beneficial effects of beta-Ecdysone on the joint, epiphyseal cartilage tissue and trabecular bone in ovariectomized rats. AB - Ecdysteroids are steroids found in invertebrates and plants. In mammals they have protein anabolic effects. We have recently published antiosteoporotic effects of Tinospora cordifolia (TC) extract and the search for the possible active ingredients yielded the presence of beta-Ecdysone (Ecd). Therefore, we investigated the effects of pure Ecd in ovariectomized rats on morphological changes in joint, epiphyseal cartilage and trabecular tissue. Following ovariectomy rats were fed for 1 month with Ecd containing food at a dose of 52.8 mg/day/animal. Positive and negative control animals received 17-beta Estradiol (E(2), 132 microg/day/animal) and soy free (sf) food respectively. At sacrifice, specimens consisting of upper tibiae-lower femurs and knee joint were harvested and processed for histomorphometry. The parameters measured included thickness of the joint cartilage, thickness of the whole epiphyseal growth plate and its three zones. Furthermore, the percentage of trabecular bone in the metaphysis region of tibiae was quantified. Ecd and E(2) induced a significant increase in the thickness of joint cartilage. The whole epiphyseal growth plate and its proliferative and hypertrophic zones were also increased by Ecd whereas E(2) reduced their size. The percentage of trabecular area in the metaphysis of tibia was significantly increased in Ecd and E(2) treated animals. Results provide a plausible explanation for the antiosteoporotic effects of TC. Hence, TC as well as other Ecd producing plants or pure Ecd may be of value in the prevention and treatment of osteoporosis and osteoarthritis which is of increasing importance due to aging and obesity among individuals. PMID- 20171073 TI - Transcriptional regulation of NKT cell development and homeostasis. AB - NKT cells comprise a distinct T cell subset that acquires effector function during development and prior to antigen exposure. NKT cells are of limited antigen specificity but possess the ability to be recruited into an immune response without the need for further differentiation or proliferation and thus may be considered to function as memory cells or as part of the innate immune system. Although the development and maturation of NKT cells share some similarities with conventional T cell populations, many transcriptional regulators and signaling molecules are known to be uniquely required for NKT cell development. Recently, new transcription factors that specify NKT lineage and effector function and novel roles for previously identified transcriptional regulators in the differentiation of the NKT cell population have been discovered. PMID- 20171075 TI - Myeloid-derived suppressor cell heterogeneity and subset definition. AB - Myeloid derived suppressor cells (MDSCs) are defined in mice on the basis of CD11b and Gr-1 marker expression and the functional ability to inhibit T lymphocyte activation. Nevertheless the term 'heterogeneous' remains the first, informal feature commonly attributed to this population. It is clear that CD11b(+)Gr-1(+) cells are part of a myeloid macropopulation, which comprises at least two subsets of polymorphonuclear and monocytic cells with different immunosuppressive properties. While recent literature shows substantial agreement on the immunoregulatory property of the monocytic MDSC subset, there is still contrasting evidence on the role of the granulocytic fraction. Moreover, this dichotomy holds true for human MDSCs. We attempt here to summarize conflicting findings in the field and provide some possible, unifying explanations. PMID- 20171074 TI - Adoptive T cell therapy of cancer. AB - Adoptive transfer of T cells specific for antigens expressed on tumor cells is an attractive strategy for producing targeted and long-lived anti-tumor activity. T cell therapies have shown activity in selected clinical applications but broader application is limited by inadequate persistence of transferred T cells and by tumor-evasion strategies. Current research focuses on defining the optimum type of cell for transfer, genetically modifying infused T cells to augment function and overcome tumor evasion strategies and modulating the host environment. PMID- 20171077 TI - Harm reduction: moving through the third decade. PMID- 20171076 TI - High BMI is related to higher incidence of asthma, while a fish and fruit diet is related to a lower- Results from a long-term follow-up study of three age groups in Sweden. AB - The causes of the worldwide increase in asthma seen during the last decades remain largely unexplained, but lifestyle and diet are suggested to play important roles. In this follow up of a large-scale population sample in Sweden, we wanted to identify modifiable risk factors for the cumulative incidence over a 13-year follow-up period. In 1990, a self-administered questionnaire was completed by 12,560 individuals from three age groups (16, 30-39 and 60-69 years of age) in two counties of Sweden. In 2003, the eligible subjects (n = 11,282) were sent a new postal questionnaire. In total 8150 (response rate 73%) answered the questionnaire. The prevalence of asthma in 2003 had increased in all ages. In the young adults, the asthma prevalence rose from 11.3% in 1990 to 25.0% in 2003. Adult asthma onset was identified in 791 of the participants. Smoking [RR (95% CI) = 1.37 (1.12-1.68)], BMI [1.49 (1.25-1.77 per inter quartile range)], and nocturnal gastro-oesophageal reflux (GOR) [2.16 (1.72-2.72)] were significant independent risk factors for the cumulative incidence of asthma. The impact of risk factors differed between the age groups where BMI and GOR had a significantly higher impact in the middle aged and the elderly (p < 0.05). High consumption of fruit and fish was protective especially in the elderly [0.52 (0.35-0.77)]. No significant difference was found in the impact of risk factors between men and women. Weight loss, smoking cessation and a diet rich in fruit and fish may be of importance in preventing onset of adult asthma. PMID- 20171078 TI - LCA comparison of container systems in municipal solid waste management. AB - The planning and design of integrated municipal solid waste management (MSWM) systems requires accurate environmental impact evaluation of the systems and their components. This research assessed, quantified and compared the environmental impact of the first stage of the most used MSW container systems. The comparison was based on factors such as the volume of the containers, from small bins of 60-80l to containers of 2400l, and on the manufactured materials, steel and high-density polyethylene (HDPE). Also, some parameters such as frequency of collections, waste generation, filling percentage and waste container contents, were established to obtain comparable systems. The methodological framework of the analysis was the life cycle assessment (LCA), and the impact assessment method was based on CML 2 baseline 2000. Results indicated that, for the same volume, the collection systems that use HDPE waste containers had more of an impact than those using steel waste containers, in terms of abiotic depletion, global warming, ozone layer depletion, acidification, eutrophication, photochemical oxidation, human toxicity and terrestrial ecotoxicity. Besides, the collection systems using small HDPE bins (60l or 80l) had most impact while systems using big steel containers (2400l) had less impact. Subsequent sensitivity analysis about the parameters established demonstrated that they could change the ultimate environmental impact of each waste container collection system, but that the comparative relationship between systems was similar. PMID- 20171079 TI - Nanostructured rough gold electrodes for the development of lactate oxidase-based biosensors. AB - The design and characterization of a lactate biosensor using a nanostructured rough gold surface as a transducer is reported. The biosensor is developed by immobilization of lactate oxidase (LOx), on a rough gold electrode modified with a self-assembled monolayer of dithiobis-N-succinimidyl propionate (DTSP). This bifunctional reagent preserves the rough gold structure and allows further covalent immobilization of the enzyme through the terminal succinimidyl groups. The rough gold electrode is characterized using field emission scanning electron microscopy (FE-SEM) and atomic force microscopy (AFM). The preferential orientation and average crystallite size are obtained by X-ray diffraction (XRD). The resulting lactate oxidase monolayers are characterized by electrochemical impedance spectroscopy (EIS). This nanostructured transducer allows higher mediated electrocatalytic activity than polycrystalline ones. The biosensor response to increasing lactate concentrations, using hydroxymethylferrocene as a redox mediator in solution, is linear up to 1.2 mM with a sensitivity of 1.49 microA mM(-1). PMID- 20171080 TI - A randomised study of magnesium sulphate as an adjuvant to intrathecal bupivacaine in patients with mild preeclampsia undergoing caesarean section. AB - BACKGROUND: Adequate analgesia following caesarean section decreases morbidity, hastens ambulation, improves patient outcome and facilitates care of the newborn. Intrathecal magnesium, an NMDA antagonist, has been shown to prolong analgesia without significant side effects in healthy parturients. We therefore studied the effect of adding intrathecal magnesium sulphate to bupivacaine-fentanyl spinal anaesthesia in patients with mild preeclampsia undergoing caesarean section. METHODS: Sixty women with mild preeclampsia undergoing caesarean section were included in a prospective, double blind, placebo-controlled trial. Patients were randomly assigned to receive spinal anaesthesia with 2 mL 0.5% hyperbaric bupivacaine and 25 microg fentanyl with either 0.1 mL of 0.9% sodium chloride (control group) or 0.1 mL of 50% magnesium sulphate (50 mg) (magnesium group). Onset, duration and recovery of sensory and motor block, time to maximum sensory block, duration of spinal anaesthesia and postoperative analgesia requirements were studied. RESULTS: The onset of both sensory and motor block was slower in the magnesium group. The duration of spinal anaesthesia (229.3 vs. 187.7 min) and motor block (200 vs. 175.3 min) were significantly longer in the magnesium group. Diclofenac requirement for 24 h following surgery was significantly lower in the magnesium group (147.5 vs.182.5 mg, P=0.02). Haemodynamic parameters and side effect profile were similar in the two groups. CONCLUSIONS: In parturients with mild preeclampsia undergoing caesarean delivery, the addition of magnesium sulphate 50 mg to the intrathecal combination of bupivacaine and fentanyl prolongs the duration of analgesia and reduces postoperative analgesic requirements without additional side effects. PMID- 20171081 TI - Audit of cell salvage use in obstetric patients: adding experience. PMID- 20171082 TI - General anesthesia is unacceptable for elective cesarean section. PMID- 20171083 TI - Abstracts and papers published in the International Journal of Obstetric Anesthesia since inception. AB - BACKGROUND: Since the International Journal of Obstetric Anesthesia (IJOA) was first published in 1991, barriers to conducting and publishing research in the UK have increased, as has the pressure to improve practitioners' curricula vitae. We speculated that the type and geographical origin of abstracts and papers published in IJOA might reflect these changes. METHODS: We analysed all substantive papers and Obstetric Anaesthetists' Association abstracts published in IJOA, using online access. Full articles and abstracts were categorised and the location of the submitting hospital recorded. Those published in the period 1991-99 inclusive were compared with those in 2000-08. RESULTS: A total of 890 substantive papers were reviewed, 387 in 1991-99 and 503 in 2000-08. We found non significant changes (P = 0.065) in the type of paper between the two time periods; the number (proportion) of observational studies increased from 178 (46%) to 256 (51%), respectively, while randomised and non-randomised interventional trials remained similar. Changes in geographical origin were also not significant (P = 0.17), with most coming from the UK and outside Europe. Non UK European papers accounted for only 54 (14%) and 65 (13%), respectively. Abstract numbers have increased greatly, from 190 in 1991-99 to 702 in 2000-08, with increases in all categories but a doubling of the proportion of observational studies and a reduced proportion of interventional trials: observational 17% and 34% respectively; randomised 23% and 13% respectively; and non-randomised interventional 29% and 26% respectively (P < 0.0001). Most abstracts were from the UK although this proportion fell from 92% in 1991-99 to 86% in 2000-08, whilst those from non-UK European countries and the rest of the world increased (respectively 2% and 6% in 1991-99; 7% and 8% in 2000-08; P = 0.001). CONCLUSION: Substantive papers and abstracts show different trends but observational studies are the most frequent type in both forms of presentation. Trends in abstracts suggest a decrease in the proportion of randomised controlled trials, although the absolute numbers of interventional trials has increased. Non UK European papers and abstracts are relatively few compared with those from the UK and rest of the world. PMID- 20171084 TI - Comparison of self-reported late effects with medical records among survivors of childhood cancer. AB - BACKGROUND: Survival rates following childhood cancer have increased, but survivors experience significant late effects. Long-term follow-up is recommended but imposes an increasing burden on health services. We report prevalence of morbidity in a cohort of survivors from South Yorkshire based on: (i) case-note analysis and (ii) self-reported late effects (parent-reported for under-16s). METHODS: Treatment information was taken from case-notes. Comparisons were made between late effects described in notes and reported by 108 survivors aged >16 years, and 45 parents of survivors (12-15 years). FINDINGS: Of 892 patients diagnosed with childhood cancer and some benign conditions registered on hospital databases from January 1990 to December 2005, 337 (37.8%) met eligibility criteria. Ninety-one survivors (16) (84.3%, confidence interval [CI]: 76.0-90.6) reported one or more late effects (mean=3.5; CI: 3.0-4.1), significantly higher than the number of late effects documented in medical notes (mean=0.7; CI: 0.5 0.9; t=-11.26, p<0.001). Thirty-five parents (77.8%, CI: 65.1-90.4) reported late effects for their children (mean=2.7; CI: 2.0-3.4), again higher than medical notes (mean=0.7; CI: 0.4-1.1; t=7.18, p<0.001). More than 30 specialties were involved in survivor care (mean=1.5; CI: 1.4-1.6; range 0-6). Those with more late effects saw more specialties (r=0.51, p<0.001). INTERPRETATION: We confirm the wide range of late effects experienced by survivors of child cancer, significantly greater than those recorded in medical notes, and requiring care from a range of specialties. Decisions about follow-up need to take account of patient-reported morbidity and concerns. PMID- 20171085 TI - Multikinase inhibitors in thyroid cancer. AB - Biological agents are rapidly developing for the treatment of metastatic RAI resistant thyroid cancer. The most promising results were shown by agents that target BRAF and VEGFR rather than RET. BRAF V600E mutation seems to be positively associated with tumour response by using BRAF targeting agents. With these agents impressive clinical responses and prolonged disease stabilisation were observed. This activity compares favourably with that of chemotherapy with less prominent toxicity, although typically associated drug side-effects should be promptly recognised and managed. To date no drug has proved to prolong survival, as such none of these agents has been approved. PMID- 20171086 TI - Prediction of normalized biodiesel properties by simulation of multiple feedstock blends. AB - A continuous process for biodiesel production has been simulated using Aspen HYSYS V7.0 software. As fresh feed, feedstocks with a mild acid content have been used. The process flowsheet follows a traditional alkaline transesterification scheme constituted by esterification, transesterification and purification stages. Kinetic models taking into account the concentration of the different species have been employed in order to simulate the behavior of the CSTR reactors and the product distribution within the process. The comparison between experimental data found in literature and the predicted normalized properties, has been discussed. Additionally, a comparison between different thermodynamic packages has been performed. NRTL activity model has been selected as the most reliable of them. The combination of these models allows the prediction of 13 out of 25 parameters included in standard EN-14214:2003, and confers simulators a great value as predictive as well as optimization tool. PMID- 20171087 TI - Novel bulking agent from clay residue for food waste composting. AB - New granular material from clay residue was investigated as a bulking agent for food waste composting. Five mixing ratios of granule were conducted in a laboratory scale reactor at the desired low rate of air (0.05 l min(-1)). The evolution of temperature and the accumulative CO(2) emissions were monitored. Physical and chemical changes, N loss, and organic matter degradation of compost were also examined. Adoption of granules of 15% V/V (FAS 31.6%) enhanced the thermophilic composting and CO(2) emissions; thus satisfying the Process to Further Reduce Pathogens (PFRP, USEPA) as well as obtaining the highest rate constant of organic matter degradation (k=0.005 day(-1)). As the amount of granules was doubled (35% V/V), the temperature was not only cooled, but also promoted the substantial N loss (54%). It was suggested that bulking agent from clay residue can be used beneficially as reusable media for microbial inoculation as analyzed by SEM. PMID- 20171088 TI - Hemicelluloses for fuel ethanol: A review. AB - Hemicelluloses currently represent the largest polysaccharide fraction wasted in most cellulosic ethanol pilot and demonstration plants around the world. The reasons are based on the hemicelluloses heterogeneous polymeric nature and their low fermentability by the most common industrial microbial strains. This paper will review, in a "from field to fuel" approach the various hemicelluloses structures present in lignocellulose, the range of pre-treatment and hydrolysis options including the enzymatic ones, and the role of different microbial strains on process integration aiming to reach a meaningful consolidated bioprocessing. The recent trends, technical barriers and perspectives of future development are highlighted. PMID- 20171089 TI - Nitrogen mineralization potential of three animal manures applied on a sandy clay loam soil. AB - Understanding the dynamics of N forms applied as manure is germane for appropriate rate and timing of applications of manure. Manure characterization and laboratory incubation were conducted for 120 days to study the mineralization of poultry, cattle and goat manures. Results showed that manure properties differ. Net immobilization of N was recorded for goat and cattle manures while poultry manure mineralized marginally. The relationship between N release and time is polynomial (cubic). The release phases were: initial rapid N release at 0 30 days; phase of constant release; 40-55 days; decline phase in N release 70-90 days and sharp increase in N release at 120 days. Increasing the N rates of manures above 120 kgNha(-1) will improve their potential as plant nutrient sources. Complementing the manures with inorganic N fertilizers in integrated nutrient management will also improve its quality and effectiveness. PMID- 20171090 TI - Effect of chemically modified Vulcan XC-72R on the performance of air-breathing cathode in a single-chamber microbial fuel cell. AB - The catalytic activity of modified carbon powder (Vulcan XC-72R) for oxygen reduction reaction (ORR) in an air-breathing cathode of a microbial fuel cell (MFC) has been investigated. Chemical modification was carried out by using various chemicals, namely 5% nitric acid, 0.2N phosphoric acid, 0.2N potassium hydroxide and 10% hydrogen peroxide. Electrochemical study was performed for ORR of these modified carbon materials in the buffer solution pH range of 6-7.5 in the anodic compartment. Although, these treatments influenced the surface properties of the carbon material, as evident from the SEM-EDX analysis, treatment with H(2)PO(4), KOH, and H(2)O(2) did not show significant activity during the electrochemical test. The HNO(3) treated Vulcan demonstrated significant ORR activity and when used in the single-chamber MFC cathode, current densities (1115mA/m(2), at 5.6mV) greater than those for a Pt-supported un treated carbon cathode were achieved. However, the power density for the latter was higher. Such chemically modified carbon material can be a cheaper alternative for expensive platinum catalyst used in MFC cathode construction. PMID- 20171091 TI - Energy efficiency of pre-treating excess sewage sludge with microwave irradiation. AB - The objective of this study is to investigate the energy consumption of pre treating excess sewage sludge with microwave irradiation using several parameters, including temperature rise, degree of cell destruction, SCOD/TCOD ratio (solids solubilization), and biogas production to evaluate the energy efficiency. It was found that water content was the most important factor that influenced the energy efficiency of raising the temperature and promoting the solubilization of solid materials. Increasing specific energy (E(s)) accelerated the biogas production, but there was a limit to this process. For quantitative comparison to the energy efficiency of different pre-treatment steps, an empirical method was also proposed based on the experimental data. PMID- 20171092 TI - Stimulation of cephalosporin C production in Acremonium chrysogenum M35 by glycerol. AB - In this study, the effects of glycerol on cephalosporin C production by Acremonium chrysogenum M35 were evaluated. The addition of glycerol increased cephalosporin production by up to 12-fold. Glycerol caused the upregulation of the transcription of the isopenicillin synthase (pcbC) and transporter (cefT) genes in early exponential phase, and affected the cell morphology since hyphal fragments differentiated into arthrospores. These results indicate that glycerol effectively enhances cephalosporin C production via stimulation of cell differentiation. PMID- 20171093 TI - Ammonia volatilization in soil treated with tannery sludge. AB - The utilization of tannery sludge in agricultural areas can be an alternative for its disposal and recycling. Despite this procedure may cause the loss of nitrogen by ammonia volatilization, there is no information about this process in tropical soils. For two years a field experiment was carried out in Rolandia (Parana State, Brazil), to evaluate the amount of NH(3) volatilization due to tannery sludge application on agricultural soil. The doses of total N applied varied from zero to 1200 kg ha(-1), maintained at the surface for 89 days, as usual in this region. The alkalinity of the tannery sludge used was equivalent to between 262 and 361 g CaCO(3) per kg. Michaelis-Menten equation was adequate to estimate NH(3)-N volatilization kinetics. The relation between total nitrogen applied as tannery sludge and the potentially volatilized NH(3)-N, calculated by the chemical-kinetics equation resulted in an average determination coefficient of 0.87 (P>0.01). In this period, the amount of volatilized NH(3) was more intense during the first 30 days; the time to reach half of the maximum NH(3) volatilization (K(m)) was 13 an 9 days for the first and second experiments, respectively. The total loss as ammonia in the whole period corresponded in average to 17.5% of the total N applied and to 35% of the NH(4)(+)-N present in the sludge. If tannery sludge is to be surface applied to supply N for crops, the amounts lost as NH(3) must be taken into consideration. PMID- 20171094 TI - A high-temperature thermal treatment of wood using a multiscale computational model: application to wood poles. AB - The present study is devoted to a numerical study with experimental validation of the high-temperature thermal treatment of three-dimensional wood pole. During the heat treatment process, the heat and mass transfer takes place between the solid and the drying medium, and the moisture evaporation occurs within the solid due to the capillarity action and diffusion. The development of the model equations, taking into account both bulk phases and interfaces of the multiphase system is described, starting from the microscopic scale. Fundamental to this model is the ability to quantify the effects of key material and geometric properties of the pole. The three-dimensional and unsteady-state mathematical model equations are solved numerically by the commercial package FEMLAB for the temperature and moisture content histories under different treatment conditions. A detailed discussion of the computational model and the solution algorithm is given. Heat treatment was applied on the test samples in an oven for three final temperatures (180, 200 and 220 degrees C). A series of experimental tests aimed at determination of heat treatment schedules kinetics curves and the temperature and moisture profiles and there time evolution were carried out. A very good agreement between the experimental and predicted results was obtained, implying that the proposed numerical algorithm can be used as a useful tool in designing high-temperature wood pole treatment processes. PMID- 20171095 TI - Simple and conveniently accessible bi-fluorescence-labeled substrates for amylases. AB - Synthesis of bi-fluorescence-labeled maltooligosaccharides for amylase assay was accomplished. Preliminary biological evaluation of both bi-fluorescence-labeled maltohexasaccharide and maltose using alpha-amylase was carried out, and the hexaosyl derivative showed unique variation on the basis of fluorescence resonance energy transfer (FRET). PMID- 20171096 TI - Synthesis, chiral resolution, and determination of novel furan lignan derivatives with potent anti-tumor activity. AB - A kind of racemic furan lignans were synthesized via a novel route, and two optical isomers were obtained through a selective hydrolization. The absolute configurations were determined by circular dichroism spectroscopy after separated through a preparative column. The different activities of isomers and the racemates were evaluated on QGY-7701 and HeLa cell lines, and compound 2c showed the best activity on QGY-7701 and HeLa cell lines with IC(50) 12 microM and 13 microM, respectively. PMID- 20171097 TI - Discovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors. Part 2: Modification of P3, P4, and P5 regions. AB - A novel class of tetrahydropyrido-pyrazole thioether amines that display potency against human Cathepsin S have been previously reported. Here, further SAR investigations of the P3, P4, and P5 regions are described. In particular, 4 fluoropiperidine is identified as a competent P3 binding element when utilized in conjunction with a (S)-2-hydroxypropyl linker-containing P5 moiety and oxamide or sulfonamide P4 substitution. PMID- 20171098 TI - Rigidified 2-aminopyrimidines as histamine H4 receptor antagonists: effects of substitution about the rigidifying ring. AB - Three novel series of histamine H(4) receptor (H(4)R) antagonists containing the 2-aminopyrimidine motif are reported. The best of these compounds display good in vitro potency in both functional and binding assays. In addition, representative compounds are able to completely block itch responses when dosed ip in a mouse model of H(4)-agonist induced scratching, thus demonstrating their activities as H(4)R antagonists. PMID- 20171099 TI - Synthesis and chain-dependent antifungal activity of long-chain 2H-azirine carboxylate esters related to dysidazirine. AB - Analogues of the antifungal marine natural product (E)-dysidazirine were prepared and evaluated in broth ro-dilution assays against a panel of fungal pathogens. A simple structure-activity relationship was developed which provides insight into the mechanism of action of long-chain 2H-azirine carboxylates. PMID- 20171100 TI - MAPK substrate competition integrates patterning signals in the Drosophila embryo. AB - Terminal regions of the Drosophila embryo are patterned by the localized activation of the mitogen-activated protein kinase (MAPK) pathway. This depends on the MAPK-mediated downregulation of Capicua (Cic), a repressor of the terminal gap genes. We establish that downregulation of Cic is antagonized by the anterior patterning morphogen Bicoid (Bcd). We demonstrate that this effect does not depend on transcriptional activity of Bcd and provide evidence suggesting that Bcd, a direct substrate of MAPK, decreases the availability of MAPK for its other substrates, such as Cic. Based on the quantitative analysis of MAPK signaling in multiple mutants, we propose that MAPK substrate competition coordinates the actions of the anterior and terminal patterning systems. In addition, we identify Hunchback as a novel target of MAPK phosphorylation that can account for the previously described genetic interaction between the posterior and terminal systems. Thus, a common enzyme-substrate competition mechanism can integrate the actions of the anterior, posterior, and terminal patterning signals. Substrate competition can be a general signal integration strategy in networks where enzymes, such as MAPK, interact with their multiple regulators and targets. PMID- 20171101 TI - Reorganization of global form and motion processing during human visual development. AB - The functional selectivity of human primary visual cortex (V1) for orientation and motion direction is established by around 3 months of age [1-3], but there have been few studies of the development of extrastriate visual areas that integrate outputs from V1 [4-8]. We investigated sensitivity and topographical organization for global form and motion with high-density visual event-related potentials (VERPs) in 4- to 5-month-old infants and adults. Responses were measured to transitions between concentrically organized elements (short arc segments for form, dot trajectories for motion) and random arrangements. Adults showed topographically separate responses, with midline motion and more lateral form responses. Of 26 infants, 25 showed significant motion responses but only 13 showed form responses, suggesting more advanced development for extrastriate motion areas than form. Infants' form and motion responses were topographically distinct but contrasted with the corresponding adult topographies, with infants' motion responses more lateral than form responses. These results imply distinct neural sources at both ages and raise the possibility of substantial reorganization of extrastriate networks between infancy and adulthood. We speculate that global motion responses arise from area V5 in infants but are dominated by more medial areas such as V3/V3A and V6 in adults. PMID- 20171102 TI - SCHIZORIZA encodes a nuclear factor regulating asymmetry of stem cell divisions in the Arabidopsis root. AB - Cell divisions generating daughter cells different in size, shape, identity, and function are indispensable for many developmental processes including fate specification, tissue patterning, and self-renewal. In animals and yeast, perturbations in factors required for well-described asymmetric cell divisions generally yield cells of equal fate. Here we report on SCHIZORIZA (SCZ), a single nuclear factor with homology to heat-shock transcription factors that controls the separation of cell fate in a set of stem cells generating different root tissues: root cap, epidermis, cortex, and endodermis. Loss-of-function, expression, and reconstitution experiments indicate that SCZ acts mainly from within its cortical expression domain in the stem cell niche, exerting both autonomous and nonautonomous effects to specify cortex identity and control the separation of cell fates in surrounding layers. Thus, SCZ defines a novel pathway for asymmetric cell division in plants. PMID- 20171103 TI - MST1 limits the kinase activity of aurora B to promote stable kinetochore microtubule attachment. AB - The establishment and maintenance of proper attachment of kinetochores to microtubules are required to prevent chromosome missegregation and consequent chromosomal instability and tumorigenesis. Although MST1 (mammalian sterile 20 like kinase 1) has been implicated in many aspects of cell cycle regulation and tumor suppression [1], its precise mechanism of action has remained largely unknown. We now show that MST1 promotes accurate kinetochore-microtubule attachment by modulating the kinase activity of Aurora B. HeLa cells depleted of MST1 failed to develop stable end-on kinetochore-microtubule attachment, giving rise to unaligned mitotic chromosomes. The misaligned chromosomes activated the Mad2- and BubR1-dependent spindle checkpoint response, resulting in a delay in anaphase onset. The kinase activity of Aurora B, which promotes destabilization of kinetochore-microtubule attachment [2-4], was increased in cells depleted of MST1 or NDR1, a downstream kinase of MST1. MST1 and NDR1 associated with Aurora B. Moreover, MST1 directly phosphorylated Aurora B and inhibited its kinase activity in vitro. Depletion of Aurora B restored the stability of kinetochore microtubule attachment in cells depleted of MST1 or NDR1. MST1 is thus a key regulator of Aurora B activity that ensures mitotic chromosome congression and accurate chromosome segregation. PMID- 20171104 TI - Pickpocket is a DEG/ENaC protein required for mechanical nociception in Drosophila larvae. AB - Highly branched class IV multidendritic sensory neurons of the Drosophila larva function as polymodal nociceptors that are necessary for behavioral responses to noxious heat (>39 degrees C) or noxious mechanical (>30 mN) stimuli. However, the molecular mechanisms that allow these cells to detect both heat and force are unknown. Here, we report that the pickpocket (ppk) gene, which encodes a Degenerin/Epithelial Sodium Channel (DEG/ENaC) subunit, is required for mechanical nociception but not thermal nociception in these sensory cells. Larvae mutant for pickpocket show greatly reduced nociception behaviors in response to harsh mechanical stimuli. However, pickpocket mutants display normal behavioral responses to gentle touch. Tissue-specific knockdown of pickpocket in nociceptors phenocopies the mechanical nociception impairment without causing defects in thermal nociception behavior. Finally, optogenetically triggered nociception behavior is unaffected by pickpocket RNAi, which indicates that ppk is not generally required for the excitability of the nociceptors. Interestingly, DEG/ENaCs are known to play a critical role in detecting gentle touch stimuli in Caenorhabditis elegans and have also been implicated in some aspects of harsh touch sensation in mammals. Our results suggest that neurons that detect harsh touch in Drosophila utilize similar mechanosensory molecules. PMID- 20171105 TI - Using ambulatory virtual environments for the assessment of functional gait impairment: a proof-of-concept study. AB - This study aimed to demonstrate the sensitivity of virtual reality (VR)/motion tracking to detect global functional gait impairment resulting from an emulated knee disability as a prelude to describing mobility changes following lower limb injury/treatment. Participants walked in a figure-8 around two virtual posts placed 6m apart while viewing the computer-generated environment in a helmet mounted display. Three-dimensional position and orientation of the participant's head were tracked and used to update the virtual scenes, measure walking path and speed, and control task parameters with real-time feedback. Participants walked with/without an emulated lower extremity disability (splint preventing normal knee flexion). Participants performed the task at self-selected Natural (NAT) speed providing a baseline measure of their turning speed and area. Turning speed and area were then in turn maintained fixed (controlled speed, CS; controlled path, CP) while the other variable was measured as a gait impairment indicator. Different adaptive strategies were used to cope with the emulated deficit during the NAT scenario: maintaining turning speed while altering path geometry; decreasing turning speed while maintaining path geometry; and combining the previous two strategies. This resulted, on average, in decreased turning speeds and increased turning areas. The CS and CP manipulations respectively generated even greater turning areas and more consistent speed decreases. The three subtests acted as intertwined filters enabling the detection of functional gait impairment in all subjects regardless of their adaptive strategies. This proof-of concept study demonstrated how VR/motion tracking technology can be used to detect and quantitatively characterize global functional mobility impairment. PMID- 20171106 TI - Validation of 3-D freehand ultrasound for the determination of the hip joint centre. AB - This paper describes the calibration process for 3-D free hand ultrasound (3 DUS). The Cambridge calibration technique was determined to produce the most repeatable and accurate results when determining the location of a reference object within a water bath. This note additionally validates 3-DUS as a potential measurement tool for the determination of the hip joint centre. It shows that 3 DUS can accurately determine the inter-HJC distance to within 4+/-2mm. This indicates potential for 3-DUS to be used as a gold standard measurement tool in the identification of the hip joint centre. PMID- 20171107 TI - Combined lateral retinacular release with drilling chondroplasty for treatment of patellofemoral osteoarthritis associated with patellar malalignment in elderly patients. AB - This paper described a less invasive surgical technique that was performed for treatment of elderly patients with isolated patellofemoral (PF) osteoarthritis (OA) associated with patellar malalignment, although their tibiofemoral joints are minimally osteoarthritic. Two hundred and thirty-four knees in 126 consecutive elderly patients (average, 72 yrs) diagnosed with combined disorders were treated by lateral retinacular release with drilling chondroplasty. The inclusion criteria were patient age >= 65 yrs, isolated stage 2 or 3 PF-OA (modified Iwano staging by radiology), and a laterally subluxed patella shown on a Merchant's axial radiograph. Outcome was judged by three parameters: clinical PF function (modified Kujala scoring), congruence angle, and PF-OA staging. Two hundred and one knees in 107 patients were followed-up for an average of 4.2 yrs (range, 2.1-7.5 yrs) and 19 patients were lost to follow-up. No surgical complications occurred through the course of treatment. Clinical PF function improved in knees that showed unsatisfactory performance (modified Kujala scoring < 32) preoperatively, with 78.1% of the knees showing satisfactory performance (modified Kujala scoring >= 32) at the latest follow-up. Congruence angle improved in 85.6% of the knees and PF-OA staging improved in 77.1% of the knees. Combined lateral retinacular release with drilling chondroplasty is a feasible alternative for treatment of PF-OA associated with patellar malalignment in elderly patients where knee arthroplasty cannot be performed by various reasons. Advantages of this combined surgical technique include a less invasive procedure, minimal complication rate, and an acceptable success rate (78%, modified Kujala scoring>=32). PMID- 20171108 TI - Synthesis and antiproliferative evaluation of certain indolo[3,2-c]quinoline derivatives. AB - The present report describes the synthesis and antiproliferative evaluation of certain indolo[3,2-c]quinoline derivatives. For the C(6) anilino-substituted derivatives, (11H-indolo[3,2-c]quinolin-6-yl)phenylamine (6a) was inactive. Structural optimization of 6a by the introduction of a hydroxyl group at the anilino-moiety resulted in the enhancement of antiproliferative activity in which the activity decreased in an order of para-OH, 7a>meta-OH, 8a>ortho-OH, 9a. For the C(6) alkylamino-substituted derivatives, 11a, 12a, 13a, 14a, and 15a exhibited comparable antiproliferative activities against all cancer cells tested and the skin Detroit 551 normal fibroblast cells. Three cancer cells, HeLa, A549, and SKHep, are very susceptible with IC(50) of less than 2.17 microM while PC-3 is relatively resistant to this group of indolo[3,2-c]quinolines. For the 2 phenylethylamino derivatives, compound 20a is active against the growth of HeLa with an IC(50) of 0.52 microM, but is less effective against the growth of Detroit 551 with an IC(50) of 19.32 microM. For the bis-indolo[3,2-c]quinolines, N,N-bis-[3-(11H-indolo[3,2-c]quinolin-6-yl)aminopropyl]amine hydrochloride (25) is more active than its N-methyl derivative 26 and the positive Doxorubicin. Mechanism studies indicated 25 can induce caspase-3 activation, gamma-H2AX phosphorylation, cleavage of poly(ADP-ribose)polymerase and DNA fragmentation. These results provide evidence that DNA, topo I, and topo II are the primary targets of indolo[3,2-c]quinoline derivatives and that consequently inhibits proliferation and causes apoptosis in cancer cells. PMID- 20171109 TI - Benzyl 1,2,3,5,11,11a-hexahydro-3,3-dimethyl-1-oxo-6H imidazo[3',4':1,2]pyridin[3,4-b]indole-2-substituted acetates: One-pot preparation, anti-tumor activity, docking toward DNA and 3D QSAR analysis. AB - To discover the anti-tumoral indoles a series of benzyl 1,2,3,5,11,11a-hexahydro 3,3-dimethyl-1-oxo-6H-imidazo[3',4':1,2]pyridin[3,4-b]indole-2-substituted acetates (2a-n) are prepared via one-pot-preparation. The IC(50) values of 2a-n in vitro against human lung carcinoma, prostate cancer, nasopharyngeal carcinoma, vincristine-resistant KB subline and human breast carcinoma cells range from 40 nM to 60 microM. On Sarcoma 180 (S180) tumor-bearing mouse model four of them (2e,g,h,i) significantly inhibited the tumor growth. At the dose of 0.1mg/kg the efficacy of the most potent 2h was equal to that of 1.0mg/kg of doxorubicin. In contrast to doxorubicin, at 1.0mg/kg of dose 2e,g,h,i did not induce the treated S180 mice to have organ atrophy and body emaciation. The healthy mice receiving 10, 100 and 500 mg/kg of 2e,g,h,i gave no any neurotoxic response. Even up to the dose of 500 mg/kg the healthy mice occurred no death. The interaction of 2a-n with DNA was confirmed by the fluorescence quenching experiments and automated flexible ligand docking. By 3D QSAR analysis the IC(50) values of 2a-n against prostate cancer cells were correlated with the structures and conformations of their side chains. To increase the data related to their physical-chemical properties the experimental LogP values were also provided. PMID- 20171110 TI - Laboratory experiments and modeling for industrial radiotracer applications. AB - This paper presents three laboratory experiments, which have been carried out using the Molybdenum-99 (Mo(99)) radiotracer to measure the residence time distribution (RTD), the mixing time and the flow rate in a water flow rig. The results of the RTD measurement experiment are preprocessed using the MATLAB software for background correction, radioactive decay correction, starting point correction, filtering, and data extrapolation. After preprocessing, six mathematical models are investigated on this data using the International Atomic Energy Agency (IAEA) RTD software. The parameters of each model are optimized to calculate the value of the RTD, and to determine the model, which gives the best match with the practical data. The selected model with the best match is used to calculate the RTD in this experiment. The mixing time experiment is carried out for different rotation speeds and repeated three times in each case. The results show that the mixing time is inversely proportional to the rotation speed. The flow rate experiment is carried out to measure the flow rate in the flow rig. The experimental results show a high reliability of the radiotracer used in the RTD, mixing time and flow rate measurements. PMID- 20171111 TI - International exercise on 124Sb photon emission intensities determination. AB - An international exercise, registered as EUROMET project no. 907, was launched to measure both the activity of a solution of (124)Sb and the photon emission intensities of its decay. The same solution was sent by LNE-LNHB to eight participating laboratories, six of which sent results for photon emission intensities both in absolute and in relative terms. From these results and including previous published values, a consistent decay scheme was worked out, proving that problems in activity measurements have not been due to decay scheme data. PMID- 20171112 TI - Differential expression of heat shock protein genes in preconditioning for photosynthetic acclimation in water-stressed loblolly pine. AB - Heat shock proteins (HSPs) are induced not only under heat stress conditions but also under other environmental stresses such as water stress. In plants, HSPs families are larger than those of other eukaryotes. In order to elucidate a possible connection between HSP expression and photosynthetic acclimation or conditioning, we conducted a water stress experiment in loblolly pine (Pinus taeda L.) seedlings involving progressive treatment consisting of one cycle of mild stress (-1 MPa) followed by two cycles of severe stress (-1.7 MPa). Net photosynthesis was measured at each stress level. Photosynthetic acclimation occurred in the progressive treatment after the first cycle, but not in the severe treatment, suggesting that a cycle of mild stress conditioned the trees to adapt to a more severe stress. Real time results indicated specific patterns in needles in the expression of HSP70, HSP90 and sHSP genes for each treatment, both at maximum stress and at recovery. We identified a pine homolog to GRP94 (ER resident HSP90) that was induced after rehydration coincident with acclimation. Further analysis of the promoter region of the pine GRP94 showed putative cis elements associated with water stress and rehydration, corresponding to the expression pattern observed in our experiment. PMID- 20171113 TI - The cellular immunological responses of patients undergoing coronary artery bypass grafting compared with those of patients undergoing valve replacement. AB - OBJECTIVE: Major surgical intervention such as cardiac surgery has been shown to have profound effects on the immune system. We conducted a prospective study comparing the effects of coronary artery bypass grafting (CABG) versus isolated valve surgery. METHODS: Blood samples were drawn from 59 patients undergoing either elective CABG or elective isolated valve replacement surgery. Samples were obtained preoperatively and on the first and third postoperative days. Total cell counts and differential counts were recorded. Several cellular immunity parameters were determined by flow cytometry. RESULTS: On all postoperative days, significant increases in white blood cell (WBC) and monocyte counts were observed. Significant decreases in all lymphocyte populations were also observed with similar decreases in both helper (CD4) and suppressor (CD8) T cells. An increase in activated T cells was noted on day 1, returning to normal on the third postoperative day. Despite the significant decrease in human leucocyte antigen-DR (HLA-DR) antigen expression on monocytes on both the first and third postoperative days, a significant increase in monocyte activation as represented by increased CD11b and CD64 expression was detected. No significant difference was found for any of the measured parameters between the CABG group and the valve replacement group. Eight patients developed early wound infections, with no correlation with any of the measured parameters, including magnitude and duration of decrease in HLA-DR antigen expression on monocytes. CONCLUSIONS: Cardiac surgery induces both a state of pro-inflammation and of immune suppression. The two major types of cardiac surgery induce similar effects to the immune system. None of the measured parameters was predictive for development of postoperative wound infection. PMID- 20171114 TI - A role for protein kinase PKR in the mediation of Epstein-Barr virus latent membrane protein-1-induced IL-6 and IL-10 expression. AB - Expression of Epstein-Barr virus-encoded oncogenic latent membrane protein 1 (LMP1) has been substantially associated with tumorigenic transformation in the virus-infected cells. The pathogenic complexity of LMP1 is partly due to the cytokine dysregulation including IL-6 and IL-10 in perturbing the host immune responses. Here we have identified an important signaling event mediated by a dsRNA-dependent serine/threonine protein kinase, PKR, in regulating LMP1-induced IL-6 and IL-10 expression. We first demonstrated that PKR plays a significant role in mediating LMP1-induced cytokine expression by using a PKR inhibitor 2 aminopurine, and the specific role of PKR involved was confirmed by the use of siRNA oligos targeting PKR and/or a dominant-negative PKR mutant. We next revealed that PKR activity mediates LMP1-enhanced NF-kappaB nuclear translocation resulting in cytokine induction. We further demonstrated at the chromatin level that LMP1 can significantly elevate the phosphorylation of histone H3 on serine 10 (Ser 10), and the process was dependent on PKR activity. Our findings thus suggest that PKR plays an important role in mediating the cytokine gene expression induced by LMP1 through NF-kappaB activation and histone H3 Ser 10 phosphorylation. PMID- 20171115 TI - Circadian variations of interleukin 6 in coronary circulations of patients with myocardial infarction. AB - We hypothesize that higher morbidity of patients with ST-segment elevation myocardial infarction (STEMI) in the out-of-office hours differences in outcome after myocardial infarction may depend on the concentrations of inflammatory cytokines. The aim of the study was to determine the relation between the time of percutaneous coronary intervention (PCI) and local concentration of interleukin 6 (IL-6) and its soluble receptors (sIL-6R and sgp130) in patients with STEMI. METHODS AND RESULTS: The study included 32 patients with invasively treated left anterior descending artery occlusion and no significant co-morbidities. Blood samples were drawn from coronary sinus and aorta before and after intervention. Patients admitted in the afternoon (13-20) presented significantly higher mean IL 6 levels in all samples than patients admitted in the morning. There was a positive correlation between time of intervention and concentrations of IL-6 in all samplings, but also with transcardiac IL-6 gradient at the end of procedure and IL-6 increase during PCI. We did not find any significant association between time of PCI and concentrations of sIL-6R and sgp130, time from pain to balloon, angiographic parameters or medical history. CONCLUSIONS: Coronary concentration of IL-6 in patients with STEMI is significantly higher in the afternoon than in the morning. This might be involved in increased morbidity of those patients. PMID- 20171116 TI - Targeted data acquisition for improved reproducibility and robustness of proteomic mass spectrometry assays. AB - Quantitative mass spectrometry-based proteomic assays often suffer from a lack of robustness and reproducibility. We here describe a targeted mass spectrometric data acquisition strategy for affinity enriched subproteomes-in our case the kinome-that enables a substantially improved reproducibility of detection, and improved quantification via isobaric tags. Inclusion mass lists containing m/z, charge state, and retention time were created based on a set of 80 shotgun-type experiments performed under identical experimental conditions. For each target protein, peptides were selected according to their frequency of observation and isobaric tag for relative and absolute quantitation (iTRAQ) reporter ion quality. Retention times of selected peptides were aligned using similarity driven pairwise alignment strategy yielding <1 min standard deviation for 4 h gradients. Multiple fragmentation of the same peptides resulted in better statistics and more precise reporter ion based quantification without any loss in coverage. Overall, 24% more target proteins were quantified using the targeted data acquisition approach, and precision of quantification improved by >1.5-fold. We also show that a combination of higher energy collisional dissociation (HCD) with collisional induced dissociation (CID) outperformed pulsed-Q-dissociation (PQD) on the OrbitrapXL. With the CID/HCD based targeted data acquisition approach 10% more quantifiable target proteins were identified and a 2-fold increase in quantification precision was achieved. We have observed excellent reproducibility between different instruments, underlining the robustness of the approach. PMID- 20171117 TI - Quantification of captopril in urine through surface-assisted laser desorption/ionization mass spectrometry using 4-mercaptobenzoic acid-capped gold nanoparticles as an internal standard. AB - We have developed a new internal standard method for the determination of the concentration of captopril (CAP) through surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS) using gold nanoparticles (Au NPs). This approach provided linearity for CAP over the concentration range 2.5 25 microM (R(2) = 0.987), with a limit of detection (signal-to-noise ratio = 3) of 1.0 microM. The spot-to-spot variations in the concentration of CAP through SALDI-MS analyses performed in the absence and presence of the internal standard were 26% and 9%, respectively (15 measurements). This approach provides simplicity, accuracy, precision, and great reproducibility to the determination of the levels of CAP in human urine samples. PMID- 20171118 TI - Charge remote fragmentation in electron capture and electron transfer dissociation. AB - Secondary fragmentations of three synthetic peptides (human alphaA crystallin peptide 1-11, the deamidated form of human betaB2 crystallin peptide 4-14, and amyloid beta peptide 25-35) were studied in both electron capture dissociation (ECD) and electron-transfer dissociation (ETD) mode. In ECD, in addition to c and z. ion formations, charge remote fragmentations (CRF) of z. ions were abundant, resulting in internal fragment formation or partial/entire side-chain losses from amino acids, sometimes several residues away from the backbone cleavage site, and to some extent multiple side-chain losses. The internal fragments were observed in peptides with basic residues located in the middle of the sequences, which was different from most tryptic peptides with basic residues located at the C terminus. These secondary cleavages were initiated by hydrogen abstraction at the alpha-, beta-, or gamma-position of the amino acid side chain. In comparison, ETD generates fewer CRF fragments than ECD. This secondary cleavage study will facilitate ECD/ETD spectra interpretation, and help de novo sequencing and database searching. PMID- 20171119 TI - Comparative dissociation of peptide polyanions by electron impact and photo induced electron detachment. AB - We compare product-ion mass spectra produced by electron detachment dissociation (EDD) and electron photodetachment dissociation (EPD) of multi-deprotonated peptides on a Fourier transform and a linear ion trap mass spectrometer, respectively. Both methods, EDD and EPD, involve the electron emission-induced formation of a radical oxidized species from a multi-deprotonated precursor peptide. Product-ion mass spectra display mainly fragment ions resulting from backbone cleavages of C(alpha)-C bond ruptures yielding a and x ions. Fragment ions originating from N-C(alpha) backbone bond cleavages are also observed, in particular by EPD. Although EDD and EPD methods involve the generation of a charge-reduced radical anion intermediate by electron emission, the product ion abundance distributions are drastically different. Both processes seem to be triggered by the location and the recombination of radicals (both neutral and cation radicals). Therefore, EPD product ions are predominantly formed near tryptophan and histidine residues, whereas in EDD the negative charge solvation sites on the backbone seem to be the most favorable for the nearby bond dissociation. PMID- 20171121 TI - The role of reversal frequency in learning noisy second order conditional sequences. AB - The hallmark of implicit learning is that complex knowledge can be acquired unconsciously. The second order conditionals (SOCs) of Reed and Johnson (1994) were developed to be complex, and they are popular materials for implicit learning research. Recently, it was demonstrated that in a sequence made noisy (by combining two SOCs), shared features of the SOCs may be learned explicitly (Fu, Fu, & Dienes, 2008). What are these shared features? We hypothesized that low reversal frequency may play a significant role. We have varied reversal frequency, and discovered that reversal frequency affected response times, inclusion exclusion behavior, and recognition ratings. Not only does it appear to be important to distinguish implicit and explicit knowledge, but also to distinguish what the knowledge is of. PMID- 20171120 TI - Electrospray ionization multiple-stage linear ion-trap mass spectrometry for structural elucidation of triacylglycerols: assignment of fatty acyl groups on the glycerol backbone and location of double bonds. AB - Linear ion-trap multiple-stage mass spectrometric approach (MS(n)) towards nearly complete structural elucidation of triacylglycerol (TAG) including (1) assignment the fatty acid substituents on the glycerol backbone and (2) location of the double bond(s) on the unsaturated fatty acyl groups is reported. The characterization is established by the findings that MS(2) on the [M + Li](+) ions of TAG yields more abundant ions reflecting losses of the outer fatty acid substituents either as free acids (i.e., [M + Li - R(1)CO(2)H](+) and [M + Li - R(3)CO(2)H](+) ions) or as lithium salts (i.e., [M + Li - R(1)CO(2)Li](+) and [M + Li - R(3)CO(2)Li](+) ions) than the ions reflecting the similar losses of the inner fatty acid substituent (i.e., [M + Li - R(2)CO(2)Li](+) and [M + Li - R(2)CO(2)Li](+) ions). Further dissociation (MS(3) of [M + Li - R(n)CO(2)H](+) (n = 1, 2, or 3) gives rise to the ion series locating the double bonds along the fatty acid chain. These ions arise from charge-remote fragmentations involving beta-cleavage with gamma-H shift, analogous to those seen for the unsaturated long-chain fatty acids characterized as initiated ions. Significant differences in abundances in the ion pairs reflecting the additional losses of the fatty acid moieties, respectively, were also seen in the MS(3) spectra of the [M + Li - R(n)CO(2)H](+) and [M + Li - R(n)CO(2)Li](+) ions, leading to confirmation of the fatty acid substituents on the glycerol backbone. MS(n) on the [M + Na](+) and [M + NH(4)](+) adduct ions also affords location of fatty acid substituents on the glycerol backbone, but not the position of the double bond(s) along the fatty acid chain. Unique ions from internal losses of the glycerol residues were seen in the MS(3) spectra of [M + Alk - R(n)CO(2)H](+) (n = 1, 2, 3) and of [M + Alk - R(n)CO(2)Alk](+) (Alk = Li, Na, NH(4); n = 1, 3). They are signature ions for glycerides and the pathways leading to their formation may involve rearrangements. PMID- 20171122 TI - Edges, colour and awareness in blindsight. AB - It remains unclear what is being processed in blindsight in response to faces, colours, shapes, and patterns. This was investigated in two hemianopes with chromatic and achromatic stimuli with sharp or shallow luminance or chromatic contrast boundaries or temporal onsets. Performance was excellent only when stimuli had sharp spatial boundaries. When discrimination between isoluminant coloured Gaussians was good it declined to chance levels if stimulus onset was slow. The ability to discriminate between instantaneously presented colours in the hemianopic field depended on their luminance, indicating that wavelength discrimination totally independent of other stimulus qualities is absent. When presented with narrow-band colours the hemianopes detected a stimulus maximally effective for S-cones but invisible to M- and L-cones, indicating that blindsight is mediated not just by the mid-brain, which receives no S-cone input, or that the rods contribute to blindsight. The results show that only simple stimulus features are processed in blindsight. PMID- 20171123 TI - Quantitative proteomics reveals subset-specific viral recognition in dendritic cells. AB - Dendritic cell (DC) populations consist of multiple subsets that are essential orchestrators of the immune system. Technological limitations have so far prevented systems-wide accurate proteome comparison of rare cell populations in vivo. Here, we used high-resolution mass spectrometry-based proteomics, combined with label-free quantitation algorithms, to determine the proteome of mouse splenic conventional and plasmacytoid DC subsets to a depth of 5,780 and 6,664 proteins, respectively. We found mutually exclusive expression of pattern recognition pathways not previously known to be different among conventional DC subsets. Our experiments assigned key viral recognition functions to be exclusively expressed in CD4(+) and double-negative DCs. The CD8alpha(+) DCs largely lack the receptors required to sense certain viruses in the cytoplasm. By avoiding activation via cytoplasmic receptors, including retinoic acid-inducible gene I, CD8alpha(+) DCs likely gain a window of opportunity to process and present viral antigens before activation-induced shutdown of antigen presentation pathways occurs. PMID- 20171124 TI - The membrane skeleton controls diffusion dynamics and signaling through the B cell receptor. AB - Early events of B cell activation after B cell receptor (BCR) triggering have been well characterized. However, little is known about the steady state of the BCR on the cell surface. Here, we simultaneously visualize single BCR particles and components of the membrane skeleton. We show that an ezrin- and actin-defined network influenced steady-state BCR diffusion by creating boundaries that restrict BCR diffusion. We identified the intracellular domain of Igbeta as important in mediating this restriction in diffusion. Importantly, alteration of this network was sufficient to induce robust intracellular signaling and concomitant increase in BCR mobility. Moreover, by using B cells deficient in key signaling molecules, we show that this signaling was most probably initiated by the BCR. Thus, our results suggest the membrane skeleton plays a crucial function in controlling BCR dynamics and thereby signaling, in a way that could be important for understanding tonic signaling necessary for B cell development and survival. PMID- 20171125 TI - In vivo requirement for Atg5 in antigen presentation by dendritic cells. AB - Autophagy is known to be important in presentation of cytosolic antigens on MHC class II (MHC II). However, the role of autophagic process in antigen presentation in vivo is unclear. Mice with dendritic cell (DC)-conditional deletion in Atg5, a key autophagy gene, showed impaired CD4(+) T cell priming after herpes simplex virus infection and succumbed to rapid disease. The most pronounced defect of Atg5(-/-) DCs was the processing and presentation of phagocytosed antigens containing Toll-like receptor stimuli for MHC class II. In contrast, cross-presentation of peptides on MHC I was intact in the absence of Atg5. Although induction of metabolic autophagy did not enhance MHC II presentation, autophagic machinery was required for optimal phagosome-to-lysosome fusion and subsequent processing of antigen for MHC II loading. Thus, our study revealed that DCs utilize autophagic machinery to optimally process and present extracellular microbial antigens for MHC II presentation. PMID- 20171128 TI - Vestibular testing: on balance... PMID- 20171126 TI - The aryl hydrocarbon receptor: regulation of hematopoiesis and involvement in the progression of blood diseases. AB - The aryl hydrocarbon receptor (AhR) is a basic helix-loop-helix protein that belongs to the superfamily of environment-sensing PAS (Per-ARNT-Sim) proteins. A large number of ligands have been described to bind AhR and promote its nuclear translocation. In the nucleus, the AhR and its dimerization partner the AhR nuclear translocator (ARNT) form a DNA-binding complex that acts as a transcriptional regulator. Animal and human data suggest that, beyond its mediating responses to xenobiotic and/or unknown endogenous ligands, the AhR has a role, although as yet undefined, in the regulation of cell cycle and inflammation. The AhR also appears to regulate the hematopoietic and immune systems during development and adult life in a cell-specific manner. While accidental exposure to xenobiotic AhR ligands has been associated with leukemia in humans, the specific mechanisms of AhR involvement are still not completely understood. However, recent data are consistent with a functional role of the AhR in the maintenance of hematopoietic stem and/or progenitor cells (HSCs/HPCs). Studies highlighting AhR regulation of HSCs/HPCs provide a rational framework to understand their biology, a role of the AhR in hematopoietic diseases, and a means to develop interventions for these diseases. PMID- 20171129 TI - [Communication and collaboration between nurses and doctors]. PMID- 20171127 TI - Effect of hypnotic drugs on body balance and standing steadiness. AB - BACKGROUND: Disturbed body balance and standing steadiness are problematic for those who wake up at night or in the morning after using hypnotic drugs. As a result, falls and hip fractures are frequently reported in patients using sleep medication. METHODS: A literature search was performed to identify double blind, placebo-controlled clinical trials that examined body balance and standing steadiness. Drugs that were searched were nitrazepam, triazolam, lorazepam, temazepam, loprazolam, flunitrazepam, flurazepam, and the Z-drugs zopiclone, zolpidem and zaleplon. RESULTS: A total of 57 studies were eligible for inclusion. Results showed that both benzodiazepine hypnotics and the Z-drugs significantly impair body balance and standing steadiness after single dose administration. Impairments correlate significantly with blood plasma levels and are greatest at peak plasma concentrations, but are sometimes still present upon awakening. Balance problems were dose-related and most pronounced in elderly. Co administration of alcohol aggravated the impairment. After repeated daily use of hypnotic drugs partial tolerance develops to the impairing effects on standing steadiness. CONCLUSION: Single dose administration of benzodiazepine hypnotics and Z-drugs significantly impair body balance in a dose-dependent manner. Zolpidem and zopiclone produced similar significant impairment as benzodiazepine hypnotics. Zaleplon significantly impaired balance up to 2 h after intake. Partial tolerance develops after repeated daily use. In conclusion, patients should be warned about the possible risk of imbalance and falls due to the use of sleep medication. PMID- 20171130 TI - [Frequency and characteristics of the dysmenorrhea of women in the zone of health of Torrijos (Toledo)]. AB - OBJECTIVE: To determine the prevalence of dysmenorrhoea in the Torrijos area of Toledo, the social-demographic and individual characteristics that could be associated with it, and the self-care measures and self-medication used. STUDY DESIGN: The study was conducted in women 15-45 years old selected by accidental or non-probability sampling during the visit to the Torrijos (Toledo) health centre between April and May 2008. All participants were interviewed about their personal data, presence of dysmenorrhea, its frequency and severity, limitations and self-care strategies. Data were entered for statistical analysis into the Windoes SPSS 9.0 program. RESULTS: A total of 290 women were included, whose mean age was 29.8 years. The prevalence was 55.9% (162) (CI95% 49.9-61.6). The pain intensity was 4.96/10. We found a higher frequency in younger women (77.9% (81) vs. 34.1% (29)), nulliparous and alcohol consumers. In the cluster analysis just the age remained associated [OR=0.92 (CI95% 0.88-0.96)]. Normal daily activities were affected in 36.9% (107) of the women interviewed and 34.1% (99)haD consulted a doctor. A total of 72.1% (209) have taken medicines (NSAIDs and analgesics were commonly used). CONCLUSION: Dysmenorrhea is a potentially incapacitating problem. It is very common, and requires more attention in Primary Health Care. PMID- 20171131 TI - First case of human spondylodiscitis due to Shewanella algae. AB - We present the first case of human spondylodiscitis due to Shewanella algae. Our patient did not have any predisposing factors. The portal of entry was probably a cutaneous lesion on the leg, exposed to seawater. Bacteria were isolated in pure culture from a needle biopsy specimen of the vertebral disk. Automated identification systems identified the organism as Shewanella putrefaciens. However, molecular biology identified it as S. algae. Treatment with ceftriaxone and amikacin, then ciprofloxacin successfully addressed the infection. We also review four published cases of human osteoarticular infections caused by Shewanella spp: two cases of arthritis and two cases of osteomyelitis. Two patients had predisposing factors, and contact with water was found in two cases. The clinical, radiological and biological characteristics of S. algae spondylodiscitis are indistinguishable from those of spondylodiscitis of other causes. A cutaneous lesion with exposure to water is a potential portal of entry. Molecular typing is necessary to obtain a precise bacteriological identification. PMID- 20171132 TI - Corynebacterium jeikeium bacteremia in a hemodialyzed patient. AB - Corynebacterium jeikeium, frequently encountered in clinical specimens, is part of the normal skin flora. Nevertheless, a few cases of C. jeikeium bacteremia followed by severe clinical manifestations have been reported. C. jeikeium has been reported to cause endocarditis, septicemia, meningitis, pneumonia and osteomyelitis, along with soft tissue and trauma infections. Herein we describe a case of C. jeikeium bacteremia in Greece. The isolation of a coryneform bacterium from a clinical specimen should not immediately be considered a superinfection by the skin flora. Clinical and laboratory investigations are essential in order to evaluate such cases before applying appropriate treatment. On the other hand, the association of coryneform bacteria and disease should be critically investigated, with a thorough identification of the strain, ideally beyond the classical methods, at a specialized center. PMID- 20171133 TI - Reactive arthritis due to Clostridium difficile. PMID- 20171134 TI - Ultrasonic synthesis and photocatalytic characterization of H3PW12O40/TiO2 (anatase). AB - A novel H(3)PW(12)O(40)/TiO(2) (anatase) composite photocatalyst was prepared by a high-intensity ultrasonic method using a lower temperature (80 degrees C) and was characterized by XRD and FT-IR. Its photocatalytic activity, using solar light, was evaluated through the degradation of organic dye methylene blue (MB) in aqueous. When MB solution (50mg/l, 200 ml) containing H(3)PW(12)O(40)/TiO(2) (anatase) (0.4 g) was degraded by solar irradiation after 90 min, the removal of concentration and TOC of MB reached 95% and 73%, respectively. The photocatalyst activity of H(3)PW(12)O(40)/TiO(2) (anatase) was much higher than TiO(2) which was prepared in the same way. H(3)PW(12)O(40)/TiO(2) remained efficient after five repeated experiments. PMID- 20171135 TI - A pilot evaluation of a neuromuscular electrical stimulation (NMES) based methodology for the prevention of venous stasis during bed rest. AB - Bed rest poses an increased risk factor for a potentially fatal venous thromboembolism (VTE). Lack of activation of the calf muscle pump during this resting period gives rise to venous stasis which may lead to deep vein thrombosis (DVT) development. Our aim was to investigate the effects that 4h of bed rest have on the lower limb hemodynamics of healthy subjects and to what extent electrically elicited contractions of the calf muscles can alleviate these effects. Outcome variables included popliteal vein blood flow and heart rate. Primary results indicated that the resting group experienced a significant decline in popliteal venous blood flow of approximately 47% with approximately 13% decrease in heart rate. The stimulated groups maintained a significantly higher venous blood flow and heart rate. Volume flow in the contralateral limb remained constant throughout the study and was comparable to that of the stimulated limb's recovery flow. The results suggest that even short periods of bed rest can significantly reduce lower limb blood flow which could have implications for DVT development. Electrically elicited calf muscle contractions significantly improve lower limb blood flow and can alleviate some debilitating effects of bed rest. PMID- 20171136 TI - Standardized simulated palpation training--development of a palpation trainer and assessment of palpatory skills in experienced and inexperienced clinicians. AB - Specific palpation skills are required to identify and treat myofascial pain. The aim of this study was to develop a device that reflects absolute pressure values during simulated palpation, and to test the hypothesis that training through standardized manual palpation results in improved skills for experienced and inexperienced examiners. Experienced (n = 30) and inexperienced (n = 30) examiners were randomly divided into either training or control. A device (Palpation Trainer) was constructed to measure pressure intensity (P(peak)) and rate of pressure development (RPD). Training consisted of 8-10 min standardized simulated palpation, during which examiners followed a standardized pressure-time curve (visualized in real-time on a pc-monitor). Controls received no training. Tests were performed at baseline, immediately post training and again after 48 h and analyzed for P(peak) and RPD. After simulated palpation training, experienced examiners improved palpatory skills related to P(peak) and RPD (i.e. performed closer to predetermined guidelines and with reduced inter-examiner variation), while inexperienced examiners only improved RPD (p < 0.05). Thus, standardized training resulted in acute and temporary (48 h) changes in selected analysis variables during simulated palpation in experienced and to some extent also in inexperienced clinicians. Whether this can be transferred to clinical in vivo setting requires further study. PMID- 20171137 TI - Tailoring plant metabolism for the production of novel polymers and platform chemicals. AB - Genetic engineering of plants for the production of novel polymers and platform chemicals can help to alleviate the demands for limited resources and potentially provide a platform to produce valuable compounds in bulk quantities. However, the success of transgenic plants as bioreactors depends on competitive high-yield production capacities. Recent advances in enhancing the production of novel compounds in transgenic plants include multigene transformation and the direction of biosynthetic pathways to specific intracellular compartments. It now appears feasible to produce interesting proteins such as spider silk or collagen, novel carbohydrates, and biopolymers that could replace petroleum-based plastics using transgenic plants. Direct production of novel compounds in biomass crops with the aim to produce bioenergy as a coproduct provides a promising way to improve economics of transgenic plants as biofactories. PMID- 20171138 TI - Protein engineering of microbial enzymes. AB - Protein engineering has emerged as an important tool to overcome the limitations of natural enzymes as biocatalysts. Recent advances have mainly focused on applying directed evolution to enzymes, especially important for organic synthesis, such as monooxygenases, ketoreductases, lipases or aldolases in order to improve their activity, enantioselectivity, and stability. The combination of directed evolution and rational protein design using computational tools is becoming increasingly important in order to explore enzyme sequence-space and to create improved or novel enzymes. These developments should allow to further expand the application of microbial enzymes in industry. PMID- 20171139 TI - Febrile neutropenia in a HIV positive individual post-chemotherapy. PMID- 20171140 TI - A double-blind, crossover study of Doxazosin and Enalapril on peripheral vascular tone and nocturnal blood pressure in sleep apnea patients. AB - OBJECTIVE: Pulse wave attenuation, which occurs in association with obstructive sleep apnea (OSA), is sympathetically mediated. We compared the effect of Doxazosin (DO, a peripheral alpha-receptor inhibitor) and Enalapril (EN, an ACE inhibitor) on digital vasoconstriction and nocturnal blood pressure (BP) in hypertensive OSA patients. METHODS: A double-blind, crossover study comparing equipotent dosages of DO (4 mg/day for 2 weeks with 8 mg/day for an additional 2 weeks) and EN (10mg/day and 20mg/day, respectively) was undertaken in 16 male OSA patients (age 55+/-7 years, body mass index 30.1+/-3.8 kg/m(2)) with hypertension. Assessments including ambulatory 24-h BP, full-night polysomnography with simultaneous peripheral arterial tone (PAT) and beat-to-beat finger BP monitoring (Finapres) were made at the end of each treatment period. Nighttime BP and digital vasoconstrictions associated with apneic events (measured as the ratio of PAT amplitudes during and after apneas) were analyzed. RESULTS: There were no differences between the two treatments in the 24-h BP profile and OSA severity. But the nighttime average beat-to-beat finger BP was significantly higher under DO treatment (systolic BP 129+/-13 vs. 119+/-23 mm Hg, P=0.02; diastolic BP 81+/-12 vs. 74+/-14 mm Hg, P=0.04, DO and EN respectively). In a linear mixed effects regression model, the PAT ratio during apnea increased 5.3% under DO compared with EN (P<0.0001). Each percentage decrease of apneic related oxygen desaturation was associated with 0.9% decrease in the PAT ratio (P<0.0001). REM sleep was associated with 2.2% decrease of PAT ratio compared to NREM sleep (P=0.002). CONCLUSION: Digital vasoconstrictions associated with apneic events are alpha-receptor mediated. DO compared to EN has a proportionally poor effect on nocturnal BP control in OSA patients, which may be due to the enhanced sympathetic nervous system activity characteristic of this condition. PMID- 20171141 TI - Vascular endothelial growth factor targeted therapy in the perioperative setting: implications for patient care. AB - Vascular endothelial growth factor (VEGF) targeted therapy, either alone or in combination with chemotherapy, has become the standard of care in several solid tumours, including colorectal cancer, renal-cell carcinoma, breast cancer, non small-cell lung cancer, and glioblastoma. VEGF is crucial in the process of angiogenesis and wound healing and, thus, its inhibition has the potential to affect wound healing in patients undergoing surgery. In this review, we summarise the data available on the use of VEGF-targeted therapies, and their effect on perioperative wound complications. Surgery in patients receiving VEGF-targeted therapies seems to be safe when an appropriate interval of time is allowed between surgical procedures and treatment. Recommendations regarding this interval are provided in a disease and agent site-specific manner. We also discuss complications arising from the use of VEGF-directed therapies that might require surgical intervention and the considerations important in their management. At this juncture, safety data on the use of VEGF-targeted therapies in the perioperative period are sparse, and investigators are urged to continue to study this issue prospectively in current and future clinical trials to establish firm guidelines. PMID- 20171142 TI - Equity of access to CVD risk management using electronic clinical decision support in the coronary care unit. AB - BACKGROUND: Cardiovascular (CVD) risk management post myocardial infarction is inconsistently delivered with those who need the most receiving the least - the 'inverse care law.' The Acute PREDICT Initiative is a nurse led computerised decision support system (CDSS), to provide point-of-care guideline-based, patient specific CVD risk management recommendations to all. METHODS: All patients admitted to Middlemore Hospital CCU over 2 years with acute CVD-related events potentially 'eligible' for PREDICT assessment were identified. Age, gender, ethnicity and a small area measure of socioeconomic status (NZDep01) were assessed. RESULTS: 1813/2246 (81%) of people admitted were eligible for a PREDICT assessment. Of those, 973 (54%) received a complete assessment. There were no important differences by quintile of deprivation or ethnicity between the patients receiving PREDICT and the rest. PREDICT assessments were less likely for the elderly (35.7% of >75years compared with 57.7% of <75years), for women (47.1% of women and 56.5% of men), and for those who had 5 or more previous admissions. CONCLUSIONS: Patients potentially at higher risk because of their ethnic or socioeconomic background received equitable access to in-hospital CVD risk management post MI using PREDICT. However, some other high-risk groups under utilised the system. PMID- 20171143 TI - Longer than expected-duration of caudal analgesia with two different doses of levobupivacaine in children undergoing hypospadias repair. AB - OBJECTIVE: To assess our study design and to obtain preliminary data for a dose effect study on levobupivacaine for caudal analgesia in patients undergoing hypospadias repair. STUDY DESIGN: non randomised, non-blinded pilot study. METHOD: For this non-randomized, non-blinded pilot study, 20 patients (median age 17 months, median weight 10.5 kg) were allocated to two groups receiving either 0.5 mL kg(-1) levobupivacaine 0.125% (Group 0) or 0.5 mL kg(-1) levobupivacaine 0.375% (Group 1) caudally after induction of anaesthesia for pain control. No further analgesia was given before, during or after the procedure. Pain scores (Children's and Infants' Postoperative Pain Scale) were recorded throughout the observation period, which lasted from the start of the procedure until hospital discharge on the following day. RESULTS: Group 0: six out of 10 patients remained pain free throughout the observation period. Group 1: six out of seven patients remained pain free throughout the observation period. CONCLUSION: Both concentrations of levobupivacaine provided excellent analgesia throughout surgery. The postoperative analgesia with both doses of levobupivacaine was found to be significantly longer lasting than previously reported. The study design, with a tight and extensive observation scheme, proved to be feasible, but given the surprisingly long-lasting analgesia, the observation period needs to be extended in future studies. PMID- 20171144 TI - Lacosamide intoxication in attempted suicide. AB - The anticonvulsant drug lacosamide selectively enhances slow inactivation of voltage-gated sodium channels and has been shown to be an effective add-on treatment for partial-onset seizures. Common adverse events (frequency 10%) of lacosamide doses up to 600 mg/day include nonspecific central nervous system effects (e.g., dizziness, ataxia, diplopia, and somnolence). There are no human data regarding the safety of very high dosages of lacosamide. We report the clinical course of a patient with bitemporal epilepsy who ingested 12 g of lacosamide, 56 g of gabapentin, 2g of topiramate, and 2.8 g of zonisamide during a suicide attempt. The patient was found comatose and experienced repeated generalized tonic-clonic seizures, aspiration with subsequent pneumonia, hypotension, and an increase in PR interval. Complete physical recovery occurred after several days of supportive treatment. We conclude that intoxication with lacosamide, in combination with overdoses of multiple AEDs, can be survived without sequelae, even after ingestion of 12 g lacosamide. PMID- 20171145 TI - Epilepsy after neuroimaging normalization in a woman with tacrolimus-related posterior reversible encephalopathy syndrome. AB - Posterior reversible encephalopathy syndrome (PRES) is known to occur after solid organ transplantation, and is caused by immunosuppressive agents such as tacrolimus. PRES onset usually occurs within the first 2months after liver transplantation. Clinical findings include seizures, headache, focal neurological deficits, visual disturbances, and altered mental status. These are associated with characteristic imaging features of subcortical white matter lesions on brain MRI. Atypical localizations of this posterior leukoencephalopathy have been reported. Expeditious recognition of the syndrome may lead to a complete recovery. Abnormalities of EEG during follow-up might be associated with unfavorable seizure outcome, even when neuroimaging changes resolve. We report a case of late-onset PRES with atypical localization following liver transplantation. The patient developed epilepsy despite resolution of MRI lesions at 8 months of follow-up. EEG was a prognostic factor of seizure persistence, suggesting an incomplete recovery of brain lesions in contrast to neuroimaging findings. PMID- 20171146 TI - A case of seizures induced by abstract reasoning. AB - We describe a case of reflex seizures induced by abstract reasoning but not other cognitive processes. The patient, a 46-year-old man, experienced myoclonic seizures whenever he played shogi (Japanese chess). To identify the critical thought processes responsible for inducing his seizures, we monitored his clinical seizures and epileptiform discharges while he performed comprehensive neuropsychological tests, including the Wechsler Adult Intelligence Scale-Revised (WAIS-R), spatial working memory, mental rotation, and Wisconsin Card Sorting Test (WCST) tasks. A myoclonic seizure occurred only during the WCST. Generalized 3- to 5-Hz spike-and-slow-wave bursts occurred repeatedly during the Block Design subtest of the WAIS-R and the WCST, whereas no discharges occurred during other subtests of the WAIS-R including the calculation, spatial working memory, and mental rotation tasks. These results indicate that abstract reasoning, independent of other cognitive processes, could induce the patient's epileptiform discharges, suggesting that his reflex seizures might be a distinct subtype of nonverbal thinking-induced seizures. PMID- 20171147 TI - The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. AB - The somatic mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) observed in gliomas can lead to the production of 2-hydroxyglutarate (2HG). Here, we report that tumor 2HG is elevated in a high percentage of patients with cytogenetically normal acute myeloid leukemia (AML). Surprisingly, less than half of cases with elevated 2HG possessed IDH1 mutations. The remaining cases with elevated 2HG had mutations in IDH2, the mitochondrial homolog of IDH1. These data demonstrate that a shared feature of all cancer-associated IDH mutations is production of the oncometabolite 2HG. Furthermore, AML patients with IDH mutations display a significantly reduced number of other well characterized AML-associated mutations and/or associated chromosomal abnormalities, potentially implicating IDH mutation in a distinct mechanism of AML pathogenesis. PMID- 20171148 TI - Plasma membrane permeabilization by trains of ultrashort electric pulses. AB - Ultrashort electric pulses (USEP) cause long-lasting increase of cell membrane electrical conductance, and that a single USEP increased cell membrane electrical conductance proportionally to the absorbed dose (AD) with a threshold of about 10 mJ/g. The present study extends quantification of the membrane permeabilization effect to multiple USEP and employed a more accurate protocol that identified USEP effect as the difference between post- and pre-exposure conductance values (Deltag) in individual cells. We showed that Deltag can be increased by either increasing the number of pulses at a constant E-field, or by increasing the E field at a constant number of pulses. For 60-ns pulses, an E-field threshold of 6 kV/cm for a single pulse was lowered to less than 1.7 kV/cm by applying 100-pulse or longer trains. However, the reduction of the E-field threshold was only achieved at the expense of a higher AD compared to a single pulse exposure. Furthermore, the effect of multiple pulses was not fully determined by AD, suggesting that cells permeabilized by the first pulse(s) in the train become less vulnerable to subsequent pulses. This explanation was corroborated by a model that treated multiple-pulse exposures as a series of single-pulse exposures and assumed an exponential decline of cell susceptibility to USEP as Deltag increased after each pulse during the course of the train. PMID- 20171150 TI - Determination of methocarbamol concentration in human plasma by high performance liquid chromatography-tandem mass spectrometry. AB - A simple and reproducible high performance liquid chromatography-tandem mass spectrometric method was developed for methocarbamol analysis in human plasma. Methocarbamol and the internal standard (IS) were extracted by a protein precipitation method. Under isocratic separation condition the chromatographic run time was 3.0 min. The calibration curve was linear over a range of 150-12,000 ng/mL with good intraday assay and interday assay precision (CV%<10.9%). The method was proven to be sensitive and selective for the analysis of methocarbamol in human plasma for bioequivalence study. PMID- 20171149 TI - A semi-automated non-radioactive system for measuring recovery of RNA synthesis and unscheduled DNA synthesis using ethynyluracil derivatives. AB - Nucleotide excision repair (NER) removes the major UV-photolesions from cellular DNA. In humans, compromised NER activity is the cause of several photosensitive diseases, one of which is the skin-cancer predisposition disorder, xeroderma pigmentosum (XP). Two assays commonly used in measurement of NER activity are 'unscheduled DNA synthesis (UDS)', and 'recovery of RNA synthesis (RRS)', the latter being a specific measure of the transcription-coupled repair sub-pathway of NER. Both assays are key techniques for research in NER as well as in diagnoses of NER-related disorders. Until very recently, reliable methods for these assays involved measurements of incorporation of radio-labeled nucleosides. We have established non-radioactive procedures for determining UDS and RRS levels by incorporation of recently developed alkyne-conjugated nucleoside analogues, 5 ethynyl-2'-deoxyuridine (EdU) and 5-ethynyuridine (EU). EdU and EU are respectively used as alternatives for (3)H-thymidine in UDS and for (3)H-uridine in RRS. Based on these alkyne-nucleosides and an integrated image analyser, we have developed a semi-automated assay system for NER-activity. We demonstrate the utility of this system for NER-activity assessments of lymphoblastoid samples as well as primary fibroblasts. Potential use of the system for large-scale siRNA screening for novel NER defects as well as for routine XP diagnosis are also considered. PMID- 20171151 TI - [Epileptic encephalopathy due to partial biotinidase deficiency]. PMID- 20171152 TI - [An evidence based Iberic-Latin American guideline for acute gastroenteritis management in infants and prescholars]. AB - Acute gastroenteritis (AG) morbidity and mortality rates in infants and prescholars continue to be high in developing countries. Authors want to develop an evidence-based document that supports decision making regarding AG therapy in infants and children younger than 5 y/o. A systematic review of the literature was performed (May, 2008). Evidence grading was established according to Oxford guidelines and Latin American experts submitted their opinions on the recommendations generated. Oral rehydration solutions are the threatment's keystone for children with AG, showing lesser complications due to therapy than IV fluids. AG is no contraindication of a normal diet. Racecadotril, zinc and smectite can contribute to AG treatment, as well as Lactobacillus GG and Saccharomycces boulardii. No other drugs are recommended. It is recommended to treat children presenting AG with oral rehydration solutions among racecadotril, zinc or smectite as well as some probiotics. PMID- 20171153 TI - Upper eyelid reconstruction with a horizontal V-Y myotarsocutaneous advancement flap. AB - Upper eyelid tumours, particularly basal cell carcinomas, are relatively frequent. Surgical ablation of these lesions creates defects of variable complexity. Although several options are available for lower eyelid reconstruction, fewer surgical alternatives exist for upper eyelid reconstruction. Large defects of this region are usually reconstructed with two step procedures. In 1997, Okada et al. described a horizontal V-Y myotarsocutaneous advancement flap for reconstruction of a large upper eyelid defect in a single operative time. However, no further studies were published regarding the use of this particular flap in upper eyelid reconstruction. In addition, this flap is not described in most plastic surgery textbooks. The authors report here their experience of 16 cases of horizontal V-Y myotarsocutaneous advancement flaps used to reconstruct full-thickness defects of the upper eyelid after tumour excision. The tumour histological types were as follows: 12 basal cell carcinomas, 2 cases of squamous cell carcinomas, 1 case of sebaceous cell carcinoma and 1 of malignant melanoma. This technique allowed closure of defects of up to 60% of the eyelid width. None of the flaps suffered necrosis. The mean operative time was 30 min. No additional procedures were necessary as good functional and cosmetic results were achieved in all cases. No recurrences were noted. In this series, the horizontal V-Y myotarsocutaneous advancement flap proved to be a technically simple, reliable and expeditious option for reconstruction of full-thickness upper eyelid defects (as wide as 60% of the eyelid width) in a single operative procedure. In the future this technique may become the preferential option for such defects. PMID- 20171154 TI - Seasonal trends and spatial relations between environmental/meteorological factors and leishmaniosis sand fly vector abundances in Central Spain. AB - This paper reports on an entomological survey performed over the period 2006-2008 in Central Spain (mainly in the Madrid province) where canine leishmaniosis (CanL) is endemic. The study area was selected on the grounds of its wide altitude range, which determines both broad climate and vegetation ranges that could affect sand fly distributions. This area was surveyed from NE to SW across its mountain range (Sistema Central) and plateau area using sticky traps mainly on embankments. In 2006 and 2007, 123 sites were sampled (9557 sand flies captured) to establish possible relations between environmental or meteorological factors and vector densities (Phlebotomus perniciosus and Phlebotomus ariasi). The factors correlated with higher vector densities were: a sample site between villages or at the edge of a village, the lack of a paved road, a rural habitat, an east or south-facing wall or wall sheltered from the wind, the presence of livestock or birds, a holm-oak wood vegetation, a lower summer mean temperature and lower annual mean precipitation. This study was followed by a seasonal survey conducted at 16 selected sites (14,353 sand flies) sampled them monthly from May to November 2008. P. perniciosus showed a diphasic seasonal trend with two abundance peaks in July and September whereas P. ariasi showed a monophasic trend with one peak in August. Comparing with data from studies performed in 1991 in the same area, vector densities are significantly higher. A possible explanation for this is that the vectors (mainly P. ariasi) are moving towards higher altitudes perhaps because of global change. This increasing trend could have an impact on CanL and its geographical distribution. PMID- 20171155 TI - Population structure of newly established Anopheles funestus populations in the Senegal River basin using paracentric chromosomal inversions. AB - Anopheles funestus is one of the major vectors of malaria in sub-saharan Africa. Because of several cycles of recurrent drought events that have occurred in the sahelian zone, this species had disappeared from this area since the 1970s following a disappearance of its specific breeding sites. Its comeback was, however, recently observed particularly in the Senegal River basin following the implementation of two dams. Because the implementation of hydro-agricultural and irrigation settings are suspected to be involved in the reestablishment of An. funestus populations and that paracentric inversions are involved in the adaptation to various environments, the present study was undertaken in 3 villages of the Senegal River basin (Keur Mbaye, Mbilor and Gankette Balla), (i) to study the chromosomal polymorphism of the newly established An. funestus populations in the Senegal River basin using paracentic inversions from ovarian nurse cells and (ii) their relationship with other populations of this species located in different environmental contexts (Dielmo in sudanian zone, Sankagne and Kouvar in northern sudano-guinean zone and Ngari in southern sudano-guinean zone) in order to know the key factors leading to their reestablishment in this area. Our results showed that the newly established An. funestus populations' exhibit low level of chromosomal polymorphism with two chromosomal inversions (the fixed 2Rs and the polymorphic 3La) out of the 9 paracentric inversions described up to now in An. funestus in Senegal. At population level, no significant deviation from Hardy-Weinberg equilibrium was observed for almost all inversions. Furthermore, significant genetic differentiation was revealed between the populations from the Senegal River basin and those from the sudanian and southern sudano-guinean zones and was not linked to geographical distance. However, the populations from the Senegal River basin were close or slightly differentiated to those from the northern sudano-guinean zone located within or near irrigated cultures. These observations suggest that the hydro-agricultural settings following the implementation of dams in the Senegal River were probably responsible to the comeback and the reestablishment of the An. funestus populations in this zone. PMID- 20171156 TI - Risk factors for Schistosoma haematobium infection and morbidity in two villages with different transmission patterns in Niger. AB - A better control of major neglected tropical diseases such as schistosomiasis is urgently needed to reduce their impact on public health in developing countries. To optimize the efficiency of intervention campaigns, we assessed the influence of individual human factors on the level of Schistosoma haematobium infection and morbidity in a typical Sahelian country (Niger). Random samples of 246 and 257 individuals were selected from general census in two villages with distinct patterns of schistosome transmission. One village (Lossa) is located in an area of perennial transmission whereas transmission is seasonal in the other village (Tara). Despite comparable levels of both egg excretion and lower tract pathology in the two villages, the inhabitants of Lossa had a higher risk (OR: 2.1, 95% CI: 1.1-3.9) of developing upper tract lesions compared to those living in Tara. In both villages, bladder lesions were more serious in males than in females. Children between 7 and 15 years old were the most at risk to experience heavy infections (OR: 3.4, 95% CI: 2.1-5.7), bladder (OR: 4.5, 95% CI: 2.6-7.8) and upper tract (OR: 10.4, 95% CI: 2.4-45.0) lesions, independently of gender and village. These results confirm that targeted intervention campaigns should include foci regardless of their schistosome transmission pattern and focus on the school-aged population. PMID- 20171157 TI - Expression of functional mammal flavocytochrome b(558) in yeast: comparison with improved insect cell system. AB - Activity of phagocyte NADPH-oxidase relies on the assembly of five proteins, among them the transmembrane flavocytochrome b(558) (Cytb(558)) which consists of a heterodimer of the gp91(phox) and p22(phox) subunits. The Cytb(558) is the catalytic core of the NADPH-oxidase that generates a superoxide anion from oxygen by using a reducing equivalent provided by NADPH via FAD and two hemes. We report a novel strategy to engineer and produce the stable and functional recombinant Cytb(558) (rCytb(558)). We expressed the gp91(phox) and p22(phox) subunits using the baculovirus insect cell and, for the first time, the highly inducible Pichia pastoris system. In both hosts, the expression of the full-length proteins reproduced native electrophoretic patterns demonstrating that the two polypeptides are present and, that gp91(phox) undergoes co-translational glycosylation. Spectroscopic analyses showed that the rCytb(558) displayed comparable spectral properties to neutrophil Cytb(558). In contrast to rCytb(558) produced in the insect cells with higher yield, the enzyme expressed in yeast displayed a superoxide dismutase-sensitive NADPH-oxidase activity, indicating a superoxide generation activity. It was also blocked by an inhibitor of the respiratory burst oxidase, diphenylene iodonium (DPI). As in neutrophil NADPH oxidase, activation occurred by the interactions with the soluble regulatory subunits suggesting comparable protein-protein contact patterns. We focus on the stability and function of the protein during solubilisation and reconstitution into liposomes. By comparing oxidase activities in different membrane types, we confirm that the lipid-protein environment plays a key role in the protein function. PMID- 20171158 TI - Calpain-mediated Hsp70.1 cleavage in hippocampal CA1 neuronal death. AB - Necrotic neuronal death is recently known to be mediated by the calpain-cathepsin cascade from simpler organisms to primates. The main event of this cascade is calpain-mediated lysosomal rupture and the resultant release of lysosomal cathepsins into the cytoplasm. However, the in-vivo substrate of calpain for inducing lysosomal destabilization still remains completely unknown. The recent proteomics data using the post-ischemic hippocampal CA1 tissues and glaucoma suffered retina from the primates suggested that heat shock protein (Hsp) 70.1 might be the in-vivo substrate of activated mu-calpain at the lysosomal membrane of neurons. Hsp70.1 is known to stabilize lysosomal membrane by recycling damaged proteins and protect cells from oxidative stresses. Here, we studied the molecular interaction between activated mu-calpain and the lysosomal Hsp70.1 in the monkey hippocampal CA1 neurons after the ischemia-reperfusion insult. Immunofluorescence histochemistry showed a colocalization of the activated mu calpain and upregulated Hsp70.1 at the lysosomal membrane of the post-ischemic CA1 neurons. In-vitro cleavage assay of hippocampal Hsp70.1 by Western blotting demonstrated that Hsp70.1 in the CA1 tissue is an in-vivo substrate of activated mu-calpain, and that carbonylated Hsp70.1 in the CA1 tissue by artificial oxidative stressors such as hydroxynonenal (HNE) or hydrogen peroxide is much more vulnerable to the calpain cleavage. These data altogether suggested that Hsp70.1 can become a target of the carbonylation by HNE, and Hsp70.1 is a modulator of calpain-mediated lysosomal rupture/permeabilization after the ischemia-reperfusion injury. PMID- 20171159 TI - Galanin receptor-1 modulates 5-hydroxtryptamine-1A signaling via heterodimerization. AB - Previous biochemical, cardiovascular and behavioral work has given evidence for the existence of antagonistic galanin receptor-5-HT1A receptor interactions in the brain. In this study we investigated the existence of GalR1-5-HT1A receptor heteromers and their functional characteristics. In mammalian cells transfected with GFP2-tagged 5-HT1A receptor and YFP-tagged GalR1 receptor, a proximity-based fluorescence resonance energy transfer technique was used and it has been demonstrated that GalR1-5-HT1A receptors heteromerize. Furthermore, signaling by either the mitogen-activated protein kinase (MAPK) or adenylyl cyclase (AC) pathways by these heteromers indicates a trans-inhibition phenomenon through their interacting interface via allosteric mechanisms that block the development of an excessive activation of G(i/o) and an exaggerated inhibition of AC or stimulation of MAPK activity. The presence of these heteromers in the discrete brain regions is postulated based on the existence of GalR-5-HT1A receptor receptor interactions previously described in the brain and gives rise to explore possible novel therapeutic strategies for treatment of depression by targeting the GalR1-5-HT1A heteromers. PMID- 20171160 TI - Activity of an enzyme immobilized on superparamagnetic particles in a rotational magnetic field. AB - We immobilize alpha-amylase extracted from Bacillus Iicheniformis on the surfaces of superparamagnetic particles and investigate the effect of a rotational magnetic field on the enzyme's activity. We find that the activity of the enzyme molecules immobilized on superparamagnetic particles increases in the rotational magnetic field and reaches maximum at a certain frequency. We clarify the effect of the cluster structures formed by the superparamagnetic particles on the activity. Enzyme reactions are enhanced even in a tiny volume of solution using the present method, which is very important for the development of efficient micro reactors and micro total analysis systems (mu-TAS). PMID- 20171161 TI - Protective effects of methyl gallate on H2O2-induced apoptosis in PC12 cells. AB - Neurodegenerative disorders are a class of diseases that have been linked to apoptosis induced by elevated levels of reactive oxygen species (ROS). ROS activates the apoptotic cascade through mitochondrial dysfunction and damage to lipids, proteins and DNA. Recently, fruit and tea-derived polyphenols have been found to be beneficial in decreasing oxidative stress and increasing overall health. Further, polyphenols including epigallocatechin gallate (EGCG) have been reported to inhibit apoptotic signaling and increase neural cell survival. In an effort to better understand the beneficial properties associated with polyphenol consumption, the aim of this study was to explore the neuroprotective effects of EGCG, methyl gallate (MG), gallic acid (GA) and N-acetylcysteine (NAC) on H(2)O(2)-induced apoptosis in PC12 cells and elucidate potential protective mechanisms. Cell viability data demonstrates that MG and NAC pre-treatments significantly increase viability of H(2)O(2)-stressed cells, while pre-treatments with EGCG and GA exacerbates stress. Quantitation of apoptosis and mitochondrial membrane potential shows that MG pre-treatment prevents mitochondria depolarization, however does not inhibit apoptosis and is thus evidence that MG can inhibit mitochondria-mediated apoptosis. Subsequent analysis of DNA degradation and caspase activation reveals that MG inhibits activation of caspase 9 and has a partial inhibitory effect on DNA degradation. These findings confirm the involvement of both intrinsic and extrinsic apoptotic pathways in H(2)O(2) induced apoptosis and suggest that MG may have potential therapeutic properties against mitochondria-mediated apoptosis. PMID- 20171162 TI - Comparative transcriptome analysis of differentially expressed genes in foxtail millet (Setaria italica L.) during dehydration stress. AB - Dehydration stress is one of the most important abiotic stresses that adversely influence crop growth and productivity. With the aim to understand the molecular mechanisms underlying dehydration stress tolerance in foxtail millet (Setaria italica L.), a drought tolerant crop, we examined its transcriptome changes at two time points (early and late) of dehydration stress. Two suppression subtractive hybridization (SSH) forward libraries were constructed from 21-day old seedlings of tolerant cv. Prasad at 0.5 and 6h PEG-induced dehydration stress. A total of 327 unique ESTs were identified from both libraries and were classified into 11 different categories according to their putative functions. The plant response against dehydration stress was complex, representing major transcripts involved in metabolism, stress, signaling, transcription regulation, translation and proteolysis. By Reverse Northern (RN) technique we identified the differential expression pattern of 327 transcripts, 86 (about 26%) of which showed > or = 1.7-fold induction. Further the obtained results were validated by quantitative real-time PCR (qRT-PCR) to have a comparative expression profiling of randomly chosen 9 up-regulated transcripts (> or =2.5 fold induction) between cv. Prasad (tolerant) and cv. Lepakshi (sensitive) upon dehydration stress. These transcripts showed a differential expression pattern in both cultivars at different time points of stress treatment as analyzed by qRT-PCR. The possible relationship of the identified transcripts with dehydration tolerance mechanism is discussed. PMID- 20171163 TI - The investigation and diagnosis of pathogenic mitochondrial DNA mutations in human urothelial cells. AB - Patients with mitochondrial DNA disease are amongst the most challenging to diagnose and manage given the striking phenotypic and genetic heterogeneity, which characterise these conditions. Recently, we and others have demonstrated the m.3243A>G mutation, one of the most common mitochondrial DNA pathogenic mutations, is present at clinically relevant levels in urinary epithelium, thus providing a practical, non-invasive test for diagnosis and mutation screening. In this study we further evaluate the use of these cells in detecting the m.3243A>G mutation, other mtDNA tRNA gene point mutations including the m.8344A>G mutation and single large-scale mtDNA deletions. We observe a robust relationship between m.3243A>G levels in urothelial cells and clinically affected tissues that does not change with time. Conversely, single large-scale mtDNA deletions can be detected in urothelial cells, with higher levels present in younger patients with more severe disease, but generally mtDNA deletion levels are not representative of those seen in a clinically affected tissue. Our results have implications for the diagnosis, management and counselling of families with mtDNA disease. PMID- 20171164 TI - Abeta-induced BACE-1 cleaves N-terminal sequence of mPGES-2. AB - We previously indicated that amyloid beta (Abeta) augments protein levels of beta site amyloid precursor protein cleaving enzyme-1 (BACE-1) through oxidative stress. In this study, we revealed that BACE-1 is involved in the cleavage of membrane-bound prostaglandin E2 synthase-2 (mPGES-2) in its N-terminal portion, which, in turn, enhanced the generation of prostaglandin E2 (PGE2). PGE2 results in increased Abeta production, initiating a cell-injuring cycle. Using rat primary cortical neurons, a 48 h treatment with Abeta 1-42 (5 microM) resulted in the enhanced extracellular PGE2 levels up to about 1 ng/mL, which was attenuated by treatment with a BACE-1 inhibitor (200 nM). A synthetic peptide sequence of 20 amino acids that included the cleavage site of mPGES-2 (HTARWHL RAQDLHERS AAQLSLSS) was cleaved by recombinant BACE-1, confirmed using reverse-phase high performance liquid chromatography. Cleaved or activated mPGES-2 augments the generation of PGE2. In addition, mPGES-2 was determined to be colocalized with BACE-1 and cyclooxygenase-2 in the perinuclear region in cells after exposure to Abeta. Exposure of neurons to PGE2 led to cell death, and Abeta production was enhanced by PGE2 (1 ng/mL, 48 h). Collectively, these results suggest that Abeta might cause neuroinflammation that aggravates Alzheimer's disease pathogenesis. PMID- 20171165 TI - Anti-tumor effects of depleting and non-depleting anti-CD27 monoclonal antibodies in immune-competent mice. AB - CD27 plays an important role in T-cell co-stimulation and is also expressed on lymphomas. In the present study, we generated novel depleting and non-depleting monoclonal antibodies (mAbs) against mouse CD27 and characterized their co stimulatory activity in vitro and anti-tumor effects in immune-competent mice bearing syngeneic T-cell lymphoma (EG7) expressing or lacking CD27. A profound anti-tumor effect was observed with a non-depleting mAb (RM27-3E5), but not with a depleting mAb (RM27-3C1), against either EG7/CD27(+) or EG7/CD27(-) tumors, which was associated with the induction of EG7-specific cytotoxic T lymphocytes (CTLs). Consistently, the anti-tumor effect of RM27-3E5 was abolished in T cell deficient nude mice. These results indicate that a non-depleting agonistic mAb against CD27 is promising for cancer therapy by co-stimulating tumor-specific CTL induction. PMID- 20171166 TI - The cytoprotection of chitosan based hydrogels in xenogeneic islet transplantation: An in vivo study in streptozotocin-induced diabetic mouse. AB - Immune rejection and scarcity of donor tissues are the restrictions of islets transplantation. In this study, the cytoprotection of chitosan hydrogels in xenogeneic islet transplantation was demonstrated. Wistar rat islets encapsulated in chitosan hydrogels were performed glucose challenge test and live/dead cell staining in vitro. Islets/chitosan hydrogels were transplanted into the renal subcapsular space of diabetic C57BL/6 mice. Non-fasting blood glucose level (NFBG), body weight, intraperitoneal glucose tolerance test (IPGTT), and glucose disappearance rate were determined perioperatively. The serum insulin level was analyzed, and the kidney transplanted with islets/chitosan hydrogels were retrieved for histological examination after sacrifice. The present results showed that islets encapsulated in chitosan hydrogels secreted insulin in response to the glucose stimulation as naked islets with higher cell survival. The NFBG of diabetic mice transplanted with islets/chitosan hydrogels decreased from 487+/-46 to 148+/-32 at one day postoperation and maintained in the range of 201+/-36 mg/dl for four weeks with an increase in body weight. IPGTT showed the glucose disappearance rate of mice transplanted with islets/chitosan hydrogels was significant faster than that of mice transplanted with naked islets; the serum insulin level increased from 0.29+/-0.06 to 1.69+/-0.65 microg/dl postoperatively. Histological examination revealed that the islets successfully engrafted at renal subcapsular space with positive insulin staining. The immunostain was negative for neither the T-cell lineages nor the monocyte/macrophages. This study indicates that the chitosan hydrogels deliver and protect encapsulated islets successfully in xenotransplantation. PMID- 20171167 TI - Antioxidants: Molecules, medicines, and myths. AB - There is an industry-driven public obsession with antioxidants, which are equated to safe, health-giving molecules to be swallowed as mega-dose supplements or in fortified foods. Sometimes they are good for you, but sometimes they may not be, and pro-oxidants can be better for you in some circumstances. This article re examines and challenges some basic assumptions in the nutritional antioxidant field. PMID- 20171168 TI - Investigation of mitochondrial sequence variants associated with aminoglycoside induced ototoxicity in South African TB patients on aminoglycosides. AB - A known side effect of aminoglycoside antibiotics is the development of permanent hearing loss. As South Africa is currently facing a tuberculosis (TB) epidemic, with an increasing number of multi-drug resistant tuberculosis (MDR-TB) infections, the use of aminoglycosides is on the increase. It is therefore important to determine whether the mitochondrial mutations associated with aminoglycoside-induced hearing loss occur at high frequencies in particular ethnic groups in our population. A total of 115 mainly MDR-TB patients all on aminoglycosides and 439 controls representative of the main ethnic groups in South Africa were screened for six mutations using the SNaPshot technique. Furthermore, the mitochondrial genomes of eight patients with ototoxicity were sequenced. Homoplasmic mutations were found in controls (A1555G in 0.9% of Black controls and A827G in 1.1% of Afrikaner controls) which reveal that a significant proportion of the South African population is genetically predisposed to developing aminoglycoside-induced hearing loss. The 961 delT+insC((n)) and T961G variants were found at frequencies of >1% indicating that both are probably non pathogenic polymorphisms. Sequencing of the entire mitochondrial genome in eight patients did not reveal any mutations in the MT-RNR1 gene. However, two potentially pathogenic variants, T10114C (I19T in MT-ND3) and T15312C (I189T in MT-CYB) were found that may impact on the oxidative phosphorylation capacity and warrant further investigation for their possible role in this disorder. It is imperative that the genetic basis of this potentially preventable condition be investigated, particularly in countries where aminoglycosides are still commonly used, in order to identify individuals and/or ethnic groups who are at risk for this type of hearing loss. PMID- 20171170 TI - Mitotic phosphorylation of Aki1 at Ser208 by cyclin B1-Cdk1 complex. AB - Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A is localized in the cytosol, nucleus, and centrosome. Aki1 plays distinct roles depending on its localization. In the cytosol, it acts as a scaffold protein in the phosphoinositide 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathway. In the nucleus, it is a transcriptional repressor of the serotonin-1A (5-HT1A) receptor. In the centrosome, it regulates spindle pole localization of the cohesin subunit Scc1, thereby mediating centriole cohesion during mitosis. Although the function of Aki1 has been well clarified, the regulatory machinery of Aki1 is poorly understood. We previously found that Aki1 in mitotic cells displayed reduced mobility on immunoblot analysis, but the reason for this was unclear. Here we show that the electrophoretic mobility shift of Aki1 is derived from mitotic phosphorylation. The cyclin B1-cyclin-dependent kinase 1 (Cdk1) complex was found to be one of the kinases responsible for Aki1 phosphorylation during mitosis. We identified the Ser(208) residue of Aki1 as a cyclin B1-Cdk1 phosphorylation site. Furthermore, cyclin B1-Cdk1 inhibitor treatment was shown to attenuate the level of Aki1 in complex with Scc1, suggesting that Aki1 phosphorylation by cyclin B1-Cdk1 contributes to Aki1-Scc1 complex formation. Our results indicate that cyclin B1-Cdk1 is a kinase of Aki1 during mitosis and that its phosphorylation of Aki1 may regulate mitotic function. PMID- 20171169 TI - The hyperleptinemia and ObRb expression in hyperphagic obese rats. AB - Leptin resistance associated with hyperleptinemia in high-fat-diet-induced obese rats and aged obese rats is well established, but it is not clear whether hyperphagia-induced obese rats also develop leptin resistance. We investigated whether Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which are a strain of hyperphagia-induced obese rats, develop leptin resistance and whether caloric restriction reversed this leptin resistance-induced leptin receptor (ObRb) deficit. Twenty male OLETF rats, 20 male Long-Evans Tokushima Otsuka (LETO) rats, and 10 male Sprague Dawley (SD) rats were used. All rats were initially studied at 10 weeks of age and were freely fed with standard rat chow and water until they were 38 weeks of age. Daily food intake, body weight, and plasma leptin levels of OLETF rats were remarkably increased compared to LETO or SD rats from 10 to 38 weeks of age. When they were 38 weeks of age, all OLETF rats were randomly divided into two groups. One group was freely fed with standard rat chow (FD, or free diet group), and the other group (RD, or restricted diet group) was fed with only 70% of the amount consumed by the FD group. The LETO and SD rats were dismissed from further study. After 4 weeks of caloric restriction, the average body weight (636+/-33 g vs. 752+/-24 g, P<0.05) and abdominal adipose tissue weight (10.6+/-3.2g vs. 15.8+/-1.5 g, P<0.05) of the RD group were decreased compared with those of the FD group. Plasma leptin levels of the RD group were significantly decreased compared with those of the FD group (3.47+/ 1.40 ng/mL vs. 11.55+/-1.16 ng/mL, P<0.05). The mRNA expression of ObRb and leptin-related suppressor of cytokine signaling 3 (SOCS3) in the hypothalamus, liver, and skeletal muscles of the RD group were significantly decreased compared with those of the FD group. Caloric restriction did not improve leptin receptor (ObRb) deficit or the downstream signaling of leptin in the liver, skeletal muscles, and hypothalamus. Thus, we demonstrated that OLETF rats, which are a strain of hyperphagia-induced obese rats, did not develop central or peripheral leptin resistance. We suggest that hyperleptinemia in OLETF rats is a compensatory mechanism to overcome obesity induced by hyperphagia. PMID- 20171171 TI - Lefty antagonises TGF-beta1 induced epithelial-mesenchymal transition in tubular epithelial cells. AB - Lefty is a novel member of the transforming growth factor (TGF) supergene family which has the potential to antagonise actions of TGF-beta1 - the main factor driving fibrotic disease in the kidney and in other organs. TGF-beta1 can induce fibrosis through several mechanisms, including epithelial-mesenchymal transition (EMT) which contributes to myofibroblast accumulation in the renal interstitium. This study examined whether Lefty can antagonise TGF-beta1 mediated EMT. A rat tubular epithelial cell line (NRK52E) was stably transfected with a Lefty expression plasmid (52E-Lefty) or control plasmid (52E-Control). 52E-Control cells underwent TGF-beta1 induced EMT with up-regulation of alpha-smooth muscle actin (alpha-SMA), down-regulation of E-cadherin, and transition to an elongated fibroblast-like morphology. In contrast, 52E-Lefty cells were substantially protected from TGF-beta1 induced EMT. Analysis of signalling pathways showed that 52E-Lefty cells had a marked reduction in TGF-beta1 induced Smad activity and suppression of the secondary phase of JNK (but not p38) signalling. Treatment of NRK52E cells with a JNK inhibitor was shown to suppress TGF-beta1 induced EMT. In conclusion, Lefty can antagonise TGF-beta1 mediated EMT in renal tubular epithelial cells. Lefty may have potential as an anti-fibrotic molecule in the treatment of renal fibrosis. PMID- 20171172 TI - Mechanism of action of the HIV-1 integrase inhibitory peptide LEDGF 361-370. AB - The HIV-1 integrase protein (IN) mediates integration of the viral cDNA into the host genome and is a target for anti-HIV drugs. We have recently described a peptide derived from residues 361-370 of the IN cellular partner protein LEDGF/p75, which inhibited IN catalytic activity in vitro and HIV-1 replication in cells. Here we performed a comprehensive study of the LEDGF 361-370 mechanism of action in vitro, in cells and in vivo. Alanine scan, fluorescence anisotropy binding studies, homology modeling and NMR studies demonstrated that all residues in LEDGF 361-370 contribute to IN binding and inhibition. Kinetic studies in cells showed that LEDGF 361-370 specifically inhibited integration of viral cDNA. Thus, the full peptide was chosen for in vivo studies, in which it inhibited the production of HIV-1 RNA in mouse model. We conclude that the full LEDGF 361-370 peptide is a potent HIV-1 inhibitor and may be used for further development as an anti-HIV lead compound. PMID- 20171174 TI - Regulation of CYP3A4 by pregnane X receptor: The role of nuclear receptors competing for response element binding. AB - Induction of the major drug metabolizing enzyme CYP3A4 by xenobiotics contributes to the pronounced interindividual variability of its expression and often results in clinically relevant drug-drug interactions. It is mainly mediated by PXR, which regulates CYP3A4 expression by binding to several specific elements in the 5' upstream regulatory region of the gene. Induction itself shows a marked interindividual variability, whose underlying determinants are only partly understood. In this study, we investigated the role of nuclear receptor binding to PXR response elements in CYP3A4, as a potential non-genetic mechanism contributing to interindividual variability of induction. By in vitro DNA binding experiments, we showed that several nuclear receptors bind efficiently to the proximal promoter ER6 and distal xenobiotic-responsive enhancer module DR3 motifs. TRalpha1, TRbeta1, COUP-TFI, and COUP-TFII further demonstrated dose dependent repression of PXR-mediated CYP3A4 enhancer/promoter reporter activity in transient transfection in the presence and absence of the PXR inducer rifampin, while VDR showed this effect only in the absence of treatment. By combining functional in vitro characterization with hepatic expression analysis, we predict that TRalpha1, TRbeta1, COUP-TFI, and COUP-TFII show a strong potential for the repression of PXR-mediated activation of CYP3A4 in vivo. In summary, our results demonstrate that nuclear receptor binding to PXR response elements interferes with PXR-mediated expression and induction of CYP3A4 and thereby contributes to the interindividual variability of induction. PMID- 20171173 TI - Tenofovir treatment of primary osteoblasts alters gene expression profiles: implications for bone mineral density loss. AB - There is strong clinical evidence that implicates tenofovir in the loss of bone mineral density during treatment of human immunodeficiency virus infection. In this study, we sought to test the hypothesis that tenofovir treatment of osteoblasts causes changes in the gene expression profile that would impact osteoblast function during bone formation. Primary osteoblasts were isolated and then treated with the tenofovir prodrug, tenofovir disoproxil fumarate (TDF). Total RNA from TDF-treated and untreated osteoblasts were extracted and used for microarray analysis to assess TDF-associated changes in the gene expression profile. Strikingly, the changes in gene expression profiles involved in cell signaling, cell cycle and amino acid metabolism, which would likely impact osteoblast function in bone formation. Our findings demonstrate for the first time that tenofovir treatment of primary osteoblasts results in gene expression changes that implicate loss of osteoblast function in tenofovir-associated bone mineral density loss. PMID- 20171175 TI - Ribosomal protein L6 promotes growth and cell cycle progression through upregulating cyclin E in gastric cancer cells. AB - Our previous study revealed that human ribosomal protein L6 (RPL6) was upregulated in multidrug-resistant gastric cancer cells and over-expression of RPL6 could protect gastric cancer cells from drug-induced apoptosis. The present study was designed to explore the role of RPL6 in tumorigenesis and development of gastric cancer. The expression of RPL6 in gastric cancer tissues and normal gastric mucosa was evaluated by immunohistochemical staining. It was found RPL6 was expressed at a higher level in gastric cancer tissues than that in normal gastric mucosa. RPL6 was then genetically overexpressed or knocked down in human immortalized gastric mucosa epithelial GES cells. It was demonstrated that upregulation of RPL6 accelerated the growth and enhanced in vitro colony forming ability of GES cells whereas downregulation of RPL6 showed adverse effects. Moreover, over-expression of RPL6 could promote G1 to S phase transition of GES cells. It was further evidenced that upregulation of RPL6 resulted in elevated cyclin E expression while downregulation of RPL6 caused decreased cyclin E expression in GES cells. Taken together, these data indicated that RPL6 was overexpressed in human gastric cancer and its over-expression could promote cell growth and cell cycle progression at least through upregulating cyclin E expression. PMID- 20171176 TI - Arabidopsis dynamin-related protein 1A polymers bind, but do not tubulate, liposomes. AB - The Arabidopsis dynamin-related protein 1A (AtDRP1A) is involved in endocytosis and cell plate maturation in Arabidopsis. Unlike dynamin, AtDRP1A does not have any recognized membrane binding or protein-protein interaction domains. We report that GTPase active AtDRP1A purified from Escherichia coli as a fusion to maltose binding protein forms homopolymers visible by negative staining electron microscopy. These polymers interact with protein-free liposomes whose lipid composition mimics that of the inner leaflet of the Arabidopsis plasma membrane, suggesting that lipid-binding may play a role in AtDRP1A function. However, AtDRP1A polymers do not appear to assemble and disassemble in a dynamic fashion and do not have the ability to tubulate liposomes in vitro, suggesting that additional factors or modifications are necessary for AtDRP1A's in vivo function. PMID- 20171177 TI - Transplanted neural progenitor cells expressing mutant NT3 promote myelination and partial hindlimb recovery in the chronic phase after spinal cord injury. AB - Neutrotrophin-3 (NT3) plays a protective role in injured central nervous system tissues through interaction with trk receptors. To enhance the regeneration of damaged tissue, a combination therapy with cell transplantation and neurotrophins has been under development. We examined whether the transplantation of neural progenitor cells (NPCs) secreting NT3/D15A, a multi-neurotrophin with the capacity to bind both trkB and trkC, would enhance the repair of damaged tissues and the functional recovery in a chronic phase of spinal cord injury. The cultured NPCs with lentiviral vector containing either GFP or NT3/D15A were transplanted into the contused spinal cord at 6 weeks after the initial thoracic injury. Eight weeks after the transplantation, the NT3/D15A transplants displayed better survival than the GFP transplants, and they exhibited enhanced myelin formation and partial improvement of hindlimb function. Our study revealed that NT3/D15A produced positive effects in injured spinal cords even in the chronic phase. These effects suggest an enhanced neurotrophin-trk signaling by NT3/D15A. PMID- 20171178 TI - Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer. AB - Mutations in the genes for isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) have been recently identified in glioblastoma. In the present study, we investigated IDH1 and IDH2 mutations in follicular thyroid cancer (FTC) and anaplastic thyroid cancer (ATC), with the latter, like glioblastoma, having a rapidly aggressive and lethal clinical course. By direct genomic DNA sequencing, we analyzed exon 4 of the IDH1 and IDH2 genes that harbored the mutation hot spots codon 132 and 172 of the two genes in glioblastoma, respectively, in 12 thyroid cancer cell lines, 20 FTC, and 18 ATC tumor samples. A novel homozygous G367A IDH1 mutation, resulting in a G123R amino acid change in codon 123, was identified in a case of ATC. A previously described IDH1 V71I mutation was found in a case of FTC and a case of ATC and no mutations were found in the cell lines. The overall prevalence of mutations was thus 1/20 (5%) in FTC and 2/18 (11%) in ATC. We did not find mutation in the IDH2 gene in these thyroid cancer cell lines and tumor samples. Sequence alignment analysis of 16 species revealed that the novel IDH1 G123R mutation was located in a highly conserved region, raising the possibility of a serious functional consequence as could also be predicted by the occurrence of a positively charged amino acid from this mutation. To test this, we created a G123R mutant by site-directed mutagenesis and demonstrated a decreased enzymatic activity of IDH1, similar to the expected reduction in the enzymatic activity of the previously described R132H IDH1 mutant measured as a control. Thus, functionally relevant IDH1 mutations can also occur in thyroid cancer, particularly ATC, suggesting a potential tumorigenic role of the IDH1 system that could represent a new therapeutic target for thyroid cancer. PMID- 20171179 TI - Diapocynin versus apocynin as pretranscriptional inhibitors of NADPH oxidase and cytokine production by peripheral blood mononuclear cells. AB - Apocynin has been extensively used as an inhibitor of NADPH oxidase (NOX) in many experimental models using phagocytic and non-phagocytic cells. Currently, there is some controversy about the efficacy of apocynin in non-phagocytic cells, but in phagocytes the reported results are consistent, which could be due to the presence of myeloperoxidase in these cells. This enzyme has been proposed as responsible for activating apocynin by generating its dimer, diapocynin, which is supposed to be the active compound that prevents NADPH oxidase complex assembly and activation. Here, we synthesized diapocynin and studied its effect on inhibition of gp91(phox) RNA expression. We found that diapocynin strongly inhibited the expression of gp91(phox)mRNA in peripheral blood mononuclear cells (PBMC). Only at a higher concentration, apocynin was able to exert the same effect. We also compared the apocynin and diapocynin efficacy as inhibitors of tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) production in response to lipopolysaccharide (LPS)-activated PBMC. Although apocynin did inhibit TNF-alpha production, diapocynin had a much more pronounced effect, on both TNF-alpha and IL-10 production. In conclusion, these findings suggest that the bioconversion of apocynin to diapocynin is an important issue not limited to enzymatic activity inhibition, but also for other biological effects as gp91(phox) mRNA expression and cytokine production. Hence, as diapocynin can be easily prepared from apocynin, a one-step synthesis, we recommend its use in studies where the biological effects of apocynin are searched. PMID- 20171180 TI - Autophagonizer, a novel synthetic small molecule, induces autophagic cell death. AB - Autophagy is an apoptosis-independent mechanism of cell death that protects the cell from environmental imbalances and infection by pathogens. We identified a novel small molecule, 2-(3-Benzyl-4-oxo-3,4,5,6,7,8-hexahydro benzo[4,5]thieno[2,3-d]pyrimidin-2-ylsulfanylmethyl)-oxazole-4-carboxylic acid (2 pyrrolidin-1-yl-ethyl)-amide (referred as autophagonizer), using high-content cell-based screening and the autophagosome marker EGFP-LC3. Autophagonizer inhibited growth and induced cell death in the human tumor cell lines MCF7, HeLa, HCT116, A549, AGS, and HT1080 via a caspase-independent pathway. Conversion of cytosolic LC3-I to autophagosome-associated LC3-II was greatly enhanced by autophagonizer treatment. Transmission electron microscopy and acridine orange staining revealed increased autophagy in the cytoplasm of autophagonizer-treated cells. In conclusion, autophagonizer is a novel autophagy inducer with unique structure, which induces autophagic cell death in the human tumor cell lines. PMID- 20171181 TI - Smad7 and Smad6 bind to discrete regions of Pellino-1 via their MH2 domains to mediate TGF-beta1-induced negative regulation of IL-1R/TLR signaling. AB - Transforming growth factor-beta1 (TGF-beta1) performs diverse cellular functions, including anti-inflammatory activity. The inhibitory Smad (I-Smad) Smad6 was previously shown to play an important role in TGF-beta1-induced negative regulation of Interleukin-1/Toll-like receptor (IL-1R/TLR) signaling through binding to Pellino-1, an adaptor protein of interleukin-1 receptor associated kinase 1(IRAK1). However, it is unknown whether Smad7, the other inhibitory Smad, also has a role in regulating IL-1R/TLR signaling. Here, we demonstrate that endogeneous Smad7 and Smad6 simultaneously bind to discrete regions of Pellino-1 upon TGF-beta1 treatment, via distinct regions of the Smad MH2 domains. In addition, the Smad7-Pellino-1 interaction abrogated NF-kappaB activity by blocking formation of the IRAK1-mediated IL-1R/TLR signaling complex, subsequently causing reduced expression of pro-inflammatory genes. Double knock down of endogenous Smad6 and Smad7 genes by RNA interference further reduced the anti-inflammatory activity of TGF-beta1 than when compared with single knock-down of Smad7. These results provide evidence that the I-Smads, Smad6 and Smad7, act as critical mediators for effective TGF-beta1-mediated suppression of IL-1R/TLR signaling, by simultaneous binding to discrete regions of Pellino-1. PMID- 20171182 TI - Tumor-targeting CTL expressing a single-chain Fv specific for VEGFR2. AB - Cytotoxic T lymphocytes (CTL) are critical effector cells in tumor immunity. Adoptive transfer therapy with in vitro-expanded tumor-specific CTL is a promising approach for preventing cancer metastasis and recurrence. Transferred CTL are not effective in clinical trials, however, due to inadequate tumor infiltration. Therefore, the development of functionally modified CTL, such as tumor-targeting CTL, is widely desired. Here, we designed the tumor-targeting CTL expressing a single-chain antibody fragment (scFv-CTL) specific for vascular endothelial growth factor receptor 2 (VEGFR2/flk1) by transducing the CTL with a retroviral vector. The scFv-CTL bound to VEGFR2/flk1-expressing cells and retained their cytotoxic activity against tumor cells. In addition, adoptive transfer of scFv-CTL into tumor-bearing mice effectively suppressed tumor growth due to the augmented accumulation of the transferred CTL in the tumor tissue. These findings indicate that the creation of CTL capable of targeting tumor vascular endothelial cells by scFv-expression technique is considerably promising for improvement of efficacy in adoptive immunotherapy. PMID- 20171183 TI - Activation of the hypoxia-inducible factor-1 in overloaded temporomandibular joint, and induction of osteoclastogenesis. AB - Vascular endothelial growth factor (Vegf) was previously shown to be expressed specifically in the condylar cartilage of temporomandibular joint-osteoarthritis (TMJ-OA) model rats. Here we demonstrate for the first time that hypoxia inducible factor-1alpha (Hif-1alpha) is activated in mature chondrocytes of temporomandibular joint-osteoarthritis (TMJ-OA) model rat by mechanical overload, and that activated Hif-1 in chondrocytes can induce osteoclastogenesis via repression of osteoprotegerin (Opg) expression. In rat TMJs, degeneration of the condylar cartilage became prominent in proportion to the duration of overloading. Hif-1alpha expression was observed specifically in mature and hypertrophic chondrocytes, and Hif-1alpha-positivity, level of Vegf expression, and tartrate resistant acid phosphatase (TRAP)-positive cell numbers all increased in the same manner. When ATDC5 cells induced differentiation by insulin were cultured under hypoxia, Hif-1alpha induction was observed in mature stage, but not in immature stage. Inductions of Hif-1-target genes showed a similar expression pattern. In addition, expression of Opg decreased in hypoxia, and Hif-1alpha played a role, in part, in its regulation. PMID- 20171184 TI - Differential apoptotic pathways activated in response to Cu-induced or HOCl induced LDL oxidation in U937 monocytic cell line. AB - We compared the apoptotic mechanism involved in U937 human monocytic cell line in presence of oxidized low-density lipoproteins (oxLDL) obtained after treatment with hypochlorous acid (HOCl) or copper (Cu). Both types of oxLDL induced U937 apoptotic cell death via the mitochondrial pathway. In contrast to HOCl-oxLDL, Cu oxLDL induced apoptosis via a caspase-independent mechanism, with no activation of pro-caspase-3, but via the release of apoptosis inducing factor (AIF) from mitochondria. The apoptotic program of the monocyte differs depending on the mode of LDL oxidation, based on differences in the oxidatively modified components of the two oxLDL types. PMID- 20171185 TI - Seizure induces activation of multiple subtypes of neural progenitors and growth factors in hippocampus with neuronal maturation confined to dentate gyrus. AB - Adult hippocampal neurogenesis is altered in response to different physiological and pathological stimuli. GFAP(+ve)/nestin(+ve) radial glial like Type-1 progenitors are considered to be the resident stem cell population in adult hippocampus. During neurogenesis these Type-1 progenitors matures to GFAP( ve)/nestin(+ve) Type-2 progenitors and then to Type-3 neuroblasts and finally differentiates into granule cell neurons. In our study, using pilocarpine-induced seizure model, we showed that seizure initiated activation of multiple progenitors in the entire hippocampal area such as DG, CA1 and CA3. Seizure induction resulted in activation of two subtypes of Type-1 progenitors, Type-1a (GFAP(+ve)/nestin(+ve)/BrdU(+ve)) and Type-1b (GFAP(+ve)/nestin(+ve)/BrdU(-ve)). We showed that majority of Type-1b progenitors were undergoing only a transition from a state of dormancy to activated form immediately after seizures rather than proliferating, whereas Type-1a showed maximum proliferation by 3 days post seizure induction. Type-2 (GFAP(-ve)/nestin(+ve)/BrdU(+ve)) progenitors were few compared to Type-1. Type-3 (DCX(+ve)) progenitors showed increased expression of immature neurons only in DG region by 3 days after seizure induction indicating maturation of progenitors happens only in microenvironment of DG even though progenitors are activated in CA1 and CA3 regions of hippocampus. Also parallel increase in growth factors expression after seizure induction suggests that microenvironmental niche has a profound effect on stimulation of adult neural progenitors. PMID- 20171186 TI - Molecular interaction between HAX-1 and XIAP inhibits apoptosis. AB - Caspase-3 is an important executor caspase that plays an essential role in apoptosis. Recently, HS1-associated protein X1 (HAX-1) was found to be a substrate of caspase-3. Although HAX-1 has serve multifunctional roles in cellular functions such as cell survival and calcium homeostasis, the detailed functional mechanism of HAX-1 remains still unclear. In this study, we performed proteomic experiments to identify the HAX-1 interactome. Through immunoprecipitation and 2D gel electrophoresis, we identified X-linked inhibitor of apoptosis protein (XIAP) as a novel HAX-1-interacting protein. By performing the GST pull-down assay, we defined the interaction domains in HAX-1 and XIAP, showing that HAX-1 binds to the BIR2 and BIR3 domains of XIAP whereas XIAP binds to the C-terminal domain of HAX-1. In addition, surface plasma resonance experiments showed that both BIR2 and BIR3 domains of XIAP bind to HAX-1 with affinity similar to that of full-length XIAP, indicating that either domain is necessary and sufficient for tight binding to HAX-1. Taken together with the observation that HAX-1 suppresses the polyubiquitination of XIAP, the cell viability assay results suggest that the formation of the HAX-1-XIAP complex inhibits apoptosis by enhancing the stability of XIAP against proteosomal degradation. PMID- 20171187 TI - Possible role of TIEG1 as a feedback regulator of myostatin and TGF-beta in myoblasts. AB - Myostatin and TGF-beta negatively regulate skeletal muscle development and growth. Both factors signal through the Smad2/3 pathway. However, the regulatory mechanism of myostatin and TGF-beta signaling remains unclear. TGF-beta inducible early gene (TIEG) 1 is highly expressed in skeletal muscle and has been implicated in the modulation of TGF-beta signaling. These findings prompted us to investigate the effect of TIEG1 on myostatin and TGF-beta signaling using C2C12 myoblasts. Myostatin and TGF-beta induced the expression of TIEG1 and Smad7 mRNAs, but not TIEG2 mRNA, in proliferating C2C12 cells. When differentiating C2C12 myoblasts were stimulated by myostatin, TIEG1 mRNA was up-regulated at a late stage of differentiation. In contrast, TGF-beta enhanced TIEG1 expression at an early stage. Overexpression of TIEG1 prevented the transcriptional activation of Smad by myostatin and TGF-beta in both proliferating or differentiating C2C12 cells, but the expression of Smad2 and Smad7 mRNAs was not affected. Forced expression of TIEG1 inhibited myogenic differentiation but did not cause more inhibition than the empty vector in the presence of myostatin or TGF-beta. These results demonstrate that TIEG1 is one possible feedback regulator of myostatin and TGF-beta that prevents excess action in myoblasts. PMID- 20171188 TI - The extracellular matrix protein Del1 induces apoptosis via its epidermal growth factor motif. AB - Mouse Del1 is an extracellular matrix protein mainly expressed in the developing embryo. Del1 has three EGF motifs and two discoidin domains. The second EGF motif reportedly contains an RGD sequence that binds to integrin receptors. Here, we provide evidence that Del1 protein induces cell death in vitro. Chromatin condensation and DNA laddering were observed, suggestive of apoptosis. The results of analysis using the TUNEL method and annexin V staining were also consistent with apoptosis. The apoptosis-inducing activity of Del1 could be mapped to the third EGF motif, which fitted the consensus sequence CX(D/N)XXXX(F/Y)XCXC, wherein the aspartic acid residue (D) could be beta hydroxylated. As little as twenty-five picomolar of recombinant E3 could induce apoptosis. PMID- 20171189 TI - Homodimeric intrinsic membrane proteins. Identification and modulation of interactions between mitochondrial transporter (carrier) subunits. AB - Transporter (carrier) proteins of the inner mitochondrial membrane link metabolic pathways within the matrix and the cytosol with transport/exchange of metabolites and inorganic ions. Their strict control of these fluxes is required for oxidative phosphorylation. Understanding the ternary complex transport mechanism with which most of these transporters function requires an accounting of the number and interactions of their subunits. The phosphate transporter (PTP, Mir1p) subunit readily forms homodimers with intersubunit affinities changeable by mutations. Cys28, likely at the subunit interface, is a site for mutations yielding transport inhibition or a channel-like transport mode. Such mutations yield a small increase or decrease in affinity between the subunits. The PTP inhibitor N-ethylmaleimide decreases subunit affinity by a small amount. PTP mutations that yield the highest (40%) and the lowest (2%) liposome incorporation efficiencies (LIE) are clustered near Cys28. Such mutant subunits show the lowest and highest subunit affinities respectively. The oxaloacetate transporter (Oac1p) subunit has an almost twofold lower affinity than the PTP subunit. The Oac1p, dicarboxylate (Dic1p) and PTP transporter subunits form heterodimers with even lower affinities. These results form a firm basis for detailed studies to establish the effect of subunit affinities on transport mode and activity and for the identification of the mechanism that prevents formation of heterodimers that surely will negatively impact oxidative phosphorylation and ATP levels with serious consequences for the cell. PMID- 20171190 TI - Identification of the cyclic AMP responsive element (CRE) that mediates transcriptional regulation of the pyruvate carboxylase gene in HepG2 cells. AB - Pyruvate carboxylase (PC) catalyzes the first committed step in gluconeogenesis. Here we investigated the effect of various hormones including cAMP, dexamethasone and insulin on the abundance of PC mRNA in the human hepatocyte cell line, HepG2. Treatment of HepG2 cells with 1 microM of glucagon increased the expression of PC mRNA threefold within 72 h. Treatment with 1mM 8-Br-cAMP caused the abundance of PC mRNA to increase by 2-3-fold by 48 h, peak at fourfold at 72 h, and remain unchanged to 96 h. This is in contrast to phosphoenolpyruvate carboxykinase (PEPCK) for which expression was decreased after 72 h, suggesting a distinct difference in the control of these two enzymes in the long term. Dexamethasone or insulin alone did not affect the abundance of PC mRNA whereas treatment of HepG2 cells with the combination of 1mM 8-Br-cAMP and 0.5 microM dexamethasone further increased the abundance of PC mRNA, suggesting the predominant role of 8-Br-cAMP over dexamethasone. Transient transfection of the luciferase reporter construct driven by a 1.95 kbp 5'-flanking sequence of the mouse PC gene and a plasmid encoding the human cAMP-responsive element binding protein increased luciferase reporter activity to 7-fold similar to that observed with a PEPCK promoter luciferase reporter construct. Deletion of the 5'-flanking region of the PC gene to 781 bp resulted in the complete loss of CREB-mediated induction of reporter gene, suggesting the presence of the cAMP-responsive unit is located between 1.95 kbp and 781 bp upstream of the mouse PC gene. Electrophoretic mobility shifted and chromatin immunoprecipitation assays demonstrated that CREB bind to -1639/ 1631 CRE of mouse PC gene in vitro and in vivo, respectively. PMID- 20171191 TI - Overexpression of MIP2, a novel WD-repeat protein, promotes proliferation of H9c2 cells. AB - WD40 repeat proteins have a wide range of diverse biological functions including signal transduction, cell cycle regulation, RNA splicing, and transcription. Myocardial ischemic preconditioning up-regulated protein 2 (MIP2) is a novel member of the WD40 repeat proteins superfamily that contains five WD40 repeats. Little is known about its biological role, and the purpose of this study was to determine the role of MIP2 in regulating cellular proliferation. Transfection and constitutive expression of MIP2 in the rat cardiomyoblast cell line H9c2 results in enhanced growth of those cells as measured by cell number and is proportional to the amount of MIP2 expressed. Overexpression of MIP2 results in a shorter cell cycle, as measured by flow cytometry. Collectively, these data suggest that MIP2 may participate in the progression of cell proliferation in H9c2 cells. PMID- 20171192 TI - Formation of parkin aggregates and enhanced PINK1 accumulation during the pathogenesis of Parkinson's disease. AB - Parkinson's disease (PD) is a devastating neurodegenerative disease characterized by a distinct set of motor symptoms. Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) or parkin have been linked to early-onset autosomal recessive forms of familial PD. We have recently shown that parkin (an E3 ubiquitin ligase) and PINK1 (a serine/threonine kinase) affect one other's stability, solubility, and tendency to form cytoprotective aggresomes (Um et al., 2009). Here we validated the functional relevance of this mutual interaction under pathologic PD conditions, by investigating the changes of expression and solubility of these factors in response to PD-linked toxins. Consistent with our previous cell culture data, exposure of human dopaminergic neuroblastoma SH-SY5Y cells to PD linked toxins (1-methyl-4-phenylpyridinium ion, 6-hydroxydopamine, or MG132) reduced Nonidet P-40-soluble parkin levels and induced PINK1 accumulation. Consistent with our previous findings from parkin knockout mice, rat models of PD (6-hydroxydopamine-, rotenone-, or MG132-induced PD) were also associated with an increase in soluble and insoluble PINK1 levels as well as enhanced formation of parkin aggregates. These findings suggest that both PINK1 and parkin play important roles in regulating the formation of Lewy bodies during the pathogenesis of sporadic and familial PD. PMID- 20171193 TI - Leptin upregulates telomerase activity and transcription of human telomerase reverse transcriptase in MCF-7 breast cancer cells. AB - The aim was to analyze the mechanism of leptin-induced activity of telomerase in MCF-7 breast cancer cells. We found that leptin activated telomerase in a dose dependent manner; leptin upregulated the expression of Human Telomerase Reverse Transcriptase (hTERT) at mRNA and protein levels; blockade of signal transducer and activator of transcription 3 (STAT3) phosphorylation significantly counteracted leptin-induced hTERT transcription and protein expression; chromatin immunoprecipitation analysis showed that leptin enhanced the binding of STAT3 to the hTERT promoter. This study uncovers a new mechanism of the proliferative effect of leptin on breast cancer cells and provides a new explanation of obesity related breast cancer. PMID- 20171194 TI - Inhibition of calcium-independent phospholipase A2 activates p38 MAPK signaling pathways during cytostasis in prostate cancer cells. AB - The p38 mitogen-activated protein kinase (MAPK) signaling pathways activated during cytostasis induced by Ca(2+)-independent phospholipase A2 (iPLA2) inhibition in prostate cancer cells were investigated. iPLA2 inhibition using siRNA, or the selective inhibitor bromoenol lactone (BEL) and it's enantiomers, decreased growth in LNCaP (p53 positive) and PC-3 (p53 negative) human prostate cancer cells. Decreased cell growth correlated to time- and concentration dependent activation of the mitogen-activated protein kinase p38 in both cell lines. Inhibition of cytosolic iPLA(2)beta using S-BEL, induced significantly higher levels of P-p53, p53, p21 and P-p38 expression than inhibition of microsomal iPLA2 gamma using R-BEL. Inhibition of p38 using SB202190 or SB203580 inhibited BEL-induced increases in P-p53 (ser15), p53 and p21, and altered the number of cells in G1 in LNCaP cells, and S-phase in PC-3 cells. BEL treatment also induced reactive species in PC-3 and LNCaP cells, which was partially reversed by pretreatment with N-acetyl-cysteine (NAC). NAC subsequently inhibited BEL-induced activation of p38 and p53 in LNCaP cells. In addition, treatment of cells with NAC partially reversed the effect of BEL on cell growth and preserved cell morphology. Collectively, these data demonstrate the novel findings that iPLA2 inhibition activates p38 by inducing reactive species, and further suggest that this signaling kinase is involved in p53 activation, cell cycle arrest and cytostasis. PMID- 20171195 TI - In vitro non-viral lipofectamine delivery of the gene for glial cell line-derived neurotrophic factor to human umbilical cord blood CD34+ cells. AB - Using a lipofection technique, we explored a non-viral delivery of plasmid DNA encoding a rat pGDNF (glial cell line-derived neurotrophic factor) to CD34+ cells derived from human umbilical cord blood (HUCB) cells in order to obtain cells stably expressing the GDNF gene. The target gene GDNF was amplified from cortex cells of newborn Sprague-Dawley rats by reverse transcriptase polymerase chain reaction (RT-PCR) and inserted into vector pEGFP-N1 to construct the eukaryotic expression vector pEGFP/GDNF. The positive clones were identified by sequencing and endonuclease digestion. The expression of pEGFP/GDNF-transfected HUCB cells CD34+ was examined by ELISA. Single fragment of 640 bp was obtained after the rat GDNF cDNA was amplified by RT-PCR. Two fragments of about 4.3 kb and 640 pb were obtained after digestion of recombinant plasmid pEGFP/GDNF with XhoI/KpnI. The nucleic acid fragment of 640 bp was confirmed to agree well with the sequence of GDNF gene published by GenBank. The expression of GDNF mRNA and the level of GDNF from pEGFP/GDNF-transfected CD34+ cells were increased substantially, compared with pEGFP control plasmid transfected CD34+ cells (P<0.05). Moreover, co-culture of primary rat cells with the pEGFP/GDNF-transfected CD34+ cells promoted enhanced neuroprotection against oxygen-glucose deprivation induced cell dysfunctions. The present results support the use of the non-viral plasmid liposome for therapeutic gene expression for stem cell therapy. PMID- 20171196 TI - TSU-16, (Z)-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone, is a potent activator of aryl hydrocarbon receptor and increases CYP1A1 and CYP1A2 expression in human hepatocytes. AB - (Z)-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone (TSU-16), is a potent anti-angiogenic agent that inhibits the tyrosine kinase of vascular endothelial growth factor receptor-2. In clinical trials with daily or twice weekly intravenous administration of TSU-16, its increased clearance was observed. To understand the mechanism underlying this observation, we have investigated the TSU-16-mediated regulation of cytochrome P450 expression. In human hepatocytes, TSU-16 increased mRNA levels of CYP1A1 and CYP1A2, but not CYP2B6 and CYP3A4. The extent of increase and profiles of the time-dependent changes in CYP1A1 and CYP1A2 mRNA levels after TSU-16 treatment were similar to those after treatment with 3-methylcholanthrene (3MC), a well-known activator of the aryl hydrocarbon receptor (AhR). In reporter assays using a plasmid construct that contained the human CYP1A1 5'-flanking region including the region crucial for the AhR dependent transcription of both human CYP1A1 and CYP1A2, TSU-16 treatment increased reporter activities to an extent similar to that obtained with 3MC. Treatment of HepG2 cells and human hepatocytes with AhR-targeting siRNA suppressed the increase in both mRNA levels and CYP1A activities after treatment with TSU-16 as well as after that with omeprazole or 3MC. TSU-16 also time dependently reduced cellular AhR protein levels in HepG2 cells to a similar extent with 3MC treatment. Furthermore, we demonstrated that unlabeled TSU-16 and 3MC but not omeprazole completely inhibited the specific binding of [(3)H]-3MC to mouse Hepa1c1c7 cytosol, suggesting TSU-16 as an AhR ligand. In conclusion, our present results suggest that TSU-16 binds to and activates AhR to enhance the expression of both human CYP1A1 and CYP1A2. Because TSU-16 is metabolized mainly by CYP1A2, its increased clearance after repeated dosing may be attributed to the enhanced expression of hepatic CYP1A2. PMID- 20171197 TI - Chemico-Biological Interactions. Editorial. PMID- 20171198 TI - Increased lipid peroxidation and impaired enzymatic antioxidant defense mechanism in thyroid tissue with multinodular goiter and papillary carcinoma. AB - OBJECTIVES: We aimed to evaluate the oxidant/antioxidant status of thyroid tissue in patients with multinodular goiter, papillary carcinoma and to compare with their nonpathologic tissues. METHODS: We studied 41 patients with multinodular goiter who underwent surgical treatment. The patients were divided into three groups according to clinical diagnosis. Malondialdehyde, selenium, total superoxide dismutase and glutathione peroxidase of thyroid tissue samples were determined in 14 toxic multinodular goiters, 18 non-toxic multinodular goiters, and 9 papillary carcinomas. RESULT: Superoxide dismutase and glutathione peroxidase and selenium were found lower but malondialdehyde was higher in both nodule and cancerous tissues compared with those of control ones. The level of malondialdehyde in non-toxic multinodular goiters group was higher than toxic multinodular goiters group in nodule tissues. CONCLUSIONS: It can be stated that the lipid peroxidation is increased and enzymatic free radical defense system was significantly impaired in patients with both multinodular goiters and papillary carcinomas. PMID- 20171199 TI - Livin gene plays a role in drug resistance of colon cancer cells. AB - OBJECTIVE: The objective of this study was to investigate the effect of knockdown of Livin expression on reversing drug resistance phenotype of colon cancer HCT 8/V cells. DESIGN AND METHODS: Specific short hairpin RNA (shRNA) was chosen and transfected in human colon cancer HCT-8/V cell line. Cell apoptosis and chemosensitivity were evaluated following downregulation of Livin expression. RESULTS: In the current study, Livin was found to be highly expressed in the HCT 8/V colon cancer cells, which were resistant to several anti-tumor drugs. Knocking down of Livin expression in HCT-8/V cells by specific RNAi facilitated the apoptosis of HCT-8/V cells in response to vincristine (VCR), etoposide (VP 16), and 5-flourouracil (5-FU). Chemosensitivity assay confirmed the results and demonstrated the reversal of drug resistance phenotype of HCT-8/V cells. CONCLUSION: These data suggest that specific silencing of Livin gene expression could be a promising target for further research in clinical chemotherapy of colon cancer. PMID- 20171200 TI - Dermal morphogenesis controls lateral line patterning during postembryonic development of teleost fish. AB - The lateral line system displays highly divergent patterns in adult teleost fish. The mechanisms underlying this variability are poorly understood. Here, we demonstrate that the lateral line mechanoreceptor, the neuromast, gives rise to a series of accessory neuromasts by a serial budding process during postembryonic development in zebrafish. We also show that accessory neuromast formation is highly correlated to the development of underlying dermal structures such as bones and scales. Abnormalities in opercular bone morphogenesis, in endothelin 1 knockdown embryos, are accompanied by stereotypic errors in neuromast budding and positioning, further demonstrating the tight correlation between the patterning of neuromasts and of the underlying dermal bones. In medaka, where scales form between peridermis and opercular bones, the lateral line displays a scale specific pattern which is never observed in zebrafish. These results strongly suggest a control of postembryonic neuromast patterns by underlying dermal structures. This dermal control may explain some aspects of the evolution of lateral line patterns. PMID- 20171201 TI - An efficient approach to isolate STAT regulated enhancers uncovers STAT92E fundamental role in Drosophila tracheal development. AB - The ventral veinless (vvl) and trachealess (trh) genes are determinants of the Drosophila trachea. Early in development both genes are independently activated in the tracheal primordia by signals that are ill defined. Mutants blocking JAK/STAT signaling at any level do not form a tracheal tree suggesting that STAT92E may be an upstream transcriptional activator of the early trachea determinants. To test this hypothesis we have searched for STAT92E responsive enhancers activating the expression of vvl and trh in the tracheal primordia. We show that STAT92E regulated enhancers can be rapidly and efficiently isolated by focusing the analysis on genomic regions with clusters of putative STAT binding sites where at least some of them are phylogenetically conserved. Detailed analysis of a vvl early tracheal enhancer shows that non-conserved sites collaborate with conserved sites for enhancer activation. We find that STAT92E regulated enhancers can be located as far 60 kb from the promoters. Our results indicate that vvl and trh are independently activated by STAT92E which is the most important transcription factor required for trachea specification. PMID- 20171202 TI - En2, Pax2/5 and Tcf-4 transcription factors cooperate in patterning the Xenopus brain. AB - Among Xenopus Lef/Tcfs, XTcf-4 has an outstanding role. In early development it is located exclusively in the midbrain where it is essential for midbrain and isthmus development. In order to identify transcription factors responsible for the restriction of XTcf-4 expression we isolated a 3.8kb fragment of the XTcf-4 promoter. We found that this promoter fragment is sufficient to mimic endogenous XTcf-4 expression in the midbrain. Characterization of putative binding sites for en2 and pax2/5 revealed that en2, but not pax2/5 directly represses XTcf-4 promoter activity. Gain-of-function experiments in Xenopus embryos confirmed this en2-mediated repression. Loss-of-function experiments demonstrate that both en2 and pax2/5 are essential for endogenous XTcf-4 expression. The primary effect of pax2/5 depletion thereby appears to be a reduced en2 expression at neurula stages. Because en2 can compensate for the depletion of pax2/5, we assume a hierarchical regulation of gene expression in the midbrain/isthmus region with pax2/5 acting upstream of en2. Furthermore, since the XTcf-4 expression domain does not overlap with the expression domains of the isthmus marker genes en2 and pax2/5, we conclude that the knock-down of en2 and pax2/5 results in a downregulation of a paracrine growth factor regulating XTcf-4 expression. We found that the growth factor for this non-cell-autonomous effect of en2 and pax2/5 is wnt-1 acting on the -1437 Lef/Tcf binding site on the XTcf-4 promoter. We provide evidence that the main nuclear wnt transducer for the autoregulation of XTcf-4 is XTcf-1. PMID- 20171203 TI - Hoxa1 lineage tracing indicates a direct role for Hoxa1 in the development of the inner ear, the heart, and the third rhombomere. AB - Loss of Hoxa1 function results in severe defects of the brainstem, inner ear, and cranial ganglia in humans and mice as well as cardiovascular abnormalities in humans. Because Hoxa1 is expressed very transiently during an early embryonic stage, it has been difficult to determine whether Hoxa1 plays a direct role in the precursors of the affected organs or if all defects result from indirect effects due to mispatterning of the hindbrain. In this study we use a Hoxa1-IRES Cre mouse to genetically label the early Hoxa1-expressing cells and determine their contribution to each of the affected organs, allowing us to conclude in which precursor tissue Hoxa1 is expressed. We found Hoxa1 lineage-labeled cells in all tissues expected to be derived from the Hoxa1 domain, such as the facial and abducens nuclei and nerves as well as r4 neural crest cells. In addition, we detected the lineage in derivatives that were not thought to have expressed Hoxa1 during development. In the brainstem, the anterior border of the lineage was found to be in r3, which is more anterior than previously reported. We also observed an interesting pattern of the lineage in the inner ear, namely a strong contribution to the otic epithelium with the exception of sensory patches. Moreover, lineage-labeled cells were detected in the atria and outflow tract of the developing heart. In conclusion, Hoxa1 lineage tracing uncovered new domains of Hoxa1 expression in rhombomere 3, the otic epithelium, and cardiac precursors, suggesting a more direct role for Hoxa1 in development of these tissues than previously believed. PMID- 20171204 TI - Evolution of oropharyngeal patterning mechanisms involving Dlx and endothelins in vertebrates. AB - In jawed vertebrates, the Dlx code, or nested expression patterns of Dlx genes, specify the dorsoventral polarity of pharyngeal arches, downstream of endothelin 1 (Edn-1) and its effectors, Bapx1 (Nkx3.2) and dHand (Hand2). To elucidate the evolution of the specification mechanism of the oropharyngeal skeletal system, lamprey homologs of Dlx, Edn, endothelin receptor (Ednr), Bapx1, and dHand were identified. Our analysis suggested that the Edn gene family emerged at the advent of vertebrates, and that gene duplications leading to the different Edn gnathostome subtypes (Edn1-3) occurred before the cyclostome-gnathostome split. This timing of gene duplications, giving rise to multiple subtypes, was also implied for Dlx, Ednr, Hand, and Bapx. In lamprey embryos, nested expressions of Dlx genes were not observed in pharyngeal arches, nor was any focal expression of Bapx1, known in gnathostomes to specify the jaw joint. The dHand homolog, however, was expressed more intensively ventrally, as in gnathostomes. Lamprey homologs of Edn-1 and EdnrA were also shown to be expressed as described in mice, indicating involvement of this signaling pathway in the craniofacial patterning early in vertebrate evolution. These results suggest that the last common ancestor of all the extant vertebrates would have possessed basic gene repertoires involved in oropharyngeal patterning in gnathostomes, but the elaborate genetic program leading to the Dlx code is likely to have been acquired uniquely in gnathostomes. PMID- 20171205 TI - Neurogenin 1 (Neurog1) expression in the ventral neural tube is mediated by a distinct enhancer and preferentially marks ventral interneuron lineages. AB - The bHLH transcription factor Neurog1 (Ngn1, Neurod3, neurogenin 1) is involved in neuronal differentiation and cell-type specification in distinct regions of the developing nervous system. Here, transgenic mouse models were developed that use a Bacterial Artificial Chromosome (BAC) containing 208kb flanking the Neurog1 gene to efficiently drive expression of GFP and Cre in all Neurog1 domains. Two characteristics of Neurog1 gene regulation were uncovered. First, a 4kb region previously shown to be sufficient for driving expression of a reporter gene to a subset of the Neurog1 pattern in the developing midbrain, hindbrain, and spinal cord is required uniformly for high levels of expression in all Neurog1 domains, even those not originally identified as being regulated by this region. Second, a 0.8 kb enhancer was identified that is sufficient to drive Neurog1-like expression specifically in the ventral neural tube. Furthermore, Neurog1 progenitor cells in the ventral neural tube are largely fated to interneuron lineages rather than to motoneurons. These studies provide new tools for directing tissue specific expression in the developing neural tube, define Neurog1 lineages in the spinal cord, and further define the complex genomic structure required for obtaining the correct levels and spatial restriction of the neuronal differentiation gene Neurog1. PMID- 20171207 TI - Changes in the level of calcyon mRNA in the brain of rats exposed to cocaine, self-administered or received passively. AB - The level of mRNA encoding calcyon (measured by in situ hybridization), one of the dopamine receptor interacting proteins, has been examined in the rat brain in the established animal model used to study the mechanisms of cocaine addiction (cocaine self-administration involving a yoked procedure). Two weeks of cocaine self-administration (maintenance) did not affect the level of calcyon mRNA, regardless of the way cocaine was delivered, except for tuberculum olfactorium, where calcyon mRNA was increased after cocaine treatment. In the reinstatement phase of the experiment cocaine alone induced an increase in the calcyon mRNA expression in most of the brain region studied (caudate putamen; tuberculum olfactorium; paraventricular thalamic nucleus; ventromedial hypothalamic nucleus and paraventricular hypothalamic nucleus) but only in the yoked saline control group. In other words, these results show that the single dose of cocaine (10 mg/kg) was able to induce an alteration in the level of calcyon mRNA in these rats which never before experienced any cocaine administration. The most significant effects were observed in the ventromedial hypothalamic nucleus and paraventricular hypothalamic nucleus. Interestingly, a similar effect was observed when the reinstatement of cocaine-seeking behaviour was evoked by cue (conditioned stimuli) that indicates that no cocaine was necessary to induce the changes in the level of calcyon mRNA expression. This effect was significant in tuberculum olfactorium, ventromedial hypothalamic nucleus and paraventricular hypothalamic nucleus. Such a result together with the brain areas involved in these effects might suggest the role of calcyon similar to the CART peptides and special vulnerability of calcyon expression rather to acute than chronic stimuli. PMID- 20171206 TI - FGF signaling regulates otic placode induction and refinement by controlling both ectodermal target genes and hindbrain Wnt8a. AB - The inner ear epithelium, with its complex array of sensory, non-sensory, and neuronal cell types necessary for hearing and balance, is derived from a thickened patch of head ectoderm called the otic placode. Mouse embryos lacking both Fgf3 and Fgf10 fail to initiate inner ear development because appropriate patterns of gene expression fail to be specified within the pre-otic field. To understand the transcriptional "blueprint" initiating inner ear development, we used microarray analysis to identify prospective placode genes that were differentially expressed in control and Fgf3(-)(/)(-);Fgf10(-)(/)(-) embryos. Several genes in the down-regulated class, including Hmx3, Hmx2, Foxg1, Sox9, Has2, and Slc26a9 were validated by in situ hybridization. We also assayed candidate target genes suggested by other studies of otic induction. Two placode markers, Fgf4 and Foxi3, were down-regulated in Fgf3(-)(/)(-);Fgf10(-)(/)(-) embryos, whereas Foxi2, a cranial epidermis marker, was expanded in double mutants, similar to its behavior when WNT responses are blocked in the otic placode. Assays of hindbrain Wnt genes revealed that only Wnt8a was reduced or absent in FGF-deficient embryos, and that even some Fgf3(-)(/)(-);Fgf10(-)(/+) and Fgf3(-)(/)(-) embryos failed to express Wnt8a, suggesting a key role for Fgf3, and a secondary role for Fgf10, in Wnt8a expression. Chick explant assays showed that FGF3 or FGF4, but not FGF10, were sufficient to induce Wnt8a. Collectively, our results suggest that Wnt8a provides the link between FGF induced formation of the pre-otic field and restriction of the otic placode to ectoderm adjacent to the hindbrain. PMID- 20171208 TI - The effects of anandamide transport inhibitor AM404 on voltage-dependent calcium channels. AB - The effects of anandamide transport inhibitor AM404 were investigated on depolarization-induced 45Ca2+ fluxes in transverse tubule membrane vesicles from rabbit skeletal muscle and on Ba2+ currents through L-type voltage-dependent Ca2+ channels in rat myotubes. AM404, at the concentration of 3 microM and higher, caused a significant inhibition of 45Ca2+ fluxes. Radioligand binding studies indicated that the specific binding of [3H]Isradipine to transverse tubule membranes was also inhibited significantly by AM404. In controls and in presence of 10 microM AM404, B(max) values were 51+/-6 and 27+/-5 pM/mg, and KD values were 236+/-43 and 220+/-37 pM, respectively. Inhibitory effects of AEA and arachidonic acid on 45Ca2+ flux and [3H]Isradipine binding reported in earlier studies, were also enhanced significantly in the presence of AM404. In the presence of VDM11 (1 microM), another anandamide transport inhibitor, AM404 continued to inhibit 45Ca2+ fluxes and [3H]Isradipine binding. In rat myotubes, Ca2+ currents through L-type Ca2+ channels recorded in whole-cell configuration of patch clamp technique were inhibited by AM404 in a concentration-dependent manner with an IC50 value of 3.2 microM. In conclusion, results indicate that AM404 inhibits directly the function of L-type voltage-dependent Ca2+ channels in mammalian skeletal muscles. PMID- 20171209 TI - Bovine lactoferricin induces caspase-independent apoptosis in human B-lymphoma cells and extends the survival of immune-deficient mice bearing B-lymphoma xenografts. AB - Although current treatments based on the use of B-cell-specific anti-CD20 monoclonal antibodies and aggressive combinatorial chemotherapy have improved the survival of patients suffering from B-cell non-Hodgkin's lymphoma (NHL), some individuals fail to respond to treatment and relapses remain common. New and more effective treatments for B-cell NHL are therefore required. Bovine lactoferricin (LfcinB) is a cationic antimicrobial peptide that is cytotoxic for several human tumor cell lines but does not harm healthy cells. Here we show that in vitro treatment with LfcinB caused Raji and Ramos human B-lymphoma cells to die by apoptosis, as indicated by DNA fragmentation, chromatin condensation, and nuclear disintegration. LfcinB killed B-lymphoma cells more efficiently at low serum concentrations and was inhibited in the presence of exogenous bovine serum albumin, suggesting partial neutralization of cationic LfcinB by anionic serum components. LfcinB-induced apoptosis in B-lymphoma cells was caspase-independent since caspase-3 activation was not detected by Western blotting and the general caspase inhibitor z-VAD-fmk did not prevent LfcinB-induced DNA fragmentation. Importantly, immune-deficient SCID/beige mice that were inoculated intravenously with Ramos B-lymphoma cells in order to model B-cell NHL exhibited extended survival following systemic administration of LfcinB, indicating that LfcinB warrants further investigation as a novel therapeutic agent for the possible treatment of B-cell NHL. PMID- 20171210 TI - Long-term culture and differentiation of CNS precursors derived from anterior human neural rosettes following exposure to ventralizing factors. AB - In this study we demonstrated that neural rosettes derived from human ES cells can give rise either to neural crest precursors, following expansion in presence of bFGF and EGF, or to dopaminergic precursors after exposure to ventralizing factors Shh and FGF8. Both regionalised precursors are capable of extensive proliferation and differentiation towards the corresponding terminally differentiated cell types. In particular, peripheral neurons, cartilage, bone, smooth muscle cells and also pigmented cells were obtained from neural crest precursors while tyrosine hydroxylase and Nurr1 positive dopaminergic neurons were derived from FGF8 and Shh primed rosette cells. Gene expression and immunocytochemistry analyses confirmed the expression of dorsal and neural crest genes such as Sox10, Slug, p75, FoxD3, Pax7 in neural precursors from bFGF-EGF exposed rosettes. By contrast, priming of rosettes with FGF8 and Shh induced the expression of dopaminergic markers Engrailed1, Pax2, Pitx3, floor plate marker FoxA2 and radial glia markers Blbp and Glast, the latter in agreement with the origin of dopaminergic precursors from floor plate radial glia. Moreover, in vivo transplant of proliferating Shh/FGF8 primed precursors in parkinsonian rats demonstrated engraftment and terminal dopaminergic differentiation. In conclusion, we demonstrated the derivation of long-term self-renewing precursors of selected regional identity as potential cell reservoirs for cell therapy applications, such as CNS degenerative diseases, or for the development of toxicological tests. PMID- 20171211 TI - Regulation of cell adhesion to collagen via beta1 integrins is dependent on interactions of filamin A with vimentin and protein kinase C epsilon. AB - Cell adhesion and spreading on collagen, which are essential processes for development and wound healing in mammals, are mediated by beta1 integrins and the actin and intermediate filament cytoskeletons. The mechanisms by which these separate cytoskeletal systems interact to regulate beta1 integrins and cell spreading are poorly defined. We previously reported that the actin cross-linking protein filamin A binds the intermediate filament protein vimentin and that these two proteins co-regulate cell spreading. Here we used deletional mutants of filamin A to define filamin A-vimentin interactions and the subsequent phosphorylation and re-distribution of vimentin during cell spreading on collagen. Imaging of fixed and live cell preparations showed that phosphorylated vimentin is translocated to the cell membrane during spreading. Knockdown of filamin A inhibited cell spreading and the phosphorylation and re-distribution of vimentin. Knockdown of filamin A and/or vimentin reduced the cell surface expression and activation of beta1 integrins, as indicated by immunoblotting of plasma membrane-associated proteins and shear force assays. In vitro pull-down assays using filamin A mutants showed that both vimentin and protein kinase Cvarepsilon bind to repeats 1-8 of filamin A. Reconstitution of filamin-A deficient cells with full-length filamin A or filamin A repeats 1-8 restored cell spreading, vimentin phosphorylation, and the cell surface expression of beta1 integrins. We conclude that the binding of filamin A to vimentin and protein kinase Cepsilon is an essential regulatory step for the trafficking and activation of beta1 integrins and cell spreading on collagen. PMID- 20171213 TI - N-terminal PH domain and C-terminal auto-inhibitory region of CKIP-1 coordinate to determine its nucleus-plasma membrane shuttling. AB - The pleckstrin homology (PH) domain-containing protein casein kinase 2 interacting protein-1 (CKIP-1) plays an important role in regulation of bone formation and muscle differentiation. How CKIP-1 localization is determined remains largely unclear. We observed that isolated CKIP-1-PH domain was predominantly localized in the nucleus and the C-terminus of CKIP-1 counteracted its nuclear localization. The net charge of basic residues and a serine-rich motif within the PH domain plays a pivotal role in the localization switch of both full-length CKIP-1 and the isolated PH domain. We propose that the N terminal PH domain and C-terminal auto-inhibitory region of CKIP-1 coordinate to determine its subcellular localization and the nucleus-plasma membrane shuttling. PMID- 20171214 TI - Unraveling evolutionary constraints: a heterogeneous conservation in dynamics of the titin Ig domains. AB - The giant protein titin, which comprises immunoglobulin (Ig) domains, acts as a bidirectional spring in muscle. The unfolding of Ig domains has been extensively studied, but their dynamics under native states have not been well-characterized. We performed molecular dynamics simulation on a single titin Ig domain and multi domains. Mobile regions displaying concerted motions were identified. The dynamics of Ig domains are constrained by evolutionary pressures, in such a way that global dominant motion is conserved, yet different flexibilities within Ig domains and in linkers connecting neighbouring domains were observed. We explain these heterogeneous conserved dynamics in relation to sequence conservation across species and the sequence diversity among neighbouring Ig domains. PMID- 20171212 TI - On the growth and internal structure of the human lens. AB - Growth of the human lens and the development of its internal features are examined using in vivo and in vitro observations on dimensions, weights, cell sizes, protein gradients and other properties. In vitro studies have shown that human lens growth is biphasic, asymptotic until just after birth and linear for most of postnatal life. This generates two distinct compartments, the prenatal and the postnatal. The prenatal growth mode leads to the formation of an adult nuclear core of fixed dimensions and the postnatal, to an ever-expanding cortex. The nuclear core and the cortex have different properties and can readily be physically separated. Communication and adhesion between the compartments is poor in older lenses. In vivo slit lamp examination reveals several zones of optical discontinuity in the lens. Different nomenclatures have been used to describe these, with the most common recognizing the embryonic, foetal, juvenile and adult nuclei as well as the cortex and outer cortex. Implicit in this nomenclature is the idea that the nuclear zones were generated at defined periods of development and growth. This review examines the relationship between the two compartments observed in vitro and the internal structures revealed by slit lamp photography. Defining the relationship is not as simple as it might seem because of remodeling and cell compaction which take place, mostly in the first 20 years of postnatal life. In addition, different investigators use different nomenclatures when describing the same regions of the lens. From a consideration of the dimensions, the dry mass contents and the protein distributions in the lens and in the various zones, it can be concluded that the juvenile nucleus and the layers contained within it, as well as most of the adult nucleus, were actually produced during prenatal life and the adult nucleus was completed within 3 months after birth, in the final stages of the prenatal growth mode. Further postnatal growth takes place entirely within the cortex. It can also be demonstrated that the in vitro nuclear core corresponds to the combined slit lamp nuclear zones. In view of the information presented in this review, the use of the terms foetal, juvenile and adult nucleus seems inappropriate and should be abandoned. PMID- 20171215 TI - High density lipoprotein inhibits the activation of sterol regulatory element binding protein-1 in cultured cells. AB - A link between cellular uptake of high density lipoprotein (HDL) and regulation of sterol regulatory element-binding protein-1 (SREBP-1) was investigated in vitro. HDL decreased nuclear SREBP-1 levels as well as SREBP-1 target gene expression in HepG2 and HEK293 cells. However, HDL did not repress an exogenously expressed, constitutively active form of SREBP-1. HDL increased cellular cholesterol levels, and cellular cholesterol depletion by methyl-beta cyclodextrin abolished the effects of HDL. These results suggest that HDL inhibits the activation of SREBP-1 through a cholesterol-dependent mechanism, which may play an important role in regulating lipid synthetic pathways mediated by SREBP-1. PMID- 20171216 TI - Discovery of a putative acetoin dehydrogenase complex in the hyperthermophilic archaeon Sulfolobus solfataricus. AB - Like many other aerobic archaea, the hyperthermophile Sulfolobus solfataricus possesses a gene cluster encoding components of a putative 2-oxoacid dehydrogenase complex. In the current paper, we have cloned and expressed the first two genes of this cluster and demonstrate that the protein products form an alpha(2)beta(2) hetero-tetramer possessing the catalytic activity characteristic of the first component enzyme of an acetoin dehydrogenase multienzyme complex. This represents the first report of an acetoin multienzyme complex in archaea, and contrasts with the branched-chain 2-oxoacid dehydrogenase complex activities characterised in two other archaea, Thermoplasma acidophilum and Haloferax volcanii. PMID- 20171217 TI - Corticosteroid regulation of Na(+),K(+)-ATPase alpha1-isoform expression in Atlantic salmon gill during smolt development. AB - The proposed mineralocorticoid-like signalling axis in teleost fish, consisting of the hormone 11-deoxycorticosterone (DOC) and a mineralocorticoid receptor (MR), has recently challenged our conception of cortisol being the only osmoregulatory corticosteroid in teleost fish. This paper aimed at comparing the osmoregulatory role of DOC with that of cortisol during the pre-adaptive development of SW-tolerance, smoltification, in Atlantic salmon. Using an in vitro gill block incubation system, the effect of DOC and cortisol in the gill was investigated from January to September, using Na(+),K(+)-ATPase alpha-subunit isoforms alpha-1a and alpha-1b mRNA levels as targets for regulation by the hormones. Cortisol and DOC both conferred significant up-regulation of alpha-1a and alpha-1b mRNA levels at specific time-points during smoltification. However, the effect of cortisol and DOC on alpha-subunit isoforms varied seasonally between isoforms and hormones. The maximum induction of alpha-1a was 3- to 4-fold compared to controls whereas a 2-fold induction was observed for alpha-1b. The pattern and capacity of stimulation of alpha-1a through smoltification were similar for cortisol and DOC, whereas cortisol had an enhanced capacity to stimulate alpha-1b as compared to DOC. Even though there was no demonstrable change in cortisol or DOC sensitivity in the gill, the magnitude of the hormonal effects were seasonally dependent. This is the first report of DOC-induced effects on osmoregulatory targets in fish, thus indicating a role for DOC and MR signalling in osmoregulation. PMID- 20171218 TI - Structural and functional comparisons and production of recombinant crustacean hyperglycemic hormone (CHH) and CHH-like peptides from the mud crab Scylla olivacea. AB - Sco-CHH and Sco-CHH-L (CHH-like peptide), two structural variants of the crustacean hyperglycemic hormone family identified in the mud crab (Scylla olivacea), are presumably alternatively spliced gene products. In this study, Sco CHH and Sco-CHH-L were isolated from the tissues using high performance liquid chromatography. Identity of the native peptides was confirmed using mass spectrometric (MS) analyses of purified materials and of trypsin-digested peptide fragments. Additionally, characterizations using circular dichroism (CD) spectrometry revealed that the 2 peptides have similar CD spectral profiles, showing they are composed mainly of alpha-helices, and are similarly thermo stable with a melting temperature of 74-75 degrees C. Results of bioassays indicated that Sco-CHH exerted hyperglycemic and molt-inhibiting activity, whereas Sco-CHH-L did not. Further, recombinant Sco-CHH-Gly (rSco-CHH-Gly, a glycine extended Sco-CHH) and Sco-CHH-L (rSco-CHH-L) were produced using an Escherichia coli expression system, refolded, and purified. rSco-CHH-Gly was further alpha-amidated at the C-terminal end to produce rSco-CHH. MS analyses of enzyme-digested peptide fragments of rSco-CHH-Gly and rSco-CHH-L showed that the two peptides share a common disulfide bond pattern: C7-C43, C23-C39, and C26-C52. Circular dichroism analyses and hyperglycemic assay revealed that rSco-CHH and rSco-CHH-L resemble their native counterparts, in terms of CD spectral profiles, melting curve profiles, and biological activity. rSco-CHH-Gly has a lower alpha helical content (32%) than rSco-CHH (47%), a structural deviation that may be responsible for the significant decrease in the biological activity of rSco-CHH Gly. Finally, modeled structure of Sco-CHH and Sco-CHH-L indicated that they are similarly folded, each with an N-terminal tail region and 4 alpha-helices. Putative surface residues located in corresponding positions of Sco-CHH and Sco CHH-L but with side chains of different properties were identified. The combined results support the notion that Sco-CHH and Sco-CHH-L are functionally different, but resemble each other at higher-level structures. Functional diversity between the 2 peptides is probably due to critical residues located in the C-terminus. The availability of large amounts of recombinant proteins will permit additional functional and structural studies of these CHH family peptides. PMID- 20171219 TI - Expression profiles of LHbeta, FSHbeta and their gonadal receptor mRNAs during sexual differentiation of Xenopus laevis tadpoles. AB - The gonadotropins, luteinising hormone (LH) and follicle stimulating hormone (FSH), are important hormones regulating reproductive biology in vertebrates, especially the processes of steroidogenesis and gamete maturation. Despite the role of gonadotropins during the reproductive cycle in amphibians is well established, much less is known about the functional maturation of the hypothalamus-pituitary-gonad axis during larval development. Therefore, the present study aimed to analyze the expression profiles of hypophyseal LHbeta and FSHbeta mRNA and of their corresponding gonadal receptors (LH-R, FSH-R) in Xenopus laevis tadpoles during their ontogeny and sexual differentiation. The first significant elevation of LHbeta and FSHbeta mRNA was observed at late premetamorphosis. A clear raise of LHbeta mRNA was present during prometamorphic stages especially in males, while the LH-R only slowly increased during ontogeny with highest levels during metamorphic climax. In contrast, FSHbeta mRNA expression only slightly increased during ontogeny, however in both sexes the FSH R mRNA was considerably elevated at prometamorphosis and further at metamorphic climax. Our results suggest that LHbeta and LH-R mRNA expression might be involved in initial maturation events of gametes, at least in males, while the gradually increase of FSH-R mRNA coincided with the advancing process of gamete maturation in both sexes. The present study provides for the first time evidence based on expression of gonadotropins and their corresponding gonadal receptors that the hypothalamus-pituitary-gonad axis evolves already at early stages of ontogeny and sexual differentiation in amphibians. PMID- 20171221 TI - Pituitary and plasma growth hormone dynamics during sexual maturation of female Atlantic salmon. AB - Growth hormone in fish regulates many important physiological processes including growth, metabolism and potentially reproduction. In salmonid fish, GH secretion is episodic with irregularly spaced GH peaks. Plasma GH reflects secretion episodes as well as the clearance rate of the hormone, and plasma levels may thus not always reflect the level of activation of the GH axis. This study measured the production dynamics of GH over a 17-month period in sexually maturing female Atlantic salmon which included final maturation and spawning. For the first time, the level of pituitary GH mRNA, pituitary GH protein and plasma GH protein were analyzed concurrently in the same individuals. mRNA and protein were extracted in parallel from the same samples with subsequent real time quantitative PCR to measure mRNA transcripts and radioimmunoassay to measure pituitary and plasma GH protein. Further, the effects of photoperiod manipulation on these parameters were studied. The results show no correlation between mRNA and protein levels except at some time points, and indicate that it is inappropriate to correlate pooled temporal data and averages in time series unless the relationship among the variables is stable over time. The results indicate complex and shifting relationships between pituitary GH mRNA expression, pituitary GH content and plasma GH levels, which could result from changes in clearance rather than secretion rate at different times and its episodic secretion. The study also suggests that there is a functionally important activation of the GH system during spring leading up to maturation and spawning. PMID- 20171220 TI - Neurohormones and neuropeptides encoded by the genome of Lottia gigantea, with reference to other mollusks and insects. AB - The Lottia gigantea genome was prospected for the presence of genes coding neuropeptides and neurohormones. Four genes code insulin-related peptides: two genes code molluscan insulin-like growth hormones, one gene an insulin very similar to vertebrate insulin, and the fourth a peptide related to drosophila insulin-like peptide 7. Four other genes encode the cysteine-knot proteins GPA2/GPB5 and bursicon/parabursicon. Another 37 genes code for precursors of the following neuropeptides: achatin, APGWamide, allatostatin C, allatotropin, buccalin (perhaps an allatostatin A homolog), cerebrin, CCAP, conopressin, elevenin (the predicted neuropeptide made by abdominal neuron 11 in Aplysia), egg laying hormone (two genes), enterin, feeding circuit activating neuropeptide (FCAP), FFamide, FMRFamide, GGNG, a GnRH-like peptide, the newly discovered LASGLVamide, LFRFamide, LFRYamide, LRNFVamide, luqin, lymnokinin, myomodulin (two genes), the newly discovered NKY, NPY, pedal peptide (three genes), PKYMDT, pleurin, PXFVamide, small cardioactive peptides, tachykinins (two genes) and WWamide (an allatostatin B homolog). One gene was found to encode FWISamide, while about 20 closely related genes were found to encode WWFamide. These small neuropeptides appear homologous to the NdWFamide, which contains d-Trp; these genes are similar to the Aplysia gene encoding NWFamide. Some of these peptides had not been previously identified from mollusks, such as the predicted hormones similar to Drosophila and vertebrate insulins, bursicon, the putative proctolin homolog PKYMDT and allatostatin C. Together with neuropeptides which are likely homologs of other insect neuropeptides, such as cerebrin and WWamide, this shows that despite significant differences the molluscan and arthropod neuropeptidomes are more similar than generally recognized. PMID- 20171222 TI - WITHDRAWN: Profiles in Comparative Endocrinology: Carl B. Schreck Howard Bern Lecturer, Annual Meeting of Society of Integrative and Comparative Endocrinology, Seattle, January 5, 2010. AB - This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 20171223 TI - Light chain fibroin and P25 genes of Corcyra cephalonica: Molecular cloning, characterization, tissue-specific expression, synchronous developmental and 20 hydroxyecdysone regulation during the last instar larval development. AB - The biologically active ecdysteroid hormone, 20-hydroxyecdysone (20E), regulates various processes like molting, metamorphosis and reproduction in insects. However, its role in expression of silk genes is obscure. The silk core in insects is generally constituted of a complex of three proteins namely, H-chain fibroin (H-fibroin), L-chain fibroin (L-fibroin) and P25. In the present study, we report full-length cDNA cloning and characterization of L-fibroin and P25 genes from rice moth, Corcyra cephalonica. Northern analyses demonstrated 1.1 and 1kb transcripts of L-fibroin and P25 respectively. The tissue expression pattern shows the presence of these transcripts specifically in the salivary gland. These two genes are developmentally regulated at transcriptional level and their maximum expression is observed during the late-last instar larval stage. Semi quantitative and real-time PCR studies revealed that 20E regulates the expression of these genes in a dose-dependant manner. This study further shows that physiological dose of 20E does not alter the normal expression of these two genes, whereas treatments with higher doses cause a significant decline in the expression. This study clearly suggests the role of 20E in the regulation of L fibroin and P25 at molecular level. PMID- 20171224 TI - Nucleotide sequence, tissue expression patterns and phylogenetic analysis of estrogen receptor one mRNA in the Murray rainbowfish (Melanotaenia fluviatilis) (Atheriniformes, Actinopterygii). AB - Estrogens are steroidal hormones that control many physiological processes in both female and male vertebrates. Like other vertebrates, fish have two distinct estrogen receptors (Esr) subtypes, Esr1 and Esr2a that have been isolated in a number of species, as well as a third subtype, Esr2b. The mRNA encoding the Esr1 was isolated from the female liver of an Australian freshwater fish, the Murray rainbowfish, Melanotaenia fluviatilis. The rainbowfish esr1 cDNA was 2569 bp in length and with an open reading frame to encode a protein of 611 amino acids. Phylogenetic analysis and multiple amino acid sequence alignment indicated close relationship and high similarity with killifish (Fundulus heteroclitus) and gilthead sea bream (Sparus aurata). Expression of rainbowfish esr1 mRNA was abundant in the liver, gonads and intestine of adult female and male rainbowfish. This is the first isolation of the full-length nucleotide sequence of an estrogen receptor from rainbowfish. This sequence provides a valuable molecular tool that can be used in future studies investigating estrogen mechanisms, actions and tissue-specific expression in juvenile and adult rainbowfish. PMID- 20171225 TI - Behavioral and physiological responses of nestling pied flycatchers to acoustic stress. AB - The extended secretion of stress hormones in fully developed animals is known to have profound consequences. However, little is known about the effects of stress on the behavior and physiology of free-living young animals, and how such responses relate to each other. We repeatedly (during 5 consecutive days, 1 h/day) exposed the nestlings of a passerine bird, the pied flycatcher (Ficedula hypoleuca), to recordings of nestling distress calls and examined their behavioral and physiological responses to the stressor on the first and the last day of the experiment (on days 9 and 13 post-hatch, respectively). In comparison with control siblings, stressed nestlings reduced the amount of time that they devoted to vocalization and locomotion and increased levels of circulating corticosterone. In 9-day-old nestlings, the level of stress-induced hormone was negatively related to locomotor activity, but not to the rate of vocalizations. The repeated presentation of the stressor increased the heterophile-to-lymphocyte ratio in nestlings but did not affect nestling growth rate. In 13-day-old nestlings, the level of stress-induced corticosterone was not related to behavioral activity. These results suggest that the high level of corticosterone released by immature nestlings in response to a stressor may promote anti predator behavior (e.g., passive avoidance behavior). Moreover, repeatedly induced stress may have a cumulative and potentially negative effect on individual physiology. PMID- 20171226 TI - Mutations in desmin's carboxy-terminal "tail" domain severely modify filament and network mechanics. AB - Inherited mutations in the gene coding for the intermediate filament protein desmin have been demonstrated to cause severe skeletal and cardiac myopathies. Unexpectedly, some of the mutated desmins, in particular those carrying single amino acid alterations in the non-alpha-helical carboxy-terminal domain ("tail"), have been demonstrated to form apparently normal filaments both in vitro and in transfected cells. Thus, it is not clear if filament properties are affected by these mutations at all. For this reason, we performed oscillatory shear experiments with six different desmin "tail" mutants in order to characterize the mesh size of filament networks and their strain stiffening properties. Moreover, we have carried out high-frequency oscillatory squeeze flow measurements to determine the bending stiffness of the respective filaments, characterized by the persistence length l(p). Interestingly, mesh size was not altered for the mutant filament networks, except for the mutant DesR454W, which apparently did not form proper filament networks. Also, the values for bending stiffness were in the same range for both the "tail" mutants (l(p)=1.0-2.0 microm) and the wild-type desmin (l(p)=1.1+/-0.5 microm). However, most investigated desmin mutants exhibited a distinct reduction in strain stiffening compared to wild-type desmin and promoted nonaffine network deformation. Therefore, we conclude that the mutated amino acids affect intrafilamentous architecture and colloidal interactions along the filament in such a way that the response to applied strain is significantly altered. In order to explore the importance of the "tail" domain as such for filament network properties, we employed a "tail"-truncated desmin. Under standard conditions, it formed extended regular filaments, but failed to generate strain stiffening. Hence, these data strongly indicate that the "tail" domain is responsible for attractive filament-filament interactions. Moreover, these types of interactions may also be relevant to the network properties of the desmin cytoskeleton in patient muscle. PMID- 20171227 TI - pH-dependent interactions guide the folding and gate the transmembrane pore of the beta-barrel membrane protein OmpG. AB - The physical interactions that switch the functional state of membrane proteins are poorly understood. Previously, the pH-gating conformations of the beta-barrel forming outer membrane protein G (OmpG) from Escherichia coli have been solved. When the pH changes from neutral to acidic the flexible extracellular loop L6 folds into and closes the OmpG pore. Here, we used single-molecule force spectroscopy to structurally localize and quantify the interactions that are associated with the pH-dependent closure. At acidic pH, we detected a pH dependent interaction at loop L6. This interaction changed the (un)folding of loop L6 and of beta-strands 11 and 12, which connect loop L6. All other interactions detected within OmpG were unaffected by changes in pH. These results provide a quantitative and mechanistic explanation of how pH-dependent interactions change the folding of a peptide loop to gate the transmembrane pore. They further demonstrate how the stability of OmpG is optimized so that pH changes modify only those interactions necessary to gate the transmembrane pore. PMID- 20171228 TI - Regions outside the alpha-crystallin domain of the small heat shock protein Hsp26 are required for its dimerization. AB - Small heat shock proteins (sHsps) are a ubiquitous family of molecular chaperones. They form homo-oligomers, composed of mostly 24 subunits. The immunoglobulin-like alpha-crystallin domain, which is flanked by N- and C terminal extensions, is the most conserved element in sHsps. It is assumed to be the dimeric building block from which the sHsp oligomers are assembled. Hsp26 from Saccharomyces cerevisiae is a well-characterized member of this family. With a view to study the structural stability and oligomerization properties of its alpha-crystallin domain, we produced a series of alpha-crystallin domain constructs. We show that a minimal alpha-crystallin domain can, against common belief, be monomeric and stably folded. Elongating either the N- or the C terminus of this minimal alpha-crystallin domain with the authentic extensions leads to the formation of dimeric species. In the case of N-terminal extensions, their population is dependent on the presence of the complete so-called Hsp26 "middle domain". For the C-terminal extensions, the presence of the conserved IXI motif of sHsps is necessary and sufficient to induce dimerization, which can be inhibited by increasing ionic strength. Dimerization does not induce major changes in secondary structure of the Hsp26 alpha-crystallin domain. A thermodynamic analysis of the monomeric and dimeric constructs revealed that dimers are not significantly stabilized against thermal and chemical denaturation in comparison to monomers, supporting our notion that dimerization is not a prerequisite for the formation of a well-folded Hsp26 alpha-crystallin domain. PMID- 20171229 TI - A kinematic model coupling stress fiber dynamics with JNK activation in response to matrix stretching. AB - The role of the actin cytoskeleton in regulating mechanotransduction in response to external forces is complex and incompletely understood. Here, we develop a mathematical model coupling the dynamic disassembly and reassembly of actin stress fibers and associated focal adhesions to the activation of c-jun N terminal kinase (JNK) in cells attached to deformable matrices. The model is based on the assumptions that stress fibers are pre-extended to a preferred level under static conditions and that perturbations from this preferred level destabilize the stress fibers. The subsequent reassembly of fibers upregulates the rate of JNK activation as a result of the formation of new integrin bonds within the associated focal adhesions. Numerical solutions of the model equations predict that different patterns of matrix stretch result in distinct temporal patterns in JNK activation that compare well with published experimental results. In the case of cyclic uniaxial stretching, stretch-induced JNK activation slowly subsides as stress fibers gradually reorient perpendicular to the stretch direction. In contrast, JNK activation is chronically elevated in response to cyclic equibiaxial stretch. A step change in either uniaxial or equibiaxial stretch results in a short, transient upregulation in JNK that quickly returns to the basal level as overly stretched stress fibers disassemble and are replaced by fibers assembled at the preferred level of stretch. In summary, the model describes a mechanism by which the dynamic properties of the actin cytoskeleton allow cells to adapt to applied forces through turnover and reorganization to modulate intracellular signaling. PMID- 20171230 TI - Reverse-engineering of biochemical reaction networks from spatio-temporal correlations of fluorescence fluctuations. AB - Recent developments of fluorescence labeling and highly advanced microscopy techniques have enabled observations of activities of biosignaling molecules in living cells. The high spatial and temporal resolutions of these video microscopy experiments allow detection of fluorescence fluctuations at the timescales approaching those of enzymatic reactions. Such fluorescence fluctuation patterns may contain information about the complex reaction-diffusion system driving the dynamics of the labeled molecule. Here, we have developed a method of identifying the reaction-diffusion system of fluorescently labeled signaling molecules in the cell, by combining spatio-temporal correlation function analysis of fluctuating fluorescent patterns, stochastic reaction-diffusion simulations, and an iterative system identification technique using a simulated annealing algorithm. In this report, we discuss the validity and usability of spatio-temporal correlation functions in characterizing the reaction-diffusion dynamics of biomolecules, and demonstrate application of our reaction-diffusion system identification method to a simple conceptual model for small GTPase activation. PMID- 20171231 TI - Optimal cytoplasmatic density and flux balance model under macromolecular crowding effects. AB - Macromolecules occupy between 34% and 44% of the cell cytoplasm, about half the maximum packing density of spheres in three dimension. Yet, there is no clear understanding of what is special about this value. To address this fundamental question we investigate the effect of macromolecular crowding on cell metabolism. We develop a cell scale flux balance model capturing the main features of cell metabolism at different nutrient uptakes and macromolecular densities. Using this model we show there are two metabolic regimes at low and high nutrient uptakes. The latter regime is characterized by an optimal cytoplasmatic density where the increase of reaction rates by confinement and the decrease by diffusion slow-down balance. More important, the predicted optimal density is in the range of the experimentally determined density of Escherichia coli. PMID- 20171232 TI - Effects of life history variation on vertical transfer of toxicants in marine mammals. AB - Toxicant bioaccumulation poses a risk to many marine mammal populations. Although individual-level toxicology has been the subject of considerable research in several species, we lack a theoretical framework to generalize the results across environments and life histories. Here we formulate a dynamic energy budget model to predict the effects of intra- and interspecific life history variation on toxicant dynamics in marine mammals. Dynamic energy budget theory attempts to describe the most general processes of energy acquisition and utilization in heterotrophs. We tailor the basic model to represent the marine mammal reproductive cycle, and we add a model of toxicant uptake and partitioning to describe vertical transfer of toxicants from mother to offspring during gestation and lactation. We first show that the model predictions are consistent with qualitative patterns reported in empirical studies and previous species-specific modeling studies. Next, we use this model to examine the dependence of offspring toxicant load on birth order, food density, and interspecific life history variation. PMID- 20171233 TI - Editorial. PMID- 20171234 TI - The eyes have it: an exploration of eye movements in action disorganisation syndrome. AB - We examined eye movements in a patient, FK, who has action disorganisation syndrome (ADS), as he performed the everyday task of making a cup of tea. We compared his eye movements with those of a person with Alzheimer's disease and with healthy volunteers. Despite showing very disorganised behaviour many aspects of FK's eye movements were relatively normal. However, unlike normal participants FK made no advance glances to objects that were about to be used, and he made increased numbers of fixations to irrelevant objects during the task. There were also differences in the durations of his eye movements during correct actions and during his perseverative and task-addition responses. We discuss the implications for understanding ADS and the cognitive processes required for correctly performing everyday tasks. PMID- 20171235 TI - Cerebral lateralization of vigilance: a function of task difficulty. AB - Functional near infrared spectroscopy (fNIRS) measures of cerebral oxygenation levels were collected from participants performing difficult and easy versions of a 12 min vigilance task and for controls who merely watched the displays without a work imperative. For the active participants, the fNIRS measurements in both vigilance tasks showed higher levels of cerebral activity than was present in the case of the no-work controls. In the easier task, greater activation was found in the right than in the left cerebral hemisphere, matching previous results indicating right hemisphere dominance for vigilance. However, for the more difficult task, this laterality difference was not found, instead activation was bilateral. Unilateral hemispheric activation in vigilance may be a result of employing relatively easy/simple tasks, not vigilance per se. PMID- 20171236 TI - Digoxin derivatives substituted by alkylidene at the butenolide part. AB - A series of digoxin derivatives containing the gamma-alkylidene butenolide moiety were synthesised by way of stereoselective vinylogous aldol reaction of the unactivated butenolide in simple conditions. The structures of compounds synthesised were characterised by infrared (IR), nuclear magnetic resonance (NMR) and HR-MS. Preliminary bioassay shows that some of them have cardiac functions, especially compound 2g that induced a marked increase in myocardial contractility at 10ngml(-1) and 20ngml(-1) concentrations without digitalis toxicity. PMID- 20171237 TI - Hydrophobicity and haemolytic potential of oxo derivatives of cholic, deoxycholic and chenodeoxycholic acids. AB - The objective of this work was to study the effect of structure of bile acids on their membranolytic potential and extent of overlapping of the information about the membranolytic potential of bile acids and their physico-chemical parameters, namely: retention index R(M0) (as a measure of bile acid hydrophobicity, reversed phase thin-layer chromatography (RPTLC)), lecithin solubilisation (measure of the interaction of bile acids with phospholipids) and critical micellar concentration (CMC). It was found that bile acid concentrations at 100% lysis of erythrocyte membranes is described best by their CMC values, whereas at 50% lysis the parameter used is lecithin solubilisation. This indicates that different mixed micelles are formed in the membrane lysis at lower and higher concentrations of bile acids. Replacement of the hydroxyl (OH) group in the bile acid molecule with an oxo group yields derivatives with lowered hydrophobicity, power of lecithin solubilisation, tendency for self-aggregation as well as the membranolytic activity. PMID- 20171238 TI - The role of organic anion transporting polypeptides (OATPs/SLCOs) in the toxicity of different microcystin congeners in vitro: a comparison of primary human hepatocytes and OATP-transfected HEK293 cells. AB - Cellular uptake of microcystins (MCs), a family of cyclic cyanobacterial heptapeptide toxins, occurs via specific organic anion transporting polypeptides (OATPs), where MCs inhibit serine/threonine-specific protein phosphatase (PP). Despite comparable PP-inhibitory capacity, MCs differ greatly in their acute toxicity, thus raising the question whether this discrepancy results from MC specific toxikokinetic rather than toxicodynamic differences. OATP-mediated uptake of MC congeners MCLR, -RR, -LW and -LF was compared in primary human hepatocytes and HEK293 cells stably expressing recombinant human OATP1B1/SLCO1B1 and OATP1B3/SLCO1B3 in the presence/absence of OATP substrates taurocholate (TC) and bromosulfophthalein (BSP) and measuring PP-inhibition and cytotoxicity. Control vector expressing HEK293 were resistant to MC cytotoxicity, while TC and BSP competition experiments reduced MC cytotoxicity in HEK293-OATP transfectants, thus confirming the requirement of OATPs for trans-membrane transport. Despite comparable PP-inhibiting capabilities, MCLW and -LF elicited cytotoxic effects at lower equimolar concentrations than MCLR and MCRR, hence suggesting congener selective transport into HEK293-OATP transfectants and primary human hepatocytes. Primary human hepatocytes appeared one order of magnitude more sensitive to MC congeners than the corresponding HEK293 -OATP transfectants. Although the latter maybe due to a much lower level of PPs in primary human hepatocytes, the presence of OATPs other than 1B1 or 1B3 may have added to an increased uptake of MCs. In view of the high sensitivity of human hepatocytes and currently MCLR-only based risk calculations, the actual risk of human MC-intoxication and ensuing liver damage could be underestimated in freshwater cyanobacterial blooms where MCLW and LF predominate. PMID- 20171240 TI - The 3 + 3 dose escalation design is not appropriate for antivenom dose finding. PMID- 20171241 TI - Antivenom: the most cost-effective treatment in the world? AB - Antivenom is the only effective treatment for envenoming by snakes, scorpions and other venomous creatures. Unfortunately, supplies of this life-saving drug in many countries are critically low, and the tragic consequence of untreated envenoming exacts a chronic humanitarian and economic burden on those communities affected. This neglected health crisis struggles to compete with higher profile illnesses for recognition, research attention and funding. Sound strategies to improve the provision of antivenoms repeatedly fail because of an inability to attract the requisite financial investment. In the highly competitive international health landscape, the greatest challenge for stakeholders is to demonstrate that antivenom constitutes an affordable, cost-effective and worthwhile investment of healthcare resources. Recent collaborations in the UK, Africa and South America, have proven that lowering the production costs of antivenom to affordable levels is sustainable. A simple healthcare-economic calculation can be used to demonstrate the superior cost-effectiveness of antivenoms in preventing death and disability. These advances may lead to antivenom becoming one of the most cost-effective treatments available to modern medicine, and provides strong justification for its inclusion in international health funding initiatives. PMID- 20171242 TI - Involvement of serotonin receptor subtypes in the antidepressant-like effect of TRIM in the rat forced swimming test. AB - Depression is a common illness with severe morbidity and mortality. Nitric oxide synthase (NOS) inhibitors are shown to elicit antidepressant-like effect in various animals models. It is widely known that serotonin plays an important role in the antidepressant-like effect of drugs. The aim of this study is to investigate the involvement of 5-HT(1) and 5-HT(2) receptor subtypes in the antidepressant-like effect of TRIM, a nNOS inhibitor, in the rat forced swimming test (FST). TRIM displays an antidepressant-like activity in FST which is blocked by pretreatment with the NOS substrate l-arginine. Depletion of endogenous serotonin using para-chlorophenylalanine (pCPA; 3x150mg/kg, i.p.) partially attenuated TRIM (50mg/kg)-induced reductions in immobility time in FST. Pretreatment with methiothepin (0.1mg/kg, i.p, a non-selective 5-HT receptor antagonist), cyproheptadine (3mg/kg i.p, a 5-HT(2) receptor antagonist) or ketanserin (5mg/kg i.p, a 5HT(2A/2C) receptor antagonist) prevented the effect of TRIM (50mg/kg) in the FST. WAY 100635 (0.1mg/kg i.p, a selective 5-HT(1A) receptor antagonist) and GR 127935 (3mg/kg i.p, a selective 5-HT(1B/1D) receptor antagonist) slightly reversed the immobility-reducing effect of TRIM in the FST, but this failed to reach a statistically significant level. The results of this study demonstrate that antidepressant-like effect of TRIM in the FST seems to be mediated, at least in part, by an interaction with 5-HT(2) receptors while non significant effects were obtained with 5-HT(1) receptors. PMID- 20171243 TI - Binding processes: neurodynamics and functional role in memory and action. PMID- 20171244 TI - Early life influences on emotional reactivity: evidence that social enrichment has greater effects than handling on anxiety-like behaviors, neuroendocrine responses to stress and central BDNF levels. AB - During the early post-natal phases the brain is experience-seeking and provided by a considerable plasticity which allows a fine tuning between the external environment and the developing organism. Since the early work of Seymour Levine, an impressive amount of research has clearly shown that stressful experiences exert powerful effects on the brain and body development. These effects can last throughout the entire life span influencing brain function and increasing the risk for depression and anxiety disorders. The mechanisms underlying the effects of early stress on the developing organism have been widely studied in rodents through experimental manipulations of the post-natal environment, such as handling, which have been shown to exert important effects on the emotional phenotype and the response to stress. In the present paper we review the relevant literature and present some original data indicating that, compared to handling, which imposes an external manipulation on the mother-infant relationship, social enrichment, in the form of communal rearing, in mice has very profound effects on animal's emotionality and the response to stress. These effects are also accompanied by important changes in central levels of brain-derived neurotrophic factor. The present data indicate that communal rearing has more pervasive effects than handling, strengthening previous data suggesting that it is a good animal model of reduced susceptibility to depression-like behavior. Overall, the availability of ever more sophisticated animal models represents a fundamental tool to translate basic research data into appropriate interventions for humans raised under traumatic or impoverished situations. PMID- 20171245 TI - The conundrum of sensitization when recording from nociceptors. AB - Nociceptors are sensory neurons that detect harmful, or potentially harmful, stimuli, and can become sensitized following injury or repetitive stimulation. When sensitized, nociceptors often exhibit activity in the absence of apparent or additional stimulation, called ongoing (or spontaneous) activity (OA). In this report, we provide evidence that OA in nociceptors can be caused by the stimuli typically used to identify and characterize the neuron, which must by definition be noxious and therefore potentially sensitizing. Such OA caused by the experimental methodology can confound interpretation. In our nerve inflammation model, OA can potentially arise from multiple sites, including the lesion site and the receptive field. We provide evidence that the OA rate recorded during these experiments may be related to the site and cause of OA generation. We suggest that there are two types of OA, characterized by their rates. Very slow rates of ongoing activity (<0.2 Hz) are likely to arise from the receptive field and may indicate sensitization during the experiment. Faster rates are likely to arise from the nerve trunk, i.e. the neuritis, or the neuronal cell body. Without appropriate methodological consideration, interpretations of results from such studies of nociceptor function may be methodologically confounded. PMID- 20171246 TI - Inhibition of Newcastle disease virus replication by RNA interference targeting the matrix protein gene in chicken embryo fibroblasts. AB - Newcastle disease (ND) is an infectious viral disease of birds caused by the Newcastle disease virus (NDV), also known as avian paramyxovirus type 1 (AMPV-1), which leads to severe economic losses in the poultry industry worldwide. In this study, the application of RNA interference (RNAi) for inhibiting the replication of NDV in cell culture by targeting the viral matrix protein gene (M) is described. Two M-specific shRNA-expressing plasmid constructs, named pS(M641) and pS(M827), were evaluated for antiviral activity against the NDV strain NA-1 by cytopathic effects (CPE), virus titration and real-time RT-PCR. After 36h of infection, both pS(M641) and pS(M827) reduced virus titers by 79.4- and 31.6 fold, respectively, and they down-regulated mRNA expression levels of the matrix protein gene M by 94.6% and 84.8%, respectively, in chicken embryo fibroblast (CEF) cells, while only pS(M641) significantly decreased CPE, compared to the control group. These results indicated that the M gene 641 and 827 sites represent potential antiviral therapy targets, and RNAi targeting of the M gene could not only represent an effective treatment in Newcastle disease but also aid as a method for studying the replication of NDV. PMID- 20171247 TI - The glycoproteins C and G are equivalent target antigens for the determination of herpes simplex virus type 1-specific antibodies. AB - Seroreactivity to the glycoproteins C and G of herpes simplex virus type 1 (HSV 1) was compared in 310 serum samples using a Western blot assay containing a whole antigen extract of HSV-1 and an ELISA employing gC1 isolated from HSV-1. The prevalence of reactivity to gC1 was 75.8% by Western blot and 73.9% by ELISA, while antibody responses to gG1 were detected in 72.9% of sera by Western blot. An absolute correlation of 96.1% between the reactivity to gC1 and gG1 was demonstrated using the Western blot. The gC1-based ELISA correlated with Western blot detection of anti-gC1 and anti-gG1 antibodies in 95.2 and 97.7% of samples, respectively. 3.2% of all sera were reactive with gC1 in Western blot and/or ELISA, but were negative for anti-gG1. For analysis of cross-reactivity, antibodies against HSV-2, Epstein-Barr virus, varicella-zoster virus and cytomegalovirus were determined. The prevalence of antibodies against each individual virus was identical in the groups of sera reactive with gC1 or gG1. These findings indicate that gC1 and gG1 are equivalent antigenic targets for the type-specific serodiagnosis of HSV-1 infections. PMID- 20171248 TI - A five-minute DNA extraction method for expedited detection of Phytophthora ramorum following prescreening using Phytophthora spp. lateral flow devices. AB - In a direct comparison with established methods for Phytophthora ramorum detection (isolation followed by morphological identification, or conventional DNA extraction followed by TaqMan real-time PCR) a rapid, simplified detection method in which membranes of lateral flow devices (LFDs) are added directly to TaqMan real-time PCR reactions was used to test 202 plant samples collected by plant health inspectors in the field. P. ramorum prevalence within the 202 samples was approximately 40% according to routine testing by isolation or TaqMan real-time PCR. The diagnostic sensitivity and specificity of the rapid detection method were 96.3% and 91.2%, respectively. This method can be used in conjunction with Phytophthora spp. lateral flow devices to reduce the number of samples requiring testing using more laborious conventional methods. The effect of combining prescreening for Phytophthora spp. with P. ramorum-specific tests is discussed in terms of the positive and negative predictive values of species specific detection when testing samples collected in different inspection scenarios. PMID- 20171249 TI - A flow cytometric assay to quantify in vivo bacterial uptake by alveolar macrophages. AB - Our laboratory has developed a flow cytometric assay to quantify alveolar macrophage (Mcapital EF, Cyrillic) phagocytosis of bacteria within a live animal. Mcapital EF, Cyrillics collected by bronchoalveolar lavage from rats infected transtracheally with Syto 9-labeled bacteria are fluorescently labeled for identification and analyzed by flow cytometry to quantify their bacterial uptake. PMID- 20171250 TI - Evaluation of diffusion and dilution methods to determine the antibacterial activity of plant extracts. AB - The aim of this study was to evaluate diffusion and dilution methods for determining the antibacterial activity of plant extracts and their mixtures. Several methods for measurement of the minimal inhibitory concentration (MIC) of a plant extract are available, but there is no standard procedure as there is for antibiotics. We tested different plant extracts, their mixtures and phenolic acids on selected gram-positive (Staphylococcus aureus, Bacillus cereus, and Listeria monocytogenes) and gram-negative bacteria (Escherichia coli O157:H7, Salmonella Infantis, Campylobacter jejuni, Campylobacter coli) with the disk diffusion, agar dilution, broth microdilution and macrodilution methods. The disk diffusion method was appropriate only as a preliminary screening test prior to quantitative MIC determination with dilution methods. A comparison of the results for MIC obtained by agar dilution and broth microdilution was possible only for gram-positive bacteria, and indicated the latter as the most accurate way of assessing the antimicrobial effect. The microdilution method with TTC (2,3,5 triphenyl tetrazolium chloride) or INT (2-p-iodophenyl-3-p-nitrophenyl-5-phenyl tetrazolium chloride) to indicate the viability of aerobic bacteria was found to be the best alternative approach, while only ATP determination was appropriate for microaerophilic Campylobacter spp. Using survival curves the kinetics of bacterial inactivation on plant extract exposure was followed for 24h and in this way the MIC values determined by the microdilution method were confirmed as the concentrations of extracts that inhibited bacterial growth. We suggest evaluation of the antibacterial activity of plant extracts using the broth microdilution method as a fast screening method for MIC determination and the macrodilution method at selected MIC values to confirm bacterial inactivation. Campylobacter spp. showed a similar sensitivity to plant extracts as the tested gram-positive bacteria, but S. Infantis and E. coli O157:H7 were more resistant. PMID- 20171251 TI - Quantitative Y2H screening: cloning and signal peptide engineering of a fungal secretory LacA gene and its application to yeast two-hybrid system as a quantitative reporter. AB - A quantitative protein/peptide screening system amenable to high-throughput screening has been developed by furnishing conventional yeast two-hybrid (Y2H) system with an engineered fungal secretory beta-galactosidase gene (designated LacA3). We describe the molecular cloning and signal peptide-optimization of the original fungal LacA gene of which extracellular expression was initially toxic to the host cell. The engineered LacA, LacA3, showed less toxicity, resulting in improved cultural properties of the host. The release of the enzyme to the medium was constant to the cell density under a certain induction condition and independent of the growth phase. The released enzyme kept the wild type properties, was highly glycosylated, stable in a wide pH range and high temperature, and had an acidic pH optimum. In the Y2H system with the novel reporter in combination with the conventional Y2H reporters, the yeast colonies are visibly stained in blue, white or red in the growth context, according to the interaction intensity. The clones with the more stable interactions are easily found as colonies with the larger blue halos, due to the increased extracellular LacA3 expression. A quantitative, high-throughput Y2H screening of cDNA library based on the novel reporter was demonstrated. An application of the novel Y2H system to directed evolution of a peptide fragment was also exemplified. PMID- 20171252 TI - Playing with food. A novel approach to understanding nutritional behaviour development. AB - This study explored the use of a novel method of collecting data on nutritional behaviour development in young children: videos posted on the Internet site YouTube. YouTube videos (n=115) of children alone and interacting with parents in toy kitchen settings were analyzed using constant comparison analysis. Results revealed that in the videos of play nutritional behaviours, children showed influences of their real social environments, and that this medium enabled the observation of parent-child interactions in a more natural context without the researcher's presence. These findings encourage further research in the development and validity of alternative methods of data collection. PMID- 20171253 TI - Resistant schizophrenia in a patient with epilepsy. PMID- 20171254 TI - Effect of Sargassum thunbergii on ROS mediated oxidative damage and identification of polyunsaturated fatty acid components. AB - In this study, we examined protective effect of Sargassum thunbergii on reactive oxygen species (ROS) mediated oxidative stress in cellular systems. In addition, polyunsaturated fatty acids from S. thunbergii were identified and quantified by gas chromatography mass spectroscopy. Intracellular ROS levels were measured using a oxidation sensitive dye, 2',7'-dichlorofluorescein diacetate (DCFH-DA). Treatment with S. thunbergii significantly reduced intracellular ROS mediated cell damage and inhibited myeloperoxidase (MPO) activity assessed in tumor necrosis factor-alpha (TNF-alpha) stimulated human monocytic leukemia in a concentration-dependent manner. Moreover, antioxidative mechanisms by S. thunbergii were evaluated by measuring the expression levels of antioxidative enzymes such as superoxide dismutase (SOD-1), catalase, glutathione peroxidase and glutathione reductase. SOD-1 and glutathione reductase were up-regulated by S. thunbergii. Furthermore, S. thunbergii contains polyunsaturated fatty acids such as arachidonic acid, arachidic acid, palmitic acid, elaidic acid, linoleic acid, stearic acid and cis-5,8,11,14,17-eicosanoic acid. Therefore, these results suggested that S. thunbergii has nutraceutical effectiveness in prevention of ROS induced tissue damage and potential natural antioxidant related to oxidative stress, which can be traceable to polyunsaturated fatty acids contained in S. thunbergii. PMID- 20171255 TI - 90-day oral toxicity study of UP446, a combination of defined extracts of Scutellaria baicalensis and Acacia catechu, in rats. AB - A standardized plant composition--UP446, with primarily baicalin from the roots of Scutellaria baicalensis and (+)-catechin from the heartwoods of Acacia catechu -has been used in both joint supplements and a prescription medical food. The in vitro and in vivo safety evaluations of UP446 have been reported previously. A supplemental 90-day oral toxicity study was conducted in Hsd:SD(R) rats to determine the potential of UP446 to produce toxicity. Four groups (10 males and 10 females per group) of dose levels of 250, 500, and 1000 mg/kg/day of the test article, as well as a control (0.5% carboxymethylcellulose) were tested. There were no test article related mortalities or ophthalmological, neurological (Functional Observational Battery and motor activity), body weight, feed consumption, clinical observation, organ weight changes, gross finding, clinical or histopathological alterations. Normal sperm count and comparable estrus staging were observed. A dose of 1000 mg/kg/day was identified as the NOAEL (no observed-adverse-effect-level) in this study. PMID- 20171256 TI - Bone marrow lymphoid and myeloid progenitor cells are suppressed in 7,12 dimethylbenz(a)anthracene (DMBA) treated mice. AB - In this study we used colony forming unit (CFU) assays to demonstrate rapid suppression (within 6h) of lymphoid (CFU-preB) and myeloid (CFU-GM) progenitor cells in DMBA-treated mice. The duration of these changes were consistent with the blood levels of DMBA and its metabolites that were achieved by either IP or oral DMBA administration. CFU-GM and CFU-preB activities returned to control levels by 2 and 7 days after oral DMBA exposure, respectively, but remained suppressed through 7 days after IP DMBA administration. The continued presence of low levels of DMBA in the bloodstream following IP administration was associated with sustained suppression of CFU-preB, total bone marrow lymphoid cells and peripheral blood lymphocytes. The changes noted above were not observed in Cyp1b1 null mice, demonstrating the need for local DMBA metabolism in the bone marrow by Cyp1b1 to impair bone marrow CFU-preB and CFU-GM. Furthermore, these data provide evidence that myeloid-lineage cells are restored more quickly than lymphoid lineage cells after DMBA exposure. PMID- 20171257 TI - Solubility study of phytochemical cross-linking agents on dentin stiffness. AB - OBJECTIVES: The effects of interactions between cross-linking proanthocyanidins (PA) in polar solvents and type-I collagen of demineralized dentin were investigated. METHODS: Three PA-rich extracts, two from grape seed (GSEP and GSES) and one from cocoa (COE), were dissolved (water, ethanol:water and acetone:water) and analyzed for their ability to increase the modulus of elasticity of demineralized dentin. Sound dentin beams (0.5mmx1.7mmx7mm) were fully demineralized and divided into 12 groups according to the type of cross linking agent and solvents used. Specimens were immersed in the respective solutions and tested at baseline, 10, 30, 60, 120 and 240min. RESULTS: The elastic modulus (EM) of dentin was significantly increased by the PA treatment regardless of time (p<0.05 for all times). The extracts showed different solubility in different solvents. GSEP showed the highest increase in EM when diluted in distilled water and acetone at all exposure times. Both GSEs showed superior results when diluted in distilled water and after 4h of treatment, while COE produced strongest enhancement when dissolved in ethanol:water. CONCLUSIONS: The results indicates that herbal extraction process and other pharmacognostic parameters have an important influence on extract solubility as well as constitution and, consequently, on the PA-dentin matrix interaction. PMID- 20171258 TI - Comparative reactivity of mismatched and unpaired bases in relation to their type and surroundings. Chemical cleavage of DNA mismatches in mutation detection analysis. AB - Systematic study of chemical reactivity of non-Watson-Crick base pairs depending on their type and microenvironment was performed on a model system that represents two sets of synthetic DNA duplexes with all types of mismatched and unmatched bases flanked by T.A or G.C pairs. Using comparative cleavage pattern analysis, we identified the main and additional target bases and performed quantitative study of the time course and efficacy of DNA modification caused by potassium permanganate or hydroxylamine. Potassium permanganate in combination with tetraethylammonium chloride was shown to induce DNA cleavage at all mismatched or bulged T residues, as well as at thymines of neighboring canonical pairs. Other mispaired (bulged) bases and thymine residues located on the second position from the mismatch site were not the targets for KMnO(4) attack. In contrast, hydroxylamine cleaved only heteroduplexes containing mismatched or unmatched C residues, and did not modify adjacent cytosines. However when G.C pairs flank bulged C residue, neighboring cytosines are also attacked by hydroxylamine due to defect migration. Chemical reactivity of target bases was shown to correlate strongly with the local disturbance of DNA double helix at mismatch or bulge site. With our model system, we were able to prove the absence of false-negative and false-positive results. Portion of heteroduplex reliably revealed in a mixture with corresponding homoduplex consists of 5% for bulge bases and "open" non-canonical pairs, and 10% for wobble base pairs giving minimal violations in DNA structure. This study provides a complete understanding of the principles of mutation detection methodology based on chemical cleavage of mismatches and clarifies the advantages and limitations of this approach in various biological and conformational studies of DNA. PMID- 20171259 TI - Carbohydrate binding specificities and crystal structure of the cholera toxin like B-subunit from Citrobacter freundii. AB - Enterotoxigenic Escherichia coli and Vibrio cholerae are well known causative agents of severe diarrheal diseases. Both pathogens produce AB(5) toxins, with one enzymatically active A-subunit and a pentamer of receptor-binding B-subunits. The primary receptor for both B-subunits is the GM1 ganglioside (Galbeta3GalNAcbeta4(NeuAcalpha3)Galbeta4GlcbetaCer), but the B-subunits from porcine isolates of E. coli also bind neolacto-(Galbeta4GlcNAcbeta-)terminated glycoconjugates and the B-subunits from human isolates of E. coli (hLTB) have affinity for blood group A type 2-(GalNAcalpha3(Fucalpha2)Galbeta4GlcNAcbeta )terminated glycoconjugates. A B-subunit with 73% sequence identity to the B subunits of cholera toxin and the heat-labile toxin of E. coli is produced by certain strains of enteropathogenic E. coli and by Citrobacter freundii. This C. freundii B-subunit (CFXB) has now been expressed in V. cholerae, and isolated in high yields. Glycosphingolipid binding studies show that CFXB binds to the GM1 ganglioside with high affinity. In addition, CFXB has high affinity for both neolacto-terminated and blood group A type 2-terminated glycoconjugates. The crystal structure of the pentameric arrangement of C. freundii B-subunits display high structural similarity with related proteins from E. coli and V. cholerae and oligosaccharide binding sites can be identified on the protein surface. Small changes in the 88-95 loop connecting the GM1 and blood group A binding sites explains the minor changes in affinity seen for these two ligands. However, the enhanced affinity of CFXB for neolacto-terminated structures can be sought in the Lys34Tyr substitution affording additional hydrogen bond interactions between the tyrosyl side chain and the GlcNAcbeta3Galb4Glcbeta1 segment of neolactotetraosylceramide via bridging water molecules. PMID- 20171260 TI - Melanin-concentrating hormone facilitates migration of preadipocytes. AB - Adipose tissue develops from differentiating preadipocytes that expand and migrate. 3T3-L1 preadipocytes respond to melanin-concentrating hormone (MCH) by increasing leptin production. Here, we investigate whether MCH elicits remodeling of the actin cytoskeleton and whether this translates into altered migratory capacity of these cells. Incubation with MCH resulted in a loss of actin stress fibers accompanied by a change in morphology from a stretched-out fibroblast to a rounded cell. PMC-3881-PI, a MCH receptor 1 antagonist blocked the effect, confirming this receptor is solely responsible for MCH-mediated actin rearrangements. Both a pharmacological activator and inhibitor of phospholipase C were used to demonstrate this molecule's importance to the signaling pathway. Finally, MCH was shown to facilitate preadipocyte migration into a scratch wound, revealing a previously unknown role for MCH in the regulation of cellular migration. We conclude that MCH could influence the expansion of adipose tissue through its ability to enhance preadipocyte migration. PMID- 20171261 TI - Potential detrimental effects of a phytoestrogen-rich diet on male fertility in mice. AB - Soy and soy-based products are widely consumed by infants and adult individuals. There has been speculation that the presence of isoflavone phytoestrogens in soybean cause adverse effects on the development and function of the male reproductive system. The purpose of this study was to examine the influence of dietary soy and phytoestrogens on testicular and reproductive functions. Male mice were fed from conception to adulthood with either a high soy-containing diet or a soy-free diet. Although adult mice fed a soy-rich diet exhibited normal male behaviour and were fertile, we observed a reduced proportion of haploid germ cells in testes correlating with a 25% decrease in epididymal sperm counts and a 21% reduction in litter size. LH and androgens levels were not affected but transcripts coding for androgen-response genes in Sertoli cells and Gapd-s, a germ cell-specific gene involved in sperm glycolysis and mobility were significantly reduced. In addition, we found that dietary soy decreased the size of the seminal vesicle but without affecting its proteolytic activity. Taken together, these studies show that long-term exposure to dietary soy and phytoestrogens may affect male reproductive function resulting in a small decrease in sperm count and fertility. PMID- 20171262 TI - PLC/CAMK IV-NF-kappaB involved in the receptor for advanced glycation end products mediated signaling pathway in human endothelial cells. AB - Advanced glycation end products (AGEs) and their interaction with the receptor for advanced glycation end products (RAGE) play an important role in diabetic vascular complications. The current study demonstrated that AGEs significantly increased RAGE expression and the release of tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6) in human umbilical vein endothelial cell-derived line ECV304 cells. RAGE antisense RNA partially inhibited the expression of TNF alpha and IL-6 induced by AGEs. Oligonucleotide microarray was used to identify the genes that respond to RAGE activation. Phospholipase C beta 1 (PLC beta 1), phospholipase C beta 4 (PLC beta 4) and calcium/calmodulin-dependent protein kinase IV (CAMK IV) which associated with Ca(2+) signaling were upregulated. The rise of intracellular calcium and the NF-kappaB promoter activity induced by AGEs were suppressed by RAGE antisense RNA, PLC inhibitor U73122 and dominant negative CAMK IV, respectively. These findings suggest that PLC/CAMK IV-NF-kappaB is involved in RAGE mediated signaling pathway in human endothelial cells. PMID- 20171263 TI - cGMP-dependent protein kinase type I promotes CREB/CRE-mediated gene expression in neurons of the lateral amygdala. AB - The process transforming newly learned information into stable long-term memory is called memory consolidation and, like the underlying long-term synaptic plasticity, critically depends on de novo RNA and protein synthesis. We have shown recently that the cGMP-dependent protein kinase Type I (cGKI) plays an important role for the consolidation of amygdala-dependent fear memory and long term potentiation (LTP) in the lateral amygdala. Signalling downstream of cGKI at the level of transcriptional regulation remained unclear. A transcription factor of major importance for learning and memory is the cAMP-response element binding protein (CREB). The representation of fear memory in the lateral amygdala strikingly depends on the activity of CREB in individual neurons. Moreover, findings from in vitro experiments demonstrate CREB phosphorylation by cGK. In the hippocampus, CREB phosphorylation increases following activation of NO/cGMP signalling contributing to the late phase of LTP. To demonstrate a link from cGKI to activation of CREB and CREB-dependent transcription in neurons of the lateral amygdala as a possible mechanism for cGKI-mediated fear memory consolidation, we examined the effect of cGMP on activation of CREB/CRE using immunohistochemical staining specific for phospho-CREB and a reporter gene in control and cGKI deficient mice, respectively. Supporting our hypothesis, marked CREB phosphorylation and CRE-mediated transcription was induced by cGMP in the lateral amygdala of control mice, but not in cGKI-deficient mice. It has been proposed that activation of cGKI is followed by its nuclear translocation that would allow direct phosphorylation of CREB. Therefore, we examined the cellular localisation of cGKI in neurons of the lateral amygdala in the presence of cGMP by double staining for cGKI and a nuclear marker in sections from areas showing prominent CREB phosphorylation, and did not observe prominent nuclear translocation of the enzyme. In summary, we provide evidence that cytosolic cGKI can support fear memory consolidation and LTP in neurons of the lateral amygdala via activation of CREB and CRE-dependent transcription. PMID- 20171264 TI - Expiration: the moment we experience retronasal olfaction in flavor. AB - Respiration is essential for smell perception. Previously we found that 8-12-Hz cortical rhythms were phase-locked to inspiration onset during the presentation of odor stimuli; this is referred to as inspiration phase-locked alpha band oscillation (I-alpha). Generators of I-alpha estimated with a dipole fitting model were found in the piriform, the entorhinal cortex (ENT), the amygdala (AMG), the hippocampus (HI) and the orbitofrontal cortex (OFC). Such olfactory perception is said to occur via the orthonasal olfaction route. Another route is the retronasal olfaction route. In this study, we investigated the link between respiration phase and retronasal olfactory perception. Electroencephalograph (EEG) and respiratory flows (separately measured with mouth and nose) were simultaneously recorded during stimulation of subjects' tongues with liquids of chocolate, sucrose and water. The percentage of subjects correctly identifying the chocolate taste was higher when subjects were asked to breathe through the nose than when they were breathing through the mouth. In the averaged EEGs triggered by the onset of expiration measured from the flow through the nose, a 8 12-Hz oscillation was observed. Generators of this potential were found in the left ENT, HI, AMG and OFC in the order of milliseconds after expiration onset. Perception of retronasal olfaction is dependent on expiration, and combining retronasal olfactory information with gustatory information and somatosensation enable us to identify flavors when drinking and feeding. PMID- 20171265 TI - Opposite effects of nitric oxide on rod and cone photoreceptors of rat retina in situ. AB - In the light-adapted vertebrate retina, nitric oxide (NO) modulates synaptic transmission between photoreceptors and second-order neurons. Although NO is believed to be a mediator of adaptation, its effect on photoreceptors in situ is not known yet. Therefore, we studied rod and cone activities in rat eyes in situ, using the electroretinogram (ERG). Rod and cone ERGs were functionally isolated by intravitreal 20mM glutamate, which suppressed the activity of all retinal cells except rods and cones for about 90min. The addition of NO-donor, SNAP, to the glutamate solution decreased the amplitude of the rod single-flash ERG by approximately 40%, compared to the amplitude of the rod ERG isolated by glutamate alone, but it increased the amplitude of the isolated, intense paired-flash cone ERG by approximately 40%. An excess of the NO-scavenger, CPTIO, had no significant effect on either rod or cone ERGs. A broad-spectrum NO-synthase inhibitor, L-NAME, increased the amplitude of the rod ERG by approximately 50%, but had no significant effect on the cone ERG. We suggest that NO directly modulates the light-evoked activity of rod and cone photoreceptors in situ, but in opposite ways. PMID- 20171266 TI - CRTAC1 homolog proteins are conserved from cyanobacteria to man and secreted by the teleost fish pituitary gland. AB - Cartilage acidic protein 1 (CRTAC1) gene expression is used as a marker for chondrocyte differentiation in stem cell-based tissue engineering. It is also transcribed outside the skeleton where at least two different transcripts are expressed in lung and brain. In the pituitary gland of the teleost fish sea bream Sparus auratus, we have found a transcript with a high degree of sequence identity to CRTAC1 family members but lacking the EGF-like calcium-binding domain encoding sequence of CRTAC1 and designated it as CRTAC2. Database searches revealed many previously unidentified members of the CRTAC1 and CRTAC2 in phylogenetically distant organisms, such as cyanobacteria, bryophyta, lancelets, and diverse representatives of vertebrates. Phylogenetic analyses showed that the genes encoding CRTAC1 and CRTAC2 proteins coexist in teleost fish genomes. Structural prediction analysis identified the N-terminal region of the CRTAC1/CRTAC2 family members as a potential seven-bladed beta-propeller structure, closely related to those of integrin alpha chains and glycosylphosphatidylinositol-specific phospholipase D1 protein families. This relationship is confirmed by phylogenetic analysis with the N-terminal domain of sea bream CRTAC2 as the most divergent sequence. Because teleost fishes are the only phylogenetic group where both CRTAC1 and CRTAC2 genes are present, they occupy a pivotal position in studies of the mechanisms governing the specific expression patterns of each gene/protein subfamily. This will be essential to elucidate their respective biological roles. PMID- 20171268 TI - The effect of hypoxia on the functional and structural development of the chick brain. AB - Decreased oxygen availability during gestation is linked with altered structural development of the brain and cognitive deficits after birth. Prehatch hypoxia can induce gross neuropathology such as brain lesions or more subtle injury including selective neuronal cell loss, white matter injury and gliosis. In the current study we used the developing chick embryo to determine whether 24h of hypoxia at different prehatch ages, embryonic day 10, 12 or 14 (E10, E12 or E14), resulted in an alteration in neuronal cell number or astrocyte density in brain areas associated with learning and memory. Twenty-four hours of hypoxia (14% oxygen) commencing at E10 resulted in an increase in the density of GFAP-positive astrocytes in the medial striatum (MSt) (P<0.05) and a significant reduction in the number of NeuN-positive neuronal nuclei in the intermediate medial mesopallium (IMM) (P<0.02). Hypoxia at E14 resulted in an increase in GFAP immunoreactivity in the hippocampus (P < or = 0.02) and a significant decrease in the number of NeuN-positive cells in the IMM (P<0.04). Memory was tested soon after hatch using a bead discrimination learning task and results showed that E10 hypoxia significantly reduced short-term memory, which subsequently affected all stages of memory formation (P<0.001), whereas 24h of hypoxia at E14 did not alter short-term memory, but impaired consolidation into long-term memory (P<0.02). Interestingly, 24h of hypoxia at E12 did not alter GFAP immunoreactivity or NeuN positive cells, nor did it result in memory deficits. We find that an alteration in the number or a disruption in the normal development of astrocytes and neurons significantly affects memory formation and consolidation in the young chick. PMID- 20171267 TI - Regulation of plasminogen activator inhibitor-1 expression in endothelial cells with exposure to metal nanoparticles. AB - Recent studies demonstrated that exposure to nanoparticles could enhance the adhesion of endothelial cells and modify the membrane structure of vascular endothelium. The endothelium plays an important role in the regulation of fibrinolysis, and imbalance of the fibrinolysis system potential contributes to the development of thrombosis. Plasminogen activator inhibitor-1 (PAI-1) is the most potent endogenous inhibitor of fibrinolysis and is involved in the pathogenesis of several cardiovascular diseases. The aim of this study was to investigate the alteration of PAI-1 expression in mouse pulmonary microvascular endothelial cells (MPMVEC) exposed to the metal nanoparticles that are known to be reactive, and the potential underlying mechanisms. We compared the alteration of PAI-1 expression in MPMVEC exposed to non-toxic doses of nano-size copper (II) oxide (Nano-CuO) and nano-size titanium dioxide (Nano-TiO(2)). Our results showed that Nano-CuO caused a dose- and time-dependent increase in PAI-1 expression. Moreover, exposure of MPMVEC to Nano-CuO caused reactive oxygen species (ROS) generation that was abolished by pre-treatment of cells with ROS scavengers or inhibitors, DPI, NAC and catalase. Exposure of MPMVEC to Nano-CuO also caused a dose- and time-dependent increase in p38 phosphorylation by Western blot. These effects were significantly attenuated when MPMVEC were pre-treated with DPI, NAC and catalase. To further investigate the role of p38 phosphorylation in Nano-CuO induced PAI-1 overexpression, the p38 inhibitor, SB203580, was used to pre-treat cells prior to Nano-CuO exposure. We found that Nano-CuO-induced overexpression of PAI-1 was attenuated by p38 inhibitor pre-treatment. However, Nano-TiO(2) did not show the same results. Our results suggest that Nano-CuO caused up-regulation of PAI-1 in endothelial cells is mediated by p38 phosphorylation due to oxidative stress. These findings have important implications for understanding the potential health effects of metal nanoparticle exposure. PMID- 20171269 TI - Long-term cultivation of HepG2 liver cells encapsulated in alginate hydrogels: a study of cell viability, morphology and drug metabolism. AB - In this study, we have evaluated the use of ultra-sterile alginate hydrogels encapsulated with HepG2 liver cells for applications in high throughput drug screening. We have studied the cellular viability and metabolic capacity of the encapsulated cells in two different alginate structures SLM100 (G:M::40:60) and SLG100 (G:M::60:40). We have also developed protocols to characterize the encapsulated cells within the alginate structure using scanning electron microscopy (SEM) and laser scanning confocal microscopy (LSCM). Further we have studied the Phase-I/II metabolic characteristics of the encapsulated cells in monolayer and 3D culture. Our results indicate that cells encapsulated within SLM100 and SLG100 class of alginates have shown high cellular viability with >80% even after 14 days in culture. As expected, the proliferation rates of the encapsulated cells are held steady and do not proliferate within the gels. Production of liver-specific enzymes such as CYP1A1 and CYP3A4 after 14 days in culture indicates the viability and functionality of the encapsulated HepG2 cells. Phase-II Glutathione activity of the encapsulated cells were also maintained in 3D culture conditions. The encapsulated cells within the 3D gels were also capable of metabolizing the pro-drug EFC (7-ethoxy-4-trifluoromethyl coumarin) to HFC (7-hydroxy-4-trifluoromethyl) in a linear fashion over a period of time. These results have provided us with baseline results to benchmark future improvements in material and design configurations for optimal pharmacokinetic response of in vitro tissue model systems. PMID- 20171270 TI - The consequence of natural selection on genetic variation in the mouse. AB - Laboratory mouse strains are known to have emerged from recent interbreeding between individuals of Mus musculus isolated populations. As a result of this breeding history, the collection of polymorphisms observed between laboratory mouse strains is likely to harbor the effects of natural selection between reproductively isolated populations. Until now no study has systematically investigated the consequences of this breeding history on gene evolution. Here we have used a novel, unbiased evolutionary approach to predict the founder origin of laboratory mouse strains and to assess the balance between ancient and newly emerged mutations in the founder subspecies. Our results confirm a contribution from at least four distinct subspecies. Additionally, our method allowed us to identify regions of relaxed selective constraint among laboratory mouse strains. This unique structure of variation is likely to have significant consequences on the use of mouse to find genes underlying phenotypic variation. PMID- 20171271 TI - The construction of a tetraploid cotton genome wide comprehensive reference map. AB - Integration of multiple genomic maps provides a higher density of markers and greater genome coverage, which not only facilitates the identification and positioning of QTLs and candidate genes, but it also provides a basic structure for the genome sequence assembly. However, the diversity in markers and populations used in individual mapping studies limits the ability to fully integrate the available data. By concentrating on marker orders rather than marker distances, published map data could be used to produce a comprehensive reference map (CRM) that includes a majority of known markers with optimally estimated order of those markers across the genome. In this study, a tetraploid cotton genome-wide CRM was constructed from 28 public cotton genetic maps. The initial CRM contained 7,424 markers and represented over 93% of the combined mapping information from the 28 individual maps. The current output is stored and displayed through CottonDB (http://www.cottondb.org), the public cotton genome database. PMID- 20171272 TI - Interpretation of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine is adversely affected by methodological inaccuracies when using a commercial ELISA. AB - The DNA lesion 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a urinary marker of oxidative stress, is produced from reactions of reactive oxygen species with host DNA 2'-deoxyribonucleotides. The current gold-standard assessment is by complex chromatographic methods using HPLC or LC-MS/MS. Several studies have reported that commercial 8-oxodG ELISA kits correlate sufficiently with chromatographic techniques to be an easier alternative for laboratories without access to gold standard techniques. However, the assumption that significant correlation translates into a similar ability to differentiate disease categories or treatment groups is yet to be tested. Using LC-MS/MS and two variants of a commercial ELISA, we measured urinary 8-oxodG and creatinine concentrations in young children with cystic fibrosis, a disease associated with oxidative stress, and age-matched controls. We show that, despite significant correlation, both ELISAs overestimate the levels of 8-oxodG, and neither ELISA accurately depicted the difference in group means that was observed by gold-standard LC-MS/MS. The implications of these findings for study outcomes add further support for chromatographic techniques, despite their cost and complexity, to remain the gold standard in urinary 8-oxodG assessment. PMID- 20171273 TI - Nox1 is involved in p53 deacetylation and suppression of its transcriptional activity and apoptosis. AB - HIPK2 is a stress-induced kinase and a transcriptional corepressor that functionally cooperates with p53 to suppress cancer. Activation of the p53 proapoptotic function requires a cascade of phosphorylations and acetylations, and HIPK2 takes part in both modifications in that it phosphorylates p53 Ser46 and induces p53 Lys382 acetylation. Here, to further investigate the role of HIPK2 in p53 activation, we started with the finding that HIPK2 inhibition upregulated Nox1, a homolog of the catalytic subunit of the superoxide-generating NADPH oxidase, involved in tumor progression and ROS production. We found that Nox1 inhibited p53 Lys382 acetylation, which is a target of SIRT1 deacetylase, and impaired p53 proapoptotic transcriptional activity. By the use of either small interfering RNAs to target SIRT1 or the SIRT1 inhibitor nicotinamide we found that Nox1-dependent inhibition of p53 transcriptional activity was SIRT1 dependent. Thus, Nox1 was unable to inhibit p53 when coexpressed with a SIRT1 deacetylase-defective mutant (SIRT1HY), suggesting a link between Nox1 and SIRT1 activity. Finally, recovery of HIPK2 function downregulated Nox1 expression with rescue of p53 Lys382 acetylation and p53 activity. Together, our findings indicate that Nox1 upregulation may activate SIRT1 and inhibit p53 and that Lys382 is important for p53 proapoptotic function. PMID- 20171274 TI - Modulation of thiol homeostasis induced by H2S-releasing aspirin. AB - The H(2)S-releasing aspirin (ACS14) containing a dithiolethione moiety has been demonstrated to maintain the thromboxane-suppressing activity of the parent compound, but it seems to spare the gastric mucosa by affecting redox imbalance through increased H(2)S/glutathione (GSH) formation. Nevertheless, the mechanisms by which ACS14 is able to elevate the levels of these agents has not been fully elucidated so far. In this manuscript the effect of an acute ip administration of ACS14 and of its dithiolethione moiety (5-(4-hydroxyphenyl)-3H-1,2-dithiole-3 thione, ADTOH) on the overall thiol content of rat tissues and on the main enzymes involved in the maintenance of thiol homeostasis is reported. ACS14 and ADTOH treatments were shown to induce a significant increase not only of GSH but also of cysteine in plasma and in several rat tissues as well as of H(2)S plasma levels. Conversely, a significant decrease of homocysteine in most rat organs and in plasma was observed. Most of these phenomena are supposed to be linked to the elevated intracellular levels of cysteine induced by treatments with either ACS14 or ADTOH. PMID- 20171275 TI - Increased levels of 4-hydroxynonenal and acrolein in the brain in preclinical Alzheimer disease. AB - Previous studies demonstrate increased levels of 4-hydroxynonenal (HNE) and acrolein in vulnerable brain regions of subjects with mild cognitive impairment and late-stage Alzheimer disease (LAD). Recently preclinical AD (PCAD) subjects, who demonstrate normal antemortem neuropsychological test scores but abundant AD pathology at autopsy, have become the focus of increased study. Levels of extractable HNE and acrolein were quantified by gas chromatography-mass spectrometry with negative chemical ionization, and protein-bound HNE and acrolein were quantified by dot-blot immunohistochemistry in the hippocampus/parahippocampal gyrus (HPG), superior and middle temporal gyri (SMTG), and cerebellum (CER) of 10 PCAD and 10 age-matched normal control (NC) subjects. Results of the analyses show a significant (P<0.05) increase in levels of extractable acrolein in the HPG of PCAD subjects compared to age-matched NC subjects and a significant decrease in extractable acrolein in PCAD CER. Significant increases in protein-bound HNE in HPG and a significant decrease in CER of PCAD subjects compared to NC subjects were observed. No significant alterations were observed in either extractable or protein-bound HNE or acrolein in the SMTG of PCAD subjects. Additionally, no significant differences in levels of protein carbonyls were observed in the HPG, SMTG, or CER of PCAD subjects compared to NC subjects. PMID- 20171276 TI - Behavioral toxicology in the 21st century: challenges and opportunities for behavioral scientists. Summary of a symposium presented at the annual meeting of the neurobehavioral teratology society, June, 2009. AB - The National Research Council (NRC) of the National Academies of Science recently published a report of its vision of toxicity testing in the 21st century. The report proposes that the current toxicity testing paradigm that depends upon whole-animal tests be replaced with a strategy based upon in vitro tests, in silico models and evaluations of toxicity at the human population level. These goals are intended to set in motion changes that will transform risk assessment into a process in which adverse effects on public health are predicted by quantitative structure-activity relationship (QSAR) models and data from suites of high-throughput in vitro tests. The potential roles for whole-animal testing in this futuristic vision are both various and undefined. A symposium was convened at the annual meeting of the Neurobehavioral Teratology Society in Rio Grande, Puerto Rico in June, 2009 to discuss the potential challenges and opportunities for behavioral scientists in developing and/or altering this strategy toward the ultimate goal of protecting public health from hazardous chemicals. R. Kavlock described the NRC vision, introduced the concept of the 'toxicity pathway' (a central guiding principle of the NRC vision), and described the current status of an initial implementation this approach with the EPA's ToxCast(R) program. K. Crofton described a pathway based upon disruption of thyroid hormone metabolism during development, including agents, targets, and outcomes linked by this mode of action. P. Bushnell proposed a pathway linking the neural targets and cellular to behavioral effects of acute exposure to organic solvents, whose predictive power is limited by our incomplete understanding of the complex CNS circuitry that mediates the behavioral responses to solvents. B. Weiss cautioned the audience regarding a pathway approach to toxicity testing, using the example of the developmental toxicity of phthalates, whose effects on mammalian sexual differentiation would be difficult to identify based on screening tests in vitro. Finally, D. Rice raised concerns regarding the use of data derived from toxicity screening tests to human health risk assessments. Discussion centered around opportunities and challenges for behavioral toxicologists regarding this impending paradigm shift. Opportunities include: identifying and characterizing toxicity pathways; informing the conditions and limits of extrapolation; addressing issues of susceptibility and variability; providing reality-checks on selected positives and negatives from screens; and performing targeted testing and dose-response assessments of chemicals flagged during screening. Challenges include: predicting behavior using models of complex neurobiological pathways; standardizing study designs and dependent variables to facilitate creation of databases; and managing the cost and efficiency of behavioral assessments. Thus, while progress is being made in approaching the vision of 21st century toxicology, we remain a long way from replacing whole-animal tests; indeed, some animal testing will be essential for the foreseeable future at least. Initial advances will likely provide better prioritization tools so that animal resources are used more efficiently and effectively. PMID- 20171277 TI - Thiolated quaternary ammonium-chitosan conjugates for enhanced precorneal retention, transcorneal permeation and intraocular absorption of dexamethasone. AB - Previously, a quaternary ammonium (N(+))-chitosan (Ch) conjugate (N(+)(60)-Ch) characterized by short pendant chains, made of 1.7+/-0.1 adjacent diethyl dimethylene-ammonium groups, substituted onto the primary amino group of the chitosan repeating units (degree of substitution, 59.2+/-4.5%) was used to synthesize a multifunctional non-cytotoxic thiomer (N(+)(60)-Ch-SH(5)), carrying 4.5+/-0.7% thiol-bearing 3-mercaptopropionamide besides quaternary ammonium groups. The present work was aimed at evaluating the potential of N(+)(60)-Ch SH(5) and N(+)(60)-Ch as bioactive excipients for dexamethasone (DMS) eyedrops. The DMS permeability across excised rabbit cornea was enhanced over the control value by the thiomer and the parent polymer to about the same extent (3.8 vs. 4.1 times). The mean precorneal retention time and AUC in the aqueous of DMS instilled in rabbit eyes via eyedrops were enhanced by the thiomer (MRT=77.96+/ 3.57 min, AUC=33.19+/-6.96 microg ml(-1) min) more than the parent polymer (MRT=65.74+/-4.91 min, AUC=21.48+/-3.81 microg ml(-1) min) over the control (MRT=5.07+/-0.25 min, AUC=6.25+/-0.65 microg ml(-1) min). The quaternary ammonium ions were responsible for both permeabilization of corneal epithelium and polymer adhesion to precorneal mucus, while the thiols increased the latter. This synergistic action is the basis of the higher thiomer bioactivity in vivo. A good ocular tolerability of the chitosan derivatives resulted from in vivo experiments. PMID- 20171278 TI - Genome-wide analysis of the VDR/RXR cistrome in osteoblast cells provides new mechanistic insight into the actions of the vitamin D hormone. AB - The vitamin D receptor (VDR) mediates the actions of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in target cells and tissues by orchestrating the expression of gene networks responsible for vitamin D-induced phenotypes. The molecular mechanisms of these regulatory systems have been studied for decades under the principle that transcriptional regulation occurs near the transcriptional start site of the gene. However, this now appears to be an outdated view of transcriptional control. In this study, we examined the genome-wide chromatin immunoprecipitation on microarray (ChIP-chip) across pre-osteoblastic cells for VDR, retinoid X receptor (RXR), RNA polymerase II, and histone H4 acetylation (H4ac). We uncovered potential regulatory mechanisms for genes important to osteoblast biology as well as skeletal formation under the control of 1,25(OH)2D3. We found that VDR, along with RXR and H4ac, binds to distal regions 43% of the time; and within gene introns and exons 44%, leaving only 13% of activation at traditional promoter regions. Here, we briefly summarize our findings for all the VDR/RXR cis acting transcriptional elements (VDR/RXR cistrome) in pre-osteoblastic cells, MC3T3-E1, provide a few examples of this dynamic control by VDR and 1,25(OH)2D3, and demonstrate that distal transcriptional control contributes to the majority of vitamin D3-mediated transcription. PMID- 20171279 TI - Recruitment and subnuclear distribution of the regulatory machinery during 1alpha,25-dihydroxy vitamin D3-mediated transcriptional upregulation in osteoblasts. AB - The architectural organization of the genome and regulatory proteins within the nucleus supports gene expression in a physiologically regulated manner. In osteoblastic cells ligand activation induces a nuclear punctate distribution of the 1alpha,25-dihydroxy vitamin D3 (1alpha,25(OH)2D3) receptor (VDR) and promotes its interaction with transcriptional coactivators such as SRC-1, NCoA-62/Skip, and DRIP205. Here, we discuss evidence demonstrating that in osteoblastic cells VDR binds to the nuclear matrix fraction in a 1alpha,25(OH)2D3-dependent manner. This interaction occurs rapidly after exposure to 1alpha,25(OH)2D3 and does not require a functional VDR DNA binding domain. The nuclear matrix-bound VDR molecules colocalize with the also nuclear matrix-associated coactivator DRIP205. We propose a model where the rapid association of VDR with the nuclear matrix fraction represents an event that follows 1alpha,25(OH)2D3-dependent nuclear localization of VDR, but that precedes 1alpha,25(OH)2D3-dependent transcriptional upregulation at target genes. PMID- 20171280 TI - Cloning the human vitamin D receptor into the pTwin-1 expression vector. AB - Many of the actions of 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] are mediated by binding to the nuclear vitamin D receptor (VDR). VDR is a member of a superfamily of nuclear receptors that are ligand-dependent transcription factors. Ligand binding induces conformational changes in the VDR that enable the receptor to interact with other coactivators to modulate gene transcription. In order to better characterize the binding of the VDR to 1,25(OH)2D3 and to analogs of 1,25(OH)2D3, we have cloned the cDNA for the human VDR into the pTwin1 expression system. The expression system results in the cDNA for a chitin-binding peptide and a yeast intein fused in frame with the N-terminal end of the cDNA for VDR. The intein cDNA codes for a self-cleaving peptide that can release VDR, without any additional amino acids, from a chitin column by changing the pH of the buffer. Western blot analysis of the VDR-fusion protein indicates that a protein of approximately 75 kDA was obtained as expected. PMID- 20171281 TI - Structural cuticular proteins from arthropods: annotation, nomenclature, and sequence characteristics in the genomics era. AB - The availability of whole genome sequences of several arthropods has provided new insights into structural cuticular proteins (CPs), in particular the distribution of different families, the recognition that these proteins may comprise almost 2% of the protein coding genes of some species, and the identification of features that should aid in the annotation of new genomes and EST libraries as they become available. Twelve CP families are described: CPR (named after the Rebers and Riddiford Consensus); CPF (named because it has a highly conserved region consisting of about forty-four amino acids); CPFL (like the CPFs in a conserved C terminal region); the TWDL family, named after a picturesque phenotype of one mutant member; four families in addition to TWDL with a preponderance of low complexity sequence that are not member of the families listed above. These were named after particular diagnostic features as CPLCA, CPLCG, CPLCW, CPLCP. There are also CPG, a lepidopteran family with an abundance of glycines, the apidermin family, named after three proteins in Apis mellifera, and CPAP1 and CPAP3, named because they have features analogous to peritrophins, namely one or three chitin binding domains. Also described are common motifs and features. Four unusual CPs are discussed in detail. Data that facilitated the analysis of sequence variation of single CP genes in natural populations are analyzed. PMID- 20171283 TI - Study on immune regulation in Hyriopsis cumingii Lea: effect of pearl-nucleus insertion in the visceral mass on immune factors present in the hemolymph. AB - This study was aimed at elucidating the mechanism of immune responses in fresh water mussels during pearl culture. Alpha-2 macroglobulin gene (alpha(2)M) expression, acid phosphatase (ACP) and superoxide dismutase (SOD) activities, and hemocyte counts were evaluated after inserting a pearl nucleus into the visceral mass of Hyriopsis cumingii Lea (H. Lea). We selected 60 H. Leas and randomly assigned them to 2 groups (each group contained 3 replicates of 10 individuals), and individuals among one group were treated by inserting pearl nucleus into the visceral mass. Real-time quantitative polymerase chain reaction (Q-PCR) was used to evaluate alpha(2)M gene expression, and the activities of ACP and SOD in hemocytes and serum were determined after 1, 2, 3, 5, and 10 days after nucleus insertion. Hemocyte morphologies and numbers on the 5th day after insertion were studied using phase-contrast microscope (PCM), optical microscope and flow cytometry (FCM). All observations suggested that the insertion of the pearl nucleus in the visceral mass had a significant effect on alpha(2)M gene expression, ACP and SOD activities, and hemocyte characteristics. The alpha(2)M gene expression was sharply up-regulated on the 3rd day after nucleus insertion, and it was significantly higher in the test groups on the 3rd, 5th, and 10th days than those in the control groups (P < 0.05). On the 1st to 3rd after treatment, ACP activity in the test group was higher than that in the control group (P < 0.05). SOD activity in the serum was remarkably higher in the test groups than in the control group, and exhibited significant differences on the 3rd, 5th, and 10th days (P < 0.05). However, the SOD activity in hemocytes was lower in the test group than in the control group, and it exhibited significant differences on all days, except on the 3rd day (P < 0.05). The hemocytes were divisible into 2 types: granulocytes (GR) and hyalinocytes (HY). The hemocyte morphology, protuberances, vesicle-like bodies, and density increased significantly (P < 0.05), and the number of GR increased, while that of HY decreased after nucleus insertion. These results indicated that the insertion of pearl nucleus enhanced the immune response in H. Lea. PMID- 20171282 TI - Epigenetic changes and non-coding expanded repeats. AB - Many neurogenetic disorders are caused by unstable expansions of tandem repeats. Some of the causal mutations are located in non-protein-coding regions of genes. When pathologically expanded, these repeats can trigger focal epigenetic changes that repress the expression of the mutant allele. When the mutant gene is not repressed, the transcripts containing the expanded repeat can give rise to a toxic gain-of-function by the mutant RNA. These two mechanisms, heterochromatin mediated gene repression and RNA dominance, produce a wide range of neurodevelopmental and neurodegenerative abnormalities. Here we review the mechanisms of gene dysregulation induced by non-coding repeat expansions, and early indications that some of these disorders may prove to be responsive to therapeutic intervention. PMID- 20171284 TI - Spleen immune status is affected after acute handling stress but not regulated by cortisol in Eurasian perch, Perca fluviatilis. AB - The effects of acute stress on immune status and its regulation by cortisol/corticosteroid receptors have received little attention in percids. To address that question, we investigated the physiological and immune responses of Eurasian perch, Perca fluviatilis to acute stress. We exposed immature perch to an 1-min exondation and measured at 1 h, 6 h, 24 h and 72 h post-stress: (1) stress-related parameters including plasma cortisol and glucose levels, (2) immune parameters in the plasma and in the spleen (complement, respiratory burst and lysozyme activity, total immunoglobulins; gene expression of lysozyme, complement unit 3, apolipoprotein A1 and 14 kDa, hepcidin and chemotaxin) (3) the corticosteroid receptors gene expression in the spleen after having cloned them. In addition, the in vitro effects of cortisol on the spleen immune parameters were also investigated. Plasma cortisol and glucose levels increased markedly 1h post-stress and returned at basal levels after 24 h. P. fluviatilis mineralocorticoid receptor, but not glucocorticoid receptors, was significantly up-regulated both in vivo after the stress and in vitro by cortisol at a physiological concentration (100 ng/ml). The plasma immune parameters were not significantly affected by the stress. In contrast, spleno-somatic index, spleen lysozyme activity, lysozyme and hepcidin gene expression were depleted and total immunoglobulins increased along the whole time-course (1-72 h). But, these immune parameters were not regulated in vitro by cortisol at physiological or supra physiological doses. Our results indicate that handling stress may affect spleen antibacterial defences without clear effects on circulating immune compounds and that the elevation of plasma cortisol after handling stress may not be related to the regulation of this splenic response. PMID- 20171285 TI - Quantifying the effects of normal ageing on white matter structure using unsupervised tract shape modelling. AB - Quantitative tractography may provide insights into regional heterogeneity of changes in white matter structure in normal ageing. Here we examine how brain atrophy and white matter lesions affect correlations between tract shape, tract integrity and age in a range of frontal and non-frontal tracts in 90 non-demented subjects aged over 65 years using an enhanced version of probabilistic neighbourhood tractography. This novel method for automatic single seed point placement employs unsupervised learning and streamline selection to provide reliable and accurate tract segmentation, whilst also indicating how the shape of an individual tract compares to that of a predefined reference tract. There were significant negative correlations between tract shape similarity to reference tracts derived from a young brain white matter atlas and age in genu and splenium of corpus callosum. Controlling for intracranial and lateral ventricle volume, the latter of which increased significantly with age, attenuated these correlations by 40% and 84%, respectively, indicating that this age-related change in callosal tract topology is significantly mediated by global atrophy and ventricular enlargement. In accordance with the "frontal ageing" hypothesis, there was a significant positive correlation between mean diffusivity (D) and age, and a significant negative correlation between fractional anisotropy (FA) and age in corpus callosum genu; correlations not seen in splenium. Significant positive correlations were also observed between D and age in bilateral cingulum cingulate gyri, uncinate fasciculi and right corticospinal tract. This pattern of correlations was not, however, reproduced when those subjects with significant white matter lesion load were analyzed separately from those without. These data therefore suggest that brain atrophy and white matter lesions play a significant role in driving regional patterns of age-related changes in white matter tract shape and integrity. PMID- 20171286 TI - White matter structures associated with creativity: evidence from diffusion tensor imaging. AB - Creativity has been essential to the development of human civilization and plays a crucial role in cultural life. However, despite literature that has proposed the importance of structural connectivity in the brain for creativity, the relationship between regional white matter integrity and creativity has never been directly investigated. In this study, we used diffusion tensor imaging and a behavioral creativity test of divergent thinking to investigate the relationship between creativity and structural connectivity. We examined associations between creativity and fractional anisotropy across the brain in healthy young adult (mean age, 21.7 years old; [SD]=1.44) men (n=42) and women (n=13). After controlling for age, sex, and score on Raven's advanced progressive matrices, a test for psychometric measures of intelligence, significant positive relationships between fractional anisotropy and individual creativity as measured by the divergent thinking test were observed in the white matter in or adjacent to the bilateral prefrontal cortices, the body of the corpus callosum, the bilateral basal ganglia, the bilateral temporo-parietal junction and the right inferior parietal lobule. As a whole, these findings indicate that integrated white matter tracts underlie creativity. These pathways involve the association cortices and the corpus callosum, which connect information in distant brain regions and underlie diverse cognitive functions that support creativity. Thus, our results are congruent with the ideas that creativity is associated with the integration of conceptually distant ideas held in different brain domains and architectures and that creativity is supported by diverse high-level cognitive functions, particularly those of the frontal lobe. PMID- 20171288 TI - Lapsing when sleep deprived: neural activation characteristics of resistant and vulnerable individuals. AB - Lapses of attention, in the form of delayed responses to salient stimuli, increase in frequency for some but not all persons after sleep deprivation (SD). To identify patterns of task-related brain activation that might explain differences in vulnerability to SD, we performed fMRI on participants during a visual, selective attention task. We analyzed the correct responses in a trial-by trial fashion to model the effects of response time. Stimulus contrast was varied to modulate perceptual difficulty. Attentional lapses and low-contrast stimuli were independently associated with increased signal in fronto-parietal regions associated with biasing attention. Sleep-deprived vulnerable individuals showed reduced top down fronto-parietal signal across all levels of image contrast and this reduction was particularly significant during lapses. There was concurrent reduction in extrastriate cortex and thalamus activation. Non-vulnerable persons showed a trend towards higher top-down biasing of attention and preserved visual cortex activation during SD lapses. A major contributor to performance degradation in SD appears to be a reduction in top-down biasing of attention that is independent of task difficulty. PMID- 20171289 TI - Mapping rabbit whisker barrels using discriminant analysis of high field fMRI data. AB - High field (>4T) functional magnetic resonance imaging (fMRI) techniques provide increased spatial resolution that enables the noninvasive, repeatable study of the sensory cortices at the level of their basic functional units. The examination of these units is important for studies of sensory information processing, learning- or experience-related brain plasticity, or the fundamental relationship between hemodynamic and neuronal activity. However functional units cannot always be distinguished from their surrounding areas by conventional activation mapping methods such as correlation or hypothesis tests, which only consider temporal variation within each individual voxel. We report a novel method to detect individual whisker barrels by using discriminant analysis to jointly characterize high order dependency among multiple voxels. Our results in the whisker barrel cortex of the awake rabbit indicate that the proposed method can differentiate reliably small clusters of activated voxels corresponding to individual whisker barrels within larger areas of functional activation, even in the case of adjacent whiskers in unanesthetized subjects. This method is computationally efficient, requires no specific experimental design for fMRI acquisition, and should be applicable to studies of other sensory systems. PMID- 20171290 TI - Construction of multi-region-multi-reference atlases for neonatal brain MRI segmentation. AB - Neonatal brain MRI segmentation is a challenging problem due to its poor image quality. Atlas-based segmentation approaches have been widely used for guiding brain tissue segmentation. Existing brain atlases are usually constructed by equally averaging pre-segmented images in a population. However, such approaches diminish local inter-subject structural variability and thus lead to lower segmentation guidance capability. To deal with this problem, we propose a multi region-multi-reference framework for atlas-based neonatal brain segmentation. For each region of a brain parcellation, a population of spatially normalized pre segmented images is clustered into a number of sub-populations. Each sub population of a region represents an independent distribution from which a regional probability atlas can be generated. A selection of these regional atlases, across different sub-regions, will in the end be adaptively combined to form an overall atlas specific to the query image. Given a query image, the determination of the appropriate set of regional atlases is achieved by comparing the query image regionally with the reference, or exemplar, of each sub population. Upon obtaining an overall atlas, an atlas-based joint registration segmentation strategy is employed to segment the query image. Since the proposed method generates an atlas which is significant more similar to the query image than the traditional average-shape atlas, better tissue segmentation results can be expected. This is validated by applying the proposed method on a large set of neonatal brain images available in our institute. Experimental results on a randomly selected set of 10 neonatal brain images indicate that the proposed method achieves higher tissue overlap rates and lower standard deviations (SDs) in comparison with manual segmentations, i.e., 0.86 (SD 0.02) for GM, 0.83 (SD 0.03) for WM, and 0.80 (SD 0.05) for CSF. The proposed method also outperforms two other average-shape atlas-based segmentation methods. PMID- 20171291 TI - Separating distinct aspects of the voluntary selection between response alternatives: N2- and P3-related BOLD responses. AB - Voluntary selection between response alternatives belongs to cognitive abilities controlling and regulating goal-directed behaviour. Voluntary selection processes are associated with increased neural activity, especially in medial and lateral frontal brain regions as well as the inferior parietal gyrus. However, the precise function of each brain region as well as the spatiotemporal characteristic of the brain regions involved is not yet clear. The aim of the present study was to disentangle distinct aspects of voluntary selection and their underlying neural processes. Hence, event-related potentials (ERPs) and functional MRI data were acquired simultaneously. Brain regions modulated by the task-induced amplitude variation of ERPs (N2, P3) were identified. The results showed N2-related hemodynamic responses, especially in medial and lateral frontal brain regions. Among other things, medial frontal brain regions are related to conflict monitoring, control of voluntary action and decision making. By contrast, the P3-amplitude proved to be predominantly related to increased BOLD responses in the temporo-parietal junction and lateral frontal brain regions. These brain regions are thought to play a decisive role in an attentional network involved in detecting auditory and visual stimuli. Overall, the results of the study indicated a whole network of brain regions to be associated with voluntary selection processes. In addition, at least some frontal brain regions seemed to be involved at an earlier stage than temporo-parietal regions, probably indicating a top-down process. PMID- 20171292 TI - Phylogenetic relationships between flies of the Tephritinae subfamily (Diptera, Tephritidae) and their symbiotic bacteria. AB - The Tephritinae is considered the most specialized subfamily of fruit flies, predominantly infesting flowerheads of Asteraceae. Some species are known to host specific non-culturable symbiont bacteria ("Candidatus Stammerula spp.") in the midgut. In this work we (i) examined the phylogenetic relationships among the insect hosts, (ii) investigated the presence of bacteria in other hitherto unexamined species, and (iii) evaluated the phylogenetic congruence between insects and symbionts. A total of 33 Tephritinae species in 17 different genera were analyzed. Two regions of the mitochondrial DNA (16S rDNA and COI-tRNALeu COII) were examined in the insect host, while the 16S was analyzed in the bacteria. From the phylogenetic trees, four of the five tribes considered were statistically supported by each of the clustering methods used. Species belonging to the tribe Noeetini never clustered at significant levels. The phylogenetic COI tRNALeu-COII tree showed internal nodes more highly supported than the 16S phylogeny. The analysis of the distribution of symbiosis across the subfamily has highlighted the presence of bacteria only in the tribe Tephritini and in the genus Noeeta from the tribe Noeetini. A cophylogenetic analysis revealed a substantial congruence between hosts and symbionts. The interesting exceptions can be justified by events like losses, duplications and hosts switching opportunities, which are likely to arise during the biological cycle of the fly in consideration of the extracellular status of these symbionts. PMID- 20171293 TI - Molecular phylogenetics and evolution of Holacanthus angelfishes (Pomacanthidae). AB - The angelfish genus Holacanthus includes seven species in the tropical Eastern Pacific and Atlantic. In this study we performed an analysis on all species, the closely related regal angelfish, and the Cortez angelfish, using four mitochondrial and one nuclear marker. Our results support a monophyletic Holacanthus. The Indo-Pacific regal angelfish, Pygoplytes diacanthus, was found to be the closest relative to Holacanthus. We found a split into two clades with divergences that were consistent with the rise of the Isthmus of Panama. An internally calibrated molecular clock thus placed the origin of Holacanthus to approximately 10.2-7.6 million years ago. PMID- 20171294 TI - Evolution of cysteine patterns in the large extracellular loop of tetraspanins from animals, fungi, plants and single-celled eukaryotes. AB - By analyzing the evolution of cysteine patterns in the large extracellular loop (LEL) of tetraspanins across all eukaryotes, we report the following: (1) the origin of the cysteine-cysteine-glycine (CCG) motif in the common ancestor of unikonts (Animalia, fungi and amoebozoa); (2) tracing cysteine motifs on an eukaryotic phylogeny which includes protists, animals and plants match organismal evolution; (3) using this evolutionary approach we have determined some of the cysteines in these proteins that are involved in specific bonds in the LEL. Our study provides a framework to better understand tetraspanin formation, diversification and the evolutionary history of these important proteins. PMID- 20171295 TI - Evolution and biogeographic diversification of the witch-hazel genus (Hamamelis L., Hamamelidaceae) in the Northern Hemisphere. AB - The evolution of the eastern Asian and eastern North American disjunction of the witch-hazel genus Hamamelis L. (Hamamelidaceae) was examined through phylogenetic and biogeographic analyses. Phylogenetic relationships of all Hamamelis species were reconstructed using parsimony and Bayesian analyses of sequence data from six plastid (trnL-F, psaA-ycf3, rps16, matK, atpB-rbcL, and psbA-trnH) and two nuclear (ITS and ETS) DNA regions. The phylogeny was then used to infer the biogeographic origin and subsequent diversification using both event-based (DIVA) and maximum likelihood (LAGRANGE) methods incorporating fossil data. The times of divergence within Hamamelis were estimated with the Bayesian approach using the program BEAST. A very low level of molecular variation was detected in both the plastid and the nuclear DNA regions within Hamamelis. The combined analyses resulted in a phylogeny of the genus with higher resolution and support values. Hamamelis was supported to be monophyletic with H. mollis from eastern China diverged first in the genus. All North American species formed a clade and was sister to the eastern Asian H. japonica. Within the North American clade, H. mexicana was sister to H. vernalis, and the recently described species H. ovalis was found to be closely related to the widespread species H. virginiana. The stem age of Hamamelis was estimated to be at the Eocene (51.2 mya, with 95% HDP: 49.0 54.6 mya), and the crown age of the genus was dated to be at the late Miocene (9.7 mya, with 95% HDP: 3.6-18.1 mya, or 10.6 mya, with 95% HDP: 4.2-19.6 mya). The disjunction between the eastern Asian and the eastern North American species was dated to be 7.1 mya (95% HDP: 3.1-13.6 mya) or 7.7 mya (95% HDP: 3.4-13.6 mya). Biogeographic analyses incorporating fossils resulted in more equally possible solutions at the stem lineage of Hamamelis than those including extant species only. Eastern Asia is inferred to be the most-likely area for the origin of Hamamelis. The current disjunction was due to the extinction in western North America and Europe from Eocene to late Miocene, and later migration from eastern Asia into North America. The Bering land bridge was hypothesized to have played an important role in the evolution of this disjunction. The current species diversity of the genus was the result of relatively recent diversification events during the late Miocene rather than long accumulation of lineages from the early Tertiary. PMID- 20171287 TI - Voxelwise genome-wide association study (vGWAS). AB - The structure of the human brain is highly heritable, and is thought to be influenced by many common genetic variants, many of which are currently unknown. Recent advances in neuroimaging and genetics have allowed collection of both highly detailed structural brain scans and genome-wide genotype information. This wealth of information presents a new opportunity to find the genes influencing brain structure. Here we explore the relation between 448,293 single nucleotide polymorphisms in each of 31,622 voxels of the entire brain across 740 elderly subjects (mean age+/-s.d.: 75.52+/-6.82 years; 438 male) including subjects with Alzheimer's disease, Mild Cognitive Impairment, and healthy elderly controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We used tensor-based morphometry to measure individual differences in brain structure at the voxel level relative to a study-specific template based on healthy elderly subjects. We then conducted a genome-wide association at each voxel to identify genetic variants of interest. By studying only the most associated variant at each voxel, we developed a novel method to address the multiple comparisons problem and computational burden associated with the unprecedented amount of data. No variant survived the strict significance criterion, but several genes worthy of further exploration were identified, including CSMD2 and CADPS2. These genes have high relevance to brain structure. This is the first voxelwise genome wide association study to our knowledge, and offers a novel method to discover genetic influences on brain structure. PMID- 20171296 TI - CD44: survival and metastasis in chondrosarcoma. AB - OBJECTIVE: Recent studies have shown abnormal expression of CD44s and some of its isoforms in many human malignancies, but little is known about the presence of CD44 in chondrosarcoma. In this study the expression of CD44s and two variant isoforms was evaluated. It was assumed that abnormalities in these receptor proteins may be associated with clinical outcome of the patients. METHOD: Thirty paraffin-embedded chondrosarcoma samples were immunostained with monoclonal antibodies for CD44s, CD44v5 and CD44v6. Two independent examiners who were unaware of the clinical status of the patients evaluated the immunohistochemical results. The percentage of CD44-positive cells was scored semiquantitatively. A rate of higher than 10% was considered as overexpression. RESULTS: Among the 30 patients (median age 50 years) there were 22 conventional chondrosarcomas, two dedifferentiated chondrosarcomas, two extraskeletal chondrosarcomas, and one periostal, mesenchymal, clear cell and myxoid chondrosarcoma each. In the immunochemistry staining overexpression (>10% of cells) of CD44s was shown in 56.7% (17 of 30), of CD44v5 in 43.3% (13 of 30) and of CD44v6 in 6.7% (two of 30) of the tumors. Four grade III chondrosarcomas (80%) and 10 (71.4%) grade II chondrosarcomas showed overexpression for CD44s, whereas CD44s was overexpressed in only three (27.3%) grade I chondrosarcomas. Cox regression suggests overexpression of CD44s to be an additional prognostic marker for chondroid bone tumors independent of grading and other covariates. CONCLUSIONS: Overexpression of CD44s correlated significantly with metastatic potential and with poorer survival in patients with chondrosarcoma. CD44s might be an independent additional marker, but small sample size remains to be considered. PMID- 20171297 TI - A statistical model of shape and density of the proximal femur in relation to radiological and clinical OA of the hip. AB - OBJECTIVE: Common radiological measures of osteoarthritis (OA) relate poorly to symptoms as experienced by patients. We created a statistical model of shape and density to see if Dual Energy X-ray (DXA) images of the hip contain symptom related information that is not captured by common radiological measures. METHODS: DXA images of the hip were made in a prospective study of patients that met the American College of Rheumatology (ACR) criteria for hip OA. From the DXA scans, we constructed a statistical model of the appearance (shape combined with density) of the proximal femur of left and right side. The model yields a number of independent descriptors of the appearance (modes) which we related to various measures of radiological and clinical OA. These outcome measures were defined using Joint Space Width (JSW), Kellgren and Lawrence (K-L) scores, Visual Analogue Scale (VAS) and Western Ontario MacMaster Universities (WOMAC) pain scores and a self-reported global assessment score. RESULTS: Various modes showed significant relations with measures of OA. Interestingly, the modes that related well with radiological OA did not relate to clinical OA and vice-versa. Moreover, the modes were predictors of status and progression of clinical OA, independent from JSW and K-L. CONCLUSION: Statistical modeling of the appearance captures the patterns of variation in projected femoral morphology as visible on DXA images. We showed that these descriptors of subtle aspects of shape and density of the hip contain information about clinical status which common radiological measures do not. The presented results warrant further careful study of the method as a monitoring tool in clinical trials. PMID- 20171299 TI - OARSI recommendations for the management of hip and knee osteoarthritis: the semantics of differences and changes. PMID- 20171298 TI - Magnitude and regional distribution of cartilage loss associated with grades of joint space narrowing in radiographic osteoarthritis--data from the Osteoarthritis Initiative (OAI). AB - OBJECTIVE: Clinically, radiographic joint space narrowing (JSN) is regarded a surrogate of cartilage loss in osteoarthritis (OA). Using magnetic resonance imaging (MRI), we explored the magnitude and regional distribution of differences in cartilage thickness and subchondral bone area associated with specific Osteoarthritis Research Society International (OARSI) JSN grades. METHOD: Seventy three participants with unilateral medial JSN were selected from the first half (2678 cases) of the OA Initiative cohort (45, 21, and 7 with OARSI JSN grades 1, 2, and 3, respectively, no medial JSN in the contra-lateral knee). Bilateral sagittal baseline DESSwe MRIs were segmented by experienced operators. Intra person between-knee differences in cartilage thickness and subchondral bone areas were determined in medial femorotibial subregions. RESULTS: Knees with medial OARSI JSN grades 1, 2, and 3 displayed a 190 microm (5.2%), 630 microm (18%), and 1560 microm (44%) smaller cartilage thickness in weight-bearing medial femorotibial compartments compared to knees without JSN, respectively. The weight bearing femoral condyle displayed relatively greater differences than the posterior femoral condyle or the medial tibia (MT). The central subregion within the weight-bearing medial femur (cMF) of the femoral condyle (30-75 degrees ), and the external and central subregions within the tibia displayed relatively greater JSN-associated differences compared to other medial femorotibial subregions. Knees with higher JSN grades also displayed larger than contra lateral femorotibial subchondral bone areas. CONCLUSIONS: This study provides quantitative estimates of JSN-related cartilage loss, with the central part of the weight-bearing femoral condyle being most strongly affected. Knees with higher JSN grades displayed larger subchondral bone areas, suggesting that an increase in subchondral bone area occurs in advanced OA. PMID- 20171300 TI - Use of PCR primers and probes based on the 23S rRNA and internal transcription spacer (ITS) gene sequence for the detection and enumerization of Lactobacillus acidophilus and Lactobacillus plantarum in feed supplements. AB - Novel polymerase chain reaction (PCR) primers designed from the 16S-23S internal transcription spacer (ITS) rRNA and 23S rRNA genes, respectively, were used for the specific detection of Lactobacillus acidophilus and Lactobacillus plantarum. Molecular weights of the PCR products were 221 and 599 bp, respectively. Strains of L. acidophilus and L. plantarum obtained from the culture center, dairy products, infant stool and other samples, could be identified with these PCR primers. DNAs from other lactic acid bacteria (LAB) species including strains of Lactobacillus pentosus which was closely related to L. plantarum, and bacteria species other than LAB, would not generate the false positive results. When this PCR primer set was used for the detection of L. acidophilus and L. plantarum in feed supplement or feed starter samples, reliable results were obtained. Furthermore, when these L. acidophilus or L. plantarum specific primers were used as DNA probes for the colony hybridization of L. acidophilus and L. plantarum, the viable cells of these LAB species in culture and feed supplements or starter products could be identified and enumerized. The method described here thus offers a rapid and economic way to inspect and assure the quality of the feed supplements or fermentation starters. PMID- 20171301 TI - Molecular regulation of Nogo-A in neural cells: Novel insights into structure and function. AB - Nogo-A is part of the reticulon family of proteins localized to the myelin and oligodendroglial plasma membranes. Nogo-A specifically initiates signal transduction cascades limiting axonal regrowth following injury and disease in the adult mammalian central nervous system (CNS). Recent novel data support the contention that neuronal Nogo-A plays an important role in regulating cytoskeletal re-organization without the requirement of signaling through its cognate receptor (Nogo receptor). These data, along with the recent findings that the N-terminus of Nogo-A can interact with integrins and that NgR1 interacts with the amyloid precursor protein extracellularly, as well as novel findings showing ubiquitin ligases binding with Nogo-A intracellularly add a layer of complexity to its functional role in the CNS. PMID- 20171302 TI - Neuronal apoptosis inhibitory protein, NAIP, is an inhibitor of procaspase-9. AB - Ability of the full length NAIP and its BIR3 domain in inhibition of the proteases of the intrinsic apoptosis pathway was investigated. Activity of endogenous executioner caspases was drastically reduced by both recombinant NAIP BIR3 (NBIR3) and the full length protein. Western blotting experiments showed that the full length NAIP and its BIR3 domain inhibited the cleavage of procaspase-3 by apoptosome activated caspase-9. Moreover, full length NAIP inhibited autocatalytic processing of procaspase-9 in the apoptosome complex indicating that unlike other inhibitor of apoptosis proteins (IAPs) human NAIP is an inhibitor of procaspase-9. Furthermore, inhibition of single-chain caspase-9 (human caspase-9, D315, D330/A point mutations that abrogate the proteolytic processing but not the catalytic activity of caspase-9) by the BIR3 domain indicated that the this domain is the caspase-9 interacting moiety. Consistently, pull-down experiments of single-chain capsase-9 in apoptosome complex by the NBIR3 but not the X-linked inhibitor of apoptosis protein (XIAP)-BIR3 domain confirmed that the protein can associate with procaspase-9 prior to its autoproteolysis upon apoptosome formation. Interaction studies revealed the association of C338W variant of the NBIR3, but not the wild type protein with both SMAC-peptide and the SMAC protein. These data indicate that mutation of C338 to Trp is sufficient to accommodate the interaction of NAIP-BIR3 with SMAC peptide and protein. Taken together, these results demonstrate that NAIP is evolved to prevent apoptosis right at the initiation stage of apoptosome formation and this inhibition cannot be antagonized by SMAC-type proteins. PMID- 20171303 TI - Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PMID- 20171305 TI - Epidemiology and economic burden of rotavirus gastroenteritis in hospitals and paediatric clinics in Taiwan, 2005-2006. AB - Baseline estimates of rotavirus disease burden and epidemiology are useful for the evaluation of newly introduced rotavirus vaccination programs. Prospective, cross-sectional surveillance for acute gastroenteritis (AGE) was conducted in hospitals and outpatient paediatric clinics in Taiwan to assess the prevalence of rotavirus gastroenteritis and associated medical costs prior to rotavirus vaccine introduction. Faecal specimens were collected from 1130 children <5 years of age from December 2004 to June 2006. The year-round rate of rotavirus detection in faecal specimens was 46% for children seen in hospitals and 14% for children seen in paediatric clinics. In the winter season, the burden was higher, reaching a peak of 60% and 21% in hospitals and paediatric clinics, respectively. The rotavirus genotype distributions were 39% (G1), 34% (G9), 12% (G2), 15% (G3), and 0.3% (G5). Total medical and nonmedical costs were US $754 for a rotavirus hospitalisation and US $60 for an outpatient clinic visit. Parental work loss averaged 4.0 days per hospital visit and 1.3 days per paediatric clinic visit. These data show that rotavirus was associated with a substantial proportion of AGE medical visits and had considerable medical costs prior to rotavirus vaccine introduction. PMID- 20171304 TI - Osteopontin deficiency increases bone fragility but preserves bone mass. AB - The ability of bone to resist catastrophic failure is critically dependent upon the material properties of bone matrix, a composite of hydroxyapatite, collagen type I, and noncollagenous proteins. These properties include elastic modulus, hardness, and fracture toughness. Like other aspects of bone quality, matrix material properties are biologically-defined and can be disrupted in skeletal disease. While mineral and collagen have been investigated in greater detail, the contribution of noncollagenous proteins such as osteopontin to bone matrix material properties remains unclear. Several roles have been ascribed to osteopontin in bone, many of which have the potential to impact material properties. To elucidate the role of osteopontin in bone quality, we evaluated the structure, composition, and material properties of bone from osteopontin deficient mice and wild-type littermates at several length scales. Most importantly, the results show that osteopontin deficiency causes a 30% decrease in fracture toughness, suggesting an important role for OPN in preventing crack propagation. This significant decline in fracture toughness is independent of changes in whole bone mass, structure, or matrix porosity. Using nanoindentation and quantitative backscattered electron imaging to evaluate osteopontin-deficient bone matrix at the micrometer level, we observed a significant reduction in elastic modulus and increased variability in calcium concentration. Matrix heterogeneity was also apparent at the ultrastructural level. In conclusion, we find that osteopontin is essential for the fracture toughness of bone, and reduced toughness in osteopontin-deficient bone may be related to the increased matrix heterogeneity observed at the micro-scale. By exploring the effects of osteopontin deficiency on bone matrix material properties, composition and organization, this study suggests that reduced fracture toughness is one mechanism by which loss of noncollagenous proteins contribute to bone fragility. PMID- 20171306 TI - Characterization of ferritin 2 for the control of tick infestations. AB - Ixodes ricinus is one the most abundant tick species in Europe and these ticks transmit pathogens causing human and animal diseases. The cattle ticks, Rhipicephalus (Boophilus) spp., affect cattle production in tropical and subtropical regions of the world. Development of vaccines directed against tick proteins may reduce tick infestations and the transmission of tick-borne pathogens. However, a limiting step in tick vaccine development has been the identification of tick protective antigens. Herein, the tick iron metabolism pathway was targeted in an effort to identify new tick protective antigens. Recombinant I. ricinus (IrFER2) and Rhipicephalus microplus (RmFER2) ferritin 2 proteins were expressed in Escherichia coli and used to immunize rabbits and cattle, respectively. Vaccination with IrFER2 reduced I. ricinus tick numbers, weight and fertility in rabbits with an overall vaccine efficacy (E) of 98%. Control of cattle tick, R. microplus and Rhipicephalus annulatus infestations was obtained in vaccinated cattle with overall E of 64% and 72%, respectively. Notably, the efficacy of the RmFER2 vaccine was similar to that obtained with Bm86 against R. microplus. These collective results demonstrated the feasibility of using ferritin 2 to develop vaccines for the control of tick infestations. PMID- 20171307 TI - Health beliefs of Taiwanese women seeking HPV vaccination. AB - In Taiwan, human papillomavirus (HPV) vaccine is recommended for women aged 9-26 years. The purpose of this study was to examine health beliefs and reasons for HPV vaccination among young adult women (aged 18-26 years), and adult women (aged over 26 years). Women who initiated HPV vaccination were recruited from three hospitals in southern Taiwan. One hundred and eighty-nine subjects completed a questionnaire on health beliefs and reasons for HPV vaccinations. 38% (n=72) of the women who initiated vaccination were over the age of 26. Health beliefs regarding HPV vaccination differ between young adult women and adult women. Recommendations from others (family, health care providers, etc.) are among the main reasons for young adult women to initiate HPV vaccination; while self awareness of the risk for HPV infection and personal gynecologic diseases are main reasons for adult women to initiate HPV vaccination. Furthermore, women aged 18-26 are more likely than women aged over 26 to consider the cost and availability of vaccination. Media also plays an important role in a woman's decision to seek HPV vaccination. PMID- 20171309 TI - The story of an active fixation coronary sinus lead: promise and peril. PMID- 20171308 TI - Donor sex and age influence the chondrogenic potential of human femoral bone marrow stem cells. AB - OBJECTIVE: Damaged articular cartilage does not heal well and can progress to osteoarthritis (OA). Human bone marrow stem cells (BMC) are promising cells for articular cartilage repair, yet age- and sex-related differences in their chondrogenesis have not been clearly identified. The purpose of this study is to test whether the chondrogenic potential of human femoral BMC varies based on the sex and/or age of the donor. DESIGN: BMC were isolated from 21 males (16-82 years old (y.o.)) and 20 females (20-77 y.o.) during orthopaedic procedures. Cumulative population doubling (CPD) was measured and chondrogenesis was evaluated by standard pellet culture assay in the presence or absence of transforming growth factor beta 1 (TGFbeta1). Pellet area was measured, and chondrogenic differentiation was determined by Toluidine blue and Safranin O-Fast green histological grading using the Bern score and by glycosaminoglycan (GAG) content. RESULTS: No difference in CPD was observed due to donor sex or age. The increase in pellet area with addition of TGFbeta1 and the Bern score significantly decreased with increasing donor age in male BMC, but not in female BMC. A significant reduction in GAG content per pellet was also observed with increasing donor age in male BMC. This was not observed in female BMC. CONCLUSIONS: This study showed an age-related decline in chondroid differentiation with TGFbeta1 stimulation in male BMC, but not in female BMC. Understanding the mechanisms for these differences will contribute to improved clinical use of autologous BMC for articular cartilage repair, and may lead to the development of customized age- or sex-based treatments to delay or prevent the onset of OA. PMID- 20171310 TI - Review: Carbon nanotube based electrochemical sensors for biomolecules. AB - Carbon nanotubes (CNTs) have been incorporated in electrochemical sensors to decrease overpotential and improve sensitivity. In this review, we focus on recent literature that describes how CNT-based electrochemical sensors are being developed to detect neurotransmitters, proteins, small molecules such as glucose, and DNA. Different types of electrochemical methods are used in these sensors including direct electrochemical detection with amperometry or voltammetry, indirect detection of an oxidation product using enzyme sensors, and detection of conductivity changes using CNT-field effect transistors (FETs). Future challenges for the field include miniaturizing sensors, developing methods to use only a specific nanotube allotrope, and simplifying manufacturing. PMID- 20171311 TI - Comparison of single and sequential extraction procedures for the study of rare earth elements remobilisation in different types of soils. AB - With the continual increase in the utilisation of rare earth elements (REE) for industrial and agricultural purposes, research into the environmental and biogeochemical behaviour of REE had attracted much interest in recent times. This study principally describes the distribution of REE in four different types of soils like lateritic soil (S-1), in situ natural soil (S-2), soil contaminated by mining activity (S-3) and accidentally polluted soil (S-4) utilizing the optimised BCR sequential extraction procedure and partial extractions with various types of single extractants such as unbuffered salt solutions 0.1 M NaNO(3), 0.01 M CaCl(2), 1 M NH(4)NO(3); complexing agents 0.005 M DTPA and 0.05 M EDTA; acid solutions 0.43 M CH(3)COOH and 1 M HCl. Comparison of the sum of the four BCR fractions, which included an aqua regia attack on the residue, with the pseudo-total aqua regia digest values to assess the accuracy of the BCR partioning approach has been undertaken. Partial extraction results with several single extractants have also been reported for all the REE elements including yttrium which have been analysed by the optimised BCR procedure. Results obtained after 24 h extraction with each of the single extractant have also been discussed. The extraction with 1 M HCl during 24 h yielded similar quantities of REE as those released under the combined steps of 1, 2 and 3 of the BCR sequential extraction for all the four different type of soil samples indicating that this reagent can be used successfully to estimate the total extractable contents of REE in various types of soil samples. PMID- 20171312 TI - Feature extraction and selection from volatile compounds for analytical classification of Chinese red wines from different varieties. AB - This work was undertaken to evaluate whether it is possible to determine the variety of a Chinese wine on the basis of its volatile compounds, and to investigate if discrimination models could be developed with the experimental wines that could be used for the commercial ones. A headspace solid-phase microextraction gas chromatographic (HS-SPME-GC) procedure was used to determine the volatile compounds and a blind analysis based on Ac/Ais (peak area of volatile compound/peak area of internal standard) was carried out for statistical purposes. One way analysis of variance (ANOVA), principal component analysis (PCA) and stepwise linear discriminant analysis (SLDA) were used to process data and to develop discriminant models. Only 11 peaks enabled to differentiate and classify the experimental wines. SLDA allowed 100% recognition ability for three grape varieties, 100% prediction ability for Cabernet Sauvignon and Cabernet Gernischt wines, but only 92.31% for Merlot wines. A more valid and robust way was to use the PCA scores to do the discriminant analysis. When we performed SLDA this way, 100% recognition ability and 100% prediction ability were obtained. At last, 11 peaks which selected by SLDA from raw analysis set had been identified. When we demonstrated the models using commercial wines, the models showed 100% recognition ability for the wines collected directly from winery and without ageing, but only 65% for the others. Therefore, the varietal factor was currently discredited as a differentiating parameter for commercial wines in China. Nevertheless, this method could be applied as a screening tool and as a complement to other methods for grape base liquors which do not need ageing and blending procedures. PMID- 20171313 TI - Self-modeling curve resolution techniques applied to comparative analysis of volatile components of Iranian saffron from different regions. AB - Volatile components of saffron from different regions of Iran were extracted by ultrasonic-assisted solvent extraction (USE) and were analyzed by gas chromatography-mass spectrometry (GC-MS). Self-modeling curve resolution (SMCR) was proposed for resolving the co-eluted GC-MS peak clusters into pure chromatograms and mass spectra. Multivariate curve resolution-objective function minimization (MCR-FMIN) and multivariate curve resolution-alternating least square (MCR-ALS) were successfully used for this purpose. The accuracy of the qualitative and quantitative results was improved considerably using SMCR techniques. Comparison of the results of saffron from different regions of Iran showed that their volatile components are different from chemical components and relative percentages points of view. Safranal is the main component of all samples. In addition, 4-hydroxy-2,6,6-trimethyl-1-cyclohexene-1-carboxaldehyde (HTCC), 2(5H)-furanone, 2,4,4-trimethyl-3-carboxaldehyde-5-hydroxy-2,5 cyclohexadien-1-one and 2(3H)-furanone, dihydro-4-hydroxy were common in all samples with high percentages. The results proved that combining of SMCR techniques with USE-GC-MS produces a powerful tool for the analysis of the complex samples. PMID- 20171314 TI - Highly selective ionic liquid-based microextraction method for sensitive trace cobalt determination in environmental and biological samples. AB - A simple and rapid dispersive liquid-liquid microextraction procedure based on an ionic liquid (IL-DLLME) was developed for selective determination of cobalt (Co) with electrothermal atomic absorption spectrometry (ETAAS) detection. Cobalt was initially complexed with 1-nitroso-2-naphtol (1N2N) reagent at pH 4.0. The IL DLLME procedure was then performed by using a few microliters of the room temperature ionic liquid (RTIL) 1-hexyl-3-methylimidazolium hexafluorophosphate [C(6)mim][PF(6)] as extractant while methanol was the dispersant solvent. After microextraction procedure, the Co-enriched RTIL phase was solubilized in methanol and directly injected into the graphite furnace. The effect of several variables on Co-1N2N complex formation, extraction with the dispersed RTIL phase, and analyte detection with ETAAS, was carefully studied in this work. An enrichment factor of 120 was obtained with only 6 mL of sample solution and under optimal experimental conditions. The resultant limit of detection (LOD) was 3.8 ng L(-1), while the relative standard deviation (RSD) was 3.4% (at 1 microg L(-1) Co level and n=10), calculated from the peak height of absorbance signals. The accuracy of the proposed methodology was tested by analysis of a certified reference material. The method was successfully applied for the determination of Co in environmental and biological samples. PMID- 20171315 TI - Integrated liquid chromatography-heated nebulizer microchip for mass spectrometry. AB - A new integrated microchip for liquid chromatography-mass spectrometry (LC-MS) is presented. The chip is made from bonded silicon and glass wafers with structures for a packed LC column channel, a micropillar frit, a channel for optional optical detection, and a heated vaporizer section etched in silicon and platinum heater elements on the glass cover. LC eluent is vaporized and mixed with nebulizer gas in the vaporizer section and the vapor is sprayed out from the chip. Nonpolar and polar analytes can be efficiently ionized in the gas phase by atmospheric pressure photoionization (APPI) as demonstrated with polycyclic aromatic hydrocarbons (PAHs) and selective androgen receptor modulators (SARMs). This is not achievable with present LC-MS chips, since they are based on electrospray ionization, which is not able to ionize nonpolar compounds efficiently. The preliminary quantitative performance of the new chip was evaluated in terms of limit of detection (down to 5 ng mL(-1)), linearity (r>0.999), and repeatability of signal response (RSD=2.6-4.0%) and retention time (RSD=0.3-0.5%) using APPI for ionization and PAHs as standard compounds. Determination of fluorescent compounds is demonstrated by using laser-induced fluorescence (LIF) for detection in the optical detection channel before the vaporizer section. PMID- 20171316 TI - Fluorescence single-molecule counting assays for protein quantification using epi fluorescence microscopy with quantum dots labeling. AB - A single-molecule counting approach for quantifying the antibody affixed to a surface using quantum dots and epi-fluorescence microscopy is presented. Modifying the glass substrates with carboxyl groups provides a hydrophilic surface that reacts with amine groups of an antibody to allow covalent immobilization of the antibody. Nonspecific adsorption of single molecules on the modified surfaces was first investigated. Then, quantum dots were employed to form complexes with surface-immobilized antibody molecules and used as fluorescent probes for single-molecule imaging. Epi-fluorescence microscopy was chosen as the tool for single-molecule fluorescence detection here. The generated fluorescence signals were taken by an electron multiplying charge-coupled device and were found to be proportional to the sample concentrations. Under optimal conditions, a linear response range of 5.0x10(-14)-3.0x10(-12) mol L(-1) was obtained between the number of single molecules and sample concentration via a single-molecule counting approach. PMID- 20171318 TI - Selective detection and estimation of C-reactive protein in serum using surface functionalized gold nano-particles. AB - A new method for the detection of C-reactive protein (CRP) in serum using functionalized gold nano-particles (GNP) is reported. The affinity towards CRP is imparted to GNP by tethering O-phosphorylethanolamine (PEA) onto their surface. GNP and modified GNP were characterized using TEM, particle size analysis, zeta potential measurements, absorption spectroscopy and FT-IR techniques. The event of binding of CRP onto the PEA-GNP is followed by visibly observable colour change. We observed a red shift as well as a decrease in absorption in the plasmon peak of the modified GNP with the concentration of CRP. When the concentration of CRP exceeded 450 ng mL(-1), particles were aggregated and the solution became turbid. The method exhibited a linear range for CRP from 50 to 450 ng mL(-1) with a detection limit of 50 ng mL(-1). The colour change and the variation in absorption of the GNP were highly specific to CRP even in the presence of albumin. We estimated CRP in blood serum collected from patients and the results obtained compared well with the estimation using the technique of nephelometry based on the antibody-antigen interaction. PMID- 20171317 TI - Immunochemical determination of oxytetracycline in fish: comparison between enzymatic and time-resolved fluorometric assays. AB - An indirect competitive enzyme-linked immunosorbent assay (ELISA) with photometric detection of horseradish peroxidase (HRP) activity, was developed in plate to detect oxytetracycline (OTC) in Gilthead sea bream (Sparus aurata) samples. The results were compared to those obtained by time-resolved fluoroimmunoassay (TR-FIA) using a secondary antibody with coproporphyrin of platinum (II) (PtCP) as marker. The limits of detection obtained in fish extract were 16 and 0.08 microg kg(-1) for photometric and fluorometric detections, respectively; therefore, they were suitable for fish quality control according to the maximum residue level established by the European Union. An extraction procedure using methanol:water 70:30 (v/v)+1 mL EDTA 0.1 M, and different clean up procedures based on solid-phase extraction (C(18), polymeric reversed phase, SCX, Si) was assayed. The matrix effects were overcome by means of an average tetracycline-free fish extract calibration curve used for quantification. The OTC optimized ELISA can also be applied to determine tetracycline and chlortetracycline residues with good results. Thus, the developed immunoassay could be considered as a generic assay for the most used tetracyclines in aquaculture antibiotic treatments. In order to confirm the utility of the developed immunoassay as a semi-quantitative methodology, fish samples obtained from different supermarkets were analyzed. Results correlate well with those obtained with a reference HPLC method. PMID- 20171319 TI - Characterization of exopolysaccharides in marine colloids by capillary electrophoresis with indirect UV detection. AB - A method was established using capillary electrophoresis with indirect UV detection for analysis of monosaccharides liberated from exopolysaccharides by acidic hydrolysis. Tangential flow filtration was used to isolate high molecular weight polysaccharides from seawater. The capillary electrophoresis method included the use of a background electrolyte consisting of 2,6-dimethoxyphenol and cetyltrimethylammonium bromide. Several neutral sugars commonly existing in marine polysaccharides were separated under optimized conditions. The relative standard deviations were between 1.3% and 2.3% for relative migration time and 1.3-2.5% for peak height. Detection limits (at S/N 3) were in the range of 27.2 47.8 microM. The proposed approach was applied to the analysis of hydrolyzed colloidal polysaccharides in seawater collected from the Baltic Sea. Nanomolar levels of liberated monosaccharides in seawater samples can be detected by preconcentration up to 30,000 times. PMID- 20171320 TI - A simple method for preparation of macroporous polydimethylsiloxane membrane for microfluidic chip-based isoelectric focusing applications. AB - A new, simple method was reported to prepare PDMS membranes with micrometer size pores for microfluidic chip applications. The pores were formed by adding polystyrene and toluene into PDMS prepolymer solution prior to spin-coating and curing. The resulting PDMS membrane has a thickness of around 10 microm and macropores with a diameter ranging from 1 to 2 microm measured using scanning electron microscope (SEM) imaging. This PDMS membrane was validated by integrating it with PDMS microfluidic chips for protein separation using isoelectric focusing mechanism coupled with whole channel imaging detection (IEF WCID). It has been shown that five standard pI markers and a mixture of two proteins, myoglobin and beta-lactoglobulin, can be separated using these chips. The results indicated that this macroporous PDMS membrane can replace the dialysis membrane in PDMS chips for the IEF-WCID technique. The preparation method of macroporous PDMS membrane may be potentially applied in other fields of microfluidic chips. PMID- 20171321 TI - Development of a novel fluorescent tag O-2-[aminoethyl]fluorescein for the electrophoretic separation of oligosaccharides. AB - This study describes the development of a novel fluorescent tag, O-2 [aminoethyl]fluorescein, for the separation of sugars by capillary electrophoresis with fluorescence detection using an argon ion laser. The tag was synthesised using three consecutive steps namely: esterification, alkylation and hydrolysis, specifically designed to offer a flexible way in which to make an assortment of fluorescent tags from cheap and readily available starting reagents (typically less than $1 per g of fluorescent tag). Via this flexible synthetic pathway, O-2-[aminoethyl]fluorescein was designed and synthesised with a spacer group to lower steric effects between the fluorescein backbone and the reducing end of the carbohydrate which were anticipated to improve the reactivity of the tag. The newly synthesised tag, O-2-[aminoethyl]fluorescein was evaluated against structurally similar commercial fluorescent motifs namely fluorescent 5 aminomethylfluorescein and non-fluorescent 5-aminofluorescein. Kinetic studies indicated that O-2-[aminoethyl]fluorescein showed similar labeling efficiencies as 5-aminomethylfluorescein, but were achieved in only 30 min, supporting the notion of improved reactivity of the spacer group. The sensitivity of O-2 [aminoethyl]fluorescein was evaluated using maltoheptaose with a detection limit of 1 nM obtained, which was slightly higher than that of 0.3 nM obtained with 5 aminomethylfluorescein, and was due to its lower quantum yield (0.24) when conjugated to the sugar. The separation performance of the tag was also benchmarked with the two commercial reagents using a range of corn syrup oligosaccharides, from 4 to 10 glucose units, typically found in rice starch. Separations were performed using an electrolyte containing 100 mM boric acid, tris at pH 8.65 as background electrolyte, 30 kV applied voltage, 50 microm I.D. x 40 cm (30 cm effective length) capillary. The novel tag showed better resolution of small oligosaccharides, G3 and G4, than the other two reagents, but slightly worse resolution for the longer oligosaccharides, most likely due to the monovalent charge state of the O-2-[aminoethyl]fluorescein compared to the divalent charge of the other two tags. PMID- 20171323 TI - Relations among symptoms of social phobia subtypes, avoidant personality disorder, panic, and depression. AB - This study's primary goal was to examine relations between symptoms of specific social phobia (SSP), generalized social phobia (GSP), avoidant personality disorder (APD), and panic and depression. Past research has suggested a single social phobia continuum in which SSP displays less symptom severity than GSP or APD. We found SSP symptoms correlated less strongly with depression but more strongly with panic relative to both GSP and APD symptoms. These findings challenge a unidimensional model of social phobia, suggesting a multidimensional model may be more appropriate. These findings also inform current research aimed at classifying mood and anxiety disorders more broadly by identifying that the different factors of fear versus distress appear to underlie different subtypes of social phobia. PMID- 20171325 TI - Development of a patient adherence scale for exposure and response prevention therapy. AB - Exposure and response prevention (EX/RP) is an evidence-based treatment for obsessive-compulsive disorder (OCD). For EX/RP to be maximally effective, it is believed that patients must adhere outside of sessions to the procedures they learn in therapy. To date, there is no standard measure of patient EX/RP adherence, despite the importance of accurately assessing EX/RP adherence in both clinical research and practice. This paper describes the development of the Patient EX/RP Adherence Scale (PEAS), which assesses the patient's between session adherence to the therapist's EX/RP instructions, and presents initial data on the scale's reliability and validity. The scale was designed to focus on the key procedures of EX/RP and to be brief enough to be used at each treatment session. The scale demonstrates excellent interrater reliability and good face and content validity. The usefulness of the scale is considered in the context of being an important tool to researchers trying to understand and improve outcomes of EX/RP for OCD as well as to EX/RP therapists in clinical practice. Future research will need to test the scale's reliability and validity in a larger sample of patients over the course of treatment. PMID- 20171324 TI - Expanding the intertrial interval during extinction: response cessation and recovery. AB - We examined trial spacing during extinction following a human contingency learning task. Specifically, we assessed if an expanding retrieval practice schedule (Bjork & Bjork, 1992, 2006), in which the spacing between extinction trials was progressively increased, would result in faster immediate extinction and less recovery from extinction than uniformly spaced extinction trials. We used an ABB vs. ABA renewal design and observed that, whereas the expanding group extinguished faster during extinction treatment, the expanding and constant groups showed the same level of extinction with an immediate test in the extinction context (ABB) and the two groups showed equivalent ABA renewal at test in the training context. We conclude that the faster extinction observed in the expanding groups could be misleading in clinical treatment, if the therapist used the absence of fear during extinction as the basis for terminating treatment. PMID- 20171326 TI - The impact of ruminative processing on the experience of self-referent intrusive memories in dysphoria. AB - The current study sought to experimentally assess the differential effects of analytical ruminative processing and distraction on the experience of self referent naturally occurring intrusive memories in a sample of dysphoric (BDI-II > or = 12) participants. Seventy-seven undergraduate participants completed a memory interview to elicit details about a self-referential intrusion and were randomly assigned to either an analytical rumination or distraction condition. Subsequent to the rumination induction, participants rated their intrusive memory as more negative, more distressing, and more evocative of a negative emotional response compared to participants who were allocated to the distraction induction. Inducing analytical rumination also resulted in participants reporting worse (i.e., more sad) mood relative to those in the distraction condition. The findings align with the suggestion that depressed individuals may get caught up in a ruminative cycle that, due to the documented effects of analytical self focus, exacerbate the emotional response elicited by intrusions and perpetuate biased attentional focus on them. Directions for future investigations of the cognitive processes that are important in the maintenance of intrusions in depressive disorders are discussed. PMID- 20171327 TI - A randomized clinical trial of cognitive-behavioral therapy and applied relaxation for adults with generalized anxiety disorder. AB - This randomized clinical trial compared cognitive-behavioral therapy (CBT), applied relaxation (AR), and wait-list control (WL) in a sample of 65 adults with a primary diagnosis of generalized anxiety disorder (GAD). The CBT condition was based on the intolerance of uncertainty model of GAD, whereas the AR condition was based on general theories of anxiety. Both manualized treatments were administered over 12 weekly 1-hour sessions. Standardized clinician ratings and self-report questionnaires were used to assess GAD and related symptoms at pretest, posttest, and at 6-, 12-, and 24-month follow-ups. At posttest, CBT was clearly superior to WL, AR was marginally superior to WL, and CBT was marginally superior to AR. Over follow-up, CBT and AR were equivalent, but only CBT led to continued improvement. Thus, direct comparisons of CBT and AR indicated that the treatments were comparable; however, comparisons of each treatment with another point of reference (either waiting list or no change over follow-up) provided greater support for the efficacy of CBT than AR. PMID- 20171329 TI - Cognitive bias modification: the critical role of active training in modifying emotional responses. AB - Training participants to select threat or nonthreat interpretations of emotionally ambiguous stimuli or passively exposing them to valenced scenarios can modify later interpretation of ambiguity. However, only when encouraged to actively select meanings do congruent changes in emotional response occur during training itself (Mathews & Mackintosh, 2000). The present study assessed the more critical question of whether active training is also necessary for modifying subsequent emotional responses to images of new ambiguous scenarios presented after training. As predicted, active training did lead participants to rate their images of emotionally ambiguous scenarios as being more unpleasant after training as compared to a matched passive condition. This finding supports the view that active generation of meaning during interpretive training is critical for the modification of later emotional responses. PMID- 20171328 TI - Diagnostic comorbidity in adults with generalized anxiety disorder: impact of comorbidity on psychotherapy outcome and impact of psychotherapy on comorbid diagnoses. AB - The current study examined the impact of comorbidity on cognitive and behavioral therapies for generalized anxiety disorder (GAD) as well as the impact of these therapies on diagnoses comorbid to GAD. Seventy-six treatment-seeking adults with principal diagnoses of GAD received 14 sessions of therapy. Most (n=46; 60.5%) of the sample had at least one comorbid diagnosis. Although the presence of comorbid diagnoses was associated with greater severity of GAD symptoms at pretreatment, greater severity of comorbid major depression, simple phobia, and social phobia was associated with greater change in symptoms of GAD in response to treatment, with no effect on maintenance of gains during a 2-year follow-up. Further, psychotherapy for principal GAD led to a reduction in number of comorbid diagnoses and in severity of social phobia, simple phobia, and major depression at posttreatment. At 2-year follow-up severity of social and simple phobia remained below pretreatment levels, whereas severity of depression was no longer significantly below pretreatment levels. These results suggest that although people with comorbid disorders enter treatment with more severe GAD symptomatology, they demonstrate greater change, and therefore such comorbidity does not diminish the efficacy of cognitive and behavioral therapies for GAD. In addition, the impact of these treatments for GAD may generalize to reduced severity of simple phobia, social phobia, and major depression; however, gains in severity of major depression are not maintained. PMID- 20171330 TI - Parent-child interactions among low-income Mexican American parents and preschoolers: do clinic-referred families differ from nonreferred families? AB - This study compared low-income Mexican American parents of young children referred for behavior problems to their nonreferred counterparts on an observational measure of parent-child interactions. Referred Mexican American parents demonstrated more negative behaviors than their nonreferred counterparts in both nondirective and highly directive situations. However, no differences were found at moderate levels of directiveness. The most and least directive situations in the Dyadic Parent-Child Interaction Coding System best differentiated referred from nonreferred Mexican American families, and families differed more in their negative behaviors than positive behaviors. Many of the parenting behaviors that have been found to differ between referred and nonreferred Caucasian families were also observed to differ between their Mexican American counterparts. PMID- 20171331 TI - Fear and loathing: a meta-analytic review of the specificity of anger in PTSD. AB - The available empirical literature suggests that anger may be characteristic of posttraumatic stress disorder (PTSD). Meta-analytic strategies were used to evaluate the extent to which the experience of anger is specific to PTSD rather than anxiety disorders in general. Thirty-four anxiety disorder patient samples (n=2,169) from 28 separate studies were included in the analysis. Results yielded a large effect size indicating greater anger difficulties among anxiety disorder patients versus controls. Compared to control samples, a diagnosis of PTSD was associated with significantly greater difficulties with anger than was any other anxiety disorder diagnosis. Other anxiety disorder diagnoses did not differ significantly from each other. However, the specific association between PTSD and anger did vary depending on the anger domain assessed. Difficulties with anger control, anger in, and anger out significantly differentiated PTSD from non-PTSD anxiety disorder samples, whereas difficulties with anger expression, state anger, and trait anger did not. These findings are discussed in the context of future research on the role of anger in PTSD. PMID- 20171332 TI - Outcome from a randomized controlled trial of group therapy for binge eating disorder: comparing dialectical behavior therapy adapted for binge eating to an active comparison group therapy. AB - Dialectical Behavior Therapy for Binge Eating Disorder (DBT-BED) aims to reduce binge eating by improving adaptive emotion-regulation skills. Preliminary findings have been promising but have only compared DBT-BED to a wait-list. To control for the hypothesized specific effects of DBT-BED, the present study compared DBT-BED to an active comparison group therapy (ACGT). Men and women (n=101) meeting DSM-IV BED research criteria were randomly assigned to 20 group sessions of DBT-BED (n=50) or ACGT (n=51). DBT-BED had a significantly lower dropout rate (4%) than ACGT (33.3%). Linear Mixed Models revealed that posttreatment binge abstinence and reductions in binge frequency were achieved more quickly for DBT-BED than for ACGT (posttreatment abstinence rate=64% for DBT BED vs. 36% for ACGT) though differences did not persist over the 3-, 6-, and 12 month follow-up assessments (e.g., 12-month follow-up abstinence rate=64% for DBT BED vs. 56% for ACGT). Secondary outcome measures revealed no sustained impact on emotion regulation. Although both DBT-BED and ACGT reduced binge eating, DBT-BED showed significantly fewer dropouts and greater initial efficacy (e.g., at posttreatment) than ACGT. The lack of differential findings over follow-up suggests that the hypothesized specific effects of DBT-BED do not show long-term impact beyond those attributable to nonspecific common therapeutic factors. PMID- 20171336 TI - Letter from the editor: food for thought. PMID- 20171333 TI - Development and validation of a child version of the obsessive compulsive inventory. AB - Surprisingly, only 3 self-report measures that directly assess pediatric obsessive-compulsive disorder (OCD) have been developed. In addition, these scales have typically been developed in small samples and fail to provide a quick assessment of symptoms across multiple domains. Therefore, the current paper presents initial psychometric data for a quick assessment of pediatric OCD across multiple symptom domains, a child version of the Obsessive Compulsive Inventory (the OCI-CV). Data from a sample of over 100 youth ages 7 to 17 with a primary DSM-IV diagnosis of OCD support the use of the 21-item OCI-CV. Results support the use of the OCI-CV as a general index of OCD symptom severity and in 6 symptom domains parallel to those assessed by the revised adult version of the scale (OCI R). The OCI-CV showed strong retest reliability after approximately 1.5 weeks in a subsample of 64 participants and was significantly correlated with clinician rated OCD symptom severity and parent and child reports of dysfunction related to OCD. Significantly stronger correlations with self-reported anxiety than with depressive symptoms provide initial support for the divergent validity of the measure. Finally, preliminary data with 88 treatment completers suggest that the OCI-CV is sensitive to change. PMID- 20171334 TI - Specific phobia in youth: phenomenology and psychological characteristics. AB - Sociodemographic and psychological characteristics of 62 youth with animal and natural environment types of specific phobia were examined in a treatment-seeking sample. Differences due to age, sex, ethnicity, family structure, and family socioeconomic status were not found between youth with the two types of specific phobia. Moreover, differences were not obtained between the two groups in the clinical severity of their phobias, the perceived dangerousness of the feared outcomes associated with their phobias, the perceived levels of coping with their phobias, or overall fearfulness. However, differences between youth with the two types of specific phobias were found on somatic/anxious symptoms, depressive symptoms, and life satisfaction. In addition, differences were noted on withdrawn, somatic complaints, anxious/depressed symptoms, and social problems as reported by the mothers of these youngsters. Finally, differences in the percent of co-occurring anxiety disorders between youth with the two types of specific phobia were found. On all of the domains in which differences were found, youth with the natural environment type fared more poorly than those with the animal type. These findings converge with those obtained in treatment studies which indicate that youth with the natural environment type are more difficult to treat than youth with the animal type. PMID- 20171337 TI - Letter from the guest editor. PMID- 20171338 TI - Case of the season: acquired cholesteatoma. PMID- 20171339 TI - Imaging of head trauma. PMID- 20171340 TI - Imaging of infections of the brain and meninges. PMID- 20171341 TI - Imaging of common adult and pediatric primary brain tumors. PMID- 20171342 TI - Applications of computed tomography angiography (CTA) in neuroimaging. PMID- 20171343 TI - Computed tomography perfusion: acute stroke and beyond. PMID- 20171344 TI - Imaging in neurodegenerative disorders. AB - This article discusses imaging findings of the cortical and subcortical neurodegenerative diseases. Spinocerebellar ataxia and neurodegenerative diseases secondary to vascular insults (multiinfarction dementia, Binswanger's disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and amyloid angiopathy) are beyond the scope of this discussion. PMID- 20171345 TI - Advanced magnetic resonance techniques in neuroimaging: diffusion, spectroscopy, and perfusion. PMID- 20171346 TI - Functional magnetic resonance imaging. PMID- 20171347 TI - Transport and fate of colloids and microbes in granular aqueous environments. PMID- 20171348 TI - Thrombosis Research--affiliation with the European Thrombosis Research Organization (ETRO). PMID- 20171349 TI - Abstracts of the 41st Annual Meeting on Women's Cancer of the Society of Gynecologic Oncologists. March 10-17, 2010. San Francisco, California, USA. PMID- 20171350 TI - Comparative evaluation of effect of preoperative oral medication of ibuprofen and ketorolac on anesthetic efficacy of inferior alveolar nerve block with lidocaine in patients with irreversible pulpitis: a prospective, double-blind, randomized clinical trial. AB - INTRODUCTION: Anesthetic efficacy of inferior alveolar nerve block decreases in patients with irreversible pulpitis. It was hypothesized that premedication with nonsteroidal anti-inflammatory drugs might improve the success rates in patients with inflamed pulps. METHODS: Sixty-nine adult volunteers who were actively experiencing pain participated in this prospective, randomized, double-blind study. The patients were divided into 3 groups on a random basis and were randomly given 1 of the 3 drugs including ibuprofen, ketorolac, and placebo 1 hour before anesthesia. All patients received standard inferior alveolar nerve block of 2% lidocaine with 1:200,000 epinephrine. Endodontic access preparation was initiated after 15 minutes of initial inferior alveolar nerve block. Pain during treatment was recorded by using a Heft Parker visual analog scale. Success was recorded as none or mild pain. RESULTS: Statistical analysis with nonparametric chi2 tests showed that placebo gave 29% success rate. Premedication with ibuprofen gave 27%, and premedication with ketorolac gave 39% success rate. There was no significant difference between the 3 groups. CONCLUSIONS: Preoperative administration of ibuprofen or ketorolac has no significant effect on success rate of inferior alveolar nerve block in patients with irreversible pulpitis. PMID- 20171351 TI - Effect of preoperative ibuprofen on the success of the inferior alveolar nerve block in patients with irreversible pulpitis. AB - INTRODUCTION: The purpose of this prospective, randomized, double-blind, placebo controlled study was to determine the effect of the administration of preoperative ibuprofen on the success of the inferior alveolar nerve block (IAN) in patients with irreversible pulpitis. METHODS: One hundred endodontic emergency patients diagnosed with irreversible pulpitis of a mandibular posterior tooth randomly received, in a double-blind manner, identical capsules of either 800 mg ibuprofen or placebo 45 minutes before the administration of a conventional IAN block. Access was begun 15 minutes after completion of the IAN block, and all patients had profound lip numbness. Success was defined as no or mild pain (visual analogue scale recordings) on access or initial instrumentation. RESULTS AND CONCLUSIONS: The success rate for the IAN block was 41% with ibuprofen and 35% with placebo, with no significant difference (P=.57) between the 2 groups. For mandibular posterior teeth, a dose of 800 mg of ibuprofen given 45 minutes before the administration of the IAN block did not result in a statistically significant increase in anesthetic success in patients with irreversible pulpitis. PMID- 20171352 TI - Critical review on methacrylate resin-based root canal sealers. AB - INTRODUCTION: Four generations of methacrylate resin-based sealers have been available commercially. Three of these were introduced during the last 5 years when the concept of simultaneous bonding of root canal sealers to root filling materials and dentin was popularized. METHODS: This article presents an overview of methacrylate resin-based sealers, with the objectives of clarifying the behavior of these materials and delineating their limitations in clinical application. RESULTS: The first generation sealer was introduced in the mid 1970s. The initial enthusiasm associated with its use eventually diminished as a result of its suboptimal physical, biologic, and clinical properties. With advances in self-etching adhesive technology acquired from adhesive dentistry, methacrylate resin-based sealers were reintroduced in the beginning of the 21st century to support the introduction of bondable root canal filling materials. Three different generations of these sealers have since been available commercially. Although some in vitro studies on the sealing ability, self-etching potential, biocompatibility, and removability of the sealers showed better potential over conventional nonbonding sealers, accomplishing the ideal goal of a monoblock in the root canal space with these materials is still regarded as a major challenge. CONCLUSIONS: On the basis of the in vitro and in vivo data available to date, there appears to be no clear benefit with the use of methacrylate resin-based sealers in conjunction with adhesive root filling materials at this point in their development. PMID- 20171353 TI - Mineral trioxide aggregate: a comprehensive literature review--Part III: Clinical applications, drawbacks, and mechanism of action. AB - INTRODUCTION: Mineral trioxide aggregate (MTA) has been recommended for various uses in endodontics. Two previous publications provided a comprehensive list of articles from November 1993-September 2009 regarding the chemical and physical properties, sealing ability, antibacterial activity, leakage, and biocompatibility of MTA. The purpose of Part III of this literature review is to present a comprehensive list of articles regarding animal studies, clinical applications, drawbacks, and mechanism of action of MTA. METHODS: A review of the literature was performed by using electronic and hand-searching methods for the clinical applications of MTA in experimental animals and humans as well as its drawbacks and mechanism of action from November 1993-September 2009. RESULTS: MTA is a promising material for root-end filling, perforation repair, vital pulp therapy, and apical barrier formation for teeth with necrotic pulps and open apexes. Despite the presence of numerous case reports and case series regarding these applications, there are few designed research studies regarding clinical applications of this material. MTA has some known drawbacks such as a long setting time, high cost, and potential of discoloration. Hydroxyapatite crystals form over MTA when it comes in contact with tissue synthetic fluid. This can act as a nidus for the formation of calcified structures after the use of this material in endodontic treatments. CONCLUSIONS: On the basis of available information, it appears that MTA is the material of choice for some clinical applications. More clinical studies are needed to confirm its efficacy compared with other materials. PMID- 20171354 TI - Comparison of classic endodontic techniques versus contemporary techniques on endodontic treatment success. AB - INTRODUCTION: Many recent technological advancements have been made in the field of endodontics; however, comparatively few studies have evaluated their impact on tooth survival. This study compared the survival rates of endodontic treatment performed by using classic techniques (eg, instrumentation with stainless steel hand files, alternating 5.25% NaOCl and 3% H2O2 irrigation, mostly multiple treatment visits, and so on) versus those performed using more contemporary techniques (eg, instrumentation with hand and rotary nickel-titanium files, frequent single-visit treatment, NaOCl, EDTA, chlorhexidine, H2O2 irrigation, warm vertical or lateral condensation obturation, use of surgical microscopes, electronic apex locators, and so on). METHODS: Using a retrospective chart review, clinical data were obtained for 984 endodontically treated teeth in 857 patients. Survival was defined as radiographic evidence of the treated tooth being present in the oral cavity 12 months or more after initial treatment. A mixed-model Poisson regression analysis was used to compare failure rates. RESULTS: Of the 459 teeth in the classic group, there was an overall survival rate of 98% with an average follow-up time of 75.7 months. Of 525 teeth in the contemporary group, there was an overall survival rate of 96%, with an average follow-up time of 34 months. Considerably more treatments in the classic group were completed in multiple appointments (91%) than in the contemporary group (39%). More teeth in the classic group underwent posttreatment interventions (6.7% vs 0.9%, respectively). CONCLUSIONS: No statistically significant difference was noted between the two technique groups or between single or multiple visits in terms of survival. PMID- 20171355 TI - Pulpal blood flow measurement with ultrasound Doppler imaging. AB - INTRODUCTION: This study compared the difference in pulpal blood flow between vital and root-filled teeth by using ultrasound Doppler imaging. METHODS: To compare the difference in pulpal blood flow between vital and root-filled teeth, 11 patients (mean age, 32.06 years; 3 male, 8 female) who had undergone root canal treatment on the anterior tooth of the maxilla or mandible and had a vital contralateral tooth were examined. Pulpal blood flow measurements were performed on the vital and root canal-treated teeth by using ultrasound Doppler imaging. The parameters examined were the maximum linear velocity (Vas), average linear velocity (Vam), minimum linear velocity (Vakd), pulsation index (PI), and circulation resistance (RI), which are indicators of the pulpal blood flow. The differences between the vital and root-filled teeth were examined by using a paired t test at the 95% confidence interval. RESULTS: There were significant differences in the Vas, Vam, Vakd, and RI between the vital and root-filled teeth (P<.05). With the root-filled teeth, ultrasound Doppler imaging revealed a linear and nonpulsed waveform, whereas the vital teeth showed a pulsed waveform that is characteristic of an arteriole. CONCLUSIONS: Ultrasound Doppler imaging can detect pulpal blood flow in vital tooth through indicators such as Vas, Vam, Vakd, PI, and RI. PMID- 20171356 TI - Evaluation of pathologists (histopathology) and radiologists (cone beam computed tomography) differentiating radicular cysts from granulomas. AB - INTRODUCTION: This study investigated the differentiation of radicular cysts from granulomas. Cone beam computed tomography (CBCT) imaging was compared with the existing standard, biopsy and histopathology. METHODS: Forty-five patients scheduled for an apicoectomy received a CBCT scan of the involved arch. Two oral and maxillofacial radiologists, working independently and using the same criteria, categorized the CBCT images as one of the following: cyst, likely cyst, likely granuloma, granuloma, or other. After apicoectomies, two oral pathologists, working independently and using the same criteria, diagnosed the surgical specimens as one of the following: radicular cyst, granuloma, or other. We examined the following: (1) interrater agreement between pathologists as to the biopsy diagnosis, (2) interrater agreement between radiologists as to the CBCT diagnosis, and (3) accuracy of radiologists' diagnostic assessments using histopathology as the standard. RESULTS: Findings showed strong interrater reliability between pathologists (kappa=0.79, z=5.46, p<0.0001) and weak interrater reliability between radiologists (kappa=0.14, p=not significant). Accuracy (true-positives plus true-negatives) for the two radiologists was 51% and 63%. CONCLUSION: Under the conditions of this study, based on the inconsistency of the radiologists' reports as evidenced by statistical analyses, it was concluded that CBCT imaging is not a reliable diagnostic method for differentiating radicular cysts from granulomas. Surgical biopsy and histopathological evaluation remain the standard procedure for differentiating radicular cysts from granulomas. PMID- 20171357 TI - A prospective, randomized single-blind study of the anesthetic efficacy of the inferior alveolar nerve block administered with a peripheral nerve stimulator. AB - INTRODUCTION: The purpose of this prospective, randomized single-blind study was to compare the degree of pulpal anesthesia obtained with the inferior alveolar nerve (IAN) block administered by using a peripheral nerve stimulator compared with a conventional IAN block by using a cartridge of 2% lidocaine with 1:100,000 epinephrine. METHODS: Forty-six adult volunteers randomly received a conventional IAN block or an IAN block administered with a peripheral nerve stimulator at 2 separate appointments. An electric pulp tester was used to test for anesthesia of the first molar, first premolar, and lateral incisor in 4-minute cycles for 60 minutes. Anesthesia was considered successful when 2 consecutive 80 readings were obtained within 15 minutes, and the 80 reading was continuously sustained through the 60th minute. RESULTS: With the peripheral nerve stimulator for the IAN block, successful pulpal anesthesia ranged from 32%-37%. For the conventional IAN block, successful pulpal anesthesia ranged from 32%-45%. There was no significant difference between the 2 IAN block techniques. CONCLUSIONS: We concluded that the IAN block administered with a peripheral nerve stimulator did not increase the success rate of pulpal anesthesia when compared with a conventional IAN block. PMID- 20171358 TI - Predicting the anatomical position of the palatal root apex in maxillary first premolars during surgical endodontic treatment. AB - INTRODUCTION: Although many studies have reported on the morphology of maxillary first premolars, to our knowledge, there has never been an investigation reporting the anatomic position of the palatal (P) root tip relative to the B root tip in mesiodistal (MD), buccopalatal (BP), and apicocoronal (AC) dimensions. Such information could help clinicians more accurately locate root apices, reduce surgical morbidity, and improve the precision and prognosis of endodontic periradicular surgery for this tooth. METHODS: Fifty extracted, bifurcated, human maxillary first premolars were individually mounted and photographed under 10x magnification and oriented to simulate a clinical view. RESULTS: The P apex was superimposed by the B apex in 25 of 50 specimens, distal to the B apex in 24 of 50, and mesial to the B apex in only 1 instance. When not superimposed by or mesial to the B apex, the P apex was usually 1.4+/-0.7 mm distal to the B apex. In 98% of specimens, the P apex was positioned palatocoronal or palatocoronodistal to the B apex. CONCLUSIONS: This knowledge can be used to clinically minimize the size of osteotomies required to locate P root apices during endodontic surgery. PMID- 20171359 TI - Anesthetic efficacy of articaine and lidocaine for incisive/mental nerve block. AB - INTRODUCTION: The incisive/mental nerve block (IMNB) could be an alternative to the inferior alveolar nerve block in the mandibular anterior teeth. The effectiveness of articaine has not been tested in IMNB. METHODS: This prospective randomized double-blind crossover study compared the anesthetic efficacy of 0.6 mL 4% articaine and 2% lidocaine, both with 1:100.000 epinephrine administered as IMNB to 40 volunteers in two sessions. Pulpal anesthesia of lateral incisor through premolars was tested with an electric pulp tester. The injection and postoperative pain were evaluated by using visual analog scales. The onset (time from the end of injection to the absence of pulpal response) and duration of pulpal anesthesia (time recorded before two positive responses to the pulp tester) and the anesthesia success (two consecutive readings of 80 without response and onset0.05). CONCLUSIONS: Articaine promoted higher anesthesia success and longer duration of anesthesia than lidocaine for most of the teeth after IMNB although anesthesia success could be considered clinically appropriated only for premolars. The volume of local anesthetic used in the present study may not be appropriate for procedures lasting longer than 10 minutes. PMID- 20171360 TI - Fracture necrosis: diagnosis, prognosis assessment, and treatment recommendations. AB - INTRODUCTION: The presence of cracks and fractures in teeth can pose difficulties in diagnosis, prognosis assessment, and treatment recommendations. When a tooth has no significant restorations or caries, whereby the pulp is nonvital in the absence of a luxation injury, it is suggested that this necrosis is likely caused by a significant longitudinal crack that extends from the occlusal surface and into the pulp. This type of presentation has been termed "fracture necrosis." METHODS: Twenty-seven teeth with nonvital pulps were evaluated that had no restorations or minimally deep restorations and no signs of caries. These teeth were extracted and evaluated as to the depth and location of any potential fracture. RESULTS: All evaluated teeth were found to have cracks that extended from the occlusal surface into the pulp and progressed to an external root surface. CONCLUSION: Pulp necrosis, in the absence of restorations, caries, or luxation injuries, is likely caused by a longitudinal fracture extending from the occlusal surface and into the pulp. Based on the available literature, these types of teeth may have a poor prognosis after endodontic treatment, with the potential ramification of extensive periodontal and/or periapical bone loss. Extraction may be considered as the primary treatment option. PMID- 20171361 TI - Simvastatin promotes odontoblastic differentiation and expression of angiogenic factors via heme oxygenase-1 in primary cultured human dental pulp cells. AB - INTRODUCTION: Although simvastatin has multiple demonstrable effects, its function in dentinogenesis remains unclear. In this study, we tested the hypothesis that the addition of simvastatin to human dental pulp cells (HDPCs) stimulates odontogenesis both by promoting odontoblastic differentiation and by favoring the release of angiogenic factors. In addition, the role of heme oxygenase-1 (HO-1) in these effects was investigated. METHODS: The expression of markers for odontoblastic differentiation and angiogenesis was analyzed by means of alkaline phosphatase (ALP) activity, alizarin red staining, and Western blotting. RESULTS: Simvastatin enhanced the differentiation of HDPCs by up regulating mineralization nodules and odontogenic markers as well as angiogenic markers. These phenomena were then correlated with the induction of HO-1 protein levels. The inducing effect of simvastatin on odontoblastic differentiation and angiogenesis was nullified by an HO-1 inhibitor and a carbon monoxide (CO) scavenger. CONCLUSIONS: These results suggested that simvastatin exerts its odontoblastic differentiation and angiogenesis-inducing effects in HDPCs through a mechanism that involves the action of HO-1 and its product CO. PMID- 20171362 TI - Side population increase after simulated transient ischemia in human dental pulp cell. AB - INTRODUCTION: Dental pulp is often exposed to ischemia in case of injury or inflammation because of narrow vascular openings at the apex and poor blood circulation in dental pulp tissue. Resident stem cell populations are thought to contribute to the postischemic regeneration process. The aim of this study was to investigate the influence of simulated ischemia (serum deprivation and hypoxia) on side population (SP) stem cells of human dental pulp cells in order to provide a better understanding of the postischemic tissue repair and regeneration process. METHODS: The proliferation of dental pulp cells (DPCs) after exposure to ischemic culture conditions (2% O2, 2% serum) for 24 hours and 48 hours was investigated by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. The SP fraction was detected by Hoechst 33342 fluorescence flow cytometry, and the expression of SP marker ABCG2 was investigated by immunofluorescence. ABCG2 and OCT4 messenger RNA levels before and after transient ischemia were determined by real-time polymerase chain reaction. RESULTS: Proliferation rate of DPCs was lower in 24- and 48-hour ischemic groups than control from day 5 to day 7. SP proportion was significantly higher 24 and 48 hours after simulated ischemic treatment, and immunofluorescence staining of ABCG2 also verified the increasing trend of side population. ABCG2 and OCT4 messenger RNA levels increased more than three folds in 48 hours ischemic group compared with control group. CONCLUSIONS: Side population in dental pulp cells increase notably after transient simulated ischemic culture, suggesting that SP may participate in post ischemic repair and regeneration process of dental pulp. PMID- 20171363 TI - Artificial dental pulp exposure injury up-regulates antigen-presenting cell related molecules in rat central nervous system. AB - INTRODUCTION: Bacterial infection and resulting inflammation of the dental pulp might not only trigger neuroimmune interactions in this tissue but also sensitize the central nervous system (CNS) such as the thalamus via nociceptive neurons. Thus, immunopathologic changes in the rat thalamus that take place after pulp inflammation were investigated. METHODS: Pulp exposure was made in mandibular right first molars of 5-week-old Wistar rats. After 24 hours, the thalamus was retrieved and subjected to either immunohistochemistry for class II major histocompatibility complex (MHC) molecules and glial fibrillary acidic protein (GFAP) or mRNA expression analysis of antigen-presenting cell-related molecules and N-methyl-D-aspartate receptor 2D subunit (NR2D) by means of reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR. RESULTS: At 24 hours after pulp exposure, the density of class II MHC molecule-expressing and GFAP-expressing cells was increased in the contralateral thalamus. Gene expression analysis revealed the up-regulation of class II MHC molecules, CD80, CD83, CD86, and NR2D in the contralateral thalamus, as compared with the ipsilateral thalamus. CONCLUSIONS: These results suggest the signal of pulp inflammation induces neuronal activation in the CNS. PMID- 20171364 TI - Expression of the inflammatory marker cyclooxygenase-2 in dental pulp cells cultured with mineral trioxide aggregate or calcium silicate cements. AB - INTRODUCTION: Mineral trioxide aggregate (MTA) and calcium silicate (CS) cements exhibit acceptable physical and chemical properties. The aim of the present study was to evaluate the effects of MTA and CS cements on inflammatory reactions in primary cultured human dental pulp cells. METHODS: The mitochondrial colorimetric assay was used to evaluate pulp cell survival rates. Fluorescent immunohistochemistry was used to observe focal adhesion kinase (FAK) and cyclooxygenase-2 (COX-2) distributions in the cells. Reverse transcription polymerase chain reaction was used to assess COX-2 expression. RESULTS: The results showed that MTA and CS are biocompatible with pulp cells (P>.05). FAK was well-distributed in pulp cells in contact with both cements. Both MTA and CS cements induced pulp cell inflammation as evidenced by increased COX-2 expression. CONCLUSIONS: The present study demonstrated that MTA and CS cements are biocompatible with primary cultured pulp cells. Both cements can induce inflammatory COX-2 expression in the pulp cells. PMID- 20171365 TI - Deciduous and permanent dental pulp mesenchymal cells acquire hepatic morphologic and functional features in vitro. AB - INTRODUCTION: Mesenchymal stem cells display extensive proliferative capacity of multilineage differentiation. The stromal compartment of mesenchymal tissues is considered to harbor stem cells. We assessed the endodermal differentiation of mesenchymal cells from deciduous and wisdom tooth pulp. METHODS: Dental mesenchymal cells were isolated and expanded in vitro. After cell cultures had been established, cells were characterized using known stem cell markers. For hepatic differentiation the media was supplemented with hepatic growth factor, dexamethasone, Insulin-Transferrin-Selenium-X, and oncostatin. RESULTS: Both cultures showed a number of cells positive for specific hepatic markers including alpha-fetoprotein, albumin, and hepatic nuclear factor 4alpha after differentiation. Also, small clusters of cells positive for insulin-like growth factor 1 were found. The concentration of urea increased significantly in the media. Moreover, a significant amount of glycogen was found in the cells. CONCLUSION: Because the cells proved to produce specific hepatic proteins and to start functions specific for hepatocytes, such as storing glycogen and urea production, we may state that the mesenchymal cell cultures from wisdom and deciduous tooth pulp acquired morphologic and functional characteristics of hepatocytes. PMID- 20171366 TI - Cysteine cathepsins in human dentin-pulp complex. AB - INTRODUCTION: Collagen-degrading matrix metalloproteinases (MMPs) are expressed by odontoblasts and present in dentin. We hypothesized that odontoblasts express other collagen-degrading enzymes such as cysteine cathepsins, and their activity would be present in dentin, because odontoblasts are known to express at least cathepsin D. Effect of transforming growth factor beta (TGF-beta) on cathepsin expression was also analyzed. METHODS: Human odontoblasts and pulp tissue were cultured with and without TGF-beta, and cathepsin gene expression was analyzed with DNA microarrays. Dentin cathepsin and MMP activities were analyzed by degradation of respective specific fluorogenic substrates. RESULTS: Both odontoblasts and pulp tissue demonstrated a wide range of cysteine cathepsin expression that gave minor responses to TGF-beta. Cathepsin and MMP activities were observed in all dentin samples, with significant negative correlations in their activities with tooth age. CONCLUSIONS: These results demonstrate for the first time the presence of cysteine cathepsins in dentin and suggest their role, along with MMPs, in dentin modification with aging. PMID- 20171367 TI - Periapical repair in dog teeth: root canal adhesive filling by using the Resilon System. AB - INTRODUCTION: New filling biomaterials with better physicochemical properties would create a favorable biologic environment for the healing of periapical tissues. The aim of this study was to evaluate periapical repair after biomechanical preparation and root filling with an adhesive system compared with the gold standard material (gutta-percha+sealer) in dog teeth. METHODS: The pulp of 25 root canals was removed. The apical cementum layer was perforated, and the root canals were prepared up to size #60 K-file followed by step-back shaping with the #90 K-file and filled by the lateral condensation technique. In the experimental group (n=15), the Resilon System (Pentron Clinical Technologies, Wallingford, CT) was used. As a control material (n=10), gutta-percha cones and pulp canal sealer were used. After 60 days, the animals were killed, and 10 histologic parameters were evaluated. Differences among the groups were analyzed by using the Mann-Whitney and Fisher exact tests. RESULTS: In radiographic and histologic evaluations, most fillings were slightly short of the apex. Progressive regenerative stages were observed; however, there was a reduced prevalence of biologic foraminal closure. No significant differences were observed between the 2 biomaterials with regard to any of the parameters evaluated (P>.05). CONCLUSIONS: The Resilon System shows periapical biocompatibility equivalent to the gold standard material. PMID- 20171368 TI - Stability of doxycycline and chlorhexidine absorbed on root canal dentin. AB - INTRODUCTION: The antimicrobial agents chlorhexidine and doxycycline bind to dentin to provide sustained antimicrobial action. This study measured the stability of these chemicals on dentin adjacent to the root canal. METHODS: Extracted human teeth were instrumented and irrigated with either MTAD or Endo CHX. After aging at 37 degrees C, the canals were enlarged by 0.3 mm, dentin debris was collected, and compounds were extracted. The amount of doxycyline or chlorhexidine was measured by using reverse-phase high-performance liquid chromatography. RESULTS: After 1 day of aging, the canals contained 3.4+/-1.3 microg doxycycline or 43+/-20 microg chlorhexidine. The half-lives of doxycycline and chlorhexidine were calculated to be 3.0 weeks and 14 weeks, respectively. Groups monitoring decomposition of dilute doxycycline or chlorhexidine in water had half-lives of 5.8 weeks and 40 weeks, respectively. The half-life of the antimicrobials on dentin is suspected to be largely due to diffusion of the antimicrobials. CONCLUSIONS: Compared with doxycycline, chlorhexidine is more stable on root canal dentin. PMID- 20171369 TI - Push-out bond strength of Resilon/Epiphany self-etch to intraradicular dentin after retreatment: a preliminary study. AB - INTRODUCTION: Retreatment procedures might affect the adhesion capability of refilling materials to dentinal walls. The purpose of this study was to compare the effect of different retreatment techniques on bond strength of Resilon (Resilon Research LLC, Madison, CT)/Epiphany (Pentron Clinical Technologies, LLC, Wallingford, CT) self-etch (SE) with radicular dentin after canal reobturation. METHODS: Sixty extracted single-rooted human teeth were prepared using Mtwo rotary files (VDW, Munich, Germany) and obturated with Resilon/Epiphany SE. The roots were randomly divided into four groups; in group 1, no retreatment procedure was done; group 2 was retreated using Mtwo R/Mtwo files; group 3 was retreated using Mtwo R/Mtwo combined with chloroform; and group 4 was retreated using Mtwo R/Mtwo combined with Endosolv R (Septodont, Paris, France). The root canals were then reobturated with Resilon/Epiphany SE. One-millimeter slices of midroot dentin were prepared for the push-out test (n=30 slices per group). Failure modes after the push-out test were examined under microscopy. The data were analyzed by using a one-way analysis of variance and the Dunnett post hoc test. RESULTS: Group 3 showed significantly the lowest mean bond strength (p<0.02). No significant difference was found between the values of groups 1, 2, and 4 (p>0.26). The mode of bond failure was predominantly adhesive for all groups. CONCLUSIONS: This study showed that the bond strength of Resilon/Epiphany SE after root canal retreatment using Mtwo files, either alone or combined with Endosolv R, was not significantly different from that of nonretreated specimens. Chloroform used for retreatment had an adverse effect on the bond strength of Resilon/Epiphany SE after root canal reobturation. PMID- 20171370 TI - Effects of three canal sealers on bond strength of a fiber post. AB - INTRODUCTION: This study evaluated the effects of three different endodontic sealers on the bond strength of a fiber post cemented with adhesive resin cement. METHODS: Forty-eight extracted maxillary central incisors were prepared with the step-back technique and randomly divided into four groups (n=12 for each group): group 1, control group (gutta-percha points only, no sealer); group 2, resin based sealer (AH plus; Dentsply De Trey GmbH, Konstanz, Germany); group 3, zinc oxide-eugenol-based sealer (Endofill; Produits Dentaires SA, Vevey, Switzerland); and group 4, calcium hydroxide-based sealer (Sealapex; Kerr, Romulus, MI). The roots were obturated with gutta-percha using the cold lateral compaction technique. Fiber posts were cemented into the prepared post spaces with the adhesive resin cement Panavia F 2.0 (Kuraray Medical, Okayama, Japan). A push-out test was performed in a universal machine, and failure modes were observed. Morphologic changes of the root canal dentin surfaces were examined with scanning electron microscopy (SEM). RESULTS: One-way analysis of variance revealed that sealers have significant effects on bond strength (p<0.05). The control group had the highest mean push-out bond strength. No statistical difference was detected between the eugenol-based sealer group and the resin-based sealer group (p>0.05). The root surfaces were covered with the smear layer and debris in all the groups after post space preparation in SEM analysis. However, some of the dentin tubules were partially open in the control and calcium hydroxide-based sealer groups after the application of the resin monomer. CONCLUSION: The results of this study showed that the type of canal sealer and chemomechanical preparation of the root canals affect the bond strength of a fiber post cemented with resin cement. PMID- 20171372 TI - Comparison of the antimicrobial efficacy of irrigation using the EndoVac to endodontic needle delivery. AB - INTRODUCTION: The purpose of this investigation was to compare the antimicrobial efficacy of root canal irrigation with the EndoVac (Discus Dental, Culver City, CA) to endodontic needle irrigation in the apical 5 mm of root canals infected with Enterococcus faecalis. METHODS: Bilaterally matched, extracted human teeth were sterilized and inoculated with E. faecalis. Specimens in the EndoVac group were irrigated using the EndoVac system, whereas those in the needle group were irrigated with a 30-G side-vented needle. After chemomechanical preparation, the apical 5 mm of the roots were removed, frozen in liquid nitrogen, and pulverized to expose E. faecalis in dentinal tubules or other morphologic irregularities. The number of colony forming units (cfus) of E. faecalis per mg dentin was determined. RESULTS: The EndoVac Group had a mean of 31.6 cfu/mg, whereas the needle group had a mean of 157 cfu/mg. This represents a bacterial reduction of 99.7% in group A and 98.8% in group B when compared with positive controls. CONCLUSION: Although there were fewer cfu/mg when using the EndoVac, there was not a statistically significant difference between the EndoVac and needle groups. PMID- 20171371 TI - Hydration characteristics of calcium silicate cements with alternative radiopacifiers used as root-end filling materials. AB - INTRODUCTION: Mineral trioxide aggregate (MTA) is composed of calcium silicate cement and bismuth oxide added for radiopacity. The bismuth oxide in MTA has been reported to have a deleterious effect on the physical and chemical properties of the hydrated material. This study aimed to investigate the hydration mechanism of calcium silicate cement loaded with different radiopacifiers for use as a root end filling material. METHODS: Calcium silicate cement loaded with barium sulfate, gold, or silver/tin alloy was hydrated, and paste microstructure was assessed after 30 days. In addition, atomic ratio plots of Al/Ca versus Si/Ca and S/Ca and Al/Ca were drawn, and X-ray energy dispersive analysis of the hydration products was performed to assess for inclusion of heavy metals. The leachate produced from the cements after storage of the cements in water for 28 days and the leaching of the radiopacifiers in an alkaline solution was assessed by using inductively coupled plasma. RESULTS: The hydrated calcium silicate cement was composed of calcium silicate hydrate, calcium hydroxide, ettringite, and monosulfate. Unhydrated cement particles were few. No heavy metals were detected in the calcium silicate hydrate except for the bismuth in MTA. Calcium was leached out early in large quantities that reduced with time. The barium and bismuth were leached in increasing amounts. Copper was the most soluble in alkaline solution followed by bismuth and barium in smaller amounts. CONCLUSIONS: The bismuth oxide can be replaced by other radiopacifiers that do not affect the hydration mechanism of the resultant material. PMID- 20171373 TI - Influence of final rinse technique on ability of ethylenediaminetetraacetic acid of removing smear layer. AB - INTRODUCTION: There is ongoing debate regarding the ideal sequence, volume, and concentration of irrigants, length of time for irrigation, and irrigation technique to achieve debridement of the root canal system. The aim of this study was to verify the impact of the final rinse technique on smear layer removal ability of 17% ethylenediaminetetraacetic acid (EDTA). METHODS: Sixteen single rooted human teeth were instrumented and divided into 2 groups at the final rinse step according to the following final rinse techniques used: continuous rinse group, continuous rinse with EDTA during 3 minutes, and rinse and soaking group, rinse with 1 mL of EDTA, soaking of the canal for 2 minutes and 30 seconds, and rinse completion with the remaining 4 mL for 30 seconds. The specimens were split lengthwise and observed under scanning electron microscope. RESULTS: Data were analyzed with Kruskal-Wallis and Dunn tests. The continuous rinse group presented more debris-free surfaces when compared with the rinse and soaking group (P<.01). When the root canal areas were compared within the groups, no statistical differences were found (P>.05). CONCLUSIONS: It can be concluded that a continuous rinse with 5 mL of EDTA for 3 minutes can more efficiently remove the smear layer from root canal walls. PMID- 20171375 TI - Minimum contact time and concentration of sodium hypochlorite required to eliminate Enterococcus faecalis. AB - INTRODUCTION: The purpose of this investigation was to determine the concentration of sodium hypochlorite and the irrigation time required to disinfect dentin cylinders infected with Enterococcus faecalis. METHODS: Four hundred fifty dentin cylinders (5 mm in diameter and 4 mm in height) with a lumen (2-3 mm in width) were prepared from freshly extracted bovine incisors. The cementum and predentin were then removed. The tubules were opened by using a 4 minute application with 17% ethylenediaminetetraacetic acid and 5.25% NaOCl and then exposed to E. faecalis (ATCC 4082) for 3 weeks in brain-heart infusion broth. The cylinders were then divided into 3 groups, and a 1.3%, 2.5%, or 5.25% concentration of NaOCl was applied in 5-, 10-, 15-, 20-, 25-, 30-, 35-, and 40 minute intervals for a total of 30 subgroups including positive and negative controls. Each test sample was placed into a tube of 2 mL brain-heart infusion broth and incubated for 72 hours. Absence of turbidity demonstrated no bacterial growth, whereas turbidity indicated presence of remaining viable bacteria. RESULTS: The most effective irrigation regimen was 5.25% at 40 minutes, whereas irrigation with 1.3% and 2.5% NaOCl for this same time interval was ineffective in removing E. faecalis from infected dentin cylinders. CONCLUSIONS: High concentration and long exposure to NaOCl are needed for elimination of E. faecalis contaminated dentin. PMID- 20171374 TI - Evaluation of inflammatory response of EDTA, EDTA-T, and citric acid in animal model. AB - INTRODUCTION: The biocompatibility of chelating agents and organic acids have been explained by a variety of methods, and suggestions for use have been based more on clinical observations and physicochemical properties than on biological aspects. The present study aimed to evaluate the inflammatory response of 17% EDTA, 17% EDTA-T, and 10% citric acid in bony defect created in rat jaws. METHODS: Mandibular through and through critical size defects were created bilaterally in 60 rats. Fibrinol (Baldacchi SA, Sao Paulo, Brazil), a cube-shaped compound of absorbable bovine fibrin foam and sodium chloride, was used as a carrier of the substances. One side had received Fibrinol (control), whereas the opposite side had received Fibrinol soaked with each substance on the 1st, on the 7th, on the 14th, and on the 28th day (n=5 for each day). Hemijaws were prepared for light microscopy, and samples were stained with hematoxylin and eosin. Digitized images were analyzed with a morphometric software (ImageJ; National Institute of Mental Health, Bethesda, MD). to obtain the number of inflammatory cells per area. Comparisons were performed by using the Kruskal-Wallis test (p=0.05). RESULTS: For all days, 10% citric acid and 17% EDTA-T showed, respectively, the lowest and highest number of inflammatory cells per area. All tested substances and controls showed the highest inflammatory cell response on the 14th day. CONCLUSION: Among the tested substances, 10% citric acid proved to be the less aggressive tested solution at 14 days. At 28 days, all solutions were similar, but EDTA-T kept showing the higher number of inflammatory cells. PMID- 20171377 TI - Comparison of the efficiency of four different ultrasonic tips to remove dentin over time. AB - INTRODUCTION: The objective of this study was to compare the efficiency of 4 ultrasonic tips to remove dentin from sectioned third molars. METHODS: The 4 groups (n = 5) were as follows: ET-18D, BUC-1, TUFI-2, and P5. A P5 Newtron XSTM ultrasonic unit was used. A universal tester applied a downward force of 15g, previously determined in a pilot study, in cycles of 20 seconds for a total of 4 minutes of instrumentation time. Efficiency was measured by change in weight of the dentin specimen measured to the nearest 0.01 mg after 2 and 4 minutes of instrumentation. RESULTS: There was no statistically significant difference in dentin removal between measurement times for any tip (P>.05). There was a statistically significant difference in dentin removal as a function of tip type (P=.0001), with the BUC-1 tip removing significantly more dentin across time. CONCLUSIONS: On the basis of the results, the BUC-1TM tip removes dentin more efficiently than the other tips tested. PMID- 20171376 TI - Physical and chemical properties of new-generation endodontic materials. AB - INTRODUCTION: Mineral trioxide aggregate (MTA), white and gray, has many uses in endodontic therapy but is limited by its difficult handling characteristics. This study compared the physical and chemical properties of white MTA (WMTA) with three experimental root-end filling materials: Capasio (Primus Consulting, Bradenton, FL), Ceramicrete-D (Tulsa Dental Specialties/Argonne National Laboratory, Argonne, IL), and Generex-A (Dentsply Tulsa Dental Specialties, Tulsa, OK). METHODS: The setting time and radiopacity were tested using International Organization for Standardization (ISO) 6876 methods. Compressive strength was measured following the ISO 9917 method. The pH of the materials was measured after mixing. A novel test was developed for washout resistance of the materials immediately after placement. Data were compared by analysis of variance and Sidak post hoc analysis (p<0.05) for compressive strength and washout resistance. RESULTS: The setting time of Generex-A was half that of WMTA. All materials met the ISO 6876 requirements for radiopacity. The compressive strengths after 7 days decreased in this order: Generex A>Capasio>WMTA>Ceramicrete-D. The initial pH of Capasio and Generex-A were alkaline, similar to WMTA, whereas that of Ceramicrete-D was acidic. Significantly, alternative materials remained in situ after the washout test, whereas WMTA was displaced from the retropreparations. CONCLUSIONS: The clinical handling and washout resistance of the alternative materials were far superior to WMTA. The radiopacity, compressive strength, and washout resistance make Generex A and Capasio materials suitable for further study. Ceramicrete-D was weaker, less radiopaque, and initially acidic. PMID- 20171378 TI - Comparison of three techniques for preparing oval-shaped root canals. AB - INTRODUCTION: This study compared three techniques for preparing oval-shaped root canals: Anatomic Endodontic Technology (AET), hand instruments (Hedstrom files; Dentsply Maillefer, Ballaigues, Switzerland), and rotary nickel-titanium (EndoWave; Morita, Osaka, Japan) instruments with regard to cleaning ability and final canal shape. METHODS: Three groups each of 13 extracted human mandibular premolars with oval-shaped canals were used. After canal preparation, teeth were sectioned at three levels (coronal, middle, and apical), photographed to assess cross-sectional canal shape, and processed for histologic evaluation of canal wall planing and the presence of debris. RESULTS: None of the techniques resulted in completely prepared and cleaned canals. No significant difference was found among the three techniques with regard to untouched surface, cross-sectional area, remaining fins, and canal shape at the three levels. Rotary NiTi instruments resulted in significantly less debris in the apical third compared with AET and hand instrumentation. CONCLUSIONS: AET did not perform better than rotary NiTi or hand instruments in oval-shaped canals. PMID- 20171379 TI - Challenges in regenerative endodontics: a case series. AB - INTRODUCTION: An immature tooth with pulpal necrosis and apical periodontitis presents a unique challenge to the endodontist. Endodontic treatment options consist of apexification, apical barriers, or more recently, revascularization. The purpose of this case series is to report three cases that used revascularization protocol as described by Banchs and Trope. Each case presented its own special circumstances and challenges. The lessons learned from each case provided guidance for more predictable outcomes on subsequent cases. METHODS: Six immature teeth with apical periodontitis (in three patients) were treated via the revascularization protocol using irrigants, a triple antibiotic paste, and a coronal seal of mineral trioxide aggregate and composite. RESULTS: For follow-up, all six teeth showed resolution of periapical radiolucencies, whereas three of six teeth showed continued root development. Two teeth displayed a positive response to vitality testing. CONCLUSIONS: Results from this case series show that revascularization is a technically challenging but effective treatment modality for the immature tooth with apical periodontitis. Based on this case series, the following recommendations are made to help with the revascularization technique: (1) clinicians should consider the use of an anesthetic without a vasoconstrictor when trying to induce bleeding, (2) a collagen matrix is useful for the controlled placement of MTA to a desired and optimal level, (3) patients/parents should be informed about the potential for staining, especially in anterior teeth when the paste contains minocycline, and (4) patient/parent compliance with the necessary multiple appointment treatment plan may be significant for case selection. PMID- 20171380 TI - Identification of independent middle mesial canal in mandibular first molar using cone-beam computed tomography imaging. AB - INTRODUCTION: The root canal treatment of a mandibular molar with aberrant canal configuration can be diagnostically and technically challenging. METHODS: This case report presents the clinical management of a mandibular first molar with three separate mesial canals including middle mesial canal, which was confirmed by cone-beam computed tomography (CBCT) images. RESULTS: Posttreatment images revealed three independent root canals in the mesial root obturated efficiently to the accepted lengths in all three canals. CONCLUSION: This case report highlights the usefulness of CBCT imaging for accurate diagnosis and management of the unusual canal morphology. PMID- 20171381 TI - Ossifying fibroma misdiagnosed as chronic apical periodontitis. AB - INTRODUCTION: Ossifying fibroma mimicking chronic apical periodontitis is extremely rare. This report describes a case of ossifying fibroma located in the periapical region of the mandibular right canine that was misdiagnosed as chronic apical periodontitis. METHODS: A 40-year-old woman complained of slight pain in the right anterior mandibular region without mucosal abnormalities or swelling. Radiographically, a well-circumscribed, unilocular, radiolucent lesion was observed that was located in the periapical region of the mandibular right canine, which presented an endodontically treated root canal. Under local anesthesia, the lesion was fully excised. RESULTS: Microscopically, there was fibrocellular connective tissue associated with a mineralized component, which consisted of lamellar or trabecular and woven bone, compatible with the diagnosis of ossifying fibroma. CONCLUSIONS: Although it is very rare, ossifying fibroma should be considered in the differential diagnosis of unusual or persistent apical radiolucencies. PMID- 20171382 TI - Childhood obesity: affecting choices. PMID- 20171383 TI - Bodies revealed, but whose? PMID- 20171384 TI - Advising the UK Government. PMID- 20171385 TI - Chemo-immunotherapy in RCC: the end of a story. PMID- 20171386 TI - Paper of the year 2009: results. PMID- 20171387 TI - Offline: AIDS is not zero sum. PMID- 20171388 TI - The Beckham test. PMID- 20171389 TI - An interview with Elisabeth Potts Dellon. PMID- 20171390 TI - An endothelin antagonist for resistant hypertension. PMID- 20171391 TI - An endothelin antagonist for resistant hypertension. PMID- 20171393 TI - An endothelin antagonist for resistant hypertension. PMID- 20171394 TI - An endothelin antagonist for resistant hypertension. PMID- 20171395 TI - The need for new antibiotics. PMID- 20171396 TI - The need for new antibiotics. PMID- 20171397 TI - GAVI's Advance Market Commitment. PMID- 20171398 TI - GAVI's Advance Market Commitment. PMID- 20171399 TI - The need for new antibiotics. PMID- 20171400 TI - Early initiation of treatment for HIV infection. PMID- 20171401 TI - HPV vaccination: waiting for evidence of effectiveness. PMID- 20171402 TI - The internet and informed dissent. PMID- 20171403 TI - Non-melanoma skin cancer. AB - The rising incidence and morbidity of non-melanoma skin cancers has generated great interest in unravelling of their pathogenesis and in the search for new non invasive treatments. Whereas the role of cumulative sun exposure in pathogenesis of squamous-cell carcinoma seems clear, the relation between sun-exposure patterns and subtypes of basal-cell carcinoma remains undetermined. Several complex genotypic, phenotypic, and environmental factors contribute to pathogenesis of non-melanoma skin cancers. Unlike basal-cell carcinoma, squamous cell carcinomas can arise from precursor lesions. Diagnosis of non-melanoma skin cancer is made clinically and confirmed by histological testing. Prognosis depends on lesion and host characteristics, which also dictate choice of treatment. Prevention strategies aim at reduction of sun exposure, but are of unproven benefit, especially for basal-cell carcinoma. Surgical excision with predetermined margins is the mainstay of treatment for squamous-cell carcinoma and for most basal-cell carcinomas. Of the new non-invasive treatments, only photodynamic therapy and topical imiquimod have become established treatments for specific subtypes of basal-cell carcinoma, and the search for more effective and tissue-salvaging therapies continues. PMID- 20171405 TI - A "fussy eater" with renal failure. PMID- 20171404 TI - Biological, clinical, and ethical advances of placebo effects. AB - For many years, placebos have been defined by their inert content and their use as controls in clinical trials and treatments in clinical practice. Recent research shows that placebo effects are genuine psychobiological events attributable to the overall therapeutic context, and that these effects can be robust in both laboratory and clinical settings. There is also evidence that placebo effects can exist in clinical practice, even if no placebo is given. Further promotion and integration of laboratory and clinical research will allow advances in the ethical use of placebo mechanisms that are inherent in routine clinical care, and encourage the use of treatments that stimulate placebo effects. PMID- 20171406 TI - Effects of oral levamisole as an adjuvant to hepatitis B vaccine in adults with end-stage renal disease: a meta-analysis of controlled clinical trials. AB - BACKGROUND: Many patients receiving long-term dialysis do not produce protective antibodies to hepatitis B virus (HBV) surface antigen (HBsAg) after HBV vaccination. The results from several studies have suggested benefit of oral levamisole as an adjuvant to HBV vaccination in patients with end-stage renal disease (ESRD). However, reliable information is still lacking. OBJECTIVE: This meta-analysis assessed the efficacy and safety profile of oral levamisole as an adjuvant to HBV vaccine in patients with ESRD. METHODS: This meta-analysis included prospective controlled clinical trials identified using literature searches of MEDLINE, SCOPUS, Institute for Scientific Information bibliographic database, and Cochrane Collaboration's Central Register of Controlled Clinical Trials for controlled clinical trials that weighted the seroprotection rate in patients with ESRD who received oral levamisole + HBV vaccine versus those who received the HBV vaccine alone (control). The fixed-effects Mantel-Haenszel model was applied with the heterogeneity and sensitivity analyses. The response rate, defined as the proportion of patients with seroprotective concentrations of antibodies to HBsAg (>10 mIU/mL) at completion and 6 to 10 months after completion of the HBV vaccine schedule, was the end point of interest and was also analyzed separately. For the tolerability assessment, studies that reported dose reduction, levamisole discontinuation, and their adverse effects including laboratory abnormalities were included. RESULTS: The literature search identified 4 studies that fulfilled the inclusion criteria (328 patients). The mean ages of the patients in these studies ranged from 41 to 53 years, and sex distribution ranged from 52.6% to 68.0% male. Twenty-two patients received oral levamisole 100 mg/d for 12 days (from 6 days before to 6 days after each vaccination). A total of 106 patients received oral levamisole 80 to 120 mg for 4 to 6 months. Aggregation of study results suggested a significant increase in response rate in the group that received levamisole + HBV vaccine compared with the control group (pooled odds ratio [OR] = 2.77 [95% CI, 1.56-4.94]) after completion and 6 to 10 months after the vaccination period (pooled OR = 3.96 [95% CI, 1.71-9.18]). The test of heterogeneity was not statistically significant in either group. Five patients underwent dose reduction due to mild adverse events. In one trial, 3 patients died, 1 of whom was receiving levamisole; however, the authors did not provide the causes of death. No other serious adverse events were reported with levamisole administration. CONCLUSION: The results from this meta-analysis suggest significant benefit in the administration of levamisole as an adjuvant to HBV vaccine to increase seroprotection in patients with ESRD. PMID- 20171407 TI - Clevidipine for the treatment of severe hypertension in adults. AB - BACKGROUND: Intravenous antihypertensive agents are used when immediate control of blood pressure (BP) is required, including during the perioperative cardiac surgery period. Controlling postoperative BP is challenging because of the need to adequately reduce BP while maintaining appropriate end-organ perfusion. Clevidipine is an intravenous, ultra-short-acting, third-generation dihydropyridine calcium channel antagonist with selectivity for arteriolar vasodilatation. It is approved by the US Food and Drug Administration for the treatment of severe hypertension. OBJECTIVE: This paper reviews the clinical pharmacology, pharmacokinetic and pharmacodynamic properties, tolerability, and clinical efficacy of clevidipine. METHODS: To minimize selection bias, each author conducted an independent search for English-language publications indexed on MEDLINE and International Pharmaceutical Abstracts through January 2010 using the term clevidipine. All identified prospective, randomized and nonrandomized Phase III trials were included in the review. RESULTS: Seven Phase III trials were identified in which clevidipine was compared with baseline, placebo, or other intravenous antihypertensive agents in the settings of severe hypertension (1 study), preoperative cardiac surgery (1), perioperative cardiac surgery (1), and postoperative cardiac surgery (4). In a multicenter, randomized, double blind, placebo-controlled study of the efficacy of clevidipine in treating preoperative hypertension, the mean reduction from baseline in mean arterial pressure was 31.2% with clevidipine and 11.2% with placebo (P < 0.001). In a randomized, open-label, prospective study involving separate comparisons of clevidipine with nitroglycerin, sodium nitroprusside, and nicardipine, the median total AUC for digression in systolic BP from the predetermined target range differed significantly between clevidipine and nitroglycerin (4.14 vs 8.87 mm Hg . min/h; respectively, P < 0.001) and between clevidipine and sodium nitroprusside (4.37 vs 10.5 mm Hg . min/h; P = 0.003), but not between clevidipine and nicardipine (1.76 and 1.69 mm Hg . min/h). Another study found no significant difference in efficacy in controlling BP during the 3-hour study period between clevidipine and sodium nitroprusside (AUC for mean [SD] arterial pressure, 106 [25] and 101 [28] mm Hg . min/h, respectively). Adverse events in these studies included atrial fibrillation (13.0%-36.1% clevidipine vs 12.0% placebo), nausea (5.0%-21.0% vs 12.0%, respectively), fever (19.0% vs 13.7%), insomnia (12.0% vs 6.1%), and acute renal failure (9.0% vs 2.0%). In the studies reviewed, only 1 case of chest discomfort in the setting of severe hypertension was considered a serious adverse event related to clevidipine therapy. CONCLUSION: In the Phase III trials reviewed, clevidipine was effective in controlling BP in the settings of perioperative cardiac surgery and severe hypertension and was associated with minimal adverse effects. PMID- 20171408 TI - Effects of oral cilostazol 100 mg BID on long-term patency after percutaneous transluminal angioplasty in patients with femoropopliteal disease undergoing hemodialysis: a retrospective chart review in Japanese patients. AB - BACKGROUND: Percutaneous transluminal angioplasty (PTA) for femoropopliteal lesions in peripheral artery disease has been performed in patients undergoing hemodialysis as well as in the general population. Cilostazol, a selective inhibitor of phosphodiesterase 3, has been reported to reduce target lesion revascularization after PTA for femoropopliteal lesions in the general population. OBJECTIVE: This study investigated the effects of cilostazol use on long-term patency after PTA in patients with femoropopliteal disease undergoing hemodialysis. METHODS: In this retrospective study, data from patients undergoing hemodialysis who underwent successful PTA for femoropopliteal disease, defined as a final luminal diameter stenosis <30% without angiographically visual arterial dissection and no in-hospital complications, were included. One study group received long-term treatment with oral cilostazol 100 mg BID after PTA; the control group did not. The duration of follow-up was 50% of the vessel diameter in femoropopliteal lesions. Data on baseline characteristics, patency, and covariates (diabetes, hypertension, hyperlipidemia, smoking, coronary artery disease, critical limb ischemia, TransAtlantic Inter-Society Consensus classification, and stenting) were obtained from electronic medical records and telephone interviews with patients. To minimize the effects of selection bias for cilostazol administration, a propensity-matched analysis using Cox univariate and multivariate models including the previously mentioned covariates was conducted. The propensity scores of the 2 groups were matched 1:1 (AUC = 0.69 [receiving operating characteristics analysis]). Data were obtained from electronic medical records and telephone interviews with patients by trained personnel who were blinded to treatment assignment. RESULTS: A total of 358 consecutive lesions of 174 patients undergoing hemodialysis were included (103 men, 71 women; mean [SD] age, 66 [11] years; cilostazol group, 61 patients, 121 lesions; control group, 113 patients, 237 lesions). The mean duration of follow-up was 37 (27) months. The 6-year event-free rate of restenosis of >50% of the vessel diameter was significantly higher in the cilostazol group than in the control group (72/121 [59.5%] vs 120/237 [50.6%]; P = 0.005 [logrank test]; hazard ratio [HR] = 0.63; 95% CI, 0.45-0.88; P = 0.008 [Cox univariate analysis]). Also, event-free rates of target lesion revascularization and limb amputation were significantly higher in the cilostazol group than in the control group (40/61 [65.6%] vs 57/113 [50.4%]; P = 0.013 [log-rank test] and 54/61 [88.5%] vs 90/113 [79.6%]; P = 0.047 [logrank test], respectively). On propensity score matching (105 lesions), the baseline characteristics were comparable between the 2 groups. The 6-year eventfree rate of restenosis was significantly higher in the cilostazol group than in the control group (66/105 [62.9%] vs 52/105 [49.5%]; HR = 0.58; 95% CI, 0.38-0.88; P = 0.012 [Cox univariate analysis]). On propensity-matched (Cox multivariate) analysis, cilostazol (HR = 0.51; 95% CI, 0.27-0.84; P = 0.008), age (HR = 1.01; 95% CI, 1.01-1.04; P = 0.031), and critical limb ischemia (HR = 2.21; 95% CI, 1.39-3.53; P = 0.001) were independent predictors of restenosis. None of the patients in the cilostazol group discontinued cilostazol treatment during the follow-up period. Four patients (6.6%) experienced mild headache. CONCLUSION: This study found that in these patients with femoropopliteal lesions in peripheral artery disease who were undergoing hemodialysis, those treated with cilostazol 100 mg BID after PTA had a higher mean rate of cumulative patency after PTA than those in the control group. PMID- 20171409 TI - Efficacy and safety profile of a topical methyl salicylate and menthol patch in adult patients with mild to moderate muscle strain: a randomized, double-blind, parallel-group, placebo-controlled, multicenter study. AB - BACKGROUND: An occlusive patch formulation containing 10% methyl salicylate and 3% l-menthol was recently approved by the US Food and Drug Administration for the treatment of mild to moderate pain. Despite widespread use of counterirritants, including methyl salicylate and menthol, for topical pain relief, published efficacy and safety data regarding the use of the agents alone or in combination are limited. OBJECTIVE: The goal of this study was to determine the efficacy and safety profile of a patch containing 10% methyl salicylate and 3% l-menthol compared with a placebo patch in adult patients with mild to moderate muscle strain. METHODS: Eligible patients were men or women aged >or=18 years with a clinical diagnosis of mild to moderate muscle strain. Patients were randomly assigned to receive either 1 active patch or 1 placebo patch applied to the skin at the affected area (ie, shoulder, upper back, upper arm, neck, calf, thigh, forearm, abdomen). Pain intensity was assessed on a 100-mm visual analog scale while at rest and with movement for 12 hours after patch application. The primary efficacy end point was the summed pain intensity difference score through 8 hours (SPID8) with movement. Analyses included use of descriptive statistics and an ANOVA model. Safety data, including adverse events, and secondary efficacy end points were also evaluated. RESULTS: A total of 208 patients (104 men, 104 women; age range, 18-78 years) were randomized to 1 of 2 study groups (105 in the active patch group [mean age, 37.3 years], 103 in the placebo-patch group [mean age, 38.1 years]). The primary efficacy analysis (SPID8 with movement) indicated that patients receiving the active patch experienced significantly greater pain relief (approximately 40%) than those patients receiving a placebo patch (mean [SD], 182.6 [131.2] vs 130.1 [144.1]; P = 0.005). Analysis of the per-protocol population also found significantly more relief (P = 0.024) in the active-patch group (176.2 [131.4]; n = 92) versus the placebo-patch group (130.2 [144.0]; n = 96). Statistical analysis of secondary efficacy measures supported the primary end-point results. The number of patients experiencing any type of adverse event was comparable between study groups (active patch, 6.7% [7 events]; placebo patch, 5.8% [6 events]). No serious adverse events were reported during the study. CONCLUSION: A single, 8-hour application of a patch containing methyl salicylate and l-menthol provided significant relief of pain associated with mild to moderate muscle strain in these adult patients compared with patients receiving a placebo patch. PMID- 20171410 TI - Comparison of the clinical effects of carbomer-based lipid-containing gel and hydroxypropyl-guar gel artificial tear formulations in patients with dry eye syndrome: a 4-week, prospective, open-label, randomized, parallel-group, noninferiority study. AB - BACKGROUND: Most marketed artificial tears are substitutes for the aqueous layers of the tear film; therefore, frequent instillation of artificial tears is necessary. Newer gel-, cellulose-, and mineral oil-based formulations have been designed to overcome the disadvantages of current aqueous tear substitutes by offering prolonged retention times. OBJECTIVES: The aim of this study was to compare the efficacy, safety, and local tolerance of artificial tears containing carbomer-based lipids or hydroxypropyl (HP)-guar gel in patients with dry eye syndrome. METHODS: A 4-week, prospective, randomized, parallel-group, comparative, noninferiority study was conducted at the Taipei Medical University Hospital (Taipei, Taiwan) in patients with dry eye syndrome who were randomly assigned to 1 of 2 treatment groups: the carbomer-based lipid-containing (CBLC) gel group and the HP-guar gel group. The primary end point was global assessment of study treatment by the patients at weeks 2 and 4. All patients met the diagnostic criteria of impaired tear function and ocular surface abnormalities. Outcomes measured at baseline and 2 and 4 weeks included Schirmer's test values, tear breakup time (TBUT), and a patient subjective assessment of symptoms. Safety and tolerability were assessed by clinically significant changes in terms of incidence of adverse events and conducted by unmasked investigators. RESULTS: A total of 30 Taiwanese patients with dry eye syndrome were included and randomly assigned to the 2 treatment groups: the mean (SD) age was 40.37 (14.96) years in the CBLC gel group and 49.49 (12.20) years in the HP-guar gel group. At baseline, the mean (SD) Schirmer's test value was 4.53 (2.28) mm in the right eye and 5.13 (2.42) mm in the left eye in the CBLC gel group; 4.40 (2.16) mm in the right eye and 4.20 (1.78) mm in the left eye for the HP-guar gel group. The mean (SD) for both eyes was 4.83 (2.36) mm in the CBLC gel group and 4.30 (2.08) mm in the HP guar gel group. There was no statistically significant difference between Schirmer's scores at baseline. Patients in both treatment groups experienced an improvement from baseline in symptoms and signs, Schirmer's test value, and TBUT at 2 and 4 weeks after treatment. The Schirmer's test score increased to a mean of 8.20 (4.49) mm in the right eye and 9.33 (4.94) mm in the left eye in the CBLC gel group after 2 weeks, and increased to 10.07 (5.56) mm in the right eye and 10.86 (5.58) mm in the left eye after 4 weeks. The increases in Schirmer's test score and TBUT were also observed in the HP-guar gel group. The Schirmer's test score increased to 5.13 (2.18) mm in the right eye and 5.60 (2.74) mm in the left eye after 2 weeks, and increased to 6.93 (3.37) mm in the right eye and 6.53 (3.16) mm in the left eye after 4 weeks. The increase in Schirmer's test values in both eyes was significantly greater at 2 and 4 weeks in the CBLC gel group than that in the HP-guar gel artificial tear group (all, P < 0.05). Subjective patient assessment was better with the CBLC group (excellent and good reported by 26.6% and 73.4%, respectively, of the CBLC gel group vs 13.4% and 33.4% of the HP guar gel group at 4 weeks; both, P = 0.004). CONCLUSIONS: Both artificial tear formulations were effective in relieving dry eye syndrome in these patients. The tolerance of CBLC gel artificial tears was comparable to that of HP-guar gel artificial tears. PMID- 20171411 TI - Warfarin and bosentan interaction in a patient with pulmonary hypertension secondary to bilateral pulmonary emboli. AB - BACKGROUND: Bosentan is an endothelin-receptor antagonist that reportedly induces both cytochrome P450 (CYP) 3A4 and CYP2C9 enzymes, which are also involved in warfarin metabolism. We present a case report describing a probable drug interaction between warfarin and bosentan in a patient with pulmonary hypertension. CASE SUMMARY: A 52-year-old black female (weight, 77 kg) diagnosed with pulmonary hypertension secondary to bilateral pulmonary emboli had a stable international normalized ratio (INR; target range, 2-3) with a weekly warfarin dose of 52.5 mg for 2 months before the initiation of bosentan therapy. Other concurrent medications included telmisartan/ hydrochlorothiazide 40/12.5 mg once daily and a daily multivitamin (which contained no vitamin K). Three weeks after starting bosentan 62.5 mg BID, a therapeutic INR concentration was reached with a weekly warfarin dose 14% higher (an increase of 7.5 mg/wk) than her weekly warfarin dose before initiation of bosentan. After a brief discontinuation (7 days) and retitration of bosentan and warfarin, the final weekly warfarin dose (75 mg/wk) was 43% greater (an increase of 22.5 mg/wk) than the previously stable dose, which enabled the patient to reach her therapeutic INR goal range of 2 to 3. CONCLUSIONS: Bosentan has CYP3A4- and CYP2C9-inducing properties and is therefore likely to cause decreased concentrations of warfarin. We describe here a probable drug interaction between bosentan and warfarin that resulted in a 43% increase in warfarin dose to maintain the patient's therapeutic INR. PMID- 20171412 TI - Melanoma onset after estrogen, thyroid, and growth hormone replacement therapy. AB - BACKGROUND: Acute sun exposure is the main risk factor for the development of melanoma, especially if associated with a large number of benign melanocytic nevi. Although epidemiologic studies have investigated the effects of exogenous triggers, particularly hormones, our understanding of melanoma is still inadequate. OBJECTIVE: The aim of this study was to report a case of melanoma that developed after hormonal therapy. CASE SUMMARY: We report a case of a 26 year-old white woman (weight, 48 kg; Fitzpatrick skin phototype IV; no previous pregnancy) who was referred to the Department of Dermatology, Casa Sollievo della Sofferenza Hospital-IRCCS, San Giovanni Rotondo, Italy, with a malignant melanoma on the left thigh. At the age of 18 years (year 2000), the patient presented with amenorrhea, but no therapy was initiated until 2004. At this time, insufficiency of the gonadal, thyroid, and growth hormone (GH) axes was diagnosed without evidence of hypothalamic-pituitary anatomic damage or of congenital or acquired causes. The patient had an inadequate level of GH (base: 0.8 g/mL; peak: 1.0 ng/mL) during an insulin tolerance test, low levels of thyroid hormones, and a blunted response of luteinizing hormone (base: 0.2 mIU/mL; peak: 10 mIU/mL) and follicle-stimulating hormone (base: 2.6 mIU/mL; peak: 18.5 mIU/mL) to a gonadotrophinreleasing hormone stimulation test. Consequently, replacement therapy with ethinyl estradiol (20 microg) plus progestin (75 microg) (once daily for 21 days/month), levothyroxine (25 microg once daily), and recombinant human GH (0.8 mg SC once daily) was initiated. GH replacement therapy was discontinued after 2 years (June 2006), and thyroid and estrogen replacement therapy were discontinued after 4 years (February 2008). The patient reported first noticing the pigmented lesion 8 months after GH withdrawal, during treatment with the estrogen/progestin combination. CONCLUSION: We report a case of melanoma onset in a patient who had received hormonal substitutive therapy, where the role of GH therapy alone or in combination with other hormones could not be ruled out. PMID- 20171413 TI - Irreversible encephalopathy after treatment with high-dose intravenous metronidazole. AB - BACKGROUND: Encephalopathy associated with metronidazole is rare and, in most cases, reversible following discontinuation. OBJECTIVE: We describe a case of fatal encephalopathy after treatment with high-dose intravenous metronidazole and the potential causes of the irreversibility. CASE SUMMARY: A 38-year-old white woman (weight, 45 kg) received metronidazole among other medications to treat osteomyelitis for 74 days after surgery to correct a spinal neuroarthropathy. An initial dose of 500 mg IV QID was administered. After 6 weeks, the patient was discharged and the dose was changed to 1500 mg IV administered once daily (over 90 minutes) by a visiting nurse. Other treatments included teicoplanin 400 mg once daily and trimethoprimsulfamethoxazole 480 mg BID for the infection, baclofen 25 mg TID for pain associated with a congenital spinal cord lesion with paraplegia, and omeprazole 20 mg once daily for pyrosis. Ten weeks after the start of metronidazole, the patient developed somnolence and dysarthria, changing to encephalopathy with coma on admission 2 weeks later. Despite discontinuation of all medication, including metronidazole, 2 days after admission, the patient's condition appeared to be irreversible. After 8 weeks, her coma was considered permanent, mechanical ventilation was discontinued, and she died. Evaluating all medicines administered, metronidazole, with a Naranjo adverse drug reaction score of 5 (probable), was the most plausible cause of the encephalopathy. The other medicines, including baclofen, had a negative score of -3 to -2 (doubtful). All tests on infections, metabolic disorders, or interactions between medications were negative. CONCLUSION: This patient had a fatal encephalopathy, probably associated with long-standing exposure to high plasma concentration peaks of metronidazole, due to a once-daily dose of 1500 mg IV over several weeks. PMID- 20171414 TI - Clinical efficacy and tolerability of linezolid in pediatric patients: a systematic review. AB - BACKGROUND: Linezolid is marketed for the treatment of severe, vancomycin resistant infections with gram-positive bacteria in adults. Most information regarding the pharmacokinetic profile, efficacy, and tolerability of linezolid is derived from adult studies. OBJECTIVE: The aim of this review was to summarize evidence regarding the use of linezolid in infants and children, focusing on the drug's clinical efficacy data and tolerability profile. METHODS: A literature search was conducted of the Cochrane Library, EMBASE, and MEDLINE databases, from their inception through July 20, 2009, using the following terms: linezolid, newborn, infant, child, pediatrics, adolescent, human, clinical trial, and case report. Articles were excluded if they were redundant or not pertinent. (Articles that did not focus on the use of linezolid in children were considered not pertinent.) Bibliographies of all relevant articles were also evaluated. RESULTS: Forty-seven publications regarding the use of linezolid in children were included in the review: 5 pharmacokinetic studies, 32 case reports, 6 randomized clinical trials (RCTs), 2 uncontrolled trials, 1 subanalysis of 2 published RCTs, and 1 subanalysis of published data about linezolid's tolerability. Pharmacokinetic data on linezolid use in children were derived from studies that enrolled 447 children. Plasma pharmacokinetics of linezolid in pediatric patients were found to be age dependent. Results from 6 vancomycinor cefadroxil-controlled RCTs (including 1480 children) evaluating linezolid treatment in children reported variable clinical cure rates, ranging from 75.0% to 93.2% in children with skin and skin-structure infections and from 77.5% to 90.0% in children with bacteremia or pneumonia. No significant difference in clinical cure rates between the linezolid group and the comparator group was observed in any study. The most frequently reported adverse events were diarrhea (from 3.1% to 16.8%), nausea and/or vomiting (from 2.9% to 11.9%), and thrombocytopenia (from 1.9% to 4.7%). To date, 3 cases of neuropathy have been described in children. CONCLUSIONS: The reviewed pediatric studies in skin and skin-structure infections, bacteremia, or pneumonia found that linezolid was associated with high clinical cure rates (75.0%-93.2%) that did not differ significantly from those of vancomycin or cefadroxil. RCTs enrolling children with other types of infection (eg, osteomyelitis, endocarditis), as well as long-term studies, are needed to draw definitive conclusions about linezolid's efficacy and tolerability in pediatric patients. Careful monitoring for adverse events and possible linezolid resistance continues to be essential. PMID- 20171415 TI - Efficacy and tolerability of a new formulation of pancrelipase delayed-release capsules in children aged 7 to 11 years with exocrine pancreatic insufficiency and cystic fibrosis: a multicenter, randomized, double-blind, placebo-controlled, two-period crossover, superiority study. AB - BACKGROUND: Pancreatic enzyme replacement therapy (PERT) is essential for maintaining adequate nutrition in children with exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF). The US Food and Drug Administration regulations now require all PERT products to undergo clinical efficacy and safety studies before they can be considered for marketing approval. OBJECTIVE: This study was conducted to compare the efficacy of a new formulation of pancrelipase (pancreatin) delayed-release 12,000-lipase unit capsules with placebo in children with EPI due to CF. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, 2-period crossover, superiority study of the new formulation of pancrelipase delayed-release 12,000-lipase unit capsules in children aged 7 to 11 years with CF and EPI. In each period, pancrelipase or identical placebo capsules were taken for 5 days. The primary outcome measure was the coefficient of fat absorption (CFA); secondary outcome measures were the coefficient of nitrogen absorption (CNA) and clinical symptoms. The latter were assessed based on patient-reported daily stool frequency, stool consistency (hard, formed/normal, soft, or watery), flatulence (none, mild, moderate, or severe), and abdominal pain (none, mild, moderate, or severe). Safety measures included vital signs, physical examinations, standard laboratory safety tests (hematology and biochemistry), and adverse events. RESULTS: Seventeen patients were randomized to treatment and 16 completed the study; 1 patient withdrew consent during the first treatment period and was not included in the efficacy analysis. Patients' median age was 8.0 years (range, 7-11 years); 12 patients (70.6%) were male. CFA values were significantly greater for pancrelipase compared with placebo, with least squares mean (SE) values of 82.8% (2.7%) and 47.4% (2.7%), respectively (P < 0.001). The results were similar for CNA, with mean values of 80.3% (3.2%) and 45.0% (3.2%) (P < 0.001). Pancrelipase treatment had significantly greater effects on CFA and CNA in patients with a placebo CFA <50% than in those with a placebo CFA >50% (both parameters, P < 0.001 and P = 0.008, respectively). Significant improvements in stool fat, weight, and nitrogen and a significant reduction in daily stool frequency were observed with pancrelipase compared with placebo (all, P < 0.001). Symptoms of EPI were less severe and remained relatively stable during pancrelipase treatment, but worsened slightly during receipt of placebo. Treatment-emergent adverse events were reported in 5 patients (29.4%) during receipt of pancrelipase and in 9 patients (56.3%) during receipt of placebo; these were predominantly gastrointestinal events. There were no discontinuations due to treatment-emergent adverse events and no serious adverse events. CONCLUSIONS: In this study in children with EPI due to CF, the new formulation of pancrelipase delayedrelease capsules was associated with improvements in CFA, CNA, stool properties, and EPI symptoms compared with placebo. Pancrelipase delayed-release capsules appeared to be well tolerated. ClinicalTrials.gov identifier: NCT00690820. (Clin Ther. PMID- 20171416 TI - The relevance of international studies to informed pharmacoeconomics and health policy decisions. PMID- 20171417 TI - Diffusion of a new drug: a comparative analysis of adoption, treatment complexity, and persistence of risperidone long-acting injectable therapy in the Netherlands. AB - OBJECTIVE: The study's objective was to analyze the adoption and persistence of risperidone long-acting injectable (RLAI) therapy after its introduction in the Netherlands in 2003 compared with the adoption and persistence of existing first generation antipsychotic (FGA) depot drugs as an example of the diffusion of a new drug in the Netherlands. METHODS: Data on antipsychotic use were obtained from the InterAction DataBase (IADB.nl), a database containing pharmacy dispensing records of patients in the northern Netherlands, from May 20, 2003, to December 31, 2006. Treatment complexity for patients prescribed RLAI was analyzed on the basis of psychotropic comedication at baseline and during treatment, as well as on the number of previous antipsychotic therapies. Differences in treatment complexity between patients using RLAI and those using FGA depot drugs were estimated using parametric regressions. To evaluate persistence, survival analysis techniques were applied to estimate the probability of patients continuing the use of RLAI or FGA depot drugs over time. RESULTS: Data on 435 patients who were treated with depot antipsychotics were extracted from the IADB.nl. Patients had a mean (SD) age of 40.7 (13.8) years, and 65% of them were male. The results of this analysis indicated that persistence for patients prescribed RLAI was significantly lower compared with other depot antipsychotics (RLAI vs zuclopenthixol, P = 0.002; RLAI vs all other depot antipsychotics, P = 0.009). At the initiation of treatment, patients prescribed RLAI had more previous psychotropic comedication and had, on average, approximately 5 and approximately 1.5 times more prior depot drug therapies compared with zuclopenthixol and any other FGA depot drug, respectively. CONCLUSIONS: The findings of this study suggest that RLAI has been prescribed more often for difficult-totreat patients than have other available depot antipsychotics. This may explain the low adoption and poor persistence observed in the first few years after the introduction of RLAI. Further research with more extensive data should be pursued to obtain better understanding of the current diffusion of RLAI in daily clinical practice. PMID- 20171418 TI - The economic implications of treating atherothrombotic disease in Australia, from the government perspective. AB - BACKGROUND: The management of atherothrombotic disease is responsible for a large proportion of direct medical costs in most countries, imposing a substantial financial burden on health care payers. There is limited knowledge about direct per-person medical costs using a "bottom-up" approach. OBJECTIVE: This study was designed to estimate the per-person direct medical costs incurred by communitybased subjects in Australia who have or are at high risk for atherothrombotic disease. The perspective was a governmental one, at the federal level for pharmaceuticals and at the state level for hospitalizations. METHODS: One-year follow-up data were obtained for Australian participants in the international REACH (Reduction of Atherothrombosis for Continued Health) Registry who were aged >or=45 years and had either established atherothrombotic disease (coronary artery disease, cerebrovascular disease, or peripheral artery disease [PAD]) or >or=3 risk factors for atherothrombotic disease. Information was extracted on the use of cardiovascular medications, hospitalizations, general practice visits, clinical pathology and imaging studies, and use of rehabilitation services. Bottom-up costing was undertaken by assigning unit costs to each health care item, based on Australian government reimbursement data for 2006-2007. Costs were estimated in Australian dollars. RESULTS: Data for 2873 Australian participants in the REACH Registry were included in the analysis. Mean (SD) annual pharmaceutical costs per person were A$1388 (A$645). Mean ambulatory care costs per person were A$704 (A$492), and mean hospitalization costs were A$10,711 (A$10,494). Compared with participants with >or=3 risk factors (adjusted for age and sex), participants with 2 to 3 affected vascular territories incurred A$160 more in mean pharmaceutical costs (95% CI, 78 to 256) and A$181 more in ambulatory care costs (95% CI, 107 to 252). Mean ambulatory care costs were A$132 greater among participants with PAD only relative to those with >or=3 risk factors (95% CI, 19 to 272). Hospital costs were not significantly increased with an increasing number of affected vascular territories. The greatest difference in direct hospital costs (A$943) was between participants with PAD relative to those with >or=3 risk factors (95% CI, -564 to 3545). CONCLUSIONS: From the government perspective, management of atherothrombotic disease in Australia was costly during the period studied, particularly among those with PAD only or disease affecting 2 to 3 vascular territories. Hospitalization accounted for the majority of health care expenditure associated with atherothrombotic disease, although the number of hospitalized participants was relatively small. PMID- 20171419 TI - Results of a retrospective database analysis of drug utilization and costs for treatment of chronic hepatitis B virus infection in the northern Netherlands between 2000 and 2006. AB - OBJECTIVES: The main aims of this work were to describe patterns of medication use in the treatment of chronic hepatitis B virus (HBV) infection in patients in the northern part of the Netherlands and to compare these practices with established guidelines. In addition, the duration of use and the costs of these treatments were investigated. METHODS: We selected subjects from the University of Groningen's IADB.nl database; by 2006, the database provided information about drug utilization from 55 community pharmacies in the northern Netherlands and included a population of 528,911 individuals, of which 49% were male. Eligible subjects had received >or=1 prescription for drugs used to treat chronic HBV infection (ie, lamivudine, pegylated interferon-alpha2a, pegylated interferon alpha2b, adefovir, tenofovir, and entecavir) between the years 2000 and 2006. The annual prevalence and cumulative incidence of HBV treatment per 1000 people covered in the database were calculated and stratified by sex. Kaplan-Meier survival analysis was used to analyze the duration of use. Drug costs in the treatment were calculated for all patients or per patient, and by drugs used per subperiod (2000-2003 and 2004-2006). Treatments for hepatitis C virus and HIV were excluded from the analyses. RESULTS: From the database, we identified 59 patients (46 male, 13 female), aged 25 to 60 years, who received >or=1 prescription for a medication to treat chronic HBV infection between 2000 and 2006. The overall prevalence of people using chronic treatments for HBV was between 0.03 and 0.06 per 1000 during the years of the study. The cumulative incidence of treatment was approximately 0.01 per 1000 per year (ranging from a high of 0.021 in 2000 to a low of 0.009 in 2006). When stratified by sex, there were more male than female subjects who received medications for HBV. Lamivudine was the most commonly prescribed drug, followed by adefovir and pegylated interferon-alpha2b. In 2000 and 2001, lamivudine was the only medication prescribed for the treatment of chronic HBV. From 2002 to 2006, the prescription rate for lamivudine dropped from 90% to 61%. In contrast, the prescription rate for adefovir increased from 4% in 2003 to 36% in 2006. Pegylated interferon alpha2b remained stable at 8% to 11% between 2002 and 2006. Twenty-five percent of patients had stopped HBV treatment by the end of 1 year. Fifty-five percent had stopped by 3 years. Seventy-seven percent of patients received their first HBV prescription from a medical specialist. Per patient, the cost of drug therapy was highest with adefovir. From 2004 to 2006, the cost of adefovir therapy accounted for 49% of total expenditures for the treatment of chronic HBV (equivalent to euro128,037; as of January 2010, euro1.00 = US $1.43). The second and third most expensive drugs were tenofovir and pegylated interferon-alpha2b (euro33,700 and euro33,250, respectively). Costs incurred per patient increased over the years of the study period. CONCLUSIONS: The overall prevalence and cumulative incidence of patients with treatments for chronic HBV were relatively low in the northern part of the Netherlands between 2000 and 2006. The prescribing and utilization patterns were in agreement with international and Dutch guidelines. Given the low numbers of prescriptions, the costs also remained relatively low. PMID- 20171420 TI - Safety and pharmacokinetics of NXN-188 after single and multiple doses in five phase I, randomized, double-blind, parallel studies in healthy adult volunteers. AB - BACKGROUND: NXN-188 is a dual-action oral therapeutic being developed for the treatment of acute migraine. The mechanism of action of NXN-188 involves inhibition of both the neuronal nitric oxide synthase enzyme isoform and affinity for serotonin (5-hydroxytryptamine1B/D) receptors. OBJECTIVES: The aims of the initial Phase I clinical studies were to compare the pharmacokinetic (PK) properties of NXN-188 administered as a single dose or multiple twice-daily doses to healthy adult volunteers and to determine the tolerability of NXN-188 in these individuals. METHODS: Healthy adult male and female subjects were enrolled in 5 Phase I, randomized, double-blind studies, all of which (except for a fed/fasted trial) were placebo controlled. In the 4 single-dose studies, which differed with respect to feeding status and the formulation used (capsules or solution), subjects received NXN-188 at doses of 2 to 800 mg (0.027-11.2 mg/kg). In the repeat-dose study, subjects received 50-mg (0.71 mg/kg) doses twice daily for 4 days. Serum samples were analyzed for NXN-188 using validated HPLC-MS/MS methods. Standard clinical laboratory analyses (chemistry, hematology, and urinalysis) and measurements of serum creatine kinase and myoglobin levels were conducted at screening, admission, discharge, and follow-up. Baseline and postexposure values were compared to assess tolerability. Electrocardiography and physical examination were conducted at screening and at discharge and follow-up if any negative change occurred from the previous findings. Vital signs (heart rate, blood pressure, respiration), including assessment for orthostatic changes, were measured at screening, check-in, and follow-up visits (1 hour before dosing, every 30 minutes for the first 4 hours, then every hour for the next 4 hours, then every 4 hours for the remainder of the 24-hour study). Adverse events were recorded, reviewed, and monitored throughout the study. RESULTS: Two hundred three subjects (102 women, 101 men) 18 to 50 years of age were enrolled in the 5 studies; 168 subjects received NXN-188 and 35 received placebo. Most (91%) of the subjects were white; weight ranged from 69.3 to 71.8 kg (body mass index, 24.5 25.8 kg/m(2)). The initial absorption phase of orally administered NXN-188 peaked at approximately 1 hour, followed by a second absorption phase with a T(max) of approximately 4 to 5 hours. Exposure (C(max) and AUC) increased in a slightly greater than dose-proportional manner across a dose range of 2 to 800 mg (0.027 11.2 mg/kg). Elimination was multiexponential, with an initial rapid plasma drug elimination (plasma concentrations decreased approximately 70%-90% from Cmax within 24 hours after dosing), followed by a prolonged clearance phase of very low NXN-188 concentrations ( approximately 1%-5% of Cmax) that persisted for several weeks. Clearance ranged from 70 to 130 L/h, and the NXN-188 halflife ranged from 11 to 178 hours. Neither food nor gender had any measurable effect on the PK properties of NXN-188. Overall, dizziness was reported more often in the NXN-188 groups than in the placebo groups (6.3% vs 2.9%, respectively). Frequently reported adverse events that occurred more often in the placebo groups than in the NXN-188 groups were somnolence (11.4% vs 6.3%, respectively), and headache (8.6% vs 6.9%). Incidences of orthostatic hypotension (6.3% vs 5.7%) and postural (orthostatic) tachycardia syndrome (6.3% vs 5.7%) were comparable in the NXN-188 and placebo groups, respectively. No serious adverse events were reported at any dose of NXN-188 up to the current maximum dose (800 mg or 11.2 mg/kg). CONCLUSION: NXN-188 exhibited linear pharmaco-kinetics over the dose range studied and appeared to be well tolerated in these healthy volunteers. PMID- 20171421 TI - Bioequivalence of two tablet formulations of clopidogrel in healthy Argentinian volunteers: a single-dose, randomized-sequence, open-label crossover study. AB - BACKGROUND: Platelet activation is a major component in the pathogenesis of coronary thrombosis and myocardial infarction. Thienopyridines, particularly clopidogrel, are highly effective in reducing in-stent thrombosis and functional inhibition of adenosine diphosphate-induced platelet activation. OBJECTIVE: The aim of this study was to evaluate the bioequivalence of a new generic formulation of clopidogrel 75-mg tablets (test) and the available branded formulation (reference) to meet regulatory criteria for marketing the test product in Argentina. METHODS: This was a randomized-sequence, open-label, 2-period crossover study conducted in healthy white volunteers in the fasted state. A single oral dose of the test or reference formulation was followed by a 7-day washout period, after which subjects received the alternative formulation. Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after dosing. Clopidogrel concentrations were determined using an LC-MS/MS method. The formulations were considered bioequivalent if the 90% CI of the geometric mean ratios (test:reference) for C(max) and AUC(0-last) were within the range from 80% to 125%. Adverse events were monitored throughout the study based on clinical parameters and patient reports. RESULTS: Twenty-four volunteers (13 male, 11 female; mean [SD] age, 33.7 [5.2] years [range, 21-42 years]; weight, 72.4 [6.83] kg [range, 59-82 kg]) were enrolled in and completed the study. The geometric mean C(max) for the test and reference formulations was 877.76 and 913.49 pg/mL, respectively. The geometric mean AUC(0-t) was 1911.53 and 2053.09 pg . h/mL, and the geometric mean AUC(0-infinity)) was 2021.33 and 2188.25 pg . h/mL. The geometric mean ratios (test:reference) for C(max), AUC(0 t), and AUC(0-infinity)) were 96.09% (90% CI, 90.71-101.78), 93.10% (90% CI, 85.57-101.3), and 92.37% (90% CI, 85.06-100.31), respectively. There were no significant differences in pharmacokinetic parameters between groups. No adverse events were reported. CONCLUSION: In this single-dose study in healthy fasted volunteers, the test formulation of clopidogrel tablets met the US and Argentinian regulatory criterion for bioequivalence to the reference formulation. PMID- 20171422 TI - Bioequivalence and pharmacokinetic comparison of two mycophenolate mofetil formulations in healthy Chinese male volunteers: an open-label, randomized sequence, single-dose, two-way crossover study. AB - BACKGROUND: Mycophenolate mofetil (MMF) is an ester prodrug of mycophenolic acid (MPA), so clinical studies measure the circulating plasma MPA concentration instead of MMF. MPA is extensively glucuronidated by several uridine diphosphate glycosyltransferases into an inactive 7-O-glucuronide and a pharmacologically active acylglucuronide. Considering the effect of racial differences and genetic factors on the pharmacokinetic (PK) properties of drugs, it is necessary to study them in Chinese populations. OBJECTIVES: The aim of this study was to compare the clinical bioequivalence and PK properties of a test (dispersible tablets) and reference (capsules) formulation of MMF 1.0 g in healthy Chinese volunteers. We also established a validated HPLC method for the determination and quantification of MPA in human plasma. The study was required to obtain Chinese regulatory approval for the test formulation. METHODS: This open-label, randomized-sequence, single-dose, 2-way crossover study was conducted at the First Hospital of Nanjing Medical University, Nanjing, China. Eligible subjects were healthy male volunteers who were randomly assigned at a 1:1 ratio to receive a single 1.0-g dose of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The plasma concentration of MPA, which is the active metabolite of MMF, was determined using a validated HPLC method. For analysis of PK properties, blood samples were collected at 0, 10, 20, 30, and 45 minutes, and 1, 1.5, 3, 5, 8, 11, 18, 36, and 48 hour(s). The PK parameters, including C(max), T(max), t((1/2)), AUC(0-48), and AUC(0-infinity), were determined from the plasma concentrations of the 2 formulations by noncompartmental analysis. Tolerability was assessed at baseline (be- fore administration) and at 30 minutes and 1, 5, 18, and 48 hours after administration by monitoring vital signs. Laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis) were performed for the identification of adverse events (AEs) (eg, leukopenia, thrombocytopenia, anemia). Patient interviews were conducted to assess the occurrence of AEs such as diarrhea, abdominal pain, nausea, vomiting, and secondary infections. The formulations were considered to meet the regulatory requirements of bioequivalence if the log transformed ratios of C(max) and AUC were within the predetermined equivalence range (80%-125%) as established by the US Food and Drug Administration (FDA). RESULTS: Eighteen healthy Chinese male volunteers (mean [range] age, 23.5 [22-30] years; weight, 63.3 [56-68] kg; height, 171 [165-184] cm) were enrolled and completed the study. The main PK parameters of the MMF test and reference formulations were as follows: mean (SD) T(max), 0.68 (0.21) and 0.81 (0.18) hour, respectively; C(max), 25.58 (4.79) and 26.47 (3.67) mg/L; AUC(0-48), 59.19 (9.23) and 58.32 (9.28) mg/L/h; t((1/2)), 15.12 (3.17) and 16.04 (4.22) hours; AUC(0 infinity)), 63.28 (10.23) and 62.41 (10.28) mg/L/h. The mean (SD) relative bioavailability was 101.5% (10.3%). No statistically significant differences were found based on ANOVA. The ratios of C(max) (0.97) and AUC (1.01) for the test and reference formulations were within the FDA bioequivalence definition intervals of 80% to 125%. No AEs were reported by subjects or found on analysis of vital signs or laboratory tests. CONCLUSIONS: In this study in healthy Chinese male volunteers, results from the PK analysis suggested that a single dose of the test and reference formulations of MMF 1.0 g met the regulatory requirements of bioequivalence, based on the FDA regulatory definition (rate and extent of absorption). Both formulations were well tolerated. PMID- 20171423 TI - Effect of eslicarbazepine acetate on the steady-state pharmacokinetics and pharmacodynamics of warfarin in healthy subjects during a three-stage, open label, multiple-dose, single-period study. AB - BACKGROUND: The anticoagulant warfarin, which is administered as a racemic mixture of R- and S-enantiomers, has been reported to interact with other drugs, including some antiepileptics. Eslicarbazepine acetate (ESL) is a once-daily voltage-gated sodium channel blocker that has been developed for the treatment of partial epilepsy and other indications. OBJECTIVE: The aim of this work was to investigate whether multiple-dose administration of ESL had any effect on the steady-state pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers stabilized on warfarin at a subtherapeutic level. METHODS: Subjects received ESL 1200 mg once daily for 8 days concomitantly with racemic warfarin, the dose of which had been individually optimized to a stable prothrombin international normalized ratio (INR) of 1.3 to 1.8 during a previous run-in phase (up to 21 days). Coadministration of ESL and warfarin was followed by a 7-day recovery period when warfarin was again administered alone. The effects of ESL on the steady-state pharmacokinetics of R- and S-warfarin and on the INR were assessed. For the R- and S-warfarin assay, blood sampling was to occur at stage 1 (run-in period), 3 days before starting ESL dosing; stage 2 (combined treatment period), on days 1 and 8 at predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose, and on days 4, 6, and 7 at predose; and stage 3 (after the combined treatment period) on days 3, 5, and 7 predose, and on day 8 at 24 hours after the final warfarin dose. For determination of INR, blood sampling was to occur at stage 2 on days 1, 2, 4, 6, 7, and 8 at predose; and at stage 3 on days 1, 3, 5, and 7 at predose and on day 8 at 24 hours after the final warfarin dose. For the assay of the racemic mixture of the S- and the R-enantiomers (eslicarbazepine and R-licarbazepine), blood sampling was to occur at stage 2 on day 8 at predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose, and on days 2, 4, 6, and 7 at predose. C(max) and AUC(0-t) were defined as primary pharmacokinetic parameters. Tolerability was evaluated by monitoring adverse events, clinical laboratory safety tests, vital signs, and 12-lead ECG. RESULTS: Of the 15 subjects enrolled, 13 (7 men and 6 women) completed the study. The mean (SD) age was 28.1 (7.3) years (range, 20-42 years), mean weight was 67.3 (10.7) kg (range, 54.0-84.4 kg), and 14 subjects (93.3%) were white. Reductions in S-warfarin C(max) (test:reference geometric means ratio [GMR] = 0.81 [90% CI, 0.76 to 0.86] and in S-warfarin AUC(ss) (test:reference GMR = 0.77 [90% CI, 0.72 to 0.82]) were observed, without any clinically relevant changes in the INR. The mean INR was 1.45 (0.10) when warfarin was used alone in stage 1 (control) and 1.51 (0.25) when ESL was added to warfarin in stage 2. In relation to stage 1, a slight mean INR increase of 4.04% [90% CI, 1.03% to 9.12%] was reported in stage 2. In stage 3, following discontinuation of ESL administration, a change of -5.42% in the INR was found [90% CI, -8.85% to -1.98%]. ESL was not associated with any clinically relevant changes in R-warfarin pharmacokinetic parameters. No deaths, serious adverse events, or discontinuations due to adverse events were noted, and no clinically relevant findings were reported for the other safety variables. During the course of the study, 9 subjects (60%) reported a total of 32 adverse events. Catheter-site ecchymosis, venipuncturesite hematoma, dizziness, vasovagal reaction, and adhesive-tape allergy were the most common adverse events reported. During coadministration of ESL and warfarin, 7 subjects reported a total of 17 adverse events, of which 6 (epigastric discomfort, asthenia, dizziness, lipothymia, irritability, and macular rash) were considered possibly related to treatment; only lipothymia reached moderate intensity, and all symptoms subsided without sequelae after ESL was discontinued. CONCLUSIONS: In this short-term study in healthy subjects, coadministration of warfarin and ESL 1200 mg once daily was associated with a small, but statistically significant, reduction in systemic exposure to S-warfarin. There was no statistically significant effect on R-warfarin pharmacokinetics or on coagulation as measured by the INR. Protocol identifier: UFH/BIA-2093-108. PMID- 20171424 TI - Pharmacodynamic (hemodynamic) and pharmacokinetic comparisons of S-amlodipine gentisate and racemate amlodipine besylate in healthy Korean male volunteers: two double-blind, randomized, two-period, two-treatment, two-sequence, double-dummy, single-dose crossover studies. AB - BACKGROUND: S-amlodipine gentisate, consisting entirely of the (S)-enantiomer, was developed to increase the potency and improve the safety profile of amlodipine. Regulatory requirements for marketing of S-amlodipine gentisate in Korea require comparison of this agent versus amlodipine racemate. OBJECTIVE: This study was conducted to compare the pharmacodynamic (PD) and pharmacokinetic (PK) characteristics of the S-amlodipine formulation (S-amlodipine gentisate) and amlodipine racemate (amlodipine besylate). METHODS: This study consisted of 2 separate substudies; PD and PK parameters were evaluated separately. Both studies were conducted using a doubleblind, randomized, 2-period, 2-treatment, 2 sequence, double-dummy, single-dose crossover design with S-amlodipine 5 mg and amlodipine racemate 10 mg, separated by a 2-week washout period. Blood pressure (BP) and heart rate were measured in the sitting position before dosing and at 1, 2, 4, 5, 6, 7, 8, 10, 12, 14, 24, 48, and 72 hours after oral administration of S amlodipine or amlodipine racemate. Impedance cardiography parameters (stroke volume, cardiac index, and systemic vascular resistance) were measured before and at 1, 2, 4, 5, 6, 7, 8, 10, and 12 hours after dosing. For PK assessments, serial blood samples were collected before dosing and at 1, 2, 4, 6, 8, 10, 12, 14, 24, 48, 72, 96, 120, 144, and 168 hours after dosing, and drug concentrations were determined by HPLC-MS/MS. Adverse events (AEs) were collected using self-report or general health-related questions. RESULTS: The PD study included 24 healthy men (mean [SD] age, 23.1 [3.1] years; weight, 69.2 [6.1] kg), and the PK study included 24 different healthy men (mean age, 25.1 [2.1] years; weight, 65.9 [5.9] kg). There were no statistically significant differences between the treatment groups in terms of systolic BP, diastolic BP, or heart rate by repeated-measures ANOVA. Likewise, in the analysis of impedance cardiography, the treatment groups did not display any significant differences in stroke volume, cardiac index, or systemic vascular resistance by repeatedmeasures ANOVA. The mean (SD) AUC(0-last) was 129.7 (62.8) ng . h/mL after dosing with S-amlodipine and 129.0 (59.6) ng . h/mL after dosing with amlodipine racemate. The geometric mean ratio (S amlodipine: amlodipine racemate) of the S-amlodipine AUC(0-last) was 1.01 (90% CI, 0.90-1.13). In the PD study, 4 AEs in 3 volunteers (3/24; 12.5%) and 8 AEs in 5 volunteers (5/24; 20.8%) were reported after dosing with S-amlodipine and amlodipine racemate, respectively. In the PK study, 18 AEs in 11 volunteers (11/24; 45.8%) and 20 AEs in 9 volunteers (9/24; 37.5%) were reported after dosing with S-amlodipine and amlodipine racemate, respectively. Five volunteers reported AEs after dosing with both S-amlodipine and amlodipine racemate. For the PD and PK studies combined, 30 AEs were judged to be possibly related to S amlodipine (16 cases) or amlodipine racemate (14 cases). Twenty AEs were judged not to be related to S-amlodipine (6 cases) or amlodipine racemate (14 cases). The most common AEs considered at least possibly related to the study drug in both studies were headache (18 cases) and nausea (3 cases). CONCLUSIONS: In these single-dose studies, no significant differences were found in PD (hemodynamic) or PK parameters between S-amlodipine 5 mg and amlodipine racemate 10 mg. S amlodipine had a safety profile comparable to that of amlodipine racemate in these healthy male volunteers. PMID- 20171425 TI - Pharmacokinetic comparison of controlled-release and immediate-release oral formulations of simvastatin in healthy Korean subjects: a randomized, open-label, parallel-group, single- and multiple-dose study. AB - BACKGROUND: A controlled-release (CR) formulation of simvastatin was recently developed in Korea. The formulation is expected to yield a lower C(max) and similar AUC values compared with the immediate-release (IR) formulation. OBJECTIVE: The goal of this study was to compare the pharmacokinetics of the new CR formulation and an IR formulation of simvastatin after single- and multiple dose administration in healthy Korean subjects. This study was developed as part of a product development project at the request of the Korean regulatory agency. METHODS: This was a randomized, open-label, parallelgroup, 2-part study. Eligible subjects were healthy male or female volunteers between the ages of 19 and 55 years and within 20% of their ideal weight. In part I, each subject received a single dose of the CR or IR formulation of simvastatin 40 mg orally (20 mg x 2 tablets) after fasting. In part II, each subject received the same dose of the CR or IR formulation for 8 consecutive days. Blood samples were obtained for 48 hours after the dose in part I and after the first and the last dose in part II. Pharmacokinetic parameters were determined for both simvastatin (the inactive prodrug) and simvastatin acid (the active moiety). An adverse event (AE) was defined as any unfavorable sign (including an abnormal laboratory finding) or symptom, regardless of whether it had a causal relationship with the study medication. Serious AEs were defined as any events that are considered life threatening, require hospitalization or prolongation of existing hospitalization, cause persistent or significant disability or incapacity, or result in congenital abnormality, birth defect, or death. AEs were determined based on patient interviews and physical examinations. RESULTS: Twenty-four healthy subjects (17 men, 7 women; mean [SD] age, 29 [7] years; age range, 22-50 years) were enrolled in part I, and 29 subjects (17 men, 12 women; mean age, 33 [9] years; age range, 19-55 years) were enrolled in part II. For simvastatin acid, C(max) was significantly smaller (1.68 vs 3.62 ng/mL; P < 0.013) and T(max) and apparent t((1/2)) significantly longer (10.33 vs 4.04 hours [P < 0.001] and 11.41 vs 4.16 hours [P < 0.011]) for the CR formulation compared with the IR formulation, respectively, after the single-dose administration. After the multiple-dose administration, for simvastatin acid, the C(max) for the CR formulation was significantly smaller (3.40 vs 5.16 ng/mL; P < 0.037), while the values for T(max) and apparent t((1/2)) were significantly longer (8.40 vs 4.57 hours and 13.09 vs 4.52 hours; both, P < 0.001) compared with the IR formulation. There was no significant difference between the CR and the IR formulations for AUC(0-last) and AUC(0-infinity)) during either the single- or multiple-dose testing. Both CR and IR formulations were well tolerated in all subjects, and no serious AEs or adverse drug reactions were found. No subjects reported any AEs during part I of the study. During part II, 6 subjects (3 from each formulation group) reported headache, 1 reported lumbago before the dose, and 1 subject had a hordeolum while receiving the CR formulation. CONCLUSIONS: The C(max) of the simvastatin CR formulation was found to be significantly smaller while the AUC of the active moiety did not differ significantly from that of the IR formulation in these healthy Korean subjects. The simvastatin CR and IR formulations were well tolerated, with no serious AEs observed. To evaluate the characteristics of the CR formulation, its clinical efficacy must be examined in patient populations. PMID- 20171426 TI - Comment on Shah et al. PMID- 20171428 TI - [Proposed goals of a French Dermatology Society (SFD) public information website]. PMID- 20171429 TI - [In vitro comparison of the efficacy and photostability of three sunscreen creams]. AB - INTRODUCTION: While sun products are considered as cosmetics within the European Union, in the United States and Japan they are considered as medicines. Following the European market launch of the first sun product considered as a class-1 medical device, Daylong actinica, we compared products having different types of status. MATERIALS AND METHODS: Three sun products underwent in vitro testing in order to determine their efficacy in terms of UVB and UVA protection, as well as their photostability. We used a classic cosmetic product (Nivea Sun 50+), a product displaying particular claims in terms of duration of efficacy (Dix20), and a medical device (Daylong actinica). The in vitro method used involves measuring the transmittance of a sample of the product applied to a polymethylmethacrylate plate using an integrating sphere spectrophotometer. RESULTS: In terms of efficacy, the three products tested were compliant with the European recommendations concerning sun products. In view of the results, the labelling for Nivea Sun 50+ and Daylong actinica) can both display the wording "50+". However, their photostability was poor under our experimental conditions. For Dix20), the labelling that may be displayed is 50. This value gradually decreases to 20 after 10hours of irradiation, accounting for the displayed claim. DISCUSSION: It is somewhat difficult to understand the coexistence on the market of products having different types of status without any prior establishment of clear limits in terms of indices, for example. PMID- 20171430 TI - [Glycopeptide-induced cutaneous adverse reaction: results of an immunoallergic investigation in eight patients]. AB - BACKGROUND: Vancomycin (V) and teicoplanin (T) are glycopeptides used in severe infections and can induce different kinds of cutaneous adverse reactions (CAR). AIMS: To determine the value of immunoallergic investigations in CAR in which glycopeptides are suspected. METHODS: Retrospective study (2000-2007) in eight patients with CAR suspected of being caused by glycopeptides. Six weeks after abatement of the reaction, in accordance with ESCD's guideline for drug testing, immunoallergic skin tests investigations were carried out (drug patch-tests, prick-tests and intradermal tests) in succession for all the drugs taken during the CAR. If negative, a glycopeptide challenge was proposed. RESULTS: The study included eight patients (five women, three men; mean age=53); three patients presented a reaction to vancomycin, four reacted to teicoplanin and one reacted to both drugs. CARs consisted of six maculopapular rashes, one case of DRESS and one of urticaria. Skin tests confirmed involvement of glycopeptides in four of eight cases with cross-reactivity between V and T in two patients. Four patients exhibited good tolerance to rechallenge tests with glycopeptides. CONCLUSIONS: This study shows that skin tests may be useful in glycopeptide-induced CAR in determining the responsible drug and also in the event of rechallenge. Allergic cross-reactivity (V and T), observed in two of our patients, although already been reported in the literature, but does not occur systematically. PMID- 20171431 TI - [Xanthelasma associated with Wegener's granulomatosis]. AB - BACKGROUND: There have been rare reports of normolipidaemic xanthelasma in Wegener's granulomatosis. Herein, we describe another case associated with a review of the literature. CASE REPORT: A 62-year-old woman was hospitalized for Wegener's disease with cutaneous, ENT, renal, joint and neurological signs. Physical examination showed bilateral palpebral xanthelasma with infiltrated lacrimal glands that had appeared simultaneously to the other clinical signs. No hyperlipidaemia was noted. Biopsy of the xanthelasma revealed a typical infiltrate of foamy histiocytes and focal vasculitis. On treatment with corticoids and cyclophosphamide, the yellow lid lesions gradually disappeared. DISCUSSION: Normolipidaemic xanthelasma is rarely reported in association with Wegener's granulomatosis. It accompanies local ophthalmological inflammation and its appearance during the course of this disease must be dealt with carefully. PMID- 20171432 TI - [Cutaneous metastasis revealing epithelioid angiosarcoma of the abdominal aorta]. AB - BACKGROUND: Epithelioid angiosarcomas (EAS) of the aorta are a rare form of tumour usually diagnosed by histopathological analysis of the aorta. We report a case revealed by skin metastasis. CASE REPORT: An 85-year-old man presented skin tumours associated with deterioration of his general condition and intense pain of the right lower limb. Physical examination showed three nodules of the lumbar area associated with an ipsilateral livedo extending to the right lower limb. The course of the disease involved distal ischaemia. Arterial ultrasound, aortography and CAT showed ectasia of the abdominal aorta with thrombosis and right subpopliteal occlusion. Histological examination of a nodule showed proliferation of malignant cells with expression of vimentin, CD 31, cytokeratins AE1/AE3 and cytokeratin 7. Stain for CD34 was negative. Histological investigation of the livedo showed a vascular embolus with epithelial-type cells positive for cytokeratin 7 and CD 31. The PET scan showed intense F-FDG uptake of the aorta extended to the iliac artery. Moreover, skin and osseous F-FDG uptake was seen. These findings suggested a diagnosis of EAS of the aorta with skin and osseous metastasis and vascular emboli. DISCUSSION: Only 27 previous case reports of EAS based on appropriate immunohistochemical analysis have been published in the literature. These tumours typically arise in the abdominal aorta in association with metastasis in more than 80% of cases. Skin metastasis causes papular eruption, nodules and peripheral vascular disease. Embolic vascular occlusion results in ischaemia and in rare cases vasculitis. Our case report emphasizes four key points: the diagnostic value of an association of localized malignant skin tumours, extensive livedo, ipsilateral distal ischaemia, deterioration of the general condition and intense pain; the diagnostic value of endothelial markers, especially CD31, and potentially misleading co-expression of cytokeratin markers; in selected cases, additional imaging, such as PET scans, performed in our case for the first time prior to surgery of the aorta, may be helpful for the diagnosis of such neoplastic lesions of the aortic wall. PMID- 20171433 TI - [Genital lymphogranuloma venereum in an HIV-1 infected patient]. AB - BACKGROUND: Lymphogranuloma venereum (LGV) is an uncommon sexually transmitted disease caused by the L serovars of Chlamydiae trachomatis. Since 2003-2004, a continued outbreak of LGV proctitis (C. trachomatis serovar L2b) has been reported in North America and Europe, including France, among homosexual males, especially with HIV co-infection. CASE REPORT: A 41-year-old man presented penile ulceration of three weeks' standing, associated with a large swollen granulomatous lesion and an inguinal lymph node but without proctitis. All lesions resolved after a three-week course of doxycycline 200mg daily. These lesions were related to a genital bubo due to LGV as confirmed by positive specific PCR for C. trachomatis (serovar L2) performed on the genital ulceration. DISCUSSION: Clinical descriptions of male genital LGV are infrequent, even during the LGV proctitis epidemic seen in Western countries in recent years. A diagnosis of LGV must be considered in the presence of sexually transmitted genital lesions, even atypical, especially among HIV-infected patients. PMID- 20171434 TI - [Fixed food eruption caused by liquorice]. AB - INTRODUCTION: Fixed drug eruption is a characteristic cutaneous adverse reaction that recurs at fixed localisations. It is due to medical drugs. However, food may sometimes be responsible for a similar eruption, known as "fixed food eruption". We report a case of fixed food eruption due to liquorice. CASE REPORT: A 22-year old woman presented with liquorice-induced fixed drug reaction. Topical challenges remained negative both at previously affected sites and in unaffected skin. Therapeutic re-exposure to liquorice confirmed the diagnosis. DISCUSSION: To our knowledge, we report the first case of food drug reaction caused by liquorice. PMID- 20171435 TI - [Baker Rosenbach erysipeloid appearing as a granulomatous cheilitis]. AB - BACKGROUND: Baker-Rosenbach's erysipeloid is a skin infection caused by Erysipelothrix rhusiopathiae. It occurs essentially in humans exposed to animals colonized with this germ such as swine. The typical skin lesion, an erythematous macule generally localized to inoculation site, frequently in the extremities, quickly resolves spontaneously. The lips are an atypical site of this infection. We describe a case of chronic granulomatosis cheilitis in a farmer caused by E. rhusiopathiae. CASE REPORT: A 40-year-old farmer, a wild-boar hunter and chronic smoker with no history of tuberculosis, injury or insect bites, presented at our dermatology unit with ulcerative macrocheilitis of the lower lip ongoing for 1 year. Its surface was purulent. A biopsy specimen showed non-caseating epithelioid granulomas. Laboratory and radiological screening for tuberculosis, sarcoidosis and Crohn's disease, and parasitological examination for Leishmaniasis proved negative. Bacteriological examination identified E. rhusiopathiae and labial Baker-Rosenbach's erysipeloid was diagnosed. The lesion healed after 15 days of treatment with parenteral penicillin G (12m IU/d), totally disappearing after 3 months. DISCUSSION: Swine erysipelas usually occurs in man as Baker-Rosenbach's erysipeloid. This localized form of infection with E. rhusiopathiae is the most frequent and the lesion typically observed is a violaceous plaque, less inflammatory with induration; spontaneous regression occurs after a mean 3 months. To our knowledge, this case is the first report of ulceration associated with macrocheilitis. Histologically, the granuloma directed our investigation towards the principal aetiologies of granulomatosis cheilitis, such as tuberculosis considering the epidemiological context, sarcoidosis or Crohn's disease. The diagnosis of erysipeloid was supported by epidemiological evidence (occupational exposure), isolation of the germ at the lesion and its regression on treatment with penicillin G. CONCLUSION: Diagnosis of E. rhusiopathiae infection was confirmed by bacteriology. However, the hypothesis concerning the pathogenesis of its chronic course in our patient remains a subject of discussion. PMID- 20171437 TI - [The role of dendritic cells in auto-inflammation seen in psoriasis]. PMID- 20171436 TI - [First cases of squamous cell carcinoma associated with cosmetic use of bleaching compounds]. AB - INTRODUCTION: We report two cases of squamous cell carcinoma (SCC) in two black women (phenotype VI) using bleaching compounds for cosmetic purposes over a period of 15 years. CASE REPORTS: Two women (aged 45 and 47 years) with a long history of cosmetic use of bleaching compounds consulted at a dermatology unit for skin tumours. A diagnosis of SCC was confirmed by histological examination of tumour biopsies. One patient was HIV-positive. Surgical treatment was performed in both cases: simple postoperative complications were seen in one patient but the other died at home following recurrence of carcinoma in the year following diagnosis. DISCUSSION: To our knowledge, theses two cases represent the first description of SCC occurring after prolonged cosmetic use of bleaching compounds. Carcinoma occurred in both cases in skin exposed to sun. In our patients, the mechanism of carcinogenesis may have involved melanin destruction, solar exposure and corticosteroid-induced immunosuppression. A direct carcinogenic effect of hydroquinone or other unidentified compounds is another possibility; the carcinogenicity of hydroquinone is well established in rodents. While these observations do not provide formal proof of any implication of depigmentation products in SCC, they emphasize the need for monitoring of dark-skinned women using skin lighteners. PMID- 20171438 TI - [Multiple lesions of focal cutaneous mucinosis: a side-effect of anti-TNF alpha therapy?]. PMID- 20171439 TI - [Topical imiquimod as palliative therapy for extensive lentigo maligna on the cheek]. PMID- 20171440 TI - [Pigmented nodular lesion of the foot]. PMID- 20171441 TI - [Erythema toxicum neonatorum]. PMID- 20171442 TI - [Body-piercing complications]. PMID- 20171443 TI - [Acquired achromic nodular lesion in an infant]. PMID- 20171444 TI - [Langerhans cell histiocytosis]. PMID- 20171445 TI - [Ichthyosis: the saga continues]. PMID- 20171446 TI - [Verrucous carcinoma of the toe]. PMID- 20171448 TI - Predictors of functional recovery (FR) for elderly hospitalized patients in a geriatric evaluation and management unit (GEMU) in Taiwan. AB - Elderly patients who are hospitalized with acute illnesses frequently have adverse outcomes. To maintain functional independence, the geriatric evaluation and management unit (GEMU) was established to provide the opportunity for functional recovery (FR). This study's aim was to investigate potential prognostic factors for functional improvement in a GEMU of Taichung Veterans General Hospital, Taiwan. A total of 117 elderly patients (age, 80.0+/-6.3 years, 84.6% males) were enrolled. A comprehensive geriatric assessment and functional status evaluation, including the functional reach test (FRT) and the timed up-and go (TUG) test, were performed. FR was defined by a greater than 10% improvement in the Barthel Index (BI) before GEMU discharge. Lower BI (44.7+/-25.2 vs. 68.7+/ 34.5, p < 0.001), lower instrumental activities of daily living (IADL) scores (1.8+/-1.5 vs. 3.5+/-2.6, p < 0.001), impaired FRT (83.3% vs. 63.5%, p = 0.028), and impaired TUG test (94.4% vs. 74.6%, p = 0.008) were predictive factors for functional improvement. On multivariate logistic regression, an impaired TUG test (Odds ratio = OR = 6.18, 95% confidence interval = 95% C.I. = 1.69-22.6, p = 0.006) was an independent variable associated with FR. The results indicate that elderly hospitalized patients, even with poor physical function, could benefit from geriatric integrated care delivered by a GEMU. PMID- 20171449 TI - Factors affecting the use of health examinations by the elderly in Taiwan. AB - This study evaluated the factors associated with use of health examinations by the elderly. Data were obtained from the 2005 National Health Interview Survey (NHIS) in Taiwan for 2,482 individuals aged 65 years or older. The Andersen model was used as the analytic framework, and all variables were categorized into four factors: predisposing, need, health-related behavioral, and enabling factors. The chi(2)-test and a hierarchical multiple logistic regression model were used to examine the association between these variables and the use of health examinations. Nearly half (46.8%) of the elderly had used the service previously. In the final model, those with older age, a spouse, Hakka origin, higher educational level, hypertension, bodily pain, and moderate to high exercise were more likely to use health examinations. On the other hand, older adults who usually used alternative medicine, were missing cognitive test results, were current smokers, and had functional limitations were less likely to use the service. The study results showed that the utilization rate of health examinations was low, suggesting that there is a need to increase its utilization through health education. Furthermore, the factors found in the study may be further used for promoting health examinations. PMID- 20171450 TI - Vitamin D insufficiency and frailty syndrome in older adults living in a Northern Taiwan community. AB - This study explored the association between vitamin D insufficiency and frailty syndrome defined by the Fried Frailty Index (FFI) and the Edmonton Frail Scale (EFS) in a northern Taiwan community. Data of 215 subjects participating in an integrated interventional trial involving community-dwelling older adults with a high frailty risk were analyzed. Subjects were first screened by telephone interview and then evaluated at a local hospital with questionnaires, physical performance tests, and serum 25(OH)D measurements. Of the 215 participants, 31% had 25(OH)D insufficiency (< 20 ng/ml). Frail subjects based on the FFI were older, had lower Mini-Mental Status Exam (MMSE) scores, Barthel Index (BI) scores, and 25(OH)D levels. Using the EFS, frailer cases were more likely to be female, have less education, higher comorbid conditions, lower MMSE scores, lower Barthel Index scores, and lower 25(OH)D levels. The associations between insufficient 25(OH)D status and both frailty scales were significant. After adjustment of variables, the odds ratio of 25(OH)D insufficiency was 10.74 (95% CI 2.60-44.31) for frail versus robust individuals. The prevalence of vitamin D insufficiency was high in this population. There was a strong association between vitamin D insufficiency and the FFI. Vitamin D measurements and supplements are suggested for high-risk older people. PMID- 20171451 TI - A hospital-based multidisciplinary approach improves nutritional status of the elderly living in long-term care facilities in middle Taiwan. AB - Improvement in nutritional status using two different care models was assessed in 374 elderly people (mean +/- S.D. age = 78.8+/-7.2 years) living in eight long term care facilities in middle Taiwan. The subjects were divided into two groups using randomized block design; a hospital-based multidisciplinary team was responsible for the care of the intervention group, and the control group received usual care for 6 months. A structured questionnaire, anthropometric measurements, and biomedical markers were checked for each subject before and after the intervention. No significant differences were observed in age, height, weight, body mass index, hemoglobin, and albumin between the intervention (n = 125) and control (n = 249) groups at baseline. After 6 months of intervention, 83 subjects in the intervention group and 182 subjects in the control group had completed the study. The change in albumin level was greater in the intervention group (1.58 g/l) than in the control group (0.15 g/l, p < 0.05). The prevalence of hypoalbuminemia (albumin < 35 g/l) decreased from 69.2% to 52.9% in the intervention group and from 70.3% to 67.0% in the control group. In conclusion, a hospital-based multidisciplinary care effectively improved the nutritional status of elderly patients living in long-term care facilities in middle Taiwan. PMID- 20171452 TI - Evaluating probability of cancer among older people with unexplained, unintentional weight loss. AB - Unexplained, unintentional weight loss (UUWL) in older people is usually multi factorial and poses a diagnostic challenge, with cancer being the major concern. The main purpose of this study was to evaluate the effectiveness of a cancer scoring system for predicting cancer in elderly UUWL patients. From 2006 to 2007, 50 patients (mean age, 78.8+/-4.7 years, 82% male) who lost > 5% of usual body weight were enrolled. The subjects' mean body weight loss was 14.1%+/-6.6% (8.7+/ 4.6 kg). After evaluation, the common diagnoses were non-malignant organic disorder (22/50, 44%), neuropsychiatric disorder (17/50, 34%), unknown (8/50, 16%), and cancer (3/50, 6%). The most rapid weight loss occurred with cancer (6.5% per month), followed by non-malignant organic disorders (5.6% per month), neuropsychiatric disorders (2.8% per month), and unknown causes (2.4% per month); the difference among the groups was significant (p = 0.023). Using a previously proposed scoring system, 42 patients (84%) had a low probability of cancer; all three cancer patients were in this category. In conclusion, the annual incidence of cancer among elderly UUWL patients was 6%, and the previously developed cancer scoring system did not effectively predict cancer occurrence. Further study is needed to develop an effective instrument to predict cancer in elderly UUWL patients. PMID- 20171453 TI - Outcomes of hospitalized elderly patients with geriatric syndrome: report of a community hospital reform plan in Taiwan. AB - The purpose of this study was to evaluate the outcomes of elderly inpatients with geriatric syndromes. A prospective study involving patients aged 65 years and older in 12 community hospitals was performed. Baseline data, which included demographic characteristics, mini mental status exam, geriatric depression scale (GDS), mini nutritional assessment (MNA), activities of daily living (ADL), and instrumental activities of daily living (IADL), were collected in geriatric assessments. The primary outcome was functional deterioration; additional outcomes included mortality, re-hospitalization, and emergency department visits, as identified by telephone interview and chart review. A total of 1,008 patients were recruited: 31.2% of the participants were ADL intact, 21.3% were IADL intact, 11.5% had depression, 29.3% had nutritional problems, and 60.3% had impaired cognition at baseline. During follow-up, 172 patients (19.3%) died, 43.8% reported ADL deterioration, and 45.9% reported IADL deterioration. On multivariate analysis, older age, low mini mental state examination (MMSE) score, and low MNA score were predictors of functional deterioration. Under the interdisciplinary team care of the Community Hospital Reform Plan (CHRP), most of the elderly patients maintained or increased their functional capacity; the one year mortality rate was higher than that of the general population but lower than that of other studies targeting the frail elderly. PMID- 20171454 TI - Health, financial stresses, and life satisfaction affecting late-life depression among older adults: a nationwide, longitudinal survey in Taiwan. AB - The purpose of this study was to determine the incidence of depression in late life and to explore associated risk factors among Taiwanese elderly. The analyses were based on nationally representative data from the Survey of Health and Living Status of the Elderly in 1999 and 2003. A total of 1,487 respondents aged 65 years and older who completed the 10-item Center for Epidemiological Survey Depression (CES-D) scale in these two surveys and without depression in 1999 were included in the final analyses. Depression was defined as a CES-D score equal to or greater than 10. The independent variables included sociodemographic characteristics, occurrence of new diseases, social support, perceived health and financial stresses, life satisfaction, and functional condition. The incidence rate of depression over 4 years was 19.7%. Multivariate regression analyses revealed that women who perceived greater health or financial stress and who had greater life dissatisfaction or worsened functional condition were more likely to suffer depression. These findings imply that healthcare programs for older adults should include cognitive and behavioral interventions in order to prevent the development of depression in late life. PMID- 20171455 TI - The effectiveness of a comprehensive geriatric assessment intervention program for frailty in community-dwelling older people: a randomized, controlled trial. AB - This randomized, controlled trial assessed the effectiveness of comprehensive geriatric assessment (CGA) and subsequent intervention in pre-frail and frail community-dwelling elderly based on the Fried Frailty Criteria (FFC) and the Barthel Index (BI) A total of 310 pre-frail or frail elderly from a single community were identified using the FFC. Of these, 152 were randomly assigned to the intervention group for CGA and appropriate intervention by medication adjustment, exercise instruction, nutrition support, physical rehabilitation, social worker consultation, and specialty referral. Clinical outcome was re evaluated by the FFC and BI 6 months later. Compared to the control group, the intervention group tended to have a better outcome, with an odds ratio (OR) = 1.19, 95% confidence interval (95% CI) = 0.48-3.04, p = 0.71) and 3.29 (95% CI = 0.65-16.64, p = 0.15), respectively, and were less likely to deteriorate, with an OR = 0.78 (95% CI = 0.34-1.79, p = 0.57) and 0.94 (95% CI = 0.42-2.12, p = 0.88), respectively. Although no significant differences were observed, the CGA and subsequent intervention showed a favorable outcome in frail and pre-frail elderly based on the frailty status and BI. Inability to complete the CGA and poor compliance with the intervention program appear to be the main reasons for unfavorable outcomes. PMID- 20171456 TI - The prevalence of subjective frailty and factors associated with frailty in Taiwan. AB - This study estimated the prevalence of frailty and identified the factors associated with frailty in Taiwan using data from the Survey of Health and Living Status of the Elderly. A nationwide probability sample including 2,238 individuals aged > or =65 years was interviewed in 2003. Based on the Cardiovascular Health Study conducted by Fried, five phenotypes of frailty were selected: poor appetite, exhaustion, low physical activity, poor walking ability, and poor twisting ability of fingers. Participants were classified as nonfrail, prefrail, and frail if they met 0, 1 or 2, and > or =3 criteria. The prevalences of nonfrailty, prefrailty, and frailty were 55.1%, 40.0%, and 4.9%, respectively. The prevalence of frailty increased with age and was greater in women. Frailty was associated with less education, no spouse, disability, higher rates of comorbid chronic diseases, depressive symptoms, and geriatric syndromes. Specific drug use, such as hypnotics, analgesics, herbal drugs, and parenteral fluid supplements was positively associated with frailty. The use of multivitamins, fish oil, and vitamin E was negatively associated with frailty. The prevalence of frailty is lower in Taiwan than in Western countries. Depressive symptoms, geriatric syndromes, and specific medication use are potential fields for frailty prevention in community-dwelling older adults. PMID- 20171457 TI - Body mass index (BMI) at an early age and the risk of dementia. AB - BMI change and BMI at an early age have not been investigated as risks for dementia. This case-control study included 286 dementia patients and 268 controls from two medical centers between 2007 and 2009. BMI information was collected from medical records and questionnaires. Men and women with low BMIs at the time of the study, in their 20s, and in their 40s had significantly increased risks of Alzheimer's disease (AD) (odds ratio = OR = 2.62-3.97) and increased vascular dementia (VaD) risk (20s and 40s: OR = 6.23-11.11) compared with those with normal BMIs. High BMI in the 20s and 40s was associated with increased VaD risk (OR = 15.29 and 10.32) among women. For BMI changes from the 20s or 40s, the second and third tertiles were significantly associated with decreased AD risk among women (OR = 0.15-0.35) compared to the first tertile. The third tertile of BMI change from the 20s or 40s was associated with decreased VaD risk among women (OR = 0.06 and 0.14). Low BMIs in the 20s and 40s were stronger predictors of AD and VaD. There was a U-shaped association between BMI at different ages and dementia among participants with VaD. PMID- 20171458 TI - Determinants of cognitive impairment over time among the elderly in Taiwan: results of the national longitudinal study. AB - This study aimed to identify the risk factors for cognitive impairment among the elderly population in Taiwan. Data were drawn from three waves of the "Survey of Health and Living Status of the Elderly in Taiwan", a national longitudinal study started in 1989. We included respondents without dementia or cognitive impairment at baseline in 1993 and followed them over a 10-year period. Cognitive function was measured by the nine-item Short Portable Mental Status Questionnaire in 1993, 1999, and 2003. Independent variables, including age, sex, marital status, education, ethnicity, ADLs, IADLs, physical function, social participation, chronic diseases, smoking, and alcohol drinking, were collected at baseline in 1993. Depressive symptoms were assessed by the 10-item Center for Epidemiologic Studies Depression Scale (CES-D). Logistic regression was used to evaluate the predictive factors for cognitive impairment. Of the eligible 1,626 respondents, 72 (4.43%) and 484 (29.77%) individuals did not complete follow-up in 1999 and 2003, respectively, mostly due to death. Our results showed that older age (OR = 2.60, 95% CI = 1.79-3.78), being female, lower educational level, IADL disability (OR = 2.06, 95% CI = 1.38-3.09), and having a history of diabetes (OR = 1.70, 95% CI = 1.06-2.74) or stroke (OR = 2.36, 95% CI = 1.06-5.26) were independent predictors for cognitive impairment in Taiwan. PMID- 20171459 TI - Diabetes mellitus and functional impairment in Taiwanese older men and women. AB - Type 2 diabetes mellitus is strongly related to many kinds of functional impairment, even after adjusting for demographic and comorbid conditions. The current study examined sex differences in the relationships between Type 2 diabetes mellitus and functional impairment in an Asian population sample. Data were obtained from a national survey, the Social Environment and Biomarkers of Aging Study (SEBAS) in Taiwan. A total of 652 older adults aged > or =65 years were included in the study. Pearson's chi(2)-test and multiple logistic regression analysis were used to examine the relationships between diabetes and functional impairments in older men and women. The reported numbers of impairments were significantly higher in women, in those aged > or =75 years, and in those with diabetes. There were sex and age differences in the relationships between diabetes and functional difficulties. Even after adjustment for age, education, and co-morbid conditions, men with diabetes were about four times more likely to have difficulties related to self-care, and women with diabetes were about two to three times more likely to have difficulties related to higher functioning than their non-diabetic counterparts. Sex differences should be considered when understanding the relationships between diabetes and functional impairments in older adults. PMID- 20171460 TI - Preface. Geriatric syndrome studies. PMID- 20171461 TI - Annals of Emergency Medicine Journal Club. Is the golden hour tarnished? Registries and multivariable regression. AB - WHAT IS ALREADY KNOWN ON THIS TOPIC: The "golden hour" concept in trauma is pervasive despite little evidence to support it. WHAT QUESTION THIS STUDY ADDRESSED: Is there an association between various emergency medical services (EMS) intervals and in-hospital mortality in seriously injured adults? WHAT THIS STUDY ADDS TO OUR KNOWLEDGE: In 3,656 injured patients with substantial perturbations of vital signs or mental status, transported by 146 EMS agencies to 51 trauma centers across North America, no association was found among any EMS interval and mortality. HOW THIS MIGHT CHANGE CLINICAL PRACTICE: This study suggests that in our current out-of hospital and emergency care system time may be less crucial than once thought. Routine lights-and-sirens transport for trauma patients, with its inherent risks, may not be warranted. PMID- 20171464 TI - Images in emergency medicine. Man with painful skin lesion. Warfarin sodium skin necrosis. PMID- 20171466 TI - News & perspective piece fails to acknowledge evidence for resident work hours limits. PMID- 20171465 TI - Severe opioid withdrawal due to misuse of new combined morphine and naltrexone product (Embeda). PMID- 20171468 TI - Maxillofacial health, beauty, and chi: Andy Gump and the avatars. PMID- 20171469 TI - Characteristics of implant failures in patients with a history of oral bisphosphonate therapy. AB - PURPOSE: This study examines the pattern of implant failures reported in a large cohort of patients who received oral bisphosphonate therapy. MATERIALS AND METHODS: A total of 8,572 individuals who received oral bisphosphonate drugs returned a dental survey that obtained information pertaining to implant placement and related complications. Among the 589 individuals reporting dental implants, 16 reported implant failures that were verified by dental records. Implant placement, timing of failure, and bisphosphonate duration were ascertained to determine the characteristics of implant loss in the setting of oral bisphosphonate exposure. RESULTS: Among the 16 patients (all women, aged 70.2 +/- 7.6 yrs) there were 26 implant failures; 8 had failure of 12 implants in the maxilla and 9 had failure of 14 implants in the mandible. Early failure (1 yr after placement) occurred in 10 patients (18 implants); 2 patients had both early and late failures. CONCLUSIONS: Overall, few patients reported implant failures. However, among these, there were more late than early failures and a slightly higher proportion of failures in the mandible versus the maxilla. Further studies should investigate the role of chronic bisphosphonate therapy in implant survival and long-term implant osseointegration. PMID- 20171470 TI - Effect of zoledronic acid on osseointegration of titanium implants: an experimental study in an ovariectomized rabbit model. AB - PURPOSE: Zoledronic acid (ZA), a new-generation intravenous bisphosphonate, exhibits the greatest affinity for bone mineral with the longest retention, thereby leading to its ability to be dosed at annual intervals in the treatment of osteoporosis. The purpose of this preliminary study was to evaluate the effects of systemic administration of a single dose of ZA on osseointegration and bone healing around titanium dental implants. MATERIALS AND METHODS: Thirty-six female New Zealand rabbits (aged 6-12 months) were used in this study. Rabbits were randomly assigned to 1 of 3 groups: sham control group (SH), ovariectomy group (OVX), and OVX and ZA group (OVX + ZA). Animals in the OVX and OVX + ZA groups were subjected to bilateral ovariectomy, whereas animals in the SH group were sham operated. Eight weeks later, 1 implant was placed in each tibia of the animals. ZA was administered in the OVX + ZA group during the implantation, whereas the OVX and SH groups received saline solution infusions. All of the subjects were sacrificed 8 weeks after the implantation, and tibial specimens were harvested. Histomorphometric bone-to-implant contact analysis, resonance frequency analysis, removal torque testing, and digital radiographic absorptiometry were administered, and the data were statistically analyzed. RESULTS: Histomorphometric, resonance frequency, and radiodensitometric analyses showed significant improvement in osseointegration of implants in the OVX + ZA group compared with the OVX group. However, the differences in removal torque results between the groups were not statistically significant. CONCLUSIONS: The results of this study suggest that systemic ZA administration may improve osseointegration of titanium implants placed in estrogen-deficient states of bone. PMID- 20171471 TI - Clinical evaluation of implants in radiated fibula flaps. AB - PURPOSE: The success of osseointegrated implants in the radiated fibula flap used for mandibular reconstruction is variable, and there are few long-term data available in the literature. The purpose of this study is to evaluate implant success in radiated fibula flaps and the native mandible after ablative tumor surgery. MATERIALS AND METHODS: The medical records of 44 patients who underwent resection and reconstruction of the mandible from 1994 to 2006 were reviewed retrospectively. A total of 206 implants were placed; 144 were placed in a fibula flap, and 92 were placed in the native mandible. Before implant placement, 22 patients (50%) received adjuvant tumoricidal doses of radiation therapy (>6,000 cGy). All patients who received radiation received a standard regimen of 20 preoperative and 10 postoperative hyperbaric oxygen treatments. The follow-up period ranged from 4 to 108 months (mean, 41.1 months). Comparisons were made between groups regarding long-term implant success based on several variables. RESULTS: Implants were considered to be successful if there was no radiographic evidence of peri-implant bone loss and if they were clinically osseointegrated. Of 206 implants, 31 failed, with an overall success rate of 85%. The success rate of implants placed in fibula flaps was 82.4%, and the success rate in native mandibles was 88%. Most of the failures in the fibula (90%) occurred within the first 6 months after implant placement, whereas most of the failures in the mandible occurred after 6 months. The cumulative survival rate was 91.9%, and there was no difference in survival between implants placed in the fibula versus the native mandible or depending on whether the patient received radiation therapy. CONCLUSION: Acceptable long-term implant success rates may be achieved in the radiated mandible with vascularized fibula flap reconstruction. PMID- 20171472 TI - Implant treatment in patients with severe hypodontia: a retrospective evaluation. AB - PURPOSE: The aim of this retrospective study was to evaluate the result of implant treatment in patients with severe hypodontia and compare some basic characteristics of patients with severe hypodontia who received conventional dental treatment or no treatment at all with those who were treated in combination with endosseous implants. PATIENTS AND METHODS: All patients who had been referred to an academic center of special dental care between 1990 and 2008 and who had been classified at their first visit as having "oligodontia" or "severe hypodontia" were selected from the hospital's database. Their charts were reviewed, and surgical treatment details and outcomes of the implants were registered from those patients who received endosseous implants. RESULTS: Of the 294 patients who met the inclusion criteria, 44 patients were treated in combination with endosseous implants. The cumulative chance of implant survival of the 214 placed implants after 5 years was 89.8% (SE, 2.6%), with a mean observation period of 2.9 years (minimum, 0.1 years; maximum, 18.3 years). No implants failed thereafter. Patients who received implants were missing fewer teeth and were treated more recently compared with those who received conventional restorative treatment or no treatment at all. CONCLUSION: Considering the compromised anatomic situation and the complexity of treatment, a 5-year survival rate of 89.8% in patients with severe hypodontia, as seen in this study, is regarded as acceptable. PMID- 20171473 TI - Island osteoperiosteal flap for alveolar bone reconstruction. AB - The island osteoperiosteal flap (I-flap) is introduced as a modified alveolar split bone grafting technique used to gain width and modify the facial or buccal bone plate position. Three case examples are shown as well as animal histology indicating the possible development of this new surgical procedure as an adjunct for alveolar augmentation and implant therapy. PMID- 20171474 TI - Evaluation of the smile: facial and dental considerations. AB - PURPOSE: The purpose of this article is to establish an evidence-based evaluation of the esthetic region of the mouth, by reviewing normal values for the face, the smile line, and the teeth. MATERIALS AND METHODS: A Medline search was performed to find evidence-based data on accepted normal ranges of facial and dental proportions. The information found was organized following a sequence of physical examinations, which then was used to develop a decision tree for diagnosis and treatment planning. CONCLUSIONS: By following this evaluation algorithm, clinicians will be able to document a standard set of data that will reveal skeletal and dental dysmorphia, which can then follow a well-organized sequence of treatment to re-establish facial and dental harmony. PMID- 20171475 TI - Characteristics of head and neck cancer patients referred to an oral and maxillofacial surgeon in the United States for management. AB - PURPOSE: The purpose of this study was to report the characteristics of patients with head and neck cancer, excluding cutaneous malignancies, referred to an oral and maxillofacial surgeon in the United States for management. MATERIALS AND METHODS: We performed a retrospective chart review of all head and neck cancer patients referred to the senior author's oral and maxillofacial surgery practice over 12 consecutive months. Data were extracted from the patients' comprehensive record and included demographics, social history, site, histologic diagnosis, staging, treatment, and referral patterns. RESULTS: A total of 90 patients, 51 men and 39 women (male-female ratio, 1.3:1), with a mean age of 64.4 years (range, 32-91 years) were referred with head and neck cancer, excluding skin cancer, over the 12-month period and were included in the study. Regarding ethnicity, 88.8% of the patients were white, 11.1% African American, and 1.1% Asian. Most of the patients, 84.4%, were referred from within the state, but only 21.1% of these resided within the metropolitan area of the senior author's practice. Of the patients in the study population, 95.5% had either private or state-provided/federally provided insurance. Social history showed that 59.9% of patients were current or past smokers, 31.1% were nonsmokers, and 8.8% were smokeless tobacco users, and only 18.8% admitted to alcohol use. Approximately 80% of patients were initially evaluated by a general dentist, oral and maxillofacial surgeon, or periodontist, and 93% of referrals were from other oral and maxillofacial surgeons. Over 90% of lesions were located in the oral cavity, and only 6.6% were oropharyngeal primary cancers. Squamous cell carcinoma made up 89% of the lesions, whereas minor salivary gland and metastatic carcinomas comprised the other 11%. At the time of diagnosis, 64.4% of the lesions were early stage (I/II) and 35.6% were late stage (III/IV). Analysis of treatment modalities showed that 87.8% underwent surgery, excluding biopsy, as part of their therapy. Of these, 83.5% were treated with surgery only, whereas the others received both surgery and some form of adjuvant therapy. Five patients were treated with concurrent chemoradiation therapy. CONCLUSION: Our results suggest that patients referred to an oral and maxillofacial surgery practice for management of head and neck cancer are different from those described in previous reports regarding demographics, social history, site, and stage of disease at diagnosis and treatment. This finding may be explained by the unique referral pattern for oral and maxillofacial surgeons treating head and neck cancer. PMID- 20171476 TI - Individual design and rapid prototyping in reconstruction of orbital wall defects. AB - PURPOSE: We examined the application of individual digital design and rapid prototyping in the reconstruction of orbital wall defects for different stages of orbital volume (OV) changes. PATIENTS AND METHODS: Patients with unilateral post traumatic orbital defects underwent individual digital design and rapid prototyping to manufacture specific titanium mesh implants to create ideal OV recovery. Features of orbital wall fracture deformities and OV changes were analyzed and measured with 3-Dimensional Medical Surface Rendering image software system. RESULTS: Most cases involving enophthalmos and diplopia were rectified, except for 5 cases of enophthalmos and 2 cases of diplopia with fresh fractures and 11 cases of enophthalmos and 7 cases of diplopia cases with old fractures. Ocular movements and facial malformations were improved. The OV values between the uninjured and injured sides had a significant deviation (P < .05). The degree of enophthalmos had no significant deviation with OV changes pre- and postoperatively in the early fracture stages. The degree of enophthalmos in the old fracture stages had a significant deviation with OV changes pre- and postoperatively. CONCLUSIONS: This study showed that orbital wall fractures can be diagnosed in early fracture stages and that the degree of long-term enophthalmos can be predicted with 3-Dimensional Medical Surface Rendering software. Our results suggest that early-stage orbital wall fractures should recover OV as early as possible, and that advanced stage orbital wall fractures should overcorrect OV. The degree of accuracy and rational of OV reconstruction can be improved by appropriate individual digitalization design and rapid prototyping technology. PMID- 20171477 TI - Treatment of oral leukoplakia with carbon dioxide and potassium-titanyl-phosphate lasers: a comparison. AB - PURPOSE: To determine whether the treatment of oral leukoplakia with potassium titanyl-phosphate (KTP) lasers versus CO(2) lasers results in lower recurrence rates. MATERIALS AND METHODS: Retrospective data were collected from the records of 30 patients (mean age 75.6 years) with 35 primary oral leukoplakia who had their lesions ablated by KTP laser, and 45 patients (mean age 59.9 years) with 59 primary oral leukoplakia who had CO(2) laser treatment. The recurrence rates of lesions between these 2 groups was then compared. RESULTS: A statistically significant (P = .049) reduction in recurrence rates for those patients treated with KTP lasers versus CO(2) lasers was found. CONCLUSION: The use of KTP lasers for the treatment of oral leukoplakia may result in lower recurrence rates than when using CO(2) lasers. PMID- 20171478 TI - Success of zygomatic plate-screw anchorage system. AB - PURPOSE: To evaluate the success of zygomatic plate-screw anchorage and to define the key points that help to improve the success of this system. MATERIALS AND METHODS: A total of 74 zygomatic plate-screw anchors were applied to 37 patients from 2 groups receiving orthodontic treatment. The first group consisted of 19 patients, and the zygoma anchors were applied bilaterally to distalize the maxillary buccal segment. The second group consisted of 18 patients, and the zygoma anchors were applied bilaterally to stabilize the maxillary molars during maxillary canine retraction. The orthodontic force was applied 1 week after the insertion of the plates. In the first group, 450 g of direct force and in the second group 150 g of indirect force were applied to the zygomatic plates. The success rate of the zygomatic plate-screw anchorage system was evaluated. RESULTS: One plate was lost and the others remained stable all through the orthodontic treatment. Mild gingival inflammation was observed in 1 patient (2 plates), and pus formation was detected in 1 patient (2 plates). One plate was covered because of mucosal hypertrophy. CONCLUSION: Zygomatic plate-screw anchorage system is a reliable technique to obtain orthodontic anchorage and may eliminate the need for extraoral force. However, the surgical insertion technique, position of the plates, and oral hygiene status of the patients certainly influence the success of the system. PMID- 20171479 TI - Clinical and anatomic study on the ducts of the submandibular and sublingual glands. AB - PURPOSE: To investigate the relationship between the ducts of the submandibular gland (SMG) and sublingual gland (SLG) and discuss its clinical application relating to SMG radiologic examinations and transfer. MATERIALS AND METHODS: The microanatomy of the SMG and SLG was investigated by use of 30 adult cadavers through anatomic dissection by use of a microscope. The relationship between the SMG and SLG ducts was observed and recorded during operations of microvascular autologous SMG transfer in 63 cases of severe keratoconjunctivitis sicca. RESULTS: There were 3 patterns of SLG and SMG duct anatomic variation: 1) The SMG and SLG have their own respective ducts that secrete separately at the orifices of the ducts in the floor of the mouth. 2) The SLG has a major duct that joins the duct of the SMG. 3) The SLG only has many fine ducts (7-15) that secrete in the floor of the mouth. CONCLUSIONS: The anatomy of the ducts of the SMG and SLG is quite complicated. More attention should be paid to the anatomy of the ducts during surgery or imaging procedures related to the SMG. PMID- 20171480 TI - Clinical follow-up examination of surgically treated fractures of the condylar process using the transparotid approach. AB - PURPOSE: The surgical approaches for the open treatment of condylar process fractures have been controversial. In our study, we evaluated the morbidity of the transparotid approach during 2 years of follow-up. PATIENTS AND METHODS: A total of 48 patients with condylar process Class II and IV fractures according to classification of Spiessl and Schroll, were included in the present study. Of the 48 patients, 16 were female and 32 male. The patient age range was 16 to 79 years (average 36.52). All patients were treated using the transparotid approach, with rigid internal fixation using miniplates. Follow-up examinations were performed for a minimum of 6.5 months and a maximum of 25 months (average 12.16) after surgical treatment. At the follow-up examination, the patients completed the Mandibular Function Impairment Questionnaire, and the examiner completed the Helkimo index. X-rays taken before, directly after, and 6 months after surgery were compared. RESULTS: None of our patients had problems with wound healing; 2 patients developed a fistula of the parotid gland; and 4 patients developed palsy of the facial nerve that was completely reversible after 6 weeks. The results of the Mandibular Function Impairment Questionnaire and the Helkimo index revealed only a few subjective and objective problems after 6 months. CONCLUSIONS: The transparotid approach to condylar process fractures is most appropriate for strongly displaced Class II fractures. Especially for very old patients with dementia, for whom maxillomandibular fixation is contraindicated, this approach is very appropriate. Another benefit to this type of patient is the short operating time, with an average of 45 minutes. PMID- 20171481 TI - Analgesic effects of intra-articular morphine in patients with temporomandibular joint disorders: a prospective, double-blind, placebo-controlled clinical trial. AB - PURPOSE: A number of reports have shown a direct analgesic effect of opioids by way of the peripheral receptors. Nevertheless, only a very few studies have reported using opioids in the temporomandibular joint (TMJ), and nearly all of them were connected to surgical patient groups. The present study was designed to evaluate the analgesic efficacy and safety of repeated intra-articular morphine applications compared with a local anesthetic and saline solution in the management of TMJ pain. PATIENTS AND METHODS: A total of 48 patients with articular pain related to the TMJ were entered in a clinical, prospective, randomized, double-blind, single-center study. The analgesic effect of repeated intra-articular infiltration with morphine (5 or 10 mg morphine sulfite), bupivacaine 0.5% (Carbostesin; AstraZeneca, London, UK), and isotonic saline solution as a placebo in the TMJ was examined. The efficiency after 3 injections of the same substance with an interval of 48 hours between each application was measured using a pain relief scale, visual analog scale, pain intensity scale, and the potential need for accessory peripheral analgesics (paracetamol). RESULTS: All patients showed, independent of the treatment group, pain relief within 60 minutes after the first injection. Patients with saline and Carbostesin reported almost complete pain recurrence before the second injection. At 1 week after the last and third injection, the 10-mg morphine group still showed a distinct effect, with 16.7% reporting complete (no pain) and 41.7% distinct pain relief. In addition, 33.3% had a poor response and 8.3% had no improvement. None of the other groups reported complete improvement; however, 25% of the patients who received 5 mg morphine had distinct pain relief, and 50% had at least poor pain relief. In the Carbostesin group, distinct improvement was reported by 8.3%, with a poor response in 41.7%, and no effect in the remaining 50%. Patients treated with saline had a poor response in 16.7%, but most (83.3%) reported no improvement 1 week after treatment. CONCLUSIONS: Independent of the applied substances, initial pain relief can be registered in the TMJ: either from the arthrocentesis effect or at least the placebo effect. Morphine at a dosage of 10 mg showed the best and most long-lasting analgesic efficiency. Morphine, in general (5 and 10 mg), and, with limitations, Carbostesin were more or less efficient for postoperative pain control but without distinct effects in the long term. With regard to our results, we can recommend intra-articular morphine application at a dose of 10 mg for pain management. Carbostesin showed no promising long-term effects. PMID- 20171482 TI - Third molar caries experience in middle-aged and older Americans: a prevalence study. AB - PURPOSE: To assess the prevalence of third molar caries experience in a middle aged and older population and the relationship of these findings to caries experience in teeth more anterior in the mouth. PATIENTS AND METHODS: Data from 6,550 Dental Atherosclerosis Risk in Communities study participants aged 52 to 74 years who underwent a clinical examination for coronal caries experience were available for these analyses. Subjects with visible third molars (N = 2,003) were divided based on third molar coronal caries experience on at least 1 third molar: no carious/decayed coronal surface (DS) or at least 1 coronal DS and no filled coronal surface (FS) or at least 1 coronal FS. Coronal DS and FS were also calculated for more anterior teeth. Covariates included ethnicity, gender, age, body mass index, education, income, smoking status, and diabetes diagnosis. Subject level outcomes for third molar and more anterior teeth were compared by descriptive statistics and chi(2) or t tests with statistical significance set at P less than .05. Multivariate modeling was performed to adjust outcome variables for covariates. RESULTS: Third molar caries experience was detected in 77% of subjects and was significantly associated with caries experience in more anterior teeth and white race (P < .01). Caries experience was detected in only third molars in 1% of subjects, and 1% of subjects were caries free. Subjects with less education (20%) and lower income (19%) were significantly more likely to have DS detected compared with subjects with more education (6%) and higher income (5%) (P < .01). Conversely, subjects with more education (75%) and higher income (77%) were significantly more likely to have FS detected compared with subjects with less education (55%) and lower income (60%) (P < .01). CONCLUSIONS: Third molar coronal caries experience was significantly associated with caries experience in teeth more anterior in the mouth in this middle-aged and older population. PMID- 20171483 TI - Mandibular ramus/coronoid process grafts in maxillofacial reconstructive surgery. AB - PURPOSE: To evaluate the utility of autogenous extended mandibular ramus and coronoid process bone grafts for maxillofacial reconstructive surgery. PATIENTS AND METHODS: Twelve patients aged 23 to 76 years (mean, 52) who underwent extended ramus/coronoid process grafts for reconstruction of maxillofacial deformities due to trauma, alveolar atrophy, or iatrogenic nasal deformity. All patients had either unilateral or bilateral combined coronoid process-mandibular ramus bone grafts for their reconstruction. There was 1 nasal reconstruction, 2 unilateral mandibles, 1 bilateral mandible, 4 unilateral maxillas, 1 unilateral maxilla and mandible combined, and 1 bilateral maxilla and mandible combined. RESULTS: The procedure was considered a success when the patient's deformities were reconstructed ad integrum and when there were no failures of the dental implants placed in the augmented areas as of the longest follow-up. All patients were successfully reconstructed. There was 1 infection at a donor site that resolved with local care and oral antibiotics. All but 1 of the maxillary and mandibular alveolar augmentations underwent endosteal implant placement approximately 4 to 6 months following grafting. The nasal reconstruction restored normal function and symmetry. CONCLUSION: Using both the coronoid process of the mandible and the mandibular ramus as a source for autogenous bone graft can provide sufficient bone in quantity and quality for selected maxillofacial reconstructions. PMID- 20171484 TI - Complication rates in the operative treatment of mandibular angle fractures: a 10 year retrospective. AB - PURPOSE: Large-scale studies assessing complication rates and correlation of complications are still missing considering different fracture locations in the mandible. In the present retrospective study, complication rates of mandibular angle fractures treated by open reduction were assessed. MATERIALS AND METHODS: Three hundred twenty-two patients (259 men, 63 women) with 335 surgically treated mandibular angle fractures were included in this study. RESULTS: Fractures were caused by fights (46.6%), falls (19.2%), traffic accidents (14.6%), sports (11.9%), wisdom tooth removal (7.3%), and 0.9% other causes. Successful treatment occurred in 93.69% of fractures with 1 open reduction and in 6.31% with 2 open reductions. Of surgically treated patients, 71.47% (238) were completely free of complications. A detailed complication correlation matrix is given in the text. Ninety-five fractures treated with 1 miniplate, 170 with 2 miniplates, and 70 with other osteosynthesis concepts were compared regarding osteosynthesis failure and pseudarthrosis. CONCLUSION: Similar osteosynthesis failure rates were shown for 1 miniplate and 2 miniplates. PMID- 20171485 TI - Andy Gump and his deformity. PMID- 20171486 TI - Who was Andy Gump? PMID- 20171487 TI - Benign cementoblastoma of the anterior maxilla. PMID- 20171488 TI - Cervical support collar: a substitute to the jaw thrust/chin lift methods of airway management during oral maxillofacial surgeries. PMID- 20171489 TI - Nasal base modification in Asian patients. PMID- 20171490 TI - Chin augmentation with thin cortical bone concomitant with advancement genioplasty. PMID- 20171491 TI - Automated 3-dimensional airway analysis from cone-beam computed tomography data. PMID- 20171492 TI - Hypotensive anesthesia monitoring using a noninvasive arterial line during orthognathic surgery. PMID- 20171493 TI - Is exposure of the jawbone mandatory for establishing the diagnosis of bisphosphonate-related osteonecrosis of the jaw? PMID- 20171494 TI - Is a modification of Kaban's protocol in treating temporomandibular joint ankylosis appropriate? PMID- 20171496 TI - The administration of antibiotics is a crucial point for success and is just as important as thoroughly rinsing the sinus preoperatively. PMID- 20171497 TI - Cost of 3-dimensional imaging-based surgery. PMID- 20171498 TI - It is the nature of the world in which we currently live. PMID- 20171499 TI - Our specialty. PMID- 20171500 TI - Mitochondrial research and medicine. PMID- 20171501 TI - Guest editor's introduction to QUANTEC: a users guide. PMID- 20171502 TI - Use of normal tissue complication probability models in the clinic. AB - The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) review summarizes the currently available three-dimensional dose/volume/outcome data to update and refine the normal tissue dose/volume tolerance guidelines provided by the classic Emami et al. paper published in 1991. A "clinician's view" on using the QUANTEC information in a responsible manner is presented along with a description of the most commonly used normal tissue complication probability (NTCP) models. A summary of organ-specific dose/volume/outcome data, based on the QUANTEC reviews, is included. PMID- 20171503 TI - Radiation dose-volume effects in the stomach and small bowel. AB - Published data suggest that the risk of moderately severe (>or=Grade 3) radiation induced acute small-bowel toxicity can be predicted with a threshold model whereby for a given dose level, D, if the volume receiving that dose or greater (VD) exceeds a threshold quantity, the risk of toxicity escalates. Estimates of VD depend on the means of structure segmenting (e.g., V15 = 120 cc if individual bowel loops are outlined or V45 = 195 cc if entire peritoneal potential space of bowel is outlined). A similar predictive model of acute toxicity is not available for stomach. Late small-bowel/stomach toxicity is likely related to maximum dose and/or volume threshold parameters qualitatively similar to those related to acute toxicity risk. Concurrent chemotherapy has been associated with a higher risk of acute toxicity, and a history of abdominal surgery has been associated with a higher risk of late toxicity. PMID- 20171504 TI - Radiation-associated kidney injury. AB - The kidneys are the dose-limiting organs for radiotherapy to upper abdominal cancers and during total body irradiation. The incidence of radiotherapy associated kidney injury is likely underreported owing to its long latency and because the toxicity is often attributed to more common causes of kidney injury. The pathophysiology of radiation injury is poorly understood. Its presentation can be acute and irreversible or subtle, with a gradual progressive dysfunction over years. A variety of dose and volume parameters have been associated with renal toxicity and are reviewed to provide treatment guidelines. The available predictive models are suboptimal and require validation. Mitigation of radiation nephropathy with angiotensin-converting enzyme inhibitors and other compounds has been shown in animal models and, more recently, in patients. PMID- 20171505 TI - Radiation dose-volume effects of the urinary bladder. AB - An in-depth overview of the normal-tissue radiation tolerance of the urinary bladder is presented. The most informative studies consider whole-organ irradiation. The data on partial-organ/nonuniform irradiation are suspect because the bladder motion is not accounted for, and many studies lack long enough follow up data. Future studies are needed. PMID- 20171506 TI - Radiation dose-volume effects in radiation-induced rectal injury. AB - The available dose/volume/outcome data for rectal injury were reviewed. The volume of rectum receiving >or=60 Gy is consistently associated with the risk of Grade >or=2 rectal toxicity or rectal bleeding. Parameters for the Lyman-Kutcher Burman normal tissue complication probability model from four clinical series are remarkably consistent, suggesting that high doses are predominant in determining the risk of toxicity. The best overall estimates (95% confidence interval) of the Lyman-Kutcher-Burman model parameters are n = 0.09 (0.04-0.14); m = 0.13 (0.10 0.17); and TD(50) = 76.9 (73.7-80.1) Gy. Most of the models of late radiation toxicity come from three-dimensional conformal radiotherapy dose-escalation studies of early-stage prostate cancer. It is possible that intensity-modulated radiotherapy or proton beam dose distributions require modification of these models because of the inherent differences in low and intermediate dose distributions. PMID- 20171507 TI - Radiation dose-volume effects and the penile bulb. AB - The dose, volume, and clinical outcome data for penile bulb are reviewed for patients treated with external-beam radiotherapy. Most, but not all, studies find an association between impotence and dosimetric parameters (e.g., threshold doses) and clinical factors (e.g., age, comorbid diseases). According to the data available, it is prudent to keep the mean dose to 95% of the penile bulb volume to <50 Gy. It may also be prudent to limit the D70 and D90 to 70 Gy and 50 Gy, respectively, but coverage of the planning target volume should not be compromised. It is acknowledged that the penile bulb may not be the critical component of the erectile apparatus, but it seems to be a surrogate for yet to be determined structure(s) critical for erectile function for at least some techniques. PMID- 20171508 TI - Accurate accumulation of dose for improved understanding of radiation effects in normal tissue. AB - The actual distribution of radiation dose accumulated in normal tissues over the complete course of radiation therapy is, in general, poorly quantified. Differences in the patient anatomy between planning and treatment can occur gradually (e.g., tumor regression, resolution of edema) or relatively rapidly (e.g., bladder filling, breathing motion) and these undermine the accuracy of the planned dose distribution. Current efforts to maximize the therapeutic ratio require models that relate the true accumulated dose to clinical outcome. The needed accuracy can only be achieved through the development of robust methods that track the accumulation of dose within the various tissues in the body. Specific needs include the development of segmentation methods, tissue-mapping algorithms, uncertainty estimation, optimal schedules for image-based monitoring, and the development of informatics tools to support subsequent analysis. These developments will not only improve radiation outcomes modeling but will address the technical demands of the adaptive radiotherapy paradigm. The next 5 years need to see academia and industry bring these tools into the hands of the clinician and the clinical scientist. PMID- 20171509 TI - Imaging for assessment of radiation-induced normal tissue effects. AB - Imaging can provide quantitative assessment of radiation-induced normal tissue effects. Identifying an early sign of normal tissue damage with imaging would have the potential to predict organ dysfunction, thereby allowing reoptimization of treatment strategies based on individual patients' risks and benefits. Early detection with noninvasive imaging may enable interventions to mitigate therapy associated injury before its clinical manifestation. Furthermore, successive imaging may provide an objective assessment of the impact of such mitigation therapies. However, many problems make application of imaging to normal tissue assessment challenging, and further work is required to establish imaging biomarkers as surrogate endpoints of clinical outcome. The performance of clinical trials in which normal tissue injury is a clearly defined endpoint would greatly aid in realization of these goals. PMID- 20171511 TI - Improving normal tissue complication probability models: the need to adopt a "data-pooling" culture. AB - Clinical studies of the dependence of normal tissue response on dose-volume factors are often confusingly inconsistent, as the QUANTEC reviews demonstrate. A key opportunity to accelerate progress is to begin storing high-quality datasets in repositories. Using available technology, multiple repositories could be conveniently queried, without divulging protected health information, to identify relevant sources of data for further analysis. After obtaining institutional approvals, data could then be pooled, greatly enhancing the capability to construct predictive models that are more widely applicable and better powered to accurately identify key predictive factors (whether dosimetric, image-based, clinical, socioeconomic, or biological). Data pooling has already been carried out effectively in a few normal tissue complication probability studies and should become a common strategy. PMID- 20171510 TI - Biomarkers and surrogate endpoints for normal-tissue effects of radiation therapy: the importance of dose-volume effects. AB - Biomarkers are of interest for predicting or monitoring normal tissue toxicity of radiation therapy. Advances in molecular radiobiology provide novel leads in the search for normal tissue biomarkers with sufficient sensitivity and specificity to become clinically useful. This article reviews examples of studies of biomarkers as predictive markers, as response markers, or as surrogate endpoints for radiation side effects. Single nucleotide polymorphisms are briefly discussed in the context of candidate gene and genomewide association studies. The importance of adjusting for radiation dose distribution in normal tissue biomarker studies is underlined. Finally, research priorities in this field are identified and discussed. PMID- 20171512 TI - The lessons of QUANTEC: recommendations for reporting and gathering data on dose volume dependencies of treatment outcome. AB - The 16 clinical articles in this issue review the dose-volume dependence of toxicities of external beam radiotherapy. They are limited by the difficulty of synthesizing results from different publications. The major problems stem from incomplete reporting of results and use of incompatible or ambiguous endpoints. Here we specify these problems; give recommendations to authors, editors, and reviewers on standards of reporting; and provide methods of defining endpoints suitable for the dose-volume analysis of toxicity. Adopting these recommendations will facilitate meta-analysis and increase the utility of individual studies of the dependence of complications on dose distributions. PMID- 20171513 TI - Radiation dose-volume effects in the brain. AB - We have reviewed the published data regarding radiotherapy (RT)-induced brain injury. Radiation necrosis appears a median of 1-2 years after RT; however, cognitive decline develops over many years. The incidence and severity is dose and volume dependent and can also be increased by chemotherapy, age, diabetes, and spatial factors. For fractionated RT with a fraction size of <2.5 Gy, an incidence of radiation necrosis of 5% and 10% is predicted to occur at a biologically effective dose of 120 Gy (range, 100-140) and 150 Gy (range, 140 170), respectively. For twice-daily fractionation, a steep increase in toxicity appears to occur when the biologically effective dose is >80 Gy. For large fraction sizes (>or=2.5 Gy), the incidence and severity of toxicity is unpredictable. For single fraction radiosurgery, a clear correlation has been demonstrated between the target size and the risk of adverse events. Substantial variation among different centers' reported outcomes have prevented us from making toxicity-risk predictions. Cognitive dysfunction in children is largely seen for whole brain doses of >or=18 Gy. No substantial evidence has shown that RT induces irreversible cognitive decline in adults within 4 years of RT. PMID- 20171514 TI - Radiation dose-volume effects of optic nerves and chiasm. AB - Publications relating radiation toxicity of the optic nerves and chiasm to quantitative dose and dose-volume measures were reviewed. Few studies have adequate data for dose-volume outcome modeling. The risk of toxicity increased markedly at doses >60 Gy at approximately 1.8 Gy/fraction and at >12 Gy for single-fraction radiosurgery. The evidence is strong that radiation tolerance is increased with a reduction in the dose per fraction. Models of threshold tolerance were examined. PMID- 20171515 TI - Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC): an introduction to the scientific issues. AB - Advances in dose-volume/outcome (or normal tissue complication probability, NTCP) modeling since the seminal Emami paper from 1991 are reviewed. There has been some progress with an increasing number of studies on large patient samples with three-dimensional dosimetry. Nevertheless, NTCP models are not ideal. Issues related to the grading of side effects, selection of appropriate statistical methods, testing of internal and external model validity, and quantification of predictive power and statistical uncertainty, all limit the usefulness of much of the published literature. Synthesis (meta-analysis) of data from multiple studies is often impossible because of suboptimal primary analysis, insufficient reporting and variations in the models and predictors analyzed. Clinical limitations to the current knowledge base include the need for more data on the effect of patient-related cofactors, interactions between dose distribution and cytotoxic or molecular targeted agents, and the effect of dose fractions and overall treatment time in relation to nonuniform dose distributions. Research priorities for the next 5-10 years are proposed. PMID- 20171516 TI - Radiation associated brainstem injury. AB - Publications relating brainstem radiation toxicity to quantitative dose and dose volume measures derived from three-dimensional treatment planning were reviewed. Despite the clinical importance of brainstem toxicity, most studies reporting brainstem effects after irradiation have fewer than 100 patients. There is limited evidence relating toxicity to small volumes receiving doses above 60-64 Gy using conventional fractionation and no definitive criteria regarding more subtle dose-volume effects or effects after hypofractionated treatment. On the basis of the available data, the entire brainstem may be treated to 54 Gy using conventional fractionation using photons with limited risk of severe or permanent neurological effects. Smaller volumes of the brainstem (1-10 mL) may be irradiated to maximum doses of 59 Gy for dose fractions 64 Gy. PMID- 20171517 TI - Radiation dose-volume effects in the spinal cord. AB - Dose-volume data for myelopathy in humans treated with radiotherapy (RT) to the spine is reviewed, along with pertinent preclinical data. Using conventional fractionation of 1.8-2 Gy/fraction to the full-thickness cord, the estimated risk of myelopathy is <1% and <10% at 54 Gy and 61 Gy, respectively, with a calculated strong dependence on dose/fraction (alpha/beta = 0.87 Gy.) Reirradiation data in animals and humans suggest partial repair of RT-induced subclinical damage becoming evident about 6 months post-RT and increasing over the next 2 years. Reports of myelopathy from stereotactic radiosurgery to spinal lesions appear rare (<1%) when the maximum spinal cord dose is limited to the equivalent of 13 Gy in a single fraction or 20 Gy in three fractions. However, long-term data are insufficient to calculate a dose-volume relationship for myelopathy when the partial cord is treated with a hypofractionated regimen. PMID- 20171518 TI - Radiation therapy and hearing loss. AB - A review of literature on the development of sensorineural hearing loss after high-dose radiation therapy for head-and-neck tumors and stereotactic radiosurgery or fractionated stereotactic radiotherapy for the treatment of vestibular schwannoma is presented. Because of the small volume of the cochlea a dose-volume analysis is not feasible. Instead, the current literature on the effect of the mean dose received by the cochlea and other treatment- and patient related factors on outcome are evaluated. Based on the data, a specific threshold dose to cochlea for sensorineural hearing loss cannot be determined; therefore, dose-prescription limits are suggested. A standard for evaluating radiation therapy-associated ototoxicity as well as a detailed approach for scoring toxicity is presented. PMID- 20171519 TI - Radiotherapy dose-volume effects on salivary gland function. AB - Publications relating parotid dose-volume characteristics to radiotherapy-induced salivary toxicity were reviewed. Late salivary dysfunction has been correlated to the mean parotid gland dose, with recovery occurring with time. Severe xerostomia (defined as long-term salivary function of <25% of baseline) is usually avoided if at least one parotid gland is spared to a mean dose of less than approximately 20 Gy or if both glands are spared to less than approximately 25 Gy (mean dose). For complex, partial-volume RT patterns (e.g., intensity-modulated radiotherapy), each parotid mean dose should be kept as low as possible, consistent with the desired clinical target volume coverage. A lower parotid mean dose usually results in better function. Submandibular gland sparing also significantly decreases the risk of xerostomia. The currently available predictive models are imprecise, and additional study is required to identify more accurate models of xerostomia risk. PMID- 20171520 TI - Radiation dose-volume effects in the larynx and pharynx. AB - The dose-volume outcome data for RT-associated laryngeal edema, laryngeal dysfunction, and dysphagia, have only recently been addressed, and are summarized. For late dysphagia, a major issue is accurate definition and uncertainty of the relevant anatomical structures. These and other issues are discussed. PMID- 20171521 TI - Radiation dose-volume effects in the lung. AB - The three-dimensional dose, volume, and outcome data for lung are reviewed in detail. The rate of symptomatic pneumonitis is related to many dosimetric parameters, and there are no evident threshold "tolerance dose-volume" levels. There are strong volume and fractionation effects. PMID- 20171522 TI - Radiation dose-volume effects in the heart. AB - The literature is reviewed to identify the main clinical and dose-volume predictors for acute and late radiation-induced heart disease. A clear quantitative dose and/or volume dependence for most cardiac toxicity has not yet been shown, primarily because of the scarcity of the data. Several clinical factors, such as age, comorbidities and doxorubicin use, appear to increase the risk of injury. The existing dose-volume data is presented, as well as suggestions for future investigations to better define radiation-induced cardiac injury. PMID- 20171523 TI - Radiation dose-volume effects in the esophagus. AB - Publications relating esophageal radiation toxicity to clinical variables and to quantitative dose and dose-volume measures derived from three-dimensional conformal radiotherapy for non-small-cell lung cancer are reviewed. A variety of clinical and dosimetric parameters have been associated with acute and late toxicity. Suggestions for future studies are presented. PMID- 20171524 TI - Radiation-associated liver injury. AB - The liver is a critically important organ that has numerous functions including the production of bile, metabolism of ingested nutrients, elimination of many waste products, glycogen storage, and plasma protein synthesis. The liver is often incidentally irradiated during radiation therapy (RT) for tumors in the upper- abdomen, right lower lung, distal esophagus, or during whole abdomen or whole body RT. This article describes the endpoints, time-course, and dose-volume effect of radiation on the liver. PMID- 20171526 TI - YouTube as a source of information on the H1N1 influenza pandemic. AB - BACKGROUND: The ongoing H1N1 influenza pandemic has created a significant amount of health concern. Adequate dissemination of correct information about H1N1 influenza could help in decreasing the disease spread and associated anxiety in the population. PURPOSE: This study aims to examine the effective use of the popular Internet video site YouTube as an information source during the initial phase of the H1N1 outbreak. METHODS: YouTube was searched on June 26, 2009, using the keywords swine flu, H1N1 influenza, and influenza for videos uploaded in the past 3 months containing relevant information about the disease. The videos were classified as useful, misleading, or as news updates based on the kind of information contained. Total viewership, number of days since upload, total duration of videos, and source of upload were noted. RESULTS: A total of 142 videos had relevant information about H1N1 influenza. In all, 61.3% of videos had useful information about the disease, whereas 23% were misleading. Total viewership share of useful videos was 70.5%, whereas that of misleading videos was 17.5%, with no significant difference in viewership/day. The CDC contributed about 12% of the useful videos, with a significant viewership share of 47%. No significant differences were seen in viewership/day for useful videos based on the kind of information they contained. CONCLUSIONS: YouTube has a substantial amount of useful information about H1N1 influenza. A source-based preference is seen among the viewers, and CDC-uploaded videos are being used in an increasing proportion as a source of authentic information about the disease. PMID- 20171527 TI - Overweight, obesity, youth, and health-risk behaviors. AB - BACKGROUND: The prevalence and severity of obesity have increased among children and adolescents. Although the medical and psychosocial consequences of youth obesity have been well documented, comparatively less information exists on the association of overweight/obesity with health-risk behaviors, which are considered to be a primary threat to adolescent health. PURPOSE: This study aims to examine the association of overweight and obesity with health-risk behaviors among U.S. youth. METHODS: Self-reported height and weight, substance use, violence, and bullying were assessed in a nationally representative sample of students aged 11-17 years (N=7825) who participated in the 2005-2006 Health Behaviors in School-Aged Children survey. Data were analyzed in 2009. RESULTS: Significant gender and age differences in the relationship of overweight/obesity with risk behaviors were observed. Overweight and obesity were significantly associated with substance use among girls only: Frequent smoking and drinking were associated with overweight and obesity among younger girls, whereas these behaviors were associated with obesity among older girls. Frequent smoking and cannabis use were associated with overweight among younger girls only. Relationships between violent behavior and overweight/obesity were mainly observed among boys: Younger obese boys were more likely to be victims of bullying, whereas older obese boys were more likely to carry weapons compared to boys of normal weight. CONCLUSIONS: Overweight and obese young people are at risk of developing health-compromising behaviors that may compound medical and social problems associated with excess weight. PMID- 20171528 TI - Neighborhood, route, and school environments and children's active commuting. AB - BACKGROUND: Walking and cycling to school represent an opportunity for children to achieve regular physical activity. These behaviors may be influenced by characteristics of the environment around homes and schools, yet few studies have quantified the potential associations between these two sets of factors. PURPOSE: This study aims to assess whether objectively measured characteristics of the neighborhood, route, and school environments are associated with active commuting to school among children, and it explores whether distance acts as a moderator in this association. METHODS: A cross-sectional study was conducted of 2012 children (899 boys and 1113 girls) aged 9-10 years attending 92 schools in the county of Norfolk, United Kingdom. Questionnaires were completed by children and parents during Summer 2007. Attributes around the home and children's route to school were assessed using a GIS. School environments were assessed using a newly developed school audit and via questionnaires completed by head teachers. Data were analyzed in 2008. RESULTS: Almost half of the children usually walked or cycled to school. Children who lived in a more deprived area and whose route to school was direct were less likely to walk or cycle to school, whereas those who had a higher density of roads in their neighborhood were more likely to walk. Further, children whose routes had a high density of streetlights were less likely to cycle to school. Distance did not moderate the observed associations. CONCLUSIONS: Objectively measured neighborhood and route factors are associated with walking and cycling to school. However, distance did not moderate the associations found here. Creating safe environments by improving urban design may influence children's commuting behavior. Intervention studies are needed to confirm the findings from this observational cross-sectional study. PMID- 20171529 TI - Exercise, body composition, and functional ability: a randomized controlled trial. AB - CONTEXT: In women, age and the menopausal transition contribute to an increase of body fat and a reduction of lean body mass associated with functional decline, affecting independent living. BACKGROUND: Sarcopenia and adiposity in the elderly has been associated with increased mortality and functional decline affecting independent living. PURPOSE: This study was conducted to determine the effect of a multipurpose exercise program on the body composition and functional ability of elderly women living in a community. DESIGN: An 18-month single-blinded RCT comparing participants in an exercise program with an active control group was conducted from May 2005 through December 2007. Analyses were conducted from January 2008 to July 2008. SETTING/PARTICIPANTS: Two hundred forty-six women (aged 69.1+/-4.0 years) living independently in the area of Erlangen-Nurnberg (Germany) participated in the study. INTERVENTION: Subjects (n=123) performed a multipurpose exercise program with special emphasis on exercise intensity but with low-level requirements for training facilities and materials. The 123 women in the control group focused primarily on well-being. MAIN OUTCOME MEASURES: Body composition was assessed by dual-energy x-ray absorptiometry. Further, strength was evaluated using isometric techniques for the back and legs. Aerobic fitness was determined from a progressive-intensity treadmill test. RESULTS: After 18 months, significant effects in favor of the exercise program for body composition were increases in appendicular skeletal muscle mass and lean body mass along with reductions in abdominal fat and total body fat. Significant performance effects also favored the exercise program and included enhanced isometric maximum trunk extensor and leg press strength, leg press power, timed up-and-go test, and aerobic fitness. CONCLUSIONS: A high-intensity multipurpose exercise program produced significant improvements in body composition and functional ability in a cohort of elderly women living in a community. PMID- 20171530 TI - Sun-protection behaviors among African Americans. AB - BACKGROUND: Data suggest that the prevalence of sun-protection behaviors is low (44%) among African Americans; the samples in such studies, however, tended to be small or nonrepresentative. PURPOSE: This article aims to examine the prevalence and correlates of sun-protection behaviors among a large, random, statewide sample of African-American adults living in California to ascertain behavioral patterns and highlight directions for targeted interventions. METHODS: From September 2006 through May 2008, an anonymous health survey collected data on sunscreen, sunglasses, and wide-brim hat use among a random sample of 2187 African-American adults, and assessed demographic, regional, skin type, and other potential correlates of these behaviors. The analysis was conducted in 2009. RESULTS: Only 31% engaged in at least one sun-protection behavior; of the three behaviors, sunscreen use was the least prevalent, with 63% never using sunscreen. Multivariate logistic regressions revealed that gender, SES, and skin type were significant predictors of sun-protection behaviors. CONCLUSIONS: Tailored interventions to increase sun-protection behaviors among African Americans (men in particular) are needed. PMID- 20171531 TI - Ultraviolet B irradiance and incidence rates of bladder cancer in 174 countries. AB - BACKGROUND: Although nearly half of bladder cancer cases are due to smoking, the cause of nearly half is unexplained. PURPOSE: This study aims to determine whether an inverse association exists between ultraviolet B (UVB) irradiance and incidence rates of bladder cancer worldwide. METHODS: This study used an ecologic approach. Age-adjusted incidence rates of bladder cancer from 2002 were obtained for all 174 countries in GLOBOCAN, a database of the International Agency for Research on Cancer. The relationship of latitude and estimated serum 25 hydroxyvitamin D [25(OH)D] with incidence rates was determined. The independent contributions to incidence rates of bladder cancer of UVB, per capita cigarette consumption in 1980, and per capita health expenditure for 2001 were assessed using multiple regression. The analyses were performed in July 2008. RESULTS: Bladder cancer incidence rates were higher in countries at higher latitudes than those nearer to the equator (r=-0.66, 95% CI=-0.74, -0.57, p<0.01). Ultraviolet B irradiance was independently inversely associated with incidence rates of bladder cancer after controlling for per capita cigarette consumption (beta=-0.28, 95% CI=-0.51, -0.05; R(2) for model=0.38, p<0.0001). Further, UVB irradiance was also inversely associated with incidence rates after controlling for per capita health expenditure (beta=-0.23, 95% CI=-0.36, -0.01; R(2) for model=0.49, p<0.0001) in a separate regression model. CONCLUSIONS: Further investigation is needed to confirm the associations identified in this study using observational studies of individuals. The focus of this research should include the association of serum 25(OH)D levels with risk of bladder cancer. PMID- 20171532 TI - Breast and cervical cancer screening specific effects of depression and obesity. AB - BACKGROUND: Obesity and depression may each be associated with lower rates of cervical and breast cancer screening. Studies have examined obesity or depression alone, but not together, despite the established link between them. PURPOSE: This article aims to disentangle the effects of depression and obesity on receipt of breast and cervical cancer screening. METHODS: A stratified sampling design was used to recruit women aged 40-65 years with information on BMI from an integrated health plan in Washington State in 2003-2005. A telephone survey included the Patient Health Questionnaire-9 for depression, weight, and height. Automated data assessed Paps for 3097 women over a 3-year period and screening mammograms over a 2-year period for 2163 women aged > or =51 years. Logistic regression models (conducted in 2008) examined the association between obesity and depression and receipt of screening tests. RESULTS: In univariate logistic regression models, women were less likely to receive a Pap if they were obese (OR=0.53, 95% CI=0.41, 0.69) or depressed (OR=0.60, 95% CI=0.42, 0.87). Further, women were less likely to receive a screening mammogram if they were depressed (OR=0.45, 95% CI=0.30, 0.67). In multivariable models, only obesity remained significantly associated with a lower likelihood of Pap screening (OR=0.67, 95% CI=0.0.49, 0.93), and only depression remained significantly associated with lower rates of screening mammography (OR=0.49, 95% CI=0.31, 0.76). Obesity and depression did not interact significantly in either model. CONCLUSIONS: Obesity and depression appear to have specific effects on receipt of different cancer-screening tests. PMID- 20171533 TI - Race-differentiated outcomes in multiple special healthcare taxing districts. AB - BACKGROUND: Communities with locally generated special healthcare taxes have demonstrated a generally favorable association with selected population health status outcomes. PURPOSE: This research attempted to determine if that positive association with health outcomes is race differentiated. METHODS: Florida counties with multiple special taxing districts were grouped and compared against counties that had either no special healthcare taxing authority or had such authority but were inactive (did not tax). Outcomes of interest were five combined groups and eight cause-specific mortality indicators and five categories of hospitalizations from the 6-year period 2000-2005 analyzed in 2007. Standard mortality ratios and standard hospitalization ratios were calculated separately for white and black populations in four age bands. RESULTS: Compared to blacks and whites living in communities without special taxing districts, black residents of communities with such districts had larger reductions in mortality for chronic conditions such as cancers, diabetes, stroke, and pneumonia/influenza. The same holds true for hospitalizations for diabetes, congestive heart failure, hypertension, and asthma. These differences were not found in mortality due to HIV, homicide, or motor vehicle crashes. Some differences by taxing district were also age and race differentiated. CONCLUSIONS: In communities with health-related taxing authorities, reductions in health disparities between whites and blacks can be demonstrated. These differences are not uniform and vary by the specific type of outcome, race, and age. These findings support the need for studies that prospectively determine whether implementing new taxing strategies may help reduce health disparities. PMID- 20171534 TI - Physical violence against U.S. women around the time of pregnancy, 2004-2007. AB - BACKGROUND: Previous research shows that the prevalence of intimate partner violence (IPV) around the time of pregnancy varies from 4% to 9%, but no studies have distinguished between abuse rates by former versus current partners. PURPOSE: This study aims to estimate the prevalence of IPV among U.S. women shortly before and during pregnancy and to compare the rates and predictors of abuse perpetrated by current partners with the rates and predictors of abuse perpetrated by former partners. METHODS: Using data from 27 states and New York City, the prevalence of physical abuse by current and former intimate male partners was estimated among 134,955 women who delivered a singleton, full-term infant in 2004-2007. Multivariable logistic regression was used to determine the demographic, pregnancy-related, and stress factors that predicted the risk of IPV. RESULTS: Prevalence of IPV from either a former or current partner was 5.3% before and 3.6% during pregnancy. Prevalence of abuse by a former partner was consistently higher than the prevalence of abuse by a current partner. The three strongest predictors of IPV during pregnancy were the woman's partner not wanting the pregnancy (current: AOR=3.47, 95% CI=3.13, 3.85; former: AOR=3.22, 95% CI=2.90, 3.76); having had a recent divorce or separation (current: AOR=3.23, 95% CI=2.92, 3.58; former: AOR=3.54, 95% CI=3.20, 3.91); and being close to someone having a drug or alcohol problem (current: AOR=3.05, 95% CI=2.78, 3.36; former: AOR=2.97, 95% CI=2.70, 3.27). Maternal characteristics (age, education, race, marital status, woman did not want the pregnancy) were less important predictors. CONCLUSIONS: Assessments of abuse should ask specifically about actions by both current and ex-partners. PMID- 20171535 TI - Poly-victimization in a national sample of children and youth. AB - BACKGROUND: Most studies of children's exposure to violence focus on separate, relatively narrow categories of victimization (such as sexual abuse, physical maltreatment, or bullying), paying less attention to exposure to multiple forms of victimization. PURPOSE: This study documents children's lifetime exposure to multiple victimization types (i.e., "poly-victimization") and examines the association between poly-victimization and extent of trauma symptomatology. METHODS: Analyses were based on telephone interviews conducted between January 2008 and May 2008 with a nationally representative sample of 4053 children aged 2 17 years and their caregivers. RESULTS: Exposure to multiple forms of victimization was common. Almost 66% of the sample was exposed to more than one type of victimization, 30% experienced five or more types, and 10% experienced 11 or more different forms of victimization in their lifetimes. Poly-victims comprise a substantial portion of the children who would be identified by screening for an individual victimization type, such as sexual assault or witnessing parental violence. Poly-victimization is more highly related to trauma symptoms than experiencing repeated victimizations of a single type and explains a large part of the associations between individual forms of victimization and symptom levels. CONCLUSIONS: Studies focusing on single forms of victimization are likely to underestimate the full burden of victimization that children experience and to incorrectly specify the risk profiles of victims. Research, clinical practice, and intervention strategies are likely to improve with more comprehensive assessments of victimization exposure. PMID- 20171536 TI - Preventing deaths in the Canadian military. AB - BACKGROUND: Combat fatalities are reported by the media as a frequent cause of military deaths, yet they may not reflect the most common and preventable ways that soldiers die. PURPOSE: The purpose of this study was to quantify the leading causes of death in the military and to identify modifiable behaviors that potentially contributed to death. METHODS: This was a retrospective chart review of all Canadian Forces members who died during the past quarter century (January 1, 1983, to December 31, 2007) and included autopsy reports, death certificates, coroner reports, hospital records, military reports, and other miscellaneous sources. Underlying cause of death and modifiable behaviors potentially contributing to death were determined. RESULTS: A total of 1889 individuals died during the study period, and a cause of death was identified for 1710 cases (91%). Traumatic injuries caused 57% of deaths, and medical disease was responsible for 43%. The four leading specific causes of death were motor-vehicle crashes (384 deaths, 22%); neoplasms (374 deaths, 22%); suicide (289 deaths, 17%); and cardiovascular disease (285 deaths, 17%). Combat deaths accounted for less than 5% of all deaths (70 deaths). Approximately 35% of all deaths were attributable to potentially modifiable behaviors, which included suicide (219 non alcohol-related deaths, 13%); smoking (159 deaths, 9%); and alcohol use (186 deaths, 11%). CONCLUSIONS: Public attention focuses on combat fatalities, yet most military members die from other causes. Avoiding future deaths requires targeting suicide, smoking, and alcohol consumption, in addition to trauma care for combat injuries. PMID- 20171537 TI - Economic impacts of the Pueblo Smoke-Free Air Act. AB - BACKGROUND: On July 1, 2003, the city of Pueblo CO enacted a smokefree ordinance (Pueblo Smoke-Free Air Act [PSFAA]) that prohibited smoking in public places and workplaces, including taverns and restaurants. Opponents to this ordinance argued that it would have a negative impact on tavern and restaurant sales. PURPOSE: The purpose of this study was to determine whether the PSFAA had a negative economic impact on tavern and restaurant sales tax revenues. METHODS: With data gathered in 2007, this study implemented an interrupted time-series model in 2008, using 42 months of pre- and post-intervention sales tax revenue data for Pueblo to determine whether implementation of this ordinance had an effect on tavern and restaurant sales tax revenues. Ratios of tavern and restaurant openings to closings were also computed for the pre- and post-intervention periods. RESULTS: Pre-post sales tax revenue data showed slight losses in sales tax revenue for taverns, and gains for restaurants, which more than offset the tavern losses. After adjusting for the consumer price index, the city of Pueblo experienced a 20.3% gain in combined tavern and restaurant sales tax revenues from the pre ordinance period to the post-ordinance period. The ratio of tavern openings to closings improved from 1:1 pre-period to 3.3:1 post-period and the restaurant ratio remained unchanged at approximately 1.78:1 from pre- to post-period. CONCLUSIONS: There is no evidence that the PSFAA had a negative economic impact on consumer price index-adjusted tavern and restaurant sales tax revenues. From a fiscal policy perspective, this ordinance may have contributed to a net increase in sales tax revenues for the city of Pueblo. The business openings/closings data suggest that the confidence Pueblo's business sector had in the local hospitality industry was not negatively influenced by the PSFAA. PMID- 20171538 TI - Patient costs as a barrier to intensive health behavior counseling. AB - BACKGROUND: Although intensive health behavior counseling has been demonstrated to help patients lose weight and quit smoking, many payers offer limited coverage for such counseling. PURPOSE: This mixed-methods case study examined how coverage affected utilization of an electronic linkage system (eLinkS) to help adult patients obtain intensive health behavior counseling, provided through a collaboration of primary care practices and community programs. METHODS: Grant support enabled patients to obtain counseling at no cost, but funds were exhausted within 5 weeks as a result of an overwhelming response. To study the influence of cost as a barrier, referrals were resumed for an additional 3 weeks, but patients were required to pay for them. Use of eLinkS, level of clinician counseling and referrals, and patient interest in referrals were measured using electronic medical record data and patient and clinician interviews. RESULTS: When counseling was free, approximately one in five patients with an unhealthy behavior and an eLinkS prompt was referred for intensive counseling. However, when patient charges were instituted, referrals decreased by 97% (from 21.8% to 0.7%, p<0.001); clinicians asked fewer patients about health behaviors (37% vs 29%, p<0.001); clinicians offered fewer patients referrals (29% vs 6%, p<0.001); and patients were less interested in accepting referrals (76% vs 14%, p<0.001). In interviews, patients and clinicians cited cost as a major barrier. CONCLUSIONS: Coverage for intensive health behavior counseling is important to utilization, particularly for interventions that involve clinician-community partnerships. The potential public health benefits of such collaborations to reduce unhealthy behaviors justify the elimination of financial barriers (e.g., copayments) by payers. PMID- 20171539 TI - A good night's sleep for a healthier population. PMID- 20171540 TI - Preface. PMID- 20171541 TI - The first atypical pneumonia: the history of the discovery of Mycoplasma pneumoniae. AB - The subject of atypical pneumonias is of great medical and historical interest to modern physicians. Although these diseases have no doubt affected humans throughout our history, it is not until the mid-twentieth century that physicians first began to differentiate certain atypical pulmonary infectious processes from typical pneumonia. Physicians at the time were unclear as to the precise etiology of these infections. As time progressed and study of these organisms continued, physicians were better able to identify the causative agent and devise tests with which to detect the disease. This article focuses on the description and ultimate identification of Mycoplasma pneumoniae. PMID- 20171542 TI - Psittacosis. AB - Psittacosis is a systemic zoonotic infection with protean clinical features. The major risk factor is exposure to birds; bird owners, veterinarians, those involved with breeding and selling birds, and commercial poultry processors are most at risk. Patients typically present with 1 week of fevers, headache, myalgias, and a nonproductive cough. Although pneumonia is the most common manifestation, all organ systems can be involved. Serology remains the mainstay of diagnosis; however, polymerase chain reaction techniques offer a rapid and specific alternative. Doxycycline is the treatment of choice. PMID- 20171543 TI - Q fever pneumonia. AB - Q fever is a disease found in both humans and animals, caused by the bacterium Coxiella burnetii. The epidemiology of Q fever is that of the animal reservoirs of the infection including both direct and indirect contact and use of a variety of products from such animals as cattle, sheep, and goats. Pneumonia is the major manifestation of Q fever in some countries. It is mild to moderate in severity, and mortality is unusual. It can occur as sporadic or outbreak cases. PMID- 20171544 TI - Tularemia pneumonia. AB - Francisella tularensis is a zoonotic infection that can be acquired in multiple ways, including a bite from an arthropod, the handling of animal carcasses, consumption of contaminated food and water, or inhalation of infected particles. The most virulent subspecies of F tularensis is type A, which is almost exclusively seen in North America. Pneumonia can occur in tularemia, as either a primary process from direct inhalation, or as a secondary manifestation of ulceroglandular or typhoidal disease. This article describes the history of this infection, epidemiology, methods of diagnosis and treatment, and its potential as a bioterrorism weapon. PMID- 20171545 TI - Mycoplasma pneumonia and its complications. AB - Mycoplasma pneumoniae continues to be the most frequent cause of atypical pneumonia. Fortunately, the antibiotics listed in this article are generally very effective. Major skills are needed to detect M pneumoniae extrapulmonary diseases, which require a special heightened awareness and sensitivity. It is not known whether early therapy prevents dreaded complications. PMID- 20171546 TI - Chlamydophila pneumoniae. AB - Chlamydophila pneumoniae is estimated to cause about 10% of community-acquired pneumonia (CAP) cases and 5% of bronchitis cases, although most patients with C pneumoniae infection are asymptomatic, and the course of respiratory illness is relatively mild. The incubation period of C pneumoniae infection is around 21 days, and such symptoms as cough and malaise show a gradual onset, yet may persist for several weeks or months despite appropriate antibiotic therapy. Diagnosis by nasopharyngeal specimen culture, serum antibody titers, or molecular techniques is usually delayed with respect to the onset of symptoms, antibiotic treatment, or disease resolution and there is no accurate, standardized, commercial US Food and Drug Administration-cleared diagnostic method available. Erythromycin, tetracycline, and doxycycline are used as first-line therapy, although some investigators report no clinical or survival benefits from treating CAP caused by atypical pathogens. Meanwhile, adequate prospective studies have met with ethical and logistic barriers. Despite these limitations, North American guidelines recommend the antimicrobial treatment of patients with acute C pneumoniae respiratory infection. PMID- 20171547 TI - Legionnaires' disease: clinical differentiation from typical and other atypical pneumonias. AB - This article describes the clinical differentiation of legionnaires' disease from typical and other atypical pneumonias, with reference to the history, microbiology, epidemiology, clinical presentation (including radiologic manifestations, clinical extrapulmonary features, nonspecific laboratory findings, clinical syndromic diagnosis, and differential diagnosis), therapy, complications, and prognosis of the disease. PMID- 20171548 TI - Pneumocystis jirovecii Pneumonia. AB - Pneumocystis jirovecii has gained attention during the last decade in the context of the AIDS epidemic and the increasing use of cytotoxic and immunosuppressive therapies. This article summarizes current knowledge on biology, pathophysiology, epidemiology, diagnosis, prevention, and treatment of pulmonary P jirovecii infection, with a particular focus on the evolving pathophysiology and epidemiology. Pneumocystis pneumonia still remains a severe opportunistic infection, associated with a high mortality rate. PMID- 20171549 TI - Acute tuberculosis. AB - Both primary and reactivation tuberculosis may present as an acute process and mimic community-acquired pneumonia. Tuberculosis should always be included in the initial differential diagnosis, and suspicion should be heightened by a variety of clinical and epidemiologic clues, as well as by multiple underlying conditions. This article reviews the pathophysiology, risk factors, and clinical manifestations of acute presentations of tuberculosis. PMID- 20171550 TI - Cytomegalovirus pneumonia: community-acquired pneumonia in immunocompetent hosts. AB - Cytomegaloviruses (CMVs) are DNA viruses and are members of the Herpesviridae family. Morphologically, CMV resembles other herpes viruses, particularly herpes simplex viruses, with important cytopathic differences. CMVs are recognized pathogens that cause community-acquired pneumonia (CAP) in compromised hosts, such as, those who undergo transplants and those on immunosuppressive drugs or steroids. This article discusses the clinical presentation, diagnosis, and therapy for this viral CAP. PMID- 20171551 TI - Hantavirus pulmonary syndrome. AB - Hantavirus pulmonary syndrome, also known as hantavirus cardiopulmonary syndrome, is a recently described infectious syndrome found throughout the Americas. Although infection is sporadic and uncommon compared with other atypical pneumonia syndromes, its high mortality rate warrants the maintenance of a high index of suspicion in rural settings. Because no specific therapies are available for the disease, prevention and early recognition play an important role in reducing mortality from the disease. This article reviews the nature of the viruses that cause hantavirus pulmonary syndrome, the epidemiology and ecology of disease transmission, and disease recognition, treatment, and prevention. PMID- 20171552 TI - Severe acute respiratory syndrome (SARS). AB - This article reviews the virology, history, pathology, epidemiology, clinical presentations, complications, radiology, laboratory testing, diagnosis, treatment, and prevention of severe respiratory distress syndrome, with reference to documented outbreaks of the disease. PMID- 20171553 TI - Swine Influenza (H1N1) pneumonia: clinical considerations. AB - Influenza is a viral zoonosis of birds and mammals that has probably existed since antiquity. Attack rates of influenza are relatively high but mortality is relatively low. Influenza mortality is highest in the very young, the very old, and the immunosuppressed. Influenza has the potential for rapid spread and may involve large populations. This article examines the swine influenza (H1N1) strain of recent origin, and compares the microbiology, epidemiology, clinical presentation, differential, clinical, and laboratory diagnosis, therapy, complications, and prognosis with previous recorded outbreaks of avian and human seasonal influenza pneumonias. PMID- 20171555 TI - Osteoporosis and hot flashes--a molecular connection? PMID- 20171556 TI - The rapidly growing field of tissue viability. PMID- 20171557 TI - Clinical and economic consequences of discharge from hospital with on-going TNP therapy: a pilot study. AB - Despite practical advantages (such as exudate management and reduced dressing changes) the adoption of topical negative pressure therapy (TNP) in home care may be restricted through logistical issues and a perception that the intervention is more expensive than the more traditionally utilised wound management products. This pilot study followed the experiences of 20 subjects with a variety of acute and chronic wounds who received TNP either in hospital (n=10), at home (n=5) or in both care settings (n=5). All except one subject showed both reductions in wound surface area and improved appearance of the wound bed during the course of treatment ranging from 2 to 74 days. The single subject, where a deterioration in their wound was noted, had presented with an unclear wound diagnosis thus highlighting the absolute need for accurate diagnosis of wound aetiology prior to commencement of any treatment regime. The cost of treatment was lower where subjects were treated at home (mean cost per day pound45.9 SD: 17.0) and highest where care was delivered exclusively in hospital (mean cost per day pound259.1 SD: 2.8). Direct comparison of these data with other published studies on the use of TNP therapies is obviously restricted through regional differences in the cost of nursing care, patterns of use of the TNP consumables and the wound outcomes followed in individual cases, however, there would appear to be a qualitative and economic benefit from home care. PMID- 20171558 TI - Drainage of collections associated with hernia mesh: is it worthwhile? AB - PURPOSE: Synthetic mesh has revolutionized abdominal wall hernia repair. However, mesh infections present a clinical problem because the standard practice of surgical excision is fraught with increased morbidity. Here, single-institutional outcomes in managing mesh-related collections via percutaneous drainage are retrospectively reviewed to assess its effectiveness. MATERIALS AND METHODS: A total of 21 patients underwent drainage of perimesh collections. Three types of mesh were employed: polytetrafluoroethylene (PTFE; n = 5), polypropylene (n = 14), and porcine dermal collagen (n = 3). One patient received both polypropylene and PTFE. Drainage was performed with ultrasound guidance (n = 19) or surgical drain exchange (n = 2). Mesh type, culture results, fluid collection size, and location were analyzed with respect to need for mesh excision. RESULTS: Sixteen of 21 patients (76%) were successfully treated with drainage. One required additional surgical capsulectomy; the mesh was salvaged. Four required mesh excision because of recurrent infection (n = 2) or lack of improvement of clinical course (n = 2). Recurrent infection occurred in six patients, with mesh salvage via conservative management or new drainage in four. Fluid cultures were positive in 68% of patients (n = 13), with Staphylococcus aureus the most common organism. Cultures did not predict mesh excision (P = .26). The PTFE excision rate trended higher compared with polypropylene (40% vs 14%; P = .27). No porcine dermal collagen mesh was excised. Neither fluid collection size nor location predicted mesh excision. Mean follow-up was 319 days (range, 6-1,406 d). CONCLUSIONS: Percutaneous drainage of suspected mesh-related abscess is effective. The use of PTFE mesh trended toward a higher excision rate. PMID- 20171559 TI - Toward an optimal position for inferior vena cava filters: computational modeling of the impact of renal vein inflow with Celect and TrapEase filters. AB - PURPOSE: To evaluate the hemodynamic effects of renal vein inflow and filter position on unoccluded and partially occluded inferior vena cava (IVC) filters with use of three-dimensional computational fluid dynamics. MATERIALS AND METHODS: Three-dimensional models of the TrapEase and Gunther Celect IVC filters, spherical thrombi, and an IVC with renal veins were constructed. Hemodynamics of steady-state flow was examined for unoccluded and partially occluded TrapEase and Gunther Celect IVC filters in varying proximity to the renal veins. RESULTS: Flow past the unoccluded filters demonstrated minimal disruption. Natural regions of stagnant/recirculating flow in the IVC were observed superior to the bilateral renal vein inflows. High flow velocities and elevated shear stresses were observed in the vicinity of renal inflow. Spherical thrombi induce stagnant/recirculating flow downstream of the thrombus. Placement of the TrapEase filter in the suprarenal position resulted in a large area of low shear stress/stagnant flow within the filter just downstream of thrombus trapped in the upstream trapping position. CONCLUSIONS: Filter position with respect to renal vein inflow influences filter trapping hemodynamics. Placement of the TrapEase filter in a suprarenal location may be thrombogenic, with redundant areas of stagnant/recirculating flow and low shear stress along the caval wall caused by the upstream trapping position and the naturally occurring region of stagnant flow from the renal veins. Infrarenal vein placement of IVC filters in a near juxtarenal position with the downstream cone near the renal vein inflow likely confers increased levels of mechanical lysis of trapped thrombi from increased shear stress from renal vein inflow. PMID- 20171560 TI - In vitro assessment of needle artifacts with an interactive three-dimensional MR fluoroscopy system. AB - PURPOSE: To perform in vitro assessment of needle artifacts with an interactive three-dimensional (3D) near-real-time magnetic resonance (MR) fluoroscopy system for musculoskeletal interventions in a 1.5-T open-bore magnet. MATERIALS AND METHODS: One MR-compatible titanium needle, one MR-compatible Inconel (nickel chromium superalloy) needle, and one MR-compatible carbon fiber needle were imaged with an interactive 3D MR sequence. Slice orientations, measurement parameters (fast low-angle shot, repetition time/echo time of 1,358/5 msec, flip angle of 15 degrees , bandwidth of 250 Hz/pixel; and true fast imaging with steady-state precession, repetition time/echo time of 770/2.2 msec, flip angle of 50 degrees , bandwidth of 558 Hz/pixel), phase encoding directions, and orientations to the main magnetic field (B(0)) were systematically varied. Artifact sizes, normalized artifact contrasts, and tip location errors were assessed for all variations of acquisition parameters and needles and compared with t tests. RESULTS: Mean artifact sizes, normalized artifact contrast, and tip location errors were 22.9 mm, 96%, and 5.4 mm, respectively, for the Inconel needle; 6.1 mm, 70%, and 0.3 mm, respectively, for the titanium needle; and 2.8 mm, 38%, and -1.9 mm, respectively, for the carbon fiber needle. Artifact widths depended on needle materials and needle orientation to B(0), with significant differences on ttests. Artifact contrast did not depend on measurement parameters. No significant influence on artifact character was found for changes in phase encoding direction and slice orientation. CONCLUSIONS: Because of its robustness in depicting needle artifacts, the interactive 3D MR fluoroscopy system appears to be suitable for MR-guided interventions. The titanium needle showed optimal artifacts with all combinations of measurement parameters. Artifacts with the other needles were too large (Inconel) or too small (carbon fiber). PMID- 20171561 TI - Delayed complication after embolotherapy of a vertebral arteriovenous fistula: spinal cord ischemia. AB - Previous reports suggest a generally successful experience with embolotherapy of vertebral arteriovenous fistulas of the neck. However, potential complications do exist, as shown by this report documenting spinal cord ischemia secondary to compromise of a dominant spinal artery arising from the proximal aspect of the right vertebral artery. PMID- 20171562 TI - Portal vein erosion: a rare hemorrhagic complication of acute pancreatitis treated by percutaneous stent-graft placement. PMID- 20171563 TI - Successful treatment of an enterocutaneous fistula with an anal fistula plug after an abdominal stab wound. PMID- 20171564 TI - 2009 Santa Fe Bone symposium. AB - Osteoporosis is a common skeletal disease with serious clinical consequences because of fractures. Despite the availability of clinical tools to diagnose osteoporosis and assess fracture risk, and drugs proven to reduce fracture risk, it remains a disease that is underdiagnosed and undertreated. When treatment is started, it is commonly not taken correctly or long enough to be effective. Recent advances in understanding of the regulators and mediators of bone remodeling have led to new therapeutic targets and the development of drugs that may offer advantages over current agents in reducing the burden of osteoporotic fractures. Many genetic factors that play a role in the pathogenesis of osteoporosis and metabolic bone disease have now been identified. At the 2009 Santa Fe Bone Symposium, held in Santa Fe, New Mexico, USA, the links between advances in genetics, basic bone science, recent clinical trials, and new and emerging therapeutic agents were presented and explored. Socioeconomic challenges and opportunities in the care of osteoporosis were discussed. This is a collection of medical essays based on key presentations at the 2009 Santa Fe Bone Symposium. PMID- 20171565 TI - Is a fixed value for the least significant change appropriate? AB - The least significant change (LSC) represents the smallest difference between successive measurements of bone mineral density (BMD) that can be considered to be a real change and not attributable to chance. The LSC is derived from same-day in vivo BMD precision measurements. Our first objective was to determine if the LSC differs between technologists. Our second objective was to determine if patient body size influenced the LSC. Each of 8 technologists measured same-day precision in groups of 30 patients for the lumbar spine and the total trochanter and neck regions of the proximal femur. At the spine, precision ranged from 0.008 to 0.011g/cm(2) and did not differ between technologists. Precision for the total region of the left proximal femur ranged from 0.006 to 0.016g/cm(2) and did differ between technologists. For the trochanter and neck regions, precision ranged from 0.008 to 0.013g/cm(2) for the former and from 0.010 to 0.020g/cm(2) for the latter, again, with inter-technologist differences. The LSC for the lumbar spine increased linearly from 0.022 to 0.031g/cm(2) when body mass index (BMI) increased from 19.5 to 31.3kg/m(2). In contrast, there was no discernable impact of BMI on the LSC for any of the proximal femur regions. The LSC at the spine is determined by the patient, whereas the LSC at the femur is determined by the technologist. Use of a single value for the LSC will lead to misinterpretations of the significance of BMD changes at both the spine and the proximal femur. PMID- 20171566 TI - Discordance in femoral neck bone density in subjects with unilateral hip osteoarthritis. AB - Osteoarthritis (OA) is a common disease that increases in incidence with age and currently affects an estimated 27 million Americans. To determine whether site specific hip bone mineral density (BMD) measures are confounded by the presence of OA, we measured bilateral hip BMD by dual X-ray absorptiometry in 34 subjects (19 women and 15 men) scheduled for hip replacement for confirmed advanced unilateral hip OA. The femoral neck (FN) BMD (p=0.035) and T-score (p=0.017) for the hip with OA was higher than those of the contralateral hip. There was a difference in osteoporosis classification depending on which hip was considered: for 11 of the 34 subjects (32%), the FN T-score was normal for OA hip, but the contralateral hip was classified as osteopenic (T-score between -1.0 and -2.5). For 1 subject, the FN T-score was normal for OA hip, but the contralateral hip was classified as osteoporotic (T-score below -2.5). Discordance was also present for trochanter values and not for total hip values. These data indicate that advanced hip OA can be associated with a higher bone density at the FN and trochanter but not at total hip and that the discrepancy between hips at the FN may have an impact on patient treatment decisions. PMID- 20171568 TI - Long-term mortality after osteoporotic hip fracture in Chiang Mai, Thailand. AB - The purpose of the study was to investigate 10-yr mortality and associated factors after osteoporotic hip fracture. A prospective cohort study of mortality and associated factors was carried out in patients who sustained hip fracture and were admitted to Chiang Mai University Hospital from 1998 through 2003. Eligibility criteria were defined as age over 50yr, hip fracture caused by simple fall, and Singh index of 3 or less.Mortality rates at 3, 6, 12, 24, 36, 60, 96, and 120mo were 10%, 14%, 18%, 27%, 32%, 45%, 55%, and 68%, respectively. One-year mortality rates were 31% in males and 16% in females. The median survival time was 6yr. Ten-year mortality was 68%. Factors correlated with higher mortality were male gender, age greater than 70yr, and nonoperative treatment. Mortality after osteoporotic hip fracture in Thais was extremely high, especially in the first year. It was about 8 times higher than that in the age-adjusted general population. PMID- 20171567 TI - How activity of inflammatory bowel disease influences bone loss. AB - Bone loss is a common problem for individuals with inflammatory bowel disease (IBD). The aim of our study was to assess bone mineral density (BMD) in patients with IBD and to investigate the role of corticosteroid (CS) use and duration and activity of disease on BMD. Ninety-two patients (56 men and 36 women) with IBD, of whom 32 had ulcerative colitis (UC) and 60 had Crohn's disease (CD), underwent clinical assessment. Lumbar and femoral neck BMDs were measured by dual-energy X ray absorptiometry. Osteopenia was observed in 14 patients (43%) with UC and in 24 patients (40%) with CD (p=0.187). Four patients (12%) with UC and 7 patients (11%) with CD had osteoporosis (p=0.308). Femoral BMD decreased in patients with long duration of CS use and correlated inversely with disease activity. Multiple regression analysis of BMD showed that statistically significant risk factors were duration of active disease and body mass index as well. Based on our results, it is necessary to take into account the risk of decreased BMD in patients with IBD. It is most important to achieve disease remission as soon as possible in addition to nutritional support. PMID- 20171569 TI - Quantitative ultrasound and dual-energy x-ray absorptiometry in children and adolescents with neurofibromatosis of type 1. AB - Reduced areal bone mineral density (aBMD) is a common feature of neurofibromatosis type 1 (NF1). Moreover, in recent years there has been a growing interest in using quantitative ultrasound (QUS) for the evaluation of bone status. In 55 NF1 subjects (mean age: 9.3+/-5.4yr) and in 51 age- and sex matched controls we measured aBMD at lumbar spine, at femoral neck (aBMD-FN), and at total femur (aBMD-T). Apparent volumetric bone mineral density (BMAD) was also calculated. In all subjects, QUS parameters at phalanges were evaluated. In NF1 subjects, the values of aBMD and BMAD were lower than in controls at all skeletal sites, but the difference reached statistical significance only at femoral sites (p<0.05). Both aBMD and QUS parameters were lower in those NF1 subjects with skeletal abnormalities than in those without abnormalities, but the difference was statistically significant (p<0.05) only for aBMD-FN and aBMD-T. Multiple regression analysis showed that the subjects with skeletal abnormalities had a higher risk of having bone transmission time (BTT) Z-score and aBMD Z-score at femoral sites less than -1. In conclusion, our results suggest that aBMD and QUS represent useful tools in evaluating the impairment of bone status in NF1 subjects. PMID- 20171570 TI - The evaluation of consistency between body composition assessments in pediatric population using pencil beam and fan beam dual-energy x-ray absorptiometers. AB - The replacement of the old dual-energy X-ray absorptiometry system with a novel one should be preceded by a cross-calibration procedure. Therefore, the study was aimed at investigating the consistency of bone and body composition measures performed in pediatric population using pencil beam (DPX-L; GE Healthcare, GE Healthcare, Madison, WI) and fan beam (Prodigy; GE Healthcare, GE Healthcare, Madison, WI) densitometers. The study group consisted of 212 healthy children aged 4-18yr. Total body (TB) and lumbar spine (S) (L2-L4) measurements were performed using DPX-L and Prodigy during the same visit. Bland-Altman analysis, linear regressions, and paired t-test were performed to evaluate the consistency of measurements and to establish a cross-calibration equation. The average Prodigy values for TB and lumbar spine bone mineral density (BMD) and content (BMC) were 2.7%, 2.4% and 1.6%, 1.6% higher than those of DPX-L, respectively (p<0.0001). Prodigy-assessed bone area (BA) was lower by 1.4% for TBBA (p<0.0001) and 1.1% for SBA (p<0.001). Lean body mass (LBM) from Prodigy was higher by 6.9% (p<0.0001), whereas fat mass (FM) was lower by 8.4% compared with those from DPX L (p<0.0001). Bland-Altman analyses revealed the effect of magnitude that was nonlinear (2nd degree polynomial) for TBBMD (r=0.32, p=0.001), TBBMC (r=0.51, p<0.0001), TBBA (r=0.34, p<0.0001), and LBM (r=0.56, p<0.0001), but not for FM (r=0.14, not significant [n.s.]). In contrast, in lumbar spine, the magnitude dependence was linear and significant for SBMC (r=0.46, p<0.0001) and SBA (r=0.34, p<0.0001) but not for SBMD (r=0.12, n.s.). Both skeletal and body composition variables assessed by DPX-L and Prodigy devices were highly correlated, showing R(2) values ranging from 0.976 for FM to 0.994 for SBMC. The results of this study document a necessity for implementation of calculated cross calibration equations to transform DPX-L-based local pediatric references into a novel Prodigy system. PMID- 20171571 TI - Association between lean mass and handgrip strength with bone mineral density in physically active postmenopausal women. AB - The present study evaluated 117 physically active postmenopausal women (67.8+/ 7.0yr) who performed neuromotor physical tests (strength, balance, and mobility). Body composition (lean mass [g], fat mass [g], and % fat) and bone mineral density (BMD) of lumbar spine (L1-L4), femoral neck, and total body were measured by dual-energy X-ray absorptiometry. Following the World Health Organization criteria, osteoporosis was found in at least 1 analyzed site in 33 volunteers (28.2%): 30 (25.6%) in lumbar spine and 9 (7.7%) in femoral neck. Body weight was strongly and positively related to BMD in all sites, but the most important component of body composition was lean mass, also significantly related to all BMD sites, whereas fat mass was weakly related to the femoral neck BMD. Percent fat did not correlate with any BMD site. Of all the physical tests, the handgrip strength was most importantly related to lumbar spine, femoral neck, and total body (r=0.49, p<0.001; r=0.56, p<0.001; and r=0.52, p<0.001, respectively). The static body balance presented a weak but significant positive correlation only with lumbar spine. Our results suggest that strategies aiming to improve muscle strength and lean mass must contribute to the bone health of physically active postmenopausal women. PMID- 20171572 TI - Atypical femoral diaphyseal fractures documented by serial DXA. PMID- 20171573 TI - DNA cytosine methylation in plant development. AB - Cytosine bases of the nuclear genome in higher plants are often extensively methylated. Cytosine methylation has been implicated in the silencing of both transposable elements (TEs) and endogenous genes, and loss of methylation may have severe functional consequences. The recent methylation profiling of the entire Arabidopsis genome has provided novel insights into the extent and pattern of cytosine methylation and its relationships with gene activity. In addition, the fresh studies also revealed the more dynamic nature of this epigenetic modification across plant development than previously believed. Cytosine methylation of gene promoter regions usually inhibits transcription, but methylation in coding regions (gene-body methylation) does not generally affect gene expression. Active demethylation (though probably act synergistically with passive loss of methylation) of promoters by the 5-methyl cytosine DNA glycosylase or DEMETER (DME) is required for the uni-parental expression of imprinting genes in endosperm, which is essential for seed viability. The opinion that cytosine methylation is indispensible for normal plant development has been reinforced by using single or combinations of diverse loss-of-function mutants for DNA methyltransferases, DNA glycosylases, components involved in siRNA biogenesis and chromatin remodeling factors. Patterns of cytosine methylation in plants are usually faithfully maintained across organismal generations by the concerted action of epigenetic inheritance and progressive correction of strayed patterns. However, some variant methylation patterns may escape from being corrected and hence produce novel epialleles in the affected somatic cells. This, coupled with the unique property of plants to produce germline cells late during development, may enable the newly acquired epialleles to be inherited to future generations, which if visible to selection may contribute to adaptation and evolution. PMID- 20171574 TI - The many roles of small RNAs in leaf development. AB - Leaf development involves many complex genetic interactions, signals between adjacent cells or between more distant tissues and consequent changes in cell fate. This review describes three stages in leaf development where regulation by small RNAs have been used to modulate gene expression patterns. PMID- 20171575 TI - Activation of gibberellin 2-oxidase 6 decreases active gibberellin levels and creates a dominant semi-dwarf phenotype in rice (Oryza sativa L.). AB - Gibberellin (GA) 2-oxidase plays a key role in the GA catabolic pathway through 2beta-hydroxylation. In the present study, we isolated a CaMV 35S-enhancer activation tagged mutant, H032. This mutant exhibited a dominant dwarf and GA deficient phenotype, with a final stature that was less than half of its wild type counterpart. The endogenous bioactive GAs are markedly decreased in the H032 mutant, and application of bioactive GAs (GA(3) or GA(4)) can reverse the dwarf phenotype. The integrated T-DNA was detected 12.8 kb upstream of the OsGA2ox6 in the H032 genome by TAIL-PCR. An increased level of OsGA2ox6 mRNA was detected at a high level in the H032 mutant, which might be due to the enhancer role of the CaMV 35S promoter. RNAi and ectopic expression analysis of OsGA2ox6 indicated that the dwarf trait and the decreased levels of bioactive GAs in the H032 mutant were a result of the up-regulation of the OsGA2ox6 gene. BLASTP analysis revealed that OsGA2ox6 belongs to the class III of GA 2-oxidases, which is a novel type of GA2ox that uses C20-GAs (GA(12) and/or GA(53)) as the substrates. Interestingly, we found that a GA biosynthesis inhibitor, paclobutrazol, positively regulated the OsGA2ox6 gene. Unlike the over-expression of OsGA2ox1, which led to a high rate of seed abortion, the H032 mutant retained normal flowering and seed production. These results indicate that OsGA2ox6 mainly affects plant stature, and the dominant dwarf trait of the H032 mutant can be used as an efficient dwarf resource in rice breeding. PMID- 20171576 TI - The Post-meiotic Deficicent Anther1 (PDA1) gene is required for post-meiotic anther development in rice. AB - To understand the molecular mechanism of male reproductive development in the model crop rice, we isolated a complete male sterile mutant post-meiotic deficient anther1 (pda1) from a gamma-ray-treated rice mutant library. Genetic analysis revealed that the pda1 mutant was controlled by a recessive nucleus gene. The pda1 mutant anther seemed smaller with white appearance. Histological analysis demonstrated that the pda1 mutant anther undergoes normal early tapetum development without obvious altered meiosis. However, the pda1 mutant displayed obvious defects in postmeiotic tapetal development, abnormal degeneration occurred in the tapetal cells at stage 9 of anther development. Also we observed abnormal lipidic Ubisch bodies from the tapetal layer of the pda1 mutant, causing no obvious pollen exine formation. RT-PCR analysis indicated that the expression of genes involved in anther development including GAMYB, OsC4 and Wax-deficient anther1 (WDA1) was greatly reduced in the pda1 mutant anther. Using map-based cloning approach, the PDA1 gene was finely mapped between two markers HLF610 and HLF627 on chromosome 6 using 3,883 individuals of F(2) population. The physical distance between HLF610 and HLF627 was about 194 kb. This work suggests that PDA1 is required for post-meiotic tapetal development and pollen/microspore formation in rice. PMID- 20171577 TI - Characterization and mapping of a novel mutant sms1 (senescence and male sterility 1) in rice. AB - Plant senescence plays diverse important roles in development and environmental responses. However, the molecular basis of plant senescence is remained largely unknown. A rice spontaneous mutant with the character of early senescence and male sterility (sms) was found in the breeding line NT10-748. In order to identify the gene SMS1 and the underlying mechanism, we preliminarily analyzed physiological and biochemical phenotypes of the mutant. The mutant contained lower chlorophyll content compared with the wild type control and was severe male sterile with lower pollen viability. Genetic analysis showed that the mutant was controlled by a single recessive gene. By the map-based cloning approach, we fine mapped SMS1 to a 67 kb region between the markers Z3-4 and Z1-1 on chromo-some 8 using 1,074 F(2) recessive plants derived from the cross between the mutant sms1 (japonica) x Zhenshan 97 (indica), where no known gene involved in senescence or male sterility has been identified. Therefore the SMS1 gene will be a novel gene that regulates the two developmental processes. The further cloning and functional analysis of the SMS1 gene is under way. PMID- 20171578 TI - Two sequence alterations, a 136 bp InDel and an A/C polymorphic site, in the S5 locus are associated with spikelet fertility of indica-japonica hybrid in rice. AB - The rice indica/japonica hybrid shows strong heterosis. However, such inter subspecific hybrid can't be directly used in rice production due to its low spikelet fertility. The S5 locus was proved to be associated with fertility of indica/japonica hybrid and its S5n allele from wide-compatibility variety (WCV) is capable to overcome fertility barrier. In the present study, we reported the causal sites in the S5 locus responsible for compatibility of indica/japonica hybrid. Fine-mapping of the S5 locus using the 11 test-cross families pinpoints a candidate S5 locus encoding aspartic protease (Asp). Intragenic recombination within the Asp gene happened in a number of recombinants, resulting in chimeric S5j-S5n alleles. Just like S5n, the chimeric S5j-S5n allele displayed higher spikelet fertility when combined with the S5i allele. In the complementary test, however, the S5n allele from WCVs failed to enhance fertilities of the indica/japonica hybrids. Compared to both indica and japonica varieties, all nine WCVs from different resources are characterized with a 136 bp deletion in the Asp N-terminus, which probably renders the S5n allele non-functional. Furthermore, an A/C polymorphic site is detected 1,233 bp downstream of the Asp start codon. The heterozygous A/C site of the Asp gene in indica/japonica hybrid is believed to be the casual factor to cause partial sterility. The functional makers based on the two polymorphic sites will be broadly used in developing wide-compatibility rice varieties. PMID- 20171579 TI - Identification and functional analysis of the MOC1 interacting protein 1. AB - Rice tillering is one of the most important agronomic traits that determine grain yields. Our previous study has demonstrated that the MONOCULM1 (MOC1) gene is a key component that controls the formation of rice tiller buds. To further elucidate the molecular mechanism of MOC1 involved in the regulation of rice tillering, we performed a yeast-two-hybrid screening to identify MOC1 interacting proteins (MIPs). Here we reported that MIP1 interacted with MOC1 both in vitro and in vivo. The overexpression of MIP1 resulted in enhanced tillering and reduced plant height. In-depth characterization of the context of MIP1 and MOC1 would further our understanding of molecular regulatory mechanisms of rice tillering. PMID- 20171580 TI - Sporophytic nondisjunction of the maize B chromosome at high copy numbers. AB - It has been known for decades that the maize B chromosome undergoes nondisjunction at the second pollen mitosis. Fluorescence in-situ hybridization (FISH) was used to undertake a quantitative study of maize plants with differing numbers of B chromosomes to observe if instability increases by increasing B dosage in root tip tissue. B chromosome nondisjunction was basically absent at low copy number, but increased at higher B numbers. Thus, B nondisjunction rates are dependent on the dosage of B's in the sporophyte. Differences in nondisjunction were also documented between odd and even doses of the B. In plants that have inherited odd numbered doses of the B chromosome, B loss is nearly twice as likely as B gain in a somatic division. When comparing plants with even doses of B's to plants with odd doses of B's, plants with even numbers had a significantly higher chance to increase in number. Therefore, the B's non disjunctive capacity, previously thought to be primarily restricted to the gametophyte, is present in sporophytic cells. PMID- 20171581 TI - A conserved unusual posttranscriptional processing mediated by short, direct repeated (SDR) sequences in plants. AB - In several stress responsive gene loci of monocot cereal crops, we have previously identified an unusual posttranscriptional processing mediated by paired presence of short direct repeated (SDR) sequences at 5' and 3' splicing junctions that are distinct from conventional (U2/U12-type) splicing boundaries. By using the known SDR-containing sequences as probes, 24 plant candidate genes involved in diverse functional pathways from both monocots and dicots that potentially possess SDR-mediated posttranscriptional processing were predicted in the GenBank database. The SDRs-mediated posttranscriptional processing events including cis- and trans-actions were experimentally detected in majority of the predicted candidates. Extensive sequence analysis demonstrates several types of SDR-associated splicing peculiarities including partial exon deletion, exon fragment repetition, exon fragment scrambling and trans-splicing that result in either loss of partial exon or unusual exonic sequence rearrangements within or between RNA molecules. In addition, we show that the paired presence of SDR is necessary but not sufficient in SDR-mediated splicing in transient expression and stable transformation systems. We also show prokaryote is incapable of SDR mediated premRNA splicing. PMID- 20171582 TI - Community-acquired methicillin resistant staphylococcus aureus and endocarditis: an emerging pathogen? PMID- 20171583 TI - The global spread of 2009 H1N1 influenza: a false pandemic? PMID- 20171584 TI - Seroprevalence of antibodies to pandemic (H1N1) 2009 influenza virus among hospital staff in a medical center in Taiwan. AB - BACKGROUND: The pandemic (H1N1) 2009 influenza emerged in April 2009 and spread rapidly and broadly all over the world. In addition to specific antiviral agents, massive vaccination is thought to be the most effective way of controlling the transmission. To understand the prevaccination status of certain risk groups, this study compared the baseline sero-prevalence of antibodies to the pandemic (H1N1) 2009 influenza virus among hospital staff with different contact risks and that of the general population. METHODS: A total of 295 serum samples from hospital staff and 244 control serum samples from people who came for physical check-up (control group) were collected between October 2009 and November 2009 before the massive vaccination campaign. The hospital staff was divided into first-line risk personnel (group 1) and second-line risk personnel (group 2) according to their potential contact risks. Hemagglutination-inhibition (HI) tests were conducted to determine the individual serological status. The seropositive rate (SPR, defined as the proportion with HI titer >/= 1:40) of antibodies to H1N1 influenza virus and its geometric mean titer (GMT) were calculated and compared among the different groups. RESULTS: The mean ages and sex ratio (% male) of the hospital staff and control groups were 36.9 +/- 10.6 years and 52.0 +/- 12.6 years, and 24.4% and 57.6%, respectively. The SPR of the antibodies to H1N1 influenza virus of the hospital staff was significantly higher than that of the control group (20.0%vs. 2.9%, p < 0.001). Furthermore, the SPR antibodies to H1N1 influenza virus of group 1 were significantly higher than that of group 2 (30.8%vs. 12.6%, p < 0.001). However, the GMT of antibodies to H1N1 influenza virus of the hospital staff was not significantly different from that of the control group (p = 0.925). CONCLUSION: The SPR of antibodies against the pandemic (H1N1) 2009 virus in the hospital staff was higher than that in the general population, reflecting a higher contact risk. Prevaccination surveillance of the immune status of different risk groups may help to prioritize which groups should be vaccinated first. PMID- 20171585 TI - Serum interleukin-12 levels in alcoholic liver disease. AB - BACKGROUND: Interleukin (IL)-12 is a proinflammatory cytokine produced by antigen presenting cells upon stimulation by diverse stimuli. This study aimed to explore the relationship between IL-12 serum levels and different stages of alcoholic liver disease, alcoholic intake status and abstinence from alcohol. METHODS: A total of 35 healthy controls without alcohol consumption and 94 patients with alcoholic liver disease (17 with alcoholic steatosis, 37 with alcoholic hepatitis, 40 with alcoholic cirrhosis) were included. Their serum IL-12 levels were measured and followed-up at the 3(rd), 6(th) and 9(th) months. Data were further analyzed according to abstinence from alcohol or not. RESULTS: Mean serum IL-12 levels were higher in the alcoholic hepatitis group (163.1 +/- 57.8 pg/mL) than in the alcoholic liver cirrhosis group (110.5 +/- 41.6 pg/mL) and alcoholic steatosis group (74.4 +/- 26.2 pg/mL). All of these 3 alcoholic groups had higher serum IL-12 levels than the control group (39.3 +/- 8.3 pg/mL; p < 0.02). Among the patients who abstained from alcohol, there was no difference in serum IL-12 levels between control and steatosis patients at the 9(th) month, but the serum IL-12 levels of the hepatitis and cirrhosis groups were still higher than in the control group (p < 0.001 and p = 0.001, respectively). In addition, the patients who continued to drink alcohol had higher serum IL-12 levels than those who abstained from alcohol in the steatosis, hepatitis and cirrhosis groups. At the cut-off value of 54 pg/mL, IL-12 had good sensitivity and specificity in the diagnosis of alcoholic liver disease. CONCLUSION: Serum IL-12 levels reflected the different stages of alcoholic liver disease and can represent the status of continuous alcohol consumption. It has the potential to be a biomarker of alcoholic liver disease. PMID- 20171586 TI - Prophylactic antibiotic administration induced bronchospasm as increased airway pressure during general anesthesia. AB - BACKGROUND: Anaphylactic reaction induced bronchospasm as wheezing and severe elevation of airway pressure was observed in a succession of patients during general anesthesia at our institute in November 2007. The aim of this survey was to investigate the suspected causes and risk factors of these anaphylactic reactions and the degree of correlation. METHODS: All patients who received general anesthesia between November 1 and November 10, 2007 were enrolled. Underlying diseases, substances including intravenous and inhalational anesthetics, antibiotics, and the degree of increase in airway pressure were recorded. Enrolled patients were divided into a significant-airway-pressure elevation group (Group P) and a no-airway-pressure-elevation group (Group N). RESULTS: A new brand of cephalexin (Roles) used as a prophylactic antibiotic was identified as the most likely causative substance of this succession of suspected anaphylactic reactions (28 in 185 patients, 15.14%), and rapid administration was a contributor to these anaphylactic reactions. CONCLUSION: In this study, we found that rapid administration of Roles was the main cause of suspected anaphylactic reaction presenting as bronchospasm with severe elevated airway pressure. Using Roles as the prophylactic antibiotic is not recommended in patients receiving general anesthesia. PMID- 20171587 TI - Features and prognostic factors for elderly with acute poisoning in the emergency department. AB - BACKGROUND: Elderly persons with acute poisoning in the emergency department (ED) and prognostic factors of outcomes have not been well addressed in previous research. This study aimed to investigate the characteristics of elderly patients with acute poisoning visiting the ED, and to identify the possible predictive factors of mortality. METHODS: Patients aged > or = 65 years with acute poisoning who visited the ED in Taipei Veterans General Hospital from January 1, 2006 through to September 30, 2008 were enrolled in the study. We collected demographic information on underlying diseases, initial presentations, causes and toxic substances, complications, dispositions, and outcomes. Analyses were conducted among different groups categorized according to age, suicide attempt, and outcome. Multiple logistic regression was applied to identify possible predictive clinical factors influencing mortality in the elderly with acute poisoning. RESULTS: A total of 250 patients were enrolled in the study, with a mean age of 77 years and male predominance. The most common cause of intoxication was unintentional poisoning. Medication accounted for 57.6% of poisonous substances, of which benzodiazepine was the most common drug, followed by warfarin. The overall mortality rate was 9.6%. The average length of stay in the ED increased significantly in the old (65-74 years), very old (75-84 years) and extremely old (> or = 85 years) groups. Suicide attempt patients experienced more complications including respiratory failure, aspiration pneumonia, hypotension and mortality. Three clinical predictive factors of mortality were identified: herbicide poisoning, hypotension and respiratory failure upon presentation. CONCLUSION: Our results demonstrated that elderly patients with acute poisoning had a mortality rate of 9.6%. Suicide attempts resulted in more serious complications. The risk factors for mortality were herbicide intoxication, hypotension and respiratory failure. PMID- 20171588 TI - The unusual presentation of gastric adenocarcinoma as a testicular mass: a favorable response to docetaxel and Cisplatin plus oral tegafur/uracil and leucovorin. AB - Gastric cancer is one of the most common malignancies in the world. The routes of metastasis include direct extension, lymphatics, and peritoneal or hematogenous spread. Testicular metastasis is rare. We present here a 23-year-old gastric cancer patient who first presented with right-side testis swelling and pain. Diagnosis of metastatic adenocarcinoma was made after right-side orchiectomy. Gastric adenocarcinoma with ascites and peritoneal seeding was found after esophagogastroscopy and abdominal computed tomography. The patient received chemotherapy consisting of docetaxel 36 mg/m(2) and cisplatin 30 mg/m(2) on day 1 and day 8, plus oral tegafur/uracil 300 mg/m(2)/day and leucovorin 90 mg/day on day 1 to day 14 in a 21-day cycle, and he had a partial response to the chemotherapy. Metastatic tumors, especially gastric adenocarcinoma, should be considered in the differential diagnosis of patients presenting with testicular mass and they may respond well to chemotherapy. PMID- 20171589 TI - Hepatocellular carcinoma with presentation of budd-Chiari syndrome. AB - Budd-Chiari syndrome is defined as hepatic venous outflow obstruction at any level from the small hepatic veins to the junction of the inferior vena cava and the right atrium independent of the underlying disease. We report here a 40-year old male patient who complained of abdominal fullness and bilateral lower leg edema for 1 month. A physical examination disclosed bilateral lower leg edema. Abdominal sonography revealed a small amount of ascites with thrombosis of the inferior vena cava and right hepatic vein. Viral hepatitis marker tests showed positive hepatitis B surface antigen. Tumor markers showed elevated serum a fetoprotein levels. Computed tomography and magnetic resonance imaging confirmed hepatocellular carcinoma with inferior vena cava and right hepatic vein thrombosis. Therefore, hepatocellular carcinoma with Budd-Chiari syndrome was diagnosed. The patient was treated with intravenous heparin, which was then changed to oral warfarin. Although it is relatively rare, clinicians should be aware of hepatocellular carcinoma with Budd-Chiari syndrome when leg edema occurs without hypoalbuminemia in patients with chronic hepatitis B, because these patients are in the high-risk group for developing hepatocellular carcinoma. Regular follow-up of chronic hepatitis B, including biochemical and sonography surveillance, should be performed. PMID- 20171590 TI - An outbreak of foxglove leaf poisoning. AB - Comfrey (Symphytum officinale) leaves resemble those of foxglove (Digitalis purpurea) when the plant is not in bloom and, therefore, cardiac glycoside poisoning may occur when people confuse foxglove with comfrey. We report an outbreak of foxglove leaf poisoning following the use of alleged "comfrey" herbal tea. Nine patients were involved and initially presented with nausea, vomiting, diarrhea and dizziness. Significant cardiotoxicity developed later among the 3 patients who also had mild hyperkalemia. Peak serum digoxin concentration measured by immunoassay was elevated in all patients and ranged from 4.4 ng/mL to 139.5 ng/mL. Patients with severe cardiotoxicity were treated with temporary cardiac pacing. Moreover, 40-80 mg of digoxin-specific antibody therapy was given without any effect. All patients recovered uneventfully. Our report highlights the potential risk of misidentification of herbs; in this case, D. purpurea was mistaken for S. officinale. Physicians should be aware that cardiac glycoside poisoning could arise from such misidentification. Public education about the toxicity of D. purpurea poisoning may reduce the risk of misidentification and subsequent poisoning. PMID- 20171591 TI - Invasive adenocarcinoma of the prostate with urethral tumor. AB - Metastases of prostate cancer to the penis and urethra are rare and often represent advanced disease. We describe a case of newly diagnosed prostatic adenocarcinoma with metastases to the corpus spongiosum, cavernosum, and the anterior urethra. A male patient, 77 years of age, initially had lower urinary tract obstruction symptoms. His prostate-specific antigen level was 5.02 ng/mL. Digital rectal examination disclosed stony hard tumors at both lobes of the prostate. Transrectal ultrasound-guided biopsy of the prostate revealed adenocarcinoma over both lobes; the Gleason score was 4 + 4 = 8. Cystoscopy showed a penile urethral tumor and biopsy disclosed metastatic adenocarcinoma of the prostate; the Gleason score was 4 + 4 = 8. The patient initially received hormone therapy. Biochemical failure developed after 15 months and rapidly progressed to a hormone-refractory stage. Docetaxel was then prescribed. The patient died in the 25(th) month after the diagnosis. PMID- 20171592 TI - Congenital rubella syndrome with autistic disorder. AB - Congenital rubella syndrome (CRS) consists of a group of abnormalities that develop in children as a result of maternal infection with rubella virus. CRS may lead to new physical symptoms during adolescence or adulthood, referred to as "late manifestations". Psychiatric disorders are often seen among CRS patients, with an incidence of 4.12-7.3% for autism. We report a case of adolescent CRS with autism. A 20-year-old man had received treatment with antipsychotics and antidepressants since the age of 12 years because of unstable moods, violence, and stereotypic behavior. During follow-up, he developed some insidious-onset physical problems, including hyperlipidemia, dyspnea, constipation, torticollis and a tilted trunk. Under careful survey and evaluation, some physical problems were recognized as side effects of psychotropics, which gradually subsided after adjustment of the medications, and some of the problems were considered partially as manifestations of CRS, such as progressive pulmonary artery stenosis-related dyspnea. We managed some of the patient's physical problems and then he received catheterization for pulmonary artery stenosis. His general physical condition improved and some further improvement in psychiatric status was noted thereafter. Because of a high comorbidity rate for patients with autistic disorder, the clinician should be aware of the possibility of CRS if the patient has multiple congenital physical abnormalities with a history of maternal rubella infection. If patients develop physical symptoms in adolescence, awareness of late manifestations of CRS and differentiation from the adverse effects of psychotropic medications are essential. In addition to psychiatric treatment, management of physical problems associated with CRS would be beneficial for the patients' psychiatric condition. PMID- 20171593 TI - Novel application of artificial dermis plus autologous vital epithelial cells: improved wound epithelialization. AB - The purpose of this study was to evaluate artificial dermis with the simultaneous addition of autologous epithelial cells for oral lesion defect reconstruction. Surgical wounds reconstructed with artificial dermis plus scraped epithelial cells were evaluated in 5 patients with oral benign lesions or squamous cell carcinoma. Clinical follow-up indices included scar formation and tissue surface texture observation. The neomucosal layers were analyzed histologically to establish the degree of epithelialization. Clinical observation showed that the oral mucosal texture was smoother in artificial dermis with added epithelial cells at 4 weeks postoperation compared with artificial dermis alone. The wound contraction and scar formation processes were slow. Viable epithelial cells with flat rete ridges remained in the artificial dermis, and a neoepithelial layer was present in the histological findings. We showed that healthy granulation tissue and neoepithelial formation in artificial dermis with epithelial cells was beneficial for the repair of oral defects. Scraping oral epithelial cells and applying them to artificial dermis assisted in the early preparation of composite grafts and minimized requirement for donor sites. This technique may improve the treatment of patients with oral benign tumors and early-stage squamous cell carcinoma. PMID- 20171595 TI - Albumin Benkovac (c.1175 A > G; p.Glu392Gly): a novel genetic variant of human serum albumin. PMID- 20171594 TI - Genetic regulation of serum cytokines in systemic lupus erythematosus. AB - Genetic association studies in systemic lupus erythematosus (SLE) have been extremely successful in recent years, identifying several loci associated with disease susceptibility. Much work remains to integrate these loci into the functional pathogenic pathways that characterize the disease. Our working hypothesis is that many genetic variations linked to SLE and autoimmunity mediate the risk of disease by altering cytokine profiles or responses to cytokine signaling. Genetic polymorphisms that affect cytokine signaling could alter thresholds for immune responses, resulting in proinflammatory presentation of self-antigens and the subsequent misdirection of adaptive immunity against self, which is observed in autoimmune disease. SLE is clinically heterogeneous and genetically complex, and we expect that individual genes and cytokine patterns will be more or less important to different disease manifestations and subgroups of patients. Defining these genotype-cytokine-phenotype relationships will increase our understanding of both initial disease pathogenesis as well as subsequent response/nonresponse to various therapies. In this review, we summarize some recent work in the area of SLE cytokine genetics and describe the implications for SLE, autoimmunity, and immune system homeostasis, which are revealed by these investigations. PMID- 20171596 TI - Is there a role for tetrathiomolybdate in the treatment of primary biliary cirrhosis? PMID- 20171597 TI - Treatment of primary biliary cirrhosis with tetrathiomolybdate: results of a double-blind trial. AB - The results of a double-blind trial of tetrathiomolybdate therapy and standard of care, versus placebo and standard of care treatment, in primary biliary cirrhosis patients are presented. Baseline studies of liver function, various safety variables, ceruloplasmin, a liver biopsy for histologic analysis, and for various cytokine analyses were carried out. Patients were observed every 4 months for up to 2 years of treatment by a hepatologist for clinical evaluation and repeat of all the baseline studies except liver biopsy, which was repeated at 2 years. The primary end points were improvement in 2 liver function tests and in 1 inflammatory cytokine. Fifteen placebo patients were followed for an average of 13 months, and 13 tetrathiomolybdate patients were followed for an average of 14 months. The predefined primary end points for efficacy were met. Tetrathiomolybdate was well tolerated. Because tetrathiomolybdate has been shown in numerous animal studies to inhibit autoimmune and inflammatory processes, and because primary biliary cirrhosis is an autoimmune attack on bile ducts, these positive findings on efficacy of tetrathiomolybdate therapy in primary biliary cirrhosis fit with the animal studies and suggest the need for a longer clinical trial to examine transplant-free survival. PMID- 20171598 TI - Dietary medium-chain triglycerides prevent chemically induced experimental colitis in rats. AB - The effects of dietary medium-chain triglycerides (MCTs) on experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid (TNBS) were investigated in rats. Male Wistar rats were given an intracolonic injection of TNBS and were then fed liquid diets containing MCTs or corn oil (AIN93) as controls. Serum and tissue samples were collected 1 week after TNBS enema. The severity of colitis was evaluated pathologically, and tissue myeloperoxidase (MPO) activity was measured. Furthermore, messenger RNA (mRNA) and protein levels for inflammatory cytokines and a chemokine were assessed by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. In another set of experiments, the protein expression of Toll-like receptor (TLR)-4 in the colon was measured 1 week after feeding of liquid diets. To investigate the effects of MCTs on macrophages, RAW246.7 macrophages were incubated with media containing albumin conjugated with MCT or linoleic acid, which is the major component of corn oil. Then, the production of tumor necrosis factor-alpha (TNF-alpha) was measured. Dietary MCTs blunted significantly the protein levels of TLR-4 in the colon. Furthermore, the expression of TLR-4 was significantly blunted in RAW264.7 cells incubated with MCTs compared with cells incubated with linoleic acid. Induction of interleukin 1beta (IL-1beta), TNF-alpha, and macrophage inflammatory protein-2 (MIP-2) in the colon was attenuated by dietary MCT. Furthermore, MPO activities in the colonic tissue were significantly blunted in animals fed the MCT diets compared with those fed the control diets. As a result, dietary MCTs improved chemically induced colitis significantly. MCTs most likely are useful for the therapy of inflammatory bowel disease as an anti-inflammatory immunomodulating nutrient. PMID- 20171599 TI - Resistin gene promoter region polymorphism and the risk of hypertrophic cardiomyopathy in patients. AB - Resistin, a novel cytokine, is associated with an inflammatory process and is suggested to induce hypertrophy in rat cardiomyocytes. Resistin gene expression has not been investigated in patients with hypertrophic cardiomyopathy (HCM). This study investigates resistin levels in HCM patients and healthy controls and the molecular basis for the regulation of the resistin gene (RETN) in a Pakistani population. Patients with HCM (n = 105) and healthy individuals (n = 110) were enrolled in this investigation. Serum resistin levels were determined by enzyme linked immunosorbent assay (ELISA). RETN genotyping was performed by polymerase chain reaction (PCR) and DNA sequencing. Our data showed a statistically significant increase in resistin levels from HCM patients compared with healthy subjects (6.3 +/- 2.7 ng/mL in patients vs 3.4 +/- 2.1 ng/mL in controls, P < 0.0001). The RETN -420 C > G polymorphism was significantly high in patients with HCM compared with the control group (P < 0.001). There was a significant difference between the C and G alleles from HCM cases and controls (odds ratio [OR] = 3.54, 95% confidence interval [CI] = 2.36-5.30, P < 0.0001). Logistic regression analysis showed that the increased resistin levels, and the RETN-420 C > G polymorphism were significantly associated with HCM. Our data suggest that the elevated resistin levels and the RETN -420 C > G polymorphism may be associated with cardiac hypertrophy in the study population. PMID- 20171600 TI - Novel technique for rapid detection of alpha-globin gene mutations and deletions. AB - Populations in Southeast Asia and South China have high frequencies of alpha thalassemia caused by alpha-globin gene mutations and/or deletions. This study was designed to find an efficient and simple diagnostic test for the mutations and deletions. A duplex polymerase chain reaction (PCR)/denaturing high-pressure liquid chromatography (DHPLC) was used to detect the mutations and deletions. A blinded study of 110 samples, which included 92 alpha-thalassemia samples with various genotypes and 18 normal DNA samples, was carried out by the methods. The duplex PCR products of the sample with known Constand spring mutation (CS)/alphaalpha, Quonsze mutation (QS)/alphaalpha, and Weastmead mutation (WS)/alphaalpha DNA showed significantly different profiles, which suggests that DHPLC analysis at 63.8 degrees C can detect potential mutations directly. The DHPLC at 50 degrees C analysis can distinguish the --SEA and nondeletional alleles. The new assay is 100% concordant with the original genotype. In conclusion, the technique including the duplex PCR assay followed by DHPLC analysis can be used to diagnose alpha-thalassemia; this methodology is simple, rapid, accurate, semiautomatic, and high output, and thus, it is suitable for large-scale screening. PMID- 20171601 TI - Twin-twin transfusion syndrome: an ethics-based and evidence-based argument for clinical research. AB - Aspects of twin-twin transfusion syndrome (TTTS) diagnosis, treatment alternatives, and research opportunities were considered during a consensus conference that was held by the North American Fetal Therapy Network in 2009. A 3 member scientific consensus panel gathered data from expert conference presentations, postconference communications, and comprehensive scientific literature database searches to develop recommendations for TTTS diagnosis, therapy, and research. The panel recommends retaining the Quintero staging system until a superior system has been validated appropriately. It concludes that there is normative equipoise to justify the performance of randomized clinical trials to identify the optimal treatment strategy for mild TTTS. Recommendations for the design and conduct of clinical trials and observational studies are also provided. PMID- 20171603 TI - Prospective trial on obstructive sleep apnea in pregnancy and fetal heart rate monitoring. AB - OBJECTIVE: Obstructive sleep apnea (OSA) involves episodic nocturnal apneas. Using polysomnography, we examined the predictive capacity of screening questionnaires (Berlin) in pregnancy. Incorporating simultaneous fetal heart rate monitoring (FHM), we examined the association of maternal apnea with FHM abnormalities. STUDY DESIGN: We enrolled 100 pregnant women at 26-39 weeks of gestation with OSA screening and baseline data ascertainment who underwent polysomnography and FHM for > or =3 hours. The relationship between maternal characteristics, OSA, and FHM was explored with multivariate analyses that were controlled for potential confounders. RESULTS: When compared with polysomnography, sensitivity and specificity by Berlin screening was 35% and 63.8%, respectively; the snoring component of the Berlin correlated better with oxygen desaturation <95% (P = .003). Body mass index was a significant confounder (r(s) = 0.44; P < .0001). No association was observed between FHM abnormalities and OSA parameters. CONCLUSION: In pregnancy, the Berlin questionnaire poorly predicts OSA. It is unclear whether fetal compromise during maternal apnea is a mechanism in OSA that is related to pregnancy outcome. PMID- 20171604 TI - The association between obesity and stage II or greater prolapse. AB - OBJECTIVE: We sought to evaluate the association between obesity and vaginal prolapse as well as pelvic organ prolapse symptoms. STUDY DESIGN: This was a cross-sectional study of women referred for urogynecologic care. The exposure was obesity and outcome, stage>or=II prolapse. Secondary outcomes were symptom bother and disease-specific quality of life. RESULTS: Our study included 721 women. No difference in stage>or=II prolapse was observed between obese (n/N 58/721 [35.8%]) and nonobese (n/N=463/721 [64.2%]) women (50.8% vs 52.7%; P=.62). Obesity was associated with increased distress on the Pelvic Floor Distress Inventory-20 (100 [+/-57.3] vs 87.4 [+/-53.1]; P=.003) due to higher scores on the Colorectal-Anal Distress Inventory-8 (22.9 [+/-21.5] vs 18.3 [+/-19.7]; P=.003) and the Urinary Distress Inventory-6 (48.8 [+/-27] vs 42.4 [+/-26.1]; P=.002). CONCLUSION: Obesity was not associated with stage>or=II prolapse but was associated with increased pelvic floor symptoms secondary to urinary and anal incontinence subscales. PMID- 20171605 TI - Questioning the importance of genetic ancestry as a contributor to preterm delivery and related traits in African American women. PMID- 20171606 TI - Amplification of the chromosome 3q26 region shows high negative predictive value for nonmalignant transformation of LSIL cytologic finding. AB - OBJECTIVE: The chromosome 3q26 region is a biomarker for cervical cancer. Women with low-grade squamous intraepithelial lesions (LSIL) currently are referred for immediate colposcopy. The objective of this study was to determine the negative predictive value of the 3q26 amplification test for the persistence or regression of LSIL. STUDY DESIGN: Archival thin layer cytologic slides of 47 women (14-67 years old) with LSIL were linked to histologic and cytologic end points. To determine 3q status, the slides were hybridized for the chromosome 3q26 region and for the centromere of chromosome 7, as a control, with the use of the standard fluorescent in situ hybridization methods. RESULTS: The negative predictive value of 3q26 gain for the development of cervical intraepithelial neoplasia grade 2/3 within 1 year was 93% (95% confidence interval, 68- 100); after 21 months, its negative predictive value was 100% (95% confidence interval, 29-100). CONCLUSION: The 3q26 gain might help identify women with LSIL who do not need colposcopy. PMID- 20171607 TI - Congenital anomalies of upper extremities: prenatal ultrasound diagnosis, significance, and outcome. AB - OBJECTIVE: We sought to assess the role of ultrasound in the prenatal characterization of fetal malformations of the upper extremities (MUE). STUDY DESIGN: Ultrasound findings, associated anomalies, pregnancy, and fetoneonatal outcome were analyzed in 100 fetuses with MUE, categorized after Swanson classification of hand congenital abnormalities. Follow-up information was available in all. RESULTS: Twelve cases had an isolated defect, while 88 showed associated abnormalities involving other organ systems. Fetuses with multiple malformations showed a 76% syndromic risk (32% chromosomal, 41% nonchromosomal), with unfavorable outcome in almost all cases (only 4 survivors, 2 with neurodevelopmental delay). In 27% of syndromic fetuses, the sonographic evidence of the MUE represented the key finding leading to the final diagnosis. The prognosis was usually favorable in cases of isolated defects. CONCLUSION: A thorough prenatal ultrasound characterization of fetal MUE can assist in the differential diagnosis of many syndromic conditions. When isolated, MUE tend to have a good outcome. PMID- 20171608 TI - Impact of pessary use on prolapse symptoms, quality of life, and body image. AB - OBJECTIVE: We sought to evaluate whether use of a vaginal pessary would change body image, bother symptoms, and quality of life in women with pelvic organ prolapse. STUDY DESIGN: Women presenting for pessary insertion completed the short forms of Pelvic Floor Distress Inventory-20, Pelvic Floor Impact Questionnaire, and Body Image Scale. After successful pessary insertion and use for at least 3 months, subjects completed the surveys again. Scores were compared with a paired t test. RESULTS: A total of 75 subjects were enrolled and follow-up responses were available for 54 subjects for analysis. Body Image Scale scores showed a significant decrease (6.1-3.4; P<.001), indicating an improvement in these women's perception of themselves, as did Pelvic Floor Distress Inventory-20 scores (81.34-45.83; P<.001) and Pelvic Floor Impact Questionnaire scores (50.32 17.98; P=.003). CONCLUSION: The use of a pessary for 3 months reduces bother symptoms and improves both quality of life and perception of body image in women. PMID- 20171609 TI - Prevalence and distribution of serotype-specific genotypes of Aggregatibacter actinomycetemcomitans in chronic periodontitis Brazilian subjects. AB - OBJECTIVE: Previous studies have suggested that Aggregatibacter actinomycetemcomitans is involved in the aetiology of aggressive periodontitis as well as chronic periodontitis. In addition, some authors have also reported that serotype-specific antigens of A. actinomycetemcomitans determine the severity of disease. This study aimed to elucidate the prevalence of A. actinomycetemcomitans and the distribution of A. actinomycetemcomitans serotypes in Brazilian subjects with chronic periodontitis. DESIGN: A total of 486 individuals were enrolled in this survey. All patients received clinical examinations that included periodontal pocket depth, clinical attachment loss, plaque, and gingival indexes. Subgingival samples were taken for microbial analysis. The genomic DNA of A. actinomycetemcomitans was provided by PCR. RESULTS: Out of 486 subjects examined, A. actinomycetemcomitans was isolated in 85 (17.5%) individuals. Out of 85 positive samples, 68 were infected by at least 1 serotype, 7 by mixed infection, and 10 were non-serotyped. Serotypes d and f were not detected. Serotype c showed the highest prevalence (52.9%), followed by serotype a (31.8%). CONCLUSIONS: Intragroup analysis revealed that, in slight/moderate periodontitis, serotypes c and a were significantly more prevalent than serotypes b and d-f; the prevalence of serotype c in severe periodontitis was significantly greater than that of serotypes a and b. Our data were similar in Asian and Eurasian populations. PMID- 20171610 TI - Solid-phase de novo synthesis of a (+/-)-2-deoxy-glycoside. AB - The solid-phase synthesis of methyl 2-deoxy-3-O-benzyl-D,L-arabino-hexopyranoside was achieved in a six-step sequence via a de novo strategy based on the hetero Diels-Alder reaction of a vinyl ether supported on an azalactone-functionalized polystyrene resin, followed by the functional modification of the heteroadduct and the final release of the methyl glycoside by acidic solvolysis. PMID- 20171611 TI - Defective B cell response to TLR9 ligand (CpG-ODN), Streptococcus pneumoniae and Haemophilus influenzae extracts in common variable immunodeficiency patients. AB - Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinaemia and antibody deficiency to both T dependent and independent antigens. Patients suffer from recurrent sinopulmonary infections mostly caused by Streptococcus pneumoniae and Haemophilus influenzae, but also gastrointestinal or autoimmune symptoms. Their response to vaccination is poor or absent. In this study we investigated B cell activation induced by the TLR9 specific ligand (CpG-ODN) and bacterial extracts from S. pneumoniae and H. influenzae known to stimulate several TLR. We found that B cells from CVID patients express lower levels of CD86 after stimulation with CpG-ODN, S. pneumoniae and H. influenzae extracts in combination with anti-IgM antibody and also display a lower proliferative index when stimulated with bacterial extracts. Our results point to a broad TLR signalling defect in B lymphocytes from CVID patients that may be related to the hypogammaglobulinaemia and poor response to vaccination characteristic of these patients. PMID- 20171612 TI - Prism adaptation does not change the rightward spatial preference bias found with ambiguous stimuli in unilateral neglect. AB - Previous research has shown that prism adaptation (prism adaptation) can ameliorate several symptoms of spatial neglect after right-hemisphere damage. But the mechanisms behind this remain unclear. Recently we reported that prisms may increase leftward awareness for neglect in a task using chimeric visual objects, despite apparently not affecting awareness in a task using chimeric emotional faces (Sarri et al., 2006). Here we explored potential reasons for this apparent discrepancy in outcome, by testing further whether the lack of a prism effect on the chimeric face task task could be explained by: i) the specific category of stimuli used (faces as opposed to objects); ii) the affective nature of the stimuli; and/or iii) the particular task implemented, with the chimeric face task requiring forced-choice judgements of lateral 'preference' between pairs of identical, but left/right mirror-reversed chimeric face tasks (as opposed to identification for the chimeric object task). We replicated our previous pattern of no impact of prisms on the emotional chimeric face task here in a new series of patients, while also similarly finding no beneficial impact on another lateral 'preference' measure that used non-face non-emotional stimuli, namely greyscale gradients. By contrast, we found the usual beneficial impact of prism adaptation (prism adaptation) on some conventional measures of neglect, and improvements for at least some patients in a different face task, requiring explicit discrimination of the chimeric or non-chimeric nature of face stimuli. The new findings indicate that prism therapy does not alter spatial biases in neglect as revealed by 'lateral preference tasks' that have no right or wrong answer (requiring forced-choice judgements on left/right mirror-reversed stimuli), regardless of whether these employ face or non-face stimuli. But our data also show that prism therapy can beneficially modulate some aspects of visual awareness in spatial neglect not only for objects, but also for face stimuli, in some cases. PMID- 20171613 TI - Prospective randomized comparison of human oocyte cryopreservation with slow-rate freezing or vitrification. AB - OBJECTIVE: To compare cryopreservation of mature human oocytes with slow-rate freezing and vitrification and determine which is most efficient at establishing a pregnancy. DESIGN: Prospective randomized. SETTING: Academically affiliated, private fertility center. PATIENT(S): Consenting patients with concerns about embryo cryopreservation and more than nine mature oocytes at retrieval were randomized to slow-rate freezing or vitrification of supernumerary (more than nine) oocytes. INTERVENTION(S): Oocytes were frozen or vitrified, and upon request oocytes were thawed or warmed, respectively. MAIN OUTCOME MEASURE(S): Oocyte survival, fertilization, embryo development, and clinical pregnancy. RESULT(S): Patient use has resulted in 30 thaws and 48 warmings. Women's age at time of cryopreservation was similar. Oocyte survival was significantly higher following vitrification/warming (81%) compared with freezing/thawing (67%). Fertilization was more successful in oocytes vitrified/warmed compared with frozen/thawed. Fertilized oocytes from vitrification/warming had significantly better cleavage rates (84%) compared with freezing/thawing (71%) and resulted in embryos with significantly better morphology. Although similar numbers of embryos were transferred, embryos resulting from vitrified oocytes had significantly enhanced clinical (38%) pregnancy rates compared with embryos resulting from frozen oocyte (13%). Miscarriage and/or spontaneous abortion rates were similar. CONCLUSION(S): Our results suggest that vitrification/warming is currently the most efficient means of oocyte cryopreservation in relation to subsequent success in establishing pregnancy. PMID- 20171614 TI - Modification of the triplet repeat primed polymerase chain reaction method for detection of the CTG repeat expansion in myotonic dystrophy type 1: application in preimplantation genetic diagnosis. AB - OBJECTIVE: To overcome problems associated with the use of triplet repeat primed polymerase chain reaction (TP-PCR) in preimplantation genetic diagnosis (PGD) of myotonic dystrophy type 1 (DM1). DESIGN: Clinical research study. SETTING: UCL Centre for PGD and Centre for Reproductive and Genetic Health. PATIENT(S): Seven couples undergoing PGD for DM1. INTERVENTION(S): A modified TP-PCR protocol (mTP PCR) for the reliable detection of both expanded and nonexpanded alleles in DMPK was optimized using single lymphocytes. Four cycles of PGD were performed with TP PCR for diagnosis and a further 10 cycles with mTP-PCR. MAIN OUTCOME MEASURE(S): Amplification efficiency, allele dropout, diagnosis rate, and delivery rate. RESULT(S): Preliminary testing showed that the TP-PCR amplification efficiency was higher using lymphocytes versus buccal cells. Single lymphocytes gave very high amplification efficiencies for both protocols (99% to 100%). There were no false-positive or false-negative results for 148 single lymphocytes tested with mTP-PCR compared with 9% (5 out of 54) false-positive results with TP-PCR, indicating the improved accuracy of the modified protocol. In embryos, the diagnosis rate was 95.6% with mTP-PCR and 75% with TP-PCR. CONCLUSION(S): For PGD of DM1, mTP-PCR is recommended. It may also be applied as a rapid screen for DMPK expansions in individuals with symptoms of DM1, relatives of known mutation carriers, or in prenatal diagnosis. PMID- 20171615 TI - Promoting implantation by local injury to the endometrium. AB - OBJECTIVE: To evaluate the association between endometrial injury, implantation and pregnancy rate. DESIGN: We performed a literature search using the keywords endometrial injury, local endometrial injury, endometrial biopsy, endometrial receptivity, implantation, in vitro fertilization, and implantation failure and conducted the search in Medline, EMBASE, and Cochrane Database of systematic reviews. SETTING: None. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): None. RESULT(S): Clinical and basic science data regarding the association between endometrial injury and improved implantation rate are limited. However, current evidence suggests that endometrial injury before IVF among women with previous repeated IVF failure is associated with increased rates of implantation, clinical pregnancy, and live birth. CONCLUSION(S): Endometrial injury may have a beneficial role in implantation and improve the pregnancy rate. However, there are still many unanswered question including patients selection, timing, technique and number of endometrial biopsies needed. PMID- 20171617 TI - Re: Clinical and biochemical presentations of polycystic ovary syndrome among obese and nonobese women. PMID- 20171619 TI - Spontaneous ovarian hyperstimuation syndrome in a naturally conceived singleton pregnancy. AB - OBJECTIVE: To report the occurrence of a rare case of spontaneous ovarian hyperstimulation syndrome in a naturally conceived singleton pregnancy. DESIGN: A case report. SETTING: The Obstetric and Gynecology Department at King Fahd Central Hospital, Jazan City, Saudi Arabia. PATIENT(S): Our reported case was a middle-aged Egyptian woman presented in the second trimester of her first pregnancy with persistent abdominal pains, shortness of breath, vomiting, and diarrhea. INTERVENTION(S): The data were collected by full history taking, clinical examination, transabdominal ultrasonographic examination, and by revision of results of the patient's laboratory tests. MAIN OUTCOME MEASURE(S): The possible event of spontaneous ovarian hyperstimulation syndrome in a naturally conceived singleton pregnancy. RESULT(S): Our case was reported as a severe case of spontaneous ovarian hyperstimulation syndrome in a naturally conceived singleton pregnancy. CONCLUSION(S): This case report emphasizes the importance of thorough evaluation of all women presented with acute abdomen and ovarian masses during pregnancy. Although the condition is extremely rare, it is a potentially lethal in its severe form if not timely diagnosed and managed conservatively. With the increasing awareness of these conditions, more and more cases could be detected and reported. PMID- 20171618 TI - Steroid profiles in ovarian follicular fluid in women with and without polycystic ovary syndrome, analyzed by liquid chromatography-tandem mass spectrometry. AB - OBJECTIVE: To compare steroid concentrations and steroid product-to-precursor ratios in ovarian follicular fluid (FF) from women with polycystic ovary syndrome (PCOS) and from regularly menstruating women in their early follicular phase, using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Polycystic ovary syndrome involves abnormal regulation of the steroidogenic enzymes, leading to arrest of follicle development. DESIGN: Case-control study. SETTING: University hospital clinic. PATIENT(S): Follicular fluid from size-matched ovarian follicles (5-8 mm) in 27 nonstimulated women with PCOS and in 21 women without PCOS was sampled. Thirteen steroids were quantitated from 40 MUL of FF, using LC-MS/MS. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Concentrations of steroids in the FF and product-to-precursor ratios (enzyme activity) were compared between the groups. RESULT(S): In women with PCOS, ovarian FF contained higher concentrations of individual and total androgens, lower individual and total estrogens (E), and a lower total E-to-androgen ratio, compared with regularly menstruating women. The product-to-precursor concentration ratios indicated higher CYP17-linked and lower CYP19-linked (aromatase) enzyme activity. Receiver operating characteristic plots indicated the early CYP17 step (17-OH5P/5P) being highly important for the prevalence of PCOS (c=0.95). CONCLUSION(S): The women with PCOS had higher ovarian CYP17-linked and lower CYP19-linked (aromatase) enzyme activity, confirming previous data. Multiple steroid assessments from minute volumes including FF from nonstimulated ovaries, using LC-MS/MS, might be useful in research, clinical endocrinology, and in IVF. PMID- 20171620 TI - Premature luteinization defined by an increased progesterone/estradiol ratio on day of human chorionic gonadotropin administration is a manifestation of diminished ovarian responsiveness to controlled ovarian hyperstimulation. PMID- 20171622 TI - Duration of fertility after fresh and frozen ovary transplantation. AB - OBJECTIVE: To evaluate the function of human ovarian transplants. DESIGN: Follow a series of fresh ovarian transplants for up to 5 years, and compare fresh and frozen ovarian tissue transplantation. SETTING: Tertiary referral community hospital. PATIENT(S): Nine women with premature ovarian failure who received an ovary donated from a monozygotic twin sibling, and 16 young cancer patients undergoing ovarian cryopreservation. Two of the transplant recipients were cancer survivors rendered sterile by their therapy. INTERVENTION(S): Fresh ovary transplantation between monozygotic twin sisters, as well as transplantation of previously frozen ovarian tissue, and study of cryopreserved tissue in cancer patients. MAIN OUTCOME MEASURE(S): Return of normal menstrual cycling, hormone levels, pregnancy, healthy babies, duration of transplant function, and ovarian tissue evaluation. RESULT(S): Normal serum FSH and regular menstrual cycles returned by 5 months after surgery in all cases, both fresh and frozen. Fourteen spontaneous pregnancies were established leading to eight healthy live births and two healthy ongoing conceptions. All three frozen tissue transplants conceived spontaneously, one delivered, and two were ongoing. Oocyte survival with slow freezing was 42% and after vitrification 89%. CONCLUSION(S): Ovarian transplantation in humans is a robust procedure, even after cryopreservation, and vitrification might prove to be more effective than slow freezing. PMID- 20171623 TI - Differential expression of genes from the homeobox A cluster in deep endometriotic nodules and peritoneal lesions. AB - OBJECTIVE: To compare expression of homeobox A (HOXA) genes involved in the differentiation of the female reproductive tract in deep endometriotic nodules and peritoneal lesions. DESIGN: Prospective experimental study. SETTING: Academic gynecology research unit. PATIENT(S): Thirty patients undergoing laparoscopy. INTERVENTION(S): During laparoscopy, deep endometriotic nodules (n=30) and peritoneal lesions (n=11) were recovered. Eutopic endometrium and vaginal tissue (n=30) were collected for control purposes. MAIN OUTCOME MEASURE(S): Quantification of HOXA-9, HOXA-10, HOXA-11, and HOXA-13 in deep nodules, peritoneal lesions, and control samples by real-time reverse-transcription polymerase chain reaction, and localization of HOXA-10 and HOXA-13 proteins by immunohistochemistry. RESULT(S): The HOXA-13 transcripts were detected in 29 out of 30 nodules, and their expression was significantly higher than in vaginal tissue, but they were barely detectable in endometrium and peritoneal lesions. Expression of HOXA-10 and HOXA-11 transcripts in deep nodules was similar to eutopic endometrium, and HOXA-10 expression was significantly lower in peritoneal endometriotic lesions. The HOXA-10 immunostaining was mainly localized in the stroma of deep endometriotic nodules, HOXA-13 in glandular structures and stroma, and neither of these proteins were detected in fibromuscular areas. CONCLUSION(S): Marked expression of HOXA-10 and HOXA-13 in the endometrium-like tissue of nodules but low expression in peritoneal endometriotic lesions supports the theory of differential origin of these two types of endometriosis. PMID- 20171624 TI - Solitary and multiple uterine leiomyomas among Caucasian women: two different disorders? AB - OBJECTIVE: To investigate whether polymorphism in CYP17A1 gene is associated with uterine leiomyomas (ULM) and to evaluate differences in epidemiologic and genetic factors among solitary and multiple leiomyomas. DESIGN: Prospective case control study. SETTING: Tertiary gynecology department. PATIENT(S): One hundred eighty one women with clinically and surgically diagnosed ULM, 41 healthy control subjects, and 92 population control subjects. INTERVENTION(S): Completing the questionnaires, peripheral venous puncture. MAIN OUTCOME MEASURE(S): Polymerase chain reaction and restriction-fragment-length polymorphism analyses were performed to genotype women regarding the CYP17A1 -34 A/G (rs743572) gene polymorphisms. Epidemiologic data was collected by questionnaire and compared between women with ULM and healthy control subjects. RESULT(S): Women with multiple ULM had higher prevalence of positive family history, lower age at menarche, lower parity, higher percentage of smoking, younger age at first sexual intercourse, lower prevalence of CYP17A1 AA genotype and lower CYP17A1 A allele frequency than healthy control subjects. These trends were not apparent among women with solitary ULM. CONCLUSION(S): Carriage of CYP17A1 AA is protective for developing ULM in our population. Women with solitary ULM mostly resembled healthy control subjects, whereas women with multiple ULM differed in CYP17A1 AA genotype and external stimuli. PMID- 20171625 TI - Polymerase chain reaction-based detection of chromosomal imbalances on embryos: the evolution of preimplantation genetic diagnosis for chromosomal translocations. AB - OBJECTIVE: To develop and assess a polymerase chain reaction (PCR)-based preimplantation genetic diagnosis (PGD) approach for detection of chromosomal imbalances in embryos. DESIGN: A prospective study of embryos derived from chromosome translocation carriers that have undergone PGD using a novel molecular based approach. SETTING: A reference molecular genetics laboratory specialized in the provision of transport PGD services and a private IVF clinic. PATIENT(S): Twenty-seven couples carrying 12 different reciprocal translocations and 2 Robertsonian translocations. INTERVENTION(S): Preimplantation genetic diagnosis from chromosome translocation carriers on blastomeres biopsied from cleavage stage embryos. MAIN OUTCOME MEASURE(S): Embryo diagnosis rate, pregnancy rate (PR), implantation rate, take-home-baby rate. RESULT(S): Overall, 241/251 (96.0%) embryos were successfully diagnosed for chromosome rearrangements. Preimplantation genetic screening was included in the protocol of 12 couples, involving analysis of 90 embryos, 84 (93.3%) of which were successfully diagnosed and 53 (63.1%) showed aneuploidies. Embryos suitable for transfer were identified in 24 cycles. Eighteen couples achieved a clinical pregnancy (75.0% PR/embryo transfer), with a total of 31 embryos implanted (59.6% implantation rate). Ten patients (1 triplet, 1 twin, and 8 singleton pregnancies) have delivered 13 healthy babies, and the other patients (3 twins and 5 singletons) have currently ongoing pregnancies. CONCLUSION(S): The PCR-based PGD protocol for translocations has the potential to overcome several inherent limitations of fluorescence in situ hybridization-based tests, providing potential improvements in terms of test performance, automation, turnaround time, sensitivity, and reliability. PMID- 20171626 TI - Conversion from assisted reproductive technology to intrauterine insemination in low responders: is it advantageous? AB - OBJECTIVE: To examine cycle outcomes among patients demonstrating an attenuated ovarian response that proceeded to oocyte retrieval to those converted to intrauterine insemination (IUI). DESIGN: Retrospective cohort study. SETTING: Large private fertility center. PATIENT(S): First planned autologous assisted reproductive technology (ART) cycles among women demonstrating a poor ovarian response to hyperstimulation (<=4 follicles>=14 mm, peak E2<1,000 IU/L at hCG administration). INTERVENTION(S): Oocyte retrieval or IUI conversion. MAIN OUTCOME MEASURE(S): Live birth and clinical pregnancy. RESULT(S): A total of 269 IUI conversions and 167 oocyte retrievals followed a poor ovarian response to gonadotropins among first planned ART cycles. Number of follicles>=14 mm (2.3 vs. 3.5) and peak E2 levels (555 vs. 743 pg/mL) were lower for IUI conversions compared with those proceeding to ART. Peak E2 was similar between groups after adjusting for follicle number (IUI: 611 pg/mL; ART: 652 pg/mL). Stimulation response was similar between treatment groups with equivalent follicle numbers. Undergoing oocyte retrieval was associated with significantly improved pregnancy (odds ratio [OR] 3.6, 95% confidence interval [CI] 1.8-7.4) and live birth outcome (OR 3.5, 95% CI 1.7-8.0) after adjusting for age and follicle number. CONCLUSION(S): Among women demonstrating a poor ovarian response to gonadotropins, proceeding with planned ART resulted in significantly higher pregnancy rates than converting these cycles to IUI. PMID- 20171627 TI - Evaluating the performance of serum antimullerian hormone concentration in predicting the live birth rate of controlled ovarian stimulation and intrauterine insemination. AB - OBJECTIVE: To evaluate the role of serum antimullerian hormone (AMH) concentration in predicting live birth outcome in controlled ovarian stimulation and intrauterine insemination (IUI). DESIGN: Retrospective analysis. SETTING: Tertiary assisted reproduction unit. PATIENTS: 243 patients undergoing IUI treatment. INTERVENTION(S): Archived early follicular phase serum samples taken at the start of the first treatment cycle before ovarian stimulation were retrieved from patients undergoing IUI treatment. MAIN OUTCOME MEASURE(S): First cycle and cumulative live birth rates. RESULT(S): Patients attaining a successful live birth, either in the first cycle or cumulatively after three cycles, had significantly higher serum AMH concentrations than those failing treatment. Serum AMH concentration correlated positively with antral follicle count (AFC) and duration of stimulation and inversely with maternal age, serum FSH concentration, and total dose of gonadotropin used. After controlling for age, body mass index, AFC, and FSH, AMH remained the only significant predictor of cumulative live birth. The area under the receiver operating characteristic curve was 0.668 in predicting cumulative live birth. Serum AMH concentration was significantly higher in overresponders. CONCLUSION(S): Serum AMH concentration was significantly higher in subjects with a live birth from the first cycle or after three cycles of stimulated IUI treatment compared with those failing treatment. Serum AMH concentration has a modest predictive value on ovarian overresponse. PMID- 20171628 TI - Proceedings from the conference on Reproductive Problems in Women of Color. AB - The purpose of the National Institutes of Health conference on Reproductive Problems in Women of Color that convened on July 25, 2009 was to bring investigators together to examine data related to reproductive health care access and ethnic disparities in reproductive problems, fertility treatments, and pregnancy outcomes. One of the goals discussed at this conference was to initiate a research network of investigators interested in studying these problems through the development of an American Society of Reproductive Medicine special interest group and Society of Assisted Reproductive Technology writing groups. PMID- 20171629 TI - Vaginal progesterone gel for luteal phase support in IVF/ICSI cycles: a meta analysis. AB - OBJECTIVE: To investigate whether vaginal progesterone gel may result in similar or higher pregnancy rates compared with all other vaginal progesterone forms when used for luteal-phase support. DESIGN: Meta-analysis of randomized controlled trials using odds ratios (OR) and 95% confidence intervals (CI). PATIENT(S): Infertile women undergoing IVF or ICSI. INTERVENTION(S): Vaginal progesterone gel 90 mg once or twice daily versus any other vaginal progesterone form for luteal phase support. MAIN OUTCOME MEASURE(S): Clinical pregnancy rates. RESULT(S): Seven randomized controlled trials, involving 2,447 patients, were included in the analysis. No difference was observed in the overall clinical pregnancy rate when comparing vaginal progesterone gel with any other vaginal progesterone form. Moreover, clinical pregnancy rates were similar in protocols using only GnRH agonists and when comparing vaginal gel with the traditional treatment of 200 mg*3 vaginal progesterone capsules. CONCLUSION(S): This meta-analysis provides solid evidence that no significant difference exists between vaginal gel and all other vaginal progesterone forms in terms of clinical pregnancy rates. PMID- 20171630 TI - Photodynamic diagnosis of endoscopically invisible flat dysplasia in patients with ulcerative colitis by visualization using local 5-aminolevulinic acid induced photosensitization. PMID- 20171631 TI - A case of small-bowel intussusception caused by intestinal lipomatosis: preoperative diagnosis and reduction of intussusception with double-balloon enteroscopy. PMID- 20171633 TI - A case of nonampullary duodenal adenoma treated by endoscopic submucosal dissection (with video). PMID- 20171632 TI - Accuracy of EUS in the evaluation of small gastric subepithelial lesions. AB - BACKGROUND: EUS combined with endoluminal resection techniques is increasingly used to provide a definitive diagnosis of small gastric subepithelial lesions seen on standard upper endoscopy. OBJECTIVE: To evaluate the accuracy of EUS in diagnosing small gastric subepithelial lesions by using histology as the criterion standard. DESIGN: A retrospective study. SETTING: Academic tertiary care center. PATIENTS: A total of 22 patients (15 women, mean age 62.2 years) with an endoscopically resected gastric subepithelial lesion were included in this 3-year retrospective study. MAIN OUTCOME MEASUREMENTS: The size, echogenicity, the layer of origin, and presumptive diagnosis were determined by EUS. The diagnostic accuracy of EUS was determined by using histology as the criterion standard. RESULTS: The mean size of the 22 lesions was 13.6 mm (range 8 20 mm). An endoscopic cap band mucosectomy device was used to resect 16 (72.7%) lesions, whereas 6 (27.3%) were resected with a saline solution-assisted and snare technique. Using histology as a criterion standard, we found that the accuracy of the EUS diagnosis was 10 of 22 (45.5%). EUS alone had an accuracy rate of 30.8% and 66.7%, respectively, in the diagnosis of neoplastic and non neoplastic lesions. LIMITATIONS: A single-center, retrospective analysis. CONCLUSION: EUS imaging had a low accuracy rate in the diagnosis of gastric subepithelial lesions, and endoscopic submucosal resection should be performed to provide a histologic diagnosis. Resection of small subepithelial lesions of 20 mm or less can be accomplished en bloc with an endoscopic cap band mucosectomy device. PMID- 20171634 TI - Technique over reason? PMID- 20171635 TI - Developing trauma centres and trauma protocols. PMID- 20171636 TI - Preclinical carotid atherosclerosis enhances the global cardiovascular risk and increases the rate of cerebro- and cardiovascular events in a five-year follow up. AB - AIM: To evaluate if the intima-media thickening (IMT) and asymptomatic carotid plaque (ACP), as expression of carotid preclinical atherosclerosis (pre-ATS), can provide further information on the global cardiovascular risk (GCVR). METHODS: We studied 454 asymptomatic subjects, with a cluster of risk factors (RF), and evaluated the incidence of a first cardiovascular (CV) event in a five-year follow-up. The subjects at admission were subdivided in three groups of risk. RESULTS: Events occurred in 38% of subjects at high risk, in 13% and 6% of subjects at intermediate and low risk (p<0.003). Among evaluated parameters, carotid pre-ATS was a predictive marker of CV events (OR 2.7, 95% IC 1.4-5.1, p<0.0024). In subjects with GCVR<20% the prevalence of events was 8% for normal carotid ultrasound findings, 13% for increased IMT and 15% for ACP. CONCLUSIONS: In primary prevention, the IMT measurement can give further information for a better stratification of GCVR. The pre-ATS of carotid arteries should be considered a strong predictor of future CV events and should suggest a more aggressive treatment of RF. PMID- 20171637 TI - Decreased number and impaired functionality of endothelial progenitor cells in subjects with metabolic syndrome: implications for increased cardiovascular risk. AB - OBJECTIVE: Metabolic syndrome (MetS) is characterized by low-grade inflammation and confers an increased risk for cardiovascular disease. Endothelial progenitor cells (EPCs) are a measure of vascular health and are decreased in patients with various risk factors for cardiovascular disease (CVD). There is a paucity of data examining the EPC status especially in terms of their functionality in MetS subjects without diabetes or cardiovascular disease. We aimed to enumerate and functionally characterize EPCs in subjects with MetS in comparison to healthy controls. METHODS: The study was performed at the University of California Davis Medical Center. Healthy controls (n=31) and MetS (n=46) subjects were included in the study. EPCs were enumerated in fasting blood by KDR/CD34 dual positivity. Functionality was assessed by the colony forming units (CFU) assay, migration and tubule formation. RESULTS: Subjects with MetS had significantly decreased number of EPCs compared to control subjects. Furthermore, EPCs from MetS subjects depicted significantly impaired clonogenic capacity, i.e., decreased colony forming units, and impaired capacity to incorporate into tubular structures suggesting functional impairment of EPCs from MetS subjects. CONCLUSIONS: We make the novel observation that MetS subjects without diabetes or CVD have decreased EPC number and impaired functionality as compared to control subjects. These findings could contribute to the increased CV risk in this population. PMID- 20171638 TI - Joint kinetic response during unexpectedly reduced plantar flexor torque provided by a robotic ankle exoskeleton during walking. AB - During human walking, plantar flexor activation in late stance helps to generate a stable and economical gait pattern. Because plantar flexor activation is highly mediated by proprioceptive feedback, the nervous system must modulate reflex pathways to meet the mechanical requirements of gait. The purpose of this study was to quantify ankle joint mechanical output of the plantar flexor stretch reflex response during a novel unexpected gait perturbation. We used a robotic ankle exoskeleton to mechanically amplify the ankle torque output resulting from soleus muscle activation. We recorded lower-body kinematics, ground reaction forces, and electromyography during steady-state walking and during randomly perturbed steps when the exoskeleton assistance was unexpectedly turned off. We also measured soleus Hoffmann- (H-) reflexes at late stance during the two conditions. Subjects reacted to the unexpectedly decreased exoskeleton assistance by greatly increasing soleus muscle activity about 60ms after ankle angle deviated from the control condition (p<0.001). There were large differences in ankle kinematic and electromyography patterns for the perturbed and control steps, but the total ankle moment was almost identical for the two conditions (p=0.13). The ratio of soleus H-reflex amplitude to background electromyography was not significantly different between the two conditions (p=0.4). This is the first study to show that the nervous system chooses reflex responses during human walking such that invariant ankle joint moment patterns are maintained during perturbations. Our findings are particularly useful for the development of neuromusculoskeletal computer simulations of human walking that need to adjust reflex gains appropriately for biomechanical analyses. PMID- 20171640 TI - Aerodynamic study of different cyclist positions: CFD analysis and full-scale wind-tunnel tests. AB - Three different cyclist positions were evaluated with Computational Fluid Dynamics (CFD) and wind-tunnel experiments were used to provide reliable data to evaluate the accuracy of the CFD simulations. Specific features of this study are: (1) both steady Reynolds-averaged Navier-Stokes (RANS) and unsteady flow modelling, with more advanced turbulence modelling techniques (Large-Eddy Simulation - LES), were evaluated; (2) the boundary layer on the cyclist's surface was resolved entirely with low-Reynolds number modelling, instead of modelling it with wall functions; (3) apart from drag measurements, also surface pressure measurements on the cyclist's body were performed in the wind-tunnel experiment, which provided the basis for a more detailed evaluation of the predicted flow field by CFD. The results show that the simulated and measured drag areas differed about 11% (RANS) and 7% (LES), which is considered to be a close agreement in CFD studies. A fair agreement with wind-tunnel data was obtained for the predicted surface pressures, especially with LES. Despite the higher accuracy of LES, its much higher computational cost could make RANS more attractive for practical use in some situations. CFD is found to be a valuable tool to evaluate the drag of different cyclist positions and to investigate the influence of small adjustments in the cyclist's position. A strong advantage of CFD is that detailed flow field information is obtained, which cannot easily be obtained from wind-tunnel tests. This detailed information allows more insight in the causes of the drag force and provides better guidance for position improvements. PMID- 20171639 TI - The region-dependent biphasic viscoelastic properties of human temporomandibular joint discs under confined compression. AB - The objective of this study was to determine the biphasic viscoelastic properties of human temporomandibular joint (TMJ) discs, correlate these properties with disc biochemical composition, and examine the relationship between these properties and disc dynamic behavior in confined compression. The equilibrium aggregate modulus (H(A)), hydraulic permeability (k), and dynamic modulus were examined between five disc regions. Biochemical assays were conducted to quantify the amount of water, collagen, and glycosaminoglycan (GAG) content in each region. The creep tests showed that the average equilibrium moduli of the intermediate, lateral, and medial regions were significantly higher than for the anterior and posterior regions (69.75+/-11.47kPa compared to 22.0+/-5.15kPa). Permeability showed the inverse trend with the largest values in the anterior and posterior regions (8.51+/-1.36x10(-15)m(4)/Ns compared with 3.75+/-0.72x10( 15)m(4)/Ns). Discs were 74.5% water by wet weight, 62% collagen, and 3.2% GAG by dry weight. Regional variations were only observed for water content which likely results in the regional variation in biphasic mechanical properties. The dynamic modulus of samples during confined compression is related to the aggregate modulus and hydraulic permeability of the tissue. The anterior and posterior regions displayed lower complex moduli over all frequencies (0.01-3Hz) with average moduli of 171.8-609.3kPa compared with 454.6-1613.0kPa for the 3 central regions. The region of the TMJ disc with higher aggregate modulus and lower permeability had higher dynamic modulus. Our results suggested that fluid pressurization plays a significant role in the load support of the TMJ disc under dynamic loading conditions. PMID- 20171641 TI - Does subcutaneous adipose tissue behave as an (anti-)thixotropic material? AB - Although subcutaneous adipose tissue undergoes large deformations on a daily basis, there is no adequate mechanical model to describe the transfer of mechanical load from the skin throughout the tissue to deeper layers. In order to develop such a non-linear model, a set of experimental data is required. Accordingly, this study examines the long term behavior of adipose tissue under small strain and its response to various large strain profiles. The results show that the shear modulus dramatically increases to about an order of magnitude after a loading period between 250 and 1250 s, but returns to its initial value within 3 h of recovery from loading. In addition, it was observed that the stress strain responses for various large strain history sequences are reproducible up to a strain of 0.15. For increasing strains, the stress decreases for subsequent loading cycles and, above 0.3 strain, tissue structure changes such that the stress becomes independent of the applied strain. From the results, it can be concluded that adipose tissue likely behaves as an (anti-) thixotropic material and that a Mooney-Rivlin model might be appropriate to simulate behavior at physiologically relevant high strains. However, before the model is developed more fully, further experimental research is needed to ratify that the material is (anti-)thixotropic. PMID- 20171642 TI - The kinematics of the scapulae and spine during a lifting task. AB - Simultaneous motion of the scapula and humerus is widely accepted as a feature of normal upper limb movement, however this has usually been investigated under conditions in which purposeful, functional tasks were not considered. The aim of this study was to investigate the synchrony and coordination of the constituent 3D movements of the shoulder girdle and trunk, during a functional activity. 45 healthy women, aged between 20 and 80 years, performed a simple lifting task, moving a loaded box from a shelf at waist level to one at shoulder level and then reversed the movement, during which the linear and angular motions of the scapulae, upper and lower thoracic spine and upper limbs were monitored and analysed using cross-correlation techniques. Results indicated a close and consistent set of coordinated movement patterns, which suggest biomechanical invariance in the responses of the structures adjacent to the upper limb during such a lifting task. These scapulohumeral relationships were, however, more constant and phase-locked when there was a specific purpose to the movement than during periods in which the arm was lowered without load. There were no age related differences in any movement responses. PMID- 20171643 TI - Shear wave induced resonance elastography of soft heterogeneous media. AB - In the context of ultrasound dynamic elastography imaging and characterization of venous thrombosis, we propose a method to induce mechanical resonance of confined soft heterogeneities embedded in homogenous media. Resonances are produced by the interaction of horizontally polarized shear (SH) waves with the mechanical heterogeneity. Due to such resonance phenomenon, which amplifies displacements up to 10 times compared to non-resonant condition, displacement images of the underlying structures are greatly contrasted allowing direct segmentation of the heterogeneity and a more precise measurement of displacements since the signal-to noise ratio is enhanced. Coupled to an analytical model of wave scattering, the feasibility of shear wave induced resonance (SWIR) elastography to characterize the viscoelasticity of a mimicked venous thrombosis is demonstrated (with a maximum variability of 3% and 11% for elasticity and viscosity, respectively). More generally, the proposed method has the potential to characterize the viscoelastic properties of a variety of soft biological and industrial materials. PMID- 20171644 TI - Preparative isolation and purification of ginsenosides Rf, Re, Rd and Rb1 from the roots of Panax ginseng with a salt/containing solvent system and flow step gradient by high performance counter-current chromatography coupled with an evaporative light scattering detector. AB - Ginseng is a popular herb worldwide and has had varied uses in traditional Asian medicine for thousands of years. There are several different species of the herb, but all share the same constituents. Ginsenosides, the most extensively studied chemical components of ginseng, are generally considered to be one of the most important active ingredients of the plant. In this study, we have developed fast and efficient methodology for isolation of four known ginsenosides Rf, Rd, Re and Rb1 from Ginseng by high performance counter-current chromatography (HPCCC) coupled with evaporative light scattering detection (ELSD). The crude sample for HPCCC was purified firstly from a ginseng extraction using macroporous resin. The enriched saponin fraction (480 mg) was separated by using methylene chloride methanol-5 mM aqueous ammonium acetate-isopropanol (6:2:4:3, v/v,) as the two phase solvent system and yielded 10.7 mg of Rf, 11.0 mg of Rd, 13.4 mg of Re and 13.9 mg of Rb1. The purity of these ginsenosides was 99.2%, 88.3%, 93.7% and 91.8%, respectively assessed by HPLC-DAD-ELSD, and their structures were characterized by electrospray ionization mass spectrometry (ESI-MS) and compared with standards. Ammonium acetate was used to shorten the separation time and eliminate emulsification together with a flow step-gradient. The salt can be removed by re-dissolving the sample using acetone. PMID- 20171645 TI - Modeling protein binding and elution over a chromatographic surface probed by surface plasmon resonance. AB - Surface plasmon resonance (SPR) spectroscopy is used as a scaled-down, analytical, pseudo-chromatography tool for analyzing protein binding and elution over an ion-exchange surface under cyclic sorption conditions. A micrometric scale adsorption surface was produced by immobilizing a typical ion exchange ligand--diethylaminoethyl (DEAE)--onto commercially available planar gold sensor chip surfaces pre-derivatized with a self-assembled monolayer of 11 mercaptoundecanoic acid with known density. An explicit mathematical formulation is provided for the deconvolution and interpretation of the SPR sensorgrams. An adsorption rate model is proposed to describe the SPR sensorgrams for bovine serum albumin, used here as model protein, when the DEAE surface is subjected to a cyclic series of binding and elution steps. Overall, we demonstrate that the adsorption rate model is capable of quantitatively describing BSA binding and elution for protein titers from dilute conditions up to overloaded conditions and a broad range of salt concentrations. PMID- 20171646 TI - Tribology of steel/steel interaction in oil-in-water emulsion; a rationale for lubricity. AB - Oil droplets are dispersed in water by an anionic surfactant to form an emulsion. The lubricity of this emulsion in steel/steel interaction is explored in a ball on flat nanotribometer. The droplet size and charge are measured using dynamic light scattering, while the substrate charge density is estimated using the pH titration method. These data are combined to calculate the DLVO forces for the droplets generated for a range of surfactant concentration and two oil to water volume ratios. The droplets have a clear bi-modal size distribution. The study shows that the smaller droplets which experience weak repulsion are situated (at the highest DLVO barrier) much closer to the substrate than the bigger droplets, which experience the same DLVO force, are. We suggest that the smaller droplets thus play a more important role in lubricity than what the bigger droplets do. The largest volume of such small droplets occurs in the 0.5 mM-1 mM range of surfactant concentration and 1% oil to water volume ratio, where the coefficient of friction is also observed to be the least. PMID- 20171647 TI - Adsorption mechanisms of metal cations from water on an oxidized carbon surface. AB - Adsorption of Cr(III), Mn(II), Cu(II) and Zn(II) on an oxidized activated carbon cloth was studied. Its surface chemistry was characterized by potentiometric titration. This technique revealed the amount of surface oxygen functionalities and their acidity constant distribution. The acidity constant range involved in the metal cation adsorption was obtained from this distribution. Metal cation adsorption increased with higher adsorption temperature due to the increase in the negative surface charge of the oxidized activated carbon. Adsorption was by proton exchange and the number, amount and strength of the surface acid groups involved could be obtained. The proton exchange was by an inner-sphere or outer sphere surface metal complex formation mechanism. In the case of divalent cation adsorption, the increase in temperature changed the adsorption mechanism from outer-sphere to inner-sphere. However, the adsorption mechanism of Cr(III) was outer-sphere and independent of temperature. Adsorption capacity augmented with the increase in the charge-to-size ratio of the hexa-aquo cations. In addition, the adsorption capacity of divalent cations increased with the rise in stability of the surface metal complex formed. PMID- 20171648 TI - Dispersion and diameter separation of multi-wall carbon nanotubes in aqueous solutions. AB - Comparative studies on dispersing of multi-wall carbon nanotubes (CNTs) using two anionic surfactants (sodium dodecyl sulphate, SDS, and sodium dodecyl benzenosulfonate, SDBS) are presented. The studies were conducted on the surfactant concentrations that were close to the critical micelle concentration (CMC). The stability of CNTs suspensions obtained for surfactant solutions at concentrations lower than the CMC was investigated. It was also found that the surfactant structure has an influence on the diameter distribution of dispersed CNTs. PMID- 20171649 TI - The rate of bloodstream infection is high in infants with short bowel syndrome: relationship with small bowel bacterial overgrowth, enteral feeding, and inflammatory and immune responses. AB - OBJECTIVE: This pilot study in parenteral nutrition-dependent infants with short bowel syndrome (SBS) evaluated the impact of feeding route and intestinal permeability on bloodstream infection (BSI), small bowel bacterial overgrowth (SBBO), and systemic immune responses, as well as fecal calprotectin as a biomarker for SBBO. STUDY DESIGN: Ten infants (ages 4.2-15.4 months) with SBS caused by necrotizing enterocolitis were evaluated. Nutritional assessment, breath hydrogen testing, intestinal permeability, fecal calprotectin, serum flagellin- and lipopolysaccharide-specific antibody titers, and proinflammatory cytokine concentrations (tumor necrosis factor-alpha [TNF-alpha], interleukin-1 beta, -6, and -8) were performed at baseline and at 60 and 120 days. Healthy, age matched control subjects (n = 5) were recruited. RESULTS: BSI incidence was high (80%), and SBBO was common (50%). SBBO increased the odds for BSI (>7-fold; P = .009). Calprotectin levels were higher in children with SBS and SBBO versus those without SBBO and healthy control subjects (P < .05). Serum TNF-alpha, was elevated at baseline versus controls. Serum TNF-alpha and interleukin-1 beta, -6, and -8 levels diminished with increased enteral nutrition. Anti-flagellin and anti-lipopolysaccharide immunoglobulin G levels in children with SBS were lower versus control subjects and rose over time. CONCLUSION: In children with SBS, SBBO increases the risk for BSI, and systemic proinflammatory response decreases with increasing enteral feeding and weaning parenteral nutrition. PMID- 20171650 TI - Suspected foreign body inhalation in children: what are the indications for bronchoscopy? PMID- 20171651 TI - Elevated serum IL-8 levels in ataxia telangiectasia. AB - Serum interleukin (IL)-8 levels were measured in 50 patients with ataxia telangiectasia (A-T) and 22 without A-T. In a cross-sectional study, the geometric mean of IL-8 level was significantly higher in the patients with A-T (P <.0001). Elevated serum IL-8 levels in patients with A-T suggest that systemic inflammation may contribute to the disease phenotype. PMID- 20171652 TI - Psychological effects of false-positive results in cystic fibrosis newborn screening: a two-year follow-up. AB - OBJECTIVE: To evaluate parental stress after a false-positive result at the time of the cystic fibrosis (CF) newborn screening (NBS), attributable to heterozygotism or persistent hypertrypsinemia. STUDY DESIGN: A prospective study was conducted in 86 French families at 3, 12, and 24 months after NBS. A psychologist conducted interviews with a questionnaire, the Perceived Stress Scale, and the Vulnerable Child Scale. RESULTS: Overall, 96.5% of parents said they had been anxious at the time of the sweat test. However, 86% felt entirely reassured 3 months after the test. The mean Perceived Stress Scale score did not differ from that observed in the French population. Mean Vulnerable Child Scale scores were high, associated with a low Parental Perception of Child Vulnerability. These results did not differ significantly at 1 and 2 years. In total, 86% to 100% of families no longer worried about CF. All parents stated that they would have the test performed again for another child. CONCLUSIONS: CF NBS can lead to false-positive results, causing parental anxiety, which quickly decreases after a sweat test performed soon after the phone call. PMID- 20171653 TI - A randomized intervention of montelukast for post-bronchiolitis: effect on eosinophil degranulation. AB - OBJECTIVE: To investigate the effect of montelukast on eosinophil degranulation and recurrent wheezing episodes in post-respiratory syncytial virus (RSV) bronchiolitis. STUDY DESIGN: Two hundred infants (age, 6-24 months) who were hospitalized with their first episode of acute RSV bronchiolitis were randomized in a double-blind, placebo-controlled, parallel comparison of 4-mg montelukast granules (RSV-MONT group) or matching placebo (RSV-PLC group) administered for 3 months. Serum eosinophil-derived neurotoxin (EDN) levels were measured (primary outcome), and recurrent wheezing was documented (secondary outcome) for 12 months. Comparisons were made with control subjects (control group, n = 50). RESULTS: At the end of the 3-month treatment period, the RSV-PLC group (n = 71) exhibited significantly elevated EDN levels (P < .0001), and the RSV-MONT group (n = 79) showed significantly decreased EDN levels (P < .01) when compared with the initial levels. As a result, EDN levels in the 2 RSV groups significantly differed at this point (P < .0001) and remained different for the entire 12-month follow-up period. Cumulative recurrent wheezing episodes at 12 months were significantly lower in the RSV-MONT group (P = .039). CONCLUSION: Montelukast treatment reduces eosinophil degranulation and is associated with a decrease in recurrent wheezing episodes in post-RSV bronchiolitis. PMID- 20171654 TI - Five-year outcome of children with "growing pains": correlations with pain threshold. AB - OBJECTIVE: To examine the 5-year outcome in a cohort of children with "growing pains" and the association with changes in pain threshold. STUDY DESIGN: Subjects were 44 children with growing pains studied previously, and controls were 38 pain free children matched by sex and age. Current status of growing pains and other pain syndromes were assessed by parental questionnaires. Pain threshold was measured with a Fisher-type dolorimeter. Outcomes were correlated with the pain threshold. RESULTS: We examined 35/44 patients (80%) after 5 years. Eighteen patients (51%) experienced resolution of growing pains. In 14 of the 17 patients with persistent growing pains (83%), episodes were less frequent and milder. The prevalence of accompanying pain syndromes decreased from 20% to 14%. No patient developed fibromyalgia. Pain thresholds were similar in the entire growing pains cohort and healthy controls, but those with continued growing pains had significantly lower thresholds than controls (P <.05) and patients with resolved growing pains (P <.02). CONCLUSIONS: We confirm that growing pains has a benign prognosis and probably represents a pain amplification syndrome of early childhood. PMID- 20171655 TI - Urinary cytokines and renal Doppler study in Kawasaki disease. AB - OBJECTIVE: To investigate whether renal vasculitis is the sole cause or merely a contributing cause of renal inflammation in Kawasaki disease (KD). STUDY DESIGN: This prospective study in a university medical center in Taiwan enrolled 24 children with KD between June 2004 and November 2005. All patients underwent a technetium-99 m dimercaptosuccinic acid scintigraphy single-photon emission computed tomography scan, the results of which were used to group the patients with KD as with or without renal involvement. Urine samples underwent a cytokine analysis. Renal Doppler ultrasonography was used to evaluate renal vasculitis by measuring the pulsatility index (PI) and resistance index (RI). RESULTS: Ten of the 24 patients (42%) with renal inflammatory foci were the study group; the remainder composed the control group. Urinary interleukin (IL)-6 levels were significantly higher in the study group (496.7 +/- 310.9 vs 115.0 +/- 65.9 ng/g urinary creatinine; P < .01), as were PI values (1.85 +/- 0.70 vs 1.44 +/- 0.53; P < .05). Urinary IL-6 levels and PI values were significantly (P < .05) correlated. CONCLUSIONS: Increased urinary IL-6 and elevated renal Doppler measures suggest that immune-mediated vasculitis is one of the mechanisms causing renal inflammation in KD. PMID- 20171656 TI - Modafinil reduces microsleep during partial sleep deprivation in depressed patients. AB - OBJECTIVE: Sleep deprivation (SD) can induce a prompt decrease in depressive symptoms within 24h. Following the recovery night, however, a relapse into depression occurs in most patients. Recovery sleep, naps and even very short episodes of sleep (microsleep; MS) during SD have been shown to provoke a rapid relapse into depression. This study tested the hypothesis that modafinil reduces MS during SD and stabilizes the treatment response to PSD compared to placebo. METHODS: A total of 28 patients (13 men, 15 women; age 45.1+/-12.1 years) with a major depressive episode and a cumulative daytime microsleep of five or more minutes were investigated using a double-blind placebo-controlled study design. All patients were treated with a stable mirtazapine monotherapy. A partial SD (PSD) was performed after one week. Additional morning treatment with modafinil vs. placebo started during PSD and was maintained over two weeks. Sleep-EEG and MS episodes were recorded with a portable EEG. Depression severity was assessed using the Hamilton Depression Rating Scale before, during and after PSD and at follow-ups after one and two weeks. RESULTS: Patients treated with modafinil showed significantly reduced microsleep during PSD (11.63+/-15.99 min) compared to the placebo group (47.77+/-65.31 min). This suppression of MS was not associated with the antidepressive effect of PSD. CONCLUSIONS: Compared to placebo, modafinil was efficient in reducing daytime microsleep following partial sleep deprivation but did not enhance the antidepressive effects of PSD and did not stabilize antidepressive effects over two weeks. PMID- 20171657 TI - The urethral motion profile before and after suburethral sling placement. AB - PURPOSE: We examined the effect of the Monarc suburethral sling on urethral mobility. MATERIALS AND METHODS: We retrospectively studied the records of 54 consecutive women who received a Monarc suburethral sling between July 2005 and November 2008. All patients were examined by volume ultrasound preoperatively and at followup (average 0.7 years). Volume data sets were analyzed using post processing software. Urethral mobility was described by vectors of movement from rest to a maximum Valsalva maneuver of 6 equidistant points marked evenly along the urethra from bladder neck (point 1) to external urethral meatus (point 6), as identified in the mid sagittal view. Measurements were made of point coordinates relative to the pubic symphysis dorsocaudal margin at rest and during maximal Valsalva maneuver. To determine the urethral motion profile we calculated mobility vectors of the 6 points using the formula, square root [(x(val) - x(rest))(2) + (y(val) - y(rest))(2)], where val represents the value during the Valsalva maneuver and rest represents the value at rest. We compared values before and after sling placement. RESULTS: The subjective cure rate for stress urinary incontinence was 78% (42 cases). There was a statistically significantly decreased mobility at points 2 to 4, corresponding to the urethral central aspect (p = 0.002 to 0.018). No significant change in mobility was noted at the bladder neck and distal urethra (p = 0.39 to 0.89). CONCLUSIONS: Monarc suburethral sling placement decreases mid urethral mobility but does not seem to affect the bladder neck. PMID- 20171660 TI - Editorial comment. PMID- 20171661 TI - Strategy to control catheter encrustation with citrated drinks: a randomized crossover study. AB - PURPOSE: Nucleation pH is the pH at which Ca and Mg come out of urine to form crystals. If the safety margin between voiding pH and nucleation pH could be increased, it would increase the possibility of an alternative to controlling the activity of urease producing bacteria as a strategy to control catheter encrustation. MATERIALS AND METHODS: We performed a 6-week randomized crossover study in 24 patients with catheter blockage who were randomly allocated to a specific sequence of 3 consecutive available treatments, including increased fluid intake, lemon juice and potassium citrate. Each patient received all available regimens. At the end of each week 24-hour urine samples were analyzed for voiding and nucleation pH, citrate, Ca and Mg. RESULTS: Mean +/- SD nucleation pH increased from 7.45 +/- 0.60 at baseline to 7.93 +/- 0.50, 7.68 +/- 0.64 and 7.96 +/- 0.37 in the lemon juice, increased fluid intake and potassium citrate groups, respectively (p <0.0001). Mean urinary citrate increased significantly (p <0.0001), in particular due to lemon juice and potassium citrate effects. The association between treatment and Ca was weak (p = 0.12) while that of Mg was negative due to lemon (p <0.001). Average increase in the safety margin (nucleation pH minus voiding pH) beyond baseline was 0.84 (95% CI 0.63-1.04), 0.57 (95% CI 0.37-0.78) and 0.41 (95% CI 0.20-0.61) for lemon juice, increased fluid intake and potassium citrate, respectively. A strong treatment effect on the safety margin was apparent even when controlling for study design (p <0.001). CONCLUSIONS: Increased fluid intake with lemon juice may be a simple, inexpensive, effective strategy to control catheter encrustation. PMID- 20171663 TI - How to use an article about prognosis. AB - PURPOSE: This article in the Users' Guide to the Urological Literature series examines studies that provide information about prognosis for evidence-based clinical practice. MATERIALS AND METHODS: Studies of prognosis are introduced to the reader in the context of a clinical scenario that raises questions about the expected outcome for a patient. Critical appraisal of prognostic studies addresses the 3 questions. 1) Are the results valid? 2) What are the results? 3) Can I apply the results to the care of my patients? RESULTS: To assess the validity of a cohort study that addresses a question of prognosis, the reader should first ask whether the sample of patients under investigation were representative and sufficiently homogeneous with respect to prognostic risk. Investigators should measure all plausible determinants of outcome (prognostic or risk factors) and present results for all subgroups in which the prognosis differs substantially. The reader should ask whether followup was sufficiently complete, and whether investigators used objective, unbiased and patient relevant outcomes. The results should address the likelihood of the outcomes of interest and the precision of the estimates. Finally the reader should ask how similar the study patients and treatment are to his/her patients, and whether followup was sufficiently long. CONCLUSIONS: Questions of prognosis have an important role in the practice of urology and are usually best answered by nonrandomized, observational studies. Urologists should critically appraise these studies for validity, impact and applicability before using the results to guide patient care. PMID- 20171664 TI - Editorial comment. PMID- 20171665 TI - Acitretin for severe lichen sclerosus of male genitalia: a randomized, placebo controlled study. AB - PURPOSE: Genital lichen sclerosus is a chronic inflammatory and fibrosclerotic disease associated with substantial morbidity. Acitretin has been reported to be of benefit in many dermatological indications including lichen sclerosus. We evaluated the efficacy and tolerability of acitretin for biopsy confirmed, severe lichen sclerosus of the male genitalia. MATERIALS AND METHODS: A randomized, double-blind, placebo controlled study was performed in which 52 male patients with severe, long-standing lichen sclerosus were randomized in a 2:1 ratio to receive daily acitretin (35 mg) or placebo for 20 consecutive weeks. Followup lasted for 36 weeks from baseline. The primary end point was complete response of active lichen sclerosus as well as improvement of patient quality of life. Secondary end points were partial response and recurrence rates after treatment discontinuation. RESULTS: A total of 49 patients completed the study and were eligible for statistical analysis. Complete response was achieved by 36.4% (12 of 33) of the acitretin group vs 6.3% (1 of 16) of the controls, while 36.4% (12 of 33) vs 12.5% (2 of 16) achieved partial resolution, respectively. Mean total clinical score of the acitretin group was significantly lower than that of the controls at week 20 [t (47) = -4.146, p = 0.00 < 0.5], which was also accompanied by a significant improvement in mean Dermatology Life Quality Index score [t (32) = 6,441, p = 0.000 < 0.05]. Acitretin was well tolerated and only minimal transient side effects were recorded. CONCLUSIONS: Acitretin is safe and effective for the management of severe, long-standing lichen sclerosus of the male genitalia. Study limitations included bias during clinical evaluation considering the expected side effects of acitretin. PMID- 20171666 TI - Segmental ureterectomy can safely be performed in patients with transitional cell carcinoma of the ureter. AB - PURPOSE: To date no study to our knowledge has compared cancer control outcomes of segmental ureterectomy relative to nephroureterectomy, which represents the standard of care for ureteral transitional cell carcinoma. We compared cancer specific mortality rates according to surgery type (nephroureterectomy vs segmental ureterectomy) in a large population based cohort of patients with ureteral transitional cell carcinoma. MATERIALS AND METHODS: Our analyses involved 2,044 patients with pathological T1-T4 N0M0 ureteral transitional cell carcinoma from the Surveillance, Epidemiology and End Results database. Survival plots and Cox regression models compared cancer specific mortality after segmental ureterectomy, or nephroureterectomy with or without bladder cuff removal. Covariates consisted of pathological stage and grade, age, race, gender and year of surgery. RESULTS: Median followup of censored patients was 30.0 months. Overall 569 (27.8%) patients underwent segmental ureterectomy vs 1,222 (59.8%) nephroureterectomy with bladder cuff removal and 253 (12.4%) nephroureterectomy without bladder cuff removal. At 5 years cancer specific mortality-free rates for segmental ureterectomy vs nephroureterectomy with bladder cuff removal vs nephroureterectomy without bladder cuff removal were 86.6% vs 82.2% vs 80.5%, respectively (all pairwise log rank comparisons p >or=0.05). On univariable and multivariable analyses of the entire cohort, as well as after stratification according to pT1-2 vs pT3-4 stage, the type of surgery (segmental ureterectomy vs nephroureterectomy with bladder cuff removal vs nephroureterectomy without bladder cuff removal) failed to affect cancer specific mortality rates (p >or=0.2). CONCLUSIONS: In patients with ureteral transitional cell carcinoma segmental ureterectomy does not undermine cancer control outcomes relative to nephroureterectomy (with or without bladder cuff removal). Therefore, segmental ureterectomy may be offered to virtually all patients with ureteral transitional cell carcinoma when it is technically feasible, which also includes carefully selected patients with T3 or even T4 lesions. PMID- 20171667 TI - Editorial comment. PMID- 20171669 TI - Honor code. PMID- 20171668 TI - Bladder afferent signaling: recent findings. AB - PURPOSE: Much current research on lower urinary tract physiology focuses on afferent mechanisms. The main goals are to define and control the signaling pathways by which afferent information is generated and conveyed to the central nervous system. We summarize recent research on bladder afferent mechanisms. MATERIALS AND METHODS: We systematically reviewed the literature by searching PubMed up to June 2009 with focus on the last 5 years. RESULTS: At least 2 signaling pathways can be identified, including the urothelial and the myogenic pathway. The urothelial pathway is a functional unit consisting of the urothelium, interstitial cells and afferent nerves in the lamina propria. Signaling occurs via muscle-mucosal mechanoreceptors, mucosal mechanoreceptors and chemoreceptors. The myogenic pathway is activated via in-series mechanoreceptors responding to distention and via spontaneous contractile activity in units of myocytes generating afferent noise. CONCLUSIONS: To control dysfunctional micturition we must know more about all components involved in normal micturition control, including how afferent information is handled by the central nervous system. PMID- 20171671 TI - Small incidentally discovered testicular masses in infertile men--is active surveillance the new standard of care? AB - PURPOSE: The management of small, incidental testicular masses found on scrotal ultrasound is controversial. Although these neoplasms are classically treated with surgical excision, ultrasound surveillance has been proposed as an alternative to surgery. MATERIALS AND METHODS: We reviewed our experience of ultrasound surveillance for small testicular masses at Mount Sinai Hospital Fertility Clinic from 2001 to 2008, offered to all patients with subcentimeter, incidentally discovered hypoechoic testicular lesions. Patient age, semen parameters, the size and growth of the lesion on serial ultrasounds, need for surgery and pathological diagnosis were collected in a database. RESULTS: Of 4,418 patients evaluated 46 (1%) met the study inclusion criteria. Mean age was 35 years, and 39 patients (85%) presented with infertility. Semen analysis revealed azoospermia, oligospermia and normospermia in 15, 18 and 7 patients, respectively, and was unavailable in 6. Mean ultrasound followup was 253 days and mean number of ultrasounds was 2.8. Mean lesion diameter was 4.3 mm (range 1 to 10). There were 38 patients with serial ultrasound followup only with a mean growth of 0.5 mm per year (95% CI -2.2-3.3). Three patients underwent immediate surgery and 5 underwent surgery following a period of ultrasound followup. Indications for surgery were interval growth in 2 patients and patient choice in 6. Larger size (p = 0.02) and presence of vascular flow (p <0.01) were associated with intervention. One patient underwent radical orchiectomy for pure seminoma identified due to interval growth from 3 to 6 mm at 3 months. The other 7 masses excised with partial orchiectomy were benign. CONCLUSIONS: Ultrasound surveillance of small (less than 1 cm) incidental testicular masses is a safe alternative to immediate surgical removal. PMID- 20171670 TI - [-2]Proenzyme prostate specific antigen is more accurate than total and free prostate specific antigen in differentiating prostate cancer from benign disease in a prospective prostate cancer screening study. AB - PURPOSE: Due to the limited specificity of prostate specific antigen for prostate cancer screening, there is an ongoing search for adjunctive biomarkers. Retrospective studies have suggested that an isoform of proenzyme prostate specific antigen called [-2]proenzyme prostate specific antigen may enhance the specificity of prostate specific antigen based screening. We examined the usefulness of this isoform in a prospective prostate cancer screening study. MATERIALS AND METHODS: From a population of 2,034 men undergoing prostate cancer screening we examined the relationship between the measurement of the [-2]isoform of proenzyme prostate specific antigen (p2PSA) and prostate cancer detection. Specifically we compared the usefulness of total prostate specific antigen, the ratio of free-to-total prostate specific antigen, the ratio of p2PSA-to-free prostate specific antigen, and a formula combining prostate specific antigen, free prostate specific antigen and p2PSA (the Beckman Coulter prostate health index or phi) to predict prostate cancer in men from the study undergoing prostate biopsy with a prostate specific antigen of 2.5 to 10 ng/ml and nonsuspicious digital rectal examination. RESULTS: Despite similar total prostate specific antigen (p = 0.88), percent free prostate specific antigen (p = 0.02) and %p2PSA (p = 0.0006) distinguished between positive and negative biopsy results. On ROC analysis %p2PSA (AUC 0.76) outperformed prostate specific antigen (AUC 0.50) and percent free prostate specific antigen (AUC 0.68) for differentiating between prostate cancer and benign disease. Setting the sensitivity at 88.5%, p2PSA led to a substantial improvement in specificity as well as positive and negative predictive values. The Beckman Coulter prostate health index (AUC 0.77) had the best overall performance characteristics. CONCLUSIONS: This is the first prospective study to our knowledge to demonstrate that p2PSA provides improved discrimination between prostate cancer and benign disease in screened men with a prostate specific antigen of 2.5 to 10 ng/ml and a negative digital rectal examination. PMID- 20171672 TI - The globalization of medical care: managing rare diseases from elsewhere. PMID- 20171673 TI - Under treatment of overactive bladder. PMID- 20171674 TI - Editorial comment. PMID- 20171675 TI - Should pelvic lymph node dissection be performed with radical prostatectomy? No. PMID- 20171676 TI - Gadolinium enhanced magnetic resonance urography for upper urinary tract malignancy. AB - PURPOSE: We retrospectively evaluated the accuracy of gadolinium enhanced magnetic resonance urography to detect upper urinary tract tumors. MATERIALS AND METHODS: A total of 91 magnetic resonance urography studies for suspected upper tract malignancy were done in 70 males and 18 females with a mean age of 71.7 years. Breath hold coronal T2-weighted single shot fast spin-echo and breath-hold coronal 3-dimensional T1-weighted spoiled gradient-recalled echo images with fat suppression were obtained during the nephrographic and excretory phases after intravenous injection of gadolinium based contrast material. Two radiologists independently reviewed magnetic resonance images for a tumor by 4 regions (right/left and renal collecting system/ureter). Sensitivity, specificity and accuracy were calculated. RESULTS: A total of 35 urinary tract regions in 18 males and 7 females with a mean age of 70.4 years were confirmed to have an upper tract malignant tumor and 219 urinary tract regions were confirmed to be tumor free. Sensitivity, specificity and accuracy to detect upper urinary tract malignancy were 74.3%, 96.8% and 93.7% for reviewer 1, and 62.9%, 96.3% and 91.7% for reviewer 2, respectively. When patients with a ureteral stent or nephrostomy tube were excluded from analysis, sensitivity, specificity and accuracy were 86.2%, 99.5% and 97.7% for reviewer 1, and 72.4%, 97.9% and 94.6% for reviewer 2, respectively. CONCLUSIONS: Gadolinium enhanced magnetic resonance urography is accurate to detect upper urinary tract malignant tumors. PMID- 20171677 TI - Randomized trial of percutaneous tibial nerve stimulation versus Sham efficacy in the treatment of overactive bladder syndrome: results from the SUmiT trial. AB - PURPOSE: The Study of Urgent PC vs Sham Effectiveness in Treatment of Overactive Bladder Symptoms (SUmiT) was a multicenter, double-blind, randomized, controlled trial comparing the efficacy of percutaneous tibial nerve stimulation to sham through 12 weeks of therapy. The improvement in global response assessment, voiding diary parameters, and overactive bladder and quality of life questionnaires was evaluated. MATERIALS AND METHODS: A total of 220 adults with overactive bladder symptoms were randomized 1:1 to 12 weeks of treatment with weekly percutaneous tibial nerve stimulation or sham therapy. Overactive bladder and quality of life questionnaires as well as 3-day voiding diaries were completed at baseline and at 13 weeks. Subject global response assessments were completed at week 13. RESULTS: The 13-week subject global response assessment for overall bladder symptoms demonstrated that percutaneous tibial nerve stimulation subjects achieved statistically significant improvement in bladder symptoms with 54.5% reporting moderately or markedly improved responses compared to 20.9% of sham subjects from baseline (p <0.001). All individual global response assessment subset symptom components demonstrated statistically significant improvement from baseline to 13 weeks for percutaneous tibial nerve stimulation compared to sham. Voiding diary parameters after 12 weeks of therapy showed percutaneous tibial nerve stimulation subjects had statistically significant improvements in frequency, nighttime voids, voids with moderate to severe urgency and urinary urge incontinence episodes compared to sham. No serious device related adverse events or malfunctions were reported. CONCLUSIONS: This pivotal multicenter, double-blind, randomized, sham controlled trial provides level I evidence that percutaneous tibial nerve stimulation therapy is safe and effective in treating overactive bladder symptoms. The compelling efficacy of percutaneous tibial nerve stimulation demonstrated in this trial is consistent with other recently published reports and supports the use of peripheral neuromodulation therapy for overactive bladder. PMID- 20171678 TI - The management of dysfunctional voiding in children: a report from the Standardisation Committee of the International Children's Continence Society. AB - PURPOSE: We present a consensus view of members of the International Children's Continence Society on the management of dysfunctional voiding in children. MATERIALS AND METHODS: Discussions were held by the board of the International Children's Continence Society and a multi-disciplinary core group of authors was appointed. The draft document review process was open to all International Children's Continence Society members via the web site. Feedback was considered by the core authors and, by agreement, amendments were made as necessary. RESULTS: Guidelines on the assessment, and nonpharmacological and pharmacological management of dysfunctional voiding are presented. CONCLUSIONS: The final document is not a systematic literature review. It includes relevant research when available as well as expert opinion on the current understanding of dysfunctional voiding in children. PMID- 20171679 TI - Editorial comment. PMID- 20171680 TI - Patient or cancer sparing urological surgery--too much or too little? PMID- 20171681 TI - Histological subtype is an independent predictor of outcome for patients with renal cell carcinoma. AB - PURPOSE: There are significant differences in clinicopathological features among renal cell carcinoma histological subtypes but controversy exists regarding the independent impact of histological subtype on patient outcome after nephrectomy. We examined the significance of histological subtype on progression to distant metastasis and cancer specific death after nephrectomy. MATERIALS AND METHODS: In a retrospective review of our institutional nephrectomy registry we identified 3,062 patients treated surgically for clear cell, papillary or chromophobe renal cell carcinoma between 1970 and 2003. RESULTS: We identified 2,466 patients (80.5%) with clear cell, 438 (14.3%) with papillary and 158 (5.2%) with chromophobe renal cell carcinoma. There were significant differences in age at surgery, gender, symptoms at presentation, tumor size, stage and grade, tumor necrosis, sarcomatoid differentiation and multifocality among the 3 renal cell carcinoma subtypes (p <0.01 for all). A significant difference in metastasis-free and cancer specific survival existed between patients with clear cell renal cell carcinoma and the 2 other subtypes, although no significant difference in these outcomes was identified between patients with the papillary and chromophobe subtypes. The clear cell renal cell carcinoma subtype remained a significant predictor of metastasis (HR 2.76, 95% CI 2.05-3.73) and cancer specific death (HR 1.77, 95% CI 1.38-2.26, each p <0.001) after multivariate adjustment for the features listed above. CONCLUSIONS: Histological subtype is an independent predictor of progression to distant metastasis and cancer specific death in patients with renal cell carcinoma. PMID- 20171682 TI - Testicular germ cell cancer incidence in an immigration perspective, Denmark, 1978 to 2003. AB - PURPOSE: The incidence rate of testicular germ cell cancer in Denmark increased up to the 1990s to become among the highest in the world. Since recently rate stabilization was suggested, we determined whether it is due to an increasing number of immigrants at lower risk for this cancer. MATERIALS AND METHODS: The immigration status of more than 3.6 million men registered in the Danish Central Population Register between 1978 and 2003 was defined by birthplace (first generation immigrant) or parental birthplace (second generation immigrant). Linkage with the Danish Cancer Registry yielded 6,478 testicular cancer cases. Differences between populations are shown as SIR with the 95% CI. RESULTS: The testicular germ cell cancer incidence rate in first generation immigrants was lower than in native born Danish men (SIR 0.4, 95% CI 0.4-0.5). The rate in second generation immigrants was similar (SIR 0.9, 95% CI 0.7-1.1). The impact of immigrant status on the incidence rate increased with time from 0.6% in 1978 to 8.2% in 2003. Recent incidence rates in all men and only in men born in Denmark suggest stabilization. CONCLUSIONS: Our finding of a higher incidence rate in second generation immigrants than in their immigrant fathers confirms the early life programming of environmental factors in the etiology of testicular cancer. Our study also shows that trend analysis of the incidence rate of this cancer should consider immigration due to considerable country specific differences in morbidity. PMID- 20171683 TI - Editorial comment. PMID- 20171684 TI - Editorial comment. PMID- 20171685 TI - Editorial comment. PMID- 20171686 TI - Plasma volume changes affect prostate specific antigen in healthy men. AB - PURPOSE: Several studies show that prostate specific antigen inversely correlates with body mass index. Hemodilution may be responsible for the lower prostate specific antigen in obese men. Hematocrit is the most popular indicator of plasma volume. We examined the effect of hematocrit changes on prostate specific antigen in healthy men during 2 years. We also investigated the association between prostate specific antigen and plasma volume changes based on combined changes in body weight and hematocrit. MATERIALS AND METHODS: We reviewed the records of 8,338 men who visited our institution for routine health assessments in 2005, 2006 and 2007. Using the combination of body weight and hematocrit changes in 1 year we defined hemodilution as weight gain with decreased hematocrit and hemoconcentration as weight loss with increased hematocrit. RESULTS: On multiple regression analysis controlling for patient age and weight change the hematocrit change was significantly associated positively with the prostate specific antigen change between 2005 and 2006 (1.2%/1 U), and between 2006 and 2007 (0.7%/1 U, each p <0.001). After controlling for age participants with hemoconcentration showed significantly greater prostate specific antigen changes than those with hemodilution, that is 6.1% between 2005 and 2006, and 4.8% between 2006 and 2007 (each p <0.001). CONCLUSIONS: Hematocrit change was positively associated with prostate specific antigen change. Compared to men with hemodilution significantly greater prostate specific antigen changes were observed in men with hemoconcentration. Thus, plasma volume may explain the inverse relationship between body mass index and prostate specific antigen. PMID- 20171687 TI - The learning curve for surgical margins after open radical prostatectomy: implications for margin status as an oncological end point. AB - PURPOSE: Surgical margin status is commonly used as an end point for surgical learning. We examined the surgical margin learning curve and investigated whether surgical margins are a good marker for oncological outcome. MATERIALS AND METHODS: The study cohort included 7,765 patients with prostate cancer treated with radical prostatectomy by 1 of 72 surgeons at a total of 4 major American academic medical centers. We calculated the learning curve for surgical margins and a concordance probability between the surgeon rates of positive surgical margins and 5-year biochemical recurrence. RESULTS: A positive surgical margin was identified in 2,059 patients (27%). On multivariate analysis surgeon experience was strongly associated with surgical margin status (p = 0.017). The probability of a positive surgical margin was 40% for a surgeon with 10 prior cases, which decreased to 25% for a surgeon with 250 (absolute difference 15%, 95% CI 11 to 18). Learning curves differed dramatically among surgeons. For surgeon pairs the surgeon with the superior positive surgical margin rate also had the better biochemical recurrence rate only 58% of the time. CONCLUSIONS: We noted a learning curve for surgical margins after open radical prostatectomy. The poor concordance between surgeon margin and recurrence rates suggests that while margins clearly matter and efforts should be made to decrease positive margin rates, surgical margin status is not a strong surrogate for cancer control. These results have implications for using the margin rate to evaluate changes in surgical technique and as surgeon feedback. PMID- 20171688 TI - Nephrectomy induced chronic renal insufficiency is associated with increased risk of cardiovascular death and death from any cause in patients with localized cT1b renal masses. AB - PURPOSE: Radical nephrectomy has traditionally been preferred to partial nephrectomy in patients with localized renal cell cancer because of its simplicity and established cancer control. Recent data suggest that these patients have significant competing risks of death, some of which may be increased by chronic renal insufficiency. Therefore, we compared overall survival, cancer specific survival and cardiac specific survival in patients undergoing partial or radical nephrectomy for cT1b tumors. MATERIALS AND METHODS: From 1999 to 2006, 1,004 patients with renal masses between 4 and 7 cm underwent extirpative surgery, partial nephrectomy (524) or radical nephrectomy (480). We generated a propensity model based on preoperative patient characteristics, and then modeled survival with the additional variables of pathological stage and new baseline renal function. RESULTS: On multivariate analysis cancer specific survival was equivalent for patients treated with partial nephrectomy or radical nephrectomy. Those patients undergoing radical nephrectomy lost significantly more renal function than those undergoing partial nephrectomy. The average excess loss of renal function observed with radical nephrectomy was associated with a 25% (95% CI 3-73) increased risk of cardiac death and 17% (95% CI 12-27) increased risk of death from any cause on multivariate analysis. CONCLUSIONS: Partial nephrectomy offers cancer specific survival equivalent to that of radical nephrectomy and is technically feasible in at least 50% of patients with cT1b tumors. Preservation of renal function was significantly better in patients treated with partial nephrectomy. Postoperative renal insufficiency was a significant independent predictor of overall and cardiovascular specific survival, and efforts should be made to limit the renal function loss associated with surgery for localized renal masses. PMID- 20171689 TI - Continence definition after radical prostatectomy using urinary quality of life: evaluation of patient reported validated questionnaires. AB - PURPOSE: After radical prostatectomy continence is commonly defined as no pads except a security pad or 0 to 1 pad. We evaluated the association of pad status and urinary quality of life to determine whether security and 1 pad status differ from pad-free status to better define 0 pads as the post-prostatectomy standard. MATERIALS AND METHODS: A total of 500 consecutive men underwent robot assisted radical prostatectomy from October 2003 to July 2007. Data were collected prospectively and entered into an electronic database. Postoperatively men completed self-administered validated questionnaires including questions on 1) daily pad use (0, security, 1, or 2 or more), 2) urine leakage (daily, about once weekly, less than once weekly or not at all), 3) urinary control (none, frequent dribbling, occasional dribbling or total control), 4) American Urological Association symptom score and 5) urinary quality of life. RESULTS: Postoperatively men who indicated 0 pad use had a mean +/- SE symptom score of 5.8 +/- 0.3 and pleased quality of life (1.16 +/- 0.08). In contrast, men with a security pad and 1 pad had a symptom score of 7.6 +/- 0.7 and 9.2 +/- 0.6 but mixed quality of life (2.78 +/- 0.18 and 3.41 +/- 0.15, respectively, p <0.0005). CONCLUSIONS: Results show a significant decrease in quality of life between no pads (1.16 or pleased), a security pad and 0 or 1 pad (2.78 and 3.41 or mixed, respectively). Findings do not support defining continence with a security pad or 0 to 1 pad. Continence should be strictly defined as 0 pads. PMID- 20171690 TI - Individualized seminal vesicle sparing cystoprostatectomy combined with ileal orthotopic bladder substitution achieves good functional results. AB - PURPOSE: We review the functional and oncologic outcomes of seminal vesicle and prostate capsule sparing cystectomy combined with ileal orthotopic bladder substitution. MATERIALS AND METHODS: Between May 2003 to April 2009 a select group of 31 patients (median age 61 years, range 30 to 77) underwent seminal vesicle sparing cystoprostatectomy for transitional cell carcinoma of the bladder. Preoperatively all 31 patients were continent, and 23 (74%) were potent and sexually active. Of these patients 17 (55%) underwent unilateral and 14 (45%) underwent bilateral seminal vesicle sparing cystoprostatectomy. Pathological disease stage was pTa/pT1 in 15 patients (48%), pT2 in 9 (29%), pT3 in 2 (7%) and pT2-4 pN1 in 5 (16%). Urinary continence and potency outcomes were assessed with validated questionnaires. All patients were followed for local tumor recurrence and distant metastasis. RESULTS: Median followup was 18 months (range 3 to 63). At 6 months 25 of the 30 evaluable patients (83%) had daytime continence and 13 of 30 (43%) had nighttime continence. At last followup (median 18 months) 27 of 29 evaluable patients (93%) had daytime continence and 19 of 29 (66%) had nighttime continence. In terms of postoperative potency 15 of 19 evaluable patients (79%) remained potent, 9 with oral medications. There was pelvic recurrence in 1 patient (3%), distant metastases developed in 4 (13%) and 1 (3%) died of metastatic transitional cell carcinoma. CONCLUSIONS: Individualized seminal vesicle and nerve sparing cystoprostatectomy resulted in a high probability of preserving potency, at least with oral medication, without putting patients at undue risk. PMID- 20171691 TI - Durability of urethral bulking agent injection for female stress urinary incontinence: 2-year multicenter study results. AB - PURPOSE: We evaluated the durability of the urethral bulking agent Macroplastique for stress urinary incontinence in a 24-month study in women with a previously documented successful outcome 12 months after the last injection. MATERIALS AND METHODS: In a multicenter study females diagnosed with stress urinary incontinence primarily due to intrinsic sphincter deficiency successfully treated with Macroplastique, defined as 1 or greater Stamey grade improvement 12 months from baseline, were followed for 24 months to assess the sustained therapeutic response. Outcome measures were Stamey grade, Patient Global Impression of Improvement, Physician Assessment of Improvement, 1-hour pad weight, Incontinence Quality of Life scores and safety assessment. RESULTS: At 24 months 56 of 67 patients (84%) had sustained success since 12 months, of whom 45 of 67 (67%) were dry (Stamey grade 0). Of the dry patients at 12 months 33 of 38 (87%) maintained cure at 24 months. Also, 12 of 29 patients (41%) considered improved at 12 months were dry at 24 months. Overall Incontinence Quality of Life scores and all subscales showed statistically significant improvement from baseline (p <0.001). Mean pad weight was 24 gm at baseline, and 4 gm at 12 and 24 months. Patient and physician assessments rated 85% of patients dry or markedly improved 24 months after the last treatment. CONCLUSIONS: Substantial, durable results were sustained during 2 years with 84% of patients maintaining significant Stamey grade improvement from the 12-month assessment. Two-thirds of patients were dry at 24 months. The durability of Macroplastique shows its effectiveness as a viable long-term therapy for female stress urinary incontinence primarily due to intrinsic sphincter deficiency. PMID- 20171692 TI - The role of race in determining 24-hour urine composition in white and Asian/Pacific Islander stone formers. AB - PURPOSE: We examined differences in 24-hour urine composition between white and Asian/Pacific Islander stone formers. MATERIALS AND METHODS: We retrospectively reviewed the 24-hour urinalysis database at a metabolic stone clinic. We identified and included in the study patients 18 years old or older who presented for the initial metabolic stone evaluation when race was marked as white or Asian/Pacific Islander in the electronic medical record. Univariate analysis was done to compare 24-hour urine composition between white and Asian/Pacific Islander stone formers. We performed multivariate linear regression adjusted for possible confounders, including age, gender, body mass index, hypertension, diabetes mellitus, thiazide use, potassium citrate use and 24-hour urine chemistry (volume, pH, calcium, citrate, creatinine, oxalate, magnesium, phosphate, potassium, sodium, sulfate and uric acid). RESULTS: Included in analysis were 371 white and 91 Asian/Pacific Islander patients. On univariate analysis Asian/Pacific Islander patients excreted significantly greater uric acid, and significantly less citrate, magnesium, phosphate and creatinine than white patients. On multivariate analysis Asian/Pacific Islander patients excreted significantly greater uric acid, and significantly less urine citrate, phosphate, creatinine and volume than white patients. CONCLUSIONS: Significant differences exist in 24-hour urine chemistry between white and Asian/PI stone formers. Knowledge of these differences would be useful to evaluate and treat these patients, and prevent stone recurrence. PMID- 20171693 TI - Resume fraud: unverifiable publications of urology training program applicants. AB - PURPOSE: We examined the incidence of resume fraud among urology residency applicants by determining the rate of misrepresented publications listed in applications to a urology residency program. MATERIALS AND METHODS: Applications from all 147 urology residency applicants to a program from the 2007 application cycle were analyzed. Verification of listed publications was attempted by querying PubMed, Google Scholar and MEDLINE. Univariate analysis was conducted to assess associations between unverifiable publications and applicant demographics. RESULTS: Of the applicants who submitted publications 19% (14 of 71) had at least 1 unverifiable publication, which represented 9% (14 of 147) of the entire applicant pool. There were no statistically significant associations between misrepresented publications and applicant demographics. CONCLUSIONS: Applicants had a low but still unacceptable rate of misrepresented publications and this trend in academic medicine is of great concern. PMID- 20171694 TI - Are sonographic characteristics associated with progression to surgery in men with Peyronie's disease? AB - PURPOSE: Traditionally, diagnosis and treatment plans for Peyronie's disease have been based on history and physical examination. Penile ultrasound provides rapid, anatomical information to establish disease severity, and to monitor progression and response to medical therapy. We determined the relationship between ultrasound characteristics and progression to surgical intervention in men with Peyronie's disease. MATERIALS AND METHODS: We conducted a retrospective cohort study of 518 patients with Peyronie's disease. Patients completed a Peyronie's disease specific questionnaire detailing medical history, health related behaviors and Peyronie's disease characteristics, and underwent sonographic evaluation of the penis. Measurements of subtunical calcifications, septal fibrosis, tunical thickening (tunica thickness greater than 2 mm) and intracavernous fibrosis were made. Progression to surgery was determined from the medical record. RESULTS: In this cohort (mean patient age 53.8 years, range 20 to 78) 31% of patients had calcifications, 50% had tunical thickening, 20% had septal fibrosis and 15% had intracavernous fibrosis. Overall 25% of the cohort progressed to surgical intervention after an average followup of 1.25 years (range 0 to 7.6). Patients who underwent surgery were more likely to have subtunical calcifications present at the first clinic visit (OR 1.75, 95% CI 1.16 2.62). No other sonographic characteristics were associated with progression to surgery. After adjustment for age, marital status, degree of curvature, additional penile deformity, difficulty with penetration, ability to have intercourse and prior treatment for Peyronie's disease, calcifications were strongly associated with progression to surgery (OR 2.75, 95% CI 1.25-3.45). CONCLUSIONS: In a large cohort of patients with Peyronie's disease the presence of sonographically detected sub-tunical calcifications during the initial office evaluation was independently associated with subsequent surgical intervention. PMID- 20171695 TI - The use of a novel reverse thermosensitive polymer to prevent ureteral stone retropulsion during intracorporeal lithotripsy: a randomized, controlled trial. AB - PURPOSE: We present the first randomized clinical study using BackStop, a novel reverse thermosensitive water-soluble polymer that is dispensed above the stone(s) and temporarily occludes the ureter to prevent retropulsion of stone fragments during ureteroscopic lithotripsy. After fragmentation is completed and concretions are extracted, conventional irrigation with saline dissolves the polymer, which is then flushed out. MATERIALS AND METHODS: A total of 68 subjects with a single stone in the proximal ureter and an indication for ureteroscopic lithotripsy were enrolled in this prospective, randomized, single-blind, controlled, multisite clinical study. Each subject was randomly assigned to the BackStop group (34) or the control group (34 with no antiretropulsion device). For subjects in the experimental group BackStop was dispensed into the ureter above the stone using a 3Fr or 5Fr catheter. Ureteroscopic lithotripsy was performed in all subjects using pneumatic or laser energy. Measured end points included the retropulsion rate, the need for subsequent procedures, the stone free rate at followup, the occurrence of adverse events and ureteral occlusion, if any, and post-stone fragmentation and extraction. RESULTS: Subjects randomized to the BackStop group experienced a statistically significant (p = 0.0002) lower rate of retropulsion (8.8%, 3 of 34) vs the control group (52.9%, 18/34). There were no adverse events in the BackStop group and BackStop was successfully dissolved in every subject, resulting in a patent ureter. CONCLUSIONS: BackStop appears to be a novel, safe and effective means of preventing stone fragment retropulsion during ureteroscopic lithotripsy for the management of ureteral stones. PMID- 20171696 TI - Correlation of penile and bulbospongiosus measurements: implications for artificial urinary sphincter cuff placement. AB - PURPOSE: We assessed penile and bulbospongiosus measurements to develop a quantitative guide to select the surgical approach (perineal vs transscrotal vs transcorporeal) to artificial urinary sphincter cuff placement. MATERIALS AND METHODS: We retrospectively reviewed the intraoperative records of 100 men who underwent artificial urinary sphincter placement (43) or anastomotic urethroplasty (57) from February 2008 to June 2009. Correlations between penile (stretched length and circumference at the shaft base) and bulbospongiosus (distal and proximal circumference) measurements were assessed. Cases were analyzed according to 2 penile circumference groups, including group 1-8.0 cm or less and group 2-8.5 or more. RESULTS: Mean proximal bulbospongiosus circumference was uniformly larger than distal bulbospongiosus circumference (4.5 vs 3.9 cm). It was about 50% of the penile shaft circumference (mean 8.9 cm, r = 0.70). In group 1 men the average distal bulbospongiosus circumference was 3.4 cm. They were more likely to undergo transcorporeal artificial urinary sphincter cuff placement than those in group 2, who had an average distal bulbospongiosus circumference of 4.1 cm (8 of 22 or 36% vs 1 of 21 or 5%, OR 11.4). Penile length correlated less robustly with distal and proximal bulbospongiosus circumference (r = 0.39 and 0.43, respectively). Patients with urethroplasty had significantly larger urethral measurements than those with the artificial urinary sphincter (proximal and distal bulbospongiosus circumference 4.9 vs 3.7 and 4.1 vs 3.2, respectively) but were significantly younger (47 vs 67 years), and less likely to have erectile dysfunction (11 of 57 vs 34 of 43) or to have undergone radical prostatectomy (0 of 57 vs 37 of 43). CONCLUSIONS: Bulbospongiosus circumference appears to be proportional to penile circumference. The distal bulbospongiosus is uniformly smaller than the proximal bulbospongiosus. The potential need for a perineal or transcorporeal approach to artificial urinary sphincter placement can be anticipated by penile circumference measurements and a combination of clinical factors, such as older patient age, history of radical prostatectomy and impotence. PMID- 20171697 TI - Under treatment of overactive bladder symptoms in patients with multiple sclerosis: an ancillary analysis of the NARCOMS Patient Registry. AB - PURPOSE: We describe the prevalence of overactive bladder symptoms in patients with multiple sclerosis as well as the rates of evaluation and treatment of urinary complaints. MATERIALS AND METHODS: Data from the fall 2005 North American Research Committee On Multiple Sclerosis survey were examined, including the Urogenital Distress Inventory plus a nocturia question, the SF-12, and inquiries regarding urological care and treatments. Data were analyzed using descriptive statistics, chi-square and Student's t tests, ANOVA and multivariable logistic regression. RESULTS: Of 16,858 surveys distributed 9,702 (58%) were completed. Participants with a surgically altered bladder were excluded from analysis (21). At least 1 moderate to severe urinary symptom (score of 2 or greater) was reported by 6,263 (65%) respondents. Increasing overactive bladder symptoms were correlated with longer disease duration (r = 0.135) and increasing physical disability (r = 0.291) (both p <0.001). Decreased quality of life was associated with increasing disability (p <0.001) and overactive bladder symptom score (p <0.001). Of patients with moderate to severe overactive bladder symptoms only 2,710 (43.3%) were evaluated by urology and 2,361 (51%) were treated with an anticholinergic medication. Treated patients more frequently reported leakage (p <0.001) and newer treatments were significantly underused (less than 10% total use). Catheter use was reported by 2,309 (36.8%) respondents, and was associated with greater disability, higher overactive bladder symptom score and reduced quality of life (all p <0.001). CONCLUSIONS: This large scale study identified high rates of overactive bladder symptoms in patients with MS, and correlations with increasing disease duration and physical disability. Despite an increasing awareness of overactive bladder symptoms and the need for evaluation and treatment, many patients remain underserved. PMID- 20171698 TI - Outcomes of patients lost to followup after mid urethral synthetic slings- successes or failures? AB - PURPOSE: We classified patients lost to followup after mid urethral synthetic sling placement as examples of treatment success or failure based on the Patient Global Impression of Improvement, and compared the outcomes of those who followed up to the outcomes of those who did not. MATERIALS AND METHODS: We reviewed the charts of 217 patients who underwent mid urethral synthetic sling placement. Telephone interviews including the Patient Global Impression of Improvement and the Medical, Epidemiological, and Social Aspects of Aging questionnaires were conducted for patients lacking 3-month followup. RESULTS: Based on the Patient Global Impression of Improvement of the 48 patients who responded 13 (27.1%) were failures. The overall failure rate of patients with at least 3-month followup was 19% (23 of 124). CONCLUSIONS: In our study success rates for patients lost to followup were similar to the rates for those who had routine followup. However, it is uncertain if these data can be applied to other study populations, especially in a randomized controlled trial. PMID- 20171699 TI - Intussusception vasoepididymostomy with longitudinal suture placement for idiopathic obstructive azoospermia. AB - PURPOSE: Surgical reconstruction is an important treatment option for obstructive azoospermia. Vasoepididymostomy results have primarily been described in men with previous vasectomy. We evaluated vaso-epididymal anastomosis outcomes using a 2 suture microsurgical intussusception technique with longitudinal suture placement in men with idiopathic obstructive azoospermia. MATERIALS AND METHODS: Between April 2007 and May 2009, 24 men with idiopathic obstructive azoospermia underwent 2-layer vaso-epididymal anastomosis using a 2-suture intussusception technique. Two double armed 10-zero polyamide sutures were placed parallel to each other longitudinally along the epididymal tubule to intussuscept the tubule into the lumen of the vas deferens for the inner layer of the anastomosis. Patency was assessed by return of sperm in the semen. RESULTS: A total of 23 men with a mean age of 31 years provided at least 1 postoperative semen sample. All had a mean 67 month history of primary infertility. In 11 men (48%) patency was noted a mean of 6.6 months (range 3 to 15) after surgery. One patient reported pregnancy by natural conception. Men with motile sperm in the epididymal fluid and those with bilateral surgery were more likely to have a patent anastomosis. CONCLUSIONS: Within 1 year after surgery approximately half of the men who underwent longitudinal vaso-epididymal anastomosis for idiopathic azoospermia had return of sperm in the ejaculate. PMID- 20171700 TI - Decreasing electrosurgical transurethral resection of the prostate surgical volume during graduate medical education training is associated with increased surgical adverse events. AB - PURPOSE: In the United States the numbers of electrosurgical transurethral prostate resection procedures have been decreasing. Since electrosurgical transurethral resection of the prostate is a difficult procedure to master, we hypothesized that recent residents are lacking in training for this procedure. We used summary case log information provided by the Accreditation Council for Graduate Medical Education to determine if the number of electrosurgical transurethral prostate resection procedures performed by graduating chief residents has decreased and if there has been an increase in surgical adverse events. In addition, we investigated whether the increased number of laser procedures impacted the rate of adverse events. MATERIALS AND METHODS: Summary operative data from graduating chief resident case logs were provided by the Accreditation Council for Graduate Medical Education for academic years 2001 to 2007. The numbers of electrosurgical transurethral prostate resection procedures, laser procedures and procedures for adverse events were recorded for each year. RESULTS: The number of electrosurgical transurethral prostate resection procedures performed by graduating chief residents has steadily decreased from 58 in 2001 to 43 in 2007. Conversely the number of laser procedures started increasing in 2004. The rate of procedures for adverse events as a percentage of electrosurgical transurethral resection of the prostate procedures increased during the study period (from 3% in 2001 to 6% in 2007), and as a percentage of electrosurgical transurethral resection of the prostate and laser procedures the rate increased until 2005 and subsequently started decreasing. CONCLUSIONS: The rate of surgical adverse events, as measured by the need for subsequent procedures, has increased during the last 7 years. However, when laser procedures are accounted for, it appears that adverse events have recently started trending down as an increasing number of laser procedures started being performed. PMID- 20171701 TI - Editorial comment. PMID- 20171702 TI - Tracing sewage and natural freshwater input in a northwest Mediterranean Bay: evidence obtained from isotopic ratios in marine organisms. AB - Elemental carbon and nitrogen levels and isotope ratios were assessed in different biological compartments of a Northwest (NW) Mediterranean bay to trace the various sources of nutrient input from natural (river runoffs) and anthropogenic (harbor outflows, fish farms and urban sewage outfall) sources. Samples from transplanted mussels and natural sea grass communities (Posidonia oceanica leaves and epiphytes) were harvested from different locations throughout the bay during the touristic summer and rainy seasons. The results from the nitrogen analysis revealed that sewage and harbor outflow promote higher nitrogen levels, enrichment of (15)N in the tissues, and a higher seasonal variability in sea grass and epiphytes. In mussel tissues, the delta(15)N was also influenced by sewage and harbor outflow, whereas delta(13)C was influenced by terrestrial inputs. These results suggest that natural and anthropogenic nutrient inputs have a temporary and localized influence and affect the sensitivity of natural isotopic ratios to changes in hydrologic conditions, especially to rain and tourism. PMID- 20171703 TI - [Simple virilizing forms of congenital adrenal hyperplasia: adaptation and prospective validation of the molecular screening]. AB - BACKGROUND AND OBJECTIVE: Congenital Adrenal Hyperplasia (CAH) is not an infrequent genetic disorder for which mutation-based analysis for CYP21A2 gene is a useful tool. Contrarily to salt-wasting forms the basic mutation screening accounts only for 83% of simple virilising (SV) phenotypes. Rare alleles with a local distribution not included in the basic panel may reduce its diagnostic accuracy. Our aim is to explore underlying prevalent mutations among our partially characterised SV forms and to evaluate their potential impact in the mutation screening. PATIENTS AND METHODS: Preliminary study: CYP21A2 gene sequencing in 13 SV patients partially characterised. Retrospective targeted study: 2,097 DNA samples (561 patients) were re-analysed for p.R426H mutation. Prospective targeted study: incorporation of the p.R426H mutation to the initial exploration of CAH in 1,041 DNA samples to validate this extended screening. RESULTS: p.R426H mutation was detected in five patients in the preliminary analysis and in ten more during targeted studies. A frequency for this mutation was 0.71% in the whole group and 7.14% in SV forms. Associated haplotypes were identical thus suggesting a preferential dissemination. The observed phenotypes correlated and confirmed the moderate-to-severe effect on the enzymatic activity. CONCLUSIONS: Our data relative to allelic frequency of the p.R426H mutation and its strong association to SV forms justify the incorporation of the p.R426H mutation into the basic screening panel because of the significant improvement in the initial characterization of affected patients, especially among those with SV forms. Two new cases detected remark the usefulness of this novel approach. PMID- 20171704 TI - Increased bone resorption and impaired bone microarchitecture in short-term and extended high-fat diet-induced obesity. AB - Although obesity traditionally has been considered a condition of low risk for osteoporosis, this classic view has recently been questioned. The aim of this study was to assess bone microarchitecture and turnover in a mouse model of high fat diet-induced obesity. Seven-week-old male C57BL/6J mice (n = 18) were randomized into 3 diet groups. One third (n = 6) received a low-fat diet for 24 weeks, one third was kept on an extended high-fat diet (eHF), and the remaining was switched from low-fat to high-fat chow 3 weeks before sacrifice (sHF). Serum levels of insulin, leptin, adiponectin, osteocalcin, and cross-linked telopeptides of type I collagen (CTX) were measured. In addition, bone microarchitecture was analyzed by micro-computed tomography; and lumbar spine bone density was assessed by dual-energy x-ray absorptiometry. The CTX, body weight, insulin, and leptin were significantly elevated in obese animals (sHF: +48%, +24%, +265%, and +102%; eHF: +43%, +52%, +761%, and +292%). The CTX, body weight, insulin, and leptin showed a negative correlation with bone density and bone volume. Interestingly, short-term high-fat chow caused similar bone loss as extended high-fat feeding. Bone volume was decreased by 12% in sHF and 19% in eHF. Bone mineral density was 25% (sHF) and 27% (eHF) lower when compared with control mice on low-fat diet. As assessed by the structure model index, bone microarchitecture changed from plate- to rod-like appearance upon high-fat challenge. Trabecular and cortical thickness remained unaffected. Short-term and extended high-fat diet-induced obesity caused significant bone loss in male C57BL/6J mice mainly because of resorptive changes in trabecular architecture. PMID- 20171705 TI - Compliance of drugstores with a national smoke-free law: a pilot survey. AB - OBJECTIVES: To examine the outcome of the recent implementation of a smoke-free policy in drugstores in Thailand, comparing participants and non-participants of the 100% smoke-free drugstore campaign promoted by the Thai Pharmacy Network for Tobacco Control (TPNTC). STUDY DESIGN: A cross-sectional survey of 3600 drugstores in Thailand. METHOD: Smoking prevalence on the premises, the number of stores displaying no-smoking signs, and the number of stores selling cigarettes were examined. RESULTS: In total, 1001 questionnaires were returned (27.8% response rate). Smoking prevalences inside and outside drugstores in the past month were 26.4% and 84.7%, respectively. Seven percent of drugstores had at least one staff member who smoked tobacco. Overall, 63.3% of drugstores displayed no-smoking signs, as required by law. Compared with non-participating drugstores, those which participated in the TPNTC smoke-free campaign more frequently reported that they had asked smokers to stop smoking/leave the premises, in addition to possessing and displaying no-smoking signs. CONCLUSION: Approximately one-third of drugstores in this survey did not meet the terms of the recent smoke free regulation. The TPNTC campaign improved the compliance of drugstores with the law in various aspects. This study was considered a pilot study, and despite the low response rate, the findings suggest a need for further action to ensure that all drugstores comply with the law and are 100% smoke-free. PMID- 20171706 TI - What difference can a decade make? PMID- 20171708 TI - Clinical progression of chikungunya fever during acute and chronic arthritic stages and the changes in joint morphology as revealed by imaging. AB - This longitudinal follow-up study of 203 patients with serologically confirmed chikungunya (CHIK) virus infection describes the clinical features of CHIK fever during the first and tenth months of illness. During the acute stage CHIK fever presents with a wide array of symptoms. The foremost chronic symptoms at the end of a month were rheumatism (75%) and fatigue (30%). During the tenth month of follow-up the symptoms/signs observed were joint pain/swelling (46%), fatigue (13%) and neuritis (6%). The cure rate at the end of 9 months was 51%. Among the patients who had joint pain, 36% (34/94) met the American College of Rheumatology criteria to classify them as having rheumatoid arthritis. A subpopulation of the patients with joint pain (20/94) was tested for rheumatoid factor (RF) and anti cyclic citrullinated peptide (anti-CCP) antibody, and the joints were imaged by X ray and magnetic resonance imaging (MRI). All tested negative for RF and one tested positive for anti-CCP. A radiolucent lesion in the X-ray was seen in the bones of five patients. The MRI findings were joint effusion, bony erosion, marrow oedema, synovial thickening, tendinitis and tenosynovitis. The study proves with relative certainty that CHIK arthritis is chronic inflammatory erosive arthritis, which has implications for management of the infection. PMID- 20171707 TI - [Use of midazolam for refractory status epilepticus in children]. AB - Morbidity and mortality are high in children with refractory status epilepticus (RSE). Here, we assess the efficacy of midazolam for RSE in children. METHODS: This was a retrospective analysis of 29 children admitted to the Lille University Hospital pediatric intensive care unit (PICU) for RSE between May 2006 and July 2008. The onset of the study corresponded with a new therapeutic protocol applied in the PICU for RSE where midazolam was proposed as the first-line treatment (bolus ten continuous infusion until control) to be replaced by thiopenthal in case of failure. RESULTS: We recorded 29 patients with RSE during the study period: 26 were treated with midazolam, including two where midazolam replaced thiopenthal because of hypotension. Midazolam successfully controlled RSE in 58% of patients. Mean delay to cessation of RSE was 48+/-65 minutes. Hypotension was observed in 8% of midazolam-treated patients and 71% of thiopenthal-treated patients. Overall mortality was 15% (4/26). Two deaths occurred long after the cessation of RSE. None of the deaths occurred in midazolam-treated patients. CONCLUSION: Midazolam is an efficient treatment for RSE in children. Morbidity and mortality appear to be lower with midazolam compared with other antiepileptic drugs used for the treatment of RSE. PMID- 20171709 TI - Sand flies naturally infected by Leishmania (L.) mexicana in the peri-urban area of Chetumal city, Quintana Roo, Mexico. AB - The surveillance of prevalent Leishmania sand fly vectors is an important issue for epidemiological studies in populated areas where leishmaniasis is endemic. In this study, we collected sand flies from a peri-urban area in the southeast of Mexico. Natural infection with Leishmania (L.) mexicana was studied by PCR using a Leishmania internal transcribed spacer of the ribosomal RNA gene for amplification. Infected Lutzomyia olmeca olmeca, Lu. shannoni and Lu. cruciata sand flies were collected mainly during the high transmission season (November to March), coinciding with the highest sand fly densities. Additionally, positive specimens of Lu. olmeca olmeca were also captured during July and August. The infected sand flies were from primary forest (subperennial forest) and secondary forest (18-25 years old and 10-15 years old respectively). Sand flies collected with Disney and Shannon traps were the ones found to be infected with L. (L.) mexicana. We conclude that the high-risk period in which L. (L.) mexicana is transmitted in the peri-urban area of Chetumal City is from July to March and that transmission is associated with both the subperennial forest and the secondary forest. PMID- 20171710 TI - The insect centriole: A land of discovery. AB - Centrioles are involved in the formation of cilia and flagella and in the organization of the centrosome, the main microtubule-organizing center of the cell. Since structural and functional centriole aberrations can contribute to several human diseases, these organelles have recently focused the attention of cell biologists. Here, we review data on the insect centrioles, reporting non canonical aspects of their behaviour, function and architecture. These findings that represent obvious exceptions to the established rule might contribute to advance our understanding in the formation and the function of centrioles. PMID- 20171712 TI - Photocatalytic degradation of nonionic surfactant, Brij 35 in aqueous TiO2 suspensions. AB - The photocatalytic oxidation of nonionic surfactant, Brij 35 in aqueous TiO2 suspensions was investigated as a function of catalysts loading, light intensity (I), initial Brij 35 concentration [Brij](0), dissolved oxygen concentration [p(O2)], and pH. A monolithic swirl-flow photoreactor was used that allowed to perform a systematic analysis of rates at various loadings of TiO22 in order to distinguish "kinetic" and "transport" limited regimes for the photocatalytic degradation of Brij 35 in TiO2 suspensions. The optimal catalyst loading was determined to be 0.1 g L(-1) TiO2 at a neutral pH. The true kinetic dependences of the photocatalytic degradation on I and [Brij](0) were determined. A small increase in oxidation rate was observed with an increase in the partial pressure of the oxygen [p(O2)] in the system. The rates as a function of [Brij](0) and [p(O2)] were interpreted using a Langmuir-Hinshelwood model. The complete photocatalytic degradation of Brij 35 was obtained in acidic to basic pH range, however, the removal of Brij 35 removal and subsequent decrease in TOC levels were more efficient at a neutral pH than acidic or basic pH. PMID- 20171711 TI - Phylogenomic analysis of 11 complete African swine fever virus genome sequences. AB - Viral molecular epidemiology has traditionally analyzed variation in single genes. Whole genome phylogenetic analysis of 123 concatenated genes from 11 ASFV genomes, including E75, a newly sequenced virulent isolate from Spain, identified two clusters. One contained South African isolates from ticks and warthog, suggesting derivation from a sylvatic transmission cycle. The second contained isolates from West Africa and the Iberian Peninsula. Two isolates, from Kenya and Malawi, were outliers. Of the nine genomes within the clusters, seven were within p72 genotype 1. The 11 genomes sequenced comprised only 5 of the 22 p72 genotypes. Comparison of synonymous and non-synonymous mutations at the genome level identified 20 genes subject to selection pressure for diversification. A novel gene of the E75 virus evolved by the fusion of two genes within the 360 multicopy family. Comparative genomics reveals high diversity within a limited sample of the ASFV viral gene pool. PMID- 20171713 TI - Impact of activated charcoal on the mineralisation of 14C-phenanthrene in soils. AB - The development of phenanthrene catabolism in four soils amended with varying concentrations of activated charcoal (AC) (0%, 0.1%, 1% and 5%), a type of black carbon, was investigated. Mineralisation of (14)C-phenanthrene was monitored after 1, 25, 50 and 100 d soil-PAH contact time; lag phases, rates and extents of mineralisation of the (14)C-phenanthrene to (14)CO(2) were determined. At concentrations >0.1% AC rates and extents of mineralisation were reduced by more than 99%. This revealed that the presence of >0.1% AC in soils may substantially diminish the rate at which the catabolic activity of indigenous soil microflora develops in contaminated soil. Soil C, which had the highest organic carbon (OC) content, consistently exhibited the highest extents of degradation. It is suggested that, in accordance with other researchers, OC may have blocked available phenanthrene sorption sites. This enhanced phenanthrene availability ultimately facilitated a greater level of catabolic activity within this soil. Such results reflect the complex nature of interactions between soil, biota and contaminants and their influence on the degradation of contaminants in the environment. PMID- 20171714 TI - Cross-species comparison of fluoxetine metabolism with fish liver microsomes. AB - Pharmaceuticals discharged in municipal wastewater are of emerging concern because of their potential for inducing biological effects in aquatic organisms. Selective serotonin reuptake inhibitors (SSRIs), pharmaceuticals prescribed to treat chronic depression, have been detected in receiving and wastewaters. Fluoxetine is a highly prescribed model SSRI used to assess impacts of antidepressants on aquatic organisms. In this study, in vitro hepaticfluoxetine metabolism was determined in several model fish species: rainbow trout, goldfish, zebrafish and killifish. Incubation of fluoxetine with hepatic microsomes from trout pre-treated with carbamazepine showed a time-dependant loss of fluoxetine, concomitant with an increase in norfluoxetine, the major mammalian demethylated metabolite. However, fluoxetine was not well metabolized in reactions with hepatic microsomes from untreated fish. Fluoxetine loss was greater than norfluoxetine production, indicating that norfluoxetine is not the predominant fluoxetine biotransformation product in fish. Furthermore, norfluoxetine was often undetected, possibly indicating that fluoxetine demethylation is a minor metabolic pathway in fish. Inter-species differences in fluoxetine metabolism were not evident because of high intra-species variability, although killifish appeared to have the highest hepatic metabolic capacity for fluoxetine. Fluoxetine metabolism in mammals is catalyzed by cytochrome P450 (CYP) enzymes. Trout were exposed to knownCYP inducers, carbamazepine and 3-methylcholanthrene, to assess potential induction of hepatic fluoxetine metabolism. Microsomes from 3 methylcholanthrene treated fish did not induce detectable changes in fluoxetine concentrations in vitro, indicating that fish CYP1s are not involved in fluoxetine metabolism; the CYPs involved are still unclear. Identification of metabolites other than norfluoxetine warrants further investigation. PMID- 20171716 TI - Tissue factor microparticles and haemophilia. AB - Treatment choices for haemophilia patients with inhibitors are suboptimal. Tissue factor-bearing microparticles home to thrombi in a cell adhesion molecule dependent fashion. Their potential utility as a procoagulant is discussed along with the challenges of evaluating this approach in mouse models of haemophilia. PMID- 20171715 TI - Pollutant fate and spatio-temporal variability in the choptank river estuary: factors influencing water quality. AB - Restoration of the Chesapeake Bay, the largest estuary in the United States, is a national priority. Documentation of progress of this restoration effort is needed. A study was conducted to examine water quality in the Choptank River estuary, a tributary of the Chesapeake Bay that since 1998 has been classified as impaired waters under the Federal Clean Water Act. Multiple water quality parameters (salinity, temperature, dissolved oxygen, chlorophyll a) and analyte concentrations (nutrients, herbicide and herbicide degradation products, arsenic, and copper) were measured at seven sampling stations in the Choptank River estuary. Samples were collected under base flow conditions in the basin on thirteen dates between March 2005 and April 2008. As commonly observed, results indicate that agriculture is a primary source of nitrate in the estuary and that both agriculture and wastewater treatment plants are important sources of phosphorus. Concentrations of copper in the lower estuary consistently exceeded both chronic and acute water quality criteria, possibly due to use of copper in antifouling boat paint. Concentrations of copper in the upstream watersheds were low, indicating that agriculture is not a significant source of copper loading to the estuary. Concentrations of herbicides (atrazine, simazine, and metolachlor) peaked during early-summer, indicating a rapid surface-transport delivery pathway from agricultural areas, while their degradation products (CIAT, CEAT, MESA, and MOA) appeared to be delivered via groundwater transport. Some in-river processing of CEAT occurred, whereas MESA was conservative. Observed concentrations of herbicide residues did not approach established levels of concern for aquatic organisms. Results of this study highlight the importance of continued implementation of best management practices to improve water quality in the estuary. This work provides a baseline against which to compare future changes in water quality and may be used to design future monitoring programs needed to assess restoration strategy efficacy. PMID- 20171717 TI - Intra-cervical application of Misoprostol at estrus alters the content of cervical hyaluronan and the mRNA expression of follicle stimulating hormone receptor (FSHR), luteinizing hormone receptor (LHR) and cyclooxygenase-2 in the ewe. AB - The complex anatomy the of ovine cervix limits the success of transcervical artificial insemination in sheep, but Misoprostol (a PGE(1) analogue) relaxes the cervix and facilitates transcervical artificial insemination. However, the mechanism by which Misoprostol causes cervical relaxation is not known. This study examined if intra-cervical Misoprostol altered the hyaluronan content and the mRNA expression of COX-2, LHR, or FSHR in the cervix of the estrus ewe. Estrus was synchronized in cyclic ewes with progestagen pessaries and 48 h after sponge removal ewes were treated intra-cervically with 0 (controls), 200, or 400 microg Misoprostol. Hyaluronan content was determined by ELISA and mRNA expression of LHR, FSHR, and COX-2 was analyzed by in situ hybridization using digoxigenin-11-uridine-5'-triphosphate labeled riboprobes. The hyaluronan content of the cervix was significantly higher in sheep that received 200 (P<0.05) or 400 (P<0.05) microg Misoprostol compared to controls. Moreover, it was significantly (P<0.05) higher in the vaginal region compared to mid and uterine regions. Misoprostol increased (P<0.05) the mRNA expression of LHR and COX-2 but not FSHR. The expression for all three genes was highest in the vaginal region and lowest in uterine region. The luminal epithelium and circular smooth muscle layers had higher (P<0.05) expression for LHR, FSHR, and COX-2 mRNAs, and the sub-epithelial stroma had the lowest (P<0.05). We propose that the intra-cervical application of Misoprostol induces the mRNA expression of LHR, FSHR, and COX-2 through a positive feedback loop. The data suggest that softening of the cervix by Misoprostol is caused by an increase in the hyaluronan content of the cervix. PMID- 20171718 TI - Effect of estrus induction on prostaglandin content and prostaglandin synthesis enzyme expression in the uterus of early pregnant pigs. AB - Prostaglandins (PGs) play a pivotal role in maternal recognition of pregnancy and implantation in pigs. In the present study, PGE(2), PGF(2alpha), and PGFM (PGF(2alpha) metabolite) content, as well as PGE(2) synthase (mPGES-1) and PGF(2alpha) synthase (PGFS) expression was investigated in early pregnant gilts with natural (n=21) and PMSG/hCG-stimulated (n=19) estrus. Endometrial tissue samples, uterine luminal flushings (ULFs), and blood serum were collected on days 10-11, 12, and 15 after insemination. Additionally, day 15 conceptuses were collected for mPGES-1 and PGFS protein expression. Effect of estrus induction was observed on day 15 of pregnancy, when the content of PGE(2) in the uterine lumen was fourfold lower in gonadotropin-stimulated gilts in comparison to controls (P<0.001). Decreased PGE(2) content in ULFs of gonadotropin-treated pigs was preceded by lower endometrial mPGES-1 gene expression in hormonally-stimulated animals in comparison to control gilts (P<0.01). On the other hand, estrus induction with PMSG/hCG resulted in higher PGE(2) accumulation in the endometrial tissue on day 15 of pregnancy (P<0.01). Furthermore, PGF(2alpha) content in the endometrium and PGFM levels in blood serum were lower in gonadotropin-treated gilts, especially on day 12 after insemination when compared to control gilts (P<0.01). Finally, PGFS expression in day 15 conceptuses was decreased in animals with hormonally-induced estrus. We conclude that PMSG/hCG stimulation of prepubertal gilts to induce estrus results in changes of PG production and secretion during early pregnancy, which, in turn, may affect conceptus development, implantation, and the course of pregnancy. PMID- 20171719 TI - Identifying non-sperm particles during flow cytometric physiological assessment: a simple approach. AB - Flow cytometry is now being used more frequently to determine sperm functional characteristics during semen assessment for artificial insemination. With this methodology, viable and potentially functional cells are detected as unstained events differentiated from non-sperm events through their light-scattering characteristics. However, it can be shown mathematically that identification of sperm on the basis of light scatter leads to significant overestimation of unstained viable cells and underestimation of responding cells in tests of sperm function (subpopulations expressing different fluorescence patterns). We have developed a simple and cost-efficient flow cytometric approach for identifying non-sperm particles that can be carried out in parallel with functional assessments. Our method is based on the sperm's osmotic intolerance. Diluted in water, lethal osmotic shock causes major damage to the cell membranes, and all sperm will stain with propidium iodide (PI). Particulate material which is not PI positive can then be quantitatively evaluated by FACS analysis and the results substituted in mathematical equations to provide true values for sperm counts and subpopulations. In practical tests, the percentage of non-sperm particles determined by this technique was closely comparable to the figure obtained either by SYBR14/PI staining or by PI/CFDA staining. As well as being valuable with respect to tests of sperm function, the procedure is also suitable for obtaining accurate sperm counts during routine semen evaluation. PMID- 20171720 TI - Calcium, parathyroid hormone, oxytocin and pH profiles in the whelping bitch. AB - Despite the high prevalence of primary uterine inertia in whelping bitches, the underlying pathogenesis remains unclear. The objectives were to i) determine serum concentrations of total calcium, ionized calcium (iCa), parathyroid hormone (PTH), and blood pH in normally whelping bitches throughout the peri-parturient period; and ii) investigate relationships among iCa, PTH, and acid-base status, and the role that they and oxytocin may have in the underlying pathogenesis of canine uterine inertia. Bitches were randomly selected from a population of German Shepherd Dog bitches with a history of uncomplicated parturition (Group 1; n=10), and from a population of Labrador bitches with a clinical history of an increased incidence of uterine inertia and stillbirths (Group 2; n=20). Jugular blood samples were collected daily from -4 d to the onset of whelping (t=0 h), and then every 4h until the last pup was born. Overall, bitches from Group 2 had higher mean+/-SEM serum concentrations of PTH (4.72+/-2.45 pmol/L, P<0.001), lower iCa (1.31+/-0.08 pmol/L, P<0.05), and higher venous pH (7.41+/-0.03, P<0.005) than bitches from Group 1 (2.9+/-1.44 pmol/L, 1.38+/-0.06 mmol/L, and 7.33+/-0.02, respectively) during the periparturient period. However, there was no significant difference between Groups 1 and 2 for serum oxytocin concentrations during the periparturient period (45.5+/-40 and 65.5+/-82 pg/mL). We inferred that low iCa resulting from a rising pH and decreasing PTH during the periparturient period may have contributed to decreased uterine contractility and increased risk of stillbirths. Therefore, manipulating the cationic/anionic difference in diets of pregnant bitches, similar to the bovine model for hypocalcamia, may reduce the incidence of stillbirths in the bitch. PMID- 20171721 TI - The role of brain-derived neurotrophic factor in mouse oocyte maturation in vitro involves activation of protein kinase B. AB - Brain-derived neurotrophic factor (BDNF) can promote developmental competence in mammalian oocytes during in vitro maturation, but the signal transduction pathways are not clear. In this study, we investigated (using western blots) the effects of BDNF on the phosphorylation of protein kinase B (PKB) and mitogen activated protein kinase (MAPK) in mouse oocytes and cumulus cells cultured in vitro. Treatment with BDNF enhanced phosphorylation of PKB in oocytes at 2h (P=0.0006) and 3h (P<0.0001) of in vitro maturation, compared with control oocytes. However, the pan-specific tyrosine kinase (Trk) inhibitor K252a together with BDNF completely inhibited phosphorylation of PKB in the oocytes. Furthermore, BDNF increased phosphorylation of MAPK in oocytes at 16h of in vitro maturation (P=0.0041), but K252a together with BDNF did not reduce phosphorylation of MAPK in the oocytes. For cumulus cells, BDNF significantly prolonged the phosphorylation of PKB and MAPK and increased the total amounts of PKB and MAPK proteins after 16h of in vitro maturation. However, BDNF did not affect apoptosis of the cumulus cells during oocyte maturation in vitro. In conclusion, the PKB pathway is likely to be one signaling cascade activated by BDNF in combination with the TrkB receptor, whereas the MAPK pathway is not involved. These findings may have relevance for BDNF-induced promotion of developmental capacity of in vitro-matured oocytes. PMID- 20171722 TI - Stimulatory effect of Rho-associated coiled-coil kinase (ROCK) inhibitor on revivability of in vitro-produced bovine blastocysts after vitrification. AB - Inhibition of Rho-associated coiled-coil kinase (ROCK) activity promoted recovery and growth of frozen-thawed human embryonic stem cells. The primary objective was to determine if a ROCK inhibitor (Y-27632) in post-thaw culture medium improved revivability of vitrified IVP bovine blastocysts. Expanding or expanded blastocysts (7 d after IVF) were vitrified (minimum volume cooling procedure, using a Cryotop) in 15% ethylene glycol, 15% DMSO and 0.5M sucrose. When post warm blastocysts were cultured in mSOF medium, survival rate (re-expansion of blastocoel at 24h of culture) was improved (P<0.05) by the addition of 10 microM Y-27632 (94.9+/-2.4%, mean+/-SEM) compared to a control (78.0+/-6.0%). Conversely, after 48 h of culture, there were no significant differences in hatching rate (62.8+/-11.1 vs. 59.6+/-9.4%) and mean total cell number (135.2+/ 13.1 vs. 146.7+/-13.3). In non-vitrified IVP bovine blastocysts, the hatching rate on Day 9 was improved by Y-27632 (91.7+/-3.8 vs. 54.7+/-8.9%, P<0.05), with no difference in mean total cell number of blastocysts (230.0+/-23.0 vs. 191.2+/ 22.2, P=0.23). In an additional experiment, Y-27632 was added to culture medium on either Day 0, Day 2, or Day 4 (and remained present until Day 8), resulting in no improvement in blastocyst yield compared to a control group (7.5+/-2.1, 31.4+/ 2.3, 36.2+/-3.2, and 28.6+/-6.9%, respectively). In conclusion, adding a ROCK inhibitor to post-thaw culture medium improved revivability of IVP bovine blastocysts after vitrification and warming. PMID- 20171723 TI - The GnRH antagonist acyline prevented ovulation, but did not affect ovarian follicular development or gestational corpora lutea in the domestic cat. AB - Two experiments were conducted to investigate the effects of the GnRH antagonist acyline (330 microg/kg, given sc) on ovarian follicular development and ovulation, as well as on pregnancy maintenance in domestic cats. In the first experiment, seven queens in proestrus (total of 24 proestrus periods), were randomly assigned to treatment with either acyline (ACY; n=17) or a placebo (PLC; n=7). All queens were mated with a fertile tomcat. In the ACY and PLC groups, cessation of estrus occurred (mean+/-SEM) 7.0+/-1.3 and 7.0+/-1.7 d after treatment (P>0.1), ovulation occurred in 2 of 17 and all seven estrus periods (P<0.05), and pregnancy rates were 1 of 16 and 7 of 7 (P<0.05), respectively. In the ACY and PLC groups, intervals from treatment to the onset of the ensuing proestrus were 18.4+/-1.7 and 120+/-17.2 d. In the second experiment, 14 pregnant queens were randomly allocated, according to their mating date, to treatment with acyline in early pregnancy (from 20 to 25 d, n=3), mid pregnancy (from 26 to 45 d; n=4), late pregnancy (> 45 d; n=3), or injection of a placebo in early (n=1), mid (n=2), or late pregnancy (n=1). Ultrasonographic assessments of the uterus were done every second day for 2 wk post treatment, and serum progesterone (P(4)) concentrations were determined before treatment, and at 7 and 14 d after treatment. No pregnancies were prematurely terminated and post-treatment P(4) concentrations did not differ among treatment groups (P>0.1). In conclusion, in the domestic cat, GnRH withdrawal by acyline prevented ovulation when given in early follicular phase (proestrus), but did not significantly affect luteal function during pregnancy. PMID- 20171724 TI - Single-layer centrifugation through colloid selects improved quality of epididymal cat sperm. AB - The objectives were to determine the: 1) extent of epithelial and red blood cell contamination in epididymal cat sperm samples recovered by the cutting method; 2) efficacy of simple washing, single-layer centrifugation (SLC), and swim-up for selecting epididymal cat sperm; and 3) effects of freezing and thawing on cat sperm selected by various techniques. Ten unit samples were studied; each contained sperm from the cauda epididymides of four cats (total, approximately 200 x 10(6) sperm) and was equally allocated into four treatments: 1) simple washing, 2) single-layer centrifugation through colloid prior to cryopreservation (SLC-PC), 3) single-layer centrifugation through colloid after cryopreservation (SLC-AC), and 4) swim-up. Centrifugation (300 x g for 20 min) was done for all methods. The SLC-PC had a better recovery rate than the SLC-AC and swim-up methods (mean+/-SD of 16.4+/-8.7, 10.7+/-8.9, and 2.3+/-1.7%, respectively; P<0.05). The SLC-PC, SLC-AC and swim-up samples contained less red blood cell contamination than simple washed samples (0.02+/-0.01, 0.02+/-0.04, 0.03+/-0.04, and 0.44+/-0.22 x 10(6) cells/mL, respectively; P<0.05). Although the proportion of sperm with head abnormalities did not differ among selection methods (P>0.05), SLC-PC yielded the highest percentage of sperm with normal midpieces and tails (P<0.05), due to the lowest proportion of coiled tails (P<0.05). Furthermore, the SLC-PC was as effective as swim-up in removing sperm with proximal droplets, and selecting motile sperm, as well as those with intact membranes and DNA (P>0.05). In conclusion, both SLC-PC and swim-up improved the quality of epididymal cat sperm, including better morphology, membrane and DNA integrity, and removal of cellular contamination. However, SLC had a better sperm recovery rate than swim up. PMID- 20171725 TI - Environmental influences on the production of pre-implantation embryos. AB - Generation and cryopreservation of transgenic mice depend on reliable and continuous production of pre-implantation embryos. To suppress circannual and circadian rhythms driving the physiological and sexual behaviour of free living animals, laboratory animals are housed under standardized conditions. It remains to be elucidated if the artificial climate can cover all environmental effects. Here, we report that the humidity in an animal facility affects the embryo yield. The weather at the location of the facility, especially the temperature, influences the climate within an animal facility; weather peaks are obviously covered in part only, even if the facility is equipped with a powerful air conditioning supply. Subsequently, external weather changes interact with the environment within the facility, influencing the production of embryos. Furthermore, noise and/or vibrations as generated by construction works, negatively affect the embryo yield. PMID- 20171726 TI - Reproductive consequences of a reciprocal chromosomal translocation in two Duroc boars used to provide semen for artificial insemination. AB - Cytogenetic analysis of 58 boars at an artificial insemination (AI) centre revealed the presence of a reciprocal chromosome translocation, rcp(1;11)(q-;p+), in two Duroc boars. Pedigree analysis of these two boars suggested familial transmission of the chromosome rearrangement. The reproductive consequences of this translocation were determined in a herd of sows that had received semen doses from these and other boars. All sows underwent multiple AI, with different groups established retrospectively depending on the percentage of semen doses provided by the carrier boars ([number of carrier boar doses/total number doses provided] x 100): 0%, 25%, 50%, 75%, 100%. The fertility rates (percentage of successful multiple AIs/total multiple AIs) recorded for multiple AI including semen doses from the carrier boars were not significantly different from those recorded when all semen doses were supplied by normal-karyotype boars. A reduction in litter size of 29.38% was observed, however, in litters sired by one of the carrier boars when its participation in multiple AI was 100%. The number of live-born piglets per litter gradually decreased (P<0.05) as the percentage participation in multiple AI (25, 50, or 75%) of the carrier boar increased. In addition, both carrier boars sired some piglets with signs of cleft palate and complex malformations of the front legs; these died soon after birth. In conclusion, the boars carrying the translocation rcp(1;11)(q-;p+) showed reduced reproductive performance. PMID- 20171727 TI - Representation of the speech effectors in the human motor cortex: somatotopy or overlap? AB - Somatotopy within the orofacial region of the human motor cortex has been a central concept in interpreting the results of neuroimaging and transcranial magnetic stimulation studies of normal and disordered speech. Yet, somatotopy has been challenged by studies showing overlap among the effectors within the homunculus. In order to address this dichotomy, we performed four voxel-based meta-analyses of 54 functional neuroimaging studies of non-speech tasks involving respiration, lip movement, tongue movement, and swallowing, respectively. While the centers of mass of the clusters supported the classic homuncular view of the motor cortex, there was significant variability in the locations of the activation-coordinates among studies, resulting in an overlapping arrangement. This "somatotopy with overlap" might reflect the intrinsic functional interconnectedness of the oral effectors for speech production. PMID- 20171728 TI - Development of novel dental nanocomposites reinforced with polyhedral oligomeric silsesquioxane (POSS). AB - OBJECTIVES: It has been the focus to develop low shrinkage dental composite resins in recent ten years. A major difficulty in developing low shrinkage dental materials is that their deficiency in mechanical properties cannot satisfy the clinical purpose. The aim of this study is to develop novel dental nanocomposites incorporated with polyhedral oligomeric silsesquioxane (POSS). It is especially interesting to evaluate the volumetric shrinkage and mechanical properties, improve the shrinkage, working performances and service life of dental composite resins. METHODS: The effect of added POSS on the composites' mechanical properties has been evaluated. The weight percentages of added POSS are 0, 2, 5, 10 and 15wt% respectively. Fourier-transform infra-red spectroscopy and X-ray diffraction were used to characterize their microstructures. Physico-mechanical properties that were investigated included volumetric shrinkage, flexural strength, flexural modulus, compressive strength, compressive modulus, Viker's hardness and fracture energy. Furthermore, the possible reinforced mechanism has been discussed. RESULTS: The shrinkage of novel nanocomposites decreased from 3.53% to 2.18%. The nanocomposites incorporated with POSS showed greatly improved mechanical properties, for example, with only 2wt% POSS added, the nanocompsite's flexural strength increased 15%, compressive strength increased 12%, hardness increased 15% and uncommonly, even the toughness of resins was obviously increased. With 5wt% POSS polymerized, compressive strength increased from 192MPa to 251MPa and compressive modulus increased from 3.93GPa to 6.62GPa, but flexure strength began to decline from 87MPa to 75MPa. This finding indicated that the reinforcing mechanism of flexure state maybe different from that of compressive state. CONCLUSIONS: The mechanical properties and volumetric shrinkage of dental composite resins polymerized with POSS can be improved significantly. In current study, the nanocomposite with 2wt% POSS incorporated is observed to achieve the best improved effects. PMID- 20171729 TI - Developments in the management of Hodgkin's lymphoma. PMID- 20171730 TI - Medical complicity, torture, and the war on terror. PMID- 20171731 TI - The effects of hyaluronic acid hydrogels with tunable mechanical properties on neural progenitor cell differentiation. AB - We report the ability to direct the differentiation pathway of neural progenitor cells (NPCs) within hydrogels having tunable mechanical properties. By modifying the polymeric sugar hyaluronic acid (HA), a major extracellular matrix component in the fetal mammalian brain, with varying numbers of photocrosslinkable methacrylate groups, hydrogels could be prepared with bulk compressive moduli spanning the threefold range measured for neonatal brain and adult spinal cord. Ventral midbrain-derived NPCs were photoencapsulated into HA hydrogels and remained viable after encapsulation. After three weeks, the majority of NPCs cultured in hydrogels with mechanical properties comparable to those of neonatal brain had differentiated into neurons (ss-III tubulin-positive), many of which had extended long, branched processes, indicative of a relatively mature phenotype. In contrast, NPCs within stiffer hydrogels, with mechanical properties comparable to those of adult brain, had differentiated into mostly astrocytes (glial fibrillary acidic protein (GFAP)-positive). Primary spinal astrocytes cultured in the hydrogel variants for two weeks acquired a spread and elongated morphology only in the stiffest hydrogels evaluated, with mechanical properties similar to adult tissue. Results demonstrate that the mechanical properties of these scaffolds can assert a defining influence on the differentiation of ventral midbrain-derived NPCs, which have strong clinical relevance because of their ability to mature into dopaminergic neurons of the substantia nigra, cells that idiopathically degenerate in individuals suffering from Parkinson's disease. PMID- 20171732 TI - Human immune responses to porcine xenogeneic matrices and their extracellular matrix constituents in vitro. AB - Several tissue engineering approaches for the treatment of cardiovascular diseases are based on a xenogeneic extracellular matrix. However, the application of engineered heart valves has failed in some patients, causing severe signs of inflammation by so far undetermined processes. Therefore we investigated the immune-mediated responses to porcine valve matrices (native, decellularized and glutaraldehyde-fixed) and to purified xenogeneic extracellular matrix proteins (ECMp). The induction of human immune responses in vitro was evaluated by analyzing the co-stimulatory effects of matrices and ECMp collagen and elastin on the proliferation of immune cell sub-populations via CFSE-based proliferation assays. The pattern of cytokine release was also determined. In porcine matrix punches we demonstrated strong immune responses with the native as well as the decellularized type, in contrast to attenuated effects with glutaraldehyde-fixed matrices. Furthermore, our results indicate that collagen type I (porcine and human) and human elastin were able to elicit proliferation in co-stimulation with anti-CD3 antibody, accompanied by a strong release of Th1 cytokines (IFN-gamma, TNF-alpha). In contrast, porcine elastin did not elicit any response at all. This low immunogenic potential of porcine elastin suggests its suitability for the creation of new tissue engineering heart valve scaffolds in the future. PMID- 20171733 TI - Quantum dots labeling using octa-arginine peptides for imaging of adipose tissue derived stem cells. AB - Quantum dots (QDs) have been used to study the effects of fluorescent probes for biomolecules and cell imaging. Adipose tissue-derived stem cells, which carry a relatively lower donor site morbidity, while yielding a large number of stem cells at harvest, were transduced with QDs using the octa-arginine peptide (R8) cell-penetrating peptide (CPP). The concentration ratio of QDs:R8 of 1 x 10(4) was optimal for delivery into ASCs. No cytotoxicity was observed in ASCs transduced with less than 16 nM of QDs655. In addition, >80% of the cells could be labeled within 1 h and the fluorescent intensity was maintained at least for 2 weeks. The ASCs transduced with QDs using R8 could be differentiated into both adipogenic and osteogenic cells, thus suggesting that the cells maintained their stem cell potency. The ASCs labeled with QDs using R8 were further transplanted subcutaneously into the backs of mice or into mice through the tail vein. The labeled ASCs could be imaged with good contrast using the Maestro in vivo imaging system. These data suggested that QD labeling using R8 could be utilized for the imaging of ASCs. PMID- 20171734 TI - Synthesis, characterization and biodegradation of functionalized amino acid-based poly(ester amide)s. AB - A series of biodegradable functional amino acid-based poly(ester amide)s (PEA-AG) were designed and synthesized by the solution co-polycondensation of amino acid (L-phenylalanine and DL-2-allylglycine) based monomers and dicarboxylic acid based monomers. Pendant carbon-carbon double bonds located in the DL-2 allylglycine were incorporated into these PEA-AGs, and the double bond contents could be adjusted by tuning the feed ratio of L-phenylalanine to DL-2 allylglycine monomers. Chemical structures of this new functional PEA-AG family were confirmed by FTIR and NMR spectra. The thermal properties of these polymers were investigated; increasing the methylene chain in both the amino acid and dicarboxlic acid segments resulted in a reduction in the polymer glass-transition temperature. The short-term in vitro biodegradation properties of PEA-AGs were investigated as a function of PEA-AG chemical structures and enzymes. Based on the weight loss data, PEA-AGs biodegraded much faster in an enzyme solution than in a PBS buffer solution. The utility of the pendant functional carbon-carbon double bonds in PEA-AG was demonstrated by synthesizing additional functional PEA derivatives. The incorporation of the functional pendant carbon-carbon double bonds along the PEA-AG chains could significantly expand the biomedical applications of these functional PEA-AGs via either their capability to conjugate bioactive agents or prepare additional useful functional derivatives. PMID- 20171735 TI - Differential repression by the transcription factor REST/NRSF of the various Ca2+ signalling mechanisms in pheochromocytoma PC12 cells. AB - Expression of the nerve cell phenotype is orchestrated by the REST/NRSF transcription repressor, working on hundreds of genes recognized at a specific regulatory binding sequence. Most PC12 clones, the most frequently employed neuronal model, maintain low levels of REST; however a few, defective of neurosecretion, express high levels. To investigate the role of REST in Ca2+ signalling we studied the [Ca2+](i) changes in single cells of four clones, two wild-type and two defective, pre-treated for 5 days with NGF. We focused on Ca2+ influxes induced by depolarization and ATP. Only a subpopulation ( approximately 15%) of the defective, high REST cells responded to depolarization (Ca(V) expression approximately 10%). The ATP-induced intracellular Ca2+ release was little changed, whereas influx via ionotropic P2X receptors was decreased, in agreement with the decreased expression of P2X2 receptors. The percentage of defective cells expressing store-operated calcium entry (SOCE) following ATP stimulation was also lower. The responses of the defective clones were little affected by their differentiated state. In conclusion, our results revealed important new aspects of REST control of Ca2+ homeostasis, of potential physiological importance. The mechanisms of this control remain to be investigated. PMID- 20171737 TI - Investigating the levels and trends of organochlorine pesticides and polychlorinated biphenyl in sewage sludge. AB - A study was completed to investigate temporal trends of organochlorine pesticides (OCPs; aldrin, chlordane, dieldrin, heptachlor, hexachlorbenzene, and DDT) and polychlorinated biphenyls (PCBs) in sewage sludge. Between 2004 and 2006 the concentration of OCPs and PCBs in Australian sewage sludge (n=829) was consistently <1000mugkg(-1) dry solids DS. Dieldrin, chlordane and DDE were detected in 68%, 27% and 13% at maximum concentrations of 770, 290 and 270 microgkg(-1) DS, respectively. Time series analysis (1995-2006) of OCPs and PCBs sewage sludge concentrations (n=2266) taken from six wastewater treatment plants (WWTPs) of the same geographic region found that lindane, aldrin HCB, heptachlor, DDT, DDD and PCBs were infrequently detected (<8%). A correlation between dieldrin and chlordane levels was found (P<0.05) which provides evidence of similar environmental mechanisms facilitating movement of dieldrin and chlordane through environment compartments. It has taken more than 10years for dieldrin and chlordane to reduce to less than detectable concentrations in freshly generated sewage sludge in Australia following government restrictions. Internationally, reported sewage sludge OCP concentrations were consistently low and often less than detection limits. Therefore, OCPs are not considered to be a contaminant of regulatory concern for countries that phased out OCP use several decades ago. Concentrations of PCBs in sewage sludge were also consistently low and rarely exceeded European contaminant limits and therefore, regulatory limits may warrant review. The authors recommend that Australian authorities revise regulatory requirements for OCP and PCBs contaminant levels in sewage sludge destined for beneficial reuse as biosolids. PMID- 20171736 TI - Arsenic trioxide and ascorbic acid demonstrate promising activity against primary human CLL cells in vitro. AB - The compromised antioxidant defense system in chronic lymphocytic leukemia (CLL) suggested a potential use for reactive oxygen species (ROS) generating arsenic trioxide (ATO) and ascorbic acid. While both ATO and ascorbic acid mediate cytotoxicity in CLL B cells as single agents, the efficacy of ATO is enhanced by ascorbic acid. This effect is dependent on increased ROS accumulation, as pretreatment of B-CLL cells with a glutathione reducing buthionine sulfoximine or catalase inhibiting aminotriazole, enhanced ATO/ascorbic acid-mediated cytotoxicity. Pretreatment with reducing agents such as catalase, or thiol antioxidant, N-acetyl cysteine or GSH also abrogated ATO/ascorbic acid-mediated cytotoxicity. Furthermore, Hu1D10-mediated cell death was enhanced with ATO and ascorbic acid, thus justifying potential combination of ATO/arsenic trioxide therapy with antibodies such as Hu1D10 that also cause accumulation of ROS. PMID- 20171738 TI - IgA ASC accumulation to the lactating mammary gland is dependent on VCAM-1 and alpha4 integrins. AB - The homing and migration of IgA antibody secreting cells (ASC) to the lactating mammary gland is essential to the passive transfer of immunity from mother to nursing neonate. Antibody secreting cells, located within the lactating mammary gland, produce high levels of antigen-specific IgA antibodies. These antibodies, which are subsequently transferred to the nursing neonate via breast milk, provide passive immune protection against antigens previously encountered by the mother to the nursing infant. The efficient homing and accumulation of lymphocytes is highly dependent on cellular adhesion molecules expressed on the vascular endothelium and their integrin ligands. Vasculature within the lactating mammary gland is known to express several adhesion molecules, including VCAM-1 and MAdCAM-1. However, the role of these molecules in vivo has not been previously described. Here we show that alpha4 integrins and VCAM-1 play essential roles in mediating the accumulation of IgA ASCs to the lactating mammary gland. Conversely, neither MAdCAM-1 nor its major ligand alpha4beta7 are required for efficient IgA ASC accumulation to this tissue. PMID- 20171739 TI - Poly(ADP-ribose) polymerase-1 modulates interferon-gamma-inducible protein (IP) 10 expression in murine embryonic fibroblasts by stabilizing IP-10 mRNA. AB - Poly(ADP-ribose) polymerase-1 (Parp-1) is a nuclear enzyme that uses NAD(+) as a substrate to catalyze the addition of ADP-ribose polymers on a variety of nuclear proteins, modifying transiently their biological functions. Parp-1 has been involved in transcription regulation of many genes involved in the inflammatory response including cytokines and chemokines. Accordingly, genetic deletion of Parp-1 (Parp-1(-/-)) or pharmacological blockade of Parp-1 activity in mice results in a defective inflammatory immune response which confers an advantage in different pathophysiological conditions associated with inflammation. In addition to the transcriptional control, increasing mRNA stability, mainly through the mitogen-activated protein kinase p38 (p38(MAPK)) might be an important mechanism for the tight regulation in the expression of several chemokines such as IP-10. Here we demonstrate that Parp-1 deficiency in embryonic fibroblasts results in diminished IFN-gamma-induced IP-10 expression despite normal STAT1 activation and IP-10 promoter activity. Therefore, we have analyzed the involvement of Parp-1 in IP-10 mRNA stability. Parp-1 deficient cells showed a decreased half-life of IFN gamma-induced IP-10 transcripts associated with a defect in p38(MAPK) activation. Our results demonstrate that Parp-1 can regulate inflammatory gene expression by increasing mRNA stability, via modulating a proper p38(MAPK) signalling pathway. PMID- 20171740 TI - Evaluation of artifacts associated with macular spectral-domain optical coherence tomography. AB - PURPOSE: To characterize the types and frequencies of image artifacts associated with macular scanning using 2 common spectral-domain optical coherence tomography (SD OCT) instruments and to evaluate the impact of artifacts on foveal thickness measurements. DESIGN: Retrospective, observational chart review. PARTICIPANTS: For the Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA), scans of 98 eyes from 58 patients were included in the study. For the Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg, Germany), scans of 88 eyes from 54 patients were included. METHODS: Macular volume scans of healthy and diseased eyes were evaluated systematically for image artifacts within each scan overall and within the center 1-mm area. The frequency of each artifact type was compared for scans stratified by diagnosis category. Artifacts in the center 1-mm area were graded for severity and were corrected manually using each instrument's software. Artifacts that resulted in errors of more than 50 microm or more than 10% of retinal thickness or that caused a misdiagnosis of macular edema or retinal thinning were defined as clinically significant and were analyzed further. MAIN OUTCOME MEASURES: Overall frequency of image artifacts by artifact type, relative frequency of artifacts in scans stratified by posterior segment disease diagnosis, and retinal thickness measurements of the center 1-mm subfield before and after artifact corrections. RESULTS: For Cirrus, 84.7% of scans had artifacts and 32.7% had at least 1 artifact in the center 1-mm area of the scan. For Spectralis, 90.9% of scans had at least 1 artifact, and 37.5% had at least 1 artifact in the center 1-mm area. Certain artifact types were observed more frequently with specific disease states. Clinically significant artifacts involving the center 1-mm area were seen in 5.1% of Cirrus and 8.0% of Spectralis scans. CONCLUSIONS: Image artifacts in SD OCT volume scanning are common and frequently involve segmentation errors. Artifacts are relatively less common in the center 1-mm area of scans, but may affect retinal thickness measurements in a clinically significant manner. Careful review of scans for artifacts is important when using SD OCT images and retinal thickness measurements in patient care or clinical trials. PMID- 20171741 TI - Macular function assessed by microperimetry in patients with enhanced S-cone syndrome. AB - PURPOSE: Enhanced S-cone syndrome (ESCS), also known as Goldmann-Favre syndrome, is a progressive retinal degeneration that frequently presents with night blindness and nummular pigment clumping around the vascular arcades and is caused by recessive mutations in the photoreceptor-specific NR2E3 transcription factor. A unique feature of this disease is the development of retinoschisis of the macula. This study used fine anatomic and functional assessments within this region to determine whether the loss of retinal function was due to progressive schisis or a primary photoreceptor loss, similar to other rod-cone dystrophies. DESIGN: Cross-sectional, prospective study. PARTICIPANTS: Nine probands (n=18 eyes) and 3 controls (n=6 eyes) were studied at Moorfields Eye Hospital in London, United Kingdom. METHODS: Histories were obtained and visual acuity was measured using Early Treatment Diabetic Retinopathy Study protocol. Autofluorescence (AF), fundus photography, and spectral domain optical coherence tomography (OCT) imaging were co-registered to detailed microperimetry (Nidek MP1; NAVIS software version 1.7.2; Nidek Technologies, Padova, Italy) data for statistical analysis. MAIN OUTCOME MEASURES: Retinal sensitivity (decibels) in a customized test grid of the macula; retinal structure assessed with OCT and AF. RESULTS: Patients were divided into 3 cohorts roughly based on life span and documentation of schisis: (1) no schisis, childhood; (2) macular schisis, young adults; (3) resolved schisis, older adults. Retinal sensitivity was significantly attenuated in those with schisis and did not recover in those whose schisis had resolved despite retinal thickness comparable to that of controls. All probands exhibited loss of AF peripherally (and corresponding loss of retinal sensitivity), but there was relative preservation of AF within the macula. CONCLUSIONS: Development of macular retinoschisis in ESCS is an important feature of the disease and contributes to attenuated retinal sensitivity that persists after resolution of retinoschisis. The central macula appears to be compromised more by foveoschisis than photoreceptor loss. In contrast, the peripheral retina (ordinarily a rod-rich region) is affected early in the disease process and degenerates rapidly because of photoreceptor loss. Thus, 2 distinct mechanisms of retinal degeneration may exist in ESCS, corresponding to regions of the retina that may experience either normal or abnormal photoreceptor development. PMID- 20171742 TI - Differences in neuroticism and extraversion between patients with bipolar I or II and general population subjects or major depressive disorder patients. AB - BACKGROUND: Whether levels of neuroticism or extraversion differ between patients with bipolar disorder (BD), major depressive disorder (MDD) and subjects from the general population, or between BD I and BD II patients, remains unclear. METHODS: BD patients (n=191) from the Jorvi Bipolar Study, and MDD patients (n=358) from both the Vantaa Depression Study and the Vantaa Primary Care Depression Study cohorts, were interviewed at baseline and at 18 months. A general population comparison group (n=347) was surveyed by mail. BD patients' neuroticism and extraversion scores, measured by Eysenck Personality Inventory, were compared at an index interview, when the levels of depression and mania were lowest, with scores of MDD patients and general population controls. Comparisons were also made between BD I (n=99) and BD II (n=92) patients. RESULTS: In multinomial logistic regression, BD patients had higher neuroticism (OR=1.17, p<0.001) and lower extraversion (OR=0.92, p=0.003) than the general population. When entered simultaneously into the model, the effect of extraversion disappeared. In logistic regression, the levels of neuroticism and extraversion did not differ between BD and MDD patients, or between BD I and II patients. LIMITATIONS: Patients' personality scores were not pre-morbid. CONCLUSIONS: Levels of neuroticism and extraversion are unlikely to differ between BD and MDD patients, or between BD I and II patients. The overall level of neuroticism is moderately higher and extraversion somewhat lower in BD patients than in the general population. High neuroticism may be an indicator of vulnerability to both bipolar and unipolar mood disorders. PMID- 20171743 TI - Organization and genomic complexity of bovine lambda-light chain gene locus. AB - Complete characterization and physical mapping of bovine lambda (lambda) light chain locus, spanning 412kbp, on chromosome 17, has revealed twenty-five V(lambda) genes, seventeen being functional, organized in three sub-clusters 23.7kbp 5' of the J(lambda)-C(lambda) units. Three V(lambda) sub-clusters are separated by two large introns of 126.8 and 138.3kbp. The predominantly expressed V(lambda)1 genes are present in the two 5' sub-clusters, while J(lambda)-proximal V(lambda) sub-cluster comprises rarely expressed V(lambda)2 and V(lambda)3 genes. The preferential expression of V(lambda)1 genes in the bovine immunoglobulin repertoire is influenced by the composition of recombination signal sequences (RSS). Of the J(lambda)-C(lambda) cluster, it is mainly J(lambda)3-C(lambda)3 unit that is expressed in reading frame 2, though J(lambda)2 and J(lambda)3 have identical RSS. The predominant expression of J(lambda)3-C(lambda)3 genes over J(lambda)2-C(lambda)2 is likely due to endogenous counter selection for J(lambda)2 encoded CDR3 and framework 4 regions. Differences in the genomic complexity of V(lambda) genes in Hereford and Holstein cattle are due to polymorphism at the lambda-light chain gene locus. Despite more potential germline encoded combinatorial diversity, restricted V(lambda)1-J(lambda)3 C(lambda)3 recombinations encode the most lambda-light chain repertoire in cattle. PMID- 20171744 TI - Increased urinary free immunoglobulin light chain excretion in patients with multiple sclerosis. AB - BACKGROUND: Plasma and B cells are implicated in multiple sclerosis (MS) and produce free light chains (FLC) that are excreted in urine. OBJECTIVE: To confirm that demyelinating diseases (DD) cause increased urinary FLCs. METHOD: Urinary FLC in 50 patients with DD were compared to 20 patients with posterior uveitis (PU), 19 with AIDS, 34 with rheumatoid arthritis (RA) and 19 normal controls (NC). RESULT: Subjects with DD, PU, RA and AIDS have higher urinary FLCs than NC (p<0.01). Urinary FLCs did not correlate with gadolinium-enhancing lesions on MRI. CONCLUSIONS: Urinary FLCs are raised in DD. Further studies are required to see if they correlate with disease activity. PMID- 20171745 TI - Do diet and activity restrictions influence recovery after adenoidectomy and partial tonsillectomy? AB - OBJECTIVE: To determine if restrictions of postoperative diet concerning hard food and hot drinks as well as excessive physical exertion influence recovery during 14 days after T&A surgery. METHODS: 800 patients aged 3-13 years (median 6) underwent curette adenoidectomy with or without scissors tonsillotomy. 413 adenoidectomies and 387 adenotonsillotomies were performed. Caregivers of the children completed a questionnaire reporting their child's postoperative activity, diet, pain level, peak and duration, episodes of nausea and fever, medication and caregivers' satisfaction scores. The children were enrolled to food and effort restricted (FER), food non-restricted (FnR), effort non restricted (EnR), and food and effort non-restricted (FEnR) groups at the end of follow-up. RESULTS: Two hemorrhages requiring repeat surgery under general anesthesia in FER group and 42 mild episodes of spontaneously subsiding bleeding from nose or mouth occurred. More than one episodes of hemorrhage were observed in other 8 individuals (total incidence of hemorrhages 9.7%). No hemorrhages were noted in the FEnR and FnR groups. There were 23 (4.4%) participants with episodes of bleeding, among them 21 mild hemorrhages, in the FER group and 21 (12.0%) in the EnR group (p<0.001). Peak pain level was lowest in FEnR group (p<0.001) and indications for antibiotics most frequent in FnR group (p<0.001). Parental satisfaction level was highest in FnR and FEnR groups (p<0.001). CONCLUSIONS: The majority of caregivers reported care of children after T&A surgery according to the instructions. Most frequently disobeyed instructions were those concerning physical exertion. Diet and activity restrictions seem to influence postoperative recovery. Parental satisfaction scores were highest in non-restricted groups. PMID- 20171746 TI - How is the children's implant profile used in the Cochlear Implant Candidacy Process? AB - OBJECTIVE: The complex process of cochlear implant candidacy assessment at The Children's Hospital of Philadelphia (CHOP) is guided by a modified version of the Children's Implant Profile (ChIP) that has been used world wide over the past 18 years. The aim of this study is to analyze the use of the modified ChIP (mChIP) in the candidacy process by the CHOP Cochlear Implant Program. Of special interest were those cases in which the recommendation regarding implantation appeared inconsistent with the mChIP score. These were further analyzed to understand the real-life decision processes. METHODS: This retrospective study involved 121 children assessed for cochlear implant candidacy at CHOP over a 2 year period. The mChIP ratings of No Concern, Some Concern and Great Concern were assigned values of 1, 2 and 3, respectively. Values of 1.5 and 2.5 were used when the check mark was on the boundary between two categories. An average score was calculated and the relationships between mChIP scores and the recommendation regarding implantation were examined. RESULTS: Eighty-seven children were considered suitable for cochlear implantation; implantation was not recommended for 20. Another 14 cases in which one or more areas of the mChIP had not been completed were excluded. Using a criterion based solely on the mean score would correctly predict 75% of the team's recommendations to implant and 75% of recommendations not to implant. Examination of the cases where implantation was not recommended illuminated the decision-making process. CONCLUSIONS: A statistical analysis of the mChIP fails to capture the complexity of the decision making process. Most important, it appears that the team's practice is generally to recommend implantation when there is at least a modest prospect of benefit, unless there are absolute contraindications or many areas of Great Concern. PMID- 20171747 TI - Circadian dysfunction in disease. AB - The classic view of circadian timing in mammals emphasizes a light-responsive 'master clock' within the hypothalamus which imparts temporal information to the organism. Recent work indicates that such a unicentric model of the clock is inadequate. Autonomous circadian timers have now been demonstrated in numerous brain regions and peripheral tissues in which molecular-clock machinery drives rhythmic transcriptional cascades in a tissue-specific manner. Clock genes also participate in reciprocal regulatory feedback with key signalling pathways (including many nuclear hormone receptors), thereby rendering the clock responsive to the internal environment of the body. This implies that circadian clock genes can directly affect previously unforeseen physiological processes, and that amid such a network of body clocks, internal desynchronisation may be a key aspect to circadian dysfunction in humans. Here we consider the implications of decentralised and internally responsive clockwork to disease, with a focus on energy metabolism and the immune response. PMID- 20171748 TI - Toxicity, uptake kinetics and behavior assessment in zebrafish embryos following exposure to perfluorooctanesulphonicacid (PFOS). AB - Perfluorooctanesulphonicacid (PFOS), a persistent organic contaminant, has been widely detected in the environment, wildlife and humans, but few studies have assessed its effect on aquatic organisms. The present study evaluated the effect of PFOS on zebrafish embryos. Zebrafish embryos exhibited developmental toxicity of bent spine, uninflated swim bladder, decreased heart rate and affected spontaneous movement after exposure to various PFOS concentrations (0-8mg/L) from 6 to 120h post-fertilization (hpf). The LC(50) at 120hpf was 2.20mg/L and the EC(50) at 120hpf was 1.12mg/L. Continuous exposure to PFOS from 1 to 121hpf resulted in a steady accumulation with no evidence of elimination. PFOS induced cell death at 24hpf was consistently found in the brain, eye, and tail region of embryos. PFOS exposure induced lesions in the muscle fibers with histological examination. Behavior assessment of PFOS in zebrafish embryos elevated the basal rate of swimming after 4 days of exposure, and larvae exposed to PFOS (0.25 4mg/L) for only 1h at 6dpf swam faster with increasing PFOS concentration. Embryos/larvae exposed to 8mg/L PFOS for 24h periods from 1 to 121hpf showed the highest incidence of malformations in the 97-121hpf window. This is the first study to define uptake kinetics and to focus on behavioral consequences following PFOS exposure in zebrafish. Our results further the understanding of the toxicity of PFOS to aquatic organisms and suggest the need for additional research to identify the mode of PFOS toxicity. PMID- 20171749 TI - Sense of coherence (SOC) related to health and mortality among the very old: the Umea 85+ study. AB - We describe associations between sense of coherence (SOC) and sense of well being, diseases, physical function and the predictive value of SOC on depression and mortality. The study included 190 participants, aged 85-103 years. Linear correlation analysis was used for relationships between SOC scores and continuous variables. The effects of SOC score on 1- and 4-year mortality, as well as on depression at the 5-year follow-up, were investigated using Cox regression models. The mean SOC score was 71.8+/-10.2 (+/-S.D.). SOC score was positively related to well-being (p<=0.001). Heart failure (p=0.009), chronic obstructive pulmonary disease (p=0.015), depression (p=0.015), and osteoarthritis (p=0.032) were significantly associated with low SOC scores, as were high scores on the Geriatric Depression Scale (GDS) (p=0.002). One-year mortality was significantly associated with the SOC score (OR=0.945, confidence interval (CI)=0.898-0.995, p=0.032), while the 4-year mortality was not (OR=0.995, CI=0.973-1.018, p=0.674). The SOC score did not predict depression at 5-year follow-up (OR=0.977, CI=0.937 1.018, p=0.267). Strong SOC was associated with well-being in this group of old people. Low SOC was found among those with diseases known to have a negative influence on daily life. PMID- 20171750 TI - IMRT-based optimization approaches for volumetric modulated single arc radiotherapy planning. AB - This paper reports on an evaluation of 5 RapidArc optimization approaches vs IMRT. This study includes 11 patients with adenocarcinoma of the prostate. Rectal Normal Tissue Complication Probability is used as a constraint in a dose escalation. RapidArc rectal NTCP's are lower than those of IMRT (p = 0.007). This allows a mean dose escalation of 2.1 Gy([0.7 Gy,3.5 Gy]). PMID- 20171751 TI - Limited benefit of inversely optimised intensity modulation in breast conserving radiotherapy with simultaneously integrated boost. AB - BACKGROUND AND PURPOSE: To examine whether in breast-conserving radiotherapy (RT) with simultaneously integrated boost (SIB), application of inversely planned intensity-modulated radiotherapy (IMRT-SIB) instead of three-dimensional RT (3D CRT-SIB) has benefits that justify the additional costs, and to evaluate whether a potential benefit of IMRT-SIB depends on specific patient characteristics. MATERIAL AND METHODS: 3D-CRT-SIB and various IMRT-SIB treatment plans were constructed and optimised for 30 patients with early stage left-sided breast cancer. Coverage of planning target volumes (PTVs) and dose delivered to organs at risk (OARs) were determined for each plan. Overlap between heart and breast PTV (OHB), size of breast and boost PTVs and boost location were examined in their ability to identify patients that might benefit from IMRT-SIB. RESULTS: All plans had adequate PTV coverage. IMRT-SIB generally reduced dose levels delivered to heart, lungs, and normal breast tissue relative to 3D-CRT-SIB. However, IMRT SIB benefit differed per patient. For many patients, comparable results were obtained with 3D-CRT-SIB, while patients with OHB>1.4 cm and a relatively large boost PTV volume (>125 cm(3)) gained most from the use of IMRT-SIB. CONCLUSIONS: In breast-conserving RT, results obtained with 3D-CRT-SIB and IMRT-SIB are generally comparable. Patient characteristics could be used to identify patients that are most likely to benefit from IMRT-SIB. PMID- 20171752 TI - Simultaneous integrated boost in breast conserving treatment of breast cancer: a dosimetric comparison of helical tomotherapy and three-dimensional conformal radiotherapy. AB - BACKGROUND AND PURPOSE: To evaluate the dosimetry of helical tomotherapy (HT) and three-dimensional conformal radiotherapy (3D-CRT) in breast cancer patients undergoing whole breast radiation with simultaneous integrated boost (SIB) of the tumor bed. MATERIAL AND METHODS: Thirteen patients with breast cancer treated by lumpectomy and requiring whole breast radiotherapy with tumor bed boost were planned using both HT and 3D-CRT using the field-in-field technique. The whole breast and tumor bed were prescribed 50.68 Gy and 64.4 Gy, respectively, in 28 fractions. Dosimetries for both techniques were compared. RESULTS: Coverage of the whole breast was adequate with both techniques (V(95%)=96.22% vs. 96.25%, with HT and 3D-CRT, respectively; p=0.64). Adequate tumor bed coverage was also achieved, although it was significantly lower with HT (V(95%)=97.18% vs. 99.72%; p<0.001). Overdose of the breast volume outside the tumor bed was significantly lower with HT (V(54.23 Gy)=12.47% vs. 30.83%; p<0.001). Ipsilateral lung V(20 Gy) (6.34% vs. 10.17%; p<0.001), V(5 Gy) (16.54% vs. 18.53%; p<0.05) and mean dose (4.05 Gy vs. 6.36 Gy; p<0.001) were significantly lower with HT. In patients with left-sided tumors, heart V(30 Gy) (0.03% vs. 1.14%; p<0.05) and mean dose (1.35 Gy vs. 2.22 Gy; p<0.01) were significantly lower with HT, but not V(5 Gy). Contralateral breast V(5 Gy) (0.27% vs. 0.00%; p<0.01) and maximum dose were significantly increased with HT. CONCLUSIONS: In breast cancer treated with SIB, both HT and 3D-CRT provided adequate target volume coverage and low heart doses. Tumor bed coverage was slightly lower with HT, but HT avoided unnecessary breast overdosage while improving ipsilateral lung dosimetry. PMID- 20171753 TI - Ecophysiology of food-borne pathogens: Essential knowledge to improve food safety. AB - The term ecophysiology suggests that a natural connection exists between microbial ecology and microbial physiology, the former being concerned with the responses of microbial populations to environmental influences, and the latter with activities within individual cells. In this contribution we choose to integrate these as far as possible and also indicate how understanding of both is benefiting from advances in molecular biology and informatics. We consider how microbial dispersal relates to microbial survival, recovery and proliferation, including the significance of random factors (stochasticity) in continuation of bacterial lineages, observing that minor environmental changes, can greatly influence the potential for food-borne disease. Homeostasis and membrane transport are identified as potential targets to control food-borne pathogens and the role of compatible solutes in stress protection is presented. Phenotypic variation in genetically homogeneous populations is highlighted as a major component of the overall microbial survival strategy. The marked influence and potential of predictive microbiology as an aid to food safety management is discussed, as is the need for greater knowledge of the ecophysiology of microbes in the growth/no growth region. The application of fundamental scientific principles, including thermodynamics, chemistry and microbial physiology is advocated as the basis for development of theory underpinning microbial ecophysiology. Advancing microbial food safety continues to require development of rapid, quantitative methods as an early warning system and mechanism to curtail microbial food-borne disease outbreaks. However, advances made by technologists and molecular biologists must be combined with knowledge of ecophysiology: e.g. biological rates will continue to constrain resolution of the recalcitrant problem of reducing the time required for enrichment processes. The discussion presented leads to the conclusion that microbial and molecular methods are appropriate for enumeration and prevalence studies but that predictive model development should continue for the purposes of comparative process control and to support the risk assessment paradigm. We conclude also that contributions of human error or complacency to microbial food-borne illness will continue to thwart the best efforts of microbiologists and technologists to reduce its incidence. Decision-support technologies reporting in real-time appear to have potential to make objective food safety decisions thereby reducing the impact of human indifference to the application of simple, but effective, food hygiene rules. PMID- 20171754 TI - Global healthcare expenditure on diabetes for 2010 and 2030. AB - AIMS: To estimate the global health expenditure on diabetes among people aged 20 79 years for the years 2010 and 2030. METHODS: Country-by-country expenditures for 193 countries, expressed in United States Dollars (USD) and in International Dollars (ID), were estimated based on the country's age-sex specific diabetes prevalence and population estimates, per capita health expenditures, and health expenditure ratios per person with and without diabetes. Diabetes prevalence was estimated from studies in 91 countries. Population estimates and health expenditures were from the United Nations and the World Health Organization. The health expenditure ratios were estimated based on utilization and cost data of a large health plan in the U.S. Diabetes expenditures for the year 2030 were projected by considering future changes in demographics and urbanization. RESULTS: The global health expenditure on diabetes is expected to total at least USD 376 billion or ID 418 billion in 2010 and USD 490 billion or ID 561 billion in 2030. Globally, 12% of the health expenditures and USD 1330 (ID 1478) per person are anticipated to be spent on diabetes in 2010. The expenditure varies by region, age group, gender, and country's income level. CONCLUSIONS: Diabetes imposes an increasing economic burden on national health care systems worldwide. More prevention efforts are needed to reduce this burden. Meanwhile, the very low expenditures per capita in poor countries indicate that more resources are required to provide basic diabetes care in such settings. PMID- 20171755 TI - Photosynthetic characteristics in genetically modified sense-RbcS silver birch lines. AB - Transgenic silver birch lines carrying extra copies of endogenous small subunit of Rubisco (RbcS)-gene under 35S CaMV promoter were used to study the carbon use efficiency of silver birch (Betula pendula Roth). A five week greenhouse experiment was carried out with four transgenic lines, R3.2, R7.2, E5 and E25, and their corresponding wild types (wt). The first fully developed leaves were used for analyses. Three of the produced lines, R3.2, E5 and E25, differed from the wt lines. Line R3.2 showed an altered growth rhythm; its chlorophyll content, Rubisco amount and activity as well as photosynthetic characteristics were reduced at the beginning of the experiment, which resulted in decreased biomass and growth. In lines E25 and E5, the biomass accumulation was shifted to roots, and in line E25, the total biomass was also reduced. In line E25, the differences were particularly marked in the dry mass, indicating a difference in water use, seen as increased transpiration. Introduction of sense RbcS decreased the Rubisco amount in birch leaves to 80% of wt at times during the tree development, but the lower amount of Rubisco was usually not seen in photosynthesis. The accumulation and distribution of biomass within the plants was altered. PMID- 20171756 TI - Educational intervention, revised instrument sterilization methods, and comprehensive preoperative skin preparation protocol reduce cesarean section surgical site infections. AB - BACKGROUND: In 2005, of the approximately 4 million births in the United States, 30% were by cesarean section (C-section) delivery, which translates to roughly over 1 million C-sections in 2005 alone. C-section is associated with higher morbidity than vaginal delivery. Women who undergo C-section are 5 times more likely to develop a postpartum infection after delivery than women who undergo vaginal delivery. OBJECTIVE: Estimates of surgical site infection (SSI) after C section range from 1.50 to 2.64. A quality improvement initiative was implemented at the University of Minnesota Medical School to reduce rates of SSI using changes based on recommended care initiatives. METHODS: The multidisciplinary team developed a comprehensive staff education and training program, added a preoperative skin preparation protocol using chlorhexidine gluconate (CHG) no rinse cloths, added CHG with alcohol for interoperative skin preparation, and modified instrument sterilization techniques. RESULTS: Data analysis revealed a statistically significant reduction in the overall SSI rate from 7.5% (33/441) in January-July 2006 to 1.2% (5/436) in January-July 2007 (chi(2) test statistic, 21.2; P < .001; relative reduction of 84%). CONCLUSION: Interventions, including staff education, use of CHG no-rinse cloths for preoperative skin prep, CHG with alcohol for intraoperative skin prep, and appropriate instrument sterilization management led to reductions in SSI rates in patients undergoing C-section at our institution. Rates of endometritis were also noted to be lower after implementation of the interventions. PMID- 20171757 TI - Interobserver variability in ventilator-associated pneumonia surveillance. AB - Three infection control personnel and 1 physician independently evaluated 50 ventilated patients for ventilator-associated pneumonia through retrospective chart reviews. The infection control reviewers used Centers for Disease Control and Prevention criteria; the physician used clinical judgment. Infection control personnel labelled between 11 and 20 patients with VAP (kappa = 0.40). The physician diagnosed 7 cases. Interobserver variability in the assessment of ventilator-associated pneumonia is high. PMID- 20171758 TI - Synthesis and biological evaluation of beta-chloro vinyl chalcones as inhibitors of TNF-alpha and IL-6 with antimicrobial activity. AB - A series of beta-chloro vinyl chalcones have been synthesized by Claisen-Schmidt condensation. beta-chloro vinyl aldehyde has been synthesized by the Vilsmayer Hack formylation reaction. The structures of the newly synthesized compounds were confirmed by 1H NMR, IR and Mass spectral analysis. All the compounds were evaluated for their anti-inflammatory activity (against TNF-alpha and IL-6) and antimicrobial (antibacterial and antifungal) activity. Compounds 5a, 5d, 5e, 5g and 5i exhibited promising activity against IL-6 with 58-83% inhibition at 10 microM concentration. None of the compound was found to be cytotoxic in CCK-8 cells at 10 microM concentration. Whereas compounds 5b, 5d, 5e and 5i showed very good antibacterial activity and compounds 5a, 5b, 5e and 5i showed good antifungal activity. PMID- 20171759 TI - Synthesis, antiproliferative, acute toxicity and assessment of antiandrogenic activities of some newly synthesized steroidal lactams. AB - The 17-oxo-17a-aza-d-homo-5-androsten-3beta-yl esters (13-22) were synthesized from commercially available (25R)-5-spirosten-3beta-ol (Diosgenin) (6) as starting material. The synthesized compounds were evaluated for their antiproliferative activity, acute toxicity and effect on serum androgen level and were compared with Finasteride as positive controls. Some of the compounds exhibited better cytotoxicity and antiandrogenic activity than the reference control. The detailed synthesis, spectroscopic data and pharmacological screening for the synthesized compounds were reported. PMID- 20171760 TI - Synthesis and antiproliferative properties of ibuprofen-oligo(3-hydroxybutyrate) conjugates. AB - Synthesis of novel conjugates of the non-steroidal anti-inflammatory drug - ibuprofen with nontoxic oligo(3-hydroxybutyrate) (OHB) is described. Presented results indicate that anionic ring-opening polymerization of (R,S)-beta butyrolactone initiated with an alkali metal salt of (S)-(+)-2-(4 isobutylphenyl)propionic acid (ibuprofen) may constitute a convenient method of conjugation of selected drugs with biodegradable OHB. Furthermore using the MTT cell proliferation assay we demonstrated that ibuprofen conjugated with OHB exhibited significantly increased, as compared to free ibuprofen, potential to inhibit proliferation of HT-29 and HCT 116 colon cancer cells. However, the conjugates of ibuprofen and OHB are less toxic as was shown in oral acute toxicity test in rats. Although the mechanism of antiproliferative activity of ibuprofen-OHB conjugates (Ibu-OHB) has to be established, we suggest that partially it can be related to more effective cellular uptake of the conjugate than the free drug. This assumption is based on the observation of much more efficient accumulation of a marker compound - OHB conjugated with fluorescein, in contrast to fluorescein sodium salt, which entered cells inefficiently. Further characterization of biological properties of the ibuprofen-OHB conjugates would provide insight into the mechanism of their antiproliferative effect and assess the potential relevance of their anticancer activity. PMID- 20171761 TI - Synthesis and potential cytotoxic activity of new phenanthrylphenol pyrrolobenzodiazepines. AB - New phenanthrylphenol-pyrrolobenzodiazepine (PP-PBD) conjugates have been synthesized and evaluated for their biological activity. One of the compounds 4a has been evaluated for its antiproliferative activity on 57 human tumour cell lines. The growth inhibition of 4a-c has been determined by MTT viability assay on MCF-7 cell line. Among them, 4c showed most potent growth inhibition. Based on this, an attempt was made to rationalize their mechanism of action through cell cycle analysis and DNA interaction studies. The effect of the lead compound 4c on MCF-7 cell growth associated with cell cycle arrest in G1 phase, followed by apoptosis. Our findings suggested the phenanthrylphenol-PBD conjugate 4c, which is a cyclin D1 inhibitor could be considered as a promising lead compound against breast cancer for further investigation. PMID- 20171762 TI - Synthesis of novel dendrimers having aspartate grafts and their ability to enhance the aqueous solubility of model drugs. AB - In this study, a series of aspartate based dendrimers with different cores were synthesized in a convergent approach and well characterized by NMR and MS techniques. The aqueous solubility of the model drugs (L-Histidine, Naproxen, Methotrexate) was measured in the presence of this kind of dendrimers at room temperature in PBS buffers at pH 6, 7 and 8. Results clearly confirmed that the solubility enhancement was due to presence of dendrimers at different pH compared to their corresponding aqueous solubility at different pH. The results indicated that the aspartate based dendrimers could be considered as an effective supplement of PAMAM dendrimers in solubility enhancement and drug delivery. The surface groups played an important role in dendrimer-mediated solubility enhancement. PMID- 20171763 TI - Synthesis and biological evaluation of some pyrazolylpyrazolines as anti inflammatory-antimicrobial agents. AB - A new series of pyrazolylpyrazolines (5a-k) was synthesized by the reaction of appropriate chalcones (3a-k) with 4-hydrazinobenzenesulfonamide hydrochloride (4) in ethanol. All the newly synthesized target compounds (5a-k) were screened for their anti-inflammatory activity using carrageenan-induced rat paw edema assay. Compounds 5g and 5j showed pronounced anti-inflammatory activity comparable to the reference standard nimesulide, whereas, compounds 5b, 5d and 5h displayed good anti-inflammatory activity. Additionally, the synthesized compounds were evaluated for their in vitro antimicrobial activity against two Gram-positive bacteria and two Gram-negative bacteria. Four compounds 5c, 5h-5j showed good broad spectrum activity against all the tested Gram-positive and Gram-negative bacterial strains. Compound 5j could be identified as the most biologically active member within this study with an interesting dual anti-inflammatory and antibacterial profile. PMID- 20171764 TI - [Arthritis revealing an osteoid osteoma in a patient with spondylarthropathy]. AB - Intra-articular osteoid osteoma is rare and difficult to diagnose. We report a 38 year-old woman who presented with an inflammatory monoarticular arthritis in the right ankle in the context of a spondylarthropathy, otherwise well-controlled by leflunomide. This monoarthritis was resistant to all types of treatment. Investigations led to the diagnosis of an intra-articular osteoid osteoma. This original observation is the first description of an osteoid osteoma developing in a patient already known to have inflammatory rheumatism. All previous reported cases were monoarthritis consecutive to the osteoid osteoma itself and interpreted as incipient inflammatory rheumatism. PMID- 20171765 TI - Value dissonance in nursing: making sense of disparate literature. PMID- 20171766 TI - Leadership in clinical education - embedding learning in everyday practice. PMID- 20171767 TI - Unusual case of spontaneous discharge of pus (infected cyst) through the dorsum of the tongue. AB - Neck swellings are often a result of infections that spread from the teeth. This case highlights an unusual presentation of spontaneous pustular discharge from the anterior dorsum of the tongue. PMID- 20171768 TI - Significance of JAK2 and TET2 mutations in myelodysplastic syndromes. AB - The pathogenesis of myelodysplastic syndromes involves a pattern of genetic, epigenetic, and immune-mediated mechanisms but little is known about what causes the specific disease features and promotes disease progression in the individual patient. The identification of JAK2 and MPL mutations, and more recently TET2, CBL and ASXL-1 mutations in these disorders provide a basis for increased understanding of disease biology and mechanisms behind progression. Such mutations are more commonly found in patients with a significant amount of marrow ring sideroblasts, and in patients belonging to the category of mixed myelodysplastic/myeloproliferative neoplasms, entities which are in focus for this review. PMID- 20171769 TI - Different stabilities of multiwalled carbon nanotubes in fresh surface water samples. AB - The stability of multiwalled carbon nanotubes (MWNTs) in particulate aggregates and surfactant-facilitated suspensions after being mixed into eight types of fresh surface water samples was investigated. MWNTs in particulate aggregates could not be stabilized in any of the water samples except for the one having relatively high content of dissolved organic matter with the aid of sonication. Sodium dodecyl benzenesulfonate (SDBS), polyethylene glycol octylphenyl ether (TX100) and cetyltrimethyl ammonium bromide (CTAB) were used to prepare MWNT suspensions. SDBS- and TX100-stabilized MWNTs could partly remain suspending after being mixed into the water samples, whereas CTAB-stabilized MWNTs readily sedimentated due to the surface charge neutralization by the surface water contained negatively-charged anions and colloids. This is a first systematic study examining the stability of carbon nanotubes in natural surface waters, the results from which will be useful for understanding the transport, fate and ecological effect of carbon nanotubes in the aqueous environment. PMID- 20171770 TI - Alteration of a Mn-rich slag in contact with soil: in-situ experiment during one year. AB - A Mn-rich slag sample coming from a pyrometallurgical plant recycling alkaline batteries was submitted to environmental conditions during one year. After crushing, the slag was buried in topsoil and the leachate was periodically collected in order to monitor the leached amounts of metallic elements (ME). Results evidenced a low release of the slag constituents (Mn: < 0.01%). The SEM/EDS investigations did not show alteration features supposing a weak dissolution of the primary phases (tephroite, bustamite and leucite). The modification of the pH induced by the slag enhanced the mobility of soil components and of the organic matter, particularly in the vicinity of the soil/slag contact zone. This suggested that the slag indirectly influenced the ME mobility through the organic matter and colloidal transports. The comparison with a classical laboratory column test evidenced the underestimation of the leached amounts due to the differences of operational conditions. PMID- 20171771 TI - An integrative mechanistic account of psychological distress, therapeutic change and recovery: the Perceptual Control Theory approach. AB - The exact nature and mechanisms of psychological change within psychological disorders remain unknown. This review aims to use a psychological framework known as Perceptual Control Theory (Powers, 1973, 2005; Powers, Clark, & McFarland, 1960) to integrate the diverse literature within psychotherapy research. The core principles of Perceptual Control Theory are explained, and key domains of psychotherapy are considered to explore how well they converge with these principles. The quantitative and qualitative empirical literature on the process of psychological change is reviewed to examine how it fits with predictions based on Perceptual Control Theory. Furthermore, the prerequisites for psychological change; client qualities, therapist qualities, the therapeutic alliance and the shifting of awareness, are also considered to examine their consistency within a Perceptual Control Theory account. Finally the strengths and limitations of a Perceptual Control Theory account in explaining the mechanism of psychological change are considered. PMID- 20171772 TI - [Nitric oxide in asthma: what good does it do?]. PMID- 20171773 TI - [Miliary tuberculosis due to BCG in an asymptomatic patient: initial onset or a condition not yet described?]. PMID- 20171774 TI - [Extramedullary plasmacytoma that simulates pulmonary metastasis]. PMID- 20171775 TI - [Palliative thoracocentesis in low income countries]. PMID- 20171776 TI - Comparison of day 2 embryo quality after conventional ICSI versus intracytoplasmic morphologically selected sperm injection (IMSI) using sibling oocytes. AB - OBJECTIVE: To evaluate whether intracytoplasmic morphologically selected sperm injection (IMSI) could influence early paternal effects by observing embryo quality at day 2. STUDY DESIGN: The study included 30 couples with at least one of the following criteria: male factor infertility, at least 2 previous failures of implantation or previous miscarriages after IVF/ICSI. Sibling oocytes of each patient were randomly assigned to either the ICSI group or the IMSI group. For IMSI, spermatozoa were selected at 8400x magnification through an inverted microscope equipped with Nomarski differential interference contrast optics, Uplan Apo 100x oil/1.35 objective lens and variable zoom lens. For conventional ICSI, spermatozoa were selected at 400x magnification. An embryo was defined as top quality if there were four identical blastomeres on day 2 with no fragments or multinucleation of blastomeres. Data were analysed using the Wilcoxon and chi squared tests. The significance level was set at P<0.05. The variables were analysed in relation to the general population and the subpopulations with or without male factor. RESULTS: A total of 331 MII oocytes (30 oocyte retrievals) were selected and injected by the ICSI (n: 172) or IMSI (n: 159) procedure. For IMSI, only spermatozoa classified as morphologically normal at high magnification were used. No differences (P>0.05) in fertilisation rate (ICSI: 70.9%; IMSI: 70.4%), early embryo cleavage rate (ICSI: 66.9%; IMSI: 60.4%) or cleavage rate (ICSI: 99.2%; IMSI: 99.1%) were observed. On day 2, as compared to ICSI, IMSI provided a similar proportion of top quality embryos (ICSI: 57.8%; IMSI: 52.2%; P>0.05). These results were not influenced by the presence or absence of male factor. CONCLUSION: In terms of embryo quality at day 2, IMSI had the same performance as conventional ICSI. However, we cannot exclude the possibility that IMSI effects occur only as a positive later paternal effect. PMID- 20171777 TI - Recurrent hydatidiform moles. AB - Hydatidiform moles (HMs) are abnormal conceptions of excessive trophoblast development resulting in abnormal human pregnancies with no embryo and cystic degeneration of the chorionic villi. Prompt diagnosis, treatment and follow-up of patients using assays for betahCG from centres that specialise in this condition enable early diagnosis of potential malignant change. Hydatidiform moles occur quite frequently and although recurrence is rare, women who have experienced one molar pregnancy should be aware that they are at an increased risk of a further molar pregnancy in comparison to other women in the general population. For some women multiple molar pregnancies occur. In these women the recurrent molar pregnancies may be non-familial, referred to as recurrent molar hydatidiform moles in this article, or may result from an inherited predisposition, which we refer to as familial recurrent hydatidiform moles. We use the term familial biparental hydatidiform moles (FBHMs) for cases in which the parental contribution to the moles has been investigated and found to be biparental. It is important to recognise, however, that in some apparently non-familial cases, the absence of female siblings, or the absence of female siblings who have tried to conceive, may not allow the inherited nature of the molar pregnancies to manifest in more than one woman and be obviously familial. This review considers our current understanding about the aetiology of HMs and explores the mechanisms of both types of recurrent hydatidiform moles. It highlights the role that genetics can play in determining the origin of multiple molar pregnancies, which should be considered essential in providing women with accurate advice about their risk of recurrence, so allowing them to make appropriate reproductive choices. PMID- 20171779 TI - Age-specific risk of incident prostate cancer and risk of death from prostate cancer defined by the number of affected family members. AB - BACKGROUND: The thorough assessment of familial prostate cancer (PCa) risk is as important as ever to provide a basis for clinical counselling and screening recommendations. OBJECTIVE: Our aim was to determine the age-specific risks of PCa and the risk of death from PCa according to the number and the age of affected first-degree relatives. DESIGN, SETTING, AND PARTICIPANTS: The nationwide Swedish Family-Cancer Database includes a record of >11.8 million individuals and their cancers from 1958 to 2006. All men from the database with identified parents (>3.9 million individuals) were followed between 1961 and 2006. The study included 26 651 PCa patients, of whom 5623 were familial. MEASUREMENTS: The age-specific hazard ratios (HRs) of PCa and the HRs of death from PCa were calculated according to the number and age of affected fathers and brothers. RESULTS AND LIMITATIONS: The HRs of PCa diagnosis increased with the number of affected relatives and decreased with increasing age. The highest HRs were observed for men <65 yr of age with three affected brothers (HR: approximately 23) and the lowest for men between 65 and 74 yr of age with an affected father (HR: approximately 1.8). The HRs increased with decreasing paternal or fraternal diagnostic age. The pattern of the risk of death from familial PCa was similar to the incidence data. CONCLUSIONS: The present results should guide clinical counselling and demonstrate the vast increases in risk when multiple first-degree relatives are affected. PMID- 20171780 TI - Experimental investigation of bio-removal of toxic organic pollutants from highly saline solutions in a triphasic system. AB - A combined solvent extraction and biphasic biodegradation process was proposed to remove organic pollutants from highly saline solutions, where the organic solvent is biocompatible and the organic-aqueous interface remains quasi-quiescent during the process. Phenol and Pseudomonas putida BCRC 14365 were selected as the model organic compound and biomass, respectively. The effects of added NaCl concentration (50-200 g/L) and pH (1.0-9.0) in synthetic solutions on phenol removal and cell growth were studied at 30 degrees C. The initial cell concentration was fixed at 0.025 g/L. Within the examined range, the adjustment of solution pH to 3.0 resulted in the best removal performance of 1100 mg/L phenol from such saline solutions (an apparent removal rate of about 20 mg/(Lh)) when using kerosene as the organic solvent. The overall process appeared to be favored when the salt concentration in saline solution was in the range of 100 150 g/L. The application potentials of such a triphasic process for the removal of toxic organics (phenol) from highly saline and acidic wastewaters were finally demonstrated in fed-batch mode. PMID- 20171781 TI - Chlorine characterization and thermal behavior in MSW and RDF. AB - Chlorine, as a key element causing high temperature corrosion and low efficiency in waste-to-energy plants, and its thermal behavior has widely drawn attention. In this study, the chlorine content in eight fractions of municipal solid waste (MSW) was quantified and characterized using five analytical methods. The influence of the operating temperature, and fuel additives like sulfur and silica on the volatilization of chlorine in combustion process was also investigated. The results showed: these fractions cover a wide range of chlorine content from 0.1 wt.% in wood to >6 wt.% in non-packaging plastics (dry basis). Polyvinylchloride (PVC) from packaging, electrical wire insulation etc. in plastics and chloride salts (mainly NaCl) in kitchen waste are the main sources of organic and inorganic chlorine. The increase of the operating temperature from 700 degrees C to 1000 degrees C has more influence on the HCl formation for kitchen waste than that for PVC. Sulfur addition leads to 20-40% higher HCl formation rate in most fractions. Silica supports the chlorine release at relatively low temperatures between 700 degrees C and 850 degrees C. These findings enhance to understand the thermal behavior of chlorine in MSW and RDF (refuse derived fuel) in waste-to-energy plants and lead to the suggestions for a fuel management for waste derived fuels in order to avoid chlorine induced corrosion. PMID- 20171782 TI - Chlorides behavior in raw fly ash washing experiments. AB - Chloride in fly ash from municipal solid waste incinerators (MSWIs) is one of the obstructive substances in recycling fly ash as building materials. As a result, we have to understand the behavior of chlorides in recycling process, such as washing. In this study, we used X-ray absorption near edge structure (XANES) and X-ray diffraction (XRD) to study the chloride behavior in washed residue of raw fly ash (RFA). We found that a combination of XRD and XANES, which is to use XRD to identify the situation of some compounds first and then process XANES data, was an effective way to explain the chlorides behavior in washing process. Approximately 15% of the chlorine in RFA was in the form of NaCl, 10% was in the form of KCl, 51% was CaCl(2), and the remainder was in the form of Friedel's salt. In washing experiments not only the mole percentage but also the amount of soluble chlorides including NaCl, KCl and CaCl(2) decreases quickly with the increase of liquid to solid (L/S) ratio or washing frequency. However, those of insoluble chlorides decrease slower. Moreover, Friedel's salt and its related compound (11CaO.7Al(2)O(3).CaCl(2)) were reliable standards for the insoluble chlorides in RFA, which are strongly related to CaCl(2). Washing of RFA promoted the release of insoluble chlorides, most of which were in the form of CaCl(2). PMID- 20171783 TI - Pituitary volume and third ventricle width in euthymic patients with bipolar disorder. AB - BACKGROUND: Many of the clinical and neuroendocrine features of bipolar disorder involve hypothalamic structures. Although current neuroimaging techniques inadequately resolve the structural components of the hypothalamus, evidence of derangement can be sought by examining the adjacent third ventricle and the functionally related pituitary. AIMS: To investigate the structure and function of the hypothalamic-pituitary-adrenal axis in euthymic patients with bipolar disorder. METHOD: Euthymic adult patients with bipolar disorder (n=49) were compared with matched normal control subjects (n=47). Pituitary volume and third ventricle width were assessed on MRI scans. Basal salivary cortisol levels were measured. RESULTS: The width of the third ventricle in patients with bipolar disorder exceeded that of controls (mean +/- SD (in mm): 3.87 +/- 1.96 versus 2.56 +/- 1.34; d=0.76, ANOVA F=12.7, p=0.001), with the greatest differences found in males. Third ventricle width increased with age across the groups (F=16.97, p<0.001). Pituitary volumes did not differ between patients and controls (mean +/- SD (in mm(3)): 632 +/- 176 versus 679 +/- 159). Overall, females had larger pituitaries than males (703 +/- 160 versus 595 +/- 161; d=0.67, F=9.65, p=0.003; all subjects), but female patients had smaller pituitaries compared to female controls (637 +/- 178 versus 756 +/- 126; d=0.65, F=5.04, p=0.03). No difference was found in a comparable analysis of males. Pituitary volume did not differ between patients prescribed and not prescribed antipsychotic drugs. Basal salivary cortisol levels did not differ between patients and controls. CONCLUSIONS: In euthymic patients with normal basal cortisol levels, pituitary volume and third ventricle width were found to differ from normal controls. These differences were related to gender, may be important in the pathogenesis of bipolar disorder and could link the vegetative and endocrine abnormalities seen in this condition. Such findings may reflect a trait abnormality or be a consequence of previous episodes. PMID- 20171784 TI - Piloting the effective therapeutic dose of adjunctive selective estrogen receptor modulator treatment in postmenopausal women with schizophrenia. AB - Estrogen treatment may enhance the recovery of schizophrenia in women. However, adverse effects on uterine and breast tissue and other physical side effects may limit the long-term therapeutic use of estrogen. Raloxifene hydrochloride is a selective estrogen receptor modulator that acts as an estrogen antagonist in breast tissue and may have agonistic actions in the brain, potentially offering mental health benefits with few estrogenic side effects. To provide an indication of the potential therapeutic dose for raloxifene hydrochloride in postmenopausal women with schizophrenia, this study pools data from an ongoing randomized controlled trial of adjunctive 120 mg/day oral raloxifene hydrochloride (n=13) versus oral placebo (n=13), with data from a previous pilot study administering 60 mg/day raloxifene hydrochloride (n=9). Analysis of variance found significant interaction effects for total (p=.01) and general (p=.02) Positive and Negative Syndrome Scale (PANSS) symptomatology. Participants randomized to receive 120 mg/day raloxifene hydrochloride experienced a significantly more rapid recovery of total and general psychotic symptoms compared to both 60 mg/day raloxifene hydrochloride and placebo. The demonstrated benefit of adjunctive treatment with 120 mg/day raloxifene hydrochloride offers support for the potential role of this selective estrogen receptor modulator in treating postmenopausal women with schizophrenia. PMID- 20171786 TI - Negative affect as a mediator of the relationship between vigorous-intensity exercise and smoking. AB - The present cross-sectional study evaluated whether people who engage in vigorous intensity exercise are better able to regulate negative affective states, thereby changing core maintenance factors of smoking. Participants were a community sample of adults (n = 270) who completed self-report measures of physical activity, cigarette smoking, anxiety sensitivity, and negative affect. Consistent with hypothesis, vigorous-intensity exercise was related to lower levels of cigarette smoking, accounting for 10% of the variance in smoking. Additionally, negative affect mediated the relationship between vigorous-intensity physical activity and cigarette smoking, accounting for about 12% of this relation. Furthermore, these relationships were stronger for individuals with high anxiety sensitivity than for those with low anxiety sensitivity; including anxiety sensitivity as a moderator of the mediated relationship increased the amount of variance accounted for by negative affect to 17%. The findings are discussed in relation to developing further scientific insight into the mechanisms and pathways relevant to understanding the association among vigorous-intensity exercise, smoking, and emotional vulnerability. PMID- 20171785 TI - Abnormal response to stress and impaired NPS-induced hyperlocomotion, anxiolytic effect and corticosterone increase in mice lacking NPSR1. AB - NPSR1 is a G protein coupled receptor expressed in multiple brain regions involved in modulation of stress. Central administration of NPS, the putative endogenous ligand of NPSR1, can induce hyperlocomotion, anxiolytic effects and activation of the HPA axis. The role of NPSR1 in the brain remains unsettled. Here we used NPSR1 gene-targeted mice to define the functional role of NPSR1 under basal conditions on locomotion, anxiety- and/or depression-like behavior, corticosterone levels, acoustic startle with prepulse inhibition, learning and memory, and under NPS-induced locomotor activation, anxiolysis, and corticosterone release. Male, but not female, NPSR1-deficient mice exhibited enhanced depression-like behavior in a forced swim test, reduced acoustic startle response, and minor changes in the Morris water maze. Neither male nor female NPSR1-deficient mice showed alterations of baseline locomotion, anxiety-like behavior, or corticosterone release after exposure to a forced swim test or methamphetamine challenge in an open-field. After intracerebroventricular (ICV) administration of NPS, NPSR1-deficient mice failed to show normal NPS-induced increases in locomotion, anxiolysis, or corticosterone release compared with WT NPS-treated mice. These findings demonstrate that NPSR1 is essential in mediating NPS effects on behavior. PMID- 20171787 TI - Mona Lisa's smile: a hypothesis based on a new principle of art neuroscience. AB - The smile on Mona Lisa's face remains enigmatous and a topic of much discussion in art circle over the centuries. In this essay the author proposes a new principle of art neuroscience or the science of aesthetics namely 'dynamism' which artists often employ to impart an illusion of movement in their art works which are essentially static. This illusion is possibly generated through imaginative thinking which involves frontal cortical activation in the viewer's brain coupled with activation of the motion area (area V5/MT) of the viewer's visual cortex. It is suggested that this principle of dynamism is somewhat different from the previously described concept of kinetic art. The author hypothesizes that the great painter Leonardo da Vinci very intelligently painted the angles of the mouth of Mona Lisa's face to evoke this illusion of movement (smile) to increase the aesthetic value of this great work of art. PMID- 20171788 TI - Evolutionary support for the hypothesis about uric acid as a neurotransmitter. PMID- 20171789 TI - There's something about passive movement... AB - The recognised (funded) stand-alone clinical status for therapeutic methods of passive movement has become increasingly threatened in recent times as the preference for active treatment (specific exercise) gains hold. This is in part due to the equivocal results for clinical trials of passive movement, queries regarding its cost-benefit and negative findings for many of the fundamental claims and recommendations of its clinical process. Linked to these issues has been the profession's difficulty in demonstrating plausible science-based mechanisms for anything more than transient effects. The present proposal is that the manual application of graduated oscillatory tensile loading to healing (or unhealed) soft tissues in the form of passive movement could facilitate optimal repair and tissue integrity (and so protection against subsequent 'stress'). The mechanism depends on the intrinsic ability for non-excitable connective tissue cells to 'sense' mechanical stimuli and to transduce mechanical into chemical signals. This leads to gene transcription and subsequent adaptive remodelling of the extracellular matrix (ECM). An outline of these events is given, emphasising their dependence on the effective interplay between internally (cellular) and externally (matrix) generated mechanical forces. In principle, it ought to be possible to investigate the proposal and other clinical passive movement issues using modern soft tissue imaging and biological techniques with suitable human subjects and animal models. PMID- 20171790 TI - Treatment-induced stress syndromes. AB - Placebo controlled trials in disease states as currently constituted are designed to show a drug "works" when in fact it may not. Efficacy of this type may be constructed in trials that demonstrate some marginal superiority of a drug over placebo in disease states that do not take into account any potentialities of the drugs being tested to cause dependence and consequent deleterious effects on withdrawal. This paper reviews the history of the concept of physical dependence. While outlined in terms of the psychotropic drugs, it will be clear that such has been the neglect of this feature of drug actions that it must, until proven otherwise, be assumed to apply to all drugs. Filling the gap in our knowledge would require studies of new compounds in healthy volunteers. In the absence of such studies, any clinical information on therapeutic agents should point to the lack of information on this matter. PMID- 20171791 TI - A proposal to rename and classify aplastic anemia as Myeloaplastic syndrome (MAS) Type I and II. PMID- 20171792 TI - Possible testable correlations between passive smoking and bipolar/cyclothymic disorder, depression and ADD/ADHD. PMID- 20171793 TI - Swine flu vaccine adjuvants and multiple sclerosis - Is there potential for harmful effect? AB - Vaccines are generally considered a simple compound and clinicians are sometimes unaware of the possible dangers related to the new adjuvanted vaccine approach. Due to their cost effectiveness and in order to obtain stronger response with a lower antigen dose, adjuvanted vaccines are preferred during pandemics. Adjuvants are strong immunostimulants and may be harmful in some special patient groups, such as in multiple sclerosis. There is a significant need for the effort among clinicians to heighten the awareness of the potential harms. In patient groups like multiple sclerosis, it is very important to advise vaccination with non adjuvanted vaccines. Pure vaccine (without adjuvant) must be obtained for these groups. PMID- 20171794 TI - Hypofractionated whole-brain radiotherapy for multiple brain metastases from transitional cell carcinoma of the bladder. AB - PURPOSE: Brain metastases in bladder cancer patients are extremely rare. Most patients with multiple lesions receive longer-course whole-brain radiotherapy (WBRT) with 10 * 3 Gy/2 weeks or 20 * 2 Gy/4 weeks. Because its radiosensitivity is relatively low, metastases from bladder cancer may be treated better with hypofractionated radiotherapy. This study compared short-course hypofractionated WBRT (5 * 4 Gy/1 week) to longer-course WBRT. METHODS AND MATERIALS: Data for 33 patients receiving WBRT alone for multiple brain metastases from transitional cell bladder carcinoma were retrospectively analyzed. Short-course WBRT with 5 * 4 Gy (n = 12 patients) was compared to longer-course WBRT with 10 * 3 Gy/20 * 2 Gy (n = 21 patients) for overall survival (OS) and local (intracerebral) control (LC). Five additional potential prognostic factors were investigated: age, gender, Karnofsky performance score (KPS), number of brain metastases, and extracranial metastases. The Bonferroni correction for multiple tests was used to adjust the p values derived from the multivariate analysis. p values of <0.025 were considered significant. RESULTS: At 6 months, OS was 42% after 5 * 4 Gy and 24% after 10 * 3/20 * 2 Gy (p = 0.31). On univariate analysis, improved OS was associated with less than four brain metastases (p = 0.021) and almost associated with a lack of extracranial metastases (p = 0.057). On multivariate analysis, both factors were not significant. At 6 months, LC was 83% after 5 * 4 Gy and 27% after 10 * 3/20 * 2 Gy (p = 0.035). Improved LC was almost associated with a KPS of >=70 (p = 0.051). On multivariate analysis, WBRT regimen was almost significant (p = 0.036). KPS showed a trend (p = 0.07). CONCLUSIONS: Short-course WBRT with 5 * 4 Gy should be seriously considered for most patients with multiple brain metastases from bladder cancer, as it resulted in improved LC. PMID- 20171795 TI - Is regional lymph node irradiation necessary in stage II to III breast cancer patients with negative pathologic node status after neoadjuvant chemotherapy? AB - PURPOSE: Neoadjuvant chemotherapy (NAC) generally induces significant changes in the pathologic extent of disease. This potential down-staging challenges the standard indications of adjuvant radiation therapy. We assessed the utility of lymph node irradiation (LNI) in breast cancer (BC) patients with pathologic N0 status (pN0) after NAC and breast-conserving surgery (BCS). METHODS AND MATERIALS: Among 1,054 BC patients treated with NAC in our institution between 1990 and 2004, 248 patients with clinical N0 or N1 to N2 lymph node status at diagnosis had pN0 status after NAC and BCS. Cox regression analysis was used to identify factors influencing locoregional recurrence-free survival (LRR-FS), disease-free survival (DFS), and overall survival (OS). RESULTS: All 248 patients underwent breast irradiation, and 158 patients (63.7%) also received LNI. With a median follow-up of 88 months, the 5-year LRR-FS and OS rates were respectively 89.4% and 88.7% with LNI and 86.2% and 92% without LNI (no significant difference). Survival was poorer among patients who did not have a pathologic complete primary tumor response (hazard ratio, 3.05; 95% confidence interval, 1.17-7.99) and in patients with N1 to N2 clinical status at diagnosis (hazard ratio = 2.24; 95% confidence interval, 1.15-4.36). LNI did not significantly affect survival. CONCLUSIONS: Relative to combined breast and local lymph node irradiation, isolated breast irradiation does not appear to be associated with a higher risk of locoregional relapse or death among cN0 to cN2 breast cancer patients with pN0 status after NAC. These results need to be confirmed in a prospective study. PMID- 20171796 TI - Stereotactic, single-dose irradiation of lung tumors: a comparison of absolute dose and dose distribution between pencil beam and Monte Carlo algorithms based on actual patient CT scans. AB - PURPOSE: Dose calculation based on pencil beam (PB) algorithms has its shortcomings predicting dose in tissue heterogeneities. The aim of this study was to compare dose distributions of clinically applied non-intensity-modulated radiotherapy 15-MV plans for stereotactic body radiotherapy between voxel Monte Carlo (XVMC) calculation and PB calculation for lung lesions. METHODS AND MATERIALS: To validate XVMC, one treatment plan was verified in an inhomogeneous thorax phantom with EDR2 film (Eastman Kodak, Rochester, NY). Both measured and calculated (PB and XVMC) dose distributions were compared regarding profiles and isodoses. Then, 35 lung plans originally created for clinical treatment by PB calculation with the Eclipse planning system (Varian Medical Systems, Palo Alto, CA) were recalculated by XVMC (investigational implementation in PrecisePLAN [Elekta AB, Stockholm, Sweden]). Clinically relevant dose-volume parameters for target and lung tissue were compared and analyzed statistically. RESULTS: The XVMC calculation agreed well with film measurements (<1% difference in lateral profile), whereas the deviation between PB calculation and film measurements was up to +15%. On analysis of 35 clinical cases, the mean dose, minimal dose and coverage dose value for 95% volume of gross tumor volume were 1.14 +/- 1.72 Gy, 1.68 +/- 1.47 Gy, and 1.24 +/- 1.04 Gy lower by XVMC compared with PB, respectively (prescription dose, 30 Gy). The volume covered by the 9 Gy isodose of lung was 2.73% +/- 3.12% higher when calculated by XVMC compared with PB. The largest differences were observed for small lesions circumferentially encompassed by lung tissue. CONCLUSIONS: Pencil beam dose calculation overestimates dose to the tumor and underestimates lung volumes exposed to a given dose consistently for 15-MV photons. The degree of difference between XVMC and PB is tumor size and location dependent. Therefore XVMC calculation is helpful to further optimize treatment planning. PMID- 20171797 TI - ATM polymorphisms are associated with risk of radiation-induced pneumonitis. AB - PURPOSE: Since the ataxia telangiectasia mutated (ATM) protein plays crucial roles in repair of double-stranded DNA breaks, control of cell cycle checkpoints, and radiosensitivity, we hypothesized that variations in this gene might be associated with radiation-induced pneumonitis (RP). METHODS AND MATERIALS: A total of 253 lung cancer patients receiving thoracic irradiation between 2004 and 2006 were included in this study. Common Terminology Criteria for Adverse Events version 3.0 was used to grade RP. Five haplotype-tagging single nucleotide polymorphisms (SNPs) in the ATM gene were genotyped using DNA from blood lymphocytes. Hazard ratios (HRs) and 95% confidence intervals (CIs) of RP for genotypes were computed by the Cox model, adjusted for clinical factors. The function of the ATM SNP associated with RP was examined by biochemical assays. RESULTS: During the median 22-month follow-up, 44 (17.4%) patients developed grade > or = 2 RP. In multivariate Cox regression models adjusted for other clinical predictors, we found two ATM variants were independently associated with increased RP risk. They were an 111G > A) polymorphism (HR, 2.49; 95% CI, 1.07 5.80) and an ATM 126713G > A polymorphism (HR, 2.47; 95% CI, 1.16-5.28). Furthermore, genotype-dependent differences in ATM expression were demonstrated both in cell lines (p < 0.001) and in individual lung tissue samples (p = 0.003), which supported the results of the association study. CONCLUSIONS: Genetic polymorphisms of ATM are significantly associated with RP risk. These variants might exert their effect through regulation of ATM expression and serve as independent biomarkers for prediction of RP in patients treated with thoracic radiotherapy. PMID- 20171798 TI - The association between biological subtype and isolated regional nodal failure after breast-conserving therapy. AB - PURPOSE: To evaluate the risk of isolated regional nodal failure (RNF) among women with invasive breast cancer treated with breast-conserving surgery (BCS) and radiation therapy (RT) and to determine factors, including biological subtype, associated with RNF. METHODS AND MATERIALS: We retrospectively studied 1,000 consecutive women with invasive breast cancer who received breast conserving surgery and RT from 1997 through 2002. Ninety percent of patients received adjuvant systemic therapy; none received trastuzumab. Sentinel lymph node biopsy was done in 617 patients (62%). Of patients with one to three positive nodes, 34% received regional nodal irradiation (RNI). Biological subtype classification into luminal A, luminal B, HER-2, and basal subtypes was based on estrogen receptor status-, progesterone receptor status-, and HER-2-status of the primary tumor. RESULTS: Median follow-up was 77 months. Isolated RNF occurred in 6 patients (0.6%). On univariate analysis, biological subtype (p = 0.0002), lymph node involvement (p = 0.008), lymphovascular invasion (p = 0.02), and Grade 3 histology (p = 0.01) were associated with significantly higher RNF rates. Compared with luminal A, the HER-2 (p = 0.01) and basal (p = 0.08) subtypes were associated with higher RNF rates. The 5-year RNF rate among patients with one to three positive nodes treated with tangents alone was 2.4%; we could not identify a subset of these patients with a substantial risk of RNF. CONCLUSIONS: Isolated RNF is a rare occurrence after breast-conserving therapy. Patients with the HER-2 (not treated with trastuzumab) and basal subtypes appear to be at higher risk of developing RNF although this risk is not high enough to justify the addition of RNI. Low rates of RNF in patients with one to three positive nodes suggest that tangential RT without RNI is reasonable in most patients. PMID- 20171799 TI - Does lymphovascular invasion predict regional nodal failure in breast cancer patients with zero to three positive lymph nodes treated with conserving surgery and radiotherapy? Implications for regional radiation. AB - PURPOSE: To examine the relationship between lymphovascular invasion (LVI) and regional nodal failure (RNF) in breast cancer patients with zero to three positive nodes treated with breast-conservation therapy (BCT). METHODS AND MATERIALS: The records of 1,257 breast cancer patients with zero to three positive lymph nodes were reviewed. All patients were treated with BCT at Massachusetts General Hospital from 1980 to December 2003. Lymphovascular invasion was diagnosed by hematoxylin and eosin-stained sections and in some cases supported by immunohistochemical stains. Regional nodal failure was defined as recurrence in the ipsilateral supraclavicular, axillary, or internal mammary lymph nodes. Regional nodal failure was diagnosed by clinical and/or radiologic examination. RESULTS: The median follow-up was 8 years (range, 0.1-21 years). Lymphovascular invasion was present in 211 patients (17%). In univariate analysis, patients with LVI had a higher rate of RNF (3.32% vs. 1.15%; p = 0.02). In multivariate analysis, only tumor size, grade, and local failure were significant predictors of RNF (p = 0.049, 0.013, and 0.0001, respectively), whereas LVI did not show a significant relationship with RNF (hazard ratio = 2.07; 95% CI, 0.8-5.5; p = 0.143). The presence of LVI in the T2/3 population did not increase the risk of RNF over that for those with no LVI (p = 0.15). In addition, patients with Grade 3 tumors and positive LVI did not have a higher risk of RNF than those without LVI (p = 0.96). CONCLUSION: These results suggest that LVI can not be used as a sole indicator for regional nodal irradiation in breast cancer patients with zero to three positive lymph nodes treated with BCT. PMID- 20171800 TI - Evaluation of the effectiveness of the stereotactic body frame in reducing respiratory intrafractional organ motion using the real-time tumor-tracking radiotherapy system. AB - PURPOSE: To evaluate the effectiveness of the stereotactic body frame (SBF), with or without a diaphragm press or a breathing cycle monitoring device (Abches), in controlling the range of lung tumor motion, by tracking the real-time position of fiducial markers. METHODS AND MATERIALS: The trajectories of gold markers in the lung were tracked with the real-time tumor-tracking radiotherapy system. The SBF was used for patient immobilization and the diaphragm press and Abches were used to actively control breathing and for self-controlled respiration, respectively. Tracking was performed in five setups, with and without immobilization and respiration control. The results were evaluated using the effective range, which was defined as the range that includes 95% of all the recorded marker positions in each setup. RESULTS: The SBF, with or without a diaphragm press or Abches, did not yield effective ranges of marker motion which were significantly different from setups that did not use these materials. The differences in the effective marker ranges in the upper lobes for all the patient setups were less than 1mm. Larger effective ranges were obtained for the markers in the middle or lower lobes. CONCLUSION: The effectiveness of controlling respiratory-induced organ motion by using the SBF+diaphragm press or SBF + Abches patient setups were highly dependent on the individual patient reaction to the use of these materials and the location of the markers. They may be considered for lung tumors in the lower lobes, but are not necessary for tumors in the upper lobes. PMID- 20171801 TI - Predictive factors of late radiation fibrosis: a prospective study in non-small cell lung cancer. AB - PURPOSE: To determine predictive factors of late radiation fibrosis (RF) after conformal radiotherapy (3D-RT) in non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Ninety-six patients with Stage IA-IIIB NSCLC were included in a prospective trial. Clinical evaluation, chest X-ray, and pulmonary functional tests including diffusion parameters were performed before and 6 months after radiotherapy. An independent panel of experts prospectively analyzed RF, using Late Effects in Normal Tissues-Subjective, Objective, Management and Analytic scales classification. Logistic regression analysis was performed to identify relationships between clinical, functional, or treatment parameters and incidence of RF. Variations of circulating serum levels of pro-inflammatory (interleukin-6, tumor necrosis factor alpha, tumor growth factor beta1) and anti-inflammatory (interleukin-10) cytokines during 3D-RT were examined to identify correlations with RF. RESULTS: Of the 96 patients included, 72 were evaluable for RF at 6 months. Thirty-seven (51.4%) developed RF (Grade >or=1), including six severe RF (Grades 2-3; 8.3%). In univariate analysis, only poor Karnofsky Performance Status and previous acute radiation pneumonitis were associated with RF (p < 0.05). Dosimetric factors (mean lung dose, percentage of lung volume receiving more than 10, 20, 30, 40, and 50 Gy) were highly correlated with RF (p < 0.001). In multivariate analysis, previous acute radiation pneumonitis and dosimetric parameters were significantly correlated with RF occurrence. It was not significantly correlated either with cytokines at baseline or with their variation during 3D-RT. CONCLUSIONS: This study confirms the importance of dosimetric parameters to limit the risk of RF. Contrary to acute radiation pneumonitis, RF was not correlated to cytokine variations during 3D-RT. PMID- 20171802 TI - Prospective imaging assessment of mortality risk after head-and-neck radiotherapy. AB - PURPOSE: The optimal roles for imaging-based biomarkers in the management of head and-neck cancer remain undefined. Unresolved questions include whether functional or anatomic imaging might improve mortality risk assessment for this disease. We addressed these issues in a prospective institutional trial. METHODS AND MATERIALS: Ninety-eight patients with locally advanced pharyngolaryngeal squamous cell cancer were enrolled. Each underwent pre- and post-chemoradiotherapy contrast-enhanced computed tomography (CT) and (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT imaging. Imaging parameters were correlated with survival outcomes. RESULTS: Low post-radiation primary tumor FDG avidity correlated with improved survival on multivariate analysis; so too did complete primary tumor response by CT alone. Although both imaging modalities lacked sensitivity, each had high specificity and negative predictive value for disease specific mortality risk assessment. Kaplan-Meier estimates confirmed that both CT and FDG-PET/CT stratify patients into distinct high- and low-probability survivorship groups on the basis of primary tumor response to radiotherapy. Subset analyses demonstrated that the prognostic value for each imaging modality was primarily derived from patients at high risk for local treatment failure (human papillomavirus [HPV]-negative disease, nonoropharyngeal primary disease, or tobacco use). CONCLUSIONS: CT alone and FDG-PET/CT are potentially useful tools in head-and-neck cancer-specific mortality risk assessment after radiotherapy, particularly for selective use in cases of high-risk HPV-unrelated disease. Focus should be placed on corroboration and refinement of patient selection for imaging-based biomarkers in future studies. PMID- 20171803 TI - Stereotactic body radiotherapy and gemcitabine for locally advanced pancreatic cancer. AB - PURPOSE: Patients with nonmetastatic locally advanced unresectable pancreatic cancer have a dismal prognosis. Conventional concurrent chemoradiotherapy requires 6 weeks of daily treatment and can be arduous. We explored the safety and effectiveness of a 3-day course of hypofractionated stereotactic body radiotherapy (SBRT) followed by gemcitabine in this population. PATIENTS AND METHODS: A total of 36 patients with nonmetastatic, locally advanced, unresectable pancreatic cancer with >=12 months of follow-up were included. They received three fractions of 8, 10, or 12 Gy (total dose, 24-36 Gy) of SBRT according to the tumor location in relation to the stomach and duodenum, using fiducial-based respiratory motion tracking on a robotic radiosurgery system. The patients were then offered gemcitabine for 6 months or until tolerance or disease progression. RESULTS: With an overall median follow-up of 24 months (range, 12 33), the local control rate was 78%, the median overall survival time was 14.3 months, the median carbohydrate antigen 19-9-determined progression-free survival time was 7.9 months, and the median computed tomography-determined progression free survival time was 9.6 months. Of the 36 patients, 28 (78%) eventually developed distant metastases. Six patients (17%) were free of progression at the last follow-up visit (range, 13-30 months) as determined by normalized tumor markers with stable computed tomography findings. Nine Grade 2 (25%) and five Grade 3 (14%) toxicities attributable to SBRT occurred. CONCLUSION: Hypofractionated SBRT can be delivered quickly and effectively in patients with nonmetastatic, locally advanced, unresectable pancreatic cancer with acceptable side effects and minimal interference with gemcitabine chemotherapy. PMID- 20171804 TI - Alternative dose for choroidal melanoma treated with an iodine-125 radioactive plaque: a single-institution retrospective study. AB - PURPOSE: The Collaborative Ocular Melanoma Study (COMS) established iodine-125 plaque brachytherapy as an accepted standard treatment for medium-size choroidal melanoma. In the COMS, the prescription dose was 85 Gy. This is a retrospective review of our outcomes in patients treated with lower doses than those used in the COMS. METHODS AND MATERIALS: From 1990 to 2004, 62 patients were treated with iodine-125 plaque brachytherapy for choroidal melanoma. COMS eye plaques were used with dose prescribed to the apex of the tumor. The median and average dose rates at the tumor apex were 63.5 cGy/h and 62.7 cGy/h, respectively. The median and average total doses were 63.0 Gy and 62.5 Gy (range, 56-69 Gy), respectively. The median and mean durations of implant were 100.0 hours and 101.1 hours (range, 71-165 hours). RESULTS: Median follow-up time was 58.2 months. The 5-year outcomes including overall survival, disease-free survival, cause-specific survival, local failure, secondary enucleation rate, and visual acuity (VA) <20/200 were estimated using the Kaplan-Meier method. Overall, there were 7 local failures, 4 distant failures, and 10 secondary enucleations (6 due to local failure and 4 due to treatment complications). Univariate analysis was performed to identify significant prognostic factors associated with disease-free survival (baseline VA in tumor eye, tumor shape), cause-specific survival (diabetic retinopathy), local failure (none found), secondary enucleation rate (diabetic retinopathy, basal tumor dimension) and VA <20/200 (diabetic retinopathy, tumor shape, age, retinal detachment, treatment depth, and history of vision-limiting condition). CONCLUSIONS: Our survival and local control outcomes are comparable to those of the COMS. However, VA at 5 years seems to be better. Lower doses of radiation could potentially lead to better visual outcomes. PMID- 20171805 TI - PSA decrease during combined-modality radiotherapy predicts for treatment outcome. AB - PURPOSE: Prostate-specific antigen (PSA) is the well-used marker in the diagnosis, prognosis, and follow-up for prostate cancer patients. Although reports have focused on the importance of pretreatment PSA levels, doubling time, and posttreatment nadirs, there is little information on the value of PSA during the course of radiotherapy. METHODS AND MATERIALS: Retrospective review of PSA values obtained midway through a course of radiotherapy treatment for prostate cancer. Patients had a PSA (midPSA) measured after a course of external beam radiation (EBRT) before planned transperineal low-dose-rate brachytherapy implant (LDR). RESULTS: A total of 717 patients were analyzed with a median follow-up of 5.8 years, all censored patients had a minimum follow-up of 2 years. A total of 277 patients had low-risk disease, 267 patients had intermediate risk, and 173 patients had high-risk disease. Androgen blockade was used in 512 patients. A total of 653 patients had a midPSA decrease after EBRT, the median decrease was 6.2 ng/mL. Patients who had a midPSA decrease >=25% compared with pretreatment PSA had improved overall survival of 10.0 vs. 7.4 years (p < 0.0004) and improved disease-free survival of 9.8 vs. 7.3 years (p < 0.01). When stratified by use of androgen blockade, midPSA remained significant for both androgen and non-androgen patients. CONCLUSIONS: PSA response after EBRT before brachytherapy predicts for long-term outcome; this may allow for risk stratification and intervention with higher LDR doses to improve outcomes. PMID- 20171806 TI - Absence of symptom and intact liver function are positive prognosticators for patients undergoing radiotherapy for lymph node metastasis from hepatocellular carcinoma. AB - PURPOSE: The positive role of radiotherapy for patients with lymph node (LN) metastasis from hepatocellular carcinoma has recently been reported. The outcome and prognostic factors for these patients were analyzed. METHODS AND MATERIALS: Between May 2004 and October 2007, 38 patients with LN metastases from hepatocellular carcinoma underwent radiotherapy. The median age was 59 years (range, 42-81). The radiation dose was 35-56 Gy with a fraction size of 1.8-3 Gy, for a biologically effective dose of 43.75-67.2 Gy(10) (median, 59.0). The median follow-up period was 8 months. RESULTS: The median survival time was 10 months. On univariate analysis, Child-Pugh class B (p = .0006), distant metastasis (p = .0095), symptoms related to metastatic LNs (p <.0001), and a biologically effective dose <60 Gy(10) (p = .0042) were significant prognostic factors predicting for poor overall survival. On multivariate analysis after adjustment using the Benjamini and Hochberg (false discovery rate) method, Child-Pugh class B (p = .04095) and the presence of symptoms (p = .04095) were associated with inferior overall survival. When patients were divided into three groups according to these two risk factors, the median survival for patients with no, either, or both risk factors was 20, 7, and 4 months, respectively (p <.0001). CONCLUSION: Patients with intact liver function and without related symptoms had the best prognosis when undergoing radiotherapy for LN metastasis from hepatocellular carcinoma. PMID- 20171807 TI - Clinical toxicities and dosimetric parameters after whole-pelvis versus prostate only intensity-modulated radiation therapy for prostate cancer. AB - PURPOSE: To assess whether whole-pelvis (WP) intensity-modulated radiation therapy (IMRT) is associated with increased toxicity compared with prostate-only (PO) IMRT. METHODS AND MATERIALS: We retrospectively analyzed all patients with prostate cancer undergoing definitive IMRT to 79.2 Gy with concurrent androgen deprivation at our institution from November 2005 to May 2007 with a minimum follow-up of 12 months. Thirty patients received initial WP IMRT to 45 Gy in 1.8 Gy fractions, and thirty patients received PO IMRT. Study patients underwent computed tomography simulation and treatment planning by use of predefined dose constraints. Bladder and rectal dose-volume histograms, maximum genitourinary (GU) and gastrointestinal (GI) Radiation Therapy Oncology Group toxicity grade, and late Grade 2 or greater toxicity-free survival curves were compared between the two groups by use of the Student t test, Fisher exact test, and Kaplan-Meier curve, respectively. RESULTS: Bladder minimum dose, mean dose, median dose, volume receiving 5 Gy, volume receiving 20 Gy, volume receiving 40 Gy, and volume receiving 45 Gy and rectal minimum dose, median dose, and volume receiving 20 Gy were significantly increased in the WP group (all p values < 0.01). Maximum acute GI toxicity was limited to Grade 2 and was significantly increased in the WP group at 50% vs. 13% the PO group (p = 0.006). With a median follow-up of 24 months (range, 12-35 months), there was no difference in late GI toxicity (p = 0.884) or in acute or late GU toxicity. CONCLUSIONS: Despite dosimetric differences in the volume of bowel, bladder, and rectum irradiated in the low dose and median-dose regions, WP IMRT results only in a clinically significant increase in acute GI toxicity, in comparison to PO IMRT, with no difference in GU or late GI toxicity. PMID- 20171808 TI - Comparison between high and low source activity seeds for I-125 permanent seed prostate brachytherapy. AB - PURPOSE: To compare low (mean 0.44, SD +/- 0.0163 mCi) with high source activity (0.61 +/- 0.0178 mCi) in I(125) permanent seed brachytherapy regarding seed loss, dosimetric outcome, and toxicity. METHODS AND MATERIALS: The study included 199 patients with prostate cancer treated by permanent seed brachytherapy alone: the first 105 with seeds of lower activity (first cohort), the following 94 with higher seed activity (second cohort). The V100, V150, V200, and D90 were analyzed on the CT scan 30 days after implantation (CTD30). The V100, V150, and D2 of the rectum were also calculated on CTD30. Seed loss was determined 30 days after implantation. Urinary toxicity was measured with the International Prostate Symptom Score (IPSS) questionnaire. RESULTS: Lower seed activity was associated with lower V150 and V200 (p = 0.01 and p <= 0.001, respectively) on CTD30. More patients had a V100 <90% and D90 <140 Gy in the lower activity cohort (p = 0.098 for D90 and p = 0.029 for V100) on CTD30. There was no difference between cohorts in dose to the rectum (p = 0.325-0.516) or difference in patients' IPSS score from baseline (p = 0.0.117-0.618), although there was a trend toward more urinary toxicity at 4 and 8 months for high activity seeds. Seed loss as a percentage of implanted seeds was not different (p = 0.324). CONCLUSIONS: Higher seed activity (I(125) >= 0.6 mCi) results in at least equal V100 and D90 on CTD30. However, dose inhomogeneity and a trend toward more urinary toxicity at 4 and 8 months after treatment may lead to a higher long-term urinary complications. PMID- 20171809 TI - Optimization of collimator trajectory in volumetric modulated arc therapy: development and evaluation for paraspinal SBRT. AB - PURPOSE: To develop a collimator trajectory optimization paradigm for volumetric modulated arc therapy (VMAT) and evaluate this technique in paraspinal stereotactic body radiation therapy (SBRT). METHOD AND MATERIALS: We propose a novel VMAT paradigm, Coll-VMAT, which integrates collimator rotation with synchronized gantry rotation, multileaf collimator (MLC) motion, and dose-rate modulation. At each gantry angle a principal component analysis (PCA) is applied to calculate the primary cord orientation. The collimator angle is then aligned so that MLC travel is parallel to the PCA-derived direction. An in-house VMAT optimization follows the geometry-based collimator trajectory optimization to obtain the optimal MLC position and monitor units (MU) at each gantry angle. A treatment planning study of five paraspinal SBRT patients compared Coll-VMAT to standard VMAT (fixed collimator angle) and static field IMRT plans. Plan evaluation statistics included planning target volume (PTV) V95%, PTV-D95%, cord D05%, and total beam-on time. RESULTS: Variation of collimator angle in Coll-VMAT plans ranges from 26 degrees to 54 degrees , with a median of 40 degrees . Patient-averaged PTV V95% (94.6% Coll-VMAT vs. 92.1% VMAT and 93.3% IMRT) and D95% (22.5 Gy vs. 21.4 Gy and 22.0 Gy, respectively) are highest with Coll-VMAT, and cord D05% (9.8 Gy vs. 10.0 Gy and 11.7 Gy) is lowest. Total beam-on time with Coll-VMAT (5,164 MU) is comparable to standard VMAT (4,868 MU) and substantially lower than IMRT (13,283 MU). CONCLUSION: Collimator trajectory optimization-based VMAT provides an additional degree of freedom that can improve target coverage and cord sparing of paraspinal SBRT plans compared with standard VMAT and IMRT approaches. PMID- 20171810 TI - A simple and effective daily pain management method for patients receiving radiation therapy for painful bone metastases. AB - PURPOSE: The incidence of painful bone metastases increases with longer survival times. Although external beam radiation therapy (EBRT) is an effective palliative treatment, it often requires several days from the start of treatment to produce a measurable reduction in pain scores and a qualitative amelioration of patient pain levels. Meanwhile, the use of analgesics remains the best approach early on in the treatment course. We investigated the role of radiation therapists as key personnel for collecting daily pain scores to supplement assessments by physician and oncology nursing staff and manage pain more effectively during radiation treatment. METHODS AND MATERIALS: Daily pain scores were obtained by the radiation therapists for 89 patients undertaking a total of 124 courses of EBRT for bone metastases and compared with pretreatment pain scores. The majority of patients (71%) were treated to 30 Gy (range, 20-37.5) in 10 fractions (range, 8 15 fractions). RESULTS: One hundred nineteen treatment courses (96%) were completed. Pain scores declined rapidly to 37.5%, 50%, and 75% of the pretreatment levels by Days 2, 4, and 10, respectively. Pain was improved in 91% of patients with only 4% of worse pain at the end of treatment. Improved pain scores were maintained in 83% of patients at 1-month follow-up, but in 35% of them, the pain was worse than at the end of treatment. CONCLUSIONS: Collection of daily pain scores by radiation therapists was associated with an effective reduction in pain scores early on during EBRT of painful osseous metastases. PMID- 20171812 TI - Magnetic resonance imaging assessment of squamous cell carcinoma of the anal canal before and after chemoradiation: can MRI predict for eventual clinical outcome? AB - PURPOSE: To describe the MRI appearances of squamous cell carcinoma of the anal canal before and after chemoradiation and to assess whether MRI features predict for clinical outcome. METHODS AND MATERIALS: Thirty-five patients (15 male, 20 female; mean age 60.8 years) with histologically proven squamous cell cancer of the anal canal underwent MRI before and 6-8 weeks after definitive chemoradiation. Images were reviewed retrospectively by two radiologists in consensus blinded to clinical outcome: tumor size, signal intensity, extent, and TNM stage were recorded. Following treatment, patients were defined as responders by T and N downstaging and Response Evaluation Criteria in Solid Tumors (RECIST). Final clinical outcome was determined by imaging and case note review: patients were divided into (1) disease-free and (2) with relapse and compared using appropriate univariate methods to identify imaging predictors; statistical significance was at 5%. RESULTS: The majority of tumors were <=T2 (23/35; 65.7%) and N0 (21/35; 60%), mean size 3.75 cm, and hyperintense (++ to +++, 24/35 patients; 68%). Following chemoradiation, there was a size reduction in all cases (mean 73.3%) and a reduction in signal intensity in 26/35 patients (74.2%). The majority of patients were classified as responders (26/35 (74.2%) patients by T and N downstaging; and 30/35 (85.7%) patients by RECIST). At a median follow-up of 33.5 months, 25 patients (71.4%) remained disease-free; 10 patients (28.6%) had locoregional or metastatic disease. Univariate analysis showed that no individual MRI features were predictive of eventual outcome. CONCLUSION: Early assessment of response by MRI at 6-8 weeks is unhelpful in predicting future clinical outcome. PMID- 20171811 TI - Quantitative ultrasonic evaluation of radiation-induced late tissue toxicity: pilot study of breast cancer radiotherapy. AB - PURPOSE: To investigate the use of advanced ultrasonic imaging to quantitatively evaluate normal-tissue toxicity in breast-cancer radiation treatment. METHODS AND MATERIALS: Eighteen breast cancer patients who received radiation treatment were enrolled in an institutional review board-approved clinical study. Radiotherapy involved a radiation dose of 50.0 to 50.4 Gy delivered to the entire breast, followed by an electron boost of 10.0 to 16.0 Gy delivered to the tumor bed. Patients underwent scanning with ultrasound during follow-up, which ranged from 6 to 94 months (median, 22 months) postradiotherapy. Conventional ultrasound images and radio-frequency (RF) echo signals were acquired from treated and untreated breasts. Three ultrasound parameters, namely, skin thickness, Pearson coefficient, and spectral midband fit, were computed from RF signals to measure radiation-induced changes in dermis, hypodermis, and subcutaneous tissue, respectively. Ultrasound parameter values of the treated breast were compared with those of the untreated breast. Ultrasound findings were compared with clinical assessment using Radiation Therapy Oncology Group (RTOG) late-toxicity scores. RESULTS: Significant changes were observed in ultrasonic parameter values of the treated vs. untreated breasts. Average skin thickness increased by 27.3%, from 2.05 +/- 0.22 mm to 2.61 +/- 0.52 mm; Pearson coefficient decreased by 31.7%, from 0.41 +/- 0.07 to 0.28 +/- 0.05; and midband fit increased by 94.6%, from -0.92 +/- 7.35 dB to 0.87 +/- 6.70 dB. Ultrasound evaluations were consistent with RTOG scores. CONCLUSIONS: Quantitative ultrasound provides a noninvasive, objective means of assessing radiation-induced changes to the skin and subcutaneous tissue. This imaging tool will become increasingly valuable as we continue to improve radiation therapy technique. PMID- 20171813 TI - Sentinel lymph node biopsy for tumors of the hand and wrist. PMID- 20171814 TI - Osteoid osteoma of the trapezium: case report. AB - Osteoid osteoma is a benign bone tumor representing approximately 10% of all benign bone tumors. Although osteoid osteoma of the long bones and carpus is frequent, the location in the trapezium is extremely rare. We found only one other report in the literature regarding osteoid osteoma of the trapezium. PMID- 20171815 TI - Clinical monitoring of systemic hemodynamics in critically ill newborns. AB - Circulatory failure is a major cause of mortality and morbidity in critically ill newborn infants. Since objective measurement of systemic blood flow remains very challenging, neonatal hemodynamics is usually assessed by the interpretation of various clinical and biochemical parameters. An overview is given about the predictive value of the most used indicators of circulatory failure, which are blood pressure, heart rate, urine output, capillary refill time, serum lactate concentration, central-peripheral temperature difference, pH, standard base excess, central venous oxygen saturation and colour. PMID- 20171816 TI - Cardiac output monitoring in newborns. AB - There is an increased interest in methods of objective cardiac output measurement in critically ill patients. Several techniques are available for measurement of cardiac output in children, although this remains very complex in newborns. Cardiac output monitoring could provide essential information to guide hemodynamic management. An overview is given of various methods of cardiac output monitoring with advantages and major limitations of each technology together with a short explanation of the basic principles. PMID- 20171817 TI - The effect of whole body vibration exposure on muscle or bone morphology and function in older adults: a systematic review of the literature. AB - CONTEXT AND OBJECTIVE: The aim of this study was to examine the effect of whole body vibration (WBV), a novel exercise modality, on muscle or bone morphology and function in older adults. METHODS: A literature search of published randomised controlled trials (RCTs) was conducted using multiple databases and hand searching for study designs reporting the effects of WBV in older adults on any outcomes related to muscle function, or muscle or bone morphology. Concomitant exercise was only included if the control group performed the same exercise as the active WBV group, but without vibration. RESULTS: Six RCTs met the inclusion criteria of this review, three reporting measures of muscle only, two assessing bone measures only and one detailing measures of both bone and muscle. Study design varied greatly across the six trials and only six of 35 musculoskeletal outcomes analysed were statistically significant. All statistically significant improvements were of muscle function. CONCLUSIONS: The published literature to date provides only weak support for the efficacy of WBV exposure for muscle function, muscle morphology, or bone architecture in older adults. Irregularities in study design and WBV protocols across the literature and poor quality trials contribute to this inconsistency, revealing the need for more uniformity in future trials. Future research should be more robust in design, include larger cohorts, longer interventions and standardisation of protocols. They should also investigate the optimal dose-response relationships and variation in vibration characteristics, to determine the true efficacy, clinical relevance, and underlying mechanisms of muscle and bone adaptations. PMID- 20171818 TI - Inverted epiglottis: a postoperative complication of supracricoid laryngectomy with cricohyoidoepiglottopexy. AB - OBJECTIVES: Among the 50 laryngeal cancer patients who received SCL-CHEP between 1997 and 2008, we experienced three patients with complete epiglottis prolapse, which obstructed the neoglottis. By defining this complication as "Inverted epiglottis" and presenting the clinical features, we intend to elucidate the mechanism, risk factors, and management of this complication. METHODS: Details of the clinical features are presented. We conducted the following analyses: (1) distance from anterior commissure to the upper resected end of the surgical specimen was grossly measured. (2) Based on the analysis of sagittal cut CT images, the level of vallecula was identified and compared with the level of hyoid bone. (3) Distance between hyoid bone and cricoid arch (cricohyoid gap) after SCL-CHEP was measured using sagittal cut CT images. RESULTS: Prolonged edema of the neoglottis and delayed stomal closure were the main symptoms. In patients with the vallecula lower than the hyoid bone, excessive resection of the epiglottic petiole (anterior commissure-upper edge>25 mm) might be a risk factor. CONCLUSIONS: We reported a post-SCL-CHEP complication "Inverted epiglottis". Extensive excision of the epiglottic petiole, patients with a low vallecula profile, and incorrect suturing of epiglottic petiole during pexis are the three factors most related. Inverted epiglottis was treatable and most of the laryngeal function could be retrieved. PMID- 20171819 TI - Bone images from dual-energy subtraction chest radiography in the detection of rib fractures. AB - OBJECTIVE: To assess the sensitivity and image quality of chest radiography (CXR) with or without dual-energy subtracted (ES) bone images in the detection of rib fractures. MATERIALS AND METHODS: In this retrospective study, 39 patients with 204 rib fractures and 24 subjects with no fractures were examined with a single exposure dual-energy subtraction digital radiography system. Three blinded readers first evaluated the non-subtracted posteroanterior and lateral chest radiographs alone, and 3 months later they evaluated the non-subtracted images together with the subtracted posteroanterior bone images. The locations of rib fractures were registered with confidence levels on a 3-grade scale. Image quality was rated on a 5-point scale. Marks by readers were compared with fracture localizations in CT as a standard of reference. RESULTS: The sensivity for fracture detection using both methods was very similar (34.3% with standard CXR and 33.5% with ES-CXR, p=0.92). At the patient level, both sensitivity (71.8%) and specificity (92.9%) with or without ES were identical. Diagnostic confidence was not significantly different (2.61 with CXR and 2.75 with ES-CXR, p=0.063). Image quality with ES was rated higher than that on standard CXR (4.08 vs. 3.74, p<0.001). CONCLUSIONS: Despite a better image quality, adding ES bone images to standard radiographs of the chest does not provide better sensitivity or improved diagnostic confidence in the detection of rib fractures. PMID- 20171820 TI - Learning curve in the detection of ovarian and deep endometriosis by using Magnetic Resonance: comparison with surgical results. AB - PURPOSE: Determining if Magnetic Resonance Imaging (MRI) accuracy in diagnosing endometriosis is related to radiologist's expertise. METHODS AND MATERIALS: Written informed consent was obtained from all patients. This study is compliant to STARD method. Thirty patients (mean age 34; range 21-45 years) who had undergone MRI study for suspected endometriosis underwent surgery were retrospectively evaluated. MRI at 1.5T was performed with SE and TSE sequences, T1 and T2-weighted with and without fat suppression. Four localizations were analyzed: ovary, uterosacral ligaments (USL), vaginal fornix and Rectum?Sigma?Douglas (R.S.D.). One radiologist evaluated each dataset; sensitivity, specificity, PPV and NPV, accuracy, LR+ and LR- were calculated according to the surgical results (first analysis). Dataset were then re-analyzed 12 months (second analysis) and 24 months (third analysis) later. McNemar test was applied to determine differences between the three analysis. RESULTS: Sensitivity, specificity and accuracy for the ovary at the first analysis were 88.9%, 87% and 88%, at the second 92.6%, 87% and 90% whereas at the third 92.6%, 91.3% and 92%. Sensitivity, specificity and accuracy for the USLs at the first analysis were 62.5%, 76.9% and 70%, at the second 72%, 80.8% and 76% whereas at the third 80%, 84.6% and 82%. Sensitivity, specificity and accuracy for the vaginal fornix at the first analysis were 63.2%, 64.5% and 64%, at the second 73.7%, 77.4% and 76% whereas at the third 73.7%, 83.9% and 80%. Sensitivity, specificity and accuracy for the R.S.D. at the first analysis were 39.1%, 81.5% and 62%, at the second 62.5%, 85.2% and 76% whereas at the third 73.9%, 88.9% and 82%. McNemar test indicated a significant statistical difference in sensitivity in detecting nodules of endometriosis in R.S.D. between first and third analysis (p=0.0215). The mean review time decreased (p=0.0001). CONCLUSIONS: Accuracy of MRI in diagnosing endometriosis increased with radiologist's expertise and the improvement was statistically significant in determining RSD involvement. PMID- 20171821 TI - The loss of reason in patient decision aid research: do checklists damage the quality of informed choice interventions? AB - OBJECTIVE: To discuss whether using the International Patient Decision Aids Standards (IPDAS) Collaboration checklist as a gold standard to judge interventions' quality is premature and potentially detrimental to the validity of resources designed to help patients make treatment choices. METHODS: Conceptual review integrating the science behind individuals' decision making with the demands of designing complex, healthcare interventions. RESULTS: Patient decision aids are promoted as interventions to help professionals engage in shared and/or patient-centred care. The IPDAS domains were informed by experts' opinions of best practice. Decision scientists study how individuals make decisions, what biases their choices and how best to support decisions. There is debate from decision scientists about which component parts are the active ingredients that help people make decisions. CONCLUSIONS: Interventions to help patients make choices have different purposes, component parts and outcomes to those facilitating professional-patient communications. The IPDAS checklist will change to respond to new evidence from the decision sciences. PRACTICE IMPLICATIONS: Adhering uncritically to the IPDAS checklist may reduce service variation but is not sufficient to ensure interventions enable good patient decision making. Developers must be encouraged to reason about the IPDAS checklist to identify those component parts that do (not) meet their intervention's purpose. PMID- 20171822 TI - Helping patients choose: how to improve the design of comparative scorecards of hospital quality. AB - OBJECTIVE: To understand how the public understand comparative quality information as presented on NHS Choices, the Department of Health website in England. We explore what quality information people value, how they understand different measures of quality, and their preferences for different types of information. METHOD: Seven focus groups were conducted. RESULTS: Participants' preferences for types of information changed at different stages of the focus groups. Participants attempted to compare hospitals option-wise, building up an overall picture of the hospital's performance. Faced with abundance of conflicting criteria, participants attempted to make trade offs, but found it difficult. Older and less numerate participants used summative measures to overcome this difficulty. Some indicators were poorly understood and the multiplicity of formats and labels was confusing. Missing data were mistrusted. CONCLUSION: The presentation of information affects what information people value, how they understand and process it. The design of scorecards is crucial in order to support use of scorecards for informed patient choice. PRACTICE IMPLICATIONS: We offer guidelines for changing presentation of comparative quality information with the aim to improve its use by patients when choosing between hospitals, especially online. PMID- 20171823 TI - Evaluating the food environment: application of the Healthy Eating Index-2005. AB - BACKGROUND: The Healthy Eating Index-2005 (HEI-2005), a tool designed to evaluate concordance with the 2005 Dietary Guidelines, has been used to monitor the quality of foods consumed by Americans. Because the HEI-2005 is not tied to individual requirements and is scored on a per 1000 kcal basis, it can be used to assess the overall quality of any mix of foods. PURPOSE: The goal of this paper is to examine whether the HEI-2005 can be applied to the food environment. METHODS: Two examples were selected to examine the application of the HEI-2005 to the food environment: the dollar menu displayed at a fast-food restaurant (coded and linked to the MyPyramid Equivalents Database and the Food and Nutrient Database for Dietary Studies) to represent the community level and the 2005 U.S. Food Supply (measured with food availability data, loss-adjusted food availability data, nutrient availability data, and Salt Institute data) to represent the macro level. RESULTS: The dollar menu and the 2005 U.S. Food Supply received 43.4 and 54.9 points, respectively (100 possible points). According to the HEI-2005, for the offerings at a local fast-food restaurant and the U.S. Food Supply to align with national dietary guidance, substantial shifts would be necessary: a concomitant addition of fruit, dark-green vegetables, orange vegetables, legumes, and nonfat milk; replacement of refined grains with whole grains; and reduction in foods and food products containing sodium, solid fats, and added sugars. CONCLUSIONS: Because the HEI-2005 can be applied to both environmental- and individual-level data, it provides a useful metric for studies linking data across various levels of the socioecologic framework of dietary behavior. The present findings suggest that new dietary guidance could target not only individuals but also the architects of our food environment. PMID- 20171825 TI - Pictorial essay: cysts and cyst-like lesions of the jaws. PMID- 20171827 TI - Provider communication and patient understanding of life-limiting illness and their relationship to patient communication of treatment preferences. AB - Medical decision making in the context of serious illness ideally involves a patient who understands his or her condition and prognosis and can effectively formulate and communicate his or her care preferences. To understand the relationships among these care processes, we analyzed baseline interview data from veterans enrolled in a randomized controlled trial of a palliative care intervention. Participants were 400 inpatient veterans admitted with a physician estimated risk of one-year mortality more than 25%; 260 (65%) had cancer as the primary diagnosis. Patients who believed that they had a life-limiting illness (89% of sample) reported that their provider had communicated this to them more frequently than those who did not share that belief (78% vs. 22%, P<0.001). Over half (53%) of the participants reported discussing their care preferences with their providers and 66% reported such discussions with their family; 35% had a living will. In multivariate analysis, greater functional impairment was associated with patients having discussed their care preferences with providers (P<0.05), whereas patient understanding of prognosis (P<0.05), better quality of life (P<0.01), and not being African American (P<0.05) were associated with patients having discussed their care preferences with family; higher education (P<0.001), and not being African American (P<0.01) were associated with having a living will. Patients with poor understanding of prognosis are less likely to discuss care preferences with family members, suggesting the importance of provider communication with patients regarding prognosis. Because functional decline may prompt physicians to discuss prognosis with patients, patients with relatively preserved function may particularly need such communication. PMID- 20171828 TI - Reliability, stability, and sensitivity to change and impairment in acoustic measures of timing and frequency. AB - Assessment of the voice for supporting classifications of central nervous system (CNS) impairment requires a different practical, methodological, and statistical framework compared with assessment of the voice to guide decisions about change in the CNS. In experimental terms, an understanding of the stability and sensitivity to change of an assessment protocol is required to guide decisions about CNS change. Five experiments (N = 70) were conducted using a set of commonly used stimuli (eg, sustained vowel, reading, extemporaneous speech) and easily acquired measures (eg, f0-f4, percent pause). Stability of these measures was examined through their repeated application in healthy adults over brief and intermediate retest intervals (ie, 30 seconds, 2 hours, and 1 week). Those measures found to be stable were then challenged using an experimental model that reliably changes voice acoustic properties (ie, the Lombard effect). Finally, adults with an established CNS-related motor speech disorder (dysarthria) were compared with healthy controls. Of the 61 acoustic variables studied, 36 showed good stability over all three stability experiments (eg, number of pauses, total speech time, speech rate, f0-f4. Of the measures with good stability, a number of frequency measures showed a change in response to increased vocal effort resulting from the Lombard effect challenge. Furthermore, several timing measures significantly separated the control and motor speech impairment groups. Measures with high levels of stability within healthy adults, and those that show sensitivity to change and impairment may prove effective for monitoring changes in CNS functioning. PMID- 20171829 TI - Measurement of Young's modulus of vocal folds by indentation. AB - OBJECTIVES: To assess the accuracy of the indentation method for stiffness measurements and to estimate the Young's modulus of the vocal fold using this technique. STUDY DESIGN: Basic science. METHODS: Indentation tests were performed using a range of indenter diameters and indentation depths on single- and double layer silicone rubber models with various cover-layer thicknesses with known geometry and Young's moduli. Measurements were repeated on intact vocal folds and isolated muscle and cover-layer samples from three cadaveric human larynges. RESULTS: Indentation on single-layer rubber models yielded Young's moduli with acceptable accuracy when the indentation depth was equal to or smaller than the indenter diameter, and both were smaller than the physical dimensions of the material sample. On two-layer models, the stiffness estimation was similarly influenced by indenter diameter and indentation depth, and acceptable accuracy was reached when indentation depth was much smaller than the height of the top cover layer. Measurements on midmembranous vocal fold tissue revealed location dependent Young's moduli (in kPa) as follows: intact hemilarynx, 8.6 (range=5.3 13.1); isolated inferior medial surface cover, 7.5 (range=7-7.9); isolated medial surface cover, 4.8 (range=3.9-5.7); isolated superior surface cover, 2.9 (range=2.7-3.2); and isolated thyroarytenoid muscle, 2.0 (range=1.3-2.7). CONCLUSIONS: Indenter diameter, indentation depth, and material thickness are important parameters in the measurement of vocal fold stiffness using the indentation technique. Measurements on human larynges showed location-dependent differences in stiffness. The stiffness of the vocal folds was also found to be higher when the vocal fold structure was still attached to the laryngeal framework compared with that when the vocal fold was separated from the framework. PMID- 20171830 TI - Morphological properties of collagen fibers in porcine lamina propria. AB - OBJECTIVES: Collagen influences the biomechanical properties of vocal folds. Altered collagen morphology has been implicated in dysphonia associated with aging and scarring. Documenting the morphological properties of native collagen in healthy vocal folds is essential to understand the structural and functional alterations to collagen with aging and disease. Our primary objective was to quantify the morphological properties of collagen in the vocal fold lamina propria. Our secondary exploratory objective was to investigate the effects of pepsin exposure on the morphological properties of collagen in the lamina propria. STUDY DESIGN: Experimental, in vitro study with porcine model. METHODS: Lamina propria was dissected from 26 vocal folds and imaged with atomic force microscopy (AFM). Morphological data on d-periodicity, diameter, and roughness of collagen fibers were obtained. To investigate the effects of pepsin exposure on collagen morphology, vocal fold surface was exposed to pepsin or sham challenge before lamina propria dissection and AFM imaging. RESULTS: The d-periodicity, diameter, and roughness values for native vocal fold collagen are consistent with literature reports of collagen fibers in other body tissues. Pepsin exposure on vocal fold surface did not appear to change the morphological properties of collagen fibers in the lamina propria. CONCLUSIONS: Quantitative data on collagen morphology were obtained at nanoscale resolution. Documenting collagen morphology in healthy vocal folds is critical for understanding the physiological changes to collagen with aging and scarring and for designing biomaterials that match the native topography of lamina propria. PMID- 20171831 TI - Prolonged ulcerative laryngitis: a new disease entity. AB - Over the last decade, a new disease entity, prolonged ulcerative laryngitis (PUL), with unique clinical presentation and prolonged disease course, has been recognized. Until now, very few studies dealing with this disease have been reported in the literature. From 1999 to 2008, we analyzed clinical data from a series of 39 PUL patients who were treated with an observational approach without implementing specific treatments. This disease affects adults, predominantly females. The age of patients in our series ranged from 26 to 76 years with a median of 49.5 years. This disease is characterized by ulcers and signs of acute inflammation on the membranous portion of the vocal folds with a prolonged clinical course. The recovery times of patients ranged from 4 to 20 weeks with an average of 9.4 weeks. The data in this study may reflect a natural history of this disease. PUL seems to be a self-limited disease, but the etiology of this disease is unknown. Specific infections or systemic inflammatory processes involving the larynx must be ruled out before diagnosis, and conservative treatments are suggested. PMID- 20171832 TI - Glottoplasty for male-to-female transsexualism: voice results. AB - OBJECTIVES: The aim of this study was to evaluate the objective voice results of Wendler's glottoplasty in male-to-female transsexuals. METHOD: We retrospectively reviewed our patients treated with Wendler's technique with minor modifications. Glottoplasty consisted in CO(2)-laser epithelial ablation of the anterior commissure and the two vocal folds in anterior third, suturing of the two vocal folds with two stitches of 3.0 resorbable thread, and application of fibrin sealant to strengthen the suture. Voice assessment was based mainly on fundamental frequency (F(0)), frequency range, jitter, maximum phonation time, phonation quotient, estimated subglottic pressure (ESGP) grade of dysphonia (G), and voice handicap index (VHI). These measures were taken before surgery and on the last follow-up visit. RESULTS: Our series included 15 patients with a mean age of 36 years. The mean follow-up period was 7.2 months. We did not observe any early complications related to the technique. The comparison between the preoperative and the postoperative measurements, using Wilcoxon signed rank test, showed a significant improvement of median F(0) from 139 to 191 Hz (P=0.006) with an increase in the grade of dysphonia (G(pre)=0.2, G(post)=1, P=0.013) and ESGP (ESGP(pre)=8.1 +/- 3.2, ESGP(post)=12.0 +/- 3.8, P=0.002). Other measurements, including VHI, did not show any significant differences pre- and postoperatively. CONCLUSION: Wendler's glottoplasty can contribute to feminize the voice. PMID- 20171833 TI - Vocal cysts: clinical, endoscopic, and surgical aspects. AB - SUMMARY: Vocal cysts are benign laryngeal lesions, which affect children and adults. They can be classified as epidermic or mucous-retention cyst. OBJECTIVE: The objective was to study the clinical, endoscopic, and surgical aspects of vocal cysts. METHODS: We reviewed the medical charts of 72 patients with vocal cysts, considering age, gender, occupation, time of vocal symptoms, nasosinusal and gastroesophageal symptoms, vocal abuse, tabagism, alcoholism, associated lesions, treatment, and histological details. RESULTS: Of the 72 cases, 46 were adults (36 females and 10 male) and 26 were children (eight girls and 18 boys). As far as occupation is concerned, there was a higher incidence of students and teachers. All the patients had symptoms of chronic hoarseness. Nasosinusal (27.77%) and gastroesophageal (32%) symptoms were not relevant. Vocal abuse was reported by 45.83%, smoking by 18%, and alcoholism by 8.4% of the patients. Unilateral cysts were seen in 93% of the cases, 22 patients had associated lesions, such as bridge, sulcus vocalis, and microweb. Surgical treatment was performed in 46 cases. Histological analysis of the epidermic cysts revealed a cavity with caseous content, covered by stratified squamous epithelium, often keratinized. Mucous cysts presented mucous content, and the walls were coated by a cylindrical ciliated epithelium. CONCLUSION: Vocal cysts are benign vocal fold lesions that affect children and adults, being often associated with vocal overuse, which frequently affects people who use their voices professionally. Vocal symptoms are chronic in course, often times since childhood, and the treatment of choice is surgical removal. A careful examination of the vocal folds is necessary during surgery, because other laryngeal lesions may be associated with vocal cysts. PMID- 20171834 TI - Observations of the relationship between noise exposure and preschool teacher voice usage in day-care center environments. AB - Although the relationship between noise exposure and vocal behavior (the Lombard effect) is well established, actual vocal behavior in the workplace is still relatively unexamined. The first purpose of this study was to investigate correlations between noise level and both voice level and voice average fundamental frequency (F0) for a population of preschool teachers in their normal workplace. The second purpose was to study the vocal behavior of each teacher to investigate whether individual vocal behaviors or certain patterns could be identified. Voice and noise data were obtained for female preschool teachers (n=13) in their workplace, using wearable measurement equipment. Correlations between noise level and voice level, and between voice level and F0, were calculated for each participant and ranged from 0.07 to 0.87 for voice level and from 0.11 to 0.78 for F0. The large spread of the correlation coefficients indicates that the teachers react individually to the noise exposure. For example, some teachers increase their voice-to-noise level ratio when the noise is reduced, whereas others do not. PMID- 20171835 TI - Cepstral analysis of voice in persons with vocal nodules. AB - OBJECTIVES: Traditional measures of dysphonia were reported to be unreliable, and the measurements of cepstral peak prominence (CPP) have been shown to correlate well with perceptions of breathiness. Hence, the present study was hypothesized that there would be abnormal reduction of the cepstral peak in the speakers with vocal nodules relative to the normal controls as they are characterized by hoarse and breathy voice due to inadequate closure of vocal folds. METHOD: Phonation of sustained vowel /a/ was subjected to acoustic analysis using Computerized Speech Lab (CSL model 4150) software. The vowels were analyzed acoustically with the measurement of CPP. RESULTS: Independent t test was employed to compare the significant differences between the clinical and the control groups in both males and females. The results revealed significant differences across the two groups at P<0.05. The obtained results were discussed with respect to the underlying pathophysiology. CONCLUSION: The present study investigated the CPP in subjects with vocal nodules. Cepstral deviations in the clinical group are explained due to the presence of laryngeal pathology leading to the lower values of CPP. PMID- 20171836 TI - Risk and protective factors for spasmodic dysphonia: a case-control investigation. AB - OBJECTIVES: Spasmodic dysphonia (SD) is a chronic, incurable, and often disabling voice disorder of unknown pathogenesis. The purpose of this study was to identify possible endogenous and exogenous risk and protective factors uniquely associated with SD. STUDY DESIGN: Prospective, exploratory, case-control investigation. METHODS: One hundred fifty patients with SD and 150 medical controls (MCs) were interviewed regarding their personal and family histories, environmental exposures, illnesses, injuries, voice use patterns, and general health using a previously vetted and validated epidemiologic questionnaire. RESULTS: Odds ratios and multiple logistic regression analyses (alpha<0.15) identified several factors that significantly increased the likelihood of having SD. These factors included (1) a personal history of mumps, blepharospasm, tremor, intense occupational and avocational voice use, and a family history of voice disorders; (2) an immediate family history of meningitis, tremor, tics, cancer, and compulsive behaviors; and (3) an extended family history of tremor and cancer. CONCLUSIONS: SD is likely multifactorial in etiology, involving both genetic and environmental factors. Viral infections/exposures, along with intense voice use, may trigger the onset of SD in genetically predisposed individuals. Future studies should examine the interaction among genetic and environmental factors to determine the pathogenesis of SD. PMID- 20171837 TI - Clinical outcome of window partial laryngectomy for stage T2-3 glottic laryngeal carcinoma. AB - OBJECTIVE: To investigate the operative impact and therapeutic value of window partial laryngectomy for the treatment of stage T2-3 glottic laryngeal carcinoma. METHODS: From October 2000 to December 2006, window partial laryngectomy and laryngeal reconstruction were performed on 48 appropriately selected patients with stage T2-3 glottic laryngeal carcinomas. Twenty-nine males and 19 females were included. Before the operation and in the sixth month after the operation, degree of hoarseness, vocal fold mobility and symmetry, glottal width during quiet breathing, degree of glottal closure during phonating, respiratory function, and swallowing function were surveyed. In addition, tumor recurrence and metastasis and patient survival time were monitored. RESULTS: With the exception of vocal fold mobility (P=0.343), there were significant differences between the two treatment groups in all areas that were investigated, including degree of hoarseness (all P<0.01), vocal fold symmetry (P=0.000), glottal width during quiet breathing (P=0.001), degree of glottal closure during phonating (P=0.001), and respiratory function (P=0.001). Swallowing function was not influenced (P=0.310). There was recurrence in one case (2.1%), cervical lymph node metastasis in one case, and hepatic metastasis in one case. The 3- and 5 year overall survival rates were 96.9% and 88.9%, respectively. CONCLUSIONS: This study showed that window partial laryngectomy was successful for treating properly selected stage T2-3 glottic laryngeal carcinoma. This operation was effective for reducing surgical invasion and facilitated the resumption of respiratory and vocal function. PMID- 20171838 TI - A review of design and reporting issues in self-reported prevalence studies of leg ulceration. AB - OBJECTIVE: The aim of this review was to examine design and reporting issues that affect prevalence estimates of leg ulceration obtained using self-report and outline strategies to strengthen the validity and reliability of research in this area. STUDY DESIGN AND SETTING: We identified leg ulcer prevalence studies and evaluated them against the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement. The authors draw upon the wider literature and their own empirical work in discussing strategies to overcome design and reporting issues. RESULTS: Common deficiencies in the design and reporting of studies include wide variations in diagnostic criteria and age parameters for participant selection, a lack of description of efforts to address bias/study size rationale, and low participation rates in clinical examination stages. These factors and differences in statistical methods of analysis affect the validity and reliability of findings and hinder interpretation, making comparisons across populations difficult. Opportunities for subgroup analyses are frequently missed. CONCLUSION: Self-report is a valuable means of capturing leg ulcer prevalence, but the future design and reporting of studies need to be strengthened, including addressing weaknesses in validation strategies. Capture-recapture analysis or a multiple-methods approach has the potential to yield the most valid and reliable prevalence estimates. PMID- 20171839 TI - There was evidence of convergent and construct validity of Physiotherapy Evidence Database quality scale for physiotherapy trials. AB - OBJECTIVE: To evaluate the convergent and construct validity of the Physiotherapy Evidence Database (PEDro) scale used to rate the methodological quality of randomized trials in physiotherapy. STUDY DESIGN AND SETTING: PEDro total scores and individual-item scores were extracted from 9,456 physiotherapy trials indexed on PEDro. Convergent validity was tested by comparing PEDro total scores with three other quality scales. Construct validity was tested by regressing the PEDro score and individual-item scores with the Institute for Scientific Information Web of Knowledge impact factors (IF) and SCImago journal rankings (SJR) for the journals in which the trials were published. RESULTS: Testing of convergent validity revealed correlations with the other quality scales ranging from 0.31 to 0.69. The PEDro total score was weakly but significantly associated with IF and SJR (P < 0.0001). Eight of the 10 individual scale items that contribute to the PEDro total score were significantly associated with IF. CONCLUSION: This study provides preliminary evidence of the convergent and construct validity of the PEDro total score and the construct validity of eight individual scale items. PMID- 20171840 TI - It is "the noise of practice". PMID- 20171842 TI - The Global Activity Limitation Index measured function and disability similarly across European countries. AB - OBJECTIVE: This work aims to validate and increase understanding of the Global Activity Limitation Index (GALI), an activity limitation measure from which the new structural indicator Healthy Life Years is generated. STUDY DESIGN AND SETTING: Data from the Survey of Health and Retirement in Europe, covering 11 European countries and 27,340 individuals older than 50 years, was used to investigate how the GALI was associated with other existing measures of function and disability and whether the GALI was consistent or reflected different levels of health in different countries. RESULTS: The GALI was significantly associated with the two subjective measures of activities of daily living score and instrumental activities of daily living (IADL) score, and the two objective measures of maximum grip strength and walking speed (P<0.001 in all cases). The GALI did not differ significantly between countries in terms of how it reflected three of the health measures, with the exception being IADL. CONCLUSION: The GALI appears to satisfactorily reflect levels of function and disability as assessed by long-standing objective and subjective measures, both across Europe and in a similar way between countries. PMID- 20171843 TI - Accuracy of gray-scale coding in lung sound mapping. AB - Stethoscope evaluation of the lungs is widely accepted and practiced; however, there are some widely recognized, major limitations with its use. A safe device that helped solve these limitations by translating sound into objective, quantifiable images would have clinical utility. Translating lung sounds into quantifiable images in which regional differences or asymmetry in intensities of breath sounds are presented as gradients in gray-scale is not a trivial process. Healthy lungs and lung pathology are characterized by different patterns of regional breath sound distribution and, therefore, the accuracy of mapping gray scale images must be ensured in a controlled systematic fashion prior to clinical use of such a technique. Vibration response imaging (VRI) maps lung sounds from 40 sensors to a two-dimensional gray-scale image. To assess mapping accuracy, a simulated lung sound map with uniform signals was compared to modified maps where sound signals were reduced (1-3db) at one sensor. Also, 8 readers evaluated the gray-scale images. The computer algorithm accurately displayed gray-scale coding changes in correct locations in 97% of images. There was 95+/-4% accuracy rate by readers to correctly identify gray-scale changes. In addition, quantitative data at different stages of signal processing were investigated in a LSM of a subject with asthma. Signal processing was 97% accurate overall in that the gray-scale values from which the image was derived corresponded with intensity values from recorded signals. These results suggest VRI accurately maps acoustic signals to a gray-scale image and that trained readers can detect small changes. PMID- 20171844 TI - Cell morphodynamics visualization from images of zebrafish embryogenesis. AB - Laser scanning microscopy provides high-resolution nondestructive in vivo imaging to capture specific structures that have been fluorescently labeled, such as cellular nuclei and membranes, throughout early zebrafish embryogenesis. An increasingly challenging problem biologists must face is how to effectively explore, follow, and study the thousands of cells contained in the resulting time varying volume data that are large in space, time, and variable domain. Visual data explorations, such as direct volume rendering, have been successfully used for the analysis of volumetric data. However, visualizing large-scale time varying fields remains a challenging problem. In this paper we present a novel Focus+Context animated volume rendering. The technique is based on the distance map of objects of interest and on a scene graph architecture. We demonstrate that distance map driven volume rendering, implemented in modern graphics hardware, is suited to generate run time and interactive representations such as ghosted rendering and cut-away rendering. The experimental results on zebrafish embryogenesis data demonstrate that the technique is suited to uncover and to analyze biological events, such as organogenesis, contained in time-varying volumetric dataset. PMID- 20171845 TI - Dietary pattern classifications with nutrient intake and health-risk factors in Korean men. AB - OBJECTIVE: This study was performed to identify dietary patterns in Korean men and to determine the associations among dietary patterns, nutrient intake, and health-risk factors. METHODS: Using baseline data from the Korean Health and Genome Study, dietary patterns were identified using factor analysis of data from a validated food-frequency questionnaire, and associations between these dietary patterns and health-risk factors were analyzed. RESULTS: Three dietary patterns were identified: 1) the "animal-food" pattern (greater intake of meats, fish, and dairy products), 2) the "rice-vegetable" pattern (greater intake of rice, tofu, kimchi, soybean paste, vegetables, and seaweed), and 3) the "noodle-bread" pattern (greater intake of instant noodles, Chinese noodles, and bread). The animal-food pattern (preferred by younger people with higher income and education levels) had a positive correlation with obesity and hypercholesterolemia, whereas the rice-vegetable pattern (preferred by older people with lower income and educational levels) was positively associated with hypertension. The noodle-bread pattern (also preferred by younger people with higher income and education levels) had a positive association with abdominal obesity and hypercholesterolemia. CONCLUSION: This study identifies three unique dietary patterns in Korean men, which are independently associated with certain health risk factors. The rice-vegetable dietary pattern, modified for a low sodium intake, might be a healthy dietary pattern for Korean men. PMID- 20171846 TI - Energy expenditure and estimated caloric intake in asthmatic adolescents with excess body weight. AB - OBJECTIVE: To measure resting energy expenditure (REE) and to estimate caloric intake of asthmatic adolescents with excess body weight and compare results with those groups of eutrophic asthmatic adolescents and non-asthmatic adolescents with excess body weight. METHODS: This cross-sectional study categorized 69 adolescents aged 10 to 18 y into three matched groups. Nutritional status was assessed using anthropometric and body composition measurements. Indirect calorimetry was used to measure energy expenditure, and caloric intake was estimated from dietary recalls. RESULTS: In each group, there were 23 adolescents (10 girls) aged 12.39 +/- 2.40 y. Results for each group were as follows. For asthmatic adolescents with excess body weight, body mass index (BMI) was 24.83 +/ 2.73 kg/m(2), REEs were 1550.24 +/- 547.23 kcal/d and 27.69 +/- 11.33 kcal . kg( 1) . d(-1), and estimated caloric intake was 2068.75 +/- 516.66 kcal/d; for eutrophic asthmatic adolescents, BMI was 19.01 +/- 2.10 kg/m(2), REEs were 1540.82 +/- 544.22 kcal/d and 36.65 +/- 15.04 kcal . kg(-1) . d(-1), and estimated caloric intake was 2174.05 +/- 500.55 kcal/d; and for non-asthmatic adolescents with excess body weight, BMI was 25.35 +/- 3.66 kg/m(2), REEs were 1697.24 +/- 379.84 kcal/d and 28.18 +/- 6.70 kcal . kg(-1) . d(-1), and estimated caloric intake was 1673.17 +/- 530.68 kcal/d. Absolute REE values between groups were not statistically different, even after correction for lean mass and fat mass (F = 0.186, P = 0.831). REE (kilocalories per kilogram per day) was significantly higher in the group of eutrophic asthmatic adolescents (P = 0.016). Estimated caloric intake was greater than REE only in the group of adolescents with asthma. CONCLUSION: The REE was not significantly different among groups, and REE (kilocalories per kilogram per day) was higher in the group of eutrophic asthmatic adolescents. Estimated caloric intake was greater than REE in the group of adolescents with asthma. PMID- 20171847 TI - Do inter-regional gray-matter volumetric correlations reflect altered functional connectivity in high-risk offspring of schizophrenia patients? AB - BACKGROUND: Schizophrenia patients and their relatives show aberrant functional connectivity in default network regions (DRs) such as the medial prefrontal, lateral temporal, cingulate and inferior parietal cortices and executive regions such as the dorsolateral prefrontal cortex (DLPFC). Gray-matter volumetric alterations may be related to these functional connectivity deficits. Also, gray matter volume inter-regional correlations may reflect altered inter-regional functional connectivity. AIMS: To examine our prediction of alterations of gray matter volumes and inter-regional volume correlations for DRs and the DLPFC in offspring of schizophrenia patients (OS). METHODS: We assessed 64 adolescent and young adult OS and 80 healthy controls (HC) using T1-MRI. Regional gray-matter volumes and inter-regional volume correlations between the DRs and between the DLPFC and DRs on each side were compared across groups. RESULTS: Compared to HC, OS had reductions in several DRs and the DLPFC after controlling age, gender, and intra-cranial volume, and correcting for multiple comparisons. OS had stronger (more positive) gray-matter volume inter-correlations between DRs and between DRs and the DLPFC. CONCLUSIONS: Volumetric deficits in the default network and in the DLPFC may be related to familial diathesis in schizophrenia and to functional connectivity abnormalities in those at familial risk. Increased inter correlations between DRs and between DR and DLPFC gray-matter volumes may serve as surrogate indices of abnormal functional connectivity. PMID- 20171849 TI - Attribution bias in ultra-high risk for psychosis and first-episode schizophrenia. AB - BACKGROUND: Attribution style bias, such as a greater tendency to perceive hostility, has been reported to be associated with paranoia in multi-episode, chronic schizophrenia patients. The aim of this study was to investigate whether young, first-episode schizophrenia patients exhibited a perceived hostility bias and if this bias was correlated with persecutory symptoms. This study also explored whether this attribution bias, associated with paranoid tendencies, also emerged in participants at ultra-high risk (UHR) for psychosis. METHODS: Thirty nine normal controls, 24 UHR participants, and 20 young, first-episode schizophrenia patients were asked to complete the Ambiguous Intentions Hostility Questionnaire (AIHQ) and other psychosocial measures. The AIHQ, specifically developed for paranoia, is a self-report questionnaire about negative outcomes that varied intentionality (i.e., intentional, accidental, and ambiguous intentions). The perceived hostility, composite blame, and aggression bias scores were calculated, in this study, from the ambiguous situations. RESULTS: First episode patients with schizophrenia were found to have a perceived hostility bias, which was associated with persecutory symptoms. The UHR participants also showed an attribution bias for perceiving hostility and blaming others, and this attribution bias was linked to the paranoia process. CONCLUSIONS: These findings suggest that a biased attribution style linked with paranoid symptoms may not only be present in first-episode psychotic patients but may already have evolved prior to the onset of frank psychotic symptoms. A biased attribution style may play a pivotal role in the persecutory process during the prodromal phase as well as a patient's first schizophrenic episode. PMID- 20171848 TI - Predicting the longitudinal effects of the family environment on prodromal symptoms and functioning in patients at-risk for psychosis. AB - The current study examined the relationship between the family environment and symptoms and functioning over time in a group of adolescents and young adults at clinical high risk for psychosis (N=63). The current study compared the ability of interview-based versus self-report ratings of the family environment to predict the severity of prodromal symptoms and functioning over time. The family environmental factors were measured by interviewer ratings of the Camberwell Family Interview (CFI), self-report questionnaires surveying the patient's perceptions of criticism and warmth, and parent reported perceptions of their own level of criticism and warmth. Patients living in a critical family environment, as measured by the CFI at baseline, exhibited significantly worse positive symptoms at a 6-month follow-up, relative to patients living in a low-key family environment. In terms of protective effects, warmth and an optimal level of family involvement interacted such that the two jointly predicted improved functioning at the 6-month follow-up. Overall, both interview-based and self report ratings of the family environment were predictive of symptoms and functioning at follow-up; however patient's self-report ratings of criticism had stronger predictive power. These results suggest that the family environment should be a specific target of treatment for individuals at risk for psychosis. PMID- 20171850 TI - Competitive adsorption of fibrinogen and albumin and blood platelet adhesion on surfaces modified with nanoparticles and/or PEO. AB - In order to evaluate the respective influence of surface nanotopography and chemical composition on blood compatibility, plasma protein adsorption (fibrinogen - Fg and albumin - HSA, quantified simultaneously by dual radioassays) and platelet adhesion were investigated on a range of materials. Reference surfaces were glass, polystyrene and poly(vinyl chloride), as well as pieces of commercial blood bags. Colloidal lithography with 65 and 470 nm polystyrene latex particles was used to prepare nanostructured surfaces with either one layer of colloids or with bimodal roughness. The surfaces were further conditioned by adsorption of poly(ethylene oxide) (PEO)-containing compounds (Pluronic F 68 and PLL-g-PEG). Study of the simultaneous adsorption of Fg and HSA on reference substrates demonstrated that the Fg/HSA adsorbed amount ratio decreases as the substrate hydrophobicity increases, the lower ratio being obtained with commercial blood bag. This is due to the higher resistance of HSA adsorbed on hydrophobic substrates to displacement by proteins from the solution. Such higher resistance was also shown to occur in the case of displacement by constituents of non-diluted blood plasma. Nanostructured substrates gave about the same Fg/HSA ratio as polystyrene and poly(vinyl chloride). Surface conditioning with Pluronic F 68 reduced the adsorption of Fg in competition with HSA on all substrates except glass, while PLL-g-PEG decreased the adsorbed amount of both Fg and HSA on glass but not on the other substrates. Positive correlations between the amount of adhering blood platelets and both the Fg/HSA ratio and the absolute amount of Fg adsorbed in competition with HSA were found for all substrates (reference and nanostructured, as such or after PEO conditioning, except native glass which had to be discarded due to the formation of clots in the liquid phase). These quantities were also related to the state of activation of adhering platelets. This supports the concept that blood compatibility of materials is primarily governed by the presence of Fg in the adsorbed phase, as a result of the competition with other plasma proteins. This is in turn strongly influenced by surface hydrophobicity. Surface nanostructuration as performed here (relief in the range of 50-500 nm) did not affect significantly the relationship between Fg adsorption and platelet adhesion. PMID- 20171851 TI - Tolerance of the resting cysts of Colpoda inflata (Ciliophora, Colpodea) and Meseres corlissi (Ciliophora, Spirotrichea) to desiccation and freezing. AB - The survival of ciliate resting cysts, in the presence and absence of soil, was studied under two environmental stresses: desiccation and freezing. Laboratory strains of the common species Colpoda inflata and the rare species Meseres corlissi were used in these experiments, which yielded the following results: 1) Freezing of cysts in soil with a residual moisture level exceeding approximately 30% was destructive for both species. 2) Survival of Meseres corlissi cysts depended largely on the presence of soil. 3) In the absence of soil, Colpoda inflata cysts had greater tolerance to desiccation and freezing than Meseres corlissi cysts. Possible consequences for the distribution of natural populations are discussed. PMID- 20171852 TI - Intensity-modulated radiotherapy allows escalation of the radiation dose to the pelvic lymph nodes in patients with locally advanced prostate cancer: preliminary results of a phase I dose escalation study. AB - AIM: Pelvic irradiation in addition to prostate irradiation may improve outcome in locally advanced prostate cancer, but is associated with dose-limiting bowel toxicity. We report the preliminary results of a dose escalation study using intensity-modulated radiotherapy. MATERIALS AND METHODS: Eligible patients had high-risk (T3, Gleason > or =8 or prostate-specific antigen > or =20 ng/ml) or lymph node-positive disease. Intensity-modulated radiotherapy was inverse planned giving 70 Gy/35 fractions to the prostate and 50 Gy/55 Gy/60 Gy in sequential cohorts to the pelvis with a 5 Gy boost to positive lymph nodes. Acute and late toxicity were recorded with Radiation Therapy Oncology Group (RTOG) and Late Effects Normal Tissue - Subjective Objective Management LENT-SOM scales. Neoadjuvant androgen suppression was given for 3 years. This report concerns the 50 and 55 Gy cohorts. RESULTS: Seventy-nine men were recruited (25 to 50 Gy/54 to 55 Gy) with a median follow-up of 2 years. Patients were divided into two groups according to the total bowel volume outlined (median 450 cm(3)). Acute RTOG (> or =2) bowel toxicity was 40 and 50% for the 50 and 55 Gy groups and 38 and 51% for bowel volume <450 cm(3) and > or =450 cm(3), respectively, suggesting both volume and dose relationships for acute effects. Late RTOG diarrhoea > or =grade 2 was only seen with bowel volume > or =450 cm(3), but no dose effect was apparent (12%/50 Gy and 10%/55 Gy). LENT-SOM bowel > or =grade 2 toxicity occurred in 22%/50 Gy and 15%/55 Gy. Only one patient had grade 3 toxicity. A dose volume histogram analysis showed increased late RTOG diarrhoea > or =grade 2 with larger bowel volume irradiated, significant for BV40 >124 cm(3) (P=0.04), BV45 >71 cm(3) (P=0.03) and BV60 >2 cm(3) (P=0.01). CONCLUSIONS: Acute and late bowel toxicity was acceptably low using a pelvic dose of up to 55 Gy over 7 weeks. Both relate to total pelvic bowel volume and dose volume constraints have been defined. PMID- 20171853 TI - Greater Mediterranean diet adherence is observed in Dutch compared with Greek university students. AB - BACKGROUND AND AIMS: Research has demonstrated that Mediterranean youth appear to abandon the traditional diet. The present study aimed to assess Mediterranean diet (MD) adherence in Greek university students, compared with a non Mediterranean (Dutch) population. METHODS AND RESULTS: The MD was assessed through the MD score (MedDietScore, MDS) in 100 nutrition students from Amsterdam and 85 from Thessaloniki. Subjects at both sites demonstrated average MDS, which was higher in the Dutch sample (27.5 +/- 3.9) compared to the Greek (26.1 +/- 3.4) (p <= 0.001). The highest score was observed in Amsterdam (39). Potatoes, non-refined cereals, vegetables and olive oil were more frequently consumed by Dutch students (p <= 0.001), but the Greeks demonstrated a higher legume intake (p <= 0.05). The Dutch diet comprised 17% protein, 50% carbohydrate and 33% fat, whereas the Greeks consumed 14% protein, 48% carbohydrate and 38% fat (p <= 0.001 and p <= 0.031 for between-country protein and fat intake, respectively). In Amsterdam, significantly greater amounts of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids as a percentage of energy intake (p <= 0.001, p <= 0.01) were consumed. CONCLUSION: The findings indicate that the MD has been transmitted to non-Mediterranean populations, probably as a result of its declared health benefits. However, it is alarming that an average adherence score was demonstrated by the Greek nutrition students and this is indicative of the need for new approaches in transmitting the Mediterranean dietary pattern. PMID- 20171854 TI - ApoB/apoA-I ratio is better than LDL-C in detecting cardiovascular risk. AB - BACKGROUND AND AIMS: Cardiovascular (CV) events occur even when LDL-C are <100mg/dL. To improve the detection of CV risk we investigated the apoB/apoA-I ratio versus LDL-C in subjects considered normal glucose tolerant (NGT) by oral glucose tolerance test (OGTT). METHODS AND RESULTS: We enrolled 616 NGT (273 men and 343 women), and we measured insulin resistance, lipid profile, apoB/apoA-I and the factors compounding the metabolic syndrome (MetS). An unfavourable apoB/apoA-I (>=0.9 for males and >=0.8 for females) was present in 13.9% of 108 patients with LDL-C <100mg/dL: compared to subjects with lower apoB/apoA-I (<0.9 for males and <0.8 for females), they had more elements of MetS and their lipid profile strongly correlated with high CV risk. Out of 314 patients with lower apoB/apoA-I, 40.12% had LDL-C >=130mg/dL: these retained a more favourable lipid profile than corresponding subjects with elevated apoB/apoA-I ratio. Finally, we found a significant correlation between LDL-C and apoB/apoA-I ratio (r=0.48, p<0.0001). CONCLUSIONS: In NGT with LDL-C <100mg/dL, a higher apoB/apoA-I exhibited an atherogenic lipid profile, indicating that LDL-C alone is insufficient to define CV risk. Independent from LDL-level, when apoB/apoA-I is lower, the lipid profile is, in fact, less atherogenic. This study demonstrates that apoB/apoA-I is at least complementary to LDL-C in identifying the "effective" CV risk profile of asymptomatic NGT subjects. PMID- 20171855 TI - Dietary antioxidant capacity is inversely associated with diabetes biomarkers: the ATTICA study. AB - BACKGROUND AND AIMS: Elevated dietary antioxidant activity has been regarded as providing potential benefits to health. The present work aimed at evaluating the association of glycemic indices with total dietary antioxidant capacity in healthy adults. METHODS AND RESULTS: The ATTICA study consisted of men and women, randomly selected from all areas of Attica region in Greece. In this work, a random sub-sample from the ATTICA study's database was studied, consisting of 551 men (41 +/- 11 years) and 467 women (38 +/- 11 years), with complete nutritional and biochemical information. Dietary habits were evaluated using a validated food frequency questionnaire. The dietary antioxidant capacity was based on published values for Italian foods measured by three different assays: ferric-reducing antioxidant power (FRAP), total radical-trapping antioxidant parameter (TRAP) and Trolox equivalent antioxidant capacity (TEAC). Inverse, age-energy adjusted correlations were observed between FRAP and log-glucose (r = -0.149, p = 0.001), log-insulin (r = -0.221, p = 0.001) and log-HOMA-IR (r = -0.186, p = 0.001) concentration, as well as with TRAP and TEAC. After controlling for age, gender, body mass index, physical activity status, smoking habits and energy intake, multi-adjusted analysis confirmed the previous relationships only among participants who were not on the Mediterranean dietary pattern. CONCLUSIONS: Although more prospective studies are required, the data presented support the view that dietary modification towards higher consumption of antioxidants should be implemented in public health strategies, in order to better control glycemic markers in individuals, and prevent the development of diabetes at the population level. PMID- 20171856 TI - Plasmid load adversely affects growth and gluconic acid secretion ability of mineral phosphate-solubilizing rhizospheric bacterium Enterobacter asburiae PSI3 under P limited conditions. AB - Effect of the metabolic load caused by the presence of plasmids on mineral phosphate-solubilizing (MPS) Enterobacter asburiae PSI3, was monitored with four plasmid cloning vectors and one native plasmid, varying in size, nature of the replicon, copy number and antibiotic resistance genes. Except for one plasmid, the presence of all other plasmids in E. asburiae PSI3 resulted in the loss of the MPS phenotype as reflected by the failure to bring about a drop in pH and release soluble P when grown in media containing rock phosphate (RP) as the sole P source. When 100 MUM soluble P was supplemented along with RP, the adverse effects of plasmids on MPS phenotype and on growth parameters was reduced for some plasmid bearing derivatives, as monitored in terms of specific growth rates, glucose consumed, gluconic acids yields and P released. When 10 mM of soluble P as the only P source, was added to the medium all transformants showed growth and pH drop comparable with native strain. It may be concluded that different plasmids impose, to varying extents, a metabolic load in the phosphate solubilizing bacterium E. asburiae PSI3 and results in diminishing its growth and P-solubilizing ability in P deficient conditions. PMID- 20171857 TI - Isolation and characterization of actinobacteria ectosymbionts from Acromyrmex subterraneus brunneus (Hymenoptera, Formicidae). AB - The ectosymbiont actinobacterium Pseudonocardia was isolated from the integument of Acromyrmex leaf-cutter ants and seems to play a crucial role in maintaining asepsis of the nest. Currently, there has been an intensive search for Pseudonocardia associated with several attine species, but few studies have indicated that other actinobacteria may be associated with these ants as well. We therefore characterized the culturable actinobacteria community associated with the integument of the fungus-growing ant Acromyrmex subterraneus brunneus Forel, 1893 (Hymenoptera: Formicidae). Ectosymbionts were isolated using four different media and characterized by morphological and molecular (16S rDNA) methods. A total of 20 strains were isolated, of which 17 were characterized as Streptomyces spp., and one isolate each as Pseudonocardia, Kitassatospora and Propionicimonas. Unlike other Acromyrmex species, A. subterraneus brunneus is associated with a diversity of actinobacteria. Even though Pseudonocardia is present on this leaf cutting ant's integument, the number and diversity of Streptomyces spp. found differs from those of previous studies with other attine ants and suggest that different culturing approaches are needed to characterize the true diversity of microbes colonizing the integument of attine ants. Moreover, understanding the diversity of the culturable actinobacteria associated with A. subterraneus brunneus should increase our knowledge of the evolutionary relationship of this intricate symbiotic association. PMID- 20171858 TI - Heterogeneity of Escherichia coli population by respiratory activity and membrane potential of cells during growth and long-term starvation. AB - Assessment of physiological states of individual bacterial cells can be useful in the monitoring of the biotechnological processes. Physiological heterogeneity of Escherichia coli population by respiration activity and membrane potential during growth and starvation in batch cultures was evaluated using 5-cyano-2,3-ditolyl tetrazolium chloride (CTC) and bis-(1,3-dibutylbarbituric acid) trimethine oxo (DiBAC4)(3) fluorescent probes in combination with flow cytometry. The shares of CTC-reducing cells (CTC(+)-cells) and cells with positively charged outside cytoplasmic membrane which were not stained by DiBAC4(3) (DeltaPsi(+)-cells), were 90% and 95% in the exponential phase of batch culture, respectively. After short-term starvation for 10 h, the shares of CTC(+)-cells and DeltaPsi(+)-cells in the samples taken from the exponential phase dropped to 78% and 72%, respectively. After long-term starvation for 40 days, the share of CTC(+)-cells dropped to 5%, whereas the share of DeltaPsi(+)-cells was about 50%. The conclusions from this research are as follows: (a) the physiological heterogeneity of bacterial population increased after starvation; (b) the cell respiratory activity is more sensitive to starvation than the cell membrane potential; (c) a probe for the cell membrane potential DiBAC4(3) is more suitable than a probe for the cell respiratory activity CTC in the detection of viable indicator bacteria in environment. PMID- 20171859 TI - Croton sonderianus essential oil samples distinctly affect rat airway smooth muscle. AB - Plants of the genus Croton have been used extensively in the northeast of Brazil for treating various clinical conditions. Previous studies have demonstrated that the essential oil of some specimens of Croton sp. have a relaxing effect on tracheal smooth muscle. Our study aimed to characterize the effects of Croton sonderianus essential oil samples, collected at 1:00 pm (EO-13) and 9:00 pm (EO 21), on rat tracheal smooth muscle. The two samples were submitted to gas chromatography (GC) and mass spectrometry (MS) analysis to identify their components. Rat tracheal smooth muscle strips were used to assess the biological activity. The major constituents of EO-21 were: spathulenol (18.32%), beta caryophyllene (14.58%) and caryophyllene oxide (8.54%) and the major constituents of EO-13 were bicyclogermacrene (16.29%), beta-phellandrene (15.42%) and beta caryophyllene (13.82%). These samples showed an antispasmodic effect on tracheal smooth muscle strips pre-contracted with high K+ concentration (80 mM) or with acetylcholine. EO-21 increased baseline tonus while EO-13 provoked a decrease. These results demonstrated that EO-13 and EO-21 have different chemical composition and showed myorelaxant activity. In conclusion, EO-13 and EO-21 may have potential therapeutic use in the treatment of bronchospasm. PMID- 20171860 TI - Potentiating effect of spinosin, a C-glycoside flavonoid of Semen Ziziphi spinosae, on pentobarbital-induced sleep may be related to postsynaptic 5-HT(1A) receptors. AB - Previous results have suggested that spinosin, a C-glycoside flavonoid of Semen Ziziphi spinosae, potentiates pentobarbital-induced sleep via the serotonergic system. The present study investigated whether spinosin potentiates pentobarbital induced sleep via serotonin-1A (5-hydroxytryptamine, 5-HT(1A)) receptors. The results demonstrated that spinosin significantly augmented pentobarbital (35 mg/kg, i.p.)-induced sleep in rats, reflected by reduced sleep latency and increased total sleep time, non-rapid eye movement (NREM) sleep time, and REM sleep time. With regard to NREM sleep duration, spinosin mainly increased slow wave sleep (SWS). Additionally, spinosin (15mg/kg, i.g.) significantly antagonized 5-HT(1A) agonist 8-OH-DPAT (0.1mg/kg, i.p.)-induced reductions in total sleep time, NREM sleep, REM sleep, and SWS in pentobarbital-treated rats. These results suggest that spinosin may be an antagonist at postsynaptic 5-HT(1A) receptors because these effects of 8-OH-DPAT were considered to be mediated via postsynaptic 5-HT(1A) receptors. Moreover, co-administration of spinosin and the 5-HT(1A) antagonist 4-iodo-N-{2-[4-(methoxyphenyl)-1-piperazinyl]ethyl}-N-2 pyridinylbenzamide (p-MPPI), at doses that are ineffective when administered alone (spinosin 5mg/kg, p-MPPI 1mg/kg), had significant augmentative effects on pentobarbital-induced sleep, reflected by reduced sleep latency and increased total sleep time, NREM sleep, and REM sleep. In contrast to the attenuating effects of p-MPPI on REM sleep via presynaptic 5-HT(1A) autoreceptors, 15mg/kg spinosin significantly increased REM sleep. These results suggest that the effect of spinosin on REM sleep in pentobarbital-treated rats may be related to postsynaptic 5-HT(1A) receptors. PMID- 20171862 TI - A whodunit: an appointment with death. AB - This is the tale of murder, suicide, evolution, and resurrection, taking place in four parts, and all in the name of antigen cross-priming. We invite you to explore the dark mysteries lurking within each of us as you are guided through circuitous cellular pathways in a merciless fight for survival... with viral immunity being the grand finale?! PMID- 20171861 TI - Microbial control of regulatory and effector T cell responses in the gut. AB - The human intestine harbors and is in constant contact with 1000 trillion microbes, composed of an estimated 15,000 strains. Recent studies have changed our perspective of commensal microbes from benign but inert passengers, to active participants in the processing of food into useful metabolic components, the postnatal development of mucosal and systemic immunity, and in its long-term steady state function. Although mucosal surfaces have to constitutively integrate a multitude of microbial derived signals, new evidence suggests that defined bacteria or microbial products can play a dominant role in the induction of distinct class of immune responses. In this review we will focus on recent findings associating microbes that colonize or invade the gut, specialized mucosal DCs, and induction of effector or regulatory response in the GI tract. PMID- 20171863 TI - Intracellular mechanisms of antigen cross presentation in dendritic cells. AB - The induction of most CD8+ T cell responses by dendritic cells (DCs) requires the presentation of peptides from internalized antigen by class I MHC molecules. Increasing number of reports have shown that cross presentation is involved in transplant rejection, in immune responses to viral infections, in certain autoimmune diseases and cancer. The precise role of cross presentation in the initiation of immune responses in vivo, however, remains a matter of debate. This ongoing controversy is, at least in part, due to a lack of understanding of the molecular machinery that determine cross presentation pathways in terms of cell biology. The present review aims to summarize recent insights and advances that help enlighten the intracellular steps of antigen cross presentation in DCs. PMID- 20171864 TI - Implementing harm reduction for heroin users in Afghanistan, the worldwide opium supplier. AB - Afghanistan has suffered decades of war, occupation and unrest. It is also the world's greatest producer of opium and drug production and trafficking account for a third of the total Afghan economy. Currently alongside the "War on Terrorism", the control and eradication of opium production and related trafficking is a main concern of the international community. However, this focus on supply reduction has meant scant attention has been paid to increasing drug use problems within the country; it is estimated there are up to 25,000 opium users and 20,000 heroin users in Kabul city. Drug use is often a response to war, poverty and under-development, however, street opium and heroin manufactured in the country are widely available, affordable and of high purity. This paper documents the efforts of non-governmental organisations to promote and develop harm reduction and treatment services for problem drug users in Afghanistan in this difficult context. PMID- 20171865 TI - The Global Fund's leadership on harm reduction: 2002-2009. AB - Injecting drug use is a major driver of the HIV epidemic globally. Whilst robust evidence points to the effectiveness of harm reduction programmes to halt and reverse injecting drug use driven epidemics, uptake of these programmes in developing and transitional countries has been slow. In part, this slow uptake stems from inadequate financial resources for harm reduction; legal, socio cultural and medical barriers leading to stigmatisation; and weak health systems unequipped to manage marginalized groups. The Global Fund to Fight AIDS, Tuberculosis and Malaria, established in 2002, has become the major multilateral source of external funding for harm reduction programmes in countries experiencing concentrated HIV epidemics driven by injecting drug use. Between 2004 to end of 2008, the Global Fund invested around US$180 million in harm reduction programmes in 42 countries. This funding has helped to initiate and scale up harm reduction programmes in settings where domestic funding was lacking. In addition to financing harm reduction programmes globally, the Global Fund has stimulated a strong dialogue between vulnerable groups and governments. Furthermore, the Global Fund has engaged in a dialogue with countries to encourage an evidence-based approach to policy-making that recognizes the immense value of harm reduction in HIV prevention and control. PMID- 20171866 TI - Effect of microwave irradiation on anaerobic degradability of model kitchen waste. AB - High temperature and pressure microwave (MW) irradiation was investigated as a pre-treatment to enhance anaerobic biodegradability and methane production from a model kitchen waste (KW). Heating rates of 7.8, 3.9 and 1.9 degrees C/min from room temperature to a final pre-treatment temperature of 175 degrees C with 1 min temperature holding time were tested. MW irradiation was successful in solubilization of particulate chemical oxygen demand (COD) resulting in higher soluble COD, protein and sugar concentrations in the supernatant phase (<0.45 microm) as well as in the whole fraction of pretreated KW compared to controls (not pretreated). Anaerobic biodegradability of the supernatant and whole fractions of pretreated KW was assessed by using a batch biochemical methane potential assay (BMP) at 33 degrees C. Although the highest level of solubilization was achieved at a heating rate of 1.9 degrees C/min, improvement in anaerobic biodegradability was observed only at the fastest heating rate of 7.8 degrees C/min for whole waste and for all conditions with the supernatant phase. BMP indicated increased biodegradability of between 5% and 16% for the supernatant fraction relative to controls. For the whole fraction, anaerobic biodegradability improved by 9% at a heating rate of 7.8 degrees C/min. PMID- 20171867 TI - Assessment of the state of food waste treatment in the United States and Canada. AB - Currently in the US, over 97% of food waste is estimated to be buried in landfills. There is nonetheless interest in strategies to divert this waste from landfills as evidenced by a number of programs and policies at the local and state levels, including collection programs for source separated organic wastes (SSO). The objective of this study was to characterize the state-of-the-practice of food waste treatment alternatives in the US and Canada. Site visits were conducted to aerobic composting and two anaerobic digestion facilities, in addition to meetings with officials that are responsible for program implementation and financing. The technology to produce useful products from either aerobic or anaerobic treatment of SSO is in place. However, there are a number of implementation issues that must be addressed, principally project economics and feedstock purity. Project economics varied by region based on landfill disposal fees. Feedstock purity can be obtained by enforcement of contaminant standards and/or manual or mechanical sorting of the feedstock prior to and after treatment. Future SSO diversion will be governed by economics and policy incentives, including landfill organics bans and climate change mitigation policies. PMID- 20171868 TI - Self-assembled, photoluminescent peptide hydrogel as a versatile platform for enzyme-based optical biosensors. AB - A self-assembled peptide hydrogel consisting of Fmoc-diphenylalanine has been employed as a biosensing platform through the encapsulation of enzyme bioreceptors (e.g., glucose oxidase or horseradish peroxidase) and fluorescent reporters (e.g., CdTe and CdSe quantum dots). Enzymes and quantum dots (QDs) were physically immobilized within the hydrogel matrix in situ in a single step by simply mixing aqueous solution containing QDs and enzymes with monomeric peptide (Fmoc-diphenylalanine) solution. By using atomic force microscopy and scanning transmission electron microscopy, we observed that the self-assembled peptide hydrogel had a three-dimensional network of nanofibers (with a diameter of approximately 70-90 nm) that physically hybridized with QDs and encapsulated enzyme bioreceptors with a minimal leakage. We successfully applied the peptide hydrogel to the detection of analytes such as glucose and toxic phenolic compounds by using a photoluminescence quenching of the hybridized QDs. The Michaelis-Menten constant (K(M)) of the photoluminescent peptide hydrogel was found to be 3.12 mM (GOx for glucose) and 0.82 mM (HRP for hydroquinone), respectively, which were much lower than those of conventional gel materials. These results suggest that the peptide hydrogel is an alternative optical biosensing platform with practical advantages such as simple fabrication via self assembly, efficient diffusion of target analytes, and high encapsulation efficiencies for fluorescent reporters and bioreceptors. PMID- 20171869 TI - Gold nanoparticles based sandwich electrochemical immunosensor. AB - In this report we have used gold nanoparticles (AuNPs) to covalently attach an antibody (Ab(1)) using a spacer arm. The AuNPs/Ab(1) modified gold electrode was used for a sandwich electrochemical immunoassay. The detection was done using cyclic voltammetry and impedance measurements using Horse Radish Peroxidase (HRP) as enzyme label on secondary antibody (Ab(2)) and 3,3', 5,5'-tertramethyl benzidine (TMB) as an electroactive dye. The cyclic voltammetric experiments showed three clear peaks at potentials 154 mV, -33 mV and -156 mV. There was an increase in the both anodic and cathodic current values for the peak at potential -33 mV, when H2O2 was added and the other peaks observed at potential 154 mV and 156 mV resulted due to the oxidation and reduction of TMB. The detection limit of this electrode was 2 ng/mL or 10 pg/5 microL of the analyte. The electrochemical impedance spectroscopy studies demonstrate that the formation of antigen-antibody complexes increases the series resistance and thus confirms the assembly on the electrode. This study showed that AuNPs was efficient in preserving the activity and orientation of the antibody and it can form a major platform in many clinical immunoassays. PMID- 20171870 TI - Application of Fourier-transform ion cyclotron resonance mass spectrometry to metabolic profiling and metabolite identification. AB - Metabolomics, as an essential part of genomics studies, intends holistic understanding of metabolic networks through simultaneous analysis of a myriad of both known and unknown metabolites occurring in living organisms. The initial stage of metabolomics was designed for the reproducible analyses of known metabolites based on their comparison to available authentic compounds. Such metabolomics platforms were mostly based on mass spectrometry (MS) technologies enabled by a combination of different ionization methods together with a variety of separation steps including LC, GC, and CE. Among these, Fourier-transform ion cyclotron resonance MS (FT-ICR/MS) is distinguished from other MS technologies by its ultrahigh resolution power in mass to charge ratio (m/z). The potential of FT ICR/MS as a distinctive metabolomics tool has been demonstrated in nontargeted metabolic profiling and functional characterization of novel genes. Here, we discuss both the advantages and difficulties encountered in the FT-ICR/MS metabolomics studies. PMID- 20171871 TI - Computational methods for metabolic reconstruction. AB - In the wake of numerous sequenced genomes becoming available, computational methods for the reconstruction of metabolic networks have received considerable attention. Here, we review recent methods and software tools useful along the reconstruction workflow, from sequence annotation and network assembly to model verification and testing against experimental data. Reconstruction methods can be divided into three categories, depending on the magnitude of network context which is taken into account in the process of assembling the metabolic model: First, each enzyme may be predicted independently by annotation transfer or machine learning methods. Second, the presence of a metabolic pathway may be detected from genome and experimental evidence, often utilizing a reference pathway database. Third, the method may attempt to directly reconstruct a consistent metabolic network without relying on predefined reference pathways. Regardless of the chosen context, all methods strive to reconstruct genome-scale metabolic reconstructions. Currently a gap exists between software platforms dedicated to genome annotation and computational tools for automatically repairing network inconsistencies and validating against measurement data. We argue that to accelerate the reconstruction efforts, computational tools need to be developed that bridge the phases of the reconstruction workflow. In particular, the goal of finding consistent metabolic models suitable for computational analysis should be taken into account already in the beginning phases of reconstruction. PMID- 20171872 TI - General anesthesia is unacceptable for elective cesarean section. PMID- 20171873 TI - Observational study of the effect of mu-opioid receptor genetic polymorphism on intrathecal opioid labor analgesia and post-cesarean delivery analgesia. AB - BACKGROUND: The purpose of this two-part prospective observational and blinded trial was to determine whether the single nucleotide polymorphism of the mu opioid receptor gene (OPRM1:c.304A>G) modifies (1) the duration of intrathecal fentanyl labor analgesia and (2) supplemental analgesic requirements after intrathecal morphine analgesia following cesarean delivery. METHODS: Labor analgesia was initiated with intrathecal fentanyl 25 microg. Patients undergoing primary cesarean delivery under spinal anesthesia received intrathecal morphine 150 microg. The primary outcome variables were duration of intrathecal fentanyl analgesia in the labor study and the requirement for supplemental systemic analgesia in the cesarean study. Outcomes were compared between 304A homozygotes (group A) and 304A>G heterozygotes and 304G homozygotes (group G). RESULTS: The labor study included 190 participants and the post-cesarean study included 103 participants; 24% subjects carried the 304A>G allele. The median (95% CI) duration of intrathecal fentanyl analgesia was 70 min (62, 78) in group A and 63 min (50, 76) in group G (P = 0.54). There was no difference in the amount of supplemental oral morphine equivalents required to treat breakthrough pain within 72 h after intrathecal morphine between groups A and G (median [IQR] 68 mg (37, 97) and 75 mg (37, 90) respectively, P = 0.99) or in the duration of intrathecal morphine analgesia (P = 0.84). The incidence of pruritus was greater in group A. CONCLUSIONS: Using the two outcome parameters duration of analgesia and treatment for breakthrough pain, we did not find a simple association between intrathecal opioid analgesia and OPRM1 304A/G polymorphism. PMID- 20171875 TI - Nuclear export complexes in the frame. AB - Protein and RNA molecules are exchanged between the nucleus and cytoplasm by members of the karyopherin beta family of transport factors. Karyopherins adopt a modular HEAT-repeat architecture and are regulated by the GTPase Ran. RanGTP acts as a signal for the nuclear compartment, dissociating molecular cargo from karyopherins that mediate nuclear import and promoting cargo uptake on those mediating nuclear export. After unraveling the mechanisms of nuclear import factors, structural studies have recently provided tremendous insights into nuclear export. The impact of RanGTP binding on the karyopherins ranges from large, global conformational changes to local, allosteric effects. A theme emerges where cargo recognition provides a molecular surveillance mechanism to prevent the transport of macromolecules in an inappropriate state. PMID- 20171874 TI - An intracellular traffic jam: Fc receptor-mediated transport of immunoglobulin G. AB - Recent advances in imaging techniques along with more powerful in vitro and in vivo models of receptor-mediated ligand transport are facilitating advances in our understanding of how cells efficiently direct receptors and their cargo to target destinations within the cytoplasm and at the plasma membrane. Specifically, light and 3D electron microscopy studies examining the trafficking behavior of the neonatal Fc receptor (FcRn), a transport receptor for immunoglobulin G (IgG), have given us new insights into the dynamic interplay between the structural components of the cytosolic trafficking machinery, its protein regulators, and the receptors it directs to various locations within the cell. These studies build upon previous biochemical characterizations of FcRn transport and are allowing us to begin formulation of a more complete model for the intracellular trafficking of receptor-ligand complexes. PMID- 20171876 TI - Targeting biomolecular flexibility with metadynamics. AB - Metadynamics calculations allow investigating structure, plasticity, and energetics in a variety of biological processes spanning from molecular docking to protein folding. Recent theoretical developments have led to applications to increasingly complex systems and processes stepping up the biological relevance of the problem solved. Here, after summarizing recent technical advances and applications, we give a perspective of the method as a tool for enzymology and for the prediction of NMR and other spectroscopic data. PMID- 20171877 TI - Influence of inorganic salts on the primary pyrolysis products of cellulose. AB - Processing bio-oil with the help of currently existing petroleum refinery infrastructure has been considered as a promising alternative to produce sustainable fuels in the future. The feasibility of bio-oil production and upgrading processes depend upon its chemical composition which in turn depends on the biomass composition and the process conditions of the fast pyrolysis reactions. The primary goal of this paper was to investigate the effect of mineral salts including mixtures of salts in the form of switchgrass ash on the chemical speciation resulting from primary pyrolysis reactions of cellulose and to gain an insight of the underlying mechanisms. Various concentrations of inorganic salts (NaCl, KCl, MgCl(2), CaCl(2), Ca(OH)(2), Ca(NO(3))(2), CaCO(3) and CaHPO(4)) and switchgrass ash were impregnated on pure cellulose. These samples were pyrolyzed in a micro-pyrolyzer connected to a GC-MS/FID system. Effects of minerals on the formation of (a) low molecular weight species - formic acid, glycolaldehyde and acetol, (b) furan ring derivatives - 2-furaldehyde and 5 hydroxy methyl furfural and (c) anhydro sugar - levoglucosan are reported exclusively. Further, the effect of reaction temperature ranging from 350 to 600 degrees C on the pyrolysis speciation of pure and ash-doped cellulose is also reported. The pyrolysis speciation revealed the competitive nature of the primary reactions. Mineral salts and higher temperatures accelerated the reactions that led to the formation of low molecular weight species from cellulose as compared to those leading to anhydro sugars. PMID- 20171878 TI - Xylan from corn cobs, a promising polymer for drug delivery: production and characterization. AB - Although many authors have reported several beneficial effects ascribed to xylan, such as inhibitory action on mutagenicity activity, antiphlogistic effects, and mitogenic and comitogenic activities, few papers have investigated a systematic study on the technological properties of this polymer. The aim of the present work was to evaluate xylan as a promise raw material for the pharmaceutical industry. The water-insoluble xylan samples were extracted from corn cobs following several steps. The obtained powered sample was analyzed by infrared and RMN spectroscopy, and characterized regarding their particle size, bulk and tap densities, compressibility index, compactability, Hausner ratio, and angle of repose. According to the results, infrared and RMN spectroscopy were shown to be able to evaluate the xylan structural conformation and composition, respectively. In addition, rheological data demonstrated that xylan powder obtained from corn cobs may be characterized as a material with low density and very cohesive flow properties. PMID- 20171879 TI - A two-population bio-electrochemical model of a microbial fuel cell. AB - This work presents a two-population model describing the competition of anodophilic and methanogenic microbial populations for a common substrate in a microbial fuel cell (MFC). Fast numerical solution of the model is provided by using ordinary differential equations to describe biomass growth and retention in the anodic compartment. The model parameters are estimated and validated using experimental results obtained in four continuous-flow air-cathode MFCs operated at various external resistances and organic loads. Model analysis demonstrates the influence of operating conditions on MFC performance and suggests ways to maximize MFC power output. The model is suitable both for process optimization and on-line control applications. PMID- 20171880 TI - Process simulation and economical evaluation of enzymatic biodiesel production plant. AB - Process simulation and economical evaluation of an enzymatic biodiesel production plant has been carried out. Enzymatic biodiesel production from high quality rapeseed oil and methanol has been investigated for solvent free and cosolvent production processes. Several scenarios have been investigated with different production scales (8 and 200 mio. kg biodiesel/year) and enzyme price. The cosolvent production process is found to be most expensive and is not a viable choice, while the solvent free process is viable for the larger scale production of 200 mio. kg biodiesel/year with the current enzyme price. With the suggested enzyme price of the future, both the small and large scale solvent free production proved viable. The product price was estimated to be 0.73-1.49 euro/kg biodiesel with the current enzyme price and 0.05-0.75 euro/kg with the enzyme price of the future for solvent free process. PMID- 20171881 TI - Comparison of sample pre-treatments for laser desorption ionization and secondary ion mass spectrometry imaging of Miscanthus x giganteus. AB - Efforts to further the potential of the large perennial grass Miscanthusxgiganteus as a biofuel feedstock would be aided by the ability to image the chemical species present during the fuel production process. Toward this end, two mass spectrometry imaging (MSI) approaches have been investigated here-laser desorption/ionization mass spectrometry (LDI-MS) and secondary ion mass spectrometry (SIMS). As a first step, cross sections of Miscanthus were subjected to a variety of sample preparation methods to optimize conditions for MSI. For LDI-MS, a thin metal coating (2 nm thick Au) provided high quality signals of saccharide-related ions. The traditional matrix-assisted laser desorption/ionization matrix, 2,5-dihydroxybenzoic acid, also showed high efficiency for the desorption of saccharide-related ions. In contrast, with alpha cyano-4-hydroxycinnamic acid matrix, these ions were nearly absent in the mass spectra. Direct laser ablation of untreated Miscanthus sections was also performed. High resolution images, where the fine structure of the vascular bundle could be clearly visualized, were obtained using SIMS. Although coating the sections with a nanometer thick Au layer can greatly enhance the quality of SIMS images, the coating had limited effect on secondary ion signal enhancement. Using the optimized mass spectrometry approaches described here, information on the spatial distribution of several saccharides was obtained. PMID- 20171882 TI - Improved poly-gamma-glutamic acid production by chromosomal integration of the Vitreoscilla hemoglobin gene (vgb) in Bacillus subtilis. AB - In order to alleviate oxygen limitation and improve the yield of poly-gamma glutamic acid (gamma-PGA) during fermentation, the Vitreoscilla hemoglobin gene (vgb) was integrated into the chromosome of Bacillus subtilis and expressed during gamma-PGA production. The activity of the expressed Vitreoscilla hemoglobin (VHb) was confirmed by CO-difference spectrum. Expression of VHb enhanced cell growth under high viscosity fermentation conditions 1.26-fold and increased the yield of gamma-PGA 2.07-fold. These results indicate that the expression of VHb could be advantageous in high viscosity fermentation media. PMID- 20171883 TI - Sulfate reduction during the acidification of sucrose at pH 5 under thermophilic (55 degrees C) conditions. II: effect of sulfide and COD/SO(2-)(4) ratio. AB - This work studied the effect of the sulfide concentration and COD/SO(2-)(4) ratios (4 and 1) on sulfate reduction and acidification in a thermophilic (55 degrees C) UASB reactor fed with sucrose (4 g COD(l(reactor)d)(-1)) operated at a reactor mixed liquor pH controlled at 5 for a period of 301 days. When implementing N(2) stripping, sulfate reduction efficiencies up to 95%, corresponding to volumetric sulfate reduction rates of 0.87 and 4.2g (l(reactor)d)(-1) at the COD/SO(2-)(4) ratios of 4 and 1, respectively, were achieved. Sulfide was toxic to sulfate reduction at a total dissolved sulfide concentration of 100 mg l(-1). Acidification was always complete and acetate was the only form of substrate in the effluent at a COD/SO(2-)(4) ratio of 1. The sludge was well retained in the reactor and kept its granular shape throughout the reactor run. PMID- 20171884 TI - Production of adventitious roots and secondary metabolites by Hypericum perforatum L. in a bioreactor. AB - We investigated the effects of different concentrations of auxin and auxin/cytokinin combinations, inoculum sizes and Murashige and Skoog (MS) medium dilutions on biomass and accumulation of total phenols and flavonoids in adventitious roots of Hypericum perforatum. The optimized conditions for the shake flask culture growth and secondary metabolites production were 0.1mg/l kinetin with 1mg/l indole-3-butyric acid (IBA), an inoculum density of 6g/l fresh weight (FW) and 1/2MS in the 5-week old cultures. By inoculating 6g/l of adventitious roots into a 3-l balloon type bubble bioreactor (BTBB) containing l/2 MS medium supplemented with 0.1mg/l kinetin with 1mg/l IBA, 104.2g/l adventitious roots were harvested containing 56.47+/-0.22 mg/g dry weight (DW) total phenolics, 35.01+/-1.26 mg/g DW flavonoids, 0.97+/-0.06 mg/g DW chlorogenic acid and 1.389+/-0.80 mg/g DW hypericin. The results of our study contribute to optimization and development of bioreactor technology for adventitious root cultures of H. perforatum for the production of hypericin. PMID- 20171885 TI - Ultrasonic treatment for improved solution properties of a high-molecular weight exopolysaccharide produced by a medicinal fungus. AB - High-power ultrasound (20 kHz) was applied to modify the physicochemical properties of a high-molecular weight (MW) exopolysaccharide (EPS) from mycelial culture of a medicinal fungus. At 35 W/cm(2) or higher ultrasound power, the apparent and intrinsic viscosities of EPS solution dropped by nearly 85% within 10 min, and the water solubility was increased by more than fourfold. The ultrasonic treatment led to a notable reduction of the maximum MW and a more uniform MW distribution, but no significant change in the primary structure of the EPS molecules. In contrast, the intrinsic viscosity of EPS was reduced by only 20% in 1.0M sulfuric acid at 50 degrees C for 9h. Ultrasound was proven an effective and favorable means for improving the solution properties of high-MW bioactive polysaccharides in mild conditions. PMID- 20171886 TI - Synthesis and evaluation of duocarmycin SA analogs incorporating the methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxazolo[2,3-e]indol-4-one-6-carboxylate (COI) alkylation subunit. AB - The design, synthesis and evaluation of methyl 1,2,8,8a tetrahydrocyclopropa[c]oxazolo[2,3-e]indol-4-one-6-carboxylate (COI) derivatives are detailed representing analogs of duocarmycin SA containing an oxazole replacement for the fused pyrrole found in the alkylation subunit. PMID- 20171887 TI - Synthesis of fluorinated C-mannopeptides as sialyl Lewisx mimics for E- and P selectin inhibition. AB - The synthesis of fluorinated C-mannopeptides and their evaluation as E- and P selectin inhibitors is described. These molecules are difluorinated analogues of CH(2)-glycopeptides already reported to act as sLe(x) mimics. The alpha and beta anomers of these CF(2)-glycopeptides have been prepared, as well as their 1 hydroxy analogues which were present in solution as an equilibrium mixture of alpha- and beta-pyranose and alpha- and beta-furanose forms. These molecules showed inhibitory activities comparable to their CH(2) counterparts with a moderate influence of the pseudo-anomeric center configuration. PMID- 20171888 TI - The p.G154S mutation of the alpha-B crystallin gene (CRYAB) causes late-onset distal myopathy. AB - Mutations in alpha-B crystallin gene (CRYAB) have been described to cause congenital cataracts, dilated cardiomyopathy and myofibrillar myopathy. For skeletal myopathy, only three different mutations have been reported within the last decade. Here we describe for the first time the missense mutation p.Gly154Ser to be associated with a late-onset distal vacuolar myopathy with protein aggregates without respiratory or cardiac dysfunction, and without significant cataracts. The mutation affects a residue in a highly preserved domain of alpha-B crystallin and has been identified earlier in patients with isolated cardiomyopathy. PMID- 20171889 TI - Recovery in parents of children and adolescents who survived septic shock caused by Neisseria meningitidis: a cross-sectional study. AB - OBJECTIVES: To assess psychological distress, styles of coping and disease related psychosocial limitations in parents of children and adolescents who survived meningococcal septic shock (MSS) 4-16 years ago. RESEARCH METHODOLOGY: An exploratory design using standardised questionnaires and interviews. SETTING: The psychological investigation took place in the department of Child and Adolescent Psychiatry of the ErasmusMC-Sophia Children's Hospital. MAIN OUTCOME MEASURES: 87 mothers and 77 fathers participated in this study. The General Health Questionnaire was used to assess parents' psychological distress; the Utrecht Coping List to assess styles of coping. A semi-structured disease specific interview served to explore long-term disease-related psychosocial limitations for parents. RESULTS: MSS parents reported similar psychiatric symptoms and styles of coping in comparison to reference groups. Severity of illness and the child's age at time of illness were not significant predictors of parental psychological distress and styles of coping. The presence of somatic sequelae, cognitive or behavioural and emotional problems was not associated with the levels of parental psychiatric symptoms or styles of coping. The vast majority of parents reported no current disease-related psychosocial limitations due to the MSS. CONCLUSION: Parents of children who survived MSS show recovery. Nevertheless a minority still experiences emotional burden and disease-related limitations. PMID- 20171890 TI - The effects of stride length and stride frequency on trunk coordination in human walking. AB - In speeding-up normal walking, relative phase between horizontal thorax and pelvis rotations changes from more in-phase (synchronous) to more out-of-phase. In pathology (stroke, Parkinson's disease, low-back pain, pregnancy-related pelvic girdle pain), this often fails to happen. Even in healthy gait, however, these phenomena remain poorly understood. Thorax-pelvis relative phase may increase with either stride length, or stride frequency. Sixteen healthy male subjects walked on a treadmill at 0.5m/s, 1.0m/s, or 1.5m/s, with small, normal, or large steps. Increasing stride length (with lower frequency) led to larger spinal rotations, larger thorax-pelvis relative phase, and lower pelvis-leg relative phase, while the thorax continued to counterrotate with respect to the leg. With small steps, speeding-up hardly affected thorax-pelvis relative phase, and spinal amplitudes remained low. From a certain walking speed onwards, pelvis rotations start to contribute to stride length, and thus to speed (the "pelvic step"). This phenomenon appears to be driven, and the present study suggests, at least for higher speeds, that also thoracic counterrotations are driven, and not determined by the passive dynamics of the system. For patients, several strategies may exist to avoid large thorax-pelvis relative phase, and the concomitant large rotations of the spine: walking slowly, walking with small steps, adapting the timing of thorax rotations to that of the pelvis, or refraining from adapting the timing of pelvis rotations to the movements of the leg. PMID- 20171891 TI - Impulsive smoking in a patient with Parkinson's disease treated with dopamine agonists. AB - Impulse control disorders, including pathological gambling, binge eating, compulsive shopping and hypersexual behaviors, have frequently been reported as a side effect of dopaminergic medications for Parkinson's disease (PD). Here we describe a patient with PD who developed an unusual manifestation of impulsive behaviors, including cigarette smoking, associated with an increase in dopamine agonist medication. We postulate this to be related to an overstimulation of mesolimbic dopamine receptors responsible for reward-seeking behaviors. Further research is needed to examine impulsive cigarette smoking in PD. PMID- 20171892 TI - Cultured autologous bone marrow stem cells inhibit bony fusion in a rabbit model of posterolateral lumbar fusion with autologous bone graft. AB - Mesenchymal stem cells (MSCs) have been isolated from various tissues and expanded in culture. MSCs add osteogenic potential to ceramic scaffolds when used together. A spinal fusion rabbit model was used to evaluate whether a pellet of cultured, autologous bone marrow MSCs (BMSCs) with osteogenic differentiation could increase the fusion rate when co-grafted with an autologous bone graft compared to autograft alone. Thirty rabbits were randomly assigned to two groups. Group 1 received bone autograft alone and Group 2 received bone autograft plus a pellet of cultured and differentiated BMSCs. Group 2 rabbits had a bone marrow puncture, after which the BMSC were cultured and osteoblastic differentiation was induced. BMSC cultures were obtained from 12 of 15 rabbits. The 27 rabbits underwent a bilateral, L4-L5 intertransverse fusion with an autograft and in Group 2 rabbits a pellet of differentiated BMSCs was added to the autograft. In Group 1, the fusion rate was 53% (8 of 15 rabbits) and in Group 2 the fusion rate was 0% (p<0.05). Adding differentiated BMSCs in a pellet without a scaffold not only failed to increase fusion rate, but completely inhibited bony growth. PMID- 20171893 TI - GM1 and nerve growth factor modulate mitochondrial membrane potential and neurofilament light mRNA expression in cultured dorsal root ganglion and spinal cord neurons during excitotoxic glutamate exposure. AB - Monosialoganglioside GM1 is a known neurotrophic factor. Nerve growth factor (NGF), a member of the neurotrophin family, is important for the survival, differentiation and maturation of neurons. The aim of this study was to test whether administration of GM1 and NGF can ameliorate glutamate (Glu) neurotoxicity in primary cultured embryonic rat dorsal root ganglia (DRG) and spinal cord neurons, and to investigate the mechanism underlying any effect. DRG and spinal cord neurons were exposed to the following treatments: Glu (2 mmol/L); Glu (2 mmol/L) plus GM1 (10mg/mL); Glu (2 mmol/l) plus NGF (10 ng/mL); Glu (2 mmol/L) plus GM1 (5mg/mL) and NGF (5 ng/mL). Cell viability was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, ultrastructural alterations were examined using inverse phase contrast microscopy and electron microscopy, mitochondrial membrane potential was measured using rhodamine 123 labeling and flow cytometry, and neurofilament light (NF-L) mRNA expression was detected by reverse transcription-polymerase chain reaction. It was found that GM1 and NGF can increase the viability of neurons incubated with Glu, which, after GM1 and NGF treatment, were almost morphologically normal. The mitochondrial membrane potential of neurons was lowest for neurons treated with Glu alone, and that for neurons treated with Glu plus GM1 and NGF was higher than that for treatment with GM1 or NGF alone. The mRNA of NF-L was expressed at the highest level in neurons treated with Glu plus GM1 and NGF. Our findings indicate that NGF and GM1 act synergistically to protect DRG and spinal cord neurons from Glu cytotoxicity. NGF and GM1 may function by maintaining normal mitochondrial membrane potential or by promoting NF-L mRNA expression. PMID- 20171895 TI - Design, synthesis and preliminary activity assay of 1,2,3,4 tetrahydroisoquinoline-3-carboxylic acid derivatives as novel Histone deacetylases (HDACs) inhibitors. AB - Histone deacetylases (HDACs) are enzymes involved in tumor genesis and development. Herein, we report a novel series of 1,2,3,4-tetrahydroisoquinoline-3 carboxylic acid derivatives as HDACs inhibitors. The preliminary biological screening showed that most of our compounds exhibited potent inhibitory activity against HDACs. Within this series, five compounds, 13a (IC(50)=0.58+/-0.10 microM), 7d (IC(50)=1.00+/-0.16 microM), 8l (IC(50)=1.06+/-0.14 microM), 7i (IC(50)=1.17+/-0.19 microM) and 7a (IC(50)=1.29+/-0.15 microM) possessed better HDACs inhibitory activity than Vorinostat (IC(50)=1.48+/-0.20 microM). So these five compounds could be used as novel lead compounds for further design of HDACs inhibitors. The anti-proliferative activities of a few compounds and the structure-activity relationships are also briefly discussed. PMID- 20171894 TI - Targeting Alzheimer's disease: Novel indanone hybrids bearing a pharmacophoric fragment of AP2238. AB - We report on a series of hybrid compounds structurally derived from donepezil and AP2238. This study was aimed at improving the activities of the reference compounds, donepezil and AP2238, and at broadening the range of activities of new derivatives as, due to the multifactorial nature of AD, molecules that modulate the activity of a single protein target are unable to significantly modify the progression of the disease. In particular, the indanone core from donepezil was linked to the phenyl-N-methylbenzylamino moiety from AP2238, through a double bond that was kept to evaluate the role of a lower flexibility in the biological activities. Moreover, SAR studies were performed to evaluate the role of different substituents in position 5 or 6 of the indanone ring in the interaction with the PAS, introducing also alkyl chains of different lengths carrying different amines at one end. Derivatives 21 and 22 proved to be the most active within the series and their potencies against AChE were in the same order of magnitude of the reference compounds. Compounds 15, 21-22, with a 5-carbon alkyl chain bearing an amino moiety at one end, better contacting the PAS, remarkably improved the inhibition of AChE-induced Abeta aggregation with respect to the reference compounds. They also showed activity against self-aggregation of Abeta(42) peptide, the most amyloidogenic form of amyloid produced in AD brains, while the reference compounds resulted completely ineffective. PMID- 20171896 TI - Bio-vaterite formation by glycoproteins from freshwater pearls. AB - A 48 kDa acidic and putative calcium-binding glycoprotein was isolated from pearls of the freshwater mussel Hyriopsis cumingii. This protein was compared with a related 46 kDa polypeptide, obtained from the nacreous shell of the same species. Separation by two-dimensional gel electrophoresis revealed that the difference in molecular weight is due to the higher extent of glycosylation of the 48 kDa protein existing in pearls. Evidence is presented that the sugar moieties of the protein contribute to crystal growth, starting with the nucleation step. In in vitro precipitation experiments, the 48 kDa glycoprotein of pearls directed the formation of round-shaped vaterite crystals while the 46 kDa glycoprotein of shells promoted formation of small irregular calcite particles. Furthermore, both proteins, 48 kDa/46 kDa, comprised carbonic anhydrase activity that has been implicated in CaCO(3) formation. Thus, a function of the isolated glycoproteins in biomineralization is proposed together with the mechanism by which they can stabilize different calcium carbonate polymorphs. PMID- 20171897 TI - Implementation of a new low cost detector for low intensity light pulses produced by a radioactive gamma-source. AB - The readout of a cheap scintillating fibre was implemented by means of a new solid-state device (Silicon Photomultiplier, SiPM), able to detect very tiny light pulses. The GEANT3.21 code was adopted to simulate the counting detection efficiency and the energy deposited inside the scintillating fibre due to the radiation of a radioactive gamma source. The results obtained show the capability to detect gamma rays producing as few as 3-4 photoelectrons. The new devices may have many applications in radioactivity metrology. PMID- 20171898 TI - Negative pressure wound therapy for post-sternotomy mediastinitis reduces mortality rate and sternal re-infection rate compared to conventional treatment. AB - OBJECTIVE: Negative pressure wound therapy (NPWT) is a recently introduced treatment modality for post-sternotomy mediastinitis. The aim of this study was to compare the mortality rate, the sternal re-infection rate and the length of hospital stay in patients with post-sternotomy mediastinitis after NPWT and conventional treatment. METHODS: We retrospectively analysed 118 patients with post-sternotomy mediastinitis after cardiac surgery. One group of 69 patients was treated with NPWT and the other group of 49 patients with conventional therapy. RESULTS: There were no major differences between the two groups concerning preoperative data (EuroScore) or primary cardiac surgery (mainly coronary artery bypass grafting). NPWT therapy was found to reduce mortality rate (P=0.005) and sternal re-infection rate (P=0.008) compared with conventional treatment and tended to lead to a shorter length of hospital stay (P=0.08). CONCLUSIONS: NPWT for post-sternotomy mediastinitis demonstrates encouraging clinical results with a reduction of the mortality rate and the sternal re-infection rate compared with conventional treatment. The results support NPWT as the first-line treatment for deep sternal wound infections. PMID- 20171899 TI - Electronic spectra of C6H+ and C6H3+ in the gas phase. AB - Measurement of the (3)Pi-(3)Pi transition of C(6)H(+) in the gas phase near 19486 cm(-1) is reported. The experiment was carried out with a supersonic slit-jet expansion discharge using cavity ringdown absorption spectroscopy. Partly resolved P lines and observation of band heads permitted a rotational contour fit. Spectroscopic constants in the ground and excited-state were determined. The density of ions being sampled is merely 2 x 10(8) cm(-3). Broadening of the spectral lines indicates the excited-state lifetime to be approximately 100 ps. The electronic transition of HC(6)H(2)(+) at 26402 cm(-1) assumed to be (1)A(1)-X (1)A(1) in C(2v) symmetry could not be rotationally resolved. PMID- 20171900 TI - Associations between duration of illicit drug use and health conditions: results from the 2005-2007 national surveys on drug use and health. AB - PURPOSE: To estimate and compare prevalence rates of lifetime health conditions by inferred duration of illicit drug use among the general U.S. adult population and to investigate associations between duration of use of each specific illicit drug (marijuana, cocaine, heroin, hallucinogens, or inhalant) and each lifetime health condition after controlling for potential confounding factors. METHODS: Data from respondents aged 35 to 49 (N = 29,195) from the 2005-2007 National Surveys on Drug Use and Health (NSDUH) were analyzed. RESULTS: The prevalence rates of a broad range of health conditions by duration of use of specific illicit drug among persons 35 to 49 years of age in the United States were estimated and compared. After adjustment for potential confounding factors, the results of 20 multivariate logistic regression models indicated positive associations between duration of marijuana use and anxiety, depression, sexually transmitted disease (STD), bronchitis, and lung cancer; between duration of cocaine use and anxiety and pancreatitis; between duration of heroin use and anxiety, hepatitis, and tuberculosis; between duration of hallucinogen use and tinnitus and STD; and between duration of inhalant use and anxiety, depression, HIV/AIDS, STD, tuberculosis, bronchitis, asthma, sinusitis, and tinnitus. CONCLUSIONS: This study provides initial analyses on the relationships between illicit drug use and health conditions based on a large nationally representative sample. These results can help prepare for treating health problems among former and continuing illicit drug users. PMID- 20171901 TI - Physical activity, cognitive function, and mortality in a US national cohort. AB - PURPOSE: Increasing physical activity is postulated to slow cognitive decline associated with aging. Low levels of both physical activity and cognitive function are associated with increased risk of mortality. We test the hypothesis that the relative protective effect of high physical activity level as related to mortality is greater in persons with impaired cognitive function than in others. METHODS: Data were analyzed from a longitudinal mortality follow-up study of 5903 American men and women aged 60 years and older examined in 1988 to 1994 who were followed an average of 8.5 years. Measurements at baseline included self-reported leisure-time physical activity (LTPA), a short index of cognitive function (SICF), sociodemographic data, health status, and physical and biochemical measurements. RESULTS: Death during follow-up occurred in 2431 persons. In bivariate cross-sectional analyses, more frequent LTPA was associated with greater cognitive function. In proportional hazards regression analysis, no significant interaction of LTPA with cognitive function was found; however, there was a significant age-LTPA interaction. After adjusting for confounding by baseline sociodemographic data and health status at ages 60 to 74, the hazards ratio (95% confidence intervals) was for LTPA more than 8 times weekly compared with none (0.51; 0.38-0.76, p < .001) and for low SICF score compared with high 1.43 (1.36; 1.00-1.84, p < .05). After controlling for health behaviors, blood pressure, and body mass, C-reactive protein, and high-density lipoprotein cholesterol, the LTPA hazards ratio was 0.52 (0.35-0.78; p = .002), but cognitive function was no longer significant. At ages 75 and older, results were similar for LTPA, but cognitive function remained significant after adjustment. CONCLUSIONS: In a nationwide cohort of older Americans, analyses demonstrated a lower risk of death independent of confounders among those with frequent LTPA. Much of the effect of low cognitive function could be explained by other risk factors at ages 60 to 74 but not 75 years and older. PMID- 20171902 TI - Provocative mesenteric angiography for lower gastrointestinal hemorrhage: results from a single-institution study. AB - PURPOSE: To determine the diagnostic capability, complication rate, and potential predictors of success for provocative mesenteric angiography in patients with obscure and recurrent lower gastrointestinal (GI) hemorrhage. MATERIALS AND METHODS: Thirty-four patients (age, 7-92 years; 22 men) underwent 36 provocative mesenteric angiograms between January 2002 and December 2008. Provocative mesenteric angiography consisted of systemic anticoagulation with heparin followed by selective transcatheter injection of vasodilator and tissue plasminogen activator into the arterial distribution of highest suspicion. Medications were administered incrementally until active extravasation was visualized or until the operator deemed the outcome negative. The pertinent clinical, radiologic, surgical, laboratory, and pathologic notes were retrospectively reviewed. RESULTS: Among 36 provocative mesenteric angiograms, 11 resulted in angiographically visible extravasation (31%) and an additional procedure resulted in angiographic visualization of an undiagnosed hypervascular mass, resulting in the identification of a source of a hemorrhage in 33% overall. In 10 of the 11 cases with visualized extravasation, transcatheter embolization successfully controlled recurrent hemorrhage, while the hypervascular mass without extravasation was successfully resected. Therefore, a total of 11 of 36 studies (31%) resulted in successful definitive treatment of recurrent hemorrhage. One embolization-related complication occurred, resulting in surgical resection of perforated ischemic bowel. No hemorrhagic complications were identified. Patients with melena and patients admitted for reasons other than acute lower GI hemorrhage were significantly less likely to benefit from provocative mesenteric angiography. CONCLUSIONS: In this series, provocative mesenteric angiography was safe and effective for eliciting the source of occult lower GI hemorrhage, leading to definitive therapy in about one third of patients. PMID- 20171903 TI - Endovascular management of inadvertent subclavian artery catheterization during subclavian vein cannulation. AB - PURPOSE: To retrospectively review a 9-year experience with endovascular management of inadvertent subclavian artery catheterization during subclavian vein cannulation. MATERIALS AND METHODS: From June 2000 through July 2009 (109 months), 13 patients underwent endovascular management of inadvertent subclavian artery catheterization. All catheters were still in situ, including one 7-F catheter, six 8-F catheters, and six large-bore 10-11-F catheters. Treatment was performed with an Angio-Seal device (n = 6) or balloon catheters (n = 7) and by additional stent-graft placement (n = 4). RESULTS: Mean follow-up was 27.3 months (range, 0.4-78 months). The 30-day mortality rate was 7.7% and the late mortality rate was 46.1%. Primary technical success was achieved in nine patients (69.2%), in four with the use of a compliant balloon catheter and in the other five with an Angio-Seal device. Complications required additional stent-graft placement in four patients (30.8%), one because of stenosis after Angio-Seal device deployment and three as a result of insufficient closure of the puncture site by balloon tamponade. Stent-graft repair was successful in all four patients, for a primary assisted technical success rate of 100%. CONCLUSIONS: Endovascular techniques offer a less invasive alternative to surgery. The present limited experience shows that the use of the Angio-Seal device is not without risks, whereas balloon tamponade is not always reliable in closing the puncture site. Stent-graft placement may be required in patients in whom balloon tamponade fails or in whom the use of the Angio-Seal device is contraindicated. PMID- 20171904 TI - Partial-thickness rotator cuff tears. PMID- 20171905 TI - Significant differentiation of focal breast lesions: calculation of strain ratio in breast sonoelastography. AB - RATIONALE AND OBJECTIVES: Initial data suggest that elastography can improve the specificity of ultrasound in differentiating benign and malignant breast lesions. The aim of this study was to compare elastography and B-mode ultrasound to determine whether the calculation of strain ratios (SRs) can further improve the differentiation of focal breast lesions. MATERIALS AND METHODS: A total of 227 women with histologically proven focal breast lesions (113 benign, 114 malignant) were included at two German breast centers. The women underwent a standardized ultrasound procedure using a high-end ultrasound system with a 9-MHz broadband linear transducer. B-mode scans and sonoelastograms were analyzed by two experienced readers using the Breast Imaging Reporting and Data System criteria. SRs were calculated from a tumor-adjusted region of interest (mean color pixel density) and a comparable region of interest placed in the lateral fatty tissue. Sensitivity, specificity, and cutoff values were calculated for SRs (receiver operating characteristic analysis). RESULTS: The women had a mean age of 54 years (range, 19-87 years). The mean lesion diameter was 1.6 +/- 0.9 cm. Sensitivity and specificity were 96% and 56% for B-mode scanning, 81% and 89% for elastography, and 90% and 89% for SRs. An SR cutoff value of 2.45 (area under the curve, 0.949) allowed significant differentiation (P < .001) of malignant (mean, 5.1 +/- 4.2) and benign (mean, 1.6 +/- 1.0) lesions. The quantitative method of SR calculation was superior to subjective interpretation of sonoelastograms and B mode scans, with a positive predictive value of 89% compared to 68% and 84% for the other two methods. CONCLUSIONS: Calculation of SRs contributes to the standardization of sonoelastography with high sensitivity and allows significant differentiation of benign and malignant breast lesions with higher specificity compared to B-mode ultrasound but not elastography. PMID- 20171906 TI - Decision analytic model for evaluation of suspected coronary disease with stress testing and coronary CT angiography. AB - RATIONALE AND OBJECTIVES: The aim of this study was to apply a decision analytic model for the evaluation of coronary artery disease (CAD) to define the optimal utilization of coronary computed tomographic angiography (cCTA) and stress testing. MATERIALS AND METHODS: The model tested in this study assumes that CAD is evaluated with a stress test and/or cCTA and that a patient with positive evaluation results undergoes cardiac catheterization. On the basis of values of sensitivity, specificity, and radiation dose from the published literature and test costs from the Medicare fee schedule, a decision tree model was constructed as a function of disease prevalence. RESULTS: The false-negative rate is lowest when cCTA is used as an isolated test. The false-positive rate is minimized when cCTA is used in combination with stress echocardiography. Effective radiation is minimized by use of stress electrocardiography or stress echocardiography alone or prior to cCTA. When the pretest probability of CAD is low, a strategy that uses stress echocardiography followed by cCTA minimizes the false-positive rate and effective radiation exposure, with relatively low imaging costs and with a false-negative rate only slightly higher than a strategy including stress myocardial scintigraphy. As the pretest probability of CAD increases above 20%, the false-negative rate of stress echocardiography followed by cCTA increases by >5% relative to cCTA alone. CONCLUSION: Effective radiation dose and imaging costs for the workup of CAD may be minimized by an appropriate combination of stress testing and cCTA. A strategy that uses stress echocardiography followed by cCTA is most appropriate for the evaluation of low-risk patients with CAD with a pretest probability < 20%, while cCTA alone may be more appropriate in intermediate-risk patients. PMID- 20171907 TI - Low-dose, time-resolved, contrast-enhanced 3D MR angiography in the assessment of the abdominal aorta and its major branches at 3 Tesla. AB - RATIONALE AND OBJECTIVES: The aims of this study were to evaluate the effectiveness of low-dose, contrast-enhanced (CE), time-resolved, three dimensional magnetic resonance angiography (MRA) in the assessment of the abdominal aorta and its major branches at 3 T and to compare the results with those of high-spatial resolution CE MRA. MATERIALS AND METHODS: Twenty-two consecutive patients (eight men, 14 women; mean age, 43.9 +/- 17.9 years) underwent CE time-resolved three-dimensional MRA and high-spatial resolution three-dimensional MRA. Studies were performed using a 3-T magnetic resonance system; gadolinium-based contrast medium was administered at a dose of 3 to 5 mL for time-resolved MRA, followed by 0.1 mmol/kg gadopentetate dimeglumine for single-phase CE MRA. For analysis purposes, the abdominal arterial system was divided into 11 arterial segments, and image quality as well as the presence and degree of vascular pathology were evaluated by two independent magnetic resonance radiologists. RESULTS: A total of 242 arterial segments were visualized with good image quality. Time-resolved MRA was able to visualize the majority of arterial segments with good definition in the diagnostic range. Vascular pathologies (stenosis, occlusion) or abnormal vascular anatomy was detected in 19 arterial segments, with good interobserver agreement (kappa = 0.78). All image findings were detected with time-resolved CE MRA by both observers and were confirmed by correlative imaging. CONCLUSION: Low-dose, time-resolved MRA at 3 T yields rapid and important anatomic and functional information in the evaluation of the abdominal vasculature. Because of its limited spatial resolution, time-resolved MRA is inferior to CE MRA in demonstrating fine vascular details. PMID- 20171908 TI - Renal oncocytoma--are there sufficient grounds to consider surveillance following prenephrectomy histologic diagnosis. AB - INTRODUCTION: Oncocytoma is a benign neoplasm of the kidney and comprises about 12% of all renal masses. A definitive preoperative diagnosis of oncocytoma is currently technically not feasible and its practical implication is controversial. OBJECTIVES: To analyze the current status of preoperative diagnostic tools for oncocytoma, study the different occurrences of oncocytoma renal cell carcinoma (RCC) coexistence, including the phenomenon of true hybrid tumors, and investigate the rare reports on the natural history of unresected oncocytoma. MATERIALS AND METHODS: A PubMed search was performed using the following key word: oncocytoma, renal cell carcinoma, natural history, electron microscopy, and cytogenetics. Medline articles and abstracts prior to August 2009 were reviewed. RESULTS AND CONCLUSIONS: At the moment, preoperative renal mass biopsy is the only way for prenephrectomy histologic diagnosis of oncocytoma. However, it is expected that some of these biopsies, although suggestive for oncocytoma, will suspect chromophobe RCC. In all the English literature, the number of true ipsilateral synchronous hybrid oncocytoma-RCC tumors is extremely low in comparison with the "pure" oncocytomas being resected worldwide. There is almost no data on the natural history of oncocytoma. PMID- 20171909 TI - Maintained geometry, elasticity and contractility of human saphenous vein segments stored in a complex tissue culture medium. AB - OBJECTIVE: Improved maintenance of endothelial function and higher viability of saphenous vein grafts stored in a complex tissue culture medium (TCM) have been demonstrated. This article studies the biomechanical properties of saphenous vein segments. DESIGN: Biomechanical properties of 72 saphenous vein segments remaining from coronary bypass grafting of 32 patients have been studied after different storage procedures. MATERIALS: The materials studied included fresh segments, segments stored in a cooled conventional physiological salt solution (normal Krebs-Ringer (nKR)) for 1-2 weeks, segments stored in a cooled chemically defined TCM (X-Vivo) for 1,2,3 and 4 weeks and segments cryopreserved for a few weeks. METHODS: Specimens were cannulated at both ends and pressure-diameter curves were recorded in the 0-85-mmHg range in nKR with 10 microM norepinephrine added to induce maximum smooth muscle contraction, as well as in Ca(2+)-free medium to induce full relaxation. Tensile strength was checked at 300 mmHg. Distensibility, elastic modulus and active strain were computed. RESULTS: Segments stored in nKR dilated morphologically, their distensibility decreased and they lost their ability to contract (1.5+/-0.7% from 10.1+/-1.5% of control) in 1 week. The TCM-stored segments preserved their contractility until 1 week, and this parameter only slowly decreased afterwards (first week, 11.5+/-7.3%; fourth week, 3.9+/-0.6%). There was a slight decrease in wall thickness but the lumen diameter was not affected. The elastic parameters of these segments were practically identical to those of fresh segments. Cryopreserved segments narrowed morphologically, their wall thickened and contractility diminished. CONCLUSIONS: Storage in TCM helps preserve the passive and active biomechanical properties of human saphenous vein segments. Such properties can be expected to improve graft tissue viability. PMID- 20171910 TI - Interobserver agreement of the TASC II classification for supra- and infrainguinal lesions. AB - OBJECTIVES: The Trans-Atlantic Inter-Society Document on Management of Peripheral Arterial Disease (TASC) gives treatment recommendations depending on the classification of aorto-iliacal or femoro-popliteal vascular pathologies. Therefore, the best treatment could only be offered if the right TASC classification was obtained. The purpose of this study was to assess the interobserver agreement of the evaluation of the TASC II classification for peripheral arterial occlusive disease (PAOD) in magnetic resonance angiography (MRA). PATIENTS AND METHODS: Three hundred arterial segments of 149 patients with a magnetic MRA for PAOD were evaluated according to the TASC II classification. A resident and a consultant for radiology and vascular surgery both performed independent grading. A comparative assessment of the consensus agreement was quantified by the marginal probabilities calculated by generalised estimation equation models, as well as by using the weighted kappa coefficient (kappa), classified according to Altman. RESULTS: In relation to the consensus, the overall agreement was good to excellent for the consultants of radiology and vascular surgery. The consultants obtained a statistically significant higher agreement than did the residents (Odds ratio (OR): 2.86, 95% confidence interval (CI): 2.21-3.69, p<0.001). A significantly higher consensus agreement probability was observed for the surgeons compared with the radiologists (OR: 1.43, 95% CI: 1.11-1.84, p=0.006) and for the femoro-popliteal regions compared with the aorto iliacal regions (OR: 1.64, 95% CI: 1.12-2.14, p=0.012). CONCLUSION: Although good results can be achieved in the assessment of vascular lesions according to the TASC II document, a simplification of this classification could increase its practicability in a daily clinical routine. PMID- 20171911 TI - Development of a novel PCR method to comprehensively analyze salivary bacterial flora and its application to patients with odontogenic infections. AB - OBJECTIVE: The objective of this study was to develop a novel polymerase chain reaction (PCR) method to comprehensively analyze salivary bacterial flora. STUDY DESIGN: The bacterial flora in the saliva of 10 healthy persons and 11 patients with odontogenic infections were examined using a DNA extraction method with a high level of cell destruction efficiency and a novel universal primer set to amplify approximately 580 bp of the 16S rDNA sequence. RESULTS: Streptococcus (54.5%), Neisseria (14.7%), Actinomyces (8.4%), Gemella (4.1%), Granulicatella (3.8%), and Prevotella (1.4%) were dominant in a total of 1655 clones examined from the saliva of the healthy subjects. The dominant genera differed among the patients with odontogenic infections (a total of 823 clones) and were entirely different from those of the healthy subjects. CONCLUSION: This novel comprehensive salivary bacterial flora analysis method may be a useful supportive method to identify causative agents of odontogenic infections. PMID- 20171912 TI - Posterior reversible encephalopathy syndrome in paediatric leukaemia. AB - This report describes four patients with acute lymphoblastic leukaemia, suffering from posterior reversible encephalopathy syndrome during the induction period of treatment. A review of the literature on posterior reversible encephalopathy syndrome in paediatric leukaemia is given. The exact mechanism of posterior reversible encephalopathy syndrome is not clear and seems to be multifactorial. Hypertension is likely to play a major role in the development but could be also secondary. All patients in this case series presented after introduction of the new induction protocol for acute lymphoblastic leukaemia. Treatment of hypertension is likely to have a favourable role and posterior reversible encephalopathy syndrome is most often reversible. It is important to consider this diagnosis during the induction phase of leukaemia treatment in the presence of neurological symptoms. The incidence of PRES in the induction scheme should be investigated, in order to optimize the ALL treatment. PMID- 20171913 TI - Molecular modeling studies of L-arabinitol 4-dehydrogenase of Hypocrea jecorina: its binding interactions with substrate and cofactor. AB - L-arabinitol 4-dehydrogenase (LAD1; EC 1.1.1.12) is an enzyme in the L-arabinose catabolic pathway of fungi that catalyzes the conversion of L-arabinitol into L xylulose. The primary objective of this work is to identify the catalytic and coenzyme binding domains of LAD1 from Hypocrea jecorina in order to provide better insight into the possible catalytic events in these domains. The 3D structure of NAD(+)-dependent LAD1 was developed based on the crystal structure of human sorbitol dehydrogenase as a template. A series of molecular mechanics and dynamics operations were performed to find the most stable binding interaction for the enzyme and its ligands. Using the verified model, a docking study was performed with the substrate L-arabinitol, Zn(2+) and NAD(+). This study found a catalytic Zn(2+) binding domain (Cys66, His91, Glu92 and Glu176) and a cofactor NAD(+) binding domain (Gly202, ILeu204, Gly205, Cys273, Arg229 and Val298) with strong hydrogen bonding contacts with the substrate and cofactor. The binding pockets of the enzyme for l-arabinitol, NAD(+), and Zn(2+) have been explicitly defined. The results from this study should guide future mutagenesis studies and provide useful clues for engineering enzymes to improve the utilization of polyols for rare sugar production. PMID- 20171914 TI - [Acute hepatitis in a patient treated with oseltamivir]. PMID- 20171915 TI - [The impact factor: a fair measure of research excellence in nursing?]. AB - Nursing in Spain is now reaching a turning point due to the expansion of its academic horizons. In order to consolidate its existence and development, it must strengthen its scientific base. Bibliometric indicators report in a quantitative way on the production, transmission and consumption of scientific information, with the impact factor (IF) being the most internationally accepted bibliometric indicator. This is a tool that compares journals and assesses the relative importance of a journal within a scientific field, and its calculation is possible by consulting certain databases recording papers published in the major journals. Thomson Scientific analyzes the production of journals for this purpose, and annually ranks journals by their IF. It has become the benchmark for excellence in the evaluation of scientific production. An article published in a journal without an IF should not be judged in advance to be of lower quality. Given that few nursing publications are indexed, have a low IF, are almost exclusively English-speaking and from the U.S., this makes publishing more difficult in IF journals for nursing professionals, especially if they are not English-speaking. The journal's IF where the author publishes has become an increasingly strong criterion for resources allocation. In Spain, it is among the evaluation criteria of the Health Research Fund (FIS), the ANECA (National Agency for Quality Assessment and accreditation) and at the National Commission for the Assessment of Research. There have been several proposals for alternative indices to the IF, aimed at assessing the scientific excellence of the journals and papers published. In the nursing and care field, what is most relevant is that the generation of knowledge strengthens the discipline, and has a social impact capable, ultimately, of improving the care and health of the population these professionals serve. This raises the need for a bibliometric indicator, which incorporates the social and clinical research findings, considers the field of knowledge and the researcher's role in it, that reduces the importance of the publication language, and leads to the dissemination to an audience that may benefit more from the findings. PMID- 20171916 TI - Multiple dengue serotypes and high frequency of dengue hemorrhagic fever at two tertiary care hospitals in Lahore during the 2008 dengue virus outbreak in Punjab, Pakistan. AB - OBJECTIVE: The objective of this study was to investigate the clinical characteristics of patients with dengue viral infection during the 2008 outbreak in Lahore in order to better understand the clinical pattern and severity of disease in Lahore. METHODS: We analyzed the clinical characteristics of 110 patients infected with dengue virus; data were collected on standardized data collection sheets at two tertiary care hospitals from September to December 2008. Dengue infection was confirmed serologically or by real-time polymerase chain reaction (RT-PCR). RESULTS: Out of the total of 110 dengue infected patients, 70 were male and 40 were female. The most common symptoms included fever (100%), myalgia (68.2%), headache (55.5%), nausea (39.1%), skin rash (53.6%), mucocutaneous hemorrhagic manifestations (58.2%), and ocular pain (20%). Classic dengue fever (DF) was seen in 41.8% of the patients, 56.4% had dengue hemorrhagic fever (DHF), and only 1.8% developed dengue shock syndrome (DSS). The mean duration of fever was 6 days. Thrombocytopenia, leukopenia, and abnormal aspartate aminotransferase (AST)/alanine aminotransferase (ALT) were more frequently encountered in DHF and DSS as compared to DF. Viral RNA detection was done by RT-PCR in 17 patients. Ten patients had DEN4, five had DEN2, and two had DEN3 serotypes. The majority of the patients recovered completely without complications. CONCLUSION: The high frequency of DHF during the 2008 outbreak and the presence of three different dengue serotypes, emphasize the need to prevent and control dengue infection. Health authorities should consider strengthening surveillance for dengue infection, given the potential for future outbreaks with increased severity. It is also suggested that primary care physicians should be educated regarding recognition of DHF and to identify patients at high risk of developing DHF and DSS. PMID- 20171917 TI - Bacille Calmette-Guerin infection and disease with fatal outcome associated with a point mutation in the interleukin-12/interleukin-23 receptor beta-1 chain in two Mexican families. AB - Patients with Mendelian susceptibility to mycobacterial diseases (MSMD) mainly suffer from Mycobacterium and Salmonella infections, which are due to mutations in genes controlling the interleukin (IL)-12/IL-23-dependent IFN-gamma production. We performed a molecular diagnosis in two Mexican patients with persistent mycobacterial infections. Patients 1 (P1) and 2 (P2) from two unrelated, non-consanguineous families from two villages near Mexico City developed bacille Calmette-Guerin (BCG) disease secondary to vaccination; patients and their families were studied at the immunological level for production and response to IFN-gamma. The beta1 subunit of the IL-12 receptor (encoded by the IL12RB1 gene) was not expressed in cells from P1 or P2, or in two siblings of P1. Sequencing of the IL12RB1 gene showed the same point mutation 1791+2 T>G, homozygous in patients and heterozygous in parents. P1 and P2 died at the ages of 4 and 16 years, respectively, with disseminated and uncontrolled BCG disease and with Candida albicans infections in spite of multiple anti mycobacterial drug treatments. One of P2's siblings also died following disseminated mycobacterial infection secondary to BCG vaccination. These are the first cases in Mexico of patients with BCG disease traced to a mutation in the IL12RB1 gene, with a fatal outcome. Doctors must be alert to the adverse reactions to BCG vaccination and to persistent Mycobacterium infections, and in such cases should investigate possible mutations in the genes of the IL-12/IL-23 IFN-gamma axis. PMID- 20171918 TI - Alveolar hemorrhage after infliximab therapy. PMID- 20171919 TI - Mesenchymal stem cells: a new biotherapy for bone disease? PMID- 20171920 TI - Targeting intracellular signaling pathways to treat rheumatoid arthritis: Pandora's box? PMID- 20171922 TI - Using of sonochemically prepared components for vapor phase growing of SbI3.3S8. AB - The using of sonochemically prepared components for growth of SbI(3).3S(8) single crystals from the vapor phase is presented for the first time. The good optical quality of the obtained crystals is important because this material is valuable for optoelectronics due to its non-linear optical properties. The products were characterized by using techniques such as X-ray crystallography, powder X-ray diffraction, scanning electron microscopy, energy dispersive X-ray analysis, high resolution transmission electron microscopy, selected area electron diffraction, optical diffuse reflection spectroscopy and optical transmittance spectroscopy. The direct and indirect forbidden energy gaps of SbI(3).3S(8) illuminated with plane polarized light with electric field parallel and perpendicular to the c axis of the crystal have been determined. The second harmonic generation of light in the grown crystals was observed. PMID- 20171921 TI - Safety of rituximab in rheumatoid arthritis patients with a history of severe or recurrent bacterial infection: observational study of 30 cases in everyday practice. AB - OBJECTIVES: To report our experience with rituximab therapy in patients with rheumatoid arthritis (RA) and a history of severe or recurrent bacterial infections. PATIENTS AND METHODS: Retrospective observational study in five rheumatology departments experienced in the use of biotherapies. Patients were included if they had RA and a history of severe or recurrent bacterial infection (requiring admission and/or intravenous antimicrobial therapy) that contraindicated the introduction or continuation of TNFalpha antagonist therapy. RESULTS: Of 161 RA patients given rituximab in the five study centers, 30 met the inclusion criteria, 23 females and seven males with a mean age of 58.4+/-11.8 years and a mean disease duration of 11.4+/-13.9 years. Among them, 22 had rheumatoid factors and 21 had received TNFalpha antagonist therapy (one agent in 15 patients, two in five patients and three in one patient). Prior infections were as follows: septicemia, n=2; lower respiratory tract infection or lung abscess, n=12; prosthesis infection, n=3; septic arthritis, n=3; endocarditis, n=1; pyelonephritis, n=2; osteitis, n=4; and various skin infections (erysipelas, cellulitis or skin abscess), n=6. Of these 33 infections, 21 occurred during TNFalpha antagonist therapy. During rituximab therapy, all patients received concomitant glucocorticoid therapy (mean dosage, 12+/-7.9 mg/day). The number of rituximab cycles was one in 13 patients, two in seven patients and three or more in 10 patients. Mean time from the single or last serious infection and the first rituximab infusion was 20.1+/-18.7 months. Mean follow-up since the first rituximab infusion was 19.3+/-7.4 months. During follow-up, six (20%) patients experienced one infection each. Immunoglobulin levels after rituximab therapy were within the normal range. CONCLUSION: Rituximab therapy was well tolerated in 24 (80%) of 30 patients with RA and a history of severe or recurrent bacterial infection. In everyday practice, rituximab therapy seems safe with regard to the recurrence of infectious episodes. However, longer follow-ups are needed. PMID- 20171923 TI - Metrological characterization of a cycle-ergometer to optimize the cycling induced by functional electrical stimulation on patients with stroke. AB - Functional electrical stimulation (FES) is a well established method in the rehabilitation of stroke patients. Indeed, a bilateral movement such as cycling induced by FES would be crucial for these patients who had an unilateral motor impairment and had to recover an equivalent use of limbs. The aim of this study was to develop a low-cost meteorologically qualified cycle-ergometer, optimized for patients with stroke. A commercial ergometer was instrumented with resistive strain gauges and was able to provide the torque produced at the right and left crank, independently. The developed system was integrated with a stimulator, obtaining a novel FES cycling device able to control in real-time the movement unbalance. A dynamic calibration of the sensors was performed and a total torque uncertainty was computed. The system was tested on a healthy subject and on a stroke patient. Results demonstrated that the proposed sensors could be successfully used during FES cycling sessions where the maximum torque produced is about 9Nm, an order of magnitude less than the torque produced during voluntary cycling. This FES cycling system will assist in future investigations on stroke rehabilitation by means of FES and in new exercise regimes designed specifically for patients with unilateral impairments. PMID- 20171924 TI - Screening for MAPT and PGRN mutations in Korean patients with PSP/CBS/FTD. PMID- 20171925 TI - The geography of belonging: the experience of birthing at home for First Nations women. AB - The number of rural hospitals offering maternity care in British Columbia has significantly declined since 2000, mirroring trends of closures and service reductions across Canada. The impact on Aboriginal women is significant, contributing to negative maternal and newborn health and social outcomes. The present qualitative case study explored the importance of local birth for Aboriginal women from a remote BC community after the closure of local maternity services. Data collection consisted of 12 interviews and 55 completed surveys. The average participant age was 32 years old at the time of the study. From the perspective of losing local services, participants expressed the importance of local birth in reinforcing the attributes that contributed to their identities, including the importance of community and kinship ties and the strength of ties to their traditional territory. PMID- 20171926 TI - The multiple-demand (MD) system of the primate brain: mental programs for intelligent behaviour. AB - A common or multiple-demand (MD) pattern of frontal and parietal activity is associated with diverse cognitive demands, and with standard tests of fluid intelligence. In intelligent behaviour, goals are achieved by assembling a series of sub-tasks, creating structured mental programs. Single cell and functional magnetic resonance imaging (fMRI) data indicate a key role for MD cortex in defining and controlling the parts of such programs, with focus on the specific content of a current cognitive operation, rapid reorganization as mental focus is changed, and robust separation of successive task steps. Resembling the structured problem-solving of symbolic artificial intelligence, the mental programs of MD cortex appear central to intelligent thought and action. PMID- 20171927 TI - Regulation of starch metabolism: the age of enlightenment? AB - Starch and sucrose are the primary products of photosynthesis in the leaves of most plants. Starch represents the major plant storage carbohydrate providing energy during the times of heterotrophic growth. Starch metabolism has been studied extensively, leading to a good knowledge of the numerous enzymes involved. In contrast, understanding of the regulation of starch metabolism is fragmentary. This review summarises briefly the known steps in starch metabolism, highlighting recent discoveries. We also focus on evidence for potential regulatory mechanisms of the enzymes involved. These mechanisms include allosteric regulation by metabolites, redox regulation, protein-protein interactions and reversible protein phosphorylation. Modern systems biology and bioinformatic approaches are uncovering evidence for extensive post-translational protein modifications that may underlie enzyme regulation and identify novel proteins which may be involved in starch metabolism. PMID- 20171928 TI - Global regulation by the seven-component Pi signaling system. AB - This review concerns how Escherichia coli detects environmental inorganic orthophosphate (P(i)) to regulate genes of the phosphate (Pho) regulon by the PhoR/PhoB two-component system (TCS). P(i) control by the PhoR/PhoB TCS is a paradigm of a bacterial signal transduction pathway in which occupancy of a cell surface receptor(s) controls gene expression in the cytoplasm. The P(i) signaling pathway requires seven proteins, all of which probably interact in a membrane associated signaling complex. Our latest studies show that P(i) signaling involves three distinct processes, which appear to correspond to different states of the sensory histidine kinase PhoR: an inhibition state, an activation state, and a deactivation state. We describe a revised model for P(i) signal transduction of the E. coli Pho regulon. PMID- 20171929 TI - Understanding handling of drug safety alerts: a simulation study. AB - PURPOSE: To study correctness of drug safety alert handling and error type in a computerized physician order entry (CPOE) system in a simulated work environment. METHODS: Disguised observation study of 18 physicians (12 from internal medicine and 6 from surgery) entering 35 orders of predefined patient cases with 13 different drug safety alerts in a CPOE. Structured interviews about how the generated drug safety alerts were handled in the simulation test and resemblance of the test to the normal work environment. Handling and reasons for this were scored for correctness and error type. RESULTS: Thirty percent of alerts were handled incorrectly, because the action itself and/or the reason for the handling were incorrect. Sixty-three percent of the errors were categorized as rule based and residents in surgery used incorrect justifications twice as often as residents in internal medicine. They often referred to monitoring of incorrect substances or parameters. One alert presented as a second alert in one screen was unconsciously overridden several times. One quarter of residents showed signs of alert fatigue. CONCLUSION: Although alerts were mainly handled correctly, underlying rules and reasoning were often incorrect, thereby threatening patient safety. This study gave an insight into the factors playing a role in incorrect drug safety alert handling that should be studied in more detail. The results suggest that better training, improved concise alert texts, and increased specificity might help. Furthermore, the safety of the predefined override reason 'will monitor' and double alert presentation in one screen is questioned. PMID- 20171930 TI - Echocardiography in the era of multimodality imaging. AB - For over 30 of its 50-year history, echocardiography has provided noninvasive, widely available and inexpensive imaging. This technique now has a huge evidence base that is incorporated in the guidelines for many cardiac diseases, to the extent that echocardiography (2DE) has a central position in modern cardiac diagnosis and management. The paradox is that in contributing the lion's share of cardiac imaging, echocardiography has become removed from the province of the imaging specialist and its role as an interesting and worthwhile source of investigation and training has been superseded by the newer methodologies including cardiac computed tomography (CCT) and cardiac magnetic resonance (CMR). However, the clinical contribution of potential advances are likely to be realised only if "advanced echocardiography" - including deformation, contrast and three-dimensional imaging - are differentiated from the "plain vanilla" of routine echocardiography. Successful translation of these advances into clinical practice will show that these new techniques are complimentary and in some cases competitive with the new imaging methodologies. This review seeks to provide a perspective of how echocardiography will integrate with the new imaging methodologies for the most common indications for cardiac imaging, with specific attention to the contribution of new methodologies including three-dimensional echocardiography (3DE) and deformation imaging. PMID- 20171931 TI - Bladder vascular anomalies. PMID- 20171932 TI - The effect of temperament and neuropsychological functioning on behavior problems in children with new-onset seizures. AB - The present study is part of a larger project that seeks to identify factors that predict children's behavioral, social, and cognitive adaptation to epilepsy. Children with seizures are more likely to have internalizing and externalizing behavior problems than either healthy children or children with other chronic illnesses. The present research examines risk factors for behavior problems. Early temperament and neuropsychological functioning, specifically executive function and language abilities, are evaluated as unique and moderating predictors of adverse behavioral outcomes in 229 children with a first recognized seizure. Parents assessed temperament, children were administered neuropsychological tests, and teachers evaluated behavior 36 months after seizure onset. Results revealed that early temperament and neuropsychological functioning, specifically executive function, predicted behavioral outcomes 3 years after seizure onset. PMID- 20171933 TI - Cryopreserved intervertebral disc with injected bone marrow-derived stromal cells: a feasibility study using organ culture. AB - BACKGROUND CONTEXT: A recent clinical study demonstrated that cryopreserved allogeneic intervertebral disc transplantation relieved pain and preserved motion, thus opening up a new treatment option for degenerative disc disease. However, these transplanted discs continued to degenerate, possibly due to a lack of viable cells. Bone marrow-derived stromal cell (BMSC) implantation has been shown to delay disc degeneration. PURPOSE: This study examined the viability over time of endogenous and injected BMSCs in cryopreserved disc under simulated physiological loading conditions. STUDY DESIGN/ SETTING: An in vitro study of BMSCs injected into cryopreserved bovine caudal discs. METHODS: Bovine caudal discs were harvested and cryopreserved at -196 degrees C. After thawing, PKH-26 labeled BMSCs embedded in peptide hydrogel carrier were injected into the nucleus pulposus. Two BMSC injection quantities, that is, 1x10(5) and 2.5x10(5) were examined. Discs with injected cells were maintained in a bioreactor for 7 days under simulated-physiological loading. Cell viability (staining), gene expression (reverse transcription-polymerase chain reaction) profile, and proteoglycan content (histologically) were evaluated. RESULTS: Forty percent of endogenous cell viability was maintained after freeze thawing. Over the 7-day culture, this did not change further. However, there was upregulation of Col1a2 and Mmp-13 and downregulation of Col2a1gene expression. Sixty percent of BMSCs survived the initial injection procedure, and only 20% remained alive after 7 days of culture. Bone marrow-derived stromal cell implantation did not alter the viability of the endogenous cells, but discs injected with 1x105 BMSCs showed significantly higher ACAN expression than sham discs. CONCLUSIONS: Although only 40% of cells survived cryopreservation, these endogeneous cells continued to survive over 7 days if maintained under simulated-physiological loading conditions. Although only a small portion of injected BMSCs survived, they did have some effect on the matrix protein gene expression profile. Their influence on native cells requires long term evaluation. PMID- 20171934 TI - Inter- and intraobserver variability in the postoperative evaluation of transpedicular stabilization: computed tomography versus magnetic resonance imaging. AB - BACKGROUND CONTEXT: Computed tomography (CT) represents the state of the art for the postoperative verification of the implant position after transpedicular stabilizations. Magnetic resonance imaging (MRI) has not challenged the CT, yet, because of susceptibility artifacts but would be favorable as a diagnostic tool for its excellent soft-tissue qualities. PURPOSE: A study that analyzed if an artifact-reduced MRI could overcome this problem and provide sufficient data for the postoperative assessment was conducted. STUDY DESIGN: The study design was a radiologic comparison of CT and MRI techniques evaluating pedicle screw placement after spinal fusion. PATIENT SAMPLE: Fifty consecutive patients were given an MRI and a CT after a transpedicular stabilization surgery. Thirty-eight patients suffered from degenerative spinal disorders; three surgeries had become necessary because of spondylodiscitis, eight patients suffered from metastatic vertebrae destruction, and one patient experienced a fracture. OUTCOME MEASURES: Any contact of a malpositioned pedicle screw with the dura and/or radicular structures was identified as an implant-associated complication and was compared with postoperative clinical patient findings. METHODS: In total, 338 pedicular screws were analyzed in regard to their intrapedicular position. The double-blind evaluation of MRI and CT data was carried out by two radiologists and two spine surgeons. Accuracy of the CT analysis was calculated based on the interobserver agreement of 100%. Magnetic resonance imaging accuracy was calculated. RESULTS: The interobserver accuracy of the CT data amounted to a median of 89.8% and in the MRI data of 86.7%. Intraobserver comparisons showed a significant difference between CT and magnetic resonance evaluations in one observer (kappa=0.293). In all other observers, the results were concordant with kappa values from kappa=0.328 to kappa=0.702. There was a high degree of agreement regarding the diagnosis of malpositioned pedicle screw and corresponding clinical symptoms between both techniques. CONCLUSIONS: The presented data show that artifact reduced MRI is equivalent to CT imaging in the postoperative evaluation of titanium spinal rod-screw systems. We therefore conclude that MRI should be considered as an alternative tool for the golden standard CT for postoperative imaging controls for its advantages in soft-tissue analysis. PMID- 20171935 TI - Systematic review of the incidence of discitis after cervical discography. AB - BACKGROUND CONTEXT: Cervical discography is not uniformly used in part because of the fear of discitis. Studies report widely varying rates of this life threatening infection. PURPOSE: The aim of this study was to estimate the incidence of discitis after cervical discography, delineate the consequences of discitis, and identify factors that may influence this complication. STUDY DESIGN: Meta-analysis. METHODS: Studies pertaining to cervical discography were identified by a literature review and bibliographic search. These were screened for inclusion into the meta-analysis by two reviewers. Data were collected on a wide range of clinical and demographic variables including age, gender, morbidities, number of patients, number of discograms, use of prophylactic antibiotics, type of surgical prep, number of needles used, and the number of patients and discs infected. Primary data were used to calculate the incidence of discitis per patient and per disc. RESULTS: Fourteen studies were included in the analysis. Both procedural details and demographic information on patients were missing from eight studies. The mean age of patients ranged from 41 to 47 years, and gender distribution varied greatly. Antibiotics use was reported in three studies. Cervical discography was complicated by postprocedural discitis in 22 of 14,133 disc injections (0.15%) and 21 of 4,804 patients (0.44%). Only one patient suffered from an infection at more than one spinal level. CONCLUSIONS: The rate of discitis after cervical discography is relatively low. This can perhaps be further decreased by the use of prophylactic intradiscal antibiotics. Should the ability of cervical discography to improve surgical outcomes be proven, the fear of discitis should not preclude performance of disc provocation. PMID- 20171936 TI - Influence of needle type on the incidence of intravascular injection during transforaminal epidural injections: a comparison of short-bevel and long-bevel needles. AB - BACKGROUND CONTEXT: Vascular penetration and injection of corticosteroids into a vessel during lumbosacral transforaminal epidural injection is a suspected cause of myelopathy. Blunt needles have been suggested to avoid vascular penetration, but they are difficult to navigate. Another alternative to the standard long bevel sharp needles is the short-bevel needles. Some have postulated that short bevel needles are the best option for high-risk spine injections because they maintain navigation characteristics while potentially reducing the risk of complications. To date, no studies have been performed to either confirm or refute this. PURPOSE: The purpose of this study was to determine if there is a difference in the incidence of vascular penetration during lumbosacral transforaminal epidural injections between short-bevel and long-bevel needles. STUDY DESIGN/SETTING: This is a prospective, observational, in vivo study. PATIENT SAMPLE: The sample comprises patients receiving lumbosacral transforaminal epidural injections at a university-based outpatient spine center. OUTCOME MEASURE: The outcome measure was the incidence of vascular contrast patterns observed under live fluoroscopy. METHODS: One interventional spine physician recorded contrast patterns observed during 158 fluoroscopically guided lumbosacral transforaminal epidural injections under live fluoroscopy using two different types of needle tips. RESULTS: Vascular injections were observed in 22 of the 158 injections, for an overall incidence of 13.9%. The incidence of vascular injections in the short-bevel group was 15.6% (10/64) and in the long bevel group was 12.8% (12/94). This difference was not statistically significant (p=.6447). A secondary analysis was performed to determine if the needle gauge influenced the incidence of vascular injections, and again, there were no statistical differences in the overall rates of vascular injection. CONCLUSIONS: In comparison with long-bevel needles, short-bevel needles do not reduce the risk of inadvertent vascular injection in lumbosacral transforaminal epidural injections. PMID- 20171937 TI - Assessment of spine surgery outcomes: inconsistency of change amongst outcome measurements. AB - BACKGROUND CONTEXT: Outcomes of spinal treatments are evaluated by clinical relevance: the proportion of patients who reach a minimum clinically important outcome change. Outcomes are evaluated through multiple measurements, and the inconsistency of outcome change across measurements is not known. PURPOSE: The primary purpose of this study was to illustrate outcome inconsistencies after spinal surgery. Secondary goals of this study were to develop an index of overall change that incorporates outcome inconsistencies, to relate the index of overall change to patients' global assessment and satisfaction with treatment, to relate the index of global change to an intuitively understandable outcome: the level of tolerable pain. STUDY DESIGN: This study is a review of prospectively collected patient-reported outcomes data. PATIENT SAMPLE: Four hundred sixty patients from a large multicenter database were chosen. Those patients were included in the sample because they had undergone lumbar surgery and had baseline and 1-year follow-up scores. Baseline and 1-year follow-up scores for Oswestry Disability Index (ODI), physical component summary (PCS) of the Medical Outcome Study Short Form-36 (SF-36), numerical back and leg pain scales, and 1-year scores for satisfaction with results were included in the study. OUTCOME MEASURES: The outcome measures of the study were preoperative and 1-year postoperative scores for ODI, PCS, back pain scale, leg pain scale, health transition item of the SF 36, and satisfaction with results scales. METHODS: Oswestry Disability Index, SF 36, and pain scales were administered before and 1 year after spinal surgery. Satisfaction with results questionnaires were administered 1 year after surgery. The following threshold values were previously established and were used to evaluate outcome changes: minimum clinically important difference (MCID), substantial clinical benefit (SCB), and standard error of the mean. The following proportions of patients were determined according to outcome changes: "deteriorated," "no change," "below MCID," "above MCID," and "above SCB." The consistency of outcome change was determined amongst the four outcome measures. An index of overall change was developed and related to patients' answers to the health transition item of the SF-36 and to the satisfaction with results scale. The overall change index was also compared with the tolerable pain level. RESULTS: Only 40.5% of patients report consistent outcome changes on all four measures. The overall change index was significantly correlated to the global change and satisfaction scale (rho=.67, p less than .001). The overall change index was clearly associated with the tolerable pain level. CONCLUSIONS: Efforts should be made to take into account the inconsistency of outcomes and to make clinical relevance more readily understandable by patients and clinicians. PMID- 20171938 TI - The role of two- and three-dimensional dynamic ultrasonography in pelvic organ prolapse. AB - The assessment of pelvic organ prolapse has to date been limited to the clinical evaluation of surface anatomy. This is clearly insufficient. As a result, imaging of pelvic floor function and anatomy is moving from the fringes to the mainstream of obstetrics and gynecology. This is mainly due to the realization that pelvic floor trauma in labor is common, generally overlooked, and a major factor in the causation of pelvic organ prolapse. Modern imaging methods such as magnetic resonance and 3-dimensional ultrasonography have enabled us to diagnose such abnormalities reliably and accurately, most commonly in the form of an avulsion of the puborectalis muscle off its insertion on the os pubis. However, ultrasonography has other advantages in the assessment of pelvic organ prolapse, most notably in the differential diagnosis of posterior compartment prolapse, which can be due to at least 5 different conditions. In this review I will try to summarize the methods of prolapse and pelvic floor assessment by translabial ultrasonography and to describe the most common abnormalities and their consequences. This article will not deal with magnetic resonance imaging because I consider this technology to be of limited clinical utility due to technical restrictions, expense, and access issues. PMID- 20171939 TI - Hemodynamic response to lower body negative pressure in children: a pilot study. AB - Although head-up tilt and upright standing are common methods used to induce orthostatic stress, lower body negative pressure (LBNP) is another safe and easy technique that induces orthostatic stress independently of gravity. However, the use of LBNP in children has never been investigated. The purpose of this pilot study was to determine whether LBNP was capable of inducing hemodynamic adaptations in pre-pubertal boys. Ten healthy pre-pubertal boys (9+/-1 years) were recruited and randomly exposed to 3 levels of LBNP (15, 20 and 25 mm Hg). Heart rate, manual and beat-by-beat systolic (SBP), diastolic and mean arterial blood pressure were monitored continuously. Aortic diameter was measured at rest and peak aortic blood velocity was recorded continuously for at least 1 min during each condition. R-R interval (RRI), heart rate, stroke volume (SV), cardiac output (Q), total peripheral resistance (TPR), low frequency (LF) and high frequency (HF) baroreceptor sensitivity (BRS), as well as LF/HF RRI ratio were calculated. With increasing LBNP TPR increased while SBP decreased (P< or =0.05). As well, a trend towards a decrease in SV (P=0.054) and Q (P=0.06) was found. However, LF and HF BRS, and LF/HF RRI ratio did not significantly change from baseline to LBNP 15, 20 or 25 mm Hg. In conclusion, the results of this pilot study suggest that low levels of LBNP are capable of inducing hemodynamic adaptations in children that are to be expected when undergoing an orthostatic stress. As well, LBNP is a safe and effective method of inducing orthostatic stress in children. PMID- 20171940 TI - Impairment of baroreflex control of heart rate and structural changes of cardiac ganglia in conscious streptozotocin (STZ)-induced diabetic mice. AB - Baroreflex control of heart rate (HR) is impaired in human diabetes mellitus and in large experimental models. However, baroreflex impairment in diabetic mouse models and diabetes-induced remodeling of baroreflex circuitry are not well studied. We examined the impairment of baroreflex control of heart rate (HR) and assessed structural remodeling of cardiac ganglia in the streptozotocin (STZ) induced diabetic mouse model. FVB mice were either injected with vehicle or STZ. Group 1: mice were anesthetized and the femoral artery and vein were catheterized at the 30th day after vehicle or STZ injection. On the second day after surgery, baroreflex-mediated HR responses to sodium nitroprusside (SNP) and phenylephrine (PE)-induced mean arterial blood pressure (MABP) changes were measured in conscious mice. Group 2: Fluoro-Gold was administered (i.p.) to label cardiac ganglia in each mouse at the 25th day after vehicle or STZ injection. After another five days, animals were perfused and cardiac ganglia were examined using confocal microscopy. Compared with control, we found in STZ mice: 1) the HR decreased, but MABP did not. 2) The PE-induced increases of MABP were decreased. 3) Baroreflex bradycardia was attenuated in the rapid MABP ascending phase but the steady-state DeltaHR/DeltaMABP was not different at all PE doses. 4) SNP induced MABP decreases were not different. 5) Baroreflex tachycardia was attenuated. 6) The sizes of cardiac ganglia and ganglionic principal neurons were decreased. 7) The ratio of nucleus/cell body of cardiac ganglionic neurons was increased. We conclude that baroreflex control of HR is impaired in conscious STZ mice. In addition, diabetes may induce a significant structural remodeling of cardiac ganglia. Such an anatomical change of cardiac ganglia may provide new information for the understanding of diabetes-induced remodeling of the multiple components within the baroreflex circuitry. PMID- 20171941 TI - Simple liquid chromatography method for the quantification of irinotecan and SN38 in sheep plasma: application to in vivo pharmacokinetics after pulmonary artery chemoembolization using drug eluting beads. AB - A rapid and simple liquid chromatography-fluorescence detection (LC-FD) method was developed and validated for the simultaneous quantification of irinotecan (CPT11) and SN38 in sheep plasma. Camptothecin (CPT) was used as the internal standard. A single step protein precipitation with acetonitrile was used for sample preparation. The separation was achieved using a 5 microm C18 column (250 mm x 4.5 mm, 5 microm) with a mobile phase composed of 36 mM sodium dihydrogen phosphate dehydrate and 4 mM sodium 1 heptane sulfonate-acetonitrile (72:28), the pH of the mobile phase was adjusted to 3. The flow rate was 1.45 mL/min and the fluorescence detection was operated at 355/515 nm (excitation/emission wavelengths). The run time was 13 min. The method was validated with respect to selectivity, extraction recovery, linearity, intra- and inter-day precision and accuracy, limit of quantification and stability. The method has a limit of quantification of 5 ng/mL for both CPT11 and SN38. The assay was linear over concentrations ranging from 5 to 5000 ng/mL and to 240 ng/mL for CPT11 and SN38, respectively. This method was used successfully to perform plasma pharmacokinetic studies of CPT11 after pulmonary artery embolization (PACE) in a sheep model. It was also validated for CPT11 and SN38 analysis in sheep lymph and human plasma. PMID- 20171942 TI - Positron emission tomography imaging of DMBA/TPA mouse skin multi-step tumorigenesis. AB - Many tumor cells have elevated rates of glucose uptake that can be measured quantitatively, noninvasively and repeatedly by positron emission tomography (PET) with 2-deoxy-2-[(18)F]-fluoro-D-glucose ((18)F-FDG). Clinical imaging with (18)F-FDG PET has been used for detection and staging of primary and metastatic tumors. High-resolution microPET scanning and murine cancer models make it possible to analyze longitudinally glucose metabolism during the appearance, development and progression of individual experimental tumors. In this study, we used (18)F-FDG microPET and micro computerized tomography (microCT) to investigate glucose uptake in the DMBA/TPA chemically-induced multistage mouse skin carcinogenesis model. (18)F-FDG uptake is significantly higher in all papillomas than in surrounding skin. Elevated (18)F-FDG uptake is observed when tumors can be identified morphologically, but not before. Although (18)F-FDG uptake is high in all fully invasive, malignant skin squamous cell carcinomas, uptake in papillomas and microinvasive malignant squamous cell carcinomas is variable and does not exhibit any correlation with tumor stage. PMID- 20171943 TI - Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee. AB - We report the evidence-based Italian Association for the Study of Liver guidelines for the appropriate diagnosis and management of patients with nonalcoholic fatty liver disease in clinical practice and its related research agenda. The prevalence of nonalcoholic fatty liver disease varies according to age, gender and ethnicity. In the general population, the prevalence of nonalcoholic fatty liver disease is about 25% and the incidence is of two new cases/100 people/year. 2-3% of individuals in the general population will suffer from nonalcoholic steatohepatitis. Uncomplicated steatosis will usually follow a benign course. Individuals with nonalcoholic steatohepatitis, however, have a reduced life expectancy, mainly owing to vascular diseases and liver-related causes. Moreover, steatosis has deleterious effects on the natural history of HCV infection. Nonalcoholic fatty liver disease is usually diagnosed in asymptomatic patients prompted by the occasional discovery of increased liver enzymes and/or of ultrasonographic steatosis. Medical history, complete physical examination, etiologic screening of liver injury, liver biochemistry tests, serum lipids and insulin sensitivity tests should be performed in every patient. Occult alcohol abuse should be ruled out. Ultrasonography is the first-line imaging technique. Liver biopsy, the gold standard in diagnosis and prognosis of nonalcoholic fatty liver disease, is an invasive procedure and its results will not influence treatment in most cases but will provide prognostic information. Assessment of fibrosis by composite scores, specific laboratory parameters and transient elastography might reduce the number of nonalcoholic fatty liver disease patients requiring liver biopsy. Dieting and physical training reinforced by behavioural therapy are associated with improved nonalcoholic fatty liver disease. Diabetes and the metabolic syndrome should be ruled out at timed intervals in nonalcoholic fatty liver disease. Nonalcoholic steatohepatitis patients should undergo periodic evaluation of cardiovascular risk and of advancement of their liver disease; those with nonalcoholic steatohepatitis-cirrhosis should be evaluated for early diagnosis of hepatocellular carcinoma. PMID- 20171944 TI - Bloody diarrhea secondary to cytomegalovirus ileitis. PMID- 20171945 TI - Introduction to mini-symposium on cholangiocyte pathophysiology--part I. PMID- 20171946 TI - Surgical tip: A cheap and readily available alternative to the 10cc syringe lock for Coleman fat grafting. PMID- 20171947 TI - Decades of change in plastic surgery training. PMID- 20171948 TI - Reviewing statin therapy in diabetes--towards the best practise. AB - Statin therapy is considered critical both in primary and secondary prevention of cardiovascular disease in diabetes. Cholesterol Treatment Trialists' Collaborators meta-analysis of 14 randomised trials of statins in 18686 people with diabetes provides the latest and largest evidence showing a significant 21% reduction in major vascular events per mmol/l reduction in LDL cholesterol. Importantly, the risk reduction was similar in both types of diabetes. Growing evidence supports the view that statin therapy reduces microvascular complications as well. This review updates the current knowledge of statin therapy in preventing micro- and macrovascular complications in both type 1 and type 2 diabetes. PMID- 20171949 TI - Maintaining ATP levels via the suppression of PERK-mediated rRNA synthesis at ER stress. AB - Currently, [(3)H]uridine is most often used to monitor rRNA synthesis in cultured cells. We show here that radiolabeled ribonucleoside triphosphates, such as [alpha-(33)P]UTP, in culture medium were also incorporated efficiently not only into cells but also into de novo RNA, particularly rRNA. Using this method, we first revealed that endoplasmic reticulum (ER) stress inducers such as tunicamycin and thapsigargin suppressed de novo rRNA synthesis, and that PERK, but not IRE1alpha or ATF6, mediated the suppression. PERK is known to mediate the suppression of de novo protein synthesis via phosphorylation of eIF2alpha. Consistently, other translational inhibitors such as PSI, proteasomal inhibitor, and cycloheximide suppressed de novo rRNA synthesis. eIF2alpha knockdown also suppressed both de novo protein and rRNA syntheses. Furthermore, ER stress reduced cellular ATP levels, and the suppression of rRNA synthesis apparently mitigated their reduction. These observations provided a close link between ATP levels and suppression of de novo rRNA synthesis at ER stress, and we proposed a novel feedback mechanism, in which ATP levels were maintained via suppression of de novo rRNA synthesis in ATP-demanding stresses, such as ER stress. PMID- 20171950 TI - FSH-receptor isoforms and FSH-dependent gene transcription in human monocytes and osteoclasts. AB - Cells of the monocyte series respond to follicle stimulating hormone (FSH) by poorly characterized mechanisms. We studied FSH-receptors (FSH-R) and FSH response in nontransformed human monocytes and in osteoclasts differentiated from these cells. Western blot and PCR confirmed FSH-R expression on monocytes or osteoclasts, although at low levels relative to ovarian controls. Monocyte and osteoclast FSH-Rs differed from FSH-R from ovarian cells, reflecting variable splicing in exons 8-10. Monocytes produced no cAMP, the major signal in ovarian cells, in response to FSH. However, monocytes and osteoclasts transcribed TNFalpha in response to the FSH. No relation of expression of osteoclast FSH-R to the sex of cell donors or to exposure to sex hormones was apparent. Controls for FSH purity and endotoxin contamination were negative. Unamplified cRNA screening in adherent CD14 cells after 2h in 25ng/ml FSH showed increased transcription of RANKL signalling proteins. Transcription of key proteins that stimulate bone turnover, TNFalpha and TSG-6, increased 2- to 3-fold after FSH treatment. Smaller but significant changes occurred in transcripts of selected signalling, adhesion, and cytoskeletal proteins. We conclude that monocyte and osteoclast FSH response diverges from that of ovarian cells, reflecting, at least in part, varying FSH-R isoforms. PMID- 20171951 TI - Further evidence for direct pro-resorptive actions of FSH. AB - We confirm that FSH stimulates osteoclast formation, function and survival to enhance bone resorption. It does so via the activation of a pertussis toxin sensitive G(i)-coupled FSH receptor that we and others have identified on murine and human osteoclast precursors and mature osteoclasts. FSH additionally enhances the production of several osteoclastogenic cytokines, importantly TNFalpha, likely within the bone marrow microenvironment, to augment its pro-resorptive action. FSH levels in humans rise before estrogen falls, and this hormonal change coincides with the most rapid rates of bone loss. On the basis of accumulating evidence, we reaffirm that FSH contributes to the rapid peri-menopausal and early post-menopausal bone loss, which might thus be amenable to FSH blockade. PMID- 20171952 TI - Combination of small molecules enhances differentiation of mouse embryonic stem cells into intermediate mesoderm through BMP7-positive cells. AB - Embryonic stem cells (ESCs) are potentially powerful tools for regenerative medicine and establishment of disease models. The recent progress in ESC technologies is noteworthy, but ESC differentiation into renal lineages is relatively less established. The present study aims to differentiate mouse ESCs (mESCs) into a renal progenitor pool, the intermediate mesoderm (IM), without addition of exogenous cytokines and embryoid formation. First, we treated mESCs with a combination of small molecules (Janus-associated tyrosine kinase inhibitor 1, LY294002, and CCG1423) and differentiated them into BMP7-positive cells, BMP7 being the presumed inducing factor for IM. When these cells were cultured with adding retinoic acid, expression of odd-skipped related 1 (Osr1), which is essential to IM differentiation, was enhanced. To simplify the differentiation protocol, the abovementioned four small molecules (including retinoic acid) were combined and added to the culture. Under this condition, more than one-half of the cells were positive for Osr1, and at the same time, Pax2 (another IM marker) was detected by real-time PCR. Expressions of ectodermal marker and endodermal marker were not enhanced, while mesodermal marker changed. Moreover, expression of genes indispensable to kidney development, i.e., Lim1 and WT1, was detected by RT-PCR. These results indicate the establishment of a specific, effective method for differentiation of the ESC monolayer into IM using a combination of small molecules, resulting in an attractive cell source that could be experimentally differentiated to understand nephrogenic mechanisms and cell-to-cell interactions in embryogenesis. PMID- 20171953 TI - Cdc42p and Rho1p are sequentially activated and mechanistically linked to vacuole membrane fusion. AB - Small monomeric GTPases act as molecular switches, regulating many biological functions via activation of membrane localized signaling cascades. Activation of their switch function is controlled by GTP binding and hydrolysis. Two Rho GTPases, Cdc42p and Rho1p, are localized to the yeast vacuole where they regulate membrane fusion. Here, we define a method to directly examine vacuole membrane Cdc42p and Rho1p activation based on their affinity to probes derived from effectors. Cdc42p and Rho1p showed unique temporal activation which aligned with distinct subreactions of in vitro vacuole fusion. Cdc42p was rapidly activated in an ATP-independent manner while Rho1p activation was kinetically slower and required ATP. Inhibitors that are known to block vacuole membrane fusion were examined for their effect on Cdc42p and Rho1p activation. Rdi1p, which inhibits the dissociation of GDP from Rho proteins, blocked both Cdc42p and Rho1p activation. Ligands of PI(4,5)P(2) specifically inhibited Rho1p activation while pre-incubation with U73122, which targets Plc1p function, increased Rho1p activation. These results define unique activation mechanisms for Cdc42p and Rho1p, which may be linked to the vacuole membrane fusion mechanism. PMID- 20171954 TI - High dose of ascorbic acid induces cell death in mesothelioma cells. AB - Malignant mesothelioma is an asbestos-related fatal disease with no effective cure. Recently, high dose of ascorbate in cancer treatment has been reexamined. We studied whether high dose of ascorbic acid induced cell death of four human mesothelioma cell lines. High dose of ascorbic acid induced cell death of all mesothelioma cell lines in a dose-dependent manner. We further clarified the cell killing mechanism that ascorbic acid induced reactive oxygen species and impaired mitochondrial membrane potential. In vivo experiment, intravenous administration of ascorbic acid significantly decreased the growth rate of mesothelioma tumor inoculated in mice. These data suggest that ascorbic acid may have benefits for patients with mesothelioma. PMID- 20171955 TI - Hydrogen-rich saline improves memory function in a rat model of amyloid-beta induced Alzheimer's disease by reduction of oxidative stress. AB - This study is to examine if hydrogen-rich saline reduced amyloid beta (Abeta) induced neural inflammation, and learning and memory deficits in a rat model. S-D male rats (n=84, 280-330g) were divided into three groups, sham-operated, Abeta1 42 injected and Abeta1-42 plus hydrogen-rich saline-treated animals. Hydrogen rich saline (5ml/kg, i.p., daily) was injected for 14days after intracerebroventricular injection of Abeta1-42. The levels of MDA, IL-6 and TNF alpha were assessed by biochemical and ELISA analysis. Morris Water Maze and open field task were used to assess the memory dysfunction and motor dysfunction, respectively. LTP were used to detect the electrophysiology changes, HNE and GFAP immunohistochemistry were used to assess the oxidative stress and glial cell activation. After Abeta1-42 injection, the levels of MDA, IL-6, and TNF-alpha were increased in brain tissues and hydrogen-rich saline treatment suppressed MDA, IL-6, and TNF-alpha concentration. Hydrogen-rich saline treatment improved Morris Water Maze and enhanced LTP in hippocampus blocked by Abeta1-42. Furthermore, hydrogen-rich saline treatment also decreased the immunoreactivitiy of HNE and GFAP in hippocampus induced by Abeta1-42. In conclusion, hydrogen-rich saline prevented Abeta-induced neuroinflammation and oxidative stress, which may contribute to the improvement of memory dysfunction in this rat model. PMID- 20171956 TI - The basolateral amygdala mediates the effects of cues associated with meal interruption on feeding behavior. AB - Considerable evidence shows that environmental cues that signal food delivery when rats are food-deprived can substantially potentiate feeding later when rats are food-sated. Similarly, cues associated with meal interruption, food removal or impending food scarcity may also induce increased eating. For example, after learning the association between a discrete "interruption" stimulus and the unexpected termination of food trials, sated rats show enhanced food consumption when exposed to that stimulus. In Experiment 1, unlike sham-lesioned controls, rats with bilateral excitotoxic lesions of the basolateral amygdala (BLA) failed to display such cue-potentiated feeding. In Experiment 2, potentiation of feeding by an interruption signal was found to be food-specific. That is, a stimulus that signaled interruption of trials with one food but not trials with a second food later only facilitated consumption of the first food. These studies extend our knowledge of the psychological and neural processes underlying cue-induced feeding. Understanding these mechanisms may contribute our understanding of the etiology and treatment of binge eating disorders. PMID- 20171958 TI - Brain self-protection: the role of endogenous neural progenitor cells in adult brain after cerebral cortical ischemia. AB - Convincing evidence has shown that brain ischemia causes the proliferation of neural stem cells/neural progenitor cells (NSCs/NPCs) in both the subventricular zone (SVZ) and the subgranular zone (SGZ) of adult brain. The role of brain ischemia-induced NSC/NPC proliferation, however, has remained unclear. Here we have determined whether brain ischemia-induced amplification of the NSCs/NPCs in adult brain is required for brain self-protection. The approach of intracerebroventricular (ICV) infusion of cytosine arabinoside (Ara-C), an inhibitor for cell proliferation, for the first 7days after brain ischemia was used to block ischemia-induced NSC/NPC proliferation. We observed that ICV infusion of Ara-C caused a complete blockade of NSC/NPC proliferation in the SVZ and a dramatic reduction of NSC/NPC proliferation in the SGZ. Additionally, as a result of the inhibition of ischemia-induced NSC/NPC pool amplification, the number of neurons in the hippocampal CA1 and CA3 was significantly reduced, the infarction size was significantly enlarged, and neurological deficits were significantly worsened after focal brain ischemia. We also found that an NSC/NPC conditioned medium showed neuroprotective effects in vitro and that adult NSC/NPC released brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) are required for NSC/NPC-conditioned medium-induced neuroprotection. These data suggest that NSC/NPC-generated trophic factors are neuroprotective and that brain ischemia-triggered NSC/NPC proliferation is crucial for brain protection. This study provides insights into the contribution of endogenous NSCs/NPCs to brain self-protection in adult brain after ischemia injury. PMID- 20171957 TI - Organic cation transporter inhibition increases medial hypothalamic serotonin under basal conditions and during mild restraint. AB - The dorsomedial hypothalamus (DMH) has been implicated in the coordination of stress responses. Restraint stress or systemic corticosterone (CORT) treatment induces a rapid increase in tissue concentrations of serotonin (5 hydroxytryptamine; 5-HT) in the DMH. Although the mechanism for rapid changes in 5-HT concentrations in the DMH is not clear, earlier results suggest that stress induced increases in CORT may inhibit 5-HT transport from the extracellular fluid by acting on corticosterone-sensitive organic cation transporters (OCTs). We tested the hypothesis that perfusion of the medial hypothalamus (MH), which includes the DMH, with the OCT blocker decynium 22 (D-22) would potentiate the effects of mild restraint on extracellular 5-HT. Male Sprague-Dawley rats, implanted with a microdialysis probe into the MH, were treated with reverse dialysis of D-22 (20 microM; 40 min) or vehicle and subjected to either 40 min mild restraint or undisturbed control conditions. Perfusates collected from a separate group of rats were evaluated for the effect of restraint on extracellular CORT concentrations in the MH. Reverse-dialysis of D-22 induced an increase (200%) in extracellular 5-HT concentrations in the MH in undisturbed control rats. Restraint in the absence of D-22 did not significantly affect MH CORT or 5-HT concentrations. However, perfusion of the MH with D-22 during restraint led to an increased magnitude and duration of extracellular 5-HT concentrations, relative to D-22 by itself. These results are consistent with the hypothesis that OCTs in the DMH contribute to the clearance of 5-HT from the extracellular fluid under both baseline conditions and mild restraint. PMID- 20171959 TI - The hyperalgesic effects induced by the injection of angiotensin II into the caudal ventrolateral medulla are mediated by the pontine A5 noradrenergic cell group. AB - The caudal ventrolateral medulla (CVLM) is a key component of the supraspinal pain modulatory system. Pain modulation from the CVLM is partially relayed by spinally projecting noradrenergic neurons of the pontine A(5) cell group, which leave collateral fibres at the CVLM. The injection of angiotensin II (Ang II) into the CVLM was recently shown to induce hyperalgesia mediated by angiotensin type 1 (AT(1)) receptors, expressed by CVLM neurons that do not project to the spinal cord. The present study evaluates the effects of lesioning the noradrenergic pontine A(5) cell group by the retrograde transport of the selective toxin anti-dopamine beta-hydroxylase-saporin (anti-DBH-SAP) from the CVLM in pain behavioural responses elicited by Ang II injection into the CVLM. The injection of anti-DBH-SAP induced neurodegeneration, identified by the marker Fluoro-Jade B, restricted to the A(5) noradrenergic cell group. These results were confirmed by the decrease in the number of noradrenergic neurons only in the A(5) group. Pain behavioural evaluation using the formalin test showed that Ang II injection into the CVLM induced hyperalgesia, which was partially prevented by lesion of the A(5) noradrenergic cell group with anti-DBH-SAP. Immunostaining of AT(1) receptors in CVLM neurons retrogradely labelled from the A(5) noradrenergic cell group showed that CVLM neurons that project to the A(5) express AT(1) receptors, indicating that Ang II can modulate directly the CVLM-A(5) connection. The results show that Ang II-induced hyperalgesia elicited from the CVLM is mediated by an indirect pathway relayed at the pontine noradrenergic A(5) group. PMID- 20171960 TI - Effects of hemoglobin C and S traits on Tosoh G8 and Siemens Advia HbA1c assays. PMID- 20171961 TI - Diagnostic performance of IgG anti-deamidated gliadin peptide antibody assays is comparable to IgA anti-tTG in celiac disease. AB - BACKGROUND: Detection of IgG antibodies against deamidated gliadin peptides (DGP) is more sensitive and more specific for celiac disease than detection of IgG antibodies against native gliadin. Our aim was to evaluate the technical performance and diagnostic accuracy of four commercial IgG anti-DGP assays. METHODS: Commercial IgG anti-DGP assays from Euroimmun, Inova, Phadia and The Binding Site were evaluated and their diagnostic accuracy (sensitivity and specificity) compared to other serologic assays for celiac disease (3IgA and 2IgG anti-tTG assays, 1IgA and 1IgG anti-gliadin assay, 1IgA anti-DGP assay). The study population consisted of 86 consecutive CD patients and 741 disease controls. RESULTS: The technical performance (linearity, interference and imprecision) of the IgG anti-DGP assays was acceptable. The sensitivity of the IgG anti-DGP assays varied between 76.7% and 86.0% at the cut-off recommended by the manufacturer and between 74.4% and 86.0% at the cut-off that corresponded to a specificity of 98%. The specificity varied between 97.3% and 99.3%. The diagnostic accuracy of the IgG anti-DGP assays was comparable to the diagnostic accuracy of the IgA anti-tTG assays. The sensitivity of the IgG anti-DGP assays was significantly better than sensitivity of the IgG anti-tTG assays (p<0.05) and the specificity was significantly better than the IgA and IgG anti-gliadin assays (p<0.05). CONCLUSIONS: The overall performance of the four IgG anti-DGP assays was acceptable and the diagnostic accuracy comparable to the three IgA anti-tTG assays. PMID- 20171962 TI - Functional analysis of Scr during embryonic and post-embryonic development in the cockroach, Periplaneta americana. AB - The cockroach, Periplaneta americana represents a basal insect lineage that undergoes the ancestral hemimetabolous mode of development. Here, we examine the embryonic and post-embryonic functions of the hox gene Scr in Periplaneta as a way of better understanding the roles of this gene in the evolution of insect body plans. During embryogenesis, Scr function is strictly limited to the head with no role in the prothorax. This indicates that the ancestral embryonic function of Scr was likely restricted to the head, and that the posterior expansion of expression in the T1 legs may have preceded any apparent gain of function during evolution. In addition, Scr plays a pivotal role in the formation of the dorsal ridge, a structure that separates the head and thorax in all insects. This is evidenced by the presence of a supernumerary segment that occurs between the labial and T1 segments of RNAiScr first nymphs and is attributed to an alteration in engrailed (en) expression. The fact that similar Scr phenotypes are observed in Tribolium but not in Drosophila or Oncopeltus reveals the presence of lineage-specific variation in the genetic architecture that controls the formation of the dorsal ridge. In direct contrast to the embryonic roles, Scr has no function in the head region during post-embryogenesis in Periplaneta, and instead, strictly acts to provide identity to the T1 segment. Furthermore, the strongest Periplaneta RNAiScr phenotypes develop ectopic wing-like tissue that originates from the posterior region of the prothoracic segment. This finding provides a novel insight into the current debate on the morphological origin of insect wings. PMID- 20171963 TI - Pitfalls in spontaneous in vitro transformation of human mesenchymal stem cells. PMID- 20171964 TI - An inducible Tet-Off-H2B-GFP lentiviral reporter vector for detection and in vivo isolation of label-retaining cells. AB - Many regenerative cells are label-retaining cells (LRCs) due to their ability to keep a DNA label over a prolonged time. Until recently, isolation of vital LRCs was hampered due to the necessary use of fixation methods. To circumvent this, we generated a lentiviral-(HIV-1) based vector expressing a Tet-Off controlled histone 2B-GFP (Tet-Off-H2B-GFP) reporter gene for the detection and isolation of viable LRCs. In initial experiments, the vector was successfully used to infect 2 and 3-dimensional tissue culture models. Infected cultures from skin and pancreatic cells showed a very tight regulation of H2B-GFP, were sensitive to minimal amounts of doxycycline (Dox) and had a stable transgenic expression over the time of this study. Our lentiviral vector represents a reliable and easy to handle system for the successful infection, detection and isolation of LRCs from various tissues in vitro, in vivo and ex vivo. PMID- 20171965 TI - From endoscopic hemostasis to bleeding peptic ulcers: strategies to prevent and treat recurrent bleeding. PMID- 20171967 TI - Exogenous androgen during development alters adult partner preference and mating behavior in gonadally intact male rats. AB - In the rat, neonatal administration of testosterone propionate to a castrated male causes masculinization of behavior. However, if an intact male is treated neonatally with testosterone (hyper-androgen condition), male sexual behavior in adulthood is disrupted. There is a possibility that the hyper-androgen treatment is suppressing male sexual behavior by altering the male's partner preference and thereby reducing his motivation to approach the female. If so, this would suggest that exposure to supra-physiological levels of androgen during development may result in the development of male-oriented partner preference in the male. To test this idea, male rats were treated either postnatally or prenatally with testosterone, and partner preference and sexual behavior were examined in adulthood. The principal finding of this study was that increased levels of testosterone during early postnatal life, but not prenatal, decreased male sexual behavior and increased the amount of time a male spent with a stimulus male, without affecting the amount of time spent with a stimulus female during partner preference tests. Thus, the reduction in male sexual behavior produced by early exposure to high levels of testosterone is not likely due to a reduction in the male's motivation to approach a receptive female. PMID- 20171966 TI - Low doses of cocaine decrease, and high doses increase, anxiety-like behavior and brain progestogen levels among intact rats. AB - There are sex and hormonal differences in response to cocaine that have been demonstrated in people and animal models. Cocaine can alter secretion of progestogens, such as progesterone (P), and its neuroactive metabolite, 5alpha pregnan-3alpha-ol-20-one (3alpha,5alpha-THP). However, little research has been done on the neuroendocrine effects in the initiation phase of cocaine use. We hypothesize that some sex/hormonal differences in initiation phase responses to cocaine may be related to formation of progestogens. To investigate the role of progestogens in sex differences in response to acute cocaine, male and female rats in the high (proestrous) or low (diestrous) progestogen phase of the estrous cycle were administered cocaine (0, 5, 10, or 20mg/kg, IP). We examined cocaine's acute neuroendocrine effects on P and 3alpha,5alpha-THP levels, as well as its effects on acute psychomotor stimulation, anxiety, and sexual behaviors. Among rats that had P and/or 3alpha,5alpha-THP levels increased in response to cocaine, enhanced acute psychomotor stimulation was observed. Results suggest that cocaine produces U-shaped curves for progestogens, and anxiety-like behaviors. Male rats were less susceptible to these effects of cocaine than were proestrous or diestrous female rats. However, cocaine's disruption of sexual behaviors was similar among males and proestrous females. These data suggest a complex interaction between hormonal milieu and the neuroendocrine and behavioral effects of cocaine. PMID- 20171968 TI - Ex vivo expansion protocol for human tumor specific T cells for adoptive T cell therapy. AB - Adoptive T cell therapy is a promising treatment strategy for patients with different types of cancer. The methods used for generation of high numbers of tumor specific T cells usually require long-term ex vivo culture, which frequently lead to generation of terminally differentiated effector cells, demonstrating low persistence in vivo. Therefore, optimization of protocols for generation of T cells for adoptive cell therapy is warranted. The aim of this work was to develop a protocol for expansion of antigen-specific T cells using Dynabeads CD3/CD28 to obtain T cells expressing markers important for in vivo persistence and survival. To achieve high numbers of antigen-specific T cells following expansion, we have tested the effect of depleting regulatory T cells using Dynabeads CD25 and including a pre-stimulation step with peptide prior to the non-specific expansion with Dynabeads. Our data demonstrate that virus- and tumor specific T cells can be expanded to high numbers using Dynabeads CD3/CD28 following optimization of the culture conditions. The expansion protocol presented here results in enrichment of antigen-specific CD8(+) T cells with an early/intermediate memory phenotype. This is observed even when the antigen specific CD8(+) T cells demonstrated a terminal effector phenotype prior to expansion. This protocol thus results in expanded T cells with a phenotypic profile which may increase the chance of retaining long-term persistence following adoptive transfer. Based on these data we have developed a cGMP protocol for expansion of tumor specific T cells for adoptive T cell therapy. PMID- 20171969 TI - Housekeeping genes; expression levels may change with density of cultured cells. AB - Western blotting is a powerful technique to characterize a multitude of cellular proteins. As an internal control, the blots are commonly probed for "housekeeping" gene products. In this communication, we show that cell confluence significantly affects the levels of two such widely used proteins, alpha-tubulin and Glyceraldehyde-3-Phosphate Dehydrogenase. On the other hand the levels of heat-shock protein-90 and beta-actin remained unchanged at a wide range of cell densities, making these proteins into more reliable loading controls. PMID- 20171970 TI - Quantitative measurement of F-actin accumulation at the NK cell immunological synapse. AB - NK cells are lymphocytes of the innate immune system that can kill target cells after activation signal-induced directional secretion of lytic granule contents. This process depends upon F-actin polymerization at the NK cell immunological synapse (NKIS), which is the dynamic organization of molecules at the interface between the NK cell and target cell. Although F-actin accumulation at the NKIS is easily visualized, the ability to quantify F-actin at the NKIS is required to understand how F-actin reorganization and accumulation enable NK cell function. Here, we demonstrate several novel algorithms for measuring the content of F actin accumulated at the NKIS with special emphasis upon actin contributed by the NK cell. These algorithms do not rely upon overexpressing fluorescent proteins or preincubating cells with vital fluorescent dyes. Using models of the activating and inhibitory NKIS as well as NK cells expressing fluorescent protein--cell surface receptor fusion proteins, these algorithms were tested and were used to quantitatively demonstrate that F-actin accumulates at the activating, but not at the inhibitory NKIS. With these approaches, we have also established mathematical formulas that should prove valuable in the comprehensive quantitative evaluation of the NKIS and be more broadly applicable in the measurement of the accumulation of any fluorophore at an intercellular junction. PMID- 20171971 TI - Susceptibility of preimaginal western cherry fruit fly, Rhagoletis indifferens (Diptera: Tephritidae) to Beauveria bassiana (Balsamo) Vuillemin Clavicipitaceae (Hypocreales). AB - Last-instar larvae of the western cherry fruit fly, Rhagoletis indifferens, were subjected to Beauveria bassiana GHA incorporated into sterile sand and non sterile orchard soil. Mycosis in the pupal stage was observed in >20% of buried R. indifferens pupae and >80% of larvae entering sand treated with either of two B. bassiana isolates. When pre-pupal larvae burrowed into conidium-treated non sterile cherry orchard soil, the incidence of mycosis, on both the puparia and internally developing pupae, increased with dose. Internal pupal tissues were found to contain B. bassiana. Increasing the soil moisture level from 20% to 35% water holding capacity did not have an effect on the percentage of mycosed pupae. This is the first evidence that the preimaginal stages of R. indifferens are susceptible to infection by B. bassiana. PMID- 20171972 TI - Effect of environmental factors on survival and growth of quahog parasite unknown (QPX) in vitro. AB - Quahog parasite unknown (QPX) is a protistan microorganism associated with mass mortalities of hard clams (Mercenaria mercenaria) along the northeastern coasts of the United States and maritime Canada. Because several studies indicate modulatory effects of prevailing environmental parameters on disease outbreaks, this study tested the effect of major environmental parameters (temperature, salinity and oxygen concentration; individually or combined) on QPX survival in artificial seawater and parasite growth in culture media in vitro. Three QPX isolates from two different geographic locations were compared. Results indicated that in vitro growth of QPX was optimal in standard culture medium at 34ppt between 20 degrees C and 23 degrees C. Additionally, significant differences in temperature optima were observed for geographically distinct QPX isolates (p<0.001) confirming previous studies suggesting the existence of different QPX strains (or ecotypes). When tested in seawater, QPX exhibited opposite trends with higher survival at 15 degrees C and 15ppt. Results also demonstrated limited survival and growth of QPX under anoxic conditions. Additionally, results showed that the parasite is able to survive extreme temperatures (-12 degrees C to 32 degrees C) suggesting that QPX could overcome short periods of extreme conditions in the field. These results contribute to a better understanding of interactions between QPX and its environment, but potential impacts of environmental conditions on QPX disease development need further work as it also involves clam response to these factors. PMID- 20171973 TI - The effect of correlations on the population dynamics of lymphocytes. AB - Recent studies of the population dynamics of a system of lymphocytes in an in vitro immune response have reported strong correlations in cell division times, both between parents and their progeny, and between those of sibling cells. The data also show a high level of correlation in the ultimate number of divisions achieved by cells within the same clone. Such correlations are often ignored in mathematical models of cell dynamics as they violate a standard assumption in the theory of branching processes, that of the statistical independence of cells. In this article we present a model in which these correlations can be incorporated, and have used this model to study the effect of these correlations on the population dynamics of a system of cells. We found that correlation in the division times between parents and their progeny can alter the mean population size of clones within the system, while all of the correlations can affect the variance in the sizes of different clones. The model was then applied to experimental data obtained from time-lapse video microscopy of a system of CpG stimulated B lymphocytes and it was found that inclusion of the correct correlation structure is necessary to accurately reproduce the observed population dynamics. We conclude that correlations in the dynamics of cells within an ensemble will affect the population dynamics of the system, and the effects will become more pronounced as the number of divisions increases. PMID- 20171974 TI - Consistent micro, macro and state-based population modelling. AB - A population system can be modelled using a micro model focusing on the individual entities, a macro model where the entities are aggregated into compartments, or a state-based model where each possible discrete state in which the system can exist is represented. However, the concepts, building blocks, procedural mechanisms and the time handling for these approaches are very different. For the results and conclusions from studies based on micro, macro and state-based models to be consistent (contradiction-free), a number of modelling issues must be understood and appropriate modelling procedures be applied. This paper presents a uniform approach to micro, macro and state-based population modelling so that these different types of models produce consistent results and conclusions. In particular, we demonstrate the procedures (distribution, attribute and combinatorial expansions) necessary to keep these three types of models consistent. We also show that the different time handling methods usually used in micro, macro and state-based models can be regarded as different integration methods that can be applied to any of these modelling categories. The result is free choice in selecting the modelling approach and the time handling method most appropriate for the study without distorting the results and conclusions. PMID- 20171975 TI - Recolonisation by diffusion can generate increasing rates of spread. AB - Diffusion is one of the most frequently used assumptions to explain dispersal. Diffusion models and in particular reaction-diffusion equations usually lead to solutions moving at constant speeds, too slow compared to observations. As early as 1899, Reid had found that the rate of spread of tree species migrating to northern environments at the beginning of the Holocene was too fast to be explained by diffusive dispersal. Rapid spreading is generally explained using long distance dispersal events, modelled through integro-differential equations (IDEs) with exponentially unbounded (EU) kernels, i.e. decaying slower than any exponential. We show here that classical reaction-diffusion models of the Fisher Kolmogorov-Petrovsky-Piskunov type can produce patterns of colonisation very similar to those of IDEs, if the initial population is EU at the beginning of the considered colonisation event. Many similarities between reaction-diffusion models with EU initial data and IDEs with EU kernels are found; in particular comparable accelerating rates of spread and flattening of the solutions. There was previously no systematic mathematical theory for such reaction-diffusion models with EU initial data. Yet, EU initial data can easily be understood as consequences of colonisation-retraction events and lead to fast spreading and accelerating rates of spread without the long distance hypothesis. PMID- 20171977 TI - Changes in mitogen-activated protein kinase in cerebellar granule neurons by polybrominated diphenyl ethers and polychlorinated biphenyls. AB - Polybrominated diphenyl ethers (PBDEs) are used as additive flame retardants and have been detected in human blood, adipose tissue, and breast milk. Both in vitro and in vivo studies have shown that the effects of PBDEs are similar to the known human developmental neurotoxicants such as polychlorinated biphenyls (PCBs) on a molar basis. Previously, we reported that PBDE mixtures and congeners, perturbed calcium homeostasis which is critical for the development and function of the nervous system. In the present study, we tested whether environmentally relevant PBDE/PCB mixtures and congeners affected mitogen-activated protein kinase (MAPK) pathways, which are down-stream events of calcium signaling in cerebellar granule neuronal cultures. In this study, phosphorylated extracellular signal-regulated kinase (pERK)1/2, a widely studied MAPK cascade and known to be involved in learning and memory, levels were quantitated using western blot technique with phospho-specific antibodies. Glutamate (a positive control) increased pERK1/2 in a time- and concentration-dependent manner reaching maximum activation at 5-30min of exposure and at doses > or =10microM. Both Aroclor 1254 (a commercial penta PCB mixture) and DE-71 (a commercial penta PBDE mixture) elevated phospho-ERK1/2, producing maximum stimulation at 30min and at concentrations > or =3microg/ml; Aroclor 1254 was more efficacious than DE-71. DE-79 (an octabrominated diphenyl ether mixture) also elevated phospho-ERK1/2, but to a lesser extent than that of DE-71. PBDE congeners 47, 77, 99, and 153 also increased phospo-ERK1/2 in a concentration-dependent manner. The data indicated that PBDE congeners are more potent than the commercial mixtures. PCB 47 also increased phospho-ERK1/2 like its structural analog PBDE 47, but to a lesser extent, suggesting that these chemicals affect similar pathways. Cytotoxicity, measured as %LDH release, data showed that higher concentrations (>30microM) and longer exposures (>30min) are required to see cell death. These results show that PBDE mixtures and congeners activate MAPK pathway at concentrations where no significant cytotoxicity was observed, suggesting that perturbed intracellular signaling including MAPK pathway might be involved in the initiation of adverse effects, including learning and memory, related to these persistent chemicals. PMID- 20171976 TI - 2,3,7,8-tetrachlorodibenzo-p-dioxin increases reactive oxygen species production in human endothelial cells via induction of cytochrome P4501A1. AB - Studies in our laboratory have demonstrated that subchronic 2,3,7,8, tetrachlorodibenzo-p-dioxin (TCDD) exposure of adult mice results in hypertension, cardiac hypertrophy, and reduced nitric oxide (NO)-mediated vasodilation. Moreover, increased superoxide anion production was observed in cardiovascular organs of TCDD-exposed mice and this increase contributed to the reduced NO-mediated vasodilation. Since cytochrome P4501A1 (CYP1A1) can contribute to some TCDD-induced toxicity, we tested the hypothesis that TCDD increases reactive oxygen species (ROS) in endothelial cells by the induction of CYP1A1. A concentration-response to 24h TCDD exposure (10pM-10nM) was performed in confluent primary human aortic endothelial cells (HAECs). Oxidant-sensitive fluorescent probes dihydroethidium (DHE) and 2',7'-dichlorofluorescin diacetate (DCFH-DA), were used to measure superoxide anion, and hydrogen peroxide and hydroxyl radical, respectively. NO was also measured using the fluorescent probe diaminofluorescein-2 diacetate (DAF-2DA). These assessments were conducted in HAECs transfected with siRNA targeting the aryl hydrocarbon receptor (AhR), CYP1A1, or CYP1B1. TCDD concentration-dependently increased CYP1A1 and CYP1B1 mRNA, protein, and enzyme activity. Moreover, 1nM TCDD maximally increased DHE (Cont=1.0+/-0.3; TCDD=5.1+/-1.0; p=0.002) and DCFH-DA (Cont=1.0+/-0.2; TCDD=4.1+/ 0.5; p=0.002) fluorescence and maximally decreased DAF-2DA fluorescence (Cont=1.0+/-0.4; TCDD=0.68+/-0.1). siRNA targeting AhR and CYP1A1 significantly decreased TCDD-induced DHE (siAhR: Cont=1.0+/-0.1; TCDD=1.3+/-0.2; p=0.093) (siCYP1A1: Cont=1.0+/-0.1; TCDD=1.1+/-0.1; p=0.454) and DCFH-DA (siAhR: Cont=1.0+/-0.2; TCDD=1.3+/-0.3; p=0.370) (siCYP1A1: Cont=1.0+/-0.1; TCDD=1.3+/ 0.2; p=0.114) fluorescence and increased DAF-2DA fluorescence (siAhR: Cont=1.00+/ 0.03; TCDD=0.97+/-0.03; p=0.481) (siCYP1A1: Cont=1.00+/-0.03; TCDD=0.92+/-0.03; p=0.034), while siRNA targeting CYP1B1 did not. These data suggest that TCDD induced increase in ROS is AhR-dependent and may be mediated, in part, by CYP1A1 induction. PMID- 20171978 TI - Estimating the time-to-passage of visual self-motion: Is the second order motion information processed? AB - Previous work demonstrated that estimating time-to-contact (TTC) of moving objects towards an observer is based only on first-order information and does not take into account the acceleration information. We investigated whether smooth and continuous speed variations are considered in the extrapolation of linear self-motion towards a stationary target. The time-to-passage (TTP) estimation task consisted in presenting a simulated forward self-motion along a street at constant, increasing or decreasing velocity. After a while, the visual target appeared (e.g. a banner) before the visual stimulation ceased. Participants were then asked to imagine that the self-motion continued, and to press a button when they believed they reached the banner. The results showed that during accelerations, TTP estimates were closer to 2nd order than to 1st order predictions for the highest speed variations and the longest expected TTPs, but were between 1st and 2nd order predictions for other cases. On the contrary, during decelerations, TTP estimates were closer to 1st order predictions in most cases. This finding suggests that during accelerations, the processing of speed variations for the TTP estimation depends on the magnitude of the speed variations, whereas during decelerations, the extrapolation depends only on the final speed. PMID- 20171979 TI - Lateral interactions across space reveal links between processing streams for luminance-modulated and contrast-modulated stimuli. AB - Foveal detection thresholds for luminance-modulated (LM) and contrast-modulated (CM) blobs in the presence of fixed modulation, laterally placed noise blobs (separations of 0-6 degrees ) were measured in four observers with normal vision. Detection thresholds measured for LM blobs placed between highly visible LM flankers (111) and for CM blobs placed between highly visible CM flankers (222) produces a similar pattern of lateral interaction effects, i.e. masking where the stimuli overlap and facilitation for separations of 4-8x blob sd units. The region of facilitation is not matched by shallow psychometric function slopes. Detection thresholds measured for LM blobs placed between highly visible CM flankers (212) are generally facilitatory but relatively raised for separations of 0.5-2 degrees . For CM blobs placed between highly visible LM flankers (121), facilitation is stronger in the 0.5-2 degrees region. A significant correlation between thresholds and psychometric function slopes is found only for the 212 condition. We propose a model with two separate but interacting processing streams for the detection of LM and CM targets that may engage different cortical loci. PMID- 20171980 TI - The molecular therapy of colorectal cancer. AB - Although colorectal cancer (CRC) is still one of the leading causes of cancer related death in the western hemisphere, new therapeutic options have increased the overall survival rate of advanced disease from 10 to 18-24months during the past decade. The new therapeutics include biological agents as bevacizumab (Avastin), a monoclonal antibody against vascular endothelial growth factor (VEGF), and cetuximab (Erbitux), an inhibitor of epithelial growth factor receptor (EGFR). Although these biologicals have entered clinical routine due to their encouraging results, their effect has been shown to be limited due to adaptation or previously existing resistance of tumor cells. This has been clearly shown in the case of patients with mutations of K-ras, which lead to resistance against cetuximab. Therefore, several new pathways are currently investigated for therapeutic targeting in CRC. These include WNT-signaling, downstream mediators of EGFR as the mitogen-activated protein kinase (MAPK)- or the phosphatidylinositol 3-kinase (PI3K)-pathway, the hypoxia response system involving hypoxia inducible factor-1 (HIF-1), mechanisms of tumor development following chronic inflammation, and many others. This article will review new molecular targets for the treatment of CRC and discuss possible implications for clinical therapy. PMID- 20171981 TI - Oral gavage subchronic neurotoxicity and inhalation subchronic immunotoxicity studies of ethylbenzene in the rat. AB - The potential for neurotoxicological and immunotoxicological effects of ethylbenzene was studied in young adult Crl:CD(SD) rats following 90-day oral (neurotoxicity) or 28-day inhalation (immunotoxicity) exposures. In the neurotoxicity study, ethylbenzene was administered orally via gavage twice daily at 0, 25, 125, or 250 mg/kg per dose (total daily dosages of 0, 50, 250, or 500 mg/kg bwt/day [mg/kg bwt/day]) for 13 weeks and the functional observational battery (FOB), automated tests for motor activity and neuropathological examination were conducted. In the immunotoxicity study, animals were exposed by inhalation to 0, 25, 100, or 500 ppm ethylbenzene (approximately 26, 90, or 342 mg/kg bwt/day as calculated from physiologically based pharmacokinetic modeling). Immunotoxicity was evaluated in female rats using the splenic antibody-forming cell plaque-forming assay in sheep red blood cell sensitized animals. The no observed-effect level for the oral gavage study was 50mg/kg bwt/day based on increased relative weights of the liver and kidneys in the male rats. The no observed-adverse-effect level (NOAEL) for adult neurotoxicity was the highest dose tested 500 mg/kg bwt/day. The NOAEL for the immunotoxicity evaluation was the highest tested exposure concentration, 500 ppm (342 mg/kg bwt/day). PMID- 20171983 TI - The effectiveness of multi-target agents in schizophrenia and mood disorders: Relevance of receptor signature to clinical action. AB - Schizophrenia, bipolar disorder and unipolar depression are multi-dimensional and severely disabling psychiatric diseases with a strong need for improved pharmacotherapies with better adherence, long-term outcome and patient functionality. Progress has been achieved with the emergence of tailored multi target agents (MTAs), such as second-generation antipsychotics for schizophrenia, with expanding clinical utility in bipolar disorder and depression. Better understanding of how these MTAs exert their beneficial and undesirable clinical effects in terms of receptor interaction remains an area for further elucidation, which may provide insight towards a new generation of individualized, and optimized therapies. This review explores to what extent the receptor signature of MTAs informs about their clinical action and therapeutic utility. Compelling clinical validation exists only for a limited number of molecular targets (e.g. D(2) receptor blockade, serotonin transport inhibition), indicating overall high attrition and poor translation of predictive preclinical pharmacology. Nevertheless, recent advances have identified promising novel approaches for schizophrenia, bipolar disorder and depression that require further clinical validation. It is hoped that the expanding clinical and mechanistic knowledge garnered from the use of existing MTAs will provide additional opportunities for "reverse translation" and towards target validation. There is considerable scope for further developing and applying the knowledge linking receptor signature to clinical activity to drive stronger target validation, and ultimately support rational development of the next generation of MTAs for the improved treatment of schizophrenia and mood disorders. PMID- 20171982 TI - Sympathetic nervous activation in obesity and the metabolic syndrome--causes, consequences and therapeutic implications. AB - The world wide prevalence of obesity and the metabolic syndrome is escalating. Contrary to earlier experimental evidence, human obesity is characterised by sympathetic nervous activation, with the outflows to both the kidney and skeletal muscle being activated. While the mechanisms responsible for initiating the sympathetic activation remain to be unequivocally elucidated, hyperinsulinemia, obstructive sleep apnoea, increased circulating adipokines, stress and beta adrenergic receptor polymorphisms are implicated. The pattern of sympathetic activation may be the pathophysiological mechanism underpinning much obesity related illnesses with the consequences including, amongst others, the development of hypertension, insulin resistance, diastolic dysfunction and renal impairment. While diet and exercise are the first line therapy for the treatment of obesity and the metabolic syndrome, pharmacological interventions targeting the sympathetic nervous system, either directly or indirectly are also likely to be of benefit. Importantly, the benefit may not necessarily be weight related but may be associated with a reduction in end organ damage. PMID- 20171984 TI - Imaging fluid flow and cilia beating pattern in Xenopus brain ventricles. AB - Brain development and health depends upon the efficient movement of the cerebrospinal fluid inside of brain ventricles. When disrupted either through mutation, disease, or physiological damage, brain function becomes significantly impaired. Here I present a simple method of following cerebrospinal fluid circulation in Xenopus tadpoles using fluorescent microspheres which can be applied to imaging fluid circulation in any transparent embryo. In particular, cilia may be labeled with these microspheres to study their dynamics and movement patterns in vivo while simultaneously measuring bulk fluid flow. This technique will facilitate the analysis of fluid dynamics in developing embryos and aid in understanding the regulation of cilia dependent fluid flow in vivo. PMID- 20171985 TI - From foraging to operant conditioning: a new computer-controlled Skinner box to study free-flying nectar gathering behavior in bees. AB - The experimental study of nectar foraging behavior in free-flying bees requires the use of automated devices to control solution delivery and measure dependent variables associated with nectar gathering. We describe a new computer-controlled artificial flower and provide calibration data to measure the precision of the apparatus. Our device is similar to a "Skinner box" and we present data of an experiment where various amounts of a 50% sugar solution are presented randomly to individual bees. These data show large individual variations among subjects across several dependent variables. Finally, we discuss possible applications of our device to problems in behavioral sciences. PMID- 20171986 TI - Corticosterone urinalysis and nicotinic receptor modulation in rats. AB - A routine method of measuring circulating corticosterone (CORT) levels in rats involves sampling of plasma from cannulated animals. However, being somewhat invasive, this method can potentially be confounded by its inherently stressful nature. This study investigated the feasibility of measuring corticosterone using a non-invasive sampling method from voided urine of male rats. Reliability was assessed pharmacologically with nicotinic compounds previously demonstrated to modulate plasma glucocorticoid levels. Nicotine (0.1-1mg/kg sc) dose-dependently increased corticosterone levels in rat urine at 30-70 min following administration. The short-lived nature of this elevation was confirmed as CORT levels measured 6 and 24h later were shown to have returned to basal levels. Both basal and nicotine-induced (0.5mg/kg sc) elevations in urinary CORT were consistent between groups of animals with weights ranging from 200 to 400 g. The magnitude of urinary CORT elevation induced by nicotine (0.5mg/kg sc) was found to be similar to that induced by a forced swim stressor in male Lister ) antagonist mecamylamine (0.05-0.5mg/kg sc) dose-dependently reversed the effects of nicotine (0.5mg/kg sc) on urinary CORT. Finally, the alpha(4)beta(2)-subunit preferring agonist TC-2559 induced a dose-dependent increase in CORT, whereas alpha(7)- and beta(4)-subunit preferring ligands had no effect, suggestive of the potential for differential involvement of nicotinic receptor subtypes in the mediation of this response. In conclusion, urinary corticosterone sampling in rats represents a robust assay sensitive to experimental manipulations of both pharmacological and behavioural relevances. PMID- 20171987 TI - Phase-dependent audiometry with low-frequency masking revisited. AB - Low-frequency masking is a psychoacoustical phenomenon, describing the modulation of a high-frequency probe tone burst by a low-frequency masker tone. The probe tone threshold is increased, if the probe tone is presented at a low-frequency phases around 90 degrees and 270 degrees . At these phases, the low-frequency masker tone induces a displacement of the basilar membrane of the inner ear which modulates the sensitivity of the inner hair cells. Measuring the modulation depth is partially applied in clinical routine to diagnose the endolymphatic hydrops. Although the modulation depth differs between normal ears and those which reveal an endolymphatic hydrops, the significance of these tests seems debatable. Here, we describe a new experimental setup, completely consisting of commercially available devices. Further, a user interface was developed to enable the application in the clinical routine. The experimental setup was approved with ten normal hearing listeners. All reveal a modulation of the probe stimulus threshold by different phases of the low-frequency masker stimulus. With this experimental setup, custom-made modifications of the essential parameters are feasible. This would be a contribution to solve open questions on the clinical relevance of the low-frequency masking phenomenon. PMID- 20171988 TI - Oral supplementation with Leu-Ile, a hydrophobic dipeptide, prevents the impairment of memory induced by amyloid beta in mice via restraining the hyperphosphorylation of extracellular signal-regulated kinase. AB - Restraining the toxic pathways of amyloid beta peptide (Abeta) by daily supplementation with dietary products has been shown effective in preventing cognitive decline. In this study, we examined the effects of the orally administered Leu-Ile, a hydrophobic dipeptide, on the neurotoxicity of Abeta(25 35) in mice. Chronic daily treatment with Leu-Ile prevented the Abeta(25-35) induced protein nitration and impairment of novel object recognition memory in mice. Protein nitration in the hippocampus induced by Abeta(25-35) was associated with the hyperphosphorylation of extracellular signal-regulated kinase (ERK) which was found responsible for the over-expression of inducible nitric oxide synthase. Sub-chronic treatment with Leu-Ile prevented the Abeta(25-35)-induced hyperphosphorylation of ERK and protein nitration in the hippocampus. The results suggested that with the protective property against the neurotoxicity of Abeta(25 35), Leu-Ile could be considered as a candidate for the dietary supplementation in the prevention of Abeta-related impairment of recognition memory. PMID- 20171989 TI - Effects of aging on hemispheric asymmetry in inferior frontal cortex activity during belief-bias syllogistic reasoning: a near-infrared spectroscopy study. AB - The belief-bias effect in syllogistic reasoning refers to the tendency for subjects to be erroneously biased when logical conclusions are incongruent with beliefs about the world. This study examined age-related differences in inferior frontal cortex (IFC) activity associated with belief-bias reasoning using near infrared spectroscopy (NIRS). The subjects were 32 older (mean age, 68.53 years) and 32 young adult volunteers (mean age, 21.50 years). They performed belief congruent and incongruent reasoning trials while right and left IFC activities were being measured by NIRS. Behavioral analysis found that older adults exhibited a larger belief-bias than young adults. NIRS analysis showed that the right IFC was more activated than the left IFC in young adults, while there was no significant hemispheric difference in older adults. On correlation analysis, there was a significant positive correlation between reasoning accuracy and IFC activation in both hemispheres for older adults, while in young adults, the correlation was significant only in the right hemisphere. These correlation patterns suggest that the right IFC is critical for resolving conflicting reasoning in young adults, but that older adults may further recruit the left IFC to compensate for the age-related decline in the inhibitory control functions. Thus, we demonstrate, for the first time, age-related differences in neural activity associated with belief-bias reasoning. PMID- 20171990 TI - Sequencing and cardiac expression of natriuretic peptide receptors A and C in normal and heart failure pigs. AB - Pharmacological treatments able to activate natriuretic receptors (NPRs) and inhibit cardiac remodelling in heart failure (HF) patients, are currently under investigation. To better understand the therapeutic potential of the NPRs activation is necessary to dispose of experimental models devoid of confounding effects. The pig constitutes an animal model largely used but its genome is not completely sequenced. Aims of this study were to sequence NPR-A and NPR-C in Susscrofa and to evaluate ANP, BNP and NPRs mRNA expression in cardiac tissue of normal and HF minipigs in order to have a starting point for future studies devoted to check new potential drugs. Cardiac tissue was collected from adult male minipigs without (n=4) and with HF (n=5). Pig NPR-A (179bp) and NPR-C (203bp) mRNA were partially sequenced (GenBank n.: FJ518622, FJ518621). Compared to control, ANP and BNP gene expression resulted higher in all the cardiac chambers of HF heart. This increase is associated to a down-regulation of NPR-A and an up-regulation of NPR-C in HF. These sequences will provide a new tool to investigate the role of natriuretic peptides and of their receptors under physiological and pathological conditions and their response to therapeutic interventions. PMID- 20171991 TI - Regulation of autonomic nerve activities by central pituitary adenylate cyclase activating polypeptide. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a peptidergic neurotransmitter that is expressed in high levels in nervous systems. Here, we investigated the roles of PACAP in autonomic system regulation by evaluating the changes caused in the autonomic nerve activities after injecting PACAP into the central nervous system (CNS) and examining stress-induced blood glucose changes in PACAP-deficient (PACAP-/-) mice. Renal sympathetic nerve activity (RSNA), blood pressure, and heart rate were elevated after injecting PACAP into the third cerebral ventricle (3CV). Similarly, other sympathetic nerve activities, including adrenal sympathetic nerve activity (ASNA), celiac sympathetic nerve activity (CSNA), and brown adipose tissue sympathetic nerve activity (BAT-SNA), were accelerated by PACAP injection. In contrast, injecting PACAP into 3CV significantly suppressed parasympathetic nerve activities, including gastric vagal nerve activity (GVNA) and celiac vagal nerve activity (CVNA). In addition, blood glucose elevations induced by stress, such as immobilization or ether exposure, were disrupted in PACAP-/- mice, although basal glucose levels in mutants were comparable to that in wild-type mice. These results suggest that CNS PACAP regulates autonomic function by maintaining a sympathetic-parasympathetic balance and contributes to peripheral homeostatic maintenance, especially under conditions of stress. PMID- 20171992 TI - The pro-angiogenic activity of urotensin-II on human vascular endothelial cells involves ERK1/2 and PI3K signaling pathways. AB - Human vascular endothelial cells express the urotensin-II (U-II) receptor and exhibit a strong in vitro angiogenic response to the peptide. Thus, in the present study an in vitro model, based on human umbilical vein endothelial cells (HUVEC) cultured on Matrigel, was used to characterize more in detail the signaling pathways that control the pro-angiogenic action of U-II. The activation of the U-II receptor (UT) was associated with an increase of intracellular calcium concentration. Both calcium rise and pro-angiogenic effect of the peptide can be blocked by U73122, a selective inhibitor of phospholipase-C, indicating that the signal transduction from UT mainly involves the phospholipase-C/IP(3) pathway. As far as the downstream signaling pathways are concerned, western blot analyses and experiments with specific inhibitors indicated that the U-II-induced self-organization of the cells into capillary-like structures was PKC dependent and involved the activation of the ERK1/2, but not p38-MAPK, transduction pathway. Interestingly, the pharmacological inhibition of PI3K (obtained with LY294002), hindered the capacity of U-II to induce a proangiogenic effect on HUVEC, suggesting that PI3K-dependent pathways also play a role in regulating the process. PMID- 20171993 TI - Differential regulation and roles of urocortins in human adrenal H295R cells. AB - Three urocortins (Ucns) are known as members of the corticotropin-releasing factor (CRF) family of peptides and serve as natural ligands for CRF receptors. Ucn1 and Ucn3 exhibit potent effects on the adrenal system via the CRF receptors. This study aimed to explore the regulation and roles of Ucns in the adrenal system using human adrenal carcinoma H295R cells, which express Ucn1, Ucn2, Ucn3, CRF receptor type 1 (CRF(1) receptor), and CRF receptor type 2a (CRF(2a) receptor) mRNA. Forskolin, which stimulates adenylate cyclase and then increases intracellular cAMP production, was shown to transiently decrease Ucn1 and Ucn2 mRNA levels, but increase Ucns 1-3 mRNA levels in H295R cells. Steroidogenic acute regulatory protein, Cyp11beta1, and Cyp11beta2 mRNA levels, and both cortisol and aldosterone secretions were elevated by Ucn1. Cell viability was reduced by both Ucn1 and Ucn3 via the CRF(2) receptor in H295R cells. Ucn1 and Ucn3 increased the expression of the cAMP-response element binding protein and extracellular signal-related kinase (ERK) phosphorylations. The ERK and protein kinase A pathways were involved in Ucn3-decreased cell viability. PMID- 20171994 TI - Distribution of a novel binding site for angiotensins II and III in mouse tissues. AB - A novel binding site for angiotensins II and III that is unmasked by parachloromercuribenzoate has been reported in rat, mouse and human brains. Initial studies of this binding site indicate that it is not expressed in the adrenal, liver or kidney of the rat and mouse. To determine if this binding site occurs in other mouse tissues, 8 tissues were assayed for expression of this binding site by radioligand binding assay and compared with the expression of this binding site in the forebrain. Particulate fractions of homogenates of testis, epididymis, seminal vesicles, heart, spleen, pancreas, lung, skeletal muscle, and forebrain were incubated with (125)I-sarcosine(1), isoleucine(8) angiotensin II in the presence or absence of 0.3mM parachloromercuribenzoate plus 10microM losartan and 10microM PD123319 (to saturate AT(1) and AT(2) receptors). Specific (3microM angiotensin II displaceable) high affinity binding occurred in the testis>forebrain>epididymis>spleen>pancreas>lung when parachloromercuribenzoate was present. Binding could not be reliably observed in heart, skeletal muscle and seminal vesicles. High affinity binding of (125)I sarcosine(1), isoleucine(8) angiotensin II was observed in the absence of parachloromercuribenzoate in the pancreas on occasion. This suggests that this novel angiotensin binding site may have a functional role in these tissues. PMID- 20171995 TI - Rikkunshito and 5-HT2C receptor antagonist improve cisplatin-induced anorexia via hypothalamic ghrelin interaction. AB - Circulating ghrelin concentration regulates appetite behavior, but no study thus far has focused on the role of central ghrelin in anorexia after chemotherapy. To clarify the action mechanisms of rikkunshito (RKT), a traditional Japanese medicine, on cisplatin-induced anorexia, we attempted to elucidate its effect on hypothalamic ghrelin receptor expression in cisplatin-induced anorexia. We first examined the effects of an intracerebroventricular (ICV) injection of exogenous ghrelin on food intake with or without cisplatin treatment, and the effects of cisplatin or m-chlorophenylpiperazine (mCPP), a 5-HT2C receptor agonist, on hypothalamic growth hormone secretagogue receptor 1a (GHS-R1a) mRNA expression. To identify the mechanism of cisplatin-induced decrease in hypothalamic GHS-R1a mRNA expression, we evaluated the effects of SB242084HCl, a 5-HT2C receptor antagonist, and RKT on hypothalamic GHS-R1a gene expression, along with the effect of coadministration of a GHS-R1a antagonist on decreased food intake. Compared to vehicle controls, an ICV-injected rat ghrelin failed to inhibit the decrease in food intake in cisplatin-treated rats. Hypothalamic GHS-R1a gene expression was significantly reduced after cisplatin or mCPP treatment, and the induced decrease was reversed by SB242084HCl or RKT, but not granisetron or ondansetron, both of which are 5-HT3 receptor antagonists. Their suppressive effect on the decrease in food intake was abolished by coadministration of the GHS-R1a antagonist. Administration of RKT or SB242084HCl reversed the decrease in food intake induced by mCPP injection. The improvement by RKT on decreased food intake after cisplatin treatment was partly mediated by hesperidin and isoliquiritigenin, components of RKT. Cisplatin-induced anorexia may worsen because of decreased hypothalamic GHS-R1a gene expression. A 5-HT2C receptor antagonist and RKT suppressed cisplatin-induced anorexia by inhibiting reduction of GHS-R1a signal transduction in the hypothalamus. PMID- 20171996 TI - Ghrelin promotes antioxidant enzyme activity and reduces lipid peroxidation in the rat ovary. AB - Antioxidant properties of ghrelin have been recently reported on various oxidative stresses in limited tissues. This study was set to examine the possible antioxidative effects of ghrelin in rat ovarian tissue. Twenty eight female adult Wistar rats were randomly allocated into control and treatment groups. Treatment group (n=14) received 2nmol of ghrelin as subcutaneous injection for 14 consecutive days or vehicle (physiological saline) to the control rats. The animals from both groups were equally killed on days 9 and 14 after beginning of ghrelin injection (n=7 from each group on each day) and their ovaries were taken for later antioxidant enzyme activity assays as well as measurement of glutathione content and thiobarbituric acid reactive substances (TBARS) level. Superoxide dismutase activity was significantly higher on days 9 (P<0.05) and 14 (P<0.01) in the treated group compared to the control rats. By contrast, lipid peroxidation, as TBARS value, reduced significantly on both experimental days in the ghrelin-exposed animals (P<0.05). Although, the mean activity of catalase and glutathione content was greater in the treated rats, however, the differences were not statistically significant. Slight changes occurred in glutathione peroxidase activity during the experimental period and there were no differences either on day 9 or on day 14 between groups. In conclusion, the results of the present investigation indicate for the first time the novel evidence of antioxidant properties of ghrelin in the rat ovary. PMID- 20171997 TI - Comparative analysis of fecal DNA extraction methods with phylogenetic microarray: effective recovery of bacterial and archaeal DNA using mechanical cell lysis. AB - Several different protocols are used for fecal DNA extraction, which is an integral step in all phylogenetic and metagenomic approaches to characterize the highly diverse intestinal ecosystem. We compared four widely used methods, and found their DNA yields to vary up to 35-fold. Bacterial, archaeal and human DNA was quantified by real-time PCR, and a compositional analysis of different extracts was carried out using the Human Intestinal Tract Chip, a 16S rRNA gene based phylogenetic microarray. The overall microbiota composition was highly similar between the methods in contrast to the profound differences between the subjects (Pearson correlations >0.899 and 0.735, respectively). A detailed comparative analysis of mechanical and enzymatic methods showed that despite their overall similarity, the mechanical cell disruption by repeated bead beating showed the highest bacterial diversity and resulted in significantly improved DNA extraction efficiency of archaea and some bacteria, including Clostridium cluster IV. By applying the mechanical disruption method a high prevalence (67%) of methanogenic archaea was detected in healthy subjects (n=24), exceeding the typical values reported previously. The assessment of performance differences between different methodologies serves as a concrete step towards the comparison and reliable meta-analysis of the results obtained in different laboratories. PMID- 20171998 TI - Motivational priming and processing interrupt: startle reflex modulation during shallow and deep processing of emotional words. AB - Valence-driven modulation of the startle reflex, that is larger eyeblinks during viewing of unpleasant pictures and inhibited blinks while viewing pleasant pictures, is well documented. The current study investigated, whether this motivational priming pattern also occurs during processing of unpleasant and pleasant words, and to what extent it is influenced by shallow vs. deep encoding of verbal stimuli. Emotional and neutral adjectives were presented for 5s, and the acoustically elicited startle eyeblink response was measured while subjects memorized the words by means of shallow or deep processing strategies. Results showed blink potentiation to unpleasant and blink inhibition to pleasant adjectives in subjects using shallow encoding strategies. In subjects using deep encoding strategies, blinks were larger for pleasant than unpleasant or neutral adjectives. In line with this, free recall of pleasant words was also better in subjects who engaged in deep processing. The results suggest that motivational priming holds as long as processing is perceptual. However, during deep processing the startle reflex appears to represent a measure of "processing interrupt", facilitating blinks to those stimuli that are more deeply encoded. PMID- 20171999 TI - The time course of novelty processing in sensation seeking: an ERP study. AB - Novelty processing is critical for human survival in a rapidly changing environment. However, how and when the orientation attention reflected by novelty processing is modulated by personality elements such as sensation seeking is still opened. The present study investigated the time course of novelty processing in sensation seeking by recording the event-related potentials (ERPs) in a visual novelty oddball task. High and low sensation seekers performed a visual oddball task, in which participants were instructed to detect an inverted triangle (target) and ignore both upright triangle (standard) and unrepeated line drawings of pseudo-objects deviant from participants' long-term memory (novelty). While there were no group differences in ERPs to standard and target stimuli, ERPs to novel stimuli showed a strong modulation by sensation seeking trait. The low sensation seekers, compared with the high sensation seekers, exhibited an increased N2 to novel stimuli at frontal sites. Moreover, the Pd3 component reflecting purely novelty processing was enhanced and less habituated in the high sensation seeking participants. The current findings implicated that low sensation seekers showed sensitivity to novelty detection, whereas high sensation seekers displayed stronger and more sustained novelty appraisal. PMID- 20172000 TI - Cardiac data increase association between self-report and both expert ratings of task load and task performance in flight simulator tasks: An exploratory study. AB - Seven professional airplane pilots participated in a one-session test in a Boeing 737-800 simulator. Mental workload for 18 flight tasks was rated by experienced test pilots (hereinafter called "expert ratings") and by study participants' self report on NASA's Task Load Index (TLX) scale. Pilot performance was rated by a check pilot. The standard deviation of R-R intervals (SDNN) significantly added 3.7% improvement over the TLX in distinguishing high from moderate-load tasks and 2.3% improvement in distinguishing high from combined moderate and low-load tasks. Minimum RRI in the task significantly discriminated high- from medium- and low-load tasks, but did not add significant predictive variance to the TLX. The low-frequency/high-frequency (LF:HF) RRI ratio based on spectral analysis of R-R intervals, and ventricular relaxation time were each negatively related to pilot performance ratings independently of TLX values, while minimum and average RRI were positively related, showing added contribution of these cardiac measures for predicting performance. Cardiac results were not affected by controlling either for respiration rate or motor activity assessed by accelerometry. The results suggest that cardiac assessment can be a useful addition to self-report measures for determining flight task mental workload and risk for performance decrements. Replication on a larger sample is needed to confirm and extend the results. PMID- 20172001 TI - Distinct effects of knocking down MEK1 and MEK2 on replication of herpes simplex virus type 2. AB - During infection, viruses hijack various host cell components and programs for their amplification, among which is the canonical ERK signaling pathway, mainly consisting of three tiered serine/threonine kinases, Raf, MEK and ERK. MEK1 and MEK2 are two isoforms of the kinase operating immediately upstream of ERK, and connecting Raf and ERK by phosphorylating ERK. Previous studies have suggested that different isoforms of MEK have distinct biological functions, although their in vitro kinase function may be redundant. However, little is known about the isoform-specific effects of these kinases on viral propagation. In this study, we showed that herpes simplex virus type 2 (HSV-2) infection of human embryonic kidney (HEK) 293 cells induced a sustained activation of ERK1/2. Inhibition of this ERK activation by U0126, a specific inhibitor of MEK1/2, severely impaired virus production. A similar reduction of virus production was also seen following transfection of cells with siRNAs for MEK1/2. Interestingly, a specific knockdown of MEK1 with siRNAs caused a marked inhibition of viral titers, viral proteins and virus-induced cytopathic effect (CPE), whereas silencing MEK2 had little effect. Therefore, our results demonstrate that MEK1 and MEK2 act differently and that HSV-2 hijacks host MEK1 for its own amplification. To our knowledge, this is the first report showing inhibition of HSV-2 replication by targeting human MEK1. This study also suggests that MEK1 could be a potential target for anti-HSV-2 therapy, which may minimize damage to the host cells engendered by targeting both MEK1 and MEK2. PMID- 20172002 TI - Monitoring intracellular degradation of exogenous DNA by FCS and FCCS. PMID- 20172003 TI - Does food planning mediate the association between living arrangements and fruit and vegetable consumption among women aged 40 years and older? AB - The objective of this paper was to investigate whether food planning strategies mediate the association between living arrangements and fruit and vegetable consumption amongst women aged 40 years and over. A community sample of 473 women aged 40 years and over from metropolitan Melbourne, Australia, provided survey data on their living arrangements, education, fruit and vegetable consumption and the amount of food planning they undertake. Fruit and vegetable consumption was significantly higher amongst women who lived with others compared to those living alone. Food planning was found to mediate the association between living arrangements and fruit consumption by 8% and vegetable consumption by 13%. This study provides evidence of a mediating effect of food planning on the relationship between living arrangements and fruit and vegetable consumption. With the ageing of the population increasing the potential for a rise in the number of single-occupant households, identifying ways of helping individuals to plan their food purchasing and preparation may increase fruit and vegetable intake. PMID- 20172004 TI - Eating attitudes and body image concerns among female university students in the United Arab Emirates. AB - OBJECTIVES: A number of socio-cultural factors have been associated with the emergence of eating disorders in non-western nations. The United Arab Emirates (UAE) is characterized by many, if not all of these socio-cultural factors. To date, however there have been very few studies exploring the prevalence of eating disorders symptomatology within the UAE. The present study investigates the prevalence of disordered eating attitudes within Emirati-female university students. It also explores the relationship between these attitudes and body image concerns. DESIGN: A correlational study design was used to explore the prevalence of abnormal eating attitudes and their relationship with body image concerns. METHOD: 228 female students attending Zayed University in the UAE completed the Eating Attitudes Test 26 item version (EAT-26), along with the Figure Rating Scale: a visual scale used to assess current body size/shape estimation, preference, and dissatisfaction. RESULTS: Exactly 24% of the sample scored above the EAT-26 cut-off, indicative of disordered eating attitudes and possible eating disorder. Additionally 74.8% of the participants were dissatisfied with their current estimated body image, furthermore disordered eating attitudes were positively correlated with body image dissatisfaction, and negatively correlated with body image ideals. CONCLUSIONS: The prevalence of disordered eating attitudes amongst the present UAE sample broadly mirrors those reported in nations where eating disorders have been widespread for decades. The widespread disordered eating attitudes in the present population may in part arise from body image dissatisfaction and ultra-thin body image ideals. PMID- 20172005 TI - Plasma and tissue levels of proangiotensin-12 and components of the renin angiotensin system (RAS) following low- or high-salt feeding in rats. AB - The renin-angiotensin system (RAS) is an essential regulator of the blood pressure and body fluid balance, but the processing cascade or role of the tissue RAS remains obscure. Proangiotensin-12 (proang-12), a novel angiotensin peptide recently discovered in rat tissues, is assumed to function as a factor of the tissue RAS. To investigate the tissue production of proang-12, we measured the circulating and tissue components of the RAS including proang-12 following low-, normal-, or high-salt feeding in rats. Twelve-week-old male Wistar rats were fed a low-salt 0.3% NaCl or high-salt 8% NaCl diet for 7 days and compared with those fed a normal-salt diet of 0.7% NaCl. Low-salt feeding elevated the plasma renin activity and aldosterone concentration, resulting in significant increases in Ang I and Ang II levels in the plasma or kidney tissue, as compared with the normal- or high-salt group. Despite the increases in plasma renin activity, Ang I, and Ang II, the proang-12 levels in plasma and various tissues including the kidneys, small intestine, cardiac ventricles, and brain remained unchanged following low salt feeding. These results suggest that peptide levels of proang-12 in rat plasma and tissues are regulated in a manner independent of the circulating RAS. PMID- 20172006 TI - Adrenomedullin 2 attenuates the pressor but not adrenal responses to angiotensin II in conscious sheep. AB - Biological actions attributed to the adrenomedullin (AM) peptides, AM and AM2, include reduction of arterial pressure and peripheral resistance. While AM has been shown to reduce aldosterone secretion from the adrenal, little information is available regarding possible actions of AM2 on aldosterone. Evidence suggests that AM may act as a functional antagonist to angiotensin II (Ang II) but such a role has not been investigated for AM2. Accordingly, we have examined hemodynamic and adrenal responses to stepped Ang II infusions with or without co-infusions of AM2 (33ng/(kgmin)) in conscious sheep under controlled conditions of a low sodium intake. The dose-dependent pressor response (5-50mmHg) of Ang II was both delayed and attenuated (p<0.001) by AM2 which also stimulated heart rate (p<0.001) and cardiac output (p<0.001). AM2 prevented Ang II-induced increases in peripheral resistance (p<0.001). In contrast, plasma aldosterone responses to Ang II were not significantly altered by concomitant AM2 infusion. In conclusion, low dose infusion of AM2 administered to conscious sheep on a low salt diet clearly antagonized the vasopressor action of administered Ang II while stimulating cardiac output and heart rate. In contrast to AM, AM2 had no restraining influence on the aldosterone response to Ang II. The data suggest a possible role for AM2 in cardiovascular homeostasis in part through antagonism of the vasopressor action of Ang II. PMID- 20172007 TI - Further studies on the pharmacological profile of the neuropeptide S receptor antagonist SHA 68. AB - Neuropeptide S (NPS) regulates various biological functions by selectively activating the NPS receptor (NPSR). Previous studies demonstrated that the non peptide molecule SHA 68 acts as a selective NPSR antagonist. In the present study the pharmacological profile of SHA 68 has been further investigated in vitro and in vivo. In cells expressing the mouse NPSR SHA 68 was inactive per se up to 10microM while it antagonized NPS-stimulated calcium mobilization in a competitive manner showing a pA(2) value of 8.06. In the 10-50mg/kg range of doses, SHA 68 counteracted the stimulant effects elicited by NPS, but not those of caffeine, in mouse locomotor activity experiments. In the mouse righting reflex assay SHA 68 fully prevented the arousal-promoting action of the peptide. The anxiolytic-like effects of NPS were slightly reduced by SHA 68 in the mouse open field, fully prevented in the rat elevated plus maze and partially antagonized in the rat defensive burying paradigm. Finally, SHA 68 was found poorly active in antagonizing the NPS inhibitory effect on palatable food intake in rats. In all assays SHA 68 did not produce any effect per se. In conclusion, the present study demonstrated that SHA 68 behaves as a selective NPSR antagonist that can be used to characterize the in vivo actions of NPS. However the usefulness of this research tool is limited by its poor pharmacokinetic properties. PMID- 20172008 TI - Alteration in chromogranin A, obestatin and total ghrelin levels of saliva and serum in epilepsy cases. AB - This study was designed to measure the levels of chromogranin A (CgA), ghrelin and obestatin in serum and saliva (including CgA expression in healthy tissue) in epileptic patients to determine any significant differences between these patients and healthy controls. Samples were obtained from a total of 91 subjects: 10 newly-diagnosed primary generalized epilepsy (PGE) patients who had started treatment with valproic acid and phenytoin for seizure control; 18 PGE patients who were previously and currently receiving treatment with valproic acid and phenytoin for seizure control; 37 patients with partial epilepsy (PE) (simple, n=17 or complex, n=20) who had been and were still being treated with carbazebime for seizures; and 26 healthy controls. CgA immunoreactivity in healthy salivary gland was analyzed by immunohistochemistry and ELISA. The levels of CgA, total ghrelin and obestatin in serum and saliva were measured by ELISA. The results revealed that normal salivary gland produces its own CgA. Before treatment, CgA levels in saliva and serum were significantly greater in patients newly-diagnosed with PGE than controls. Ghrelin and CgA concentrations were also greater in PGE patients previously or currently treated with drugs, and in patients with simple or complex partial epilepsy (PE) previously or currently treated with drugs, than in healthy normal controls. In conclusion, salivary concentrations of CgA, ghrelin and obestatin were similar to their serum levels, so saliva might be a desirable alternative to serum for measuring these hormones because it is easy and painless to collect. PMID- 20172009 TI - Exercise increases the angiotensin II effects in isolated portal vein of trained rats. AB - Training in rats adapts the portal vein to respond vigorously to sympathetic stimuli even when the animal is re-exposed to exercise. Moreover, changes in the exercise-induced effects of angiotensin II, a potent venoconstrictor agonist, in venous beds remain to be investigated. Therefore, the present study aimed to assess the effects of angiotensin II in the portal vein and vena cava from sedentary and trained rats at rest or submitted to an exercise session immediately before organ bath experiments. We found that training or exposure of sedentary animals to a single bout of running exercise does not significantly change the responses of the rat portal vein to angiotensin II. However, the exposure of trained animals to a single bout of running exercise enhanced the response of the rat portal vein to angiotensin II. This enhancement appeared to be territory-specific because it was not observed in the vena cava. Moreover, it was not observed in endothelium-disrupted preparations and in preparations treated with N(omega)-nitro-l-arginine methyl ester hydrochloride, indomethacin, BQ-123 or BQ-788. These data indicate that training causes adaptations in the rat portal vein that respond vigorously to angiotensin II even upon re-exposure to exercise. This increased response to angiotensin II requires an enhancement of the vasocontractile influence of endothelin beyond the influence of nitric oxide and vasodilator prostanoids. PMID- 20172010 TI - Omega-3 fatty acids deprivation affects ontogeny of glutamatergic synapses in rats: relevance for behavior alterations. AB - Essential omega-3 polyunsaturated fatty acids (omega3) are crucial to brain development and function, being relevant for behavioral performance. In the present study we examined the influence of dietary omega3 in the development of the glutamatergic system and on behavior parameters in rats. Female rats received isocaloric diets, either with omega3 (omega3 group) or a omega3 deficient diet (D group). In ontogeny experiments of their litters, hippocampal immunocontent of ionotropic NMDA and AMPA glutamatergic receptors subunits (NR2 A?B and GluR1, respectively) and the alpha isoform of the calcium-calmodulin protein kinase type II (alphaCaMKII) were evaluated. Additionally, hippocampal [(3)H]glutamate binding and uptake were assessed. Behavioral performance was evaluated when the litters were adult (60 days old), through the open-field, plus-maze, inhibitory avoidance and flinch-jump tasks. The D group showed decreased immunocontent of all proteins analyzed at 02 days of life (P2) in comparison with the omega3 group, although the difference disappeared at 21 days of life (except for alphaCaMKII, which content normalized at 60 days old). The same pattern was found for [(3)H]glutamate binding, whereas [(3)H]glutamate uptake was not affected. The D group also showed memory deficits in the inhibitory avoidance, increased in the exploratory pattern in open-field, and anxiety-like behavior in plus-maze. Taken together, our results suggest that dietary omega3 content is relevant for glutamatergic system development and for behavioral performance in adulthood. The putative correlation among the neurochemical and behavioral alterations caused by dietary omega3 deficiency is discussed. PMID- 20172011 TI - Incorporation of particle size differences between animal studies and human workplace aerosols for deriving exposure limit values. AB - Inhalation animal studies usually employ homogeneous aerosols of small particle diameter. By contrast, workers are usually exposed to coarser and more heterogeneous aerosols. The particle size distribution of an aerosol will determine the deposited fraction of inhaled particles in the various regions of the respiratory tract in rodents and humans. The deposited, and subsequently retained, doses in these regions correlate closely with long-term toxic effects. Yet, differences in deposited doses between animals and humans due to particle size differences of aerosols have not been consistently taken into account in risk assessment. This paper describes an approach to calculate equivalent human concentrations (EHC) for respiratory tract effects after inhalation using workplace particle size information. Worker's exposure to the EHC results in the same deposited dose in the respiratory tract as achieved in animals exposed to the experimental particle size distribution. Example data for nickel compounds demonstrate that exposure levels used in the rat studies are equivalent to 4-11 fold higher levels of human workplace exposures. This approach is equally applicable to other metal/inorganic particulates that exert adverse effects on the respiratory tract after inhalation. Dosimetric extrapolation should be a first step in the derivation of limit values based on animal local respiratory effects. PMID- 20172012 TI - Comparison of models to analyze mortality data and derive concentration-time response relationship of inhaled chemicals. AB - The derivation of thresholds for lethal effects for inhaled chemicals is a key issue in accidental risk management because they largely determine the outcome of land use planning, among which localization of habitations in the vicinity of a factory. This derivation is generally performed on the basis of rodent lethality data analyzed by statistical models able to extrapolate effects for different times and concentrations of exposure. A model commonly used in France is the standard probit model. In this model, effects is related to exposure concentration and duration according to the Haber's law and considers that individual thresholds, corresponding to the maximum tolerated effects before dying, are log-normally distributed among the population. This approach has been criticized for its lack of biological parameters and its inability to treat data characterized by only one time of exposure. In order to improve the current state of modeling, we proposed three alternative models. Two of them (DEBtox and Haber TKTD models) incorporate the kinetics of the chemicals. The third one (Loguniform model) is a linearization of the standard probit model. We evaluated their performance by analyzing real data and simulated data generated with each model. For data characterized by several times of exposure, the standard probit model outperformed all other models in terms of goodness of fits and estimation of parameters. For data characterized by only one time of exposure, only DEBtox model was able to fit the data and estimate parameters, provided we dispose of several observation times, typically just after exposure and a long period afterwards. PMID- 20172013 TI - Drastic changes in fecal and mucosa-associated microbiota in adult patients with short bowel syndrome. AB - Short bowel syndrome (SBS) is observed in Humans after a large resection of gut. Since the remnant colon and its associated microbiota play a major role in the outcome of patients with SBS, we studied the overall qualitative and quantitative microbiota composition of SBS adult patients compared to controls. The population was composed of 11 SBS type II patients (with a jejuno-colonic anastomosis) and 8 controls without intestinal pathology. SBS patients had 38 +/- 30 cm remnant small bowel length and 66 +/- 19% of residual colon. The repartition of proteins, lipids, carbohydrates and fibres was expressed as % of total oral intake in patients and controls. The microbiota was profiled from stool and biopsy samples with temporal temperature gradient gel electrophoresis and quantitative PCR. We show here that microbiota of SBS patients is unbalanced with a high prevalence of Lactobacillus along with a sub-dominant presence and poor diversity of Clostridium leptum, Clostridium coccoides and Bacteroidetes. In addition, Lactobacillus mucosae was detected within the fecal and mucosa-associated microbiota of SBS patients, whereas it remained undetectable in controls. Thus, in SBS the microbial composition was deeply altered in fecal and mucosal samples, with a shift between dominant and sub-dominant microbial groups and the prevalence of L. mucosae. PMID- 20172014 TI - Enhancement of the adhesive and spreading potentials of ovarian carcinoma RMG-1 cells due to increased expression of integrin alpha5beta1 with the Lewis Y structure on transfection of the alpha1,2-fucosyltransferase gene. AB - Le(Y) antigen is known to be associated with malignant properties including metastasis and a poor prognosis of ovarian carcinomas. To clarify the mechanisms underling these properties, we established ovarian carcinoma-derived cells exhibiting enhanced expression of Le(Y) by transfection with alpha1,2 fucosyltransferase and compared their cellular properties with those of the original cells. So the human alpha1,2-fucosyltransferase gene was transfected into ovarian carcinoma-derived RMG-1 cells, which are known to contain Le(X), a precursor of Le(Y), and RMG-1-hFUT cells exhibiting enhanced expression of Le(Y) were established by selection with anti-Le(Y) antibodies, and their adhesive and spreading potentials on fibronectin-coated plates were compared with those of RMG 1 cells. Results showed that the relative expression of Le(Y) in RMG-1-hFUT cells was about 20-fold that in RMG-1 cells, and that of integrin alpha5beta1 and an integrin-mediated signal transduction molecule, focal adhesion kinase, was also increased in RMG-1-hFUT cells. Interestingly, anti-Le(Y) antibodies were revealed to immunoprecipitate integrin alpha5beta1, indicating that its oligosaccharides are composed of Le(Y), the amounts of which was substantially elevated in RMG-1 hFUT cells. The adhesion and spreading potentials on fibronectin-coated plates of RMG-1-hFUT cells were significantly enhanced in comparison to those of RMG-1 cells, and were greatly suppressed by anti-Le(Y) antibodies, indicating that Le(Y) is involved in the integrin-fibronectin interaction. These results suggested that transfection of the alpha1,2-fucosyltransferase gene into ovarian carcinoma-derived cells brought about elevated expression of integrin alpha5beta1 with Le(Y), resulting in enhancement of the adhesion and spreading potentials of cells through the integrin-fibronection interaction, which was inhibited by anti Le(Y) antibodies. Thus, Le(Y) in integrin alpha5beta1 was thought to be involved in the enhanced cell adhesion properties of malignant ovarian carcinomas. PMID- 20172015 TI - Defense reactions to interoceptive threats: a comparison between loaded breathing and aversive picture viewing. AB - Human fear research has mostly applied exteroceptive stimuli to induce fear. Interoceptive sensations however can also be very threatening and play a major role in a number of anxiety disorders. In this study, we compared affective responses to inspiratory resistive loads with those to aversive pictures. During repeated administrations of two loads, a light and a moderate one, and five aversive pictures we measured electrodermal activity, startle blink responses, subjective fear and ratings on valence, arousal and dominance. Results indicate that loads evoke affective reactions comparable or stronger than those evoked by the pictures. Startle data did not follow this pattern with an absence of startle potentiation during the moderate load, suggesting that fear potentiated startle does not occur when the background aversive stimulus is of an interoceptive nature. PMID- 20172016 TI - Natural-killer cell amplification for adoptive leukemia relapse immunotherapy: comparison of three cytokines, IL-2, IL-15, or IL-7 and impact on NKG2D, KIR2DL1, and KIR2DL2 expression. AB - OBJECTIVE: Natural killer (NK) cells are a lymphocyte subset that, in a hematopoietic stem cell transplantation setting, mediates a graft-vs-leukemia effect without any graft-vs-host disease. We aimed to evaluate an isolation method that can be used with Good Manufacturing Practices-grade reagents and to compare three cytokines for expansion in order to design future clinical protocols based on donor NK-cell infusions to cure relapse after allograft. MATERIALS AND METHODS: NK cells were enriched using a CD3/CD19 depletion method and expanded for 13 days in the presence of 2, 10, and 50 ng/mL interleukin (IL) 2, IL-15, or IL-7. NK-cell cytotoxicity was evaluated after isolation and culture. Expression of NKG2D, KIR2DL2, and KIR2DL1 was monitored during expansion. RESULTS: Highly T- and B-cell-depleted NK cells were obtained and enriched 2.6-fold. The optimal cytokine concentration for expansion was 10 ng/mL for IL-2 or 50 ng/mL for IL-15. NK-cell cytotoxicity was significantly improved after an overnight incubation with 10 or 50 ng/mL IL-2 or with 2, 10, or 50 ng/mL IL-15, and after 13 days with 50 ng/mL IL-15. The use of a combination of IL-2 and IL-15 showed no additional benefit and negative results were obtained with IL 7. The three NK cell receptors were significantly upregulated after culture, mainly with IL-2 or IL-15. CONCLUSION: In our study, 10 ng/mL IL-2 or 50 ng/mL IL 15 were the optimal concentrations for expansion and were equivalent in significantly enhancing cytotoxicity and modifying NK-cell receptor expression patterns. PMID- 20172017 TI - Activation of muscarinic M-1 cholinoceptors by curcumin to increase contractility in urinary bladder isolated from Wistar rats. AB - Curcumin is an active principle contained in rhizome of Curcuma longa, and it has been recently mentioned to show affinity to muscarinic M-1 cholinoceptors (M(1) mAChR). In the present study, we found that curcumin caused a concentration dependent increase of muscle tone in urinary bladder isolated from Wistar rats. This action was inhibited by pirenzepine at concentration enough to block M(1) mAChR. In radioligand-binding assay, specific binding of [(3)H]-oxotremorine (OXO M) in the rat bladder homogenates was also displaced by curcumin in a concentration-dependent manner. In the presence of inhibitors for PLC-PKC pathway, either U73122 (phospholipase C inhibitor) or chelerythrine (protein kinase C inhibitor), curcumin-stimulated contraction in urinary bladder was markedly reduced. In conclusion, the obtained results suggest that curcumin can activate M(1)-mAChR at concentrations lower than to scavenge free radicals to increase of muscle tone in urinary bladder through PLC-PKC pathway. PMID- 20172018 TI - Involvement of p120 in LPS-induced NF-kappaB activation and IL-8 production in human bronchial epithelial cells. AB - P120-catenin (p120), a prototypic member of a subfamily of Armadillo repeat domain (Arm domain) proteins, not only participates in cell-cell adhesion, but also mediates inflammatory responses in the skin. In the present study, we demonstrated the effect of p120 on lipopolysaccharide (LPS)-induced inflammatory responses in human bronchial epithelial cells (BECs). We first confirmed that p120 expression was significantly reduced after LPS stimulation in BECs, the p65 subunit of nuclear factor-kappaB (NF-kappaB) nuclear translocation was promoted and NF-kappaB activity was rapidly induced. Moreover, the expression level of interleukin-8 (IL-8) increased after LPS treatment. Over-expression of p120 attenuated LPS-stimulated NF-kappaB reporter gene expression and IL-8 mRNA expression and protein synthesis. On the contrary, transfection with p120 small interfering RNA (siRNA) significantly elevated LPS-stimulated NF-kappaB transcriptional activity, p65 nuclear translocation and IL-8 expression. Collectively, these results indicate an anti-inflammatory effect of p120 in BECs, through its modulation of NF-kappaB signaling. PMID- 20172019 TI - A role for p53 in mitochondrial stress response control of longevity in C. elegans. AB - As in the case of aging, many degenerative disorders also result from progressive mitochondrial deterioration and cellular damage accumulation. Therefore, preventing damage accumulation may delay aging and help to prevent degenerative disorders, especially those associated with mitochondrial dysfunction. In the nematode Caenorhabditis elegans a mild mitochondrial dysfunction prolongs the lifespan. We previously proposed that, following a mild mitochondrial dysfunction, protective stress responses are activated in a hormetic-like fashion, and ultimately account for extended animal's lifespan. We recently showed that in C. elegans, lifespan extension induced by reduced expression of different mitochondrial proteins involved in electron transport chain functionality requires p53/cep-1. In this paper we find that reducing the expression of frataxin, the protein defective in patients with Friedreich's ataxia, triggers a complex stress response, and that the associated induction of the antioxidant glutathione-S-transferase is regulated by cep-1. Given the high percentage of homology between human and nematode genes and the conservation of fundamental intracellular pathways between the two species, identification of molecular mechanisms activated in response to frataxin suppression in C. elegans may suggest novel therapeutic approaches to prevent the accumulation of irreversible damage and the consequent appearance of symptoms in Friedreich's ataxia and possibly other human mitochondrial-associated diseases. The same pathways could be exploitable for delaying the aging process ascribed to mitochondrial degeneration. PMID- 20172020 TI - Reactor design for minimizing product inhibition during enzymatic lignocellulose hydrolysis: II. Quantification of inhibition and suitability of membrane reactors. AB - Product inhibition of cellulolytic enzymes affects the efficiency of the biocatalytic conversion of lignocellulosic biomass to ethanol and other valuable products. New strategies that focus on reactor designs encompassing product removal, notably glucose removal, during enzymatic cellulose conversion are required for alleviation of glucose product inhibition. Supported by numerous calculations this review assesses the quantitative aspects of glucose product inhibition on enzyme-catalyzed cellulose degradation rates. The significance of glucose product inhibition on dimensioning of different ideal reactor types, i.e. batch, continuous stirred, and plug-flow, is illustrated quantitatively by modeling different extents of cellulose conversion at different reaction conditions. The main operational challenges of membrane reactors for lignocellulose conversion are highlighted. Key membrane reactor features, including system set-up, dilution rate, glucose output profile, and the problem of cellobiose are examined to illustrate the quantitative significance of the glucose product inhibition and the total glucose concentration on the cellulolytic conversion rate. Comprehensive overviews of the available literature data for glucose removal by membranes and for cellulose enzyme stability in membrane reactors are given. The treatise clearly shows that membrane reactors allowing continuous, complete, glucose removal during enzymatic cellulose hydrolysis, can provide for both higher cellulose hydrolysis rates and higher enzyme usage efficiency (kg(product)/kg(enzyme)). Current membrane reactor designs are however not feasible for large scale operations. The report emphasizes that the industrial realization of cellulosic ethanol requires more focus on the operational feasibility within the different hydrolysis reactor designs, notably for membrane reactors, to achieve efficient enzyme-catalyzed cellulose degradation. PMID- 20172021 TI - Biosurfactants, bioemulsifiers and exopolysaccharides from marine microorganisms. AB - Marine biosphere offers wealthy flora and fauna, which represents a vast natural resource of imperative functional commercial grade products. Among the various bioactive compounds, biosurfactant (BS)/bioemulsifiers (BE) are attracting major interest and attention due to their structural and functional diversity. The versatile properties of surface active molecules find numerous applications in various industries. Marine microorganisms such as Acinetobacter, Arthrobacter, Pseudomonas, Halomonas, Myroides, Corynebacteria, Bacillus, Alteromonas sp. have been studied for production of BS/BE and exopolysaccharides (EPS). Due to the enormity of marine biosphere, most of the marine microbial world remains unexplored. The discovery of potent BS/BE producing marine microorganism would enhance the use of environmental biodegradable surface active molecule and hopefully reduce total dependence or number of new application oriented towards the chemical synthetic surfactant industry. Our present review gives comprehensive information on BS/BE which has been reported to be produced by marine microorganisms and their possible potential future applications. PMID- 20172022 TI - In vitro-Ishikawa cell test for assessing tissue-specific chemical effects on human endometrium. AB - The human endometrium is a fertility-determining factor. Its receptivity during the implantation window may be altered by chemicals. Since human embryo implantation is unique chemical risk assessment cannot be based solely on animal studies. We established a tissue-specific in vitro test based on human endometrial adenocarcinoma (Ishikawa) cells. Progesterone receptor (PR) was selected as primary target gene for estrogenic effects. Changes of mRNA levels were investigated by reverse transcription quantitative real-time PCR. Sigmoidal dose-response curves for up-regulation of PR mRNA and EC(50) values were established for 17beta-estradiol, diethylstilbestrol and the weak xenoestrogen bisphenol A. Nonylphenol also had a clear PR mRNA up-regulating effect. Several other chemicals were characterized as negative compounds. Among them was methoxyacetic acid which may produce false positive results in reporter gene assays. Up-regulation of PR protein by 17beta-estradiol, diethylstilbestrol, bisphenol A and nonylphenol was confirmed by Western Blotting. PMID- 20172023 TI - Slit1 promotes regenerative neurite outgrowth of adult dorsal root ganglion neurons in vitro via binding to the Robo receptor. AB - Secreted Slit proteins have previously been shown to signal through Roundabout (Robo) receptors to negatively regulate axon guidance and cell migration. During vertebrate development, Slit proteins have also been shown to stimulate branching and elongation of sensory axons and cortical dendrites. In this study, Slit1/Robo2 mRNA and protein expressions were detected in adult rat dorsal root ganglion (DRG) and in cultured DRG neurons. Treatment of both models with recombinant, soluble Slit1 protein was found to promote neurite outgrowth and elongation. In contrast, treatment with a recombinant human Robo2/Fc chimera inhibited neurite outgrowth and elongation. When adult DRG and cultured DRG neurons were pretreated with soluble recombinant human Robo2/Fc chimera, neurite outgrowth and elongation was not induced. These findings indicate that Slit1/Robo2 signaling may have a role in regulating peripheral nerve regeneration. PMID- 20172024 TI - Iron-mediated oxidative stress plays an essential role in ferritin-induced cell death. AB - Previously, we have demonstrated an apoptosis-inducing activity of an acidic, H chain-rich isoferritin secreted from primary rat hepatocytes in vitro. Because this proapoptotic property may be responsible for the growth-inhibitory and immunosuppressive effects described for certain ferritin species, we aimed to address the mechanism by which ferritin can trigger cell death. Suggesting a pivotal role for iron, iron chelation by desferrioxamine significantly abrogates ferritin-mediated apoptosis and necrosis in primary rat hepatocytes and substantially lowers the extent of protein modification by 4-hydroxynonenal (HNE) a major lipid peroxidation (LPO) product. Furthermore, supplementing the cultures with the radical-scavenging compound trolox also provided significant protection from ferritin-mediated apoptosis. Moreover, a significant increase in micronucleated cells upon exposure to ferritin indicates that ferritin also introduces damage to DNA. Based on these observations we therefore propose that endocytosis of extracellular ferritin increases the level of free ferrous iron in the lysosomal compartment, promoting Fenton chemistry-based oxidative stress involving LPO and increased lysosomal membrane permeability. Subsequently, the release of reactive lysosomal content leads to cellular damage, in particular modification of protein and DNA induced by HNE and other reactive aldehydic LPO products. Together, these effects will trigger apoptosis and necrosis based on the upregulation of p53, increased mitochondrial membrane permeability, and proapoptotic Fas signaling as described recently. In conclusion, based on their iron-storing ability, secreted acidic isoferritins may act as soluble mediators of oxidative stress under certain physiological and pathophysiological conditions. PMID- 20172025 TI - Action of 6-amino-3-pyridinols as novel antioxidants against free radicals and oxidative stress in solution, plasma, and cultured cells. AB - Free radical-mediated lipid peroxidation has been implicated in the pathogenesis of various diseases. Lipid peroxidation products are cytotoxic and they modify proteins and DNA bases, leading eventually to degenerative disorders. Various synthetic antioxidants have been developed and assessed for their capacity to inhibit lipid peroxidation and oxidative stress induced by free radicals. In this study, the capacity of novel 6-amino-2,4,5-trimethyl-3-pyridinols for scavenging peroxyl radicals, inhibiting plasma lipid peroxidation in vitro, and preventing cytotoxicity induced by glutamate, 6-hydroxydopamine, 1-methyl-4-phenylpyridium (MPP(+) ), and hydroperoxyoctadecadienoic acid was assessed. It was found that they exerted higher reactivity toward peroxyl radicals and more potent activity for inhibiting the above oxidative stress than alpha-tocopherol, the most potent natural antioxidant, except against the cytotoxicity induced by MPP(+). These results suggest that the novel 6-amino-3-pyridinols may be potent antioxidants against oxidative stress. PMID- 20172026 TI - Can low-dose combination products for inhalation be formulated in single crystalline particles? AB - This study aims to produce and test the performance of novel crystalline respirable particles containing two low-dose active ingredients and mannitol. This technique overcomes the usual requirement of blending with lactose carriers in formulating combination inhalation products. Ternary powders were produced by co-spray drying solutions containing an inhaled corticosteroid (ICS), a long acting beta2-agonist (LABA), and mannitol as a crystalline excipient. Two formulations comprising widely used ICS and LABA were studied: budesonide/formoterol fumarate dihydrate/mannitol (B/F/M-SD) and fluticasone propionate/salmeterol xinafoate/mannitol (F/S/M-SD). Various physicochemical properties of the powders were analyzed. Aerosol performance was evaluated by dispersing each powder from an Aerolizer at 60 and 100 L/min into a Next Generation Impactor. We obtained partially hollow spherical particles (volume median diameters of 2 microm) with drug-enriched surfaces. Both formulations contained alpha-mannitol, and the ICSs were crystalline. The content of each drug component in the powder was found to conform to the theoretical dose. The ternary powders generated high fine particle fractions (>50% of the loaded dose), with concomitant drug deposition on the impactor stages. The aerosol performance of B/F/M-SD was maintained after storage over silica gel at 22 degrees C for 11 weeks. In conclusion, co-spray dried particles of ICS/LABA/M-SD were largely crystalline, stable and showed excellent aerosol performance. They may provide an attractive alternative strategy to develop combination products without lactose blends. PMID- 20172027 TI - Formation of nano/micro-dispersions with improved dissolution properties upon dispersion of ritonavir melt extrudate in aqueous media. AB - The objective of the study was to characterise the aqueous dispersions of ritonavir melt extrudates. More specifically to look into the particular system formed when melt extrudate of a poorly soluble drug dissolved in a hydrophilic polymer matrix containing a surfactant is dispersed in an aqueous medium. Melt extrudates with and without ritonavir were studied. The drug containing extrudate was confirmed to be molecular dispersions of drug in a polymer/surfactant matrix. Particulate dispersions were formed in water from both drug and placebo extrudates. The dispersions were investigated with respect to mean particle size and particle size distribution (photon correlation spectroscopy and optical particle counting), surface charge (zeta potential), particle composition (ultracentrifugation), tendency to form aggregates and precipitate (turbidity), in vitro dissolution rate and drug release. It was concluded that dispersion of melt extrudates in aqueous medium give rise to nano/micro-dispersions. The stability of the nano/micro-dispersion is sensitive to anions and may be subjected to association/aggregation/flocculation as time proceeds after preparation of dispersion. Melt extrudate showed improved dissolution rate and drug release properties compared to crystalline raw material. From studies of single components and physical mixtures of the formulation composition it can be concluded that the drug delivery system itself, namely solid dispersion prepared by melt extrusion technology, plays a key role for the formation of the observed particles. PMID- 20172028 TI - Synchrotron X-ray microtomographic study of tablet swelling. AB - Tablet swelling behaviour was investigated by following the movements of embedded glass microsphere tracers, using X-ray microtomography (XmicroT) with intense illumination from a synchrotron. Specimens were prepared using combinations of hydroxypropyl-methyl-cellulose (HPMC) and microcrystalline cellulose (MCC) or pre gelatinised starch (PGS), three materials commonly used as excipients for compacted tablets. The results revealed significant differences in swelling behaviour due to excipient type and compaction conditions. In particular, a sudden change was observed from gel-forming behaviour of formulations containing PGS or high HPMC content, to more rapid expansion and disintegration for formulations above 70% MCC. Although some radial expansion was observable with the higher PGS formulations and during later stages of swelling, axial expansion (i.e. the reverse of the compaction process) appeared to dominate in most cases. This was most pronounced for the 10/90 HPMC/MCC specimens, which rapidly increased in thickness, while the diameter remained almost unchanged. The expansion appeared to be initiated by hydration and may be due to the relaxation of residual compaction stress. This occurred within 'expansion zones', which initially appeared as thin bands close to the compacted (upper and lower) faces, but gradually advanced towards the centre and spread around the sides of the tablets. These zones exhibited lower X-ray absorbance, probably because they contained significant amounts of bubbles, which were formed by air released from the swelling excipients. Although, in most cases, these bubbles were too small to be resolved (<60 microm), larger bubbles (diameter up to 1mm) were clearly evident in the rapidly swelling 10/90 HPMC/MCC specimens. It is suggested that the presence of these bubbles may affect subsequent water ingress, by increasing the tortuosity and occluding part of the gel, which may affect the apparent diffusion kinetics (i.e. Fickian or Case II). These observations also suggested that axial expansion, initiated by water ingress, may be an important mechanism during tablet swelling. PMID- 20172029 TI - Codon optimization enhances secretory expression of Pseudomonas aeruginosa exotoxin A in E. coli. AB - Pseudomonas aeruginosa exotoxin A (PEA) is a number of family of bacterial ADP ribosylating toxins and possesses strong immunogenicity. The detoxified exotoxin A, as a potent vaccine adjuvant and vaccine carrier protein, has been extensively used in human and animal vaccinations. However, the expression level of PEA gene in Escherichia coli is relative low which is likely due to the presence of rare codon and high levels of GC content. In order to enhance PEA gene expression, we optimized PEA gene using E. coli preferred codons and expressed it in E. coli BL21 (DE3) by using pET-20b(+) secretory expression vector. Our results showed that codon optimization significantly reduced GC content and enhanced PEA gene expression (70% increase compared with that of the wild-type). Moreover, the codon-optimized PEA possessed biological activity and had the similar toxic effects on mouse L292 cells compared with the wild-type PEA gene. Codon optimization will not only improve PEA gene expression but also benefit further modification of PEA gene using nucleotide-mediated site-directed mutagenesis. A large number of purified PEA proteins will provide the necessary conditions for further PEA functional research and application. PMID- 20172030 TI - Differential expansion of the merozoite surface protein (msp)-7 gene family in Plasmodium species under a birth-and-death model of evolution. AB - MSP-7 is a surface protein expressed by the Plasmodium merozoite as part of a protein-complex involved in initial interaction between merozoite and erythrocyte. Contigs of seven Plasmodium species were analyzed in order to identify all msp-7 family genes. The search identified annotated and unannotated open reading frames (ORFs) and showed an uneven number of msp-7 genes among the different species of the Plasmodium lineage. A phylogenetic analysis established the presence of at least two ancestral genes and identified various lineage- and species-specific duplication events. An estimation of synonymous (d(S)) and non synonymous substitutions (d(N)) showed higher d(S) values compared to d(N) values, suggesting the action of purifying selection on these genes, moreover no changes in omega (evolutive rates) were found in codon models test. These data together with the data obtained from the Gu's type-I functional divergence test and comparisons between evolutionary rates among orthologous and paralogous genes suggest functional redundancy. Finally, an analysis of recombination events suggests that several sequences are undergoing such process and that this mechanism could therefore be playing an important role in the emergence of new sequences. We conclude that evolution of the msp-7 family is in agreement with a birth-and-death model of evolution, as msp-7 genes have expanded until reaching an optimal gene copy number in each Plasmodium species in order to adapt to different niches. PMID- 20172031 TI - Biogeography of the genus Craterocephalus (Teleostei: Atherinidae) in Australia. AB - The genus Craterocephalus is one of the 11 genera within the family Atherinidae. It is the only genus in the family that has undergone an extensive radiation within freshwater habitats. Five species groups are represented within the genus, with 18 species found in Australia, six in New Guinea and one in East Timor. Craterocephalus is the equal fourth most widespread genus in Australian freshwater environments (occurring in 21 out of 31 biogeographic regions), and the most speciose (13 species). This allows identification of broad biogeographic patterns that can later be contrasted with other groups that overlap geographically. Phylogenetic relationships of Craterocephalus were examined using the cytochrome b gene. Results confirmed the monophyly of five species groups, with the marine "new honoriae" group being basal, suggesting a single invasion of freshwater habitats. The "capreoli" group and one species, C. munroi represents reversals back into marine/estuarine conditions. The most striking result from this study is the degree of differentiation between species in the separate freshwater groups within Craterocephalus. Despite often occurring sympatrically in river systems, interspecies and population divergences from "eyresii" and "stramineus" groups were substantially larger than divergences within "stercusmuscarum." Despite being one of the best freshwater groups characterized morphologically within Australia, it is clear that additional morphological work is required to clarify taxonomic problems within Craterocephalus, as molecular data suggest some species are synonymous, while others appear to represent multiple unrecognized taxa. PMID- 20172032 TI - Chloroplast DNA phylogeography of Clintoniaudensis Trautv. & Mey. (Liliaceae) in East Asia. AB - In this paper, we report the phylogeographic history of Clintoniaudensis Trautv. & Mey. (Liliaceae) inferred from two types of chloroplast DNA markers, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequences. Eighty samples were collected from 20 natural populations, 19 located in China and one in Japan, across the entire range of the species in East Asia. High genetic diversity (h(T)(PCR-RFLP)=0.972, h(T)(sequencing)=0.874) and significant differentiation (N(ST)(PCR-RFLP)=0.893, N(ST)(sequencing)=0.988 and G(ST)(PCR-RFLP)=0.777, G(ST)(sequencing)=0.978) were detected at the species level. These findings are consistent with a scenario of clonal reproduction and locally restricted gene exchange. The level of diversity of tetraploid populations was slightly greater than that of diploid populations. Significant molecular variation was found between tetraploids and diploids. Tetraploids may be autopolyploids and may have formed repeatedly in different locations. At least three regions of origin could be recognized. Twenty-six distinct haplotypes were identified. Haplotype frequency distributions were strongly skewed, with most haplotypes (n=25) represented by only one sample each and thus restricted to a single population. Non-overlapping distributions of cpDNA haplotypes and strong genetic differentiation among populations and/or different ploid level were consistent with the findings of a nested clade analysis, which inferred long distance colonization as the major process influencing the spatial haplotype distribution of this species. Nested clade analysis showed that the 26 haplotypes formed two 3-step, four 2-step and eleven 1-step clades, with twelve clades showing significant geographical associations. Higher N(ST) than G(ST) (P<0.05) suggested a distinct phylogeographical pattern. Based on mismatch distribution analysis and neutrality tests, we found no evidence of population expansion in the species. Our analyses indicate that the history of C.udensis involved both long-distance migration and the tectonic events of Mountains in East Asia. PMID- 20172033 TI - Evolutionary dynamics of introns and homing endonuclease ORFs in a region of the large subunit of the mitochondrial rRNA in Glomus species (arbuscular mycorrhizal fungi, Glomeromycota). AB - The large subunit of the mitochondrial ribosomal RNA genes (mtLSU) has previously been identified as a highly sensitive molecular marker for intraspecies diversity in the arbuscular mycorrhizal fungus Glomus intraradices. In this study, the respective region was analyzed in five species of Glomus (G. mosseae, G. geosporum, G. caledonium, G. clarum, G. coronatum) from the same major clade (Glomus group A), Glomus sp. ISCB 34 from the related Glomus group B and two species of Scutellospora. Results show low level of genetic polymorphism between related morphospecies. Introns homologous to those found in G. intraradices were detected as well as new ones, some of them containing putative ORFs for homing endonucleases (HEs). Introns without ORFs for HEs seem to have been inherited strictly vertically from the ancestors of Glomus groups A and B while other introns indicate occasional horizontal transfer and possibly maintenance, degeneration and loss together with their associated HE ORFs. Overall, we provide first insights into the evolutionary dynamics of introns and HEs in this ecologically important group of fungi, which was previously not analyzed in this respect. PMID- 20172034 TI - Interferences of the autonomic nervous system with drug induced QT prolongation: a point to consider in non-clinical safety studies. AB - INTRODUCTION: QT interval assessment by telemetry has become one of the most useful models in testing strategies adopted for detection of drug induced QT prolongation in non-clinical safety pharmacology studies. This study reports experimental data showing that the autonomic nervous system might influence drug induced QT prolongation. METHODS: Animals were instrumented with telemetric transmitters and epicardial ECG leads. Effects on QT interval of reference drugs such as thioridazine and terfenadine were analysed with different approaches, the Holzgrefe's probabilistic method, the QT shift method and an individual analysis of beat-to-beat QT/RR pair distribution visualised as points-cloud. RESULTS: Two cases of unexpected absence of QT interval prolongation are reported with thioridazine and terfenadine in conscious beagle dogs under conditions of concomitant tachycardia. The pro-arrhythmic properties of these two molecules were unmasked by co-treatment with sympatholytic agents, atenolol and clonidine respectively suggesting that sympathetic activation and/or parasympathetic withdrawal might impair a drug induced QT prolongation. DISCUSSION: The apparent absence of changes in the QT interval due to novel drug candidates should be interpreted cautiously under conditions of concomitant tachycardia or elevated heart rate levels in non-clinical safety studies. PMID- 20172035 TI - Metabolic and cardiac changes in high cholesterol-fructose-fed rats. AB - INTRODUCTION: High cholesterol-fructose (HCF) fed rats have previously been described as an animal model of impaired cardiac insulin signaling and decreased contractile performance. In this study, we evaluated the metabolic and cardiac effects of a HCF diet in rats. METHODS: Male Sprague-Dawley rats received a HCF diet for 16 to 17weeks. Body weight was measured weekly and mean arterial blood pressure, fasting blood glucose, fasting plasma insulin, glucose tolerance, and blood lipid levels were measured following 15weeks of feeding. One to 2weeks later, while still on the HCF diet, cardiac function was examined by in vivo pressure-volume measurements in the left ventricle. Finally, protein and glucose content in the urine was measured and all organs were weighed at the end of the study. RESULTS: Rats fed a HCF diet showed increased cholesterol and decreased high-density lipoprotein (HDL) levels in serum compared to control fed rats and they had more than a twofold increase in liver weight. However, in contrast to what has previously been reported, HCF diet had no effect on body weight, blood pressure, fasting blood glucose, fasting plasma insulin, glucose tolerance, or cardiac function during unstressed conditions. DISCUSSION: We were unable to reproduce previous findings that a HCF diet causes changes in glucose tolerance and cardiac contractile performance. Therefore, further studies are warranted to evaluate specific interactions between genetic, environmental, and dietary factors on metabolic and cardiovascular disease progression associated with intake of a westernized diet. PMID- 20172036 TI - Investigating dynamic protocol-dependence of hERG potassium channel inhibition at 37 degrees C: Cisapride versus dofetilide. AB - INTRODUCTION: Pharmacological inhibition of cardiac potassium channels encoded by hERG (human ether-a-go-go-related gene) is associated with QT interval prolongation and torsades de pointes arrhythmia. Electrophysiological assays of hERG channel inhibition are integral to the safety testing of novel drug candidates. This study was conducted to compare, for the high affinity hERG inhibitors dofetilide and cisapride, hERG blockade between action potential (AP) and conventional (step and step-ramp) screening waveforms. Furthermore, it evaluated dynamic (pulse-by-pulse) protocol-dependence of hERG channel inhibition by these drugs. METHODS: Whole-cell patch-clamp recordings were made at 37 degrees C from hERG-expressing HEK 293 cells. Half-maximal inhibitory concentrations (IC(50) values) for I(hERG) blockade were obtained using conventional voltage clamp and action potential clamp, using previously digitised ventricular and Purkinje fibre (PF) AP waveforms. RESULTS: A more marked variation in IC(50) values with different command waveforms was observed for cisapride (ranging from 7 to 72 nM) than for dofetilide (ranging from 4 to 15 nM), with higher IC(50)s obtained with AP than step or step-ramp commands. The two drugs differed little from one another in effects on voltage-dependent activation; however, I(hERG) blockade by each drug was initially voltage dependent, but at steady-state was only voltage-dependent for cisapride. There was comparatively little difference between the two drugs in effects on I(hERG) availability or time constants of development of inactivation. Features of time dependence of blockade and the use of protocols employing varying rest periods in drug or commands of alternating duration highlighted a pronounced ability of cisapride, but not dofetilide, to dissociate and reassociate from hERG on a pulse by-pulse basis. DISCUSSION: Protocols described here that demonstrated dynamic variation (drug dissociation/reassociation) in hERG channel current blockade at 37 degrees C for cisapride may have future value for investigating drug interactions with the hERG channel. Downloadable digitised ventricular and PF AP waveforms that can be used in AP clamp experiments also accompany this article. PMID- 20172037 TI - Prevalence, pattern and determinants of radiographic hand osteoarthritis in five Russian community-based samples. AB - OBJECTIVE: The aim of the study was to evaluate the prevalence and pattern of radiographic hand osteoarthritis (OA) and its association with age, sex, body mass index (BMI), and place of residence in five Russian community-based samples. DESIGN: Cross-sectional observational study: The study population comprised ethnic Russians [821 males and 1076 females, aged 18-90 (mean 46.2+/-15.3)], living in five different geographic areas. OA was evaluated for 14 joints of the left hand according to the Kellgren and Lawrence grading scheme. Statistical analyses included prevalence estimation, logistic and generalized model regressions, and chi(2) tests. RESULTS: We present extensive data on the prevalence of radiographic hand OA in a total Russian sample. After the age of 65, 98.5% of males and 96.8% of females had at least one affected joint. In individuals younger than 50, OA was most prevalent in the metacarpophalangeal joints, and after age 50, was most prevalent in the distal interphalangeal joints. Prevalence of hand OA was significantly higher in males than in females in ages 35-50. After adjustment for age, age(2) and place of residence, there were no associations between prevalence or severity of hand OA and BMI. CONCLUSIONS: Significant differences in prevalence and severity of hand OA were found between the Russian samples living in different geographic areas. Additional studies are needed to discover the mechanism defining the association between places of residence and development of hand OA. PMID- 20172038 TI - Second unrelated donor hematopoietic cell transplantation for primary graft failure. AB - Failure to engraft donor cells is a devastating complication after allogeneic hematopoietic cell transplantation (HCT). We describe the results of 122 patients reported to the National Marrow Donor Program between 1990 and 2005, who received a second unrelated donor HCT after failing to achieve an absolute neutrophil count of >or=500/microL without recurrent disease. Patients were transplanted for leukemia (n = 83), myelodysplastic disorders (n = 16), severe aplastic anemia (n = 20), and other diseases (n = 3). The median age was 29 years. Twenty-four patients received second grafts from a different unrelated donor. Among 98 patients who received a second graft from the same donor, 28 received products that were previously collected and cryopreserved for the first transplantation. One-year overall survival (OS) after second transplant was 11%, with 10 patients alive at last follow-up. We observed no differences between patients who received grafts from the same or different donors, or in those who received fresh or cryopreserved product. The outcomes after a second allogeneic HCT for primary graft failure are dismal. Identifying risk factors for primary graft failure can decrease the incidence of this complication. Further studies are needed to test whether early recognition and hastened procurement of alternative grafts can improve transplant outcomes for primary graft failure. PMID- 20172039 TI - Re: An approach to predicting HSCT outcome using HLA-mismatch information mapped on protein structure data. PMID- 20172040 TI - Favorable outcome in patients with acute myelogenous leukemia with the nucleophosmin gene mutation autografted after conditioning with high-dose continuous infusion of idarubicin and busulfan. AB - Mutations of the nucleophosmin gene (NPM1), in the absence of concurrent FLT3 internal tandem duplication (FLT3-ITD) have impressive prognostic value in patients with acute myelogenous leukemia (AML), carrying normal karyotype (NK). In this study we describe treatment results from a series of 19 patients with NPM+/FLT3- autografted in first complete remission (CR) after conditioning with a regimen, named BuI, based on high-dose continuous infusion of idarubicin and Busulfan. Ninety-nine consecutive patients (median age of 54 years) with NK AML autografted in first CR were analyzed. Nineteen of 99 patients (19%) had NPM1 mutation in the absence of FLT3 mutations. The control group, accounting for 80 patients, included 16 cases (15%) with both mutations, 10 (12%) with FLT3/ITD mutation and no NPM mutation, and 54 (68%) in whom neither NPM1 nor FLT3 mutations were detectable. The median overall survival (OS) for the whole patient population was 34 months, the median disease-free survival (DFS) was 22 months. Median OS and DFS were significantly longer for patients with isolated NPM1 mutation as opposed to controls (OS: not reached versus 25 months, P = .02; DFS: not reached versus 16 months, P = .007, respectively). Of interest, patients with isolated NPM1 mutation had a better outcome in terms of either OS or DFS compared to the group of 16 NMP1+/FLT3+ patients. In conclusion, our study suggest that BuI regimen results in favorable clinical outcome in patients with isolated NPM1 mutation, and could be investigated in a randomized study versus other regimes or repeated courses of high dose cytosine-arabinoside. PMID- 20172041 TI - Profiles of antioxidant gene expression and physiological changes by thermal and hypoosmotic stresses in black porgy (Acanthopagrus schlegeli). AB - We determined oxidative stress by measuring the expression and activity of 3 antioxidant enzymes [Cu/Zn-superoxide dismutase (Cu/Zn-SOD), catalase (CAT) and glutathione peroxidase (GPX)] in black porgy exposed to thermal (20 degrees C- >30 degrees C) and hypoosmotic (35 psu-->10 psu and 0 psu) stresses. The expression and activity of antioxidant enzymes were significantly higher after exposure to 30 degrees C, 10 psu, and 0psu. Furthermore, we measured H(2)O(2) and lipid peroxidation (LPO) levels. As a result, H(2)O(2) and LPO levels were significantly increased after exposure to thermal (20 degrees C-->30 degrees C) and hypoosmotic stress (35 psu-->10 psu and 0 psu) stress. These results indicate that thermal and hypoosmotic stress induces oxidative stress in black porgy. Additionally, we investigated the changes due to thermal and hypoosmotic stress by measuring plasma cortisol and ion (Na(+) and Cl(-)) levels. Plasma cortisol levels increased at 30 degrees C and at 10 psu and then decreased at 0 psu. However, plasma Na(+) and Cl(-) levels did not change after exposure to thermal stress (30 degrees C), and decreased at 10 psu and 0 psu. In conclusion, thermal and hypoosmotic environments increase oxidative stress, thereby these results may be indicators of oxidative stress in black porgy. PMID- 20172042 TI - Stable isotopes document mainland-island divergence in resource use without concomitant physiological changes in the lizard Liolaemus pictus. AB - Shifts in feeding ecology are believed to promote island-mainland divergence. The lizard Liolaemus pictus has several different subspecies on Chilean islands and mainland. These subspecies inhabit contrastingly different habitats both in different islands and mainland, which suggests the potential for habitat related dietary variation. We investigated the dietary habits of L. pictus by both stomach content analyses and by nitrogen stable isotope analyses (delta(15)N), which we used as a proxy variable for trophic level. We also compared the morphology of the digestive tract and the activity of intestinal digestive enzymes of mainland and island lizards. We hypothesized differences in diet and trophic level among populations and that these differences would predict the expression of the morphological and biochemical features of the digestive tract. More specifically, we predicted shorter intestines and higher levels of peptidases in more insectivorous than in more frugivorous/herbivorous lizards. The diet of L. pictus was characterized by the consumption of a wide diversity of food types, including fruit and insects, in all populations. Stable isotopes revealed higher trophic level, and hence probably higher protein intake, in mainland than in island populations, but contrary to our prediction, they had shorter intestines and higher relative activity of intestinal peptidases than mainland lizards. Furthermore, the proportion of fruit items in the stomach content was higher in the population that exhibited the lowest tropic level. These results suggest that morphological and physiological differences among populations of L. pictus are not correlated with feeding ecology, suggesting that the lizard's first responses to the selective pressure represented by a diet shift are behavioral. PMID- 20172043 TI - Chlamydomonas starchless mutant defective in ADP-glucose pyrophosphorylase hyper accumulates triacylglycerol. AB - Many microalgae and plants have the ability to synthesize large amounts of triacylglycerol (TAG) that can be used to produce biofuels. Presently, TAG-based biofuel production is limited by the feedstock supply. Metabolic engineering of lipid synthesis pathways to overproduce TAGs in oleaginous microalgae and oil crop plants has achieved only modest success. We demonstrate that inactivation of ADP-glucose pyrophosphorylase in a Chlamydomonas starchless mutant led to a 10 fold increase in TAG, suggesting that shunting of photosynthetic carbon partitioning from starch to TAG synthesis may represent a more effective strategy than direct manipulation of the lipid synthesis pathway to overproduce TAG. PMID- 20172044 TI - Inhibition of active HIV-1 replication by NF-kappaB inhibitor DHMEQ. AB - Previous reports indicate that nuclear factor (NF)-kappaB regulates induction of human immunodeficiency virus type 1 (HIV-1) gene expression in latently infected cells. However, the role of NF-kappaB in cells with active HIV-1 replication is not well understood. In this study, we examined the effect of a new NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on HIV-1 replication in a human T cell line and phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PHA-PBMCs). We further explored the mechanism of DHMEQ mediated inhibition of HIV-1 replication. DHMEQ inhibited HIV-1 replication in HIV-1-infected Molt-4 and PHA-PBMCs. DHMEQ inhibited constitutive NF-kappaB activity in HIV-1-infected PHA-PBMCs and HIV long terminal repeat promoter activity driven by tumor necrosis factor (TNF)-alpha and the trans-activator Tat. The single-round assay using vesicular stomatitis virus-pseudotyped virus in the human T cell line M8166 indicated that DHMEQ treatment resulted in decreased integration of HIV-1 provirus into the host genome and decreased HIV-1 expression. These results indicate that NF-kappaB regulates early events as well as the initial and accelerated expression of HIV-1 in its life cycle. Therefore, we conclude that NF-kappaB is a molecular target for controlling active HIV-1 replication. PMID- 20172045 TI - Relative contribution of Panton-Valentine leukocidin to PMN plasma membrane permeability and lysis caused by USA300 and USA400 culture supernatants. AB - Panton-Valentine leukocidin (PVL) is a cytolytic toxin associated with severe community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections. However, the relative contribution of PVL to host cell lysis during CA-MRSA infection remains unknown. Here we investigated the relative contribution of PVL to human polymorphonuclear leukocyte (PMN) plasma membrane permeability and lysis in vitro by using culture supernatants from wild-type and isogenic lukS/F-PV negative (Deltapvl) USA300 and USA400 strains. Using S. aureus culture conditions that favor selective high production of PVL (CCY medium), there was on average more PMN plasma membrane permeability and cell lysis caused by supernatants derived from wild-type strains compared with those from Deltapvl strains. Unexpectedly, plasma membrane permeability did not necessarily correlate with ultimate cell lysis. Moreover, the level of pore formation caused by culture supernatants varied dramatically (e.g., range was 0.32-99.09% for wild-type USA300 supernatants at 30 min) and was not attributable to differences in PMN susceptibility to PVL among human blood donors. We conclude that PMN pore formation assays utilizing S. aureus culture supernatants have limited ability to estimate the relative contribution of PVL to pathogenesis (or cytolysis in vitro or in vivo), especially when assayed using culture media that promote selective high production of PVL. PMID- 20172046 TI - Particulate depleted uranium is cytotoxic and clastogenic to human lung epithelial cells. AB - Depleted uranium (DU) is commonly used in military applications and consequently exposure to soldiers and non-combatants is potentially frequent and widespread. DU is suspected to be a carcinogen, potentially affecting the bronchial cells of the lung. Few studies have considered DU in human bronchial cells. Accordingly, we determined the cytotoxicity and clastogenicity of particulate DU in human bronchial epithelial cells (BEP2D cells). DU-induced concentration-dependent cytotoxicity in human bronchial epithelial cells, and was not clastogenic after 24h but induced chromosomal aberrations after 48h. These data indicate that if DU is a human bronchial carcinogen, it is likely acting through a mechanism that involves DNA breaks after longer exposures. PMID- 20172047 TI - Functional anatomy of the vagina muscles in the adult western conifer seed bug, Leptoglossus occidentalis (Heteroptera: Coreidae), and its implication for the egg laying behaviour in insects. AB - The anatomy of the female reproductive tract and the nerve-evoked contractions of the vagina muscles and their association with the ovipositor in the western conifer seed bug, Leptoglossus occidentalis (Heidemann) are investigated for the first time. The reproductive tract consists of a set of paired telotrophic ovaries, each containing seven ovarioles, located in the anterior lateral regions of the abdomen. Each ovary is attached to a lateral oviduct which spans most of the abdomen to attach to a relatively short common oviduct that joins the vagina near the rear of the animal. The vagina is associated with a pair of bilaterally symmetrical muscles attached at their posterior ends to lateral extensions of sternite VIII, the valvifer of the Type II ovipositor. From this attachment site, the muscles fan out medially and anteriorly to converge along the dorsal midline of the vagina up to the base of the common oviduct. Vagina muscles respond to a single stimulation of their motor nerves by producing a smooth contraction lasting approximately 1 s. With increasing frequencies of stimulation, the muscle contractions summate to create a tetanic response. The muscles are fatigue resistant being able to maintain the same degree of tension for up to 10 min at 10 Hz stimulation. Visual observation shows that other muscles associated with the valves of the ovipositor behave in a similar fashion to that of the vagina muscles from which the tension recordings were obtained. Fatigue-resistant vagina muscles are discussed in relation to copulation, sperm transport and this insect's ability to deposit a series of eggs directly onto the surface of a conifer needle in a manner by which eight or more blunt-ended eggs are packed end to-end in a single row. PMID- 20172048 TI - Hypoxemic and ischemic tolerance in emperor penguins. AB - Oxygen store depletion and a diving bradycardia in emperor penguins (Aptenodytes forsteri) expose tissues to critical levels of hypoxemia and ischemia. To assess the prevention of re-perfusion injury and reactive oxygen species (ROS) damage in emperor penguins, superoxide radical production, lipid peroxidation (thiobarbituric acid reactive substances (TBARS)), and antioxidant enzyme activity profiles in biopsy samples from muscle and liver were determined and compared to those in the chicken and 8 species of flighted marine birds (non divers and plunge divers). In muscle of emperor penguins, superoxide production and TBARS levels were not distinctly different from those in the other species; among the antioxidant enzymes, catalase (CAT) and glutathione-S-transferase (GST) activities were significantly elevated above all species. In the liver of emperor penguins, TBARS levels were not significantly different from other species; only CAT activity was significantly elevated, although GST and glutathione peroxidase (GPX) activities were 2-3 times higher than those in other species. The potential for ROS formation and lipid peroxidation is not reduced in the pectoral muscle or liver of the emperor penguin. Scavenging of hydrogen peroxide by CAT and the conjugation of glutathione with reactive intermediates and peroxides by GST and GPX appear to be important in the prevention of ROS damage and re-perfusion injury in these birds. PMID- 20172049 TI - Upstream therapy in atrial fibrillation: traveling up the river to find the source. PMID- 20172050 TI - In vitro evaluation of novel polymer-coated magnetic nanoparticles for controlled drug delivery. AB - Previously uncharacterized poly(N-isopropylacrylamide-acrylamide-allylamine) coated magnetic nanoparticles (MNPs) were synthesized using silane-coated MNPs as a template for radical polymerization of N-isopropylacrylamide, acrylamide, and allylamine. Properties of these nanoparticles such as size, biocompatibility, drug loading efficiency, and drug release kinetics were evaluated in vitro for targeted and controlled drug delivery. Spherical core-shell nanoparticles with a diameter of 100 nm showed significantly lower systemic toxicity than did bare MNPs, as well as doxorubicin encapsulation efficiency of 72%, and significantly higher doxorubicin release at 41 degrees C compared with 37 degrees C, demonstrating their temperature sensitivity. Released drugs were also active in destroying prostate cancer cells (JHU31). Furthermore, the nanoparticle uptake by JHU31 cells was dependent on dose and incubation time, reaching saturation at 500 MUg/mL and 4 hours, respectively. In addition, magnetic resonance imaging capabilities of the particles were observed using agarose platforms containing cells incubated with nanoparticles. Future work includes investigation of targeting capability and effectiveness of these nanoparticles in vivo using animal models. FROM THE CLINICAL EDITOR: In this paper, previously uncharacterized magnetic nanoparticles were synthesized using silane-coated MNPs as a template for radical polymerization of N-isopropylacrylamide, acrylamide, and allylamine. Various properties of these nanoparticles were evaluated in vitro for targeted drug delivery. PMID- 20172051 TI - Cerium oxide nanoparticles protect gastrointestinal epithelium from radiation induced damage by reduction of reactive oxygen species and upregulation of superoxide dismutase 2. AB - The ability of rare earth cerium oxide (CeO(2)) nanoparticles to confer radioprotection against gastrointestinal epithelium was examined. The pretreatment of normal human colon cells (CRL 1541) with varying concentrations of CeO(2) nanoparticles 24 hours before single-dose radiation exposure conferred protection from radiation-induced cell death by reducing the amount of reactive oxygen species produced and increasing the expression of superoxide dismutase 2 (SOD2), in a dose-dependent manner. In subsequent experiments athymic nude mice were pretreated with intraperitoneal injections of CeO(2) nanoparticles before a single dose of radiation to the abdominal area. Immunohistochemical analysis show a decrease in TUNEL- and caspase 3-positive cells in the colonic crypt, 4 hours after radiation. In sharp contrast, a significant increase in SOD2 expression was observed. In the end, these studies suggest that CeO(2) nanoparticles protect the gastrointestinal epithelium against radiation-induced damage by (1) acting as free-radical scavengers and (2) increasing the production of SOD2 before radiation insult. FROM THE CLINICAL EDITOR: In this study, the ability of rare earth cerium oxide (CeO(2)) nanoparticles to confer radioprotection was examined. The results suggest that CeO(2) nanoparticles protect the gastrointestinal epithelium against radiation-induced damage both by acting as free-radical scavengers and by increasing the production of SOD2 before radiation insult. PMID- 20172052 TI - Discriminated effects of thiolated chitosan-coated pMMA paclitaxel-loaded nanoparticles on different normal and cancer cell lines. AB - The aim of the present work was to prepare and characterize poly(methyl methacrylate) nanoparticles coated by chitosan-glutathione conjugate so as to encapsulate insoluble anticancer drugs. Nanoparticles were synthesized through radical polymerization of methyl methacrylate initiated by cerium (IV) ammonium nitrate. Paclitaxel (PTX), a model anticancer drug, was encapsulated in nanoparticles with a maximal encapsulation efficiency of 98.27%. These nanoparticles showed sustained in vitro release of the incorporated PTX (75% of the loaded dose was released in 10 days). All nanoparticles had positive charge and were spherical, with a size range of about 130-250 nm. The PTX-loaded nanoparticles showed cytotoxicity for NIH 3T3 and T47D breast carcinoma cells, along with no cytotoxicity for two colon cell lines (HT29, Caco2). FROM THE CLINICAL EDITOR: The aim of this work was to prepare and characterize poly(methyl methacrylate) nanoparticles coated by chitosan-glutathione conjugate in an effort to encapsulate Paclitaxel as a model of insoluble anticancer drugs. These nanoparticles showed sustained in vitro drug release. PMID- 20172053 TI - Design of adaptive two-stage double-arm clinical trials for dichotomous variables. AB - It is well known that flexibility is one of the major advantages of an adaptive two-stage design, and the intended adaptation should be as preplanned as possible to maintain the integrity of the clinical trial. The design of adaptive two-stage double-arm clinical trials for dichotomous variables was proposed by simulation and forecasting procedure at the planning stage. To further ensure the integrity of the clinical trial, the sample size scheme for each scenario, which was supposed to be based on the first stage, was provided in the protocol by Monte Carlo simulation. In addition, the study parameters were determined by comparing the assessment indexes such as total sample size, expected sample size and the test power at the first stage. Furthermore, Fisher's combination test and pooled data analysis were considered and compared through the simulation. The latter, which has the larger overall power and the better overall type I error control, with the same sample size was adopted for further simulation and statistical analysis in the clinical trial. PMID- 20172055 TI - Successful treatment of autoimmune thrombocytopenic purpura with rituximab in a dialysis patient with systemic lupus erythematosus. AB - Autoimmune thrombocytopenic purpura (ATP) in systemic lupus erythematosus involves autoantibody mediated destruction of platelets. In dialysis patients with refractory ATP which is unresponsive to corticosteroid and immunosuppressive agents, the management is difficult. B cell targeted therapy with rituximab has emerged as a promising agent by reducing the levels of pathogenic autoantibodies. However, its safety and efficacy in dialysis patients are uncertain. In this report, we described a dialysis patient with refractory lupus-related ATP, whose platelet counts responded only to rituximab. Furthermore, no severe side effects were noted during the treatment period, suggesting that rituximab can be administered safely in dialysis patients. PMID- 20172056 TI - Immunosenescence and juvenile idiopathic arthritis. AB - Aging of the immune system (immunosenescence) is characterized by diminished thymus function, decreased output of recent thymic emigrants, compensatory peripheral proliferation of mature T cells and oligoclonal expansions of specific CD28(-) T cells. Clinical consequences are poor responses to new antigens or vaccinations, increased infection rates with higher morbidity and mortality, and increasing incidence of autoimmune diseases with advancing age. Premature immunosenescence is suggested to play a role in the pathogenesis of adult rheumatoid arthritis and in children with juvenile idiopathic arthritis (JIA). However, so far, there is not enough evidence for supporting one of the two theories: the first, favoring premature immunosenscence in children developing autoimmune conditions as the primary defect causing break-down of self-tolerance; the second, that premature immunosenescence in children with autoimmune disorders is secondary to chronic stimulation and activation of the immune system by inflammatory processes by the autoimmune disease itself. This contradictory view of etiology and pathogenesis of autoimmune diseases in the very young underlines the need for population-based longitudinal studies on immune-risk factors for autoimmune diseases beginning at infancy. PMID- 20172057 TI - The history of biodegradable magnesium implants: a review. AB - Today, more than 200years after the first production of metallic magnesium by Sir Humphry Davy in 1808, biodegradable magnesium-based metal implants are currently breaking the paradigm in biomaterial science to develop only highly corrosion resistant metals. This groundbreaking approach to temporary metallic implants is one of the latest developments in biomaterials science that is being rediscovered. It is a challenging topic, and several secrets still remain that might revolutionize various biomedical implants currently in clinical use. Magnesium alloys were investigated as implant materials long ago. A very early clinical report was given in 1878 by the physician Edward C. Huse. He used magnesium wires as ligature for bleeding vessels. Magnesium alloys for clinical use were explored during the last two centuries mainly by surgeons with various clinical backgrounds, such as cardiovascular, musculoskeletal and general surgery. Nearly all patients benefited from the treatment with magnesium implants. Although most patients experienced subcutaneous gas cavities caused by rapid implant corrosion, most patients had no pain and almost no infections were observed during the postoperative follow-up. This review critically summarizes the in vitro and in vivo knowledge and experience that has been reported on the use of magnesium and its alloys to advance the field of biodegradable metals. PMID- 20172058 TI - Serum visfatin levels in acute appendicitis. AB - The clinical importance of the novel adipokine visfatin are still largely unknown. Our aim was to evaluate diagnostic accuracy of visfatin serum concentrations in Acute appendicitis(AA). Total of 34 patients with preoperative AA diagnosis (18 men and 16 women, mean age 28.8 +/- 10.9 years) were enrolled this study. The appendix specimens were classified as normal appendix (10 patients), acute appendicitis (24 patients). The serum levels of visfatin measured Diagnostic value of the preoperative serum visfatin levels as assessed through the corresponding ROC curve was well. (area under the curve [AUC] = 0.926, P < .001). In this small case series, visfatin level was found to be useful marker for diagnosis of AA. PMID- 20172060 TI - Comparison between electroanatomic and pathologic findings in a patient with arrhythmogenic right ventricular cardiomyopathy/dysplasia treated with orthotopic cardiac transplant. PMID- 20172059 TI - The challenge of Chagas' disease: has the human pathogen, Trypanosoma cruzi, learned how to modulate signaling events to subvert host cells? AB - Chagas' disease, caused by Trypanosoma cruzi, is an urgent and highly prevalent danger that is endemic to Latin America, and which the research community continues to ignore. Each year, Chagas' disease kills more people in Latin America compared to any other parasite-borne disease, including malaria. In addition, between 15 and 18 million people worldwide are afflicted with this potentially lethal disease. Despite these devastating numbers, less than 0.5% of worldwide research and development for neglected diseases was aimed at Chagas' disease. The aim of this review is to draw the attention of biotechnologists to the intriguing parasite that causes Chagas' disease, which is T. cruzi. Additionally, we would also like to convince the community that basic science research can have a profound impact on the diagnosis and treatment of Chagas' disease. In this review, we introduce distinct features of T. cruzi such as its complex life cycle (e.g. the potentially infective extracellular amastigote form), its genome and genomics, as well as proteomic analysis of this parasite. Notably, the PIK pathway has been widely acknowledged as an excellent target for drug discovery to combat this pathogen. Furthermore we also describe how the identification and characterization of PIK genes can aid in neutralizing Trypanosoma infections. PMID- 20172061 TI - Peer review should continue after publication. PMID- 20172063 TI - Current research in biostatistics. PMID- 20172062 TI - Central serous chorioretinopathy: a personal perspective. PMID- 20172064 TI - Study designs in epidemiology and levels of evidence. PMID- 20172065 TI - Posterior vitreous detachment: evolution and complications of its early stages. AB - PURPOSE: To summarize emerging concepts regarding the onset and progression, traction effects, and complications of the early stages of age-related posterior vitreous detachment (PVD). DESIGN: Interpretive essay. METHODS: Review and synthesis of selected literature, with clinical illustrations, interpretation, and perspective. RESULTS: Imaging of the vitreoretinal interface with optical coherence tomography has shown that PVD begins in the perifoveal macula. Recent longitudinal studies have demonstrated conclusively that early PVD stages persist chronically and progress slowly over months to years. Vitreous traction forces resulting from perifoveal PVD with a small vitreofoveolar adhesion (500 microm or less) may cause localized cystoid foveal thickening or one of several macular hole conditions. Traction associated with larger adhesion zones may cause or exacerbate a separate group of macular disorders. Ultrastructural studies suggest that epiretinal membrane develops from cortical vitreous remnants left on the retinal surface after PVD and plays an important role in traction vitreomaculopathies. CONCLUSIONS: Age-related PVD is an insidious, chronic event that begins in the perifoveal macula and evolves over a prolonged period before vitreopapillary separation. Although asymptomatic in most individuals, its early stages may be complicated by a variety of macular and optic disc pathologic features, determined in part by the size and strength of the residual vitreoretinal adhesion. PMID- 20172066 TI - Complications and clinical outcomes of descemet stripping automated endothelial keratoplasty with intraocular lens exchange. AB - PURPOSE: To evaluate complications and clinical outcomes of Descemet stripping automated endothelial keratoplasty (DSAEK) with intraocular lens (IOL) exchange compared with DSAEK alone. DESIGN: Retrospective, interventional case series. METHODS: DSAEK was performed in 19 eyes in which the anterior chamber IOL was exchanged for a posterior chamber IOL (study group) and in 188 eyes in which the posterior chamber IOL was left in place (comparison group). The complications of graft dislocations, primary graft failure episodes, and pupillary block were recorded for all eyes. Six-month best spectacle-corrected visual acuity and mean central endothelial cell density were measured prospectively and then compared with preoperative values for all eyes. RESULTS: Dislocations occurred in 0 (0%) of 19 eyes in the study group and in 5 (3%) of 188 eyes in the comparison group (P = .47), with 0 primary graft failures and 0 pupillary block episodes in either group. Preoperative mean best spectacle-corrected visual acuity for those eyes without any underlying ocular comorbidities was 20/205 and 20/100 in the study and comparison groups, respectively (P = .18). Mean best spectacle-corrected visual acuity at 6 months improved to 20/48 in the study group and to 20/34 in the comparison group, a statistically significant difference (P = .01). Mean donor cell loss at 6 months was 33% in the study group and 26% in the comparison group (P = .18). CONCLUSIONS: Concurrent IOL exchange with DSAEK surgery does not increase the dislocation, primary graft failure, or pupillary block rates in the immediate postoperative period. Donor endothelial cell loss in DSAEK was not increased significantly by IOL exchange. Visual acuity was slightly worse after combined surgery than after DSAEK alone. PMID- 20172067 TI - Non-syndromic supernumerary caruncles causing ocular irritation after cataract surgery: a critical review of caruncular dysgeneses. AB - PURPOSE: To describe a patient with 2 ipsilateral supernumerary caruncles and to determine if they are predictive of associated abnormalities. DESIGN: Retrospective and interventional clinicopathologic study with a critical review of the literature over the past 100 years. METHODS: Assessment of clinical features and histopathologic findings in paraffin-embedded tissue sections stained with hematoxylin and eosin, Masson trichrome, periodic acid-Schiff (PAS) reaction with and without diastase, and Ziehl-Neelsen method. RESULTS: Two placoid lesions causing ocular irritation after routine phacoemulsification were discovered in the inferomedial palpebral conjunctiva. They were totally separate from a normal caruncle. Their surface was studded with yellowish micronodules with projecting white vellus hairs. There were no associated local ophthalmic or systemic abnormalities. Microscopically, they were covered by a goblet cell-rich, nonkeratinizing squamous epithelium with subadjacent pilosebaceous units, the hairs of which were highlighted by the Masson trichrome and Ziehl-Neelsen stains, and small lobules of lacrimal gland tissue. The ocular irritation has not returned after surgery. CONCLUSIONS: A literature review confirms that supernumerary (extra) caruncles coexisting with a normal caruncle are always unilateral and unassociated with any other ocular anomalies, as in the current case. They may, however, cause ocular irritation. They must be distinguished from ectopic (topographically displaced) or dysplastic caruncles that are generally bilateral and often associated with ocular adnexal abnormalities or Goldenhar syndrome. Ectopic or dysplastic caruncles, but not supernumerary ones, are characteristically accompanied by plical abnormalities or its absence. Well documented supernumerary and ectopic caruncles have always been located in the inferior palpebral conjunctiva. PMID- 20172068 TI - Quality of life in keratoconus patients after penetrating keratoplasty. AB - PURPOSE: To determine vision-related quality of life (QoL) measured with the National Eye Institute Visual Function Questionnaire (NEI-VFQ) in keratoconus (KCN) patients who have undergone penetrating keratoplasty (PK) in 1 or both eyes and to compare the results of our study to those of historical controls. DESIGN: Clinical-based, cross-sectional study. METHODS: SETTING: Wills Eye Institute, Cornea Service, Thomas Jefferson University, Philadelphia, Pennsylvania. STUDY POPULATION: This study included 149 consecutive patients who had undergone PK for KCN. INTERVENTION: Between June 1, 2008 and December 31, 2008, the NEI-VFQ was administered to 149 patients. The relationship between demographic and clinical factors and NEI-VFQ subscale scores was evaluated. MAIN OUTCOME MEASURE: Vision related quality of life. RESULTS: Eighty-three of 149 patients (55.7%) were male. Approximately half of the patients (76/149; 51.0%) had PK in both eyes. Visual acuity with current correction in the better eye was better than 20/40 in 80% of patients (119/149). Our sample had significantly lower (worse) NEI-VFQ scores compared to Collaborative Longitudinal Evaluation of Keratoconus (CLEK) historical control group for the subscales of role difficulties, dependency, driving, and peripheral vision. In general, scores of our sample were between scores of patients with age-related macular degeneration (AMD) category 3 and 4. Patients with visual acuity better than 20/40 (in the better eye) showed significantly higher scores in all subscales except color vision. There was a significant relationship between minimum time since the graft of 5 years or greater and NEI-VFQ overall score better than AMD category 3 (P = .004). CONCLUSION: Despite satisfactory results on visual outcome measures obtained after PK, vision-related QoL in KCN patients remains impaired. PMID- 20172070 TI - Association between the efficacy of photodynamic therapy and indocyanine green angiography findings for central serous chorioretinopathy. AB - PURPOSE: To determine the efficacy of photodynamic therapy (PDT) and indocyanine green angiography (ICGA) findings for treating chronic central serous chorioretinopathy (CSC). DESIGN: Observational case series. METHODS: Thirty-two eyes of 27 patients with chronic CSC and symptoms for at least 6 months were recruited. The minimum follow-up was 1 year. The total PDT energy was reduced to about 36 to 42 mJ/cm(2). The baseline middle-phase ICGA findings were classified as intense, intermediate, or no hyperfluorescence depending on the degree of hyperfluorescence. The resolution of the subretinal fluid and recurrence rates were assessed in relation to each ICGA finding at baseline. RESULTS: ICGA before PDT showed intense hyperfluorescence in 23 eyes (72%), intermediate hyperfluorescence in 6 eyes (19%), and no hyperfluorescence in 3 eyes (9%). The subretinal fluid resolved completely 3 months after 1 application of PDT in 23 eyes (100%) with intense hyperfluorescence, 6 eyes (100%) with intermediate hyperfluorescence, and no eyes (0%) with no hyperfluorescence. In the last group, the subretinal fluid did not resolve throughout the follow-up period despite additional applications of PDT. The subretinal fluid recurred in 7 of 29 eyes (24%) in which the subretinal fluid resolved at 3 months; recurrence was frequent in eyes with intermediate hyperfluorescence (5 eyes; 83%). CONCLUSION: The PDT success rate in eyes with chronic CSC depends on the degree of hyperpermeability on ICGA. PDT is not effective or the recurrence rate is predicted to be high in eyes without intense hyperfluorescence. PMID- 20172069 TI - Viral retinitis after intravitreal triamcinolone injection in patients with predisposing medical comorbidities. AB - PURPOSE: To review the cases of viral retinitis after intravitreal steroid administration at a single center, to estimate the incidence, and to propose risk factors for its occurrence. DESIGN: Retrospective, observational case series. METHODS: Seven hundred thirty-six intravitreal triamcinolone (IVTA) injections were administered in the clinic and operating room by 3 retina specialists at a single academic medical center between September 2002 and November 2008. Inclusion criteria were simply a history of 1 or more IVTA injections during the period. The overall incidence of viral retinitis after IVTA injection was calculated. Subsequently, a chart audit was performed to estimate the number of patients with immune-altering conditions who had received IVTA during the period, and the incidence within this subgroup was calculated. RESULTS: Viral retinitis developed after IVTA injection in 3 patients, yielding an overall incidence of 3 in 736 or 0.41%. An estimated 334 injections were administered to patients with an immune-altering condition, including diabetes. All 3 of the patients in whom viral retinitis developed after IVTA injection possessed abnormal immune systems, yielding an incidence rate of 3 in 334 or 0.90% within this subgroup. CONCLUSIONS: Our high reported incidence for this potentially devastating complication can be attributed to multiple factors, including coexisting medical immunocompromising comorbidities, a higher dose with a longer duration of local immunosuppression in the vitreous, multiple injections, as well as previous viral retinitis. Caution with a high index of clinical suspicion and frequent follow-up is advised in patients receiving IVTA injection with potentially immune-altering conditions, even after apparent immune recovery. PMID- 20172071 TI - Primary retinectomy in proliferative vitreoretinopathy. AB - PURPOSE: To describe the functional and anatomic results of retinectomy without scleral buckling for anterior proliferative vitreoretinopathy in eyes that did not undergo previous buckling surgery. DESIGN: Retrospective, nonrandomized, interventional case series. METHODS: We reviewed the results of 123 consecutive cases of retinectomy for rhegmatogenous retinal detachment complicated by anterior proliferative vitreoretinopathy. The primary outcome measure was anatomic success, defined as complete retinal reattachment. Secondary outcome measures were final anatomic success, final visual acuity outcome, number of operations required for retinal reattachment, baseline extent of proliferative vitreoretinopathy, ocular pressure at final follow-up, extent of retinectomy, and occurrence of complications. RESULTS: The anatomic success rate was 77.2%. Final attachment rate was 95.9%, reached after 1 rhegmatogenous retinal detachment reoperation in 21 cases and after 2 rhegmatogenous retinal detachment reoperations in 4 cases. We had a low rate of postoperative hypotony (4.1%). Visual acuity was significantly improved from 2.10 to 1.44 logarithm of the minimal angle of resolution units (P < .001). Improvement was related significantly to retinectomy extent and primary anatomic success. CONCLUSIONS: Our results show that primary retinectomy without scleral buckling has good anatomic and functional results. PMID- 20172072 TI - Choroidal neovascularization in pathologic myopia: intravitreal ranibizumab versus bevacizumab--a randomized controlled trial. AB - PURPOSE: To compare the short-term efficacy and safety of intravitreal ranibizumab versus bevacizumab in treating myopic choroidal neovascularization (CNV). DESIGN: Prospective, comparative, randomized, interventional study. METHODS: Thirty-two eyes from 32 patients with myopic CNV were consecutively enrolled and randomly treated, in a 1:1 ratio, with intravitreal ranibizumab (0.5 mg) or bevacizumab (1.25 mg) as needed, after the first injection. ETDRS best corrected visual acuity (BCVA), foveal center thickness (FCT) on optical coherence tomography (OCT), and fluorescein angiographic findings were examined before and after treatment. Patients were followed up for 6 months. RESULTS: No statistically significant difference in the BCVA improvement, as well as in the FCT reduction, was found between groups during follow-up (P value at 1, 3, 6 months > .05). Complete resolution of fluorescein leakage was observed in all 16 bevacizumab-treated eyes and in 15 out of 16 (93.7%) ranibizumab-treated eyes. No ocular or systemic adverse effects from treatment were encountered. CONCLUSION: This randomized clinical study cannot determine a statistically significant difference in anti-VEGF treatment effect between ranibizumab and bevacizumab for the treatment of CNV secondary to pathologic myopia. A larger study is required to determine the relative efficacy and duration of action of these drugs. PMID- 20172073 TI - Pattern electroretinogram and psychophysical tests of visual function for discriminating between healthy and glaucoma eyes. AB - PURPOSE: To compare the diagnostic accuracy of the pattern electroretinogram (pattern ERG) to that of standard automated perimetry (SAP), short-wavelength automated perimetry (SWAP), and frequency-doubling technology (FDT) perimetry for discriminating between healthy and glaucomatous eyes. DESIGN: Cross-sectional study. METHODS: Eighty-three eyes of 42 healthy recruits and 92 eyes of 54 glaucoma patients (based on optic disc appearance) from the University of California, San Diego, Diagnostic Innovations in Glaucoma Study were tested with pattern ERG for glaucoma detection (PERGLA; Lace Elettronica, Pisa, Italy), SAP, SWAP, and FDT within 9 months. Receiver operating characteristic (ROC) curves were generated and compared for pattern ERG amplitude and SAP, SWAP, and FDT mean deviation and pattern standard deviation (PSD). Sensitivities and specificities were compared and agreement among tests was described. RESULTS: The area under the ROC curve for pattern ERG amplitude was 0.744 (95% confidence interval = 0.670, 0.818). The ROC curve area was 0.786 (0.720, 0.853) for SAP PSD, 0.732 (0.659, 0.806) for SWAP PSD, and 0.818 (0.758, 0.879) for FDT PSD. At 95% specificity, sensitivities of SAP and FDT PSD were significantly higher than that of pattern ERG amplitude; at 80% specificity, similar sensitivities were observed among tests. Agreement among tests was slight to moderate. CONCLUSION: The diagnostic accuracy of the pattern ERG amplitude was similar to that of SAP and SWAP, but somewhat worse than that of FDT. Nevertheless, the pattern ERG may hold some advantage over psychophysical testing because of its largely objective nature. PMID- 20172074 TI - The development of myopia among children with intermittent exotropia. AB - PURPOSE: To describe the long-term refractive error changes in children diagnosed with intermittent exotropia (IXT) in a defined population. DESIGN: Retrospective, population-based observational study. METHODS: Using the resources of the Rochester Epidemiology Project, the medical records of all children (<19 years) diagnosed with IXT as residents of Olmsted County, Minnesota, from January 1, 1975 through December 31, 1994 were retrospectively reviewed for any change in refractive error over time. RESULTS: One hundred eighty-four children were diagnosed with IXT during the 20-year study period; 135 (73.4%) had 2 or more refractions separated by a mean of 10 years (range, 1-27 years). The Kaplan-Meier rate of developing myopia in this population was 7.4% by 5 years of age, 46.5% by 10 years, and 91.1% by 20 years. There were 106 patients with 2 or more refractions separated by at least 1 year through 21 years of age, of which 43 underwent surgery and 63 were observed. The annual overall progression was -0.26 diopters (SD +/- 0.24) without a statistically significant difference between the observed and surgical groups (P = .59). CONCLUSION: In this population-based study of children with intermittent exotropia, myopia was calculated to occur in more than 90% of patients by 20 years of age. Observation versus surgical correction did not alter the refractive outcome. PMID- 20172075 TI - Testability of vision and refraction in preschoolers. PMID- 20172077 TI - Recovery of corneal hysteresis after reduction of intraocular pressure in chronic primary angle-closure glaucoma. PMID- 20172078 TI - Re: Outcome of raised intraocular pressure in uveitic eyes with and without a corticosteroid-induced hypertensive response. PMID- 20172081 TI - Increased likelihood of glaucoma at the same intraocular pressure in subjects with pseudoexfoliation. PMID- 20172083 TI - Stratus OCT signal strength and reliability of retinal nerve fiber layer measurements. PMID- 20172085 TI - Re: Angle-closure glaucoma--simpler answers to complex mechanisms. PMID- 20172087 TI - Re: Spontaneous corneal clearance despite graft detachment in Descemet membrane endothelial keratoplasty. PMID- 20172088 TI - Hydrodynamic gating valve for microfluidic fluorescence-activated cell sorting. AB - Microfluidic cell sorter allows efficient separation of small number of cells, which is beneficial in handling cells, especially primary cells that cannot be expanded to large populations. Here, we demonstrate a microfluidic fluorescence activated cell sorter (muFACS) with a novel sorting mechanism, in which automatic on-chip sorting is realized by turning on/off the hydrodynamic gating valve when a fluorescent target is detected. Formation of the hydrodynamic gating valve was investigated by both numerical simulation and flow visualization experiment. Separation of fluorescent polystyrene beads was then conducted to evaluate this sorting mechanism and to optimize the separation conditions. Isolation of fluorescent HeLa-DsRed cells was further demonstrated with high purity and recovery rate. Viability of the sorted cells was also examined, suggesting a survival rate of more than 90%. We expect this sorting approach to find widespread applications in bioanalysis. PMID- 20172089 TI - Prediction of lambda(max) of 1,4-naphthoquinone derivatives using ant colony optimization. AB - Ant colony optimization (ACO) is a meta-heuristic algorithm, which is derived from the observation of real ants. In this paper, ACO algorithm is proposed to feature selection in quantitative structure property relationship (QSPR) modeling and to predict lambda(max) of 1,4-naphthoquinone derivatives. Feature selection is the most important step in classification and regression systems. The performance of the proposed algorithm (ACO) is compared with that of a stepwise regression, genetic algorithm and simulated annealing methods. The average absolute relative deviation in this QSPR study using ACO, stepwise regression, genetic algorithm and simulated annealing using multiple linear regression method for calibration and prediction sets were 5.0%, 3.4% and 6.8%, 6.1% and 5.1%, 8.6% and 6.0%, 5.7%, respectively. It has been demonstrated that the ACO is a useful tool for feature selection with nice performance. PMID- 20172090 TI - Matrix-free analysis of aflatoxins in pistachio nuts using parallel factor modeling of liquid chromatography diode-array detection data. AB - In the present study a second-order calibration strategy for high performance liquid chromatography with diode-array detection (HPLC-DAD) has been developed using parallel factor analysis (PARAFAC) and has been applied for simultaneous determination of aflatoxins B(1), B(2), G(1) and G(2) in pistachio nuts in the presence of matrix interferences. Sample preparation was based on solvent extraction (SE) followed by solid phase extraction (SPE) on Bond Elut C18 cartridges. Since the sample preparation procedure was not selective to the analytes of interest, exploiting second-order advantage to obtain concentrations of individual analytes in the presence of uncalibrated interfering compounds seemed necessary. Appropriate pre-processing steps have been applied to correct background signals and the effect of retention time shifts. Transferred calibration data set obtained from standardization of solvent based calibration data has been used in prediction step. The results of PARAFAC on a set of spiked and naturally contaminated pistachio nuts indicated that the four aflatoxins could be successfully determined. The method was validated and multivariate analytical figures of merit were calculated. The advantages of the proposed method are using a low-cost SPE step relative to standard method of aflatoxin analysis (immune affinity column assay), a unique and simple isocratic elution program for all samples and a calibration transfer for saving both chemicals and time of analysis. This study show that coupling of SPE-HPLC-DAD with PARAFAC as a powerful second-order calibration method can be considered as an alternative method for resolution and quantification of aflatoxins in the presence of unknown interferences obtained through analysis of highly complex matrix of pistachio samples and cost per analysis can be reduced significantly. PMID- 20172091 TI - Electrochemical behavior of biocatalytical composite based on heme-proteins, didodecyldimethylammonium bromide and room-temperature ionic liquid. AB - A novel biocompatible composite film based on a water-insoluble surfactant, didodecyldimethylammonium bromide (DDAB), and a hydrophobic room-temperature ionic liquid (RTIL), 1-hexyl-3-methyl-imidazolium hexafluorophosphate (HIMIMPF(6)), for the immobilization of biocatalytical proteins was reported. Differential scanning calorimetry (DSC) showed that the DDAB-HIMIMPF(6) composite film has higher thermal stability than the DDAB film alone. SEM images indicated that different microstructures existed between the DDAB film and the composite film, indicating the interaction between DDAB and RTILs. This composite can be used as the immobilization matrix of proteins and other biomacromolecules. Heme proteins, including hemoglobin (Hb), myoglobin (Mb) and horseradish peroxidase (HRP), were used as model proteins for studying the electrochemical behaviors of the resulting biocatalytical composite films. In the case of Hb, a pair of well defined quasi-reversible redox peaks was obtained when the composite film containing Hb was modified on a glassy carbon electrode. The formal potential (E degrees '), the surface coverage (Gamma(*)) and the electron transfer rate constant (k(s)) were calculated as -0.308V, 1.32x10(-11)molcm(-2) and 11.642s( 1), respectively. While, these parameters for Hb on DDAB films alone were 0.309V, 7.20x10(-12)molcm(-2) and 2.748s(-1), respectively. Therefore, the composite are more suitable for the direct electron transfer between Hb than DDAB alone. The native conformation and bioactivity of Hb adsorbed on the composite film was proved to be maintained, reflected by the unchanged ultraviolet-visible (UV-vis) as well as the catalytic activity toward hydrogen peroxide (H(2)O(2)) and nitric oxide (NO) compared with the free Hb molecules. Furthermore, Hb on the composite film are more sensitive for the detection of hydrogen peroxide (H(2)O(2)) and nitric oxide (NO) than that on DDAB film alone. The linear range of H(2)O(2) on Hb/DDAB-RTILs/GC electrode is from 0.5 to 57.5microM with linear regression equations I(microA)=0.149+0.00904C(microM), while, the linear range of H(2)O(2) on Hb/DDAB/GC electrode is from 0.5 to 57.5microM with linear regression equations I(microA)=0.0938+0.00553C(microM). For NO, its linear range on Hb/DDAB RTILs/GC electrode is from 1.8 to 21.6microM with linear regression equations I(microA)=0.0937+0.0232C(microM). But its linear range on Hb/DDAB/GC electrode is from 1.8 to 21.6microM with linear regression equations I(microA)=0.0285+0.0167C(microM). Similar results were observed for Mb and HRP in the DDAB-HIMIMPF(6) composite film. PMID- 20172092 TI - Pressurized Hot Water Extraction of anthocyanins from red onion: A study on extraction and degradation rates. AB - Pressurized Hot Water Extraction (PHWE) is a quick, efficient and environmentally friendly technique for extractions. However, when using PHWE to extract thermally unstable analytes, extraction and degradation effects occur at the same time, and thereby compete. At first, the extraction effect dominates, but degradation effects soon take over. In this paper, extraction and degradation rates of anthocyanins from red onion were studied with experiments in a static batch reactor at 110 degrees C. A total extraction curve was calculated with data from the actual extraction and degradation curves, showing that more anthocyanins, 21 36% depending on the species, could be extracted if no degradation occurred, but then longer extraction times would be required than those needed to reach the peak level in the apparent extraction curves. The results give information about the different kinetic processes competing during an extraction procedure. PMID- 20172093 TI - Synthesis and applications of diethylstilbestrol-based molecularly imprinted polymer-coated hollow fiber tube. AB - A novel molecularly imprinted polymer-coated polypropylene hollow fiber tube (MIP HFT) was photoinitiated for the copolymerization of diethylstilbestrol (DES) as a template molecule, alpha-methacrylic acid as a functional monomer, and ethylene glycol dimethacrylate as a crosslinking agent. The characteristics and applications of the MIP-HFT were investigated. In order to compare its characteristics with those of a non-imprinted polymer-immersed hollow fiber tube, the selectivity of the MIP-HFT was investigated using dienestrol and hexestrol as the structural analogues of a DES template, and phenol and methylbenzene were taken as reference compounds. The MIP-HFT was employed in the HPLC analysis of spiked milk samples. The detection limits of the method were found to be in the range 2.5-3.3microgL(-1) for DES, dienestrol and hexestrol and the RSD% were in the range 6.4-8.9. The limits of quantitation were found to be in the range 8.7 9.4microgL(-1) in milk for DES, dienestrol and hexestrol, and their average recoveries were 83.7-90.6% in the spiked milk samples. The experimental results revealed that the MIP-HFT provides a good carrier for the selective adsorption of DES and its chemical structure analogs, and can be used for the preconcentration of these compounds in complicated samples. PMID- 20172094 TI - A technique for sequential leaching of coal and fly ash resulting in good recovery of trace elements. AB - Coal and fly ash contain many elements. These elements exist in different forms which may change throughout the coal combustion process. There are several processes, including X-ray techniques and leaching techniques by which studies have attempted to assess the form of a particular element in a sample. This work focuses on determining the leachability of selected elements sequentially leached in four extraction solutions: water, 1M ammonium acetate, 3M hydrochloric acid and 50% hydrofluoric acid. The emphasis is on evaluating the steps involved in the leaching process with the mass recovery for each element being the basis for evaluation. The total amount of each element that will leach out under the given extraction condition is presented as a fraction of the total present in the material. The materials evaluated were NIST coal and fly ash standards. The elements measured in this study include aluminum, barium, beryllium, calcium, chromium, cobalt, iron, magnesium, manganese, nickel, potassium, sodium, strontium, vanadium and zinc. PMID- 20172095 TI - Evaluation of Soxhlet extraction, accelerated solvent extraction and microwave assisted extraction for the determination of polychlorinated biphenyls and polybrominated diphenyl ethers in soil and fish samples. AB - Three commonly applied extraction techniques for persistent organic chemicals, Soxhlet extraction (SE), accelerated solvent extraction (ASE) and microwave assisted extraction (MAE), were applied on soil and fish samples in order to evaluate their performances. For both PCBs and PBDEs, the two more recent developed techniques (ASE and MAE) were in general capable of producing comparable extraction results as the classical SE, and even higher extraction recoveries were obtained for some PCB congeners with large octanol-water partitioning coefficients (K(ow)). This relatively uniform extraction results from ASE and MAE indicated that elevated temperature and pressure are favorable to the efficient extraction of PCBs from the solid matrices. For PBDEs, difference between the results from MAE and ASE (or SE) suggests that the MAE extraction condition needs to be carefully optimized according to the characteristics of the matrix and analyte to avoid degradation of higher brominated BDE congeners and improve the extraction yields. PMID- 20172096 TI - An improved headspace solid-phase microextraction method for the analysis of free base nicotine in particulate phase of mainstream cigarette smoke. AB - The content of free-base nicotine in cigarette smoke is a controversial subject, partly due to methodological issues. In this investigation, an improved method to measure free-base nicotine in cigarette smoke using headspace solid-phase microextraction (HS-SPME) combined with GC/MS analysis, was developed and validated for this purpose. Cigarette smoke particulate phase (PP) was collected onto a 44mm glass fiber filter pad. The pad was cut in halves with one half used to determine the concentrations of total nicotine and water. The remaining half was analyzed by HS-SPME for free-base nicotine. The following factors were found to have a significant impact on the responses of free-base nicotine: SPME fiber type, pre-equilibrium time before HS-SPME, extraction time and temperature, PP water content, and the solvent used for the preparation of standards. It was also found that the impact of PP water content on the determination of free-base nicotine from smoke sample could be corrected by a water correction factor calculated based on an experimentally determined reciprocal model. The precision of the method was evaluated with smoke samples of reference cigarettes: Canadian flue-cured monitor and Kentucky reference 2R4F. The RSD values obtained were in the 12.8-16.8% range. PMID- 20172097 TI - Analysis of benzophenone and 4-methylbenzophenone in breakfast cereals using ultrasonic extraction in combination with gas chromatography-tandem mass spectrometry (GC-MS(n)). AB - Benzophenone (BP) and 4-methylbenzophenone (4MBP) are photo-initiators that are generally used to cure ink on carton boards. In this contribution, a fast and reliable method for the determination of BP and 4MBP in breakfast cereals is described. The sample was extracted ultrasonically using a mixture of dichloromethane and acetonitrile (1:1), followed by a clean-up of the extract using solid phase extraction with a silica cartridge. Finally, the extract was analysed by GC-MS(n). Benzophenone-d(10) was used as internal standard. The presented method is validated in terms of linearity, recovery, repeatability and intra-laboratory reproducibility, specificity, limit of detection and limit of quantification. In conclusion, this method is able to detect both BP and 4MBP at very low concentrations (LOD=2microg kg(-1)) in breakfast cereals. PMID- 20172098 TI - Global characterization of the photosynthetic glycerolipids from a marine diatom Stephanodiscus sp. by ultra performance liquid chromatography coupled with electrospray ionization-quadrupole-time of flight mass spectrometry. AB - The photosynthetic glycerolipids composition of algae is crucial for structural and physiological aspects. In this work, a comprehensive characterization of the photosynthetic glycerolipids of the diatom Stephanodiscus sp. was carried out by ultra performance liquid chromatography-electrospray ionization-quadrupole-time of flight mass spectrometry (UPLC-ESI-Q-TOF MS). By use of the MS(E) data collection mode, the Q-TOF instrument offered a very viable alternative to triple quadrupoles for precursor ion scanning of photosynthetic glycerolipids and had the advantage of high efficiency, selectivity, sensitivity and mass accuracy. Characteristic fragment ions were utilized to identify the structures and acyl compositions of photosynthetic glycerolipids. Comparing the abundance of fragment ions, it was possible to determine the position of the sn-glycerol-bound fatty acyl chains. As a result, four classes of photosynthetic glycerolipid in the extract of Stephanodiscus sp. were unambiguously identified, including 16 monogalactosyldiacylglycerols (MGDGs), 9 digalactosyldiacylglycerols (DGDGs), 23 sulfoquinovosyldiacylglycerols (SQDGs) and 8 phosphatidylglycerols (PGs). As far as our knowledge, this is the first report on global identification of photosynthetic glycerolipids, including lipid classes, fatty acyl composition within lipids and the location of fatty acids in lipids (sn-1 vs. sn-2), in the extract of marine microalgae by UPLC-ESI-Q-TOF MS directly. PMID- 20172099 TI - A comprehensive aerosol spray method for the rapid photocatalytic grid area analysis of semiconductor photocatalyst thin films. AB - Indicator inks, previously shown to be capable of rapidly assessing photocatalytic activity via a novel photo-reductive mechanism, were simply applied via an aerosol spray onto commercially available pieces of Activ self cleaning glass. Ink layers could be applied with high evenness of spread, with as little deviation as 5% upon UV-visible spectroscopic assessment of 25 equally distributed positions over a 10cmx10cm glass cut. The inks were comprised of either a resazurin (Rz) or dichloroindophenol (DCIP) redox dye with a glycerol sacrificial electron donor in an aqueous hydroxyethyl cellulose (HEC) polymer media. The photo-reduction reaction under UVA light of a single spot was monitored by UV-vis spectroscopy and digital images attained from a flat-bed scanner in tandem for both inks. The photo-reduction of Rz ink underwent a two step kinetic process, whereby the blue redox dye was initially reduced to a pink intermediate resorufin (Rf) and subsequently reduced to a bleached form of the dye. In contrast, a simple one-step kinetic process was observed for the reduction of the light blue redox dye DCIP to its bleached intermediates. Changes in red-green-blue colour extracted from digital images of the inks were inversely proportional to the changes seen at corresponding wavelengths via UV-visible absorption spectroscopy and wholly indicative of the reaction kinetics. The photocatalytic activity areas of cuts of Activ glass, 10cmx10cm in size, were assessed using both Rz and DCIP indicator inks evenly sprayed over the films; firstly using UVA lamp light to activate the underlying Activ film (1.75mWcm(-2)) and secondly under solar conditions (2.06+/-0.14mWcm(-2)). The photo-reduction reactions were monitored solely by flat-bed digital scanning. Red-green-blue values of a generated 14x14 grid (196 positions) that covered the entire area of each film image were extracted using a custom-built program entitled RGB Extractor(C). A homogenous degradation over the 196 positions analysed for both Rz (Red colour deviation=19% UVA, 8% Solar; Green colour deviation=17% UVA, 12% Solar) and DCIP (Red colour deviation=22% UVA, 16% Solar) inks was seen in both UVA and solar experiments, demonstrating the consistency of the self-cleaning titania layer on Activ. The method presented provides a good solution for the high-throughput photocatalytic screening of a number of homogenous photocatalytically active materials simultaneously or numerous positions on a single film; both useful in assessing the homogeneity of a film or determining the best combination of reaction components to produce the optimum performance photocatalytic film. PMID- 20172100 TI - Thiourea based novel chromogenic sensor for selective detection of fluoride and cyanide anions in organic and aqueous media. AB - Novel chromogenic thiourea based sensors 4,4'-bis-[3-(4-nitrophenyl) thiourea] diphenyl ether 1 and 4,4'-bis-[3-(4-nitrophenyl) thiourea] diphenyl methane 2 having nitrophenyl group as signaling unit have been synthesized and characterized by spectroscopic techniques and X-ray crystallography. The both sensors show visual detection, UV-vis and NMR spectral changes in presence of fluoride and cyanide anions in organic solvent as well as in aqueous medium. The absorption spectra indicated the formation of complex between host and guest is in 1:2 stoichiometric ratios. PMID- 20172101 TI - A highly selective fluorescent probe for Hg(2+) based on a rhodamine-coumarin conjugate. AB - A fluorescent probe 1 for Hg(2+) based on a rhodamine-coumarin conjugate was designed and synthesized. Probe 1 exhibits high sensitivity and selectivity for sensing Hg(2+), and about a 24-fold increase in fluorescence emission intensity is observed upon binding excess Hg(2+) in 50% water/ethanol buffered at pH 7.24. The fluorescence response to Hg(2+) is attributed to the 1:1 complex formation between probe 1 and Hg(2+), which has been utilized as the basis for the selective detection of Hg(2+). Besides, probe 1 was also found to show a reversible dual chromo- and fluorogenic response toward Hg(2+) likely due to the chelation-induced ring opening of rhodamine spirolactam. The analytical performance characteristics of the proposed Hg(2+)-sensitive probe were investigated. The linear response range covers a concentration range of Hg(2+) from 8.0x10(-8) to 1.0x10(-5)molL(-1) and the detection limit is 4.0x10(-8)molL( 1). The determination of Hg(2+) in both tap and river water samples displays satisfactory results. PMID- 20172102 TI - Combination of an e-nose, an e-tongue and an e-eye for the characterisation of olive oils with different degree of bitterness. AB - An electronic panel has been used to characterise the organoleptic characteristics of twenty-five extra virgin olive oils from varieties Hojiblanca, Picual and Arbequina, with different degree of bitterness. The method consists in the combination of three systems: electronic nose, electronic tongue and electronic eye. The Principal Component Analysis (PCA), where PC1, PC2 and PC3 explained 59% of the total variance between the samples, has demonstrated that the capability of discrimination of the combined system is superior to that obtained with the three instruments separately. This improvement is due to the increased information extracted from each sample. Partial Least Squares Discriminant Analysis (PLS-DA) has allowed separation of the groups in function of olive variety with a root mean square error of prediction (RMSEP) lower than 0.099. Using PLS1 and PLS2 regression models, good correlations have been found between the signals obtained from the electronic tongue and the polyphenolic content (measured by chromatographic methods) or the bitterness index (scored by a panel of experts) with correlation coefficients higher than 0.9 in calibration and validation. These preliminary results indicate that the combination of an e nose, an e-tongue and an e-eye can be a useful tool for the analysis of olive oil bitterness. PMID- 20172103 TI - Trend analysis of time-series data: A novel method for untargeted metabolite discovery. AB - A new strategy for biomarker discovery is presented that uses time-series metabolomics data. Data sets from samples analysed at different time points after an intervention are searched for compounds that show a meaningful trend following the intervention. Obviously, this requires new data-analytical tools to distinguish such compounds from those showing only random variation. Two univariate methods, autocorrelation and curve-fitting, are used either as stand alone methods or in combination to discover unknown metabolites in data sets originating from target-compound analysis. Both techniques reduce the long list of detected compounds in the kinetic sample set to include only those having a pre-defined interesting time profile. Thus, new metabolites may be discovered within data structures that are usually only used for target-compound analysis. The new strategy is tested on a sample set obtained from a gut fermentation study of a polyphenol-rich diet. For this study, the initial list of over 9000 potentially interesting features was reduced to less than 150, thus significantly reducing the expensive and time-consuming manual examination. PMID- 20172104 TI - Quantitative determination of glucoraphanin in Brassica vegetables by micellar electrokinetic capillary chromatography. AB - Glucoraphanin, a glucosinolate, is found naturally in plants and is present in relatively high concentrations in broccoli. Glucosinolates have received much attention as studies have indicated that a diet rich in them may provide some protection from certain cancers. A micellar electrokinetic chromatography (MEKC) method using sodium cholate as the micellar phase has been developed to quantify for glucoraphanin in broccoli (seeds and florets) and Brussels sprouts. The glucoraphanin peak elutes just under 5min with a theoretical plate number of 380,000 per metre of capillary. The method is suitable for crude extracts of broccoli and Brussels sprouts. Glucoraphanin in broccoli seeds (1330mg/100g) broccoli florets (89mg/100g) and Brussels sprouts (3mg/100g) was determined and agreed with the data obtained by high performance liquid chromatography. The LODs were 10-100 times below the levels typically found in broccoli seeds (4mg/100g), broccoli florets (0.9mg/100g) and Brussels sprouts (0.1mg/100g). PMID- 20172105 TI - Non-ionic surfactant modified ligand exchange chromatography using copper (II) complex of N,N-dimethyl-L-phenylalanine as the chiral additive for enantioselective amino acids separation. AB - The influence of non-ionic surfactants on the selectivity and retention in the ligand exchange chromatography for the enantioselective separation of racemic mixtures of the amino acids dl-methionine, dl-leucine, dl-valine and dl-tyrosine applying chiral mobile phases was investigated, whereas five different surfactants were tested as modifiers. The experiments were carried out using a commercially available non-chiral RP-C8 column and the copper (II) complex of N,N dimethyl-l-phenylalanine as the chiral additive. Varying the surfactant concentrations the retention factors and the selectivity could be controlled and in general no negative influence on the separation (due to surfactant adsorption on the non-chiral stationary phase) occurred. Changing the temperature the van't Hoff plots were obtained and the thermodynamic parameters calculated. Temperature had influence on the selectivity for each surfactant and lowered the retention times as expected. PMID- 20172106 TI - "Gastric bascule": an unusual form of gastric volvulus. AB - Gastric volvulus can occur along the organoaxial axis or the mesenteroaxial axis. We present a patient with a gastric bascule: a gastric volvulus due to two lead points. A 17-year-old boy with dextrogastria, asplenia, and left diaphragmatic eventration presented with acute onset of nonbilious emesis, jaundice, and diffuse abdominal tenderness. Surgical exploration demonstrated a gastric volvulus, with lead points of torsion at the gastroesophageal junction and the second part of the duodenum, causing biliary obstruction. After decompression, reduction, and gastropexy, the patient recovered well. Gastric bascule is a subtype of gastric volvulus, whereby two lead points cause gastric rotation and folding of the stomach upon itself. PMID- 20172107 TI - Using Society of Thoracic Surgeons risk models for risk-adjusting cardiac surgery results. AB - The Society of Thoracic Surgeons National Adult Cardiac Surgery Database (STS NCD) has become the national benchmark for cardiac surgery reporting. Several important aspects of its risk-adjustment reporting are discussed, with special emphasis on using the reported individual STS risk scores for analysis and evaluation: (1) Different risk models are used in different STS NCD versions. (2) STS calibrates risk scores annually to make the annual predicted rates equal the observed rates. (3) The risk scores given by the STS, whether in the approved STS data collection software programs, published risk models, or online calculator, are not calibrated. (4) The end-user is required to calibrate the STS risk scores before using them. (5) After calibration, the STS predicted risk for any given patient is usually smaller, sometimes less than half of the uncalibrated value. (6) STS uses an observed/expected ratio method to calibrate the risk scores; for technical reasons, it is preferable to use an odds ratio method. PMID- 20172108 TI - Increased graft occlusion or string sign in composite arterial grafting for mildly stenosed target vessels. AB - BACKGROUND: Composite grafting is a useful technique that avoids the need for aortic manipulation and enables a wide range of target vessels to be revascularized, effectively using the limited arterial grafts available. However, it has not been clarified whether composite grafting can achieve angiographic outcomes equivalent to those obtained with individual grafting for specific target vessels. METHODS: We retrospectively reviewed 830 distal arterial graft anastomoses in 256 patients who underwent off-pump coronary artery bypass surgery and also underwent 1-year follow-up coronary angiograms. Four hundred and ten anastomoses using a composite grafting technique were compared with 420 anastomoses using individual grafting. RESULTS: In target vessels with mild stenosis, the incidence of graft occlusion or string sign was significantly higher in composite internal thoracic arteries (ITA) than in individual ITA grafts (composite 20.3% versus individual 7.3%; p = 0.018) and showed a higher tendency in composite radial arteries (RA) than in individual RA grafts (59.3% versus 36.4%, p = 0.09). In contrast, the incidence was similar between composite and individual ITA grafts (5.7% versus 3.3%, p = 0.278) and composite and individual RA grafts (11.5% versus 29.6%, p = 0.297) in target vessels with severe stenosis. CONCLUSIONS: The angiographic outcomes of composite grafts were closely related to the severity of stenosis of the target coronary artery. In target vessels with mild stenosis, composite grafting resulted in a higher incidence of graft occlusion or string sign than individual grafting did. PMID- 20172109 TI - Invited commentary. PMID- 20172110 TI - Serum cystatin C in elderly cardiac surgery patients. AB - BACKGROUND: Elderly cardiac surgery patients are more prone to develop postoperative acute kidney injury (AKI). The common clinical glomerular filtration marker, plasma creatinine, is considered to be inadequate to discover AKI in its early stage. The aim of this study was to determine if serum cystatin C can detect mild renal failure earlier than plasma creatinine. METHODS: From 110 cardiac surgery patients aged 70 or greater years, serum cystatin C and plasma creatinine samples were collected preoperatively and on postoperative days 1 to 5. Their urine output, creatinine, and estimated glomerular filtration rate were calculated and AKI was determined by the risk-injury-failure-loss-end-stage kidney disease criteria (RIFLE). The correlation of plasma creatinine and serum cystatin C to AKI was calculated. RESULTS: After cardiac surgery, 62 of the 110 patients (56.4%) developed AKI according to the RIFLE classification. In this group, both serum cystatin C and plasma creatinine peaked on postoperative day 3. Cystatin C and creatinine correlated equally with AKI at different time points calculated with receiver operating characteristic curves. On postoperative day 1 the area under the curve (AUC) for creatinine was 0.66 (0.55 to 0.76) and for cystatin C 0.71 (0.61 to 0.81); Delta AUC 0.05 (0.01 to 0.12), p = 0.11. On postoperative day 2 the AUC for creatinine was 0.74 (0.64 to 0.83) and for cystatin was C 0.77 (0.68 to 0.86); Delta AUC -0.03 (-0.09 to 0.03), p = 0.32. CONCLUSIONS: Elderly cardiac surgery patients have a high incidence of AKI, as defined by the RIFLE criteria. After cardiac surgery serum cystatin C and plasma creatinine detected AKI similarly. PMID- 20172111 TI - Invited commentary. PMID- 20172112 TI - Preoperative cardiac troponin I to assess midterm risks of coronary bypass grafting operations in patients with recent myocardial infarction. AB - BACKGROUND: The optimal timing for coronary artery bypass grafting (CABG) in patients with recent acute myocardial infarction (AMI) is unclear. Cardiac troponin I (cTnI) is a widely accepted biomarker of myocardial damage. The objective of this study was to determine whether preoperative cTnI values could be used to determine risk stratification for CABG operations in patients with recent AMI. METHODS: Evaluated were 184 patients who sustained an AMI within 21 days of undergoing nonurgent CABG operations. They were divided into two groups according to their preoperative cTnI values: 117 patients with cTnI of 0.15 ng/mL or less and 67 with cTnI exceeding 0.15 ng/mL. Associations between study variables and events were assessed with logistic regression modelling. Time from AMI to operation was evaluated to define preoperative cTnI variation. RESULTS: Values of cTnI tended to decrease when the interval between AMI and the operation increased. Preoperative cTnI values were significantly associated with a higher incidence of major postoperative complications (low cardiac output syndrome, intraaortic balloon pump necessity, mechanical ventilation >72 hours, acute renal failure, in-hospital mortality). Perioperative myocardial damage was more pronounced in patients with cTnI exceeding 0.15 ng/mL. Multivariate analyses revealed cTnI exceeding 0.15 ng/mL was an independent predictor for 6-month mortality (odds ratio, 3.7; p = 0.043). CONCLUSIONS: Preoperative cTnI exceeding 0.15 ng/mL in patients with recent AMI undergoing CABG is associated with higher postoperative myocardial damage and is a strong determinant of postoperative morbidity and mortality within the 6-month period. PMID- 20172113 TI - Invited commentary. PMID- 20172114 TI - Preoperative atrial fibrillation and elevated C-reactive protein levels as predictors of mediastinitis after coronary artery bypass grafting. AB - BACKGROUND: Mediastinitis is a serious complication after coronary artery bypass grafting (CABG). We studied the risk factors for the development of postoperative mediastinitis in a large group of patients who underwent isolated CABG at Catharina Hospital, Eindhoven, The Netherlands. METHODS: Data of all patients undergoing an isolated CABG between January 1998 and December 2008 were analyzed. Univariate and multivariate logistic regression analyses were performed to investigate the effect of biomedical variables on the development of mediastinitis. Multivariate analyses were used to test for the confounding effect of various risk factors on outcomes. RESULTS: Mediastinitis was present in 100 out of the 11,748 patients. Preoperative atrial fibrillation [odds ratio = 4.26 (2.26 to 8.02)] and an elevated preoperative C-reactive protein level [odds ratio = 1.013 (1.007 to 1.020)] were important independent predictors of the development of mediastinitis. Other significant risk factors were the following: age, chronic obstructive pulmonary disease, diabetes, morbid obesity, use of extracorporeal circulation, use of bilateral internal mammary arteries, reexploration for ischemia, and perioperative myocardial infarction. CONCLUSIONS: Apart from previously described risk factors for the development of postoperative mediastinitis, we found preoperative atrial fibrillation and an elevated C reactive protein level to be significant predictors of mediastinitis in patients undergoing CABG. PMID- 20172115 TI - The complement system is activated in a biphasic pattern after coronary artery bypass grafting. AB - BACKGROUND: The complement system is a key component in the inflammatory response after coronary artery bypass grafting (CABG). The routes of complement activation and deactivation after cardiac surgery are not clear. The aim of this study was to analyze routes of complement activation after uncomplicated CABG. METHODS: Complement components and activation products were measured in 20 nondiabetic adult patients undergoing elective CABG at several times postoperatively starting at admission to the intensive care unit. RESULTS: Complement activation after uncomplicated CABG showed a biphasic pattern. In the first 8 hours after admission to the intensive care unit, complement activation was initiated by the classical lectin pathway and augmented by the alternative pathway. Ultimately, this resulted in terminal pathway activation and formation of terminal complement complex. In the second phase, starting at 8 hours after the operation, complement was still activated by the classical lectin pathway, but there was no augmentation by the alternative pathway and no terminal complement complex formation. This implies that during this second stage, inhibitory mechanisms beyond C3b are engaged. CONCLUSIONS: Complement activation after cardiac surgery is regulated in a complex biphasic way, with additional inhibitory mechanisms engaged from 8 hours postoperatively onward. PMID- 20172116 TI - Off-pump right coronary artery bypass with saphaneous vein or in-situ right internal thoracic artery. AB - BACKGROUND: The ideal conduit for the right coronary artery (RCA) is yet to be determined. The purpose of this study was to compare the clinical results between the right internal thoracic artery (RITA) in situ with free saphenous vein (SV) graft for RCA in off-pump coronary artery bypass graft surgery (OPCABG). METHODS: Three hundred and fifty-eight patients who underwent isolated OPCABG with RCA anastomosis either by RITA in situ (n = 199) or free SV graft (n = 159) were included. We evaluated the graft patency and the incidence of RCA reintervention considering the degree of native RCA stenosis. The follow-up rate was 97.8%, and the mean follow-up duration was 57.6 months. RESULTS: The overall mortality and the incidence of major cardiac and cerebrovascular event showed no difference between the two groups (p = 0.495 and p = 0.338, respectively). The 5-year freedom from graft occlusion rate was 87.4% +/- 3.2% in the RITA group and 94.3% +/- 2.0% in the SV group (p = 0.011), with a statistically significant difference only in the moderate stenosis (< 75%) group (p = 0.020). The 5-year freedom from RCA reintervention rate was 95.7% +/- 1.6% in the RITA group and 99.3% +/- 0.7% in the SV group (p = 0.055). CONCLUSIONS: Both RITA and SV showed favorable graft patency for the RCA system in OPCABG. The SV graft showed better patency in patients with moderate stenosis of RCA compared with RITA in situ. A longer follow-up period is necessary to clarify our current results. PMID- 20172117 TI - Retrograde arterial perfusion, not incision location, significantly increases the risk of stroke in reoperative mitral valve procedures. AB - BACKGROUND: A recent report suggested that a thoracotomy approach for reoperative mitral valve (MV) procedures was associated with an equivalent mortality and an unacceptable risk of stroke. We assessed these outcomes in a single institution's experience. METHODS: From 1992 through 2007, 905 patients underwent reoperative MV procedures. The approach was a median sternotomy in 612 (67.6%), right anterior thoracotomy in 242 (26.7%), and left posterior thoracotomy in 51 (5.6%). Concomitant procedures in 411 patients (67.6%) included aortic procedures in 189, tricuspid procedures in 170, and coronary artery bypass grafting in 90. Hypothermic fibrillation was used in 65 patients. Logistic analysis was used to analyze risk factors and outcomes. RESULTS: Overall mortality was 12.7% (115 of 905), 6.7% (25 of 371) for first time isolated MV reoperations, and 10.1% (50 of 494) for all isolated MV operations. Overall incidence of stroke was 3.8% (34 of 905); 10.9% (9 of 82) with retrograde arterial perfusion and 3.0% (25 of 824) with central aortic cannulation (p < 0.001). For isolated MV reoperations, the incidence of stroke was 4.3% (21 of 494): 2.9% (7 of 241) for antegrade perfusion and 5.5% (14 of 253) for retrograde perfusion (p = 0.15). Risk factors for death were age (p < 0.001), renal failure (p < 0.01), tricuspid valve disease (p < 0.001), chronic obstructive pulmonary disease (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.8 to 4.9; p < 0.001), emergency procedure (OR, 2.9; 95% CI, 1.2 to 6.9; p = 0.02), and ejection fraction less than 0.30 (OR, 1.9; 95% CI, 1.1 to 3.3, p = 0.018). Risk factors for stroke were retrograde perfusion (OR, 4.4; 95% CI, 1.8 to 10.3; p < 0.01) and ejection fraction below 0.30 (OR, 2.1; 95% CI, 0.9 to 5.0; p = 0.09). CONCLUSIONS: The incidence of stroke in reoperative MV operations is associated with perfusion strategies, not with the incisional approach. Reoperative sternotomy and minithoracotomy with central cannulation are both useful for reoperative MV procedures and are associated with low stroke rates. PMID- 20172118 TI - Survival benefit of aortic valve replacement in older patients with asymptomatic chronic severe aortic regurgitation. AB - BACKGROUND: According to American College of Cardiology/American Heart Association guidelines, isolated aortic valve replacement (AVR) is a class III indication for patients with asymptomatic chronic severe aortic regurgitation (AR), left ventricular (LV) ejection fraction (EF) greater than 50%, LV end diastolic dimension less than 70 mm, and LV end-systolic dimension less than 50 mm. METHODS: We screened our echocardiographic database for all chronic severe AR patients between 1993 and 2007. Chart reviews were performed to collect clinical, demographic, and pharmacological data. Mortality was analyzed as a function of AVR. RESULTS: In all, 123 patients were found to have chronic severe asymptomatic AR; they had a mean age of 60 +/- 17 years and mean LVEF of 60% +/- 15%. A subgroup of 79 patients was found to have asymptomatic severe AR with an LVEF greater than 50%, LV end-diastolic dimension less than 70 mm, and LV end-systolic dimension less than 50 mm. By Kaplan-Meier analysis, patients not undergoing AVR had 1-, 5-, and 10-year survival rates of 86%, 71%, and 46%, respectively, compared with 100%, 94%, and 94%, respectively, for patients who underwent AVR (p = 0.004). Aortic valve replacement remained an independent predictor of increased survival after adjusting for group differences and univariate predictors of mortality. The benefit of AVR was further supported by propensity score analysis. CONCLUSIONS: Despite serving as a class III indication, AVR is independently associated with increased survival among patients with severe asymptomatic AR, LVEF greater than 50%, LV end-diastolic dimension less than 70 mm, and LV end systolic dimension less than 50 mm. PMID- 20172119 TI - Chronic atrial fibrillation is associated with reduced survival after aortic and double valve replacement. AB - BACKGROUND: Although chronic atrial fibrillation (AF) is thought to negatively affect survival after aortic valve replacement (AVR), evidence is limited and intraoperative methods to restore sinus rhythm are not widely adopted. This study investigated long-term outcome in valve prosthesis patients with or without AF. METHODS: Between 1994 and 2006, 420 patients with the same mechanical prosthesis were prospectively entered into a database; 90 had chronic AF preoperatively. Medical therapy was used to attempt to restore sinus rhythm postoperatively, but none had intraoperative ablation. All were anticoagulated with warfarin and monitored serially in National Health Service (United Kingdom) clinics. Survival and adverse events were determined by detailed review. RESULTS: Mean follow-up was 79.5 months (range, 18 months to 13.5 years); 12 were lost to follow-up. Procedures included 225 AVRs with or without coronary bypass (AVR with CABG), 151 mitral valve replacements (MVR) with CABG, and 32 double-valve replacements (DVR). Preoperative AF patients remained in the same rhythm 6 months postoperatively. Prosthesis-related events were infrequent. For chronic AF patients, mortality at 10 years was greater after AVR (64.3% vs 19.2% p < 0.001), AVR with CABG (83.3% vs 21.3% p < 0.001), and DVR (80.0% vs 17.6% p < 0.001). Survival after isolated MVR or MVR with CABG (p > 0.05) was similar. Most MVR with CABG patients in sinus rhythm had acute ischemic mitral regurgitation. Greater age (p = 0.001) and preoperative AF (p = 0.02) were risk factors for death. CONCLUSIONS: Chronic AF negatively affects survival after AVR with or without CABG and DVR with a mechanical prosthesis. Prospective randomized evaluation of AF ablation is suggested for these patients. PMID- 20172120 TI - Postoperative left ventricular mass regression after aortic valve replacement for aortic stenosis. AB - BACKGROUND: Small valve size and prosthetic patient mismatch are both considered to have harmful effects on residual left ventricular hypertrophy after aortic valve replacement for aortic stenosis. In general, it is believed that the effective orifice area index of the prosthesis must not be less than 0.85 cm(2)/m(2) in order to avoid prosthetic patient mismatch. On the other hand, studies have shown that valve type and valve size had no effects on postoperative left ventricular mass (LVM). The objective of this report was to examine the relationships between patient characteristics or the prosthetic valve and postoperative LVM. METHODS: To evaluate the factors that influence postoperative LVM, we formulated the hypothesis that postoperative LVM is proportional to the sum total of pressure at the prosthetic valve orifice and inner surface area of the left ventricle in systole. We present a conceptually new index for postoperative LVM and compare the index with postoperative LVM. RESULTS: The results indicated a strong correlation between the new index and postoperative LVM six years after surgery (r(2) =0.67, p < 0.0001). As might be expected, LVM increased gradually as the value of the new index increased. CONCLUSIONS: The results of the present study indicate that postoperative left ventricular hypertrophy can be avoided by preventing postoperative hypertension in patients without left ventricular dilatation and an effective orifice area index is greater than 0.77 cm(2)/m(2). PMID- 20172121 TI - Contemporary perioperative results of isolated aortic valve replacement for aortic stenosis. AB - BACKGROUND: Transcatheter aortic valve implantation may become a potential treatment for high-risk patients with aortic stenosis (AS). We analyzed our contemporary series of isolated aortic valve replacement (AVR) for AS to determine implications for patients referred for AVR. METHODS: From April 2004 through December 2008, 190 patients (mean age, 68 years; 68% men) underwent isolated AVR for AS. Mean ejection fraction was 0.58. Sixty-one percent underwent minimally invasive AVR and 18% were reoperations. Twenty-one percent were aged 80 years or older, and 34% were in New York Heart Association functional class III IV. Estimated operative mortality was 3.6%. RESULTS: Thirty-day mortality was 0%. One in-hospital death (0.5%) occurred from complications of an esophageal perforation. Reoperation for bleeding occurred in 4.7%. Acute renal failure developed in 2.1%. Actuarial survival was 97% at 1 year and 94% at 3 years. Hospital length of stay was 7.0 days for patients aged 80 and older vs 5.0 days (p < 0.001), and they were less likely to be discharged to home (50% vs 83%, p < 0.001). CONCLUSIONS: Contemporary results show that AVR for AS can be performed with low operative mortality and morbidity, although patients aged 80 years and older are at increased risk of prolonged recovery. Transcatheter aortic valve implantation may be an alternative for high-risk patients, but AVR is still appropriate for low-risk patients. The low risk of AVR supports the argument that asymptomatic patients who have a high likelihood of progression of AS may be considered for earlier surgical referral. PMID- 20172122 TI - Invited commentary. PMID- 20172123 TI - Effect of concomitant coronary artery disease on procedural and late outcomes of transcatheter aortic valve implantation. AB - BACKGROUND: Previous coronary artery bypass grafting increases predicted operative risk for conventional valve replacement, according to the Society of Thoracic Surgeons risk algorithm. Additionally, the presence of coronary artery disease (CAD) has been demonstrated to increase procedural risk with conventional aortic valve replacement. Significant coexisting CAD requires preemptive percutaneous coronary intervention (PCI) in patients under consideration for transcatheter aortic valve implantation (TAVI). This study examined the impact of previous coronary artery bypass grafting or PCI on procedural outcomes and overall survival in patients having TAVI. METHODS: Two hundred and one high-risk patients were enrolled in two international feasibility studies from December 2005 to February 2008 for the treatment of aortic stenosis using TAVI. Thirty patients were excluded from analysis due to failure to successfully deploy the valve in the aortic annulus. Data were collected concurrently using an ad hoc database that included operative and long-term survival. Previous cardiovascular intervention prior to TAVI was used to identify the existence of concomitant CAD. Logistic regression along with Kaplan-Meier estimates were employed to establish the association between CAD and survival from TAVI. RESULTS: Overall mortality after TAVI was significantly higher among the CAD group (35.7%) in contrast with the non-CAD patients (18.4%), p = 0.01. Logistic regression analysis found that patients who had CAD were 10.1 times more likely to die (95% confidence interval 2.1 to 174.8) within 30 days of the procedure than those who did not. Proportional hazards analysis established that the risk of dying at any point in time was 2.3 times higher among the patients with CAD (95% confidence interval 1.29 to 4.17). Kaplan-Meier survival curves demonstrate improved long-term survival among patients without CAD. CONCLUSIONS: Coexisting coronary artery disease negatively impacts procedural outcomes and long-term survival in patients undergoing TAVI, and implies that risk assessment and anticipated outcomes might be inaccurate due to stratification as isolated aortic valve replacement rather than AVR+CABG. Comparison of procedural outcomes, based on operative approach without controlling for unequal distribution of CAD in the cohorts, are likely invalid. PMID- 20172124 TI - Increased radial force improves stent deployment in tricuspid but not in bicuspid stenotic native aortic valves. AB - BACKGROUND: Stent deployment within stenotic native aortic valves has been shown to depend on valve anatomy (presence of bicuspid valve or not). This study investigated the influence of stent stiffness on stent expansion. METHODS: The study included 88 patients with severe aortic stenosis, and 36 (41%) had bicuspid aortic valves. Two self-expandable stents with different radial force were deployed intraoperatively inside stenotic aortic valves before surgical aortic valve replacement. Patients in group B received a stent stiffer than that in group A. Effect of stent radial force on stent shape and incidence of paraprosthetic gaps was determined. RESULTS: Noncircular stent deployment was more frequent in bicuspid (81%) than in tricuspid aortic valves (33%; p < 0.0001). Increasing stent radial force significantly improved stent shape in tricuspid valves (circular shape: 60% in group A vs 93% in group B; p = 0.005) but had no significant effect in bicuspid valves (12.5% in group A vs 27% in group B;p = 0.394). Likewise, incidence of paraprosthetic gaps was significantly reduced with the stiff stent in tricuspid valves (64% in group A vs 30% in group B, p = 0.025) but not in bicuspid valves (50% in group A vs 60% in group B; p= 0.722). CONCLUSIONS: Increased stent radial force had a favorable effect on stent deployment in tricuspid but not in bicuspid valves. In bicuspid valves, stent maldeployment was constant. Leaflet distortion of implanted valved stent might be a concern in this setting. PMID- 20172125 TI - Invited commentary. PMID- 20172126 TI - Effect of preoperative statin therapy on patients undergoing isolated and combined valvular heart surgery. AB - BACKGROUND: It is unknown whether patients undergoing valve surgery benefit from preoperative statin therapy. We examined the effects of statin treatment in a large group of patients undergoing valve surgery. METHODS: Between October 2001 and May 2008, a total of 10,061 patients underwent isolated or combined valve surgery at our institution. Patients were divided into those who received preoperative statin therapy (group 1, n = 4,216) versus those who did not receive statin therapy (group 2, n = 5,538). Patients in whom preoperative statin therapy status was unknown (n = 307) were excluded. Follow-up survival information was available in all patients. RESULTS: Group 1 patients had more comorbidities, were more likely to undergo concomitant coronary artery bypass grafting (46.0% versus 20.7%; p < 0.001), and had a higher mean EuroSCORE predicted risk of mortality (12.4% +/- 13.5% versus 11.5% +/- 13.9%; p = 0.002). Patients receiving preoperative statin therapy had a higher incidence of low cardiac output syndrome (8.4% versus 6.0%; p < 0.001) and the combined cardiac outcome of myocardial infarction, low cardiac output syndrome, and 30-day mortality (11.8% versus 9.6%; p < 0.001) by univariate analysis. Multivariable analyses, however, revealed no significant effect of statin therapy on perioperative cardiac outcomes. Cox multivariable regression revealed no significant effect of statin therapy on long term survival in the entire patient cohort, but statin therapy was associated with a long-term survival benefit (hazard ratio, 0.81; 95% confidence interval, 0.70 to 0.93; p = 0.003) in patients who underwent concomitant coronary artery bypass grafting. CONCLUSIONS: Our large series failed to detect a protective effect of preoperative statin therapy on perioperative outcomes or long-term survival in patients undergoing isolated valve surgery. Valve patients undergoing concomitant coronary artery bypass grafting, however, appear to receive a long term survival benefit from statins. PMID- 20172127 TI - Cardioprotective effects of electroacupuncture pretreatment on patients undergoing heart valve replacement surgery: a randomized controlled trial. AB - BACKGROUND: Cardiac ischemia-reperfusion injury after cardiopulmonary bypass contributes to postoperative morbidity and mortality in patients with open-heart surgery. This randomized controlled trial was designed to address the protective effects of electroacupuncture (EA) pretreatment on myocardial injury in patients undergoing heart valve replacement surgery. METHODS: Sixty patients with acquired heart valve disease were randomly allocated to the EA pretreatment group or the control group. Patients in the EA group received EA stimulus at bilateral Neiguan (PC 6), Lieque (LU 7), and Yunmen (LU 2) for 30 minutes each day for five consecutive days before surgery. Hemodynamic data, mechanical ventilation time, inotropic drug use in the intensive care unit, serum cardiac troponin I concentrations, morbidities, and mortalities were compared between the two groups. This trial is registered with ClinicalTrials.gov, number NCT00732459. RESULTS: At 6 hours, 12 hours, and 24 hours after reperfusion, levels of serum cardiac troponin I were significantly decreased in the EA group (5.74 +/- 0.67, 6.22 +/- 0.66, and 5.21 +/- 0.58) compared with that in the control group (7.89 +/- 0.74, 8.34 +/- 1.08, and 7.57 +/- 0.89, p < 0.05). The EA pretreatment significantly reduced overall serum troponin I release at 6 hours, 12 hours, and 24 hours after aortic cross-clamp removal. Meanwhile, EA pretreatment also reduced the inotrope score at 12 hours, 24 hours, and 48 hours after the intensive care unit arrival and shortened intensive care unit stay time (p < 0.05). CONCLUSIONS: The present study demonstrated that EA pretreatment may alleviate cardiac ischemia-reperfusion injury in adult patients undergoing heart valve replacements. This simple and convenient treatment has the potential to be used in the clinic for reducing myocardial injury in patients with heart valve replacement surgery. PMID- 20172128 TI - Invited commentary. PMID- 20172129 TI - EuroSCORE performance in valve surgery: a meta-analysis. AB - BACKGROUND: The European System for Cardiac Operative Risk Evaluation (EuroSCORE) was developed to predict immediate outcomes after adult cardiac operations, but less than 30% of the cases used to develop this score were valve procedures. We studied EuroSCORE performance in valve procedures. METHODS: We performed a meta analysis of published studies reporting the assessment of discriminatory power of the EuroSCORE by receiver operating characteristics (ROC) curve analysis in adult valve operations. A comparison of observed and predicted mortality rates was also performed. RESULTS: A literature search identified 37 potentially eligible studies, and 12 were selected for meta-analysis comprising 26,621 patients with 1250 events (mortality rate, 4.7%). Meta-analysis of these studies provided an average area under the curve (AUC) value of 0.730 (95% confidence interval [CI], 0.717 to 0.743). The same results were obtained when meta-analyses were performed separately in studies categorized on reliability of uncertainty estimation: in the seven studies reporting reliable uncertainty estimation (8175 patients with 358 events; mortality rate, 4.4%), the ROC curve provided an average AUC value of 0.724 (95% CI, 0.699 to 0.749). The five studies not reporting reliable uncertainty estimation (18,446 patients with 892 events; mortality rate, 4.8%) had an average AUC of 0.732 (95% CI, 0.717 to 0.747). We documented a constant trend to overpredict mortality by EuroSCORE, both in the additive and especially in the logistic form. CONCLUSIONS: The EuroSCORE has low discrimination ability for valve surgery, and it sensibly overpredicts risk. Alternative risk scoring algorithms should be seriously considered. PMID- 20172130 TI - Fate of the false lumen after combined surgical and endovascular repair treating Stanford type A aortic dissections. AB - BACKGROUND: The purpose of this study was to evaluate the alterations of the aorta by using a new combined surgical and endovascular technique for the treatment of aortic type A dissections. The diameter of the descending aorta, the implanted stent graft, and the false lumen were evaluated. METHODS: Between August 2005 and February 2009, 14 patients (aged 49 +/- 13 years; 11 men, 3 women) with type A dissection in the aorta were operated on the thoracic aorta by the frozen elephant trunk technique. The size dynamics of the false lumen were analyzed by deducting the diameter of the stent graft obtained on computed tomography from the maximum dimension of the aorta. RESULTS: The technical success rate was 100%. All patients survived during the follow-up period. The mean follow-up period was 21.4 months. No redisection or aortic rupture occurred during the follow-up period. Postoperative computed tomography scans showed complete thrombus formation of the false lumen in the perigraft space within the entire zone of the stented segment of the hybrid prosthesis during the first 2 weeks after surgery in 12 patients (86%), whereas all patients showed complete obliteration of the false lumen at the 3-month control. The follow-up computed tomography scan obtained after 12 months revealed shrinkage of the false lumen in 9 patients (64%). CONCLUSIONS: The combined surgical and endovascular technique described in this report proved effective for the treatment of extended aortic lesions. The perigraft space thrombosed completely and had shrunken after successful placement of the stent graft. PMID- 20172131 TI - Cannulation of the innominate artery with a side graft in arch surgery. AB - BACKGROUND: The purpose of this study was to examine the safety and efficacy of cannulation of the innominate artery with a side graft in arch surgery. METHODS: Between January 2004 and March 2009, 46 patients received arch surgery under hypothermia circulatory arrest (HCA) and hemispheric antegrade cerebral perfusion (HACP). There were 36 men and 10 women with an average age of 48.0 +/- 12.8 years. Thirty-four patients had type A aortic dissection. Four patients had type B aortic dissection. The remaining 8 patients had aortic aneurysm involving the ascending aorta and arch. The innominate artery was free of diseases in all patients. The diameter of the innominate artery was 12.1 +/- 1.6 mm (range, 9 to 16 mm). An 8-mm vascular graft, which was anastomosed to the innominate artery in an end-to-side manner, was used for arterial cannulation. Ascending aorta and arch replacement in combination with open stent-graft implantation was conducted in 42 patients. Four patients received open stent-graft implantation through the aortic arch only. RESULTS: The aortic cross-clamp time was 87.2 +/- 36.0 minutes. The lowest nasopharyngeal temperature was 21.0 +/- 3.6 degrees C. The HCA and the HACP time was 29.6 +/- 14.0 minutes. The HACP flow was 8.3 +/- 2.3 mL x kg(-1) x min(-1). Five patients (10.9%) had temporary postoperative neurologic dysfunction. There was no permanent neurologic dysfunction. Three patients died within 30 days postoperatively, and the 1-month mortality rate was 6.5%. All of the surviving patients were followed for 24.9 +/- 18.0 months (range, 1 to 63). There were no deaths or severe complications during the follow-up. CONCLUSIONS: Cannulation of the innominate artery with a side graft is safe and effective in arch surgery. PMID- 20172132 TI - Invited commentary. PMID- 20172133 TI - Cardiac surgery in octogenarians: long-term survival, functional status, living arrangements, and leisure activities. AB - BACKGROUND: A prospective study of survival, functional outcome, living arrangements, daily activities and leisure engagements among octogenarians up to 5 years after cardiac surgery was performed. METHODS: The study consisted of a cohort of 300 consecutive octogenarians with three interviews made at 6-month intervals for a total of 593 postoperative interviews. Functional outcomes were measured using the Barthel index and Karnofsky performance scores and divided into autonomous, semiautonomous, or dependent. Living arrangements and leisure activities within the social, physical, cognitive, and creative domains were recorded in an open-ended questionnaire. RESULTS: There were 150 men and 150 women with a mean age 82.6 years. The 30-day survival was 84.3%. Actuarial survival at 1, 3, and 5 years was 76.6%, 66.6%, and 57.8%, respectively. Among the survivors at the first interview, 2.2 years postoperatively, there were 63.9% autonomous, 31.7% semiautonomous, and 4.3% dependent patients versus at the last interview, 3.6 years postoperatively, in which there were 64.9% autonomous, 28.1% semiautonomous, and 9.2% dependent. At the first interview, 76.4% were at home, 19.2 % in a residence, and 4.3% in a supervised setting. At the third interview, 71.8% were at home, 21.2% in a residence, and 6.9% in a supervised setting. Nearly all patients were involved in leisure activities in the social (98.9%), cognitive (98.4%), and physical (93.1%) domains. At the end of the last interview, activities within the social and cognitive domains were maintained with a small decrease in the physical domain. CONCLUSIONS: Surviving octogenarians remain at home, function independently, and engage in regular leisure activities years after cardiac surgery. This information might help physicians and surgeons regarding long-term outcome of open cardiac surgery in octogenarians. PMID- 20172134 TI - Invited commentary. PMID- 20172135 TI - Risk factor analysis in patients with liver cirrhosis undergoing cardiovascular operations. AB - BACKGROUND: Variable outcomes of cardiac operations have been reported in cirrhotic patients, but no definitive predictive prognostic factors have been established. This retrospective study assessed operative results to identify risk factors associated with morbidity after cardiovascular operations in cirrhotic patients. METHODS: The study comprised 42 cirrhotic patients who underwent cardiovascular operations from January 1991 to January 2009. Thirty patients were Child-Turcotte-Pugh class A, and 12 were class B. Hospital morbidity occurred in 13 patients (31.0%; M group), including 4 who died in-hospital. Patients without severe complications (N group) were compared with the M group patients. The Model for End-Stage Liver Disease (MELD) score was evaluated in 25 patients. RESULTS: Significant differences in hospital morbidity between the M vs N groups were identified for platelet count (8.7 +/- 3.8 vs 12.1 +/- 4.2 x 10(4)/microL), MELD score (17.8 +/- 5.3 vs 9.8 +/- 4.9), operation time (370 +/- 88 vs 313 +/- 94 minutes), and cardiopulmonary bypass time (174 +/- 46 vs 149 +/- 53 minutes) in univariate analyses (p < 0.005). Platelet count, operation time, and age were significantly associated with hospital morbidity in multivariate analyses (p < 0.005). Platelet count of 9.6 x 10(4)/microL and MELD score of 13 were cutoff values for hospital morbidity. CONCLUSIONS: Careful consideration of operative indications and methods are necessary in cirrhotic patients with low platelet counts or high MELD scores. A high incidence of hospital morbidity is predicted in patients with platelet counts of less than 9.6 x 10(4)/microL or MELD scores exceeding 13. PMID- 20172136 TI - Invited commentary. PMID- 20172137 TI - Use of human umbilical cord blood-derived progenitor cells for tissue-engineered heart valves. AB - BACKGROUND: Tissue engineering of autologous heart valves with the potential to grow and to remodel represents a promising concept. Here we describe the use of cryopreserved umbilical cord blood-derived CD133(+) cells as a single cell source for the tissue engineering of heart valves. METHODS: After expansion and differentiation of CD133(+) cells, phenotypes were analyzed by immunohistochemistry and cryopreserved. Heart valve scaffolds fabricated from a biodegradable polymer (n = 8) were seeded with blood-derived myofibroblasts and subsequently coated with blood-derived endothelial cells. Afterward, the heart valve constructs were grown in a pulse duplicator system. Analysis of all heart valves, including histology, immunohistochemistry, electron microscopy, fluorescence imaging, and biochemical and biomechanical examination, was performed. RESULTS: The tissue-engineered heart valves showed endothelialized layered tissue formation including connective tissue between the inside and the outside of the scaffold. The notion of an intact endothelial phenotype was substantiated by fluorescence imaging studies of cellular nitric oxide production and Ca(2+) signaling. Electron microscopy showed that the cells had grown into the pores and formed a confluent tissue layer. Biochemical examination showed extracellular matrix formation (77% +/- 9% collagen of human pulmonary leaflet tissue [HPLT], 85% +/- 61% glycosaminoglycans of HPLT and 67% +/- 17% elastin of HPLT). CONCLUSIONS: Importantly, this study demonstrates in vitro generation of viable human heart valves based on CD133(+) cells derived from umbilical cord blood. These findings constitute a significant step forward in the development of new clinical strategies for the treatment of congenital defects. PMID- 20172138 TI - Engraftment is optimal when myoblasts are transplanted early: the role of hepatocyte growth factor. AB - BACKGROUND: In a recent clinical trial, skeletal myoblast (SKMB) transplantation performed late after myocardial infarction (MI) did not improve left ventricular function. We hypothesized that (1) delaying SKMB transplantation until a chronic infarct scar has developed reduces engraftment, and (2) hepatocyte growth factor (HGF), a main regulator of SKMBs, is present in acute but not chronic MI, potentially influencing engraftment. METHODS: Rats underwent coronary artery ligation followed by SKMB transplantation immediately (n = 12) or delayed by 5 weeks (n = 11). The volume of engrafted SKMBs was quantified 6 weeks later. Hepatocyte growth factor was evaluated by computerized analysis of immunohistochemical labeling of rat heart sections 48 hours, 1 week, 2 weeks, and 5 weeks after coronary artery ligation. The impact of HGF on SKMB proliferation and its ability to protect against oxidative stress and hypoxia was evaluated in vitro. RESULTS: Skeletal myoblast transplantation immediately after MI resulted in an engraftment volume of 29.1 +/- 2.9 mm(3). However, delaying SKMB transplantation 5 weeks caused a 95% drop in engraftment (1.4 +/- 0.3 mm(3); p < 0.001). Hepatocyte growth factor labeling in MIs 48 hours after coronary artery ligation was similar to control myocardium (18.0 +/- 2.0 versus 16.8 +/- 1.3 units). However, HGF declined progressively at 1, 2, and 5 weeks after MI (9.1 +/ 1.4, 4.2 +/- 0.4, and 3.1 +/- 0.6 units, respectively; p < 0.05 versus 48 hours). Hepatocyte growth factor caused a dose-dependent increase in SKMB proliferation in vitro and protected against oxidative stress and hypoxia. CONCLUSIONS: These results demonstrate that engraftment of SKMBs is impaired when transplantation is delayed until a chronic infarct has developed. Hepatocyte growth factor in MI declines with time and may enhance engraftment of SKMBs transplanted early after MI. Delivery of exogenous HGF to enhance SKMB engraftment in chronic infarcts warrants further investigation. PMID- 20172139 TI - Invited commentary. PMID- 20172140 TI - Use of oral budesonide in the management of protein-losing enteropathy after the Fontan operation. AB - BACKGROUND: Intestinal inflammation is a component of the pathophysiology of protein-losing enteropathy after the Fontan operation. Oral controlled-release budesonide is 90% metabolized at first pass through the liver, has high enteric anti-inflammatory activity and relatively low systemic effects, and may be an ideal agent for use in treating this disease. METHODS: Budesonide was administered to 9 patients (4 male) with protein-losing enteropathy after the Fontan operation. The median interval between the Fontan operation and diagnosis of protein-losing enteropathy was 4 years (range, 0.1 to 13.3). Prior interventional therapy included pulmonary artery stent (1), fenestration (3), pacemaker placement (3) and Fontan revision (2). Prior medical therapy included oral prednisone (5), heparin (4), sildenafil (2), infliximab (1), and octreotide (1), all without persistent success. The starting daily dose of budesonide was 9 mg for patients 4 years old or older, and 6 mg for patients less than 4 years of age. RESULTS: Mean serum albumin level 3 months before starting budesonide was 1.9 g/dL (range, 1 to 2.4 g/dL). Serum albumin level improved in all patients within 6 months of starting budesonide (mean 2.9 g/dL; range, 2.2 to 3.8 g/dL). Albumin levels of 3 g/dL or more were achieved in 8 of 9 patients within a median of 4.3 months (range, 2 to 25). Side effects included Cushingoid features and osteoporosis (3), infection requiring antibiotic treatment (5), and acne exacerbation (1). Weaning from high initial dose to a lower dose was possible with sustained effect; however, discontinuation of budesonide resulted in recurrence of hypoalbuminemia. CONCLUSIONS: Oral budesonide is an effective therapy for treating protein-losing enteropathy after the Fontan operation. To maintain response, low-dose therapy must be continued. PMID- 20172141 TI - Major infection after pediatric cardiac surgery: a risk estimation model. AB - BACKGROUND: In pediatric cardiac surgery, infection is a leading cause of morbidity and mortality. We created a model to predict risk of major infection in this population. METHODS: Using the Society of Thoracic Surgeons Congenital Heart Surgery Database, we created a multivariable model in which the primary outcome was major infection (septicemia, mediastinitis, or endocarditis). Candidate independent variables included demographic characteristics, comorbid conditions, preoperative factors, and cardiac surgical procedures. We created a reduced model by backward selection and then created an integer scoring system using a scaling factor with scores corresponding to percent risk of infection. RESULTS: Of 30,078 children from 48 centers, 2.8% had major infection (2.6% septicemia, 0.3% mediastinitis, and 0.09% endocarditis). Mortality and postoperative length of stay were greater in those with major infection (mortality, 22.2% versus 3.0%; length of stay >21 days, 69.9% versus 10.7%). Young age, high complexity, previous cardiothoracic operation, preoperative length of stay more than 1 day, preoperative ventilator support, and presence of a genetic abnormality were associated with major infection after backward selection (p < 0.001). Estimated infection risk ranged from less than 0.1% to 13.3%; the model discrimination was good (c index, 0.79). CONCLUSIONS: We created a simple bedside tool to identify children at high risk for major infection after cardiac surgery. These patients may be targeted for interventions to reduce the risk of infection and for inclusion in future clinical trials. PMID- 20172142 TI - Selective use of left heart bypass for aortic coarctation. AB - BACKGROUND: We evaluated left heart bypass (LHB) for spinal cord protection during aortic coarctation repair in patients with mild (primary, postsurgical, or intervention) and complex coarctation. METHODS: Between 1990 and 2008, 19 patients (mean age, 21 years; weight, 70 +/- 16 kg) using LHB were compared with 27 patients (mean age, 16 years; weight, 65 +/- 8 kg) undergoing coarctation repair without LHB (non-LHB). Follow-up was similar (LHB, 5 +/- 4 vs non-LHB 4 +/ 3 years; p = 0.81). RESULTS: Cohorts were similar in age and body surface area. No non-LHB patient lost somatosensory evoked potential or had a femoral artery pressure below 45 mm Hg with test clamping. LHB more often allowed graft interposition (18 of 19 [95%] vs non-LHB, 7 of 27 [26%]; p < 0.003) and a longer clamp time (LHB 44 +/- 16 vs non-LHB 31 +/- 12 minutes p < 0.003) without spinal cord ischemia. Two non-LHB patients had temporary spinal cord paresis. No early or late deaths occurred. Reintervention (LHB, 2 of 19 [11%] vs non-LHB, 2 of 27 [7%]; p = 0.82) and antihypertensive requirements were similar (LHB, 9 of 19 [40%] vs non-LHB, 8 of 27 [30%]; p = 0.35). The late peak transcoarctation gradient was 8 +/- 6 mm Hg in the LBH cohort vs 18 +/- 11 mm Hg in non-LBH patients (p= 0.001). CONCLUSIONS: Although the adequacy of spinal cord collateral assessment in coarctation repair is imperfect, no spinal cord ischemia occurred with coarctation repair and LHB. We recommend LHB in patients with mild or complex coarctation. PMID- 20172143 TI - Symptomatic neonatal tetralogy of Fallot: repair or shunt? AB - BACKGROUND: The management of neonates with symptomatic tetralogy of Fallot (TOF) requiring surgical intervention in the first month of life remains controversial. We reviewed our experience with neonates 30 days or greater with TOF from 2002 to 2008 requiring surgical intervention. METHODS: Thirty-seven consecutive symptomatic nonrandomized neonates with TOF or its variants (including TOF with complete atrioventricular septal defect or absent pulmonary valve but excluding pulmonary atresia) had either a shunt (n = 17) or primary repair (n = 20). The shunted patients more commonly required emergency operation (24% vs 0%; p = 0.036); otherwise, the two groups were similar. RESULTS: One infant with preoperative bowel ischemia died one day postoperatively after emergency shunting. There were two late deaths 11 and 12 months postoperatively, both in primary repair patients. The 16 surviving shunted patients had TOF repair 216 +/- 99 days after the original shunt. The shunted patients had shorter intensive care unit and hospital stays for the first operation, which became equivalent when the second hospitalization (repair) values were added. The primary repair patients more frequently had a transannular patch and a tendency to more frequent delayed sternal closure. Four primary repair (20%) and two shunted (12.5%) patients required subsequent cardiac operations after complete repair (p = not significant). CONCLUSIONS: Shunting or primary repair of neonates with symptomatic TOF provides equivalent mortality and results. Shunted patients had fewer transannular patch repairs despite having more emergent initial operations. Compared with the primary repair group, shunted patients had decreased intensive care unit and hospital stays for the first hospitalization, which were neutralized when the second operation (repair) values were added. PMID- 20172144 TI - Prognostic significance of intratumoral blood vessel invasion in pathologic stage IA non-small cell lung cancer. AB - BACKGROUND: The 5-year survival rate of pathologic stage IA non-small cell lung cancer (NSCLC) is excellent; however, up to 10% of patients with pathologic stage IA NSCLC still relapse postoperatively and die. This study retrospectively analyzed the clinicopathologic features of patients with pathologic stage IA NSCLC to identify the prognostic factors and investigate the effect of a combination of intratumoral vessel invasion and tumor size. METHODS: From December 1991 to December 2003, 217 consecutive patients with stage IA NSCLC were selected, and disease-free survival (DFS) was analyzed. RESULTS: Intratumoral blood vessel invasion (BVI) was identified as an independent poor prognostic factor (p = 0.0006). The relative risk for patients with BVI was 4.599 times higher than that for patients without BVI (95% confidence interval, 1.913 to 11.056). According to the new T N M system, the difference in DFS between the patients with and without BVI was statistically significant, not only in tumors exceeding 2 cm (T1b with BVI vs T1b without BVI, p = 0.0020) but also in tumors smaller than 2 cm (T1a with BVI vs T1a without BVI, p < 0.0001). The survival curve of T1b patients without BVI was similar to that of T1a patients without BVI (p = 0.0892). Distant recurrence was frequently observed in both T1a and T1b patients with BVI. CONCLUSIONS: BVI is an independent poor prognostic factor in patients with pathologic stage IA NSCLC. These T1a and T1b patients with BVI both might benefit from adjuvant chemotherapy. PMID- 20172145 TI - Microscopic residual disease after resection for lung cancer: a multifaceted but poor factor of prognosis. AB - BACKGROUND: Many studies focus on bronchial microscopic residual disease (R1) after resection for lung cancer, although R1 also concerns vascular and soft tissues. Our purpose was to study the R1 prognosis at different resection margins and to compare it with the prognosis for those having complete resection (R0). METHODS: We reviewed the clinical records of 4,026 patients from two centers who underwent surgery in view of cure. Despite perioperative frozen section, 216 patients (5.4%) proved R1 and were classified into seven types according to R1 anatomic site: bronchus, peribronchus, great vessels and atrium, mediastinum and pericardium, chest wall, lung tissue, and lymph nodes. Patients who were classified as R0 and R1 were compared, and R1 patients were further studied according to R1 margins. RESULTS: Frequency of R1 increased with the T and N values and type of resection (lobectomies, 3.3% [70 of 2,041 patients]; pneumonectomies, 8.8% [126 of 1,308 patients]; p < 10(-6)). Five-year survival rates for R1 patients were lower than those for R0 patients (20% versus 46%; p < 10(-6)), and were not modified by the degree of T and N involvement or adjuvant therapy, but were better in bronchial and peribronchial (48.4% of R1 patients) than in extrabronchial R1 (26.3% versus 15.6%; p = 0.023). Multivariate analysis confirmed R1 to be an independent factor of poor prognosis (p = 0.0008), after N, T, and age. CONCLUSIONS: Long-term survival is possible in case of an R1 margin, but 5-year survival rates are jeopardized. Poor efficacy of adjuvant therapy and global outcome indicate advanced disease or reflect tumor cell aggressiveness, rather than surgical insufficiency, when prevention of R1 margins is guided by frozen-section examination and scrupulously respected. PMID- 20172146 TI - Invited commentary. PMID- 20172148 TI - Invited commentary. PMID- 20172147 TI - Superselective segmentectomy for deep and small pulmonary nodules under the guidance of three-dimensional reconstructed computed tomographic angiography. AB - BACKGROUND: Three-dimensional computed tomographic angiography (3D-CT angio) allows selective access to peripheral segments. Superselective segmentectomy (SSS) was applied to the surgical management of indeterminate small and deep pulmonary nodules. METHODS: Thirty patients with indeterminate pulmonary nodules less than 25 mm in diameter and located deeper than 20 mm from the pleural surface were enrolled in this study between 2002 and 2009. All patients underwent exploratory thoracotomy. The SSS with a surgical margin from the nodule larger than the nodule diameter or 20 mm was directed toward the target pulmonary arteries by 3D-CT angio using a multidetector-row CT scanner. The SSS was evaluated for resected area, surgical margin, regional lymph nodes, morbidity, lung function, and survival rate. RESULTS: Three patients received SSS at the daughter segment, 23 patients that at the subsegment, and the remaining four underwent miscellaneous SSS without major complications. Twenty patients exhibited early lung cancer, one patient stage IIA lung cancer, and the remaining nine patients had metastatic or benign tumors. Five patients with primary cancer subsequently underwent standard lobectomy. The remaining 16 patients with early lung cancer did not undergo lobectomy because of their major comorbidities or refusal of a second thoracotomy. The surgical margins were free of disease in all patients. The actual and disease-free five-year survival rates were 100% for the lung cancer patients, excluding those who subsequently underwent lobectomy. The lung function after SSS was well preserved. CONCLUSIONS: Superselective segmentectomy is an applicable optional strategy for the surgical management of indeterminate small and deep pulmonary nodules. PMID- 20172149 TI - Transition from mediastinoscopy to endoscopic ultrasound for lung cancer staging. AB - BACKGROUND: Esophageal endoscopic ultrasound (EUS) and endobronchial ultrasound (EBUS) are gaining popularity for mediastinal staging of patients with lung cancer. Endoscopic ultrasound and then EBUS were introduced into a single-surgeon thoracic surgical practice. Records were reviewed to determine what effect this had on performance of mediastinoscopy for lung cancer staging, and on discovery of unsuspected N2 disease at the time of resection. METHODS: Endoscopic ultrasound and EBUS were introduced 10 months apart. Records were reviewed for the 10 months before EUS (phase 1), the 10 months between EUS and EBUS (phase 2), 8 months after the introduction of EBUS (phase 3), and 11 months after that (phase 4). The number of staging procedures, patients undergoing resection after negative staging, and patients with N2 disease discovered at resection were determined. RESULTS: Two hundred fifty-three patients met inclusion criteria. Eighty-two had resection without staging; staging was positive in 62, negative in 90 who went on to resection, and negative in 19 who had no further evaluation. There was a strong trend toward preferential use of EUS in phase 2 and EBUS in phases 3 and 4. Nine patients (10%) had N2 disease found at surgery: 0 of 16 in phase 1, 4 of 24 in phase 2, 3 of 24 in phase 3, and 2 of 25 in phase 4. Overall sensitivity and negative predictive value of EUS and EBUS were 84% and 87%, respectively. CONCLUSIONS: Introduction of EUS and EBUS reduced use of mediastinoscopy. Discovery of N2 disease at surgery was higher than expected initially, but with experience results proved comparable to those of mediastinoscopy. PMID- 20172150 TI - Incidence and risk factors of persistent air leak after major pulmonary resection and use of chemical pleurodesis. AB - BACKGROUND: Persistent air leak (PAL; defined as air leak > 5 days) after major pulmonary resection is prevalent and associated with significant morbidity. This study examines an incompletely characterized treatment for the management of PAL, chemical pleurodesis. METHODS: A retrospective case-control study examining all isolated lobectomies and bilobectomies by thoracotomy was performed. The PALs (1997 to 2006) and controls (2002 to 2006) were identified from a prospective database. Incidence, risk factors, management, and outcome were defined. RESULTS: Over 9 years, 78 PALs were identified in 1,393 patients (5.6%). Controls consisted of 700 consecutive patients. Propensity score analysis matching case and controls showed no predictive risk factors for air leak using a logistic regression model. Univariate analysis demonstrated that female gender, smoking history, and forced vital capacity were predictive risk factors. Treatment of PAL consisted of observation (n = 33, 42.3%), pleurodesis (n = 41, 52.6%), Heimlich valve (n = 3, 3.8%), and reoperation (n = 1, 1.3%). Seventy-three patients (93.6%) required no further intervention. One patient required a muscle flap, one readmission for pneumothorax, and one empyema resulting in death. Sclerosis was successful in 40 of 41 patients (97.6%). Mean time to treatment was 8.4 +/- 3.6 days, mean duration of air leak was 10.7 +/- 4.5, and mean duration of air leak postsclerotherapy was 2.8 +/- 2.2 days. Postoperative pneumonia occurred with increased frequency in PAL patients (6 of 45 [13.3%] vs 34 of 700 [4.9%], p = 0.014). PAL was associated with increased length of stay (14.2 vs 7.1 days, p < 0.001) and time with chest tube (11.5 vs 3.4 days, p < 0.001). CONCLUSIONS: Air leaks remain an important cause of morbidity. Pleurodesis is an effective option in management of PAL after major pulmonary resection. PMID- 20172151 TI - Unilateral extrapulmonary airway bypass in advanced emphysema. AB - BACKGROUND: Gas trapping in emphysema results in resting and dynamic hyperinflation. We tested the hypothesis that a direct connection between the lung parenchyma and the atmosphere could increase expiratory flow and thereby potentially improve dyspnea through the relief of gas trapping. METHODS: Ex vivo we studied 7 emphysematous lungs and 3 fibrotic lungs (as controls) and measured expiratory flow before and after airway bypass insertion during a forced maneuver in an artificial thorax. Pilot studies were conducted in vivo in 6 patients with advanced emphysema using a size 9 endotracheal tube as a bypass surgically placed through the chest wall into the upper lobe. RESULTS: In the ex vivo emphysematous lungs the volume expelled during a forced expiratory maneuver increased from 169 to 235 mL (p < 0.05). In the in vivo group 4 patients retained the bypass tube for 3 months or more; total lung capacity was reduced, and the forced expiratory volume in 1 second increased by 23% (mean percent predicted at baseline versus 3 months, 24.4% versus 29.5%). CONCLUSIONS: An extrapulmonary airway bypass increases expiratory flow in emphysema. This may be a useful approach in hyperinflated patients with homogeneous emphysema. PMID- 20172152 TI - Therapeutic surgery for nonepithelioid malignant pleural mesothelioma: is it really worthwhile? AB - BACKGROUND: Debate remains about the relative prognostic importance of the histologic subtype of malignant pleural mesothelioma. METHODS: From a prospective database, the details of 312 malignant pleural mesothelioma surgical patients were reviewed. A comparison was made of the survival from the three major cell types. RESULTS: One hundred ninety-five patients underwent radical surgery, and 117 underwent nonradical surgery. Final histologic subtype was epithelioid in 218 patients, biphasic in 66 patients, and sarcomatoid in 28 patients. The median survival was 15.3 months in the epithelioid group, 10.1 months in the biphasic group, and 5.0 months in the sarcomatoid group. On univariate analysis in the epithelioid group, age (p = 0.005), International Mesothelioma Interest Group stage (p = 0.001), radicality of the procedure (p = 0.001), leukocytosis (p = 0.016), and preoperative or postoperative chemotherapy (p = 0.012) were significant prognostic factors influencing postoperative survival. In the biphasic group, preoperative anemia was the only significant factor (p = 0.007). In sarcomatoid patients, International Mesothelioma Interest Group stage and radicality of the surgical procedure were significant prognostic variables (p = 0.012 and p = 0.015, respectively). Multivariate analysis in the epithelioid group identified International Mesothelioma Interest Group stage (p = 0.001), radicality of the procedure (p = 0.008), and preoperative or postoperative chemotherapy (p = 0.007) as significant prognostic factors, whereas in the sarcomatoid group, only the International Mesothelioma Interest Group stage (p = 0.012) was significant and the radicality of surgery had no effect. CONCLUSIONS: The extremely poor prognosis of sarcomatoid malignant pleural mesothelioma is independent of the extent of surgery unlike other cell types. Patients with sarcomatoid histology should therefore be considered separately in trials evaluating radical procedures and adjuvant treatment. The treatment of biphasic pleural mesothelioma remains debatable. PMID- 20172153 TI - Masaoka stage and histologic grade predict prognosis in patients with thymic carcinoma. AB - BACKGROUND: Thymic carcinoma is a rare tumor. Limited data are available regarding the effectiveness of treatment and the prognosis of thymic carcinoma. The present study aimed to clarify the prognostic factors in patients who underwent resection. METHODS: The study retrospectively reviewed 21 patients (15 men, 6 women) with thymic carcinoma who had undergone resection at Niigata University Hospital. RESULTS: Masaoka stage was II in 4 patients, III in 9, IVa in 2, and IVb in 6. Histologic subtypes were squamous cell carcinoma in 14 patients, adenocarcinoma in 2, atypical carcinoid in 3, and undifferentiated carcinoma in 2. Histologic grade by degree of differentiation was low in 4 tumors, intermediate in 12, and high in 5. Treatment comprised resection alone in 6 patients and resection along with multimodal therapies in 15. Complete resection was achieved in 14 (67%). Eight patients died of tumor. Recurrence was documented in 7 of 14 patients with complete resection, and 5 received additional treatment. The overall 5-year survival rate was 61.1%, and the disease-free 5 year survival rate was 66.8% for the 14 with complete resection. By multivariate analysis, Masaoka stage and histologic grade were significant independent prognostic factors for overall survival. CONCLUSIONS: The surgical outcome of patients with thymic carcinoma depends on the Masaoka stage and histologic grade. Patients with early Masaoka stage and low or intermediate histologic grade had favorable prognoses. PMID- 20172154 TI - Long-term outcome after external tracheal stabilization due to congenital tracheal instability. AB - BACKGROUND: Long-segment tracheobronchial malacia may cause life-threatening dysfunction of the airway system at different levels. This study presents the long-term follow-up (1992 through 2008) of patients who received surgical treatment with external tracheal stabilization in our institution. METHODS: Eleven patients fulfilled the inclusion criteria. In surviving patients who presented for reexamination, pulmonary function testing, ergometry, and magnetic resonance imaging (MRI) were performed. RESULTS: All patients could be weaned from the ventilator and discharged. Patients were aged a median 11 months (range, 3 to 48 months) at operation for tracheal compression. Age at follow-up was 9.1 years (range, 0.5 to 16.3 years). Median follow-up was 7.3 years (range, 0.1 to 15.1 years). Postoperatively, 1 patient was lost to follow-up, and 4 died at 2.6 years (range, 0.5 to 6.6 years) of comorbidities. Pulmonary function testing showed a moderate residual airflow restriction, with maximal vital capacity at 75% of normal (range, 45% to 92%). Treadmill exercise testing demonstrated 70% to 89% of the expected normal values for age. Magnetic resonance imaging examination confirmed tracheal patency, but the lumen of the left main bronchus in 2 patients was 50% smaller than on the right. Diaphragmatic motion was normal in all patients. CONCLUSIONS: Children with congenital tracheal stenosis benefit from external tracheal stabilization. Survival in patients after external tracheal stabilization is significantly influenced by concomitant conditions. PMID- 20172155 TI - A thoracic surgeon-directed tobacco cessation intervention. AB - BACKGROUND: Thoracic surgeons receive little training in promoting tobacco cessation despite the impact of tobacco use on their patients. There are only a few prospective reports of tobacco cessation efforts involving thoracic surgeons in the scientific literature. The purpose of this study was to prospectively evaluate a brief tobacco cessation intervention offered by surgeons in an outpatient thoracic surgery clinic. METHODS: Adult smokers from a single institution thoracic surgery clinic were enrolled in a single-arm prospective pilot trial between January and December 2008. Patients received a 10-minute intervention including discussing their motivation for quitting, offering tobacco cessation medication, and promoting a free telephone quitline. The primary outcome was abstinence at 3 months. Univariate logistic regression identified factors associated with tobacco cessation. RESULTS: Forty of 60 eligible smokers enrolled in the study. The mean age and standard deviation of participants was 52.1 +/- 12.6 years with a 39.9 +/- 11.2 pack-year smoking history. The 3-month quit rate was 35% (14 of 40). Fifty percent (20 of 40) of participants used at least one tobacco cessation medication. Only 7.5% (3 of 40) of patients called the quitline, but each of these participants quit smoking. Successful tobacco cessation was associated with a malignant diagnosis and being the only tobacco user in the home (odds ratio, 4.2; 95% confidence interval, 1.0 to 17.2; and odds ratio, 6.1; 95% confidence interval, 1.4 to 26.3, respectively). CONCLUSIONS: Thoracic surgeons can successfully implement a tobacco cessation program with an excellent rate of abstinence compared with reported cessation rates at 3 months from the literature. Further investigation with a larger sample size, longer follow-up, and improved utilization of the quitline is warranted. PMID- 20172156 TI - Utility of removable esophageal covered self-expanding metal stents for leak and fistula management. AB - BACKGROUND: Esophageal or gastric leakage from anastomotic wound dehiscence, perforation, staple line dehiscence, or trauma can be a devastating event. Traditional therapy has often consisted of either surgical repair for rapidly diagnosed leaks or diversion for more complicated cases, commonly associated with a delayed diagnosis. This study summarizes our experience treating leaks or fistulas with novel, covered self-expanding metal stents (cSEMS). The primary objective of this study was to determine the efficacy and safety of covered self expanding metal stents when used to treat complicated leaks and fistulas. METHODS: Over 15 months, 25 patients with esophageal or gastric leaks were evaluated for stenting as primary treatment. A prospective database was used to collect data. Stents were placed endoscopically, with contrast evaluation used for leak evaluation. Patients who did not improve clinically after stenting or whose leak could not be sealed underwent operative management. RESULTS: During a mean follow-up of 15 months, 23 of the 25 patients with esophageal or gastric leaks during a 15-month period were managed with endoscopic stenting as primary treatment. Healing occurred in patients who were stented for anastomotic leakage after gastric bypass or sleeve gastrectomy (n = 10). One patient with three esophageal iatrogenic perforations healed with stenting. Eight patients successfully avoided esophageal diversion and healed with stenting and adjunctive therapy. Two of the 4 patients with tracheoesophageal fistulas sealed with the assistance of a new pexy technique to prevent stent migration; 1 additional patient had this same technique used to successfully heal an upper esophageal perforation. CONCLUSIONS: Esophageal leaks and fistulas can be effectively managed with cSEMS as a primary modality. The potential benefits of esophageal stenting are healing without diversion or reconstruction and early return to an oral diet. PMID- 20172157 TI - Modified Bentall operation with a novel biologic valved conduit. AB - PURPOSE: The optimal conduit for a modified Bentall operation remains unknown. The current study tested hemodynamics and early clinical results of the newly developed valved conduit composed of the 3f Aortic Bioprosthesis (ATS Medical, Minneapolis, MN) and the Vascutek Gelweave Valsalva Aortic Root Graft (Terumo Cardiovascular Systems, Ann Arbor, MI). DESCRIPTION: Between December 1, 2008, and April 6, 2009, 20 patients underwent a modified Bentall operation with this valved conduit and their clinical records were retrospectively reviewed. EVALUATION: The indication for aortic root replacement in the 20 patients was aortic root aneurysm in 14, acute type A dissection in 5, and structural deterioration of an aortic root homograft in 1. Four patients had had previous cardiac operations, and 8 patients required concomitant procedures. Mean cardiopulmonary bypass and aortic cross-clamp times were 146 +/- 110 minutes and 110 +/- 32 minutes, respectively. There were no perioperative deaths. The average mean pressure gradient across the bioprosthesis assessed with intraoperative transesophageal echocardiogram was 4.0 +/- 1.7 mm Hg. CONCLUSIONS: Our initial experience with our new valved conduit showed favorable results. Further accumulation of cases and longer follow-up are warranted. PMID- 20172158 TI - Invited commentary. PMID- 20172159 TI - A new sinus prosthesis for aortic valve-sparing surgery maintaining the shape of the root at systemic pressure. AB - PURPOSE: We describe a new prosthetic graft aiming to restore normal valve configuration in systemic circulation. In vitro evaluation data and first clinical results are presented. DESCRIPTION: The aortic valve consists of three separate leaflets and sinuses of Valsalva interconnected through three straight interleaflet triangles. This shape has important implications on valve function. EVALUATION: In vitro tests showed nearly normal hemodynamics, although root distensibility was decreased and bending deformation of the leaflets was increased due to the nonflexibility of the graft material. However, the anatomical shape of the aortic root was well preserved in vitro and also in vivo without contact of leaflets to the prosthesis wall. CONCLUSIONS: This new sinus prosthesis maintains normal configuration of the aortic root with three distinct sinuses of Valsalva and straight commissural pillars in systemic circulation. The noncompliant material induces abnormal leaflet bending during systole, but leaflets do not collide with the wall of prosthesis. PMID- 20172160 TI - Delayed malignant hyperthermia after routine coronary artery bypass. AB - Malignant hyperthermia is a rare but well-described hypermetabolic disorder of skeletal muscle that can be potentially fatal if untreated. In our patient, malignant hyperthermia developed several minutes after discontinuation of the known triggering agent after an uncomplicated coronary revascularization. This case illustrates the dramatic presentation and successful management of a rare disease with a rare onset. PMID- 20172161 TI - Coronary artery bypass grafting in cold-induced urticaria. AB - Cold-induced urticaria is an unusual systemic disorder that develops in response to exposures to cold temperatures in susceptible individuals. Patients with cold urticaria are potentially at risk of severe systemic anaphylactic shock-like reactions. This disorder is of unique clinical importance in cardiac surgery, considering the use of cardiopulmonary bypass and hypothermia. Contact of blood with hypothermia and subsequent warming can be associated with hemodynamic instability, hypotension, and cardiovascular collapse, mainly during the period of rewarming. We report the case of a 41-year-old woman with chronic cold-induced urticaria, who underwent a successful coronary bypass grafting, and describe perioperative management of this rare disorder. PMID- 20172162 TI - Simultaneous rupture of bronchus and aortic valve from blunt trauma. AB - We report the case of a 29-year-old woman with combined bronchial rupture and aortic valve tear after blunt chest trauma. She was successfully treated with primary repair of both lesions. The importance of chest computed tomography and transthoracic echocardiography in the diagnosis of these lesions is discussed. PMID- 20172163 TI - Left main coronary artery occlusion after percutaneous aortic valve implantation. AB - Left main coronary artery occlusion occurred immediately after transfemoral aortic valve implantation in an 87-year-old woman, which resulted in ventricular fibrillation and hemodynamic collapse. This life-threatening complication was promptly diagnosed with transesophageal echocardiography, which showed the disappearance of diastolic left main coronary artery jet flow and was confirmed with aortic root angiography. After prompt defibrillation, hemodynamic support was obtained with intra-aortic balloon pump and inotropic drugs. Functional recovery and survival were achieved with coronary stenting. This report highlights the importance of an integrated team approach of highly skilled specialists for these novel interventions. PMID- 20172164 TI - Recurrent mitral regurgitation due to calcified synthetic chordae. AB - We report a case of recurrent mitral regurgitation due to calcification of the expanded polytetrafluoroethylene sutures. According to pathologic findings, it was believed that due to the dystrophic calcification of the fibrous tissue covering the expanded polytetrafluoroethylene sutures, there was increased hyalinization, leading to sclerosis and shortening of the chordae. Calcification of expanded polytetrafluoroethylene sutures after mitral valve repair is a rare complication; however, careful follow-up should be needed because such change may occur in long-term periods after implantation. PMID- 20172165 TI - Infectious endocarditis caused by Rhodococcus equi. AB - Rhodococcus equi is an unusual cause of infection. Furthermore, this infection also tends to be typically described in immunocompromised patients. This report describes a 25-year-old previously healthy man with infectious endocarditis that was found to have been caused by R equi complicated by a subarachnoid hemorrhage, subdural hematoma, and a superior mesenteric artery aneurysm. The patient was successfully treated with antibiotic therapy, followed by a resection of the superior mesenteric artery aneurysm and a repair of the mitral valve. PMID- 20172166 TI - Ventricular septal perforation caused by right-sided infective endocarditis associated with giant vegetation. AB - A 71-year-old man presented with general fatigue associated with syncope and fever, and was admitted to our hospital and treated with antibiotics for pneumonia. On day 10 after admission, cardiac echocardiography showed a ventricular septal perforation and giant vegetation floating in the right ventricle near the tricuspid valve, which had not been detected at the time of admission. An emergency operation (including vegetation excision, debridement, ventricular septal perforation patch closure, and tricuspid valve replacement) was performed. A permanent pacemaker was implanted on postoperative day 34, and the patient was discharged without any complications. A culture of the excised vegetation and blood culture revealed methicillin-susceptible Staphylococcus aureus. There has been no previous report of a presenting ventricular septal perforation caused by right-sided infective endocarditis. PMID- 20172167 TI - High anomalous origin of the right coronary artery associated with aortic stenosis: a word of caution. AB - We report a case with rare anomalous origins of the right coronary artery that arises from the ascending aorta. An 82-year-old woman scheduled for aortic valve replacement for severe aortic stenosis was incidentally found to have an unusual origin of the right coronary artery during routine screening for coronary artery disease by preoperative 64-slice multi-detector row computed tomographic angiography. The artery originated from the left surface of the ascending aorta approximately 2 cm above the sinotubular junction, where the transverse aortotomy is routinely placed. This detection resulted in avoidance of an intraoperative interruption of the right coronary artery. A preoperative multi-detector row computed tomography angiographic scan was very useful not only for evaluation of the coronary artery disease, but also for detection of a rare anomalous origin of the right coronary artery. PMID- 20172168 TI - Giant coronary artery aneurysm with pulmonary artery fistula in a patient on chronic hemodialysis. AB - The combination of coronary artery aneurysm and pulmonary artery fistula is extremely rare and its common cause is atherosclerosis. A 61-year-old woman presented with a giant coronary artery aneurysm with pulmonary artery fistula and intramyocardial calcifications of the left ventricle associated with progressive atherosclerosis due to chronic hemodialysis. The coronary artery aneurysm was resected under cardiopulmonary bypass because of hemodynamic instability due to restrictive cardiac dysfunction. The patient's restrictive cardiac dysfunction was improved after aneurysm resection. Surgical resection should be considered for giant coronary artery aneurysm with restrictive cardiac dysfunction. PMID- 20172169 TI - Pedunculated endocardial left ventricular fibroma presenting with cerebral and bilateral peripheral embolization. AB - Left ventricular fibroma is a rare benign tumour of the heart. We present the case of a 24-year-old man with left hemiplegia and bilateral popliteal artery occlusion associated with left ventricular mass. The patient underwent successful excision of a pedunculated mass attached to the trabeculae of left ventricular cavity. Histopathologic examination confirmed the presence of fibroma associated with septic thrombus. The association of fibroma and embolization is rare. PMID- 20172170 TI - Intracardiac malignant Triton tumor: a first presentation. AB - We present the first case of an intracardiac malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation (malignant Triton tumor) in a 63-year old man who underwent elective, uncomplicated resection of his symptomatic left atrial mass. PMID- 20172171 TI - Giant calcified pseudoaneurysm of right coronary artery presenting as a right intra-atrial mass. AB - We present a case of a giant right coronary artery pseudoaneurysm that presented as a right atrial intracardiac mass. Preoperatively, a two-dimensional echocardiogram, a computed tomographic scan, a magnetic resonance image, and cardiac catheterization were performed to diagnose and assess the origins of the mass. PMID- 20172172 TI - Kawashima procedure after staged unifocalizations in asplenia with major aortopulmonary collateral arteries. AB - We report a Kawashima procedure (total cavopulmonary shunt) successfully carried out for asplenia syndrome, pulmonary atresia, and major aortopulmonary collateral arteries. At the age of 8, the patient underwent staged bilateral unifocalizations using confluent central pulmonary arteries concomitant with bilateral modified Blalock-Taussig shunts. As the result of an interrupted inferior vena cava with azygous continuation, the patient required a Kawashima procedure with augmentation of the central pulmonary arteries for definitive palliation 1 year later. Cyanosis, respiratory distress, and ventricular function improved. PMID- 20172173 TI - Staged repair of truncus arteriosus with interrupted aortic arch: adjustable pulmonary artery banding. AB - We report a successful two-stage treatment for an infant with truncus arteriosus with aortic arch interruption. The treatment consisted of flow-adjustable bilateral pulmonary artery banding using clipping and postoperative balloon dilation, followed by staged repair. The merits of this strategy are as follows: (1) bilateral pulmonary artery banding is less invasive than neonatal one-stage repair; (2) use of cardiopulmonary bypass can be avoided in the newborn period; and (3) control of pulmonary blood flow adjusted for body size is possible. Although further studies are needed, our therapeutic strategy might provide a clinically important option for managing severe congenital heart disease. PMID- 20172174 TI - Transplant pneumonectomy in a patient with an acutely thrombosed allograft. AB - Transplant pneumonectomy is most commonly performed in the setting of retransplantation and is rare for other indications. We present a case of an elderly woman who is 3 years postoperative left, single lung transplantation with a history of emphysema that developed extensive infarction of her transplanted lung secondary to thromboembolic disease. She required an allograft pneumonectomy as treatment for this and was eventually discharged on bi-level nasal positive pressure at night and 3 L nasal cannula oxygen during the day. PMID- 20172175 TI - Severe tracheal compression causing respiratory failure after transhiatal esophagectomy. AB - Complications after transhiatal esophagectomy include pneumonia, recurrent laryngeal nerve injury, and anastomotic leak. Although damage to the trachea is a potential complication, there are minimal reports of tracheal compression after esophagectomy with gastric pull-through. We report a case of severe tracheal compression and obstruction requiring mechanical ventilation presenting 2 days postoperatively. Placement of a silicone tracheal stent relieved the obstruction in the distal trachea and facilitated extubation. PMID- 20172176 TI - Lateral mediastinal tracheostomy in benign disease: an uncommon procedure for a rare indication. AB - Tracheostomy is sometimes required for long-term ventilation in patients with a challenging cervical anatomy. We present a case of a patient requiring prolonged mechanical ventilation with prohibitive cervical anatomy for standard tracheostomy secondary to severe ankylosing spondylitis and a cervical spine fracture. PMID- 20172177 TI - Inhaled epoprostenol during one-lung ventilation. AB - We used inhaled epoprostenol (with intravenous phenylephrine) during one-lung ventilation to improve oxygenation in a patient with severe interstitial lung disease undergoing video-assisted thoracoscopic surgery. The pharmacologic manipulation of pulmonary blood flow remains an underused strategy for the management of hypoxemia during one-lung ventilation. PMID- 20172178 TI - Chondroid syringoma: a rare tumor of the chest wall. AB - Chondroid syringoma, an uncommon, slow-growing, benign, sweat-gland tumor located on the upper right chest wall of a 66-year-old woman is presented. This skin adenexal tumor is typically located on the head and neck region. The unusual location of chondroid syringoma made an accurate preoperative diagnosis difficult, and diagnosis was achieved only by excisional biopsy and histopathologic examination. Total surgical excision remains the best therapeutic option to avoid tumor recurrence and close follow-up is recommended because of a rare possibility of malignant transformation and visceral metastases. PMID- 20172179 TI - The Nuss procedure for pectus excavatum at the time of atrial septal closure. AB - A 25-year-old man with severe pectus excavatum and an atrial septal defect had simultaneous repair of the defects, using a patch for closure of the defect and placement of a Nuss bar for the chest wall defect. Details of the procedure and outcome are described. PMID- 20172180 TI - Aneurysm of right superior pulmonary vein. PMID- 20172181 TI - Progredient neurogenic and vascular thoracic outlet syndrome due to bilateral cervical ribs. PMID- 20172182 TI - Primary sarcoma of the clavicle. PMID- 20172183 TI - An aortic cinch to quell suture line bleeding. AB - Bleeding from an aortic suture line or cannula site may be difficult to control, especially in the patient with a fragile or dilated aorta. This method of wrapping a vascular graft around the aorta to relieve tension on the suture line and control bleeding is simple and effective, and it facilitates obtaining the proper tension of the wrapped graft. PMID- 20172184 TI - Novel wrapping technique with insertion of fat tissue for hemostasis in aortic surgery. AB - The standard techniques and prosthetic materials for graft replacement in aortic surgery have been dramatically improved. However, persistent oozing and bleeding during aortic surgery sometimes occur and lead to life-threatening problems because of severe coagulopathy, which results from induced hypothermia, long cardiopulmonary bypass time, or fragile aortic walls by acute aortic dissection. Although various techniques and devices for reduction of bleeding have been already documented, these techniques are not always perfect and are sometimes complex. A new wrapping technique with insertion of fat tissue, as described in this report, is simple and provides a perfect hemostasis. PMID- 20172185 TI - Technique for left ventricular apical cannulation for short-term mechanical circulatory support. AB - The ABIOMED BVS 5000 ventricular assist system (ABIOMED Cardiovascular Inc, Danvers, MA) is the most commonly used mechanical circulatory support device for post-cardiotomy and post-myocardial infarction cardiogenic shock after placement of an intra-aortic balloon pump. We describe a simple and reliable technique for left ventricular apical cannulation for this device, which also facilitates decannulation without the use of cardiopulmonary bypass. PMID- 20172186 TI - The sinker technique: a simple, effective technique for exposing coronary arteries in off-pump surgery. AB - Exposure and stabilization of coronary arteries in the circumflex and right territory is essential for off-pump coronary artery bypass grafting. A new, easy technique of exposing and stabilizing coronary arteries using a sinker (weight) hung on a silicone elastomer suture for hemostasis from the arteriotomy is described. PMID- 20172187 TI - Management of carcinoid tumors. AB - Primary bronchopulmonary carcinoids comprise a significant proportion of carcinoid tumors. The clinical presentation allows prediction of the diagnosis and cell type and directs evaluation and treatment. Young age, central tumor, and no nodal enlargement are highly suggestive of typical carcinoid. These patients require no further diagnostic or staging tests beyond chest computed tomography and bronchoscopy before resection using parenchyma-sparing techniques. All bronchopulmonary carcinoids are malignant (though indolent), and surgical intervention is the mainstay of treatment. Mediastinoscopy is suggested when there is moderate suspicion of atypical carcinoid (central cN1 or peripheral cN0), with lobectomy and lymphadenectomy if the mediastinal nodes are benign. For a high suspicion of atypical carcinoid (central cN2, peripheral cN1, 2), imaging for distant metastases and mediastinoscopy is suggested, with multimodality treatment for an atypical carcinoid with N2 involvement. PMID- 20172188 TI - Nael Martini: a leader in thoracic surgical oncology. AB - Nael Martini was one of the leading academic general thoracic surgeons of the late 20th century. His most notable contributions related to the surgical and multimodality treatment of lung cancer. PMID- 20172189 TI - Thyroid function and cardiac surgery: what should we measure, and when? PMID- 20172190 TI - Multidisciplinary rounds: the work, not more work. PMID- 20172192 TI - Extracorporeal membrane oxygenation use for mediastinal tumor resection. PMID- 20172193 TI - Choroidal metastasis revealing a lung adenocarcinoma. PMID- 20172199 TI - [The role of perioperative chemotherapy in patients with resectable colorectal liver metastases]. AB - Surgical resection remains the only treatment of colorectal liver metastases that can ensure long-term survival and cure in some patients, but only a minority of patients with liver metastases is directly amenable to surgery. Cancer relapse is observed in the majority of patients after resection of liver metastases despite progress in surgical technique and improved surgical skills. In order to decrease the risk of cancer relapse, it has been proposed to combine surgery and chemotherapy, which could be administered before, after or before and after surgery. It has been demonstrated that perioperative chemotherapy can reduce the risk of cancer relapse and should be considered as the standard of care for most patients with resectable colorectal liver metastases. However perioperative chemotherapy has also potential disadvantages. This review will summarize the current data on the rationale, benefits and potential disadvantages of perioperative chemotherapy in patients with resectable colorectal liver metastases. PMID- 20172200 TI - [The safety of perioperative bevacizumab use]. AB - AIM: Patients with colorectal cancer and liver metastases can benefit from preoperative chemotherapy and liver disease resection. Adjunction of bevacizumab (BV) to chemotherapy improves survival in these patients, but its impact on surgical complications remains to be fully determined. METHODS: We reviewed all studies addressing mortality and morbidity following hepatectomy in patients preoperatively treated with a combination of BV and chemotherapy. RESULTS: All available data are retrospective. For all patients, the interval between BV and surgery was at least one month. As compared to chemotherapy alone, they demonstrate no significant increase of the incidence of surgical complications, including wound healing delays, hepatocellular insufficiency, infections, and bleeding. CONCLUSION: We still recommend managing an interval of at least 6 weeks from discontinuation of bevacizumab to hepatic resection, and at least 4 weeks from surgery to retreatment with bevacizumab. This recommendation is based on retrospective data and small numbers of patients, all indicating that BV use has no deleterious impact on postoperative morbidity and mortality. PMID- 20172201 TI - [Does bevacizumab have a protective effect on hepatotoxicity induced by chemotherapy?]. AB - Although the prognosis of patients with colorectal liver metastases (CLM) has improved dramatically with oxaliplatin and irinotecan, the enthusiasm for the preoperative use of these cytotoxic agents is being tempered by concerns about their impact on the nontumoral liver parenchyma. Bevacizumab, an anti-angiogenic agent that specifically targets the vascular endothelial growth factor, exerts an antitumor effect by inhibiting the development of the vascular network that is promoted by the tumor and mandatory for its growth. Yet angiogenesis is also a physiologic event contributing to wound healing and tissue regeneration. To date, it is well documented that the use of bevacizumab in combination with cytotoxic agents greatly improves pathologic response. Also well described is the protective effect of bevacizumab against sinusoidal injuries induced by oxaliplatin-based chemotherapy. Up to now, no side effects related to the perioperative use of bevacizumab have been reported in the setting of liver resection for CLM, and bevacizumab was shown not to impair liver regeneration following portal vein embolization. The clinical consequences of the protective effect of bevacizumab against sinusoidal injuries are hard to evaluate as patient selection and preparation have improved and these improvements contribute greatly to the favorable outcomes following liver resection for CLM. Indeed, patient safety in the setting of hepatic resection for CLM mainly depends on a careful preoperative evaluation of liver volumes and a limited use of cytotoxic agents followed by a delay of at least 5 weeks before the surgery. PMID- 20172202 TI - [Chemotherapy's hepatotoxicity: what is the impact on surgery?]. AB - Hepatotoxic effect of oxaliplatin and irinotecan on the non-tumourous liver parenchyma has been reported. These two main drugs have been linked to injuries such as vascular changes (sinusoidal obstruction syndrome (SOS) and chemotherapy associated steatohepatitis (CASH)). Oxaliplatin-based regimens have been associated with an increased risk of vascular lesions and irinotecan-containing regimens have been also associated with increased risks of steatosis and steatohepatitis. SOS increased morbidity after major liver resection, mostly after administration of more than six cycles of neoadjuvant systemic chemotherapy. CASH increased morbidity and mortality rates after hepatectomy. Preliminary results demonstrated that the addition of targeted molecular therapy (bevacizumab or cetuximab) to conventional chemotherapy does not increase the postoperative morbidity and mortality rates after hepatectomy. Furthermore, there was no additional injury to the non-tumorous liver parenchyma. PMID- 20172203 TI - Characterization of wine rennet and its kinetics by gel electrophoresis. AB - The rennet of glutinous rice wine (wine rennet) is an exclusive clotting agent for Chinese Royal cheese production. Some characterizations are reported herein in an attempt to provide evidence about the use of the protease as either a rennet substitute or an accelerator in cheese making and ripening. The results showed that wine rennet was a monomeric and unglycosylated protease. The N sequencing indicated a high degree of similarity to other fungal rennets. The cleavage sites of wine rennet on oxidized insulin B chain identified by HPLC-mass spectrometry included Gln(4)-His(5), Ala(14)-Leu(15), Leu(15)-Tyr(16), Tyr(16) Leu(17), and Phe(24)-Phe(25) at pH 6.5, which were similar to those observed for Mucor rennet, but different from calf chymosin except for Leu(15)-Tyr(16). A comparison study of the kinetic properties of wine rennet on bovine caseins with that of rennets from calf and Mucor miehei by gel electrophoresis showed that these rennets had similar coagulation efficiency but different reaction rates. Wine rennet exhibited a higher degree of degradation than the calf and Mucor enzymes at pH 6.5 and 40 degrees C. Therefore, wine rennet would be an adjunct for calf rennet or an accelerator in cheese making. PMID- 20172204 TI - The effect of storage temperatures and packaging methods on properties of Motal cheese. AB - The effects of storage temperature (+4 degrees C and -18 degrees C) and packaging method (nonvacuum and vacuum) on biogenic amines in Motal cheese during storage periods were investigated. In addition, dry matter, titratable acidity, total nitrogen, water-soluble nitrogen, trichloroacetic acid-soluble nitrogen, phosphotungstic acid-soluble nitrogen, free amino group (proteolysis), electrophoretic patterns of casein, and amounts of lactic acid bacteria and coliforms were determined. Storage period had a significant effect on all of the biogenic amines. When compared with vacuum packaging, normal packaging had higher amounts of putrescine, cadaverine, histamine, and tyramine. Coliforms were not found at detectable levels (<100cfu/g) in all cheese samples. Results of urea PAGE analysis of cheese samples were in good agreement with biogenic amine results and other proteolysis parameters. PMID- 20172205 TI - A novel real-time polymerase chain reaction-based method for the detection and quantification of lactose-fermenting Enterobacteriaceae in the dairy and other food industries. AB - The presence of lactose-fermenting Enterobacteriaceae and coliforms is routinely assessed to determine the hygienic quality of water and foods, particularly dairy products. This paper reports the use of lacZ-specific primers in an SYBR green I based real-time PCR method for the easy and rapid detection of coliforms in dairy products. A large number of bacterial species were assayed to establish the specificity of the method. The sensitivity of the method was assessed using artificially contaminated cheeses. The limit of detection was 1 coliform cell in cheese samples enriched for 8h in a culture medium. The entire procedure, including sample processing, enrichment, DNA extraction, and real-time PCR amplification, can be completed within 10 to 12h, making it a single-day assay. PMID- 20172206 TI - Major proteins of the goat milk fat globule membrane. AB - Fat is present in milk as droplets of triglycerides surrounded by a complex membrane derived from the mammary epithelial cell called milk fat globule membrane (MFGM). Although numerous studies have been published on human or bovine MFGM proteins, to date few studies exist on MFGM proteins from goat milk. The objective of this study was thus to investigate the protein composition of the goat MFGM. Milk fat globule membrane proteins from goat milk were separated by 6% and 10% sodium dodecyl sulfate-PAGE and were Coomassie or periodic acid-Schiff stained. Most of MFGM proteins [mucin-1, fatty acid synthase, xanthine oxidase, butyrophilin, lactadherin (MFG EGF-8, MFG-E8), and adipophilin] already described in cow milk were identified in goat milk using peptide mass fingerprinting. In addition, lectin staining provided a preliminary characterization of carbohydrate structures occurring on MFGM proteins from goat milk depending on alpha(S1) casein genotype and lactation stage. We provide here first evidence of the presence of O-glycans on fatty acid synthase and xanthine oxidase from goat milk. A prominent difference between the cow and the goat species was demonstrated for lactadherin. Indeed, whereas 2 polypeptide chains were easily identified by peptide mass fingerprinting matrix-assisted laser desorption/ionization-time of flight analysis within bovine MFGM proteins, lactadherin from goat milk consisted of a single polypeptide chain. Another striking observation was the presence of caseins associated with MFGM preparations from goat milk, whereas virtually no caseins were found in MFGM extracts from bovine milk. Taken together, these observations strongly support the existence of a singular secretion mode previously hypothesized in the goat. PMID- 20172207 TI - Maintenance of breast milk Immunoglobulin A after high-pressure processing. AB - Human milk is considered the optimal nutritional source for infants. Banked human milk is processed using low-temperature, long-time pasteurization, which assures microbial safety but involves heat denaturation of some desirable milk components such as IgA. High-pressure processing technology, the subject of the current research, has shown minimal destruction of food macromolecules. The objective of this study was to investigate the influence of pressure treatments on IgA content. Moreover, bacterial load was evaluated after pressure treatments. The effects of high-pressure processing on milk IgA content were compared with those of low-temperature, long-time pasteurization. Mature human milk samples were heat treated at 62.5 degrees C for 30min or pressure processed at 400, 500, or 600MPa for 5min at 12 degrees C. An indirect ELISA was used to measure IgA in human milk whey obtained after centrifugation at 800xg for 10min at 4 degrees C. All 3 high pressure treatments were as effective as low-temperature, long-time pasteurization in reducing the bacterial population of the human milk samples studied. After human milk pressure processing at 400MPa, 100% of IgA content was preserved in milk whey, whereas only 72% was retained in pasteurized milk whey. The higher pressure conditions of 500 and 600MPa produced IgA retention of 87.9 and 69.3%, respectively. These results indicate that high-pressure processing at 400MPa for 5min at 12 degrees C maintains the immunological protective capacity associated with IgA antibodies. This preliminary study suggests that high pressure processing may be a promising alternative to pasteurization in human milk banking. PMID- 20172208 TI - Identification of angiotensin I-converting enzyme inhibitory peptides from koumiss, a traditional fermented mare's milk. AB - Angiotensin I-converting enzyme (ACE) inhibitory activities in untreated koumiss and koumiss digested with ACE, pepsin, trypsinase, and chymotrypsin were compared and analyzed. Four novel ACE inhibitory peptides (P(I), P(K), P(M), and P(P)) were purified using ultrafiltration and high performance liquid chromatography (HPLC). The classification study showed that these 4 peptides were of the true inhibitor type. The amino acid sequences of these peptides are YQDPRLGPTGELDPATQPIVAVHNPVIV, PKDLREN, LLLAHLL, and NHRNRMMDHVH, respectively. Their individual IC(50) (50% inhibitory concentration) values were as follows: 14.53+/-0.21microM, 9.82+/-0.37microM, 5.19+/-0.18microM, and 13.42+/-0.17microM. From sequence analysis, we determined that P(I) was part of beta-casein in mare's milk. The 3 peptides P(K), P(M), and P(P) did not correspond with any known milk protein. The results suggest that koumiss is rich in ACE inhibitory peptides, and the ACE inhibitors in koumiss are of the pro-drug type or a mixture of the pro drug type and the true inhibitor type. These results may provide evidence about the beneficial effects of koumiss, especially on cardiovascular health. PMID- 20172209 TI - Short communication: separation and quantification of caseins and casein macropeptide using ion-exchange chromatography. AB - The aim of this work was to improve an existing method to separate and quantify the 4 major caseins from milk samples (i.e., containing whey proteins) using ion exchange chromatography. The separation process was carried out using a mini preparative cation exchange column (1 or 5mL of column volume), using urea acetate as elution buffer at pH 3.5 with a NaCl gradient. All 4 major caseins were separated, and the purity of each peak was assessed using sodium dodecyl sulfate-PAGE. Purified casein fractions were also added to raw milk to confirm their elution volumes. The quantification was carried out using purified caseins in buffer as well as added directly to fresh skim milk. This method can also be employed to determine the decrease in kappa-casein and the release of the casein macropeptide during enzymatic hydrolysis using rennet. In this case, the main advantage of using this method is the lack of organic solvents compared with the conventional method for separation of macropeptide (using reversed phase HPLC). PMID- 20172210 TI - Interrelationships between herd-level reproductive performance measures based on intervals from initiation of the breeding program in year-round and seasonal calving dairy herds. AB - In year-round calving herds, reproductive performance has traditionally been described in relation to each cow's calving date. This research described reproductive performance in year-round and seasonal calving dairy herds using herd-level measures based on interval from each cow's initiation of breeding program date, and assessed interrelationships between such measures. A large, prospective, single cohort study, implemented in 1997 and 1998, included 29,327 cows from 167 Australian dairy herds. Herd reproductive performance was described using 2 measures of primary importance to herd managers: the proportion of cows that became pregnant by 6wk after their initiation of breeding program date (6-wk pregnancy rate) and the proportion of cows that were nonpregnant 21wk after their initiation of breeding program date (21-wk nonpregnancy rate). Measures that contribute to these primary measures (secondary measures) were calculated for each herd for both the first and second 3-wk periods of each cow's breeding program; submission rates were calculated as proportions of cows that were inseminated at least once in the 3-wk period, and conception rates were calculated as the proportions of inseminations in the 3-wk period that resulted in pregnancy. The individual herd was the unit of analysis. The study results indicate that high submission rates are essential if herd reproductive performance is to be achieved. Six-week pregnancy rate was predicted to increase by 6 to 8 percentage points following a 10-percentage-point increase in submission rates in both 3-wk periods, and by 6 to 10 percentage points following a 10-percentage-point increase in conception rates. Submission rates were more variable than conception rates, indicating that managers may be able to achieve large increases in submission rates more easily than substantial increases in conception rates. However, the predicted benefits of increasing submission rates were greatest when conception rates were high and vice versa, highlighting the need to improve both submission and conception rates when both are low. The study results indicate that some herd managers can concurrently achieve high submission and conception rates. PMID- 20172211 TI - Naturally occurring mastitis effects on timing of ovulation, steroid and gonadotrophic hormone concentrations, and follicular and luteal growth in cows. AB - The effects of naturally occurring subclinical chronic or clinical short-term mastitis on time of ovulation, plasma steroid and gonadotropin concentrations, and follicular and luteal dynamics were examined in 73 lactating Holstein cows. Cows were sorted by milk somatic cell count and bacteriological examination into an uninfected group (n=22), a clinical mastitis group (n=9; events occurring 20+/ 7 d before the study), and a subclinical chronic mastitis group (n=42). In addition, uninfected and mastitic cows were further sorted by their estrus to ovulation (E-O) interval. About 30% of mastitic cows (mainly subclinical) manifested an extended E-O interval of 56+/-9.2h compared with 28+/-0.8h in uninfected cows and 29+/-0.5h in the other 70% of mastitic cows. In mastitic cows with extended E-O interval, the concentration of plasma estradiol at onset of estrus was lower than that of uninfected cows or mastitic cows that exhibited normal E-O intervals (3.1+/-0.4, 5.8+/-0.5, and 5.5+/-0.5 pg/mL, respectively). The disruptive effect of mastitis on follicular estradiol probably does not involve alterations in gonadotropin secretion because any depressive effects of mastitis on pulsatile LH concentrations were not detected. Cortisol concentrations did not differ among groups. The preovulatory LH surge in mastitic cows with delayed ovulation varied among individuals, being lower, delayed, or with no surge noted compared with the normal LH surge exhibited by uninfected cows or mastitic cows with normal E-O interval (6.8+/-0.7 ng/mL). The diameter of the second-wave dominant follicle was larger and the number of medium follicles was smaller in uninfected and subclinical cows with normal intervals compared with subclinical cows with extended intervals (13.4+/-0.5 vs. 10.9+/-0.9mm, and 3.8+/-0.2 vs. 6.7+/-0.14 follicles, respectively). Mid-luteal progesterone concentrations were similar in uninfected and mastitic cows. These results indicate for the first time that around 30% of cows with subclinical chronic mastitis exhibit delayed ovulation that is associated with low plasma concentrations of estradiol and a low or delayed preovulatory LH surge. PMID- 20172212 TI - Supplementation of progesterone via controlled internal drug release inserts during ovulation synchronization protocols in lactating dairy cows. AB - Our objective was to determine the effect of exogenous progesterone (P4) during a timed artificial insemination (TAI) protocol on pregnancies per AI (P/AI) in dairy cows not previously detected in estrus. Lactating cows (n=3,248) from 7 commercial dairy herds were submitted to a presynchronization protocol (2 injections of PGF(2alpha) 14 d apart; Presynch), and cows in estrus after the second PGF(2alpha) received AI (EDAI; n=1,583). Cows not inseminated by 12 to 14 d after the second PGF(2alpha) injection were submitted to a TAI protocol (GnRH on d 0, PGF(2alpha) on d 7, and GnRH+TAI 72h after PGF(2alpha)). At onset of the TAI protocol, cows were balanced by parity and days in milk and assigned randomly to receive no exogenous P4 (control, n=803) or a controlled internal drug release (CIDR) insert containing 1.38g of P4 from d 0 to 7 (CIDR, n=862). Blood samples were collected at the second PGF(2alpha) injection of the Presynch and on the day of the first GnRH injection of the TAI protocol for P4 determination. When P4 in both samples was <1 ng/mL, cows were classified as anovular, whereas cows having at least 1 sample >or=1 ng/mL were classified as cyclic. Concentration of P4 at 11 to 14 d after AI was determined in a subgroup of cows (n=453) from 2 herds. Pregnancy was diagnosed at 40+/-5 and 65+/-5 d after AI. Proportion of cows inseminated on estrus after the second PGF(2alpha) injection of the Presynch protocol differed among herds (range=26.7 to 59.8%). Overall P/AI for EDAI cows at 40+/-5 and 65+/-5 d were 36.2 and 33.7%, respectively, and pregnancy loss was 8.8%. Proportion of cyclic cows at the onset of the TAI protocol differed among herds (range from 66.5 to 86.3%), but did not differ between treatments (control=72.4%, CIDR=74.1%). Treatment affected P/AI at 40+/-5 (control=33.3%, CIDR=38.1%) and 65+/-5 (control=30.0%, CIDR=35.1%) d after AI but did not affect pregnancy loss (8.6%). Cyclic cows had greater P/AI at 40+/-5 (38.2 vs. 29.3%) and 65+/-5 d (35.1 vs. 26.1%) after AI, but cyclic status had no effect on pregnancy loss. Treatment affected P4 concentration after AI, with more CIDR cows having P4 >or=1 ng/mL (94.4 vs. 86.9%) and P4 >or=3.2 ng/mL (81.8 vs. 68.0%) at 11 to 14 d after AI compared with control cows. Treatment of cows not previously detected in estrus with a CIDR insert during a TAI protocol increased proportion of cows with functional CL after AI and P/AI. PMID- 20172213 TI - Assessment of lameness prevalence and associated risk factors in dairy herds in England and Wales. AB - Visits were made to 205 dairy farms in England and Wales between October 2006 and May 2007 by 1 or more of 4 researchers. At each visit, all milking cows were locomotion scored (lameness scored) using a 4-point scale (0=sound locomotion, 1=imperfect locomotion, 2=lame, 3=severely lame). The mean prevalence of lameness (scores 2 and 3) across the study farms was 36.8% (range=0-79.2%). On each farm, the presence within the housing and grazing environments of commonly reported risks for increased lameness was recorded. Each farmer was interviewed to gauge the ability of the farm staff to detect and treat lameness. A multivariable linear regression model was fitted. Risk factors for increased lameness were the presence of damaged concrete in yards, cows pushing each other or turning sharply near the parlor entrance or exit, cattle grazing pasture also grazed by sheep, the use of automatic scrapers, not treating lame cows within 48h of detection, and cows being housed for 61 d or longer at the time they were locomotion scored by the visiting researcher. Having a herd consisting entirely of a breed or breeds other than Holstein-Friesian was associated with a reduction in lameness prevalence compared with having a herd consisting entirely of Holstein-Friesians. PMID- 20172214 TI - Increasing the revenues from automatic milking by using individual variation in milking characteristics. AB - The objective of this study was to quantify individual variation in daily milk yield and milking duration in response to the length of the milking interval and to assess the economic potential of using this individual variation to optimize the use of an automated milking system. Random coefficient models were used to describe the individual effects of milking interval on daily milk yield and milking duration. The random coefficient models were fitted on a data set consisting of 4,915 records of normal uninterrupted milkings collected from 311 cows kept in 5 separate herds for 1 wk. The estimated random parameters showed considerable variation between individuals within herds in milk yield and milking duration in response to milking interval. In the actual situation, the herd consisted of 60 cows and the automatic milking system operated at an occupation rate (OR) of 64%. When maximizing daily milk revenues per automated milking system by optimizing individual milking intervals, the average milking interval was reduced from 0.421 d to 0.400 d, the daily milk yield at the herd level was increased from 1,883 to 1,909 kg/d, and milk revenues increased from euro498 to euro507/d. If an OR of 85% could be reached with the same herd size, the optimal milking interval would decrease to 0.238 d, milk yield would increase to 1,997 kg/d, and milk revenues would increase to euro529/d. Consequently, more labor would be required for fetching the cows, and milking duration would increase. Alternatively, an OR of 85% could be achieved by increasing the herd size from 60 to 80 cows without decreasing the milking interval. Milk yield would then increase to 2,535 kg/d and milk revenues would increase to euro673/d. For practical implementation on farms, a dynamic approach is recommended, by which the parameter estimates regarding the effect of interval length on milk yield and the effect of milk yield on milking duration are updated regularly and also the milk production response to concentrate intake is taken into account. PMID- 20172215 TI - Measures of weight distribution of dairy cows to detect lameness and the presence of hoof lesions. AB - There is increasing interest in automated methods of detecting lame cows. Hoof lesion data and measures of weight distribution from 61 lactating cows were examined in this study. Lame cows were identified with different numerical rating scores (NRS) used as thresholds (NRS >3 and NRS >or=3.5) for lameness. The ratio of weight applied to a pair of legs (LWR) when the cow was standing was calculated using a special weigh scale, and the cows were gait scored using a 1 to 5 NRS. Hoof lesions were scored and the cows placed into 1 of 4 mutually exclusive categories of hoof lesion: a) no lesions, b) moderate or severe hemorrhages, c) digital dermatitis, and d) sole ulcers. Regression analysis and receiver operating characteristic (ROC) curves were used to analyze the relation between hoof lesions and LWR. A clear relationship was found between NRS and LWR for the cows with sole ulcers (R(2)=0.79). The LWR could differentiate cows with sole ulcers from sound cows with no hoof lesions [area under the curve (AUC)=0.87] and lame cows from nonlame cows with lameness thresholds NRS >3 (AUC=0.71) and NRS >or=3.5 (AUC=0.88). There was no relationship between LWR and NRS for cows with digital dermatitis. Measurement of how cows distribute their weight when standing holds promise as a method of automated detection of lameness. PMID- 20172216 TI - Effect of heat treatment of bovine colostrum on bacterial counts, viscosity, and Immunoglobulin G concentration. AB - A study was conducted to identify the optimal temperature and time at which heat treatment of bovine colostrum would least change viscosity and IgG concentrations yet reduce bacterial count. First-milking colostrum with >50g of immunoglobulins/L (measured by colostrometer) was collected from 30 Holstein cows. Aliquots of colostrum were heated for 0, 30, 60, or 90min at 57, 60, or 63 degrees C in a water bath. Samples were examined for viscosity, IgG(1), and IgG(2) concentrations, standard plate count, coagulase-negative staphylococci, environmental streptococci, coliform, gram-negative noncoliform, Streptococcus agalactiae, and Staphylococcus aureus counts. All heat treatments reduced counts of all bacteria groups measured compared with untreated colostrum samples. Heat treatment at >or=60 degrees C denatured IgG(1) compared with untreated colostrum; however, colostral IgG(2) levels were not reduced when temperature was held at 60 degrees C for <60min. Viscosity was not affected when temperature was held at 60 degrees C for <60min. In this study, heat treatment of bovine colostrum at 60 degrees C for 30 or 60min reduced bacterial count, slightly reduced IgG concentration, and did not affect viscosity. PMID- 20172217 TI - Effect of days to conception in the previous lactation on the risk of death and live culling around calving. AB - The objective was to quantify the effect of days to conception (days open) in the previous parity on the risk of death and live culling (excluding the disposal reasons "dairy purposes" and "death") in the proximity of a subsequent calving in Holstein cows enrolled in the Dairy Herd Improvement program. After edits, 2,075,834 observations of cows calving between 2001 and 2007 in herds located in 36 US states primarily east of the Mississippi river were available. The period at risk included the time between 14 d before expected calving to 60 d after calving. Days open were categorized in 6 periods: 0 to 45 d, 46 to 90 d, 91 to 150 d, 151 to 210 d, 211 to 300 d, and 301 to 600 d after calving in the previous parity. Other variables of interest included parity, length of the dry period before calving, relative last test-day milk yield before dry off before calving, season of calving, and the cow's relative 305-d mature equivalent (305ME) milk yield before calving. Control variables were calving year, herd size, and relative herd 305ME milk yield. All variables were categorized. Generalized mixed models were used and included herd as random effect. Interactions between days open and the variables of interest were included in the models. Least squares means for the risk of death between -14 and 60 d after calving were 2.5, 2.5, 2.9, 3.6, 4.4, and 5.8% for increasing categories of days open. Similarly, for the same categories, least squares means for the risk of live culling were 4.5, 5.0, 5.4, 6.1, 6.9, and 8.1%. The effect of days open on the risk of death was slightly greater for third-parity cows, for long dry periods, for cows with low test-day milk yield before dry off before calving, for spring calvings, and for intermediate relative 305ME milk yield before calving. Similar trends for these interactions were found for the risk of live culling, except for relative 305ME milk yield before calving, where the effect of days open was more pronounced for high-producing cows. In conclusion, increased days open in the previous parity were associated with a greater risk of death and live culling around calving. PMID- 20172218 TI - The effect of injectable butaphosphan and cyanocobalamin on postpartum serum beta hydroxybutyrate, calcium, and phosphorus concentrations in dairy cattle. AB - The objective of this study was to determine the effect of an injection of 10% butaphosphan and cyanocobalamin (Catosal, Bayer, Shawnee Mission, KS) on the day of calving and 1 d later on the prevalence of subclinical ketosis in dairy cattle in the early postpartum period. Cows from 4 herds (n=1,122) were randomized to receive either 25mL of 10% butaphosphan and cyanocobalamin or 25mL of sterile water subcutaneously on both days. Each milliliter of Catosal contained 0.05mg of cyanocobalamin and 100mg of butaphosphan, which provided 17.3mg of P in the form of [1-(butylamino)-1-methylethyl]-phosphonic acid. Serum was sampled for beta hydroxybutyrate (BHBA) concentration at calving (pretreatment) and again between 3 and 10 d in milk. A subset of samples from mature cows was also evaluated for serum Ca and P concentrations. When cows from all age groups were included in the analysis, there was no difference between the median serum BHBA concentrations of cows in the 2 treatment groups, and no difference in the proportion of hyperketonemic cows (serum BHBA >or=1,200micromol/L) during the first week postpartum. When the analysis was restricted to mature cows (lactation >or=3), both the median BHBA concentration and the proportion of hyperketonemic cows were significantly lower in the treatment group than in the placebo group. Serum Ca and P concentrations did not differ between treatment groups. Our results suggest that injection of butaphosphan and cyanocobalamin on the day of calving and 1 d later may decrease the prevalence of subclinical ketosis during the week after calving in mature dairy cows, but not in first- and second-lactation animals. PMID- 20172219 TI - Pharmacokinetics of progesterone in lactating dairy cows: gaining some insights into the metabolism from kinetic modeling. AB - Progesterone pharmacokinetics were analyzed for plasma hormone concentrations ranging from linear to saturated metabolism in lactating Holstein cows with differing daily milk yields. The adequacy of 2-coupled first-order (bi exponential equation), hyperbolic (Michaelis-Menten equation), and sigmoidal (Hill equation) kinetic models to describe the experimental progesterone pharmacokinetic profiles was examined on a statistical basis. After nonlinear regression and statistical analysis of the data-fitting capability, a simple one compartment model based on Hill equation proved to be most adequate. This model indicates an enzyme-catalyzed metabolism of progesterone involving cooperative substrate-binding sites, resulting from allosteric effects that yield a sigmoidal saturation rate curve. Kinetic parameters were estimated for 2 groups of lactating Holstein cows with different daily milk yields. We found, for the first time, a remarkable quantitative agreement of the Hill coefficient value with that reported in pharmacokinetic studies involving cytochrome P450, family 3, subfamily A (CYP3A)-mediated reactions in other mammals, humans included. It seems that positive cooperativity makes enzymes much more sensitive to plasma progesterone concentration, and their activities can undergo significant changes in a narrow range of concentration as characteristic of sigmoidal behavior. Therefore, the values of classical pharmacokinetic parameters, such as the elimination constant, half-life, and clearance rate, were found to be highly dependent on the plasma progesterone concentration. PMID- 20172220 TI - Up-regulation of expression of interferon-stimulated gene 15 in the bovine corpus luteum during early pregnancy. AB - Interferon-tau (IFNT), the pregnancy recognition signal in ruminant species, is secreted by conceptus trophectoderm cells and induces expression of IFN stimulated gene 15 (ISG15) in the uterus and corpus luteum (CL) in ewes. Expression of ISG15 in ovine CL is speculated to be through an endocrine pathway, but it is unclear whether expression of ISG15 in bovine CL is via such a pathway. In this study, CL were obtained from cows on d 16, 25, 60, 120, 180, and 270 of pregnancy, and endometrium, mammary gland, ovarian stroma, and CL were also collected from cows on d 18 of pregnancy and on d 15 and 18 of the estrous cycle. All tissue explants from d 15 of the estrous cycle were cultured in the absence or presence of 100ng/mL of recombinant bovine IFNT for 24h. The results indicated that ISG15 and conjugated proteins were expressed in CL of both cyclic and pregnant cows regardless of pregnancy status and were upregulated during early pregnancy. The mammary gland from d 18 of pregnancy did not express ISG15, but explants of the mammary gland from d 15 of the estrous cycle did express ISG15 after being treated with IFNT. However, luteal explants from d 15 of the estrous cycle did not express ISG15 after being cultured for 24h. In conclusion, ISG15 expression is upregulated in the bovine CL during early pregnancy. Interestingly, cultured CL cells do not respond to IFNT, suggesting that the pregnancy-dependent stimulation of ISG15 expression is controlled by something other than IFNT in the bloodstream. PMID- 20172221 TI - Effect of a high cornstarch diet on hepatic cytochrome P450 2C and 3A activity and progesterone half-life in dairy cows. AB - In the cow, inadequate concentrations of progesterone during gestation may lead to an abrupt termination of pregnancy. The primary organ involved in progesterone catabolism is the liver, which contains an abundance of cytochrome P450 isozymes (EC 1.14.14.1; mixed-function monooxygenases). The objectives of the current experiment were to determine the effect of feeding 2 isoenergetic and isonitrogenous diets, formulated to cause divergent insulin secretion, on hepatic cytochrome P450 2C (CYP2C) and 3A (CYP3A) activity as well as the resulting biological half-life of progesterone. Twenty-two Holstein cows averaging 80+/-7 d in milk were randomly assigned to either a high cornstarch diet or a high fiber diet in a crossover experimental design consisting of two 14-d periods. Dry matter intake, milk yield, milk lactose yield, and milk lactose percentage were similar between the 2 diets. Milk fat yield and milk fat percentage were higher in cows fed the high fiber diet, whereas milk protein yield tended to be higher and milk protein percentage was higher in cows fed the high cornstarch diet. Energy balance tended to be improved by 57% in cows consuming the high cornstarch diet. Insulin concentrations at the time of liver biopsy (3.16+/-0.04h post feeding) were increased by 44% in cows consuming the high cornstarch diet compared with cows consuming the high fiber diet. Cytochrome P450 2C activity was decreased by 45%, whereas CYP3A activity tended to be lowered by 34% in cows consuming the high cornstarch diet. Cytochrome P450 2C mRNA expression tended to be decreased by 21% in cows fed the high cornstarch diet, whereas CYP3A mRNA expression was not different between the dietary treatments. The fractional rate constant of progesterone decay was not different between the 2 diets; however, the half-life of progesterone tended to be longer in cows fed the high cornstarch diet compared with cows fed the high fiber diet (85 vs. 64min, respectively). In summary, cows consuming the high cornstarch diet had increased insulin concentrations and lower hepatic CYP2C and CYP3A activity and tended to have a longer progesterone half-life compared with cows consuming the high fiber diet. Feeding diets that stimulate insulin secretion could alter progesterone clearance during lactation, when dairy cows have increased rates of progesterone inactivation because of high energy demands and increased DMI. PMID- 20172222 TI - Contribution of the female reproductive tract to low fertility in postpartum lactating dairy cows. AB - Infertility in dairy cattle is a multifactorial problem that may be linked to follicle development and the quality of the ovulated oocyte, to sperm transport and fertilization, to the reproductive tract environment, or to a combination of these factors. Using a state-of-the-art endoscopic embryo transfer technique, the aim of this study was to compare the ability of the reproductive tract of postpartum dairy cows and nulliparous heifers to support the development of early embryos to the blastocyst stage. Bovine embryos of 2 to 4 cells (n=1,800) were produced by in vitro maturation and fertilization of oocytes derived from the ovaries of slaughtered cattle. The estrus cycles of nulliparous Holstein heifers (n=10) and postpartum Holstein cows (n=8, approximately 60 d postpartum) were synchronized using an 8-d controlled internal drug release device coupled with prostaglandin injection. On d 2, one hundred 2- to 4-cell embryos were endoscopically transferred to the oviduct ipsilateral to the corpus luteum. Five days later, on d 7, the oviduct and uterus were flushed nonsurgically to recover the embryos. The number of embryos developing to the blastocyst stage was recorded immediately at recovery and following overnight culture in vitro. A representative number of blastocysts from heifers and cows were stained to assess cell number. Progesterone concentrations were lower in cows than in heifers on d 5, 6, and 7 (d 7=2.39+/-0.33 vs. 5.34+/-0.77ng/mL, respectively). More embryos were recovered from heifers than cows (79.0+/-7.0 vs. 57.2+/-11.4%). Of the embryos recovered, 33.9+/-3.6% had developed to the blastocyst stage in the heifer oviduct compared with 18.3+/-7.9% in the postpartum cow oviduct. There was no evidence of a difference in blastocyst quality as evidenced by total cell number in the blastocysts (71.2+/-5.7 vs. 67.0+/-5.3, respectively). In conclusion, the reproductive tract of the postpartum lactating dairy cow may be less capable of supporting early embryo development than that of the nonlactating heifer, and this may contribute to the lower conception rates observed in such animals. PMID- 20172223 TI - Association between Mycobacterium avium subspecies paratuberculosis infection and milk production in two California dairies. AB - The association between Mycobacterium avium ssp. paratuberculosis (MAP) and milk production was estimated on 2 California dairies using longitudinal data from 5,926 cows. Both study herds had moderate MAP seroprevalence, housed cows in freestalls, and had Johne's disease control programs. Cow MAP status was determined using both serum ELISA and fecal culture results from cows tested at dry-off and from whole-herd tests. Potential confounders were evaluated based on a causal diagram. Mixed models with 2 functions (splines) for days in milk (DIM) representing milk production pre- and postpeak used in similar studies were further modified to use each cow's observed DIM at peak and lactation length. Cows that were seropositive produced 2.5kg less 4% fat-corrected milk (FCM) per day than their seronegative herdmates. In addition, cows that were fecal-culture positive by liquid culture and confirmed by PCR produced 2.2kg less 4% FCM per day than their fecal-culture negative herdmates. The decrease in milk production in MAP test-positive compared with test-negative cows started in the second lactation. A switch in MAP status in either ELISA or fecal culture results from positive to negative had no significant association with milk production. Modified DIM functions that used the observed DIM at peak had better model fit than another function that assumed a fixed peak at 60 DIM. Cows that tested positive for MAP on serum ELISA or fecal culture produced less milk than cows that tested negative, and the association between MAP and milk production was not confounded by mastitis, elevated somatic cell counts, or uterine or metabolic cow conditions. PMID- 20172224 TI - Modulation of the bovine innate immune response by production of 1alpha,25 dihydroxyvitamin D(3) in bovine monocytes. AB - In cattle, the kidney has been the only known site for production of 1,25 dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] from 25-hydroxyvitamin D(3) [25(OH)D(3)] by 1alpha-hydroxylase (1alpha-OHase). Based on human studies, it was hypothesized that bovine monocytes could produce 1,25(OH)(2)D(3) upon activation and 1,25(OH)(2)D(3) would regulate expression of vitamin D-responsive genes in monocytes. First, the effects of 1,25(OH)(2)D(3) on bovine monocytes isolated from peripheral blood were tested. Treatment of nonstimulated monocytes with 1,25(OH)(2)D(3) increased expression of the gene for the vitamin D 24-hydroxylase (24-OHase) enzyme by 51+/-13 fold, but 1,25(OH)(2)D(3) induction of 24-OHase expression was blocked by lipopolysaccharide (LPS) stimulation. In addition, 1,25(OH)(2)D(3) increased the gene expression of inducible nitric oxide synthase and the chemokine RANTES (regulated upon activation, normal T-cell expressed and secreted) in LPS-stimulated monocytes 69+/-13 and 40+/-12 fold, respectively. Next, the ability of bovine monocytes to express 1alpha-OHase and produce 1,25(OH)(2)D(3) was tested. Activation of monocytes with LPS, tripalmitoylated lipopeptide (Pam3CSK4), or peptidoglycan caused 43+/-9, 17+/-3, and 19+/-3 fold increases in 1alpha-OHase gene expression, respectively. Addition of 25(OH)D(3) to LPS-stimulated monocytes enhanced expression of inducible nitric oxide synthase and RANTES and nitric oxide production in a dose-dependent manner, giving evidence that activated monocytes convert 25(OH)D(3) to 1,25(OH)(2)D(3). In conclusion, bovine monocytes produce 1,25(OH)(2)D(3) in response to toll-like receptor signaling, and 1,25(OH)(2)D(3) production in monocytes increased the expression of genes involved in the innate immune system. Vitamin D status of cattle might be important for optimal innate immune function because 1,25(OH)(2)D(3) production in activated monocytes and subsequent upregulation of inducible nitric oxide synthase and RANTES expression was dependent on 25(OH)D(3) availability. PMID- 20172225 TI - Application of one injection of prostaglandin F(2alpha) in the five-day Co Synch+CIDR protocol for estrous synchronization and resynchronization of dairy heifers. AB - The objective was to determine if the 5-d Co-Synch+CIDR (controlled internal drug releasing insert) protocol can be used in dairy heifers for a synchronized timed artificial insemination (TAI) with one injection of PGF(2alpha) for first and second services. In experiment 1, heifers were assigned randomly to receive 1 (n=295) or 2 (n=298) injections of PGF(2alpha) in the 5-d Co-Synch+CIDR protocol. Corpus luteum (CL) regression was measured in one replicate (n=218). No difference in pregnancy per TAI (P/TAI; 46.1 and 48.6%) or CL regression (86.9 and 92.8%) was detected for 1 versus 2 injections of PGF(2alpha), respectively. In experiment 2, nonpregnant heifers (n=86) were assigned to a resynchronized 5-d Co-Synch+CIDR with 1 PGF(2alpha)/TAI or insemination at detected estrus. There was no difference in P/TAI (52.2 and 55%) between groups. In experiment 3, nonpregnant heifers (n=110) were assigned randomly to receive a CIDR (n=54) or no CIDR insert (n=56) in the 5-d Co-Synch protocol for resynchronization of TAI. Pregnancy per TAI was lower without the CIDR device (39.3 vs. 51.8%). In a commercial field evaluation, 416 heifers were synchronized for the first and resynchronized TAI with the 5-d Co-Synch+CIDR protocol with 1 injection of PGF(2alpha). Pregnancy per TAI on d 60 was 58.2 and 47.5% for first and second TAI, respectively; there was a sire effect to the second TAI. In conclusion, the 5-d Co-Synch+CIDR protocol with 1 injection of PGF(2alpha) is an effective reproductive management program for first and second TAI in dairy heifers. PMID- 20172226 TI - Acidification of calf bedding reduces fly development and bacterial abundance. AB - Environmental stressors, such as high fly density, can affect calf well-being. Sodium bisulfate (SBS) is an acidifier that reduces the pH of flooring and bedding, creating a medium that neither bacteria nor immature flies (also known as larvae or maggots) can thrive in. Two experiments were conducted to investigate the application of SBS to a mixture of rice hull calf bedding and calf slurry (BED) to reduce house fly (Musca domestica L.) larval density and the abundance of bacteria. In experiment 1, dish pans containing 1L of BED and 3,000 house fly eggs were treated with SBS at concentrations of 0, 8.9, 17.7, and 26.5g of SBS/0.05m(2) of BED (CON, LOW, MED, and HIGH, respectively), with each SBS concentration applied to 4 individual pans (16 pans total). Reapplication of the same SBS concentrations in each pan occurred 3 times/wk throughout the 23-d trial. Larval house fly survival was significantly reduced in all pans with SBS relative to CON pans, with lowest survival rates in the MED and HIGH pans (99% and 100% reduction, respectively). The mean pH for each treatment was inversely related to the SBS concentration. In experiment 2, pans containing 1L of BED and 3,000 house fly eggs were treated with either 0g of SBS (CON), 8.9g of SBS/0.05m(2) of BED with reapplication of the acidifier 3 times/wk (SB3x), or 8.9g of SBS/0.05m(2) of BED applied only once at 48h before the end of the 8 d trial (SB48). Larval house fly survival and bacterial concentrations were reduced (90% larval reduction and 68% bacterial reduction) in the SB3x treatment relative to the CON. Mean pH was also reduced in SB3x pans relative to CON or SB48 pans. Overall, acidification of calf BED using the acidifier SBS resulted in a reduction of bacteria and house fly larval survival. This form of fly control might be expected to reduce adult fly production and, therefore, fly-related stress in calves. PMID- 20172227 TI - Short communication: survey of fresh cow management practices of dairy cattle on small and large commercial farms. AB - The objective was to conduct a survey of current fresh cow management practices that have an effect on health and diseases postpartum considering different herd sizes of commercial dairy farms. A mail survey regarding aspects of the fresh cow program including general management issues, calving, diseases, and veterinary service was conducted utilizing a convenience sample. A total of 429 survey forms were returned (12.0% response rate) and could be used for final analysis. Only 21.6% of the farms had a designated fresh cow pen. Almost every farm executed some type of fresh cow examination. Only 18.5% of farm managers documented the observations. Most of the dairy managers used more or less subjective criteria such as general appearance (97.0%) and appetite (69.7%). Only a minority of the responding dairy managers monitored their fresh cows using objective (fever 33.6%) or semiquantitative measures (subclinical ketosis 2.8%; body condition score 36.4%). On most farms, the veterinarian visited the herd only if needed (72.6%). Most cases of retained fetal membranes were treated by manual removal (72.3%) and antibiotic pills (89.5%). Several challenges and opportunities were identified to improve cow management practices. PMID- 20172228 TI - Technical note: variation in daily milk yield calculations for dairy cows milked in an automatic milking system. AB - An accurate estimation of the daily milk yield of dairy cows milked in an automatic milking system is not obvious because of variations in milking intervals and frequencies. Daily harvested milk varies substantially, and developing a method to be used for estimating daily milk production is of great importance. Three calculation methods (simple, semiadvanced, and advanced) were used. The simple method calculated rough daily milk production by summing up the yield per day. The semiadvanced used yield in combination with time since last milking to calculate the milk production per hour between milking; an average of the milk production per hour over the day was calculated and multiplied by 24. The advanced method calculated the milk production from midnight to midnight by using information about yield and time since last milking to calculate the exact milk production. The results show a clear preference for the advanced calculation method because the variation [variation for the advanced method=ln(1.79) for first lactation and ln(2.28) for later lactations] between days was reduced significantly (3 to 4 times lower compared with the simple method). Variation in daily harvested milk can be used as a management tool. PMID- 20172229 TI - Variability in in situ ruminal degradation parameters causes imprecision in estimated ruminal digestibility. AB - The ruminal digestibility of dietary ingredients is frequently estimated with degradation parameters (e.g., rate and extent of degradation). Mean degradation parameters (e.g., those in a feed library) are often used, but limited data suggest considerable variation around these means, potentially leading to imprecise digestibility estimates. This experiment quantified degradation parameter variation for forage hays and determined the impact of this variation on the precision of ruminal digestibility estimates. Degradation data were those previously published by our laboratory and included degradation rate, lambda(d) (h(-1)), fraction instantly degraded, a (g x g(-1)), potential extent of degradation, (a + b) (g x g(-1)), and fraction not instantly degraded that is potentially degradable, b (g x g(-1)) of alfalfa, grass, and grass-legume hays. Ruminal digestibilities of chemical fractions (dry matter, neutral detergent fiber, acid detergent fiber, hemicellulose, crude protein) were estimated using these data. Ninety-five percent confidence limits of digestibility were determined using propagation of uncertainty with measured standard deviations of degradation parameters. Values for coefficients of variation of degradation parameters were large; averaged across chemical fractions, they were 24.8, 28.6, 20.7, and 12.6% for lambda(d), a, b, and (a + b). Ninety-five percent confidence limits of digestibility were large (80.5% of digestibility means) and often overlapped each other, even when digestibility means differed greatly numerically. Consequently, digestibility values computed with mean degradation parameters may have little biological and practical significance. When uncertainty in all parameters but lambda(d) was set to zero (lambda(d) alone had uncertainty), 95% confidence limits still encompassed 54.5% of digestibility means. Thus, uncertainty in lambda(d) alone caused considerable imprecision in estimated digestibility. These results caution against using mean degradation parameters to estimate digestibility. PMID- 20172230 TI - Replacement of starch from corn with nonforage fiber from distillers grains and soyhulls in diets of lactating dairy cows. AB - Forty Holstein cows were used in a completely randomized design with a 2-wk covariate period followed by a 6-wk experimental period to evaluate incremental substitution of nonforage fiber provided by dried distillers grains with solubles (DDGS) and soyhulls (SH) for starch provided by corn in the diet. Diets provided decreasing concentrations of starch: 29% starch with 0% DDGS; 26% starch with 7% DDGS; 23% starch with 14% DDGS; and 20% starch with 21% DDGS. Diets contained 27% corn silage, 22% alfalfa hay, and 51% concentrate mix and were formulated to be 17% crude protein, 4.7% fat, and 23% neutral detergent fiber from forage. Total neutral detergent fiber increased as DDGS and SH were included in the diet. Soyhulls were included in a linear fashion along with DDGS to replace soybean meal and expeller soybean meal, thereby maintaining a similar crude protein content across diets. Dry matter intake decreased linearly; consequently, feed efficiency tended to increase linearly as starch was replaced by nonforage fiber. There was no effect of diet on milk production or milk fat and protein percentage or yield. Milk fatty acid profiles were similar across diets. Other response variables, including 4% fat-corrected milk, total solids, and milk urea nitrogen, were unaffected by dietary treatments. Ruminal volatile fatty acid concentration did not differ between diets. Concentrations of blood glucose and beta hydroxybutyrate were similar across diets. Results from this research suggest that nonforage fiber from DDGS can partially substitute for starch from corn in dairy cow diets without affecting milk production and milk composition. Economic analysis of the diets showed that feeding DDGS and SH in substitution of corn was cost-effective. Results from this experiment indicate that DDGS and SH can replace corn as an energy source to decrease feed costs. PMID- 20172231 TI - Control of Escherichia coli O157:H7 in corn silage with or without various inoculants: efficacy and mode of action. AB - This study aimed to evaluate the effectiveness of 3 commercial bacterial inoculants at controlling Escherichia coli O157:H7 in corn silages during ensiling and feedout phases of silage production. A second objective was to determine whether the inoculants exhibited and transferred antibacterial activity against E. coli O157:H7 to the silages. Chopped corn forage was ensiled after treatment with the following: distilled water (control); 5 x 10(5) cfu/g of E. coli O157:H7 (EC); EC and 1 x 10(6) cfu/g of Pediococcus pentosaceus and Propionibacterium freudenreichii (EC+BII); EC and 1 x 10(6) cfu/g of Lactobacillus buchneri (EC+LB); and EC and 1 x 10(6) cfu/g of L. buchneri and P. pentosaceus (EC+B500). Each treatment was ensiled in triplicate in mini silos for 3, 7, 31, and 82 d and analyzed for pH and E. coli O157:H7 counts. Samples from d 82 were also analyzed for volatile fatty acids, lactate, and aerobic stability. Antibacterial activity of inoculants and silages was determined by the Kirby Bauer disc diffusion test. The pH of silages from all treatments decreased below 4 within 3 d of ensiling and remained low until d 82. Therefore, E. coli O157:H7 was not detected in silages after any of the ensiling durations. Applying inoculants containing L. buchneri resulted in less lactate, more acetate, and greater aerobic stability compared with the control. Applying EC+BII containing P. freudenreichii did not increase propionate or aerobic stability. Subsamples of d 82 silages were reinoculated with 1 x 10(5) cfu/g of E. coli O157:H7 either immediately after silo opening on d 82 or after 144h of aerobic exposure (d 88), and E. coli were enumerated 24h later. All silages reinoculated with the pathogen on d 82 had similar, low pH values (<4) and no E. coli were detected 24h later. Control, EC, and EC+BII silages reinoculated with the pathogen after 144h of aerobic exposure had relatively greater pH values (4.71, 5.67, and 6.03, respectively) and E. coli counts (2.87, 6.73, and 6.87 log cfu/g, respectively) 24h later, whereas those treated with L. buchneri had low pH values (<4) and undetectable (EC+B500) or 10-fold lower (1.97, cfu/g; EC+LB) E. coli counts. All pure cultures of commercial bacterial inoculants exhibited antibacterial activity independent of pH against E. coli O157:H7, but the pH-independent activity did not persist in the treated silages, suggesting that E. coli elimination from silages was mediated by pH reduction. PMID- 20172232 TI - Effect of milk replacer program on digestion of nutrients in dairy calves. AB - There are concerns with feeding young dairy calves amounts of milk solids approaching 0.9kg of dry matter (DM) or more because of slumps in average daily gain (ADG) at weaning and low starter intakes. Additionally, programs feeding more than 0.6kg of DM have not been thoroughly tested for success at different weaning ages. Four milk replacer (MR) programs were compared in trial 1. Program A was 0.44kg of DM of a 21% crude protein (CP), 21% fat MR powder fed daily for 42 d. Program B was 0.66kg of DM of a 27% CP, 17% fat MR powder fed daily for 42 d. Program C was 0.66kg of DM of a 27% CP, 17% fat MR powder daily fed for 28 d. Program D was up to 1.09kg of DM of a 29% CP, 21% fat MR daily fed for 49 d. Digestibility estimates were made and blood was sampled for serum constituents on d 53 to 56, and performance was measured for 84 d. Three programs feeding a 27% CP, 17% fat MR powder were compared in trial 2 over 56 d. Calves on program A were fed 0.66kg of DM powder daily and weaned at 28 d. Calves on program B were fed 0.66kg of DM powder daily and weaned at 42 d. Calves on program C were fed up to 1.09kg of DM powder daily and weaned at 42 d. Digestibility estimates were made and blood was sampled for serum constituents d 21 to 24, d 36 to 39, and d 53 to 56. In trial 1, calves fed program A had the least overall ADG. Calves fed program D had the greatest ADG from 0 to 56 d, the least ADG from d 56 to 84, the least digestibility estimates, and the least concentrations of serum amylase. At 84 d, there were no differences in body weights of calves fed programs B, C, and D. In trial 2, calves fed program A had the greatest starter intake and greatest concentrations of serum amylase. Calves fed program C had the least estimates of digestibility from d 53 to 56 and the least serum concentrations of amylase. Calves fed up to 1.09 kg/d of 27 to 29% MR powders and weaned at 42 or 49 d had lower starter intakes, concentrations of serum amylase, and digestion of starter postweaning compared with calves fed conventional 21% CP, 21% fat MR powders fed at 0.44 kg/d. Calves fed 0.66 kg/d of a 27% CP, 17% fat MR powder and weaned at 28 or 42 d of age had no reductions in intake or digestion compared with calves fed conventional MR and gained as much total body weight from 0 to 84 d as calves stepped up to 1.09kg of MR. PMID- 20172233 TI - Effects of an acute feed restriction at the onset of the seasonal breeding period on reproductive performance and milk production in pasture-grazed dairy cows. AB - Reproduction and milk production responses were compared between dairy cows offered a high (HPA; n=453 in 4 replicates) or low (LPA; n=317 in 3 replicates) pasture allowance for the first 14 d after the planned start of mating (d 0 of experiment) in 2 seasonal, pasture-based dairy herds. Estimated pasture dry matter intake (DMI) between d -1 and 13 were 14.3+/-2.8 and 8.0+/-1.7kg of DM/cow per day for HPA and LPA cows, respectively. The LPA cows produced 22% less energy corrected milk during the 14-d feeding treatment period, and milk yield remained less in LPA cows at d 53 despite all cows receiving pasture allowances to support DMI of 16kg of dry matter/cow per day from d 14 onwards. The 3-wk submission rate (percentage of cows inseminated at least once from d 0 to 20) and the 3- and 6-wk pregnancy rates of LPA cows (88, 45, and 71%, respectively) were lower than those of HPA cows (94, 53, and 78%, respectively), but conception rates to first (50%) or second (47%) service and final pregnancy rates (93%) did not differ between treatments. These results quantify the immediate and subsequent responses in reproductive performance and milk production to a severe restriction in DMI at the onset of a seasonal breeding period in pasture-grazed dairy cows. PMID- 20172234 TI - Effects of dietary supplementation of rumen-protected conjugated linoleic acid to grazing cows in early lactation. AB - Conjugated linoleic acids (CLA) are potent anticarcinogens in animal and in vitro models as well as inhibitors of fatty acid synthesis in mammary gland, liver, and adipose tissue. Our objective was to evaluate long-term CLA supplementation of lactating dairy cows in tropical pasture on milk production and composition and residual effects posttreatment. Thirty crossbred cows grazing stargrass (Cynodon nlemfuensis Vanderyst var. nlemfuensis) were blocked by parity and received 150 g/d of a dietary fat supplement of either Ca-salts of palm oil fatty acids (control) or a mixture of Ca-salts of CLA (CLA treatment). Supplements of fatty acids were mixed with 4 kg/d of concentrate. Grazing plus supplements were estimated to provide 115% of the estimated metabolizable protein requirements from 28 to 84 d in milk (treatment period). The CLA supplement provided 15 g/d of cis-9,trans-11 and 22g of cis-10,trans-12. Residual effects were evaluated from 85 to 112 d in milk (residual period) when cows were fed an 18% crude protein concentrate without added fat. The CLA treatment increased milk production but reduced milk fat concentration from 2.90 to 2.14% and fat production from 437 to 348 g/d. Milk protein concentration increased by 11.5% (2.79 to 3.11%) and production by 19% (422 to 504 g/d) in the cows fed CLA. The CLA treatment decreased milk energy concentration and increased milk volume, resulting in unchanged energy output. Milk production and protein concentration and production were also greater during the residual period for the CLA-treated cows. The CLA treatment reduced production of fatty acids (FA) of all chain lengths, but the larger effect was on short-chain FA, causing a shift toward a greater content of longer chain FA. The CLA treatment increased total milk CLA content by 30% and content of the trans-10,cis-12 CLA isomer by 88%. The CLA treatment tended to decrease the number of days open, suggesting a possible effect on reproduction. Under tropical grazing conditions, in a nutritionally challenging environment, CLA-treated cows decreased milk fat content and secreted the same amount of milk energy by increasing milk volume and milk protein production. PMID- 20172235 TI - Estimation of rumen outflow in dairy cows fed grass silage-based diets by use of reticular sampling as an alternative to sampling from the omasal canal. AB - A study was conducted to compare nutrient flows determined by a reticular sampling technique with those made by sampling digesta from the omasal canal. Six lactating dairy cows fitted with ruminal cannulas were used in a design with a 3 x 2 factorial arrangement of treatments and 4 periods. Treatments were 3 grass silages differing mainly in neutral detergent fiber (NDF) concentrations: 412, 530, or 639 g/kg of dry matter, each combined with 1 of 2 levels of concentrate feed. Digesta was collected from the reticulum and the omasal canal to represent a 24-h feeding cycle. Nutrient flow was calculated using the reconstitution system based on 3 markers (Co, Yb, and indigestible NDF) and using (15)N as a microbial marker. Large and small particles and the fluid phase were recovered from digesta collected at both sampling sites. Bacterial samples from the reticulum and the omasum were separated into liquid- and particle-associated bacteria. Reticular samples were sieved through a 1-mm sieve before isolation of digesta phases and bacteria. Composition of the large particle phase differed mainly in fiber content of the digesta obtained from the 2 sampling sites. Sampling site did not affect marker concentration in any of the phases with which the markers were primarily associated. The (15)N enrichment of bacterial samples did not differ between sampling sites. The reticular and omasal canal sampling techniques gave similar estimates of marker concentrations in reconstituted digesta, estimates of ruminal flow, and ruminal digestibility values for dry matter, organic matter, starch, and N. Sampling site x diet interactions were also not significant. Concentration of NDF was 2.2% higher in reconstituted omasal digesta than in reconstituted reticular digesta. Ruminal NDF digestibility was 2.7% higher when estimated by sampling the reticulum than by sampling the omasal canal. The higher estimate of ruminal NDF digestibility with the reticular sampling technique was due to differences in NDF concentration of reconstituted digesta. This study shows that nutrient and microbial protein outflow from the rumen can be measured using a reticular sampling technique. The reticular sampling technique provides a promising alternative to sampling from the omasal canal because there is less interference with the animal and it does not require advanced sampling equipment. PMID- 20172236 TI - Effects of spontaneous heating on forage protein fractions and in situ disappearance kinetics of crude protein for alfalfa-orchardgrass hays packaged in large round bales. AB - During 2006 and 2007, forages from 3 individual hay harvests were used to assess the effects of spontaneous heating on concentrations of crude protein (CP), neutral detergent insoluble CP (NDICP), acid detergent insoluble CP (ADICP), and in situ disappearance kinetics of CP and NDICP for large round bales of mixed alfalfa (Medicago sativa L.) and orchardgrass (Dactylis glomerata L.). Over the 3 harvests, 96 large round bales were made at preset bale diameters of 0.9, 1.2, or 1.5m and at moisture concentrations ranging from 9.3 to 46.6%. Internal bale temperatures were monitored daily during an outdoor storage period. The change in concentrations of NDICP (poststorage - prestorage) increased with heating degree days (HDD) >30 degrees C in a relationship best explained with a nonlinear model {Y=24.9 - [22.7 x (e(-0.000010 x x x x))]; R(2)=0.892} that became asymptotic at +24.9 percentage units of CP, thereby indicating that NDICP increases rapidly within bales that heat spontaneously. When maximum internal bale temperature (MAX) was used as the independent variable, the best regression model was quadratic and the coefficient of determination was still relatively high (R(2)=0.716). The change in concentrations of ADICP (poststorage - prestorage; DeltaADICP) also increased with HDD and was best fitted to a nonlinear model {Y=14.9 - [15.7 x (e(-0.0000019 x x x x))]} with a very high coefficient of determination (R(2)=0.934). A similar quartic response was observed for the regression of DeltaADICP on MAX (R(2)=0.975). Increases in DeltaADICP as a result of heating (HDD or MAX) were paralleled by concurrent increases in hemicellulose at relatively low increments of heating, but the inverse relationship was observed as hemicelluloses likely became reactive and concentrations decreased in more severely heated hays. Changes in ruminal disappearance rate of CP were best fitted to cubic models for regressions on both HDD (R(2)=0.939) and MAX (R(2)=0.876); these changes represented an approximate 50% rate reduction in severely heated hays relative to prestorage controls. Within ranges of heating most commonly encountered under field conditions, changes in rumen-degradable protein decreased in a primarily linear relationship with HDD or MAX. However, the mean change in rumen-degradable protein for the 4 most severely heated hays was only -2.6 percentage units of CP, which represents a minimal reduction from prestorage controls and is far less than the maximum of -7.9 percentage units of CP observed with less-severe heating. Interpretation of these results was complicated by poor recovery of NDICP from our most severely heated hays following machine rinsing of 0-h Dacron bags; theoretically, and by definition, this unrecovered pool of NDICP is assumed to be entirely degradable in the rumen. It remains unclear whether these responses could be corroborated in vivo or by other analytical techniques, or whether the magnitude of HDD or MAX for our most severely heated hays exceeds the reliable limits for estimating RDP via in situ methodology. PMID- 20172237 TI - Technical note: common analytical errors yielding inaccurate results during analysis of fatty acids in feed and digesta samples. AB - The basic rules governing the proper fatty acid analysis of feed and digesta samples are sometimes overlooked, leading to potential errors in reporting the fatty acid content or composition of feed and digesta samples. The direct transesterification procedure of Sukhija and Palmquist (1988, J. Agric. Food Chem. 36:1202-1206) has become popular in analyzing fatty acids in feed and digesta samples obtained from animal feeding trials. One shortcoming of the Sukhija and Palmquist transesterification procedure is inaccurate analysis of fatty acids with conjugated double bonds. Digesta and milk samples from ruminant species typically contain a multitude of conjugated linoleic acid (CLA) isomers that easily undergo isomerization and epimerization following prolonged exposure to methanolic HCl. Modifications to the Sukhija and Palmquist procedure are given in this paper that allow successful determination of CLA isomers. Errors in fatty acid analysis also occur from misuse of internal standards; use of an internal standard is recommended in the Sukhija and Palmquist procedure as the preferred method to quantify total fatty acid content. The choice of internal standard may sometimes be important for obtaining accurate results. As an example, applying the direct transesterification procedure to a fat supplement high in saturated fatty acids yielded 613 mg/g of total fatty acids when C17 was used as the internal standard compared with 930 mg/g total fatty acids when C19 was used as the internal standard. Fatty acid content further increased to 952 mg/g when a unique unsaturated fatty acid (C13:1) was used as the internal standard. PMID- 20172238 TI - Preliminary investigation on reliability of genomic estimated breeding values in the Danish Holstein population. AB - This study investigated the reliability of genomic estimated breeding values (GEBV) in the Danish Holstein population. The data in the analysis included 3,330 bulls with both published conventional EBV and single nucleotide polymorphism (SNP) markers. After data editing, 38,134 SNP markers were available. In the analysis, all SNP were fitted simultaneously as random effects in a Bayesian variable selection model, which allows heterogeneous variances for different SNP markers. The response variables were the official EBV. Direct GEBV were calculated as the sum of individual SNP effects. Initial analyses of 4 index traits were carried out to compare models with different intensities of shrinkage for SNP effects; that is, mixture prior distributions of scaling factors (standard deviation of SNP effects) assuming 5, 10, 20, or 50% of SNP having large effects and the others having very small or no effects, and a single prior distribution common for all SNP. It was found that, in general, the model with a common prior distribution of scaling factors had better predictive ability than any mixture prior models. Therefore, a common prior model was used to estimate SNP effects and breeding values for all 18 index traits. Reliability of GEBV was assessed by squared correlation between GEBV and conventional EBV (r(2)(GEBV, EBV)), and expected reliability was obtained from prediction error variance using a 5-fold cross validation. Squared correlations between GEBV and published EBV (without any adjustment) ranged from 0.252 to 0.700, with an average of 0.418. Expected reliabilities ranged from 0.494 to 0.733, with an average of 0.546. Averaged over 18 traits, r(2)(GEBV, EBV) was 0.13 higher and expected reliability was 0.26 higher than reliability of conventional parent average. The results indicate that genomic selection can greatly improve the accuracy of preselection for young bulls compared with traditional selection based on parent average information. PMID- 20172239 TI - The genetic relationship of body weight and early-lactation health disorders in two experimental herds. AB - The objectives of this study were to estimate genetic parameters for body weight (BW) and BW change (BWC) and genetic correlations of BW and BWC with diseases and genomic predicted transmitting abilities (PTA) of productive and conformation traits of Holsteins during the first 120 DIM. Daily BW data were from the Afiweigh cow body weighing system (SAE Afikim, Kibbutz Afikim, Israel), which records BW as a cow exits the milking parlor. Disease categories included metabolic diseases, ketosis, infectious diseases, mastitis, reproductive diseases, and other diseases. Edited data included 68,914 and 11,615 daily BW observations from 441 Pennsylvania State University and 72 Virginia Tech Holstein cows, respectively. Two-trait random regression models were used to estimate relationships between BW, BWC, and diseases at 25, 38, and 58 mo of age at calving. Fixed effects for BW were age at calving nested within lactation group, week of lactation, and herd date; random effects for BW included animal, permanent environment, and error. Fixed effects for disease were herd-year-season of calving and age at calving nested within lactation group; random effects for disease were animal, permanent environment (for mastitis only), and error. Correlations of PTA for BW and BWC with genomic PTA for productive and type traits were also estimated with data from 117 cows. Heritability estimates for daily BW ranged from 0.34 to 0.63. Greater BW and less BWC were favorably correlated with ketosis, metabolic diseases, infectious diseases, and other diseases. The genetic correlation estimate between BW and ketosis was strongest at 60 DIM (-0.51), and genetic correlation estimates at 60 DIM with metabolic diseases (-0.52), infectious diseases (-0.81), and other diseases (-0.48) followed the same trend as ketosis. The genetic correlation estimate between BWC and ketosis was strongest for the change from 5 to 20 DIM (0.70) and was similar for metabolic diseases (0.37), infectious diseases (0.74), and other diseases (0.49). Correlations of BW and BWC with reproductive diseases tended to be in the reverse direction of those reported for ketosis. A larger PTA for BW was significantly correlated with smaller genomic PTA for milk yield, dairy form, rear udder height, and udder cleft. Predicted transmitting ability for BWC was negatively correlated with genomic PTA for protein percentage, strength, and hip width (ranging from -0.26 to -0.13 across lactation) and was positively correlated with dairy form, rear udder height, and udder cleft (ranging from 0.20 to 0.37 across lactation). Selection for reduced BW loss can be implemented with automated body weighing systems and may be successful in decreasing disease incidence in the early stages of lactation. PMID- 20172240 TI - A model for the genetic evaluation of number of clinical mastitis cases per lactation in Czech Holstein cows. AB - Cases of mastitis from 9,550 lactations of 6,242 cows were recorded on 5 farms in the Czech Republic from 1996 to 2008. The number of clinical mastitis (CM) cases per cow adjusted to a lactation length of 305 d was analyzed with 4 linear single trait animal models and one 3-trait model, which also included lactation mean somatic cell score (SCS) and 305-d milk yield. Factors included in the model of choice were parity, combined effect of herd and a 2-yr calving period, calving season, permanent environmental effect of the cow, and additive genetic effect of the cow. From both the single-trait and multiple-trait models, estimated heritability of number of CM cases was 0.11 (+/-0.015 for the multiple-trait model). Permanent environmental effects accounted for approximately one-third of the phenotypic variance. Heritability estimates for lactation mean SCS and 305-d milk yield were 0.17+/-0.019 and 0.25+/-0.011, respectively, and genetic correlations of these traits with number of CM cases were 0.80+/-0.059 and 0.34+/ 0.079, respectively. Genetic evaluation of the number of CM cases in Czech Holsteins could be carried out including data from all parities using a 3-trait animal model with SCS and milk yield as additional traits. PMID- 20172241 TI - Quantitative trait loci mapping of calving and conformation traits on Bos taurus autosome 18 in the German Holstein population. AB - Linkage, linkage disequilibrium, and combined linkage and linkage disequilibrium analyses were performed to map quantitative trait loci (QTL) affecting calving and conformation traits on Bos taurus autosome 18 (BTA18) in the German Holstein population. Six paternal half-sib families consisting of a total of 1,054 animals were genotyped on 28 genetic markers in the telomeric region on BTA18 spanning approximately 30 Mb. Calving traits, body type traits, and udder type traits were investigated. Using univariately estimated breeding values, maternal and direct effects on calving ease and stillbirth were analyzed separately for first- and further-parity calvings. The QTL initially identified by separate linkage and linkage disequilibrium analyses could be confirmed by a combined linkage and linkage disequilibrium analysis for udder composite index, udder depth, fore udder attachment, front teat placement, body depth, rump angle, and direct effects on calving ease and stillbirth. Concurrence of QTL peaks and a similar shape of restricted log-likelihood ratio profiles were observed between udder type traits and for body depth and calving traits, respectively. Association analyses were performed for markers flanking the most likely QTL positions by applying a mixed model including a fixed allele effect of the maternally inherited allele and a random polygenic effect. Results indicated that microsatellite marker DIK4234 (located at 53.3 Mb) is associated with maternal effects on stillbirth, direct effects on calving ease, and body depth. A comparison of effects for maternally inherited DIK4234 alleles indicated a favorable, positive correlation of maternal and direct effects on calving. Additionally, the association of maternally inherited DIK4234 marker alleles with body depth implied that conformation traits might provide the functional background of the QTL for calving traits. For udder type traits, the strong coincidence of QTL peaks and the position of the QTL in a region previously reported to harbor QTL for somatic cell score indicated that effects of QTL for udder type traits might be correlated with effects of QTL for udder health traits on BTA18. Our results suggest that loci in the middle to telomeric region on BTA18 with effect on conformation traits may also contribute to the genetic variance of calving and udder health traits. Further analyses are required to identify the causal mutations affecting conformation and calving traits and to investigate the correlation of effects for loci associated with conformation, calving, and udder health traits. PMID- 20172242 TI - Relationships between milk yield and somatic cell score in Canadian Holsteins from simultaneous and recursive random regression models. AB - Multiple-trait random regression animal models with simultaneous and recursive links between phenotypes for milk yield and somatic cell score (SCS) on the same test day were fitted to Canadian Holstein data. All models included fixed herd test-day effects and fixed regressions within region-age at calving-season of calving classes, and animal additive genetic and permanent environmental regressions with random coefficients. Regressions were Legendre polynomials of order 4 on a scale from 5 to 305 d in milk (DIM). Bayesian methods via Gibbs sampling were used for the estimation of model parameters. Heterogeneity of structural coefficients was modeled across (the first 3 lactations) and within (4 DIM intervals) lactation. Model comparisons in terms of Bayes factors indicated the superiority of simultaneous models over the standard multiple-trait model and recursive parameterizations. A moderate heterogeneous (both across- and within lactation) negative effect of SCS on milk yield (from -0.36 for 116 to 265 DIM in lactation 1 to -0.81 for 5 to 45 DIM in lactation 3) and a smaller positive reciprocal effect of SCS on milk yield (from 0.007 for 5 to 45 DIM in lactation 2 to 0.023 for 46 to 115 DIM in lactation 3) were estimated in the most plausible specification. No noticeable differences among models were detected for genetic and environmental variances and genetic parameters for the first 2 regression coefficients. The curves of genetic and permanent environmental variances, heritabilities, and genetic and phenotypic correlations between milk yield and SCS on a daily basis were different for different models. Rankings of bulls and cows for 305-d milk yield, average daily SCS, and milk lactation persistency remained the same among models. No apparent benefits are expected from fitting causal phenotypic relationships between milk yield and SCS on the same test day in the random regression test-day model for genetic evaluation purposes. PMID- 20172243 TI - Evidence of genetic resistance of cattle to infection with Mycobacterium bovis. AB - Anecdotal evidence points to genetic variation in resistance of cattle to infection with Mycobacterium bovis, the causative agent of bovine tuberculosis (BTB), and published experimental evidence in deer and cattle suggests significant genetic variation in resistance and reactivity to diagnostic tests. However, such genetic variation has not been properly quantified in the United Kingdom dairy cattle population; it is possible that it exists and may be a factor influencing the occurrence of BTB. Using models based on the outcome of the process of diagnosis (ultimate fate models) and on the outcome of a single stage of diagnosis (continuation ratio models, herd test-date models), this study shows that there is heritable variation in individual cow susceptibility to BTB, and that selection for milk yield is unlikely to have contributed to the current epidemic. Results demonstrate that genetics could play an important role in controlling BTB by reducing both the incidence and the severity of herd breakdowns. PMID- 20172244 TI - Genomic predictions for New Zealand dairy bulls and integration with national genetic evaluation. AB - A method is described for the prediction of breeding values incorporating genomic information. The first stage involves the prediction of genomic breeding values for genotyped individuals. A novel component of this is the estimation of the genomic relationship matrix in the context of a multi-breed population. Because not all ancestors of genotyped animals are genotyped, a selection index procedure is used to blend genomic predictions with traditional ancestral information that is lost between the process of deregression of the national breeding values and subsequent re-estimation using the genomic relationship matrix. Finally, the genomically enhanced predictions are filtered through to nongenotyped descendants using a regression procedure. PMID- 20172245 TI - Polymorphisms in the bovine lactoferrin promoter are associated with reproductive performance and somatic cell count. AB - Lactoferrin plays an important role in the innate immune system, with well characterized antibacterial, antiviral, and immune modulatory properties. The objective of this study was to determine the allele and haplotype frequency of polymorphisms at positions -586, -190, and -28 of the bovine lactoferrin promoter in Holstein-Friesians and to quantify their association with performance using phenotypic data on progeny from 848 sires. Associations between genotypes and performance were quantified using weighted mixed models with genotyped individuals included as a random effect, and average expected relationships among individuals accounted for through a numerator relationship matrix. The dependent variables were daughter yield deviation for production traits and deregressed predicted transmitting ability for calving interval and functional survival. The C to T polymorphism at -586, which distorts a putative activating protein 2 (AP 2) binding site, was associated with a shorter calving interval and higher somatic cell score. The G to A polymorphism at -190, located in a putative selective promoter factor 1 (SP-1) binding site, was associated with a longer calving interval and decreased functional survival. A third polymorphism (A to C) at position -28, found within the noncanonical TATA box, had a tendency to associate with functional survival. On the basis of the data we proposed a haplotype combination that was associated with improved reproductive performance in the Holstein-Friesian breed. We hypothesized that the observable phenotypic associations with lactoferrin promoter polymorphisms can potentially be explained by allele-specific differences in constitutive or inducible levels of gene expression. The lack of a pleiotropic effect of the single nucleotide polymorphisms studied on both fertility and milk production traits strengthens the importance of these polymorphisms, or at least the lactoferrin promoter, in selection for improved fertility. PMID- 20172246 TI - Short communication: milk protein genetic variation and casein haplotype structure in the Original Pinzgauer cattle. AB - Milk protein genetic polymorphisms are often used for characterizing domesticated mammalian species and breeds, and for studying associations with economic traits. The aim of this work was to analyze milk protein genetic variation in the Original Pinzgauer, a dual-purpose (dairy and beef) cattle breed of European origin that was influenced in the past by human movements from different regions as well as by crossbreeding with Red Holstein. A total of 485 milk samples from Original Pinzgauer from Austria (n=275) and Germany (n=210) were typed at milk proteins alpha(S1)-casein, beta-casein, kappa-casein, alpha-lactalbumin, and beta lactoglobulin by isoelectrofocusing to analyze the genetic variation affecting the protein amino acid charge. The Original Pinzgauer breed is characterized by a rather high genetic variation affecting the amino acid charge of milk proteins, with a total of 15 alleles, 12 of which were found at a frequency >0.05. The most polymorphic protein was beta-casein with 4 alleles detected. The prevalent alleles were CSN1S1*B, CSN2*A(2), CSN1S2*A, CSN3*A, LGB*A, and LAA*B. A relatively high frequency of CSN1S2*B (0.202 in the whole data set) was found, mainly occurring within the C-A(2)-B-A haplotype (in the order CSN1S1-CSN2-CSN1S2 CSN3), which seems to be peculiar to the Original Pinzgauer, possibly because the survival of an ancestral haplotype or the introgression of Bos indicus. PMID- 20172247 TI - The carbon footprint of dairy production systems through partial life cycle assessment. AB - Greenhouse gas (GHG) emissions and their potential effect on the environment has become an important national and international issue. Dairy production, along with all other types of animal agriculture, is a recognized source of GHG emissions, but little information exists on the net emissions from dairy farms. Component models for predicting all important sources and sinks of CH(4), N(2)O, and CO(2) from primary and secondary sources in dairy production were integrated in a software tool called the Dairy Greenhouse Gas model, or DairyGHG. This tool calculates the carbon footprint of a dairy production system as the net exchange of all GHG in CO(2) equivalent units per unit of energy-corrected milk produced. Primary emission sources include enteric fermentation, manure, cropland used in feed production, and the combustion of fuel in machinery used to produce feed and handle manure. Secondary emissions are those occurring during the production of resources used on the farm, which can include fuel, electricity, machinery, fertilizer, pesticides, plastic, and purchased replacement animals. A long-term C balance is assumed for the production system, which does not account for potential depletion or sequestration of soil carbon. An evaluation of dairy farms of various sizes and production strategies gave carbon footprints of 0.37 to 0.69kg of CO(2) equivalent units/kg of energy-corrected milk, depending upon milk production level and the feeding and manure handling strategies used. In a comparison with previous studies, DairyGHG predicted C footprints similar to those reported when similar assumptions were made for feeding strategy, milk production, allocation method between milk and animal coproducts, and sources of CO(2) and secondary emissions. DairyGHG provides a relatively simple tool for evaluating management effects on net GHG emissions and the overall carbon footprint of dairy production systems. PMID- 20172248 TI - Extended lactations in a seasonal-calving pastoral system of production to modulate the effects of reproductive failure. AB - This study was conducted to determine whether extending the calving interval (CI) to 24 mo would be an alternative to culling and replacing cows that had failed to become pregnant. Forty-six nonpregnant lactating cows were assembled in November 2004 and assigned to receive either 3kg (low) or 6kg (high) of concentrate supplement and a basal diet of grass silage and maize silage over the winter period (13 wk). Cows returned to pasture in late March and received 1kg of concentrate/d until dry-off (milk yield <5 kg/d). Cumulative milk production was calculated from calving to the end of November 2004 (12-mo CI) and from the start of December 2004 until dry off in 2005 (extended lactation part of 24-mo CI). High winter feeding resulted in greater milk production over the winter confinement (20.0+/-0.3 vs. 17.8+/-0.3 kg/d for high and low winter feeding, respectively) and had a carryover effect during the remainder of the 24-mo CI period (5,177 vs. 4,686kg; SEM=173kg). At the end of the study, cows were ranked on cumulative milk solids and separated into 3 groups (R1, R2, and R3). During the 24-mo CI, milk yields were 7,287, 6,267, and 5,273kg (SEM=308kg) in yr 1, and 5,738, 4,836, and 4,266 (SEM=241kg) in yr 2 for R1, R2, and R3, respectively. Eighty-five percent of the cows became pregnant during the breeding season of yr 2, with a conception rate to first service of 52%. An economic analysis of different ranks with a 12-mo CI, a 24-mo CI, and an annualized herd effect, which compared an efficient spring calving system with 30% recycled cows in R1 and 10% recycled cows in R3, was carried out. Farm profit was reduced by 60% and 65% at a milk price of 22.3 euro-cents (c)/L with the corresponding values of 17% and 30% for a milk price of 30 c/L, respectively, when R1 and R3 systems were compared with an efficient spring milk (12-mo CI) production system. Within a spring system where 30% and 10% of R1 and R3 animals were subjected to extended lactations, the profit difference was reduced compared with an efficient spring system, The results indicated that lactations with a 24-mo CI may be a viable alternative to culling nonpregnant cows and be economically more suited to higher producing cows. PMID- 20172249 TI - Debunking the myth of the hard-to-reach farmer: effective communication on udder health. AB - Worldwide, programs to control mastitis are implemented using different strategies to reach farmers. Even though education materials and best practices may be technically optimal, they need to be used to be successful. Thus, effective communication with farmers is essential in order to change their behavior and to improve their farm management. During a Dutch national mastitis control program, a substantial number of farmers seemed to be hard to reach with information on udder health. Consequently, this study was designed to provide insight into the attitude and motivation of such farmers. In the period of October 2007 to July 2008, 24 in-depth, semistructured interviews were conducted with farmers whose veterinarians considered to be difficult to approach with advice on udder health management (8 practices, 3 farmers from each practice). The interviews included questions about the farms and the farmers, their attitude and behavior regarding mastitis, and their information sources and social environment. The results show that so-called hard-to-reach farmers were not always badly informed about udder health and did not always experience problems with mastitis. These ostensibly unreachable farmers were not a homogeneous group, but rather could be divided into 4 categories based on their trust in external information sources regarding mastitis and their orientation toward the outside world: proactivists, do-it-yourselfers, wait-and-see-ers, and reclusive traditionalists. There are ample opportunities to reach hard-to-reach farmers, provided that the communication strategies are tailored to their specific needs. There is especially much to gain in communication with do-it-yourselfers and wait and-see-ers, but this demands a more proactive role on the part of veterinarians and extension specialists. Different types of farmers need to be approached in different ways and through different channels with information on udder health. Consequently, this study can contribute to the optimization of future programs designed to control and prevent diseases. PMID- 20172250 TI - A survey of dairy calf management practices in Canada that affect animal welfare. AB - There is growing interest among the public in farm animal welfare and a need for methods to assess animal welfare on farm. A survey on calf rearing practices that might affect dairy calf welfare was performed via a 1-h interview on 115 dairy farms (mean +/- SD: herd size=52.5+/-20.9 cows; milk production=8,697+/-1,153L) distributed throughout the province of Quebec. Despite frequent recommendations, many dairy producers continue to use management practices that increase the health risks of milk-fed calves. Major risk factors for poor calf welfare identified were 1) no use of calving pen in 51.3% of herds and low level of surveillance of calvings, especially at nighttime (once every 12h), 2) no disinfection of newborn's navel in 36.8% of herds, and delayed identification and, hence, calf monitoring (3 d), 3) 15.6% of farms relied on the dam to provide colostrum and none checked colostrum quality or passive transfer of immunity, 4) dehorning and removal of extra teats proceeded at late ages (6.4 wk and 6.7 mo, respectively) and without adequate pain control, 5) use of traditional restrictive milk feeding and waste milk distributed to unweaned calves without precaution in 48.2% of herds, 6) abrupt weaning performed in 16.5% of herds, and 7) calves housed individually in 87.9% of herds, and most inappropriate housing systems (crate=27.0%, tie-stall=13.9%, attached against a wall=5.7%) remained. This risk factor assessment was the first step in an intervention strategy to improve calf welfare on dairy farms. PMID- 20172251 TI - Cough specialists collaborate for an interdisciplinary problem. PMID- 20172252 TI - Cough: a worldwide problem. AB - Cough is a common and important respiratory symptom that can produce significant complications for patients and be a diagnostic challenge for physicians. An organized approach to evaluating cough begins with classifying it as acute, subacute, or chronic in duration. Acute cough lasting less than 3 weeks may indicate an acute underlying cardiorespiratory disorder but is most commonly caused by a self-limited viral upper respiratory tract infection (eg, common cold). Subacute cough lasting 3 to 8 weeks commonly has a postinfectious origin; among the causes, Bordetella pertussis infection should be included in the differential diagnosis. Chronic cough lasts longer than 8 weeks. When a patient is a nonsmoker, is not taking an angiotensin-converting enzyme inhibitor, and has a normal or near-normal chest radiograph, chronic cough is most commonly caused by upper airway cough syndrome, asthma, nonasthmatic eosinophilic bronchitis, or gastroesophageal reflux disease alone or in combination. PMID- 20172254 TI - Mucus and mucins. AB - A variety of mucoactive medications are used to treat chronic lung disease. When evaluating the role of the cough, it must be considered as an important protective mechanism. Therefore, it may be more important to improve the effectiveness of cough than to suppress or eliminate a chronic cough in patients with chronic lung disease. This article discusses the composition of mucus and phlegm, the process of mucin secretion and mucus clearance, and reviews current therapy and mucolytics in use or being studied for mucus clearance disorders. PMID- 20172253 TI - Afferent nerves regulating the cough reflex: mechanisms and mediators of cough in disease. AB - Bronchopulmonary C fibers and acid-sensitive, capsaicin-insensitive mechanoreceptors innervating the larynx, trachea, and large bronchi regulate the cough reflex. These vagal afferent nerves may interact centrally with sensory input arising from afferent nerves innervating the intrapulmonary airways or even extrapulmonary afferents such as those innervating the nasal mucosa and esophagus to produce chronic cough or enhanced cough responsiveness. The mechanisms of cough initiation in health and in disease are briefly described. PMID- 20172255 TI - Cough and swallowing dysfunction. AB - The symptom of cough may result from a multitude of etiologies involving different parts of the aerodigestive tract. This article focuses on the association of cough and swallowing dysfunction in the sense that cough may be an indicator of swallow dysfunction and in the importance of cough in preventing aspiration and aspiration-related disorders. Whereas these associations have been known for a long time, research is starting to connect the dots, allowing targeting of strategies aimed at diagnosing and preventing illness in certain dysphagic patients. PMID- 20172256 TI - Vocal cord dysfunction, paradoxic vocal fold motion, or laryngomalacia? Our understanding requires an interdisciplinary approach. AB - This article presents disorders of periodic occurrence of laryngeal obstruction (POLO) resulting in noisy breathing and dyspnea and a variety of secondary symptoms. Included in this classification are glottic disorders, such as paradoxic vocal fold movement and vocal cord dysfunction. The supraglottic disorder, termed, intermittent arytenoid region prolapse or laryngomalacia, is also reviewed. Three categories of POLO are defined as irritant, exertional, and psychological. PMID- 20172257 TI - Evidence for sensory neuropathy and pharmacologic management. AB - Recent literature points to postviral sensory neuropathy as a possible cause for refractory chronic cough. Vagal neuropathy may affect the sensory branches, inducing chronic cough or laryngospasm. Although the clinical presentation is fairly well described, there is little in the way of diagnostic criteria to establish this diagnosis. This article highlights the clinical picture of this disease and the efficacy, side-effect profiles of the currently used pharmacological interventions. PMID- 20172258 TI - The role of voice therapy in the management of paradoxical vocal fold motion, chronic cough, and laryngospasm. AB - This article describes the assessment and behavioral treatment for paradoxical vocal fold motion disorder (PVFM), chronic cough, and laryngospasm. Behavioral treatment for these disorders is coordinated by the speech-language pathologist. Assessment of PVFM involves a detailed behavioral analysis of the triggers for the conditions and incorporation of the medical findings as they relate to the symptoms. Treatments developed originally by the group at the National Jewish Hospital in Denver, Colorado, and then expanded by others have been shown to reduce or eliminate the symptoms and improve overall quality of life in patients who have these diagnoses. PMID- 20172259 TI - Occupational, environmental, and irritant-induced cough. AB - Occupational and environmental irritants play a role in the pathogenesis of chronic cough. An irritant is a non-corrosive chemical, which causes a reversible inflammatory change on living tissue by chemical action at the site of contact. The clinical and pathologic spectrum of chemically induced respiratory tract irritation ranges from neurogenically mediated alterations in regional blood flow, mucus secretion, and airway caliber to the initiation of cough. In an evolutionary perspective, two types of cough reflexes were created for different protective purposes, but each type used the same anatomic and physiologic neural and muscular structures. The mechanosensory type evolved as human ancestors adapted phonation over olfaction and the larynx moved in close proximity to the esophageal opening. The chemosensory type evolved to protect against an injured lung from a respiratory tract infection or after inhaling high levels of irritant gases and particulates that accumulated in confined quarters of early times. For this latter type of cough reflex, normally quiescent transient receptor potential (TRP) cation channels TRPV1(vanilloid) and TRPA1 (ankyrin) become activated or hyperactivated after lung injury, with lung inflammation, or in response to chemicals. Although animal and laboratory investigations support the possibility of human TRPpathies, further investigations are essential for the further elucidation of the role of TRP cationic channels in instigating chronic cough in humans. PMID- 20172260 TI - Reflux and cough. AB - Reflux is a significant contributor to cough in otolaryngology practice; cough is just one marker of its many negative effects on the upper aerodigestive tract. Reflux causes cough both by direct irritation/inflammation and by increasing sensitivities to other noxious agents. Detailed and diligent clinical evaluation, including laryngoscopy, is useful in advancing the working diagnosis of reflux associated cough. Supplemental testing, including impedance monitoring of esophageal refluxate, can be important to evaluate for both acidic and nonacidic reflux exposure. The mainstay of treatment continues to be dietary and other lifestyle interventions and drug therapy. Although proton-pump inhibitor therapy is effective in most patients, especially those with acid reflux disease, prokinetic therapy is probably very important with those with combined acid and nonacid disease and those with pure nonacid disease. It is likely that failure to improve can be due to behavioral and drug compliance issues. Antireflux surgery can yield long-lasting positive outcomes in carefully selected patients despite the lower efficacy of treatment for primary upper aerodigestive tract symptoms (cough, hoarseness, sore throat) compared with heartburn and regurgitation. PMID- 20172261 TI - Rhinogenic laryngitis, cough, and the unified airway. AB - Over the past 10 years, there has been increasing recognition of the interaction between the upper and lower airways in patients with a variety of infectious and inflammatory illnesses, including allergic rhinitis, rhinosinusitis, and asthma. Epidemiologic and mechanistic links have been proposed to demonstrate these relationships and to offer possible etiologic explanations to account for these observations. Among patients with upper respiratory illnesses, cough can be seen as a common symptom, both from the direct influences of upper airway inflammation, which incite reflex changes and bronchospasm, and from the exacerbation of associated pulmonary processes, such as asthma. Despite this increasing awareness of interaction between the upper and lower airways, the influence of both upstream and downstream respiratory inflammatory processes on laryngeal pathophysiology has not been extensively studied. Research suggests, however, that both direct stimulatory effects on the larynx and secondary effects of mucus production and mucus trafficking can create a range of laryngeal symptoms, including cough. This review discusses the interaction of the upper and lower airway in respiratory disease, and focuses on the effect of these respiratory processes on laryngeal inflammation, function, and symptoms. PMID- 20172262 TI - Cough due to asthma, cough-variant asthma and non-asthmatic eosinophilic bronchitis. AB - Among the most common causes of chronic cough are asthma (25%) and nonasthmatic eosinophilic bronchitis (10%). In asthma, cough may present as an isolated symptom, in which case it is known as cough variant asthma. Variable airflow obstruction and airway hyper-responsiveness are cardinal features of asthma, which are absent in nonasthmatic eosinophilic bronchitis. The presence of eosinophilic airway inflammation is a common feature of asthma and is a diagnostic criterion for nonasthmatic eosinophilic bronchitis. At a cellular level, mast cell infiltration into the airway smooth muscle bundle, narrowing of the airway wall, and increased interleukin-13 expression are features of asthma and not nonasthmatic eosinophilic bronchitis. In most cases, the trigger that causes the cough is uncertain, but occasionally occupational exposure to a sensitizer is identified, and avoidance is recommended. In both conditions, there is improvement following treatment with inhaled corticosteroids, which is associated with the presence of an airway eosinophilia and increased exhaled nitric oxide. Generally, response to therapy in both conditions is very good, and the limited long-term data available suggest that both usually have a benign course, although in some cases fixed airflow obstruction may occur. PMID- 20172263 TI - The spectrum of nonasthmatic inflammatory airway diseases in adults. AB - When the airways are overwhelmed by noxious particles, gases, or microorganisms, inflammatory and immune responses occur that may cause permanent structural changes. One consequence may be an overproduction of mucus and this may overwhelm mucociliary clearance mechanisms and cause a chronic cough phlegm syndrome. The expectorated mucus is usually clear or white (mucoid) but when it becomes infected, the mucus may become purulent and have a yellow or green color. Diseases associated with chronic productive cough discussed in this article include chronic bronchitis, bronchiectasis, and infectious and noninfectious bronchiolitis and their diagnosis and treatment. PMID- 20172265 TI - Assessing efficacy of therapy for cough. AB - An antitussive agent should reduce the amount of coughing experienced by the patient sufficiently for the patient to appreciate an improvement in cough severity and regard the improvement as sufficient to outweigh any adverse effects or risks associated with the treatment. In recent years the development of objective cough counting devices and cough-specific quality of life tools have vastly improved our ability to appropriately assess the effectiveness of anti tussive agents and hopefully will lead to the development of safe and effective treatments in the future. This article summarizes current knowledge of methodologies available for assessing cough therapies, the patient groups to study, and the design of clinical trials. PMID- 20172264 TI - Pharmacologic management of cough. AB - This review is an update of recent advances in our understanding of cough suppressants and impairment of cough. Low-dose oral morphine has recently been shown to significantly suppress chronic cough, but the side effect profile of this opioid may limit its widespread utility. Several studies have demonstrated a dissociation between the efficacy of antitussives in some metrics of pathologic cough and their effects on cough sensitivity to inhaled irritants. The relevance of widely used inhaled irritants in understanding pathologic cough and its response to antitussives is questionable. A recent advance in the field is the identification and measurement of an index of sensation related to cough: the urge to cough. This measure highlights the potential involvement of suprapontine regions of the brain in the genesis and potential suppression of cough in the awake human. There are no new studies showing that mucolytic agents are of value as monotherapies for chronic cough. However, some of these drugs, presumably because of their antioxidant activity, may be of use as adjunct therapies or in selected patient populations. The term dystussia (impairment of cough) has been coined recently and represents a common and life-threatening problem in patients with neurologic disease. Dystussia is strongly associated with severe dysphagia and the occurrence of both indicates that the patient has a high risk for aspiration. No pharmacologic treatments ae available for dystussia, but scientists and clinicians with experience in studying chronic cough are well qualified to develop methodologies to address the problem of impaired cough. PMID- 20172266 TI - Unexplained cough in the adult. AB - Unexplained cough is a diagnosis of exclusion that should not be made until a thorough validated diagnostic evaluation is performed, specific and appropriate validated treatments have been tried and failed, and uncommon causes have been ruled out. When chronic cough remains troublesome after the initial work up, determine that a protocol has been used that has been shown to lead to successful results. If such a protocol has been used, next consider whether or not pitfalls in management have been avoided. If they have been, the frequency of truly unexplained chronic cough usually should not exceed 10%. While patients with truly unexplained coughs have an overly sensitive cough reflex, the mere presence of an overly sensitive cough reflex does not by itself explain why they do not get better, because most patients with chronic cough, even those who respond to treatment and get better, have demonstrable heightened cough sensitivity. Management options include referral to a cough clinic with interdisciplinary expertise, speech therapy, and self-limited trials of drugs, preferentially with those shown to be effective in randomized, double-blind placebo-controlled trials in patients with unexplained chronic cough. PMID- 20172267 TI - Cough in the pediatric population. AB - Children with cough, in particular chronic cough, are sometimes referred to otolaryngologists for assessment, diagnosis, and management. Although the likely diagnoses encountered by otolaryngologists are rhinosinusitis, foreign body aspiration, and tracheomalacia, otolaryngologists should be cognizant of the many other possible diagnoses and the evidence for and against their association. This article highlights and focuses the discussion on the cough issues relevant to otolaryngologists. PMID- 20172268 TI - Future directions in treating cough. AB - Cough is a common and troublesome symptom that can be difficult to treat. New therapeutic options that are safe and more effective than those currently available are needed. In this article, the authors offer opinion on future directions in the treatment of cough, with a particular emphasis on the clinical syndrome associated with cough reflex hypersensitivity. In addition, the article provides an overview of some of the diagnostic technologies and promising drug targets likely to emerge from current clinical and scientific endeavor. PMID- 20172269 TI - Long-term outcomes of short bowel syndrome requiring long-term/home intravenous nutrition compared in children with gastroschisis and those with volvulus. AB - INTRODUCTION: Short bowel syndrome (SBS) is a malabsorptive state that occurs following extensive small intestinal resection. The most severely affected children require intravenous feeding/parenteral nutrition (PN). Two common causes in infancy/early childhood are intestinal resection for volvulus and resection of necrotic small intestine in infants with gastroschisis. The aim of this study was to review the long-term outcomes of children with severe intestinal failure who remained dependent on PN for many months or years. We evaluated the outcomes among gastroschisis cases versus those following resection of mid-gut volvulus or congenital short gut. METHODS: We reviewed the case records over a 10-year period from 1997 of children presenting by 5 years of age with volvulus and/or congenital short gut or gastroschisis and who were dependent on long-term/home PN. We obtained data regarding the diagnosis, the small intestinal length, the presence of the ileo-cecal valve, the survivals, and the incidences of weaning from PN. RESULTS: Six children underwent resection following volvulus or congenital short gut syndromes and 7 had gastroschisis. Ten of the 13 children underwent surgery as neonates and 3 from 2-5 years of age. The residual small intestinal length was <10 cm in 1, 10-25 cm in 4, 25-50 cm in 5, 50-100 cm in 2, and >100 cm in 1 case. The ileo-cecal valve was removed in 8 children. All children were treated with PN after surgery for at least 7 months. All 7 children with gastroschisis and 1 with <10 cm small intestine after intestinal resection for volvulus still required PN after 14-120 months. Three with gastroschisis died. All 5 children with volvulus and >10 cm small intestine were weaned from PN, thriving at our review 7 months-7 years later. CONCLUSIONS: Infants and young children with short gut and >10 cm small intestine gain intestinal autonomy. In contrast, those with gastroschisis have poor outcomes and should be referred for intestinal transplantation assessment more readily than those with after intestinal resection for volvulus short gut. PMID- 20172270 TI - Chronic intestinal pseudo-obstruction related to viral infections. AB - Chronic intestinal pseudo-obstruction (CIPO), one of the most severe gastrointestinal motility disorders, is a condition characterized by a clinical picture mimicking small bowel occlusion with related symptoms and signs in the absence of demonstrable mechanical obstruction. Analysis of full-thickness biopsy samples may unravel structural changes of the neuromuscular layer involving the whole gut, although the midgut is usually worst affected. Intestinal pseudo obstruction can occur in association with systemic neurological, endocrine, and connective tissue diseases or malignancy but, when no recognizable etiology is found, CIPO is referred to as idiopathic (CIIPO). The latter form can be diagnosed early in life due to a genetic etiology or in adulthood when a viral origin may be considered. This review addresses the hypothesis that some systemic neurotrophic viral infections can affect the enteric nervous system thereby altering normal peristaltic activity. Available data are reviewed, focusing specifically on herpesviruses or polyomaviruses (JC virus). These suggest that in comparison to a proportion of CIIPO patients, healthy controls rarely harbor viral DNA in the myenteric plexus, leaving open the possibility that a viral infection might have an etiologic role in the development of CIIPO. The review thus provides some new perspectives in the pathophysiology and perhaps targeted treatment of CIIPO. PMID- 20172271 TI - Natural history of intestinal failure induced by chronic idiopathic intestinal pseudo-obstruction. AB - Chronic intestinal pseudo-obstruction is a severe, often unrecognized disease characterized by disabling and potentially life-threatening complications over time. The diagnosis is based on the evidence of typical clinical manifestations, radiological evidence of distended bowel loops with air-fluid levels, and the exclusion of any organic obstruction of the gut lumen. The radiological sign of intestinal occlusion allows the distinction from enteric dysmotility, which is characterized by better outcomes. Manometry can play a supportive role in defining the diagnosis, and differences in the manometric pattern of chronic intestinal pseudo-obstruction and enteric dysmotility have been shown. The disease is often unrecognized, and the diagnosis, therefore, delayed by several years. Thus, the majority of patients undergo useless and potentially dangerous surgeries. Long-term outcomes are generally poor despite surgical and medical therapies characterized by disabling and potentially life-threatening complications over time. A substantial percentage of patients requires parenteral nutrition. Failure of this nutritional support represents an indication for small bowel transplantation. PMID- 20172272 TI - Cambridge-Miami score for intestinal transplantation preoperative risk assessment: initial development and validation. AB - INTRODUCTION: Preoperative quantification of survival after transplantation would assist in assessing patients. We have developed a preliminary preoperative scoring system, called the Cambridge-Miami (CaMi) score, for transplantation of the small intestine either alone or as a composite graft. METHODS: The score combines putative risk factors for early-, medium-, and long-term survival. Factors included were loss of venous access and impairment of organs or systems not corrected by transplantation. Each factor was scored 0-3. A score of 3 indicated comorbidity approaching a contraindication for transplantation, that which might lead to but was not currently an adverse risk factor scored 1, and that presenting a definite but moderate increase in risk scored 2. The preoperative scores of 20 patients who had received intestinal transplants either isolated or as part of a cluster graft, who had either been followed up postoperatively for at least 10 years, or died within 10 years were compared with their survivals. RESULTS: Postoperative survival and CaMi score inversely correlated when analysed using Spearman test (r(s) = -0.82; P = .0001). A score of <3 associated with survival > or =3 years (12/12 patients) and >3 with survival of <6 months (4/4). Patient Kaplan-Meier (KM) survival curves for patients grouped according to CaMi score became significantly different from group 0 to group 3. Using this as a threshold score patients grouped as either >2 or <3 had significantly different survival rates (log-rank; P = .0001), KM median survival hazard ratio (HR) = 6, and rate of death KM HR = 5. Receiver-operator characteristics indicate a high degree of accuracy for prediction of death with an area under the curve (C statistic) at 3 years of 0.98, at 5 years of 0.82, and at 10 years of 0.65. CONCLUSION: This initial validation suggested that the preoperative CaMi score predicted postoperative survival. PMID- 20172273 TI - Review of the diagnoses predisposing infants to intestinal failure on hospitalized parenteral nutrition. AB - During the last 3 decades the use of parenteral nutrition (PN) and the aggressive introduction of enteral feeding in daily practice have transformed the outcome for even the sickest of these infants. More than 90% of infants and children now survive after extensive small bowel resection in the neonatal period. During the last 3 decades the use of parenteral nutrition (PN) and the aggressive introduction of enteral feeding in daily practice have transformed the outcome for even the sickest of these children. The aim of this study was to review the diagnoses (other than infants purely premature) that predispose infants to intestinal failure (IF) and dependency on PN as well as their outcomes. A total of 63 children less than 1 year old received PN for more than 28 days including 35 (56%) boys; 29% of cases were preterm infants with a median gestational age of 26.5 weeks (range, 24-33 weeks). The median age at the start of PN was 0.25 years or 3 months. Median duration of PN treatment was 62 days and median duration of hospitalization was 128 days. Twenty-three (36.5%) children had a primary nondigestive disorder (PNDD) and 40 (63.5%), a primary digestive disorder (PDD). Forty (63.5%) children with severe intestinal failure were successfully weaned off PN; whereas 8 (13%) infants with severe gastrointestinal diseases remained dependent on IV nutrition. Fourteen (22%) patients died. Infants less than 1 year of age with severe intestinal failure have up to a 75% survival rate, with a 65% chance of achieving intestinal autonomy. For children presenting with PDD in infancy, there is a high risk of needing long-term PN. PMID- 20172274 TI - Sepsis and its etiology among hospitalized children less than 1 year of age with intestinal failure on parenteral nutrition. AB - Infections accompany intestinal failure (IF) more commonly in children than in adults, with reported incidences of 2% to 29%. Appropriate care of the central venous catheter is the most important factor preventing infections; but in addition, bacteria translocate from the dysmotile gut as a possible source of septicemia. The aim of this retrospective analysis was to investigate the rate and the epidemiologic profile of septicemia in the patient group at greatest risk, namely, children less than 1 year of age with IF on parenteral nutrition (PN). Among 63 children less than 1 year of age who were included over a 2-year period, 55% were boys. The overall median age at the start of PN was 0.3 years, with a mean duration of 80 days. Some 68% of patients had at least one episode of septicemia, experiencing a mean of 1.5 episodes (range, 1-12). Also, 19% of children displayed polymicrobial bloodstream infections. The most common Gram positive pathogens were Staphylococcus spp and Enterococcus spp; the Gram negative pathogens were Klebsiella spp followed by Enterobacter spp and E. coli. Infants less than 1 year of age with IF >28 days experienced a high (68%) rate of sepsis. There was no difference in the incidence of catheter-related blood stream infection according to the primary underlying diagnosis. The most common pathogens were Staphylococcus spp and Enterococcus spp, similar to etiologies of sepsis among children in intensive care units. PMID- 20172275 TI - Preliminary experience with alemtuzumab induction therapy combined with maintenance low-dose tacrolimus monotherapy in small-bowel transplantation in China. AB - INTRODUCTION: The goal of combining alemtuzumab induction therapy with low-dose tacrolimus monotherapy in small-bowel transplantation (SBTx) is to enable improved graft acceptance without immunologic unresponsiveness caused by stronger immunosuppression regimens. Herein, we report preliminary experience using this protocol in 5 patients who underwent SBTx in China. METHODS: Patients received methylprednisolone sodium succinate (Solu-Medrol), 1 g, followed by alemtuzumab infusion, 30 mg, during SBTx and another gram of prednisolone before reperfusion. Tacrolimus monotherapy without steroid was used for maintenance immunosuppression. Tacrolimus trough levels were 10 to 15 ng/dL during the first 3 months, and weaned to 5 to 10 ng/mL after 3 months. RESULTS: Three recipients have survived for longer than 1 year; 1 patient is currently alive at 9 months, and another at 5 months post-SBTx. Grafts in these 5 recipients achieved excellent function, and in all patients, total parenteral nutrition was discontinued at 2 to 3 weeks postoperatively and normal oral intake was resumed. One recipient died at 13 months post-SBTx of severe rejection; the condition of the other 4 recipients who were still alive was good. Pathologic analysis of ileoscopic biopsy specimens revealed 4 episodes of indeterminate to mild acute cellular rejection (ACR) at 1 to 3 months, 3 episodes of indeterminate to mild ACR at 4 to 6 months, 3 episodes of moderate ACR at 7 to 12 months, and 1 episode of severe ACR at 13 months. All episodes of indeterminate to moderate ACR were totally resolved; only treatment of severe ACR failed. One patient experienced an episode of invasive fungal infection and another episode of cytomegaloviral infection, with total recovery after treatment. CONCLUSIONS: Our preliminary experience in these 5 cases showed that the protocol combining alemtuzumab induction therapy with low-dose tacrolimus monotherapy without maintenance steroid therapy past-SBTx can effectively control rejection with excellent graft function. Nevertheless, close surveillance of ACR should be still performed after 6 months. PMID- 20172277 TI - Comprehensive surgical intestinal rescue and transplantation program in adult patients: Bologna experience. AB - INTRODUCTION: Surgical approaches to complicated benign intestinal failure are accepted worldwide, especially in the pediatric population. Intestinal transplant surgery is thought to rescue patients in whom complications of total parenteral nutrition (TPN) develop. OBJECTIVE: To report our experience with surgical intestinal rescue in an adult population with intestinal failure. PATIENTS AND METHODS: An intestinal rehabilitation program initiated at our institution included comprehensive medical rehabilitation, surgical bowel rescue, and transplantation. From 2000 to 2009, of 81 adult patients referred by our gastroenterologists for bowel rehabilitation, 42 (51,8%) underwent 43 transplantations (32 isolated intestinal grafts and 11 multivisceral grafts). Underlying diseases were primarily short-bowel syndrome, Gardner syndrome, and intestinal pseudo-obstruction. Thirty-nine patients (48,2%) underwent surgical rescue (40 cases) consisting of bowel resection, adhesiolysis, stricturoplasty, liver transplantation with portocaval hemitransposition (6 cases in 5 patients). Underlying diseases were primarily intestinal fistulas, stenosis, or perforations, short-bowel syndrome, cocoon syndrome, and complete portal thrombosis. RESULTS: After a mean (SD) follow-up of 1043 (1016) days, in the transplantation population, 21 patients (50%) are alive, with a 1-, 3-, 5-year patient survival of 76%, 59%, and 52%, respectively, and graft survival of 66%, 54%, and 48%, respectively. After 901 (404) days in the rescue population, 32 patients (82%) are alive (2 died, and 5 were lost to follow-up); in 75%, TPN 25% was discontinued, and are receiving oral feeding with TPN support. The 1- and 3 year survival rate was 100% and 83%, respectively. CONCLUSIONS: Deaths occurred primarily in the transplantation population. Intestinal surgical rescue, when possible, is optimal. PMID- 20172276 TI - Daclizumab and alemtuzumab as induction agents in adult intestinal and multivisceral transplantation: rejection and infection rates in 40 recipients during the early postoperative period. AB - BACKGROUND: Allograft rejection in intestinal transplantation occurs frequently, and bacterial, fungal, and viral infections related to strong immunosuppression regimens remain an important complication posttransplantation. Induction therapy has enabled improvement in graft and patient survival rates. OBJECTIVES: In analyze the effects of daclizumab and alemtuzumab as induction therapies on inflections complications and incidence of acute cellular rejection (ACR) during the early posttransplantation period. PATIENTS AND METHODS: Between December 2000 and August 2009, we performed 43 intestinal transplantation procedures in 42 adult recipients (median [SD] age, 34.8 [9.5] years; male-female ratio, 22:20; isolated or multivisceral graft, 32/11), and compared findings during the first 30 days posttransplantation in 40 recipients. Patients were divided into 2 groups: 12 treated with daclizumab (Zenapax; Hoffman-La Roche Ltd, Basel, Switzerland): 8 isolated intestinal grafts and 4 multivisceral grafts) and 28 treated with alemtuzumab (Campath-1H: 22 isolated intestinal grafts and 6 multivisceral grafts). Maintenance immunosuppression was based on tacrolimus and steroids in the first group and low-dose tacrolimus in the second group. RESULTS: During the first month posttransplantation, 8 daclizumab recipients (66.6%) experienced 9 episodes of mild ACR, which were successfully treated with steroid therapy, and 8 patients (66.6%) developed a bacterial infection requiring treatment. Fourteen episodes of ACR occurred in 12 alemtuzumab recipients (42.8%): 11 mild, 1 mild to moderate, and 2 moderate; 16 patients (57.1%) required treatment for infections. Five-year patient cumulative survival was 66% in daclizumab recipients and 43% in alemtuzumab recipients. Five-year graft survivals was 66% in daclizumab recipients and 41% in alemtuzumab recipients. In both groups, P was not statistically significative. CONCLUSIONS: The infection rate is considerably high with both protocols. Alemtuzumab seems to offer better immunosuppression against ACRs during the first month posttransplantation. PMID- 20172278 TI - Psychological adaptation and quality of life of adult intestinal transplant recipients: University of Bologna experience. AB - INTRODUCTION: Intestinal transplantation has become an accepted therapy for individuals permanently dependent on total parenteral nutrition (TPN) with life threatening complications. Quality of life and psychological well-being can be seen as important outcome measures of transplantation surgery. METHODS: We evaluated 24 adult intestinal transplant recipients and 24 healthy subjects (a control group). All subjects were administered the Italian Version of the Psychological Well-Being Scales (PWB) by C. Ryff, the World Health Organization Quality of Life-Brief (WHOQOL), and the Symptom Questionnaire (SQ) by R. Kellner and G.A. Fava, a symptomatology scale. Quality of life and psychological well being were assessed in transplant recipients in relationship to the number of rejections, the number of admissions, and the immunosuppressive protocol. RESULTS: Intestinal transplant recipients reported significantly higher scores in the "personal growth" category (P = .036) and lower scores in the "positive relation with others" (P = .013) and "autonomy" (P = .007) dimensions of PWB, compared with the controls. In the WHOQOL, the scores of transplant recipients were lower only in the psychological domain (P = .011). Transplant recipients reported significantly higher scores in the "somatic symptom" (P = .027) and "hostility" (P = .018) dimensions of the SQ, compared with the controls. Transplant recipients with number of admissions >8 reported higher scores in "anxiety" (P = .019) and "depression" (P = .021) scales of the SQ, and the patients with a Daclizumab protocol reported higher scores in "depression" (P = .000) and "somatic symptom" (P = .008) of the SQ. There were no significant differences regarding number of rejections and socio-demographic variables. CONCLUSION: Improvement of psychological well-being in the transplant population may be related to the achievement of the goal of transplantation: recovery of bowel function. But the data confirmed that the transplant experience required a long and difficult adaptation trial to the new condition of "transplant recipient." PMID- 20172279 TI - International grading scheme for acute cellular rejection in small-bowel transplantation: single-center experience. AB - A standardized grading scheme for the assessment of acute cellular rejection (ACR) in small-intestine transplantation was proposed in 2003 at the Eighth International Small Intestinal Transplantation Symposium. We have implemented the current grading scheme for ACR in small-bowel transplantation since October 2003. The pathologic diagnoses of those small-intestine biopsy samples, including ACR grade and other supplementary findings were evaluated. A total of 3484 small intestine biopsy samples from 155 patients were available for evaluation in this study. Frequency of grades 0, indeterminate, 1, 2, and 3 acute cellular rejection was 33.9%, 49.1%, 12.6%, 3.7%, and 0.8%, respectively. Duration of ACR episode strongly correlated with grade of ACR episode (P < .001). Other supplementary findings included acute vascular rejection component, 2.2%; increase in lymphoplasmacytic infiltrate in lamina propria, 15.7%; mucosal fibrosis, 0.4%; and regenerative changes, 0.3%. Our data substantiate that this grading system is reliable and useful for clinical decision making in bowel transplantation. We suggest that an assessment and quantification of supplementary findings be considered a component of the International Pathology Grading Scheme. PMID- 20172280 TI - Citrulline evaluation in bowel transplantation. AB - INTRODUCTION: The purpose of this study was to evaluate the correlation of plasma citrulline and rejection episodes in intestinal transplantation. METHODS: From January 2007 until present, we performed citrulline assays on our small bowel patients. We investigated the correlation of these assays with the rejection status of the patients. The rejection status of the graft was defined based on graft biopsies. RESULTS: Of 5195 citrulline samples, average serum citrulline levels decreased significantly when the patients presented a rejection episode. We found the following: no rejection, 17.38 microm/L; mild rejection, 13.05 microm/L; moderate rejection, 7.98 microm/L; and severe rejection, 6.05 microm/L. Our current emphasis is to determine the predictive power of citrulline with other biomarkers versus as a separate and isolated measurement. CONCLUSIONS: In our study, citrulline levels correlated significantly with the rejection status of the graft. Serial follow-up of the patients using this assay may alert us to the possibility of increased alloreactivity and rejection episodes. PMID- 20172281 TI - Evaluation of calprotectin level in intestinal content as an early marker for graft rejection. AB - INTRODUCTION: The diagnosis of rejection after intestinal transplantation is still performed by endoscopic biopsy monitoring. Less invasive diagnostic procedures are desirable, although they are not available so far. Calprotectin, a stable cytosolic granulocyte protein, which previously was used as a marker of inflammatory processes, has been proposed to be a biochemical marker for rejection. The aim of the present work was to analyze the concordance between calprotectin levels in intestinal content and the presence of graft rejection after small bowel transplantation. METHODS: Calprotectin level was measured using a commercial ELISA kit on 137 samples of intestinal content randomly collected during endoscopies performed on 11 intestinal transplantation patients during 2 years' follow-up. Calprotectin determinations were correlated with histological and clinical findings. The cut-off level was determined retrospectively by receiver-operator curve analysis. RESULTS: Based on histological findings and clinical records, samples were discerned as rejection positive (37 of 137), versus negative (35 of 137) samples or those with no clinical, endoscopic, or histological findings (65 of 137 samples). A cut-off value of 65 microg of calprotectin/g of intestinal content provided the best assay parameter according to the clinical findings: a 76% sensitivity and a 47% specificity. False positive results corresponded to patients with gastrointestinal infections (13%), systemic infections (13%), ulcers (10%), or nonspecific histological alterations of the mucosa (15%). The other false positive cases corresponded to postsurgical samples (4%), or patients with concomitant gastrointestinal symptoms (2%). Most false negative results (78%) were observed during recovery from severe acute rejection episodes, among successfully treated patients. In these cases, epithelial reconstitution and no mucosal infiltration was observed. If the latter group were discarded, sensitivity rose to 93%, and specificity, to 50% with a 96% negative predictive value. Furthermore, a weak correlation was observed between calprotectin levels and the severity of rejection. CONCLUSIONS: This study confirmed the results obtained by other groups: fecal calprotectin dosage showed a good sensitivity but low specificity for the diagnosis of intestinal rejection because high calprotectin levels can also be observed in other clinical conditions. Nevertheless, it might be used as a first line for continuous evaluation of intestinal transplantation status, like other biochemical parameters that are used in kidney or liver transplantation, before considering the need for a biopsy. PMID- 20172282 TI - Gene expression profiling of MicroRNAs in small-bowel transplantation paraffin embedded mucosal biopsy tissue. AB - BACKGROUND: The molecular mechanisms and regulation of immune-mediated rejection of organ allografts remains unclear. Recent studies have reported that small non coding RNAs, microRNAs (miRNAs) play a critical role in the immune system via modulation of transcription and translation. PURPOSE: We hypothesized that particular miRNAs provide regulation of an ensuing intragraft immune effector response. The aim of our study was to detect miRNAs involved in acute cellular rejection (AR) in human small intestinal allografts. MATERIALS: We examined 12 small intestinal mucosal biopsies (AR, 7 cases, all grade 2 or 3) and non rejecting (NR) allografts (5 cases, all grade 0) obtained from recipients after small bowel or multivisceral transplantation. RNA was isolated from the formalin fixed paraffin-embedded (FFPE) biopsy samples and transcribed to cDNA. After preamplification we utilized a PCR based TaqMan Low Density Array (TLDA) containing 365 mature human miRNAs. Relative quantification was done based on pooled normal intestine using a comparative Ct method. RESULTS: We identified 62 miRNA upregulated genes in small bowels with ACR, and 35 were downregulated. Forty-two miRNA genes were upregulated in non-ACR small bowel biopsy samples (grade IND), and 45 were downregulated. The relative fold change ratio of ACR to non-ACR was calculated, and 50 upregulated and 8 downregulated miRNAs were detected as significant. Several interesting miRNAs will be evaluated further from this preliminary study. Our data suggests that intragraft miRNAs are potentially involved in the activation of a host alloimmune response to donor. These miRNAs may serve as targets for appropriate intervention and may be useful to monitor the allograft status. PMID- 20172283 TI - Monitoring cytomegalovirus T-cell immunity in small bowel/multivisceral transplant recipients. AB - BACKGROUND: Cytomegalovirus (CMV) is a major cause of graft failure and posttransplantation mortality in intestinal/multivisceral transplantation. CMV infection exhibits a wide range of clinical manifestations from asymptomatic infection to severe CMV disease. STUDY'S PURPOSE: The purposes of this study were to assess the utility of measuring CMV-specific cellular immunity in bowel/multivisceral transplant recipients and to provide additional information on the risk of infection and development of CMV disease. METHODS: We studied 10 bowel/multivisceral transplant recipients to investigate the kinetics of CMV infection using real-time polymerase chain reaction (on blood and biopsy tissue samples) and CMV-specific T-cell reconstitution by Enzyme-linked ImmunoSPOT Assay (ELISPOT) that enumerates Interferon-gamma-secreting CMV-specific T cells upon in vitro stimulation with viral antigens (pp65 and IE-1). RESULTS: All patients were seropositive for CMV. According to the pattern of T-cell reconstitution occurring either within the first month after transplantation or later, patients were classified as early (n = 7) or late responders (n = 3). Clinically, early responder patients (3/7; 43%) experienced asymptomatic or mild CMV infections, whereas all late responders (3/3; 100%) developed moderate or severe CMV disease. A reduction in mean and peak CMV viral load was observed in early responders, whereas the onset time of infection did not differ significantly between early and late CMV responders. CONCLUSIONS: A good and early reconstitution of CMV specific T-cell immune responses after transplantation is a critical determinant in controlling CMV infections. Simultaneous monitoring of CMV infection and CMV specific T-cell immunity predicts T-cell-mediated control of CMV infection. PMID- 20172284 TI - Early and late virological monitoring of cytomegalovirus, Epstein-Barr virus, and human herpes virus 6 infections in small bowel/multivisceral transplant recipients. AB - BACKGROUND: Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are the major causes of graft failure and posttransplantation mortality among small bowel and multivisceral transplantations (SB/MVT). Little is known about human herpes virus 6 (HHV-6) infections in transplant recipients. STUDY PURPOSE: The purposes of this study were to analyze the clinical relevance of CMV, EBV, and HHV-6 infections after small bowel transplantation and to establish whether routine monitoring for HHV-6 infection should be recommended for the prevention of severe complications in this population. METHODS: Ten adult patients were monitored based on CMV, EBV, and HHV6 DNA quantifications in blood and biopsy tissue samples. Three patients were monitored for at least 5 months (early period) and 7 patients were monitored for 1 to 5 years after transplantation (late period). RESULTS: In the early period, despite prophylaxis all 3 patients developed symptomatic CMV infections: 1 fever/diarrhea, 1 enteritis and rejection, as well as 1 fever and pneumonia. Only 1 patient developed EBV and HHV-6 infections. The average time of onset of CMV infection was 3 months after transplantation and only 24 days for HHV6 infection. In the late period, of the 7 SB/MVT recipients only 1 developed an EBV infection at 2 years after transplantation. No CMV or HHV 6 infections were identified in any patient. CONCLUSIONS: CMV infection is a major cause of organ disease and rejection in the early period after transplantation. EBV infection in adult recipients must be considered also in the late period, particularly in association with severe immunosuppression. Because HHV-6 infection occurs earlier than CMV/EBV, it may serve as an indicator for more intense virological surveillance. PMID- 20172285 TI - Thrombotic microangiopathy following intestinal transplantation: a single center experience. AB - BACKGROUND: Transplant-related thrombotic microangiopathy (TMA) is a well recognized complication of all types of transplantations. Despite its known relationship with immunosuppressive therapy, only a few cases have been reported following intestinal transplantation. METHODS: We retrospectively reviewed the medical files of nine consecutive intestinal transplant patients between 2000 and 2008. RESULTS: The diagnosis of TMA was established in 3 patients (33%). At diagnosis the immunosuppressive therapy consisted of tacrolimus (n = 3), combined with azathioprine (n = 1) or sirolimus (n = 2) and steroids (n = 2). The median time between transplantation and TMA was 104 days (range, 55-167 days). Levels of ADAMTS13, a von Willebrand protease, were within normal ranges in all 3 patients. Treatment consisted of stopping/tapering of tacrolimus, together with initiation of plasma therapy, leading to complete remission in all 3 patients. During further follow-up, all 3 patients showed severe graft rejection necessitating more profound immunosuppressive therapy, leading to graft loss in 1 patient and infection-related death in the 2 others. At a median follow-up of 52 months (range, 9-100 months) all remaining TMA-free patients (n = 6) were alive with functioning grafts under minimal immunosuppression. CONCLUSION: Herein we have described 3 intestinal transplant patients who were diagnosed with transplantation-related TMA. Despite excellent disease control the final outcomes were dismal, which clearly contrasts with the outcome among TMA-free patients, who were all well with functioning grafts at last follow-up. PMID- 20172286 TI - Mycophenolate mofetil-related gastrointestinal mucosal injury in multivisceral transplantation. AB - Mycophenolate mofetil (MMF) has become an important and commonly used drug for maintenance immunosuppression therapy in recipients of all types of organ transplants. The drug is an antimetabolite that blocks the de novo pathway of purine synthesis. Although it selectively inhibits B- and T-lymphocyte proliferation, enterocytes are partially susceptible to MMF. One of the main limitations of this drug is gastrointestinal toxicity, with diarrhea the most frequently reported adverse effect. Most studies of MMF-associated gastrointestinal toxicity have been performed in patients with solid-organ transplants, although no data on changes related to MMF toxicity in bowel allografts have been published in the English literature. We evaluated mucosal intestinal biopsy tissue from patients with multivisceral transplants receiving MMF therapy. Our objective was to find morphologic changes that might be attributed to MMF toxicity, as well as changes that could differentiate MMF toxicity from acute rejection. Examination of the surface epithelium, lamina propria, and crypts in this small group of patients showed no specific changes that could be associated with MMF toxicity. Changes such as graft-vs-host disease or inflammatory bowel disease described in previous studies of solid-organ transplantation were not observed. Larger studies and the use of special stains and new markers might be necessary to characterize possible patterns of MMF toxicity and their differences from acute rejection. PMID- 20172287 TI - Evaluation of hemodynamic, metabolic, and electrolytic changes after graft reperfusion in a porcine model of intestinal transplantation. AB - BACKGROUND: We sought to establish an anesthetic protocol to evaluate the hemodynamic, metabolic, and electrolytic changes after graft reperfusion in pigs undergoing orthotopic intestinal transplant (ITx). METHODS: Fifteen pigs were distributed into two groups: GI (n = 6), without immunosuppression, and GII (n = 9), immunosuppressed before surgery with tacrolimus (0.3 mg/kg). The animals were premedicated at 1 hour before surgery with IM acepromazine (0.1 mg/kg), morphine (0.4 mg/kg), ketamine (10 mg/kg), and atropine (0.044 mg/kg IM). Anesthesia induction used equal proportions of diazepam and ketamine (0.1-0.15 mL/kg/IV) and for maintenance in IV infusion of xylazine (1 mg/mL), ketamine (2 mg/mL), and guaiacol glyceryl ether 5% (50 mg/mL), diluted in 250 mL of 5% glucose solution. In addition, recipient pigs were treated with isofluorane inhalation. Heart rate (HR), systolic (SAP), mean (MAP), and diastolic (DAP) arterial pressure, pulse oximetry, respiratory frequency (f), capnography, body temperature (T), blood gas analysis (pH, Paco(2), Pao(2), base excess, BE; Hco(3)(-), Sato(2)), serum potassium (K), calcium (Ca), sodium, hematocrit (Hct), and glucose (Glu) were measured at four times; M0: after incision (basal value); M1: 10 minutes before reperfusion; and M2 and M3: 10 and 20 minutes after graft reperfusion. RESULTS: All groups behaved in a similar pattern. There was significant hypotension after graft reperfusion in GI and GII (M2 = 56.2 +/- 6.4 and M3 = 57.2 +/- 8.3 mm Hg and M2 = 65.7 +/- 10.2 and M3 = 67.8 +/- 16.8 mm Hg, respectively), accompanied by elevated HR. The ETco(2) was elevated at M2 (42 mm Hg) and M3 (40 mm Hg). Metabolic acidosis was observed after reperfusion, with significant increase in K levels. CONCLUSION: The anesthetic protocol for donors and recipients was safe to perform the procedure, allowing control of hemodynamic and metabolic changes after reperfusion without differences regarding immunosuppression. PMID- 20172288 TI - Immediate antibody-mediated (hyperacute) rejection in small-bowel transplantation and relationship to cross-match status and donor-specific C4d-binding antibodies: case report. AB - BACKGROUND: The role of preformed donor-specific antibodies (DSAs) as a barrier to isolated intestinal transplantation (ITx) remains ambiguous; thus, a positive cross-match has not been a contraindication to ITx. OBJECTIVE: To report the case of a patient with Crohn's disease who underwent ITx and developed immediate antibody-mediated rejection on reperfusion of the allograft. METHODS: Percent reactive antibody testing was performed using pretransplantation serum samples and at transplantation using bead-based assays (Luminex, Luminex Corp, Austin, Tex) and flow cytometry solid-phase assays (FlowPRA single-antigen beads (One Lambda, Inc, Canoga Park, Calif). Serologic tests, flow cytometry cross-matching, and flow cytometry assays of C4d-binding serum antibodies were also performed. Histologic and immunofluorescent analysis of biopsy specimens was performed. RESULTS: HLA typing revealed no sharing of class I or II antigens between donor and recipient. Pretransplantation donor-specific antibodies (DSA) were present at transplantation. Cross-matching (performed during surgery) was positive for class I and II by serologic testing and flow cytometry. After reperfusion, the graft immediately developed severe ischemic injury and arteritis on mucosal biopsy specimens, with immunoglobulin deposition. The DSA C4d binding antibodies were also present. After intense immunosuppression and plasmapheresis, the graft and the biopsy histologic findings showed marked improvement (day 2). By day 7 posttransplantation, patient and graft status were stable. The patient has remained clinically stable for more than a year after transplantation. CONCLUSIONS: Pretransplant DSA in ITx can be a risk factor for immediate (hyperacute) but potentially reversible antibody-mediated rejection. Thus, pretransplantation DSA and cross-match results are critical components to be considered in patients awaiting or undergoing ITx. PMID- 20172289 TI - Outcome of exfoliative rejection after isolated intestinal transplantation in an adult: case report. AB - A 34-year-old-man with short-bowel syndrome received an isolated small bowel graft. On postoperative day (POD) 11, ileal biopsy specimen demonstrated mild to moderate rejection that did not respond to corticosteroid bolus therapy. On POD 14, endoscopy and histologic examination revealed exfoliative rejection that was not controlled after 14 days of therapy with thymoglobulin. On POD 95, the patient underwent surgery again because of intestinal obstruction. The graft was removed 6 months after transplantation because of continuous severe abdominal pain with weight loss. After enterectomy, the patient developed multiple-organ failure and died on POD day 8. This case underlines the severity of exfoliative rejection and suggests that early enterectomy be performed when the diagnosis is made, before deterioration of clinical status and development of infectious and nutritional complications. PMID- 20172290 TI - Esophageal varices in chronic intestinal insufficiency in absence of portal hypertension or liver cirrhosis: case report. AB - We report the case of a 62-year-old man with short-bowel syndrome, referred for intestinal transplantation, who had esophageal varices (EV) due to superior vena cava (SVC) thrombosis. Pretransplantation work-up revealed protein S deficiency. Results of liver function tests were normal. Upper endoscopy showed grade II to III EV in the upper and middle segments of the esophagus. Computed tomography demonstrated thrombosis of the jugular, subclavian, and SVC veins and marked collateral vessels in the chest. Transient elastography yielded normal findings. A liver biopsy specimen showed a normal aspect of the liver, without fibrosis or liver cirrhosis. Presence of EV in a patient with chronic intestinal insufficiency may be related to collateral venous circulation associated with SVC thrombosis in the absence of portal hypertension. In this situation, an isolated intestinal graft is indicated. PMID- 20172293 TI - The PIERDUB project: International Project on Education and Research in Donation at University of Barcelona: training university students about donation and transplantation. AB - INTRODUCTION: Donation and transplantation is an accepted therapeutic option when organ failure or tissue replacements are needed to save or improve the quality of life. However, in most medical schools there is no specific training for it, thus disregarding the key role of university students for the future success of the process. OBJECTIVES: Knowledge diffusion about the donation procedure to clarify doubts and stimulate positive attitudes toward donation. Training university students in the donation and transplantation process. Research about the previous donation knowledge and the impact in donation indexes. METHODS: Three different phases have been designed: (1) Training the University of Barcelona Health Sciences School students; (2) Training the Health Sciences School students in other faculties of Catalonia, Spain, and International; and (3) research. RESULTS: Since 2005, we have offered yearly an Optional Credits Course to medical students with duration of 45 hours, and two Donation days opened to health sciences students. Since 2007, promotional campaigns have been carried out in medicine and other health sciences faculties. Until now, 818 answered surveys have been collected to evaluate previous knowledge among university students. CONCLUSION: Training medical and other health sciences students in the donation process will improve quality of medical education and develop a trainer role for future professionals to help improve donation rates. PMID- 20172294 TI - A national program toward improving renal health: advancing organ donation awareness. AB - BACKGROUND: Despite the national advocacy campaign for kidney transplantation from deceased donors in the Philippines 96% of kidneys transplanted into 721 kidney transplants from 1999 to 2001 came from living donors. A national survey on the knowledge, attitudes and perceptions of Filipinos on organ donation in 2001 showed factors that disadvantaged deceased organ donation to be poor understanding of "brain death," religion, and fear of the operation. These concerns were addressed and another survey was conducted in 2005. OBJECTIVES: To compare knowledge, attitudes, and perceptions of Filipinos on organ donation between 2001 and 2005, and compare the number of kidney transplants from deceased donors between 2001 until 2008. METHODS: Two surveys in 15 regions of the Philippines were conducted using multistage sampling. Using a structured questionnaire there were 2000 respondents in 2001, and 2140 in 2005. Analysis was performed using chi-square analysis. RESULTS: The majority of respondents knew about kidney donation. Between 2001 and 2005, there was increased awareness that transplants came from both living and deceased donors (37% to 41%) and a decline in those believing transplants came only from deceased donors (14% to 9%). Willingness to become a living (59% to 87%) or a deceased donor (35% to 49%) increased. The increase in transplantation from deceased donors from an average of 10 per year from 1999 to 2001 to 31 per year from 2006 to 2008. CONCLUSION: Increased awareness about kidney donation among Filipinos, improved consent to become an organ donor, and an increase in kidney transplantation from deceased donors occurred from 2001 to 2008. PMID- 20172295 TI - Donor compensation: an ethical imperative! AB - The number of living organ donors is increasing worldwide, but donor needs are widely neglected in support of anticommodification policies. This article argues that the warrant of donor autonomy during the decision process to donate is only one requirement of adequate donor care. Another is the donor's protection against the systematic and institutional exploitation of his altruistic dispositions. People with the disposition to support those, who are in desperate need, with a nonrenewable part of their own body, despite a small but unavoidable risk of death or health impairment, do not deserve to be additionally burdened with further disincentives, such as financial risks and uncompensated costs of donation. And although the borderline between a morally required disincentive removal and a more controversial net incentive to boost donation might be vague and open to discussion, to disadvantage living donors by design constitutes a serious barrier to the fairness of living organ donation-a barrier that should be removed. PMID- 20172296 TI - Attitude of health care professionals to organ donation: two surveys among the staff of a German university hospital. AB - The persistent shortage of organs for transplantation could be minimized by increasing the number of potential donors. The opinion of the staff of a university hospital toward organ donation is of special interest because they are directly involved in solid organ transplantation. In 2007, we conducted a first voluntary survey concerning organ donation among the staff of the university hospital of Essen. A short information campaign and further opinion poll among staff as well as visitors was performed in 2009 to compare professional and public attitudes toward organ donation. The first poll comprised 242 questionnaires showing 55% of the hospital staff carrying organ donor cards, particularly more women (60%) than men (46%). After this survey, an additional 19% of the hospital staff imagined they might carrying an organ donor card in the future. In the second survey, we analyzed 151 questionnaires, showing 66% of staff members carrying an organ donor card, an incidence significantly greater than among visitors (48%). The need for information regarding organ donation was greater among visitors (35%). However, 21% of the hospital staff still also need education concerning organ donation. More education and increased transparency of transplantation practice are necessary for hospital staff to act successfully as initiators. Hospital staff with positive attitudes toward organ donation may have a positive impact on the attitudes of the general public toward organ donation. PMID- 20172297 TI - Organ transplant education: the way to form altruistic behaviors among secondary school students toward organ donation. AB - BACKGROUND: Organ shortage for transplantation is a crucial problem all over the world. Educational intervention may appeal to young people's altruism, increasing organ donation and decreasing the opposition. AIM: This study assessed the influence of an educational program, including organ donation and transplantation, to forming students' altruistic behaviors. METHODS: A total 680 students of 25 secondary schools were asked about their attitudes, intentions, and knowledge about organ donation and transplantation from September 2008 to June 2009 during a 45-minute lesson. RESULTS: In this study, altruistic attitudes were measured through questions about the expression of will to give organs away after death; to give one kidney to relatives; to use the bone marrow from a foreign person; and to sign a donor card. Attitudes were assessed by questions about conversations with relatives, an evaluation of the educational project. More than 1500 donor card were distributed and more than 90% of students wanted to sign them; 73.6% agreed to sign a donor card with the ID card. Before the project, only 8% of students had a signed donor card. Almost everybody is ready to agree to give their organs after death (80.6% male; 92.2% female), or to relatives (100% male; 90.38% female), or bone marrow (80% male; 55.7% female). The students talked to their family, informing them about their decision (36.9% male; 45.9% female). CONCLUSIONS: The proposed educational project successfully encouraged teenagers to make well-considered choices with regard to organ donation and created altruistic behaviors. PMID- 20172298 TI - Health content analysis of organ donation and transplantation news on Turkish television channels and in Turkish print media. AB - The media affects individuals' behaviors, especially by means of news and advertisements. In this study, we evaluated health content of organ donation and transplantation news in the printed media and on television programs for a 1-year period in Turkey. We examined 2449 news items in 230 newspapers and magazines; 1179 news programs on 45 television channels, all concerning organ donation and transplantation. The news obtained from the Media Pursuit Center were transferred to an electronic file to evaluate the format and content of the news. Nine variables were examined about the scope and the formal characteristics of the news: the publication name, its type, the province, the date, the headline, the title length, the presence of a photograph, or its kind, the news size, and the page number. In the content analysis of the news, we also examined 9 variables: the topic, the message of the headline, the property of the words in the title, the identification of photographs in the news, the age, gender of actors in the news, as well as donor or recipient. In a summary, print media and television channels, failed to show sufficient information about organ donation and transplantation. The percentage of news about organ donation and transplantation was small and mostly negative items in the media. On television channels, sufficient place was not given to organ donation and transplantation. The news in printed media and on television channels was not about motivated or altruistic behavior. The pattern of organ donation and transplantation news is important in terms of perception and comment by the public. Furthermore it directly affects the perception of the news by the reader. PMID- 20172299 TI - The role of an interdisciplinary transplant team on living donation kidney transplantation program. AB - During the last decades, the disparity between the organ supply and the demand for kidney transplantation in Europe has led to consider living donors as a more acceptable option. In the last 7 years, we have established an interdisciplinary supporting transplant team to increase the rate of living donation. After 2001, the new interdisciplinary transplant team consisted of a transplant surgeon, a nephrologist, a pediatrician, a radiologist, a psychologist, a transplant coordinator, and a transplant nurse. We performed a prospective analysis to examine the effect of implementing this team on our living donation program. Demographic data, the annual number of procedures, the duration of waiting, and the cold ischemia time were evaluated among brain-dead and living donors. From January 2002 until December 2008, the number of patients who were annually on the waiting list increased 42% (from 377 to 536 patients). Consequently, the number of the total kidney transplants increased from 81 to 120 with an annual median of 98 cases. By implementing the interdisciplinary transplant team, a significant increase of living kidney donors was observed: from 18 to 42 cases; median = 27). In the last 7 years, a total number of 796 kidney transplants have been performed: 567 from brain-dead and 229 from living donors. In 2001, the waiting list times for recipients who received grafts from brain-dead versus living donors were 1356 versus 615 days respectively. Compared with 2008, the duration on the waiting list decreased significantly for patients receiving a living donor graft, whereas there was a slight increase for the patients in the brain-dead group: brain death versus living donors: 1407 versus 305 days. The interdisciplinary approach has also reduced the cold ischemia time for the living donor recipients: 3 hours and 42 minutes in 2001 versus 2 hours and 50 minutes in 2008. During the last years, by implementing an interdisciplinary transplant team, supporting living donor procedures has produce a gradual increase in the number of kidney transplants from living donors with a remarkable decrease in waiting and cold ischemia times, the latter presumably influencing graft quality. PMID- 20172300 TI - The rate of organ and tissue donation after brain death: causes of donation failure in a Romanian university city. AB - AIM: To evaluate the rate of organ donation after brain death in 2 tertiary care medical centers of a Romanian city, the reasons for donation exclusion (donors or organs), and identification of potential strategies for improvement. MATERIAL AND METHODS: The study retrospectively evaluated potential organ donors with brain death (BD) who were identified between January 2006 and June 2009 in an university city of Romania. The potential donors were considered patients with severe intracranial pathology and clinical signs of brain death who were reported to the regional transplant team. The BD declaration was completed according to the Law of Transplant Procurement and Management in Romania: clinical signs of brain stem death, apnea test, and flat EEG, criteria that must be fulfilled twice at a 6 hour interval. According to Romanian law, family consent is mandatory for organ harvesting. RESULTS: The study included 35 potential donors, of whom 22 had a declaration of BD. Failure of potential donors to be declared BD was caused by positive viral serology (n = 7), improvement in clinical status (n = 2), sudden cardiac arrest (n = 2), and refusal of physician in charge (n = 2). Among the 22 with a BD declaration, organ harvesting was performed in only 12 cases due to family refusal (n = 10). In 4 cases the planned organ harvesting was aborted owing to unexpected intraoperative findings. DISCUSSION: Factors that generate the low rate of organ procurement include local organizational particularities, a high rate of viral infections, poor education, (both of lay persons and of medical personnel), restrictive criteria for BD declaration and the mandatory need for family approval. CONCLUSION: The rate of donation in this university city of Romania is still low. Several strategies have been identified to improve the rate: better identification of potential donors, better management, and education of the public and of health care personnel. PMID- 20172301 TI - Presumed consent for organ donation: is Romania prepared for it? AB - INTRODUCTION: In November 2007, a legislative initiative regarding the presumed consent for organ donation was proposed for parliamentary debate in Romania and was followed by public debate. The study aimed to asses public opinions expressed in the Romanian media. MATERIALS AND METHODS: An Internet search was made. The pro and con reasons, the affiliation of parts involved in the debate and suggested future direction of action were identified. RESULTS: The Internet search had 8572 results. The parts involved in the pro and con debate consisted of governmental structures, physicians, ethicists, politicians, media, religious authorities, nongovernmental associations, and lay persons. The main pros were the low rate of organ donation and the long waiting lists, enhancement of organ procurement, avoidance of wasting valuable organs, avoiding responsibility, and the stress imposed to the family in giving the donation consent, humanitarian purposes (saving lives), going along with the scientific progress, and less bureaucracy. The main cons were an unethical issue, violation of human rights, denial of brain death, unethical advantage of public ignorance, unethical use of underprivileged people, little results in terms of organ procurement, but huge negative effects on public opinion, public mistrust in transplant programs and impossibility of refusal identification due to particularities of the Romanian medical system. CONCLUSION: The con opinions prevailed. For the moment, Romania seems to be unprepared to accept presumed consent. A future change in public perception regarding organ transplantation may modify the terms of a public debate. PMID- 20172302 TI - Functional improvement between brain death declaration and organ harvesting. AB - INTRODUCTION: The quality of harvested organs is crucial for graft survival and for posttransplant evolution. This study sought to investigate the evolution of the functional status of brain death (BD) patients during the period between declaration and organ harvesting (BD duration). MATERIALS AND METHODS: The study included all BD patients who underwent organ harvesting between January 2006 and June 2009. We compared the functional status regarding hemodynamics, respiration, kidney and liver function, coagulation, water, electrolytes, and acid-base balance evaluated at the moment of BD declaration (P1) and just before organ harvesting (P2). The results of the comparison were expressed as improvement, stable, or aggravation. We calculated mean values of the functional parameters in P1 and P2 and the statistical significance of the differences. RESULTS: Twelve BD patients were included in the study. The time interval between P1 and P2 was 16.08 +/- 8.54 hours (range, 6-32). The number of patients with vasopressor support was 9/12 at P1 and 0/12 at P2, oxygenation disturbances 1/12 in P1 and 0/12 in P2, renal dysfunction 9/12 in P1 and 2/12 in P2, liver dysfunction 7/12 in P1 and 1/12 in P2, coagulopathy 4/12 in P1 and 0/12 in P2, hypernatremia 8/12 in P1 and 3/12 in P2, and metabolic acidosis 9/12 in P1 and 1/12 in P2. The overall assessment showed improvement in all patients. The most statistically significant improvement was registered in the cardiovascular, respiratory, renal, liver, and acid-base status (P < .05). CONCLUSION: With early, aggressive, protocolized donor management, functional improvement may be achieved during BD duration. PMID- 20172303 TI - The Donor Action Project: a valuable tool to measure quality and efficacy of the donation process in Emilia-Romagna. AB - INTRODUCTION: The international project Donor Action (DA) started in Emilia Romagna (ER) in July 1998, involving 24 main regional intensive care units (ICUs) of which 6 have neurosurgery units. Using a data-analysis computer system, we sought to measure the efficiency and quality of the donation process. METHODS: Our study analyzed all data collected by the DA system from July 1998 to December 2008. In particular, we evaluated the following markers: patients with brain damage (BD)/total ICU deaths (Index I); brain death assessments/potential donors (PD, patients in the ICU for more than 6 hours; Index II); refusals/consent requests (Index III); effective donors/total encephalic deaths (PROC 1); and brain death assessments/total encephalic deaths (PROC 2). After collection, data were analyzed by the Regional Transplant Reference Center (CRT)-ER and sent to the National Transplant Centre (CNT) using Q-pido software for comparison with other Italian regions. RESULTS: During the study period, despite a significant decrease in Index I, we observed a considerable increase in Index II, and, consequently, in donation efficacy. Additionally, we reported a slight increase in Index III. Finally, both PROC 1 and PROC 2 increased through the years, suggesting an improved efficacy of the donation/transplantation system. CONCLUSIONS: Based on our experience, the DA project to increase the level of attention of ICU medical staff about organ donation and to increase interactions between transplantation coordinators and CRT-ER seemed to ameliorate both procurement and transplantation activities. PMID- 20172304 TI - Machine perfusion preservation for kidney grafts with a high creatinine from uncontrolled donation after cardiac death. AB - BACKGROUND: This study evaluated the usefulness of machine perfusion preservation parameters as selection criteria for donation after cardiac arrest (DCD) with high creatinine level. The aim of this study is to evaluate to whether DCD donor >50 years old and with high creatinine are acceptable. METHODS: We examined 17 kidneys from uncontrolled DCD who showed creatinine levels >3.0 mg/dL before procurement. The study included the following two groups: group 1 (n = 9), donor age <50 years old versus group 2 (n = 8), donor age >50 years old. RESULTS: There were no significant differences in donors or preservation conditions among the 2 groups, including age, terminal creatinine, warm ischemic time, cold perfusion time, and total ischemic time. A greater resistance of 47.9 mmHg/mL per min/g was observed among group 2, compared with 42.5 mmHg/mL per min/g in group 1. A shorter ATN period (8.2 days) was noted in group 1, compared with 21.2 days for group 2. The flow rate (mL/g/min) was not significantly different between the two groups. The best-Cr level was 1.22 mg/dL in group 1 and 1.94 mg/dL in group 2. CONCLUSION: Machine perfusion flow was a reliable indicator of graft viability in uncontrolled DCD, particularly kidneys with high creatinine level. Even older donors were acceptable if the machine perfusion preservation parameters such as flow rate and pressure were acceptable; however, they may show severe delayed graft function. PMID- 20172305 TI - New insights into fatty liver preservation using Institute Georges Lopez preservation solution. AB - Institute Georges Lopez preservation solution (IGL-1) has been demonstrated to be useful for fatty liver preservation. The mechanisms responsible for this effective graft protection against ischemia-reperfusion injury are pivotal actions on generation of nitric oxide a diffusible molecule with vasodilator properties, that facilitates the up-regulation of other well-known cytoprotective genes, such as hypoxia-inducible factor-1 alpha (HIF-1alpha) and heme-oxygenase 1 (HO-1). During normoxic reperfusion, the presence of nitric oxide permits HIF 1alpha accumulation to inhibit prolyl-hydoxylases, thus promoting an additional overexpression of the HO-1 in steatotic and nonsteatotic graft livers preserved in IGL-1. PMID- 20172306 TI - A fast and safe living donor "finger-assisted" nephrectomy technique: results of 359 cases. AB - OBJECTIVE: To determine operative parameters and complications, using a modified approach to mini-incision living donor nephrectomy. METHODS: Three hundred fifty nine consecutive living donor procedures were performed between October 2000 and November 2008 using the finger-assisted, mini-incision living donor nephrectomy. Patient demographics, intraoperative parameters, and postoperative complications were prospectively recorded, including operative time, blood loss, incision length, warm ischemia time, and intraoperative adverse events. RESULTS: Mean donor age was 44.2 +/- 12.3 years (range, 21-75 years), with an average body mass index of 28.2 +/- 5.3 kg/m(2) (range, 17.1-44.9 kg/m(2)). Right-sided donor nephrectomies were performed on 23 patients (6%), and 41 donors (11%) were found to have multiple renal arteries. Median incision length was 6.8 cm (range, 3.5-15 cm). Average operative time was 117 minutes (range, 50-265 minutes), with a median blood loss of 109 mL (range, 20-500 mL) and an average warm ischemia time of 4.5 minutes (range, 1.5-10 minutes). Four patients (1%) required perioperative blood transfusions. There were no other intraoperative complications, no patients required reexploration, and there were no donor deaths. Thirteen patients (4%) developed minor postoperative complications, including two incisional herniae, but no patients developed chronic wound pain, over a median follow-up period of 19 months (range, 2-97 months). CONCLUSION: This prospective series demonstrated that a modified approach to open mini-incision nephrectomy can result in a smaller incision length while maintaining patient safety, with few postoperative complications. PMID- 20172307 TI - Deceased donor organ transplantation with expanded criteria donors: a single center experience from India. AB - INTRODUCTION: Deceased donor organ transplantation (DDOT) accounts for <4% of renal transplants in India. Many volunteers come forth for organ donation with increasing awareness; unfortunately, the majority are marginal donors, but their rejection would hamper the DDOT program. Judicious use of marginal organs is a challenge for developing countries. PATIENTS AND METHODS: We performed 29 renal transplants from 21 expanded criteria donors (ECD) out of 115 DDOT between January 2006 to April 2009-10 dual (DKT) and 19 single (SKT). Fourteen donors had hypertension, a cerebrovascular accident as the cause of death, 9 had both, and 4 had diabetes. Mean donor age was 70.3 +/- 8.9 years. Decisions on the procedure were based upon frozen section biopsy in 13 of 21 donors. Mean DKT donor age was 76 +/- 9.7 years versu 64 +/- 5.7 years of SKT donors. The native kidney diseases were chronic glomerulonephritis (n = 14), diabetic nephropathy (n = 7), tubulointerstitial nephritis (n = 4) and polycystic kidney disease, focal segmental glomerulosclerosis, lupus nephritis and patchy cortical necrosis, (n = 1 each). Mean recipient age of DKT versus SKT was 43.5 versus 42.3 years. All recipients received rabbit anti-thymocyte globulin, followed by steroid, mycophenolate mofetil/calcinueurin inhibitor. RESULTS: Over a mean follow-up of 341 days, the mean serum creatinine (SCr) of 25/29 patients was 1.60 mg/dL (range, 1.0-2.6). The mean SCr of SKT patients was 1.59 +/- 0.63 mg/dL and of DKT, 1.62 +/- 0.48 mg/dL. Ten patients had delayed graft function and 11 had biopsy proven acute tubular necrosis. Seven (24%) patients had rejection (grade 3 Banff update '05, type IA; 4, type 2A); 6 responded to antirejection; 1 graft was lost at 7 months due to chronic rejection. Three (10.3%) patients were lost, 1 each due to AMI, sepsis, and CMV disease. CONCLUSION: In the circumstances of organ shortage, DDOT with expanded criteria donor is a feasible option. PMID- 20172308 TI - Liver transplantation utilizing old donor organs: a German single-center experience. AB - INTRODUCTION: Due to the current profound lack of suitable donor organs, transplant centers are increasingly forced to accept so-called marginal organs. One criterion for marginal donors is the donor age >65 years. We have presented herein the impact of higher donor age on graft and patient survival. PATIENTS AND METHODS: Since 2004, 230 liver transplantations have been performed at our center, including 54 donor organs (23.5%) from individuals >65 years of age. We performed a retrospective analysis of recipient and graft survivals. RESULTS: The overall 1-year mortality was 22.2% (12/54) among recipients of organs from older donors versus 19.5% among recipients whose donors were <65 years. When donor organs were grouped according to age, the 1-year mortality in patients receiving organs from donors aged 65-69 years was 30% (6/20); 70-74 years, 29.4% (5/17); and donors >75 years, 5.9% (1/17). There was no significant correlation between mortality rate and the number of additional criteria of a marginal donor organ. DISCUSSION: The current lack of donor organs forces transplant centers to accept organs from older individuals; increasingly older patients are being recruited for the donor pool. Our results showed that older organs may be transplanted with acceptable outcomes. This observation was consistent with data from the current literature. It should be emphasized, however, that caution is advised when considering the acceptance of older organs for patients with hepatitis C-related cirrhosis. PMID- 20172309 TI - Preprocurement pancreas allocation suitability score does not correlate with long term pancreas graft survival. AB - BACKGROUND: Within recent years, more marginal donors have been offered to Eurotransplant. To help identify suitable pancreas donors, the Eurotransplant Pancreas Advisory Committee introduced a donor score system (P-PASS). Little is known about the influence of P-PASS on long-term pancreas graft survival. METHODS: From June 1994 to September 2009, we performed 405 pancreas transplantations. In a retrospective study we analyzed P-PASS in 318 cases. Pancreas grafts from donors with P-PASS < 17 (n = 146) analyzed for graft and patient survival as well as for surgical complications were compared with donors of a PASS > or = 17 (n = 172). The mean follow-up was 7.2 +/- 4.3 years. RESULTS: Recipient characteristics were comparable in both groups. Mean P-PASS was 16.7 +/ 2.7 for both groups: 14.3 +/- 1.5 for P-PASS < 17 and 18.8 +/- 1.6 for P-PASS > or = 17. Pancreas graft survival rates for 1, 5, and 10 years were 85%, 77%, and 73% among P-PASS < 17 and 81%, 73%, and 64% among P-PASS > or = 17 groups (P = .12). There were 12 (8.2%) cases of venous thrombosis in the <17 group and 22 (12.7%) in the > or =17 group (P < .05). The relaparotomy rate was significant higher (38.7% vs 28.7%) and duration of hospital treatment longer (40.2 vs 32 days) in the P-PASS > or = 17 group (P < .05). There was no significant difference in patient or kidney graft survival between groups. CONCLUSIONS: The data demonstrated that utilization of pancreas grafts from donors with a P-PASS > or = 17 resulted in good overall outcomes and could expand the organ donor pool. There was no correlation between P-PASS and long-term patient or graft outcome. Complications requiring relaparotomy were more frequent among patients after transplantation from donors with higher P-PASS. PMID- 20172310 TI - European homograft bank: twenty years of cardiovascular tissue banking and collaboration with transplant coordination in Europe. AB - Established in 1989 in Brussels as an international nonprofit association, the European Homograft Bank (EHB) has been collaborating closely with the transplant coordination of the different centers in Belgium and other European countries. Donor selection is made after discussion of exclusion criteria with the transplant coordinator of the procurement center. EHB collaborates with 15 Belgian, 11 German, 10 French, 10 Swiss, 3 Italian, 3 Dutch, and some other procurement and/or implantation centers. Donor ages range from newborn to 65 years. Tissue preparation, morphologic evaluation, and functional testing are performed under Class A laminar flow. After decontamination in a cocktail of 3 antibiotics (lincomycin, vancomycin, and polymixin B) during 20-48 hours, the tissues cryopreserved with liquid nitrogen to -100 degrees C are stored in vapors of liquid nitrogen below -150 degrees C for a maximum of 5 years. Systematic virologic examination of donor blood is performed for HIV, HTLV, hepatitis B/C, and syphilis, as well as for enteroviruses, Q fever, malaria, and West Nile virus by indication. Bacteriologic examination for anaerobic and aerobic contamination is performed at the different steps of processing. Histologic examination for malignant disease and infection is performed systematically. Indications for implantation are discussed with the requesting surgeon. Transport to the implantation center is carried out safely in a dry shipper at -150 degrees C or in dry ice at -76 degrees C. The EHB received 4,511 hearts and 1,169 batches of arteries from January 1989 to December 2008. The 5,133 heart valves (1,974 aortic, 3,106 pulmonary, and 53 mitral) and 2,066 arterial segments have been prepared and stored; 4,600 cryopreserved valvular (2,717 pulmonary, 1,835 aortic, and 48 mitral) and 1,937 arterial allografts have been distributed for implantation in various European Cardiovascular Centers. EHB is not always able to meet the increased demand for heart valves and arterial allografts. Collaboration between the EHB and the Transplant Coordination is satisfactory. Donor selection criteria are discussed with the transplant coordinator; whereas, implantation indication, with the implanting surgeon. Because the EHB is not always able to meet demands for the cryopreserved valves and arterial segments, there is a need to increase number of procurements. Cardiovascular surgeons need to play more active roles in the resolution of this problem. PMID- 20172311 TI - Tissue procurement system in Japan: the role of a tissue bank in medical center for translational research, Osaka University Hospital. AB - Although organ procurement has been regulated by The Organ Transplantation Law (brain-dead donors since 1997, donors after cardiac death since 1979), there has been no law or governmental procurement network (except for cornea) in Japan. Since the late 1980s, some university hospitals have developed original banks. Finally, in 2001 guidelines for tissue procurement were established by The Japanese Society of Tissue Transplantation and Japan Tissue Transplant Network (JTTN) to coordinate tissue harvesting. Five tissue banks were joined to the tissue transplant network (skin in one, heart valves in two, and bone in two). As the number of tissue banks is small, each bank cooperates on procurement, but cannot cover the entire country. With regard to skin transplantation, only one skin bank-The Japan Skin Bank Network (JSBN), which is located in Tokyo-has organized skin procurement. Therefore, it has been difficult to procure skin in areas distant from Tokyo, especially around Osaka. In order to improve such a situation, a tissue bank collaborating with the JSBN was established at The Medical Center for Translational Research (MTR), Osaka University Hospital in April 2008. The bank has played a role in skin procurement center in western Japan and supported procurement and preservation at the time of the skin procurement. Between April 2008 and September 2009, the bank participated in eight tissue procurements in the western area. In the future, the bank is planning to procure and preserve pancreatic islets and bones. Moreover, there is a plan to set up an induced pluripotent stem cells center and stem cell bank in MTR. This tissue bank may play a role to increase tissue procurement in Japan, especially in the western area. PMID- 20172312 TI - Protective effects of N-acetylcysteine on the liver of brain-dead Ba-Ma mini pig. AB - OBJECTIVE: To investigate liver injury after brain-death in BA-Ma mini pigs and the protective effects of N-acetylcysteine (NAC) on hepatic function and on nuclear factor (NF)-kappaB mRNA and protein expression. METHODS: Fifteen Ba-Ma mini pigs were equally divided into three groups at random: brain-dead group (group B), NAC-pretreated group (group N), and control group (group C). A brain death model was established by increasing intracranial pressure in a modified, slow, and intermittent way. At 6, 12, and 24 hours after the initial brain death, we determined the levels of serum aspartate transferase (AST), alanine transferase (ALT), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6. At the same times, hepatic tissue samples were obtained to assess morphological changes in hepatic tissues and the expression of NF-kappaB mRNA and protein was detected by reverse transcriptase polymerase chain reaction and immunohistochemistry, respectively. RESULTS: The levels of AST and ALT in groups B and N began to increase at 12 hours after brain death; the levels among group N were lower than those in group B (P < .05). The levels of serum IL-1beta, IL-6, and TNF-alpha in group B and group N began to increase gradually at 6 hours after brain death; those of group B were all significantly greater than those among group N at each time (P < .05). The mRNA and protein levels of NF-kappaB among groups B and N began to increase at 6 hours after brain death; however, those of group B were all significantly higher than those of group N (P < .05). Light and electron microscopy showed only mild edema of liver cells in group N. At 12 hours after brain death, mitochondrial swelling and edema in liver cells were observed among group B, with more severe morphological lesions in this group than group N. CONCLUSIONS: NAC inhibited the degree of NF-kappaB mRNA transcription and its protein translation, decreasing the release of inflammatory factors, and thus alleviating hepatic injury during brain death. PMID- 20172313 TI - Terlipressin as rescue therapy in catecholamine-resistant hypotension in solid organ donors: a case report. AB - OBJECTIVE: The objective of this study was to report the effects of Terlipressin treatment in 2 potential organ donors with intractable, catecholamine-resistant hypotension. DESIGN AND SETTING: This study was based on case reports in the intensive care unit of a general hospital. PATIENTS: Patients included 2 adult patients with cerebral death and catecholamine-resistant hypotension. INTERVENTIONS: A low dose of Terlipressin (3.5 microg/kg) by intravenous bolus was added to the standard treatment. MEASUREMENT AND RESULTS: In both cases, Terlipressin induced a rapid improvement in arterial pressure with a consequent increase in urine output and the appearance of diabetes insipidus. In 1 patient it allowed for the withdrawal of norepinephrine infusion. No related adverse effects were detected in either patient. Organ removal was not possible in the second case due to lack of family consent. CONCLUSIONS: Terlipressin might be considered as a rescue therapy for potential organ donors with intractable, catecholamine-resistant hypotension. In spite of the positive results obtained here and by other authors in the treatment of septic shock, its judicious use is recommended, and an optimal administration schedule must still be elucidated. PMID- 20172314 TI - Review of the Uruguayan Kidney Allocation System: the solution to a complex problem, preliminary data. AB - The National Kidney Transplant Program with cadaveric donors is based on centralized and unique waitlist, serum bank, and allocation criteria, approved by Instituto Nacional de Donacion y Trasplante (INDT) in agreement with clinical teams. The median donor rates over last 3 years is 20 per million population and the median number of waitlist candidates is 450. The increased number of waiting list patients and the rapid aging of our populations demanded strategies for donor acceptance, candidate assignment, and analysis of more efficient and equitable allocation models. The objectives of the new national allocation system were to improve posttransplant patient and graft survivals, allow equal access to transplantation, and reduce waitlist times. The objective of this study was to analyze variables in our current allocation system and to create a mathematical/simulation model to evaluate a new allocation system. We compared candidates and transplanted patients for gender, age, ABO blood group, human leukocyte agents (HLA), percentage of reactive antibodies (PRA), and waiting list and dialysis times. Only 2 factors showed differences: highly sensitized and patients >65 years old (Bernoulli test). An agreement between INDT and Engineering Faculty yielded a major field of study. During 2008 the data analysis and model building began. The waiting list data of the last decade of donors and transplants were processed to develop a virtual model. We used inputs of candidates and donors, with outputs and structure of the simulation system to evaluate the proposed changes. Currently, the INDT and the Mathematics and Statistics Institute are working to develop a simulation model, that is able to analyze our new national allocation system. PMID- 20172315 TI - Spanish and Latin American nursing personnel and deceased organ donation: a study of attitude. AB - OBJECTIVE: To analyze the attitude of nursing personnel about organ donation and transplantation in hospitals in Spain and Latin America, and factors that affect this attitude. METHODS: Data were selected from 12 hospitals and 32 primary care centers participating in an international study (Proyecto Donante, Murcia) in 4 countries including Spain (n = 650), Mexico (n = 428), Cuba (n = 89), and Costa Rica (n = 27). The sample was random and stratified by type of service among nursing personnel (n = 1194). Attitude was evaluated using a psychosocial questionnaire. RESULTS: Of nursing personnel surveyed, 77% (n = 922) were in favor of organ donation. No differences were found according to whether they were directly involved in transplantation-related services (P < .05). Attitude in favor of organ donation varied between countries: 92% in Cuba, 85% in Costa Rica, 80% in Mexico, and 73% in Spain (P < .001) This attitude was also related to donation of a family member's organs (P < .001), having discussed organ donation and transplantation within the family (P < .001), the concept of brain death (P < .001), fear of body mutilation (P < .001), and manipulation of the body after death (P = .001). CONCLUSION: Attitude toward deceased organ donation among nurses varies between countries. There is a discrepancy between those in favor vs actual donation rates in countries and work centers. These fears may become worse when donation is seen as common in daily clinical practice. PMID- 20172316 TI - Level of acceptance of a clinical solid organ xenotransplantation program among personnel in organ transplant-related services in Spanish, Mexican, and Cuban hospital centers. AB - INTRODUCTION: Xenotransplantation is far from becoming a clinical reality. However, in vital organs it could be used as a bridge until a human organ becomes available, in an emergency situation. We analyzed the attitude toward xenotransplantation among personnel in transplant-related services in several hospitals in Spain and Latin America. METHODS: A random sample stratified by type of service and job category (n = 738), in transplant-related services (procurement units, transplant units, and transplant patient follow-up units) was examined in eight hospital centers from three different countries: Spain (n = 349), Mexico (n = 269), and Cuba (n = 120). A self-administered validated questionnaire was completed anonymously. RESULTS: Based on the assumption that all the results of xenotransplantation were similar to those achieved with human donors, most respondents [66% (n = 484)] would be in favor. The employees from Cuban centers had the most favorable attitudes (72% in favor), followed by the Spanish (64%) and the Mexicans (61%; P = .013). However, the differences were mainly determined by job category: Physicians showed the most favorable attitudes and auxiliary staff the least (67% vs 40%; P = .010). Attitudes were significantly related to beliefs about different types of human donation [deceased (P < .001) and living (P < .001)], the possibility of needing a transplant for oneself (P < .001), and a favorable attitude toward donating the organs of a deceased family member (P = .004). CONCLUSIONS: Currently, a third of health care employees working in transplant-related services are not in favor of xenotransplantation. More information should be provided about the subject, especially in centers with preclinical xenotransplantation programs. PMID- 20172317 TI - Attitudes toward living kidney donation in transplant hospitals: a Spanish, Mexican, and Cuban multicenter study. AB - INTRODUCTION: Living donor kidney (LKD) transplantation provides better results than deceased donor donation, involving minimum risk for the donor. However, LKD donation rates are low in most countries. We analyzed attitudes toward LKD in transplant hospitals in Spain, Mexico, and Cuba. MATERIALS AND METHODS: Data were obtained from five transplant hospitals through the International Collaborative Program "Proyecto Donante Vivo, Murcia" in three countries: Spain (n = 1168), Mexico (n = 903), and Cuba (n = 202). The random sample (2273 employees) was stratified according to job category. The instrument used to evaluate attitude was a validated questionnaire. Statistical analysis included Student t test, the chi(2) test, and multivariate analysis. RESULTS: Eighty eight percent (n = 2002) of Spanish, Mexican, and Cuban transplant hospital personnel were in favor of related LKD and 24% nonrelated LKD (n = 555). Attitudes were more favorable among centers in Cuba 97% (n = 195), followed by Mexico 88% (n = 793) and by Spain 87% (n = 1014; P < .001). According to job category, 91% (n = 617) of physicians were in favor, 88% (n = 543) of nurses, 85% (n = 198) of health care assistants, and 85% (n = 198) of auxiliary personnel. Attitudes were related to variables of: attitude toward deceased donation (P < .001), discussion about organ donation and transplantation (P < .001), concern about body mutilation after donation (P = .001), a possible need for a transplant in the future (P < .001), and attitude toward living liver donation (P < .001). CONCLUSIONS: Attitudes toward LKD in Hispanic/Latin Transplant Hospitals were favorable and could encourage an increase in LKD in the coming years assuming suitable sociopolitical and economic condition, as well as support from nephrologists. PMID- 20172318 TI - Attitudes of Spanish and Mexican resident physicians faced with solid organ donation and transplantation. AB - INTRODUCTION: The attitudes of specialist physicians toward organ donation and transplantation are of great interest because promotion of this activity depends on them. Our objective was to analyze the attitudes of residents in health centers in Spain (MIR) and in Mexico (ENARM). MATERIALS AND METHODS: A random stratified sample was obtained in six teaching hospitals: two in Spain (n = 246) and four in Mexico (n = 139) as part of the International Collaborative Program "Proyecto Donante, Murcia." The sample consisting of 385 trainee physicians completed a psychosocial questionnaire as the instrument to test their opinions. RESULTS: Most residents (93%; n = 359), were in favor of deceased organ donation with 90% (n = 348) in favor of living kidney donation and 87% (n = 335) in favor of liver donation. Attitudes toward donation were similar among Spanish and Mexican residents regarding deceased donation (93% vs 94%; P > .05), living kidney donation (88% vs 94%; P > .05), and living liver donation (86% vs 89%; P > .05). None of the attitudes toward donation was associated with the classic psychosocial factors related to attitudes toward donation or job factors. Discussion within the family was associated with more positive attitudes toward deceased donation (P < .001), living donation of the kidney (P = .01), and of the liver (P = .019). CONCLUSION: Attitudes toward various types of donation were favorable among both Spanish and Mexican trainee physicians, so that they could potentially act as a group to promote this activity, raising hopes for increased donation rates in the future. PMID- 20172319 TI - Organ donation and transplantation training for future professional nurses as a health and social awareness policy. AB - INTRODUCTION: Training and information for university nursing students about the organ donation and transplantation process is necessary because it will influence their attitudes toward the subject. We analyzed attitudes toward organ donation among nursing students in a donation and transplantation training course and any changes in opinions as a result of the course. MATERIALS AND METHODS: We questioned 48 students in the third year of nursing (University of Murcia, Spain) who were attending a 32-hour training course about donation and transplantation. We used a descriptive concurrent study, through the completion of a validated opinion survey with 27 items before and after the training course. RESULTS: Attitudes toward donation were favorable in 87% of respondents increasing to 94% after course completion. Before starting the course, 87% believed that there were not enough transplantable organs available to cover needs compared to 96% after the course. Before the course, 46% stated that they did not have complete information about the subject. Taking part in the course has encouraged family discussion about the subject (85% to 90%) and improved knowledge about family opinions (64% to 83%; P = .031). Attitudes toward living donation did not change after the course. However, there was an improvement in knowledge of the Spanish organ distribution system. CONCLUSIONS: Attitudes toward organ donation among third-year nursing students were favorable, and increased after undergoing a course about donation and transplantation. The most important part of the course was the increase in theoretical knowledge about the matter as well as the health education. PMID- 20172320 TI - Effects of immunosuppressive drugs on rat renal ischemia reperfusion injury. AB - INTRODUCTION: Recent evidence has demonstrated that the immune response and, more specifically, lymphocytes (T and B) and dendritic cells participate as mediators of renal ischemia reperfusion injury (IRI). The aim of this study was, therefore, to evaluate the effect of various immunosuppressive drugs with known activity to prevent IRI among rats undergoing a scheme that is potentially applicable in the clinic. METHODS: Male Sprague-Dawley rats (200-300 g) underwent 60 minutes of ischemia by renal artery clamping and contralateral nephrectomy. The experimental groups (n = 6-7) were as follows: I, Sham; II, Control; III, Rapamycin (R; 1 mg/kg); IV, Methylprednisolone (M; 15 mg/kg); V, Vitamin D3 (VD3; 2 microg/kg); VI, VD3 (1 microg/kg); and VII, M (15 mg/kg) + R (1 mg/kg). Each drug was administered in 2 doses at 6 hours and 1 hour before surgery. Creatinine (Cr) was determined on days 0.1, 2, 3, 5, and 7, and Cr clearance was determined on days 3 and 7. At 7 days nephrectomy was performed to obtain samples for histology to evaluate the degree of acute tubular necrosis. RESULTS: Mortality from renal insufficiency was between 0 and 33%, except in group V (66%; 4/6; P = .01). Kidney function was similar to controls in all groups except for creatinine at 7 days between group VI (VD3) and control (1.05 vs 0.65; P < .05) but no difference in Cr clearance. Histologically moderate to severe renal damage was greater in groups V and VI (VD3) than controls (P = .04). CONCLUSION: We observed that none of the drugs conferred protection against IRI in a time setting relevant to kidney transplantation. Controversy exists regarding R, because some prior studies have shown a deleterious effect on IRI injury, although we did not observe any deleterious effect. PMID- 20172321 TI - Evaluation of the stages involved in cold ischemia time in renal transplants in Chile. AB - INTRODUCTION: Cold ischemia time (CIT) is one of the factors that determine the evolution of a renal transplant; taking measures to reduce this time requires knowledge of its stages. The objective of this study was to evaluate the times in the stages that determine CIT in renal transplants. METHODS: We analyzed 108 donors and 201 kidney transplantations performed in Chile in 2008, establishing the CIT for the kidney transplanted by the center that extracted the kidneys (local kidney) and for the kidney transplanted in another center (shared kidney). RESULTS: Average CIT was 18.8 hours: namely, 16.9 hours for local and 20.2 hours for shared kidneys (P = .0001484). CIT for cases in which samples were sent to histocompatibility laboratory prior to nephrectomy was 7.3 hours less than for those sent postnephrectomy. The mean time between the allocation of the kidney and the transplant was 7.3 hours; 5.6 hours for local kidneys and 8.4 hours for shared kidneys (P = .000007124). CONCLUSION: We identified the stages at which intervention is possible to reduce the CIT, mainly for shared kidneys. All involved parties should make an effort to reduce this time. PMID- 20172322 TI - Evaluation of late immunologic parameters among renal transplant recipients induced with Campath-1H. AB - Organ transplantation success depends principally on avoiding rejection, a purpose almost accomplished with immunosuppressant therapy. Nevertheless, drug side effects have promoted the search for other mechanisms to restrain alloresponses. T-regulatory cells (Treg) might exert that function. Campath 1H (C1H) induces Treg proliferation in the period subsequent to T-cell depletion following C1H administration. In the present study, the status of Treg and de novo HLA antibody production was determined posttransplantation when T-cell repopulation had been completed. In 14 patients, the following parameters were analyzed: renal function, rejection, Treg, panel-reactive antibody (PRA), and HLA antibodies. Patient and graft survivals were 100%. At the moment of Treg determination (20 months following transplant) the mean tacrolimus level was 8.4 ng/mL. One patient experienced an antibody-mediated rejection at 15 months after transplantation while having 3.2% Treg, with excellent treatment responses. Mean leukocyte and lymphocyte counts were 5752 and 1183 cells/mm(3); the mean peripheral blood percentage of Treg of 7.1% +/- 5.9% was not different from that observed in subjects without induction (mean 5.5% +/- 2.5%). Three patients (21%) showed Treg greater than 8.0%. In seven patients, we compared Treg at 4 and 20 months posttransplant, observing a decline from a mean of 19.9% to 5.9% (P = .05). In seven recipients, posttransplant PRA was determined; five of them became "de novo" sensitized, three with a mean class I PRA of 16% and two with a mean class II PRA of 37%. In conclusion, patient and graft survivals were excellent, mean Treg percentage was not elevated with results lower than in the early posttransplant period. Rejection incidence was negligible. Late "de novo" sensitization occurred in 70% showing that B cell-mediated alloresponses were only partially controlled among recipients induced with C1H even when associated with sustained anticalcineurin treatment. PMID- 20172324 TI - Prediction of renal function after living donor kidney transplantation. AB - There is no reliable method to predict the ideal expected function after a kidney transplantation. Herein we have described our experience in the living donor kidney transplant setting, comparing donor and recipient renal function (body surface area adjusted) before the LDKT, and during six months after this procedure. We determined the expected relation between donor and recipient renal function as well as its evolution over time. PMID- 20172323 TI - Pharmacogenetics of immunosuppressant polymorphism of CYP3A5 in renal transplant recipients. AB - The tacrolimus is metabolized primarily by CYP3A5, a member of the single nucleotide polymorphism family. It shows cytochrome P450 (SNP) in intron 3, which consists of a change of base, G for A, producing a stop codon. The result is a nonfunctional protein (allele *3). Allele *1 is the wild type. The patients that show the allelic variant *3 in homozygosis (G/G) are slow metabolizers of the immunosuppressant, increasing its concentration in blood. In contrast, heterozygote A/G alleles *1/*3 are intermediate metabolizers, whereas those of allele *1 in homozygosis (A/A) are normal metabolizers. The aim of this study was to determine CYP 3A5 polymorphism among adult renal transplant recipients and the general Argentinean population. We analyzed 21 recipients and 36 healthy controls. All subjects gave written informed consent approved by the local committee. To determine the polymorphism, we extracted DNA from peripheral blood and used polymerase chain reaction (PCR) to amplify intron 3 of the CYP 3A5. The presence of variant was confirmed by direct sequencing. Among the controls the CYP3A5 genotype *3/*3 (G/G) was detected in 32 individuals, 4 showed *1/*3 (A/G), and none had *1/*1 (A/A); among the recipients, the results were as follows: 18, 2, and 1, respectively. The frequencies of polymorphism in both groups were similar, although they differed from those published for other populations. These results are the basis for the development of a pharmacogenomic program applied to organ transplantation. The genetic polymorphisms can determine responses to drugs. The molecular diagnosis must be transferred to clinical practice so as to guide selection of medicine and drug doses to be optimal for each individual. PMID- 20172325 TI - Parameters of Doppler ultrasound at five days posttransplantation as predictors of histology and renal function at one year. AB - INTRODUCTION: In our center, a Doppler ultrasound (DU) is performed at 5 days after transplantation. The normal upper limit of flow velocity (FV) in the renal artery is 200-250 cm/s. The resistance index (RI) is considered elevated when >0.8. Elevation of the RI can be shown in all the forms of graft dysfunction. OBJECTIVE: The objective of this study was to evaluate the capacity of the DU to predict the prognosis of graft function and histological damage at 1 year. METHODS: We examined a retrospective cohort of patients undergoing renal transplantation between January 2004 and May 2007. The renal function was evaluated with serum creatinine measurements and glomerular filtration rate (GFR) estimates by the quadratic Modification of Diet in Renal Disease study equation. The biopsy specimen was evaluated according to the Banff 1997 classification. RESULTS: The overall average age was 35 years, and 58% of the subjects were men. Eight cases (25.8%) showed abnormal DU. The Delta among those with normal DU was 0.94 versus 0.27 +/- 0.39 with abnormal DU (P < .005). There was no significance as far as the biopsy at 1 year. CONCLUSIONS: Renal DU allows physicians to suspect complications at the first posttransplantation year. It shows a tendency to elevated blood pressure, as well as increased deterioration of renal function over the first year. PMID- 20172326 TI - Evaluation of HLA Matchmaker compatibility as predictor of graft survival and presence of Anti-HLA antibodies. AB - BACKGROUND: HLA Matchmaker is a computer algorithm developed to evaluate donor/receptor compatibility comparing sequences of polymorphic aminoacids (eplets) present in human leukocyte antigen (HLA) molecules. The aim of this study was to evaluate the predictive value of HLA Matchmaker for patient and graft survival, graft survival free of rejection, and the presence of anti HLA antibodies. METHODS: Using this program, 62 of 173 kidney transplant patients, were retrospectively analyzed. HLA-I loci eplet mismatch value (EMM) was determined and correlated with graft survival, graft survival free of rejection, and the presence of anti HLA-I antibodies. EMM was compared with the traditional HLA antigen mismatch value (MM) in terms of the presence of anti HLA-I antibodies. RESULTS: Graft survival and graft survival free of rejection showed no statistical differences (P-value .975 and .365, respectively) while comparing patients with less or more than 10 HLA-I EMM. Patients with > or =6 HLA-B EMM had an odds ratio (OR) of 5.6 (95% confidence interval [CI], 0.47-66.45) of presenting anti HLA-I antibodies, with a sensitivity of 80% and specificity of 58.3%. For > or =2 HLA-B MM, the OR was 2.58 (95% CI, 0.46-14.5), with a sensitivity of 40% and specificity of 75%. CONCLUSION: Even though in our study population compatibility by HLA Matchmaker did not correlate with graft survival or rejection-free graft survival, it showed a better sensitivity than traditional HLA antigen matching for the presence of anti HLA-I antibodies. HLA Matchmaker is a promising tool in predicting the appearance of anti-HLA antibodies. PMID- 20172327 TI - Everolimus versus azathioprine in a cyclosporine and ketoconazole-based immunosuppressive therapy in kidney transplant: 3-year follow-up of an open label, prospective, cohort, comparative clinical trial. AB - In cyclosporine-based protocols, everolimus is more effective than azathioprine to reduce acute rejection. Ketoconazole may reduce cyclosporine and everolimus requirements. We compared kidney transplant patients treated with everolimus or azathioprine in a ketoconazole- and cyclosporine-based immunosuppressive regimen. This open-label, prospective trial of low immunologic risk patients. Included one group (n = 11) who received everolimus (target blood level, 3-8 ng/mL) and the other (n = 11) azathioprine (2.0-2.5 mg/kg/d). Both received steroids, ketoconazole, and cyclosporine with C(0) targets (ng/mL) in the everolimus group of 200-250, 100-125, and 50-65 for months 1 and 2 and thereafter and in the azathioprine group of 250-300 in month 1, 200-250 in month 2, 180-200 until month 6, and 100-125 thereafter. Their baseline characteristics were similar. Two biopsy-proven acute rejections occurred in each group. Three-year graft and patient survival in both groups was 100%. Creatinine clearances at months 6, 12, 24, and 36 were 63.7 +/- 25.4, 58.9 +/- 24.9, 56.0 +/- 22.9, and 57.0 +/- 27.6 in the everolimus group versus 72.6 +/- 20, 68.6 +/- 21.3, 71.4 +/- 23.2, and 68.4 +/- 19.2 in the azathioprine group (NS for every comparison). Major complications were rare and similar in both groups. Five patients in the everolimus group received simvastatin versus 4 in the azathioprine cohort (P = .53). The average cyclosporine doses to achieve targets were 0.8-1.2 mg/kg in the everolimus group and 1.6-2.2 mg/kg in the azathioprine group. The average everolimus dose after month 2 was 0.75-0.9 mg/d. We concluded that with cyclosporine, ketoconazole, and steroids, everolimus was as effective and safe as azathioprine. Cyclosporine reduction with everolimus did not influence graft survival or function at 3 years. PMID- 20172328 TI - Impact of recipient and donor nonimmunologic factors on the outcome of deceased donor kidney transplantation. AB - OBJECTIVE: To study the influence of nonimmunologic factors on the outcome of extended criteria deceased donor (DD) kidney transplants. METHOD: This is a retrospective study of DD transplantation carried out from January 1, 2003 to December 31, 2007, to investigate the impact on graft survival and function of donor renal function at retrieval, cold ischemia time (CIT), delayed graft function (DGF), acute rejection episodes (ARE), age, and weight of donors and recipients, transplant center activities, cause of donor death, donor-recipient gender pairing and size of the donating intensive care unit (ICU). RESULTS: At retrieval, the frequency of donors with a creatinine clearance <60 mL/min, using the Cockcroft-Gault formula, and age >40 years were 31.7% and 32%, respectively. CIT > 24 hours, DGF, and ARE occurred in 27.1%, 33.4%, and 16.5% of cases, respectively. The overall 1- and 5-year graft and patient survival rates were 88% and 79.8% and 96.6% and 92.3%, respectively. The graft function was inferior with occurrences of ARE (P = .0001), DGF (P = .0001), CIT > 20 hours (P = .005), nontraumatic the donor death (P = .022), and donor ICUs bed capacity <20 (P = .03). The odds ratio (OR) for graft loss with DGF, ARE, and donors right kidneys were 7.74 (95% confidence interval [CI] 6-13.4; P = .0001), 4.47 (95% CI, 2.6 7.6; P = .0001) and 1.7 (95% CI, 1-2.8; P = .045), respectively. Graft function was not influenced by donor renal function at retrieval, donor weight, or donor- recipient gender pairings. CONCLUSION: CIT and ARE had an impact on both graft survival and function. DGF and cerebrovascular accidents as the cause of donor death negatively affected graft function during follow-up. ICU center experience had a positive impact on graft survival. Patient survival was affected by recipient age >50 years and female to male donation versus other gender pairings. Neither donor age nor acute terminal rise in the donor serum creatinine affected graft function or survival, or patient mortality. PMID- 20172329 TI - Results of the conversion to everolimus in renal transplant recipients with posttransplantation malignancies. AB - Management of posttransplantation malignancies should include control of the neoplasia and preservation of renal function. Conversion to everolimus (EVL) would potentially have both effects. Twenty-one patients were converted to EVL due to posttransplantation neoplasms. We have presented herein descriptive data and postconversion (PC) outcomes among subjects of mean age 53.6 +/- 10.1 years (range, 36-69), 57.1% were males, undergoing conversion at 108.2 +/- 74.7 (range, 5-316) months after transplantation. All patients received standard immunosuppressive therapy and 9.5% had been induced with thymoglobulin. Malignant neoplasms were as follows: skin (n = 7), gynecological (n = 3), gastrointestinal (n = 3), PTLD (n = 2), renal (n = 2), CNS (n = 1), seminoma (n = 1), Kaposi's sarcoma (n = 1), and prostate cancer (n = 1). PC to EVL, calcineurin inhibitors (CNIs) were discontinued in 18 of 19 patients, mycophenolate in 9/12, and azathioprine in 5/7; all patients continued to receive steroids. In 16 patients (79%) tumors were removed. Chemotherapy was performed in 2 patients with PTLD and radiotherapy was performed in 1 patient with prostate cancer. Mean follow-up was 505 days (range, 59-1151); baseline glomerular filtration rate (GFR) was 53.5 +/- 21.6 mL/min versus 48.5 +/- 25.7 mL/min (P = not significant [NS]) at the last control. One patient experienced graft loss at day 744 after conversion due to chronic rejection. Adverse events were observed in 57% of patients and 28% displayed infections; no patient discontinued EVL. There were 2 deaths: 1 due to an infection and the other due to postsurgical complication. No deaths due to cancer progression were observed. The results observed in this series suggested that conversion to EVL for a posttransplantation neoplasm is a valid therapeutic alternative to preserve graft function and control disease progression. PMID- 20172330 TI - Risk factors for urinary tract infections during the first year after kidney transplantation. AB - INTRODUCTION: Urinary tract infections (UTI) have been reported to occur with frequencies ranging from 30% to 60% in kidney transplant recipients during the first year posttransplantation. UTI is the main cause of infectious complications in this period. The objective of this study was to evaluate the incidence of UTI, during the first year posttransplantation and to identify the risk factors associated with its development, as well as its impact on graft function. PATIENTS AND METHODS: This retrospective cohort study had as a primary outcome the development of UTI, defined as the presence of more than 100,000 colony forming units (CFU) of a pathogenic organism by mL of urine. The univariate analysis was performed with chi-square test for categorical variables and Student t test for continuous ones metrics. We performed multivariate analysis with logistic regression. P < .05 was considered statistically significant. RESULTS: We studied 176 kidney transplant recipients, including 54.5% of male gender and with an overall average age of 37 +/- 12 years. The UTI incidence was of 35.8% (n = 63). The bacterium most frequently found in urine cultures was Escherichia coli (n = 46). In this study, the risk factors that were independently associated with UTI development were age, female gender, days of bladder catheterization, genitourinary anatomic alterations, and UTI during 1 month prior to kidney transplantation. CONCLUSION: This type of study makes it possible to identify risk factors and to formulate strategies focused on particular risk factors. PMID- 20172331 TI - Thrombophilic mutations: no association with thrombotic events in renal transplant recipients. AB - Factor V Leiden and mutation of prothrombin gene G20210A have been associated with poor results in the early post-kidney transplantation period. Its long-term importance in stable patients has yet to be evaluated. We studied the prevalence of these inherited mutations and their relationship to thrombotic events in 82 Argentine renal transplant recipients with adequate long-term kidney function. In aggregate, 7.2% of patients were carriers of these mutations; however, their presence did not show any association with thrombotic events or renal function alterations. The routine evaluation for these mutations does not seem to be cost effective in renal transplant patients. PMID- 20172332 TI - Effectiveness and cost of replacing a calcineurin inhibitor with sirolimus to slow the course of chronic kidney disease in renal allografts. AB - Renal grafts suffer a progressive decrease in glomerular filtration rate (GFR) because of several factors including calcineurin inhibitor (CNI) nephrotoxicity. Switching CNIs to sirolimus may improve this adverse prognosis. We performed a prospective, open-label clinical trial among 18 kidney transplant patients with more than 12 months of evolution (range, 385-1826 days), showing progressive GFR decreases and biopsies with interstitial fibrosis and tubular atrophy (IFTA). Immunosuppressive treatment included cyclosporine, ketoconazole, and steroids associated with azathioprine or mycophenolate mofetil. After signing an Institutional Review Board-approved written consent, cyclosporine was switched to sirolimus seeking to achieve a trough blood sirolimus concentration of 6-15 ng/mL. Wilcoxon and Student's t-tests were used to compare the values in the annual periods before and after the switch. GFR was estimated by the Modification of Diet in Renal Disease formula. There were no acute rejection episodes. Estimated GFR on the day of the switch was 38.0 +/- 12.1 mL/min. After CNI switch, the slope of the estimated GFR significantly improved from -6.5 +/- 9.2 to 8.1 +/- 14.0 mL/min/year (P < .01). The estimated GFR 1 year after the switch was 47.2 +/- 16.9 mL/min (P = .003 vs baseline). Total expenditures increased. The ratio of post-switch versus baseline total expenditures was 1.93 (95% confidence interval, 1.54-2.31) and the ratio of sirolimus to CNI cost was 2.16 (95% confidence interval, 1.53-2.78). Switching from CNI to sirolimus for kidney transplants with decreasing GFR and a biopsy with IFTA changes, suggesting progressive graft nephropathy, almost doubled total expenses. It is necessary to conduct trials using clinical end points to definitively validate this therapeutic intervention. PMID- 20172333 TI - National survey of anemia prevalence after kidney transplantation in Argentina. AB - Anemia is prevalent in kidney transplant recipients and likely contributes to morbidity and mortality. The definition of anemia as established by the World Health Organization and subsequently adopted by the American Society of Transplantation is a hemoglobin concentration of 12 g/dL or less in women and 13 g/dL or less in men. Using this definition, the prevalence of anemia is nearly 30%. The National Survey of Post Transplant Anemia (PTA) in kidney transplant recipients in Argentina was conducted to evaluate the incidence of PTA at 1 year and its relationship to variables that influence transplantation outcome. At 1 year posttransplantation, mean (SD) hemoglobin concentration was 12.43 (1.77) g/dL (n = 379), hematocrit concentration was 38.26% (5.59%) (n = 379), serum creatinine concentration was 1.51 (0.72) mg/dL (n = 380), and creatinine clearance was 60.8 (22.47) mL/min (n = 334). The prevalence of PTA in Argentina at 1 year posttransplantation was 42.25%. At univariate analysis, female sex, immunosuppression regimen (mycophenolate mofetil plus mammalian target of rapamycin), and pediatric age group were associated with anemia. At multivariate analysis, only renal function and pediatric age group were associated with anemia. The mean hemoglobin level at year of transplant was 12.43 g/dL +/-1.77 and the prevalence of PTA in Argentina at year of transplant is 42.25%. Results of our survey show a correlation between Hb levels and graft function and pediatric recipient. PMID- 20172334 TI - Chilean experience in liver transplantation for acute liver failure in children. AB - BACKGROUND: Acute liver failure (ALF) in children is a life-threatening condition, associated with high mortality, and in almost one third of the cases, with no other therapeutic option than orthotopic liver transplant (OLT). The aim of this study was to present our experience with OLT for ALF in pediatric patients in Chile. Patients fulfilling the criteria for ALF who were transplanted in our centers were prospectively included in an excel Microsoft database. We analyzed demographics, etiology, surgical techniques, complications, and long term results. PATIENTS AND METHODS: Between 1994 and 2009, we transplanted 52 pediatric patients with ALF. The most frequent known etiology was acute hepatitis A in 9 cases (18%), but in 26 cases (50%) it was impossible to determine the etiology. Thirty- one patients were males (63%). The overall mean age was 7.5 years and the mean weight, 28.1 kg. Thirty-five (67%) received a cadaveric graft. Among them in 18 cases (34%) the liver had to be reduced but 17 (33%) received whole livers. There were 17 (33%) recipients of living-related livers. Twenty-two patients needed reoperation, including 13 due to surgical complications (59%) and 9 (41%) as planned interventions. Ten patients were retransplanted. RESULTS: Actuarial survival of patients at 1 year was 80% and at 5 and 10 years, 72%. Graft survival at 1 year was 79%, at 5 years 69%, and at 10 years 50%. CONCLUSION: We have reported a series of pediatric liver transplant patients due to ALF whose results were comparable to other reported series. Living donor transplantation for ALF should be considered and offers a low morbidity rate without mortality. PMID- 20172335 TI - Bridge therapy in hepatocellular carcinoma before liver transplantation: the experience of two Chilean centers. AB - BACKGROUND: Orthotopic liver transplantation (OLT) is currently an established therapy for small, early-stage hepatocellular carcinoma (HCC) within the Milan criteria. Long waiting times due to the shortage of donor organs can result in tumor progression and drop-out from OLT candidacy. Therefore a wide variety of procedures are necessary before OLT. The aim of this retrospective study was to review our experience in relation to bridge therapy prior to OLT for HCC. METHODS: This was a retrospective database review of all of the patient who underwent transplantation in our institutions between January 1993 and June 2009. We analyzed patients with a diagnosis of HCC in the explant. RESULTS: Among 29 patients, including 12 who were diagnosed by the explant and 17 prior to transplantation, 88% underwent bridge therapy during a mean waiting time to OLT of 12 months. Among the 23 procedures, namely 1.5 procedures per patient, included most frequently chemoembolization (48%), alcohol ablation (30%), radiofrequency ablation (13%), and surgery (9%). Thirty-three percent of the explants contained lesions within the Milan criteria. In our series the 5-year survival rate for patients transplanted for HCC was 86%; in the bridge therapy group, it was 73%. CONCLUSIONS: The incidence of patients who underwent bridge therapy (52%) was similar to other reported experiences, but the fulfillment of Milan criteria in the explants was lower. Among the bridge therapy group, the survival was slightly lower, probably because this group displayed more advanced disease. PMID- 20172336 TI - Liver transplantation results for hepatocellular carcinoma in Chile. AB - Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. Liver transplantation is the best treatment for HCC; it improves survival, cures cirrhosis, and abolishes local recurrence. We describe the outcomes of patients with HCC who underwent liver transplantation in two liver transplantation centers in Chile. METHODS: This study is a clinical series elaborated from the liver transplantation database of Pontificia Universidad Catolica and Clinica Alemana between 1993 and 2009. The survival of patients was calculated using the Kaplan Meier survival analysis. The significant alpha level was defined as <.05. RESULTS: From 250 liver transplantations performed in this period, 29 were due to HCC. At the end of the study, 25 patients (86%) were alive. The mean recurrence free survival was 30 months (range 5 months to 8 years). The 5-year survival for patients transplanted for HCC was >80%; however, the 5-year overall survival of patients who exceeded the Milan criteria in the explants was 66%. There was no difference in overall survival between patients transplanted for HCC versus other diagnosis (P = .548). CONCLUSION: This series confirmed that liver transplantation is a good treatment for patients with HCC within the Milan criteria. PMID- 20172337 TI - Importance of introduction of a psychological care unit in a liver transplantation unit. AB - BACKGROUND: Psychological changes in terminally ill patients with liver disease are underestimated. Therefore, a psychological care unit was introduced in the liver transplantation unit in a transplantation hospital in Spain. OBJECTIVES: To describe the establishment of the psychological care unit in a liver transplantation unit and to review its operation, and to evaluate and diagnose psychological changes in patients on the waiting list for liver transplantation. MATERIALS AND METHODS: Variables evaluated included consultations, interviews, level of care provided, appointments postponed, difficulties, and cost effectiveness. Psychopathologic symptoms were evaluated using the Symptom Assessment-45 questionnaire (Derogatis, 1975), examining 9 psychopathologic dimensions. RESULTS: Thirty-eight patients were given an appointment, and 28 were interviewed. Twelve postponed the appointment. The level of support provided to patients on the waiting list was 70%. The hospital structure was used to develop the care unit, which is why it was only necessary to employ 1 professional psychologist. Of patients assessed, 54% exhibited relevant clinical symptoms of depression, and 47 demonstrated anxiety. Patients with symptoms of depression reported "loss of interest"; those with anxiety reported feeling "worried and tense." Of these patients, an increased presence of symptoms was associated with various emotional problems such as hostility (33%), somatization (60%), obsession/compulsion (73%), interpersonal sensitivity (40%), phobic anxiety (20%), paranoid ideation (20%), and psychosis (6%). CONCLUSIONS: Patients on the waiting list for liver transplantation demonstrate increased clinical symptoms of depression and anxiety. Therefore, it is of great importance to introduce a psychological care unit to detect and treat these conditions. Introduction of the liver transplant unit program has improved multidisciplinary care and is cost effective. PMID- 20172338 TI - Conversion to sirolimus allows preservation of renal function in kidney and kidney-pancreas allograft recipients. AB - The major causes of graft failure are chronic allograft nephropathy (CAN) and patient mortality. Sirolimus (SRL) is a powerful immunosuppressant with a less nephrotoxic profile as well as a lower incidence of cancer. The aim of this study was to evaluate the impact of conversion to SRL from calcineurin inhibitor (CNI) based therapy in kidney (KT) and kidney-pancreas (SPK) allograft recipients. We analyzed renal function, allograft and patient survival, and SRL-associated adverse effects in 93 adult patients (86 KT and 7 SPK), who were converted to SRL between January 2001 and November 2008. The main reason for conversion was CAN (76; 9%) and 52 (7%) were receiving tacrolimus. Conversion occurred at a median 26.2 months. There was a significant improvement in creatinine clearance (CCr) at 6 months after conversion (CCr(baseline) 51.4 vs CCr(6m) 60.4 mL/min; P < .0001), without changes at 12 and 24 months. However, proteinuria increased significantly at 6 months compared with the baseline: 150 mg/24 hours (0-453) versus 0 mg/24 hours (range, 0-309), respectively (P < .0001), but did not progress at 12 or 24 months. At the same time we observed more extensive use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers: 60/5%; 65/3% and 70/2% at 6, 12, and 24 months. There were no changes in blood pressure control. Cholesterol significantly increased at 6 months (218.2 +/- 37 vs. 186.6 +/- 44 mg/dL; P < .0001). Graft and patient survivals at 4 years were 88% and 95%, respectively. Our experience suggested that conversion to SRL constituted a safe alternative with excellent results in patient and graft survival. PMID- 20172339 TI - Pancreas transplantation: experience at University of Texas, Houston. AB - INTRODUCTION: Diabetes mellitus is a spectrum of diseases characterized by the absence of glycemic control and the development of secondary complications. Type 1 diabetes (insulin-dependent) accounts for a minority of cases, but it usually presents in younger age groups. This disease significantly affects quality of life. METHODS: We retrospectively reviewed the cases of pancreas transplantation performed at University of Texas, Houston, from February 2008 to August 2009. All patients received immunosuppression induction with thymoglobulin (1.5 mg/kg). We used 3 drugs for maintenance: tacrolimus, mycophenolic acid, and prednisone. All patients received cytomegalovirus prophylaxis. RESULTS: We transplanted 54 organs in 29 patients with type 1 diabetes mellitus. The mean patient age was 42 years. Patients had diabetes mellitus type 1 for an average of 28.82 years and were on dialysis for an average of 2 years. Nineteen patients were male (65%). Complications ensued in 68% of cases (20 patients), 9 of which required surgical exploration (31%). We lost 3 pancreatic allografts. DISCUSSION: Pancreas transplant recipients constitute a unique population with a high risk of complications in the acute setting. During the first 3 months after simultaneous pancreas-kidney transplantation the relative mortality risk is increased but after a year it has clear advantage over diabetic patients on dialysis waiting for a transplant. To date, 26 patients have functional pancreatic allografts and 29 are dialysis-free. Pancreas transplantation is a challenging procedure. Surgeons must be prepared to aggressively manage the possible complications. PMID- 20172340 TI - Importance of technical aspects in the beginnings of a pancreas transplantation program. AB - Pancreas and kidney transplantation is the treatment of choice for patients with type 1 diabetes mellitus and terminal renal insufficiency. Herein we have presented a series of 35 patients transplanted between 2002 and 2009 including periods before and after 2007 divided based on introduction of some technical aspects. In the first phase (learning period) we have noted complications related to pancreatic surgery with a morbidity among 12 of 18 patients (66.6%). In the second period (stabilization period), complications appeared in 6 out of 17 patients (35.2%; P < .028). The reoperation rate was 83.3% in the learning period and 23.5% in the stabilization period (P < .03). Seven transplantectomies were performed in the first period (P < .004). Five patients died, all of them in the learning group (P < .019). Changes in the technical aspects of the procedure were responsible for improved outcomes obtained among pancreas and kidney transplantations. PMID- 20172341 TI - Results of heart transplantation: 16 years' experience in a center in Argentina. AB - Heart transplantation (HTx) is the treatment of choice for advanced heart failure refractory to other treatments. OBJECTIVE: To report the outcomes of patients undergoing orthotopic HTx in a center with 16 years' experience. METHODS: We retrospectively examined the outcomes from three hundred nine HTx recipients between February 1993 and March 2009. The mean recipient age was 46 +/- 16 years, and 80% were male. Ischemic cardiomyopathy was present in 37%; 43% (n = 133) were elective procedures and 57% (n = 176) were urgent/emergency procedures. The mean donor age was 26 years; their main cause of death was head/brain trauma. Survival was studied using Kaplan-Meier curves. RESULTS: The global survival rates at 1, 5, 10, and 15 years were 80%, 74%, 71%, and 65%, respectively. Excluding losses during the first year after transplantation (conditional survival), the survival rate at 5 and 10 years reached 92% and 88.5%, respectively. The median follow-up was 7.7 years. The etiology and the urgent/emergency nature of the procedures did not show significant differences regarding the mortality rate (P = .8). The main causes of death were sepsis (28%) and primary nonfunction (18%). In-hospital mortality reached 16%. No significant differences were observed between the urgent/emergency versus the elective transplant procedures (P = .06). During the follow-up, the incidence of severe acute cellular rejection episodes was <3% after 5 years. The global incidence of antibody-mediated rejection reached 4.5%. Eleven subjects (3.5%) were diagnosed with post-transplantation lymphoproliferative disorder. During long-term follow-up, the incidences of kidney failure, diabetes mellitus, hypertension, and dyslipemia were 21%, 24%, 69%, and 70%, respectively. One percent required chronic dialysis. CONCLUSION: In our center, post-HTx survival rates at 1, 5, 10, and 15 years were 80%, 74%, 71%, and 65%, respectively, which were similar to those reported by the International Society of Heart and Lung Transplantation (ISHLT). PMID- 20172342 TI - South American Heart Transplantation Registry of patients receiving everolimus in their immunosuppressive regimens. AB - The increasing number of heart transplant recipients receiving immunosuppression with mammalian target of rapamycin inhibitors prompted the implementation of a South American Transplant Physicians Group to register these patients in a database. Everolimus (EVL) is a signal proliferation inhibition that reduces graft vascular disease when used de novo. Recently, its administration has expanded to subjects with resistant rejection or with side effects due to other immunosuppressive drugs (calcineurin inhibitors and/or steroids), allowing for better regulation of the immunosuppressive regimen. Herein we have shown the data collected from patients receiving EVL in ten South American Heart Transplant Centers. We have concluded that the administration of EVL is a useful adjunctive therapy that allows the reduction or suspension of other immunosuppressive drugs that caused unwanted side effects, without a loss of immunosuppressive efficacy, with manageable side effects, and constituting a valuable therapeutic option. PMID- 20172343 TI - Everolimus in lung transplantation in Chile. AB - Everolimus has shown good results in kidney and heart transplantation, achieving low rates of rejection, of infections, and of tumors compared with calcineurin inhibitors (CNI). Some publications have shown beneficial effects in bronchiolitis obliterans syndrome (BOS). We have presented herein the initial experience with everolimus among lung allograft recipients in Chile. METHODS: We retrospectively evaluated, charts of lung-transplanted patients who used everolimus (Certican) based on 2 years' follow-up, evaluating the indication for therapy; blood levels, rejection episodes, lung and kidney function, and side effects. RESULTS: Eight of 55 lung transplantation patients were switched to everolimus, targeting a (mean drug level of 4.2 ng/dL), in combination with low dose tacrolimus (mean levels 5.5 ng/dL) and steroids. The Reasons for conversion were: CNI nephropathy (n = 3), BOS (n = 4), and lymphoma (n = 1). In patients with renal dysfunction, serum creatinine had risen from 1.1 to 1.8 mg/dl, but at 3 months after everolimus conversion, they had returned to baseline values, maintaining that level for at least 2 years' follow-up. Patients with BOS had decreased their ventricular ejection fraction (VEF(1)) by 50%. Using everolimus, they maintained that VEF(1) with little improvement. The patient with lymphoma died 11 months after conversion. No patient experienced a rejection episode, and they suffered from fewer infections than the other lung allograft recipients. There were no adverse events related to everolimus, but one patient discontinued the drug after 1 year owing to intolerance. CONCLUSION: Everolimus was effective to reverse CNI renal dysfunction in lung transplantation patients, possibly retarding the progression of BOS, without side effects over a 2-year follow-up. PMID- 20172344 TI - Bronchiolitis obliterans syndrome development in lung transplantation patients. AB - The main cause of death in lung transplantation patients is chronic rejection, known as bronchiolitis obliterans syndrome (BOS). There are many variables associated with its appearance. The aim of this study was to identify factors associated with BOS and its impact on survival among lung transplantation patients. METHODS: We retrospectively analyzed charts of lung transplant patients from 1999 to 2009, evaluating survival, BOS, and associated factors. RESULTS: Fifty-six patients have been transplanted with a 5-year survival of 55%. Eighteen (32%) developed BOS, at a mean age at diagnosis of 57 years (range 16-74). According to BOS classification, seven patients (38.8%) were type 2 and six (33.3%) type 3. Half the patients developed BOS at a mean of 8.5 months after transplantation with a mean survival of 18.5 months (range 2-61). Among the factors analyzed, 13 patients (72%) displayed acute cellular rejection and nine (50%) gastroesophageal reflux disease (GERD) diagnosed by pHmetry, both of which were significantly associated with BOS (P = .005). Among seven lung transplantation patients with invasive cytomegalovirus disease, the four who developed BOS (P = .04) showed the worst survival (P = .05). Four of the six patients with severe BOS (66.6%) died at a mean of 10.6 months after the diagnosis. The main cause of death was respiratory insufficiency. CONCLUSIONS: BOS was associated with worse survival. The presence of acute cellular rejection episodes, CMV disease, and GERD were factors associated with chronic lung rejection. PMID- 20172345 TI - Early and late infections in lung transplantation patients. AB - Infections are an important cause of morbidity and mortality among transplanted patients. Their pathophysiology is associated with anatomic factors, immunosuppression, and pretransplant viral exposure. The aim of this investigation was to characterize infections following lung transplantation. We retrospectively analyzed the charts of 51 lung transplant recipients, who were transplanted between 1999 and 2008. Infections were classified according to their origin, etiology, occurrence time, and risk factors. The patient mean age was 55 years (range 13-71), 65% were male, and pulmonary fibrosis was the lung disease etiology in 59% of cases. Seventy-one episodes of infection were reported in the 51 patients, including (75%) during the first year after transplantation and 30 within the first 3 months (42%). Between the 4th and 11th months the number of infections decreased to 23 (32%), and afterwards there were 18 additional cases. The original site of infection was pulmonary in 43 episodes (60%), and the etiology was bacterial in 34 (48%), with Pseudomonas in 12 instances (35% of bacterial infections). Viruses were involved in 25 episodes, especially cytomegalovirus (CMV) in seronegative patients. The nine infections of fungal etiology (13%) were all caused by Aspergillus and always associated with either an acute rejection episode or suture damage. Three cases of tuberculosis were diagnosed, including two in the late post-transplant period. Three patients died of early infections. CONCLUSIONS: The critical period for infections in lung transplantation patients is the first 3 months, especially for those of bacterial etiology. CMV diseases were more common in seronegative patients and fungal infections in airway injury cases. PMID- 20172347 TI - The next generation of burns treatment: intelligent films and matrix, controlled enzymatic debridement, and adult stem cells. AB - We describe a novel technology based on nanoengineered multifunctional acellular biologic scaffolds combined with wound dressings and films of the same kind. This method allows selective delivery and release of shielded biomaterials and bioactive substances to a desired wound or damaged tissue while stimulating the selective anchoring and adhesion of endogenous circulating repairing cells, such as mesenchymal stem cells, to obtain a faster and more physiologic healing process. We also present a new controlled enzymatic debridement process for more effective burned tissue scarolysis. In light of our preliminary in vitro and in vivo data, we are convinced that these approaches can include the use of other kinds of adult stem cells, such as endometrial regenerative cells, to improve the vascularization of the constructs, with great potential in the entire tissue and organ regeneration field but especially for the treatment of severely burned patients, changing the way these lesions may be treated in the future. PMID- 20172346 TI - Mobilization and collection of peripheral blood stem cells: guidelines for blood volume to process, based on CD34-positive blood cell count in adults and children. AB - We report 189 mobilizations and 489 collections of peripheral blood stem cells (PBSC) performed in 139 autologous transplantation patients and in 28 donors for allogeneic transplantations whose ages ranged from 2-68 years. We observed a correlation (P < .001; Pearson's coefficient 0.64) between CD34-positive cells and granulocyte-macrophage colony-forming units examined to estimate PBSC. In a subset of 287 collections (97 adults and 49 children) we obtained peripheral blood (PB) CD34-positive cell counts at 2 to 4 hours before leukapheresis. We noted a correlation between PB CD34-positive cell counts before leukapheresis and the number of CD34-positive cells per kilogram of body weight collected in the whole apheresis of the day (P < .001; Pearson's coefficient 0.82). An even better correlation was obtained between PB CD34-positive cells preapheresis and the yield of each individual blood volume (BV) processed (P < .001; Pearson's coefficient 0.87). Healthy donors and patients in each age group behaved similarly. In addition, the collection yield was greater among children than adults. These findings allowed us to develop a simple predictive model to estimate the BV to process for a target dose of CD34-positive cells per kilogram, based on the level of PBSC before apheresis in children and adults. PMID- 20172348 TI - Comparison of dissolution properties of 2 enteric-coated formulations containing mycophenolate sodium: Myfortic vs Femulan. AB - Enteric-coated tablets containing mycophenolate sodium have been developed to reduce gastric toxicity. The objective of this study was to compare 2 enteric coated formulations containing 360 mg of mycophenolate sodium: the innovator product, Myfortic, and an agent that recently became available in Mexico, Femulan. For both formulations, mycophenolate sodium content was within the 90% to 110% range of the label claimed dose, and no impurities were present as determined at high-performance liquid chromatography. Mycophenolate sodium release was assayed by applying the US Pharmacopeia apparatus 2 dissolution test at 2 different pH values (1.2 and 6.8) to mimic conditions in the stomach and the small intestine, respectively. At pH 1.2, mycophenolate sodium release was less than 2%, with respect to the label claimed dose, for both formulations. At pH 6.8, mean (range) mycophenolate sodium release with Myfortic was 104.9% (104.0% 105.6%), and with femulan was 62.3% (51.3%-67.7%); the difference between formulations achieved statistical significance (P = .04). Moreover, intratablet variability with the generic formulation was unacceptable. Variation between the highest and lowest drug release was 32.0% for Femulan, and 1.02% for Myfortic. Thus, it is likely that Femulan results in insufficient and irreproducible absorption of mycophenolate sodium in the small intestine, leading to inadequate immunosuppressive efficacy. It is concluded that Femulan and myfortic are not equivalent formulations. Furthermore, Femulan is not a suitable formulation for clinical use in organ transplantation because it does not meet pharmaceutical quality standards. PMID- 20172350 TI - Monitoring cyclosporine microemulsion at two hours post dosing in pediatric maintenance liver transplant recipients. AB - Cyclosporine absorption has been key to obtaining adequate results in immunosuppressive regimens. Since 2005, we have used a different monitoring program for Cyclosporine among pediatric liver transplant recipients namely, two hours post dosing concentrations (O(2)). This study of 128 patients included 50.8% males and 64.8% recipients of cadaveric livers. Their main reasons for transplantation were as follows: 43.8% acute liver failure and 37.5% biliary atresia. Mean age at time of transplantation was 5.4 +/- 4.5 years for boys and 3.4 +/- 3.3 years for girls. Mean age at the beginning of C(2) monitoring was 8.9 +/- 4.8 years and time elapsed since transplantation was 53.6 +/- 36.4 months. The initial Cyclosporine dose of 5.5 +/- 5 mg/kg/d had been reduced by month 24 to 4.5 +/- 1.5 mg/kg/d. Estimation of glomerular filtration rate (eGFR) was performed using the Schwartz formula. Baseline creatinine and eGFR were 0.73 +/- 0.49 mg/dL and 111.99 +/- 28.27 mL/min.m(2) versus 24-month creatinine and eGFR of 0.69 +/- 0.20 mg/dL and 122.26 +/- 24.47 mL/min.m(2), respectively (P < .05). Eight patients experienced acute rejection episodes, 4 had chronic rejection, 3 posttransplantation proliferative diseases (PTLD) were reported, and 2 patients died. Cyclosporine C2 monitoring allowed a trend toward long-term dose reduction. Consequently we observed significant improvement in renal function. Acute/chronic rejection rates were low, which suggested that C(2) monitoring was effective to control immunosuppressive therapy.The low incidence of PTLD and patient mortality showed that there was an adequate balance between safety and efficacy profiles. PMID- 20172349 TI - Individualized Neoral doses in pediatric renal transplantation. AB - We propose a model to calculate individualized Neoral doses based on individual oral clearance (CL/F)(i) and AUC((0-12h)) values. The equation proposed by Dr. Ke Hua Wu (2005), was employed to calculate the CL/F(i) = 28,5 - (1.24*POD) - 0.252*(TBil-11) + 0,188*(Weight o-58) -0,191*(Age-42) - 2,42*INHI - 0,212*(HCT 28), where CI/F = (L/h), POD = postoperative days, Bil.T = total bilirubin level (umol/L), CBW = in kilograms, age = in years, INHI = concurrent metabolic inhibitors present (1) or absence (0), and HCT = hematocrit percentage. The AUC((0-12h)) was calculated from the C(2) value using the equation AUC((0-12h)) = 815,578 + 4,44696*C(2), derived from the linear correlation observed in earlier work at Clinica Las Condes Hospital. The studied population were 30 kidney transplanted children at Luis Calvo Mackenna Hospital, between 2002 and 2006, who were divided into 2 similar groups according to accurate C(2) sampling time collections. The control group 1 was composed of 13 patients of age 9.85 +/- 4 years whose samples were collected correctly. Group 2 was composed of 17 patients of age 10.43 +/- 6 years with 252 C(2) samples, which were obtained at medical control. All patients were under oral treatment with prednisone, azathioprine, nifedipine, and Neoral administered twice day according the weight of the patient and the C(2) level. Relating Neoral administered doses to calculated doses according to the proposed model, the control group showed a linear correlation coefficient r = 0.924; r(2) = 85.4%; (P < .05), and group 2, r = 0.54; r(2) = 29.1 (P < .05). The proposed model to calculate Neoral doses had a predictive value of 85.0% when C(2) samples were collected correctly. PMID- 20172351 TI - Sirolimus in kidney transplant donors and clinical and histologic improvement in recipients: rat model. AB - BACKGROUND: Ischemia-reperfusion (I/R) injury is one of the risk factors for delayed graft function, acute rejection episodes, and impaired long-term allograft survival after kidney transplantation. This antigen-independent inflammatory process produces tissue damage. Isogeneic transplantation in a rat model is a useful method for study of nonimmunologic risk factors for kidney damage. OBJECTIVE: To study the effect of sirolimus on I/R injury using only 1 dose of the drug in the donor. MATERIALS AND METHODS: Eighteen rats were allocated to 3 groups of 6 rats each: sham group, control group, and rapamycin group. RESULTS: Improved renal function and systemic inflammatory response were observed in the rapamycin group compared with the control group (Deltaurea, Deltacreatinine, and DeltaC3, all P < .01). The number of apoptotic nuclei in the renal medulla in the control group was higher than in the rapamycin group (P < .01). Tubular damage was less severe in the rapamycin group compared with the control group (P < .01). Complement 3 and tumor necrosis factor-alpha expression in the kidney samples were significantly decreased when rapamycin was given to the donor rats (P > .01). Bcl-2 protein was upregulated in the rapamycin group compared with the control group (P < .01). CONCLUSION: Administration of rapamycin in donors attenuates the I/R injury process after kidney transplantation in a rat model. PMID- 20172352 TI - Dendritic cells and B cells cooperate in the generation of CD4(+)CD25(+)FOXP3(+) allogeneic T cells. AB - BACKGROUND: CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) play an essential role in immune tolerance, suppressing responses against self-antigens. Additionally, Treg play an important role in maintaining immunosuppression to alloantigens as well as to other antigens. It is well known that in the gut, a subset of dendritic cells produces retinoic acid (RA), which together with transforming growth factor (TGF-beta) is able to differentiate naive T cells into Treg. The aim of this study was to establish the role of antigen-presenting cells (APC) in the differentiation of allogeneic Tregs under the effect of RA and TGF beta. METHODS: Splenic CD4(+)CD25(-) naive T cells from C57BL/6 mice were co cultured with splenic CD11c-enriched APC from Balb/c mice in the presence of TGF beta, RA, and interleukin (IL-2). After 6 days of culture, cells were analyzed for the expression of Foxp3 by flow cytometry. Additionally, we investigated the role of B cells and dendritic cells (DCs) and their stimulatory capacity in the generation of Tregs. RESULTS: Our results showed that co-culture of naive T cells with the appropriate level of stimulation by APC in the presence of TGF-beta, RA, and IL-2 provided a new powerful approach to generate allogeneic Treg cells. We demonstrated that although B cells and DCs can generate Tregs by themselves, a mixure of both APC improved their capacity to efficiently generate Tregs. Also, we observed that although the addition of IL-2 to the cultures was not crucial to generate Tregs, it was required to optimize their expansion and cell survival. PMID- 20172353 TI - Induction of tolerance in renal transplantation using splenic transplantation: experimental study in a canine model. AB - OBJECTIVE: To evaluate in a canine model the induction of tolerance to renal transplantation after splenectomy and splenosis. MATERIALS AND METHODS: This prospective, experimental, comparative, longitudinal study included 4 experimental groups, each comprising 4 dogs. Group 1 (control group) underwent renal transplantation only; group 2 underwent renal transplantation and splenectomy; group 3 underwent renal transplantation and splenosis; and group 4 underwent renal transplantation, splenectomy, and splenosis. Survival and degree of rejection were compared between the 4 groups. RESULTS: Splenosis improved renal function after transplantation, as indicated by increased serum creatinine concentration (group 3, 6.2 mg/dL vs group 1, 12.9 mg/dL). Comparison of weighted survival curves (corrected for degree of rejection) demonstrated a significant difference between group 2 (66.0 days) and group 4 (66.2 days) vs group 1 (52.7 days) and group 3 (41.2 days) (P = .05, Wilcoxon rank sum test). CONCLUSION: These results suggest that in this experimental model of renal transplantation, splenosis and splenectomy induce clinical tolerance, as indicated by improved renal function and prolonged recipient survival. PMID- 20172354 TI - Isolation of viable porcine islets by selective osmotic shock without enzymatic digestion. AB - Islet transplantation is a potential cure for type 1 diabetes, but clinical results have been disappointing. Currently, islet isolation is by enzymatic digestion of the pancreas which has significant pitfalls: warm ischemia exposure, collagenase-induced damage to the islet mass and viability, poor reproducibility, high cost, a relatively low number of islets obtained per whole pancreas, and selection of islets for collagenase resistance rather than for glucose responsiveness. In the present study we performed a series of experiments in a porcine model to demonstrate the feasibility of a new isolation method based on selective osmotic shock (SOS) using very high glucose solutions, doubling or tripling physiological osmotic strength. The SOS method can be carried out at room temperature or in the cold eliminating warm ischemia time which damages the islets. The SOS method does not depend on the texture of the pancreas so all pancreases can be processed identically and the process can be fully automated. The SOS method isolates all the islets of the pancreas regardless of size and shape allowing a greater number of islets to be harvested. The SOS method avoids exposure to toxins in collagenase solutions, is inexpensive and selects for islets with high concentrations of Glut 2 transporters, representing the best glucose responding islets. The SOS method showed a comparable recovery of islets from young pig pancreas and the islets showed improved viability. We conclude that the selective osmotic shock (SOS) method of separating islets from the pancreatic tissue is superior to the collagenase method. PMID- 20172355 TI - Irregular xenoantibodies against human red blood cells in Papio anubis, P ursinus, P hamadryas, P papio, Saimiri sciureus, and Macaca mulatta: possible effect on xenotransplantation results. AB - OBJECTIVE: To assess the presence of irregular xenoantibodies against human red blood cells (RBCs) in 6 primate species used in xenotransplantation and other experimental procedures. MATERIALS AND METHODS: Serum samples from 109 baboons of 4 different species (olive, chacma, sacred, and Guinea), 38 rhesus macaques, and 30 squirrel monkeys were tested for irregular xenoantibodies using an agglutination test using human RBCs of known phenotype for Rh, Kell, Kidd, Lewis, Lutheran, P1, and Duffy antigens, commercially available as RBC I, II, and III. RESULTS: We found hemagglutination for RBC I in 49%, 22%, 100%, 57%, 32%, and 33% of olive, chacma, sacred, and Guinea baboons, rhesus macaques, and squirrel monkey, respectively. The frequency for RBC II was 49%, 50%, 100%, 57%, 37%, and 33%, respectively, and for RBC III was 56%, 37%, 100%, 79%, 34%, and 33%, respectively. There were differences in frequency depending on the sex of the rhesus macaques; all 3 RBCs tested were higher in the females: 44% vs 0%, P = .008; 48% vs 1%, P = .02, and 44% vs 9.1%, P = .04 for RBC I, II, and III, respectively. There were differences due to age in only olive baboons, and a higher frequency in younger animals compared with juvenile, subadult, and adult animals for all 3 human RBCs. CONCLUSIONS: Assessment of irregular antibodies in the presence of primate serum should be taken into account during any experimental xenotransplantation protocol. PMID- 20172356 TI - Prophylaxis and treatment of Chagas disease in renal transplant donor and recipient: case report. AB - Chagas disease is a prevalent zoonosis in Latin America, caused by the protozoa Trypanosoma cruzi and transmitted by Triatoma infestans. Part of the infectious cycle consists of chronic subclinical parasitemia, causing in the long term end organ damage. Amastigotes have been isolated from various organs including native and allograft renal parenchyma; thus, transplantation plus immunosuppression therapy is another mode of disease transmission and reactivation. Herein, we report 2 successful kidney transplantations cases in which either infection or reactivation was averted using prophylactic nitroderivates. PMID- 20172357 TI - Residual disease after neoadjuvant chemotherapy for breast cancer. PMID- 20172358 TI - The role of anti-tumor necrosis factor receptor agents in cancer survivors: does the risk justify the benefit? PMID- 20172359 TI - The many uses of cancer prediction tools. PMID- 20172360 TI - What is a real nomogram? AB - The current resurgence in the use of nomograms as diagnostic and prognostic tools has legitimate roots in their effectiveness in facilitating communication between the doctor and patient. By returning to a more classical approach to nomography, graphical insights can further enlighten the patient beyond what can be achieved with current methods, while at the same time simplifying the process. We propose a going-forward extension that addresses the issue of further use of computing technology to continue to enhance understanding. PMID- 20172361 TI - Whither TNM? AB - Cancer staging has been the lynchpin of diagnosis, treatment, and prognosis for several years. However, new advances in molecular genetics, statistics, and computer science have been mounting a challenge to cancer staging in accurate prognostication. Staging systems, such as tumor-node-metastasis (TNM) classification, have been reacting to these challenges by increasing the number of stage groupings. In this article we examine the history of the number of increases in stage groups and argue that recent increases have not been accompanied by increased ease of use or better prognostic ability. We recommend that parsimony should be considered to counterbalance the instinct to increase the number of categories in future revisions of staging systems such as TNM. PMID- 20172362 TI - Traditional statistical methods for evaluating prediction models are uninformative as to clinical value: towards a decision analytic framework. AB - Cancer prediction models are becoming ubiquitous, yet we generally have no idea whether they do more good than harm. This is because current statistical methods for evaluating prediction models are uninformative as to their clinical value. Prediction models are typically evaluated in terms of discrimination or calibration. However, it is generally unclear how high discrimination needs to be before it is considered "high enough"; similarly, there are no rational guidelines as to the degree of miscalibration that would discount clinical use of a model. Classification tables do present the results of models in more clinically relevant terms, but it is not always clear which of two models is preferable on the basis of a particular classification table, or even whether either model should be used at all. Recent years have seen the development of straightforward decision analytic techniques that evaluate prediction models in terms of their consequences. This depends on the simple approach of weighting true and false positives differently, to reflect that, for example, delaying the diagnosis of a cancer is more harmful than an unnecessary biopsy. Such decision analytic techniques hold the promise of determining whether clinical implementation of prediction models would do more good than harm. PMID- 20172363 TI - Adjuvant chemotherapy for resected stage II and III colon cancer: comparison of two widely used prognostic calculators. AB - Two Web-based prognostic calculators (Adjuvant! and Numeracy) are widely used to individualize decisions regarding adjuvant therapy among patients with resected stage II and III colon cancer. However, these tools have not been directly compared. Hypothetical scenarios were formulated for the Numeracy calculator based on all potential combinations of age, lymph nodes status, tumor stage, and grade of tumor. These were then applied to three postsurgical therapy choices: observation, 5-fluorouracil (5-FU), or FOLFOX (5-FU, leucovorin, and oxaliplatin chemotherapy) to obtain the predicted 5-year disease-free survival (DFS) and overall survival (OS). Wilcoxon signed rank tests were used to compare the numerical predictions between the Adjuvant! and Numeracy calculators for each combination. A total of 192 hypothetical patient scenarios were obtained. For these patients, DFS and OS predictions from Adjuvant! were statistically significantly different than Numeracy (P <.05), except for four of 144 categories. While the estimated benefit in DFS and OS for 5-FU compared to surgery obtained from Adjuvant! and Numeracy were similar, the benefit in DFS and OS for FOLFOX over 5-FU, obtained from the Adjuvant! tool was slightly lower than that estimated from Numeracy. Among patients with resected stage II and III colon cancer, the DFS and OS estimates obtained from Numeracy and Adjuvant!, regarding the benefit of 5-FU over surgery, are similar, but the benefits of FOLFOX over 5 FU differ. Validation studies are needed to clarify the discrepancy and to assess the accuracy of these tools for predicting actual patient outcomes. PMID- 20172364 TI - Tailored cancer outcome prediction and informed consent. AB - Clinically relevant disparities in the outcomes of cancer treatment between institutions are well established. Some authors have argued that physicians have an ethical obligation to disclose these disparities as part of the informed consent process.(1) We believe that preservation of patient autonomy requires disclosure of treatment institution-specific outcomes and that statistical prediction models tailored to individual patients are the best way to frame this discussion. We describe a utopian system to gather and disseminate cancer outcome data based on the United Network for Organ Sharing and articulate why accurate and equitable prediction models are feasible both scientifically and logistically. We also discuss strategies of design and oversight required to mitigate any unintended negative downstream consequences of such a system. PMID- 20172365 TI - The use of central laboratories and remote electronic data capture to risk-adjust therapy for pediatric acute lymphoblastic leukemia and neuroblastoma. AB - The Children's Oncology Group (COG) is a National Cancer Institute (NIH) sponsored cooperative clinical trials group with the primary mission of conducting pediatric cancer clinical trials. COG has complex risk classification systems that are used to deliver risk-stratified therapy for many pediatric cancers, including clinical trials for acute lymphoblastic leukemia (ALL) and neuroblastoma (NB). Classification of patients is based on biological, clinical, and genomic data obtained at initial diagnosis and during the initial phases of therapy. The COG Web-based remote data entry (RDE) system enables submission of data in real time from central laboratories and treating institutions. The data are then used in an automated fashion to determine the risk group and corresponding treatment assignment for individual patients enrolled in COG clinical trials. PMID- 20172366 TI - Digitization and its discontents: future shock in predictive oncology. AB - Clinical cancer care is being transformed by a high-technology informatics revolution fought out between the forces of personalized (biomarker-guided) and depersonalized (bureaucracy-controlled) medicine. Factors triggering this conflict include the online proliferation of treatment algorithms, rising prices of biological drug therapies, increasing sophistication of genomic-based predictive tools, and the growing entrepreneurialism of offshore treatment facilities. The resulting Napster-like forces unleashed within the oncology marketplace will deliver incremental improvements in cost-efficacy to global healthcare consumers. There will also be a price to pay, however, as the rising wave of digitization encourages third-party payers to make more use of biomarkers for tightening reimbursement criteria. Hence, as in other digitally transformed industries, a new paradigm of professional service delivery-less centered on doctor-patient relationships than in the past, and more dependent on pricing and marketing for standardized biomarker-defined indications-seems set to emerge as the unpredicted deliverable from this brave new world of predictive oncology. PMID- 20172367 TI - Learning curves in classification with microarray data. AB - The performance of many repeated tasks improves with experience and practice. This improvement tends to be rapid initially and then decreases. The term "learning curve" is often used to describe the phenomenon. In supervised machine learning, the performance of classification algorithms often increases with the number of observations used to train the algorithm. We use progressively larger samples of observations to train the algorithm and then plot performance against the number of training observations. This yields the familiar negatively accelerating learning curve. To quantify the learning curve, we fit inverse power law models to the progressively sampled data. We fit such learning curves to four large clinical cancer genomic datasets, using three classifiers (diagonal linear discriminant analysis, K-nearest-neighbor with three neighbors, and support vector machines) and four values for the number of top genes included (5, 50, 500, 5,000). The inverse power law models fit the progressively sampled data reasonably well and showed considerable diversity when multiple classifiers are applied to the same data. Some classifiers showed rapid and continued increase in performance as the number of training samples increased, while others showed little if any improvement. Assessing classifier efficiency is particularly important in genomic studies since samples are so expensive to obtain. It is important to employ an algorithm that uses the predictive information efficiently, but with a modest number of training samples (>50), learning curves can be used to assess the predictive efficiency of classification algorithms. PMID- 20172368 TI - Reagent specificity and scientific integrity: a necessary combination. PMID- 20172369 TI - Neuroblastoma. PMID- 20172370 TI - The future of otolaryngology training threatened: the negative impact of residency training reforms. AB - Resident training regulations developed by the Accreditation Council for Graduate Medical Education (ACGME) in 2003 have limited resident work hours and autonomy. Proposed to improve patient safety and resident education, these regulations have not had their intended effects. They have acted to dilute otolaryngology residents' experiences, thereby weakening their training. The ACGME is currently considering tightening these regulations. By advocating for residency guidelines that are more conducive to the needs of otolaryngology education, otolaryngologists can guarantee continued superlative training for future residents. PMID- 20172371 TI - Diagnostic efficacy of surgeon-performed ultrasound-guided fine needle aspiration: a randomized controlled trial. AB - OBJECTIVE: To evaluate the clinical efficacy of surgeon-performed, office-based head and neck ultrasound in facilitating diagnostic fine needle aspiration (FNA) of lesions in the head and neck. STUDY DESIGN: A randomized controlled trial of ultrasound-guided FNA versus traditional palpation-guided technique for palpable masses in the head and neck. SETTING: An office-based study performed in a military academic medical center. SUBJECTS AND METHODS: Eighty-one adults older than 18 years of age with a palpable head and neck mass (less than 3 cm in largest diameter) were randomized to ultrasound-guided or traditional palpation guided FNA of a head and neck mass. Measured variables and outcomes for the study included tissue adequacy rates, tissue type, and operator variability. RESULTS: Following three passes using either palpation or ultrasound guidance, a comparative tissue adequacy rate of 84 percent for ultrasound guidance versus 58 percent for standard palpation was established (P < 0.014). With regard to tissue type, a statistically significant comparative diagnostic advantage for ultrasound guidance was observed in thyroid tissue while remaining statistically insignificant for lymphatic and salivary tissues. No statistical significance was found when comparing the ability of otolaryngology residents versus attending otolaryngologists to obtain ultrasound-guided diagnostic samples. CONCLUSION: Office-based surgeon-performed ultrasound-guided FNA of palpable lesions in the head and neck yields a statistically significant higher diagnostic rate compared to standard palpation technique. Our institutional experience supports the utility of surgeon-performed ultrasound as a core competency in clinical practice. PMID- 20172372 TI - Primary care approach to dysphonia. AB - OBJECTIVE: To understand how primary care physicians manage patients with dysphonia and the barriers they face when evaluating patients for voice problems. STUDY DESIGN: Cross-sectional survey. SETTING: Primary care community. SUBJECTS AND METHODS: A total of 933 internal and family medicine physicians were randomly selected from a database of physicians in a referral basin of a tertiary care medical center and mailed a questionnaire. Questions concerned physician comfort level in recognizing an abnormal voice, their view of the quality of life impact of dysphonia, frequency of evaluating patients for voice problems, barriers to the evaluation of voice problems, reasons for referral, and common treatments prior to referral. RESULTS: A total of 271 physicians responded, for a response rate of 29.0 percent. Of those who responded, 36.5 percent routinely evaluate their patients for voice problems. Reasons for not evaluating patients for voice problems were patients not complaining about hoarseness, more pressing issues, not feeling comfortable assessing patients for voice problems, and time constraints. Chronic voice changes and not being able to understand patients' speech were the most common reasons for referral. Reflux and allergy treatment were common treatment modalities prior to referral. A total of 67.5 percent of respondents were interested in learning more about voice problems. CONCLUSION: Primary care physicians face limitations with respect to evaluating patients for voice problems. Otolaryngologists must continue outreach efforts and collaboration with primary care colleagues in order to enhance the screening for voice problems. PMID- 20172373 TI - Endoscopic management of sphenoclival neoplasms: anatomical correlates and patient outcomes. AB - OBJECTIVE: To characterize the endoscopic anatomy of the sphenoid sinus and the adjacent clivus and cavernous sinus, and to review patient outcomes for neoplasms in this region. STUDY DESIGN: Cadaver dissection and chart review. SETTING: Cadaver laboratory and tertiary care center. SUBJECTS AND METHODS: Fresh-frozen cadaver heads were dissected to study the endoscopic anatomy of the sphenoclival region. Retrospective chart review of patients undergoing endoscopic resection of sphenoclival neoplasms between 2000 and 2008 was performed. RESULTS: Transnasal endoscopic access to the sphenoid sinus was obtained in 10 cadaver heads. A clival window with mean dimensions of 1.4 cm x 1.7 cm was created. Through the clival window, identification and dissection of the basilar and vertebral arteries, mamillary bodies, third ventricle, cranial nerves III through VI, and cervical rootlets were possible. Nineteen patients with mean age of 56.2 years were treated. The most common pathologies were inverted papilloma (5), chordoma (4), squamous cell carcinoma (2), and adenoid cystic carcinoma (2). None of the patients required adjunct craniotomies. Nine patients received adjuvant therapies. Thirteen (68.4%) patients had no evidence of disease, five (26.3%) patients were alive with disease, and one (5.3%) patient died of disease at mean follow-up of 32.6 months. CONCLUSION: The sphenoclival region poses a significant surgical challenge given its central location at the skull base and proximity to critical structures. This study demonstrates that transnasal endoscopic access to the sphenoclival region is technically feasible and allows successful surgical extirpation of tumors with a low complication rate and acceptable patient outcomes. PMID- 20172374 TI - Maxillary removal and reinsertion: a favorable approach for extensive anterior cranial base tumors. AB - OBJECTIVE: To analyze the long-term results and the complications related to an expanded series of maxillary removal and reinsertion (MRRI) with 18-year surgical experience. STUDY DESIGN: Case series with chart review of the MRRI patients in the last 18 years. SETTING: The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute. SUBJECTS AND METHODS: Seventy-eight patients who underwent MRRI from February 1990 through February 2007. The median age was 51 years (range 11-77 yrs). Sixty-two (80%) patients had malignant lesions. RESULTS: MRRI has been successfully completed in all 78 patients, with no intraoperative mortality. The most commonly encountered malignant neoplasm was squamous cell cancer (40.3%), followed by esthesioneuroblastoma (24.1%), adenoid cystic cancer (8%), and other neoplasms (27.4%). The most commonly encountered postoperative complication was diplopia, which has persisted in five (6.4%) patients in the short-term and in three (4%) patients in the long-term follow-up. Nasal asymmetry was the most common long term complication (17.9%), followed by plate-associated problems (10.2%) and midface asymmetry (10.2%). Overall five-year survival for the patients with squamous cell carcinoma was 62 percent. CONCLUSION: MRRI is a favorable surgical technique for the treatment of anterior cranial base (ACB) tumors in adults and even in children. It improves operative morbidity by preserving both function and form of the maxillary region and gives excellent exposure to ACB. PMID- 20172375 TI - Janus flap: bilateral nasoseptal flaps for anterior skull base reconstruction. AB - OBJECTIVE: Large dural defects after extended endoscopic endonasal skull base resections require meticulous reconstruction to prevent a cerebrospinal fluid leak postoperatively. The nasoseptal flap is a vascularized tissue graft developed to aid in the multilayer reconstruction of the skull base. The purpose of this study is to describe the first experiences with bilateral nasoseptal flaps for reconstruction of very large skull base defects. STUDY DESIGN: Prospective, observational study. SETTING: Large tertiary referral center (New York Presbyterian Hospital). SUBJECTS AND METHODS: Five patients underwent a multilayer reconstruction after an extended endoscopic transsphenoidal skull base surgery that included bilateral nasoseptal flaps. Pathologies consisted of two pituitary macroadenomas, one planum sphenoidale meningioma, one craniopharyngioma, and one cavernous sinus hemangioma. RESULTS: All five patients underwent successful skull base reconstruction without a cerebrospinal fluid leak, complication at the reconstruction site, or anterior extension of the posterior septal perforation. CONCLUSION: Bilateral nasoseptal flaps are a viable option for large dural defects of the anterior and ventral skull base when one nasoseptal flap may not completely seal the entire defect. PMID- 20172376 TI - Expression of cell-cycle regulators (cyclin D1, cyclin E, p27kip1, p57kip2) in papillary thyroid carcinoma. AB - OBJECTIVE: To evaluate the expression of cell-cycle regulators in papillary thyroid carcinoma in relation to lymph node metastatic features, and to determine whether immunohistochemical staining of cell-cycle markers can predict lymph node metastasis. STUDY DESIGN: Cross-sectional study of prior surgical specimens. SETTING: Academic tertiary referral center. SUBJECTS AND METHODS: We reviewed the clinical records of patients who had undergone surgery for thyroid cancer and follicular adenoma between January 2005 and May 2008 at our clinic. Among these cases, 92 patients, comprising 28 patients with follicular adenoma, 32 with papillary thyroid carcinoma without lymph node metastasis, and 32 with papillary thyroid carcinoma with lymph node metastasis, were selected randomly. Formalin fixed, paraffin-embedded tissues from the 92 patients were immunohistochemically stained for cyclin D1, cyclin E, p27(kip1), and p57(kip2), and protein expression levels were quantified and compared among the groups. RESULTS: Tumor specimens from the papillary thyroid carcinoma group had significantly higher expression levels of cyclin D1 and cyclin E, and cytoplasmic expression of p57(kip2) than the other two groups (P < 0.05). In particular, all malignant cases expressed cyclin D1, and cytoplasmic p57(kip2) was expressed only in malignant cases. Furthermore, differences in the grade of cyclin D1 expression according to lymph node metastasis were statistically significant (P < 0.05). CONCLUSION: Our results suggest that immunohistochemistry of certain cell-cycle regulators may be helpful in the diagnosis of papillary thyroid carcinoma, and that cyclin D1 in particular may be a useful marker for evaluating lymph node metastasis. PMID- 20172377 TI - Stereotactic body radiotherapy for refractory cervical lymph node recurrence of nonanaplastic thyroid cancer. AB - OBJECTIVE: To investigate the feasibility and efficacy of stereotactic body radiotherapy as salvage treatment for cervical node recurrence from nonanaplastic thyroid cancer refractory to other modalities. STUDY DESIGN: Pilot study. SETTING: A single institution-based practice. SUBJECTS AND METHODS: Between August 2002 and November 2007, nine patients with recurrent nonanaplastic thyroid cancer were treated with stereotactic body radiotherapy for nodal metastases. Radiotherapy was delivered in one to three fractions, and the median dose was 36 Gy (range 30-39 Gy). RESULTS: Twenty-nine nodes in nine patients were treated. Seven patients had papillary carcinoma, and two had medullary carcinoma. These patients developed nodal recurrence after they received salvage surgery and/or radioisotope (RI) treatment for recurrent thyroid cancer. All nodes were in the cervical or supraclavicular areas, excepting one hilar node. Retropharyngeal node metastases were present in five patients. The median follow-up period was 23 months (range 4-63 mo). No local progression was observed in nodes treated by stereotactic body radiotherapy. Four patients developed new metastases in nontarget regional nodes after radiotherapy, and in two of these, regional failure was salvaged by additional stereotactic body radiotherapy. No serious adverse events were observed in any patient. CONCLUSION: In select patients, stereotactic body radiotherapy may be a feasible option for treating refractory nodal recurrence from nonanaplastic thyroid cancer. Further studies are necessary to define the role of stereotactic body radiotherapy in the management of thyroid cancer. PMID- 20172378 TI - Outcomes of laser thermal therapy for recurrent head and neck cancer. AB - OBJECTIVE: To review the outcomes of a phase II study using laser-induced thermal therapy (LITT) as a palliative treatment for 106 patients with recurrent head and neck tumors. STUDY DESIGN: Retrospective study. SETTING: Tertiary hospital in the United States. SUBJECTS AND METHODS: The primary endpoints were tumor response and survival. Prognostic values were assessed by the Kaplan-Meier method. RESULTS: The best results were seen in oral cavity tumors, in which mean survival was 29.1 months, as compared to neck tumors (mean 14.4 +/- 6.9 months; range 7.5 20.7 months; with a 95% confidence interval). Further analysis showed that clinical factors such as gender, smoking, and alcohol use were not indicators of poor prognosis, whereas neck disease and tumor stage at first treatment were relevant factors. CONCLUSION: In this study, 40 out of 106 patients treated by LITT remained alive at the end of our follow-up, and a complete response was seen in 24 (22.6%) patients. The highest response rate was seen in oral cavity tumors, which suggests that tumor location at this site may be a predictor of favorable outcome with LITT. PMID- 20172379 TI - Computed tomographic angiography with three-dimensional reconstruction for transoral laser microsurgery. AB - OBJECTIVE: To identify major arteries in relationship to large pharyngeal tumors during transoral laser microsurgery. STUDY DESIGN: Case series with planned data collection. SETTING: Mayo Clinic, Jacksonville, Florida. SUBJECTS AND METHODS: We developed a new technique that combines three-dimensional CT angiography and enhanced soft-tissue neck CT for evaluation of pharyngeal tumors before transoral laser microsurgery. Data from CT angiography were used to create three dimensional images of the tumor and adjacent arterial branches to better orient the surgeon to the spatial relationships of major arteries and pharyngeal tumors. Included were selected patients who had large tumors involving the pharynx and who underwent transoral laser microsurgery. RESULTS: Eighteen patients were studied from June 2008 through January 2009. Tumor enhancement was absent or modest in four of 18 patients. Three of these four patients had superficial squamous cell carcinomas and one had adenoid cystic carcinoma. The remaining 14 patients had good tumor enhancement. The tumor involved the lingual artery in three and displaced the lingual or facial artery in two of these 14 patients. One anomalous right inferior thyroid artery was identified. Compared with routine enhanced soft-tissue neck CT, three-dimensional CT angiography greatly enhanced the anatomical relationships of the major arteries. In one patient, the surgeon's approach was changed after three-dimensional CT angiography demonstrated an encased lingual artery. CONCLUSION: Three-dimensional CT angiography was useful in identifying the anatomical orientation of major arteries and the planning of transoral laser microsurgery to treat tumors involving the pharynx. PMID- 20172380 TI - When to address level I lymph nodes in neck dissections? AB - OBJECTIVE: To investigate the involvement of level I neck lymph node groups in head and neck carcinoma and compare the effect of primary tumor sites, such as oral cavity (OC), oropharynx (OP), hypopharynx (HP), and larynx (Lx), on level I lymph node metastasis. STUDY DESIGN: Case series with chart review. SETTING: Comprehensive Cancer Center. SUBJECTS AND METHODS: A total of 243 patients with OC and laryngopharyngeal carcinoma who underwent neck dissections in the last three years were included in the study. The primary tumor site was OC, followed by OP, Lx, HP, and carcinoma of unknown primary (CUP). RESULTS: Level I was involved in 29 of 243 (11.9%) patients. The other levels were also positive in all but five (17.2%) level I-involved patients. The primary tumor site with level I lymph node metastasis was OC (19.1%), followed by CUP (11.1%), OP (9.8%), Lx (4.4%), and HP (0%). The Lx primary site involved level I only if there were multiple other adverse prognostic features, such as N3 neck, extracapsular spread, pathologic involvement of all resected lymph nodes, involvement of all levels I-V, and invasion of the submandibular gland. CONCLUSION: Although the submandibular content is resected as part of radical and modified radical neck dissections, level I-sparing selective neck dissections could be a safe and effective surgical neck management strategy in appropriately selected patients with OP, Lx, and HP carcinoma. PMID- 20172381 TI - Transfusion criteria in free flap surgery. AB - OBJECTIVE: The ideal hematocrit for patients undergoing free flap reconstruction is unknown. It is standard practice to keep hematocrit levels above 30 percent, although there is evidence that blood transfusions are associated with both infectious and noninfectious complications. We propose that lowering the trigger for postoperative transfusions from 30 percent to 25 percent will not increase flap-related complications and may reduce unnecessary blood transfusions. STUDY DESIGN: Observational cohort study. SETTING: Tertiary care center. SUBJECTS AND METHODS: Patients undergoing free tissue transfer from January 2007 through February 2008 received blood transfusions for hematocrit < 30 percent, whereas patients having surgery from March 2008 through April 2009 received blood transfusions for hematocrit < 25 percent. Outcomes include flap-related complications, length of stay, number of units transfused, and lowest postoperative hematocrit. RESULTS: In the group transfused for hematocrit < 30 percent, 123 patients underwent 129 free flaps. In the group transfused for hematocrit < 25 percent, 122 patients underwent 135 flaps. The mean lowest postoperative hematocrit levels were significantly lower in the group transfused for hematocrit < 25 percent compared with the group transfused for hematocrit < 30 percent (26.6% vs 28.4%, respectively, P < 0.0001). The group with hematocrit < 25 percent also received fewer units of blood transfused (1.47 vs 2.11, P = 0.028). Complication rates between the two groups were not significantly different aside from higher rates of fistula and respiratory failure in the group transfused for hematocrit < 30 percent. Flap loss was 2.3 percent compared with 6.7 percent (P = 0.138). CONCLUSION: For patients undergoing free flap surgery, a postoperative transfusion trigger of hematocrit < 25 percent decreases blood transfusion rates without increasing rates of flap-related complications. PMID- 20172382 TI - Role of nasal muscles in nasal valve collapse. AB - OBJECTIVE: This study was performed to determine the role of nasal muscle function in patients with dynamic or static nasal valve collapse by comparing the electromyographic activities of nasal muscles in healthy individuals. STUDY DESIGN: Cross-sectional clinical study. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Twenty adult patients with dynamic nasal valve collapse, 18 patients with unilateral static nasal valve stenosis (septum deviation), and 20 healthy adults were included in the study. The activity of their nasal muscles was measured by surface electromyography (EMG), and the results were compared for the patient and control groups. RESULTS: No abnormal finding was found in any of the nasal muscles of the control group. In the majority of patients with dynamic nasal valve pathology, statistically significant functional disorders were detected in the m dilator naris anterior and m nasalis transversalis muscles compared with the controls. During inspiration and expiration in patients with static nasal valve pathology, some revealed muscular abnormities during inspiration. Normal muscle activation was observed in all of the patients during expiration. CONCLUSION: Determination of agents involved in pathologies of the nasal valve region is necessary for planning appropriate treatment. The role of nasal muscles in dynamic nasal valve pathologies, which has not been previously recognized, should be considered. A more effective and adequate solution for the nasal sidewalls than static pathologies should be considered in these patients by taking into account the muscular activity disorders detected by EMG at the stage of surgical treatment. PMID- 20172383 TI - Effect of oral tolerance in a mouse model of allergic rhinitis. AB - OBJECTIVE: Induction of oral tolerance (OT) is known to prevent allergic inflammation in models of asthma. This study investigated the preventive effect of OT and airway remodeling in a mouse model of allergic rhinitis (AR). STUDY DESIGN: An in vivo study using an animal model. SETTING: Catholic Research Institutes of Medical Science. METHODS: Forty six-week-old, female BALB/c mice were divided into four groups: control, AR, low-dose OT, and high-dose OT. To induce OT, mice were fed ovalbumin (OVA) before sensitization with OVA/aluminum hydroxide, 1 mg for six days in the low-dose OT group and a 25 mg single dose in the high-dose OT group. Mice in the AR group were fed phosphate-buffered saline. After sensitization followed by challenges with OVA during six weeks, nasal behaviors, interleukin (IL)-13 and interferon gamma (IFN-gamma) levels in nasal lavage (NAL) fluids, as well as OVA-specific IgE levels in serum, were measured. The degree of goblet cell hyperplasia and thickness of lamina propria were observed in nasal tissues by periodic acid-Schiff and Masson's trichrome stain. A P value < 0.05 was accepted as statistically significant. RESULTS: Both OT groups showed a significant decrease in inflammatory cells, IL-13 and IFN-gamma in NAL fluids, as well as OVA-specific IgE levels in serum compared with the AR group. In addition, the degree of goblet cell hyperplasia and thickness of lamina propria were attenuated in both OT groups compared with the AR group. Further, these alterations did not differ significantly between the two OT groups. CONCLUSION: These results suggest that OT may effectively reduce allergic inflammation as well as airway remodeling in a mouse model of AR. PMID- 20172384 TI - Impact of pretreatment nasal symptoms on treatment outcome in allergic rhinitis. AB - OBJECTIVE: The Allergic Rhinitis and its Impact on Asthma (ARIA) classification of allergic rhinitis (AR) is based on the severity and duration of nasal symptoms. Whether nasal symptoms have an impact on treatment outcome is unclear. The aim of this study was to evaluate the correlation between pretreatment nasal symptoms and therapeutic response in AR. STUDY DESIGN: Case series with planned data collection. SETTING: Tertiary medical center. SUBJECTS AND METHODS: Sixty nine AR patients were classified according to ARIA class: mild or moderate-severe intermittent AR (MIAR or MSIAR) and mild or moderate-severe persistent AR (MPAR or MSPAR). All patients were treated over 28 days with 220 microg of intranasal triamcinolone acetonide once daily. Nasal symptoms, peak expiratory flow index, and global symptom control were used to evaluate treatment outcome. RESULTS: At 28 days after treatment, MSPAR patients showed the worst global symptom control, followed by MSIAR, MPAR, and MIAR (mean global symptom controls were 76.5%, 83.8%, 87.7%, and 89.0%, respectively). Pretreatment total nasal symptom score was inversely correlated with global symptom control (rho = -0.405, P < 0.001), but positively correlated with percent total nasal symptom score and peak expiratory flow index improvements (rho = 0.271, P = 0.024; and rho = 0.371, P = 0.002, respectively). Blocked nose had the best inverse correlation with global symptom control (rho = -0.389, P = 0.001). CONCLUSION: A worse treatment outcome despite more clinical improvements during the treatment period in a higher severity score suggests the therapeutic predictive value of pretreatment nasal symptom scoring and the need for more dosing and continuing medication in higher scores, especially in blocked nose. PMID- 20172385 TI - Pulsating aerosols for drug delivery to the sinuses in healthy volunteers. AB - OBJECTIVE: Approximately 10 to 15 percent of the European and U.S. population have chronic rhinosinusitis, but effective treatment remains a challenge. There has been limited success using topical drug delivery to the nose and the paranasal cavities/sinuses, in part because most nasally administered aerosol drug formulations are efficiently filtered at the nasal valve and fail to reach the osteomeatal area and sinuses. STUDY DESIGN: Feasibility study. SETTING: Nuclear medicine department. SUBJECTS AND METHODS: Pulsating airflows were applied to the nasal cavity and sinus ventilation was studied in five healthy human volunteers using dynamic (81m)Kr-gas gamma camera imaging. Furthermore, deposition and retention of (99m)Tc-DTPA radiolabeled aerosols delivered by nasal pump sprays or by pulsating aerosols was assessed in each volunteer over a 24 hour period. RESULTS: Only the pulsating airflow demonstrated efficient (81m)Kr gas ventilation of the paranasal sinuses. No drug was deposited into the sinuses using nasal pump sprays, but up to 6.5 percent of the nasally administered drug was deposited into the sinuses using pulsating airflow. Clearance kinetics of the drug was reduced after pulsating aerosol delivery compared to nasal pump sprays. Residence time of the drug at the site of deposition was up to three-fold longer with pulsating aerosol delivery than with nasal pump sprays. CONCLUSION: Our data support the hypothesis that topical drug delivery in relevant quantities to the nose and osteomeatal areas, including the paranasal sinuses, is possible using pulsating airflows. Furthermore, the frequency of drug applications may be reduced due to a delayed clearance and longer residence time. PMID- 20172386 TI - Experience with endoscopic dacryocystorhinostomy using four methods. AB - OBJECTIVE: Evaluation of four methods of endoscopic dacryocystorhinostomy (EDCR) for treating chronic dacryocystitis. STUDY DESIGN: Case series with chart review. MATERIALS AND METHODS: A total of 1450 patients underwent EDCR for epiphora, chronic dacryocystitis, and blocked nasolacrimal ducts. Relief from epiphora, dacryocystitis, and patency of the fistula for all four techniques was compared. A total of 292 patients underwent incision and drainage, 343 patients had grommets inserted, 258 had silastic lacrimal stents inserted, and 557 had the medial wall of the lacrimal sac (LS) removed. Parameters of success were 1) resolution of epiphora, 2) no further attacks of dacryocystitis, and 3) patency of the new fistula. RESULTS: Sixty-five percent failed the incision method, and 68 percent of the patients who underwent the grommet method failed. All 258 patients with lacrimal stents experienced success while the stent remained in situ. Ten patients required removal because the stents created corneal opacities. One required removal because of a foreign body granuloma at the punctum. Only eight (1.4%) patients with removal of the LS failed. On multivariate analysis, female sex (OR = 5.6) was found to be associated with a higher rate of failure. Incision and drainage (OR = 100.1) and grommet insertion (OR = 60.6) were associated with increased risk of failure. Removal of the medial wall of the LS (OR = 0.069) and findings of a clear sac (OR = 0.001) or mucus (OR = 0.204) were associated with success. CONCLUSION: The best EDCR results are achieved by stenting or removal of the medial wall of the LS. In our experience, excision of the medial wall of the LS was as successful as insertion of silastic lacrimal intubation stents, without the disadvantage of causing corneal opacities. PMID- 20172387 TI - Comparative outcomes of using fibrin glue in septoplasty and its effect on mucociliary activity. AB - OBJECTIVE: Our objective was to determine the efficacy of fibrin glue to prevent complications and nasal mucociliary clearance (MCC) after septoplasty compared with a nonabsorbable packing requiring removal (polyvinyl alcohol [PVA] sponge). STUDY DESIGN: Prospective clinical trial with planned data collection. SETTING: The study was conducted at Haydarpasa Numune Education and Research Hospital. METHODS: A total of 44 patients, who had septoplasty operations, were included in the study. We evaluated postoperative pain, sleep disturbance on the night of surgery, bleeding, septal hematoma, synechia, infection, and MCC values in the fibrin glue and PVA sponge groups. RESULTS: The pain scores in the fibrin glue group were significantly lower than in the PVA sponge group (P < 0.01). A statistically significant difference was noted in the number of patients who had mild bleeding in favor of the fibrin glue group (P < 0.05). In the fibrin glue group, 95.7 percent of patients reported that they had normal sleep; in the PVA sponge group, only 23.8 percent of patients reported normal sleep (P < 0.01). In the fibrin glue group, a significant decrease was noted in postoperative MCC values compared with preoperative values (P < 0.01). However, in the PVA sponge group, a significant increase was noted in postoperative clearance values compared with preoperative values (P < 0.01). CONCLUSION: In our series of patients, we have seen no gross complications from fibrin glue usage. Fibrin glue can be readily used in septoplasty; it requires no special treatment, has an adequate hemostatic effect, and appears to promote the regeneration of mucociliary activity of the injured mucosa postoperatively. PMID- 20172388 TI - Acoustic tumor observation and failure to follow-up. AB - OBJECTIVE: To review the clinical course of patients undergoing observation for their acoustic tumor with evaluation of the incidence and contributing variables to failure to follow-up. STUDY DESIGN: Case series with chart review and telephone interview. SETTING: Single subspecialty practice. SUBJECTS AND METHODS: One hundred twenty-two patients underwent an observation period after their unilateral acoustic tumor was diagnosed. Follow-up patterns were noted and multiple patient variables were analyzed to determine risk factors that contributed to risk of failing to keep prescribed follow-up. Telephone interviews and/or public record reviews were conducted to determine the reasons for failing to follow-up. RESULTS: Fifty-two (42.6%) patients failed to keep prescribed follow-up. No preoperative patient or tumor variables were correlated with the risk of failure to follow-up. The investigators were able to contact and interview 20 patients to determine reasons for not keeping follow-up. Of these patients, nine (45%) electively chose not to follow-up, six (30%) did not appear to have a clear understanding of their diagnosis or treatment options despite adequate counseling, and five (25%) had medical problems that took precedence over the acoustic tumor. Very few patients elected to reschedule follow-up even after contact was made. CONCLUSION: Failure to follow-up is a serious problem with acoustic tumor observation protocols. It is difficult to detect which patients are at risk for noncompliance. Patient noncompliance with observation protocols should be considered when determining the most appropriate treatment for each acoustic tumor patient. PMID- 20172389 TI - Safety and efficacy of carbomethylcellulose foam in guinea pig middle ear surgery. AB - OBJECTIVE: Carbomethylcellulose (CMC) foam has been widely adopted to promote hemostasis and healing in sinus surgery. There has been interest in the use of CMC in middle ear surgery. The purpose of this study was to evaluate the safety and efficacy of CMC foam for use in middle ear surgery. STUDY DESIGN: Prospective, controlled. SETTING: Academic research laboratory. SUBJECTS AND METHODS: Adult guinea pigs underwent experimental tympanoplasty followed by packing of the middle ear (n = 19 per group) with CMC, hyaluronic acid (HA), or gelatin sponge (GS). Auditory evoked brainstem response testing and otomicroscopy were performed before and serially for eight weeks after surgery. Tympanic membrane healing, hemostasis, and retention of packing material were assessed. RESULTS: All tympanic membranes treated with CMC healed by week eight. Less postoperative bleeding was observed with CMC than with HA or GS. Surgery elevated auditory thresholds, at least temporarily, in all groups. However, CMC was associated with greater auditory threshold elevation (15-25 dB) at eight weeks across all test frequencies relative to HA or GS (P < 0.01). Residual CMC and scarring were not found in the middle ear, indicating that the hearing loss was sensorineural. No head tilt posturing suggestive of vestibulopathy was seen. CONCLUSION: CMC was associated with hearing loss and may be ototoxic. Therefore, CMC should not be used in human middle ears given the presence of several nontoxic alternative materials. PMID- 20172390 TI - Audiological and transient evoked otoacoustic emission findings in patients with vitiligo. AB - OBJECTIVE: To investigate hearing loss in patients with vitiligo. STUDY DESIGN: Case-control study. SETTING: University hospital. SUBJECTS AND METHODS: Conventional pure-tone and high-frequency audiometric tests were obtained, and pure-tone average hearing thresholds were calculated for 22 consecutive cases with vitiligo and 22 sex- and age-matched controls. Transient evoked otoacoustic emission testing was also performed. RESULTS: There was sensorineural hearing loss on pure-tone audiogram in 16 (36.4%) ears in patients with vitiligo. The hearing thresholds (in dB) were 16.02 +/- 6.61 versus 12.39 +/- 6.05, 15.68 +/- 6.34 versus 13.18 +/- 3.75, 15.80 +/- 13.93 versus 7.39 +/- 6.95, 25.11 +/- 17.40 versus 15.91 +/- 12.91, 29.89 +/- 18.57 versus 17.84 +/- 12.36, and 45.91 +/- 23.31 versus 33.86 +/- 15.99 in the patient and control groups at 0.25, 1, 4, 8, 10, and 12.5 kHz, respectively, and were statistically significantly different. Reduction of transient evoked otoacoustic emission amplitude was statistically significant at 4 kHz in patients with vitiligo (6.34 +/- 3.98 dB vs 8.63 +/- 5.15 dB, P = 0.023). There was no significant difference in reproducibility, stimulus intensity, stability, and average transient evoked otoacoustic emission amplitudes in patients with vitiligo. CONCLUSION: Hearing thresholds at pure-tone and high-frequency audiometry were higher in patients with vitiligo. Also, significantly lower high-frequency amplitudes were recorded during transient evoked otoacoustic emission testing in the disease group. PMID- 20172391 TI - Preoperative predictors of incudal necrosis in chronic suppurative otitis media. AB - OBJECTIVE: To determine the predictive value of preoperative clinical, audiological, and radiological factors in diagnosing incudal necrosis in patients with tubotympanic chronic suppurative otitis media (CSOM). STUDY DESIGN: Case series with planned data collection. SETTING: Tertiary care referral center. SUBJECTS AND METHODS: Patients older than five years of age diagnosed with tubotympanic CSOM who underwent tympanomastoid surgery were recruited. Findings on otoscopy, x-ray mastoid, pure-tone audiometry, and intraoperative otomicroscopy were recorded. RESULTS: Incus necrosis occurred in 24 (16%) of a total of 150 patients. On bivariate analysis, findings of active ear discharge (P = 0.01), anterosuperior location of perforation (P = 0.03), exposure of incudostapedial joint (P = 0.05), edematous middle ear mucous membrane (P = 0.05), middle ear granulations (P = 0.004), foreshortening of the handle of malleus (P = 0.04), moderate to moderately severe hearing loss (41-70 dB HL) (P = 0.000), and air-bone gap > 40 dB (P = 0.001) were found to be associated with incus necrosis. Intraoperative findings of aditus block (P = 0.001) and mastoid granulations (P = 0.005) were also found to be significantly associated with incus necrosis. Mastoid pneumatization and perforation size and site were not associated with incus necrosis. On multivariate analysis, only middle ear granulations (P = 0.04; odds ratio [OR] 3.161; 95% confidence interval [95% CI] 1.087-9.196) and a moderate to moderately severe hearing loss (41-70 dB HL) (P = 0.03; OR 1.720; CI 1.064-2.782) were found to be significant risk factors. CONCLUSION: Incus necrosis is best predicted by the presence of middle ear granulations and moderate to moderately severe hearing loss (41-70 dB HL). Knowledge of this information preoperatively can influence surgical decision making and preparedness regarding ossiculoplasty and patient consent. PMID- 20172392 TI - Percutaneous cochlear implant drilling via customized frames: an in vitro study. AB - OBJECTIVE: Percutaneous cochlear implantation (PCI) surgery uses patient-specific customized microstereotactic frames to achieve a single drill-pass from the lateral skull to the cochlea, avoiding vital anatomy. We demonstrate the use of a specific microstereotactic frame, called a "microtable," to perform PCI surgery on cadaveric temporal bone specimens. STUDY DESIGN: Feasibility study using cadaveric temporal bones. SUBJECTS AND METHODS: PCI drilling was performed on six cadaveric temporal bone specimens. The main steps involved were 1) placing three bone-implanted markers surrounding the ear, 2) obtaining a CT scan, 3) planning a safe surgical path to the cochlea avoiding vital anatomy, 4) constructing a microstereotactic frame to constrain the drill to the planned path, and 5) affixing the frame to the markers and using it to drill to the cochlea. The specimens were CT scanned after drilling to show the achieved path. Deviation of the drilled path from the desired path was computed, and the closest distance of the mid-axis of the drilled path from critical structures was measured. RESULTS: In all six specimens, we drilled successfully to the cochlea, preserving the facial nerve and ossicles. In four of six specimens, the chorda tympani was preserved, and in two of six specimens, it was sacrificed. The mean +/- standard deviation error at the target was found to be 0.31 +/- 0.10 mm. The closest distances of the mid-axis of the drilled path to structures were 1.28 +/- 0.17 mm to the facial nerve, 1.31 +/- 0.36 mm to the chorda tympani, and 1.59 +/- 0.43 mm to the ossicles. CONCLUSION: In a cadaveric model, PCI drilling is safe and effective. PMID- 20172394 TI - Pediatric otogenic intracranial abscesses. AB - OBJECTIVE: To describe the presentation and management of otogenic intracranial abscesses in a tertiary care pediatric hospital. STUDY DESIGN: Case series and chart review. SETTING: Tertiary care pediatric hospital. SUBJECTS AND METHODS: An inpatient database was queried for the following diagnostic codes from 2000 to 2008: [383.2] petrositis, [383] acute mastoiditis, [386.3] labyrinthitis, [351.0] facial paralysis (Bell's palsy), [351.9] facial nerve disorder unspecified, [351.8] other facial nerve disorders, [383.01] subperiosteal abscess, [383.02] Gradenigo's syndrome, [320] meningitis, [324.9] extradural or subdural abscess, [324.0] intracranial abscess, [325] thrombosis of intracranial venous sinus, and [348.2] otic hydrocephalus. Presenting signs and symptoms, microbiology, length of stay, surgical findings, and outcomes were recorded for each patient. RESULTS: Forty patients were identified with an otogenic intracranial complication. Thirty patients had evidence of an intraparenchymal, epidural, subdural, or petrous apex suppurative complication of otitis media. Twenty-four of 30 (80%) patients had a canal wall up mastoidectomy, three (10%) patients had a craniotomy without a mastoidectomy, and three (10%) patients were managed with intravenous antibiotics with or without pressure equalization tubes. There were no mortalities in this series of patients. CONCLUSION: Patients with intracranial abscesses, in selected cases, can be managed with intravenous antibiotics without mastoidectomy. The use of canal wall up mastoidectomy is an acceptable alternative to radical mastoidectomy when surgical intervention is necessary. PMID- 20172393 TI - Assessment of self-selection bias in a pediatric unilateral hearing loss study. AB - OBJECTIVE: To examine the differences between participants and nonparticipants in a study of children with unilateral hearing loss that might contribute to selection bias. STUDY DESIGN: Case-control study. SETTING: Academic pediatric otolaryngology practice. SUBJECTS AND METHODS: Comparison of clinical and sociodemographic characteristics between the 81 participants and 78 nonparticipants with unilateral hearing loss in a case-control study. RESULTS: Compared with nonparticipants, the study participants were younger but were diagnosed at an older age. Participants were more likely to have been diagnosed through a primary care screen and have normal ear anatomy, and less likely to have an attributed etiology for their unilateral hearing loss or tried assistive hearing devices. No other significant demographic, socioeconomic, or clinical differences were identified. CONCLUSION: Self-selection bias may jeopardize both internal and external validity of study results and should be evaluated whenever possible. Methods to minimize self-selection bias should be considered and implemented during the planning stages of clinical studies. PMID- 20172395 TI - Functional testing of a tissue-engineered vocal fold cover replacement. AB - OBJECTIVES: Tissue engineering may provide a treatment for severe vocal fold scars. This study quantifies mechanical properties and demonstrates vibration of a tissue-engineered vocal fold cover replacement. METHODS: Tissue-engineered constructs were produced from fibrin and adipose-derived stem cells. Optimized bilayered constructs contained epithelial and mesenchymal cell phenotypes in a stratified geometry. For comparison, homogeneous constructs did not have epithelial differentiation. Elastic modulus was determined using indentation. Immunohistochemical labeling for type I collagen was performed. A bilayered construct was also tested in phonation in an excised larynx model. RESULTS: Bilayered vocal fold cover replacements had indentation moduli similar to human vocal fold covers (mean construct modulus 6.8 kPa). Collagen deposition occurred in the middle of the construct. Homogeneous constructs had a mean modulus of 8.3 kPa, and collagen was concentrated at the surface. An excised larynx with unilateral vocal fold cover replacement phonated and exhibited mucosal waves at physiologic airflow. CONCLUSION: Bilayered tissue-engineered constructs were produced that exhibited indentation modulus, microstructure, and vibration similar to that exhibited by human vocal fold covers. PMID- 20172396 TI - The -509 C/T genotype of TGFbeta1 might contribute to the pathogenesis of benign airway stenosis. AB - Benign airway stenosis (BAS) is one of the most severe complications of endotracheal intubation. The aim of this pilot study was to compare the frequencies of four polymorphisms of the transforming growth factor (TGF) beta1 gene in patients with BAS due to endotracheal intubation (n = 36) and a control group of intensive care patients who had also undergone endotracheal intubation but did not present BAS (n = 30). One of the studied polymorphisms, the -509 C/T, demonstrated a differential genotype distribution between the affected and the control population: the ratio of heterozygous mutants was significantly (P = 0.0116) higher among the control patients. These data suggest a protective function of the frequent heterozygous C/T genotype against BAS; alternatively, the C/C genotype might be a susceptibility factor for BAS (OR 4.5; 95% CI 1.5123 13.3902). Our findings suggest that, besides other iatrogenic factors, a genetic predisposition might contribute to the pathogenesis of BAS. PMID- 20172397 TI - Porcine dermal collagen graft for tracheoesophageal fistula repair. PMID- 20172398 TI - A convenient, practical adapter for bronchotracheoscopy through a tracheostomy tube in a ventilator-dependent patient. PMID- 20172399 TI - Endoscopic resection of supraglottic (T1-T2-T3) and glottic (T2-T3) carcinomas using microdissection electrodes. PMID- 20172400 TI - Pituitary adenoma manifests as blood-tinged sputum. PMID- 20172401 TI - Multiple head and neck tuberculosis granulomas in a patient with thymoma and immunodeficiency (Good's syndrome). PMID- 20172402 TI - Intranasal mycetoma-induced Splendore-Hoeppli phenomenon. PMID- 20172403 TI - A case of paranasal sinus lesions in IgG4-related sclerosing disease. PMID- 20172404 TI - Ectopic olfactory neuroblastoma arising in the pterygopalatine fossa. PMID- 20172405 TI - Minimally invasive radioguided parathyroidectomy performed for primary hyperparathyroidism. PMID- 20172407 TI - Propranolol may become first-line treatment in obstructive subglottic infantile hemangiomas. PMID- 20172408 TI - Treatment of head and neck cancer at academic centers. PMID- 20172409 TI - [Spectrum of cardiovascular disease in HIV-infected patients]. AB - A large body of evidence indicates that HIV-infected patients, both men and women, as well as adults and children, have a higher risk of developing arteriosclerotic cardiovascular disease. This evidence comes from studies whose main primary variables were the clinical manifestations of arteriosclerotic cardiovascular disease (acute myocardial infarction, silent myocardial ischemia, stroke and peripheral arterial disease) and the distinct markers of premature atherosclerosis and endothelial dysfunction determined in different sites (carotid, coronary or peripheral arteries) and with distinct diagnostic procedures (carotid intimamedia thickening, coronary artery calcification, flow mediated vasodilation, arterial rigidity, ankle/arm index, etc.). This excess risk of arteriosclerotic cardiovascular disease in HIV-positive patients is clearly associated with the HIV infection per se and with classical cardiovascular risk factors, and, to a lesser extent and less uniformly, with the use of first-generation protease inhibitors. Hypertension, whose association with HIV infection is far less clear, is related to both traditional cardiovascular risk factors and to lipodystrophy. PMID- 20172411 TI - [HIV-related cardiovascular risk factors]. AB - Evidence from experimental and observational studies suggests that HIV infection per se and the associated proinflammatory state can increase the risk of cardiovascular disease. HIV infection can activate several inflammatory pathways in the vascular wall with cytokine release and expression of endothelial adhesion molecules. Many of these alterations can be suppressed by highly-active antiretroviral therapy (HAART). The role of HIV in cardiovascular risk has been demonstrated in studies of treatment interruption, mainly in the SMART trial, in which greater cardiovascular mortality was observed in the group interrupting HAART. The abrupt change to a more proinflammatory state produced by sudden resumption of viral replication could induce an increase in platelet adhesion and migration of inflammatory cells with plaque instability. Some studies suggest that HIV can also produce endothelial damage; a decrease in markers of endothelial activation and improvement of endothelial function after initiation of HAART have been described, and these changes have been correlated with the decrease in HIV viral load. Finally, HIV can induce cardiovascular disease through its effect on high-density lipoprotein cholesterol, which can decrease in patients with uncontrolled infection. Although the association of HIV with cardiovascular risk is controversial, coinfection with hepatitis C infection has been associated with a higher frequency of insulin resistance and acute myocardial infarction in some cohorts. PMID- 20172410 TI - [Patient-related cardiovascular risk factors in the HIV-infected population]. AB - The pathogenesis of arteriosclerosis in HIV-infected patients is complex. Both patient-related cardiovascular risk factors (CVRF) established for the general population and those related to highly-active antiretroviral therapy (HAART) and HIV infection per se are involved. Some traditional CVRF are more frequent in HIV infected patients than in the general population. In developed countries, HIV infection is more frequent among men and, due to HAART, their life expectancy has significantly increased. The prevalence of smoking (37-72%) is higher than in the general population, as is that of diabetes mellitus (17%), insulin resistance (17 51%), dyslipidemia (22-49%) and hypertriglyceridemia (34%). The higher prevalence in these patients is probably due to lifestyle and length of exposure to HAART, especially to certain antiretroviral drugs. Although overall cardiovascular risk in patients with HIV remains low, CVRF established for the general population become more important with increasing age. Longitudinal cohort studies indicate the magnitude of the association of these risk factors with cardiovascular disease in patients with HIV infection. In view of all the factors that intervene in HIV infection, specific mathematical models should be designed for this population that would allow individual cardiovascular risk to be calculated in each patient and measures for cardiovascular prevention to be established. PMID- 20172412 TI - [Cardiovascular risk factors associated with antiretroviral therapy]. AB - HIV-infected patients share traditional cardiovascular risk factors with the general population. Moreover, HIV per se significantly increases the risk of cardiovascular disease. Consequently, control of HIV infection with highly-active antiretroviral therapy (HAART) helps to reduce vascular risk in HIV-infected patients. However, there is evidence that HAART increases cardiovascular risk and the use of abacavir, didanosine, lopinavir/ritonavir and indinavir has been associated with the development of acute myocardial infarction (AMI). However, the absolute risk of AMI in patients receiving HAART is very low in relation to the benefit obtained with antiretroviral therapy. PMID- 20172413 TI - [Physiopathology of cardiovascular disease in HIV-infected patients]. AB - Patients with HIV have an increased risk of cardiovascular events related to arteriosclerosis. The virus is able to replicate in the arterial wall, implying severe inflammatory dysfunction. When this inflammatory dysfunction is accompanied by the metabolic disorders associated with HIV infection and its treatment, progression of the atheroma plaque is accelerated. HIV shows high replication in CD4+ T lymphocytes, which accumulate in the subendothelial space. CD4+ T lymphocytes produce viral proteins such as Tat, which leads to synthesis of chemokines such as monocyte chemoattractant protein-1 (MCP-1) or vascular cell adhesion molecule-1. This combination will attract monocytes into the subendothelial space, which penetrate rapidly if infected. These monocytes will also infect the smooth muscle cells, producing the initiation of endothelial dysfunction. Dyslipidemia and insulin resistance will then provoke modification of lipoproteins, which will be phagocytized through CD36 receptors by macrophages of the subendothelial space. Reverse cholesterol transport will be damaged, since the Nef viral protein is able to block the ABCA1 receptor. These events will produce rapid cholesterol accumulation in the atheroma plaque nucleus. Subsequently, the plaque will become complicated, either by rupture or erosion. Then, a juxtalesional thrombus is formed, where the platelet is activated. PMID- 20172414 TI - [Cardiovascular risk assessment and intervention in HIV-infected patients]. AB - Because of the increased cardiovascular risk (CVR) in HIV-positive patients, preventive measures are essential, requiring algorithms for risk estimation, such as the Framingham risk equation, the Prospective Cardiovascular Munster Study (PROCAM) algorithm and the Systematic Coronary Risk Evaluation (SCORE) chart. Classical cardiovascular risk factors (CVRF) are closely related to CVR in HIV infected patients but whether this risk is comparable to that in the general population is unknown. Therefore, these algorithms probably underestimate the risk in these patients. Currently, application of the same strategies as those used in the general population is recommended, without forgetting the specific characteristics of HIV positive patients or the importance of their inflammatory status, which can accelerate the development of arteriosclerosis and lead to an increase in cardiovascular morbidity and mortality. Therefore, in addition to traditional CVRF, biological markers of inflammation could help to identify the patients most at risk of a cardiovascular event. These markers, as well as the diverse techniques for assessment of subclinical atherosclerosis that could help in the early identification of at-risk patients, are reviewed in the present study. Lifestyle changes (healthy diet, smoking cessation, maintaining a healthy weight and daily physical exercise) reduce the probability of a coronary event by up to 80% in the general population. Traditional therapeutic measures (dyslipidemia, hypertension, diabetes mellitus) and those specific to HIV infection (viral suppression, discontinuous treatment, etc.) are reviewed. PMID- 20172415 TI - [Controversies and future of the approach to cardiovascular disease in HIV patients]. AB - Cardiovascular diseases are an increasing problem in patients with HIV infection. The causes of the increased cardiovascular risk in HIV-infected patients are multifactorial. Currently, the question of which factor has the most weight in this equation - whether traditional risk factors, the virus per se or antiretroviral therapy - remains to be determined. The absolute risk of cardiovascular disease in a particular patient depends on the composite risk profile. At present, there are no data to support a distinct approach to cardiovascular risk evaluation in HIV-infected patients. Cardiovascular risk equations should be incorporated into routine daily clinical assessment in order to identify patients in need of specific interventions. PMID- 20172416 TI - [Analysis of the results of the SEIMC External Quality Control Program. Year 2008]. AB - The External Quality Control Program of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) include controls for bacteriology, serology, mycology, parasitology, mycobacteria and virology. This article present the most relevant conclusions and lessons from the 2008 controls. As a whole, the results obtained in 2008 confirm the excellent skill and good technical standards of the microbiology laboratories in Spain found in previous editions. However, a few deviations can be obtained in any laboratory, even in clinically relevant determinations. Once again, the results of this program highlighted the need to implement both internal an external controls in order to assure the maximal quality of the microbiological tests. PMID- 20172418 TI - [Extended-spectrum beta-lactamases in enterobacteria other than Escherichia coli and Klebsiella]. AB - Methods for detecting ESBL-producing Enterobacteriaceae begin by a correct interpretation of the susceptibility profiles, applying the usual criteria for interpretative reading of the antibiogram. Appropriate confirmatory methods will be consequently chosen, based on the inhibition of the enzyme by betalactamases inhibitors, generally clavulanic acid. In case of non-AmpC-producing Enterobacteriaceae, at least two substrates should be used -cefotaxime or ceftriaxone and ceftazidime- to detect enzymes with a low hydrolytic activity against both substrates. Cefepime or AmpC-inhibitors should be recommended for AmpC-producing microorganisms. The identification of the enzymes responsible for the confirmed ESBL phenotype can be performed, either in the clinical laboratory or in reference centres, following a protocol of biochemical and molecular reactions able to detect and characterize, at least, those genes more frequently related to the predominant phenotypic profiles in our region. It is important to know which are the most prevalent combinations enzyme-microorganism, the vehicles for the genetic transmission involved in their dissemination, and the main epidemiological characteristics of the infections that they produce, in order to establish the dimensions of the problem and conduct surveillance studies, with the aim of achieving measures to control the wide spread. PMID- 20172417 TI - [Analysis of the results of the SEIMC External Quality Control Program for HIV-1 and HCV viral loads. Year 2008]. AB - BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) viral load determinations are among the most relevant markers for the follow up of patients infected with these viruses. External quality control tools are crucial to ensure the accuracy of results obtained by microbiology laboratories. This article summarized the results obtained from the 2008 SEIMC External Quality Control Program for HIV-1 and HCV viral loads. METHODS AND RESULTS: In the HIV-1 program, a total of five standards were sent. One standard consisted in seronegative human plasma, while the remaining four contained plasma from 3 different viremic patients, in the range of 2-5 log(10) copies/mL; two of these standards were identical aiming to determine repeatability. The specificity was complete for all commercial methods, and no false positive results were reported by the participants. A significant proportion of the laboratories (24% on average) obtained values out of the accepted range (mean +/- 0.2 log(10) copies/mL), depending on the standard and on the method used for quantification. Repeatability was very good, with up to 95% of laboratories reporting results within the limits (D < 0.5 log(10) copias/mL). The HCV program consisted of two standards with different viral load contents. Most of the participants (88,7%) obtained results within the accepted range (mean +/- 1.96 SD log(10) UI/mL). Post analytical errors due to mistranscription of the results were detected for HCV, but not for the HIV-1 program. CONCLUSIONS: Data from this analysis reinforce the utility of proficiency programmes to ensure the quality of the results obtained by a particular laboratory, as well as the importance of the post-analytical phase on the overall quality. Due to the remarkable interlaboratory variability, it is advisable to use the same method and the same laboratory for patient follow up. PMID- 20172419 TI - [Carbapenemases in Pseudomonas spp]. AB - Pseudomonas aeruginosa is one of the most relevant nosocomial pathogens, as well as one of the main causes of chronic respiratory infections in patients with underlying diseases such as cystic fibrosis or chronic obstructive pulmonary disease. The high intrinsic antibiotic resistance of this pathogen, together with its extraordinary capacity for acquiring additional resistances through chromosomal mutations, determines a major threat for antimicrobial therapy in hospitals worldwide. Even more concerning is the increasing detection of multiple antimicrobial resistance determinants in this microorganism, frequently located on integrons, acquired by horizontal transfer through plasmids and/or transposons. Among these mechanisms, the carbapenemases are particularly relevant, due to the wide spectrum of antibiotics affected. This work reviews the epidemiology, impact, and detection of the carbapenemases described so far in the Pseudomonas spp., that mainly include class B enzymes (metallo-beta-lactamases [MBL]: IMP, VIM, SPM, GIM, AIM, or DIM), but also, to a lower extent, class A (GES y KPC) and D (OXA) beta-lactamases. The presence of transferable carbapenemases is not only important in P. aeruginosa, but also in other less clinically-relevant species of the genus, since they can act as reservoires and dispersion vectors of these resistance determinants. The growing prevalence of carbapenemase-producing clinical isolates calls for the implementation of multidisciplinary strategies to optimize the detection and minimize the dissemination of these multidrug resistant strains and the involved transferable genetic elements. PMID- 20172420 TI - [Infection by Coxiella burnetii (Q fever)]. AB - In spite of being described over 60 years, Q fever is still a little known disease. The exact prevalence is also unknown, but probably the number of cases of Q fever is underestimated. There is much variation in the clinical presentation, including severe forms with a poor prognosis. Acute cases often present as an asymptomatic infection, flu-like syndrome, pneumonia or hepatitis. Presumably, host factors play an important role in the development of chronic disease, which may present as endocarditis with negative blood culture. The diagnosis of Q fever should be considered in cases of fever of unknown origin, especially if the subject has been in contact with mammals suspicious to be infected. The best methods of microbiological diagnosis are those that allow direct detection of bacteria (cell culture and PCR), although these procedures should be performed in laboratories with adequate biosafety measures, and with specialized personnel. For serological diagnosis, the reference method is indirect immunofluorescence (IIF), which is very sensitive and specific. In suspected cases of acute Q fever, diagnosis should be confirmed by serum titers (IgG and/or IgM), obtained by immunofluorescence above the cutoff calculated for each geographic area, or by seroconversion. PMID- 20172421 TI - [Diagnostic of intestinal parasitosis by coproantigen detection]. AB - Intestinal parasites are highly prevalent in tropical areas and developing countries, but are also common in industrialised countries as well. Traditionally, their diagnosis has been made by microscopic examinations of the faeces of the patient. These have been shown to have poor sensitivity, require serial samples, are very time-consuming and require a specialised technique. In the last few years, advances in the molecular biology of these parasites and research into the specific immune response of the patient, has made it possible to develop more efficient detection systems that help the clinician, allow treatments to be followed up and make it easier to carry out epidemiological studies. Among these systems are the methods for detecting faecal antigens, which, in general, have good specificity and sensitivity; properties which make them a useful tool in microbiology laboratories. PMID- 20172422 TI - [Microbiological aspects of the cryptococcosis in the post-HAART era]. AB - Cryptococcosis is a mycoses that increased considerably with the AIDS epidemic. However, with the introduction in the late 90's of the highly active antiretroviral therapy (HAART), this incidence has significantly decreased, especially in developed countries, in contrast with that of developing countries. The introduction of HAART not only has affected the incidence rate, but also the clinical presentation as a consequence of the immune recovery of the host, leading to the description of the so called immune reconstitution inflammatory syndrome. In addition, some rare clinical manifestations of cyptococcosis are currently shown, such as lymphadenitis and cutaneous involvement. Besides clinical presentation, diagnostic tests have also changed, with a high percentage of cases with negative cerebrospinal fluid (CSF) and blood cultures, negative direct CSF microscopy, and delayed antigen positive results. Antifungal susceptibility patterns have also changed towards a recuperation of susceptibility, which is related to the decrease in both the incidence of cryptococcosis and less use of antifungal agents. PMID- 20172423 TI - [Cutaneous and soft skin infections due to non-tuberculous mycobacteria]. AB - The frequency of isolation as well as the number of species of non-tuberculous mycobacteria (NTM) has increased in the last years. Nearly every pathogenic species of NTM may cause skin and soft tissue infections, but rapidly growing mycobacteria (Mycobacterium fortuitum, Mycobacterium chelonae and Mycobacterium abscessus), Mycobacterium marinum and Mycobacterium ulcerans are the most commonly involved. Many of these cutaneous mycobacteriosis, such as rapidly growing mycobacteria, M. marinum, Mycobacterium avium complex, Mycobacterium kansasii or Mycobacterium xenopi are world-wide distributed. In contrast, some others have a specific geographical distribution. This is the case of M. ulcerans, which causes a cutaneous diseases endemic of Central and West Africa (Buruli ulcer) and Australia (Bairnsdale ulcer), being the third mycobacterial infection after tuberculosis and leprosy. Cutaneous mycobacteriosis usually appear either after contact of traumatic or surgical wounds with water or other contaminated products, or, secondarily, as a consequence of a disseminated mycobacterial disease, especially among immunosuppressed patients. For an early diagnosis, it is necessary to maintain a high degree of suspicion in patients with chronic cutaneous diseases and a history of trauma, risk exposure and negative results of conventional microbiological studies. In general, individualized susceptibility testing is not recommended for most NTM infections, except for some species, and in case of therapeutic failure. Treatment includes a combination of different antimicrobial agents, but it must be taken into account that NTM are resistant to conventional antituberculous drugs. Severe cases or those with deep tissues involvement could also be tributary of surgical resection. PMID- 20172424 TI - [Norovirus infections]. AB - Noroviruses infect persons of all ages, often causing epidemic outbreaks of acute gastroenteritis as well as sporadic cases. The application of novel molecular methods to the diagnosis of norovirus infections is now revealing their real impact. Molecular epidemiology studies have identified the most common viral genotypes responsible for human infections. Norovirus gastroenteritis is usually mild and of short duration, although the disease can also be severe, especially in the elderly, or may become chronic, as occurred in the immunocompromised patients. Several factors have been identified regarding the differential susceptibility to norovirus infection among individuals, consisting of several histo-blood antigens (ABO, Lewis and secretor) that are involved in the binding process of noroviruses to the enterocytes. The expression of these antigens in humans is genetically encoded, and shows a high polymorphism, which combined with the genetic diversity of noroviruses, makes the virus-host relationship rather complex. The diagnosis of norovirus infections is not performed routinely in many laboratories, but those involved in epidemiological surveillance have identified norovirus strains that evolve sequentially over time, similarly to Influenza viruses. PMID- 20172425 TI - [Laboratory diagnosis of lymphocytic meningitis]. AB - Lymphocytic meningitis, mainly those with an acute and benign course, are caused by viruses. In our area, the most commonly involved agents are enteroviruses, herpes simplex, varicella zoster and Toscana viruses. Nucleic acids amplification techniques (NAAT) are the methods of choice to diagnose viral meningitis from cerebrospinal fluid (CSF) samples. They are more rapid and sensitive, and indeed, they are not influenced by the viability of the virus in the clinical specimen as traditional methods are. The development of commercial equipments, the degree of automation, and the use of real-time polymerase chain reaction (PCR) systems are the most important premises to choose the molecular method in each laboratory. Recently, commercial kits of real-time PCR are available for the detection of enteroviruses and herpesviruses, which are the most frequently viruses involved in meningitis. Although NAAT from the clinical sample have replaced cell culture for diagnostic purposes, the combination of both methods remain useful. When the detection of the causal agent from the CSF sample is not possible, other specimens (pharyngeal exudates, stools) or serological methods can be used. Serology is the reference method for meningitis caused by West Nile virus and lymphocytic choriomeningitis virus, which are less frequently detected in our area. PMID- 20172428 TI - Bronchoscopy: the past, the present, and the future. AB - This article discusses bronchoscopy: its history, including development of instruments and techniques and important historical figures; current techniques and issues; and future possibilities and potential controversies. PMID- 20172426 TI - [A review on new commercial methods for HIV-1 and HCV viral load determinations]. AB - Viral load techniques are more and more demanded in Clinical Microbiology, regarding with transplanted patients or long time follow-up of chronic diseases as those caused by human inmunodeficiency (HIV) and hepatitis C (HCV) viruses. In the last 2 years, pharmaceutical companies, interested to develop more efficient and accurate methods for the diagnosis and correct viral quantification of HIV and HCV, have converged in the real time-polymerase chain reaction (PCR) technique. This process is due to the increased sensitiviy, accuracy, linearity and correct detection of genomic viral variants of real time PCR techniques, in comparison with classical molecular methods applied since the nineties of the past century. In spite real time PCR appears as the best tool for the immediate future, new questions regarding the high variability of these viruses should be considered. This could affect the correctness of viral quantifications, while being difficult to detect it because of the methodological uniformity in the clinical laboratories. PMID- 20172429 TI - Bronchoscopes of the twenty-first century. AB - Over the past century, bronchoscopy has become an essential tool for pulmonologists and thoracic surgeons, who for many years have employed bronchoscopy with such therapeutic modalities as laser therapy, electrocautery, cryotherapy, and stent placement. Over the past decade, advanced imaging techniques, such as autofluoresence bronchoscopy, electromagnetic navigation, narrow-band imaging, confocal fluorescence microendoscopy, and endobronchial ultrasound, have greatly expanded the diagnostic utility of bronchoscopy. This article reviews the technological advances in the field of diagnostic bronchoscopy. PMID- 20172430 TI - Interventional bronchoscopy from bench to bedside: new techniques for early lung cancer detection. AB - Lung cancer is a leading cause of cancer-related death in the world, and it accounts for more deaths than breast, colon, and prostate cancer combined in the United States. From a historical perspective, the premise behind early lung cancer detection strategy is that early detection of lung cancer is justified if early treatment improves the outcome. New optical technologies such as those presented in this article allow dynamic study of these processes at the cellular level, and it is hoped that opportunities for targeted therapy will be provided in the future. Investigators are on the verge of discovering a multidimensional bronchoscopic platform that can be used to narrow in on airway structures, explore vascular flow and angiogenesis, and discover new features of bronchogenic carcinogenesis. PMID- 20172431 TI - Early diagnosis of lung cancer. AB - Early detection and surgical resection is essential for the treatment of lung cancer. Although the introduction of low-dose spiral computed tomography (CT) is considered to be one of the most promising clinical research developments, CT screening is used for detecting small peripheral lesions. Tumors arising in the central airways require other techniques for early detection. Centrally arising squamous cell carcinoma of the airway, especially in heavy smokers, is thought to develop through multiple stages from squamous metaplasia to dysplasia, followed by carcinoma in situ (CIS), progressing to invasive cancer. It would be ideal to be able to detect and treat preinvasive bronchial lesions defined as dysplasia and CIS before progressing to invasive cancer. Great efforts have been made to develop new mucosal imaging techniques. Bronchoscopic imaging techniques capable of detecting preinvasive lesions and currently available in clinical practice include autofluorescence bronchoscopy (AFB), high magnification ronchovideoscope, and narrow band imaging (NBI). For a more precise evaluation of newly detected preinvasive lesions, endobronchial ultrasound (EBUS) and optical coherence tomography (OCT) can be used. PMID- 20172432 TI - Role of bronchoscopy in the evaluation of solitary pulmonary nodules. AB - The past decade has witnessed the application of many advanced bronchoscopic modalities to improve access to the solitary pulmonary nodule (SPN). Although many of the techniques are applied on a regular basis by bronchoscopists, which technique-or which combination of techniques-will offer the best performance and cost-effectiveness remains to be determined. The authors anticipate that bronchoscopic approaches to the SPN will continue to proliferate as technologic advances and clinical data accumulate. Research should focus on combinations of techniques, cost-effectiveness, and incorporation of these tools in diagnostic algorithms for lung nodules/masses. PMID- 20172433 TI - Electromagnetic navigation. AB - Electromagnetic navigation bronchoscopy using overlaid CT Images is a safe procedure. It improves the diagnostic yield of the flexible bronchoscopy for peripheral lesions and also allows sampling of the mediastinal lymph nodes. Additionally, the system provides several other advantages: there is no additional radiation, and it has a short learning curve. It can also be used for fiducial marker placement for brachytherapy or stereotactic radiosurgery. It plays a complementary role to other modalities such as ultrathin bronchoscopy or an endobronchial ultrasonography. PMID- 20172434 TI - Virtual bronchoscopic navigation. AB - Virtual bronchoscopic navigation (VBN) is a method for the guidance of a bronchoscope to peripheral lesions using virtual bronchoscopy (VB) images of the bronchial path. Irrespective of the bronchoscopist's skill level, the bronchoscope can be readily guided to the target in a short time. A system to automatically search for the bronchial path to the target has been developed and clinically applied; this system produces VB images of the path to the fourth- to twelfth- (median, sixth-) generation bronchi, and displays the VB images simultaneously with real bronchoscopic images. In this article, the author discusses VBN and the automatic VBN system, reviews the published literature, and describes its usefulness and limitations. PMID- 20172435 TI - Flexible bronchoscopy and its role in the staging of non-small cell lung cancer. AB - Technologic advances in bronchoscopy continue to improve the ability to perform minimally invasive, accurate evaluations of the tracheobronchial tree and to perform an ever-increasing array of diagnostic, staging, therapeutic, and palliative interventions. The role of both old and new diagnostic bronchoscopy will continue to evolve as further improvements are made in bronchoscopes, accessory equipment, and imaging technologies. The major challenge is the adoption of the many new bronchoscopic techniques into routine clinical practice. There is a need for well-designed studies to delineate the appropriate use of these interventions and to better define their limitations and cost effectiveness. PMID- 20172436 TI - Interventional bronchoscopy from bench to bedside: new techniques for central and peripheral airway obstruction. AB - This article discusses how basic scientific concepts, based on a greater understanding of airway physiology, support the development and dissemination of multidimensional classification systems for tracheal stenosis, expiratory central airway collapse, and innovative interventional bronchoscopic procedures for patients with asthma and chronic obstructive pulmonary disease. PMID- 20172437 TI - Endoscopic management of emphysema. AB - Lung volume reduction surgery has proven benefits in emphysema. However, high postoperative morbidity and stringent selection criteria for suitable candidates are limitations in clinical practice. Endoscopic approaches to lung volume reduction have used a range of different techniques such as endobronchial blockers, airway bypass, endobronchial valves, biologic sealants, and airway implants to address the limitations of surgery. The underlying physiologic mechanisms of endoscopic modalities vary, and homogeneous and heterogeneous emphysema are targeted. Currently available data on efficacy of bronchoscopic lung volume reduction are not consistently conclusive, and subjective benefit in dyspnea scores is a more frequent finding than improvements on spirometry or exercise tolerance. The safety data are more promising, with rare procedure related mortality, fewer complications than lung volume reduction surgery, and short hospital length of stay. The field of bronchoscopic lung volume reduction continues to evolve as ongoing prospective randomized trials aim to clarify the efficacy data from earlier feasibility and safety studies. PMID- 20172438 TI - Bronchoscopic management of prolonged air leak. AB - Prolonged pulmonary parenchymal air leaks are an important clinical problem. Standard treatment of prolonged air leaks include continued chest tube drainage, pleural sclerosis, or surgery. Approaches that are less invasive than bedside sclerosis or surgery are desirable but bronchoscopy approaches tried over the years have had limited success. In 2001, an American College of Chest Physicians (ACCP) consensus statement concluded there was no role for bronchoscopy for the treatment of prolonged air leaks. The development of bronchial valves for treatment of emphysema allowed the use of these devices for air leaks under compassionate use regulations. Multiple reports of successful bronchial valve treatments, along with the US Food and Drug Administration's (FDA) humanitarian use approval of a bronchial valve for certain postsurgical air leaks, provide new evidence that there is likely a role for endobronchial treatment of prolonged air leaks in selected patients. PMID- 20172439 TI - Bronchial thermoplasty. AB - Asthma, by definition is a variable disease. When there is more than normal natural variation in airflow, asthma can be provoked by a wide range of stimuli that include infectious, allergic, and environmental agents. Bronchoconstriction determines much of the short-term variability in airflow that characterizes asthma. Current treatments do not redress the excess smooth muscle mass that is present in the remodeled airway in chronic asthma. Thus, it is intriguing to consider the potential contribution of bronchial thermoplasty (a procedure that involves controlled heat treatment to reduce the mass of the airway smooth muscle) as an effective therapy for poorly controlled asthma. PMID- 20172440 TI - Airway stents. AB - Stents are used for palliation of symptoms of central airway obstruction caused by either malignant or benign conditions. Stents may be applied for maintaining airway patency after dilatation of postinflammatory and infectious strictures, for airway dehiscence after lung transplantation, and for the management of tracheobronchomalacia. Fistulas between trachea or bronchi and the esophagus and dehiscence of pneumonectomy stump can be protected with covered stents. Choice of stent depends on careful patient selection, characteristics of airway stenosis, physician's expertise, and availability of equipment. Placement of tube stents requires rigid bronchoscopy and dilatation of strictures beforehand, whereas metal stents can be applied using a flexible bronchoscope. Advantages and disadvantages of commonly used airway stents are discussed. PMID- 20172441 TI - Radiofrequency ablation of lung tumors. AB - Lung cancer is the commonest cause of cancer-related mortality throughout the world. Only 25% of patients are diagnosed early and are candidates for surgical resection with curative intent. Many early-stage patients are medically inoperable owing to comorbidities. For these patients, and for selected patients with pulmonary metastases, radiofrequency ablation is a minimally invasive therapeutic alternative. Radiofrequency ablation can be performed percutaneously, under conscious sedation, and as an outpatient or with a short hospital stay. Outcomes are similar or even superior to those obtained with more aggressive procedures, with lower complication rates. Human studies describing the feasibility, safety, and outcomes of radiofrequency ablation for the treatment of primary and secondary lung malignancies are the focus of this article. PMID- 20172442 TI - Current status of medical pleuroscopy. AB - Medical pleuroscopy (MP) offers a safe and minimally invasive tool for interventional pulmonologists. It allows diagnosis of unexplained effusion, while at the same time allowing drainage and pleurodesis. It can also help in the diagnosis of diffuse interstitial disease or associated peripheral lung abnormality in the presence of effusion. It can have a therapeutic role in pneumothorax and hyperhidrosis or chronic pancreatic pain. This article reviews the technical aspects and range of applications of MP. PMID- 20172443 TI - National Kidney Foundation's Kidney Early Evaluation Program (KEEP) annual data report 2009: executive summary. PMID- 20172445 TI - Prevalence of CKD and comorbid illness in elderly patients in the United States: results from the Kidney Early Evaluation Program (KEEP). AB - BACKGROUND: Elderly individuals with chronic kidney disease (CKD) have high rates of comorbid conditions, including cardiovascular disease and its risk factors, and CKD-related complications. In individuals aged > or = 65 years, we sought to describe the prevalence of CKD determined from laboratory test results in the Kidney Early Evaluation Program (KEEP; n = 27,017) and National Health and Nutrition Examination Survey (NHANES) 1999-2006 (n = 5,538) and the prevalence of diagnosed CKD determined from billing codes in the Medicare 5% sample (n = 1,236,946). In all 3 data sources, we also explored comorbid conditions and CKD related complications. METHODS: CKD was identified as decreased estimated glomerular filtration rate (<60 mL/min/1.73 m(2)) or increased albumin-creatinine ratio in KEEP and NHANES; CKD was identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes in Medicare. Investigated comorbid conditions included diabetes, hypertension, high cholesterol level, coronary artery disease, congestive heart failure, cerebrovascular disease, peripheral vascular disease, and cancer, and CKD-related complications included anemia, hypocalcemia, hyperphosphatemia, and hyperparathyroidism. RESULTS: The prevalence of CKD was approximately 44% in both KEEP and NHANES participants, and the prevalence of diagnosed CKD was 7% in Medicare beneficiaries. In all 3 data sets, the prevalence of CKD or diagnosed CKD was higher in participants aged > or = 80 years and those with comorbid conditions. For KEEP and NHANES participants, the prevalence of most comorbid conditions and CKD complications increased with decreasing estimated glomerular filtration rate. For participants with CKD stages 3-5, a total of 29.2% (95% CI, 27.8-30.6) in KEEP and 19.9% (95% CI, 17.0-23.1) in NHANES had anemia, 0.7% (95% CI, 0.4-0.9) and 0.6% (95% CI, 0.3-1.3) had hypocalcemia, 5.4% (95% CI, 4.7-6.1) and 6.4% (95% CI, 5.1-8.0) had hyperphosphatemia, and 52.0% (95% CI, 50.4-53.6) and 30.0% (95% CI, 25.9-34.3) had hyperparathyroidism, respectively. CONCLUSIONS: CKD is common in the elderly population and is associated with high frequencies of concomitant comorbid conditions and biochemical abnormalities. Because CKD is not commonly diagnosed, greater emphasis on physician education may be beneficial. PMID- 20172444 TI - Racial and ethnic differences in albuminuria in individuals with estimated GFR greater than 60 mL/min/1.73 m(2): results from the Kidney Early Evaluation Program (KEEP). AB - BACKGROUND: Albuminuria is an important marker for chronic kidney disease and progression to end-stage renal disease in the general population; understanding racial and ethnic differences can help inform efforts to reduce health disparities. We sought to estimate independent associations of race/ethnicity with albuminuria to determine whether observed differences were attributable to known kidney disease risk factors. METHODS: This cross-sectional study included 64,161 Kidney Early Evaluation Program (KEEP) participants, 2000-2008, with estimated glomerular filtration rate > or = 60 mL/min/1.73 m(2), not on regular dialysis therapy, and without a previous kidney transplant. Albuminuria (urine albumin-creatinine ratio > or = 30 mg/g) was examined by self-reported race and ethnicity. Covariates were age, sex, educational level, body mass index, diabetes status or glucose level, hypertension status or blood pressure measurement, smoking status, health insurance status, and geographic region. RESULTS: Albuminuria prevalences were 8% (n = 2,303) in whites, 11% (n = 2,310) in African Americans, 9% (n = 730) in Hispanics, 10% (n = 381) in Asians, and 15% (n = 344) in American Indians/Alaska Natives. Compared with whites, odds of albuminuria were higher for all groups after multivariate adjustment. Odds were highest for American Indians/Alaska Natives (adjusted OR, 1.93; 95% CI, 1.70-2.20), then Asians (adjusted OR, 1.42; 95% CI, 1.26-1.61), African Americans (adjusted OR, 1.38; 95% CI, 1.29-1.47), and Hispanics (adjusted OR, 1.19; 95% CI, 1.08-1.31). CONCLUSIONS: In the KEEP study population, albuminuria prevalence was higher in African Americans, Hispanics, Asians, and American Indians/Alaska Natives than in non-Hispanic whites, suggesting a need for screening for early detection of kidney damage, especially in people at increased risk, in the community primary care setting. PMID- 20172446 TI - Racial differences in kidney function among individuals with obesity and metabolic syndrome: results from the Kidney Early Evaluation Program (KEEP). AB - BACKGROUND: Obesity and metabolic syndrome may differ by race. For participants in the National Kidney Foundation's Kidney Early Evaluation Program (KEEP), we examined whether African American and white participants with obesity and metabolic syndrome differ regarding albuminuria, estimated glomerular filtration rate (eGFR), anemia, and bone/mineral metabolism derangements in chronic kidney disease (CKD). METHODS: 3 study cohorts were assembled: (1) eligible African American and white KEEP participants with body mass index > or = 30 kg/m(2), (2) a subgroup meeting criteria for metabolic syndrome, and (3) a subgroup with eGFR < 60 mL/min/1.73 m(2) and laboratory measurements for hemoglobin, parathyroid hormone, calcium, and phosphorus. Patient characteristics and kidney function assessments were compared and tested using chi(2) (categorical variables) and t test (continuous variables). Univariate and multivariate logistic regression analyses were performed to evaluate associations of race with kidney disease measures. RESULTS: Of 37,107 obese participants, 48% were African American and 52% were white. Whites were more likely to have metabolic syndrome components (hypertension, 87.1% vs 84.8%; dyslipidemia, 81.6% vs 66.7%; diabetes, 42.7% vs 34.9%) and more profoundly decreased eGFR than African Americans (CKD stages 3-5 prevalence, 23.6% vs 13.0%; P < 0.001). African Americans were more likely to have abnormal urinary albumin excretion (microalbuminuria, 12.5% vs 10.2%; OR, 1.60 [95% CI, 1.45-1.76]; macroalbuminuria, 1.3% vs 1.2%; OR, 1.61 [95% CI, 1.23 2.12]) and CKD stages 1-2 (10.3% vs 7.1%; OR, 1.54 [95% CI, 1.38-1.72]). For participants with CKD stages 3-5, anemia prevalence was 32.4% in African Americans and 14.1% in whites; corresponding values for secondary hyperparathyroidism were 66.2% and 46.6%, respectively. CONCLUSIONS: Obesity and metabolic syndrome may be heterogeneous disease states in African Americans and whites, possibly explaining differences in long-term kidney and cardiovascular outcomes. PMID- 20172447 TI - Dendritic cells loaded with ultrasound-ablated tumour induce in vivo specific antitumour immune responses. AB - Previous studies have shown that high-intensity focused ultrasound (HIFU) ablation can induce a local inflammation with marked infiltration of dendritic cells (DCs). The purpose of this study was to investigate whether DCs could capture and present activating signals delivered by necrotic tumour cells that remain in situ after HIFU, thus initiating specific antitumour immunity. Tumour debris was derived from a mouse H22 tumour model after HIFU ablation. Bone marrow derived DCs were loaded with HIFU-treated tumour, tumour lysate and mouse serum. Syngeneic naive C57BL/6J mice were immunised with three loaded DCs followed by a subsequent H22 tumour challenge. Tumour size and survival were then recorded in each vaccinated mouse. The results showed that both HIFU-ablated tumour and tumour lysate could significantly increase the number of mature DCs and the secretion of IL-12 and IFN-gamma (p<0.001). The proliferation of splenic lymphocytes co-incubated with the loaded-DCs was significantly higher in both HIFU-ablated tumour and tumour lysate groups (p<0.01). Cytotoxocity and TNF-alpha and IFN-gamma secretion of cytotoxic T lymphocytes against H22 cells were significantly higher in HIFU-ablated tumour group than that in tumour lysate group (p<0.01). After the H22 tumour challenge, a significant decrease of tumour volume was observed in HIFU-ablated tumour group (p<0.01). However, there was no statistical difference of long-term survival rates among three groups (p>0.05). It is concluded that DCs can be activated by HIFU-ablated tumour debris and, thus, initiate host specific antitumour immune response after HIFU therapy. PMID- 20172448 TI - Automatic localization of intimal and adventitial carotid artery layers with noninvasive ultrasound: a novel algorithm providing scan quality control. AB - Transcutaneous ultrasound measurements of common carotid artery (CCA) diameter and intima-media thickness (IMT) give insight on arterial dynamics and anatomy, both correlating well with atherosclerosis and risk of cardiovascular disease. We propose a novel automatic algorithm to estimate CCA diameter and IMT in ultrasound (US) images, based on separate analysis of anterior and posterior CCA walls and able to distinguish internal (intima-intima) and external (adventitia adventitia) diameter. The method combines off-line signal- and image-processing techniques to accommodate echo images acquired at a frame rate of 30 Hz and composed directly from RF data, circumventing digital video-grabbing. Segmentation consists of automatic CCA recognition, followed by adventitial delineation performed with a sustain-attack filter with exponentially decaying reference functions. Intimal delineation is then based on the multiscale anisotropic barycenter (MAB), which is an extension of a known delineation method involving the "first order absolute central moment" of the echo amplitude. An automatic measure of the quality of the US beam incidence for each wall is superimosed on the CCA contour overlays for visual feedback. Validation is carried out on 36 US CCA acquisitions from 12 healthy volunteers, as well as on synthetic US images. Results indicate good accuracy on synthetic US images (within 1.3% for diameter and 3% for IMT). The in vivo intra-recording beat-to beat variations are on average lower than 50 microm for external diameter and IMT, and lower than 100 microm for internal diameter. A comparison with a commercial device (ART.LAB system) shows that the proposed algorithm performs better in terms of inter-recording precision. The beam incidence control significantly improves the repeatability of IMT estimates, and motivates sonographers actively to maintain a proper scan plane throughout the acquisition to minimize the incidence of confounding factors. The method is clinically viable, providing robust estimates of CCA internal and external diameter and IMT waveforms for both CCA walls, even at a low B-mode update rate of 30 Hz. PMID- 20172449 TI - The E-wave delayed relaxation pattern to LV pressure contour relation: model based prediction with in vivo validation. AB - The transmitral Doppler E-wave "delayed relaxation" (DR) pattern is an established sign of diastolic dysfunction (DD). Furthermore, chambers exhibiting a DR filling pattern are also expected to have a prolonged time-constant of isovolumic relaxation (tau). The simultaneous observation of a DR pattern and normal tau in the same heart is not uncommon, however. The simultaneous hemodynamic equivalent of the DR pattern has not been proposed. To determine the feature of the left ventricular (LV) pressure contour during the E-wave that is causally related to its DR pattern we applied kinematic and fluid mechanics based arguments to derive the pressure recovery ratio (PRR). The PRR is dimensionless and is defined by the left ventricular pressure difference between diastasis and minimum pressure, normalized to the pressure difference between a fiducial diastolic filling pressure and minimum pressure [PRR=(P(Diastasis) P(Min))/(P(Fiducial)-P(Min))]. We analyzed 354 cardiac cycles from 40 normal sinus rhythm (NSR) subjects and 113 beats from nine atrial fibrillation (AF) subjects from our database of simultaneous transmitral flow-micromanometric LV pressure recordings. The fiducial pressure is defined by the end diastolic pressure in NSR and by the pressure at dP/dt(MIN) in the setting of AF. Consistent with derivation, PRR was linearly related to a DR pattern related, model-based relaxation parameter (R(2) = 0.77, 0.83 in NSR and AF, respectively). Furthermore, the PRR successfully differentiated subjects with a DR pattern from subjects with partial DR or normal E-wave pattern (p < 0.05). We conclude that the PRR may differentiate between subjects having a DR pattern and subjects with normal E-waves, even when tau cannot. PMID- 20172450 TI - Quantitative assessment of articular cartilage with morphologic, acoustic and mechanical properties obtained using high-frequency ultrasound. AB - Osteoarthritis (OA) is one of the most common joint diseases among adults, and its early detection is still not possible. In this study, high-frequency ultrasound and ultrasound-assisted mechanical testing systems were used to quantitatively measure the morphologic, acoustic and mechanical properties of normal and enzymatically degraded bovine articular cartilages in vitro. A total of 40 osteochondral cartilage plugs were prepared from 20 bovine patellae (n=20x2) and divided into two groups for collagenase and trypsin digestions, respectively. A high-frequency ultrasound system (center frequency: 40 MHz) was used to analyze the surface integrity (ultrasound roughness index, URI), thickness and acoustic properties of the articular cartilages before and after enzymatic degradations. Acoustic parameters included the integrated reflection coefficient (IRC) from the cartilage surface, reflection from the cartilage-bone interface (AIB(bone)), integrated attenuation (IA) and integrated backscatter (IBS) of the internal cartilage tissue. A newly developed ultrasound water jet indentation system was used to assess the mechanical properties of the cartilage samples. The results showed that the URI increased significantly (p<0.05) after collagenase digestion while no significant change (p>0.05) was found after trypsin digestion. With regard to acoustic parameters, the IRC decreased significantly (p<0.05) after collagenase digestion while no significant change (p>0.05) was found after trypsin digestion. The AIB(bone) demonstrated an insignificant change after collagenase digestion (p>0.05) but a significant decrease after trypsin digestion (p<0.05). Both enzymatic degradation groups showed insignificant differences (p>0.05) in the IA but a significant increase (p<0.05) in the IBS after both enzymatic degradations. The apparent stiffness measured by ultrasound water jet indentation suggested that articular cartilage from both groups became significantly softer (p<0.05) after the enzymatic degradations. A significant relationship was found to exist between the IRC and URI (p<0.05). This study showed that high-frequency ultrasound can be a comprehensive tool to quantitatively and systematically analyze the morphologic, acoustic and mechanical properties of articular cartilage in association with its degeneration. PMID- 20172451 TI - [The child between medical decision and parental wish]. PMID- 20172452 TI - [Paradoxes in the judicial institution concerning decision-making in pediatric oncology]. AB - In paediatric oncology, the medical decision-making process is characterized by the importance of what is at stake: the vital prognosis. Refusal of care, or, more specifically, refusal of a treatment, always appears "at the crossroads of multiple stakes... implicating an entourage [family members], a medical team, and rules of law that sometimes give rise to contradictory interpretations". Paradoxes in the judicial institution are evident on two levels: i) in the values established by the law; where adults are concerned, the law explicitly refuses to consider the biological survival of an individual as the supreme value; it gives priority to respect of the patient's wishes and his or her autonomy; for children, in contrast, the supreme value established by the law is biological survival; the physician must provide the care indispensable to protect the health of a minor at all cost; ii) between legal texts and jurisprudence; while the law authorizes a physician to override the parental authority when he judges a treatment necessary to protect the health of a minor, jurisprudence in pediatric oncology has always declined to define the best therapeutic strategy where a child's chances of survival are concerned. PMID- 20172453 TI - [Parenting in 2008: between resignation and authoritarianism]. AB - The contradictory media messages, even paradoxical, make many parents think that to have a child changes nothing in their lives. However, to grow, the baby requires initially that is established a narrow dependence between him and his/her parents, so that, in the second time, he can take his autonomy. With through its experiment clinical and a review of a certain number of media messages, the author shows how much certain adults are in lack of reference, which prevents them from correctly transmitting the limits essential to child education. The concept of "extimity" and the problems of the sexualisation of the culture are also approached. Lastly, media used by children (video games and internet) are analyzed. A strategy of parentality assistance is then proposed. PMID- 20172454 TI - [Judicial framework for medical decision-making concerning minors]. AB - One aim of the law promulgated in France on March 4, 2002 concerning patients' rights and the quality of the health care system was to reconsider the bases of the physician-patient relationship. The new legal framework recommends establishment of a true dialogue between the two protagonists, and it assigns decisional priority to the patient rather than to the physician or third parties. In the case of minors, the principle of parental authority requires that the physician consults the holders of this authority before making any medical decision. However, the law of March 4, 2002 also reinforced the participation of minors in medical decisions concerning them. The lawmaker explicitly envisaged the possibility of overruling the principle of parental authority. This new "balance of power" obliges the physician to inform the minor of his or her medical condition in a manner appropriate to the child's degree of maturity. The minor may even put forward the principle of medical secrecy to prevent the sharing of information with his or her parents. This new "autonomy" of minors gives rise to at least two reservations: i) the difficulty involved in assessment of a minor's degree of discernment; ii) the minor's vulnerability with respect to his or her entourage. PMID- 20172455 TI - [Justice and equity as determinants of medical decision-making]. AB - Every medical decision-making is to do justice to the one who suffers and who considers his pain as nonsensical. This requirement falls into 3 universal ethical principles, governing the patient-doctor relationship: the autonomy of the person even if it is a young child, beneficence and non-maleficence. Adhering to these principles gives medical decision-making its ethical dimension. It implies that the doctor makes the best use of the emotions that he feels in front of his patient and/or in front of his relatives: respect for autonomy, the beneficent compassion and the fear of maleficence in diagnosis and care. If a paediatrician combines these 3 affects harmoniously, his attitude is in keeping with the requirement of justice, which is the quintessence of Ethics. However, reality is often more complex, a source of conflicting emotions and, in fine, a source of an anguish whose benefit is yet to alert on the necessity to carry on looking for the right decision-making: the emotional revision consists of a meta analysis of the objective and subjective data of the problem. It preciously helps to establish a compromise of justice. Eventually, in order to be just, the doctor must include the concern of equity amongst the criteria of his decision-making, in other words a fair allocation of the goods and of the care services. Unfortunately, this concern is undermined by geopolitical, socio-economic and cultural factors, which vary greatly according to the environmental conditions that might mar what should be optimal ethical decisionmaking. The doctor cannot solve these problems on his own, but he has to know them in order to deal with them. PMID- 20172456 TI - [Issues related to consent to healthcare decisions in children and adolescents]. AB - The process of consent to healthcare decisions in children and adolescents often set physicians difficult problems. From what age is a child able to understand the information given to him or her about illness and treatment? Is an ill child indeed in the capacity to give his or her voluntary consent to treatment? How to define and to assess the capacity of an ill child to take part in treatment decisions? More than the age of the child, it is his or her level of cognitive, emotional and social development and its interactions with illness that will determine his or her degree of involvement in the decision-making process. There is a moral and ethical need to respect the rights and autonomy of every individual, regardless of age. This does not mean viewing children and adolescents as rational and autonomous decision-makers. This implies that we must promote their developmentally appropriate participation in shared decision-making with parents and physicians. Therefore, instead of asking, "should children and adolescents be granted absolute autonomy in decision making?" we ought to ask, "should we treat children and adolescents like people?" PMID- 20172457 TI - Positive youth development as a strategy to promote adolescent sexual and reproductive health. PMID- 20172458 TI - Connectedness as a predictor of sexual and reproductive health outcomes for youth. AB - To review research examining the influence of "connectedness" on adolescent sexual and reproductive health (ASRH). Connectedness, or bonding, refers to the emotional attachment and commitment a child makes to social relationships in the family, peer group, school, community, or culture. A systematic review of behavioral research (1985-2007) was conducted. Inclusion criteria included examination of the association between a connectedness sub-construct and an ASRH outcome, use of multivariate analyses, sample size of >or=100, and publication in a peer-reviewed journal. Results were coded as protective, risk, or no association, and as longitudinal, or cross sectional. Findings from at least two longitudinal studies for a given outcome with consistent associations were considered sufficient evidence for a protective or risk association. Eight connectedness sub-constructs were reviewed: family connectedness (90 studies), parent-adolescent general communication (16 studies), parent-adolescent sexuality communication (58 studies), parental monitoring (61 studies), peer connectedness (nine studies), partner connectedness (12 studies), school connectedness (18 studies), and community connectedness (four studies). There was sufficient evidence to support a protective association with ASRH outcomes for family connectedness, general and sexuality-specific parent-adolescent communication, parental monitoring, partner connectedness, and school connectedness. Sufficient evidence of a risk association was identified for the parent overcontrol sub construct of parental monitoring. Connectedness can be a protective factor for ASRH outcomes, and efforts to strengthen young people's pro-social relationships are a promising target for approaches to promote ASRH. Further study regarding specific sub-constructs as well as their combined influence is needed. PMID- 20172459 TI - Confidence as a predictor of sexual and reproductive health outcomes for youth. AB - PURPOSE: To assess the association between four positive youth development (PYD) constructs of confidence and adolescent sexual and reproductive health (ASRH) outcomes. METHODS: We searched nine online databases to locate behavioral research that examined the association between four constructs of confidence (belief in the future, self-determination, clear and positive identity, and self efficacy) and ASRH outcomes (e.g., ever had sex, condom use, contraception use, number of partners, pregnancy/birth, and sexually transmitted infection). Findings were coded as "protective," "risk," or "no association." The presence of at least two longitudinal studies reporting consistent significant associations for at least one ASRH outcome indicated evidence for a protective or risk association. RESULTS: We found evidence to support two of the four PYD constructs of confidence (belief in the future and self-determination) as protective factors for ASRH outcomes. Evidence was insufficient to draw conclusions about clear and positive identity as a protective factor, and was mixed for self-efficacy. Measures of confidence varied considerably across the studies reviewed, reflecting varying definitions; often, the measures used had limited information on reliability. Few longitudinal investigations were identified, and available studies were inconsistent in how they examined the association between the PYD constructs and ASRH outcomes. Evidence for most constructs was insufficient to identify their influence on specific sub-groups of youth. CONCLUSIONS: Despite the need for additional research, this review suggests that belief in the future and self-determination are promising protective factors. Further research is needed to better understand the potential for self-efficacy and clear and positive identity as protective factors. PMID- 20172460 TI - Character as a predictor of reproductive health outcomes for youth: a systematic review. AB - To review research examining the influence of character on adolescent sexual and reproductive health (ASRH). We defined character as comprising two positive youth development constructs: prosocial norms and spirituality. We conducted a systematic review of behavioral research published from 1985 through 2007 that examined the association between two character constructs (prosocial norms and spirituality) and ASRH outcomes. We coded results as showing a protective association, risk association, or no association, and as longitudinal, or cross sectional. We considered consistent associations from at least two longitudinal studies for a given outcome to be sufficient evidence for a protective or risk association. There is sufficient evidence to indicate that prosocial norms and spirituality can be protective factors for some ASRH outcomes including intention to have sex, early sex or ever having sex, contraceptive and condom use, frequency of sex, and pregnancy. The generalizability of findings by age, race/ethnicity, and gender was unclear. Findings suggest that some character sub constructs are associated with a reduced likelihood of several adverse ASRH outcomes and with an increased likelihood of using contraceptives and intending to use condoms. Further research is needed to better understand mixed results and results showing some character sub-constructs, such as religious affiliation, to be associated with adverse ASRH outcomes. PMID- 20172461 TI - Competence as a predictor of sexual and reproductive health outcomes for youth: a systematic review. AB - To examine the association between "competence" and adolescent sexual and reproductive health (ASRH) outcomes. Competence refers to the development of skills to perform tasks successfully in four areas including social and behavioral, cognitive, emotional, and moral competence. We conducted a systematic review of research published from 1985 through 2007. Inclusion criteria included use of multivariate analyses, a sample size of >or=100, publication in a peer reviewed journal, and measurement of an ASRH outcome. We coded findings as protective, risk, or no association and as longitudinal or cross-sectional. We considered the presence of two longitudinal studies with consistent findings for at least one outcome to be sufficient evidence for a risk or protective association. We identified 77 studies that examined cognitive competence, 27 studies that examined social and behavioral competence, 12 studies that examined emotional competence, and no studies that met inclusion criteria for moral competence. The evidence indicated that cognitive competence and social and behavioral competence can be protective factors for ASRH, with findings from at least two longitudinal studies demonstrating a protective association with an ASRH outcome. Findings across cognitive, social and behavioral subconstructs and ASRH outcomes were more mixed. There was insufficient evidence to draw conclusions about emotional and moral competence and ASRH. Helping adolescents to achieve cognitive, social, and behavioral competence may reduce the likelihood of sexual activity and teen pregnancy, and increase contraceptive use. Additional research is needed to examine other outcomes and the generalizability of findings. PMID- 20172462 TI - A review of positive youth development programs that promote adolescent sexual and reproductive health. AB - PURPOSE: Positive youth development (PYD) may be a promising strategy for promoting adolescent health. A systematic review of the published data was conducted to identify and describe PYD programs that improve adolescent sexual and reproductive health. METHODS: Eight databases were searched for articles about PYD programs published between 1985 and 2007. Programs included met the following criteria: fostered at least one of 12 PYD goals in multiple socialization domains (i.e., family, school, community) or addressed two or more goals in at least one socialization domain; allocated at least half of the program activities to promoting general PYD outcomes (as compared with a focus on direct sexual health content); included youth younger than 20 years old; and used an experimental or quasi-experimental evaluation design. RESULTS: Thirty programs met the inclusion criteria, 15 of which had evidence of improving at least one adolescent sexual and reproductive health outcome. Program effects were moderate and well-sustained. Program goals addressed by approximately 50% or more of the effective programs included promoting prosocial bonding, cognitive competence, social competence, emotional competence, belief in the future, and self determination. Effective programs were significantly more likely than those that did not have an impact to strengthen the school context and to deliver activities in a supportive atmosphere. Effective programs were also more likely to build skills, enhance bonding, strengthen the family, engage youth in real roles and activities, empower youth, communicate expectations, and be stable and relatively long-lasting, although these differences between effective and ineffective programs were not statistically significant. CONCLUSION: PYD programs can promote adolescent sexual and reproductive health, and tested, effective PYD programs should be part of a comprehensive approach to promoting adolescent health. However, more research is needed before a specific list of program characteristics can be viewed as a "recipe" for success. PMID- 20172463 TI - Future directions for positive youth development as a strategy to promote adolescent sexual and reproductive health. AB - PYD has tremendous potential to promote not only ASRH but adolescent health more broadly. This review has identified 15 tested, effective models that have demonstrated impact on ASRH; most also affected other youth outcomes, and several produced long-lasting, sustainable effects. These model programs should be prepared for broader dissemination, replication, and effectiveness trials. Broader dissemination will entail investments in developing training, technical assistance, and monitoring models that will aid in ensuring and sustaining implementation with fidelity and tracking program adaptations in broad settings. Evaluations of existing national youth-serving organizations and existing PYD programs that are unevaluated should be encouraged if they are evaluable, address the most strongly supported PYD constructs, have a clearly developed logic model that connects program elements to youth development constructs and outcomes, and program manuals are developed. Support is also provided here for the impact of youth development constructs on later ASRH outcomes, suggesting that new PYD programs, especially those targeting PYD constructs with longitudinal evidence of promotive or protective effects, should be developed and evaluated to identify long-term results. There is much work to be done on examining the ability of PYD constructs to impact ASRH. While there is sufficient evidence for a number of PYD constructs, more longitudinal research is needed. We have argued here that investigation of existing longitudinal datasets may efficiently increase our understanding of the evidence for the promotive and protective effects of understudied constructs or those with mixed evidence. Further, there is a need for the development of standardized measures of PYD constructs and the development and use of measures of positive sexual and reproductive health outcomes. We also recommend that future studies compare the relative strength of the PYD constructs and devote more resources to understanding how these constructs work together to promote ASRH. PMID- 20172464 TI - Just get over it. PMID- 20172465 TI - Iodine Efficiency. Preface. PMID- 20172466 TI - Epidemiology of iodine deficiency: Salt iodisation and iodine status. AB - Universal salt iodisation (USI) and iodine supplementation are highly effective strategies for preventing and controlling iodine deficiency. USI is now implemented in nearly all countries worldwide, and two-thirds of the world's population is covered by iodised salt. The number of countries with iodine deficiency as a national public health problem has decreased from 110 in 1993 to 47 in 2007. Still one-third of households lack access to adequately iodised salt. Iodine deficiency remains a major threat to the health and development of populations around the world, particularly in children and pregnant women in low income countries. Data on iodine status are available from 130 countries and approximately one-third of the global population is estimated to have a low iodine intake based on urinary iodine (UI) concentrations. Insufficient control of iodine fortification levels has led to excessive iodine intakes in 34 countries. The challenges ahead lie in ensuring higher coverage of adequately iodised salt, strengthening regular monitoring of salt iodisation and iodine status in the population, together with targeted interventions for vulnerable population groups. PMID- 20172467 TI - Iodine intake as a determinant of thyroid disorders in populations. AB - Depending on the availability of iodine, the thyroid gland is able to enhance or limit the use of iodine for thyroid hormone production. When compensation fails, as in severely iodine-deficient populations, hypothyroidism and developmental brain damage will be the dominating disorders. This is, out of all comparison, the most serious association between disease and the level of iodine intake in a population. In less severe iodine deficiency, the normal thyroid gland is able to adapt and keep thyroid hormone production within the normal range. However, the prolonged thyroid hyperactivity associated with such adaptation leads to thyroid growth, and during follicular cell proliferation there is a tendency to mutations leading to multifocal autonomous growth and function. In populations with mild and moderate iodine deficiency, such multifocal autonomous thyroid function is a common cause of hyperthyroidism in elderly people, and the prevalence of thyroid enlargement and nodularity is high. The average serum TSH tends to decrease with age in such populations caused by the high frequency of autonomous thyroid hormone production. On the other hand, epidemiological studies have shown that hypothyroidism is more prevalent in populations with a high iodine intake. Probably, this is also a complication to thyroid adaptation to iodine intake. Many thyroid processes are inhibited when iodine intake becomes high, and the frequency of apoptosis of follicular cells becomes higher. Abnormal inhibition of thyroid function by high levels of iodine is especially common in people affected by thyroid autoimmunity (Hashimoto's thyroiditis). In populations with high iodine intake, the average serum thyroid-stimulating hormone (TSH) tends to increase with age. This phenomenon is especially pronounced in Caucasian populations with a genetically determined high tendency to thyroid autoimmunity. A small tendency to higher serum TSH may be observed already when iodine intake is brought from mildly deficient to adequate, but there is at present no evidence that slightly elevated serum TSH in elderly people leads to an increase in morbidity and mortality. CONCLUSION: Even minor differences in iodine intake between populations are associated with differences in the occurrence of thyroid disorders. Both iodine intake levels below and above the recommended interval are associated with an increase in the risk of disease in the population. Optimally, iodine intake of a population should be kept within a relatively narrow interval where iodine deficiency disorders are prevented, but not higher. Monitoring and adjusting of iodine intake in a population is an important part of preventive medicine. PMID- 20172468 TI - Iodine deficiency in pregnancy, infancy and childhood and its consequences for brain development. AB - Iodine deficiency during foetal development and early childhood is associated with cognitive impairment. Randomised clinical studies in school-aged children encountered in the literature indicate that cognitive performance can be improved by iodine supplementation, but most studies suffer from methodological constraints. Tests to assess cognitive performance in the domains that are potentially affected by iodine deficiency need to be refined. Maternal iodine supplementation in areas of mild-to-moderate iodine deficiency may improve cognitive performance of the offspring, but randomised controlled studies with long-term outcomes are lacking. Studies in infants or young children have not been conducted. The best indicators for iodine deficiency in children are thyroid stimulating hormone (TSH) in newborns and thyroglobulin (Tg) in older children. Urinary iodine may also be useful but only at the population level. Adequate salt iodisation will cover the requirements of infants and children as well as pregnant women. However, close monitoring remains essential. PMID- 20172469 TI - Cretinism revisited. AB - Endemic cretinism includes two syndromes: a more common neurological disorder with brain damage, deaf mutism, squint and spastic paresis of the legs and a less common syndrome of severe hypothyroidism, growth retardation and less severe mental defect. Both conditions are due to dietary iodine deficiency and can be prevented by correction of iodine deficiency before pregnancy. Endemic cretinism is now included in the spectrum of the effects of iodine deficiency in a population termed the 'iodine deficiency disorders (IDDs)', which also includes a wide range of lesser degrees of cognitive defect that can be prevented by the correction of iodine deficiency. Iodine deficiency is now recognised by the World Health Organization (WHO) as the most common preventable cause of brain damage with in excess of 2 billion at risk from 130 countries. A global United Nations (UN) programme of prevention has achieved 68% household usage of iodised salt by the year 2000 compared with less than 20% prior to 1990. PMID- 20172470 TI - Assessment of nodular goitre. AB - Nodular goitres are enlargements of the thyroid gland. In the absence of thyroid dysfunction, autoimmune thyroid disease, thyroiditis and thyroid malignancy, they constitute an entity described as non-toxic nodular goitre, which occurs both endemically and sporadically. In the early phase of goitrogenesis, goitres are diffuse and, with time, such goitres tend to become nodular. Concomitantly, thyroid function often becomes autonomous, and therefore the patients gradually develop hyperthyroidism. Some non-toxic goitre patients have no symptoms at all, or just complaints of cosmetic disfigurement. In the diagnostic evaluation protocol, neck palpation and several imaging methods are available: ultrasonography (US), the new developed US elastography, scintigraphy, computed tomography (CT) scan and magnetic resonance imaging (MRI). Fine-needle aspiration biopsy (FNAB) provides the most direct and specific information about a thyroid nodule. Recently, a combination of cytology and molecular testing has shown significant improvement in the diagnostic accuracy and allowed for better prediction of malignancy in thyroid nodular disease. PMID- 20172471 TI - Neonatal TSH screening: is it a sensitive and reliable tool for monitoring iodine status in populations? AB - Iodine deficiency is the most common cause of preventable brain damage in the newborn. The indicators for assessing iodine nutritional status include urinary iodine excretion, thyroid size, thyroid stimulating hormone (TSH) and thyroglobulin (Tg) concentrations in the blood. Neonatal TSH concentration is increased when the supply of thyroid hormone and iodine from the maternal circulation to the foetus has been compromised. The World Health Organization (WHO) has suggested that when a sensitive assay is used on samples collected 3-4 days after birth, a <3% frequency of TSH concentrations >5 mIUl(-1) indicates iodine sufficiency in a population. However, many studies have attempted to apply the frequency of neonatal TSH values >5 mIUl(-1) in determining population iodine status and monitoring intervention programmes, and although some have proven to be successful, most have provided conflicting or uncertain data. This is due to the many technical issues that remain unresolved on the use of neonatal TSH screening for monitoring iodine status, making it doubtful as a sensitive and reliable quantitative tool. More research is required to resolve these issues. In the interim, WHO should consider withdrawing its current guidelines for neonatal TSH screening for monitoring iodine deficiency in populations. PMID- 20172472 TI - Methods for determination of iodine in urine and salt. AB - Good quality data on iodine concentrations in urine and salt samples are indispensable for the efficient management of national salt iodisation programmes and for evaluating iodine interventions. Most of the analytical methods for urinary iodine concentration are based on the manual spectrophotometric measurement of Sandell-Kolthoff reduction reaction catalysed by iodine using different oxidising reagents in the initial digestion step. Other analytical methods include semi-quantitative methods, a microplate method, automated methods; and the technologically advanced methods include the inductively coupled plasma mass-spectrometer method. Iodine in salt is determined quantitatively by the titration method, colorimetrically by the WYD iodine checker or by a technologically advanced potentiometric method. Worldwide, titration is the method of choice because of its accuracy, ease of operation and low cost. Rapid test kits are suitable for qualitative use in situations where iodised salt need to be distinguished from non-iodised salt, preferably with titration back-up. PMID- 20172473 TI - The challenges of iodine supplementation: a public health programme perspective. AB - An adequate iodine intake during pregnancy, lactation and early childhood is particularly critical for optimal brain development of the foetus and of children 7-24 months of age. While the primary strategy for sustainable elimination of iodine deficiency remains universal salt iodisation, the World Health Organization and the United Nations Children's Fund recommend a complementary strategy of iodine supplements as a temporary measure when salt iodisation could not be implemented. This article aims to review current evidence on efficacy and implications of implementing iodine supplementation as a public health measure to address iodine deficiency. Iodine supplementation seems unlikely to reach high coverage in a rapid, equitable and sustained way. Implementing the programme requires political commitment, effective and efficient supply, distribution and targeting, continuous education and communication and a robust monitoring system. Thus, universal salt iodisation should remain the primary strategy to eliminate iodine deficiency. PMID- 20172474 TI - The challenges of implementing and monitoring of salt iodisation programmes. AB - Assuring adequate iodine nutrition is key to preventing iodine deficiency disorders (IDDs). The primary strategy to assuring adequate iodine nutrition in most populations is through the iodisation of salt. The challenges of implementing and monitoring salt iodisation programmes are described. In particular, issues relating to legislation, regulation and enforcement are presented, as well as the integration of this information with household-based surveys on the proportion of households using iodised salt and the iodine status of the population. PMID- 20172475 TI - Iodine excess. AB - Several mechanisms are involved in the maintenance of normal thyroid hormone secretion, even when iodine intake exceeds physiologic needs by a factor of 100. The sodium-iodide symporter system contributes most to this stability. Faced with an iodine excess, it throttles the transport of iodide into the thyroid cells, the rate-limiting step of hormone synthesis. Even before the iodine symporter reacts, a sudden iodine overload paradoxically blocks the second step of hormone synthesis, the organification of iodide. This so-called Wolff-Chaikoff effect requires a high (>or=10(-3) molar) intracellular concentration of iodide. The block does not last long, because after a while the sodium-iodide symporter shuts down; this allows intracellular iodide to drop below 10(-3) molar and the near normal secretion to resume. In some susceptible individuals (e.g., after radio iodine treatment of Graves' disease or in autoimmune thyroiditis), the sodium iodide symporter fails to shut down, the intracellular concentration of iodide remains high and chronic hypothyroidism ensues. To complicate matters, iodine excess may also cause hyperthyroidism. The current explanation is that this happens in persons with goitres, for example, after long-standing iodine deficiency. These goitres may contain nodules carrying a somatic mutation that confers a 'constitutive' activation of the TSH receptor. Being no more under pituitary control, these nodules overproduce thyroid hormone and cause iodine induced hyperthyroidism, when they are presented with sufficient iodine. These autonomous nodules gradually disappear from the population after iodine deficiency has been properly corrected. More recent studies suggest that chronic high iodine intake furthers classical thyroid autoimmunity (hypothyroidism and thyroiditis) and that iodine-induced hyperthyroidism may also have an autoimmune pathogenesis. PMID- 20172476 TI - The impact of common micronutrient deficiencies on iodine and thyroid metabolism: the evidence from human studies. AB - Deficiencies of micronutrients are highly prevalent in low-income countries. Inadequate intake of iodine impairs thyroid function and results in a spectrum of disorders. Other common deficiencies of micronutrients such as iron, selenium, vitamin A, and possibly zinc may interact with iodine nutrition and thyroid function. Randomised controlled intervention trials in iodine- and iron-deficient populations have shown that providing iron along with iodine results in greater improvements in thyroid function and volume than providing iodine alone. Vitamin A supplementation given alone or in combination with iodised salt can have a beneficial impact on thyroid function and thyroid size. Despite numerous studies of the effect of selenium on iodine and thyroid metabolism in animals, most published randomised controlled intervention trials in human populations failed to confirm an impact of selenium supplementation on thyroid metabolism. Little evidence is available on interactions between iodine and zinc metabolism. PMID- 20172478 TI - Iodine in enteral and parenteral nutrition. AB - Iodine deficiency (ID) has multiple adverse effects on growth and development due to inadequate thyroid hormone production. Methods for assessment of iodine nutrition in individuals include the urinary iodine concentration (UI), thyroid size and thyroid function tests. The UI measured in several repeat 24-h urine samples can detect inadequate iodine intake in individuals receiving enteral or parenteral nutrition (PN) and allow for iodine supplementation before the onset of hypothyroidism. A daily dose of 1 microg iodine/kg body weight is currently recommended for children receiving PN, but this is far below their requirements. Daily iodine requirements in adults receiving enteral nutrition or PN are estimated to be 70-150 microg, but most PN formulations do not contain iodine. Despite this, ID has been unlikely because absorption from iodine-containing skin antiseptics and other adventitious sources can provide sufficient iodine. However, if chlorhexidine replaces iodine-containing antiseptics for catheter care, ID may occur during long-term PN, and periodic testing of UI and thyroid function may be prudent. Infants may be particularly vulnerable to ID because of their small thyroidal iodine store. In this review, we describe three recent patients (an infant, a child and an adult) who developed ID and thyroid hypofunction during PN. PMID- 20172479 TI - [Has the most appropriate insulin regimen in type 2 diabetes been established yet?]. PMID- 20172480 TI - Clinical differences between patients with MODY-3, MODY-2 and type 2 diabetes mellitus with I27L polymorphism in the HNF1alpha gene. AB - OBJECTIVE: The aim of our study was to describe and evaluate the clinical and metabolic characteristics of patients with MODY-3, MODY-2 or type 2 diabetes who presented I27L polymorphism in the HNF1alpha gene. METHODS: The study included 31 previously diagnosed subjects under follow-up for MODY-3 (10 subjects from 5 families), MODY-2 (15 subjects from 9 families), or type 2 diabetes (6 subjects) with I27L polymorphism in the HNF1alpha gene. The demographic, clinical, metabolic, and genetic characteristics of all patients were analyzed. RESULTS: No differences were observed in distribution according to sex, age of onset, or form of diagnosis. All patients with MODY-2 or MODY-3 had a family history of diabetes. In contrast, 33.3% of patients with type 2 diabetes mellitus and I27L polymorphism in the HNF1alpha gene had no family history of diabetes (p < 0.05). No differences were observed in body mass index, prevalence of hypertension, or microvascular or macrovascular complications. Drug therapy was required by 100% of MODY-3 patients, but not required by 100% of MODY-2 patients or 16.7% of patients with type 2 diabetes mellitus and I27L polymorphism in the HNF1alpha gene (p < 0.05). CONCLUSIONS: Occasional difficulties may be encountered when classifying patients with MODY-2, MODY-3 or type 2 diabetes of atypical characteristics, in this case patients who present I27L polymorphism in the HNF1alpha gene. PMID- 20172481 TI - [Influence of previous psychiatric disorders on postoperative course in patients undergoing bariatric surgery]. AB - INTRODUCTION: Presurgical evaluation of patients undergoing bariatric surgery includes, among others, a psychological/psychiatric evaluation. Psychiatric disorders that did not contraindicate surgery may persist and influence on weight loss and postoperative clinical course, hindering the success of the procedure. The aim of our study was to analyze the postoperative evolution of our series of patients with and without psychiatric symptoms before surgery. PATIENTS AND METHODS: Retrospective analysis of 109 patients undergoing bariatric surgery with duodenal switch from 2003 to 2008 (follow up > 6 months). We studied weight changes, immediate and delayed complications of surgery and nutritional deficiencies in post-surgical follow-up in patients with previous psychiatric disorders (group 1, n = 17) compared with patients without psychiatric disorders (group 2, n = 92). RESULTS: Patients in group 1 showed a greater tendency for weight gain. They regained a 9.4% of the initial excess weight lost between 18 months after surgery and 36 months after surgery, while patients in group 2 regained only 0.2% in the same period (p < 0.05). There was no difference in immediate surgical complications (5/17 vs 25/92 patients). The mean incidence of late surgical complications was 0.71 per patient in group 1 and 0.22 complications per patient in group 2 (p = 0.02). 52.9% of patients in group 1 had at least one late complication compared to 19.6% of patients in group 2 (p = 0.003). The three most common complications in patients with previous psychiatric disorders were chronic diarrhea, vomits and malnutrition. The presence of nutritional deficiencies were common in both groups, mainly soluble vitamins, iron and zinc. During postoperative follow-up, we found 3.1 +/- 1.6 nutritional deficiencies per patient in group 1 and 2.5 +/- 1.7 in group 2 (p = 0.04). More than three nutritional deficiencies were found in 8 patients in group 1 (52.9%) compared to 23 patients in group 2 (25%) (p = 0.03). CONCLUSIONS: The presence of previous psychiatric disorders may be a predictor of a less positive outcome in morbidly obese patients who undergo bariatric surgery. PMID- 20172477 TI - Perchlorate, iodine and the thyroid. AB - In pharmacologic doses, perchlorate inhibits thyroidal iodine uptake and subsequently decreases thyroid hormone production. Although pharmacologic doses may be used in the treatment of hyperthyroidism, recent literature has focussed on the detection of low levels of perchlorate in the environment, groundwater and foodstuffs and their potential adverse effects on human thyroid function. This is of particular concern to the developing foetus and infant, whose normal neurodevelopment depends on adequate iodine intake for the production of thyroid hormones. Further research is needed to clarify the potential health effects of low-level chronic environmental perchlorate exposure. The health impact of environmental perchlorate may be dependent upon adequate iodine intake and should be interpreted in combination with other environmental exposures that are also potential thyroidal endocrine disruptors. PMID- 20172482 TI - [Effects of a revision program on the control of type 2 diabetics followed at the primary care level. Diabetes First program]. AB - BACKGROUND AND OBJECTIVE: To analyze the evolution of the glycosylated hemoglobin and other parameters after performing a control program and follow-up by nurses to improve the control of the patients with type 2 diabetes mellitus (Diabetes First). PATIENTS AND METHOD: Intervention study in type 2 diabetes mellitus patients from Murcia. The inclusion criterium was to be a type 2 diabetes mellitus patient badly controlled on diabetes parameters (glycosylated haemoglobin > or = 7%). We included 831 patients from 8 primary care centers. The program consisted of three visits (first one, after three months and after six months), where the patients received diabetic education. RESULTS: The mean initial glycosylated haemoglobin value was 8.1% +/- 1.3%, after 3 months it decreased to 7.5% +/- 1.1%, and after 6 months from the first visit its value was 7.5% +/- 2.6%. There was a statistically significant (p < 0.001) difference between the initial glycosylated haemoglobin and the values three months later. There was not such a difference between the second and third visit. Total and low density liporpotein cholesterol decreased significantly after 3 months (p < 0.05). High-density lipoprotein cholesterol and triglycerides showed no difference. Systolic and diastolic blood pressure significantly decreased after three months (p < 0.0001 and p < 0.005). CONCLUSIONS: A simple nursing intervention program performed in primary care centers has a very positive impact on the control and treatment of patients with type 2 diabetes mellitus. PMID- 20172483 TI - [Development and evolution of laparoscopic adrenalectomy in an specialized team: from the beginning to the outpatient setting]. AB - BACKGROUND: After the first reports in 1992, laparoscopic adrenalectomy (LA) has evolved technically until becoming the standard approach for the treatment of most of the adrenal gland diseases. MATERIAL AND METHODS: Retrospective and descriptive study of 67 patients who underwent 68 LA between January-1998 and December-2008 in the Laparoscopic Surgery Unit of the General and Digestive Surgery Service in a third level hospital (only one case of bilateral LA). The group was divided in 2 periods, P-1 (1998-2003, 22 cases) and P-2 (2004-2008, 45 cases), which have been compared to evaluate the evolution of the LA technique. RESULTS: Indications for LA were: 19 incidentalomas, 19 primary hyperaldosteronism, 18 pheocromocitoms, 5 cases of symptomatic and non functioning adrenal masses, 4 Cushing adenomas and 2 metastases. There was no mortality, only 4 patients had minor complications (6%) and conversion rate was only 3% (2 cases). Mean size of adrenal glands resected was 3.83 cm and the mean operative time was 86 minutes. Mean postoperative hospital stay was 3 days and in P-2 seventeen patients were discharged on an outpatient basis (hospital stay less than 23 hours). CONCLUSIONS: In our experience, LA for the treatment of adrenal diseases has shown to be safe, effective and reproducible with low complications and excellent tolerance by patients. When the learning curve is overcome, hospital stay and operative time clearly decrease. As a consequence, LA can be planned in selected cases as outpatient surgery with good results. PMID- 20172484 TI - [Rol of pituitary tumour-transforming gene (PTTG) in the pituitary adenomas]. AB - The pathogenesis of pituitary tumours is far to be understood. Pituitary transforming tumour gene (PTTG), a gen that induces aneuploidy, genetic instability, cellular proliferation and to stimulate angiogenesis, has been involved in neoplasic transformation and shown overexpressed in many neoplasm as lung, breast, endometrium, thyroid and colon malignant tumours. On the other hand, PTTG has been inconsistently studied in pituitary tumours. The majority of studies have been performed in animals and there is a great variability in the methods used in its determination. The goal of this review is to resume the role of PTTG in tumourogenesis and critically to revise the studies published in humans in order to advance in the knowledge of the pathogenesis of pituitary adenomas and to find clinical useful predictors of the behavior of these tumours. PMID- 20172485 TI - [Catecholamine - producing paraganglioma of the eardrum]. PMID- 20172486 TI - [Influenza A virus (H1N1) infection as a cause of severe diabetic ketoacidosis in type 1 diabetes]. PMID- 20172487 TI - A brief review on the mechanisms of miRNA regulation. AB - MicroRNAs (miRNAs) are a class of short, endogenously-initiated non-coding RNAs that post-transcriptionally control gene expression via either translational repression or mRNA degradation. It is becoming evident that miRNAs are playing significant roles in regulatory mechanisms operating in various organisms, including developmental timing and host-pathogen interactions as well as cell differentiation, proliferation, apoptosis and tumorigenesis. Likewise, as a regulatory element, miRNA itself is coordinatively modulated by multifarious effectors when carrying out basic functions, such as SNP, miRNA editing, methylation and circadian clock. This mini-review summarized the current understanding of interactions between miRNAs and their targets, including recent advancements in deciphering the regulatory mechanisms that control the biogenesis and functionality of miRNAs in various cellular processes. PMID- 20172489 TI - Significant deviations in the configurations of homologous tandem repeats in prokaryotic genomes. AB - We explored the possibilities of whole-genome duplication (WGD) in prokaryotic species, where we performed statistical analyses of the configurations of the central angles between homologous tandem repeats (TRs) on the circular chromosomes. At first, we detected TRs on their chromosomes and identified equivalent tandem repeat pairs (ETRPs); here, an ETRP is defined as a pair of tandem repeats sequentially similar to each other. Then we carried out statistical analyses of the central angle distributions of the detected ETRPs on each circular chromosome by way of comparisons between the detected distributions and those generated by null models. In the analyses, we estimated a P value by a simulation using the Kullback-Leibler divergence as a distance measure between two distributions. As a result, the central angle distributions for 8 out of the 203 prokaryotic species showed statistically significant deviations (P<0.05). In particular, we found out the characteristic feature of one round of WGD in Photorhabdus luminescens genome and that of two rounds of WGD in Escherichia coli K12. PMID- 20172488 TI - Nucleosomal context of binding sites influences transcription factor binding affinity and gene regulation. AB - Transcription factor (TF) binding to its DNA target site plays an essential role in gene regulation. The location, orientation and spacing of transcription factor binding sites (TFBSs) also affect regulatory function of the TF. However, how nucleosomal context of TFBSs influences TF binding and subsequent gene regulation remains to be elucidated. Using genome-wide nucleosome positioning and TF binding data in budding yeast, we found that binding affinities of TFs to DNA tend to decrease with increasing nucleosome occupancy of the associated binding sites. We further demonstrated that nucleosomal context of binding sites is correlated with gene regulation of the corresponding TF. Nucleosome-depleted TFBSs are linked to high gene activity and low expression noise, whereas nucleosome-covered TFBSs are associated with low gene activity and high expression noise. Moreover, nucleosome covered TFBSs tend to disrupt coexpression of the corresponding TF target genes. We conclude that nucleosomal context of binding sites influences TF binding affinity, subsequently affecting the regulation of TFs on their target genes. This emphasizes the need to include nucleosomal context of TFBSs in modeling gene regulation. PMID- 20172490 TI - Codon usage biases of transposable elements and host nuclear genes in Arabidopsis thaliana and Oryza sativa. AB - Transposable elements (TEs) are mobile genetic entities ubiquitously distributed in nearly all genomes. High frequency of codons ending in A/T in TEs has been previously observed in some species. In this study, the biases in nucleotide composition and codon usage of TE transposases and host nuclear genes were investigated in the AT-rich genome of Arabidopsis thaliana and the GC-rich genome of Oryza sativa. Codons ending in A/T are more frequently used by TEs compared with their host nuclear genes. A remarkable positive correlation between highly expressed nuclear genes and C/G-ending codons were detected in O. sativa (r=0.944 and 0.839, respectively, P<0.0001) but not in A. thaliana, indicating a close association between the GC content and gene expression level in monocot species. In both species, TE codon usage biases are similar to that of weakly expressed genes. The expression and activity of TEs may be strictly controlled in plant genomes. Mutation bias and selection pressure have simultaneously acted on the TE evolution in A. thaliana and O. sativa. The consistently observed biases of nucleotide composition and codon usage of TEs may also provide a useful clue to accurately detect TE sequences in different species. PMID- 20172491 TI - In silico characterization and homology modeling of thylakoid-bound ascorbate peroxidase from a drought tolerant wheat cultivar. AB - Ascorbate peroxidase, a haem protein (EC 1.11.1.11), efficiently scavenges hydrogen peroxide (H(2)O(2)) in cytosol and chloroplasts of plants. In this study, a full-length coding sequence of thylakoid-bound ascorbate peroxidase cDNA (TatAPX) was cloned from a drought tolerant wheat cultivar C306. Homology modeling of the TatAPX protein was performed by using the template crystal structure of chloroplastic ascorbate peroxidase from tobacco plant (PDB: 1IYN). The model structure was further refined by molecular mechanics and dynamic methods using various tools such as PROCHECK, ProSA and Verify3D. The predicted model was then tested for docking with H(2)O(2), the substrate for TatAPX enzyme. The results revealed that Arg233 and Glu255 in the predicted active site of the enzyme are two important amino acid residues responsible for strong hydrogen bonding affinity with H(2)O(2), which might play an important role in scavenging of H(2)O(2) from the plant system. PMID- 20172492 TI - Large-scale analyses of glycosylation in cellulases. AB - Cellulases are important glycosyl hydrolases (GHs) that hydrolyze cellulose polymers into smaller oligosaccharides by breaking the cellulose beta (1-->4) bonds, and they are widely used to produce cellulosic ethanol from the plant biomass. N-linked and O-linked glycosylations were proposed to impact the catalytic efficiency, cellulose binding affinity and the stability of cellulases based on observations of individual cellulases. As far as we know, there has not been any systematic analysis of the distributions of N-linked and O-linked glycosylated residues in cellulases, mainly due to the limited annotations of the relevant functional domains and the glycosylated residues. We have computationally annotated the functional domains and glycosylated residues in cellulases, and conducted a systematic analysis of the distributions of the N linked and O-linked glycosylated residues in these enzymes. Many N-linked glycosylated residues were known to be in the GH domains of cellulases, but they are there probably just by chance, since the GH domain usually occupies more than half of the sequence length of a cellulase. Our analysis indicates that the O linked glycosylated residues are significantly enriched in the linker regions between the carbohydrate binding module (CBM) domains and GH domains of cellulases. Possible mechanisms are discussed. PMID- 20172493 TI - A modified ant colony optimization algorithm for tumor marker gene selection. AB - Microarray data are often extremely asymmetric in dimensionality, such as thousands or even tens of thousands of genes but only a few hundreds of samples or less. Such extreme asymmetry between the dimensionality of genes and samples can lead to inaccurate diagnosis of disease in clinic. Therefore, it has been shown that selecting a small set of marker genes can lead to improved classification accuracy. In this paper, a simple modified ant colony optimization (ACO) algorithm is proposed to select tumor-related marker genes, and support vector machine (SVM) is used as classifier to evaluate the performance of the extracted gene subset. Experimental results on several benchmark tumor microarray datasets showed that the proposed approach produces better recognition with fewer marker genes than many other methods. It has been demonstrated that the modified ACO is a useful tool for selecting marker genes and mining high dimension data. PMID- 20172494 TI - [How to effectively control inflammation and the nutritional status of dialysis patients?]. PMID- 20172495 TI - [Inflammation and vascular calcifications]. AB - Vascular calcifications are feature of late stages of atherosclerosis and are associated with cardiovascular disease. Numerous pathologies like diabetes or chronic renal insufficiency were also associated with the development of vascular calcification, particularly in the artery media. In the past, vascular calcifications were considered like a passive and degenerative event. Several studies have allowed demonstrating that they are the results of an active and inflammatory regulated process. A new idea emerges related to the role of calcifications as a cause of inflammation resulting in a vicious circle between inflammation and vascular calcification. This revue proposes to present an update on these different phenomenons. PMID- 20172496 TI - [Nutrition of patients with diabetes and chronic kidney disease]. AB - One third of the patients with Diabetes present a Chronic Kidney Disease. Despite cardiovascular events and increased mortality, Diabetes is the first cause of End Stage Renal Disease. The nutritional status of theses patients widely varies, from obesity to malnutrition, according to their type of diabetes, the severity of the renal disease, and the frequent concurrent diseases: it conditions their dietary counselling. The patients with type 2 diabetes and obesity have to moderate and well choose their alimentary lipids, for body weight control and to reduce their cardiovascular risk; this works in the context of a multifactorial approach as demonstrated by the Steno 2 trial. The use of insulin or conventional insulin-secretagogues (sulfonylureas, glinids) needs patients to be educated about their carbohydrate intake, especially when the good glucose control exposes to hypoglycaemia. Moderation of protein intake reduces proteinuria, an improved outcome has been demonstrated for patients with type 1 diabetes and nephropathy on a Low Protein Diet. The patients who require dialysis often deteriorate their nutritional status, the protein intake must be increased at this stage. PMID- 20172497 TI - [What is the benefit of the new European nutritional guidelines for dialysis?]. AB - Nutritional guidelines are scarce for patients receiving maintenance hemodialysis. In this review, we address the recent European guidelines released in 2007. They include diagnosis and follow-up criteria for malnutrition to be performed routinely. They provide new values for protein and energy requirements, based on physical activity. Vitamins and trace elements requirements are proposed. The renutrition therapies are addressed, i.e., oral supplement, enteral and intradialytic parenteral nutrition. Finally, androgens, quotidian dialysis and acidosis treatment are also considered. PMID- 20172498 TI - [Inflammation and insulin resistance: chronic renal disease features]. AB - Chronic renal disease is a state of microinflammation and insulin resistance. They both impact on the patient's outcome with an increased cardiovascular morbi mortality and malnutrition. Current evidence suggests that there is a link between these two abnormal conditions. Recent data show a multiple organ regulatory pathway with a key role of bone, adipose tissue, immune system and central nervous system in energy balance control and glucose homeostasis. Thus, in searching for effective therapies, we should use an integrated approach aimed at modifying integrated outcomes rather than targeting single molecules. PMID- 20172499 TI - Rapid and dynamic alterations of gene expression profiles of adult porcine bone marrow-derived stem cell in response to hypoxia. AB - This study sought to identify the gene expression patterns of porcine bone marrow derived MSC in response to hypoxia and to investigate novel specific hypoxic targets that may have a role in determining MSC proliferation/survival and differentiation. MSC from 15 animals were incubated in 1% oxygen and 8% carbon dioxide for 6, 12, and 24 h. RNA samples were isolated and assayed with Affymetrix porcine arrays and quantitative reverse-transcription PCR. Significant gene expression levels among the four groups of normoxia, 6-, 12-, and 24-h hypoxia were identified. The pattern in the 12-h hypoxia group was similar to that of the 24-h group. Of 23,924 probes, 377 and 210 genes were regulated in the 6- and 24-h hypoxia groups, respectively. Functional classification of the hypoxic regulated genes was mainly clustered in cell proliferation and response to stress. However, the major upregulated genes in the 6-h group were activated in cell cycle phases; the genes in the 24-h hypoxia were evenly separated into cell differentiation, apoptosis, and cellular metabolic processes. Twenty-eight genes were upregulated in all hypoxia groups; these genes are considered as hypoxic targets. Our results identified a genome-wide hypoxia-induced gene expression pattern in porcine MSC. This study provides a global view of molecular events in the cells during exposure to hypoxia and revealed a set of novel candidate hypoxic targets. PMID- 20172500 TI - [Oncogenic osteomalacia due to phosphaturic mesenchymal tumour in infratemporal fossa]. AB - Oncogenic osteomalacia is an uncommon syndrome characterized by phosphaturic tumours that produce mineral metabolism abnormalities. Head and neck is the second most frequent location of these tumours. We describe a case of a phosphaturic mesenchymal tumour in the infratemporal fossa that caused oncogenic osteomalacia, resolved by means of surgical excision. PMID- 20172501 TI - Emotion regulation in pathological skin picking: findings from a non-treatment seeking sample. AB - Pathological skin picking (PSP) is characterized by excessive picking of the skin, resulting in significant distress or functional impairment. The aim of the present study was to investigate the emotion regulation hypothesis of PSP. University students with PSP (n = 55) and without history of PSP (n = 55) were asked to retrospectively rate the intensity of affective states before, during, and after skin picking episodes. The results showed that for a majority of the PSP sufferers, intensity of certain negative affective states (i.e. anxiety, tension or boredom) was pronounced just before picking, and diminished significantly in the period from before to after picking. Relief and gratification increased during picking whereas guilt increased afterwards. A similar pattern emerged in the control group, although a much lower level of intensity was reported. Participants were also asked to fill out questionnaires concerning emotion regulation difficulties, emotion reactivity, depression, anxiety and worry. Hierarchical logistic regressions demonstrated that emotion regulation difficulties as well as emotion reactivity predicted PSP diagnosis after depression, anxiety and worry were controlled for. Furthermore, emotion regulation difficulties statistically mediated the relationship between emotion reactivity and PSP. Overall, the findings support an emotion regulation model of PSP. PMID- 20172502 TI - Relative risk of probabilistic category learning deficits in patients with schizophrenia and their siblings. AB - BACKGROUND: Although patients with schizophrenia display an overall probabilistic category learning performance deficit, the extent to which this deficit occurs in unaffected siblings of patients with schizophrenia is unknown. There are also discrepant findings regarding probabilistic category learning acquisition rate and performance in patients with schizophrenia. METHODS: A probabilistic category learning test was administered to 108 patients with schizophrenia, 82 unaffected siblings, and 121 healthy participants. RESULTS: Patients with schizophrenia displayed significant differences from their unaffected siblings and healthy participants with respect to probabilistic category learning acquisition rates. Although siblings on the whole failed to differ from healthy participants on strategy and quantitative indexes of overall performance and learning acquisition, application of a revised learning criterion enabling classification into good and poor learners on the basis of individual learning curves revealed significant differences between percentages of sibling and healthy poor learners: healthy (13.2%), siblings (34.1%), patients (48.1%), yielding a moderate relative risk. CONCLUSIONS: These results clarify previous discrepant findings pertaining to probabilistic category learning acquisition rate in schizophrenia and provide the first evidence for the relative risk of probabilistic category learning abnormalities in unaffected siblings of patients with schizophrenia, supporting genetic underpinnings of probabilistic category learning deficits in schizophrenia. These findings also raise questions regarding the contribution of antipsychotic medication to the probabilistic category learning deficit in schizophrenia. The distinction between good and poor learning might be used to inform genetic studies designed to detect schizophrenia risk alleles. PMID- 20172504 TI - Serotonin 1B receptor imaging in alcohol dependence. AB - BACKGROUND: Although animal models suggest that alcohol dependence (AD) is associated with elevations in the number of serotonin 1B receptors (5-HT(1B)R), 5 HT(1B)R levels have not been investigated in people with AD. The selective 5 HT(1B)R antagonist radioligand, [(11)C]P943, permits in vivo assessment of central 5-HT(1B)R binding potential (BP(ND)) with positron emission tomography. Because of its central role in AD, we were particularly interested in ventral striatal 5-HT(1B)R BP(ND) values. METHODS: Twelve medication-free, recently abstinent (at least 4 weeks) patients with AD (mean age 35.2 +/- 10.2 years, 5 women) and 12 healthy control subjects (HC) (mean age 30.6 +/- 9.2 years, 5 women) completed [(11)C]P943 positron emission tomography on a high-resolution research tomograph. Individual magnetic resonance imaging scans were collected to exclude individuals with anatomical abnormalities and for coregistration. Imaging data were analyzed with a multilinear reference tissue model. RESULTS: Ventral striatal 5-HT(1B)R BP(ND) values (2.01 +/- .57% and 1.55 +/- .09%, respectively; 29% between-group difference, p = .006) were increased in AD compared with HC subjects. No influence of demographic or clinical variables or amount of injected radiotracer was observed. CONCLUSIONS: This study provides the first evidence that AD in humans is, like in rodent models, associated with increased levels of ventral striatal 5-HT(1B)Rs. PMID- 20172503 TI - Short- and long-term functional consequences of fluoxetine exposure during adolescence in male rats. AB - BACKGROUND: Fluoxetine (FLX), a selective serotonin reuptake inhibitor, is prescribed for the treatment of major depressive disorder in young populations. Here, we explore the short- and long-term consequences of adolescent exposure to FLX on behavioral reactivity to emotion-eliciting stimuli. METHODS: Adolescent male rats received FLX (10 mg/kg) twice daily for 15 consecutive days (postnatal days 35-49). The influence of FLX on behavioral reactivity to rewarding and aversive stimuli was assessed 24 hours (short-term) or 3 weeks after FLX treatment (long-term). A separate group of adult rats was also treated with FLX (postnatal days 65-79) and responsiveness to forced swimming was assessed at identical time intervals as with the adolescents. RESULTS: Fluoxetine exposure during adolescence resulted in long-lasting decreases in behavioral reactivity to forced swimming stress and enhanced sensitivity to sucrose and to anxiety eliciting situations in adulthood. The FLX-induced anxiety-like behavior was alleviated by re-exposure to FLX in adulthood. Fluoxetine treatment during adolescence also impaired sexual copulatory behaviors in adulthood. Fluoxetine treated adult rats did not show changes in behavioral reactivity to forced swim stress as observed in those treated during adolescence and tested in adulthood. CONCLUSIONS: Treating adolescent rats with FLX results in long-lived complex outputs regulated by the emotional valence of the stimulus, the environment in which it is experienced, and the brain circuitry likely being engaged by it. Our findings highlight the need for further research to improve our understanding of the alterations that psychotropic exposure may induce on the developing nervous system and the potential enduring effects resulting from such treatments. PMID- 20172505 TI - Carbon dioxide hypersensitivity in separation-anxious offspring of parents with panic disorder. AB - BACKGROUND: Similar patterns of vulnerability to carbon dioxide (CO(2)) inhalation have been reported in adults with panic disorder (PD) and children with separation anxiety disorder (SAD), suggesting a link between the adult and child conditions. This study examines the influence of familial risk for PD on CO(2) responses in children with SAD. We hypothesized that offspring with SAD of parents with PD would have distinct CO(2) responses. METHODS: Two hundred twelve 9- to 20-year-old offspring of parents with or without PD were exposed to maintained 5% CO(2) inhalation in the participants' homes. Anxiety symptoms, panic attacks, and respiratory physiology (respiratory frequency and tidal volume) were monitored during baseline and 15-min maintained CO(2) breathing. RESULTS: As hypothesized, significant offspring SAD x parent PD interactions were obtained for anxiety symptoms, respiratory frequency, tidal volume, and a panting index during CO(2) inhalation. Offspring with both SAD and parental PD exhibited more anxiety symptoms at termination of 5% CO(2) breathing than the other offspring groups and had the most extreme values on measures of respiratory physiology. CONCLUSIONS: Youth with both SAD and parental PD have respiratory responses to CO(2) similar to adult PD. They might be a subtype of SAD at particularly high risk for adult PD. PMID- 20172506 TI - Effects of early-life stress on serotonin(1A) receptors in juvenile Rhesus monkeys measured by positron emission tomography. AB - BACKGROUND: Traumatic experiences in early childhood are associated with increased risk for developing mood and anxiety disorders later in life. Low serotonin(1A) receptor (5-HT(1A)R) density during development has been proposed as a trait-like characteristic leading to increased vulnerability of stress related neuropsychiatric disorders. METHODS: To assess the relationship between early-life stress and alterations in the serotonin system during development, we used positron emission tomography to measure in vivo 5-HT(1A)R density and apparent dissociation constant (K(D)(app)) in the brain of juvenile Rhesus monkeys exposed to the early-life stress of peer-rearing. RESULTS: In general, 5 HT(1A)R density and K(D)(app) were decreased in peer-reared compared with control mother-reared animals. However, increase in receptor density was found in the dorsomedial prefrontal cortex of peer-reared females. CONCLUSIONS: These findings suggest that exposure to an adverse early-life environment during infancy is associated with long-term alterations in the serotonin system and support previous studies suggesting that reduced 5-HT(1A)R density during development might be a factor increasing vulnerability to stress-related neuropsychiatric disorders. Furthermore, alterations in the serotonin system seemed to be gender- and region-specific, providing a biological basis for the higher prevalence of affective disorders in women. PMID- 20172507 TI - Early environmental enrichment moderates the behavioral and synaptic phenotype of MeCP2 null mice. AB - BACKGROUND: Rett syndrome (RTT) is an X-linked progressive neurodevelopmental disorder characterized by a variety of symptoms including motor abnormalities, mental retardation, anxiety, and autism. Most of RTT cases are caused by mutations of MeCP2. In mice, impaired MeCP2 function results in synaptic deficits associated with motor, cognitive, and emotional alterations. Environmental enrichment (EE) is a rearing condition that enhances synapse formation and plasticity. Previous studies analyzing the effects of postweaning EE found limited effects on motor performance of male MeCP2 mutants. However, EE during early postnatal development produces powerful effects on neural development and plasticity. Thus, we tested whether early EE could ameliorate several phenotypes of male homozygous and female heterozygous MeCP2 mutants. METHODS: We investigated the effects of early EE on motor coordination, structural and functional synaptic plasticity, and brain-derived neurotrophic factor expression in male MeCP2 null mice. Anxiety-related behavior and spatial learning was analyzed in heterozygous MeCP2 female mice. RESULTS: In male mutants, EE modified excitatory and to a lesser extent inhibitory synaptic density in cerebellum and cortex, reversed the cortical long-term potentiation deficit and augmented cortical brain-derived neurotrophic factor levels. Environmental enrichment also ameliorated motor coordination and motor learning. In female heterozygous mice, a model closely mimicking some aspects of RTT symptoms, EE rescued memory deficits in the Morris water maze and decreased anxiety-related behavior. CONCLUSIONS: Early EE dramatically improves several phenotypes of MeCP2 mutants. Thus, environmental factors should be taken into account when analyzing phenotypes of MeCP2 knockout mice, an accepted model of RTT. Early EE might be beneficial in RTT patients. PMID- 20172509 TI - Actions of calcium influx blockers in human neutrophils support a role for receptor-operated calcium entry. AB - The action of two potent store operated Ca2+ entry (SOCE) inhibitors, ML-9 and GdCl3 on Ca2+ fluxes induced by the pro-inflammatory agonists FMLP, PAF, LTB(4) as well as the receptor-independent stimulus thapsigargin has not been documented in human neutrophils. In this study, ML-9 enhanced both release and subsequent Ca2+ influx in response to agonists whereas it enhanced Ca2+ release by thapsigargin, but inhibited Ca2+ influx. In contrast, 1muM GdCl3 completely inhibited Ca2+ influx in response to thapsigargin, but only partially blocked Ca2+ influx after agonist stimulation. These results strongly suggest a major role for receptor-operated Ca2+ influx in human neutrophils. PMID- 20172510 TI - Line bisection in unilateral homonymous visual field defects. AB - The contralesional line bisection error in unilateral homonymous hemianopia is a frequent but neglected clinical phenomenon. Our knowledge about this bisection error is based on small samples of hemianopic patients. Moreover, horizontal line bisection has never been investigated in other unilateral visual field defects. The present study is the first to examine line bisection in a large, representative sample of patients with unilateral homonymous visual field defects. We investigated horizontal line bisection in 129 patients with left- or right-sided homonymous hemianopia (60.5%), upper and lower quadranopia (24.8%), and paracentral scotoma (14.7%), and determined the magnitude and direction of line bisection error. The contralesional horizontal line bisection error was present not only in patients with hemianopia but also in those with upper or lower quadranopia or paracentral scotoma. Neither the type nor the severity of the visual field defect was found to determine the bisection error. Only the side of the field defect seemed to determine the horizontal direction of the bisection error (left-/rightward). The contralesional bisection error is not a specifically "hemianopic" phenomenon. It is frequently associated with any unilateral homonymous visual field defect, i.e., hemianopia, upper/lower quadranopia, paracentral scotoma. Moreover, our results further support the recent finding that the contralesional bisection error is not a direct consequence of the visual field defect. Yet, they also suggest that, although the visual field defect does not seem to be the primary cause of the contralesional bisection error, it may nevertheless contribute to it. PMID- 20172508 TI - Brain reactivity to smoking cues prior to smoking cessation predicts ability to maintain tobacco abstinence. AB - BACKGROUND: Developing the means to identify smokers at high risk for relapse could advance relapse prevention therapy. We hypothesized that functional magnetic resonance imaging (fMRI) reactivity to smoking-related cues, measured before a quit attempt, could identify smokers with heightened relapse vulnerability. METHODS: Before quitting smoking, 21 nicotine-dependent women underwent fMRI during which smoking-related and neutral images were shown. These smokers also were tested for possible attentional biases to smoking-related words using a computerized emotional Stroop (ES) task previously found to predict relapse. Smokers then made a quit attempt and were grouped based on outcomes (abstinence vs. slip: smoking > or = 1 cigarette after attaining abstinence). Prequit fMRI and ES measurements in these groups were compared. RESULTS: Slip subjects had heightened fMRI reactivity to smoking-related images in brain regions implicated in emotion, interoceptive awareness, and motor planning and execution. Insula and dorsal anterior cingulate cortex (dACC) reactivity induced by smoking images correlated with an attentional bias to smoking-related words. A discriminant analysis of ES and fMRI data predicted outcomes with 79% accuracy. Additionally, smokers who slipped had decreased fMRI functional connectivity between an insula-containing network and brain regions involved in cognitive control, including the dACC and dorsal lateral prefrontal cortex, possibly reflecting reduced top-down control of cue-induced emotions. CONCLUSIONS: These findings suggest that the insula and dACC are important substrates of smoking relapse vulnerability. The data also suggest that relapse-vulnerable smokers can be identified before quit attempts, which could enable personalized treatment, improve tobacco-dependence treatment outcomes, and reduce smoking-related morbidity and mortality. PMID- 20172511 TI - [Reactive hemophagocytic syndrome. Is this condition underdiagnosed?]. PMID- 20172512 TI - Conventional testicular sperm extraction combined with the microdissection technique in nonobstructive azoospermic patients: a prospective comparative study. AB - OBJECTIVE: To perform conventional and microdissection testicular sperm extraction (TESE) at the same session and compare their effectiveness. DESIGN: Prospective comparative study. SETTING: University hospital setting. PATIENT(S): The study included 335 patients with nonobstructive azoospermia. INTERVENTION(S): Microdissection TESE was performed to 77 patient with atrophic testes. An additional 258 patients underwent conventional TESE using three incisions on three quadrants of the testis (upper, middle, and lower). Microdissection TESE was performed by enlarging the middle incision vertically when no spermatozoa could be detected using the conventional technique. MAIN OUTCOME MEASURE(S): Sperm retrieval, fertilization, clinical pregnancy rate (PR), and live birth rate were evaluated. The relation between sperm retrieval rate and FSH level and testis volume was also investigated. RESULT(S): Spermatozoa was detected in 33.7% of patients using conventional TESE. The spermatozoa detected increased to 50.8% using microdissection TESE. The increase was statistically significant. In the primary microdissection TESE group, the surgical retrieval rate was 20.8%. The overall sperm retrieval rate was 43.9%. There was a significant relation between the sperm retrieval rate and testis volume, whereas there was no relation between sperm retrieval rate and FSH levels. The overall fertilization rate, clinical PR, and live birth rate were 57.1%, 50.4%, 36.4%, respectively. CONCLUSION(S): Conventional TESE combined with microdissection TESE can be used in selected patients. Sperm retrieval rate of TESE can be low in patients with atrophic testes. PMID- 20172513 TI - Mayer-Rokitansky-Kuster-Hauser syndrome: fertility counseling and treatment. AB - To date, no literature has focused on the counseling of patients with Mayer Rokitansky-Kuster-Hauser syndrome as relates to their unique fertility challenges. This article is presented as a guide to practitioners in the counseling of patients with varying Mayer-Rokitansky-Kuster-Hauser phenotypes regarding individual reproductive potential. PMID- 20172514 TI - Vaginal management of a "late" ectopic pregnancy after vaginal hysterectomy. AB - OBJECTIVE: To describe the first vaginal approach to an ectopic pregnancy after hysterectomy. DESIGN: Case report. SETTING: Private hospital. PATIENT(S): A 38 year-old woman presenting with an ectopic pregnancy 5 months after having a vaginal hysterectomy due to uterine myomatosis. INTERVENTION(S): Vaginal adnexectomy. MAIN OUTCOME MEASURE(S): Vaginal surgery as a plausible approach for this very particular situation (ectopic pregnancy in hysterectomized patient). RESULT(S): After vaginal surgery with removal of the left tube (containing a gestacional sac) and ovary, the patient fully recovered. CONCLUSION(S): Vaginal surgery can be a safe option for ectopic pregnancy resolution in noncomplicated cases. PMID- 20172515 TI - Intestinal vaginoplasty: seven years' experience of a tertiary center. AB - OBJECTIVE: To investigate the long-term effects of intestinal vaginoplasty in cases with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. DESIGN: Prospective study. SETTING: Division of Pelvic Reconstructive Surgery, Department of Gynecology and Obstetrics, at a women's and children disease education and research hospital. PATIENT(S): Between 2003 and 2009, 29 patients with MRKH syndrome underwent intestinal vaginoplasty. INTERVENTION(S): Two of the patients were treated with ileal and 27 with sigmoid vaginoplasty. MAIN OUTCOME MEASURE(S): The age, marital status, associated anomalies, method used for bowel transposition (isoperistaltic/antiperistaltic), type of abdominal incision, and intra- and postoperative complications were evaluated. RESULT(S): One of the patients for whom ileal vaginoplasty was performed had 40 cm ileal necrosis requiring bilateral ileostomy for 2 months. Introital stenosis was detected in 15 cases (79%) who were unmarried, while none of the married cases had introital stenosis. However, all patients responded to finger-dilatation. All married patients were sexually satisfied after operation. An intraluminal abscess developed in the proximal segment of the neovagina owing to stricture occurring above abdominoperineal tunnel 2 years after operation. In another patient who had a rudimentary uterine horn, hematometra developed 3 years after operation and treated with resection. CONCLUSION(S): In our experience, sigmoid vaginoplasty seems to be a favorable procedure which provides excellent long-term results for the patients with vaginal agenesis. PMID- 20172516 TI - Successful pregnancy by insemination of spermatozoa in a woman with a human seminal plasma allergy: should in vitro fertilization be considered first? AB - OBJECTIVE: To raise the possibility that pregnancy can be obtained by assisted reproductive techniques in patients with human seminal plasma allergy. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A woman consulted for a 3 year primary infertility. She reported lack of intercourse because of a seminal plasma allergy. INTERVENTION(S): One intrauterine insemination associated with antihistamine treatment was performed with carefully washed spermatozoa. RESULT(S): Immediately after the insemination, the patient had an allergic reaction treated by steroids. Fortunately, this single attempt led to a successful pregnancy, and the patient gave birth to a healthy girl. CONCLUSION(S): Pregnancies can be obtained in patients with seminal plasma hypersensitivity by means of intrauterine insemination. However, serious complications may occur after performing intrauterine insemination, which is not a totally reliable method to prevent an allergic reaction. Thus a multidisciplinary team should follow such patients carefully and watch for the potential risks and side effects. In vitro fertilization may represent the more cautious option. PMID- 20172517 TI - Management of transverse vaginal septum using the Olbert balloon catheter to mobilize the proximal vaginal mucosa and facilitate low anastomosis. AB - OBJECTIVE: To mobilize and make available for anastomosis the maximal amount of mucosa from the expanded upper vaginal tissue and avoid postoperative narrowing of the vagina. DESIGN: Technique paper. SETTING: Tertiary care medical center. PATIENT(S): Patients with a hematocolpos due to transverse vaginal septum. INTERVENTION(S): Pull through of proximal distended vagina using an Olbert balloon catheter. MAIN OUTCOME MEASURE(S): To avoid midvaginal narrowing due to retraction of the suture line in the surgical management of transverse vaginal septum with hematocolpos. RESULT(S): High-pressure balloon expansion of the proximal hematocolpos optimizes the vaginal mucosa available for final anastomosis. CONCLUSION(S): The use of a high-pressure dilatation balloon permits high intraballoon pressures that facilitate the surgical management of transverse vaginal septum and limit postoperative narrowing of the vagina. PMID- 20172518 TI - Seminal plasma levels of anti-Mullerian hormone and inhibin B are not predictive of testicular sperm retrieval in nonobstructive azoospermia: a study of 139 men. AB - OBJECTIVE: To evaluate the seminal levels of the Sertoli anti-Mullerian hormone (AMH) and inhibin B in the testicular sperm extraction (TESE) in nonobstructive azoospermia. DESIGN: Prospective study. SETTING: Reproductive biology division in a university hospital. PATIENT(S): One hundred thirty-nine men. INTERVENTION(S): Men were classified on the basis of positive and negative TESE. MAIN OUTCOME MEASURE(S): Seminal levels of AMH and inhibin B, serum levels of FSH and inhibin B, testicular volume, sperm retrieval, and spermatogenesis. RESULT(S): The mean serum FSH and inhibin B concentrations were 21.4 IU/L and 54.68 pg/mL. Spermatozoa were retrieved in 43.17% of the men. Mean seminal AMH and inhibin B concentrations were 12.06+/-37.30 pmol/L and 142.72+/-950.91 pmol/L, respectively. Seminal AMH and inhibin B levels were simultaneously undetectable in 35.97% of subjects. Seminal plasma levels of AMH and inhibin B were positively correlated, as were seminal and serum inhibin B concentrations. The successful and failed TESE groups did not differ significantly in terms of either AMH or inhibin B seminal plasma concentrations. Combining the latter parameters with the serum FSH level did not improve the predictive value for successful TESE. The presence or absence of germ cells did not have a statistically significant relationship with seminal plasma AMH and inhibin B concentrations. CONCLUSION(S): There is no value in seminal plasma levels of AMH and inhibin B as criteria for sperm extraction in men with nonobstructive azoospermia. PMID- 20172519 TI - Correction of malalignment in proximal femoral nailing--Reduction technique of displaced proximal fragment. AB - INTRODUCTION: External rotation, abduction, and flexion of the proximal fragment in proximal femoral fracture are one of the main obstacles in nailing. We introduced simple surgical technique using a long hemostatic forceps to achieve fracture reduction and to facilitate preparation of the nail entry site. METHOD: Using this reduction method, 16 patients with displaced subtrochanteric or proximal femoral shaft fracture were treated through cephalomedullary or femoral nailing between January 2005 and May 2007. RESULTS: The difference of the neck shaft angle in the AP view compared to the normal side was 2.2 degrees (range, 0 5 degrees). Anterior angulation in the lateral view was 1.6 degrees (range, 0-15 degrees). One case of malunion was caused by too anterior nail insertion in the lateral view. Bone union was achieved in all cases with an average consolidation time of 5.1 months (range, 3-9 months). CONCLUSION: A simple reduction technique using readily available instruments in the operating room (hemostatic forceps) is quite useful in reducing proximal femoral fragments in cephalomedullary or femoral nailing. PMID- 20172520 TI - The U.S. trauma system: model or misadventure? PMID- 20172521 TI - Peripartum hysterectomy: an evolving picture. AB - Peripartum hysterectomy (PH) is one of the obstetric catastrophes. Evidence is emerging that the role of PH in modern obstetrics is evolving. Improving management of postpartum hemorrhage and newer surgical techniques should decrease PH for uterine atony. Rising levels of repeat elective cesarean deliveries should decrease PH following uterine scar rupture in labor. Increasing cesarean rates, however, have led to an increase in the number of PHs for morbidly adherent placenta. In the case of uterine atony or rupture where PH is required, a subtotal PH is often sufficient. In the case of pathological placental localization involving the cervix, however, a total hysterectomy is required. Furthermore, the involvement of other pelvic structures may prospectively make the diagnosis difficult and the surgery challenging. If resources permit, PH for pathological placental localization merits a multidisciplinary approach. Despite advances in clinical practice, it is likely that peripartum hysterectomy will be more challenging for obstetricians in the future. PMID- 20172522 TI - Translational research in women's health: from bedside to bench and from bench to bedside. PMID- 20172523 TI - Genetic variations at ABCG5/G8 genes modulate plasma lipids concentrations in patients with familial hypercholesterolemia. AB - OBJECTIVE: To investigate the association of four common single nucleotide polymorphisms (SNPs) at ABCG5 (i7892A>G, i18429C>T, Gln604GluC>G, i11836G>A) and five at ABCG8 (5U145T>G, Tyr54CysA>G, Asp19HisG>C, i14222T>C, and Thr400LysG>T) with plasma lipids concentrations and to explore the interaction between those SNPs and smoking in patients with FH. METHODS AND RESULTS: ABCG5/G8 SNPs were genotyped in 500 subjects with genetic diagnosis of FH. Carriers of the minor A allele at the ABCG5_i11836G>A SNP displayed significantly higher HDL-C concentrations (P=0.023) than G/G subjects. In addition, carriers of the minor G allele at the ABCG5_Gln604GluC>G SNP had significantly lower VLDL-C (P=0.011) and lower TG (P=0.017) concentrations than homozygous C/C. Interestingly, a significant gene-smoking interaction was found, in which carriers of the minor alleles at ABCG5 (i7892A>G, i18429C>T, i11836G>A) SNPs displayed significantly lower HDL-C, higher TC and higher TG respectively, only in smokers. On the other hand, nonsmokers carriers of the minor alleles at ABCG5 (i18429C>T and Gln604GluC>G) SNPs had significantly lower TG concentrations (P=0.012 and P=0.035) compared with homozygous for the major allele. CONCLUSIONS: Our data support the notion that ABCG5/G8 genetic variants modulate plasma lipids concentrations in patients with FH and confirm that this effect could be influenced by smoking. Therefore, these results suggest that gene-environmental interactions can affect the clinical phenotype of FH. PMID- 20172524 TI - Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway. AB - Hyperglycemia-induced oxidative stress is known to play an important role in the development of several diabetic complications, including atherosclerosis. Although a number of antioxidants are available, none have been found to be suitable for regulating the oxidative stress response and enhancing antioxidative defense mechanisms. In this study, we evaluated the effects of magnesium lithospermate B (LAB) against oxidative stress. We also endeavored to identify the target molecule of LAB in vascular smooth muscle cells (VSMCs) and the underlying biochemical pathways related to diabetic atherosclerosis. Modified MTT and transwell assays showed that the increased proliferation and migration of rat aortic VSMCs in culture with high glucose was significantly inhibited by LAB. LAB also attenuated neointimal hyperplasia after balloon catheter injury in diabetic rat carotid arteries. To determine molecular targets of LAB, we studied the effects of LAB on aldose reductase (AR) activity, O-GlcNAcylation, and protein kinase C (PKC) activity in VSMCs under normoglycemic or hyperglycemic conditions and showed the improvement of major biochemical pathways by LAB. Potential involvement of the nuclear factor erythroid 2-related factor-2 (Nrf2)- antioxidant responsive element (ARE)-NAD(P)H: quinone oxidoreductase-1 (NQO1) pathway was assessed using siRNA methods. We found that LAB activates the NQO1 via the Nrf2-ARE pathway, which plays an important role in inhibition of the major molecular mechanisms that lead to vascular damage and the proliferation and migration of VSMCs. Together, these findings demonstrate that the induction of the Nrf2-ARE-NQO1 pathway by LAB could be a new therapeutic strategy to prevent diabetic atherosclerosis. PMID- 20172525 TI - Material and surface factors influencing backside fretting wear in total knee replacement tibial components. AB - Retrieval studies have shown that the interface between the ultra-high molecular weight polyethylene insert and metal tibial tray of fixed-bearing total knee replacement components can be a source of substantial amounts of wear debris due to fretting micromotion. We assessed fretting wear of polyethylene against metal as a function of metal surface finish, alloy, and micromotion amplitude, using a three-station pin-on-disc fretting wear simulator. Overall, the greatest reduction in polyethylene wear was achieved by highly polishing the metal surface. For example, highly polished titanium alloy surfaces produced nearly 20 times less polyethylene wear compared with blasted titanium alloy, whereas, decreasing the micromotion amplitude from 200 to 50microm produced approximately four times less polyethylene wear for the same blasted titanium alloy surface. Although the effect of the metal alloy was much smaller than the effect of metal surface roughness or the micromotion amplitude, CoCr discs produced slightly greater polyethylene fretting wear than titanium alloy discs under each condition. The results are essential in design and manufacturing decisions related to fixed-bearing total knee replacements. PMID- 20172526 TI - Alterations in damage processes in dense cancellous bone following gamma radiation sterilization. AB - Structurally intact cancellous bone allograft is an attractive tissue form because its high porosity can provide space for delivery of osteogenic factors and also allows for more rapid and complete in-growth of host tissues. Gamma radiation sterilization is commonly used in cancellous bone allograft to prevent disease transmission. Commonly used doses of gamma radiation sterilization (25-35 kGy) have been shown to modify cortical bone post-yield properties and crack propagation but have not been associated with changes in cancellous bone material properties. The purpose of this study was to determine the effects of irradiation on the elastic and yield properties and microscopic tissue damage processes in dense cancellous bone. Cancellous bone specimens (13 control, 14 irradiated to 30 kGy) from bovine proximal tibiae were tested in compression to 1.3% apparent strain and examined for microscopic tissue damage. The yield strain in irradiated specimens (0.93+/-0.11%, mean+/-SD) did not differ from that in control specimens (0.90+/-0.11%, p=0.44). No differences in elastic modulus were observed between groups after accounting for differences in bone volume fraction. However, irradiated specimens showed greater residual strain (p=0.01), increased number of microfractures (p=0.02), and reduced amounts of cross-hatching type damage (p<0.01). Although gamma radiation sterilization at commonly used dosing (30 kGy) does not modify elastic or yield properties of dense cancellous bone, it does cause modifications in damage processes, resulting in increased permanent deformation following isolated overloading. PMID- 20172527 TI - Experimental evidence of a delta-shock in nonlinear chromatography. AB - We report about a new type of composition front in nonlinear chromatography that is called delta-shock, which has to be added to the family of classical transitions, i.e. simple waves, shocks and semi-shocks. Recently, the occurrence of delta-shocks in the case of mixed competitive-cooperative isotherms of the following type n(i) = H(i)c(i)/(1 - K1c1 + K2c2) (i = 1, 2), (with H2 > H1, where components 1 and 2 have anti-Langmuir and Langmuir adsorption behavior, respectively) was predicted theoretically and their behavior was analyzed in the frame of the equilibrium theory of chromatography. The delta-shock can be viewed as a growing traveling spike superimposed to the discontinuity separating the initial and the feed state, which propagates along the column at constant speed and constant rate of growth. In this work we complement these findings from an experimental point of view. The binary system consisting of phenetole (component 1) and 4-tert-butylphenol (component 2) in methanol-water (about 2:1, v/v) on a Zorbax 300StableBond-C18 column from Agilent has been shown, through a series of overloaded pulse experiments and of frontal analysis experiments with the pure compounds, to be subject to the competitive-cooperative isotherm of the type above, up to rather large concentrations. This system does exhibit a delta-shock when the operating conditions are chosen according to theory, namely when phenetole initially saturating the column is displaced by 4-tert-butylphenol, both at high concentrations (the minimum concentrations exhibiting a fully developed delta-shock in this series of experiments were c1 = 20 g/L and c2 = 75 g/L). The propagation of the delta-shock matches the theoretical predictions in terms of both the effect of concentration and the effect of column length. This is the first experimental observation ever of a delta-shock in chromatography. It is noteworthy that the proof of the occurrence of the delta-shock reported here has been obtained in both laboratories cooperating in this project. PMID- 20172528 TI - Independent evaluation of a commercial deconvolution reporting software for gas chromatography mass spectrometry analysis of pesticide residues in fruits and vegetables. AB - The gas chromatography mass spectrometry (GC-MS) deconvolution reporting software (DRS) from Agilent Technologies has been evaluated for its ability as a screening tool to detect a large number of pesticides in incurred and fortified samples extracted with acetone/dichloromethane/light petroleum (Mini-Luke method). The detection of pesticides is based on fixed retention times using retention time locking (RTL) and full scan mass spectral comparison with a partly customer built automated mass spectral deconvolution and identification system (AMDIS) database. The GC-MS was equipped with a programmable temperature vaporising (PTV) injector system which enables more sample to be injected. In a blind study of 52 real samples a total number of 158 incurred pesticides were found. In addition to the 85 pesticides found by manual interpretation of GC-NPD/ECD chromatograms, the DRS revealed 73 more pesticides (+46%). The DRS system also shows its potential to discover pesticides which are normally not searched for (EPN in long beans from Thailand). A spiking experiment was performed to blank matrices of apple, orange and lettuce with 177 different pesticides at concentration levels 0.02 and 0.1 mg/kg. The samples were analysed on GC-MS full scan and the AMDIS match factor was used as a mass spectral quality criterion. The threshold level of the AMDIS match factor was set at 20 to eliminate most of the false positives. AMDIS match factors from 20 up to 69 are regarded only as indication of a positive hit and must be followed by manual interpretation. Pesticides giving AMDIS match factors at > or = 70 are regarded as identified. To simplify and decrease the large amount of data generated at each concentration level, the AMDIS match factors > or = 20 was averaged (mean AMF) for each pesticide including the commodities and their replicates. Among 177 different pesticides spiked at 0.02 and 0.1 mg/kg level, the percentage of mean AMF values > or = 70 were 23% and 80%, respectively. For 531 individual detections of pesticides (177 pesticides x 3 replicates) giving AMDIS match factor 20 in apple, orange and lettuce, the detection rates at 0.02 mg/kg were 71%, 63% and 72%, respectively. For the 0.1 mg/kg level the detection rates were 89%, 85% and 89%, respectively. In real samples some manual interpretation must be performed in addition. However, screening by GC-MS/DRS is about 5-10 times faster compared to screening with GC NPD/ECD because the time used for manual interpretation is much shorter and there is no need for re-injection on GC-MS for the identification of suspect peaks found on GC-NPD/ECD. PMID- 20172529 TI - Characterization and photochemical and antibacterial properties of highly stable silver nanoparticles prepared on montmorillonite clay in n-hexanol. AB - Ag nanoparticles (NPs) of approximately 2.5+/-0.6 nm in size with high stability were prepared on montmorillonite clay in n-hexanol ([Ag NP/clay]). The aqueous suspensions of Ag NP/clay obtained were colored pale yellow to gray, and an intense yellow surface plasmon band was observed at approximately 397-422 nm at a [Ag(+)] concentration of 0.01-1 M. Fluorescence peaks of these Ag NP/clay suspensions, which were due to interband transitions of Ag NPs, were observed at approximately 447 nm upon excitation at approximately 341 nm. Photoinduced charge separation and electron accumulation in the presence of 2-propanol were observed in the Ag NPs on the clay. The photogenerated holes indicate a reaction with OH( ) because the generation of (.)OH radicals decreased in the presence of 2 propanol, as observed using a spin-trapping electron spin resonance (ESR) method. The amount of H(2) produced depended on the amount of Ag NPs on the clay and the concentration of 2-propanol in the suspension. Antibacterial activity of Ag NPs on clay was also observed against Escherichia coli even after 12 years. This simple method of preparation in n-hexanol led to the successful formation of highly stable and photoactive Ag NPs on montmorillonite clay. PMID- 20172530 TI - Functionalization of adsorbent with different aliphatic polyamines for heavy metal ion removal: characteristics and performance. AB - This paper examines the characteristics of poly(glycidyl methacrylate) (PGMA) beads functionalized with different aliphatic polyamines as adsorbents and their performance in copper ion adsorption. The four aliphatic polyamines evaluated include ethylenediamine (EDA), diethylenetriamine (DETA), triethylenetetramine (TETA), and tetraethylenepentamine (TEPA). Various analytical tools, including elemental analysis, BET, and XAFS (XANES+EXAFS), were used to characterize the adsorbents in terms of their immobilized amine contents, polyamine densities, and their coordination structures for the adsorption of a typical heavy metal ion, Cu(2+). It was found that the immobilized polyamine densities followed the order of EDA>DETA>TETA>TEPA, but the immobilized amine contents followed the opposite order of TEPA>TETA>DETA>EDA. XAFS analysis for the adsorbents after copper ion adsorption revealed that the average coordination number of copper ion with the nitrogen atoms (in the range between 3 and 4) followed the order of DETA0.05) or p-Akt-to-t-Akt ratios (p = 0.22) between the groups at sacrifice. CONCLUSIONS: In this xenograft model we found no difference in tumor growth or survival between low fat vs Western fed mice when the fat source was saturated fat. These results conflict with those of other studies in which corn oil was used to show that low fat diets delay prostate cancer growth, suggesting that fat type may be as important as fat amount in the prostate cancer setting. PMID- 20172551 TI - HAMLET treatment delays bladder cancer development. AB - PURPOSE: HAMLET is a protein-lipid complex that kills different types of cancer cells. Recently we observed a rapid reduction in human bladder cancer size after intravesical HAMLET treatment. In this study we evaluated the therapeutic effect of HAMLET in the mouse MB49 bladder carcinoma model. MATERIALS AND METHODS: Bladder tumors were established by intravesical injection of MB49 cells into poly L-lysine treated bladders of C57BL/6 mice. Treatment groups received repeat intravesical HAMLET instillations and controls received alpha-lactalbumin or phosphate buffer. Effects of HAMLET on tumor size and putative apoptotic effects were analyzed in bladder tissue sections. Whole body imaging was used to study HAMLET distribution in tumor bearing mice compared to healthy bladder tissue. RESULTS: HAMLET caused a dose dependent decrease in MB49 cell viability in vitro. Five intravesical HAMLET instillations significantly decreased tumor size and delayed development in vivo compared to controls. TUNEL staining revealed selective apoptotic effects in tumor areas but not in adjacent healthy bladder tissue. On in vivo imaging Alexa-HAMLET was retained for more than 24 hours in the bladder of tumor bearing mice but not in tumor-free bladders or in tumor bearing mice that received Alexa-alpha-lactalbumin. CONCLUSIONS: Results show that HAMLET is active as a tumoricidal agent and suggest that topical HAMLET administration may delay bladder cancer development. PMID- 20172552 TI - Editorial comment. PMID- 20172550 TI - Variation among internet based calculators in predicting spontaneous resolution of vesicoureteral reflux. AB - PURPOSE: An increasing number of parents and practitioners use the Internet for health related purposes, and an increasing number of models are available on the Internet for predicting spontaneous resolution rates for children with vesicoureteral reflux. We sought to determine whether currently available Internet based calculators for vesicoureteral reflux resolution produce systematically different results. MATERIALS AND METHODS: Following a systematic Internet search we identified 3 Internet based calculators of spontaneous resolution rates for children with vesicoureteral reflux, of which 2 were academic affiliated and 1 was industry affiliated. We generated a random cohort of 100 hypothetical patients with a wide range of clinical characteristics and entered the data on each patient into each calculator. We then compared the results from the calculators in terms of mean predicted resolution probability and number of cases deemed likely to resolve at various cutoff probabilities. RESULTS: Mean predicted resolution probabilities were 41% and 36% (range 31% to 41%) for the 2 academic affiliated calculators and 33% for the industry affiliated calculator (p = 0.02). For some patients the calculators produced markedly different probabilities of spontaneous resolution, in some instances ranging from 24% to 89% for the same patient. At thresholds greater than 5%, 10% and 25% probability of spontaneous resolution the calculators differed significantly regarding whether cases would resolve (all p <0.0001). CONCLUSIONS: Predicted probabilities of spontaneous resolution of vesicoureteral reflux differ significantly among Internet based calculators. For certain patients, particularly those with a lower probability of spontaneous resolution, these differences can significantly influence clinical decision making. PMID- 20172553 TI - Adrenomedullin increases renal nitric oxide production and ameliorates renal injury in mice with unilateral ureteral obstruction. AB - PURPOSE: We evaluated the effects of adrenomedullin (Peptide Institute, Minoh shi, Osaka, Japan) on mediators, including nitric oxide and transforming growth factor-beta, and parameters of renal injury in a murine unilateral ureteral obstruction model. MATERIALS AND METHODS: Three study groups of control, adrenomedullin treated and adrenomedullin plus L-NAME treated BALB/C mice, respectively, underwent left unilateral ureteral obstruction. A 24-hour urine sample was collected to measure urinary NO(2)/NO(3) 1 day before unilateral ureteral obstruction and kidneys were harvested on postoperative day 14. Tubulointerstitial damage markers were evaluated by immunohistochemistry. Tissue transforming growth factor-beta was determined by enzyme-linked immunosorbent assay. Endothelial and inducible nitric oxide synthase immunolocalization was also determined. RESULTS: Urinary NO(2)/NO(3) was significantly higher in the adrenomedullin group than in controls, confirming increased renal nitric oxide production. Immunohistochemistry showed increased endothelial nitric oxide synthase in vascular endothelial cells in the adrenomedullin group but tissue transforming growth factor-beta did not significantly differ in controls vs the adrenomedullin group. Interstitial collagen deposition and fibroblasts in the obstructed kidney were significantly decreased in the adrenomedullin group. The number of leukocytes and apoptotic cells in the obstructed kidney were significantly decreased by adrenomedullin. Renal injury amelioration resulting from adrenomedullin was blunted by the nitric oxide synthase inhibitor L-NAME. CONCLUSIONS: Adrenomedullin increased renal nitric oxide, and suppressed tubular apoptosis, interstitial fibrosis and inflammatory cell infiltration in mice with unilateral ureteral obstruction. The renoprotective peptide adrenomedullin may be useful for that condition. PMID- 20172555 TI - Photoselective laser vaporization prostatectomy versus transurethral prostate resection: a cost analysis. AB - PURPOSE: Laser procedures to treat symptomatic benign prostatic hyperplasia are becoming more common despite concern for potentially increasing cost burdens often associated with new technologies. MATERIALS AND METHODS: Actual costs associated with photoselective laser vaporization prostatectomy and transurethral prostate resection were measured using the EPSi and TSI (Eclipsys) hospital cost accounting systems at 2 large tertiary referral centers for the first 12 months that GreenLight HPS was performed. Only patients who presented for photoselective laser vaporization prostatectomy or transurethral prostate resection as the principal treatment during the hospital visit were included in study. RESULTS: A total of 250 men underwent transurethral prostate resection and 220 underwent photoselective laser vaporization prostatectomy, including 194 (78%) and 209 (95%), respectively, treated on an outpatient basis with less than 23 hours of hospitalization. Overall costs of laser vaporization were lower than those of transurethral prostate resection ($4,266 +/- $1,182 vs $5,097 +/- $5,003, p = 0.01). Average inpatient length of stay was also longer in the resection group. CONCLUSIONS: The actual costs of photoselective laser vaporization prostatectomy at our affiliated hospitals are lower than those of transurethral prostate resection. The primary reason is likely that most patients who undergo laser vaporization are treated on an outpatient basis compared to those who undergo resection. While significant complications are uncommon, those that prolong inpatient hospitalization such as hyponatremia (transurethral resection syndrome), which is associated with transurethral prostate resection but not with photoselective laser vaporization prostatectomy, can add substantial expense. Further studies are warranted to investigate these findings on a broader scale. PMID- 20172556 TI - Stone formation and pregnancy: pathophysiological insights gained from morphoconstitutional stone analysis. AB - PURPOSE: We examined whether stone composition in pregnant women reflects peculiar pathophysiological conditions. MATERIALS AND METHODS: We analyzed in detail the composition of stones from 244 pregnant women 17 to 44 years old and from 5,712 nonpregnant women in the same age range, as recorded between January 1991 and December 2007. Clinical features were also recorded. All stones were analyzed by morphological examination coupled with infrared spectroscopy. The 2 patient groups were compared by clinical and biochemical characteristics. RESULTS: Stone episodes in pregnant women manifested mainly in trimesters 2 and 3 (39% and 46%, respectively). Spontaneous passage was noted in 81% of pregnant vs 47% of nonpregnant women (p <0.0001). Calcium phosphate, mainly in the form of carbapatite, was the main stone component in 65.6% of pregnant vs 31.4% of nonpregnant women (p <0.0001). Octacalcium phosphate pentahydrate, a transition phase in calcium phosphate stone formation, was found in a 5-fold higher proportion in carbapatite stones in pregnant than in nonpregnant women, a finding also suggesting recent stone formation during pregnancy. CONCLUSIONS: The composition of stones manifesting during pregnancy clearly differs from that of stones formed in nonpregnant women of childbearing age, suggesting a different pathophysiology specific to the pregnant state. In view of the pH dependency of calcium phosphate stones factors that increase the physiological elevation in maternal urinary calcium excretion and pH are likely to have a role in the preferential formation of calcium phosphate stones during pregnancy. PMID- 20172557 TI - Editorial comment. PMID- 20172558 TI - Risk factors for breakthrough infection in children with primary vesicoureteral reflux. AB - PURPOSE: Despite the widespread application of endoscopic therapy and the debate surrounding the use of prophylactic antibiotics to treat children with vesicoureteral reflux, many pediatric urologists still favor medical management. Breakthrough infection is one of the absolute indications for surgery. Data to predict breakthrough infection are warranted to manage cases of primary reflux. MATERIALS AND METHODS: We reviewed medical records of 72 girls and 138 boys (mean +/- SD age at diagnosis 2.66 +/- 3.23 years) with primary vesicoureteral reflux who were followed with antibiotic prophylaxis at Aichi Children's Health and Medical Center. We examined multiple factors by univariate/multivariate analysis to elucidate risk factors for breakthrough infection. RESULTS: Breakthrough infection developed in 59 children (28%). On univariate analysis higher reflux grade (p <0.05) and abnormal renal scan determined by (99m)technetium dimercapto succinic acid (p <0.0001) were significantly associated with breakthrough infection. On multivariate analysis abnormal renal scan was an independent risk factor for breakthrough infection (OR 11.08, 95% CI 0.76-1.72, p <0.0001). CONCLUSIONS: Abnormal renal scan is an independent risk factor for breakthrough infection. Parents and physicians should remain aware that these patients are at high risk for breakthrough infection, which potentially could lead to renal damage. PMID- 20172559 TI - Regional variation in total cost per radical prostatectomy in the healthcare cost and utilization project nationwide inpatient sample database. AB - PURPOSE: Surgical treatment for prostate cancer represents a large national health care expenditure. We determined whether state level variation in the cost of radical prostatectomy exists and whether we could explain this variation by adjusting for covariates associated with cost. MATERIALS AND METHODS: Using the 2004 Healthcare Cost and Utilization Project National Inpatient Sample of 7,978,041 patients we identified 9,917 who were 40 years old or older with a diagnosis of prostate cancer who underwent radical prostatectomy without cystectomy. We used linear regression to examine state level regional variation in radical prostatectomy costs, controlling for the local area wage index, patient demographics, case mix and hospital characteristics. RESULTS: The mean +/ SD unadjusted cost was $9,112 +/- $4,434 (range $2,001 to $49,922). The unadjusted mean cost ranged from $12,490 in California to $4,650 in Utah, each significantly different from the mean of $8,903 in the median state, Washington (p <0.0001). After adjusting for all potential confounders total cost was highest in Colorado and lowest in New Jersey, which were significantly different from the median, Washington ($10,750 and $5,899, respectively, vs $8,641, p <0.0001). The model explained 85.9% of the variance with regional variation accounting for the greatest incremental proportion of variance (35.1%) and case mix variables accounting for an incremental 32.3%. CONCLUSIONS: The total cost of radical prostatectomy varies significantly across states. Controlling for known total cost determinants did not completely explain these differences but altered ordinal cost relationships among states. Cost variation suggests inefficiencies in the health care market. Additional studies are needed to determine whether these variations in total cost translate into differences in quality or outcome and how they may be translated into useful policy measures. PMID- 20172560 TI - Editorial comment. PMID- 20172561 TI - Can advance transobturator sling suspension cure male urinary postoperative stress incontinence? AB - PURPOSE: In a prospective 2-center study we confirmed and extended published results of the positive effect on post-prostatectomy stress incontinence of transobturator sling suspension using an Advance male sling. MATERIALS AND METHODS: From September 2007 to June 2008 a male sling was placed and evaluated in 36 men according to the Rehder and Gozzi method. Diagnosis was based on 24 hour urine loss measured by a pad test, a 24-hour micturition frequency volume chart and cystoscopy. A visual analog scale for continence and bother, and a pad test were used preoperatively and postoperatively to objectively evaluate operative results. RESULTS: At 1-year followup cure was achieved in 9.0% of patients and improvement was achieved in 45.5%. No effect on incontinence was seen in 36.5% of patients and 9.0% experienced worsening incontinence by pad test. The mean +/- SD visual analogue scale score of 6.1 +/- 2.2 (range 0 to 10) preoperatively improved significantly to 4.6 +/- 3.0 at 3 months (p = 0.024) and not significantly to 4.9 +/- 3.1 by 1 year postoperatively (p = 0.39). Improved incontinence did not correlate with patient age or incontinence severity. Complications developed in 2 patients, including sling infection and postoperative urinary retention in 1 each. CONCLUSIONS: The transobturator sling suspension operation is a minimally invasive, safe procedure for male postoperative stress incontinence. Significantly improved continence was not observed on pad test but significant improvement in continence and bother was seen on the visual analog scale at 3 months. PMID- 20172562 TI - Melamine related bilateral renal calculi in 50 children: single center experience in clinical diagnosis and treatment. AB - PURPOSE: We investigated the clinical diagnosis and treatment features of bilateral renal calculi in young children who ingested melamine tainted infant milk formula. MATERIALS AND METHODS: We retrospectively analyzed clinical data on 50 children (mean +/- SE age 23.4 +/- 3.1 months) with a history of ingesting melamine tainted infant milk formula and suffering from bilateral renal calculi. All patients underwent ultrasound and renal function evaluation. Treatment included cessation of melamine tainted formula consumption, hydration, urine basification and hemodialysis if necessary. RESULTS: Bilateral renal calculi peaked in 6 to 18-month-olds (58% of cases). The male-to-female ratio was 3.1:1.0. Calculi ranged in diameter from 4 to 10 mm in 33 patients (66%) and 2.5 to 4 mm in 17 (34%). Of the 11 patients with renal failure 8 underwent 1 to 4 sessions of hemodialysis. Of the 9 bilateral obstruction cases with renal failure 8 did not require surgical intervention but 1 required ureteral catheterization to drain the renal pelvis. All children experienced a good outcome and were discharged home after a mean +/- SE hospitalization of 8.1 +/- 0.7 days. CONCLUSIONS: Melamine related urinary calculi were most often seen in patients 6 to 18 months old. Conservative management has been sufficient in most cases. However, these children need to be monitored for long-term effects of melamine tainted milk formula consumption. PMID- 20172563 TI - Editorial comment. PMID- 20172565 TI - A prospective, randomized trial of management for asymptomatic lower pole calculi. AB - PURPOSE: We determined the natural course and compared the deleterious effects in kidneys of shock wave lithotripsy, percutaneous nephrolithotomy and observation for asymptomatic lower caliceal stones. MATERIALS AND METHODS: Between April 2007 and August 2008 patients with asymptomatic lower caliceal calculi were enrolled in the study. To assess stone status noncontrast abdominal helical computerized tomography was done 3 and 12 months after intervention. All patients were evaluated by dimercapto-succinic acid renal scintigraphy 6 weeks and 12 months after intervention. RESULTS: A total of 94 patients were prospectively randomized to percutaneous nephrolithotomy (31), shock wave lithotripsy (31) and observation (32). Mean +/- SD followup was 19.3 +/- 5 months (range 12 to 29). In the percutaneous nephrolithotomy group all patients were stone-free at month 12. Scintigraphy revealed a scar in 1 patient (3.2%) on month 3 followup imaging. In the shock wave lithotripsy group the stone-free rate was 54.8%. Scintigraphy revealed scarring in 5 patients (16.1%). In the observation group 7 patients (18.7%) required intervention during followup. Median time to intervention was 22.5 +/- 3.7 months (range 18 to 26). One patient (3.1%) had spontaneous stone passage. Scintigraphy did not reveal scarring in any patient. CONCLUSIONS: Stone related events were noted in more than 20% of patients with asymptomatic lower caliceal stones observed expectantly. To manage lower caliceal stones percutaneous nephrolithotomy has a significantly higher stone-free rate with less renal scarring than shock wave lithotripsy. Thus, patients with asymptomatic lower caliceal stones must be informed in detail about all management options, especially focusing on percutaneous nephrolithotomy with its outstanding outcome. PMID- 20172566 TI - Editorial comment. PMID- 20172567 TI - Editorial comment. PMID- 20172568 TI - Use of rectus abdominis muscle flap as adjunct to bladder neck closure in patients with neurogenic incontinence: preliminary experience. AB - PURPOSE: Vesicoureteral fistula is a well-known potential complication following bladder neck closure for neurogenic incontinence. Various maneuvers, including omental interposition, have been described to prevent this problem. Unfortunately omentum is not always available or feasible for use. We describe the surgical anatomy and use of a rectus abdominis muscle flap as an adjunctive maneuver during bladder neck closure to correct or prevent development of bladder neck fistula. MATERIALS AND METHODS: We performed a retrospective chart review of all patients at our institution undergoing rectus abdominis muscle flap by a single surgeon (EAS). Patient demographics, indications for surgery, intraoperative and postoperative complications, and long-term efficacy were assessed. Cadaveric dissection was also performed to gain a greater understanding of the surgical anatomy relevant to this procedure. RESULTS: In 6 patients with neurogenic bladder dysfunction a rectus abdominis muscle flap was interposed between the bladder neck and urethral stump at bladder neck closure. There were no intraoperative or postoperative complications associated with this procedure. At a mean followup of 45.5 months (range 18 to 120) all 6 patients were continent of urine. There have been no urinary fistulas related to use of the rectus abdominis muscle flap. Cadaveric dissections confirmed the inferior epigastric artery to be the dominant and readily mobile blood supply of the rectus abdominis muscle flap. CONCLUSIONS: The rectus abdominis muscle flap is easily harvested without significant risk of morbidity and offers a well vascularized tissue for coverage of a bladder neck closure when an omental flap is not available. PMID- 20172569 TI - How do you tell whether a change in surgical technique leads to a change in outcome? AB - PURPOSE: Surgeons routinely evaluate and modify their surgical technique to improve patient outcome. It is also common for surgeons to analyze results before and after a change in technique to determine whether the change led to better results. Simple comparison of results before and after surgical modification may be confounded by the surgical learning curve. We developed a statistical method applicable to analyzing before/after surgical studies. MATERIALS AND METHODS: We used simulation studies to compare different statistical analyses of before/after studies. We evaluated a simple 2-group comparison of results before and after the modification by the chi-square test and a novel bootstrap method that adjusts for the surgical learning curve. RESULTS: In the presence of the learning curve a simple 2-group comparison almost always showed an ineffective surgical modification to be of benefit. When the surgical modification was harmful, leading to a 10% decrease in the success rate, 2-group comparison nonetheless showed a statistically significant improvement in outcome about 80% of the time. The bootstrap method had only moderate power but did not show that ineffective surgical modifications were beneficial more than would be expected by chance. CONCLUSIONS: Simplistic approaches to the analysis of before/after surgical studies may lead to grossly erroneous results under the surgical learning curve. A straightforward alternative statistical method allows investigators to separate the effects of the learning curve from those of the surgical modification. PMID- 20172570 TI - Editorial comment. PMID- 20172571 TI - Creative potential: mental well-being impact assessment of the Liverpool 2008 European capital of culture programme. AB - OBJECTIVES: Culture has a number of potential impacts upon health and well-being. This project was undertaken to assess the potential impacts of the Liverpool 2008 European Capital of Culture programme upon mental well-being, so that positive effects can be maximized and negative impacts reduced, in order that health and well-being are promoted and inequalities are reduced. STUDY DESIGN: A mental well being impact assessment (MWIA) toolkit has been developed, and was piloted in this study. MWIA uses a sequence of procedures designed to systematically assess the effect of projects, programmes and policies upon people's mental well-being and health. METHODS: The MWIA toolkit was used to explore the potential positive and negative impacts on mental well-being of a sample of projects and policies from the European Capital of Culture programme. This was achieved by asking stakeholders to answer a series of questions, holding participative workshops, constructing a community profile and reviewing the research literature. Recommendations were developed which aim to enhance the impact of the programme on people's mental well-being. RESULTS: As expected, both positive and negative impacts of the European Capital of Culture programme on mental well-being were identified. Fourteen themes were identified as emerging from the workshops, screening and reviewing the research evidence. Based on these data, 33 recommendations were developed by the project steering group and have been presented to the Liverpool Culture Company. CONCLUSIONS: The process of conducting the assessment, particularly its participatory nature and its awareness-raising role, had impacts upon mental well-being. The findings demonstrate the potential for the Culture Company programme to have a profound impact upon mental well-being, and highlight areas which could be addressed to optimize the impact of the programme. PMID- 20172572 TI - Analysis of 16S rDNA sequences from pathogenic Leptospira serovars and use of single nucleotide polymorphisms for rapid speciation by D-HPLC. AB - Leptospira have a worldwide distribution and include important zoonotic pathogens yet diagnosis and differentiation still tend to rely on traditional bacteriological and serological approaches. In this study a 1.3 kb fragment of the rrs gene (16S rDNA) was sequenced from a panel of 22 control strains, representing serovars within the pathogenic species Leptospira interrogans, Leptospiraborgpetersenii, and Leptospirakirschneri, to identify single nucleotide polymorphisms (SNPs). These were identified in the 5' variable region of the 16S sequence and a 181 bp PCR fragment encompassing this region was used for speciation by Denaturing High Performance Liquid Chromatography (D-HPLC). This method was applied to eleven additional species, representing pathogenic, non pathogenic and intermediate species and was demonstrated to rapidly differentiate all but 2 of the non-pathogenic Leptospira species. The method was applied successfully to infected tissues from field samples proving its value for diagnosing leptospiral infections found in animals in the UK. PMID- 20172573 TI - Axial time-averaged acoustic radiation force on a cylinder in a nonviscous fluid revisited. AB - OBJECTIVE: The present research examines the acoustic radiation force of axisymmetric waves incident upon a cylinder of circular surface immersed in a nonviscous fluid. The attempt here is to unify the various treatments of radiation force on a cylinder with arbitrary radius and provide a formulation suitable for any axisymmetric incident wave. METHOD AND RESULTS: Analytical equations are derived for the acoustic scattering field and the axial acoustic radiation force. A general formulation for the radiation force function, which is the radiation force per unit energy density per unit cross-sectional surface, is derived. Specialized forms of the radiation force function are provided for several types of incident waves including plane progressive, plane standing, plane quasi-standing, cylindrical progressive diverging, cylindrical progressive converging and cylindrical standing and quasi-standing diverging waves (with an extension to the case of spherical standing and quasi-standing diverging waves incident upon a sphere). SIGNIFICANCE AND SOME POTENTIAL APPLICATIONS: This study may be helpful essentially due to its inherent value as a canonical problem in physical acoustics. Potential applications include particle manipulation of cylindrical shaped structures in biomedicine, micro-gravity environments, fluid dynamics properties of cylindrical capillary bridges, and the micro-fabrication of new cylindrical crystals to better control light beams. PMID- 20172574 TI - Episomal replication timing of gamma-herpesviruses in latently infected cells. AB - This study addresses the timing of gammaherpesviral episomal DNA replication with respect to the cell cycle. For the first time we analyzed a rhadinovirus, the prototype Herpesvirus saimiri (HVS), and compared it to the lymphocryptovirus Epstein-Barr virus (EBV). Newly synthesized DNA of latently infected B- or T cells was first BrdU-labeled; then we sorted the cells corresponding to cell cycle phases G(0/1), G(2/M), and S (4 fractions S(1)-S(4)) and performed anti BrdU chromatin immunoprecipitation. Next, DNA of different viral gene loci was quantitatively detected together with cellular control genes of known replication time. The sensitive technique is further enhanced by an internal coprecipitation standard for increased precision. Both gammaherpesviruses replicated very early in S-phase, together with cellular euchromatin. Our work suggests that early S phase DNA replication is a general characteristic of episomal herpesviral genomes. PMID- 20172575 TI - Vesicular stomatitis virus infects resident cells of the central nervous system and induces replication-dependent inflammatory responses. AB - Vesicular stomatitis virus (VSV) infection of mice via intranasal administration results in a severe encephalitis with rapid activation and proliferation of microglia and astrocytes. We have recently shown that these glial cells express RIG-I and MDA5, cytosolic pattern recognition receptors for viral RNA. However, it is unclear whether VSV can replicate in glial cells or if such replication is required for their inflammatory responses. Here we demonstrate that primary microglia and astrocytes are permissive for VSV infection and limited productive replication. Importantly, we show that viral replication is required for robust inflammatory mediator production by these cells. Finally, we have confirmed that in vivo VSV administration can result in viral infection of glial cells in situ. These results suggest that viral replication within resident glial cells might play an important role in CNS inflammation following infection with VSV and possibly other neurotropic nonsegmented negative-strand RNA viruses. PMID- 20172576 TI - Glycoprotein gene sequence variation in rhesus monkey rhadinovirus. AB - Gene sequences for seven glycoproteins from 20 independent isolates of rhesus monkey rhadinovirus (RRV) and of the corresponding seven glycoprotein genes from nine strains of the Kaposi's sarcoma-associated herpesvirus (KSHV) were obtained and analyzed. Phylogenetic analysis revealed two discrete groupings of RRV gH sequences, two discrete groupings of RRV gL sequences and two discrete groupings of RRV gB sequences. We called these phylogenetic groupings gH(a), gH(b), gL(a), gL(b), gB(a) and gB(b). gH(a) was always paired with gL(a) and gH(b) was always paired with gL(b) for any individual RRV isolate. Since gH and gL are known to be interacting partners, these results suggest the need of matching sequence types for function of these cooperating proteins. gB phylogenetic grouping was not associated with gH/gL phylogenetic grouping. Our results demonstrate two distinct, distantly-related phylogenetic groupings of gH and gL of RRV despite a remarkable degree of sequence conservation within each individual phylogenetic group. PMID- 20172577 TI - The capsid-spacer peptide 1 Gag processing intermediate is a dominant-negative inhibitor of HIV-1 maturation. AB - The human immunodeficiency virus type 1 (HIV-1) maturation inhibitor bevirimat disrupts virus replication by inhibiting the cleavage of the capsid-spacer peptide 1 (CA-SP1) Gag processing intermediate to mature CA. The observation that bevirimat delays but does not completely block CA-SP1 processing suggests that the presence of uncleaved CA-SP1 may disrupt the maturation process in trans. In this study, we validate this hypothesis by using a genetic approach to demonstrate that a non-cleavable CA-SP1 mutant exerts a dominant-negative effect on maturation of wild-type HIV-1. In contrast, a mutant in which cleavage can occur internally within SP1 is significantly less potent as a dominant-negative inhibitor. We also show that bevirimat blocks processing at both the major CA-SP1 cleavage site and the internal site. These data underscore the importance of full CA-SP1 processing for HIV-1 maturation and highlight the therapeutic potential of inhibitors that target this Gag cleavage event. PMID- 20172578 TI - Deep sequencing analysis of viruses infecting grapevines: Virome of a vineyard. AB - Double stranded RNA, isolated from 44 pooled randomly selected vines from a diseased South African vineyard, has been used in a deep sequencing analysis to build a census of the viral population. The dsRNA was sequenced in an unbiased manner using the sequencing-by-synthesis technology offered by the Illumina Genome Analyzer II and yielded 837 megabases of metagenomic sequence data. Four known viral pathogens were identified. It was found that Grapevine leafroll associated virus 3 (GLRaV-3) is the most prevalent species, constituting 59% of the total reads, followed by Grapevine rupestris stem pitting-associated virus and Grapevine virus A. Grapevine virus E, a virus not previously reported in South African vineyards, was identified in the census. Viruses not previously identified in grapevine were also detected. The second most prevalent virus detected was a member of the Chrysoviridae family similar to Penicillium chrysogenum virus. Sequences aligning to two other mycoviruses were also detected. PMID- 20172579 TI - Clinical resistance to vicriviroc through adaptive V3 loop mutations in HIV-1 subtype D gp120 that alter interactions with the N-terminus and ECL2 of CCR5. AB - The HIV-1 CCR5 co-receptor is a member of the chemokine receptor family of G protein coupled receptors; for which a number of small molecule antagonists, such as vicriviroc (VCV), have been developed to inhibit HIV-1 R5-tropic replication. In this study, we analyzed an HIV-1 subtype D envelope gene from a clinical trial subject who developed complete resistance to VCV. The HIV-1 resistant envelope has six predominant amino acid changes in the V3 loop, together with one change in the C4 domain of gp120, which are fully responsible for the resistance phenotype. V3 loop mutations Q315E and R321G are essential for resistance to VCV, whereas E328K and G429R in C4 contribute significantly to the infectivity of the resistant variant. Collectively, these amino acid changes influenced the interaction of gp120 with both the N-terminus and ECL2 region of CCR5. PMID- 20172580 TI - Effect of solution chemistry on the adsorption of perfluorooctane sulfonate onto mineral surfaces. AB - Perfluorooctane sulfonate (PFOS) is an emergent contaminant of substantial environmental concerns, yet very limited information has been available on PFOS adsorption onto mineral surfaces. PFOS adsorption onto goethite and silica was investigated by batch adsorption experiments under various solution compositions. Adsorption onto silica was only marginally affected by pH, ionic strength, and calcium concentration, likely due to the dominance of non-electrostatic interactions. In contrast, PFOS uptake by goethite increased significantly at high [H+] and [Ca2+], which was likely due to enhanced electrostatic attraction between the negatively charged PFOS molecules and positively charged goethite surface. The effect of pH was less significant at high ionic strength, likely due to electrical double layer compression. PFOS uptake was reduced at higher ionic strength for a strongly positively charged goethite surface (pH 3), while it increased for a weakly charged surface (pH 7 and 9), which could be attributed to the competition between PFOS-surface electrostatic attraction and PFOS-PFOS electrostatic repulsion. A conceptual model that captures PFOS-surface and PFOS PFOS electrostatic interactions as well as non-electrostatic interaction was also formulated to understand the effect of solution chemistry on PFOS adsorption onto goethite and silica surfaces. PMID- 20172581 TI - Iron amendment and Fenton oxidation of MTBE-spent granular activated carbon. AB - Fenton-driven regeneration of methyl tert-butyl ether (MTBE)-spent granular activated carbon (GAC) involves an Fe amendment step to increase the Fe content and to enhance the extent of MTBE oxidation and GAC regeneration. Four forms of iron (ferric sulfate, ferric chloride, ferric nitrate, ferrous sulfate) were amended separately to GAC. Following Fe amendment, MTBE was adsorbed to the GAC followed by multiple applications of H2O2. Fe retention in GAC was high (83.8 99.9%) and decreased in the following order, FeSO(4).7H2O>Fe2(SO4)(3).9H2O>Fe(NO3)(3).9H2O>FeCl3. A correlation was established between the post-sorption aqueous MTBE concentrations and Fe on the GAC for all forms of Fe investigated indicating that Fe amendment interfered with MTBE adsorption. However, the mass of MTBE adsorbed to the GAC was minimally affected by Fe loading. Relative to ferric iron amendments to GAC, ferrous iron amendment resulted in lower residual iron in solution, greater Fe immobilization in the GAC, and less interference with MTBE adsorption. MTBE oxidation was Fe limited and no clear trend was established between the counter-ion (SO4(2-), Cl-, NO3-) of the ferric Fe amended to GAC and H2O2 reaction, MTBE adsorption, or MTBE oxidation, suggesting these processes are anion independent. PMID- 20172582 TI - Effect of antiscalants on precipitation of an RO concentrate: metals precipitated and particle characteristics for several water compositions. AB - Inland brackish water reverse osmosis (RO) is economically and technically limited by the large volume of salty waste (concentrate) produced. The use of a controlled precipitation step, followed by solid/liquid separation (filtration), has emerged as a promising side-stream treatment process to treat reverse osmosis concentrate and increase overall system recovery. The addition of antiscalants to the RO feed prevents precipitation within the membrane system but might have a deleterious effect on a concentrate treatment process that uses precipitation to remove problematic precipitates. The effects of antiscalant type and concentration on salt precipitation and precipitate particle morphology were evaluated for several water compositions. The primary precipitate for the synthetic brackish waters tested was calcium carbonate; the presence of magnesium, sulfate, minor ions, and antiscalant compounds affected the amount of calcium precipitated, as well as the phases of calcium carbonate formed during precipitation. Addition of antiscalant decreased calcium precipitation but increased incorporation of magnesium and sulfate into precipitating calcium carbonate. Antiscalants prevented the growth of nucleated precipitates, resulting in the formation of small (100-200 nm diameter) particles, as well as larger (6 10 microm) particles. Elemental analysis revealed changes in composition and calcium carbonate polymorph with antiscalant addition and antiscalant type. Results indicate that the presence of antiscalants does reduce the extent of calcium precipitation and can worsen subsequent filtration performance. PMID- 20172583 TI - Inactivation of MS2 coliphage by Fenton's reagent. AB - Fenton's reagent (i.e., Fe[II]/H2O2) is known to generate strong oxidants capable of oxidizing a broad spectrum of organic compounds in aqueous solution. This study demonstrates the successful inactivation of MS2 coliphage (MS2) by the oxidants produced from Fenton's reagent. The inactivation process of MS2 by Fenton's reagent was found to proceed in two distinct stages. The first stage inactivation, which took place rapidly within 1 min reaction time, was mainly achieved by the reaction of Fe(II) with H2O2 (i.e., the Fenton reaction). The second stage, which occurred by the catalytic reactions of Fe(III) with H2O2, exhibited much slower inactivation than the first stage. The rate of MS2 inactivation increased as pH decreased from 8.0 to 6.0. The addition of oxalate and humic acids significantly inhibited the MS2 inactivation, whereas 1,10 phenanthroline and bipyridine resulted in a gradual and steady inactivation of MS2. These observations on the effects of pH and iron-chelating agents indicate that oxidants formed on the surface or inside MS2 are responsible for the inactivation. PMID- 20172584 TI - Phytotoxicity of hexachlorocyclohexane: Effect on germination and early growth of different plant species. AB - The aim of the present study was to select candidate plant species for phytoremediation of soils contaminated with hexachlorocyclohexane (HCH). For this purpose, an experiment was carried out under controlled conditions of germination and growth, with nine plant species of economic and/or agricultural interest, in a soil contaminated with a heterogeneous mixture (at eight different levels of contamination) of the main HCH isomers (alpha-, beta-, gamma- and delta-HCH). The results revealed differences in the plant responses to the control soil and the soils containing HCH. Germination was not as strongly affected as other parameters such as the rate of germination and seedling vigour. In general, all of the species displayed signs of stress in response to the presence of HCH, although to different degrees. Some of the species used in the experiment (Hordeum vulgare L., Brassica sp., Phaseoulus vulgaris L.) were capable of mitigating the negative effects of HCH, and displayed a certain degree of resistance, as their biomass production was not greatly affected by the contaminant. These (tolerant) plants therefore appear to be ideal for phytoremediation purposes. PMID- 20172585 TI - The production and degradation of trichloroacetic acid in soil: results from in situ soil column experiments. AB - Previous work has indicated that the soil is important to understanding biogeochemical fluxes of trichloroacetic acid (TCA) in the rural environment, in forests in particular. Here, the hydrological and TCA fluxes through 22 in situ soil columns in a forest and moorland-covered catchment and an agricultural grassland field in Scotland were monitored every 2 weeks for several months either as controls or in TCA manipulation (artificial dosing) experiments. This was supplemented by laboratory experiments with radioactively-labelled TCA and with irradiated (sterilised) soil columns. Control in situ forest soil columns showed evidence of net export (i.e. in situ production) of TCA, consistent with a net soil TCA production inferred from forest-scale mass balance estimations. At the same time, there was also clear evidence of substantial in situ degradation within the soil ( approximately 70% on average) of applied TCA. The laboratory experiments showed that both the formation and degradation processes operate on time scales of up to a few days and appeared related more with biological rather than abiotic processes. Soil TCA activity was greater in more organic-rich soils, particularly within forests, and there was strong correlation between TCA and soil biomass carbon content. Overall it appears that TCA soil processes exemplify the substantial natural biogeochemical cycling of chlorine within soils, independent of any anthropogenic chlorine flux. PMID- 20172586 TI - Sediment toxicity and deformities of chironomid larvae in Lake Piediluco (Central Italy). AB - The chemical analysis of the bottom sediments of the Lake Piediluco (Central Italy) has been carried out in order to individuate the potential correlation between the sediment toxicity and the high incidence of mouthpart deformities in chironomid larvae (biological indicators) found in this lake. The environmental contamination has been analyzed by determining the concentrations of the main heavy metals (lead, copper, cadmium, chromium, zinc and nickel), and the concentrations of organic compounds of anthropic source: PAHs, NPPs and OCPs. Heavy metals concentrations have pointed out a non-elevated contamination grade for the Lake Piediluco. The highest level of metals has been detected in the western area that feels the effect of the continuous tributaries incoming load. Also, concerning PAHs, NPPs and OCPs the lake does not present high values of pollution. The highest concentrations of the organic toxicants has been observed in the eastern sector of the lake, which presents typical lentic characteristics. A clear relationship has not found between the toxic substances present in the lacustrine sediments and the deformities incidence for chironomid larvae, which represent an index of environmental alteration. Probably, the mouthpart deformities found in the chironomid larvae of Chironomus plumosus are affected by a synergic action due to the whole toxic mixture present in the sediments of the Lake Piediluco. PMID- 20172587 TI - Exploiting lipid-free tubing passive samplers and embryonic zebrafish to link site specific contaminant mixtures to biological responses. AB - The Biological Response Indicator Devices Gauging Environmental Stressors (BRIDGES) bio-analytical tool was developed in response to the need for a quantitative technology for assessing the toxicity of environmentally relevant contaminant mixtures. This tool combines passive samplers with the embryonic zebrafish model. When applied in an urban river it effectively linked site specific, bioavailable contaminant mixtures to multiple biological responses. Embryonic zebrafish exposed to extracts from lipid-free passive samplers that were deployed at five locations, within and outside of the Portland Harbor Superfund Megasite, displayed different responses. Six of the eighteen biological responses observed in 941 exposed zebrafish were significantly different between sites. This demonstrates the sensitivity of the bio-analytical tool for detecting spatially distinct toxicity in aquatic systems; bridging environmental exposure to biological response. PMID- 20172588 TI - The effects of fungicides on non-target mites can be mediated by plant pathogens. AB - Field tests are useful for the evaluation of the pesticides' impact in realistic use situations. However, the distinction between the direct and indirect effects of a pesticide is not always possible in field, with consequences on the conclusions about pesticides toxicity. Generalist predatory mites belonging to the Phytoseiidae family are widely considered as non-target organisms in pesticide side-effect evaluations. Plant pathogens of several cultivated plants can be of importance as food resources for various phytoseiids. Pesticides with fungicidal activity may have a direct impact on phytoseiids, but they can also have an indirect effect reducing food availability for predatory mites. Here, we present the results of field experiments performed on grapevine, where we investigate whether the availability of the plant pathogen grape downy mildew has an effect on fungicides impact on the predatory mites Typhlodromus pyri Scheuten and Amblyseius andersoni (Chant). In these experiments we used fungicides characterized by differential selectivity to predatory mites in laboratory: copper compounds, folpet, and mancozeb. Results indicated that the abundance of predatory mites was associated with the plant pathogen foliar symptoms presence. The presence of predatory mites was different among treatments in response of the toxicological traits of a pesticide (direct effects), but also as consequences of differential plant pathogen availability induced by fungicide applications (indirect effects). During the investigation, the variable plant pathogen spread on untreated control determined contrasting results on pesticides effect. We segregated the direct effects from the indirect food resource-mediated effects including a non-toxic reference in the experimental protocols. PMID- 20172589 TI - Estrogens in streams associated with a concentrated animal feeding operation in upstate New York, USA. AB - Estrogens (estrone, 17 alpha-estradiol, 17beta-estradiol, and estriol) in three headwater streams within a concentrated animal feed operation (CAFO) site were monitored on a monthly base for a year (November 2006-October 2007). This CAFO is certified as organic (no growth promoters are administrated) and uses many Whole Farm Planning practices (e.g., 12-month-capacity waste storage lagoons). In general, estrogen concentrations in the streams are low (<1 ng L(-1)), and appeared to increase in spring, likely due to the mobilization of estrogens from soils upon snow melting/precipitation. Estrogens were detected in the streams during dry periods, indicating the contribution of estrogens from groundwater. The low concentrations of estrogens in stream water were probably the result of the long residence time (approximately 8 months) of the manure in the lagoons where most of the estrogens were degraded during storage. An analysis of liquid manure at the beginning of manure application season (after approximately 8 months storage) showed that over 99.8% of the estrogens potentially excreted by the cows were degraded. Moreover, about 90% of the estrogens in the liquid manure were associated with particulates larger than 0.7 microm. Batch experiments with spiked deuterium-labeled 17beta-estradiol-16,16,17-d(3) (d(3)-E2 beta) in the liquid manure demonstrated sorption of d(3)-E2 beta onto particulates in the liquid manure, and rapid degradation of d(3)-E2 beta in the aqueous phase and on particulates of the liquid manure under aerobic conditions. PMID- 20172591 TI - Historic brownfields and industrial activity in Kingston, Ontario: assessing potential contributions to mercury contamination in sediment of the Cataraqui River. AB - The waterfront of historic Kingston, Ontario (pop: 113,000) has been used for industrial activities for over a century. More than 40 industries have existed within the inner harbour, and while many of these industries are no longer present, the properties that they operated on remain as potential sources of persistent contamination to the present day, including mercury. To assess the extent and distribution of total mercury (THg) contamination, 21 sediment cores as well as pore water samples were collected within the inner harbour of Kingston. The spatial distribution of THg in the surface sediment is not homogenous; with concentrations in the surface sediment along the southwestern shoreline, adjacent to the former industrial properties, are significantly greater (p<0.01) than the rest of the inner harbour, and were above the Federal severe effect limit (>2000 microg/kg;) guideline for sediment. MeHg was detected in some sediment cores, and was found to have a significant, positive correlation with [THg] in the surface sediment (0-5 cm). THg was not found in storm sewer discharges, but was detected in terrestrial soil near the Kingston Rowing Club at a concentration of more than 4000 microg/kg. Significant [THg] was detected in runoff draining from contaminated shoreline soils, indicating that erosion from terrestrial sources may be an ongoing source of Hg to the sediment. It can be concluded that there is an increased risk over time to surrounding ecosystems where properties with historical contamination are not remediated until they are developed. PMID- 20172590 TI - Hominoid visual brain structure volumes and the position of the lunate sulcus. AB - It has been argued that changes in the relative sizes of visual system structures predated an increase in brain size and provide evidence of brain reorganization in hominins. However, data about the volume and anatomical limits of visual brain structures in the extant taxa phylogenetically closest to humans-the apes-remain scarce, thus complicating tests of hypotheses about evolutionary changes. Here, we analyze new volumetric data for the primary visual cortex and the lateral geniculate nucleus to determine whether or not the human brain departs from allometrically-expected patterns of brain organization. Primary visual cortex volumes were compared to lunate sulcus position in apes to investigate whether or not inferences about brain reorganization made from fossil hominin endocasts are reliable in this context. In contrast to previous studies, in which all species were relatively poorly sampled, the current study attempted to evaluate the degree of intraspecific variability by including numerous hominoid individuals (particularly Pan troglodytes and Homo sapiens). In addition, we present and compare volumetric data from three new hominoid species-Pan paniscus, Pongo pygmaeus, and Symphalangus syndactylus. These new data demonstrate that hominoid visual brain structure volumes vary more than previously appreciated. In addition, humans have relatively reduced primary visual cortex and lateral geniculate nucleus volumes as compared to allometric predictions from other hominoids. These results suggest that inferences about the position of the lunate sulcus on fossil endocasts may provide information about brain organization. PMID- 20172592 TI - Performance of UV disinfection and the microbial quality of greywater effluent along a reuse system for toilet flushing. AB - This paper examines the microbial quality of treated RBC (Rotating Biological Contactor) and MBR (Membrane Bioreactor) light greywater along a continuous pilot scale reuse system for toilet flushing, quantifies the efficiency of UV disinfection unit, and evaluates the regrowth potential of selected microorganisms along the system. The UV disinfection unit was found to be very efficient in reducing faecal coliforms and Staphylococcus aureus. On the other hand, its efficiency of inactivation of HPC (Heterotrophic Plate Count) and Pseudomonas aeruginosa was lower. Some regrowth occurred in the reuse system as a result of HPC regrowth which included opportunistic pathogens such as P. aeruginosa. Although the membrane (UF) of the MBR system removed all bacteria from the greywater, bacteria were observed in the reuse system due to "hopping phenomenon." The microbial quality of the disinfected greywater was found to be equal or even better than the microbial quality of "clean" water in toilet bowls flushed with potable water (and used for excretion). Thus, the added health risk associated with reusing the UV-disinfected greywater for toilet flushing (regarding P. aeruginosa and S. aureus), was found to be insignificant. The UV disinfection unit totally removed (100%) the viral indicator (F-RNA phage, host: E. coli F(amp)(+)) injected to the treatment systems simulating transient viral contamination. To conclude, this work contributes to better design of UV disinfection reactors and provides an insight into the long-term behavior of selected microorganisms along on-site greywater reuse systems for toilet flushing. PMID- 20172593 TI - Bosentan for chronic thromboembolic pulmonary hypertension: findings from a systematic review and meta-analysis. AB - BACKGROUND: After acute pulmonary embolism, chronic thromboembolic pulmonary hypertension (CTEPH) is diagnosed in about 1% of patients. We performed a systematic review and meta-analysis aimed at assessing the effects of bosentan therapy in patients with CTEPH. METHODS: We searched in MEDLINE and Embase using the terms 'pulmonary hypertension' AND 'bosentan'. Papers were included in this review if they reported on patients with objectively confirmed CTEPH treated with bosentan. Efficacy measures were the improvement in NYHA class, in 6 minute walking distance (6 mwd) and in hemodynamics (cardiac index, pulmonary artery pressure, pulmonary vascular resistance). Mortality and safety were also assessed. RESULTS: Overall, 543 papers were found. Eight single-arm cohort studies (175 patients), one randomized double-blind study, one case-control study and one case report were included in the analysis. A 35.9 meters weighted mean increase in 6 minute walking distance was observed after 3-6 months of treatment (9 studies, 208 patients) (95% CI 33.6 to 38.2; p<0.001) and an additional increase of 21 meters after one year (4 studies, 80 patients). About 25% of patients had an improvement on functional NYHA class at 3-6 months. Data on hemodynamics were available in seven studies, 185 patients. The mean weighted increase in cardiac index at 3-6 months was 0.23 l/min/m2 (95% CI 0.22 to 0.25); the mean weighted decrease in pulmonary artery pressure at 3-6 months was 2.62 mmHg (95% CI 2.44 to 2.80). Three patient died within 3-6 months (1.4%) and 3 additional patients died within one year. CONCLUSIONS: Bosentan therapy is associated with an improvement of hemodynamics and probably exercise capacity in patients with CTEPH. Controlled data on mortality and time to clinical worsening in patients with CTEPH are needed. PMID- 20172594 TI - Calmodulin antagonists induce platelet apoptosis. AB - Calmodulin (CaM) antagonists induce apoptosis in various tumor models and inhibit tumor cell invasion and metastasis, thus some of which have been extensively used as anti-cancer agents. In platelets, CaM has been found to bind directly to the cytoplasmic domains of several platelet receptors. Incubation of platelets with CaM antagonists impairs the receptors-related platelet functions. However, it is still unknown whether CaM antagonists induce platelet apoptosis. Here we show that CaM antagonists N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W7), tamoxifen (TMX), and trifluoperazine (TFP) induce apoptotic events in human platelets, including depolarization of mitochondrial inner transmembrane potential, caspase-3 activation, and phosphatidylserine exposure. CaM antagonists did not incur platelet activation as detected by P-selectin surface expression and PAC-1 binding. However, ADP-, botrocetin-, and alpha-thrombin-induced platelet aggregation, platelet adhesion and spreading on von Willebrand factor surface were significantly reduced in platelets pre-treated with CaM antagonists. Furthermore, cytosolic Ca(2+) levels were obviously elevated by both W7 and TMX, and membrane-permeable Ca(2+) chelator BAPTA-AM significantly reduced apoptotic events in platelets induced by W7. Therefore, these findings indicate that CaM antagonists induce platelet apoptosis. The elevation of the cytosolic Ca(2+) levels may be involved in the regulation of CaM antagonists-induced platelet apoptosis. PMID- 20172595 TI - Letter to the Editor referring to the manuscript entitled: "Phase II trial of trastuzumab in women with advanced or recurrent HER-positive endometrial carcinoma: a Gynecologic Oncology Group study" recently reported by Fleming et al., (Gynecol Oncol., 116;15-20;2010). PMID- 20172596 TI - Lectin-binding sites on ejaculated stallion sperm during breeding and non breeding periods. AB - Stallion sperm from semen collected in Southern Italy during the breeding (June July) and non-breeding (December-January) periods were analyzed by means of twelve lectins to evaluate the glycoconjugate pattern and to verify whether there are any seasonal differences in the glycosylation pattern of the sperm glycocalyx. The acrosomal cap showed reactivity for Maackia amurensis (MAL II), Sambucus nigra (SNA), Arachis hypogaea (PNA), Glycine max (SBA), Helix pomatia (HPA), Canavalia ensiformis (Con A) Triticum vulgaris (WGA), and Griffonia simplicifolia isolectin II (GSA II) in breeding and non-breeding ejaculated sperm, suggesting the presence of oligosaccharides terminating with Neu5Ac alpha 2,3Gal beta 1,4GlcNAc, Neu5Ac alpha 2,6Gal/GalNAc, with Gal beta 1,3GalNAc, alpha/beta GalNAc and glycans with terminal/internal alpha Man and GlcNAc. During the non-breeding period, the acrosomal cap expressed oligosaccharides terminating with Gal beta 1,4GlcNAc (Ricinus communis(120) affinity) (RCA(120)) and L-Fuc alpha 1,2Gal beta 1,4GlcNAc beta (Ulex europaeus affinity) (UEA I). The equatorial segment placed between the acrosomal cap and post-acrosomal region did not display glycans terminating with GalNAc, GlcNAc, and alpha L-Fuc. The post acrosomal region of sperm collected in the breeding and non-breeding periods bound Con A, MAL II, SNA, and SBA, thus showing the presence of N-linked oligosaccharides from high-Man content, terminating with Neu5Ac alpha 2,3Gal beta 1,4GlcNAc, Neu5Ac alpha 2,6Gal/GalNAc and GalNAc. In winter, the post-acrosomal region also expressed oligosaccharides terminating with alpha GalNAc, GlcNAc, and L-Fuc alpha 1,2Gal beta 1,4GlcNAc beta (HPA, GSA II, and UEA I staining). The tail of sperm from semen collected during the breeding and non-breeding periods showed a lectin binding pattern similar to the post-acrosomal region, except for the absence of HPA staining in sperm collected during the winter season. These results indicate that the surface of stallion sperm contains different glycocalyx domains and that the glycosylation pattern undergoes changes during the breeding and non-breeding periods. PMID- 20172597 TI - Evaluating the effectiveness of different treatments of uterine infections in female camels (Camelus dromedarius). AB - A total of 480 female camels with a history of conception failure were examined through transrectal palpation, ultrasonography, and vaginal exploration. Animals were categorized according to parity (nulliparous n=200 vs. multiparous n=280), and type of uterine infection (endometritis n=360 vs. metritis n=120). They were randomly assigned to receive one of three intrauterine treatments: (i) 100mL acriflavin 0.1% (group 1, n=170), (ii) 100mL lotagen 4% (group 2, n=200), or (iii) 300mg/100mL gentamicin sulphate (group 3, n=110). All groups received 500microg cloprostenol IM at infusion. Animals were exposed for breeding 7 d later and received 5000 IU hCG im at mating. The criteria for efficacy of treatment were 90 days non-return rate (90 d NRR) and calving rate (CR). The results showed that the 90 d NRR and CR were significantly influenced by parity, type of uterine infection, regime of treatment, and their interactions, P<0.05. Treatment regimes were approximately equally efficient in treating females with endometritis (90 d NRR were 64%, 53.1% and 53.3% and CR were 58.9%, 49.3%, and 42.5% for groups 1, 2, and 3, respectively, P>0.05). In contrast, regimes differed in treating those with metritis (90 d NRR were 55.6%, 75%, and 28.6% and CR were 31.6%, 54.8%, and 12.5% for groups 1, 2, and 3, respectively, P<0.05). In conclusion, a regime consisted of intrauterine lotagen infusion and administration of PGF(2)alpha at infusion and hCG at mating was more efficient for treating female camels with metritis. PMID- 20172598 TI - Semen cryopreservation in the Indian rhinoceros (Rhinoceros unicornis). AB - The objective was to identify an extender and cryoprotectant combination for Indian rhinoceros (Rhinoceros unicornis) sperm that yielded high post-thaw sperm quality. Male Indian rhinoceroses (n=6; 7.5-34 yr old) were anesthetized and subjected to a regimented electroejaculation procedure (75-100 mAmps; 4-10 volts; 7-150 stimuli; total of 10 electroejaculation procedures). High quality semen fractions from each ejaculate were divided into four aliquots and a 2 x 2 factorial design used to compare the effect of two sperm extenders (standard equine [EQ] and skim milk-egg-yolk-sugar [SMEY]), and two cryoprotectants (glycerol and dimethylsulfoxide [DMSO]). Cyropreserved samples were thawed and assessed for motility, viability and acrosome integrity over time. Electroejaculate fractions processed for cryopreservation had high sperm concentration (516 x 10(6)/mL) and motility (79%). Post-thaw sperm characteristics were higher (P<0.05) when semen was cryopreserved in EQ versus SMEY. Post-thaw motility of sperm cyropreserved in EQ averaged 50-55% compared to 22-37% in SMEY, with no significant differences in sperm characteristics of samples cyropreserved in glycerol and DMSO. In conclusion, sperm collected from Indian rhinoceroses via electroejaculation were cryopreserved using EQ extender with either glycerol or DMSO; post-thaw quality was adequate for use in assisted reproductive procedures. PMID- 20172599 TI - Generation of a recloned transgenic cat expressing red fluorescence protein. AB - Somatic cells from a first-generation red fluorescence protein transgenic cat (first RFP TG cat) were used to produce a recloned RFP transgenic cat (Re-RFP TG cat) (Felis catus) that systemically expressed RFP. A total of 281 RFP cloned embryos were transferred into 13 surrogate mothers (mean=21+/-7.7 embryos/recipient). One surrogate cat was diagnosed pregnant (7.7%) and delivered one live kitten. The presence of the RFP gene in the mRNA and genomic DNA of the Re-RFP TG cat was confirmed by polymerase chain reaction analyses, and red fluorescence was detected in its internal organs and placental tissue samples. Analysis of nine feline-specific microsatellite loci confirmed that the Re-RFP TG cat was genetically identical to the donor cat. To test whether results such as normality of offspring and a low cloning success were due to epigenetic modifications, global methylation of placenta from the two first cloned RFP TG cats (77.08% and 82.29%) and the Re-RFP TG cat (76.38%) were compared by bisulfite mutagenesis sequencing analysis. In conclusion, although cloning efficiency was low, we demonstrated the successful use of a cloned first RFP TG cat as a donor cat to produce a Re-RFP TG cat. These results may facilitate future developments in biomedical models for human therapeutic applications. PMID- 20172600 TI - Effects of different cryoprotective agents on ram sperm morphology and DNAintegrity. AB - This study investigates the effects of glycerol, 1,2 propanediol, sucrose, and trehalose on post-thaw motility, morphology, and genome integrity of Awassi ram semen. Ejaculates of thick consistency with rapid wave motion (>+++) and >70% initial motility were pooled. Sperm were diluted to a final concentration of 1/5 (semen/extender) in 0% cryoprotectant, 6% glycerol, 6% 1,2 propanediol, 62.5 mM sucrose or 62.5 mM trehalose using a two-step dilution method. The equilibrated semen was frozen in 0.25-ml straws. Semen samples were examined for sperm motility, defective acrosomes (FITC-Pisum sativum agglutinin (FITC PSA)), DNA integrity (acridine orange staining (AO)) and apoptotic activity (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and Caspase 3 activity) at four time points: after dilution with extender A, after cooling to 5 degrees C, after equilibration and post-thaw. Freezing and thawing procedures (cooling at 5 degrees C, dilution, equilibration, and thawing) had negative effects on motility (P<0.001), acrosome integrity (P<0.001), and DNA integrity as determined by AO (P<0.001) and TUNEL (P<0.001) assays. There were positive correlations between sperm with defective acrosomes and apoptotic (AO- and TUNEL positive) spermatozoa. In contrast, a significant negative correlation was found between sperm motility and defective acrosomes and AO- and TUNEL positivity (P<0.01). The cryopreservation process acts as an apoptotic inducer in ram semen; all cryoprotectants used in the present study allowed apoptosis to some extent, with negative effects on sperm morphology and DNA integrity. The glycerol group performed better than the propanediol, sucrose, trehalose, and control groups in terms of post-thaw sperm motility but not DNA integrity. PMID- 20172601 TI - Substantiation of ovarian effects of leptin by challenging a mouse model of obesity/type 2 diabetes. AB - The goal of the current was to elucidate if treatment with gonadotrophins and leptin can circumvent infertility in obese mice and to establish whether reproductive effects of leptin are influenced at the hypothalamus-hypophysis or ovarian level by using a leptin deficient mouse model of obesity/type 2 diabetes (ob/ob) treated with leptin. The ovulatory response and the fertilization success were compared with the results obtained in ob/ob dams pretreated with a gonadotrophin-replacement therapy or in two groups (ob/ob and wild-type) of control non-pretreated females. The number of corpora lutea was significantly lower in control ob/ob mice than in wild-type dams. Treatment with gonadotrophin replacement therapy did not increase significantly the ovulation rate in ob/ob, but the administration of leptin-replacement treatment allowed the authors to obtain a number of corpora lutea and oocytes/zygotes similar to those obtained in wild-type females. Furthermore, the leptin supply succeeded in producing fertilized zygotes, although in a lower number than found in the wild-type control. Thus, the hypogonadotrophic state in obese mice may be circumvented by the administration of a gonadotrophin-replacement therapy combined with a protocol for controlled ovarian stimulation, but fertile ovulations are only obtained after applying leptin-replacement therapy. Current results strongly support the existence of direct local effects of leptin on the ovary. PMID- 20172602 TI - Hormonal concentrations in bitches with primary uterine inertia. AB - Normal labor is accompanied by sequential changes in blood concentrations of prostaglandin F2alpha (measured as 15-ketodihydro-PGF2 alpha=PGFM), progesterone, estradiol, oxytocin, vasopressin, and of elevated cortisol levels. The aim of this study was to investigate hormone concentrations in dogs diagnosed with primary uterine inertia before and during treatment by cesarean section. The hypothesis was the dogs would have abnormally low plasma concentrations in one or several of the hormones involved in parturition. The study comprised seven bitches with total primary uterine inertia (dystocia group) treated with cesarean section and six healthy bitches (control group) subjected to planned cesarean section. Blood samples were taken before anesthesia, before surgery started, on delivery of the first puppy and on delivery of the last puppy. The progesterone:PGFM ratio in plasma was higher in the dystocia group than in the control group, but the serum estradiol concentration did not differ between groups. The plasma concentrations of oxytocin and vasopressin increased in both groups when the first puppies were delivered, but both hormones were more elevated in the control group than in the dystocia group on delivery of the last puppies. The plasma cortisol concentration increased to the same level in both groups. In conclusion, the ratio between progesterone and PGFM was higher and the oxytocin and vasopressin concentrations lower in the dystocia dogs than in the control dogs. The findings indicate that these hormones are involved in the pathophysiology of total primary uterine inertia in bitches. PMID- 20172603 TI - Mental health problems during puberty: Tanner stage-related differences in specific symptoms. The TRAILS study. AB - The aim of this study was to investigate associations between specific mental health problems and pubertal stage in (pre)adolescents participating in the Dutch prospective cohort study TRAILS (first assessment: N=2230, age 11.09+/-0.56, 50.8% girls; second assessment: N=2149, age 13.56+/-0.53, 51.0% girls). Mental health was assessed by the Youth Self-Report, pubertal (Tanner) stage by parent rated drawings of secondary sex characteristics. Overall, higher Tanner stages were related to more reported tiredness, irritability, rule-breaking behaviors, and substance use; and fewer fears and somatic complaints. Girls showed increases in social uncertainty, depressed mood, and worries; boys a decrease in self criticism. Increasing problems during puberty were mostly related to the process of physical maturation, whereas decreasing problems were rather related to general age-related developments. Pubertal timing was associated with different symptoms than pubertal status or age. Puberty seems to affect girls more negatively than boys. PMID- 20172604 TI - Red blood cell membrane grafting of multi-functional hyperbranched polyglycerols. AB - The covalent attachment of hydrophilic polymers or biopharmaceuticals to the surface of red blood cells (RBCs) has previously been shown as a relatively compatible and effective method for a range of applications. Here, the first example of cell-surface grafting with a hyperbranched and multi-functional macromolecule is described. A range (3 kDa-101 kDa) of dense, globular, and blood compatible hyperbranched polyglycerols (HPG) were synthesized and functionalized with cell-surface reactive, succinimidyl succinate groups (1-12 groups per polymer). Subsequently, HPG was grafted to the RBCs, which were analyzed using physical characterization techniques such as aqueous two-phase partitioning and particle electrophoresis. It was found that the extent of grafting was enhanced by increasing HPG molecular weight, the number of reactive groups per HPG, HPG concentration, and reaction time. Good in vitro cell viability - as measured by lipid peroxidation, hemoglobin oxidation, cell lysis, osmotic fragility, stability in fresh serum and aggregation behavior - was observed for grafting concentrations up to 4.8 mm. The multi-functional aspect of HPG is highlighted by the following observations: using fluorescein-labeled Anti-D (monoclonal) antibody and flow cytometry, the detection of cell-surface Rhesus (RhD) antigens were significantly reduced upon HPG grafting. Secondly, the potential for using HPG as a multi-functional, delivery agent was demonstrated by attaching fluorescent markers to the HPG via degradable linkages prior to grafting. PMID- 20172605 TI - Mineralization behavior with mesenchymal stromal cells in a biomimetic hyaluronic acid-based scaffold. AB - A biomimetic hyaluronic acid (HA)-based polymer scaffold was analysed in vitro for its characteristics and potential to support mineralization as carrier vehicle. Biomimetic apatite crystal nucleation on the scaffold surface was obtained by a fine control of the pH level that increased ionic solubility thus controlling apatite formation kinetic. Different concentrations of human mesenchymal stromal cells (h-MSCs) were seeded on the scaffold, osteogenesis was induced in the presence or absence of fibroblast growth factor -2 and mineralization was analysed at different time points. We found that only at the highest h-MSCs concentration tested, the cells were uniformly distributed inside and outside the scaffold and proliferation started to decrease from day 7. Electron microscopy analysis evidenced that h-MSCs produced extracellular matrix but did not establish a direct contact with the scaffold. We found mineralized calcium-positive areas mainly present along the backbone of the scaffold starting from day 21 and increasing at day 35. FGF-2 treatment did not accelerate or increase mineralization. Non-biomimetic HA-based control scaffold showed immature mineralized areas only at day 35. Our data demonstrate that the biomimetic treatment of an HA-based scaffold promotes a faster mineralization process suggesting its possible use in clinics as a support for improving bone repair. PMID- 20172606 TI - A poly(propylene fumarate)--calcium phosphate based angiogenic injectable bone cement for femoral head osteonecrosis. AB - Osteonecrosis of the femoral head commonly occurs when the blood supply to bone was disrupted. The general treatment for early stages of necrosis in the femoral head is core decompression. However, the long-term outcome of this operation is usually compromised due to collapse of the necrotic bone. In this study, poly(propylene fumarate) (PPF) and calcium phosphate cement (CPC) were combined to provide appropriate mechanical strength after core-decompressed femoral heads and offer the properties of osteoconductivity. Effects of different ratios of CPC to PPF on mechanical and cytotoxicity were investigated. Results show that bone cement is less cytotoxic with the C/P ratio raise, and the increment of the CPC proportion also strengthens the mechanical strength, reduces the crosslinking temperature and diminishes excessive swelling of the cement. With addition of ginsenoside Rg1 the bone cement composite can also offer angiogenic effect. The drug release profiles were analyzed and the angiogenecity of released Rg1 was confirmed by the assay of tube formation in human umbilical vein endothelial cells (HUVECs). In summary, the newly developed angiogenic bone cement composite possesses remarkable development potential for application to treating osteonecrosis of the femoral head. PMID- 20172607 TI - Near infrared photoacoustic detection of sentinel lymph nodes with gold nanobeacons. AB - Detection of sentinel lymph node (SLN) using photoacoustic imaging is an emerging technique for noninvasive axillary staging of breast cancer. Due to the absence of intrinsic contrast inside the lymph nodes, exogenous contrast agents are used for photoacoustic detection. In this work, we have demonstrated near infrared detection of SLN with gold nanobeacons (GNBs) providing the photoacoustic contrast in a rodent model. We found that size dictates the in vivo characteristics of these nanoparticles in SLN imaging. Larger nanobeacons with high payloads of gold were not as efficient as smaller size nanobeacons with lower payloads for this purpose. Colloidal GNBs were designed as a nanomedicine platform with "soft" nature that is amenable to bio-elimination, an essential feature for in vivo efficacy and safety. The GNBs were synthesized as lipid- or polymer-encapsulated colloidal particles incorporating tiny gold nanoparticles (2 4 nm) in three tunable sizes (90 nm, 150 nm and 290 nm). Smaller GNBs were noted trafficking through the lymphatic system and accumulating more efficiently in the lymph nodes in comparison to the bigger nanoagents. At 20 min, the GNBs reached the SLN and were no longer observed within the draining lymphatic vessel. Within 1 h post-injection, the contrast ratio of the lymph nodes with the surrounding blood vessels was 9:1. These findings were also supported by analytical measurements of the ex vivo tissue samples. Results indicate that cumulative nanoparticle deposition in lymph nodes is size dependent and that high payloads of gold, although offering greater contrast in vitro, may yield nanoagents with poor intradermal migration and lymphatic transport characteristics. PMID- 20172608 TI - Human decidual NK cells from gravid uteri and NK cells from cycling endometrium are distinct NK cell subsets. AB - Human NK cells from the decidua basalis of gravid uteri and from the cycling endometrium of women undergoing hysterectomy were isolated and compared by gene expression profiling using Affymetrix microarrays with probes representing approximately 47,400 transcripts. Substantial differences indicate that these two types of NK cells represent distinct subsets. PMID- 20172609 TI - Differential roles of STIM1, STIM2 and Orai1 in the control of cell proliferation and SOCE amplitude in HEK293 cells. AB - Orai1, together with STIM1 and STIM2, constitutes the molecular basis for store operated calcium entry (SOCE) and we have investigated their role in cell proliferation and cell cycle progression in HEK293 cells. 48-h serum deprival, and a 24-h treatment with 1 mM hydroxyurea or with 10 microM RO-3306--a cyclin dependent kinase 1 inhibitor--induced cell cycle block in G1, S and G2/M, respectively. SOCE amplitude, monitored in whole-cell voltage clamped cells, was markedly reduced (60-70%) in all conditions, with full reversibility within 4h. Silencing of Orai and STIM1 using siRNA resulted in a large inhibition of SOCE (70-80%) whereas siSTIM2 had a smaller but significant effect (30%). However, the cell population doubling time was not affected in siSTIM1 cells (18 h, the same as in control cells) but was increased in both siOrai1 cells (29 h) and in siSTIM2 (23 h) even when combined with siSTIM1. This suggests that STIM1 plays no role in cell proliferation in HEK293 cells while STIM2 is involved in both SOCE and cell proliferation in these cells. Finally, the cell cycle block induced SOCE inhibition was associated with reduced Orai1 expression with full recovery within 4h, whereas the expression of STIM1 and STIM2 remained unaltered. These observations reveal a tight relation between cell proliferation, calcium entry and Orai1 expression in HEK293 cells. PMID- 20172610 TI - Development of a bioassay to monitor circulating plasma Ki-67. PMID- 20172611 TI - Stressful life events and the brain-derived neurotrophic factor gene in bipolar disorder. AB - BACKGROUND: Gene-environment interactions may contribute to the high heritability of bipolar affective disorder. The aim of the present study was to examine the interplay between the BDNF Val(66)Met polymorphism and stressful life events (SLEs) in bipolar disorder. METHOD: A total of 1085 participants were recruited, including 487 bipolar I cases and 598 psychiatrically healthy controls. All participants completed the List of Threatening Life Events Questionnaire; bipolar subjects reported the events that occurred 6 months leading up to their worst manic episode and 6 months prior to their worst depressive episode, controls recorded events experienced 6 months before interview. The sample was genotyped for the BDNF Val(66)Met polymorphism (rs6265). RESULTS: Both Met carrier BDNF genotype and SLEs were significantly associated with the worst depressive episode of bipolar disorder. For the worst depressive episodes the effects of SLEs were also significantly moderated by BDNF genotype (gene x environment interaction). LIMITATIONS: The use of a self report questionnaire to measure stressful life events may increase recall inaccuracies, therefore caution should be taken when interpreting these results. DISCUSSION: The findings of this study highlight the importance of the interplay between genes and the environment in bipolar disorder. PMID- 20172612 TI - Antibodies to gangliosides and ganglioside complexes in Guillain-Barre syndrome and Fisher syndrome: mini-review. AB - Antiganglioside antibodies play a pathogenic role in the pathophysiology of Guillain-Barre syndrome (GBS) and Fisher syndrome (FS). Antiganglioside antibody mediated nerve injury is likely to result from nerve damage through complement activation or dysfunction of molecules such as voltage-gated sodium and calcium channels. Clustered epitopes of complexes of two gangliosides in the cell membrane can be targeted by serum antibodies in GBS and FS and may regulate the accessibility and avidity of antiganglioside antibodies. The glycolipid environment or the specific distribution of target gangliosides in the peripheral nervous system may also influence the pathogenic effect of antiganglioside antibodies in GBS and FS. Structural and functional analyses of glycoepitopes of ganglioside complexes in membranes will provide new vistas on antibody-antigen interaction in GBS and shed light on microdomain function mediated by carbohydrate-carbohydrate interactions, which may lead to novel treatments for GBS and FS. PMID- 20172614 TI - Aorta-right ventricular fistulisation following staphylococcal aureus endocarditis of prosthetic aortic valve in a Tetralogy of Fallot patient. PMID- 20172615 TI - A "Red Shell" concept of increased radiation damage hazard to normal tissues just outside the PTV target volume. PMID- 20172613 TI - Emerging applications of nanomedicine for the diagnosis and treatment of cardiovascular diseases. AB - Nanomedicine is an emerging field that utilizes nanotechnology concepts for advanced therapy and diagnostics. This convergent discipline merges research areas such as chemistry, biology, physics, mathematics and engineering. It therefore bridges the gap between molecular and cellular interactions, and has the potential to revolutionize medicine. This review presents recent developments in nanomedicine research poised to have an important impact on the treatment of cardiovascular disease. This will occur through improvement of the diagnosis and therapy of cardiovascular disorders as atherosclerosis, restenosis and myocardial infarction. Specifically, we discuss the use of nanoparticles for molecular imaging and advanced therapeutics, specially designed drug eluting stents and in vivo/ex vivo early detection techniques. PMID- 20172617 TI - Survival of Salmonella Enteritidis during salting and drying of horse mackerel (Trachurus trachurus) fillets. AB - Survival of Salmonella Enteritidis inoculated (5-6 log cfu/g) on horse mackerel fillets was studied during salting and/or drying processes at 4 degrees C for up to 70days. Sample groups were as follows: group A (salt/fish=80/100), group B (salt/fish=30/100), group C (salted as group A and dried after 15days), group D (salted as group B and dried after 15days), and group E (dried without salting). The salt content increased in all groups with a maximum level of 29.36%. Final salt contents (%) were higher (P<0.05) in salted-dried groups (C and D) than the salted groups (A and B). Total reductions in a(w) values were found as group E>group D>group C>groups A and B (P<0.05). Salmonella survived 60days in group A, 65days in group B, 35days in group C, 45days in group D and 20days in group E. Drying process following salting accelerated the elimination of this pathogen. Salmonella survived longer in salted samples than in salted-dried and dried samples. This work demonstrated that Salmonella may be inhibited by one of salting, drying and salting-drying techniques; however, processing periods should be long enough to reduce a(w) sufficient to inhibit this pathogen. PMID- 20172618 TI - Photosynthetic response of pepper plants to wilt induced by Verticillium dahliae and soil water deficit. AB - Greenhouse experiments were conducted to compare stress effects caused by Verticillium dahliae and drought on gas exchange, chlorophyll (Chl) fluorescence and photosynthetic pigments of pepper plants. Three treatments were compared: Verticillium inoculated plants (+V), non-inoculated well-watered plants (-V) and non-inoculated plants subjected to progressive drought (D). Gas exchange, fluorescence and photosynthetic pigments were measured and represented along a gradient of relative water content (RWC) and stomatal conductance (g(s)). Net photosynthesis (A) and electron transport rate (ETR) decreased, as RWC and g(s) declined, similarly in both +V and D plants. However, dark respiration (R(D)) and photorespiration (R(L)) tended to increase in inoculated plants compared to those subjected to soil drought, as g(s) decreased. Photoinhibitory damage was not observed in infected or in droughted plants. Soil drought decreased intrinsic PSII efficiency (Phi(exc.)), which seemed to result in part from enhanced xanthophyll cycle- and/or lutein-related thermal energy dissipation. Nevertheless, the fact that 1-Phi(exc.) increased in D only at high values of the de-epoxidation state of the xanthophyll cycle (DPS) suggests that DeltapH could be the major factor controlling thermal energy dissipation in this treatment. By contrast, antheraxanthin, zeaxanthin and lutein, as well as Phi(exc.), were not markedly affected in +V. Water stress appeared to be the main limitation to photosynthesis in Verticillium infected plants, probably through stomatal closure, together with impaired mesophyll conductance (g(m)). However, our results indicate differential effects of V. dahliae on dark respiration, photorespiration, g(m) and on the capability of thermal energy dissipation under low g(s) values. PMID- 20172619 TI - Photoprotective function of chloroplast avoidance movement: in vivo chlorophyll fluorescence study. AB - Light-induced chloroplast avoidance movement has long been considered to be a photoprotective mechanism. Here, we present an experimental model in which this function can be shown for wild type Arabidopsis thaliana. We used blue light of different fluence rates for chloroplast positioning, and strong red light inactive in chloroplast positioning as a stressing light. The performance of photosystem II was measured by means of chlorophyll fluorescence. After stressing light treatment, a smaller decrease in photosystem II quantum yield was observed for leaves with chloroplasts in profile position as compared with leaves with chloroplasts in face position. Three Arabidopsis mutants, phot2 (no avoidance response), npq1 (impaired zeaxanhtin accumulation) and stn7 (no state transition), were examined for their chloroplast positioning and chlorophyll fluorescence parameters under identical experimental conditions. The results obtained for these mutants revealed additional stressing effects of blue light as compared with red light. PMID- 20172620 TI - Chlororespiration and tolerance to drought, heat and high illumination. AB - Sun (Chrysanthemum morifolium) and shade (Spathiphyllum wallisii) plants were used to study the effects of drought, heat and high illumination. The stress conditions caused a greater accumulation of hydrogen peroxide in Chrysanthemum morifolium than in Spathiphyllum wallisii leaves. They also resulted in down regulation of linear electron transport in the leaves of both species, as indicated by a gradual reduction in the photochemistry efficiency of PS II, which was associated with an increase in the non-photochemical quenching of fluorescence. Only a slight decrease in F(v)/F(m) was observed under stress conditions in either plant species, suggesting that the chloroplast is protected by mechanisms that dissipate excess excitation energy to prevent damage to the photosynthetic apparatus. In addition to the effects on photosynthetic activity, changes were also observed by immunoblot analysis in the plastidial NADH DH complex, PTOX and PGR5. The quantities of the PTOX and NDH-H subunit of the thylakoidal NADH DH complex, and the NADH DH activity in the thylakoid membranes were similar in control plants of both species and increased in stressed plants, particularly in Spathiphyllum wallisii. The level of PGR5 polypeptide was higher in Chrysanthemum morifolium than in Spathiphyllum wallisii control plants, while after stress, the quantity of PGR5 increased significantly in Chrysanthemum morifolium and remained constant in Spathiphyllum wallisii. These results indicate that the relative importance of chlororespiration and the cyclic electron pathways in the tolerance to drought, heat and high illumination differs in sun and shade plants, indicating different adaptive mechanisms to the environment. In the conditions studied, the PGR5-dependent cyclic pathway is more active in Chrysanthemum morifolium, a sun species, whereas in Spathiphyllum wallisii, a shade species, other ways involving the NADH DH complex and PTOX are stimulated in response to stress, which results in lower levels of ROS accumulation in the leaves. PMID- 20172621 TI - [Vogt-Koyanagi-Harada disease associated with interferon-alpha and ribavirin therapy for chronic hepatitis C infection]. AB - The complex immunological effects of interferon and ribavirin therapy in hepatitis C virus may also exacerbate or trigger the development of autoimmunity. A rare case of Vogt-Koyanagi-Harada disease associated with ribavirin and interferon-alpha treatment for chronic hepatitis C infection is presented. The potential role of interferon and/or ribavirin therapy is discussed. Physicians should be aware of the association between interferon-alpha 2a and ribavirin use for hepatitis C infection and the development of Harada disease. This severe ophthalmological complication requires close follow-up of hepatitis C virus infected patients on interferon-alpha treatment. PMID- 20172622 TI - Disseminated Strongyloides stercoralis: hyperinfection during medical immunosuppression. AB - Hyperinfection caused by Strongyloides stercoralis in iatrogenically immunosuppressed patients is becoming more frequently observed. Here, we review the relevant literature and present a recent case of hyperinfection syndrome of S stercoralis in a patient chronically treated with systemic corticosteroids and methotrexate for dermatomyositis. The patient was born in Guatemala but no history of Strongyloides infection was documented. Disseminated Strongyloides is often associated with the immunocompromised state and is commonly seen with cutaneous lesions, respiratory failure, and sepsis. In this patient, a protracted course of progressive muscle weakness and multiple hospital stays for respiratory distress led to acute respiratory failure, septic shock, and rapid physical decline. A few days preceding his death, the patient developed petechiae and multiple purpuric macules and patches over the abdomen and thighs. Histologic review of skin biopsy specimens demonstrated multiple intravascular and interstitial filariform larvae. Dermatologists should be aware of patient populations at risk for infection with S stercoralis and be able to make this diagnosis to initiate earlier treatment of hyperinfection and dissemination. PMID- 20172623 TI - Drug samples in dermatology: special considerations and recommendations for the future. AB - BACKGROUND: The use of drug samples is a controversial issue in medicine. OBJECTIVE: We sought to determine the pros and cons of drug sampling, and how drug sampling in general medicine differs from dermatology. METHODS: Literature searches were conducted on PubMed, Google, and Yahoo!. Articles were found pertaining to drug sampling in general, and for dermatology specifically. RESULTS: Numerous pros and cons for drug sampling were found in the literature search. We divided these by cost-related issues, such as the industry-wide cost of sampling and the use of sampling to assist the underinsured and poor, and quality of care issues, such as adherence, patient education, and safety considerations. Articles also suggested that dermatology may differ from general medicine as topical treatments have fewer side effects, are more complicated to use, and come in different vehicles. LIMITATIONS: We identified few studies specifically focused on issues relevant to sampling in dermatology. CONCLUSION: There are strong arguments for and against drug sampling involving both cost and quality of care issues. Dermatology-specific medications clearly differ from oral medications in several regards. We ultimately conclude that the benefits of drug sampling outweigh the risks, but give recommendations on how drug sampling can be done ethically and effectively, including limiting personal use, not selling samples, properly documenting sample release, teaching patients about proper use, teaching students and residents ethical use of samples, working with pharmaceutical representatives in an ethical manner, prescribing the drug that is best for the patient, and securing samples appropriately to prevent theft and misuse. PMID- 20172624 TI - Individual drug sampling does not supplant the need for head-to-head trials in dermatology. AB - A growing body of evidence has highlighted several risks and benefits associated with in-office sampling of prescription medications. While use-testing dermatologic medications from a sample closet may benefit some patients, it seems that the stunning lack of head-to-head trials comparing therapeutic options is a much larger and more important impediment to our determination of when the increased cost of newer agents is justified by superior efficacy, safety, or tolerability. If physicians are to retain the critical autonomy to make independent prescribing decisions in concert with our individual patients, we must take responsibility to call for and generate the comparative data we need to evaluate therapeutic options. PMID- 20172625 TI - Vomiting calls to NHS Direct provide an early warning of norovirus outbreaks in hospitals. AB - A wintertime peak of norovirus activity occurs each year, affecting institutions including schools and hospitals. Traditional laboratory and outbreak surveillance systems for norovirus are too vulnerable to reporting delay to act as a timely signal of activity in the community. Calls to the National Health Service (NHS) telephone service NHS Direct have the potential to be an early warning tool for public health purposes. We investigated whether NHS Direct vomiting calls can be used as a reliable indicator of norovirus activity and, if so, whether the increase in calls precedes the epidemic of hospital outbreaks. Laboratory reports were used as the reference standard to define the norovirus season. From 2004 to 2008, four series of NHS Direct call data were compared with laboratory data held at the Health Protection Agency Centre for Infections in order to identify the best predictor of the season start. The four series included: (1) modelled and extracted the proportion of calls likely to be for 'non-rotavirus' gastroenteritis; (2) the mean proportion of weekly vomiting calls in children aged <5 years; (3) the mean proportion of weekly vomiting calls for all ages; (4) the slope of the vomiting call data. Issuing an alert when 4% or more of NHS Direct vomiting calls in all age groups for two weeks in a row should provide up to four weeks' advance warning of forthcoming norovirus pressures on the health service. PMID- 20172626 TI - Extracorporeal life support in a case of fatal flecainide and betaxolol poisoning allowing successful cardiac allograft. AB - Use of cardiac allograft for transplantation from donors after acute poisoning is a matter of debate because of potential toxic organ injuries, especially if death results from massive ingestion of cardiotoxic drugs. We report successful allograft cardiac transplantation from a brain-dead patient after severe flecainide and betaxolol self-poisoning requiring extracorporeal life support. Extracorporeal life support was initiated in the emergency department because of a refractory cardiac arrest caused by the cardiotoxicants' ingestion and continued after the onset of brain death to facilitate organ donation of the heart, liver, and kidneys. Forty-five months later, each organ recipient was alive, with normal graft function. PMID- 20172627 TI - Are we looking for superiority, equivalence, or noninferiority? Asking the right question and answering it correctly. PMID- 20172628 TI - Uterine artery pseudoaneurysm rupture: a life-threatening presentation of vaginal bleeding. AB - Uterine artery pseudoaneurysm rupture is a rare, yet life-threatening, cause of postpartum hemorrhage. Prompt recognition and management are critical in severe vaginal bleeding. In this case, diagnosis by bedside ultrasonography and initial management with vaginal packing and fluid resuscitation were performed in the emergency department. Definitive treatment by selective arterial embolization was performed to achieve hemostasis. This article discusses options available in the diagnosis, management, and treatment of uterine artery pseudoaneurysm hemorrhage. PMID- 20172629 TI - Role of BDNF val66met polymorphism on the association between physical activity and incident dementia. AB - BACKGROUND: Increased physical activity may have beneficial effects on cognitive outcomes; a role of brain-derived neurotrophic factor (BDNF) has been suggested in animal models but not yet tested in humans. This study investigated modification by BDNF val66met polymorphism of the association between physical activity, incident dementia and other cognitive outcomes. METHODS: Of 732 community elders, 107 had dementia at baseline, and 518 (83%) of the remainder were followed over 2.4 years. Cognitive impairment and decline were defined from Mini-Mental State Examination scores. Self-reported level of physical activity was recorded on a 4-point scale. BDNF val66met and apolipoprotein E genotypes were ascertained. Covariates included age, sex, education, depression, vascular risk factors, and instrumental activities of daily living. RESULTS: Baseline lower physical activity was significantly associated with incident dementia as well as with baseline dementia and cognitive impairment and incident cognitive decline. BDNF val66met polymorphism itself was not associated with any cognitive outcome. However, the strength of association between lower activity and all cognitive outcomes increased incrementally with the number of met alleles, and was strongest in those with the met/met genotype. BDNF*activity interaction terms were stronger for prospective outcomes (incident dementia, cognitive decline) compared to cross-sectional outcomes (prevalent dementia, cognitive impairment no dementia). CONCLUSIONS: This study supports a previously suggested neurobiological basis for the effects of physical activity on dementia involving the BDNF system since the met allele is recognised to be associated with lower activity-dependent secretion of BDNF. PMID- 20172630 TI - Synthesis and pharmacological evaluation of novel 5-substituted-1 (phenylsulfonyl)-2-methylbenzimidazole derivatives as anti-inflammatory and analgesic agents. AB - A series of novel 5-substituted-1-(phenylsulfonyl)-2-methylbenzimidazole derivatives have been synthesized. The structures of these compounds were established by IR, 1H NMR, 13C NMR, Mass spectral data and elemental analyses. Compounds were evaluated for their anti-inflammatory and analgesic activity as well as gastric ulcerogenic effects. Derivatives 4a, 4b and 4c exhibited moderate to good anti-inflammatory and analgesic activity in carrageenan-induced rat paw edema and acetic acid-induced writhing in mice, respectively, with low ulcerogenicity compared with the standard drug indomethacin. PMID- 20172631 TI - Lipophilicity of novel antitumour and analgesic active 8-aryl-2,6,7,8 tetrahydroimidazo[2,1-c][1,2,4]triazine-3,4-dione derivatives determined by reversed-phase HPLC and computational methods. AB - Eight novel antitumour and analgesic active 8-aryl-2,6,7,8-tetrahydroimidazo[2,1 c][1,2,4]triazine-3,4-diones (1-8) have been obtained as a bioactive set of substances and their lipophilicity has been studied. The logk values of fifteen reference compounds and eight newly synthesised imidazotriazine-3,4-dione derivatives were determined by reversed-phase high performance liquid chromatography (RP-HPLC) using mixtures of methanol and water as mobile phases with different methanol concentrations. The relationships between logk values of a set of reference compounds (fifteen compounds) and investigated ones (eight compounds) and concentration of methanol was used for determination of the logkwater values by extrapolation. The partition coefficients (logP) values for reference compounds measured experimentally were taken from the literature. The calibration equation was then obtained for the standards of known lipophilicity (logPHPLC) and logkwater. In next step the partition coefficients of new synthesised solutes were calculated from the calibration equation. For the comparison purpose, additionally the partition coefficients (logPcalc.) of the examined imidazotriazine-3,4-diones were calculated by means of the Pallas 3.1.1.2. software. It was found that logkwater values as a lipophilicity measure of derivatives correlate well with partition coefficients measured experimentally (logPHPLC). Correlation between the logPHPLC and the logarithm of partition coefficient calculated by Pallas software (logPcalc.) is not so satisfactory as that for values determined experimentally. Furthermore, it has been found that the lipophilicity variation of investigated imidazotriazine-3,4-diones (1-8) correlates well with their acute toxicity expressed as log(1/LD50). The drug likeness of all the bioactive 8-aryl-2,6,7,8-tetrahydroimidazo[2,1 c][1,2,4]triazine-3,4-diones was assessed on the basis of their structural properties by applying Lipniski's rule of five. The solutes have all four parameters important for the favourable pharmacokinetics in the human body that would make them likely orally active drugs in humans. PMID- 20172632 TI - Scavenging activity of aminoantipyrines against hydroxyl radical. AB - The pyrazolone derivatives antipyrine and 4-(N,N-dimethyl)-aminoantipyrine (aminopyrine) have long been used as analgesic, antipyretic and anti-inflammatory drugs. However, in spite of its recognized therapeutic benefits, the use of pyrazolones has been associated with agranulocytosis. Though the oxidation of aminopyrine by neutrophil-generated hypochlorous acid (HOCl), leading to the formation of a cation radical, has been considered responsible for the potential bone marrow toxicity, the reaction mechanisms of pyrazolones against other reactive oxygen species (ROS) remains elusive. Thus, the reactions of 4 aminoantipyrine and methylated derivatives with hydroxyl radicals (HO*) were studied as a model of their reactivity against ROS. The results show that 4-(N,N dimethyl)-aminoantipyrine (aminopyrine) undergoes demethylation when reacting with HO. radical, leading to 4-(N-methyl)-aminoantipyrine, which is further demethylated to 4-aminoantipyrine. In addition, it was also observed that another favorable reaction of 4-aminoantipyrines in these conditions is the hydroxylation on the aromatic ring, a reaction that is common to aminopyrine, 4-(N-methyl) aminoantipyrine, and 4-aminoantipyrine. Whether these reaction mechanisms give rise to harmful reactive intermediates requires further chemico-biological evaluation. PMID- 20172633 TI - Still looking for leadership--who is responsible for student nurses' learning in practice? AB - The study on which this paper reports examined how the widespread changes in the NHS workforce and in higher education which have transformed nurse education in recent decades have impacted on responsibility for the leadership of student nurse learning in clinical practice. Findings from this mixed methods case study carried out at four English higher education institutions between 2006 and 2007 suggest that link lecturers' presence in clinical areas is diminishing, and that practice nurses' involvement with pre-registration students' learning may be limited. Ward managers lead learning at ward level but changes to their role limit their presence on the wards, so that mentors lead student learning on a day to day basis, which they must balance with caring for patients. Changes to the nurse's role mean that modelling bedside care often falls to health care assistants. This deficit of leadership for learning may be understood as a manifestation of the 'uncoupling' of education and practice following the move of nurse education into higher education and subsequent changes to nursing roles. Strengthening leadership for learning is likely to be associated with recoupling practice and education and indicators to assess the quality of leadership for learning in clinical practice are suggested. PMID- 20172634 TI - Sources and distributions of 137Cs, 238Pu, 239,240Pu radionuclides in the north western Barents Sea. AB - Sediment deposits are the ultimate sink for anthropogenic radionuclides entering the marine environment. The major sources of anthropogenic radionuclides to the Barents Sea are fallout from nuclear weapons tests, long range transport from other seas, and river and non-point freshwater supplies. In this study we investigated activity concentrations, ratios, and inventories of the anthropogenic radionuclides, 137Cs, 238Pu, 239,240Pu in dated sediment cores collected along a north-south transect in the northwestern Barents Sea. The data were used to evaluate the influence of different sources on the derived spatial and temporal patterns of anthropogenic radionuclides in seafloor sediment deposits. Activity concentrations of 137Cs ranged from <0.1 Bq/kg to 10.5 Bq/kg while 239,240Pu ranged from <0.01 Bq/kg to 2.74 Bq/kg and 238Pu activity concentrations ranged from <0.01 Bq/kg to 0.22 Bq/kg. Total inventories of 137Cs ranged from 29.5+/-1.5 Bq/m2 to 152.7+/-5.6 Bq/m2 and for 239,240Pu inventories (6 sediment layers only) ranged from 9.5+/-0.3 Bq/m2 to 29.7+/-0.4 Bq/m2. Source contributions varied among stations and between the investigated radionuclides. The 238Pu/239,240Pu ratios up to 0.18 indicate discharges from nuclear fuel reprocessing plants as a main contributor of plutonium. Based on 238Pu/239,240Pu ratio, it was calculated that up to 19-27% of plutonium is supplied from sources other than atmospheric global fallout. Taking into account Atlantic current flow trajectories and that both activity concentrations and inventories of plutonium negatively correlate with latitude, Sellafield is a major source for the Barents Sea. Concentrations and inventories of 137Cs correlate positively with latitude and negatively with distance from the Svalbard archipelago. The 137Cs concentrations are highest in an area of intensive melting of sea ice formed along the Siberian coast. Thus, sea ice and supplies from Svalbard may be important source of 137Cs to the Barents Sea seafloor. PMID- 20172635 TI - Comparison of maternal-and paternal-fetal attachment in Turkish couples. AB - OBJECTIVE: to compare maternal-fetal attachment (MFA) and paternal-fetal attachment (PFA) in terms of selected variables. DESIGN: cross-sectional study. SETTING: three training hospitals in Ankara, Turkey. The study was performed between December 2005 and March 2006. PARTICIPANTS: a total of 144 pregnant women and 144 partners participated in the study; the response rate was 98%. FINDINGS: there was a statistically significant difference between MFA and PFA scores (p<0.001). A comparison of MFA and PFA scores according to the selected variables (education, employment status, planning of pregnancy, pregnancy risk status) revealed that the MFA scores for pregnant women were significantly higher than the PFA scores of their partners, except for unemployed partners. The MFA (rho= 0.24, p<0.004) and PFA (rho=-0.32, p<0.001) scores decreased with increasing age of both pregnant women and their partners. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: although partners have lower fetal attachment scores than pregnant women, it is important to recognise factors influencing the attachment of the mother and father towards their fetus. Prenatal midwives and nurses are in a unique position to assess attachment and to intervene to promote attachment behaviours. PMID- 20172636 TI - In situ transverse elasticity and blood perfusion change of sciatic nerves in normal and diabetic rats. AB - BACKGROUND: Diabetic neuropathy is the most pervasive complication of diabetes mellitus and its etiopathology is not completely elucidated. The existing literature focuses on the histological and structural changes as well as the longitudinal mechanical properties of nerves. The main objective of this study is to investigate the in situ transverse biomechanical properties and changes of microcirculation of sciatic nerves in diabetic and normal control rats. METHODS: Quasi-static circular compression experiments were conducted on sciatic nerves of six normal and six diabetic Wistar rats. Local blood perfusion during the compression was also measured by laser Doppler flowmetry. The compressive stress and strain were estimated, in order to calculate the apparent Young's modulus. The impact of diabetes on peripheral nerves was examined by analyzing the transverse elasticity and microcirculation changes. FINDINGS: The mean transverse apparent Young's modulus of the sciatic nerves in diabetic rats was 210.7 kPa, which was nearly two times greater than that of normal controls (116.3 kPa). The pressure threshold that blood perfusion started to decrease in diabetic rats (24.1 mm Hg) was smaller than in the normal controls (47.1 mm Hg). INTERPRETATION: These results suggest that the sciatic nerve was stiffer in the diabetic rats. The structural changes in microvessels might lead to earlier decrease of blood perfusion in diabetic nerves under radial compression. These results provide information about the biomechanical and microcirculation changes of peripheral nerves inflicted by diabetes and may also serve as a reference for clinical nerve repair and regeneration for patients with diabetic neuropathy. PMID- 20172637 TI - Linking desorption kinetics to phenanthrene biodegradation in soil. AB - The desorption of polycyclic aromatic hydrocarbons (PAHs) often exhibits a biphasic profile similar to that observed for biodegradation whereby an initial rapid phase of degradation or desorption is followed by a phase of much slower transformation or release. Most investigations to-date have utilised a polymeric sorbent, such as Tenax, to characterise desorption, which is methodologically unsuitable for the analysis of soil. In this study, desorption kinetics of (14)C phenanthrene were measured by consecutive extraction using aqueous solutions of hydroxypropyl-beta-cyclodextrin (HPCD). The data indicate that the fraction extracted after 24 h generally approximated the linearly sorbed, rapidly desorbing fraction (F(rap)), calculated using a three-compartment model. A good linear correlation between phenanthrene mineralised and F(rap) was observed (r(2) = 0.89; gradient = 0.85; intercept = 8.20). Hence HPCD extraction (24 h) and first-order three-compartment modelling appear to provide an operationally straightforward tool for estimating mass-transfer limited biodegradation in soil. PMID- 20172638 TI - Credit where credit is due? Regulation, research integrity and the attribution of authorship in the health sciences. AB - Despite attempts at clear direction in international, national and journal guidelines, attribution of authorship can be a confusing area for both new and established researchers. As journal articles are valuable intellectual property, authorship can be hotly contested. Individual authors' responsibilities for the integrity of article content have not been well explored. Semi-structured interviews (n = 17) were conducted with staff, student advocates and doctoral candidates working in health research in two universities in Australia. Stratified sampling ensured participants reflected a range of experience across biomedical, clinical and social science disciplines. Participants were asked about their experience with research publication and their views on the responsibilities of authorship. Participants gave a variety of reasons for attribution of authorship including: writing the paper; seniority; and student supervision. Gift authorship was seen by some participants as: a way of maintaining relationships; a reward; a means to increase a paper's credibility; or a demonstration of collaboration between authors. Norms and beliefs differed markedly between disciplines for authorship attribution and, to a lesser extent, for authors' responsibility for content integrity. Discussions about the effect of power differentials on authorship were common across disciplines. This paper describes a broad range of beliefs, values and practice norms held by health science researchers with respect to attribution of authorship and author responsibility for scientific publications. The findings support the need for clarity in relation to authorship, and a research environment which is supportive of ethical behaviour in the publication of research. PMID- 20172639 TI - National independence, women's political participation, and life expectancy in Norway. AB - This study investigates the role of national independence and women's political participation on population health using historical lifespan data from Norway. We use time-series methods to analyze data measuring the actual length of time lived by Norwegian birth cohorts spanning a 61 year period surrounding the political emancipation of Norway from Sweden in 1905 and the establishment of a Norwegian monarchy in 1906. The use of a discrete, historical event improves our ability to interpret the population health effects of national independence and women's political participation as causal. We find a large and significant positive effect on the lifespan of Norwegian females born in the 1906 cohort. Interestingly, the effect does not extend to all living females during the Norwegian drive toward sovereignty. We conclude that the beneficial effects were likely conferred through intrauterine biological transfers and/or neonatal investments specific to the first year of life. PMID- 20172640 TI - Cancer-related health behaviours and health service use among Inuit and other residents of Canada's north. AB - This article identifies the extent to which demographic, socio-economic and geographic factors account for differences between Inuit and other Northern Canadian residents in health-related behaviours and health service use related to cancer incidence and diagnosis. The study population includes Inuit, Metis, First Nation and non-Aboriginal residents aged 21-65 who live in Nunavut, Northwest Territories, Labrador, Nunavik and Jamesie in northern Quebec, and the northern regions of Saskatchewan and Manitoba. Data are drawn from confidential versions of the 2000-2001 and 2004-2005 Canadian Community Health Surveys and the 2001 Aboriginal People's Survey produced by Statistics Canada. Multivariate Logistic regression analysis is applied to a set of health-related behaviours including cigarette smoking, binge drinking and obesity, and a set of basic health service use measures including consultation with a physician, consultation with a nurse, Pap smear testing and mammography. We found that significantly higher smoking and binge drinking rates and lower rates of female cancer screening among Inuit are found not to be accounted for by differences in observable demographic and socio economic characteristics, location of residence or distance from a hospital. As such we conclude that health-related behaviours leading to increased cancer risk and to a lower utilization of diagnostic cancer screening appear to be due to unobserved factors specific to Inuit and their unique social-cultural context. Policy interventions to address these problems may need to be targeted specifically to Inuit Canadians and should not be considered in isolation of their broader health, economic and social environment. PMID- 20172641 TI - Pediatric out-of-hospital cardiac arrest in Korea: A nationwide population-based study. AB - STUDY OBJECTIVES: Our objective was to describe the incidence and demographics of pediatric out-of-hospital cardiac arrest (OHCA) in Korea. METHODS: We identified non-traumatic OHCA patients aged less than 20 years from a Korean nationwide OHCA registry (2006-2007). Data from emergency medical service (EMS) run-sheets and hospital records were reviewed. We excluded cases with unknown hospital outcomes. Patient characteristics, treatment by EMS, and outcomes were compared by age groups: infant (<1 year), children (1-11 years), and adolescents (12-19 years). RESULTS: A total of 971 patients including infants (n=299, 30.8%), children (n=305, 31.4%), and adolescents (n=367, 37.8%) met inclusion criteria. The incidence of pediatric OHCA was 4.2 per 100,000 person-years (67.1 in infants, 2.5 in children, and 3.5 in adolescents). The rate of cardiopulmonary resuscitation administered was 82.1% (infants 80.6%, children 82.0%, and adolescent 83.4%). The rate of applying automated external defibrillators and advanced airway management (endotracheal intubation or laryngeal mask airway), was only 4.1% and 2.5%, respectively. 7.4% showed ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) in the initial ECG. Survival to hospital discharge for all pediatric OHCA was 4.9% (2.9% for infants, 4.7% for children, and 7.2% of adolescents). For EMS-treated pediatric OHCA or patients with VF or pulseless VT, the rate was 5.0% and 31.6%, respectively. CONCLUSION: Incidence and hospital outcomes in pediatric OHCA in Korea were comparable to other population-based nationwide reports. PMID- 20172642 TI - Continuous chest compression resuscitation in arrested swine with upper airway inspiratory obstruction. AB - BACKGROUND: This study was designed to compare 24-h survival rates and neurological function of swine in cardiac arrest treated with one of three forms of simulated basic life support CPR. METHODS: Thirty swine were randomized equally among three experimental groups to receive either 30:2 CPR with an unobstructed endotracheal tube (ET) or continuous chest compression (CCC) CPR with an unobstructed ET or CCC CPR with a collapsable rubber sleeve on the ET allowing air outflow but completely restricting air inflow. The swine were anesthetized but not paralyzed. Two min of untreated VF was followed by 9 min of simulated single rescuer bystander CPR. In the 30:2 CPR group, each set of 30 chest compressions was followed by a 15-s pause to simulate the realistic duration of interrupted chest compressions required for a single rescuer to deliver 2 mouth-to-mouth ventilations. The other two groups were provided continuous chest compressions (CCC) without assisted ventilations. At 11 min post arrest a biphasic defibrillation shock (150 J) was administered followed by a period of advanced cardiac life support. RESULTS: In the 30:2 group, 8 of 10 animals had good neurological function at 24-h post-resuscitation. In the CCC open airway group, 10 of 10, and in the CCC inspiratory obstructed group, 9 of 10. The number of shocks (P<0.05) and epinephrine doses (P<0.05) required for ROSC was greater in the 30:2 CPR group than in the other two groups. CONCLUSIONS: There were no differences in 24-h survival with good neurological function among these three different CPR protocols. PMID- 20172643 TI - Two simple questions to assess neurologic outcomes at 3 months after out-of hospital cardiac arrest: experience from the public access defibrillation trial. AB - BACKGROUND: Two simple questions have been used to classify neurologic outcome in patients with stroke. Could they be similarly applied to patients with cardiac arrest? METHODS: As part of a randomized trial, study personnel interviewed by telephone survivors of out-of-hospital cardiac arrest to assess their outcomes 3 months after discharge. They asked two simple questions: (1) In the last 2 weeks, did you require help from another person for your everyday activities? and (2) Do you feel that you have made a complete mental recovery form your heart arrest? Next they administered the Mini-Mental State Examination (MMSE) from the Adult Lifestyles and Function Interview (ALFI) to assess cognition on a scale from 0 to 22 and the Health Utilities Index Mark 3 (HUI3) to assess quality of life on a scale from 0 (death) to 1 (perfect health). RESULTS: Based on responses to the two simple questions, 32 survivors were classified as dependent (n=5, 16%), independent (n=3, 9%) and full recovery (n=24, 75%). The mean ALFI-MMSE score was 19.1 (standard deviation 5.1), and the mean HUI3 score was 0.76 (standard deviation 0.28). The classification based on the two simple questions was significantly correlated with ALFI-MMSE (p=0.002) and HUI3 (p=0.001). Scores for the HUI3 were missing in eight survivors. CONCLUSIONS: Neurologic outcomes based on the two simple questions after cardiac arrest can be easily determined, sensibly applied, and readily interpreted. These preliminary findings justify further evaluation of this simple and practical approach to classify neurologic outcome in survivors of cardiac arrest. PMID- 20172644 TI - Peter Baskett in daily student life. PMID- 20172645 TI - The effects of the new CPR guideline on attitude toward basic life support in Japan. AB - BACKGROUND: There is no study regarding the influence of cardiopulmonary resuscitation (CPR) guideline renewal on citizen's attitude towards all basic life support (BLS) actions. METHODS AND RESULTS: We conducted a questionnaire survey to new driver licence applicants who participated in the BLS course at driving schools either before (January 2007 to April 2007) or after (October 2007 to April 2008) the revision of the textbook. Upon completion of the course, participants were given a questionnaire concerning willingness to participate in CPR, early emergency call, telephone-assisted chest compression and use of an automated external defibrillator (AED). After the revision, the proportions of positive respondents to use of AED as well as to all the four scenarios significantly increased from 2331/3564 to 3693/5156 (odds ratio (OR)=1.34) and from 1889/3443 to 3028/5126 (OR=1.18), respectively. However, the new guideline slightly but significantly augmented the unwillingness to make an early call (236/3568 vs. 416/5283, OR=0.83). Approximately 95% of respondents were willing to follow the telephone-assisted instruction of chest compression, while approximately 85% were eager to perform CPR on their own initiative. Multiple logistic regression analysis confirmed the results of mono-variate analysis, and identified previous CPR training, sex, rural area and student as other significant factors relating to attitude. CONCLUSIONS: Future guidelines should emphasise the significance and benefit of early call in relation to telephone assisted instruction of CPR or chest compression. The course instructors should be aware of the backgrounds of participants as to how this may relate to their willingness to participate. PMID- 20172646 TI - Serum ischemia-modified albumin as a novel marker of ovarian torsion: an experimental study. AB - OBJECTIVE: To evaluate the effect of ovarian torsion on serum levels of ischemia modified albumin (IMA) in an experimental model. STUDY DESIGN: Sixteen female adult Sprague-Dawley rats were involved in the study. Rats were allocated randomly to group I or group II on the day of the experiment. Group I (eight rats) comprised the control (sham operated) group. In group II (eight rats), a torsion model was created by using atraumatic vascular clips just above and below the right ovary. At the end of a 3-h period of ischemia, the ovaries were removed. Blood was sampled before and after operation to assess serum IMA levels. Serum IMA levels (absorbance units) and histopathologic damage scores were evaluated. RESULTS: Initial serum IMA levels were similar in both groups. After the operation, significant elevation was observed in group II in contrast to group I (0.191+/-0.034 and 0.277+/-0.089 ABSU, p=0.05). Histologic specimens of the ovaries in group II had higher scores of follicular cell degeneration, vascular congestion, hemorrhage and inflammatory cell infiltration than those in group I (p<0.001). CONCLUSIONS: The elevated serum IMA levels observed in the ovarian torsion model seem to have a potential role as a serum marker in the early diagnosis of ovarian torsion. PMID- 20172647 TI - Involvement of Neptune in induction of the hatching gland and neural crest in the Xenopus embryo. AB - Neptune, a Kruppel-like transcription factor, is expressed in various regions of the developing Xenopus embryo and it has multiple functions in the process of development in various organs. In situ hybridization analysis showed that Neptune is expressed in the boundary region between neural and non-neural tissues at the neurula stage, but little is known about the function of Neptune in this region. Here, we examined the expression and function of Neptune in the neural plate border (NPB) in the Xenopus embryo. Depletion of Neptune protein in developing embryos by using antisense MO caused loss of the hatching gland and otic vesicle as well as malformation of neural crest-derived cranial cartilages and melanocytes. Neptune MO also suppressed the expression of hatching gland and neural crest markers such as he, snail2, sox9 and msx1 at the neurula stage. Subsequent experiments showed that Neptune is necessary and sufficient for the differentiation of hatching gland cells and that it is located downstream of pax3 in the signal regulating the differentiation of these cells. Thus, Neptune is a new member of hatching gland specifier and plays a physiological role in determination and specification of multiple lineages derived from the NPB region. PMID- 20172648 TI - Preparation of ordered mesoporous Ag/WO3 and its highly efficient degradation of acetaldehyde under visible-light irradiation. AB - A highly active photocatalyst, silver loaded mesoporous WO(3), was successfully synthesized by an ultrasound assisted insertion method. The photodegradation of a common air pollutant acetaldehyde was adopted to evaluate the photocatalytic performance of the as-prepared sample under visible-light irradiation. The photocatalytic activity was about three and six times higher than that of pure mesoporous WO(3) and nitrogen-doped TiO(2), respectively. The photocatalytic mechanism was investigated to understand the much enhanced photocatalytic activity, which was mainly attributed to the largely improved electron-hole separation in the Ag-WO(3) heterojunction. PMID- 20172649 TI - Low temperature conversion of plastic waste into light hydrocarbons. AB - Advance recycling through pyrolytic technology has the potential of being applied to the management of plastic waste (PW). For this purpose 1 l volume, energy efficient batch reactor was manufactured locally and tested for pyrolysis of waste plastic. The feedstock for reactor was 50 g waste polyethylene. The average yield of the pyrolytic oil, wax, pyrogas and char from pyrolysis of PW were 48.6, 40.7, 10.1 and 0.6%, respectively, at 275 degrees C with non-catalytic process. Using catalyst the average yields of pyrolytic oil, pyrogas, wax and residue (char) of 50 g of PW was 47.98, 35.43, 16.09 and 0.50%, respectively, at operating temperature of 250 degrees C. The designed reactor could work at low temperature in the absence of a catalyst to obtain similar products as for a catalytic process. PMID- 20172650 TI - Inhibition of respiration and distribution of Cd, Pb, Hg, Ag and Cr species in a nitrifying sludge. AB - The study investigated the inhibitory effects of the heavy metals Cd, Pb, Hg, Ag and Cr (as Cr(3+) and Cr(6+)) on a nitrifying sludge. The aim was to assess the IC(50) concentrations leading to 50% inhibition. The method is based on respiration of nitrifying sludge in the presence of these metals. Both O(2) consumption and CO(2) production were taken into account. The order of the inhibitory effect was Ag>Hg>Cd>Cr(3+)=Cr(6+). Metal speciation was calculated in terms of free metal, inorganic metal complexes and bound metal. Pb largely precipitated and 50% inhibition was never reached. Ag was always in the form of the free ion or labile complexes. Hg had apparently a lower toxicity than Ag, since most of it was initially highly complexed with ammonia. Cd was present in the form of free ion and complexes which caused inhibition although a large part of them were precipitated. The inhibitory effects of trivalent chromium (Cr(3+)) and hexavalent chromium (Cr(6+)) were similar. The latter was present in the form of the anion CrO(4)(2-) and was not taken up by biomass. The study highlighted that IC(50) values alone do not have an explanatory power of inhibition unless speciation is also considered. PMID- 20172651 TI - Preparation of highly ordered cubic NaA zeolite from halloysite mineral for adsorption of ammonium ions. AB - Well-ordered cubic NaA zeolite was first synthesized using natural halloysite mineral with nanotubular structure as source material by hydro-thermal method. SEM and HRTEM images indicate that the synthesized NaA zeolite is cubic-shaped crystal with planar surface, well-defined edges and symmetrical and uniform pore channels. The adsorption behavior of ammonium ions (NH(4)(+)) from aqueous solution onto NaA zeolite was investigated as a function of parameters such as equilibrium time, pH, initial NH(4)(+) concentration, temperature and competitive cations. The Langmuir and Freundlich adsorption models were applied to describe the equilibrium isotherms. A maximum adsorption capacity of 44.3 mg g(-1) of NH(4)(+) was achieved. The regeneration and reusable ability of this adsorbent was evaluated, and the results indicated that the recovered adsorbent could be used again for NH(4)(+) removal with nearly constant adsorption capacity. Thermodynamic parameters such as change in free energy (DeltaG(0)), enthalpy (DeltaH(0)) and entropy (DeltaS(0)) were also determined, which indicated that the adsorption was a spontaneous and exothermic process at ambient conditions. Compared with other adsorbents, the as-synthesized NaA zeolite displays a faster adsorption rate and higher adsorption capacity, which implies potential application for removing NH(4)(+) pollutants from wastewaters. PMID- 20172652 TI - Inclusion of authorized deception in the informed consent process does not affect the magnitude of the placebo effect for experimentally induced pain. AB - The ethics of placebo research have been of paramount concern since the discovery of the phenomenon. To address these ethical concerns, Miller and colleagues (PLoS Med 2005 Sep;2(9):e262, 0853-0859) propose an alternate approach to placebo research, called "authorized deception", in which participants are alerted of the use of deception in the research prior to study enrollment and thus knowingly permit its use if they decide to participate. The present study sought to investigate the authorized deception methodology in experimentally induced placebo analgesia. The participants were randomly assigned to an authorized deception or non-authorized deception group. A commonly used protocol was employed wherein heat pain stimulation was surreptitiously lowered following the application of a placebo cream during a series of conditioning trials and the magnitude of the placebo effect was subsequently assessed in test trials for which the stimulus intensity was the same for both the placebo and control creams. Authorized deception did not have any negative impact on the magnitude of the placebo effect, recruitment and retention of participants, nor did it result in any significant psychological harm. The majority of participants who received this form of consent preferred it to the traditional approach in which the participants are not alerted to the presence of deception. These findings suggest that the use of authorized deception is a viable and ethically preferable alternative consent process for laboratory-based studies on placebo analgesia. Further studies are needed to examine the effect of authorized deception in clinical trials and other placebo research within a clinical setting. PMID- 20172653 TI - Cellular basis for opioid potentiation in the rostral ventromedial medulla of rats with persistent inflammatory nociception. AB - Direct inhibition of pain facilitatory neurons in the rostral ventromedial medulla (RVM) is one mechanism by which mu opioid receptor (MOPr) agonists are proposed to produce antinociception. The antinociceptive and anti-hyperalgesic effects of the MOPr agonist DAMGO are enhanced after intraplantar injection of complete Freund's adjuvant (CFA). This study therefore examined whether CFA treatment similarly enhanced the ability of DAMGO to induce outward currents in spinally projecting RVM neurons. It further examined whether the electrophysiological properties of RVM neurons are altered by CFA treatment. Whole-cell patch clamp recordings were made from three types of serotonergic as well as non-serotonergic spinally projecting RVM neurons obtained from control rats and rats 4h or four days after CFA. Persistent, but not acute inflammatory nociception increased the percentage of Type 2 non-serotonergic neurons that responded to DAMGO from 17% to 57% and the percentage of Type 3 serotonergic neurons that responded to DAMGO from 5% to 55%. These same two populations of RVM neurons exhibited significant differences in their passive membrane properties or spontaneous discharge rate. The outward currents produced by the GABA(B) receptor agonist baclofen were not enhanced, suggesting that the enhancement does not reflect global changes in levels of G(i/o) or activity of G-protein regulated inwardly rectifying potassium channels. These results provide a cellular basis for the enhanced anti-hyperalgesic and antinociceptive effects of MOPr agonists under conditions of persistent inflammatory nociception. These results also provide intriguing, albeit indirect, evidence for two different populations of pain facilitatory neurons in the RVM. PMID- 20172654 TI - Low-dose amitriptyline for treatment of persistent arm pain due to repetitive use. AB - Amitriptyline is sometimes used to treat arm pain related to repetitive use, but rigorous evidence of its benefit is lacking. This randomized controlled trial investigated whether amitriptyline provided greater pain relief or improved arm function than a placebo pill in adults with arm pain associated with repetitive use that had persisted for at least 3 months. Participants (N=118) were randomly assigned to receive 25mg of amitriptyline or a placebo pill for 6 weeks. The primary outcome was intensity of pain (10-point numerical rating scale) and secondary outcomes were arm symptoms, arm function, grip strength, mood, and sleep. Assessments were done at baseline, 3 and 6 weeks of treatment, and 1 month after the treatment ended. Changes in arm pain were not statistically significant. However, the amitriptyline group improved more than the placebo group in arm function (p=0.023) and sense of well being (p=0.034). In a longitudinal analysis, the amitriptyline group's arm function score improved 0.45 points per week faster than placebo after adjusting for subject characteristics (p=0.015). At the treatment's midpoint, the amitriptyline group reported more "troublesome side-effects" than the placebo group (52.5% vs. 27.1%, p=0.005), but this difference decreased by the end of the treatment (30.5% vs. 22.0%, p=0.30). The most frequent side effect was drowsiness. In conclusion, this study found that low-dose amitriptyline did not significantly decrease arm pain among these participants but did significantly improve arm function and well being. Future research is needed to explore the effects of higher doses and longer duration of treatment. PMID- 20172655 TI - A response to O'Connell et al. letter "a failure of the review process? Comment on Ahsin et al. Clinical and endocrinological changes after electro-acupuncture treatment in patients with osteoarthritis of the knee. Pain 2009;147: 60-6". PMID- 20172656 TI - Dietary constituents of broccoli and other cruciferous vegetables: implications for prevention and therapy of cancer. AB - Over the past several decades, research on the action of bioactive constituents of plants has focused predominantly on their cancer-preventive properties. Today it can be explained why the consumption of fruits and vegetables may lead to a reduced frequency of certain cancer entities and why certain foods have therapeutic effects. Secondary plant products and especially glucosinolates from vegetables of the cruciferae family are supposed to have anti-carcinogenic potential. The present article gives an overview about secondary plant products in general and focuses to mechanisms of preventive and therapeutic effects of cruciferae, particular the brassica family and their famous member broccoli. Also, this article summarizes our knowledge of safety, tolerance and metabolism of glucosinolates and their therapeutic active degradation products isothiocyanates in animals and clinical studies. PMID- 20172657 TI - Pathogenesis of leukoaraiosis: role of jugular venous reflux. AB - Leukoaraiosis (LA) is a major cause of vascular dementia and disability in the elderly. Age and hypertension are the most two important risk factors. Despite its clinical significance, the etiology is so far unclear. Chronic cerebral hypoperfusion associated with vasogenic edema, microbleeding or/and endothelial dysfunction found in LA favors venous ischemia, in stead of arterial ischemia, as its pathogenesis. The involved regions in LA, periventricular and subcortical regions, are the drainage territory of deep cerebral venous system and the watershed region between the superficial and deep cerebral venous system respectively. Adding the facts that periventricular venule collagenosis, and retinal and intraparenchymal venules dilatation are related to the severity of LA, cerebral venous hypertension caused by downstream venous outflow impairment might play a major role in the pathogenesis of LA. Internal jugular vein is the main venous outflow pathway for cerebral venous drainage. The frequency of jugular venous reflux (JVR) is increased with aging. Hypertension, which has a decreased venous distensibility, might further exacerbate the sustained or long term repetitive retrograde-transmitted cerebral venous pressure and venous outflow insufficiency caused by JVR. Clinically, JVR caused by a dural AV fistula does lead to cerebral hypoperfusion, white matter abnormalities, vasogenic edema and cognitive impairment in several published reports. JVR is suggested to play a key role in the pathogenesis of LA through a sustained or long-term repetitive retrograde-transmitted cerebral venous pressure and venous outflow insufficiency, which might lead to chronic cerebral venous hypertensions, abnormal cerebral venules structural changes, decreased cerebral blood flow, endothelial dysfunction, and vasogenic edema in cerebral white matters. PMID- 20172658 TI - Atypical trigeminal neuralgia: a consequence of central sensitization? AB - Trigeminal neuralgia (TN) is characterized by sudden, recurrent, usually unilateral, severe brief stabbing pains in the distribution of trigeminal nerve. Although it is widely accepted that blood vessel or tumor compression contributes to paroxysms of TN, the pathogenesis of persistent background pain in atypical TN patient is unclear. Central sensitization is pain hypersensitivity caused by central neural plasticity. It is responsible for many temporal and symptomatic features of acute and chronic pain. We hypothesize that central sensitization might account for some symptoms of atypical TN. Based on this hypothesis, we postulate that early medical intervention predicts good outcomes in TN and medicines which are effective on central sensitization may be potential agents for the treatment of atypical TN. PMID- 20172659 TI - Drug-induced gingival hyperplasia and scaffolds: they may be valuable for horizontal food impaction. AB - Food impaction is a severe clinical trouble that bothers most people especially middle aged and old people. It is reported that the rate of food impaction is 92.2%. The incidence of 40-59 years old is 98.9%. It is a disease of high prevalence in population. It has influenced people's social intercourse and everyday life because it may cause halitosis, gingivalitis, periodontitis, gingival abscess, alveolar bone absorption, root caries, eventually lead to severe results from teeth loose to deletion and so on. Several reasons are involved with food impaction such as gingival recession, periodontal disease, caries, age, excessive attrition, etc. Food impaction can be divided into two kinds: vertical and horizontal food impaction. At present, there are some clinical methods such as crown or dental filling for vertical one, but horizontal food impaction is still difficult to deal with. Though some methods are being adopted like making crowns and removable obstructers, the problems have never been settled effectively for the injury to teeth and inconvenience of these treatments. Here we put forward a hypothesis that periodontal tissues can regenerate much the same as normal situation by way of using drug to induce gingiva hyperplasia initiatively and implanting scaffolds. Then horizontal food impaction will be cured when the interproximal clearance is filled with periodontal tissues. It will bring the patient hope. PMID- 20172660 TI - Did viral disease of humans wipe out the Neandertals? AB - Neandertals were an anatomically distinct hominoid species inhabiting a vast geographical area ranging from Portugal to western Siberia and from northern Europe to the Middle East. The species became extinct 28,000 years ago, coinciding with the arrival of anatomically modern humans (AMHs) in Europe 40,000 years ago. There has been considerable debate surrounding the main causes of the extinction of Neandertals. After at least 200,000 years of successful adaption to the climate, flora and fauna of Eurasia, it is not clear why they suddenly failed to survive. For many years, climate change or competition with anatomically modern human (AMH) have been the leading hypotheses. Recently these hypotheses have somewhat fallen out of favour due to the recognition that Neandertals were a highly developed species with complex social structure, culture and technical skills. Were AMHs lucky and survived some catastrophe that eradicated the Neandertals? It seems unlikely that this is the case considering the close timing of the arrival of AMHs and the disappearance of Neandertals. Perhaps the arrival of AMHs also brought additional new non-human microscopic inhabitants to the regions where Neandertals lived and these new inhabitants contributed to the disappearance of the species. We introduce a medical hypothesis that complements other recent explanations for the extinction of Neandertals. After the ancestors of Neandertals left Africa, their immune system adapted gradually to the pathogens in their new Eurasian environment. In contrast, AMHs continued to co evolve with east African pathogens. More than 200,000 years later, AMHs carried pathogens that would have been alien to pre-historic Europe. First contact between long separated populations can be devastating. Recent European and American history provides evidence for similar events, where introduction of viral, protozoan or bacterial pathogens to immunologically naive populations lead to mass mortality and local population extinction. We propose that a virus, possibly from the family Herpesviridae, contributed to Neandertal extinction. PMID- 20172661 TI - Radiotherapy with or without concurrent chemotherapy for lymph node recurrence after radical surgery of thoracic esophageal squamous cell carcinoma. AB - PURPOSE: To retrospectively compare the outcomes of patients with lymph node recurrence after radical surgery of esophageal cancer, when given radiotherapy with or without concurrent chemotherapy. METHODS AND MATERIALS: Between January 1996 and December 2005, the data from 73 patients with lymph node recurrence after radical surgery of thoracic esophageal squamous cell carcinoma were retrospectively reviewed. The patients were separated into two groups: radiochemotherapy (RC, 31 patients) and radiotherapy alone (RA, 42 patients). Patients in the RC group received at least two cycles of 5-fluorouracil/cisplatin chemotherapy concurrently with radiotherapy. RESULTS: The median duration of follow-up was 11 months (range, 2-48). The overall survival rate for all patients was 46.7% and 4.7% at 1 and 3 years, respectively. The median overall survival time was 9 months (95% confidence interval, 6.96-11.04) and 17 months (95% confidence interval, 13.61-20.39) for RA and RC groups, respectively. The survival rate at 1 and 3 years was 62.5% and 10.5% in the RC group and 33.8% and 0% in the RA group (p = .0049, log-rank test; hazard ratio for death, 0.52; 95% confidence interval, 0.30-0.92). Acute toxicities were more frequent in the RC group than in the RA group. No significant differences were found in the late toxicity profiles between the two groups. CONCLUSION: The results of the present retrospective analysis suggest that RC should be considered an effective and well tolerated treatment of patients with thoracic esophageal squamous cell carcinoma and postoperative lymph node recurrence. PMID- 20172662 TI - Attentional bias, inhibitory control and acute stress in current and former opiate addicts. AB - BACKGROUND: Drug dependence is associated with both attentional biases to drug related cues and inhibitory control deficits. Although acute stress is known to increase craving, it is not known whether this effect is mediated via changes in attentional bias and inhibitory control. OBJECTIVES: To examine the effect of a mild stressor on inhibitory control, attentional bias and craving in current opiate users (methadone maintained), ex-users (currently abstinent) and non-users (healthy controls). METHOD: Forty-eight participants (16 in each group) were exposed to both stress and non-stress conditions, after which inhibitory control and attentional bias was assessed using a Go-No-go and dot probe task respectively. Subjective ratings of stress levels and drug craving were repeatedly monitored. RESULTS: Current opiate users had significantly higher cravings ratings than both other groups at all times, and their craving tended to increase following the stress task. Current users had a greater attentional bias towards drug-related stimuli than the ex-users. Interestingly, ex-users showed a bias away from drug-related stimuli in the stress condition and this correlated positively with their length of abstinence. On the Go/No-go task, all groups had fewer false alarms in the stress condition. CONCLUSIONS: These results indicate that successful treatment is associated with a bias away from drugs, and that this bias may be protective against the effects of stress. PMID- 20172663 TI - Disk prediffusion is a reliable method for testing colistin susceptibility in porcine E. coli strains. AB - During the last few years, acquired resistance to colistin in Escherichia coli, but also in other bacterial species, has been reported. It has been shown that the disk diffusion test is not a reliable method for the detection of this resistance. Therefore, there is a need for a reliable and cheap test to determine colistin susceptibility of pathogenic E. coli strains. In the current research, the colistin susceptibility of E. coli isolated during the period 2005-2006 from pigs was determined. Results obtained with the Kirby Bauer disk diffusion test (Neosensitabs, Rosco), the disk prediffusion test (Neosensitabs, Rosco) and the E test (AB Biodisk) were compared with the results of the reference agar dilution assay. The MIC values or inhibition zones showed a bimodal distribution for the results obtained by all test methods, except the disk diffusion assay, suggesting acquired resistance in 15 strains (9.6%). The E-test and disk prediffusion assay generated results within acceptable levels compared to the reference agar dilution assay. The categorical agreement with the results obtained by the agar dilution method were good to very good for all tests, except the disk diffusion assay. In conclusion, current results suggest that, in addition to the E-test, the disk prediffusion test is a reliable, alternative agar-based colistin susceptibility method for testing colistin susceptibility of E. coli isolates in diagnostic bacteriology. PMID- 20172664 TI - A longitudinal study of differences in electroencephalographic activity among breastfed, milk formula-fed, and soy formula-fed infants during the first year of life. AB - BACKGROUND: The extent to which adequate nutrition from infant diets differentially influence developmental outcomes in healthy infants has not been determined. AIM: To compare the effects of the major infant diets on the development of brain electrical activity during infancy. STUDY DESIGN: Scalp EEG signals (124 sites) recorded from the same infants during quiet wakefulness at 3, 6, 9, and 12months. SUBJECTS: Healthy, full-term infants (40/group; gender matched) either breastfed (BF) or fed milk formula (MF) or soy formula (SF) through the first 6months. OUTCOME MEASURES: Power spectral values for frequencies in the 0.1-30Hz range. RESULTS: Significant diet-related differences were present across frequency bands and included effects that were time- [peaks in 0.1-3Hz at 6 (MF,SF) and 9months (BF); 3-6Hz at 6months (MF, SF>BF); increases in 6-9Hz from 3 to 6months (MF>BF) and from 6 to 9months (MF>SF)] and gender related (9-12Hz and 12-30Hz: at 9months BF>MF, SF boys, and MF>SF girls). CONCLUSIONS: The development of brain electrical activity during infancy differs between those who are breastfed compared with those fed either milk or soy formula, but is generally similar for formula-fed groups. These variations in EEG activity reflect diet-related influences on the development of brain structure and function that could put infants on different neurodevelopmental trajectories along which cognitive and brain function development will proceed. PMID- 20172665 TI - Bilateral loss of cortical somatosensory evoked potential at birth predicts cerebral palsy in term and near-term newborns. AB - Bilateral loss of cortical somatosensory evoked potential (SEP) is considered the single best indicator of adverse outcome in acute encephalopathy of adult patients and older children. This study determines whether the presence or absence of the neonatal cortical SEP can predict cerebral palsy at two years in survivors of neonatal encephalopathy scored according to Sarnat criteria. We also compare SEPs with visual evoked potentials (VEPs), the EEG and neonatal neurological status. Fifty-nine neonates admitted to the neonatal intensive care unit had SEP, VEP and EEG recordings analysed according to the presence (n=37, 63%) or absence (n=22, 37%) of neonatal encephalopathy (score >or=1). Cortical SEP was always present in the perinatal period in those surviving without major neurological disability, while it was bilaterally absent in all but one patient with a subsequent diagnosis of cerebral palsy. Multivariate analysis using the logistic regression model showed that bilateral loss of cortical SEP and Sarnat Score correctly classified the neurological outcome in all patients. Bilateral absence of cortical SEP indicates early identification of neonates at risk of cerebral palsy indicating that EPs have a clinical role in the workup of neonatal encephalopathy. PMID- 20172666 TI - Functional echocardiography; from physiology to treatment. AB - Functional echocardiography (fECHO) is the bedside use of ultrasound to longitudinally assess myocardial function, systemic and pulmonary blood flow, and intra and extracardiac shunts. This review will focus on fECHO as a tool for the clinician to assess the hemodynamic condition of sick neonates and describe situations where fECHO can help determine a pathophysiological choice for cardiovascular support. The very low birth weight infant with hypotension during the first 24h of life, assessment and monitoring of the ductus arteriosus, assessment and response to treatment of infants with pulmonary hypertension, the infant with perinatal asphyxia and the infant with sepsis and cardiovascular compromise are reviewed. Close cooperation with pediatric cardiology, proper logistics and training programs are mandatory to achieve a 24h a day fECHO service run by bedside clinicians. PMID- 20172667 TI - New therapeutic targets and agents for osteoporosis. PMID- 20172668 TI - Deaths involving serotonergic drugs. AB - Serotonin-active drugs are detected relatively frequently in Victorian deaths. During 2002-2008, there were 1123 fatalities where one or more of the serotonin active drugs tramadol, venlafaxine, fluoxetine, sertraline, citalopram, paroxetine and MDMA, were detected. These deaths were reviewed using pathology, toxicology and police reports, to determine the contribution of these drugs to the cause of death, particularly if serotonin toxicity was the mechanism of death. There were 28 cases of most interest to this research because of the presence of the target drugs and the circumstances suggesting the likelihood of serotonin toxicity involvement in death. There were 5 cases of reported serotonin toxicity and 23 other deaths suspected to have involved this form of toxicity. Tramadol featured most commonly out of the seven target drugs and was frequently detected in combination with serotonergic antidepressants. MDMA was also detected relatively commonly and was associated with moclobemide in 4 cases of confirmed serotonin toxicity. There were an additional 1095 cases where natural disease, external injury or the misuse of other drugs caused death, of which 2 reported the incidental contribution of serotonin toxicity. PMID- 20172669 TI - Evaluation of swallowing pressure in a patient with amyotrophic lateral sclerosis before and after cricopharyngeal myotomy using high-resolution manometry system. AB - BACKGROUND: This study aimed to evaluate the pharyngeal pressure of a patient with, amyotrophic lateral sclerosis (ALS) before and after cricopharyngeal myotomy by high-resolution manometry (HRM) system. METHODS: A 60-year-old man with ALS underwent cricopharyngeal myotomy for his intractable, aspiration. The swallowing pressure along the velopharynx and upper esophagus was measured using, the HRM 1 month before and 3 months after the surgery. RESULTS: Before cricopharyngeal myotomy, the maximum values of the resting UES pressure, the dry swallowing, pressures in the velopharyngeal muscle zone and in the UES zone were 89, 95, and 171 mmHg, respectively. After surgery, the maximum values of both the resting pressure and dry swallowing, pressure in the UES zone remarkably decreased to 21 and 75 mmHg, respectively. CONCLUSIONS: This is the first report showing the effect of cricopharyngeal myotomy by demonstrating, the difference in the swallowing pressure along the velopharynx and upper esophagus before and after, the surgery in an ALS patient using this HRM system. PMID- 20172670 TI - Syringoid eccrine carcinoma of external auditory canal. A case report. AB - First described in 1969, syringoid eccrine carcinoma (SEC) is a rare cutaneous tumor with some controversy regarding its correct definition. It consists of solid nests and small cords in a dense fibrocollagenous stroma. As it is rare, its clinical appearance is not well characterized and its biological behaviour is not defined. It usually affects skin of the scalp, extremities and more rarely, other sites. It behaves as locally aggressive tumor but metastases are rare. Although there have been some previous reports describing clinical presentation and management of SEC in the skin, there has been no previous reports describing clinical findings and management of this tumor in the external auditory canal. We report a case of a 57-year-old female with small solitary mass in left external auditory canal associated with discharge, severe itching and bleeding on manipulation. Complete local excision is the recommended method for diagnosis and treatment of this tumor in the external auditory canal. This extremely rare case serves as a springboard for the diagnosis as well as the management of SEC in external auditory canal. PMID- 20172671 TI - [Contribution of Toxoplasma gondii-specific PCR for the diagnosis of disseminated toxoplasmosis in a non-HIV and non-grafted adult patient]. PMID- 20172673 TI - [Endobronchial chicken pox]. PMID- 20172672 TI - [Urinary pneumococcal or Legionella antigen detection tests and low-spectrum antibiotic therapy for community-acquired pneumonia]. AB - We performed urinary antigen tests for pneumococcus and Legionella for patients with community-acquired pneumonia (CAP), to prescribe a documented antibiotic therapy. We report the efficiency of low-spectrum antibiotic treatment, illustrating the inappropriateness of bacteriological respiratory sampling. PATIENTS AND METHODS: Patients with CAP were enrolled from three different units; the pneumonia severity index was used to assess the disease. Respiratory samples were also listed. Low-spectrum antibiotic therapy was amoxicillin for pneumococcal infection, and macrolides or non-anti-pneumococcal fluoroquinolone for legionellosis. RESULTS: Six hundred and seventy-five CAP were diagnosed during the study period,, 150 with positive urinary antigen tests (23%), among which 108 pneumococcal infections (73%), 40 legionellosis (26%), and two mixed infections. The pneumonia severity index was 106+/-38. Amoxicillin was prescribed in 108 cases, fluoroquinolone in 24 cases, macrolide in 18 cases. The outcome was favourable for 138 patients (92%). Eighty three respiratory samples allowed identification of a bacterium for 58 patients (39%), among which 24 strains were not in the antibiotic spectrum: Haemophilus influenzae and Pseudmomonas aeruginosa in six cases, Staphylococcus aureus in five cases, Klebsiella pneumoniae in two cases, and another Gram negative bacillus in five cases. These strains were resistant in vitro to the prescribed treatment in 19/24 cases (79%). One out of 12 patients who died had a respiratory sample positive for Enterobacter spp strain resistant to the ongoing antibiotic treatment. CONCLUSION: The low-spectrum antibiotic therapy based on urinary antigen tests is efficient, and demonstrates respiratory tract colonisation with bacteriological strains usually considered as pathogenic. PMID- 20172674 TI - [Typhoid fever-associated hemophagocytic syndrome in a Comoros child]. PMID- 20172675 TI - [Impact of regional guidelines on the management of urinary tract infections with antibiotics]. AB - AIM AND METHOD: We assessed the impact of a committed guideline at the end of the first quarter 2008 on the management of urinary tract infection (UTI) with antibiotic prescription (fluoroquinolone, fosfomycin, and nitrofurantoin), by analysing reimbursement data for ambulatory care provided by the regional health insurance agency. RESULTS: During the survey, we observed a 13.2% decrease of norfloxacin prescriptions between the first quarter 2008 and the first quarter 2009. The (fosfomycin+nitrofurantoin)/norfloxacin ratio increased between the third quarter 2007 and the first quarter 2009 from 0.55 to 0.72 and from 0.82 to 1.13 for general practitioners and hospital physicians respectively. The global number of patients treated with these antibiotics remained stable during the period. The number of fluoroquinolone prescription was stable between the first quarter 2008 and the first quarter 2009 with 28,427 DDD and 28,363 DDD, respectively; while the number of single dose rise in the same time from 151 DDD to 427.5 DDD, respectively. DISCUSSION: The three messages which seem to be essential for an optimal use of fluoroquinolones in UTIs are: no treatment for bacterial colonisation (asymptomatic bacteriuria) except for specific cases, no indication for fluoroquinolones in non-complicated acute cystitis and for elderly women, UTI is complicated only if it occurs in women with co-morbidities regardless of age. CONCLUSION: Our indicators suggest that our guideline had an impact on the prescription of fluoroquinolones for uncomplicated acute cystitis. PMID- 20172676 TI - Role of FDG-PET and PET/CT in the diagnosis and management of vasculitis. AB - PURPOSE: to investigate the role of FDG-PET and PET/CT in the evaluation of vasculitis. MATERIALS AND METHODS: a systematic revision of the papers published in PubMed/Medline until December 2009 was done. RESULTS: FDG-PET and PET/CT have been proven to be valuable in the diagnosis of large-vessel vasculitis, especially giant cells arteritis with sensitivity values ranging 77% to 92%, and specificity values ranging 89% to 100%. In particular, FDG-PET/CT has demonstrated the potential to non-invasively diagnose the onset of the vasculitis earlier than traditional anatomical imaging techniques, thus enabling prompt treatment. False positive results mainly occur in the differential diagnosis between vasculitis and atherosclerotic vessels in elderly patients. Another area where FDG-PET/CT is gaining wider acceptance is in monitoring response to therapy; it can reliably detect the earliest changes of disease improvement post therapy, and persistent activity is an indicator of non-responders to therapy. A few data have been reported about medium/small vessel vasculitis. DISCUSSION: FDG PET and PET/CT have proven utility: (a) in the initial diagnosis of patients suspected of having vasculitis particularly in those who present with non specific symptoms; (b) in the identification of areas of increased FDG uptake in which a biopsy should be done for obtaining a diagnosis; (c) in evaluating the extent of the disease; (d) in assessing response to treatment. PMID- 20172677 TI - DWI in breast MRI: role of ADC value to determine diagnosis between recurrent tumor and surgical scar in operated patients. AB - INTRODUCTION: Purpose of our study is to evaluate the role of the apparent diffusion coefficient (ADC) in the diagnosis of recurrent tumor on the scar in patients operated for breast cancer. Assess, therefore, the weight of diagnostic diffusion echo-planar sequence, in association with the morphological and dynamic sequences in the diagnosis of tumor recurrence versus surgical scar. MATERIALS AND METHODS: From September 2007 to March 2009, 72 patients operated for breast cancer with suspected recurrence on the scar were consecutively subjected to magnetic resonance imaging (MRI), including use of a diffusion sequence. All patients with pathological enhancement in the scar were then subjected to histological typing. MRI was considered negative in the absence of areas of suspicious enhancement. In all cases it was measured the ADC value in the scar area or in the area with pathological enhancement. The ADC values were compared with MRI findings and histological results obtained. RESULTS: 26 cases were positive/doubtful at MRI and then subjected to histological typing: of these recurrences were 20 and benign were 6. 46 cases were judged negative at MRI and therefore not sent to cyto-histology. The average ADC value of recurrences was statistically lower of scarring (p<0.001). CONCLUSIONS: ADC value can be a specific parameter in differential diagnosis between recurrence and scar. The diffusion sequence, in association with the morphological and dynamic sequences, can be considered a promising tool for the surgical indication in suspected recurrence of breast cancer. PMID- 20172678 TI - Study on similar traditional Chinese medicines cornu Cervi pantotrichum, cornu Cervi and cornu Cervi degelatinatum by FT-IR and 2D-IR correlation spectroscopy. AB - As complicated mixture systems, traditional Chinese medicines (TCM) are very difficult to identify and discriminate, especially for the drug samples have the same source. Therefore, finding a rapid and effective identification method for the similar TCM is the most pressing task in TCM research. In this paper, the macroscopic IR fingerprint method including Fourier transform infrared spectroscopy (FT-IR), the second derivative spectra and two-dimensional correlation infrared spectroscopy (2D-IR), were applied to studying and identifying three very similar traditional Chinese animal drugs Cornu Cervi Pantotrichum (CCP), Cornu Cervi (CC) and Cornu Cervi Degelatinatum (CCD). On the basis of the different FT-IR and 2D-IR spectra ratios of amide I bands, amide II bands and Ca(3)(PO(4))(2), three similar animal drugs of the same source were successfully identified and discriminated. Then the FT-IR spectra data of total 30 samples, comprising 10 samples each of above three drugs, were obtained and analyzed with the soft independent modeling of class analogy (SIMCA) pattern recognition technique. The result showed that the three kinds of drug samples located in three different clusters separately. As a result, it was demonstrated that the macroscopic IR fingerprint method could discriminate the three similar TCM, CCP, CC and CCD, rapidly, effectively and non-destructively. PMID- 20172679 TI - Determination of potassium, sodium, calcium and magnesium in total parenteral nutrition formulations by capillary electrophoresis with contactless conductivity detection. AB - A simple method based on capillary electrophoresis with a capacitively coupled contactless conductivity detector (CE-C(4)D) was developed for the determination of potassium, sodium, calcium and magnesium in parenteral nutrition formulations. A hydro-organic mixture, consisting of 100 mM Tris-acetate buffer at pH 4.5 and acetonitrile (80:20, v/v), was selected as the background electrolyte. The applied voltage was 30 kV, and sample injection was performed in hydrodynamic mode. All analyses were carried out in a fused silica capillary with an internal diameter of 50 microm and a total length of 64.5 cm. Under these conditions, complete separation between all cations was achieved in less than 4 min. The CE C(4)D method was validated, and trueness values between 98.6% and 101.8% were obtained with repeatability and intermediate precision values of 0.4-1.3% and 0.8 1.8%, respectively. Therefore, this method was found to be appropriate for controlling potassium, sodium, calcium and magnesium in parenteral nutrition formulations and successfully applied in daily quality control at the Geneva University Hospitals. PMID- 20172681 TI - Development and validation of an EI-GC-MS method for the determination of benzodiazepine drugs and their metabolites in blood: applications in clinical and forensic toxicology. AB - Benzodiazepines are used widely in daily clinical practice, due to their multiple pharmacological actions. The frequent problems associated with the wide use of benzodiazepines, as well as the multiple incidents of poisonings, led to the necessity for the development of a precise, sensitive and rapid method for the simultaneous determination of the 23 most commonly used benzodiazepines (diazepam, nordiazepam, oxazepam, bromazepam, alprazolam, lorazepam, medazepam, flurazepam, fludiazepam, tetrazepam, chlordiazepoxide, clobazam, midazolam, flunitrazepam, 7-amino-flunitrazepam, triazolam, prazepam, nimetazepam, nitrazepam, temazepam, lormetazepam, clonazepam, camazepam) in blood. A gas chromatographic method combined with mass spectrometric detection was developed, optimized and validated for the determination of the above substances. This method includes liquid-liquid extraction with chloroform at pH 9 and two stages of derivatization using tetramethylammonium hydroxide and propyliodide (propylation), as well as a mixture of triethylamine:propionic anhydride (propionylation). The recoveries were higher than 74% for all the benzodiazepines. The calibration curves were linear within the dynamic range of each benzodiazepine with a correlation coefficient higher than 0.9981. The limits of detection and quantification for each analyte were statistically calculated from the relative calibration curves. Accuracy and precision were also calculated and were found to be less than 8.5% and 11.1%, respectively. The developed method was successfully applied for the investigation of both forensic and clinical toxicological cases of accidental and suicidal poisoning. PMID- 20172680 TI - Development and validation of a fast and sensitive bioanalytical method for the quantitative determination of glucocorticoids--quantitative measurement of dexamethasone in rabbit ocular matrices by liquid chromatography tandem mass spectrometry. AB - A sensitive, selective, accurate and robust LC-MS/MS method was developed and validated for the quantitative determination of glucocorticoids in rabbit ocular tissues. Samples were processed by a simple liquid-liquid extraction procedure. Chromatographic separation was performed on Phenomenex reversed phase C18 gemini column (50mmx4.6mm i.d.,) with an isocratic mobile phase composed of 30% of acetonitrile in water containing 0.1% of formic acid, at a flow rate 0.2mL/min. Dexamethasone (DEX), prednisolone (PD) and hydrocortisone (HD) were detected with proton adducts at m/z 393.20-->355.30, 361.30-->147.20 and 363.20-->121.0 in multiple reaction monitoring (MRM) positive mode respectively. Finally, 50microL of 0.1% novel DEX mixed micellar formulation was topically administered to a rabbit eye and concentrations were measured. The method was validated over a linear concentration range of 2.7-617.6ng/mL. Lower limit of quantitation (LLOQ) of DEX and PD was measured in the concentration range of 2.7 and 11.0ng/mL respectively. The resulting method demonstrated intra and inter-day precision within 13.3% and 11.1% and accuracy within 19.3% and 12.5% for DEX and PD, respectively. Both analytes were found to be stable throughout freeze-thaw cycles and during bench top and postoperative stability studies (r(2)>0.999). DEX concentrations in various ocular tissue samples i.e., aqueous humor, cornea, iris ciliary body, sclera and retina choroid were found to be 344.0, 1050.07, 529.6, 103.9 and 48.5ng/mg protein respectively. Absorption of DEX after topical administration from a novel aqueous mixed micellar formulation achieved therapeutic concentration levels in posterior segment of the rabbit eye. PMID- 20172682 TI - Quantification of 4'-geranyloxyferulic acid, a new natural colon cancer chemopreventive agent, by HPLC-DAD in grapefruit skin extract. AB - Oxyprenylated natural products (isopentenyloxy-, geranyloxy- and the less spread farnesyloxy-compounds and their biosynthetic derivatives) represent a family of secondary metabolites that have been consider for years merely as biosynthetic intermediates of the most abundant C-prenylated derivatives. Many of the isolated oxyprenylated natural products were shown to exert in vitro and in vivo remarkable anti-cancer and anti-inflammatory effects. 4'-Geranyloxyferulic acid [3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic] has been discovered as a valuable chemopreventive agent of several types of cancer. After development of a high yield and "eco-friendly" synthetic scheme of this secondary metabolite, starting from cheap and non-toxic reagents and substrates, we developed a new HPLC-DAD method for its quantification in grapefruit skin extract. A preliminary study on C18 column showed the separation between GOFA and boropinic acid (having the same core but with an isopentenyloxy side chain), used as internal standard. The tested column were thermostated at 28+/-1 degrees C and the separation was achieved in gradient condition at a flow rate of 1 mL/min with a starting mobile phase of H(2)O:methanol (40:60, v/v, 1% formic acid). The limit of detection (LOD, S/N=3) was 0.5 microg/mL and the limit of quantification (LOQ, S/N=10) was 1 microg/mL. Matrix-matched standard curves showed linearity up to 75 microg/mL. In the analytical range the precision (RSD%) values were or=75 years), whereas the use of postoperative radiotherapy decreased. Administration of chemotherapy to patients with stage IV disease increased over time from 21% to 66% for patients younger than 75 years. Both males and females exhibited an increase in five-year relative survival from 53% to 60%. The highest increase in survival was found for patients with stage III disease. In the multivariate analyses survival improved over time for patients with stages II-IV disease. After adjustment for treatment variables, this improvement remained significant for patients with stages III and IV disease. CONCLUSIONS: The changes in therapy for rectal cancer have led to a markedly increased survival. Patients with stage III disease experienced the greatest improvement in survival. PMID- 20172712 TI - Expression profiles of viral responsive genes in oral and oropharyngeal cancers. AB - The association between Human Papillomavirus (HPV) DNA and oropharyngeal squamous cell carcinoma (SCC) has been supported by numerous studies strongly implicating HPV infection as a factor in the development of this cancer. In contrast, squamous cell carcinoma of the oral cavity has not been associated with HPV DNA, suggesting alternate aetiologic factors. The possibility that viral agents other than HPV could contribute to the development of oral cavity SCC should be given consideration, especially given the association of Epstein-Barr virus (EBV) with nasopharyngeal cancer. We used quantitative polymerase chain reaction (qPCR) studies to compare the expression levels of genes that may act as indicators of persistent stimulation by viral antigen in both oral cavity and oropharyngeal squamous cell cancers. Our results demonstrate that HPV-positive oropharyngeal tumours displayed gene expression patterns indicative of a viral signature and that HPV-negative oropharyngeal tumours do not display similar expression patterns. In contrast, we saw no evidence of either a viral or bacterial signature in the oral tumours examined. This would suggest that either an as of yet unidentified virus present in the oral tumour samples is not eliciting a typical immune response, or that there are no novel viral sequences or viruses present in the oral tumours examined. PMID- 20172713 TI - The use of piassava fibers (Attalea funifera) in the preparation of activated carbon. AB - The piassava fiber, residue of the broom industry, was used as precursor for the preparation of activated carbons (AC). AC were prepared by chemical activation with zinc chloride (AC ZnCl(2)) or phosphoric acid (AC H(3)PO(4)) and by physical activation with carbon dioxide (AC CO(2)) or water vapor (AC H(2)O). These materials were characterized by adsorption/desorption of N(2) to determine the BET areas, elemental analysis (CHN), thermogravimetric analysis (TG, DTA) and scanning electron microscopy (SEM). The carbons were tested with respect to their adsorption capacity of methylene blue, reactive red, phenol and metallic ions (Cr(+6), Cu(+2) and Zn(+2)). AC ZnCl(2) presented the highest surface area (1190 m(2)g(-1)) and AC H(3)PO(4), the largest pore volume (0.543 cm(3)g(-1)). AC ZnCl(2) was more efficient in the adsorption of methylene blue, Cr(+6) and Cu(+2) ions. AC H(2)O was the better adsorbent for phenol, while AC CO(2) was better for Zn(+2) ions. PMID- 20172714 TI - Multivariate statistical analysis of X-ray data from cellulose: a new method to determine degree of crystallinity and predict hydrolysis rates. AB - The enzymatic hydrolysis of cellulose by cellulases is one of the major steps in the production of ethanol from lignocellulosics. However, cellulosic biomass is not particularly susceptible to enzymatic attack and crystallinity of the substrates is one of the key properties that determine the hydrolysis rates. In this work, by quantifying the respective contributions of amorphous and crystalline cellulose to the X-ray diffraction spectra of cellulose with intermediate degrees of crystallinity, a new method to obtain consistent crystallinity index values was developed. Multivariate statistical analysis was applied to spectra obtained from phosphoric acid pretreated cellulose samples of various intermediate (but undetermined) crystallinity indices to reduce their dimensionality. The crystallinity indices obtained were found to be linearly related to the enzymatic hydrolysis rates. The method was validated by predicting the degree of crystallinity of samples containing various ratios of microcrystalline cellulose and amorphous cellulose, both of known crystallinity indices. Dimensionality reduction of the spectra was also used to predict the enzymatic hydrolysis rates of various cellulose samples from X-ray data. The method developed in this work could be generalized to accurately assess the degree of crystallinity for a wide range of varieties of cellulose. PMID- 20172715 TI - Competitive biosorption of cadmium(II) and zinc(II) ions from binary systems by Sargassum filipendula. AB - The present work describes our study on the competitive biosorption of Cd(II) and Zn(II) ions onto Sargassum filipendula from single component and binary systems. Results showed that S. filipendula was an efficient biosorbent for the removal of Cd(II) and Zn(II) ions from an aqueous solution. The equilibrium experimental data for the single component system for the two metallic species fitted well to Langmuir and Langmuir-Freundlich isotherm models. Seven isotherm models were tested with the equilibrium data for modeling of the binary system. Based on the sum of squares error, the Langmuir-Freundlich isotherm model showed the best fit to the binary adsorption data. The influence of the additional cation on the behavior of the biosorption of Cd(2+) and Zn(2+) was analyzed comparing single component and binary isotherms. It was observed that Zn(2+) had a relevant effect on the Cd(2+) biosorption, but the interference of Cd(2+) on the sorption of Zn(2+) was considerably less intense. PMID- 20172716 TI - Ultrasmall particle of iron oxide--RGD peptidomimetic conjugate: synthesis and characterisation. AB - Ultrasmall particles of iron oxide (USPIOs) coated with 3,3' bis(phosphonate)propionic acid were covalently coupled to a home-made Arg-Gly-Asp (RGD) peptidomimetic molecule via a short oligoethylene-glycol (OEG) spacer. The conjugation rate was measured by X-ray photoelectron spectroscopy (XPS). The particle size and magnetic characteristics were kept. Our novel conjugate targeted efficiently Jurkat cells (increase of 229% vs the control). PMID- 20172717 TI - Structure-based design and synthesis of novel P2/P3 modified, non-peptidic beta secretase (BACE-1) inhibitors. AB - Starting from peptidomimetic BACE-1 inhibitors, the P2 amino acid including the P2/P3 peptide bond was replaced by a rigid 3-aminomethyl cyclohexane carboxylic acid. Co-crystallization revealed an unexpected binding mode with the P3/P4 amide bond placed into the S3 pocket resulting in a new hydrogen bond interaction pattern. Further optimization based on this structure resulted in highly potent BACE-1 inhibitors with selectivity over BACE-2 and cathepsin D. PMID- 20172718 TI - Design of two new chemotypes for inhibiting the Janus kinase 2 by scaffold morphing. AB - JAK2 is a target of high interest in chronic myeloproliferative disorders drug research. Starting from a screening hit, two new JAK2 inhibitor chemotypes were designed by scaffold morphing. The prototype compounds of these new series showed nanomolar inhibition of the kinase. PMID- 20172719 TI - Novel powerful water-soluble lipid immunoadjuvants inducing mouse dendritic cell maturation and B cell proliferation using TLR2 pathway. AB - Four novel water-soluble lipid immunoadjuvants were designed, synthesized and characterized by MS and NMR. They all induce mouse dendritic cell maturation and B cell proliferation. We demonstrate that in spite of the chemical modification, the four compounds remain TLR2 agonists. PMID- 20172720 TI - Synthesis and evaluation of a library of 2,5-bisdiamino-benzoquinone derivatives as probes to modulate protein-protein interactions in prions. AB - A small library combining two different benzoquinone cores with seven (L) amino acid methyl esters (alanine, Nomega-nitro-arginine, Nepsilon-BOC-lysine, isoleucine, methionine, phenylalanine and tryptophan) was prepared and tested for prion replication inhibition in ScGT1 cells. The most potent hit, 6a, displayed an EC(50) value of 0.87 microM, which is very close to that of quinacrine (0.4 microM). PMID- 20172721 TI - Identification of a urea bioisostere of a triazole oxytocin antagonist. AB - A series of azetidine ureas were investigated as potential bioisosteres of previously reported azetidinyltriazole oxytocin antagonists. Although potency was somewhat reduced in several close-in analogues, one compound, 9, was both a potent oxytocin antagonist and demonstrated significant selectivity over the closely related vasopressin V(1A) receptor. PMID- 20172722 TI - Synthesis, characterization, and in vitro antimicrobial activities of 5 alkenyl/hydroxyalkenyl-2-phenylamine-1,3,4-oxadiazoles and thiadiazoles. AB - The long-chain alkenoic acid hydrazides (1a-d) on reaction with phenylisocyanate and phenylthiocyanate gave their corresponding semicarbazides (2a-d) and thiosemicarbazides (4a-d), which on further refluxing with POCl(3) and Ac(2)O yielded corresponding 1,3,4-oxadiazoles (3a-d) and thiadiazoles (5a-d), respectively. The structure elucidation of synthesized compounds is based on the elemental analysis and spectral data (IR, (1)H NMR, (13)C NMR and MS). The synthesized oxadiazoles and thiadiazoles have been screened for antibacterial and antifungal activities. The investigation of antimicrobial screening revealed that compounds 3c, 3d, 5c, 5d and compounds 3b, 5b, showed good antibacterial and antifungal activities, respectively. PMID- 20172723 TI - Syntheses of water-soluble [60]fullerene derivatives and their enhancing effect on neurite outgrowth in NGF-treated PC12 cells. AB - Water-soluble [60]fullerene (C(60)) derivatives were synthesized to examine their bioactivities. PC12 cells were used as a model of nerve cells and the bioactivities of synthesized C(60) derivatives together with some reported ones were tested. Among the compounds tested, C(60)/(gamma-CyD)(2), C(60)-bis(gamma CyD) (5) containing C(60)-mono(gamma-CyD) (5'), and C(60)/PVP were sufficiently soluble in water and showed an enhancing effect on the neurite outgrowth of NGF treated PC12 cells. PMID- 20172724 TI - Ethacrynic acid analogues lacking the alpha,beta-unsaturated carbonyl unit- potential anti-metastatic drugs. AB - A series of ethacrynic acid analogues, lacking the alpha,beta-unsaturated carbonyl unit, was synthesized and subsequently evaluated for their ability to inhibit the migration of human breast cancer cells, MCF-7/AZ. Several of the analogues were already active in the low micromolar range, whereas ethacrynic acid itself shows no potential to inhibit the migration of these cancer cells. Preliminary studies show that the presence of one or more methoxy groups at the phenyl ring of ethacrynic acid is important in order for the ethacrynic acid analogues to demonstrate an inhibitory effect on the migration. PMID- 20172725 TI - Discovery and SAR of hydantoin TACE inhibitors. AB - We disclose inhibitors of TNF-alpha converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X ray structures of TACE with a hydantoin zinc ligand. PMID- 20172726 TI - The rise and fall in menopausal hormone therapy and breast cancer incidence. AB - Studies conducted in different areas of North America and Europe showed a 5-10% decline in the incidence of breast cancer following reductions up to 70% in menopause hormone therapy (HT) use after 2002. The observation that the decline was larger in (or limited to) women aged > or =50 years weighs in favour of an effect of reduced HT use on breast cancer incidence. However, changes in screening are also likely to play a role in the decreasing incidence of breast cancer observed in several countries. In particular, the technical improvements and the increased effectiveness of breast cancer screening and detection during the 1990s led to a decreased number of pre-clinical cases found by screening in subsequent years. Further, disentangling the effects of HT use and screening is difficult, as women who stop using HT may also undergo mammography screening less frequently. Thus, the reasons of the falls in incidence remain open to discussion. PMID- 20172727 TI - A vision to optimise the management of primary breast cancer in older women. AB - Majority of breast cancer are diagnosed at >65 years. Efforts to develop clinical service and research are spent mainly on younger patients. Little is known about the biology and long-term clinical outcome of breast cancer in the elderly. However there is data suggesting that there are differences. Knowledge related to breast cancer in the elderly is urgently needed and we need to optimise their management - not 'over' or 'under' treating them, taking into account of both physical and psychosocial dimensions. The Nottingham Breast Services established a dedicated elderly primary breast cancer service from its inception over 30 year ago, which has recently developed into a combined surgical/oncology facility. A joint effort and team approach are required in both developing clinical service and research, in order to optimise management. There is an immense need to develop a dedicated elderly breast cancer service and to support ongoing research. PMID- 20172728 TI - Disparities in access to breast care nurses for breast surgeons: a National Breast Cancer Audit survey. AB - The involvement of a breast care nurse (BCN) in breast cancer treatment can improve the physical and psychological outcomes and provide the continuity of care and better information about the disease and treatment process. This survey examined the current status of BCNs access to determine the extent and how BCNs were accessed by breast surgeons across Australia and New Zealand in different geographical settings or health service sectors. The survey was disseminated in December 2006. Response rate was 91%. The results show that the majority of Australian and New Zealand breast surgeons either work with a BCN in their practice or can access a BCN outside their practice. Patients are more likely to have access to a BCN immediately after diagnosis while around a third of practices have access to a BCN more than once, usually "after diagnosis" and "after surgery". More public practices have direct access to a BCN than private practices, particularly in the metropolitan and regional areas while access to BCN is poor in rural public and private practices. The difference in overall access, either in the practice or external access (Yes or No but can access a BCN), to a BCN between public and private practices is smaller. Access to a BCN was best in metropolitan public practices and worst in rural private practices with one quarter rural private practices had no access to a BCN and no rural patients can access a BCN more than once in private practice. The results of this survey demonstrated some evidence of disparity in access to a BCN which needs to be reduced through more attention and/or extra resources in this area. PMID- 20172730 TI - Kinematic differences between normal and low arched feet in children using the Heidelberg foot measurement method. AB - The purpose of this study was to investigate the kinematics of normal arched and low arched feet in children and use this data to quantify the differences between the two foot types during walking gait. Multi-segment foot motion was measured, using the Heidelberg foot measurement method (HFMM), for 25 normal arched feet and 27 low arched feet in 9-12-year-old children. The kinematic differences in the foot between the two groups during walking were relatively small, except for the medial arch and forefoot supination angles. The magnitude of the medial arch angle was approximately 10 degrees greater in the low arched group than the normal arched group throughout the gait cycle. There was a significant difference found in the forefoot supination angle (p<0.03), relative to the midfoot, between the two groups at initial heel strike, and maximum and minimum values throughout the gait cycle. The values for the normal group were significantly higher in all these angles indicating that the forefoot of the low arched foot remains less pronated during the gait cycle. There was no significant difference in the motion of the rearfoot between the two foot types. The results of this study provide normative values for children's feet and highlight the mechanical differences in flexible flat feet in this age group. This data contributes to knowledge on foot kinematics in children and will be valuable for future research on the structure, function and potential treatment of the flexible flat foot. PMID- 20172731 TI - Radiological study of the sandwich method in cervical anterior fusion using autologous vertebral bone grafts. AB - Autologous bone grafts from cervical vertebral bodies (Williams-Isu method) are used for anterior fusion of the cervical spine. When adequate amounts of bone cannot be harvested from the vertebral body, hydroxyapatite (a ceramic) is placed between the bone grafts (the sandwich method). We conducted a radiological study to examine the efficacy of the sandwich method by comparing the alignment of the whole spine and the fused segment between patients who had received a sandwich graft (n=20) and a control group (n=20). Although there was no difference between the two groups with respect to the alignment of the whole spine, the alignment and height of the fused segment was significantly better in the patients in the sandwich graft group. In both groups the position of the anterior edge of the graft and the loss in the angle of the fused segment were significantly correlated (p<0.05). We found that the sandwich method not only reinforced the graft, but also yielded better results with respect to the angle and height of the fused segment. PMID- 20172732 TI - Bridging the gap between basic and clinical investigation. AB - This article focuses on the increasing importance of effective communication between scientists and their clinical colleagues. Some recent and innovative programs to facilitate these interactions are also discussed. PMID- 20172729 TI - The p53 orchestra: Mdm2 and Mdmx set the tone. AB - The activities of p53 cover diverse aspects of cell biology, including cell cycle control, apoptosis, metabolism, fertility, differentiation and cellular reprogramming. Although loss of p53 function engenders tumor susceptibility, hyperactivation of p53 is lethal. Therefore, p53 activity must be strictly regulated to maintain normal tissue homeostasis. Critical for the control of p53 function are its two main negative regulators: Mdm2 and Mdmx. Recent reports have provided insight into the complex mechanisms that regulate these two proteins and have revealed novel functions for each. Here, we review and evaluate models of Mdm2- and Mdmx-dependent regulation of p53 activity. Both Mdm2 and Mdmx receive input from numerous signaling pathways and interact with many proteins in addition to p53. Therefore, we also consider roles for Mdm2 and Mdmx in additional cancer-related networks, including Notch signaling and the epithelial to-mesenchymal transition. PMID- 20172733 TI - A novel link to base excision repair? AB - DNA interstrand crosslinks (ICLs) can arise from reactions with endogenous chemicals, such as malondialdehyde - a lipid peroxidation product - or from exposure to various clinical anti-cancer drugs, most notably bifunctional alkylators and platinum compounds. Because they covalently link the two strands of DNA, ICLs completely block transcription and replication, and, as a result, are lethal to the cell. It is well established that proteins that function in nucleotide excision repair and homologous recombination are involved in ICL resolution. Recent work, coupled with a much earlier report, now suggest an emerging link between proteins of the base excision repair pathway and crosslink processing. PMID- 20172734 TI - A concise synthesis of 1,4-dihydro-[1,4]diazepine-5,7-dione, a novel 7-TM receptor ligand core structure with melanocortin receptor agonist activity. AB - Finding small non-peptide molecules for G protein-coupled receptors (GPCR) whose endogenous ligands are peptides, is a very important task for medicinal chemists. Over the years, compounds mimicking peptide structures have been discovered, and scaffolds emulating peptide backbones have been designed. In our work on GPCR ligands, including cholecystokinin receptor-1 (CCKR-1) agonists, we have employed benzodiazepines as a core structure. Looking for ways to reduce molecular weight and possibly improve physical properties of GPCR ligands, we embarked on the search for molecules providing similar scaffolds to the benzodiazepine with lower molecular weight. One of our target core structures was 1,4-dihydro [1,4]diazepine-5,7-dione. There was not, however, a known synthetic route to such molecules. Here we report the discovery of a simple and concise method for synthesis of 2-[6-(1H-indazol-3-ylmethyl)-5,7-dioxo-4-phenyl-4,5,6,7-tetrahydro [1,4]diazepin-1-yl]-N-isopropyl-N-phenyl-acetamide as an example of a compound containing the tetrahydrodiazepine-5,7-dione core. Compounds from this series were tested in numerous GPCR assays and demonstrated activity at melanocortin 1 and 4 receptors (MC1R and MC4R). Selected compounds from this series were tested in vivo in Peptide YY (PYY)-induced food intake. Compounds dosed by intracerebroventricular and oral routes reduced PYY-induced food intake and this effect was reversed by the cyclic peptide MC4R antagonist SHU9119. PMID- 20172735 TI - Helianthus tuberosus and polyamine research: past and recent applications of a classical growth model. AB - The earliest studies concerning polyamines (PAs) in plants were performed by using in vitro cultured explants of Helianthus tuberosus dormant tuber. This parenchyma tissue was particularly useful due to its susceptibility to several growth substances, including PAs. During tuber dormancy, PA levels are too low to sustain cell division; thus Helianthus represents a natural PA-deficient model. When cultivated in vitro in the presence of auxins, Helianthus tuber dormant parenchyma cells at the G(0) stage start to divide synchronously acquiring meristematic characteristics. The requirement for auxins to induce cell division can be substituted by aliphatic PAs such as putrescine, spermidine or spermine. Cylinders or slices of explanted homogeneous tuber parenchyma were cultured in liquid medium for short-term studies on the cell cycle, or on solid agar medium for long-term experiments. Morphological and physiological modifications of synchronously dividing cells were studied during the different phases of the cell cycle in relation to PAs biosynthesis and oxidation. Long-term experiments led to the identification of the PAs as plant growth regulators, as the sole nitrogen source, as tuber storage substances and as essential factors for morphogenetic processes and cell homeostasis. More recently this system was used to study the effects on plant cell proliferation of platinum- or palladium-derived drugs (cisplatin and platinum or palladium bi-substituted spermine) that are used in human cancer cell lines as antiproliferative and cytotoxic agents. Cisplatin was the most active both in cell proliferation inhibition and on PA metabolism. Similar experiments were performed using three agmatine analogous. Different effects of these compounds were observed on cell proliferation, free PA levels and enzyme activities, leading to a hypothesis of a correlation between their chemical structure and the agmatine metabolism in plants. PMID- 20172736 TI - Imaging of the mechanical heart valve pannus formation with multidetector computerised tomography. PMID- 20172737 TI - Extracts from Alternanthera maritima as natural photosensitizers in photodynamic antimicrobial chemotherapy (PACT). AB - This study investigated the effect of photodynamic antimicrobial chemotherapy (PACT) using extracts from Alternanthera maritima on the viability of Candida dubliniensis. Human infections constitute a great health problem. Several antifungal drugs are currently available, but their uses are limited by a number of factors, such as low potency, poor solubility, microbial resistance, and drug toxicity. Therefore, the search for new and more effective antimicrobial agents and the development of alternative therapies, such as PACT, are necessary. Crude hexane and ethanol extracts of A. maritima were produced. The prepared extracts presented absorption at 650-700 nm. For bioassays, 50 microL of culture medium, 50 microL of extract (25 mg/mL) or control, and 5 microL of a suspension of the microorganism to be tested (C. dubliniensis ATCC 778157 or ATCC 777, 10(7)CFU/mL) were placed in a sterile 96-well microtiter plate (well cross section=0.38 cm(2)). The contents of each well were irradiated with a 685-nm diode laser with an output power of 35 mW, which was distributed through the well cross section yielding an energy dosage of 28 J/cm(2). In each assay (n=6), one plate was subjected to irradiation, and one was not. For each active sample, the number of colony-forming units per milliliter (CFU/mL) was obtained, and data were analyzed by the Tukey test. The chemical compositions of the extracts were determined by chromatographic and spectroscopic techniques. The results suggest inhibition of the growth of C. dubliniensis when irradiated with a diode laser in the presence of hexane and ethanol extracts from A. maritima as photosensitizers. Laser irradiation alone or crude extracts at 25mg/mL did not significantly reduce the number of CFU/mL. Steroids, triterpenes, and flavonoids were identified in the analyzed extracts. In conclusion, the photoactivation of crude hexane and ethanol extracts of A. maritima by red laser radiation at 685 nm promoted an antimicrobial effect, showing that these natural products can be used as photosensitizers in PACT. PMID- 20172739 TI - The role of invariant NKT cells at the interface of innate and adaptive immunity. PMID- 20172738 TI - Cervical remodeling during pregnancy and parturition. AB - Appropriate and timely cervical remodeling is key for successful birth. Premature cervical opening can result in preterm birth which occurs in 12.5% of pregnancies. Research focused on the mechanisms of term and preterm cervical remodeling is essential to prevent prematurity. This review highlights recent findings that better define molecular processes driving progressive disorganization of the cervical extracellular matrix. This includes studies that redefine the role of immune cells and identify diverse functions of the cervical epithelia and hyaluronan in remodeling. New investigations proposing that infection-induced premature cervical remodeling is distinct from the normal process are presented. Recent advances in our understanding of term and preterm cervical remodeling provide new directions for investigation and compel investigators to reevaluate currently accepted models. PMID- 20172740 TI - A noninvasive, log-transform method for fiber type discrimination using mechanomyography. AB - This study examined the log-transformed mechanomyographic (MMG(RMS)) and electromyographic (EMG(RMS)) amplitude vs. force relationships for aerobically trained (AT), resistance-trained (RT), and sedentary (SED) individuals. Subjects performed isometric ramp contractions from 5% to 90% maximal voluntary contraction. Muscle biopsies were collected and thigh skinfolds, MMG and EMG were recorded from the vastus lateralis muscle. Linear regression models were fit to the log-transformed EMG(RMS) and MMG(RMS) vs. force relationships. The slope (b coefficient) and the antilog of the y-intercept (a coefficient) were calculated. The AT group had the highest percentage of type I fiber area, the RT group had the highest percentage of type IIa fiber area, and the SED group had the highest percentage of type IIx fiber area. The a coefficients were higher for the AT group than the RT and SED groups in both the MMG(RMS) and EMG(RMS) vs. force relationships, whereas the b coefficients were lower for the AT group than the RT and SED groups only in the MMG(RMS) vs. force relationship. The group differences among the a coefficients may have reflected subcutaneous fat acting as a filter thereby reducing EMG(RMS) and MMG(RMS). The lower b coefficients for the AT group in the MMG(RMS) patterns may have reflected fiber area-related differences in motor unit activation strategies. PMID- 20172741 TI - Agreement between competing imaging measures of response of hepatocellular carcinoma to yttrium-90 radioembolization. AB - PURPOSE: There are currently at least six major competing criteria used to determine response to yttrium-90 and other liver-directed therapies, including: (i) Response Evaluation Criteria in Solid Tumors (RECIST); (ii) World Health Organization (WHO), (iii) volumetric, (iv) two-dimensional (2D) European Association for the Study of the Liver (EASL), and (v) three-dimensional (3D) EASL criteria; and (vi) functional diffusion-weighted (DW) magnetic resonance (MR) imaging. This study evaluated agreement among these competing tumor response classification schemes based on quantitative measurements of tumor size, necrosis, and changes in water mobility. MATERIALS AND METHODS: In this retrospective study, 20 patients with hepatocellular carcinoma (HCC) underwent (90)Y radioembolization. The patients' tumor burden before and 3-6 months after treatment was assessed with MR imaging. The percent change in size of tumors was used to classify patients into response categories. kappa and agreement statistics were used to compare concordance among the different criteria. RESULTS: Conventional size criteria (RECIST, WHO, and volumetric) all had a substantial level of agreement (kappa = 0.76-0.78) when classifying patients into response categories. However, the conventional size criteria in relation to 2D or 3D EASL had only slight to moderate concurrence, with kappa statistics as low as 0.06. Two-dimensional EASL criteria and functional DW MR imaging resulted in the highest response rates, 55% (n = 11) and 75% (n = 15), respectively, whereas conventional size criteria produced lower response rates. CONCLUSIONS: Classification of HCC response to (90)Y radioembolization is related to which of the competing criteria are used. It is recommended that anatomic imaging criteria be used as the primary method to determine response and functional imaging criteria be used as a complementary secondary method. PMID- 20172742 TI - Radiologic versus endoscopic placement of percutaneous gastrostomy in amyotrophic lateral sclerosis: multivariate analysis of tolerance, efficacy, and survival. AB - PURPOSE: To compare percutaneous radiologic gastrostomy (PRG) and percutaneous endoscopic gastrostomy (PEG) in terms of tolerance, efficacy, and survival in patients with amyotrophic lateral sclerosis (ALS). MATERIALS AND METHODS: Forty patients with ALS (17 men; mean age, 66.1 years; range, 39-83 y) underwent 21 PEG and 22 PRG attempts (including three unsuccessful PEG attempts) from 1999 to 2005. To assess tolerance and efficacy, a successful and well tolerated placement was defined as any successful placement with no major or minor local complications or pain requiring opioid analgesic agents. Univariate analysis was performed for all recorded parameters, followed by multivariate analysis for successful and well tolerated placement, 6-month mortality rate, and survival. RESULTS: General success rates were 85.7% for PEG and 100% for PRG. Pain was more frequent in PRGs (81.8% vs 52.4%; P = .05). Successful and well tolerated placement was seen in 81.8% of PRGs and 57.1% of PEGs (P = 0.1). Advanced age (P = .02) and PRG (P = .07) were predictive of successful and well tolerated placement. The interval from diagnosis to placement (P = .001) and ability to perform spirometry (P = .002) were predictive of survival. Oximetry measurements (P = .007) and interval from diagnosis to placement (P = .02) were predictive of mortality at 6 months. CONCLUSIONS: PRG is more efficacious and better tolerated than PEG, essentially because it avoids the respiratory decompensation that may occur in PEG. Therefore, PRG should be preferred in cases of ALS. Survival is linked to ALS evolution and not to the choice of PRG or PEG placement. PMID- 20172743 TI - The prevalence, risk factors, and clinical outcome of balloon rupture in balloon occluded retrograde transvenous obliteration of gastric varices. AB - PURPOSE: To evaluate the prevalence, risk factors, and clinical outcome after balloon rupture during balloon-occluded retrograde transvenous obliteration (BRTO). MATERIALS AND METHODS: Sixty-nine patients who underwent the BRTO procedure from August 1999 to January 2009 were analyzed retrospectively. The occurrence of balloon rupture was recorded by a review of medical records and imaging studies. The chi(2) test was used to analyze risk factors for balloon rupture including balloon type and size, amount of sclerosant, and the use of microcatheters. The influence of balloon rupture on migration of the sclerosant and in-hospital mortality was analyzed with the Fisher exact test. RESULTS: The prevalence of balloon rupture was 8.7% (six of 69 patients). No significant risk factor for balloon rupture was identified because of the small number of balloon rupture cases. Migration of the sclerosant occurred in three patients with early balloon rupture within 1 hour. One of these patients died of recurrent gastric variceal bleeding and another experienced dyspnea and died of fungal sepsis. Among the 63 patients without rupture, no migration of the sclerosant was noted, and one patient died of sepsis caused by liver abscess. Incidences of sclerosant migration and in-hospital mortality were significantly higher in patients with balloon rupture versus patients without balloon rupture (P = .018 and P < .001, respectively). CONCLUSIONS: Balloon rupture during BRTO occurred in 8.7% of patients. Balloon rupture may cause rapid migration of sclerosant, pulmonary embolism, and recurrent gastric variceal bleeding. PMID- 20172744 TI - Angioplasty and stent placement in symptomatic internal carotid occlusion. AB - PURPOSE: To report a series of patients with symptomatic internal carotid artery (ICA) occlusion treated with angioplasty and stents. MATERIALS AND METHODS: From a consecutive series of 50 patients experiencing neurologic ischemic symptoms and shown by conventional ultrasonography (US) to have a total ICA occlusion, 16 patients (ages 45-79 years; mean, 63 y; 10 men) were selected between August 2006 to September 2008 to be treated with angioplasty based on discovery of an open ICA distal to the occlusion through contrast-enhanced echo Doppler imaging and/or multislice contrast computed tomography (CT). Angioplasty and stent placement were performed under cerebral protection. Follow-up duplex imaging was performed at 14 days and 3 months and every 6 months thereafter and CT follow-up was performed at 2-9 months; the mean follow-up period was 9.9 months. RESULTS: Lesion crossing and stent placement was successful in 13 of 16 patients. There were no deaths, conversions, cardiac complications, or major strokes. One patient had a transient mild hemiparesis in the upper limb, with total recovery in 3 months. At follow-up, all 13 patients with a good initial result remained with patent arterial lumens and resolution of neurologic ischemic symptoms. After 2-9 months, ICAs with a "string sign" had calibers close or equal to those of normal arteries. CONCLUSIONS: Angioplasty with stent placement is an effective treatment with a low morbidity rate for selected patients who continue to experience neurologic ischemic symptoms despite US findings of total occlusion of the ICA. PMID- 20172745 TI - Empiric embolization of a diverticular bleed with CT angiographic mapping: enlarging the therapeutic window of transcatheter arterial intervention. PMID- 20172746 TI - Unusual consequences of status epilepticus in Dravet syndrome. AB - Although status epilepticus (SE) affects the course of Dravet syndrome (DS), it rarely alters dramatically psychomotor outcome. We report an unusual pattern in 3 patients who following refractory SE lasting respectively 2, 7 and 12h experienced persistent and severe cognitive and motor deterioration. We compared these patients to published data and to personal experience in Necker hospital, to find links between severe outcome and clinical features such as treatment or duration of refractory SE. The key point was that anoxoischemic-like lesions appeared on MRI although cardiovascular function had remained stable. Therefore, neither hemodynamic failure, nor abnormalities of cardiac rhythm could explain the lesions and neurological worsening. For theoretical reasons the responsibility of therapy common for the 3 patients, e.g., barbiturates was suspected. PMID- 20172747 TI - Impact of long-term corticosteroid therapy on the distribution pattern of lower limb atherosclerosis. AB - OBJECTIVE: Ectopic calcification and mediacalcinosis can be promoted by corticosteroid use. Aim of the present investigation is to describe macrovascular disease features in patients with long-term corticosteroid therapy and symptomatic lower limb peripheral arterial occlusive disease (PAD). METHODS: A consecutive series of 2783 patients undergoing clinical and angiographic work-up of PAD were screened for long-term (>5 years) corticosteroid use (group A). Comparison was performed to a randomly selected age-, sex- and risk factor matched PAD control cohort from the same series without corticosteroid use (group B). Patients with diabetes mellitus or severe renal failure were excluded. Arterial calcification was evaluated by qualitative assessment on radiographic images. Severity of atherosclerotic lesions was analysed from angiographic images using a semi-quantitative score (Bollinger score). RESULTS: In general, 12 patients (5 males, mean age 78.5 +/- 9.0 years) with 15 ischaemic limbs qualified to be enrolled in group A and were compared to 23 matching control patients (6 2 males, mean age 79.5 +/- 6 years) with 32 ischaemic limbs. Incompressibility of ankle arteries determined by measurement of the ankle-brachial index was seen in 12 limbs (80%) in group A compared to 3 limbs (9%) in group B (p = 0.0009). No significant difference was found comparing group A and B for segmental calcification, whereas comparison of the atherosclerotic burden using the angiographic severity score showed a significantly higher score at the infragenicular arterial level in group A (p = 0.001). CONCLUSION: Findings suggest that the long-term corticosteroid therapy is associated with a distally accentuated, calcifying peripheral atherosclerosis inducing arterial incompressibility. This occlusion pattern is comparable to patients with renal failure or diabetes. Further research is required to support our observations. PMID- 20172748 TI - Fenestrated stent grafting for aortic aneurysm in Europe. PMID- 20172749 TI - Short leukocyte telomere length is associated with abdominal aortic aneurysm (AAA). AB - OBJECTIVE: Telomeres are specialised DNA structures present at the ends of linear chromosomes, which shorten with each successive cell division and the length of which represents cellular biological age. The aim of this study was to determine the relationship between abdominal aortic aneurysm (AAA) and white cell telomere length. METHODS: Peripheral blood samples were collected from 190 patients with AAA and 183 controls. Genomic DNA was extracted from white cells and telomere lengths determined using a chemiluminescence technique. RESULTS: The mean white cell telomere length was significantly lower in AAA patients compared to controls (median age 66 years in both groups), with a mean difference of 189 base pairs (bp) (95% confidence interval 77 bp to 301 bp, P=0.005). This relationship between case-control status and mean telomere restriction fragment (TRF) length did not change after adding other risk factors into a multiple regression model. The risk of having AAA doubled in patients with a mean TRF length in the lowest quartile compared to patients with a mean TRF length in the highest quartile (odds ratio 2.30, 95% Confidence Interval 1.28-4.13, P=0.005). CONCLUSION: Our data show that patients with AAA have shorter leukocyte telomere length compared to controls. This suggests that vascular biological aging may have a role in the pathogenesis of AAA. PMID- 20172750 TI - Magnetic resonance imaging for aortic dissection. PMID- 20172751 TI - Basilic vein transposition: what is the optimal technique? AB - OBJECTIVES: To compare the outcome of the one-stage basilic vein transposition (BVT) fistula with a modified, two-stage technique. DESIGN: Retrospective case controlled study, performed in an academic centre. MATERIAL: A total of 173 candidates for BVT fistula (87 males, mean age 61 years). METHODS: In one-stage BVT, the basilic vein is mobilised through a single incision, placed inside an anterolateral arm tunnel and anastomosed with the brachial artery. In two-stage procedures, the fistula-arterial anastomosis is created first, followed by the second stage, after fistula maturation several weeks later, when the basilic vein is mobilised through two skip incisions, transected near the anastomosis, placed inside an anterolateral arm tunnel and reanastomosed. Morbidity and fistula maturation rate were the main outcome measures. RESULTS: In one-stage BVT (n=76), the incidence of venous hypertension, wound haematomas and all complications (17%, 13% and 43%, respectively) was significantly higher than in two-stage procedures (n=98) (4%, p=0.004, 3%, p=0.012 and 11%, p<0.001, respectively). Time (68 days) to fistula use was significantly decreased in one-stage BVT than in two stage procedures (132 days, p<0.001) but failure to mature rate was equivalent (15% vs. 18%, p=0.49). CONCLUSIONS: Our results indicate that the two-stage BVT fistula through two skip-arm incisions is superior to the established one-stage procedure in terms of less morbidity but at the cost of a second operation and longer time to access use. Further research comparing these two techniques is necessary. Until this issue is resolved, an individualised approach is suggested. PMID- 20172752 TI - Unrecognized basilic vein variation leading to complication during basilic vein transposition arteriovenous fistula creation: case report and implications for access planning. AB - INTRODUCTION: Knowledge about variations of the venous arm anatomy is limited despite its importance for a successful arteriovenous fistula creation. REPORT: We describe a complication of a basilic vein transposition (BVT) resulting from failure to recognize aberrant anatomy. The brachial-basilic junction was located in an unusual position near the antecubital fossa leading to inadvertent distal brachial vein ligation and transposition of basilic and the proximal and unusually unpaired brachial vein. DISCUSSION: This case highlights the prevalence of anomalies of upper extremity veins and the need for thorough Duplex vein mapping before surgery for the preservation and planning of future access. PMID- 20172753 TI - Association of variant alleles of MBL2 gene with vasoocclusive crisis in children with sickle cell anemia. AB - Vasoocclusive crisis (VOC) is the major cause of morbidity and mortality in sickle cell anemia (SCA), which is caused by the occlusion of blood vessels, followed by ischemia or infarct, resulting in progressive damage to organs. However, this clinical manifestation is variable, indicating that this process could be influenced by modifier genes. The gene MBL2 which codes for mannose binding lectin (MBL) has been associated with modifications in the progression of infectious and inflammatory vascular diseases. The aim of this study was to determine the frequency of the polymorphisms of exon 1 (alleles A/O) and promoter region -221 (alleles Y/X) of MBL2 in children with SCA and to verify their association with VOC. The determination of the polymorphism of exon 1 and the promoter region of MBL2 was performed by SYBR GREEN((R)) and Taqman((R)) system, respectively. In the patients with SCA, the frequency of the genotype related to high production of MBL was 0.46 (YA/YA) and for intermediate/low production was 0.54 (YA/XA, XA/XA, YA/YO, XA/YO, YO/YO). The frequency of the genotypes and haplotypes of MBL2 in patients with SCA did not differ from control individuals. The populations were in Hardy-Weinberg equilibrium. The patients were divided into two groups. The groups were separated by the frequency of VOC, which was defined by the total of VOC episodes divided by the age of the children at the end of this study. Since, we choose a cut point in FVOC <1 (n=48) (which we considered of mild presentation of disease) and FVOC >or=1 (n=39) (higher severity). In children with SCA, the frequency of the genotypes of MBL2 of intermediate/low expression for MBL was associated with FVOC >or=1 (p=0.0188 OR=3.15 CI=1.19-8.50). The results suggest that MBL2 polymorphism at promoter and first exon of MBL2 associated with low serum levels and structural alterations of MBL could modify the phenotype of the child with SCA related to VOC. PMID- 20172754 TI - Practical considerations for the design of sparse-spokes pulses. AB - Sparse-spokes pulses are 2D slice-selective pulses that effectively mitigate inhomogeneities in the transmitted RF field and reduce unwanted RF artifacts in MR images. Here we consider the practical design of such pulses for high-field MRI and demonstrate limitations of the technique. We analyze the performance of pulses considering input noise as well as other effects such as saturation and T2( *) relaxation. We discuss in detail the correspondence between the reduction of RF inhomogeneities and the fidelity of the input parameters, such as the transmit B1+ field map and combined phase of the main B0 field and eddy-currents. Results include simulations, utilizing 7 T field maps acquired in phantoms and in vivo, as well as in-vivo experiments. The necessary performance of system hardware components to achieve significant improvements is described. PMID- 20172755 TI - Inborn Errors of Metabolism: the metabolome is our world. Presidential address for the 11th International Congress of Inborn Errors of Metabolism (ICIEM). AB - Thank you for honoring me by allowing me to serve as president of the 11th International Congress of Inborn Errors of Metabolism (ICIEM). The science brought by the IEM community to the Congress was quite impressive and demonstrated the quality of research within this community. In this address, I will consider briefly the history of IEMs to determine how we have arrived where we are, and will spend more time ascertaining our place in the current biomedical community and our role in determining the future of personalized medicine. In the 1950s-1970s new tools were added to expand our ability to interrogate the metabolome and the result was an explosive increase in the number of IEMs. This set the stage for expanded newborn screening (NBS) by tandem mass spectrometry (MS/MS) to identify these patients and to intervene pre-symptomatically. The complexity of the metabolome has led us to utilize the mathematical algorithms of systems biology to reduce high dimensionality data to low dimensionality output. However, the metabolome does not exist in isolation and we must learn how to integrate the metabolome with other xomics. The metabolome is our world and the IEM community has much to share with the broader xomics communities by integrating what we have learned with the other xomics communities. They are seeking access to the metabolome as a closer measure of phenotype, and we are already extremely comfortable and competent in the metabolomic space. But we should not be insular in our occupation of this space. NBS should be the model for personalized medicine, because it is already functioning as testing system for predictive, preventive and personalized care. We have been working in the area of NBS for nearly a half century and have many lessons learned that will be valuable to the practitioners of personalized medicine - lessons that they should not have to rediscover. We must embrace the international IEM community to meet population trends and to improve the care for individuals - children and adults - with IEMs. Demographic projections indicate the countries with largest population growth during the next four decades will be in Asia and we need to work collaboratively to build capacity in the IEM community in Asia and beyond to other underserved regions of the world. PMID- 20172756 TI - Comparison of monitor units calculated by radiotherapy treatment planning system and an independent monitor unit verification software. AB - In radiation therapy, the monitor units (MU) needed to deliver a treatment plan are calculated by treatment planning systems (TPS). The essential part of quality assurance is to verify the MU with independent monitor unit calculation to correct any potential errors prior to the start of treatment. In this study, we have compared the MU calculated by TPS and by independent MU verification software. The MU verification software was commissioned and tested for the data integrity to ensure that the correct beam data was considered for MU calculations. The accuracy of the calculations was tested by creating a series of test plans and comparing them with ion chamber measurements. The results show that there is good agreement between the two. The MU difference (MUdiff) between the monitor unit calculations of TPS and independent MU verification system was calculated for 623 fields from 245 patients and was analyzed by treatment site for head & neck, thorax, breast, abdomen and pelvis. The mean MUdiff of -0.838% with a standard deviation of 3.04% was observed for all 623 fields. The site specific standard deviation of MUdiff was as follows: abdomen and pelvis (<1.75%), head & neck (2.5%), thorax (2.32%) and breast (6.01%). The disparities were analyzed and different correction methods were used to reduce the disparity. PMID- 20172757 TI - [Influence of palmar digital artery patency on neurological recovery of palmar digital nerve lesions]. AB - Should the palmar digital artery be repaired in the pedicular section of the finger? This repair is discussed in the case of a unilateral pedicular lesion on a vascularised finger, and often neglected in current surgical practice. The problem is knowing the role of a permeable artery in sensory recovery and cold intolerance. The author presents a retrospective study on palmar digital nerve reinnervation after section with or without palmar digital artery section. Artery permeability was studied by doppler ultrasonography. Forty nerves in 35 patients were studied after at least 3 years had passed. Twenty-five nerves were associated with a permeable artery, 15 with a non permeable artery. The functional result was evaluated with the Weber test (S2PD) and by the presence or absence of cold intolerance. This work demonstrates the statistically significant role of the palmar digital artery in sensitive recovery quality and cold intolerance appearance. Its permeability ensures a better sensitive result with an 8.84 mm S2PD versus 13.47 mm with a non permeable artery. The benefit of the systematic repair of palmar digital artery is thus demonstrated for the first time. This repair is all the more justified if local conditions are unfavorable, in particular in contuse wounds with associated lesions (tendinous or bone). PMID- 20172758 TI - Excited state structural dynamics and Herzberg-Teller coupling of tetraphenylporphine explored via resonance Raman spectroscopy and density functional theory calculation. AB - Resonance Raman spectra of free-base tetraphenylporphine (TPP) were obtained with 397.9, 416, and 435.7nm excitation wavelengths and density functional calculations were done to elucidate the electronic transitions and the resonance Raman spectra (RRs) of TPP. The RRs indicate that the Franck-Condon region photodynamics for S(0)-->S(4) electronic state is predominantly along the C(m)-ph stretch while that for S(0)-->S(3) electronic state is predominantly along the porphin ring C(beta)C(beta) stretch. Non-totally symmetric vibrational modes were regularly presented in resonance Raman spectra: the shorter the excitation wavelengths were, the stronger intensity the modes had, which can be interpreted in terms of electric dipole transition moments caused by Franck-Condon and Herzberg-Teller coupling. Four non-total symmetry vibrational mode upsilon(52,)upsilon(64), upsilon(97) and upsilon(130) in A(2) irreducible representative of TPP were observed in 397.9, 416 and 435.7nm resonance Raman spectrum. With the shorter wavelength laser excitations at 416 or 397.9nm, the A(2) vibrational modes show more enhanced Raman intensity by comparison with those in the TPP spectrum excited at 435.7nm. PMID- 20172759 TI - Impact of extensive HIV-1 variability on molecular diagnosis in the Congo basin. AB - BACKGROUND: Previous studies have shown a high HIV-1 genetic variability in the Republic of Congo. This can greatly influence the performance of molecular assays for HIV-1 diagnosis. OBJECTIVES: To define a reliable test for detection of HIV-1 DNA in this area. STUDY DESIGN: We compared a commercial nested PCR (C-PCR) assay and an in house nested PCR (H-PCR) assay for the detection of HIV-1 DNA in the first 30 seropositive pregnant women enrolled into the ongoing "Kento-Mwana" project, for the prevention of HIV mother-to-child transmission in the city of Pointe Noire, Republic of Congo, Africa. Sequencing and phylogenetic analysis of partial HIV-1 pol sequences were also performed. RESULTS: C-PCR detected HIV-1 DNA in only 15/30 samples from seropositive women (50.0%), as opposed to 29/30 (96.6%) by H-PCR (P<0.0001). Phylogenetic analysis and bootscanning showed that only 10 sequences could be assigned to known clades (seven pure subtypes and three circulating recombinant forms), whereas the other 20 sequences were unique recombinant forms. CONCLUSIONS: The great genetic variability of HIV-1 in this area strongly advises to for using molecular methods only after local validation to avoid false negative results. PMID- 20172760 TI - Microsatellite analysis of HSV-1 isolates: from oropharynx reactivation toward lung infection in patients undergoing mechanical ventilation. AB - BACKGROUND: According to recent reports, herpes simplex virus type 1 (HSV-1) induces bronchopneumonitis (BPn) in immunocompetent patients undergoing prolonged mechanical ventilation (MV), whose respiratory functions deteriorate with a poor outcome. HSV-1 BPn is associated with HSV symptomatic or symptomless reactivation in the oropharynx. OBJECTIVES: We sought to systematically and genetically characterize HSV-1 strains isolated from immunocompetent patients receiving prolonged MV and to characterize the genetic relationship of strains sequentially isolated from oropharyngeal samples (OPS) and broncho-alveolar liquids (BAL) to determine the natural course of HSV BPn. STUDY DESIGN: In this molecular epidemiological study, microsatellite technology was used to determine genetic relationships between 211 HSV-1 strains isolated from OPS and/or BAL from 106 patients receiving MV. RESULTS: Microsatellite haplotypes of HSV-1 strains sequentially isolated from the same individual were identical, and HSV-1 isolates from the lung were genetically indistinguishable from strains isolated from the oral cavity. Each patient was characterized by their own HSV-1 microsatellite haplotype, and no nosocomial transmission of strains between patients was observed. CONCLUSION: Our results demonstrate that, in patients who receive MV, the HSV-1 pulmonary infection results from the reactivation of genetically related HSV-1 in the oropharynx, which progressively infects the lower respiratory tract. PMID- 20172761 TI - Pharmacology of TNF blockade in rheumatoid arthritis and other chronic inflammatory diseases. AB - Tumor necrosis factor-alpha (TNF) has been unequivocally validated as a therapeutic target in a number of immune-mediated inflammatory disorders (IMIDs). There is now increasing choice of biologic agents within the class all of which successfully neutralize sTNF. But approaches to TNF inhibition differ and currently include mAbs (infliximab, adalimumab, and golimumab), either chimeric or human in sequence, a PEGylated Fab' fragment (certolizumab), and an IgG1-TNFR2 fusion protein (etanercept). It is emerging that the pharmacological properties of these three anti-TNF subtypes differ with respect to Fc function, binding of tmTNF and the possible consequences of this, as well as the ability to form complexes. The mode of administration of each agent, clearance and the local tissue concentrations achieved may also confer unique characteristics of relevance with respect to efficacy and safety. PMID- 20172762 TI - Epidemiologic and zoonotic aspects of ascarid infections in dogs and cats. AB - Toxocaracanis and Toxocara cati of dogs and cats, respectively, can cause significant disease in people. Human seroprevalence for Toxocara antibodies varies with factors such as geographic location, socio-economic status, and dietary habits. Risk factors for infection include geophagia and low-level education. Toxocara canis is better recognized as a cause of human toxocariasis, but Toxocara cati should not be overlooked. In addition, patent infections with Baylisascaris procyonis, the raccoon ascarid, have been increasingly recognized in dogs. Pet owners need to be properly educated about zoonotic risks, and veterinarians should institute regular parasite screening and treatment for all pets. Establishment of national surveillance programs to determine the incidence and specific etiological agent in human larva migrans patients would aid in the development of targeted intervention strategies. PMID- 20172763 TI - Single-stage dorsal inlay full-thickness genital skin grafts for hypospadias reoperations: extended follow up. AB - PURPOSE: To report our extended experience with single-stage genital skin graft urethroplasty for complex hypospadias reoperations. MATERIALS AND METHODS: Thirty one patients with failed hypospadias surgery were included. The urethral plate had been removed or was scarred in all. After excision of fibrotic tissue a free full-thickness skin graft was quilted to the corpora cavernosa. The neourethra was then tubularized followed by glanuloplasty. Voiding cystograms, urethral ultrasound and flow measurements were performed in all. Outcome was considered a failure when postoperative instrumentation was needed. RESULTS: Follow up was 78.45 +/- 18.18 months. Shaft skin was used in 13 and internal prepuce in 18. Average graft length was 3.66 +/-1.56cm. Eighteen patients required glanuloplasty. Initial graft healing was successful in all. There was no postoperative infection involving the inlay. We did not note complications from the graft donor sites. Four patients underwent redo surgery yielding a complication rate of 12.9%. Urethral stricture of the proximal anastomosis was most frequent. CONCLUSIONS: This single-stage approach using dorsal inlay skin grafts is reliable, creating a substitute urethral plate in the long term. Complication rates are equivalent to those of staged strategies. This is a safe option for hypospadias reoperations if the urethral plate is compromised. PMID- 20172764 TI - More than just SCID--the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2. AB - Combined immunodeficiencies with impaired numbers and function of T- and B-cells can be attributed to defects in the recombinase activating genes (RAG). The products of these genes, the RAG1 and 2 proteins, are key players in the V(D)J recombination process leading to the assembly of antigen receptor genes. Complete RAG deficiency (RAGD) with no V(D)J (<1% recombination activity of wild type) is associated with classical SCID and absence of T- and B-cells. In RAGD with residual V(D)J activity (>1% recombination activity of wild type), several clinical and immunological subtypes have been described: RAGD with skin inflammation and alphabeta T-cell expansion (classical Omenn syndrome), RAGD with skin inflammation and without T-cell expansion (incomplete Omenn syndrome), RAGD with gammadelta T-cell expansion and RAGD with granulomas. Engraftment of maternal T-cells can add to variation in phenotype. The potential role of epigenetic factors that influence the emergence of these phenotypes is discussed. Thorough assessment and interpretation of clinical and immunological findings will guide treatment modalities as intense as hematopoietic stem cell transplantation. PMID- 20172765 TI - Determination of GDC-0449, a small-molecule inhibitor of the Hedgehog signaling pathway, in human plasma by solid phase extraction-liquid chromatographic-tandem mass spectrometry. AB - To support clinical development, a solid phase extraction (SPE) liquid chromatographic-tandem mass spectrometry (LC-MS/MS) method for the determination of GDC-0449 concentrations in human plasma has been developed and validated. Samples (200 microl) were extracted using an Oasis MCX 10 mg 96-well SPE plate and the resulting extracts were analyzed using reverse-phase chromatography coupled with a turbo-ionspray interface. The method was validated over calibration curve range 5-5000 ng/mL. Quadratic regression and 1/x(2) weighing were used. Within-run relative standard deviation (%RSD) was within 10.1% and accuracy ranged from 88.6% to 109.0% of nominal. Between-run %RSD was within 8.6% and accuracy ranged from 92.4% to 105.3% of nominal. Extraction recovery of GDC 0449 was between 88.3% and 91.2% as assessed using quality control sample concentrations. GDC-0449 was stable in plasma for 315 days when stored at -70 degrees C and stable in reconstituted sample extracts for 117 h when stored at room temperature. Quantitative matrix effect/ion suppression experiment was performed and no significant matrix ion suppression was observed. This assay allows for the determination of GDC-0449 plasma concentrations over a sufficient time period to determine pharmacokinetic parameters at relevant clinical doses. PMID- 20172766 TI - Simultaneous quantitation of perfluoroalkyl acids in human serum and breast milk using on-line sample preparation by HPLC column switching coupled to ESI-MS/MS. AB - A high throughput analytical method using a column switching high-performance liquid chromatography combined with isotope dilution tandem mass spectrometry (column switching-HPLC-MS/MS) was developed to simultaneously quantitate the concentrations of 7 perfluoroalkyl acids (PFAAs) in serum and 3 PFAAs in breast milk samples. The sample preparation includes addition of the isotope-labelled internal standard solution to breast milk and serum, enzymatic hydrolysis and filtration of milk samples, precipitation of proteins and analysis by column switching-HPLC-MS/MS. The limits of quantitation ranged from 0.1 to 0.4 MUg/l for serum and 0.02 to 0.15 MUg/l for breast milk samples. The method accuracies ranged between 73.2% and 100.2% for the different analytes at two concentrations in PFAAs spiked samples. The validity of the method was confirmed by analysing 20 serum and 20 breast milk samples. PMID- 20172767 TI - Quantification of nortriptyline in plasma by HPLC and fluorescence detection. AB - A simple, sensitive and specific high-performance liquid chromatography method has been developed for the determination of nortriptyline (NT) in plasma samples. The assay involved derivatization with 9H-fluoren-9-ylmethyl chloroformate (Fmoc Cl) and isocratic reversed-phase (C(18)) chromatography with fluorescence detection. The developed method required only 100 microl of plasma sample, deproteinized and derivatized in one step. Calibration curves were lineal over the concentration range of 5-5000 ng/ml. The derivatization reaction was performed at room temperature in 20 min and the obtained NT derivative was stable for at least 48 h at room temperature. The within-day and between-day relative standard deviation was below 8%. The limit of detection (LOD) was 2 ng/ml, and the lower limit of quantification (LLOQ) was established at 10 ng/ml. The method was applied on plasma collected from rats, at different time intervals, after intravenous administration of 0.5 mg of NT. PMID- 20172768 TI - Stable adducts of nerve agents sarin, soman and cyclosarin with TRIS, TES and related buffer compounds--characterization by LC-ESI-MS/MS and NMR and implications for analytical chemistry. AB - Buffering compounds like TRIS are frequently used in chemical, biochemical and biomedical applications to control pH in solution. One of the prerequisites of a buffer compound, in addition to sufficient buffering capacity and pH stability over time, is its non-reactivity with other constituents of the solution. This is especially important in the field of analytical chemistry where analytes are to be determined quantitatively. Investigating the enzymatic hydrolysis of G-type nerve agents sarin, soman and cyclosarin in buffered solution we have identified stable buffer adducts of TRIS, TES and other buffer compounds with the nerve agents. We identified the molecular structure of these adducts as phosphonic diesters using 1D (1)H-(31)P HSQC NMR and LC-ESI-MS/MS techniques. Reaction rates with TRIS and TES are fast enough to compete with spontaneous hydrolysis in aqueous solution and to yield substantial amounts (up to 20-40%) of buffer adduct over the course of several hours. A reaction mechanism is proposed in which the amino function of the buffer serves as an intramolecular proton acceptor rendering the buffer hydroxyl groups nucleophilic enough for attack on the phosphorus atom of the agents. Results show that similar buffer adducts are formed with a range of hydroxyl and amino function containing buffers including TES, BES, TRIS, BIS-TRIS, BIS-TRIS propane, Tricine, Bicine, HEPES and triethanol amine. It is recommended to use alternative buffers like MOPS, MES and CHES when working with G-type nerve agents especially at higher concentrations and over prolonged times. PMID- 20172769 TI - The original sin of oesophageal mucosa. PMID- 20172770 TI - Contrast-enhanced ultrasonography in evaluating hepatic metastases from neuroendocrine tumours. AB - OBJECTIVES: At presentation, gastroenteropancreatic neuroendocrine tumours (GEP NETs) frequently show prognostically negative hepatic involvement. The aim of this study was to characterise hepatic metastases of GEP NETs as revealed by contrast-enhanced ultrasonography (CEUS), which allows the fine definition of the microvascular system, and to correlate these findings to the biological behaviour of the tumour. METHODS: Eighteen out of 62 GEP NET patients examined between January 2007 and September 2008 had histologically proven hepatic metastases from primary ileal (#6), gastric (#1) or rectal (#1) carcinoids, pancreatic tumours (#7), or primary duodenal (#2) or occult gastrinomas (#1), and all underwent low mechanical index real-time CEUS with SonoVue injection. RESULTS: Strong early enhancement in the arterial phase was observed in 15 cases (83%), and a rapid wash-out in the portal venous phase in 14 (78%). In the late venous phase, the lesions were hypoechoic in 12 cases (67%), isoechoic in five (28%), and hyperechoic in one (0.05%). The time of arterial enhancement correlated with the Ki-67 proliferative index (r(s)=0.516; p=0.028). CONCLUSIONS: Most of the neuroendocrine liver metastases showed increased arterial enhancement at CEUS, a behaviour that is similar to that of hepatocellular carcinomas and the opposite of that of other metastases. CEUS can be a useful diagnostic means of characterising such metastases. PMID- 20172771 TI - Cooperative genotyping for Helicobacter pylori virulence determinants strengthens the predictive value of gastric cancer risk assessment. PMID- 20172772 TI - Update on primary sclerosing cholangitis. AB - Early studies in primary sclerosing cholangitis (PSC) were concerned with disease characterization, and were followed by epidemiological studies of PSC and clinical subsets of PSC as well as a large number of treatment trials. Recently, the molecular pathogenesis and the practical handling of the patients have received increasing attention. In the present review we aim to give an update on the pathogenesis of PSC and cholangiocarcinoma in PSC, as well as to discuss the current opinion on diagnosis and treatment of PSC in light of the recent European Association for the Study of the Liver and the American Association for the Study of Liver Diseases practice guidelines. PMID- 20172773 TI - An application of multidimensional time-frequency analysis as a base for the unified watermarking approach. AB - A watermarking approach based on multidimensional time-frequency analysis is proposed. It represents a unified concept that can be used for different types of data such as audio, speech signals, images or video. Time-frequency analysis is employed for speech signals, while space/spatial-frequency analysis is used for images. Their combination is applied for video signals. Particularly, we focus on the 2-D case: space/spatial-frequency based image watermarking procedure that will be subsequently extended to video signal. A method that selects coefficients for watermarking by estimating the local frequency content is proposed. In order to provide watermark imperceptibility, the nonstationary filtering is used to model the watermark which corresponds to the host signal components. Furthermore, the watermark detection within the multidimensional time-frequency domain is proposed. The efficiency and robustness of the procedure in the presence of various attacks is proven experimentally. PMID- 20172774 TI - Quantitative analysis of protective effect of erythropoietin on diabetic retinal cells using molecular hyperspectral imaging technology. AB - A molecular hyperspectral imaging (MHI) system was developed to evaluate the protective effects of erythropoietin (EPO) on early diabetic retinopathy in rats. The system was used to capture hyperspectral images of rat retinal sections selected from three groups: normal control, diabetic, and EPO. Three biochemical parameters were defined, namely, the spectral transmittance index, thickness of outer nuclear layer, and cell area percentage. The corresponding algorithms to calculate these were likewise presented. Experimental results show that, after treatment, the newly defined biochemical parameters of the EPO group become more similar to those of the normal control group compared with those of the diabetic group. This indicates that, to some degree, EPO provides protective effects on the retinal cells of chemically induced diabetic rats after it is injected intravitreally at the onset of diabetes. The results likewise show that the MHI system could provide useful quantitative information regarding retinal sections, which ophthalmologists can use to determine the pathogenesis of diabetic retinopathy and evaluate the protective effect of EPO on diabetic retinal cells. PMID- 20172775 TI - Prediction of acoustic feature parameters using myoelectric signals. AB - It is well-known that a clear relationship exists between human voices and myoelectric signals (MESs) from the area of the speaker's mouth. In this study, we utilized this information to implement a speech synthesis scheme in which MES alone was used to predict the parameters characterizing the vocal-tract transfer function of specific speech signals. Several feature parameters derived from MES were investigated to find the optimal feature for maximization of the mutual information between the acoustic and the MES features. After the optimal feature was determined, an estimation rule for the acoustic parameters was proposed, based on a minimum mean square error (MMSE) criterion. In a preliminary study, 60 isolated words were used for both objective and subjective evaluations. The results showed that the average Euclidean distance between the original and predicted acoustic parameters was reduced by about 30% compared with the average Euclidean distance of the original parameters. The intelligibility of the synthesized speech signals using the predicted features was also evaluated. A word-level identification ratio of 65.5% and a syllable-level identification ratio of 73% were obtained through a listening test. PMID- 20172776 TI - A computer-aided diagnosis system of nuclear cataract. AB - Cataracts are the leading cause of blindness worldwide, and nuclear cataract is the most common form of cataract. An algorithm for automatic diagnosis of nuclear cataract is investigated in this paper. Nuclear cataract is graded according to the severity of opacity using slit lamp lens images. Anatomical structure in the lens image is detected using a modified active shape model. On the basis of the anatomical landmark, local features are extracted according to clinical grading protocol. Support vector machine regression is employed for grade prediction. This is the first time that the nucleus region can be detected automatically in slit lamp images. The system is validated using clinical images and clinical ground truth on >5000 images. The success rate of structure detection is 95% and the average grading difference is 0.36 on a 5.0 scale. The automatic diagnosis system can improve the grading objectivity and potentially be used in clinics and population studies to save the workload of ophthalmologists. PMID- 20172777 TI - A simulation tool to study high-frequency chest compression energy transfer mechanisms and waveforms for pulmonary disease applications. AB - High-frequency chest compression (HFCC) can be used as a therapeutic intervention to assist in the transport and clearance of mucus and enhance water secretion for cystic fibrosis patients. An HFCC pump-vest and half chest-lung simulation, with 23 lung generations, has been developed using inertance, compliance, viscous friction relationships, and Newton's second law. The simulation has proven to be useful in studying the effects of parameter variations and nonlinear effects on HFCC system performance and pulmonary system response. The simulation also reveals HFCC waveform structure and intensity changes in various segments of the pulmonary system. The HFCC system simulation results agree with measurements, indicating that the HFCC energy transport mechanism involves a mechanically induced pulsation or vibration waveform with average velocities in the lung that are dependent upon small air displacements over large areas associated with the vest-chest interface. In combination with information from lung physiology, autopsies and a variety of other lung modeling efforts, the results of the simulation can reveal a number of therapeutic implications. PMID- 20172778 TI - Differential evolution approach for regularized bioluminescence tomography. AB - Bioluminescence tomography (BLT) is an inverse source problem that localizes and quantifies bioluminescent probe distribution in 3-D. The generic BLT model is ill posed, leading to nonunique solutions and aberrant reconstruction in the presence of measurement noise and optical parameter mismatches. In this paper, we introduce the knowledge of the number of bioluminescence sources to stabilize the BLT problem. Based on this regularized BLT model, we develop a differential evolution-based reconstruction algorithm to determine the source locations and strengths accurately and reliably. Then, we evaluate this novel approach in numerical, phantom, and mouse studies. PMID- 20172779 TI - Estimation of three- and four-element windkessel parameters using subspace model identification. AB - A windkessel model is widely used to operationalize vascular characteristics. In this paper, we employ a noniterative subspace model identification (SMI) algorithm to estimate parameters in a three- and four-element windkessel model by application of physical foreknowledge. Simulation data of the systemic circulation were used to investigate systematic and random errors in the parameter estimations. Results were compared with different methods as proposed in the literature: one closed-loop and two iterative methods for the three element model, and one iterative method for the four-element model. For the three element model, no significant systematic errors were observed using SMI. Concerning random errors, SMI appeared more robust in parameter estimations compared with the other methods (P < 0.05 for a signal-to-noise ratio of 18 dB). For the four-element model, a significant systematic error in the estimate of the arterial inertance L was observed (P = 0.011). However, for all methods, an increasing number of outliers in parameter estimates were observed at increased noise levels. These outliers were almost exclusive due to errors in estimates of L. In conclusion, with SMI physical parameters can mathematically be derived by application of physiological foreknowledge. For a three-element windkessel model, SMI appeared a very robust method to estimate parameters. However, application to a four-element windkessel model was less accurate because of low identifiability of L. Therefore, based on the simulation results, the use of the four-element windkessel model is questionable. PMID- 20172780 TI - Expectation-maximization-driven geodesic active contour with overlap resolution (EMaGACOR): application to lymphocyte segmentation on breast cancer histopathology. AB - The presence of lymphocytic infiltration (LI) has been correlated with nodal metastasis and tumor recurrence in HER2+ breast cancer (BC). The ability to automatically detect and quantify extent of LI on histopathology imagery could potentially result in the development of an image based prognostic tool for human epidermal growth factor receptor-2 (HER2+) BC patients. Lymphocyte segmentation in hematoxylin and eosin (H&E) stained BC histopathology images is complicated by the similarity in appearance between lymphocyte nuclei and other structures (e.g., cancer nuclei) in the image. Additional challenges include biological variability, histological artifacts, and high prevalence of overlapping objects. Although active contours are widely employed in image segmentation, they are limited in their ability to segment overlapping objects and are sensitive to initialization. In this paper, we present a new segmentation scheme, expectation maximization (EM) driven geodesic active contour with overlap resolution (EMaGACOR), which we apply to automatically detecting and segmenting lymphocytes on HER2+ BC histopathology images. EMaGACOR utilizes the expectation-maximization algorithm for automatically initializing a geodesic active contour (GAC) and includes a novel scheme based on heuristic splitting of contours via identification of high concavity points for resolving overlapping structures. EMaGACOR was evaluated on a total of 100 HER2+ breast biopsy histology images and was found to have a detection sensitivity of over 86% and a positive predictive value of over 64%. By comparison, the EMaGAC model (without overlap resolution) and GAC model yielded corresponding detection sensitivities of 42% and 19%, respectively. Furthermore, EMaGACOR was able to correctly resolve over 90% of overlaps between intersecting lymphocytes. Hausdorff distance (HD) and mean absolute distance (MAD) for EMaGACOR were found to be 2.1 and 0.9 pixels, respectively, and significantly better compared to the corresponding performance of the EMaGAC and GAC models. EMaGACOR is an efficient, robust, reproducible, and accurate segmentation technique that could potentially be applied to other biomedical image analysis problems. PMID- 20172781 TI - Fully wireless implantable cardiovascular pressure monitor integrated with a medical stent. AB - This paper presents a fully wireless cardiac pressure sensing system. Food and Drug Administration (FDA) approved medical stents are explored as radiating structures to support simultaneous transcutaneous wireless telemetry and powering. An application-specific integrated circuit (ASIC), designed and fabricated using the Texas Instruments 130-nm CMOS process, enables wireless telemetry, remote powering, voltage regulation, and processing of pressure measurements from a microelectromechanical systems (MEMS) capacitive sensor. This paper demonstrates fully wireless-pressure-sensing functionality with an external 35-dB.m RF powering source across a distance of 10 cm. Measurements in a regulated pressure chamber demonstrate the ability of the cardiac system to achieve pressure resolutions of 0.5 mmHg over a range of 0-50 mmHg using a channel data-rate of 42.2 kb/s. PMID- 20172782 TI - Thyroid segmentation and volume estimation in ultrasound images. AB - Physicians usually diagnose the pathology of the thyroid gland by its volume. However, even if the thyroid glands are found and the shapes are hand-marked from ultrasound (US) images, most physicians still depend on computed tomography (CT) images, which are expensive to obtain, for precise measurements of the volume of the thyroid gland. This approach relies heavily on the experience of the physicians and is very time consuming. Patients are exposed to high radiation when obtaining CT images. In contrast, US imaging does not require ionizing radiation and is relatively inexpensive. US imaging is thus one of the most commonly used auxiliary tools in clinical diagnosis. The present study proposes a complete solution to estimate the volume of the thyroid gland directly from US images. The radial basis function neural network is used to classify blocks of the thyroid gland. The integral region is acquired by applying a specific-region growing method to potential points of interest. The parameters for evaluating the thyroid volume are estimated using a particle swarm optimization algorithm. Experimental results of the thyroid region segmentation and volume estimation in US images show that the proposed approach is very promising. PMID- 20172783 TI - Characterizing nonlinear heartbeat dynamics within a point process framework. AB - Human heartbeat intervals are known to have nonlinear and nonstationary dynamics. In this paper, we propose a model of R-R interval dynamics based on a nonlinear Volterra-Wiener expansion within a point process framework. Inclusion of second order nonlinearities into the heartbeat model allows us to estimate instantaneous heart rate (HR) and heart rate variability (HRV) indexes, as well as the dynamic bispectrum characterizing higher order statistics of the nonstationary non gaussian time series. The proposed point process probability heartbeat interval model was tested with synthetic simulations and two experimental heartbeat interval datasets. Results show that our model is useful in characterizing and tracking the inherent nonlinearity of heartbeat dynamics. As a feature, the fine temporal resolution allows us to compute instantaneous nonlinearity indexes, thus sidestepping the uneven spacing problem. In comparison to other nonlinear modeling approaches, the point process probability model is useful in revealing nonlinear heartbeat dynamics at a fine timescale and with only short duration recordings. PMID- 20172784 TI - Mechanical characterization of atherosclerotic arteries using finite-element modeling: feasibility study on mock arteries. AB - Clinical studies on lipid-lowering therapy have shown that changing the composition of lipid pools reduced significantly the risk of cardiac events associated with plaque rupture. It has been shown also that changing the composition of the lipid pool affects its mechanical properties. However, knowledge about the mechanical properties of human atherosclerotic lesions remains limited due to the difficulty of the experiments. This paper aims to assess the feasibility of characterizing a lipid pool embedded in the wall of a pressurized vessel using finite-element simulations and an optimization algorithm. Finite-element simulations of inflation experiments were used together with nonlinear least squares algorithm to estimate the material model parameters of the wall and of the inclusion. An optimal fit of the simulated experiment and the real experiment was sought with the parameter estimation algorithm. The method was first tested on a single-layer polyvinyl alcohol (PVA) cryogel stenotic vessel, and then, applied on a double-layered PVA cryogel stenotic vessel with a lipid inclusion. PMID- 20172785 TI - Intuitionistic fuzzy segmentation of medical images. AB - This paper proposes a novel and probably the first method, using Attanassov intuitionistic fuzzy set theory to segment blood vessels and also the blood cells in pathological images. This type of segmentation is very important in detecting different types of human diseases, e.g., an increase in the number of vessels may lead to cancer in prostates, mammary, etc. The medical images are not properly illuminated, and segmentation in that case becomes very difficult. A novel image segmentation approach using intuitionistic fuzzy set theory and a new membership function is proposed using restricted equivalence function from automorphisms, for finding the membership values of the pixels of the image. An intuitionistic fuzzy image is constructed using Sugeno type intuitionistic fuzzy generator. Local thresholding is applied to threshold medical images. The results showed a much better performance on poor contrast medical images, where almost all the blood vessels and blood cells are visible properly. There are several fuzzy and intuitionistic fuzzy thresholding methods, but these methods are not related to the medical images. To make a comparison with the proposed method with other thresholding methods, the method is compared with six nonfuzzy, fuzzy, and intuitionistic fuzzy methods. PMID- 20172786 TI - Heart rate variability on 7-day Holter monitoring using a bootstrap rhythmometric procedure. AB - Heart rate variability (HRV) markers have been widely used to characterize the autonomous regulation state of the heart from 24-h Holter monitoring, but long term evolution of HRV indexes is mostly unknown. A dataset of 7-day Holter recordings of 22 patients with congestive heart failure was studied. A rhythmometric procedure was designed to characterize the infradian, circadian, and ultradian components for each patient, as well as circadian and ultradian fluctuations. Furthermore, a bootstrap test yielded automatically the rhythmometric model for each patient. We analyzed the temporal evolution of relevant time-domain (AVNN, SDNN, and NN50), frequency-domain (LF, HF, HFn, and LF/HF), and nonlinear (alpha(1) and SampEn) HRV indexes. Circadian components were the most significant for all HRV indexes, but the infradian ones were also strongly present in NN50, HFn, LF/HF, alpha(1), and SampEn indexes. Among ultradian components that one corresponding to 12 h, was the most relevant. Long term monitoring of HRV conveys new potentially relevant rhythmometric information, which can be analyzed by using the proposed automatic procedure. PMID- 20172787 TI - Array-gain constraint minimum-norm spatial filter with recursively updated gram matrix for biomagnetic source imaging. AB - This paper proposes a novel spatial filter for biomagnetic source imaging. The proposed spatial filter is derived based on a modified version of the minimum norm spatial filter and is designed to have a performance close to that of the adaptive minimum-variance spatial filter through the use of an estimated covariance matrix. In this method, the theoretical form of the measurement covariance matrix is estimated as an updated gram matrix in a recursive procedure. Since the proposed method does not use the sample covariance matrix, it is free of the well-known weaknesses of the minimum-variance spatial filter, namely, the proposed spatial filter does not require a large number of time samples, and it can even be applied to single-time-sample data. It is also robust to source correlation. We have validated the method's effectiveness by our computer simulations as well as through experiments using auditory-evoked magnetoencephalographic data. PMID- 20172788 TI - A self-propelled inflatable earthworm-like endoscope actuated by single supply line. AB - Design of a self-propelling endoscope has been of interest for decades, as it allows for simplified medical examination techniques and improved patient comfort, together with advanced analysis capacity. In this paper, we describe the development of a fully automatic, multiple-balloon system achieving peristaltic locomotion, controlled by a single supply channel. The system employs the nonlinear pressure-radius characteristics of elastic balloons to simultaneously control numerous balloons with a constant inlet pressure. The balloons are connected in series and the flow is controlled by small orifices, which delay the flow between them. The proposed multiple-balloon system requires no moving parts, no electronics, and relies on dynamics of the fluid flow between serially interconnected inflatable balloons. The entire system is made of disposable silicone and is plastic-modeled by injection molding. Additionally, the cost of such a system is expected to be low and suitable for numerous biomedical applications as it can be easily scaled down due to the need for only one supply line. Mathematical modeling, and simulation and experimental results of a system prototype are presented in this paper. Experimental results in the straight cylinder show close correlation to simulated system. PMID- 20172789 TI - Electronic cleansing for computed tomography (CT) colonography using a scale invariant three-material model. AB - A well-known reading pitfall in computed tomography (CT) colonography is posed by artifacts at T-junctions, i.e., locations where air-fluid levels interface with the colon wall. This paper presents a scale-invariant method to determine material fractions in voxels near such T-junctions. The proposed electronic cleansing method particularly improves the segmentation at those locations. The algorithm takes a vector of Gaussian derivatives as input features. The measured features are made invariant to the orientation-dependent apparent scale of the data and normalized in a way to obtain equal noise variance. A so-called parachute model is introduced that maps Gaussian derivatives onto material fractions near T-junctions. Projection of the noisy derivatives onto the model yields improved estimates of the true, underlying feature values. The method is shown to render an accurate representation of the object boundary without artifacts near junctions. Therefore, it enhances the reading of CT colonography in a 3-D display mode. PMID- 20172790 TI - A novel metric for bone marrow cells chromosome pairing. AB - Karyotyping is a set of procedures, in the scope of the cytogenetics, that produces a visual representation of the 46 chromosomes observed during the metaphase step of the cellular division, called mitosis, paired and arranged in decreasing order of size. Automatic pairing of bone marrow cells is a difficult task because these chromosomes appear distorted, overlapped, and their images are usually blurred with undefined edges and low level of detail. In this paper, a new metric is proposed to compare this type of chromosome images toward the design of an automatic pairing algorithm for leukemia diagnostic purposes. Besides the features used in the traditional karyotyping procedures, a new feature, based on mutual information , is proposed to increase the discriminate power of the G-banding pattern dissimilarity between chromosomes and improve the performance of the classifier. The pairing algorithm is formulated as a combinatorial optimization problem where the distances between homologous chromosomes are minimized and the distances between nonhomologous ones are maximized. The optimization task is solved by using an integer programming approach. A new bone marrow chromosome dataset--Lisbon-K1 (LK1) chromosome dataset with 9200 chromosomes---was build for this study. These chromosomes have much lower quality than the classic Copenhagen, Edinburgh, and Philadelphia datasets, and its classification and pairing is therefore more difficult. Experiments using real images from the LK(1) and Grisan et al. datasets based on a leave-one-out cross-validation strategy are performed to test and validate the pairing algorithm. PMID- 20172791 TI - 3-D augmented reality for MRI-guided surgery using integral videography autostereoscopic image overlay. AB - A 3-D augmented reality navigation system using autostereoscopic images was developed for MRI-guided surgery. The 3-D images are created by employing an animated autostereoscopic image, integral videography (IV), which provides geometrically accurate 3-D spatial images and reproduces motion parallax without using any supplementary eyeglasses or tracking devices. The spatially projected 3 D images are superimposed onto the surgical area and viewed via a half-silvered mirror. A fast and accurate spatial image registration method was developed for intraoperative i.v. image-guided therapy. Preliminary experiments showed that the total system error in patient-to-image registration was 0.90 +/- 0.21 mm, and the procedure time for guiding a needle toward a target was shortened by 75%. An animal experiment was also conducted to evaluate the performance of the system. The feasibility studies showed that augmented reality of the image overlay system could increase the surgical instrument placement accuracy and reduce the procedure time as a result of intuitive 3-D viewing. PMID- 20172792 TI - Double-edge detection of radiographic lumbar vertebrae images using pressurized open DGVF snakes. AB - The detection of double edges in X-ray images of lumbar vertebrae is of prime importance in the assessment of vertebral injury or collapse that may be caused by osteoporosis and other spine pathology. In addition, if the above double-edge detection process is conducted within an automatic framework, it would not only facilitate inexpensive and fast means of obtaining objective morphometric measurements on the spine, but also remove the human subjectivity involved in the morphometric analysis. This paper proposes a novel force-formulation scheme, termed as pressurized open directional gradient vector flow snakes, to discriminate and detect the superior and inferior double edges present in the radiographic images of the lumbar vertebrae. As part of the validation process, this algorithm is applied to a set of 100 lumbar images and the detection results are quantified using analyst-generated ground truth. The promising nature of the detection results bears testimony to the efficacy of the proposed approach. PMID- 20172793 TI - Digestive activity evaluation by multichannel abdominal sounds analysis. AB - This paper introduces a complete methodology for abdominal sounds analysis, from signal acquisition to statistical data analysis. The goal is to evaluate if and how phonoenterograms can be used to detect different functioning modes of the normal gastrointestinal tract, both in terms of localization and of time evolution during the digestion. After the description of the acquisition protocol and the employed instrumentation, several signal processing steps are presented: wavelet denoising and segmentation, artifact suppression, and source localization. Next, several physiological features are extracted from the processed signals issued from a database of 14 healthy volunteers, recorded during 3 h after a standardized meal. Data analysis is performed using a multifactorial statistical method. Based on the introduced approach, we show that the abdominal regions of healthy volunteers present statistically significant phonoenterographic characteristics, which evolve differently during the normal digestion. The most significant feature allowing us to distinguish regions and time differences is the number of recorded sounds, but important information is also carried by sound amplitudes, frequencies, and durations. Depending on the considered feature, the sounds produced by different abdominal regions (especially stomach, ileocaecal, and lower abdomen regions) present a specific distribution over space and time. This information, statistically validated, is usable in further studies as a comparison term with other normal or pathological conditions. PMID- 20172795 TI - Application of covariate shift adaptation techniques in brain-computer interfaces. AB - A phenomenon often found in session-to-session transfers of brain-computer interfaces (BCIs) is nonstationarity. It can be caused by fatigue and changing attention level of the user, differing electrode placements, varying impedances, among other reasons. Covariate shift adaptation is an effective method that can adapt to the testing sessions without the need for labeling the testing session data. The method was applied on a BCI Competition III dataset. Results showed that covariate shift adaptation compares favorably with methods used in the BCI competition in coping with nonstationarities. Specifically, bagging combined with covariate shift helped to increase stability, when applied to the competition dataset. An online experiment also proved the effectiveness of bagged-covariate shift method. Thus, it can be summarized that covariate shift adaptation is helpful to realize adaptive BCI systems. PMID- 20172794 TI - Large-scale propagation of ultrasound in a 3-D breast model based on high resolution MRI data. AB - A 40 x 35 x 25-mm(3) specimen of human breast consisting mostly of fat and connective tissue was imaged using a 3-T magnetic resonance scanner. The resolutions in the image plane and in the orthogonal direction were 130 microm and 150 microm, respectively. Initial processing to prepare the data for segmentation consisted of contrast inversion, interpolation, and noise reduction. Noise reduction used a multilevel bidirectional median filter to preserve edges. The volume of data was segmented into regions of fat and connective tissue by using a combination of local and global thresholding. Local thresholding was performed to preserve fine detail, while global thresholding was performed to minimize the interclass variance between voxels classified as background and voxels classified as object. After smoothing the data to avoid aliasing artifacts, the segmented data volume was visualized using isosurfaces. The isosurfaces were enhanced using transparency, lighting, shading, reflectance, and animation. Computations of pulse propagation through the model illustrate its utility for the study of ultrasound aberration. The results show the feasibility of using the described combination of methods to demonstrate tissue morphology in a form that provides insight about the way ultrasound beams are aberrated in three dimensions by tissue. PMID- 20172796 TI - A fast and efficient method to compensate for brain shift for tumor resection therapies measured between preoperative and postoperative tomograms. AB - In this paper, an efficient paradigm is presented to correct for brain shift during tumor resection therapies. For this study, high resolution preoperative (pre-op) and postoperative (post-op) MR images were acquired for eight in vivo patients, and surface/subsurface shift was identified by manual identification of homologous points between the pre-op and immediate post-op tomograms. Cortical surface deformation data were then used to drive an inverse problem framework. The manually identified subsurface deformations served as a comparison toward validation. The proposed framework recaptured 85% of the mean subsurface shift. This translated to a subsurface shift error of 0.4 +/- 0.4 mm for a measured shift of 3.1 +/- 0.6 mm. The patient's pre-op tomograms were also deformed volumetrically using displacements predicted by the model. Results presented allow a preliminary evaluation of correction both quantitatively and visually. While intraoperative (intra-op) MR imaging data would be optimal, the extent of shift measured from pre- to post-op MR was comparable to clinical conditions. This study demonstrates the accuracy of the proposed framework in predicting full volume displacements from sparse shift measurements. It also shows that the proposed framework can be extended and used to update pre-op images on a time scale that is compatible with surgery. PMID- 20172797 TI - A model predictive control strategy toward optimal structured treatment interruptions in anti-HIV therapy. AB - In this paper, model predictive control (MPC) strategies are applied to the control of human immunodeficiency virus infection, with the final goal of implementing an optimal structured treatment interruptions protocol. The MPC algorithms proposed in this paper use a dynamic model recently developed in order to mimic both transient responses and ultimate behavior, and to describe accordingly the different effect of commonly used drugs in highly active antiretroviral therapy (HAART). Simulation studies show that the proposed methods achieve the goal of reducing the drug consumption (thus minimizing the severe side effects of HAART drugs) while respecting the desired constraints on CD4+ cells and free virions concentration. Such promising results are obtained with realistic assumptions of infrequent (possibly noisy) measurements of a subset of model state variables. Furthermore, the control objectives are achieved even in the presence of mismatch between the dynamics of true patients and that of the MPC model. PMID- 20172798 TI - A robust uniaxial force sensor for minimally invasive surgery. AB - This paper presents a novel miniature uniaxial force sensor for use within a beating heart during mitral valve annuloplasty. The sensor measures 5.5 mm in diameter and 12 mm in length and provides a hollow core to pass instrumentation. A soft elastomer flexure design maintains a waterproof seal. Fiber optic transduction eliminates electrical circuitry within the heart, and acetal components minimize ultrasound-imaging artifacts. Calibration uses a nonlinear viscoelastic method, and in vitro tests demonstrate a 0-4-N force range with rms errors of 0.13 N (< 3.2%). In vivo tests provide the first endocardial measurements of tissue-minimally invasive surgery instrument interaction forces in a beating heart. PMID- 20172799 TI - Robust estimation of HDR in fMRI using H(infinity) filters. AB - Estimation and detection of the hemodynamic response (HDR) are of great importance in functional MRI (fMRI) data analysis. In this paper, we propose the use of three H (infinity) adaptive filters (finite memory, exponentially weighted, and time-varying) for accurate estimation and detection of the HDR. The H (infinity) approach is used because it safeguards against the worst case disturbances and makes no assumptions on the (statistical) nature of the signals [B. Hassibi and T. Kailath, in Proc. ICASSP, 1995, vol. 2, pp. 949-952; T. Ratnarajah and S. Puthusserypady, in Proc. 8th IEEE Workshop DSP, 1998, pp. 1483 1487]. Performances of the proposed techniques are compared to the conventional t test method as well as the well-known LMSs and recursive least squares algorithms. Extensive numerical simulations show that the proposed methods result in better HDR estimations and activation detections. PMID- 20172800 TI - Two-stage approach for detection and reduction of motion artifacts in photoplethysmographic data. AB - Corruption of photopleythysmograms (PPGs) by motion artifacts has been a serious obstacle to the reliable use of pulse oximeters for real-time, continuous state of-health monitoring. In this paper, we propose an automated, two-stage PPG data processing method to minimize the effects of motion artifacts. The technique is based on our prior work related to motion artifact detection (stage 1) [R. Krishnan, B. Natarajan, and S. Warren, "Analysis and detection of motion artifacts in photoplethysmographic data using higher order statistics,'' in Proc. IEEE Int. Conf. Acoust., Speech, Signal Process. (ICASSP 2008), Las Vegas, Nevada, Apr. 2008, pp. 613-616] and motion artifact reduction (stage 2) [R. Krishnan, B. Natarajan, and S. Warren, "Motion artifact reduction in photoplethysmography using magnitude-based frequency domain independent component analysis,'' in Proc. 17th Int. Conf. Comput. Commun. Network, St. Thomas, Virgin Islands, Aug. 2008, pp. 1-5]. Regarding stage 1, we present novel and consistent techniques to detect the presence of motion artifact in PPGs given higher order statistical information present in the data. We analyze these data in the time and frequency domains (FDs) and identify metrics to distinguish between clean and motion-corrupted data. A Neyman-Pearson detection rule is formulated for each of the metrics. Furthermore, by treating each of the metrics as observations from independent sensors, we employ hard fusion and soft fusion techniques presented in [Z. Chair and P. Varshney, "Optimal data fusion in multiple sensor detection systems,'' IEEE Trans. Aerosp. Electron. Syst., AES, vol. 1, no. 1, pp. 98-101, Jan. 1986] and [C. C. Lee and J. J. Chao, "Optimum local decision space partitioning for distributed detection,'' IEEE Trans. Aerosp. Electron. Syst., AES, vol. 25, no. 7, pp. 536-544, Jul. 1989], respectively, in order to fuse individual decisions into a global system decision. For stage two, we propose a motion artifact reduction method that is effective even in the presence of severe subject movement. The approach involves an enhanced preprocessing unit consisting of a motion detection unit (MDU, developed in this paper), period estimation unit, and Fourier series reconstruction unit. The MDU identifies clean data frames versus those corrupted with motion artifacts. The period estimation unit determines the fundamental frequency of a corrupt frame. The Fourier series reconstruction unit reconstructs the final preprocessed signal by utilizing the spectrum variability of the pulse waveform. Preprocessed data are then fed to a magnitude-based FD independent component analysis unit. This helps reduce motion artifacts present at the frequencies of the reconstruction components. Experimental results are presented to demonstrate the efficacy of the overall motion artifact reduction method. PMID- 20172801 TI - Orthogonal fuzzy neighborhood discriminant analysis for multifunction myoelectric hand control. AB - Developing accurate and powerful electromyogram (EMG) driven prostheses controllers that can provide the amputees with effective control on their artificial limbs, has been the focus of a great deal of research in the past few years. One of the major challenges in such research is extracting an informative subset of features that can best discriminate between the different forearm movements. In this paper, a new dimensionality reduction method, referred to as orthogonal fuzzy neighborhood discriminant analysis (OFNDA), is proposed as a response to such a challenge. Unlike existing attempts in fuzzy linear discriminant analysis, the objective of the proposed OFNDA is to minimize the distance between samples that belong to the same class and maximize the distance between the centers of different classes, while taking into account the contribution of the samples to the different classes. The proposed OFNDA is validated on EMG datasets collected from seven subjects performing a range of 5 to 10 classes of forearm movements. Practical results indicate the significance of OFNDA in comparison to many other feature projection methods (including locality preserving and uncorrelated variants of discriminant analysis) with accuracies ranging from 97.66% to 87.84% for 5 to 10 classes of movements, respectively, using only two EMG electrodes. PMID- 20172802 TI - An automatic personal calibration procedure for advanced gaze estimation systems. AB - Gaze estimation systems use calibration procedures to estimate subject-specific parameters that are needed for the calculation of the point-of-gaze. In these procedures, subjects are required to fixate on a specific point or points in space at specific time instances. Advanced remote gaze estimation systems can estimate the optical axis of the eye without any personal calibration procedure, but use a single calibration point to estimate the angle between the optical axis and the visual axis (line-of-gaze). This paper presents a novel calibration procedure that does not require active user participation. To estimate the angles between the optical and visual axes of each eye, this procedure minimizes the distance between the intersections of the visual axes of the left and right eyes with one or more observation surfaces (displays) while subjects look naturally at these displays (e.g., watching a video clip). Theoretical analysis and computer simulations show that the performance of the proposed procedure improves when the range of angles between the visual axes and vectors normal to the observation surfaces increases. Experiments with four subjects show that the subject-specific angles between the optical and visual axes can be estimated with an rms error of 0.5 degrees. PMID- 20172803 TI - Relevance vector machine learning for neonate pain intensity assessment using digital imaging. AB - Pain assessment in patients who are unable to verbally communicate is a challenging problem. The fundamental limitations in pain assessment in neonates stem from subjective assessment criteria, rather than quantifiable and measurable data. This often results in poor quality and inconsistent treatment of patient pain management. Recent advancements in pattern recognition techniques using relevance vector machine (RVM) learning techniques can assist medical staff in assessing pain by constantly monitoring the patient and providing the clinician with quantifiable data for pain management. The RVM classification technique is a Bayesian extension of the support vector machine (SVM) algorithm, which achieves comparable performance to SVM while providing posterior probabilities for class memberships and a sparser model. If classes represent "pure" facial expressions (i.e., extreme expressions that an observer can identify with a high degree of confidence), then the posterior probability of the membership of some intermediate facial expression to a class can provide an estimate of the intensity of such an expression. In this paper, we use the RVM classification technique to distinguish pain from nonpain in neonates as well as assess their pain intensity levels. We also correlate our results with the pain intensity assessed by expert and nonexpert human examiners. PMID- 20172805 TI - Real-time epileptic seizure prediction using AR models and support vector machines. AB - This paper addresses the prediction of epileptic seizures from the online analysis of EEG data. This problem is of paramount importance for the realization of monitoring/control units to be implanted on drug-resistant epileptic patients. The proposed solution relies in a novel way on autoregressive modeling of the EEG time series and combines a least-squares parameter estimator for EEG feature extraction along with a support vector machine (SVM) for binary classification between preictal/ictal and interictal states. This choice is characterized by low computational requirements compatible with a real-time implementation of the overall system. Moreover, experimental results on the Freiburg dataset exhibited correct prediction of all seizures (100 % sensitivity) and, due to a novel regularization of the SVM classifier based on the Kalman filter, also a low false alarm rate. PMID- 20172804 TI - Using point process models to compare neural spiking activity in the subthalamic nucleus of Parkinson's patients and a healthy primate. AB - Placement of deep brain stimulating electrodes in the subthalamic nucleus (STN) to treat Parkinson's disease (PD) also allows the recording of single neuron spiking activity. Analyses of these unique data offer an important opportunity to better understand the pathophysiology of PD. Despite the point process nature of PD neural spiking activity, point process methods are rarely used to analyze these recordings. We develop a point process representation of PD neural spiking activity using a generalized linear model to describe long- and short-term temporal dependencies in the spiking activity of 28 STN neurons from seven PD patients and 35 neurons from one healthy primate (surrogate control) recorded, while the subjects executed a directed-hand movement task. We used the point process model to characterize each neuron's bursting, oscillatory, and directional tuning properties during key periods in the task trial. Relative to the control neurons, the PD neurons showed increased bursting, increased 10-30 Hz oscillations, and increased fluctuations in directional tuning. These features, which traditional methods failed to capture accurately, were efficiently summarized in a single model in the point process analysis of each neuron. The point process framework suggests a useful approach for developing quantitative neural correlates that may be related directly to the movement and behavioral disorders characteristic of PD. PMID- 20172806 TI - Acute dosimetry and estimation of threshold-inducing behavioral signs of thermal stress in rabbits at 2.45-GHz microwave exposure. AB - In the current international guidelines and standards for human exposure to microwaves (MWs), the basic restriction is determined by the whole-body average specific absorption rate (SAR). The basis for the guidelines is the adverse effect such as work stoppage in animals for whole-body average SARs above a certain level. Although it is known that absorbed MW energy causes the behavioral sign of thermal stress, the relationship of whole-body average SAR with temperature/temperature elevation has not been sufficiently investigated. In the present study, we performed experiments on rabbits exposed to 2.45-GHz MWs. A total of 24 measurements were conducted for power densities from approximately 100 to 1000 W/m(2). Our computational code for electromagnetic-thermal dosimetry was used to set the exposure time duration and incident power density. Our experimental results suggest that a core temperature elevation of 1 degrees C is an estimate of the threshold-inducing complex behavioral signs of MW-induced thermal stress in rabbits for different whole-body average SARs and exposure time durations. The whole-body average SAR required for MW-induced behavioral sign in rabbits was estimated as approximately 1.3 W/kg for 2.45-GHz MWs. PMID- 20172807 TI - 3-D visualization of acute RF ablation lesions using MRI for the simultaneous determination of the patterns of necrosis and edema. AB - Catheter ablation using RF energy is a common treatment for atrial arrhythmias. Although this treatment provides a potential cure, currently, there remains a high proportion of patients returning for repeat ablations. Electrophysiologists have little information to verify that a lesion has been created in the myocardium. Temporary electrical block can be created from edema, which will subside. MRI can visualize acute and chronic ablation lesions using delayed enhancement techniques. However, the ablation patterns cannot be determined from 2-D images alone. Using the combination of T(2)-weighted and delayed-enhancement MRI, ablation lesions can be characterized in terms of necrosis and edema. A novel 3-D visualization technique is presented that projects the image intensity due the lesions onto a 3-D cardiac surface, allowing the complete, simultaneous visualization of the delayed-enhancement and T(2)-weighted ablation patterns. Results show successful visualization of ablation patterns in 18 patients, and an application of this technique is presented in which electroanatomical mapping systems can be validated by overlaying the acquired ablation points onto the cardiac surfaces and assessing the correlation with the lesion maps. PMID- 20172808 TI - Feasibility study of lesion classification via contrast-agent-aided UWB breast imaging. AB - This letter investigates the feasibility of applying contrast agents for lesion classification in ultra wideband (UWB) breast imaging. Previous study has focused on distinguishing benign from malignant masses by exploiting their morphology dependent backscatter signature via the complex natural resonances of the late time target response. The tissue differentiation capability, however, deteriorates severely if the intrinsic contrast between the dielectric properties of dysplastic and normal tissues are small. A possible solution to this problem is proposed in this letter via the use of microwave contrast agents, where the damping factors of the differential backscatter responses before and after the infusion of contrast agents to a dysplastic inclusion are used to correlate with the anomaly shapes. The feasibility of this approach for lesion classification is demonstrated through comprehensive simulation studies using realistic numerical breast models. PMID- 20172809 TI - Motion artifact removal for functional near infrared spectroscopy: a comparison of methods. AB - Near infrared spectroscopy (NIRS) is rapidly gaining popularity for functional brain imaging. It is well suited to studies of patients or children; however, in these populations particularly, motion artifacts can present a problem. Here, we propose the use of imaging channels with negligible distance between light source and detector to detect subject motion, without the need for an additional motion sensor. Datasets containing deliberate motion artifacts were obtained from three subjects. Motion artifacts could be detected in the signal from the co-located channels with a minimum sensitivity of 0.75 and specificity of 0.98. Five techniques for removing motion artifact from the functional signals were compared, namely two-input recursive least squares (RLS) adaptive filtering, wavelet-based filtering, independent component analysis (ICA), and two-channel and multiple-channel regression. In most datasets, the median change in SNR across all channels was the greatest using ICA or multiple-channel regression. RLS adaptive filtering produced the smallest increase in SNR. Where sharp spikes were present, wavelet filtering produced the largest SNR increase. ICA and multiple-channel regression are promising ways to reduce motion artifact in functional NIRS without requiring time-consuming manual techniques. PMID- 20172810 TI - Magnetic eye tracking: a new approach employing a planar transmitter. AB - A new scleral search coil (SSC) tracking approach employing a planar transmitter has been developed theoretically and tested experimentally. A thin and flat transmitter is much more convenient in installation, operation, and maintenance than the conventional large cubic one. A planar transmitter also increases the mobility of SSC systems, simplifies their accommodation in a limited clinical space, enables bedside testing, and causes no visual distractions and no discomfort to the users. Moreover, it allows tracking not only the SSC orientation, but also its location, which is very important for many medical and scientific applications. The suggested approach provides the speed and precision that are required in SSC applications. The experimental results show that it can be used for the diagnosis of vestibular disorders. The tracking precision is in good agreement with its theoretical estimation. PMID- 20172811 TI - A wearable sensor for unobtrusive, long-term assessment of electrodermal activity. AB - Electrodermal activity (EDA) is a sensitive index of sympathetic nervous system activity. Due to the lack of sensors that can be worn comfortably during normal daily activity and over extensive periods of time, research in this area is limited to laboratory settings or artificial clinical environments. We developed a novel, unobtrusive, nonstigmatizing, wrist-worn integrated sensor, and present, for the very first time, a demonstration of long-term, continuous assessment of EDA outside of a laboratory setting. We evaluated the performance of our device against a Food and Drug Administration (FDA) approved system for the measurement of EDA during physical, cognitive, as well as emotional stressors at both palmar and distal forearm sites, and found high correlations across all the tests. We also evaluated the choice of electrode material by comparing conductive fabric with Ag/AgCl electrodes and discuss the limitations found. An important result presented in this paper is evidence that the distal forearm is a viable alternative to the traditional palmar sites for EDA measurements. Our device offers the unprecedented ability to perform comfortable, long-term, and in situ assessment of EDA. This paper opens up opportunities for future investigations that were previously not feasible, and could have far-reaching implications for diagnosis and understanding of psychological or neurological conditions. PMID- 20172812 TI - A hyperelastic finite-element model of human skin for interactive real-time surgical simulation. AB - A finite-element (FE) model of human skin is proposed for future use in an interactive real-time surgical simulation to teach surgeons procedures, such as facial reconstruction using skin-flap repair. For this procedure, skin is cut into flaps that are stretched to cover openings in the face. Thus, the model must recreate the visual, haptic, and force feedback expected by the surgeon. To develop the FE model, a series of in vitro experiments were conducted on samples of human skin, subjected to uniaxial and planar tensile straining. Reduced polynomial hyperelastic (HE) materials were found to fit many of the samples' stress-strain data well. Finally, an explicit dynamic FE mesh was developed based on the fitted HE material models. A total Lagrangian formulation with the half step central difference method was employed to integrate the dynamic equation of motion of the mesh. The mesh was integrated into two versions of a real-time skin simulator: a single-threaded version running on a computer's main central processing unit and a multithreaded version running on the computer's graphics card. The latter was achieved by exploiting recent advances in programmable graphics technology. PMID- 20172813 TI - Phase-compensated averaging for analyzing electroencephalography and magnetoencephalography epochs. AB - Stimulus-locked averaging for electroencephalography and/or megnetoencephalography (EEG/MEG) epochs cancels out ongoing spontaneous activities by treating them as noise. However, such spontaneous activities are the object of interest for EEG/MEG researchers who study phase-related phenomena, e.g., long-distance synchronization, phase-reset, and event-related synchronization/desynchronization (ERD/ERS). We propose a complex-weighted averaging method, called phase-compensated averaging, to investigate phase related phenomena. In this method, any EEG/MEG channel is used as a trigger for averaging by setting the instantaneous phases at the trigger timings to 0 so that cross-channel averages are obtained. First, we evaluated the fundamental characteristics of this method by performing simulations. The results showed that this method could selectively average ongoing spontaneous activity phase-locked in each channel; that is, it evaluates the directional phase-synchronizing relationship between channels. We then analyzed flash evoked potentials. This method clarified the directional phase-synchronizing relationship from the frontal to occipital channels and recovered another piece of information, perhaps regarding the sequence of experiments, which is lost when using only conventional averaging. This method can also be used to reconstruct EEG/MEG time series to visualize long-distance synchronization and phase-reset directly, and on the basis of the potentials, ERS/ERD can be explained as a side effect of phase reset. PMID- 20172814 TI - Attractor structure discriminates sleep states: recurrence plot analysis applied to infant breathing patterns. AB - Breathing patterns are characteristically different between infant active sleep (AS) and quiet sleep (QS), and statistical quantifications of interbreath interval (IBI) data have previously been used to discriminate between infant sleep states. It has also been identified that breathing patterns are governed by a nonlinear controller. This study aims to investigate whether nonlinear quantifications of infant IBI data are characteristically different between AS and QS, and whether they may be used to discriminate between these infant sleep states. Polysomnograms were obtained from 24 healthy infants at six months of age. Periods of AS and QS were identified, and IBI data extracted. Recurrence quantification analysis (RQA) was applied to each period, and recurrence calculated for a fixed radius in the range of 0-8 in steps of 0.02, and embedding dimensions of 4, 6, 8, and 16. When a threshold classifier was trained, the RQA variable recurrence was able to correctly classify 94.3% of periods in a test dataset. It was concluded that RQA of IBI data is able to accurately discriminate between infant sleep states. This is a promising step toward development of a minimal-channel automatic sleep state classification system. PMID- 20172815 TI - A flow quantification method using fluid dynamics regularization and MR tagging. AB - This paper presents a new method for improved flow analysis and quantification using MRI. The method incorporates fluid dynamics to regularize the flow quantification from tagged MR images. Specifically, the flow quantification is formulated as a minimization problem based on the following: 1) the Navier-Stokes equation governing the fluid dynamics; 2) the flow continuity equation and boundary conditions; and 3) the data consistency constraint. The minimization is carried out using a genetic algorithm. This method is tested using both computer simulations and MR flow experiments. The results are evaluated using flow vector fields from the computational fluid dynamics software package as a reference, which show that the new method can achieve more realistic and accurate flow quantifications than the conventional method. PMID- 20172816 TI - Simultaneous identification of oculomotor subsystems using a hybrid system approach: introducing hybrid extended least squares. AB - The oculomotor system plays an essential role in our daily activities. It keeps the images of the world steady on the retina and enables us to track visual targets, or switch between targets. The modeling and identification of this system is key in the diagnosis and treatment of various diseases and lesions. Today, clinical protocols incorporate mathematical techniques to test the functionality of patients' oculomotor modalities through the analysis of the patients' responses to various stimuli. We have developed a new tool for simultaneous identification of the two modes of oculomotor responses, using hybrid extended least squares (HybELS), a novel identification method tailored for hybrid autoregressive moving average with exogenous input models. Previously, modified extended least squares (MELS) was proposed for the identification of vestibular nystagmus dynamics, one mode at a time. It involved searching for segment initial conditions (ICs) to avoid biased results. HybELS identifies both modes simultaneously, and does not require estimation of ICs. Results on experimental vestibuloocular reflex (VOR) data show that HybELS proves to be more robust than MELS with respect to identification of complex models. Furthermore, it is notably less computationally expensive than MELS. In the multi-input case, HybELS outperforms other tested methods, including MELS, both in parameter estimation and prediction error. PMID- 20172817 TI - Spatio-temporal data fusion for 3D+T image reconstruction in cerebral angiography. AB - This paper provides a framework for generating high resolution time sequences of 3D images that show the dynamics of cerebral blood flow. These sequences have the potential to allow image feedback during medical procedures that facilitate the detection and observation of pathological abnormalities such as stenoses, aneurysms, and blood clots. The 3D time series is constructed by fusing a single static 3D model with two time sequences of 2D projections of the same imaged region. The fusion process utilizes a variational approach that constrains the volumes to have both smoothly varying regions separated by edges and sparse regions of nonzero support. The variational problem is solved using a modified version of the Gauss-Seidel algorithm that exploits the spatio-temporal structure of the angiography problem. The 3D time series results are visualized using time series of isosurfaces, synthetic X-rays from arbitrary perspectives or poses, and 3D surfaces that show arrival times of the contrasted blood front using color coding. The derived visualizations provide physicians with a previously unavailable wealth of information that can lead to safer procedures, including quicker localization of flow altering abnormalities such as blood clots, and lower procedural X-ray exposure. Quantitative SNR and other performance analysis of the algorithm on computational phantom data are also presented. PMID- 20172818 TI - Improved delay-dependent stability condition of discrete recurrent neural networks with time-varying delays. AB - This brief investigates the problem of global exponential stability analysis for discrete recurrent neural networks with time-varying delays. In terms of linear matrix inequality (LMI) approach, a novel delay-dependent stability criterion is established for the considered recurrent neural networks via a new Lyapunov function. The obtained condition has less conservativeness and less number of variables than the existing ones. Numerical example is given to demonstrate the effectiveness of the proposed method. PMID- 20172819 TI - Lattice point sets for deterministic learning and approximate optimization problems. AB - In this brief, the use of lattice point sets (LPSs) is investigated in the context of general learning problems (including function estimation and dynamic optimization), in the case where the classic empirical risk minimization (ERM) principle is considered and there is freedom to choose the sampling points of the input space. Here it is proved that convergence of the ERM principle is guaranteed when LPSs are employed as training sets for the learning procedure, yielding up to a superlinear convergence rate under some regularity hypotheses on the involved functions. Preliminary simulation results are also provided. PMID- 20172820 TI - Black-box identification of a class of nonlinear systems by a recurrent neurofuzzy network. AB - This brief presents a structure for black-box identification based on continuous time recurrent neurofuzzy networks for a class of dynamic nonlinear systems. The proposed network catches the dynamics of a system by generating its own states, using only input and output measurements of the system. The training algorithm is based on adaptive observer theory, the stability of the network, the convergence of the training algorithm, and the ultimate bound on the identification error as well as the parameter error are established. Experimental results are included to illustrate the effectiveness of the proposed method. PMID- 20172821 TI - Boosting through optimization of margin distributions. AB - Boosting has been of great interest recently in the machine learning community because of the impressive performance for classification and regression problems. The success of boosting algorithms may be interpreted in terms of the margin theory. Recently, it has been shown that generalization error of classifiers can be obtained by explicitly taking the margin distribution of the training data into account. Most of the current boosting algorithms in practice usually optimize a convex loss function and do not make use of the margin distribution. In this brief, we design a new boosting algorithm, termed margin-distribution boosting (MDBoost), which directly maximizes the average margin and minimizes the margin variance at the same time. This way the margin distribution is optimized. A totally corrective optimization algorithm based on column generation is proposed to implement MDBoost. Experiments on various data sets show that MDBoost outperforms AdaBoost and LPBoost in most cases. PMID- 20172822 TI - Large-scale pattern storage and retrieval using generalized brain-state-in-a-box neural networks. AB - In this paper, a generalized Brain-State-in-a-Box (gBSB)-based hybrid neural network is proposed for storing and retrieving pattern sequences. The hybrid network consists of autoassociative and heteroassociative parts. Then, a large scale image storage and retrieval neural system is constructed using the gBSB based hybrid neural network and the pattern decomposition concept. The notion of the deadbeat stability is employed to describe the stability property of the vertices of the hypercube to which the trajectories of the gBSB neural system are constrained. Extensive simulations of large scale pattern and image storing and retrieval are presented to illustrate the results obtained. PMID- 20172823 TI - Generalized low-rank approximations of matrices revisited. AB - Compared to singular value decomposition (SVD), generalized low-rank approximations of matrices (GLRAM) can consume less computation time, obtain higher compression ratio, and yield competitive classification performance. GLRAM has been successfully applied to applications such as image compression and retrieval, and quite a few extensions have been successively proposed. However, in literature, some basic properties and crucial problems with regard to GLRAM have not been explored or solved yet. For this sake, we revisit GLRAM in this paper. First, we reveal such a close relationship between GLRAM and SVD that GLRAM's objective function is identical to SVD's objective function except the imposed constraints. Second, we derive a lower bound of GLRAM's objective function, and discuss when the lower bound can be touched. Moreover, from the viewpoint of minimizing the lower bound, we answer one open problem raised by Ye (Machine Learning, 2005), i.e., a theoretical justification of the experimental phenomenon that, under given number of reduced dimension, the lowest reconstruction error is obtained when the left and right transformations have equal number of columns. Third, we explore when and why GLRAM can perform well in terms of compression, which is a fundamental problem concerning the usability of GLRAM. PMID- 20172824 TI - Conformation-based hidden Markov models: application to human face identification. AB - Hidden Markov models (HMMs) and their variants are capable to classify complex and structured objects. However, one of their major restrictions is their inability to cope with shape or conformation intrinsically: HMM-based techniques have difficulty predicting the n-dimensional shape formed by the symbols of the visible observation (VO) sequence. In order to fulfill this crucial need, we propose a novel paradigm that we named conformation-based hidden Markov models (COHMMs). This new formalism classifies VO sequences by embedding the nodes of an HMM state transition graph in a Euclidean vector space. This is accomplished by modeling the noise contained in the shape composed by the VO sequence. We cover the one-level as well as the multilevel COHMMs. Five problems are assigned to a multilevel COHMM: 1) sequence probability evaluation, 2) statistical decoding, 3) structural decoding, 4) shape decoding, and 5) learning. We have applied the COHMMs formalism to human face identification tested on different benchmarked face databases. The results show that the multilevel COHMMs outperform the embedded HMMs as well as some standard HMM-based models. PMID- 20172825 TI - Exponential synchronization of hybrid coupled networks with delayed coupling. AB - This paper investigates exponential synchronization of coupled networks with hybrid coupling, which is composed of constant coupling and discrete-delay coupling. There is only one transmittal delay in the delayed coupling. The fact is that in the signal transmission process, the time delay affects only the variable that is being transmitted from one system to another, then it makes sense to assume that there is only one single delay contributing to the dynamics. Some sufficient conditions for synchronization are derived based on Lyapunov functional and linear matrix inequality (LMI). In particular, the coupling matrix may be asymmetric or nondiagonal. Moreover, the transmittal delay can be different from the one in the isolated system. A distinctive feature of this work is that the synchronized state will vary in comparison with the conventional synchronized solution. Especially, the degree of the nodes and the inner delayed coupling matrix heavily influence the synchronized state. Finally, a chaotic neural network is used as the node in two regular networks to show the effectiveness of the proposed criteria. PMID- 20172826 TI - State-space analysis of Boolean networks. AB - This paper provides a comprehensive framework for the state-space approach to Boolean networks. First, it surveys the authors' recent work on the topic: Using semitensor product of matrices and the matrix expression of logic, the logical dynamic equations of Boolean (control) networks can be converted into standard discrete-time dynamics. To use the state-space approach, the state space and its subspaces of a Boolean network have been carefully defined. The basis of a subspace has been constructed. Particularly, the regular subspace, Y-friendly subspace, and invariant subspace are precisely defined, and the verifying algorithms are presented. As an application, the indistinct rolling gear structure of a Boolean network is revealed. PMID- 20172827 TI - An adaptive multiobjective approach to evolving ART architectures. AB - In this paper, we present the evolution of adaptive resonance theory (ART) neural network architectures (classifiers) using a multiobjective optimization approach. In particular, we propose the use of a multiobjective evolutionary approach to simultaneously evolve the weights and the topology of three well-known ART architectures; fuzzy ARTMAP (FAM), ellipsoidal ARTMAP (EAM), and Gaussian ARTMAP (GAM). We refer to the resulting architectures as MO-GFAM, MO-GEAM, and MO-GGAM, and collectively as MO-GART. The major advantage of MO-GART is that it produces a number of solutions for the classification problem at hand that have different levels of merit [accuracy on unseen data (generalization) and size (number of categories created)]. MO-GART is shown to be more elegant (does not require user intervention to define the network parameters), more effective (of better accuracy and smaller size), and more efficient (faster to produce the solution networks) than other ART neural network architectures that have appeared in the literature. Furthermore, MO-GART is shown to be competitive with other popular classifiers, such as classification and regression tree (CART) and support vector machines (SVMs). PMID- 20172828 TI - On high-order denoising models and fast algorithms for vector-valued images. AB - Variational techniques for gray-scale image denoising have been deeply investigated for many years; however, little research has been done for the vector-valued denoising case and the very few existent works are all based on total-variation regularization. It is known that total-variation models for denoising gray-scaled images suffer from staircasing effect and there is no reason to suggest this effect is not transported into the vector-valued models. High-order models, on the contrary, do not present staircasing. In this paper, we introduce three high-order and curvature-based denoising models for vector-valued images. Their properties are analyzed and a fast multigrid algorithm for the numerical solution is provided. AMS subject classifications: 68U10, 65F10, 65K10. PMID- 20172829 TI - Enhanced local texture feature sets for face recognition under difficult lighting conditions. AB - Making recognition more reliable under uncontrolled lighting conditions is one of the most important challenges for practical face recognition systems. We tackle this by combining the strengths of robust illumination normalization, local texture-based face representations, distance transform based matching, kernel based feature extraction and multiple feature fusion. Specifically, we make three main contributions: 1) we present a simple and efficient preprocessing chain that eliminates most of the effects of changing illumination while still preserving the essential appearance details that are needed for recognition; 2) we introduce local ternary patterns (LTP), a generalization of the local binary pattern (LBP) local texture descriptor that is more discriminant and less sensitive to noise in uniform regions, and we show that replacing comparisons based on local spatial histograms with a distance transform based similarity metric further improves the performance of LBP/LTP based face recognition; and 3) we further improve robustness by adding Kernel principal component analysis (PCA) feature extraction and incorporating rich local appearance cues from two complementary sources- Gabor wavelets and LBP--showing that the combination is considerably more accurate than either feature set alone. The resulting method provides state-of the-art performance on three data sets that are widely used for testing recognition under difficult illumination conditions: Extended Yale-B, CAS-PEAL R1, and Face Recognition Grand Challenge version 2 experiment 4 (FRGC-204). For example, on the challenging FRGC-204 data set it halves the error rate relative to previously published methods, achieving a face verification rate of 88.1% at 0.1% false accept rate. Further experiments show that our preprocessing method outperforms several existing preprocessors for a range of feature sets, data sets and lighting conditions. PMID- 20172830 TI - Visual-context boosting for eye detection. AB - Eye detection plays an important role in many practical applications. This paper presents a novel two-step scheme for eye detection. The first step models an eye by a newly defined visual-context pattern (VCP), and the second step applies semisupervised boosting for precise detection. VCP describes both the space and appearance relations between an eye region (region of eye) and a reference region (region of reference). The context feature of a VCP is extracted by using the integral image. Aiming to reduce the human labeling efforts, we apply semisupervised boosting, which integrates the context feature and the Haar-like features for precise eye detection. Experimental results on several standard face data sets demonstrate that the proposed approach is effective, robust, and efficient. We finally show that this approach is ready for practical applications. PMID- 20172831 TI - Output feedback fuzzy controller design with local nonlinear feedback laws for discrete-time nonlinear systems. AB - This paper considers the output feedback control problem for nonlinear discrete time systems, which are represented by a type of fuzzy systems with local nonlinear models. By using the estimations of the states and nonlinear functions in local models, sufficient conditions for designing observer-based controllers are given for discrete-time nonlinear systems. First, a separation property, i.e., the controller and the observer can be independently designed, is proved for the class of fuzzy systems. Second, a two-step procedure with cone complementarity linearization algorithms is also developed for solving the H( infinity) dynamic output feedback (DOF) control problem. Moreover, for the case where the nonlinear functions in local submodels are measurable, a convex condition for designing H(infinity) controllers is given by a new DOF control scheme. In contrast to the existing methods, the new methods can design output feedback controllers with fewer fuzzy rules as well as less computational burden, which is helpful for controller designs and implementations. Lastly, numerical examples are given to illustrate the effectiveness of the proposed methods. PMID- 20172832 TI - Multiview spectral embedding. AB - In computer vision and multimedia search, it is common to use multiple features from different views to represent an object. For example, to well characterize a natural scene image, it is essential to find a set of visual features to represent its color, texture, and shape information and encode each feature into a vector. Therefore, we have a set of vectors in different spaces to represent the image. Conventional spectral-embedding algorithms cannot deal with such datum directly, so we have to concatenate these vectors together as a new vector. This concatenation is not physically meaningful because each feature has a specific statistical property. Therefore, we develop a new spectral-embedding algorithm, namely, multiview spectral embedding (MSE), which can encode different features in different ways, to achieve a physically meaningful embedding. In particular, MSE finds a low-dimensional embedding wherein the distribution of each view is sufficiently smooth, and MSE explores the complementary property of different views. Because there is no closed-form solution for MSE, we derive an alternating optimization-based iterative algorithm to obtain the low-dimensional embedding. Empirical evaluations based on the applications of image retrieval, video annotation, and document clustering demonstrate the effectiveness of the proposed approach. PMID- 20172833 TI - Robust state estimation for neural networks with discontinuous activations. AB - Discontinuous dynamical systems, particularly neural networks with discontinuous activation functions, arise in a number of applications and have received considerable research attention in recent years. In this paper, the robust state estimation problem is investigated for uncertain neural networks with discontinuous activations and time-varying delays, where the neuron-dependent nonlinear disturbance on the network outputs are only assumed to satisfy the local Lipschitz condition. Based on the theory of differential inclusions and nonsmooth analysis, several criteria are presented to guarantee the existence of the desired robust state estimator for the discontinuous neural networks. It is shown that the design of the state estimator for such networks can be achieved by solving some linear matrix inequalities, which are dependent on the size of the time derivative of the time-varying delays. Finally, numerical examples are given to illustrate the theoretical results. PMID- 20172834 TI - An approach to solve group-decision-making problems with ordinal interval numbers. AB - The ordinal interval number is a form of uncertain preference information in group decision making (GDM), while it is seldom discussed in the existing research. This paper investigates how the ranking order of alternatives is determined based on preference information of ordinal interval numbers in GDM problems. When ranking a large quantity of ordinal interval numbers, the efficiency and accuracy of the ranking process are critical. A new approach is proposed to rank alternatives using ordinal interval numbers when every ranking ordinal in an ordinal interval number is thought to be uniformly and independently distributed in its interval. First, we give the definition of possibility degree on comparing two ordinal interval numbers and the related theory analysis. Then, to rank alternatives, by comparing multiple ordinal interval numbers, a collective expectation possibility degree matrix on pairwise comparisons of alternatives is built, and an optimization model based on this matrix is constructed. Furthermore, an algorithm is also presented to rank alternatives by solving the model. Finally, two examples are used to illustrate the use of the proposed approach. PMID- 20172835 TI - Toward emotion aware computing: an integrated approach using multichannel neurophysiological recordings and affective visual stimuli. AB - This paper proposes a methodology for the robust classification of neurophysiological data into four emotional states collected during passive viewing of emotional evocative pictures selected from the International Affective Picture System. The proposed classification model is formed according to the current neuroscience trends, since it adopts the independency of two emotional dimensions, namely arousal and valence, as dictated by the bidirectional emotion theory, whereas it is gender-specific. A two-step classification procedure is proposed for the discrimination of emotional states between EEG signals evoked by pleasant and unpleasant stimuli, which also vary in their arousal/intensity levels. The first classification level involves the arousal discrimination. The valence discrimination is then performed. The Mahalanobis (MD) distance-based classifier and support vector machines (SVMs) were used for the discrimination of emotions. The achieved overall classification rates were 79.5% and 81.3% for the MD and SVM, respectively, significantly higher than in previous studies. The robust classification of objective emotional measures is the first step toward numerous applications within the sphere of human-computer interaction. PMID- 20172836 TI - Motion-tolerant magnetic earring sensor and wireless earpiece for wearable photoplethysmography. AB - This paper addresses the design considerations and critical evaluation of a novel embodiment for wearable photoplethysmography (PPG) comprising a magnetic earring sensor and wireless earpiece. The miniaturized sensor can be worn comfortably on the earlobe and contains an embedded accelerometer to provide motion reference for adaptive noise cancellation. The compact wireless earpiece provides analog signal conditioning and acts as a data-forwarding device via a radio frequency transceiver. Using Bland-Altman and correlation analysis, we evaluated the performance of the proposed system against an FDA-approved ECG measurement device during daily activities. The mean +/- standard deviation (SD) of the differences between heart rate measurements from the proposed device and ECG (expressed as percentage of the average between the two techniques) along with the 95% limits of agreement (LOA = +/-1.96 SD) was 0.62% +/- 4.51% (LOA = -8.23% and 9.46%), 0.49% +/- 8.65% (-17.39% and 16.42%), and -0.32% +/- 10.63% (-21.15% and 20.52%) during standing, walking, and running, respectively. Linear regression indicated a high correlation between the two measurements across the three evaluated conditions (r = 0.97, 0.82, and 0.76, respectively with p < 0.001). The new earring PPG system provides a platform for comfortable, robust, unobtrusive, and discreet monitoring of cardiovascular function. PMID- 20172837 TI - Design and implementation of a portable long-term physiological signal recorder. AB - This paper describes a design and implementation of a portable physiological signal recorder. The device is designed for measuring electrocardiography, bioimpedance, and user's activity. The bioimpedance measures the dynamic changes in the impedance, and its main application is monitoring user's respiration. Activity is measured with three-axis acceleration sensor. During the design, a special attention is paid on the device's power consumption and the target has been set to a 24-h operating time. Functionality of the implemented measurement device is proven with test measurements, which include, e.g., comparison of measurement signals against reference signals, testing the device operation under vigorous upper body movements, and during a light exercise. In order to verify the device operation during real-life activities, one full day, 24-h long, measurement is carried out. The measurement system is tested with both commercial Ag/AgCl gel-paste electrodes and custom-made textile electrodes. Device is proven to be operational with both electrodes, but textile electrodes are found to be more sensitive for movement artifacts. This paper also gives a small review of other existing portable and wearable physiological measurement devices and discusses some general requirements of these devices. PMID- 20172838 TI - Quantifying palpation techniques in relation to performance in a clinical prostate exam. AB - This paper seeks to quantify finger palpation techniques in the prostate clinical exam, determine their relationship with performance in detecting abnormalities, and differentiate the tendencies of nurse practitioner students and resident physicians. One issue with the digital rectal examination (DRE) is that performance in detecting abnormalities varies greatly and agreement between examiners is low. The utilization of particular palpation techniques may be one way to improve clinician ability. Based on past qualitative instruction, this paper algorithmically defines a set of palpation techniques for the DRE, i.e., global finger movement (GFM), local finger movement (LFM), and average intentional finger pressure, and utilizes a custom-built simulator to analyze finger movements in an experiment with two groups: 18 nurse practitioner students and 16 resident physicians. Although technique utilization varied, some elements clearly impacted performance. For example, those utilizing the LFM of vibration were significantly better at detecting abnormalities. Also, the V GFM led to greater success, but finger pressure played a lesser role. Interestingly, while the residents were clearly the superior performers, their techniques differed only subtly from the students. In summary, the quantified palpation techniques appear to account for examination ability at some level, but not entirely for differences between groups. PMID- 20172839 TI - An EMG-based robot control scheme robust to time-varying EMG signal features. AB - Human-robot control interfaces have received increased attention during the past decades. With the introduction of robots in everyday life, especially in providing services to people with special needs (i.e., elderly, people with impairments, or people with disabilities), there is a strong necessity for simple and natural control interfaces. In this paper, electromyographic (EMG) signals from muscles of the human upper limb are used as the control interface between the user and a robot arm. EMG signals are recorded using surface EMG electrodes placed on the user's skin, making the user's upper limb free of bulky interface sensors or machinery usually found in conventional human-controlled systems. The proposed interface allows the user to control in real time an anthropomorphic robot arm in 3-D space, using upper limb motion estimates based only on EMG recordings. Moreover, the proposed interface is robust to EMG changes with respect to time, mainly caused by muscle fatigue or adjustments of contraction level. The efficiency of the method is assessed through real-time experiments, including random arm motions in the 3-D space with variable hand speed profiles. PMID- 20172841 TI - Hair loss in elderly women. AB - Hair loss in elderly women has been becoming a major topic in the daily practice of dermatology. Aging of hair follicles seems to affect hair growth and pigmentation, the molecular mechanisms of which remain to be elucidated. Further senile changes in physiology and immunity may influence the onset and course of hair diseases. Some preexisting diseases such as androgenetic alopecia usually worsen after menopause, while others, like discoid lupus erythematosus, may attenuate. Hormone surveying, especially with regard to internal androgen producing tumors, is indicated in postmenopausal women with androgenetic alopecia of sudden exacerbation or with unusual manifestation or other virilizing signs. The prevalence of alopecia totalis and alopecia universalis appears to be much lower in postmenopausal ages as compared to earlier onset. Acute or chronic telogen effluvium is not uncommonly superimposed on androgenetic alopecia. Trichotillomania shows a marked female predominance in the senile age group with a higher rate of psychopathology. Worldwide, tinea capitis has been increasingly observed in postmenopausal women. Frontal fibrosing alopecia, giant cell arteritis and erosive pustular dermatosis involve mainly elder women leading to scarring alopecia. Alopecia induced by tumor metastasis to the scalp must be considered in women with underlying neoplasms, especially breast cancer. Overall, hair loss in postmenopausal women is often multifactorial and warrants a close inspection. PMID- 20172842 TI - Focal epithelial hyperplasia (Heck's Disease) in two siblings: response to treatment with imiquimod 5% cream. PMID- 20172840 TI - Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. AB - BACKGROUND: Hepatocellular carcinoma (HCC), or liver cancer, is the third leading cause of cancer deaths worldwide, with prevalence 16-32 times higher in developing countries than in developed countries. Aflatoxin, a contaminant produced by the fungi Aspergillus flavus and Aspergillus parasiticus in maize and nuts, is a known human liver carcinogen. OBJECTIVES: We sought to determine the global burden of HCC attributable to aflatoxin exposure. METHODS: We conducted a quantitative cancer risk assessment, for which we collected global data on food borne aflatoxin levels, consumption of aflatoxin-contaminated foods, and hepatitis B virus (HBV) prevalence. We calculated the cancer potency of aflatoxin for HBV-postive and HBV-negative individuals, as well as the uncertainty in all variables, to estimate the global burden of aflatoxin-related HCC. RESULTS: Of the 550,000-600,000 new HCC cases worldwide each year, about 25,200-155,000 may be attributable to aflatoxin exposure. Most cases occur in sub-Saharan Africa, Southeast Asia, and China where populations suffer from both high HBV prevalence and largely uncontrolled aflatoxin exposure in food. CONCLUSIONS: Aflatoxin may play a causative role in 4.6-28.2% of all global HCC cases. PMID- 20172843 TI - Stimulus-sensitive post-anoxic focal motor seizures evolving into generalised myoclonic status epilepticus: a video-EEG study. AB - We describe the case of a 62-year-old man who developed stimulus-induced focal motor seizures after prolonged cardiac arrest. During a video-EEG study, these focal motor seizures progressed into a generalised myoclonic status epilepticus. Both the severely decremented background activity on the EEG, and the absence of median and trigeminal somatosensory evoked potentials were in keeping with a devastating post-hypoxic encephalopathy and the patient died. Our clinical and electrophysiology data suggest that generalised myoclonic status epilepticus may occur in patients in whom the existence of severe cerebral damage prevents a complete development of all phases of classic generalised tonic-clonic seizures. PMID- 20172844 TI - [Essential medicines and access to primary health care in the medical district of Mambere-Kadei]. AB - OBJECTIVE: To assess whether people in Mambere-Kadei have access to essential medicines for primary health care. SETTING: The study was conducted in 14 public health care centres of the medical district of Mambere-Kadei (Central African Republic). METHOD: This cross-sectional study assessed the drugs prescribed for 40 randomly selected outpatients consulting in each of 14 randomly selected public health centres from June 1, 2000, through March 30, 2001. The methodology used was adapted from the World Health Organization study protocol (WHO indicators) and the International Network for Rational Use of Drugs (INRUD). MAIN OUTCOME MEASURE: Accessibility and affordability of key medicines. RESULTS: Complete data were available for 512 study consultations. A mean of 79.3%( 95% Confidence Interval (CI): 77.5-81.7%) of the 14 essential generic drugs monitored were available in the health centre pharmacies. A median prescription cost 2800 Francs FCA ($4.5), a cost within the ability to pay of 73.2% (CI: 72.8-76.2). CONCLUSION: These results suggest that the population in Mambere-Kadei had access to affordable essential medicines. Although availability and accessibility of the generic essential drugs are good in this medical district, the study also showed the need for action to improve access to primary health care for the patients too poor to pay: 26.8% (95% CI: 23.8-28.2). PMID- 20172845 TI - [Physicochemical composition of bottled drinking water marketed in Ouagadougou (Burkina Faso)]. AB - The bottled drinking water marketed in urban areas includes natural mineral water, spring water, and treated drinking water. Their physicochemical qualities depend on the type and quantity of their components and define their safe use. Bottled water is widely consumed in Ouagadougou (Burkina Faso), and many brand names exist. Although many publications have examined the microbiological qualities of such water, no study has examined the physicochemical quality of water from Burkina Faso. This study, conducted from March 2005 through January 2006, aimed to assess the physicochemical composition of drinking water sold in Ouagadougou to facilitate better choices and use by consumers. Results showed that all the water analyzed in Ouagadougou is soft (TH < 50 ppm) or moderately soft (50 < TH < 200 ppm) and weakly mineralized (total dissolved solid content < 500 mg/L, sulfates [SO(2-)(4)] < 200 mg/L, [Ca(++)] < 150 mg/L, [Mg(2+)] < 50 mg/L, and [HCO(3)-] < 600 mg/l). Some imported water, however, is hard and highly mineralized. French standards do not set limit values for the natural mineral water parameters described above, and much of the water sold in Ouagadougou was natural mineral water. The spring water met potability standards, except for the Montagne d'Arree brand, which had a pH value of 5.8, below the WHO standards of 6.5 < pH 8.5. PMID- 20172846 TI - Seizures in Alzheimer's disease: a retrospective study of a cohort of outpatients. AB - PURPOSE: The aim of our study was to define the frequency of seizures in a population of outpatients attending a cognitive function clinic in Italy and to identify risk factors for seizures in patients with Alzheimer's disease. METHODS: In this retrospective study, we analyzed our clinical records to gather information on patients' demographic, metabolic, cardiovascular and cognitive features. We sought to determine the significance of abnormal neuroimaging findings and the use of potentially epileptogenic drugs on the onset of seizures. From the records of 583 patients referred to the clinic for cognitive disturbances, we identified 145 patients with Alzheimer's disease. RESULTS: Of these 145 patients, 14 (9.7%) had a history of complex partial or generalised seizures, or both. Of the risk factors identified, onset of seizures was associated with male gender and none of the patients with seizures had diabetes. The risk of seizure onset was higher in Alzheimer's disease patients with hyperlipaemia and severe dementia. No other risk factors were identified, although hypertensive patients seemed to be protected. CONCLUSIONS: Seizures in Alzheimer's disease are frequent and often under-recognized. In elderly patients, especially those with Alzheimer's disease, correct diagnosis and treatment are important to prevent disease from worsening and disability from increasing. Patients with dementia should routinely undergo history-taking designed to elicit a history of seizures and define patients at high risk. PMID- 20172847 TI - Differential diagnosis of pearly penile papules and penile condyloma acuminatum by dermoscopy. PMID- 20172848 TI - Rosaceiform eruption induced by cetuximab. PMID- 20172849 TI - Serological cardiovascular and mortality risk predictors in dialysis patients receiving sevelamer: a prospective study. AB - BACKGROUND: Cardiovascular morbidity and mortality are massively increased in patients with chronic kidney disease (CKD). Sevelamer hydrochloride has been shown to attenuate cardiovascular calcifications in CKD and end-stage renal disease (ESRD) patients. We assessed how sevelamer hydrochloride influences the evolution of serum fetuin-A and other serological factors predicting cardiovascular outcome and survival in haemodialysis patients. METHODS: Fifty seven prevalent haemodialysis patients were included in a three-phase prospective interventional trial (A-B-A design; 8 weeks per phase). Sevelamer was only administered in the middle phase of the study. Within the other two phases, >or=90% of the patients received calcium acetate for phosphate binding. Detailed time courses of serum biochemistries were analysed in order to obtain detailed insight into the influence of sevelamer upon CKD-mineral and bone disorder (MBD) parameters as well as serum fetuin-A, fibroblast growth factor 23 (FGF23) and uraemic toxin levels [uric acid, indoxyl sulphate, hippuric acid, indole acetic acid, p-cresol and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF)]. RESULTS: Forty-one patients finished the three prospective study phases (intention-to-treat analysis). After treatment with sevelamer, serum fetuin-A significantly increased (+21%), showing a delayed increase outlasting the third (non-sevelamer) study period. Total and low-density lipoprotein (LDL) cholesterol levels, as well as serum calcium, decreased significantly. The opposite occurred with albumin, C-reactive protein and intact parathyroid hormone (iPTH). FGF23, uric acid, indoxyl sulphate, hippuric acid, indole acetic acid, CMPF and serum phosphate did not change significantly during sevelamer treatment. In contrast, in parallel to sevelamer treatment, there was a significant rise in serum P cresol. CONCLUSIONS: In haemodialysis patients, treatment with sevelamer over 8 weeks was associated with a delayed yet long-lasting increase in serum fetuin-A levels. Increasing the serum level of fetuin-A, a negative acute-phase protein and systemic calcification inhibitor, might be one of the potential anti calcification mechanisms of sevelamer. Since we failed to detect a decrease in systemic inflammation and uraemic toxins, the exact mechanisms by which sevelamer treatment affects serum fetuin-A remain to be determined. PMID- 20172851 TI - Effects of icodextrin on the peritoneal membrane. PMID- 20172850 TI - Nineteen novel NPHS1 mutations in a worldwide cohort of patients with congenital nephrotic syndrome (CNS). AB - BACKGROUND: Recessive mutations in the NPHS1 gene encoding nephrin account for approximately 40% of infants with congenital nephrotic syndrome (CNS). CNS is defined as steroid-resistant nephrotic syndrome (SRNS) within the first 90 days of life. Currently, more than 119 different mutations of NPHS1 have been published affecting most exons. METHODS: We here performed mutational analysis of NPHS1 in a worldwide cohort of 67 children from 62 different families with CNS. RESULTS: We found bi-allelic mutations in 36 of the 62 families (58%) confirming in a worldwide cohort that about one-half of CNS is caused by NPHS1 mutations. In 26 families, mutations were homozygous, and in 10, they were compound heterozygous. In an additional nine patients from eight families, only one heterozygous mutation was detected. We detected 37 different mutations. Nineteen of the 37 were novel mutations (approximately 51.4%), including 11 missense mutations, 4 splice-site mutations, 3 nonsense mutations and 1 small deletion. In an additional patient with later manifestation, we discovered two further novel mutations, including the first one affecting a glycosylation site of nephrin. CONCLUSIONS: Our data hereby expand the spectrum of known mutations by 17.6%. Surprisingly, out of the two siblings with the homozygous novel mutation L587R in NPHS1, only one developed nephrotic syndrome before the age of 90 days, while the other one did not manifest until the age of 2 years. Both siblings also unexpectedly experienced an episode of partial remission upon steroid treatment. PMID- 20172852 TI - The FIM instrument to identify patients at risk of falling in geriatric wards: a 10-year retrospective study. AB - OBJECTIVES: the main objective was to evaluate if the admission functional independence measure (FIM) score could be used to predict the risk of falls in geriatric inpatients. DESIGN: a 10-year retrospective study was performed. SETTING: the study was conducted in a 298-bed geriatric teaching hospital in Geneva, Switzerland. SUBJECTS: all patients discharged from the hospital from 1 January 1997 to 31 December 2006 were selected. MAIN OUTCOME MEASURES: measures used were FIM scores at admission using the FIM instrument and number of falls extracted from the institution's fall report forms. RESULTS: during the study period, there were 23,966 hospital stays. A total of 8,254 falls occurred. Of these, 7,995 falls were linked to 4,651 stays. Falls were recorded in 19.4% of hospital stays, with a mean incidence of 7.84 falls per 1,000 patients-days. Although there was a statistically significant relationship between total FIM score, its subscales, and the risk of falling, the sensitivity, specificity, positive predictive value and negative predictive value obtained with receiver operating characteristic curves were insufficient to permit fall prediction. This might be due in part to a non-linear relationship between FIM score and fall risk. CONCLUSION: in this study, the FIM instrument was found to be unable to predict risk of falls in general geriatric wards. PMID- 20172853 TI - All-trans-retinoic acid promotes trafficking of human concentrative nucleoside transporter-3 (hCNT3) to the plasma membrane by a TGF-beta1-mediated mechanism. AB - Human concentrative nucleoside transporter-3 (hCNT3) is a sodium-coupled nucleoside transporter that exhibits high affinity and broad substrate selectivity, making it the most suitable candidate for mediating the uptake and cytotoxic action of most nucleoside-derived drugs. The drug of this class most commonly used in the treatment of chronic lymphocytic leukemia (CLL) is the pro apoptotic nucleoside analog fludarabine (Flu), which enters CLL cells primarily through human equilibrative nucleoside transporters (hENTs). Although CLL cells lack hCNT3 activity, they do express this transporter protein, which is located mostly in the cytosol. The aim of our study was to identify agents and mechanisms capable of promoting hCNT3 trafficking to the plasma membrane. Here, we report that all-trans-retinoic acid (ATRA), currently used in the treatment of acute promyelocytic leukemia (APL), increases hCNT3-related activity through a mechanism that involves trafficking of pre-existing hCNT3 proteins to the plasma membrane. This effect is mediated by the autocrine action of transforming growth factor (TGF)-beta1, which is transcriptionally activated by ATRA in a p38 dependent manner. TGF-beta1 acts through activation of ERK1/2 and the small GTPase RhoA to promote plasma membrane trafficking of the hCNT3 protein. PMID- 20172854 TI - A proprotein convertase subtilisin-like/kexin type 9 (PCSK9) C-terminal domain antibody antigen-binding fragment inhibits PCSK9 internalization and restores low density lipoprotein uptake. AB - PCSK9 binds to the low density lipoprotein receptor (LDLR) and leads to LDLR degradation and inhibition of plasma LDL cholesterol clearance. Consequently, the role of PCSK9 in modulating circulating LDL makes it a promising therapeutic target for treating hypercholesterolemia and coronary heart disease. Although the C-terminal domain of PCSK9 is not involved in LDLR binding, the location of several naturally occurring mutations within this region suggests that it has an important role for PCSK9 function. Using a phage display library, we identified an anti-PCSK9 Fab (fragment antigen binding), 1G08, with subnanomolar affinity for PCSK9. In an assay measuring LDL uptake in HEK293 and HepG2 cells, 1G08 Fab reduced 50% the PCSK9-dependent inhibitory effects on LDL uptake. Importantly, we found that 1G08 did not affect the PCSK9-LDLR interaction but inhibited the internalization of PCSK9 in these cells. Furthermore, proteolysis and site directed mutagenesis studies demonstrated that 1G08 Fab binds a region of beta strands encompassing Arg-549, Arg-580, Arg-582, Glu-607, Lys-609, and Glu-612 in the PCSK9 C-terminal domain. Consistent with these results, 1G08 fails to bind PCSK9DeltaC, a truncated form of PCSK9 lacking the C-terminal domain. Additional studies revealed that lack of the C-terminal domain compromised the ability of PCSK9 to internalize into cells, and to inhibit LDL uptake. Together, the present study demonstrate that the PCSK9 C-terminal domain contribute to its inhibition of LDLR function mainly through its role in the cellular uptake of PCSK9 and LDLR complex. 1G08 Fab represents a useful new tool for delineating the mechanism of PCSK9 uptake and LDLR degradation. PMID- 20172855 TI - Dimeric arrangement of the parathyroid hormone receptor and a structural mechanism for ligand-induced dissociation. AB - The parathyroid hormone receptor (PTH1R) is a class B G protein-coupled receptor that is activated by parathyroid hormone (PTH) and PTH-related protein (PTHrP). Little is known about the oligomeric state of the receptor and its regulation by hormone. The crystal structure of the ligand-free PTH1R extracellular domain (ECD) reveals an unexpected dimer in which the C-terminal segment of both ECD protomers forms an alpha-helix that mimics PTH/PTHrP by occupying the peptide binding groove of the opposing protomer. ECD-mediated oligomerization of intact PTH1R was confirmed in living cells by bioluminescence and fluorescence resonance energy transfer experiments. As predicted by the structure, PTH binding disrupted receptor oligomerization. A receptor rendered monomeric by mutations in the ECD retained wild-type PTH binding and cAMP signaling ability. Our results are consistent with the hypothesis that PTH1R forms constitutive dimers that are dissociated by ligand binding and that monomeric PTH1R is capable of activating G protein. PMID- 20172856 TI - PB1-F2 influenza A virus protein adopts a beta-sheet conformation and forms amyloid fibers in membrane environments. AB - The influenza A virus PB1-F2 protein, encoded by an alternative reading frame in the PB1 polymerase gene, displays a high sequence polymorphism and is reported to contribute to viral pathogenesis in a sequence-specific manner. To gain insights into the functions of PB1-F2, the molecular structure of several PB1-F2 variants produced in Escherichia coli was investigated in different environments. Circular dichroism spectroscopy shows that all variants have a random coil secondary structure in aqueous solution. When incubated in trifluoroethanol polar solvent, all PB1-F2 variants adopt an alpha-helix-rich structure, whereas incubated in acetonitrile, a solvent of medium polarity mimicking the membrane environment, they display beta-sheet secondary structures. Incubated with asolectin liposomes and SDS micelles, PB1-F2 variants also acquire a beta-sheet structure. Dynamic light scattering revealed that the presence of beta-sheets is correlated with an oligomerization/aggregation of PB1-F2. Electron microscopy showed that PB1-F2 forms amorphous aggregates in acetonitrile. In contrast, at low concentrations of SDS, PB1-F2 variants exhibited various abilities to form fibers that were evidenced as amyloid fibers in a thioflavin T assay. Using a recombinant virus and its PB1-F2 knock-out mutant, we show that PB1-F2 also forms amyloid structures in infected cells. Functional membrane permeabilization assays revealed that the PB1-F2 variants can perforate membranes at nanomolar concentrations but with activities found to be sequence-dependent and not obviously correlated with their differential ability to form amyloid fibers. All of these observations suggest that PB1-F2 could be involved in physiological processes through different pathways, permeabilization of cellular membranes, and amyloid fiber formation. PMID- 20172857 TI - Identification and characterization of high molecular weight complexes formed by matrix AAA proteases and prohibitins in mitochondria of Arabidopsis thaliana. AB - We identify and characterize two matrix (m)-AAA proteases (AtFtsH3 and AtFtsH10) present in the mitochondria of Arabidopsis thaliana. AtFtsH3 is the predominant protease in leaves of wild type plants. Both proteases assemble with prohibitins (PHBs) into high molecular weight complexes (approximately 2 MDa), similarly to their yeast counterparts. A smaller PHB complex (approximately 1 MDa), without the m-AAA proteases, was also detected. Unlike in yeast, stable prohibitin independent high molecular weight assemblies of m-AAA proteases could not be identified in A. thaliana. AtFtsH3 and AtFtsH10 form at least two types of m-AAA PHB complexes in wild type plants. The one type contains PHBs and AtFtsH3, and the second one is composed of PHBs and both AtFtsH3 and AtFtsH10. Complexes composed of PHBs and AtFtsH10 were found in an Arabidopsis mutant lacking AtFtsH3 (ftsh3). Thus, both AtFtsH3 and AtFtsH10 may form hetero- and homo-oligomeric complexes with prohibitins. The increased level of AtFtsH10 observed in ftsh3 suggests that functions of the homo- and hetero-oligomeric complexes containing AtFtsH3 can be at least partially substituted by AtFtsH10 homo-oligomers. The steady-state level of the AtFtsH10 transcripts did not change in ftsh3 compared with wild type plants, but we found that almost twice more of the AtFtsH10 transcripts were associated with polysomes in ftsh3. Based on this result, we assume that the AtFtsH10 protein is synthesized at a higher rate in the ftsh3 mutant. Our results provide the first data on the composition of m-AAA and PHB complexes in plant mitochondria and suggest that the abundance of m-AAA proteases is regulated not only at the transcriptional but also at the translational level. PMID- 20172858 TI - The BCL-2 protein BAK is required for long-chain ceramide generation during apoptosis. AB - The BCL-2 family members BAK and BAX are required for apoptosis and trigger mitochondrial outer membrane permeabilization (MOMP). Here we identify a MOMP independent function of BAK as a required factor for long-chain ceramide production in response to pro-apoptotic stress. UV-C irradiation of wild-type (WT) cells increased long-chain ceramides; blocking ceramide generation prevented caspase activation and cell death, demonstrating that long-chain ceramides play a key role in UV-C-induced apoptosis. In contrast, UV-C irradiation did not increase long-chain ceramides in BAK and BAX double knock-out cells. Notably, this was not specific to the cell type (baby mouse kidney cells, hematopoietic) nor the apoptotic stimulus employed (UV-C, cisplatin, and growth factor withdrawal). Importantly, long-chain ceramide generation was dependent on the presence of BAK, but not BAX. However, ceramide generation was independent of the known downstream actions of BAK in apoptosis (MOMP or caspase activation), suggesting a novel role for BAK in apoptosis. Finally, enzymatic assays identified ceramide synthase as the mechanism by which BAK regulates ceramide metabolism. There was no change in CerS expression at the message or protein level, indicating regulation at the post-translational level. Moreover, CerS activity in BAK KO microsomes can be reactivated upon addition of BAK-containing microsomes. The data presented indicate that ceramide-induced apoptosis is dependent upon BAK and identify a novel role for BAK during apoptosis. By establishing a unique role for BAK in long-chain ceramide metabolism, these studies further demonstrate that the seemingly redundant proteins BAK and BAX have distinct mechanisms of action during apoptosis induction. PMID- 20172859 TI - Calcium activates Nedd4 E3 ubiquitin ligases by releasing the C2 domain-mediated auto-inhibition. AB - Nedd4 E3 ligases are members of the HECT E3 ubiquitin ligase family and regulate ubiquitination-mediated protein degradation. In this report, we demonstrate that calcium releases the C2 domain-mediated auto-inhibition in both Nedd4-1 and Nedd4 2. Calcium disrupts binding of the C2 domain to the HECT domain. Consistent with this, calcium activates the E3 ubiquitin ligase activity of Nedd4. Elevation of intracellular calcium by ionomycin treatment, or activation of acetylcholine receptor or epidermal growth factor receptor by carbachol or epidermal growth factor stimulation induced activation of endogenous Nedd4 in vivo evaluated by assays of either Nedd4 E3 ligase activity or ubiquitination of Nedd4 substrate ENaC-beta. The activation effect of calcium on Nedd4 E3 ligase activity was dramatically enhanced by a membrane-rich fraction, suggesting that calcium mediated membrane translocation through the C2 domain might be an activation mechanism of Nedd4 in vivo. Our studies have revealed an activation mechanism of Nedd4 E3 ubiquitin ligases and established a connection of intracellular calcium signaling to regulation of protein ubiquitination. PMID- 20172861 TI - Common variations in PSMD3-CSF3 and PLCB4 are associated with neutrophil count. AB - Neutrophils are the most abundant subtype of white blood cells (WBCs). Although the regulation of the numbers of neutrophils would have substantial clinical impacts, the studies on the variations associated with neutrophil count had not been performed further. To investigate genetic variations that regulate neutrophil count, we performed a genome-wide association study in 5771 Japanese subjects and a replication study using independent 1894 Japanese subjects. We identified two genetic loci significantly associated with neutrophil count (rs4794822 in PSMD3-CSF3 at 17q21.1, P = 6.3 x 10(-10); rs2072910 in PLCB4 at 20p12, P = 3.1 x 10(-10)). As these loci did not indicate significant associations with the counts of the other subtypes of WBCs (lymphocytes, monocytes, eosinophils and basophils), their specific associations with neutrophils were suggested. The combination of the single nucleotide polymorphisms (SNPs) in these two loci explained 1.0% of the total variance of the log-transformed values of the neutrophil count in our study populations. The subjects who were homozygous for 'neutrophil-increasing alleles' in both of the SNPs (T alleles for rs4794822 and rs2072910) had 1.17-fold (95% confidence interval: 1.10-1.24) higher neutrophil count when compared with the subjects homozygous for 'neutrophil-decreasing alleles' (C alleles for rs4794822 and rs2072910). In conclusion, our study would demonstrate the significant contribution of PSMD3-CSF3 and PLCB4 loci to the regulation of neutrophil count. PMID- 20172863 TI - OncoRx-IQ: a tool for quality assessment of online anticancer drug interactions. AB - OBJECTIVE: The quality of online anticancer drug interaction information varies among online drug databases. We describe the creation of OncoRx-IQ, a tool which assesses the information quality of online drug databases for anticancer drug interactions, and a pilot study done with the tool. DESIGN: OncoRx-IQ was designed in the form of a questionnaire containing 25 questions in three quality domains, separated into two sections (Section A: content accuracy and Section B: ease-of-use and reliability). Each question was scored based on the number of options assigned. SETTING: A pilot study utilizing this tool was done on four drug databases (Drugs.com, Drug Digest, Medscape and Micromedex). Statistical analyses of the composite and domain scores were done using descriptive statistics, Spearman's correlation coefficient and Friedman and Wilcoxon signed rank tests. PARTICIPANTS: Six pre-registration pharmacists participated in the pilot study. MAIN OUTCOME MEASURES: The drug databases were evaluated based on the accuracy of their drug interaction content, usability and reliability, as well as their overall quality. RESULTS: Micromedex (66.9%) and Drug Digest (35.8%) were the highest and lowest scoring databases, respectively. Micromedex scored the highest in all quality domains (content accuracy 56.3%, ease-of-use 75.0% and reliability 73.6%), whereas Drug Digest scored the lowest in content accuracy (8.0%) and reliability (48.2%). CONCLUSIONS: We have created and pilot tested OncoRx-IQ, a quality assessment tool, which helps clinicians systematically evaluate the quality and information accuracy of drug databases for anticancer drug interaction information. We hope this tool can lay the groundwork for future long-term evaluation of online drug interaction information. PMID- 20172860 TI - Uromodulin is expressed in renal primary cilia and UMOD mutations result in decreased ciliary uromodulin expression. AB - Uromodulin (UMOD) mutations are responsible for three autosomal dominant tubulo interstitial nephropathies including medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy and glomerulocystic kidney disease. Symptoms include renal salt wasting, hyperuricemia, gout, hypertension and end-stage renal disease. MCKD is part of the 'nephronophthisis-MCKD complex', a group of cystic kidney diseases. Both disorders have an indistinguishable histology and renal cysts are observed in either. For most genes mutated in cystic kidney disease, their proteins are expressed in the primary cilia/basal body complex. We identified seven novel UMOD mutations and were interested if UMOD protein was expressed in the primary renal cilia of human renal biopsies and if mutant UMOD would show a different expression pattern compared with that seen in control individuals. We demonstrate that UMOD is expressed in the primary cilia of renal tubules, using immunofluorescent studies in human kidney biopsy samples. The number of UMOD-positive primary cilia in UMOD patients is significantly decreased when compared with control samples. Additional immunofluorescence studies confirm ciliary expression of UMOD in cell culture. Ciliary expression of UMOD is also confirmed by electron microscopy. UMOD localization at the mitotic spindle poles and colocalization with other ciliary proteins such as nephrocystin-1 and kinesin family member 3A is demonstrated. Our data add UMOD to the group of proteins expressed in primary cilia, where mutations of the gene lead to cystic kidney disease. PMID- 20172862 TI - Cholesterol depletion alters amplitude and pharmacology of vascular calcium activated chloride channels. AB - AIMS: Calcium-activated chloride channels (CACCs) share common pharmacological properties with Kcnma1-encoded large conductance K(+) channels (BK(Ca) or K(Ca)1.1) and it has been suggested that they may co-exist in a macromolecular complex. As K(Ca)1.1 channels are known to localize to cholesterol and caveolin rich lipid rafts (caveolae), the present study investigated whether Ca(2+) sensitive Cl(-) currents in vascular myocytes were affected by the cholesterol depleting agent methyl-beta-cyclodextrin (M-betaCD). METHODS AND RESULTS: Calcium activated chloride and potassium currents were recorded from single murine portal vein myocytes in whole cell voltage clamp. Western blot was undertaken following sucrose gradient ultracentrifugation using protein lysates from whole portal veins. Ca(2+)-activated Cl(-) currents were augmented by 3 mg mL(-1) M-betaCD with a rapid time course (t(0.5) = 1.8 min). M-betaCD had no effect on the bi modal response to niflumic acid or anthracene-9-carboxylate but completely removed the inhibitory effects of the K(Ca)1.1 blockers, paxilline and tamoxifen, as well as the stimulatory effect of the K(Ca)1.1 activator NS1619. Discontinuous sucrose density gradients followed by western blot analysis revealed that the position of lipid raft markers caveolin and flotillin-2 was altered by 15 min application of 3 mg mL(-1) M-betaCD. The position of K(Ca)1.1 and the newly identified candidate for CACCs, TMEM16A, was also affected by M-betaCD. CONCLUSION: These data reveal that CACC properties are influenced by lipid raft integrity. PMID- 20172864 TI - Pregnancy outcome in female childhood cancer survivors. AB - BACKGROUND: The number of childhood cancer survivors has dramatically increased and consequently, an increasing number of survivors may now wish to conceive. Recently, several studies have described that previous treatment with abdominal radiotherapy may increase the risk of adverse pregnancy outcome. METHODS: We conducted a retrospective single centre cohort study of childhood cancer survivors with a singleton live birth between January 2000 and December 2005. Pregnancy outcome was compared with data from the Netherlands Perinatal Registry, a nationwide database of pregnancy outcome parameters of all births in the Netherlands registered by midwives, obstetricians and paediatricians. RESULTS: Data were available on 40 survivors and 9031 controls. Median age at diagnosis was 6.9 years (range 0.1-16.8 years). The median interval between diagnosis and date of delivery was 21.6 years (range 7.4-36.1 years). In the whole cohort, pregnancy outcome was not different between survivors and controls. However, survivors treated with abdominal radiotherapy delivered preterm and had post partum haemorrhage (mean gestational age in survivors = 34.9 versus 39.2 weeks in controls, P = 0.001; 33% in survivors versus 5% in controls, P = 0.007, respectively). The offspring of survivors had normal birthweight after adjustment for gestational age (mean birthweight in offspring of survivors 2503 versus 1985 g; P = 0.22). CONCLUSION: Childhood cancer survivors irradiated to the abdomen have an earlier delivery and higher incidence of post-partum haemorrhage. This stresses the need for close monitoring of the delivery, including inpatient perinatal care, in this group of childhood cancer survivors. PMID- 20172866 TI - Offering excess oocyte aspiration and vitrification to patients undergoing stimulated artificial insemination cycles can reduce the multiple pregnancy risk and accumulate oocytes for later use. AB - BACKGROUND: The prevention of multiple pregnancies remains a major challenge in patients treated with ovarian stimulation prior to intrauterine insemination (IUI). The pilot study presented here investigates whether multiple pregnancies can be minimized by a microscopically confirmed aspiration of oocytes from supernumerary follicles immediately before intrauterine insemination and evaluates the benefit of concomitant excess oocyte cryopreservation for future use. METHODS: Thirty-four aspirations of supernumerary follicles were performed immediately prior to IUI in 31 patients undergoing ovarian stimulation. sIUI was only performed if cumulus-oocyte complexes were microscopically observed in the aspirated follicular fluid. All collected mature excess oocytes were cryopreserved using the vitrification technique. RESULTS: Only four sIUI procedures had to be cancelled due to failed oocyte retrieval or premature ovulation. IUI treatment resulted in a clinical pregnancy rate of 23.5% per cycle. All were singleton pregnancies. A total of 111 oocytes were cryopreserved. Patients with polycystic ovary syndrome (PCOS) had an average of 6.07 oocytes vitrified, whereas patients without PCOS had 1.3 oocytes vitrified per cycle. CONCLUSION: Microscopically confirmed collection of excess oocytes prior to stimulated IUI reduced cancellation rates, further reduced the risk for multiple pregnancy and may lead to future additional pregnancies because, based on current information, approximately 5% of the vitrified oocytes could potentially establish a pregnancy. PMID- 20172867 TI - Xenografting of testicular tissue from an infant human donor results in accelerated testicular maturation. AB - BACKGROUND: Grafting of testicular tissue into immunodeficient mice has been used to differentiate the neonatal testes from different animal species up to the level of complete spermatogenesis; however, this approach has not been successful for human testicular tissue. The aim of this study was to evaluate the capacity for differentiation of infant human testicular tissue grafts. METHODS AND RESULTS: Testicular tissue from a 3-month-old patient with testicular cancer was grafted into immunodeficient nude mice. At the time of grafting, A spermatogonia were the only germ cells present in the testicular tissue. B spermatogonia and first spermatocytes were observed at 7 months and 1 year after grafting, respectively. Positive immunostaining with antibodies against BOULE and CDC25A suggested that spermatocytes in the graft were not arrested but in meiosis. Furthermore, ultrastructural and immunohistochemical analyses showed that the onset of both Sertoli cell maturation and partial differentiation of Leydig cells preceded the appearance of spermatocytes. Differentiation of testicular cells was accelerated compared with in vivo development. CONCLUSIONS: Spermatogenesis in the xenograft of infant human testicular tissues proceeded successfully from the stage of spermatogonial stem cells until pachytene spermatocyte formation. The differentiation of Sertoli cells and Leydig cells was reproduced in a manner similar to that in normal testicular development. Grafting of infant human testicular tissue may be a powerful tool to examine the early period of human spermatogenesis and may pave the way for fertility preservation among infant patients. PMID- 20172865 TI - A prospective study of body size during childhood and early adulthood and the incidence of endometriosis. AB - BACKGROUND: An inverse association between adult body mass index (BMI) and risk of endometriosis has frequently been reported. However, the association between body size during childhood and early adulthood and endometriosis is not as well documented. METHODS: Using data collected from the Nurses' Health Study II, a prospective cohort study of premenopausal US nurses, that began in 1989, we have attempted to clarify this relationship. Data are updated every 2 years with follow-up for these analyses through 2001. In 1989 women recalled their body size at ages 5, 10 and 20 years using a validated 9-level figure drawing. RESULTS: During 831 910 person-years of follow-up, 1817 cases of self-reported laparoscopically-confirmed endometriosis were observed among women with no past infertility. After adjusting for age, birthweight, age at menarche, parity, oral contraceptive use and adult BMI, we observed a significant reduction in the incidence of endometriosis with increasing body size for all time periods. The relative risks (RRs) comparing the smallest and largest figure sizes to the middle category during childhood (ages 5-10) were 1.18 (95% confidence interval 1.02-1.36) and 0.82 (0.66-1.02), P-trend = 0.0002. At age 20, the RRs for the same comparisons were 1.32 (1.06-1.65) and 0.87 (0.74-1.03), P-trend = 0.04. Additional adjustment by menstrual cycle length and regularity yielded similar associations. The associations were stronger among nulliparous women than among parous women, although not all differences were statistically significant. CONCLUSION: In this large cohort of premenopausal women, there was evidence of a persistent inverse association between childhood and early adulthood body size and incidence of laparoscopically confirmed endometriosis, independent of adult BMI and menstrual cycle characteristics. PMID- 20172868 TI - Sperm donor limits that control for the 'relative' risk associated with the use of open-identity donors. AB - The majority of countries that support the use of donor insemination (DI) in artificial reproductive technology (ART) limit the number of children born from one donor. The setting of these donor limits, though intended to control for the risk of inadvertent half-sibling unions between the offspring of anonymous donors, actually have no evidence base. Controlling for the risk of inadvertent half-sibling unions may soon become unnecessary due to the increasing world-wide use of open-identity sperm donors and the revocation of donor anonymity in many countries. With the shift from anonymous to open-identity donation, the central issue is not the risk of genetic abnormality from inadvertent half-sibling consanguinity; it is the psycho-social impact of the multiple use of open identity sperm donors. Despite this, the jurisdictions that allow or mandate the use of open-identity donors continue to observe existing limits that do not consider nor specifically control for the psycho-social impact of the multiple use of open-identity sperm donors. It is proposed that: (i) conservative interim donor limits be placed on the multiple use of open-identity donors, while research into the psycho-social impact of disclosure is undertaken to inform the establishment of evidence-based limits; and (ii) the existing limits in jurisdictions where anonymity is still commonly practiced or protected could be raised, if an updated mathematical model was used for calculating evidence-based anonymous donor limits. PMID- 20172869 TI - The first woman to give birth to two children following transplantation of frozen/thawed ovarian tissue. AB - Worldwide eight children have been born as a result of transplanting frozen/thawed ovarian tissue. Two of these children were born in Denmark following transport of the ovarian tissue for a period of 5 h prior to cryopreservation. One of these women, who was originally transplanted with six pieces of ovarian cortex, after having experienced a period of menopause has now conceived again following natural conception. She gave birth to a healthy girl on 23 September 2008 and is therefore the first woman in the world to have had two children, from separate pregnancies, born as a result of transplanting frozen/thawed ovarian tissue. This result encourages further development of cryopreservation of ovarian tissue for fertility preservation as a clinical procedure for girls and young women facing gonadotoxic treatment. PMID- 20172870 TI - The roles of thioredoxin and thioredoxin-binding protein-2 in endometriosis. AB - BACKGROUND: Oxidative stress is considered to be involved in the establishment and development of endometriosis. Thioredoxin (TRX) is an endogenous redox regulator that protects cells against oxidative stress, and TRX-binding protein-2 (TBP-2) is a negative regulator of TRX in the biological function and expression. The aim of this study was to investigate the roles of TRX and TBP-2 in the pathophysiology of endometriosis. METHODS: A total of 35 patients with histologically confirmed endometriosis and 31 patients without endometriosis participated in this study. Real-time polymerase chain reaction was used to quantify TRX and TBP-2 mRNA levels, and immunohistochemistry (IHC) was used to assess TRX and TBP-2 protein localization in the endometrium. Serum and peritoneal fluid levels of TRX and TBP-2 were measured using a specific commercial ELISA. RESULTS: There were no significant differences in TRX mRNA levels in the endometrium of patients with endometriosis and the control groups. However, TBP-2 mRNA levels in the endometrium were lower, and the TRX to TBP-2 ratio was higher in patients with endometriosis than in the control group. In particular, the TRX to TBP-2 ratio was significantly higher during late secretory and menstrual phase in patients with endometriosis compared with the control group. IHC studies also showed the decreased TBP-2 immunoreactivity in patients with endometriosis compared with the control group. There was no correlation between TRX and TBP-2 mRNA levels in patients with endometriosis, whereas TRX mRNA levels were positively correlated with TBP-2 mRNA levels in the control group. There were no significant differences between the two groups in TRX and TBP-2 levels in serum or peritoneal fluid. CONCLUSIONS: Aberrant expression of TRX and TBP-2 in the endometrium may be associated with the establishment of endometriosis. PMID- 20172871 TI - Home self-administration of vaginal misoprostol for medical abortion at 50-63 days compared with gestation of below 50 days. AB - BACKGROUND: Home use of misoprostol for termination of pregnancy is still controversial in many countries. Acceptability of home use of misoprostol has been investigated in pregnancies below 49 days gestation. In this study, we aimed to assess efficacy, feasibility and acceptability of home use of vaginal misoprostol for medical termination of pregnancy at 50-63 days compared with gestation of below 50 days among women who chose to administer misoprostol at home. METHODS: In this prospective study, mifepristone 200 mg was given in hospital under nursing supervision in the university hospital outpatient family planning clinic. Women self-administered misoprostol 800 microg vaginally 36-48 h later at home. Follow-up was 2 weeks later. Women with gestation of 50-63 days on the day of mifepristone administration were compared with women with gestation of below 50 days. Efficacy and feasibility were assessed by review of patient records and questionnaires. Acceptability was assessed using questionnaires where women reported on future choice of abortion method were they to have another abortion. RESULTS: Among the 2992 women who had a medical abortion during the study period, 395 women chose to administer misoprostol at home and were included in the study. A total of 203 women were below 50 days gestation and 192 were between 50 and 63 days gestation. Efficacy was 97.5% and did not differ between the groups. Surgical intervention was needed in 10 patients, of whom four were in the lower gestational band (P = 0.36). No serious adverse events or blood transfusions were reported. Preference for home administration of misoprostol, were they to have another induced abortion in the future, was high, 92.3 and 86.6% respectively, and did not differ between the groups (P = 0.097). Need for extra analgesia significantly influenced women's experiences in both gestational groups. CONCLUSIONS: Medical abortion with mifepristone followed by home administration of vaginal misoprostol is safe and highly acceptable also to women with gestational length of 50-63 days as compared with shorter gestations. Efficacy, acceptability and preference for future place of administration of misoprostol, were women to have another abortion, did not differ between women with gestation below 50 days or between 50 and 63 days. PMID- 20172872 TI - Appropriate BMI levels for PCOS patients in Southern China. AB - BACKGROUND: This study was designed to establish appropriate body mass index (BMI) level for PCOS women and to compare metabolic abnormalities between PCOS women and control women in Southern China. METHODS: This clinical cross-sectional study included 999 PCOS patients (857 adults and 142 adolescents) and 922 age matched controls (742 adults and 180 adolescents). RESULTS: The proportion of PCOS patients with a BMI above 23 kg/m(2) was 34.63%. Serum insulin, triglycerides, waist and waist/hip (W/H) measurements were all correlated positively with BMI in PCOS women. Prevalence of metabolic syndrome in Chinese PCOS patients was 18.9%. Receiver-operating characteristic analysis suggested that at the point of BMI > or =23 kg/m(2), the diagnostic power to detect metabolic disorders was at its best. CONCLUSIONS: PCOS patients with a BMI of 23 kg/m(2) or beyond may have a higher risk of metabolic disorders. Using an appropriate BMI level may help to improve attention to metabolic disorders among PCOS patients in Southern China. PMID- 20172873 TI - Vitamin D receptor and vitamin D metabolizing enzymes are expressed in the human male reproductive tract. AB - BACKGROUND: The vitamin D receptor (VDR) is expressed in human testis, and vitamin D (VD) has been suggested to affect survival and function of mature spermatozoa. Indeed, VDR knockout mice and VD deficient rats show decreased sperm counts and low fertility. However, the cellular response to VD is complex, since it is not solely dependent on VDR expression, but also on cellular uptake of circulating VD and presence and activity of VD metabolizing enzymes. Expression of VD metabolizing enzymes has not previously been investigated in human testis and male reproductive tract. Therefore, we performed a comprehensive analysis of the expression of VDR, VD activating (CYP2R1, CYP27A1, CYP27B1) and inactivating (CYP24A1) enzymes in the testis, epididymis, seminal vesicle (SV), prostate and spermatozoa. METHODS: Tissue samples were obtained after orchiectomy (testis n = 13; epididymis n = 7), prostatectomy (prostate n = 5 and SVs n = 3) and semen samples obtained after ejaculation (n = 13). mRNA was detected with RT-PCR and expression of proteins was determined by immunohistochemistry. RESULTS: VDR and VD metabolizing enzymes were concomitantly expressed in round and elongated spermatids, vesicles within the caput epididymis, and glandular epithelium of cauda epididymis, SV and prostate. The expression pattern in ejaculated spermatozoa varied, although, concomitant expression of VDR, CYP2R1, CYP27B1 and CYP24A1 was observed in neck and midpiece in a subpopulation of mature spermatozoa. CONCLUSION: On the basis of the marked expression of VDR and the VD metabolizing enzymes in human testis, ejaculatory tract and mature spermatozoa, we suggest that VD is important for spermatogenesis and maturation of human spermatozoa. PMID- 20172874 TI - A scholarly discipline comes of age. PMID- 20172875 TI - Effectiveness of patient safety training in equipping medical students to recognise safety hazards and propose robust interventions. AB - OBJECTIVES: In an effort to improve patient safety attitudes and skills among third-year medical students, two patient safety training sessions were added to their curriculum, complementing a previously implemented second-year curriculum on quality improvement, patient safety and teamwork. METHODS: Safety attitudes and skills were assessed before and after students completed the medicine clerkship training and were compared with historical controls. Students identified and reported on observed safety events, with their reports matched to event type and harm score with contemporaneous safety reports from University of Missouri's Patient Safety Network (PSN). Comparisons were assessed by five internal safety experts using criteria for report submission "worthiness", blame tone, target of blame and presence/strength of proposed solutions. RESULTS: Students completing the third-year safety booster conferences expressed statistically higher comfort levels with identifying the cause of an error than did the student control group (p<0.05). Medical students proposed safety interventions that were more robust than those suggested by event reporters regarding similar events within our health system (p<0.0001). The worthiness and blame tone of medical student reports were not statistically different than event reports in PSN. CONCLUSIONS: Completion of two 1-h patient safety booster conferences in the third year of medical school led to increased student comfort in safety event analysis. Students documented stronger resolution robustness scores, suggesting similar training should be offered to PSN reporters. Medical students represent an underutilised resource for identifying and proposing solutions for patient safety issues. PMID- 20172876 TI - The hospital standardised mortality ratio: a powerful tool for Dutch hospitals to assess their quality of care? AB - AIM OF THE STUDY: To use the hospital standardised mortality ratio (HSMR), as a tool for Dutch hospitals to analyse their death rates by comparing their risk adjusted mortality with the national average. METHOD: The method uses routine administrative databases that are available nationally in The Netherlands--the National Medical Registration dataset for the years 2005-2007. Diagnostic groups that led to 80% of hospital deaths were included in the analysis. The method adjusts for a number of case-mix factors per diagnostic group determined through a logistic regression modelling process. RESULTS: In The Netherlands, the case mix factors are primary diagnosis, age, sex, urgency of admission, length of stay, comorbidity (Charlson Index), social deprivation, source of referral and month of admission. The Dutch HSMR model performs well at predicting a patient's risk of death as measured by a c statistic of the receiver operating characteristic curve of 0.91. The ratio of the HSMR of the Dutch hospital with the highest value in 2005-2007 is 2.3 times the HSMR of the hospital with the lowest value. DISCUSSION: Overall hospital HSMRs and mortality at individual diagnostic group level can be monitored using statistical process control charts to give an early warning of possible problems with quality of care. The use of routine data in a standardised and robust model can be of value as a starting point for improvement of Dutch hospital outcomes. HSMRs have been calculated for several other countries. PMID- 20172877 TI - Health service accreditation as a predictor of clinical and organisational performance: a blinded, random, stratified study. AB - BACKGROUND: Despite the widespread use of accreditation in many countries, and prevailing beliefs that accreditation is associated with variables contributing to clinical care and organisational outcomes, little systematic research has been conducted to examine its validity as a predictor of healthcare performance. OBJECTIVE: To determine whether accreditation performance is associated with self reported clinical performance and independent ratings of four aspects of organisational performance. DESIGN: Independent blinded assessment of these variables in a random, stratified sample of health service organisations. SETTINGS: Acute care: large, medium and small health-service organisations in Australia. Study participants Nineteen health service organisations employing 16 448 staff treating 321 289 inpatients and 1 971 087 non-inpatient services annually, representing approximately 5% of the Australian acute care health system. MAIN MEASURES: Correlations of accreditation performance with organisational culture, organisational climate, consumer involvement, leadership and clinical performance. Results Accreditation performance was significantly positively correlated with organisational culture (rho=0.618, p=0.005) and leadership (rho=0.616, p=0.005). There was a trend between accreditation and clinical performance (rho=0.450, p=0.080). Accreditation was unrelated to organisational climate (rho=0.378, p=0.110) and consumer involvement (rho=0.215, p=0.377). CONCLUSIONS: Accreditation results predict leadership behaviours and cultural characteristics of healthcare organisations but not organisational climate or consumer participation, and a positive trend between accreditation and clinical performance is noted. PMID- 20172878 TI - Using a clinical decision support system to determine the quality of antimicrobial dosing in intensive care patients with renal insufficiency. AB - BACKGROUND: The benefits on clinical practice of a clinical decision support system (CDSS) are predominantly determined by the quality of the clinical rules used in this system. Therefore, it is essential to investigate the performance and potential benefits on quality of care of these rules. METHODS: A clinical rule assisting physicians in selecting the appropriate dosage according to renal function of frequently prescribed antimicrobials was developed. In 2004, 1788 patients admitted to the intensive care unit (ICU) for more than 12 h were included in this retrospective study. The actual number of dosage adjustments without the support of the CDSS was compared with the theoretical number of dosage adjustments determined by the clinical rule in patients with moderate (creatinine clearance (Cl(creat)) 10-50 ml/min) and severe (Cl(creat) <10 ml/min) renal dysfunction. If dosage adjustment was omitted, the duration of excessive anti-infective dosing and extra drug costs involved was determined. RESULTS: Dosage adjustment of antimicrobials was omitted in 163 patients (86%) with moderate renal failure and 13 patients (54%) with severe renal failure. Excessive exposure was most frequently detected in patients receiving fluconazole and ciprofloxacin (median duration of 6 days). In our ICU alone, more than 16,000 euro ($19 000) can be saved annually by adjusting the dosage according to renal function of frequently prescribed antimicrobials. CONCLUSIONS: Despite intensive monitoring of patients in the ICU, dosage adjustment of antimicrobials is often omitted. Implementing this clinical rule has the potential to contribute to a significant improvement in medication safety and is expected to generate substantial savings. PMID- 20172879 TI - Quality improvement capacity: a survey of hospital quality managers. AB - Background Skilled managers are an important component of quality improvement (QI) infrastructure, but there has been little evaluation of QI infrastructure, which is needed to guide enhancement of this capacity. Methods Quality managers at 97 acute care hospitals in Ontario, Canada, were surveyed by mail to describe how their roles were integrated with QI performance objectives. Binary and scaled responses were analysed quantitatively, and open-ended responses were analysed thematically. Results The response rate was 79.4%. Many QI managers were new to their role and had no support staff despite responsibility for multiple portfolios. Respondents thought that QI objectives should be less reactive to hospital executives or boards, adverse events or demands from government and accreditation bodies, and recommended that dedicated QI managers proactively apply explicit strategic plans and engage executives and clinicians. Findings were consistent regardless of rank, staffing or hospital type. Those with master's training and greater experience were more involved in strategic planning, data analysis and communication. Conclusions QI is not well resourced in most acute care hospitals in Ontario. To develop QI capacity, investment and QI training may be required. Research should empirically establish objective performance measures of QI capacity to guide investment and evaluation. PMID- 20172880 TI - Evidence-based commissioning: using population impact measures to help primary care trusts estimate the benefit of interventions in diabetes and heart failure. AB - OBJECTIVE: To test the feasibility of applying population impact measures utilising local population data on established interventions for heart failure and diabetes mellitus. DESIGN: Modelling study. Setting Registered general practitioner (GP) population in a primary care trust (PCT) Data sources Local data sources included the quality and outcomes framework, chronic disease registers for coronary heart disease and diabetes, hospital episode statistics and a range of published risk data in heart failure and diabetes. MAIN OUTCOME MEASURES: Number of events prevented in the population (NEPP) by increasing the uptake of established interventions expressed as the number of deaths, hospitalisations and cardiovascular events prevented. RESULTS: Data from 17 GP practices (representing 55% of the PCT GP registered population) were used to derive the NEPP. A 10% increase in the number of eligible patients receiving ACE inhibitors (n = 191) could result in at least 18 fewer deaths (95% CI 9.8 to 27.1) and 32 fewer hospitalisations (95% CI 24.9 to 40.7) for heart failure every year. Only 45% of persons with diabetes with an above target total cholesterol were receiving a statin; increasing this to 75% (additional 921) could lead to 44 (95% CI 15.6 to 73.1) fewer cardiovascular disease (CVD) events over 5 years. Similarly, more rigorous blood pressure control in an additional 662 diabetic patients could result in 26 (95% CI -2.7 to 55.6) fewer CVD events over 5 years. There were differences in the potential impact of these interventions according to subgroups within the PCT, as defined by age and geography (locality). CONCLUSIONS: Local data and published literature estimates can be successfully combined to produce the number of events prevented within a locally defined PCT population (NEPP). Commissioners have shown interest in the utility of such a measure in identifying and quantifying areas for improvement. PMID- 20172881 TI - If only....: failed, missed and absent error recovery opportunities in medication errors. AB - BACKGROUND: Systematic analysis of error recovery can provide hospitals with important information to help them improve their ability to detect and correct errors. Because errors will always crop up and 100% safety can never be achieved, hospitals should be able to prevent patient harm by timely and effective error recovery. METHODS: In this study, failed, missed and absent recovery opportunities were identified in 52 medication errors which all resulted in severe patient harm or patient death. For all identified recovery opportunities, the underlying failure factors were identified and classified according to the Eindhoven classification model. Those failure factors represent negative influences on error recovery. RESULTS: The number of recovery opportunities per error ranged from 0 to 11; on average, 2.4 recovery opportunities were identified. Of 127 identified recovery opportunities, 94 (74%) were planned and 33 (26%) were unplanned or ad hoc. Most failure factors underlying the planned recovery opportunities were organisational failure factors; most failure factors underlying the unplanned recovery opportunities were human failure factors. CONCLUSIONS: From this study, it can be concluded that actual accidents can be used as an alternative data source to near misses for the analysis and understanding of error recovery. By using both sources, hospitals can enhance their resilience by reinforcing the positive influences on error recovery as well as reducing the negative ones. Together with traditional error reduction methodologies, which only concentrate on eliminating failure factors, hospitals thus have numerous opportunities to improve patient safety. PMID- 20172882 TI - Patient safety research: an overview of the global evidence. AB - BACKGROUND: Unsafe medical care may cause substantial morbidity and mortality globally, despite imprecise estimates of the magnitude of the problem. To better understand the extent and nature of the problem of unsafe care, the WHO World Alliance for Patient Safety commissioned an overview of the world's literature on patient safety research. METHODS: Major patient safety topics were identified through a consultative and investigative process and were categorised into the framework of structure, process and outcomes of unsafe care. Lead experts examined current evidence and identified major knowledge gaps relating to topics in developing, transitional and developed nations. The report was reviewed by internal and external experts and underwent improvements based on the feedback. FINDINGS: Twenty-three major patient safety topics were examined. Much of the evidence of the outcomes of unsafe care is from developed nations, where prevalence studies demonstrate that between 3% and 16% of hospitalised patients suffer harm from medical care. Data from transitional and developing countries also suggest substantial harm from medical care. However, considerable gaps in knowledge about the structural and process factors that underlie unsafe care globally make solutions difficult to identify, especially in resource-poor settings. INTERPRETATION: Harm from medical care appears to pose a substantial burden to the world's population. However, much of the evidence base comes from developed nations. Understanding the scope of and solutions for unsafe care for the rest of the world is a critical component of delivering safe, effective care to all of the world's citizens. PMID- 20172883 TI - Measures of patient safety in developing and emerging countries: a review of the literature. AB - CONTEXT: The World Alliance for Patient Safety was formed to accelerate worldwide research progress towards measurably improving patient safety. Although rates of adverse events have been studied in industrialised countries, little is known about the rates of adverse events in developing and emerging countries. PURPOSE: To review the literature on patient safety issues in developing and emerging countries, to identify patient safety measures presently used in these countries and to propose a method of measurably improving patient safety measurement in these countries. METHODS: Using the Medline database for 1998 to 2007, we identified and reviewed 23 English-language articles that examined patient safety measurement in developing and emerging countries. Results Our review included 12 studies that prospectively measured patient safety and 11 studies that retrospectively measured safety. Two studies used measures of structure and the remaining used process measures, outcome measures or both. Whereas a few studies used surveys or direct observation, most studies used chart audits to measure patient safety. Most studies addressed safety at a single facility. CONCLUSIONS: Investigation of patient safety in developing and emerging countries has been infrequent and limited in scope. Establishing fundamental safe patient practices, integrating those processes into routine health services delivery and developing patients' expectations that such processes be present are necessary prerequisites to measuring and monitoring progress towards safe patient care in emerging and developing countries. PMID- 20172884 TI - A comparison of voluntarily reported medication errors in intensive care and general care units. AB - BACKGROUND: Few institutions currently track intensive care unit (ICU)-specific medication safety data. A comparison of medication error data for intensive care and general care units may determine if ICU-specific surveillance is needed. OBJECTIVE: To compare the type, cause, contributing factors, level of staff initiating an error, medication use process node, drug classes and patient outcomes for voluntarily reported medication errors occurring in ICUs and general care units. DESIGN: Retrospective evaluation of voluntarily reported medication errors over 4.5 years at a 647-bed academic medical centre containing greater than 120 ICU beds. Adult patients with a reported medication error in intensive care and general care units were included. Medication error data were compared for ICUs with general care units. MAIN MEASURES AND RESULTS: There were a total of 3252 medication errors reported with 541 and 2711 occurring in ICUs and general care units, respectively. Primary types of medication errors were prescribing in the ICUs and omission in the general care units. Leading causes of medication errors were procedure/protocol not followed and knowledge deficit in the ICU and general care units. More frequently there was no contributing factor identified for medication errors in the ICUs. The top three drugs associated with medication errors in the ICUs were opioid analgesics, beta-lactam antimicrobials and blood coagulation modifiers compared with anti-asthma/bronchodilators, narcotic analgesics and vaccines in the general care units. The level of care provided after the error was observation increased/initiated in ICUs and no additional care in general care units. Prolonged hospitalisation was a result of medication errors in 1% of ICU cases and 0.4% of general care unit errors (p = 0.056). Medication errors were associated with harm in 12% and 6% of cases in the ICUs and general care units, respectively (p<0.001). CONCLUSION: Type, contributing factors, drug classes and patient outcomes associated with voluntarily reported medication errors differ in intensive care and general care units so it is important to develop surveillance systems that analyse ICU specific data allowing systematic changes for this patient population. PMID- 20172885 TI - Teamwork behaviours and errors during neonatal resuscitation. AB - OBJECTIVE: To describe relationships between teamwork behaviours and errors during neonatal resuscitation. METHODS: Trained observers viewed video recordings of neonatal resuscitations (n = 12) for the occurrence of teamwork behaviours and errors. Teamwork state behaviours (such as vigilance and workload management, which extend for some duration) were assessed as the percentage of each resuscitation that the behaviour was observed and correlated with the percentage of observed errors. Teamwork event behaviours (such as information sharing, inquiry and assertion, which occur at specific times) were counted in 20-s intervals before and after resuscitation steps, and a generalised linear mixed model was calculated to evaluate relationships between these behaviours and errors. RESULTS: Resuscitation teams who were more vigilant committed fewer errors (Spearman's rho for vigilance and errors = -0.62, 95% CI -0.07 to -0.87, p = 0.031). Assertions were more likely to occur before errors than correct steps (OR = 1.44, 95% CI 1.10 to 1.89, p = 0.008) and teaching/advising occurred less frequently after errors (OR = 0.59, 95% CI 0.37 to 0.94, p = 0.028). Though not statistically significant, there was less information sharing before errors (OR = 0.90, 95% CI 0.77 to 1.05, p = 0.172). CONCLUSIONS: Vigilance is an important behaviour for error management. Assertion may have caused errors, or perhaps was an indicator for some other factor that caused errors. Teams may have preferred to resolve errors directly, rather than using errors as opportunities to teach their teammates. These observations raise important questions about the appropriate use of some teamwork behaviours and how to include them in team training programmes. PMID- 20172886 TI - Do pre-existing complications affect the failure to rescue quality measures? AB - BACKGROUND: A project sponsored by the University Health System Consortium has addressed the inaccuracy and high variability across institutions concerning the use of the failure to rescue (FTR) quality indicator defined by the Agency for Healthcare Research and Quality (AHRQ). Results indicated that of the complications identified by the quality indicator, 29.5% were pre-existing upon hospital admission. OBJECTIVE: The purpose of our study was to investigate the possible bias to FTR measures by including cases of complications that were pre existing at admission. METHODS: Hospital discharges between 1 January 1996 and 30 September 2007 were retrospectively gathered from administrative databases. Using definitions outlined by the AHRQ and the National Quality Forum (NQF), FTR rates were calculated. Using present on admission coding, FTR rates were recalculated to differentiate between the rates of pre-existing and that of acquired cases. RESULTS: Using the AHRQ definition, the overall FTR rate was 11.60%. The FTR rate for patients with pre-existing complications was 8.85%, whereas patients with complications acquired during hospitalisation had an FTR rate of 18.46% (p<0.001). The NQF FTR rate was 9.93%. Pre-existing and acquired FTR rates using the NQF measure were 9.42% and 12.77%, respectively (p<0.001). CONCLUSIONS: Current definitions of FTR measures meant to identify inhospital complications appear biased by the inclusion of problems at admission. Furthermore, many patients with these complications are excluded from the algorithms. When taking into account the timing of the "complications", these measures can be useful for internal quality control. However, it should be stressed that the usefulness of the measures to compare institutions will be dependent on coding practices of institutions. Validation using chart review may be required. PMID- 20172887 TI - Promoting patient safety through prospective risk identification: example from peri-operative care. AB - BACKGROUND: Investigation of patient safety incidents has focused on retrospective analyses once incidents have occurred. Prospective risk analysis techniques complement this but have not been widely used in healthcare. STUDY DESIGN: Prospective risk identification of non-operative risks associated with adult elective surgery under general anaesthesia using a customised structured "what if" checklist and development of risk matrix. Prioritisation of recommendations arising by cost, ease and likely speed of implementation. PARTICIPANTS AND SETTING: Groups totalling 20 clinical and administrative healthcare staff involved in peri-operative care and risk experts convened by the UK National Patient Safety Agency. FINDINGS: 102 risks were identified and 95 recommendations made. The top 20 recommendations together were judged to encompass about 75% of the total estimated risk attributable to the processes considered. Staffing and organisational issues (21% of total estimated risk) included recommendations for removing distractions from the operating theatre, ensuring the availability of senior anaesthetists and promoting standards and flexible working among theatre staff. Devices and equipment (19% of total estimated risk) could be improved by training and standardisation; airway control and temperature monitoring were identified as two specific areas. Pre-assessment of patients before admission to hospital (12% of estimated risk) could be improved by defining a data set for adequate pre-assessment and making this available throughout the NHS. CONCLUSIONS: This technique can be successfully applied by healthcare staff but expert facilitation of groups is advisable. Such wider-ranging processes can potentially lead to more comprehensive risk reduction than "single-issue" risk alerts. PMID- 20172888 TI - How will it work? A qualitative study of strategic stakeholders' accounts of a patient safety initiative. AB - OBJECTIVES: Implementation of quality improvement programmes may suffer if the stakeholders involved do not share a common understanding of the theory of change or do not accept it as legitimate. We aimed to identify how strategic stakeholders understood and responded to the first phase of the Health Foundation's Safer Patients Initiative, a programme aimed at making hospitals safer for patients in the UK. METHODS: Semistructured telephone interviews were conducted with 60 strategic-level hospital stakeholders and with five stakeholders involved in commissioning, designing and introducing the initiative. Analysis was based on the constant comparative method. RESULTS: The aims of the initiative were seen as legitimate and sound by most hospital stakeholders, and the theory of change was generally understood and accepted, but seven hospital stakeholders were unable to describe it. Although participants had specific doubts, particularly relating to feasibility of implementation and scientific legitimacy of some elements of the initiative, overall there was a broadly shared vision and commitment to the principles and practices associated with the theory of change, and considerable enthusiasm and optimism. Contestations about the legitimacy and relevance of the initiative among front-line staff, local resistance to changes that went against established norms, and resource and structural issues were, however, seen as potentially threatening to implementation. CONCLUSIONS: It is possible to get strategic-level individuals, even when widely dispersed, to understand and agree upon a theory of change that can be used in their organisations. These individuals are also able to recognise the contexts of negotiation in which programmes of change are enacted. PMID- 20172889 TI - No obligation to report adverse effects in British complementary and alternative medicine: evidence for double standards. PMID- 20172890 TI - Workforce implications of a centralised teaching hospital respiratory opinion service. PMID- 20172891 TI - Discharge: have you advised on driving? PMID- 20172892 TI - Advanced care planning in children with life-limiting conditions - the Wishes Document. PMID- 20172893 TI - Could CT scan avoid unnecessary flexible bronchoscopy in children with active pulmonary tuberculosis? A retrospective study. AB - BACKGROUND: Systematic flexible bronchoscopy is advocated in the initial management of childhood pulmonary tuberculosis. METHODS: Our aim was to describe and to compare the systematic flexible bronchoscopy findings of 53 children (6.5 + or - 4.4 years; 52.8% boys) with active pulmonary tuberculosis to their initial clinical and radiological (chest x-ray, n=53; CT, n=45) features in an 11-year retrospective study. RESULTS: Flexible bronchoscopy was normal in 51% of cases. A severe tracheobronchial involvement (extrinsic compression >50% or obstructive endoluminal mass >25% of the lumen) was found in 10 patients. Flexible bronchoscopy guided therapy in 13 cases (steroids n=12, bronchoscopic extraction of a granuloma n=1) and permitted isolation of Mycobacterium tuberculosis in three patients (5.7%). No useful information was obtained by flexible bronchoscopy in 73.5% of cases. No correlation was found between flexible bronchoscopy findings and clinical features or x-ray findings. Conversely, a strong correlation was found between severe bronchoscopic involvement and tracheobronchial luminal narrowing on CT. The CT negative predictive value was 100% (95% CI 91% to 100%). Based on CT results, flexible bronchoscopy could have been avoided in about 60% of our patients. CONCLUSIONS: Flexible bronchoscopy remains a very relevant tool in the diagnostic and therapeutic management of childhood pulmonary tuberculosis but resulted in treatment modification or microbiological proof in a minority of our patients. We propose that flexible bronchoscopy in children with pulmonary tuberculosis be limited to those who show tracheobronchial luminal narrowing on an initial CT scan. PMID- 20172895 TI - Long-term steroid treatment and growth: a study in steroid-dependent nephrotic syndrome. AB - OBJECTIVE: High-dose steroid therapy in children is known to impair growth. What is unknown is the level of steroid therapy at which children continue to grow normally. This study was designed to deduce a dosage of prednisolone compatible with normal growth. PATIENTS AND DESIGN: The growth of 41 children (age 1.92-13.2 years) with steroid-dependent nephrotic syndrome (SDNS) was studied using recordings from clinic visits over the course of their follow-up at Great Ormond Street Hospital (study period range 1.38-8.43 years, mean 4.2 years, total 172 years). The height standard deviation score (SDS) and the SDS velocity between clinics were calculated, and compared to the contemporary dose of prednisolone (converted to an equivalent daily dose when on an alternate day regime). RESULTS: The mean dose of prednisolone was 0.44 mg/ kg/day (range 0.06-1.45 mg/kg/day). The mean change in height SDS velocity over the course of recording was -0.02 SDS/year (boys -0.14 SDS/year, girls +0.16 SDS/year). Overall, there was no negative effect on growth seen at doses of prednisolone of less than 0.75 mg/kg/day. At doses higher than 0.75 mg/kg/day, there was a small decline in height SDS velocity (-0.14 SDS/ year). CONCLUSIONS: Overall, prednisolone treatment in these children was not shown to adversely affect their height SDS. This was true even at doses of prednisolone up to 0.5-0.75 mg/kg/day. There was some decline in height SDS seen during periods of higher steroid use (over 0.75 mg/kg/day), but periods on lower doses allowed for adequate catch up growth. PMID- 20172896 TI - Images in paediatrics: a tight airway. PMID- 20172898 TI - Lucina. PMID- 20172897 TI - Aminoglycoside-induced deafness during treatment of acute leukaemia. AB - Three unrelated children from ethnically diverse backgrounds who were treated for acute leukaemia became profoundly and irreversibly deaf during treatment. Aminoglycoside levels were within the therapeutic range. Genetic testing showed all three to have a maternally inherited mutation of mitochondrial DNA, m.1555A>G, known to cause sensitivity to the ototoxic effects of aminoglycosides. One child has received a cochlear implant, and another will be implanted shortly. Children diagnosed with acute leukaemia should be tested for this mutation at diagnosis, and alternative antibiotics chosen for the treatment of sepsis. Consideration should be given to elective testing of other groups of patients likely to receive aminoglycosides. PMID- 20172899 TI - Induction of oxidative damage in the testes and spermatozoa and hematotoxicity in rats exposed to multiple doses of ethylene glycol monoethyl ether. AB - The effects of ethylene glycol monoethyl ether (EGEE) on the antioxidant systems of the testes and epididymal spermatozoa were investigated in rats at dose levels of 0, 100, 200 and 400 mg kg(-1) body weight (bw) administered orally by gavage for 14 consecutive days. The bw gain of the EGEE-treated rats decreased significantly at 200 and 400 mg kg(- 1) bw compared with the control group. There were no significant changes in the weights of the testes, epididymis, seminal vesicles and prostate glands of the EGEE-treated rats. In the testes, while EGEE treatment resulted in significant decrease in glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) activities, it markedly increased the malondialdehyde (MDA) level, glutathione-S-transferase (GST) and lactate dehydrogenase (LDH) activities at 200 and 400 mg kg(-1) dose levels but vitamin C content remained unaffected in all the groups. In the spermatozoa, administration of EGEE caused significant decrease in the activities of CAT, GST and LDH as well as in the levels of vitamin C and GSH but significantly increased the MDA level and SOD activity compared with the control rats. Histopathological examination showed severe degeneration of the testes, such as generalized erosion and necrosis of the germinal epithelium of the testes, but mildly affected the epididymis at 400 mg kg(-1) dose only. Data on spermatozoa analysis of EGEE treated rats revealed significant decrease in the epididymal spermatozoa number, testicular spermatozoa number, daily spermatozoa production and spermatozoa motility but significantly increased the total spermatozoa abnormalities without affecting the spermatozoa live-dead ratio at all dose levels when compared with the control group. Results of haematological examination showed that white blood cells (WBC), platelets neutrophils and mean corpuscular haemoglobin concentration (MCHC) were significantly lower whereas lymphocytes were increased in 200 and 400 mg/kg EGEE-exposed rats than in the controls. EGEE at 100 mg/kg bw produced minor effect on haematological parameters but adversely affected testes and spermatozoa. In summary, short term administration of EGEE is hematotoxic and gonadotoxic and its effects on male reproduction could be due to the induction of oxidative stress in testes and spermatozoa. PMID- 20172901 TI - The new role of the perfusionist in adult extracorporeal life support. AB - Adult and pediatric extracorporeal life support (ECLS) has been transformed by the European(1) and Australian( 2) experiences with a reduction of the circuit to its most basic form (Figure 1). Many factors have converged at this point in time to allow us to offer this support. The availability in the U.S.A. of an advanced oxygenator (Quadrox(D)) (Maquet Inc., Bridgewater, NJ), long-term centrifugal pumps and circuit coatings offers us the means to provide ECLS. The other equally important factor is the intensivist trained in extracorporeal therapies. Once the intensive care unit registered nurse (ICU RN) is trained to safely and effectively manage both the patient and ECLS circuit, this support may be offered. The perfusionist is in an unique position to educate and mentor the ICU RN in ECLS. There is, perhaps, no one in a better position to explain this equipment and its uses in an interdisciplinary-oriented pediatric and adult ECLS program than a perfusionist. PMID- 20172900 TI - Comparable biocompatibility of Phisio- and Bioline-coated cardiopulmonary bypass circuits indicated by the inflammatory response. AB - BACKGROUND: The biocompatibility of cardiopulmonary bypass surfaces has been improved by heparin and polymer surface modifications. The present study compared the effect of two such coatings on the inflammatory reactions after open heart surgery. METHODS: Thirty patients undergoing elective heart surgery were randomly assigned to receive one of two types of coated circuits: Bioline (n=15) or phosphorylcholine (Phisio, n=15). The platelet and leukocyte counts, neutrophil activation (myeloperoxidase), complement activation (C3a and TCC), concentrations of lactate dehydrogenase, 27 cytokines (including interleukins, chemokines and growth factors), thrombin-antithrombin complexes, and the endothelial cell marker syndecan-1 were analyzed at five predetermined time points until 24 hrs post operatively. RESULTS: Most measurements were comparable in both groups. However, myeloperoxidase was significantly higher in the Bioline group (p < 0.001). Postoperative lactate dehydrogenase concentrations were significantly higher in the Phisio group (p<0.01) and the maximal concentration of thrombin-antithrombin complexes 2 hours postoperatively tended to be higher in the Phisio group (p=0.08), consistent with a longer aortic cross-clamp and cardiopulmonary bypass time. CONCLUSIONS: The two circuits exhibited a comparable degree of in vivo biocompatibility. PMID- 20172902 TI - Environmental volunteering and health outcomes over a 20-year period. AB - PURPOSE: This study tested the hypothesis that volunteering in environmental organizations in midlife is associated with greater physical activity and improved mental and physical health over a 20-year period. DESIGN AND METHODS: The study used data from two waves (1974 and 1994) of the Alameda County Study, a longitudinal study of health and mortality that has followed a cohort of 6,928 adults since 1965. Using logistic and multiple regression models, we examined the prospective association between environmental and other volunteerism and three outcomes (physical activity, self-reported health, and depression), with 1974 volunteerism predicting 1994 outcomes, controlling for a number of relevant covariates. RESULTS: Midlife environmental volunteering was significantly associated with physical activity, self-reported health, and depressive symptoms. IMPLICATIONS: This population-based study offers the first epidemiological evidence for a significant positive relationship between environmental volunteering and health and well-being outcomes. Further research, including intervention studies, is needed to confirm and shed additional light on these initial findings. PMID- 20172904 TI - Predictors of C-reactive protein in the national social life, health, and aging project. AB - OBJECTIVE: Inflammation plays an important role in many chronic degenerative diseases associated with aging, and social, economic, and behavioral factors that contribute to inflammation may lead to differential burdens of morbidity and mortality in later life. This study examines socioeconomic status and race/ethnicity as predictors of C-reactive protein (CRP) among older adults in the United States and considers the degree to which health behaviors, medical conditions and medication use, and psychosocial factors account for these associations. METHODS: Multiple linear regression analysis of survey data for 1,580 participants, 57-85 years of age, in a population-based nationally representative sample of community-residing older adults in the United States. RESULTS: Educational attainment, household wealth, and race/ethnicity were independently associated with CRP, with limited evidence for interactions with age. Health-related behaviors and usage of medications related to inflammation accounted for substantial proportions of these associations. DISCUSSION: These results highlight the fundamental causes of inflammation among older adults and suggest pathways through which social disparities in inflammation may be reduced. PMID- 20172906 TI - Clinical impact and predisposing factors of delayed-onset neutropenia after autologous hematopoietic stem-cell transplantation for B-cell non-Hodgkin lymphoma: association with an incremental risk of infectious events. AB - BACKGROUND: Clinical significance of delayed-onset neutropenia (DON) after autologous hematopoietic stem-cell transplantation (ASCT) has not been well described. We conducted a retrospective cohort study to examine risk factors and clinical impact of DON. DESIGN AND METHODS: Subjects were consecutive 108 patients with B-cell lymphoma receiving ASCT. We defined DON as absolute neutrophil counts <1.0 x 10(9)/l at any point from 30 days onward after ASCT without apparent causes of neutropenia. Documented infectious events were reviewed from 1 to 18 months after ASCT. RESULTS: Fifty-two percent of patients received rituximab. Cumulative incidence of DON was 50% at 1 year. Rituximab usage was identified as an independent risk factor of DON. A total of 117 infectious events were documented, of which 24 events occurred during DON period. Cumulative incidence of total infectious events was 75% and 42% in the groups with and without DON, respectively (P = 0.001). Varicella-zoster virus (P = 0.033) and upper respiratory infection (P = 0.016) were frequent in the patients experiencing DON. In a multivariable analysis, DON remained a significant factor for total infectious events and upper respiratory infection. CONCLUSIONS: Rituximab usage is an independent risk factor of DON. DON correlates with increased occurrence of infectious events. Careful follow-up would be needed after the onset of DON. PMID- 20172905 TI - In situ trans ligands of CD22 identified by glycan-protein photocross-linking enabled proteomics. AB - CD22, a regulator of B-cell signaling, is a siglec that recognizes the sequence NeuAcalpha2-6Gal on glycoprotein glycans as ligands. CD22 interactions with glycoproteins on the same cell (in cis) and apposing cells (in trans) modulate its activity in B-cell receptor signaling. Although CD22 predominantly recognizes neighboring CD22 molecules as cis ligands on B-cells, little is known about the trans ligands on apposing cells. We conducted a proteomics scale study to identify candidate trans ligands of CD22 on B-cells by UV photocross-linking CD22 Fc chimera bound to B-cell glycoproteins engineered to carry sialic acids with a 9-aryl azide moiety. Using mass spectrometry-based quantitative proteomics to analyze the cross-linked products, 27 glycoproteins were identified as candidate trans ligands. Next, CD22 expressed on the surface of one cell was photocross linked to glycoproteins on apposing B-cells followed by immunochemical analysis of the products with antibodies to the candidate ligands. Of the many candidate ligands, only the B-cell receptor IgM was found to be a major in situ trans ligand of CD22 that is selectively redistributed to the site of cell contact upon interaction with CD22 on the apposing cell. PMID- 20172907 TI - Staphylococcus aureus pericardial abscess presenting as a localized bulge of the heart contour. AB - Purulent pericarditis usually presents as an acute illness with diffuse involvement of the whole pericardium, but can rarely present as a localized effusion. Here, we present a patient with a pericardial abscess caused by Staphylococcus aureus. After surgical drainage of the abscess, the patient made a good recovery. To the best of our knowledge, this is the first case of a pericardial abscess presenting as a localized bulge of the heart contour on the chest X-ray. PMID- 20172908 TI - Is the mediastinal lymphadenectomy during pulmonary metastasectomy of colorectal cancer necessary? AB - The aim of study was to investigate the pattern of mediastinal lymph node metastases in patients with colorectal cancer metastasis. Twenty-four pulmonary metastasectomies with mediastinal lymphadenectomies were performed on 19 patients (14 unilateral and five bilateral operations). The metastases were centrally localised in eight cases; the primary tumour was colon cancer in 15 patients and rectal cancer in nine cases. The number and the localisation of metastases were recorded, as the clinico-pathological data of the primary tumours. The results were compared with the pattern of metastases in mediastinal lymph nodes. The data were subjected to statistical processing with the chi(2)-test and Mann-Whitney test. Mediastinal lymph node metastases were confirmed in eight cases (33.3%). The proportion of positive lymph nodes was significantly higher for central metastases (62.5% vs. 18.8%, P=0.032). When the pathological stage of the primary tumour was more advanced, the proportion of lymph node metastases displayed a statistically not significant increase. The pattern of lymph node metastases did not correlate with the localisation of the lung metastases, disease-free interval and the diameter of the greatest pulmonary metastasis. The frequency of lymph node metastasis is relatively high, therefore, mediastinal lymphadenectomy during the resection of colorectal cancer metastases is necessary. PMID- 20172909 TI - Effect of mild renal dysfunction (s-crea 1.2-2.2 mg/dl) on presentation characteristics and short- and long-term outcomes of on-pump cardiac surgery patients. AB - OBJECTIVES: The objective of this study is to evaluate differences in patient presentation and short- and long-term outcomes between patients dichotomized by the level of preoperative s-creatinine (s-crea) without renal failure and to use EuroSCORE (ES) risk stratification for validating differences and for predictive purposes. METHODS: A thousand consecutive cardiac surgery patients from January 1999 through May 2000 were analyzed. Patients with off-pump surgery or s-crea >200 micromol/l (>2.2 mg/dl) were excluded leaving 885 patients for analysis. Group 1 (n=703) had s-crea 0.5-1.2 mg/dl and Group 2 (n=182) had elevated s-crea 1.3-2.2 mg/dl but no renal insufficiency. RESULTS: Group 2 patients were older (P<0.0001), had a higher percentage of males (P=0.008), had lower left ventricular ejection fraction (LVEF) (P=0.001), had higher New York Heart Association (NYHA) classification (P<0.0001), had more diabetics (P=0.001) and had more patients with a history of congestive heart failure (CHF) (P<0.0001). Both additive ES (AES) and logistic ES (LES) variables were higher in Group 2 patients, AES 8.45+/-4.28% vs. 6.05+/-3.80% (P<0.0001) and LES 17.7+/-19.1% vs. 9.57+/-13.3% (P<0.0001). Proportions of emergency operations and use of intra aortic balloon pulsation (IABP) support did not differ. There were more coronary artery bypass grafting (CABG) with or without concomitant procedures in Group 1 but otherwise the procedures performed were similar. Cardiopulmonary bypass (CPB) times did not differ (P=0.1). Operative mortality was similar (P=0.06) but hospital mortality was higher in Group 2: 19/10.4% vs. 25/3.6% (P<0.0001), odds ratio (OR) 3.16. Total length of stay (LOS) and length of stay in the postoperative intensive care unit (ICU) did not differ. Postoperative renal failure (PORF) (s-crea increase to >2.25 mg/dl or >200 micromol/l) developed in 38/4.5% patients in Group 1 and in 41/22.5% patients in Group 2 (P<0.0001), OR=5.08. Follow-up all-cause mortality was higher in Group 2: 68/37.4% vs. 167/23.8% (P<0.0001), OR=1.91. Both ES definitions predicted hospital mortality, LOS, ICU, PORF and long-term mortality well, while increased s-crea predicted PORF and long-term mortality in both groups. CONCLUSIONS: Mild increase in s-crea is a marker for patients with increased cardiac risk factors and the risk for poor outcomes. Both ES definitions are highly predictive of the outcomes. PMID- 20172910 TI - Hypogastric artery bypass in open repair of abdominal aortoiliac aneurysm: a safe procedure. AB - OBJECTIVES: The aim of this study is to assess the immediate and mid-term results of hypogastric artery bypass (HAB) in open repair of abdominal aortic aneurysm (AAA). METHODS: The clinical data of 24 patients with an average age of 70.4 years [standard deviation (S.D.)+/-8.1 years] with AAA treated between January 2005 and December 2008 with HAB during open repair of aortoiliac aneurysm were reviewed. Eighteen patients received unilateral and six bilateral hypogastric bypasses, using a segment of Dacron graft prosthesis. Concomitant hypogastric eversion endarterectomy was associated in six cases (25%). Follow-up was complete in all the 24 patients and averaged 16.2 months (range 1-35). Postoperative imaging protocol involved a conventional Echocolordoppler and CT-scan. With respect to the operating time, the blood loss, the intensive care unit (ICU) and the length of ward admission (LWA) stay, we compared the 24 patients who underwent hypogastric bypass (group A) with the 50 patients who had bifurcated graft without hypogastric bypass (group B). RESULTS: Between the two groups, statistically different results were demonstrated only with respect to the duration of operation (h) (group A 5.19+/-1.38 vs. group B 4.39+/-1.32, P=0.0195). No statistical differences were noted for ICU stay (h) (group A median 21.50 vs. group B median 21.3, range 1 degrees -3 degrees quartile 19.75-23.50) and LWA stay (days) (group A median 8.50, range 1 degrees -3 degrees quartile 7.00-11.50 vs. group B median 8.0, range 1 degrees -3 degrees quartile 7.00 9.00). There were no operative deaths, bowel or intestinal ischemia in the early postoperative period between the two groups. In group A, one patient had transient renal failure and one patient had an acute coronary syndrome. In group B, one patient had a peripheral ischemia who required tibioperoneal embolectomy. The patency of the hypogastric grafts was demonstrated in all cases. CONCLUSIONS: In our experience, direct revascularization of the hypogastric artery to ensure pelvic vascularization in aortoiliac surgery appears a safe procedure. PMID- 20172912 TI - Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. AB - BACKGROUND: In 1994, an International Task Force proposed criteria for the clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) that facilitated recognition and interpretation of the frequently nonspecific clinical features of ARVC/D. This enabled confirmatory clinical diagnosis in index cases through exclusion of phenocopies and provided a standard on which clinical research and genetic studies could be based. Structural, histological, electrocardiographic, arrhythmic, and familial features of the disease were incorporated into the criteria, subdivided into major and minor categories according to the specificity of their association with ARVC/D. At that time, clinical experience with ARVC/D was dominated by symptomatic index cases and sudden cardiac death victims-the overt or severe end of the disease spectrum. Consequently, the 1994 criteria were highly specific but lacked sensitivity for early and familial disease. METHODS AND RESULTS: Revision of the diagnostic criteria provides guidance on the role of emerging diagnostic modalities and advances in the genetics of ARVC/D. The criteria have been modified to incorporate new knowledge and technology to improve diagnostic sensitivity, but with the important requisite of maintaining diagnostic specificity. The approach of classifying structural, histological, electrocardiographic, arrhythmic, and genetic features of the disease as major and minor criteria has been maintained. In this modification of the Task Force criteria, quantitative criteria are proposed and abnormalities are defined on the basis of comparison with normal subject data. CONCLUSIONS: The present modifications of the Task Force Criteria represent a working framework to improve the diagnosis and management of this condition. Clinical Trial Registration clinicaltrials.gov Identifier: NCT00024505. PMID- 20172913 TI - Cardiovascular flashlight. Detection of cardiac tumour-surface thrombus: utilization of cardiac magnetic resonance imaging avascular tissue nulling sequence. PMID- 20172911 TI - Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. AB - BACKGROUND: In 1994, an International Task Force proposed criteria for the clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) that facilitated recognition and interpretation of the frequently nonspecific clinical features of ARVC/D. This enabled confirmatory clinical diagnosis in index cases through exclusion of phenocopies and provided a standard on which clinical research and genetic studies could be based. Structural, histological, electrocardiographic, arrhythmic, and familial features of the disease were incorporated into the criteria, subdivided into major and minor categories according to the specificity of their association with ARVC/D. At that time, clinical experience with ARVC/D was dominated by symptomatic index cases and sudden cardiac death victims-the overt or severe end of the disease spectrum. Consequently, the 1994 criteria were highly specific but lacked sensitivity for early and familial disease. METHODS AND RESULTS: Revision of the diagnostic criteria provides guidance on the role of emerging diagnostic modalities and advances in the genetics of ARVC/D. The criteria have been modified to incorporate new knowledge and technology to improve diagnostic sensitivity, but with the important requisite of maintaining diagnostic specificity. The approach of classifying structural, histological, electrocardiographic, arrhythmic, and genetic features of the disease as major and minor criteria has been maintained. In this modification of the Task Force criteria, quantitative criteria are proposed and abnormalities are defined on the basis of comparison with normal subject data. CONCLUSIONS: The present modifications of the Task Force Criteria represent a working framework to improve the diagnosis and management of this condition. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00024505. PMID- 20172914 TI - Inflammatory cytokines in heart failure: roles in aetiology and utility as biomarkers. PMID- 20172915 TI - Cardiovascular flashlight. An unusual cause of cardiogenic shock. PMID- 20172916 TI - Cardiovascular flashlight. Cocaine-induced myocardial injury seen as multiple mid wall foci of late enhancement by contrast-enhanced cardiac magnetic resonance imaging. PMID- 20172917 TI - UK smoke-free legislation: changes in PM2.5 concentrations in bars in Scotland, England, and Wales. AB - OBJECTIVE: Evaluate the effect of smoke-free legislation on fine particulate [particulate matter <2.5 microm in diameter (PM(2.5))] air pollution levels in bars in Scotland, England, and Wales. DESIGN: Air quality was measured in 106 randomly selected bars in Scotland, England, and Wales before and after the introduction of smoking restrictions. METHODS: PM(2.5) concentrations were measured covertly for 30-min periods before smoke-free legislation was introduced, again at 1-2 months post-ban (except Wales) and then at 12-months post-baseline (except Scotland). In Scotland and England, overt measurements were carried out to assess bar workers' full-shift personal exposures to PM(2.5). Postcode data were used to determine socio-economic status of the bar location. RESULTS: PM(2.5) levels prior to smoke-free legislation were highest in Scotland (median 197 microg m(-3)), followed by Wales (median 184 microg m(-3)) and England (median 92 microg m(-3)). All three countries experienced a substantial reduction in PM(2.5) concentrations following the introduction of the legislation with the median reduction ranging from 84 to 93%. Personal exposure reductions were also within this range. There was evidence that bars located in more deprived postcodes had higher PM(2.5) levels prior to the legislation. CONCLUSIONS: Prior to legislation PM(2.5) concentrations within bars across the UK were much higher than the 65 microg m(-3) 'unhealthy' threshold for outdoor air quality as set by the US Environmental Protection Agency. Concentrations in Scottish and Welsh bars were, on average, two or more times greater than in English bars for which seasonal influences may be responsible. Legislation in all three countries produced improvements in indoor air quality that are consistent with other international studies. PMID- 20172918 TI - Quartz exposure in agriculture: literature review and South African survey. AB - OBJECTIVES: To review the published literature on respirable quartz exposure and associated disease in agricultural related settings systematically and to describe personal respirable dust and quartz measurements collected on a sandy soil farm in the Free State province of South Africa. METHODS: The published studies on exposure to respirable silica and quartz in agriculture and related settings (to June 2009) were searched systematically through 'PubMed' and critiqued. A farm in the sandy soil region of the Free State province of South Africa producing typical crops for the region was identified and 138 respirable dust and respirable quartz measurements were collected from July 2006-August 2008 during major farming operations. RESULTS: In total, 17 studies were identified: 11 investigated respirable quartz exposure on farms and 6 quartz-related diseases in agricultural settings. They provided convincing evidence of a respirable quartz risk on sandy soil farms but scant evidence of associated disease. Respirable quartz measurements from the South African farm ranged from not detectable to 626 microg m(-3) and confirmed the quartz risk as some concentrations exceeded generally accepted occupational exposure limits in all jobs evaluated, even though the majority of respirable dust concentrations were well below a commonly used occupational exposure limit of 2 mg m(-3). Twelve of 138 respirable dust measurements (9%) and 18 of 138 respirable quartz measurements (13%) exceeded commonly used occupational exposure limits of 2 mg m( 3) and 100 microg m(-3), respectively. The highest time weighted average respirable quartz concentration of 626 microg m(-3) was during wheat planting activities. Fifty-seven percent of the respirable quartz measurements exceeded the American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Value (TLV) of 25 microg m(-3). Quartz percentages of the respirable dust ranged from 0.3 to 94.4% with an overall median of 13.4%. CONCLUSION: Despite its ubiquity, little is known about quartz exposure in the agricultural industry; but this study demonstrates significant potential for overexposure in some settings. Further research is required to quantify quartz exposure and identify settings and tasks that place farmers and farmworkers at risk of quartz-associated diseases so that controls can be implemented. PMID- 20172919 TI - Dietary calcium and magnesium intake and mortality: a prospective study of men. AB - The authors examined the association of dietary calcium and magnesium intake with all-cause, cardiovascular disease (CVD), and cancer mortality among 23,366 Swedish men, aged 45-79 years, who did not use dietary supplements. Cox proportional hazards regression models were used to estimate the multivariate hazard ratios and 95% confidence intervals of mortality. From baseline 1998 through December 2007, 2,358 deaths from all causes were recorded in the Swedish population registry; through December 2006, 819 CVD and 738 cancer deaths were recorded in the Swedish cause-of-death registry. Dietary calcium was associated with a statistically significant lower rate of all-cause mortality (hazard ratio (HR) = 0.75, 95% confidence interval (CI): 0.63, 0.88; P(trend) < 0.001) and a nonsignificantly lower rate of CVD (HR = 0.77, 95% CI: 0.58, 1.01; P(trend) = 0.064) but not cancer mortality (HR = 0.87, 95% CI: 0.65, 1.17; P(trend) = 0.362) when the highest intake tertile (mean = 1,953 mg/day; standard deviation (SD), 334) was compared with the lowest (990 mg/day; SD, 187). Dietary magnesium intake (means of tertiles ranged from 387 mg/day (SD, 31) to 523 mg/day (SD, 38) was not associated with all-cause, CVD, or cancer mortality. This population-based, prospective study of men with relatively high intakes of dietary calcium and magnesium showed that intake of calcium above that recommended daily may reduce all-cause mortality. PMID- 20172920 TI - The changing distribution and determinants of obesity in the neighborhoods of New York City, 2003-2007. AB - Obesity (body mass index >or=30 kg/m(2)) is a growing urban health concern, but few studies have examined whether, how, or why obesity prevalence has changed over time within cities. This study characterized the individual- and neighborhood-level determinants and distribution of obesity in New York City from 2003 to 2007. Individual-level data from the Community Health Survey (n = 48,506 adults, 34 neighborhoods) were combined with neighborhood measures. Multilevel regression assessed changes in obesity over time and associations with neighborhood-level income and food and physical activity amenities, controlling for age, racial/ethnic identity, education, employment, US nativity, and marital status, stratified by gender. Obesity rates increased by 1.6% (P < 0.05) each year, but changes over time differed significantly between neighborhoods and by gender. Obesity prevalence increased for women, even after controlling for individual- and neighborhood-level factors (prevalence ratio = 1.021, P < 0.05), whereas no significant changes were reported for men. Neighborhood factors including increased area income (prevalence ratio = 0.932) and availability of local food and fitness amenities (prevalence ratio = 0.889) were significantly associated with reduced obesity (P < 0.001). Findings suggest that policies to reduce obesity in urban environments must be informed by up-to-date surveillance data and may require a variety of initiatives that respond to both individual and contextual determinants of obesity. PMID- 20172921 TI - Prospective study of dietary fiber and risk of chronic obstructive pulmonary disease among US women and men. AB - Little is known about the relation between dietary fiber intake and the incidence of respiratory diseases, especially chronic obstructive pulmonary disease (COPD). The authors investigated this issue among 111,580 US women and men (Nurses' Health Study and Health Professionals Follow-up Study), with 832 cases of newly diagnosed COPD being reported between 1984 and 2000. The cumulative average intake of total fiber and of fiber from specific sources (cereal, fruit, and vegetables) was calculated from food frequency questionnaires and a food composition database and divided into quintiles. After adjustment for 11 factors (age, sex, smoking, energy intake, body mass index, US region, physician visits, physical activity, diabetes, and intakes of omega-3 and cured meat), total dietary fiber intake was negatively associated with risk of newly diagnosed COPD (for highest vs. lowest intake, relative risk = 0.67, 95% confidence interval: 0.50, 0.90; P(trend) = 0.03). For specific fiber sources (cereal, fruit, and vegetables), only cereal fiber was significantly associated with newly diagnosed COPD independently of other fiber sources (for highest vs. lowest intake, relative risk = 0.77, 95% confidence interval: 0.59, 0.99; P(trend) = 0.04). These data suggest that a diet high in fiber, and possibly specifically cereal fiber, may reduce risk of developing COPD. PMID- 20172922 TI - Traditional Chinese practitioner breaches Medicine Act. PMID- 20172924 TI - Psychiatrist accused of dishonesty for prescribing drugs to a patient under a false name. PMID- 20172925 TI - Linking up for better health care. PMID- 20172926 TI - Acquired brain injury. PMID- 20172927 TI - Tiotropium and chronic obstructive pulmonary disease. PMID- 20172928 TI - An approach to the evaluation and management of syncope in adults. PMID- 20172930 TI - Study fails to show link previously found between virus and chronic fatigue syndrome. PMID- 20172931 TI - The hydrological impact assessment in the decision support of nuclear emergency response. AB - The paper presents several aspects believed to be relevant for the integration in the decision support systems for the management of radiological emergencies, of assessment tools addressing surface water contamination. Three exemplary cases are discussed in the context-the CONVEX 2005 international alert exercise, AXIOPOLIS 09, a national drill targeting a CANDU reactor at Cernavoda nuclear power plant in Romania, and Oltenia 07-a nation-wide drill around a scenario, involving trans-border effects of a virtual accident at a VVER reactor at Kozloduy, Bulgaria. The capability of different analytic tools were tested, including public deliverables like real-time, online decision support system's HDM module and model-based computerised system for management support to identify optimal remedial strategies for restoring radionuclide-contaminated aquatic ecosystems and drainage areas, as well as research-grade, home-made facilities, in order to identify and sort out merits and issues of interest in steering their effective utilisation. PMID- 20172933 TI - Simulated dose reduction by adding artificial noise to measured raw data: a validation study. AB - The purpose of this study was to verify and validate a noise simulation tool called Dose Tutor (VAMP GmbH) in terms of level and texture of the simulated noise. By adding artificial noise to measured computed tomography (CT) raw data, a scan acquired with a lower dose (mAs) than the actual one can be simulated. A homogeneous polyethylene phantom and an anthropomorphic chest phantom were scanned for different mAs levels, tube voltages, slice thicknesses and reconstruction kernels. The simulated noise levels were compared with the noise levels in real transverse slice images actually acquired with corresponding mAs values. In general, the noise comparisons showed acceptable agreement in magnitude (<20 % deviation in pixel standard deviation). Also, the calculated noise power spectra were similar, which indicates that the noise texture is correctly reproduced. In conclusion, this study establishes that the Dose Tutor might be a useful tool for estimating the dose reduction potential for CT protocols. PMID- 20172932 TI - Investigation of biokinetics of radioiodine with a population kinetics approach. AB - The dosimetric studies required for planning individually tailored radioiodine therapy of benign thyroid pathologies may be too complex and time-demanding for many ordinary nuclear medicine departments. In this work, a preliminary population kinetics approach was applied to a model structure for iodine biokinetics in order to identify those model features that actually need to be individually investigated, in order to simplify the protocol for data collection in patients. Data from 29 patients undergoing radioiodine therapy for the treatment of the autonomous nodule syndrome were used in the analysis. The greatest inter-individual variations were observed in the parameters describing the transformation of iodide into organic iodine in the thyroid and in the kinetics of the organic form. PMID- 20172934 TI - Experimental evaluation of neutron performance in boron-doped low activation concrete. AB - Reaction rate distribution in concrete with/without boron dopant up to a thickness of 60 cm was measured using Yayoi fast reactor located at University of Tokyo. The 7 reaction rates such as (197)Au(n,gamma), (59)Co(n,gamma), (115)In(n,n'), (55)Mn(n,gamma), (23)Na(n,gamma), (94)Zr(n,gamma) and (96)Zr(n,gamma) were measured at 12 different depths, and the reduction of the reaction rate as a result of boron doping was quantitatively analysed. These reaction rates were also used to determine epithermal neutron spectrum shape parameter. Monte Carlo simulations of the experimental setup were performed using the MCNP-5 code. Simulated depth profiles of reaction rates and the epithermal neutron spectrum shape parameter agreed with the experimental results with fair accuracy. This experimental results provide useful data to benchmark the accuracy of neutron transport codes in the prediction of transmission and neutron spectrum distortion in boron-doped concrete. PMID- 20172935 TI - Determination of the detective quantum efficiency of gamma camera systems: a Monte Carlo study. AB - The purpose of the present work was to investigate the validity of using the Monte Carlo technique for determining the detective quantum efficiency (DQE) of a gamma camera system and to use this technique in investigating the DQE behaviour of a gamma camera system and its dependency on a number of relevant parameters. The Monte Carlo-based software SIMIND, simulating a complete gamma camera system, was used in the present study. The modulation transfer function (MTF) of the system was determined from simulated images of a point source of (99m)Tc, positioned at different depths in a water phantom. Simulations were performed using different collimators and energy windows. The MTF of the system was combined with the photon yield and the sensitivity, obtained from the simulations, to form the frequency-dependent DQE of the system. As figure-of merit (FOM), the integral of the 2D DQE was used. The simulated DQE curves agreed well with published data. As expected, there was a strong dependency of the shape and magnitude of the DQE curve on the collimator, energy window and imaging position. The highest FOM was obtained for a lower energy threshold of 127 keV for objects close to the detector and 131 keV for objects deeper in the phantom, supporting an asymmetric window setting to reduce scatter. The Monte Carlo software SIMIND can be used to determine the DQE of a gamma camera system from a simulated point source alone. The optimal DQE results in the present study were obtained for parameter settings close to the clinically used settings. PMID- 20172936 TI - An updated assessment of radon exposure in Canada. AB - Based on data from a national residential radon survey performed in 18 cities in Canada in the 1970s, an annual effective dose to the Canadian population due to indoor radon exposure was estimated at 0.71 mSv. An updated estimate of radon exposure in Canada has been made using additional indoor radon data from recent surveys in Ontario and Nova Scotia, and in 28 communities of British Columbia and 15 regions of Quebec. The associated annual effective dose to the Canadian population is now estimated to be 1.15 mSv. The percentage of homes in Canada with radon concentrations above the Canadian Radon Guideline of 200 Bq m(-3) is estimated to be about 3.3 %. As might be expected, this number varies significantly (from a low of 1 % of homes above the Guideline to a high of 19 %) from region to region. Because more radon data are included in the current assessment, and the data set covers broader geographical areas, the current assessment better represents the radon exposure in Canada. PMID- 20172937 TI - Better radiation weighting factors for neutrons generated from proton treatment are needed. PMID- 20172938 TI - Sevoflurane preserves the endothelial glycocalyx against ischaemia-reperfusion injury. AB - BACKGROUND: Healthy vascular endothelium is coated by the glycocalyx, important in multiple endothelial functions, but destroyed by ischaemia-reperfusion. The impact of volatile anaesthetics on this fragile structure has not been investigated. We evaluated the effect of cardiac pre- and post-conditioning with sevoflurane on integrity of the endothelial glycocalyx in conjunction with coronary vascular function. METHODS: Isolated guinea pig hearts perfused with Krebs-Henseleit buffer underwent 20 min stopped-flow ischaemia (37 degrees C), either without or with 1 MAC sevoflurane. This was applied for 15 min before, for 20 min after, or both before and after ischaemia. Transudate was collected for assessing coronary net fluid extravasation and histamine release by mast cells. Coronary release of syndecan-1 and heparan sulphate was measured. In additional experiments with and without continuous sevoflurane, cathepsin B and tryptase beta-like protease activity were measured in effluent. Hearts were perfusion fixed to visualize the endothelial glycocalyx. RESULTS: Ischaemia led to a significant (P<0.05) increase by 70% in transudate formation during reperfusion only in hearts without sevoflurane. This was accompanied by significant (P<0.05) increases in heparan sulphate (four-fold) and syndecan release (6.5-fold), with electron microscopy revealing massive degradation of glycocalyx. After ischaemia, histamine was released into transudate, and cathepsin B activity increased in effluent (P<0.05). Sevoflurane application attenuated all these changes, except for histamine release. CONCLUSIONS: Sevoflurane protects the endothelial glycocalyx from ischaemia-reperfusion-induced degradation, with both preconditioning and rapid post-conditioning being successful. The mechanism seems to involve attenuation of lysosomal cathepsin B release and to be independent from tissue mast cell degranulation. PMID- 20172939 TI - Patient selection for left ventricular assist devices. AB - Heart transplantation (HTx) improves symptoms and prolongs life in advanced heart failure (HF), but organ supply is limited. In recent years, mechanical circulatory support and specifically implantable left ventricular assist devices (LVADs) have undergone technical improvements, and outcomes have improved dramatically. Left ventricular assist devices are now viable options for patients with severe HF as bridge to transplantation, destination therapy, or as bridge to recovery. Many believe that LVADs may soon provide outcomes similar to, or better than, HTx, launching a new era of end-stage HF management. The key to improving outcomes is patient selection, but the field is changing rapidly and guidelines and consensus are limited. This review summarizes recent reports of predictors of poor outcomes and provides an overview of selection for LVAD therapy. PMID- 20172940 TI - Adherence to the medical regime in patients with heart failure. AB - AIMS: To assess adherence to medical treatment in patients with heart failure (HF) using a specific questionnaire and measurement of the serum concentration of digoxin. METHODS AND RESULTS: Forty patients with symptomatic HF and a clinical indication for digoxin were included in this pilot study. The assessment of adherence to the medical regime was based on two different methods: (i) the CARDIA-Questionnaire and (ii) the measurement of serum digoxin concentration (SDC) at 1 and 6 months. All patients were placed on digoxin treatment (target SDC 0.6-0.8 ng/mL) at baseline. Poor adherence was defined if the patient self reported taking < or =75% of the prescribed HF medication or had an SDC < 0.4 ng/mL (subtherapeutic range) at the follow-up visits. During the entire follow up, the proportion of patients with poor adherence was 15% as assessed by the questionnaire, 20% as assessed by the SDC, and 25% if both methods were combined. CONCLUSION: Although HF is a symptomatic disease, the proportion of patients with poor adherence to the medical regime in our study was high (up to 25%). The objective methodology based on the measurement of the SDC identified a higher number of patients with poor adherence when compared with the CARDIA Questionnaire. PMID- 20172941 TI - Treephyler: fast taxonomic profiling of metagenomes. AB - SUMMARY: Assessment of phylogenetic diversity is a key element to the analysis of microbial communities. Tools are needed to handle next-generation sequencing data and to cope with the computational complexity of large-scale studies. Here, we present Treephyler, a tool for fast taxonomic profiling of metagenomes. Treephyler was evaluated on real metagenome to assess its performance in comparison to previous approaches for taxonomic profiling. Results indicate that Treephyler is in terms of speed and accuracy prepared for next-generation sequencing techniques and large-scale analysis. AVAILABILITY: Treephyler is implemented in Perl; it is portable to all platforms and applicable to both nucleotide and protein input data. Treephyler is freely available for download at http://www.gobics.de/fabian/treephyler.php. PMID- 20172942 TI - CandiSNPer: a web tool for the identification of candidate SNPs for causal variants. AB - SUMMARY: Human single nucleotide polymorphism (SNP) chips which are used in genome-wide association studies (GWAS) permit the genotyping of up to 4 million SNPs simultaneously. To date, about 1000 human SNPs have been identified as statistically significantly associated with a disease or another trait of interest. The identified SNP is not necessarily the causal variant, but it is rather in linkage disequilibrium (LD) with it. CandiSNPer is a software tool that determines the LD region around a significant SNP from a GWAS. It provides a list with functional annotation and LD values for the SNPs found in the LD region. This list contains not only the SNPs for which genotyping data are available, but all SNPs with rs-IDs, thus increasing the likelihood to include the causal variant. Furthermore, plots showing the LD values are generated. CandiSNPer facilitates the preselection of candidate SNPs for causal variants. AVAILABILITY AND IMPLEMENTATION: The CandiSNPer server is freely available at http://www2.hu berlin.de/wikizbnutztier/software/CandiSNPer. The source code is available to academic users 'as is' upon request. The web site is implemented in Perl and R and runs on an Apache server. The Ensembl database is queried for SNP data via Perl APIs. PMID- 20172943 TI - A meta-analysis of two-dimensional electrophoresis pattern of the Parkinson's disease-related protein DJ-1. AB - MOTIVATION: The two-dimensional electrophoresis (2-DE) pattern of proteins is thought to be specifically related to the physiological or pathological condition at the moment of sample preparation. On this ground, most proteomic studies move to identify specific hallmarks for a number of different conditions. However, the information arising from these investigations is often incomplete due to inherent limitations of the technique, to extensive protein post-translational modifications and sometimes to the paucity of available samples. The meta analysis of proteomic data can provide valuable information pertinent to various biological processes that otherwise remains hidden. RESULTS: Here, we show a meta analysis of the PD protein DJ-1 in heterogeneous 2-DE experiments. The protein was shown to segregate into specific clusters associated with defined conditions. Interestingly, the DJ-1 pool from neural tissues displayed a specific and characteristic molecular weight and isoelectric point pattern. Moreover, changes in this pattern have been related to neurodegenerative processes and aging. These results were experimentally validated on human brain specimens from control subjects and PD patients. AVAILABILITY: ImageJ is a public domain image processing program developed by the National Institutes of Health and is freely available at http://rsbweb.nih.gov/ij. All the ImageJ macros used in this study are available as supplementary material and upon request at info@biodigitalvalley.com. XLSTAT can be purchased online at http://www.xlstat.com/en/home/ at a current cost of approximately 300 EUR. PMID- 20172944 TI - A principal skeleton algorithm for standardizing confocal images of fruit fly nervous systems. AB - MOTIVATION: The fruit fly (Drosophila melanogaster) is a commonly used model organism in biology. We are currently building a 3D digital atlas of the fruit fly larval nervous system (LNS) based on a large collection of fly larva GAL4 lines, each of which targets a subset of neurons. To achieve such a goal, we need to automatically align a number of high-resolution confocal image stacks of these GAL4 lines. One commonly employed strategy in image pattern registration is to first globally align images using an affine transform, followed by local non linear warping. Unfortunately, the spatially articulated and often twisted LNS makes it difficult to globally align the images directly using the affine method. In a parallel project to build a 3D digital map of the adult fly ventral nerve cord (VNC), we are confronted with a similar problem. RESULTS: We proposed to standardize a larval image by best aligning its principal skeleton (PS), and thus used this method as an alternative of the usually considered affine alignment. The PS of a shape was defined as a series of connected polylines that spans the entire shape as broadly as possible, but with the shortest overall length. We developed an automatic PS detection algorithm to robustly detect the PS from an image. Then for a pair of larval images, we designed an automatic image registration method to align their PSs and the entire images simultaneously. Our experimental results on both simulated images and real datasets showed that our method does not only produce satisfactory results for real confocal larval images, but also perform robustly and consistently when there is a lot of noise in the data. We also applied this method successfully to confocal images of some other patterns such as the adult fruit fly VNC and center brain, which have more complicated PS. This demonstrates the flexibility and extensibility of our method. AVAILABILITY: The supplementary movies, full size figures, test data, software, and tutorial on the software can be downloaded freely from our website http://penglab.janelia.org/proj/principal_skeleton. PMID- 20172945 TI - DASS-GUI: a user interface for identification and analysis of significant patterns in non-sequential data. AB - SUMMARY: Many large 'omics' datasets have been published and many more are expected in the near future. New analysis methods are needed for best exploitation. We have developed a graphical user interface (GUI) for easy data analysis. Our discovery of all significant substructures (DASS) approach elucidates the underlying modularity, a typical feature of complex biological data. It is related to biclustering and other data mining approaches. Importantly, DASS-GUI also allows handling of multi-sets and calculation of statistical significances. DASS-GUI contains tools for further analysis of the identified patterns: analysis of the pattern hierarchy, enrichment analysis, module validation, analysis of additional numerical data, easy handling of synonymous names, clustering, filtering and merging. Different export options allow easy usage of additional tools such as Cytoscape. AVAILABILITY: Source code, pre-compiled binaries for different systems, a comprehensive tutorial, case studies and many additional datasets are freely available at http://www.ifr.ac.uk/dass/gui/. DASS-GUI is implemented in Qt. PMID- 20172946 TI - Challenging mental health-related stigma through social contact. PMID- 20172947 TI - The association between parent's and healthcare professional's behavior and children's coping and distress during venepuncture. AB - OBJECTIVES: Examine the association between children's distress and coping during venepuncture with parent's and healthcare professional's behavior in a sample from the UK. METHODS: Fifty children aged 7-16 years accompanied by a carer were videotaped while having venepuncture. Verbalizations of children, parents, and healthcare professionals were coded using the Child-Adult Medical Procedure Interaction Scale-Revised. RESULTS: Children's distress was associated with child's age, anxiety, and distress promoting behavior of adults (R(2) = .91). Children's coping was associated with age, anxiety, and coping promoting behaviors of adults (R(2) = .57). Associations were stronger between healthcare professional's behavior and child coping; and between parent's behaviors and child distress. Empathizing, apologizing, and criticism were not frequently used by adults in this sample (<12%). CONCLUSION: This study supports and extends previous research showing adult's behavior is important in children's distress and coping during needle procedures. Clinical implications and methodological issues are discussed. PMID- 20172948 TI - Preprocessing and downstream analysis of microarray DNA copy number profiles. AB - Analysis of DNA copy number profiles requires methods tailored to the specific nature of these data. The number of available data analysis methods has grown enormously in the last 5 years. We discuss the typical characteristics of DNA copy number data, as measured by microarray technology and review the extensive literature on preprocessing methods such as segmentation and calling. Subsequently, the focus narrows to applications of DNA copy number in cancer, in particular, several downstream analyses of multi-sample data sets such as testing, clustering and classification. Finally, we look ahead: what should we prepare for and which methodology-related topics may deserve attention in the near future? PMID- 20172949 TI - Polymorphisms of estrogen receptors and risk of biliary tract cancers and gallstones: a population-based study in Shanghai, China. AB - Biliary tract cancer encompasses tumors of the gallbladder, bile duct and ampulla of Vater. Gallbladder cancer is more common in women, whereas bile duct cancer is more common in men, suggesting that sex hormones may play a role in the etiology of these cancers. The intracellular action of estrogens is regulated by the estrogen receptor (ESR); thus, we examined the role of common genetic variants in ESR genes on the risk of biliary tract cancers and stones in a population-based case-control study in Shanghai, China (411 cancer cases, 895 stone cases and 786 controls). We genotyped six single-nucleotide polymorphisms (SNPs), four in ESR1 (rs2234693, rs3841686, rs2228480 and rs1801132) and two in ESR2 (rs1256049 and rs4986938). In all participants, the ESR1 rs1801132 (P325P) G allele was associated with excess risks of bile duct [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.1-2.8] and ampulla of Vater cancers (OR = 2.1, 95% CI 0.9-4.9) compared with the CC genotype. The association with bile duct cancer was apparent among men (OR = 2.8, 95% CI 1.4-5.7) but not among women (P-heterogeneity = 0.01). Also, the ESR2 rs4986938 (38 bp 3' of STP) GG genotype was associated with a higher risk of bile duct cancer (OR = 3.3, 95% CI 1.3-8.7) compared with the AA genotype, although this estimate was based on a small number of subjects. None of the other SNPs examined was associated with biliary tract cancers or stones. False discovery rate-adjusted P-values were not significant (P > 0.1). No association was found for ESR1 haplotype based on four SNPs. These preliminary results suggest that variants in ESR genes could play a role in the etiology of biliary tract cancers, especially bile duct cancer in men. PMID- 20172950 TI - Transforming growth factor beta1 enhances tumor promotion in mouse skin carcinogenesis. AB - Transforming growth factor beta1 (TGFbeta1) expression is elevated by tumor promoters in the mouse skin, but its role in tumor promotion has not been well defined. To investigate this, we have compared TGFbeta1+/+ and +/- mice in a two stage skin chemical carcinogenesis protocol. Surprisingly, TGFbeta1+/- mice had fewer number and incidence of benign papillomas, reduced epidermal and tumor cell proliferation and reduced epidermal TGFbeta1 and nuclear p-Smad2 localization in response to the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) compared with TGFbeta1+/+ mice. Maximal TPA activation of protein kinase C (PKCalpha) as measured by activity assays and activation of target genes and induction of cornified envelopes correlated with TGFbeta1 gene dosage in keratinocytes and addition of exogenous TGFbeta1 restored the cornification defect in TGFbeta1+/- keratinocytes. Similarly, inhibition of ALK5-suppressed TPA mediated PKCalpha activation suggesting that physiological levels of TGFbeta1 are required for maximal activation of PKC-dependent mitogenic responses. Paradoxically, the TPA-induced inflammatory response was greater in TGFbeta1+/- skin, but TGFbeta1+/+ papillomas had more tumor infiltrating myeloperoxidase positive cells and pro-inflammatory gene expression was elevated in v-ras(Ha) transduced TGFbeta1+/+ but not TGFbeta1+/- keratinocytes. Thus, ras activation switches TGFbeta1 to a pro-inflammatory cytokine. Despite this differential proliferative and inflammatory response to TPA and enhanced papilloma formation in the TGFbeta1+/+ mice, the frequency of malignant conversion was reduced compared with TGFbeta1+/- mice. Therefore, TGFbeta1 promotes benign tumors by modifying tumor promoter-induced cell proliferation and inflammation but retains a suppressive function for malignant conversion. PMID- 20172951 TI - Chorioamnionitis stimulates angiogenesis in saccular stage fetal lungs via CC chemokines. AB - The fetal lung vasculature forms in tandem with developing airways. Whereas saccular airway morphogenesis is arrested in bronchopulmonary dysplasia (BPD), the potential vascular phenotype in BPD at this stage of development is less well understood. As inflammation increases the risk of BPD and induces arrest of saccular airway morphogenesis, we tested the effects of Escherichia coli LPS on fetal mouse lung vascular development. Injecting LPS into the amniotic fluid of Tie2-lacZ endothelial reporter mice at embryonic day 15 stimulated angiogenesis in the saccular stage fetal lung mesenchyme. LPS also increased the number of endothelial cells in saccular stage fetal mouse lung explants. Inflammation appeared to directly promote vascular development, as LPS stimulated pulmonary microvascular endothelial cell angiogenesis, cell migration, and proliferation in vitro. Whereas LPS did not increase expression of VEGF, angiopoietin-1 (Ang-1), Tie2, fetal liver kinase-1 (Flk-1), fms-like tyrosine kinase-1 (Flt-1), PDGFA, PDGFB, heparin-binding EGF-like growth factor (HB-EGF), or connective tissue growth factor (CTGF), LPS did stimulate the production of the angiogenic CC chemokines macrophage inflammatory protein-1alpha (MIP-1alpha) and monocyte chemoattractant protein-1 (MCP-1). Both MIP-1alpha and MCP-1 increased angiogenesis in fetal mouse lung explants. In addition, inhibitory antibodies against MIP-1alpha and MCP-1 blocked the effects of LPS on fetal lung vascular development, suggesting these chemokines are downstream mediators of LPS-induced angiogenesis. We speculate that an inflammation-mediated surge in angiogenesis could lead to formation of aberrant alveolar capillaries in the lungs of patients developing BPD. PMID- 20172952 TI - A role for caveolin-1 in mechanotransduction of fetal type II epithelial cells. AB - Mechanical forces are critical for fetal lung development. Using surfactant protein C (SP-C) as a marker, we previously showed that stretch-induced fetal type II cell differentiation is mediated via the ERK pathway. Caveolin-1, a major component of the plasma membrane microdomains, is important as a signaling protein in blood vessels exposed to shear stress. Its potential role in mechanotransduction during fetal lung development is unknown. Caveolin-1 is a marker of type I epithelial cell phenotype. In this study, using immunocytochemistry, Western blotting, and immunogold electron microscopy, we first demonstrated the presence of caveolin-1 in embryonic day 19 (E19) rat fetal type II epithelial cells. By detergent-free purification of lipid raft-rich membrane fractions and fluorescence immunocytochemistry, we found that mechanical stretch translocates caveolin-1 from the plasma membrane to the cytoplasm. Disruption of the lipid rafts with cholesterol-chelating agents further increased stretch-induced ERK activation and SP-C gene expression compared with stretch samples without disruptors. Similar results were obtained when caveolin-1 gene was knocked down by small interference RNA. In contrast, adenovirus overexpression of the wild-type caveolin-1 or delivery of caveolin-1 scaffolding domain peptide inside the cells decreased stretch-induced ERK phosphorylation and SP-C mRNA expression. In conclusion, our data suggest that caveolin-1 is present in E19 fetal type II epithelial cells. Caveolin-1 is translocated from the plasma membrane to the cytoplasm by mechanical stretch and functions as an inhibitory protein in stretch-induced type II cell differentiation via the ERK pathway. PMID- 20172953 TI - Complete lack of vitamin C intake generates pulmonary emphysema in senescence marker protein-30 knockout mice. AB - Vitamin C (VC) is a potent antioxidant and plays an essential role in collagen synthesis. As we previously reported, senescence marker protein-30 (SMP30) knockout (KO) mice cannot synthesize VC due to the genetic disruption of gluconolactonase (i.e., SMP30). Here, we utilized SMP30 KO mice deprived of VC and found that VC depletion caused pulmonary emphysema due to oxidative stress and a decrease of collagen synthesis by the third month of age. We grew SMP30 KO mice and wild-type (WT) mice on VC-free chow and either VC water [VC(+)] or plain water [VC(-)] after weaning at 4 wk of age. Morphometric findings and reactive oxygen species (ROS) in the lungs were evaluated at 3 mo of age. No VC was detected in the lungs of SMP30 KO VC(-) mice, but their ROS increased 50.9% over that of the VC(+) group. Moreover, their collagen content in the lungs markedly decreased, and their collagen I mRNA decreased 82.2% compared with that of the WT VC(-) group. In the SMP30 KO VC(-) mice, emphysema developed [21.6% increase of mean linear intercepts (MLI) and 42.7% increase of destructive index compared with VC(+) groups], and the levels of sirtuin 1 (Sirt1) decreased 16.8%. However, VC intake increased the MLI 16.2% and thiobarbituric acid reactive substances 22.2% in WT mice, suggesting that an excess of VC can generate oxidative stress and may be harmful during this period of lung development. These results suggest that VC plays an important role in lung development through affecting oxidant antioxidant balance and collagen synthesis. PMID- 20172959 TI - Characterization of EndoTT, a novel single-stranded DNA-specific endonuclease from Thermoanaerobacter tengcongensis. AB - EndoTT encoded by tte0829 of Thermoanaerobacter tengcongensis binds and cleaves single-stranded (ss) and damaged double-stranded (ds) DNA in vitro as well as binding dsDNA. In the presence of a low concentration of NaCl, EndoTT cleaved ss regions of damaged dsDNA efficiently but did not cleave DNA that was entirely ss or ds. At high concentrations of NaCl or MgCl(2) or ATP, there was also specific cleavage of ssDNA. This suggested a preference for ss/ds junctions to stimulate cleavage of the DNA substrates. EndoTT has six specific sites (a-f) in the oriC region (1-70 nt) of T. tengcongensis. Substitutions of nucleotides around site c prevented cleavage by EndoTT of both sites c and d, implying that the cleavage specificity may depend on both the nucleotide sequence and the secondary structure of the ssDNA. A C-terminal sub-fragment of EndoTT (residues 107-216) had both endonucleolytic and DNA-binding activity, whereas an N-terminal sub fragment (residues 1-110) displayed only ssDNA-binding activity. Site-directed mutations showed that G(170), R(172) and G(177) are required for the endonuclease activity of EndoTT, but not for DNA-binding, whereas D(171), R(178) and G(189) are partially required for the DNA-binding activity. PMID- 20172960 TI - GOing Bayesian: model-based gene set analysis of genome-scale data. AB - The interpretation of data-driven experiments in genomics often involves a search for biological categories that are enriched for the responder genes identified by the experiments. However, knowledge bases such as the Gene Ontology (GO) contain hundreds or thousands of categories with very high overlap between categories. Thus, enrichment analysis performed on one category at a time frequently returns large numbers of correlated categories, leaving the choice of the most relevant ones to the user's; interpretation. Here we present model-based gene set analysis (MGSA) that analyzes all categories at once by embedding them in a Bayesian network, in which gene response is modeled as a function of the activation of biological categories. Probabilistic inference is used to identify the active categories. The Bayesian modeling approach naturally takes category overlap into account and avoids the need for multiple testing corrections met in single category enrichment analysis. On simulated data, MGSA identifies active categories with up to 95% precision at a recall of 20% for moderate settings of noise, leading to a 10-fold precision improvement over single-category statistical enrichment analysis. Application to a gene expression data set in yeast demonstrates that the method provides high-level, summarized views of core biological processes and correctly eliminates confounding associations. PMID- 20172961 TI - 17beta-hydroxysteroid dehydrogenase type 1 stimulates breast cancer by dihydrotestosterone inactivation in addition to estradiol production. AB - The active estrogen estradiol (E2) stimulates breast cancer cell (BCC) growth, whereas the androgen dihydrotestosterone (DHT) has shown an antiproliferative effect. The principal product synthesized by the 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is E2, although we have demonstrated that the purified enzyme also inactivates DHT. However, the direct roles of 17beta-HSD1 in sex-hormone regulation and BCC proliferation have not been completely established. Here, we show that 17beta-HSD1 inhibition suppresses DHT catabolism by 19%, whereas knockdown of the gene expression increases the concentration of DHT by 41% in the T47D BCC line. The 17beta-HSD1/DHT complex crystal structure reveals that DHT binds in both normal and reverse modes, but the latter mode leading to O3 reduction is preferred with stronger interactions. Using RNA interference and an inhibitor of 17beta-HSD1, we demonstrate that 17beta-HSD1 expression is negatively correlated to DHT levels in BCC but positively correlated to estrone reduction, E2 levels, and cell proliferation. 17beta-HSD1 inhibition reduces DHT inactivation, increasing the antiproliferative effect by DHT in T47D cells after 8 d treatment. Thus, 17beta-HSD1 up-regulates BCC growth by a dual action on estradiol synthesis and DHT inactivation. We have further demonstrated that 17beta-HSD1 can enhance the E2-induced expression of the endogenous estrogen-responsive gene pS2, providing an important information regarding the modulation of the estrogen responsiveness by 17beta-HSD1 that may also contribute to BCC growth. These results strongly support the rationale for inhibiting 17beta-HSD1 in breast cancer therapy to eliminate estrogen activation via the sulfatase pathway while avoiding the deprivation of DHT. PMID- 20172962 TI - Dehydroepiandrosterone sulfate directly activates protein kinase C-beta to increase human neutrophil superoxide generation. AB - Dehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid in the human circulation and is secreted by the adrenals in an age-dependent fashion, with maximum levels during the third decade and very low levels in old age. DHEAS is considered an inactive metabolite, whereas cleavage of the sulfate group generates dehydroepiandrosterone (DHEA), a crucial sex steroid precursor. However, here we show that DHEAS, but not DHEA, increases superoxide generation in primed human neutrophils in a dose-dependent fashion, thereby impacting on a key bactericidal mechanism. This effect was not prevented by coincubation with androgen and estrogen receptor antagonists but was reversed by the protein kinase C inhibitor Bisindolylmaleimide 1. Moreover, we found that neutrophils are unique among leukocytes in expressing an organic anion-transporting polypeptide D, able to mediate active DHEAS influx transport whereas they did not express steroid sulfatase that activates DHEAS to DHEA. A specific receptor for DHEAS has not yet been identified, but we show that DHEAS directly activated recombinant protein kinase C-beta (PKC-beta) in a cell-free assay. Enhanced PKC-beta activation by DHEAS resulted in increased phosphorylation of p47(phox), a crucial component of the active reduced nicotinamide adenine dinucleotide phosphate complex responsible for neutrophil superoxide generation. Our results demonstrate that PKC-beta acts as an intracellular receptor for DHEAS in human neutrophils, a signaling mechanism entirely distinct from the role of DHEA as sex steroid precursor and with important implications for immunesenescence, which includes reduced neutrophil superoxide generation in response to pathogens. PMID- 20172963 TI - Mutations in the hyperosmotic stress-responsive mitochondrial BASIC AMINO ACID CARRIER2 enhance proline accumulation in Arabidopsis. AB - Mitochondrial carrier family proteins are diverse in their substrate specificity, organellar location, and gene expression. In Arabidopsis (Arabidopsis thaliana), 58 genes encode these six-transmembrane-domain proteins. We investigated the biological role of the basic amino acid carrier Basic Amino Acid Carrier2 (BAC2) from Arabidopsis that is structurally and functionally similar to ARG11, a yeast ornithine and arginine carrier, and to Arabidopsis BAC1. By studying the expression of BAC2 and the consequences of its mutation in Arabidopsis, we showed that BAC2 is a genuine mitochondrial protein and that Arabidopsis requires expression of the BAC2 gene in order to use arginine. The BAC2 gene is induced by hyperosmotic stress (with either 0.2 m NaCl or 0.4 m mannitol) and dark-induced senescence. The BAC2 promoter contains numerous stress-related cis-regulatory elements, and the transcriptional activity of BAC2:beta-glucuronidase is up regulated by stress and senescence. Under hyperosmotic stress, bac2 mutants express the P5CS1 proline biosynthetic gene more strongly than the wild type, and this correlates with a greater accumulation of Pro. Our data suggest that BAC2 is a hyperosmotic stress-inducible transporter of basic amino acids that contributes to proline accumulation in response to hyperosmotic stress in Arabidopsis. PMID- 20172964 TI - Nonhost resistance of barley to different fungal pathogens is associated with largely distinct, quantitative transcriptional responses. AB - Nonhost resistance protects plants against attack by the vast majority of potential pathogens, including phytopathogenic fungi. Despite its high biological importance, the molecular architecture of nonhost resistance has remained largely unexplored. Here, we describe the transcriptional responses of one particular genotype of barley (Hordeum vulgare subsp. vulgare 'Ingrid') to three different pairs of adapted (host) and nonadapted (nonhost) isolates of fungal pathogens, which belong to the genera Blumeria (powdery mildew), Puccinia (rust), and Magnaporthe (blast). Nonhost resistance against each of these pathogens was associated with changes in transcript abundance of distinct sets of nonhost specific genes, although general (not nonhost-associated) transcriptional responses to the different pathogens overlapped considerably. The powdery mildew- and blast-induced differences in transcript abundance between host and nonhost interactions were significantly correlated with differences between a near isogenic pair of barley lines that carry either the Mlo wild-type allele or the mutated mlo5 allele, which mediates basal resistance to powdery mildew. Moreover, during the interactions of barley with the different host or nonhost pathogens, similar patterns of overrepresented and underrepresented functional categories of genes were found. The results suggest that nonhost resistance and basal host defense of barley are functionally related and that nonhost resistance to different fungal pathogens is associated with more robust regulation of complex but largely nonoverlapping sets of pathogen-responsive genes involved in similar metabolic or signaling pathways. PMID- 20172965 TI - Tracing cadmium from culture to spikelet: noninvasive imaging and quantitative characterization of absorption, transport, and accumulation of cadmium in an intact rice plant. AB - We characterized the absorption and short-term translocation of cadmium (Cd) in rice (Oryza sativa 'Nipponbare') quantitatively using serial images observed with a positron-emitting tracer imaging system. We fed a positron-emitting 107Cd (half life of 6.5 h) tracer to the hydroponic culture solution and noninvasively obtained serial images of Cd distribution in intact rice plants at the vegetative stage and at the grain-filling stage every 4 min for 36 h. The rates of absorption of Cd by the root were proportional to Cd concentrations in the culture solution within the tested range of 0.05 to 100 nm. It was estimated that the radial transport from the culture to the xylem in the root tissue was completed in less than 10 min. Cd moved up through the shoot organs with velocities of a few centimeters per hour at both stages, which was obviously slower than the bulk flow in the xylem. Finally, Cd arrived at the panicles 7 h after feeding and accumulated there constantly, although no Cd was observed in the leaf blades within the initial 36 h. The nodes exhibited the most intensive Cd accumulation in the shoot at both stages, and Cd transport from the basal nodes to crown root tips was observed at the vegetative stage. We conclude that the nodes are the central organ where xylem-to-phloem transfer takes place and play a pivotal role in the half-day travel of Cd from the soil to the grains at the grain-filling stage. PMID- 20172966 TI - Glucagon-like peptide (GLP)-1(9-36)amide-mediated cytoprotection is blocked by exendin(9-39) yet does not require the known GLP-1 receptor. AB - The widely expressed dipeptidyl peptidase-4 enzyme rapidly cleaves the gut hormone glucagon-like peptide-1 [GLP-1(7-36)amide] at the N terminus to generate GLP-1(9-36)amide. Both intact GLP-1(7-36)amide and GLP-1(9-36)amide exert cardioprotective actions in rodent hearts; however, the mechanisms underlying the actions of GLP-1(9-36)amide remain poorly understood. We used mass spectrometry of coronary effluents to demonstrate that isolated mouse hearts rapidly convert infused GLP-1(7-36)amide to GLP-1(9-36)amide. After ischemia-reperfusion (I/R) injury of isolated mouse hearts, administration of GLP-1(9-36)amide or exendin-4 improved functional recovery and reduced infarct size. The direct actions of these peptides were studied in cultured neonatal mouse cardiomyocytes. Both GLP 1(9-36)amide and exendin-4 increased levels of cAMP and phosphorylation of ERK1/2 and the phosphoinositide 3-kinase target protein kinase B/Akt. In I/R injury models in vitro, both peptides improved mouse cardiomyocyte viability and reduced lactate dehydrogenase release and caspase-3 activation. These effects were attenuated by inhibitors of ERK1/2 and phosphoinositide 3-kinase. Unexpectedly, the cardioprotective actions of GLP-1(9-36)amide were blocked by exendin(9-39) yet preserved in Glp1r(-/-) cardiomyocytes. Furthermore, GLP-1(9-36)amide, but not exendin-4, improved the survival of human aortic endothelial cells undergoing I/R injury, actions sensitive to the nitric oxide synthase inhibitor, N(G)-nitro l-arginine methyl ester (L-NAME). In summary, our findings demonstrate separate actions for GLP-1(9-36)amide vs. the GLP-1R agonist exendin-4 and reveal the existence of a GLP-1(9-36)amide-responsive, exendin(9-39)-sensitive, cardioprotective signaling pathway distinct from that associated with the classical GLP-1 receptor. PMID- 20172969 TI - Transforming growth factor-{beta} (TGF{beta}) receptors I/II differentially regulate TGF{beta}1 and IGF-binding protein-3 mitogenic effects in the human placenta. AB - Maternal IGFs regulate cytotrophoblast proliferation and, thereby, placental growth and function. IGF bioavailability is controlled by IGF-binding proteins (IGFBPs); in placenta, IGFBP-3 is particularly abundant. In other systems, IGFBP 3 can regulate cellular events independently of IGFs; these effects are thought to be mediated by TGFbeta receptors (TbetaR). We have examined IGFBP-3 regulation of IGF-dependent and -independent cytotrophoblast proliferation in first trimester placental explants and the role of TbetaRII in mediating these effects. In the presence of IGFBP-3 (50 nm), IGF-induced (10 nm) proliferation (monitored by immunohistochemical analysis of Ki67 expression and bromodeoxyuridine incorporation) was significantly reduced (P < 0.05). IGFBP-3 also reduced basal proliferation independently of IGF receptor signaling. Immunohistochemical analysis demonstrated that TGFbeta signaling molecules [TGFbeta receptor I (TbetaRI), TbetaRII, TbetaRV, Smad-2, and ERK] are expressed in syncytium and/or cytotrophoblast. TGFbeta1 (10 ng/ml) enhanced cytotrophoblast proliferation and activated both Smad-2 and ERK-1/2, whereas IGFBP-3 activated only Smad-2. The function of both TGFbeta1 and IGFBP-3 was attenuated by a TbetaRII function blocking antibody and by small interfering RNA-mediated knockdown of TbetaRII (P < 0.05); this was accompanied by a reduction in Smad-2 activation. This study demonstrates that both TGFbeta1 and IGFBP-3 signal through TbetaRI/II to influence human cytotrophoblast proliferation. However, downstream pathways are distinct, because IGFBP-3 acts only through Smad-2, whereas TGFbeta1 also phosphorylates ERK, resulting in opposite effects on cytotrophoblast proliferation. The effects of maternal growth signals on placental growth and function therefore depend on the balance of ligands, receptors, and signaling molecules at the syncytiotrophoblast surface. Therapeutic manipulation of this balance might offer a strategy to optimize placental development and pregnancy outcome. PMID- 20172967 TI - Altered metabolism and lipodystrophy in the early B-cell factor 1-deficient mouse. AB - We previously reported that mice deficient for the transcription factor early B cell factor (Ebf1) exhibit markedly increased numbers of osteoblasts, bone formation rate, and serum osteocalcin, but the bone marrow of Ebf1(-/-) mice is also striking in its increased marrow adiposity. The purpose of this work was to analyze the metabolic phenotype that accompanies the altered bone morphology of Ebf1(-/-) mice. Whereas marrow adiposity was increased, deposition of white adipose tissue in other regions of the body was severely reduced (sc 40-50%, abdominally 80-85%). Brown adipose exhibited decreased lipid deposition. Subcutaneous and perigonadal white adipose tissue showed a decrease in mRNA transcripts for peroxisomal proliferator-activated receptor-gamma2 and CCAAT/enhancer-binding protein-beta in Ebf1(-/-) tissue compared with wild type. Circulating levels of leptin were decreased in Ebf1(-/-) animals compared with their littermate controls (down 65-95%), whereas adiponectin remained comparable after 2 wk of age. Serum analysis also found the Ebf1(-/-) animals were hypoglycemic and hypotriglyceridemic. After ip injection of insulin, the serum glucose levels in Ebf1(-/-) mice took longer to recover, and after a glucose challenge the Ebf1(-/-) animals reached serum glucose levels almost twice that of their wild-type counterparts. Measurement of circulating pancreatic hormones revealed normal or reduced insulin levels in the Ebf1(-/-) mice, whereas glucagon was significantly increased (up 1.7- to 8.5-fold). Metabolically the Ebf1(-/-) mice had increased O(2) consumption, CO(2) production, food and water intake, and activity. Markers for gluconeogenesis, however, were decreased in the Ebf1(-/-) mice compared with controls. In conclusion, the Ebf1-deficient animals exhibit defects in adipose tissue deposition with increased marrow adiposity and impaired glucose mobilization. PMID- 20172968 TI - Female mice expressing constitutively active mutants of FSH receptor present with a phenotype of premature follicle depletion and estrogen excess. AB - Strong gain-of-function mutations have not been identified in humans in the FSH receptor (FSHR), whereas such mutations are common among many other G protein coupled receptors. In order to predict consequences of such mutations on humans, we first identified constitutively activated mutants of the mouse (m) Fshr and then expressed them under the human anti-Mullerian hormone promoter in transgenic mice or created knock-in mutation into the mouse genome. We show here that mutations of Asp580 in the mFSHR significantly increase the basal receptor activity. D580H and D580Y mutations of mFSHR bind FSH, but the activity of the former is neither ligand-dependent nor promiscuous towards LH/human choriogonadotropin stimulation. Transgenic expression of mFshr(D580H) in granulosa cells leads to abnormal ovarian structure and function in the form of hemorrhagic cysts, accelerated loss of small follicles, augmented granulosa cell proliferation, increased estradiol biosynthesis, and occasional luteinized unruptured follicles or teratomas. The most affected mFshr(D580H) females are infertile with disturbed estrous cycle and decreased gonadotropin and increased prolactin levels. Increased estradiol and prolactin apparently underlie the enhanced development of the mammary glands, adenomatous pituitary growth, and lipofuscin accumulation in the adrenal gland. The influence of the mFSHR(D580Y) mutation is milder, mainly causing hemorrhagic cysts in transgenic mFSHR(D580Y) and mFSHR(D580Y) -knock-in mice. The results demonstrate that gain-of-function mutations of the FSHR in mice bring about distinct and clear changes in ovarian function, informative in the search of similar mutations in humans. PMID- 20172970 TI - Does short-term estrogen therapy produce lasting benefits in brain? PMID- 20172971 TI - Whatever way weight goes, inflammation shows. PMID- 20172972 TI - "Sumer is icumen in:" lessons from the lungfish. PMID- 20172973 TI - Gut-brain communications: not the same at all ages. PMID- 20172975 TI - A molecular strategy for routine preimplantation genetic diagnosis in both reciprocal and Robertsonian translocation carriers. AB - Preimplantation genetic diagnosis (PGD) for structural chromosome abnormalities traditionally uses fluorescence in situ hybridization (FISH) techniques. Although relatively straight forward, FISH is technically demanding with several process problems which include cell loss, cell overlap, variable cell fixation and hybridization as well as sample mosaicism. Increasingly, alternative techniques for chromosome analysis in embryos are being investigated in an attempt to improve on current test outcomes. Here, we report on the first routine application of a polymerase chain reaction (PCR)-based protocol for translocation analysis utilizing multiplexed short tandem repeat (STR) markers located on both segments of the translocated chromosomes. Resulting STR profiles permit the analysis of qualitative dosage of each chromosomal segment to identify translocation malsegregants from the balanced/normal chromosome complements. A total of 29 patients have undergone clinical PGD testing of 78 embryos using this method. The proportion of alternate segregations (i.e. balanced carrier and non carriers) detected for reciprocal and Robertsonian translocation carriers was 33% and 77%, respectively. Fetal heart pregnancy rates per embryo transferred was 46% for reciprocal carriers and 40% for Robertsonian carriers (mean number of embryos transferred was 1.0). This novel approach can be applied easily within any existing PGD PCR laboratory and allows for a significant improvement in the identification of segregation types when compared with the standard FISH protocol using combinations of distal and proximal probes. This approach increases test robustness and reliability with improved interpretation of segregation outcomes, decreased analysis time and also enables the straight forward combining of structural chromosome analysis with monogenic testing. PMID- 20172974 TI - TORC: a new twist on corticotropin-releasing hormone gene expression. PMID- 20172976 TI - Prokineticins: novel mediators of inflammatory and contractile pathways at parturition? AB - The onset of labour is associated with inflammatory cascades in the uteroplacental unit, and these are prematurely activated in preterm labour. Infection can induce an inflammatory response, which results in premature onset of the pro-inflammatory parturient cascades and preterm delivery. We have become interested in two proteins called prokineticins and the role they may play in labour and its premature onset. Prokineticin 1 and 2 bind to two G-protein coupled receptors, called prokineticin receptor 1 and 2. Expression of the prokineticins and their receptors is elevated in the uteroplacental unit during labour and they can induce expression of a host of genes known to be important in initiating the inflammatory and contractile events of labour. Prokineticins have also been shown to directly induce contractility of smooth muscles. Analysing the promoter regions of the prokineticins and their receptors highlights their potential regulation by pathways activated by infectious agents. Hence, we propose that infection can result in premature activation of prokineticin expression and signalling in the uteroplacental unit and this initiates a premature inflammatory and contractile cascade leading to preterm birth. Antagonism of prokineticin action may provide a suitable therapy for preterm labour that targets both inflammation and contractile pathways. PMID- 20172977 TI - New standards back down from intensive glucose control in hospitals. PMID- 20172978 TI - Dalfampridine approved for MS. PMID- 20172979 TI - Children's hospitals seek drug-cost savings through 340B participation. PMID- 20172980 TI - Cigna clinical pharmacists engage patients in care. PMID- 20172981 TI - Psychological effect of ambulatory blood pressure monitoring. PMID- 20172982 TI - Medication-administration errors in an emergency department. PMID- 20172983 TI - Single standard for education, training, and certification of pharmacy technicians. PMID- 20172984 TI - Clevidipine: a new intravenous option for the management of acute hypertension. AB - PURPOSE: The pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, and place in therapy of clevidipine are reviewed. SUMMARY: Clevidipine is a new lipophilic, short-acting, third-generation dihydropyridine calcium channel blocker (CCB) approved for use in the management of acute hypertension when oral agents are not feasible. It exerts its hemodynamic effects through selective arterial vasodilation without effects on the venous circulation. Clevidipine has a half-life of approximately two minutes after i.v. administration, resulting in very rapid onset and offset of antihypertensive action. Unlike many current i.v. antihypertensive agents that are metabolized by the kidneys or liver, clevidipine is metabolized in the blood and tissues and does not accumulate in the body. Clevidipine does not appear to inhibit or induce cytochrome P-450 isoenzymes. Several Phase III clinical trials have reported the clinical efficacy and safety of clevidipine in patients with severe hypertension and in cardiac surgical patients with perioperative hypertension. The most frequent adverse events reported in clinical trials of clevidipine were headache, nausea, and vomiting. Risk of rebound hypertension, especially in patients not transitioned from clevidipine to oral antihypertensive therapy after prolonged infusions, should be monitored for at least eight hours after the drug is discontinued. CONCLUSION: Clevidipine, a novel third-generation dihydropyridine CCB, has demonstrated efficacy and safety in patients with acute hypertension and preoperative, perioperative, and postoperative hypertension. While its short duration of action and short half-life are appropriate for use in acute settings, more information on its safety is needed to assess its appropriate use in therapy. PMID- 20172985 TI - Coagulation factor VIIa (recombinant) for warfarin-induced intracranial hemorrhage. AB - PURPOSE: The use of coagulation factor VIIa (recombinant) for the treatment of warfarin-induced intracranial hemorrhage (ICH) is described. SUMMARY: ICH is a devastating disorder that can be exacerbated by the use of oral anticoagulation. The treatment of warfarin-associated ICH involves the prompt reversal of anticoagulation to allow for surgical procedures, if necessary. Despite limited labeled indications, factor VIIa (recombinant) has been used to reverse warfarin induced anticoagulation in patients with active hemorrhage, partly due to the rapid effect of factor VIIa on the International Normalized Ratio and the ability to administer the drug quickly in acute settings. The efficacy of factor VIIa (recombinant) for the reversal of anticoagulation in patients with warfarin associated ICH has been described in several case reports, case series, and retrospective cohort studies. Based on these reports, the use of factor VIIa (recombinant) for the treatment of warfarin-associated ICH may be a viable alternative or adjunct therapy to standard treatment with fresh-frozen plasma and vitamin K. However, due to the nature of these reports, future controlled trials should be conducted to verify the exact place for factor VIIa (recombinant) for this indication. Thromboembolic complications are rare but serious complications secondary to the use of factor VIIa (recombinant). Though differences exist in the reported rate of thromboembolic complications associated with factor VIIa (recombinant), factor VIIa (recombinant) should be used with caution in patients with a predisposition to thromboembolic complications. CONCLUSION: Use of factor VIIa (recombinant) may be considered for reversal of anticoagulation in patients with warfarin-associated ICH. However, patients should be screened for increased risk of thrombosis before administration of the drug. PMID- 20172986 TI - Nontraditional pharmacy residency at a large teaching hospital. AB - PURPOSE: The structure and implementation of a nontraditional pharmacy residency program in a large teaching hospital are described. SUMMARY: A nontraditional track of the postgraduate year 1 (PGY1) residency program at a large teaching hospital in Detroit, Michigan, was developed for clinical staff pharmacists employed by the hospital. The program, accredited by the American Society of Health-System Pharmacists, allows pharmacists to complete 10 four-week rotations, in addition to three longitudinal rotations, over a three-year period. Required four-week rotations include 1 orientation rotation, 6 adult medicine rotations, 1 intensive care unit rotation, and 2 elective rotations. Because a pharmacist must first be employed by the hospital before applying to the nontraditional residency program, a staff pharmacist position is used to fund the nontraditional residency program. Since the inception of the nontraditional PGY1 residency program in 2005, two residents have graduated from the program. After completion of the residency, the first resident remained at the institution as a clinical staff pharmacist. The current and recently graduated nontraditional residents have demonstrated significant advancement of their clinical skills as a result of their participation in the program. Challenges faced during program implementation included scheduling and coordinating the resident's rotations and activities. CONCLUSION: A three-year nontraditional residency program was developed at a large teaching hospital to provide an alternative method for enhancing a pharmacist's clinical practice skills beyond those of an entry-level practitioner through completion of a systematic training program. PMID- 20172987 TI - Weight-based heparin protocol using antifactor Xa monitoring. AB - PURPOSE: The performance of a weight-based dosing protocol for unfractionated heparin (UFH) infusions using antifactor Xa monitoring was evaluated. METHODS: The first 50 patients to receive a UFH infusion per the new protocol for over 24 hours, regardless of indication, were included in the analysis. All patients received a bolus dose of 26 units/kg, followed by an i.v. infusion of 15 units/kg/ hr based on actual body weight, with no maximum dosage. Antifactor Xa levels were measured every 6 hours after infusion initiation and after every rate change until stable, defined as two consecutive results within the target range of 0.3-0.7 unit/mL, and every 24 hours thereafter. If a level was outside of the target range, the infusion rate was adjusted. Primary outcomes measured included the percentage of patients with a target level at the first test (obtained 6 hours after the start of therapy) and within the first 24 hours. The success of the protocol in obese patients versus nonobese patients was also analyzed. RESULTS: Of the 50 patients enrolled, 26 (52%) achieved a target antifactor Xa concentration 6 hours after infusion initiation. Only 4 patients did not have an antifactor Xa concentration in the target range within 24 hours. Of the 17 patients weighing more than 100 kg, 16 (94%) had a value within the target range within 24 hours. CONCLUSION: A weight-based UFH dosing nomogram using antifactor Xa monitoring resulted in a high percentage of patients achieving target antifactor Xa values within the first 24 hours of therapy. PMID- 20172988 TI - Strategies for implementing emergency department pharmacy services: results from the 2007 ASHP Patient Care Impact Program. AB - PURPOSE: Strategies proposed during a patient care impact program for implementing emergency department (ED) pharmacy services are described. SUMMARY: In June 2007, the American Society of Health-System Pharmacists developed a patient care impact program entitled "Introducing an Emergency Department Pharmacist into Your Institution" to provide experiential training to practicing pharmacists seeking to establish ED services in their institutions. Under the guidance of four mentors, 19 pharmacists from a variety of practice settings, including community-based hospitals and academic and tertiary-care-based institutions, were selected for participation the six-month program. Participants were divided into two groups, and each group was assigned two mentors. During their initial meeting, participants identified anticipated challenges to implementation of pharmacy services in the ED and began to define strategies with their mentors for effectively managing the anticipated challenges. Each group participated in one-hour monthly teleconferences with their mentors. In addition to monthly teleconferences, participants regularly contacted their mentors for additional assistance and several visited their mentors' institutions. Participants developed job descriptions for an ED pharmacist, developed a rationale and justification for implementing pharmacy services in the ED, obtained approval and support from appropriate parties for the ED pharmacist's role, developed plans for introducing a pharmacist to the ED, and developed quality-assurance methods to monitor the effectiveness of the pharmacist's role. CONCLUSION: Despite the diversity in practice settings, participants of the program faced similar challenges in implementing ED pharmacy services at their institutions. Various strategies toward solutions to these challenges were shared among participants and mentors. PMID- 20172989 TI - Effective use of workload and productivity monitoring tools in health-system pharmacy, part 2. AB - PURPOSE: The current status of external and internal workload and productivity measurement systems and strategies to improve their use to maximize overall pharmacy department operational performance and staffing effectiveness are described. SUMMARY: The use of operational benchmarking is increasing within health systems as a tool for continuously measuring and improving departmental performance and evaluating departmental success. Unfortunately, software used for benchmarking purposes is available through a limited number of commercial vendors and consultants, and these systems are unable to effectively measure department operations and overall performance. The theoretical value of benchmarking and productivity measurement systems, including a description of the various definitions, tools, and data sources for comparing pharmacy productivity data, is summarized. The limitations of commercially available vendor productivity monitoring systems and desired strategies for improving their use are also reviewed. Preferred productivity and cost metrics for measuring pharmacy department effectiveness are suggested, and strategies for obtaining value from external and internal productivity monitoring systems are explored. CONCLUSION: Challenges with external operational benchmarking and internal productivity monitoring systems are numerous. These systems rarely measure the quality of pharmacy services provided and their effect on patient care outcomes and the total cost of care. Benchmarking vendors must modernize their software and develop internal checks to confirm data integrity in order to make their products more useful and reliable. In addition, data supporting the patient care role of the pharmacist should be integrated into all productivity monitoring systems and be used to demonstrate the positive impact of pharmacy services on the total cost and quality of patient care. PMID- 20172990 TI - Minimizing human intervention in intravenous admixture practice. PMID- 20172991 TI - Developing and implementing clinical decision support for use in a computerized prescriber-order-entry system. AB - PURPOSE: The development and implementation of clinical decision support (CDS) in a computerized prescriber-order-entry (CPOE) system in a large, tertiary care, academic health care system are described. SUMMARY: CDS is generally considered to be a key factor in promoting successful system adoption, patient safety, and positive patient outcomes for CPOE implementation. The impact of CDS depends on the methods used by the institution to implement CPOE using both passive and active system design features. At the University of Michigan Health System, interdisciplinary project teams were assembled to plan, build, and implement the CDS component of CPOE using several underlying fundamental principles to ensure the usability and safety of the system, including standardization of system configuration, workflow design, and prioritization of the number and types of interruptive alerts that would be deployed. Passive CDS rules were established for nomenclature, links to information, relevant results, and order sets. Active CDS rules were developed for noninterruptive alerts (patient list alert flags and form-called medical logic modules) and interruptive alerts, including alerts for allergies, dose checks, drug-drug interactions, drug-food interactions, and drug disease interactions. The institution provided sufficient staffing and institutional governance to implement and sustain CDS. CONCLUSION: Through an interdisciplinary collaboration, an academic health care system planned, designed, and implemented institution-specific, CPOE-integrated CDS to improve clinical efficiency and facilitate the compliance with regulatory policies and guidelines. PMID- 20172992 TI - Comment on: An analysis of MRI and ultrasound imaging in patients with gout who have normal plain radiographs. PMID- 20172993 TI - Do we really need five TNF antagonists? PMID- 20172994 TI - Biochemical dissection of the ATPase TraB, the VirB4 homologue of the Escherichia coli pKM101 conjugation machinery. AB - Type IV secretion (T4S) systems are involved in several secretion processes, including secretion of virulence factors, such as toxins or transforming molecules, or bacterial conjugation whereby two mating bacteria exchange genetic material. T4S systems are generally composed of 12 protein components, three of which, termed VirB4, VirB11, and VirD4, are ATPases. VirB4 is the largest protein of the T4S system, is known to play a central role, and interacts with many other T4S system proteins. In this study, we have biochemically characterized the protein TraB, a VirB4 homologue from the pKM101 conjugation T4S system. We demonstrated that TraB is a modular protein, composed of two domains, both able to bind DNA in a non-sequence-specific manner. Surprisingly, both TraB N- and C terminal domains can bind ATP, revealing a new degenerated nucleotide-binding site in the TraB N-terminal domain. TraB purified from the membrane forms stable dimers and is unable to hydrolyze ATP while, when purified from the soluble fraction, TraB can form hexamers capable of hydrolyzing ATP. Remarkably, both the N- and C-terminal domains display ATP-hydrolyzing activity. These properties define a new class of VirB4 proteins. PMID- 20172995 TI - The nonmevalonate pathway of isoprenoid biosynthesis in Mycobacterium tuberculosis is essential and transcriptionally regulated by Dxs. AB - Mycobacterium tuberculosis synthesizes isoprenoids via the nonmevalonate or DOXP pathway. Previous work demonstrated that three enzymes in the pathway (Dxr, IspD, and IspF) are all required for growth in vitro. We demonstrate the essentiality of the key genes dxs1 and gcpE, confirming that the pathway is of central importance and that the second homolog of the synthase (dxs2) cannot compensate for the loss of dxs1. We looked at the effect of overexpression of Dxr, Dxs1, Dxs2, and GcpE on viability and on growth in M. tuberculosis. Overexpression of dxs1 or dxs2 was inhibitory to growth, whereas overexpression of dxr or gcpE was not. Toxicity is likely to be, at least partially, due to depletion of pyruvate from the cells. Overexpression of dxs1 or gcpE resulted in increased flux through the pathway, as measured by accumulation of the metabolite 4-hydroxy-3-methyl-but 2-enyl pyrophosphate. We identified the functional translational start site and promoter region for dxr and demonstrated that it is expressed as part of a polycistronic mRNA with gcpE and two other genes. Increased expression of this operon was seen in cells overexpressing Dxs1, indicating that transcriptional control is effected by the first enzyme of the pathway via an unknown regulator. PMID- 20172996 TI - Spontaneous excision of the Salmonella enterica serovar Enteritidis-specific defective prophage-like element phiSE14. AB - Salmonella enterica serovar Enteritidis has emerged as a major health problem worldwide in the last few decades. DNA loci unique to S. Enteritidis can provide markers for detection of this pathogen and may reveal pathogenic mechanisms restricted to this serovar. An in silico comparison of 16 Salmonella genomic sequences revealed the presence of an approximately 12.5-kb genomic island (GEI) specific to the sequenced S. Enteritidis strain NCTC13349. The GEI is inserted at the 5' end of gene ydaO (SEN1377), is flanked by 308-bp imperfect direct repeats (attL and attR), and includes 21 open reading frames (SEN1378 to SEN1398), encoding primarily phage-related proteins. Accordingly, this GEI has been annotated as the defective prophage SE14 in the genome of strain NCTC13349. The genetic structure and location of phiSE14 are conserved in 99 of 103 wild-type strains of S. Enteritidis studied here, including reference strains NCTC13349 and LK5. Notably, an extrachromosomal circular form of phiSE14 was detected in every strain carrying this island. The presence of attP sites in the circular forms detected in NCTC13349 and LK5 was confirmed. In addition, we observed spontaneous loss of a tetRA-tagged version of phiSE14, leaving an empty attB site in the genome of strain NCTC13349. Collectively, these results demonstrate that phiSE14 is an unstable genetic element that undergoes spontaneous excision under standard growth conditions. An internal fragment of phiSE14 designated Sdf I has been used as a serovar-specific genetic marker in PCR-based detection systems and as a tool to determine S. Enteritidis levels in experimental infections. The instability of this region may require a reassessment of its suitability for such applications. PMID- 20172997 TI - Interaction of an essential Escherichia coli GTPase, Der, with the 50S ribosome via the KH-like domain. AB - Der, an essential Escherichia coli tandem GTPase, has been implicated in 50S subunit biogenesis. The rrmJ gene encodes a methyltransferase that modifies the U2552 residue of 23S rRNA, and its deletion causes a severe growth defect. Peculiarly, overexpression of Der suppresses growth impairment. In this study, using an rrmJ-deletion strain, we demonstrated that two GTPase domains of Der regulate its association with 50S subunit via the KH-like domain. We also identified a region of Der that is critical for its specific interaction with 50S subunit. PMID- 20172998 TI - In the Staphylococcus aureus two-component system sae, the response regulator SaeR binds to a direct repeat sequence and DNA binding requires phosphorylation by the sensor kinase SaeS. AB - Staphylococcus aureus uses the SaeRS two-component system to control the expression of many virulence factors such as alpha-hemolysin and coagulase; however, the molecular mechanism of this signaling has not yet been elucidated. Here, using the P1 promoter of the sae operon as a model target DNA, we demonstrated that the unphosphorylated response regulator SaeR does not bind to the P1 promoter DNA, while its C-terminal DNA binding domain alone does. The DNA binding activity of full-length SaeR could be restored by sensor kinase SaeS induced phosphorylation. Phosphorylated SaeR is more resistant to digestion by trypsin, suggesting conformational changes. DNase I footprinting assays revealed that the SaeR protection region in the P1 promoter contains a direct repeat sequence (GTTAAN(6)GTTAA [where N is any nucleotide]). This sequence is critical to the binding of phosphorylated SaeR. Mutational changes in the repeat sequence greatly reduced both the in vitro binding of SaeR and the in vivo function of the P1 promoter. From these results, we concluded that SaeR recognizes the direct repeat sequence as a binding site and that binding requires phosphorylation by SaeS. PMID- 20172999 TI - Genomic content of Neisseria species. AB - The physical properties of most bacterial genomes are largely unexplored. We have previously demonstrated that the strict human pathogen Neisseria gonorrhoeae is polyploid, carrying an average of three chromosome copies per cell and only maintaining one pair of replication forks per chromosome (D. M. Tobiason and H. S. Seifert, PLos Biol. 4:1069-1078, 2006). We are following up this initial report to test several predictions of the polyploidy model of gonococcal chromosome organization. We demonstrate that the N. gonorrhoeae chromosomes exist solely as monomers and not covalently linked dimers, and in agreement with the monomer status, we show that distinct nucleoid regions can be detected by electron microscopy. Two different approaches to isolate heterozygous N. gonorrhoeae resulted in the formation of merodiploids, showing that even with more than one chromosome copy, these bacteria are genetically haploid. We show that the closely related bacterium Neisseria meningitidis is also polyploid, while the commensal organism Neisseria lactamica maintains chromosomes in single copy. We conclude that the pathogenic Neisseria strains are homozygous diploids. PMID- 20173000 TI - A DNA-binding peroxiredoxin of Coxiella burnetii is involved in countering oxidative stress during exponential-phase growth. AB - Coxiella burnetii is a Gram-negative, obligate intracellular bacterial pathogen that resides within the harsh, acidic confines of a lysosome-like compartment of the host cell that is termed a parasitophorous vacuole. In this study, we characterized a thiol-specific peroxidase of C. burnetii that belongs to the atypical 2-cysteine subfamily of peroxiredoxins, commonly referred to as bacterioferritin comigratory proteins (BCPs). Coxiella BCP was initially identified as a potential DNA-binding protein by two-dimensional Southwestern (SW) blots of the pathogen's proteome, probed with biotinylated C. burnetii genomic DNA. Confirmation of the identity of the DNA-binding protein as BCP (CBU_0963) was established by matrix-assisted laser desorption ionization-tandem time of flight mass spectrometry (MALDI-TOF/TOF MS). Recombinant Coxiella BCP (rBCP) was generated, and its DNA binding was demonstrated by two independent methods, including SW blotting and electrophoretic mobility shift assays (EMSAs). rBCP also demonstrated peroxidase activity in vitro that required thioredoxin thioredoxin reductase (Trx-TrxR). Both the DNA-binding and peroxidase activities of rBCP were lost upon heat denaturation (100 degrees C, 10 min). Functional expression of Coxiella bcp was demonstrated by trans-complementation of an Escherichia coli bcp mutant, as evidenced by the strain's ability to grow in an oxidative-stress growth medium containing tert-butyl hydroperoxide to levels that were indistinguishable from, or significantly greater than, those observed with its wild-type parental strain and significantly greater than bcp mutant levels (P < 0.05). rBCP was also found to protect supercoiled plasmid DNA from oxidative damage (i.e., nicking) in vitro. Maximal expression of the bcp gene coincided with the pathogen's early (day 2 to 3) exponential-growth phase in an experiment involving synchronized infection of an epithelial (Vero) host cell line. Taken as a whole, the results show that Coxiella BCP binds DNA and likely serves to detoxify endogenous hydroperoxide byproducts of Coxiella's metabolism during intracellular replication. PMID- 20173001 TI - Amnibacterium kyonggiense gen. nov., sp. nov., a new member of the family Microbacteriaceae. AB - A Gram-positive, non-motile bacterium, designated KSL51201-037(T), was isolated from Anyang stream, Republic of Korea, and was characterized using a polyphasic taxonomic approach. Comparative 16S rRNA gene sequence analysis showed that strain KSL51201-037(T) belonged to the family Microbacteriaceae of the class Actinobacteria and exhibited 96.9 % gene sequence similarity to Labedella gwakjiensis KSW2-17(T), 96.0 % to Leifsonia ginsengi wged11(T) and 95.9 % to Microterricola viridarii KV-677(T). The G+C content of the genomic DNA was 72.7 mol%. Strain KSL51201-037(T) had l-2,4-diaminobutyric acid as the diagnostic cell wall diamino acid, MK-11 and MK-12 as the major menaquinones, anteiso-C(15 : 0) (47.8 %) and iso-C(16 : 0) (24.0 %) as the major fatty acids and phosphatidylglycerol and three unknown phospholipids as the major polar lipids. On the basis of phenotypic and genotypic properties and phylogenetic distinctiveness, it is suggested that strain KSL51201-037(T) represents a novel species of a new genus in the family Microbacteriaceae for which the name Amnibacterium kyonggiense gen. nov., sp. nov. is proposed. The type strain of the type species is KSL51201-037(T) (=KEMC 51201-037(T)=JCM 16463(T)). PMID- 20173002 TI - Litoreibacter albidus gen. nov., sp. nov. and Litoreibacter janthinus sp. nov., members of the class Alphaproteobacteria isolated from the seashore. AB - Two Gram-negative, strictly aerobic, non-motile bacteria designated strains KMM 3851(T) and KMM 3842(T) were respectively isolated from a marine snail specimen (Umbonium costatum) and from surrounding sediments collected simultaneously from the shore of the Sea of Japan. Phylogenetic analysis based on 16S rRNA gene sequences showed that strains KMM 3851(T) and KMM 3842(T) were affiliated with the Roseobacter lineage of the class Alphaproteobacteria as a separate phylogenetic line adjacent to the members of the genus Thalassobacter. These novel isolates shared 98.5 % 16S rRNA gene sequence similarity and 15 % DNA-DNA relatedness. The major isoprenoid quinone of both strains was Q-10 and polar lipids consisted of phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and aminophospholipids. In addition, strain KMM 3851(T) contained two unknown lipids, whereas strain KMM 3842(T) contained diphosphatidylglycerol. Fatty acid analysis revealed C(18 : 1)omega7c and C(16 : 0) as major components and small amounts of C(18 : 2). The DNA G+C contents were 60.4 mol% (KMM 3851(T)) and 58.5 mol% (KMM 3842(T)). Based on distinctive phenotypic characteristics, DNA-DNA hybridization data and phylogenetic distance, strains KMM 3851(T) and KMM 3842(T) should be classified as representatives of two novel species in a new genus, Litoreibacter gen. nov., with the type species Litoreibacter albidus sp. nov. (type strain KMM 3851(T) =NRIC 0773(T) =JCM 16493(T)) and a second species Litoreibacter janthinus sp. nov. (type strain KMM 3842(T) =NRIC 0772(T) =JCM 16492(T)). PMID- 20173003 TI - Methanobacterium arcticum sp. nov., a methanogenic archaeon from Holocene Arctic permafrost. AB - A mesophilic, non-motile, hydrogenotrophic, rod-shaped methanogen, designated M2(T), was isolated from Holocene permafrost sediments of the Kolyma lowland in the Russian Arctic. Cells were 3-6 MUm long and 0.45-0.5 MUm wide. Strain M2(T) grew on H(2)/CO(2) and formate. Optimum conditions for growth were 37 degrees C, pH 6.8-7.2 and 0.1 M NaCl. The DNA G+C content was 38.1 mol%. On the basis of 16S rRNA gene sequence comparison with known methanogens, strain M2(T) was affiliated with the genus Methanobacterium and was most closely related to Methanobacterium veterum MK4(T) and Methanobacterium bryantii DSM 863(T) (both 99 % 16S rRNA gene sequence similarity). However, no significant DNA-DNA relatedness was observed between strain M2(T) and these type strains. We propose that strain M2(T) represents a novel species, with the name Methanobacterium arcticum sp. nov., with type strain M2(T) (=DSM 19844(T) =VKM B-2371(T)). PMID- 20173004 TI - Methanobacterium petrolearium sp. nov. and Methanobacterium ferruginis sp. nov., mesophilic methanogens isolated from salty environments. AB - Two methane-producing archaea, designated Mic5c12(T) and Mic6c05(T), were isolated from sludge deposited in a crude oil storage tank and a tubercle on the interior of a pipe transporting natural gas-containing brine, respectively. The isolates were Gram-staining-variable, non-motile rods and grew only on H(2)/CO(2). Strain Mic6c05(T) produced methane from some alcohols without showing any growth; strain Mic5c12(T) did not utilize alcohols. The optimum growth conditions for strain Mic5c12(T) were 35 degrees C, pH 6.5 and 0-0.68 M NaCl and for strain Mic6c05(T) were 40 degrees C, pH 6.0-7.5 and 0.34 M NaCl. Strain Mic5c12(T) was halotolerant and strain Mic6c05(T) was halophilic. Comparative 16S rRNA gene sequence analysis revealed that strains Mic5c12(T) and Mic6c05(T) belonged to the genus Methanobacterium and their closest relative was Methanobacterium subterraneum A8p(T) (97.3 and 97.9 % 16S rRNA gene sequence similarity, respectively). The findings from the 16S rRNA gene sequence analyses were supported by analysis of McrA, the alpha subunit of methyl-coenzyme M reductase. On the basis of phylogenetic analyses and phenotypic characteristics, two novel species are proposed, Methanobacterium petrolearium sp. nov. and Methanobacterium ferruginis sp. nov., with type strains Mic5c12(T) (=NBRC 105198(T) =DSM 22353(T)) and Mic6c05(T) (=NBRC 105197(T) =DSM 21974(T)), respectively. PMID- 20173005 TI - Thiomonas islandica sp. nov., a moderately thermophilic, hydrogen- and sulfur oxidizing betaproteobacterium isolated from a hot spring. AB - A novel, hydrogen- and sulfur-oxidizing bacterium, designated strain 6C(T), was isolated from a hot spring in Graendalur, south-western Iceland. Cells of this organism were Gram-reaction-negative, rod-shaped and motile. The strain grew aerobically and was capable of chemolithotrophic growth on thiosulfate and hydrogen, heterotrophic growth on pyruvate, oxalate, acetate and on glutamate in the presence of yeast extract and mixotrophic growth on several organic compounds, thiosulfate and/or hydrogen. During growth on thiosulfate, the final product was sulfate, resulting in a drop in pH from 6.8 to 2.7. Heterotrophic growth on pyruvate was observed at pH 4-7 (optimum pH 4) and 35-50 degrees C (optimum 45 degrees C). The DNA G+C content was 65.2 mol%. As determined by 16S rRNA gene sequence analysis, strain 6C(T) represents a distinct species belonging to the class Betaproteobacteria and is most closely related to Thiomonas intermedia DSM 18155(T) and Thiomonas perometabolis DSM 18570(T). DNA-DNA hybridization between strain 6C(T) and Thiomonas intermedia DSM 18155(T) and Thiomonas perometabolis DSM 18570(T) gave relatedness values below 32 %. These results, together with physiological characteristics, showed that strain 6C(T) represents a novel species within the genus Thiomonas, for which the name Thiomonas islandica sp. nov. is proposed. The type strain is 6C(T) (=DSM 21436(T) =JCM 16107(T)). PMID- 20173006 TI - Jiangella muralis sp. nov., from an indoor environment. AB - A Gram-stain-positive, non-spore-forming actinobacterium, designated 15-Je 017(T), was isolated from wall material of an indoor environment. The isolate formed a rudimentary substrate mycelium that fragmented into rod-shaped cells. On the basis of 16S rRNA gene sequence analysis, strain 15-Je-017(T) was shown to belong to the genus Jiangella and was most closely related to Jiangella alba YIM 61503(T) (99.7 % 16S rRNA gene sequence similarity), Jiangella alkaliphila D8 87(T) (99.0 %) and Jiangella gansuensis YIM 002(T) (99.0 %). The predominant menaquinone was MK-9(H(4)). Whole-cell hydrolysates contained ll-diaminopimelic acid as the diagnostic diamino acid in the cell wall and rhamnose and glucose as the main sugars. Mycolic acids were absent. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside and seven unknown phospholipids. The fatty acid profile contained major amounts (>5 %) of anteiso-C(15 : 0), iso-C(16 : 0), iso C(15 : 0), iso-C(17 : 0), anteiso-C(17 : 0) and C(17 : 1)omega8c, which supported the affiliation of strain 15-Je-017(T) to the genus Jiangella. DNA-DNA relatedness and physiological and biochemical tests allowed the differentiation of strain 15-Je-017(T) from the type strains of the three known Jiangella species. Strain 15-Je-017(T) represents a novel Jiangella species, for which we propose the name Jiangella muralis sp. nov., with type strain 15-Je-017(T) (=DSM 45357(T) =CCM 7680(T)). PMID- 20173007 TI - Miniimonas arenae gen. nov., sp. nov., an actinobacterium isolated from sea sand. AB - A Gram-positive, non-motile, coccoid- to rod-shaped, non-spore-forming bacterium, designated strain YM18-15(T), was isolated from sea sand and studied using a polyphasic taxonomic approach. Strain YM18-15(T) grew under both aerobic and anaerobic conditions. The cell-wall peptidoglycan type was A4beta and ornithine was the diagnostic diamino acid. The polar lipids were phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol and an unknown phospholipid, MK 8(H(4)) was the major menaquinone and the predominant fatty acids were anteiso C(15 : 0) and C(16 : 0). The DNA G+C content was 74.2 mol%. High 16S rRNA gene sequence similarities (96.3-97.3 %) were found with the sequences of the type strains of the three genera of the family Beutenbergiaceae. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain YM18-15(T) formed a clade with Serinibacter salmoneus, Salana multivorans and Beutenbergia cavernae. Strain YM18-15(T) differed from these three type strains in chemotaxonomic characteristics and in 16S rRNA gene signature nucleotides. Based on genetic and chemotaxonomic evidence, it is suggested that strain YM18-15(T) represents a novel species of a new genus within the family Beutenbergiaceae, for which the name Miniimonas arenae gen. nov., sp. nov. is proposed. The type strain of the type species is YM18-15(T) (=NBRC 106267(T)=KCTC 19750(T)=MBIC 08348(T)). PMID- 20173008 TI - Anoxybacillus tengchongensis sp. nov. and Anoxybacillus eryuanensis sp. nov., facultatively anaerobic, alkalitolerant bacteria from hot springs. AB - Two novel thermophilic, spore-forming bacterial strains, T-11(T) and E-112(T), were isolated from hot springs in Tengchong and Eryuan counties of Yunnan province in south-west China. The strains were Gram-stain-positive rods, occurring singly or in chains. Growth of strain T-11(T) was observed between 30 and 75 degrees C (optimum 50 degrees C) and at pH 7-11 (optimum pH 8.5), while the temperature range for strain E-112(T) was 35-70 degrees C (optimum 55 degrees C) and the pH range was 7.0-11.0 (optimum pH 8.0). The DNA G+C contents of strains T-11(T) and E-112(T) were 41.1 and 42.6 mol%, respectively. On the basis of 16S rRNA gene sequence similarity, the two strains were shown to be related most closely to Anoxybacillus species. The chemotaxonomic characteristics [predominant isoprenoid quinone menaquinone 7 (MK-7); major fatty acids iso-C(15 : 0) and iso-C(17 : 0)] also supported the affiliation of strains T-11(T) and E 112(T) to the genus Anoxybacillus. The results of DNA-DNA hybridization and physiological and biochemical tests allowed genotypic and phenotypic differentiation of strains T-11(T) and E-112(T) from Anoxybacillus species with validly published names. Strains T-11(T) and E-112(T) therefore represent two novel species, for which the names Anoxybacillus tengchongensis sp. nov. (type strain T-11(T) =CCTCC AB209237(T) =KCTC 13721(T)) and Anoxybacillus eryuanensis sp. nov. (type strain E-112(T) =CCTCC AB209236(T) =KCTC 13720(T)) are proposed. PMID- 20173009 TI - Nocardioides caricicola sp. nov., an endophytic bacterium isolated from a halophyte, Carex scabrifolia Steud. AB - A Gram-staining-positive, coccoid to rod-shaped bacterium, designated strain YC6903(T), was isolated from a halophytic plant (Carex scabrifolia Steud.) collected from sand dunes at Namhae Island, Korea, and its taxonomic position was investigated by using a polyphasic approach. Strain YC6903(T) grew optimally at 30 degrees C and at pH 8.0. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain YC6903(T) belongs to the genus Nocardioides in the family Nocardioidaceae. Strain YC6903(T) was related most closely to Nocardioides pyridinolyticus OS4(T) (97.0 % 16S rRNA gene sequence similarity), Nocardioides dokdonensis FR1436(T) (96.6 %), Nocardioides aquiterrae GW-9(T) (96.6 %) and Nocardioides hankookensis DS-30(T) (96.6 %). The cell-wall peptidoglycan contained LL-diaminopimelic acid and MK-8(H(4)) was the major respiratory quinone. The mean (+/-SD) level of DNA-DNA relatedness between strain YC6903(T) and N. pyridinolyticus OS4(T) was 53.5+/-5.5 %. The predominant cellular fatty acid of strain YC6903(T) was iso-C(16 : 0) (28.9 %). The DNA G+C content was 71.7 mol%. Phenotypic, phylogenetic and chemotaxonomic data indicated that strain YC6903(T) represents a novel species of the genus Nocardioides, for which the name Nocardioides caricicola sp. nov. is proposed. The type strain is YC6903(T) (=KACC 13778(T) =DSM 22177(T)). PMID- 20173010 TI - Neisseria wadsworthii sp. nov. and Neisseria shayeganii sp. nov., isolated from clinical specimens. AB - An analysis of 16S rRNA gene sequences from archived clinical reference specimens has identified two novel Neisseria species. For each species, two strains from independent sources were identified. Amongst species with validly published names, the closest species to the newly identified organisms were Neisseria canis, N. dentiae, N. zoodegmatis, N. animaloris and N. weaveri. DNA-DNA hybridization studies demonstrated that the newly identified isolates represent species that are distinct from these nearest neighbours. Analysis of partial 23S rRNA gene sequences for the newly identified strains and their nearest neighbours provided additional support for the species designation. Bayesian analysis of 16S rRNA gene sequences suggested that the newly identified isolates belong to distinct but related species of the genus Neisseria, and are members of a clade that includes N. dentiae, N. bacilliformis and N. canis. The predominant cellular fatty acids [16 : 0, summed feature 3 (16 : 1omega7c and/or iso-15 : 0 2-OH) and 18 : 1omega7c], as well as biochemical and morphological analyses further support the designation of Neisseria wadsworthii sp. nov. (type strain 9715(T) =DSM 22247(T) =CIP 109934(T)) and Neisseria shayeganii sp. nov. (type strain 871(T) =DSM 22246(T) =CIP 109933(T)). PMID- 20173011 TI - Spirochaeta perfilievii sp. nov., an oxygen-tolerant, sulfide-oxidizing, sulfur- and thiosulfate-reducing spirochaete isolated from a saline spring. AB - A novel strain of fermenting, aerotolerant, chemo-organoheterotrophic spirochaete designated P(T) was isolated from a sulfur 'Thiodendron' mat in a saline spring at the Staraya Russa resort (Novgorod Region, Russia). Cells of strain P(T) exhibited a helical shape. The spirochaete required sulfide in the growth medium and was able to oxidize it non-enzymically to elemental sulfur via the interaction of H(2)O(2) with sulfide and deposit it in the periplasmic space. Growth occurred at 4-32 degrees C (optimum at 28-30 degrees C), pH 6.0-8.5 (optimum pH 7.0-7.5), and in 0.1-1 M NaCl (optimum 0.35 M). The isolate used several sugars and polysaccharides as carbon or energy sources but did not use peptides, amino acids, organic acids or alcohols. The products of glucose fermentation were formate, acetate, ethanol, pyruvate, CO(2) and H(2). The genomic DNA G+C content was 41.7 mol%. 16S rRNA gene sequence analysis showed that strain P(T) fell within a group of species in the genus Spirochaeta, including Spirochaeta litoralis, S. isovalerica and S. cellobiosiphila, with which it shared less then 89 % sequence similarity. On the basis of its morphology, physiology and other phenotypic properties, as well as its phylogenetic position, the new isolate is considered to represent a novel species of the genus Spirochaeta, for which the name Spirochaeta perfilievii sp. nov. is proposed. The type strain is P(T) (=DSM 19205(T) =VKM B-2514(T)). PMID- 20173012 TI - Sporosalibacterium faouarense gen. nov., sp. nov., a moderately halophilic bacterium isolated from oil-contaminated soil. AB - A novel strictly anaerobic, moderately halophilic and mesophilic bacterium, designated strain SOL3f37(T), was isolated from a hydrocarbon-polluted soil surrounding a deep petroleum environment located in south Tunisia. Cells of strain SOL3f37(T) stained Gram-positive and were motile, straight and spore forming. Strain SOL3f37(T) had a typical Gram-positive-type cell-wall structure, unlike the thick, multilayered cell wall of its closest relative Clostridiisalibacter paucivorans. The major fatty acids were iso-C(15 : 0) (41 %), iso-C(14 : 0) 3-OH and/or iso-C(15 : 0) dimethyl acetal (21.6 %), iso-C(13 : 0) (4.4 %), anteiso-C(15 : 0) (3.9 %) and iso-C(15 : 1) (2.8 %). Strain SOL3f37(T) grew between 20 and 48 degrees C (optimum 40 degrees C) and at pH 6.2-8.1 (optimum pH 6.9). Strain SOL3f37(T) required at least 0.5 NaCl l(-1) and grew in the presence of NaCl concentrations up to 150 g l(-1) (optimum 40 g l( 1)). Yeast extract (2 g l(-1)) was required for degradation of pyruvate, fumarate, fructose, glucose and mannitol. Also, strain SOL3f37(T) grew heterotrophically on yeast extract, peptone and bio-Trypticase, but was unable to grow on Casamino acids. Sulfate, thiosulfate, sulfite, elemental sulfur, fumarate, nitrate and nitrite were not reduced. The DNA G+C content was 30.7 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain SOL3f37(T) was a member of the family Clostridiaceae in the order Clostridiales; strain SOL3f37(T) was related to members of various genera of the family Clostridiaceae. It exhibited highest 16S rRNA gene sequence similarity (93.4 %) with Clostridiisalibacter paucivorans 37HS60(T), 91.8 % with Thermohalobacter berrensis CTT3(T) and 91.7 % with Caloranaerobacter azorensis MV1087(T). On the basis of genotypic, phenotypic and phylogenetic data, it is suggested that strain SOL3f37(T) represents a novel species in a new genus. The name Sporosalibacterium faouarense gen. nov., sp. nov. is proposed, with SOL3f37(T) (=DSM 21485(T) =JCM 15487(T)) as the type strain of Sporosalibacterium faouarense. PMID- 20173013 TI - Streptomyces lacticiproducens sp. nov., a lactic acid-producing streptomycete isolated from the rhizosphere of tomato plants. AB - A novel actinomycete, designated strain GIMN4.001(T), was isolated from the rhizosphere of tomato plants grown in Guangzhou, China. The strain produced greyish white aerial mycelia, lactic acid and a large quantity of double diamond shaped crystals on potato dextrose agar and yeast extract-malt extract agar. The colour of the substrate mycelium was not sensitive to pH. Microscopic observations revealed that strain GIMN4.001(T) produced verticillate chains of cylindrical spores. Chemotaxonomic data confirmed that strain GIMN4.001(T) belonged to the genus Streptomyces. Melanin pigments were not produced. No antibacterial activity was observed against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis or Candida albicans, but inhibitory activity was observed against Penicillium citrinum. 16S rRNA gene sequence analysis revealed that strain GIMN4.001(T) was related most closely to Streptomyces morookaense ATCC 19166(T) (98.9 % similarity) and Streptomyces lavenduligriseus ATCC 13306(T) (98.7 %). Levels of DNA-DNA relatedness between strain GIMN4.001(T) and the type strains of these species were low (14-20 %). Furthermore, strain GIMN4.001(T) could be differentiated from S. morookaense, S. lavenduligriseus and other closely related species of the genus Streptomyces based on morphological, physiological and biochemical characteristics. On the basis of its physiological and molecular properties, strain GIMN4.001(T) is considered to represent a novel species of the genus Streptomyces, for which the name Streptomyces lacticiproducens sp. nov. is proposed. The type strain is GIMN4.001(T) (=CCTCC M208214(T)=NRRL B-24800(T)). PMID- 20173014 TI - 17{beta}-Estradiol modulates the macrophage migration inhibitory factor secretory pathway by regulating ABCA1 expression in human first-trimester placenta. AB - Successful pregnancy involves a series of events, most of them mediated by hormones and cytokines. Estrogens, besides being important for placental growth and embryo development, have a marked effect on the immune system exerting either pro- or anti-inflammatory properties. Numerous studies suggest that estrogens directly affect cellular function, including cytokine production. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in pregnancy, particularly during the earlier stages of placentation. Since reports on mice have shown that estrogens modulate MIF, herein we investigated the effect of estrogens on human placental MIF. By using an in vitro model of first trimester chorionic villous explants, we found that 17beta-estradiol (E(2)) was able to modulate the release of MIF in a dose-dependent manner (10(-12) vs. 10( 9) M, P < 0.05; 10(-9) vs. 10(-5) M, P < 0.05; 10(-12) vs. 10(-5) M, P < 0.001). Unlike MIF release, no significant change in tissue MIF protein or MIF mRNA was observed. We showed evidence that E(2) concentrations (10(-9) and 10(-5) M) act on placental tissue downregulating the mRNA and protein expression of the ATP binding cassette transporter protein A1, a membrane transporter involved in MIF secretion. These findings emphasize the mutual cooperation between hormones and cytokines and suggest that increasing estrogen levels with advancing gestation may have a major role in regulating placental MIF secretion. PMID- 20173015 TI - Improved ejection fraction after exercise training in obesity is accompanied by reduced cardiac lipid content. AB - CONTEXT: Skeletal muscle and cardiac lipid accumulation are associated with diminished insulin sensitivity and cardiac function, respectively. In skeletal muscle, physical activity paradoxically increases fat accumulation, despite improvement in insulin sensitivity. Whether cardiac muscle responds similarly remains unknown. OBJECTIVE: The objective of the study was to investigate cardiac lipid content and cardiac function after a 12-wk training program. DESIGN: This was an intervention study with pre/postmeasurements. SETTING: The study was conducted at Maastricht University Medical Center. PARTICIPANTS: Participants included 14 healthy, male overweight/obese subjects (age 58.4 +/- 0.9 yr, body mass index 29.9 +/- 0.01 kg/m(2)). INTERVENTION: Intervention included a supervised 12-wk training program with three sessions per week (endurance and strength training). MAIN OUTCOME MEASURES: Maximal whole-body oxygen uptake, fasting plasma parameters, systolic function (by CINE-magnetic resonance imaging), and cardiac lipid content (by proton magnetic resonance spectroscopy) were measured. RESULTS: Maximal whole-body oxygen uptake increased (from 2559 +/- 131 to 2702 +/- 124 ml/min after training, P = 0.05). Plasma concentrations of glucose decreased (from 6.3 +/- 0.2 to 5.7 +/- 0.2 mmol/liter, P < 0.001); plasma triacylglycerols and (free) fatty acids did not change. Also, body weight (from 94.2 +/- 3.6 to 92.9 +/- 3.6 kg, P = 0.10) and fat percentage (from 33.6 +/- 1.7 to 32.5 +/- 2.0%, P = 0.14) was unchanged. Left ventricular ejection fraction improved (from 52.2 +/- 1.3 to 54.2 +/- 1.2%, P = 0.02), and cardiac lipid content in the septum was decreased after training (0.99 +/- 0.15 to 0.54 +/- 0.04%, P = 0.02). CONCLUSIONS: Twelve weeks of endurance/strength training significantly reduced cardiac lipid content in overweight subjects and was paralleled by improved ejection fraction. This is in line with a lipotoxic action of (excess) cardiac lipids on cardiac function, although a causal relationship cannot be derived from this study. Further research is needed to clarify the clinical relevance of cardiac lipid content in the etiology of cardiovascular complications. PMID- 20173016 TI - Effect of polymorphisms in selected genes involved in pituitary-testicular function on reproductive hormones and phenotype in aging men. AB - CONTEXT: Polymorphisms in genes involved in regulation, biosynthesis, metabolism, and actions of testicular sex hormones may influence hormone balance and phenotype of aging men. OBJECTIVE: We investigated the relationships between polymorphisms in genes related to pituitary-testicular endocrine function and health status. DESIGN AND SETTING: Using cross-sectional baseline data, we conducted a multinational prospective cohort observational study consisting of a population survey of community-dwelling men. PARTICIPANTS: A total of 2748 men, aged 40-79 (mean +/- sd, 60.2 + 11.2) yr, were randomly recruited from eight European centers. Forty-three polymorphisms were genotyped in the following genes: androgen receptor (AR), estrogen receptor-alpha and -beta (ESR1 and ESR2), steroid 5alpha-reductase type II (SRD5A2), 17alpha-hydroxylase/17,20-lyase (CYP17A1), aromatase (CYP19A1), sex hormone-binding globulin (SHBG), LH beta subunit (LHB), and LH receptor (LHCGR). MAIN OUTCOME MEASURES: We measured the associations between gene polymorphisms and endocrine, metabolic, and phenotypic parameters related to aging and sex hormone action. RESULTS: Several polymorphisms in SHBG, ESR2, AR, CYP19A1, and LHB were significantly associated with circulating levels of SHBG, LH, total, free, and bioavailable testosterone and estradiol, the LH x testosterone product, and indices of insulin sensitivity. Apart from several previously reported associations between genes affecting estrogen levels and heel ultrasound parameters, no associations existed between polymorphisms and nonhormonal variables (anthropometry, blood lipids, blood pressure, hemoglobin, prostate symptoms, prostate-specific antigen, sexual dysfunction, cognition). CONCLUSION: In aging men, polymorphisms in genes related to the pituitary-testicular endocrine function significantly influence circulating LH, testosterone, and estradiol levels, but the downstream effects may be too small to influence secondary phenotypic parameters. PMID- 20173017 TI - Long-term use of bisphosphonates in osteoporosis. AB - CONTEXT: Bisphosphonates have been widely used in the treatment of osteoporosis. Uncommon side effects have emerged in postapproval use. Because bisphosphonates accumulate in bone and are released for months or years after treatment is stopped, it is reasonable to consider the clinical question of how long to treat. OBJECTIVE: In this personal perspective, we review the pharmacology and mechanism of action of bisphosphonates and the clinical studies that support their efficacy. We then review the literature for longer-term studies and reports of possible side effects that were not seen in clinical trials. RESULTS: Bisphosphonates have demonstrated antifracture efficacy in randomized, placebo controlled trials of 3 and 4 yr duration and have been widely used since the initial release of alendronate in 1995. For zoledronic acid and risedronate, an early effect (fractures reduced within 6-12 months of starting therapy) has been shown. A sustained effect for risedronate has been shown through 5 yr and suggested through 7 yr. Ten-year data with alendronate and 8 yr data with risedronate indicated good tolerability and safety; it is unlikely that longer term studies will be done. Side effects that emerged in clinical trials include esophageal irritation with oral administration and acute phase response with iv treatment or high-dose oral therapy. Uncommon side effects that have been noted with wide clinical use include osteonecrosis of the jaw, musculoskeletal complaints, and atypical fractures. The numbers of events are small, and a clear cause-and-effect relationship between these events and bisphosphonate treatment has not been established. Because bisphosphonates accumulate in bone, they create a reservoir leading to continued release from bone for months or years after treatment is stopped. Studies with risedronate and alendronate suggest that if treatment is stopped after 3-5 yr, there is persisting antifracture efficacy, at least for 1-2 yr. CONCLUSIONS: Bisphosphonates are popular and effective for treatment of osteoporosis. Because they accumulate in bone and provide some residual antifracture reduction when treatment is stopped, we recommend a drug holiday after 5-10 yr of bisphosphonate treatment. The duration of treatment and length of the holiday are based on fracture risk and pharmacokinetics of the bisphosphonate used. Patients at mild risk might stop treatment after 5 yr and remain off as long as bone mineral density is stable and no fractures occur. Higher risk patients should be treated for 10 yr, have a holiday of no more than a year or two, and perhaps be on a nonbisphosphonate treatment during that time. PMID- 20173019 TI - Development of a sensitive and specific quantitative reverse transcription polymerase chain reaction assay for blood thyroglobulin messenger ribonucleic acid in the follow-up of patients with differentiated thyroid carcinoma. AB - CONTEXT: Serum thyroglobulin is a sensitive tumor marker in the follow-up of patients with differentiated thyroid carcinoma (DTC), but the presence of endogenous anti-thyroglobulin antibodies (TgAb) can interfere on its measurement. To prevent interference by TgAb, several investigators have tried to quantify blood mRNA Tg by real-time RT-PCR, but the results have been variable, not reporting a correlation between mRNA Tg and the presence of metastases. OBJECTIVE: The aim of the study was to evaluate the development of a sensitive and specific quantitative RT-PCR assay for blood mRNA Tg in the follow-up of patients with DTC. DESIGN AND PATIENTS: An assay employing primers located in a region not affected by alternative splicing or single nucleotide polymorphisms was developed to study 104 DTC patients (13 of 104 with positive TgAb). RESULTS: The assay is specific for thyroid tissue because we found mRNA Tg expression in normal thyroid tissue, but we did not find any mRNA Tg expression in any extrathyroidal tissues. Quantitative mRNA Tg levels were significantly different between patients "free of disease" (82 of 104) and those with metastases (22 of 104) (2.61 +/- 0.26 vs. 27.58 +/- 1.62 pg mRNA Tg/microg RNA) (P < 0.0001). A cutoff point of 5.51 was able to discriminate between the two groups. In addition, the measurement of mRNA Tg was not affected by the presence of TgAb. CONCLUSION: This new mRNA Tg quantification is a reliable method that allowed us to differentiate patients free of disease from those with metastases, and it could represent an appropriate molecular marker for the follow-up of patients with DTC, especially those with positive TgAb. PMID- 20173018 TI - Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. AB - CONTEXT: The diagnosis of late-onset hypogonadism (LOH) in older men with age related declines in testosterone (T) is currently not well characterized. OBJECTIVE: Our objective was to investigate whether different forms of hypogonadism can be distinguished among aging men. DESIGN: The study was a cross sectional survey on 3369 community-dwelling men aged 40-79 yr in eight European centers. METHODS: Four groups of subjects were defined: eugonadal (normal T and normal LH), secondary (low T and low/normal LH), primary (low T and elevated LH), and compensated (normal T and elevated LH) hypogonadism. Relationships between the defined gonadal status with potential risk factors and clinical symptoms were investigated by multilevel regression models. RESULTS: Among the men, 11.8, 2.0, and 9.5% were classified into the secondary, primary, and compensated hypogonadism categories, respectively. Older men were more likely to have primary [relative risk ratio (RRR) = 3.04; P < 0.001] and compensated (RRR = 2.41; P < 0.001) hypogonadism. Body mass index of 30 kg/m(2) or higher was associated with secondary hypogonadism (RRR = 8.74; P < 0.001). Comorbidity was associated with both secondary and primary hypogonadism. Sexual symptoms were more prevalent in secondary and primary hypogonadism, whereas physical symptoms were more likely in compensated hypogonadism. CONCLUSIONS: Symptomatic elderly men considered to have LOH can be differentiated on the basis of endocrine and clinical features and predisposing risk factors. Secondary hypogonadism is associated with obesity and primary hypogonadism predominately with age. Compensated hypogonadism can be considered a distinct clinical state associated with aging. Classification of LOH into different categories by combining LH with T may improve the diagnosis and management of LOH. PMID- 20173020 TI - Cardiovascular and metabolic risk profile and acylation-stimulating protein levels in children with Prader-Willi syndrome and effects of growth hormone treatment. AB - CONTEXT: Reports on the cardiovascular and metabolic risk profile in children with Prader-Willi syndrome (PWS) and the effects of GH treatment are scarce. Acylation-stimulating protein (ASP) stimulates glucose uptake and triglyceride storage in adipose tissue. OBJECTIVES: The aim was to study the metabolic and cardiovascular risk profile and ASP levels and to investigate the effects of GH treatment. DESIGN: We conducted a randomized controlled GH trial. Infants and prepubertal children were assigned to receive GH (1 mg/m(2) . d) or to serve as controls for 12 and 24 months, respectively. PATIENTS: Eighty-five children with PWS (mean +/- sd age of 4.9 +/- 3.0 yr) participated in the study. MAIN OUTCOME MEASURES: We measured fat percentage (fat%) with dual-energy x-ray absorptiometry, blood pressure, fasting insulin and glucose levels, serum lipids, and ASP levels. RESULTS: Mean +/- SD fat% was 28.4 +/- 6.2 in infants and 36.9 +/ 8.5 in prepubertal children. Fat% sd score (SDS) was above 2 SDS in 95% of prepubertal children. In addition, 63% of infants and 73% of prepubertal children demonstrated at least one cardiovascular risk factor, defined as hypertension or dyslipidemia. The metabolic syndrome was demonstrated in 5% of all children. Mean +/- sd baseline ASP was 107 +/- 45 nmol/liter (normal < 58 nmol/liter) and correlated with fat mass and TG levels. GH improved fat%SDS and the HDLc/LDLc ratio (P < 0.0001 and P = 0.04). GH had no effect on mean ASP levels in this population. CONCLUSIONS: Many children with PWS had dyslipidemia and high ASP levels. GH improved fat% and high-density lipoprotein cholesterol/low-density lipoprotein cholesterol, but not ASP. High ASP levels may prevent complete normalization of fat%SDS during GH treatment but may contribute in keeping glucose and insulin levels within normal range. PMID- 20173021 TI - Diet-induced obesity impairs the T cell memory response to influenza virus infection. AB - The Centers for Disease Control and Prevention has suggested that obesity may be an independent risk factor for increased severity of illness from the H1N1 pandemic strain. Memory T cells generated during primary influenza infection target internal proteins common among influenza viruses, making them effective against encounters with heterologous strains. In male, diet-induced obese C57BL/6 mice, a secondary H1N1 influenza challenge following a primary H3N2 infection led to a 25% mortality rate (with no loss of lean controls), 25% increase in lung pathology, failure to regain weight, and 10- to 100-fold higher lung viral titers. Furthermore, mRNA expression for IFN-gamma was >60% less in lungs of obese mice, along with one third the number of influenza-specific CD8(+) T cells producing IFN-gamma postsecondary infection versus lean controls. Memory CD8(+) T cells from obese mice had a >50% reduction in IFN-gamma production when stimulated with influenza-pulsed dendritic cells from lean mice. Thus, the function of influenza-specific memory T cells is significantly reduced and ineffective in lungs of obese mice. The reality of a worldwide obesity epidemic combined with yearly influenza outbreaks and the current pandemic makes it imperative to understand how influenza virus infection behaves differently in an obese host. Moreover, impairment of memory responses has significant implications for vaccine efficacy in an obese population. PMID- 20173022 TI - PI3K-dependent upregulation of Mcl-1 by human cytomegalovirus is mediated by epidermal growth factor receptor and inhibits apoptosis in short-lived monocytes. AB - Monocytes are a primary target for human CMV (HCMV) infection and are a key cell type responsible for hematogenous dissemination of the virus. Biologically, these cells have a short lifespan of 1-3 d in the circulation, yet infected cells remain viable for weeks despite the lack of viral antiapoptotic gene expression during this period. To understand the mechanism by which HCMV inhibits the initial phase of monocyte apoptosis, we focused on the viral modulation of early prosurvival cell signaling events after infection. We demonstrate in this study that the viral upregulation of the PI3K pathway promotes an early block in apoptosis after infection. Temporal transcriptome and protein analyses revealed Mcl-1, a member of the Bcl-2 family, was transiently induced in a PI3K-dependent manner during the early stages of HCMV infection. In accord with the survival studies, virally induced levels of Mcl-1 expression dissipated to mock levels by 72 h postinfection. Through the use of Mcl-1-specific small interfering RNA, we confirmed the functional role that Mcl-1 plays as a key early regulator of apoptosis in monocytes. Lastly, we showed that HCMV engagement and activation of the epidermal growth factor receptor during viral binding triggered the upregulation of Mcl-1. Overall, our data indicates that activation of the epidermal growth factor receptor/PI3K signaling pathway, via the PI3K-dependent upregulation of Mcl-1, is required to circumvent apoptosis in naturally short lived monocytes during the early stages of HCMV infection, thus ensuring the early steps in the viral persistence strategy. PMID- 20173023 TI - Dendritic cell inhibition is connected to exhaustion of CD8+ T cell polyfunctionality during chronic hepatitis C virus infection. AB - Although chronic viral infections have evolved mechanisms to interfere with aspects of pathogen recognition by dendritic cells (DCs), the role that these APCs play in virus-specific T cell exhaustion is unclear. Herein we report that NS3-dependent suppression of Toll/IL-1 domain-containing adapter-inducing IFN beta- and IFN-beta promoter stimulator-1- but not MyD88-coupled pathogen recognition receptor-induced synthesis of proinflammatory cytokines (IL-12 and TNF-alpha) from DCs by hepatitis C virus (HCV) is a distinctive feature of a subgroup of chronically infected patients. The result is decreased CD8(+) T cell polyfunctional capacities (production of IFN-gamma, IL-2, TNF-alpha, and CD107a mobilization) that is confined to HCV specificities and that relates to the extent to which HCV inhibits DC responses in infected subjects, despite comparable plasma viral load, helper T cell environments, and inhibitory programmed death 1 receptor/ligand signals. Thus, subjects in whom pathogen recognition receptor signaling in DCs was intact exhibited enhanced polyfunctionality (i.e., IL-2-secretion and CD107a). In addition, differences between HCV-infected patients in the ability of CD8(+) T cells to activate multiple functions in response to HCV did not apply to CD8(+) T cells specific for other immune-controlled viruses (CMV, EBV, and influenza). Our findings identify reversible virus evasion of DC-mediated innate immunity as an additional important factor that impacts the severity of polyfunctional CD8(+) T cell exhaustion during a chronic viral infection. PMID- 20173024 TI - IL-17 contributes to angiogenesis in rheumatoid arthritis. AB - Angiogenesis is an early and a critical event in the pathogenesis of rheumatoid arthritis (RA). Neovascularization is dependent on endothelial cell activation, migration and proliferation, and inhibition of angiogenesis may provide a novel therapeutic approach in RA. In this study, we document a novel role of IL-17 in mediating angiogenesis. Local expression of IL-17 in mouse ankles increases vascularity. We further demonstrate that IL-17 is angiogenic by showing its ability to promote blood vessel growth in Matrigel plugs in vivo. Additionally, IL-17, in concentrations present in the RA joint, induces human lung microvascular endothelial cell (HMVEC) migration mediated through the PI3K/AKT1 pathway. Furthermore, suppression of the PI3K pathway markedly reduces IL-17 induced tube formation. We also show that both IL-17-induced HMVEC chemotaxis and tube formation are mediated primarily through IL-17 receptor C. Neutralization of either IL-17 in RA synovial fluids or IL-17 receptor C on HMVECs significantly reduces the induction of HMVEC migration by RA synovial fluid. Finally, RA synovial fluid immunoneutralized with anti-IL-17 and antivascular endothelial growth factor does not reduce HMVEC migration beyond the effect detected by immunodepleting each factor alone. These observations identify a novel function for IL-17 as an angiogenic mediator in RA, supporting IL-17 as a therapeutic target in RA. PMID- 20173026 TI - Immunological property of antibodies against N-glycolylneuraminic acid epitopes in cytidine monophospho-N-acetylneuraminic acid hydroxylase-deficient mice. AB - The generation of pigs devoid of Galalpha1,3Galbeta1,4GlcNAc (Gal) residues has stimulated interest in non-Gal Ags as potentially important targets for Ab binding leading to rejection of pig organ xenografts in humans. Although N glycolylneuraminic acid (NeuGc) epitopes, which are widely expressed on the endothelial cells of all mammals except humans, are likely targets of anti-non Gal Abs, this aspect has not been investigated intensively owing to the absence of an appropriate animal model. In this study, we used CMAH(-/-) mice, which are completely deficient in NeuGc and thus produce anti-NeuGc Abs. Sera obtained from CMAH(-/-) mice and healthy human volunteers having anti-NeuGc Abs initiated complement-mediated lysis against CMAH(+/+) cells in vitro. The cytotoxic activity of anti-NeuGc Abs was also determined in vivo (i.e., NeuGc-expressing CMAH(+/+) mouse splenocytes that had been i.v. injected were completely eliminated in syngeneic CMAH(-/-) mice). CMAH(-/-) mice rejected the islets transplanted from syngeneic CMAH(+/+) mice. Thus, the anti-NeuGc Ab-mediated response may be crucially involved in xenograft loss. This is the first direct demonstration of the immunogenic property of NeuGc determinants as targets of the corresponding Abs in CMAH(+/+)-to-CMAH(-/-) transplantation setting. PMID- 20173025 TI - Dibutyl phthalate-induced thymic stromal lymphopoietin is required for Th2 contact hypersensitivity responses. AB - Thymic stromal lymphopoietin (TSLP) is an IL-7-related cytokine, produced by epithelial cells, that has been linked to atopic dermatitis and asthma; however, it remains unclear how TSLP shapes the adaptive immune response that causes these allergic disorders. In this study, we demonstrate a role for TSLP in a Th2 model of contact hypersensitivity in mice. TSLP is required for the development of Th2 type contact hypersensitivity induced by the hapten FITC in combination with the sensitizing agent dibutyl phthalate. TSLPR-deficient mice exhibited a dramatically reduced response, including markedly reduced local infiltration by eosinophils, Th2 cytokine production, and serum IgE levels, following FITC sensitization and challenge. The reduced response by TSLPR-deficient mice is likely due to decreased frequency and reduced T cell stimulatory function of skin derived Ag-bearing FITC(+)CD11c(+) dendritic cells in draining lymph nodes following FITC sensitization. These data suggest that skin-derived dendritic cells are direct or indirect targets of TSLP in the development of type 2 immune responses in the skin, where TSLP drives their maturation, accumulation in skin draining lymph nodes, and ability to induce proliferation of naive allergen specific T cells. PMID- 20173028 TI - Modulation of T lymphocyte function by the pregnane X receptor. AB - The pregnane X receptor (PXR) is a ligand-activated transcription factor regulating genes central to drug and hormone metabolism in the liver. Previous reports indicated that PXR is expressed in PBMC, but the role of PXR in immune cells remains unknown. In this paper, we report increased PXR expression in mouse and human T lymphocytes upon immune activation. Furthermore, pharmacologic activation of PXR inhibits T lymphocyte proliferation and anergizes T lymphocytes by decreasing the expression of CD25 and IFN-gamma and decreasing phosphorylated NF-kappaB and MEK1/2. Although these effects are preceded by an increase of suppressor of cytokine signaling 1, a master switch for IFN-gamma expression, in a PXR-dependent manner, T-bet expression remains unchanged. Conversely, PXR deficient mice exhibit an exaggerated T lymphocyte proliferation and increased CD25 expression. Furthermore, PXR-deficient lymphocytes produce more IFN-gamma and less of the anti-inflammatory cytokine IL-10. In summary, these results reveal a novel immune-regulatory role of PXR in T lymphocytes and identify suppressor of cytokine signaling 1 as an early signal in PXR-mediated T lymphocyte suppression. PMID- 20173027 TI - Endoplasmic reticulum aminopeptidase associated with antigen processing defines the composition and structure of MHC class I peptide repertoire in normal and virus-infected cells. AB - The MHC class I (MHC-I) molecules ferry a cargo of peptides to the cell surface as potential ligands for CD8(+) cytotoxic T cells. For nearly 20 years, the cargo has been described as a collection of short 8-9 mer peptides, whose length and sequences were believed to be primarily determined by the peptide-binding groove of MHC-I molecules. Yet the mechanisms for producing peptides of such optimal length and composition have remained unclear. In this study, using mass spectrometry, we determined the amino acid sequences of a large number of naturally processed peptides in mice lacking the endoplasmic reticulum aminopeptidase associated with Ag processing (ERAAP). We find that ERAAP deficiency changed the oeuvre and caused a marked increase in the length of peptides normally presented by MHC-I. Furthermore, we observed similar changes in the length of viral peptides recognized by CD8(+) T cells in mouse CMV-infected ERAAP-deficient mice. In these mice, a distinct CD8(+) T cell population was elicited with specificity for an N-terminally extended epitope. Thus, the characteristic length, as well as the composition of MHC-I peptide cargo, is determined not only by the MHC-I peptide-binding groove but also by ERAAP proteolysis in the endoplasmic reticulum. PMID- 20173029 TI - The anti-inflammatory actions of platelet endothelial cell adhesion molecule-1 do not involve regulation of endothelial cell NF-kappa B. AB - PECAM-1 is a cell adhesion and signaling receptor that is expressed on many hematopoietic cells and at endothelial cell-cell junctions. Accumulating evidence from a number of in vitro and in vivo model systems suggests that PECAM-1 suppresses cytokine production and vascular permeability induced by a wide range of inflammatory stimuli. In several of these models of inflammatory disease, endothelial, and not leukocyte or platelet, PECAM-1 conferred protection against inflammatory insult. However, the mechanism by which endothelial PECAM-1 functions as an anti-inflammatory protein is poorly understood. It was recently suggested that PECAM-1 exerts its anti-inflammatory effects in endothelial cells by inhibiting the activity of NF-kappaB, a proinflammatory transcription factor. To confirm and extend these observations, we examined the effect of engaging, cross-linking, or expressing PECAM-1 on NF-kappaB activation in a variety of human cells. PECAM-1 had no effect on the phosphorylation of the NF-kappaB inhibitory protein, IkappaBalpha; on the nuclear translocation of NF-kappaB; on the suppression of cytokine-induced transcriptional activation of an NF-kappaB luciferase reporter plasmid; or on the cytokine-stimulated upregulation of ICAM 1, an NF-kappaB target gene, in endothelial cells. Taken together, these studies strongly suggest that the anti-inflammatory actions of PECAM-1 in endothelial cells are not likely to involve its regulation of NF-kappaB. PMID- 20173030 TI - Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus. AB - Human thymus contains major dendritic cell (DC) subsets, myeloid DCs (mDCs), and plasmacytoid DCs (pDCs). We previously showed that mDCs, educated by thymic stromal lymphopoietin (TSLP) produced by the epithelial cells of the Hassall's corpuscles, induced differentiation of CD4(+)CD25(-) thymocytes into Forkhead Box P3(+) (FOXP3(+)) regulatory T cells (T(R)) within the medulla of human thymus. In this study, we show that pDCs expressed the TSLP receptor and IL-7 receptor alpha complexes upon activation and became responsive to TSLP. TSLP-activated human pDCs secrete macrophage-derived chemokine CCL-22 and thymus- and activation regulated chemokine CCL-17 but not Th1- or Th2-polarizing cytokines. TSLP activated pDCs induced the generation of FOXP3(+) T(R) from CD4(+)CD8(-)CD25(-) thymocytes, which could be strongly inhibited by Th1-polarizing cytokine IL-12 or Th2-polarizing cytokine IL-4. Interestingly, the FOXP3(+) T(R) induced by the TSLP-pDCs expressed more IL-10 but less TGF-beta than that induced by the TSLP mDCs. These data suggest that TSLP expressed by thymic epithelial cells can activate mDCs and pDCs to positively select the FOXP3(+) T(R) with different cytokine production potential in human thymus. The inability of TSLP to induce DC maturation without producing Th1- or Th2-polarizing cytokines may provide a thymic niche for T(R) development. PMID- 20173031 TI - Intense antiextracellular adaptive immune response to human cytomegalovirus in very old subjects with impaired health and cognitive and functional status. AB - Human aging is characterized by expanded and altered adaptive immune responses to human CMV (HCMV). It is unclear whether this expansion has its origins in age related homeostatic disturbances or viral reactivation, whether anti-CMV immune surveillance may still be effective, and what are the consequences of this expanded immune response for health and longevity. We conducted an observational cross-sectional study in groups of HCMV-seropositive subjects aged >or=65 y of variable health status to compare the intensity of Ab responses against HCMV with those against EBV and with CD4(+) and CD8(+) T cell proinflammatory effector responses directed to HCMV-derived pp65 and immediate-early protein 1 synthetic peptides. Ab responses to HCMV, but not to EBV, and anti-HCMV CD4(+), but not CD8(+), T cell responses were more intense in elderly subjects aged >or=85 y in poor health and were inversely correlated with markers of functional activity and cognitive function. Therefore, humoral and CD4(+) T cell anti-HCMV responses were specifically intensified in advanced aging associated with comorbidity and cognitive and functional impairments. Such a distinctive pattern of adaptive immunity indicates that immune responses targeting the extracellular phase of HCMV are increased in these elderly subjects and could represent an indirect effect of localized and undetectable HCMV reactivation. This study demonstrates that the oldest subjects in poor health with physical and mental impairment express intense functional immune responses to extracellular HCMV and suggests that they may be at risk for direct pathogenic effects by HCMV reactivation as well as indirect pathogenic effects linked to proinflammatory anti-HCMV effector responses. PMID- 20173033 TI - Returning home to Haiti--providing medical care after the earthquake. PMID- 20173032 TI - Substrain differences reveal novel disease-modifying gene candidates that alter the clinical course of a rodent model of multiple sclerosis. AB - Experimental autoimmune encephalomyelitis (EAE) is a rodent model of multiple sclerosis that is executed in animals by immunization with myelin Ag in adjuvant. The SJL/J autoimmune-prone strain of mouse has been used to model relapsing remitting multiple sclerosis. However, significant variations in peak scores, timing of onset, and incidence are observed among laboratories, with the postacute (relapse) phase of the disease exhibiting significant inconsistency. We characterized two substrains of SJL/J mice that exhibit profoundly different EAE disease parameters. Induction of EAE in the first SJL/J substrain resulted in many cases of chronic EAE that was dominated by an aggressive B cell response to the immunizing Ag and to endogenous CNS Ags. In contrast, the other SJL/J substrain exhibited a relapsing-remitting form of EAE concomitant with an elevated number of cytokine-producing CD4(+) T cells in the CNS. Exploiting these interstrain differences, we performed a genome-wide copy number analysis on the two disparate SJL/J substrains and discovered numerous gene-dosage differences. In particular, one inflammation-associated gene, Naip1, was present at a higher copy number in the SJL/J substrain that exhibited relapsing-remitting EAE. These results demonstrate that substrain differences, perhaps at the level of genomic copy number, can account for variability in the postacute phase of EAE and may drive chronic versus relapsing disease. PMID- 20173034 TI - Use of the kinase inhibitor analog 1NM-PP1 reveals a role for Toxoplasma gondii CDPK1 in the invasion step. AB - Toxoplasma gondii CDPK1 (TgCDPK1) was found to be the target of the toxoplasmocidal compound 1NM-PP1. When TgCDPK1 was mutated at position 128 from glycine to methionine, resistance was gained. Inhibition of gliding motility without inhibition of micronemal secretion by 1NM-PP1 suggests a function for TgCDPK1 in gliding motility. PMID- 20173035 TI - Mapping of Vps21 and HOPS binding sites in Vps8 and effect of binding site mutants on endocytic trafficking. AB - Vps8 is a subunit of the CORVET tethering complex, which is involved in early-to late endosome fusion. Here, we examine the role of Vps8 in membrane fusion at late endosomes in Saccharomyces cerevisiae. We demonstrate that Vps8 associates with membranes and that this association is independent of the class C/HOPS core complex and, contrary to a previous report, also independent of the Rab GTPase Vps21. Our data indicate that Vps8 makes multiple contacts with membranes. One of these membrane binding regions could be mapped to the N-terminal part of the protein. By two-hybrid analysis, we obtained evidence for a physical interaction between Vps8 and the Rab5 homologue Vps21. In addition, the interaction with the HOPS core complex was confirmed by immunoprecipitation experiments. By deletion analysis, the Vps21 and HOPS binding sites were mapped in Vps8. Deletions that abrogated HOPS core complex binding had a strong effect on the turnover of the endocytic cargo protein Ste6 and on vacuolar sorting of carboxypeptidase Y. In contrast, deletions that abolished Vps21 binding showed only a modest effect. This suggests that the Vps21 interaction is not essential for endosomal trafficking but may be important for some other aspect of Vps8 function. PMID- 20173036 TI - Metabolic and developmental effects resulting from deletion of the citA gene encoding citrate synthase in Aspergillus nidulans. AB - Citrate synthase is a central activity in carbon metabolism. It is required for the tricarboxylic acid (TCA) cycle, respiration, and the glyoxylate cycle. In Saccharomyces cerevisiae and Arabidopsis thaliana, there are mitochondrial and peroxisomal isoforms encoded by separate genes, while in Aspergillus nidulans, a single gene, citA, encodes a protein with predicted mitochondrial and peroxisomal targeting sequences (PTS). Deletion of citA results in poor growth on glucose but not on derepressing carbon sources, including those requiring the glyoxylate cycle. Growth on glucose is restored by a mutation in the creA carbon catabolite repressor gene. Methylcitrate synthase, required for propionyl-coenzyme A (CoA) metabolism, has previously been shown to have citrate synthase activity. We have been unable to construct the mcsADelta citADelta double mutant, and the expression of mcsA is subject to CreA-mediated carbon repression. Therefore, McsA can substitute for the loss of CitA activity. Deletion of citA does not affect conidiation or sexual development but results in delayed conidial germination as well as a complete loss of ascospores in fruiting bodies, which can be attributed to loss of meiosis. These defects are suppressed by the creA204 mutation, indicating that McsA activity can substitute for the loss of CitA. A mutation of the putative PTS1-encoding sequence in citA had no effect on carbon source utilization or development but did result in slower colony extension arising from single conidia or ascospores. CitA-green fluorescent protein (GFP) studies showed mitochondrial localization in conidia, ascospores, and hyphae. Peroxisomal localization was not detected. However, a very low and variable detection of punctate GFP fluorescence was sometimes observed in conidia germinated for 5 h when the mitochondrial targeting sequence was deleted. PMID- 20173038 TI - Interaction between activated chemokine receptor 1 and FcepsilonRI at membrane rafts promotes communication and F-actin-rich cytoneme extensions between mast cells. AB - Chemokines play important regulatory roles in immunity, but their contributions to mast cell function remain poorly understood. We examined the effects of FcepsilonRI-chemokine receptor (CCR) 1 co-stimulation on receptor localization and cellular morphology of bone marrow-derived mast cells. Whereas FcepsilonRI and CCR1 co-localized at the plasma membrane in unsensitized cells, sensitization with IgE promoted internalization of CCR1 molecules. Co-stimulation of FcepsilonRI and CCR1 with antigen and macrophage inflammatory protein-1alpha was more effective than FcepsilonRI stimulation alone in causing leading edge formation, flattened morphology, membrane ruffles and ganglioside (GM1(+)) lipid mediator release. Co-stimulation resulted in phalloidin-positive cytoneme-like cellular extensions, also known as tunneling nanotubes, which originated at points of calcium accumulation. This is the first report of cytoneme formation by mast cells. To determine the importance of lipid rafts for mast cell function, the cells were cholesterol depleted. Cholesterol depletion enhanced degranulation in resting, sensitized and co-stimulated cells, but not in FcepsilonRI-cross linked cells, and inhibited formation of filamentous actin(+) cytonemes but not GM1(+) cytonemes. Treatment with latrunculin A to sequester globular-actin abolished cytoneme formation. The cytonemes may participate in intercellular communication during allergic and inflammatory responses, and their presence in the co-stimulated mast cells suggests new roles for CCRs in immunopathology. PMID- 20173039 TI - Long-term functional improvement and gene expression changes after bone marrow derived multipotent progenitor cell transplantation in myocardial infarction. AB - The study examined the long-term outcome of cardiac stem cell transplantation in hearts with postinfarction left ventricular (LV) remodeling. Myocardial infarction (MI) was created by ligating the first and second diagonal branches of the left anterior descending coronary artery in miniature swine. Intramyocardial injections of 50 million LacZ-labeled bone marrow-derived multipotent progenitor cells (MPC) were performed in the periscar region (Cell, n = 7) immediately after MI, whereas, in control animals (Cont, n = 7), saline was injected. Functional outcome was assessed monthly for 4 mo with MRI and (31)P-magnetic resonance spectroscopy. Engraftment was studied on histology, and gene chip (Affymetrix) array analysis was used to study differential expression of genes in the two groups. MPC treatment resulted in improvement of ejection fraction as early as 10 days after MI (Cell, 43.4 +/- 5.1% vs. Cont, 32.2 +/- 5.5%; P < 0.05). This improvement was seen each month and persisted to 4 mo (Cell, 51.2 +/- 4.8% vs. Cont, 35.7 +/- 5.0%; P < 0.05). PCr-to-ATP ratio (PCr/ATP) improved with MPC transplantation, which was most pronounced at high cardiac work states (subendocardial PCr/ATP was 1.70 +/- 0.10 vs. 1.34 +/- 0.14, P < 0.05). There was no significant difference in scar size (scar/LV area * 100) at 10 days postinfarction. However, at 4 mo, there was a significant decrease in scar size in the Cell group (Cell, 4.6 +/- 1.0% vs. Cont, 8.6 +/- 2.4%; P < 0.05). No significant engraftment of MPC was observed. MPC transplantation was associated with a downregulation of mitochondrial oxidative enzymes and increased levels of myocyte enhancer factor 2a and zinc finger protein 91. In conclusion, MPC transplantation leads to long-term functional and bioenergetic improvement in a porcine model of postinfarction LV remodeling, despite no significant engraftment of stem cells in the heart. MPC transplantation reduces regional wall stresses and infarct size and mitigates the adverse effects of LV remodeling, as seen by a reduction in LV hypertrophy and LV dilatation, and is associated with differential expression of genes relating to metabolism and apoptosis. PMID- 20173040 TI - Toll-like receptor 2 mediates mesenchymal stem cell-associated myocardial recovery and VEGF production following acute ischemia-reperfusion injury. AB - Toll-like receptor 2 (TLR2), a key component of the innate immune system, is linked to inflammation and myocardial dysfunction after ischemia-reperfusion injury (I/R). Treatment of the heart with mesenchymal stem cells (MSCs) is known to improve myocardial recovery after I/R in part by paracrine factors such as VEGF. However, it is unknown whether TLR2 activation on the MSCs affects MSC mediated myocardial recovery and VEGF production. We hypothesized that the knockout of TLR2 on the MSCs (TLR2KO MSCs) would 1) improve MSC-mediated myocardial recovery and 2) increase myocardial and MSC VEGF release. With the isolated heart perfusion system, Sprague-Dawley rat hearts were subjected to I/R and received one of three intracoronary treatments: vehicle, male wild-type MSCs (MWT MSCs), or TL2KO MSCs. All treatments were performed immediately before ischemia, and heart function was measured continuously. Postreperfusion, heart homogenates were analyzed for myocardial VEGF production. Contrary to our hypothesis, only MWT MSC treatment significantly improved the recovery of left ventricular developed pressure and the maximal positive and negative values of the first derivative of pressure. In addition, VEGF production was greatest in hearts treated with MWT MSCs. To investigate MSC production of VEGF, MSCs were activated with TNF in vitro and the supernatants collected for ELISA. In vitro basal levels of MSC VEGF production were similar. However, with TNF activation, MWT MSCs produced significantly more VEGF, whereas activated TLR2KO MSC production of VEGF was unchanged. Finally, we observed that MWT MSCs proliferated more rapidly than TLR2KO MSCs. These data indicate that TLR2 may be essential to MSC-mediated myocardial recovery and VEGF production. PMID- 20173041 TI - Sex-related resistance to myocardial ischemia-reperfusion injury is associated with high constitutive ARC expression. AB - The female sex has been associated with improved myocardial salvage after ischemia and reperfusion (I/R). Estrogen, specifically 17beta-estradiol, has been demonstrated to mediate this phenomenon by limiting cardiomyocyte apoptosis. We sought to quantitatively assess the effect of sex, ovarian hormone loss, and I/R on myocardial Bax, Bcl-2, and apoptosis repressor with caspase recruitment domain (ARC) expression. Male (n = 48), female (n = 26), and oophorectomized female (n = 20) rabbits underwent 30 min of regional ischemia and 3 h of reperfusion. The myocardial area at risk and infarct size were determined using a double-staining technique and planimetry. In situ oligo ligation was used to assess apoptotic cell death. Western blot analysis was used to determine proapoptotic (Bax) and antiapoptotic (Bcl-2 and ARC) protein levels in all three ischemic groups and, additionally, in three nonischemic groups. Infarct size (43.7 +/- 3.2%) and apoptotic cell death (0.51 +/- 0.10%) were significantly attenuated in females compared with males (56.4 +/- 1.6%, P < 0.01, and 4.29 +/- 0.95%, P < 0.01) and oophorectomized females (55.7 +/- 3.4%, P < 0.05, and 4.36 +/- 0.51%, P < 0.01). Females expressed significantly higher baseline ARC levels (3.62 +/- 0.29) compared with males (1.78 +/- 0.18, P < 0.01) and oophorectomized females (1.08 +/- 0.26, P < 0.01). Males expressed a significantly higher baseline Bax-to-Bcl-2 ratio (4.32 +/- 0.99) compared with females (0.65 +/- 0.13, P < 0.01) and oophorectomized females (0.42 +/- 0.10, P < 0.01). I/R significantly reduced Bax to-Bcl-2 ratios in males. In all other groups, ARC levels and Bax-to-Bcl-2 ratios did not significantly change. These results support the conclusion that in females, endogenous estrogen limits I/R-induced cardiomyocyte apoptosis by producing a baseline antiapoptotic profile, which is associated with estrogen dependent high constitutive myocardial ARC expression. PMID- 20173042 TI - Chronic AT1 receptor blockade normalizes NMDA-mediated changes in renal sympathetic nerve activity and NR1 expression within the PVN in rats with heart failure. AB - Exercise training normalizes enhanced glutamatergic mechanisms within the paraventricular nucleus (PVN) concomitant with the normalization of increased plasma ANG II levels in rats with heart failure (HF). We tested whether ANG II type 1 (AT(1)) receptors are involved in the normalization of PVN glutamatergic mechanisms using chronic AT(1) receptor blockade with losartan (Los; 50 mg.kg( 1).day(-1) in drinking water for 3 wk). Left ventricular end-diastolic pressure was increased in both HF + vehicle (Veh) and HF + Los groups compared with sham operated animals (Sham group), although it was significantly attenuated in the HF + Los group compared with the HF + Veh group. The effect of Los on cardiac function was similar to exercise training. At the highest dose of N-methyl-d aspartate (NMDA; 200 pmol) injected into the PVN, the increase in renal sympathetic nerve activity was 93 +/- 13% in the HF + Veh group, which was significantly higher (P < 0.05) than the increase in the Sham + Veh (45 +/- 2%) and HF + Los (47 +/- 2%) groups. Relative NMDA receptor subunit NR(1) mRNA expression within the PVN was increased 120% in the HF + Veh group compared with the Sham + Veh group (P < 0.05) but was significantly attenuated in the HF + Los group compared with the HF + Veh group (P < 0.05). NR(1) protein expression increased 87% in the HF + Veh group compared with the Sham + Veh group but was significantly attenuated in the HF + Los group compared with the HF + Veh group (P < 0.05). Furthermore, in in vitro experiments using neuronal NG-108 cells, we found that ANG II treatment stimulated NR(1) protein expression and that Los significantly ameliorated the NR(1) expression induced by ANG II. These data are consistent with our hypothesis that chronic AT(1) receptor blockade normalizes glutamatergic mechanisms within the PVN in rats with HF. PMID- 20173043 TI - Does respiratory sinus arrhythmia serve a buffering role for diastolic pressure fluctuations? AB - Though many consider the magnitude of respiratory sinus arrhythmia as an index of cardiac vagal control, its physiological origins remain unclear. One influential model postulates that the systolic pressure rise within a given beat stimulates the baroreflex arc to adjust the following heart period such that diastolic pressure is "stabilized" and hence displays lesser fluctuation. Accordingly, the magnitude of diastolic pressure fluctuations with respiration should change reciprocally after augmentation or inhibition of respiratory sinus arrhythmia. To test this, we augmented and subsequently inhibited respiratory sinus arrhythmia with vagotonic and vagolytic atropine administration in 19 healthy young volunteers to assess the relation between respiratory R-R interval and diastolic pressure fluctuations. Respiratory diastolic pressure fluctuations showed parallel rather than inverse changes in relation to those in respiratory sinus arrhythmia: they increased with augmented respiratory sinus arrhythmia (138 and 190% of baseline in the frequency and time domains, both P < 0.05) and tended to decrease with inhibited respiratory sinus arrhythmia (82 and 93% of baseline in frequency and time domains, P = 0.20 and P = 0.07). Furthermore, >60% of the change in diastolic pressure fluctuations was explained by the change in respiratory sinus arrhythmia (R(2) = 0.62; P < 0.001), that is, an approximately 50-ms increase or decrease in respiratory sinus arrhythmia resulted in a parallel approximately 1-mmHg change in diastolic pressure fluctuations. Thus, in young healthy individuals during supine rest, respiratory fluctuations in R-R interval do not buffer against diastolic pressure fluctuations but actually cause diastolic pressure fluctuations. Therefore, our data provide little evidence for a predominant role of a baroreflex feedback mechanism underlying respiratory sinus arrhythmia during supine rest. PMID- 20173044 TI - Knockout of Na+/Ca2+ exchanger in smooth muscle attenuates vasoconstriction and L type Ca2+ channel current and lowers blood pressure. AB - Mice with smooth muscle (SM)-specific knockout of Na(+)/Ca(2+) exchanger type-1 (NCX1(SM-/-)) and the NCX inhibitor, SEA0400, were used to study the physiological role of NCX1 in mouse mesenteric arteries. NCX1 protein expression was greatly reduced in arteries from NCX1(SM-/-) mice generated with Cre recombinase. Mean blood pressure (BP) was 6-10 mmHg lower in NCX1(SM-/-) mice than in wild-type (WT) controls. Vasoconstriction was studied in isolated, pressurized mesenteric small arteries from WT and NCX1(SM-/-) mice and in heterozygotes with a global null mutation (NCX1(Fx/-)). Reduced NCX1 activity was manifested by a marked attenuation of responses to low extracellular Na(+) concentration, nanomolar ouabain, and SEA0400. Myogenic tone (MT, 70 mmHg) was reduced by approximately 15% in NCX1(SM-/-) arteries and, to a similar extent, by SEA0400 in WT arteries. MT was normal in arteries from NCX1(Fx/-) mice, which had normal BP. Vasoconstrictions to phenylephrine and elevated extracellular K(+) concentration were significantly reduced in NCX1(SM-/-) arteries. Because a high extracellular K(+) concentration-induced vasoconstriction involves the activation of L-type voltage-gated Ca(2+) channels (LVGCs), we measured LVGC-mediated currents and Ca(2+) sparklets in isolated mesenteric artery myocytes. Both the currents and the sparklets were significantly reduced in NCX1(SM-/-) (vs. WT or NCX1(Fx/-)) myocytes, but the voltage-dependent inactivation of LVGCs was not augmented. An acute application of SEA0400 in WT myocytes had no effect on LVGC current. The LVGC agonist, Bay K 8644, eliminated the differences in LVGC currents and Ca(2+) sparklets between NCX1(SM-/-) and control myocytes, suggesting that LVGC expression was normal in NCX1(SM-/-) myocytes. Bay K 8644 did not, however, eliminate the difference in myogenic constriction between WT and NCX1(SM-/-) arteries. We conclude that, under physiological conditions, NCX1 mediated Ca(2+) entry contributes significantly to the maintenance of MT. In NCX1(SM-/-) mouse artery myocytes, the reduced Ca(2+) entry via NCX1 may lower cytosolic Ca(2+) concentration and thereby reduce MT and BP. The reduced LVGC activity may be the consequence of a low cytosolic Ca(2+) concentration. PMID- 20173046 TI - Structural inhomogeneity and fiber orientation in the inner arterial media. AB - The microstructural orientation of vascular wall constituents is of interest to scientists and clinicians because alterations in their native states are associated with various cardiovascular diseases. In the arterial media, the orientation of these constituents is often described as circumferential. However, it has been noted that, just below the endothelial surface, the vascular wall constituents are oriented axially. To further study this reported change in orientation, and to resolve previous observations (which were made under conditions of no load), we used nonlinear optical microscopy to examine the orientation of collagen and elastin fibers in the inner medial region of bovine common carotid arteries. Images were obtained from this part of the arterial wall under varying degrees of mechanical strain: 0%, 10% axial, 10% circumferential, and 10% biaxial. We observed that close to the endothelium these components are aligned in the axial direction but abruptly change to a circumferential alignment at a depth of approximately 20 mum from the endothelial surface. The application of mechanical strain resulted in a significantly greater degree of fiber alignment, both collagen and elastin, in the strain direction, regardless of their initial unloaded orientation. Furthermore, variations in strain conditions resulted in an increase or a decrease in the overall degree of fiber alignment in the subendothelial layer depending on the direction of the applied strain. This high-resolution investigation adds more detail to existing descriptions of complex structure-function relationships in vascular tissue, which is essential for a better understanding of the pathophysiological processes resulting from injury, disease progression, and interventional therapies. PMID- 20173045 TI - Targeted ablation of cardiac sympathetic neurons reduces the susceptibility to ischemia-induced sustained ventricular tachycardia in conscious rats. AB - The Cardiac Arrhythmia Suppression Trial demonstrated that antiarrhythmic drugs not only fail to prevent sudden cardiac death, but actually increase overall mortality. These findings have been confirmed in additional trials. The "proarrhythmic" effects of most currently available antiarrhythmic drugs makes it essential that we investigate novel strategies for the prevention of sudden cardiac death. Targeted ablation of cardiac sympathetic neurons may become a therapeutic option by reducing sympathetic activity. Thus cholera toxin B subunit (CTB) conjugated to saporin (a ribosomal inactivating protein that binds to and inactivates ribosomes; CTB-SAP) was injected into both stellate ganglia to test the hypothesis that targeted ablation of cardiac sympathetic neurons reduces the susceptibility to ischemia-induced, sustained ventricular tachycardia in conscious rats. Rats were randomly divided into three groups: 1) control (no injection); 2) bilateral stellate ganglia injection of CTB; and 3) bilateral stellate ganglia injection of CTB-SAP. CTB-SAP rats had a reduced susceptibility to ischemia-induced, sustained ventricular tachycardia. Associated with the reduced susceptibility to ventricular arrhythmias were a reduced number of stained neurons in the stellate ganglia and spinal cord (segments T(1)-T(4)), as well as a reduced left ventricular norepinephrine content and sympathetic innervation density. Thus CTB-SAP retrogradely transported from the stellate ganglia is effective at ablating cardiac sympathetic neurons and reducing the susceptibility to ventricular arrhythmias. PMID- 20173048 TI - A real-time device for converting Doppler ultrasound audio signals into fluid flow velocity. AB - A Doppler signal converter has been developed to facilitate cardiovascular and exercise physiology research. This device directly converts audio signals from a clinical Doppler ultrasound imaging system into a real-time analog signal that accurately represents blood flow velocity and is easily recorded by any standard data acquisition system. This real-time flow velocity signal, when simultaneously recorded with other physiological signals of interest, permits the observation of transient flow response to experimental interventions in a manner not possible when using standard Doppler imaging devices. This converted flow velocity signal also permits a more robust and less subjective analysis of data in a fraction of the time required by previous analytic methods. This signal converter provides this capability inexpensively and requires no modification of either the imaging or data acquisition system. PMID- 20173047 TI - Mice deficient in Mkp-1 develop more severe pulmonary hypertension and greater lung protein levels of arginase in response to chronic hypoxia. AB - The mitogen-activated protein (MAP) kinases are involved in cellular responses to many stimuli, including hypoxia. MAP kinase signaling is regulated by a family of phosphatases that include MAP kinase phosphatase-1 (MKP-1). We hypothesized that mice lacking the Mkp-1 gene would have exaggerated chronic hypoxia-induced pulmonary hypertension. Wild-type (WT) and Mkp-1(-/-) mice were exposed to either 4 wk of normoxia or hypobaric hypoxia. Following chronic hypoxia, both genotypes demonstrated elevated right ventricular pressures, right ventricular hypertrophy as demonstrated by the ratio of the right ventricle to the left ventricle plus septum weights [RV(LV + S)], and greater vascular remodeling. However, the right ventricular systolic pressures, the RV/(LV + S), and the medial wall thickness of 100- to 300-microm vessels was significantly greater in the Mkp-1(-/-) mice than in the WT mice following 4 wk of hypobaric hypoxia. Chronic hypoxic exposure caused no detectable change in eNOS protein levels in the lungs in either genotype; however, Mkp-1(-/-) mice had lower levels of eNOS protein and lower lung NO production than did WT mice. No iNOS protein was detected in the lungs by Western blotting in any condition in either genotype. Both arginase I and arginase II protein levels were greater in the lungs of hypoxic Mkp-1(-/-) mice than those in hypoxic WT mice. Lung levels of proliferating cell nuclear antigen were greater in hypoxic Mkp-1(-/-) than in hypoxic WT mice. These data are consistent with the concept that MKP-1 acts to restrain hypoxia-induced arginase expression and thereby reduces vascular remodeling and the severity of pulmonary hypertension. PMID- 20173050 TI - Expanded clinical presentation of community-acquired methicillin-resistant Staphylococcus aureus pneumonia. AB - BACKGROUND: Community-acquired methicillin-resistant Staphylococcus aureus (CA MRSA) has been documented to cause community-acquired pneumonias (CAP), notable for necrotizing features. The frequency of occurrence, risk factors, and optimal treatment of CA-MRSA CAP are unclear. METHODS: This was a retrospective analysis of patients admitted to Northwestern Memorial Hospital from January 2005 to April 2007 with initial clinical presentation of pneumonia and respiratory or blood culture positive for CA-MRSA. Definition of CA-MRSA was based on sensitivity to trimethoprim/sulfamethoxazole and clindamycin. RESULTS: Fifteen patients with CA MRSA CAP were identified during the 28-month period. Only one of the 14 patients tested had evidence of preceding influenza, and no seasonal pattern was seen. Seven patients were never admitted to the ICU. Eight of 14 with chest CT scans had evidence of lung necrosis. Nine of 15 had evidence of pleural effusions early in their hospital course, and five of nine required at least one pleural drainage procedure. Seven of 15 were immunocompromised (three HIV, one acute lymphocytic leukemia [ALL], one high-dose steroids, and two immunoglobulin deficiency) with an additional three patients with diabetes. Mortality was only 13% (two of 15); both deaths occurred in patients with severe immunocompromise (ALL post chemotherapy and AIDS). Fourteen of 15 patients were treated with antimicrobials that inhibit exotoxin production (clindamycin or linezolid). CONCLUSIONS: CA-MRSA pneumonia is not necessarily a post-influenza infection. Despite necrotizing features in many, the mortality of CA-MRSA pneumonia in our series is lower than previously reported, and patients do not routinely require ICU care. Treatment with antibiotics that inhibit exotoxin production and/or nontoxigenic strains may explain this improved outcome. PMID- 20173051 TI - Exhaled nitric oxide and exhaled breath condensate pH in severe refractory asthma. AB - BACKGROUND: Distinct inflammatory cellular phenotypes of severe refractory asthma (SRA) have been reported. Fractional exhaled nitric oxide (FeNO) primarily is related to eosinophilic inflammation. Exhaled breath condensate (EBC) pH has been suggested as a noninvasive tool in the assessment of patients with asthma. We sought to determine whether FeNO and EBC pH could identify the presence and type of the underlying cellular inflammation in patients with SRA. METHODS: Twenty nine patients with SRA, 27 patients with moderate asthma, and 17 healthy subjects underwent FeNO measurement, EBC collection for pH measurement, and sputum induction for cell count identification. RESULTS: FeNO was significantly higher and pH significantly lower in patients with SRA than in the other groups. In SRA, FeNO levels of > 19 parts per billion were associated with a sensitivity of 0.78 and a specificity of 0.73 for sputum eosinophilia, whereas FeNO levels of < 19 parts per billion were associated with a sensitivity of 0.63 and a specificity of 0.9 for sputum neutrophilia irrespective of the presence of eosinophils. The pH failed to predict the cellular profile in SRA, but a cutoff value of < 7.37 could predict sputum eosinophilia in moderate asthma. CONCLUSIONS: In patients with SRA, different FeNO threshold values can identify those with predominant eosinophilia as well as those with neutrophilia. FeNO levels were reduced in patients with predominant neutrophilia regardless of the concomitant presence of eosinophilia. Although pH could not identify the cellular profile in SRA, it seemed to be a better index for predicting eosinophilia in moderate asthma. PMID- 20173052 TI - Outcomes of home-based diagnosis and treatment of obstructive sleep apnea. AB - BACKGROUND: Home diagnosis and therapy for obstructive sleep apnea (OSA) may improve access to testing and continuous positive airway pressure (CPAP) treatment. We compared subjective sleepiness, sleep quality, quality of life, BP, and CPAP adherence after 4 weeks of CPAP therapy in subjects in whom OSA was diagnosed and treated at home and in those evaluated in the sleep laboratory. METHODS: A randomized trial was performed consisting of home-based level 3 testing followed by 1 week of auto-CPAP and fixed-pressure CPAP based on the 95% pressure derived from the auto-CPAP device, and in-laboratory polysomnography (PSG) (using mostly split-night protocol) with CPAP titration; 102 subjects were randomized (age, 47.4 +/- 11.4 years; 63 men; BMI, 32.3 +/- 6.3 kg/m(2); Epworth Sleepiness Scale [ESS]: 12.5 +/- 4.3). The outcome measures were daytime sleepiness (ESS), sleep quality (Pittsburgh Sleep Quality Index [PSQI]), quality of life (Calgary Sleep Apnea Quality of Life Index [SAQLI], 36-Item Short-Form Health Survey [SF-36], BP, and CPAP adherence after 4 weeks. RESULTS: After 4 weeks of CPAP therapy, there were no significant differences in ESS (PSG 6.4 +/- 3.8 vs home monitoring [HM] 6.5 +/- 3.8, P = .71), PSQI (PSG 5.4 +/- 3.1 vs HM 6.2 +/- 3.4, P = .30), SAQLI (PSG 4.5 +/- 1.1 vs HM 4.6 +/- 1.1, P = .85), SF-36 vitality (PSG 62.2 +/- 23.3 vs HM 64.1 +/- 18.4, P = .79), SF-36 HM (PSG 84.0 +/- 10.4 vs HM 81.3 +/- 14.9, P = .39), and BP (PSG 129/84 +/- 11/0 vs HM 125/81 +/- 13/9, P = .121). There was no difference in CPAP adherence (PSG 5.6 +/- 1.7 h/night vs HM 5.4 +/- 1.0 h/night, P = .49). CONCLUSIONS: Compared with the home based protocol, diagnosis and treatment of OSA in the sleep laboratory does not lead to superior 4-week outcomes in sleepiness scores, sleep quality, quality of life, BP, and CPAP adherence. TRIAL REGISTRATION: clinicaltrials.gov; Identifier: NCT00139022. PMID- 20173049 TI - NFATc4 is negatively regulated in miR-133a-mediated cardiomyocyte hypertrophic repression. AB - Activation of NFAT (nuclear factor of activated T cells)-mediated hypertrophic signaling is a major regulatory response to hypertrophic stimuli. A recent study unveiled potential regulatory roles for microRNA-133a (miR-133a) in cardiac hypertrophy. To date, however, no connection has been made between miR-133a and NFAT signaling. In this study, we determined that NFATc4, a hypertrophy associated mediator, is negatively regulated by miR-133a. Two conserved base pairing sites between the NFATc4 3'-untranslated region (UTR) and miR-133a were verified. Mutation of these sites in the NFATc4 3'-UTR completely blocked the negative effect of miR-133a on NFATc4, suggesting that NFATc4 is a direct target for miR-133a regulation. Using a gain-of-function approach, we demonstrate that miR-133 significantly reduces the endogenous level of, as well as the hypertrophic stimulus-mediated increase in, NFATc4 gene expression. This latter effect of miR-133a on NFATc4 gene expression was coincided with an attenuated cardiomyocyte hypertrophy induced by an alpha-adrenergic receptor agonist. Conversely, cells treated with miR-133a inhibitor resulted in an increase in NFATc4 expression level. Application of miR-133a had no apparent effect on NFATc4 nuclear localization. We conclude that the negative regulation of NFATc4 expression contributes to miR-133a-mediated hypertrophic repression. PMID- 20173053 TI - Factors associated with nonadherence to early goal-directed therapy in the ED. AB - BACKGROUND: Protocol-driven early goal-directed therapy (EGDT) has been shown to reduce mortality in patients with severe sepsis and septic shock in the ED. EGDT appears to be underused, even in centers with formalized protocols. The aim of our study was to identify factors associated with not initiating EGDT in the ED. METHODS: This was a cohort study of 340 EGDT-eligible patients presenting to a single center ED from 2005 to 2007. EGDT eligibility was defined as a serum lactate >or= 4 mmol/L or systolic BP< 90 mm Hg after volume resuscitation. EGDT initiation was defined as the measurement of central venous oxygen saturation via central venous catheter. Multivariable logistic regression was used to adjust for potential confounding. RESULTS: EGDT was not initiated in 142 eligible patients (42%). EGDT was not completed in 43% of patients in whom EGDT was initiated. Compliance with the protocol varied significantly at the physician level, ranging from 0% to 100%. Four risk factors were found to be associated independently with decreased odds of initiating EGDT: female sex of the patient (P = .001), female sex of the clinician (P = .041), serum lactate (rather than hemodynamic) criterion for EGDT (P = .018), and nonconsultation to the Severe Sepsis Service (P < .001). CONCLUSIONS: Despite a formalized protocol, we found that EGDT was underused. We identified potential barriers to the effective implementation of EGDT at the patient, clinician, and organizational level. The use of a consultation service to facilitate the implementation of EGDT may be an effective strategy to improve protocol adherence. PMID- 20173055 TI - Longitudinal growth and lung function in pediatric non-cystic fibrosis bronchiectasis: what influences lung function stability? AB - BACKGROUND: Longitudinal FEV(1) data in children with non-cystic fibrosis (non CF) bronchiectasis (BE) are contradictory, and there are no multifactor data on the evolution of lung function and growth in this group. We longitudinally reviewed lung function and growth in children with non-CF BE and explored biologically plausible factors associated with changes in these parameters over time. METHODS: Fifty-two children with > or = 3 years of lung function data were retrospectively reviewed. Changes in annual anthropometry and spirometry at year 3 and year 5 from baseline were analyzed. The impact of sex, age, cause, baseline FEV(1), exacerbation frequency, radiologic extent, socioeconomic status, environmental tobacco smoke exposure, and period of diagnosis was evaluated. RESULTS: Over 3 years, the group mean forced expiratory flow midexpiratory phase percent predicted and BMI z-score improved by 3.01 (P = .04; 95% CI, 0.14-5.86) and 0.089 (P = .01; 95% CI, 0.02-0.15) per annum, respectively. FEV(1)% predicted, FVC% predicted, and height z-score all showed nonsignificant improvement. Over 5 years, there was improvement in FVC% predicted (slope 1.74; P = .001) annually, but only minor improvement in other parameters. Children with immunodeficiency and those with low baseline FEV(1) had significantly lower BMI at diagnosis. Frequency of hospitalized exacerbation and low baseline FEV(1) were the only significant predictors of change in FEV(1) over 3 years. Decline in FEV(1)% predicted was large (but nonsignificant) for each additional year in age of diagnosis. CONCLUSIONS: Spirometric and anthropometric parameters in children with non-CF BE remain stable over a 3- to 5-year follow-up period once appropriate therapy is instituted. Severe exacerbations result in accelerated lung function decline. Increased medical cognizance of children with chronic moist cough is needed for early diagnosis, better management, and improving overall outcome in BE. PMID- 20173054 TI - Marital status and the epidemiology and outcomes of sepsis. AB - BACKGROUND: Sepsis is a major public health problem. Social factors may affect health behaviors, economic resources, and immune response, leading to hospitalization for infection. This study examines the association between marital status and sepsis incidence and outcomes in a population-based cohort. METHODS: We analyzed 1,113,581 hospitalizations in New Jersey in 2006. We estimated risk-adjusted incidence rate ratios (IRRs) for sepsis among divorced, widowed, legally separated, single, and married subjects using population data from the American Community Survey. We used multivariable logistic regression to estimate marital status-specific hospital mortality. RESULTS: We identified 37,524 hospitalizations for sepsis, of which 40% were among married (14,924), 7% were among divorced (2,548), 26% were among widowed (9,934), 2% (763) were among legally separated, and 26% (9355) were among single subjects. The incidence of hospitalization for sepsis was 5.8 per 1,000 population. The age, sex, and race adjusted IRR for hospitalization with sepsis was greatest for single (IRR = 3.47; 95% CI, 3.1, 3.9), widowed (IRR = 1.38; 95% CI, 1.2, 1.6), and legally separated (IRR = 1.46; 95% CI, 1.2, 1.8) subjects compared with married (referent). We observed that single men and women and divorced men had greater odds of in hospital mortality compared with married men; widowed and legally separated men and all ever-married women had no excess mortality during hospitalization for sepsis. CONCLUSIONS: Hospitalization for sepsis is more common among single, widowed, and legally separated individuals, independent of other demographic factors. Among patients hospitalized for sepsis, single and divorced men and single women experience greater hospital mortality, highlighting the need to characterize the potentially modifiable mechanisms linking marital status to its greater burden of critical illness. PMID- 20173056 TI - C-reactive protein levels and post-ICU mortality in nonsurgical intensive care patients. AB - BACKGROUND: There are no data on the association between acute inflammation during critical illness and long-term mortality in ICU patients. METHODS: Nonsurgical patients with an ICU length of stay > 24 h surviving until ICU discharge were included into this prospective, observational, follow-up study. Demographics, chronic diseases, admission diagnosis, the Simplified Acute Physiology Score (SAPS) II, length of ICU stay, maximum C-reactive protein (CRP) levels during the ICU stay (CRPmax), and CRP levels at ICU discharge (CRPdis) were documented. After a follow-up time of 1.88 +/- 1.16 years (range, 0.5-4 years), the survival status was determined. RESULTS: Seven hundred sixty-five patients were enrolled into the study protocol. One hundred fifty-eight patients (20.7%) died within 0.62 +/- 0.88 years after ICU discharge. Cumulative survival rates differed between patients grouped into the CRPmax and CRPdis quartiles. Patients in the first and second CRPmax quartiles had better cumulative survival rates than those in higher CRPmax quartiles (all P < .001). Patients in the first CRPdis quartile had better cumulative survival rates than those in higher CRPdis quartiles (all P < .001). Using adjusted Cox proportional hazards models, both CRPmax and CRPdis were independently associated with post-ICU mortality (both P < .001). Furthermore, the number of chronic diseases (P < .001), age (P < .001), and the SAPS II (P = .03) were associated with post-ICU mortality in both Cox models. CONCLUSIONS: CRP levels during critical illness seem independently associated with post-ICU survival in nonsurgical ICU patients. Future research focusing on the association between acute systemic inflammation and post-ICU outcome is warranted in order to improve long-term survival of critically ill patients. PMID- 20173057 TI - Prevalence and risk factors of habitual snoring in primary school children. AB - OBJECTIVE: Our study aimed to determine the prevalence of habitual snoring (HS) in primary school children and to evaluate the diurnal symptoms and conditions that may be associated with it. METHODS: A validated questionnaire completed by parents was used to assess the sleep and daytime behaviors of Chinese children aged 5 to 14 years. Thirteen primary schools in two representative districts were randomly selected. RESULTS: A total of 6,349 out of 9,172 questionnaires (response rate 69.2%) with complete answers were returned. The prevalence rate of HS was 7.2%. Male sex (odds ratio [OR] [95% CI]: 2.5 [1.7-3.6]), BMI z score (OR [95% CI]: 1.4 [1.1-1.6]), maternal HS (OR [95% CI]: 3.4 [2.0-5.7]), paternal HS (OR [95% CI]: 3.8 [2.7-5.5]), allergic rhinitis (OR [95% CI]: 2.9 [2.0-4.2]), asthma (OR [95% CI]: 2.4 [1.2-5.2]), nasosinusitis (OR [95% CI]: 4.0 [1.5-10.6]), and tonsillitis (OR [95% CI]: 3.1 [1.9-5.1]) in the past 12 months were identified to be independent risk factors associated with HS. HS was also associated with daytime, nocturnal, parasomniac, and sleep-related breathing symptoms. HS was demonstrated to be an independent risk factor for parent reported poor temper (OR [95% CI]: 1.9 [1.4-2.5]), hyperactivity (OR [95%CI]: 1.7 [1.2-2.5]), and poor school performance (OR [95% CI]: 1.7 [1.2-2.5]). CONCLUSIONS: HS was a significant and prevalent problem in primary school children. Male sex, obesity, parental HS, atopic symptoms, and history of upper respiratory infections were significant risk factors. HS was also associated with sleep-disordered breathing symptoms and adverse neurobehavioral outcomes. PMID- 20173058 TI - Autonomous growth of isolated single Listeria monocytogenes and Salmonella enterica serovar typhimurium cells in the absence of growth factors and intercellular contact. AB - The aim of this study was to observe growth of isolated single bacterial cells in the absence of growth factors and intercellular contact. In order to exclude stochastic uncertainties induced by dilution series, a new micromanipulation method was developed to ensure explicit results under visual control. This was performed with particular care for production of single prokaryotic cells and subsequent investigation of their autonomous growth. Over 450 single isolated Listeria monocytogenes and Salmonella enterica subsp. enterica serovar Typhimurium cells in lag, log, and stationary growth phases were investigated by this method, which included thoroughly washing the cells. The proportion of living cells within the initial cultures was compared to the proportion of positive samples after enrichment of the separated single cells. This resulted in P values of >/=0.05 using the chi-square test for statistical analysis, indicating no significant difference, and clearly demonstrates reproduction of isolated single bacterial cells without the need for growth factors or intercellular contact. Ease of handling of the apparatus and good performance of the cleaning procedures were achieved, as was validation of the method, demonstrating its suitability for routine laboratory use. PMID- 20173059 TI - Role of GlnR in acid-mediated repression of genes encoding proteins involved in glutamine and glutamate metabolism in Streptococcus mutans. AB - The acid tolerance response (ATR) is one of the major virulence traits of Streptococcus mutans. In this study, the role of GlnR in acid-mediated gene repression that affects the adaptive ATR in S. mutans was investigated. Using a whole-genome microarray and in silico analyses, we demonstrated that GlnR and the GlnR box (ATGTNAN(7)TNACAT) were involved in the transcriptional repression of clusters of genes encoding proteins involved in glutamine and glutamate metabolism under acidic challenge. Reverse transcription-PCR (RT-PCR) analysis revealed that the coordinated regulation of the GlnR regulon occurred 5 min after acid treatment and that prolonged acid exposure (30 min) resulted in further reduction in expression. A lower level but consistent reduction in response to acidic pH was also observed in chemostat-grown cells, confirming the negative regulation of GlnR. The repression by GlnR through the GlnR box in response to acidic pH was further confirmed in the citBZC operon, containing genes encoding the first three enzymes in the glutamine/glutamate biosynthesis pathway. The survival rate of the GlnR-deficient mutant at pH 2.8 was more than 10-fold lower than that in the wild-type strain 45 min after acid treatment, suggesting that the GlnR regulon participates in S. mutans ATR. It is hypothesized that downregulation of the synthesis of the amino acid precursors in response to acid challenge would promote citrate metabolism to pyruvate, with the consumption of H(+) and potential ATP synthesis. Such regulation will ensure an optimal acid adaption in S. mutans. PMID- 20173060 TI - Increased crystalline cellulose activity via combinations of amino acid changes in the family 9 catalytic domain and family 3c cellulose binding module of Thermobifida fusca Cel9A. AB - Amino acid modifications of the Thermobifida fusca Cel9A-68 catalytic domain or carbohydrate binding module 3c (CBM3c) were combined to create enzymes with changed amino acids in both domains. Bacterial crystalline cellulose (BC) and swollen cellulose (SWC) assays of the expressed and purified enzymes showed that three combinations resulted in 150% and 200% increased activity, respectively, and also increased synergistic activity with other cellulases. Several other combinations resulted in drastically lowered activity, giving insight into the need for a balance between the binding in the catalytic cleft on either side of the cleavage site, as well as coordination between binding affinity for the catalytic domain and CBM3c. The same combinations of amino acid variants in the whole enzyme, Cel9A-90, did not increase BC or SWC activity but did have higher filter paper (FP) activity at 12% digestion. PMID- 20173061 TI - Effects of polyphosphate additives on Campylobacter survival in processed chicken exudates. AB - Campylobacter spp. are responsible for a large number of the bacterial food poisoning cases worldwide. Despite being sensitive to oxygen and nutritionally fastidious, Campylobacter spp. are able to survive in food processing environments and reach consumers in sufficient numbers to cause disease. To investigate Campylobacter persistence on processed chicken, exudates from chickens produced for consumer sale were collected and sterilized. Two types of exudates from chicken products were collected: enhanced, where a marinade was added to the chickens during processing, and nonenhanced, where no additives were added during processing. Exudates from enhanced chicken products examined in this study contained a mixture of polyphosphates. Exudate samples were inoculated with Campylobacter jejuni or Campylobacter coli strains and incubated under a range of environmental conditions, and viable bacteria present in the resultant cultures were enumerated. When incubated at 42 degrees C in a microaerobic environment, exudates from enhanced chicken products resulted in increased survival of C. jejuni and C. coli compared with that in nonenhanced exudates in the range of <1 to >4 log CFU/ml. Under more relevant food storage conditions (4 degrees C and normal atmosphere), the exudates from enhanced chicken products also demonstrated improved Campylobacter survival compared with that in nonenhanced exudates. Polyphosphates present in the enhanced exudates were determined to be largely responsible for the improved survival observed when the two types of exudates were compared. Therefore, polyphosphates used to enhance chicken quality aid in sustaining the numbers of Campylobacter bacteria, increasing the opportunity for disease via cross-contamination or improperly cooked poultry. PMID- 20173062 TI - Surface display of metal fixation motifs of bacterial P1-type ATPases specifically promotes biosorption of Pb(2+) by Saccharomyces cerevisiae. AB - Biosorption of metal ions may take place by different passive metal-sequestering processes such as ion exchange, complexation, physical entrapment, and inorganic microprecipitation or by a combination of these. To improve the biosorption capacity of the potential yeast biosorbent, short metal-binding NP peptides (harboring the CXXEE metal fixation motif of the bacterial Pb(2+)-transporting P1 type ATPases) were efficiently displayed and covalently anchored to the cell wall of Saccharomyces cerevisiae. These were fusions to the carboxyl-terminal part of the sexual adhesion glycoprotein alpha-agglutinin (AGalpha1Cp). Compared to yeast cells displaying the anchoring domain only, those having a surface display of NP peptides multiplied their Pb(2+) biosorption capacity from solutions containing a 75 to 300 microM concentration of the metal ion up to 5-fold. The S-type Pb(2+) biosorption isotherms, plus the presence of electron-dense deposits (with an average size of 80 by 240 nm, observed by transmission electron microscopy) strongly suggested that the improved biosorption potential of NP-displaying cells is due to the onset of microprecipitation of Pb species on the modified cell wall. The power of an improved capacity for Pb biosorption was also retained by the isolated cell walls containing NP peptides. Their Pb(2+) biosorption property was insensitive to the presence of a 3-fold molar excess of either Cd(2+) or Zn(2+). These results suggest that the biosorption mechanism can be specifically upgraded with microprecipitation by the engineering of the biosorbent with an eligible metal-binding peptide. PMID- 20173063 TI - Identification of multiresistant Salmonella isolates capable of subsisting on antibiotics. AB - This study assessed the ability of Salmonella (572 isolates) to subsist on 12 different antibiotics. The majority (11/12) of the antibiotics enabled subsistence for at least 1 of 140 isolates. Furthermore, 40 isolates were able to subsist on more than one antibiotic. Antibiotic resistance and antibiotic subsistence do not appear to be equivalent. PMID- 20173064 TI - Bacterial and protozoal communities and fatty acid profile in the rumen of sheep fed a diet containing added tannins. AB - This study evaluated the effects of tannins on ruminal biohydrogenation (BH) due to shifts in the ruminal microbial environment in sheep. Thirteen lambs (45 days of age) were assigned to two dietary treatments: seven lambs were fed a barley based concentrate (control group) while the other six lambs received the same concentrate with supplemental quebracho tannins (9.57% of dry matter). At 122 days of age, the lambs were slaughtered, and the ruminal contents were subjected to fatty acid analysis and sampled to quantify populations of Butyrivibrio fibrisolvens, which converts C(18:2) c9-c12 (linoleic acid [LA]) to C(18:2) c9 t11 (rumenic acid [RA]) and then RA to C(18:1) t11 (vaccenic acid [VA]); we also sampled for Butyrivibrio proteoclasticus, which converts VA to C(18:0) (stearic acid [SA]). Tannins increased (P < 0.005) VA in the rumen compared to the tannin free diet. The concentration of SA was not affected by tannins. The SA/VA ratio was lower (P < 0.005) for the tannin-fed lambs than for the controls, suggesting that the last step of the BH process was inhibited by tannins. The B. proteoclasticus population was lower (-30.6%; P < 0.1), and B. fibrisolvens and protozoan populations were higher (+107% and +56.1%, respectively; P < 0.05) in the rumen of lambs fed the tannin-supplemented diet than in controls. These results suggest that quebracho tannins altered BH by changing ruminal microbial populations. PMID- 20173065 TI - Rickettsia symbionts cause parthenogenetic reproduction in the parasitoid wasp Pnigalio soemius (Hymenoptera: Eulophidae). AB - Bacteria in the genus Rickettsia are intracellular symbionts of disparate groups of organisms. Some Rickettsia strains infect vertebrate animals and plants, where they cause diseases, but most strains are vertically inherited symbionts of invertebrates. In insects Rickettsia symbionts are known to have diverse effects on hosts ranging from influencing host fitness to manipulating reproduction. Here we provide evidence that a Rickettsia symbiont causes thelytokous parthenogenesis (in which mothers produce only daughters from unfertilized eggs) in a parasitoid wasp, Pnigalio soemius (Hymenoptera: Eulophidae). Feeding antibiotics to thelytokous female wasps resulted in production of progeny that were almost all males. Cloning and sequencing of a fragment of the 16S rRNA gene amplified with universal primers, diagnostic PCR screening of symbiont lineages associated with manipulation of reproduction, and fluorescence in situ hybridization (FISH) revealed that Rickettsia is always associated with thelytokous P. soemius and that no other bacteria that manipulate reproduction are present. Molecular analyses and FISH showed that Rickettsia is distributed in the reproductive tissues and is transovarially transmitted from mothers to offspring. Comparison of antibiotic-treated females and untreated females showed that infection had no cost. Phylogenetic analyses of 16S rRNA and gltA gene sequences placed the symbiont of P. soemius in the bellii group and indicated that there have been two separate origins of the parthenogenesis-inducing phenotype in the genus Rickettsia. A possible route for evolution of induction of parthenogenesis in the two distantly related Rickettsia lineages is discussed. PMID- 20173066 TI - Promotion of efficient Saccharification of crystalline cellulose by Aspergillus fumigatus Swo1. AB - Swollenin is a protein from Trichoderma reesei that has a unique activity for disrupting cellulosic materials, and it has sequence similarity to expansins, plant cell wall proteins that have a loosening effect that leads to cell wall enlargement. In this study we cloned a gene encoding a swollenin-like protein, Swo1, from the filamentous fungus Aspergillus fumigatus, and designated the gene Afswo1. AfSwo1 has a bimodular structure composed of a carbohydrate-binding module family 1 (CBM1) domain and a plant expansin-like domain. AfSwo1 was produced using Aspergillus oryzae for heterologous expression and was easily isolated by cellulose-affinity chromatography. AfSwo1 exhibited weak endoglucanase activity toward carboxymethyl cellulose (CMC) and bound not only to crystalline cellulose Avicel but also to chitin, while showing no detectable affinity to xylan. Treatment by AfSwo1 caused disruption of Avicel into smaller particles without any detectable reducing sugar. Furthermore, simultaneous incubation of AfSwo1 with a cellulase mixture facilitated saccharification of Avicel. Our results provide a novel approach for efficient bioconversion of crystalline cellulose into glucose by use of the cellulose-disrupting protein AfSwo1. PMID- 20173067 TI - Characterization of a novel LysM domain from Lactobacillus fermentum bacteriophage endolysin and its use as an anchor to display heterologous proteins on the surfaces of lactic acid bacteria. AB - The endolysin Lyb5, from Lactobacillus fermentum temperate bacteriophage phiPYB5, showed a broad lytic spectrum against Gram-positive as well as Gram-negative bacteria. Sequence analysis revealed that the C terminus of the endolysin Lyb5 (Ly5C) contained three putative lysin motif (LysM) repeat regions, implying that Ly5C was involved in bacterial cell wall binding. To investigate the potential of Ly5C for surface display, green fluorescent protein (GFP) was fused to Ly5C at its N or C terminus and the resulting fusion proteins were expressed in Escherichia coli. After being mixed with various cells in vitro, GFP was successfully displayed on the surfaces of Lactococcus lactis, Lactobacillus casei, Lb. brevis, Lb. plantarum, Lb. fermentum, Lb. delbrueckii, Lb. helveticus, and Streptococcus thermophilus cells. Increases in the fluorescence intensities of chemically pretreated L. lactis and Lb. casei cells compared to those of nonpretreated cells suggested that the peptidoglycan was the binding ligand for Ly5C. Moreover, the pH and concentration of sodium chloride were optimized to enhance the binding capacity of GFP-Ly5C, and high-intensity fluorescence of cells was observed under optimal conditions. All results suggested that Ly5C was a novel anchor for constructing a surface display system for lactic acid bacteria (LAB). To demonstrate the applicability of the Ly5C-mediated surface display system, beta-galactosidase (beta-Gal) from Paenibacillus sp. strain K1, replacing GFP, was functionally displayed on the surfaces of LAB cells via Ly5C. The success in surface display of GFP and beta-Gal opened up the feasibility of employing the cell wall anchor of bacteriophage endolysin for surface display in LAB. PMID- 20173068 TI - Cre-lox-based method for generation of large deletions within the genomic magnetosome island of Magnetospirillum gryphiswaldense. AB - Magnetosome biomineralization and magnetotaxis in magnetotactic bacteria are controlled by numerous, mostly unknown gene functions that are predominantly encoded by several operons located within the genomic magnetosome island (MAI). Genetic analysis of magnetotactic bacteria has remained difficult and requires the development of novel tools. We established a Cre-lox-based deletion method which allows the excision of large genomic fragments in Magnetospirillum gryphiswaldense. Two conjugative suicide plasmids harboring lox sites that flanked the target region were subsequently inserted into the chromosome by homologous recombination, requiring only one single-crossover event, respectively, and resulting in a double cointegrate. Excision of the targeted chromosomal segment that included the inserted plasmids and their resistance markers was induced by trans expression of Cre recombinase, which leaves behind a scar of only a single loxP site. The Cre helper plasmid was then cured from the deletant strain by relief of antibiotic selection. We have used this method for the deletion of 16.3-kb, 61-kb, and 67.3-kb fragments from the genomic MAI, either in a single round or in subsequent rounds of deletion, covering a region of approximately 87 kb that comprises the mamAB, mms6, and mamGFDC operons. As expected, all mutants were Mag(-) and some were Mot(-); otherwise, they showed normal growth patterns, which indicates that the deleted region is not essential for viability in the laboratory. The method will facilitate future functional analysis of magnetosome genes and also can be utilized for large-scale genome engineering in magnetotactic bacteria. PMID- 20173069 TI - Activation of the ustilagic acid biosynthesis gene cluster in Ustilago maydis by the C2H2 zinc finger transcription factor Rua1. AB - The phytopathogenic basidiomycetous fungus Ustilago maydis secretes, under conditions of nitrogen starvation, large amounts of the biosurfactant ustilagic acid (UA). This secreted cellobiose glycolipid is toxic for many microorganisms and confers biocontrol activity to U. maydis. Recently, a large gene cluster that is responsible for UA biosynthesis was identified. Here, we show that expression of all cluster genes depends on Rua1, a nuclear protein of the C(2)H(2) zinc finger family, whose gene is located within the gene cluster. While deletion of rua1 results in complete loss of UA production, overexpression of rua1 promotes increased UA synthesis even in the presence of a good nitrogen source. Bioinformatic analysis allowed us to identify a conserved sequence element that is present in the promoters of all structural genes involved in UA biosynthesis. Deletion analysis of several promoters within the cluster revealed that this DNA element serves as an upstream activating sequence (UAS) and mediates Rua1 dependent expression. We used the yeast one-hybrid system to demonstrate specific recognition of this DNA element by Rua1. Introduction of nucleotide exchanges into the consensus sequence interfered with Rua1-dependent activation, suggesting that this sequence element acts as a direct binding site for Rua1. PMID- 20173070 TI - Thiosulfate-dependent chemolithoautotrophic growth of Bradyrhizobium japonicum. AB - Thiosulfate-oxidizing sox gene homologues were found at four loci (I, II, III, and IV) on the genome of Bradyrhizobium japonicum USDA110, a symbiotic nitrogen fixing bacterium in soil. In fact, B. japonicum USDA110 can oxidize thiosulfate and grow under a chemolithotrophic condition. The deletion mutation of the soxY(1) gene at the sox locus I, homologous to the sulfur-oxidizing (Sox) system in Alphaproteobacteria, left B. japonicum unable to oxidize thiosulfate and grow under chemolithotrophic conditions, whereas the deletion mutation of the soxY(2) gene at sox locus II, homologous to the Sox system in green sulfur bacteria, produced phenotypes similar to those of wild-type USDA110. Thiosulfate-dependent O(2) respiration was observed only in USDA110 and the soxY(2) mutant and not in the soxY(1) mutant. In the cells, 1 mol of thiosulfate was stoichiometrically converted to approximately 2 mol of sulfate and consumed approximately 2 mol of O(2). B. japonicum USDA110 showed (14)CO(2) fixation under chemolithotrophic growth conditions. The CO(2) fixation of resting cells was significantly dependent on thiosulfate addition. These results show that USDA110 is able to grow chemolithoautotrophically using thiosulfate as an electron donor, oxygen as an electron acceptor, and carbon dioxide as a carbon source, which likely depends on sox locus I including the soxY(1) gene on USDA110 genome. Thiosulfate oxidation capability is frequently found in members of the Bradyrhizobiaceae, which phylogenetic analysis showed to be associated with the presence of sox locus I homologues, including the soxY(1) gene of B. japonicum USDA110. PMID- 20173071 TI - Impact of endochitinase-transformed white spruce on soil fungal biomass and ectendomycorrhizal symbiosis. AB - The impact of transgenic white spruce [Picea glauca (Moench) Voss] containing the endochitinase gene (ech42) on soil fungal biomass and on the ectendomycorrhizal fungi Wilcoxina spp. was tested using a greenhouse trial. The measured level of endochitinase in roots of transgenic white spruce was up to 10 times higher than that in roots of nontransformed white spruce. The level of endochitinase in root exudates of three of four ech42-transformed lines was significantly greater than that in controls. Analysis soil ergosterol showed that the amount of fungal biomass in soil samples from control white spruce was slightly larger than that in soil samples from ech42-transformed white spruce. Nevertheless, the difference was not statistically significant. The rates of mycorrhizal colonization of transformed lines and controls were similar. Sequencing the internal transcribed spacer rRNA region revealed that the root tips were colonized by the ectendomycorrhizal fungi Wilcoxina spp. and the dark septate endophyte Phialocephala fortinii. Colonization of root tips by Wilcoxina spp. was monitored by real-time PCR to quantify the fungus present during the development of ectendomycorrhizal symbiosis in ech42-transformed and control lines. The numbers of Wilcoxina molecules in the transformed lines and the controls were not significantly different (P > 0.05, as determined by analysis of covariance), indicating that in spite of higher levels of endochitinase expression, mycorrhization was not inhibited. Our results indicate that the higher levels of chitinolytic activity in root exudates and root tissues from ech42-transformed lines did not alter the soil fungal biomass or the development of ectendomycorrhizal symbiosis involving Wilcoxina spp. PMID- 20173072 TI - Use of ichip for high-throughput in situ cultivation of "uncultivable" microbial species. AB - One of the oldest unresolved microbiological phenomena is why only a small fraction of the diverse microbiological population grows on artificial media. The "uncultivable" microbial majority arguably represents our planet's largest unexplored pool of biological and chemical novelty. Previously we showed that species from this pool could be grown inside diffusion chambers incubated in situ, likely because diffusion provides microorganisms with their naturally occurring growth factors. Here we utilize this approach and develop a novel high throughput platform for parallel cultivation and isolation of previously uncultivated microbial species from a variety of environments. We have designed and tested an isolation chip (ichip) composed of several hundred miniature diffusion chambers, each inoculated with a single environmental cell. We show that microbial recovery in the ichip exceeds manyfold that afforded by standard cultivation, and the grown species are of significant phylogenetic novelty. The new method allows access to a large and diverse array of previously inaccessible microorganisms and is well suited for both fundamental and applied research. PMID- 20173074 TI - New efficient recombinant expression system to engineer Candida antarctica lipase B. AB - Here, we report the use of Yarrowia lipolytica as a versatile expression host for developing protein engineering approaches to modify the properties of Candida antarctica lipase B. A reliable screening protocol was defined and validated using a saturation mutagenesis library, yielding mutants displaying higher catalytic efficiencies than the wild-type enzyme. PMID- 20173073 TI - Immobilization of Cr(VI) and its reduction to Cr(III) phosphate by granular biofilms comprising a mixture of microbes. AB - We assessed the potential of mixed microbial consortia, in the form of granular biofilms, to reduce chromate and remove it from synthetic minimal medium. In batch experiments, acetate-fed granular biofilms incubated aerobically reduced 0.2 mM Cr(VI) from a minimal medium at 0.15 mM day(-1) g(-1), with reduction of 0.17 mM day(-1) g(-1) under anaerobic conditions. There was negligible removal of Cr(VI) (i) without granular biofilms, (ii) with lyophilized granular biofilms, and (iii) with granules in the absence of an electron donor. Analyses by X-ray absorption near edge spectroscopy (XANES) of the granular biofilms revealed the conversion of soluble Cr(VI) to Cr(III). Extended X-ray absorption fine-structure (EXAFS) analysis of the Cr-laden granular biofilms demonstrated similarity to Cr(III) phosphate, indicating that Cr(III) was immobilized with phosphate on the biomass subsequent to microbial reduction. The sustained reduction of Cr(VI) by granular biofilms was confirmed in fed-batch experiments. Our study demonstrates the promise of granular-biofilm-based systems in treating Cr(VI)-containing effluents and wastewater. PMID- 20173075 TI - AiiM, a novel class of N-acylhomoserine lactonase from the leaf-associated bacterium Microbacterium testaceum. AB - N-Acylhomoserine lactones (AHLs) are used as quorum-sensing signal molecules by many Gram-negative bacteria. We have reported that Microbacterium testaceum StLB037, which was isolated from the leaf surface of potato, has AHL-degrading activity. In this study, we cloned the aiiM gene from the genomic library of StLB037, which has AHL-degrading activity and shows high homology with the alpha/beta hydrolase fold family from Actinobacteria. Purified AiiM as a maltose binding fusion protein showed high degrading activity of AHLs with both short- and long-chain AHLs with or without substitution at carbon 3. High-performance liquid chromatography analysis revealed that AiiM works as an AHL lactonase that catalyzes AHL ring opening by hydrolyzing lactones. In addition, expression of AiiM in the plant pathogen Pectobacterium carotovorum subsp. carotovorum reduced pectinase activity markedly and attenuated soft rot symptoms on potato slices. In conclusion, this study indicated that AiiM might be effective in quenching quorum sensing of P. carotovorum subsp. carotovorum. PMID- 20173076 TI - A new stretch for muscle spindle research. PMID- 20173077 TI - Open channel block and beyond. PMID- 20173078 TI - Advances and hold-ups in the study of structure, function and regulation of Cys loop ligand-gated ion channels and receptors. PMID- 20173080 TI - Families of young pediatric cancer survivors: A cross-sectional survey examining physical activity behavior and health-related quality of life. AB - The present study examined physical activity levels within young families of pediatric cancer survivors and the relationship between physical activity and health-related quality of life (HRQL). Nineteen families were recruited, including 33 parents, 17 pediatric cancer survivors, and 10 siblings. Families completed a self-report survey on background information, physical activity levels, and PedsQL generic core scale for child HRQL. Results of this cross sectional study indicate that families were generally active, with mothers more frequently participating in overall physical activity (P < .001). Within families, parent-child physical activity levels were associated, but not survivor sibling physical activity. Survivors and siblings did not differ in their self reported physical activity levels or HRQL, and no association was observed between physical activity and HRQL. However, discrepancies between sibling self report and parent proxy-reported HRQL were notable. Overall, results from this exploratory pilot work will assist in further research into physical activity behaviors and HRQL in families of pediatric cancer survivors.The nurse should consider the varied experiences of family members, particularly those of siblings, through long-term follow-up. PMID- 20173079 TI - Persistent Nav1.6 current at axon initial segments tunes spike timing of cerebellar granule cells. AB - Cerebellar granule (CG) cells generate high-frequency action potentials that have been proposed to depend on the unique properties of their voltage-gated ion channels. To address the in vivo function of Nav1.6 channels in developing and mature CG cells, we combined the study of the developmental expression of Nav subunits with recording of acute cerebellar slices from young and adult granule specific Scn8a KO mice. Nav1.2 accumulated rapidly at early-formed axon initial segments (AISs). In contrast, Nav1.6 was absent at early postnatal stages but accumulated at AISs of CG cells from P21 to P40. By P40-P65, both Nav1.6 and Nav1.2 co-localized at CG cell AISs. By comparing Na(+) currents in mature CG cells (P66-P74) from wild-type and CG-specific Scn8a KO mice, we found that transient and resurgent Na(+) currents were not modified in the absence of Nav1.6 whereas persistent Na(+) current was strongly reduced. Action potentials in conditional Scn8a KO CG cells showed no alteration in threshold and overshoot, but had a faster repolarization phase and larger post-spike hyperpolarization. In addition, although Scn8a KO CG cells kept their ability to fire action potentials at very high frequency, they displayed increased interspike-interval variability and firing irregularity in response to sustained depolarization. We conclude that Nav1.6 channels at axon initial segments contribute to persistent Na(+) current and ensure a high degree of temporal precision in repetitive firing of CG cells. PMID- 20173081 TI - Adolescents' and parents' experiences of managing the psychosocial impact of appearance change during cancer treatment. AB - Using combined qualitative data from multiple case study interviews and an online survey, this study explored the impact of appearance change on 22 adolescents receiving cancer treatment aged 13 to 18 years and six of their parents. Data were analyzed using template analysis. Appearance changes were a major concern. Adolescents typically struggled to adapt to new experiences and concerns related to this highly sensitive issue. Many felt anxious and self-conscious and were reluctant to reveal appearance changes in public. These feelings were compounded by the negative reactions of others (e.g., staring, teasing, and inappropriate questioning), which sometimes lead to avoidance of social activity and threats of noncompliance. Parents of these children felt ill-prepared to manage appearance related anxieties. Adolescents wanted support to develop the practical and social skills necessary to maintain a "normal" appearance and manage the negative responses of others. However, some adolescents showed resilience and, with support from friends and family, developed strategies to manage their altered appearance and its social consequences. These strategies are explored, which can inform interventions to support adolescents and parents. PMID- 20173082 TI - Single- and multiple-dose pharmacokinetics and tolerability of telcagepant, an oral calcitonin gene-related peptide receptor antagonist, in adults. AB - Telcagepant is a novel, orally active, and selective calcitonin gene-related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. Three separate clinical studies were conducted to evaluate the pharmacokinetics and tolerability of telcagepant following single oral doses in healthy young and elderly men and women and multiple oral doses in men. Telcagepant was rapidly absorbed with a time to maximum concentration of approximately 1.5 hours. The terminal half-life was approximately 6 hours. A greater than dose-proportional increase was observed in the area under the plasma concentration versus time curve from zero to infinity. Following twice-daily dosing, with each dose separated by 2 hours, steady state was achieved in approximately 3 to 4 days with an accumulation ratio of approximately 2. There were no clinically meaningful pharmacokinetic differences when compared across age and gender. Telcagepant was generally well tolerated up to single doses of 1200 mg and multiple doses of 400 mg twice daily. PMID- 20173083 TI - Genetic variation in metabolizing enzyme and transporter genes: comprehensive assessment in 3 major East Asian subpopulations with comparison to Caucasians and Africans. AB - The advent of high-throughput technologies has proven valuable in the assessment of genetic differences and their effects on drug activation, metabolism, disposition, and transport. However, most studies to date have focused on a small number of genes or few alleles, some of which are rare and therefore observed infrequently or lacked rigorous ethnic characterization, thus reducing the ability to extrapolate within and among populations. In this study, the authors comprehensively assessed the allele frequencies of 165 variants comprising 27 drug-metabolizing enzyme and transporter (DMET) genes from 2188 participants across 3 major ethnic populations: Caucasians, Africans, and East Asians. This sample size was sufficiently large to demonstrate genetic differences among these major ethnic groups while concomitantly confirming similarities among East Asian subpopulations (Korean, Han Chinese, and Japanese). A comprehensive presentation of allele and genotype frequencies is included in the online supplement, and 3 of the most widely studied cytochrome P450 (CYP) genes, CYP2D6, CYP2C19, and CYP2C9; 2 non-CYP enzymes, NAT1 and TMPT; and 2 transporter genes, SLCO1B1 and SLCO2B1, are presented herein according to ethnic classification. PMID- 20173084 TI - Lisdexamfetamine dimesylate: linear dose-proportionality, low intersubject and intrasubject variability, and safety in an open-label single-dose pharmacokinetic study in healthy adult volunteers. AB - The pharmacokinetics of lisdexamfetamine dimesylate, a long-acting prodrug stimulant, and its active moiety, d-amphetamine, including dose-proportionality and variability, were assessed in 20 healthy adults. Subjects received a single dose, sequentially, of 50, 100, 150, 200, and 250 mg of lisdexamfetamine dimesylate. Plasma lisdexamfetamine dimesylate and d-amphetamine were measured before dosing and 0.25 to 96 hours postdose. Dose-proportionality and intersubject and intrasubject variability of pharmacokinetic parameters were examined. Safety assessments included adverse events. All 20 subjects received 50 and 100 mg while 18, 12, and 9 subjects received 150, 200, and 250 mg of lisdexamfetamine dimesylate, respectively. Ten subjects were discontinued during the study for prespecified stopping rules (2 consecutive hourly readings of blood pressure: systolic >160 mm Hg or diastolic >100 mm Hg). Mean maximum observed plasma concentration (C(max)) and area under the concentration-time curve from time 0 to infinity (AUC(0-infinity)) increased linearly and dose-dependently for d-amphetamine. Median time to C(max) ranged from 4 to 6 hours for d-amphetamine and 1.0 to 1.5 hours for lisdexamfetamine dimesylate. Intersubject and intrasubject variability over doses from 50 to 150 mg was low (<20%) for both C(max) and AUC(0-infinity). Adverse events included nausea, dizziness, headache, psychomotor hyperactivity, and dysuria. These findings indicate that the pharmacokinetic parameters of d-amphetamine were dose-proportional and predictable over a wide range of lisdexamfetamine dimesylate doses. PMID- 20173085 TI - Effect of raltegravir on the pharmacokinetics of methadone. AB - A randomized, placebo-controlled, 2-period crossover study in subjects on methadone maintenance therapy was conducted to assess the effect of the HIV-1 integrase inhibitor, raltegravir, on the pharmacokinetics of methadone. Twelve HIV-negative male and female subjects stabilized on an oral methadone program were enrolled. Subjects maintained their prescribed oral doses of methadone throughout the study and, in each of 2 periods, received either 400 mg of raltegravir or matching placebo every 12 hours on days 1 through 10 of each treatment period with a washout of 7 days between periods. Plasma samples for analysis of methadone pharmacokinetics were collected over 24 hours postdose on day 10 of each treatment period. Safety and tolerability were assessed throughout the study. The geometric mean ratio (90% confidence interval) for methadone when administered with raltegravir relative to methadone alone was 1.00 (0.93-1.09) for area under the methadone concentration time curve from time 0 to 24 hours and 1.00 (0.94-1.07) for maximal concentration. There were no serious clinical or laboratory adverse experiences. There were no discontinuations due to an adverse experience. Coadministration of raltegravir and methadone is generally well tolerated. Raltegravir has no clinically meaningful effect on methadone pharmacokinetics. No dose adjustment is required for methadone when coadministered with raltegravir. PMID- 20173086 TI - Dose proportionality of once-daily trazodone extended-release caplets under fasting conditions. AB - An extended-release trazodone HCl formulation, Trazodone Contramid OAD (TzCOAD), was developed as scored 150-mg and 300-mg caplets for once-daily administration. Dose proportionality of intact and bisected caplets (dose range, 75-375 mg) was evaluated in a single-dose, randomized, 5-way crossover study. Plasma trazodone and m-chlorophenylpiperazine (mCPP) levels were determined using a validated liquid chromatography-tandem mass spectroscopy method. Dose proportionality was assessed based on confidence intervals for logarithmically transformed, dose normalized maximum plasma concentration (C(max)), area under the plasma concentration versus time data pairs (AUC(0-t)), and area under the curve from time 0 to infinity (AUC(0-infinity)) in relation to the acceptance range of 80% to 125% (bioequivalence approach). The power method, combined with confidence interval criteria, was also used to assess proportionality. The conclusion of dose proportionality was generally supported using the bioequivalence approach. Based on the power model, values of the slope and corresponding 90% confidence interval for trazodone C(max), AUC(0-t), and AUC(0-infinity) were 0.948 (0.899 0.997), 0.920 (0.875-0.964), and 0.913 (0.867-0.958), respectively. All were within the acceptance interval (0.861-1.139). Results for mCPP also fell within the acceptance interval. TzCOAD exhibits linear pharmacokinetics over doses ranging from 75 to 375 mg and maintains its controlled-release properties when the caplets are bisected along the score line. PMID- 20173087 TI - Population pharmacokinetics and pharmacodynamics of cisplatinum during hyperthermic intraperitoneal chemotherapy using a closed abdominal procedure. AB - The aim of this work was to study the pharmacokinetics of cisplatinum during closed abdominal hyperthermic intraperitoneal chemotherapy (HIPEC) using a population pharmacokinetics approach. Forty patients were treated between January 2003 and December 2004. Peritoneal and blood concentrations of cisplatinum were used to develop a pharmacokinetic model of the peritoneal and plasma compartments using NONMEM software. Different covariables were analyzed to identify those that explain part of the interindividual variability of the pharmacokinetic parameters. Relationships between the area under the concentration-time curve (AUC) and hematological and renal toxicity and efficiency were explored. The pharmacokinetics of cisplatinum were modeled with a 3-compartment model. Estimations of the plasma and peritoneal pharmacokinetic parameters were obtained. No clinical or biological covariates correlated with these parameters. No direct relationship between the AUC of the peritoneal or plasma and toxicity or efficiency was demonstrated. The pharmacokinetics during HIPEC could be modeled with a 3-compartment model using a population pharmacokinetics approach. This work is the basis of further studies. Notably, studies including new patients will analyze the impact of abdominal cavity volume and the variation of the abdominal pressure during HIPEC on the pharmacokinetics of cisplatinum. PMID- 20173088 TI - Bioequivalence studies of omnitrope, the first biosimilar/rhGH follow-on protein: two comparative phase 1 randomized studies and population pharmacokinetic analysis. AB - This article discusses the bioequivalence of Omnitrope (Sandoz's rhGH biosimilar) and Genotropin (reference rhGH product), assessed in the first 2 clinical phase 1 studies conducted during the development of Omnitrope. Both of these phase 1 studies were randomized, double-blind, crossover studies, each involving 24 healthy volunteers who underwent pituitary somatrope cell down-regulation using octreotide. Three different formulations of recombinant human growth hormone (rhGH) were compared: Omnitrope lyophilisate, Omnitrope liquid and Genotropin (lyophilized powder for injection). Both pharmacokinetics (area under the curve [AUC], C(max), t(max) and t(1/2)) and pharmacodynamics (serum levels of insulin like growth factor 1, insulin-like growth factor binding protein-3 and non esterified fatty acid) were assessed after a single subcutaneous injection of 5 mg rhGH. The 3 formulations had comparable pharmacokinetics and pharmacodynamics. All the 90% confidence intervals of the ratios of the least squares means for the pharmacokinetic and pharmacodynamic parameters AUC and C(max) were within the predefined FDA and EMEA acceptance range of 80%-125% for bioequivalence. In addition, a comparative population pharmacokinetic analysis further supports that Omnitrope lyophilisate, Omnitrope liquid and Genotropin can be regarded as equivalent in terms of pharmacokinetics. Therefore, Omnitrope lyophilisate was demonstrated to be bioequivalent to both Genotropin and the Omnitrope liquid formulation. PMID- 20173089 TI - In vitro metabolism and identification of human enzymes involved in the metabolism of methylnaltrexone. AB - Methylnaltrexone (MNTX) is a peripherally acting mu-opioid receptor antagonist and is currently indicated for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Sulfation to MNTX-3-sulfate (M2) and carbonyl reduction to methyl-6alpha-naltrexol (M4) and methyl-6beta-naltrexol (M5) are the primary metabolic pathways for MNTX in humans. The objectives of this study were to investigate MNTX in vitro metabolism in human and nonclinical species and to identify the human enzymes involved in MNTX metabolism. Of the five commercially available sulfotransferases investigated, only SULT2A1 and SULT1E1 catalyzed M2 formation. Formation of M4 and M5 was catalyzed by NADPH dependent hepatic cytosolic enzymes, which were identified using selective chemical inhibitors (10 and 100 microM) for aldo-keto reductase (AKR) isoforms, short-chain dehydrogenase/reductase including carbonyl reductase, alcohol dehydrogenase, and quinone oxidoreductase. The results were then compared with the effects of the same inhibitors on 6beta-naltrexol formation from naltrexone, a structural analog of MNTX, which is catalyzed mainly by AKR1C4. The AKR1C inhibitor phenolphthalein inhibited MNTX and naltrexone reduction up to 98%. 5beta-Cholanic acid 3alpha,7alpha-diol, the AKR1C2 inhibitor, and medroxyprogesterone acetate, an inhibitor of AKR1C1, AKR1C2, and AKR1C4, inhibited MNTX reduction up to 67%. Other inhibitors were less potent. In conclusion, the carbonyl reduction of MNTX to M4 and M5 in hepatic cytosol was consistent with previous in vivo observations. AKR1C4 appeared to play a major role in the carbonyl reduction of MNTX, although multiple enzymes in the AKR1C subfamily may be involved. Human SULT2A1 and SULT1E1 were involved in MNTX sulfation. PMID- 20173090 TI - Differentiation among the ARGONAUTES. PMID- 20173092 TI - Positive allosteric modulators of the human sweet taste receptor enhance sweet taste. AB - To identify molecules that could enhance sweetness perception, we undertook the screening of a compound library using a cell-based assay for the human sweet taste receptor and a panel of selected sweeteners. In one of these screens we found a hit, SE-1, which significantly enhanced the activity of sucralose in the assay. At 50 microM, SE-1 increased the sucralose potency by >20-fold. On the other hand, SE-1 exhibited little or no agonist activity on its own. SE-1 effects were strikingly selective for sucralose. Other popular sweeteners such as aspartame, cyclamate, and saccharin were not enhanced by SE-1 whereas sucrose and neotame potency were increased only by 1.3- to 2.5-fold at 50 microM. Further assay-guided chemical optimization of the initial hit SE-1 led to the discovery of SE-2 and SE-3, selective enhancers of sucralose and sucrose, respectively. SE 2 (50 microM) and SE-3 (200 microM) increased sucralose and sucrose potencies in the assay by 24- and 4.7-fold, respectively. In human taste tests, 100 microM of SE-1 and SE-2 allowed for a reduction of 50% to >80% in the concentration of sucralose, respectively, while maintaining the sweetness intensity, and 100 microM SE-3 allowed for a reduction of 33% in the concentration of sucrose while maintaining the sweetness intensity. These enhancers did not exhibit any sweetness when tasted on their own. Positive allosteric modulators of the human sweet taste receptor could help reduce the caloric content in food and beverages while maintaining the desired taste. PMID- 20173091 TI - The Arabidopsis RNA-directed DNA methylation argonautes functionally diverge based on their expression and interaction with target loci. AB - Argonaute (AGO) effectors of RNA silencing bind small RNA (sRNA) molecules and mediate mRNA cleavage, translational repression, or epigenetic DNA modification. In many organisms, these targeting mechanisms are devolved to different products of AGO multigene families. To investigate the basis of AGO functional diversification, we characterized three closely related Arabidopsis thaliana AGOs (AGO4, AGO6, and AGO9) implicated in RNA-directed DNA methylation. All three AGOs bound 5' adenosine 24-nucleotide sRNAs, but each exhibited different preferences for sRNAs from different heterochromatin-associated loci. This difference was reduced when AGO6 and AGO9 were expressed from the AGO4 promoter, indicating that the functional diversification was partially due to differential expression of the corresponding genes. However, the AGO4-directed pattern of sRNA accumulation and DNA methylation was not fully recapitulated with AGO6 or AGO9 expressed from the AGO4 promoter. Here, we show that sRNA length and 5' nucleotide do not account for the observed functional diversification of these AGOs. Instead, the selectivity of sRNA binding is determined by the coincident expression of the AGO and sRNA-generating loci, and epigenetic modification is influenced by interactions between the AGO protein and the different target loci. These findings highlight the importance of tissue specificity and AGO-associated proteins in influencing epigenetic modifications. PMID- 20173093 TI - Topographic organization of macaque area LIP. AB - Despite several attempts to define retinotopic maps in the macaque lateral intraparietal area (LIP) using histological, electrophysiological, and neuroimaging methods, the degree to which this area is topographically organized remains controversial. We recorded blood oxygenation level-dependent signals with functional MRI from two macaques performing a difficult visual search task on stimuli presented at the fovea or in the periphery of the visual field. The results revealed the presence of a single topographic representation of the contralateral hemifield in the ventral subdivision of the LIP (LIPv) in both hemispheres of both monkeys. Also, a foveal representation was localized in rostral LIPv rather than in dorsal LIP (LIPd) as previous experiments had suggested. Finally, both LIPd and LIPv responded only to contralateral stimuli. In contrast, human studies have reported multiple topographic maps in intraparietal cortex and robust responses to ipsilateral stimuli. These blood oxygenation level-dependent functional MRI results provide clear evidence for the topographic organization of macaque LIP that complements the results of previous electrophysiology studies, and also reveal some unexpected characteristics of this organization that have eluded these previous studies. The results also delineate organizational differences between LIPv and LIPd, providing support for these two histologically defined areas may subserve different visuospatial functions. Finally, these findings point to potential evolutionary differences in functional organization with human posterior parietal cortex. PMID- 20173094 TI - Membrane protein folding makes the transition. PMID- 20173095 TI - Molecular mechanism of the sweet taste enhancers. AB - Positive allosteric modulators of the human sweet taste receptor have been developed as a new way of reducing dietary sugar intake. Besides their potential health benefit, the sweet taste enhancers are also valuable tool molecules to study the general mechanism of positive allosteric modulations of T1R taste receptors. Using chimeric receptors, mutagenesis, and molecular modeling, we reveal how these sweet enhancers work at the molecular level. Our data argue that the sweet enhancers follow a similar mechanism as the natural umami taste enhancer molecules. Whereas the sweeteners bind to the hinge region and induce the closure of the Venus flytrap domain of T1R2, the enhancers bind close to the opening and further stabilize the closed and active conformation of the receptor. PMID- 20173096 TI - Bioorganometallic mechanism of action, and inhibition, of IspH. AB - We have investigated the mechanism of action of Aquifex aeolicus IspH [E-4 hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) reductase], together with its inhibition, using a combination of site-directed mutagenesis (K ( M ),V (max)), EPR and (1)H, (2)H, (13)C, (31)P, and (57)Fe-electron-nuclear double resonance (ENDOR) spectroscopy. On addition of HMBPP to an (unreactive) E126A IspH mutant, a reaction intermediate forms that has a very similar EPR spectrum to those seen previously with the HMBPP "parent" molecules, ethylene and allyl alcohol, bound to a nitrogenase FeMo cofactor. The EPR spectrum is broadened on (57)Fe labeling and there is no evidence for the formation of allyl radicals. When combined with ENDOR spectroscopy, the results indicate formation of an organometallic species with HMBPP, a pi/sigma "metallacycle" or eta (2)-alkenyl complex. The complex is poised to interact with H(+) from E126 (and H124) in reduced wt IspH, resulting in loss of water and formation of an eta (1)-allyl complex. After reduction, this forms an eta (3)-allyl pi-complex (i.e. containing an allyl anion) that on protonation (at C2 or C4) results in product formation. We find that alkyne diphosphates (such as propargyl diphosphate) are potent IspH inhibitors and likewise form metallacycle complexes, as evidenced by (1)H, (2)H, and (13)C ENDOR, where hyperfine couplings of approximately 6 MHz for (13)C and 10 MHz for (1)H, are observed. Overall, the results are of broad general interest because they provide new insights into IspH catalysis and inhibition, involving organometallic species, and may be applicable to other Fe(4)S(4)-containing proteins, such as IspG. PMID- 20173097 TI - Rontgen's electrode-free elastomer actuators without electromechanical pull-in instability. AB - Electrical actuators made from films of dielectric elastomers coated on both sides with stretchable electrodes may potentially be applied in microrobotics, tactile and haptic interfaces, as well as in adaptive optical elements. Such actuators with compliant electrodes are sensitive to the pull-in electromechanical instability, limiting operational voltages and attainable deformations. Electrode-free actuators driven by sprayed-on electrical charges were first studied by Rontgen in 1880. They withstand much higher voltages and deformations and allow for electrically clamped (charge-controlled) thermodynamic states preventing electromechanical instabilities. The absence of electrodes allows for direct optical monitoring of the actuated elastomer, as well as for designing new 3D actuator configurations and adaptive optical elements. PMID- 20173098 TI - RFWD3-Mdm2 ubiquitin ligase complex positively regulates p53 stability in response to DNA damage. AB - In unstressed cells, the tumor suppressor p53 is maintained at low levels by ubiquitin-mediated proteolysis mainly through Mdm2. In response to DNA damage, p53 is stabilized and becomes activated to turn on transcriptional programs that are essential for cell cycle arrest and apoptosis. Activation of p53 leads to accumulation of Mdm2 protein, a direct transcriptional target of p53. It is not understood how p53 is protected from degradation when Mdm2 is up-regulated. Here we report that p53 stabilization in the late phase after ionizing radiation correlates with active ubiquitination. We found that an E3 ubiquitin ligase RFWD3 (RNF201/FLJ10520) forms a complex with Mdm2 and p53 to synergistically ubiquitinate p53 and is required to stabilize p53 in the late response to DNA damage. This process is regulated by the DNA damage checkpoint, because RFWD3 is phosphorylated by ATM/ATR kinases and the phosphorylation mutant fails to stimulate p53 ubiquitination. In vitro experiments suggest that RFWD3 is a p53 E3 ubiquitin ligase and that RFWD3-Mdm2 complex restricts the polyubiquitination of p53 by Mdm2. Our study identifies RFWD3 as a positive regulator of p53 stability when the G(1) cell cycle checkpoint is activated and provides an explanation for how p53 is protected from degradation in the presence of high levels of Mdm2. PMID- 20173099 TI - Sampling the N-terminal proteome of human blood. AB - The proteomes of blood plasma and serum represent a potential gold mine of biological and diagnostic information, but challenges such as dynamic range of protein concentration have hampered efforts to unlock this resource. Here we present a method to label and isolate N-terminal peptides from human plasma and serum. This process dramatically reduces the complexity of the sample by eliminating internal peptides. We identify 772 unique N-terminal peptides in 222 proteins, ranging over six orders of magnitude in abundance. This approach is highly suited for studying natural proteolysis in plasma and serum. We find internal cleavages in plasma proteins created by endo- and exopeptidases, providing information about the activities of proteolytic enzymes in blood, which may be correlated with disease states. We also find signatures of signal peptide cleavage, coagulation and complement activation, and other known proteolytic processes, in addition to a large number of cleavages that have not been reported previously, including over 200 cleavages of blood proteins by aminopeptidases. Finally, we can identify substrates from specific proteases by exogenous addition of the protease combined with N-terminal isolation and quantitative mass spectrometry. In this way we identified proteins cleaved in human plasma by membrane-type serine protease 1, an enzyme linked to cancer progression. These studies demonstrate the utility of direct N-terminal labeling by subtiligase to identify and characterize endogenous and exogenous proteolysis in human plasma and serum. PMID- 20173100 TI - Joint modeling of intercourse behavior and human fecundability using structural equation models. AB - Human fecundability is defined as the probability of conception during a menstrual cycle among couples at risk for pregnancy. It is highly relevant for understanding human reproduction and represents a series of highly interrelated and timed processes. The statistical literature has recognized the need to incorporate both biological and behavioral factors (Barrett and Marshall, 1969; Dunson and Stanford, 2005) when modeling conception probabilities, given that intercourse during the fertile window is a necessary but not sufficient criterion for conception. The heterogeneity of behaviors such as the timing and frequency of intercourse in a menstrual cycle needs to be considered when estimating conception. Here we propose a joint model of intercourse behavior and human fecundability through a classic conception probability model and a structural equation model (SEM) to accommodate intercourse during the menstrual cycle. The SEM part of the proposed model allows the dependency between intercourse behaviors on consecutive days in a menstrual cycle to vary across days. Consequently, the proposed model can accommodate not only a broad variety of intercourse patterns and dependency structures but also general covariate effects. Finally, we present a detailed analysis of the New York State Angler Cohort Prospective Pregnancy Study to illustrate the proposed methodology. PMID- 20173101 TI - Transparency and reproducibility in data analysis: the Prostate Cancer Prevention Trial. AB - With the analysis of complex, messy data sets, the statistics community has recently focused attention on "reproducible research," namely research that can be readily replicated by others. One standard that has been proposed is the availability of data sets and computer code. However, in some situations, raw data cannot be disseminated for reasons of confidentiality or because the data are so messy as to make dissemination impractical. For one such situation, we propose 2 steps for reproducible research: (i) presentation of a table of data and (ii) presentation of a formula to estimate key quantities from the table of data. We illustrate this strategy in the analysis of data from the Prostate Cancer Prevention Trial, which investigated the effect of the drug finasteride versus placebo on the period prevalence of prostate cancer. With such an important result at stake, a transparent analysis was important. PMID- 20173102 TI - 3.0-T evaluation of knee cartilage by using three-dimensional IDEAL GRASS imaging: comparison with fast spin-echo imaging. AB - PURPOSE: To compare the diagnostic performance of iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) gradient recalled acquisition in steady-state (GRASS) imaging with a routine magnetic resonance (MR) imaging protocol for evaluating knee cartilage at 3.0 T in patients by using arthroscopy as the reference standard. MATERIALS AND METHODS: This prospective Health Insurance Portability and Accountability Act-compliant study was performed with a waiver of informed consent from the institutional review board. IDEAL GRASS was added to routine 3.0-T knee MR protocol performed in 95 symptomatic patients (48 males, mean age, 34.5 years; 47 females, mean age, 35.5 years) who underwent subsequent arthroscopic surgery. Radiologists used the routine MR protocol during the first review and IDEAL GRASS during the second to grade each articular surface and to determine the presence of meniscal tears. By using arthroscopy as the reference standard, the sensitivity, specificity, and accuracy of both imaging methods for detecting cartilage lesions and meniscal tears were determined. RESULTS: By using the z test to compare parameters between methods, the respective sensitivity, specificity, and accuracy for detecting all 192 cartilage lesions were 68.5%, 92.6%, and 84.5% for IDEAL GRASS and 66.1%, 92.9%, and 83.9% for the routine MR protocol. There was no significant difference (P = .34-.83) in parameters between methods for detecting cartilage lesions. The respective parameters for detecting 50 medial meniscal tears were 85.0%, 91.1%, and 87.9% for IDEAL GRASS and 94.0%, 90.0%, and 92.1% for the routine MR protocol. The parameters for detecting 31 lateral meniscal tears were 58.0%, 90.6%, and 80.0% for IDEAL GRASS and 80.1%, 91.4%, and 87.9% for the routine MR protocol. The routine MR protocol had a significantly higher sensitivity for detecting medial meniscal tears (P = .04) and lateral meniscal tears (P = .01) and significantly higher accuracy for detecting lateral meniscal tears (P = .03) than IDEAL GRASS. CONCLUSION: IDEAL GRASS has similar diagnostic performance as routine MR protocol for evaluating the articular cartilage of the knee in clinical patients at 3.0 T but has significantly lower sensitivity and accuracy for detecting meniscal tears. PMID- 20173103 TI - Risk of upgrade of atypical ductal hyperplasia after stereotactic breast biopsy: effects of number of foci and complete removal of calcifications. AB - PURPOSE: To determine if patients with fewer than three foci of atypical ductal hyperplasia (ADH) who have all of their calcifications removed after stereotactic 9- or 11-gauge vacuum-assisted breast biopsy (VABB) have a rate of upgrade to malignancy that is sufficiently low to obviate surgical excision. MATERIALS AND METHODS: An institutional review board-approved, HIPAA-compliant retrospective review of 991 cases of consecutive 9- or 11-gauge stereotactic VABB performed during a 65-month period revealed 147 cases of atypia. One pathologist performed a blinded review of the results of procedures performed to assess for calcifications and confirmed ADH in 101 cases with subsequent surgical excision. Each large duct or terminal duct-lobular unit containing ADH was considered a focus and counted. Postbiopsy mammograms were reviewed to determine whether all calcifications were removed. Upgrade to malignancy was determined from excisional biopsy pathology reports. Upgrade rates as a function of both number of foci and presence or absence of residual calcifications were calculated and compared by using chi(2) tests. RESULTS: Upgrade to malignancy occurred in 20 (19.8%) of the 101 cases. The upgrade rate was significantly higher in cases of three or more foci of ADH (15 [28%] of 53 cases) than in cases of fewer than three foci (five [10%] of 48 cases) (P = .02). Upgrade rates were similar, regardless of whether all mammographic calcifications were removed (seven [17%] of 41 cases) or all were not removed (nine [20%] of 45 cases) (P = .77). Upgrade occurred in two (12%) of 17 cases in which there were fewer than three ADH foci and all calcifications were removed. CONCLUSION: The upgrade rate is significantly higher when ADH involves at least three foci. Surgical excision is recommended even when ADH involves fewer than three foci and all mammographic calcifications have been removed, because the upgrade rate is 12%. PMID- 20173105 TI - Quantitative epidemiology in the 21st century. PMID- 20173104 TI - Transient part-solid nodules detected at screening thin-section CT for lung cancer: comparison with persistent part-solid nodules. AB - PURPOSE: To retrospectively investigate clinical and computed tomographic (CT) features of transient part-solid nodules (PSNs) initially detected at screening thin-section CT for lung cancer and to determine predictive factors that may differentiate transient PSNs from persistent PSNs. MATERIALS AND METHODS: This study was approved by the institutional review board. From January 2006 to August 2008, 93 individuals with 126 PSNs were identified from among 16777 individuals who underwent chest CT. Clinical features and CT characteristics of PSNs were reviewed, and clinical and thin-section CT features were compared between transient and persistent PSNs. To identify predictive factors of transient PSNs and evaluate predictive performance, logistic regression analysis and C statistic analysis were performed. RESULTS: Eighty-eight (69.8%) of 126 PSNs were transient. Between transient and persistent PSNs, there were significant differences (P < .05) in patient age, patient sex, risk of lung cancer, presence of eosinophilia, mode of detection, lesion size, lesion multiplicity, size of solid portion, and lesion border. Multivariate analysis revealed that young patient age, detection of the lesion at follow-up, blood eosinophilia, lesion multiplicity, large solid portion, and ill-defined border were significant (P < .05) independent predictors of transient PSNs. The performance in the discrimination of transient PSNs from persistent PSNs of the logistic regression model that incorporated both clinical and thin-section CT features was significantly higher than the performance of the models that incorporated clinical features or thin-section CT features alone. CONCLUSION: A substantial proportion of PSNs detected at screening CT were transient. Transient PSNs could be predicted with high accuracy by using the features of young patient age, detection of the PSN at follow-up, blood eosinophilia, lesion multiplicity, large solid portion, and ill-defined lesion border. PMID- 20173106 TI - Review of the safety and efficacy of long-term NSAID use in the treatment of canine osteoarthritis. AB - The published, peer-reviewed literature was systematically searched for information on the safety and efficacy of long-term (defined as 28 days or more of continuous therapy) NSAID use in the treatment of canine osteoarthritis. Online databases were reviewed in June 2008 and papers were selected based on their relevance. Fifteen papers were identified and evaluated. Six of seven papers indicated a benefit of long-term treatment over short-term treatment in terms of the reduction of clinical signs or lameness; one study showed no benefit. Fourteen papers evaluated safety with calculated experimental (adverse) event rates (EER) between 0 and 0.31, but there was no correlation between study length and EER (rs=-0.109, P=0.793). The balance of evidence for the efficacy of NSAIDs supports longer-term use of these agents for increased clinical effect. There is no indication in the literature that such an approach is associated with a reduction in safety, although robust data on the safety of long-term NSAID use are lacking in large numbers of dogs. PMID- 20173107 TI - Uterine disorders in 59 rabbits. AB - The medical records of 59 rabbits with uterine disorders were assessed retrospectively. Ten animals were presented because of vaginal discharge; the reasons for presentation of the remaining 49 rabbits included mammary masses, skin tumours, anorexia and poor general health. All the rabbits underwent a clinical examination, and 54 were examined by ultrasonography and/or radiography. Forty-five rabbits underwent ovariohysterectomy and the other 14 rabbits were euthanased, three because of pulmonary metastases and 11 because of very poor health unrelated to their uterine disease. The genital tracts of all the rabbits were submitted for histological examination. Endometrial hyperplasia (in 24 rabbits) and adenocarcinoma (in 18 rabbits) were the most common uterine disorders; in a further 11 cases both conditions were observed. The remaining six rabbits had other uterine disorders. Four rabbits that were presented with adenocarcinoma of the mammary gland were found to have concurrent uterine disorders. The mean age of the rabbits with endometrial hyperplasia was 4.5 years, and that of the rabbits with adenocarcinoma was 6.1 years. Four rabbits had ovarian tumours. PMID- 20173108 TI - Homeopathic prescribing for chronic conditions in equine veterinary practice in the UK. AB - Twelve Faculty of Homeopathy veterinarians recorded data systematically at 777 consecutive homeopathic appointments for horses over a period of 12 months. A spreadsheet enabled the recording of information, which included the date of appointment; horse and owner identity (anonymised); sex of horse; main medical problem treated; whether the condition was chronic or acute; whether the appointment was new or a follow-up; owner-assessed clinical outcome on a seven point scale, ranging from -3 to +3, compared with the first appointment; homeopathic medicine(s) prescribed; and whether any conventional or other complementary/alternative medicine (CAM) was being used concurrently to treat the condition. Data from 289 horses comprised a total of 305 individual conditions identified as chronic in nature, of which 234 had a follow-up assessment. At the final appointment for chronic cases during the study period, 4.3 per cent were receiving conventional medication and 17.1 per cent were being given another CAM treatment in addition to homeopathy. The eight chronic conditions most frequently treated with homeopathy were: arthritis, headshaking, laminitis, chronic obstructive pulmonary disease, sweet itch, dermatitis, sarcoidosis and Cushing's syndrome. PMID- 20173109 TI - Use of a field-enabled nucleic acid extraction and PCR instrument to detect BVDV. PMID- 20173110 TI - Serum acute phase proteins as a marker of inflammation in dairy cattle with hoof diseases. PMID- 20173112 TI - Official bovine tuberculosis-free status in Scotland. PMID- 20173113 TI - Apparent low toxicity of yew in muntjac deer and Soay sheep. PMID- 20173114 TI - Streptococcus pluranimalium in ovine reproductive material. PMID- 20173115 TI - X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options. AB - A large proportion of patients with mutations in the Wiskott-Aldrich syndrome (WAS) protein gene exhibit the milder phenotype termed X-linked thrombocytopenia (XLT). Whereas stem cell transplantation at an early age is the treatment of choice for patients with WAS, therapeutic options for patients with XLT are controversial. In a retrospective multicenter study we defined the clinical phenotype of XLT and determined the probability of severe disease-related complications in patients older than 2 years with documented WAS gene mutations and mild-to-moderate eczema or mild, infrequent infections. Enrolled were 173 patients (median age, 11.5 years) from 12 countries spanning 2830 patient-years. Serious bleeding episodes occurred in 13.9%, life-threatening infections in 6.9%, autoimmunity in 12.1%, and malignancy in 5.2% of patients. Overall and event-free survival probabilities were not significantly influenced by the type of mutation or intravenous immunoglobulin or antibiotic prophylaxis. Splenectomy resulted in increased risk of severe infections. This analysis of the clinical outcome and molecular basis of patients with XLT shows excellent long-term survival but also a high probability of severe disease-related complications. These observations will allow better decision making when considering treatment options for individual patients with XLT. PMID- 20173117 TI - Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events. AB - BACKGROUND: Molecular tools may provide insight into cardiovascular risk. We assessed whether metabolites discriminate coronary artery disease (CAD) and predict risk of cardiovascular events. METHODS AND RESULTS: We performed mass spectrometry-based profiling of 69 metabolites in subjects from the CATHGEN biorepository. To evaluate discriminative capabilities of metabolites for CAD, 2 groups were profiled: 174 CAD cases and 174 sex/race-matched controls ("initial"), and 140 CAD cases and 140 controls ("replication"). To evaluate the capability of metabolites to predict cardiovascular events, cases were combined ("event" group); of these, 74 experienced death/myocardial infarction during follow-up. A third independent group was profiled ("event-replication" group; n=63 cases with cardiovascular events, 66 controls). Analysis included principal components analysis, linear regression, and Cox proportional hazards. Two principal components analysis-derived factors were associated with CAD: 1 comprising branched-chain amino acid metabolites (factor 4, initial P=0.002, replication P=0.01), and 1 comprising urea cycle metabolites (factor 9, initial P=0.0004, replication P=0.01). In multivariable regression, these factors were independently associated with CAD in initial (factor 4, odds ratio [OR], 1.36; 95% CI, 1.06 to 1.74; P=0.02; factor 9, OR, 0.67; 95% CI, 0.52 to 0.87; P=0.003) and replication (factor 4, OR, 1.43; 95% CI, 1.07 to 1.91; P=0.02; factor 9, OR, 0.66; 95% CI, 0.48 to 0.91; P=0.01) groups. A factor composed of dicarboxylacylcarnitines predicted death/myocardial infarction (event group hazard ratio 2.17; 95% CI, 1.23 to 3.84; P=0.007) and was associated with cardiovascular events in the event-replication group (OR, 1.52; 95% CI, 1.08 to 2.14; P=0.01). CONCLUSIONS: Metabolite profiles are associated with CAD and subsequent cardiovascular events. PMID- 20173118 TI - Movement of genes in nucleus may someday aid diagnosis. PMID- 20173116 TI - Alternative modes of GM-CSF receptor activation revealed using activated mutants of the common beta-subunit. AB - Granulocyte/macrophage colony-stimulating factor promotes growth, survival, differentiation, and activation of normal myeloid cells and plays an important role in myeloid leukemias. The GM-CSF receptor (GMR) shares a signaling subunit, beta(c), with interleukin-3 and interleukin-5 receptors and has recently been shown to induce activation of Janus kinase 2 (JAK2) and downstream signaling via formation of a unique dodecameric receptor complex. In this study we use 2 activated beta(c) mutants that display distinct signaling capacity and have differential requirements for the GMR alpha-subunit (GMR-alpha) to dissect the signaling pathways associated with the GM-CSF response. The V449E transmembrane mutant selectively activates JAK2/signal transducer and activator of transcription 5 and extracellular signal-regulated kinase (ERK) pathways, resulting in a high level of sensitivity to JAK and ERK inhibitors, whereas the extracellular mutant (FIDelta) selectively activates the phosphoinositide 3 kinase/Akt and IkappaKbeta/nuclear factorkappaB pathways. We also demonstrate a novel and direct interaction between the SH3 domains of Lyn and Src with a conserved proline-rich motif in GMR-alpha and show a selective requirement for Src family kinases by the FIDelta mutant. We relate the nonoverlapping nature of signaling by the activated mutants to the structure of the unique GMR complex and propose alternative modes of receptor activation acting synergistically in the mature liganded receptor complex. PMID- 20173119 TI - Fertility preservation during treatment is a growing issue for women. PMID- 20173120 TI - New law may be having some effect on publication bias. PMID- 20173121 TI - European Commission considers revisions to clinical trials directive. PMID- 20173122 TI - StatBite: Key findings from the "Impact on clinical research of European legislation" report. PMID- 20173123 TI - Slope of emphysema index: an objective descriptor of regional heterogeneity of emphysema and an independent determinant of pulmonary function. AB - OBJECTIVE: The purpose of this study was to compare quantitative and visual assessments of regional heterogeneity of emphysema and to investigate the influence of regional heterogeneity on pulmonary function in smoking-related emphysema. MATERIALS AND METHODS: We developed an automatic computerized algorithm to quantitatively assess heterogeneity in the upper-lower, anterior posterior, and central-peripheral directions. The emphysema index was plotted with a linear function (emphysema index slopes: slope of emphysema index in upper lower direction, slope of emphysema index in anterior-posterior direction, and slope of emphysema index in central-peripheral direction) for consecutive 1-pixel thick slices using volumetric CT data of 59 patients (58 men and one woman; mean age, 65.7 years). Emphysema index was defined as the percentage area of lung with attenuation values below -950 HU. Visual assessment was performed using a 5-point scoring system. Quantitative and visual assessments were compared. Multiple linear regression was performed to evaluate the influence of emphysema index and emphysema index slopes on the pulmonary function test. RESULTS: Quantitative and visual assessments were significantly correlated in both upper-lower (r(2) = 0.40 and r(2) = 0.67 for observers 1 and 2, respectively) and central-peripheral (r(2) = 0.51 and r(2) = 0.47, respectively) directions. Multiple linear regression revealed that emphysema index, slope of emphysema index in upper-lower direction, and slope of emphysema index in anterior-posterior direction were independent determinants of forced expiratory volume in 1 second (FEV(1)) (r(2) = 0.30; p < 0.001). Emphysema index and slope of emphysema index in upper-lower direction were independent determinants of the ratio of FEV(1) to forced vital capacity (FEV(1)/FVC) (r(2) = 0.32; p < 0.001). In addition to higher emphysema index, lower and posterior lung dominance was associated with a decrease in FEV(1) and FEV(1)/FVC. CONCLUSION: Computerized, quantitative assessment using the emphysema index slope is comparable to visual assessment in the evaluation of regional heterogeneity of emphysema. In addition to the emphysema index, regional heterogeneity of smoking-related emphysema contributes to impairment of pulmonary function. PMID- 20173124 TI - In vitro evaluation of metallic coronary artery stents with 64-MDCT using an ECG gated cardiac phantom: relationship between in-stent visualization, stent type, and heart rate. AB - OBJECTIVE: The purpose of this study was to assess the accuracy of 64-MDCT in the visualization of different coronary artery stents and in the appraisal of in stent stenosis. MATERIALS AND METHODS: Five different coronary stent types with three diameters (2.5, 3.0, and 4.0 mm) were analyzed using anthropomorphic dynamic cardiac phantom. All stents were mounted on polyurethane sticks of defined outer diameter and contained a default concentric stenosis of 50% each. Imaging was performed at four different heart rates (no motion, 60 beats/min, 75 beats/min, and 90 beats/min). Apparent stent diameter, degree of stenosis, in stent attenuation, and diagnostic accuracy were assessed. RESULTS: A significant (p < 0.05) overestimation of the degree of stenosis (41.1% +/- 41.4%), underestimation of the stent lumen (-42.7% +/- 41.4%), and increase in in-stent attenuation (36.6 +/- 29.2 HU) were observed for all stents and heart rates. In stent stenosis > 50% was detected with an overall sensitivity of 88.9% (95% CI, 75.9-96.3%) and an overall specificity of 51.1% (95% CI, 35.8-66.3%) by observer 1 and with an overall sensitivity of 86.7% (95% CI, 73.2-94.9%) and an overall specificity of 57.8% (95% CI, 42.2-72.3%) by observer 2. A trend toward higher specificity was observed for increasing stent diameter, however, without reaching statistical significance (p = 0.63). CONCLUSION: In an experimental setting, 64 MDCT allows a reliable detection of instent stenosis but significantly overestimates the actual degree of stenosis. Within the range of physiologic heart rates, diagnostic accuracy is restricted by spatial, not temporal, resolution. PMID- 20173125 TI - Triphasic contrast bolus for whole-chest ECG-gated 64-MDCT of patients with nonspecific chest pain: evaluation of arterial enhancement and streak artifact. AB - OBJECTIVE: The purpose of this study was to evaluate the use of a triphasic contrast bolus for ECG-gated CT in the assessment of chest pain by measuring vascular luminal attenuation and determining the degree of contrast-related streak artifact. MATERIALS AND METHODS: We reviewed the images from 44 ECG-gated CT examinations performed with a coronary contrast bolus modified for imaging of the entire chest. Luminal attenuation achieved with the resulting triphasic bolus was measured at specified vascular locations in the right side of the heart, pulmonary arteries, coronary arteries, and thoracic aorta. The occurrence of contrast-related streak artifact was recorded, and artifact severity was scored on a subjective 4-point scale. RESULTS: The mean attenuation values in the pulmonary arteries (345.3 +/- 136.7 HU), coronary arteries (340.8 +/- 82.5 HU), and thoracic aorta (386.4 +/- 67.2 HU) were above a diagnostic threshold of 200 HU. Although there was no significant difference between the mean arterial values, the right-heart attenuation (281.6 +/- 121.8 HU) was significantly lower than the attenuation in the other two locations. On a location basis, 92.2% of the 1,972 arterial measurements were above the 200-HU threshold. Streak artifacts were found in 21 examinations (47.7%), and none was scored as severe. Statistical analysis revealed that the occurrence of streak artifact increased with higher right-heart attenuation. CONCLUSION: In this series, a triphasic contrast bolus for ECG-gated whole-chest CT consistently achieved arterial attenuation above a diagnostic threshold in the pulmonary arteries, coronary arteries, and aorta. Right-heart attenuation was simultaneously reduced, which is important for decreasing the prevalence and severity of streak artifacts. PMID- 20173127 TI - Discrepancy rates of on-call radiology residents' interpretations of CT angiography studies of the neck and circle of Willis. PMID- 20173126 TI - Scan length adjustment of CT coronary angiography using the calcium scoring scan: effect on radiation dose. AB - OBJECTIVE: The objective of our study was to prospectively investigate the effect of adjusting the scan length of CT coronary angiography using the calcium scoring images instead of the scout view with regard to radiation dose. SUBJECTS AND METHODS: One hundred twenty-five consecutive patients (mean age +/- SD, 62 +/- 10 years) undergoing both calcium scoring and CT coronary angiography were included in our study. The scan length of calcium scoring was planned on the scout view; the scan length of CT coronary angiography was planned on the axial images of the calcium scoring by identifying the origin of the left main artery and cardiac apex and adding 1 cm cranially and caudally. Effective radiation doses were calculated for CT coronary angiography using both scout view-derived and calcium scoring-derived scan lengths. RESULTS: The scout view-derived scan length (mean +/- SD, 139 +/- 13 mm) was significantly greater than the calcium scoring-derived scan length (117 +/- 9 mm; p < 0.01). The average radiation dose was 0.8 +/- 0.3 mSv (range, 0.6-1.5 mSv) for calcium scoring and 9.0 +/- 0.6 mSv (range, 6.5-10.2 mSv) for CT coronary angiography. Using the scout view-derived scan length would have been associated with an effective radiation dose of 10.7 +/- 1.2 mSv (mean +/- SD) for CT coronary angiography, which is significantly higher than that using the calcium scoring-derived scan length (p < 0.05). The average difference between CT coronary angiography using a calcium scoring-derived scan length and that using a scout view-derived scan length was 1.7 +/- 0.9 mSv, corresponding to a radiation dose reduction of 16%. The average dose reduction when using a calcium scoring-derived instead of a scout view-derived scan length for CT coronary angiography-including the radiation dose of the calcium scoring scan-was 1.2 +/- 0.8 mSv (range, 0.1-2.7 mSv) (p < 0.05). CONCLUSION: Adjustment of the scan length of CT coronary angiography using the images from calcium scoring instead of the scout view is feasible and is associated with a 16% reduction in radiation dose of dual-source CT coronary angiography. PMID- 20173128 TI - Tuberculosis: a benign impostor. AB - OBJECTIVE: The purpose of this article is to illustrate the overlapping radiologic patterns in proven tuberculosis cases in patients initially referred to our cancer center for presumed malignancy. CONCLUSION: Tuberculosis can simulate malignancy both clinically and radiologically, especially in its extrapulmonary form. PMID- 20173129 TI - A radiologic review of the new TNM classification for lung cancer. AB - OBJECTIVE: In 2009, a new TNM staging system was published by the International Union Against Cancer and the American Joint Committee on Cancer. The new edition will encompass non-small cell lung cancer, small cell lung cancer, and bronchopulmonary carcinoids. This article will review many important changes that have been made in the revised staging system. CONCLUSION: It is important that radiologists learn the new system and understand the reasons for the changes to provide more accurate clinical staging. PMID- 20173130 TI - Preoperative evaluation in aortic endocarditis: findings on cardiac CT. AB - OBJECTIVE: The purpose of this study was to study the feasibility and diagnostic capability of preoperative cardiac CT for depicting aortic valvular pseudoaneurysms and vegetations in patients referred for aortic endocarditis requiring surgical intervention. MATERIALS AND METHODS: Consecutive patients presenting with active aortic endocarditis requiring surgical intervention were included. CT scan examinations were performed for assessing coronary artery status. Aortic valves were retrospectively analyzed. Contrast-enhanced CT scans were retrospectively gated to the ECG and obtained without the administration of a beta-blocker. The CT and intraoperative findings were systematically compared. RESULTS: During a 4-year period, 19 consecutive patients (18 men and one woman) were included (mean age +/- SD, 55 +/- 13 years). Results are expressed on a per patient basis. The sensitivity, specificity, positive predictive value, and negative predictive value of MDCT in depicting aortic valve pseudoaneurysms were 100%, 87.5%, 91.7%, and 100%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of the MDCT in depicting the extension of the aortic valve pseudoaneurysms into the intervalvular fibrous body were each 100%. The sensitivity, specificity, positive predictive value, and negative predictive value of MDCT in depicting aortic valve vegetations were 71.4%, 100%, 100%, and 55.5%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of MDCT for depicting aortic valve vegetations larger than 1 cm were all 100%. CONCLUSION: Our study shows the feasibility of preoperative CT in aortic infective endocarditis for providing relevant data about the presence and relationships of aortic valvular pseudoaneurysms. A larger prospective study including a systematic comparison with transesophageal echocardiography should be performed to determine the respective value of each technique. PMID- 20173131 TI - Mitral valve prolapse: evaluation with ECG-gated cardiac CT angiography. AB - OBJECTIVE: The purpose of our study was to evaluate the feasibility of detecting mitral valve prolapse with ECG-gated 64-MDCT angiography in comparison with the reference standard, transthoracic echocardiography. MATERIALS AND METHODS: The charts of patients consecutively referred for clinically indicated 64-MDCT angiography were reviewed. The study cohort consisted of patients who had undergone transthoracic echocardiography. Two experienced radiologists performed blinded consensus review of the MDCT angiograms of 20 patients, and the findings were compared with those of transthoracic echocardiography, which was the reference standard. RESULTS: With the findings on each anterior and posterior leaflet as separate data points, sensitivity was calculated to be 69.2-84.6% and specificity, 100%. The positive and negative predictive values were estimated to be 100% and 87.0-93.1%. CONCLUSION: ECG-gated cardiac 64-MDCT angiography can be used reliably to detect mitral valve prolapse. PMID- 20173133 TI - Right ventricular involvement in acute left ventricular myocardial infarction: prognostic implications of MRI findings. AB - OBJECTIVE: The purpose of this study was to investigate the prevalence and prognostic importance of the cardiac MRI finding of right ventricular involvement in patients with acute ST-segment elevation myocardial infarction (MI). SUBJECTS AND METHODS: Fifty patients (41 men, nine women; mean age, 58 +/- 11 years) with first-ST-segment elevation MI underwent 1.5-T cardiac MRI immediately after successful percutaneous coronary intervention. The cardiac MRI protocol included steady-state free precession cine sequences for functional assessment of the left, right, and both ventricles and inversion recovery FLASH delayed enhancement sequences after contrast administration for the quantification of myocardial damage. The prevalence of right ventricular involvement detected with ECG and echocardiography was compared with the prevalence detected with cardiac MRI, which was the reference standard. Patients underwent follow-up for 32 +/- 8 months. RESULTS: Right ventricular involvement was diagnosed with cardiac MRI in 27 patients (54%): 14 of 30 patients (47%) with inferior ST-segment elevation MI and 13 of 20 patients (65%) with anterior ST-segment elevation MI. ECG and echocardiographic findings showed only moderate agreement with cardiac MRI findings in the detection of right ventricular involvement in inferior acute MI (kappa = 0.38). Patients with right ventricular involvement in anterior ST segment elevation MI had larger infarcts (delayed enhancement, 25.9% +/- 14.5% vs 11.4% +/- 10.1%; p = 0.030), lower left ventricular ejection fraction (34.3% +/- 8.2% vs 45.2% +/- 9.5%; p < 0.015), and lower right ventricular ejection fraction (39.8% +/- 6.6% vs 54.9% +/- 8.8%; p < 0.001) than those without right ventricular involvement. In a multivariate logistic regression model, right ventricular involvement was a strong independent predictor (odds ratio, 15.8; 95% CI, 4-63%) of major cardiac adverse events. CONCLUSION: Right ventricular involvement in ST-segment elevation MI is detected more frequently with cardiac MRI than with ECG and echocardiography and is an independent prognostic indicator. PMID- 20173132 TI - Accuracy of emphysema quantification performed with reduced numbers of CT sections. AB - OBJECTIVE: The purpose of this study was to assess the accuracy of emphysema measurements obtained from systematic samples of evenly spaced CT images compared with measurements obtained from the entire scan. MATERIALS AND METHODS: Evenly spaced transverse sections from the CT studies of 136 heavy smokers who underwent screening for lung cancer in the National Lung Screening Trial and of 112 subjects who underwent imaging before lung volume reduction surgery were sampled retrospectively. The samples were acquired both by selection of specific numbers of evenly spaced images and by selection of images at specific distance intervals. The percentage of lung pixels with attenuation below specific thresholds was used as an emphysema index. The image sample error was determined as the difference in emphysema index between the image samples and the entire scan. RESULTS: The largest absolute image sample errors in the National Lung Screening Trial cohort with image sample sizes of five, 10, and 20 were 2.2, 0.8, and 0.5 index percentage points, respectively, at 1-mm section thickness (-960 HU threshold), and 2.6, 1.1, and 0.5 index percentage points at 5-mm section thickness (-930 HU threshold). The largest errors in the lung volume reduction surgery cohort for image sample sizes of five and 10 were 5.6 and 2.3 index percentage points at 8- to 10-mm section thickness (-900 HU threshold). Image sample errors were equivalent for the two sampling methods. CONCLUSION: Systematic sampling resulted in very small errors in emphysema quantification and may be useful for decreasing radiation exposure in clinical research studies of emphysema. PMID- 20173134 TI - Migrating azygos vein and vanishing azygos lobe: MDCT findings. AB - OBJECTIVE: The purpose of this study was to describe six cases of migrating azygos vein and to explain the etiologic factors that contribute to the migration. Six patients with migrating azygos vein were studied by MDCT before and after migration. Five patients had right pneumothorax. All patients had repeated episodes of cough, vomiting, and a short mesoazygos. CONCLUSION: Pneumothorax, increased intrathoracic pressure, and a short mesoazygos, in combination or alone, are the main factors in azygos vein migration. PMID- 20173135 TI - Dual-energy CT for assessment of the severity of acute pulmonary embolism: pulmonary perfusion defect score compared with CT angiographic obstruction score and right ventricular/left ventricular diameter ratio. AB - OBJECTIVE: The purpose of this study was to prospectively evaluate the usefulness of scoring perfusion defects on perfusion images at dual-energy CT for assessment of the severity of pulmonary embolism. SUBJECTS AND METHODS: Thirty patients (13 men, 17 women; mean age, 55 +/- 15 [SD] years; range, 26-81 years) with pulmonary thromboembolism underwent dual-source CT at two voltages (140 and 80 kV). The weighted average image of two acquisitions was used for CT angiograms, and a color-coded iodine image was used for perfusion images. Two thoracic radiologists with 15 and 6 years of clinical experience independently assigned perfusion defect scores to perfusion images and both a CT angiographic (CTA) obstruction score and right ventricular-to-left ventricular (RV/LV) diameter ratio to CT angiograms. The CTA obstruction score was based on the Qanadli method. The perfusion defect score was defined as Sigma (n . d) / 40 x 100, where n is the number of segments and d is the degree of perfusion from 0 to 2. Correlations between perfusion defect score, CTA obstruction score, and RV/LV diameter ratio were evaluated. Agreement between perfusion defect score and CTA score was assessed per patient and per segment. Interobserver agreement regarding perfusion defect and CTA obstruction scores was analyzed. RESULTS: Perfusion defect and CTA obstruction scores had good correlation with RV/LV diameter ratio (r = 0.69, r = 0.66; all p < 0.001). Per patient, correlation between perfusion defect score and CTA obstruction score also was good (reader 1, r = 0.87; reader 2, r = 0.85; all p < 0.001). Per segment, moderate agreement was found between perfusion defect score and CTA obstruction score (reader 1, kappa = 0.56; reader 2, kappa = 0.51; all p < 0.05). Both readers were in strong agreement on perfusion defect score and CTA obstruction score. CONCLUSION: The proposed perfusion defect score had good correlation with RV/LV diameter ratio and CTA obstruction score. Therefore, acquisition of perfusion images at dual-energy CT may be helpful for assessing the severity of acute pulmonary embolism. PMID- 20173136 TI - Resectability of pancreatic adenocarcinoma in patients with locally advanced disease downstaged by preoperative therapy: a challenge for MDCT. AB - OBJECTIVE: The purpose of this study was to determine whether preoperative neoadjuvant therapy in patients with locally advanced pancreatic cancer affects the ability of multiphasic MDCT to predict successful surgical resection. MATERIALS AND METHODS: From 2000 to 2006, there were 12 patients with prior neoadjuvant therapy successfully downstaged by CT and 31 age-matched pancreatic cancer patients without preoperative therapy who underwent pancreatic MDCT followed by attempted pancreaticoduodenectomy. Three readers blinded to surgical findings independently analyzed immediate preoperative MDCT scans of 43 patients comprising the retrospective data set in random order for vascular involvement (degree of contact and narrowing) and distant metastases. Individual reader sensitivity and specificity for resectability prediction were compared for study and control groups using the Fisher's exact test. Interobserver agreement was assessed using the kappa statistic. RESULTS: Seven (58%) of 12 neoadjuvant treated adenocarcinomas and 10 (32%) of 31 control pancreatic carcinomas were resectable (p > 0.05). For resectable disease, sensitivities were 86%, 71%, and 14% for the neoadjuvant group and 90%, 90%, and 60% for the control group (p > 0.05). Specificities were 80%, 100%, and 100% for the neoadjuvant group and 57%, 43%, and 76% for the control group (reader 2 specificity difference, p = 0.04). The multi rater kappa value of resectability prediction for neoadjuvant patients was 0.28, and that for control subjects was 0.63 (p < 0.001). In the neoadjuvant group, the majority of individual reader errors were false-negative resectability interpretations resulting from overestimation of vascular involvement. Consideration of degrees of venous abutment did not improve estimation of resectability in patients with neoadjuvant therapy. CONCLUSION: Sensitivity for prediction of resectability tends to be lower for patients with locally advanced pancreatic cancer that has been downstaged by neoadjuvant therapy, but this trend is not statistically significant. Interobserver variability for determination of resectability is statistically higher than for controls who did not receive preoperative therapy. PMID- 20173137 TI - Hepatic steatosis (fatty liver disease) in asymptomatic adults identified by unenhanced low-dose CT. AB - OBJECTIVE: The purpose of this study was to investigate the prevalence of hepatic steatosis in an asymptomatic U.S. adult population using attenuation values at unenhanced CT as the reference standard. We also assessed the utility of known clinical risk factors for diagnosis. MATERIALS AND METHODS: For 3,357 consecutive asymptomatic adults (1,865 women and 1,492 men; mean age, 57.0 years), hepatic and splenic CT attenuation values (Hounsfield units) were obtained by unenhanced CT using a low-dose colonography technique for colorectal cancer screening. Multiple attenuation criteria for steatosis were applied, including liver thresholds and comparison of liver and spleen attenuation. Relevant clinical risk factors were compared against a CT liver attenuation < or = 40 HU, which has been shown to exclude mild steatosis. RESULTS: Mean liver attenuation was 58.8 +/- 10.8 (SD) HU. The prevalence of moderate-to-severe hepatic steatosis (defined by liver attenuation < or = 40 HU) was 6.2% (208/3,357). For CT attenuation criteria that include milder degrees of steatosis, prevalence increased to as high as 45.9% (1,542/3,357) for a liver-to-spleen attenuation ratio of < or = 1.1. Overweight status (body mass index > 25) was a sensitive indicator for moderate to-severe steatosis (92.8%) but was highly nonspecific (37.5%). Other clinical risk factors, such as diabetes, dyslipidemia, hypertension, alcohol overuse, and hepatitis, were more specific (77.6-92.4%) but highly insensitive (1.9-37.5%). Combining clinical risk factors did not substantially increase the accuracy for screening. CONCLUSION: Assessment of liver attenuation by use of unenhanced CT represents an objective and noninvasive means for detection of asymptomatic hepatic steatosis, whereas clinical risk factor assessment is unreliable. Further longitudinal investigation is needed to determine the most appropriate attenuation threshold and the risk for disease progression to steatohepatitis and cirrhosis. PMID- 20173138 TI - Value of CT enteroclysis in suspected small-bowel carcinoid tumors. AB - OBJECTIVE: The purpose of this study was to evaluate the value of CT enteroclysis in depicting small-bowel carcinoid tumors in symptomatic patients with surgical, histologic, or clinical follow-up findings as a reference standard. SUBJECTS AND METHODS: At our institution, 44 patients with symptoms of suspected gastrointestinal carcinoid tumors underwent CT enteroclysis. Clinical symptoms were as follows: carcinoid syndrome (n = 3), abdominal pain with diarrhea (n = 24), hypervascular liver metastases (n = 7), subileus condition (n = 1), hypervascular peritoneal lesion (n = 3), abnormal ileal stenosis on optical colonoscopy (n = 3), and follow-up extraintestinal carcinoid lesion (n = 3). Positive CT enteroclysis findings were compared with pathology results after surgical procedures (n = 19). Negative examinations were compared with surgery results (n = 3) or clinical follow-up (n = 22). RESULTS: CT enteroclysis findings were positive in 19 patients and negative in 25 patients. The sizes of the carcinoid tumors identified were 5-30 mm in axial diameter. These tumors were depicted as focal nodular lesions located in the small-bowel wall or as intraluminal polypoid masses with marked enhancement. Twenty-two patients underwent only clinical follow-up, with a mean clinical follow-up time of 20 months. The overall sensitivity and specificity of CT enteroclysis in identifying patients with small-bowel carcinoid tumors were 100% and 96.2%, respectively. The negative predictive value of CT enteroclysis was 100% and the positive predictive value, 94.7%. Pathologic findings confirmed small-bowel carcinoid tumors in 18 patients. CONCLUSION: CT enteroclysis should be considered an excellent tool for the diagnosis of the carcinoid tumor before any surgical procedures. PMID- 20173139 TI - Liver MRI at 3 T using a respiratory-triggered time-efficient 3D T2-weighted technique: impact on artifacts and image quality. AB - OBJECTIVE: The purpose of this retrospective study was to qualitatively and quantitatively compare image quality of a time-efficient 3D T2-weighted sequence the sampling perfection with application-optimized contrasts using different flip angle evolutions (SPACE) sequence-with a standard 2D T2-weighted turbo spin-echo (TSE) sequence for liver imaging at 3 T. MATERIALS AND METHODS: Twenty patients underwent liver MRI at 3 T using T2-weighted breath-hold 2D TSE and respiratory triggered SPACE sequences. Two radiologists independently assessed image quality for both sequences during separate sessions, followed by a side-by-side comparison. One reader performed a quantitative analysis of the estimated signal to-noise ratio (SNR) and the relative contrast between the liver and other tissues. RESULTS: Image quality scores for the SPACE sequence were significantly better than those for the 2D TSE sequence for motion (p < 0.0001) and pulsation (p < 0.0001) artifact, flow signal suppression (p = 0.0015), sharpness of intrahepatic vessels (p < 0.0001), and sharpness of liver edge (p = 0.0015), with motion and pulsation artifacts being nearly eliminated using the SPACE sequence. However, the scores for B(1) inhomogeneity artifact were significantly worse for the SPACE sequence (p = 0.0117). Overall, both readers preferred SPACE sequence, although this difference was significant for only one reader (p = 0.025, p = 0.275). There was no significant difference between the sequences for estimated liver SNR (p = 0.1564), but the SPACE sequence showed significantly higher relative contrast between the liver and the kidney (p < 0.0001), gallbladder (p = 0.0476), and spleen (p < 0.0001). Relative contrast between the liver and parenchymal lesions was higher with the SPACE sequence than with the TSE sequence, although this difference was not statistically significant (p = 0.125). CONCLUSION: For T2-weighted liver imaging at 3 T, the respiratory-triggered SPACE sequence shows better image quality with near elimination of motion and pulsation artifacts and improved tissue contrast than the breath-hold 2D TSE sequence, but suffers from increased B(1) inhomogeneity artifact and longer scanning time. PMID- 20173140 TI - Radiologic and anatomic study of the extraperitoneal space associated with the rectum. AB - OBJECTIVE: The objective of our study was to clarify the anatomic and radiologic features of the extraperitoneal fasciae and fascial spaces associated with the rectum. MATERIALS AND METHODS: Fourteen embalmed cadavers were studied: two for gross anatomy; six for sectional anatomy, of which two underwent histologic study; and six for space perfusion study. These examinations were followed by CT and cross dissection to observe the pelvic extraperitoneal fasciae and the role of the fasciae in the anatomic subdivision and communication of the fascial spaces. Eighty healthy subjects underwent CT or MRI to identify the imaging characteristics of the pelvic fasciae. RESULTS: Cadaver dissection and histologic study revealed a distinct sheath consisting of dense connective tissue encasing the rectum and surrounding adipose tissue like a sleeve that divided the rectal extraperitoneal space into the perirectal space and pararectal space. Perfusion studies showed communication between the pararectal spaces and the vesical extraperitoneal space anteriorly and the anterior pararenal space superiorly, but not with the perirectal space. In healthy subjects, both CT (95.0%) and MRI (97.5%) showed a circular or linear structure representing the rectal fascia outside the rectum encasing the rectum and its surrounding adipose tissue. CONCLUSION: The extraperitoneal segment of the rectum and its surrounding adipose tissue are encased by a fascia, like a sleeve, that can be seen on CT and MRI in healthy populations. The fascia divides the rectal extraperitoneal space into the perirectal space and pararectal space, and it may prevent lesions of the rectum from spreading to other pelvic extraperitoneal spaces. PMID- 20173141 TI - Pseudoenhancement within the local ablation zone of hepatic tumors due to a nonlinear artifact on contrast-enhanced ultrasound. AB - OBJECTIVE: Pseudoenhancement of an avascular region on contrast-enhanced ultrasound often occurs within an echogenic region of a radiofrequency ablation zone due to nonlinear ultrasound propagation through intervening microbubble perfused tissue. The purpose of this study was to describe the imaging features of this artifact. MATERIALS AND METHODS: Twenty-six patients with no tumor recurrence within ablation zones were included. Two radiologists assessed contrast-enhanced ultrasound pseudoenhancement in the arterial (< 30 seconds), portal (30-90 seconds), and late (> 90 seconds) phases. If pseudoenhancement was present, the following information was recorded: the degree, time to first appearance, progression over time, and location. The corresponding gray-scale echogenicity (hypo-, iso-, or hyperechoic) and lesion depth were also noted. RESULTS: Fourteen lesions (14/26, 54%) showed pseudoenhancement on contrast enhanced ultrasound. Fourteen (100%) corresponded to the hyperechoic area within the ablation zone on gray-scale ultrasound and were nonmarginal in location. Pseudoenhancement occurred more frequently in deep lesions (> or = 5 cm) than in superficial lesions (< 5 cm) (p = 0.002). Pseudoenhancement was initiated most frequently in the portal phase (9/14, 64%), followed by the arterial phase (4/14, 29%) and late phase (1/14, 7%). Progression in the degree of pseudoenhancement was shown in most cases (12/14, 86%) and no washout was seen. CONCLUSION: Pseudoenhancement is frequently seen within ablation zones on contrast-enhanced ultrasound, particularly in deep echogenic lesions. However, pseudoenhancement follows enhancement of the parenchyma between the transducer and target. This observation is consistent with nonlinear propagation of the ultrasound beam, which increases with bubble concentration. Pseudoenhancement shows relatively late initiation, progression over time, and nonmarginal location; these findings are different from those seen in typical tumor recurrence, which shows early enhancement and washout at the margin of the ablation zone. PMID- 20173142 TI - MDCT of the abdomen: common misdiagnoses at a busy academic center. AB - OBJECTIVE: At our busy academic institution, we have noticed repeated examples of certain misdiagnoses, even by experienced abdominal imagers, both in our own department and at outside institutions. This is likely related to many factors. Discussed here are a variety of common diagnostic errors on body CT examinations. CONCLUSION: For each diagnostic error, we explore the reasons for the misdiagnosis and provide experience-based advice to avoid these mistakes. PMID- 20173143 TI - Pathways of extrapancreatic perineural invasion by pancreatic adenocarcinoma: evaluation with 3D volume-rendered MDCT imaging. AB - OBJECTIVE: The purpose of this article is to familiarize radiologists with the common pathways of extrapancreatic perineural invasion of pancreatic adenocarcinoma and to highlight the potential value of 3D volume-rendered MDCT in its diagnosis. CONCLUSION: The perineural plexuses closely follow peripancreatic vessels, which are well depicted by contrast-enhanced 3D volume-rendered imaging, thus facilitating the diagnosis of extrapancreatic perineural invasion of pancreatic adenocarcinoma. PMID- 20173144 TI - Differentiation of prostate cancer from normal prostate tissue: role of hotspots in pharmacokinetic MRI and histologic evaluation. AB - OBJECTIVE: The purpose of this study was to investigate whether analysis of voxels with the highest perfusion and blood volume (hotspots) within a whole region affected by prostate cancer can improve differentiation of cancerous and normal prostate tissue at pharmacokinetic MRI. SUBJECTS AND METHODS: Fifty-three patients with biopsy-proven prostate cancer were examined with 1.5-T MRI performed with endorectal and body phased-array coils and a dynamic contrast enhanced inversion-prepared dual-contrast gradient-echo sequence (temporal resolution, 1.65 seconds). Perfusion and blood volume maps were generated with a sequential three-compartment model. A total of 110 regions (62 prostate cancer, 48 normal prostate tissue) and their MRI perfusion and blood volume hotspots were analyzed and correlated with histologic mean vessel density and mean vessel area. RESULTS: In patients with prostate cancer, median perfusion in the entire region was 0.71 mL/cm(3)min(-1) (hotspot, 1.53 mL/cm(3)min(-1)) with a median blood volume of 1.06% (hotspot, 2.23%). In the corresponding histologic areas, median mean vessel density was 77 vessels/mm(2) (hotspot, 156 vessels/mm(2)) with a median mean vessel area of 1.61% (hotspot, 2.50%). In normal prostate tissue, median perfusion was 0.33 mL/cm(3)min(-1) (hotspot, 1.38 mL/cm(3)min(-1)) with a median blood volume of 0.62% (hotspot, 2.6%). In the corresponding histologic regions, median mean vessel density in the entire area was 57 vessels/mm(2) with a median mean vessel area of 1.21% (no hotspots). MRI perfusion in the entire region was the most suitable parameter for differentiating prostate cancer and facilitated correct classification in 61.8% of cases (blood volume hotspots, 58.2%; perfusion hotspots, 56.4%). CONCLUSION: In differentiation of cancerous and normal prostate tissue, use of perfusion in the entire region is superior to use of perfusion and blood volume in MRI hotspots. PMID- 20173145 TI - MRI in the characterization and local staging of testicular neoplasms. AB - OBJECTIVE: The purpose of this study was to assess the role of MRI in the preoperative characterization and local staging of testicular neoplasms. SUBJECTS AND METHODS: MRI was performed on 33 patients referred because a testicular mass had been detected clinically and sonographically. Both T1- and T2-weighted sequences were performed with a 1.5-T MRI unit. Gadolinium chelate was administered IV in all cases. We recorded the presence of a lesion and whether the histologic diagnosis of testicular malignancy could have been predicted on the basis of MRI features. For testicular neoplasms, local extension of disease was studied. The MRI findings were correlated with the surgical and histopathologic results. RESULTS: Histologic examination revealed 36 intratesticular lesions, 28 (78%) of which were malignant and eight benign. Thirteen malignant testicular tumors (46%) were confined within the testis, 12 (43%) had invaded the testicular tunicae or epididymis, and three (11%) had invaded the spermatic cord. The sensitivity and specificity of MRI in differentiating benign from malignant intratesticular lesions were 100% (95% CI, 87.9-100%) and 87.5% (95% CI, 52.9-97.7%). The rate of correspondence between MRI and histologic diagnosis in the local staging of testicular tumors was 92.8% (26/28). CONCLUSION: MRI is a good diagnostic tool for the evaluation of testicular disease. It is highly accurate in the preoperative characterization and local staging of testicular neoplasms. PMID- 20173146 TI - Role of CT in postoperative evaluation of patients undergoing urinary diversion. AB - OBJECTIVE: The purpose of this article is to discuss and illustrate the MDCT findings of potential complications after cystectomy and urinary diversion. CONCLUSION: Multiple complications may occur after urinary diversion. Tumor recurrence is a major concern in patients with bladder cancer. CT has an important role in postoperative evaluation of patients with urinary diversion to identify correctable causes early to prevent deterioration in renal function and detect tumor recurrence in patients who had bladder cancer. PMID- 20173147 TI - Who's underworked and who's overworked now? An update on radiologist shortage and surplus. AB - OBJECTIVE: The purpose of this study was to present an updated report on the radiologist surplus and shortage situation using a recently developed improved measure-namely, the extent to which radiologists desire less or more work if their income were to change by the same percentage as their workload. MATERIALS AND METHODS: Non-individually identifiable data from the American College of Radiology's (ACR's) 2007 Survey of Diagnostic Radiologists were used. Responses were weighted to be representative of all posttraining professionally active radiologists in the United States. Information is presented for all radiologists and according to such factors as type and size of practice, radiologist subspecialty, and geographic region. Multivariable regression analysis was used to identify the probable causal links between desired workload change and characteristics of radiologists and the practices where they work. Comparisons were made with ACR's similar 2003 Survey of Radiologists. RESULTS: The net average workload change sought in 2007 was an approximately 3% increase. In 2003, radiologists on average did not desire a statistically significant change in workload. Regression analysis for 2007 showed a pattern of relative shortages and surpluses that was generally, but not entirely, different from that found in 2003. CONCLUSION: The overall balance between the demand and the supply of radiologists shifted toward a surplus between 2003 and 2007. According to our measure, we judge there was a close balance in 2003, but a 3% surplus in 2007. The employment market seems generally, but not universally, to self-correct relative shortages and surpluses in individual geographic areas and subspecialties within a few years. PMID- 20173148 TI - Views of radiology program directors on the role of mentorship in the training of radiology residents. AB - OBJECTIVE: The successful mentoring of resident physicians has been linked to several beneficial outcomes for trainees including increased research productivity, improved career satisfaction, and retention in academics. Female residents may have greater difficulty establishing mentoring relationships than male residents. The purpose of this study was to assess the attitudes of radiology residency program directors toward the subject of mentorship, to determine the prevalence of formal mentoring programs, and to evaluate several issues specifically pertaining to the mentoring of female residents. MATERIALS AND METHODS: An anonymous, voluntary survey was sent to 156 members of the Association of Program Directors in Radiology. The survey assessed views on mentorship during residency training, the potential role of mentorship in resident career development, and the prevalence of mentorship programs in residency programs. Subanalyses evaluated survey responses according to program director sex. RESULTS: Seventy program directors (45%) responded to the survey. The majority of respondents (85%) agreed it is important for residents to have mentors, but only 52% thought that current residents had identified mentors. Compared with male program directors, female program directors differed in their views on the role of mentorship and of the importance of female resident access to female mentors. CONCLUSION: Program directors consider mentoring relationships to be an important resource for resident professional development and a potential resource to increase the proportion of residents pursuing academic careers and positions of leadership. Female residents may have specific mentoring needs that should be explored with further study. PMID- 20173149 TI - Acetabular labral tears and cartilage lesions of the hip: indirect MR arthrographic correlation with arthroscopy--a preliminary study. AB - OBJECTIVE: The purpose of this study was to assess the diagnostic correlation between indirect MR arthrography, conventional MRI, and arthroscopy in acetabular labral and cartilage lesions of the hip. MATERIALS AND METHODS: Fourteen patients who underwent conventional and indirect MR arthrography with arthroscopic correlation were studied over the course of 18 months. MR studies were performed on a 1.5-T magnet. Sequences consisted of unilateral sagittal turbo spin-echo proton density fat-suppressed, axial turbo spin-echo T2 fat-saturated, and coronal turbo spin-echo proton density fat-saturated images. Whole-pelvis coronal T1 and STIR sequences were also performed. Patients received IV gadolinium contrast material and exercised for 15 minutes. Gadolinium-enhanced fat-saturated T1 sequences were obtained in three planes. Arthroscopy was performed by two orthopedic surgeons who specialize in treating hip disorders. Cases were then retrospectively reviewed by two experienced musculoskeletal radiologists who were blinded to the arthroscopic findings. Cases were examined for acetabular labral tears and chondral lesions. Extraarticular findings of femoral acetabular impingement were recorded. Unenhanced and gadolinium-enhanced images of the labrum were compared for differences and changes in diagnosis. Comparison was made between the arthroscopic and MR findings for analysis of the results. RESULTS: Of the 13 labral tears found at arthroscopy, 85% were detected by conventional MRI, whereas 100% were identified via indirect MR arthrography. Seventy percent of the labral tears identified on conventional MRI were better delineated by indirect MR arthrography. Identification of chondral abnormalities was not improved via indirect MR arthrography over conventional MRI. CONCLUSION: IV contrast-enhanced indirect MR arthrography appears to be an effective means of hip evaluation for labral tears. It does not appear to improve detection of cartilage abnormalities when compared with conventional MRI. PMID- 20173150 TI - The role of dynamic contrast-enhanced MRI in the differential diagnosis of psoriatic and rheumatoid arthritis. AB - OBJECTIVE: The purpose of this study was to investigate the role of dynamic contrast-enhanced MRI in the differential diagnosis of psoriatic and rheumatoid arthritis in the hand and wrist. SUBJECTS AND METHODS: Forty-five consecutive patients (31 patients with rheumatoid arthritis and 14 patients with psoriatic arthritis) were examined in a 3-T whole-body MR unit. After contrast injection, a 3D encoded spoiled gradient-echo sequence was used for measurement of the time course of contrast-medium uptake in the synovial tissue. On the basis of the gained uptake curves, the rate of early enhancement was calculated after 35 and 52 seconds, and the relative enhancement rate was calculated after 35 seconds, 52 seconds, 3 minutes, and 15 minutes (late enhancement). Dynamic contrast-enhanced MRI rates of patients with rheumatoid arthritis and psoriatic arthritis were compared and correlated with laboratory and clinical data. RESULTS: A statistically significant difference between the two groups was found regarding the relative enhancement rate after 15 minutes (p < 0.01). In contrast, no difference in relative enhancement rate was found 35 seconds, 52 seconds, or 3 minutes after contrast injection (p = 0.695, p = 0.573, and p = 0.278, respectively). Regarding the rate of early enhancement at 35 and 52 seconds, no significant difference between patients with rheumatoid arthritis and those with psoriatic arthritis was found. Significant correlations were found between inflammatory parameters and dynamic contrast-enhanced parameters in patients with rheumatoid arthritis but not in those with psoriatic arthritis. CONCLUSION: Fifteen minutes after contrast injection, a statistically significant difference between rheumatoid arthritis and psoriatic arthritis was found in synovial enhancement that might play an important role in differentiating the two diseases. PMID- 20173151 TI - Analysis of the patellofemoral region on MRI: association of abnormal trochlear morphology with severe cartilage defects. AB - OBJECTIVE: The objective of our study was to assess patellofemoral measurements on MRI and to correlate the measurements with different grades of cartilage defect. MATERIALS AND METHODS: Axial and sagittal MR images of 100 patients with various pathologic knee conditions were analyzed. The patients were divided into two age groups: < 40 years and > or = 40 years. Patellar measurements of facet asymmetry, the patella-to-patellar tendon ratio, and the amount of patellotrochlear cartilage overlap were obtained in each subject. Similarly, trochlear measurements of the ventral trochlear prominence, trochlear depth, facet asymmetry, sulcus angle, and lateral inclination were obtained. Axial and sagittal MR images were reviewed to grade the severity of focal cartilage defects in the patellofemoral region on the basis of the depth of the lesion. Measurements in knees without a chondral defect were compared with knees with mild and severe chondral defects. RESULTS: There was a statistically significant difference in the trochlear measurements of the ventral prominence (p = 0.012), trochlear depth (p = 0.001), sulcus angle (p = 0.208), and lateral inclination (p = 0.154) between normal knees and knees with severe cartilage defects in patients younger than 40 years. No significant difference was seen in the patellar measurements between normal knees and knees with severe cartilage defects. CONCLUSION: There is an association between abnormal trochlear morphology and severe patellofemoral cartilage defects in patients younger than 40 years. PMID- 20173152 TI - Relationship between fatty degeneration of thigh muscles and vitamin D status in the elderly: a preliminary MRI study. AB - OBJECTIVE: The purpose of this study was to study the relationship between fatty degeneration of thigh muscles and vitamin D status in elderly adults. SUBJECTS AND METHODS: For six months, 121 patients 65 years old or older were evaluated. Myopathy, muscular impairment, and conditions influencing vitamin D status other than diet and sunlight were exclusion criteria. Twenty patients (10 men and 10 women; mean age, 77.6 years) underwent MRI. Thigh muscles were scanned from the hip to the knee with T1- and T2-weighted spin-echo sequences. Skeletal muscles were evaluated for fatty degeneration and atrophy from grade 0 to 3 (grade 0 = normal appearance, grade 3 = severe changes). The relationship between muscular fatty degeneration, 25-hydroxyvitamin D (25-OHD) levels, and scores on Tinetti scales for balance and gait were examined. RESULTS: In the evaluation of the extensor muscles for fatty degeneration and atrophy, grade 0 was present in three patients (15%), grade 1 in 11 (55%), and grade 2 in six (30%). In the flexor muscles, grade 0 was found in one patient (5%), grade 1 in five (25%), and grade 2 in 14 (70%); grade 3 changes were not seen. Muscular fatty degeneration negatively correlated with 25-OHD levels (r = -0.50, p < 0.01) and the Tinetti scores (balance: r = -0.40, p < 0.05; gait: r = -0.50, p < 0.05). In 11 vitamin D deficient patients (55%), there was selective complete atrophy of at least one thigh muscle. The gracilis and sartorius muscles were spared. CONCLUSION: In elderly adults, fatty degeneration of thigh muscles was associated with vitamin D deficiency and impaired balance and gait. Selective complete fatty degeneration of single muscles was observed. PMID- 20173153 TI - Locoregional spread of cutaneous melanoma: sonography findings. AB - OBJECTIVE: This article reviews various aspects of locoregional spread of malignant cutaneous melanoma, as imaged with gray-scale sonography and Doppler techniques. The scenarios illustrated include disease staging (primary melanoma, satellite metastasis, in-transit metastasis, and lymphadenopathies), sentinel lymph node biopsy procedure, patient follow-up, recurrence detection, cutaneous metastasis, and sonographically guided intervention. CONCLUSION: High-resolution sonography allows recognition of small, clinically-occult melanomatous foci. It plays a major role in locoregional staging and follow-up of patients with cutaneous melanoma. PMID- 20173154 TI - Patterns of soft-tissue tumor extension in and out of the pelvis. AB - OBJECTIVE: The purpose of this article is to present the route of extension in nine soft-tissue tumors and tumorlike lesions of the pelvic wall. CONCLUSION: Soft-tissue tumors of the pelvis, particularly malignant ones, extend into other compartments through specific pathways that are bordered by bones, ligaments, and fasciae. Such pathways include the greater sciatic foramen, the obturator foramen, the femoral canal, the muscular lacuna, the pelvic outlet, and the inguinal canal. PMID- 20173156 TI - Evaluation of 188Re-DTPA-deoxyglucose as a potential cancer radiopharmaceutical. AB - OBJECTIVE: We aimed to synthesize diethylenetriamine pentaacetic acid deoxyglucose (DTPA-DG) radiolabeled with (188)Re and to evaluate its biologic characteristics using mammary tumor-bearing mice. MATERIALS AND METHODS: The biodistribution of the radiolabeled compound was determined by tissue counting at 3, 12, and 24 hours after injection in experimental animals. Scintigraphic examinations of nude mice bearing breast cancer (MCF-7 cells) were performed after (188)Re-DTPA-DG (18.5 MBq) was injected in the tail vein. For the tumor inhibitory portion of this work, tumor volumes were measured and recorded every 3 days until the 21st day after injection. RESULTS: The radiochemical purity of (188)Re-DTPA-DG was 95.0%. Based on biodistribution measurements, (188)Re-DTPA-DG was taken up at high levels by the tumor. The mean tumoral percent injected dosages per gram (% ID/g) were 1.98 +/- 0.29 (SD), 2.89 +/- 0.43, and 0.42 +/- 0.06 % ID/g at 3, 12, and 24 hours, respectively, after injection. In the (188)Re DTPA-DG scintigraphic examinations, the tumors were clearly delineated on the images recorded 2, 4, 8, 12, and 24 hours after injection. In the tumor inhibitory evaluations, the tumor volume of the (188)Re-DTPA-DG-treated group increased more slowly than that of the control groups, which were treated with (188)Re-perrhenate or saline (p < 0.01). Rhenium-188-DTPA-DG showed excellent tumor targeting and tumor growth suppression properties on MCF-7 tumor cells. CONCLUSION: Rhenium-188-DTPA-DG may be a potential agent for the diagnosis and radiotherapy of tumors. PMID- 20173155 TI - CT and MRI findings of human herpesvirus 6-associated encephalopathy: comparison with findings of herpes simplex virus encephalitis. AB - OBJECTIVE: It is important to differentiate human herpesvirus 6 (HHV-6) associated encephalopathy from herpes simplex encephalitis (HSE). Although these conditions are similar with regard to involvement of the mesial temporal lobe, HSE is sensitive to acyclovir but HHV-6 encephalopathy is not. We compared the imaging findings of the two conditions. MATERIALS AND METHODS: We encountered eight cases of HHV-6 encephalopathy and nine cases of HSE. We divided an observation time into early, middle, and late periods defined as 0-2, 3-30, and more than 30 days from the onset of neurologic symptoms. Differences between HHV 6 encephalopathy and HSE on CT scans in the early period and in distribution and temporal changes in the affected regions on MR images in the three periods were analyzed. RESULTS: At MRI in the early and middle periods, all eight patients with HHV-6 encephalopathy had exclusive involvement of the mesial temporal lobes, and all nine patients with HSE had involvement of both the mesial temporal lobes and the extratemporal regions (p < 0.01). Among patients who underwent head MRI, six of six with HHV-6 encephalopathy but none of six with HSE had resolution of high signal intensity on T2-weighted and FLAIR images (p < 0.01). Among patients who underwent head CT in the early period, none of the four with HHV-6 encephalopathy and six of the seven with HSE had abnormal findings, including parenchymal swelling, decreased attenuation of affected regions, and abnormal gyral enhancement (p < 0.05). CONCLUSION: Serial MRI showed transient abnormal signal intensity in the mesial temporal lobes in patients with HHV-6 encephalopathy but persistent abnormal signal intensity in both the mesial temporal lobes and the extratemporal regions in patients with HSE. CT in the early period showed no abnormality in patients with HHV-6 encephalopathy but definite abnormal findings in patients with HSE. These differences may be useful in the differential diagnosis of the two conditions. PMID- 20173157 TI - Assessment of tumor recurrence in patients with colorectal cancer and elevated carcinoembryonic antigen level: FDG PET/CT versus contrast-enhanced 64-MDCT of the chest and abdomen. AB - OBJECTIVE: The purpose of this study was to compare FDG PET/CT and contrast enhanced 64-MDCT of the chest, abdomen, and pelvis in the detection of tumor recurrence in patients with colorectal cancer and an elevated level of carcinoembryonic antigen (CEA). MATERIALS AND METHODS: A retrospective analysis included 50 patients (31 men, 19 women; mean age, 61 years; range, 28-89 years) with 55 clinical events of elevated or increasing CEA level who underwent FDG PET/CT and MDCT for suspected tumor recurrence. RESULTS: Recurrent or metastatic disease was found in 36 of 55 events (65.5%) of elevated CEA. Fifty-four of 61 tumor sites suspected as tumor recurrence with any imaging technique were found to be local recurrence or metastatic colorectal cancer at final analysis. The other seven sites were one separate malignant tumor (small lymphocytic lymphoma) and six benign lesions. Diagnosis was based on histopathologic findings (n = 27) or clinical and imaging findings (n = 35) during a median follow-up period of 12 months (range, 6-31 months). One site of tumor recurrence was missed prospectively at both MDCT and PET/CT. On an event-based analysis, the sensitivity of PET/CT and MDCT was 97.3% and 70.3% (p = 0.002); the specificity of both techniques was 94.4% (p = 1.0). In a tumor site-based analysis, the sensitivities of PET/CT and MDCT were 98.1% and 66.7% (p < 0.0001), and the specificities were 75% and 62.5% (p = 0.56). Tumors correctly identified with PET/CT and missed with MDCT were local recurrence in the presacral space (n = 5), metastatic subcentimeter lymph nodes (n = 4), peritoneal deposits (n = 3), and recurrences at the periphery of radiofrequency ablated metastatic lesions of the liver (n = 2) and in the abdominal wall (n = 1), liver (n = 1), and uterine cervix (n = 1). CONCLUSION: FDG PET/CT has higher sensitivity than MDCT in the identification of sites of recurrent and metastatic disease in patients with colorectal cancer and an elevated CEA level. The two techniques appear to have similar specificity. PMID- 20173158 TI - CT characteristics of lung nodules present at diagnosis of extrapulmonary malignancy in children. AB - OBJECTIVE: The purpose of this study was to evaluate the CT characteristics of lung nodules present at diagnosis of extrapulmonary malignancies in children. MATERIALS AND METHODS: We performed a retrospective analysis of CT images of children seen in our oncology service over a 6-year period. We included all children diagnosed with a non-CNS solid extrapulmonary malignancy or lymphoma who had also undergone chest CT at presentation. Images were reviewed for the presence of lung nodules; if present, the following nodular characteristics were recorded: sidedness, number, distribution, CT attenuation, shape, margins, calcification, and size. When available, pathology results were correlated with the nodules found on CT. RESULTS: One hundred eleven infants and children (age range, 14 days-17 years 10 months; median age, 11 years 8 months) had lung nodules on CT. The nodules showed a variety of patterns, but the most common findings were bilateral lung nodules (71 of 111 patients), between two and 10 in number (60 patients), peripheral distribution (98 patients), < or = 5 mm (48 patients), oval shape (45 patients), solid attenuation (74 patients), smoothly marginated (91 patients), and noncalcified (107 patients). Twenty-seven patients underwent biopsy. Seventeen biopsies showed benign lesions and nine, malignant lesions; the results for the remaining biopsy were inconclusive. In the subgroup of lung nodules that underwent biopsy, none of the CT characteristics was able to differentiate benignity from malignancy. CONCLUSION: Lung nodules in children with extrapulmonary malignancies showed a variety of patterns on CT. In the subgroup of lung nodules that underwent biopsy, none of the nodule features studied on CT reliably differentiated benignity from malignancy. PMID- 20173159 TI - Hydrodisplacement in the percutaneous cryoablation of 50 renal tumors. AB - OBJECTIVE: The purpose of this article is to describe the technique, safety, and effectiveness of percutaneous hydrodisplacement during the course of percutaneous renal cryoablation. MATERIALS AND METHODS: We retrospectively reviewed our experience in performing percutaneous hydrodisplacement during the cryoablation of renal tumors. In this subset of patients, we addressed tumor location within the kidney, tumor position relative to critical structures, effectiveness of hydrodisplacement, and complications in performing this adjunct technique. Comparisons between the two groups were made using Wilcoxon's rank sum test or chi-square test, as appropriate. RESULTS: Hydrodisplacement was attempted 52 times in 50 (24%) of 206 percutaneous renal tumor cryoablations. Tumors that were located anteriorly (p < 0.0001) or in the lower pole (p = 0.001) of the kidney were more likely to require hydrodisplacement. The colon required displacement most often (n = 41), followed by the body wall (n = 3), duodenum (n = 2), jejunum and ileum (n = 2), ureter (n = 1), and psoas muscle (n = 1). There was a single complication of hemorrhage resulting from injury to an intercostal artery branch that required termination of the procedure before fluid infusion. When fluid was infused, the critical structure was displaced in 50 (96%) of 52 attempts, displacing the critical structure from its initial location by a mean distance of 16 mm (range, 3-46 mm). Both failures occurred early in our experience with hydrodisplacement, and both required balloon displacement. CONCLUSION: Hydrodisplacement is a safe, effective, and commonly needed technique for displacement of critical structures before percutaneous cryoablation of renal tumors, particularly for tumors located anteriorly or in the lower pole of the kidney. PMID- 20173160 TI - Incidence of bleeding after 15,181 percutaneous biopsies and the role of aspirin. AB - OBJECTIVE: The objective of our study was to report the incidence of bleeding after imaging-guided percutaneous core biopsy at a single center using a standardized technique. MATERIALS AND METHODS: We performed a retrospective review of percutaneous core biopsies performed at our institution from January 2002 through February 2008. Data were collected at the time of biopsy, and clinical information was obtained 24 hours and 3 months after the biopsy. The specific information that was collected included the results of coagulation studies, aspirin use, the organ biopsied, the size of the biopsy needle, and the number of needle passes. Bleeding complications were defined using the Common Terminology Criteria for Adverse Events (CTCAE, version 3.0) established by the National Cancer Institute. RESULTS: Among the 15,181 percutaneous core biopsies performed during the study period, 70 hemorrhages (0.5%) that were CTCAE grade 3 or greater were identified within 3 months of biopsy. The incidence of bleeding in patients taking aspirin within 10 days before biopsy was 0.6% (18/3,195), which was not statistically different compared with the incidence of bleeding in those not taking aspirin (52/11,986, 0.4%; p = 0.34). The incidence of bleeding after liver biopsy was 0.5%; kidney biopsy, 0.7%; lung biopsy, 0.2%; pancreas biopsy, 1.0%; and other biopsy, 0.2%. There were significant associations between major bleeding and serum platelet count and international normalized ratio (p < 0.001), although the association between major bleeding and the size of the biopsy needle was not significant (p = 0.97). CONCLUSION: The overall incidence of major bleeding after imaging-guided percutaneous core needle biopsy is low. Recent aspirin therapy does not appear to significantly increase the risk of such bleeding complications. PMID- 20173161 TI - MRI after technically successful renal cryoablation: early contrast enhancement as a common finding. AB - OBJECTIVE: The purpose of this study was to assess the MRI appearance and enhancement of renal masses within 36 hours after cryoablation. MATERIALS AND METHODS: From March 2003 through January 2008, 129 patients underwent imaging guided cryoablation for renal masses. Twenty-three of these patients underwent MRI within 36 hours after ablation. During MRI, acquisition of axial T1- and T2 weighted images was followed by administration of a gadolinium contrast agent. Standard follow-up included MRI 3-6 months after ablation. RESULTS: Eight of the 23 renal masses imaged within 6-36 hours after ablation were enhanced on MR images. Five of the eight lesions exhibited homogeneous enhancement, and the other three had heterogeneous or rim enhancement. Seven of the eight lesions exhibited no enhancement at the 6-month follow-up examination. One patient underwent follow-up imaging 10 months rather than 3-6 months after the procedure, but no enhancement was seen. T2-weighted signal intensity was mixed among the 23 renal masses. T1-weighted signal intensity was mixed among the 23 renal masses and the eight lesions that became enhanced, but there was a trend for higher T1 signal intensity at the 3- to 6-month follow-up examination. CONCLUSION: The high proportion of enhancing lesions 3 months after treatment and the resolution of enhancement 6 months afterward suggest that it may be reasonable to wait 6 months after technically successful renal cryoablation before performing contrast enhanced MRI. PMID- 20173162 TI - Nonenhanced free-breathing ECG-gated steady-state free precession 3D MR angiography of the renal arteries: comparison between 1.5 T and 3 T. AB - OBJECTIVE: The purpose of our study was to compare the image quality of free breathing ECG-gated nonenhanced steady-state free precession (SSFP) MR angiography of renal arteries at 1.5 T and 3 T. SUBJECTS AND METHODS: Twenty volunteers (11 men, nine women; mean age, 23.2 +/- 2.3 years) without a history of renovascular disease participated in the study. Nonenhanced SSFP MR angiography was performed on all subjects at both 1.5 T and 3 T with a maximum interval of 2 weeks between the imaging sessions. The subjective image quality of axial and coronal maximum-intensity-projection reconstructions of four segments (1, abdominal aorta and ostium of renal artery; 2, main renal artery; 3, segmental branches outside renal parenchyma; 4, segmental branches inside renal parenchyma) was evaluated independently by two radiologists using a 4-point scale (4, excellent; 1, nondiagnostic). Relative signal-to-noise ratio, contrast-to noise ratio, and maximum visible vessel length of the right and left renal arteries also were determined. RESULTS: No significant difference in image quality at 1.5 T and 3 T was found for segments 1 and 2. The mean image quality for segments 3 and 4 was significantly greater at 3 T (3.88 +/- 0.32, 3.17 +/- 0.70) than at 1.5 T (3.32 +/- 0.73, 2.09 +/- 0.81) (p < 0.001). At 3 T, the maximal vessel length of the right (9.85 +/- 0.82 cm) and left (8.3 +/- 0.79 cm) renal arteries was significantly greater than at 1.5 T (8.94 +/- 1.38 cm and 7.58 +/- 1.18 cm, respectively). CONCLUSION: Performing nonenhanced SSFP MR angiography at 3 T significantly improves visualization of peripheral renal arterial segments in healthy subjects as compared to 1.5 T. PMID- 20173164 TI - Incidence of and risk factors for pneumothorax and chest tube placement after CT fluoroscopy-guided percutaneous lung biopsy: retrospective analysis of the procedures conducted over a 9-year period. AB - OBJECTIVE: The objective of our study was to retrospectively evaluate the incidence of and the risk factors for pneumothorax and chest tube placement after CT fluoroscopy-guided lung biopsy. MATERIALS AND METHODS: We analyzed 1,098 CT fluoroscopy-guided lung biopsies conducted with 20-gauge coaxial cutting needles for 1,155 lesions in 1,033 patients. Apart from evaluating the incidence of pneumothorax and chest tube placement, the independent risk factors for pneumothorax and chest tube placement for pneumothorax were determined using multivariate logistic regression analysis. RESULTS: The overall incidence of pneumothorax was 42.3% (464/1,098). Chest tube placement was required for 11.9% (55/464) of pneumothoraces (5.0% [55/1,098] of the total number of procedures). The significant independent risk factors for pneumothorax were no prior pulmonary surgery (p = 0.001), lesions in the lower lobe (p < 0.001), greater lesion depth (p < 0.001), and a needle trajectory angle of < 45 degrees (p = 0.014); those for chest tube placement for pneumothorax were pulmonary emphysema (p < 0.001) and greater lesion depth (p < 0.001). CONCLUSION: Pneumothorax frequently occurred and placement of a chest tube was occasionally required for pneumothorax after CT fluoroscopy-guided lung biopsy. To reduce the risk of pneumothorax necessitating chest tube placement, physicians should adopt the shortest needle path to the lesion. PMID- 20173165 TI - Management of abdominal and pelvic abscesses that persist despite satisfactory percutaneous drainage catheter placement. AB - OBJECTIVE: The purposes of this study were to determine the frequency with which percutaneous abdominopelvic abscess drainage catheters must be replaced because of inadequate drainage, to assess the effect of percutaneous catheter exchange on clinical outcome, and to determine the predictors of clinical success after catheter exchange. MATERIALS AND METHODS: A database of interventional radiology procedures performed at a single tertiary care hospital from 2001 to 2006 was searched to identify the cases of patients who underwent percutaneous catheter drainage of abdominal or pelvic abscesses that was followed by exchange of the drainage catheter at a later date. The electronic medical records and imaging studies of these patients were retrospectively reviewed to determine the abscess characteristics, details of drainage catheter manipulation, and clinical outcome. RESULTS: Among the 3,027 percutaneous abscess drainage catheters placed, 82 were exchanged because of lack of improvement (imaging evidence of undrained fluid and persistent fever and leukocytosis), for an overall frequency of catheter exchange of 2.7% of abscesses in 3.7% of patients. The success rate of catheter replacement, defined as resolution of the fluid collection without open surgical drainage, was 76.8% (63/82). Prognostic factors favorably influencing the clinical success of catheter exchange included a larger number of drainage catheter sideholes, absence of a fistula, low residual abscess volume after initial catheter drainage, and low CT attenuation of abscess fluid. CONCLUSION: In cases of persistent abscess despite adequate catheter placement, percutaneous catheter exchange over a wire is useful for salvage after the large majority of primary failures. In addition, performance of CT and fluoroscopic catheter injection before catheter exchange facilitates recognition of the predictors of a likely response to catheter exchange. PMID- 20173163 TI - Prospective analysis of the pattern and risk for severe vital sign changes during percutaneous radiofrequency ablation of the liver under opioid analgesia. AB - OBJECTIVE: The aims of this study were to evaluate the pattern of vital sign changes and to elucidate significant risk factors for severe cardiovascular inhibition caused by percutaneous hepatic radiofrequency ablation (RFA). SUBJECTS AND METHODS: A total of 102 patients (male-to-female ratio, 73:29; age range, 35 85 years; mean age, 58.1 years) with 119 malignant hepatic tumors were enrolled and analyzed prospectively. The patients underwent percutaneous RFA with IV infusion of opioid analgesics. Changes in blood pressure (BP) and heart rate (HR) and the occurrence of significant cardiovascular inhibition (BP or HR < 70% of baseline) were monitored during the procedure. Respiratory rate and skin body temperature were recorded before and after the procedure. RESULTS: Whereas the mean BP was elevated (36%, 43/119) or depressed (36%, 43/119) with a similar frequency, the HR was predominantly depressed (56%, 66/119) during the procedure. The BP and HR were stable in only 18% cases (21/119), respectively. The respiratory rate showed no significant change (p = 0.521) after RFA; however, body temperature decreased (p < 0.001) after RFA. Although significant cardiovascular inhibition occurred in 41 cases (35%), all of the cases could be managed successfully and the technical success rate was 100% (119/119). Among the risk factors analyzed, old age (B = -0.003, p = 0.019) was significant for systolic BP depression, and contact of the RFA zone with the central portal vein (B = -0.096, p = 0.014) and female sex (B = -0.078, p = 0.033) were significant risk factors for HR depression as determined by multivariate analysis. CONCLUSION: Changes in BP and HR, especially bradycardia, are common during percutaneous RFA of hepatic lesions. Significant risk factors for severe cardiovascular inhibition include contact of the RFA zone with the branches of the central portal vein, old age, and female sex. PMID- 20173166 TI - Contrast material for abdominal dynamic contrast-enhanced 3D MR angiography with parallel imaging: intraindividual equimolar comparison of a macrocyclic 1.0 M gadolinium chelate and a linear ionic 0.5 M gadolinium chelate. AB - OBJECTIVE: The purpose of this study was to compare a macrocyclic 1.0 M contrast agent with a linear ionic 0.5 M contrast agent at equimolar dosage in regard to image quality and number of vessel segments visualized at abdominal dynamic contrast-enhanced 3D MR angiography. SUBJECTS AND METHODS: In an intraindividual comparative study, 15 patients (six women, nine men; mean age, 53 +/- 12.1 years; range, 25-72 years) underwent 32 1.5-T whole-body contrast-enhanced 3D MR angiographic examinations performed with parallel imaging technique. At random and in separate sessions, each patient was examined after IV injection of 0.1 mmol/kg body weight 1.0 M macrocyclic gadobutrol and 0.5 M linear ionic gadopentetate dimeglumine. Three-dimensional data sets were acquired in the arterial, portal venous, and venous phases with identical imaging protocols. Quantitative analysis included contrast measurements of vessels compared with adjacent background tissue (Student's t test). Qualitative analysis was performed independently by two radiologists with regard to visualization of arterial and venous vessel segments and overall image quality (Wilcoxon's test). RESULTS: Visualization of individual vessel segments was rated significantly better after administration of 1.0 M macrocyclic gadobutrol compared with 0.5 M linear ionic gadopentetate dimeglumine (p < 0.001). Overall image quality was superior with 1.0 M macrocyclic gadobutrol, but the difference was not significant. Vessel-to background contrast after injection of 1.0 M macrocyclic gadobutrol was significantly higher (arterial phase, 0.90, p = 0.02; portal venous phase, 0.78, p = 0.0002; venous phase, 0.74, p = 0.0002) compared with 0.5 M linear ionic gadopentetate dimeglumine (arterial phase, 0.89; portal venous phase, 0.73; venous phase, 0.67). CONCLUSION: At abdominal contrast-enhanced 3D MR angiography, depiction of small abdominal vessels was significantly better and vessel-to-tissue contrast significantly higher with 1.0 M macrocyclic gadobutrol than with an equimolar dose of 0.5 M linear ionic gadopentetate dimeglumine. PMID- 20173167 TI - Overall survival after transarterial lipiodol infusion chemotherapy with or without embolization for unresectable hepatocellular carcinoma: propensity score analysis. AB - OBJECTIVE: Although iodized oil transarterial chemoembolization (TACE) has been found to have survival benefit in the care of patients with unresectable hepatocellular carcinoma, iodized oil infusion chemotherapy without embolization has not been clearly found inferior to or equal to TACE. The purpose of this study was to determine whether one of these therapies is superior to the other or the two are equal in survival benefit and whether embolization with gelatin sponge particles is indispensable to prolonging survival. SUBJECTS AND METHODS: A prospective nonrandomized observational cohort study was conducted over 8 years. Among 11,030 patients with unresectable hepatocellular carcinoma, 8,507 underwent TACE, and 2,523 underwent transarterial infusion therapy with an emulsion of iodized oil and an anticancer agent as initial treatment. Patients with extrahepatic metastasis or any previous treatment were excluded. The primary end point was all-cause mortality. To minimize selection bias, propensity score analysis was used to compare the two groups. RESULTS: During the follow-up period, 5,044 patients (46%) died. In the analysis of all patients, TACE was associated with a significantly higher survival rate than infusion therapy without embolization (hazard ratio, 0.60; 95% CI, 0.56-0.64; p = 0.0001). The propensity score analysis showed that the hazard ratio for death in the TACE group (n = 1,699 patients) compared with the group who underwent infusion therapy without embolization (n = 1,699) was 0.70 (95% CI, 0.63-0.76; p = 0.0001). The median survival time of the TACE group was 2.74 years, and the 1-, 3-, and 5-year survival rates were 81%, 46%, and 25%. The corresponding values for the group who underwent transarterial infusion therapy without embolization were 1.98 years and 71%, 33%, and 16%. CONCLUSION: Propensity score analysis showed that in the treatment of patients with unresectable hepatocellular carcinoma, TACE was associated with significantly better overall survival rates than was transarterial infusion therapy without embolization. TACE can be recommended as initial treatment of these patients. PMID- 20173168 TI - Arteriovenous fistula and graft evaluation in hemodialysis patients using MDCT: a primer. AB - OBJECTIVE: Patent arteriovenous fistula (AVF) is related to better prognosis and quality of life for patients on long-term dialysis. When AVF dysfunction is suspected, MDCT is a good noninvasive tool for evaluating the entire AVF structure and determining reversible conditions for treatment. The aim of this article is to introduce the scanning and interpretation techniques and to illustrate the conditions related to early and late fistula failures. CONCLUSION: MDCT is a fast, noninvasive, and accurate technique for diagnosing AVF complications. Radiologists familiar with these techniques can help to improve the prognosis and quality of life for hemodialysis patients. PMID- 20173169 TI - Imaging of primary and secondary inflammatory diseases involving large and medium sized vessels and their potential mimics: a multitechnique approach. AB - OBJECTIVE: The purpose of this article is to illustrate multitechnique imaging findings in patients with primary and secondary vasculitides involving large and medium-sized vessels and their mimics. CONCLUSION: Large and medium-sized vessels are affected by many primary and secondary inflammatory disorders or mimicking conditions, often presenting similar imaging characteristics. Knowledge of distinctive imaging features such as location, length, and degree of vessel wall enhancement as well as the particular clinical settings will help the clinician in appropriately narrowing down the differential diagnosis. PMID- 20173170 TI - Difficulty accepting a terminal prognosis linked with depression, anxiety, and suffering. PMID- 20173171 TI - New joint outpatient chemotherapy administration standards. PMID- 20173172 TI - Evaluating the older patient with cancer: understanding frailty and the geriatric assessment. AB - The majority of cancer incidence and mortality occurs in individuals aged older than 65 years, and the number of older adults with cancer is projected to significantly increase secondary to the aging of the US population. As such, understanding the changes accompanying age in the context of the cancer patient is of critical importance. Age-related changes can impact tolerance of anticancer therapy and can shift the overall risk-benefit ratio of such treatment. A challenge in implementing evidence-based approaches in older adults is the under representation of this group in oncology clinical trials. In addition, although older adults are particularly vulnerable to the side effects of cancer therapy, few oncology studies to date have incorporated a measure of health status other than the Eastern Cooperative Oncology Group or Karnofsky performance scales. Novel metrics such as frailty indices or the geriatric assessment recognize heterogeneity among older adults, and may allow for risk-adapted approaches to therapy. It is increasingly recognized that several laboratory markers may predict morbidity and mortality in older adults; these biologic variables may further aid in stratifying this group of patients based on risk. This review describes key studies from the geriatric literature that provide principles for assessing health status in the older patient, and ways that these principles can be applied to oncology care in an older population are proposed. PMID- 20173173 TI - Radiographic evaluation of scoliosis: self-assessment module. AB - OBJECTIVE: The educational objectives for this self-assessment module are for the participant to exercise, self-assess, and improve his or her understanding of evaluation of scoliosis using radiography. CONCLUSION: The solutions to the questions in this activity review the imaging characteristics of radiologic evaluation of scoliosis. PMID- 20173174 TI - Congenital spine and spinal cord malformations--pictorial review. PMID- 20173175 TI - Congenital spine and spinal cord malformations--self-assessment module. AB - The educational objectives of this self-assessment module are for the participants to exercise, self-assess, and improve their understanding of the most important features of congenital spine and spinal cord malformations. PMID- 20173176 TI - Topics in pediatric head and neck imaging: self-assessment module. AB - OBJECTIVE: The educational objectives for this self-assessment module are for the participant to exercise, self-assess, and improve his or her understanding of radiology in pediatric congenital sensorineural hearing loss, posterior plagiocephaly, and midline nasofrontal mass. CONCLUSION: The activities in these articles guide the participant to understanding the key concepts of radiology in pediatric congenital sensorineural hearing loss, posterior plagiocephaly, and midline nasofrontal mass. PMID- 20173177 TI - Radiographic evaluation of scoliosis: review. PMID- 20173178 TI - Radiological reasoning: congenital sensorineural hearing loss. PMID- 20173179 TI - Radiological reasoning: pediatric midline nasofrontal mass. PMID- 20173180 TI - Radiological reasoning: a child with posterior plagiocephaly. PMID- 20173181 TI - Brachyspira murdochii colitis in pigs. AB - The weakly beta-hemolytic porcine spirochete Brachyspira murdochii is considered a normal intestinal commensal. In the present study, however, a field case of B murdochii-associated catarrhal colitis was identified in a pig, as characterized by extensive spirochetal colonization of the surface epithelium. Experimentally, 8 weaned pigs were challenged with the B murdochii isolate, reproducing catarrhal colitis in 2 animals. By applying fluorescent in situ hybridization using a species-specific oligonucleotide probe targeting 23S rRNA, B murdochii organisms were found in high numbers and were closely associated with the surface epithelium in the pigs with catarrhal colitis. The results indicate that, when present in high numbers, B murdochii is low pathogenic for pigs. PMID- 20173182 TI - Competing roles of TGFbeta and Nma/BAMBI in odontoblasts. AB - Nma/BAMBI is a novel pseudoreceptor with homology to a TGFbeta type I receptor that lacks a serine/threonine kinase domain. Nma/BAMBI functions as a dominant negative protein that regulates reciprocal epithelial-mesenchymal interactions during organogenesis. Therefore, we hypothesized that Nma/BAMBI regulates TGFbeta signaling and downstream gene expression during dentinogenesis. To test this hypothesis, we examined the downstream gene expression profiles of major dentin extracellular matrix proteins in response to Nma/BAMBI, and we examined the roles of Nma/BAMBI and TGFbeta-1 during dentinogenesis. Overexpression of Nma/BAMBI in the mouse odontoblast-like cell line MD10-A2 down-regulated expression of DSPP by 66% and up-regulated expression of DMP1 four-fold. TGFbeta treatment reversed Nma/BAMBI's negative effect on DSPP expression. Furthermore, we demonstrated that TGFbeta negatively regulates Nma/BAMBI's expression levels in MD10-A2 odontoblast like cells. Analysis of these data, together, indicates that TGFbeta and Nma/BAMBI are inversely regulated and that the sequence of expression determines the net effect on downstream gene expression. PMID- 20173183 TI - In vitro remineralization of severely compromised bonded dentin. AB - Biomimetic remineralization is potentially useful for the remineralization of incompletely resin-infiltrated collagen matrices created by etch-and-rinse adhesives. In this study, we tested the hypothesis that structurally altered dentin collagen cannot be remineralized to the same hierarchical order and dimension seen in structurally intact dentin collagen. The remineralization medium consisted of a set Portland cement/simulated body fluid system containing polycarboxylic acid and polyvinylphosphonic acid as biomimetic analogs. Remineralization of air-dried, collapsed hybrid layers was apparent after one month, with hybrid layers remineralized to 80-90% of their thickness after 2-4 months. A hypermineralized layer was seen on the hybrid layer surface, and tubular orifices were occluded with apatite deposits that resembled those present in non-carious cervical dentin. Structurally altered collagen is unlikely to be remineralized to the same hierarchical order and dimension as seen in intact dentin. The aggressively air-dried acid-etched dentin remineralization model also sheds light on the mechanism of sclerotic dentin formation. PMID- 20173185 TI - Emotional context at learning systematically biases memory for facial information. AB - Emotion influences memory in many ways. For example, when a mood-dependent processing shift is operative, happy moods promote global processing and sad moods direct attention to local features of complex visual stimuli. We hypothesized that an emotional context associated with to-be-learned facial stimuli could preferentially promote global or local processing. At learning, faces with neutral expressions were paired with a narrative providing either a happy or a sad context. At test, faces were presented in an upright or inverted orientation, emphasizing configural or analytical processing, respectively. A recognition advantage was found for upright faces learned in happy contexts relative to those in sad contexts, whereas recognition was better for inverted faces learned in sad contexts than for those in happy contexts. We thus infer that a positive emotional context prompted more effective storage of holistic, configural, or global facial information, whereas a negative emotional context prompted relatively more effective storage of local or feature-based facial information. PMID- 20173184 TI - Apo B100 similarities to viral proteins suggest basis for LDL-DNA binding and transfection capacity. AB - LDL mediates transfection with plasmid DNA in a variety of cell types in vitro and in several tissues in vivo in the rat. The transfection capacity of LDL is based on apo B100, as arginine/lysine clusters, suggestive of nucleic acid binding domains and nuclear localization signal sequences, are present throughout the molecule. Apo E may also contribute to this capacity because of its similarity to the Dengue virus capsid proteins and its ability to bind DNA. Synthetic peptides representing two apo B100 regions with prominent Arg/Lys clusters were shown to bind DNA. Region 1 (0014Lys-Ser0160) shares sequence motifs present in DNA binding domains of Interferon Regulatory Factors and Flaviviridae capsid/core proteins. It also contains a close analog of the B/E receptor ligand of apo E. Region 1 peptides, B1-1 (0014Lys-Glu0054) and B1-2 (0055Leu-Ala0096), mediate transfection of HeLa cells but are cytotoxic. Region 2 (3313Asp-Thr3431), containing the known B/E receptor ligand, shares analog motifs with the human herpesvirus 5 immediate-early transcriptional regulator (UL122) and Flaviviridae NS3 helicases. Region 2 peptides, B2-1 (3313Asp-Glu3355), and B2 2 (3356Gly-Thr3431) are ineffective in cell transfection and are noncytotoxic. These results confirm the role of LDL as a natural transfection vector in vivo, a capacity imparted by the apo B100, and suggest a basis for Flaviviridae cell entry. PMID- 20173186 TI - Recognition and context memory for faces from own and other ethnic groups: a remember-know investigation. AB - People are more accurate at recognizing faces from their own ethnic group than at recognizing faces from other ethnic groups. This other-ethnicity effect (OEE) in recognition may be produced by a deficit in recollective memory for other ethnicity faces. In a single study, White and Black participants saw White and Black faces presented within several different visual contexts. The participants were then given an old/new recognition task. Old responses were followed by remember-know-guess judgments and context judgments. Own-ethnicity faces were recognized more accurately, were given more remember responses, and produced more accurate context judgments than did other-ethnicity faces. These results are discussed in a dual-process framework, and implications for eyewitness memory are considered. PMID- 20173187 TI - Distinguishing between attributional and mnemonic sources of familiarity: the case of positive emotion bias. AB - Does familiarity arise from direct access to memory representations (a mnemonic account) or from inferences and diagnostic cues (an attributional account)? These theoretically distinct explanations can be difficult to distinguish in practice, as is shown by the positivity effect, the increase in feelings of familiarity that accompanies positive emotion. Experiment 1 manipulated mnemonic and attributional sources of positivity via word valence and physical expressions of emotion, respectively. Both sources influenced the tendency to call items old, but receiver-operating characteristic analysis revealed a change in accuracy only with the mnemonic source. To further contrast the mnemonic and attributional accounts, Experiment 2 varied the ratio of positive to neutral words. A higher proportion of positive words exaggerated the pattern of increased old judgments and decreased accuracy for positive words, relative to neutral ones, consistent with the mnemonic account but inconsistent with the attributional account. PMID- 20173188 TI - Contributions of category and fine-grained information to location memory: when categories don't weigh in. AB - Several studies have shown that people's memory for location can be influenced by categorical information. According to a model proposed by Huttenlocher, Hedges, and Duncan (1991), people estimate location by combining fine-grained item-level information in memory with category-level information. When the fine-grained information is inexact, category-level information is given greater weight, which leads to biased responses. We manipulated the distribution of locations presented in order to alter the usefulness of category information, and we manipulated background texture in order to alter accuracy of fine-grained memory. The distributional information reduced bias without altering overall accuracy of responding, whereas the background texture manipulation affected accuracy without changing bias. Our results suggest that category information may weigh in only when it is actively processed. PMID- 20173190 TI - The role of phonological and visual working memory in complex arithmetic for Chinese- and Canadian-educated adults. AB - Two experiments were conducted to test cultural differences in the role of phonological and visual working memory in complex arithmetic. Canadian- and Chinese-educated students solved complex subtraction problems (e.g., 85 - 27; Experiment 1) and complex multiplication problems (e.g., 6 x 13; Experiment 2) under phonological and visual working memory loads. Problem complexity (i.e., borrow or carry operations) and presentation format (i.e., horizontal vs. vertical) were also manipulated. The results showed that both Chinese- and Canadian-educated participants relied on both phonological and visual working memory resources when solving complex subtraction and multiplication problems. Selective involvement of phonological and visual working memory as a function of operation (Lee & Kang, 2002) or presentation format (Trbovich & LeFevre, 2003) was found only for Chinese-educated participants and not for Canadian-educated participants, calling into question the generalizability of these findings across arithmetic operations and cultural groups. PMID- 20173189 TI - Musicians' and nonmusicians' short-term memory for verbal and musical sequences: comparing phonological similarity and pitch proximity. AB - Language-music comparative studies have highlighted the potential for shared resources or neural overlap in auditory short-term memory. However, there is a lack of behavioral methodologies for comparing verbal and musical serial recall. We developed a visual grid response that allowed both musicians and nonmusicians to perform serial recall of letter and tone sequences. The new method was used to compare the phonological similarity effect with the impact of an operationalized musical equivalent-pitch proximity. Over the course of three experiments, we found that short-term memory for tones had several similarities to verbal memory, including limited capacity and a significant effect of pitch proximity in nonmusicians. Despite being vulnerable to phonological similarity when recalling letters, however, musicians showed no effect of pitch proximity, a result that we suggest might reflect strategy differences. Overall, the findings support a limited degree of correspondence in the way that verbal and musical sounds are processed in auditory short-term memory. PMID- 20173191 TI - In conflict with ourselves? An investigation of heuristic and analytic processes in decision making. AB - Many theorists propose two types of processing: heuristic and analytic. In conflict tasks, in which these processing types lead to opposing responses, giving the analytic response may require both detection and resolution of the conflict. The ratio bias task, in which people tend to treat larger numbered ratios (e.g., 20/100) as indicating a higher likelihood of winning than do equivalent smaller numbered ratios (e.g., 2/10), is considered to induce such a conflict. Experiment 1 showed response time differences associated with conflict detection, resolution, and the amount of conflict induced. The conflict detection and resolution effects were replicated in Experiment 2 and were not affected by decreasing the influence of the heuristic response or decreasing the capacity to make the analytic response. The results are consistent with dual-process accounts, but a single-process account in which quantitative, rather than qualitative, differences in processing are assumed fares equally well in explaining the data. PMID- 20173192 TI - Strategic behavior without awareness? Effects of implicit learning in the Eriksen flanker paradigm. AB - This experiment investigated whether subjects' selection and use of strategies in detecting a target letter in a flanker task requires intention. Subjects' expectancies for compatible and incompatible trials (trials on which the response to the flanker stimulus was consistent or inconsistent with the target response) were manipulated by presenting cues that signaled the occurrence of these types of trials. Three groups of subjects received explicit, partially explicit, or implicit instructions about the meaning of the cues. By the end of the experiment, all the groups were able to select and use strategies based on the cues to improve their performance. However, this strategy selection developed slowly with practice in the latter two groups, whereas it was present from the outset in the first group. In addition, forced choice tests performed after the experiment showed that the subjects in the implicit condition could not intentionally indicate which stimuli were most likely to follow a given cue. Thus, the data suggest that the selection of strategies occurred outside the subjects' awareness, and without their intention. PMID- 20173193 TI - A model of rotated mirror/normal letter discriminations. AB - Rotated mirror/normal letter discriminations are thought to require mental rotation in order to determine the direction of facing of the stimulus. The response time (RT) function over orientation tends to be curved, rather than the linear function found for other mental rotation tasks. The present study investigated the possibility that the curved RT function is a result of a mixture of trials requiring and not requiring mental rotation. The results suggested that the frequency of mental rotation is also a linear function of stimulus orientation. Moreover, the relationship between an individual's rate of plane rotation and the mean difference in RT between mirror and normal stimuli was replicated, supporting the suggestion that mirrored stimuli are flipped after they are spun (Hamm, Johnson, & Corballis, 2004). On the basis of the present findings, the entire RT function can be modeled by using only the mean RTs for upright and inverted stimuli. PMID- 20173194 TI - Implementation intention encoding does not automatize prospective memory responding. AB - An implementation intention encoding, one that specifies the concrete situation that is appropriate for initiating an intended action and links that situational cue to the intended action, has been shown to improve prospective memory. One proposed mechanism is that implementation intentions create automatized prospective remembering. This view anticipates that implementation intentions should prevent prospective memory decline in highly cognitively demanding situations. Contrary to this expectation, although implementation intention encoding enhanced prospective memory (Experiments 1 and 2), implementation intention encoding did not buffer against significant prospective memory decline in high-cognitive-demand conditions (Experiments 1-3), and in Experiment 3, implementation intention encoding produced lower levels of prospective memory performance than did behavioral practice in the high-cognitive-demand situation. We suggest that although implementation intentions may stimulate a strong associative encoding (between an anticipated environmental cue and an intended action), that encoding does not support a completely automatized prospective memory response. PMID- 20173195 TI - Enactment and retrieval. AB - The enactment effect is one of a number of effects (e.g., bizarreness, generation, perceptual interference) that have been treated in common theoretical frameworks, most of them focusing on encoding processes. Recent results from McDaniel, Dornburg, and Guynn (2005) call into question whether bizarreness and, by association, related phenomena such as enactment are better conceptualized as arising due to retrieval processes. Four experiments investigated the degree to which retrieval processes are responsible for enhanced memory for enacted phrases. Participants were presented with two pure study lists and later recalled the lists separately (inducing pure retrieval sets) or recalled the lists together in a single test (inducing a combined or mixed retrieval set). Across all four experiments, the combined recall condition consistently failed to enhance the size of the enactment effect. The results provide no support for the retrieval account but are generally consistent with encoding accounts. PMID- 20173196 TI - Optimizing retrieval as a learning event: when and why expanding retrieval practice enhances long-term retention. AB - Retrieving information from memory makes that information more recallable in the future than it otherwise would have been. Optimizing retrieval practice has been assumed, on the basis of evidence and arguments tracing back to Landauer and Bjork (1978), to require an expanding-interval schedule of successive retrievals, but recent findings suggest that expanding retrieval practice may be inferior to uniform-interval retrieval practice when memory is tested after a long retention interval. We report three experiments in which participants read educational passages and were then repeatedly tested, without feedback, after an expanding or uniform sequence of intervals. On a test 1 week later, recall was enhanced by the expanding schedule, but only when the task between successive retrievals was highly interfering with memory for the passage. These results suggest that the extent to which learners benefit from expanding retrieval practice depends on the degree to which the to-be-learned information is vulnerable to forgetting. PMID- 20173197 TI - Transcatheter aortic valve implantation: role of multi-detector row computed tomography to evaluate prosthesis positioning and deployment in relation to valve function. AB - AIMS: Aortic regurgitation after transcatheter aortic valve implantation (TAVI) is one of the most frequent complications. However, the underlying mechanisms of this complication remain unclear. The present evaluation studied the anatomic and morphological features of the aortic valve annulus that may predict aortic regurgitation after TAVI. METHODS AND RESULTS: In 53 patients with severe aortic stenosis undergoing TAVI, multi-detector row computed tomography (MDCT) assessment of the aortic valve apparatus was performed. For aortic valve annulus sizing, two orthogonal diameters were measured (coronal and sagittal). In addition, the extent of valve calcifications was quantified. At 1-month follow-up after procedure, MDCT was repeated to evaluate and correlate the prosthesis deployment to the presence of aortic regurgitation. Successful procedure was achieved in 48 (91%) patients. At baseline, MDCT demonstrated an ellipsoid shape of the aortic valve annulus with significantly larger coronal diameter when compared with sagittal diameter (25.1 +/- 2.4 vs. 22.9 +/- 2.0 mm, P < 0.001). At follow-up, MDCT showed a non-circular deployment of the prosthesis in six (14%) patients. Moderate post-procedural aortic regurgitation was observed in five (11%) patients. These patients showed significantly larger aortic valve annulus (27.3 +/- 1.6 vs. 24.8 +/- 2.4 mm, P = 0.007) and more calcified native valves (4174 +/- 1604 vs. 2444 +/- 1237 HU, P = 0.005) at baseline and less favourable deployment of the prosthesis after TAVI. CONCLUSION: Multi-detector row computed tomography enables an accurate sizing of the aortic valve annulus and constitutes a valuable imaging tool to evaluate prosthesis location and deployment after TAVI. In addition, MDCT helps to understand the underlying mechanisms of post procedural aortic regurgitation. PMID- 20173198 TI - Developing standards of care for patients with juvenile idiopathic arthritis. PMID- 20173199 TI - BSPAR Standards of Care for children and young people with juvenile idiopathic arthritis. PMID- 20173200 TI - Adaptation of a hyperthermophilic group II chaperonin to relatively moderate temperatures. AB - Group II chaperonins exist in archaea and the eukaryotic cytosol, and mediate protein folding in an ATP-dependent manner. We have been studying the reaction mechanism of group II chaperonins using alpha chaperonin, the recombinant chaperonin alpha subunit homo-oligomer from a hyperthermophilic archaeon, Thermococcus sp. strain KS-1 (T. KS-1). Although the high stability and activity of T. KS-1 alpha chaperonin provided advantages for our study, its high thermophilicity caused the difficulty in using various analytical methods. To resolve this problem, we tried to adapt T. KS-1 alpha chaperonin to moderate temperatures by mutations. The comparison of amino acid sequences between 26 thermophilic and 17 mesophilic chaperonins showed that three amino acid replacements are likely responsible for the difference of their optimal temperatures. We introduced three single mutations and also their double combinations into T. KS-1 alpha chaperonin. Among them, K323R single mutant exhibited the improvements of the folding activity and the ATP-dependent conformational change ability at lower temperatures, such as 50 degrees C and 40 degrees C. Since K323 may secure helix 12 in the closed conformation by interacting with D198, the replacement of Lys to Arg likely induced the higher mobility of the built-in lid, resulting in the higher activity at relatively low temperatures. PMID- 20173203 TI - Behcet's disease. PMID- 20173201 TI - Inflammatory stimuli regulate caspase substrate profiles. AB - The inflammatory caspases, human caspases-1, -4, and -5, proteolytically modulate diverse physiological outcomes in response to proinflammatory signals. Surprisingly, only a few substrates are known for these enzymes, including other caspases and the interleukin-1 family of cytokines. To more comprehensively characterize inflammatory caspase substrates, we combined an enzymatic N-terminal enrichment method with mass spectrometry-based proteomics to identify newly cleaved proteins. Analysis of THP-1 monocytic cell lysates treated with recombinant purified caspases identified 82 putative caspase-1 substrates, three putative caspase-4 substrates, and no substrates for caspase-5. By contrast, inflammatory caspases activated in THP-1 cells by mimics of gout (monosodium urate), bacterial infection (lipopolysaccharide and ATP), or viral infection (poly(dA.dT)) were found to cleave only 27, 16, and 22 substrates, respectively. Quantitative stable isotope labeling with amino acids in cell culture (SILAC) comparison of these three inflammatory stimuli showed that they induced largely overlapping substrate profiles but different extents of proteolysis. Interestingly, only half of the cleavages found in response to proinflammatory stimuli were contained within our set of 82 in vitro cleavage sites. These data provide the most comprehensive set of caspase-1-cleaved products reported to date and indicate that caspases-4 and -5 have far fewer substrates. Comparisons between the in vitro and in vivo data highlight the importance of localization in regulating inflammatory caspase activity. Finally, our data suggest that inducers of inflammation may subtly alter caspase-1 substrate profiles. PMID- 20173204 TI - Do non-antiarrhythmic drugs have enough pleiotropic power to reduce atrial fibrillation? PMID- 20173205 TI - Iatrogenic atrial septal defect after catheter ablation of atrial fibrillation: do we have to worry? PMID- 20173206 TI - Four types of complications in paroxysmal atrial fibrillation ablation. PMID- 20173207 TI - Representing the patient perspective in the treatment of atrial fibrillation. PMID- 20173208 TI - Primary prevention of sudden cardiac death after acute myocardial infarction: lessons from Leiden. PMID- 20173209 TI - Cardiac resynchronization therapy: relevance of right ventricular function evaluation. PMID- 20173210 TI - Ganglionated plexi ablation for longstanding persistent atrial fibrillation. AB - AIMS: To study the potential efficacy of ganglionated plexi (GP) ablation in the setting of longstanding persistent atrial fibrillation (AF). METHODS AND RESULTS: Anatomic ablation at the areas of GP in the left atrium was performed in 89 patients with symptomatic, drug-refractory, persistent AF (71 men, 56 +/- 7 years of age). In 29 patients, a second procedure by means of circumferential pulmonary vein (PV) isolation was performed, and 5 of them were subjected to a third circumferential ablation. At 16 +/- 7 months after the final ablation procedure, 53 (59.6%) of the 89 patients were in sinus rhythm in the absence of antiarrhythmic drug therapy, 5 (5.6%) patients had permanent AF, and 31 (34.8%) patients had paroxysmal AF. The long-term success rate for patients who underwent a single ablation procedure with only GP ablation was 38.2% over a follow-up of 24 +/- 3 months. Independent predictors of later arrhythmia recurrences were left atrial diameter [HR 1.039 (1.00-1.07), P = 0.028] and duration of AF prior to ablation [HR 1.116 (1.02-1.22), P = 0.008]. CONCLUSION: Ganglionated plexi ablation in chronic AF results in long-term maintenance of sinus rhythm in 38.2% of cases. Repeat procedures with circumferential isolation of all PV offer a success rate of 59.6% over a follow-up of 16 +/- 7 months. PMID- 20173211 TI - Efficacy of catheter ablation for atrial fibrillation in hypertrophic cardiomyopathy: impact of age, atrial remodelling, and disease progression. AB - AIMS: In patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF), radiofrequency catheter ablation (RFCA) represents a promising option. However, the predictors of RFCA efficacy remain largely unknown. We assessed the outcome of a multicentre HCM cohort following RFCA for symptomatic AF refractory to medical therapy. METHODS AND RESULTS: Sixty-one patients (age 54 +/- 13 years; time from AF onset 5.7 +/- 5.5 years) with paroxysmal (n = 35; 57%), recent persistent (n = 15; 25%), or long-standing persistent AF (n = 11; 18%) were enrolled. A scheme with pulmonary vein isolation plus linear lesions was employed. Of the 61 patients, 32 (52%) required redo procedures. Antiarrhythmic therapy was maintained in 22 (54%). At the end of a 29 +/- 16 months follow-up, 41 patients (67%) were in sinus rhythm, including 17 of the 19 patients aged < or = 50 years, with marked improvement in New York Heart Association (NYHA) functional class (1.2 +/- 0.5 vs. 1.9 +/- 0.7 at baseline; P < 0.001). In the remaining 20 patients (33%), with AF recurrence, there was less marked, but still significant, improvement following RFCA (NYHA class 1.8 +/- 0.7 vs. 2.3 +/- 0.7 at baseline; P = 0.002). Independent predictors of AF recurrence were increased left atrium volume [hazard ratio (HR) per unit increase 1.009, 95% confidence interval (CI) 1.001-1.018; P = 0.037] and NYHA functional class (HR 2.24, 95% CI 1.16-4.35; P = 0.016). Among 11 genotyped HCM patients (6 with MYBPC3, 2 with MYH7, 1 with MYL2 and 2 with multiple mutations), RFCA success rate was comparable with that of the overall cohort (n = 8; 73%). CONCLUSION: RFCA was successful in restoring long-term sinus rhythm and improving symptomatic status in most HCM patients with refractory AF, including the subset with proven sarcomere gene mutations, although redo procedures were often necessary. Younger HCM patients with small atrial size and mild symptoms proved to be the best RFCA candidates, likely due to lesser degrees of atrial remodelling. PMID- 20173212 TI - Very long-chain fatty acid accumulation causes lipotoxic response via 5 lipoxygenase in cerebral adrenoleukodystrophy. AB - Childhood adrenoleukodystrophy (cALD) is a metabolic disorder in which very long chain fatty acids (VLCFA) accumulate due to ALD protein gene defects, ultimately leading to lipotoxicity-induced neuroinflammatory demyelinating disease. Therefore, we examined VLCFA-mediated alterations in the metabolism of lipoxidative enzymes and inflammatory mediators in the cALD brain. 5-Lipoxygenase (5-LOX)-derived leukotrienes were significantly elevated in all the areas of white matter in the cALD brain. Unlike cyclooxygenase-2 expression, which was moderately high only in the plaque area, expression of 5-LOX and cytosolic phospholipase A2 was prominent in all the areas. This lipoxidative burden in the cALD brain was further shown by reduced levels of glutathione and enhanced expression of heat shock protein-70/manganese superoxide dismutase. These pathological observations were confirmed through in vitro mechanistic investigation. After increasing VLCFA through silencing Abcd1+Abcd2 in mouse primary astrocytes, enhanced expression of 5-LOX was observed, and this increased expression was blocked by treatment with monoenoic fatty acids. These results link the previously observed accumulation of VLCFA in cALD to the 5-LOX enzyme pathway. A similar increase in 5-LOX expression in astrocytes was also detected following treatment with exogenous VLCFA (C26:0). In sum, through 5-LOX activation, VLCFA accumulation causes a lipotoxic response consistent with cALD brain pathology. PMID- 20173214 TI - Recurrence of discordant congenital heart defects in families. AB - BACKGROUND: Variation within a single gene might produce different congenital heart defects (CHDs) within a family, which could explain the previously reported familial aggregation of discordant CHDs. We investigated whether certain groups of discordant CHDs are more common in families than others. METHODS AND RESULTS: Using Danish national population and health registers, we identified CHDs among all singletons born in Denmark during 1977-2005 and their first-degree relatives. In a cohort of 1 711 641 persons, 16 777 had CHDs, which we classified into 14 phenotypes. We estimated relative risks of discordant CHDs by history of specific CHDs in first-degree relatives. The relative risk of any dissimilar CHD given the specified CHD in first-degree relatives was as follows: heterotaxia, 2.00 (95% CI, 0.96 to 4.17); conotruncal defects, 2.78 (95% CI, 2.12 to 3.66); atrioventricular septal defects, 2.25 (95% CI, 1.39 to 3.66); anomalous pulmonary venous return, 1.76 (95% CI, 0.66 to 4.64); left- and right-ventricular outflow tract obstruction, 2.55 (95% CI, 1.87 to 3.48) and 3.09 (95% CI, 2.03 to 4.71), respectively; isolated atrial septal defects, 2.76 (95% CI, 2.11 to 3.61); isolated ventricular septal defects, 2.27 (95% CI, 1.75 to 2.94); persistent ductus arteriosus, 1.92 (95% CI, 1.32 to 2.79); other specified CHDs, 3.29 (95% CI, 2.51 to 4.32); and unspecified CHDs, 2.30 (95% CI, 1.76 to 3.00). Relative risks for all pairwise combinations of discordant CHD phenotypes gave no indications that certain constellations of CHDs cluster more in families than others. CONCLUSIONS: We documented strong familial aggregation of discordant CHD phenotypes. However, we observed no excess clustering of specific CHD phenotypes among the first-degree relatives. PMID- 20173213 TI - A phosphoethanolamine-modified glycosyl diradylglycerol in the polar lipids of Clostridium tetani. AB - The polar lipids of the anaerobic bacterium Clostridium tetani, the causative agent of tetanus, have been examined by two-dimensional thin layer chromatography, ESI mass spectrometry, and NMR spectroscopy. Plasmalogen and di- and tetra-acylated species of phosphatidylethanolamine, phosphatidylglycerol, cardiolipin, and N-acetylglucosaminyl diradylglycerol were the major lipids present in most strains examined except for strain ATCC 10779, the parent of strain E88, the first C. tetani strain to have its genome sequenced. This strain contained the same di- and tetra-acylated species but did not contain plasmalogens. All strains contained a novel derivative of N-acetylglucosaminyl diradylglycerol in which a phosphoethanolamine unit is attached to the 6' position of the sugar, as judged by selective 31P-decoupled, 1H-detected NMR difference spectroscopy. The N-acetylglucosamine (GlcNAc) residue is presumably linked to the 3-positon of the diradylglycerol moiety, and it has the beta anomeric configuration. Very little plasmalogen component was detected by mass spectrometry in the precursors phosphatidic acid and phosphatidylserine, consistent with the idea that plasmalogens are formed from diacylated phospholipids at a late stage of phospholipid assembly in anaerobic clostridia. PMID- 20173216 TI - Mass estimation of native proteins by blue native electrophoresis: principles and practical hints. AB - Blue native electrophoresis is one of the most popular techniques for mass estimation of native membrane proteins, but the use of non-optimal mass markers and acrylamide gels can compromise accuracy and reliability of the results. We present short protocols taking 10-30 min to prepare optimal sets of membrane protein markers from chicken, rat, mouse, and bovine heart. Especially heart materials from local supermarkets or butcher's shops, e.g. chicken or bovine heart, are ideal sources of high mass membrane protein standards. Considerable discrepancies between the migration behavior of membrane and soluble markers suggest using membrane protein markers for mass estimation of membrane proteins. Soluble standard proteins can be used, with some limitations, when soluble proteins are the focus. Principles and general rules for the determination of mass and oligomeric state of native membrane and soluble proteins are elaborated, and potential pitfalls are discussed. PMID- 20173215 TI - LAMP2 microdeletions in patients with Danon disease. AB - BACKGROUND: Danon disease is an X-linked dominant disorder characterized by the clinical triad of hypertrophic cardiomyopathy, skeletal myopathy, and variable mental retardation. Pathologically, autophagic vacuoles are noted in both skeletal and cardiac muscle. It exhibits an X-linked dominant mode of inheritance, and male carriers are severely affected, whereas female carriers develop milder and later-onset cardiac symptoms. Danon disease has been associated with mutations in the lysosome-associated membrane glycoprotein 2 (LAMP2) gene located at Xq24, typically resulting in splicing defects or protein truncation affecting the LAMP2. Because of its rarity, the full spectrum of genetic mutation resulting in Danon disease has not been elucidated. METHODS AND RESULTS: We analyzed 3 male cases with clinical and pathological findings consistent with Danon disease. Comprehensive mutational analysis failed to yield detectable products for selected LAMP2 exons, and genomic DNA deletion was suspected. Genomic junction fragment polymerase chain reaction analysis in case 1 identified a novel Alu-mediated 34-kb microdeletion encompassing the entire 5' untranslated region and exon 1 of LAMP2. In case 2 and 3, junctional polymerase chain reaction and Southern blot analyses mapped the breakpoint to an MIRb and (TA)(n) simple repeats present in intron 3, which determined a 64-kb and a 58-kb deletion, respectively, thereby ablating exons 4 to 10. Western blot analysis confirmed the absence of LAMP2 in protein extract from lymphocytes of index case 2. CONCLUSIONS: This article is the first report of Danon disease caused by microdeletions at Xq24, which functionally ablate LAMP2. The microdeletion mechanism appears to involve 1 Alu-mediated unequal recombination and 2 chromosomal breakage points involving TA-rich repeat sequences. PMID- 20173217 TI - [The role of selected matrix metalloproteinases and their inhibitors in colorectal cancer development]. AB - Colorectal cancer is one of the most common malignant tumors of the gastrointestinal tract. The development of this tumor is a complex, long-term, and multi-step process, from small dysplastic lesions of normal colorectal mucosa, through adenomatous polyps, to carcinoma in situ. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play an important role in colorectal carcinogenesis. MMP-9 is able to degrade collagen IV from basement membranes and extracellular matrix, which is associated with tumor progression, including invasion, metastasis,growth, migration, and angiogenesis. It was demonstrated that increased expression of MMP-9plays a crucial role in the development of several human malignancies, including colorectal cancer.Increased expression of MMP-9 correlated with tumor stage, invasiveness, and poor survival of colorectal cancer patients. PMID- 20173218 TI - [An involvement of the mitochondrial fatty acid transporters in the development of myocellular insulin resistance]. AB - Long-chain fatty acids (LCFAs) are an important source of energy for working skeletal muscles. The predominant mechanism of LCFA influx into skeletal muscle involves sarcolemmal proteins, namely fatty-acid transporters. Recent studies imply strong correlations between increased plasmalemmal expression of FA transporters and the development of insulin resistance in skeletal muscles. However, it seems that a major feature of myocyte insulin resistance is the imbalance in lipid transport into the cells and the capacity of mitochondria for LCFA oxidation. Excess deposition of myocellular fatty acids leads to the accumulation of triacylglycerols, diacylglycerols, and ceramides. Most likely, the accumulation of intramuscular lipid fractions is responsible for disturbances in the insulin signaling pathway and the subsequent development of skeletal muscle insulin resistance. PMID- 20173219 TI - [Cadmium--element completely unnecessary for the organism]. AB - Cadmium (Cd) is the main environmental pollutant. This metal presents a serious threat to the health of people and animals. The environmental risk can lead to the absorption of large quantities of cadmium and its toxic action on the organism. It adversely affects a number of organs in humans and animals, including the kidneys, liver, lungs, pancreas, and testis. The liver and kidneys, which are the primary organs involved in the elimination of this metal from the organism, are especially sensitive to its toxic effects. This paper presents the current state of knowledge related to the molecular mechanisms of the toxic action of cadmium in cells. Different mechanisms are discussed: the disruption of the cellular antioxidant system and decrease in thiol status, the generation of reactive oxygen species, inhibition of DNA repair and DNA methylation, the activation of cellular signals and protooncogenes, disruption of cell adhesion, cell damage leading to apoptosis, the promotion of cell proliferation, and the initiation of mutagenesis/carcinogenesis. PMID- 20173220 TI - [Genetic factors in the development and progression of chronic kidney disease]. AB - The factors influencing the onset and progression of chronic kidney disease (CKD) are not completely known. It is believed that genetic factors may play a significant role. The article presents the results of population, family, and animal studies which indicate the participation of genetic factors in CKD development. The main strategies for identifying genes involved in CKD development(genome scan studies and candidate gene studies) are described. Polymorphisms of selected candidate genes for CKD are reviewed. Special attention is paid to studies concerning the genes of the renin-angiotensin-aldosterone system (angiotensin-converting enzyme and angiotensin II type 1 receptor genes), cytokine genes (IL-10, IL-4, IL-6, IL-1beta, TNF-alpha, TGF-beta1,MCP, RANTES), and the gene encoding methylenetetrahydrofolate reductase. The results of studies on the role of TGFB1 gene in kidney diseases are analyzed. The genetic basis of IgA nephropathy and kidney insufficiency progression in the course of the disease is shown. The results of genetic studies of CKD are inconclusive. The article underlines the importance of identifying the genetic background of CKD to individualize patient therapy. PMID- 20173221 TI - [Onconase: a ribonuclease with antitumor activity]. AB - Onconase (ranpirnase) is a homologous protein obtained from Rana pipiens frog eggs. The activity of onconase, and particularly its antitumor effect, is strictly connected with ribonuclease(RN-ase) activity. Onconase induces cell death through the decomposition of inner cellular RNA,inhibition of protein synthesis, and inhibition of cell growth and proliferation and it also specifically triggers tumor cell apoptosis. A very important mechanisms of its cytotoxicity is also its antioxidant activity. The results of preclinical trials demonstrated a high activity of onconase against tumor cells, also those resistant to cytostatics. Moreover, onconase showed synergic activity with other commonly used anticancer drugs. Several clinical trials were performed on patients suffering from kidney, breast, and pancreatic cancers. Most recently a phase III study of onconase in patients with mesothelioma was completed. There are also ongoing phase I and II clinical trials with non-small-cell lung cancer (NSCLC). PMID- 20173222 TI - [Dermatological treatment during pregnancy and lactation]. AB - Since wellbeing and health have become fashionable and widespread polypragmasia is popular, adverse drug reactions are particularly important medical problem. Pregnant women as well as breast-feeding mothers need very particular care from the physician. Treatment during pregnancy or lactation is a more complicated issue not only because it concerns at least two persons, but also because of the many anatomical and functional differences between the adult and fetus or newborn organism. The safety aspects of dermatological treatment during pregnancy and lactation are presented. Both topical and systemic treatment, mainly for bacterial, viral, fungal, and parasitic dermatoses and acne, alopecia, psoriasis, and autoimmunological processes, are discussed.Moreover, the most recent methods of dermatological treatment are mentioned taking into consideration their safety during pregnancy and lactation. Furthermore, the traditional drug classification made by the United States Food and Drug Administration as well as the most modern division, which is under construction, are presented. PMID- 20173223 TI - Stages in molecular beam epitaxy growth of GaAs nanowires studied by x-ray diffraction. AB - GaAs nanowires were grown by molecular beam epitaxy and studied by glancing-angle x-ray diffraction during five different stages of the growth process. An entire forest of randomly positioned epitaxial nanowires was sampled simultaneously and a large variation in the Au-Ga catalyst was found. Au, AuGa, AuGa(2) and the hexagonal beta phase were all identified in several orientations and in similar amounts. The nanowires are shown to consist of regular zinc blende crystal, its twin and the hexagonal wurtzite. The evolution of the various Au-Ga catalysts and the development in the twin to the wurtzite abundance ratio indicate that the Au catalyst is saturated upon initiation of growth leading to an increased amount of wurtzite structure in the wires. A specular x-ray scan identifies the various Au Ga alloys, three Au lattice constants and a rough interface between nanowires and catalyst. Reciprocal space maps were obtained around Au Bragg points and show the development of the Au catalyst from a distribution largely oriented with respect to the lattice to a non-uniform distribution with several well-defined lattice constants. PMID- 20173224 TI - Electrical properties and memory effects of field-effect transistors from networks of single- and double-walled carbon nanotubes. AB - We study field-effect transistors made of single- and double-walled carbon nanotube networks for applications as memory devices. The transfer characteristics of the transistors exhibit a reproducible hysteresis which enables their use as nano-sized memory cells with operations faster than 10 ms, endurance longer than 10(+4) cycles and charge retention of a few hours in air. We propose water enhanced charge trapping at the SiO(2)/air interface close to the nanotubes as the dominant mechanism for charge storage. We show that charge storage can be improved by limiting exposure of the device to air. PMID- 20173225 TI - Interfacial shear strengths between carbon nanotubes. AB - Interfacial shear strengths or static frictions between carbon nanotubes (CNT) in contact at different cross angles are studied by using atomic mechanics. It is shown that the axial interfacial shear strengths between parallel CNTs in commensurate are two orders of magnitude greater than those in incommensurate. This strong chiral dependence is not surprising and is similar to that of the friction between two graphite basal planes. In contrast, we find that the interfacial shear strengths of crossly contacted CNT pairs are much less dependent upon chirality. The estimated values of interfacial shear strengths, ranging from 0.05 to 0.35 GPa, agree very well with experimentally measured results available in the literature. These results may thus be used as a basis for explaining the observed tension strengths of CNT bundles and films that are mainly bonded by van der Waals interactions and the mechanical behaviors of composite materials with highly concentrated CNTs. PMID- 20173226 TI - Optical sensing of triethylamine using CdSe aerogels. AB - The photoluminescence (PL) response of highly porous CdSe aerogels to triethylamine (TEA) is investigated and compared to results from prior studies on single crystals and nanoparticle-polymer composites. As-prepared CdSe aerogels show significant and reversible enhancement of luminescence intensity upon exposure to TEA relative to the intensity in pure argon carrier gas. The enhancement in the PL response is dependent on the concentration and linear over the range of TEA concentration studied (4.7 x 10(3)-75 x 10(3) ppm). The sensing response of previously tested samples exhibits saturation behavior that is modeled using Langmuir adsorption isotherms, yielding adsorption equilibrium constants in the range 300-380 atm( - 1). The response is sensitively affected by the surface characteristics of the aerogel; when the wet gels are treated with pyridine prior to aerogel formation, the response to TEA is diminished, and when as-prepared aerogels are heated in a vacuum, no subsequent response is observed. Deactivation is attributed to an increase in surface oxide (SeO(2)) and decrease in surface Cd(2 + ) Lewis acid sites. Sensing runs of approximately one hour have little impact on the morphology or crystallinity of the aerogels, but do result in partial removal of residual thiolate ligands left over from the gelation process. PMID- 20173227 TI - Quantum confined Stark effect of InGaN/GaN multi-quantum disks grown on top of GaN nanorods. AB - We have investigated, using micro-photoluminescence, the quantum confined Stark effect in an In(x)Ga(1-x)N/GaN multi-quantum disk structure at the tip of a single GaN nanorod. A strong and sharp emission line from the In(x)Ga(1-x)N/GaN quantum disks near 3.26 eV was observed. The peak energy of the emission line was observed to blue-shift with increasing excitation power, indicating a quantum confined Stark effect. Furthermore, both the blue-shift and the intensity of the emission saturate with increasing excitation power. The temperature-dependence of the 3.26 eV emission line has also been investigated. PMID- 20173228 TI - Synthesis of nanoporous spheres of cubic gallium oxynitride and their lithium ion intercalation properties. AB - Cubic spinel structured gallium oxynitride has been synthesized through the reaction of metallic gallium and water in the presence of organic ethylenediamine. The relative content of the mixed solvent of water and ethylenediamine controls the product morphology and structure. A novel well defined nanoporous structure has finally been obtained, whose large surface area and peculiar surface chemistry will generate novel physical and chemical properties. As an example, lithium intercalation properties for prospective applications in lithium ion batteries are demonstrated in this work. PMID- 20173229 TI - Temperature controlled dip-pen nanolithography. AB - Dip-pen nanolithography (DPN) has emerged as a powerful tool for creating sophisticated micron- and nanoscale features of various molecules, such as small organic molecules, on a variety of substrates. Despite significant advances in recent years, the influence of temperature on molecular transport for nanostructure fabrication has not been fully explored. Herein, it is shown how the dimensions of patterned organic nanostructures can be controlled by using a cooling/heating module. This method allows nanometer-sized feature fabrication of a variety of small organic molecules, including 'inks' that have been deemed very difficult to write under ambient conditions. Features with dimensions as small as 30 nm have been successfully reproduced using the newly developed temperature control device in conjunction with DPN. PMID- 20173230 TI - Processing of loose carbon nanotubes into isolated, high density submicron channels. AB - Loose multi-wall carbon nanotubes (MWNTs) were processed into a bundle of 19,600 individual channels with an individual channel diameter of 0.4 microm using a fiber drawing process. First, a powder of sodium silicate solution containing purified MWNTs was created. A glass capillary tube was filled with the powder and drawn into fibers. The fibers were cut into segments, bundled and redrawn multiple times to create fibers with multiple channels containing MWNTs. This processing approach created thousands of uniformly ordered channels containing dispersed MWNTs in a glass matrix while simultaneously aligning the MWNTs. The bulk resistivity of the MWNT-silicate channel has been improved by 38% after two consecutive draws as a result of the increased MWNT fraction. PMID- 20173231 TI - Adsorption of monovalent metal atoms on graphene: a theoretical approach. AB - This work investigates, using first-principles calculations, electronic and structural properties of hydrogen, lithium, sodium, potassium and rubidium that are adsorbed, in a regular pattern, on a graphene surface. The results for H graphene (graphane) and Li-graphene were compared with previous calculations. The present results do not support previous claims that the Li-C bond in such a layer would result in an sp(2) to an sp(3) transition of carbon orbitals, being more compatible with some ionic character for the covalent bond and with lithium acting as an electron acceptor in a bridging environment. Calculations were also performed for the Na, K, and Rb-graphene systems, resulting in a similar electronic behaviour but with a more pronounced ionic character than for Li graphene. Energy calculations indicate the possible stability of such ad-graphene layers, with only the Li-graphene being possible to be spontaneously obtained. PMID- 20173232 TI - Improved localization of cellular membrane receptors using combined fluorescence microscopy and simultaneous topography and recognition imaging. AB - The combination of fluorescence microscopy and atomic force microscopy has a great potential in single-molecule-detection applications, overcoming many of the limitations coming from each individual technique. Here we present a new platform of combined fluorescence and simultaneous topography and recognition imaging (TREC) for improved localization of cellular receptors. Green fluorescent protein (GFP) labeled human sodium-glucose cotransporter (hSGLT1) expressed Chinese Hamster Ovary (CHO) cells and endothelial cells (MyEnd) from mouse myocardium stained with phalloidin-rhodamine were used as cell systems to study AFM topography and fluorescence microscopy on the same surface area. Topographical AFM images revealed membrane features such as lamellipodia, cytoskeleton fibers, F-actin filaments and small globular structures with heights ranging from 20 to 30 nm. Combined fluorescence and TREC imaging was applied to detect density, distribution and localization of YFP-labeled CD1d molecules on alpha galactosylceramide (alphaGalCer)-loaded THP1 cells. While the expression level, distribution and localization of CD1d molecules on THP1 cells were detected with fluorescence microscopy, the nanoscale distribution of binding sites was investigated with molecular recognition imaging by using a chemically modified AFM tip. Using TREC on the inverted light microscope, the recognition sites of cell receptors were detected in recognition images with domain sizes ranging from approximately 25 to approximately 160 nm, with the smaller domains corresponding to a single CD1d molecule. PMID- 20173233 TI - Controlling nanopore size, shape and stability. AB - Solid-state nanopores are considered a promising tool for the study of biological polymers such as DNA and RNA, due largely to their flexibility in size, potential in device integration and robustness. Here, we show that the precise shape of small nanopores (approximately 5 nm diameter in 20 nm SiN membranes) can be controlled by using transmission electron microscope (TEM) beams of different sizes. However, when some of these small nanopores are immersed in an aqueous solution, their resistance is observed to decrease over time. By comparing nanopores of different shapes using (scanning) TEM both before and after immersion in aqueous solution, we demonstrate that the stability of small nanopores is related to their three-dimensional geometry, which depends on the TEM beam size employed during pore fabrication. Optimal stability is obtained using a TEM beam size of approximately the same size as the intended nanopore diameter. In addition, we show that thermal oxidation can serve as a means to independently control nanopore size following TEM fabrication. These observations provide key guidelines for the fabrication of stable solid-state nanopores on the scale of nucleic acids and small proteins. PMID- 20173234 TI - Electron beam induced current measurements on single-walled carbon nanotube devices. AB - We report on electron beam induced current (EBIC) from individual carbon nanotubes (CNTs) which are in contact with metal electrodes. The EBIC signals originate from the diffusion of excess carriers induced by the electron beam bombardment. The EBIC image enables us to locate the individual CNTs efficiently. From the polarity of the EBIC signals we can identify the electrical contacts to the metal electrodes. More importantly, we demonstrate that the EBIC can be used to characterize the local electrical properties of CNT-based devices, such as asymmetry in metal contacts and the presence of defects. EBIC is also observed regardless of the presence of insulating surfaces, indicating that the EBIC is a result of the direct interaction between the CNTs and the electron beams. PMID- 20173235 TI - Thermo-mechanical stability and strength of peptide nanostructures from molecular dynamics: self-assembled cyclic peptide nanotubes. AB - Peptide nanostructures present a wide range of opportunities for applications in biomedicine and bionanotechnology; hence experimental and theoretical studies aiming at determination of thermo-mechanical stability of peptide-based nanostructures are critical for the design and development of their technological applications. Here, we present a homogeneous deformation method combined with the finite elasticity theory and molecular dynamics simulations (MD) for the calculation of second-order anisotropic elastic constants for a membrane model made up of self-assembled cyclic peptide nanotubes. We have computed the values of all anisotropic elastic constants at 300 K. The value of the engineering Young's modulus (in the z direction) is 19.6 GPa. We observed a yield behavior in the z direction for a strain value of 6%. Furthermore, we also report calculated heat capacity, thermal expansion coefficient and isothermal compressibility of the system under study. PMID- 20173236 TI - Granular Co-C nano-Hall sensors by focused-beam-induced deposition. AB - We investigated the performance of Hall sensors with different Co-C ratios, deposited directly in nanostructured form, using Co(2)(CO)(8) gas molecules, by focused-electron or ion-beam-induced deposition. Due to the enhanced intergrain scattering in these granular wires, the extraordinary Hall effect can be increased by two orders of magnitude with respect to pure Co, up to a magnetic field sensitivity of 1 Omega T(-1). We show that the best magnetic field resolution at room temperature is obtained for Co ratios between 60% and 70% and is better than 1 microT Hz(-1/2). For an active area of the sensor of 200 x 200 nm(2), the room temperature magnetic flux resolution is phi(min) = 2 x 10( 5)phi(0) in the thermal noise frequency range, i.e. above 100 kHz. PMID- 20173237 TI - Optical properties and plasmon resonances of titanium nitride nanostructures. AB - We examine the optical properties of nanostructures comprised of titanium nitride, TiN, an electrically conducting intermetallic-like compound. This material can be deposited in the form of durable films by physical vapor deposition. Use of nanosphere templating techniques extends the range of nanostructures that can be produced to include the versatile semi-shell motif. The dielectric properties of TiN(1-x) depend upon stoichiometry and are favorable for plasmon resonance phenomena in the mid-visible to near-infrared range of the spectrum and for x approximately 0. We analyze the optical phenomena operating in such structures using a combination of experiment and simulation and show that semi-shells of TiN exhibit a tunable localized plasmon resonance with light. The material is, however, unsuitable for applications in which a long-distance surface plasmon polariton is desired. PMID- 20173238 TI - Ultraviolet photodetector arrays assembled by dielectrophoresis of ZnO nanoparticles. AB - Sensitive and fast ultraviolet sensor arrays have been produced by dielectrophoretic assembling of ZnO nanoparticles. The sub-micron device dimensions induce low operating voltage and low power consumption. The devices are long-term stable and operate in air, oxygen and nitrogen. We have determined the absorption and desorption dynamics from the time-resolved photoresponse and conclude that oxygen or carbon dioxide are the photodesorbed species. We could derive the charge carrier concentration and mobility of the device from measurements of the low-bias and high-bias photocurrent. The presence of defects is discussed by comparing electroluminescence spectra from biased devices with photoluminescence spectral maps of ZnO dispersions. PMID- 20173239 TI - Stimulation of neuronal neurite outgrowth using functionalized carbon nanotubes. AB - Low concentrations (0.11-1.7 microg ml(-1)) of functionalized carbon nanotubes (CNTs), which are multi-walled CNTs modified by amino groups, when added with nerve growth factor (NGF), promoted outgrowth of neuronal neurites in dorsal root ganglion (DRG) neurons and rat pheochromocytoma cell line PC12h cells in culture media. The quantity of active extracellular signal-regulated kinase (ERK) was higher after the addition of both 0.85 microg ml(-1) CNTs and NGF than that with NGF alone. CNTs increased the number of cells with neurite outgrowth in DRG neurons and PC12h cells after the inhibition of the ERK signaling pathway using a mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor. Active ERK proteins were detected in MEK inhibitor-treated neurons after the addition of CNTs to the culture medium. These results demonstrate that CNTs may stimulate neurite outgrowth by activation of the ERK signaling pathway. Thus, CNTs are biocompatible and are promising candidates for biological applications and devices. PMID- 20173240 TI - Mechanical properties of methyl functionalized graphene: a molecular dynamics study. AB - Molecular dynamics simulations have been performed to study the mechanical properties of methyl (CH(3)) functionalized graphene. It is found that the mechanical properties of functionalized graphene greatly depend on the location, distribution and coverage of CH(3) radicals on graphene. Surface functionalization exhibits a much stronger influence on the mechanical properties than edge functionalization. For patterned functionalization on graphene surfaces, the radicals arranged in lines perpendicular to the tensile direction lead to larger strength deterioration than those parallel to the tensile direction. For random functionalization, the elastic modulus of graphene decreases gradually with increasing CH(3) coverage, while both the strength and fracture strain show a sharp drop at low coverage. When CH(3) coverage reaches saturation, the elastic modulus, strength and fracture strain of graphene drop by as much as 18%, 43% and 47%, respectively. PMID- 20173241 TI - ZnO nanowire-embedded Schottky diode for effective UV detection by the barrier reduction effect. AB - A zinc oxide nanowire (ZnO NW)-embedded Schottky diode was fabricated for UV detection. Two types of devices were prepared. The ZnO NW was positioned onto asymmetric metal electrodes (Al and Pt) for a Schottky device or symmetric metal electrodes (Al and Al) for an ohmic device, respectively. The Schottky device provided a rectifying current flow and was more sensitive to UV illumination than the ohmic device. The Schottky barrier plays an important role for UV detection by a UV-induced barrier reduction effect. The fabrication of the ZnO NW-embedded Schottky diode and the UV reaction mechanism are discussed in light of the UV light-induced Schottky barrier reduction effect. PMID- 20173242 TI - The preparation of an elastomer/silicate layer nanocompound with an exfoliated structure and a strong ionic interfacial interaction by utilizing an elastomer latex containing pyridine groups. AB - A great variety of polymer/layered silicate (PLS) nanocomposites have been reported, however, there are few exfoliated PLS nanocomposites and their inorganic-organic interfaces are still a great problem, especially for the elastomers. In this research, a kind of exfoliated elastomer/silicate layer nanocompound was prepared and proved by XRD and TEM, in which 10 phr Na(+) montmorillonite was dispersed in butadiene-styrene-vinyl pyridine rubber by latex compounding method with acidic flocculants. Moreover, a dynamic mechanical thermal analyzer (DMTA) suggested a strong interfacial interaction (interaction parameter B(H) = 4.91) between the silicate layers and macromolecules in addition to the weak inorganic-organic interfacial interaction, and solid state (15)N NMR indicated the formation of a strong ionic interface through the acidifying pyridine. Subsequently, a remarkable improvement of the dispersing morphology, mechanical performance and gas barrier property appeared, compared to that using calcium ion flocculants. This supports the formation of an exfoliated structure and an improved interfacial interaction. PMID- 20173243 TI - Barrier layer non-uniformity effects in anodized aluminum oxide nanopores on ITO substrates. AB - Nanoporous anodic aluminum oxide (AAO) has been used widely as a template for device fabrication. In many nanostructured electro-optical device designs, AAO grown on an ITO substrate is the desired configuration. However, a residual thin aluminum oxide barrier layer between ITO and the AAO pores remains and process non-uniformities during the template fabrication can cause serious problems in the quality of nanowires deposited later in these pores. It was observed that in many templates, even the pores closest to each other could have their barrier layer thicknesses differ by as much as 10-20 nm. In this paper, causes and remedies for this non-uniformity are investigated, including the effects of a thin Ti interlayer inserted between the ITO and AAO. Templates with different Ti layer thickness and annealing conditions were compared. Mechanisms for the formation of voids beneath the barrier layer were analyzed and studied experimentally. Reactive ion etch (RIE) was found to be the preferred method to mitigate process non-uniformities. Using the above methods, barrier-free AAO templates on ITO substrates were obtained; their thicknesses ranged from 200 to 1000 nm. The characteristics of CdS nanowires electrodeposited into the initial templates with non-uniform barrier layer thicknesses and into the processed, barrier-free templates were compared. PMID- 20173244 TI - White light emission from Mn2 + doped ZnS nanocrystals through the surface chelating of 8-hydroxyquinoline-5-sulfonic acid. AB - White light emitting semiconductor nanocrystals (NCs) have been successfully synthesized from 8-hydroxyquinoline-5-sulfonic acid (HQS) decorated manganese doped ZnS NCs through fine tuning the surface-coordination emission and dopant emission of the NC host. The HQS functionalized manganese doped ZnS NCs (QS ZnS:Mn), with a cubic crystal structure, have the same diameter of about 4.0 nm as ZnS:Mn NCs without HQS. The intensity of the surface-coordination emission peak increased with increasing HQS content or augmenting excited wavelength. The emission of white light was achieved by carefully controlling the dosage of HQS in NCs and appropriately tuning the excited wavelength. The color coordinates (0.35, 0.34) for the efficient white light emitting NCs were very close to the ideal Commission Internationale de l'Eclairage (CIE) chromaticity coordinates for pure white light (0.33, 0.33). The photoluminescence (PL) decay study revealed that the white light emitting NCs exhibited maximum lifetime values at different emission peaks for different NC samples. The study results also indicated that the HQS molecules were attached to the surface of ZnS:Mn NCs in a single coordination fashion due to the steric hindrance effect of the special spherical surface of NCs, which made the QS-ZnS:Mn NCs possess stable and high fluorescent properties in different organic solvents as compared with the conventional small molecule complexes. PMID- 20173245 TI - pH-responsive silica nanoparticles for controllable 1O2 generation. AB - pH-responsive (1)O(2) photosensitizing systems may serve as selective photodynamic therapy (PDT) agents by targeting the acidic interstitial fluid of many kinds of tumors. In this work, we present a pH-responsive nanoparticle-based platform for controllable (1)O(2) generation, in which a hydrophobic (1)O(2) photosensitizer (meso-tetraphenylporphyrin, TPP) and a pH indicator (Bromocresol Purple, BCP, or Bromothymol Blue, BTB) are simultaneously encapsulated in organically modified silica nanoparticles (OSNP). In basic conditions, the pH indicator absorbs light competitively and thus restricts sensitizer excitation. In acidic solution, the blue shifted absorption of the pH indicator allows the efficient excitation of the sensitizer. The pH indicator serves as an 'inner filter' to modulate effectively the excitation of the sensitizer and thus the (1)O(2) generation efficiency. PMID- 20173246 TI - Ultrathin SiO2 layer with a low leakage current density formed with approximately 100% nitric acid vapor. AB - An ultrathin silicon dioxide (SiO(2)) layer with 0.65-1.5 nm thickness has been formed by approximately 100% nitric acid (HNO(3)) vapor oxidation, and its electrical characteristics and physical properties are investigated. The oxidation kinetics follows a parabolic law except for the ultrathin (0.05). In CAD patients with a high level of sICAM-1, C. albicans DNA was found more frequently than in patients without elevated levels of sICAM-1 (P<0.05). CONCLUSIONS: Mycotic DNA was found in the non-atherosclerotic aortic wall of CAD patients as well as in patients with AS. In the CAD patients C. albicans DNA was related to sICAM-1 expression. PMID- 20173304 TI - Effect of vessel size on lipid content of coronary plaques assessed by integrated backscatter intravascular ultrasound. AB - BACKGROUND: Tissue characterization of coronary plaques is feasible using integrated backscatter intravascular ultrasound (IB-IVUS), and higher lipid content has been found in the target lesions of acute coronary syndrome (ACS). The present study was performed to identify clinical and IVUS parameters that correlate with plaque composition assessed by IB-IVUS. METHODS AND RESULTS: A total of 109 patients (age 60.0+/-9.7 years) were evaluated with IVUS and IB-IVUS prior to percutaneous coronary intervention. Patients with ACS had a larger vessel size and higher plaque burden in the target lesion than those with stable angina. Relative lipid content of the target lesion by IB-IVUS was also higher in ACS (43.6%+/-12.0% vs 29.9%+/-14.2%; P<0.001). The remodeling index (r=0.403, P<0.001), plaque burden (%) (r=0.495, P<0.001), and vessel size (r=0.572, P<0.001) significantly correlated with lipid content. In the multiple regression analysis, vessel size was the most important independent predictor of lipid content followed by presence of ACS and the remodeling index. CONCLUSIONS: ACS, positive remodeling, and larger plaque burden were associated with higher lipid content of coronary plaque. However, the lipid content on IB-IVUS was also significantly affected by vessel size. Therefore, qualitative, morphologic assessment of coronary plaque rather than simple quantitative analysis of tissue components seems to be more appropriate for the identification of vulnerable plaque using IB-IVUS. PMID- 20173303 TI - Impact of high-responsiveness to dual antiplatelet therapy on bleeding complications in patients receiving drug-eluting stents. AB - BACKGROUND: Few studies have examined whether high-responsiveness to antiplatelet therapy is associated with an increased risk of bleeding in patients receiving dual antiplatelet therapy. METHODS AND RESULTS: Elective drug-eluting stent implantation was performed in 184 patients treated with aspirin and a thienopyridine (200 mg/day of ticlopidine or 75 mg/day of clopidogrel). The subjects were divided into 3 groups according to post-treatment platelet reactivity before stenting as measured by the response to adenosine diphosphate: the 1(st) quartile group was defined as high-responders, the 4(th) as low responders, and the other 2 quartiles as middle-responders. Major bleeding occurred more frequently in high-responders than in middle- or low-responders during an average of 16 months' follow-up (15 vs 4, 2%, P=0.02). High responsiveness was the independent predictor of major bleeding (odds ratio 4.26, P=0.03). Adverse cardiac events were less frequent in high- and middle-responders than in low-responders (24, 16 vs 37%, P=0.02). Middle-responders had better net clinical outcomes, defined as the sum of major bleeding and adverse cardiac events, than did high- or low-responders (21 vs 39, 39%, P=0.02). CONCLUSIONS: In the present study high-responsiveness to antiplatelet therapy was associated with an increased risk of bleeding with no reduction in adverse cardiac events. Measuring platelet reactivity may be useful for risk stratification according to bleeding complications, as well as adverse cardiac events, in patients treated with drug-eluting stents. PMID- 20173305 TI - Protective effects of estrogen against reperfusion arrhythmias following severe myocardial ischemia in rats. AB - BACKGROUND: Female sex hormones may have protective effects against arrhythmias, including reperfusion arrhythmias (RAs), but the mechanisms are still not completely known. METHODS AND RESULTS: Serial changes in rat hearts (rhythm, apoptosis and the its infuencing factors; cardiac vinculin mRNA expression and connexin43 (Cx43) dephosphorylation) were examined during periods of ischemia reperfusion with and without estrogen treatment. After reperfusion, although the incidence of arrhythmias became higher in both the vehicle-group and estrogen group, compared with the ischemia period, estrogen prevented reperfusion-induced upregulation of the incidence of arrhythmias, especially ventricular premature beats (VPB) and ventricular tachycardia (VT). The duration of VT and fibrillation, and the number of VPB and VT, were all significantly decreased in the estrogen-group. The expression of cardiac vinculin mRNA decreased significantly in the vehicle-group but not in the estrogen-group. Cx43 dephosphorylation and myocyte apoptosis increased in both groups, but the values for the estrogen-group were all markedly lower than those for the vehicle-group. A selective estrogen receptor (ER) beta agonist prevented reperfusion-induced upregulation of the incidence of both VPB and VT significantly; a selective ERalpha agonist had no significant influence. CONCLUSIONS: Estrogen can protect the heart against RAs, at least in part, mediated through gap junctions. Upregulation of ERbeta but not ERalpha mediated most of the estrogen-induced cardioprotection against RA. PMID- 20173306 TI - Glucocorticoid-induced gene tripartite motif-containing 63 (TRIM63) promotes differentiation of osteoblastic cells. AB - Glucocorticoids exert their function by regulating glucocorticoid-responsive genes through interaction with glucocorticoid receptor alpha (GRalpha), a nuclear receptor. Glucocorticoids also affect bone metabolism; this is evidenced by the fact that GRalpha is expressed in several kinds of cells in bone tissue, including osteoblasts, osteocytes, osteoclasts, mononuclear cells in bone marrow, and hypertrophic chondrocytes. Glucocorticoids are known to induce osteoblastic differentiation and bone formation. However, this effect of glucocorticoids on bone tissue is still controversial since long-term use of glucocorticoids results in osteoporosis in vivo. To identify glucocorticoid-regulated genes in human osteoblastic cells, SaOS2 cells were treated with dexamethasone (10(-8) M) for 6 hours, and were then subjected to microarray analysis. Genes such as C/EBPdelta, DUSP1, Per1 and TRIM63 were found to be induced by dexamethasone. The induction of mRNAs of these genes by dexamethasone (10(-8) M, 10(-7) M, and 10(-6) M) was confirmed by quantitative real-time polymerase chain reaction (PCR). TRIM63, also called muscle-specific ring finger protein 1 (MuRF1), was reported to be an E3 ubiquitin ligase expressed mainly in muscular tissue. SaOS2 cells overexpressing exogenous TRIM63 showed increased expression of an osteoblastic differentiation marker gene, alkaline phosphatase, with reduced proliferation. These results suggest that TRIM63 is a candidate for genes mediating the glucocorticoid-induced promotion of osteoblastic differentiation. PMID- 20173307 TI - Chronic CRP-exposure inhibits VEGF-induced endothelial cell migration. AB - C-reactive protein (CRP) is a pluripotent mediator of inflammation and is present at sites of vascular injury and in atherosclerotic lesions. CRP stimulates endothelial cell adhesion molecule expression and monocyte migration, thereby contributing to the development and progression of vascular lesion formation. In addition, chronic exposure to CRP is known to inhibit angiogenesis and endothelial cell (EC) proliferation. AIM: Whether CRP also affects EC migration, however, has yet to be determined. The present study investigates how long-term exposure to CRP interacts with vascular endothelial growth factor (VEGF) -induced EC migration. METHODS AND RESULTS: Using a Transwell chamber migration assay, VEGF (20 ng/mL, 5 h incubation)-induced migration of human umbilical vein EC was significantly inhibited in cells pretreated with CRP (10 microg/mL) for 24 h by more than 75%. EC migration in response to VEGF is known to require activation of the protein kinase B (Akt)/endothelial NO synthase (eNOS)- and the extracellular signal-regulated protein kinase 1/2 (ERK1/2) pathway. We therefore investigated the long-term effects of CRP on these signalling events. Immunoblotting with phosphospecific antibodies revealed rapid and transient activation/phosphorylation of the protein kinase Akt within 20 minutes after stimulation with VEGF, which was inhibited by 86% in EC pretreated with CRP (10 microg/mL, 24 h, p<0.05). Subsequent VEGF-induced phosphorylation of eNOS downstream of Akt was completely inhibited in CRP-treated EC. In contrast, CRP pretreatment did not affect VEGF-induced phosphorylation of ERK1/2. Interestingly, stimulation of EC with CRP for 16-24 h induced marked expression of the phosphatase and tensin homolog (PTEN), which functions as a negative regulator of phosphatidylinositol 3 kinase (PI3K) -->Akt signalling. CONCLUSION: The observed time course for CRP-mediated PTEN upregulation corresponds to the exposure time needed for inhibition of Akt phosphorylation and migration and may therefore constitute a potential mechanism by which CRP inhibits inducible Akt phosphorylation and EC migration. PMID- 20173309 TI - Blockade of glycine transporter (GlyT) 2, but not GlyT1, ameliorates dynamic and static mechanical allodynia in mice with herpetic or postherpetic pain. AB - Glycine is an inhibitory neurotransmitter in the spinal dorsal horn and its extracellular concentration is regulated by glial glycine transporter (GlyT) 1 and neuronal GlyT2. This study was conducted to elucidate the effects of intrathecal injections of GlyT1 and GlyT2 inhibitors on two distinct types of mechanical allodynia, dynamic and static allodynia, in mice with herpetic or postherpetic pain. The GlyT2 inhibitor ALX1393, but not the GlyT1 inhibitor sarcosine, suppressed dynamic and static allodynia at the herpetic and postherpetic stages. Intrathecal ALX1393 suppressed dynamic allodynia induced by intrathecal strychnine and N-methyl-D-aspartate (NMDA). Intrathecal sarcosine suppressed dynamic allodynia induced by intrathecal strychnine, but not NMDA. Expression level of GlyT1, but not GlyT2, mRNA in the lumbar dorsal horn was decreased at the herpetic and postherpetic stages. Glycine receptor alpha1 subunit mRNA was decreased in the lumbar dorsal horn at the herpetic, but not postherpetic stage, without alteration in alpha3-subunit mRNA. The results suggest that GlyT2 is a potential target for treatment of dynamic and static allodynia in patients with herpes zoster and postherpetic neuralgia. The lack of efficacy of GlyT1 inhibitor may be explained by activation of NMDA receptors and the down-regulation of GlyT1 in the lumbar dorsal horn. PMID- 20173308 TI - Factors to consider in the association between soy isoflavone intake and breast cancer risk. AB - It has been suggested that soy isoflavones have protective effects against breast cancer. However, data from epidemiological studies are not conclusive. A recent meta-analysis showed that soy intake was inversely associated with breast cancer risk in Asian but not Western populations, which indicates that protection against breast cancer may require that women consume levels of soy typical in Asian diets. In addition to the amount of soy isoflavones consumed, the form and food source of isoflavones, timing of isoflavone exposure, estrogen receptor status of tumors, and equol-producer status and hormonal profile of individuals may modify the association between soy isoflavone intake and the risk of breast cancer. These factors might explain the heterogeneity of results from studies. This present report contrasts background data from Japanese and Western women to identify the potential modifying of these factors. PMID- 20173310 TI - Dictyostelium differentiation-inducing factor-1 binds to mitochondrial malate dehydrogenase and inhibits its activity. AB - We have reported that the differentiation-inducing factors (DIFs) DIF-1 and DIF 3, morphogens secreted from Dictyostelium discoideum, inhibit proliferation of several cancer cells via suppression of the Wnt/beta-catenin signaling pathway. However, the target molecules of DIFs involved in the anti-proliferative effects are still unknown. In the present study, DIF-1-tethered resins were synthesized to explore the target molecules of DIFs, and mitochondrial malate dehydrogenase (mMDH) was identified as one of the target molecules. In the in vitro assay, DIF 1 and other analogs including 2-MIDIF-1, DIF-3, and 6-MIDIF-3 were found to be capable of binding to mMDH but not to cytoplasmic MDH. However, only DIF-1 and 2 MIDIF-1 inhibited the enzymatic activity of mMDH. The effects of DIF analogs on ATP content and cell proliferation were then analyzed using HeLa cells. DIF-1 and 2-MIDIF-1 were found to lower the ATP content and both chemicals inhibited HeLa cell proliferation, suggesting that inhibition of mMDH activity affected cell energy production, probably leading to the inhibition of proliferation. These results suggest that the inhibition of mMDH activity by DIF-1 and 2-MIDIF-1 could be one of the mechanisms to induce anti-proliferative effects, independent of the inhibition of the Wnt/beta-catenin signaling pathway. PMID- 20173311 TI - Cellular Ca2+ dynamics in urinary bladder smooth muscle from transgenic mice overexpressing Na+-Ca2+ exchanger. AB - The rise of Ca(2+) concentration ([Ca(2+)](i)) by reducing external Na(+) in urinary bladder smooth muscle cells (UBSMCs) from transgenic mice overexpressing Na(+)/Ca(2+) exchanger type-1.3 (NCX1.3(tg/tg)) was about 4 times as large as that in the wild-type (WT). NCX1 protein expression in UB increased about 4-fold in NCX1.3(tg/tg). The Ca(2+) release by caffeine in UBSMCs was comparable between NCX1.3(tg/tg) and WT, but [Ca(2+)](i) decay was faster in NCX1.3(tg/tg). Contractions induced by acetylcholine, 60 mM K(+), or electrical stimulation were significantly smaller in UB segments of NCX1.3(tg/tg). NCX worked in Ca(2+) extrusion mode during these contractions in UBSMCs of both WT and NCX1.3(tg/tg). PMID- 20173312 TI - Mechanisms of chronic nicotine treatment-induced enhancement of the sensitivity of cortical neurons to the neuroprotective effect of donepezil in cortical neurons. AB - We have previously shown that chronic donepezil treatment induces nicotinic acetylcholine receptor up-regulation and enhances the sensitivity of the neurons to the neuroprotective effect of donepezil. Further analyses revealed that the nicotinic receptor is involved in this enhancement. In this study, we examined whether nicotinic receptor stimulation is sufficient to make neurons more sensitive to donepezil. We treated primary cultures of rat cortical neurons with nicotine and confirmed that chronic nicotine treatment induced nicotinic receptor up-regulation and made the neurons more sensitive to the neuroprotective effects of donepezil. Analyses with receptor antagonists and kinase inhibitors revealed that the effects of chronic nicotine treatment are mediated by nicotinic receptors and their downstream effectors including phosphatidylinositol 3-kinase. In contrast to chronic donepezil treatment that enhanced the level of nicotine induced Ca(2+) influx, chronic nicotine treatment did not significantly alter the level of Ca(2+) influx. PMID- 20173313 TI - Current advancement in radiation therapy for uterine cervical cancer. AB - Radiation therapy is one of the effective curative treatments for uterine cervical cancer. However poor clinical results for the advanced stages require further improvement of the treatment. Intensive studies on basic and clinical research have been made to improve local control, primarily important for long term survival in radiation therapy. Regarding current advancement in radiation therapy for uterine cervical cancer, the following three major subjects are pointed out; technological development to improve dose distribution by image guided radiation therapy technology, the concomitant anticancer chemotherapy with combination of radiation therapy, and radiation biological assessment of the radiation resistance of tumors. The biological factors overviewed in this article include hypoxia relating factors of HIF-1alpha, SOD, cell cycle parameters of pMI, proliferation factors of Ki67, EGFR, cerbB2, COX-2, cycle regulation proteins p53, p21, apoptosis regulation proteins Bcl2 and Bax and so on. Especially, the variety of these radiation biological factors is important for the selection of an effective treatment method for each patient to maximize the treatment benefit. PMID- 20173301 TI - Sex-related differences in the risk factor profile and medications of patients with atrial fibrillation recruited in J-TRACE. AB - BACKGROUND: Clinical characteristics, including risk factors for thromboembolism, and medications differ between men and women with atrial fibrillation (AF) in Western countries. Whether such a difference exists for Japanese patients with AF is unclear, so data from J-TRACE were used to investigate this issue. METHODS AND RESULTS: A total of 2,892 patients (2,028 men, 864 women; 70.3 years old) with AF were analyzed for the respective prevalences of risk factors and medications. CHADS2 score was calculated to determine thromboembolic risk level. Women were older (P<0.001), and more frequently had heart failure (P<0.001), and hypertension (P=0.051) than men. The proportion of subjects aged 75 years or older was higher among women than among men (P<0.001). CHADS2 score was therefore significantly higher in women than in men (2.05+/-1.29 vs 1.88+/-1.33, P<0.001). Sex-related differences were not observed for the prevalence of diabetes mellitus, myocardial infarction or ischemic stroke, nor did warfarin usage differ between men and women. CONCLUSIONS: Sex-related differences were observed in the risk factor profile and medications of Japanese patients with AF. CHADS2 score was higher in women than in men. PMID- 20173314 TI - Comparison of DNA breaks at entrance channel and Bragg peak induced by fast C6+ ions--influence of the addition of platinum atoms on DNA. AB - When energetic carbon ion beam (GeV range) goes through the matter, inelastic processes such as electronic ionization, molecular and nuclear fragmentation occur. For carbontherapy (hadrontherapy) purpose, it is of interest to compare the number of DNA breaks -single SSB or double DSB- for a given dose at the entrance channel and at the Bragg peak to look for a possible differential effect in the number of DNA breaks induced at these two locations. Samples of free plasmids DNA and complexes of plasmids DNA added with molecules containing platinum have been placed at different locations of an experimental setup simulating penetration depths of the ion beam in water and irradiated by carbon ions 290 MeV/amu. The DNA breaks have been quantified by subsequent electrophoresis on agarose gels. To disentangle the respective role of the direct and indirect effect, a free radical scavenger of hydroxyl radicals HO degree dimethylsulfoxide DMSO- has been added in some of the experiments. In the range of Linear Energy Transfer-LET 13 - 110 keV/microm-, the number of the DSB was found to be constant versus the LET for a given dose. Contrary, the number of the SSB decreases at the Bragg peak compared to the entrance channel. In the presence of platinum, the number of single and double breaks was considerably enhanced, and follows a similar behaviour than in the free-DNA experiments. Quantitative results on DNA damages do not show significant enhancement due to the nuclear or to the molecular fragmentation in the present experiments. PMID- 20173315 TI - Hepatic cholesterol metabolism following a chronic ingestion of cesium-137 starting at fetal stage in rats. AB - The Chernobyl accident released many radionuclides in the environment. Some are still contaminating the ground and thus the people through dietary intake. The long-term sanitary consequences of this disaster are still unclear and several biological systems remain to be investigated. Cholesterol metabolism is of particular interest, with regard to the link established between atherosclerosis and exposure to high-dose ionizing radiations. This study assesses the effect of cesium-137 on cholesterol metabolism in rats, after a chronic exposure since fetal life. To achieve this, rat dams were contaminated with cesium-137 supplemented water from two weeks before mating until the weaning of the pups. Thereafter, the weaned rats were given direct access to the contaminated drinking water until the age of 9 months. After the sacrifice, cholesterol metabolism was investigated in the liver at gene expression and protein level. The cholesterolemia was preserved, as well as the cholesterol concentration in the liver. At molecular level, the gene expressions of ACAT 2 (a cholesterol storage enzyme), of Apolipoprotein A-I and of RXR (a nuclear receptor involved in cholesterol metabolism) were significantly decreased. In addition, the enzymatic activity of CYP27A1, which catabolizes cholesterol, was increased. The results indicate that the rats seem to adapt to the cesium-137 contamination and display modifications of hepatic cholesterol metabolism only at molecular level and within physiological range. PMID- 20173316 TI - The foci of DNA double strand break-recognition proteins localize with gammaH2AX after heat treatment. AB - Recently, there have been many reports concerning proteins which can recognize DNA double strand break (DSBs), and such proteins include histone H2AX phosphorylated at serine 139 (gammaH2AX), ataxia telangiectasia mutated (ATM) phospho-serine 1981, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) phospho-threonine 2609, Nijmegen breakage syndrome 1 (NBS1) phospho-serine 343, checkpoint kinase 2 (CHK2), phospho-threonine 68, and structural maintenance of chromosomes 1 (SMC1) phospho-serine 966. Thus, it should be possible to follow the formation of DSBs and their repair using immunohistochemical methods with multiple antibodies to detect these proteins. When normal human fibroblasts (AG1522 cells) were exposed to 3 Gy of X-rays as a control, clearly discernable foci for these proteins were detected, and these foci localized with gammaH2AX foci. After heat treatment at 45.5 degrees C for 20 min, these proteins are partially localized with gammaH2AX foci. Here we show that there were slight differences in the localization pattern among these proteins, such as a disappearance from the nucleus (phospho-ATM) and translocation to the cytoplasm (phospho-NBS1) at 30 min after heat treatment, and some foci (phospho-DNA-PKcs and phospho-CHK2) appeared at 8 h after heat treatment. These results are discussed from perspectives of heat-induced denaturation of proteins and formation of DSBs. PMID- 20173318 TI - Ultrasound in labor and delivery. AB - Ultrasound may play an important role in the management of labor and delivery. Induction of labor is a common obstetric intervention, performed in about 20% of pregnancies. Pre-induction cervical length, measured by transvaginal sonography, has been shown to have a significant association with the induction-to-delivery interval and the risk for cesarean section. In the management of labor there is extensive evidence that digital pelvic examination does not provide accurate assessment of the position and descend of the fetal head both during the first but also in the second stage of labor. Several recent studies using both two- and three-dimensional ultrasound have now described objective measures of progression of the fetal head during labor. In instrumental deliveries an important determinant of a successful and safe use of vacuum and forceps is the correct determination of the fetal head position and appropriate application of the instrument. However, ultrasound studies have shown that digital examination before instrumental delivery fails to identify the correct fetal position in a high proportion of cases. The use of ultrasound is of crucial importance in performing a safe operative delivery and can help in the prediction of whether a vaginal delivery would be successful. PMID- 20173319 TI - Current-day prevalence of Meniere's syndrome. AB - Previously reported prevalence rates of Meniere's syndrome (MS) have ranged from 3.5 per 100000 to 513 per 100000. Recent data regarding the prevalence in the United States are lacking. To further assess the current-day prevalence of MS in the US, data from a medical and pharmaceutical claims database containing information for over 60 million unique patients were analyzed. Patients in the database are representative of the national, commercially insured population on a variety of demographic measures including age, gender, health plan type, and geographic location. A 3-year period from 2005 to 2007 was analyzed. The prevalence of MS was 190 per 100000 with a female:male ratio of 1.89:1. The prevalence increased with increasing age, ranging from 9 per 100000 for patients under age 18 to 440 per 100000 for patients 65 years and older. PMID- 20173321 TI - Perfusion-weighted MRI as a predictor of clinical outcomes following medullary infarctions. AB - BACKGROUND: Perfusion-weighted imaging (PWI) is rarely used to evaluate cases of posterior circulation infarctions. We evaluated clinical outcomes, diffusion weighted imaging (DWI) patterns and angiographic findings in patients experiencing medullary infarctions according to PWI results. METHODS: Data from consecutive patients with acute ischemic lesions primarily involving the medulla were analyzed. All patients underwent MRI including DWI, PWI and MR angiography. The patients were grouped according to the presence or absence of a perfusion delay in the medulla and/or inferior cerebellum. RESULTS: Among 35 patients, all but 1 had a PWI of interpretable quality. Of these 34 patients, 18 had a normal perfusion status, while 16 had perfusion defects in the medulla and/or inferior cerebellum. The abnormal PWI group had poor clinical outcomes at 7 days and 1 month after the onset of symptoms. There was no difference in DWI patterns between these 2 groups. The angiographic findings demonstrated that a stenosis of >or=50% or an occlusion of the ipsilesional vertebral artery was frequently observed in the abnormal PWI group (p = 0.001). Multivariate analysis revealed that abnormal PWI and DWI patterns were independently associated with poor early and late outcomes following medullary infarctions. CONCLUSIONS: PWI may be a feasible modality for assessing the perfusion status of the posterior circulation and predicting clinical outcomes following medullary infarctions. PMID- 20173322 TI - Dynamic susceptibility contrast perfusion MRI identifies persistent vessel pathology in acute pontine stroke. AB - BACKGROUND: In large territorial stroke of the anterior and the posterior circulation, the extent of affected tissue can be characterized by the demonstration of vessel occlusion on MR angiography (MRA), while the extent of hypoperfusion can be shown on dynamic susceptibility contrast perfusion-weighted MRI (PWI). The ability of MRA and conventional MRI sequences to demonstrate branches of the basilar artery (BA) is very limited. This study analyzes the value of the combined use of diffusion-weighted MRI (DWI), MRA and PWI in acute pontine stroke. METHODS: A series of 24 consecutive patients with acute pontine stroke received an extensive MRI stroke workup including DWI, PWI and MRA. RESULTS: In 11/24 patients visual analysis of PWI demonstrated persisting hypoperfusion, and in 1/24 patients indication of hyperperfusion was found. Vessel abnormalities were seen in 19/24 patients (15/24 hypoplastic vertebral artery, 9/24 stenosis or occlusion of the BA, 1/20 ectatic BA). Persistent pontine hypoperfusion was more frequently associated with BA pathology (9/11 vs. 1/13, p = 0.001), large-vessel disease (8/11 vs. 1/13; p = 0.001) and a more pronounced clinical deficit (NIHSS score on day 1: 7 vs. 3, p = 0.01). CONCLUSIONS: In pontine ischemia areas of hypoperfusion can be identified due to the strong contrast induced by ischemia on PWI and can be easily related to DWI lesion size. This is of use particularly as small vessels are frequently missed by MRA and occlusion of the BA can be better characterized with the help of PWI. PMID- 20173320 TI - Fluid overload in critically ill patients with acute kidney injury. AB - Fluid overload may occur in critically ill patients as a result of aggressive resuscitation therapies. In such circumstances, persistent fluid overload must be avoided since it does not benefit the patient while it may be harmful. In the septic patient, early volume expansion seems to be beneficial. Beyond that threshold, when organ failure develops, fluid overload has been shown to be associated with worse outcomes in multiple disparate studies. One well-designed randomized controlled trial showed the benefit of a conservative fluid management strategy based on limited fluid intake and use of furosemide in such patients. Use of diuretics should be only short term as long as it is effective, generally at high doses, while avoiding simultaneous utilization of nephrotoxins such as aminoglycosides. Multiple randomized controlled trials have not shown benefit in the use of diuretics, either to prevent AKI or to treat established AKI. If fluid overload (defined as fluid accumulation >10% over baseline) develops and the patient does not respond to diuretics, persistent use of these drugs will only lead to a delay in the initiation of dialysis or ultrafiltration and an increased risk of negative patient outcomes. In that setting, early initiation of continuous renal replacement therapies may be preferable. PMID- 20173324 TI - Favorable outcome of pregnancy with an elective use of epoprostenol and sildenafil in women with severe pulmonary hypertension. AB - BACKGROUND: Pulmonary hypertension carries significant maternal and fetal risk during pregnancy and the postpartum period. As maternal mortality is high, specific targeted therapy for pulmonary hypertension may be required during pregnancy. CASES: We describe 2 pregnant patients who presented with severe secondary pulmonary arterial hypertension during their last trimester. They were electively treated in the late antepartum and early postpartum periods with sildenafil and intravenous epoprostenol and successfully delivered healthy infants via cesarean section without postpartum complications. CONCLUSION: Although pulmonary hypertension is associated with a risk of maternal mortality and most women are advised against pregnancy, new therapies may improve the outcome of pregnancy in patients with pulmonary hypertension. PMID- 20173323 TI - Associations of clinical stroke misclassification ('clinical-imaging dissociation') in acute ischemic stroke. AB - BACKGROUND: Up to 20% of lacunar infarcts are clinically misdiagnosed as cortical infarcts and vice versa. The reasons for this discrepancy are unclear. We assessed clinical and imaging features which might explain this 'clinical-imaging dissociation' (C-ID). METHODS: Patients with an acute stroke syndrome (cortical or lacunar) underwent magnetic resonance imaging including diffusion-weighted imaging (DWI). We recorded DWI-positive infarcts and proximity to cortex for small subcortical infarcts. We examined factors associated with C-ID. RESULTS: 137 patients with a mild cortical or lacunar syndrome had an acute ischemic lesion on DWI. Of these, 21/93 (23%) with a cortical syndrome had an acute lacunar infarct and 7/44 (16%) with a lacunar syndrome had an acute cortical infarct. From 72 patients with an acute lacunar infarct on DWI, lesion proximity to cortex (odds ratio (OR) 14.5, 95% confidence interval (CI) 1.61-130.1), left hemisphere location (OR 8.95, 95% CI 1.23-64.99) and diabetes (OR 17.1, 95% CI 1.49-196.16) predicted C-ID. On multivariate analysis of all 137 patients, C-ID was associated with diabetes (OR 7.12, 95% CI 1.86-27.2). CONCLUSIONS: C-ID occurs in a fifth of patients with mild stroke. Lacunar infarcts lying close to cortex are more likely to cause cortical symptoms. Diabetes is associated with any clinical-imaging mismatch. Stroke misclassification which can arise with clinical classification alone should be minimized in research by verification with high-sensitivity imaging. PMID- 20173325 TI - Nano-indentation characterisation of natural carious white spot lesions. AB - The aim of this paper was to characterise the mechanical properties (MPs) and microstructural features of natural enamel white spot lesions (WSLs) using nano indentation. Five natural WSLs from 4 extracted sound premolar teeth were cross sectioned. Elastic modulus and hardness were measured systematically across the WSLs at intervals of 25 and 50 microm. The WSLs showed a large reduction in MPs compared to sound counterpart: elastic modulus was up to 83% lower (77.0 +/- 2.2 to 13.4 +/- 2.1 GPa) and hardness up to 91% lower (3.39 +/- 0.41 to 0.29 +/- 0.07 GPa). The intact surface layer above WSLs had less than 34% reduction in MPs. Detailed MP measurements were mapped as two-dimensional contour plots. Typically, WSLs displayed steep MP gradients at the lesion boundary and more uniform MPs with isolated variations in the lesion body. Despite the large reduction in MPs, the microstructure of WSLs remained intact. We postulate that loss of mineral and change of the hierarchical microstructure at the crystallite level contributed to the overall MPs of WSLs. PMID- 20173326 TI - Transcranial Doppler for brain death in infants: the role of the fontanelles. AB - OBJECTIVE: Transcranial Doppler (TCD) is a sensitive technique for circulatory arrest diagnosis in brain death when patterns such as reverberant flow and short systolic spikes are observed. In infants, the nonossified fontanelles compensate for intracranial hypertension. We describe TCD patterns in infants with brain death, different from adults, with the hemodynamic modifications induced by anterior fontanelle compression. METHOD: TCD was performed in 2 infants with diagnosed brain death admitted to the neonatal intensive care unit. RESULTS: TCD showed a large peak 'reverberant' flow, with a high peak systolic velocity and a consistent retrograde component, away from the brain. Compression of the anterior fontanelle induced, at first, a reduction in systolic flow with the subsequent appearance of the characteristic short systolic spikes. Upon compression removal, a brief increase in the systolic flow was observed before the prompt reappearance of the reverberant flow. CONCLUSION: TCD for brain death diagnosis should be done cautiously in infants. In these cases, reverberating flow may be indicative of circulatory arrest even if with a large peak and with a high peak systolic velocity. Heavy fontanelle compression may reproduce the classical adult TCD patterns of brain death, thus supporting the diagnosis of cerebral circulatory arrest. PMID- 20173327 TI - Administration of intravenous albumin around the time of oocyte retrieval reduces pregnancy rate without preventing ovarian hyperstimulation syndrome: a systematic review and meta-analysis. AB - BACKGROUND/AIM: The aim of this meta-analysis was to evaluate whether IV albumin infusion around the time of oocyte retrieval prevents ovarian hyperstimulation syndrome (OHSS) and affects the pregnancy rate. METHODS: A meta-analysis of data from 9 randomized controlled trials including 1,613 women at high risk for developing OHSS in in vitro fertilization cycles was performed. RESULTS: The combined incidence of severe OHSS was 6.0% in the IV albumin group and 7.9% in saline or no treatment groups. These rates were statistically not different (RR = 0.80, 95% CI = 0.57-1.12). Treatment with IV albumin significantly lowered the pregnancy rates (RR = 0.85, 95% CI = 0.74-0.98). CONCLUSIONS: The combined data presented in this meta-analysis do not support a benefit for IV albumin around the time of oocyte retrieval in preventing OHSS and even showed a deleterious effect on the pregnancy rate. PMID- 20173328 TI - Acetylcholinesterase variants in Alzheimer's disease: from neuroprotection to programmed cell death. AB - BACKGROUND: In Alzheimer's disease (AD), cholinergic neurons are particularly vulnerable for as yet unclear reasons. Here, we report that modified composition, localization and properties of alternative splice variants encoding the acetylcholine-hydrolyzing enzyme acetylcholinesterase (AChE) may be variably involved in disease progression or in systemic efforts to attenuate its progression. OBJECTIVE: The purpose of this study was to explore the implications for AD of the cellular and biochemical properties of the various AChE proteins, differing in their N and C termini. METHODS: We have used cell transfection with genetically engineered vectors as well as microinjection to overexpress specific AChE variants and explore the consequences to cellular well-being and survival. Additionally, we employed highly purified recombinant AChE-R and AChE-S to explore putative interactions with the AD beta-amyloid peptide. RESULTS: Our findings demonstrate distinct, and in certain cases inverse cell fate outcome under enforced expression of the human N- and C-terminally modified AChE variants, all of which have similar enzymatic activities. CONCLUSION: The N terminal extension in conjunction with the primary helical C-terminal peptide of 'tailed' AChE-S facilitates, whereas the shorter, naturally unfolded C-terminus of the stress-induced AChE-R variant attenuates Alzheimer's pathology. PMID- 20173329 TI - Neuroprotective and neurotoxic phenotypes of activated microglia in neonatal mice with respective MPTP- and ethanol-induced brain injury. AB - Activated microglia play important roles in the inflammatory process and progression in Parkinson's disease. These cells produce various cytokines, nitric oxide, and neurotrophins, which are pleiotropic in their action, i.e., neuroprotective or neurotoxic. In an in vivo study on a mouse model with nigrostriatal lesions produced by the administration of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), microglia activated by systemic lipopolysaccharide (LPS) were neurotoxic toward dopamine neurons in aged mice, but unexpectedly, neuroprotective in neonatal mice. In contrast to microglia in the MPTP model, LPS activated microglia in neonatal mice in a model made by the stereotaxic injection of ethanol into the striatum were neurotoxic, and systemic LPS administration in the ethanol-injury model caused marked increases both in the volume of necrotic lesions and in the number of degenerative neurons in the striatum. Thus, activated microglia in the neonatal mouse brain play either a neuroprotective or neurotoxic role depending on the type of brain injury. PMID- 20173331 TI - Misframed proteins and neurodegeneration: a novel view on Alzheimer's and Parkinson's diseases. AB - Sporadic forms of Alzheimer's and Parkinson's diseases are the most frequent forms of their kind. Together with Huntington's disease, they belong to the so called 'conformational diseases' as they share a common feature in the accumulation of insoluble protein deposits. In this review, we focus on the significance of the ubiquitin-proteasome system in conformational diseases and the possible consequences due to the accumulation of aberrant proteins. In all forms of Alzheimer's and Huntington's diseases, but not in Parkinson's disease, we have shown the presence of misframed proteins such as misframed ubiquitin (UBB(+1)) of which we have determined the functional relevance in vitro and in vivo.Misframed proteins are the result of the inaccurate transcription of monotonic sequences in the genome and their subsequent translation. This process has been called 'molecular misreading'. In the present review, we will discuss the present state of the art with regard to UBB(+1) and amyloid precursor protein APP(+1). PMID- 20173330 TI - LRRK2 and the stress response: interaction with MKKs and JNK-interacting proteins. AB - Increasing evidence supports a putative link between LRRK2 function and the MAP kinase cascades. We recently demonstrated that LRRK2 binds to MKK6, -3, and -7. Previous studies demonstrated that scaffold proteins are essential in the regulation of subcellular localization of stress kinase complexes. The c-jun NH2 terminal kinase (JNK)-interacting proteins (JIPs) are a group of scaffold proteins that play an important role in the regulation of MAP kinase signaling cascades. JIP1-3 are known to regulate the specificity and localization of the JNK pathway, while JIP4 is a specific scaffolding protein for the p38 pathway. We demonstrate that LRRK2 binds to JIP1-4, and is associated with increased levels of total JIP1, -3, -4, oligomeric JIP and ubiquitinated JIP. These results are consistent with a putative role of LRRK2 in regulating the stress kinase cascade. PMID- 20173333 TI - Stem cell biology in the study of pathological conditions. AB - The current focus of researchers is to create certain types of cells in vitroas transplantation materials. The problem of this approach is that terminally differentiated cells may not integrate into the host. To overcome this problem, we may want to transplant premature cells, which can migrate and differentiate due to environmental cues received from the host, allowing for intrinsic proper functioning of the cells. Thus, we have to consider the effects that the pathological environment might have on the transplanted cells. Here, we show the effects of amyloid precursor protein and reelin on neural stem cell (NSC) differentiation, and demonstrate how we have regulated this effect to produce desirable cells under pathological conditions. We found that amyloid precursor protein increases glial differentiation via the notch and cytokine-signaling pathway, while reelin induces radial glial differentiation followed by neuronal differentiation via increasing phosphorylation of adapter protein disabled-1. Since amyloid and reelin are found in plaques within Alzheimer's disease, these findings may closely associate with NSC biology in the context of its pathology. By regulating these factors in Alzheimer's disease, we may be able to not only guide differentiation of transplanted NSCs, but also to modify progression of disease by guiding differentiation of endogenous NSCs. PMID- 20173332 TI - Impaired neurotransmitter release in Alzheimer's and Parkinson's diseases. AB - Mutations in several causative genes have been linked to monogenic forms of Alzheimer's disease (AD) or Parkinson's disease (PD). To look for possible common pathogenic mechanisms underlying age-related neurodegeneration in AD and PD, we employed genetic approaches to investigate systematically the roles of these gene products (e.g. presenilins (PS) for AD; Parkin, DJ-1, PINK1 and LRRK2 for PD) in the mouse brain, especially in neural circuits that are particularly vulnerable in AD or PD. Our series of genetic studies revealed that PS play cell type specific roles in the developing brain with the most prominent function in the maintenance of neural progenitor cells. In the adult cerebral cortex, where the pathogenesis of AD occurs, loss of PS results in progressive memory impairment and age-related neurodegeneration. Specifically, PS are involved in the regulation of long-term potentiation and NMDA receptor functions. Interestingly, our further genetic dissection in the hippocampal Schaeffer collateral pathway highlighted the importance of presynaptic PS in the activity-dependent regulation of glutamate release and long-term potentiation induction via modulation of calcium release from intracellular stores. Intriguingly, our independent genetic analysis of Parkin, DJ-1, PINK1 and LRRK2 showed a common defect in activity dependent dopamine release caused by PD-linked mutations in these genes. Together, our genetic studies suggest that presynaptic dysfunction might be a converging early pathogenic event before neurodegeneration in AD and PD. PMID- 20173334 TI - Possible involvement of transthyretin in hippocampal beta-amyloid burden and learning behaviors in a mouse model of Alzheimer's disease (TgCRND8). AB - BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss, possibly triggered by the accumulation of beta amyloid (Abeta) peptides and the hyperphosphorylation of Tau neurofilament protein. Recent findings have shown that transthyretin (TTR) is a potent scavenger of Abeta peptide deposits, suggesting a possible neuroprotective role for TTR in neurodegenerative processes associated with amyloidogenesis, such as AD. METHODS: To investigate the relationship between TTR and Abeta deposition, we crossed mouse carrying a deletion of TTR (TTR(- or -)) with a transgenic mouse model of AD (TgCRND8), and Abeta burden and spatial learning capacities were evaluated at 4 and 6 months of age (exclusion of the 6 month-old TgCRND8/TTR(- or -) group due to low survival rate). RESULTS: Rather surprisingly, Abeta plaque burden was significantly reduced in the hippocampus of 4-month-old TgCRND8/TTR(+ or -), and to a lesser extent in TgCRND8/TTR(- or -), as compared to age-matched TgCRND8/TTR(+ or +). No difference in plaque burden was found between any groups in 6-month-old animals. At 4 and 6 months of age, all populations of these hybrid transgenic mice displayed similar magnitude of spatial memory deficits in the Morris water maze task. CONCLUSION: Since TgCRND8 mice represent an aggressive model of Abeta deposition with plaques developing as early as 3 months of age, along with spatial learning deficits, it may be already too late at 4 and 6 months of age to observe significant changes due to the deletion of the TTR gene. PMID- 20173335 TI - Early-stage inflammation and experimental therapy in transgenic models of the Alzheimer-like amyloid pathology. AB - BACKGROUND: Intracellular accumulation of beta-amyloid (Abeta) is one of the early features in the neuropathology of Alzheimer's disease (AD) and Down's syndrome. This can be reproduced in cell and transgenic animal models of the AD like amyloid pathology. In a transgenic rat model, our lab has previously shown that the intracellular accumulation of Abeta is sufficient to provoke cognitive impairments and biochemical alterations in the cerebral cortex and hippocampus in the absence of amyloid plaques. OBJECTIVE: To investigate an early, pre-plaque inflammatory process in AD-like transgenic models and establish whether the neurotoxic effects of Abeta oligomers and proinflammatory responses can be arrested with minocycline. METHODS: For these studies, we used naive mice and transgenic animal models of the AD-like amyloid pathology and applied neurochemical, immunohistochemical and behavioral experimental approaches. RESULTS: In the early stages of the AD-like amyloid pathology, intracellular Abeta oligomers accumulate within neurons of the cerebral cortex and hippocampus. Coincidental with this, behavioral impairments occur prior to the appearance of amyloid plaques, together with an upregulation of MHC-II, i-NOS and COX-2, well known proinflammatory markers. Treatment with minocycline corrected behavioral impairments, lowered inflammatory markers and levels of Abeta trimers. CONCLUSION: A pharmacological approach targeting the early neuroinflammatory effects of Abeta might be a promising strategy to prevent or delay the onset of AD. PMID- 20173336 TI - Transgenic zebrafish as a novel animal model to study tauopathies and other neurodegenerative disorders in vivo. AB - Our ageing society is confronted with a dramatic increase in patients suffering from tauopathies such as Alzheimer's disease, frontotemporal dementia and others. Typical neuropathological lesions including tangles composed of hyperphosphorylated tau protein as well as severe neuronal cell death characterize these disorders. No mechanism-based cures are available at present. Genetically modified animals are invaluable models to understand the molecular disease mechanisms and to screen for modifying compounds. We recently introduced tau-transgenic zebrafish as a novel model for tauopathies. Our model allows recapitulating key pathological features of tauopathies within an extremely short time. Moreover, life imaging of tau-dependent neuronal cell death was performed for the very first time. This demonstrated tau-dependent neuronal cell loss independent of tangle formation. Finally, we exemplified that the zebrafish frontotemporal dementia model can be used to screen for drugs that prevent abnormal tau phosphorylation and neuronal cell death. PMID- 20173337 TI - Generation of tau aggregates and clearance by autophagy in an inducible cell model of tauopathy. AB - We have studied the mechanism of aggregation in an inducible cell model of Tau pathology. When the repeat domain of human Tau (Tau(RD)) carrying the FTDP-17 mutation DeltaK280 is expressed, the cells develop aggregates, as seen by thioflavin S fluorescence, electron microscopy, and sarkosyl extraction methods. By contrast, mutants of Tau(RD) that are unable to generate beta-structure do not aggregate. Enhanced aggregation leads to enhanced toxicity, visible by live cell microscopy and LDH release assay. The aggregation process is initiated by the sequential cleavage of Tau(RD) which yields highly amyloidogenic fragments. This cleavage occurs only with proaggregant Tau(RD), and not with the nonaggregating mutants, indicating that beta-structure makes Tau(RD) vulnerable to both proteolytic degradation and aggregation. Aggregation is reversed by switching off the expression of Tau(RD), by inhibitor compounds, and by certain protease inhibitors. In all cases, the enhanced toxicity is rescued. The clearance of the aggregates involves autophagy, whereas proteasomal degradation plays only a minor role. PMID- 20173338 TI - Silencing/overexpressing selected genes as a model of sporadic Parkinson's disease. AB - BACKGROUND: High-throughput gene-based platform studies in human postmortem substantia nigra (SN) from sporadic Parkinson's disease (PD) cases have revealed significant dysregulation of genes involved in biological processes linked to previously established neurodegenerative mechanisms in both sporadic and hereditary PD. OBJECTIVE: Our study aimed to develop a new genetic model of PD by modulating the expression of single genes that were found to be most significantly affected in SN of sporadic PD. METHODS: SN-derived cell line (SN4741 cells) was infected with short hairpin RNA lentiviruses carrying different gene-specific sequences. RESULTS: Silencing of the E3 ligase ubiquitin SKP1A resulted in a decline in the expression of dopaminergic phenotypic markers together with progression into an aberrant cell cycle and death. Furthermore, added knockout of the dopamine-metabolizing enzyme aldehyde dehydrogenase, found almost absent in sporadic PD SN pars compacta, exacerbated the vulnerability of SKP1A-silenced neurons to MPP(+) and neurotrophin deprivation. CONCLUSION: Future studies should focus on a careful consideration of crucial dopaminergic gene network interactions as emerged from human sporadic PD, which will serve as a basis for the development of a slowly progressive genetic animal model of sporadic PD, with the potential of evaluating drugs with 'disease-modifying activity'. PMID- 20173339 TI - Prevalence and impact of cerebrovascular lesions in Alzheimer and lewy body diseases. AB - BACKGROUND: Data on the prevalence of cerebrovascular lesions (CVLs) and their impact on cognitive decline in Alzheimer disease (AD) and Lewy body disease are conflicting. OBJECTIVE: Retrospective examination of the prevalence of CVL in a consecutive autopsy series. MATERIAL AND METHODS: 1,339 cases of autopsy-proven AD, Parkinson disease (PD), dementia with Lewy bodies (+ or - AD), and 486 age matched controls were examined according to standardized neuropathologic methods including immunohistochemistry. Diagnoses followed current consensus criteria, classification of CVLs and of cerebral amyloid angiopathy (CAA) in 5 grades [Acta Neurol Scand 2006;114:38-46; Acta Neuropathol 2005;110:345-359]. RESULTS: Lewy body variant of AD and AD showed significantly more frequent CVLs (91.9 and 67.8%) than the other groups (29.4 to 45.7%), with the highest frequency of severe CVLs (old, recent infarcts and hemorrhages) in AD (23.6%), but 2.0-8.3% in the other groups. Severe CAA was most frequent in AD and the Lewy body variant of AD (97.9 and 85%), less in PD (36%) and controls (30%). CAA was more frequent/severe in demented than in nondemented cases. CVLs in cortico subcortical and hippocampal areas were most frequent in AD; subcortical CVLs (lacunes) in both AD and PD were more frequent than in controls. The incidence and severity of CVLs significantly correlated with neuritic Braak stages. Cognitive impairment was largely independent of coexisting CVLs, but related to the severity/location of AD and/or Lewy pathology. CONCLUSIONS: The present data confirm the importance of CVLs in AD and in dementia with Lewy bodies with severe AD, and the little impact of CVLs alone, but show a close association of CAA with clinical dementia associated with AD pathology. PMID- 20173340 TI - The vascular hypothesis of Alzheimer's disease: bench to bedside and beyond. AB - The vascular hypothesis of Alzheimer's disease (AD) which we first proposed in 1993, has become a useful concept in identifying vascular risk factors for AD or vascular dementia that can be modified through appropriate treatment to prevent, reduce or delay the onset of cognitive impairment and dementia onset. Among the more than two dozen vascular risk factors already identified for AD, are cardiovascular disease and carotid artery atherosclerosis, which may exert their pathology by chronically lowering cerebral hypoperfusion during aging. We propose and plan to initiate a clinical study to screen middle-aged, cognitively intact individuals, with carotid artery ultrasound and echocardiography to identify potentially progressive pathology in the heart and carotid artery that is considered modifiable with optimal medical treatment. This clinical strategy, if found effective in preventing pathologic conditions suspected of contributing to severe cognitive impairment, could significantly reduce AD prevalence if applied on a wide scale and help promote healthier mental and physical aging while providing a compelling economic benefit to society. PMID- 20173341 TI - Vascular dementia and Alzheimer's disease - are we in a dead-end road? AB - BACKGROUND: Diagnostic criteria separating vascular dementia from other dementias, particularly Alzheimer's disease (AD) neglect the real world in which most AD cases present with at least some vascular brain lesions. Most importantly, vascular lesions, even if subtle, exert significant effects on the patients' cognitive functioning if they coexist with AD pathology. OBJECTIVES: To emphasize the need for an integrative dementia concept in which the vascular component represents an important end point in trial planning and a possibility for disease modification along the whole spectrum of combined vascular and primary degenerative pathology. METHODS: Review of the literature on possible surrogate markers to study the contribution of vascular brain damage in dementia. RESULTS: The longitudinal change in volume of white matter lesions is the best elaborated putative surrogate marker for the study of the vascular component in dementia. Validation of the role of lacunes and microbleeds as surrogate end points is poor. Loss of brain volume is an important adjunct outcome measure even though the vascular origin of atrophy remains uncertain. CONCLUSIONS: A focus on pure vascular dementia distracts from the importance of vascular factors in dementia. Consideration of the vascular component in future clinical trials will improve our pathophysiological understanding and provide options for treatment. PMID- 20173342 TI - Vascular contribution to dementia in Parkinson's disease. AB - Parkinson's disease is one of the most common neurodegenerative diseases. Although its motor symptoms are presently relatively well controlled, other manifestations are less well understood and poorly treated. Among these, the cognitive changes have a prominent role. Dementia is usually ascribed to changes in the nucleus basalis of Meynert and the cerebral cortex. This article discusses the possible contribution of vascular factors to the cognitive impairment in Parkinson's disease and its implication for the management. PMID- 20173343 TI - Continuous renal replacement therapy does not have a clear role in the treatment of poisoning. AB - Extracorporeal removal of drugs and other poisons is occasionally indicated in the management of intoxications. The available modalities include hemodialysis and several methods of continuous renal replacement therapy (CRRT), including continuous venovenous hemofiltration with or without dialysis augmenting drug removal. A growing literature promoting CRRT for extracorporeal removal has been published and is reviewed here. Estimates of clearance achieved by these techniques uniformly demonstrate that hemodialysis achieves higher clearances. CRRT may be appropriate for more hypotensive and unstable patients, though these might be the patients most in need of a more rapidly effective technique. For the most part, these case reports have not demonstrated that CRRT was necessary because of hemodynamic instability. Hemodialysis remains the first choice among modalities of extracorporeal removal with CRRT reserved for patients who truly cannot tolerate hemodialysis. PMID- 20173345 TI - Measures of disease frequency: prevalence and incidence. AB - To describe how often a disease or another health event occurs in a population, different measures of disease frequency can be used. The prevalence reflects the number of existing cases of a disease. In contrast to the prevalence, the incidence reflects the number of new cases of disease and can be reported as a risk or as an incidence rate. Prevalence and incidence are used for different purposes and to answer different research questions. In this article, we discuss the different measures of disease frequency and we explain when to apply which measure. PMID- 20173344 TI - Physical exercise in patients with severe kidney disease. AB - Patients with advanced chronic kidney disease (CKD), especially those on long term dialysis, often suffer from muscle wasting and excessive fatigue. It is known that inactivity, muscle wasting and reduced physical functioning are associated with increased mortality in CKD. Known causes include uraemic myopathy and neuropathy, inactivity, and anaemia. Exercise in patients receiving regular dialysis treatment for end-stage renal disease was first introduced 3 decades ago, but is still only offered in a minority of renal units around the world, despite a significant body of evidence to support its use. Work is needed to increase awareness of the potential benefits of increased physical activity for patients with advanced CKD. This review summarizes the mechanisms of exercise intolerance and debility in advanced CKD patients, the methods used for the estimation of functional capacity, the options currently available for exercise training, and their influence on the well-being of this group of patients. PMID- 20173346 TI - Clinical outcome and prognosis of anti-neutrophil cytoplasmic antibody-associated vasculitis in Japan. AB - BACKGROUND/AIMS: We conducted a broad survey of 99 patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and investigated both prognosis and outcomes. METHODS: Clinical data evaluated were age, sex, patient survival, renal survival, serum albumin, serum creatinine, urinary protein, hematuria, C reactive protein (CRP), ANCA titer, IgG and the Birmingham Vasculitis Activity Score (BVAS). RESULTS: The patient survival rate at 6 months after onset was 84.8%, and that at 2 years after onset was 82.0%. Most deaths were within 6 months of onset. Infection accounted for 9 deaths (60.0%). Infection together with pulmonary involvement of active vasculitis accounted for 2 deaths (13.3%). Organ-specific involvement of active vasculitis alone caused 3 deaths (20.0%). Others died of cardiac events. At 1 and 3 months after onset, BVAS (p < 0.0001, p = 0.002), albumin (p = 0.006, p = 0.0004) and CRP (p = 0.04, p = 0.0002) were also associated with patient death. CONCLUSION: To improve the prognosis of those with ANCA-associated vasculitis, the intensity of initial treatment should be aimed at disease severity. Employing BVAS improved the ability to evaluate therapeutic responses. Finally, prescription with sulfamethoxazole-trimethoprim during the induction therapy with immunosuppressive agents may be advised. PMID- 20173347 TI - Factors predicting mortality in elderly patients on dialysis. AB - Elderly patients are increasingly enrolled in dialysis programs and present a series of special characteristics due to their high morbidity and mortality. OBJECTIVE: To describe the characteristics of incident dialysis patients aged >75 years, their comorbidities and their admissions, with a view to determining the factors that influence their course and mortality. PATIENTS AND METHODS: The study included all patients aged >75 years who started dialysis in our center since January 2000. The mean duration of follow-up was 3.3 +/- 2.2 years. Data were collected on incident comorbidity, admissions and their causes. A total of 139 patients were included, with a mean age of 78.6 +/- 2.6 years (67.6% males, 33.8% diabetic and 7.9% on peritoneal dialysis). Three groups were established according to age: 75-79, 80-85 and >85 years. The most frequent comorbidities were chronic obstructive pulmonary disease (25.9%), ischemic heart disease (25.2%), heart failure (25.9%), neoplasms (23.7%), peripheral vascular disease (23.7%), cerebrovascular disease (18.7%) and arterial hypertension (81%). The Charlson index was calculated, not adjusted for age, and comorbidity tertiles were established. RESULTS: During follow-up, the patients presented 0.82 +/- 0.99 admissions/patient/year, with a duration of 12.1 +/- 20.6 days/patient/year. The main causes of admission were infection (33%), vascular access problems (27%) and peripheral vascular events (14%). A total of 61 patients died (44%), and 4 underwent kidney transplantation (2.9%). The mean duration of follow-up of the transplanted patients was 3.6 +/- 1.8 years. The main causes of death were infection (32%), cardiovascular problems (28.3%) and neoplastic disease (11.3%). The global survival rate was 90, 82 and 53% after 1, 2 and 5 years, respectively. No significant differences in survival or annual admission rate were found in relation to age group and dialysis technique. In contrast, the annual admission rate and days of admission were directly correlated to the Charlson index (p = 0.009 and p = 0.032, respectively). No significant differences in the Charlson index were found between the patients on hemodialysis and those subjected to peritoneal dialysis. In the univariate model, the factors associated to mortality were diabetes, chronic obstructive pulmonary disease, heart failure and the Charlson index. In the multivariate model, only the Charlson index remained as an independent predictive factor (p = 0.006). CONCLUSIONS: Unlike the general population, age does not influence mortality or admissions in elderly patients on dialysis. Incident comorbidity is the factor exerting the greatest influence upon mortality and admissions. Advanced age in itself should not be regarded as an excluding factor for starting dialysis. PMID- 20173348 TI - Depression as a potential explanation for gender differences in health-related quality of life among patients on maintenance hemodialysis. AB - BACKGROUND/AIMS: The reasons for lower health-related quality of life (HRQOL) scores in women compared to men on maintenance hemodialysis (MHD) are unknown. We investigated whether depression accounts for gender differences in HRQOL. METHODS: Cross-sectional study of 868 (40.9% women) Brazilian MHD patients (PROHEMO Study). We used the Kidney Disease Quality of Life Short Form to assess HRQOL and the Center for Epidemiological Studies Depression (CES-D) scale (scores from 0-60) to assess depression with scores >or=18 indicating high depression probability. RESULTS: Higher depression scores were associated with lower HRQOL in both sexes. Women had higher depression scores; 51.8% of women versus 38.2% of men (p < 0.001) had CES-D scores >or=18. Women scored lower on all 9 assessed HRQOL scales. The female-to-male differences in HRQOL were slightly reduced with inclusion of Kt/V and comorbidities in regression models. Substantial additional reductions in female-to-male differences in all HRQOL scales were observed after including depression scores in the models, by 50.9% for symptoms/problems related to renal failure, by 71.6% for mental health and by 87.1% for energy/vitality. CONCLUSIONS: Lower HRQOL among women was largely explained by depression symptoms. Results support greater emphasis on treating depression to improve HRQOL in MHD patients, particularly women. PMID- 20173349 TI - Predictors of declining glomerular filtration rate in a population-based chronic kidney disease cohort. AB - BACKGROUND/AIM: A high percentage of patients with chronic kidney disease has nonprogressive disease. Classification with respect to rate of change in glomerular filtration rate (GFR) would permit a more targeted approach to these patients. The aim of this study was to study predictors of rate of change in GFR in a population-based cohort. METHODS: All prevalent patients with chronic kidney disease stage 3 in a well-defined population in Northern Europe between 1994 and 2003 were included. Clinical and biochemical data were collected from primary care and hospital medical records. GFR was estimated from creatinine with the recalibrated Modification of Diet in Renal Disease Study equation. Rate of change in GFR were explored in two-level multivariate linear regression models. RESULTS: A total of 1,224 patients were included. The mean age (76.5 years) was higher and mean rate of decline in GFR slower (1.5 ml/min/1.73 m(2)/year) than in studies of selected patient groups. A total of 60% of the patients suffered from comorbid conditions, 90% had hypertension. Male gender, diabetes, proteinuria and higher mean arterial pressure were independent predictors of a faster decline in GFR. CONCLUSION: The similarity of the identified predictors with those found in clinical trials of more selected patients may indicate the potential for improved treatment of older chronic kidney disease patients with multiple comorbidities by better adherence to existing guidelines. PMID- 20173350 TI - Calcium-corrected intact PTH: a clinically useful parameter for quantifying parathyroid function in patients undergoing hemodialysis. AB - BACKGROUND/AIMS: Serum parathyroid hormone (PTH) concentration provides a rough index of the severity of secondary hyperparathyroidism (SHPT) due to chronic renal failure. Since serum PTH inversely related to calcium (Ca) level, we attempted to create a new index based on the relationship. METHODS: Our subjects were 70 patients undergoing maintenance hemodialysis (HD) in a single facility. Using multiple pairs of serum Ca corrected for albumin (cCa) and intact PTH (iPTH) values drawn simultaneously, we determined the steepest slope of cCa-iPTH relationship for each individual patient to get a line closely resembling the cCa PTH sigmoidal curve. RESULTS: Based on the slopes, the following equation was obtained: iPTH2 = iPTH1 + (cCa1 - cCa2) x (43 + 0.47 x iPTH1), where the PTH values at any 2 arbitrary values of cCa1 and cCa2 were assumed to be iPTH1 and iPTH2, respectively. When 'corrected PTH' is defined as the predicted value of iPTH at cCa = 9.0 mg/dl, its correlation was better than iPTH with the total volume of the parathyroid glands estimated by ultrasonography. Similar results were found in 30 parathyroidectomized patients at other facilities. CONCLUSION: 'Corrected PTH' may represent a useful parameter for assessing the severity of SHPT from single determinations of cCa and iPTH drawn at the same time. PMID- 20173351 TI - A comparison of nonoliguric and oliguric severe acute kidney injury according to the risk injury failure loss end-stage (RIFLE) criteria. AB - BACKGROUND: Risk, Injury, Failure, Loss, and End-Stage (RIFLE) criteria have been proposed as a standard definition of acute kidney injury (AKI). The most severe form of AKI, class F AKI, can be defined by either severe oliguria or a 3-fold increase in serum creatinine concentrations. We hypothesized that the outcomes of patients with these 2 alternative criteria of severe AKI were different. METHODS: A prospective cohort study was conducted of all patients attaining RIFLE class F AKI during a 12-month period in a tertiary critical care facility. RESULTS: Among a total of 2,379 critical care admissions, 129 (5.4%) fulfilled the serum creatinine criteria without oliguria (RIFLE class F) and 99 (4.2%) fulfilled oliguric (RIFLE class F) AKI criteria. Patients with oliguric AKI suffered a more severe disease process than nonoliguric AKI. Oliguric AKI was associated with a significantly higher risk of requiring acute dialysis (70.7 vs. 22.4%, p = 0.001), long-term dialysis >90 days (15 vs. 1.9%, p = 0.006), and hospital mortality (adjusted hazard ratio 3.33, 95% confidence interval, p = 0.001) than nonoliguric AKI. CONCLUSIONS: Oliguric RIFLE class F AKI is a more severe form of AKI than nonoliguric class F AKI. These 2 forms of AKI should be considered separately when AKI is evaluated in a clinical trial. PMID- 20173352 TI - Clinical usefulness of novel biomarkers for the detection of acute kidney injury following elective cardiac surgery. AB - BACKGROUND/AIMS: Acute kidney injury (AKI) is common following cardiac surgery and predicts a poor outcome. However, the early detection of AKI has proved elusive and most cases are diagnosed only following a significant rise in serum creatinine (SCr). We compared a panel of early biomarkers of AKI for the detection of AKI in patients undergoing heart surgery. This study included serum cystatin C (CyC) and urinary levels of neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), retinol-binding protein (RBP) and N-acetyl-beta-D glucosaminidase (NAG). METHODS: We retrospectively identified 15 patients undergoing open cardiac surgery who developed AKI within 72 h postoperatively. For these, we identified 15 matched controls also having undergone surgery but without AKI. Serial serum and urine samples had prospectively been postoperatively obtained from all patients at 0, 2, 4, 6, 10, 24, 48 and 72 h after admission to the intensive care unit. AKI was defined as a >50% increase in SCr. CyC was measured by nephelometry, while NGAL, IL-18, and RBP were measured by ELISA and NAG was measured by spectrophotometry. The urinary biomarkers were normalized to urinary creatinine (UCr) concentration. Each marker was assessed at each time point for its predictive value using receiver operating characteristic curves to predict AKI. RESULTS: Following the exclusion of 1 case due to a urinary tract infection, the final cohort consisted of 29 patients aged 62.9 +/- 13.7 years with baseline SCr of 73.2 +/- 11.9 micromol/l. While there were no differences in the demographics between cases and controls, the aortic clamp time was predictably higher in AKI cases than in controls (60.6 +/- 13.9 vs. 43.0 +/- 9.2 min, p < 0.05). Each biomarker differed significantly between cases and controls for at least one time point. The optimal area under the curve (AUC) was for CyC at 10 h (sensitivity 0.71, specificity 0.92, cutoff 1.31 mg/l), NGAL at 0 h (sensitivity 0.84, specificity 0.80, cutoff 49.15 microg/g UCr), IL-18 at 2 h (sensitivity 0.85, specificity 0.73, cutoff 285.65 ng/g UCr), RBP at 0 h (sensitivity 0.75, specificity 0.67, cutoff 2,934.65 microg/g UCr) and NAG at 4 h (sensitivity 0.86, specificity 0.67, cutoff 37.05 U/mg UCr). Using a combination of all 5 biomarkers analyzed at the optimal time point as above, we were able to obtain an AUC of 0.98 (0.93-1.02, p < 0.001) in this limited sample. CONCLUSION: The use of serum and urinary biomarkers for the prediction of AKI in patients undergoing cardiac surgery is highly dependent on the sampling time. Of the evaluated markers urinary NGAL had the best predictive profile. The previously unstudied marker of urinary RBP showed similar predictive power as more established markers. By combining all 5 studied biomarkers we were able to predict significantly more cases, suggesting that the use of more than one marker may be beneficial clinically. PMID- 20173353 TI - Estrogen replacement reverses olanzapine-induced weight gain and hepatic insulin resistance in ovariectomized diabetic rats. AB - OBJECTIVES: We investigated whether estrogen replacement modulated energy and glucose metabolic changes induced by olanzapine (OZP) and risperidone (RPD) in 90% pancreatectomized diabetic rats, some of whom had also been ovariectomized (OVX) and some of whom had not (sham). METHODS: OVX diabetic rats were subcutaneously injected with estrogen replacement (17beta-estradiol, 30 microg/kg/day) or a vehicle. Each group was divided into 3 subgroups, and each subgroup was orally either given a placebo, RPD (0.5 mg/kg body weight/day) or OZP (2 mg/kg body weight/day) for 8 weeks. Sham rats were also divided into 3 subgroups and given drugs in the same manner as the OVX rats were. All rats were fed high-fat diets. RESULTS: OZP increased body weight and epididymal fat pads more than the control (vehicle) in sham and OVX rats. Increased body weight in OZP-treated sham and OVX rats was due to the increment in food intake, which was associated with potentiating the phosphorylation of hypothalamic adenosine monophosphate-activated protein kinase. At euglycemic hyperinsulinemic clamping, OZP decreased glucose infusion rates and increased hepatic glucose output in OVX diabetic rats. In sham rats, OZP increased hepatic glucose output but not as much as in OVX rats. Hepatic insulin signaling and glucose sensing were attenuated in OZP-treated OVX rats, and the attenuation increased hepatic phosphoenolpyruvate carboxykinase expression to induce gluconeogenesis. These negative and harmful effects noted among OZP-treated OVX rats were reversed by estrogen replacement treatment. However, RPD did not alter body weight and peripheral insulin sensitivity in sham and OVX rats. CONCLUSIONS: OZP treatment should be avoided when treating diabetic and schizophrenic women, especially those in their postmenopausal period. PMID- 20173354 TI - Role of the left DLPFC in endogenous task preparation: experimental repetitive transcranial magnetic stimulation study. AB - The precise role of the dorsolateral prefrontal cortex (DLPFC) in attentional set activation is still not entirely clear. Hence, repetitive transcranial magnetic stimulation (rTMS) can be applied to interfere with neural processing to determine whether a specific brain area is required in task performance. In this study, the influence of one session of high-frequency (HF)-rTMS of the left DLPFC on a reaction task using visual and auditory trials was investigated. Participants were instructed to pay constant attention to the visual stimuli, and they were informed that distracting auditory stimuli could also appear. Participants had to respond to both stimuli. Results indicate that after one session of HF-rTMS of the left DLPFC, performance was improved for the primary task, but not for the distracters. Specifically, we found decreased response time for an endogenous component of attentional control which embodies the online representations of task-relevant information. To conclude, the current results highlight a specific role of the left DLPFC in actively preparing for a specific task in the presence of a distracting task. PMID- 20173355 TI - Pellet injuries to the orbit. PMID- 20173357 TI - Effects of bevacizumab on apoptosis, Na+ -K+ -adenosine triphosphatase and zonula occludens 1 expression on cultured corneal endothelial cells. AB - BACKGROUND: This laboratory study was undertaken to investigate the influence of bevacizumab on apoptosis, Na(+)-K(+)-adenosine triphosphatase (Na(+)-K(+)-ATPase) and zonula occludens 1 (ZO-1) expression on cultured human corneal endothelial cells (HCECs). METHODS: Annexin V binding combined with propidium iodide (PI) costaining was used to distinguish viable, early and late apoptotic cells. Immunolocalization of ZO-1 and Na(+)-K(+)-ATPase was performed to analyze intercellular cell integrity after exposure to 5.0 mg/ml bevacizumab for 24 h. RESULTS: No significant induction of apoptosis or necrosis was seen in HCECs after exposure to 5.0 mg/ml bevacizumab (p = 0.689, p = 0.516, respectively). The mean number of annexin-V-FITC- and PI-positive cells did not change significantly. Additionally, no significant changes in expression were detectable, neither for ZO-1 nor for Na(+)-K(+)-ATPase in comparison with the control. For ZO-1, 70.0% of the cells stained intensely, 24.7% stained moderately, and 5.3% stained weakly in the control group. After exposure to 5.0 mg bevacizumab, only minor changes were observable: 68.8% stained intensely, 25.4% moderately and 5.8% weakly (p = 0.524). For Na(+)-K(+)-ATPase, 19.3% of the cells stained intensely, 59.4% moderately, and 21.3% weakly in the control group. After exposure to 5.0 mg bevacizumab, again only minor changes were observable in the expression pattern: 18.2% stained intensely, 60.3% moderately and 21.5% weakly. The changes were not significant compared with the control (p = 0.492). CONCLUSIONS: Bevacizumab, at concentrations used clinically, did not induce apoptosis or necrosis in HCECs in vitro. Additionally, no alteration of ZO-1 or Na(+)/K(+)-ATPase expression was detected after exposure to 5.0 mg/ml bevacizumab for 24 h. PMID- 20173358 TI - Transoral robotic tongue base resection in obstructive sleep apnoea-hypopnoea syndrome: a preliminary report. AB - PURPOSE OF THE STUDY: To evaluate the feasibility, tolerability and efficacy of tongue base management by means of transoral robotic surgery (TORS) in patients suffering from the obstructive sleep apnoea-hypopnoea syndrome (OSAHS) primarily related to hypertrophy of the tongue base. PROCEDURE: Seventeen patients with OSAHS principally related to tongue base hypertrophy were managed by means of TORS (Intuitive da Vinci(R)). Patients with a minimum follow-up of 3 months were evaluated. RESULTS: Ten patients [mean preoperative apnoea-hypopnoea index (AHI): 38.3 +/- 23.5 SD] were included in the study. By means of robotic technology, the tongue base and the epiglottis could be managed. The postoperative polysomnographic results were fairly good (mean postoperative AHI: 20.6 +/- 17.3 SD), and the functional results (pain, swallowing and quality of life) are very encouraging; altogether, complications were rare and of minor importance. CONCLUSIONS: Transoral robotic tongue base management in patients with OSAHS primarily related to tongue base hypertrophy is feasible and well tolerable. These preliminary results are encouraging and worthy of further evaluation. PMID- 20173359 TI - Personalized prognosis and diagnosis of type 2 diabetes--vision or fiction? AB - Typical civilization diseases, such as type 2 diabetes, share several features: their worldwide frequency, the complexity of the underlying pathogenic mechanisms, heterogeneity in the phenotypes and their multifactorial nature due to a wide variety of possible combinations of disease susceptibility or protective genes in different tissues and negative or positive environmental factors. This is in sharp contrast to classical inherited diseases, such as Huntington's chorea, which are often caused by complete loss- or gain-of-function mutations in a single gene. The causative polymorphisms of susceptibility genes, however, are characterized by relatively subtle alterations in the function of the corresponding gene products, i.e. low penetrance and effect size, which do not support the pathogenesis per se, and by their high frequency; these two characteristics result in high expenditures for their identification and a rather low predictive value. In the future, the reliable and early diagnosis of common diseases will thus depend on the determination of all (or as many as possible) polymorphisms of each susceptibility gene together with the corresponding gene products and the metabolites emerging thereof for each individual. Great hopes are currently associated with systems biology to cover these demands in time (i.e. along the pathogenesis) and space (i.e. in all relevant tissues). PMID- 20173360 TI - Infrared densitometry: a fast and non-destructive method for exact stratum corneum depth calculation for in vitro tape-stripping. AB - The investigation of drug penetration into the stratum corneum (SC) by tape stripping requires an accurate measure of the amount of SC on each tape-strip in order to determine the depth inside the SC. This study applies infrared densitometry (IR-D) to in vitro tape-stripping using the novel Squame Scan(R) 850A. The device had recently been shown to provide accurate measurements of the SC depth for tape-stripping in vivo. Furthermore, the suitability of IR-D for determining the endpoint of tape-stripping, i.e. complete SC removal, was tested. The SC depth was computed from the IR-D data of sequential tape-strips and compared to the results of a protein assay as gold standard. IR-D provided accurate depth results both for freshly excised skin and for skin stored frozen for up to 3 months. In addition, the lower limit of quantification of IR-D indicates the complete removal of the SC (less than 5% of the total SC remaining) and can be used for adjusting the number of tapes applied in situ. Therefore, IR D is an accurate, fast and non-destructive method for SC depth determination. PMID- 20173361 TI - Surgical reconstruction of pelvic floor descent: anatomic and functional aspects. AB - INTRODUCTION: The human pelvic floor is a complex structure and pelvic floor dysfunction is seen frequently in females. MATERIALS AND METHODS: This review focuses on the surgical reconstruction of the pelvic floor employing recent findings on functional anatomy. A selective literature research was performed by the authors. RESULTS: Pelvic floor activity is regulated by 3 main muscular forces that are responsible for vaginal tension and suspension of the pelvic floor organs, bladder and rectum. A variety of symptoms can derive from pelvic floor dysfunctions, such as urinary urge and stress incontinence, abnormal bladder emptying, fecal incontinence, obstructive bowel disease syndrome and pelvic pain. These symptoms mainly derive, for different reasons, from laxity in the vagina or its supporting ligaments as a result of altered connective tissue. Pelvic floor reconstruction is nowadays driven by the concept that in case of pelvic floor symptoms, restoration of the anatomy will translate into restoration of the physiology and ultimately improve patients' symptoms. CONCLUSION: The surgical reconstruction of the anatomy is almost exclusively focused on the restoration of the lax pelvic floor ligaments. Exact preoperative identification of the anatomical lesions is necessary to allow for exact anatomical reconstruction with respect to the muscular forces of the pelvic floor. PMID- 20173362 TI - A simplified preputial covering technique to correct buried penis. AB - OBJECTIVE: We report on refinements of a technique for preputial covering to prevent complications of redundant prepuce, possibly caused by inadequate surgery for buried penis. PATIENTS AND METHODS: From July 2006 to July 2008, 20 consecutive patients (mean age 4.3 years) underwent surgery for buried penis. The surgical techniques consisted of complete unfurling of the penile shaft, fixation of the penile base skin to Buck's fascia and 1 pedicle flap for skin coverage. Our method for preputial covering is novel in that we create a unique 1-flap covering for the ventral skin defect. Patients were monitored postoperatively at 2 weeks, 1 month and 3 months. RESULTS: All patients had good or excellent outcomes, with fewer postoperative complications. Two patients developed subcutaneous hematomas that resolved in 2 weeks with conservative treatment. The mean increase in length of penile projection after surgery was 1.7 cm, a statistically significant difference. All patients had good cosmetic results, with increased visualization of the penile shaft. CONCLUSIONS: The preputial covering technique we devised avoided postoperative bulky prepuce caused by residual redundant prepuce. Repeat surgery was also unnecessary for our patients. Furthermore, parents judged the cosmetic results as excellent. PMID- 20173363 TI - Accuracy of the extent of bladder cancer nodal metastases found at pelvic lymphadenectomy at the time of cystectomy: relation to primary tumor stage. AB - OBJECTIVES: To determine the minimum number of nodes (n(min)) that need to be removed to ascertain N(0) status with 90/95% certainty, and to determine the maximum number of nodes theoretically involved for a given number 'm' of involved nodes reported out of a total of 'n' nodes examined. METHODS: 2,025 patients underwent cystectomy and pelvic lymphadenectomy, with pathologic stage < or =pT(2) in 1,132 (55.9%) and > or =pT(3) in 893 (44.1%). A mathematical model was utilized, using incidences derived from those having > or =10 nodes retrieved. RESULTS: For stage < or =pT(2) and 0, 1, or 2 positive nodes reported, n(min) are 2, 27, and 28, respectively, for 90% accuracy and 12, 29, and 29, respectively, for 95% accuracy. For stage > or =pT(3) and 0, 1, or 2 positive nodes reported, n(min) are 19, 28, and 29, respectively, for 90% accuracy and 24, 29, and 30, respectively, for 95% accuracy. CONCLUSIONS: Accuracy of the extent of nodal involvement depends on the number of positive nodes reported, total number of nodes retrieved, and pathologic stage. This model allows clinicians to assess potential underestimation of the 'true' number of involved nodes for a given number of positive nodes out of a total number reported. PMID- 20173364 TI - Bacillus Calmette-Guerin versus gemcitabine for intravesical therapy in high-risk superficial bladder cancer: a randomised prospective study. AB - OBJECTIVE: To evaluate the safety, tolerability and efficacy of adjuvant intravesical gemcitabine versus bacillus Calmette-Guerin (BCG) in the treatment of high-risk superficial bladder cancer. METHOD: 64 patients with high-risk superficial bladder cancer (pT1 and/or G3 and/or CIS) were assigned to interventions (gemcitabine or BCG) in a randomised controlled trial. All the patients were evaluated for recurrence and progression rates (primary endpoint) and safety and tolerability (secondary endpoint). RESULTS: The two groups were comparable in terms of baseline characteristics. Tolerability was better for gemcitabine, whereas the BCG group experienced the need for delayed treatment or withdrawal in 12.5% of cases. At a mean follow-up of 44 months, the recurrence rate in patients treated with BCG was 28.1%; the recurrence rate in patients who received gemcitabine was 53.1% (p = 0.037). Time to recurrence was shorter in patients treated with BCG (25.6 vs. 39.4 months, p = 0.042). No patients developed disease progression. CONCLUSIONS: Gemcitabine is significantly inferior to BCG, but given its favourable toxicity profile, it may be useful for patients intolerant to or otherwise unable to receive BCG. PMID- 20173365 TI - Comparison of hand-assisted laparoscopic and open radical cystectomy for bladder cancer. AB - PURPOSE: To present our experience of hand-assisted laparoscopic radical cystectomy (HALRC) and compare it with open radical cystectomy (ORC). PATIENTS AND METHODS: During the period between May 2004 and November 2007, 31 patients underwent HALRC and 39 patients underwent ORC for bladder cancer. The patient demographics, intraoperative variables and postoperative outcomes were compared retrospectively. RESULTS: There was no statistically significant difference with regard to age, sex, body mass index, and urinary diversion in the 2 groups. In the HALRC group, 20 patients had stage pT2 or less, 7 had pT3 disease, and 4 had stage pT4 disease. In the ORC group, 29 patients had stage pT2 or less, 5 had pT3 disease, and 5 had stage pT4 disease. All margins in both groups were negative. The HALRC group had decreased blood loss (250.9 vs. 812.8 ml, p < 0.001) and a lower rate of transfusion (9.7 vs. 76.9%, p < 0.001), but similar mean operative time (365.7 vs. 362.6 min, p = 0.862). Time to liquid diet was significantly less in the HALRC group versus the ORC group (4.3 vs. 6.3 days, p < 0.001). The median number of lymph nodes were similar between the HALRC and ORC groups (14 vs. 15, p = 0.377). Six patients developed perioperative complications in the HALRC group and 12 patients had complications in the ORC group (19.4 vs. 30.8%, p = 0.278). Late complications occurred in 3 patients (2 parastomal hernias and 1 ureteroenteral stricture) in the HALRC group. CONCLUSIONS: Compared with ORC, HALRC patients had decreased blood loss, less transfusion requirements, and quicker intestinal recovery. Long-term follow-up in a larger cohort of patients is needed to assess the long-term oncological and functional outcomes. PMID- 20173366 TI - Experience with various types of orthotopic neobladder in Japanese men: long-term follow-up. AB - INTRODUCTION: The objective of this study was to review the long-term outcomes of orthotopic neobladder (NB) creation. MATERIALS AND METHODS: This study included 235 Japanese men who underwent NB reconstruction after radical cystectomy and were followed for at least 3 years. The types of NB used in this series were Studer, Reddy, Hautmann and Mainz NB in 136, 51, 32 and 16, respectively. RESULTS: Early and late complications occurred in 70 and 33 men, respectively. Of the 235 men, 210 could void spontaneously, and day- and nighttime continence were achieved in 189 and 149, respectively. The mean maximal flow rate, voided volume and post-void residual were 15.9 ml/s, 209.6 and 38.0 ml, respectively. SF-36 survey for postoperative quality of life showed no significant differences in 7 of the 8 scale scores between the 235 men and an age-matched control population in Japan. The 5-year overall and cancer-specific survival rates were 71.2 and 75.7%, respectively. There were no significant differences in any parameters examined among the four groups except for post-void residual, which was significantly smaller in the Reddy group than in the other three groups. CONCLUSION: The orthotopic NB could generally provide satisfactory outcomes on long-term follow-up, irrespective of the types of NB. PMID- 20173367 TI - Role of patient-physician dialogue in selecting the type of urinary diversion. AB - INTRODUCTION: We analyze patient-physician dialogue prior to radical cystectomy (RC) when choosing the type of urinary diversion (UD). METHODS: 132 patients operated by one surgical team between 2003 and 2005 were included. Physician's recommendation, patient's decision and UD (neobladder (NB) or ileal conduit (IC)) performed were analyzed. Patients were grouped based on age, considering that age is often a limiting factor for NB. RESULTS: When offered either NB or IC, 85% (49/58) in group I (<70 years) and 55% (12/22) in group II (> or =70 years) elected NB. An IC was suggested for 16% (11/69) in group I and 65% (41/63) in group II. Six patients (2 in group I, 4 in group II) wanted a NB even though an IC was suggested. CONCLUSIONS: Counseling patients is important. When an IC was suggested, over 80% accepted this advice. When both were offered, younger patients usually elected a NB. Older patients preferred an IC. PMID- 20173368 TI - Urine cytology in the evaluation of urological malignancy revisited: is it still necessary? AB - OBJECTIVE: We aim to determine if urine cytology was still necessary as a routine part of the evaluation for the presence of urological malignancy and to evaluate its cost effectiveness. METHODS: Urine cytology reports over a 6-year period (2000-2005) were retrieved from our institution's pathology department database. Patients with urine cytology positive for malignant cells were identified. We retrospectively reviewed the charts of these patients for age, sex, flexible cystoscopy and radiological imaging results. The cost of urine cytology was retrieved from the pathology department. RESULTS: There were a total of 2,568 urine cytological examinations. Of these, 25 were positive for malignant cells. There were 19 male (76%) and 6 female (24%) patients with a mean age of 72 years (range: 49-97). In 21 patients with positive cytology, a bladder tumor was identified at flexible cystoscopy and/or imaging studies. For a positive cytology yield of 1%, EUR 210,000 was spent. CONCLUSIONS: Routine urine cytology was not cost effective and did not add to the diagnostic yield beyond cystoscopy and diagnostic imaging. It may be omitted in the initial evaluation of urological malignancy. PMID- 20173369 TI - Outcome of surgical treatment of patients with upper versus lower urinary tract urothelial carcinoma: stage-by-stage comparison. AB - OBJECTIVES: It remains controversial whether we can apply similar principles in the management of upper urinary tract urothelial carcinoma (UUT-UC) based on the behavior of bladder urothelial carcinoma (B-UC). We sought to assess whether UUT UC and B-UC have similar biology and performed a stage-by-stage comparative analysis of outcome between the 2 groups. METHODS: A retrospective review was performed on patients who underwent nephroureterectomy for UUT-UC and radical cystectomy for B-UC from 1991 to 2006. Standard variables were collected and recurrence-free and overall survival (OS) rates were calculated. RESULTS: 280 patients with a median age of 69 years were included (99 UUT-UC treated via nephroureterectomy and 181 B-UC treated via radical cystectomy). Median follow-up was 29 months. None received neoadjuvant chemotherapy. Patients with UUT-UC presented less commonly with invasive disease compared to those with B-UC (44 vs. 77% were >pT2). Overall, 5-year OS for the B-UC group was significantly lower than for the UUT-UC group (60.8 vs. 74.5%, p = 0.02). However, when patients were stratified by stage (>pT2), patients with B-UC had similar OS compared to those with UUT-UC (54.6 vs. 60.8%, p = 0.74). CONCLUSION: Invasive UUT-UC appears to have similar tumor biology compared to B-UC. Whether we can safely extrapolate on the benefit of neoadjuvant and adjuvant strategies to patients with UUT-UC requires further investigation. PMID- 20173370 TI - Magnetic resonance imaging as the sole radiological assessment for living donor nephrectomy. AB - INTRODUCTION: Planification of living donor nephrectomy requires exact knowledge of the renal vascular architecture because of the high prevalence of anatomical variants. After magnetic resonance angiography (MRA) challenged CT angiography for preoperative assessment over the last years, we revisit in this study the reliability of MRA as the sole preoperative assessment for living donor nephrectomy. METHOD: We compared the radiological findings of MRA performed as the sole radiological procedure in 44 living kidney donors with perioperative anatomy to verify its sensitivity and to validate its systematic use in the preoperative assessment for living donor nephrectomy. RESULTS: 22 anatomical variants were found in 16 patients (16/44 = 36%). In 4 patients, a polar artery (3 superior, 1 inferior) was not seen by MRA and was detected during surgery (open nephrectomy). Supposing the anatomical variants it described on the opposite side of the nephrectomy are real, sensitivity of this technique in this series is 40/44 (91%) for arterial and 100% for venous imaging. CONCLUSION: MRA as the sole radiological preoperative assessment performed by a single radiologist with specific expertise and preoperatively reviewed with the harvesting surgeon has been validated as the sole radiological preoperative assessment for living donor nephrectomy at our institution. PMID- 20173371 TI - Early and late graft function after laparoscopic hand-assisted donor nephrectomy for living kidney transplantation: comparison with open donor nephrectomy. AB - BACKGROUND AND PURPOSE: Laparoscopic donor nephrectomy has become the procedure of choice for living kidney transplantation in many centers. We report on our experience with laparoscopic hand-assisted donor nephrectomy, in particular concerning graft function compared with open donor nephrectomy. MATERIALS AND METHODS: Between 1995 and March 2007, 72 patients with end-stage renal disease have received kidney transplantation from living donors. Open living donor nephrectomy (ODN) was performed in 35 donors, whereas 37 donors had undergone laparoscopic hand-assisted nephrectomy (HALDN). Immediate graft function, serum creatinine and serum cystatin C 1 year after the transplantation were evaluated. RESULTS: Median operative time was 138 min (113-180 min) in the HALDN group and 112 min (91-162 min) in the ODN group (p < 0.05). Warm ischemia time was 87 s (63 150 s) in the HALDN and 81 s (56-123 s) in the ODN groups, respectively (p = 0.13). Both the rate of primary graft function as well as kidney graft function parameters serum creatinine and serum cystatin C 1 year after transplantation showed no statistically significant difference between the two groups of patients. CONCLUSIONS: Laparoscopic hand-assisted donor nephrectomy is safe and has no negative impact on the transplanted graft function when compared with open donor nephrectomy. PMID- 20173373 TI - Does G force increase the incidence of varicocele in Air Force pilot cadets? AB - OBJECTIVE: Air Force pilots are subjected to acceleration (G) forces with a known effect upon the vascular system. Specific training and anti-G maneuvers are used to counteract this effect, and allow pilots to operate at the limits of human endurance. The objective of the present study is to determine whether acceleration affects the incidence of varicocele. SUBJECTS AND METHODS: The incidence of varicocele during training in 234 Air Force pilots was assessed. Height, weight, BMI and testicular volume were recorded for every participant. A group of 35 pilots with an absence of varicocele, randomly selected, acted as the control group. RESULTS: Left-sided varicocele was confirmed in 23 (9.8%) pilots. Affected pilots tended to be taller (p = 0.073) and had a smaller mean left testicular volume (p < 0.001) than the control group. Eight cases (35%) were grade I, 10 (43%) were grade II, and 5 (22%) were grade III. For grades I and II, there was a trend for the testicular volume to decrease (p = 0.349 and 0.067, respectively). In grade III varicocele, this difference was statistically significant (p < 0.05). CONCLUSIONS: The incidence of varicocele in fighter pilots during training is not higher than in other groups of the same age. Affected individuals tend to be taller, with ipsilateral testicular hypotrophy. PMID- 20173372 TI - The use of the American Society of Anesthesiology Classification as a prognostic factor in patients with renal cell carcinoma. AB - OBJECTIVES: We analyzed whether the American Society of Anesthesiology (ASA) classification could be used as a prognostic factor in renal cell carcinoma. METHODS: ASA classification's impact on cancer-specific survival (CSS) and on overall survival in 145 patients submitted to radical or partial nephrectomy was evaluated, and was compared with clinicopathological variables. RESULTS: CSS was influenced by ASA in uni- and multivariate analyses. Five-year CSS was 95.7, 71.1 and 39.8% for ASA 1, ASA 2 and ASA 3, respectively (p = 0.007). The ASA classification influenced the overall survival too (p < 0.001). When 18 patients with metastases were excluded, the CSS was 95.7, 83.9 and 42.9% for ASA 1, ASA 2 and ASA 3, respectively (p = 0.001). ASA 3 patients had ten times more metastases than ASA1 patients and two times more than ASA 2 patients (p = 0.001). ASA 3 patients had fewer incidental tumors (p = 0.043) than ASA 2 and 3 patients. CONCLUSION: In this series, the ASA classification could be used as a prognostic factor in renal cell carcinoma. PMID- 20173374 TI - Substitution urethroplasty for anterior urethral strictures: buccal versus lingual mucosal graft. AB - AIM: To compare the results of substitution urethroplasty and donor site morbidity between buccal mucosal graft (BMG) and lingual mucosal graft (LMG). PATIENTS AND METHODS: Patients who underwent single-stage dorsal onlay free oral mucosal graft substitution urethroplasty by Barbagli's technique between January 2004 and August 2008 were included in this study. Patients who underwent buccal (cheek, lip) mucosal graft urethroplasty were included in group I and those who underwent LMG urethroplasty (tongue) were included in group II. All patients underwent complete evaluation of the stricture including inspection of the oral cavity. Exclusion criteria were stricture length <3 cm and complex strictures which required a multistage procedure. RESULTS: The results of urethroplasty were similar in both groups in terms of blood loss, duration of postoperative hospitalization, complications encountered at urethroplasty site, mean postoperative Q(max) and mean postoperative AUA symptom score. Early slurring of speech complications was seen in group II, but not in group I. The long-term complications of persistent oral discomfort, perioral numbness and tightness of the mouth were seen only in group I. CONCLUSION: LMG urethroplasty is a good substitute for BMG urethroplasty with equally good results of urethroplasty with lower donor site morbidity. PMID- 20173375 TI - Success of trigonoplasty anti-reflux surgery and its predictive factors. AB - INTRODUCTION: This study was designed to evaluate factors contributing to failure in Gil-Vernet antireflux operation. MATERIALS AND METHODS: 96 patients (150 refluxing units; median (range) age, 60 (12-180) months; M/F, 11/85) with primary vesico-ureteral reflux were included. Trigonoplasty was done according to a modified Gil-Verent procedure. Relapse was diagnosed on the postoperative direct radionuclide cystography (DRNC) 3 or 6 months after operation. Demographic and intraoperative data were used to assess factors contributing to failure. RESULTS: Resolution of reflux in postoperative DRNC was observed in 87 patients (90.6%) and in 138 refluxing units (92.0%). In patients who were followed 3-6 months, one relapse occurred (3%) versus 8 relapses in those who were followed 24-39 months (12%). Relapse in refluxing units was related to the history of voiding symptoms (30 vs. 3%, p < 0.001), history of breakthrough infections (20 vs. 3%, p = 0.001), golf or stadium like ureteral orifice appearance (15 vs. 4%, p = 0.02), and less distance of ureteral orifices from each other (p < 0.001). CONCLUSIONS: Trigonoplasty success rate may decrease with long-term follow-up. In multivariable analysis, patients with history of voiding dysfunction, breakthrough infection, golf/stadium like ureteral orifices, and less distant ureteral orifices are at a higher risk of relapse. PMID- 20173376 TI - Urodynamic evaluation of urinary disturbances following traumatic brain injury. AB - OBJECTIVES: To identify the incidence and the type of voiding dysfunction by doing urodynamic studies (UDS) in head injury patients. The purpose of this paper is to present our findings and promote research in this field. PATIENTS AND METHODS: A prospective study was conducted recruiting patients sustaining head injuries with positive CT scan findings. Clinical and radiological evaluation was done. Patients then underwent standardized UDS. The urodynamic findings were correlated with outcome and analyzed. RESULTS: Three out of 11 patients (27.3%) had unstable bladder with multiple involuntary contractions in the filling phase. All of them had significant contusions in the right frontal region and 2 of them had subarachnoid hemorrhage. All of these patients had normal proprioception, voluntary detrusor contractions and nil post-void residue. Two out of the 3 patients had catheter in situ and 1 patient had complaints of frequency and urgency. At 1 year of follow-up, all 3 patients had a normal voiding pattern and the upper tracts were normal on ultrasound in all patients. CONCLUSIONS: Voiding dysfunction is a significant problem in patients with head injury. Bladder hyperreflexia is seen in patients with injuries above the pontine micturition center. The voiding abnormality has good prognosis and resolves spontaneously. Treatment in the acute phase may require anticholinergics for a few months. PMID- 20173377 TI - Bone marrow mesenchymal stem cells induce angiogenesis and promote bladder cancer growth in a rabbit model. AB - OBJECTIVES: To investigate the effect of mesenchymal stem cells (MSCs) in the process of tumor development and the possibility of MSCs differentiating into vascular endothelial cells in the tumor microenvironment. MATERIAL AND METHODS: Twenty male New Zealand rabbits were randomly divided into 2 groups: a test group and a control group. MSCs were isolated and cultured by bone marrow cell adherence. The bladder tumor models were built by embedding a VX2 mass in swelled bladder mucosa in all of the rabbits (n = 20). One week later, 4',6-diamidino-2 phenylindole-labeling MSCs were transplanted into tumor tissue in the test group (n = 10). Culture medium was injected into the tumor tissue of the control group (n = 10). The maximum diameter of the tumor mass was measured by ultrasound at 2 and 4 weeks after the VX2 tumor mass was embedded. All animals were sacrificed at 4 weeks. The double labeling immunofluorescence for CD146 was performed to reveal whether engrafted cells can differentiate into vascular endothelial cells. Vascular density was compared between the 2 groups. RESULTS: There was no significant difference in the maximum diameters of the tumor masses between the 2 groups at 2 weeks (test group 0.77 +/- 0.15 cm vs. control group 0.71 +/- 0.15 cm, p > 0.05). The maximum diameters appeared larger in the test group at 4 weeks (test group 3.82 +/- 0.94 cm vs. control group 2.28 +/- 0.54 cm, p < 0.05). Immunofluorescence studies revealed some engrafted MSCs expressing a vascular endothelial cell phenotype (CD146). Furthermore, vascular density was augmented in the test group in comparison to the control group (10.1 +/- 0.70/0.2 mm(2) vs. 8.24 +/- 0.81/0.2 mm(2), p < 0.05). CONCLUSIONS: Engrafted MSCs can differentiate into vascular endothelial cells and contribute to angiogenesis in the tumor microenvironment, which may be the major pathway of promoting tumor growth. PMID- 20173378 TI - Quantitative study of mast cells in experimentally induced benign prostatic hyperplasia. AB - INTRODUCTION: Mast cells are involved in a number of biological responses to exocrine and endocrine stimuli, by releasing growth factors and certain cytokines. The aim of this study was to evaluate their number and distribution in experimentally induced benign prostatic hyperplasia in rats. MATERIALS AND METHODS: Adult Wistar rats (100 days old) were given citral transdermally for 1 month. Morphological characteristics and mast cell concentration were studied in proximal and distal zones after staining with hematoxylin-eosin and Giemsa, respectively. RESULTS: Citral induced mild benign prostatic hyperplasia. Mast cell numbers were increased significantly in both the proximal (2.97 +/- 0.52 vs. 1.4 +/- 0.17, p = 0.004) and distal zone (2.8 +/- 0.68 vs. 1.16 +/- 0.11, p = 0.011). CONCLUSION: Transdermal citral application resulted in a significant increase of mast cell numbers in the stroma of the rat ventral prostate. Furthermore, these mast cells were larger, contained a significant number of intracytoplasmic granules and degranulated. This finding suggests a role for mast cells in the pathogenesis of benign prostatic hyperplasia. PMID- 20173379 TI - Effect of dexmedetomidine on testicular torsion/detorsion damage in rats. AB - BACKGROUND AND OBJECTIVE: We assessed the antioxidant activity of dexmedetomidine (DEX) during an ischemic period in a rat model of testicular torsion/detorsion (T/DT) by using biochemical and histopathological methods. METHODS: Wistar Albino male rats weighing 250-300 g were divided into three groups: sham (group S, n = 7); torsion/detorsion (group T/DT, n = 7), and DEX treatment (group DEX, n = 7). In the T/DT group, right testes were rotated 720 degrees for 1 h. Group S served for normal basal values. Rats in group T/DT were operated to make T/DT, this group served as a control group. Group DEX received intraperitoneal DEX 10 microg . kg(-1) after the 30-min torsion period. For measurement of total antioxidant enzyme activities and malondialdehyde (MDA) levels, testes of 7 animals in each group were excised after 4 h of reperfusion. Germ cell apoptosis was evaluated using the apoptosis protease-activating factor 1 (APAF-1) antibody in all groups and also on the expressions of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) were assessed within the bilateral testes. RESULTS: Mean MDA levels in group T/DT were significantly higher than in groups S and DEX (p < 0.05). There were also significant decreases in mean total antioxidant activities in group T/DT when compared to groups S and DEX (p < 0.05). These values were significantly higher in group DEX than group T/DT. Germ cell apoptosis, eNOS and iNOS levels were significantly higher in group T/DT when compared to groups S and DEX (p < 0.05). CONCLUSIONS: DEX treatment has potential biochemical and histopathological benefits by preventing ischemia/reperfusion related cellular damage in an experimental testicular torsion model. Preference of DEX for anesthesia during the detorsion procedure may attenuate ischemia reperfusion injury. PMID- 20173380 TI - An ancient case of bifid scrotum. PMID- 20173381 TI - The worst case: giant exulcerating seminoma. AB - Ten years after his brother had been treated for seminoma, a 36-year-old male presented with a giant exulcerating mass involving the right testis and both inguinal regions. Subsequent biopsy revealed pure seminoma. Staging computed tomography (CT) showed bulky retroperitoneal and pelvic lymph node metastases. After seven courses of cisplatin-based chemotherapy, positron emission tomography suggested residual tumor in the right groin. The suspicious lesion and the right testis were resected showing no vital tumor tissue. Eight months after surgery there were no signs of disease progression at follow-up CT. PMID- 20173382 TI - Successful treatment with paclitaxel/carboplatin chemotherapy in advanced adenocarcinoma of the urinary tract producing carcinoembryonic antigen, carbohydrate antigen 19-9 and carbohydrate antigen 125. AB - Primary adenocarcinoma of the urinary tract producing tumor markers is extremely rare. We report 2 cases of advanced adenocarcinoma of the urinary tract producing carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9) and carbohydrate antigen 125 (CA125), which were completely resected after induction chemotherapy with paclitaxel and carboplatin. Patient 1 was a 72-year-old woman with adenocarcinoma of the right renal pelvis and ureter. Patient 2 was a 73-year old woman with adenocarcinoma of the bladder. Serum levels of CEA, CA19-9 and CA125 were extremely elevated in both cases. They were successfully treated with paclitaxel puls carboplatin followed by surgery. Both patients were proved to have achieved pathological complete regression by surgical specimens and have been alive without recurrence for more than 18 and 6 months, respectively. PMID- 20173383 TI - Plasma N-terminal pro-brain natriuretic peptide as prognostic marker in fatal cardial decompensation with sunitinib malate therapy. AB - A 74-year-old man with metastatic renal cell carcinoma and a history of cardiac failure was treated with sunitinib malate. MUGA echocardiography could not detect a relevant change in the ejection fraction although the clinical situation of the patient worsened dramatically. The only parameter to hint at the deteriorated cardiac function was plasma N-terminal pro-brain natriuretic peptide (BNP). Finally, the patient died after only one cycle of sunitinib treatment. We propose to prospectively include BNP for the early detection of cardiovascular decompensation in high-risk patients. Future studies concerning the relevance of BNP in drug-related cardiotoxicity are urgently needed. PMID- 20173384 TI - The first description of an extramedullary plasmacytoma of the ureter. AB - Causes for acquired unilateral obstruction of the ureter are numerous: calculi, infections, blood clots and tumors are the most common underlying pathologies. Hematologic tumors with initial clinical manifestation in the lower urinary tract are rare. Primary localization of plasmocytoma has been described in kidney, bladder and urethra. Herein, we describe the first manifestation of a primary solitary extramedullary plasmacytoma of the ureter. The tumor was discovered upon diagnostic workup of gross hematuria and asymptomatic hydronephrosis. Thus far, after radical surgery the patient remains free of disease. PMID- 20173385 TI - Cellular mechanisms of TNF function in models of inflammation and autoimmunity. AB - The TNF/TNF receptor (TNFR) system has a prominent role in the pathogenesis of chronic inflammatory and autoimmune disorders. Extensive research in animal models with deregulated TNF expression has documented that TNF may initiate or sustain inflammatory pathology, while at the same time may exert immunomodulatory or disease-suppressive activities. The TNF/TNFR system encompassing both the soluble and the transmembrane form of TNF with differential biological activities, as well as the differential usage of its receptors, mediating distinct functions, appears to confer complexity but also specificity in the action of TNF. The inherent complexity in TNF-mediated pathophysiology highlights the requirement to address the role of TNF taking into account both proinflammatory tissue-damaging and immunomodulatory functions in a cellular and receptor-specific manner. In this review, we discuss our current understanding of the involvement of TNF in chronic inflammation and autoimmunity, focusing on TNF mediated cellular pathways leading to the pathogenesis or progression of joint and intestinal inflammatory pathology. Knowledge of the mechanisms by which TNF either initiates or contributes to disease pathology is fundamentally required for the design of safe and effective anti-TNF/TNFR therapies for human inflammatory and autoimmune disorders. PMID- 20173387 TI - Posttranscriptional regulation of TNF mRNA: a paradigm of signal-dependent mRNA utilization and its relevance to pathology. AB - The relationship between TNF and immune pathology forced an intense research into the regulation of its biosynthesis that extends to multiple mechanisms controlling the utilization of its mRNA. These posttranscriptional mechanisms gradually and variably impose a series of flexible rate-limiting controls to modify the abundance of the TNF mRNA and the rate of its translation in response to environmental signals. Mechanistically, these controls consist of signaling networks converging to RNA-binding proteins and microRNAs, which in turn target a code of secondary or tertiary ribonucleotide structures located on the TNF mRNA. The outcome of these interactions is the stringent control of this mRNA's maturation, localization, turnover and translation. A wealth of molecular and genetic data highlighted that if these posttranscriptional interactions fail, they perturb cellular responses to provide the impetus for TNF-mediated inflammatory disease. Here, we highlight the parameters guiding the posttranscriptional regulation of TNF mRNA and their relevance to homeostasis and pathology. PMID- 20173388 TI - Role of TNF in pathologies induced by nuclear factor kappaB deficiency. AB - TNF is a potent cytokine with an important role in the regulation of a multitude of cellular responses and in coordinating immune and inflammatory reactions. TNF exerts its effects by binding to the TNFR1- and TNFR2-specific cell surface receptors, which activate a number of intracellular signaling cascades including the nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase pathways. Activation of NF-kappaB mediates many of the functions of TNF by transmitting information from the cell surface TNF receptors to the nucleus, where it coordinates a gene expression program that allows the cell to survive and elicit its responses. The intimate interplay of TNF with the NF-kappaB signaling pathway is highlighted by results obtained in transgenic and knockout mice with defects in NF-kappaB signaling components, where TNF has been shown to contribute to different pathologies observed in these mice. This chapter focuses on the function of TNF in pathologies induced by NF-kappaB deficiency and discusses the implications of these findings for our understanding of inflammatory diseases. PMID- 20173389 TI - Type I interferon: a new player in TNF signaling. AB - TNF and type I interferons (IFNs) are induced by microbial stimuli and mediate innate immune responses. They are also involved in the pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Activated macrophages are an important driving force of inflammatory reactions and one of the major producers of TNF in innate immunity and chronic inflammation. Despite the fact that cells at sites of damage are continuously exposed to both cytokines, little is known about mechanisms regulating TNF and type I IFN interactions during inflammation. In this review, we discuss the role of an IFN-beta-mediated autocrine loop in the regulation of gene expression program induced by TNF in myeloid cells. PMID- 20173390 TI - T cells as sources and targets of TNF: implications for immunity and autoimmunity. AB - TNF is a pleiotropic cytokine produced by many cell types upon different stimuli and in various physiological and pathological conditions. In this review, we focus on the role of TNF in T cell responses as demonstrated by in vitro and in vivo observations in mice and humans. TNF has an impact on all aspects of T cell biology such as development in the thymus, peripheral homeostasis, primary antigenic responses, apoptosis, effector functions, memory cell formation and tolerance induction and maintenance. In most cases, TNF has an immunostimulatory role in T cell responses; however, under certain conditions, TNF can exert immunomodulatory effects on T cells. We also review how T cell-derived TNF is an important component of T cell immunity as exemplified by many studies involving intracellular pathogens and tumors. Finally, we summarize how TNF T cells interplay contributes to pathology in autoimmune disorders and what is known about the effect of widely used TNF blockers on T cell differentiation/function. PMID- 20173391 TI - TNF-alpha: an activator of CD4+FoxP3+TNFR2+ regulatory T cells. AB - TNF-alpha (TNF) is a pleiotropic cytokine which can have proinflammatory or immunosuppressive effects, depending on the context, duration of exposure and disease state. The basis for the opposing actions of TNF remains elusive. The growing appreciation of CD4+FoxP3+ regulatory T cells (Tregs), which comprise approximately 10% of peripheral CD4 cells, as pivotal regulators of immune responses has provided a new framework to define the cellular and molecular basis underlying the contrasting action of TNF. TNF by itself can overcome the profound anergic state of T cell receptor-stimulated Tregs. Furthermore, in concert with IL-2, TNF selectively activates Tregs, resulting in proliferation, upregulation of FoxP3 expression and increases in their suppressive activity. Both human and mouse Tregs predominantly express TNFR2, making it possible for TNF to enhance Treg activity, which helps limit the collateral damage caused by excessive immune responses and eventually terminates immune response. TNFR2-expressing CD4+FoxP3+ Tregs comprise approximately 40% of peripheral Tregs in normal mice and present the maximally suppressive subset of Tregs. In this review, studies describing the action of TNF on Treg function will be discussed. The role of Tregs in the autoimmune disorders and cancer as well as the effect of anti-TNF therapy on Tregs, especially in rheumatoid arthritis, will also be considered. PMID- 20173386 TI - Transcriptional control of the TNF gene. AB - The cytokine TNF is a critical mediator of immune and inflammatory responses. The TNF gene is an immediate early gene, rapidly transcribed in a variety of cell types following exposure to a broad range of pathogens and signals of inflammation and stress. Regulation of TNF gene expression at the transcriptional level is cell type- and stimulus-specific, involving the recruitment of distinct sets of transcription factors to a compact and modular promoter region. In this review, we describe our current understanding of the mechanisms through which TNF transcription is specifically activated by a variety of extracellular stimuli in multiple cell types, including T cells, B cells, macrophages, mast cells, dendritic cells, and fibroblasts. We discuss the role of nuclear factor of activated T cells and other transcription factors and coactivators in enhanceosome formation, as well as the contradictory evidence for a role for nuclear factor kappaB as a classical activator of the TNF gene. We describe the impact of evolutionarily conserved cis-regulatory DNA motifs in the TNF locus upon TNF gene transcription, in contrast to the neutral effect of single nucleotide polymorphisms. We also assess the regulatory role of chromatin organization, epigenetic modifications, and long-range chromosomal interactions at the TNF locus. PMID- 20173392 TI - TNF and bone. AB - Bone is subject to permanent remodeling during development and through life. This activity is essential for (a) proper shaping and growth of each bone during development; (b) maintenance of bone mass as well as structural integrity of the micro architecture of bone through adult life, and (c) tissue repair needed for healing of fracture as well as of micro-damage. In addition to genetically linked rare developmental diseases, disturbances in bone remodeling are causing common bone pathologies, which severely impair the quality of life of patients. Among them are postmenopausal osteoporosis and local as well as systemic bone loss observed in chronic inflammatory diseases such as rheumatoid arthritis. The role of TNF-alpha in mediating bone remodeling will be presented and discussed in this chapter. PMID- 20173393 TI - TNF-alpha and obesity. AB - Obesity, an epidemic of our times with rates rising to alarming levels, is associated with comorbidities including cardiovascular diseases, arthritis, certain cancers, and degenerative diseases of the brain and other organs. Importantly, obesity is a leading cause of insulin resistance and type 2 diabetes. As emerging evidence has shown over the last decade, inflammation is one of the critical processes associated with the development of insulin resistance, diabetes and related diseases, and obesity is now considered as a state of chronic low-grade inflammation. Adipose tissue, apart from its classical role as an energy storage depot, is also a major endocrine organ secreting many factors, whose local and circulating levels are affected by the degree of adiposity. Obesity leads to infiltration of the expanded adipose tissue by macrophages and increased levels in proinflammatory cytokines. The first indication for increased cytokine release in obesity was provided by the identification of increased expression of TNF-alpha, a proinflammatory cytokine, in the adipose tissue of obese mice in the early 1990s. TNF-alpha is expressed in and secreted by adipose tissue, its levels correlating with the degree of adiposity and the associated insulin resistance. Targeting TNF-alpha and/or its receptors has been suggested as a promising treatment for insulin resistance and type 2 diabetes. This review will summarize the available knowledge on the role of TNF-alpha in obesity and related processes and the potential implications of the above in the development of new therapeutic approaches for obesity and insulin resistance. Recent data from clinical studies will also be described together with late findings on the pathogenesis of obesity and insulin resistance. PMID- 20173394 TI - TNF in host resistance to tuberculosis infection. AB - TNF is essential to control Mycobacterium tuberculosis infection and cannot be replaced by other proinflammatory cytokines. Overproduction of TNF may cause immunopathology, while defective TNF production results in uncontrolled infection. The critical role of TNF in the control of tuberculosis has been illustrated recently by primary and reactivation of latent infection in some patients under pharmacological anti-TNF therapy for rheumatoid arthritis or Crohn's disease. In this review, we discuss results of recent studies aimed at better understanding of molecular, cellular and kinetic aspects of TNF-mediated regulation of host-mycobacteria interactions. In particular, recent data using either mutant mice expressing solely membrane TNF or specific inhibitor sparing membrane TNF demonstrated that membrane TNF is sufficient to control acute M. tuberculosis infection. This is opening the way to selective TNF neutralization that might retain the desired anti-inflammatory effect but reduce the infectious risk. PMID- 20173395 TI - The first decade of biologic TNF antagonists in clinical practice: lessons learned, unresolved issues and future directions. AB - Results from clinical trials of biologic anti-TNF drugs performed in the late 1990s confirmed the biological relevance of TNF function in the pathogenesis of chronic noninfectious inflammation of joints, skin and gut, which collectively affects 2-3% of the population. Up to April 2009, more than two million patients worldwide have received the first marketed drugs, namely the monoclonal anti-TNF antibodies infliximab and adalimumab and the soluble TNF receptor etanercept. All three are equally effective in rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, but, for not clearly defined reasons, only the monoclonal antibodies are effective in inflammatory bowel disease. About 60% of patients who do not benefit from standard nonbiologic treatments for these diseases respond to TNF antagonists. Less than half of responding patients achieve complete remission of disease. Importantly, some of those patients with rheumatoid arthritis in whom long-term anti-TNF therapy induced disease remission remain disease-free after discontinuation of any kind of treatment. There are not yet reliable predictors of which patients will or will not respond on anti-TNF therapy, whereas subsequent loss of an initial clinical response occurs frequently. The spectrum of efficacy anti-TNF therapies widens to include diseases such as systemic vasculitis and sight-threatening uveitis. While paradoxical new adverse effects are recognized, i.e. exacerbation or development of new onset psoriasis, reactivation of latent tuberculosis remains the most important safety issue of anti-TNF therapies. Clinical practice guidelines and consensus statements on the criteria of introduction, duration of treatment and cessation of TNF antagonists, including safety issues, are under constant revision as data from longer periods of patient exposure accumulate. It is hoped that more efficacious drugs that will ideally target the deleterious proinflammatory properties of TNF without compromising its protective role in host defense and (auto)immunity will be available in the near future. PMID- 20173396 TI - [Fluorescence diagnostics of skin tumors using 5-aminolevulinic acid and its methyl ester]. AB - OBJECTIVE: The incidence of malignant skin tumors is rapidly increasing. Early diagnosis, determining the margins of the tumor, is extremely important to achieve good treatment results. We investigated fluorescence of protoporphyrin IX in skin carcinomas. The study aimed to compare the effectiveness of topical 5 aminolevulinic acid and methyl-aminolevulinate in determining the exact margins of skin tumors. MATERIALS AND METHODS: Fluorescence measurements were performed in 126 patients with malignant, premalignant, and benign skin lesions for detection of the margins of squamous cell carcinoma and basal cell carcinoma. 5 Aminolevulinic acid or its methyl ester was applied to the skin lesion for 2-4 h, and the data of evaluated protoporphyrin IX fluorescence were correlated with the data of morphological tissue examination. RESULTS: Malignant tissue shows a specific red fluorescence when illuminated with blue-violet light, whereas no fluorescence was observed in normal skin. In 30% of cases, the delineation of neoplastic lesions excited by 5-aminolevulinic acid was slightly weaker than using methyl-aminolevulinate. A sensitivity of 95.4% and a specificity of 88.6% as well as positive and negative predictive values of 86.1% and 96.3%, respectively, were obtained. CONCLUSIONS: Fluorescence diagnostics can be used for complete visualization of malignant skin lesions after topical application of 5-aminolevulinic acid or methyl aminolevulinate. It has been shown to be highly effective in the diagnostics of malignant superficial skin lesion. This method is applicable for detecting early superficial tumors, margins of tumors, and follow up after therapy. Topical application of methyl aminolevulinate is slightly superior to 5-aminolevulinic acid in detection of lesion margins. PMID- 20173397 TI - [Assessment of disease control in patients with asthma]. AB - International guidelines indicate that the main criterion of asthma management is asthma control level. The aim of this study was to assess asthma control and its relation with age, gender, and lung function. MATERIAL AND METHODS: A total of 106 family physicians and 13 pulmonologists and allergists took part in this study. Each doctor had selected 10-15 asthma patients and had sent invitations to them by post. On the visit day, the patients themselves filled in the Asthma Control Test. The doctors interviewed the patients and filled in a special questionnaire. Pulmonologists and allergists also assessed lung function by performing spirometry. According to the results of the Asthma Control Test, the disease control level was indicated as "totally controlled" (25 points), "well controlled" (24-20 points), and "uncontrolled" (19 points or less). RESULTS: A total of 876 asthma patients were examined. Uncontrolled asthma was diagnosed to 56.2% of the patients, 36.5% of patients had well controlled and 7.3% totally controlled asthma. There was no significant difference in asthma control level comparing men and women. A correlation between asthma control level and age was found revealing poorer asthma control in older patients. Ninety-five percent of patients were treated with inhaled steroids; most of them had used inhaled steroids in combination with long-acting beta(2) agonists. It was found that lung function correlated with clinical symptoms of asthma, the demand of short-acting beta(2) agonists, and asthma control level. CONCLUSION: The study showed that uncontrolled asthma was diagnosed to more than half of the patients, despite most of them used inhaled steroids. Asthma control was worsening with the age of patients with asthma and it correlated with lung function. We suggest that periodical assessment of asthma control should help to optimize asthma management. PMID- 20173398 TI - [Effectiveness of radiologic examination methods in diagnosis of pulmonary tuberculosis]. AB - OBJECTIVE OF THE STUDY: To determine an optimal noninvasive radiologic examination method (computed tomography or roentgenography) in early diagnostics of pulmonary tuberculosis. MATERIALS AND METHODS: We have selected 43 patients with diagnosis of pulmonary tuberculosis, who were examined using roentgenography and computed tomography during 2002-2006. Data were confirmed by biopsy or bacteriological test. Evaluation criteria were anamnesis, prolonged cough productive of sputum, prolonged fever, roentgenologic and laboratory findings (lymphocytosis, monocytosis), antibiotic therapy without response. RESULTS: Diagnostic signs of pulmonary tuberculosis were infiltration (89%), lymphadenopathy (63%), calcification in lymph nodes (49%), pneumofibrosis (56%), focus of tuberculosis (54%), foci in lung segments (67%). Other features were as follows: adhesions, pleural effusion, coated pleura, calcified tuberculoma. Biopsy was performed to 25% of patients: in 6 patients during fibrobronchoscopy, in 3 during operation, and in 2 during pleural puncture. Fibrobronchoscopy was done in 70% of patients, and findings were as follows: mucus (31%), blood (2%), bronchial deformations (22%), edema of bronchial wall (18%), and no pathology (31%). Only 8% had acid-resistant cocci. CONCLUSIONS: Computed tomography is 2 times more efficient than roentgenography in detection of lung alterations, dissemination with focal infiltration in the bronchioles, coated pleura, pleuritis, adhesions and 8 times more efficient in diagnosis of mediastinal lymphadenopathy. In evaluation of pulmonary consolidation, there was no significance difference between diagnostic methods. PMID- 20173400 TI - Soluble interleukin-2 receptor and tumor necrosis factor levels in depressed patients in Estonia. AB - Several studies have reported immune system alterations in depressed patients. Furthermore, correlations between some interleukins and specific depressive symptoms have been found, but results are ambiguous. It might be caused by heterogeneous patient population and concomitant administration of antidepressants. The aim of our study was to look at differences in the levels of soluble interleukin-2 receptor (sIL-2R) and tumor necrosis factor-alpha (TNFalpha) between currently depressed patients with first or recurrent episode of depression, patients in full remission and healthy controls. Secondly, we looked for correlations between sIL-2R and TNFalpha and different depressive symptoms. A total of 75 medication-free currently depressed patients (76% of females), 17 patients in the full remission phase of major depression (58.8% of females), and 55 healthy controls (58.2% of females) participated in this study. The results showed that the level of sIL-2R was significantly lower in depressed patients in remission phase compared to the healthy controls and subjects with recurrent depression. Drug-nalve patients with major depressive disorder with recurrent episode had higher levels of sIL-2R than previously treated or patients with the first episode. TNFalpha levels were higher in drug-nalve patients with major depressive disorder with recurrent episode compared with previously treated patients. Further analysis of patients revealed that sIL-2R was positively correlated with decreased activity and agitation. TNFalpha was associated with decreased activity and suicidality. PMID- 20173399 TI - Atrial fibrillation and changes in serum and urinary electrolyte levels after coronary artery bypass grafting surgery. AB - OBJECTIVE: Our study was designed to assess the incidence of atrial fibrillation, changes in serum electrolyte concentrations and urinary electrolyte excretion following coronary artery bypass grafting surgery. MATERIAL AND METHODS: A total of 165 patients who underwent elective coronary artery bypass grafting surgery at the Department of Cardiac Surgery (Heart Center) during the period of 2004-2005 were enrolled. Serum K(+), Na(+), Mg(2+), Ca(2+), Cl(-), and P(-) concentrations were measured before cardiopulmonary bypass (CPB), on the arrival to an intensive care unit, and 15-18 hours after the surgery. Urinary excretion of K(+), Na(+), Mg(2+), Ca(2+), Cl(-), and P(-) was estimated 24 hours before the surgery, during the surgery, and 24 hours after the surgery. Cardiac rhythm was monitored throughout the study. All patients randomly were divided into the group 1 (n=55), which received magnesium sulphate infusion, and group 2 (n=110), which did not receive magnesium sulphate. RESULTS: The overall incidence of atrial fibrillation was 27.4%. The patients in the group 1 had significantly higher levels of serum magnesium before CPB and serum chloride after the surgery. Urinary magnesium and calcium excretion was significantly higher in the group 1 during and after the surgery. Before the surgery and 24 hours after the surgery, phosphate excretion was significantly higher in the group 1. CONCLUSIONS: The incidence of atrial fibrillation after myocardial revascularization surgery remains high (27.4%). Serum electrolyte concentrations after myocardial revascularization varied within normal ranges. Magnesium sulphate infusion did not decrease the rate of postoperative atrial fibrillation during the early postoperative period in normomagnesemic patients. PMID- 20173402 TI - Successful treatment of upper ureteral injury using renal autotransplantation. AB - INTRODUCTION: Ureteral injuries are uncommon. Upper ureteral defect more than 7-8 cm in length is a challenge for urologists, requiring experience and several steps in its management. We report a case of iatrogenic upper urinary tract injury and successful treatment of 8-cm ureteral defect using autotransplantation of the kidney. CASE REPORT: A male patient underwent surgery due to retroperitoneal tumor. Iatrogenic ureteral injury was recognized 18 days after operation. Three-step management of urinary tract injury was performed. The first step included minimally invasive recovery of the urine flow and treatment of infection. The second step was unsuccessful renal descensus and new formation ureteropyeloanastomosis because of difficulties of kidney mobilization caused by previous surgery. The third step included a successful autotransplantation of the kidney and complete reconstruction of the urinary tract. CONCLUSIONS: Autotransplantation can be successfully used for the management of long upper ureteral injury in referral urological centers. PMID- 20173401 TI - [Usefulness of assessment of voice capabilities in female patients with reflux related dysphonia]. AB - OBJECTIVES: To analyze vocal capabilities in patients diagnosed with reflux related dysphonia versus controls with healthy voice with selection of the most informative discriminating quantitative parameters and to assess voice changes following treatment. MATERIAL AND METHODS: Six parameters of voice range profile (VRP) and five parameters of speech range profile were taken and analyzed from 60 dysphonic outpatient females with laryngopharyngeal reflux (LPR) diagnosed by reflux-related atypical and typical symptoms, videolaryngoscopic findings, upper gastrointestinal endoscopy, and positive response to empiric 3-month omeprazole treatment. Seventy-six females with healthy voice served as controls. RESULTS: All six parameters of voice range profile and three of 5 parameters of speech range profile showed significant differences comparing LPR patients with controls before omeprazole treatment (P<0.05). Logistic regression analysis revealed VRP maximum-minimum intensity range to be the most informative parameter for discrimination between reflux-related dysphonic and healthy voices (overall prediction accuracy, 86.8%). A threshold value of significant parameter was stated using the receiver operating characteristic curve. Treatment with omeprazole significantly improved voice quality showing the greatest changes in the mean scores of majority of voice range profile parameters. CONCLUSIONS: Vocal capabilities, especially evaluated by voice range profile, are restricted in LPR female patients in comparison to subjects with healthy voice. Quantitative voice assessment with voice range profile may add more objective aspect for screening dysphonia and could be used as a criterion of evaluation of treatment efficacy in such patients. PMID- 20173403 TI - Phenolics and anthocyanins in berries of European cranberry and their antimicrobial activity. AB - European cranberry is a berry plant rich in biologically active substances, making it valued by both the phyto-pharmaceutical and food industries. The aim of this study was to examine the accumulation of phenolic compounds and anthocyanins in berries of European cranberry and to assess their antibacterial activity. MATERIAL AND METHODS: Different wild clones of European cranberry were investigated according to berry weight and the amounts of total phenolics and anthocyanins. Anthocyanin profiles of extracts were evaluated by HPLC, whereas the antimicrobial properties were determined by the agar well diffusion method. A strong negative correlation between berry weight and the amount of anthocyanins was found. The amount of total phenolics among different cranberry clones in the field collection ranged from 224.0 mg/100 g to 498.0 mg/100 g, and the amount of total anthocyanins ranged from 40.7 mg/100 g to 207.3 mg/100 g. Quantitative HPLC UV analysis revealed six anthocyanins in the berries of European cranberry, among which the anthocyanin peonidin-3-galactoside was most prevalent. CONCLUSIONS: Investigation of the antimicrobial properties showed that European cranberry extracts inhibited the growth of wide range of human pathogenic bacteria, both gram-negative (Escherichia coli and Salmonella typhimurium) and gram-positive (Enterococcus faecalis, Listeria monocytogenes, Staphylococcus aureus, and Bacillus subtilis). PMID- 20173404 TI - [Associations between mortality and alcohol consumption in Lithuanian population]. AB - The objective of the study was to assess alcohol-related mortality that potentially might explain an increasing trend in overall mortality of Lithuanian population, which started after 2000 and peaked in 2005. MATERIAL AND METHODS: An empiric analysis of national mortality and other statistical data as well as their international comparisons. RESULTS: An analysis of available data clearly indicates that a decline in mortality in 1998-2000, i.e. during the beginning of the National Programme of Health, as well as its increase in 2001 and 2005 were predominantly determined by cause-specific deaths of two groups: deaths from diseases of the circulatory system (mainly ischemic heart disease) and alcohol consumption-related deaths (liver cirrhosis, accidental poisoning by alcohol, accidents, etc.). A certain proportion of deaths, which were caused by alcohol, were wrongly assigned to the deaths from diseases of the circulatory system due to uncertainties in filling-in death certificates. By approximate estimates, at least one-quarter of increase in all-cause mortality between 2002-2004 and 2005 2007 could be explained by an increase in alcohol consumption, accounting for additional 880 deaths on average per year. In the year 2007, 12.6% (n=5760) of all deaths were somehow related to alcohol consumption. A comparative analysis demonstrated that mortality and alcohol consumption trends were going in parallel over the last decade. The systemic decline in mortality observed in Lithuania from 1995 stopped in 2000 after a decrease in alcohol taxes, which resulted in an increase in alcohol accessibility and consumption. An average annual increase in alcohol consumption over the period of 2001-2004 was 7%; it increased up to 17% in 2005 and accounted for 12% annual increase on average within 2005-2007. CONCLUSIONS: Negative trends in alcohol-related morbidity and mortality in Lithuanian population most notably registered in 2001 and 2005 were largely influenced by uncontrollable increase in alcohol consumption over the last decade. Economic and commercial arguments in decision-making process that neglected health interest of Lithuanian population (decrease of alcohol taxes in 1999, other factors increasing alcohol accessibility and consumption) were those counteracting the implementation of balanced health policy in the country. PMID- 20173405 TI - Nonadherence to medications among pharmacy clients and their attitude toward medications kept a medicine cabinet at home. AB - OBJECTIVES: To assess self-reported adherence among pharmacy clients and to detect if there are any differences in medication use or storage between genders. MATERIAL AND METHODS: The data were collected by means of questionnaires. A standard 45-item questionnaire was developed and used to assess adherence and nonadherence to medications. It was distributed to all pharmacy customers who entered pharmacies chosen by us. RESULTS: Of the 162 (45 men and 117 women) pharmacy clients participating in the study, 36.42% were considered nonadherent. No significant difference in adherence rates between genders was observed (P>0.05). Women more often named themselves as being responsible for a medicine cabinet at home (P<0.001) and used more sources of information on medications (P<0.05). Women also more frequently checked the expiry date of medications in a medicine cabinet home than men (P<0.05). CONCLUSIONS: The problem of nonadherence to medications exists among pharmacy clients. There is no significant difference in the rate of self-reported adherence between male and female pharmacy clients. Women are the ones named as responsible for a medicine cabinet at home. They also are important health decision makers. Women are more interested in information on medicines and their use; therefore, this demand should be satisfied. PMID- 20173406 TI - [Relationship of renal cell carcinoma and hypertension]. AB - The morbidity and mortality due to renal cell carcinoma has increased worldwide over the last 30 years. Renal cell carcinoma accounts for about 90-95% of all renal tumors. The mean age of patients with this type of tumor ranges between 50 and 70 years. It is important to note that primary arterial hypertension as well as obesity and smoking are considered as independent risk factors for renal cell carcinoma. The increase in both systolic and diastolic blood pressure as well as the severity of arterial hypertension may have an impact on development of renal cell carcinoma. We describe the case of a 45-year-old male patient with hypertensive crisis. Computed tomography scan revealed renal cell carcinoma, which was confirmed histologically after surgical treatment. PMID- 20173407 TI - Vaccines against malaria: perspectives from Papua New Guinea. AB - Despite its small population and isolated location Papua New Guinea (PNG) with a malaria burden comparable to sub-Saharan Africa, its intense transmission of all four human Plasmodium species and an unrivalled combination of environmental and human variation offers unique perspectives on malaria vaccines. Building on a long history of malaria research, in this article we review past achievements, highlight current research and outline future directions in malaria vaccine research. With intensive transmission of all four species of human malaria, a full range of malaria endemicities, well described epidemiology and a demonstrated capacity to evaluate a malaria vaccine, PNG currently has the only field site that is ready to conduct proof-of-principle studies of currently available P. vivax vaccine candidates and future combined P. falciparum / P. vivax vaccines and also offers unique opportunities for P. falciparum vaccine research. PNG is thus ready to contribute significantly in the global malaria vaccine endeavor. PMID- 20173408 TI - The past decade in malaria synthetic peptide vaccine clinical trials. AB - Over the past decade (2000-2009), there have been nine clinical trials of synthetic malaria peptide vaccines designed to target the pre-erythrocytic and erythrocytic stages of the Plasmodium falciparum parasite. Recent advances in parasite immunology and cell biology have been utilized to improve peptide design and adjuvant formulations. The clinical trials demonstrated the potential of second generation peptide vaccines to elicit antibodies that can neutralize sporozoite infectivity and cooperate with monocytes in ADCI to inhibit blood stage parasites. In addition, peptide-induced malaria-specific human CD4(+) and CD8(+) T cells were shown in vitro to have similar fine specificity and function as parasite-induced T cells. The results of these clinical trials, while encouraging, have emphasized the critical roles of immunological assays, in particular functional assays, for the evaluation of potential vaccine candidates. Additional challenges include the need for potent adjuvants for the development of synthetic peptide vaccines that can effectively target multiple stages of the Plasmodium parasite. PMID- 20173410 TI - Sequence divergences between cyst nematode effector protein orthologs may contribute to host specificity. PMID- 20173411 TI - Positioning of the auxin maximum affects the character of cells occupying the root stem cell niche. PMID- 20173412 TI - Shedding light on the role of AT-hook/PPC domain protein in Arabidopsis thaliana. PMID- 20173413 TI - New insights into the retrograde signaling pathway between the plastids and the nucleus. PMID- 20173414 TI - Hormone-mediated promotion of trichome initiation in plants is conserved but utilizes species- and trichome-specific regulatory mechanisms. PMID- 20173415 TI - Microgravity environment uncouples cell growth and cell proliferation in root meristematic cells: the mediator role of auxin. PMID- 20173416 TI - Evolution of serine carboxypeptidase-like acyltransferases in the monocots. PMID- 20173417 TI - AtTZF gene family localizes to cytoplasmic foci. PMID- 20173418 TI - Structural features of plant subtilases. PMID- 20173419 TI - Subcellular localization and turnover of Arabidopsis phototropin 1. PMID- 20173420 TI - Plant-specific multisubunit RNA polymerase in gene silencing. AB - In recent years, a major breakthrough in the study of epigenetic silencing in eukaryotes came with the discovery that the RNA-interference pathway (RNAi) is generally implicated in heterochromatin assembly and gene silencing. An important and paradoxical feature of the RNAi-mediated heterochromatin pathways is their requirement for some form of transcription. In fission yeast, Schizosaccharomyces pombe, centromeric siRNAs have been shown to derive from chromatin-bound nascent transcripts produced by RNA polymerase II (PolII) at the site of heterochromatin formation. Likewise, chromatin-bound nascent transcripts generated by a PolII related DNA-dependent RNA polymerase, known as PolIVb/PolV, have recently been implicated in RNA-directed DNA methylation (RdDM), the prominent RNAi-mediated chromatin pathway in plants. In this review we discuss recent work on the plant specific PolII variant enzymes and discuss the mechanistic convergences that have been observed in the role of these enzymes in their respective siRNA-mediated heterochromatin formation pathways. PMID- 20173422 TI - Subsyndromal depression and services delivery: at a crossroad? PMID- 20173423 TI - Exergames for subsyndromal depression in older adults: a pilot study of a novel intervention. AB - OBJECTIVES: Subsyndromal depression (SSD) is several times more common than major depression in older adults and is associated with significant negative health outcomes. Physical activity can improve depression, but adherence is often poor. The authors assessed the feasibility, acceptability, and short-term efficacy and safety of a novel intervention using exergames (entertaining video games that combine game play with exercise) for SSD in older adults. METHODS: Community dwelling older adults (N = 19, aged 63-94 years) with SSD participated in a 12 week pilot study (with follow-up at 20-24 weeks) of Nintendo's Wii sports, with three 35-minute sessions a week. RESULTS: Eight-six percent of enrolled participants completed the 12-week intervention. There was a significant improvement in depressive symptoms, mental health-related quality of life (QoL), and cognitive performance but not physical health-related QoL. There were no major adverse events, and improvement in depression was maintained at follow-up. CONCLUSIONS: The findings provide preliminary indication of the benefits of exergames in seniors with SSD. Randomized controlled trials of exergames for late life SSD are warranted. PMID- 20173424 TI - Outcomes of subsyndromal depression in older primary care patients. AB - OBJECTIVES: Most older persons in primary care suffering clinically significant depressive symptoms do not meet criteria for major or minor depression. The authors tested the hypothesis that patients with subsyndromal depression (SSD) would have poorer psychiatric, medical, and functional outcomes at follow-up than nondepressed patients but not as poor as those with minor or major depression. The authors also explored the relative outcomes of three definitions of SSD to determine their relative prognostic value. DESIGN: Prospective observational cohort study. SETTING: Primary care practices in Monroe County, NY. PARTICIPANTS: Four hundred eighty-one primary care patients aged 65 years and older who completed research assessments at intake and at least 1 year of follow-up evaluation. MEASUREMENTS: Depression diagnoses and three definitions of SSD were determined by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and the 24-item Hamilton Depression Rating Scale. Other validated measures assessed anxiety, cognition, medical burden, and functional status. RESULTS: Patients with SSD had poorer 1-year lagged outcomes than nondepressed subjects in terms of psychiatric symptoms and functional status, often not significantly different than major or minor depression. Two of the SSD definitions identified subjects with poorer psychiatric and functional outcomes than the third SSD definition. CONCLUSIONS: Clinicians should be vigilant in caring for patients with SSD, monitoring for persistent, or worsening depressive symptoms including suicidality, anxiety, cognitive impairment, and functional decline. Researchers may use particular SSD definitions to identify individuals at higher risk of poor outcomes, to better understand the relationships of SSD to functional disability, and to test innovative preventive and therapeutic interventions. PMID- 20173425 TI - Constraint-induced therapy versus control intervention in patients with stroke: a functional magnetic resonance imaging study. AB - OBJECTIVE: This study compared the effects of a distributed form of constraint induced therapy with control intervention in motor recovery and brain reorganization after stroke. DESIGN: A two-group randomized controlled trial with pretreatment and posttreatment measures was conducted. Thirteen patients with stroke were randomly assigned to the distributed form of constraint-induced therapy (n = 5) or the control intervention group (n = 8). Outcome measures included the Fugl-Meyer Assessment, the Motor Activity Log, and functional magnetic resonance imaging examination. The number of activation voxels and laterality index were determined from the functional magnetic resonance imaging data for the study of brain reorganization. RESULTS: The distributed form of constraint-induced therapy group exhibited significantly greater improvements in the Fugl-Meyer Assessment and Motor Activity Log than the control intervention group. The functional magnetic resonance imaging data showed that distributed form of constraint-induced therapy significantly increased activation in the contralesional hemisphere during movement of the affected and unaffected hand. The control intervention group showed a decrease in primary sensorimotor cortex activation of the ipsilesional hemisphere during movement of the affected hand. CONCLUSIONS: The preliminary findings indicate that brain adaptation may be modulated by specific rehabilitation practices, although generalization of the functional magnetic resonance imaging findings is limited by sample size. Further research is needed to identify the specific neural correlates of the behavioral gains achieved after rehabilitation therapies. PMID- 20173426 TI - Wheelchair users' perceptions of and experiences with power assist wheels. AB - OBJECTIVE: To assess wheelchair users' perceptions of and experiences with power assist wheels using qualitative interview methods. DESIGN: Qualitative evaluations were conducted in a laboratory setting with a focus on users' experiences using power assist wheel in their naturalistic environments. Participants consisted of seven women and 13 men (M(age) = 42.75, SD = 14.68) that included one African American, one Hispanic, 17 whites, and one individual from Zambia. Qualitative interviews were conducted before, during, and after use of a power assist wheel. Main outcome measures included the wheelchair users' evaluations and experiences related to the use of power assist wheels. RESULTS: The primary evaluations included wheeling on challenging terrains, performance of novel activities, social/family aspects, fatigue, and pain. These descriptions indicated that most participants perceived positive experiences with the power assist wheels, including access to new and different activities. Secondary evaluations indicated that the unit was cumbersome and prohibitive for some participants because of difficulties with transport in and out of a vehicle and battery life. Most participants felt that power assist wheels provided more independence and social opportunities. CONCLUSIONS: The power assist wheel seems to offer physical and social benefits for most wheelers. Clinicians should consider users' home environment and overall life circumstances before prescribing. PMID- 20173427 TI - Reliability of the physical medicine and rehabilitation resident observation and competency assessment tool: a multi-institution study. AB - OBJECTIVES: To assess the psychometric qualities of a method of resident physician evaluation by faculty. DESIGN: Multicenter study by seven Physical Medicine and Rehabilitation training programs. Faculty physicians observed residents in brief patient encounters or teaching sessions, rated specific competencies, and provided residents with immediate feedback. The resident observation and competency assessment form included competencies in patient care, professionalism, interpersonal and communication skills, systems-based practice, and practice-based learning and improvement. Residents and faculty rated satisfaction with the process. RESULTS: Three hundred sixty-two ratings were completed on 88 different residents. Each resident received an average of 3.8 ratings across two academic years. Overall internal consistency reliability was high (0.98); reliability of the individual competencies ranged from 0.74 to 0.76. Item means were correlated with year of training for two skill sets, with higher means for more experienced residents. The majority of participants gave high ratings of satisfaction; correlation between satisfaction ratings of attending and resident physicians was 0.63 (P < 0.01). CONCLUSIONS: The resident observation and competency assessment is a reliable method to assess resident skills in five of six general competencies. Construct validity of the tool is supported by the fact that faculty rated two skill sets higher for senior residents. PMID- 20173428 TI - "How bad is it?": the role of nursing research in prognostication. PMID- 20173429 TI - Impact of articles published in the Clinical Journal of Pain: most frequently cited papers published from 2002 to 2009. PMID- 20173430 TI - Frequencies of polymorphisms in cytokines, neurotransmitters and adrenergic receptors in patients with complex regional pain syndrome type I after distal radial fracture. AB - OBJECTIVES: The complex regional pain syndrome type I (CRPS I) is one of the main complications after a fracture of the distal radius. The underlying pathology is not fully understood. Different theories have been put forward to explain the pathogenesis of this disease, some including genetic models. The aim of this study was to find a possible genetic involvement in the occurrence of CRPS I. METHODS: We tested for known single nucleotide polymorphisms in cytokines, adrenergic receptors, and inflammatory neuropeptides in a cohort of patients at risk to develop CRPS I after a distal radius fracture. Subjective pain and functional parameters were recorded during the course of 1 year after trauma. RESULTS: Fifteen of 163 patients with fractures of the distal radius were diagnosed with CRPS I according to the International Association for the Study of Pain research criteria. A significant association was detected for the rs1048101 polymorphism of the alpha1a-adrenoceptor. All other tested variants were not associated with CRPS I. Patients with CRPS I fared worse in all functional tests compared with the control group. DISCUSSION: This study suggests the rs1048101 single nucleotide polymorphism within the alpha1a-adrenoceptor as one risk factor for the development of CRPS I after the distal radius fracture. PMID- 20173431 TI - Sensitivity and specificity of 3-phase bone scintigraphy in the diagnosis of complex regional pain syndrome of the upper extremity. AB - OBJECTIVES: Joint and bone alterations are seldom mentioned in the diagnostic criteria for complex regional pain syndrome (CRPS) even though they are important for long-term outcome. Altered periarticular bone metabolism can be detected by 3 phase bone scintigraphy (TPBS). Although frequently examining the diagnostic efficacy of TPBS is debatable. METHODS: In all, 78 TPBS (45 CRPS/33 control group) were evaluated qualitatively and quantitatively. Sensitivity and specificity of the qualitative blinded reviewer analysis (n=57) compared with quantitative region of interest (ROI)-based analysis over the metacarpophalangeal, proximal, and distal interphalangeal joints (n=74) were evaluated. Patients' sex, age, duration of CRPS, inciting event, extent of joint alteration, and handedness were included as covariables. RESULTS: Qualitative blinded reviewer TPBS analysis had a high specificity (83%-100%). However, sensitivity was 31% to 50%. Interrater reliability was moderate (kappa score 0.56). Using the ROI-based evaluation, the highest sensitivity (69%) and specificity (75%) (ROI score > or =1.32) was shown for phase 3, whereas sensitivity of phases 1 and 2 rapidly declined to 50%. Duration of CRPS until TPBS was the only variable with significant impact on ROI scores of phase 3 (F=23.7; P=0.000; R=0.42). ROI scores declined with increasing duration of CRPS. DISCUSSION: In conclusion, TPBS is a highly specific tool for diagnosing CRPS of the upper limb. ROI evaluation of phase 3 within the first 5 months after onset of CRPS is an appropriate additional diagnostic tool to confirm or exclude CRPS of the upper extremity. PMID- 20173432 TI - Ongoing pain despite aggressive opioid pain management among persons with HIV. AB - BACKGROUND: Chronic pain is a common problem among persons living with HIV and opioids are frequently used in its treatment. However, data on the variables associated with opioids use and the efficacy of this practice are lacking. METHODS: We performed a cross-sectional cohort study of self-reported pain during the year 2005 in our clinic. Patients were grouped into 3 cohorts: those receiving daily opioid therapy for chronic pain (cohort 1, n=115), those with a chronic pain diagnosis but not on daily opioid therapy (cohort 2, n=209), and those without a chronic pain diagnosis (cohort 3, n=796). RESULTS: In multivariate analysis comparing cohorts 1 and 2, patients in cohort 1 were significantly more likely to be on a benzodiazepine or gamma-aminobutyric receptor agonist [odds ratio (OR)=15.2], have injection drug use as a HIV risk factor (OR=4.27), lack private insurance (OR=3.51), have been abused (OR=3.08), have a history of AIDS (OR=2.21), and be seen more frequently (OR=1.18). Patients in cohort 1 reported significantly more pain [mean pain scores (0 to 10): 4.3 cohort 1; 1.9 cohort 2; 0.7 cohort 3], and were more likely to have pain that was of moderate or greater severity (58.6% cohort 1; 15.5% cohort 2; 4.9% cohort 3). CONCLUSIONS: Psychosocial variables and a history of AIDS were associated with opioid use in our clinic. Persons on opioids continued to experience significantly more pain than other patients in our clinic. PMID- 20173433 TI - A comparison of analgesic management for emergency department patients with sickle cell disease and renal colic. AB - OBJECTIVES: To determine whether there is a difference in time to initial analgesic for patients with acute pain from sickle cell disease (SCD) versus renal colic (RC) and to identify factors contributing to variance in time to analgesic. METHODS: A retrospective cohort study of the adult emergency department (ED) patients with acute pain from SCD and RC in an urban ED (final ED discharge ICD-9 diagnosis codes were included). A structured medical record review abstracted the demographics, arrival shift, triage level, initial pain score, triage time, and time of initial analgesic dose. Data were compared with Kaplan-Meier plots of time to initial analgesic for both RC and SCD with the log rank test to test for differences by disease category. A multivariable Cox regression model estimated differences in time to initial analgesic by disease category while controlling for other possible confounders. RESULTS: Median time to initial analgesic was 80 minutes for patients with SCD (interquartile range, 48 to 145) versus 50 minutes for patients with RC (interquartile range: 30 to 96). Patients with SCD reported a higher pain score on arrival when compared with RC patients and were more frequently assigned a higher triage priority level (P=0.05). Covariates that contributed the most delays to the model were afternoon arrival [hazard ratio (HR): 0.35, P<0.01], low acuity triage level (HR: 0.42, P<0.01), SCD diagnosis (HR: 0.61, P<0.01), and inability to obtain intravenous access (HR: 0.71, P=0.01). DISCUSSION: ED patients with SCD experienced longer delays in the administration of the initial analgesic compared with RC patients, despite higher arrival pain scores and triage acuity levels. PMID- 20173434 TI - Comparison of a pain management program with usual care in a pain management center for people with spinal cord injury-related chronic pain. AB - OBJECTIVE: To evaluate the effectiveness of a specifically modified group-based, multidisciplinary cognitive-behavioral pain management program (PMP) in comparison to usual care in a clinical sample of people with spinal cord injury (SCI)-related chronic pain. METHOD: Changes over time on a range of measures, including usual pain intensity, pain catastrophizing and self-efficacy, mood, SCI acceptance and self-efficacy, and interference due to pain were examined in 2 groups with SCI-related chronic pain after a multidisciplinary pain assessment. One group (n=19) attended the PMP, and the other (n=17) received standard care on an individualized basis in a pain management center. RESULTS: The groups were significantly different at baseline, with the PMP group scoring more negatively on a number of the measures, including usual pain intensity. The PMP group showed an overall improvement in mood and life interference due to pain at the end of the PMP when compared with the usual care group. Within the PMP group, there was a significant improvement over time in anxiety and pain catastrophizing. No changes in SCI-related psychologic variables (acceptance and self-efficacy) were observed in either group. DISCUSSION: This study demonstrates that a PMP may offer benefits to clinical populations with SCI-related chronic pain in a pain management center. The reported improvements were of a magnitude to be clinically significant. However, some of the initial benefits reported were not maintained at the nine month follow-up. The interventions may need to be augmented to address the effects of SCI-related psychologic variables that may impact upon the individual's ability to benefit from a PMP. PMID- 20173435 TI - Chronic pain after lung transplantation: a nationwide study. AB - OBJECTIVES: Little is known about persistent postsurgical pain after lung transplantation with the associated intensive and continuous immunosuppressive treatment. Therefore, we investigated the nationwide incidence of chronic pain after lung transplantations. METHODS: Detailed questionnaires were sent to all 110 Danish surviving recipients of lung transplantation from September 2002 to September 2007. RESULTS: Seventy-nine patients fulfilled the inclusion criteria with a mean follow-up time of 39 months. Excluded patients were 1 death during survey, 14 with previous thoracic surgery, and 16 patients who did not respond to an initial mailed questionnaire or a reminder. Fourteen patients (18%) reported persistent pain, whereas only 8 patients (10%) reported pain score >3 (numeric rating scale 0 to 10) and 4 patients (5%) >5 (numeric rating scale 0 to 10). Seventy-one percent of the patients with postsurgical pain also had pain from another part of the body. In patients with persistent postsurgical pain, this was a limiting factor for daily social activities in 29% to 92% dependent on the activity and 54% in pain felt quality of life was compromised due to the pain. Seventy-three percent of persistent postsurgical pain patients (lateral thoracotomy) experienced sensory disturbances compared with 46% of nonpain patients. DISCUSSION: Moderate-to-severe persistent postsurgical pain occurred in 5% to 10% of patients after lung transplantation, which is lower than reported after nontransplant thoracotomy. The specific role of the peritransplant immunosuppression on persistent post-thoracotomy pain should be explored further. PMID- 20173436 TI - Preemptive analgesic effect of ketamine in patients undergoing elective cesarean section. AB - OBJECTIVES: In this study, the preemptive effect of a small dose of ketamine on postoperative wound pain and morphine consumption in patients undergoing elective cesarean section was evaluated. METHODS: In a randomized, double-blind clinical trial, 60 women with American Society of Anesthesiologists class I and II identification undergoing elective cesarean section were enrolled. In the case group, the patients received 0.5 mg/kg ketamine, and in the control group, they received isotonic saline, 5 minutes before the induction of anesthesia. Anesthesia was induced with 4 mg/kg thiopental followed by 1.5 mg/kg succinylcholine. A further neuromuscular block was achieved by using 0.2 mg/kg of atracurium. Anesthesia was maintained with nitrous oxide 50% and halothane in oxygen. The lungs were mechanically ventilated. After fetus delivery, fentanyl (2 microg/kg) and morphine (0.15 mg/kg) were given intravenously. In the postanesthesia care unit and in the ward, all patients received morphine. Pain was assessed by the Visual Analog Scales at 2, 6, 12, and 24 hours postoperatively; the amount of morphine used and side effects were recorded. RESULTS: There was no significant difference between the patients considering their operative details, homodynamic variables, side effects, and Apgar scores of their babies at first and fifth minutes. Significantly, lower amounts of morphine were used in the case group (4.8 mg+/-2.5 mg vs. 8.1 mg+/-4.2 mg) during the first 2 hours after surgery (P=0.01), but the difference was not significant during 2 to 24 hours (3.2+/-2.2 vs. 3.1+/-2.3). There were no statistical differences between the groups in pain 2, 6, 12, and 24 hours postoperatively. DISCUSSION: Intraoperative low-dose ketamine had no effect on morphine consumption during 2 to 24 hours after surgery. No significant differences were seen in the pain scores of the 2 groups during the study period. The preoperative administration of 0.5 mg/kg ketamine in patients undergoing cesarean section did not elicit a preemptive analgesic effect. PMID- 20173438 TI - Patient self-report measures of chronic pain consultation measures: a systematic review. AB - BACKGROUND: Earlier studies have associated improvements in chronic pain outcomes with various consultation attributes, including: the legitimization of people's chronic pain experience, affective components of the therapeutic relationship, and reaching decisions about people's care through collaboration. Although studies have used patient self-report measures to examine how certain aspects of consultations contribute to managing chronic pain. The psychometric quality of these measures seems to have not been independently appraised to date. OBJECTIVES: This review aimed to evaluate the psychometric properties and administrative feasibility of published patient self-report consultation measures that were validated for people with chronic pain. METHODS: Databases were searched to identify patient self-report consultation measures validated in chronic pain populations. Explicit review criteria for 8 measure attributes were developed for this review by synthesizing information from available guidelines. In total, 58 potentially relevant consultation measures were identified. Of these, 4 measures satisfied the inclusion/exclusion criteria and were critically appraised by 2 independent reviewers. Overall, the psychometric quality of the included measures was modest, particularly in terms of evidence for content validity, test-retest reliability, responsiveness, and interpretability. DISCUSSION: Each of the included measures assessed differing aspects of consultations, and their potential clinical and research uses are discussed. Recommendations are made to improve the psychometric quality of the included measures. In summary, more psychometric research needs to be undertaken to improve the existing measures' quality and broaden the scope of chronic pain consultation measures before studies may be conducted to develop a comprehensive understanding of the manner in which consultation attributes influence chronic pain outcomes. PMID- 20173437 TI - Self-efficacy for coping with cancer in a multiethnic sample of breast cancer patients: associations with barriers to pain management and distress. AB - OBJECTIVES: This study examined the interrelations of self-efficacy for coping with cancer, perceived barriers to pain management, distress, and pain outcomes in a multiethnic sample of breast cancer patients. The extent to which ethnicity (Black, Latina, or White), language (English or Spanish), and level of education and income predicted these variables was also assessed. METHODS: Participants were breast cancer patients with persistent pain (N=87) who were recruited from oncology clinics in New York City. Patients completed an assessment battery that included measures of self-efficacy for coping with cancer, barriers to pain management, distress, and pain outcomes. RESULTS: Greater self-efficacy for coping with cancer was associated with older age, less time since diagnosis, and less distress. In addition, less self-efficacy for seeking and understanding medical information, Spanish language preference, and greater distress predicted greater barriers to pain management. Average pain severity was higher among Spanish-speaking individuals and those with lower incomes. DISCUSSION: Findings point to the potential importance of self-efficacy for seeking and understanding medical information and perceived barriers to pain management in understanding the psychologic well-being of breast cancer patients with pain, especially those who are Spanish-speaking. PMID- 20173439 TI - Attentional bias toward pictorial representations of pain in individuals with chronic headache. AB - OBJECTIVES: This study investigated attentional biases for pictorial headache related stimuli in individuals with chronic headache and healthy controls. METHODS: Attentional bias was assessed using a visual probe task that presented headache-related images and neutral images at 2 exposure duration conditions, 500 and 1250 ms. RESULTS: The results indicated that individuals with chronic daily headache showed a significantly greater overall attentional bias across presentation times toward headache-related stimuli compared with the controls, which indicates a bias in both initial orienting and maintained attention to pain cues in this group. DISCUSSION: It is concluded that both hypervigilance and sustained processing are critical factors for the maintenance of chronic pain. PMID- 20173440 TI - Comparison of miniscalpel-needle release, acupuncture needling, and stretching exercise to trigger point in myofascial pain syndrome. AB - OBJECTIVE: Myofascial pain syndrome (MPS) is one of the most common causes of chronic musculoskeletal pain. Several methods have been recommended for the inactivation of trigger points (TrPs). We carried out this study to investigate the effectiveness of miniscalpel-needle (MSN) release and acupuncture needling and self neck-stretching exercises on myofascial TrPs of the upper trapezius muscle. METHODS: Eighty-three TrPs in 43 patients with MPS were treated and randomly assigned to 3 groups: group 1 received MSN release in conjunction with self neck-stretching exercises; group 2 received acupuncture needling treatment and performed self neck-stretching exercises; and group 3, the control group, was assigned self neck-stretching exercises only. The therapeutic effectiveness was evaluated using subjective pain intensity (PI) with a visual analog scale, pressure pain threshold (PPT), and contralateral bending range of motion (ROM) of cervical spine at pretreatment, 2 weeks, and 3 months after treatment. RESULTS: The improvement of PI, PPT, and contralateral bending ROM of cervical spine was significantly greater in group 1 and 2 than that in control group at 2 weeks and 3 months follow-up. Compared with group 2, patients in group 1 had a statistically significant reduction in PI, an increase in PPT, contralateral bending ROM of cervical spine at 3 months follow-up. DISCUSSION: The effectiveness of MSN release for MPS is superior to that of acupuncture needling treatment or self neck-stretching exercises alone. The MSN release is also safe, without severe side effects in treatment of MPS. PMID- 20173441 TI - Psychologic factors in the development of complex regional pain syndrome: history, myth, and evidence. AB - OBJECTIVE: The present paper examines the literature that addresses psychologic aspects involved in complex regional pain syndrome from a historic perspective to provide a rationale for the emergence of psychologic theories to explain its pathogenesis. The support of such perspective is then analyzed through the review of evidence-based studies. METHODS: A review of the literature from a historic perspective was presented since its first description to the present time, including the clinical presentation and associated symptoms. An evidence-based approach was used to review the literature on complex regional pain syndrome and psychologic factors associated with the etiology or as predictors in the development of the disorder. RESULTS: After reviewing the literature on the history and the myths associated with complex regional pain syndrome, a hypothesis is provided based on an analysis of the Zeitgeist in the development of the psychologic theory associated with the disorder. We also concluded there is no evidence to support a linear relationship that establishes a psychologic predisposition to develop the disorder. DISCUSSION: An analysis of the Zeitgeist when complex regional pain syndrome was first described helps to understand the long-standing theories associated with a psychological theory of its etiology. This understanding should help to undermine the perpetuation of such claims which may contribute to undertreatment and misdiagnosis. To be consistent with todays Zeitgeist we must incorporate psychologic aspects, which while not causal in nature or exclusive of complex regional pain syndrome, are strongly associated with a wide spectrum of chronic pain disorders. PMID- 20173442 TI - Treating acute tonsillitis and pharyngitis: is acupuncture effective compared with sham acupuncture? PMID- 20173443 TI - Ectopic parathyroid adenoma localized with MIBI scintigraphy and excised with guide of macroaggregated human serum albumin injection. AB - Primary hyperparathyroidism is caused by an excessive amount of parathyroid hormone secreted by one or more enlarged parathyroid glands. Most commonly primary hyperparathyroidism is caused by a parathyroid adenoma. Ectopic parathyroid adenomas are rare, but they can complicate the surgical treatment and have an increased morbidity and poorer success rate. Thus, preoperative imaging is particularly valuable in this group of patients with hyperparathyroidism. Preoperative imaging has opened up a new era of minimally invasive parathyroid surgery procedures. The radioguided occult lesion localization technique has become the preferred approach to preoperative localization of nonpalpable breast lesions in several breast units. In this report, we investigated the usefulness of the radio-guided occult lesion localization technique in the identification of ectopic parathyroid adenomas. We describe the case of a 66-year-old woman who was diagnosed to be hypercalcemic. Tc-99m methoxy-isobutyl-isonitrile scintigraphy identified an ectopic parathyroid adenoma. The patient's cervical region was scanned with the probe to localize an area of maximal radiotracer uptake and the hot area was identified by a gamma probe. Careful dissection was then carried out and an enlarged ectopic parathyroid gland was removed. In conclusion, the preoperative imaging of an ectopic parathyroid adenoma and the excision of this tissue with radioguided occult lesion localization technique can open up a new era of minimally invasive parathyroid surgery. PMID- 20173444 TI - Early prediction of histopathological tumor response to preoperative chemotherapy by Tc-99m MIBI imaging in bone and soft tissue sarcomas. AB - PURPOSE: Tc-99m-methoxyisobutylisonitrile (MIBI) accumulates in only viable cells. In patients with bone and soft tissue sarcomas, preoperative chemotherapy is essential and the early prediction of the tumor response to chemotherapy would be beneficial for the planning of treatment strategy. The purpose of this study was to assess whether the change of Tc-99m-MIBI images from the prechemotherapy state to the early to midportion of chemotherapy can predict the final histopathological tumor response as accurately as the change of imaging after completion of chemotherapy. METHODS: Seventy-three patients with bone and soft tissue sarcomas underwent Tc-99m-MIBI scintigraphy before chemotherapy and at least 2 times after the second or third or fifth course of chemotherapy. The changes of the tracer uptake (DeltaUR) and perfusion (DeltaPI) from prechemotherapy to postchemotherapy were compared with histologic response. RESULTS: The sensitivity, specificity, and accuracy for the prediction of effective chemotherapy in DeltaPI were 88%, 83%, 85% after second, 85%, 72%, 78% after third, and 81%, 71%, 76% after 5th chemotherapy, and those in DeltaUR were 88%, 83%, 85% after 2nd, 85%, 92%, 89% after 3rd, and 94%, 77%, 85% after fifth chemotherapy, respectively. The area under the receiver operator characteristic curve of the DeltaPI after second, third, and fifth chemotherapy were similarly good (0.842, 0.858, 0.811, respectively) and those of DeltaUR were similarly excellent (0.915, 0.936, 0.931, respectively). CONCLUSION: In patients with bone and soft tissue sarcomas, the change of Tc-99m-MIBI images from prechemotherapy to early to middle of chemotherapy can predict the final histopathological tumor response to chemotherapy as accurately as the change of Tc-99m-MIBI images from prechemotherapy to the completion of the preoperative chemotherapy. PMID- 20173445 TI - Can carbonated lime drink intake prior to myocardial perfusion imaging with Tc 99m MIBI reduce the extracardiac activity that degrades the image quality and leads to fallacies in interpretation? AB - BACKGROUND: During myocardial perfusion imaging with Tc-99m sestamibi, intestinal and hepatic radiotracer activity commonly interfere with visualization of the inferior wall of the myocardium leading to difficulties in interpretation. This study was undertaken to assess if carbonated lime drink ingestion prior to imaging prevents the said interference and improves the quality of images. MATERIALS AND METHODS: The study group comprised 33 consecutive patients including 26 males (age range: 30-80 years) and 7 females (42-62 years) who were referred for myocardial perfusion imaging. Of 33 patients, 21 (18 males, 3 females) were imaged at rest, 5 patients (3 males, 2 females) underwent physical stress, and 7 patients (5 males, 2 females) had pharmacological stress with adenosine. Five to 10 minutes after intravenous injection of 296 to 444 MBq (8-12 mCi) Tc-99m MIBI, anterior, and left anterior oblique (LAO) 45 degree planar views were acquired with a gamma camera using LEHR collimator. Each view was acquired for 100 seconds in a 256 x 256 matrix in all patients. Thereafter each patient was administered about 250 mL of a carbonated lime drink and repeat views were acquired within 5 minutes with the same parameters. Quantitative assessment of counts in the inferior wall of myocardium (M) to those in adjacent abdomen (A) was performed on both pre- and postintervention studies by drawing an ROI of about 50 +/- 5 pixels. M/A ratios were recorded for each patient in both the groups. The student t test was performed to evaluate the significance of difference between pre- and postintervention images. P < 0.05 was considered significant. All patients underwent myocardial perfusion single photon emission computed tomography. RESULTS: It was found that the inferior wall of the myocardium was better visualized, and there was no interference from gut or hepatic tracer activity in postintervention planar and single photon emission computed tomography reconstructed views as compared with preintervention images in all patients. The M/A ratio expressed as mean +/- SD was significantly higher in the postintervention group, viz. 2.19 +/- 0.71 in the anterior and 2.07 +/- 0.70 in the LAO45 views as compared with those of preintervention values of 1.50 +/- 0.59 in the anterior and 1.41 +/- 0.49 in the LAO 45 views, respectively (P < 0.001). CONCLUSION: We conclude that intake of carbonated lime drink is a simple and an effective technique to improve the image quality of the inferior wall of the myocardium on myocardial perfusion imaging with Tc-99m MIBI. This technique may also help in reducing the time interval between injection of radiotracer and imaging, which is otherwise delayed in routine practice. PMID- 20173446 TI - Tc-99m sestamibi SPECT/CT with volumetric reconstruction for radioguided occult lesion localization and surgical excision of melanoma metastasis. PMID- 20173447 TI - Lymphoscintigraphy of a breast tumor showing focal tracer accumulation along the falciform ligament of the liver. PMID- 20173448 TI - SPECT-CT improves scintigraphic accuracy of osteoid osteoma diagnosis. PMID- 20173450 TI - Myositis ossificans mimics an osteoid osteoma: a pitfall for Tc-99m MDP planar and SPECT scintigraphy. PMID- 20173449 TI - Diagnosing SAPHO syndrome in suspected metastatic bone tumors. PMID- 20173451 TI - Iodized contrast: a possible confusion factor in parathyroid dual-tracer scintigraphy. PMID- 20173452 TI - Colonic schwannoma visualized on FDG PET/CT. PMID- 20173453 TI - Metastatic colon cancer to the lung with no detectable primary tumor, mimicking advanced primary lung cancer on F-18 FDG PET/CT imaging. AB - An 83-year-old man was referred with a right lung mass on dynamic chest computed tomography (CT). F-18 fluoro-deoxy-glucose positron emission tomography (FDG PET)/CT showed intense FDG uptake in the right lung mass and bilateral hypermetabolic mediastinal lymph nodes. CT-guided biopsy of the right lung mass revealed metastatic adenocarcinoma from the colon, but a colon cancer lesion was not detected by dynamic abdominal CT and colonoscopy. PMID- 20173454 TI - Discordant emptying from hiatal hernia and stomach with severe esophageal reflux demonstrated by gastric scintigraphy. PMID- 20173455 TI - Perineural recurrence of buccal cancer demonstrated by F-18 FDG PET/CT. PMID- 20173456 TI - FDG PET-CT evaluation of granular cell tumor of the soft tissue. PMID- 20173457 TI - Focal uptake of F-18 fluorodeoxyglucose in pseudoangiomatous stromal hyperplasia. PMID- 20173458 TI - I-123 MIBG uptake in a gastrointestinal stromal tumor (GIST). PMID- 20173459 TI - F-18 FDG PET/CT imaging of multifocal extramedullary pancreatic myeloma. PMID- 20173460 TI - F-18 FDG PET/CT imaging of a Leydig cell tumor. AB - We report the F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) findings of a patient with a testicular Leydig cell tumor. A 43-year-old man was referred for whole body FDG PET/CT imaging for health care screening. FDG PET/CT imaging demonstrated the presence of a focal hypermetabolic lesion in the right testicle and no specific findings in other areas. Based on the preoperative impression, right testis-sparing surgery was attempted. The tumor was pathologically confirmed as a Leydig cell tumor. PMID- 20173461 TI - Primary pituitary lymphoma diagnosis by FDG-PET/CT. PMID- 20173462 TI - Findings of pulmonary amyloidosis on dual phase FDG PET/CT imaging. PMID- 20173463 TI - Progressive visual loss due to obstruction of an optic nerve sheath fenestration demonstrated on SPECT/CT radionuclide cisternography. PMID- 20173464 TI - F-18 FDG PET/CT imaging in recurrent mantle cell lymphoma presenting with cauda equina syndrome. PMID- 20173465 TI - Subdural hematoma mimicking skeletal metastasis on I-131 scan. PMID- 20173466 TI - The New American College of Nuclear Medicine (ACNM). PMID- 20173467 TI - Current readings in nuclear medicine. PMID- 20173468 TI - Ex vivo sentinel lymph node mapping in patients undergoing proctectomy for rectal cancer. AB - PURPOSE: Controversy exists over the utility of sentinel lymph node mapping in the treatment of rectal cancer. The purpose of this study was to evaluate the use of ex vivo sentinel lymph node mapping in the setting of proctectomy for rectal cancer, with and without multilevel sectioning and immunohistochemistry. METHODS: A prospective phase 2 clinical study of subjects undergoing proctectomy for rectal cancer from 2003 to 2008 was conducted. Sentinel lymph node mapping was performed with ex vivo injection of isosulfan blue. Sentinel lymph nodes were examined by hematoxylin and eosin evaluation, and when the results were negative, they were examined by multilevel sectioning and immunohistochemistry. RESULTS: The study population consisted of 58 subjects; 88% received neoadjuvant therapy. Tumors were downstaged in 25 (49%) subjects receiving neoadjuvant therapy, 24% were clinical complete responders, and 20% were pathologic complete responders. The mean total lymph node harvest was 12.1 nodes per patient. Twenty-five subjects had positive nodal disease on final pathology. The sentinel lymph node detection rate was 85%, with a mean sentinel lymph node harvest of 2.2 nodes per subject. Fifteen (26%) subjects had sentinel lymph node nodal metastasis on routine hematoxylin and eosin examination. Neither multilevel sectioning nor immunohistochemistry evaluation improved detection of sentinel lymph node positivity. The accuracy of sentinel lymph node mapping was 71%, the sensitivity was 53%, the negative predictive value was 79%, and the false negative rate was 47%. Seven subjects were determined to have nodal disease only in the sentinel lymph node. CONCLUSION: Ex vivo sentinel lymph node mapping is feasible after proctectomy for rectal cancer but did not improve staging. Neither multilevel sectioning nor immunohistochemistry improved the sensitivity of sentinel lymph node mapping. PMID- 20173469 TI - Downstaging after chemoradiotherapy for locally advanced rectal cancer: is there more (tumor) than meets the eye? AB - PURPOSE: Preoperative chemoradiotherapy can lead to pathologic complete response of rectal cancer. This study was designed to determine the relationship between postchemoradiotherapy pathologic T stage (ypT stage) and nodal metastases and to evaluate whether pathologic complete response of the primary tumor results in sterilization of mesorectal lymph nodes. METHODS: Clinicopathological data from 1997 to 2007 of a prospectively maintained colorectal cancer database were examined. Inclusion criteria were patients with extraperitoneal rectal cancer who underwent preoperative chemoradiotherapy and subsequent radical resection. Statistical analysis was performed by use of Kruskall-Wallis and Wilcoxon rank sum tests. RESULTS: Two hundred forty-two patients were identified (73.1% male, median age, 57 y (range, 36-85 y)). Data regarding preoperative chemoradiotherapy were available for 177 patients (73.1%). The median dose of radiotherapy was 5040 cGy (3060-6100 cGy). The mean preoperative radiotherapy dose and interval between chemoradiotherapy and surgery are similar when stratified by ypT stage (P = .55 and P = .72, respectively). Low anterior resection was performed in 174 patients (71.6%), and the remainder underwent abdominoperineal resection. A mural pathologic complete response was achieved in 62 patients (25.6%). In this pathologic complete-response group, positive lymph nodes were found in 2 patients (3.2%). The rate of metastatic lymph nodes increased as ypT stage increased (ypT1 = 11.1%, ypT2 = 29.2%, ypT3 = 37.3%). CONCLUSION: Patients with a mural pathologic complete response have a low rate of positive lymph nodes. These findings may have implications for the management strategies of these patients, including the use of local resection or a watch-and-wait policy. When the response to chemoradiotherapy is not complete, radical surgery should remain the treatment based on high rates of lymph node involvement. PMID- 20173470 TI - Tumor necrosis factor alpha induces p53 up-regulated modulator of apoptosis expression in colorectal cancer cell lines. AB - PURPOSE: Inflammatory bowel disease (IBD)-associated colorectal carcinogenesis involves dysregulation of multiple cellular pathways, including p53 signaling and cytokine action. The purpose of the current study was to evaluate the effects of tumor necrosis factor alpha (TNF-alpha) on p53 and p53 up-regulated modulator of apoptosis (PUMA), a downstream effector of p53 in the apoptotic pathway in colorectal cancer cells. METHODS: The cell lines HT29 (which express mutant p53) and HCT116 (which express wild-type p53) were treated with TNF-alpha (0, 50, 100, or 500 ng/mL) for 1, 12, 24, or 48 hours. Protein expression and subcellular localization of p53 and PUMA were determined by immunoblot and immunofluorescence. Changes in p53 and PUMA mRNA expression were determined by quantitative real time polymerase chain reaction. RESULTS: Nuclear p53 expression was increased in TNF-alpha-treated HT29 cells; in contrast, expression was decreased or minimally changed in TNF-alpha-treated HCT116 cells, as determined by immunoblot and immunofluorescence. At 24 hours, p53 mRNA transcript levels were minimally increased in HT29 cells, whereas PUMA increased 34-fold. CONCLUSIONS: TNF-alpha increased nuclear p53 expression in HT29 cells, which express p53 mutation, but not in HCT116 cells, which are wild type for p53. In addition, TNF-alpha markedly up-regulated PUMA mRNA levels in HT29 cells. Our findings suggest that TNF-alpha may be a factor in carcinogenesis in IBD in cells carrying a p53 mutation. PMID- 20173471 TI - Sacral nerve stimulation is a valid approach in fecal incontinence due to sphincter lesions when compared to sphincter repair. AB - PURPOSE: Anal sphincter lesions represent the major cause of fecal incontinence, particularly in women. Sphincteroplasty with overlap is the traditional treatment, but a significant reduction in benefits within 5 years of surgery has been reported. More recently, sacral nerve stimulation has been suggested following sphincteroplasty or as primary treatment. METHODS: Overall, 24 women with fecal incontinence in the presence of anal sphincter lesions underwent sphincteroplasty (14 patients, mean age 47.6 +/- 15.6 years, range 26-70) or definitive implant of sacral nerve stimulation (10 patients, mean age 60.7 +/- 17.6 years, range 26-73), using identical selection criteria. At baseline, patients were studied with clinical evaluation, 3-dimensional endoanal ultrasound, and anorectal manometry (ARM), repeated at follow-up (median 60.0 months, range 6-96 in sphincteroplasty group; median 33.0 months, range 6-84 in sacral nerve stimulation group). RESULTS: At baseline, both groups presented similar characteristics. Two sphincteroplasty patients (14.3%) experienced relapse of fecal incontinence at 6 and 19 months after treatment, whereas good to excellent continence was observed in all of the sacral nerve stimulation patients. Compared to baseline, both groups showed a significant improvement in clinical parameters, and ARM data remained unchanged. In 12 of 14 sphincteroplasty patients, the repaired sphincter at endoanal ultrasound was found to overlap. At follow-up, comparison between sphincteroplasty and sacral nerve stimulation showed no significant differences in clinical and ARM parameters, if related to lesion of internal, external, or both sphincters. CONCLUSIONS: These data appear to confirm that sacral nerve stimulation could represent a valid alternative in the treatment of fecal incontinence patients presenting with sphincter lesion that was not preceded by sphincteroplasty. PMID- 20173472 TI - Sacral nerve neuromodulation is effective treatment for fecal incontinence in the presence of a sphincter defect, pudendal neuropathy, or previous sphincter repair. AB - PURPOSE: To assess the effectiveness of sacral nerve neurostimulation in the setting of sphincter defects, previous sphincter repair, or pudendal neuropathy. METHODS: A total of 55 patients underwent insertion of a sacral nerve neurostimulator for fecal incontinence. There were 52 female and 3 male patients, with a mean age of 51 (range, 25-65) years and a median follow-up of 37 (range, 15-41) months. RESULTS: There was a significant improvement in the median Cleveland Clinic continence score for all of the patients, from a median of 15 (13-18) before insertion of the neurostimulator, to a median of between 4 and 7 during the follow-up period of up to 48 months. (P < .001-.008). Patients with a sphincter defect on endoanal ultrasound, a pudendal neuropathy, or a previous sphincter repair did not show any significant differences in continence scores during the follow-up period (P = .46, .25, and .81, respectively). The Fecal Incontinence Quality of Life score also showed a significant improvement on all 4 scales, Lifestyle (median 2.00 baseline to 3.00-3.70 P = .001-.008), Coping/Behavior (median 1.56 baseline to 2.89-3.22 P = .001-.007), Depression/Self-Perception (median 2.29 baseline to 2.93-3.71 P = .001-.005), and Embarrassment (median 1.50 baseline to 2.17-3.00 P = .001-.013) after insertion at all time intervals up to 36 months. The Fecal Incontinence Quality of Life score was higher than the baseline at 48 months but only statistically significant for Lifestyle (median 3.10, P = .04) and Coping/Behavior (median 2.63, P = .03) scores. There were 6 device-related complications. CONCLUSIONS: Sacral nerve neuromodulation results in a significant improvement in fecal incontinence and Fecal Incontinence Quality of Life scores after medium-term follow-up, even when there is a sphincter defect or pudendal neuropathy. PMID- 20173473 TI - Short-term outcomes with the use of bioprosthetics for the management of parastomal hernias. AB - PURPOSE: This study was undertaken to determine the safety and short-term outcomes using bioprosthetics for the management of parastomal hernias. METHODS: A retrospective review of prospectively collected data for all of the patients who underwent repair of a parastomal hernia was conducted. RESULTS: Between April 2004 and September 2007, 20 consecutive patients had 22 parastomal hernias repaired through a midline incision using a bioprosthetic with the stoma entering the abdomen lateral to the graft. A colostomy was present in 17 patients; an ileostomy was present in 3 patients. All of the patients had parastomal hernia related complications. Postoperatively there were no infections of the midline wound or the prosthetic, and none of the grafts were removed. There were 4 seromas (40%) that required aspiration in the 10 procedures performed before the routine placement of a drain. No incisional hernias have developed in the midline wound. There have been 2 (9%) recurrent parastomal hernias on physical examination at a median follow-up of 18 months (range, 12-54). CONCLUSIONS: These data suggest that bioprosthetics are safe and are effective in the short term for the repair of parastomal hernias. PMID- 20173474 TI - Single-incision laparoscopic colectomy: early experience. AB - PURPOSE: Single-incision laparoscopic surgery was developed recently and has the benefit of reducing the number of incisions. Its application in colectomy has been published only in case reports. The present study evaluated our early results of single-incision laproscopic surgery in a series of 8 patients who underwent colectomy for various colorectal pathologies. METHODS: Eight patients underwent single-incision laparoscopic colectomy for cancer (n = 5), polyps (n = 2), and diverticulitis (n = 1) during the study period. The data on the operations and outcomes were collected prospectively and analyzed. RESULTS: The median age of the patients was 78 years (range, 49-88). The operations were right colectomy (n = 6), left colectomy (n = 1), and anterior resection (n = 1). The median operating time was 175 minutes (range, 103-260) and the median blood loss was 55 mL (range, 20-200). The average length of the incision was 3.4 cm (range, 3.0-5.0). One patient required conversion to hand-assisted laparoscopy with a 5 cm incision. The median hospital stay was 3.5 days (range, 3-6) and 1 patient had ileus after the operation. There was no mortality and no reintervention within 30 days. In patients with cancer, all of the resection margins were clear. The median number of lymph nodes examined was 13.5 (range, 9-36). CONCLUSIONS: Single incision laparoscopic surgery can be applied to colectomy safely. Oncologic resection similar to conventional laparoscopy can be performed with this technique. Further studies are needed to evaluate the outcomes against those of conventional laparoscopic resection. PMID- 20173475 TI - Long-term consequences of not closing the mesenteric defect after laparoscopic right colectomy. AB - PURPOSE: The controversy regarding closing the mesenteric defect after laparoscopic right colectomy remains a subject of debate. This study describes the consequences of not closing the mesenteric defect. METHODS: A 7-year prospective database revealed 530 consecutive patients who underwent laparoscopic right colectomy for neoplasia. No mesenteric defects were closed. Small bowel obstruction was determined by clinical assessment and diagnostic imaging. Statistical analysis included the Student t test and Mann-Whitney U test. RESULTS: On average, the 530 patients (44% male) were 69.6 years old +/- 12.5 years with American Society of Anesthesiologists' category 2, body mass index 26.6 +/- 5.7, operative time 175 +/- 65 minutes, incision length 5.7 +/- 3.0 cm. Thirty-six patients (6.8%) were converted. Median length of stay was 5 days (interquartile range 4-7). Median follow-up was 20 months (interquartile range 8 45). Four patients (0.8%) had complications attributed to the mesenteric defect: 2 had small bowel obstruction due to internal herniation and 2 had torsion of the anastomosis through the defect. Twenty-six patients (4.9%) had a small bowel obstruction during the follow-up period. Nonoperative treatment was successful in 12 patients. In the 14 patients who were operated on, small bowel obstruction was due to adhesions (4), incarcerated abdominal wall hernias (4), mesenteric defect (4), and cancer recurrence (2). The small bowel obstruction group (n = 26) had a significantly higher percentage of males than the non-small bowel obstruction group (n = 504; 69% vs 43%; P = .008). CONCLUSIONS: These data do not support routinely closing the mesenteric defect after laparoscopic right colectomy for neoplasia. Additional studies with extended long-term follow-up are needed. PMID- 20173476 TI - Preoperative wireless capsule endoscopy does not predict outcome after ileal pouch-anal anastomosis. AB - PURPOSE: The extent of preoperative small-bowel mucosal inflammation may be an important predictor of pouchitis after ileal pouch-anal anastomosis. This study examined the value of preoperative wireless capsule endoscopy in predicting outcome of ileal pouch-anal anastomosis in patients with ulcerative colitis or indeterminate colitis. METHODS: Patients undergoing complete wireless capsule endoscopy before ileal pouch-anal anastomosis were identified. Findings on wireless capsule endoscopy were classified as positive (erosions, ulcers or erythema) or negative. Outcome was assessed prospectively and included no pouchitis, acute pouchitis, chronic pouchitis, or de novo Crohn disease. Patients with acute pouchitis, chronic pouchitis, or de novo Crohn disease were considered to have pouch inflammation. RESULTS: The 68 study patients (48 ulcerative colitis; 20 indeterminate colitis) had a median age of 38 years and included 34 males. Median follow-up time after ileostomy closure was 12 months (range, 3-63 months). Wireless capsule endoscopy was positive in 15 patients (22%) and negative in 53 patients (78%). Pouch inflammation was observed in 23 patients (34%), and included 8 patients with acute pouchitis, 3 patients with chronic pouchitis, and 12 patients with de novo Crohn disease. The incidence of acute pouchitis, chronic pouchitis, de novo Crohn disease, and pouch inflammation in the wireless capsule endoscopy-positive patient group was 7%, 7%, 20%, and 33% compared with 13%, 4%, 17%, and 34% in the wireless capsule endoscopy-negative patient group (all P = NS). CONCLUSION: There was no statistical association between the results of preoperative wireless capsule endoscopy and outcome after ileal pouch-anal anastomosis in patients with ulcerative colitis or indeterminate colitis. There seems to be little value of wireless capsule endoscopy in the preoperative evaluation of these patients. PMID- 20173477 TI - Tumor budding and survival after potentially curative resection of node-positive colon cancer. AB - PURPOSE: The aim of this study was to investigate the relationship between tumor budding and other pathology features and overall survival after resection of clinicopathological stage III colon cancer. METHODS: The number of buds and other histopathological features were assessed in 477 patients who were operated on between 1971 and 2001, with follow-up to December 2006. Overall survival was analyzed using the Kaplan-Meier method and Cox regression. RESULTS: The number of buds was dichotomized as low (0 to 8) vs high (>or=9). High budding was more common in men, in high-grade tumors, in the presence of venous invasion, and where the tumor had involved a free serosal surface, but budding was not associated with 8 other clinical and pathological features. The 5-year survival rate for patients with 0 to 8 buds was 51.0% (95% confidence interval, 44.9 55.1), whereas that for patients with 9 or more buds was 33.9% (95% confidence interval, 25.2-42.8). This association, however, disappeared after adjustment for other variables independently associated with survival (hazard ratio, 1.2; 95% confidence interval, 0.94-1.54; P = .139). CONCLUSION: In stage III colon cancer, tumor budding did not provide additional independent prognostic information beyond that given by routine pathology reporting. PMID- 20173478 TI - Can CT replace MRI in preoperative assessment of the circumferential resection margin in rectal cancer? AB - The surgical circumferential resection margin in total mesorectal excision surgery is defined by the relationship of the tumor to the mesorectal fascia. Patients with anticipated tumor invasion of the mesorectal fascia receive neoadjuvant therapy to downstage/downsize the tumor and to obtain tumor-free resection margins.Tumor relationship to the mesorectal fascia is accurately determined by MRI. Compared with MRI, multidetector-row computed tomography is more widely available, faster, less costly, and provides the ability to simultaneously assess the liver, peritoneum, and retroperitoneum for metastases. PURPOSE: The objective of this study was to compare the accuracy of multidetector row CT with conventional MRI in diagnosis of rectal cancer invasion of the mesorectal fascial envelope. MATERIALS AND METHODS: During a 2-year period, all patients were enrolled in this study who had biopsy-proven rectal carcinoma and were referred, as a part of the routine preoperative staging workup, for a CT scan of the abdomen and pelvis and also an MRI of the pelvis.All examinations were reviewed independently by 2 radiologists who were blinded from one another, from the findings of the other modality, and from clinical information. Both observers were dedicated abdominal radiologists who are experienced in reading pelvic CT and MRI. Categorical agreement between MRI and multidetector-row CT for all the evaluated parameters of the tumor position, mesorectal fascia, and lymph nodes, as well as the interobserver agreement between CT and MRI, was determined by the intraclass correlation weighted kappa statistic to measure the data set's consistency. RESULTS: Among the study's 92 patients, the tumor characteristics suggested by multidetector-row CT agreed with those of MRI, with a weighted kappa ranging from 0.488 to 0.748 for the first reader and 0.577 to 0.800 for the second reader. Interobserver agreement ranged from 0.506 to 0.746.Agreement regarding mesorectal fascia characteristics differed significantly between multidetector-row CT and MRI, depending on the level of assessment. In the distal rectum, agreement was 0.207 for the first reader and 0.385 for the second reader. In the mid rectum, agreement was 0.420 and 0.527, respectively, and in the proximal rectum agreement was 0.508 and 0.520. Interobserver agreement was 0.737 at the distal level and 0.700 at the mid and proximal levels. Agreement regarding measurement of the distance from the tumor to the mesorectal fascia was 0.425 for the first reader and 0.723 for the second reader, with interobserver agreement of 0.766. Agreement in assessment of the number of lymph nodes ranged from 0.743 to 0.787 for the first reader and 0.754 to 0.840 for the second reader. Interobserver agreement ranged from 0.779 to 0.841. Agreement in assessment of the size of the lymph nodes ranged from 0.540 to 0.830 for the first reader and 0.850 to 0.940 for the second reader. Interobserver agreement ranged from 0.900 to 0.920. Agreement in assessment of the distance from nodes to the mesorectal fascia was 0.320 for the first reader and 0.401 for the second reader, with interobserver agreement of 0.950. CONCLUSION: The results of this study differ from previously published data by demonstrating substantial agreement between readers in multidetector-row CT assessment of the tumor, mesorectal fascia, and lymph nodes. With the exceptions of mesorectal fascia in the distal rectum and the distance from the nodes to mesorectal fascia, other evaluated parameters were assessed with moderate and substantial agreement between multidetector-row CT and MRI. However, our findings suggest that multidetector-row CT does not correlate well enough with MRI findings to replace it in rectal cancer staging. PMID- 20173479 TI - Central representation of the inferior rectal nerve of the rat. AB - PURPOSE: Obstetric injury to the pudendal nerve contributes significantly to fecal incontinence. The inferior rectal nerve, a terminal branch of the motor division of the pudendal nerve, innervates the external anal sphincter. Animal models have been developed to establish the scientific basis of sacral neuromodulation. The aims of this study were to determine the spinal location of inferior rectal nerve motoneurons projecting to the external anal sphincter and whether the inferior rectal nerve carries sensory fibers. METHODS: Ten female virgin Wistar rats were used; 7 underwent bilateral inferior rectal nerve section and application of the neuronal tracer fluorogold. Five days later dorsal root ganglia L5 to S2 and the lumbosacral spinal cord were harvested and stained for activating transcription factor 3, a molecular marker of nerve injury. Three animals were used to confirm the specificity of activating transcription factor 3 nuclear labeling as a marker of axotomy. RESULTS: Fluorogold-labeled motoneurons were found exclusively at L6 in the dorsomedial sections of Onuf's nuclei (left and right), which contained 30 +/- 9 motoneurons with a median diameter of 28.3 microm (24.4-31.0) (25th-75th centiles). Double-labeled sensory neurons (fluorogold-labeled cytoplasm and activating transcription factor 3-labeled nuclei) were found in dorsal root ganglia L6 to S2 and were smaller in diameter (20.5 microm (17.8-26.7); median (25th-75th centiles)) than motoneurons (P < .0,001). CONCLUSIONS: The external anal sphincter receives both motor and sensory innervation from the inferior rectal nerve. Activating transcription factor 3 nuclear staining may prove useful for quantifying the degree of nerve injury in animal models of fecal incontinence. PMID- 20173480 TI - Urinary bladder catheter drainage following pelvic surgery--is it necessary for that long? AB - PURPOSE: Urinary bladder drainage for several days after pelvic surgery is a common surgical practice, despite insufficient evidence supporting its routine use. The aim of this study was to prospectively evaluate the utility of urinary bladder drainage after pelvic colorectal surgery. METHODS: Patients undergoing pelvic surgery were prospectively randomly assigned to 3 groups. In group A, the Foley catheter was removed on postoperative day 1, and in groups B and C it was removed on postoperative days 3 and 5, respectively. Male patients with severe prostatic symptoms were excluded from the study. The main outcome criterion was acute urinary retention requiring reinsertion of the Foley catheter. RESULTS: A total of 118 patients (68 males) at a mean age of 55 years were included in this study (group A, 41 patients; group B, 38; and group C, 39). Overall, urinary retention after removal of the Foley catheter occurred in 12 (10%) of the patients: 6 (14.6%) in group A, 2 (5.3%) in group B, and 4 (10.5%) in group C (P = .39). Symptomatic urinary tract infection was diagnosed in 5 patients in group A, 3 in group B, and 9 in group C, but this difference did not reach statistical significance. Likewise, there were no significant differences in anastomotic leak and intra-abdominal abscess rates among the 3 groups. CONCLUSIONS: Routine prolonged urinary bladder catheterization after pelvic surgery may not be required, and the Foley catheter may be safely removed on postoperative day 1. Larger studies are needed to confirm the findings of this study. PMID- 20173482 TI - Presentation and treatment outcome of diverticulitis in younger adults: a different disease than in older patients? AB - PURPOSE: The severity and most appropriate treatment of diverticulitis in young patients are still controversial. The aim of this study is to compare young patients (50 years) regarding clinical and radiologic parameters of acute left colonic diverticulitis and to determine whether differences exist in presentation and treatment. METHODS: We reviewed medical records of 271 consecutive patients with left colonic acute diverticulitis admitted to our institution from 2001 through 2004: 71 patients were aged 50 years or younger and 200 patients were older than 50. Clinical and radiologic parameters were analyzed. Conservative treatment was standardized, and included antibiotic therapy and bowel rest. Criteria for emergency surgical treatment were diffuse peritonitis, pneumoperitoneum, and septic shock. RESULTS: Conservative treatment alone was successful in 64 patients (90.1%) in the younger group and in 152 patients (76%) in the older group (P = .017). The percentage of patients requiring surgery at admission or during the hospital stay was significantly lower in younger than in older patients (5.6% vs 20.5%, P = .007), and the percentage of patients requiring emergency end colostomy was higher (although not significantly) in the older group (1.4% vs 9.0%, P = .059). No differences in rate of successful conservative treatment were observed between patients with a first episode and those with recurrence in either age group (P = .941 in the younger group; P = .227 in the older group). CONCLUSION: Young age is not a predictive factor of poor outcome in the management of first or recurrent episodes of acute diverticulitis. Patients older than 50 years more frequently need emergency surgical treatment. PMID- 20173481 TI - Ureteric obstruction in familial adenomatous polyposis-associated desmoid disease. AB - PURPOSE: Intra-abdominal desmoid disease is the second leading cause of death in familial adenomatous polyposis patients. The aim of this study was to identify the incidence, management, and outcomes for familial adenomatous polyposis associated intra-abdominal desmoids causing ureteric obstruction. METHODS: Clinical data were abstracted from an institutional review board-approved, prospectively maintained familial polyposis registry. RESULTS: Of 107 patients identified with familial adenomatous polyposis related desmoid disease, 30 (28%) had documented CT scan evidence of ureteric obstruction. There was a 1:2.3 female predominance. Preceding surgery was the most prominent risk factor for development of desmoid disease (28 of 30 patients); 2 patients were diagnosed with desmoids before abdominal surgery. Overall, 11 patients had ureteric obstruction at the time of diagnosis. In the other 19 patients, median time from desmoid diagnosis to ureteric obstruction was 2 years. Pharmacologic management alone was effective in 8 patients. Eighteen patients (60%) underwent retrograde ureteric stent insertion. Five patients (17%) required percutaneous nephrostomy tubes. Three patients (10%) underwent autotransplant of 4 kidneys, and 4 patients (13%) required nephrectomy. One patient underwent ureterolysis, and another underwent ureteric resection with reimplantation. One-third of patients required more than one urologic procedure, and 63% had extensive small-bowel involvement with desmoid. CONCLUSIONS: The majority of patients with familial adenomatous polyposis associated desmoid disease who develop hydronephrosis require stenting. Complete obstruction may necessitate a nephrostomy. Renal autotransplant is an option for persistent symptomatic obstruction. Physicians treating patients with familial adenomatous polyposis and desmoid disease must be aware of the potential for development of ureteric obstruction and available treatment options. PMID- 20173483 TI - Yield of high-grade dysplasia based on polyp size detected at colonoscopy: a series of 2295 examinations following a positive fecal occult blood test in a population-based study. AB - PURPOSE: The aim was to determine the rate of high-grade dysplasia among patients with all adenomas, and its prevalence in patients with adenomas of different sizes in a well-defined population-based study. POPULATION AND METHODS: We performed a secondary analysis of the 2295 colonoscopies performed following a positive fecal occult blood test result during the first round of colorectal cancer screening in one French district. The rates of high-grade dysplasia were calculated for 3 size categories of adenoma (diminutive, or=10 mm). Predictive factors for high-grade dysplasia were assessed by univariate and multivariate analyses. RESULTS: A total of 1284 adenomas were detected in 784 subjects. High-grade dysplasia was present in 32.1% of the 784 subjects and in 2.7%, 16.0%, and 51.1% of those whose adenomas were diminutive, small, and large, respectively. Among subjects with no more than 2 small adenomas, the proportion of those with high-grade dysplasia was 12.4%. Both adenoma size and a villous component within adenomas were found to be independent predictive factors for high-grade dysplasia by multivariate analysis. CONCLUSIONS: Because of the high rate of high-grade dysplasia among small adenomas, our results reinforce the need to remove all small adenomas detected at colonoscopy. Furthermore, the results suggest that opting for CT colonography surveillance instead of colonoscopic removal among subjects with one or 2 small polyps revealed by CT colonography would have led to missed high-grade dysplasia in 12.4% of them. PMID- 20173484 TI - Rectal trauma and associated hemorrhage with the use of the ConvaTec Flexi-Seal fecal management system: report of 3 cases. AB - The management of fecal incontinence is a struggle to maintain patient hygiene and limit the transmission of nosocomial infections. Intrarectal devices that cause diversion and collection of the fecal stream have been used with increasing frequency. This method can effectively control patient waste if used in an appropriate setting. We examine a series of 3 patients in whom rectal trauma resulting in life-threatening hemorrhage was associated with use of the ConvaTec Flexi-Seal fecal management system. In 2 patients there was a history of traumatic removal, and the third developed a rectal pressure ulcer associated with use of this device. All 3 patients required surgical or endoscopic intervention to achieve hemostasis. Although effective, the Flexi-Seal fecal management system should be used with caution to avoid rectal trauma. Injury is most likely to occur because of traumatic removal or rectal ulceration secondary to pressure necrosis. PMID- 20173485 TI - Uterine retroversion for vaginoperineal reconstruction following resection of distal rectal tumors. AB - PURPOSE: Vaginal and perineal reconstruction following wide resection of locally invasive rectal cancer can be challenging. Various techniques have been reported, all of which contribute the additional morbidity inherent in tissue procurement. We present a technique applicable to nonhysterectomized patients who undergo posterior vaginal wall reconstruction with retroversion of the in situ uterus. METHODS: Four nonhysterectomized patients with recurrent rectal carcinoma and abdominoperineal resection with en bloc resection of the posterior vagina leaving a large defect necessitating reconstruction of the vagina, perineum, or both, have undergone posterior vaginal wall and perineal reconstruction with uterine retroversion into the posterior pelvis and fixation to the perineum. RESULTS: Satisfactory vaginoperineal reconstruction was achieved in all our patients at 3 months. In addition, patients are able to resume sexual activity after tissue re epithelialization. CONCLUSION: Uterine retroversion is a viable option for vaginal and perineal reconstruction. PMID- 20173486 TI - Endo-satinsky clamp for rectal transection during laparoscopic total mesorectal excision. AB - BACKGROUND: We describe a technique of intracorporeal rectal transection using an endo-Satinsky clamp during laparoscopic total mesorectal excision. METHODS: We use an abdominal approach through 5 trocars. The rectum and mesorectum are mobilized completely. A flexible trocar is placed at the site of a 12-mm right lower abdominal port after the trocar originally placed there is pulled out. The 12-mm trocar originally placed in the right lower abdomen is moved to the suprapubic site, in which a Pfannenstiel incision is anticipated. The endo Satinsky clamp is inserted through the flexible trocar, and the rectum is grasped with the endo-Satinsky clamp just above the anticipated point of transection. The endostapler is introduced through the 12-mm suprapubic port and is positioned just distal to the clamp. The rectum is then transected. The transected bowel is resected extracorporeally. Anastomosis is completed intracorporeally by use of a double-stapling technique. RESULTS: From February 2007 to March 2009, we performed low anterior resection with use of the endo-Satinsky clamp for 11 patients with rectal cancer (laparoscopic, 10 patients; robot-assisted, 1 patient). There were no operative complications or deaths. Mean operation time was 179.5 minutes (range, 120-265 min). The average number of cartridges used for rectal transection was 1.6 per patient. CONCLUSION: The endo-Satinsky clamp is a useful device for rectal transection and irrigation. The use of this device makes it easier to place an endostapler just distal to the clamp and to transect the rectum in a more appropriate position. PMID- 20173488 TI - Tumor regression grade and rectal cancer. PMID- 20173490 TI - ODS score and obstructed defecation. PMID- 20173491 TI - High-resolution anoscopy is a crucial component of anal dysplasia screening. PMID- 20173494 TI - Primary ovarian mucinous carcinoma of intestinal type: significance of pattern of invasion and immunohistochemical expression profile in a series of 31 cases. AB - Primary ovarian mucinous carcinomas of the intestinal type are uncommon and earlier reports have included cases diagnosed according to older, less stringent, criteria (which would now be considered borderline tumors) and variable numbers of cases of metastatic adenocarcinoma. This study was conducted to identify all cases of primary mucinous carcinoma of the ovary in a population-based registry, diagnosed according to WHO 2003 criteria, and to characterize their histologic features, immunohistochemical expression profile, and outcome. Thirty-one cases of primary ovarian mucinous carcinoma were included in this study. Immunostaining for 33 markers was performed. Mean age of the patients was 55.4+/-13.5 years. Thirty tumors were stage I or II at presentation. Twenty-six of 31 (83.9%) tumors had expansile stromal invasion, 4 of 31 (12.9%) showed destructive invasion, and 1 of 31 (3.2%) had anaplastic carcinoma in a mural nodule. All cases with destructive invasion showed grade 3 nuclear atypia whereas only 3 of 26 (11.5%) cases with expansile invasion had grade 3 nuclear atypia (P=0.0003). At follow up, 6 of 26 patients (23.1%) with tumors showing expansile invasion experienced a recurrence, compared with 1 of 4 patients (25%) with destructive invasion and the single patient (100%) with anaplastic carcinoma. There was CK7 positivity in 26 of 31 cases (86.7%), and CK20 and Cdx-2 were each positive in 33.3% of cases. D2 40, calretinin, mesothelin, CA-125, Pax-8, TTF, and WT1 were completely negative in all cases. NHERF1 staining was present in 19 of 26 cases (73%) and its expression was associated with poor prognosis (P=0.05). Our findings support current diagnostic criteria for primary ovarian mucinous carcinoma, that is, the presence of expansile invasion, in the absence of destructive invasion, warrants a diagnosis of carcinoma. A large majority of mucinous carcinomas show only an expansile pattern of invasion and are confined to the pelvis at diagnosis. PMID- 20173495 TI - Ovarian intestinal type mucinous borderline tumors: are we ready for a nomenclature change? AB - At a National Cancer Institute-sponsored workshop it was proposed that the borderline category of ovarian intestinal-type mucinous tumors (OInMTs) could be eliminated if the apparent benign behavior of these tumors could be confirmed. We reviewed 33 cases of borderline OInMT, with either optimal or adequate sampling and with at least 5 years of follow-up, to investigate their behavior. Optimal sampling and adequate sampling were defined as at least 1 section per centimeter of maximum tumor dimension and at least 1 section per 2 cm of maximum tumor dimension, respectively. The patients' age ranged from 16 to 89 years (mean 49 yr). Tumor size ranged from 8 to 39 cm (mean 20 cm). The sampling of the ovarian tumor was optimal in 28 cases and adequate in 5 cases. The patients were treated surgically as follows: cystectomy (1), unilateral oophorectomy or unilateral salpingo-oophorectomy with or without total abdominal hysterectomy (13), and bilateral salpingo-oophorectomy with or without total abdominal hysterectomy (19). Complete or partial staging was obtained in 26 patients. All of them had Federation of Gynecology and Obstetrics stage I disease. Thirty-one patients with a follow-up ranging from 5 to 18 years (mean 10 yr) had no recurrences. Two patients had recurrences 12 and 14 months after their initial surgery. The first patient underwent a left salpingo-oophorectomy and limited staging for a borderline OInMT adherent to the ileum and sigmoid. The tumor was incompletely removed and recurred in the pelvis 1 year later. It was again incompletely excised. Ten months later, the tumor re-recurred in the pelvis and could only be drained because of the patient's advanced age and her poor medical status. She died of other causes 5 years later. The second patient with recurrent tumor had undergone a cystectomy and full staging for a borderline OInMT. Fourteen months later, she developed a recurrence in the residual ovary. She underwent a right salpingo-oophorectomy and total abdominal hysterectomy and has been without evidence of disease for 11 years. In this study of 33 Federation of Gynecology and Obstetrics stage I borderline OInMTs that were optimally or adequately sampled to exclude intraepithelial carcinoma, microinvasion, or invasive carcinoma, there were only 2 cases with recurrence, secondary to incomplete excision or cystectomy, and no deaths from disease. However, borderline OInMTs are usually large and heterogeneous, and the standard sampling protocol for them is not evidence based. As indicated by one of our consultation cases, there remains the potential for a sampling artifact in which a focus of carcinoma is missed. Caution dictates retaining the current nomenclature to ensure the follow up of patients affected by this disease until uncertainty regarding the extent of sampling needed to exclude the presence of carcinoma is resolved. PMID- 20173496 TI - Peritoneal melanosis associated with mucinous cystadenoma of the ovary and adenocarcinoma of the colon. AB - Peritoneal melanosis, a diffuse, black pigmentation of the peritoneum, is a very rare condition characterized by melanin pigment deposition in the peritoneum. In this paper, we describe a case of peritoneal melanosis associated with a mucinous cystadenoma on an ovary and adenocarcinoma in the colon of 68-year-old women. The patient was referred for an evaluation of lower abdominal pain and distension. Laboratory results showed anemia and elevated CA 125 levels. A pelvic computed tomographic scan revealed a huge multicystic mass on the right ovary and a well enhancing intraluminal mass located at the rectosigmoid junction. During a surgical procedure, India-ink-colored (black) pigmentation was seen in the peritoneum, in the omentum, and on the surface of the ovary. Biopsies of the omentum and peritoneum showed pigment in the stroma and pigment-laden histiocytic aggregation. Pigment was also present in the wall of the mucinous cystadenoma of the ovary and colonic serosa. An ultrastructural study found melanosome in the cytoplasm of the histiocytes. PMID- 20173497 TI - Vascular involvement in adenomyosis: report of a large series of a common phenomenon with observations on the pathogenesis of adenomyosis. AB - The occurrence of vascular involvement in adenomyosis has been noted earlier, but there has been little detailed study of this phenomenon. In this study, we examined a large series of uteri with adenomyosis (n=434), specifically looking for the presence of adenomyotic foci within vascular channels. Vascular involvement was identified in 54 cases (12.4%). In 19 of 54 cases (35%) a single vessel was involved, in 16 cases (30%) 2 to 3 vessels, and in 19 cases (35%) multiple vessels. In 34 cases (63%), the intravascular component comprised endometrial stroma only and in 20 cases (37%) there was a mixture of glands and stroma, although even in these cases some of the individual foci exhibiting vascular involvement consisted of stroma only. In most cases, the intravascular component protruded into the vessel lumen beneath an intact endothelial lining. Immunohistochemistry performed in a small number of cases confirmed the intravascular location and showed the intravascular tissue to be lined on the luminal surface with endothelial cells. Pathologists should be aware of the phenomenon of vascular involvement in adenomyosis, which is relatively common and, when widespread, may result in the consideration of a neoplastic process. The pattern of vascular involvement raises the possibility that adenomyosis develops from cells intimately associated with myometrial blood vessels, perhaps multipotential perivascular cells. PMID- 20173498 TI - Pleomorphic rhabdomyosarcoma of the uterine corpus: a clinicopathologic study of 4 cases and a review of the literature. AB - We report the clinicopathologic features of 4 cases of pure pleomorphic rhabdomyosarcoma of the uterine corpus with an emphasis on their frequent expression of CD10 and CD56, review the relevant literature, and discuss differential diagnostic considerations. The patients ranged from 51 to 79 years (mean 68 y). All were FIGO stage IIIC to IV at initial surgical staging, and 3 were dead from the disease at an average of 8.6 months follow-up. In addition to the expected findings, other notable morphologic features included tumor giant cells (4/4), osteoclast-like giant cells (1/4), patchy myxoid stroma (4/4), and only infrequent cytoplasmic cross striations (1/4). The tumors in all 4 cases were positive for myogenin, myo-D1, smooth muscle actin, desmin, muscle-specific actin (HHF-35), and CD10; 3 (75%) of 4 cases were positive for calponin and CD56; all cases were negative for cytokeratin 7, synaptophysin, epithelial membrane antigen, placental-like alkaline phosphatase, chromogranin, and a pan-keratin. Twenty-three cases have been reported earlier in the English-language literature between 1969 and 2009. In combination with the current 4, the 27 patients had an age range of 35 to 87 years (mean 66.33 y). Only 1 patient was deemed inoperable; most had staging operations. Following their initial evaluations, 16 (59%) were found to have extrauterine extension of disease. At follow-up, 73% (19/27) were dead from the disease and 19.2% had no evidence of recurrence. Ten (53%) of the 19 deaths occurred within 6.5 months of initial evaluation. Stage at presentation did not have any significant impact on outcome: 73% of the 11 patients with uterus-confined disease at presentation were dead from the disease at follow-up, a rate of disease-associated death that was nearly identical to the 75% in the 16 patients with extrauterine disease at presentation. A wide variety of neoadjuvant and adjuvant therapies were administered, which did not appear to significantly impact outcomes. These data indicate that pleomorphic rhabdomyosarcoma of the uterine corpus is a highly aggressive, rapidly progressive tumor with a high case fatality rate. PMID- 20173499 TI - p300 expression is related to high-risk human papillomavirus infections and severity of cervical intraepithelial neoplasia but not to viral or disease outcomes in a longitudinal setting. AB - To evaluate the role of the expression of the transcription factor p300 as an independent predictor of high-risk human papillomavirus (HR-HPV) infections and outcome of the cervical disease.Cervical biopsy samples taken at enrolment from 225 women of the Latin American Screening study cohort were analyzed for p300 using immunohistochemistry to assess its value as predictor of (a) cervical intraepithelial neoplasia (CIN) grade, and (b) HR-HPV at baseline, as well as (c) outcomes of HR-HPV infections, and (d) development of incident CIN as surrogate endpoints of progressive disease.There was a significant linear trend in increasing upregulation (=pattern shift) of p300 (P=0.0001) in parallel with increasing grade of CIN. When dichotomized (normal/moderately increase vs. strong intense), upregulated p300 expression predicted CIN3+ with odds ratio=4.16 (95% confidence interval: 1.95-8.86) (P=0.0001) and CIN2+ with odds ratio=3.48 (95% confidence interval: 1.86-6.48) (P=0.0001). p300 was upregulated more often in HR HPV+ lesions than in those remaining negative. Semiquantitative viral loads were also directly related to upregulation of p300 (P=0.036), but p300 was not a significant predictor of disease progression to either CIN1+ or CIN2+.p300 expression was upregulated in CIN lesions and related to detection and viral load of HR-HPV but not to their outcome or to incident CIN. PMID- 20173500 TI - Endometrial endometrioid adenocarcinoma of the uterine corpus involving the cervix: some cases probably represent independent primaries. AB - The majority of endometrial endometrioid adenocarcinomas involving the cervix have tumor morphology that is similar in the endometrium and the endocervix. There are, however, some cases in which the morphology of the tumor in the endocervix is different from the endometrial carcinoma, in which it is more invasive than the endometrial carcinoma, or in which invasion only occurs in the endocervix while there is no or only minimal myometrial invasion. The goal of this study was to investigate whether tumors involving the endometrium and the endocervix are similar or 2 independent primaries by hematoxylin and eosin stain, immunohistochemistry (IHC), human papillomavirus (HPV) DNA in situ hybridization, RNA reverse transcriptase in situ polymerase chain reaction (PCR) analyses to reveal HPV, and DNA clonality studies. We selected 14 cases of endometrial endometrioid adenocarcinomas involving the cervix with complete pathology material available from the years between 1968 and 2004. Immunohistochemical studies for vimentin, carcinoembryonic antigen, estrogen receptor, progesterone receptor, and p16 were performed in 12 cases; HPV DNA/RNA analyses in 4 cases; and clonality studies in 9 cases. The patients' ages ranged from 42 to 81 years (mean: 62 y). Follow-up information was obtained in 11 patients. Histologic features varied between the tumors in the endometrium and the endocervix in 8 cases, and 5 of these cases had uniform, dilated glands having a microcystic appearance in the cervix. In 6 cases, the tumors in the endometrium and the endocervix had similar histologic features. The immunohistochemical studies showed some differences between the endometrial and endocervical adenocarcinomas in 8 of the 12 cases, independent of differing or similar histologic features. HPV testing in 4 of the cases (3 with similar and 1 with different histology) yielded similar results in the endometrium and endocervix: 2 cases were negative, 1 was positive and 1 was equivocal for HPV DNA/RNA analyses. Clonality studies showed differences between the adenocarcinoma in the endometrium and the endocervix in 7 cases, including 5 cases with different histologic appearances; 2 cases had similar loss of heterozygosity patterns. In conclusion, as suggested by clonality studies, coexisting endometrial and endocervical carcinomas with different histologic features are most likely independent neoplasms. Endometrial and endocervical carcinomas that have similar appearances can represent either the same neoplasm or independent primaries. Clonality tests may help determine their relationship. IHC studies may not be helpful for synchronous endometrial and endocervical tumors, especially those of endometrioid type. It is possible that IHC identifies cell differentiation, rather than site of origin. HPV studies are important to identify endocervical tumors associated with high-risk HPV. However, endometrial tumors involving the cervix and endocervical tumors unrelated to HPV are both negative for high-risk HPV. PMID- 20173501 TI - Amplification of the human telomerase gene in liquid-based preparations is associated with cervical dysplasia and carcinoma. AB - The aim of this study was to analyze the amplification of the human telomerase gene (TERC) in cervical specimens by fluorescence in situ hybridization (FISH), and FISH findings were compared with cytologic and histologic diagnoses. Slides prepared from 123 liquid-based preparations from cervical specimens with cytologic diagnoses of negative for squamous intraepithelial lesion or malignancy (n=20), atypical squamous cells of undetermined significance (n=22), low-grade squamous intraepithelial lesion (n=55), high-grade squamous intraepithelial lesion (n=21), or invasive cervical carcinomas (n=5) were analyzed for the amplification of TERC using a 2-color FISH probe. The results of the cytologic analysis and those of concurrent or subsequent biopsies were compared with the FISH findings. Results showed that amplification of TERC was significantly associated with both cytologic and histologic diagnoses (P<0.05). Patients with high-grade squamous intraepithelial lesion or squamous cell carcinoma cytology diagnoses had significantly higher percentages of cells with the amplification of TERC than did patients with low-grade squamous intraepithelial lesion, ASC-US, and negative for squamous intraepithelial lesion or malignancy (P<0.005). FISH can be performed on cervical liquid-based preparations to detect the amplification of TERC. This test may be an adjunct to cytology screening, early detection of cervix neoplasm, and may determine the progressive potential of individual lesions, especially in high-risk patients. PMID- 20173502 TI - Frozen section analysis of vulvectomy specimens: results of a 5-year study period. AB - The most important goals of surgical treatment in vulvar cancer (VCX) are complete tumor resection and adequate treatment of inguinal nodes. The status of resection margins and inguinal node involvement might be the subject of intraoperative frozen section examination. During a study period of 5 yr we determined the frequency of all gynecologic specimens among all the specimens sent for frozen section evaluation with a special focus on VCX. In the cases of VCX we determined the time necessary for frozen section, its accuracy and described our practical approach to their handling. In the 7,921 frozen section analyses, 17.5% resulted from gynecologic surgery (29.2% of the latter ones resulted from ovarian samples, 26.8% from the cervix, 15.0% from the endometrium, 17.5% from the breast, including sentinel lymph nodes, 10.6% from the vulva, and 0.8% from the vagina). The accuracy rate of vulval frozen section analyses was 100% for the evaluation of Cloquet node, and 98.6% for the margin status. The mean time necessary for frozen section analysis of the vulvectomy specimens was 24.5 min (range 6 to 44 min). Gynecologic specimens are frequently submitted for intraoperative consultation. Regardless of the high degree of individualized surgical treatment of VCX, some procedures in the handling of vulvectomy specimens can be tailored and might be subject to standardization, including frozen section evaluation. Therefore, all cutaneous vulvar resection margins, and the vaginal, urethral, and anal (mucosal) margin as well as the deep soft tissue margin should also be examined. PMID- 20173503 TI - Isolated and synchronous vulvar granular cell tumors: a clinicopathologic study of 17 cases in 13 patients. AB - Granular cell tumors (GCTs) are benign Schwann cell-derived neoplasms occurring throughout the body. Vulvar GCTs are usually isolated, but occasionally multifocal. On account of their anatomic location, surgical interventions aiming for negative resection margins can result in significant morbidity. We describe the clinicopathologic features of 17 vulvar GCTs in 13 patients followed for an average of 7 years. The average age at presentation was 46 years, and 84% of the patients were black. The tumors were multifocal in 3 (23%) patients, and all, either at presentation or subsequently also developed extravulvar foci. Patients with multifocal vulvar GCTs were nearly 10 years younger at presentation than patients in whom the disease was isolated. The most common complaint was a slow enlarging mass occasionally associated with pruritus or overlying hyperpigmentation. Clinically, the tumors were subcutaneous, mobile, and nodular (2.1 cm on average), without overlying ulceration, and most often were found in the labia majora (6/17). The neoplasms were histologically heterogeneous, but exhibited either a predominantly nodular (3/17) or infiltrative (13/17) pattern of invasion. Cytologically, the tumors displayed round to polygonal cells with a granular cytoplasm, small hyperchromatic nuclei with minimal pleomorphism, and less than 2 mitoses per 10 high power fields. One tumor (1/17) consisted of cells with predominantly vesicular nuclei and prominent nucleoli and was classified as an atypical vulvar GCT. All tumors so examined were reactive for S-100 protein. Eight of 17 tumor excision specimens had positive margins. Of these, 5 tumors remained stable whereas the other 2 with follow-up progressed to require reexcisions after periods of 14 and 8.0 years, respectively. All patients with excisions with negative margins remained stable. Patients with multifocal tumors did not have a higher risk of recurrence per tumor, compared with patients with isolated disease, regardless of the margin status. No patient died from her disease. As granular cell neoplasms have such a low risk or recurrence and behave generally in an indolent manner, aggressive therapy is usually unwarranted. PMID- 20173504 TI - Primary signet-ring cell carcinoma of the cervix: case report and review of the literature. AB - Mucinous adenocarcinoma of the cervix has 5 subtypes: endocervical, intestinal, signet-ring cell, minimal deviation, and villoglandular. There are only rare reports of primary signet-ring cell carcinoma of the cervix in the literature. Herein we report a 53-year-old woman with cervical adenocarcinoma with signet ring cell morphology. Thorough systemic examination did not reveal another primary focus. DNA extraction from paraffin-embedded tissue revealed the presence of human papilloma virus (HPV) type 18, which supports the cervical origin of the tumor. Signet-ring cell morphology can be observed in both benign and malignant lesions of the uterine cervix. Most of the malignant lesions are metastatic. Histological features and immunohistochemical profiles are discussed, and a review of signet-ring cell morphology in the uterine cervix is included. PMID- 20173505 TI - Polypoid endometriosis of the uterine cervix with Arias-Stella reaction in a patient taking phytoestrogens. AB - We report for the first time a case of 2.5 cm polypoid cervical endometriosis with a superficial growth pattern in a 48-year-old patient with past tubal ligation. The lesion showed metaplastic changes (clear cell, eosinophilic, micropapillary) and a prominent Arias Stella reaction in the absence of concomitant pregnancy but presumably related to phytoestrogenic treatment. The eutopic endometrium, however, had a usual proliferative appearance, implying that it showed a different response from the endometriotic tissues, suggesting the possibility of a metaplastic origin for the endocervical polypoid endometriosis. The unusual histology of the lesion led to an erroneous diagnosis of papillary serous carcinoma in the biopsy. This was subsequently excluded on finding endometrial-type stroma surrounding glands, and was confirmed immunohistochemically by a low Ki-67 index and negativity for p53. PMID- 20173506 TI - Solitary fibrous tumor of the uterine cervix. AB - A 68-year-old woman with stage pT1b1 N0 cervical squamous carcinoma had an incidental cervical polyp. The polyp measured 1.7 cm in maximal diameter and histologic evaluation showed it to be composed of spindle-shaped cells with hypercellular and hypocellular foci. The stroma was collagenized and contained several dilated vascular channels that imparted a hemangiopericytic pattern to the lesion. Immunohistochemistry showed the spindle cells to be positive for vimentin, CD99, CD34, bcl-2, ER, PR, and beta-catenin (cytoplasmic) but negative for EMA, S100, factor XIIIa, AE1/AE3, caldesmon, desmin, CD31, and smooth muscle actin. The morphology and immunophenotype was in keeping with a diagnosis of a solitary fibrous tumor (SFT). SFT shares several histologic features of a superficial cervicovaginal myofibroblastoma; the cellular variability, pattern and distribution of vessels, stromal collagenization, and desmin negativity favors SFT. PMID- 20173507 TI - Primary vaginal adenocarcinoma arising in vaginal adenosis after CO2 laser vaporization and 5-fluorouracil therapy. AB - We present a case of a 45-year-old woman with a long-standing history of persistent cervical dysplasia that resulted in a hysterectomy. Subsequent vaginal smears revealed high-grade vaginal intraepithelial neoplasia (VAIN III) on Pap smear with positive human papilloma virus (HPV) testing. Over the course of 2 years, the patient underwent 2 CO(2) laser vaporization procedures of the upper vagina and intermittent 5-fluorouracil therapy. A biopsy performed at the time of the second laser procedure revealed endocervical-type well-differentiated adenocarcinoma, associated with VAIN III. HPV in situ hybridization for HPV types 16 and 18 was positive in both the glandular and squamous mucosa. The patient has no known history of intrauterine diethylstilbestrol exposure or mullerian developmental abnormalities. Subsequently, the patient underwent a radical upper vaginetcomy with bilateral pelvic lymph nodes dissection and bilateral salpingo oophorectomy. The vaginectomy specimen showed residual adenocarcinoma associated with VAIN-III and extensive vaginal adenosis with free resection margins. This is the second reported case in the literature of adenocarcinoma arising in vaginal adenosis after 5-fluorouracil. Herein, we highlight these important findings and shed some light on the pathogenesis of vaginal adenosis and the subsequent development of vaginal adenocarcinoma. PMID- 20173508 TI - Immature teratoma of the vulva with an inguinal lymph node metastasis: report of a case and review of literature. AB - Neoplasms of the vulva are rare and most commonly reported amongst them are epithelial tumors. Teratomas have been reported in many extragonadal sites. We report the only case of an immature teratoma of the vulva with inguinal lymph node metastasis. PMID- 20173510 TI - The management of craniovertebral junction disorders. Foreword. PMID- 20173509 TI - Effects of endogenous nitric oxide and of DETA NONOate in arteriogenesis. AB - Previous studies showed that targeted endothelial nitric oxide synthase (eNOS) disruption in mice with femoral artery occlusion does not impede and transgenic eNOS overexpression does not stimulate collateral artery growth after femoral artery occlusion, suggesting that nitric oxide from eNOS does not play a role in arteriogenesis. However, pharmacologic nitric oxide synthase inhibition with L NAME markedly blocks arteriogenesis, suggestive of an important role of nitric oxide. To solve the paradox, we studied targeted deletion of eNOS and of inducible nitric oxide synthase (iNOS) in mice and found that only iNOS knockout could partially inhibit arteriogenesis. However, the combination of eNOS knockout and treatment with the iNOS inhibitor L-NIL completely abolished arteriogenesis. mRNA transcription studies (reverse transcriptase-polymerase chain reaction) performed on collateral arteries of rats showed that eNOS and especially iNOS (but not neural nitric oxide synthase) become upregulated in shear stress stimulated collateral vessels, which supports the hypothesis that nitric oxide is necessary for arteriogenesis but that iNOS plays an important part. This was strengthened by the observation that the nitric oxide donor DETA NONOate strongly stimulated collateral artery growth, activated perivascular monocytes, and increased proliferation markers. Shear stress-induced nitric oxide may activate the innate immune system and activate iNOS. In conclusion, arteriogenesis is completely dependent on the presence of nitric oxide, a large part of it coming from mononuclear cells. PMID- 20173511 TI - Lateral transcondylar approach for tumors at the anterior aspect of the craniovertebral junction. AB - BACKGROUND: Tumors at the craniovertebral junction are difficult to remove because of their location and complex anatomic relations. The lateral transcondylar approach is a versatile approach to this area and allows access to a variety of intra- and extradural tumors. The lateral transcondylar approach has been used for a series of chordomas in this location. OBJECTIVE: The nuances of this operation and its effectiveness in this group of patients are presented. METHODS: There were 29 chordomas (1991-2007) in this region treated by one of the authors (CS) that were retrospectively reviewed. The imaging studies and medical records were evaluated. The location and extent of the tumor were defined, and the postoperative images were studied to determine the degree of resection. RESULTS: There were 11 male and 18 female patients; their age range was 7 to 67 years. Headache and neck pain were the predominant presenting symptoms, and hypoglossal nerve palsy was the most common cranial nerve palsy. Twelve patients had previous surgery and 9 had previous radiation. Anterior midline and lateral approaches were used independently or in combination to treat these patients. Dural invasion was found in 27 patients requiring resection of the dura. Surgery was performed in 1 stage in 19 patients, and the tumor resection in the remaining patients was done in 2 stages. The lateral transcondylar approach was used in 19 patients. The occipital condyle was involved in all these patients. Radical tumor resection was achieved in 17 patients. Patients who had complete removal of the occipital condyle required occipitocervical fusion (20 patients) in the immediate postoperative period. CONCLUSION: The lateral transcondylar approach is an effective approach to chordomas in this region. Most of the tumors were large and extended into multiple anatomic compartments. The approach allowed resection of all the involved tissues, intra- and extracranial, and afforded excellent neurovascular control. PMID- 20173512 TI - Metastases to the craniovertebral junction. AB - OBJECTIVE: This study reviews the relevant literature regarding the management of craniovertebral junction (CVJ) metastases. These rare tumors present significant diagnostic and treatment challenges. METHODS: A PubMed search of cervical spine, cervical spine metastasis, craniovertebral junction, atlantoaxial spine, and metastasis radiation was conducted to define the epidemiology, imaging, and treatment protocols in the management of metastatic CVJ tumors. RESULTS: CVJ tumors represent less than 1% of spinal metastases, and the literature is limited to small case series. CVJ tumors present with flexion, extension, and rotational pain, often associated with occipital neuralgia. Magnetic resonance imaging is the most sensitive imaging modality for the detection of spinal metastases, but plain x-rays, computed tomography, and [18F]2-fluoro-2-deoxy-D-glucose play a role in diagnosis and management. Conventional external beam radiation therapy or stereotactic radiosurgery effectively treat the majority of patients with normal spinal alignment or minimal fracture subluxations. Surgery should be considered in patients with fracture subluxations greater than 5 mm, or 3.5 mm subluxation with 11-degree angulation. The palliative goals for surgery favor posterior approaches only including laminectomy for decompression, without the need for anterior approaches with the associated morbidity. Occipitocervical instrumentation using screw-rod systems are effective for irreducible subluxations, but posterior strategies using C1-C2 or C1-C3 can be used for patients with reducible subluxations. CONCLUSION: Effective management of CVJ tumors using radiation and/or surgery results in significant pain and functional improvement in properly selected patients. Advanced surgical techniques and stereotactic radiation may improve outcomes with less morbidity. PMID- 20173513 TI - Transoral approaches to the cervical spine. AB - A number of anterior approaches to the craniocervical junction have been described to allow exposure to the midline and lateral aspects of both the cranial base and upper cervical spine. The transoral-transpharyngeal approach, a technique that is well known to many spine surgeons, provides surgical access to the anterior clivus, C1, and C2. Transoral approaches provide the fundamental anatomy and technique upon which the more complex jaw-splitting approaches are based. This article discusses fundamental concepts regarding anatomy, perioperative considerations, and technical aspects critical to this important approach to the craniocervical junction. The transoral-transpharyngeal approach remains the "gold standard" for anterior approaches to the cervical spine. Endoscopic endonasal and endoscopic transcervical approaches are promising alternatives that may become more mainstream as experience with these approaches increases. PMID- 20173514 TI - Extended transoral approaches: surgical technique and analysis. AB - BACKGROUND: The transoral approach provides the most direct exposure to extradural lesions of the ventral craniovertebral junction. Lesions that extend beyond the exposure provided by the standard transoral approach require an extended transoral modification. The exposure can be expanded in the sagittal and axial planes by adding mandibulotomy, mandibuloglossotomy, palatotomy, and transmaxillary approaches to the standard transoral approach. Extended transoral approaches increase the surgical complexity and the risk of cosmetic and functional complications. Until recently, selection of an extended approach has been arbitrary and dependent on the surgeon's familiarity with the surgical approach. OBJECTIVE: We review the literature of extended transoral approaches and analyze the different modifications in terms of the technical aspects, added exposure, and complications. METHODS: Classic approaches and recently published morphometric studies that objectively document the gain in exposure provided by several modifications were analyzed and tabulated to outline the limits of exposure and risk of complications associated with the various modifications. RESULTS: Transmaxillary approaches expand the exposure to include the sphenoid sinus and upper lateral clivus. To expand the exposure more inferiorly to C4-C5, mandibulotomy or mandibuloglossotomy can be applied. Mandibuloglossotomy increases the rostral exposure as well to the upper third of the clivus. Palatotomy increases rostral exposure without requiring a facial incision or perioperative tracheostomy, but is associated with a significant risk of velopharyngeal insufficiency. CONCLUSION: Surgical decisions can be based on comprehensive preoperative evaluation of anatomy, pathology, and radiographic studies to maximize exposure while minimizing complications. PMID- 20173515 TI - Neurologic findings of craniovertebral junction disease. AB - In this review, we explain the origins of central cord syndrome and Bell's cruciate paralysis and the intricate detail of neural pathways located in this region and their influence on motor and sensory function. Although lesion studies and tract tracing studies on primates over the past 50 years refute the theory of a somatotopically organized corticospinal tract, this concept continues to pervade many neuroanatomic texts. We categorized the various pathologies of the craniovertebral junction and their unique neurologic presentations. New developments in the fields of neuroscience of spinal tract lesioning are also discussed. PMID- 20173516 TI - Posterolateral approaches to the craniovertebral junction. AB - OBJECTIVE: The indications and operative technique for a number of posterolateral approaches to the craniovertebral junction (CVJ) are reviewed. METHODS: The literature addressing posterolateral approaches to the CVJ is reviewed, and illustrative cases are presented. RESULTS: The far lateral approach and its variants, including the transcondylar, supracondylar, and paracondylar approaches, are an effective means of addressing intradural anterior and anterolateral CVJ lesions. These approaches provide exposure of the lower third of the clivus, the foramen magnum, and the upper cervical spine; do not cross contaminated regions; and enable a watertight dural closure to be performed. They are associated with minimal morbidity and usually do not significantly decrease the stability of the CVJ. CONCLUSION: All surgeons treating lesions of the CVJ should be familiar with the posterolateral approach and its modifications. PMID- 20173517 TI - Nuances of occipitocervical fixation. AB - OBJECTIVE: To describe the indications and techniques for occipitocervical (OC) fixation. METHODS: The operative nuances of current OC fixation techniques are described. A surgical technique video is included. RESULTS: Pertinent literature is reviewed regarding OC fixation techniques. CONCLUSION: OC fixation systems have evolved from wire and cable techniques to plates, rods, and screws. Screw rod constructs are easy to implant and biomechanically more rigid than wire techniques. PMID- 20173518 TI - Fixation of the axis. AB - OBJECTIVE: To review and compare the techniques of fixation of the axis vertebral segment. Also, to review the anatomy of the axis vertebrae, ligamentous attachments, and unique biomechanics of this segment. METHODS: The use of wire, cable, screw, and plate fixation techniques are reviewed and discussed in the treatment of fractures of C1 and C2 along with utilization of the halo vest and cervical collar during the postoperative period. RESULTS: All fixation methods were useful. However, the appropriate fixation technique is best determined by the local anatomy (eg, anomalous vertebral artery), posterior element fractures, or the necessity to remove the posterior elements for treatment of the underlying condition. CONCLUSION: New techniques for fixation and instrumentation for fixation of the axis are available. Advanced imaging allows for advanced aggressive instrumentation while avoiding injury to adjacent structures. Biomechanical studies have influenced the utility and popularity of each technique. PMID- 20173519 TI - C1 lateral mass fixation: a comparison of constructs. AB - OBJECTIVE: We review our experience and technique for C1 lateral mass screw fixation. We compare the results of 3 different constructs incorporating C1 lateral mass screws: occipitocervical (OC) constructs, C1-C2 constructs, and C1 to mid/low cervical constructs. METHODS: We performed a retrospective chart review of 42 consecutive patients who underwent C1 lateral mass fixation by 2 of the authors (PVM and DC). The patient population consisted of 24 men and 18 women with a mean age of 64 years. Twenty-two patients had C1-C2 constructs. Twelve patients had constructs that started at C1 and extended to the mid/low cervical spine (one extended to T1). Eight patients underwent OC fusions incorporating C1 screws (2 of which were OC-thoracic constructs). All constructs were combined either with a C2 pars screw (38 patients), C2 translaminar screw (1 patient), or C3 lateral mass screw (3 patients). No C2 pedicle screws were used. Fusion was assessed using flexion-extension x-rays in all patients and computed tomographic scans in selected cases. Clinical outcomes were assessed with preoperative and postoperative visual analog scale neck pain scores and Nurick grading. The nuances of the surgical technique are reviewed, and a surgical video is included. RESULTS: Two patients (5%) were lost to follow-up. The mean follow-up for the remaining patients was 2 years. During the follow-up period, there were 4 deaths (none of which were related to the surgery). For patients with follow-up, the visual analog scale neck pain score improved a mean of 3 points after surgery (P < .001). For patients with myelopathy, the Nurick score improved by a mean of 1 grade after surgery (P < .001). The postoperative complication rate was 12%. The complication rate was 38% in OC constructs, 17% in C1 to mid/low cervical constructs, and 0% for C1-C2 construct cases. Patients with OC constructs had the statistically highest rate of complications (P < .001). Patients with C1 to mid/low cervical constructs had more complications than those with C1-C2 constructs (P < .001). Of the 42 cases, there were 3 pseudoarthroses (1 in an OC case, 1 in a C1 to midcervical construct, and 1 in a C1-C2 construct). OC constructs had the highest risk of pseudoarthrosis (13%) (P < .001). CONCLUSION: Patients treated with C1 lateral mass fixation constructs have a high fusion rate, reduced neck pain, and improved neurologic function. Constructs using C1 lateral mass screws do not need to incorporate C2 pedicle screws. Constructs incorporating C1 lateral mass screws are effective when combined with C2 pars screws, C2 translaminar screws, and C3 lateral mass screws. Constructs using C1 screws are associated with a higher complication rate and a higher pseudoarthrosis rate if extended cranially to the occiput or if extended caudally below C2. PMID- 20173520 TI - Atlantoaxial rotatory fixation. AB - OBJECTIVE: Atlantoaxial rotatory fixation (AARF) remains a recondite entity. Our normative study using CT motion analysis shows that there is a high degree of concordance for rotational behavior of C1 and C2 in children 0 to 18 years. C1 always crosses C2 at or near 0 degree. The predictable relationship between C1 and C2 is depicted by 3 distinct regions on the motion curve: when C1 rotates from 0 to 23 degrees, it moves alone while C2 remains stationary at 0 (the single motion phase). When C1 rotates from 24 to 65 degrees, C1 and C2 move together (the double-motion phase), but C1 always moves faster as C2 is being pulled by yoking ligaments. From 65 degrees onward, C1 and C2 move in unison (the unison motion phase) with a fixed, maximal separation angle of approximately 43 degrees, the head rotation being carried exclusively by the subaxial segments. Because of this high concordance among patients and a relatively narrow variance from the mean, the physiological composite motion curve can be used as a normal template for the diagnosis and classification of AARF. METHODS: Using a 3-position CT protocol to obtain the diagnostic motion curve, we identified 3 distinct types of AARF. Type I AARF patients show essentially unaltered ("locked") C1-C2 coupling regardless of corrective counterrotation, with curves that are horizontal lines in the upper 2 quadrants of the template. Type II AARF patients show reduction of the C1-C2 separation angle with forced correction, but C1 cannot be made to cross C2. Their curves slope downward from the right to left upper quadrants but never traverse the x axis. Type III AARF patients show C1-C2 crossover but only when the head is cranked far to the opposite side. Their motion curves traverse the x axis far left of 0 degree (C1 < -20). Thus, type I, II, and III AARF are in descending degrees of pathological stickiness. A fourth group of patients showing motion curve features between normal and type III AARF are designated as belonging to a diagnostic gray zone (DGZ). The AARF patients are further classified as acute if treatment is started less than 1 month from the onset of symptoms, as subacute if the delay in treatment is 1 to 3 months, and chronic if treatment delay exceeds 3 months. The treatment protocol for AARF consists of reduction using either halter or caliper traction and then immobilization with brace or halo, depending on the AARF type and chronicity. Recurrent slippage and irreducibility are treated with C1-C2 fusion. RESULTS: The treatment course and outcome of AARF are analyzed according to the AARF type and chronicity. The difficulty and duration of treatment, the number of recurrent slippage, the rate of irreducibility, the need for halo and fusion, and the percentage ultimately losing normal C1-C2 rotation are significantly greater in type I patients than type III patients, with type II patients somewhere in between. Likewise, all parameters are much worse in patients with any type of chronic AARF than acute AARF. The worse subgroup is chronic type I versus the best subgroup of acute type III. Recurrent AARF patients do much worse than nonrecurrent AARF patients. Recurrence is, in turn, adversely influenced by both the severity (type) and chronicity of AARF. The symptoms of most DGZ patients will resolve with analgesics, but a few remain symptomatic or deteriorate to true AARF requiring the full treatment. CONCLUSION: Thus, children with painful torticollis should undergo the 3-position CT protocol not only to confirm the diagnosis of AARF but also to grade its severity. Closed reduction with traction should be instituted immediately to avoid the serious consequences of chronicity. Proper typing and reckoning of the pretreatment delay are requisites for selecting treatment modalities. Recurrent dislocation and incomplete reduction should be treated with posterior C1-C2 fusion in the best achievable alignment. PMID- 20173521 TI - Atlantoaxial transarticular screw fixation: update on technique and outcomes in 269 patients. AB - BACKGROUND: Transarticular screw (TAS) fixation is our preferred method for stable internal fixation of the atlantoaxial joint because of its excellent outcomes, versatility, and cost-effectiveness. OBJECTIVE: In this article, we update our series of patients who have undergone TAS fixation, with attention to surgical technique, planning, complication avoidance, and anatomic suitability. METHODS: We retrospectively reviewed 269 patients (150 women, 119 men; average age, 52.9 years; age range, 17-90 years) who underwent placement of at least 1 TAS. In total, 491 TASs were placed for stabilization necessitated by various pathologic conditions. The mean follow-up period was 15.7 months (range, 0-106 months). RESULTS: Fusion was achieved in 99% of 198 patients monitored until fusion or nonunion requiring revision, or for 2 years. Forty-five patients had a complication, for a rate of 16.7%. Five early patients had vertebral artery injuries, 1 of which was bilateral and fatal. No recent patients had vertebral artery injuries. Other complications did not result in neurologic morbidity. Review of all atlantoaxial fusions by the senior author (R.I.A.) revealed that the TAS fixation technique could be successfully applied in 86.7% of sides considered. The main reasons for inapplicability were anatomic (recognized on preoperative planning) in 77% and abandonment secondary to concern about possible vertebral artery injury on the first side attempted in 13.8%. CONCLUSION: The placement of TASs is safe and effective for stabilizing the atlantoaxial articulation. Refinements in technique, such as 3-dimensional stereotactic workstation for trajectory planning, have reduced the rate of serious complications. Clinical outcomes are excellent, with nearly 100% of patients achieving stable bony union. PMID- 20173522 TI - Minimally invasive atlantoaxial fusion. AB - BACKGROUND: C1-C2 fusion has significantly advanced from predominantly wiring/cable modalities to more biomechanically stable screw-rod techniques. Minimally invasive surgical techniques represents the most recent modification of atlantoaxial fixation. The indications, rationale, and surgical technique of this novel procedure are described. METHODS: Six patients requiring C1-C2 fusion (5 type II odontoid fractures and 1 os odontoideum) underwent minimally invasive C1 C2 fusion over a 2-year period. The cohort consisted of 5 men and 1 woman with a mean age of 51 years (age range, 39-64 y). All 6 patients underwent bilateral segmental atlantoaxial fixation using an expandable tubular retractor. RESULTS: The mean follow-up time was 32 months (age range, 24-46 mo) There were no intraoperative complications, and the mean estimated blood loss was 100 mL. Solid fusion was achieved in all 6 patients, without pathological motion on dynamic studies. Postoperative computed tomographic images showed no hardware malposition in the scanned patients (4 of the 6 patients). CONCLUSIONS: Placement of C1 and C2 instrumentation using minimally invasive techniques is technically feasible. Because the instrumentation and the means of obtaining arthrodesis do not differ substantively from the standard approach, we would not anticipate long-term results to be different from those of an open procedure, apart from the approach related morbidity. PMID- 20173523 TI - Anatomic and biomechanical considerations of the craniovertebral junction. AB - An understanding of the regional anatomy and specific biomechanics of the craniovertebral junction is relevant to the specific diseases that affect the region as well as instrumentation of the occiput, atlas, and axis. This article reviews the bony, ligamentous, and vascular anatomy of the region, in relation to the posterior surgical approach to this anatomically unique segment of the cervical spine. Anatomic variations of the area are also discussed. Basic principles of instrumentation of the region are also reviewed. The kinematics of the region as they pertain to the anatomic discussion are reviewed and discussed. PMID- 20173524 TI - Os odontoideum: etiology and surgical management. AB - OBJECTIVE: Os odontoideum is an independent ossicle of variable size with smooth circumferential cortical margins separated from the foreshortened odontoid peg. The etiology of os odontoideum remains controversial, but there is now emerging consensus on the traumatic etiology of os odontoideum rather than a congenital source. RESULTS: We reviewed the literature of os odontoideum. Patients with this condition can be asymptomatic or present with wide range of neurological dysfunctions. Although the diagnosis of os odontoideum can be made with plain x rays, further imaging modalities including magnetic resonance imaging and computed tomography angiography have improved the preoperative planning. CONCLUSION: There is a role for conservative treatment of an asymptomatic incidentally found, radiologically stable, and noncompressive os odontoideum. Conversely, surgery has a definite role in symptomatic cases. The main method of surgical treatment today is posterior decompression after reduction and fusion via independent C1 and C2 instrumentation. Irreducible, persistent anterior compression from os odontoideum can be approached by a transoral route with good results in experienced hands. PMID- 20173525 TI - Craniovertebral junction abnormalities in Down syndrome. AB - Children with Down syndrome may have occipitocervical and atlantoaxial instability. To prevent neurologic injury during athletic competitions, such as the Special Olympics, radiographic cervical spine screening was established in 1983 as a prerequisite for participation in some events. This review discusses the biomechanics underlying upper cervical instability in children with Down syndrome, the evolution of cervical spine screening protocols, and current opinion regarding management for children with Down syndrome and upper cervical instability. PMID- 20173526 TI - Basilar invagination. AB - BACKGROUND: Basilar invagination is a developmental anomaly of the craniovertebral junction in which the odontoid abnormally prolapses into the foramen magnum. It is often associated with other osseous anomalies of the craniovertebral junction, including atlanto-occipital assimilation, incomplete ring of C1, and hypoplasia of the basiocciput, occipital condyles, and atlas. Basilar invagination is also associated with neural axis abnormalities, including Chiari malformation, syringomyelia, syringobulbia, and hydrocephalus. Patients frequently present with neurologic symptoms and deficits and warrant surgical treatment to prevent progression. OBJECTIVE: To review the management of basilar invagination. METHODS: The literature was reviewed in reference to the evaluation and management of basilar invagination, with particular emphasis on the surgical treatment. RESULTS: Reducible basilar invagination may be treated with posterior decompression and stabilization. Ventral decompression may be necessary for basilar invagination with neural compression that is not reducible with axial cervical traction. Posterior cervical stabilization is necessary after ventral decompression. Modern rod and screw systems combined with autogenous bone graft enable correction of deformity, immediate stabilization, and high fusion rates. CONCLUSION: Basilar invagination is a developmental anomaly and commonly presents with neurologic findings. Treatment is typically surgical and involves anterior decompression followed by posterior stabilization for irreducible invagination and posterior decompression and stabilization for reducible invagination. PMID- 20173527 TI - Occipitoatlantal dislocation. AB - Occipitoatlantal dislocation (OAD) can be devastating. This injury may be fatal in many cases, but more survivors are reported because of improvements in diagnosis and treatment. This article describes the diagnosis and treatment of OAD. To diagnose and treat OAD appropriately, neurosurgeons must have a detailed understanding of the anatomy of the craniocervical junction. Various radiographic criteria are used to establish the diagnosis of OAD. A destabilizing injury such as OAD requires surgical fixation. Many surgical techniques are available for fixation of the craniocervical junction. Future studies will continue to refine the diagnostic criteria for OAD and to develop improved methods for craniocervical stabilization. PMID- 20173528 TI - Occipital condyle fractures. AB - OBJECTIVE: The anatomy, clinical presentation, radiologic evaluation, treatment, and outcome of occipital condyle fractures are reviewed. METHODS: We review and discuss the literature on occipital condyle fractures. RESULTS: Occipital condyle fractures are best diagnosed with computed tomography. The neurologic presentation is variable. The majority of these injuries may be treated nonoperatively, but an occipitocervical fusion is necessary to restore stability across the craniovertebral junction. CONCLUSION: Occipital condyle fractures are a rare but serious injury that requires prompt diagnosis and treatment. PMID- 20173529 TI - Atlas fractures. AB - OBJECTIVE: To provide a comprehensive review of the biomechanics, pathophysiology, and clinical management of atlas fractures. METHODS: Selected literature review. RESULTS: Atlas fractures account for 25% of craniocervical injuries, 3% to 13% of cervical spine injuries, and 1% to 3% of all spinal injuries. Motor vehicle accidents account for 80% to 85% of atlas fractures, and the mechanism of injury is axial loading. Isolated atlas fractures are more common; however, 40% to 44% of atlas fractures have concomitant axis fractures. Fractures of isolated anterior or posterior arches are more common and typically seen with concomitant spine fractures. Isolated burst fractures are the second most common type and rarely cause neurological injury. Treatment of atlas fractures is based on whether they occur in isolation or in combination with other cervical spine injuries and on the integrity of the transverse ligament, which is best assessed with high-resolution magnetic resonance imaging. Isolated atlas fractures without injury of the transverse ligament or associated with bony avulsion of the transverse ligament can be treated with halo-brace immobilization and should be followed for instability with flexion-extension radiography. Surgical fixation is recommended for nonbony avulsion of the transverse ligament or if instability is present. The type of surgical fixation is determined by the concomitant craniocervical injuries if present. CONCLUSION: Atlas fractures can be treated with halo-brace immobilization with acceptable outcomes. The role of surgical fixation, especially for atlas burst fractures, requires further study for clarification. PMID- 20173530 TI - Axis fractures. AB - BACKGROUND: Traumatic fractures of the second cervical vertebra are common, representing nearly 20% of all acute cervical spinal fracture-dislocation injuries. They are divided into 3 distinct injury patterns: odontoid fractures, hangman's fracture injuries, and fractures of the axis body, involving all other fracture injuries to the C2 vertebra. OBJECTIVE: An evidence-based overview of the medical and surgical treatment strategies for each axis fracture injury sub type. RESULTS: Current medical and surgical management of traumatic fractures of the axis. PMID- 20173531 TI - Craniovertebral junction: biomechanical considerations. AB - The craniovertebral junction is a complex region that incorporates the occiput-C1 C2 portions of the spine. It is a transition between the cranium and the mobile cervical spine that permits significant motion. The motions afforded and the anatomy are vastly different at the occiput-C1 and C1-C2 articulations. These differences make treating pathology in this region very difficult. Problems include bony fixation of the cranium and the cervical spine (specifically C1 and C2), which limits complex motions, and limited bony sites available for arthrodesis. A thorough knowledge of the normal anatomy and biomechanics is required for fixation of this region. Moreover, an understanding of pathologic motions and the biomechanics of fixation is needed for successful construct design and good patient outcome. PMID- 20173532 TI - Rheumatoid arthritis of the craniovertebral junction. AB - BACKGROUND: Rheumatoid arthritis (RA) is the most common inflammatory disease involving the spine. It has a predilection for involving the craniocervical spine. Despite widespread involvement of the cervical spine with RA, few patients need surgery. The 3 major spinal manifestations of RA in the cervical spine are basilar invagination, atlantoaxial instability, and subaxial subluxations. Surgical management of RA involving the craniovertebral junction remains a challenge despite a decline in severe cases and an improvement in surgical techniques. METHODS: We conducted an exhaustive review of English-language publications discussing RA involving the craniovertebral junction. We paid special attention to publications detailing modern surgical management of these conditions. In addition, we outline our own surgical experience with such patients. RESULTS: We discuss alternative surgical methods for treating basilar invagination, atlantoaxial instability, and concurrent subaxial subluxations. We detail our surgical technique for transoral odontoidectomy, occipital cervical fusion, and atlantoaxial fusion. We detail the use of spinal surgical navigation in both of these procedures. CONCLUSION: Surgical management of RA remains a challenging field. There clearly has been a decrease in cases of mutilating RA involving the craniovertebral junction. Surgical techniques for managing these conditions have steadily improved. PMID- 20173533 TI - Ventral surgical approaches to craniovertebral junction chordomas. AB - BACKGROUND: Chordomas are primarily malignant tumors encountered at either end of the neural axis; the craniovertebral junction and the sacrococcygeal junction. In this article, we discuss the surgical management of craniovertebral junction chordomas. OBJECTIVE: In this paper, we discuss the surgical management of craniovertebral junction chordomas. RESULTS: The following approaches are illustrated: transoral-transpalatopharyngeal approach, high anterior cervical retropharyngeal approach, endoscopic transoral approach, and endoscopic transnasal approach. No single operative approach can be used for all craniovertebral chordomas. Therefore, the location of the tumor dictates which approach or approaches should be used. PMID- 20173535 TI - Minimally invasive circumferential spinal decompression and stabilization for symptomatic metastatic spine tumor: technical case report. AB - OBJECTIVE: Metastatic epidural spinal cord compression is a potentially devastating complication of cancer and is estimated to occur in 5% to 14% of all cancer patients. It is best treated surgically. Minimally invasive spine surgery has the potential benefits of decreased surgical approach-related morbidity, blood loss, hospital stay, and time to mobilization. CLINICAL PRESENTATION: A 36 year-old man presented with worsening back pain and lower extremity weakness. Workup revealed metastatic adenocarcinoma of the lung with spinal cord compression at T4 and T5. INTERVENTION AND TECHNIQUE: T4 and T5 vertebrectomy with expandable cage placement and T1-T8 pedicle screw fixation and fusion were performed using minimally invasive surgical techniques. RESULT: The patient improved neurologically and was ambulatory on postoperative day 1. At the 9-month follow-up point, he remained neurologically intact and pain free, and there was no evidence of hardware failure. CONCLUSION: Minimally invasive surgical circumferential decompression may be a viable option for the treatment of metastatic epidural spinal cord compression. PMID- 20173536 TI - Infectious aneurysm of the cavernous carotid artery in a child treated with a new generation of flow-diverting stent graft: case report. AB - OBJECTIVE: To report a unique case of wide-necked mycotic cerebral aneurysm treated with a new generation of intracranial stent. CLINICAL PRESENTATION: A 10 year-old girl presented with meningitis complicated by an infectious intracavernous large aneurysm revealed by cranial nerve palsy. INTERVENTION: The aneurysm was treated by a new-generation, flow-diverting, endoluminal implant (SILK; BALT EXTRUSION, Montmorency, France) placed across the aneurysm neck without coiling. Angiographic controls showed complete thrombosis of the aneurysmal sac with dramatic improvement of symptoms a couple of weeks after the procedure. Follow-up magnetic resonance imaging and digital subtraction angiography 3 months after the procedure, confirmed total occlusion of the aneurysm with normal circulation in the parent vessel CONCLUSION: This is a simple and highly effective way to exclude an aneurysm from the parent vessel without the difficulties observed with the semi-rigid stents. Flow-disrupting stent grafting may be a safe and effective alternative treatment for large intracranial aneurysms. PMID- 20173539 TI - Giant aneurysm clipping under protection of an excimer laser-assisted non occlusive anastomosis bypass. AB - OBJECTIVE: To define the safety and clinical value of giant aneurysm clipping under protection of an excimer laser-assisted non-occlusive anastomosis (ELANA) bypass. METHODS: We report 32 patients with an uncoilable intracerebral giant aneurysm, operated on with the aid of an ELANA protective bypass between January 1, 1994, and January 1, 2008. We retrospectively collected data from patient records. Follow-up data were updated by telephone interview. We defined a favorable outcome as a successfully treated aneurysm and a better or equal postoperative modified Rankin scale (mRS) score compared with the preoperative mRS. RESULTS: In total 33 bypasses were constructed, of which 31 (94%) were patent during the rest of the procedure. The first failed bypass was salvaged during a second procedure. Of the second failed bypass, the ELANA anastomosis could be reused during second bypass surgery. All 32 aneurysms could be treated. The bypasses served as protection during temporary parent vessel occlusion (n = 24, 75%), control during aneurysm rupture (n = 3, 9%), and in all patients as an indicator for recipient artery narrowing during clip placement. Four bypasses (12%) eventually had to partially (n = 3) or fully (n = 1) replace recipient artery flow at the end of surgery. Postoperatively, 3 patients (9%) had a hemorrhagic complication and 2 patients (6%) had an ischemic complication. At long-term follow-up (mean, 6.1 +/- 3.4 y), 28 patients (88%) had a favorable functional outcome. CONCLUSION: The ELANA protective bypass is a safe and useful instrument for the treatment of these difficult aneurysms. PMID- 20173540 TI - Insertion of intracranial pressure monitors in fulminant hepatic failure patients: early experience using recombinant factor VII. AB - BACKGROUND: Cerebral edema contributes to the high morbidity and mortality of fulminant hepatic failure (FHF). OBJECTIVE: We report the results of our early experience with insertion of intraparenchymal intracranial pressure (ICP) monitors in these highly coagulopathic patients. METHODS: Eleven consecutive patients with FHF met the criteria for invasive ICP monitoring. Recombinant activated factor VII (rFVIIa) was administered at an average dose of 3 mg intravenous bolus (average, 36.7 microg/kg). We inserted the intraparenchymal ICP monitor within 15 minutes to 2 hours after rFVIIa administration, without waiting for the repeat coagulation results. Postprocedure computed tomographic scans of the brain were obtained in all patients. RESULTS: No hemorrhagic complications were detected on the immediate postprocedure computed tomographic scans. There were no thrombotic complications in this group of patients. CONCLUSION: In this group of patients with FHF, placement of an ICP monitor without hemorrhagic or thrombotic complications was feasible after administration of rFVIIa. This is a report of our early experience, and caution is advised. Further collaborative randomized studies are needed to prove the efficacy, optimal dosing, and cost effectiveness of rFVIIa for the placement of ICP monitors in this group of patients. PMID- 20173541 TI - Endoscopic choroid plexus cauterization versus ventriculoperitoneal shunt for hydranencephaly and near hydranencephaly: a prospective study. AB - OBJECTIVE: To prospectively evaluate the results of endoscopic choroid plexus cauterization (ECPC) and ventriculoperitoneal shunts (VPSs) in infants with hydranencephaly or near hydranencephaly. METHODS: We prospectively collected clinical data from all untreated hydranencephalic and near hydranencephalic children from October 2006 to March 2008. All patients treated were randomly divided into 2 groups, ECPC or VPS, and submitted to either endoscopic choroid plexus cauterization or ventriculoperitoneal shunt placement. RESULTS: Seventeen patients were entered into the study. ECPC was completed in 9 patients; the procedure successfully controlled excessive head circumference and signs of increased intracranial pressure in 8 of these patients (88.8%). One endoscopic procedure in a hydranencephalic child failed after 7 months, resulting in VPS placement. Thus, of the 10 patients randomized to ECPC, 8 were treated successfully by ECPC (80%), and 2 went on to have a VPS. There were no complications related to this method of treatment. Seven children were randomized to the VPS group; and of these, 2 patients (28.5%) required shunt revisions during follow-up. There were no complications related to shunt placement. There was no difference in the success rate between patients randomized to ECPC and VPS, but the ECPC was more economical. CONCLUSION: ECPC is an acceptable alternative to VPS for treatment of hydranencephaly and near hydranencephaly. It is a single, definitive, safe, effective, and economical treatment that may avoid the complications of shunting. PMID- 20173542 TI - The adjustable proGAV shunt: a prospective safety and reliability multicenter study. AB - OBJECTIVE: To evaluate the reliability of the gravitation-assisted adjustable proGAV shunt system with a prospective multicenter study conducted in 10 German hospitals. METHODS: Enrollment for this observational study began in April 2005 and concluded in February 2006. The protocol required re-examinations 3 and 6 months postoperatively and fixed the endpoint of follow-up at 12 months after implantation. Patients with different types of adult, juvenile, and pediatric hydrocephalus were included and 165 patients were enrolled; 9 died and 12 had incomplete follow-up. RESULTS: Of the assessable 144 patients, 130 completed the protocol after 12 months, whereas 14 failed because of the need to explant the device, mainly because of infection. In 12 patients, components of the shunt, not the valve, were revised. In 65 of the 144 patients, there were 102 readjustments of the valve in 67 incidences because of underdrainage and in 35 because of overdrainage. In 1 case, readjustment was not possible. Determination of pressure level with the verification instrument was safe and corresponded to the required x-ray controls after adjustments. No unintended readjustments were noted. CONCLUSION: The proGAV is a safe and reliable device. PMID- 20173543 TI - T1/T2 matching to differentiate tumor growth from radiation effects after stereotactic radiosurgery. AB - OBJECTIVE: We define magnetic resonance imaging (MRI) and clinical criteria that differentiate radiation effect (RE) from tumor progression after stereotactic radiosurgery (SRS). METHODS: We correlated postoperative imaging and histopathological data in 68 patients who underwent delayed resection of a brain metastasis after SRS. Surgical resection was required in these patients because of clinical and imaging evidence of lesion progression 0.3 to 27.7 months after SRS. At the time of SRS, the median target volume was 7.1 mL (range, 0.5-26 mL), which increased to 14 mL (range, 1.3-81 mL) at the time of surgery. After initial SRS, routine contrast-enhanced MRI was used to assess tumor response and to detect potential adverse radiation effects. We retrospectively correlated these serial MRIs with the postoperative histopathology to determine if any routine MRI features might differentiate tumor progression from RE. RESULTS: The median time from SRS to surgical resection was 6.9 months (range, 0.3-27.7 months). A shorter interval from SRS to resection was associated with a higher rate of tumor recurrence (P = .014). A correspondence between the contrast-enhanced volume on T1-weighted images and the low signal-defined lesion margin on T2-weighted images ("T1/T2 match") was associated with tumor progression at histopathology (P < .0001). Lack of a clear and defined lesion margin on T2-weighted images compared to the margin of contrast uptake on T1-weighted images ("T1/T2 mismatch") was significantly associated with a higher rate of RE in pathological specimens (P < .0001). The sensitivity of the T1/T2 mismatch in identifying RE was 83.3%, and the specificity was 91.1%. CONCLUSIONS: We found that time to progression and T1/T2 mismatch were able to differentiate tumor progression from RE in most patients. When REs are suspected, surgery may not be necessary if patients respond to conservative measures. When tumor progression is suspected, resection or repeat radiosurgery can be effective, depending on the degree of mass effect. PMID- 20173544 TI - How safe is arteriovenous malformation surgery? A prospective, observational study of surgery as first-line treatment for brain arteriovenous malformations. AB - OBJECTIVES: Existing studies reporting the risk of surgery for brain arteriovenous malformations (AVMs) are often biased by the exclusion of patients not offered surgery. In this study, we examine the risk of surgery, including cases excluded from surgery because of the high surgical risk. METHODS: Data were collected on 640 consecutively enrolled AVMs in a database that included all patients not considered for surgery. RESULTS: Patients with Spetzler-Martin grade 1 to 2 AVMs (n = 296) were treated with a surgical risk of 0.7% (95% confidence interval [CI], 0%-3%); patients with Spetzler-Martin grade 3 to 4 AVMs in noneloquent cortex (n = 65) were treated with a surgical risk of 17% (95% CI, 10% 28%). Patients with Spetzler-Martin grade 3 to 5 AVMs in eloquent cortex (n = 168) were treated with a surgical risk of 21% (95% CI, 15%-28%). However, because 14% of patients in this series with similar AVMs were refused surgery because of perceived surgical risk, these results are not generalizable to the population of patients with similar AVMs. CONCLUSION: The results of this series suggest that it is reasonable to offer surgery as a preferred treatment option for Spetzler Martin grade 1 to 2 AVMs. This study also reinforces the predictive value of the Spetzler-Martin grading system, with some caveats. PMID- 20173545 TI - Pericranial flap for endoscopic anterior skull-base reconstruction: clinical outcomes and radioanatomic analysis of preoperative planning. AB - BACKGROUND: One of the major challenges of cranial base surgery is reconstruction of the dural defect and prevention of postoperative cerebrospinal fluid (CSF) fistula. The introduction of endoscopic techniques and an endonasal approach to the ventral skull base has created new challenges for reconstruction. OBJECTIVE: We have developed an endoscopic pericranial flap (PCF) for skull base reconstruction and hereby present the initial cohort of patients who had endonasal reconstruction with a PCF after endoscopic skull base resection. We also demonstrate a method to radiographically incorporate anticipated skull base defects for preoperative planning of PCF length. METHODS: Dural defects after endonasal skull base resection of invasive tumors were reconstructed with an onlay PCF (n = 10). We performed radiological studies to assist preoperative planning for where to make incisions while harvesting a PCF for anterior skull base, sellar, and clival defects. RESULTS: Each of the 10 patients had excellent healing of their skull base and had no evidence of any postoperative cerebrospinal fluid leaks. Eight patients had radiation therapy without flap complications. Radiographic studies demonstrate that the adequate PCF length, covering defects of the anterior skull base, sellar, and clival defects are 11.31 to 12.44 cm, 14.31 to 15.57 cm, and 18.5 to 20.42 cm, respectively. CONCLUSION: The PCF provides an option for endonasal reconstruction of cranial base defects and can be harvested endoscopically. Pre-operative radiographic evaluation may guide surgical planning. There is minimal donor site morbidity, and the flap provides enough surface area to cover the entire ventral skull base. PMID- 20173546 TI - Principal risk of peritumoral edema after stereotactic radiosurgery for intracranial meningioma is tumor-brain contact interface area. AB - OBJECTIVE: Stereotactic radiosurgery (SRS) of meningiomas is associated with posttreatment peritumoral edema (PTE). The purpose of this study was to evaluate the prevalence and risk factors of post-SRS PTE for intracranial meningiomas. METHODS: A total of 163 patients with 182 meningiomas treated with SRS were retrospectively reviewed. Tumors were divided into 4 pre-SRS groups according to whether they had undergone previous surgery and whether they had preexisting PTE. Several risk factors were investigated by univariate and multivariate analysis in all tumors, tumors without previous surgery, tumors without preexisting PTE, and preexisting PTE. RESULTS: Of 182 tumors, 45 (24.7%) developed post-SRS PTE. Compared with tumors without preexisting PTE, the odds of developing post-SRS PTE in tumors with preexisting PTE were 6.0 times higher in all tumors, and 6.9 times higher in tumors without previous surgery. A 1-cm2 increase in tumor-brain contact interface area increased the odds of developing post-SRS PTE by 17% in all tumors, 16% in tumors without previous surgery, and 26% in tumors without preexisting PTE. Of 118 tumors without previous surgery, 13 had preexisting PTE, the existence of which had a significant relationship to both tumor-brain contact interface area and tumor volume. CONCLUSION: Post-SRS PTE is common in patients with meningioma. Tumor-brain contact interface area and preexisting PTE were the most significant risk factors for post-SRS PTE. Tumor volume and tumor-brain contact interface area were significant risk factors for the development of preexisting PTE. PMID- 20173547 TI - Awake surgery for nonlanguage mapping. AB - OBJECTIVE: During the past decade, numerous reports have supported the contribution of awake mapping in surgical removal of brain lesions in eloquent areas, with a significant increase of the extent of resection while minimizing the risk of permanent deficit--and even improving quality of life. METHODS: Most of these awake procedures were performed in patients with lesions in language areas, to avoid postoperative aphasia. Surprisingly, mapping of nonlanguage functions received less attention, despite the possible consequences of deficits other than aphasia on daily life. Visuospatial and cognitive deficits are reported after brain surgery, because of more objective and extensive neuropsychological assessments. RESULTS AND CONCLUSION: This review provides new insights into the indications of awake craniotomies for nonlanguage mapping in surgery for lesions in areas not related to language processing. PMID- 20173548 TI - Combination of intracranial temozolomide with intracranial carmustine improves survival when compared with either treatment alone in a rodent glioma model. AB - BACKGROUND: Local delivery of temozolomide (TMZ) through polymers is superior to oral administration in a rodent glioma model. OBJECTIVE: We hypothesized that the observed clinical synergy of orally administered TMZ and carmustine (BCNU) wafers would translate into even greater effectiveness with the local delivery of BCNU and TMZ and the addition of radiotherapy in animal models of malignant glioma. METHODS: TMZ and BCNU were incorporated into biodegradable polymers that were implanted in F344 rats bearing established intracranial tumors. We used 2 different rodent glioma models: the 9L gliosarcoma and the F98 glioma. RESULTS: In the 9L rodent glioma model, groups treated with the combination of local TMZ, local BCNU, and radiation therapy (XRT) had 75% long-term survivors (defined as animals alive 120 days after tumor implantation), which was superior to the combination of local TMZ and local BCNU (median survival, 95 days; long-term survival, 25%) and the combination of oral TMZ, local BCNU, and XRT (median survival, 62 days; long-term survival, 12.5%). To simulate the effect of this treatment in chemoresistant gliomas, a second rodent model was used with the F98 glioma, a cell line relatively resistant to alkylating agents. F98 glioma cells express high levels of alkyltransferase, an enzyme that deactivates alkylating agents and is the major mechanism of resistance of gliomas. The triple therapy showed a significant improvement in survival when compared with controls (P = .0004), BCNU (P = .0043), oral TMZ (P = .0026), local TMZ (P = .0105), and the combinations of either BCNU and XRT (P = .0378) or oral TMZ and BCNU (P = .0154). CONCLUSION: The survival of tumor-bearing animals in the 9L and F98 glioma models was improved with the local delivery of BCNU and TMZ combined with XRT when compared with either treatment alone or oral TMZ, local BCNU, and XRT. PMID- 20173549 TI - Temporal expression of angiogenesis-related genes in developing neonatal rodent retina: a novel in vivo model to study cerebral vascular development. AB - BACKGROUND: Experimental models to study cerebrovascular malformations are limited therefore we used the neonatal rodent retina as a model to study cerebral angiogenesis. OBJECTIVE: We performed a gene expression analysis to define temporal changes in the expression of 96 angiogenesis-related genes during retinal vascularization. METHODS: A total of 72 retinas from 36 newborn C57BL/6 mice were used. Sets of neonatal mouse retinas were surgically isolated by 2-day intervals starting from postnatal day 0 to day 20 and at the 32nd day (representing adult retinas). For each of these 12 time points in the postnatal developmental period of mouse retinas, separate sets of 6 retinas from 3 mice were pooled, and their RNA was hybridized to an angiogenesis-specific gene array. Temporal expression patterns of each of the 96 angiogenesis-related genes were analyzed. For confirmation, vascular endothelial growth factor protein expression was also studied by immunohistochemistry. RESULTS: Twenty-two of the 96 genes analyzed displayed a significantly different temporal expression profile, and the rest exhibited a static expression, as compared to the human glyceraldehyde-3 phosphate dehydrogenase gene. Among these genes, the temporal pattern of expression was variable, but peaks were seen mostly on days 8, 10, 12, and 16. This timing corresponds well to morphologic changes that occur in the retina during different stages of angiogenesis. CONCLUSION: The neonatal rodent retina, which has a cellular architecture similar to that of the brain, has active and quantifiable angiogenic activity during the neonatal period and can be used as a simple and convenient model to study cerebral angiogenesis. PMID- 20173550 TI - A novel murine elastase saccular aneurysm model for studying bone marrow progenitor-derived cell-mediated processes in aneurysm formation. AB - BACKGROUND: Although there are several large-species animal models for saccular aneurysms, there is a need for a simple, reproducible saccular aneurysm model in mice. OBJECTIVE: To develop a murine saccular aneurysm model, which replicates key characteristics that occur in the formation of human cerebral aneurysms. METHODS: Elastase is applied extravascularly to the right common carotid artery. We induced saccular aneurysm formation by our method in C57BL/6 mice (n = 30). Aneurysms and control arteries (left common carotid arteries) were harvested at 1 week, 2 weeks, and 3 weeks postinjury (n = 10 for each time point), measured, and stained for elastin content. To demonstrate BMP-derived cell recruitment to the aneurysms, bone marrow from UBC-gfp transgenic mice was transplanted into irradiated C57BL/6 recipients to create C57BL/6.gfp chimeras. Additionally, bone marrow from DsRed transgenic mice was transplanted into irradiated C57BL/6 recipients to create C57BL/6.DsRed chimeras, and bone marrow from B5/EGFP transgenic mice was transplanted into irradiated FVB recipients to create FVB.gfp chimeras. The elastase injury or sham operations were performed in the C57BL/6.gfp, C57BL/6.DsRed, and FVB.gfp chimeras. Aneurysms and sham vessels were harvested at 3 weeks and examined for BMP-derived cell recruitment. Additionally, aneurysms were stained for matrix metalloproteinase-9, which is overexpressed in human cerebral aneurysm tissue. RESULTS: Aneurysms consistently demonstrated significant loss of elastin in the vessel wall and had significantly larger diameters than control vessels (591 +/- 238 microm vs 328 +/- 61 microm; P = .003 for aneurysms 3 weeks postinjury). Aneurysms from C57BL/6.gfp, FVB.gfp, and C57BL/6.DsRed chimeras consistently revealed significant BMP-derived cell recruitment in the aneurysm wall that was not seen in sham-operated vessels nor in control left common carotid arteries. Aneurysms demonstrated overexpression of matrix metalloproteinase-9. CONCLUSION: We describe a novel murine elastase saccular aneurysm model that replicates the histopathology and BMP-derived cell mediated processes that will be a valuable instrument for studying the cell mediated processes in cerebral aneurysm formation. PMID- 20173551 TI - Nerve repair by end-to-side nerve coaptation: histologic and morphometric evaluation of axonal origin in a rat sciatic nerve model. AB - OBJECTIVE: We compared the origin and quality of regenerating myelinated axons after end-to-side neurorrhaphy or end-to-end neurorrhaphy. METHODS: Transected adult rat tibial nerves were either end-to-end coapted or the distal stump was sutured to a perineurial window of the fibular nerve. Electromyographic recordings from the gastrocnemius muscle 8 weeks later revealed reinnervation by tibial nerve axons. Retrograde tracing of neurons projecting across the coaptation sites was performed with Dil for the tibial nerve and FluoroGold for the fibular nerve to reveal the origin of regenerating axons. Orientation of regenerating axons was demonstrated by immunohistochemical staining of the coaptation sites. Nerve cross-sections proximal and distal to the coaptation sites were evaluated regarding quality and quantity of myelinated axons inside the donor and acceptor nerves in comparison to nonoperated nerve samples. RESULTS: Compound muscle action potential responses were not different 8 weeks after end-to-side as compared with end-to-end coaptation. Double fluorescence of spinal motoneurons (L4-L6) and dorsal root ganglion neurons (L4-L6) elucidated events of collateral sprouting of sensory and motor donor axons. Morphometric analysis demonstrated significantly higher numbers of regenerated myelinated axons distal to end-to-end as distal to end-to-side repair. Furthermore, events of axonal sprouting in the donor nerve proximal to the end-to-side coaptation site were discovered. However, with quantitative parameters such as fiber density and g-ratio, no impairment of the donor nerve was evident. CONCLUSION: The current study supports the hypothesis that end-to-side neurorrhaphy represents an opportunity for peripheral nerve repair when a proximal nerve stump is not available. PMID- 20173552 TI - Differential expression of genes in elastase-induced saccular aneurysms with high and low aspect ratios. AB - BACKGROUND: Morphologic features are thought to play a critical role in the rupture of intracranial, saccular aneurysms. OBJECTIVE: The objective of this study was to investigate the gene expression pattern of saccular aneurysms with distinct morphologic patterns. METHODS: Elastase-induced saccular aneurysms with high (>or= 2.4) and low (or= 1.5 and